PMID- 28645720 TI - Direct circulating tumor DNA detection from unpurified plasma using a digital PCR platform. AB - BACKGROUND: In standard pre-analytical conditions, an isolation step is required for circulating tumor DNA (ctDNA) analysis. The need for this step remains unclear with the development of ultrasensitive detection technologies such as digital PCR (dPCR). The aim of our study was to evaluate the ctDNA detection by dPCR platform either directly from plasma (plasma group, PG) or after an isolation step (isolation group, IG). METHODS: We included 17 patients corresponding to a selection of 43 blood samples in metastatic colorectal cancer patients. For each sample, ctDNA was analyzed with or without isolation step (IG and PG, respectively) using KRAS, NRAS and BRAF mutations identified from the tumor tissue. ctDNA detection was performed after a preamplication step using dPCR platform (QuantStudioTM 3D Digital PCR System). ctDNA detection rate and mutant allelic frequencies (MAF) were compared between IG and PG. RESULTS: Our results showed a detection rate at 93% in IG vs. 88% in PG. The concordance rate between the two groups was 91% (39/43) for ctDNA detection with the four discordant cases occurring in patients with low MAF (<0.5%). The mean value of MAF were 16.9+/-18.9 and 18.5+/-18.9 for IG and PG, respectively (p=0.24). The correlation coefficient r2 for MAF was 0.82 between the two methods (p<0.0001). CONCLUSION: In conclusion, our results show that direct detection of ctDNA from unpurified plasma is a feasible approach, particularly from sample with high MAF (>0.5%). PMID- 28645721 TI - Comparison of different inactivation methods on the stability of Indian vaccine strains of foot and mouth disease virus. AB - In this study, the efficiency of binary ethyleneimine (BEI) in combination with formaldehyde (FA) and glutaraldehyde (GTA) in inactivating the Indian FMDV vaccine strains is compared. The acceptable safety of virus inactivation was faster and the inactivation rates were increased many-folds with combination of inactivants than BEI alone. FMDV A was inactivated rapidly than the other two serotypes with BEI + FA combination. Inactivation plots were linear for all the serotypes irrespective of inactivation process. Further, the integrity studies on 146S using serotype specific ELISA indicated no significant change in the antigenic mass of all the serotypes throughout the inactivation process. However, the loss of 146S antigen occurred in the subsequent steps of downstream processing. Further, the studies on intactness of viral RNA using real time PCR indicated the amplification of 1D gene sequences in all the preparations of timed samples irrespective of serotypes/inactivation process. Further, inactivated virus preparation (146S) was more stable at lower temperatures for all the serotypes/inactivation process. Among the combinations of inactivants, BEI + FA out performed compared to BEI + GTA and BEI in terms of inactivation rates, 146S yield and its storage stability, irrespective of the serotypes. PMID- 28645722 TI - Circulating Bone-related Markers and YKL-40 Versus HER2 and TOPO2a in Bone Metastatic and Nonmetastatic Breast Cancer: Diagnostic Implications. AB - BACKGROUND: The bone represents one of the most common sites of metastases in breast cancer. The aim of the current study was to evaluate the diagnostic potential of several circulating markers to detect metastasis to bones in patients with breast cancer. PATIENTS AND METHODS: Receptor activator of Nuclear Factor-kappa beta (NF-Kbeta) ligand (RANKL), osteoprotegrin (OPG), vitamin D (VIT D), Chitinase-3-like protein 1; also known as YKL-40, topoisomerase IIalpha (TOPO2a), and human epidermal growth factor receptor 2 (HER2) were measured in blood samples obtained from 122 patients with breast cancer and 25 healthy controls. RESULTS: All biomarkers were significantly elevated in patients with breast cancer with bone metastasis compared with nonmetastatic patients except YKL-40. RANKL had the highest diagnostic performance for bone metastasis detection with an area under the curve of 97.3, a sensitivity of 85%, and a specificity of 98.6%. Furthermore, logistic regression analysis resulted in a model of RANKL combined with HER2 that had even higher discriminatory power of metastasis to bones than that of RANKL alone. Overall correct classification of the model was 98.9%. CONCLUSION: We recommend that measuring RANKL together with HER2 can be routinely applied to allow early detection of bone metastases in patients with breast cancer. PMID- 28645723 TI - Doublet tracer tests to determine the contaminant flushing properties of a municipal solid waste landfill. AB - This paper describes a programme of research investigating horizontal fluid flow and solute transport through saturated municipal solid waste (MSW) landfill. The purpose is to inform engineering strategies for future contaminant flushing. Solute transport between injection/abstraction well pairs (doublets) is investigated using three tracers over five separate tests at well separations between 5m and 20m. Two inorganic tracers (lithium and bromide) were used, plus the fluorescent dye tracer, rhodamine-WT. There was no evidence for persistent preferential horizons or pathways at the inter-well scale. The time for tracer movement to the abstraction wells varied with well spacing as predicted for a homogeneous isotropic continuum. The time for tracer movement to remote observation wells was also as expected. Mobile porosity was estimated as ~0.02 (~4% of total porosity). Good fits to the tracer breakthrough data were achieved using a dual-porosity model, with immobile regions characterised by block diffusion timescales in the range of about one to ten years. This implies that diffusional exchanges are likely to be very significant for engineering of whole site contaminant flushing and possibly rate-limiting. PMID- 28645724 TI - Micronutrient Deficiencies and the Human Gut Microbiota. AB - Little is known about how micronutrient deficiencies affect the human gut microbiota. A study by Hibberd et al. illustrates how these deficiencies affect the composition and function of gut microbiota, and further, how different species realize changes in gene expression and cellular metabolism to cope with micronutrient shortages. PMID- 28645725 TI - Cell surface N-glycan alteration in HepAD38 cell lines expressing Hepatitis B virus. AB - Hepatitis B virus (HBV) is the smallest partially double-stranded DNA virus known to infect humans. Worldwide, more than 50% of hepatocellular carcinoma (HCC) cases are related to chronic Hepatitis B. Development of HCC from normal liver cells is characterized by changes in cell surface N-glycans, which can promote the invasive behavior of tumor cells, leading ultimately to the progression of cancer. However, little is understood about the cell surface N-glycans of HBV infected liver cells. We try to address this by taking advantage of the HepAD38 cell line, which can replicate HBV in the absence of tetracycline [tet(-)] in growth medium. In the presence of tetracycline [tet(+)], this cell line is free from the virus due to the repression of pregenomic (pg) RNA synthesis. In culture medium without tetracycline, cells express viral pgRNA and start to secrete virions into the supernatant. Here we studied the expression of glycosyltransferases and the cell surface N-glycan composition of tet(+) and tet( ) HepAD38. Among the glycosyltransferases upregulated by the expression of HBV were GnT-II, GnT-IVa, ST6Gal1, and GnT-V, whereas GnT-I, GnT-III, beta4GalT1, and FUT8 were downregulated. About one-third of the total cell surface N-glycans found on tet(-)HepAD38 were sialylated. As for tet(+)HepAD38, sialylation was 6% lower compared to the tet(-) cells. Neither treatment changed the cell surface N glycans expression of the total complex type or the total fucosylated type, which were about 50% or 60%, respectively. Our results showed that the expression of HBV triggers higher sialylation in HepAD38 cells. Altogether, the results show that HBV expression triggered the alteration of the cell surface N-glycosylation pattern and the expression levels of glycosyltransferases of HepAD38 cells. PMID- 28645728 TI - Feasibility of average volume-assured pressure support ventilation in the treatment of acute hypercapnic respiratory failure associated with chronic obstructive pulmonary disease: What are its limits? PMID- 28645727 TI - Inhibition of Non Canonical HIV-1 Tat Secretion Through the Cellular Na+,K+ ATPase Blocks HIV-1 Infection. AB - Besides its essential role in the activation of HIV-1 gene expression, the viral Tat protein has the unusual property of trafficking in and out of cells. In contrast to Tat internalization, the mechanism involved in extracellular Tat release has so far remained elusive. Here we show that Tat secretion occurs through a Golgi-independent pathway requiring binding of Tat with three short, non-consecutive intracytoplasmic loops at the C-terminus of the cellular Na+,K+ ATPase pump alpha subunit. Ouabain, a pump inhibitor, blocked this interaction and prevented Tat secretion; virions produced in the presence of this drug were less infectious, consistent the capacity of virion-associated Tat to increase HIV 1 infectivity. Treatment of CD4+ T-cells with short peptides corresponding to the Tat-binding regions of the pump alpha subunit impaired extracellular Tat release and blocked HIV-1 replication. Thus, non canonical, extracellular Tat secretion is essential for viral infectivity. PMID- 28645729 TI - The Dietary Approaches to Stop Hypertension (DASH) diet-Promise Unmet. PMID- 28645730 TI - The relation of digital vascular function to cardiovascular risk factors in African-Americans using digital tonometry: the Jackson Heart Study. AB - Digital vascular tone and function, as measured by peripheral arterial tonometry (PAT), are associated with cardiovascular risk and events in non-Hispanic whites. There are limited data on relations between PAT and cardiovascular risk in African-Americans. PAT was performed on a subset of Jackson Heart Study participants using a fingertip tonometry device. Resting digital vascular tone was assessed as baseline pulse amplitude. Hyperemic vascular response to 5 minutes of ischemia was expressed as the PAT ratio (hyperemic/baseline amplitude ratio). Peripheral augmentation index (AI), a measure of relative wave reflection, also was estimated. The association of baseline pulse amplitude (PA), PAT ratio, and AI to risk factors was assessed using stepwise multivariable models. The study sample consisted of 837 participants from the Jackson Heart Study (mean age, 54 +/- 11 years; 61% women). In stepwise multivariable regression models, baseline pulse amplitude was related to male sex, body mass index, and diastolic blood pressure (BP), accounting for 16% of the total variability of the baseline pulse amplitude. Age, male sex, systolic BP, diastolic BP, antihypertensive medication, and prevalent cardiovascular disease contributed to 11% of the total variability of the PAT ratio. Risk factors (primarily age, sex, and heart rate) explained 47% of the total variability of the AI. We confirmed in our cohort of African-Americans, a significant relation between digital vascular tone and function measured by PAT and multiple traditional cardiovascular risk factors. Further studies are warranted to investigate the utility of these measurements in predicting clinical outcomes in African-Americans. PMID- 28645731 TI - Aortic backward waves rather than stiffness account for independent associations between pulse pressure amplification and left ventricular mass in a young to middle-aged sample. AB - A decreased aortic-to-brachial pulse pressure (PP) amplification, which is independently associated with cardiovascular outcomes, may index several aortic functional changes. However, that aortic functional change most likely to account for this effect is uncertain. In 706 randomly selected community participants of African ancestry with a mean age of 44.4 +/- 18.2 years, we assessed aortic function using radial applanation tonometry and SphygmoCor software (including forward [Pf] and backward [Pb] wave separation analysis assuming a triangular flow waveform) and left ventricular mass index (LVMI) (echocardiography). In multivariate models with the inclusion of brachial PP, 1/PP amplification (partial r = 0.12, P < .005), reflected wave pressures (partial r = 0.09, P < .05), and aortic pulse wave velocity (PWV; partial r = 0.09, P < .05) were independently associated with LVMI. Similarly, in multivariate models with the inclusion of brachial PP, 1/PP amplification (P < .005), the reflected wave pressure (P < .01), and aortic PWV (P < .01) were independently associated with LVH. With adjustments for reflected wave pressures, the brachial PP-independent relationships between 1/PP amplification and LVMI or LVH were abolished (P > .08 for both). However, adjustments for PWV failed to modify brachial PP-independent relations between 1/PP amplification and LVMI or LVH. Similar results were noted when brachial systolic blood pressure rather than PP was included in regression models and in sensitivity analysis conducted in participants not receiving antihypertensive therapy. In conclusion, the independent relations between the reciprocal of aortic-to-brachial PP amplification and LVMI or LVH in a largely young to middle-aged sample are accounted for by variations in backward wave pressures rather than aortic stiffness. PMID- 28645732 TI - Severe infusion-related toxicity after a second unrelated cord blood transplantation. PMID- 28645733 TI - Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion. PMID- 28645734 TI - The influence of temperature treatment before cryopreservation on the viability and potency of cryopreserved and thawed CD34+ and CD45+ cord blood cells. AB - BACKGROUND: Hematopoietic stem cell (HSC) viability and potency is crucial for qualified cord blood (CB) transplants. This study analyzes time and temperature condition before cryopreservation for the viability of CD34+/CD45+ cells after cryopreservation. METHODS: Cell viabilities were determined by antibody co staining with 7-aminoactinomycin D detecting necrotic cells, and subsequent flow cytometric analysis. Additionally, Annexin V staining for determination of apoptotic cells and colony-forming unit (CFU) assays for testing functional potency of HSCs were performed. RESULTS: For all cell types assessed (CD45+/CD34+ cells, lymphocytes and granulocytes), the highest viabilities were obtained for CB maintained at 4 degrees C or room temperature (RT; 22 +/- 4 degrees C) and cryopreserved directly after collection. Starting material were CB units with an age of 24.7 +/- 3.5 h after birth. Post-thaw CD34+ cell results were > 90% after temperature treatment of t = 24 h (48 h total age) and > 70% after t = 48 h (72 h total age) at 4 degrees C (48 h, 91.4 +/- 5.5%; 72 h, 75.0 +/- 12.0%) and RT (48 h, 84.2 +/- 9.7%; 72 h, 72.6 +/- 0.6%). Viabilities for 30 degrees C samples were < 80% after t = 24 h (48 h total age, 79.8 +/- 3.1%) and < 50% after t = 48 h of treatment (72 h total age, 46.8 +/- 14.3%). Regarding CFU recovery of pre-freeze (without volume reduction) and thawed CB, a trend toward the highest recoveries was observed at 4 degrees C/RT. The difference between 4 degrees C (77.5 +/- 12.0%) and 30 degrees C samples (53.9 +/- 4.8%) was shown to be significant in post-thaw samples after t = 24 h treatment (48 h total age; P = 0.0341). DISCUSSION: Delays between collection and cryopreservation should be minimized because increasing time reduces numbers of viable cells and CFUs before/after cryopreservation. CB units should be maintained at 4 degrees C/RT to retain the highest possible potency of the cells after thawing. PMID- 28645735 TI - Serum amyloid A self-assembles with phospholipids to form stable protein-rich nanoparticles with a distinct structure: A hypothetical function of SAA as a "molecular mop" in immune response. AB - Serum amyloid A (SAA) is an acute-phase protein whose action in innate immunity and lipid homeostasis is unclear. Most circulating SAA binds plasma high-density lipoproteins (HDL) and reroutes lipid transport. In vivo SAA binds existing lipoproteins or generates them de novo upon lipid uptake from cells. We explored the products of SAA-lipid interactions and lipoprotein remodeling in vitro. SAA complexes with palmitoyl-oleoyl phosphocholine (POPC) were analyzed for structure and stability using circular dichroism and fluorescence spectroscopy, electron microscopy, gel electrophoresis and gel filtration. The results revealed the formation of 8-11nm lipoproteins that were~50% alpha-helical and stable at near physiological conditions but were irreversibly remodeled at Tm~52 degrees C. Similar HDL-size nanoparticles formed spontaneously at ambient conditions or upon thermal remodeling of parent lipoproteins containing various amounts of proteins and lipids, including POPC and cholesterol. Therefore, such HDL-size particles formed stable kinetically accessible structures in a wide range of conditions. Based on their size and stoichiometry, each particle contained about 12 SAA and 72 POPC molecules, with a protein:lipid weight ratio circa 2.5:1, suggesting a structure distinct from HDL. High stability of these nanoparticles and their HDL like size suggest that similar lipoproteins may form in vivo during inflammation or injury when SAA concentration is high and membranes from dead cells require rapid removal. We speculate that solubilization of membranes by SAA to generate lipoproteins in a spontaneous energy-independent process constitutes the primordial function of this ancient protein, providing the first line of defense in clearing cell debris from the injured sites. PMID- 28645736 TI - Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-on-chronic liver failure grade 3. AB - BACKGROUND & AIMS: Liver transplantation (LT) for the most severely ill patients with cirrhosis, with multiple organ dysfunction (accurately assessed by the acute on-chronic liver failure [ACLF] classification) remains controversial. We aimed to report the results of LT in patients with ACLF grade 3 and to compare these patients to non-transplanted patients with cirrhosis and multiple organ dysfunction as well as to patients transplanted with lower ACLF grade. METHODS: All patients with ACLF-3 transplanted in three liver intensive care units (ICUs) were retrospectively included. Each patient with ACLF-3 was matched to a) non transplanted patients hospitalized in the ICU with multiple organ dysfunction, or b) control patients transplanted with each of the lower ACLF grades (three groups). RESULTS: Seventy-three patients were included. These severely ill patients were transplanted following management to stabilize their condition with a median of nine days after admission (progression of mean organ failure from 4.03 to 3.67, p=0.009). One-year survival of transplanted patients with ACLF-3 was higher than that of non-transplanted controls: 83.9 vs. 7.9%, p<0.0001. This high survival rate was not different from that of matched control patients with no ACLF (90%), ACLF-1 (82.3%) or ACLF-2 (86.2%). However, a higher rate of complications was observed (100 vs. 51.2 vs. 76.5 vs. 74.3%, respectively), with a longer hospital stay. The notion of a "transplantation window" is discussed. CONCLUSIONS: LT strongly influences the survival of patients with cirrhosis and ACLF-3 with a 1-year survival similar to that of patients with a lower grade of ACLF. A rapid decision-making process is needed because of the short "transplantation window" suggesting that patients with ACLF-3 should be rapidly referred to a specific liver ICU. Lay summary: Liver transplantation improves survival of patients with very severe cirrhosis. These patients must be carefully monitored and managed in a specialized unit. The decision to transplant a patient must be quick to avoid a high risk of mortality. PMID- 28645737 TI - Alfapump(r) system vs. large volume paracentesis for refractory ascites: A multicenter randomized controlled study. AB - BACKGROUND AND AIMS: Patients with refractory ascites (RA) require repeated large volume paracenteses (LVP), which involves frequent hospital visits and is associated with a poor quality-of-life. This study assessed safety and efficacy of an automated, low-flow pump (alfapump(r) [AP]) compared with LVP standard of care [SoC]. METHODS: A randomized controlled trial, in seven centers, with six month patient observation was conducted. Primary outcome was time to first LVP. Secondary outcomes included paracentesis requirement, safety, health-related quality-of-life (HRQoL), and survival. Nutrition, hemodynamics, and renal injury biomarkers were assessed in a sub-study at three months. RESULTS: Sixty patients were randomized and 58 were analyzed (27 AP, 31 SoC, mean age 61.9years, mean MELD 11.7). Eighteen patients were included in the sub-study. Compared with SoC, median time to first LVP was not reached after six months in the AP group, meaning a significant reduction in LVP requirement for the AP patients (AP, median not reached; SoC, 15.0days (HR 0.13; 95%CI 13.0-22.0; p<0.001), and AP patients also showed significantly improved Chronic Liver Disease Questionnaire (CLDQ) scores compared with SoC patients (p<0.05 between treatment arms). Improvements in nutritional parameters were observed for hand-grip strength (p=0.044) and body mass index (p<0.001) in the sub-study. Compared with SoC, more AP patients reported adverse events (AEs; 96.3% vs. 77.4%, p=0.057) and serious AEs (85.2 vs. 45.2%, p=0.002). AEs consisted predominantly of acute kidney injury in the immediate post-operative period, and re-intervention for pump related issues, and were treatable in most cases. Survival was similar in AP and SoC. CONCLUSIONS: The AP system is effective for reducing the need for paracentesis and improving quality of life in cirrhotic patients with RA. Although the frequency of SAEs (and by inference hospitalizations) was significantly higher in the AP group, they were generally limited and did not impact survival. Lay summary: The alfapump(r) moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, the alfapump reduces the need for large volume paracentesis (manual fluid removal by needle) in patients with medically untreatable ascites. This can improve life quality for these patients. www.clinicaltrials.gov#NCT01528410. PMID- 28645739 TI - miR-1224 inhibits cell proliferation in acute liver failure by targeting the antiapoptotic gene Nfib. AB - BACKGROUND AND AIMS: Patient outcome in acute liver failure (ALF) is crucially determined by the appropriate balance between cell death and compensatory cell proliferation. MicroRNAs (miRNAs) - small non-coding RNAs that function as guide molecules in RNA silencing - have evolved as crucial mediators of nearly all developmental and pathological processes, including the physiology and pathology of the liver. We investigated the role of miR-1224 during ALF. METHODS: We measured miR-1224 in livers of mice in various acute liver disease murine models and in, patients with ALF, using quantitative real-time PCR. We studied the regulation of miR-1224 in AML12 cells and primary hepatocytes upon H2O2 stimulation. Cell proliferation and cell death were analysed by 5-bromo-2' deoxyuridine and terminal deoxynucleotide transferase nick end labelling stainings, respectively. RESULTS: We found that miR-1224 was up-regulated in hepatocytes upon ischaemia-reperfusion in vivo and in vitro. This was accompanied by impaired proliferation and elevated apoptosis. This function of miR-1224 was mediated by repressing the anti-apoptotic gene Nfib in hepatocytes. Strikingly, miR-1224 was also up-regulated in human livers and the serum of patients with ALF and indicated an unfavourable prognosis with an excellent prognostic value compared to other known serum markers in this clinical setting. CONCLUSIONS: miR 1224 is a previously unrecognised regulator of proliferation after ALF in hepatocytes and represents a novel and specific biomarker of liver injury with prognostic value in ALF. Thus, miR-1224 may represent a target for novel therapeutic and diagnostic strategies in the context of ALF and warrants further testing as a biomarker in prospective trials. Lay summary: In acute liver failure, miR-1224 expression is modulated by oxidative stress. This leads to a decrease in hepatocyte cell proliferation and increase in apoptosis. Increased serum levels of miR-1224 could be a useful diagnostic marker in patients with acute liver failure. PMID- 28645738 TI - Human germline hedgehog pathway mutations predispose to fatty liver. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. METHODS: Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2+/-) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. RESULTS: Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2+/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro inflammatory genes, and increased expression of PPARgamma, a potent anti fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/- mice exposed to a high fat diet. CONCLUSIONS: Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous buildup (scar tissue) and inflammation of the liver tissue. For the first time patients with holoprosencephaly, a disease caused by SHH signaling mutations, are shown to have increased liver steatosis independent of obesity. This observation was recapitulated in a mouse model of attenuated SHH signaling that also showed increased liver steatosis but with decreased fibrosis and inflammation. While SHH inhibition is associated with a good NAFLD prognosis, this increase in liver fat accumulation in the context of SHH signaling inhibition must be studied prospectively to evaluate its long-term effects, especially in individuals with Western-type dietary habits. PMID- 28645741 TI - Chylous ascites due to idiopathic chronic pancreatitis managed with endoscopic stenting. AB - Chylous ascites is an uncommon clinical entity, which usually results from congenital or acquired abnormality in proper lymphatic flow. While the common causes are related to trauma, malignancy or tuberculosis, pancreatic disorders can occasionally result in chylous ascites. Sporadic cases of chylous ascites due to acute or chronic pancreatitis or surgery for pancreatitis have been reported. The usual management is with medium chain triglycerides (MCT), total parenteral nutrition and octreotide. We report a case of a young male with idiopathic chronic pancreatitis who presented with chylous ascites which did not respond to MCT based diet and octreotide. The patient improved with endoscopic pancreatic duct stenting. PMID- 28645740 TI - Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - A pooled analysis. AB - BACKGROUND & AIMS: Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r+/-DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis. METHODS: Twelve phase II or III clinical trials of the 2 DAA regimen of OBV/PTV/r+/-ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV+/-RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported. RESULTS: In 1,066 patients with Child Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2). CONCLUSIONS: This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r+/-DSV+/-RBV in this population. These results support the use of OBV/PTV/r+/-DSV+/-RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients. PMID- 28645742 TI - Gastrointestinal stromal tumors (GIST) presenting in the liver: Diagnostic, prognostic and therapeutic issues. AB - CONTEXT: Extra-gastrointestinal stromal tumors (E-GIST) presenting in the liver are exceedingly rare and raise difficult diagnostic and therapeutic challenges. METHODS: We report on two cases of liver E-GIST with different clinical presentations. We describe their clinical and imaging features, their histopathological and molecular characteristics, their treatment and their course. RESULTS: The first case was that of a 56-year-old male presenting with a 10-cm liver mass; the initial diagnosis, made in 1986 from a biopsy sample, was leiomyosarcoma; liver transplantation was performed in 1987; no extra-hepatic tumor was found; the course was uneventful until 1999, when tumor recurrence was diagnosed along the initial biopsy route; after reevaluation of available material, the definitive pathological diagnosis was GIST; imatinib treatment resulted in major response; the patient died of end-stage kidney disease 22 years after the initial diagnosis and 9 years after tumor recurrence. The second case is that of a 59-year-old female presenting with a 23-cm abdominal mass connected to the liver; on biopsy, the tumor was diagnosed as epithelioid GIST with exon 11 KIT mutation; imatinib treatment resulted in stable disease. CONCLUSIONS: The diagnosis of E-GIST must be for any sarcoma presenting in the liver and confirmed by immunohistochemical and molecular techniques. Treatment might require aggressive strategies, which can be successful despite apparently adverse histoprognostic factors. PMID- 28645743 TI - Role of TRPC3 and TRPC6 channels in the myocardial response to stretch: Linking physiology and pathophysiology. AB - Transient receptor potential (TRP) channels constitute a large family of versatile multi-signal transducers. In particular, TRP canonical (TRPC) channels are known as receptor-operated, non-selective cation channels. TRPC3 and TRPC6, two members in the TRPC family, are highly expressed in the heart, and participate in the pathogenesis of cardiac hypertrophy and heart failure as a pathological response to chronic mechanical stress. In the pathological response, myocardial stretch increases intracellular Ca2+ levels and activates nuclear factor of activated T cells to induce cardiac hypertrophy. Recent studies have revealed that TRPC3 and TRPC6 also contribute to the physiological stretch induced slow force response (SFR), a slow increase in the Ca2+ transient and twitch force during stretch. In the physiological response, a stretch-induced increase in intracellular Ca2+ mediated by TRPC3 and TRPC6 causes the SFR. We here overview experimental evidence of the involvement of TRPC3 and TRPC6 in cardiac physiology and pathophysiology in response to stretch. PMID- 28645744 TI - Reversible hemispheric hypoperfusion in two cases of SMART syndrome. AB - Stroke-like migraine attacks after radiation therapy (SMART) syndrome manifests as prolonged episodes of cortical dysfunction, years after cranial irradiation. We present two cases demonstrating reversible hemispheric hypoperfusion. Case 1 presented with left hemispheric symptoms following previous similar episodes. CT perfusion (CTP) demonstrated reversible hemispheric hypoperfusion; subsequent investigations were consistent with SMART syndrome. Case 2 presented following the third episode of a hemispheric syndrome with near-identical CTP abnormalities. L-arginine was administered with rapid reversal of clinical and CTP abnormalities. We conclude that SMART syndrome may demonstrate significant hypoperfusion on hyperacute CTP without subsequent infarction. Impaired cerebrovascular autoregulation probably contributes to cortical dysfunction in SMART syndrome. L-arginine warrants investigation as a potential treatment. PMID- 28645745 TI - DNA methylation of DLG4 and GJA-1 of human hippocampus and prefrontal cortex in major depression is unchanged in comparison to healthy individuals. AB - Epigenetic alterations provide a potential mechanism to account for the numerous gene-environment interactions that have been reported in association with neuropsychiatric phenotypes. In context to major depression disorder (MDD), where postmortem and neuroimaging studies provide insights into dysfunctional brain regions, involvement of genetic heterogeneity also revealed the complexity of this disorder. Despite intensive research during the past several decades and information from genome wide studies, pathophysiology of depressive disorders remained elusive. To evaluate the impact of epigenetic pressure on this disease, we took advantage of DNA isolated from different sections of human brain (prefrontal cortex and hippocampus) from clinically well defined depressed patients and healthy individuals and performed pyrosequencing for DNA methylation analysis. Herein, we focused on two genes DLG4 (PSD-95) and GJA-1 (Connexin43) known to be associated with neuropsychiatric behavior. Comparing MDD with controls we found no differences of DNA methylation. Our results clearly demonstrate that DNA methylation levels on these particular genes are not associated with depression related phenotype. PMID- 28645746 TI - Cortical Aquaporin-4 in relation to brain oedema and neurological function of cortical cryo-injured mice. AB - To estimate the spatial and temporal expression of Aquaporin-4 (AQP-4) in a murine model of automated cerebral cryoinjury and correlate AQP-4 expression with development of brain oedema and neurological function. AQP-4 levels were determined quantitatively by Western blots at site of injury and at sites adjacent to and distant from injury in brains of cryoinjured (experimental) (n=18), sham injured (n=18) & normal mice at 24, 48, 72h post injury. AQP-4 expression was correlated with percentage water content of brain, Neurological Severity Score (NSS) and rotarod scores. We found a 1.4-fold increase in expression of AQP-4 at the site of injury and at sites distant from injury at 24h when compared to normal mice (p=0.05). The increase in expression of AQP-4 24h post injury was significantly higher in experimental group at the site of injury and at the site adjacent to the injury in the ipsilateral hemisphere when compared to the sham injured mice (p=0.05). At 24h post injury the median NSS score in the experimental group was 9 (interquartile range 7.25-10) and that in the sham group was 0.5 (interquartile range 0.0-1.0) (p<0.001). At 48 and 72h, AQP-4 expression remained elevated in the experimental group when compared to normal brain, but the levels were not significantly different from that in sham group. AQP-4 expression was significantly elevated in the ipsilateral hemisphere in the first 24h following cerebral cortical injury in mice and this could be correlated with worsening of neurological function. Over the next 48h, there was a trend towards decrease in AQP-4 expression that was associated with partial recovery of neurological function. PMID- 28645747 TI - A review of DNA methylation in depression. AB - As one of the most common psychiatric disorders, depression has been a major public health problem. Growing evidence suggests that epigenetic modification is essential in biological processes of depression. Recently, DNA methylation has been regarded as a potential link between environment and depression. In this review, we reviewed current studies of the association between DNA methylation and depression. The association between DNA methylation of seven genes, including BDNF, SLC6A4, NR3C1, 5-HTR (1A, 2A, and 3A), FKBP5, MAO-A and OXTR, and depression were reviewed in this study. Most studies showed BDNF and NR3C1 gene methylation levels were correlated with depression while the connection of SLC6A4 and depression was conflicting. Although evidence provided insights to epigenetic processes in depression, the findings were inconsistent. Therefore, longitudinal studies in animal models and in patients with depression are needed to further investigate the diagnostic predictive value of DNA methylation reliably. PMID- 28645748 TI - Developmental and genetic mechanisms of neural circuit evolution. AB - Regardless of how a nervous system is genetically built, natural selection is acting on the functional outcome of its activity. To understand how nervous systems evolve, it is essential to analyze how their functional units - the neural circuits - change and adapt over time. A neural circuit can evolve in many different ways, and the underlying developmental and genetic mechanisms involve different sets of genes. Therefore, the comparison of gene expression can help reconstructing circuit evolution, as demonstrated by several examples in sensory systems. Functional constraints on neural circuit evolution suggest that in nervous systems developmental and genetic variants do not appear randomly, and that the evolution of neuroanatomy might be biased. Sensory systems, in particular, seem to evolve along trajectories that enhance their evolvability, ensuring adaptation to different environments. PMID- 28645750 TI - The effect of future time perspective on delay discounting is mediated by the gray matter volume of vmPFC. AB - Although several previous studies have shown that individuals' attitude towards time could affect their intertemporal preference, little is known about the neural basis of the relation between time perspective (TP) and delay discounting. In the present study, we quantified the gray matter (GM) cortical volume using voxel-based morphometry (VBM) methods to investigate the effect of TP on delay discounting (DD) across two independent samples. For group 1 (102 healthy college students; 46 male; 20.40 +/- 1.87 years), behavioral results showed that only Future TP was a significant predictor of DD, and higher scores on Future TP were related to lower discounting rates. Whole-brain analysis revealed that steeper discounting correlated with greater GM volume in the ventromedial prefrontal cortex (vmPFC) and ventral part of posterior cingulate cortex (vPCC). Also, GM volume of a cluster in the vmPFC was correlated with Future TP. Interestingly, there was an overlapping region in vmPFC that was correlated with both DD and Future TP. Region-of-interest analysis further indicated that the overlapping region of vmPFC played a partially mediating role in the relation between Future TP and DD in the other independent dataset (Group 2, 36 healthy college students; 14 male; 20.18+/-1.80 years). Taken together, our results provide a new perspective from neural basis for explaining the relation between DD and future TP. PMID- 28645749 TI - A population of G2-arrested cells are selected as sensory organ precursors for the interommatidial bristles of the Drosophila eye. AB - Cell cycle progression and differentiation are highly coordinated during the development of multicellular organisms. The mechanisms by which these processes are coordinated and how their coordination contributes to normal development are not fully understood. Here, we determine the developmental fate of a population of precursor cells in the developing Drosophila melanogaster retina that arrest in G2 phase of the cell cycle and investigate whether cell cycle phase-specific arrest influences the fate of these cells. We demonstrate that retinal precursor cells that arrest in G2 during larval development are selected as sensory organ precursors (SOPs) during pupal development and undergo two cell divisions to generate the four-cell interommatidial mechanosensory bristles. While G2 arrest is not required for bristle development, preventing G2 arrest results in incorrect bristle positioning in the adult eye. We conclude that G2-arrested cells provide a positional cue during development to ensure proper spacing of bristles in the eye. Our results suggest that the control of cell cycle progression refines cell fate decisions and that the relationship between these two processes is not necessarily deterministic. PMID- 28645751 TI - Psychometric evaluation of the German version of the Intuitive Eating Scale-2 in a community sample. AB - Intuitive eating is based on a strong physical connection with the body, aligned to internal cues of hunger and satiety, and a low preoccupation with food. The aim of this study was to provide a German version of the Intuitive Eating Scale-2 (IES-2) and to examine its psychometric properties with data collected from 532 participants aged 18-91 years. The IES-2 was translated into German following the World Health Organization guidelines (2016). Cronbach's alpha as a measure of internal consistency was 0.89 for the IES-2 total score, as well as 0.73 - 0.92 for the IES-2 subscale scores. For group differences, the results were as hypothesized: men had higher IES-2 scores than women, and participants with under and average weight showed higher IES-2 scores than participants with overweight and obesity. Participants without a dieting history had higher IES-2 scores than former or current dieters. In line with our hypotheses regarding construct validity, the IES-2 score had negative associations with emotional eating, restraint eating, external eating, binge eating and eating disorder symptomatology, as well as positive associations with self-efficacy and mental health-related quality of life. Second-order confirmatory factor analysis replicated the four-factor solution, with intuitive eating as a higher-order factor. These findings demonstrate that the German version of the IES-2 is a useful tool to assess intuitive eating in the general German population. PMID- 28645752 TI - Exercise training intensity and connexin 43 expression in hypertrophic cardiomyopathy. PMID- 28645753 TI - Multi-immunoreaction-based dual-color capillary electrophoresis for enhanced diagnostic reliability of thyroid gland disease. AB - Thyroid-stimulating hormone (TSH) secretion plays a critical role in regulating thyroid gland function and circulating thyroid hormones (i.e., thyroxine (T4) and triiodothyronine (T3)). A novel multi-immunoreaction-based dual-color capillary electrophoresis (CE) technique was investigated in this study to assess its reliability in diagnosing thyroid gland disease via simultaneous detection of TSH, T3, and T4 in a single run of CE. Compared to the conventional immunoreaction technique, multi-immunoreaction of biotinylated streptavidin antibodies increased the selectivity and sensitivity for individual hormones in human blood samples. Dual-color laser-induced fluorescence (LIF) detection-based CE performed in a running buffer of 25mM Na2B4O7-NaOH (pH 9.3) allowed for fast, simultaneous quantitative analysis of three target thyroid hormones using different excited wavelengths within 3.2min. This process had excellent sensitivity and detection limits of 0.05-5.32 fM. The results showed 1000-100,000 times higher detection sensitivity than previous methods. Method validation with enzyme linked immunosorbent assay for application with human blood samples showed that the CE method was not significantly different at the 98% confidence level. Therefore, the developed CE-LIF method has the advantages of high detection sensitivity, faster analysis time, and smaller sample amount compared to the conventional methods The combined multi-immunoreaction and dual-color CE-LIF method should have increased diagnostic reliability for thyroid gland disease compared to conventional methods based on its highly sensitive detection of thyroid hormones using a single injection and high-throughput screening. PMID- 28645754 TI - Tunable separations based on a molecular size effect for biomolecules by poly(ethylene glycol) gel-based capillary electrophoresis. AB - We report novel capillary gel electrophoresis (CGE) with poly(ethylene glycol) (PEG)-based hydrogels for the effective separations of biomolecules containing sugars and DNAs based on a molecular size effect. The gel capillaries were prepared in a fused silica capillary modified with 3 (trimethoxysilyl)propylmethacrylate using a variety of the PEG-based hydrogels. After the fundamental evaluations in CGE regarding the separation based on the molecular size effect depending on the crosslinking density, the optimized capillary provided the efficient separation of glucose ladder (G1 to G20). In addition, another capillary showed the successful separation of DNA ladder in the range of 10-1100 base pair, which is superior to an authentic acrylamide-based gel capillary. For both glucose and DNA ladders, the separation ranges against the molecular size were simply controllable by alteration of the concentration and/or units of ethylene oxide in the PEG-based crosslinker. Finally, we demonstrated the separations of real samples, which included sugars carved out from monoclonal antibodies, mAbs, and then the efficient separations based on the molecular size effect were achieved. PMID- 28645755 TI - Microwave-assisted micellar extraction of organic and inorganic iodines using zwitterionic surfactants. AB - Zwitterionic surfactant, used as extractant in microwave-assisted extraction (MAE) was investigated for the first time to extract organic and inorganic iodines from kelp samples. Optimized conditions for the MAE were 200W of microwave irradiation power, 100 degrees C of extraction temperature, 10min of microwave irradiation time, 1g of sample, and 20mL of solvent volume. Ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used for the quantitative and qualitative analyses of the iodines. Under the optimum experimental conditions, KI, MIT and DIT were identified in kelp samples, the limits of detection of these analytes were ranged between 3.39 and 6.31ng/mL. The recoveries for spiked samples obtained from different areas were all higher than 92.48%. Compared with the ultrasound-assisted extraction, the proposed method is faster and more effective. Thus, the combination of zwitterionic surfactant-MAE and UHPLC-Q-TOF/MS made up a simple, rapid and effective approach for extraction and determination of iodine compounds in complex seaweed materials. PMID- 28645756 TI - An aptamer-based PCR method coupled with magnetic immunoseparation for sensitive detection of Salmonella Typhimurium in ground turkey. AB - Aptamers are single-stranded oligonucleotide ligands that can bind to targets with high affinity and specificity. They have been widely studied in the field of diagnostics as alternatives to antibodies due to their favorable features such as easy labeling, temperature tolerance, lower cost and recognition of a wide variety of targets. In this study, an aptamer-based PCR method coupled with magnetic immunoseparation was developed to detect S. Typhimurium from ground turkey. Firstly, biotinylated polyclonal anti-S. Typhimurium antibody was immobilized on streptavidin-coated magnetic nanobeads to capture S. Typhimurium. Secondly, the aptamers were added and bound to the surface of S. Typhimurium after blocking the magnetic nanobeads with short ssDNA. Finally, the aptamers were released by heating and amplified by PCR. After optimization, this assay was able to detect 102 CFU/mL of S. Typhimurium in pure culture, and 103 CFU/mL of S. Typhimurium in ground turkey. This study demonstrated the feasibility and application of an aptamer-based PCR method coupled with magnetic immunoseparation for sensitive detection of S. Typhimurium in ground turkey. PMID- 28645757 TI - Sympathetic Response and Outcomes Following Renal Denervation in Patients With Chronic Heart Failure: 12-Month Outcomes From the Symplicity HF Feasibility Study. AB - BACKGROUND: Heart failure (HF) is associated with chronic sympathetic activation. Renal denervation (RDN) aims to reduce sympathetic activity by ablating the renal sympathetic nerves. We investigated the effect of RDN in patients with chronic HF and concurrent renal dysfunction in a prospective, multicenter, single-arm feasibility study. METHODS AND RESULTS: Thirty-nine patients with chronic systolic HF (left ventricular ejection fraction [LVEF] <40%, New York Heart Association class II-III,) and renal impairment (estimated glomerular filtration rate [eGFR; assessed with the use of the Modification of Diet in Renal Disease equation] < 75 mL * min-1 * 1.73 m-2) on stable medical therapy were enrolled. Mean age was 65 +/- 11 years; 62% had ischemic HF. The average number of ablations per patient was 13 +/- 3. No protocol-defined safety events were associated with the procedure. One subject experienced a renal artery occlusion that was possibly related to the denervation procedure. Statistically significant reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1530 +/- 1228 vs 1428 +/- 1844 ng/mL; P = .006) and 120-minute glucose tolerance test (11.2 +/- 5.1 vs 9.9 +/- 3.6; P = .026) were seen at 12 months, but there was no significant change in LVEF (28 +/- 9% vs 29 +/- 11%; P= .536), 6-minute walk test (384 +/- 96 vs 391 +/- 97 m; P= .584), or eGFR (52.6 +/- 15.3 vs 52.3 +/- 18.5 mL * min-1 * 1.73 m-2; P= .700). CONCLUSIONS: RDN was associated with reductions in NT-proBNP and 120-minute glucose tolerance test in HF patients 12 months after RDN treatment. There was no deterioration in other indices of cardiac and renal function in this small feasibility study. PMID- 28645758 TI - Urgently awaiting implementation: The right to be free from exploitation, violence and abuse in Article 16 of the Convention on the Rights of Persons with Disabilities (CRPD). AB - The Convention on the Rights of Persons with Disabilities (CRPD) enshrines the freedom from exploitation, violence and abuse, a provision, which has hitherto received little attention. Exploring the contents of Article 16, this paper seeks to unpack both the potential for violence prevention as well as the implementation challenges. It situates violence protection within related treaty provisions and touches on specific challenges in institutional care as well as the private realm. PMID- 28645759 TI - Microplastics in the sediments of Terra Nova Bay (Ross Sea, Antarctica). AB - This is the first survey to investigate the occurrence and extent of plastic contamination in sediments collected in Terra Nova Bay (Ross Sea, Antarctica). Plastic debris extracted from 31 samples of sediments were counted, weighted and identified by Fourier-transform infrared spectroscopy (FT-IR). All sediment samples contained plastics: a total of 1661 items of debris (3.14g) were recorded from the 31 samples of sediment. Plastic particles in the samples ranged from 0.3 to 22mm in length. Fibres were the most frequent type of small plastics debris detected. In terms of abundance, microplastics (<5mm) accounted for 78.4% of debris. 9 polymer types were found: the most common material (94.13% by weight) was styrene-butadiene-styrene copolymer (SBS), widely used in pneumatic tires, etc. A decreasing concentration of plastic debris at increasing distances from the Mario Zucchelli Base was evidenced. PMID- 28645760 TI - Effects of endocrine disrupting chemicals (EDCs) on bacterial communities in mangrove sediments. AB - The diversity and composition of bacterial communities in mudflat and mangrove sediments were investigated under the stresses of endocrine-disrupting chemicals (EDCs) using high-throughput sequencing technique. Bacterial diversity in the original sediments was highest among all samples, followed by non-sterilized and sterilized sediments after 84-day incubation. Proteobacteria were the predominant phylum in both mangrove and mudflat sediments, which accounted for 40-60% of the total tags, followed by Cyanobacteria, Chloroflexi, Planctomycetes and Acidobacteria. Although the total population of bacteria was not significantly declined due to the addition of EDCs, bacterial community structures were considerably altered. The number of bacterial genera promoted or inhibited by EDCs was 288 and 324, respectively. Bacterial genera affected by EDCs varied greatly with the types of sediments and the initial status of bacterial communities. Overall, our results suggested that bacterial community structure in mangrove sediments were closely related to their re-development and responses to EDC contamination. PMID- 28645761 TI - Beach macro-litter monitoring and floating microplastic in a coastal area of Indonesia. AB - Qualitative analysis of the structures of the polymers composing floating plastic debris was performed using attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and the aging of the debris was assessed by measuring carbonyl group formation on the particle surfaces. Plastic material made up >75% of the 2313 items collected during a three-year survey. The size, shape and color of the microplastic were correlated with the polymer structure. The most abundant plastic materials were polypropylene (68%) and low-density polyethylene (11%), and the predominant colors of the plastics were white, blue and green. Cilacap Bay, Indonesia, was contaminated with microplastic at a concentration of 2.5mg.m3. The carbonyl index demonstrated that most of the floating microplastic was only slightly degraded. This study highlights the need to raise environmental awareness through citizen science education and adopting good environmental practices. PMID- 28645762 TI - Calculating in situ degradation rates of hydrocarbon compounds in deep waters of the Gulf of Mexico. AB - Biodegradation is an important process for hydrocarbon weathering that influences its fate and transport, yet little is known about in situ biodegradation rates of specific hydrocarbon compounds in the deep ocean. Using data collected in the Gulf of Mexico below 700m during and after the Deepwater Horizon oil spill, we calculated first-order degradation rate constants for 49 hydrocarbons and inferred degradation rate constants for an additional 5 data-deficient hydrocarbons. Resulting calculated (not inferred) half-lives of the hydrocarbons ranged from 0.4 to 36.5days. The fastest degrading hydrocarbons were toluene (k= 1.716), methylcyclohexane (k=-1.538), benzene (k=-1.333), and C1-naphthalene (k= 1.305). The slowest degrading hydrocarbons were the large straight-chain alkanes, C-26 through C-33 (k=-0.0494 through k=-0.007). Ratios of C-18 to phytane supported the hypothesis that the primary means of degradation in the subsurface was microbial biodegradation. These degradation rate constants can be used to improve models describing the fate and transport of hydrocarbons in the event of an accidental deep ocean oil spill. PMID- 28645763 TI - Monitoring nitrogen pollution in seasonally-pulsed coastal waters requires judicious choice of indicator species. AB - We compared the sensitivity of algae and hermit crabs to seasonal shifts in the dominance of continuous sewage discharge vs. pulsed inputs of terrestrial material to a subtropical bay. During periods of low rainfall, when sewage was proportionately more important than diffuse loads from adjacent catchments, algae and crabs provided comparable information on the spatial distribution of N pollution. Conversely, during the wet season, when diffuse nitrogen loads from the catchment were of greater importance, the isotope signal of algae decoupled from that of crabs, indexing a greater magnitude of change and a more pronounced spatial gradient. Overall, algae better indexed the short-term impacts of anthropogenic nitrogen pollution whereas the signals provided by crabs provided a longer-term integrated measure of N inputs. Our results demonstrate the value of including multiple taxa with variable traits when monitoring the spatial and temporal extent of nitrogen inputs to coastal waters. PMID- 28645764 TI - Electrochemical behavior of Pb (II) on a heparin modified chitosan/graphene nanocomposite film coated glassy carbon electrode and its sensitive detection. AB - In this study, we developed a novel composite material containing biological macromolecules like heparin and chitosan coated on reduced graphene oxide (rGO) for the modification of glassy carbon electrode (hep/CS-rGO/GC). It can be applied for the sensitive electrochemical detection of Pb2+ by square wave anodic stripping voltammetry (SWASV). The physicochemical analysis such as XRD, FTIR, FESEM and Raman spectroscopy techniques revealed that an effective functionalization occurred at the rGO surface. The consequence of deposition and stripping of metal ions by various electrochemical parameters such as supporting electrolytes, pH value, deposition potential, and deposition time were carefully studied and optimized. Under the optimized conditions, the linear calibration curve was calculated to be from 1.125 to 8.25MUgL-1 for Pb2+ with the correlation coefficient (R2) 0.9988. The detection limit and sensitivity achieved for the modified electrode were 0.03MUgL-1 and 1.34MUA/nM respectively. Furthermore, the electrochemical investigation indicates that the hep/CS-rGO composite electrode exhibits high selectivity, strong adherence to the electrode surface, good stability and reproducibility towards the detection of Pb2+. Finally, hep/CS rGO/GC electrode was assessed by the quantity of Pb2+ present in the practical samples, and the determined results were consistent with that of AAS. PMID- 28645765 TI - Chitosan surface modified electrospun poly(epsilon-caprolactone)/carbon nanotube composite fibers with enhanced mechanical, cell proliferation and antibacterial properties. AB - The surface modification is one of the most effective methods to improve the bioactivity and cell affinity effect of electrospun poly(epsilon-caprolactone) (PCL) fibers. In the present study, chitosan (CS), a cationic polysaccharide, was used to modify the surface of electrospun PCL fibers. To obtain strong interaction between CS and PCL fibers, negatively charged PCL fibers were prepared by the incorporation of acid-treated carbon nanotubes (CNTs) into the fibers. In this way, the positively charged chitosan could be immobilized onto the surface of PCL fibers tightly by the electrostatic attraction. Besides, the incorporation of CNTs could significantly improve the mechanical strength of electrospun PCL fibers even after the CS modification, which guaranteed their usability in practical applications. The CS modification could effectively improve the wettability and bioactivity of electrospun PCL fibers. Cultivation of L929 fibroblast cells on the obtained fibers and the antibacterial activity were both evaluated to discuss the influence of chitosan modification. The results indicated that this modification could enhance the cell proliferation and antibacterial ability in comparison to the non-modified groups. PMID- 28645766 TI - Phylogenomic analysis supports multiple instances of polyphyly in the oomycete peronosporalean lineage. AB - The study of biological diversification of oomycetes has been a difficult task for more than a century. Pioneer researchers used morphological characters to describe this heterogeneous group, and physiological and genetic tools expanded knowledge of these microorganisms. However, research on oomycete diversification is limited by conflicting phylogenies. Using whole genomic data from 17 oomycete taxa, we obtained a dataset of 277 core orthologous genes shared among these genomes. Analyses of this dataset resulted in highly congruent and strongly supported estimates of oomycete phylogeny when we used concatenated maximum likelihood and coalescent-based methods; the one important exception was the position of Albugo. Our results supported the position of Phytopythium vexans (formerly in Pythium clade K) as a sister clade to the Phytophthora Hyaloperonospora clade. The remaining clades comprising Pythium sensu lato formed two monophyletic groups. One group was composed of three taxa that correspond to Pythium clades A, B and C, and the other group contained taxa representing clades F, G and I, in agreement with previous Pythium phylogenies. However, the group containing Pythium clades F, G and I was placed as sister to the Phytophthora Hyaloperonospora-Phytopythium clade, thus confirming the lack of monophyly of Pythium sensu lato. Multispecies coalescent methods revealed that the white blister rust, Albugo laibachii, could not be placed with a high degree of confidence. Our analyses show that genomic data can resolve the oomycete phylogeny and provide a phylogenetic framework to study the evolution of oomycete lifestyles. PMID- 28645767 TI - Assessing the potential of RAD-sequencing to resolve phylogenetic relationships within species radiations: The fly genus Chiastocheta (Diptera: Anthomyiidae) as a case study. AB - Determining phylogenetic relationships among recently diverged species has long been a challenge in evolutionary biology. Cytoplasmic DNA markers, which have been widely used, notably in the context of molecular barcoding, have not always proved successful in resolving such phylogenies. However, with the advent of next generation-sequencing technologies and associated techniques of reduced genome representation, phylogenies of closely related species have been resolved at a much higher detail in the last couple of years. Here we examine the potential and limitations of one of such techniques-Restriction-site Associated DNA (RAD) sequencing, a method that produces thousands of (mostly) anonymous nuclear markers, in disentangling the phylogeny of the fly genus Chiastocheta (Diptera: Anthomyiidae). In Europe, this genus encompasses seven species of seed predators, which have been widely studied in the context of their ecological and evolutionary interactions with the plant Trollius europaeus (Ranunculaceae). So far, phylogenetic analyses using mitochondrial markers failed to resolve monophyly of most of the species from this recently diversified genus, suggesting that their taxonomy may need a revision. However, relying on a single, non recombining marker and ignoring potential incongruences between mitochondrial and nuclear loci may provide an incomplete account of the lineage history. In this study, we applied both classical Sanger sequencing of three mtDNA regions and RAD sequencing, for reconstructing the phylogeny of the genus. Contrasting with results based on mitochondrial markers, RAD-sequencing analyses retrieved the monophyly of all seven species, in agreement with the morphological species assignment. We found robust nuclear-based species assignment of individual samples, and low levels of estimated contemporary gene flow among them. However, despite recovering species' monophyly, interspecific relationships varied depending on the set of RAD loci considered, producing contradictory topologies. Moreover, coalescence-based phylogenetic analyses revealed low supports for most of the interspecific relationships. Our results indicate that despite the higher performance of RAD-sequencing in terms of species trees resolution compared to cytoplasmic markers, reconstructing inter-specific relationships among recently diverged lineages may lie beyond the possibilities offered by large sets of RAD sequencing markers in cases of strong gene tree incongruence. PMID- 28645768 TI - Robot-Assisted Training for People With Spinal Cord Injury: A Meta-Analysis. AB - OBJECTIVE: To investigate the effects of robot-assisted training on the recovery of people with spinal cord injury (SCI). DATA SOURCES: Randomized controlled trials (RCTs) or quasi-RCTs involving people with SCI that compared robot assisted upper limbs or lower limbs training with a control of other treatment approach or no treatment. We included studies involving people with complete or incomplete SCIs. STUDY SELECTION: We searched MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (Cochrane Library), and Embase to August 2016. Bibliographies of relevant articles on the effect of body-weight-supported treadmill training on subjects with SCI were screened to avoid missing relevant articles from the search of databases. DATA EXTRACTION: All kinds of objective assessments concerning physical ability, mobility, and/or functional ability were included. Assessments could be clinical tests (ie, 6-minute walk test, FIM) or laboratory tests (ie, gait analysis). Subjective outcome measures were excluded from this review. DATA SYNTHESIS: Eleven RCT studies involving 443 subjects were included in the study. Meta-analysis was performed on the included studies. Walking independence (3.73; 95% confidence interval [CI], -4.92 to -2.53; P<.00001; I2=38%) and endurance (53.32m; 95% CI, -73.15 to -33.48; P<.00001; I2=0%) were found to have better improvement in robot-assisted training groups. Lower limb robot-assisted training was also found to be as effective as other types of body-weight-supported training. There is a lack of upper limb robot assisted training studies; therefore, performing a meta-analysis was not possible. CONCLUSIONS: Robot-assisted training is an adjunct therapy for physical and functional recovery for patients with SCI. Future high-quality studies are warranted to investigate the effects of robot-assisted training on functional and cardiopulmonary recovery of patients with SCI. PMID- 28645769 TI - Access to Preventive Services for Working-Age Adults With Physical Limitations. AB - OBJECTIVE: To examine differences in access to preventive services for working age adults with physical limitations, nonphysical limitations, and no limitations. DESIGN: Observational data were pooled across calendar years 2003 through 2012 from the Medical Expenditure Panel Survey (MEPS), a nationally representative survey of noninstitutionalized U.S. adults. SETTING: Community. PARTICIPANTS: Working-age adults (N=75,145; age range, 18-64y) who responded to all 5 rounds of the MEPS during 2003 through 2012. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Blood pressure checks, flu shots, and dental visits, in the last 12 months. RESULTS: Multivariate analyses showed that adults with physical limitations were more likely to receive a blood pressure check (92.2% vs 69.6%, respectively; P<.001) or flu shot (39.7% vs 23.4%, respectively; P<.001) than adults with no limitations. However, those with physical limitations were less likely to have a dental checkup (44.7% vs 59.4%, respectively; P<.001) than those with no limitation. Having a usual source of care increased the odds of receiving preventive services. CONCLUSIONS: The study has implications for providers and policymakers. Policies that support the adequacy of provider networks and continuity with a usual source of care may increase the use of preventive services in adults with physical limitations. PMID- 28645770 TI - Association Between Sedentary Time and Quality of Life From the Osteoarthritis Initiative: Who Might Benefit Most From Treatment? AB - OBJECTIVE: To investigate the relationship between sedentary behavior and quality adjusted life years (QALYs) among participants in the Osteoarthritis Initiative. DESIGN: Longitudinal, observational design. SETTING: Osteoarthritis Initiative cohort. PARTICIPANTS: Individuals (N=1794) from a prospective, multicenter longitudinal cohort were classified into quantile groups based on average daily sedentary time (most sedentary, quartile 1 [Q1] >=11.6h; 10.7h<= Q2 <11.6h; 9.7h<= Q3 <10.7h; least sedentary, Q4 <9.7h). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Individual QALYs were estimated over 2 years from the area under the curve of health-related utility scores derived from the Medical Outcomes Study 12-Item Short-Form Health Survey versus time. The relationship between baseline sedentary behavior and median 2-year QALYs was estimated using quantile regression adjusted for socioeconomic factors and body mass index. RESULTS: Lower QALYs over 2 years were more frequently found among the most sedentary (Q1, median 1.59), and QALYs increased as time spent in baseline sedentary behavior decreased (median QALYs for Q2, 1.64; Q3, 1.65; Q4, 1.65). The relationship of sedentary time and median QALY change was only significant for the most sedentary Q1 group, where an additional hour of sedentary behavior significantly reduced QALYs by -.072 (95% confidence interval, -.121 to -.020). CONCLUSIONS: Our findings suggest that individuals with the most extreme sedentary profiles may be vulnerable to additional losses of quality of life if they become more sedentary. Targeting these individuals to decrease sedentary behavior has the potential to be cost-effective. PMID- 28645771 TI - Dectin-1 expression by macrophages and related antifungal mechanisms in a murine model of Sporothrix schenckii sensu stricto systemic infection. AB - The available information about the role of Dectin-1 in sporotrichosis is scarce. Hence, we aimed to assess Dectin-1 expression by macrophages and the activation of some related antifungal mechanisms during the Sporothrix schenckii sensu stricto infection as a first attempt to elucidate the role of this receptor in sporotrichosis. Balb/c mice were intraperitoneally infected with S. schenckii sensu stricto yeast ATCC 16345 and euthanized on days 5, 10 and 15 post infection, when the following parameters were evaluated: fungal burden in spleen, Dectin-1 expression and nitric oxide (NO) production by peritoneal macrophages, as well as IL-1beta, TNF-alpha and IL-10 ex vivo secretion by these same cells. Peritoneal macrophages were ex vivo challenged with either the alkali-insoluble fraction (F1) extracted from the S. schenckii cell wall, a commercially available purified beta-1,3-glucan or whole heat-killed S. schenckii yeasts (HKss). Additionally, a Dectin-1 antibody-mediated blockade assay was performed on day 10 post-infection to assess the participation of this receptor in cytokine secretion. Our results showed that Dectin-1 expression by peritoneal macrophages was augmented on days 10 and 15 post-infection alongside elevated NO production and ex vivo secretion of IL-10, TNF-alpha and IL-1beta. The antibody-mediated blockade of Dectin-1 inhibited cytokine production in both infected and non infected mice, mainly after beta-1,3-glucan stimulation. Our results suggest a role for Dectin-1 in triggering the immune response during S. schenckii infection. PMID- 28645772 TI - Increased of the hepatocytes and splenocytes apoptosis accompanies clinical improvement and higher survival in mice infected with Trypanosoma cruzi and treated with highly diluted Lycopodium clavatum. AB - Recent evidence includes apoptosis as a defense against Trypanosoma cruzi infection, which promotes an immune response in the host induced by T cells, type 1, 2 and 17. Currently, there is no medicine completely preventing the progression of this disease. We investigated the immunological and apoptotic effects, morbidity and survival of mice infected with T. cruzi and treated with dynamized homeopathic compounds 13c: Kalium causticum (GCaus), Conium maculatum, (GCon), Lycopodium clavatum (GLy) and 7% alcohol solution (control, vehicle compounds, GCI). There was significant difference in the increase of apoptosis in the treated groups, compared with GCI, which might indicate action of the compounds in these cells. Infected animals treated with Lycopodium clavatum presented better performance compared with other groups. GLy showed a higher amount of hepatocytes and splenocytes undergoing apoptosis, higher number of apoptotic bodies in the liver, predominance of Th1 response, increased TNF-alpha and decreased IL-6, higher survival, lower morbidity, higher water consumption, body temperature, tendency to higher feed intake and weight gain compared with GCI. Conium maculatum had worse results with increased Th2 response with increased IL-4, worsening of the infection with early mortality of the animals. Together, these data suggest that highly diluted medicines modulate the immune response and apoptosis, affecting the morbidity of animals infected with a highly virulent strain of T. cruzi, being able to minimize the course of infection, providing more alternative approaches in the treatment of Chagas disease. PMID- 28645773 TI - ABC protein CgABCF2 is required for asexual and sexual development, appressorial formation and plant infection in Colletotrichum gloeosporioides. AB - ATP-binding cassette (ABC) proteins are exclusively found in both prokaryotes and eukaryotes. In this study, we have characterized a gene from Glomerella leaf spot pathogen Colletotrichum gloeosporioides that encodes an ABC protein, whose function to date remains unknown. We designated this gene as CgABCF2. Deletion of CgABCF2 showed drastic reduction both growing rate and conidial production in C. gloeosporioides. The Deltacgabcf2 mutant did not form the appressoria, lost the capability to infect apple and failed to form lesions on the wounded leaves and fruits. The C. gloeosporioides native CgABCF2 fully recovered defect of the Deltacgabcf2 mutant. These data indicated that CgABCF2 was required for fungal development and invasion. The transcriptions of six pectolytic enzymes genes (CgPG1, CgPG2, pnl-1, pnl-2, pelA and pelB) significantly reduced in the Deltacgabcf2 mutant, indicating that deletion of CgABCF2 impaired the fungal necrotrophic growth. In addition, CgABCF2 mediated sexual development through the positive regulation of the gene MAT1-2-1 expression. These results indicated that CgABCF2 underlies the complex process governing morphogenesis, sexual and asexual reproduction, appressorial formation and pathogenicity in C. gloeosporioides. PMID- 28645774 TI - Evaluation of selected Indian medicinal plants for antagonistic potential against Malassezia spp. and the synergistic effect of embelin in combination with ketoconazole. AB - The genus Malassezia comprises of extremely lipophilic yeasts secreting lipases as a vital factor for survival. They are emerging as opportunistic pathogens in medical microbiology and dermatology by causing recurring and recalcitrant infection. Combinatorial therapy is a constructive way to combat infectious diseases. In that prospect, totally 16 Indian medicinal plants were screened, among which a maximum degree of antimicrobial activity was ascertained in Embelia ribes. Subsequently embelin was identified as the bioactive principle with antagonistic potential by comparative antimicrobial assay and FTIR analysis. The MIC of embelin was determined as 400 MUg/ml exhibiting ~75% of growth inhibition. Further, a fungistatic activity based on anti-lipase potential (65-89%) of embelin has been clearly substantiated by XTT and lipase assay. In addition, embelin exhibited a synergistic effect with the antifungal drug ketoconazole (KTZ) against four different Malassezia spp. with FIC index of 0.5. Therefore, the combinations of embelin and KTZ may represent a promising therapeutic regimen to treat Malassezia infections with subjugated clinical and environmental toxicity. To the best of our knowledge, this is the first report delineating the anti-lipase activity of embelin and in vitro synergistic interaction between embelin and KTZ against Malassezia spp. PMID- 28645775 TI - Altered populations of natural killer cells, cytotoxic T lymphocytes, and regulatory T cells in major depressive disorder: Association with sleep disturbance. AB - A subset of individuals with major depressive disorder (MDD) have impaired adaptive immunity characterized by a greater vulnerability to viral infection and a deficient response to vaccination along with a decrease in the number and/or activity of T cells and natural killer cells (NKC). Nevertheless, it remains unclear which specific subsets of lymphocytes are altered in MDD, a shortcoming we address here by utilizing an advanced fluorescence-activated cell sorting (FACS) method that allows for the differentiation of important functionally distinct lymphocyte sub-populations. Furthermore, despite evidence that sleep disturbance, which is a core symptom of MDD, is itself associated with alterations in lymphocyte distributions, there is a paucity of studies examining the contribution of sleep disturbance on lymphocyte populations in MDD populations. Here, we measured differences in the percentages of 13 different lymphocytes and 6 different leukocytes in 54 unmedicated MDD patients (partially remitted to moderate) and 56 age and sex-matched healthy controls (HC). The relationship between self-reported sleep disturbance and cell counts was evaluated in the MDD group using the Pittsburgh Sleep Quality Index (PSQI). The MDD group showed a significantly increased percentage of CD127low/CCR4+ Treg cells, and memory Treg cells, as well as a reduction in CD56+CD16- (putative immunoregulatory) NKC counts, the latter, prior to correction for body mass index. There also was a trend for higher effector memory CD8+ cell counts in the MDD group versus the HC group. Further, within the MDD group, self-reported sleep disturbance was associated with an increased percentage of effector memory CD8+ cells but with a lower percentage of CD56+CD16- NKC. These results provide important new insights into the immune pathways involved in MDD, and provide novel evidence that MDD and associated sleep disturbance increase effector memory CD8+ and Treg pathways. Targeting sleep disturbance may have implications as a therapeutic strategy to normalize NKC and memory CD8+ cells in MDD. PMID- 28645777 TI - Increased food intake after starvation enhances sleep in Drosophila melanogaster. AB - Feeding and sleep are highly conserved, interconnected behaviors essential for survival. Starvation has been shown to potently suppress sleep across species; however, whether satiety promotes sleep is still unclear. Here we use the fruit fly, Drosophila melanogaster, as a model organism to address the interaction between feeding and sleep. We first monitored the sleep of flies that had been starved for 24 h and found that sleep amount increased in the first 4 h after flies were given food. Increased sleep after starvation was due to an increase in sleep bout number and average sleep bout length. Mutants of translin or adipokinetic hormone, which fail to suppress sleep during starvation, still exhibited a sleep increase after starvation, suggesting that sleep increase after starvation is not a consequence of sleep loss during starvation. We also found that feeding activity and food consumption were higher in the first 10-30 min after starvation. Restricting food consumption in starved flies to 30 min was sufficient to increase sleep for 1 h. Although flies ingested a comparable amount of food at differing sucrose concentrations, sleep increase after starvation on a lower sucrose concentration was undetectable. Taken together, our results suggest that increased food intake after starvation enhances sleep and reveals a novel relationship between feeding and sleep. PMID- 28645776 TI - Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. AB - BACKGROUND: Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. FINDINGS: Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. FUNDING: Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro. PMID- 28645778 TI - Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia. AB - Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive. We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN, p.S2506T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations (CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size. PMID- 28645779 TI - Schizophrenia and neurogenesis: A stem cell approach. AB - Several recent research findings indicate that schizophrenia (SCZ) may begin with an abnormal neuro-genesis from embryonic Neural Stem Cells (NSCs) and that this process may be particularly vulnerable to a number of genetic and/or environmental disturbances of early brain development. Since it is now well known that neurogenesis is not confined to the womb, but is a protracted process continuing in postnatal life well into adolescence and beyond, and since in the majority of subjects diagnosed with SCZ the first psychotic break occurs in late adolescence or early adulthood, the aim of our paper is to summarize the main findings supporting a possible link between changes in developmental postnatal neurogenesis and SCZ, with a specific focus on the critical period of adolescence and associated environmental risk factors. Establishing a significant role of adult neurogenesis in the emergence of psychosis will help us not only to better understand the pathogenesis of this neuopsychiatric disorder, but also to provide the key to potential strategies toward possible treatments and/or early corrective interventions. PMID- 28645780 TI - Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Danshen is a crude herbal drug isolated from dried roots of Salvia miltiorrhiza Bunge. This plant is widely used in oriental medicine for the treatment of cardiovascular and cerebrovascular diseases. The supercritical CO2 extract from Danshen (SCED) (57.85%, 5.67% and 4.55% for tanshinone IIA, tanshinone I and cryptotanshinone respectively) was studied in this article, whose potential molecular mechanism remains unclear, especially in anti-thrombosis. AIM OF THE STUDY: The present study was designed to observe the protective effect of SCED on ischemic stroke in rats and to explore the underlying anti-thrombosis mechanism. MATERIALS AND METHODS: Following induction of cerebral ischemia in rats by permanent middle cerebral artery occlusion (pMCAO). Neurological defect score, cerebral blood flow, infarct size, and brain edema were measured to evaluate the injury. Arteriovenous shunt thrombosis model and adenosine 5'-diphosphate (ADP) induced acute pulmonary embolism model were conducted to estimate the antithrombotic effect of SCED. In order to investigate the effects of SCED on platelet aggregation, rat platelet-rich-plasma (PRP) were incubated with SCED prior to the addition of the stimuli (ADP or 9, 11-dideoxy 11alpha, 9alpha-epoxymethanoprostaglandin F2alpha (U46619)). Aggregation was monitored in a light transmission aggregometer. Inhibitory effect of SCED on thromboxane A2 (TXA2) release was detected by ELISA kit. Phospholipase C (PLC)/ Protein kinase C (PKC) signaling pathway was analyzed by a Western blot technique. The effect of the SCED was also studied in vivo on bleeding time in mice. RESULTS: SCED improved the neurological defect score, increased cerebral blood flow, reduced infarct size and alleviated brain edema in rats exposed to pMCAO. After administration of SCED, thrombosis formation in arteriovenous shunt was inhibited and recovery time in pulmonary embolism was shortened. The inhibitory effect of SCED on platelet activation was further confirmed by TXB2 ELISA kit and Western blot analysis of PLC/PKC signaling pathway. CONCLUSIONS: SCED attenuates cerebral ischemic injury. The possible mechanism is that SCED inhibits thrombosis formation, platelet aggregation and activation of PLC/PKC pathway. On this basis, this new extract could be a promising agent to inhibit thrombosis formation and protect against cerebral ischemia injury. PMID- 28645781 TI - Immunomodulatory mechanism of Bushen Huoxue Recipe alleviates cyclophosphamide induced diminished ovarian reserve in mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Huoxue recipe (BHR) is a Chinese herbal prescription composed of ten herbs and it is widely used for the treatment of diminished ovarian reserve (DOR). This study investigates the potentially beneficial effects and underlying mechanism of BHR on a cyclophosphamide (CTX) induced model of DOR in mice. MATERIALS AND METHODS: Granules of BHR were first subjected to high performance liquid chromatography (HPLC) to determine the exact ingredients within the mixture. We then induced DOR in mice by injecting them with 90mg/kg of CTX. Following the single intraperitoneal injection, mice then received either saline or BHR for 21 days. To assess the effects of BHR on DOR, we examined splenic and ovarian morphology, estrous cycle duration, ovarian index, follicle number, body weight, and concentration of serum E2 and FSH. To explore the immunological mechanism behind the effects, mouse splenocytes were isolated in order to analyze the proportion of CD4+, CD8+ T cells and Th1, Th17 and Treg subsets by flow cytometry. The serum levels of IFN-gamma, TNF-alpha, IL 4, IL-17A, IL-6 and IL-10 were detected using Cytometric Bead Array (CBA). Additionally, the mRNA expression levels of T-bet, RORgammat and Foxp3 were measured with quantitative real-time PCR. RESULTS: Our results show that following treatment with BHR in DOR mice, several measures showed significant improvement. The morphology of the ovary and spleen, estrous cycle duration, body weight, ovarian index, and serum levels of E2 and FSH recovered to approximately normal levels and the loss of follicles at all stages was significantly attenuated. Furthermore, the elevated proportions of CD4+ T cells, Th1, Th17, Treg subsets and the increased serum levels of IFN-gamma, TNF-alpha, IL-17A, IL-6 and IL-10 as well as the mRNA expressions of T-bet, RORgammat and Foxp3 in DOR mice were significantly decreased. CONCLUSIONS: Our results show that BHR is a promising candidate to treat DOR mice and this beneficial effect may be mediated through the downregulation of augmented autoimmunity. PMID- 28645782 TI - Cysteine-stabilised peptide extract of Morinda lucida (Benth) leaf exhibits antimalarial activity and augments antioxidant defense system in P. berghei infected mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cysteine-stabilised peptides (CSP) are majorly explored for their bioactivities with applications in medicine and agriculture. Morinda lucida leaf is used indigenously for the treatment of malaria; it also contains CSP but the role of CSP in the antimalarial activity of the leaf has not been evaluated. AIM OF THE STUDY: This study was therefore performed to evaluate the antimalarial activity of partially purified cysteine-stabilised peptide extract (PPCPE) of Morinda lucida leaf and its possible augmentation of the antioxidant systems of liver and erythrocytes in murine malaria. MATERIALS AND METHODS: PPCPE was prepared from Morinda lucida leaf. The activity of PPCPE was evaluated in vitro against Plasmodium falciparum W2 and its cytotoxicity against a BGM kidney cell line. PPCPE was also evaluated for its antimalarial activity and its effects on selected liver and erythrocyte antioxidant parameters in P. berghei NK65-infected mice. RESULTS: PPCPE was not active against P. falciparum W2 (IC50: >50ug/ml) neither was it cytotoxic (MLD50: >1000ug/ml). However, PPCPE was active against P. berghei NK65 in vivo, causing 51.52% reduction in parasitaemia at 31.25mg/Kg body weight on day 4 post-inoculation. PPCPE significantly reduced (P < 0.05) malondialdehyde concentrations in the liver and erythrocyte at higher doses compared to untreated controls. PPCPE increased glutathione concentration and activities of glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase in a dose-dependent manner, which was significant (P < 0.05) at higher doses compared to the untreated controls. CONCLUSION: The results suggest that PPCPE may require bioactivation in vivo in order to exert its antimalarial effect and that PPCPE may augment the antioxidant defense system to alleviate the reactive oxygen species-mediated complications of malaria. PMID- 28645783 TI - Maerua angolensis stem bark extract reverses anxiety and related behaviours in zebrafish-Involvement of GABAergic and 5-HT systems. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Maerua angolensis DC (Capparaceae) has been employed in the management of several central nervous system (CNS) disorders including anxiety. This study evaluated the anxiolytic effects of the petroleum ether/ethyl acetate fraction stem bark extract and its possible mechanism(s) using zebrafish anxiety models. METHODS: Adult zebrafish, tested in the novel tank and light dark tests, have shown by previous authors to be sensitive to the anxiolytic effects of known anxiolytic drugs. Adult zebrafish were treated with M. angolensis extract, fluoxetine, desipramine, and diazepam followed by testing in the novel tank and light dark tests. We further assessed the effect of the extract on anxiety after inducing an anxiogenic phenotype using the ethanol withdrawal and chronic unpredictable stress (CUS) tests. The anxiolytic effect was further investigated after pretreatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. RESULTS: M. angolensis extract, similar to fluoxetine and desipramine, demonstrated significant anxiolytic behaviour at doses that did not reduce locomotor activity significantly. Similar anxiolytic effects were recorded in the ethanol withdrawal-induced anxiety test. Furthermore, the anxiogenic effects induced by the CUS paradigm were significantly reversed by treatment M. angolensis extract and fluoxetine. The anxiolytic effects of M. angolensis extract were however reversed after pre treatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. CONCLUSIONS: Taken together, this suggests that the petroleum ether/ ethyl acetate fraction of M. angolensis possesses significant anxiolytic activity, which could partly be accounted for by an interaction with the serotoninergic system and the GABAA receptor. PMID- 28645784 TI - The effect of antimicrobial photodynamic therapy on the expression of novel methicillin resistance markers determined using cDNA-AFLP approach in Staphylococcus aureus. AB - BACKGROUND: Widespread methicillin resistant Staphylococcus aureus (MRSA) and absence of effective antimicrobial agents has led to limited therapeutic options for treating MRSA infection. We aimed to evaluate the effect of antimicrobial photodynamic therapy (aPDT) on the expression of novel identified methicillin resistance markers (NIMRMs) in S. aureus using complementary DNA-Amplified Fragment Length Polymorphism (cDNA-AFLP) approaches to address the therapeutic alternatives for MRSA infections. MATERIALS AND METHODS: We used cDNA-AFLP to compare MRSA and methicillin susceptible S. aureus (MSSA) for identification of target genes implicated in methicillin resistance. To determine the sub-lethal aPDT (sPDT), MRSA and MSSA clinical isolates photosensitized with toluidine blue O (TBO), and then were irradiated with diode laser. After sPDT, the colony forming units/mL was quantified. Antimicrobial susceptibility against methicillin was assessed for cell-surviving aPDT. Effects of sPDT on the expression of NIMRMs were evaluated by real-time quantitative reverse transcription PCR. RESULTS: According to our results, serine hydrolase family protein (Shfp) encoding gene and a gene encoding a conserved hypothetical protein (Chp) were implicated in methicillin resistance in MRSA. sPDT reduced the minimum inhibitory concentrations of methicillin by 3-fold in MRSA. sPDT could lead to about 10- and 6.2- fold suppression of expression of the Chp and Shfp encoding genes, respectively. CONCLUSION: sPDT would lead to reduction in resistance to methicillin of MRSA in surviving cells by suppressing the expression of the Shfp and Chp encoding genes associated with methicillin resistance. This may have potential implications of aPDT for the treatment of MRSA infections. PMID- 28645785 TI - Contraceptive counseling in reproductive-aged women treated for breast cancer at a tertiary care institution: a retrospective analysis. AB - OBJECTIVE: The objective was to assess the frequency of documented contraceptive and fertility preservation counseling for women treated for breast cancer. STUDY DESIGN: We conducted a chart analysis of female breast cancer patients (n=211) ages 18-45 years receiving chemotherapy treatment at Stanford Comprehensive Cancer Center from 2010 to 2014. Primary outcomes of contraceptive counseling and fertility preservation counseling documentation were assessed for frequency. Secondary outcomes included pregnancy testing, contraception use and pregnancy during treatment. RESULTS: Among the total sample (n=211), sexual activity was documented in 24% of patients (n=51). Fifty-one percent (n=108) of patients received pregnancy testing prior to initiation of treatment. Past contraception use was documented in 74% of patients (n=156) and current contraception use in 25% (n=53). Twenty-six percent of patients received fertility preservation counseling alone (n=54), 10% received contraceptive counseling alone (n=22), and 12% received both types of counseling (n=25). Patients were three times more likely to receive contraceptive counseling if using contraception at diagnosis [odds ratio (OR) 3.1, confidence interval (CI) 1.1-9.1, p=.04], and older women were significantly less likely to receive counseling (OR 0.2, CI 0.1-1.0, p=.04). Two patients became pregnant and had an abortion during treatment (1%), and neither patient was using contraception nor received contraceptive or fertility preservation counseling. CONCLUSIONS: Documentation of fertility preservation counseling occurs more frequently than contraceptive counseling, but both occur suboptimally. Lack of documentation does not allow us to conclude that counseling did not occur, but it suggests the need to improve documentation and increase awareness of contraceptive needs and counseling. IMPLICATIONS: Women undergoing breast cancer treatment do not consistently receive counseling on contraception or fertility preservation as a part of their care. Efforts are needed to ensure that women treated for breast cancer routinely receive counseling about fertility preservation and contraceptive options. PMID- 28645786 TI - Defining quality in contraceptive counseling to improve measurement of individuals' experiences and enable service delivery improvement. PMID- 28645787 TI - Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor. AB - Glial cell line-derived neurotrophic factor (GDNF) positively regulates the development and maintenance of in vitro dopaminergic neurons. However, the in vivo influences of GDNF signals on the brain dopamine system are controversial and not fully defined. To address this question, we analyzed dopaminergic phenotypes of the transgenic mice that overexpress GDNF under the control of the glial Gfap promoter. Compared with wild-type, the GDNF transgenic mice contained higher levels of GDNF protein and phosphorylated RET receptors in the brain. However, there were reductions in the levels of tyrosine hydroxylase (TH), dopamine, and its metabolite homovanillic acid in the striatum of transgenic mice. The TH reduction appeared to occur during postnatal development. Immunohistochemistry revealed that striatal TH density was reduced in transgenic mice with no apparent signs of neurodegeneration. In agreement with these neurochemical traits, basal levels of extracellular dopamine and high K+-induced dopamine efflux were decreased in the striatum of transgenic mice. We also explored the influences of GDNF overexpression on lomomotor behavior. GDNF transgenic mice exhibited lower stereotypy and rearing in a novel environment compared with wild-type mice. These results suggest that chronic overexpression of GDNF in brain astrocytes exerts an opposing influence on nigrostriatal dopamine metabolism and neurotransmission. PMID- 28645788 TI - Effects of acute altered gravity during parabolic flight and/or vestibular loss on cell proliferation in the rat dentate gyrus. AB - Both parabolic flight, i.e. a condition of altered gravity, and loss of vestibular function, have been suggested to affect spatial learning and memory, which is known to be influenced by neurogenesis in the hippocampus. In this study we investigated whether short alternated micro- and hyper-gravity stimulations during parabolic flight and/or loss of vestibular function, would alter cell proliferation in the hippocampal dentate gyrus of rats, by measuring the number of bromodeoxyuridine (BrdU)-incorporated cells. Rats were randomly allocated to the following experimental groups: (1) sham transtympanic saline injection only (n=5); (2) bilateral vestibular deafferentation (BVD) by sodium arsanilate transtympanic injection only (n=5); (3) sham treatment and parabolic flight (n=5); (4) BVD and parabolic flight (n=6). Forty-two days following transtympanic injection, the animals were subjected to parabolic flight in an awake restrained condition after habituation. A modified Airbus A300 aircraft was flown on a parabolic path, creating 20s of 1.8G during both climbing and descending and 22s of 0G at the apex of each parabola. The no flight animals were subjected to the same housing for the same duration. Immediately after the parabolic flight or control ground condition, animals were injected with BrdU (300mg/kg, i.p). Twenty four hs after BrdU injection, rats were sacrificed. BrdU immunolabelling was performed and the number of BrdU+ve cells in the dentate gyrus of the hippocampus was quantified using a modified fractionator method. BVD caused a large and significant reduction in the number of BrdU-positive cells compared to sham animals (P<=0.0001); however, flight and all interactions were non-significant. These results indicate that BVD significantly decreased cell proliferation irrespective of the short exposure to altered/modified gravity. PMID- 28645789 TI - Disruption of GABA(A)-mediated intracortical inhibition in patients with chorea acanthocytosis. AB - Chorea-acanthocytosis (Ch-Ac) is an autosomal recessive neurodegenerative disorder characterized by adult-onset chorea, acanthocytes in the peripheral blood, and Huntington's disease-like neuropsychiatric symptoms. Animal studies have shown mutation-related dysregulated cortical gamma-aminobutyric acid (GABA)ergic inhibitory networks in its pathophysiology. Herein we found that in patients with Ch-Ac there is a striking alteration of intracortical inhibitory circuits detected by using paired pulse transcranial magnetic stimulation protocols. Our findings show in vivo the functional disruption of GABA(A) mediated networks in humans with Ch-Ac supporting the existing data in mice models with this condition. PMID- 28645791 TI - Large Labial Endometrioma in an Older Elderly Nulligravida Woman. PMID- 28645792 TI - Vaginal Salpingectomy Techniques in the Presence of Ovarian Conservation. AB - STUDY OBJECTIVE: To demonstrate vaginal salpingectomy techniques in the presence of ovarian conservation. DESIGN: Technical video demonstrating 2 methods of Fallopian tube removal with illustrations (Canadian Task Force classification III). SETTING: The prevalence of salpingectomy at the time of hysterectomy has increased significantly since 1998 [1]. One reason for the increased rate of salpingectomy is the relationship of serous ovarian carcinomas to fimbrial serous tubal intraepithelial carcinomas [2]. A Swedish population-based study reported that salpingectomy is an effective measure to reduce ovarian cancer risk in the general population [3]. Prophylactic salpingectomy and delayed oophorectomy may be an acceptable alternative in some BRCA mutation carriers [4]. A retrospective cohort study of 425 vaginal hysterectomies showed that 88% of patients were able to successfully undergo concomitant salpingectomy [5]. Mayo Clinic Institutional Review Board approval was not required for this video article. INTERVENTION: Two methods of salpingectomy are demonstrated differing in the final disposition of the proximal Fallopian tube (segment). The 2 different methods are shown to increase clarity and understanding of the technique. CONCLUSION: Salpingectomy without concomitant removal of the ovaries at vaginal hysterectomy is a feasible and beneficial procedure. PMID- 28645790 TI - Vitamin E deficiency during embryogenesis in zebrafish causes lasting metabolic and cognitive impairments despite refeeding adequate diets. AB - Vitamin E (alpha-tocopherol; VitE) is a lipophilic antioxidant required for normal embryonic development in vertebrates, but the long-term effects of embryonic VitE deficiency, and whether they are ameliorated by feeding VitE adequate diets, remain unknown. We addressed these questions using a zebrafish (Danio rerio) model of developmental VitE deficiency followed by dietary remediation. Adult zebrafish maintained on VitE-deficient (E-) or sufficient (E+) diets were spawned to obtained E- and E+ embryos, respectively, which we evaluated up to 12 days post-fertilization (dpf). The E- group suffered significantly increased morbidity and mortality as well as altered DNA methylation status through 5 dpf when compared to E+ larvae, but upon feeding with a VitE-adequate diet from 5 to 12 dpf both the E- and E+ groups survived and grew normally; the DNA methylation profile also was similar between groups by 12 dpf. However, 12 dpf E- larvae still had behavioral defects. These observations coincided with sustained VitE deficiency in the E- vs. E+ larvae (p < 0.0001), despite adequate dietary supplementation. We also found in E- vs. E+ larvae continued docosahexaenoic acid (DHA) depletion (p < 0.0001) and significantly increased lipid peroxidation. Further, targeted metabolomics analyses revealed persistent dysregulation of the cellular antioxidant network, the CDP-choline pathway, and glucose metabolism. While anaerobic processes were increased, aerobic metabolism was decreased in the E- vs. E+ larvae, indicating mitochondrial damage. Taken together, these outcomes suggest embryonic VitE deficiency causes lasting behavioral impairments due to persistent lipid peroxidation and metabolic perturbations that are not resolved via later dietary VitE supplementation. PMID- 28645793 TI - Biocompatible polymer microneedle for topical/dermal delivery of tranexamic acid. AB - Recently-introduced biocompatible polymeric microneedles offer an efficient method for drug delivery. Tranexamic acid is a novel drug for treating melasma that is administered both locally and orally and inhibits excessive melanin via melanocyte. The tranexamic acid biocompatible polymer microneedle used in this study was fabricated from PVP and methacrylic acid, using the lithography method. The required mechanical strength to pierce skin was attained by optimizing the ratio of PVP to methacrylic acid. Acute dermal toxicity was done, and drug diffusion in skin layers was simulated by calculating the diffusion coefficient of tranexamic acid in interstitial fluid (plasma). The biocompatible polymer microneedle was fabricated at 60 degrees C. Needles could sustain 0.6N that is enough to pierce stratum corneum. 34% of the released drug was locally effective and the rest permeated through the skin. The pyramidal polymer microneedle in this study was fully released in skin in approx. 7h. This polymer microneedle has no dermal toxicity. PMID- 28645794 TI - European distribution for metacercariae of the North American digenean Posthodiplostomum cf. minimum centrarchi (Strigeiformes: Diplostomidae). AB - Metacercariae of a North American digenean Posthodiplostomum cf. minimum centrarchi (Strigeiformes: Diplostomidae), have been reported from seven localities in Europe, with cysts recorded in the mesentery and internal organs of two invasive non-indigenous fishes (Lepomis gibbosus and Micropterus salmoides) from sites in Bulgaria, the Czech Republic and Portugal. Analysis of rDNA locus ITS1-ITS2-28S confirmed a closer relationship to the American Posthodiplostomum species than the common European species P. cuticola or P. brevicaudatum. Our data indicate limited potential of this parasite for switch to local fish fauna and confirm the occurrence at distant sites across Europe, suggesting that birds as definitive parasite hosts may play an important role for parasite dispersal. Further detailed studies are needed to confirm the actual means of introduction to Europe. PMID- 28645795 TI - High-Frame-Rate Power Doppler Ultrasound Is More Sensitive than Conventional Power Doppler in Detecting Rheumatic Vascularisation. AB - Early recognition of joint inflammation will increase treatment efficacy in rheumatoid arthritis (RA). Yet, conventional power Doppler (PD) ultrasound might not be sufficiently sensitive to detect minor inflammation. We investigated the sensitivity of high-frame rate Doppler, combined with singular value decomposition technique, to suppress tissue signals, for microvascular flow in a flow phantom setup and in a proof-of-principle study in healthy controls and in RA patients with different disease activities. In the flow phantom, minimal detectable flow velocity was a factor 3 lower with high-frame-rate PD than with conventional PD ultrasound. In the proof-of-principle study we detected a positive PD signal in all volunteers, diseased or healthy, with high-frame-rate PD ultrasound. We saw a gradual increase in PD signal in RA patients depending on disease activity. In conclusion, high-frame rate Doppler is more sensitive in detecting vascularisation than conventional PD ultrasound. PMID- 28645796 TI - Preclinical Testing of Frequency-Tunable Capacitive Micromachined Ultrasonic Transducer Probe Prototypes. AB - In intracardiac echocardiography (ICE) it may be beneficial to generate ultrasound images acquired at multiple frequencies, having the possibility of high penetration or high-resolution imaging in a single device. The objective of the presented work is to test two frequency-tunable probe prototypes in a preclinical setting: a rigid probe having a diameter of 11 mm and a new flexible and steerable 12-Fr ICE catheter. Both probes feature a forward-looking 32 element capacitive micromachined ultrasonic transducer array (aperture of 2 * 2 mm2) operated in collapse mode, which allows for frequency tuning in the 6-MHz-18 MHz range. The rigid probe prototype is tested ex vivo in a passive heart platform. Images of an aortic valve acquired in high-penetration (6 MHz), generic (12 MHz) and high-resolution (18 MHz) mode combine satisfying image quality and penetration depth between 2.5 cm and 10 cm. The ICE catheter prototype is tested in vivo using a porcine animal model. Images of an aortic valve are acquired in the 3 imaging modes with the ICE catheter placed in an ascending aorta at multiple depths. It was found that the combination of the forward-looking design and frequency-tuning capability allows visualizing intracardiac structures of various sizes at different distances relative to the catheter tip, providing both wide overviews and detailed close-ups. PMID- 28645797 TI - Transcranial Doppler and Microemboli Detection: Relationships to Symptomatic Status and Histopathology Findings. AB - The purpose of this study was to determine the relationship between symptomatic status, transcranial Doppler (TCD) microemboli presence and plaque histopathology findings. TCD was performed on 60 patients (37 symptomatic, 23 asymptomatic) before undergoing clinically indicated carotid endarterectomy. The frequency of microemboli signals was not significantly different between symptomatic and asymptomatic subject groups (p = 0.88) and there were no differences observed in the macroscopic or histopathology scoring of these plaques (p-values all > 0.05). The presence of microemboli was associated with an ulceration score (regardless of symptomatic or asymptomatic status, p = 0.034), with a one-level increase in ulceration rating associated with an odds ratio of 5.86 (95% [CI] 1.55, 43.4). These findings suggest that both symptomatic and asymptomatic patients may have plaque with similar features of instability and ability to create emboli. Thus, identifying new ways to measure plaque instability may provide important information for optimizing treatment to prevent future stroke. PMID- 28645798 TI - Left Atrial Mechanics and Integrated Calibrated Backscatter in Anthracycline Treated Long-Term Survivors of Childhood Cancers. AB - We tested the hypothesis that left atrial (LA) mechanics and myocardial calibrated integrated backscatter (cIB) are altered in anthracycline-treated long term survivors of childhood cancers. Forty-nine survivors and 25 controls were studied. Survivors had significantly smaller maximal (p = 0.009) and minimal (p = 0.017) LA volumes and lower peak negative LA strains (p = 0.011). For left ventricular (LV) indices, survivors had significantly lower shortening fraction (p < 0.001), ejection fraction (p < 0.001) and mitral annular late diastolic velocity (p = 0.003). Myocardial cIB of the LA posterior wall, ventricular septum and LV posterior wall was significantly greater in survivors than controls (all p values <0.05). Peak negative LA strain was related to late diastolic mitral annular velocity (r = 0.27, p = 0.018), whereas LA cIB was related to the average of septal and LV posterior wall cIB (r = 0.54, p < 0.001). In conclusion, LA remodeling as characterized by contractile dysfunction and increased cIB suggestive of fibrosis occurs in adult survivors of childhood cancers. PMID- 28645799 TI - Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation. AB - A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in ~30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene. PMID- 28645800 TI - High-throughput sequencing of the entire genomic regions of CCM1/KRIT1, CCM2 and CCM3/PDCD10 to search for pathogenic deep-intronic splice mutations in cerebral cavernous malformations. AB - Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease associated mutations have been identified in three genes: CCM1/KRIT1, CCM2 and CCM3/PDCD10. The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non coding variants. NGS detected all six CCM1/KRIT1, two CCM2 and four CCM3/PDCD10 mutations that had previously been identified by Sanger sequencing. Two of the pathogenic variants presented here are novel. Additionally, 20 stringently selected CCM index cases that had remained mutation-negative after conventional sequencing and exclusion of copy number variations were screened for deep intronic mutations. The combination of bioinformatics filtering and transcript analyses did not reveal any deep-intronic splice mutations in these cases. Our results demonstrate that target enrichment by LR-PCR combined with NGS can be used for a comprehensive analysis of the entire genomic regions of the CCM genes in a research context. However, its clinical utility is limited as deep-intronic splice mutations in CCM1/KRIT1, CCM2 and CCM3/PDCD10 seem to be rather rare. PMID- 28645801 TI - Reply to Bianchi et al. PMID- 28645802 TI - Comparative effects of long and short-acting loop diuretics on mortality in patients with chronic heart failure. AB - BACKGROUND: We previously reported that the long-acting loop diuretic azosemide improves cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF), compared with short-acting furosemide. However, its influence on mortality has not been determined. METHODS: The present study was a further analysis of our previously published study in which azosemide showed improved 123I-metaiodobenzylguanidine scintigraphic findings compared with furosemide in CHF patients with reduced left ventricular ejection fraction (LVEF). Patients with CHF were identified according to their histories of acute decompensated heart failure requiring hospitalization. A total of 108 patients were selected and propensity score matching was used to compare patients treated with azosemide (n=54) or furosemide (n=54). RESULTS: During the median follow-up period of 5.22years, 24 out of 108 patients experienced cardiac death events. In multivariate Cox regression analysis (adjusted for age, non-beta-blocker treatments, and impaired CSNA), furosemide treatment was an independent predictor of cardiac death events (p=0.034, hazard ratio 2.624, 95% confidence interval 1.074 to 6.047). On Kaplan-Meier analysis, the cardiac death-free rate in the azosemide group was significantly higher than that in the furosemide group (p<0.05). CONCLUSIONS: These findings indicate the superior effectiveness of azosemide in reducing mortality compared with furosemide. PMID- 28645803 TI - GRACE risk score: Sex-based validity of in-hospital mortality prediction in Canadian patients with acute coronary syndrome. AB - BACKGROUND: Although there are sex differences in management and outcome of acute coronary syndromes (ACS), sex is not a component of Global Registry of Acute Coronary Events (GRACE) risk score (RS) for in-hospital mortality prediction. We sought to determine the prognostic utility of GRACE RS in men and women, and whether its predictive accuracy would be augmented through sex-based modification of its components. METHODS: Canadian men and women enrolled in GRACE and Canadian Registry of Acute Coronary Events were stratified as ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation ACS (NSTE-ACS). GRACE RS was calculated as per original model. Discrimination and calibration were evaluated using the c-statistic and Hosmer-Lemeshow goodness-of-fit test, respectively. Multivariable logistic regression was undertaken to assess potential interactions of sex with GRACE RS components. RESULTS: For the overall cohort (n=14,422), unadjusted in-hospital mortality rate was higher in women than men (4.5% vs. 3.0%, p<0.001). Overall, GRACE RS c-statistic and goodness-of-fit test p-value were 0.85 (95% CI 0.83-0.87) and 0.11, respectively. While the RS had excellent discrimination for all subgroups (c-statistics >0.80), discrimination was lower for women compared to men with STEMI [0.80 (0.75-0.84) vs. 0.86 (0.82-0.89), respectively, p<0.05]. The goodness-of-fit test showed good calibration for women (p=0.86), but suboptimal for men (p=0.031). No significant interaction was evident between sex and RS components (all p>0.25). CONCLUSIONS: The GRACE RS is a valid predictor of in-hospital mortality for both men and women with ACS. The lack of interaction between sex and RS components suggests that sex based modification is not required. PMID- 28645804 TI - Prognostic impact of anemia and iron-deficiency anemia in a contemporary cohort of patients undergoing transcatheter aortic valve implantation. AB - INTRODUCTION: Anemia is frequent in patients undergoing transcatheter aortic valve implantation (TAVI) with a strong negative prognostic impact. The prevalence and prognosis of anemia and separately of iron-deficiency anemia in contemporary patients are unclear. METHODS AND RESULTS: In total, 549 consecutive patients undergoing transfemoral TAVI were included in the single-center study. Baseline anemia was defined as a hemoglobin level <13g/dL in men and <12g/dL in women. In an unselected subgroup of anemic patients (n=115), a complete iron status was obtained and anemia was classified as iron-deficiency versus non-iron deficiency. The primary endpoint was death or re-hospitalization for worsening heart failure within one year after TAVI. Anemia was present in 45% (249/549) of the population and was significantly associated with a higher rate of the primary endpoint (25% (63/249) vs. 8% (25/300); p<0.001). In a multivariable model adjusted for variables associated with the primary endpoint, baseline anemia was an independent predictor of the primary endpoint (hazard ratio 2.81, 95% confidence interval [1.69-4.67]; p<0.001). Iron-deficiency anemia was present in 79% (91/115) of the subgroup and the rate of the primary endpoint was comparable to non-iron-deficiency anemia (31% (28/91) vs. 21% (5/24); p=0.338). CONCLUSION: In contemporary TAVI patients, anemia remains a common comorbidity and independently predicts adverse outcome. In an unselected subgroup of anemic patients, iron-deficiency was common and had similar clinical outcome compared to non-iron-deficiency. Whether correction of iron-deficiency anemia impacts prognosis remains to be investigated. PMID- 28645805 TI - Pre-admission CHA2DS2-VASc score and outcome of patients with acute cerebrovascular events. AB - BACKGROUND: The CHA2DS2-VASc score has been recommended for the assessment of thromboembolic risk in patients with atrial fibrillation. Data regarding the association between the pre-admission CHA2DS2-VASc score and the outcome of patients with stroke and TIA are scarce. We aimed to assess the predictive value of pre-admission CHA2DS2-VASc score for early risk stratification of patients with acute cerebrovascular event. METHODS: The study group consisted of 8309 patients (53% males, mean age of 70+/-13.3years) with acute stroke and TIA included in the prospective National Acute Stroke Israeli (NASIS) registry. The two-primary end-points were in-hospital mortality and severe disability at discharge. We divided the study population into 4 groups according to their pre admission CHA2DS2-VASc score (0-1, 2-3, 4-5, >5). RESULTS: Following a multivariate analysis odds ratios (OR) for all-cause mortality increased for CHA2DS2-VASc score >1 (OR=2.1 95% CI=1.2-3.6, OR=1.8 95% CI=1.1-3.2, OR=1.8 95% CI 1.1-3.3, for patients with CHA2DS2-VASc score of 2-3, 4-5 and >5, respectively, p<0.001). OR for severe disability (mRS 4-5) at discharge increased significantly in direct association with the CHA2DS2-VASc score (OR=1.55 95% CI=1.14-2.12, OR=2.42 95% CI=1.8-3.3, OR=3 95% CI 2.19-4.27, for patients with CHA2DS2-VASc score of 2-3, 4-5 and >5, respectively as compared with 0-1, p<0.001). Each 1-point increase in the CHA2DS2-VASc score was associated with a 21% increase in the risk for severe disability. CONCLUSIONS: High-risk pre admission CHA2DS2-VASc score among patients with acute cerebrovascular events is associated with higher in-hospital mortality and severe disability at discharge. PMID- 28645806 TI - Brugada syndrome: A general cardiologist's perspective. AB - Brugada syndrome (BrS) is one of the commonest inherited primary arrhythmia syndromes typically presenting with arrhythmic syncope or sudden cardiac death (SCD) due to polymorphic ventricular tachycardia and ventricular fibrillation precipitated by vagotonia or fever in apparently healthy adults, less frequently in children. The prevalence of the syndrome (0.01%-0.3%) varies among regions and ethnicities, being the highest in Southeast Asia. BrS is diagnosed by the "coved type" ST-segment elevation>=2mm followed by a negative T-wave in >=1 of the right precordial leads V1-V2. The typical electrocardiogram in BrS is often concealed by fluctuations between normal, non-diagnostic and diagnostic ST-segment pattern in the same patient, thus hindering the diagnosis. Presently, the majority of BrS patients is incidentally diagnosed, and may remain asymptomatic for their lifetime. However, BrS is responsible for 4-12% of all SCDs and for ~20% of SCDs in patients with structurally normal hearts. Arrhythmic risk is the highest in SCD survivors and in patients with spontaneous BrS electrocardiogram and arrhythmic syncope, but risk stratification for SCD in asymptomatic subjects has not yet been fully defined. Recent achievements have expanded our understanding of the genetics and electrophysiological mechanisms underlying BrS, while radiofrequency catheter ablation may be an effective new approach to treat ventricular tachyarrhythmias in BrS patients with arrhythmic storms. The present review summarizes our contemporary understanding and recent advances in the inheritance, pathophysiology, clinical assessment and treatment of BrS patients. PMID- 28645807 TI - Prognostic implication of ERCC1 protein expression in resected oropharynx and oral cavity cancer. AB - BACKGROUND: Excision repair cross complement group 1 (ERCC1) expression is a predictive biomarker for platinum-containing treatment in squamous cell carcinoma of head and neck (SCCHN). However, the prognostic significance after surgical resection is not well understood. METHODS: Oropharynx (n=143) or oral cavity (n=61) SCCHN patients undergoing surgery were included. ERCC1 protein expression and HPV status were assessed by ERCC1 and p16 immunohistochemistry. RESULTS: The ERCC1, over-expressed in 66.7% of patients, was associated with oral cavity cancer (P<0.001), well differentiation (P=0.036), and HPV negativity (P<0.001). In TCGA database, ERCC1 mRNA upregulation was enriched in HPV-negative and oral cavity cancers, and associated with HRAS mutation (P<0.001). The prognostic role of ERCC1 was not different according to HPV status. High ERCC1 expression showed a trend toward poor prognosis in patients with an advanced stage (P=0.079) with marginal significance. CONCLUSIONS: The ERCC1 expression was not prognostic in surgically resected oropharynx/oral cavity SCCHN, irrespective of HPV status. However, it could provide additional prognostic information for advanced stage patients. PMID- 28645808 TI - Primary undifferentiated small round cell sarcoma of the deep abdominal wall with a novel variant of t(10;19) CIC-DUX4 gene fusion. AB - We experienced a 38-year-old Japanese male with t(10;19) CIC-DUX4 -positive undifferentiated small round cell sarcoma in the deep abdominal wall. Three months before his first visit to our hospital, he noticed a mass in his right abdominal wall. Computed tomography on admission revealed a solid abdominal tumor 70*53mm in size and multiple small tumors in both lungs. The biopsy of the abdominal tumor revealed undifferentiated small round cell sarcoma, suggestive of Ewing sarcoma. Under the clinical diagnosis of Ewing-like sarcoma of the abdominal wall with multiple lung metastases, several cycles of ICE (ifosfamide, carboplatin and etoposide) therapy were performed. After the chemotherapy, the lung metastases disappeared, while the primary lesion rapidly grew. Additional VDC (vincristine, doxorubicin and cyclophosphamide) therapy was carried out without apparent effect. Although the surgical removal of the primary lesion was done, peritoneal dissemination and a huge metastatic liver tumor appeared thereafter. The patient died of disease progression two months after the surgery. The total clinical course was approximately one year, showing that the tumor was extremely aggressive. The tumor cells of the surgical specimen were positive for CD99, WT1, calretinin, INI1, ERG and Fli1 by immunohistochemistry. Fusion gene analyses using the frozen surgical material revealed negativity for EWSR1-Fli1, EWSR1-ERG and t(4;19) CIC-DUX4 fusions, but positivity for t(10;19) CIC-DUX4 fusion. Thus, we made a final pathological diagnosis of t(10;19) CIC-DUX4 positive undifferentiated small round cell sarcoma. To our knowledge, this is the 13th case of t(10;19) CIC-DUX4 undifferentiated small round cell sarcoma with precise clinicopathological information. Especially in our case, two types of t(10;19) CIC-DUX4 fusion transcripts were observed, both of which are in-frame and novel. PMID- 28645810 TI - Cerebral protection for transcatheter aortic valve implantation: A no brainer? PMID- 28645809 TI - Enhanced in vivo retention of low dose BMP-2 via heparin microparticle delivery does not accelerate bone healing in a critically sized femoral defect. AB - : Bone morphogenetic protein-2 (BMP-2) is an osteoinductive growth factor used clinically to induce bone regeneration and fusion. Some complications associated with BMP-2 treatment have been attributed to rapid release of BMP-2 from conventional collagen scaffolds, motivating the development of tunable sustained release strategies. We incorporated BMP-2-binding heparin microparticles (HMPs) into a hydrogel scaffold to improve spatiotemporal control of BMP-2 delivery to large bone defects. HMPs pre-loaded with BMP-2 were mixed into alginate hydrogels and compared to hydrogels containing BMP-2 alone. BMP-2 release from scaffolds in vitro, BMP-2 retention within injury sites in vivo, and bone regeneration in a critically sized femoral defect were evaluated. Compared to hydrogel delivery alone, BMP-2-loaded HMPs reduced BMP-2 release in vitro and increased early BMP-2 retention in the bone defect. BMP-2-loaded HMPs induced bone formation at both ectopic and orthotopic sites; however, the volume of induced bone was lower for defects treated with BMP-2-loaded HMPs compared to hydrogel delivery. To better understand the effect of HMPs on BMP-2 release kinetics, a computational model was developed to predict BMP-2 release from constructs in vivo. The model suggested that HMPs limited BMP-2 release into surrounding tissues, and that changing the HMP density could modulate BMP-2 release. Taken together, these experimental and computational results suggest the importance of achieving a balance of BMP-2 retention within the bone defect and BMP-2 release into surrounding soft tissues. HMP delivery of BMP-2 may provide a method of tuning BMP-2 release in vivo that can be further investigated to improve current methods of bone regeneration. STATEMENT OF SIGNIFICANCE: The development of effective biomaterials for sustained protein delivery is a crucial component of tissue engineering strategies. However, in most applications, including bone repair, the optimal balance between protein presentation in the injury site and protein release into the surrounding tissues is unknown. Herein, we introduced heparin microparticles (HMPs) into a tissue engineered construct to increase in vivo retention of bone morphogenetic protein-2 (BMP-2) and enhance healing in femoral defects. Although HMPs induced bone regeneration, no increase in bone volume was observed, leading to further experimental and computational analysis of the effect of HMP-BMP-2 interactions on protein retention and release. Ultimately, this work provides insight into designing tunable protein-material interactions and their implications for controlling BMP-2 delivery. PMID- 28645811 TI - To find the least common denominator-or better-do not merely reduce to the max. PMID- 28645812 TI - Transprosthetic leak after biological aortic valve replacement: There's a hole in the valve! PMID- 28645813 TI - Who determines the timing of delayed sternal closure, the surgeon or the patient? PMID- 28645814 TI - Do apples equal oranges in access for transcatheter aortic valve replacement? PMID- 28645815 TI - From cellular senescence to regeneration: A quest for the holy grail for the next generation of surgeons? PMID- 28645816 TI - You spin me right round. PMID- 28645817 TI - Dumb pumps, smart flow, and a genius. PMID- 28645818 TI - Valve-sparing root replacement: Still so much to learn. PMID- 28645819 TI - Understanding tools. PMID- 28645820 TI - Prognostic significance of early aortic remodeling in acute uncomplicated type B aortic dissection and intramural hematoma: Tell us what to do. PMID- 28645821 TI - Don't worry, I've got it covered. PMID- 28645822 TI - A new attachment. PMID- 28645823 TI - Recombinant human soluble thrombomodulin prevents acute lung injury in a rat cardiopulmonary bypass model. AB - BACKGROUND: Cardiopulmonary bypass (CPB) may induce systemic inflammatory responses causing acute lung injury. Recombinant human soluble thrombomodulin (rTM) is reported to attenuate the secretion of inflammatory cytokines and the high-mobility group box 1 (HMGB1) protein, which is critical in controlling systemic inflammation and apoptosis. We investigated the protective effects of rTM on CPB-induced lung injury in a rat model. METHODS: Eighteen male Sprague Dawley rats were divided into 3 groups: sham, control (CPB alone), and rTM (CPB + rTM). CPB was conducted in the control group and the rTM group. A bolus of rTM (3 mg/kg) was administered to the rTM group rats before CPB establishment. RESULTS: The ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen only dropped markedly from before CPB in the control group (P < .001). Serum tumor necrosis factor alpha, interleukin (IL) 6, and HMGB1 levels were significantly higher in the control group after CPB. Pathologic study revealed significantly more severe congestion, alveolar hemorrhage, neutrophil accumulation, and edema, and the number of lung cells expressing HMGB1 increased in the control group. The mRNA expression levels of tumor necrosis factor alpha, IL-6, IL-1beta, and HMGB1 in the control group were significantly higher than those in other groups. According to Western blot analysis, nuclear factor-kappaB p65 in lung tissue was significantly downregulated in the rTM group. The number of apoptotic cells and the protein of cleaved Caspase-3 were reduced in the rTM group. CONCLUSIONS: These results suggest that rTM prevents acute lung injury through attenuating inflammation and apoptosis during and after CPB in a rat model. PMID- 28645824 TI - Beyond proof of concepts for ideal cardiac regenerative therapy. PMID- 28645825 TI - When pigs fly: Early endoscopy after esophagectomy is safe. PMID- 28645826 TI - Continuous-flow ventricular assist device support in children: A paradigm change. PMID- 28645827 TI - The persistence of cognitive deficits into adulthood after the arterial switch procedure: Can we change things? PMID- 28645828 TI - Cardiac surgery training in the present era: Does the emperor have new clothes? PMID- 28645829 TI - From sutures to wires: The evolving necessities of cardiac surgery training. PMID- 28645830 TI - Getting to the meat of the matter: It's about more than sparing muscle. PMID- 28645831 TI - Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors. AB - Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells. PMID- 28645832 TI - The relation between elbow range of motion and patient satisfaction after open release of stiff elbow. AB - OBJECTIVE: The aim of this retrospective study was to find out whether a cut off value existed for elbow flexion and extension after open surgical release of elbow contracture that would correlate with subjective patient satisfaction. METHODS: The study enrolled 77 patients (53 males and 24 females with a mean age of 35.1 (18-77) years at the time of operation) with elbow contracture who attended regular follow-up appointments for more than 12 months. The mean follow up period was 44.2 months (12-186). The preoperative and postoperative modified MAYO elbow scores, objective parameters of increase in both flexion and extension end point measurements and improvement in total ROM were compared in order to determine the cut off degree of ROM in both flexion and extension that significantly correlated with patient satisfaction. RESULTS: Of the 77 participating patients, 26 patients had an extrinsic (33.8%) and 51 patients had an intrinsic elbow contracture (66.2%). Surgeries performed involved 40 cases of lateral release and 37 cases of both lateral and medial (progressive) release. The median preoperative total flexion-extension arch (ROM) was 45 degrees (20 degrees -65 degrees ). The median postoperative total flexion-extension arch (ROM) was 110 degrees (97.5 degrees -125 degrees ). The modified MAYO elbow score improved from 60 to 85 points postoperatively. The postoperative flexion cut off value was 115 degrees for an excellent or good postoperative modified MAYO elbow score. CONCLUSION: Post-operative flexion cut off value was 115 degrees and had a positive effect on the postoperative patient satisfaction. The cut off value for postoperative extension was 20 degrees but it was not a significant variable on patient satisfaction as was the total increase in ROM. LEVEL OF SIGNIFICANCE: Level IV Therapeutic Study. PMID- 28645833 TI - Binding Kinetics and Pathways of Ligands to GPCRs. AB - Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug-target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD). The kinetics of drug binding to GPCRs are complex and depend on several factors, including charge distribution on the receptor surface, ligand-receptor interactions in the binding channel and the binding site, or solvation. PMID- 28645834 TI - Left Ventricular Assist Device Therapy for Destination Therapy: Is Less Invasive Surgery a Safe Alternative? AB - INTRODUCTION AND OBJECTIVES: The number of older patients with congestive heart failure has dramatically increased. Because of stagnating cardiac transplantation, there is a need for an alternative therapy, which would solve the problem of insufficient donor organ supply. Left ventricular assist devices (LVADs) have recently become more commonly used as destination therapy (DT). Assuming that older patients show a higher risk-profile for LVAD surgery, it is expected that the increasing use of less invasive surgery (LIS) LVAD implantation will improve postoperative outcomes. Thus, this study aimed to assess the outcomes of LIS-LVAD implantation in DT patients. METHODS: We performed a prospective analysis of 2-year outcomes in 46 consecutive end-stage heart failure patients older than 60 years, who underwent LVAD implantation (HVAD, HeartWare) for DT in our institution between 2011 and 2013. The patients were divided into 2 groups according to the surgical implantation technique: LIS (n = 20) vs conventional (n = 26). RESULTS: There was no statistically significant difference in 2-year survival rates between the 2 groups, but the LIS group showed a tendency to improved patient outcome in 85.0% vs 69.2% (P = .302). Moreover, the incidence of postoperative bleeding was minor in LIS patients (0% in the LIS group vs 26.9% in the conventional surgery group, P < .05), who also showed lower rates of postoperative extended inotropic support (15.0% in the LIS group vs 46.2% in the conventional surgery group, P < .05). CONCLUSIONS: Our data indicate that DT patients with LIS-LVAD implantation showed a lower incidence of postoperative bleeding, a reduced need for inotropic support, and a tendency to lower mortality compared with patients treated with the conventional surgical technique. PMID- 28645835 TI - Circulating Amyloid-Beta (1-40) Predicts Clinical Outcomes in Patients With Heart Failure. PMID- 28645836 TI - Percutaneous Treatment of the Tricuspid Valve Disease: New Hope for the "Forgotten" Valve. AB - Tricuspid valve disease is a frequent condition but is currently undertreated. A limited number of patients undergo an isolated surgical tricuspid repair, and this intervention is associated with poor outcomes, especially in patients with previous cardiac surgery. Most patients are only medically treated, despite the impact of severe tricuspid regurgitation on functional status and long-term survival. Transcatheter therapies represent a promising alternative for patients with severe tricuspid regurgitation and high surgical risk. In the last few years, several percutaneous alternatives have been developed for the treatment of functional tricuspid regurgitation. Imaging techniques play an indispensable role in patient selection, procedural guidance and follow-up. The current available transcatheter options for native tricuspid valve disease can be divided into 3 main groups: heterotopic caval valve implantation, annuloplasty devices, and coaptation devices. In patients with previous tricuspid valve surgery, transcatheter valve-in-valve and valve-in-ring procedures have been reported. This review provides a detailed analysis of the novel transcatheter alternatives for the treatment of tricuspid valve disease that have already been successfully implanted in humans, as well as the most important aspects of tricuspid valve anatomy and imaging assessment. PMID- 28645837 TI - Residual ethylene glycol and dimethyl sulphoxide concentration in human ovarian tissue during warming/thawing steps following cryopreservation. AB - There have been 60 births after transplantation of cryopreserved ovarian tissue: 58 using the slow freezing method, and two using the vitrification method. DMSO and EG are widely used as cryoprotectants. However DMSO is a known epimutagen, and EG has been reported to be toxic in high concentrations. In this study, we measured residual DMSO and EG in ovarian tissue after vitrification and slow freezing. Cryoprotectants remained at a high concentration in the vitrified/warmed ovarian tissue just before transplantation (DMSO: 9.8 mg/g, EG: 9.8 mg/g). We must consider the impact of the cryoprotectants on the mother and the baby. PMID- 28645838 TI - Sensitivity Analysis and Uncertainty Quantification in Pulmonary Drug Delivery of Orally Inhaled Pharmaceuticals. AB - In spite of widespread use of modeling tools in inhalation dosimetry, it remains difficult to quantify the output uncertainties when subjected to various sources of input variability. This study aimed to develop a computational model that can quantify the input sensitivity and output uncertainty in pulmonary drug delivery by coupling probabilistic analysis package NESSUS with ANSYS Fluent. An image based mouth-lung model was used to simulate the transport and deposition of drug particles and variability in particle size, density, and inhalation speed were considered. Results show that input variables have different importance levels on the delivered doses to lungs. For a given level of variability, the delivered dose is more sensitive to the variance of particle diameter than that of the inhalation speed and particle density. The range of input scatters has a profound impact on the outcome probability of delivered efficiencies, while the input distribution type (normal vs. log-normal) appears to have an insignificant effect. Despite normal distributions for all input variables, the output exhibits a non-normal distribution. The proposed model in this study allows easy specification of input distributions to conduct multivariable probabilistic analysis of inhalation drug deliveries, which can facilitate more reliable treatment planning and outcome assessment. PMID- 28645839 TI - Antibiotic prophylaxis adequacy in knee arthroplasty and surgical wound infection: Prospective cohort study. AB - OBJECTIVE: Antibiotic prophylaxis is the most suitable tool for preventing surgical wound infection. This study evaluated adequacy of antibiotic prophylaxis in surgery for knee arthroplasty and its effect on surgical site infection. MATERIAL AND METHOD: Prospective cohort study. We assessed the degree of adequacy of antibiotic prophylaxis, the causes of non-adequacy, and the effect of non adequacy on surgical site infection. Incidence of surgical site infection was studied after a maximum incubation period of a year. To assess the effect of prophylaxis non-adequacy on surgical site infection we used the relative risk adjusted with the aid of a logistic regression model. RESULTS: The study covered a total of 1749 patients. Antibiotic prophylaxis was indicated in all patients and administered in 99.8% of cases, with an overall protocol adequacy of 77.6%. The principal cause of non-compliance was the duration of prescription of the antibiotics (46.5%). Cumulative incidence of surgical site infection was 1.43%. No relationship was found between prophylaxis adequacy and surgical infection (RR=1.15; 95% CI: .31-2.99) (P>.05). DISCUSSION: Surveillance and infection control programs enable risk factors of infection and improvement measures to be assessed. Monitoring infection rates enables us to reduce their incidence. CONCLUSIONS: Adequacy of antibiotic prophylaxis was high but could be improved. We did not find a relationship between prophylaxis adequacy and surgical site infection rate. PMID- 28645840 TI - Autoreject: Automated artifact rejection for MEG and EEG data. AB - We present an automated algorithm for unified rejection and repair of bad trials in magnetoencephalography (MEG) and electroencephalography (EEG) signals. Our method capitalizes on cross-validation in conjunction with a robust evaluation metric to estimate the optimal peak-to-peak threshold - a quantity commonly used for identifying bad trials in M/EEG. This approach is then extended to a more sophisticated algorithm which estimates this threshold for each sensor yielding trial-wise bad sensors. Depending on the number of bad sensors, the trial is then repaired by interpolation or by excluding it from subsequent analysis. All steps of the algorithm are fully automated thus lending itself to the name Autoreject. In order to assess the practical significance of the algorithm, we conducted extensive validation and comparisons with state-of-the-art methods on four public datasets containing MEG and EEG recordings from more than 200 subjects. The comparisons include purely qualitative efforts as well as quantitatively benchmarking against human supervised and semi-automated preprocessing pipelines. The algorithm allowed us to automate the preprocessing of MEG data from the Human Connectome Project (HCP) going up to the computation of the evoked responses. The automated nature of our method minimizes the burden of human inspection, hence supporting scalability and reliability demanded by data analysis in modern neuroscience. PMID- 28645841 TI - How do self-interest and other-need interact in the brain to determine altruistic behavior? AB - Altruistic behavior, i.e., promoting the welfare of others at a cost to oneself, is subserved by the integration of various social, affective, and economic factors represented in extensive brain regions. However, it is unclear how different regions interact to process/integrate information regarding the helper's interest and recipient's need when deciding whether to behave altruistically. Here we combined an interactive game with functional Magnetic Resonance Imaging (fMRI) and transcranial direct current stimulation (tDCS) to characterize the neural network underlying the processing/integration of self interest and other-need. At the behavioral level, high self-risk decreased helping behavior and high other-need increased helping behavior. At the neural level, activity in medial prefrontal cortex (MPFC) and right dorsolateral prefrontal cortex (rDLPFC) were positively associated with self-risk levels, and activity in right inferior parietal lobe (rIPL) and rDLPFC were negatively associated with other-need levels. Dynamic causal modeling further suggested that both MPFC and rIPL were extrinsically connected to rDLPFC; high self-risk enhanced the effective connectivity from MPFC to rDLPFC, and the modulatory effect of other-need on the connectivity from rIPL to rDLPFC positively correlated with the modulatory effect of other-need on individuals' helping rate. Two tDCS experiments provided causal evidence that rDLPFC affects both self interest and other-need concerns, and rIPL selectively affects the other-need concerns. These findings suggest a crucial role of the MPFC-IPL-DLPFC network during altruistic decision-making, with rDLPFC as a central node for integrating and modulating motives regarding self-interest and other-need. PMID- 28645842 TI - OpenNFT: An open-source Python/Matlab framework for real-time fMRI neurofeedback training based on activity, connectivity and multivariate pattern analysis. AB - Neurofeedback based on real-time functional magnetic resonance imaging (rt-fMRI) is a novel and rapidly developing research field. It allows for training of voluntary control over localized brain activity and connectivity and has demonstrated promising clinical applications. Because of the rapid technical developments of MRI techniques and the availability of high-performance computing, new methodological advances in rt-fMRI neurofeedback become possible. Here we outline the core components of a novel open-source neurofeedback framework, termed Open NeuroFeedback Training (OpenNFT), which efficiently integrates these new developments. This framework is implemented using Python and Matlab source code to allow for diverse functionality, high modularity, and rapid extendibility of the software depending on the user's needs. In addition, it provides an easy interface to the functionality of Statistical Parametric Mapping (SPM) that is also open-source and one of the most widely used fMRI data analysis software. We demonstrate the functionality of our new framework by describing case studies that include neurofeedback protocols based on brain activity levels, effective connectivity models, and pattern classification approaches. This open source initiative provides a suitable framework to actively engage in the development of novel neurofeedback approaches, so that local methodological developments can be easily made accessible to a wider range of users. PMID- 28645843 TI - Longitudinal changes in reading network connectivity related to skill improvement. AB - Attempts to characterize the neural differences between individuals with and without dyslexia generally point to reduced activation in and connectivity between brain areas in a reading network composed of the inferior frontal gyrus, the ventral occipito-temporal cortex, and the dorsal temporo-parietal circuit. However, developmental work on brain activity during reading has indicated that some brain areas show developmental decreases in activation with age. Thus, reading network connectivity may also show decreases that are positively associated with increases in reading ability. However, the developmental trajectory of reading network connectivity in typically developing readers is not yet well established. In the current study, we use a longitudinal design to determine how connectivity changes over time, and how these changes relate to changes in reading skill. We find that longitudinal increases in reading ability are associated with higher initial connectivity in the dorsal stream between fusiform and inferior parietal cortex, implicated in phonological decoding, followed by decreases in connectivity in this stream over time. We further find that increases in reading ability are supported by maintenance of connectivity in the ventral stream between inferior occipital and fusiform cortex, suggesting a more mature automatic orthographic recognition strategy. Readers who show little reading improvement over time do not attain high levels of connectivity in the dorsal stream at any time point, and their ventral stream connectivity decreases over time. These results together suggest that superior reading ability is initially supported by phonological decoding, with a decreased reliance on this strategy as reading becomes more automated. Our results indicate that development of the dorsal and ventral streams are closely linked, and support the hypothesis that a decrease in the dorsal stream is important for ventral stream development. PMID- 28645845 TI - The feature-weighted receptive field: an interpretable encoding model for complex feature spaces. AB - We introduce the feature-weighted receptive field (fwRF), an encoding model designed to balance expressiveness, interpretability and scalability. The fwRF is organized around the notion of a feature map-a transformation of visual stimuli into visual features that preserves the topology of visual space (but not necessarily the native resolution of the stimulus). The key assumption of the fwRF model is that activity in each voxel encodes variation in a spatially localized region across multiple feature maps. This region is fixed for all feature maps; however, the contribution of each feature map to voxel activity is weighted. Thus, the model has two separable sets of parameters: "where" parameters that characterize the location and extent of pooling over visual features, and "what" parameters that characterize tuning to visual features. The "where" parameters are analogous to classical receptive fields, while "what" parameters are analogous to classical tuning functions. By treating these as separable parameters, the fwRF model complexity is independent of the resolution of the underlying feature maps. This makes it possible to estimate models with thousands of high-resolution feature maps from relatively small amounts of data. Once a fwRF model has been estimated from data, spatial pooling and feature tuning can be read-off directly with no (or very little) additional post processing or in-silico experimentation. We describe an optimization algorithm for estimating fwRF models from data acquired during standard visual neuroimaging experiments. We then demonstrate the model's application to two distinct sets of features: Gabor wavelets and features supplied by a deep convolutional neural network. We show that when Gabor feature maps are used, the fwRF model recovers receptive fields and spatial frequency tuning functions consistent with known organizational principles of the visual cortex. We also show that a fwRF model can be used to regress entire deep convolutional networks against brain activity. The ability to use whole networks in a single encoding model yields state-of-the art prediction accuracy. Our results suggest a wide variety of uses for the feature-weighted receptive field model, from retinotopic mapping with natural scenes, to regressing the activities of whole deep neural networks onto measured brain activity. PMID- 28645846 TI - Heparan sulfate proteoglycans in Drosophila neuromuscular development. AB - Heparan sulfate proteoglycans (HSPGs) are glycoconjugates bearing heparan sulfate (HS) chains covalently attached to core proteins, which are ubiquitously distributed on the cell surface and in the extracellular matrix. HSPGs interact with a number of molecules mainly through HS chains, which play critical roles in diverse physiological and disease processes. Among these, recent vertebrate studies showed that HSPGs are closely involved in synapse development and function. However, the detailed molecular mechanisms remain elusive. Genetic studies from fruit flies, Drosophila melanogaster, have begun to reveal the molecular mechanisms by which HSPGs regulate synapse formation at neuromuscular junctions (NMJs). In this review, we introduce Drosophila studies showing how HSPGs regulate various signaling pathways in developing NMJs. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28645844 TI - Modeling and interpreting mesoscale network dynamics. AB - Recent advances in brain imaging techniques, measurement approaches, and storage capacities have provided an unprecedented supply of high temporal resolution neural data. These data present a remarkable opportunity to gain a mechanistic understanding not just of circuit structure, but also of circuit dynamics, and its role in cognition and disease. Such understanding necessitates a description of the raw observations, and a delineation of computational models and mathematical theories that accurately capture fundamental principles behind the observations. Here we review recent advances in a range of modeling approaches that embrace the temporally-evolving interconnected structure of the brain and summarize that structure in a dynamic graph. We describe recent efforts to model dynamic patterns of connectivity, dynamic patterns of activity, and patterns of activity atop connectivity. In the context of these models, we review important considerations in statistical testing, including parametric and non-parametric approaches. Finally, we offer thoughts on careful and accurate interpretation of dynamic graph architecture, and outline important future directions for method development. PMID- 28645847 TI - Cardiovascular morphometry with high-resolution 3D magnetic resonance: First application to left ventricle diastolic dysfunction. AB - In this study, an image-based morphometry toolset quantifying geometric descriptors of the left ventricle, aorta and their coupling is applied to investigate whether morphological information can differentiate between subjects affected by diastolic dysfunction (patient group) and their age-matched controls (control group). The ventriculo-aortic region of 20 total participants (10 per group) were segmented from high-resolution 3D magnetic resonance images, from the left ventricle to the descending aorta. Each geometry was divided into segments in correspondence of anatomical landmarks. The orientation of each segment was estimated by least-squares fitting of the respective centerline segment to a plane. Curvature and torsion of vessels' centerlines were automatically extracted, and aortic arch was characterized in terms of height and width. Tilt angle between subsequent best-fit planes in the left ventricle and ascending aorta regions, curvature and cross-sectional area in the descending aorta resulted significantly different between patient and control groups (P-values< 0.05). Aortic volume (P = 0.04) and aortic arch width (P = 0.03) resulted significantly different between the two groups. The observed morphometric differences underlie differences in hemodynamics, by virtue of the influence of geometry on blood flow patterns. The present exploratory analysis does not determine if aortic geometric changes precede diastolic dysfunction, or vice versa. However, this study (1) underlines differences between healthy and diastolic dysfunction subjects, and (2) provides geometric parameters that might help to determine early aortic geometric alterations and potentially prevent evolution toward advanced diastolic dysfunction. PMID- 28645848 TI - FE and experimental study on how the cortex material properties of synthetic femurs affect strain levels. AB - The primary aim of this work was to validate the "numerical" cortex material properties (transversely isotropic) of synthetic femurs and to evaluate how the strain level of the cancellous bone can be affected by the FE modeling of the material's behavior. Sensitivity analysis was performed to find out if the parameters of the cortex material affect global strain results more than the Polyurethane (PU) foam used to simulate cancellous bone. Standard 4th generation composite femurs were made with 0.32g/cm3 solid PU foam to model healthy cancellous bone, while 0.2g/cm3 cellular PU was used to model unhealthy cancellous bone. Longitudinal and transversal Young's moduli of cortical bone were defined according the manufacturer data, while shear modulus and Poisson's ratios were defined from the literature. All femurs were instrumented with rosette strain gauges and loaded according to ISO7206 standards, simulating a one legged stance. The experimental results were then compared with those from finite element analysis. When cortical bone was modelled as transversely isotropic, an overall FE/experimental error of 11% was obtained. However, with isotropic material the error rose to 20%. Strain field distributions predicted inside the two bone models were similar, but the strain state of a healthy cancellous bone was much more a compression state than that of unhealthy bone, the compression state decreased about 90%. Strain magnitudes show that average strain-levels of cancellous bone can be significantly affected by the properties of the cortical bone material and, therefore, simulations of femur-implanted systems must account for the composite behavior of the cortex, since small shear strains would develop near isotropic cancellous bone-implant interfaces. Moreover, the authors suggest that changing the volume fraction of glass fibers used to manufacture the cortical bone would allow a more realistic osteoporotic synthetic femurs to be produced. PMID- 28645849 TI - Thermal management in closed incubators: New software for assessing the impact of humidity on the optimal incubator air temperature. AB - BACKGROUND: Low-birth-weight (LBW) neonates are nursed in closed incubators to prevent transcutaneous water loss. The RH's impact on the optimal incubator air temperature setting has not been studied. METHODS: On the basis of a clinical cohort study, we modelled all the ambient parameters influencing body heat losses and gains. The algorithm quantifies the change in RH on the air temperature, to maintain optimal thermal conditions in the incubator. RESULTS: Twenty-three neonates (gestational age (GA): 30.0 [28.9-31.6] weeks) were included. A 20% increase and a 20% decrease in the RH induced a change in air temperature of between -1.51 and +1.85 degrees C for a simulated 650g neonate (GA: 26 weeks), between -1.66 and +1.87 degrees C for a 1000g neonate (GA: 31 weeks), and between -1.77 and +1.97 degrees C for a 2000g neonate (GA: 33 weeks) (p<0.001). According to regression analyses, the optimal incubator air temperature=a+b relative humidity +c age +d weight (p<0.001). CONCLUSIONS: We have developed new mathematical equations for calculating the optimal temperature for the incubator air as a function of the latter's relative humidity. The software constitutes a decision support tool for improving patient care in routine clinical practice. PMID- 28645850 TI - Biomechanical analysis using FEA and experiments of a standard plate method versus three cable methods for fixing acetabular fractures with simultaneous THA. AB - Acetabular fractures potentially account for up to half of all pelvic fractures, while pelvic fractures potentially account for over one-tenth of all human bone fractures. This is the first biomechanical study to assess acetabular fracture fixation using plates versus cables in the presence of a total hip arthroplasty, as done for the elderly. In Phase 1, finite element (FE) models compared a standard plate method versus 3 cable methods for repairing an acetabular fracture (type: anterior column plus posterior hemi-transverse) subjected to a physiological-type compressive load of 2207N representing 3 x body weight for a 75kg person during walking. FE stress maps were compared to choose the most mechanically stable cable method, i.e. lowest peak bone stress. In Phase 2, mechanical tests were then done in artificial hemipelvises to compare the standard plate method versus the optimal cable method selected from Phase 1. FE analysis results showed peak bone stresses of 255MPa (Plate method), 205MPa (Mears cable method), 250MPa (Kang cable method), and 181MPa (Mouhsine cable method). Mechanical tests then showed that the Plate method versus the Mouhsine cable method selected from Phase 1 had higher stiffness (662versus 385N/mm, p=0.001), strength (3210versus 2060N, p=0.009), and failure energy (8.8versus 6.2J, p=0.002), whilst they were statistically equivalent for interfragmentary sliding (p>=0.179) and interfragmentary gapping (p>=0.08). The Plate method had superior mechanical properties, but the Mouhsine cable method may be a reasonable alternative if osteoporosis prevents good screw thread interdigitation during plating. PMID- 28645851 TI - Nanotubes connecting B lymphocytes: High impact of differentiation-dependent lipid composition on their growth and mechanics. AB - Nanotubes (NTs) are thin, long membranous structures forming novel, yet poorly known communication pathways between various cell types. Key mechanisms controlling their growth still remained poorly understood. Since NT-forming capacity of immature and mature B cells was found largely different, we investigated how lipid composition and molecular order of the membrane affect NT formation. Screening B cell lines with various differentiation stages revealed that NT-growth linearly correlates with membrane ganglioside levels, while it shows maximum as a function of cholesterol level. NT-growth of B lymphocytes is promoted by raftophilic phosphatidylcholine and sphingomyelin species, various glycosphingolipids, and docosahexaenoic acid-containing inner leaflet lipids, through supporting membrane curvature, as demonstrated by comparative lipidomic analysis of mature versus immature B cell membranes. Targeted modification of membrane cholesterol and sphingolipid levels altered NT-forming capacity confirming these findings, and also highlighted that the actual lipid raft number may control NT-growth via defining the number of membrane-F-actin coupling sites. Atomic force microscopic mechano-manipulation experiments further proved that mechanical properties (elasticity or bending stiffness) of B cell NTs also depend on the actual membrane lipid composition. Data presented here highlight importance of the lipid side in controlling intercellular, nanotubular, regulatory communications in the immune system. PMID- 28645852 TI - G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux. AB - The discovery of adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) provided a major paradigm shift in the understanding of intracellular lipolysis in both adipocytes and nonadipocyte cells. The subsequent discovery of G0/G1 switch gene 2 (G0S2) as a potent endogenous inhibitor of ATGL revealed a unique mechanism governing lipolysis and fatty acid (FA) availability. G0S2 is highly conserved in vertebrates, and exhibits cyclical expression pattern between adipose tissue and liver that is critical to lipid flux and energy homeostasis in these two tissues. Biochemical and cell biological studies have demonstrated that a direct interaction with ATGL mediates G0S2's inhibitory effects on lipolysis and lipid droplet degradation. In this review we examine evidence obtained from recent in vitro and in vivo studies that lends support to the proof-of-principle concept that G0S2 functions as a master regulator of tissue-specific balance of TG storage vs. mobilization, partitioning of metabolic fuels between adipose and liver, and the whole-body adaptive energy response. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28645854 TI - Deep brain stimulation in Tourette's syndrome: new insights. PMID- 28645853 TI - Anterior pallidal deep brain stimulation for Tourette's syndrome: a randomised, double-blind, controlled trial. AB - BACKGROUND: Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. METHODS: In this randomised, double-blind, controlled trial, we recruited patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. FINDINGS: Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68.5 [IQR 34.0 to 83.5] at the beginning and 62.5 [51.5 to 72.0] at the end, median change 1.1% [IQR -23.9 to 38.1]; sham group 73.0 [69.0 to 79.0] and 79.0 [59.0 to 81.5], median change 0.0% [-10.6 to 4.8]; p=0.39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). INTERPRETATION: 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. FUNDING: French Ministry of Health. PMID- 28645856 TI - The impact of radiation on the development of lung cancer. AB - Environment factors such as radiation play an important role in the incidence of lung cancer. In spite of substantial efforts in experimental study and mathematical modeling, it is still a significant challenge to estimate lung cancer risk from radiation. To address this issue, we propose a stochastic model to investigate the impact of radiation on the development of lung cancer. The proposed three-stage model with clonal expansion is used to match the data of the male and female patients in the Osaka Cancer Registry (OCR) and Life Span Study (LSS) cohort of atomic bomb survivors in Hiroshima and Nagasaki. Our results indicate that the major effect of radiation on the development of lung cancer is to induce gene mutations for both male and female patients. In particular, for male patients, radiation affects the mutation in normal cells and the transformation from premalignant cells to malignant ones. However, radiation for female patients increases the mutation rates of the first two mutations in the stochastic model. The established relationship between parameters and radiation will provide insightful prediction for the lung cancer incidence in the radiation exposure. PMID- 28645855 TI - Training Surgical Residents With a Haptic Robotic Central Venous Catheterization Simulator. AB - OJECTIVE: Ultrasound guided central venous catheterization (CVC) is a common surgical procedure with complication rates ranging from 5 to 21 percent. Training is typically performed using manikins that do not simulate anatomical variations such as obesity and abnormal vessel positioning. The goal of this study was to develop and validate the effectiveness of a new virtual reality and force haptic based simulation platform for CVC of the right internal jugular vein. DESIGN: A CVC simulation platform was developed using a haptic robotic arm, 3D position tracker, and computer visualization. The haptic robotic arm simulated needle insertion force that was based on cadaver experiments. The 3D position tracker was used as a mock ultrasound device with realistic visualization on a computer screen. Upon completion of a practice simulation, performance feedback is given to the user through a graphical user interface including scoring factors based on good CVC practice. The effectiveness of the system was evaluated by training 13 first year surgical residents using the virtual reality haptic based training system over a 3 month period. RESULTS: The participants' performance increased from 52% to 96% on the baseline training scenario, approaching the average score of an expert surgeon: 98%. This also resulted in improvement in positive CVC practices including a 61% decrease between final needle tip position and vein center, a decrease in mean insertion attempts from 1.92 to 1.23, and a 12% increase in time spent aspirating the syringe throughout the procedure. CONCLUSIONS: A virtual reality haptic robotic simulator for CVC was successfully developed. Surgical residents training on the simulation improved to near expert levels after three robotic training sessions. This suggests that this system could act as an effective training device for CVC. PMID- 28645857 TI - Exploring the effect of end-binding proteins and microtubule targeting chemotherapy drugs on microtubule dynamic instability. AB - Microtubules (MTs) play a key role in normal cell development and are a primary target for many cancer chemotherapy MT targeting agents (MTAs). As such, understanding MT dynamics in the presence of such agents, as well as other proteins that alter MT dynamics, is extremely important. In general, MTs grow relatively slowly and shorten very fast (almost instantaneously), an event referred to as a catastrophe. These dynamics, referred to as dynamic instability, have been studied in both experimental and theoretical settings. In the presence of MTAs, it is well known that such agents work by suppressing MT dynamics, either by promoting MT polymerization or promoting MT depolymerization. However, recent in vitro experiments show that in the presence of end-binding proteins (EBs), low doses of MTAs can increase MT dynamic instability, rather than suppress it. Here, we develop a novel mathematical model, to describe MT and EB dynamics, something which has not been done in a theoretical setting. Our MT model is based on previous modeling efforts, and consists of a pair of partial differential equations to describe length distributions for growing and shortening MT populations, and an ordinary differential equation (ODE) system to describe the time evolution for concentrations of GTP- and GDP-bound tubulin. A new extension of our approach is the use of an integral term, rather than an advection term, to describe very fast MT shortening events. Further, we introduce an ODE system to describe the binding and unbinding of EBs with MTs. To compare simulation results with experiment, we define novel mathematical expressions for time- and distance-based catastrophe frequencies. These quantities help to define MT dynamics in in vivo and in vitro settings. Simulation results show that increasing concentrations of EBs work to increase time-based catastrophe while distance-based catastrophe is less affected by changes in EB concentration, a result that is consistent with experiment. We further describe how EBs and MTAs alter MT dynamics. In the context of this modeling framework, we show that it is likely that MTAs and EBs do not work independently from one another. Thus, we propose a mechanism for how EBs can work synergistically with MTAs to promote MT dynamic instability at low MTA dose. PMID- 28645858 TI - Vascular Adaptation: Pattern Formation and Cross Validation between an Agent Based Model and a Dynamical System. AB - Myocardial infarction is the global leading cause of mortality (Go et al., 2014). Coronary artery occlusion is its main etiology and it is commonly treated by Coronary Artery Bypass Graft (CABG) surgery (Wilson et al, 2007). The long-term outcome remains unsatisfactory (Benedetto, 2016) as the graft faces the phenomenon of restenosis during the post-surgery, which consists of re-occlusion of the lumen and usually requires secondary intervention even within one year after the initial surgery (Harskamp, 2013). In this work, we propose an extensive study of the restenosis phenomenon by implementing two mathematical models previously developed by our group: a heuristic Dynamical System (DS) (Garbey and Berceli, 2013), and a stochastic Agent Based Model (ABM) (Garbey et al., 2015). With an extensive use of the ABM, we retrieved the pattern formations of the cellular events that mainly lead the restenosis, especially focusing on mitosis in intima, caused by alteration in shear stress, and mitosis in media, fostered by alteration in wall tension. A deep understanding of the elements at the base of the restenosis is indeed crucial in order to improve the final outcome of vein graft bypass. We also turned the ABM closer to the physiological reality by abating its original assumption of circumferential symmetry. This allowed us to finely replicate the trigger event of the restenosis, i.e. the loss of the endothelium in the early stage of the post-surgical follow up (Roubos et al., 1995) and to simulate the encroachment of the lumen in a fashion aligned with histological evidences (Owens et al., 2015). Finally, we cross-validated the two models by creating an accurate matching procedure. In this way we added the degree of accuracy given by the ABM to a simplified model (DS) that can serve as powerful predictive tool for the clinic. PMID- 28645859 TI - Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAFV600E mutant cancer. AB - AIMS: BRAF mutations, especially BRAF V600E, are a frequent occurrence in malignant melanomas. The BRAF inhibitors are used as the care standard for BRAF mutant metastatic melanomas. However, melanomas rapidly develop resistance to BRAF inhibitors after a median response duration of 6months, and the subsequent rapid development of cutaneous toxicity is enhanced by the paradoxical activation of CRAF. In this study, we discovered a potent and selective pan-RAF inhibitor: INU-152. The goal of this study was to investigate whether the inhibition of pan RAF with INU-152 completely disrupts the MAPK pathway in cancer cells bearing BRAF or RAS mutations. MAIN METHODS: Using a structure-based molecular modeling, we discovered INU-152, which is a potent and selective pan-RAF inhibitor. In kinase assays against RAF proteins, INU-152 exhibited a potent effect against RAF isoforms. INU-152 was tested for its inhibitory effect on the growth of human cancer cells bearing BRAFV600E. To study in vivo effects, INU-152 was administered using human melanoma and colorectal cancer xenograft models. To explore INU-152's potential as a prospective drug candidate, pharmacokinetic studies and toxicity tests were performed using mice. KEY FINDINGS: To inhibit and suppress paradoxical activation in mutant RAS cancer cells completely, it is important for RAF inhibitors to exhibit potent inhibitory activities against RAF isoforms. SIGNIFICANCE: INU-152 inhibits all RAF isoforms and inhibits MAPK pathways in mutant BRAF cells. More importantly, INU-152 exhibits minimal paradoxical pathway activation in melanoma cells with mutant RAS. INU-152 exhibits anti-tumor activities in xenograft models carrying BRAF mutations. PMID- 28645860 TI - GPER agonist dilates mesenteric arteries via PI3K-Akt-eNOS and potassium channels in both sexes. AB - AIM: The action of oestrogen has traditionally been attributed to the activation of nuclear receptors (ERalpha and ERbeta). A third receptor, the G protein coupled oestrogen receptor (GPER), has been described as mediator of the rapid action of oestrogen. Based on the possible protective role of oestrogen in the cardiovascular system, the present study was designed to determine whether selective GPER activation induces relaxation of mesenteric resistance arteries in both sexes and which signalling pathways are involved. MAIN METHODS: Third-order mesenteric arteries were isolated, and concentration-response curves were plotted following the cumulative addition of the selective GPER agonist G-1 (1nM-10MUM) following induction of contraction with phenylephrine (3MUM). The vasodilatory effects of G-1 were assessed before and after removal of the endothelium or incubation for 30min with nitric oxide synthase (Nomega-nitro-L-arginine methyl ester - L-NAME, 300MUM) and cyclooxygenase (indomethacin - INDO, 10MUM) inhibitors alone or combined, PI3K-Akt pathway inhibitor (LY-294,002, 2.5MUM) or a potassium channel blocker (tetraethylammonium - TEA, 5mM). GPER immunolocalisation was also performed on the investigated arteries. KEY FINDINGS: The tested GPER agonist induced concentration-dependent relaxation of the mesenteric resistance arteries without differences related to sex that were partially endothelium dependent, mainly mediated by the PI3K-Akt-eNOS pathway and attenuated by nonspecific potassium channel blockade. In addition, the endothelial GPER immunolocalisation was stronger among females. SIGNIFICANCE: This evidence provides a new perspective for understanding the mechanisms involved in the vascular responses triggered by oestrogen via GPER in both sexes. PMID- 28645861 TI - Protective effect of Lycium Barbarum polysaccharides on dextromethorphan-induced mood impairment and neurogenesis suppression. AB - Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers. PMID- 28645862 TI - Seroprevalence and susceptibility to hepatitis A in the European Union and European Economic Area: a systematic review. AB - Most of the European Union (EU) and European Economic Area (EEA) is considered a region of very low hepatitis A virus (HAV) endemicity; however, geographical differences exist. We did a systematic review with the aim of describing seroprevalence and susceptibility in the general population or special groups in the EU and EEA. We searched databases and public health national institutes websites for HAV seroprevalence records published between Jan 1, 1975, and June 30, 2014, with no language restrictions. An updated search was done on Aug 10, 2016. We defined seroprevalence profiles (very low, low, and intermediate) as the proportion of the population with age-specific anti-HAV antibodies at age 15 and 30 years, and susceptibility profiles (low, moderate, high, and very high) as the proportion of susceptible individuals at age 30 and 50 years. We included 228 studies from 28 of 31 EU and EEA countries. For the period 2000-14, 24 countries had a very low seroprevalence profile, compared with five in 1975-89. The susceptibility among adults ranged between low and very high and had a geographical gradient, with three countries in the low susceptibility category. Since 1975, EU and EEA countries have shown decreasing seropositivity; however, considerable regional variability exists. The main limitations of this study are that the studies retrieved for analysis might not be representative of all EU and EEA publications about HAV and might have poor national representativeness. A large proportion of EU and EEA residents are now susceptible to HAV infection. Our Review supports the need to reconsider specific prevention and control measures, to further decrease HAV circulation while providing protection against the infection in the EU and EEA, and could be used to inform susceptible travellers visiting EU and EEA countries with different HAV endemicity levels. PMID- 28645863 TI - Toxicology of octamethylcyclotetrasiloxane (D4). AB - Octamethylcyclotetrasiloxane (D4) is a volatile cyclic siloxane used primarily as a monomer or intermediate in the production of some silicon-based polymers widely used in industrial and consumer applications and may be present as a residual impurity in a variety of consumer products. A robust toxicological data set exists for D4. Treatment-related results from a chronic inhalation study conducted in rats are limited to mild effects on the respiratory tract, increases in liver weight, increases in the incidence of uterine endometrial epithelial hyperplasia, and a dose-related trend in the incidence of endometrial adenomas. The observed increases in liver weight appear to be related to the induction of hepatic metabolizing enzymes, similar to those that are induced in the presence of phenobarbital. D4 is not mutagenic or genotoxic in standard in vitro and in vivo tests; therefore, the benign uterine tumors observed likely occur by a non genotoxic mechanism. Results from mechanistic studies suggest that D4 has very weak estrogenic and antiestrogenic activity, as well as dopamine agonist-like activity. In rats, D4 exposure delays ovulation and hypothesized to prolong exposure of the uterine endometrium to endogenous estrogen. Though this mode of action may play a role in the development of benign uterine tumors in the rat, it is considered unlikely to occur in the human due to the marked differences in cycle regulatory mechanisms. Reproductive effects were observed following D4 exposure in female rats. These effects appear to be related to a delay of the luteinizing hormone (LH) surge, which fails to induce complete ovulation in the rat. However, based on differences in ovulatory control in rats and humans, it appears these effects may be species-specific with no risk or relevance to human health. Results from pharmacokinetic studies indicate that dermal absorption of D4 is limited, due to its high volatility and, if absorbed via dermal, oral or inhalation exposure, the majority of D4 is rapidly cleared from the body, indicating bioaccumulation is unlikely. PMID- 28645864 TI - Cross-border healthcare: Implementation of Directive 2011/24/EU and National Contact Point in Italy. PMID- 28645865 TI - Atrial fibrillation recurrence after pulmonary vein isolation in patients with paroxysmal atrial fibrillation and the use of a pacemaker by single catheter vs. multiple catheter approach - Clinical and economic evaluation. PMID- 28645866 TI - Peripheral neuroectodermal tumor in the nasal cavity - a case report. PMID- 28645867 TI - Psychophysical and Electrophysiological Evidence for Enhanced Pain Facilitation and Unaltered Pain Inhibition in Acute Low Back Pain Patients. AB - : The aim of this case-control study was to examine differences in neural correlates of pain facilitatory and inhibitory mechanisms between acute low back pain (LBP) patients and healthy individuals. Pressure pain tolerance, electrical pain detection thresholds, pain ratings to repetitive suprathreshold electrical stimulation (SES) and conditioned pain modulation (CPM) were assessed in 18 patients with acute LBP and 18 healthy control participants. Furthermore, event related potentials (ERPs) in response to repetitive SES were obtained from high density electroencephalography. Results showed that the LBP group presented lower pressure pain tolerance and higher pain ratings to SES compared with the control group. Both groups displayed effective CPM, with no differences in CPM magnitude between groups. Both groups presented similar reductions in ERP amplitudes during CPM, but ERP responses to repetitive SES were significantly larger in the LBP group. In conclusion, acute LBP patients presented enhanced pain facilitatory mechanisms, whereas no significant changes in pain inhibitory mechanisms were observed. These results provide new insight into the central mechanisms underlying acute LBP. PERSPECTIVE: This article present evidence that acute LBP patients show enhanced pain facilitation and unaltered pain inhibition compared with pain-free volunteers. These results provide new insight into the central mechanisms underlying acute LBP. PMID- 28645868 TI - Natural History of Contralateral Hypertrophy in Patients with Multicystic Dysplastic Kidneys. AB - PURPOSE: We evaluated predictive factors for compensatory hypertrophy and renal outcomes in a large cohort of patients with multicystic dysplastic kidneys. MATERIALS AND METHODS: We conducted a retrospective review from 1997 to 2016. Contralateral kidney and multicystic dysplastic kidney length were recorded from all ultrasounds as well as creatinine when available. We used generalized estimating equations to determine predictors of contralateral kidney length. RESULTS: A total of 443 children with multicystic dysplastic kidneys were identified based on sonographic findings and lack of function on nuclear scan. Average followup was 3.2 years (IQR 1.5 to 5.7). Median time to involution in patients diagnosed before age 2 years was 5.5 years (95% CI 3.8-7.0). In all patients the median time to contralateral hypertrophy was 2.7 years (95% CI 2.2 3.3), and 90% of patients manifested contralateral hypertrophy by 10 years. After adjusting for age, gender, multicystic dysplastic kidney side and cohort status for each year of involution after age 2 years, the contralateral kidney grows 0.35 cm longer (95% CI 0.01-0.68, p = 0.04) compared to cases without involution. Patients with contralateral hypertrophy had greater creatinine clearance at followup (83 vs 61 ml per minute, p = 0.07), although this finding was not statistically significant due to limited data. CONCLUSIONS: The majority of children with multicystic dysplastic kidneys will have contralateral hypertrophy by age 3 years. Multicystic dysplastic kidney involution predicts contralateral kidney growth rate after age 2 years. A small cohort of patients with multicystic dysplastic kidneys will not exhibit contralateral hypertrophy and may be at risk for renal insufficiency. PMID- 28645869 TI - Real-Time Changes in Brain Activity during Sacral Neuromodulation for Overactive Bladder. AB - PURPOSE: We performed functional magnetic resonance imaging to identify changes in brain activity during sacral neuromodulation in women with overactive bladder who were responsive to therapy. MATERIALS AND METHODS: Women recruited into the study had nonneurogenic refractory overactive bladder, responded to sacral neuromodulation and had had a stable program for at least 3 months with no subsequent overactive bladder treatment. Enrolled patients completed validated symptom and quality of life instruments before functional magnetic resonance imaging. Stimulus settings were recorded, devices were switched off for a 5-day washout and instruments were repeated. Three functional magnetic resonance imaging scans with simultaneous sacral neuromodulation stimulation were performed below, at and above stimulus sensory threshold using a block design. This yielded brain activity maps represented by changes in blood oxygenation level dependence. A total of 5 stimulator off and 4 stimulator on cycles of 42 seconds each were imaged. Group analysis was done using a single voxel p value of 0.05 with a false positive error of 0.05 on cluster analysis. RESULTS: Six of the 13 patients enrolled completed functional magnetic resonance imaging. Median age was 52 years (range 36 to 64). Urinary symptoms and voiding diary data worsened with washout. Overall brain activation generally progressed with increasing stimulation amplitude. However, activation of the right inferior frontal gyrus remained stable while deactivation of the pons and the periacqueductal gray matter only occurred with subsensory stimulation. Sensory stimulation activated the insula but deactivated the medial and superior parietal lobes. Suprasensory stimulation activated multiple structures and the expected S3 somatosensory region. All devices had normal impedance after functional magnetic resonance imaging. CONCLUSIONS: Functional magnetic resonance imaging confirmed that sacral neuromodulation influences brain activity in women with overactive bladder who responded to therapy. These changes varied with stimulus intensity. PMID- 28645870 TI - Impact on environment, ecosystem, diversity and health from culturing and using GMOs as feed and food. AB - Modern agriculture provides the potential for sustainable feeding of the world's increasing population. Up to the present moment, genetically modified (GM) products have enabled increased yields and reduced pesticide usage. Nevertheless, GM products are controversial amongst policy makers, scientists and the consumers, regarding their possible environmental, ecological, and health risks. Scientific-and-political debates can even influence legislation and prospective risk assessment procedure. Currently, the scientifically-assessed direct hazardous impacts of GM food and feed on fauna and flora are conflicting; indeed, a review of literature available data provides some evidence of GM environmental and health risks. Although the consequences of gene flow and risks to biodiversity are debatable. Risks to the environment and ecosystems can exist, such as the evolution of weed herbicide resistance during GM cultivation. A matter of high importance is to provide precise knowledge and adequate current information to regulatory agencies, governments, policy makers, researchers, and commercial GMO-releasing companies to enable them to thoroughly investigate the possible risks. PMID- 28645871 TI - Aflatoxin B1-induced epigenetic alterations: An overview. AB - Aflatoxin B1 (AFB1) is widely distributed in nature, especially in a variety of food commodities. It is confirmed to be the most toxic of all the aflatoxins. The toxicity of AFB1 has been well investigated, and it may result in severe health problems including carcinogenesis, mutagenesis, growth retardation, and immune suppression. Epigenetic modifications including DNA methylation, histone modifications and regulation of non-coding RNA play an important role in AFB1 induced disease and carcinogenesis. To better understand the evidence for AFB1 induced epigenetic alterations and the potential mechanisms of the toxicity of AFB1, we conducted a review of published studies of AFB1-induced epigenetic alterations. PMID- 28645872 TI - Two obesity susceptibility loci in LYPLAL1 and ETV5 independently associated with childhood hypertension in Chinese population. AB - AIMS: Genome-wide association studies have identified novel obesity-associated susceptibility loci. Associations of these variants with childhood obesity have been studied in our previous research. The purpose of this study is to investigate if these loci are associated with hypertension being independent of obesity in Chinese children and adolescents. METHODS: Nineteen candidate SNPs were genotyped using Sequenom MassARRAY platform among Chinese children (N=2954, 514 hypertension and 2440 controls, aged 7-17years). Dietary behaviors were assessed through face to face investigations. RESULTS: Of the nineteen obese related SNPs, ten SNPs were found to be associated with systolic blood pressure (SBP) or diastolic blood pressure (DBP) in Chinese children. After adjusting for age, sex and WHtR, rs2605100 in LYPLAL1was found to be associated with high blood pressure (HBP) under dominant model (P=0.024) with the OR of 1.274 (95% CI =1.033 1.572, effect genotype=GG). The distribution of genotype of rs7647305 in ETV5 showed significant difference between HBP and non-HBP subjects under dominant model (P=0.011) with the OR of 0.654 (95% CI=0.471-0.909, effect genotype=CC). Using rs2605100 and rs7647305, the genetic risk score (GRS) analysis showed that, after adjusted for age, sex and WHtR, subjects carrying one or two risk alleles had the risks of hypertension with the ORs 1.797 (95% CI, 1.168-2.765), 2.149 (95% CI, 1.375-3.357) comparing with the subjects with non-risk-allele. CONCLUSIONS: Genetic variations of obesity-associated loci, LYPLAL1 rs2605100 and ETV5 rs7647305 independently associate with the risk of childhood hypertension in China. PMID- 28645873 TI - Generation of nitric oxide by olive (Olea europaea L.) pollen during in vitro germination and assessment of the S-nitroso- and nitro-proteomes by computational predictive methods. AB - Nitric oxide is recognized as a signaling molecule involved in a broad range of physiological processes in plants including sexual reproduction. NO has been detected in the pollen grain at high levels and regulates pollen tube growth. Previous studies demonstrated that NO as well as ROS are produced in the olive reproductive tissues in a stage- and tissue-specific manner. The aim of this study was to assess the production of NO throughout the germination of olive (Olea europaea L.) pollen in vitro. The NO fluorescent probe DAF-2DA was used to image NO production in situ, which was correlated to pollen viability. Moreover, by means of a fluorimetric assay we showed that growing pollen tubes release NO. GSNO -a mobile reservoir of NO, formed by the S-nitrosylation of NO with reduced glutathione (GSH) - was for the first time detected and quantified at different stages of pollen tube growth using a LC-ES/MS analysis. Exogenous NO donors inhibited both pollen germination and pollen tube growth and these effects were partially reverted by the specific NO-scavenger c-PTIO. However, little is known about how NO affects the germination process. With the aim of elucidating the putative relevance of protein S-nitrosylation and Tyr-nitration as important post translational modifications in the development and physiology of the olive pollen, a de novo assembled and annotated reproductive transcriptome from olive was challenged in silico for the putative capability of transcripts to become potentially modified by S-nitrosylation/Tyr-nitration according to well established criteria. Numerous gene products with these characteristics were identified, and a broad discussion as regards to their potential role in plant reproduction was built after their functional classification. Moreover, the importance of both S-nitrosylation/Tyr-nitrations was experimentally assessed and validated by using Western blotting, immunoprecipitation and proteomic approaches. PMID- 28645874 TI - Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state. AB - The IL-2/IL-2R pathway is implicated in type 1 diabetes (T1D). While its role in regulatory T cell (Treg) biology is well characterized, mechanisms that influence IL-2 responses in effector T cells (Teff) are less well understood. We compared IL-2 responses in 95 healthy control and 98 T1D subjects. In T1D, low IL-2 responsiveness was most pronounced in memory Teff. Unlike Treg, CD25 expression did not influence the Teff responses. Reduced IL-2 responses in memory Teff were not rescued by resting, remained lower after activation and proliferation, and were absent in type 2 diabetes. Comparing basal IL-2 responses in resting versus activated cells, memory Teff displayed lower, but more sustained, responses to IL 2 overtime. These results suggest that T1D-associated defects in the Teff compartment are due to intrinsic factors related to activation. Evaluation of both Teff and Treg IL-2R signaling defects in T1D subjects may inform selection of therapies. PMID- 28645876 TI - Erratum. PMID- 28645875 TI - High resolution IgH repertoire analysis reveals fetal liver as the likely origin of life-long, innate B lymphopoiesis in humans. AB - The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM+ B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM+ B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime. PMID- 28645877 TI - Corrigendum. PMID- 28645878 TI - 6th Zing Bionanomaterials Conference Proceedings Preface. PMID- 28645879 TI - Risk for Venous Thromboembolism Recurrence Among Rivaroxaban-treated Patients Who Continued Versus Discontinued Therapy: Analyses Among Patients with VTE. AB - PURPOSE: The EINSTEIN-Extension trial showed that an extended rivaroxaban treatment significantly reduced the risk for venous thromboembolic (VTE) recurrence. The present study assessed the risk for VTE recurrence and major bleeding associated with extended rivaroxaban treatment in a clinical practice setting among patients with VTE. METHODS: A retrospective study was conducted using claims data from February 2011 to April 2015. It included adult patients who initiated rivaroxaban therapy within 7 days after their first VTE and who continuously used rivaroxaban for at least 3 months (index date: end of initial 3 month treatment). Categorized into discontinued and continued cohorts, patients were followed up from the index date until the end of continuous treatment (continued cohort) or end of data or reinitiation of oral anticoagulant therapy (discontinued cohort). Using inverse probability of treatment weights controlling for confounders, adjusted Kaplan-Meier rates of recurrent VTE and major bleeding events were compared. FINDINGS: The analysis showed that, compared with the discontinued cohort (n = 1,536), the continued cohort (n = 5,933) had a significantly lower VTE recurrence rate after an additional 3 months (0.70% vs 1.70%), 6 months (1.41% vs 2.34%), 9 months (1.82% vs 3.01%), and 12 months (1.97% vs 3.01%) of treatment (all, p < 0.05). The difference in the cumulative event rates for major bleeding was not statistically significant. Similar results were obtained in an analysis among patients with VTE receiving rivaroxaban for >=6 months. IMPLICATIONS: Our results suggest that, in clinical practice settings, patients with VTE who continued rivaroxaban therapy after the initial 3 or 6-month treatment period had a significantly lower risk for VTE recurrence without a statistically significant increased risk for major bleeding. PMID- 28645880 TI - Biomarkers of airway and systemic inflammation in obese asthmatic paediatric patients. AB - BACKGROUND: It is thought that airway inflammation is more common in obese asthmatic patients because inflammation is harder to control and does not respond well to glucocorticoid treatment. OBJECTIVE: This study's aim was to investigate the effect of obesity on airway and systemic inflammation in children with asthma and to identify the biomarkers that play a role in this inflammation. METHODS: The study included patients aged 6-16 years who were diagnosed with asthma in the paediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. Complete blood count parameters were compared between three groups: obese asthmatic (n=43), obese non-asthmatic (n=45), and non-obese non-asthmatic (control group, n=30). Levels of high-sensitive CRP (hs-CRP), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and matrix metalloproteinase-9 (MMP-9), and 25(OH)-vitamin D were compared between the groups. RESULTS: No statistically significant differences were observed in 25(OH) vitamin D, NGAL, OPN, hs-CRP, and MMP-9 levels between groups. There was a statistically significant negative correlation between FEV1/FVC and NGAL and MMP 9. CONCLUSION: This is the first study to investigate levels of hs-CRP, NGAL, OPN, MMP-9, and 25(OH)-vitamin D in obese asthmatic children. Larger studies with sputum and BAL examinations are required to determine the potential of biomarkers for identifying inflammation in obese asthmatic children. PMID- 28645881 TI - Helicobacter pylori seropositivity protects against childhood asthma and inversely correlates to its clinical and functional severity. AB - BACKGROUND: In recent years, the prevalence of asthma has risen in developed countries, and its extent related to a change in our indigenous microbiota. Helicobacter pylori disappearance across the population represents a fundamental change in our human microbiota and has preceded the rise in asthma prevalence. OBJECTIVE: To assess the relationship between childhood asthma and Helicobacter pylori infection. METHODS: Quantitative determination of Helicobacter pylori IgG among 90 asthmatic children and 90 - age and gender - matched non-atopic, non asthmatic healthy children was performed using ELISA in serum of all participants. RESULTS: Helicobacter pylori IgG seropositivity was found in 25.6% of asthmatics compared to 44.4% of controls. Asthmatics showed lower median Helicobacter pylori IgG titre compared to healthy controls. We also detected a significant inverse relationship between Helicobacter pylori IgG titre and asthma severity. CONCLUSION: Helicobacter pylori seropositivity protects against childhood asthma and inversely correlates to its clinical and functional severity. PMID- 28645882 TI - Cardiopreventive effect of ethanolic extract of Date Palm Pollen against isoproterenol induced myocardial infarction in rats through the inhibition of the angiotensin-converting enzyme. AB - The present study aimed to examine the putative preventive effect of the ethanolic extract Date Palm Pollen (DPP, Phoenix dactylifera L., family Arecaceae) on isoproterenol-induced myocardial infarction (MI) in rats. Twenty four rats were randomly divided into four groups including control. They were treated with DPP extract (400mg/kg) and clopidogrel (0.2mg/kg) for 7days followed by myocardial injury induction using subcutaneous isoproterenol (100mg/kg) with an interval of 24h for two days (6th and 7th day). Administration of isoproterenol exhibited indicative changes in the ECG pattern evidenced by significant elevation of ST-segment and cardiac injury markers viz.; troponin-T, creatine phosphokinase (CPK), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) by 315%, 71%, 64% and 170%, respectively as compared to control. Additionally, the angiotensin-converting enzyme (ACE) activity in plasma was increased by 33% associated to histological myocardial necrosis. However, pre co-treatment with DPP extract improved the cardiac biomarkers injury, normalized cardiac function indices and prevented the ventricular remodeling process through inhibition of ACE activity by 34% and the inhibition of the generation of radical oxygen species. Extensive characterization of this DPP extract using LC-HRMS revealed numerous flavonoids and phenols compounds which could be endowed with cardiopreventive actions. Overall, these results proved that DPP extract has preventive effects on cardiac remodeling process. PMID- 28645884 TI - Investigation of the effects of Lycium barbarum polysaccharides against cadmium induced damage in testis. AB - This study describes the effects of Lycium barbarum polysaccharides (LBP) on testicular damage induced by cadmium (Cd). Adult male rats were i.p. injected with CdCl2 (4mg/Kg, once) with or without LBP pretreatment (300mg/Kg orally, once a day, for 30days). Testis weight, morphological/histological structure and oxidative stress parameters were evaluated. Several adverse effects were observed after CdCl2 injection, with a significant decrease in body/testis weight ratio (P<0.05), gross morphological changes with hyperemia of the parenchyma, increased volume and alteration in the structure of the seminiferous tubules. Furthermore, Cd intoxication caused a significant decrease of glutathione (GSH) and Trolox equivalent antioxidant capacity (TEAC) in testis (P<0.05) together with a significant increase (P<0.01) of 3-nitro-l-tyrosine (3NT) while malondialdehyde (MDA) did not change. LBP pretreatment caused slight signs of improvement in the morphology of the seminiferous tubules. Our results confirm that Cd induces testicular damage and suggest the oxidative stress involvement. LBP could ameliorate Cd testicular damage but further investigations are needed. PMID- 28645883 TI - The first nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan. AB - To investigate the trends of antimicrobial resistance in pathogens isolated from skin and soft-tissue infections (SSTI) at dermatology departments in Japan, a Japanese surveillance committee conducted the first nationwide survey in 2013. Three main organisms were collected from SSTI at 30 dermatology departments in medical centers and 10 dermatology clinics. A total of 860 strains - 579 of Staphylococcus aureus, 240 of coagulase-negative Staphylococci, and 41 of Streptococcus pyogenes - were collected and shipped to a central laboratory for antimicrobial susceptibility testing. The patient profiles were also studied. Among all 579 strains of S. aureus, 141 (24.4%) were methicillin-resistant (MRSA). Among 97 Staphylococcus epidermidis strains, 54 (55.7%) were methicillin resistant (MRSE). MRSA and MRSE were more frequently isolated from inpatients than from outpatients. Furthermore, these methicillin-resistant strains were also isolated more frequently from patients with histories of taking antibiotics within 4 weeks and hospitalization within 1 year compared to those without. However, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains between patients with a history of hospitalization within 1 year and those without. Therefore, most of the isolated MRSA cases at dermatology departments are not healthcare-acquired, but community-acquired MRSA. S. pyogenes strains were susceptible to most antibiotics except macrolides. The information in this study is not only important in terms of local public health but will also contribute to an understanding of epidemic clones of pathogens from SSTI. PMID- 28645885 TI - The Threshold of Toxicological Concern for prenatal developmental toxicity in rats and rabbits. AB - The Threshold Toxicological Concern (TTC) is based on the concept that in absence of experimental data reasonable assurance of safety can be given if exposure is sufficiently low. Using the REACH database the low 5th percentile of the NO(A)EL distribution, for prenatal developmental toxicity (OECD guideline 414) was determined. For rats, (434 NO(A)ELs values) for maternal toxicity, this value was 10 mg/kg-bw/day. For developmental toxicity (469 NO(A)ELs): 13 mg/kg-bw/day. For rabbits, (100 NO(A)ELs), the value for maternal toxicity was 4 mg/kg-bw/day, for developmental toxicity, (112 NO(A)EL values): 10 mg/kg-bw/day. The maternal organism may thus be slightly more sensitive than the fetus. Combining REACH- (industrial chemicals) and published BASF-data (mostly agrochemicals), 537 unique compounds with NO(A)EL values for developmental toxicity in rats and 150 in rabbits were evaluated. The low 5th percentile NO(A)EL for developmental toxicity in rats was 10 mg/kg-bw/day and 9.5 mg/kg-bw/day for rabbits. Using an assessment factor of 100, a TTC value for developmental toxicity of 100 MUg/kg-bw/day for rats and 95 MUg/kg-bw/day for rabbits is calculated. These values could serve as guidance whether or not to perform an animal experiment, if exposure is sufficiently low. In emergency situations this value may be useful for a first tier risk assessment. PMID- 28645886 TI - Uterovaginal Anastomosis for Cases of Cryptomenorrhea Due to Cervical Atresia with Vaginal Aplasia: Benefits and Risks. AB - STUDY OBJECTIVE: The objective of this study was to assess short-term benefits and risks of utero-vaginal anastomosis done for cases of cryptomenorrhea due to cervical atresia with vaginal aplasia. DESIGN: Prospective study. SETTING: Surgical procedures were done between December 2013 and September 2015 at the department of Obstetrics and Gynecology, Cairo University Hospital. PARTICIPANTS: Five patients who had cryptomenorrhea due to cervical atresia associated with vaginal aplasia were included. INTERVENTIONS: Utero-vaginal anastomoses were performed in 2 stages; a stage of McIndoe vaginoplasty and a stage of excision of the atretic cervical tissue and anastomosing the uterus to the neovagina. Follow up was done by gynecological and ultrasound examination in a duration ranged from 12 to 36 months. MAIN OUTCOME MEASURES: Occurrence of regular menstrual flow and relief of the severe cyclic pain. RESULTS: All patients had relief of the severe cyclic pain. Four patients had regular menstrual flow. One patient developed occlusion of the track after 1 year and needed dilatation once. Three patients developed low vaginal stenosis without occlusion of the track. One patient had rectal injury repaired without causing postoperative morbidity. CONCLUSION: Uterovaginal anastomosis is a promising conservative management option for cervical atresia with vaginal aplasia, which has benefits but is not free of risks. Long-term follow-up is still needed to judge its feasibility. We recommend performing McIndoe vaginoplasty as a starting stage before the anastomosis preferably in a separate setting. PMID- 28645887 TI - Perspectives of Family Members on Using Technology in Youth Mental Health Care: A Qualitative Study. AB - BACKGROUND: Information and communication technologies (ICTs) are increasingly recognized as having an important role in the delivery of mental health services for youth. Recent studies have evaluated young people's access and use of technology, as well as their perspectives on using technology to receive mental health information, services, and support; however, limited attention has been given to the perspectives of family members in this regard. OBJECTIVE: The aim of this study was to explore the perspectives of family members on the use of ICTs to deliver mental health services to youth within the context of specialized early intervention for a first-episode psychosis (FEP). METHODS: Six focus groups were conducted with family members recruited from an early intervention program for psychosis. Twelve family members participated in the study (target sample was 12-18, and recruitment efforts took place over the duration of 1 year). A 12-item semistructured focus group guide was developed to explore past experiences of technology and recommendations for the use of technology in youth mental health service delivery. A qualitative thematic analysis guided the identification and organization of common themes and patterns identified across the dataset. RESULTS: Findings were organized by the following themes: access and use of technology, potential negative impacts of technology on youth in recovery, potential benefits of using technology to deliver mental health services to youth, and recommendations to use technology for (1) providing quality information in a manner that is accessible to individuals of diverse socioeconomic backgrounds, (2) facilitating communication with health care professionals and services, and (3) increasing access to peer support. CONCLUSIONS: To our knowledge, this is among the first (or the first) to explore the perspectives of family members of youth being treated for FEP on the use of technology for mental health care. Our results highlight the importance of considering diverse experiences and attitudes toward the role of technology in youth mental health, digital literacy skills, phases of recovery, and sociodemographic factors when engaging family members in technology-enabled youth mental health care research and practice. Innovative methods to recruit and elicit the perspectives of family members on this topic are warranted. It is also important to consider educational strategies to inform and empower family members on the role, benefits, and use of ICTs in relation to mental health care for FEP. PMID- 28645888 TI - HIV Strategic Information in Non-European Union Countries in the World Health Organization European Region: Capacity Development Needs. AB - BACKGROUND: Capacity building of the national HIV strategic information system is a core component of the response to the HIV epidemic as it enables understanding of the evolving nature of the epidemic, which is critical for program planning and identification of the gaps and deficiencies in HIV programs. OBJECTIVE: The study aims to describe the results of the assessment of the needs for further development of capacities in HIV strategic information systems in the non European Union (EU) countries in the World Health Organization European Region (EUR). METHODS: Self-administered questionnaires were distributed to national AIDS programs. The first questionnaire was sent to all countries (N=18) to find out, among other issues, the priority level for strengthening a range of HIV surveillance areas and their key gaps and weaknesses. The second questionnaire was sent to 15 countries to more specifically determine capacities for the analysis of the HIV care cascade. RESULTS: Responses to the first questionnaire were received from 10 countries, whereas 13 countries responded to the second questionnaire. Areas that were most frequently marked as being of high to moderate priority for strengthening were national electronic patient monitoring systems, evaluation of HIV interventions and impact analysis, implementation science, and data analysis. Key weaknesseses were lack of electronic reporting of HIV cases, problems with timeliness and completeness of reporting in HIV cases, under-estimates of the reported number of HIV-related deaths, and limited CD4 count testing at the time of HIV diagnosis. Migrant populations, internally displaced persons, and refugees were most commonly mentioned as groups not covered by surveillance, followed by clients of sex workers and men who have sex with men. The majority of countries reported that they were able to provide the number of people diagnosed with HIV who know their HIV status, which is important for the analysis of cross-sectional and longitudinal HIV care cascades. Ability to report on some of the key impact indicators of HIV programs-viral load suppression and mortality-should be considerably strengthened. CONCLUSIONS: The assessment found a substantial need to invest in surveillance capacities, which is a cornerstone in the development of an evidence-informed response to HIV epidemics. PMID- 28645889 TI - A Review of the Theoretical Basis, Effects, and Cost Effectiveness of Online Smoking Cessation Interventions in the Netherlands: A Mixed-Methods Approach. AB - BACKGROUND: Tobacco smoking is a worldwide public health problem. In 2015, 26.3% of the Dutch population aged 18 years and older smoked, 74.4% of them daily. More and more people have access to the Internet worldwide; approximately 94% of the Dutch population have online access. Internet-based smoking cessation interventions (online cessation interventions) provide an opportunity to tackle the scourge of tobacco. OBJECTIVE: The goal of this paper was to provide an overview of online cessation interventions in the Netherlands, while exploring their effectivity, cost effectiveness, and theoretical basis. METHODS: A mixed methods approach was used to identify Dutch online cessation interventions, using (1) a scientific literature search, (2) a grey literature search, and (3) expert input. For the scientific literature, the Cochrane review was used and updated by two independent researchers (n=651 identified studies), screening titles, abstracts, and then full-text studies between 2013 and 2016 (CENTRAL, MEDLINE, and EMBASE). For the grey literature, the researchers conducted a Google search (n=100 websites), screening for titles and first pages. Including expert input, this resulted in six interventions identified in the scientific literature and 39 interventions via the grey literature. Extracted data included effectiveness, cost effectiveness, theoretical factors, and behavior change techniques used. RESULTS: Overall, many interventions (45 identified) were offered. Of the 45 that we identified, only six that were included in trials provided data on effectiveness. Four of these were shown to be effective and cost effective. In the scientific literature, 83% (5/6) of these interventions included changing attitudes, providing social support, increasing self-efficacy, motivating smokers to make concrete action plans to prepare their attempts to quit and to cope with challenges, supporting identity change and advising on changing routines, coping, and medication use. In all, 50% (3/6) of the interventions included a reward for abstinence. Interventions identified in the grey literature were less consistent, with inclusion of each theoretical factor ranging from 31% to 67% and of each behavior change technique ranging from 28% to 54%. CONCLUSIONS: Although the Internet may provide the opportunity to offer various smoking cessation programs, the user is left bewildered as far as efficacy is concerned, as most of these data are not available nor offered to the smokers. Clear regulations about the effectiveness of these interventions need to be devised to avoid disappointment and failed quitting attempts. Thus, there is a need for policy regulations to regulate the proliferation of these interventions and to foster their quality in the Netherlands. PMID- 28645890 TI - Tailored Communication Within Mobile Apps for Diabetes Self-Management: A Systematic Review. AB - BACKGROUND: The prevalence of diabetes is increasing and with the requirements for self-management and risk of late complications, it remains a challenge for the individual and society. Patients can benefit from support from health care personnel in their self-management, and the traditional communication between patients and health care personnel is changing. Smartphones and apps offer a unique platform for communication, but apps with integrated health care personnel communication based on patient data are yet to be investigated to provide evidence of possible effects. OBJECTIVE: Our goal was to systematically review studies that aimed to evaluate integrated communication within mobile apps for tailored feedback between patients with diabetes and health care personnel in terms of (1) study characteristics, (2) functions, (3) study outcomes, (4) effects, and (5) methodological quality. METHODS: A systematic literature search was conducted following our International Prospective Register of Systematic Reviews (PROSPERO) protocol, searching for apps with integrated communication for persons with diabetes tested in a controlled trial in the period 2008 to 2016. We searched the databases PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central, Excerpta Medica database (EMBASE), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. The search was closed in September 2016. Reference lists of primary articles and review papers were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and we applied the Cochrane risk of bias tool to assess methodological quality. RESULTS: We identified 2822 citations and after duplicate removal, we assessed 1128 citations. A total of 6 papers were included in this systematic review, reporting on data from 431 persons participating in small trials of short duration. The integrated communication features were mostly individualized as written non-real-time feedback. The number of functions varied from 2 to 9, and blood glucose tracking was the most common. HbA1c was the most common primary outcome, but the remaining reported outcomes were not standardized and comparable. Because of both the heterogeneity of the included trials and the poor methodological quality of the studies, a meta-analysis was not possible. A statistically significant improvement in the primary measure of outcome was found in 3 of the 6 included studies, of which 2 were HbA1c and 1 was mean daytime ambulatory blood pressure. Participants in the included trials reported positive usability or feasibility postintervention in 5 out of 6 trials. The overall methodological quality of the trials was, however, scored as an uncertain risk of bias. CONCLUSIONS: This systematic review highlights the need for more trials of higher methodological quality. Few studies offer an integrated function for communication and feedback from health care personnel, and the research field represents an area of heterogeneity with few studies of highly rigorous methodological quality. This, in combination with a low number of participants and a short follow-up, is making it difficult to provide reliable evidence of effects for stakeholders. PMID- 28645891 TI - Health App Use Among Individuals With Symptoms of Depression and Anxiety: A Survey Study With Thematic Coding. AB - BACKGROUND: Researchers have largely turned to commercial app stores, randomized trials, and systematic reviews to make sense of the mHealth landscape. Few studies have approached understanding by collecting information from target end users. The end user perspective is critical as end user interest in and use of mHealth technologies will ultimately drive the efficacy of these tools. OBJECTIVE: The purpose of this study was to obtain information from end users of mHealth technologies to better understand the physical and mental health apps people use and for what purposes. METHODS: People with depressive or anxious symptoms (N=176) seeking entry into a trial of mental health and well-being apps for Android devices completed online questionnaires assessing depression and anxiety (Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7), past and current mental health treatment-seeking behavior, overall mobile device use, and use of mobile health apps. Participants reported the physical health and mental health apps on their devices and their reasons for using them. Data were extracted from the participant self-reports and apps and app purposes were coded in order to categorize them. RESULTS: Participants were largely white, middle aged females from the Midwest region of the United States recruited via a health care organization and Web-based advertising (135 female, 41 male, mean age 38.64 years, age range 19-75 years.) Over three-quarters (137/176, 77.8%) of participants indicated having a health app on their device. The top 3 kinds of apps were exercise, fitness, and pedometers or heart rate monitoring apps (93/176, 52.8%); diet, food, or calorie counting apps (65/177, 36.9%); and mental health/wellness apps (46/177, 26.1%). The mean number of mobile physical and mental health apps on a participant's phone was 2.15 (SD 3.195). Of 176 participants, 107 (60.8%) specifically reported the top 5 health apps that they used and their purposes. Across the 107 participants, a total of 285 apps were reported, with 139 being unique apps. The majority of these apps were free (129/139, 92.8%). Almost two-thirds of participants (67/107, 62.6%) reported using health apps at least on a daily basis. CONCLUSIONS: Among those seeking support for their well-being via physical and mental health apps, people are using a variety of health apps. These people use health apps on a daily basis, especially free apps. The most common reason for using a health app is to track some health-related data; for mental health apps specifically, training or habit building was the most popular reason. Understanding the end user perspective is important because it allows us to build on the foundation of previously established mHealth research and may help guide future work in mHealth. TRIAL REGISTRATION: Clinicaltrials.gov NCT02176226; https://clinicaltrials.gov/ct2/show/NCT02176226 (Archived by WebCite at http://www.webcitation.org/6rGc1MGyM). PMID- 28645893 TI - Introductory Biology Students' Use of Enhanced Answer Keys and Reflection Questions to Engage in Metacognition and Enhance Understanding. AB - Providing feedback to students as they learn to integrate individual concepts into complex systems is an important way to help them to develop robust understanding, but it is challenging in large, undergraduate classes for instructors to provide feedback that is frequent and directed enough to help individual students. Various scaffolds can be used to help students engage in self-regulated learning and generate internal feedback to improve their learning. This study examined the use of enhanced answer keys with added reflection questions and instruction as scaffolds for engaging undergraduate students in self-regulated learning within an introductory biology course. Study findings show that both the enhanced answer keys and reflection questions helped students to engage in metacognition and develop greater understanding of biological concepts. Further, students who received additional instruction on the use of the scaffolds changed how they used them and, by the end of the semester, were using the scaffolds in significantly different ways and showed significantly higher learning gains than students who did not receive the instruction. These findings provide evidence for the benefit of designing scaffolds within biology courses that will support students in engaging in metacognition and enhancing their understanding of biological concepts. PMID- 28645892 TI - Meis1: effects on motor phenotypes and the sensorimotor system in mice. AB - MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it. PMID- 28645894 TI - Community land titles alone will not protect forests. PMID- 28645895 TI - Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk. AB - Females show a varying degree of ischemic sensitivity throughout their lifespan, which is not fully explained by hormonal or genetic factors. Epidemiological data suggest that sex-specific life experiences such as pregnancy increase stroke risk. This work evaluated the role of parity on stroke outcome. Age-matched virgin (i.e., nulliparous) and multiparous mice were subjected to 60 min of reversible middle cerebral artery occlusion and evaluated for infarct volume, behavioral recovery, and inflammation. Using an established mating paradigm, fetal microchimeric cells present in maternal mice were also tracked after parturition and stroke. Parity was associated with sedentary behavior, weight gain, and higher triglyceride and cholesterol levels. The multiparous brain exhibited features of immune suppression, with dampened baseline microglial activity. After acute stroke, multiparous mice had smaller infarcts, less glial activation, and less behavioral impairment in the critical recovery window of 72 h. Behavioral recovery was significantly better in multiparous females compared with nulliparous mice 1 mo after stroke. This recovery was accompanied by an increase in poststroke angiogenesis that was correlated with improved performance on sensorimotor and cognitive tests. Multiparous mice had higher levels of VEGF, both at baseline and after stroke. GFP+ fetal cells were detected in the blood and migrated to areas of tissue injury where they adopted endothelial morphology 30 d after injury. Reproductive experience has profound and complex effects on neurovascular health and disease. Inclusion of female mice with reproductive experience in preclinical studies may better reflect the life-long patterning of ischemic stroke risk in women. PMID- 28645896 TI - Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1. AB - Dynamin-like proteins (DLPs) mediate various membrane fusion and fission processes within the cell, which often require the polymerization of DLPs. An IFN inducible family of DLPs, the guanylate-binding proteins (GBPs), is involved in antimicrobial and antiviral responses within the cell. Human guanylate-binding protein 1 (hGBP1), the founding member of GBPs, is also engaged in the regulation of cell adhesion and migration. Here, we show how the GTPase cycle of farnesylated hGBP1 (hGBP1F) regulates its self-assembly and membrane interaction. Using vesicles of various sizes as a lipid bilayer model, we show GTP-dependent membrane binding of hGBP1F In addition, we demonstrate nucleotide-dependent tethering ability of hGBP1F Furthermore, we report nucleotide-dependent polymerization of hGBP1F, which competes with membrane binding of the protein. Our results show that hGBP1F acts as a nucleotide-controlled molecular switch by modulating the accessibility of its farnesyl moiety, which does not require any supportive proteins. PMID- 28645897 TI - Versatility of presenilin 1. PMID- 28645898 TI - DNA-PK facilitates piggyBac transposition by promoting paired-end complex formation. AB - The involvement of host factors is critical to our understanding of underlying mechanisms of transposition and the applications of transposon-based technologies. Modified piggyBac (PB) is one of the most potent transposon systems in mammals. However, varying transposition efficiencies of PB among different cell lines have restricted its application. We discovered that the DNA-PK complex facilitates PB transposition by binding to PB transposase (PBase) and promoting paired-end complex formation. Mass spectrometry analysis and coimmunoprecipitation revealed physical interaction between PBase and the DNA-PK components Ku70, Ku80, and DNA-PKcs Overexpression or knockdown of DNA-PK components enhances or suppresses PB transposition in tissue culture cells, respectively. Furthermore, germ-line transposition efficiency of PB is significantly reduced in Ku80 heterozygous mutant mice, confirming the role of DNA-PK in facilitating PB transposition in vivo. Fused dimer PBase can efficiently promote transposition. FRET experiments with tagged dimer PBase molecules indicated that DNA-PK promotes the paired-end complex formation of the PB transposon. These data provide a mechanistic explanation for the role of DNA PK in facilitating PB transposition and suggest a transposition-promoting manipulation by enhancing the interaction of the PB ends. Consistent with this, deletions shortening the distance between the two PB ends, such as PB vectors with closer ends (PB-CE vectors), have a profound effect on transposition efficiency. Taken together, our study indicates that in addition to regulating DNA repair fidelity during transposition, DNA-PK also affects transposition efficiency by promoting paired-end complex formation. The approach of CE vectors provides a simple practical solution for designing efficient transposon vectors. PMID- 28645899 TI - Cloning the sigma2 receptor: Wandering 40 years to find an identity. PMID- 28645900 TI - Reply to Robinson et al.: Building the evidence base on the forest cover effects of community titling. PMID- 28645901 TI - Antenatal thoracoamniotic shunting in congenital cystic adenomatoid malformation. PMID- 28645902 TI - The cause of the stroke: a diagnostic uncertainty. AB - A 39-year-old man with a history of sickle cell disease (SCD) presented with left leg weakness. He had a normal CT head and CT angiogram, but MRI head showed multiple acute bilateral cortical infarcts including in the right precentral gyrus. The MRI findings were more in keeping with an embolic source rather than stroke related to SCD, although it could not be ruled out. He also had an echocardiogram which revealed a patent foramen ovale. He was treated with antiplatelet therapy and also had red blood cell exchange transfusion. His symptoms improved significantly and he was discharged with follow-up as an outpatient and a cardiology review. PMID- 28645903 TI - An unusual case of abdominal pains. PMID- 28645904 TI - Intra-articular lipoma of the hip. AB - Intra-articular lipoma of the hip is a rare entity, with only two reports published in the English-language literature. We present a case of successful arthroscopic resection of an intra-articular peripheral compartment lipoma in a 69-year-old woman with a coincident labral tear. This woman presented with left hip pain that developed gradually over 2 years and increased over 2 months. MRI showed a fat-intense mass in the anterior aspect of the hip joint, convincing for intra-articular lipoma. Physical examination in the operating room reproduced decreased range of motion and evidence of impingement but with a soft endpoint. Arthroscopy revealed an anterior intrasubstance labral tear, which was debrided. The mass was excised and confirmed as true lipoma on histology. The soft endpoint on examination illustrates that a large lipoma of the hip joint can cause clinical symptoms of impingement in the absence of bony abnormality or trauma. PMID- 28645905 TI - Obesity-related hypogonadism: a reversible condition. AB - Obesity is associated with hypogonadism. While this association is widely accepted, the underlying mechanisms remain unclear. Furthermore, obesity is a risk factor for hypogonadism and conversely hypogonadism may be a risk factor for obesity. We present the case of a morbidly obese man aged 30 years with hypogonadotrophic hypogonadism that underwent a Roux-en-Y gastric bypass operation. Following the surgical treatment of his obesity, the testosterone level returned to normal with improvements in hypogonadal symptoms, which allowed discontinuation of exogenous testosterone therapy. This case report demonstrates reversal of hypogonadism following weight loss with restoration of gonadal function. PMID- 28645912 TI - On being sick: Musings about kindness, side effects, and slowing down. PMID- 28645906 TI - An umbilical bleeding nodule. PMID- 28645913 TI - Enteroviral T-cell encephalitis related to immunosuppressive therapy including rituximab. PMID- 28645914 TI - Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone. AB - The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. PMID- 28645915 TI - Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats. AB - Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 MUg/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 hour) access to cocaine, whereas it did not affect the self administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects. PMID- 28645916 TI - Structures and dynamics of hibernating ribosomes from Staphylococcus aureus mediated by intermolecular interactions of HPF. AB - In bacteria, ribosomal hibernation shuts down translation as a response to stress, through reversible binding of stress-induced proteins to ribosomes. This process typically involves the formation of 100S ribosome dimers. Here, we present the structures of hibernating ribosomes from human pathogen Staphylococcus aureus containing a long variant of the hibernation-promoting factor (SaHPF) that we solved using cryo-electron microscopy. Our reconstructions reveal that the N-terminal domain (NTD) of SaHPF binds to the 30S subunit as observed for shorter variants of HPF in other species. The C-terminal domain (CTD) of SaHPF protrudes out of each ribosome in order to mediate dimerization. Using NMR, we characterized the interactions at the CTD-dimer interface. Secondary interactions are provided by helix 26 of the 16S ribosomal RNA We also show that ribosomes in the 100S particle adopt both rotated and unrotated conformations. Overall, our work illustrates a specific mode of ribosome dimerization by long HPF, a finding that may help improve the selectivity of antimicrobials. PMID- 28645920 TI - Common garden test of range limits as predicted by a species distribution model in the annual plant Mimulus bicolor. AB - PREMISE OF THE STUDY: Direct tests of a species distribution model (SDM) were used to evaluate the hypothesis that the northern and southern edges of Mimulus bicolor's geographical range are limited by temperature and precipitation. METHODS: Climatic suitability was predicted using an SDM informed only by temperature and precipitation variables. These predictions were tested by growing plants in growth chambers with temperature and watering treatments informed by weather stations characteristic of environments at the geographic center, edges, and outside the range. An Aster analysis was used to assess whether treatments significantly affected lifetime flower production and to test for local adaptation. The relationship between climatic suitability and lifetime flower number in the growth chambers was also evaluated. KEY RESULTS: The temperature and watering treatments significantly affected lifetime flower number, although local adaptation was not detected. Flower production was significantly lower under the two edge treatments compared to the central treatment. While no flowers were produced under the beyond-south treatments, flower production was greatest under the beyond-north treatment. These results suggest a hard abiotic limit at the southern edge, and suitable temperature and precipitation conditions beyond the northern edge. While predicted climatic suitability was significantly lower at the range edges, there was no correlation between the climatic suitability of the weather stations' locations and flower production. CONCLUSIONS: These results suggest that temperature and precipitation play a significant role in defining the distribution of M. bicolor, but also indicate that dispersal limitation or metapopulation dynamics are likely important factors restricting access to habitable sites beyond the northern range limit. PMID- 28645917 TI - Multivalent binding of PWWP2A to H2A.Z regulates mitosis and neural crest differentiation. AB - Replacement of canonical histones with specialized histone variants promotes altering of chromatin structure and function. The essential histone variant H2A.Z affects various DNA-based processes via poorly understood mechanisms. Here, we determine the comprehensive interactome of H2A.Z and identify PWWP2A as a novel H2A.Z-nucleosome binder. PWWP2A is a functionally uncharacterized, vertebrate specific protein that binds very tightly to chromatin through a concerted multivalent binding mode. Two internal protein regions mediate H2A.Z-specificity and nucleosome interaction, whereas the PWWP domain exhibits direct DNA binding. Genome-wide mapping reveals that PWWP2A binds selectively to H2A.Z-containing nucleosomes with strong preference for promoters of highly transcribed genes. In human cells, its depletion affects gene expression and impairs proliferation via a mitotic delay. While PWWP2A does not influence H2A.Z occupancy, the C-terminal tail of H2A.Z is one important mediator to recruit PWWP2A to chromatin. Knockdown of PWWP2A in Xenopus results in severe cranial facial defects, arising from neural crest cell differentiation and migration problems. Thus, PWWP2A is a novel H2A.Z-specific multivalent chromatin binder providing a surprising link between H2A.Z, chromosome segregation, and organ development. PMID- 28645921 TI - The East Asian origin of the giant lobelias. AB - PREMISE OF THE STUDY: Rapid radiations are difficult to reconstruct when organismal diversification and biogeographic movement outpace the evolution of genes typically used in phylogenetic analyses. The 125 kb of unique sequence from complete plastid genomes (= plastomes) largely solves the molecular sampling problem, and taxon sampling that triangulates the base of each major subclade largely solves the long-branch attraction problem. This combination of molecular and phylogenetic sampling is used to reconstruct the cosmopolitan radiation of lobeliads, with special focus on the origin of the giant lobelias. METHODS: An alignment of 18 previously generated and 61 new plastomes was analyzed to produce the phylogenetic estimate upon which the biogeographic reconstruction was based. KEY RESULTS: Originating in southern Africa, the Lobeliaceae underwent a spectacular cosmopolitan radiation about 20 million years ago. One lineage colonized Madagascar and eastern Asia, which was the source area for the evolution of the giant lobelias. A second lineage colonized the Mediterranean and North America, in quick succession. South America and Australia were also colonized from South Africa, most likely as independent events, but detailed biogeographic reconstruction is limited by inferred extinction events. The south Pacific segregate genera Apetahia and Sclerotheca are inferred to have Hawaiian ancestry. The East African radiation independently reached Ethiopia, West Africa, and Brazil. CONCLUSIONS: With adequate molecular and taxon sampling, many details of rapid radiations can be accurately inferred. However, not all lineages survived, and analyses of extant species cannot recover details that have been lost due to extinction. PMID- 28645918 TI - Phosphorylation of Argonaute proteins affects mRNA binding and is essential for microRNA-guided gene silencing in vivo. AB - Argonaute proteins associate with microRNAs and are key components of gene silencing pathways. With such a pivotal role, these proteins represent ideal targets for regulatory post-translational modifications. Using quantitative mass spectrometry, we find that a C-terminal serine/threonine cluster is phosphorylated at five different residues in human and Caenorhabditis elegans In human, hyper-phosphorylation does not affect microRNA binding, localization, or cleavage activity of Ago2. However, mRNA binding is strongly affected. Strikingly, on Ago2 mutants that cannot bind microRNAs or mRNAs, the cluster remains unphosphorylated indicating a role at late stages of gene silencing. In C. elegans, the phosphorylation of the conserved cluster of ALG-1 is essential for microRNA function in vivo Furthermore, a single point mutation within the cluster is sufficient to phenocopy the loss of its complete phosphorylation. Interestingly, this mutant retains its capacity to produce and bind microRNAs and represses expression when artificially tethered to an mRNA Altogether, our data suggest that the phosphorylation state of the serine/threonine cluster is important for Argonaute-mRNA interactions. PMID- 28645922 TI - Management of high-grade dysplasia of the cystic duct after cholecystectomy. AB - High-grade dysplasia (HGD) of the cystic duct margin without evidence of concurrent malignancy is a rare occurrence. We present a case of a 36-year-old woman who developed gallstone pancreatitis and subsequently underwent a laparoscopic cholecystectomy. On histopathology, she was found to have HGD at the cystic duct margin. Following evaluation, she underwent excision of the cystic duct remnant with no malignancy being present on final pathology. We present this case to discuss the management of cystic duct dysplasia in the absence of gallbladder malignancy. PMID- 28645923 TI - The connection between acute otitis media and the acute abdomen. AB - A female aged 9 years with a recent episode of acute otitis media (AOM) presented to her primary care physician with complaints of severe abdominal pain with right lower quadrant rebound tenderness, suggestive of an acute surgical abdomen. Neurological examination was normal on presentation. She was transferred to the local children's hospital for workup of appendicitis, during which she began exhibiting ataxia and slurred speech. Further evaluation revealed mastoiditis, venous sinus thrombosis and subdural empyema. Appendicitis was ruled out. We describe the first documented case of neurological complications of AOM presenting as an acute surgical abdomen without initial neurological findings. PMID- 28645924 TI - Anterior abdominal wall extraosseous osteosarcoma, occurring 40 years after para aortic irradiation. AB - Extraskeletal osteosarcomas (OSs) are highly malignant soft tissue tumours associated with a poor prognosis. Only a few records of these rare aggressive neoplasms have been reported in the literature.We describe the case of a 49-year old man, who presented to our tertiary care centre with a painful isolated lump around the umbilicus. After surgical biopsy, imaging and subsequent pathological analysis, the swelling was diagnosed to be a localised extraskeletal OS. He received previous radiation as treatment for testicular seminoma 40 years ago, which has been in remission ever since. He also happens to have testicular hydrocele since 10 years. He was subjected to resection and free flap reconstruction complicated by lower anterior abdominal wall haematoma and large pseudoaneurysm of the left femoral artery. Patient completed 60 Gy of adjuvant electron beam irradiation for close margins and is scheduled for adjuvant chemotherapy. We describe a brief account of his illness. PMID- 28645925 TI - Strangulated gastric prolapse through a gastrostomy site requiring emergent partial gastrectomy. AB - Strangulated gastric prolapse through a percutaneous endoscopic gastrostomy tract is a rare and potentially life-threatening complication that requires surgical intervention. We describe a case of a 74-year-old woman who was debilitated and ventilator-dependent and who presented with acute gastric prolapse with resultant ischaemic necrosis. The patient underwent an emergent exploratory laparotomy, partial gastrectomy, repair of gastrostomy defect and placement of a gastrojejunostomy feeding tube remote to the previous location. Literature on gastric prolapse in adult patients is sparse, and therefore treatment is not standardised. In this patient with strangulated tissue, the principles of management included the assessment of gastric mucosa viability, resection of ischaemic tissue and closure of the gastrostomy defect. PMID- 28645926 TI - Nasopharyngeal glial heterotopia with delayed postoperative meningitis. AB - A male infant, who underwent radical resection of a large glial heterotopia at the nasopharynx at 8 days, developed delayed postoperative bacterial meningitis at 9 months. Neuroradiological examination clearly demonstrated that meningitis had occurred because of the intracranial and extracranial connections, which were scarcely seen in the perioperative period. A transsphenoidal extension of hypothalamic hamartoma is possible because the connection started from the right optic nerve, running through the transsphenoidal canal in the sphenoid bone and terminating at the recurrent mass in the nasopharyngeal region. PMID- 28645927 TI - Is this muscle pain caused by my statin? PMID- 28645928 TI - Molecular mechanisms in cardiomyopathy. AB - Cardiomyopathies represent a heterogeneous group of diseases that negatively affect heart function. Primary cardiomyopathies specifically target the myocardium, and may arise from genetic [hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), mitochondrial cardiomyopathy] or genetic and acquired [dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM)] etiology. Modern genomics has identified mutations that are common in these populations, while in vitro and in vivo experimentation with these mutations have provided invaluable insight into the molecular mechanisms native to these diseases. For example, increased myosin heavy chain (MHC) binding and ATP utilization lead to the hypercontractile sarcomere in HCM, while abnormal protein-protein interaction and impaired Ca2+ flux underlie the relaxed sarcomere of DCM. Furthermore, expanded access to genetic testing has facilitated identification of potential risk factors that appear through inheritance and manifest sometimes only in the advanced stages of the disease. In this review, we discuss the genetic and molecular abnormalities unique to and shared between these primary cardiomyopathies and discuss some of the important advances made using more traditional basic science experimentation. PMID- 28645929 TI - Biophysical stimulation for in vitro engineering of functional cardiac tissues. AB - Engineering functional cardiac tissues remains an ongoing significant challenge due to the complexity of the native environment. However, our growing understanding of key parameters of the in vivo cardiac microenvironment and our ability to replicate those parameters in vitro are resulting in the development of increasingly sophisticated models of engineered cardiac tissues (ECT). This review examines some of the most relevant parameters that may be applied in culture leading to higher fidelity cardiac tissue models. These include the biochemical composition of culture media and cardiac lineage specification, co culture conditions, electrical and mechanical stimulation, and the application of hydrogels, various biomaterials, and scaffolds. The review will also summarize some of the recent functional human tissue models that have been developed for in vivo and in vitro applications. Ultimately, the creation of sophisticated ECT that replicate native structure and function will be instrumental in advancing cell-based therapeutics and in providing advanced models for drug discovery and testing. PMID- 28645931 TI - A potential role of the unfolded protein response in post-transplant cancer. AB - Cancer is one of the major causes of mortality in organ transplant patients receiving immunosuppressive regimen based on Cyclosporin A (CsA). Organ transplantation and chronic immunosuppression are typically associated with skin cancers (both squamous cell carcinoma and melanoma) and renal cell carcinoma (RCC). Recent studies have shown that in addition to its immunosuppressive effects, accounted for by the inhibition of calcineurin and the modulation of the transcriptional programme of lymphocytes, CsA also directly stimulates the growth and aggressive behaviour of various cancer cells. Using renal carcinogenesis as an example, we discuss the current evidence for a role of cellular proteostasis, i.e. the regulation of the production, maturation and turnover of proteins in eukaryotic cells, in tumorigenesis arising under conditions of chronic immunosuppression. We present the recent studies showing that CsA induces the unfolded protein response (UPR) in normal and transformed kidney cells. We examine how the UPR might be important, considering in particular the genomic analyses showing the existence of a correlation between the levels of expression of the actors of the UPR, the chaperones of the endoplasmic reticulum (ER) and the aggressiveness of renal carcinoma. The UPR may offer a possible explanation for how immunosuppressive regimens based on CsA promote renal carcinogenesis. We discuss the opportunities offered by this biological knowledge in terms of screening, diagnosis and treatment of post-transplant cancers, and propose possible future translational studies examining the role of tumour proteostasis and the UPR in this context. PMID- 28645930 TI - Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. AB - The principle steroidal androgens are testosterone and its metabolite 5alpha dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5alpha-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. PMID- 28645932 TI - A Functional NaV1.7-NaVAb Chimera with a Reconstituted High-Affinity ProTx-II Binding Site. AB - The NaV1.7 voltage-gated sodium channel is implicated in human pain perception by genetics. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations results in congenital insensitivity to pain. Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a surrogate target strategy approach employing chimeras with the bacterial channel NaVAb. In this report we describe the design, synthesis, purification, and characterization of a chimera containing part of the voltage sensor domain 2 (VSD2) of NaV1.7. Importantly, this chimera, DII S1-S4, forms functional sodium channels and is potently inhibited by the NaV1.7 VSD2 targeted peptide toxin ProTx-II. Further, we show by [125I]ProTx-II binding and surface plasmon resonance that the purified DII S1-S4 protein retains high affinity ProTx-II binding in detergent. We employed the purified DII S1-S4 protein to create a scintillation proximity assay suitable for high-throughput screening. The creation of a NaV1.7-NaVAb chimera with the VSD2 toxin binding site provides an important tool for the identification of novel NaV1.7 inhibitors and for structural studies to understand the toxin-channel interaction. PMID- 28645933 TI - Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species-Mediated Mitochondrial Dysfunction. AB - BACKGROUND: Pulmonary arterial remodeling, a main characteristic of hypoxic pulmonary hypertension, can gradually reverse once oxygen has been restored. Previous studies documented that apoptosis increased markedly during the reversal of remodeled pulmonary arteries, but the types of cells and mechanisms related to the apoptosis have remained elusive. This study aimed to determine whether pulmonary artery smooth muscle cell (PASMC)-specific apoptosis was involved in the reoxygenation-induced reversal of hypoxic pulmonary arterial remodeling and elucidate the underlying mechanism. METHODS AND RESULTS: Hypoxic pulmonary hypertension was induced in adult male Sprague-Dawley rats (n=6/group) by chronic hypobaric hypoxia. and the hypoxic pulmonary hypertension rats were then transferred to a normoxia condition. During reoxygenation, hypoxia-induced pulmonary arterial remodeling gradually reversed. The reversal of remodeled pulmonary arteries was associated with increased H2O2 and with changes in lung expression of cleaved caspase3/PARP, Bax, and Bcl-2, consistent with increased apoptosis. The PASMC apoptosis, in particular, increased remarkably during this reversal. In vitro, reoxygenation induced the apoptosis of cultured rat primary PASMCs accompanied by increased mitochondrial reactive oxygen species, mitochondrial dysfunction, and the release of cytochrome C from mitochondria to cytoplasm. Clearance of reactive oxygen species alleviated mitochondrial dysfunction as well as the release of cytochrome C and, finally, decreased PASMC apoptosis. CONCLUSIONS: Reoxygenation-induced apoptosis of PASMCs is implicated in the reversal of hypoxic pulmonary arterial remodeling, which may be attributed to the mitochondrial reactive oxygen species-mediated mitochondrial dysfunction. PMID- 28645934 TI - Repeated Measurements of Cardiac Biomarkers in Atrial Fibrillation and Validation of the ABC Stroke Score Over Time. AB - BACKGROUND: Cardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker-based ABC stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short-term variability of the cardiac biomarkers and evaluate whether the ABC stroke risk score provides a stable short-term risk estimate. METHODS AND RESULTS: According to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide were measured with high-sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the ABC stroke score at 2 months. The average changes in biomarker levels during 2 months were small (median change cardiac troponin T +2.8%, troponin I +2.0%, and N terminal pro-B-type natriuretic peptide +13.5%) and within-subject correlation was high (all >=0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person years of follow-up and 96 stroke/systemic embolic events, the ABC stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65-0.76) as compared with 0.70 (95% CI, 0.65-0.75) at baseline. The ABC stroke score remained well calibrated using predefined risk classes. CONCLUSIONS: In patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker based ABC stroke score during 2 months are small. The prognostic information by the ABC stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. PMID- 28645935 TI - Liver Cirrhosis in Patients With Atrial Fibrillation: Would Oral Anticoagulation Have a Net Clinical Benefit for Stroke Prevention? AB - BACKGROUND: Patients with liver cirrhosis have been excluded from randomized clinical trials of oral anticoagulation therapy for stroke prevention in atrial fibrillation. We hypothesized that patients with liver cirrhosis would have a positive net clinical benefit for oral anticoagulation when used for stroke prevention in atrial fibrillation. METHODS AND RESULTS: This study used the National Health Insurance Research Database in Taiwan. Among 289 559 atrial fibrillation patients aged >=20 years, there were 10 336 with liver cirrhosis, and 9056 of them having a CHA2DS2-VASc score >=2 were divided into 3 groups, that is, no treatment, antiplatelet therapy, and warfarin. Patients with liver cirrhosis had a higher risk of ischemic stroke (hazard ratio=1.10, P=0.046) and intracranial hemorrhage (hazard ratio=1.20, P=0.043) compared with those without. Among patients with liver cirrhosis, patients taking antiplatelet therapy had a similar risk of ischemic stroke (hazard ratio=1.02, 95%CI=0.88-1.18) compared to those without antithrombotic therapies, but the risk was significantly lowered among warfarin users (hazard ratio=0.76, 95%CI=0.58-0.99). For intracranial hemorrhage, there were no significant differences between those untreated and those taking antiplatelet therapy or warfarin. The use of warfarin was associated with a positive net clinical benefit compared with being untreated or receiving only antiplatelet therapy. CONCLUSIONS: For atrial fibrillation patients with liver cirrhosis in the current analysis of an observational study, warfarin use was associated with a lower risk of ischemic stroke and a positive net clinical benefit compared with nontreatment, and thus, thromboprophylaxis should be considered for such patients. PMID- 28645936 TI - Angiopoietin-Like Protein 4 Is a High-Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type-2 Diabetic Patients. AB - BACKGROUND: ANGPTL4 (angiopoietin-like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high-density lipoprotein (HDL). However, it is not defined whether ANGPTL4 in HDLs could affect HDL metabolism and function in type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: ANGPTL4 levels in the circulation and HDLs were quantified in nondiabetic participants (n=201, 68.7% females) and T2DM patients (n=185, 66.5% females). HDLs were isolated from nondiabetic controls and T2DM patients to assess cholesterol efflux or subjected to endothelial lipase (EL)-overexpressed HEK293 cells for EL hydrolysis in vitro. The association between ANGPTL4 in HDLs and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDLs of ANGPTL4+/+ and ANGPTL4-/- mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL4 levels in the plasma and HDLs were 1.7- and 2.0-fold higher in T2DM patients than nondiabetic controls, respectively (P<0.0001). Multivariable analysis demonstrated that per 1 doubling increase of ANGPTL4 levels in HDLs, the changes amounted to +0.27% cholesterol efflux (P=0.03), +0.06 MUg/mL apolipoprotein A-I (P=0.09) and -9.41 MUg/L serum amyloid A (P=0.02) in nondiabetic controls. In T2DM patients, the corresponding estimates were -0.06% cholesterol efflux (P=0.10), -0.06 MUg/mL apolipoprotein A-I (P=0.38), and +3.64 MUg/L serum amyloid A (P=0.72). HDLs isolated from ANGPTL4-/- mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL4+/+ littermates. CONCLUSIONS: Physically, ANGPTL4 in HDLs protected HDLs from hydrolysis. Resulting from increased circulating ANGPTL4 levels in T2DM, ANGPTL4 levels in HDLs were elevated but with compromised inhibitory effect on EL, leading to increased HDL hydrolysis and dysfunction. PMID- 28645937 TI - Quality of Care in Chinese Hospitals: Processes and Outcomes After ST-segment Elevation Myocardial Infarction. AB - BACKGROUND: China has gaps in the quality of care provided to patients with ST elevation myocardial infarction, but little is known about how quality varies between hospitals. METHODS AND RESULTS: Using nationally representative data from the China PEACE-Retrospective AMI Study, we characterized the quality of care for ST-elevation myocardial infarction at the hospital level and examined variation between hospitals. Two summary measures were used to describe the overall quality of care at each hospital and to characterize variations in quality between hospitals in 2001, 2006, and 2011. The composite rate measured the proportion of opportunities a hospital had to deliver 6 guideline-recommended treatments for ST elevation myocardial infarction that were successfully met, while the defect-free rate measured the proportion of patients at each hospital receiving all guideline recommended treatments for which they were eligible. Risk-standardized mortality rates were calculated. Our analysis included 12 108 patients treated for ST elevation myocardial infarction at 162 hospitals. The median composite rate increased from 56.8% (interquartile range [IQR], 45.9-72.0) in 2001 to 80.5% (IQR, 74.7-84.8) in 2011; however, substantial variation remained in 2011 with defect-free rates ranging from 0.0% to 76.9%. The median risk-standardized mortality rate increased from 9.9% (IQR, 9.1-11.7) in 2001 to 12.6% (IQR, 10.9 14.6) in 2006 before falling to 10.4% (IQR, 9.1-12.4) in 2011. CONCLUSIONS: Higher rates of guideline-recommended care and a decline in variation between hospitals are indicative of an improvement in quality. Although some variation persisted in 2011, very top-performing hospitals missed few opportunities to provide guideline-recommended care. Quality improvement initiatives should focus on eliminating residual variation as well as measuring and improving outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883. PMID- 28645938 TI - Practice Patterns for Acute Ischemic Stroke Workup: A Longitudinal Population Based Study. AB - BACKGROUND: We examined practice patterns of inpatient testing to identify stroke etiologies and treatable risk factors for acute ischemic stroke recurrence. METHODS AND RESULTS: We identified stroke cases and related diagnostic testing from four 1-year study periods (July 1993 to June 1994, 1999, 2005, and 2010) of the Greater Cincinnati/Northern Kentucky Stroke Study. Patients aged >=18 years were included. We focused on evaluation of extracranial arteries for carotid stenosis and assessment of atrial fibrillation because randomized controlled trials supported treatment of these conditions for stroke prevention across all 4 study periods. In each study period, we also recorded stroke etiology, as determined by diagnostic testing and physician adjudication. An increasing proportion of stroke patients received assessment of both extracranial arteries and the heart over time (50%, 58%, 74%, and 78% in the 1993-1994, 1999, 2005, and 2010 periods, respectively; P<0.0001 for trend), with the most dramatic individual increases in echocardiography (57%, 63%, 77%, and 83%, respectively). Concurrently, we observed a decrease in strokes of unknown etiology (47%, 48%, 41%, and 38%, respectively; P<0.0001 for trend). We also found a significant increase in strokes of other known causes (32%, 25%, 45% and 59%, respectively; P<0.0001 for trend). CONCLUSIONS: Stroke workup for treatable causes of stroke are being used more frequently over time, and this is associated with a decrease in cryptogenic strokes. Future study of whether better determination of treatable stroke etiologies translates to a decrease in stroke recurrence at the population level will be essential. PMID- 28645939 TI - Combined BTK and PI3Kdelta Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model. AB - Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kdelta is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3Kdelta and BTK inhibitors.Experimental Design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kdelta inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. Although single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over 2 weeks compared with either single agent. The combination reduced tumor proliferation, NF-kappaB signaling, and expression of BCL-xL and MCL-1 more potently than single-agent therapy.Conclusions: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies. Clin Cancer Res; 23(19); 5814-23. (c)2017 AACR. PMID- 28645940 TI - T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk. AB - Adoptive therapy with T-cell receptor (TCR)-engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross reactivity toward noncognate peptides. Clin Cancer Res; 23(20); 6012-20. (c)2017 AACR. PMID- 28645941 TI - A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta Selective Inhibitor, in Patients with Advanced Solid Tumors. AB - Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110beta could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate competitive, selective inhibitor of PI3Kbeta.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (>=24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (>=34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981-92. (c)2017 AACR. PMID- 28645942 TI - Mutational Heterogeneity in APC and KRAS Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis. AB - Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model.Experimental Design: High-depth next generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n = 59) and crypts (n = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues.Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed.Conclusions: The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. Clin Cancer Res; 23(19); 5936-47. (c)2017 AACR. PMID- 28645945 TI - How can we ensure that the coroner's autopsy is not an invasion of human rights? AB - BACKGROUND: Despite public inquiries, and some changes to legislation following high-profile multiple homicides that were not detected by autopsy, coroners continue to rely largely on the autopsy. Regardless of the extent of quality failings and excess deaths at some hospitals, not detected through the coroner system, the autopsy is scarcely used by hospitals to monitor standards and educate. OBJECTIVE: To explore when a compulsory medicolegal autopsy should, and should not, be used. METHOD: Two hundred and thirty-six cases referred to a senior coroner were evaluated by pathologists with long experience of forensic, coronial and hospital autopsies, using detailed antecedent medical and circumstantial information: after their advice, the senior coroner decided what kind of autopsy provided sufficient information for his purposes. RESULTS: In nearly 40% (n=88) of deaths where the senior coroner accepted jurisdiction, issues raised could be resolved through analysis of medical records and antecedent information, supplemented only by detailed external examination of the body. CONCLUSIONS: Timely provision of sufficient information allows informed decisions about the requirement for, and nature and extent of, medical investigations into a death: unnecessary post mortem dissection is avoided, protecting the rights, under Articles 8 and 9 of the Human Rights Act 1998, of the bereaved to privacy, family life and religious practice. Although improvements in healthcare can undoubtedly result from detailed coroners' inquiries, those deaths where the matters investigated relate only to the accuracy of a natural cause of death or sit with a healthcare provider's internal quality assurance, should be investigated by the healthcare system in collaboration with the bereaved. PMID- 28645943 TI - The structure of the tetanus toxin reveals pH-mediated domain dynamics. AB - The tetanus neurotoxin (TeNT) is a highly potent toxin produced by Clostridium tetani that inhibits neurotransmission of inhibitory interneurons, causing spastic paralysis in the tetanus disease. TeNT differs from the other clostridial neurotoxins by its unique ability to target the central nervous system by retrograde axonal transport. The crystal structure of the tetanus toxin reveals a "closed" domain arrangement stabilised by two disulphide bridges, and the molecular details of the toxin's interaction with its polysaccharide receptor. An integrative analysis combining X-ray crystallography, solution scattering and single particle electron cryo-microscopy reveals pH-mediated domain rearrangements that may give TeNT the ability to adapt to the multiple environments encountered during intoxication, and facilitate binding to distinct receptors. PMID- 28645946 TI - Risk factors for admission at three urban emergency departments in England: a cross-sectional analysis of attendances over 1 month. AB - OBJECTIVE: To investigate factors associated with unscheduled admission following presentation to emergency departments (EDs) at three hospitals in England. DESIGN AND SETTING: Cross-sectional analysis of attendance data for patients from three urban EDs in England: a large teaching hospital and major trauma centre (site 1) and two district general hospitals (sites 2 and 3). Variables included patient age, gender, ethnicity, deprivation score, arrival date and time, arrival by ambulance or otherwise, a variety of ED workload measures, inpatient bed occupancy rates and admission outcome. Coding inconsistencies in routine ED data used for this study meant that diagnosis could not be included. OUTCOME MEASURE: The primary outcome for the study was unscheduled admission. PARTICIPANTS: All adults aged 16 and older attending the three inner London EDs in December 2013. Data on 19 734 unique patient attendances were gathered. RESULTS: Outcome data were available for 19 721 attendances (>99%), of whom 6263 (32%) were admitted to hospital. Site 1 was set as the baseline site for analysis of admission risk. Risk of admission was significantly greater at sites 2 and 3 (adjusted OR (AOR) relative to site 1 for site 2 was 1.89, 95% CI 1.74 to 2.05, p<0.001) and for patients of black or black British ethnicity (AOR 1.29, 1.16 to 1.44, p<0.001). Deprivation was strongly associated with admission. Analysis of departmental and hospital-wide workload pressures gave conflicting results, but proximity to the "4-hour target" (a rule that limits patient stays in EDs to 4 hours in the National Health Service in England) emerged as a strong driver for admission in this analysis (AOR 3.61, 95% CI 3.30 to 3.95, p<0.001). CONCLUSION: This study found statistically significant variations in odds of admission between hospital sites when adjusting for various patient demographic and presentation factors, suggesting important variations in ED-level and clinician-level behaviour relating to admission decisions. The 4-hour target is a strong driver for emergency admission. PMID- 28645947 TI - Role, structure and effects of medical tourism in Africa: a systematic scoping review protocol. AB - INTRODUCTION: Some patients travel out of, while others come into Africa for medical care through a growing global phenomenon referred to as medical tourism (MT): the travel in search of medical care that is either unavailable, unaffordable or proscribed at home healthcare systems. While some castigate MT as promoting healthcare inequity, others endorse it as a revenue generator, promising local healthcare system strengthening. Currently, however, the understanding of this component of healthcare in Africa is inadequate. This study seeks to determine the level of knowledge on the role, structure and effect of MT in Africa as it relates to healthcare systems in the region. METHODS: Conduct a systematic scoping review to outline the role, structure and effect of MT in Africa. Databases: Academic Search Complete, Business Source Complete. Studies mapped in two stages: (1) mapping the studies based on the relevance of their titles and subject descriptors; (2) applying further inclusion criteria on studies from stage 1. Two reviewers will independently assess study quality and abstract data. Both quantitative and qualitative data analysis will be performed, using STATA V.13 and NVIVO, respectively. ETHICS AND DISSEMINATION: The study results will be disseminated by publication in peer-reviewed journals and findings presented at academic and industry conferences related to MT, public health, health systems strengthening and tourism. DISCUSSION: MT spurs cutting edge medical technologies, techniques and best practices in healthcare delivery. The two-tier healthcare landscape in Africa, however, presents an exceptionally unique context in which to situate this study. Much has been written about MT globally, but not much is known about the phenomenon in Africa; hence the appropriateness of this scientific assessment of MT in the region. By elucidating the role, structure and effect of this phenomenon, this study hopes to contribute to health systems strengthening in Africa. PROSPERO REGISTRATION NUMBER: CRD42016039745. PMID- 28645948 TI - The relationship between bicycle commuting and perceived stress: a cross sectional study. AB - INTRODUCTION: Active commuting - walking and bicycling for travel to and/or from work or educational addresses - may facilitate daily, routine physical activity. Several studies have investigated the relationship between active commuting and commuting stress; however, there are no studies examining the relationship between solely bicycle commuting and perceived stress, or studies that account for environmental determinants of bicycle commuting and stress. The current study evaluated the relationship between bicycle commuting, among working or studying adults in a dense urban setting, and perceived stress. METHODS: A cross-sectional study was performed with 788 adults who regularly travelled to work or study locations (excluding those who only commuted on foot) in Barcelona, Spain. Participants responded to a comprehensive telephone survey concerning their travel behaviour from June 2011 through to May 2012. Participants were categorised as either bicycle commuters or non-bicycle commuters, and (based on the Perceived Stress Scale, PSS-4) as either stressed or non-stressed. Multivariate Poisson regression with robust variance models of stress status based on exposures with bicycle commuting were estimated and adjusted for potential confounders. RESULTS: Bicycle commuters had significantly lower risk of being stressed than non-bicycle commuters (Relative Risk; RR (95% CI)=0.73 (0.60 to 0.89), p=0.001). Bicycle commuters who bicycled 4 days per week (RR (95% CI)=0.42 (0.24 to 0.73), p=0.002) and those who bicycled 5 or more days per week (RR (95% CI)=0.57 (0.42 to 0.77), p<0.001) had lower risk of being stressed than those who bicycled less than 4 days. This relationship remained statistically significant after adjusting for individual and environmental confounders and when using different cut-offs of perceived stress. CONCLUSIONS: Stress reduction may be an important consequence of routine bicycle use and should be considered by decision makers as another potential benefit of its promotion. PMID- 28645949 TI - Double-blind randomised controlled trial of the independent and synergistic effect of Spirulina maxima with exercise (ISESE) on general fitness, lipid profile and redox status in overweight and obese subjects: study protocol. AB - INTRODUCTION: In order to reduce cardiovascular disease risk factors, a healthy diet must include dietary antioxidants from different sources (eg, Spirulina maxima) and regular practice of exercise should be promoted. There is some evidence from animal studies that S. maxima and exercise decrease cardiovascular disease risks factors. However, very few studies have proved the independent or synergistic effect of S. maxima plus exercise in humans. This study attempts to address the independent and synergistic effects in overweight and obese subjects participating in a systematic physical exercise programme at moderate intensity on general fitness, plasma lipid profile and antioxidant capacity. METHODS AND ANALYSIS: Using a randomised, double-blind, placebo-controlled, counterbalanced crossover study design, 80 healthy overweight and obese subjects will be evaluated during a 12-week isoenergetic diet accompanied by 4.5 g/day S. maxima intake and/or a physical systematic exercise programme at moderate intensity. Body composition, oxygen uptake, heart rate, capillary blood lactate, plasma concentrations of triacylglycerols, total, low-density and high-density lipoprotein cholesterol, antioxidant status, lipid oxidation, protein carbonyls, superoxide dismutase, catalase, glutathione, glutathione peroxidase, glutathione reductase and paraoxonase will be assessed. ETHICS AND DISSEMINATION: This study and all the procedures have been approved by the Universidad Autonoma de Ciudad Juarez Bioethics Committee. Findings will be disseminated through peer-reviewed journals, national and international conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02837666. PMID- 28645950 TI - Variation in the prevalence of urinary catheters: a profile of National Health Service patients in England. AB - INTRODUCTION: Harm from catheter-associated urinary tract infections is a common, potentially avoidable, healthcare complication. Variation in catheter prevalence may exist and provide opportunity for reducing harm, yet to date is poorly understood. This study aimed to determine variation in the prevalence of urinary catheters between patient groups, settings, specialities and over time. METHODS: A prospective study (July 2012 to April 2016) of National Health Service (NHS) patients surveyed by healthcare professionals, following a standardised protocol to determine the presence of a urinary catheter and duration of use, on 1 day per month using the NHS Safety Thermometer. RESULTS: 1314 organisations (253 NHS trusts) and 9 266 284 patients were included. Overall, 12.9% of patients were catheterised, but utilisation varied. There was higher utilisation of catheters in males (15.7% vs 10.7% p<0.001) and younger people (18-70 year 14.0% vs >70 year 12.8% p<0.001), utilisation was highest in hospital settings (18.6% p<0.001), particularly in critical care (76.6% p<0.001). Most catheters had been in situ <28 days (72.9% p<0.001). No clinically significant changes were seen over time in any setting or specialty. CONCLUSION: Catheter prevalence in patients receiving NHS-funded care varies according to gender, age, setting and specialty, being most prevalent in males, younger people, hospitals and critical care. Utilisation has changed only marginally over 46 months, and further guidance is indicated to provide clarity for clinicians on the insertion and removal of catheters to supplement the existing guidance on care. PMID- 28645951 TI - Effects of socioeconomic factors on cardiovascular-related symptoms among residents in Fukushima after the Great East Japan Earthquake: a cross-sectional study using data from the Fukushima Health Management Survey. AB - OBJECTIVE: To investigate the association between socioeconomic factors and the exacerbation of cardiovascular symptoms among evacuees after the Great East Japan Earthquake. METHODS: A sample of 73 433 individuals was included in the Fukushima Health Management Survey. Self-report questionnaires were used to determine the influence of socioeconomic factors including living arrangements, loss of employment and decreased income on the exacerbation of headache, dizziness, palpitations and shortness of breath. Odds ratios (ORs) and 95% CIs of the effect of socioeconomic factors were estimated for each symptom using multiple logistic regression analyses. RESULTS: Exacerbation of headaches was reported by 1893 individuals, dizziness by 1229, palpitations by 1085 and shortness of breath by 626 individuals. Evacuation accommodation was associated with all of these symptoms. Compared with participants living in their own home (OR=1.00), individuals living in relatives' homes had increased probability of experiencing exacerbation of headache (1.58; 95% CI 1.19 to 2.09) and dizziness (1.42; 95% CI 1.02 to 1.98); those living in rental housing or apartments experienced exacerbation of headache (1.54; 95% CI 1.32 to 1.80), dizziness (1.45; 95% CI 1.20 to 1.75), palpitations (1.25; 95% CI 1.03 to 1.51) and shortness of breath (1.76; 95% CI 1.35 to 2.28); participants living in evacuation shelters experienced exacerbation of headache (1.80; 95% CI 1.09 to 2.96); and refugees living in temporary housing also experienced exacerbation of headache (1.42; 95% CI 1.15 to 1.72), dizziness (1.40; 95% CI 1.09 to 1.79) and shortness of breath (1.49; 95% CI 1.07 to 2.08). Compared with the evacuees who retained their jobs, unemployed individuals showed increased probability of exacerbation of headache (1.28, 95% CI 1.12 to 1.46), dizziness (1.26, 95% CI 1.07 to 1.48) and palpitations (1.21, 95% CI 1.01 to 1.45). Decreased income was associated with exacerbation of headache (1.39, 95% CI 1.22 to 1.60). CONCLUSION: After the earthquake, living in non-home conditions was more likely to result in exacerbated cardiovascular symptoms among evacuees. Loss of employment was another risk factor related to exacerbated headache and dizziness. PMID- 28645952 TI - Title: Cervical cancer survivors' perceived cognitive complaints and supportive care needs in mainland China: a qualitative study. AB - OBJECTIVES: This study explores Chinese cervical cancer survivors' perceived cognitive complaints and relevant supportive care needs after primary cancer treatment. DESIGN: This study utilised a qualitative research design. A semi structured interview was used to probe cervical cancer patients' perceived cognitive complaints and supportive care needs. SETTING: This study was conducted at a secondary cancer care centre located in South China. PARTICIPANTS: 31 women with cervical cancer after primary cancer treatment, aged 18-60 years, were purposively selected using non-random sampling procedures. RESULTS: 31 cervical cancer survivors joined this study. Of these, 20 women (64.5%) reported cognitive complaints after cancer treatment. The most common complaint was loss of concentration (n=17, 85.0%). Perceived contributing factors to these cognitive complaints included chemotherapy (n=15, 75.0%) and ageing (n=8, 40.0%). These cognitive problems most commonly impacted daily living (n=20, 100%). Common supportive care needs included symptom management strategies (n=11, 55.0%) and counselling services (n=8, 40.0%). CONCLUSION: This study adds new insight into the growing body of research on cognitive complaints by cancer survivors, in particular Chinese cervical cancer survivors. Improved understanding of cognitive complaints could subsequently facilitate the development of relevant therapeutic interventions for prevention as well as the provision of supportive care services, such as educational and counselling services, to reduce cognitive impairment in women with cervical cancer. PMID- 28645953 TI - Effect of two additional interventions, test and reflection, added to standard cardiopulmonary resuscitation training on seventh grade students' practical skills and willingness to act: a cluster randomised trial. AB - OBJECTIVES: The aim of this research is to investigate if two additional interventions, test and reflection, after standard cardiopulmonary resuscitation (CPR) training facilitate learning by comparing 13-year-old students' practical skills and willingness to act. SETTINGS: Seventh grade students in council schools of two municipalities in south-east Sweden. DESIGN: School classes were randomised to CPR training only (O), CPR training with a practical test including feedback (T) or CPR training with reflection and a practical test including feedback (RT). Measures of practical skills and willingness to act in a potential life-threatening situation were studied directly after training and at 6 months using a digital reporting system and a survey. A modified Cardiff test was used to register the practical skills, where scores in each of 12 items resulted in a total score of 12-48 points. The study was conducted in accordance with current European Resuscitation Council guidelines during December 2013 to October 2014. PARTICIPANTS: 29 classes for a total of 587 seventh grade students were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: The total score of the modified Cardiff test at 6 months was the primary outcome. Secondary outcomes were the total score directly after training, the 12 individual items of the modified Cardiff test and willingness to act. RESULTS: At 6 months, the T and O groups scored 32 (3.9) and 30 (4.0) points, respectively (p<0.001), while the RT group scored 32 (4.2) points (not significant when compared with T). There were no significant differences in willingness to act between the groups after 6 months. CONCLUSIONS: A practical test including feedback directly after training improved the students' acquisition of practical CPR skills. Reflection did not increase further CPR skills. At 6-month follow-up, no intervention effect was found regarding willingness to make a life-saving effort. PMID- 28645954 TI - Assessing the impact of colonoscopy complications on use of colonoscopy among primary care physicians and other connected physicians: an observational study of older Americans. AB - OBJECTIVES: Psychological biases can distort treatment decision-making. The availability heuristic is one such bias, wherein events that are recent, vivid or easily imagined are readily 'available' to memory and are therefore judged more likely to occur than expected based on epidemiological data. We assessed if the occurrence of a serious colonoscopy complication for a primary care physician's patient influenced colonoscopy rates for the physician's other patients. DESIGN: Longitudinal study with time-varying exposure variables. SETTING/PARTICIPANTS: Individuals living in 51 hospital referral regions across the USA identified based on enrolment in fee-for-service Medicare during 2005-2010. We assigned patients to a primary care physician based on office visits during the prior 2 years. EXPOSURES: For each physician in each month, we calculated the proportion of patients assigned to them who had a colonoscopy. We identified two serious complications of which the primary care provider would very likely be aware: gastrointestinal bleed or perforation leading to hospitalisation or death within 14 days of colonoscopy. MAIN OUTCOME MEASURES: We employed Poisson regression models including physician fixed effects to assess the change in number of colonoscopies in the four quarters following an adverse colonoscopy event. RESULTS: We identified 5 360 191 patients assigned to 30 704 physicians. 4864 physicians (16%) had at least one patient with an adverse event. The estimated change in the quarterly number of colonoscopies among physicians' patients was significantly lower in quarter 2 following an adverse colonoscopy event (change= 2.1% (95% CI -3.4 to -0.8%)), before returning to the rate expected in the absence of an adverse event. CONCLUSIONS: Having a patient experience a serious adverse colonoscopy event was associated with a small and temporary decline in colonoscopy rates among a physician's other patients. This finding provides empirical evidence for the influence of notable adverse events on care, possibly due to the availability heuristic. PMID- 28645955 TI - Is there an ethnic variation in the epidemiology of gonorrhoea? A retrospective population-based study from northern Israel over 15 years between 2001 and 2015. AB - OBJECTIVE: To investigate the trends in the incidence of gonorrhoea through an extended period of time and to compare the epidemiology of gonorrhoea infection between 2 distinct ethnic groups (Jews and Arabs). DESIGN: A retrospective population-based cohort study was conducted on all consecutive patients diagnosed with gonorrhoea through the years 2001-2015. SETTING: National Department of Epidemiology of the Ministry of Health, Haifa District, Israel. PARTICIPANTS: A total of 837 reports on gonorrhoea were received, derived from 779 (93.1%) male and 58 (6.9%) female patients. Approximately 1 million people reside in the Haifa region. PRIMARY AND SECONDARY OUTCOME MEASURES: We examined the incidence rate of gonorrhoea among residents of Haifa District, northern Israel from 2001 to 2015, by reviewing archives of the Department of Epidemiology, Israeli Ministry of Health. Notified cases were stratified by age, gender and ethnicity. RESULTS: The overall gonorrhoea incidence was 6.4 cases per 100 000 population per year. The annual incidence rate dropped from 20.5 per 100 000 population in 2001 to a period of 2.2 cases per 100 000 population in 2005, showing a >9-fold decline. This was followed by a relatively steady increase of incidence of 2.5-4.5 per 100 000 population from 2006 to 2015. Men were predominantly more affected than women, with a 13.4-fold higher incidence rate. The most affected age group was residents between 25 and 34 years old. The estimated rate among Jews was 2.5-fold higher relative to Arabs. Only 1.3% recurrent episodes of gonorrhoea were reported. The prevalence of HIV positivity among patients with gonorrhoea is significantly higher than that of the general population (500.0 vs 88.1 cases per 100 000 population, respectively, p<0.001). CONCLUSIONS: Gonorrhoea incidence rate decreased dramatically until 2005, with no substantial subsequent fluctuations. The infection is much more prevalent among patients of Jewish ethnicity, possibly due to riskier sex practices. PMID- 28645956 TI - Exploring the components of physician volunteer engagement: a qualitative investigation of a national Canadian simulation-based training programme. AB - OBJECTIVES: Conceptual clarity on physician volunteer engagement is lacking in the medical literature. The aim of this study was to present a conceptual framework to describe the elements which influence physician volunteer engagement and to explore volunteer engagement within a national educational programme. SETTING: The context for this study was the Acute Critical Events Simulation (ACES) programme in Canada, which has successfully evolved into a national educational programme, driven by physician volunteers. From 2010 to 2014, the programme recruited 73 volunteer healthcare professionals who contributed to the creation of educational materials and/or served as instructors. METHOD: A conceptual framework was constructed based on an extensive literature review and expert consultation. Secondary qualitative analysis was undertaken on 15 semistructured interviews conducted from 2012 to 2013 with programme directors and healthcare professionals across Canada. An additional 15 interviews were conducted in 2015 with physician volunteers to achieve thematic saturation. Data were analysed iteratively and inductive coding techniques applied. RESULTS: From the physician volunteer data, 11 themes emerged. The most prominent themes included volunteer recruitment, retention, exchange, recognition, educator network and quasi-volunteerism. Captured within these interrelated themes were the framework elements, including the synergistic effects of emotional, cognitive and reciprocal engagement. Behavioural engagement was driven by these factors along with a cue to action, which led to contributions to the ACES programme. CONCLUSION: This investigation provides a preliminary framework and supportive evidence towards understanding the complex construct of physician volunteer engagement. The need for this research is particularly important in present day, where growing fiscal constraints create challenges for medical education to do more with less. PMID- 28645957 TI - Effect of e-cigarette advertisements and antismoking messages on explicit and implicit attitudes towards tobacco and e-cigarette smoking in 18-65-year-olds: a randomised controlled study protocol. AB - INTRODUCTION: Since the advent of e-cigarettes, e-cigarette advertising has escalated and companies are able to use marketing strategies that are not permissible for tobacco products. Research into the effect of e-cigarette advertising on attitudes towards tobacco and e-cigarettes is in its infancy. To date, no research has compared indirect (implicit) measures of attitude towards e cigarettes with direct (explicit) measures. Furthermore, little consideration has been given to how viewing online advertisements may have an effect on attitudes towards e-cigarettes or how positive attitudes to e-cigarettes may undermine antismoking public health messages. The objectives of this study are to investigate (1) the relationship between explicit and implicit attitudes towards tobacco and e-cigarettes, (2) the effect of e-cigarette advertising on these attitudes and (3) the effect of these attitudes on the efficacy of antismoking health messages. METHODS AND ANALYSIS: In experiment 1 an analysis of covariance will be conducted to determine whether viewing an e-cigarette advertisement, compared with a neutral image, has an effect on implicit or explicit attitudes towards tobacco and e-cigarettes, and if these attitudes differ between smokers, vapers and non-smokers aged 18 - 25 years. In experiment 2, moderation analysis will be conducted to assess whether attitudes towards e-cigarettes moderate the psychological efficacy of antismoking health messages in participants aged 18-65 years. In each experiment, attitudes will be measured preintervention and postintervention and 1 week later (n=150) in participants who are smokers (n=50), vapers (n=50) or non-smokers (n=50). ETHICS AND DISSEMINATION: Approval for this study has been given by the London South Bank University's (LSBU) Research Ethics Committee. The findings of these studies will be submitted for publication and disseminated via conferences. The results will be integrated into course provision for practitioners training at LSBU. PMID- 28645958 TI - Factors predicting self-reported medication low adherence in a large sample of adults in the US general population: a cross-sectional study. AB - OBJECTIVES: The study objective was to determine the level and correlates of self reported medication low adherence in the US general population. SETTING: A 30 min cross-sectional online survey was conducted with a national sample of adults. PARTICIPANTS: 9202 adults (aged 18+) who had filled at least three or more prescriptions at a community pharmacy in the past 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES: Self-reported medication adherence was measured with the 8-item Morisky Medication Adherence Scale. RESULTS: Low adherence was reported by 42.0%, 29.4% had medium adherence and 28.6% had high adherence. Low adherence was significantly associated with: lower age, being of Hispanic origin or African-American, having difficulty with healthcare, medication or transportation costs, needing the support of others to access primary care, health limiting activity, using multiple providers, infrequent visits to primary care providers and visiting an emergency department >3 times in last 12 months. CONCLUSIONS: A very high level of low medication adherence is seen in the general population, particularly for ethnic minorities, those who use multiple healthcare providers and those who experience barriers to access for regular primary care. As clinical, patient education and counselling, and healthcare policy initiatives are directed to tracking the problem of low medication adherence, these should be priority populations for research and interventions. PMID- 28645959 TI - Formal consensus to identify clinically important changes in management resulting from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. AB - OBJECTIVE: To define important changes in management arising from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Formal consensus study using literature review and cardiologist expert opinion to formulate consensus statements and setting up a consensus panel to review the statements (by completing a web-based survey, attending a face-to-face meeting to discuss survey results and modify the survey to reflect group discussion and completing the modified survey to determine which statements were in consensus). PARTICIPANTS: Formulation of consensus statements: four cardiologists (two CMR and two interventional) and six non-clinical researchers. Formal consensus: seven cardiologists (two CMR and three interventional, one echocardiography and one heart failure). Forty-nine additional cardiologists completed the modified survey. RESULTS: Thirty-seven draft statements describing changes in management following CMR were generated; these were condensed into 12 statements and reviewed through the formal consensus process. Three of 12 statements were classified in consensus in the first survey; these related to the role of CMR in identifying the cause of out-of-hospital cardiac arrest, providing a definitive diagnosis in patients found to have unobstructed arteries on angiography and identifying patients with left ventricular thrombus. Two additional statements were in consensus in the modified survey, relating to the ability of CMR to identify patients who have a poor prognosis after PPCI and assess ischaemia and viability in patients with multivessel disease. CONCLUSION: There was consensus that CMR leads to clinically important changes in management in five subgroups of patients who activate the PPCI pathway. PMID- 28645960 TI - Efficacy of adding a physiotherapy rehabilitation programme to arthroscopic management of femoroacetabular impingement syndrome: a randomised controlled trial (FAIR). AB - OBJECTIVES: Although several rehabilitation programmes following hip arthroscopy for femoracetabular impingement (FAI) syndrome have been described, there are no clinical trials evaluating whether formal physiotherapy-prescribed rehabilitation improves recovery compared with self-directed rehabilitation. The objective of this study was to evaluate the efficacy of adding a physiotherapist-prescribed rehabilitation programme to arthroscopic surgery for FAI syndrome. DESIGN: Randomised controlled trial. METHODS: People aged >=16 years with FAI syndrome scheduled for hip arthroscopy were recruited and randomly allocated to physiotherapy (PT) or control. The PT group received seven PT sessions (one preoperative and six postoperative) incorporating education, manual therapy and a progressive rehabilitation programme of home, aquatic and gym exercises while the control group did not undertake PT rehabilitation. Measurements were taken at baseline (2 weeks presurgery) and 14 and 24 weeks postsurgery. The primary outcomes were the International Hip Outcome Tool (iHOT-33) and the sport subscale of the Hip Outcome Score (HOS) at week 14. RESULTS: Due to slower than expected recruitment and funding constraints, recruitment was ceased after 23 months. Thirty participants (14 PT and 16 control) were randomised and 28 (14 PT and 14 control; 93%) and 22 (11 PT and 11 control; 73%) completed week 14 and 24 measurements, respectively. For the 14-week primary outcomes, the PT group showed significantly greater improvements on the iHOT-33 (mean difference 14.2 units; 95% CI 1.2 to 27.2) and sport subscale of the HOS (13.8 units; 95% CI 0.3 to 27.3). There were no significant between-group differences at week 24. CONCLUSIONS: An individual PT treatment and rehabilitation programme may augment improvements in patient-reported outcomes following arthroscopy for FAI syndrome. However, given the small sample size, larger trials are needed to validate the findings. TRIAL REGISTRATION NUMBER: Trial registered with the Australian New Zealand Clinical Trials Registry :ACTRN12613000282785, Results. PMID- 28645961 TI - Cognitive screening and behavioural observation of functional ability in patients with multiple episode schizophrenia: an exploratory study. AB - OBJECTIVES: To evaluate the usability of a neuropsychological screening instrument and two observation scales of everyday behaviour to describe cognitive and functional capacity of patients with multiepisode schizophrenia and considerable care needs, who frequently refuse to participate in cognitive testing or performance-based functional measurement. SETTING: One psychiatric unit specialised in severe mental illness at the Sahlgrenska University Hospital, Gothenburg, Sweden. PARTICIPANTS: Patients were included consecutively from date of admission to the unit. INCLUSION CRITERIA: age 18-65 years, International Classification of Diseases 10 diagnoses F20.0-F20.9 (schizophrenia) or F25.0 F25.9 (schizoaffective disorder) since at least 5 years. EXCLUSION CRITERIA: acute serious psychotic episodes or physical illness, alcohol or drug abuse during the year before the study, diagnosed cerebral disorder at admission to the unit, and insufficient ability to speak Swedish. 64 patients filled the criteria and 19 accepted participation: 14 males, 5 females, median age 56 years. OUTCOME MEASURES: Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) scores, measured by a psychologist; Frontal Systems Behaviour Scale (FrSBe) Family Version and Functional Independence Measure (FIM) V.4.0 scores, measured by nursing staff. Non-parametric statistics were consistently applied to process the data. RESULTS: Failure analysis showed differences regarding gender and subdiagnoses between participants and non-participants. All participants had BNIS scores indicating cognitive dysfunction. FrSBe group medians showed apathy and executive problems, indicating possible frontal lobe disturbance. FIM showed dependency on others for linguistic and social communication, everyday problem solving, and remembering persons and daily routines. Correlations between FrSBe and FIM (p<=0.01) suggested executive dysfunction being crucial to explain difficulties in performing activities of daily functioning. CONCLUSIONS: Indications of considerable cognitive and functional difficulties found among the participants suggestedthat the instruments are clinically applicable for tentative assessment of cognitive and functional ability among patients with multiepisode schizophrenia and considerable care needs. PMID- 28645962 TI - Diagnosis and treatment for hyperuricaemia and gout: a protocol for a systematic review of clinical practice guidelines and consensus statements. AB - INTRODUCTION: Gout and hyperuricaemia are major health issues and relevant guidance documents have been released by a variety of national and international organisations. However, these documents contain inconsistent recommendations with unclear quality profiles. We aim to conduct a systematic appraisal of the clinical practice guidelines and consensus statements pertaining to the diagnosis and treatment for hyperuricaemia and gout, and to summarise recommendations. METHODS: We will search PubMed, EMBASE and guideline databases to identify published clinical practice guidelines and consensus statements. We will search Google and Google Scholar for additional potentially eligible documents. The quality of included guidelines and consensus statements will be assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument and be presented as scores. We will also manually extract recommendations for clinical practice from all included documents. ETHICS AND DISSEMINATION: The results of this systematic review will be disseminated through relevant conferences and peer-reviewed journals. PROTOCOL REGISTRATION NUMBER: PROSPERO CRD42016046104. PMID- 28645963 TI - Effectiveness and safety of moxibustion treatment for non-specific lower back pain: protocol for a systematic review. AB - INTRODUCTION: Many patients experience acute lower back pain that becomes chronic pain. The proportion of patients using complementary and alternative medicine to treat lower back is increasing. Even though several moxibustion clinical trials for lower back pain have been conducted, the effectiveness and safety of moxibustion intervention is controversial. The purpose of this study protocol for a systematic review is to evaluate the effectiveness and safety of moxibustion treatment for non-specific lower back pain patients. METHODS AND ANALYSIS: We will conduct an electronic search of several databases from their inception to May 2017, including Embase, PubMed, Cochrane Central Register of Controlled Trial, Allied and Complementary Medicine Database, Wanfang Database, Chongqing VIP Chinese Science and Technology Periodical Database, China National Knowledge Infrastructure Database, Korean Medical Database, Korean Studies Information Service System, National Discovery for Science Leaders, Oriental Medicine Advanced Searching Integrated System, the Korea Institute of Science and Technology, and KoreaMed. Randomised controlled trials investigating any type of moxibustion treatment will be included. The primary outcome will be pain intensity and functional status/disability due to lower back pain. The secondary outcome will be a global measurement of recovery or improvement, work-related outcomes, radiographic improvement of structure, quality of life, and adverse events (presence or absence). Risk ratio or mean differences with a 95% confidence interval will be used to show the effect of moxibustion therapy when it is possible to conduct a meta-analysis. ETHICS AND DISSEMINATION: This review will be published in a peer-reviewed journal and will be presented at an international academic conference for dissemination. Our results will provide current evidence of the effectiveness and safety of moxibustion treatment in non specific lower back pain patients, and thus will be beneficial to patients, practitioners, and policymakers. TRIAL REGISTRATION NUMBER: CRD42016047468 in PROSPERO 2016. PMID- 28645964 TI - The predictive value of serial changes in diaphragm function during the spontaneous breathing trial for weaning outcome: a study protocol. AB - INTRODUCTION: There is a variety of tools being used in clinical practice for the prediction of weaning success from mechanical ventilation. However, their diagnostic performances are less than satisfactory. The purpose of this study is to investigate the value of serial changes in diaphragm function measured by ultrasound during the spontaneous breathing trial (SBT) as a weaning predictor. METHODS AND ANALYSIS: This is a prospective observational study conducted in a 10 bed medical emergency intensive care unit (EICU) in a university-affiliated hospital. The study will be performed from November 2016 to December 2017. All patients in the EICU who are expected to have mechanical ventilation for more than 48 hours through endotracheal tube are potentially eligible for this study. Patients will be included if they fulfil the criteria for SBT. All enrolled patients will be ventilated with an Evita-4 by using volume assist control mode prior to SBT. Positive end-expiratory pressure (PEEP) will be set to 5 cmH2O and fractional inspired oxygen (FiO2) will be set to a value below 0.5 that guarantees oxygen saturation by pulse oximetry (SpO2) greater than 90%. Enrolled patients will undergo SBT for 2 hours in semirecumbent position. During the SBT, the patients will breathe through the ventilator circuit by using flow triggering (2 L/min) with automatic tube compensation of 100% and 5 cmH2O PEEP. The FiO2 will be set to the same value as used before SBT. If the patients fail to tolerate the SBT, the trial will be discontinued immediately and the ventilation mode will be switched to that used before the trial. Patients who pass the 2-hour SBT will be extubated. Right diaphragm excursion and bilateral diaphragm thickening fraction will be measured by ultrasonography during spontaneous breathing. Images will be obtained immediately prior to the SBT, and at 5, 30, 60, 90 and 120 min after the initiation of SBT. Rapid shallow breathing index will be simultaneously calculated at the bedside by a respiratory nurse. ETHICS AND DISSEMINATION: The study protocol is approved by the ethics committee of Sir Run Run Shaw Hospital, an affiliate of Zhejiang University, Medical College. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION NUMBER: ISRCTN42917473; Pre results. PMID- 28645965 TI - The perspective of European researchers of national occupational safety and health institutes for contributing to a European research agenda: a modified Delphi study. AB - OBJECTIVES: This study, developed within the frame of the Partnership for European Research on Occupational Safety and Health joint research activities and based on the frame designed by the 2013 European Agency for Safety and Health at Work (EU-OSHA) study, is the first example of using the points of view of European occupational safety and health (OSH) researchers.The objective is to identify priorities for OSH research that may contribute to the achievement of present and future sustainable growth objectives set by the European strategies. METHODS: The study was carried out using a modified Delphi method with a two round survey. Each round involved a panel of about 110 researchers representing the network member institutes was selected according to specific criteria, including the ownership of research expertise in at least one of the four macroareas identified by the reference report developed by EU-OSHA in 2013. RESULTS: The study identified some innovative research topics (for example, 'Emerging technological devices' and 'OSH consequences of markets integration') and research priorities (ie, crowdsourcing, e-work, zero-hours contracts) that are not reflected in previous studies of this nature.The absence of any reference to violence and harassment at work among the researchers' proposals is a major difference from previous similar studies, while topics related to gender issues and electromagnetic fields show a lower importance. CONCLUSIONS: The innovative design of a research priorities identification process, which takes advantage of a large, representative and qualified panel of European researchers allowed the definition of a number of research priorities able to support the inclusion of innovative OSH research issues in the scope of the next European research agenda. PMID- 28645966 TI - Effectiveness of metacognitive interventions for mental disorders in adults: a systematic review protocol (METACOG). AB - INTRODUCTION: Whereas the efficacy of cognitive-behavioural therapy has been demonstrated for a variety of mental disorders, there is still need for improvement, especially regarding less prevalent or more severe disorders. Recently, metacognitive interventions have been developed and are now available for a variety of diagnoses. Still, a systematic review investigating the effectiveness of different metacognitive interventions for various mental disorders is missing. METHODS AND ANALYSIS: Randomised controlled trials (RCTs), cross-over and cluster RCTs and non-randomised controlled trials on metacognitive interventions (ie, metacognitive therapy, metacognitive training, others) in adults with any mental disorder will be included. As comparators, another psychological or pharmacological treatment, a combined psychological and pharmacological treatment, treatment as usual or no active treatment are eligible. Outcomes refer to efficacy and acceptability of metacognitive interventions. ETHICS AND DISSEMINATION: In light of the popularity of metacognitive interventions, the systematic review will provide researchers, clinicians and patients with substantial information on the intervention's effectiveness across different mental disorders. Results will be published in peer-reviewed journals and disseminated through a patient workshop. PMID- 28645967 TI - The Bipolar Illness Onset study: research protocol for the BIO cohort study. AB - INTRODUCTION: Bipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%-2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5-10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder. METHODS AND ANALYSIS: The study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period. ETHICS AND DISSEMINATION: The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers. TRIAL REGISTRATION NUMBER: NCT02888262. PMID- 28645968 TI - Development of a meta-algorithm for guiding primary care encounters for patients with multimorbidity using evidence-based and case-based guideline development methodology. AB - OBJECTIVE: The study aimed to develop a comprehensive algorithm (meta-algorithm) for primary care encounters of patients with multimorbidity. We used a novel, case-based and evidence-based procedure to overcome methodological difficulties in guideline development for patients with complex care needs. STUDY DESIGN: Systematic guideline development methodology including systematic evidence retrieval (guideline synopses), expert opinions and informal and formal consensus procedures. SETTING: Primary care. INTERVENTION: The meta-algorithm was developed in six steps:1. Designing 10 case vignettes of patients with multimorbidity (common, epidemiologically confirmed disease patterns and/or particularly challenging health care needs) in a multidisciplinary workshop.2. Based on the main diagnoses, a systematic guideline synopsis of evidence-based and consensus based clinical practice guidelines was prepared. The recommendations were prioritised according to the clinical and psychosocial characteristics of the case vignettes.3. Case vignettes along with the respective guideline recommendations were validated and specifically commented on by an external panel of practicing general practitioners (GPs).4. Guideline recommendations and experts' opinions were summarised as case specific management recommendations (N of-one guidelines).5. Healthcare preferences of patients with multimorbidity were elicited from a systematic literature review and supplemented with information from qualitative interviews.6. All N-of-one guidelines were analysed using pattern recognition to identify common decision nodes and care elements. These elements were put together to form a generic meta-algorithm. RESULTS: The resulting meta-algorithm reflects the logic of a GP's encounter of a patient with multimorbidity regarding decision-making situations, communication needs and priorities. It can be filled with the complex problems of individual patients and hereby offer guidance to the practitioner. Contrary to simple, symptom-oriented algorithms, the meta-algorithm illustrates a superordinate process that permanently keeps the entire patient in view. CONCLUSION: The meta-algorithm represents the back bone of the multimorbidity guideline of the German College of General Practitioners and Family Physicians. This article presents solely the development phase; the meta-algorithm needs to be piloted before it can be implemented. PMID- 28645969 TI - Protocol for the residents in action pilot cluster randomised controlled trial (RiAT): evaluating a behaviour change intervention to promote walking, reduce sitting and improve mental health in physically inactive older adults in retirement villages. AB - INTRODUCTION: Ageing is accompanied by increased risks of chronic disease, declined functioning and increased dependency. Physical activity is critical to retaining health and independence, but the majority of older people are insufficiently physically active to achieve these benefits and have high levels of sedentary (sitting) time. Activity programmes are often offered in retirement villages; however, their uptake is limited. Furthermore, although the physical environment in and around these villages can play an important role in decisions to be physically active, its role is often overlooked by research in these settings. We aim to develop, implement and evaluate a proof-of-concept motivationally embellished intervention designed to increase walking, reduce sitting and improve mental health in residents in retirement villages. METHODS AND ANALYSIS: This will be a 16-week pilot intervention using a cluster randomised design with retirement villages as the unit of randomisation and residents as the unit of assessment. Fourteen retirement villages around Perth, Western Australia, will be recruited for the intervention. Objective audits of neighbourhood environments around each village will be completed using the Pathway Environmental Audit Tool. Seven villages will be randomised to the experimental arm and seven to the control arm. Only participants in the experimental arm will receive motivational training. All outcomes will be assessed at baseline, end of intervention and 6-month follow-up. Changes in physical activity levels, sitting time and mental health will be examined. Multilevel modelling will be used to analyse the data. A mixed methods process evaluation will also be conducted. ETHICS AND DISSEMINATION: Ethics approval was granted by Curtin University's Human Research Ethics Committee (HREC2016-0187). The results of the study will be disseminated via peer-reviewed publications, conference presentations and reports to, and seminars with, stakeholders. TRIAL REGISTRATION: The trial is registered with the Australian New Zealand Clinical Trials Registry: ACTRN12616001177448. PMID- 28645970 TI - The relation between birthweight, childhood body mass index, and overweight and obesity in late adolescence: a longitudinal cohort study from Norway, The Tromso Study, Fit Futures. AB - OBJECTIVES: Childhood overweight/obesity is associated with later overweight/obesity. However, the association between birth weight and later overweight/obesity has not been established. The aim of this study was to investigate the relation between both birth weight and childhood body mass index (BMI), and adolescent overweight/obesity in a Norwegian population. METHODS: The Tromso Study - Fit Futures is a population-based cohort study conducted in 2010 2011 and 2012-2013 in Tromso, Norway. A representative sample of 961 adolescents participated. Longitudinal anthropometric data were obtained from the Medical Birth Registry of Norway, childhood health records at 2-4 and 5-7 years of age, and repeated measurements at 15-18 and 18-20 years of age. Outcome was defined as normal weight (adult BMI <25 kg/m2) or overweight/obese (adult BMI >=2 5 kg/m2) at 15-20 years of age according to international age- and sex-specific cut-off values for children. Associations were investigated using generalised estimating equations. RESULTS: In adjusted analyses, a 1-SD (586 g) higher birth weight was associated with a higher OR for overweight/obesity at 15-20 years of age (OR 1.25, 95% CI 1.06 to 1.48). Childhood BMI was also associated with overweight/obesity at 15-20 years of age: a 1-SD (1.35 kg/m2) increase in BMI at age 2-4 years rendered an OR of 1.66 (95% CI 1.40 to 1.96); a 1-SD (1.83 kg/m2) increase in BMI at age 5-7 years rendered an OR of 3.23 (95% CI 2.56 to 4.07). When compared with normal-weight children, those with severe overweight/obesity in childhood (adult BMI >=27 kg/m2) showed stronger associations with overweight/obesity at 15-20 years of age: OR 3.01 (95% CI 1.47 to 6.18) and OR 11.51 (95% CI 6.63 to 19.99) at ages 2-4 and 5-7, respectively. CONCLUSION: Associations between birth weight and overweight/obesity at 15-20 years of age were modest, whereas the influence of BMI at 2-4 and 5-7 years on overweight/obesity at 15-20 years was moderate to strong. PMID- 28645971 TI - Association between chronic obstructive pulmonary disease and increased risk of benign prostatic hyperplasia: a retrospective nationwide cohort study. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) and benign prostatic hyperplasia (BPH) are common disorders in ageing male populations. Nevertheless, the relationship between the two diseases has rarely been explored. The objective of this study was to examine whether patients with COPD are at an increased risk of BPH. DESIGN: Retrospective nationwide cohort study. SETTING: Data retrieved from the Taiwan National Health Insurance Research Database. PARTICIPANTS: Overall, 19 959 male patients aged 40 years and over with newly diagnosed COPD between 2000 and 2006 were included as the COPD group, and 19 959 sex-matched and age-matched enrollees without COPD were included as the non-COPD group. Both groups were followed-up until the end of 2011. OUTCOME MEASURES: A Cox proportional hazards regression model was used to compute the risk of BPH in patients with COPD compared with enrollees without COPD. RESULTS: The overall incidence rate of BPH was 1.53 times higher in the COPD group than that in the non-COPD group (44.7 vs 25.7 per 1000 person-years, 95% CI 1.46 to 1.60) after adjusting for covariates. An additional stratified analysis revealed that this increased risk of BPH in patients with COPD remained significantly higher than that in enrollees without COPD in all men aged 40 years and over. CONCLUSION: After adjustment for covariates, male patients with COPD were found to be at a higher risk of BPH. We suggest that clinicians should be cautious about the increased risk of BPH in male patients with COPD. PMID- 28645972 TI - Does non-invasive brain stimulation modify hand dexterity? Protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Dexterity is described as coordinated hand and finger movement for precision tasks. It is essential for day-to-day activities like computer use, writing or buttoning a shirt. Integrity of brain motor networks is crucial to properly execute these fine hand tasks. When these networks are damaged, interventions to enhance recovery are frequently accompanied by unwanted side effects or limited in their effect. Non-invasive brain stimulation (NIBS) are postulated to target affected motor areas and improve hand motor function with few side effects. However, the results across studies vary, and the current literature does not allow us to draw clear conclusions on the use of NIBS to promote hand function recovery. Therefore, we developed a protocol for a systematic review and meta-analysis on the effects of different NIBS technologies on dexterity in diverse populations. This study will potentially help future evidence-based research and guidelines that use these NIBS technologies for recovering hand dexterity. METHODS AND ANALYSIS: This protocol will compare the effects of active versus sham NIBS on precise hand activity. Records will be obtained by searching relevant databases. Included articles will be randomised clinical trials in adults, testing the therapeutic effects of NIBS on continuous dexterity data. Records will be studied for risk of bias. Narrative and quantitative synthesis will be done. ETHICS AND DISSEMINATION: No private health information is included; the study is not interventional. Ethical approval is not required. The results will be reported in a peer-review journal. REGISTRATION DETAILS: PROSPERO International prospective register of systematic reviews registration number: CRD42016043809. PMID- 28645973 TI - Effect of ultrasonography surveillance in patients with liver cancer: a population-based longitudinal study. AB - OBJECTIVE: Liver cancer is a growing global public health problem. Ultrasonography is an imaging tool widely used for the early diagnosis of liver cancer. However, the effect of ultrasonography surveillance (US) on the survival of patients with liver cancer is unknown. Therefore, this study examined the association between survival and US frequency during the 2 years preceding patients' liver cancer diagnosis. METHODS: This population-based longitudinal study was conducted in Taiwan, a region with high liver cancer incidence, by using the National Health Insurance Research Database. We compared survival between patients who received US three times or more (>=3 group) and less than three times (<3 group) during the 2 years preceding their liver cancer diagnosis, and identified the predictors for the >=3 group. RESULTS: This study enrolled 4621 patients with liver cancer who had died between 1997 and 2010. The median survival rate was higher in the >=3 group (1.42 years) than in the <3 group (0.51 years). Five-year survival probability was also significantly higher in the >=3 group (14.4%) than in the <3 group (7.7%). The multivariate logistic regression results showed that the three most common positive predictors for receiving three or more US sessions were indications of viral hepatitis, gallbladder diseases and kidney-urinary-bladder diseases; the most common negative predictors for receiving three or more US sessions were male sex and indications of abdominal pain. CONCLUSION: Patients with liver cancer who received US three times or more during the 2 years preceding their liver cancer diagnosis exhibited a higher 5 year survival probability. PMID- 28645974 TI - Assessing medical student knowledge and attitudes about shared decision making across the curriculum: protocol for an international online survey and stakeholder analysis. AB - INTRODUCTION: Shared decision making (SDM) is a goal of modern medicine; however, it is not currently embedded in routine care. Barriers include cliniciansa?TM attitudes, lack of knowledge and training and time constraints. Our goal is to support the development and delivery of a robust SDM curriculum in medical education. Our objective is to assess undergraduate medical studentsa?TM knowledge of and attitudes towards SDM in four countries. METHODS AND ANALYSIS: The first phase of the study involves a web-based cross-sectional survey of undergraduate medical students from all years in selected schools across the United States (US), Canada and undergraduate and graduate students in the Netherlands. In the United Kingdom (UK), the survey will be circulated to all medical schools through the UK Medical School Council. We will sample students equally in all years of training and assess attitudes towards SDM, knowledge of SDM and participation in related training. Medical students of ages 18 years and older in the four countries will be eligible. The second phase of the study will involve semistructured interviews with a subset of students from phase 1 and a convenience sample of medical school curriculum experts or stakeholders. Data will be analysed using multivariable analysis in phase 1 and thematic content analysis in phase 2. Method, data source and investigator triangulation will be performed. Online survey data will be reported according to the Checklist for Reporting the Results of Internet E-Surveys. We will use the COnsolidated criteria for REporting Qualitative research for all qualitative data. ETHICS AND DISSEMINATION: The study has been approved for dissemination in the US, the Netherlands, Canada and the UK. The study is voluntary with an informed consent process. The results will be published in a peer-reviewed journal and will help inform the inclusion of SDM-specific curriculum in medical education worldwide. PMID- 28645975 TI - The impact of weight misperception on health-related quality of life in Korean adults (KNHANES 2007-2014): a community-based cross-sectional study. AB - BACKGROUND/OBJECTIVES: Weight perception, especially misperception, might affect health-related quality of life (HRQoL); however, related research is scarce and results remain equivocal. We examined the association between HRQoL and weight misperception by comparing obesity level as measured by body mass index (BMI) and weight perception in Korean adults. METHODS: Study subjects were 43 883 adults aged 19 years or older from cycles IV (2007-2009), V (2010-2012) and VI (2013 2014) of the Korean National Health and Nutrition Examination Survey. Multiple regression analyses comprising both logit and tobit models were conducted to evaluate the independent effect of obesity level as measured by BMI, weight perception and weight misperception on HRQoL after adjusting for demographics, socioeconomic status and number of chronic diseases. We also performed multiple regressions to explore the association between weight misperception and HRQoL stratified by BMI status. RESULTS: Obesity level as measured by BMI and weight perception were independently associated with low HRQoL in both separate and combined analyses. Weight misperception, including underestimation and overestimation, had a significantly negative impact on HRQoL. In subgroup analysis, subjects with BMI ranges from normal to overweight who misperceived their weight also had a high risk of low HRQoL. Overestimation of weight among obese subjects associated with low HRQoL, whereas underestimation of weight showed no significant association. CONCLUSIONS: Both obesity level as measured by BMI and perceiving weight as fat were significant risk factors for low HRQoL. Subjects who incorrectly perceived their weight relative to their BMI status were more likely to report impaired HRQoL, particularly subjects with BMI in the normal to overweight range. Based on these findings, we recommend political and clinical efforts to better inform individuals about healthy weight status and promote accurate weight perception. PMID- 28645976 TI - A combined randomised and observational study of surgery for fractures in the distal radius in the elderly (CROSSFIRE)-a study protocol. AB - : Fractures of the distal radius are common and occur in all age groups. The incidence is high in older populations due to osteoporosis and increased falls risk. Considerable practice variation exists in the management of distal radius fractures in older patients ranging from closed reduction with cast immobilisation to open reduction with plate fixation. Plating is currently the most common surgical treatment. While there is evidence showing no significant advantage for some forms of surgical fixation over conservative treatment, and no difference between different surgical techniques, there is a lack of evidence comparing two of the most common treatments used: closed reduction and casting versus plating. Surgical management involves significant costs and risks compared with conservative management. High-level evidence is required to address practice variation, justify costs and to provide the best clinical outcomes for patients. METHODS AND ANALYSIS: This pragmatic, multicentre randomised comparative effectiveness trial aims to determine whether plating leads to better pain and function and is more cost-effective than closed reduction and casting of displaced distal radius fractures in adults aged 60 years and older. The trial will compare the two techniques but will also follow consenting patients who are unwilling to be randomised in a separate, observational cohort. Inclusion of non randomised patients addresses selection bias, provides practice and outcome insights about standard care, and improves the generalisability of the results from the randomised trial. ETHICS AND DISSEMINATION: CROSSFIRE(Combined Randomised and Observational Study of Surgery for Fractures In the distal Radius in the Elderly) was reviewed and approved by The Hunter New England HREC (HNEHREC Reference No: 16/02/17/3.04). The results of the trial will be published in a peer-reviewed journal and will be disseminated via various forms of media. Results will be incorporated in clinical recommendations and practice guidelines produced by professional bodies. REGISTRATION: CROSSFIRE has been registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR: ACTRN12616000969460). PMID- 28645977 TI - Vitamin D status and associated factors among Portuguese older adults: results from the Nutrition UP 65 cross-sectional study. AB - OBJECTIVES: To evaluate vitamin D status and its associated factors in Portuguese older adults from the Nutrition UP 65 study. DESIGN: Cross-sectional observational study. PARTICIPANTS AND METHODS: Nationwide cluster sample of 1500 Portuguese subjects >=65 years old. Participants were classified, according to US Institute of Medicine cut-offs, as presenting normal 25-hydroxyvitamin D (25(OH)D) levels (>=50.0 nmol/L), at risk of inadequacy (30.0-49.9 nmol/L) or at risk of deficiency (<30 nmol/L). The association between individuals' characteristics and 25(OH)D levels was analysed through multinomial logistic regression analysis. RESULTS: Median 25(OH)D serum value was 36.1 (interquartile range (IQR): 35.5) nmol/L. According to the used cut-offs, 39.6% of participants were at risk of 25(OH)D deficiency and 29.4% were at risk of 25(OH)D inadequacy. In the adjusted model, having higher skin pigmentation and waist circumference >88 cm for women and >102 cm for men were associated with higher odds of 25(OH)D deficiency. Otherwise, living in Lisbon Metropolitan Area and in Madeira, 1-12 years of schooling, being married or in a common-law marriage, monthly income >=?1000, alcohol consumption, medication or supplements with vitamin D supplement use, and blood samples collected in spring or summer were associated with lower odds of being at risk of 25(OH)D deficiency. In this model, season of blood sample collection, medication or supplements use, and waist circumference were the factors more strongly associated with 25(OH)D levels. CONCLUSIONS: Despite using the conservative Institute of Medicine cut-offs, over two-thirds of these study participants presented inadequate 25(OH)D levels, warranting the implementation of corrective measures. Potentially modifiable factors were strongly associated with 25(OH)D levels in this study. These findings may be particularly relevant to the development of public health policies in southern European countries. PMID- 28645978 TI - Model-based methods for case definitions from administrative health data: application to rheumatoid arthritis. AB - OBJECTIVE: This research proposes a model-based method to facilitate the selection of disease case definitions from validation studies for administrative health data. The method is demonstrated for a rheumatoid arthritis (RA) validation study. STUDY DESIGN AND SETTING: Data were from 148 definitions to ascertain cases of RA in hospital, physician and prescription medication administrative data. We considered: (A) separate univariate models for sensitivity and specificity, (B) univariate model for Youden's summary index and (C) bivariate (ie, joint) mixed-effects model for sensitivity and specificity. Model covariates included the number of diagnoses in physician, hospital and emergency department records, physician diagnosis observation time, duration of time between physician diagnoses and number of RA-related prescription medication records. RESULTS: The most common case definition attributes were: 1+ hospital diagnosis (65%), 2+ physician diagnoses (43%), 1+ specialist physician diagnosis (51%) and 2+ years of physician diagnosis observation time (27%). Statistically significant improvements in sensitivity and/or specificity for separate univariate models were associated with (all p values <0.01): 2+ and 3+ physician diagnoses, unlimited physician diagnosis observation time, 1+ specialist physician diagnosis and 1+ RA-related prescription medication records (65+ years only). The bivariate model produced similar results. Youden's index was associated with these same case definition criteria, except for the length of the physician diagnosis observation time. CONCLUSION: A model-based method provides valuable empirical evidence to aid in selecting a definition(s) for ascertaining diagnosed disease cases from administrative health data. The choice between univariate and bivariate models depends on the goals of the validation study and number of case definitions. PMID- 28645979 TI - The 2015 Middle Childhood Survey (MCS) of mental health and well-being at age 11 years in an Australian population cohort. AB - PURPOSE: The Middle Childhood Survey (MCS) was designed as a computerised self report assessment of children's mental health and well-being at approximately 11 years of age, conducted with a population cohort of 87 026 children being studied longitudinally within the New South Wales (NSW) Child Development Study. PARTICIPANTS: School Principals provided written consent for teachers to administer the MCS in class to year 6 students at 829 NSW schools (35.0% of eligible schools). Parent or child opt-outs from participation were received for 4.3% of children, and MCS data obtained from 27 808 children (mean age 11.5 years, SD 0.5; 49.5% female), representing 85.9% of students at participating schools. FINDINGS TO DATE: Demographic characteristics of participating schools and children are representative of the NSW population. Children completed items measuring Social Integration, Prosocial Behaviour, Peer Relationship Problems, Supportive Relationships (at Home, School and in the Community), Empathy, Emotional Symptoms, Conduct Problems, Aggression, Attention, Inhibitory Control, Hyperactivity-Inattention, Total Difficulties (internalising and externalising psychopathology), Perceptual Sensitivity, Psychotic-Like Experiences, Personality, Self-esteem, Daytime Sleepiness and Connection to Nature. Distributions of responses on each item and construct demarcate competencies and vulnerabilities within the population: most children report mental health and well-being, but the population distribution spanned the full range of possible scores on every construct. FUTURE PLANS: Multiagency, intergenerational linkage of the MCS data with health, education, child protection, justice and early childhood development records took place late in 2016. Linked data were used to elucidate patterns of risk and protection across early and middle child development, and these data will provide a foundation for future record linkages in the cohort that will track mental and physical health, social and educational/occupational outcomes into adolescence and early adulthood. PMID- 28645980 TI - Association between human herpesvirus infections and dementia or mild cognitive impairment: a systematic review protocol. AB - INTRODUCTION: Persisting neurotropic viruses are proposed to increase the risk of dementia, but evidence of association from robust, adequately powered population studies is lacking. This is essential to inform clinical trials of targeted preventive interventions. METHODS AND ANALYSIS: We will carry out a comprehensive systematic review of published and grey literature of the association between infection with, reactivation of, vaccination against or treatment of any of the eight human herpesviruses and dementia or mild cognitive impairment. We will search the Cochrane Library, Embase, Global Health, Medline, PsycINFO, Scopus, Web of Science, clinical trials registers, the New York Academy of Medicine Grey Literature Report, Electronic Theses Online Service through the British Library and the ISI Conference Proceedings Citation Index for randomised controlled trials, cohort, casea?"control, case crossover or self-controlled case series studies reported in any language up to January 2017. Titles, abstracts and full text screening will be conducted by two researchers independently. Data will be extracted systematically from eligible studies using a piloted template. We will assess risk of bias of individual studies in line with the Cochrane Collaboration tool. We will conduct a narrative synthesis, grouping studies by exposure and outcome definitions, and will describe any differences by population subgroups and dementia subtypes. We will consider performing meta-analyses if there are adequate numbers of sufficiently homogeneous studies. The overall quality of cumulative evidence will be assessed using selected Grading of Recommendations, Assessment, Development and Evaluations criteria. ETHICS AND DISSEMINATION: As this is a review of existing studies, no ethical approval is required. Results will be disseminated through a peer-reviewed publication and at national and international conferences. We anticipate the review will clarify the current extent and quality of evidence for a link between herpesviruses and dementia, identify gaps and inform the direction of future research. PROSPERO REGISTRATION NUMBER: CRD42017054684. PMID- 28645981 TI - Work-related psychosocial factors and onset of metabolic syndrome among workers: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Metabolic syndrome is an important public health target because of its high prevalence worldwide. Work-related psychosocial factors have been identified as determinants of metabolic syndrome components. However, there have been no systematic reviews or meta-analyses conducted to evaluate the relationship between work-related psychosocial factors and metabolic syndrome as an aggregated cluster. The aim of this study is to examine this association from published prospective studies. METHODS AND ANALYSIS: The systematic review and meta-analysis will be conducted using published studies that will be identified from electronic databases (ie, PubMed, EMBASE, PsycINFO, PsycARTICLES and Japan Medical Abstracts Society). Studies that (1) examined the association between work-related psychosocial factors and the onset of metabolic syndrome, (2) had a longitudinal or prospective cohort design, (3) were conducted among workers, (4) provided sufficient data for calculating ORs or relative risk with a 95% CI, (5) were published as original articles written in English or Japanese, and (6) having been published until the end of 2016 will be included. Study selection, data collection, quality assessment and statistical syntheses will be conducted based on discussions among investigators. ETHICS AND DISSEMINATION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. The findings from this study could be useful for assessing metabolic syndrome risk factors in the workplace, and determining approaches for prevention of metabolic syndrome in the future. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016039096 (http://www.crd.york.ac.uk/PROSPERO_REBRANDING/display_record.asp?ID=CRD420160390 6). PMID- 28645982 TI - A multicentre, randomised controlled, non-inferiority trial, comparing nasal high flow with nasal continuous positive airway pressure as primary support for newborn infants with early respiratory distress born in Australian non-tertiary special care nurseries (the HUNTER trial): study protocol. AB - INTRODUCTION: Nasal high-flow (nHF) therapy is a popular mode of respiratory support for newborn infants. Evidence for nHF use is predominantly from neonatal intensive care units (NICUs). There are no randomised trials of nHF use in non tertiary special care nurseries (SCNs). We hypothesise that nHF is non-inferior to nasal continuous positive airway pressure (CPAP) as primary support for newborn infants with respiratory distress, in the population cared for in non tertiary SCNs. METHODS AND ANALYSIS: The HUNTER trial is an unblinded Australian multicentre, randomised, non-inferiority trial. Infants are eligible if born at a gestational age >=31 weeks with birth weight >=1200 g and admitted to a participating non-tertiary SCN, are <24 hours old at randomisation and require non-invasive respiratory support or supplemental oxygen for >1 hour. Infants are randomised to treatment with either nHF or CPAP. The primary outcome is treatment failure within 72 hours of randomisation, as determined by objective oxygenation, apnoea or blood gas criteria or by a clinical decision that urgent intubation and mechanical ventilation, or transfer to a tertiary NICU, is required. Secondary outcomes include incidence of pneumothorax requiring drainage, duration of respiratory support, supplemental oxygen and hospitalisation, costs associated with hospital care, cost-effectiveness, parental stress and satisfaction and nursing workload. ETHICS AND DISSEMINATION: Multisite ethical approval for the study has been granted by The Royal Children's Hospital, Melbourne, Australia (Trial Reference No. 34222), and by each participating site. The trial is currently recruiting in eight centres in Victoria and New South Wales, Australia, with one previous site no longer recruiting. The trial results will be published in a peer-reviewed journal and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614001203640; pre-results. PMID- 28645983 TI - The effect of magnesium supplementation on vascular calcification in chronic kidney disease-a randomised clinical trial (MAGiCAL-CKD): essential study design and rationale. AB - INTRODUCTION: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease and mortality, which is thought to be caused by increased propensity towards vascular calcification (VC). Magnesium (Mg) inhibits phosphate-induced VC in vitro and in animal models and serum Mg is inversely associated with cardiovascular mortality in predialysis CKD and in end-stage renal disease. This paper will describe the design and rationale of a randomised double-blinded placebo-controlled multicentre clinical trial, which will investigate whether oral Mg supplementation can prevent the progression of coronary artery calcification (CAC) in subjects with predialysis CKD. METHODS AND ANALYSIS: We will randomise 250 subjects with estimated glomerular filtration rate of 15 to 45 mL/min/1.73 m2 to 12 months treatment with either slow-release Mg hydroxide 30 mmol/day or matching placebo in a 1:1 ratio. The primary end point is change in CAC score as measured by CT at baseline and after 12 months treatment. Secondary end points include change in pulse wave velocity, bone mineral density, measures of mineral metabolism and clinical end points related to cardiovascular and renal events. ETHICS AND DISSEMINATION: This trial has been approved by the local biomedical research ethics committees and data protection agencies and will be performed in accordance with the latest revision of the Helsinki Declaration. The trial will examine for the first time the effect of increasing the uptake of a putative VC inhibitor (ie, Mg) on progression of CAC in subjects with predialysis CKD. TRIAL REGISTRATION NUMBER: NCT02542319, pre results. PMID- 28645984 TI - Facilitators and barriers to participation of private sector health facilities in government-led schemes for maternity services in India: a qualitative study. AB - OBJECTIVE: Despite provision of accreditation of private sector health providers in government-led schemes for maternity services in India, their participation has been low. This has led to an underutilisation of their presence, resources and expertise for providing quality maternal and newborn health services. This study explores the perception of various stakeholders on expectations, benefits, barriers and facilitators to private sector participation in government-led schemes-specifically Janani Suraksha Yojana (JSY)-for maternity service delivery. DESIGN: Narrative-based qualitative study. Face-to-face in-depth interviews were conducted with study participants. The interviews were transcribed, translated and analysed using a reflexive and inductive approach to allow codes, categories and themes to emerge from within the data. SETTING: Private obstetricians, government health officials and FOGSI (Federation of Obstetrics and Gynaecological Societies of India) members, Jharkhand and Uttar Pradesh, India. PARTICIPANTS: Eighteen purposefully selected private obstetricians from 9 cities across states of Uttar Pradesh and Jharkhand, 11 government health officials and 2 FOGSI members. RESULTS: The major factors serving as barriers to participation of private practitioners in JSY-which emerged on thematic analysis-were low reimbursement amounts, delayed reimbursements, process of interaction with the government and administrative issues, previous experiences and trust deficit, lack of clarity on the accreditation process and patient-level barriers. On the other hand, factors which were facilitators to participation of private practitioners were ease of process, better communication, branding, motivation of increasing clientele as well as satisfaction of doing social service. CONCLUSION: Factors such as financial processes and administrative delays, mistrust between the stakeholders, ambiguity in processes, lack of transparency and lack of ease in the process of empanelment of private sector are hindering effective public private partnerships under JSY. Simplifying and strengthening the processes, communication strategies and branding can help revitalise it. PMID- 28645985 TI - A study protocol for a randomised controlled trial of an interactive web-based intervention: CancerCope. AB - INTRODUCTION: Approximately 35% of patients with cancer experience clinically significant distress, and unmet psychological supportive care needs are prevalent. This study describes the protocol for a randomised controlled trial (RCT) to assess the efficacy and cost-effectiveness of an internet-based psychological intervention for distressed patients with cancer. METHODS AND ANALYSIS: In phase I, the intervention was developed on an interactive web platform and pilot tested for acceptability using a qualitative methodology with 21 patients with cancer. Phase II is an RCT underway with patients with or at risk of elevated psychological distress comparing: (1) static patient education website with (2) individualised web-delivered cognitive behavioural intervention (CancerCope). Participants were recruited through the Queensland Cancer Registry and Cancer Council Helpline and met the following inclusion criteria: (1) recently diagnosed with cancer; (2) able to read and speak English; (3) no previous history of head injury, dementia or psychiatric illness; (4) no other concurrent cancer; (5) phone and internet access; (5) scored >=4 on the Distress Thermometer. Participants are assessed at four time points: baseline/recruitment and 2, 6 and 12 months after recruitment and intervention commencement. Of the 163 participants recruited, 50% met caseness for distress. The area of highest unmet supportive care needs were psychological followed by physical and daily living needs. Primary outcomes are psychological and cancer-specific distress and unmet psychological supportive care needs. Secondary outcomes are positive adjustment, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Griffith University Human Research Ethics Committee (Approval: PSY/70/13/HREC) and the Metro South Human Research Ethics Committee (HREC/13/QPAH/601). All participants provide informed consent prior to taking part in the study. Once completed, this study will provide recommendations about the efficacy of web-based cognitive behavioural interventions to facilitate better psychosocial adjustment for people with cancer. TRIAL REGISTRATION NUMBER: ANZCTR (ACTRN12613001026718). PMID- 28645988 TI - New drugs and dosage forms. PMID- 28645987 TI - New codeine warnings prompt action on newborns. PMID- 28645986 TI - Feasibility study of a randomised controlled trial to investigate the effectiveness of using a humanoid robot to improve the social skills of children with autism spectrum disorder (Kaspar RCT): a study protocol. AB - INTRODUCTION: Interventions using robot-assisted therapy may be beneficial for the social skills development of children with autism spectrum disorder (ASD); however, randomised controlled trials (RCTs) are lacking. The present research aims to assess the feasibility of conducting an RCT evaluating the effectiveness of a social skills intervention using Kinesics and Synchronisation in Personal Assistant Robotics (Kaspar) with children with ASD. METHODS AND ANALYSIS: Forty children will be recruited. Inclusion criteria are the following: aged 5-10 years, confirmed ASD diagnosis, IQ over 70, English-language comprehension, a carer who can complete questionnaires in English and no current participation in a private social communication intervention. Children will be randomised to receive an intervention with a therapist and Kaspar, or with the therapist only. They will receive two familiarisation sessions and six treatment sessions for 8 weeks. They will be assessed at baseline, and at 10 and 22 weeks after baseline. The primary outcome of this study is to evaluate whether the predetermined feasibility criteria for a full-scale trial are met. The potential primary outcome measures for a full-scale trial are the Social Communication Questionnaire and the Social Skills Improvement System. We will conduct a preliminary economic analysis. After the study has ended, a sample of 20 participants and their families will be invited to participate in semistructured interviews to explore the feasibility and acceptability of the study's methods and intervention. ETHICS AND DISSEMINATION: Parents/carers will provide informed consent, and children will give assent, where appropriate. Care will be taken to avoid pressure or coercion to participate. Aftercare is available from the recruiting NHS Trust, and a phased withdrawal protocol will be followed if children become excessively attached to the robot. The results of the study will be disseminated to academic audiences and non-academic stakeholders, for example, families of children with ASD, support groups, clinicians and charities. TRIAL REGISTRATION NUMBER: ISRCTN registry (ISRCTN14156001); Pre-results. PMID- 28645989 TI - Joseph A. Oddis honored at ASHP headquarters dedication. PMID- 28645990 TI - Attention turns to nonpharmacy sterile compounding activities. PMID- 28645991 TI - Correction. PMID- 28645993 TI - Educating students about dementia with virtual-learning experiences. PMID- 28645994 TI - Improvement of patient wait times in an outpatient pharmacy. PMID- 28645995 TI - Mepolizumab for the treatment of severe eosinophilic asthma. AB - PURPOSE: Published data on the pharmacology, pharmacokinetics and pharmacodynamics, and clinical efficacy and safety of the interleukin-5 antagonist mepolizumab are reviewed. SUMMARY: Asthma of the eosinophilic phenotype is characterized by persistent eosinophilic airway inflammation promoted primarily by T-helper type 2 cytokines, the key regulator of eosinophils. Patients with severe eosinophilic asthma are burdened by the need to administer high doses of corticosteroids to help manage their symptoms. In November 2015, mepolizumab (Nucala, GlaxoSmithKline) gained U.S. marketing approval for use as an add-on maintenance treatment for severe eosinophilic asthma in patients 12 years of age or older, making it the first personalized targeted therapy for this population. Efficacy results from clinical trials provided evidence of the corticosteroid-sparing effects of mepolizumab and its ability to reduce both blood and sputum eosinophil counts. Safety data from several Phase II or III studies involving a total of more than 1,300 patients indicated that mepolizumab was generally well tolerated, and types and rates of adverse events in mepolizumab recipients were comparable to those reported with placebo use; the only mepolizumab-associated serious adverse drug events were asthma exacerbations in 2 patients. The recommended dosage of mepolizumab is 100 mg administrated via subcutaneous injection every 4 weeks. CONCLUSION: Mepolizumab is a safe and efficacious novel add-on therapy for a small subgroup of patients with severe eosinophilic asthma whose asthma is not adequately controlled by standard regimens for asthma treatment. PMID- 28645996 TI - Treatment of suspected pulmonary embolism in a morbidly obese patient. AB - PURPOSE: A case highlighting challenges with enoxaparin dosage and monitoring in obese patients is presented. SUMMARY: A morbidly obese 22-year-old Caucasian female (height, 168 cm; weight, 322 kg; body mass index [BMI], 114 kg/m2) who presented to the emergency department with acute-onset dyspnea and hypoxia was empirically initiated on enoxaparin for suspected pulmonary embolism at the institution's standard maximum dosage (160 mg subcutaneously every 12 hours). On hospital day 2, a peak anti-factor Xa (anti-Xa) level of 0.4 IU/mL was documented about 4 hours after the fourth enoxaparin dose. On hospital day 3, the enoxaparin dose was increased to 200 mg, a dose equivalent to 0.62 mg per kilogram of actual body weight (ABW), much lower than the guideline-recommended dose for venous thromboembolism prophylaxis (1 mg/kg). Four hours after her third 200-mg dose of enoxaparin, the patient had an anti-Xa value of 0.64 IU/mL (goal range, 0.5-1.1 IU/mL), with no evidence of bleeding or other adverse drug events. Follow-up anti Xa testing on hospital day 4 yielded a value of 0.78 IU/mL. The case highlights the need for research to better delineate strategies for enoxaparin dosage and monitoring in the context of extreme obesity. CONCLUSION: A female patient with a BMI of 114 kg/m2 was safely and effectively treated using an initial twice-daily dose of enoxaparin less than the recommended 1-mg/kg dose based on ABW. Dosage adjustments were made according to anti-Xa levels, and no adverse drug reactions were noted. PMID- 28645997 TI - Temperature profiles of antibiotic-containing elastomeric infusion devices used by ambulatory care patients. AB - PURPOSE: The temperature profiles of antibiotic-containing elastomeric infusion devices used by ambulatory care patients under various environmental conditions were evaluated. METHODS: A prospective, descriptive survey of temperature exposure was conducted in 4 publically funded hospitals. Over a 12-month period, electronic temperature-recording devices were attached to the antibiotic infusion devices (infusers) of prospectively randomized hospital-in-the-home (HITH) participants. Temperatures were recorded immediately after infuser connection and every 5 minutes thereafter for 24 hours. A structured data collection form was used to collect information on basic clinical and demographic characteristics and aspects of daily living (i.e., how and where the infuser was carried during the day, times the participant went to and arose from bed, location of the infuser while sleeping, and dates and times the infuser was connected and disconnected). RESULTS: A total of 115 patients successfully completed the study (17-91 years old, 55% males). A total of 31,298 temperature readings were collected. The storage location of the infuser did not influence daytime readings. However, the overnight storage location did have a significant impact on the temperatures recorded overnight. The mean temperatures of infusers stored on the bed or on the body overnight were significantly higher than those for infusers stored away from the bed. Diurnal and seasonal influences were also detected. Significantly warmer temperatures were recorded in afternoons and evenings and during the summer months. CONCLUSION: Antibiotics administered to HITH patients via continuous infusion were frequently exposed to temperatures in excess of 25 degrees C. Specific patient behaviors and seasonal and chronological factors influenced temperatures. The findings challenge the validity of current fixed-temperature models for testing stability, which do not reflect conditions found in clinical practice. PMID- 28645998 TI - Stability of tacrolimus ophthalmic solution. AB - PURPOSE: The stability of 0.3-mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. METHODS: A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2-8, or -15 to -25 degrees C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high-performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3-mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. RESULTS: When stored at 2-8 degrees C and between -15 and -25 degrees C, at least 90% of the initial tacrolimus concentration remained throughout the 85-day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 degrees C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. CONCLUSION: Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 degrees C and for at least 85 days when stored at 2-8 degrees C or between -15 and -25 degrees C in polypropylene bottles and protected from light. PMID- 28645999 TI - Ambulatory care pharmacy: Realizing the potential for patient access and operational excellence. PMID- 28646000 TI - ASHP Practitioner Recognition Program-2017 Fellows of the American Society of Health-System Pharmacists. PMID- 28646002 TI - Preparation for Transition to Adult Care Among Medicaid-Insured Adolescents. AB - BACKGROUND: Parents of children with chronic illness consistently report suboptimal preparation for transition from pediatric- to adult-focused health care. Little data are available on transition preparation for low-income youth in particular. METHODS: We conducted a mailed survey of youth with chronic illness enrolled in 2 large Medicaid health plans to determine the quality of transition preparation using the Adolescent Assessment of Preparation for Transition (ADAPT). ADAPT is a new 26-item survey designed for 16- to 17-year-old youth to report on the quality of health care transition preparation they received from medical providers. ADAPT generates composite scores (possible range: 0%-100%) in 3 domains: counseling on transition self-management, counseling on prescription medication, and transfer planning. We examined differences in ADAPT scores based on clinical and demographic characteristics. RESULTS: Among 780 and 575 respondents enrolled in the 2 health plans, respectively, scores in all domains reflected deficiencies in transition preparation. The highest scores were observed in counseling on prescription medication (57% and 58% in the 2 plans, respectively), and lower scores were seen for counseling on transition self management (36% and 30%, respectively) and transfer planning (5% and 4%, respectively). There were no significant differences in composite scores by health plan, sex, or type of chronic health condition. CONCLUSIONS: The ADAPT survey, a novel youth-reported patient experience measure, documented substantial gaps in the quality of transition preparation for adolescents with chronic health conditions in 2 diverse Medicaid populations. PMID- 28646004 TI - Assisted death in "healthy" old age needs consideration. PMID- 28646003 TI - Implicit Weight Bias in Children Age 9 to 11 Years. AB - OBJECTIVES: Assess implicit weight bias in children 9 to 11 years old. METHODS: Implicit weight bias was measured in children ages 9 to 11 (N = 114) by using the Affect Misattribution Procedure. Participants were shown a test image of a child for 350 milliseconds followed by a meaningless fractal (200 milliseconds), and then they were asked to rate the fractal image as "good" or "bad." We used 9 image pairs matched on age, race, sex, and activity but differing by weight of the child. Implicit bias was the difference between positive ratings for fractals preceded by an image of a healthy-weight child and positive ratings for fractals preceded by an image of an overweight child. RESULTS: On average, 64% of abstract fractals shown after pictures of healthy-weight children were rated as "good," compared with 59% of those shown after pictures of overweight children, reflecting an overall implicit bias rate of 5.4% against overweight children (P < .001). Healthy-weight participants showed greater implicit bias than over- and underweight participants (7.9%, 1.4%, and 0.3% respectively; P = .049). CONCLUSIONS: Implicit bias toward overweight individuals is evident in children aged 9 to 11 years with a magnitude of implicit bias (5.4%) similar to that in studies of implicit racial bias among adults. PMID- 28646005 TI - The only way is up: the "special measures" trust that got back on its feet. PMID- 28646006 TI - High-Frequency Jet Ventilation in Preterm Infants: Is There Still Room for It? PMID- 28646007 TI - Understanding, Facilitating, and Researching Interprofessional Education. PMID- 28646008 TI - So That's How You Use It: How Effective Is Education on Inhaler Use? PMID- 28646009 TI - Patient-Ventilator Asynchrony and Standard Waveforms: Looks Can Be Deceiving. PMID- 28646010 TI - Patient-Ventilator Asynchrony and Standard Waveforms: Looks Can Be Deceiving Reply. PMID- 28646012 TI - Scatter Correction with Combined Single-Scatter Simulation and Monte Carlo Simulation Scaling Improved the Visual Artifacts and Quantification in 3 Dimensional Brain PET/CT Imaging with 15O-Gas Inhalation. AB - In 3-dimensional PET/CT imaging of the brain with 15O-gas inhalation, high radioactivity in the face mask creates cold artifacts and affects the quantitative accuracy when scatter is corrected by conventional methods (e.g., single-scatter simulation [SSS] with tail-fitting scaling [TFS-SSS]). Here we examined the validity of a newly developed scatter-correction method that combines SSS with a scaling factor calculated by Monte Carlo simulation (MCS SSS). Methods: We performed phantom experiments and patient studies. In the phantom experiments, a plastic bottle simulating a face mask was attached to a cylindric phantom simulating the brain. The cylindric phantom was filled with 18F FDG solution (3.8-7.0 kBq/mL). The bottle was filled with nonradioactive air or various levels of 18F-FDG (0-170 kBq/mL). Images were corrected either by TFS-SSS or MCS-SSS using the CT data of the bottle filled with nonradioactive air. We compared the image activity concentration in the cylindric phantom with the true activity concentration. We also performed 15O-gas brain PET based on the steady state method on patients with cerebrovascular disease to obtain quantitative images of cerebral blood flow and oxygen metabolism. Results: In the phantom experiments, a cold artifact was observed immediately next to the bottle on TFS SSS images, where the image activity concentrations in the cylindric phantom were underestimated by 18%, 36%, and 70% at the bottle radioactivity levels of 2.4, 5.1, and 9.7 kBq/mL, respectively. At higher bottle radioactivity, the image activity concentrations in the cylindric phantom were greater than 98% underestimated. For the MCS-SSS, in contrast, the error was within 5% at each bottle radioactivity level, although the image generated slight high-activity artifacts around the bottle when the bottle contained significantly high radioactivity. In the patient imaging with 15O2 and C15O2 inhalation, cold artifacts were observed on TFS-SSS images, whereas no artifacts were observed on any of the MCS-SSS images. Conclusion: MCS-SSS accurately corrected the scatters in 15O-gas brain PET when the 3-dimensional acquisition mode was used, preventing the generation of cold artifacts, which were observed immediately next to a face mask on TFS-SSS images. The MCS-SSS method will contribute to accurate quantitative assessments. PMID- 28646013 TI - Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational 18F-FDG PET/CT Observation. AB - The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 +/- 4.4 nmol * min-1 * g-1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard dose (27.9 +/- 9 nmol * min-1 * g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 +/- 7.8 nmol * min-1 * g-1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 +/- 0.9 vs. 3.34 +/- 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis. PMID- 28646014 TI - The Impact of 68Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. AB - 68Ga-PSMA PET/CT scanning has been shown to be more sensitive than conventional imaging techniques in patients with prostate cancer. This prospective Australian multicenter study assessed whether 68Ga-PSMA PET/CT imaging affects management intent in patients with primary or recurrent prostate cancer. Methods: Before undertaking 68Ga-PSMA PET imaging, referring medical specialists completed a questionnaire detailing relevant demographic and clinical data as well as their proposed management plan. A separate follow-up questionnaire was completed after the 68Ga-PSMA PET/CT scan results were available to determine whether the management plan would change. Results: A total of 431 patients with prostate cancer from 4 Australian centers had pre- and post-68Ga-PSMA management plans completed. Scans were obtained for primary staging of intermediate- and high-risk disease in 25% of patients and for restaging/biochemical recurrence in 75% of patients. Overall, 68Ga-PSMA PET/CT scanning led to a change in planned management in 51% of patients. The impact was greater in the group of patients with biochemical failure after definitive surgery or radiation treatment (62% change in management intent) than in patients undergoing primary staging (21% change). Imaging with 68Ga-PSMA PET/CT revealed unsuspected disease in the prostate bed in 27% of patients, locoregional lymph nodes in 39%, and distant metastatic disease in 16%. Conclusion:68Ga-PSMA PET/CT scans detect previously unsuspected disease and may influence planned clinical management in a high proportion of patients with prostate cancer. The impact was greater in patients with biochemical recurrence. These results demonstrate the potential clinical value of 68Ga-PSMA PET/CT in management of prostate cancer. PMID- 28646015 TI - Determination of the Heart-to-Mediastinum Ratio of 123I-MIBG Uptake Using Dual Isotope (123I-MIBG/99mTc-Tetrofosmin) Multipinhole Cadmium-Zinc-Telluride SPECT in Patients with Heart Failure. AB - The aim of this retrospective study was to compare the heart-to-mediastinum ratio (HMR) of 123I-metaiodobenzylguanidine (123I-MIBG) uptake obtained using a multipinhole cadmium-zinc-telluride (CZT) camera with that obtained using conventional planar imaging. Methods: Forty consecutive heart failure patients underwent planar acquisition 4 h after 123I-MIBG injection (191 +/- 41 [mean +/- SD] MBq). To localize the heart using the CZT camera, 99mTc-tetrofosmin (358 +/- 177 MBq) was administered and dual-isotope acquisition was performed. The HMRs were calculated with conventional planar imaging (HMRplanar), with anterior reprojection images using the CZT camera (HMRreproj), and with transaxial reconstructed images using the CZT camera (HMRtransaxial). In a phantom study, we estimated a linear model fitting the CZT camera data to the planar data, and we applied it to provide corrected CZT camera-determined HMRs in patients (cHMRreproj and cHMRtransaxial). Results: Thirty-four men and 6 women (71 +/- 9 y old) with ischemic (22 patients) and nonischemic (18 patients) heart failure completed the study. For 22 of the 40 patients (55%), the New York Heart Association classification was class II and the ejection fraction was 35% +/- 9%. HMRreproj (1.12 +/- 0.19) and HMRtransaxial (1.35 +/- 0.34) were lower than HMRplanar (1.44 +/- 0.14) (P < 0.0001 and P < 0.01, respectively). cHMRreproj (1.54 +/- 0.09) and cHMRtransaxial (1.45 +/- 0.14) were significantly different (P < 0.0001). Lin concordance correlation and Bland-Altman analysis demonstrated an almost perfect concordance and a high agreement between HMRplanar and cHMRtransaxial (P was not significant) but not between HMRplanar and cHMRreproj (P < 0.0001). Conclusion: This study demonstrated that determination of the late HMR of cardiac 123I-MIBG uptake using dual-isotope (123I and 99mTc) acquisition on a multipinhole CZT camera was feasible in patients with heart failure. However, this determination should be performed using transaxial reconstructed images and linear correction based on phantom data acquisitions. PMID- 28646016 TI - TSHB mRNA is linked to cholesterol metabolism in adipose tissue. AB - Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-beta (TSHB) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N-stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH alpha/beta administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.-Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jove, M., Pissios, P., Bluher, M., Ricart, W., Portero-Otin, M., Fernandez-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue. PMID- 28646017 TI - RORalpha modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. AB - Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood. Here we showed that retinoic acid receptor-related orphan receptor alpha (RORalpha), a nuclear receptor and transcription factor, is a novel transcriptional regulator of SEMA3E mediated neurovascular coupling in a mouse model of oxygen-induced proliferative retinopathy. We found that genetic deficiency of RORalpha substantially induced Sema3e expression in retinopathy. Both RORalpha and SEMA3E were expressed in retinal ganglion cells. RORalpha directly bound to a specific ROR response element on the promoter of Sema3e and negatively regulated Sema3e promoter-driven luciferase expression. Suppression of Sema3e using adeno-associated virus 2 carrying short hairpin RNA targeting Sema3e promoted disoriented pathological neovascularization and partially abolished the inhibitory vascular effects of RORalpha deficiency in retinopathy. Our findings suggest that RORalpha is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in pathological retinal angiogenesis.-Sun, Y., Liu, C.-H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., Kamenecka, T. M., Solt, L. A., Chen, J. RORalpha modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. PMID- 28646018 TI - The amyloid precursor protein modulates alpha2A-adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment. AB - The amyloid precursor protein (APP) has long been appreciated for its role in Alzheimer's disease (AD) pathology. However, less is known about the physiologic function of APP outside of AD. Particularly, whether and how APP may regulate functions of cell surface receptors, including GPCRs, remains largely unclear. In this study, we identified a novel direct interaction between APP and the alpha2A adrenergic receptor (alpha2AAR) that occurs at the intracellular domains of both proteins. The APP interaction with alpha2AAR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor. Consequently, the presence of APP attenuates alpha2AAR internalization and desensitization, which are arrestin-dependent processes. Furthermore, in neuroblastoma neuro-2A cells and primary superior cervical ganglion neurons, where APP is highly expressed, the lack of APP leads to a dramatic increase in plasma membrane recruitment of endogenous arrestin 3 following alpha2AAR activation. Concomitantly, agonist induced internalization of alpha2AAR is significantly enhanced in these neuronal cells. Our study provided the first evidence that APP fine tunes GPCR signaling and trafficking. Given the important role of alpha2AAR in controlling norepinephrine release and response, this novel regulation of alpha2AAR by APP may have an impact on modulation of noradrenergic activity and sympathetic tone. Zhang, F., Gannon, M., Chen, Y., Zhou, L., Jiao, K., Wang, Q. The amyloid precursor protein modulates alpha2A-adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment. PMID- 28646019 TI - Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma. AB - RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517-29. (c)2017 AACR. PMID- 28646020 TI - MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway. AB - Despite favorable responses to initial therapy, small-cell lung cancer (SCLC) relapse occurs within a year and exhibits resistance to multiple drugs. Because of limited accessibility of patient tissues for research purposes, SCLC patient derived xenografts (PDX) have provided the best opportunity to address this limitation. Here, we sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines and in chemoresistant PDX compared with matched treatment-naive tumors. MCAM depletion in chemoresistant cells reduced cell proliferation and reduced the IC50 inhibitory concentration of chemotherapeutic drugs in vitro This MCAM-mediated sensitization to chemotherapy occurred via SOX2-dependent upregulation of mitochondrial 37S ribosomal protein 1/ATP-binding cassette subfamily C member 1 (MRP1/ABCC1) and the PI3/AKT pathway. Metabolomic profiling revealed that MCAM modulated lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. Our results suggest that MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC. Cancer Res; 77(16); 4414-25. (c)2017 AACR. PMID- 28646021 TI - EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas. AB - Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS RAS pathway mutations were mutually exclusive; however, we found significant co occurrence of mutations in NRAS and EIF1AX Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res; 77(16); 4268-78. (c)2017 AACR. PMID- 28646022 TI - NF1+/- Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response. AB - Haploinsufficiency in the tumor suppressor NF1 contributes to the pathobiology of neurofibromatosis type 1, but a related role has not been established in malignant peripheral nerve sheath tumors (MPNST) where NF1 mutations also occur. Patients with NF1-associated MPNST appear to have worse outcomes than patients with sporadic MPNST, but the mechanism underlying this correlation is not understood. To define the impact of stromal genetics on the biology of this malignancy, we developed unique mouse models that reflect the genetics of patient associated MPNST. Specifically, we used adenovirus-Cre injections to generate MPNST in Nf1Flox/Flox; Ink4a/ArfFlox/Flox and Nf1Flox/-; Ink4a/ArfFlox/Flox paired littermate mice to model tumors from NF1-wild-type and NF1-associated patients, respectively. In these models, Nf1 haploinsufficiency in hematopoietic cells accelerated tumor onset and increased levels of tumor-infiltrating immune cells comprised of CD11b+ cells, monocytes, and mast cells. We observed that mast cells were also enriched in human NF1-associated MPNST. In a coclinical trial to examine how the tumor microenvironment influences the response to multiagent chemotherapy, we found that stromal Nf1 status had no effect. Taken together, our results clarify the role of the NF1-haploinsufficient tumor microenvironment in MPNST. Cancer Res; 77(16); 4486-97. (c)2017 AACR. PMID- 28646023 TI - Amlexanox Downregulates S100A6 to Sensitize KMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNFalpha Treatment. AB - Acute lymphoblastic leukemias (ALL) positive for KMT2A/AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo HSCT). This poor prognosis is due to one of two factors, either resistance to TNFalpha, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-alpha. In KMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human KMT2A/AFF1-positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of KMT2A/AFF1-positive ALL to TNFalpha by downregulating S100A6 expression, with immediate potential implications for improving clinical management of KMT2A/AFF1-positive ALL. Cancer Res; 77(16); 4426-33. (c)2017 AACR. PMID- 28646024 TI - Metabolic reprogramming via PPARalpha signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics. AB - Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARalpha signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARalpha per se does not always explain the energetic state in the heart. The transcriptional activities of PPARalpha are dynamic, yet highly coordinated. An additional level of complexity in the PPARalpha regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARalpha regulatory mechanisms in cardiac metabolism and the possible role of PPARalpha in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARalpha in the progression of cardiac hypertrophy and failure. PMID- 28646026 TI - Exosomes: promising sacks for treating ischemic heart disease? AB - Ischemic heart disease(IHD) is the leading cause of death worldwide. Despite the development of continuously improving therapeutic strategies, morbidity and mortality of patients with IHD remain relatively high. Exosomes are a subpopulation of vesicles that are universally recognized as major mediators in intercellular communication. Numerous preclinical studies have shown that these tiny vesicles were protective in IHD, through such actions as alleviating myocardial ischemia-reperfusion injury, promoting angiogenesis, inhibiting fibrosis, and facilitating cardiac regeneration. Our review focused on these beneficial exosome-mediated processes. In addition, we discuss in detail how to fully exploit the therapeutic potentials of exosomes in the field of IHD. Topics include identifying robust sources of exosomes, loading protective agents into exosomes, developing heart-specific exosomes, optimizing isolation methods, and translating the cardioprotective effects of exosomes into clinical practice. Finally, both the advantages and disadvantages of utilizing exosomes in clinical settings are addressed. PMID- 28646027 TI - Revisiting protein acetylation and myocardial fatty acid oxidation. PMID- 28646028 TI - Exercise is good for the heart, but the intensity matters. PMID- 28646025 TI - Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model. AB - Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na+ and Ca2+ in the development of HCM, but the role of repolarizing K+ currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K+ currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K+ currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K+ channel subunits. In conclusion, decrease in repolarizing K+ currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility.NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K+ currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy. PMID- 28646029 TI - Are EETs at the heart of the b"EET" in obesity-induced cardiomyopathy? PMID- 28646030 TI - Metabolic remodeling in hypertrophied and failing myocardium: a review. AB - The energy starvation hypothesis proposes that maladaptive metabolic remodeling antedates, initiates, and maintains adverse contractile dysfunction in heart failure (HF). Better understanding of the cardiac metabolic phenotype and metabolic signaling could help identify the role metabolic remodeling plays within HF and the conditions known to transition toward HF, including "pathological" hypertrophy. In this review, we discuss metabolic phenotype and metabolic signaling in the contexts of pathological hypertrophy and HF. We discuss the significance of alterations in energy supply (substrate utilization, oxidative capacity, and phosphotransfer) and energy sensing using observations from human and animal disease models and models of manipulated energy supply/sensing. We aim to provide ways of thinking about metabolic remodeling that center around metabolic flexibility, capacity (reserve), and efficiency rather than around particular substrate preferences or transcriptomic profiles. We show that maladaptive metabolic remodeling takes multiple forms across multiple energy-handling domains. We suggest that lack of metabolic flexibility and reserve (substrate, oxidative, and phosphotransfer) represents a final common denominator ultimately compromising efficiency and contractile reserve in stressful contexts. PMID- 28646031 TI - Metabolism and acetylation contribute to leucine-mediated inhibition of cardiac glucose uptake. AB - High plasma leucine levels strongly correlate with type 2 diabetes. Studies of muscle cells have suggested that leucine alters the insulin response for glucose transport by activating an insulin-negative feedback loop driven by the mammalian target of rapamycin/p70 ribosomal S6 kinase (mTOR/p70S6K) pathway. Here, we examined the molecular mechanism involved in leucine's action on cardiac glucose uptake. Leucine was indeed able to curb glucose uptake after insulin stimulation in both cultured cardiomyocytes and perfused hearts. Although leucine activated mTOR/p70S6K, the mTOR inhibitor rapamycin did not prevent leucine's inhibitory action on glucose uptake, ruling out the contribution of the insulin-negative feedback loop. alpha-Ketoisocaproate, the first metabolite of leucine catabolism, mimicked leucine's effect on glucose uptake. Incubation of cardiomyocytes with [13C]leucine ascertained its metabolism to ketone bodies (KBs), which had a similar negative impact on insulin-stimulated glucose transport. Both leucine and KBs reduced glucose uptake by affecting translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Finally, we found that leucine elevated the global protein acetylation level. Pharmacological inhibition of lysine acetyltransferases counteracted this increase in protein acetylation and prevented leucine's inhibitory action on both glucose uptake and GLUT4 translocation. Taken together, these results indicate that leucine metabolism into KBs contributes to inhibition of cardiac glucose uptake by hampering the translocation of GLUT4-containing vesicles via acetylation. They offer new insights into the establishment of insulin resistance in the heart.NEW & NOTEWORTHY Catabolism of the branched-chain amino acid leucine into ketone bodies efficiently inhibits cardiac glucose uptake through decreased translocation of glucose transporter 4 to the plasma membrane. Leucine increases protein acetylation. Pharmacological inhibition of acetylation reverses leucine's action, suggesting acetylation involvement in this phenomenon.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/leucine-metabolism inhibits-cardiac-glucose-uptake/. PMID- 28646034 TI - Prognostic Value of Serum Troponin T in Unstable Angina. PMID- 28646033 TI - Implementing a Reference Measurement System for C-Peptide: Successes and Lessons Learned. AB - BACKGROUND: Assessment of endogenous insulin secretion by measuring C-peptide concentrations is widely accepted. Recent studies have shown that preservation of even small amounts of endogenous C-peptide production in patients with type 1 diabetes reduces risks for diabetic complications. Harmonization of C-peptide results will facilitate comparison of data from different research studies and later among clinical laboratory results at different sites using different assay methods. CONTENT: This review provides an overview of the general process of harmonization and standardization and the challenges encountered with implementing a reference measurement system for C-peptide. SUMMARY: Efforts to harmonize C-peptide results are described, including those by the National Institute of Diabetes and Digestive and Kidney Diseases-led C-peptide Standardization Committee in the US, activities in Japan, efforts by the National Institute for Biological Standards and Control in the UK, as well as activities led by the Bureau International des Poids et Mesures and the National Metrology Institute in China. A traceability scheme is proposed along with the next steps for implementation. Suggestions are made for better collaboration to optimize the harmonization process for other measurands. PMID- 28646032 TI - The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase. AB - Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 +/- 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 +/- 7.0% over the preceding baseline during saline infusion (P < 0.01), and this was reduced to 26 +/- 7.0% in the presence of the selective nNOS inhibitor S-methyl-l-thiocitrulline (0.625 umol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 +/- 3.7% (P = 0.02) and 0.5 +/- 2.8% (P = 0.51) in the presence of S-methyl-l-thiocitrulline. The response to substance P did not predict the response to mental stress (r2 = 0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels.NEW & NOTEWORTHY Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/nnos-and-coronary-flow-during-mental stress/. PMID- 28646035 TI - A matter of life and death. AB - Cases concerning the withdrawal or withholding of artificial nutrition and hydration from patients in a vegetative or minimally conscious state raise difficult medical, legal and ethical questions including the diagnosis and classification of disorders of consciousness, the legal processes to be followed, and the legal and ethical principles to be applied when making decisions. There is also an issue as to whether it is necessary or appropriate for such decisions to be taken by judges. This article, based on a lecture given in Oxford in October 2016, considers a number of these issues and concludes that any consideration of the question from the patient's point of view must include an objective analysis of what is in his or her best interests, as well as subjective expressions of wishes and feelings. Whilst noting that it has been suggested that applications to the court should be confined to those cases where there is a dispute as to whether withdrawal of artificial nutrition and hydration (ANH) would be in the patient's best interests, the author proposes that, until such time as we have greater clarity and understanding about the disorders of consciousness, and about the legal and ethical principles to be applied, there remains a need for independent oversight and that applications to the court should continue to be obligatory in all cases where the withdrawal of ANH is proposed, at least for the time being. PMID- 28646036 TI - Feeding on ripening and over-ripening fruit: interactions between sugar, ethanol and polyphenol contents in a tropical butterfly. AB - In ripe fruit, energy mostly derives from sugar, while in over-ripe fruit, it also comes from ethanol. Such ripeness differences may alter the fitness benefits associated with frugivory if animals are unable to degrade ethanol when consuming over-ripe fruit. In the tropical butterfly Bicyclus anynana, we found that females consuming isocaloric solutions mimicking ripe (20% sucrose) and over-ripe fruit (10% sucrose, 7% ethanol) of the palm Astrocaryum standleyanum exhibited higher fecundity than females consuming a solution mimicking unripe fruit (10% sucrose). Moreover, relative to butterflies consuming a solution mimicking unripe fruit, survival was enhanced when butterflies consumed a solution mimicking either ripe fruit supplemented with polyphenols (fruit antioxidant compounds) or over-ripe fruit devoid of polyphenols. This suggests that (1) butterflies have evolved tolerance mechanisms to derive the same reproductive benefits from ethanol and sugar, and (2) polyphenols may regulate the allocation of sugar and ethanol to maintenance mechanisms. However, variation in fitness owing to the composition of feeding solutions was not paralleled by corresponding physiological changes (alcohol dehydrogenase activity, oxidative status) in butterflies. The fitness proxies and physiological parameters that we measured therefore appear to reflect distinct biological pathways. Overall, our results highlight that the energy content of fruit primarily affects the fecundity of B. anynana butterflies, while the effects of fruit consumption on survival are more complex and vary depending on ripening stage and polyphenol presence. The actual underlying physiological mechanisms linking fruit ripeness and fitness components remain to be clarified. PMID- 28646037 TI - Early exposure to chronic hypoxia induces short- and long-term regulation of hemoglobin gene expression in European sea bass (Dicentrarchus labrax). AB - European sea bass (Dicentrarchus labrax) inhabits coastal waters and may be exposed to hypoxia at different life stages, requiring physiological and behavioral adaptation. In the present study, we attempted to determine whether regulation of hemoglobin (Hb) gene expression plays a role in the physiological response to chronic moderate hypoxia in whole larvae and hematopoietic tissues (head kidney and spleen) of juveniles. We also tested the hypothesis that hypoxia exposure at the larval stage could induce a long-term effect on the regulation of Hb gene expression. For this purpose, D. labrax were exposed to a non-lethal hypoxic condition (40% air saturation) at the larval stage from 28 to 50 days post-hatching (dph) and/or at the juvenile stage from 196 to 296 dph. Data obtained from larvae indicate that hypoxia induced a subtype-specific regulation of Hb gene expression, with a significant decrease of MN-Hbalpha3, MN-Hbbeta4 and MN-Hbbeta5 and increase of MN-Hbalpha2, LA-Hbalpha1 and LA-Hbbeta1 transcript levels. Hypoxia did not induce regulation of Hb gene expression in juveniles, except in the head kidney for those that experienced hypoxia at the larval stage. The latter exhibited a significant hypoxia-induced stimulation of MN-Hbalpha2, LA Hbalpha1 and LA-Hbbeta1 gene expression, associated with stimulation of the PHD-3 gene involved in the hypoxia-inducible factor oxygen-sensing pathway. We conclude that subtype- and stage-specific regulation of Hb gene expression plays a role in the physiological response of D. labrax to cope with hypoxia and that early exposure to low oxygen concentration has a long-term effect on this response. PMID- 28646038 TI - Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. AB - Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses. PMID- 28646039 TI - Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin alphaVbeta3 in Mycobacterium tuberculosis Infection. AB - In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that integrin signaling might regulate monocyte MMP secretion in pulmonary TB during cell adhesion to the extracellular matrix (ECM). Adhesion to type I collagen and fibronectin by Mycobacterium tuberculosis stimulated monocytes increased MMP-1 gene expression by 2.6-fold and 4.3-fold respectively, and secretion by 60% (from 1208.1 +/- 186 to 1934.4 +/- 135 pg/ml; p < 0.0001) and 63% (1970.3 +/- 95 pg/ml; p < 0.001). MMP-10 secretion increased by 90% with binding to type I collagen and 55% with fibronectin, whereas MMP-7 increased 57% with collagen. The ECM did not affect the secretion of tissue inhibitors of metalloproteinases-1 or -2. Integrin alphaVbeta3 surface expression was specifically upregulated in stimulated monocytes and was further increased after adhesion to type I collagen. Binding of either beta3 or alphaV integrin subunits increased MMP-1/10 secretion in M. tuberculosis-stimulated monocytes. In a cohort of TB patients, significantly increased integrin beta3 mRNA accumulation in induced sputum was detected, to our knowledge, for the first time, compared with control subjects (p < 0.05). Integrin alphaVbeta3 colocalized with areas of increased and functionally active MMP-1 on infected monocytes, and alphaVbeta3 blockade markedly decreased type I collagen breakdown, and impaired both monocyte adhesion and leukocyte migration in a transwell system (p < 0.0001). In summary, our data demonstrate that M. tuberculosis stimulation upregulates integrin alphaVbeta3 expression on monocytes, which upregulates secretion of MMP-1 and -10 on adhesion to the ECM. This leads to increased monocyte recruitment and collagenase activity, which will drive inflammatory tissue damage. PMID- 28646040 TI - IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus. AB - The IL-23/IL-17 pathway is important in multiple autoimmune diseases, but its effect on lupus pathology remains unclear, with opposing trials in murine models of the disease. In this study, we show a disease activity-related upregulation of serum IL-23 and IL-23 receptor in patients with systemic lupus erythematosus (SLE) as compared with healthy controls. When added in SLE T cell in vitro cultures, IL-23 induced IL-17 and limited IL-2 production, whereas T follicular helper and double negative (DN) T cells significantly expanded. To further dissect the role of IL-23 in the expression of autoimmunity and related pathology, we generated IL-23 receptor-deficient MRL.lpr mice. These IL-23R-/ MRL.lpr mice displayed attenuated lupus nephritis with a striking decrease in the accumulation of DN T cells in the kidneys and secondary lymphoid organs. Moreover, T cells from IL-23R-/-MRL.lpr mice produced increased amounts of IL-2 and reduced amounts of IL-17 compared with T cells from wild type animals. In vitro IL-23 treatment promoted IL-17 production and downregulated IL-2 production. The IL-23R-/-MRL.lpr had fewer T follicular helper cells, B cells, and plasma cells, leading to decreased production of anti-dsDNA Abs. Our results show that IL-23 accounts for the main aspects of human and murine lupus including the expansion of DN T cells, decreased IL-2, and increased IL-17 production. We propose that blockade of IL-23 should have a therapeutic value in patients with SLE. PMID- 28646041 TI - Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity. AB - Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease. PMID- 28646046 TI - Wales to selectively target badgers in the fight against bovine TB. PMID- 28646042 TI - On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes. AB - Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic beta cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Ralpha/IL-13Ralpha1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Ralpha1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This is likely due to an increase in the frequency of mTGFbeta+Foxp3int regulatory T cells and the persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D. PMID- 28646043 TI - An Efficient FLP-Based Toolkit for Spatiotemporal Control of Gene Expression in Caenorhabditis elegans. AB - Site-specific recombinases are potent tools to regulate gene expression. In particular, the Cre (cyclization recombination) and FLP (flipase) enzymes are widely used to either activate or inactivate genes in a precise spatiotemporal manner. Both recombinases work efficiently in the popular model organism Caenorhabditis elegans, but their use in this nematode is still only sporadic. To increase the utility of the FLP system in C. elegans, we have generated a series of single-copy transgenic strains that stably express an optimized version of FLP in specific tissues or by heat induction. We show that recombination efficiencies reach 100% in several cell types, such as muscles, intestine, and serotonin producing neurons. Moreover, we demonstrate that most promoters drive recombination exclusively in the expected tissues. As examples of the potentials of the FLP lines, we describe novel tools for induced cell ablation by expression of the PEEL-1 toxin and a versatile FLP-out cassette for generation of GFP-tagged conditional knockout alleles. Together with other recombinase-based reagents created by the C. elegans community, this toolkit increases the possibilities for detailed analyses of specific biological processes at developmental stages inside intact animals. PMID- 28646047 TI - RCVS Council overwhelmingly rejects position statement on CAM therapies. PMID- 28646048 TI - Stark warning over non-UK EU vets as government starts Brexit negotiations. PMID- 28646057 TI - Differentiating structural from idiopathic epilepsy in cats. PMID- 28646060 TI - Human behaviour in slaughterhouses. PMID- 28646058 TI - Semen collection methods in alpacas. AB - South American camelids, particularly alpacas, are gaining in popularity outside their native lands. Reproductive biotechnologies, such as artificial insemination or embryo transfer with cryopreserved embryos, are more complicated in these species than many others due to differences in their reproductive physiology compared to the more commonly encountered domestic livestock. This article reviews the methods currently available for obtaining semen or spermatozoa from alpacas and describes some of the problems associated with handling the viscous seminal plasma characteristic of camelids. Possibilities and limitations of reproductive biotechnologies in this species are discussed, and future developments are outlined, especially some new techniques which are currently being developed for use with camel semen and may be transferable to alpacas. PMID- 28646061 TI - Bovine TB controls. PMID- 28646062 TI - Hunting dogs and bovine TB. PMID- 28646063 TI - Scottish government and tail docking of working dogs. PMID- 28646064 TI - Remembering our predecessors. PMID- 28646065 TI - Second UK isolation of Brucella canis. PMID- 28646066 TI - Hunting with hounds. PMID- 28646067 TI - Diagnosing acute larval paramphistomosis in ruminants. PMID- 28646068 TI - What exactly is an internship or new graduate programme? PMID- 28646069 TI - Bill Mulligan. AB - A popular and charismatic lecturer who became an expert in the use of nuclear techniques in farm animal science. He went on to become dean of Glasgow vet school. PMID- 28646070 TI - Media work adds a new dimension to my clinical practice. AB - Pete Wedderburn describes his media career as 'accidental and unexpected', but having dipped his toe in the water, he found he enjoyed it. Here, he explains how it started. PMID- 28646071 TI - Top 10 tips for working in the media. AB - Pete Wedderburn shares his own top 10 tips for building good relationships with magazine, radio and television editors and producers. PMID- 28646072 TI - Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study. AB - OBJECTIVE: We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS: Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS: Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor. CONCLUSIONS: These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity. PMID- 28646073 TI - Gordon Waddell. PMID- 28646075 TI - BEN, ROB, and the Making of a Petunia Flower. PMID- 28646074 TI - Divergence of the Floral A-Function between an Asterid and a Rosid Species. AB - The ABC model is widely used as a genetic framework for understanding floral development and evolution. In this model, the A-function is required for the development of sepals and petals and to antagonize the C-function in the outer floral whorls. In the rosid species Arabidopsis thaliana, the AP2-type AP2 transcription factor represents a major A-function protein, but how the A function is encoded in other species is not well understood. Here, we show that in the asterid species petunia (Petunia hybrida), AP2B/BLIND ENHANCER (BEN) confines the C-function to the inner petunia floral whorls, in parallel with the microRNA BLINDBEN belongs to the TOE-type AP2 gene family, members of which control flowering time in Arabidopsis. In turn, we demonstrate that the petunia AP2-type REPRESSOR OF B-FUNCTION (ROB) genes repress the B-function (but not the C-function) in the first floral whorl, together with BEN We propose a combinatorial model for patterning the B- and C-functions, leading to the homeotic conversion of sepals into petals, carpels, or stamens, depending on the genetic context. Combined with earlier results, our findings suggest that the molecular mechanisms controlling the spatial restriction of the floral organ identity genes are more diverse than the well-conserved B and C floral organ identity functions. PMID- 28646077 TI - Indemnity provider calls for urgent reform of negligence payouts. PMID- 28646076 TI - Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy. AB - IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell-positive standard genes than podocyte positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell-positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell-positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN. PMID- 28646078 TI - Stereospecific Metabolism of R- and S-Warfarin by Human Hepatic Cytosolic Reductases. AB - Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world; however, its clinical use is often challenging because of its narrow therapeutic range and interindividual variations in response. A critical contributor to the uncertainty is variability in warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction of each warfarin enantiomer yields two warfarin alcohol isomers, and the corresponding four alcohols retain varying levels of anticoagulant activity. Studies on the kinetics of warfarin reduction have often lacked resolution of parent-drug enantiomers and have suffered from coelution of pairs of alcohol metabolites; thus, those studies have not established the importance of individual stereospecific reductive pathways. We report the first steady-state analysis of R- and S-warfarin reduction in vitro by pooled human liver cytosol. As determined by authentic standards, the major metabolites were 9R,11S-warfarin alcohol for R-warfarin and 9S,11S-warfarin alcohol for S-warfarin. R-warfarin (Vmax 150 pmol/mg per minute, Km 0.67 mM) was reduced more efficiently than S-warfarin (Vmax 27 pmol/mg per minute, Km 1.7 mM). Based on inhibitor phenotyping, carbonyl reductase-1 dominated R-and S-warfarin reduction, followed by aldo-keto reductase-1C3 and then other members of that family. Overall, the carbonyl at position 11 undergoes stereospecific reduction by multiple enzymes to form the S alcohol for both drug enantiomers, yet R warfarin undergoes reduction preferentially. This knowledge will aid in assessing the relative importance of reductive pathways for R- and S-warfarin and factors influencing levels of pharmacologically active parent drugs and metabolites, thus impacting patient dose responses. PMID- 28646081 TI - A disconnect between disease activity and functional ability already in patients with early rheumatoid arthritis, depending on large joint involvement. PMID- 28646080 TI - Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control. AB - The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines. Questions were collated from IQ member companies as to which aspects of the guidelines require further evaluation. The EMA was then approached to provide insights into their recommendations on the following: 1) evaluation of downregulation, 2) in vitro assessment of CYP2C induction, 3) the use of CITCO as the positive control for CYP2B6 induction by CAR, 4) data interpretation (a 2-fold increase in mRNA as evidence of induction), and 5) the duration of incubation of hepatocytes with test article. The IWG conducted an anonymous survey among IQ member companies to query current practices, focusing specifically on the aforementioned key points. Responses were received from 19 companies. All data and information were blinded before being shared with the IWG. The results of the survey are presented, together with consensus recommendations on downregulation, CYP2C induction, and CYP2B6 positive control. Results and recommendations related to data interpretation and induction time course will be reported in subsequent articles. PMID- 28646079 TI - Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria. AB - We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5-/- mice). In comparison with wild-type (WT) counterparts, Fmo5-/- mice are resistant to age related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals. When fed a high-fat diet, they are protected against weight gain and reduction of insulin sensitivity. The phenotype of Fmo5-/- mice is independent of diet and the gut microbiome and is determined solely by the host genotype. Fmo5-/- mice have metabolic characteristics similar to those of germ-free mice, indicating that FMO5 plays a role in sensing or responding to gut bacteria. In WT mice, FMO5 is present in the mucosal epithelium of the gastrointestinal tract where it is induced in response to a high-fat diet. In comparison with WT mice, Fmo5-/- mice have fewer colonic goblet cells, and they differ in the production of the colonic hormone resistin-like molecule betaFmo5-/- mice have lower concentrations of tumor necrosis factor alpha in plasma and of complement component 3 in epididymal white adipose tissue, indicative of improved inflammatory tone. Our results implicate FMO5 as a regulator of body weight and of glucose disposal and insulin sensitivity and, thus, identify FMO5 as a potential novel therapeutic target for obesity and insulin resistance. PMID- 28646082 TI - Subcutaneous magnesium in the advanced cancer setting. AB - Hypomagnesaemia can arise from a variety of causes but is particularly prevalent in cancer populations. This case report describes a patient with recurrent symptomatic hypomagnesaemia, on the background of advanced ovarian cancer and a high-output ileostomy, who was successfully managed on a daily continuous subcutaneous infusion of magnesium via a syringe pump. There is limited published information on the subcutaneous administration of magnesium and, to our knowledge, this is the first case to report its routine delivery over 24 hours in a syringe pump. This novel but effective approach for administering magnesium can be delivered in the community and can, therefore, prevent repeated hospital admissions for patients with recurrent symptomatic hypomagnesaemia who would otherwise need intravenous replacement. PMID- 28646083 TI - Does depression increase the risk of stroke in patients with rheumatoid arthritis? A population-based cohort study. AB - OBJECTIVES: Comorbid depression is common and undertreated in patients with rheumatoid arthritis (RA). It remains uncertain whether comorbid depression provoked the risk of poor clinical outcome, stroke in particular, among patients with RA. This work aimed to determine if depression onset during the treatment process increases stroke risk for patients with RA as compared with those with (1) neither RA nor depression, (2) RA only and (3) depression only. DESIGN: A nationwide, population-based cohort study. SETTING: Taiwan's Longitudinal Health Insurance Database. PARTICIPANTS: We identified 8045 subjects with a newly diagnosed RA between 1997 and 2010, together with 32 600 subjects without RA matched by age, gender and index date. All subjects were further divided into four groups based on whether they were diagnosed with comorbid depression during the follow-up period. MAIN OUTCOME MEASURE: The incidence rate and HR for incident stroke were estimated by the end of 2012 using Cox proportional hazard regression. RESULTS: We discovered that patients with RA with the comorbid depression exhibited the highest risk of stroke, with an adjusted HR of 2.18 (95% CI 1.87 to 2.54). Those with RA only or those with depression only still had the higher risk of stroke by 43% and 57% as compared with subjects without either condition. Multivariate analysis showed RA subjects who were male or older, incurred the onset of depression, or had comorbidities such as hypertension, diabetes as well as heart disease, had a greater risk of stroke. CONCLUSIONS: This study cleared up the significant association between RA and the subsequent risk of stroke, and further highlighted that the onset of depression within the treatment process may increase stroke risk for RA subjects. Findings could assist healthcare providers to pinpoint individuals with RA with a higher predisposition of stroke, which could facilitate the provision of appropriate rehabilitation. PMID- 28646084 TI - A Novel Mechanism, Linked to Cell Density, Largely Controls Cell Division in Synechocystis. AB - Many studies have investigated the various genetic and environmental factors regulating cyanobacterial growth. Here, we investigated the growth and metabolism of Synechocystis sp. PCC 6803 under different nitrogen sources, light intensities, and CO2 concentrations. Cells grown on urea showed the highest growth rates. However, for all conditions tested, the daily growth rates in batch cultures decreased steadily over time, and stationary phase was obtained with similar cell densities. Unexpectedly, metabolic and physiological analyses showed that growth rates during log phase were not controlled primarily by the availability of photoassimilates. Further physiological investigations indicated that nutrient limitation, quorum sensing, light quality, and light intensity (self-shading) were not the main factors responsible for the decrease in the growth rate and the onset of the stationary phase. Moreover, cell division rates in fed-batch cultures were positively correlated with the dilution rates. Hence, not only light, CO2, and nutrients can affect growth but also a cell-cell interaction. Accordingly, we propose that cell-cell interaction may be a factor responsible for the gradual decrease of growth rates in batch cultures during log phase, culminating with the onset of stationary phase. PMID- 28646086 TI - Photo Quiz: A 25-Year-Old Male with Chronic Firm Mass of the Foot. PMID- 28646085 TI - Generation of a Collection of Mutant Tomato Lines Using Pooled CRISPR Libraries. AB - The high efficiency of clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mutagenesis in plants enables the development of high throughput mutagenesis strategies. By transforming pooled CRISPR libraries into tomato (Solanum lycopersicum), collections of mutant lines were generated with minimal transformation attempts and in a relatively short period of time. Identification of the targeted gene(s) was easily determined by sequencing the incorporated guide RNA(s) in the primary transgenic events. From a single transformation with a CRISPR library targeting the immunity-associated leucine rich repeat subfamily XII genes, heritable mutations were recovered in 15 of the 54 genes targeted. To increase throughput, a second CRISPR library was made containing three guide RNAs per construct to target 18 putative transporter genes. This resulted in stable mutations in 15 of the 18 targeted genes, with some primary transgenic plants having as many as five mutated genes. Furthermore, the redundancy in this collection of plants allowed for the association of aberrant T0 phenotypes with the underlying targeted genes. Plants with mutations in a homolog of an Arabidopsis (Arabidopsis thaliana) boron efflux transporter displayed boron deficiency phenotypes. The strategy described here provides a technically simple yet high-throughput approach for generating a collection of lines with targeted mutations and should be applicable to any plant transformation system. PMID- 28646087 TI - The Brief Case: A Fishy Tale Prevents Digital Doom following Polly's Peck-the Importance of Pets in a Comprehensive Medical History. PMID- 28646088 TI - Closing the Brief Case: A Fishy Tale Prevents Digital Doom following Polly's Peck the Importance of Pets in a Comprehensive Medical History. PMID- 28646089 TI - Answer to July 2017 Photo Quiz. PMID- 28646092 TI - Deletion analysis of AGD1 reveals domains crucial for plasma membrane recruitment and function in root hair polarity. AB - AGD1, a plant ACAP-type ADP-ribosylation factor-GTPase activating protein (ARF GAP), functions in specifying root hair polarity in Arabidopsis thaliana To better understand how AGD1 modulates root hair growth, we generated full-length and domain-deleted AGD1-green fluorescent protein (GFP) constructs, and followed their localization during root hair development. AGD1-GFP localized to the cytoplasm and was recruited to specific regions of the root hair plasma membrane (PM). Distinct PM AGD1-GFP signal was first detected along the site of root hair bulge formation. The construct continued to mark the PM at the root hair apical dome, but only during periods of reduced growth. During rapid tip growth, AGD1 GFP labeled the PM of the lateral flanks and dissipated from the apical-most PM. Deletion analysis and a single domain GFP fusion revealed that the pleckstrin homology (PH) domain is the minimal unit required for recruitment of AGD1 to the PM. Our results indicate that differential recruitment of AGD1 to specific PM domains is an essential component of the membrane trafficking machinery that facilitates root hair developmental phase transitions and responses to changes in the root microenvironment. PMID- 28646091 TI - Stress-specific p38 MAPK activation is sufficient to drive EGFR endocytosis but not its nuclear translocation. AB - EGF receptor (EGFR) endocytosis is induced by stress in a manner dependent on the p38 MAPK family. Ligand and stresses such as X-rays, reportedly promote nuclear trafficking of endocytosed EGFR for regulation of gene transcription and DNA repair. We fail to detect EGFR endocytosis or nuclear transport following X-ray treatment of HeLa or head and neck cancer cells, despite extensive DNA damage induction. Apparent nuclear staining with EGFR extracellular domain antibody remained present despite reduced/absent EGFR expression, and so did not represent nuclear EGFR. UVB and UVC, but not X-ray or UVA, treatment induced p38 activation and EGFR endocytosis, although all of these stresses induced DNA damage, indicating that DNA damage alone is not sufficient to induce EGFR endocytosis. Increased reactive oxygen species (ROS) levels following UVB treatment, compared to that seen with X-rays, do not alone explain differences in p38 activation. UVB, like UVC, induced EGFR accumulation predominantly in perinuclear endosomes, rather than in the nucleus. Our morphological techniques identifying major changes in receptor distribution do not exclude the possibility that small but biologically relevant amounts of EGFR enter the nucleus. This study highlights the importance and limitations of morphological analyses of receptor distribution in understanding signaling outcome. PMID- 28646090 TI - Cellular functions of WASP family proteins at a glance. AB - Proteins of the Wiskott-Aldrich syndrome protein (WASP) family function as nucleation-promoting factors for the ubiquitously expressed Arp2/3 complex, which drives the generation of branched actin filaments. Arp2/3-generated actin regulates diverse cellular processes, including the formation of lamellipodia and filopodia, endocytosis and/or phagocytosis at the plasma membrane, and the generation of cargo-laden vesicles from organelles including the Golgi, endoplasmic reticulum (ER) and the endo-lysosomal network. Recent studies have also identified roles for WASP family members in promoting actin dynamics at the centrosome, influencing nuclear shape and membrane remodeling events leading to the generation of autophagosomes. Interestingly, several WASP family members have also been observed in the nucleus where they directly influence gene expression by serving as molecular platforms for the assembly of epigenetic and transcriptional machinery. In this Cell Science at a Glance article and accompanying poster, we provide an update on the subcellular roles of WHAMM, JMY and WASH (also known as WASHC1), as well as their mechanisms of regulation and emerging functions within the cell. PMID- 28646093 TI - Emerging roles of mechanical forces in chromatin regulation. AB - Cells are constantly subjected to a spectrum of mechanical cues, such as shear stress, compression, differential tissue rigidity and strain, to which they adapt by engaging mechanisms of mechanotransduction. While the central role of cell adhesion receptors in this process is established, it has only recently been appreciated that mechanical cues reach far beyond the plasma membrane and the cytoskeleton, and are directly transmitted to the nucleus. Furthermore, changes in the mechanical properties of the perinuclear cytoskeleton, nuclear lamina and chromatin are critical for cellular responses and adaptation to external mechanical cues. In that respect, dynamic changes in the nuclear lamina and the surrounding cytoskeleton modify mechanical properties of the nucleus, thereby protecting genetic material from damage. The importance of this mechanism is highlighted by debilitating genetic diseases, termed laminopathies, that result from impaired mechanoresistance of the nuclear lamina. What has been less evident, and represents one of the exciting emerging concepts, is that chromatin itself is an active rheological element of the nucleus, which undergoes dynamic changes upon application of force, thereby facilitating cellular adaption to differential force environments. This Review aims to highlight these emerging concepts by discussing the latest literature in this area and by proposing an integrative model of cytoskeletal and chromatin-mediated responses to mechanical stress. PMID- 28646094 TI - Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model. AB - OBJECTIVE: HCV is characterised by its ability to establish chronic infection in hepatocytes and to replicate in the presence of an inflammation. We mimicked this situation in vivo in immune-competent mice by syngeneic transplantation of HCV replicon-containing mouse hepatoma cells. DESIGN: A total of 5 million H-2b positive Hep56.1D cells, carrying a subgenomic genotype (gt) 2a replicon (HCV replicon cells) or stably expressing comparable levels of the HCV NS3/4A protease/helicase complex (NS3/4A hepatoma cells), were injected subcutaneously into syngeneic H-2b-restricted mice. Kinetics of tumour growth, HCV RNA replication levels and HCV-specific immune responses were monitored. For immune monitoring, new H-2b-restricted cytotoxic T cell epitopes within the gt2a NS3/4A region were mapped. Immune mice were generated by DNA-based vaccination. RESULTS: HCV replicon and NS3/4A hepatoma cells generated solid tumours in vivo. Similar to what is seen in human HCV infection did HCV RNA replicate in the presence of inflammation. NS3/4A-specific CD8+ T cells seemed to transiently reduce HCV RNA levels. Both CD4+ and CD8+ T cells were required for protection against tumour growth. Vaccine-induced NS3/4A(gt2a)-specific T cells protected against HCV replicon tumours in wild-type, but not in HCV NS3/4A(gt1a)-transgenic mice with dysfunctional HCV-specific T cells. Importantly, as in human HCV infection, HCV replicon cells neither primed nor boosted a strong NS3/4A-specific T cell response. CONCLUSION: Syngeneic transplantation of mouse HCV replicon cells into immune-competent animals mirrors many in vivo events in humans. This system is versatile and can be applied to any genetically modified H-2b-restricted mouse strain. PMID- 28646095 TI - Estimated reductions in provider-initiated preterm births and hospital length of stay under a universal acetylsalicylic acid prophylaxis strategy: a retrospective cohort study. AB - BACKGROUND: Hypertensive disorders, especially preeclampsia, are the leading reason for provider-initiated preterm birth. We estimated how universal acetylsalicylic acid (ASA) prophylaxis might reduce rates of provider-initiated preterm birth associated with preeclampsia and intrauterine growth restriction, which are related conditions. METHODS: We performed a cohort study of singleton hospital births in 2013 in Canada, excluding Quebec. We estimated the proportion of term births and provider-initiated preterm births affected by preeclampsia and/or intrauterine growth restriction, and the corresponding mean maternal and newborn hospital length of stay. We projected the potential number of cases reduced and corresponding hospital length of stay if ASA prophylaxis lowered cases of preeclampsia and intrauterine growth restriction by a relative risk reduction (RRR) of 10% (lowest) or 53% (highest), as suggested by randomized clinical trials. RESULTS: Of the 269 303 singleton live births and stillbirths in our cohort, 4495 (1.7%) were provider-initiated preterm births. Of the 4495, 1512 (33.6%) had a diagnosis of preeclampsia and/or intrauterine growth restriction. The mean maternal length of stay was 2.0 (95% confidence interval [CI] 2.0-2.0) days among term births unaffected by either condition and 7.3 (95% CI 6.1-8.6) days among provider-initiated preterm births with both conditions. The corresponding values for mean newborn length of stay were 1.9 (95% CI 1.8-1.9) days and 21.8 (95% CI 17.4-26.2) days. If ASA conferred a 53% RRR against preeclampsia and/or intrauterine growth restriction, 3365 maternal and 11 591 newborn days in hospital would be averted. If ASA conferred a 10% RRR, 635 maternal and 2187 newborn days in hospital would be averted. INTERPRETATION: A universal ASA prophylaxis strategy could substantially reduce the burden of long maternal and newborn hospital stays associated with provider-initiated preterm birth. However, until there is compelling evidence that administration of ASA to all, or most, pregnant women reduces the risk of preeclampsia and/or intrauterine growth restriction, clinicians should continue to follow current clinical practice guidelines. PMID- 28646096 TI - Heat stress causes dysfunctional autophagy in oxidative skeletal muscle. AB - We have previously established that 24 h of environmental hyperthermia causes oxidative stress and have implicated mitochondria as likely contributors to this process. Given this, we hypothesized that heat stress would lead to increased autophagy/mitophagy and a reduction in mitochondrial content. To address this hypothesis pigs were housed in thermoneutral (TN; 20 degrees C) or heat stress (35 degrees C) conditions for 1- (HS1) or 3- (HS3) days and the red and white portions of the semitendinosus collected. We did not detect differences in glycolytic muscle. Counter to our hypothesis, upstream activation of autophagy was largely similar between groups as were markers of autophagosome nucleation and elongation. LC3A/B-I increased 1.6-fold in HS1 and HS3 compared to TN (P < 0.05), LC3A/B-II was increased 4.1-fold in HS1 and 4.8-fold in HS3 relative to TN, (P < 0.05) and the LC3A/B-II/I ratio was increased 3-fold in HS1 and HS3 compared to TN suggesting an accumulation of autophagosomes. p62 was dramatically increased in HS1 and HS3 compared to TN Heat stress decreased mitophagy markers PINK1 7.0-fold in HS1 (P < 0.05) and numerically by 2.4-fold in HS3 compared to TN and BNIP3L/NIX by 2.5-fold (P < 0.05) in HS1 and HS3. Markers of mitochondrial content were largely increased without activation of PGC-1alpha signaling. In total, these data suggest heat-stress-mediated suppression of activation of autophagy and autophagosomal degradation, which may enable the persistence of damaged mitochondria in muscle cells and promote a dysfunctional intracellular environment. PMID- 28646098 TI - Head injuries in professional male football (soccer) over 13 years: 29% lower incidence rates after a rule change (red card). AB - BACKGROUND: Absolute numbers of head injuries in football (soccer) are considerable because of its high popularity and the large number of players. In 2006 a rule was changed to reduce head injuries. Players were given a red card (sent off) for intentional elbow-head contact. AIMS: To describe the head injury mechanism and examine the effect of the rule change. METHODS: Based on continuously recorded data from the German football magazine "kicker", a database of all head injuries in the 1st German Male Bundesliga was generated comprising seasons 2000/01-2012/13. Injury mechanisms were analysed from video recordings. Injury incidence rates (IR) and 95% confidence intervals (95% CI) as well as incidence rate ratios (IRR) to assess differences before and after the rule change were calculated. RESULTS: 356 head injuries were recorded (IR 2.22, 95% CI 2.00 to 2.46 per 1000 match hours). Contact with another player caused most head injuries, more specifically because of head-head (34%) or elbow-head (17%) contacts. After the rule change, head injuries were reduced by 29% (IRR 0.71, 95% CI 0.57 to 0.86, p=0.002). Lacerations/abrasions declined by 42% (95% CI 0.39 to 0.85), concussions by 29% (95% CI 0.46 to 1.09), contusions by 18% (95% CI 0.43 to 1.55) and facial fractures by 16% (95% CI 0.55 to 1.28). CONCLUSIONS: This rule change appeared to reduce the risk of head injuries in men's professional football. PMID- 28646097 TI - Highly suggestive preliminary evidence that the renal interstitium contracts in vivo. AB - To learn more about controlling renal interstitial hydrostatic pressure (RIHP), we assessed its response to renal medullary direct interstitial volume expansion (rmDIVE = 100 MUL bolus infusion/30 sec). Three experimental series (S) were performed in hydropenic, anesthetized, right-nephrectomized, acute left renal denervated and renal perfusion pressure-controlled rats randomly assigned to groups in each S. S1: Rats without hormonal clamp were contrasted before and after rmDIVE induced via 0.9% saline solution bolus (SS group) or 2% albumin in SS bolus (2% ALB + SS group). Subcapsular DeltaRIHP rose slowly, progressively and similarly in both groups by ~3 mmHg. S2: Rats under hormonal clamp were contrasted before and after sham rmDIVE (time CTR group) and real rmDIVE induced via either SS bolus (SS group) or SS bolus containing the subcutaneous tissue fibroblast relaxant dibutyryl-cAMP (SS + db-cAMP group). DeltaRIHP showed time, group, and time*group interaction effects with a biphasic response (early: ~1 mmHg; late: ~4 mmHg) in the SS group that was absent in the SS + db-cAMP group. S3: Two groups of rats (SS and SS + db-cAMP) under hormonal clamp were contrasted as in S2, producing similar DeltaRIHP results to those of S2 but showing a slow, progressive, and indistinct decrease in renal outer medullary blood flow in both groups. These results provide highly suggestive preliminary evidence that the renal interstitium is capable of contracting reactively in vivo in response to rmDIVE with SS and demonstrate that such a response is abolished when db-cAMP is interstitially and concomitantly infused. PMID- 28646099 TI - Rocking the shoulder surgeon's world. PMID- 28646100 TI - The athlete monitoring cycle: a practical guide to interpreting and applying training monitoring data. PMID- 28646101 TI - Serum androgen profile and physical performance in women Olympic athletes. AB - BACKGROUND: The role of endogenous androgens for body composition and physical performance in women athletes is still not elucidated. AIM: To examine the serum androgen profile in relation to body composition and physical performance in women Olympic athletes and to compare endocrine variables and body composition to controls. STUDY DESIGN: Cross-sectional study, conducted between 2011 and 2015 at the Women's Health Research Unit, Karolinska University Hospital, Stockholm. METHODS: Swedish women Olympic athletes (n=106) and age-matched and body mass index-matched sedentary controls (n=117) were included in the study. Blood sampling was performed in a rested, fasting state for the measurement of serum androgens and their metabolites by liquid chromatography-tandem mass spectrometry. Body composition was determined by dual-energy X-ray absorptiometry (controls n=100, athletes n=65). The athletes performed standardised performance tests (n=59) (squat jump (SJ) and countermovement jump (CMJ). RESULTS: The athletes demonstrated significantly higher levels of the precursor androgens dehydroepiandrosterone (DHEA) and 5-androstene-3beta, 17beta-diol (5-DIOL) and the metabolite etiocholanolone glucuronide (Etio-G), significantly lower levels of estrone (p<0.05, respectively), higher bone mineral density (p<0.001) and more lean mass (p<0.001) compared with controls. Serum levels of DHEA, 5-DIOL and Etio G correlated positively to lean mass variables and physical performance in the athletes. DHEA and lean mass legs explained 66% of the variance in SJ, whereas lean mass explained 52% of the variance in CMJ. CONCLUSIONS: The present data suggest that endogenous androgens are associated with a more anabolic body composition and enhanced performance in women athletes. These results are of importance for the current discussion regarding hyperandrogenism in women athletes. PMID- 28646102 TI - Tips for publishing your clinical cardiology research. PMID- 28646103 TI - Long-term and short-term outcomes of using bilateral internal mammary artery grafting versus left internal mammary artery grafting: a meta-analysis. AB - BACKGROUND: A substantial body of evidence demonstrates that myocardial revascularisation using bilateral internal mammary arteries (BIMA) improves long term survival compared with single/left internal mammary artery (LIMA) grafting. To date, limited analyses have been made regarding other short-term and long-term outcomes in BIMA strategy. OBJECTIVES: The primary aim of the present review is to update the difference in long-term survival between BIMA and LIMA grafting and to thoroughly investigate other secondary short-term and long-term clinical outcomes between these two grafting procedures. METHODS: Electronic searches were performed using three databases from their inception to November 2015. Relevant studies comparing long-term survival between BIMA and LIMA grafting were identified. Data were extracted by two independent reviewers and analysed according to predefined clinical outcomes. RESULTS: Twenty-nine observational studies were identified, with a total of 89 399 patients. Overall, BIMA cohort had significantly improved long-term survival compared with LIMA cohort (HR 0.78; p<0.00001). BIMA cohort also had significantly reduced hospital mortality rates (1.2% vs 2.1%, p=0.04), cerebrovascular accidents (1.3% vs 2.9%, p=0.0003) and need for revascularisation (4.8% vs 10%, p=0.005), although the incidence of deep sternal wound infection (DSWI) was increased (1.8% vs 1.4%, p=0.0008) in this grafting strategy. Long-term cardiac-free, myocardial infarction-free and angina free survivals were also superior for the BIMA cohort. CONCLUSIONS: BIMA grafting is associated with enhanced overall long-term outcomes compared with LIMA grafting. While the BIMA cohort demonstrates an increased incidence of DSWI, the survival benefits and other morbidity advantages outweigh this short-term risk. PMID- 28646106 TI - Optimising load to optimise outcomes. PMID- 28646105 TI - The glycolytic enzyme phosphofructokinase-1 assembles into filaments. AB - Despite abundant knowledge of the regulation and biochemistry of glycolytic enzymes, we have limited understanding on how they are spatially organized in the cell. Emerging evidence indicates that nonglycolytic metabolic enzymes regulating diverse pathways can assemble into polymers. We now show tetramer- and substrate dependent filament assembly by phosphofructokinase-1 (PFK1), which is considered the "gatekeeper" of glycolysis because it catalyzes the step committing glucose to breakdown. Recombinant liver PFK1 (PFKL) isoform, but not platelet PFK1 (PFKP) or muscle PFK1 (PFKM) isoforms, assembles into filaments. Negative-stain electron micrographs reveal that filaments are apolar and made of stacked tetramers oriented with exposed catalytic sites positioned along the edge of the polymer. Electron micrographs and biochemical data with a PFKL/PFKP chimera indicate that the PFKL regulatory domain mediates filament assembly. Quantified live-cell imaging shows dynamic properties of localized PFKL puncta that are enriched at the plasma membrane. These findings reveal a new behavior of a key glycolytic enzyme with insights on spatial organization and isoform-specific glucose metabolism in cells. PMID- 28646107 TI - Become one with the force: optimising mechanotherapy through an understanding of mechanobiology. PMID- 28646108 TI - Give patients direct access to physiotherapy. They want it, and it would benefit GPs too. PMID- 28646109 TI - Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-alpha induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2. AB - Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte-endothelial interactions using an in vitro flow adhesion assay. Herein, we report that whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized with tumor necrosis factor-alpha (TNFalpha) to increase recruitment to the vascular endothelium. The BMP9/BMP10 mediated increase in monocyte recruitment in the presence of TNFalpha was associated with up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10 induced surface expression of E-selectin, and both ALK1 and ALK2 in the up regulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The up-regulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFalpha was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFalpha and BMP9/10. BMP9/10 increased basal IkappaBalpha protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergize with TNFalpha to induce the up-regulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling. PMID- 28646110 TI - The Mcm2-7-interacting domain of human mini-chromosome maintenance 10 (Mcm10) protein is important for stable chromatin association and origin firing. AB - The protein mini-chromosome maintenance 10 (Mcm10) was originally identified as an essential yeast protein in the maintenance of mini-chromosome plasmids. Subsequently, Mcm10 has been shown to be required for both initiation and elongation during chromosomal DNA replication. However, it is not fully understood how the multiple functions of Mcm10 are coordinated or how Mcm10 interacts with other factors at replication forks. Here, we identified and characterized the Mcm2-7-interacting domain in human Mcm10. The interaction with Mcm2-7 required the Mcm10 domain that contained amino acids 530-655, which overlapped with the domain required for the stable retention of Mcm10 on chromatin. Expression of truncated Mcm10 in HeLa cells depleted of endogenous Mcm10 via siRNA revealed that the Mcm10 conserved domain (amino acids 200-482) is essential for DNA replication, whereas both the conserved and the Mcm2-7-binding domains were required for its full activity. Mcm10 depletion reduced the initiation frequency of DNA replication and interfered with chromatin loading of replication protein A, DNA polymerase (Pol) alpha, and proliferating cell nuclear antigen, whereas the chromatin loading of Cdc45 and Pol epsilon was unaffected. These results suggest that human Mcm10 is bound to chromatin through the interaction with Mcm2-7 and is primarily involved in the initiation of DNA replication after loading of Cdc45 and Pol epsilon. PMID- 28646111 TI - A Bacillus paralicheniformis Iron-Containing Urease Reduces Urea Concentrations in Rice Wine. AB - Urease, a nickel-containing metalloenzyme, was the first enzyme to be crystallized and has a prominent position in the history of biochemistry. In the present study, we identified a nickel urease gene cluster, ureABCEFGDH, in Bacillus paralicheniformis ATCC 9945a and characterized it in Escherichia coli Enzymatic assays demonstrate that this oxygen-stable urease is also an iron containing acid urease. Heterologous expression assays of UreH suggest that this accessory protein is involved in the transmembrane transportation of nickel and iron ions. Moreover, this iron-containing acid urease has a potential application in the degradation of urea in rice wine. The present study not only enhances our understanding of the mechanism of activation of urease but also provides insight into the evolution of metalloenzymes.IMPORTANCE An iron-containing, oxygen-stable acid urease from B. paralicheniformis ATCC 9945a with good enzymatic properties was characterized. This acid urease shows activities toward both urea and ethyl carbamate. After digestion with 6 U/ml urease, approximately 92% of the urea in rice wine was removed, suggesting that this urease has great potential in the food industry. PMID- 28646112 TI - CRISPR-Cas12a-Assisted Recombineering in Bacteria. AB - Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas12a (Cpf1) has emerged as an effective genome editing tool in many organisms. Here, we developed and optimized a CRISPR-Cas12a-assisted recombineering system to facilitate genetic manipulation in bacteria. Using this system, point mutations, deletions, insertions, and gene replacements can be easily generated on the chromosome or native plasmids in Escherichia coli, Yersinia pestis, and Mycobacterium smegmatis Because CRISPR-Cas12a-assisted recombineering does not require introduction of an antibiotic resistance gene into the chromosome to select for recombinants, it is an efficient approach for generating markerless and scarless mutations in bacteria.IMPORTANCE The CRISPR-Cas9 system has been widely used to facilitate genome editing in many bacteria. CRISPR-Cas12a (Cpf1), a new type of CRISPR-Cas system, allows efficient genome editing in bacteria when combined with recombineering. Cas12a and Cas9 recognize different target sites, which allows for more precise selection of the cleavage target and introduction of the desired mutation. In addition, CRISPR-Cas12a-assisted recombineering can be used for genetic manipulation of plasmids and plasmid curing. Finally, Cas12a assisted recombineering in the generation of point mutations, deletions, insertions, and replacements in bacteria has been systematically analyzed. Taken together, our findings will guide efficient Cas12a-mediated genome editing in bacteria. PMID- 28646113 TI - Aerosolization of mycotoxins after growth of toxinogenic fungi on wallpaper. AB - Many fungi can develop on building material in indoor environments if moisture is high enough. Among species that are frequently observed, some are known to be potent mycotoxin producers. This presence of toxinogenic fungi in indoor environments raises the question of the possible exposure of occupants to these toxic compounds by inhalation after aerosolization.This study investigated the mycotoxin production by Penicillium brevicompactum, Aspergillus versicolor and Stachybotrys chartarum during their growth on wallpaper and the possible subsequent aerosolization of produced mycotoxins from contaminated substrates.We demonstrated that mycophenolic acid, sterigmatocystin and macrocyclic trichothecenes (sum of 4 major compounds) could be produced at levels of 1.8, 112.1 and 27.8 mg/m2, respectively on wallpaper. Moreover, part of the produced toxins could be aerosolized from substrate. The propensity to aerosolization differed according to the fungal species. Thus, particles were aerosolized from wallpaper contaminated with P. brevicompactum when air velocity of just 0.3 m/s was applied, where S. chartarum required air velocity of 5.9 m/s. A versicolor was intermediate since aerosolization occurred under air velocity of 2 m/s.Quantification of the toxic content revealed that toxic load was mostly associated with particles of size equal or higher of 3 MUm, which may correspond to spores. However, some macrocyclic trichothecenes (especially satratoxin H and verrucarin J) can also be found on smaller particles that can penetrate deeply in the respiratory tract upon inhalation. These elements are important for risk assessment related to mouldy environments.IMPORTANCE The possible colonisation of building material by toxinogenic fungi in case of moistening raises the question of the subsequent exposure of occupants to aerosolized mycotoxins. In this study, we demonstrated that three different toxinogenic species produce mycotoxins during their development on wallpaper. These toxins can subsequently be aerosolized, at least partly, from mouldy material. This transfer to air requires air velocities that can be encountered in " real life conditions " in buildings. The most part of the aerosolized toxic load is found in particles whose size corresponds to spores or mycelium fragments. However, some toxins were also found on particles smaller than spores that are easily respirable and can deeply penetrate into human respiratory tract. All these data are important for risk assessment related to fungal contamination of indoor environments. PMID- 28646114 TI - Staphylococcus aureus Strain Newman Photoinactivation and Cellular Response to Sunlight Exposure. AB - Sunlight influences microbial water quality of surface waters. Previous studies have investigated photoinactivation mechanisms and cellular photostress responses of fecal indicator bacteria (FIB), including Escherichia coli and enterococci, but further work is needed to characterize photostress responses of bacterial pathogens. Here we investigate the photoinactivation of Staphylococcus aureus (strain Newman), a pigmented, waterborne pathogen of emerging concern. We measured photodecay using standard culture-based assays and cellular membrane integrity and investigated photostress response by measuring the relative number of mRNA transcripts of select oxidative stress, DNA repair, and metabolism genes. Photoinactivation experiments were performed in both oxic and anoxic systems to further investigate the role of oxygen-mediated and non-oxygen-mediated photoinactivation mechanisms. S. aureus lost culturability much faster in oxic systems than in anoxic systems, indicating an important role for oxygen in photodecay mechanisms. S. aureus cell membranes were damaged by sunlight exposure in anoxic systems but not in oxic systems, as measured by cell membrane permeability to propidium iodide. After sunlight exposure, S. aureus increased expression of a gene coding for methionine sulfoxide reductase after 12 h of sunlight exposure in the oxic system and after 6 h of sunlight exposure in the anoxic system, suggesting that methionine sulfoxide reductase is an important enzyme for defense against both oxygen-dependent and oxygen-independent photostresses. This research highlights the importance of oxygen in bacterial photoinactivation in environmentally relevant systems and the complexity of the bacterial photostress response with respect to cell structure and transcriptional regulation.IMPORTANCEStaphylococcus aureus is a pathogenic bacterium that causes gastrointestinal, respiratory, and skin infections. In severe cases, S. aureus infection can lead to life-threatening diseases, including pneumonia and sepsis. Cases of community-acquired S. aureus infection have been increasing in recent years, pointing to the importance of considering S. aureus transmission pathways outside the hospital environment. Associations have been observed between recreational water contact and staphylococcal skin infections, suggesting that recreational waters may be an important environmental transmission pathway for S. aureus However, prediction of human health risk in recreational waters is hindered by incomplete knowledge of pathogen sources, fate, and transport in this environment. This study is an in-depth investigation of the inactivation of a representative strain of S. aureus by sunlight exposure, one of the most important factors controlling the fate of microbial contaminants in clear waters, which will improve our ability to predict water quality changes and human health risk in recreational waters. PMID- 28646115 TI - Genome Analysis of Endomicrobium proavitum Suggests Loss and Gain of Relevant Functions during the Evolution of Intracellular Symbionts. AB - Bacterial endosymbionts of eukaryotes show progressive genome erosion, but detailed investigations of the evolutionary processes involved in the transition to an intracellular lifestyle are generally hampered by the lack of extant free living lineages. Here, we characterize the genome of the recently isolated, free living Endomicrobium proavitum, the second member of the Elusimicrobia phylum brought into pure culture, and compare it to the closely related "Candidatus Endomicrobium trichonymphae" strain Rs-D17, a previously described but uncultured endosymbiont of termite gut flagellates. A reconstruction of the metabolic pathways of Endomicrobium proavitum matched the fermentation products formed in pure culture and underscored its restriction to glucose as the substrate. However, several pathways present in the free-living strain, e.g., for the uptake and activation of glucose and its subsequent fermentation, ammonium assimilation, and outer membrane biogenesis, were absent or disrupted in the endosymbiont, probably lost during the massive genome rearrangements that occurred during symbiogenesis. While the majority of the genes in strain Rs-D17 have orthologs in Endomicrobium proavitum, the endosymbiont also possesses a number of functions that are absent from the free-living strain and may represent adaptations to the intracellular lifestyle. Phylogenetic analysis revealed that the genes encoding glucose 6-phosphate and amino acid transporters, acetaldehyde/alcohol dehydrogenase, and the pathways of glucuronic acid catabolism and thiamine pyrophosphate biosynthesis were either acquired by horizontal gene transfer or may represent ancestral traits that were lost in the free-living strain. The polyphyletic origin of Endomicrobia in different flagellate hosts makes them excellent models for future studies of convergent and parallel evolution during symbiogenesis.IMPORTANCE The isolation of a free-living relative of intracellular symbionts provides the rare opportunity to identify the evolutionary processes that occur in the course of symbiogenesis. Our study documents that the genome of "Candidatus Endomicrobium trichonymphae," which represents a clade of endosymbionts that have coevolved with termite gut flagellates for more than 40 million years, is not simply a subset of the genes present in Endomicrobium proavitum, a member of the ancestral, free-living lineage. Rather, comparative genomics revealed that the endosymbionts possess several relevant functions that were either prerequisites for colonization of the intracellular habitat or might have served to compensate for genes losses that occurred during genome erosion. Some gene sets found only in the endosymbiont were apparently acquired by horizontal transfer from other gut bacteria, which suggests that the intracellular bacteria of flagellates are not entirely cut off from gene flow. PMID- 28646116 TI - Tonic B-cell receptor signaling in diffuse large B-cell lymphoma. AB - We used clustered regularly interspaced short palindromic repeats/Cas9-mediated genomic modification to investigate B-cell receptor (BCR) signaling in cell lines of diffuse large B-cell lymphoma (DLBCL). Three manipulations that altered BCR genes without affecting surface BCR levels showed that BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to Bruton tyrosine kinase inhibition by ibrutinib, and the activated B-cell (ABC) subtype. Replacing antigen-binding BCR regions had no effect on BCR signaling in GCB-DLBCL lines, reflecting this subtype's exclusive use of tonic BCR signaling. Conversely, Y188F mutation in the immunoreceptor tyrosine-based activation motif of CD79A inhibited tonic BCR signaling in GCB-DLBCL lines but did not affect their calcium flux after BCR cross-linking or the proliferation of otherwise unmodified ABC-DLBCL lines. CD79A-GFP fusion showed BCR clustering or diffuse distribution, respectively, in lines of ABC and GCB subtypes. Tonic BCR signaling acts principally to activate AKT, and forced activation of AKT rescued GCB-DLBCL lines from knockout (KO) of the BCR or 2 mediators of tonic BCR signaling, SYK and CD19. The magnitude and importance of tonic BCR signaling to proliferation and size of GCB-DLBCL lines, shown by the effect of BCR KO, was highly variable; in contrast, pan-AKT KO was uniformly toxic. This discrepancy was explained by finding that BCR KO-induced changes in AKT activity (measured by gene expression, CXCR4 level, and a fluorescent reporter) correlated with changes in proliferation and with baseline BCR surface density. PTEN protein expression and BCR surface density may influence clinical response to therapeutic inhibition of tonic BCR signaling in DLBCL. PMID- 28646117 TI - Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma. AB - Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/P-TEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. We evaluated the therapeutic potential of BAY 1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY 1143572 decreased c-Myc and Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n = 11), and CD4+ cells from healthy volunteers (n = 5) were 0.535, 0.30, and 0.36 MUM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572 treated ATL-bearing mice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n = 7 for both). Collectively, this study indicates that BAY 1143572 showed strong potential as a novel treatment of ATL. PMID- 28646118 TI - Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. AB - Direct oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score >=4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4% 11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban. PMID- 28646119 TI - REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways. AB - Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons (iNs), was achieved for the first time 6 years ago. This technology offers a promising shortcut for obtaining patient- and disease specific neurons for disease modeling, drug screening, and other biomedical applications. However, fibroblasts from adult donors do not reprogram as easily as fetal donors, and no current reprogramming approach is sufficiently efficient to allow the use of this technology using patient-derived material for large scale applications. Here, we investigate the difference in reprogramming requirements between fetal and adult human fibroblasts and identify REST as a major reprogramming barrier in adult fibroblasts. Via functional experiments where we overexpress and knockdown the REST-controlled neuron-specific microRNAs miR-9 and miR-124, we show that the effect of REST inhibition is only partially mediated via microRNA up-regulation. Transcriptional analysis confirmed that REST knockdown activates an overlapping subset of neuronal genes as microRNA overexpression and also a distinct set of neuronal genes that are not activated via microRNA overexpression. Based on this, we developed an optimized one-step method to efficiently reprogram dermal fibroblasts from elderly individuals using a single-vector system and demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's, as well as Alzheimer's disease. PMID- 28646120 TI - miR-223 represents a biomarker in acute and chronic liver injury. AB - BACKGROUND: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis. PMID- 28646121 TI - AT1-receptor blockade attenuates outward aortic remodeling associated with diet induced obesity in mice. AB - The renin-angiotensin system (RAS) and obesity have been implicated in vascular outward remodeling, including aneurysms, but the precise mechanisms are not yet understood. We investigated the effect of the angiotensin receptor type 1 (AT1 receptor) antagonist telmisartan on aortic outward remodeling in a diet-induced obesity model in mice. C57/Black6J mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 14 weeks. One group of HFD mice was additionally exposed to telmisartan (3 mg/kg per day) for the last 4 weeks. HFD led to aortic outward remodeling, characterized by increased proteolysis, along with structural changes, such as fragmentation of elastic fibers and decreased elastin content. Vascular damage was associated with up-regulation of matrix metalloproteinase (MMP)-2 (MMP-2), MMP-3, MMP-12, cathepsin D, and cathepsin B. HFD aortae exhibited an enhanced inflammatory status, characterized by tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) colocalized with adipocytes in the adventitia. HFD resulted in a significant increase in aortic dimensions, evident by ultrasound measurements. Telmisartan abolished aortic dilatation and preserved elastin content. HFD induced enhanced expression of aortic MMP-2, MMP 9, and TNF-alpha was abrogated by telmisartan. Adventitial proteolytic and inflammatory factors were also examined in samples from human abdominal aneurysms. The expression of TNF-alpha, IL-1beta, and MMP-9 was higher in the adventitial fat of diseased vessels compared with healthy tissues. Finally, adipocytes treated with TNF-alpha showed enhanced MMP-2, MMP-3, and cathepsin D, which was prevented by telmisartan. Taken together, HFD in mice induced aortic dilatation with up-regulation of matrix degrading and inflammatory pathways similar to those seen in human aortic aneurysmatic tissue. The HFD-induced vascular pathology was reduced by AT1-receptor antagonist telmisartan. PMID- 28646122 TI - Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. AB - Nintedanib (BIBF1120) is a triple kinase inhibitor of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptor (VEGFR), and Src family kinase, which has recently been approved by FDA to treat idiopathic pulmonary fibrosis. Whether it affects renal fibrosis remains unknown. Here, we demonstrated that administration of nintedanib immediately or 3 days after unilateral ureteral obstruction (UUO) injury and with folic acid (FA) injection attenuated renal fibrosis and inhibited activation of renal interstitial fibroblasts. Delayed administration of nintedanib also partially reversed established renal fibrosis. Treatment with nintedanib blocked UUO-induced phosphorylation of PDGFRbeta, FGFR1, FGFR2, VEGFR2, and several Src family kinases including Src, Lck, Lyn as well as activation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-kappaB (NF-kappaB), and Smad-3 in the kidney. Furthermore, nintedanib inhibited UUO-elicited renal proinflammatory cytokine expression and macrophage infiltration. These data indicate that nintedanib is a potent anti-fibrotic agent in the kidney and may hold therapeutic potential as a treatment of chronic fibrotic kidney disease. PMID- 28646123 TI - Expression of miR-23a induces telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease. AB - Telomeric repeat binding factor (TRF) 2 (TRF2) plays an important role in telomere maintenance. miR-23a may directly inhibit TRF2 expression, thereby, inducing telomere shortening and cellular senescence. The present study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels. The present study included 104 patients with CAD and 50 controls. Patients with CAD were randomly divided into two subgroups (a moderate lipid lowering therapy (LLT) group and an aggressive LLT group). Peripheral blood mononuclear cells (PBMCs) were taken from patients with CAD and from controls at baseline and after 12 months. Levels of miR-23a were higher in the CAD group than in the controls. Levels of TRF2 protein were lower in the CAD group than in the controls. Our randomized clinical study showed that aggressive LLT decreased miR-23a and increased TRF2 levels, whereas moderate LLT generated no change in these levels. Our transfected cell model showed that miR-23a controlled TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR 23a, low TRF2 or low relative telomere length. Multivariate analysis showed that levels of miR-23a (RR: 4.9, 95% CI: 1.9-14.3) were a strong predictor of cardiovascular events after adjustment for baseline characteristics. In conclusion, elevated levels of miR-23a play an important role in coronary atherosclerosis via down-regulated TRF2, and may provide important prognostic information in patients with CAD. Additionally, aggressive LLT may prevent telomere erosion via down-regulated miR-23a. PMID- 28646124 TI - Nickel ions inhibit histone demethylase JMJD1A and DNA repair enzyme ABH2 by replacing the ferrous iron in the catalytic centers. PMID- 28646125 TI - The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition. PMID- 28646126 TI - How a helix imposes palmitoylation of a membrane protein: What one can learn from NCX. AB - Palmitoylation is a critical post-translational modification that anchors proteins to, and regulates transport across, the lipid bilayer. Palmitoylation enzymes have been assumed to select their substrates based on a protein's primary sequence, but a consensus sequence has been slow to emerge. A study of the sodium/calcium exchanger now suggests that secondary structure may hold the key to understanding the determinants of this modification. PMID- 28646127 TI - Induction of labour at 37 weeks for suspected fetal macrosomia may reduce birth trauma. PMID- 28646128 TI - gamma-COPI mediates the retention of kAE1 G701D protein in Golgi apparatus - a mechanistic explanation of distal renal tubular acidosis associated with the G701D mutation. AB - Mutations of the solute carrier family 4 member 1 (SLC4A1) gene encoding kidney anion (chloride/bicarbonate ion) exchanger 1 (kAE1) can cause genetic distal renal tubular acidosis (dRTA). Different SLC4A1 mutations give rise to mutant kAE1 proteins with distinct defects in protein trafficking. The mutant kAE1 protein may be retained in endoplasmic reticulum (ER) or Golgi apparatus, or mis targeted to the apical membrane, failing to display its function at the baso lateral membrane. The ER-retained mutant kAE1 interacts with calnexin chaperone protein; disruption of this interaction permits the mutant kAE1 to reach the cell surface and display anion exchange activity. However, the mechanism of Golgi retention of mutant kAE1 G701D protein, which is otherwise functional, is still unclear. In the present study, we show that Golgi retention of kAE1 G701D is due to a stable interaction with the Golgi-resident protein, coat protein complex I (COPI), that plays a role in retrograde vesicular trafficking and Golgi-based quality control. The interaction and co-localization of kAE1 G701D with the gamma COPI subunit were demonstrated in human embryonic kidney (HEK-293T) cells by co immunoprecipitation and immunofluorescence staining. Small interference RNA (siRNA) silencing of COPI expression in the transfected HEK-293T cells increased the cell surface expression of transgenic kAE1 G701D, as shown by immunofluorescence staining. Our data unveil the molecular mechanism of Golgi retention of kAE1 G701D and suggest that disruption of the COPI-kAE1 G701D interaction could be a therapeutic strategy to treat dRTA caused by this mutant. PMID- 28646129 TI - Microscope Enhanced the Efficacy and Safety of Anterior Cervical Surgery for Managing Cervical Ossification of the Posterior Longitudinal Ligament. AB - BACKGROUND We aimed to compare microscope-assisted anterior cervical surgery with traditional open-base surgery for treating cervical ossification of the posterior longitudinal ligament (OPLL). MATERIAL AND METHODS Patients were grouped into microscope-assisted anterior cervical surgery group (case group, n=30) and conventional anterior cervical surgery group (control group, n=30). Baseline characteristics, intraoperative and post-operative indexes including operation time, blood loss amount, duration of hospitalization, visual analogue scale (VAS), and complication rate were recorded. The neurological functions of patients were assessed using the Japanese Orthopaedic Association (JOA) score. Furthermore, the corresponding rate of improved JOA score (RIS) in each group was also calculated to evaluate surgery outcomes. RESULTS The average blood loss amount and hospital stay duration in the case group were lower than in the control group (p<0.05). The post-operative VAS scores of both groups were decreased significantly. Particularly the post-operative VAS score in the case group was significantly lower than that in the control group (p<0.05). While the improvement rate of JOA scores in the case group was significantly higher than that in control group after cervical spine surgery. A significantly higher RIS rate was observed in the case group (p<0.05). Furthermore, post-operative complications of patients in the case group were lower than those in the control group (p<0.05). CONCLUSIONS Compared to conventional anterior cervical surgery, surgeries operated with microscope exhibit higher efficacy and safety including less bleeding amount, shorter operation time, released pain degree, improved neurological functions, and fewer incidences of complications. PMID- 28646130 TI - Congenital Chloride Diarrhea (CCD): A Case Report of CCD Suspected by Prenatal Ultrasonography and Magnetic Resonance Imaging (MRI). AB - BACKGROUND Congenital chloride diarrhea (CCD) is a rare autosomal recessive disorder that is difficult to distinguish from fetal lower intestinal obstruction. A prenatal diagnosis will make a contribution to the prognosis of the newborn. CASE REPORT We report a rare case of congenital chloride diarrhea (CCD) prenatally suspected by ultrasound and MRI. The prenatal ultrasound revealed signs of intestinal dilatation suggesting lower intestinal obstruction. MRI findings also revealed intestinal dilatation that continued from the rectum. On T1-weighted images, fluid accumulation within the bowel was hypointense. CCD was strongly suspected rather than obstruction of the lower intestinal tract or Hirschsprung's disease. At 37 weeks and 3 days' gestation, cesarean section was performed because of fetal distress. The newborn was a 2396 g male with the Apgar scores 8 (1 min) and 9 (5 min). Watery diarrhea subsequently persisted, and on the 3rd day, hyponatremia and hypochloremia were present. The infant stool was hyperchloremic, so we diagnosed CCD. CONCLUSIONS When ultrasonography reveals signs of fetal gastrointestinal dilatation, lower intestinal obstruction is considered first. CCD is infrequent and has signs of intestinal dilatation similar to those of other intestinal ailments, so distinguishing these conditions is difficult. However, if CCD is suspected early, then use of MRI will allow its diagnosis. If the condition is diagnosed before birth, the prognosis of the newborn will improve. PMID- 28646131 TI - Insights on the drivers of genetic divergence in the European anchovy. AB - Anchovies represent the largest world's marine fish catches and the current threats on their populations impose a sustainable exploitment based on sound scientific information. In the European anchovy (Engraulis encrasicolus), the existence of several populations has been proposed but a global view is missing. Using a multidisciplinary approach, here we assessed the divergence among different ecotypes and its possible causes. SNPs have revealed two functionally distinct ecotypes overlapping in the Central Mediterranean, with one ecotype confined near the river estuaries. The same SNPs outliers also segregated two distinct populations in the near Atlantic, despite their large spatial distance. In addition, while most studies suggested that adaptation to low salinity is key to divergence, here we show that the offshore ecotype has higher environmental tolerance and an opportunistic feeding behaviour, as assessed by the study of environmental conditions, anchovy diet and trophic levels, and passive egg dispersal. These results provide insights into the anchovy evolutionary history, stressing the importance of behaviour in shaping ecotypes. PMID- 28646132 TI - Global rainfall erosivity assessment based on high-temporal resolution rainfall records. AB - The exposure of the Earth's surface to the energetic input of rainfall is one of the key factors controlling water erosion. While water erosion is identified as the most serious cause of soil degradation globally, global patterns of rainfall erosivity remain poorly quantified and estimates have large uncertainties. This hampers the implementation of effective soil degradation mitigation and restoration strategies. Quantifying rainfall erosivity is challenging as it requires high temporal resolution(<30 min) and high fidelity rainfall recordings. We present the results of an extensive global data collection effort whereby we estimated rainfall erosivity for 3,625 stations covering 63 countries. This first ever Global Rainfall Erosivity Database was used to develop a global erosivity map at 30 arc-seconds(~1 km) based on a Gaussian Process Regression(GPR). Globally, the mean rainfall erosivity was estimated to be 2,190 MJ mm ha-1 h-1 yr 1, with the highest values in South America and the Caribbean countries, Central east Africa and South east Asia. The lowest values are mainly found in Canada, the Russian Federation, Northern Europe, Northern Africa and the Middle East. The tropical climate zone has the highest mean rainfall erosivity followed by the temperate whereas the lowest mean was estimated in the cold climate zone. PMID- 28646133 TI - Effects of energetic ion irradiation on WSe2/SiC heterostructures. AB - The remarkable electronic properties of layered semiconducting transition metal dichalcogenides (TMDs) make them promising candidates for next-generation ultrathin, low-power, high-speed electronics. It has been suggested that electronics based upon ultra-thin TMDs may be appropriate for use in high radiation environments such as space. Here, we present the effects of irradiation by protons, iron, and silver ions at MeV-level energies on a WSe2/6H-SiC vertical heterostructure studied using XPS and UV-Vis-NIR spectroscopy. It was found that with 2 MeV protons, a fluence of 1016 protons/cm2 was necessary to induce a significant charge transfer from SiC to WSe2, where a reduction of valence band offset was observed. Simultaneously, a new absorption edge appeared at 1.1 eV below the conduction band of SiC. The irradiation with heavy ions at 1016 ions/cm2 converts WSe2 into a mixture of WOx and Se-deficient WSe2. The valence band is also heavily altered due to oxidation and amorphization. However, these doses are in excess of the doses needed to damage TMD-based electronics due to defects generated in common dielectric and substrate materials. As such, the radiation stability of WSe2-based electronics is not expected to be limited by the radiation hardness of WSe2, but rather by the dielectric and substrate. PMID- 28646134 TI - Complete mitochondrial genome of Clistocoeloma sinensis (Brachyura: Grapsoidea): Gene rearrangements and higher-level phylogeny of the Brachyura. AB - Deciphering the animal mitochondrial genome (mitogenome) is very important to understand their molecular evolution and phylogenetic relationships. In this study, the complete mitogenome of Clistocoeloma sinensis was determined. The mitogenome of C. sinensis was 15,706 bp long, and its A+T content was 75.7%. The A+T skew of the mitogenome of C. sinensis was slightly negative (-0.020). All the transfer RNA genes had the typical cloverleaf structure, except for the trnS1 gene, which lacked a dihydroxyuridine arm. The two ribosomal RNA genes had 80.2% A+T content. The A+T-rich region spanned 684 bp. The gene order within the complete mitogenome of C. sinensis was identical to the pancrustacean ground pattern except for the translocation of trnH. Additionally, the gene order of trnI-trnQ-trnM in the pancrustacean ground pattern becomes trnQ-trnI-trnM in C. sinensis. Our phylogenetic analysis showed that C. sinensis and Sesarmops sinensis cluster together with high nodal support values, indicating that C. sinensis and S. sinensis have a sister group relationship. The results support that C. sinensis belongs to Grapsoidea, Sesarmidae. Our findings also indicate that Varunidae and Sesarmidae species share close relationships. Thus, mitogenomes are likely to be valuable tools for systematics in other groups of Crustacea. PMID- 28646135 TI - Active translocation of a semiflexible polymer assisted by an ATP-based molecular motor. AB - In this work we study the assisted translocation of a polymer across a membrane nanopore, inside which a molecular motor exerts a force fuelled by the hydrolysis of ATP molecules. In our model the motor switches to its active state for a fixed amount of time, while it waits for an ATP molecule which triggers the motor, during an exponentially distributed time lapse. The polymer is modelled as a beads-springs chain with both excluded volume and bending contributions, and moves in a stochastic three dimensional environment modelled with a Langevin dynamics at a fixed temperature. The resulting dynamics shows a Michaelis-Menten translocation velocity that depends on the chain flexibility. The scaling behavior of the mean translocation time with the polymer length for different bending values is also investigated. PMID- 28646136 TI - Recurrent background mutations in WHI2 impair proteostasis and degradation of misfolded cytosolic proteins in Saccharomyces cerevisiae. AB - Proteostasis promotes viability at both the cellular and organism levels by maintaining a functional proteome. This requires an intricate protein quality control (PQC) network that mediates protein folding by molecular chaperones and removes terminally misfolded proteins via the ubiquitin proteasome system and autophagy. How changes within the PQC network can perturb proteostasis and shift the balance between protein folding and proteolysis remain poorly understood. However, given that proteostasis is altered in a number of conditions such as cancer and ageing, it is critical that we identify the factors that mediate PQC and understand the interplay between members of the proteostatic network. In this study, we investigated the degradation of a thermally unstable cytosolic model substrate and identified a surprisingly high number of strains in the yeast knockout collection that displayed impaired turnover of the misfolded substrate. We found that this phenotype was caused by frequent background mutations in the general stress response gene WHI2. We linked this proteostatic defect to the lack of activity of the stress response transcription factor Msn2, potentially under conditions where the TOR pathway is active. Our results underscore how changes to the elaborate PQC network can perturb proteostasis and impair degradation of misfolded cytosolic proteins. PMID- 28646137 TI - Three-Dimensional Multi-Doped Porous Carbon/Graphene Derived from Sewage Sludge with Template-Assisted Fe-pillared Montmorillonite for Enhanced Oxygen Reduction Reaction. AB - Three-dimensional multi-doped porous carbon/graphene (Fe-Mt-SS-C) was prepared by carbonization of sewage sludge with template-assisted Fe-pillared montmorillonite. The material consisted of nanosheet- and particle- carbon had a high specific surface area (784.46 m2.g-1) and hierarchical porous structure of micro-, meso- and macropores. The prepared Fe-Mt-SS-C had a high degree of graphitization and large amount of defect atoms. The pyrolysis process made full use of the C, N, Fe, and S by turning them into the carbon framework of the as obtained material in situ. Template-assisted Fe-pillared montmorillonite contributed to more characteristics of morphology and composition on Fe-Mt-SS-C than other three materials (SS-C, Mt-SS-C and Fe-SS-C), and enhanced the electrocatalytic ORR activity by providing more adsorption sites and the electronic structure, resulting in the increase of conductivity and electrochemical activity. The ORR activity performance of Fe-Mt-SS-C, including the value of onset potential (0.03 V) and E1/2 (-0.09 V), was better than that of commercial 20 wt% Pt/C (-0.02 V and -0.18 V, respectively). Moreover, the Fe-Mt SS-C possessed excellent durability and outstanding immunity toward methanol crossover effects. Therefore, the resultant Fe-Mt-SS-C has great potential to applied as a high-efficiency ORR electrocatalyst, more importantly, it realizes the utilization of the sludge at the same time. PMID- 28646138 TI - Uniting the neuro developmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia. AB - Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naive patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL 10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia. PMID- 28646139 TI - Genome-wide identification of Major Intrinsic Proteins in Glycine soja and characterization of GmTIP2;1 function under salt and water stress. AB - In different plant species, aquaporins (AQPs) facilitate water movement by regulating root hydraulic conductivity under diverse stress conditions such as salt and water stresses. To improve survival and yield of crop plants, a detailed understanding of stress responses is imperative and required. We used Glycine soja genome as a tool to study AQPs, considering it shows abundant genetic diversity and higher salt environment tolerance features and identified 62 Gs AQP genes. Additionally, this study identifies major aquaporins responsive to salt and drought stresses in soybean and elucidates their mode of action through yeast two-hybrid assay and BiFC. Under stress condition, the expression analysis of AQPs in roots and leaves of two contrasting ecotypes of soybean revealed diverse expression patterns suggesting complex regulation at transcriptional level. Based on expression analysis, we identify GmTIP2;1 as a potential candidate involved in salinity and drought responses. The overexpression of GmTIP2;1 in Saccharomyces cerevisiae as well as in-planta enhanced salt and drought tolerance. We identified that GmTIP2;1 forms homodimers as well as interacts with GmTIP1;7 and GmTIP1;8. This study augments our knowledge of stress responsive pathways and also establishes GmTIP2;1 as a new stress responsive gene in imparting salt stress tolerance in soybean. PMID- 28646140 TI - Effect of dietary advanced glycation end products on inflammation and cardiovascular risks in healthy overweight adults: a randomised crossover trial. AB - Diets high in advanced glycation end products (AGEs) are thought to be detrimental to cardiovascular health. However, there remains uncertainty about the beneficial effect of a low AGE diet on cardiovascular risk factors and inflammatory markers in overweight individuals. We thus performed a randomised, double blind, crossover trial to determine whether consumption of low AGE diets reduce inflammation and cardiovascular risks in overweight and obese otherwise healthy adults. All participants (n = 20) consumed low and high AGE diets alternately for two weeks and separated by a four week washout period. Low AGE diets did not change systolic (p = 0.2) and diastolic blood pressure (p = 0.3), mean arterial pressure (p = 0.8) and pulse pressure (p = 0.2) compared to high AGE diets. Change in total cholesterol (p = 0.3), low-density lipoprotein (p = 0.7), high-density lipoprotein (p = 0.2), and triglycerides (p = 0.4) also did not differ and there was no difference in inflammatory markers: interleukin-6 (p = 0.6), monocyte chemoattractant protein-1 (p = 0.9), tumour necrosis factor alpha (p = 0.2), C-reactive protein (p = 0.6) and nuclear factor kappa beta (p = 0.2). These findings indicate that consumption of low AGE diets for two weeks did not improve the inflammatory and cardiovascular profiles of overweight and obese adults. PMID- 28646141 TI - Human Sialidase Neu3 is S-Acylated and Behaves Like an Integral Membrane Protein. AB - Membrane-bound sialidase Neu3 is involved in the catabolism of glycoconjugates, and plays crucial roles in numerous biological processes. Since the mechanism of its association with membranes is still not completely understood, the aim of this work was to provide further information regarding this aspect. Human Neu3 was found to be associated with the plasma membrane and endomembranes, and it was not released from the lipid bilayer under conditions that typically release peripheral membrane proteins. By different experimental approaches, we demonstrated that its C-terminus is exposed to the cytosol while another portion of the protein is exposed to the extracellular space, suggesting that Neu3 possesses the features of a transmembrane protein. However, in silico analysis and homology modeling predicted that the sialidase does not contain any alpha helical transmembrane segment and shares the same beta-propeller fold typical of viral and bacterial sialidases. Additionally, we found that Neu3 is S-acylated. Since this post-translational modification is restricted to the cytosolic side of membranes, this finding strongly supports the idea that Neu3 may contain a cytosolic-exposed domain. Although it remains to be determined exactly how this sialidase crosses the lipid bilayer, this study provides new insights about membrane association and topology of Neu3. PMID- 28646142 TI - Efficacy and safety of tenofovir disoproxil fumarate in preventing vertical transmission of hepatitis B in pregnancies with high viral load. AB - This study was a meta-analysis of the literature on the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission of hepatitis B in pregnancies with high viral load. Four observational studies and one randomized controlled trial involving 585 pregnant women and 595 newborns were included in the meta-analysis. TDF was more effective than the placebo in reducing vertical transmission in HBeAg-positive chronic hepatitis B (CHB) pregnancies with high serum HBV-DNA levels (OR = 0.21, 95% CI = 0.07-0.61) at 4 12 months, infant HBV DNA seropositivity at delivery (OR = 0.16, 95% CI = 0.07 0.37), and a severe flair in maternal alanine aminotransferase (ALT) levels (OR = 0.43, 95% CI = 0.19-0.95) during pregnancy. In addition, TDF showed more improvement in HBV DNA suppression at delivery (OR = 254.46, 95% CI = 28.39 2280.79). No significant differences were found in HBeAg seroconversion or ALT normalization; or in rates of cesarean section, emergent cesarean section, postpartum hemorrhage, prematurity, congenital malformations, or infant death. However, TDF induced more drug-related adverse events (OR = 2.33, 95% CI = 1.39 3.89) and elevated creatine kinase (CK) (OR = 9.56, 95% CI = 1.17-78.09) than in controls. The available evidence suggests that TDF is effective and safe in preventing vertical transmission of hepatitis B in pregnancies exhibiting a high viral load. PMID- 28646143 TI - A comparison between sphere and rod nanoparticles regarding their in vivo biological behavior and pharmacokinetics. AB - In recent years, spherical nanoparticles has been studied extensively on biomedical applications including bioimaging and biosensing, diagnostics and theranostics, but the effect of the shape of nanoparticles has received little attention. In the present study, we designed three different shaped fluorescent mesoporous silica nanoparticles (MSNs), long rod nanoparticles (NLR), short rod nanoparticles (NSR), and spherical nanoparticles (NS) to systematically examine their behavior in vivo after oral administration. The results of the ex vivo optical imaging study in mice indicated that rod nanoparticles had a longer residence time in the gastrointestinal compared with spherical nanoparticles. The in vivo biodistribution showed that all the orally administered MSNs were mainly taken up by the liver, and kidney. NLR had a great capacity to overcoming rapid clearance by the RES and exhibited a longer circulation in the blood than NSR and NS. During renal excretion, the spherical nanoparticles were cleared faster than rod nanoparticles. In addition, it was also found that MSNs can be degraded in vivo and NSR were degraded faster than NLR and NS probably owing to their higher specific surface area. The pharmacokinetic results demonstrated that nifedipine(NI)-loaded NLR had a higher bioavailability than NI-loaded NSR and NS. PMID- 28646144 TI - Using Fractional Intensities of Time-resolved Fluorescence to Sensitively Quantify NADH/NAD+ with Genetically Encoded Fluorescent Biosensors. AB - In this paper, we propose a novel and sensitive ratiometric analysis method that uses the fractional intensities of time-resolved fluorescence of genetically encoded fluorescent NADH/NAD+ biosensors, Peredox, SoNar, and Frex. When the conformations of the biosensors change upon NADH/NAD+ binding, the fractional intensities (alpha i tau i ) have opposite changing trends. Their ratios could be exploited to quantify NADH/NAD+ levels with a larger dynamic range and higher resolution versus commonly used fluorescence intensity and lifetime methods. Moreover, only one excitation and one emission wavelength are required for this ratiometric measurement. This eliminates problems of traditional excitation ratiometric and emission-ratiometric methods. This method could be used to simplify the design and achieve highly sensitive analyte quantification of genetically encoded fluorescent biosensors. Wide potential applications could be developed for imaging live cell metabolism based on this new method. PMID- 28646145 TI - The calmodulin fused kinase novel gene family is the major system in plants converting Ca2+ signals to protein phosphorylation responses. AB - Eukaryotes utilize Ca2+ as a universal second messenger to convert and multiply environmental and developmental signals to downstream protein phosphorylation responses. However, the phylogenetic relationships of the genes that convert Ca2+ signal (CS) to protein phosphorylation responses (PPRs) remain highly controversial, and their origin and evolutionary trajectory are unclear, which greatly hinders functional studies. Here we examined the deep phylogeny of eukaryotic CS converter gene families and identified a phylogenetically and structurally distinctive monophyly in Archaeplastida. This monophyly can be divided into four subfamilies, and each can be traced to ancestral members that contain a kinase domain and a calmodulin-like domain. This strongly indicates that the ancestor of this monophyly originated by a de novo fusion of a kinase gene and a calmodulin gene. This gene family, with a proposed new name, Calmodulin Fused Kinase (CFK), had expanded and diverged significantly both in sizes and in structures for efficient and accurate Ca2+ signalling, and was shown to play pivotal roles in all the six major plant adaptation events in evolution. Our findings elucidated the common origin of all CS-PPR converter genes except CBL-CIPK converter genes, and revealed that CFKs act as the main CS conversion system in plants. PMID- 28646146 TI - Optical coherence microscopy as a novel, non-invasive method for the 4D live imaging of early mammalian embryos. AB - Imaging of living cells based on traditional fluorescence and confocal laser scanning microscopy has delivered an enormous amount of information critical for understanding biological processes in single cells. However, the requirement for a high numerical aperture and fluorescent markers still limits researchers' ability to visualize the cellular architecture without causing short- and long term photodamage. Optical coherence microscopy (OCM) is a promising alternative that circumvents the technical limitations of fluorescence imaging techniques and provides unique access to fundamental aspects of early embryonic development, without the requirement for sample pre-processing or labeling. In the present paper, we utilized the internal motion of cytoplasm, as well as custom scanning and signal processing protocols, to effectively reduce the speckle noise typical for standard OCM and enable high-resolution intracellular time-lapse imaging. To test our imaging system we used mouse and pig oocytes and embryos and visualized them through fertilization and the first embryonic division, as well as at selected stages of oogenesis and preimplantation development. Because all morphological and morphokinetic properties recorded by OCM are believed to be biomarkers of oocyte/embryo quality, OCM may represent a new chapter in imaging based preimplantation embryo diagnostics. PMID- 28646147 TI - Whole organ vascular casting and microCT examination of the human placental vascular tree reveals novel alterations associated with pregnancy disease. AB - Experimental methods that allow examination of the intact vascular network of large organs, such as the human placenta are limited, preventing adequate comparison of normal and abnormal vascular development in pregnancy disease. Our aims were (i) to devise an effective technique for three-dimensional analyses of human placental vessels; (ii) demonstrate the utility of the technique in the comparison of placental vessel networks in normal and fetal growth restriction (FGR) complicated pregnancies. Radiopaque plastic vessel networks of normal and FGR placentas (n = 12/group) were created by filling the vessels with resin and corroding the surrounding tissues. Subsequently, each model was scanned in a microCT scanner, reconstructed into three-dimensional virtual objects and analysed in visualisation programmes. MicroCT imaging of the models defined vessel anatomy to our analyses threshold of 100 um diameter. Median vessel length density was significantly shorter in arterial but longer in venous FGR networks compared to normals. No significant differences were demonstrable in arterial or venous tortuosity, diameter or branch density. This study demonstrates the potential effectiveness of microCT for ex-vivo examination of human placental vessel morphology. Our findings show significant discrepancies in vessel length density in FGR placentas. The effects on fetoplacental blood flow, and hence nutrient transfer to the fetus, are unknown. PMID- 28646148 TI - miR-15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kappaB/XIAP axis. AB - Drug resistance, which is closely correlated with an imbalance in apoptosis, endows colorectal cancer (CRC) with enhanced progression capacity irrespective of the treatment with therapeutics. We report that miR-15b-5p is a tumor suppressor whose level is globally decreased in CRC cells and tissues. Over-expression of miR-15b-5p not only promoted 5-fluorouracil (5-FU)-induced cellular apoptosis but also reversed the chemoresistance of 5-FU in vitro and in vivo. As a key mediator of inflammation-induced cancer, miR-15b-5p enhances these therapeutic effects are mainly attributed to targeting of the NF-kappaB signaling pathway through negative regulation of NF-kappaB1 and one of its kinase complexes IKK-alpha. miR 15b-5p mediates NF-KB regulation by targeting the anti-apoptosis protein XIAP in vitro. Together, these results establish an axis of miR-15b-mediated apoptosis regulation, which reverses chemoresistance and suppresses CRC progression. These findings suggest that miR-15b-5p may be a potential agent for CRC treatment, particularly for 5-FU-resistant CRC. PMID- 28646149 TI - Crucial role of 4-deoxy-L-erythro-5-hexoseulose uronate reductase for alginate utilization revealed by adaptive evolution in engineered Saccharomyces cerevisiae. AB - In brown macroalgae, alginate and D-mannitol are promising carbohydrates for biorefinery. Saccharomyces cerevisiae is widely used as a microbial cell factory, but this budding yeast is unable to utilize either alginate or D-mannitol. Alginate can be depolymerized by both endo-type and exo-type alginate lyases, yielding a monouronate, 4-deoxy-L-erythro-5-hexoseulose uronate (DEH), a key intermediate in the metabolism of alginate. Here, we constructed engineered two S. cerevisiae strains that are able to utilize both DEH and D-mannitol on two different strain backgrounds, and we also improved their aerobic growth in a DEH liquid medium through adaptive evolution. In both evolved strains, one of the causal mutations was surprisingly identical, a c.50A > G mutation in the codon optimized NAD(P)H-dependent DEH reductase gene, one of the 4 genes introduced to confer the capacity to utilize DEH. This mutation resulted in an E17G substitution at a loop structure near the coenzyme-binding site of this reductase, and enhanced the reductase activity and aerobic growth in both evolved strains. Thus, the crucial role for this reductase reaction in the metabolism of DEH in the engineered S. cerevisiae is demonstrated, and this finding provides significant information for synthetic construction of a S. cerevisiae strain as a platform for alginate utilization. PMID- 28646150 TI - Global Trends and Regional Variations in Studies of HIV/AIDS. AB - We conduct textual analysis of a sample of more than 200,000 papers written on HIV/AIDS during the past three decades. Using the Latent Dirichlet Allocation method, we disentangle studies that address behavioral and social aspects from other studies and measure the trends of different topics as related to HIV/AIDS. We show that there is a regional variation in scientists' approach to the problem of HIV/AIDS. Our results show that controlling for the economy, proximity to the HIV/AIDS problem correlates with the extent to which scientists look at the behavioral and social aspects of the disease rather than biomedical. PMID- 28646151 TI - Optimal surveillance strategies for bovine tuberculosis in a low-prevalence country. AB - Bovine tuberculosis (bTB) is a chronic disease of cattle that is difficult to control and eradicate in part due to the costly nature of surveillance and poor sensitivity of diagnostic tests. Like many countries, bTB prevalence in Uruguay has gradually declined to low levels due to intensive surveillance and control efforts over the past decades. In low prevalence settings, broad-based surveillance strategies based on routine testing may not be the most cost effective way for controlling between-farm bTB transmission, while targeted surveillance aimed at high-risk farms may be more efficient for this purpose. To investigate the efficacy of targeted surveillance, we developed an integrated within- and between-farm bTB transmission model utilizing data from Uruguay's comprehensive animal movement database. A genetic algorithm was used to fit uncertain parameter values, such as the animal-level sensitivity of skin testing and slaughter inspection, to observed bTB epidemiological data. Of ten alternative surveillance strategies evaluated, a strategy based on eliminating testing in low-risk farms resulted in a 40% reduction in sampling effort without increasing bTB incidence. These results can inform the design of more cost effective surveillance programs to detect and control bTB in Uruguay and other countries with low bTB prevalence. PMID- 28646152 TI - Differentiating Thamnocalamus Munro from Fargesia Franchet emend. Yi (Bambusoideae, Poaceae): novel evidence from morphological and neural-network analyses. AB - Fargesia Franchet emend. Yi is closely allied with Thamnocalamus Munro but differs in many major morphological characteristics. Based on traditional morphological characters, it is difficult to differentiate these two genera. The current study measured 19 species in these two genera to determine whether variations in 12 categories of major characters are continuous. In addition, a self-organizing map (SOM) and cluster analysis were used together to reveal whether the known species of Fargesia represent discontinuous sampling of Thamnocalamus. The results show that 46 morphological characteristics exhibited high variation at the generic and species levels. In addition, the cluster analysis showed that 32 morphological characteristics of Thamnocalamus and Fargesia were divided between two species and well separated from the outgroup. Additionally, significant differences (P < 0.01) were observed in the reproductive structures between these two genera. The unrooted dendrogram, which was based on the SOM neural network, shows the same results as the cluster analysis of morphological characteristics. These data indicate that Fargesia is not a result of discontinuous sampling of Thamnocalamus; thus, Fargesia should not be treated as a synonym for Thamnocalamus. PMID- 28646153 TI - Giant Rashba effect at the topological surface of PrGe revealing antiferromagnetic spintronics. AB - Rashba spin-orbit splitting in the magnetic materials opens up a new perspective in the field of spintronics. Here, we report a giant Rashba spin-orbit splitting on the PrGe [010] surface in the paramagnetic phase with Rashba coefficient alpha R = 5 eVA. We find that alpha R can be tuned in this system as a function of temperature at different magnetic phases. Rashba type spin polarized surface states originates due to the strong hybridization between Pr 4f states with the conduction electrons. Significant changes observed in the spin polarized surface states across the magnetic transitions are due to the competition between Dzyaloshinsky-Moriya interaction and exchange interaction present in this system. Presence of Dzyaloshinsky-Moriya interaction on the topological surface give rise to Saddle point singularity which leads to electron-like and hole-like Rashba spin split bands in the [Formula: see text] and [Formula: see text] directions, respectively. Supporting evidences of Dzyaloshinsky-Moriya interaction have been obtained as anisotropic magnetoresistance with respect to field direction and first-order type hysteresis in the X-ray diffraction measurements. A giant negative magnetoresistance of 43% in the antiferromagnetic phase and tunable Rashba parameter with temperature makes this material a suitable candidate for application in the antiferromagnetic spintronic devices. PMID- 28646154 TI - Investigation of the removal mechanism of antibiotic ceftazidime by green algae and subsequent microbic impact assessment. AB - The present study provides an integrated view of algal removal of the antibiotic ceftazidime and its basic parent structure 7-aminocephalosporanic acid (7-ACA), including contribution analysis, bacteriostatic and aquatic toxic assessment and metabolite verification. 92.70% and 96.07% of the two target compounds was removed after the algal treatment, respectively. The algal removal can be separated into three steps: a rapid adsorption, a slow cell wall-transmission and the final biodegradation. Additionally, while ceftazidime demonstrated an excellent inhibitory effect on Escherichia coli, there was no bacteriostasis introduced after the algal treatment, which could avoid favoring the harmful selective pressure. On the other hand, no significant aquatic impact of the two target compounds on rotifers was observed and it was not enhanced after the algal treatment. To better reveal the mechanism involved, metabolite analyses were performed. Delta-3 ceftazidime and trans-ceftazidime were regarded as the metabolites of ceftazidime and the metabolite of 7-ACA was regarded as a compound which shared the similar structure with 4-chlorocinnamic acid. Our study indicated that the green algae performed a satisfactory growth capacity and played a dominant role for the biodegradation of the target antibiotics, which achieved high removal efficiency and low environmental impact. PMID- 28646155 TI - Breast Cancer Multi-classification from Histopathological Images with Structured Deep Learning Model. AB - Automated breast cancer multi-classification from histopathological images plays a key role in computer-aided breast cancer diagnosis or prognosis. Breast cancer multi-classification is to identify subordinate classes of breast cancer (Ductal carcinoma, Fibroadenoma, Lobular carcinoma, etc.). However, breast cancer multi classification from histopathological images faces two main challenges from: (1) the great difficulties in breast cancer multi-classification methods contrasting with the classification of binary classes (benign and malignant), and (2) the subtle differences in multiple classes due to the broad variability of high resolution image appearances, high coherency of cancerous cells, and extensive inhomogeneity of color distribution. Therefore, automated breast cancer multi classification from histopathological images is of great clinical significance yet has never been explored. Existing works in literature only focus on the binary classification but do not support further breast cancer quantitative assessment. In this study, we propose a breast cancer multi-classification method using a newly proposed deep learning model. The structured deep learning model has achieved remarkable performance (average 93.2% accuracy) on a large-scale dataset, which demonstrates the strength of our method in providing an efficient tool for breast cancer multi-classification in clinical settings. PMID- 28646156 TI - Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis. AB - Earlier we have established a carbazole alkaloid (mahanine) isolated from an Indian edible medicinal plant as an anticancer agent with minimal effect on normal cells. Here we report for the first time that mahanine-treated drug resistant and sensitive virulent Leishmania donovani promastigotes underwent apoptosis through phosphatidylserine externalization, DNA fragmentation and cell cycle arrest. An early induction of reactive oxygen species (ROS) suggests that the mahanine-induced apoptosis was mediated by oxidative stress. Additionally, mahanine-treated Leishmania-infected macrophages exhibited anti-amastigote activity by nitric oxide (NO)/ROS generation along with suppression of uncoupling protein 2 and Th1-biased cytokines response through modulating STAT pathway. Moreover, we have demonstrated the interaction of a few antioxidant enzymes present in parasite with mahanine through molecular modeling. Reduced genetic and protein level expression of one such enzyme namely ascorbate peroxidase was also observed in mahanine-treated promastigotes. Furthermore, oral administration of mahanine in acute murine model exhibited almost complete reduction of parasite burden, upregulation of NO/iNOS/ROS/IL-12 and T cell proliferation. Taken together, we have established a new function of mahanine as a potent antileishmanial molecule, capable of inducing ROS and exploit antioxidant enzymes in parasite along with modulation of host's immune response which could be developed as an inexpensive and nontoxic therapeutics either alone or in combination. PMID- 28646157 TI - Current Induced Resistive State in Fe(Se,Te) Superconducting Nanostrips. AB - We study the current-voltage characteristics of Fe(Se,Te) thin films deposited on CaF2 substrates in form of nanostrips (width w ~ lambda, lambda the London penetration length). In view of a possible application of these materials to superconductive electronics and micro-electronics we focus on transport properties in small magnetic field, the one generated by the bias current. From the characteristics taken at different temperatures we derive estimates for the pinning potential U and the pinning potential range delta for the magnetic flux lines (vortices). Since the sample lines are very narrow, the classical creep flow model provides a sufficiently accurate interpretation of the data only when the attractive interaction between magnetic flux lines of opposite sign is taken into account. The observed voltages and the induced depression of the critical current of the nanostrips are compatible with the presence of a low number ([Formula: see text]) magnetic field lines at the equilibrium, a strongly inhomogeneous current density distribution at the two ends of the strips and a reduced Bean Livingston barrier. In particular, we argue that the sharp corners defining the bridge geometry represent points of easy magnetic flux lines injection. The results are relevant for creep flow analysis in superconducting Fe(Se,Te) nanostrips. PMID- 28646158 TI - Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic beta cell proliferation after the withdrawal of OSI-906. AB - Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and beta cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling. PMID- 28646159 TI - YvcK, a protein required for cell wall integrity and optimal carbon source utilization, binds uridine diphosphate-sugars. AB - In Bacillus subtilis, Listeria monocytogenes and in two Mycobacteria, it was previously shown that yvcK is a gene required for normal cell shape, for optimal carbon source utilization and for virulence of pathogenic bacteria. Here we report that the B. subtilis protein YvcK binds to Uridine diphosphate-sugars like Uridine diphosphate-Glucose (UDP-Glc) and Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) in vitro. Using the crystal structure of Bacillus halodurans YvcK, we identified residues involved in this interaction. We tested the effect of point mutations affecting the ability of YvcK to bind UDP-sugars on B. subtilis physiology and on cell size. Indeed, it was shown that UDP-Glc serves as a metabolic signal to regulate B. subtilis cell size. Interestingly, we observed that, whereas a yvcK deletion results in the formation of unusually large cells, inactivation of YvcK UDP-sugar binding site does not affect cell length. However, these point mutations result in an increased sensitivity to bacitracin, an antibiotic which targets peptidoglycan synthesis. We thus propose that UDP GlcNAc, a precursor of peptidoglycan, could be a good physiological ligand candidate of YvcK. PMID- 28646160 TI - Loss of Galphai proteins impairs thymocyte development, disrupts T-cell trafficking, and leads to an expanded population of splenic CD4+PD-1+CXCR5+/- T cells. AB - Thymocyte and T cell trafficking relies on signals initiated by G-protein coupled receptors. To address the importance of the G-proteins Galphai2 and Galphai3 in thymocyte and T cell function, we developed several mouse models. Galphai2 deficiency in hematopoietic progenitors led to a small thymus, a double negative (DN)1/DN2 thymocyte transition block, and an accumulation of mature single positive (SP) thymocytes. Loss at the double positive (DP) stage of thymocyte development caused an increase in mature cells within the thymus. In both models an abnormal distribution of memory and naive CD4 T cells occurred, and peripheral CD4 and CD8 T cells had reduced chemoattractant responses. The loss of Galphai3 had no discernable impact, however the lack of both G-proteins commencing at the DP stage caused a severe T cell phenotype. These mice lacked a thymic medullary region, exhibited thymocyte retention, had a peripheral T cell deficiency, and lacked T cell chemoattractant responses. Yet a noteworthy population of CD4+PD 1+CXCR5+/- cells resided in the spleen of these mice likely due to a loss of regulatory T cell function. Our results delineate a role for Galphai2 in early thymocyte development and for Galphai2/3 in multiple aspects of T cell biology. PMID- 28646161 TI - Circulating exosomal miR-125a-3p as a novel biomarker for early-stage colon cancer. AB - Circulating exosome holds great potentials as biomarker for diagnosis and prognosis of human cancers. Previously, we have applied small RNA sequencing to identify aberrantly expressed exosomal miRNAs as candidates for diagnostic markers in colon cancer patients. In this validation cohort, plasma derived exosomal miRNA was isolated from 50 early-stage colon cancer patients and 50 matched healthy volunteers. Real-time qRT-PCR revealed that miR-125a-3p, miR-320c were significantly up-regulated in plasma exosomes of the patients with early stage colon cancer. ROC curve showed that miR-125a-3p abundant level may predict colon cancer with an area of under the curve (AUC) of 68.5%, in comparison to that of CEA at 83.6%. Combination of miR-125a-3P and CEA improved the AUC to 85.5%. In addition, plasma exosome level of miR-125a-3p and miR-320c showed significant correlation with nerve infiltration (P < 0.01), but not with tumor size, infiltration depth, and differentiation degree (P > 0.05). On the contrary, plasma CEA level is correlated with tumor size, infiltration depth, and differentiation degree (P < 0.05, r = 0.3009-0.7270), but not with nerve infiltration (P = 0.744). In conclusion, this follow-up study demonstrated circulating plasma exosomal miR-125a-3p is readily accessible as diagnosis biomarker for early-stage colon cancer. When combined with conventional diagnostic markers, miR-125a-3p can improve the diagnostic power. PMID- 28646162 TI - Associations between Global DNA Methylation and Telomere Length in Healthy Adolescents. AB - Emerging evidence suggests that epigenetics regulates telomere dynamics in adults. However, the relationship between these pathways in children and youth remains unknown. Thus, we examined this association in 542 healthy adolescents aged 14 to 18 years old (44.8% African Americans; 55.2% females). Global DNA methylation level (%5-mC) was quantified using ELISA method. Leukocyte telomere length (LTL) was defined as relative telomere to single copy gene (T/S) ratio. Multiple linear regression models, adjusted for age, gender, ethnicity, Tanner stage, BMI, PA, and batch effect, revealed that %5 mC was associated with LTL (adjusted beta = 0.17, p < 0.01). %5 mC accounted for 5.0% of the variation for LTL. A significant gender interaction was identified (p < 0.01). There was an association between %5 mC and LTL in females (all ps < 0.01), but not in males. Further sensitivity analyses by race revealed similar associations in African Americans and whites (all ps < 0.03). The present study, for the first time, shows that lower levels of global DNA methylation are associated with shorter telomere lengths in youth, which may decrease genome stability and augment the susceptibility to diseases. Longitudinal studies are warranted to establish the effects of global DNA methylation on LTL maintenance over time. PMID- 28646163 TI - Aldosterone Modulates the Association between NCC and ENaC. AB - Distal sodium transport is a final step in the regulation of blood pressure. As such, understanding how the two main sodium transport proteins, the thiazide sensitive sodium chloride cotransporter (NCC) and the epithelial sodium channel (ENaC), are regulated is paramount. Both are expressed in the late distal nephron; however, no evidence has suggested that these two sodium transport proteins interact. Recently, we established that these two sodium transport proteins functionally interact in the second part of the distal nephron (DCT2). Given their co-localization within the DCT2, we hypothesized that NCC and ENaC interactions might be modulated by aldosterone (Aldo). Aldo treatment increased NCC and alphaENaC colocalization (electron microscopy) and interaction (coimmunoprecipitation). Finally, with co-expression of the Aldo-induced protein serum- and glucocorticoid-inducible kinase 1 (SGK1), NCC and alphaENaC interactions were increased. These data demonstrate that Aldo promotes increased interaction of NCC and ENaC, within the DCT2 revealing a novel method of regulation for distal sodium reabsorption. PMID- 28646164 TI - Regulation of Drosophila Lifespan by bellwether Promoter Alleles. AB - Longevity varies among individuals, but how natural genetic variation contributes to variation in lifespan is poorly understood. Drosophila melanogaster presents an advantageous model system to explore the genetic underpinnings of longevity, since its generation time is brief and both the genetic background and rearing environment can be precisely controlled. The bellwether (blw) gene encodes the alpha subunit of mitochondrial ATP synthase. Since metabolic rate may influence lifespan, we investigated whether alternative haplotypes in the blw promoter affect lifespan when expressed in a co-isogenic background. We amplified 521 bp upstream promoter sequences containing alternative haplotypes and assessed promoter activity both in vitro and in vivo using a luciferase reporter system. The AG haplotype showed significantly greater expression of luciferase than the GT haplotype. We then overexpressed a blw cDNA construct driven by either the AG or GT haplotype promoter in transgenic flies and showed that the AG haplotype also results in greater blw cDNA expression and a significant decrease in lifespan relative to the GT promoter haplotype, in male flies only. Thus, our results show that naturally occurring regulatory variants of blw affect lifespan in a sex-specific manner. PMID- 28646165 TI - Selective inhibition of sterolO-acyltransferase 1 isozyme by beauveriolide III in intact cells. AB - Beauveriolide III (BeauIII) inhibited sterol O-acyltransferases 1 and 2 (SOAT1 and SOAT2), which are endoplasmic reticulum (ER) membrane proteins, in an enzyme based assay, and selectively inhibited SOAT1 in a cell-based assay using SOAT1 /SOAT2-CHO cells. This discrepancy in SOAT inhibition by BeauIII was investigated. In the enzyme-based assay, BeauIII inhibited SOAT1 and SOAT2 to a similar extent using microsomes prepared from cells disrupted under the strongest sonication condition. In semi-intact SOAT1-/SOAT2-CHO cells prepared by a treatment with digitonin (plasma membrane permeabilized), BeauIII selectively inhibited SOAT1 (IC50; 5.0 uM (SOAT1) vs >90 uM (SOAT2)), while in those treated with saponin (plasma membrane and ER membrane permeabilized), BeauIII inhibited SOAT1 (IC50, 1.8 uM) and SOAT2 (5.9 uM). SOAT1-selective inhibition by BeauIII was reproduced in intact ER fractions prepared from SOAT1/SOAT2-CHO cells. A Western blotting analysis revealed that biotin-labeled beauveriolide bound to the SOAT1 protein prepared from SOAT1-CHO cells. We concluded that BeauIII binds to a putative active site responsible for SOAT1 that is located on the cytosolic side of the ER, while BeauIII is not accessible to the corresponding active site for SOAT2 located on the luminal side. PMID- 28646167 TI - Effectively infinite optical path-length created using a simple cubic photonic crystal for extreme light trapping. AB - A 900 nm thick TiO2 simple cubic photonic crystal with lattice constant 450 nm was fabricated and used to experimentally validate a newly-discovered mechanism for extreme light-bending. Absorption enhancement was observed extending 1-2 orders of magnitude over that of a reference TiO2 film. Several enhancement peaks in the region from 600-950 nm were identified, which far exceed both the ergodic fundamental limit and the limit based on surface-gratings, with some peaks exceeding 100 times enhancement. These results are attributed to radically sharp refraction where the optical path length approaches infinity due to the Poynting vector lying nearly parallel to the photonic crystal interface. The observed phenomena follow directly from the simple cubic symmetry of the photonic crystal, and can be achieved by integrating the light-trapping architecture into the absorbing volume. These results are not dependent on the material used, and can be applied to any future light trapping applications such as phosphor-converted white light generation, water-splitting, or thin-film solar cells, where increased response in areas of weak absorption is desired. PMID- 28646166 TI - ATP release during cell swelling activates a Ca2+-dependent Cl- current by autocrine mechanism in mouse hippocampal microglia. AB - Microglia cells, resident immune cells of the brain, survey brain parenchyma by dynamically extending and retracting their processes. Cl- channels, activated in the cellular response to stretch/swelling, take part in several functions deeply connected with microglia physiology, including cell shape changes, proliferation, differentiation and migration. However, the molecular identity and functional properties of these Cl- channels are largely unknown. We investigated the properties of swelling-activated currents in microglial from acute hippocampal slices of Cx3cr1 +/GFP mice by whole-cell patch-clamp and imaging techniques. The exposure of cells to a mild hypotonic medium, caused an outward rectifying current, developing in 5-10 minutes and reverting upon stimulus washout. This current, required for microglia ability to extend processes towards a damage signal, was carried mainly by Cl- ions and dependent on intracellular Ca2+. Moreover, it involved swelling-induced ATP release. We identified a purine dependent mechanism, likely constituting an amplification pathway of current activation: under hypotonic conditions, ATP release triggered the Ca2+-dependent activation of anionic channels by autocrine purine receptors stimulation. Our study on native microglia describes for the first time the functional properties of stretch/swelling-activated currents, representing a key element in microglia ability to monitor the brain parenchyma. PMID- 28646168 TI - The causal relationship between dyslexia and motion perception reconsidered. AB - It is well established that visual sensitivity to motion is correlated with reading skills. Yet, the causal relationship between motion sensitivity and reading skills has been debated for more than thirty years. One hypothesis posits that dyslexia is caused by deficits in the motion processing pathway. An alternative hypothesis explains the motion processing deficit observed in dyslexia as the consequence of a lack, or poor quality, of reading experience. Here we used an intensive reading intervention program to test the causal relationship between learning to read and motion processing in children. Our data show that, while the reading intervention enhanced reading abilities, learning to read did not affect motion sensitivity. Motion sensitivity remained stable over the course of the intervention. Furthermore, the motion sensitivity deficit did not negatively impact the learning process. Children with poor motion sensitivity showed the same improvement in reading skills as children with typical motion sensitivity. Our findings call into question the view that motion processing deficits are due to poor reading experience. We propose that the correlation between the two measures arises from other common mechanisms, or that motion processing deficits are among a collection of correlated risk factors for reading difficulties. PMID- 28646169 TI - Improving Dialysis Adherence for High Risk Patients Using Automated Messaging: Proof of Concept. AB - Comorbidities and socioeconomic barriers often limit patient adherence and self management with hemodialysis. Missed sessions, often associated with communication barriers, can result in emergency dialysis and avoidable hospitalizations. This proof of concept study explored using a novel digital messaging platform, EpxDialysis, to improve patient-to-dialysis center communication via widely available text messaging and telephone technology. A randomized controlled trial was conducted through Washington University affiliated hemodialysis centers involving ESRD patients with poor attendance, defined as missing 2-6 sessions over the preceding 12 weeks. A cross-over study design evaluated appointment adherence between intervention and control groups. Comparing nonadherence rates eight weeks prior to enrollment, median appointment adherence after using the system increased by 75%, and median number of unintended hospitalization days fell by 31%. A conservative cost-benefit analysis of EpxDialysis demonstrates a 1:36 savings ratio from appointment adherence. EpxDialysis is a low-risk, cost-effective, intervention for increasing hemodialysis adherence in high-risk patients, especially at centers caring for vulnerable and low-income patients. PMID- 28646170 TI - Triphenyltin recognition by primary structures of effector proteins and the protein network of Bacillus thuringiensis during the triphenyltin degradation process. AB - Herein, triphenyltin (TPT) biodegradation efficiency and its transformation pathway have been elucidated. To better understand the molecular mechanism of TPT degradation, the interactions between amino acids, primary structures, and quaternary conformations of effector proteins and TPT were studied. The results verified that TPT recognition and binding depended on amino acid sequences but not on secondary, tertiary or quaternary protein structure. During this process, TPT could change the molecular weight and isoelectric point of effector proteins, induce their methylation or demethylation, and alter their conformation. The effector proteins, alkyl hydroperoxide reductase and acetyl-CoA acetyltransferase, recognizing TPT were crucial to TPT degradation. Electron transfer flavoprotein subunit alpha, phosphoenolpyruvate carboxykinase, aconitate hydratase, branched-chain alpha-keto acid dehydrogenase E1 component, biotin carboxylase and superoxide dismutase were related to energy and carbon metabolism, which was consistent with the results in vivo. The current findings develop a new approach for investigating the interactions between proteins and target compounds. PMID- 28646171 TI - A new type of homodiploid fish derived from the interspecific hybridization of female common carp * male blunt snout bream. AB - It is commonly believed that hybridization might lead to the formation of new polyploidy species, but it is unclear whether hybridization can produce a new homodiploid species. Here, we report the spontaneous occurrence of a new crucian carp-like homodiploid fish (2n = 100) that originated from the interspecific hybridization of female common carp (Cyprinus carpio, Cyprininae, 2n = 100) * male blunt snout bream (Megalobrama amblycephala, Cultrinae, 2n = 48). The phenotype and reproductive traits of this new crucian carp-like homodiploid fish were found to be very similar to those of the existing diploid species (diploid crucian carp; Carassius auratus). FISH and 5S rDNA analyses revealed that the genotype of the crucian carp-like homodiploid fish differs from those of its parents but is closely related to that of diploid crucian carp. The results provide evidence of the existence of a possible route through which the distant hybridization of this cross can generate crucian carp. The new type of homodiploid fish is of great value in fish genetic breeding and for studying the early evolutionary process. PMID- 28646172 TI - Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells. AB - Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC. In this report, we show that dacomitinib, a pan-ErbB receptor inhibitor, diminished growth, clonogenic potential, anoikis resistance and induced apoptotic cell death in therapy-resistant EOC cells. Dacominitib inhibited PLK1-FOXM1 signalling pathway and its down-stream targets Aurora kinase B and survivin. Moreover, dacomitinib attenuated migration and invasion of the EOC cells and reduced expression of epithelial-to-mesenchymal transition (EMT) markers ZEB1, ZEB2 and CDH2 (which encodes N-cadherin). Conversely, the anti tumour activity of single-targeted ErbB agents including cetuximab (a ligand blocking anti-EGFR mAb), transtuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small-molecule tyrosine kinase inhibitor) were marginal. Our results provide a rationale for further investigation on the therapeutic potential of dacomitinib in treatment of the chemoresistant EOC. PMID- 28646174 TI - A GPU-accelerated algorithm for biclustering analysis and detection of condition dependent coexpression network modules. AB - In the analysis of large-scale gene expression data, it is important to identify groups of genes with common expression patterns under certain conditions. Many biclustering algorithms have been developed to address this problem. However, comprehensive discovery of functionally coherent biclusters from large datasets remains a challenging problem. Here we propose a GPU-accelerated biclustering algorithm, based on searching for the largest Condition-dependent Correlation Subgroups (CCS) for each gene in the gene expression dataset. We compared CCS with thirteen widely used biclustering algorithms. CCS consistently outperformed all the thirteen biclustering algorithms on both synthetic and real gene expression datasets. As a correlation-based biclustering method, CCS can also be used to find condition-dependent coexpression network modules. We implemented the CCS algorithm using C and implemented the parallelized CCS algorithm using CUDA C for GPU computing. The source code of CCS is available from https://github.com/abhatta3/Condition-dependent-Correlation-Subgroups-CCS. PMID- 28646173 TI - Transmembrane Interactions of Full-length Mammalian Bitopic Cytochrome-P450 Cytochrome-b5 Complex in Lipid Bilayers Revealed by Sensitivity-Enhanced Dynamic Nuclear Polarization Solid-state NMR Spectroscopy. AB - The dynamic protein-protein and protein-ligand interactions of integral bitopic membrane proteins with a single membrane-spanning helix play a plethora of vital roles in the cellular processes associated with human health and diseases, including signaling and enzymatic catalysis. While an increasing number of high resolution structural studies of membrane proteins have successfully manifested an in-depth understanding of their biological functions, intact membrane-bound bitopic protein-protein complexes pose tremendous challenges for structural studies by crystallography or solution NMR spectroscopy. Therefore, there is a growing interest in developing approaches to investigate the functional interactions of bitopic membrane proteins embedded in lipid bilayers at atomic level. Here we demonstrate the feasibility of dynamic nuclear polarization (DNP) magic-angle-spinning NMR techniques, along with a judiciously designed stable isotope labeling scheme, to measure atomistic-resolution transmembrane transmembrane interactions of full-length mammalian ~72-kDa cytochrome P450 cytochrome b5 complex in lipid bilayers. Additionally, the DNP sensitivity enhanced two-dimensional 13C/13C chemical shift correlations via proton driven spin diffusion provided distance constraints to characterize protein-lipid interactions and revealed the transmembrane topology of cytochrome b5. The results reported in this study would pave ways for high-resolution structural and topological investigations of membrane-bound full-length bitopic protein complexes under physiological conditions. PMID- 28646175 TI - Ribosome RNA Profiling to Quantify Ovarian Development and Identify Sex in Fish. AB - Terminologies of ovary development, by somewhat subjective describing and naming main changes of oocytes, have been criticized for confusing and inconsistency of terms and classifications, and the incurred consequences impede communication among researchers. In the present work, we developed regression between ovary development and three ribosome RNA (rRNA) indexes, namely 5S rRNA percent, 18S rRNA percent, and 5S-18S rRNA ratio, using close relationship between volume percent of primary growth stage oocytes or gonadosomatic index and rRNA content, demonstrating species-specific quantification of ovary development can be established in species with either synchronous and asynchronous oogenesis. This approach may be extended to any species with primary growth oocytes, e.g. anurans and reptiles, to predict maturity stages in females. We further confirmed that 5S rRNA percent and 5S/18S rRNA ratio can serve as markers to distinguish sexes unambiguously. A micro-invasive sampling method may be invented for non-lethal prediction of ovary development and sex because only a small amount of ovary sample (<50 mg) is needed for the approach established in the current work. Researchers who work with ovary RNA-seq in these taxa should realize that insufficient depletion of rRNA will probably lead to incorrect quantification of gene expression and inaccurate conclusions. PMID- 28646176 TI - Enhanced Atomic Desorption of 209 and 210 Francium from Organic Coating. AB - Controlled atomic desorption from organic Poly-DiMethylSiloxane coating is demonstrated for improving the loading efficiency of 209,210Fr magneto-optical traps. A three times increase in the cold atoms population is obtained with contact-less pulsed light-induced desorption, applied to different isotopes, either bosonic or fermionic, of Francium. A six times increase of 210Fr population is obtained with a desorption mechanism based on direct charge transfer from a triboelectric probe to the adatom-organic coating complex. Our findings provide new insight on the microscopic mechanisms of atomic desorption from organic coatings. Our results, obtained at room temperature so as to preserve ideal vacuum conditions, represent concrete alternatives, independent from the atomic species in use, for high-efficiency laser cooling in critical conditions. PMID- 28646177 TI - Hyperspectral Imaging for Presymptomatic Detection of Tobacco Disease with Successive Projections Algorithm and Machine-learning Classifiers. AB - We investigated the feasibility and potentiality of presymptomatic detection of tobacco disease using hyperspectral imaging, combined with the variable selection method and machine-learning classifiers. Images from healthy and TMV-infected leaves with 2, 4, and 6 days post infection were acquired by a pushbroom hyperspectral reflectance imaging system covering the spectral range of 380-1023 nm. Successive projections algorithm was evaluated for effective wavelengths (EWs) selection. Four texture features, including contrast, correlation, entropy, and homogeneity were extracted according to grey-level co-occurrence matrix (GLCM). Additionally, different machine-learning algorithms were developed and compared to detect and classify disease stages with EWs, texture features and data fusion respectively. The performance of chemometric models with data fusion manifested better results with classification accuracies of calibration and prediction all above 80% than those only using EWs or texture features; the accuracies were up to 95% employing back propagation neural network (BPNN), extreme learning machine (ELM), and least squares support vector machine (LS-SVM) models. Hence, hyperspectral imaging has the potential as a fast and non-invasive method to identify infected leaves in a short period of time (i.e. 48 h) in comparison to the reference images (5 days for visible symptoms of infection, 11 days for typical symptoms). PMID- 28646178 TI - Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice. AB - The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific shRNA construct significantly attenuated Ang II-induced GFR decline in rats. Furthermore, Ang II-stimulated contraction and Ca2+ entry were significantly suppressed in primary MCs isolated from TRPC6 deficient mice, and the Ca2+ response could be rescued by re-introducing TRPC6. Moreover, inhibition of reverse mode of Na+-Ca2+ exchange by KB-R7943 significantly reduced Ca2+ entry response in TRPC6-expressing, but not in TRPC6 knocked down MCs. Ca2+ entry response was also significantly attenuated in Na+ free solution. Single knockdown of TRPC6 and TRPC1 resulted in a comparable suppression on Ca2+ entry with double knockdown of both. These results suggest that TRPC6 may regulate GFR by modulating MC contractile function through multiple Ca2+ signaling pathways. PMID- 28646179 TI - Herbal medicine Yinchenhaotang protects against alpha-naphthylisothiocyanate induced cholestasis in rats. AB - Cholestasis is a clinical disorder defined as an impairment of bile flow, and that leads to toxic bile acid (BA) accumulation in hepatocytes. Here, we investigated the hepatoprotective effect of Yinchenhaotang (YCHT), a well-known formulae for the treatment of jaundice and liver disorders, against the cholestasis using the alpha-naphthylisothiocyanate (ANIT)-induced cholestasis in male Wistar rats. ANIT feeding induced significant cholestasis with substantially increased intrahepatic retention of hydrophobic BAs. The dynamic changes of serum and liver BAs indicated that YCHT was able to attenuate ANIT-induced BA perturbation, which is consistent with the histopathological findings that YCHT significantly decreased the liver damage. YCHT treatment substantially reduced serum alanine aminotransferase (ALT), alkaline phosphatase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) with minimal bile duct damage in the ANIT treated rats. Elevated mRNA expression of liver IL-6, IL-17A, IL-17F, TGF-beta1, alpha-SMA, TGR5, NTCP, OATP1a1, and ileum ASBT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP2, MRP3, MRP4 was also observed in ANIT-induced cholestasis but were attenuated or normalized by YCHT. Our results demonstrated that the BA profiles were significantly altered with ANIT intervention and YCHT possesses the hepatoprotective potential against cholestatic liver injury induced by hepatotoxin such as ANIT. PMID- 28646180 TI - Sustained release from a metal - Analgesics entrapped within biocidal silver. AB - Matrices for sustained release of drugs have been based on polymers, biomaterials and oxides. The use of the major family of metals as matrices for sustained release is, to the best of our knowledge, unknown. In this context we describe a new family of bio-composites for sustained release of drugs, namely analgesic drugs entrapped within metallic silver. Synthetic methodologies were developed for the preparation of ibuprofen@Ag, naproxen@Ag, tramadol@Ag and bupivacaine@Ag composites. Detailed kinetic analysis of the release of the drugs from within the metal, is provided, demonstrating that metals can indeed serve as reservoirs for drug release. The metal in our case acts not only as a drug releasing source, but also as an antibacterial agent and this property of the composites was studied. Unexpectedly, it was found that the entrapment of the analgesics within silver, dramatically enhances the growth inhibition activity of wild type Pseudomonas aeruginosa, exceeding by far the inhibition activity of the separate components. A mechanism for this interesting observation is provided. The strong antimicrobial activity combined with the analgesic activity open the road for future applications of these materials as dual-purpose components in wound treatment. PMID- 28646181 TI - Surface bioactivation through the nanostructured layer on titanium modified by facile HPT treatment. AB - Facile fabrication of nanostructured surface is of great importance for the use of titanium (Ti) implants in biomedical field. In this study, a low-cost and easy to-operate method called HPT (hydrothermal & pressure) here has been developed and used to fabricate the expected nanostructured surface on Ti substrates. The effects of experimental parameters on the morphology of Ti surface were investigated and characterized. The results indicated that by altering the hydrothermal pressure, NaOH concentration and treating time, surface nanostructure like nanopetals or nanoflakes could be formed on the surface of Ti substrates. The orthogonal experiments were conducted to demonstrate the optimized operation conditions. A formation mechanism of the nanostructured titanate layer was proposed, revealing that the nanostructured layer could be formed via a special upward and downward co-growth manner. In vitro cell culture showed that the HPT treated Ti substrates, especially the T-10 sample, could greatly enhance the cell-material interactions, i.e. the cell proliferation and differentiation, focal protein adhesion, and osteogenic factor expression. The HPT method paves a new way to modify the surface of Ti implants with better bioactivity and promising prospect for future biomedical applications. PMID- 28646182 TI - High-intensity Interval Training Improves Mitochondrial Function and Suppresses Thrombin Generation in Platelets undergoing Hypoxic Stress. AB - This study elucidates how high-intensity interval training (HIT) and moderate intensity continuous training (MCT) affect mitochondrial functionality and thrombin generation (TG) in platelets following hypoxic exercise (HE, 100 W under 12% O2 for 30 min). Forty-five healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n = 15) or MCT (sustained 60%VO2max, n = 15) for 30 minutes/day, 5 days/week for 6 weeks, or to a control group (CTL, n = 15) that did not received exercise intervention. Before the intervention, HE (i) reduced the ATP-linked O2 consumption rate (OCR), the reserve capacity of OCR, and the activities of citrate synthase (CS) and succinate dehydrogenase (SDH), (ii) lowered mitochondrial membrane potential (MP) and elevated matrix oxidant burden (MOB) in platelets, and (iii) enhanced dynamic TG in platelet-rich plasma (PRP), which responses were attenuated by pretreating PRP with oligomycin or rotenone/antimycin A. However, 6-week HIT (i) increased mitochondrial OCR capacity with enhancing the CS and SDH activities and (ii) heightened mitochondrial MP with depressing MOB in platelets following HE, compared to those of MCT and CTL. Moreover, the HIT suppressed the HE-promoted dynamic TG in PRP. Hence, we conclude that the HIT simultaneously improves mitochondrial bioenergetics and suppresses dynamic TG in platelets undergoing hypoxia. PMID- 28646183 TI - Differences in nature of electrical conductions among Bi4Ti3O12-based ferroelectric polycrystalline ceramics. AB - Bismuth titanate Bi4Ti3O12 (BiT), was one of the most promising lead-free high temperature piezoelectric materials, due to high Curie temperature (675 degrees C) and large spontaneous polarization (50 uC/cm2); however, extensive studies had revealed that high leakage conductivity interferes with the poling process, hindering its practical applications. In this paper, an electrically insulating property was achieved by a low level Nb donor substitution to suppress a high level of holes associated with high oxygen vacancy concentration. Bi4Ti2.97Nb0.03O12 ceramic showed significant enhancements of electrical resistivity by more than three order of magnitude and activity energy with value >1.2 eV, which are significant for piezoelectric applications of BiT-based materials. However, pure and A2O3-excess (A = Bi, La and Nd; 3 at %) BiT ceramics, were mixed hole and oxygen ion conductors. Schottky barriers were both formed at grain boundary region and the sample-electrode interface, because of the existence of semiconducting bulk. Interestingly, the electron conduction could be suppressed in N2, as a consequence, they became oxide ion conductors with conductivity of about 4 * 10-4 S cm-1 at 600 degrees C. PMID- 28646184 TI - Homing of Cultured Endothelial Progenitor Cells and Their Effect on Traumatic Brain Injury in Rat Model. AB - Transplanted endothelial progenitor cells (EPCs) may play an important role in reestablishing the endothelial integrity of the vessels after brain injury, and contribute to neurogenesis. We, therefore, tested the homing of ex vivo cultured peripheral blood-derived EPCs and their effect on injured brain tissue after intravenous administration. To track the homing of implanted EPCs in injured brain tissues, EPCs were labeled with DAPI and BrdU in vitro before transplantation. EPCs were transplanted into the host animal through peripheral administration through the femoral vein, and homing of EPCs was evaluated. The integration of intravenously injected EPCs into the injured brain tissue was demonstrated. Immunohistochemical staining showed that microvessel density in the perifocal region of EPCs-transplanted rats was significantly increased, and the numbers of BrdU+ cells in the DG of subventricular zone were increased in EPCs transplanted rats as compared to the control group. Transplanted EPCs may play an important role in reestablishing the endothelial integrity in the vessels after brain injury and further contribute to neurogenesis. EPCs enhanced recovery following brain injury in a rat model of TBI. PMID- 28646185 TI - The relation between residual stress, interfacial structure and the joint property in the SiO2f/SiO2-Nb joints. AB - In order to achieve a high-quality joint between SiO2f/SiO2 and metals, it is necessary to address the poor wettability of SiO2f/SiO2 and the high residual stress in SiO2f/SiO2-Nb joint. Here, we simultaneously realize good wettability and low residual stress in SiO2f/SiO2-Nb joint by combined method of HF etching treatment and Finite Element Analysis (FEA). After etching treatment, the wettability of E-SiO2f/SiO2 was improved, and the residual stress in the joint was decreased. In order to better control the quality of joints, efforts were made to understand the relationship between surface structure of E-SiO2f/SiO2 and residual stress in joint using FEA. Based on the direction of FEA results, a relationship between residual stress, surface structure and joint property in the brazed joints were investigated by experiments. As well the FEA and the brazing test results both realized the high-quality joint of E-SiO2f/SiO2-Nb and the shear strength of the joint reached 61.9 MPa. PMID- 28646186 TI - Magnetisation switching of FePt nanoparticle recording medium by femtosecond laser pulses. AB - Manipulation of magnetisation with ultrashort laser pulses is promising for information storage device applications. The dynamics of the magnetisation response depends on the energy transfer from the photons to the spins during the initial laser excitation. A material of special interest for magnetic storage are FePt nanoparticles, for which switching of the magnetisation with optical angular momentum was demonstrated recently. The mechanism remained unclear. Here we investigate experimentally and theoretically the all-optical switching of FePt nanoparticles. We show that the magnetisation switching is a stochastic process. We develop a complete multiscale model which allows us to optimize the number of laser shots needed to switch the magnetisation of high anisotropy FePt nanoparticles in our experiments. We conclude that only angular momentum induced optically by the inverse Faraday effect will provide switching with one single femtosecond laser pulse. PMID- 28646187 TI - MicroRNA-148 as a negative regulator of the common TLR adaptor mediates inflammatory response in teleost fish. AB - MicroRNAs are small endogenous noncoding RNAs implicating in the regulation of diverse biological processes, including proliferation, differentiation, cancer, apoptosis, and viral infections. MicroRNAs regulate gene expression by either mRNA degradation or inhibition of protein translation. Although microRNAs have emerged as important controller involved in regulation of inflammatory response, the microRNA-mediated regulatory mechanism remains less clear in teleost. Here, we report that miR-148 targets MyD88 and down-regulates its expression by inhibition protein translation rather than degradation mRNA in miiuy croaker. Additionally, we found that miR-148 was significantly upregulated in miiuy croaker after treated with Vibro harveyi, as well as LPS. Overexpression of miR 148 inhibited LPS-induced inflammatory cytokines production, such as IL-6 and IL 1beta, which then avoid excessive inflammation response. miR-148 has also been identified to suppress NF-kappaB pathway through targeting and repressing MyD88 expression. Taken together, our findings indicate that miR-148 participates in bacteria-induced inflammatory response and act as a negative regulator for MyD88 mediated NF-kappaB signaling, which may clarify the mechanism of microRNAs for avoiding excessive inflammation in teleost fish. PMID- 28646188 TI - Mitochondrial haplotypes influence metabolic traits across bovine inter- and intra-species cybrids. AB - In bovine species, mitochondrial DNA polymorphisms and their correlation to productive or reproductive performances have been widely reported across breeds and individuals. However, experimental evidence of this correlation has never been provided. In order to identify differences among bovine mtDNA haplotypes, transmitochondrial cybrids were generated, with the nucleus from MAC-T cell line, derived from a Holstein dairy cow (Bos taurus) and mitochondria from either primary cell line derived from a domestic Chinese native beef Luxi cattle breed or central Asian domestic yak (Bos grunniens). Yak primary cells illustrated a stronger metabolic capacity than that of Luxi. However, all yak cybrid parameters illustrated a drop in relative yak mtDNA compared to Luxi mtDNA, in line with a mitonuclear imbalance in yak interspecies cybrid. Luxi has 250 divergent variations relative to the mitogenome of Holsteins. In cybrids there were generally higher rates of oxygen consumption (OCR) and extracellular acidification (ECAR), and lower mRNA expression levels of nuclear-encoded mitochondrial genes, potentially reflecting active energy metabolism and cellular stress resistance. The results demonstrate that functional differences exist between bovine cybrid cells. While cybrid viability was similar between Holstein and Luxi breeds, the mitonuclear mismatch caused a marked metabolic dysfunction in cattle:yak cybrid species. PMID- 28646189 TI - Heterogeneous environments shape invader impacts: integrating environmental, structural and functional effects by isoscapes and remote sensing. AB - Spatial heterogeneity of ecosystems crucially influences plant performance, while in return plant feedbacks on their environment may increase heterogeneous patterns. This is of particular relevance for exotic plant invaders that transform native ecosystems, yet, approaches integrating geospatial information of environmental heterogeneity and plant-plant interaction are lacking. Here, we combined remotely sensed information of site topography and vegetation cover with a functional tracer of the N cycle, delta15N. Based on the case study of the invasion of an N2-fixing acacia in a nutrient-poor dune ecosystem, we present the first model that can successfully predict (R 2 = 0.6) small-scale spatial variation of foliar delta15N in a non-fixing native species from observed geospatial data. Thereby, the generalized additive mixed model revealed modulating effects of heterogeneous environments on invader impacts. Hence, linking remote sensing techniques with tracers of biological processes will advance our understanding of the dynamics and functioning of spatially structured heterogeneous systems from small to large spatial scales. PMID- 28646190 TI - Brain-to-brain entrainment: EEG interbrain synchronization while speaking and listening. AB - Electroencephalographic hyperscanning was used to investigate interbrain synchronization patterns in dyads of participants interacting through speech. Results show that brain oscillations are synchronized between listener and speaker during oral narratives. This interpersonal synchronization is mediated in part by a lower-level sensory mechanism of speech-to-brain synchronization, but also by the interactive process that takes place in the situation per se. These results demonstrate the existence of brain-to-brain entrainment which is not merely an epiphenomenon of auditory processing, during listening to one speaker. The study highlights the validity of the two-person neuroscience framework for understanding induced brain activity, and suggests that verbal information exchange cannot be fully understood by examining the listener's or speaker's brain activity in isolation. PMID- 28646191 TI - Prednisolone induces apoptosis in corneal epithelial cells through the intrinsic pathway. AB - Glucocorticoid eye drops are one of the most widely used medications in ophthalmology. However, little is known about the effects of glucocorticoids on corneal epithelial cells that are directly exposed to topically-administered glucocorticoids. Here we investigated the effects of prednisolone, a synthetic glucocorticoid analogue frequently used in the clinic, on corneal epithelial cells. Results showed that prednisolone decreased survival of corneal epithelial cells by inhibiting proliferation and inducing apoptosis in a dose-dependent manner. The levels of mitochondrial reactive oxygen species (mtROS), cleaved caspase-3, and -9 were increased by prednisolone. The effects of prednisolone on apoptosis and mtROS were blocked 1) by the glucocorticoid receptor (GR) antagonist RU-38486, 2) in cells with GR siRNA knockdown, and 3) by treatment with N-acetylcysteine. Transcript levels of pro-inflammatory cytokines were increased in corneal epithelial cells upon hyperosmolar stress, but repressed by prednisolone. In NOD.B10.H2b mice, topical administration of 1% prednisolone increased apoptotic cells in the corneal epithelium. Together, data indicate that prednisolone induces apoptosis in corneal epithelial cells through GR and the intrinsic pathway involving mtROS, caspase-9, and -3. The pro-apoptotic effects of glucocorticoids along with their anti-inflammatory effects should be considered when glucocorticoid eye drops are used in patients with ocular surface disease. PMID- 28646192 TI - Effect of H2O Adsorption on Negative Differential Conductance Behavior of Single Junction. AB - Large negative differential conductance (NDC) at lower bias regime is a very desirable functional property for single molecular device. Due to the non conjugated segment separating two conjugated branches, the single thiolated arylethynylene molecule with 9,10-dihydroanthracene core (denoted as TADHA) presents excellent NDC behavior in lower bias regime. Based on the ab initio calculation and non-equilibrium Green's function formalism, the NDC behavior of TADHA molecular device and the H2O-molecule-adsorption effects are studied systematically. The numerical results show that the NDC behavior of TADHA molecular junction originates from the Stark effect of the applied bias which splits the degeneration of the highest occupied molecular orbital (HOMO) and HOMO 1. The H2O molecule adsorbed on the terminal sulphur atom strongly suppresses the conductance of TADHA molecular device and destroys the NDC behavior in the lower bias regime. Single or separated H2O molecules adsorbed on the backbone of TADHA molecule can depress the energy levels of molecular orbitals, but have little effects on the NDC behavior of the TADHA molecular junction. Aggregate of several H2O molecules adsorbed on one branch of TADHA molecule can dramatically enhance the conductance and NDC behavior of the molecular junction, and result in rectifier behavior. PMID- 28646193 TI - Fabrication of nitrogen-doped nano-onions and their electrocatalytic activity toward the oxygen reduction reaction. AB - Nitrogen-doped nano-onions (NNO) were prepared as electrocatalytic materials for the oxygen reduction reaction (ORR). The nano-onions (NO), spherical graphitic material particles, were prepared by pyrolysis of nanodiamonds (ND). Oxidized NO (ONO) was prepared from NO by a modified Hummers' method, and this was mixed with urea, followed by pyrolysis, resulting in the formation of NNO. The nitrogen content and molar ratio of nitrogen-containing groups in the NNOs were varied by controlling the oxygen content of ONO to explore the effect of nitrogen content on the ORR activity. The formation of NO was confirmed by Raman spectroscopy, X ray diffraction analysis, and high-resolution transmission electron microscopy. X ray photoelectron spectroscopy analyses were conducted to confirm the formation of the NNO and the structures of the nitrogen-containing groups in the NNOs. The ORR activities of the NNOs were investigated using a rotating disk electrode. The NNOs showed a higher onset potential than that of NO, and the ORR activity of the NNO could be improved by increasing the number of active sites (nitrogen containing groups) in the NNO. In addition, the NNO exhibited better long-term stability and resistance toward methanol crossover in the ORR than the platinum based catalysts. PMID- 28646194 TI - Magnetic resonance imaging of fetal persistent left superior vena cava. AB - This study aimed to evaluate the diagnostic accuracy of fetal magnetic resonance imaging (MRI) for persistent left superior vena cava (LSVC). Prenatal echocardiography (echo) and/or ultrasound (US) and MRI data for 49 fetuses with persistent LSVC, confirmed via postnatal diagnoses between January 2010 and October 2015, were retrospectively reviewed. All prenatal MRI was performed at 1.5 T. Imaging sequences included steady-state free-precession (SSFP), single shot turbo spin echo (SSTSE), and other sequences. All 49 cases of fetal persistent LSVC were correctly diagnosed via MRI, but only 34 cases (69.4%) were correctly diagnosed via an initial US and/or echo before MRI. Of the 15 cases that were not correctly diagnosed via US and/or echo, 8 had congenital heart diseases (CHDs) and 7 were without CHDs; however, they were associated with extracardiac abnormalities or maternal obesity. Thirty-five cases were associated with other cardiovascular abnormalities; 8, with extracardiac abnormalities; and 6, with no associated condition. In 44 (89.8%) cases, the innominate veins were absent; the remaining cases had innominate veins. In 14.3% of patients (7 cases), the persistent LSVC drained directly into the atrium. Fetal MRI can detect persistent LSVC and play an adjunctive role along with US in the evaluation of persistent LSVC. PMID- 28646195 TI - Structural alteration of a BYDV-like translation element (BTE) that attenuates p35 expression in three mild Tobacco bushy top virus isolates. AB - To identify the molecular effects of Tobacco bushy top virus (TBTV) evolution on the degeneration of tobacco bushy top disease, three TBTV isolates with mild virulence were compared with wild-type TBTV to assess the translation of p35, which relies on a BYDV-like translation element (BTE) in a cap-independent manner. The in vitro expression of p35 in the mild isolates was only 20% to 40% of the expression observed in wt TBTV. Based on translation data from chimeric TBTV RNA, low-level p35 expression in the three mild isolates was associated with two regions: the 5' terminal 500 nt region (RI) and the 3' internal region (RV), which included the BTE. For the RV region, low level p35 expression was mainly associated with structural alterations of the BTE instead of specific sequence mutations within the BTE based on SHAPE structural probing and mutation analysis. Additionally, structural alteration of the TBTV BTE resulted from mutations outside of the BTE, implying structural complexity of the local region surrounding the BTE. This study is the first report on the structural alteration of the 3' cap-independent translation element among different isolates of a given RNA virus, which is associated with variations in viral virulence. PMID- 28646196 TI - Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling. AB - HAART is very effective in suppressing HIV-1 replication in patients. However, patients staying on long-term HAART still develop various HIV-associated neurological disorders, even when the viral load is low. The underlying pathogenic mechanisms are largely unknown. Emerging evidence implicated that persistent neuroinflammation plays an important role in NeuroAIDS. Although residual virus or viral proteins are commonly thought as the causal factors, we are interested in the alternative possibility that HAART critically contributes to the neuroinflammation in the central nervous system (CNS). To test this hypothesis, we have determined the effect of NRTIs on the expression of proinflammatory cytokines in the various CNS regions. Mice (C57Bl/6) were administered with AZT (Zidovudine 100 mg/kg/day), 3TC (Lamivudine 50 mg/kg/day) or D4T (Stavudine 10 mg/kg/day) for 5 days, and cortices, hippocampi and spinal cords were collected for immunoblotting. Our results showed that NRTI administration up-regulated cytokines, including IL-1beta, TNF-alpha and IL-6 in various CNS regions. In addition, we found that NRTIs also up-regulated Wnt5a protein. Importantly, BOX5 attenuated NRTI-induced cytokine up-regulation. These results together suggest that NRTIs up-regulate proinflammatory cytokines via a Wnt5a signaling-dependent mechanism. Our findings may help understand the potential pathogenic mechanisms of HAART-associated NeuroAIDS and design effective adjuvants. PMID- 28646197 TI - Upregulate KIF4A Enhances Proliferation, Invasion of Hepatocellular Carcinoma and Indicates poor prognosis Across Human Cancer Types. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive and heterogeneous cancers worldwide. Herein, we demonstrate KIF4A (Chromosome-associated kinesin KIF4A) as a potential biomarker, is up-regulated in most samples of HCC. The expression level of KIF4A in tumor tissue is significantly associated with the survival time, and a significant correlation between KIF4A expression and clinical information stage, metastasis and tumor dimension was observed. We further measured the proliferation and migration ability of two HCC cell lines, HCC-LM3 and PLC/PRF/5, following KIF4A-siRNA transfection. Knocking down of KIF4A significantly reduced migration and proliferation ability. Moreover, we also measured the proliferation and migration ability of two HCC cell lines through KIF4A overexpression, and found that KIF4A overexpression could enhance migration and proliferation ability, indicating that KIF4A exhibits oncogenic effects. Besides, study based on TCGA cohorts also reveals high KIF4A mRNA expression are significantly associated with shorter overall survival in multiple cancer types. Gene sets enrichment analysis exhibited that cell cycle related pathways and p53 signaling pathways to be top altered pathways of in KIF4A-high expression group in HCC, suggesting the potential role of KIF4A in mediating tumor initiation and progression. In summary, our work identified KIF4A as a potential predictive and prognostic marker for hepatocellular carcinoma. PMID- 28646198 TI - Spatiotemporal dynamics of grassland aboveground biomass on the Qinghai-Tibet Plateau based on validated MODIS NDVI. AB - Spatiotemporal dynamics of aboveground biomass (AGB) is a fundamental problem for grassland environmental management on the Qinghai-Tibet Plateau (QTP). Moderate Resolution Imaging Spectroradiometer (MODIS) Normalized Difference Vegetation Index (NDVI) data can feasibly be used to estimate AGB at large scales, and their precise validation is necessary to utilize them effectively. In our study, the clip-harvest method was used at 64 plots in QTP grasslands to obtain actual AGB values, and a handheld hyperspectral spectrometer was used to calculate field measured NDVI to validate MODIS NDVI. Based on the models between NDVI and AGB, AGB dynamics trends during 2000-2012 were analyzed. The results showed that the AGB in QTP grasslands increased during the study period, with 70% of the grasslands undergoing increases mainly in the Qinghai Province. Also, the meadow showed a larger increasing trend than steppe. Future AGB dynamic trends were also investigated using a combined analysis of the slope values and the Hurst exponent. The results showed high sustainability of AGB dynamics trends after the study period. Predictions indicate 60% of the steppe and meadow grasslands would continue to increase in AGB, while 25% of the grasslands would remain in degradation, with most of them distributing in Tibet. PMID- 28646199 TI - Orthogonal quasi-phase-matched superlattice for generation of hyperentangled photons. AB - A crystal superlattice structure featuring nonlinear layers with alternating orthogonal optic axes interleaved with orthogonal poling directions, is shown to generate high-quality hyperentangled photon pairs via orthogonal quasi-phase matched spontaneous parametric downconversion. We demonstrate that orthogonal quasi-phase matching (QPM) processes in a single nonlinear domain structure correct phase and group-velocity mismatches concurrently. Compared with the conventional two-orthogonal-crystals source and the double-nonlinearity single crystal source, the orthogonal QPM superlattice is shown to suppress the spatial and temporal distinguishability of the generated photon pairs by several orders of magnitude, depending on the number of layers. This enhanced all-over-the-cone indistinguishability enables the generation of higher fluxes of photon-pairs by means of the combined use of (a) long nonlinear crystal in noncollinear geometry, (b) low coherence-time pumping and ultra-wide-band spectral detection, and (c) focused pumping and over-the-cone detection. While each of these three features is challenging by itself, it is remarkable that the orthogonal QPM superlattice meets all of these challenges without the need for separate spatial or temporal compensation. PMID- 28646200 TI - Mesenchymal stem cells secretome-induced axonal outgrowth is mediated by BDNF. AB - Mesenchymal stem cells (MSCs) have been used for cell-based therapies in regenerative medicine, with increasing importance in central and peripheral nervous system repair. However, MSCs grafting present disadvantages, such as, a high number of cells required for transplantation and low survival rate when transplanted into the central nervous system (CNS). In line with this, MSCs secretome which present on its composition a wide range of molecules (neurotrophins, cytokines) and microvesicles, can be a solution to surpass these problems. However, the effect of MSCs secretome in axonal elongation is poorly understood. In this study, we demonstrate that application of MSCs secretome to both rat cortical and hippocampal neurons induces an increase in axonal length. In addition, we show that this growth effect is axonal intrinsic with no contribution from the cell body. To further understand which are the molecules required for secretome-induced axonal outgrowth effect, we depleted brain-derived neurotrophic factor (BDNF) from the secretome. Our results show that in the absence of BDNF, secretome-induced axonal elongation effect is lost and that axons present a reduced axonal growth rate. Altogether, our results demonstrate that MSCs secretome is able to promote axonal outgrowth in CNS neurons and this effect is mediated by BDNF. PMID- 28646201 TI - Comprehensive investigation of temporal and autism-associated cell type composition-dependent and independent gene expression changes in human brains. AB - The functions of human brains highly depend on the precise temporal regulation of gene expression, and the temporal brain transcriptome profile across lifespan has been observed. The substantial transcriptome alteration in neural disorders like autism has also been observed and is thought to be important for the pathology. While the cell type composition is known to be variable in brains, it remains unclear how it contributes to the temporal and pathological transcriptome changes in brains. Here, we applied a transcriptome deconvolution procedure to an age series RNA-seq dataset of healthy and autism samples, to quantify the contribution of cell type composition in shaping the temporal and autism pathological transcriptome in human brains. We estimated that composition change was the primary factor of both types of transcriptome changes. On the other hand, genes with substantial composition-independent expression changes were also observed in both cases. Those temporal and autism pathological composition independent changes, many of which are related to synaptic functions, indicate the important intracellular regulatory changes in human brains in both processes. PMID- 28646202 TI - The Microbiome of Endophytic, Wood Colonizing Bacteria from Pine Trees as Affected by Pine Wilt Disease. AB - Pine wilt disease (PWD) is a devastating forest disease present worldwide. In this study we analyzed the effects of the invasion of the pinewood nematode Bursaphelenchus xylophilus, the major pathogen causing PWD, on the endophytic microbiome of adult P. pinaster trees. Wood samples from trees with different degrees of PWD disease were collected at two sites (A and M) in Portugal. Endophytic bacteria were characterized based on directly extracted DNA by fingerprinting and barcoding using the 16S rRNA gene as marker. Furthermore, cultivation-based approaches were used to obtain isolates of the major taxa to study their ecophysiology. The endophytic microbiome from P. pinaster trees differed significantly between the two sampling sites. Main bacterial OTUs belonged to the Proteobacteria (39% (site M) - 97% (site A)), and Firmicutes (0.70% (site A) - 44% (site M)). However, consequences of the invasion with the pathogen were comparable. Interestingly diversity of wood endophytic bacteria increased with the severity of the diseases, with highest diversity levels observed in in the most affected trees. Our results suggest that in the first stages of the disease, the defence mechanisms of plants are repressed by the pathogen, resulting in a colonization of the wood interior by soil microorganisms. PMID- 28646203 TI - Incoherent-mediator for quantum state transfer in the ultrastrong coupling regime. AB - We study quantum state transfer between two qubits coupled to a common quantum bus that is constituted by an ultrastrong coupled light-matter system. By tuning both qubit frequencies on resonance with a forbidden transition in the mediating system, we demonstrate a high-fidelity swap operation even though the quantum bus is thermally populated. We discuss a possible physical implementation in a realistic circuit QED scheme that leads to the multimode Dicke model. This proposal may have applications on hot quantum information processing within the context of ultrastrong coupling regime of light-matter interaction. PMID- 28646204 TI - Optogenetic protein clustering through fluorescent protein tagging and extension of CRY2. AB - Protein homo-oligomerization is an important molecular mechanism in many biological processes. Therefore, the ability to control protein homo oligomerization allows the manipulation and interrogation of numerous cellular events. To achieve this, cryptochrome 2 (CRY2) from Arabidopsis thaliana has been recently utilized for blue light-dependent spatiotemporal control of protein homo oligomerization. However, limited knowledge on molecular characteristics of CRY2 obscures its widespread applications. Here, we identify important determinants for efficient cryptochrome 2 clustering and introduce a new CRY2 module, named ''CRY2clust'', to induce rapid and efficient homo-oligomerization of target proteins by employing diverse fluorescent proteins and an extremely short peptide. Furthermore, we demonstrate advancement and versatility of CRY2clust by comparing against previously reported optogenetic tools. Our work not only expands the optogenetic clustering toolbox but also provides a guideline for designing CRY2-based new optogenetic modules.Cryptochrome 2 (CRY2) from A. thaliana can be used to control light-dependent protein homo-oligomerization, but the molecular mechanism of CRY2 clustering is not known, limiting its application. Here the authors identify determinants of CRY2 clustering and engineer fusion partners to modulate clustering efficiency. PMID- 28646205 TI - Comparative NanoUPLC-MSE analysis between magainin I-susceptible and -resistant Escherichia coli strains. AB - In recent years the antimicrobial peptides (AMPs) have been prospected and designed as new alternatives to conventional antibiotics. Indeed, AMPs have presented great potential toward pathogenic bacterial strains by means of complex mechanisms of action. However, reports have increasingly emerged regarding the mechanisms by which bacteria resist AMP administration. In this context, we performed a comparative proteomic study by using the total bacterial lysate of magainin I-susceptible and -resistant E. coli strains. After nanoUPLC-MSE analyses we identified 742 proteins distributed among the experimental groups, and 25 proteins were differentially expressed in the resistant strains. Among them 10 proteins involved in bacterial resistance, homeostasis, nutrition and protein transport were upregulated, while 15 proteins related to bacterial surface modifications, genetic information and beta-lactams binding-protein were downregulated. Moreover, 60 exclusive proteins were identified in the resistant strains, among which biofilm and cell wall formation and multidrug efflux pump proteins could be observed. Thus, differentially from previous studies that could only associate single proteins to AMP bacterial resistance, data here reported show that several metabolic pathways may be related to E. coli resistance to AMPs, revealing the crucial role of multiple "omics" studies in order to elucidate the global molecular mechanisms involved in this resistance. PMID- 28646206 TI - CRISPR/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B mice. AB - Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B. Mutation-specific gene editing by simultaneous induction of homology-directed repair (HDR) sufficiently increased FIX levels to correct the disease phenotype. Insertion of F9 cDNA into the intron more efficiently restored haemostasis via both processes of non homologous end-joining (NHEJ) and HDR following DSB. Notably, these therapies also cured neonate mice with haemophilia, which cannot be achieved with conventional gene therapy with AAV vector. Ongoing haemophilia therapy targeting the antithrombin gene with antisense oligonucleotide could be replaced by SaCas9/sgRNA-expressing AAV8 vector. Our results suggest that CRISPR/Cas9 mediated genome editing using an AAV8 vector provides a flexible approach to induce DSB at target genes in hepatocytes and could be a good strategy for haemophilia gene therapy. PMID- 28646207 TI - Computer-aided implant design for the restoration of cranial defects. AB - Patient-specific cranial implants are important and necessary in the surgery of cranial defect restoration. However, traditional methods of manual design of cranial implants are complicated and time-consuming. Our purpose is to develop a novel software named EasyCrania to design the cranial implants conveniently and efficiently. The process can be divided into five steps, which are mirroring model, clipping surface, surface fitting, the generation of the initial implant and the generation of the final implant. The main concept of our method is to use the geometry information of the mirrored model as the base to generate the final implant. The comparative studies demonstrated that the EasyCrania can improve the efficiency of cranial implant design significantly. And, the intra- and inter rater reliability of the software were stable, which were 87.07 +/- 1.6% and 87.73 +/- 1.4% respectively. PMID- 28646208 TI - A Comprehensive Mouse Transcriptomic BodyMap across 17 Tissues by RNA-seq. AB - The mouse has been widely used as a model organism for studying human diseases and for evaluating drug safety and efficacy. Many diseases and drug effects exhibit tissue specificity that may be reflected by tissue-specific gene expression profiles. Here we construct a comprehensive mouse transcriptomic BodyMap across 17 tissues of six-weeks old C57BL/6JJcl mice using RNA-seq. We find different expression patterns between protein-coding and non-coding genes. Liver expressed the least complex transcriptomes, that is, the smallest number of genes detected in liver across all 17 tissues, whereas testis and ovary harbor more complex transcriptomes than other tissues. We report a comprehensive list of tissue-specific genes across 17 tissues, along with a list of 4,781 housekeeping genes in mouse. In addition, we propose a list of 27 consistently and highly expressed genes that can be used as reference controls in expression-profiling analysis. Our study provides a unique resource of mouse gene-expression profiles, which is helpful for further biomedical research. PMID- 28646209 TI - Upregulation of circulating microRNA-134 in adult-onset Still's disease and its use as potential biomarker. AB - Adult-onset Still's disease (AOSD) is a multi-systemic inflammatory disorder of unknown etiology. To date, no single diagnostic test is available for AOSD. Herein, we investigated the pathogenic role of microRNAs in AOSD. MicroRNA profiles in plasma from AOSD patients and healthy controls were analyzed by microarray analysis, followed by quantitative reverse transcription PCR validation. The biological functions of microRNAs were evaluated using in vitro cell-based assay. Among the differentially expressed microRNAs, microRNA-134 (miR 134) expression was positively correlated with AOSD activity scores and significantly decreased after effective treatment. An increased miR-134 level is significantly associated with the activation of Toll-like receptor 3 (TLR3). The reporter assay identified IL-18 binding protein (IL-18BP) as the target of miR 134. A negative correlation between miR-134 expression and IL-18BP mRNA levels were detected in peripheral blood cells following TLR3 ligand treatment. Lower plasma IL-18BP levels and higher IL-18 levels were also observed in active AOSD patients who had higher miR-134 expression than inactive patients. Upregulation of circulating miR-134 was associated with elevated IL-18 levels by targeting IL 18BP in AOSD patients and was positively correlated with disease activity, suggesting its involvement in AOSD pathogenesis. MiR-134 may be a novel activity indicator or potential prognostic biomarker in AOSD. PMID- 28646210 TI - Identification of introns harboring functional sequence elements through positional conservation. AB - Many human introns carry out a function, in the sense that they are critical to maintain normal cellular activity. Their identification is fundamental to understanding cellular processes and disease. However, being noncoding elements, such functional introns are poorly predicted based on traditional approaches of sequence and structure conservation. Here, we generated a dataset of human functional introns that carry out different types of functions. We showed that functional introns share common characteristics, such as higher positional conservation along the coding sequence and reduced loss rates, regardless of their specific function. A unique property of the data is that if an intron is unknown to be functional, it still does not mean that it is indeed non functional. We developed a probabilistic framework that explicitly accounts for this unique property, and predicts which specific human introns are functional. We show that we successfully predict function even when the algorithm is trained on introns with a different type of function. This ability has many implications in studying regulatory networks, gene regulation, the effect of mutations outside exons on human disease, and on our general understanding of intron evolution and their functional exaptation in mammals. PMID- 28646211 TI - Increasing cell density globally enhances the biogenesis of Piwi-interacting RNAs in Bombyx mori germ cells. AB - Piwi proteins and their bound Piwi-interacting RNAs (piRNAs) are predominantly expressed in the germline and play crucial roles in germline development by silencing transposons and other targets. Bombyx mori BmN4 cells are culturable germ cells that equip the piRNA pathway. Because of the scarcity of piRNA expressing culturable cells, BmN4 cells are being utilized for the analyses of piRNA biogenesis. We here report that the piRNA biogenesis in BmN4 cells is regulated by cell density. As cell density increased, the abundance of Piwi proteins and piRNA biogenesis factors was commonly upregulated, resulting in an increased number of perinuclear nuage-like granules where Piwi proteins localize. Along with these phenomena, the abundance of mature piRNAs also globally increased, whereas levels of long piRNA precursor and transposons decreased, suggesting that increasing cell density promotes piRNA biogenesis pathway and that the resultant accumulation of mature piRNAs is functionally significant for transposon silencing. Our study reveals a previously uncharacterized link between cell density and piRNA biogenesis, designates cell density as a critical variable in piRNA studies using BmN4 cell system, and suggests the alteration of cell density as a useful tool to monitor piRNA biogenesis and function. PMID- 28646212 TI - Direct observation of a non-crystalline state of Li2S-P2S5 solid electrolytes. AB - There are two types of solid electrolytes which has been recently expected to be applied to all-solid-state batteries. One is the glasses characterized by an amorphous state. The other is the glass ceramics containing crystalline in an amorphous matrix. However, the non-crystalline state of glasses and glass ceramics is still an open question. It has been anticipated that sea-island and core-shell structures including crystalline nanoparticles have been proposed as candidate models for glass ceramics. Nevertheless, no direct observation has been conducted so far. Here we report the non-crystalline state of Li2S-P2S5 glasses and glass ceramics, and the crystallization behavior of the glasses during heating via direct transmission electron microscopy (TEM) observation. High resolution TEM images clearly revealed the presence of crystalline nanoparticles in an amorphous region. Eventually we suggest that the precipitation and connection of crystalline nanoparticles in an amorphous matrix are key to achieving high ionic conductivity. PMID- 28646213 TI - Contrasting the complexity of the climate of the past 122,000 years and recent 2000 years. AB - The complexity of the climate of the past 122;000 years and recent 2000 years was investigated by analyzing the delta 18 O records of ice cores based on the sample entropy (SampEn) method and Lempel-Ziv (LZ) complexity. In using SampEn method, the climate complexity is measured by the sample entropy, which is a modified approximate entropy defined in terms of the occurring probability of new modes in a record. A larger sample entropy reflects a higher probability to spot a new mode in the data, and in this sense signals a larger complexity of the sample. The delta 18 O record of the past 122,000-year is found to have smaller SampEn than the recent 2000-year. This result suggests that the climate of the past 122;000-year has less complexity than that of the recent 2000 years, even though the record for the former exhibits stronger fluctuations and multifractality than the latter. This diagnosis is additionally supported by calculations of LZ complexity, which has smaller value for the record of the past 122;000 years than the recent 2000 years. Our theoretical findings may further contribute to ongoing explorations into the nonlinear statistical character of the climate change. PMID- 28646214 TI - Structural and biochemical studies of sulphotransferase 18 from Arabidopsis thaliana explain its substrate specificity and reaction mechanism. AB - Sulphotransferases are a diverse group of enzymes catalysing the transfer of a sulfuryl group from 3'-phosphoadenosine 5'-phosphosulphate (PAPS) to a broad range of secondary metabolites. They exist in all kingdoms of life. In Arabidopsis thaliana (L.) Heynh. twenty-two sulphotransferase (SOT) isoforms were identified. Three of those are involved in glucosinolate (Gl) biosynthesis, glycosylated sulphur-containing aldoximes containing chemically different side chains, whose break-down products are involved in stress response against herbivores, pathogens, and abiotic stress. To explain the differences in substrate specificity of desulpho (ds)-Gl SOTs and to understand the reaction mechanism of plant SOTs, we determined the first high-resolution crystal structure of the plant ds-Gl SOT AtSOT18 in complex with 3'-phosphoadenosine 5' phosphate (PAP) alone and together with the Gl sinigrin. These new structural insights into the determination of substrate specificity were complemented by mutagenesis studies. The structure of AtSOT18 invigorates the similarity between plant and mammalian sulphotransferases, which illustrates the evolutionary conservation of this multifunctional enzyme family. We identified the essential residues for substrate binding and catalysis and demonstrated that the catalytic mechanism is conserved between human and plant enzymes. Our study indicates that the loop-gating mechanism is likely to be a source of the substrate specificity in plants. PMID- 28646215 TI - Single molecule and multiple bond characterization of catch bond associated cytoadhesion in malaria. AB - The adhesion of malaria infected red blood cells (iRBCs) to host endothelial receptors in the microvasculature, or cytoadhesion, is associated with severe disease pathology such as multiple organ failure and cerebral malaria. Malaria iRBCs have been shown to bind to several receptors, of which intercellular adhesion molecule 1 (ICAM-1) upregulation in brain microvasculature is the only one correlated to cerebral malaria. We utilize a biophysical approach to study the interactions between iRBCs and ICAM-1. At the single molecule level, force spectroscopy experiments reveal that ICAM-1 forms catch bond interactions with Plasmodium falciparum parasite iRBCs. Flow experiments are subsequently conducted to understand multiple bond behavior. Using a robust model that smoothly transitions between our single and multiple bond results, we conclusively demonstrate that the catch bond behavior persists even under flow conditions. The parameters extracted from these experimental results revealed that the rate of association of iRBC-ICAM-1 bonds are ten times lower than iRBC-CD36 (cluster of differentiation 36), a receptor that shows no upregulation in the brains of cerebral malaria patients. Yet, the dissociation rates are nearly the same for both iRBC-receptor interactions. Thus, our results suggest that ICAM-1 may not be the sole mediator responsible for cytoadhesion in the brain. PMID- 28646216 TI - Effects of naftopidil on double-J stent-related discomfort: a multicenter, randomized, double-blinded, placebo-controlled study. AB - To evaluate the effect of naftopidil 75 mg once daily for ureteral double-J (DJ) stent-related discomfort after a ureteroscopic procedure using a multicenter, randomized, double-blinded, placebo-controlled study. 100 patients with indwelled retrograde DJ ureteral stents after ureteroscopic stone removal or retrograde intrarenal surgery (RIRS) were randomized 1:1 to receive either placebo or naftopidil during the stenting period. At the time of stent removal, the Ureteral Stent Symptom Questionnaire (USSQ), the International Prostate Symptom Score and the total amount of used analgesics were reported. Of the 92 patients who completed the study, 49 patients were enrolled in the placebo group, and 43 patients in the naftopidil group. USSQ urinary symptom scores (30.90 vs. 29.23, p = 0.299) and USSQ body pain scores (22.28 vs. 19.58, respectively, p = 0.286) were lower in the naftopidil group than in the placebo group, but the difference was not significant. Multivariate analysis showed that the use of a ureteral access sheath during RIRS was the only significant predictor of postoperative DJ related pain (OR = 2.736, p = 0.031). The use of naftopidil once daily did not significantly reduce DJ ureteral stent-related discomfort. Larger-scaled prospective studies should be conducted to evaluate the effects of naftopidil on DJ stent-related symptoms and surgeries. PMID- 28646217 TI - Why do physicians lack engagement with smoking cessation treatment in their COPD patients? A multinational qualitative study. AB - : Smoking cessation is the only effective intervention to slow down the accelerated decline in lung function in smokers with chronic obstructive pulmonary disease. Nevertheless, physicians often do not routinely provide evidence-based smoking cessation treatment to their patients. To understand underlying reasons, we explored how physicians engage in smoking cessation treatment in their chronic obstructive pulmonary disease patients. In total, 21 focus group discussions were held with general practitioners and pulmonologists in seven different countries in Europe and Asia. We generated three themes, whereby some of the issues concerned smokers in general: first, 'physicians' frustration with chronic obstructive pulmonary disease patients who smoke'. These frustrations interfered with the provision of evidence-based treatment and could result in this group of patients being treated unequally. Second: 'physicians' limited knowledge of, and negative beliefs about, smoking cessation treatment'. This hindered treating smokers effectively. Third: 'healthcare organisational factors that influence the use of smoking cessation treatments'. Money and time issues, as well as the failure to regard smoking as a disease, influenced how physicians engaged in smoking cessation treatment. Our results indicate that there is a number of barriers to the provision of effective smoking cessation treatment in patients with chronic obstructive pulmonary disease and smokers in general. Introducing an informative smoking cessation programme, including communication skills and ethical issues, in the vocational and postgraduate medical training may help to address these barriers. This is important in order to increase engagement with smoking cessation treatment and to improve quality of chronic obstructive pulmonary disease care. CHRONIC LUNG DISEASE: CHANGING ATTITUDES TO HELP PATIENTS STOP SMOKING: Doctors should be given careful, ethically-informed guidance during medical training to help them to support patients to quit smoking. The most important part of treatment for patients with chronic obstructive pulmonary disease (COPD) is help to stop smoking. However, there is evidence to suggest that doctors don't always motivate COPD patients to quit. Eva Anne Marije van Eerd at Maastrict University, The Netherlands, together with an international team of scientists, conducted focus group interviews with doctors in seven different countries to assess barriers to smoking cessation. They found that doctors' frustration with and negative attitudes towards patients who continued to smoke contributed to poor cessation management and treatment inequalities in some cases. Many doctors also cited a lack of experience with smoking cessation techniques alongside time and money issues as barriers to effective treatment. PMID- 28646218 TI - Suppression of collapse for two-dimensional Airy beam in nonlocal nonlinear media. AB - Dynamics and collapse of two-dimensional Airy beams are investigated numerically in nonlocal nonlinear media with split step Fourier transform method. In particular, the stability and self-healing properties of the Airy beams depend crucially on the location and topological charge of the vortex when the beams carry angular momentum. The propagation of abruptly autofocusing Airy beams is also demonstrated in local and nonlocal media. In strongly self-focusing regime, with the help of nonlocality, stationary propagation of two-dimensional Airy beams can be obtained, which always collapse in local nonlinear media. PMID- 28646219 TI - Efficient and unbiased metagenomic recovery of RNA virus genomes from human plasma samples. AB - RNA viruses cause significant human pathology and are responsible for the majority of emerging zoonoses. Mainstream diagnostic assays are challenged by their intrinsic diversity, leading to false negatives and incomplete characterisation. New sequencing techniques are expanding our ability to agnostically interrogate nucleic acids within diverse sample types, but in the clinical setting are limited by overwhelming host material and ultra-low target frequency. Through selective host RNA depletion and compensatory protocol adjustments for ultra-low RNA inputs, we are able to detect three major blood borne RNA viruses - HIV, HCV and HEV. We recovered complete genomes and up to 43% of the genome from samples with viral loads of 104 and 103 IU/ml respectively. Additionally, we demonstrated the utility of this method in detecting and characterising members of diverse RNA virus families within a human plasma background, some present at very low levels. By applying this method to a patient sample series, we have simultaneously determined the full genome of both a novel subtype of HCV genotype 6, and a co-infecting human pegivirus. This method builds upon earlier RNA metagenomic techniques and can play an important role in the surveillance and diagnostics of blood-borne viruses. PMID- 28646220 TI - Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. AB - Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe -/- mice infused with AngII. While adoptive transfer of B cells in Apoe -/- /Baffr -/- mice reversed atheroprotection in the absence of AngII, infusion of AngII in B cell replenished Apoe -/- /Baffr -/- mice unexpectedly prevented the progression of atherosclerosis. Atheroprotection observed in these mice was associated with a significant increase in regulatory CD1dhiCD5+ B cells, which produced high levels of interleukin (IL)-10 (B10 cells). Replenishment of Apoe -/- /Baffr -/- mice with Il10 -/- B cells reversed AngII-induced B cell-dependent atheroprotection, thus highlighting a protective role of IL-10+ regulatory B cells in this setting. Transfer of AngII type 1A receptor deficient (Agtr1a -/-) B cells into Apoe -/- /Baffr -/- mice substantially reduced the production of IL-10 by B cells and prevented the AngII-dependent atheroprotective B cell phenotype. Consistent with the in vivo data, AngII synergized with BAFF to induce IL-10 production by B cells in vitro via AngII type 1A receptor. Our data demonstrate a previously unknown synergy between AngII and BAFF in inducing IL-10 production by B cells, resulting in atheroprotection. PMID- 28646221 TI - Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice. AB - Sexual dimorphisms are prevalent in development, physiology and diseases in humans. Currently, the contributions of the genes on the male-specific region of the Y chromosome (MSY) in these processes are uncertain. Using a transgene activation system, the human sex-determining gene hSRY is activated in the single cell embryos of the mouse. Pups with hSRY activated (hSRYON) are born of similar sizes as those of non-activated controls. However, they retard significantly in postnatal growth and development and all die of multi-organ failure before two weeks of age. Pathological and molecular analyses indicate that hSRYON pups lack innate suckling activities, and develop fatty liver disease, arrested alveologenesis in the lung, impaired neurogenesis in the brain and occasional myocardial fibrosis and minimized thymus development. Transcriptome analysis shows that, in addition to those unique to the respective organs, various cell growth and survival pathways and functions are differentially affected in the transgenic mice. These observations suggest that ectopic activation of a Y located SRY gene could exert male-specific effects in development and physiology of multiple organs, thereby contributing to sexual dimorphisms in normal biological functions and disease processes in affected individuals. PMID- 28646222 TI - Effects of chemical alternation on damage accumulation in concentrated solid solution alloys. AB - Single-phase concentrated solid-solution alloys (SP-CSAs) have recently gained unprecedented attention due to their promising properties. To understand effects of alloying elements on irradiation-induced defect production, recombination and evolution, an integrated study of ion irradiation, ion beam analysis and atomistic simulations are carried out on a unique set of model crystals with increasing chemical complexity, from pure Ni to Ni80Fe20, Ni50Fe50, and Ni80Cr20 binaries, and to a more complex Ni40Fe40Cr20 alloy. Both experimental and simulation results suggest that the binary and ternary alloys exhibit higher radiation resistance than elemental Ni. The modeling work predicts that Ni40Fe40Cr20 has the best radiation tolerance, with the number of surviving Frenkel pairs being factors of 2.0 and 1.4 lower than pure Ni and the 80:20 binary alloys, respectively. While the reduced defect mobility in SP-CSAs is identified as a general mechanism leading to slower growth of large defect clusters, the effect of specific alloying elements on suppression of damage accumulation is clearly demonstrated. This work suggests that concentrated solid solution provides an effective way to enhance radiation tolerance by creating elemental alternation at the atomic level. The demonstrated chemical effects on defect dynamics may inspire new design principles of radiation-tolerant structural alloys for advanced energy systems. PMID- 28646223 TI - Regular exercise participation improves genomic stability in diabetic patients: an exploratory study to analyse telomere length and DNA damage. AB - Physical activity has been demonstrated to be effective in the prevention and treatment of different chronic conditions, including type 2 diabetes (T2D). In particular, several studies highlighted how the beneficial effects of physical activity may be related to the stability of the DNA molecule, such as longer telomeric ends. Here we analyze the effect of exercise training on telomere length, spontaneous and H2O2-induced DNA damage, as well as the apoptosis level in leukocytes from untrained or trained T2D patients vs. age-matched control subjects (CS) (57-66 years). Moreover, expression analysis of selected genes belonging to DNA repair systems, cell cycle control, antioxidant and defence systems was performed. Subjects that participated in a regular exercise program showed a longer telomere sequence than untrained counterparts. Moreover, ex vivo treatment of leukocytes with H2O2 highlighted that: (1) oxidative DNA damage induced similar telomere attrition in all groups; (2) in T2D subjects, physical activity seemed to prevent a significant increase of genomic oxidative DNA damage induced by chronic exposure to pro-oxidant stimulus, and (3) decreased the sensitivity of leukocytes to apoptosis. Finally, the gene expression analysis in T2D subjects suggested an adaptive response to prolonged exercise training that improved the response of specific genes. PMID- 28646224 TI - Role of new Immunophenotypic Markers on Prognostic and Overall Survival of Acute Myeloid Leukemia: a Systematic Review and Meta-Analysis. AB - Despite technological advances, the prognosis and survival of acute myeloid leukemia (AML) adult patients remain low, compared with other hematologic malignancies. Some antigens detected by immunophenotyping may soon play a significant role in the pathophysiologic, prognostic, and overall survival (OS) rate of AML patients. Therefore, we conducted a systematic review and meta analysis of PubMed, Scopus, Science Direct, Web of Science, and the Cochrane Library (using PRISMA guidelines). We analyzed 11 studies and 13 antigens, detected through the immunophenotyping of 639 patients. From them, twelve exhibited a negative impact with AML prognosis. The meta-analysis demonstrated a high expression of AML markers, which have been associated with a decrease in survival over 10 months (RR 2.55; IC 95%; 1.49-4.37) and over 20 months (RR 2.46; IC 95%; 1.75-3.45). Knowing that the expression of immunophenotypic markers, which are not used on a routine basis, might be able to influence disease behavior, looks promising. However, they have been associated with a poor prognosis as well as a decrease in survival. This may allow for different chemotherapeutical protocols, including future studies for new therapeutic targets. PMID- 28646225 TI - A High-Power Broadband Terahertz Source Enabled by Three-Dimensional Light Confinement in a Plasmonic Nanocavity. AB - The scope and potential uses of time-domain terahertz imaging and spectroscopy are mainly limited by the low optical-to-terahertz conversion efficiency of photoconductive terahertz sources. State-of-the-art photoconductive sources utilize short-carrier-lifetime semiconductors to recombine carriers that cannot contribute to efficient terahertz generation and cause additional thermal dissipation. Here, we present a novel photoconductive terahertz source that offers a significantly higher efficiency compared with terahertz sources fabricated on short-carrier-lifetime substrates. The key innovative feature of this source is the tight three-dimensional confinement of the optical pump beam around the terahertz nanoantennas that are used as radiating elements. This is achieved by means of a nanocavity formed by plasmonic structures and a distributed Bragg reflector. Consequently, almost all of the photo-generated carriers can be routed to the terahertz nanoantennas within a sub-picosecond time scale. This results in a very strong, ultrafast current that drives the nanoantennas to produce broadband terahertz radiation. We experimentally demonstrate that this terahertz source can generate 4 mW pulsed terahertz radiation under an optical pump power of 720 mW over the 0.1-4 THz frequency range. This is the highest reported power level for terahertz radiation from a photoconductive terahertz source, representing more than an order of magnitude of enhancement in the optical-to-terahertz conversion efficiency compared with state of-the-art photoconductive terahertz sources fabricated on short-carrier-lifetime substrates. PMID- 28646226 TI - A microRNA signature of response to erlotinib is descriptive of TGFbeta behaviour in NSCLC. AB - Our previous work identified a 13-gene miRNA signature predictive of response to the epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in Non-Small Cell Lung Cancer cell lines. Bioinformatic analysis of the signature showed a functional convergence on TGFbeta canonical signalling. We hypothesized that TGFbeta signalling controls expression of the miRNA genes comprising an erlotinib response signature in NSCLC. Western analysis revealed that TGFbeta signalling via Smad2/3/4 occurred differently between erlotinib-resistant A549 and erlotinib sensitive PC9 cells. We showed that TGFbeta induced an interaction between Smad4 and putative Smad Binding Elements in PC9. However, qRT-PCR analysis showed that endogenous miR-140/141/200c expression changes resulted from time in treatments, not the treatments themselves. Moreover, flow cytometry indicated that cells exited the cell cycle in the same manner. Taken together these data indicated that the miRNA comprising the signature are likely regulated by the cell cycle rather than by TGFbeta. Importantly, this work revealed that TGFbeta did not induce EMT in PC9 cells, but rather TGFbeta-inhibition induced an EMT intermediate. These data also show that growth/proliferation signals by constitutively-activated EGFR may rely on TGFbeta and a possible relationship between TGFbeta and EGFR signalling may prevent EMT progression in this context rather than promote it. PMID- 28646228 TI - Coronal mass ejections are not coherent magnetohydrodynamic structures. AB - Coronal mass ejections (CMEs) are episodic eruptions of solar plasma and magnetic flux that travel out through the solar system, driving extreme space weather. Interpretation of CME observations and their interaction with the solar wind typically assumes CMEs are coherent, almost solid-like objects. We show that supersonic radial propagation of CMEs away from the Sun results in geometric expansion of CME plasma parcels at a speed faster than the local wave speed. Thus information cannot propagate across the CME. Comparing our results with observed properties of over 400 CMEs, we show that CMEs cease to be coherent magnetohydrodynamic structures within 0.3 AU of the Sun. This suggests Earth directed CMEs are less like billiard balls and more like dust clouds, with apparent coherence only due to similar initial conditions and quasi homogeneity of the medium through which they travel. The incoherence of CMEs suggests interpretation of CME observations requires accurate reconstruction of the ambient solar wind with which they interact, and that simple assumptions about the shape of the CMEs are likely to be invalid when significant spatial/temporal gradients in ambient solar wind conditions are present. PMID- 28646227 TI - Size Dependent Uptake and Hemolytic Effect of Zinc Oxide Nanoparticles on Erythrocytes and Biomedical Potential of ZnO-Ferulic acid Conjugates. AB - Despite zinc oxide nanoparticles (ZnONPs) being increasingly used as carriers in biomedical fields due to their multifaceted properties and therapeutic importance, better understanding of the mechanisms and cellular consequences resulting from their interaction with cells and cellular components has been warranted. In the present study, we investigate the size-dependent interaction of ZnONPs on RBCs, and its impact on cell viability, DNA damage, ROS generation and morphological changes, employing cellular and analytical methods. Size, charge, stability and solubility were confirmed by DLS, zeta potential, ICP-AES and TEM analysis. Further ICP-AES, TEM, spectroscopic observations and cell based assays showed that ZnONPs exhibited a size dependent impact on RBCs and haemoglobin (Hb), particularly size <50 nm. Conversely, ferulic acid (FA) conjugates and serum albumin significantly reduced the adverse effects exhibited by ZnONPs. The extent of DNA damage and ROS generation is comparatively low in ZnONPs-FA than in ZnONPs alone treated cells. Thus our study documents a novel conceptualization delineating the influence of size on the material properties and therapeutic potential of nanoparticle. PMID- 28646229 TI - Amplified surface temperature response of cold, deep lakes to inter-annual air temperature variability. AB - Summer lake surface water temperatures (LSWTs) have previously been shown to respond more rapidly to climatic warming compared to local summer surface air temperatures (SATs). In a global-scale analysis, we explore the factors underpinning the observation of an amplified response of summer LSWT to SAT variability using 20 years of satellite-derived temperatures from 144 lakes. We demonstrate that the degree of amplification in inter-annual summer LSWT is variable, and is greater for cold lakes (e.g. high latitude and high altitude), which are characterised by a short warming season, and deep lakes, that exhibit long correlation timescales of temperature anomalies due to increased thermal inertia. Such lakes are more likely to display responses in excess of local inter annual summer SAT variability. Climatic modification of LSWT has numerous consequences for water quality and lake ecosystems, so quantifying this amplified response at a global scale is important. PMID- 28646230 TI - IL-1beta increases asporin expression via the NF-kappaB p65 pathway in nucleus pulposus cells during intervertebral disc degeneration. AB - Disc degeneration (DD) is a multifaceted chronic process that alters the structure and function of intervertebral discs. The pathophysiology of degeneration is not completely understood, but the consensus is that changes in genes encoding extracellular matrix (ECM) proteins in the disc are the leading factors contributing to DD. Asporin is an ECM protein that has been shown to be increased in degenerated intervertebral discs, but little is known about how asporin is regulated during DD. In exploring the intricate mechanism, we confirmed that asporin was abundantly increased in patients' degenerated nucleus pulposus. Consistently, the increased asporin expression with degeneration was also proved by rabbit intervertebral disc degeneration (IDD) model. Mechanistically, IL-1beta upregulated asporin expression by activating the p65 pathway in human nucleus pulposus cells. Furthermore, p65 mediated asporin expression by binding to -41/-31 bp on asporin promoter. Functionally, asporin was the intermediator of IL-1beta-inhibited aggrecan and collagen Pi expression and played a negative role in TGF-beta-induced aggrecan and collagen Pi formation in human nucleus pulposus cells. Therefore, identifying asporin as a negative regulator of aggrecan and collagen Pi and elucidating its induction mechanisms in human nucleus pulposus cells provides new insight for asporin induction during IDD. PMID- 28646231 TI - Inter-annual variability of transparent exopolymer particles in the Arctic Ocean reveals high sensitivity to ecosystem changes. AB - Transparent exopolymer particles (TEP) are a class of marine gel particles and important links between surface ocean biology and atmospheric processes. Derived from marine microorganisms, these particles can facilitate the biological pumping of carbon dioxide to the deep sea, or act as cloud condensation and ice nucleation particles in the atmosphere. Yet, environmental controls on TEP abundance in the ocean are poorly known. Here, we investigated some of these controls during the first multiyear time-series on TEP abundance for the Fram Strait, the Atlantic gateway to the Central Arctic Ocean. Data collected at the Long-Term Ecological Research observatory HAUSGARTEN during 2009 to 2014 indicate a strong biological control with highest abundance co-occurring with the prymnesiophyte Phaeocystis pouchetii. Higher occurrence of P. pouchetii in the Arctic Ocean has previously been related to northward advection of warmer Atlantic waters, which is expected to increase in the future. Our study highlights the role of plankton key species in driving climate relevant processes; thus, changes in plankton distribution need to be accounted for when estimating the ocean's biogeochemical response to global change. PMID- 28646232 TI - Inhibition of ERK1/2 Restores GSK3beta Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis. AB - Tuberous sclerosis (TS) is a multi-organ autosomal dominant disorder that is best characterized by neurodevelopmental deficits and the presence of benign tumors. TS pathology is caused by mutations in tuberous sclerosis complex (TSC) genes and is associated with insulin resistance, decreased glycogen synthase kinase 3beta (GSK3beta) activity, activation of the mammalian target of rapamycin complex 1 (mTORC1), and subsequent increase in protein synthesis. Here, we show that extracellular signal-regulated kinases (ERK1/2) respond to insulin stimulation and integrate insulin signaling to phosphorylate and thus inactivate GSK3beta, resulting in increased protein synthesis that is independent of Akt/mTORC1 activity. Inhibition of ERK1/2 in Tsc2 -/- cells-a model of TS-rescues GSK3beta activity and protein synthesis levels, thus highlighting ERK1/2 as a potential therapeutic target for the treatment of TS. PMID- 28646233 TI - Identifying community thresholds for lotic benthic diatoms in response to human disturbance. AB - Although human disturbance indirectly influences lotic assemblages through modifying physical and chemical conditions, identifying thresholds of human disturbance would provide direct evidence for preventing anthropogenic degradation of biological conditions. In the present study, we used data obtained from tributaries of the Three Gorges Reservoir in China to detect effects of human disturbance on streams and to identify disturbance thresholds for benthic diatoms. Diatom species composition was significantly affected by three in-stream stressors including TP, TN and pH. Diatoms were also influenced by watershed % farmland and natural environmental variables. Considering three in-stream stressors, TP was positively influenced by % farmland and % impervious surface area (ISA). In contrast, TN and pH were principally affected by natural environmental variables. Among measured natural environmental variables, average annual air temperature, average annual precipitation, and topsoil % CaCO3, % gravel, and total exchangeable bases had significant effects on study streams. When effects of natural variables were accounted for, substantial compositional changes in diatoms occurred when farmland or ISA land use exceeded 25% or 0.3%, respectively. Our study demonstrated the rationale for identifying thresholds of human disturbance for lotic assemblages and addressed the importance of accounting for effects of natural factors for accurate disturbance thresholds. PMID- 28646234 TI - Electroporation as a vaccine delivery system and a natural adjuvant to intradermal administration of plasmid DNA in macaques. AB - In vivo electroporation (EP) is used to enhance the uptake of nucleic acids and its association with DNA vaccination greatly stimulates immune responses to vaccine antigens delivered through the skin. However, the effect of EP on cutaneous cell behavior, the dynamics of immune cell recruitment and local inflammatory factors, have not been fully described. Here, we show that intradermal DNA vaccination combined with EP extends antigen expression to the epidermis and the subcutaneous skin muscle in non-human primates. In vivo fibered confocal microscopy and dynamic ex vivo imaging revealed that EP promotes the mobility of Langerhans cells (LC) and their interactions with transfected cells prior to their migration from the epidermis. At the peak of vaccine expression, we detected antigen in damaged keratinocyte areas in the epidermis and we characterized recruited immune cells in the skin, the hypodermis and the subcutaneous muscle. EP alone was sufficient to induce the production of pro inflammatory cytokines in the skin and significantly increased local concentrations of Transforming Growth Factor (TGF)-alpha and IL-12. Our results show the kinetics of inflammatory processes in response to EP of the skin, and reveal its potential as a vaccine adjuvant. PMID- 28646235 TI - Over Expression of Long Non-Coding RNA PANDA Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8. AB - It has been reported that long non-coding RNA PANDA was disregulated in varieties types of tumor, but its expression level and biological role in hepatocellular carcinoma (HCC) remains contradictory. We detected PANDA expression in two independent cohorts (48 HCC patients following liver transplantation and 84 HCC patients following liver resection), and found that PANDA was down-regulated in HCC. Thereafter we explored its function in cancer biology by inversing its low expression. Surprisingly, overexpression of PANDA promoted HCC proliferation and carcinogenesis in vitro and in vivo. Mechanistically, PANDA repressed transcriptional activity of senescence associated inflammatory factor IL8, which leaded to inhibition of cellular senescence. Therefore, our research help to better understand the complex role of PANDA in HCC, and suggest more thoughtful strategies should be applied before it can be treated as a potential therapeutic target. PMID- 28646236 TI - Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model. AB - Influenza virus infection often causes severe disease and acute respiratory distress syndrome. It is a common belief that overwhelming immune response contributes to the severe illness. Physicians and researchers have put forth immune modulation as salvage therapy for better recovery. However, empiric corticosteroid failed in both humans and animal models. Reported success with Rapamycin in humans prompted a comprehensive animal study and mechanistic dissection. Here we report the effect of Rapamycin alone or in combination with Oseltamivir for severe influenza in BALB/c mice. We found that Rapamycin had no antiviral effect against H1N1, H3N2 and novel-H1N1 influenza viruses in vitro. Rapamycin alone aggravated the severe disease of PR8 H1N1 influenza virus infection in mice. Timely Oseltamivir anti-viral therapy abolished the disease. Delayed Oseltamivir treatment could not prevent severe illness and Rapamycin adjuvant was associated with exacerbated disease. Rapamycin adjuvant suppressed influenza hemagglutinin antigen-specific T cell immunity and impaired virus clearance from the lungs. It also resulted in intensified lung pathology with increased intra-alveolar edema and hyaline deposition. Rapamycin may work as the salvage therapy for severe influenza but it is very difficult to define the appropriate window for such treatment to take effect. PMID- 28646237 TI - Insulin-like Growth Factor 1 in relation to future hearing impairment: findings from the English Longitudinal Study of Ageing. AB - Insulin-like Growth Factor 1 (IGF-1) is associated with cardiovascular disease, itself a risk factor for hearing impairment, and, in animal studies, molecular evidence suggests a role for IGF-1 in hearing function. However, the link between IGF-1 and the occurrence of hearing impairment is untested in population-based studies of humans. A total of 4390 participants aged >=50 y (mean [SD] age 64.2 [8.0] years at baseline, 55% women) from the English Longitudinal Study of Ageing provided serum levels of IGF-1 in 2008 and again in 2012. Hearing acuity was assessed by an objective hearing test (HearCheck handheld device) in 2014 when the prevalence was 38.2%. In the full cohort, IGF-1 was not associated with subsequent hearing impairment (OR5nmol/L increase; 95% CI: 1.01; 0.94, 1.09). However, this relationship appeared to differ by age (p-value for interaction = 0.03). Thus, in younger participants (aged 50-60 y, n = 1400), IGF-1 was associated with lower odds of hearing impairment (0.86; 0.73, 1.00) after adjustment for a range of potential confounders. Among people >=60 y (n = 2990) there was a non-significant 'J'-shaped association. Our observational evidence that higher levels of IGF-1 appeared to confer some protection against hearing impairment in some older adults warrants replication in other prospective cohort studies. PMID- 28646238 TI - [Bladder neck sclerosis following prostate surgery : Which therapy when?] AB - Secondary bladder neck sclerosis represents one of the more frequent complications following endoscopic, open, and other forms of minimally invasive prostate surgery. Therapeutic decisions depend on the type of previous intervention (e.g., radical prostatectomy, TURP, HoLEP, radiotherapy, HIFU) and on associated complications (e.g., incontinence, fistula). Primary treatment in most cases represents an endoscopic bilateral incision. No specific advantages of any type of the applied energy (i.e., mono-/bipolar HF current, cold incision, holmium/thulium YAG laser) could be documented. Adjuvant measures such as injection of corticosteroids or mitomycin C have not been helpful in clinical routine. In case of first recurrence, a transurethral monopolar or bipolar resection can usually be performed. Recently, the ablation of the scared tissue using bipolar vaporization has been recommended providing slightly better long term results. Thereafter, surgical reconstruction is strongly recommended using an open, laparoscopic, or robot-assisted approach. Depending on the extent of the bladder neck sclerosis and the underlying prostate surgery, a Y-V/T-plasty, urethral reanastomosis, or even a radical prostatectomy with new urethravesical anastomosis should be performed. Stent implantation should be reserved for patients who are not suitable for surgery. The final palliative measure is a cystectomy with urinary diversion or a (continent) cystostomy. PMID- 28646239 TI - Intake of omega-3 fatty acids contributes to bone mineral density at the hip in a younger Japanese female population. AB - : This study investigated the relationships between intakes of polyunsaturated fatty acids, omega-3 fatty acids, and omega-6 fatty acids and bone mineral density in Japanese women aged 19 to 25 years. Intakes of omega-3 fatty acids (n 3) were positively associated with peak bone mass at the hip. INTRODUCTION: Lifestyle factors such as physical activity and nutrition intake are known to optimize the peak bone mass (PBM). Recently, intake of polyunsaturated fatty acids (PUFAs) has been reported to contribute to bone metabolism. In this study, the relationships of intakes of n-3 and omega-6 (n-6) fatty acids with PBM were evaluated in Japanese female subjects. METHODS: A total of 275 healthy female subjects (19-25 years) having PBM were enrolled, and lumbar and total hip bone mineral density (BMD) and bone metabolic parameters were measured. Dietary intakes of total energy, total n-3 fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and total n-6 fatty acids were assessed by a self administered questionnaire. Physical activity information was also assessed. RESULTS: The mean +/- SD age was 20.6 +/- 1.4 years, and BMI was 21.2 +/- 2.7 kg/m2. BMI and serum bone alkaline phosphatase contributed significantly to lumbar BMD on multiple regression analysis. Intake of n-3 fatty acids and physical activity were also significantly related to total hip BMD. Using EPA or DHA instead of total n-3 fatty acids in the model did not result in a significant result. CONCLUSION: Adequate total n-3 fatty acid intake may help maximize PBM at the hip. PMID- 28646240 TI - Delineating function and connectivity of optokinetic hubs in the cerebellum and the brainstem. AB - Optokinetic eye movements are crucial for keeping a stable image on the retina during movements of the head. These eye movements can be differentiated into a cortically generated response (optokinetic look nystagmus) and the highly reflexive optokinetic stare nystagmus, which is controlled by circuits in the brainstem and cerebellum. The contributions of these infratentorial networks and their functional connectivity with the cortical eye fields are still poorly understood in humans. To map ocular motor centres in the cerebellum and brainstem, we studied stare nystagmus using small-field optokinetic stimuli in the horizontal and vertical directions in 22 healthy subjects. We were able to differentiate ocular motor areas of the pontine brainstem and midbrain in vivo for the first time. Direction and velocity-dependent activations were found in the pontine brainstem (nucleus reticularis, tegmenti pontis, and paramedian pontine reticular formation), the uvula, flocculus, and cerebellar tonsils. The ocular motor vermis, on the other hand, responded to constant and accelerating velocity stimulation. Moreover, deactivation patterns depict a governing role for the cerebellar tonsils in ocular motor control. Functional connectivity results of these hubs reveal the close integration of cortico-cerebellar ocular motor and vestibular networks in humans. Adding to the cortical concept of a right hemispheric predominance for visual-spatial processing, we found a complementary left-sided cerebellar dominance for our ocular motor task. A deeper understanding of the role of the cerebellum and especially the cerebellar tonsils for eye movement control in a clinical context seems vitally important and is now feasible with functional neuroimaging. PMID- 28646241 TI - Never forget a name: white matter connectivity predicts person memory. AB - Through learning and practice, we can acquire numerous skills, ranging from the simple (whistling) to the complex (memorizing operettas in a foreign language). It has been proposed that complex learning requires a network of brain regions that interact with one another via white matter pathways. One candidate white matter pathway, the uncinate fasciculus (UF), has exhibited mixed results for this hypothesis: some studies have shown UF involvement across a range of memory tasks, while other studies report null results. Here, we tested the hypothesis that the UF supports associative memory processes and that this tract can be parcellated into sub-tracts that support specific types of memory. Healthy young adults performed behavioral tasks (two face-name learning tasks, one word pair memory task) and underwent a diffusion-weighted imaging scan. Our results revealed that variation in UF microstructure was significantly associated with individual differences in performance on both face-name tasks, as well as the word association memory task. A UF sub-tract, functionally defined by its connectivity between face-selective regions in the anterior temporal lobe and orbitofrontal cortex, selectively predicted face-name learning. In contrast, connectivity between the fusiform face patch and both anterior face patches had no predictive validity. These findings suggest that there is a robust and replicable relationship between the UF and associative learning and memory. Moreover, this large white matter pathway can be subdivided to reveal discrete functional profiles. PMID- 28646242 TI - The Role of Health Plans in Supporting Behavioral Health Integration. AB - Health plan policies can influence delivery of integrated behavioral health and general medical care. This study provides national estimates for the prevalence of practices used by health plans that may support behavioral health integration. Results indicate that health plans employ financing and other policies likely to support integration. They also directly provide services that facilitate integration. Behavioral health contracting arrangements are associated with use of these policies. Delivery of integrated care requires systemic changes by both providers and payers thus health plans are key players in achieving this goal. PMID- 28646243 TI - Provitamin A carotenoids from an engineered high-carotenoid maize are bioavailable and zeaxanthin does not compromise beta-carotene absorption in poultry. AB - High-carotenoid (HC) maize, a biofortified staple crop which accumulates beta carotene, beta-cryptoxanthin, lutein and zeaxanthin, was used as a feed component in a chicken feeding trial to assess the bioavailability of provitamin A (PVA) carotenoids in the kernel matrix compared to the synthetic and natural color additives routinely used in the poultry industry. We found that the PVA carotenoids in HC maize were not metabolized in the same manner: beta-carotene was preferentially converted into retinol in the intestine whereas beta cryptoxanthin accumulated in the liver. We also considered the effect of zeaxanthin on the absorption of PVA carotenoids because zeaxanthin is the major carotenoid component of HC maize. We found that chickens fed on diets with low levels of zeaxanthin accumulated higher levels of retinol in the liver, suggesting that zeaxanthin might interfere with the absorption of beta-carotene, although this observation was not statistically significant. Our results show that HC maize provides bioavailable carotenoids, including PVA carotenoids, and is suitable for use as a feed component. PMID- 28646245 TI - Six-Minute Walk Test as a Predictor of Diagnosis, Disease Severity, and Clinical Outcomes in Scleroderma-Associated Pulmonary Hypertension: The DIBOSA Study. AB - BACKGROUND: Pulmonary hypertension (PH) is a common complication of scleroderma (SSc) and is a leading cause of morbidity and mortality. OBJECTIVES: To explore the utility of the 6MWT in the prediction of SSc-PH and to assess its prognostic implications. METHODS: A retrospective review of SSc patients from 2003 to 2013, with 6MWT and echocardiogram (n = 286), was conducted. Presence of PH was defined by right heart catheterization. Patients were randomized into development and validation cohorts. Using regression techniques, we developed a scoring system to predict the presence of SSc-PH and tested it in our validation cohort. Trends of mortality and disease severity were studied for incremental scores. RESULTS: The DIBOSA scoring system includes DIstance walked in 6 min, BOrg dyspnea index, and SAturation of oxygen at 6 min. The DIBOSA score in the development cohort ranged from 0 to 3, resulting in an area of 0.858 (P < 0.0001) under the ROC curve. A score of 0 had a NPV of 100% and a score of 3 had a PPV of 86.58%. The validation cohort had an area under the ROC curve of 0.842. The DIBOSA score correlated with both pulmonary artery pressures and mortality. The 3-year survival rates for DIBOSA scores of 0, 1, 2, and 3 were 100, 100, 87.67, and 66.67%, respectively (HR = 3.92, P < 0.0001). CONCLUSIONS: DIBOSA score is a sensitive tool for the prediction of SSc-PH. The DIBOSA score is a direct predictor of mortality in SSc PH and strongly correlates with pulmonary pressures. 6MWT can be used to predict clinical outcomes in SSc-PH. PMID- 28646246 TI - Identification of Particles in Raw Materials. AB - Raw materials need to be of a certain quality with respect to physical and chemical composition. They also need to have no contaminants in the form of particles because these could get into the product or indicate the raw materials are not pure enough to make a good quality product. When particles are found, it is important to identify their chemical and elemental composition to correct any process errors that can cause them and to have acceptable quality of the final product. Sources of materials can be the environment, process equipment and processing, and packaging. Microscope versions of Raman spectroscopy, laser induced breakdown spectroscopy (LIBS), and IR spectroscopy are excellent tools for identifying particles in materials because they are fast and accurate techniques needing minimal sample preparation that can provide chemical composition as well as images that can be used for identification. The micro analysis capabilities allow for easy analysis of different portions of samples so that multiple components can be identified and sample preparation can be reduced or eliminated. The complementarity of the techniques provides the advantage of identifying various chemical components, as well as elemental and image analyses. The sources of materials were seen to be the environment, process equipment and processing, and packaging. PMID- 28646244 TI - Increased Soluble VCAM-1 and Normal P-Selectin in Cystic Fibrosis: a Cross Sectional Study. AB - PURPOSE: As life expectancy in cystic fibrosis (CF) increases, questions regarding its potential impact on cardiovascular health arise. Soluble vascular cell adhesion molecule 1 (sVCAM-1), P-selectin (sP-selectin) are proposed as biomarkers of cardiovascular disease. We aimed to: compare their concentrations in clinically stable CF patients and healthy subjects (HS) and verify whether they independently correlate with CF characteristics. METHODS: Serum sVCAM-1 and sP-selectin levels were measured using ELISA. CF was characterized using: forced expiratory volume in 1 s, exocrine pancreatic and CF-related liver disease status, Pseudomonas aeruginosa colonization, serum high-sensitivity C-reactive protein, and body mass index (BMI). CFTR genotypes were classified as severe (classes I and II) or other. RESULTS: 108 CF patients and 51 healthy subjects volunteered for the study. In the CF group BMI was lower (median [IQR]: 20.5 kg/m2 [18.4-22.2] vs. 21.6 kg/m2 [19.9-23.4], p = 0.02) and hsCRP levels were higher (3.6 mg/L [1.1-7.1] vs. 0.5 mg/dL [0.3-1.0], p < 10-10). While sVCAM-1 concentrations were greater in CF patients (1018 ng/mL [851-1279] vs. 861 ng/mL [806-979], p < 10-4), sP-selectin levels did not differ (155 ng/mL [129-188] vs. 156 ng/mL [144-177], p = 0.48). None of the multivariable regression models was valid for the prediction of sVCAM-1 and sP-selectin in CF. CONCLUSIONS: We found higher sVCAM-1 concentrations in CF patients than in healthy subjects, which were not explained by CF characteristics. Further research is required to check whether sVCAM-1 is a marker of microangiopathy in CF. PMID- 28646247 TI - Sucrose Octaacetate Chemical Kinetics and Shelf Lives at Various Formulation pHs. AB - Developing pediatric friendly dosage forms is a high priority worldwide. Sucrose octaacetate (SOA) has been recommended for use as a surrogate for bitter tasting active pharmaceutical ingredients. Even though SOA has found a number of human use applications and has been employed for decades, there are no rigorous chemical kinetic studies reported. A recently reported SOA stability-indicating method was used to perform SOA chemical kinetic and stability studies. As part of the chemical kinetic study, reaction order, activation energies, extrapolated rate constants, pH-rate profiles at 4 and 25 degrees C, and estimated shelf lives at 4 and 25 degrees C at different buffer pHs are provided. The estimated SOA shelf lives at 25 degrees C and pHs 4.00, 5.20, and 6.00 were 25.3, 114, and 27.4 days, respectively. At 4 degrees C, SOA's estimated shelf lives were 0.478, 5.26, and 1.47 years at pHs 4.00, 5.20, and 6.00, respectively. SOA can be formulated at pHs 4 to 6 and stored at 25 degrees C for short-duration (less than 25 days) uses such as a bitter tasting surrogate for fundamental taste mechanism studies or brief taste masking assessment clinical studies. For longer term solution studies, like being used as a bitter tasting control for blinded clinical trials, SOA should be formulated at the optimum pH of 5.40 and refrigerated at 4 degrees C for maximum stability. The reported data can be used as a starting point for developing stable SOA formulations and estimating shelf life. PMID- 28646248 TI - [Psychiatric care of refugees in Africa and the Middle East : Challenges and solutions]. AB - Violence, flight, famine, and natural disasters as well as the absence of a psychosocial healthcare system are major psychological burdens for refugees. The level of provision of mental healthcare is particularly low in developing countries. Internally displaced people and refugees place high demands on the healthcare system because they often suffer from psychiatric disorders, such as depression, posttraumatic stress disorder, and substance use disorders. We present first initiatives to improve psychiatric care in refugee camps in Ethiopia, Kenya, and Sudan. Moreover, we provide first insights into a project based in Northern Iraq and Germany aimed at the treatment of people who were severely traumatized by the terror regime of the so-called Islamic State (IS). PMID- 28646249 TI - Public acceptability of financial incentives to reward pregnant smokers who quit smoking: a United Kingdom-France comparison. AB - A substantial amount of research has been conducted on financial incentives to increase abstinence from smoking among pregnant smokers. If demonstrated to be effective, financial incentives could be proposed as part of health care interventions to help pregnant smokers quit. Public acceptability is important; as such interventions could be publicly funded. Concerns remain about the acceptability of these interventions in the general population. We aimed to assess the acceptability of financial incentives to reward pregnant smokers who stop smoking using a survey conducted in the UK and then subsequently in France, two developed countries with different cultural and social backgrounds. More French than British respondents agreed with financial incentives for rewarding quitting smoking during pregnancy, not smoking after delivery, keeping a smoke free household, health service payment for meeting target and the maximum amount of the reward. However, fully adjusted models showed significant differences only for the two latter items. More British than French respondents were neutral toward financial incentives. Differences between the representative samples of French and British individuals demonstrate that implementation of financial incentive policies may not be transferable from one country to another. PMID- 28646250 TI - Assessing competence at a higher level among older adults: development of the Japan Science and Technology Agency Index of Competence (JST-IC). AB - BACKGROUND AND AIMS: Older adults' ever-improving health and changing lifestyles necessitate the development of a scale that can better measure their competence at a higher level. We developed the Japan Science and Technology Agency Index of Competence (JST-IC) via item analysis and assessed its psychometric properties. METHODS: Participants were 1306 community-dwelling older adults (623 men and 683 women, 74.0 +/- 2.8 years old) who completed the 54-item draft JST-IC to determine their level of independence. Three procedures (including item selection, factor analyses, and reliability and validity analyses) were conducted to finalize the JST-IC and evaluate its psychometric properties. RESULTS: The item selection resulted in exclusion of 26 items for the following reasons: (a) 15 because of very high ratios (80% or more) of responders who answered "yes", (b) one because of gender differences (phi coefficient = 0.34), (c) five because of their weak association with the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) (Pearson correlation coefficient of 0.30 or smaller), and (d) five because of redundancy of meaning with other items. Through factor analyses, we selected 16 items with a four-factor solution for the final version. JST-IC score exhibited a near-normal distribution and significant gender and age differences, and had moderate correlations with size of social network and level of subjective well-being and strong correlations with TMIG-IC score, physical fitness, and health literacy. CONCLUSIONS: The JST-IC is useful for assessing competence at a higher level in community-dwelling older adults. PMID- 28646251 TI - Cardiac dose-sparing effects of deep-inspiration breath-hold in left breast irradiation : Is IMRT more beneficial than VMAT? AB - BACKGROUND: Given the reduction in death from breast cancer, as well as improvements in overall survival, adjuvant radiotherapy is considered the standard treatment for breast cancer. However, left-sided breast irradiation was associated with an increased rate of fatal cardiovascular events due to incidental irradiation of the heart. Recently, considerable efforts have been made to minimize cardiac toxicity of left-sided breast irradiation by new treatment methods such as deep-inspiration breath-hold (DIBH) and new radiation techniques, particularly intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). The primary aim of this study was to evaluate the effect of DIBH irradiation on cardiac dose compared with free-breathing (FB) irradiation, while the secondary objective was to compare the advantages of IMRT versus VMAT plans in both the FB and the DIBH position for left-sided breast cancer. METHODS: In all, 25 consecutive left-sided breast cancer patients underwent CT simulation in the FB and DIBH position. Five patients were excluded with no cardiac displacement following DIBH-CT simulation. The other 20 patients were irradiated in the DIBH position using respiratory gating. Four different treatment plans were generated for each patient, an IMRT and a VMAT plan in the DIBH and in the FB position, respectively. The following parameters were used for plan comparison: dose to the heart, left anterior descending coronary artery (mean dose, maximum dose, D25% and D45%), ipsilateral, contralateral lung (mean dose, D20%, D30%) and contralateral breast (mean dose). The percentage in dose reduction for organs at risk achieved by DIBH for both IMRT and VMAT plans was calculated and compared for each patient by each treatment plan. RESULTS: DIBH irradiation significantly reduced mean dose to the heart and left anterior descending coronary artery (LADCA) using both IMRT (heart -20%; p = 0.0002, LADCA -9%; p = 0.001) and VMAT (heart -23%; p = 0.00003, LADCA -16%; p = 0.01) techniques as compared with FB radiation. There were no significant changes in left lung dose by IMRT; however, with VMAT planning, mean dose to the left lung was reduced by -4% (p = 0.0004). In addition, DIBH significantly increased the mean dose to the contralateral breast with IMRT (+14%, p = 0.002) and significantly reduced the dose to the contralateral breast with VMAT planning ( 9%, p = 0.003) compared with the FB position. Additionally, in comparison with VMAT, the IMRT technique reduced mean heart dose both in the FB and the DIBH position by -30% (p = 0.0004) and -26% (p = 0.002), respectively. Furthermore, IMRT increased the mean dose to the left lung in both the FB and the DIBH position (+5%, p = 0.003, p = 0.006), respectively. There were no significant changes in dose to the right lung and contralateral breast either in the FB or DIBH position between IMRT and VMAT techniques. CONCLUSION: Left-sided breast irradiation is best performed in the DIBH position, since a considerable dose sparing to the heart and LADCA can be achieved by using either IMRT or VMAT techniques. A significant additional decrease in heart and LADCA dose by IMRT in both FB and DIBH irradiation was seen compared with VMAT. PMID- 28646253 TI - [Ventricular tachyarrhythmias 2017]. PMID- 28646255 TI - Protocol to perform pressurized blister tests on thin elastic films. AB - This work aims to identify common challenges in the preparation of the blister test devices designed for the measurement of the energy release rate for brittle thin films and to propose easy-to-implement solutions accordingly. To this end, we provide a step-by-step guide for fabricating a blister test device comprised of thin polystyrene films adhered to glass substrates. Thin films are first transferred from donor substrates to an air-water interface, which is then used as a platform to locate them on a receiver substrate. We embed a microchannel at the back of the device to evacuate the air trapped in the opening, through which the pressure is applied. We quantify the height and the radius of the blister to estimate the adhesion energy using the available expressions correlating the normal force and the moment with the shape of the blister. The present blister test provided an adhesion energy per unit area of G = 18+/-2 mJ/m^2 for polystyrene on glass, which is in good agreement with the measurement of G = 14+/ 2 mJ/m^2 found in our independent cleavage test. PMID- 28646252 TI - Childhood Brain Tumors: a Systematic Review of the Structural Neuroimaging Literature. AB - Due to medical advances, a large portion of children survive brain tumor diagnosis and treatment. Therefore, it is important to identify the neuroanatomical and neurocognitive outcomes associated with survivorship. This review summarizes the specific regional structural neuroimaging findings, the broad structural findings, as well as the corresponding neurocognitive domains affected in brain tumor populations. Across studies, damage is commonly reported near the cerebellum, brain stem, and subcortical regions, as well as the frontal lobes. These results are consistent with the expected neuroanatomical damage following posterior fossa brain tumors, which was the most common tumor location of the studies in this review. Damage to these regions impacts a broad range of neurocognitive outcomes, as well as a number of specific neurocognitive domains. Damage to more ventral and subcortical brain regions correlated with lower motor speed, processing speed, attention, and memory. Relevant limitations and future directions are discussed with a focus on disentangling the complex and multifaceted factors associated with the consequences of brain tumor survivorship. PMID- 28646254 TI - Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy. AB - Sodium valproate (VP) is an important antiepileptic drug, although it can produce deleterious hepatotoxic reactions. Diallyl trisulfide (DATS) is the principle component of garlic oil that possesses antioxidant properties. This study explored the potential hepatoprotective activity of DATS against VP-induced hepatic damage and its underlying mechanisms. In addition, the study assessed the effect of DATS on VP antiepileptic activity. Rats were given DATS once daily at two different doses along with VP for 2 weeks. Results have shown the ability of DATS to counteract VP-induced hepatic damage as it decreased elevated serum transaminases (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase. Liver histopathology indicated that DATS preserved the hepatic structural integrity and protected against VP-induced hepatic steatosis and necro-inflammation injury. DATS ameliorated VP-induced oxidative stress and increased the antioxidant capacity of the liver. Immunohistochemical analysis showed activation of nuclear factor kappa-B along with high expression of cyclo oxygenase-2 (COX-2) upon VP administration. This was accompanied by overproduction of proinflammatory mediators (TNF-alpha, IL-1beta, IL-6). Tracing the apoptotic pathway, VP administration induced marked apoptosis using TUNEL staining. Furthermore, VP-treated animals exhibited high immunoexpression of Bax protein and increased levels of Bax and caspase-3 while level of Bcl2 was significantly decreased in hepatic tissue. However, DATS simultaneous treatment counteracted all of these molecular pathological changes. Using pentylenetetrazole (PTZ)-induced seizures model in mice, the effect of DATS on the anticonvulsant activity of VP was found to be positive, meaning that combination of DATS with VP can confer protection against VP-induced hepatic injurious effects through its antioxidant, antiinflammatory, and antiapoptotic properties without affecting VP antiepileptic activity. PMID- 28646256 TI - A dose-response relation exists between different classes of pre-gravid obesity and selected perinatal outcomes. AB - OBJECTIVE: To examine if a "dose-response" relation exists between different classes of pre-gravid obesity and selected perinatal outcomes. METHODS: We evaluated 16,566 obese mothers, including 12,064 (72.8%), 3410 (20.6%), and 1092 (6.6%) with obesity class I, II, and III, respectively. We compared maternal age, primiparity, gestational age at birth, birth weight, GDM, hypertensive disorders, and the incidence of cesarean sections. RESULTS: There was a significantly increased incidence (from class I to class III) for GDM (8.5-14.4%), chronic hypertension (2.8-9.0%), gestational hypertension (6.7-14.2%), and for preeclampsia (5.3-9.3%). No such relationship existed for birth weight and gestational duration. CONCLUSION: Classes of obesity during pregnancy exhibit a "dose-response" relationship with maternal morbidity, but no such relationship was found with pregnancy duration and birth weight. PMID- 28646257 TI - Effect of epilepsy in pregnancy on fetal growth restriction: a systematic review and meta-analysis. AB - PURPOSE: Epilepsy is one of the most common neurological diseases during pregnancy. However, the influence of epilepsy on fetal growth is not understood. Thus, this study conducted a meta-analysis to determine the influence of epilepsy during pregnancy on fetal growth restriction (FGR). METHODS: BIOSIS, Medline, Embase, and PubMed databases were searched between January 2000 and January 2016. Without imposing language or regional restrictions, referenced articles were selected. RESULTS: Final analysis included 684 citations from 11 studies. Estimated risk of FGR was 1.28-fold higher in epileptic pregnant women than in non-epileptic women [95% confidence interval (95% CI) 1.09-1.50, p < 0.05]. Given the course of previous studies, hierarchical analysis of pregnant women who use antiepileptic drugs (AEDs) was conducted. Results show that FGR rate is significantly increased even if AEDs were taken [odds ratio 1.26, 95% CI 1.13 1.41, p < 0.05]. CONCLUSIONS: Although modest bias cannot be avoided, our meta analysis indicated that epilepsy participates in fetal development as an unfavorable factor, and AEDs seemed to be useless in decreasing the occurrence rate of FGR. PMID- 28646258 TI - Selective survival advantage associated with primary tumor resection for metastatic gastric cancer in a Western population. AB - BACKGROUND: The prognosis of metastatic gastric cancer (GC) remains dismal, with a median survival of 10 months. Historically, primary tumor resection was not thought to confer any survival benefit. Although high-level data exist guiding treatment of metastatic GC for patients in the East, no such data exist for Western patients despite inherent ethnic differences in GC biology. METHODS: The 2006-2012 National Cancer Database was queried for adult patients with metastatic gastric adenocarcinoma. Patients were classified into those who underwent primary tumor resection and chemotherapy (PTRaC) and those who received chemotherapy only. Groups were propensity score matched, and survival was compared using advanced statistical modeling. RESULTS: A total of 7026 patients met the inclusion criteria: 6129 (87%) patients were treated with chemotherapy alone and 897 (13%) patients were treated with PTRaC. After multivariable adjustment, patients who underwent PTRaC had a significantly better overall survival (OS) than patients who received systemic therapy only (HR, 0.60; 95% CI, 0.56-0.64; p < 0.001). Following full bipartite propensity score-adjusted analysis, 2-year OS for patients who received chemotherapy only was 12.6% (95% CI, 11.7-13.5%), whereas it was 34.2% (95% CI, 31.3-37.5%) for patients who underwent PTRaC (HR for resection: 0.52; 95% CI, 0.47-0.57; p < 0.001). CONCLUSION: Our data suggest that there exists a subset of patients with metastatic GC for which PTRaC may improve OS. As significant uncertainty still remains, our results support the need for further prospective trials investigating the influence of palliative gastrectomy on survival among Western patients. PMID- 28646259 TI - Chronic Administration of S-Allylcysteine Activates Nrf2 Factor and Enhances the Activity of Antioxidant Enzymes in the Striatum, Frontal Cortex and Hippocampus. AB - Oxidative stress plays an important role in neurodegenerative diseases and aging. The cellular defense mechanisms to deal with oxidative damage involve the activation of transcription factor related to NF-E2 (Nrf2), which enhances the transcription of antioxidant and phase II enzyme genes. S-allylcysteine (SAC) is an antioxidant with neuroprotective properties, and the main organosulfur compound in aged garlic extract. The ability of SAC to activate the Nrf2 factor has been previously reported in hepatic cells; however this effect has not been studied in normal brain. In order to determine if the chronic administration of SAC is able to activate Nrf2 factor and enhance antioxidant defense in the brain, male Wistar rats were administered with SAC (25, 50, 100 and 200 mg/kg-body weight each 24 h, i.g.) for 90 days. The activation of Nrf2, the levels of p65 and 8-hydroxy-2-deoxyguanosine (8-OHdG) as well as the activities of the enzymes glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) were evaluated in the hippocampus, striatum and frontal cortex. Results showed that SAC activated Nrf2 factor in the hippocampus (25-200 mg/kg) and striatum (100 mg/kg) and significantly decreased p65 levels in the frontal cortex (25-200 mg/kg). On the other hand, SAC increased GPx, GR, CAT and SOD activities mainly in the hippocampus and striatum, but it did not change GST activity. Finally, no changes were observed in 8-OHdG levels mediated by SAC in any brain region, but the hippocampus showed a major level of 8-OHdG compared with the striatum and frontal cortex. All these results suggest that in the hippocampus, the observed increase in the activity of antioxidant enzymes could be associated with the ability of SAC to activate Nrf2 factor; however, a different mechanism could be involved in the striatum and frontal cortex, since no changes were found in Nrf2 activation and p65 levels. PMID- 28646260 TI - Salt Appetite, and the Influence of Opioids. AB - Due to the biological importance of sodium and its relative scarcity within many natural environments, 'salt appetite' has evolved whereby dietary salt is highly sought after and palatable when tasted. In addition to peripheral responses, salt depletion is detected within the brain via circumventricular organs and 11beta hydroxysteroid dehydrogenase type 2 (HSD2) neurons to increase salt appetite. Salt appetite is comprised of two main components. One component is the incentive salience or motivation for salt (i.e. how much salt is 'wanted'). Incentive salience is dynamic and largely depends on internal homeostatic conditions in combination with the detection of relevant cues. It involves the mesolimbic system and structures such as the central amygdala, and opioid signalling within these regions can increase salt intake in rodents. A second key feature is the hedonic palatability of salt (i.e. how much it is 'liked') when it is tasted. After detection on the tongue, gustatory information passes through the brainstem nucleus of the solitary tract and thalamus, before being consciously detected within the gustatory cerebral cortex. The positive or negative hedonic value of this stimulus is also dynamic, and is encoded by a network including the nucleus accumbens, ventral pallidum, and lateral parabrachial nucleus. Opioid signalling within these areas can alter salt intake, and 'liking'. The overconsumption of dietary salt likely contributes to hypertension and associated diseases, and hence further characterising the role played by opioid signalling has important implications for human health. PMID- 28646261 TI - Hepatic arterial infusion chemotherapy for extensive liver metastases of breast cancer: efficacy, safety and prognostic parameters. AB - PURPOSE: Hepatic arterial infusion chemotherapy (HAIC) is an option for patients with liver-predominant metastatic breast cancer (LMBC), when no further systemic treatment is available. But systematic reports are limited. Here we conducted a retrospective analysis of LMBC patients treated at an expert center. METHODS: Individual patient data were retrieved from the clinical data base of the West German Cancer Center. Primary endpoints included hepatic response (RECIST), progression-free survival (PFS), overall survival (OS), and toxicity. A score based on LDH, AST, ALT and bilirubine was developed to estimate the hepatic metastasis load. RESULTS: Data from 70 consecutive patients were included. All patients were heavily pretreated (median 7 treatment lines for LMBC). HAIC protocols included mitomycin/5-FU (70%), mitomycin (14.3%), melphalan (12.9%) and 5-FU (7.1%), with selection based on patient characteristics. Partial hepatic remission was obtained as best response in 14 patients (20.0%), stable disease in 27 patients (38.6%), and progressive disease in 29 patients (41.4%). Median PFS and OS from initiation of HAIC were 2 (range 0-10) and 7 months (range 1-37). Mainly hepatic and hematopoietic HAIC-related toxicities were observed; there was no treatment-related death. The hepatic metastasis score effectively separated two prognostic groups: Patients with a score <3 had significantly superior PFS (15 vs 7 weeks, p = 0.017) and OS (12 vs 5 months, p = 0.002). CONCLUSION: HAIC offers a safe and effective salvage treatment strategy in heavily pretreated patients with LMBC and no further treatment options. The hepatic metastasis score may help to identify patients with sustained clinical benefit. PMID- 28646262 TI - Martin Heinrich Rathke (1793-1860) and his pouch and cyst. PMID- 28646263 TI - Cerebello-pontine angle eosinophilic granuloma; a reappraisal in the management of intracranial eosinophilic granuloma. PMID- 28646264 TI - Magnitude and Temporal Trends in Avoidable Blindness in Children (ABC) in India. AB - The World Health Organization estimates that 19 million children are visually impaired, among whom, 1.4 million are blind. Childhood blindness is an excellent indicator of the state of child health and primary care services in a country. Childhood blindness is important not just due to the number of children blind but also because the number of years that the surviving child has to live with blindness (blind years lived). Childhood blindness is next only to adult cataract in terms of the number of blind person years lived. Under-five mortality rates have been used as a proxy measure to compute the prevalence of childhood blindness in low and middle income countries due to limitations of other methods of data collection. In India, it is estimated that there are 0.8 blind for 1000 children. Whole globe lesions, corneal scarring, retinal pathology and afflictions of the lens are important anatomical sites in children. Causes operating in childhood and hereditary causes are important in etiology of childhood blindness. In 38.2%-68.4% cases across the region, a specific cause of blindness could not be identified in South Asia. The proportion of blindness that can be prevented or treated (avoidable) in children is less than 50%. Therefore a comprehensive eye care system needs to be in place to cater to the needs of children with avoidable and those with incurable blindness. Early detection and prompt management are critical for success of programs targeting avoidable blindness in children. PMID- 28646266 TI - Pericytes promote abnormal tumor angiogenesis in a rat RG2 glioma model. AB - In glioma angiogenesis, tumor vessels cause morphological and functional abnormalities associated with malignancy and tumor progression. We hypothesized that certain structural changes or scantiness of functional pericytes may be involved in the formation of dysfunctional blood vessels in gliomas. In this study, we performed morphological examinations to elucidate the possible involvement of pericytes in brain tumor vessel abnormalities using a rat RG2 glioma model. After implantation of RG2 glioma cells in the syngeneic rat brain, gliomas were formed as early as day 7. In immunohistochemical examinations, desmin-positive pericytes, characterized by morphological abnormalities, were abundantly found on leaky vessels, as assessed by extravasation of lectin and high-molecular-weight dextrans. Interestingly, desmin-positive pericytes seemed to be characteristic of gliomas in rats. These pericytes were also found to express heat-shock protein 47, which plays an important role in the formation of the basement membrane, suggesting that RG2 pericytes promoted angiogenesis by producing basement membrane as a scaffold for newly forming blood vessels and caused functional abnormalities. We concluded that RG2 pericytes may be responsible for abnormal tumor angiogenesis lacking the functional ability to maintain the blood-brain barrier. PMID- 28646265 TI - Omega-3 and Omega-6 Fatty Acids Act as Inhibitors of the Matrix Metalloproteinase 2 and Matrix Metalloproteinase-9 Activity. AB - Polyunsaturated fatty acids have been reported to play a protective role in a wide range of diseases characterized by an increased metalloproteinases (MMPs) activity. The recent finding that omega-3 and omega-6 fatty acids exert an anti inflammatory effect in periodontal diseases has stimulated the present study, designed to determine whether such properties derive from a direct inhibitory action of these compounds on the activity of MMPs. To this issue, we investigated the effect exerted by omega-3 and omega-6 fatty acids on the activity of MMP-2 and MMP-9, two enzymes that actively participate to the destruction of the organic matrix of dentin following demineralization operated by bacteria acids. Data obtained (both in vitro and on ex-vivo teeth) reveal that omega-3 and omega 6 fatty acids inhibit the proteolytic activity of MMP-2 and MMP-9, two enzymes present in dentin. This observation is of interest since it assigns to these compounds a key role as MMPs inhibitors, and stimulates further study to better define their therapeutic potentialities in carious decay. PMID- 28646267 TI - Quantitative EEG Metrics Differ Between Outcome Groups and Change Over the First 72 h in Comatose Cardiac Arrest Patients. AB - BACKGROUND: Forty to sixty-six percent of patients resuscitated from cardiac arrest remain comatose, and historic outcome predictors are unreliable. Quantitative spectral analysis of continuous electroencephalography (cEEG) may differ between patients with good and poor outcomes. METHODS: Consecutive patients with post-cardiac arrest hypoxic-ischemic coma undergoing cEEG were enrolled. Spectral analysis was conducted on artifact-free contiguous 5-min cEEG epochs from each hour. Whole band (1-30 Hz), delta (delta, 1-4 Hz), theta (theta, 4-8 Hz), alpha (alpha, 8-13 Hz), beta (beta, 13-30 Hz), alpha/delta power ratio, percent suppression, and variability were calculated and correlated with outcome. Graphical patterns of quantitative EEG (qEEG) were described and categorized as correlating with outcome. Clinical outcome was dichotomized, with good neurologic outcome being consciousness recovery. RESULTS: Ten subjects with a mean age = 50 yrs (range = 18-65) were analyzed. There were significant differences in total power (3.50 [3.30-4.06] vs. 0.68 [0.52-1.02], p = 0.01), alpha power (1.39 [0.66 1.79] vs 0.27 [0.17-0.48], p < 0.05), delta power (2.78 [2.21-3.01] vs 0.55 [0.38 0.83], p = 0.01), percent suppression (0.66 [0.02-2.42] vs 73.4 [48.0-97.5], p = 0.01), and multiple measures of variability between good and poor outcome patients (all values median [IQR], good vs. poor). qEEG patterns with high or increasing power or large power variability were associated with good outcome (n = 6). Patterns with consistently low or decreasing power or minimal power variability were associated with poor outcome (n = 4). CONCLUSIONS: These preliminary results suggest qEEG metrics correlate with outcome. In some patients, qEEG patterns change over the first three days post-arrest. PMID- 28646268 TI - The role of perceived sleep norms in subjective sleep appraisals and sleep related illness behavior. AB - The present investigation sought to extend extant research on subjective sleep complaints by examining their relation to perceived sleep norms. Results from two studies showed that individuals' distress and illness behavior in response to symptoms of fatigue and non-restorative sleep was influenced by their perceptions of peer norms for those symptoms. Individuals who believed they experienced a greater degree of fatigue and non-restorative sleep than their peers reported more distress arising from those symptoms, and were also more likely to seek social support and medical treatment for them. Furthermore, participants who scored higher in neuroticism were more likely to believe they experienced worse fatigue and non-restorative sleep than their peers, and thus reported higher symptom-related distress, and higher likelihood of engaging in illness behaviors. These results provide preliminary evidence of the clinical relevance of perceived norms in the way individuals respond to and manage sleep related problems. PMID- 28646269 TI - The role of visual experience in the production of emotional facial expressions by blind people: a review. AB - Facial expressions of emotion are nonverbal behaviors that allow us to interact efficiently in social life and respond to events affecting our welfare. This article reviews 21 studies, published between 1932 and 2015, examining the production of facial expressions of emotion by blind people. It particularly discusses the impact of visual experience on the development of this behavior from birth to adulthood. After a discussion of three methodological considerations, the review of studies reveals that blind subjects demonstrate differing capacities for producing spontaneous expressions and voluntarily posed expressions. Seventeen studies provided evidence that blind and sighted spontaneously produce the same pattern of facial expressions, even if some variations can be found, reflecting facial and body movements specific to blindness or differences in intensity and control of emotions in some specific contexts. This suggests that lack of visual experience seems to not have a major impact when this behavior is generated spontaneously in real emotional contexts. In contrast, eight studies examining voluntary expressions indicate that blind individuals have difficulty posing emotional expressions. The opportunity for prior visual observation seems to affect performance in this case. Finally, we discuss three new directions for research to provide additional and strong evidence for the debate regarding the innate or the culture-constant learning character of the production of emotional facial expressions by blind individuals: the link between perception and production of facial expressions, the impact of display rules in the absence of vision, and the role of other channels in expression of emotions in the context of blindness. PMID- 28646270 TI - Release from PI: An analysis and a model. AB - Recall decreases across a series of subspan immediate-recall trials but rebounds if the semantic category of the words is changed, an example of release from proactive interference (RPI). The size of the rebound depends on the semantic categories used and ranges from 0% to 95%. We used a corpus of novels to create vectors representing the meaning of about 40,000 words using the BEAGLE algorithm. The distance between categories and spread within categories jointly predicted the size of the RPI. We used a holographic model for recall equipped with a lexicon of BEAGLE vectors representing the meaning of words. The model captured RPI using a hologram as an interface to bridge information from episodic and semantic memory; it is the first account of RPI to capture release at the level of individual words in categorized lists. PMID- 28646271 TI - Characterization of Adipose-Derived Stem Cells Following Burn Injury. AB - Severe burns induce a prolonged inflammatory response in subcutaneous adipose tissue that modulates signaling in adipose-derived stem cells (ASCs), which hold potential for healing burn wounds or generating skin substitutes. Using a 60% rat scald burn model, we conducted a series of experiments to determine which cells isolated from the adipose tissue produced inflammatory mediators and how these changes affect ASC fate and function. The stromal vascular fraction (SVF), adipocytes, and ASCs were isolated from adipose tissue at varying times up to 4 weeks postburn and from non-injured controls. Endpoints included inflammatory marker expression, expression of ASC-specific cell-surface markers, DNA damage, differentiation potential, and proliferation. Inflammatory marker expression was induced in adipocytes and the SVF at 24 and 48 h postburn; expression of inflammatory marker mRNA transcripts and protein returned to normal in the SVF isolated 1 week postburn. In enriched ASCs, burns did not alter cell-surface expression of stem cell markers, markers of inflammation, differentiation potential, or proliferative ability. These results suggest that adipocytes and the SVF produce large quantities of inflammatory mediators, but that ASCs do not, after burns and that ASCs are unaffected by burn injury or culturing procedures.. They also suggest that cells isolated over 48 h after injury are best for cell culture or tissue engineering purposes. PMID- 28646272 TI - Rhesus Cochlear and Vestibular Functions Are Preserved After Inner Ear Injection of Saline Volume Sufficient for Gene Therapy Delivery. AB - Sensorineural losses of hearing and vestibular sensation due to hair cell dysfunction are among the most common disabilities. Recent preclinical research demonstrates that treatment of the inner ear with a variety of compounds, including gene therapy agents, may elicit regeneration and/or repair of hair cells in animals exposed to ototoxic medications or other insults to the inner ear. Delivery of gene therapy may also offer a means for treatment of hereditary hearing loss. However, injection of a fluid volume sufficient to deliver an adequate dose of a pharmacologic agent could, in theory, cause inner ear trauma that compromises functional outcome. The primary goal of the present study was to assess that risk in rhesus monkeys, which closely approximates humans with regard to middle and inner ear anatomy. Secondary goals were to identify the best delivery route into the primate ear from among two common surgical approaches (i.e., via an oval window stapedotomy and via the round window) and to determine the relative volumes of rhesus, rodent, and human labyrinths for extrapolation of results to other species. We measured hearing and vestibular functions before and 2, 4, and 8 weeks after unilateral injection of phosphate-buffered saline vehicle (PBSV) into the perilymphatic space of normal rhesus monkeys at volumes sufficient to deliver an atoh1 gene therapy vector. To isolate effects of injection, PBSV without vector was used. Assays included behavioral observation, auditory brainstem responses, distortion product otoacoustic emissions, and scleral coil measurement of vestibulo-ocular reflexes during whole-body rotation in darkness. Three groups (N = 3 each) were studied. Group A received a 10 MUL transmastoid/trans-stapes injection via a laser stapedotomy. Group B received a 10 MUL transmastoid/trans-round window injection. Group C received a 30 MUL transmastoid/trans-round window injection. We also measured inner ear fluid space volume via 3D reconstruction of computed tomography (CT) images of adult C57BL6 mouse, rat, rhesus macaque, and human temporal bones (N = 3 each). Injection was well tolerated by all animals, with eight of nine exhibiting no signs of disequilibrium and one animal exhibiting transient disequilibrium that resolved spontaneously by 24 h after surgery. Physiologic results at the final, 8-week post-injection measurement showed that injection was well tolerated. Compared to its pretreatment values, no treated ear's ABR threshold had worsened by more than 5 dB at any stimulus frequency; distortion product otoacoustic emissions remained detectable above the noise floor for every treated ear (mean, SD and maximum deviation from baseline: -1.3, 9.0, and -18 dB, respectively); and no animal exhibited a reduction of more than 3 % in vestibulo-ocular reflex gain during high-acceleration, whole-body, passive yaw rotations in darkness toward the treated side. All control ears and all operated ears with definite histologic evidence of injection through the intended site showed similar findings, with intact hair cells in all five inner ear sensory epithelia and intact auditory/vestibular neurons. The relative volumes of mouse, rat, rhesus, and human inner ears as measured by CT were (mean +/- SD) 2.5 +/- 0.1, 5.5 +/- 0.4, 59.4 +/- 4.7 and 191.1 +/- 4.7 MUL. These results indicate that injection of PBSV at volumes sufficient for gene therapy delivery can be accomplished without destruction of inner ear structures required for hearing and vestibular sensation. PMID- 28646273 TI - Pulmonary vascular volume ratio measured by cardiac computed tomography in children and young adults with congenital heart disease: comparison with lung perfusion scintigraphy. AB - BACKGROUND: Lung perfusion scintigraphy is regarded as the gold standard for evaluating differential lung perfusion ratio in congenital heart disease. OBJECTIVE: To compare cardiac CT with lung perfusion scintigraphy for estimated pulmonary vascular volume ratio in patients with congenital heart disease. MATERIALS AND METHODS: We included 52 children and young adults (median age 4 years, range 2 months to 28 years; 31 males) with congenital heart disease who underwent cardiac CT and lung perfusion scintigraphy without an interim surgical or transcatheter intervention and within 1 year. We calculated the right and left pulmonary vascular volumes using threshold-based CT volumetry. Then we compared right pulmonary vascular volume percentages at cardiac CT with right lung perfusion percentages at lung perfusion scintigraphy by using paired t-test and Bland-Altman analysis. RESULTS: The right pulmonary vascular volume percentages at cardiac CT (66.3 +/- 14.0%) were significantly smaller than the right lung perfusion percentages at lung perfusion scintigraphy (69.1 +/- 15.0%; P=0.001). Bland-Altman analysis showed a mean difference of -2.8 +/- 5.8% and 95% limits of agreement (-14.1%, 8.5%) between these two variables. CONCLUSION: Cardiac CT, in a single examination, can offer pulmonary vascular volume ratio in addition to pulmonary artery anatomy essential for evaluating peripheral pulmonary artery stenosis in patients with congenital heart disease. However there is a wide range of agreement between cardiac CT and lung perfusion scintigraphy. PMID- 28646274 TI - Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients. AB - BACKGROUND AND OBJECTIVES: Diltiazem is a benzothiazepine calcium blocker and widely used in renal transplant patients since it improves the level of tacrolimus or cyclosporine A concentration. Several population pharmacokinetic (PopPK) models had been established for cyclosporine A and tacrolimus but no specific PopPK model was established for diltiazem. The aim of the study is to develop a PopPK model for diltiazem in renal transplant recipients and provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study. METHODS: Patients received tacrolimus as primary immunosuppressant agent after renal transplant and started administration of diltiazem 90 mg twice daily on 5th day. The concentration of diltiazem at 0, 0.5, 1, 2, 8, and 12 h was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Genotyping for CYP3A4*1G, CYP3A5*3, and MDR1 3435 was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). 25 covariates were considered in the stepwise covariate model (SCM) building procedure. RESULTS: One-compartment structural pharmacokinetic model with first-order absorption and elimination was used to describe the pharmacokinetic characteristics of diltiazem. Total bilirubin (TBIL) influenced apparent volume of distribution (V/F) of diltiazem in the forward selection. The absorption rate constant (K a), V/F, and apparent oral clearance (CL/F) of the final population pharmacokinetic (PopPK) model of diltiazem were 1.96/h, 3550 L, and 92.4 L/h, respectively. CONCLUSION: A PopPK model of diltiazem is established in Chinese renal transplant recipients and it will provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study. PMID- 28646276 TI - Rhizopus arrhizus Invasive Infection due to Self-Inflicted Scratch Injuries in a Diabetic Patient with Non-ketotic Acidosis. AB - Mucormycosis is a rare infection caused by members included in the subphylum Mucoromycotina. Characterized by the histopathological hallmark of angioinvasion, these infections affect most often patients with certain underlying conditions carrying immunosuppression (haematological neoplasias, diabetic ketoacidosis and other forms of acidosis, and iron overload) or immunocompetent patients with traumatic mucocutaneous barriers breakdown and direct inoculation of the mould. A case is presented in which a rare underlying condition (non-ketotic acidosis) and a rare cause of cutaneous injuries collide. Prognosis, treatment options and management decisions are described thoroughly. PMID- 28646277 TI - Standardization and Prevalence of the Booster Phenomenon: Evaluation Using a Two Step Skin Test with 43 kDa Glycoprotein in Individuals from an Endemic Region of Paracoccidioidomycosis. AB - BACKGROUND: We estimated the occurrence rate of the booster phenomenon by using an intradermal test with 43 kDa glycoprotein in an endemic area of paracoccidioidomycosis in the central-west region of Brazil. METHODS: Individuals who had a negative result on a survey performed by using an intradermal test with 43 kDa glycoprotein in an endemic area of paracoccidioidomycosis underwent a second intradermal test after 10-15 days to determine the presence or absence of the booster phenomenon. Statistical analyses were performed using the Chi-square test, Chi-square for linear trend test, Student's t test, and binomial test; p < 0.05 was considered significant. RESULTS: For the first time, we reported the occurrence of the booster phenomenon to an intradermal reaction caused by 43 kDa glycoprotein at a rate of 5.8-8.4%, depending on the test's cutoff point. This suggests that a cutoff point should be considered for the booster phenomenon in intradermal tests with 43 kDa glycoprotein: a difference of 6-7 mm between readings according to the first and second tests, depending on the purpose of the evaluation. CONCLUSION: The results indicate that the prevalence of paracoccidioidal infection in endemic areas is underestimated, as the booster phenomenon has not been considered in epidemiological surveys for this infection. PMID- 28646279 TI - Response to "How best to quantify and express the levels of substances in the urine?" PMID- 28646278 TI - Liver involvement in kidney disease and vice versa. AB - The liver and kidneys are often similarly affected by a single disease. This is the case in metabolic, immunological, toxic, and infectious diseases, and in the different congenital malformation syndromes. Also, an enzymatic defect in an otherwise healthy liver or the consequences of advanced liver disease by itself can cause kidney disease as a secondary phenomenon. In this review, we describe numerous pathogenic mechanisms leading to dysfunction or malformations of the liver and kidneys in children. We encourage multidisciplinary management for optimal care. A combined liver-kidney transplantation is sometimes needed. PMID- 28646280 TI - Bubble removal with the use of a vacuum pressure generated by a converging diverging nozzle. AB - Bubbles are an intrinsic problem in microfluidic devices and they can appear during the initial filling of the device or during operation. This report presents a generalizable technique to extract bubbles from microfluidic networks using an adjacent microfluidic negative pressure network over the entire microfluidic channel network design. We implement this technique by superimposing a network of parallel microchannels with a vacuum microfluidic channel and characterize the bubble extraction rates as a function of negative pressure applied. In addition, we generate negative pressure via a converging-diverging (CD) nozzle, which only requires inlet gas pressure to operate. Air bubbles generated during the initial liquid filling of the microfluidic network are removed within seconds and their volume extraction rate is calculated. This miniaturized vacuum source can achieve a vacuum pressure of 7.23 psi which corresponds to a bubble extraction rate of 9.84 pL/s, in the microfluidic channels we characterized. Finally, as proof of concept it is shown that the bubble removal system enables bubble removal on difficult to fill microfluidic channels such as circular or triangular shaped channels. This method can be easily integrated into many microfluidic experimental protocols. PMID- 28646281 TI - Relations between work and upper extremity musculoskeletal problems (UEMSP) and the moderating role of psychosocial work factors on the relation between computer work and UEMSP. AB - PURPOSE: Computer work has been identified as a risk factor for upper extremity musculoskeletal problems (UEMSP). But few studies have investigated how psychosocial and organizational work factors affect this relation. Nor have gender differences in the relation between UEMSP and these work factors been studied. We sought to estimate: (1) the association between UEMSP and a range of physical, psychosocial and organizational work exposures, including the duration of computer work, and (2) the moderating effect of psychosocial work exposures on the relation between computer work and UEMSP. METHODS: Using 2007-2008 Quebec survey data on 2478 workers, we carried out gender-stratified multivariable logistic regression modeling and two-way interaction analyses. RESULTS: In both genders, odds of UEMSP were higher with exposure to high physical work demands and emotionally demanding work. Additionally among women, UEMSP were associated with duration of occupational computer exposure, sexual harassment, tense situations when dealing with clients, high quantitative demands and lack of prospects for promotion, and among men, with low coworker support, episodes of unemployment, low job security and contradictory work demands. Among women, the effect of computer work on UEMSP was considerably increased in the presence of emotionally demanding work, and may also be moderated by low recognition at work, contradictory work demands, and low supervisor support. CONCLUSIONS: These results suggest that the relations between UEMSP and computer work are moderated by psychosocial work exposures and that the relations between working conditions and UEMSP are somewhat different for each gender, highlighting the complexity of these relations and the importance of considering gender. PMID- 28646282 TI - Surgery for pancreatic ductal adenocarcinoma. AB - Surgical resection is the only potentially curative option in the treatment of pancreatic ductal adenocarcinoma. Preoperative radiological imaging allows to rule out the presence of metastases. Three resectability categories are established based on the radiological findings depending on the degree of contact between the tumor and the blood vessels. Histological confirmation of malignancy is only required in cases of borderline or non-resectable tumors, prior to neoadjuvant treatment initiation. Diagnostic laparoscopy is recommended in the presence of large tumors of the body or tail and in borderline tumors to explore the possibility of resection and to apply treatment with curative intent, as well as in those cases with high level of biomarkers to rule out peritoneal involvement. Prior to surgery preoperative nutritional measures as well as endoscopic biliary drainage can be applied to optimize patient's conditions. Cephalic pancreaticoduodenectomy is the recommended surgical technique in tumors located in the head of the pancreas. The benefits from pyloric preservation, type or reconstruction (one vs. two loops), type of anastomosis (pancreaticojejunostomy vs. pancreaticogastrostomy), intraoperative biopsy of the pancreatic resection margin or the use of intraperitoneal drainages are inconclusive. Total pancreatectomy and/or portal resection should only be performed in particular cases; however, arterial resections have shown no benefits. Radical antegrade modular pancreaticosplenectomy, that can be performed laparoscopically, is the technique used for those tumors located in the pancreatic body-tail. PMID- 28646283 TI - CD4 T Cells in IBD: Crossing the Line? PMID- 28646284 TI - CHD1L Expression Increases Tumor Progression and Acts as a Predictive Biomarker for Poor Prognosis in Pancreatic Cancer. AB - BACKGROUND: The chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) plays a key role in controlling various cellular phenomena, including immune-mediated inflammation, transformation, apoptosis, cell cycle progression, and proliferation. METHODS: This study investigated the function and clinical significance of CHD1L protein expression in pancreatic cancer (PC). We analyzed CHD1L expression in surgical specimens from 112 PC patients. The correlation between the clinical characteristics and prognosis was also determined. Futhermore, cell proliferation were measured using EDU, and a molecular mechanism of Wnt/beta-catenin pathway regulation by CHD1L was explored. RESULT: CHD1L protein expression was significantly higher in PC patients with regard to the tumor grade, stage, size, differentiation and lymph node status. Increased CHD1L protein expression was significantly associated with poor overall survival. Multivariate analyses revealed that high CHD1L expression was an independent predictive marker for the recurrence and poor prognosis of pancreatic cancer. Furthermore, silencing of CHD1L expression by RNAi effectively abolished the proliferative abilities of CHD1L in vivo and in vitro. We found that the Wnt/beta catenin pathway contributed to the effect of CHD1L-mediated pancreatic cancer proliferation. CONCLUSION: Taken together, our data provide a novel evidence for the biological and clinical significance of CHD1L as a potential biomarker, and we demonstrate that CHD1L-Wnt/beta-catenin might be a novel pathway involved in pancreatic cancer progression. PMID- 28646285 TI - Growing Concerns: A 3-Year-Old Girl with Multiple Hepatic Masses and Gastrointestinal Bleeding. PMID- 28646286 TI - Rifaximin Re-treatment in Patients with Irritable Bowel Syndrome: Feels Like the First Time? PMID- 28646287 TI - Assessing the effects of price regulation and freedom of choice on quality: evidence from the physiotherapy market. AB - In health care, many aspects of the delivery of services are subject to regulation. Often the purpose of the regulated health care system is to encourage providers to keep costs down without skimping on quality. The purpose of this paper is to analyse the effect of price regulation and free choice on quality in physiotherapy organised by the Social Insurance Institution of Finland for the disabled individuals.We use the difference-in-differences method in our effort to isolate the effect of the regulation and for this task we have defined the regulated and non-regulated firms and their quality before and after the regulation. The variables needed in the econometric modelling were collected from several registers as well as by carrying out questionnaires on the firms.We show that price regulation decreased quality in physiotherapy statistically significantly and the mechanism was unable to incentivise firms to invest in quality. Most likely, our results are caused by cost reduction associated with price regulation. It seems that cost reduction was carried out through quality reductions in physiotherapy instead of increasing productivity. The result is sensible because comparable quality information is not published to support patient choice in this sector. PMID- 28646290 TI - 2017 In Vitro Biology Meeting, June 10-14, Raleigh, North Carolina : Late Submission Abstracts. PMID- 28646288 TI - Extremophilic proteases as novel and efficient tools in short peptide synthesis. AB - The objective of this review is to outline the crucial role that peptides play in various sectors, including medicine. Different ways of producing these compounds are discussed with an emphasis on the benefits offered by industrial enzyme biotechnology. This paper describes mechanisms of peptide bond formation using a range of proteases with different active site structures. Importantly, these enzymes may be further improved chemically and/or genetically to make them better suited for their various applications and process conditions. The focus is on extremophilic proteases, whose potential does not seem to have been fully appreciated to date. The structure of these proteins is somewhat different from that of the common commercially available enzymes, making them effective at high salinity and high or low temperatures, which are often favorable to peptide synthesis. Examples of such enzymes include halophilic, thermophilic, and psychrophilic proteases; this paper also mentions some promising catalytic proteins which require further study in this respect. PMID- 28646289 TI - Delta neutrophil index (DNI) as a novel diagnostic and prognostic marker of infection: a systematic review and meta-analysis. AB - OBJECTIVE: Delta neutrophil index (DNI) representing the number of immature granulocytes is an emerging marker used in diagnosis of infections and prediction of mortality in infected patients. The present study evaluated the diagnostic accuracy of DNI as a predictive and prognostic factor in infected patients. METHODS: We performed a PubMed search on January 1st, 2017 and identified studies that evaluated DNI as either a predictive or prognostic factor in infected patients. Studies with appropriate information to construct 2 * 2 contingency tables were extracted. We calculated pooled sensitivity and specificity. Meta analysis of the multivariate logistic regression data set was performed to assess whether DNI functions as an independent factor. RESULTS: Overall, 12 articles fulfilled the inclusion criteria and a total of 499 cases and 9549 controls were examined. As a predictive factor of infection, DNI's pooled sensitivity was 0.67 (95% CI 0.62-0.71, I 2 = 86.0%) and pooled specificity was 0.94 (95% CI 0.94 0.95, I 2 = 92.8%). Area under the receiver operating characteristics (ROC) curve was 0.89. As a prognostic factor for death in infected patients, DNI's pooled sensitivity was 0.70 (95% CI 0.56-0.81, I 2 = 0.0%) and pooled specificity was 0.78 (95% CI 0.73-0.83, I 2 = 26.6%). Area under the ROC curve was 0.84. Meta analysis of the multivariate logistic regression data set showed insignificant results. CONCLUSIONS: DNI is a potentially useful diagnostic tool and predicts mortality among infected patients and should be more widely used in the clinical practice. PMID- 28646291 TI - Application of open-access databases to determine functional connectivity between resveratrol-binding protein QR2 and colorectal carcinoma. AB - Colorectal cancer (CRC) is a major cause of cancer-associated deaths worldwide. Recently, oral administration of resveratrol (trans-3,5,4'-trihydroxystilbene) has been reported to significantly reduce tumor proliferation in colorectal cancer patients, however, with little specific information on functional connections. The pathogenesis and development of colorectal cancer is a multistep process that can be categorized using three phenotypic pathways, respectively, chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator (CIMP). Targets of resveratrol, including a high-affinity binding protein, quinone reductase 2 (QR2), have been identified with little information on disease association. We hypothesize that the relationship between resveratrol and different CRC etiologies might be gleaned using publicly available databases. A web-based microarray gene expression data-mining platform, Oncomine, was selected and used to determine whether QR2 may serve as a mechanistic and functional biotarget within the various CRC etiologies. We found that QR2 messenger RNA (mRNA) is overexpressed in CRC characterized by CIN, particularly in cells showing a positive KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation, as well as by the MSI but not the CIMP phenotype. Mining of Oncomine revealed an excellent correlation between QR2 mRNA expression and certain CRC etiologies. Two resveratrol-associated genes, adenomatous polyposis coli (APC) and TP53, found in CRC were further mined, using cBio portal and Colorectal Cancer Atlas which predicted a mechanistic link to exist between resveratrol >QR2/TP53->CIN. Multiple web-based data mining can provide valuable insights which may lead to hypotheses serving to guide clinical trials and design of therapies for enhanced disease prognosis and patient survival. This approach resembles a BioGPS, a capability for mining web-based databases that can elucidate the potential links between compounds to provide correlations of these interactions with specific diseases. PMID- 28646292 TI - Sudden cardiac death in patients with chronic heart failure: Rule of thumb in prediction studies. PMID- 28646293 TI - Diagnostic implications of CZT SPECT and impact of CT attenuation correction. PMID- 28646295 TI - The role of socio-economic status and neighborhood social capital on loneliness among older adults: evidence from the Sant Boi Aging Study. AB - PURPOSE: The aim of the present study is to analyze the role of age in the association between socio-economic status (SES) and loneliness as well as the role of neighborhood social capital (NSC) in the association between individual social capital and loneliness. METHODS: Data include a representative population based sample from Sant Boi de Llobregat (a suburb of Barcelona) of 1124 adults aged 50 and over. Logistic regression models were used to analyze the survey data. Interactions between SES and age, and NSC and individual social capital were explored. RESULTS: Among the poorest older adults, older individuals showed a lower likelihood of loneliness (OR 0.09, 95% CI 0.02, 0.30, p < 0.05) compared with the youngest cohort after adjusting for covariates, while among the richest individuals there were no significant differences among age cohorts. Individuals living in an area with high NSC and high individual social capital showed a lower likelihood of loneliness (OR 0.36, 95% CI 0.17, 0.73, p < 0.05) compared with those with low individual social capital after adjusting for covariates. The effect of individual social capital was not significant among individuals living in an area with low NSC. CONCLUSION: Interventions focusing on low SES middle aged (50-59 years old) individuals and those aiming to increase NSC could be effective strategies to reduce the prevalence of loneliness in older people. PMID- 28646296 TI - Lonely in a crowd: invited commentary on Webber and Frendt-Newlin (2017). A review of social participation interventions for people with mental health problems. PMID- 28646297 TI - Simultaneous determination of aflatoxins, T-2 and HT-2 toxins, and fumonisins in cereal-derived products by QuEChERS extraction coupled with LC-MS/MS. AB - A fast, easy, and cheap method for the simultaneous determination and quantification of aflatoxins (B1, B2, G1, G2), T-2 and HT-2 toxins, and fumonisins (B1, B2) in cereal-derived products was developed. This method involved a quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction coupled with liquid chromatography-tandem mass spectrometry. The method validation was performed by analyzing samples spiked at four levels, and the recoveries ranged from 83.6 to 102.9%, whereas the maximum values of repeatability and within-laboratory reproducibility were 14.3 and 15.7% following the performance criteria set by the European legislation. The method was then applied for the analysis of 21 cereal-derived products purchased on the Italian market, which were correctly packaged and labeled as intended for human consumption. The co-occurrence of more than one mycotoxin in the analyzed samples could represent a risk for consumers, and the described method could be a valid alternative for their simultaneous detection in the framework of official control. Graphical Abstract ?. PMID- 28646298 TI - An "on-off-on" fluorescent probe for ascorbic acid based on Cu-ZnCdS quantum dots and alpha-MnO2 nanorods. AB - This work established a fluorescence approach for detecting ascorbic acid (AA) based on Cu-ZnCdS quantum dots (Cu-ZnCdS QDs) and alpha-MnO2 nanorods. Cu-ZnCdS QDs and alpha-MnO2 nanorods were characterized by high-resolution transmission electron microscopy (HRTEM), fluorescence spectroscopy, inductively coupled plasma optical emission spectroscopy (ICP-OES) and X-ray diffraction (XRD). In the presence of alpha-MnO2 nanorods, the fluorescence of Cu-ZnCdS QDs was greatly quenched through the inner filter effect (IFE). Subsequently, AA can trigger the decomposition of the alpha-MnO2 nanorods which can reduce alpha-MnO2 to Mn2+ and recover the fluorescence. Under optimal conditions, a linear relation was obtained over the range 5.02-401.77 MUM with a 31.62 MUM detection limit. Through applying the fluorescent sensing system for detecting AA, a satisfactory result is obtained with recoveries ranging from 89.23% to 110.99%. PMID- 28646299 TI - Effective combined water and sideband suppression for low-speed tissue and in vivo MAS NMR. AB - High-resolution magic angle spinning (HR-MAS) NMR is a powerful technique that can provide metabolic profiles and structural constraints on intact biological and environmental samples such as cells, tissues and living organisms. However, centripetal force from fast spinning can lead to a loss of sample integrity. In analyses focusing on structural organization, metabolite compartmentalization or in vivo studies, it is critical to keep the sample intact. As such, there is growing interest in slow spinning studies that preserve sample longevity. In this study, for example, reducing the spinning rate from 2500 to 500 Hz during the analysis of a living freshwater shrimp increased the 100% survivability threshold from ~14 to 40 h. Unfortunately, reducing spinning rate decreases the intensity of the isotropic signals and increases both the intensity and number of spinning sidebands, which mask spectral information. Interestingly, water suppression approaches such as excitation sculpting and W5 WATERGATE, which are effective at higher spinning rates, fail at lower spinning rates (<2500 Hz) while simpler approaches such as presaturation are not able to effectively suppress water when the ratio of water to biomass is very high, as is the case in vivo. As such there is a considerable gap in NMR approaches which can be used to suppress water signals and sidebands in biological samples at lower spinning rates. This research presents simple but practically important sequences that combine PURGE water suppression with both phase-adjusted spinning sidebands and an analogue of TOSS termed TOSS.243. The result is simple and effective water and sideband suppression even in extremely dilute samples in pure water down to ~100 Hz spinning rate. The approach is introduced, described and applied to a range of samples including, ex vivo worm tissue, Daphnia magna (water fleas), and in vivo Hyalella azteca (shrimp). PMID- 28646300 TI - Methodology for non-target screening of sewage sludge using comprehensive two dimensional gas chromatography coupled to high-resolution mass spectrometry. AB - To investigate the wide range of pollutants occurring in sewage sludge, an analytical method for comprehensive non-target screening is needed. To the best of our knowledge, no procedures currently exist for the full screening of organic contaminants in sewage sludge, which is the ultimate goal of this project. We developed non-discriminating sample preparation methods for gas chromatography mass spectrometry (GC-MS) analysis. Pressurized liquid extraction (PLE) was used for extraction, with in-line (silica gel selective PLE, SPLE) or off-line clean up (gel permeation chromatography, GPC). This combination allowed the analysis of non-polar compounds of all sizes and small semi-polar and non-polar compounds. The results show that the combination of SPLE and PLE with GPC is suitable for analysis of established as well as new contaminants. Both methods were validated for 99 compounds with different properties. For all GC suitable analytes, either one of the methods produced acceptable recoveries (64 to 136%). As a test, the two methods were used for non-target screening of Swedish sewage sludge. A tiered approach was used to tentatively identify the sludge contaminants. In total, 1865 and 1593 compounds were found of which 321 and 192 compounds were tentatively identified for the PLE and SPLE method, respectively. For a comprehensive coverage of contaminants, the two methods should be used together, with the PLE method covering a wider polarity range and the SPLE method a wider size range. In addition, polar substances will require liquid chromatography-mass spectrometry analysis, the method for which will be developed soon. PMID- 28646301 TI - Random Initialisation of the Spectral Variables: an Alternate Approach for Initiating Multivariate Curve Resolution Alternating Least Square (MCR-ALS) Analysis. AB - Multivariate curve resolution alternating least square (MCR-ALS) analysis is the most commonly used curve resolution technique. The MCR-ALS model is fitted using the alternate least square (ALS) algorithm that needs initialisation of either contribution profiles or spectral profiles of each of the factor. The contribution profiles can be initialised using the evolve factor analysis; however, in principle, this approach requires that data must belong to the sequential process. The initialisation of the spectral profiles are usually carried out using the pure variable approach such as SIMPLISMA algorithm, this approach demands that each factor must have the pure variables in the data sets. Despite these limitations, the existing approaches have been quite a successful for initiating the MCR-ALS analysis. However, the present work proposes an alternate approach for the initialisation of the spectral variables by generating the random variables in the limits spanned by the maxima and minima of each spectral variable of the data set. The proposed approach does not require that there must be pure variables for each component of the multicomponent system or the concentration direction must follow the sequential process. The proposed approach is successfully validated using the excitation-emission matrix fluorescence data sets acquired for certain fluorophores with significant spectral overlap. The calculated contribution and spectral profiles of these fluorophores are found to correlate well with the experimental results. In summary, the present work proposes an alternate way to initiate the MCR-ALS analysis. PMID- 28646303 TI - Three-dimensional fine structure of the organization of microtubules in neurite varicosities by ultra-high voltage electron microscope tomography. AB - Neurite varicosities are highly specialized compartments that are involved in neurotransmitter/ neuromodulator release and provide a physiological platform for neural functions. However, it remains unclear how microtubule organization contributes to the form of varicosity. Here, we examine the three-dimensional structure of microtubules in varicosities of a differentiated PC12 neural cell line using ultra-high voltage electron microscope tomography. Three-dimensional imaging showed that a part of the varicosities contained an accumulation of organelles that were separated from parallel microtubule arrays. Further detailed analysis using serial sections and whole-mount tomography revealed microtubules running in a spindle shape of swelling in some other types of varicosities. These electron tomographic results showed that the structural diversity and heterogeneity of microtubule organization supported the form of varicosities, suggesting that a different distribution pattern of microtubules in varicosities is crucial to the regulation of varicosities development. PMID- 28646302 TI - T-regulatory cells exhibit a biphasic response to prolonged endurance exercise in humans. AB - PURPOSE: T-regulatory cells (Tregs) are a sub-population of lymphocytes that act to suppress aberrant immune responses. We investigated changes in the numbers of naive and terminally differentiated Tregs in the peripheral blood to establish their role in the immuno-suppressive response to prolonged exercise. METHODS: Blood was drawn from seventeen experienced runners (age 40 +/- 12 years; height 1.75 +/- 0.08 m; mass 71.4 +/- 10.8 kg) before, ~1 h after (POST-1h), and on the day following the marathon (POST-1d). Tregs (CD3+CD4+Foxp3+CD25++CD127-) were analysed in peripheral blood mononuclear cells using flow cytometry. The markers CD45RA and HLA-DR were included to define naive and terminally differentiated Tregs, respectively. RESULTS: The absolute number of Tregs decreased (27%) POST 1h marathon (P < 0.001) but increased (21%) at POST-1d (P < 0.01). Naive CD45RA+ Tregs fell by 39% POST-1h (P < 0.01) but were unaffected POST-1d (P > 0.05). In contrast, an increased number of Tregs expressing HLA-DR was observed at POST-1d (P < 0.01). Interleukin (IL)-1beta, IL-6, IL-8 and IL-10 levels in the serum all increased POST-1h (P > 0.05) but returned to pre-exercise levels POST-1d. The suppressive cytokine, transforming growth factor-beta, was unaffected by the marathon (P > 0.05). CONCLUSIONS: These results suggest that Tregs do not play a major role in immune suppression in the early hours of recovery from a marathon. However, terminally differentiated HLA-DR+ Tregs are mobilized the following day, which could represent a compensatory attempt by the host to restore immune homeostasis and limit excessive cell damage. PMID- 28646304 TI - NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF beta1/Smad3 pathway. AB - Renal fibrosis is a common pathological pathway of various chronic kidney diseases progressing to end-stage renal disease and is characterized by tubular atrophy, fibroblast/myofibroblast activation and excessive deposition of extracellular matrix (ECM). N-Myc downstream-regulated gene-2 (NDRG2) is reported to be associated with liver fibrosis in rats. However, the biological function of NDRG2 in renal fibrosis remains unclear. Therefore, we investigate the effect of NDRG2 on renal fibrosis and the underlying mechanism of NDRG2 in TGF-beta1 induced renal tubular epithelial cells (HK-2). Our results show that TGF-beta1 down-regulates NDRG2 mRNA and protein expression in HK-2 cells. Moreover, NDRG2 knockdown dramatically reduces the TGF-beta1-induced protein and mRNA of E cadherin and increases the TGF-beta1-induced protein and mRNA expression level of alpha-SMA, Vimentin, Snail, Col-I, Col-III and FN; this is reversed by NDRG2 overexpression. Furthermore, NDRG2 silencing significantly increases the phosphorylation level of Smad3 (p-Smad3), which is decreased by NDRG2 overexpression, although these have no effect on the protein expression of p Smad2 and Smad7. In addition, SIS3, a specific inhibitor of Smad3 phosphorylation, partly reverses the effect of NDRG2 knockdown on the protein and mRNA expression of epithelial-mesenchymal transition (EMT) markers and ECM components in TGF-beta1-induced HK-2 cells. Taken together, our results indicate that NDRG2 knockdown promotes renal fibrosis through its effect on the protein and mRNA expression of EMT markers and ECM components by regulating the downstream Smad3 signaling pathway in renal tubular epithelial cells. Modulation of NDRG2 expression might provide a new therapy for renal fibrosis. PMID- 28646305 TI - The effect of hydrodynamic and thermodynamic factors and the addition of citric acid on the precipitation of calcium oxalate dihydrate. AB - This paper reports on the investigation of experimental conditions relevant for spontaneous precipitation of significant amount of pure calcium oxalate dihydrate (COD). For this purpose, the hydrodynamic and thermodynamic parameters, such as mode of agitation, temperature, supersaturation and concentration of additives (citrate ions), have been studied. The results show that in the model systems, without the citrate addition and applied mechanical stirring, calcium oxalate monohydrate (COM) was observed as dominant modification after 20 min of aging, while the magnetic stirring resulted in a formation of a mixture of COM and calcium oxalate trihydrate (COT), regardless of the temperature applied. In the mechanically stirred systems, the addition of citrate ions in the range of concentrations, 0.001 mol dm-3 < c i (Na3C6H5O7) < 0.012 mol dm-3, caused the formation of COM and COD mixture at all temperatures. At the same conditions and in the magnetically stirred systems formation of COD, in a mixture with COT or COM, has been observed. The highest COD content in the mechanically stirred system was obtained at 45 degrees C and c i (Na3C6H5O7) = 0.001 mol dm-3 (w = 89.5%), while in the magnetically stirred system almost pure COD was obtained at 37 degrees C and c i (Na3C6H5O7) = 0.008 mol dm-3 (w = 96.5%). PMID- 28646306 TI - Evaluation of stone volume distribution in renal collecting system as a predictor of stone-free rate after percutaneous nephrolithotomy: a retrospective single center study. AB - We analyzed our stone-free rates of PNL with regard to stone burden and its ratio to the renal collecting system volume. Data of 164 patients who underwent PNL were analyzed retrospectively. Volume segmentation of renal collecting system and stones were done using 3D segmentation software with the images obtained from CT data. Analyzed stone volume (ASV) and renal collecting system volume (RCSV) were measured and the ASV-to-RCSV ratio was calculated after the creation of a 3D surface volume rendering of renal stones and the collecting system. Univariate and multivariate statistical analyses were performed to determine factors affecting stone-free rates; also we assessed the predictive accuracy of the ASV to-RCSV ratio using the receiving operating curve (ROC) and AUC. The stone-free rate of PNL monotherapy was 53% (164 procedures).The ASV-to-RCSV ratio and calyx number with stones were the most influential predictors of stone-free status (OR 4.15, 95% CI 2.24-7.24, <0.001, OR 2.62, 95% CI 1.38-4.97, p < 0.001, respectively). Other factors associated with the stone-free rate were maximum stone size (p < 0.029), stone surface area (p < 0.010), and stone burden volume (p < 0.001). Predictive accuracy of the ASV-to-RCSV ratio was AUC 0.76. Stone burden volume distribution in the renal collecting system, which is calculated using the 3D volume segmentation method, is a significant determinant of the stone-free rate before PCNL surgery. It could be used as a single guide variable by the clinician before renal stone surgery to predict extra requirements for stone clearance. PMID- 28646307 TI - A step by step selection method for the location and the size of a waste-to energy facility targeting the maximum output energy and minimization of gate fee. AB - This study attempts the development of an algorithm in order to present a step by step selection method for the location and the size of a waste-to-energy facility targeting the maximum output energy, also considering the basic obstacle which is in many cases, the gate fee. Various parameters identified and evaluated in order to formulate the proposed decision making method in the form of an algorithm. The principle simulation input is the amount of municipal solid wastes (MSW) available for incineration and along with its net calorific value are the most important factors for the feasibility of the plant. Moreover, the research is focused both on the parameters that could increase the energy production and those that affect the R1 energy efficiency factor. Estimation of the final gate fee is achieved through the economic analysis of the entire project by investigating both expenses and revenues which are expected according to the selected site and outputs of the facility. In this point, a number of commonly revenue methods were included in the algorithm. The developed algorithm has been validated using three case studies in Greece-Athens, Thessaloniki, and Central Greece, where the cities of Larisa and Volos have been selected for the application of the proposed decision making tool. These case studies were selected based on a previous publication made by two of the authors, in which these areas where examined. Results reveal that the development of a "solid" methodological approach in selecting the site and the size of waste-to-energy (WtE) facility can be feasible. However, the maximization of the energy efficiency factor R1 requires high utilization factors while the minimization of the final gate fee requires high R1 and high metals recovery from the bottom ash as well as economic exploitation of recovered raw materials if any. PMID- 28646308 TI - Photochemical generation of reactive intermediates from urban-waste bio-organic substances under UV and solar irradiation. AB - Singlet oxygen (1O2), hydroxyl radicals (*OH), and excited triplet states of organic matter (3OM*) play a key role in the degradation of pollutants in aquatic environments. The formation rates and quantum yields (Phi) of these reactive intermediates (RI) through photosensitized reactions of dissolved organic matter (DOM) have been reported in the literature for decades. Urban biowaste-derived substances (UW-BOS), a form of organic matter derived from vegetative and urban waste, have recently been shown to be efficient sensitizers in the photo degradation of different contaminants. Nevertheless, no quantitative measurements of photo-oxidant generation by UW-BOS have been reported. In this study, the formation quantum yields of 1O2 and *OH, as well as quantum yield coefficients of TMP degradation (indicative of 3OM* formation), were quantified for two UW-BOS samples, under 254-nm UV radiation or simulated sunlight and compared to a DOM standard from the Suwanee River (SRNOM). Values of Phi for UW-BOS samples ranged from Phi(+1O2) = 8.0 to 8.8 * 10-3, Phi(+*OH) = 4.1 to 4.3 * 10-6, and f TMP = 1.22 to 1.23 * 102 L Einstein-1 under simulated sunlight and from Phi(+1O2) = 1.4 to 2.3 * 10-2, Phi(+*OH) = 1.3 to 3.5 * 10-3, and f TMP = 3.3 to 3.9 * 102 L Einstein-1 under UV. Although UW-BOS are not necessarily better than natural DOM regarding photosensitizing properties, they do sensitize the production of RI and could potentially be used in engineered treatment systems. PMID- 28646309 TI - Influence of polymethyl acrylate additive on the formation of particulate matter and NOX emission of a biodiesel-diesel-fueled engine. AB - The aim of this study is to investigate the effect of the polymethyl acrylate (PMA) additive on the formation of particulate matter (PM) and nitrogen oxide (NOX) emission from a diesel coconut and/or Calophyllum inophyllum biodiesel fueled engine. The physicochemical properties of 20% of coconut and/or C. inophyllum biodiesel-diesel blend (B20), 0.03 wt% of PMA with B20 (B20P), and diesel fuel were measured and compared to ASTM D6751, D7467, and EN 14214 standard. The test results showed that the addition of PMA additive with B20 significantly improves the cold-flow properties such as pour point (PP), cloud point (CP), and cold filter plugging point (CFPP). The addition of PMA additives reduced the engine's brake-specific energy consumption of all tested fuels. Engine emission results showed that the additive-added fuel reduce PM concentration than B20 and diesel, whereas the PM size and NOX emission both increased than B20 fuel and baseline diesel fuel. Also, the effect of adding PMA into B20 reduced Carbon (C), Aluminum (Al), Potassium (K), and volatile materials in the soot, whereas it increased Oxygen (O), Fluorine (F), Zinc (Zn), Barium (Ba), Chlorine (Cl), Sodium (Na), and fixed carbon. The scanning electron microscope (SEM) results for B20P showed the lower agglomeration than B20 and diesel fuel. Therefore, B20P fuel can be used as an alternative to diesel fuel in diesel engines to lower the harmful emissions without compromising the fuel quality. PMID- 28646310 TI - Effects of a dark septate endophyte (DSE) on growth, cadmium content, and physiology in maize under cadmium stress. AB - Dark septate endophytes (DSE) are widely distributed in plant roots grown in stressful habitats, especially in heavy metal-polluted soils. But little is known about the physiological interactions between DSE and plants under heavy metal stress. In the present study, the growth, Cd content, and physiological response of Zea mays L. to a root-colonized DSE, Exophiala pisciphila, were analyzed under Cd stress (0, 5, 10, 20, and 40 mg/kg) in a sand culture experiment. Under high Cd (10, 20, and 40 mg/kg) stress, the DSE colonization in roots increased the maize growth, kept more Cd in roots, and decreased Cd content in shoots. The DSE colonization improved the photosynthesis and induced notable changes on phytohormones but had no significant effect on the antioxidant capability in the maize leaves. Moreover, there were significant positive correlations between the gibberellic acid (GA) content and transpiration rate, zeatin riboside (ZR) content, and photosynthetic rate in maize leaves. These results indicated that the DSE's ability to promote plant growth was related to a decrease on Cd content and the regulation on phytohormone balance and photosynthetic activities in maize leaves. PMID- 28646311 TI - Removal of arsenic(III,V) by a granular Mn-oxide-doped Al oxide adsorbent: surface characterization and performance. AB - In order to remove arsenic (As) from contaminated water, granular Mn-oxide-doped Al oxide (GMAO) was fabricated using the compression method with the addition of organic binder. The analysis results of XRD, SEM, and BET indicated that GMAO was microporous with a large specific surface area of 54.26 m2/g, and it was formed through the aggregation of massive Al/Mn oxide nanoparticles with an amorphous pattern. EDX, mapping, FTIR, and XPS results showed the uniform distribution of Al/Mn elements and numerous hydroxyl groups on the adsorbent surface. Compression tests indicated a satisfactory mechanical strength of GMAO. Batch adsorption results showed that As(V) adsorption achieved equilibrium faster than As(III), whereas the maximum adsorption capacity of As(III) estimated from the Langmuir isotherm at 25 degrees C (48.52 mg/g) was greater than that of As(V) (37.94 mg/g). The As removal efficiency could be maintained in a wide pH range of 3~8. The presence of phosphate posed a significant adverse effect on As adsorption due to the competition mechanisms. In contrast, Ca2+ and Mg2+ could favor As adsorption via cation-bridge involvement. A regeneration method was developed by using sodium hydroxide solution for As elution from saturated adsorbents, which permitted GMAO to keep over 75% of its As adsorption capacity even after five adsorption-regeneration cycles. Column experiments showed that the breakthrough volumes for the treatment of As(III)-spiked and As(V)-spiked water (As concentration = 100 MUg/L) were 2224 and 1952, respectively. Overall, GMAO is a potential adsorbent for effectively removing As from As-contaminated groundwater in filter application. PMID- 28646313 TI - Domestic wastewater treatment by constructed wetlands enhanced with bioremediating rhizobacteria. AB - Constructed wetlands (CWs) offer several advantages for treating waters; however, the successful application of these systems remains a challenge. Practical solutions to pollution through CWs remain incipient because wetlands are still studied as "black boxes"; further studies are required regarding the involvement of rhizosphere bacteria in the removal of pollutants. This research focused on increasing the performance of CWs treatment systems for the removal of inorganic and organic pollutants from domestic wastewater, by the application of native bioremediating rhizobacteria. A bacterial consortium (CAD/1S) was designed with four rhizobacteria strains isolated from Typha domingensis plants of natural wetlands. Each individual strain was identified by 16S ribosomal RNA (rRNA) gene sequencing. This consortium removed organic matter, ammonium, and phosphate with percentages over 70% from model wastewater. The evaluation of abiotic and biotic factors' influence on pollutant removal indicated the best conditions to remove pollutants: a neutral pH, a 72-h contact time, and an inoculum from single growth of each strain. The subsequent bioaugmentation with the consortium of CWs at laboratory scale allowed 100%, greater than 70 and 55% removal of organic matter, ammonium, and phosphate, respectively. The set of results allowed the proposal of a new strategy for the improvement of CWs technology for the treatment of domestic wastewater pollutants. PMID- 28646312 TI - Silicon and Rhizophagus irregularis: potential candidates for ameliorating negative impacts of arsenate and arsenite stress on growth, nutrient acquisition and productivity in Cajanus cajan (L.) Millsp. genotypes. AB - Arsenic (As) gets accumulated in plants via phosphorous transporters and water channels and interferes with nutrient and water uptake, adversely affecting growth and productivity. Although, Si and AM have been reported to combat arsenic stress, their comparative and interactive roles in ameliorating As V and As III toxicities have not been reported. Study evaluated effects of Si and Rhizophagus irregularis on growth, As uptake and yield under arsenate and arsenite stress in two pigeonpea genotypes (metal tolerant-Pusa 2002 and metal sensitive-Pusa 991). Higher As accumulation and translocation was observed in As III treated roots of Pusa 991 than those of Pusa 2002 when compared with As V. Roots were more negatively affected than shoots which led to a significant decline in nutrient uptake, leaf chlorophylls, and yield, with As III inducing more negative effects. Pusa 2002 established more effective mycorrhizal symbiosis and had higher biomass than Pusa 991. Si was more effective in inducing shoot biomass while AM inoculation significantly improved root biomass. AM enhanced Si uptake in roots and leaves in a genotype dependent manner. Combined application of Si and AM were highly beneficial in improving leaf water status, chlorophyll pigments, biomass, and productivity. Complete amelioration of negative impacts of both concentrations of As V and lower concentration of As III were recorded under +Si +AM in Pusa 2002. Results highlighted great potential of Si in improving growth and productivity of pigeonpea through R. irregularis under As V and As III stresses. PMID- 28646314 TI - Ozone and desiccation tolerance in chlorolichens are intimately connected: a case study based on two species with different ecology. AB - Tropospheric ozone (O3) causes severe damage to many vascular plants but not to lichens. It was recently suggested that this may be due to their high levels of natural defences against the oxidative bursts associated to their fluctuating water content. In this study, the combined effects of watering regime (with or without a daily spray of distilled water), air relative humidity (20 +/- 5 vs. 80 +/- 5% RH) and O3 (250 vs. 0 ppb, 5 h day-1 for 2 weeks) were monitored in two chlorolichens with different ecology, Parmotrema perlatum and Xanthoria parietina. Modulated chlorophyll a fluorescence (Chl a F), superoxide anion radical (O2*-) and hydrogen peroxide (H2O2) production, antioxidant content and enzyme activity of the ascorbate/glutathione cycle were measured after exposure and, for Chl a F, after 1 and 2 days of recovery. The species differed in the antioxidant profile (ascorbate was higher in X. parietina, glutathione in P. perlatum), and in the activity of ROS-scavenging enzymes, more intense in the hygrophilous P. perlatum than in the meso-xerophilous X. parietina. O3 slightly modified Chl a F parameters related to the controlled dissipation, with reduction of Fm, Fv/Fm (both species) and ETR (in P. perlatum), and increase in NPQ and qN (in X. parietina). It also influenced, particularly in P. perlatum, the content of H2O2, glutathione (GSH) and oxidized glutathione (GSSG) (but not that of O2*- and AsA + DHA) and the activity of superoxide dismutase, ascorbate peroxidase and dehydroascorbate reductase. These parameters, however, were more heavily affected by water availability. The hypothesis that lichens are O3-tolerant thanks to the constitutive antioxidant systems, intimately related to their poikilohydric life style, is thus confirmed. PMID- 28646315 TI - Chilling tolerance in three tomato transgenic lines overexpressing CBF3 gene controlled by a stress inducible promoter. AB - Plants integrate and monitor low temperature signals to cope with the continual variations in their environment. Arabidopsis thaliana cold responsive-element binding factor 3 (AtCBF3) plays its role in various cellular activities by modulating multiple genes induced under chilling stress. In this work, AtCBF3 transcription was remarkably induced following chilling stress. AtCBF3 overexpressors namely AtCBF3-Rio Grande, AtCBF3-Moneymaker, and AtCBF3-Roma showed defensible response to various levels of chilling stress, while their isogenic wild type plants indicated hypersensitive response to chilling stress. Detailed photosynthetic studies revealed that AtCBF3 gene has harmonious influences on the expression of a large set of genes by virtue of improved stomatal conductance, transpiration rate, intercellular CO2 concentration, and photosynthetic rate compared to wild type plants. The AtCBF3 lines limited the water status-mediated hypersensitive response by lowering leaf osmotic potential due to overexpression of AtCBF3 under chilling stress. Biochemical analyses followed by phenotypic studies demonstrated that AtCBF3 plants exhibited membrane stability and lush green appearance by limiting membrane ions leakage and malondialdehyde contents and by accumulating more proline, soluble sugars, chlorophyll contents, carotenoid contents, and antioxidant enzymes relative to wild type plants. Hence, with a several lines of evidence, these findings support that tomato transgenic plants overexpressing Arabidopsis CBF3 show enhanced chilling tolerance. PMID- 28646316 TI - Identifying major events in two sturgeons' life using pectoral fin spine ring structure: exploring the use of a non-destructive method. AB - Maturation is one of the most important life history traits that influences on many ecological characteristics of animals. This study aimed to describe the indirect distinguish of first reproduction and habitat shift (transition from the pelagic to benthic environment), using the width of translucent and annuluses of the pectoral fin spine of two sturgeon species, Persian sturgeon, Acipenser persicus, and starry sturgeon, Acipenser stellatus. Interpretation of growth bands in pectoral fin sections was done objectively using direct reading of thin sections and image analysis. The results showed that changes in the profiles of translucent and annuluses occurred at the time of habitat shift and first reproduction. Females of both sturgeons move to the deeper waters earlier than males, which can be considered as strategy for the prolonged gonad development of female individuals. Estimated age at maturity for A. persicus (9 years for female and 7 years for male) was higher than A. stellatus (7 years for female and 6 years for male), which coincide with abrupt reduction in annuli width. Marks of habitat shift and first reproduction in the pectoral fin spine are species specific characters and enable life history traits to be identified. PMID- 28646317 TI - Di-n-butyl phthalate prompts interruption of spermatogenesis, steroidogenesis, and fertility associated with increased testicular oxidative stress in adult male rats. AB - Di-n-butyl phthalate (DBP) is extensively used as plasticizer, and it was ubiquitary released into the environment. The present study was aimed to investigate the effect of DBP on reproductive competence in adult male rats. Adult male rats were received corn oil or DBP injection intraperitoneally (ip) at 100 and 500 mg/kg body weight on 90, 97, 104, and 111 days. Following completion of the experimental period, adult male rats were cohabitated with untreated proestrus female rats for determination of fertilization capacity. Then, adult male rats were sacrificed, and other reproductive endpoints were determined by histopathology and biochemical analysis. The results revealed significant reduction of fertilization potential by decrease mating, fertility indices with increase pre-implantation and post-implantation losses, and resorptions in normal female rat cohabitation with DBP-treated adult male rats. The testes, seminal vesicle tissue somatic indices, epididymal sperm count, motility, viability, and hypoosmotic swelling (HOS) sperm were significantly decreased with increased sperm morphological abnormalities in DBP-treated adult male rats. The disorientation of spermatogenic cells decreased the diameter and epithelial thickness of seminiferous tubule in the testicular histopathology of DBP-exposed rats. Significant reduction of testicular 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase enzyme levels and serum testosterone with increased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were observed in DBP-treated groups. Higher testicular oxidative stress marker (lipid peroxidation product) with lower antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase levels in DBP-exposed groups was observed. From these results, it can be concluded that DBP increases oxidative stress; it leads to impairment of spermatogenesis, steroidogenesis, and fertility in adult male rats. PMID- 28646318 TI - Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel-Lindau (VHL), Succinate Dehydrogenase (SDHX) and Transmembrane Protein 127 (TMEM127). AB - Alterations of von Hippel-Lindau (VHL), succinate dehydrogenase (SDHX), and TMEM127 have been associated with the development of pheochromocytomas (PCs) and paragangliomas (PGLs) and are also associated with the development of renal neoplasms. This study involved 2 primary renal PGL and 12 cases of PC/PGL with associated renal neoplasia with a mean follow up of 74 months. Germline VHL and SDHX mutation status was obtained from the medical record. Immunohistochemistry for SDHB and mutation analysis for TMEM127 was performed, in addition to analysis of The Cancer Genome Atlas datasets for SDHX and TMEM127 mutated renal cell carcinomas (RCCs). The spectrum of renal neoplasia included clear cell and tubulocystic and papillary RCC, as well as a case of multiple papillary adenomas. Three patients had metastatic PC/PGL and three patients had VHL syndrome. Previously unreported TMEM127 alterations were identified in two patients, both without evidence of VHL syndrome or SDH-deficiency, and were classified as variants of uncertain significance. Primary renal PGL and neoplasia was associated with about 2% of 710 cases of PC/PGL. These were diagnosed concurrently or on average 27 months prior to the PC/PGL, and most were low grade, low-stage clear cell RCCs. Up to half of patients with PC/PGL and renal neoplasia had VHL syndrome, SDH deficiency, or alterations in TMEM127. One (of three) case of metastatic PC/PGL had SDHB mutation and loss of SDHB by immunohistochemistry. The other two cases had retained SDHB expression. PMID- 28646319 TI - Presence of enthesopathy in patients with primary Sjogren's syndrome: ultrasonographic study of a local cohort. AB - BACKGROUND: Musculoskeletal findings in Sjogren's syndrome are arthralgia, arthritis, myalgia, myositis, fibromyalgia, and chronic fatigue. Enthesis zones are important in the formation of pain in the musculoskeletal system. Musculoskeletal ultrasound (US) may show subclinical enthesitis in the synovial joints and in the axial skeleton before joint swelling in inflammatory diseases characterized by arthritis. OBJECTIVE: In this study, we aimed to determine the presence of enthesopathy using the Madrid sonographic enthesitis index (MASEI) in patients with primary Sjogren's syndrome (PSS). PATIENTS AND METHODS: Consecutive patients with PSS and age-matched healthy controls were included in this study. All the patients met the 2002 American College of Rheumatology/European League against Rheumatism classification criteria for PSS. The demographic characteristics of the patients were recorded. Six enthesis sites were evaluated using gray-scale and Doppler US with a linear transducer, and they were scored using the MASEI. They were assessed by the EULAR Sjogren's syndrome disease activity index (ESSDAI). RESULTS: We evaluated 40 patients with PSS (average age 48.67 +/- 11.23 years) and 30 healthy controls (average age 45.40 +/- 8.24 years). Patients with PSS had significantly higher MASEI scores than the healthy controls. Plantar fascia, Achilles tendon, and distal patellar tendons were significantly thicker in the PSS group than in the healthy controls. The MASEI total score had a positive correlation with age. There was no correlation between MASEI total score and BMI and ESSDAI. CONCLUSION: In this study, it was shown that the MASEI scores assessed by US were significantly higher in patients with PSS than in healthy controls. Plantar fascia, Achilles tendon, and distal patellar tendon were significantly thicker in the PSS group than in the healthy controls. This result suggests that PSS may be one of the causes of musculoskeletal pain that can be seen in patients with PSS. Our study was the first study to use an enthesis index ultrasonographically in patients with PSS. In addition, it is the first study to investigate the relationship between the presence of enthesopathy and disease activity by means of US. PMID- 28646320 TI - Erratum to: Robotic versus laparoscopic rectal resection for sphincter-saving surgery: pathological and short-term outcomes in a single-center analysis of 130 consecutive patients. PMID- 28646321 TI - Early outcomes of robotic-assisted inguinal hernia repair in obese patients: a multi-institutional, retrospective study. AB - BACKGROUND: Minimally invasive inguinal hernia repair (IHR) in general and particularly in obese patients has not been widely adopted, potentially due to the perceived technical challenges and the well-documented learning curve associated with laparoscopic repair. Outcomes in robotic-assisted IHR in obese (BMI >= 30 kg/m2) patients have not been described and warrant study. METHODS: Seven surgeons conducted a multicenter retrospective chart review of their early robotic-assisted IHR (RHR) cases and compared them with their open IHR (OHR) cases. Demographics, operative characteristics, and perioperative morbidity were compared for unadjusted and propensity-matched populations. RESULTS: 651 robotic assisted cases and 593 open cases were collected. The outcomes of 148 RHRs to 113 OHRs in obese patients were compared. For obese populations-whether unadjusted (robotic-assisted, n = 148; open, n = 113) or matched (1:1) (robotic-assisted, n = 95; open, n = 93)-the robotic-assisted and open cohorts were comparable in terms of demographics and baseline characteristics. Significantly higher percentages of OHR patients experienced postoperative complications post discharge (unadjusted: 11.5% vs. 2.7%, p = 0.005; and matched: 10.8% vs. 3.2%, p = 0.047). More concomitant procedures and bilateral repairs were conducted in obese RHR patients than in obese OHR patients (unadjusted 29.7% vs. 16.8%, p = 0.019; and unadjusted 35.1% vs. 11.5%, p < 0.0001-respectively). Prior laparoscopic IHR experience did not affect 30-day outcomes. CONCLUSIONS: Obese patients who undergo RHR have a lower rate of postoperative complications compared to obese patients who undergo OHR. Previous laparoscopic IHR experience, more bilateral repairs, and more concomitant procedures were not associated with increased complications in RHR patients. These outcomes may facilitate increased adoption of minimally invasive IHR approaches in the obese population. PMID- 28646322 TI - Does chess instruction improve mathematical problem-solving ability? Two experimental studies with an active control group. AB - It has been proposed that playing chess enables children to improve their ability in mathematics. These claims have been recently evaluated in a meta-analysis (Sala & Gobet, 2016, Educational Research Review, 18, 46-57), which indicated a significant effect in favor of the groups playing chess. However, the meta analysis also showed that most of the reviewed studies used a poor experimental design (in particular, they lacked an active control group). We ran two experiments that used a three-group design including both an active and a passive control group, with a focus on mathematical ability. In the first experiment (N = 233), a group of third and fourth graders was taught chess for 25 hours and tested on mathematical problem-solving tasks. Participants also filled in a questionnaire assessing their meta-cognitive ability for mathematics problems. The group playing chess was compared to an active control group (playing checkers) and a passive control group. The three groups showed no statistically significant difference in mathematical problem-solving or metacognitive abilities in the posttest. The second experiment (N = 52) broadly used the same design, but the Oriental game of Go replaced checkers in the active control group. While the chess-treated group and the passive control group slightly outperformed the active control group with mathematical problem solving, the differences were not statistically significant. No differences were found with respect to metacognitive ability. These results suggest that the effects (if any) of chess instruction, when rigorously tested, are modest and that such interventions should not replace the traditional curriculum in mathematics. PMID- 28646323 TI - Erratum to: Quantitative 18F-fluorocholine positron emission tomography for prostate cancer: correlation between kinetic parameters and Gleason scoring. PMID- 28646324 TI - Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life Stages of the Malaria-Causing Plasmodium falciparum Parasite. AB - PURPOSE: Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. METHODS: GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability was analysed by RP-HPLC, SEC-HPLC, 2 site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. RESULTS: CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins encompassing similar parts of Pfs48/45. CONCLUSION: GMZ2'.10C, combining GMZ2' and correctly-folded Pfs48/45 can be produced by the Lactoccus lactis P170 based expression system in purity and quality for pharmaceutical development and elicit high level of TB antibodies. The cysteine connectivity for the 10C region of Pfs48/45 was revealed experimentally, providing an important guideline for employing the Pfs48/45 antigen in vaccine design. PMID- 28646325 TI - Anti-Tuberculosis Bacteriophage D29 Delivery with a Vibrating Mesh Nebulizer, Jet Nebulizer, and Soft Mist Inhaler. AB - PURPOSE: To compare titer reduction and delivery rate of active anti-tuberculosis bacteriophage (phage) D29 with three inhalation devices. METHODS: Phage D29 lysate was amplified to a titer of 11.8 +/- 0.3 log10(pfu/mL) and diluted 1:100 in isotonic saline. Filters captured the aerosolized saline D29 preparation emitted from three types of inhalation devices: 1) vibrating mesh nebulizer; 2) jet nebulizer; 3) soft mist inhaler. Full-plate plaque assays, performed in triplicate at multiple dilution levels with the surrogate host Mycobacterium smegmatis, were used to quantify phage titer. RESULTS: Respective titer reductions for the vibrating mesh nebulizer, jet nebulizer, and soft mist inhaler were 0.4 +/- 0.1, 3.7 +/- 0.1, and 0.6 +/- 0.3 log10(pfu/mL). Active phage delivery rate was significantly greater (p < 0.01) for the vibrating mesh nebulizer (3.3x108 +/- 0.8x108 pfu/min) than for the jet nebulizer (5.4x104 +/- 1.3x104 pfu/min). The soft mist inhaler delivered 4.6x106 +/- 2.0x106 pfu per 11.6 +/- 1.6 MUL ex-actuator dose. CONCLUSIONS: Delivering active phage requires a prudent choice of inhalation device. The jet nebulizer was not a good choice for aerosolizing phage D29 under the tested conditions, due to substantial titer reduction likely occurring during droplet production. The vibrating mesh nebulizer is recommended for animal inhalation studies requiring large amounts of D29 aerosol, whereas the soft mist inhaler may be useful for self-administration of D29 aerosol. PMID- 28646327 TI - An Adapted Measure of Sibling Attachment: Factor Structure and Internal Consistency of the Sibling Attachment Inventory in Youth. AB - Parent-youth and peer relationship inventories based on attachment theory measure communication, trust, and alienation, yet sibling relationships have been overlooked. We developed the Sibling Attachment Inventory and evaluated its psychometric properties in a sample of 172 youth ages 10-14 years. We adapted the 25-item Sibling Attachment Inventory from the Inventory of Parent and Peer Attachment-Revised peer measure. Items loaded onto three factors, identified as communication, trust, and alienation, alpha = 0.93, 0.90, and 0.76, respectively. Sibling trust and alienation correlated with depression (r s = -0.33, r s = 0.48) and self-worth (r s = 0.23; r s = -0.32); sibling trust and alienation correlated with depression after controlling for parent trust and parent alienation (r s = -0.23, r s = 0.22). Preliminary analyses showed good internal consistency, construct validity, and incremental predictive validity. Following replication of these properties, this measure can facilitate large cohort assessments of sibling attachment. PMID- 28646326 TI - Transposable Elements Mediate Adaptive Debilitation of Flagella in Experimental Escherichia coli Populations. AB - Although insertion sequence (IS) elements are generally considered genomic parasites, they can mediate adaptive genetic changes in bacterial genomes. We discovered that among 12 laboratory-evolved Escherichia coli populations, three had experienced at least six different IS1-mediated deletions of flagellar genes. These deletions all involved the master flagellar regulator flhDC, and as such completely incapacitate motility. Two lines of evidence strongly suggest that these deletions were adaptive in our evolution experiment: (1) parallel evolution in three independent populations is highly unlikely just by chance, and (2) one of these deletion mutations swept to fixation within ~1000 generations, which is over two million times faster than expected if this deletion was instead selectively neutral and thus evolving by genetic drift. Because flagella are energetically expensive to synthesize and operate, we suspect that debilitating their construction conferred a fitness advantage in our well-stirred evolution experiment. These findings underscore the important role that IS elements can play in mediating adaptive loss-of-function mutations in bacteria. PMID- 28646328 TI - Parent Perceptions of Medication Treatment for Preschool Children with ADHD. AB - This study sought to examine parent perceptions of medication use for 151 preschool children (M age = 5.05 years, 78% male, 82% Hispanic/Latino) with or at-risk for ADHD who were medication naive. Parents completed questionnaires regarding family background and perceptions of medication treatment. Parents and teachers completed ratings of child diagnostic symptomatology, behavioral functioning, and functional impairment. Results indicate that only 45% of parents were open to the possibility of medication. No associations were found between child demographics, severity of ADHD symptoms, or level of functional impairment and parental openness to medication. On the other hand, children of parents who were open to medication tended to have higher levels of oppositionality and aggression (as reported by parents but not teachers) compared with children of parents who were not open to medication. These findings are discussed in the context of early intervention given their implications for a variety of treatment providers. PMID- 28646329 TI - [Unconsciousness and clouded awareness]. AB - Stupor and coma are clinical states in which patients have impaired responsiveness or are unresponsive to external stimulation and are either difficult to arouse or are unarousable. The term stupor refer to states between alertness and coma. An alteration in arousal represents an acute life-threatening emergency, requiring prompt intervention for preservation of life and brain function. PMID- 28646330 TI - [Imaging of vessels supplying the brain]. AB - Nowadays, several technically validated modalities are available for imaging both the extracranial and intracranial segments of arteries supplying blood to the brain. In the acute stroke setting, computed tomography (CT) angiography is of utmost importance because it provides the key diagnostic criteria indicative for the use of catheter-based recanalization techniques. Ultrasound imaging of extracranial arteries is most suitable for detecting an underlying stenosis of the internal carotid artery (ICA) in patients with stroke, transient ischemic attacks (TIA), retinal vessel occlusion and amaurosis fugax. Ultrasound imaging enables measurement of the methodologically most reliable criteria for grading stenosis of the ICA, which defines the indications for revascularization procedures in this territory. Magnetic resonance imaging (MRI) in the cross sectional mode is of greatest value in confirming or excluding an arterial dissection even in short arterial segments, whereas MR angiography generates a more global view of the cerebral circulation. In most cases classical digital subtraction angiography (DSA) is no longer needed for diagnostic purposes only. Conversely, it is an indispensable component of any interventional approach and thus of growing importance. Ultrasound imaging is not indicated for the clarification of vertigo or syncope. In addition, there is no evidence that ultrasound screening of the ICA adds any value to the care of asymptomatic persons. PMID- 28646331 TI - Textural features of 18F-FDG PET after two cycles of neoadjuvant chemotherapy can predict pCR in patients with locally advanced breast cancer. AB - OBJECTIVE: This study was designed to evaluate the utility of textural features for predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). METHODS: Sixty-one consecutive patients with locally advanced breast cancer underwent 18F-FDG PET/CT scanning at baseline and after the second course of NAC. Changes to imaging parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG)] and textural features (entropy, coarseness, skewness) between the 2 scans were measured by two independent radiologists. Pathological responses were reviewed by one pathologist, and the significance of the predictive value of each parameter was analyzed using a Chi-squared test. Receiver operating characteristic curve analysis was used to compare the area under the curve (AUC) for each parameter. RESULTS: pCR was observed more often in patients with HER2-positive tumors (22 patients) than in patients with HER2-negative tumors (5 patients) (71.0 vs. 16.7%, p < 0.001). ? %SUVmax, ? %entropy and ? %coarseness were significantly useful for differentiating pCR from non-pCR in the HER2-negative group, and the AUCs for these parameters were 0.928, 0.808 and 0.800, respectively (p = 0.003, 0.032 and 0.037). In the HER2-positive group, ? %SUVmax and ? %skewness were moderately useful for predicting pCR, and the respective AUCs were 0.747 and 0.758 (p = 0.033 and 0.026). Although there was no significant difference in the AUCs between groups for these parameters, an additional 3/22 patients in the HER2 positive group with pCR were identified when ? %skewness and ? %SUVmax were considered together (p = 0.031). The absolute values for each parameter before NAC and after 2 cycles cannot predict pCR in our patients. Neither ? %MTV nor ? %TLG was efficiently predictive of pCR in any group. CONCLUSIONS: The early changes in the textural features of 18F-FDG PET images after two cycles of NAC are predictive of pCR in both HER2-negative and HER2-positive patients; this evidence warrants confirmation by further research. PMID- 28646332 TI - A rational approach for the improvement of biomass production and lipid profile in cacao cell suspensions. AB - Cocoa butter (CB) is produced in the seeds of Theobroma cacao representing 50% of its dry weight. The lipid composition plays an important role in the physicochemical, rheological, and sensory properties of the CB, making this fat a valuable resource for the production of chocolates, cosmetics, and pharmaceuticals. In this paper, are described experimental strategies used for a rational improvement of biomass production and fatty acids in cacao cell suspension cultures. First, the lipid profile in four cacao varieties is characterized, and then, one variety is selected to induce cell suspensions using a direct method without previous establishment of a callus phase. To improve growth and total fat production in cell suspension cultures, modified DKW media and newly designed media culture, based on the mineral concentrations of cacao seeds (cacao biomass production, "CBP"), are analyzed and compared. In addition, the effect of acetate in the lipid profile of cell suspensions is evaluated. Ultrastructural histological analysis of lipid vesicles in cacao seeds and cell suspensions is also performed. The results will show that it is feasible to establish cacao suspensions without the calli step and increase the biomass production by selecting a suitable cacao variety and tissue and also applying a new culture media formulation. In addition, it is possible to synthesize fatty acids in cell cultures and modify the lipid profile adding a precursor of the novo biosynthesis of fatty acids such as the acetate. Transmission electronic microscopy examinations and differential interference contrast microscopy analysis will demonstrate that lipid vesicles are the main reserve substance in both cacao seeds and cell suspensions. PMID- 28646333 TI - Feeding Jejunostomy-Associated Small Bowel Necrosis After Elective Esophago Gastric Resection. AB - BACKGROUND: Feeding jejunostomy has increasingly become a standard adjunctive procedure during major esophago-gastric resections. They provide nutritional support during the post-operative period as required. However, significant early complications have been reported, most notably small bowel necrosis. Literature reports have been restricted to case reports or series. This study aims to determine the frequency of this complication in a cohort of patients undergoing esophago-gastric resection, and identify any difference in the risk of this complication between patients undergoing esophagectomy and gastrectomy. METHODS: Consecutive patients who had esophago-gastric resections for malignancy and who had a feeding jejunostomy placed were identified from a prospectively maintained database at Leicester Royal Infirmary during the years 2009-2015. Case notes were reviewed to extract information relating to demographics, presenting features and clinical outcome. RESULTS: The study included 360 patients, 285 of which had esophagectomy and 75 had gastrectomy. There were no small bowel complications among esophagectomy patients (0%), while six patients who had total gastrectomy developed small bowel ischemia or necrosis (8%), p = 0.05, in spite of an identical feeding regimen. Every patient that developed the complication underwent surgery with five out six having resection of the infarcted segment and double-barrel stoma formation. A 6-8-week period of parenteral nutrition was required before stoma reversal. One patient had leucocytosis on the day of diagnosis. The other five patients showed no derangements in biochemical or clinical parameters in the preceding 48 h. Five of the six patients survived. CONCLUSIONS: Small bowel necrosis and perforation is a life-threatening complication of feeding jejunostomy. In our cohort, it happened exclusively in total gastrectomy patients. Antecedent signs were lacking. The condition requires prompt attention with earlier use of CT scanning and a return to the operating room. The presence of pneumatosis intestinalis on CT scan should prompt surgical intervention that improves survival. PMID- 28646335 TI - The Role of Physical Activity and Sedentary Behavior in Predicting Daily Pain and Fatigue in Older Adults: a Diary Study. AB - Background: Little attention has been paid to within-person daily associations among light physical activity (PA), moderate-to-vigorous physical activity (MVPA), and sedentary behavior (SB) with subsequent bodily pain and fatigue. Daily reports of pain and fatigue are less likely to be affected by recall bias and to conflate days of high and low pain/ fatigue into one overall score. Purpose: The purpose of this study was to examine daily within-person associations between pain, fatigue, and physical health and ascertain whether such associations are moderated by individual differences in these variables. Methods: Participants were 63 community-living older adults (female n = 43, mean age = 70.98 years). Questionnaires measured typical levels of PA, SB, bodily pain, fatigue, and physical health. Subsequently, on a daily basis over a 1-week period, participants' levels of light PA, MVPA, and SB were measured using accelerometers. Participants completed a questionnaire rating their pain and fatigue at the end of each day. Results: Multilevel modeling revealed positive within-person associations between daily light PA, dailyMVPA, and pain, as well as negative within-person associations between daily SB and pain. For individuals with higher typical levels of fatigue, there was a negative association between daily light PA, MVPA, and fatigue. For individuals with better levels of physical health, there was also a negative association between daily MVPA and fatigue. For those with higher typical levels of fatigue and better levels of physical health, there was a positive association between daily SB and fatigue. No such interaction effects were found between high levels of typical pain and PA or SB. Conclusions: Our findings indicate that efforts to promote daily PA in older adults might be more effective for those who report high typical levels of fatigue and physical health, compared to those who report high levels of daily physical pain. PMID- 28646334 TI - Extent of Mediastinal Lymphadenectomy and Survival in Superficial Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: The aim of this study is to investigate the utility of total mediastinal lymphadenectomy (ML) in superficial esophageal squamous cell carcinoma (ESCC). METHODS: The medical records of 129 patients who underwent esophagectomy and lymph node dissection for pathologically confirmed pT1 ESCC between July 2006 and December 2014 were retrospectively reviewed. Limited ML, such as traditional 2-field or transhiatal esophagectomy, was performed in 42 patients (group 1), and total ML, including the bilateral recurrent laryngeal nerve nodes, was performed in 87 patients (group 2). RESULTS: R0 resection was achieved in all patients, and the number of dissected nodes was 28.0 +/- 11.4 and 44.8 +/- 16.1 in groups 1 and 2 (p < 0.001), respectively. The complication profile was similar in the two groups, but there were two operative mortalities in group 2. During a median follow-up of 32.4 months, loco-regional failure was found in 14.3% of group 1 and 3.5% of group 2 (p = 0.001). There was a significant difference in the 3-year overall survival (95.1% in group 2 vs. 83.3% in group 1, p = 0.043), and the 3-year disease-free survival rates (92.3% in group 2 vs. 73.7% in group 1, p = 0.001). On multivariate analysis, the extent of ML (HR, 5.200; 95% CI, 1.532 ~ 17.645; p = 0.008) and pT1b lesion classification (HR, 4.747; 95% CI, 1.024 ~ 21.997; p = 0.047) was a factor predictive of disease free survival. CONCLUSIONS: Total ML might be beneficial, especially in cases of pT1b ESCC, because it could lead to a lower incidence of recurrence and longer survival times. PMID- 28646336 TI - Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology. AB - Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution. PMID- 28646337 TI - [Epidemiology of refractive errors]. AB - Refractive errors are very common and can lead to severe pathological changes in the eye. This article analyzes the epidemiology of refractive errors in the general population in Germany and worldwide and describes common definitions for refractive errors and clinical characteristics for pathologicaal changes. Refractive errors differ between age groups due to refractive changes during the life time and also due to generation-specific factors. Current research about the etiology of refractive errors has strengthened the influence of environmental factors, which led to new strategies for the prevention of refractive pathologies. PMID- 28646339 TI - Roles of Non-coding RNAs in Respiratory Syncytial Virus (RSV) Infection. AB - Analysis of host gene expression profiles following viral infections of target cells/tissues can reveal crucial insights into the host: virus interaction and enables the development of novel therapeutics and prophylactics. Regions of the host genome that do not code for protein, encode structural, and functional non coding RNAs that are important not only in regulation of host gene expression but also may impact viral replication. This review summarizes the role of host non coding RNAs during replication of multiple respiratory viruses with a focus on Respiratory Syncytial Virus (RSV), an important pediatric pathogen. This review highlights the current state of knowledge and understanding regarding the function(s) of ncRNAs for respiratory viral infection and host immunity in general. PMID- 28646340 TI - Clinical Management of Ebola Virus Disease Patients in Low-Resource Settings. AB - The low-resource environment deprives healthcare providers caring for patients with Ebola virus disease (EVD) of many of the means employed for the critically ill that are available in better resourced settings, such as advanced therapeutic interventions and abundant staff. In addition to these limitations may be added those imposed by the remote tropical locations, where EVD outbreaks occur. In this setting, a safe environment is created where healthcare workers may care for their patients over the evolving course of their acute illness into their convalescent period. Clinical management of EVD combines supportive and symptomatic care while also addressing the patient's emotional and mental health needs. A variety of specific therapies directly targeting the virus has become available, but none of these has, as of yet, conclusively demonstrated an impact. Healthcare workers caring for EVD patients must be constantly aware that they are part of a larger epidemic control operation, and their actions have consequences that go beyond their patients to their families and the community affected by the outbreak. PMID- 28646338 TI - Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats. AB - PURPOSE: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT. METHODS: A total of 48 male Sprague Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR). RESULTS: Irinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)3 moieties and decreased the levels of Krebs cycle metabolites and free amino acids. CONCLUSIONS: Chemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes. PMID- 28646341 TI - Steroidal Saponins from the Genus Smilax and Their Biological Activities. AB - The Smilax species, widely distributed in tropical region of the world and the warm areas of East Asia and North America, are extensively used as folk medicine to treat inflammatory disorders. Chemical investigation on Smilax species showed they are rich sources of steroidal saponins with diversified structure types, including spirostane, isospirostane, furostane, pregnane, and cholestane. This review mainly summarizes the steroidal saponins (1-104) reported from the genus Smilax between 1967 and 2016, and their biological activities. The relationship between structures of steroidal saponins and related biological activities were briefly discussed. PMID- 28646342 TI - A case of malignant peritoneal mesothelioma suggesting the utility of combining double-contrast radiography and endoscopy with computed tomography for diagnosis. AB - A 68-year-old woman presented with abdominal pain, weight loss, and vomiting. Enhanced computed tomography (CT) showed slightly increased density in the mesentery and edema of the third portion of the duodenum and proximal jejunum. Little ascites, but no primary lesion, lymph node metastases, or distant metastases, were observed. Endoscopic findings included erythema and edema in the distal duodenum and proximal jejunum without epithelial lesions. Double-contrast radiography revealed transverse ridging with convergence, suggesting a serosal lesion. We suspected disease involving the serosa, such as mesenteric panniculitis. However, the lesion was definitively diagnosed as malignant peritoneal mesothelioma based on a biopsy specimen obtained at laparotomy. The combination of transverse ridging with convergence on double-contrast radiography and mucosal edema without epithelial lesions on endoscopy was consistent with a disorder involving the serosa. Transverse ridging with convergence is helpful to diagnose serosal pathology such as malignant peritoneal mesothelioma. Combining the findings of double-contrast radiography and endoscopy with computed tomography may facilitate diagnosis of malignant peritoneal mesothelioma. Thus, in case of increased density of mesentery and wall thickness on CT image with transverse ridging with convergence on double-contrast radiography and without epithelial lesion on endoscopy, malignant peritoneal mesothelioma must be considered. PMID- 28646343 TI - Clinical outcome following anterior cervical discectomy and fusion with and without anterior cervical plating for the treatment of cervical disc herniation-a 25-year follow-up study. AB - Extreme long-term clinical outcome studies following anterior cervical discectomy and fusion (ACDF) with an autologous iliac crest with and without Caspar plating (ACDF + CP) for the treatment of radiculopathy caused by cervical disc herniation (CDH) are extremely rare. Hospital records of patients who underwent ACDF or ACDF + CP for the treatment of CDH at least 17 years ago were reviewed. Information about diagnosis, surgery, pre- and postoperative clinical process, and repeated procedure was analyzed. At final follow-up, patients were reviewed with a standardized questionnaire including the current neurological status, Neck Disability Index (NDI), Odom's criteria, a modified EQ-5D, and limitations in quality of life. One hundred twenty-two patients with a mean follow-up of 25 years were evaluated. ACDF was performed in 80 and ACDF + CP in 42 patients, respectively. At final follow-up, 81.1% of patients were free of radicular pain and had no repeated procedure. According to Odom's criteria, 86.1% of good to excellent functional recovery was noted. The mean NDI and EQ-5D was 14% and 5 points, respectively. There was no significant difference in the assessed clinical outcome parameters between patients treated with ACDF and ACDF + CP. The rate for repeated procedure due to degenerative cervical disorders was 10.7 and 7.4% due to symptomatic adjacent segment disease with 25 years. ACDF and ACDF + CP achieved a high rate radicular pain relief (89.3%) and clinical success (86.1%) for the treatment of CDH within a 25 years follow-up. No statistical difference concerning clinical outcome and rate of repeated procedure was detected. PMID- 28646345 TI - Increasing utilization of regional nodal irradiation in elderly node-positive women and declining emphasis on demographic factors. AB - PURPOSE: To evaluate the practice patterns for the use of regional nodal irradiation (RNI) in treatment of elderly women with low volume node-positive breast cancer in the setting of breast conservation surgery (BCS). METHODS: Women aged 70-89 diagnosed with unilateral, pathologic T1-2N1M0 breast cancer from 2004 to 2013, who underwent BCS and received radiotherapy were identified from the National Cancer Database. In 2011, two major trials were presented that helped define indications for RNI. Patients were dichotomized into "early", i.e. diagnosed up to 2010, and "late" cohorts. Patient and treatment characteristics were compared between the cohorts and logistic regression used to determine independent factors associated with the receipt of RNI. RESULTS: 7228 women met inclusion criteria; 4330 (59.9%) in early and 2898 (40.1%) in late cohorts. Utilization of RNI increased from 33.9% in early to 42.5% in late cohorts (P <= 0.001) and was independent of a general increase in RNI utilization. RNI in the early and late cohorts was not different between the study population and younger women (P > 0.05). RNI utilization increased in both cohorts with increasing number of positive lymph nodes. In the early cohort, RNI was also associated with higher grade, white race and lower income. In the late cohort, RNI increased with the presence of multiple, predefined risk factors. CONCLUSIONS: There was an increase in utilization of RNI for elderly patients from 2004 to 2013. In more recent years, the primary factors associated with receipt of RNI were tumor related with declining importance of demographic factors. PMID- 28646344 TI - Does biomarker information impact breast cancer patients' preferences and physician recommendation for adjuvant chemotherapy? AB - PURPOSE: This study aimed to examine how biomarker information would impact patients' preferences and physicians' recommendations for adjuvant breast cancer therapy. METHODS: At the 18-month follow-up, participants in a large, double blind randomized controlled trial of adjuvant chemotherapy with bevacizumab or placebo (E5103) were surveyed about their preferred treatment (either chemotherapy A alone or chemotherapy A+B) in two hypothetical scenarios: (1) without biomarker information; and (2) after learning that they tested positive for a "B-receptor" which modestly increased both the benefit and toxicity expected with chemotherapy A+B. We performed a cross-sectional analysis of the prospectively collected survey data and used the McNemar's test to examine changes in treatment preferences. A one-time survey of clinical investigators who enrolled patients on the trial evaluated physician recommendations in response to the same biomarker information. RESULTS: 439 patients completed both scenarios on 18-month survey. Most participants preferred A+B in both scenario 1 and 2 (77 and 76% respectively). The increase in benefit and toxicity associated with the positive biomarker information in scenario 2 led 60/439 (14%) of patients to switch their treatment preference. The corresponding physician survey revealed that most physicians chose regimen A+B in scenario 1 (77%), and moreso after the biomarker information was available in scenario 2 (84%). CONCLUSIONS: Information about a positive biomarker indicating increased benefit and toxicity from additional chemotherapy did not change many participants' preferred treatment. The majority preferred the most effective course in both scenarios. Similarly, most investigators discounted increased toxicity and valued increased benefit. Parent Trial Registration: NCT00433511. PMID- 28646346 TI - Adenosine and Sleep. AB - The classic endogenous somnogen adenosine promotes sleep via A1 and A2A receptors. In this chapter, we present an overview of the current knowledge regarding the regulation of adenosine levels, adenosine receptors, and available pharmacologic and genetic tools to manipulate the adenosine system. This is followed by a summary of current knowledge of the role of adenosine and its receptors in the regulation of sleep and wakefulness. Despite strong data implicating numerous brain areas, including the basal forebrain, the tuberomammillary nucleus, the lateral hypothalamus, and the nucleus accumbens, in the adenosinergic control of sleep, the complete neural circuitry in the brain involved in the sleep-promoting effects of adenosine remains unclear. Moreover, the popular demand for natural sleep aids has led to a search for natural compounds that can promote sleep via adenosine receptor activation. Finally, we discuss the effects of caffeine in man and the possible use of more selective adenosine receptor drugs for the treatment of sleep disorders. PMID- 28646347 TI - Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line. AB - Alendronate (ALD), one among the nitrogen-containing bisphosphonates (NBPs), is currently used for the treatment of many pathological conditions. Unfortunately, although generally tolerated, NBPs treatment has been associated with central nervous system (CNS) adverse outcomes, such as amnesia, hallucinations and visual disturbances. So, we analyzed the effect of ALD treatment in glial cells, the main sources of cholesterol for neurons and principal cells involved in the immunological defense of the brain. We treated a glial cell line (U87-MG) with increasing doses of ALD (0.1, 1, 10, 25, 50 MUM) for 48 h, aimed at evaluating the influence of this drug treatment on IL-1B expression, NLRP3 and CASP1 expression, mitochondrial activity and apoptotic cell death. We observed that ALD treatment, at the higher concentrations, induced a significant increase of IL-1B, NLRP3, CASP1 expression, provoked apoptosis and also mitochondrial damage in U87 MG. Considering the reported CNS adverse outcomes of NBPs treatment, our results confirm ALD side-effects on glial cell model. PMID- 28646348 TI - Tau-Induced Ca2+/Calmodulin-Dependent Protein Kinase-IV Activation Aggravates Nuclear Tau Hyperphosphorylation. AB - Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells. Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca2+ concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca2+ concentration with a simultaneous increase in the phosphorylation of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca2+/CaMKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation of the Ca2+/calmodulin complex abolished the okadaic acid-induced tau hyperphosphorylation in the nuclear fraction. We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca2+/CaMKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca2+ concentration may induce a self-perpetuating harmful loop to promote neurodegeneration. PMID- 28646349 TI - Modeling Pain Using fMRI: From Regions to Biomarkers. AB - Pain is a subjective and complex phenomenon. Its complexity is related to its heterogeneity: multiple component processes, including sensation, affect, and cognition, contribute to pain experience and reporting. These components are likely to be encoded in distributed brain networks that interact to create pain experience and pain-related decision-making. Therefore, to understand pain, we must identify these networks and build models of these interactions that yield testable predictions about pain-related outcomes. We have developed several such models or 'signatures' of pain, by (1) integrating activity across multiple systems, and (2) using pattern-recognition to identify processes related to pain experience. One model, the Neurologic Pain Signature, is sensitive and specific to pain in individuals, involves brain regions that receive nociceptive afferents, and shows little effect of expectation or self-regulation in tests to date. Another, the 'Stimulus Intensity-Independent Pain Signature', explains substantial additional variation in trial-to-trial pain reports. It involves many brain regions that do not show increased activity in proportion to noxious stimulus intensity, including medial and lateral prefrontal cortex, nucleus accumbens, and hippocampus. Responses in this system mediate expectancy and perceived control effects in several studies. Overall, this approach provides a pathway to understanding pain by identifying multiple systems that track different aspects of pain. Such componential models can be combined in unique ways on a subject-by-subject basis to explain an individual's pain experience. PMID- 28646350 TI - Abnormal Rich-Club Organization Associated with Compromised Cognitive Function in Patients with Schizophrenia and Their Unaffected Parents. AB - Schizophrenia is considered to be a disorder of brain connectivity, which might result from a disproportionally impaired rich-club organization. The rich-club is composed of highly interconnected hub regions that play crucial roles in integrating information between different brain regions. Few studies have yet investigated whether the structural rich-club organization is impaired in patients and their first-degree relatives. In this study, we established a weighted network model of white matter connections using diffusion tensor imaging of 19 patients and 39 unaffected parents, 22 young healthy controls for the patients, and 25 old healthy controls for the parents. Feeder edges between rich club nodes and non-rich-club nodes were significantly decreased in both schizophrenic patients and their unaffected parents compared with controls. Furthermore, the feeder edges showed significant positive correlations with the scores in Category Fluency Test-animal naming in the unaffected parents. Specific feeder edges exhibited discriminative power with accuracy of 84.4% in distinguishing unaffected parents from old healthy controls. Our findings suggest that impaired rich-club organization, especially impaired feeder edges, may be related to familial vulnerability to schizophrenia, possibly reflecting a genetic predisposition for schizophrenia. PMID- 28646351 TI - Rare Cyclophosphamide-Induced Hemorrhagic Cystitis in a Chinese Population with Rheumatic Diseases. AB - OBJECTIVE: The aim of this study was to investigate the prevalence, severity, risk factors, and treatment outcomes of cyclophosphamide (CYC)-induced hemorrhagic cystitis (HC) in patients with rheumatic diseases. METHODS: We collected the clinical data from 1284 consecutive patients admitted to The First Affiliated Hospital of Sun Yat-Sen University who were treated with CYC between 2006 and 2016, and then conducted a retrospective analysis. RESULTS: The mean cumulative dose of CYC was 18.3 +/- 13.4 g, and the mean treatment duration of CYC was 10.0 +/- 7.2 months. We identified four patients with HC, yielding a crude prevalence of 0.3%. The average time from initial primary diagnosis to HC onset was 51.6 months (33-86 months). All of the four patients with HC were exposed to a high cumulative CYC dose (>60 g). Severity was assessed as grade II in one, grade III in one and grade IV in two patients. One had resolution of hematuria after hydration, and one case resolved after combination therapy of clot removal by cystoscopy, hydration, and bladder irrigation. The other two were unresponsive to the above treatment and finally had resolution after cystectomy. The average resolution time of hematuria was 39.5 days (7-56 days). There were no deaths in our cohort. CONCLUSION: CYC-induced HC was rare and highly variable in Chinese patients with rheumatic diseases. Individualized treatment should be performed according to the severity of HC for each patient. More aggressive treatment strategies might improve the outcomes of patients with high-grade HC (grades III and IV). Our findings strengthened the link between HC events and higher cumulative CYC exposure (>60 g). PMID- 28646352 TI - Lead enhancement of 3T3-L1 fibroblasts differentiation to adipocytes involves ERK, C/EBPbeta and PPARgamma activation. AB - Lead (Pb) is an environmental and industrial contaminant that still represents a public health problem. Elevated Pb exposure has been inversely correlated with femoral bone density and associated with osteoporosis. In the last years, it has been shown that inhibition of osteogenesis from mesenchymal stem cells activates adipogenesis and vice versa. In this paper, we investigated the effect of Pb on the differentiation of 3T3-L1 fibroblasts to adipocytes which is the cell model most used to study adipogenesis. After induction of differentiation, 2 days post confluent cells re-enter the cell cycle and undergo mitotic clonal expansion (MCE) followed by expression of genes that produce the adipocyte phenotype. The presence of concentrations of Pb up to 10 MUM during differentiation of 3T3-L1 fibroblasts did not interfere with MCE but enhanced the accumulation of cytosolic lipids that occur during adipogenesis, as well as, the induction of PPARgamma, the master gene in adipogenesis. It is known that PPARgamma upregulation is subsequent to induction of C/EBPbeta and ERK activation, which are early events in adipogenesis. We found that both events were enhanced by Pb treatment. Our results support a stimulatory effect of Pb on adipogenesis which involves ERK activation and C/EBPbeta upregulation prior to PPARgamma and adipogenesis activation. PMID- 28646353 TI - CREB1 regulates glucose transport of glioma cell line U87 by targeting GLUT1. AB - Glioma is stemmed from the glial cells in the brain, which is accounted for about 45% of all intracranial tumors. The characteristic of glioma is invasive growth, as well as there is no obvious boundary between normal brain tissue and glioma tissue, so it is difficult to resect completely with worst prognosis. The metabolism of glioma is following the Warburg effect. Previous researches have shown that GLUT1, as a glucose transporter carrier, affected the Warburg effect, but the molecular mechanism is not very clear. CREB1 (cAMP responsive element binding protein1) is involved in various biological processes, and relevant studies confirmed that CREB1 protein regulated the expression of GLUT1, thus mediating glucose transport in cells. Our experiments mainly reveal that the CREB1 could affect glucose transport in glioma cells by regulating the expression of GLUT1, which controlled the metabolism of glioma and affected the progression of glioma. PMID- 28646354 TI - Associations between Race and Eating Disorder Symptom Trajectories in Black and White Girls. AB - Epidemiological research suggests racial differences in the presentation of eating disorder symptoms. However, no studies have examined associations between race and eating disorder symptom trajectories across youth and adolescence, which is necessary to inform culturally sensitive prevention programs. The purpose of the current study was to examine the trajectories of eating disorder symptoms from childhood to young adulthood and to examine whether race was associated with trajectory group membership. Data were drawn from 2,305 Black and White girls who participated in a community-based longitudinal cohort study (Pittsburgh Girls Study) examining the development of psychopathology. The child and adult versions of the Eating Attitudes Test assessed self-reported eating disorder symptoms at six time points between ages 9 and 21 years. Growth mixture modeling was used to examine developmental trajectories of dieting, bulimia/food preoccupation, and total eating disorder symptom scores. Given potential confounds with race and disordered eating, financial strain (i.e., receiving public assistance) and weight were included as covariates. Four to six distinct developmental patterns were found across eating disorder symptoms, including none, increasing, decreasing, or increasing-decreasing trajectories. Black girls had a greater likelihood of being in the decreasing trajectories for dieting, bulimia/food preoccupation, and total eating disorder symptom scores. White girls were more likely to follow increasing trajectories of dieting and total eating disorder symptom scores compared to Black girls. These results highlight the importance of examining the influence of racial background on eating disorder symptoms and the potential need for differences in the timing and focus of prevention interventions in these groups. PMID- 28646355 TI - Racial Disparities in Menu-Labeling Usage: Analysis of the 2012 Behavioral Risk Factor Surveillance System (BRFSS) Sugar-Sweetened Beverage and Menu-Labeling Module. AB - OBJECTIVES: Race/ethnic disparities in obesity are widely reported and are often attributed to diet-related factors, such as menu-labeling usage. We aimed to determine whether racial difference exists in menu-labeling usage. METHODS: Data from the 2012 Behavioral Risk Factor Surveillance System were used. Menu labeling was measured from the Sugar-Sweetened Beverages and Menu Labeling module administered in 18 states. We stratified the population into four race/ethnic categories: non-Hispanic whites (reference, n = 66,019, 63%), non-Hispanic blacks (n = 13,623, 13%), Hispanics (n = 14,671, 14%), and others (n = 7336, 7%). Logistic regression was used to examine the racial/ethnic differences in menu labeling usage. Analyses were conducted adjusting for sociodemographic characteristics, sugar-sweetened beverage intake, and exercise. RESULTS: The prevalence of menu-labeling usage was approximately 55% overall. Hispanics (adjusted odds ratio [AOR], 1.35; 95% confidence interval [CI], 1.14-1.60) and other race/ethnic groups (AOR, 1.39; 95% CI, 1.18-1.64) used menu labeling more compared to non-Hispanic whites. After stratification by race/ethnicity, menu labeling usage was not associated with exercise or soda consumption among Hispanics, but significant associations were observed among the other three race/ethnic groups. CONCLUSIONS: The findings suggest that participation in healthy behaviors was associated with the higher usage of menu labeling across all racial/ethnic groups except Hispanics. Future studies are needed to explore this mechanism among individuals engaging in unhealthier behavior as well as how it affects Hispanics. PMID- 28646356 TI - Pharmacotherapy in the Management of Pediatric Obesity. AB - PURPOSE OF REVIEW: This review provides a rationale for the use of pharmacotherapy in pediatric weight management, summarizes results of some of the key pediatric clinical trials of approved and "off-label" obesity medications, introduces new options in the pediatric pipeline, and offers a glimpse into the future of pediatric obesity medicine. RECENT FINDINGS: Despite the need for adjunctive treatments to enhance the outcomes of lifestyle modification therapy among youth with obesity, none of the obesity medications evaluated to date have been shown to meaningfully reduce BMI or cardiometabolic risk factors. Promising medications recently approved for the treatment of obesity in adults will soon be tested in pediatric trials, offering hope that new therapeutic options will soon be available. As new medications are approved to treat pediatric obesity, it will be important to evaluate the safety and efficacy of combination pharmacotherapy and investigate predictors of response. Application of precision medicine approaches to the field of pediatric obesity management will improve the long term outlook for the tens of millions of youth afflicted with this serious and recalcitrant disease. PMID- 28646357 TI - Management of Hyperglycemia and Diabetes in the Emergency Department. AB - PURPOSE OF REVIEW: Hyperglycemia in the emergency department (ED) is being recognized as a public health problem and presents a clinical challenge. This review critically summarizes available evidence on the burden, etiology, diagnosis, and practical management strategies for hyperglycemia in the ED. RECENT FINDINGS: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are hyperglycemic emergencies that commonly present to the ED. However, the most common form of hyperglycemia in ED is associated with non-hyperglycemic medical emergencies. The presence of hyperglycemia increases the mortality and morbidity associated with the primary condition. The related hospital admission rates and costs are also elevated. The frequency of DKA or HHS related mortality and morbidity has remained high over the last decade. However, attempts have been made to improve management of all hyperglycemia in the ED. Evidence suggests that better management of hyperglycemia in the ED with proper follow-up improves clinical outcomes and prevents readmission. Optimization of the hyperglycemia management in the ED may improve clinical outcomes. However, more clinical trial data on the outcomes and cost-effectiveness of various management strategies or protocols are needed. PMID- 28646358 TI - Metabolomics of Diabetes in Pregnancy. AB - PURPOSE OF REVIEW: The purpose of this review is to describe ways in which metabolomics may enhance understanding of gestational diabetes mellitus (GDM) etiology and refine current diagnostic criteria. RECENT FINDINGS: Current clinical recommendations suggest screening for GDM between 24 and 28 of gestational weeks using an oral glucose tolerance test. Despite this consensus, there are discrepancies regarding the exact criteria for GDM diagnosis. Further, emerging evidence has unveiled heterogeneous physiological pathways underlying GDM-specifically, GDM with defective insulin secretion vs. sensitivity-that have important implications for disease diagnosis and management. The objectives of this review are threefold. First, we seek to provide a brief summary of current knowledge regarding GDM pathophysiology. Next, we describe the potential role of metabolomics to refine and improve the prediction, screening, and diagnosis of GDM. Finally, we propose ways in which metabolomics may eventually impact clinical care and risk assessment for GDM and its comorbidities. PMID- 28646359 TI - Music as an Adjunct to Opioid-Based Analgesia. AB - Epidemic increases in opioid use in the USA and globally highlight the need for effective adjunctive therapies to opioid-based analgesia. Given the shortcomings of behavioral adjuncts to opioid-based pain treatment, an urgent need exists for pain-related behavioral interventions that resonate with broad patient populations, can be delivered confidentially in any environment, and can incorporate new content automatically. Understanding the potential for automated behavioral therapies like music therapy in modulating the experience of pain may unlock methods to transition patients to lower doses of pharmacologic therapy or provide alternatives to opioids during acute exacerbations of pain. This manuscript describes the neurologic mechanism of action, theoretical basis, and potential applications of personalized music as a smartphone-based mHealth intervention for acute and chronic pain management. PMID- 28646361 TI - Erratum to: Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV. PMID- 28646360 TI - Does the Risk of Rerevision Vary Between Porous Tantalum Cups and Other Cementless Designs After Revision Hip Arthroplasty? AB - BACKGROUND: Earlier results with porous tantalum acetabular cups in revision THA generally have been favorable. Recently there has been some evidence presented that porous tantalum cups might decrease the risk of rerevision in the setting of revision hip surgery performed owing to prosthetic joint infection (PJI). As the data supporting this assertion come from a study with a limited study population, examining this issue with a large registry approach may be enlightening. QUESTIONS/PURPOSES: By combining results from two large, national registries, we asked: (1) Do porous tantalum cups show improved survival after revision THA compared with other cementless designs? (2) Does the use of porous tantalum cups influence survivorship when rerevision for PJI is the endpoint? METHODS: A total of 2442 first-time THA revisions with porous tantalum cups and 4401 first-time revisions with other uncemented cups were included in this collaborative study between the Australian and Swedish national joint registries. The mean age of the patients was 69 years (range, 19-97 years), 3754 (55%) of the patients were women, and the mean followup for the porous tantalum and uncemented control groups were 3.0 years (SD, +/- 2.1 years) and 3.4 years (SD, +/- 2.3 years), respectively. Concomitant stem revision was more common in the porous tantalum group (43% versus 36%). The use of porous tantalum augments also was analyzed as a proxy for more complex acetabular reconstructions. In an attempt to further reduce selection bias, we performed subgroup analysis for primary operations attributable to osteoarthritis and first revision attributable to aseptic loosening. RESULTS: Kaplan-Meier survivorship with rerevisison for any reason up to 7 years was comparable between the porous tantalum cup group and the uncemented cup control group (86% [95% CI, 85%-89%] and 87% [95% CI, 85%-89%], respectively; p = 0.85) and the overall survivorship up to 7 years with a second revision for PJI as the endpoint (97% [95% CI, 95%-98%] and 97% [95% CI, 96% 98%], respectively; p = 0.64). Excluding procedures where augments had been used or studying primary osteoarthritis and first revision owing to aseptic loosening subgroups did not change this result. CONCLUSIONS: Implant survival for a porous tantalum cup in first-time THA revision was similar to the survival of the uncemented cup control group. With the numbers available, no benefit in survival with rerevision for infection as the endpoint could be ascribed to the porous tantalum cup group, as has been suggested by earlier work. Further studies with acetabular bone deficiency data, greater insight into host comorbidity factors, and a longer followup are needed to corroborate or refute these results. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28646362 TI - [Theories of Social Work and Geriatrics]. AB - Medical practitioners commonly do not have much knowledge of the professional side of social workers, even those that work together in a geriatric team. The current article aims to further this knowledge and to show that the potentials of social work support may exceed administration, as well as in the consultation of patients by so-called social workers in hospitals. These potentials are not empirically reasoned, instead social pedagogic theories are used for support of this argument. Three theories will be introduced as examples and furthermore, the possible meaning this has for geriatric medicine will be explained by means of a case example. PMID- 28646363 TI - The many routes of mental navigation: contrasting the effects of a detailed and gist retrieval approach on using and forming spatial representations. AB - Navigated routes can be recalled by remembering a schematic layout or with additional sensory and perceptual details, engaging episodic memory processes. In this study, we contrasted the effects of these remembering approaches on retrieving real-world navigated routes, the impact on flexibly using familiar route information and on learning new spatial representations. In a within subjects design, participants were oriented to recall familiar routes under two remembering conditions-a detail condition that promoted episodic memory processes and a gist condition in which routes were recalled via schematic processes. In each condition, participants performed two subsequent navigation tasks. They first described solutions to navigation problems that involved the recalled familiar route (e.g., navigating around a road block or to a new destination) and then learned and recalled a route within a novel spatial environment. All navigation descriptions were scored for the number of spatial references, entities, and sensory descriptions. We report the following findings. First, when describing the familiar routes, more details were generated in the detail condition, but a higher proportion of these details were spatial references in the gist condition. Route descriptions in the gist condition also relied more on egocentric spatial representations than in the detail condition. Next, when solving navigation problems in the familiar environment, solution routes were described with more details in the detail condition and deviated less from the familiar route than in the gist condition. Finally, the detail condition led to the preferential encoding of entity and sensory descriptive details of new spatial representations. These findings suggest that activating episodic processes at retrieval has distinct effects on how familiar information can be flexibly used and how new spatial representations are formed. PMID- 28646364 TI - Sinonasal malignancies: incidence and histological distribution in Jamaica, 1973 2007. AB - PURPOSE: To determine the histological distribution and trends in incidence of sinonasal malignancies in Jamaica. METHODS: Cases of all sinonasal malignancies diagnosed between 1973 and 2007 were extracted from the archives of the Jamaica Cancer Registry. Data recorded for each case included age at diagnosis, sex, year of diagnosis, topography, and histology. Data were used to calculate frequencies, age-specific incidence rates, and age-standardized incidence rates (ASRs). Linear regression analysis was used to determine significance of trends in incidence rates; p values of <=0.05 were significant. RESULTS: Sinonasal malignancies were commoner in males (male: female ratio, 1.1:1), and the median ages were 62 (males) and 66 years (females). Most were located in either the maxillary sinus (61.3%) or nasal cavity (24.3%). The commonest histological types were squamous cell carcinoma (SCC) (55.9%) and non-Hodgkin's lymphoma (17.1%), which were predominantly of T-cell immunophenotype, in both the nasal cavity and sinuses. There was no documentation in registry data regarding separation into NK/T and peripheral T-subtypes. The ASRs in males and females were consistently less than 1.5 per 100,000 per year. In males, there was a significant decrease in SCC ASR (p = 0.014) over time. CONCLUSIONS: The age, gender, and anatomical and histological distribution patterns of sinonasal malignancies in Jamaica are similar to those reported internationally, and the low ASRs are in keeping with previous global reports. Broader local immunohistochemistry panels are warranted for further delineation of sinonasal T-cell lymphomas. Investigation into factors contributing to the decreasing incidence of sinonasal SCC is also required. PMID- 28646365 TI - Post-diagnosis serum insulin-like growth factors in relation to dietary and lifestyle changes in the Prostate testing for cancer and Treatment (ProtecT) trial. AB - PURPOSE: The insulin-like growth factor (IGF) system is modifiable by diet and lifestyle, and has been linked to prostate cancer development and progression. METHODS: We conducted a prospective cohort study of 621 men diagnosed with localized prostate cancer to investigate the associations of dietary and lifestyle changes with post-diagnosis circulating levels of IGF-I and IGFBP-3. We used analysis of covariance to estimate the associations, controlling for baseline IGF-I or IGFBP-3, respectively. RESULTS: Mean IGF-I levels were 6.5% (95% CI -12.8, -0.3%, p = 0.04) lower in men who decreased their protein intake after diagnosis compared to men who did not change. Men who changed their fruit and vegetable intake had lower IGF-I levels compared to non-changers [Decreased intake: -10.1%, 95% CI -18.4, -1.8%, p = 0.02; Increased intake: -12.0%, 95% CI 18.4, -1.8%, p = 0.002]. IGFBP-3 was 14.6% (95% CI -24.5, -4.8%, p = 0.004) lower in men who achieved a healthy body mass index after diagnosis. Men who became inactive had 9.5% higher average IGF-I levels (95% CI 0.1, 18.9%, p = 0.05). CONCLUSIONS: Decreased protein intake and body mass index, and increased physical activity and fruit and vegetable intake, following a prostate cancer diagnosis were associated with reduced post-diagnosis serum IGF-I and IGFBP-3. Counterintuitively, reduced fruit and vegetable intake was also associated with reduced IGF-I, but with weak statistical support, possibly implicating chance. If confirmed in other studies, our findings may inform potential lifestyle interventions in prostate cancer. ProtecT was registered at International Standard Randomised Controlled Trial Registry, http://isrctn.org as ISRCTN20141297. PMID- 28646367 TI - IFNgamma-producing CD4+ T lymphocytes: the double-edged swords in tuberculosis. AB - IFNgamma-producing CD4+ T cells (IFNgamma+CD4+ T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis (Mtb). Primarily, these cells act by enabling Mtb-infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNgamma+CD4+ T cells in TB pathogenesis. High frequency of IFNgamma+CD4+ T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNgamma+CD4+ T cell response to mycobacterial antigens and demonstrate an IFNgamma-inducible transcriptomic signature. IFNgamma+CD4+ T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb coinfected people. The pathological face of IFNgamma+CD4+ T cells during mycobacterial infection is further uncovered by studies in the animal model of TB IRIS and in Mtb-infected PD-1-/- mice. This manuscript encompasses the evidence supporting the dual role of IFNgamma+CD4+ T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis. PMID- 28646366 TI - Endothelial cell apoptosis in angiogenesis and vessel regression. AB - Blood vessel regression is an essential process for ensuring blood vessel networks function at optimal efficiency and for matching blood supply to the metabolic needs of tissues as they change over time. Angiogenesis is the major mechanism by which new blood vessels are produced, but the vessel growth associated with angiogenesis must be complemented by remodeling and maturation events including the removal of redundant vessel segments and cells to fashion the newly forming vasculature into an efficient, hierarchical network. This review will summarize recent findings on the role that endothelial cell apoptosis plays in vascular remodeling during angiogenesis and in vessel regression more generally. PMID- 28646368 TI - TNFalpha blockers followed by continuation of sulfasalazine and methotrexate combination: a retrospective study on cost saving options of treatment in Spondyloarthritis. AB - High cost deters continuous use of tumor necrosis factor alpha blockers (TNFi) in developing countries. The objective of this study was to evaluate outcome and expenditure incurred in Spondyloarthritis (SpA) patients beyond a year of follow up after receiving four doses of infliximab (IFX) over and above background therapy of methotrexate (MTX) and sulfasalazine (SSZ) combination. Electronic medical records were screened for patients with SpA satisfying the Assessment of Spondyloarthritis International Society (ASAS) criteria between 2008 and 2014. Patients who completed at least 1 year of follow-up after receiving four doses of IFX (5 mg/kg at 0, 2, 6, and 14 weeks) on a background therapy of MTX (10-25 mg/week) and SSZ (2-3 g/day) combination were enrolled after obtaining an informed consent. Primary outcome assessed was "time to disease flare". Changes in acute phase reactants, patient reported outcomes (BASDAI, BASFI), and cost were also assessed. Forty-five patients were enrolled. Mean (SD) duration of follow up after fourth IFX dose was 28.9 (18.7) months. Disease flare occurred in 33.3% (15/45) after a mean (SD) duration of 14.5 (10.8) months as compared to 4-6 months described in literature on discontinuing TNFi. Reduction in ESR, CRP, BASDAI and BASFI continued to be statistically significant at follow-up as compared to baseline. As compared to continuous IFX therapy, this treatment reduced cost by 57.1% for each patient-month of follow-up. Short course IFX dosing followed by continuation of MTX and SSZ combination can prolong time to disease flare and decrease requirement for additional IFX dose in SpA. This regimen could be a cost saving option for patients with SpA. PMID- 28646369 TI - Impacts of a Temporary Urban Pop-Up Park on Physical Activity and Other Individual- and Community-Level Outcomes. AB - Physical inactivity is a known risk factor for obesity and a number of chronic diseases. Modifying the physical features of neighborhoods to provide residents with equitable and convenient access to spaces for physical activity (PA) is a promising strategy for promoting PA. Public urban recreation spaces (e.g., parks) play an important role in promoting PA and are potentially an important neighborhood element for optimizing social capital and liveability in cities. Most studies examining the effects of park availability and use on PA have focused on traditional, permanent parks. The aims of this study were to (1) document patterns of park use and park-based PA at a temporary urban pop-up park implemented in the downtown business district of Los Altos, California during July-August 2013 and May-June 2014, (2) identify factors associated with park based PA in 2014, and (3) examine the effects of the 2014 pop-up park on additional outcomes of potential benefit for park users and the Los Altos community at large. Park use remained high during most hours of the day in 2013 and 2014. Although the park attracted a multigenerational group of users, children and adolescents were most likely to engage in walking or more vigorous PA at the park. Park presence was significantly associated with potentially beneficial changes in time-allocation patterns among users, including a reduction in screen-time and an increase in overall park-time and time spent outdoors. Park implementation resulted in notable use among people who would otherwise not be spending time at a park (85% of surveyed users would not be spending time at any other park if the pop-up park was not there-2014 data analysis). Our results (significantly higher odds of spending time in downtown Los Altos due to park presence) suggest that urban pop-up parks may also have broader community benefits, such as attracting people to visit downtown business districts. Pending larger, confirmatory studies, our results suggest that temporary urban pop-up parks may contribute to solving the limited access to public physical activity recreation spaces many urban residents face. PMID- 28646370 TI - Place-Based Predictors of HIV Viral Suppression and Durable Suppression Among Men Who Have Sex With Men in New York City. AB - We explore relationships between place characteristics and HIV viral suppression among HIV-positive men who have sex with men (MSM) in New York City (NYC). We conducted multilevel analyses to examine associations of United Hospital Fund (UHF)-level characteristics to individual-level suppression and durable suppression among MSM. Individual-level independent and dependent variables came from MSM in NYC's HIV surveillance registry who had been diagnosed in 2009-2013 (N = 7159). UHF-level covariates captured demographic composition, economic disadvantage, healthcare access, social disorder, and police stop and frisk rates. 56.89% of MSM achieved suppression; 35.49% achieved durable suppression. MSM in UHFs where 5-29% of residents were Black had a greater likelihood of suppression (reference: >=30% Black; adjusted relative risk (ARR) = 1.07, p = 0.04). MSM in UHFs with <30 MSM-headed households/10,000 households had a lower likelihood of achieving durable suppression (reference: >=60 MSM-headed households/10,000; ARR = 0.82; p = 0.05). Place characteristics may influence viral suppression. Longitudinal research should confirm these associations. PMID- 28646371 TI - Objective assessment of reconstructed breast hardness using a durometer. AB - BACKGROUND: Whether a durometer was suitable for objectively measuring reconstructed breast hardness was evaluated. METHODS: Subjects were 81 women who underwent expander-implant reconstructions following breast cancer ablation. Capsular contracture was evaluated with Baker grading. Capsular thickness was measured with T1-weighted MRI at the upper areola area. The durometer was placed on the upper areola. Multiple logistic regression analysis was performed to compare variables. RESULTS: On Baker grading, 17 breasts were Baker grade I, 52 breasts were Baker grade II, 11 breasts were Baker grade III, and 1 breast was Baker grade IV. Mean capsular thickness on MRI was 1.1 (SD 0.4) mm with Baker grade I, 1.2 (SD 0.3) mm with Baker grade II, 1.4 (SD 0.4) mm with Baker grade III, and 1.9 mm with Baker grade IV. Mean durometer value was 0 with Baker grade I, 0.2 (SD 0.5) with Baker grade II, 2.0 (SD 1.7), with Baker grade III, and 8 with Baker grade IV. Baker grade IV was excluded from analysis because there was only one case. When Baker grade III was defined as positive for hardness, multiple logistic regression analysis showed that durometer value was associated with Baker grade III (p = 0.0005), but capsular thickness was not. On receiver operating characteristic curve analysis of the durometer value for Baker grade III, the optimal cutoff value was 0.5 (sensitivity 0.92, 1-specificity 0.17, area under the curve 0.92). CONCLUSIONS: The durometer offers an objective index of hardness that might replace the subjective Baker grading. Further studies are needed to confirm the utility of this index. PMID- 28646372 TI - Psychophysiological and Behavioral Responses to a Novel Intruder Threat Task for Children on the Autism Spectrum. AB - We measured skin conductance response (SCR) to escalating levels of a direct social threat from a novel, ecologically-relevant experimental paradigm, the Intruder Threat Task. We simultaneously evaluated the contribution of social symptom severity and behavioral movement. Children with AS group showed less psychophysiological reactivity to social threat than controls across all three phases of the experiment. In the AS group, greater social impairment was significantly associated with reduced SCR. However, movement activity predicted SCR while diagnosis did not. Research and treatment need to account for the complex interplay of emotional reactivity and social behavior in AS. Psychophysiology studies of AS should consider the impact of possible confounds such as movement. PMID- 28646373 TI - Ethical Challenges Unique to the Primary Care Behavioral Health (PCBH) Model. AB - The interprofessional nature of the Primary Care Behavioral Health (PCBH) model invites potential conflicts between different ethical guidelines and principles developed by separate professional disciplines. When the foundational model of care and training on which ethical principles were developed shifts, the assumptions underlying the guidance also shifts, revealing gaps and mismatches. This article reviews the extant literature in this realm, and proposes a more unifying set of ethical guidance for interprofessional, integrated primary care practice. We discuss common ethical dilemmas unique to the PCBH model through case examples, and then apply the newly proposed ethical guideline model to these cases to illustrate how the newly proposed model can be efficient and effective navigating these dilemmas. PMID- 28646374 TI - Item usage in a multidimensional computerized adaptive test (MCAT) measuring health-related quality of life. AB - PURPOSE: Examining item usage is an important step in evaluating the performance of a computerized adaptive test (CAT). We study item usage for a newly developed multidimensional CAT which draws items from three PROMIS domains, as well as a disease-specific one. METHODS: The multidimensional item bank used in the current study contained 194 items from four domains: the PROMIS domains fatigue, physical function, and ability to participate in social roles and activities, and a disease-specific domain (the COPD-SIB). The item bank was calibrated using the multidimensional graded response model and data of 795 patients with chronic obstructive pulmonary disease. To evaluate the item usage rates of all individual items in our item bank, CAT simulations were performed on responses generated based on a multivariate uniform distribution. The outcome variables included active bank size and item overuse (usage rate larger than the expected item usage rate). RESULTS: For average theta-values, the overall active bank size was 9-10%; this number quickly increased as theta-values became more extreme. For values of 2 and +2, the overall active bank size equaled 39-40%. There was 78% overlap between overused items and active bank size for average theta-values. For more extreme theta-values, the overused items made up a much smaller part of the active bank size: here the overlap was only 35%. CONCLUSIONS: Our results strengthen the claim that relatively short item banks may suffice when using polytomous items (and no content constraints/exposure control mechanisms), especially when using MCAT. PMID- 28646375 TI - Comparative efficacy and safety in ESA biosimilars vs. originators in adults with chronic kidney disease: a systematic review and meta-analysis. AB - BACKGROUND: Several Erythropoiesis-stimulating agents (ESAs) are available to treat anemia in patients with chronic kidney disease (CKD). Questions about the comparability of such therapeutic options are not purely a regulatory or economical matter. Appropriate use of originator or biosimilar in these patients need to be supported by clinical data. Regarding the prevention of blood transfusion, reduction of fatigue, breathlessness and mortality or cardiovascular events, a summary of the comparative efficacy and safety data of these drugs is lacking. METHODS: We performed a systematic literature search of CENTRAL, PubMed, and Embase through November 11, 2015. Our inclusion criteria encompassed randomized, controlled clinical trials that evaluated the comparative effectiveness of different ESAs originators and/or biosimilar. The considered participants were adults aged 18 years or older with anemia due to CKD. The overall quality of evidence was assessed using the GRADE system. RESULTS: We identified 30 eligible studies including 7843 patients with CKD, and 21/30 studies included patients using hemodialysis or peritoneal dialysis. Compared with ESA biosimilars, epoetin alpha did not statistically differ for any of the ten measured outcomes. The quality of evidence varied from low to very low. In the comparison between epoetin alpha vs. darbepoetin alpha, no differences were observed for all outcomes, but blood transfusions showed favorable results for darbepoetin alpha: RR 2.18 (1.31-3.62). The quality of evidence varied from low to very low. No differences were observed between epoetin beta and methoxy polyethylene glycol-epoetin beta, and between darbepoetin alpha and methoxy polyethylene glycol-epoetin beta, the quality of evidence varied from moderate to very low. CONCLUSIONS: Data from 31 included studies allowed to pool data in meta analysis related to four different comparisons and eleven outcome measures. Nevertheless, only one result was statistically significant in favor of darbepoetin alpha in the comparison with epoetin alpha concerning blood transfusions. For all the other outcomes and comparisons, we did not find any differences in terms of efficacy and security between the EPO considered. The quality of evidence is quite low, and further research could change these results. Further high quality studies examining the comparative effectiveness of ESAs need to be conducted. PMID- 28646376 TI - Morphologic and molecular pathway of cushing syndrome cardiomyopathy. PMID- 28646377 TI - Efficacy of an education course delivered to community health workers in diabetes control: A randomized clinical trial. AB - BACKGROUND: Community health workers are community members who provide education and care for patients for a broad range of health issues, including diabetes mellitus. However, few community health workers are trained for diabetes education and little is known about the effectiveness of their interventions. The aim of this study is to evaluate the effect of a diabetes education program delivered to community health workers in improving the metabolic control of patients with type 2 diabetes mellitus. METHODS: Eight community health workers, providing care for 118 patients, were randomized in two groups to receive a 1 month diabetes education program (intervention, patients n = 62) or an education course in other health issues (control, patients n = 56). Each community health worker was responsible for transmitting the acquired knowledge to patients. Primary outcome was changed in HbA1C 3 months after the intervention. RESULTS: PARTICIPANTS: Mean age was 61 +/- 11 years, 35% were men and 62% were whites. HbA1c levels reduced in both groups (intervention: 9.1 +/- 2.2 vs. 7.9 +/- 1.9%; control: 9.1 +/- 2.1 vs. 8.4 +/- 2.5%, p < 0.001), but no statistically significant differences were observed between groups (p between groups = 0.13). Total cholesterol (intervention: 192 +/- 43 vs. 182 +/- 39 mg/dl; control: 197 +/ 44 vs. 191 +/- 45 mg/dl, p between groups = 0.035) and triglycerides (intervention: 158 [106-218] vs. 135 [106-215]; control: 128 [100-215] mg/dl vs. 146 [102-203] mg/dl, p between groups = 0.03) reduced overtime only in intervention group. CONCLUSIONS: In this study, a significant decrease in HbA1c was observed during patients' follow-up, but it was similar in intervention and control groups. The diabetes mellitus education course delivered to community health workers was able to improve patients' lipid profile. PMID- 28646378 TI - Glucagon stimulation test: has its time come? PMID- 28646379 TI - Comment on "The pros and cons of continuous glucose monitoring for patients with type 1 diabetes on multiple daily injections of insulin." PMID- 28646380 TI - Isolation, selection, and biological characterization research of highly effective electricigens from MFCs for phenol degradation. AB - The microbial fuel cells (MFCs) are recognized to be highly effective for the biodegradation of phenol. For isolating the phenol-degrading bacteria, the sample containing 500 mg/L phenol was collected from the MFCs. The strain (WL027) was identified basing on the 16S rRNA gene analysis and phylogenetic analysis as Bacillus cereus. The effects of pH, temperature, concentrations of phenol, heavy metal ions, and salt on the growth of strain as well as the degradation of phenol have been carefully studied. The WL027-strain exhibited favorable tolerance for the metal cations including Cr2+, Co2+, Pb2+, and Cu2+ with the concentration of 0.2 mg/L and NaCl solution with a high concentration of 30 g/L. In 41 h, 86.44% of 500 mg/L phenol has been degraded at the initial pH at 6 and the temperature of 30 degrees C. The strain was highly active electrogenesis bacteria and the coulombic efficiency reached 64.25%, which showed significant advantage on the efficient energy conversion. Therefore, due to the highly efficient degradation of phenol, WL027-strain could be used in the treatment of phenol-containing wastewater. PMID- 28646381 TI - Stenotic intercondylar notch type is correlated with anterior cruciate ligament injury in female patients using magnetic resonance imaging. AB - PURPOSE AND HYPOTHESIS: The principal purpose of this paper was to identify whether femoral notch morphology was different in females without anterior cruciate ligament (ACL) injury from those with ACL injury. Magnetic resonance imaging (MRI) was used to assess the femoral notch type, notch width index and 'alpha angle' in female patients and measure these differences. METHODS: This is a retrospective case control study of 119 female patients, 58 with ACL injury and 61 patients without ACL injury who underwent knee MRI between March 2014 and April 2016. The morphometric measurements were taken by two independent observers. The femoral notch width index was calculated as the ratio between the central notch width and transcondylar or intercondylar width; values >0.27 were considered normal. The femoral notch shape was classified as Type A, Type U or Type W, with Type A describing a stenotic notch, Type U a notch with a wider contour and Type W a wider Type U with two apices apparent. The angle between the longitudinal femoral axis and the Blumensaat line was identified as the 'alpha angle'. The statistical analysis was performed with t tests, simple and multivariable logistic regression analysis to evaluate the strength of these specific femoral notch morphometric values as predictive factors to ACL rupture. RESULTS: Stenotic femoral notch Type A was identified as a high risk factor to ACL injury (odds ratio [OR] = 2.8; p = 0.03). There was no significant difference between the two groups for the notch width index (OR = 0.7; p = n.s.) and the 'alpha angle' (OR 1.02; p = n.s.). Significant association between NWI and stenotic notch was found (p < 0.01). CONCLUSIONS: This study showed that Type A stenotic femoral notch can be considered as a valuable predictive factor for ACL injury. Notch width index and 'alpha angle' are weak indicators in ACL injury prognosis. Ligament impingement may be inferred as an important mechanism in female ACL rupture. Injury prevention strategies, such as prehabilitation programmes, could be introduced in the benefit of young females with stenotic notch. LEVEL OF EVIDENCE: III. PMID- 28646382 TI - High incidence of acute and recurrent patellar dislocations: a retrospective nationwide epidemiological study involving 24.154 primary dislocations. AB - PURPOSE: The purpose of this study was to investigate the Danish population as a whole from 1994 to 2013 to find the incidence of acute and recurrent patellar dislocation. METHODS: The study was performed as a descriptive epidemiological study. The Danish National Patient Registry was retrospectively searched from 1994 to 2013 to find the number of acute and recurrent patellar dislocation. National population data were collected from Statistics Denmark. RESULTS: The period 1994-2013 saw a total registration of 24,154 primary patellar dislocations. A mean incidence of 42 (95% CI 37-47) per 100,000 person-years at risk was found, and young females aged 10-17 had the highest incidence of 108 (95% CI 101-116). In a 10-year follow-up, patients were at an overall risk of 22.7% (95% CI 22.2-23.2) of suffering a recurrent dislocation, with young girls aged 10-17 experiencing the highest risk, namely 36.8% (95% CI 35.5-38.0). The overall risk of suffering a patellar dislocation in the contralateral knee was 5.8% (95% CI 5.5-6.1) and 11.1% (95% CI 10.4-11.7) for patients aged 10-17. CONCLUSION: A high incidence rate of primary patellar dislocation was found both as a mean in the population (42/100,000), and particularly in patients aged 10-17 (108/100,000). The risk of recurrent dislocation in the affected knee (22.7%) and the contralateral knee (5.8%) was high, which could indicate the influence of an underlying pathomorphology. This is relevant knowledge to the clinician, as he/she should be aware of the high risk of recurrent dislocation when deciding on treatment, especially in young patients. LEVEL OF EVIDENCE: IV. PMID- 28646383 TI - Anterior cruciate ligament graft fixation first in anterior and posterior cruciate ligament reconstruction best restores knee kinematics. AB - PURPOSE: To evaluate the effect of different graft fixation sequences in one stage anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstruction on (1) knee biomechanics and (2) tibiofemoral alignment. METHODS: Twelve porcine knees were used in this study. Five fixation sequences were performed (angle indicating knee flexion): (a) PCL at 30 degrees and ACL at 30 degrees , (b) PCL at 90 degrees and ACL at 30 degrees , (c) ACL at 30 degrees and PCL at 30 degrees , (d) ACL at 30 degrees and PCL at 90 degrees , and (e) ACL and PCL simultaneous fixation at 30 degrees . Anterior and posterior tibial translation was measured under an 89 N load. A 3-D digitizer was used to measure the change in anteroposterior (AP) tibiofemoral position. RESULTS: None of the graft fixation sequences restored the AP laxity of the intact knee, and there are minimal differences in the in situ tissue forces in the ACL and PCL grafts. The reconstructions with fixation of the PCL graft first resulted in a significantly larger change in AP tibiofemoral position from the intact knee at 60 degrees and 90 degrees of knee flexion than the reconstructions with fixation of the ACL graft first (p < 0.05). CONCLUSION: Fixation of the ACL graft at 30 degrees of knee flexion followed by fixation of the PCL graft can best restore the tibiofemoral position of the intact knee. This study has clinical relevance in regard to the effect of graft fixation sequence on the position of the tibia relative to the femur in one-stage ACL and PCL reconstruction. PMID- 28646384 TI - Lipophilicity Influences Drug Binding to alpha1-Acid Glycoprotein F1/S Variants But Not to the A Variant. AB - OBJECTIVE: Human alpha1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their affinity of binding to several drugs. In this study, we investigated the factors determining drug binding to these alpha1-acid glycoprotein genetic variants using disopyramide, warfarin, and tamsulosin as marker compounds. METHODS: Binding of the marker drugs to human alpha1-acid glycoprotein was determined by ultra-filtration in the presence or absence of various other drugs. For screening of the alpha1-acid glycoprotein variants to which the marker drugs became bound, the effects of various other drugs on their binding were studied. The binding data were analyzed using a competitive inhibition model and the relationship between the estimated dissociation constants and physicochemical properties, such as log P, was also analyzed. RESULTS: The binding of tamsulosin was significantly decreased by aprindine, carvedilol, erythromycin, thioridazine, and warfarin, but not by disopyramide. The dissociation constants of drugs bound to F1/S variants were significantly correlated with their lipophilicity, but those for the A variant were not. CONCLUSIONS: We were able to develop a simple screening method for determining individual alpha1-acid glycoprotein variants to which drugs would bind. The binding of drugs to F1/S variants may be determined mainly by drug lipophilicity. PMID- 28646388 TI - Skin Conductance Reactivity to Standardized Virtual Reality Combat Scenes in Veterans with PTSD. AB - Interest in virtual reality (VR) as a clinical tool to augment posttraumatic stress (PTSD) treatment has grown substantially in recent years due to advances in VR technology. Moreover, its potential assisted use in the PTSD diagnostic process has been recognized. In this study we examined physiological responding, skin conductance, to a standardized presentation of non-personalized combat related VR events (e.g. encountering enemy fire; explosions) as compared to non combat classroom VR events in 19 Veterans with and 24 Veterans without combat related PTSD who had been deployed to Iraq and Afghanistan. Veterans watched a total of 12 VR scenarios-six combat-related and six non-combat-related-with each scenario gradually increasing in emotional intensity by adding more VR events in addition to repeating prior VR events. Results show that Veterans with PTSD displayed larger skin conductance reactivity across VR combat events, but not for non-combat VR events, as compared to combat Veterans without PTSD. Nevertheless, Veterans with and without PTSD showed a similar reduction of emotional arousal to repeated presentation of the same VR combat events. Within the PTSD sample, the elevated level of VR combat-related arousal correlated marginally with severity of hyperarousal symptoms. This study confirms that the use of a non-personalized and standardized VR presentation successfully distinguishes Veterans with PTSD from those without on a measure of psychophysiological arousal to combat-related VR stimuli. The assessment of physiological reactivity during the repeated presentation of standardized, trauma-related VR events highlights its use for PTSD assessment as well as treatment. PMID- 28646385 TI - Imaging of the pediatric peritoneum, mesentery and omentum. AB - The normal peritoneal structures, including the mesenteries and the omenta, are only a few cell layers thick and are visible on imaging based upon the tissues (e.g., fat) and structures (e.g., blood vessels and lymph nodes) contained within them. These structures become more visible and change in appearance when involved by pathological processes. In this pictorial essay, we discuss the normal anatomy of the various abdominopelvic peritoneal structures and illustrate numerous developmental and acquired diagnoses that involve these structures in the pediatric and young adult population. PMID- 28646389 TI - Photodynamic therapy controls of Staphylococcus aureus intradermal infection in mice. AB - Infections caused by Staphylococcus aureus lead to skin infections, as well as soft tissues and bone infections. Given the communal resistance to antibiotics developed by strains of this bacterium, photodynamic therapy emerges as a promising alternative treatment to control and cure infections. Females of the Balb/C mice were infected with 108 CFU of methicillin-resistant S. aureus (MRSA) and divided into four distinct groups: P-L- (negative control group), P+L- (group exposed only to curcumin), P-L+ (group exposed only to LED incidence of 450 nm, 75 mW/cm2, and 54 J/cm2 for 10 min), and P+L+ (group exposed to curcumin followed by 10 min of LED irradiation) (n = 24). The mice were euthanized 48 and 72 h after infection, and biologic materials were collected for analysis of the bacterial load, peripheral blood leukocyte counts, and draining lymph nodes cell counts. The normalization of data was checked and the ANOVA test was applied. The bacterial load in the draining lymph node of P+L+ group was lower when compared to the control groups 72 h post infection (p < 0.0001), indicating that the LED incidence associated with curcumin controls of the staphylococci intradermal infection. The number of the total lymph node cells shows to be lower than control groups in the two availed times (p < 0.01). The histological analysis and the counting of white blood cells did not show differences among cells in the blood and in the tissue of infection. This is the first report showing that photodynamic therapy may be effective against MRSA infection in a murine model of intradermal infection. PMID- 28646390 TI - 2940-nm Er:YAG fractional laser enhanced the effect of topical drug for psoriasis. AB - We observed the promoting effects of the 2940-nm erbium:YAG (Er:YAG) fractional laser in topical drug delivery for psoriasis. A total of five (four males and one female) recalcitrant psoriasis patients were given laser treatment eight times at 1-week intervals with the following parameters: 5-11% spot density and 100-MUm energy depth. The psoriatic skin lesions on the left knee and the corresponding lesions at the right ones of each psoriasis patient were randomly divided into two groups: laser + topical drug group (L) and drug alone group (D). The psoriatic lesions in both groups were treated with the same topical treatment (calcipotriol ointment). The corresponding psoriatic lesions in the L group received extra 2940-nm Er:YAG laser irradiation before topical treatment. The photos of psoriatic lesions were taken before each treatment. The final photos were obtained from the patients at the seventh day after the final treatment. Drug alone or in combination with laser Er:YAG both reduced psoriatic lesions. However, with the increase in the number of treatments, increasing differences were observed between the treatment and the control sides. The therapeutic outcomes in the L groups were better than those in the D groups. Psoriasis area and severity index (PASI) scores for five cases of both groups were decreased. However, the scores in the L groups were lower than those in the D groups. The use of 2940 nm Er:YAG promoted the absorption of topical drugs for psoriasis, improving the therapeutic effect. PMID- 28646391 TI - The Changing Landscape of Alopecia Areata: An Introduction. AB - Alopecia areata is an extremely common autoimmune condition affecting hair. Severe forms of alopecia areata exist, with existing treatments consisting of systemic immunosuppressants with numerous side effects. Recently, breakthroughs have been made in both understanding the pathogenesis of alopecia areata and the treatment thereof, which hold the promise of being able to target severe cases of alopecia areata with more efficacy and better tolerability. This article serves as an introduction to review papers from two of the leading researchers in the field of alopecia areata. PMID- 28646392 TI - The Changing Landscape of Alopecia Areata: The Translational Landscape. AB - Recent genetic and preclinical studies have increased our understanding of the immunopathogenesis of alopecia areata (AA). This has allowed expedited development of targeted therapies for the treatment of AA, and a paradigm shift in our approach and understanding of autoimmunity and the hair follicle. The synergy between preclinical studies, animal models, and translational studies has led to unprecedented advances in the treatment options for AA, ultimately benefiting patients who have had little recourse. In this review, we summarize the scientific field of contemporary AA research, and look forward to potential new technologies and developments. PMID- 28646394 TI - The Antihypertensive Efficacy of the Triple Fixed Combination of Perindopril, Indapamide, and Amlodipine: The Results of the PETRA Study. AB - INTRODUCTION: The etiology of essential hypertension is multifactorial. Therefore, treatment with combinations of antihypertensive agents acting on multiple targets is necessary for successful therapy in the majority of patients. According to the experience and clinical data accumulated so far, combination therapy with three agents from different pharmacological classes is required in approx. 30% of patients in order to achieve long-term blood pressure control. The primary objective of the PETRA study was to evaluate the efficacy of blood pressure (BP) control with once daily administration of the different dosage strengths of the once-daily, triple fixed combination of perindopril, indapamide, and amlodipine. The evaluation was based on office BP readings and ambulatory blood pressure monitoring (ABPM) data gathered in routine clinical practice. METHODS: Data from 11,209 hypertensive patients (the proportion of female subjects was 47.6%) were processed and interpreted in a 3-month-long prospective, observational, non-interventional, open-label study conducted in 997 centers in Hungary. RESULTS: Mean baseline office BP was 156.58 +/- 16.10/91.56 +/- 9.33 mmHg (mean +/- SD), whereas the mean duration of hypertension was 9.48 +/- 7.19 years. Mean office BP decreased by 24.81 +/- 15.47/11.41 +/- 9.90 mmHg after switching to the triple fixed combination of perindopril, indapamide, and amlodipine (p < 0.0001). At the final visit 45.1% of patients took the 5/1.25/5 mg, 33.5% of them 10/2.5/5 mg, and 21.4% of them 10/2.5/10 mg strength of the perindopril/indapamide/amlodipine triple fixed combination. The 24-h blood pressure was obtained in 76 subjects. The mean 24-h BP decreased from 155.51 +/- 17.43/85.28 +/- 11.48 to 134.63 +/- 12.51/77.83 +/- 8.99 mmHg (p < 0.0001). Statistically significant (p < 0.0001) and clinically relevant improvement of a number of metabolic parameters-including total cholesterol (-8.6%), LDL cholesterol (-11.4%), triglyceride (-12.1%), and fasting blood glucose (-6.6%) levels-was observed over the 3-month study period. CONCLUSIONS: During the 3 months of the PETRA study, the outstanding 24-h antihypertensive efficacy of the triple fixed combination of perindopril, indapamide, and amlodipine was confirmed both by office BP readings and by ABPM recordings. This combination may offer a new therapeutic option for hypertensive patients who have failed to achieve the desired BP target on their previous dual combination therapy. FUNDING: EGIS Pharmaceuticals PLC. PMID- 28646395 TI - Translocation of Trace Elements from Sewage Sludge Amendments to Plants in a Reclaimed Area. AB - The goal of the study was to evaluate bioaccumulation of trace elements in plants grown in post-mining soils amended with the biosolids material. Phaseolus vulgaris was investigated on the laboratory scale, and a mixture of grasses, Melilotus albus, Beta vulgaris, Zea mays L. and Miscanthus * giganteus were evaluated on the field scale. The results of the research showed that P. vulgaris fertilized with the Carbocrash substrate was able to grow. In addition, growth was enhanced following stimulation with gibberellic acid. Transfer of trace elements should be evaluated on the plot scale. Therefore, we monitored the level of trace elements on an experimental plot in a reclaimed area. Crops plants were sown in multi-year periods. During the growing season the mixture of grasses and crop plants had a low bioaccumulation factor, which also showed a positive effect of fertilization with the Carbocrash substrate. PMID- 28646396 TI - Enhanced Phytoextraction of Lead from Artificially Contaminated Soil by Mirabilis jalapa with Chelating Agents. AB - A microcosm experiment was conducted to compare how different chelating agents enhance the phytoextraction of lead (Pb) by Mirabilis jalapa from an artificially Pb-contaminated soil. Chelating agents used included ethylene diamine tetraacetic acid (EDTA), nitrilotriacetic acid (NTA), ethylene diamine disuccinic acid (EDDS), oxalic acid, humic acid, citric acid and tartaric acid, with concentrations ranging from 0 to 2000 mg/kg. Results show that with increasing concentrations of chelating agents, the concentrations, bioaccumulation coefficients, and translocation factors of Pb in M. jalapa gradually increased. Of all chelating agents used, the concentrations, bioaccumulation coefficients and translocation factors of Pb in M. jalapa were higher for EDTA and NTA than for the other chelating agents. Given the potential environmental risks of EDTA, we recommend NTA be used as a suitable chelating agent to increase the phytoremediation of Pb-contaminated soil with M. jalapa. PMID- 28646393 TI - The Changing Landscape of Alopecia Areata: The Therapeutic Paradigm. AB - Alopecia areata (AA), a prevalent inflammatory cause of hair loss, lacks FDA approved therapeutics for extensive cases, which are associated with very poor rates of spontaneous hair regrowth and major psychological distress. Current treatments for severe cases include broad immune-suppressants, which are associated with significant adverse effects, precluding long-term use, with rapid hair loss following treatment termination. As a result of the extent of the disease in severe cases, topical contact sensitizers and intralesional treatments are of limited use. The pathogenesis of AA is not yet fully understood, but recent investigations of the immune activation in AA skin reveal Th1/IFN-gamma, as well as Th2, PDE4, IL-23, and IL-9 upregulations. Tissue analyses of both animal models and human lesions following broad-acting and cytokine-specific therapeutics (such as JAK inhibitors and ustekinumab, respectively) provide another opportunity for important insights into the pathogenesis of AA. As reviewed in this paper, numerous novel therapeutics are undergoing clinical trials for AA, emphasizing the potential transformation of the clinical practice of AA, which is currently lacking. Dermatologists are already familiar with the revolution in disease management of psoriasis, stemming from better understanding of immune dysregulations, and atopic dermatitis will soon follow a similar path. In light of these recent developments, the therapeutic arena of AA treatments is finally getting more exciting. AA will join the lengthening list of dermatologic diseases with mechanism-targeted drugs, thus changing the face of AA. PMID- 28646397 TI - Concentrations of Environmental Chemicals in Urine and Blood Samples of Children from San Luis Potosi, Mexico. AB - Human biomonitoring (HBM) is an appreciated tool used to evaluate human exposure to environmental, occupational or lifestyle chemicals. Therefore, the aim of this study was to evaluate the exposure levels for environmental chemicals in urine and blood samples of children from San Luis Potosi, Mexico (SLP). This study identifies environmental chemicals of concern such as: arsenic (45.0 +/- 15.0 ug/g creatinine), lead (5.40 +/- 2.80 ug/dL), t,t-muconic acid (266 +/- 220 ug/g creatinine), 1-hydroxypyrene (0.25 +/- 0.15 umol/mol creatinine), PBDEs (28.0 +/- 15.0 ng/g lipid), and PCBs (33.0 +/- 16.0 ng/g lipid). On the other hand, low mercury (1.25 +/- 1.00 ug/L), hippuric acid (0.38 +/- 0.15 ug/g creatinine) and total DDT (130 +/- 35 ng/g lipid) exposure levels were found. This preliminary study showed the tool's utility, as the general findings revealed chemicals of concern. Moreover, this screening exhibited the need for HBM in the general population of SLP. PMID- 28646398 TI - The timing of bud break in warming conditions: variation among seven sympatric conifer species from Eastern Canada. AB - Phenological changes are expected with the ongoing global warming, which could create mismatches in the growth patterns among sympatric species or create synchrony with insect herbivores. In this study, we performed a comparative assessment of the timings of bud break among seven conifer species of Eastern Canada by evaluating seedling development in growth chambers under different temperatures (16, 20 and 24 degrees C). Bud break occurred earliest in Larix laricina, while Pinus strobus and Pinus resinosa had the latest. Warmer conditions advanced bud break, with the greatest effects being observed at the lower temperatures. Mixed models estimated that one additional degree of temperature produced advancements of 5.3 and 2.1 days at 16 and 20 degrees C, respectively. The hypothesis of an asynchronous change between species under warming was demonstrated only for the last phenological phases (split buds and exposed shoots), and principally in pines. Abies balsamea showed changes in bud break comparable with the other species analysed, rejecting the hypothesis of mismatches under warmer conditions. The observed non-linear responses of the timings of bud break to warming suggest that the major changes in bud phenology should be expected at the lowest temperatures. PMID- 28646399 TI - Mousetrap: An integrated, open-source mouse-tracking package. AB - Mouse-tracking - the analysis of mouse movements in computerized experiments - is becoming increasingly popular in the cognitive sciences. Mouse movements are taken as an indicator of commitment to or conflict between choice options during the decision process. Using mouse-tracking, researchers have gained insight into the temporal development of cognitive processes across a growing number of psychological domains. In the current article, we present software that offers easy and convenient means of recording and analyzing mouse movements in computerized laboratory experiments. In particular, we introduce and demonstrate the mousetrap plugin that adds mouse-tracking to OpenSesame, a popular general purpose graphical experiment builder. By integrating with this existing experimental software, mousetrap allows for the creation of mouse-tracking studies through a graphical interface, without requiring programming skills. Thus, researchers can benefit from the core features of a validated software package and the many extensions available for it (e.g., the integration with auxiliary hardware such as eye-tracking, or the support of interactive experiments). In addition, the recorded data can be imported directly into the statistical programming language R using the mousetrap package, which greatly facilitates analysis. Mousetrap is cross-platform, open-source and available free of charge from https://github.com/pascalkieslich/mousetrap-os . PMID- 28646400 TI - A brief assessment tool for investigating facets of moral judgment from realistic vignettes. AB - Humans make moral judgments every day, and research demonstrates that these evaluations are based on a host of related event features (e.g., harm, legality). In order to acquire systematic data on how moral judgments are made, our assessments need to be expanded to include real-life, ecologically valid stimuli that take into account the numerous event features that are known to influence moral judgment. To facilitate this, Knutson et al. (in Social Cognitive and Affective Neuroscience, 5(4), 378-384, 2010) developed vignettes based on real life episodic memories rated concurrently on key moral features; however, the method is time intensive (~1.4-3.4 h) and the stimuli and ratings require further validation and characterization. The present study addresses these limitations by: (i) validating three short subsets of these vignettes (39 per subset) that are time-efficient (10-25 min per subset) yet representative of the ratings and factor structure of the full set, (ii) norming ratings of moral features in a larger sample (total N = 661, each subset N = ~220 vs. Knutson et al. N = 30), (iii) examining the generalizability of the original factor structure by replicating it in a larger sample across vignette subsets, sex, and political ideology, and (iv) using latent profile analysis to empirically characterize vignette groupings based on event feature ratings profiles and vignette content. This study therefore provides researchers with a core battery of well characterized and realistic vignettes, concurrently rated on key moral features that can be administered in a brief, time-efficient manner to advance research on the nature of moral judgment. PMID- 28646401 TI - A standardized set of 3-D objects for virtual reality research and applications. AB - The use of immersive virtual reality as a research tool is rapidly increasing in numerous scientific disciplines. By combining ecological validity with strict experimental control, immersive virtual reality provides the potential to develop and test scientific theories in rich environments that closely resemble everyday settings. This article introduces the first standardized database of colored three-dimensional (3-D) objects that can be used in virtual reality and augmented reality research and applications. The 147 objects have been normed for name agreement, image agreement, familiarity, visual complexity, and corresponding lexical characteristics of the modal object names. The availability of standardized 3-D objects for virtual reality research is important, because reaching valid theoretical conclusions hinges critically on the use of well controlled experimental stimuli. Sharing standardized 3-D objects across different virtual reality labs will allow for science to move forward more quickly. PMID- 28646402 TI - A "spoon full of sugar" helps the medicine go down: How a participant friendly version of a psychophysics task significantly improves task engagement, performance and data quality in a typical adult sample. AB - Few would argue that the unique insights brought by studying the typical and atypical development of psychological processes are essential to building a comprehensive understanding of the brain. Often, however, the associated challenges of working with non-standard adult populations results in the more complex psychophysical paradigms being rejected as too complex. Recently we created a child- (and clinical group) friendly implementation of one such technique - the reverse-correlation Bubbles approach - and noted an associated performance boost in adult participants. Here, we compare the administration of three different versions of this participant-friendly task in the same adult participants to empirically confirm that introducing elements in the experiment with the sole purpose of improving the participant experience, not only boosts the participant's engagement and motivation for the task but results in a significantly improved objective task performance and stronger statistical results. PMID- 28646403 TI - Routine CT angiography to detect severe coronary artery disease prior to transcatheter aortic valve replacement. AB - Patients undergoing TAVR undergo routine CT angiography (CTA) to assess aorto iliac pathology and annular dimensions. While coronary CTA may exclude severe CAD in younger patients, its efficacy in defining CAD severity prior to TAVR may be limited. We retrospectively studied 50 consecutive patients undergoing both invasive coronary angiography (ICA) and routine pre-TAVR CTA. Severe CAD was defined as >=50% stenosis by quantitative coronary angiography and compared to a blinded CTA visual estimation of >=50% stenosis. The analysis was confined to four segments: left main and three proximal to mid major coronaries to maximize myocardial territory at risk. Coronary assessment was performed using standard reconstructed ECG phases from pre-TAVR chest CTA on a Philips 256 iCT scanner. Nearly 3/4 of patients were >=75 years old, 57% were female, half were diabetic and 45% had prior PCI. By ICA, 49% had significant coronary calcification. The incidence of severe proximal to mid vessel CAD by ICA was 39%. Similarly, a third of patients required PCI prior to TAVR. CTA was unable to exclude severe proximal to mid vessel CAD in 88% of patients in all four segments: non-diagnostic CTA readings were mainly due to calcification (60%) or motion artifact (28%). Non diagnostic coronary CTA readings ranged from 25 to 72% according to segment analyzed: only the left main segment had diagnostic quality CTA in the majority of patients (p < 0.01). PCI is performed frequently prior to TAVR based upon invasive coronary angiographic assessment. Routine chest CTA algorithms do not provide adequate diagnostic information to exclude severe CAD, primarily due to severe coronary calcification in the TAVR population. PMID- 28646404 TI - Latinas' Colorectal Cancer Screening Knowledge, Barriers to Receipt, and Feasibility of Home-Based Fecal Immunochemical Testing. AB - Latinas' high colorectal cancer (CRC) mortality makes them a priority population for CRC screening. CRC screening knowledge, perceived barriers, and feasibility of using the Fecal Immunochemical Test (FIT) was assessed among Latinas in Utah. Participants aged >=50 (n = 95) were surveyed about knowledge and barriers to CRC screening. 27 participants completed a FIT and evaluation survey. Fisher's exact tests assessed sociodemographic correlates of CRC screening outcomes. Most participants were overdue for CRC screening (n = 81, 85%). Age, acculturation, education, and employment were significantly associated with CRC screening status and/or reasons for being overdue (e.g., not knowing about the test, cost). All participants who received a FIT completed it, felt it was easy to use, and reported they would use it again. Latinas had limited awareness of CRC, CRC screenings, and experienced barriers to CRC screening (e.g., limited access, cost), but were willing to utilize a low-cost home-based FIT. PMID- 28646405 TI - Revealing the importance of linkers in K-series oxime reactivators for tabun inhibited AChE using quantum chemical, docking and SMD studies. AB - Inhibition of acetylcholinesterase (AChE) with organophosphorus compounds has a detrimental effect on human life. Oxime K203 seems to be one of the promising reactivators for tabun-inhibited AChE than (K027, K127, and K628). These reactivators differ only in the linker units between the two pyridinium rings. The conformational analyses performed with quantum chemical RHF/6-31G* level for K027, K127, K203 and K628 showed that the minimum energy conformers have different orientations of the active and peripheral pyridinium rings for these reactivator molecules. K203 with (-CH2-CH=CH-CH2-) linker unit possesses more open conformation compared to the other reactivators. Such orientation of K203 experiences favorable interaction with the surrounding residues of catalytic anionic site (CAS) and peripheral anionic site (PAS) of tabun-inhibited AChE. From the steered molecular dynamics simulations, it has been observed that the oxygen atom of the oxime group of K203 reactivator approaches nearest to the P atom of the SUN203 (3.75 A) at lower time scales (less than ~1000 ps) as compared to the other reactivators. K203 experiences less number of hydrophobic interaction with the PAS residues which is suggested to be an important factor for the efficient reactivation process. In addition, K203 crates large number of H-bonding with CAS residues SUN203, Phe295, Tyr337, Phe338 and His447. K203 barely changes its conformation during the SMD simulation process and hence the energy penalty to adopt any other conformation is minimal in this case as compared to the other reactivators. The molecular mechanics and Poisson-Boltzmann surface area binding energies obtained for the interaction of K203 inside the gorge of tabun inhibited AChE is substantially higher (-290.2 kcal/mol) than the corresponding K628 reactivator (-260.4 kcal/mol), which also possess unsaturated aromatic linker unit. PMID- 28646406 TI - Podocytes and the quest for precision medicines for kidney diseases. AB - In this review, I describe a 30-year journey in the quest for precision medicines for patients with kidney diseases. In 1987, when I started my reseach career, most scientists studying glomerular disease biology were focused on mesangial cells. The crucial role of the podocyte in many kidney diseases characterized by proteinuria, including focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, had not yet been recognized. We were not aware of genetic causes or drivers of kidney diseases nor of molecular markers and cell culture systems for mechanistic studies of podocyte biology. Tools for generating podocyte-specific knockout mice did not exist, and the key role of the podocyte actin cytoskeleton in the pathogenesis of proteinuria had not yet been identified. Clinically, treatment options for proteinuric kidney diseases were empiric, non-specific, and restricted to steroids and cyclosporine, without an understanding of their underlying mechanism of action. Since then, we have come a long way: a host of genetic causes for FSGS affecting podocytes has been identified, and with the advent of next generation sequencing approaches, the number of genetic causes continues to increase. Thinking "outside the box," empowered me to turn my attention to podocytes, develop the first differentiated podocyte cell culture system, and pioneer studies on the critical role of the podocyte actin cytoskeleton. Now, with the advent of iPSCs, we can build on these efforts by generating human podocytes and kidney organoids from patient cells, which, in combination with CRISPR-Cas9 gene editing and big data analyses, represent important next generation tools for bringing urgently needed precision medicines to patients with kidney disease. These new directions in kidney research should also increase the feasibility of much needed clinical trials in the kidney space. From Heidelberg to Boston, it has been an amazing scientific adventure. I will close with my thoughts about the path forward in making precision medicines for kidney diseases a reality. PMID- 28646407 TI - Associations of red and processed meat intake with major molecular pathological features of colorectal cancer. AB - Red and processed meat is an established risk factor for colorectal cancer (CRC). However, exact mechanisms to explain the associations remain unclear. Few studies have investigated the association with CRC by molecular tumor features, which could provide relevant information on associated molecular pathways. In this population-based case-control study from Germany (DACHS), 2449 cases and 2479 controls provided information on risk factors of CRC and completed a food frequency questionnaire. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between meat intake and risk of CRC by molecular pathologic features and specific subtypes. Red and processed meat intake was associated with increased risk of colorectal (>1 time/day vs <=1 time/week OR 1.66, 95% CI 1.34-2.07), colon and rectal cancer. Among the single molecular tumor features investigated, the results were similar for associations of red and processed meat with CRC risk by microsatellite instability, CpG island methylator phenotype, BRAF, oestrogen receptor-beta and p53 status. Red and processed meat intake was associated less strongly with risk of KRAS-mutated CRC (OR >1 time/day vs <=1 time/week: 1.49, 95% CI 1.09-2.03) than with risk of KRAS-wildtype CRC (OR 1.82, 95% CI 1.42-2.34; p heterogeneity 0.04). These results support an association between red and processed meat and CRC risk similar for subsites of CRC and most of the investigated major molecular pathological features. Potential differences were observed in more specific subtype analyses. Further large studies are needed to confirm these results and to help further elucidate potential underlying mechanisms. PMID- 28646408 TI - A Mechanism-Based PK/PD Model for Hematological Toxicities Induced by Antibody Drug Conjugates. AB - Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris(r), SGN-35) and adotrastuzumab emtansine (Kadcyla(r), T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia. Murine xenograft experiments and data from literature were combined, and the PK of both ADCs and their analytes were described with two-compartment models, with linear elimination and first-order payload release rate constants (k rel). ADC associated hematotoxicities were captured with a previously published PD model for myelosuppression driven by various analytes. ADC half-lives were about 5 days, and k rel values were 0.46 (T-DM1) and 0.12 h-1 (SGN-35). The lifespans of platelets following T-DM1 and neutrophils following SGN-35 were 3.73 and 4.72 days. Comparison of alternate model structures suggested that mechanisms of myelosuppression are payload-driven for SGN-35 and ADC pinocytosis-dependent for T-DM1. Model simulations suggested that a 4-fold increase (T-DM1) and 70% decrease (SGN-35) in k rel would improve hematotoxicity to grade 1. The proposed model successfully captured the PK and associated myelosuppression of both ADCs and might serve as a general PK/PD platform for assessing hematological toxicities to ADCs. PMID- 28646409 TI - Neuroprotective effects of G-CSF administration in microglia-mediated reactive T cell activation in vitro. AB - G-CSF is a growth factor that has known neuroprotective effects in a variety of experimental brain injury models. As both antigen-presenting microglia and reactive T cells are key components in the development and progression of EAE, the aim of this study is to investigate the neuroprotective effects of recombinant human G-CSF, as administered in microglia-mediated reactive T cell assay in vitro. Our results indicate that G-CSF treatment has no apparent effect for the resting un-activated microglia. G-CSF pre-protection of microglia increased protective cytokine IL-4 production and effectively inhibited the productions of NO and other inflammatory mediators (IFN-gamma, TNF-alpha, IL 1beta, IL-17, and chemokine MCP-1) after LPS stimulation. G-CSF suppressed the proliferative response of microglia-mediated MOG35-55 reactive T cells. G-CSF microglia-T cells increased IL-4 and IL-10 secretions and decreased IFN-gamma, TNF-alpha, and IL-17 productions. G-CSF significantly elevated CD4+CD25+ regulatory T cell subset in microglia-mediated reactive T cells. Moreover, G-CSF inhibited MHC-II expression of microglia after LPS activation or in the interactions of microglia and reactive T cells. G-CSF administration induced the apoptosis and enhanced the G0/G1 to S phase transition and elevated the gene expression of apoptosis markers in microglia-mediated reactive T cells after stimulated by specific antigen MOG35-55. These findings reveal that G-CSF administration potently neuroprotects the central nervous system (CNS) from immune-mediated damage in microglia-mediated reactive T cell activation. Apoptosis of reactive T cells in CNS is important in attenuating the development of autoimmune CNS diseases. G-CSF administration has neuroprotective effects in CNS and the potential to be a therapeutic agent in multiple sclerosis. PMID- 28646410 TI - Symbiont Spillover from Invasive to Native Woodwasps. AB - Hosts and their associated microbes are being increasingly introduced around the world, which can lead to novel host/microbe associations via new sympatries. Woodwasps (Hymenoptera: Siricidae) are able to utilize wood for its nutrients due to obligate mutualistic associations with white rot fungi in the genus Amylostereum and when invasive woodwasps are introduced to new areas, their symbionts accompany them. There is increasing evidence that woodwasp-fungus associations previously believed to be highly specific are actually flexible. We show that in North America, both Urocerus albicornis and Urocerus cressoni, which develop in trees in the Pinaceae, usually use Amylostereum chailletii but sometimes carry an Amylostereum areolatum strain putatively introduced to North America by the invasive woodwasp Sirex noctilio. Symbiont spillover from invasive to native hosts is a source of new host/introduced symbiont associations that could result in changes in microbes and host fitness with the potential to impact communities. PMID- 28646411 TI - Achievement of Glycated Hemoglobin Goals in the US Remains Unchanged Through 2014. AB - INTRODUCTION: Previous research has found that the percentage of US adults with diabetes achieving a glycated hemoglobin (HbA1c) target of <7.0% with currently available treatments has been fairly constant from 2003 to 2010, remaining at just over 50% [1]. The objective of this study was to compare the most recent data (2011-2014) with earlier data to track progress on HbA1c target achievement, for both the general target of <7.0% and inferred individualized targets based on age and the presence of complications. METHODS: Data from 2677 adults with self reported diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2014 were examined to determine the percentage of adults who achieved HbA1c targets of <7% and an individualized target based on age and comorbidities. National estimates are reported by using weights that account for the complex sampling design of the NHANES. RESULTS: The percentage of people with diabetes and HbA1c <7.0% slightly declined from 52.2% (95% CI 48.7-55.7%) to 50.9% (95% CI 47.2-54.7%) between the two most recent waves of data. Achievement of individualized targets declined from 69.8% (95% CI 66.5-73.0%) to 63.8% (95% CI 60.1-67.5%). The percentage with HbA1c >9.0% increased from 12.6% (95% CI 10.5 14.8%) to 15.5% (95% CI 12.9-18.2%). Achievement of individualized targets varied by age group and presence of comorbidities, but exhibited similar trends as general target achievement. CONCLUSIONS: Despite the development of many new medications to treat diabetes during the past decade, the proportion of patients achieving glycemic control targets has not improved. FUNDING: Intarcia Therapeutics. PMID- 28646412 TI - Efficacy of Additional Canagliflozin Administration to Type 2 Diabetes Patients Receiving Insulin Therapy: Examination of Diurnal Glycemic Patterns Using Continuous Glucose Monitoring (CGM). AB - INTRODUCTION: The efficacy of administering a sodium-glucose cotransporter 2 inhibitor during insulin therapy has not been established. In this study, we examined its effects based on diurnal glycemic patterns using continuous glucose monitoring (CGM). METHODS: The subjects were 15 patients who had received insulin therapy for 1 year or more. A CGM device was attached to all subjects for 1 week. The administration of canagliflozin at 100 mg was started 4 days after attachment. The mean glucose concentrations, standard deviation (SD), mean amplitude of glycemic excursions (MAGE), mean of daily difference of blood glucose (MODD), and area under the curve (AUC) (>=180, <70 mg h/dL) after the start of administration were compared with the pretreatment values. In addition, we compared changes in the number of insulin units between basal and bolus insulin. Furthermore, we investigated the influence of canagliflozin on oxidative stress markers and cytokines using 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor-alpha (TNF-alpha), and adiponectin as parameters. RESULTS: The mean glucose concentrations decreased from 161.1 to 139.1 mg/dL (P < 0.01). The SD decreased from 36.5 to 29.6 mg/dL (P = 0.05). The MAGE decreased from 89.2 to 77.4 mg/dL (P < 0.01), and the MODD decreased from 34.3 to 25.5 mg/dL (P < 0.05). All parameters showed significant improvements in diurnal changes. AUC of >=180, i.e., the total area of blood glucose levels at or above 180 on the blood glucose curve of CGM, decreased from 339.1 to 113.6 mg/dL (P < 0.05). AUC of <70, i.e., the total area of blood glucose levels below 70 on the blood glucose curve of CGM, slightly decreased from 1.6 to 0.3 mg/dL (P = 0.08). The total number of basal insulin units decreased from 128 to 76, and that of bolus insulin decreased from 266 to 154; the dose of insulin could be markedly decreased. In addition, the mean 8-OHdG level decreased from 11.4 to 10.8 ng/mg Cre (P < 0.05), and the mean TNF-alpha level decreased from 2.31 to 1.79 pg/mL (P = 0.10). The mean adiponectin level increased from 5.01 to 5.53 MUg/mL (P < 0.05). CONCLUSION: Canagliflozin improved blood glucose changes in type 2 diabetes using insulin. In addition, the results suggest its antioxidant actions. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN no. 000019429). PMID- 28646413 TI - Integrated In Silico-In Vitro Identification and Characterization of the SH3 Mediated Interaction between Human PTTG and its Cognate Partners in Medulloblastoma. AB - The human pituitary tumor-transforming gene is an oncogenic protein which serves as a central hub in the cellular signaling network of medulloblastoma. The protein contains two vicinal PxxP motifs at its C terminus that are potential binding sites of peptide-recognition SH3 domains. Here, a synthetic protocol that integrated in silico analysis and in vitro assay was described to identify the SH3-binding partners of pituitary tumor-transforming gene in the gene expression profile of medulloblastoma. In the procedure, a variety of structurally diverse, non-redundant SH3 domains with high gene expression in medulloblastoma were compiled, and their three-dimensional structures were either manually retrieved from the protein data bank database or computationally modeled through bioinformatics technique. The binding capability of these domains towards the two PxxP-containing peptides m1p: 161LGPPSPVK168 and m2p: 168KMPSPPWE175 of pituitary tumor-transforming gene were ranked by structure-based scoring and fluorescence based assay. Consequently, a number of SH3 domains, including MAP3K and PI3K, were found to have moderate or high affinity for m1p and/or m2p. Interestingly, the two overlapping peptides exhibits a distinct binding profile to these identified domain partners, suggesting that the binding selectivity of m1p and m2p is optimized across the medulloblastoma expression spectrum by competing for domain candidates. In addition, two redesigned versions of m1p peptide ware obtained via a structure-based rational mutation approach, which exhibited an increased affinity for the domain as compared to native peptide. PMID- 28646415 TI - IFSO 2017 22nd World Congress. PMID- 28646414 TI - Dynamic Meso-Scale Anchorage of GPI-Anchored Receptors in the Plasma Membrane: Prion Protein vs. Thy1. AB - The central mechanism for the transmission of the prion protein misfolding is the structural conversion of the normal cellular prion protein to the pathogenic misfolded prion protein, by the interaction with misfolded prion protein. This process might be enhanced due to the homo-dimerization/oligomerization of normal prion protein. However, the behaviors of normal prion protein in the plasma membrane have remained largely unknown. Here, using single fluorescent-molecule imaging, we found that both prion protein and Thy1, a control glycosylphosphatidylinositol-anchored protein, exhibited very similar intermittent transient immobilizations lasting for a few seconds within an area of 24.2 and 3.5 nm in diameter in CHO-K1 and hippocampal neurons cultured for 1- and 2-weeks, respectively. Prion protein molecules were immobile during 72% of the time, approximately 1.4* more than Thy1, due to prion protein's higher immobilization frequency. When mobile, prion protein diffused 1.7* slower than Thy1. Prion protein's slower diffusion might be caused by its transient interaction with other prion protein molecules, whereas its brief immobilization might be due to temporary association with prion protein clusters. Prion protein molecules might be newly recruited to prion protein clusters all the time, and simultaneously, prion protein molecules in the cluster might be departing continuously. Such dynamic interactions of normal prion protein molecules would strongly enhance the spreading of misfolded prion protein. PMID- 28646416 TI - Assessing Preference-Based Outcome Measures for Overactive Bladder: An Evaluation of Patient-Reported Outcome Data from the BESIDE Clinical Trial. AB - OBJECTIVES: The aim of this study was to compare outcomes using two preference based measures of health status (EQ-5D-5L and OAB-5D) in patients with overactive bladder (OAB) treated with solifenacin plus mirabegron or solifenacin monotherapy in the BESIDE trial. METHODS: Patients with OAB who remained incontinent after 4 weeks' treatment with solifenacin 5 mg were randomized 1:1:1 to combination treatment (solifenacin 5 mg plus mirabegron [25 mg for the first 4 weeks/50 mg for the last 8 weeks]), solifenacin 5 mg, or solifenacin 10 mg. EQ-5D-5L and OAB q were administered at baseline, weeks 4, 8, 12, and end of treatment (EoT). OAB 5D scores were derived from OAB-q results. Responder analysis was carried out using several definitions of minimally important difference. RESULTS: A total of 2054 patients received one or more doses of study treatment (combination, n = 694; solifenacin 5 mg, n = 684; solifenacin 10 mg, n = 676). EQ-5D-5L Index mean score changes (from baseline to EoT) were greater with combination (0.059) than with solifenacin 5 mg (0.040) and 10 mg (0.044) monotherapy, but the differences were not statistically significant. A significantly greater improvement was observed for combination on OAB-5D (0.107 vs 0.085 for 5 mg, and 0.087 for 10 mg; p <= 0.01). The dimensions most improved overall were anxiety/depression, pain/discomfort, and usual activities on EQ-5D-5L, and urge, urine loss, and coping on OAB-5D. The proportion of responders was significantly greater with combination compared with monotherapy using OAB-5D only. CONCLUSIONS: Improvements were observed in all study arms on both the EQ-5D-5L and OAB-5D, although only the OAB-5D showed a statistically significant benefit for combination versus solifenacin monotherapy. Combining generic and condition specific preference-based health status measures allowed for assessment of dimensions that were particularly relevant to this patient population, while permitting comparison with outcomes from other studies, treatments, and populations via EQ-5D. PMID- 28646417 TI - Mesenchymal stem cell therapy for acute and chronic pancreatitis. AB - Mesenchymal stem cells (MSCs) have attracted attention as a cell source for regenerative medicine. In particular, MSCs have an anti-inflammatory effect by secreting several kinds of bioactive molecules. MSC therapy is now being applied to various gastrointestinal diseases, such as graft-versus-host disease, inflammatory bowel disease, and liver cirrhosis. Therefore, MSC therapy has the potential to be a novel treatment for acute and chronic pancreatitis by suppressing inflammation. Several studies have investigated the effect of MSC therapy on acute and chronic pancreatitis, but the underlying mechanisms remain unknown. In this review, we summarize the present status of MSC therapy for acute and chronic pancreatitis. PMID- 28646418 TI - In vivo NMR as a tool for probing molecular structure and dynamics in intact Chlamydomonas reinhardtii cells. AB - We report the application of NMR dynamic spectral editing for probing the structure and dynamics of molecular constituents in fresh, intact cells and in freshly prepared thylakoid membranes of Chlamydomonas reinhardtii (Cr.) green algae. For isotope labeling, wild-type Cr. cells were grown on 13C acetate enriched minimal medium. 1D 13C J-coupling based and dipolar-based MAS NMR spectra were applied to distinguish 13C resonances of different molecular components. 1D spectra were recorded over a physiological temperature range, and whole-cell spectra were compared to those taken from thylakoid membranes, evaluating their composition and dynamics. A theoretical model for NMR polarization transfer was used to simulate the relative intensities of direct, J coupling, and dipolar-based polarization from which the degree of lipid segmental order and rotational dynamics of the lipid acyl chains were estimated. We observe that thylakoid lipid signals dominate the lipid spectral profile of whole algae cells, demonstrating that with our novel method, thylakoid membrane characteristics can be detected with atomistic precision inside intact photosynthetic cells. The experimental procedure is rapid and applicable to fresh cell cultures, and could be used as an original approach for detecting chemical profiles, and molecular structure and dynamics of photosynthetic membranes in vivo in functional states. PMID- 28646419 TI - Repetition blindness in priming in perceptual identification: Competitive effects of a word intervening between prime and target. AB - University students named a 72-ms masked target word that was preceded by two 120 ms consecutively presented words, a prime word followed by a distractor. In Experiment 1, all words were in lowercase letters, whereas in Experiment 2, the target word was changed to uppercase letters. In both experiments there was an accuracy and latency cost (repetition blindness: RB) when the prime was the same word as the target, with the cost much less severe in Experiment 2 than in Experiment 1. A low-frequency distractor impaired target identification compared with a high-frequency distractor. Distractor frequency interacted with target frequency such that high-frequency targets preceded by low-frequency distractors had the lowest accuracy. The results are consistent with a frequency-dependent competition for access to working memory among briefly displayed words. However, there was no clear evidence that effects of target repetition on interword competition play a role in RB. The effects of a letter case change for the target are consistent with a contribution of token distinctiveness to word-order recovery in the intervening-word priming task. PMID- 28646420 TI - Composite reverse shoulder arthroplasty can provide good function and quality of life in cases of malignant tumour of the proximal humerus. AB - PURPOSE: Management of proximal humeral tumours remains a surgical challenge. No study to date has assessed the quality of life scores following the composite reverse shoulder arthroplasty for this indication. We, therefore, evaluated function and quality of life following reconstruction with allograft for malignant tumour of the humerus. METHODS: A series of six cases of humeral tumour treated by a single surgeon in a single centre was reviewed after a mean follow up of 5.9 years. The tumours included two chondrosarcomas, one plasmocytoma and three metastases. Resection involved bone epiphysis, metaphysis and diaphysis in five cases (S3S4S5A) and epiphysis and metaphysis in one case (S3S4A). For reconstruction, an allograft composite reverse shoulder arthroplasty was used in all the cases. Outcomes were assessed with range of motion, the QuickDash score and the Short Form 12 (SF-12) Health Survey. Radiographs assessed osseointegration and complications. RESULTS: At the final follow-up, the mean shoulder range of motion were respectively 95 degrees , 57 degrees and 11 degrees for forward flexion, abduction and external rotation. Mean QuickDASH score improved from 28 to 41 and VAS-pain scores improved from 5.1 to 2.3. The post-operative MSTS score was 73% and the Constant score was 46.1/100. The SF-12 PCS and MCS scores were also improved, respectively from 44.4 and 39.7 to 45.5 and 56.1. The mean satisfaction score was 8.1/10. CONCLUSIONS: Composite reverse shoulder arthroplasty is a viable alternative for reconstruction after resection of malignant humeral tumour. Although total tumour resection was the most important objective, the functional and quality of life scores were satisfactory. PMID- 28646421 TI - How safe and effective is denosumab for bone giant cell tumour? AB - Recent clinical studies have suggested that denosumab is associated with beneficial tumour response, surgical down-staging, and reduced surgical morbidity in patients with giant cell tumour of bone. However, these studies reported results of patients still on denosumab treatment, or patients after denosumab treatment but with a short follow-up. Other studies reported that the new osseous tumour matrix and thickened cortical bone that develop with denosumab treatment does not allow the surgeon to delineate the true extent of the tumour, and probably increases the risk for local recurrence. A study showed that cell proliferation is only diminished by denosumab; the cells continue to proliferate in vitro, albeit at a slower rate. More importantly, nine cases of malignant transformation of GCT during denosumab therapy without previous radiation exposure have been reported; inhibition of RANKL may increase the risk of new malignancies due to immunosuppression. With these concerns in mind, this article is an attempt to put essential information in one place, creating a comprehensive review that the curious reader would find interesting and informative. PMID- 28646422 TI - How to avoid and to manage post-operative complications in thyroid surgery. AB - Complications of thyroidectomy are hypoparathyroidism, recurrent laryngeal nerve palsy, and hemorrhage. These complications have a low incidence. Hypoparathyroidism is the most frequent complication of total thyroidectomy. Its incidence varies between 0.5 and 65%. This complication is also visible after reoperation for recurrent disease and in patients previously treated with radioiodine. Damage to the recurrent laryngeal nerve can be temporary or permanent, unilateral or bilateral. The bilateral lesion, associated with severe episodes of breathlessness, is a rare complication (0.4%). Intraoperative control of nerves is crucial to prevent damage. The hematoma creates an obstacle to venous and lymphatic flow and consequently breathing difficulties. The preventive hemostasis during surgery is important. Therapeutic treatment is described. PMID- 28646423 TI - Updates in primary hyperparathyroidism. AB - This is a review of the latest papers on PHPT with the purpose of assessing the most recent evidence in the management of PHPT and to give updated recommendations for its evaluation, diagnosis, and treatment. I used my personal experience to collect papers that reinforce my ideas for the diagnosis and treatment of PHPT. Perhaps, in the near future, we will have more information about genetics, localization studies, surgical techniques, medical treatments, and statements that we have presented today will be obsolete. PMID- 28646424 TI - Proteasome properties of hemocytes differ between the whiteleg shrimp Penaeus vannamei and the brown shrimp Crangon crangon (Crustacea, Decapoda). AB - Crustaceans are intensively farmed in aquaculture facilities where they are vulnerable to parasites, bacteria, or viruses, often severely compromising the rearing success. The ubiquitin-proteasome system (UPS) is crucial for the maintenance of cellular integrity. Analogous to higher vertebrates, the UPS of crustaceans may also play an important role in stress resistance and pathogen defense. We studied the general properties of the proteasome system in the hemocytes of the whiteleg shrimp, Penaeus vannamei, and the European brown shrimp Crangon crangon. The 20S proteasome was the predominant proteasome population in the hemocytes of both species. The specific activities of the trypsin-like (Try like), chymotrypsin-like (Chy-like), and caspase-like (Cas-like) enzymes of the shrimp proteasome differed between species. P. vannamei exhibited a higher ratio of Try-like to Chy-like activities and Cas-like to Chy-like activities than C. crangon. Notably, the Chy-like activity of P. vannamei showed substrate or product inhibition at concentrations of more than 25 mmol L-1. The K M values ranged from 0.072 mmol L-1 for the Try-like activity of P. vannamei to 0.309 mmol L-1 for the Cas-like activity of C. crangon. Inhibition of the proteasome of P. vannamei by proteasome inhibitors was stronger than in C. crangon. The pH profiles were similar in both species. The Try-like, Chy-like, and Cas-like sites showed the highest activities between pH 7.5 and 8.5. The proteasomes of both species were sensitive against repeated freezing and thawing losing ~80-90% of activity. This study forms the basis for future investigations on the shrimp response against infectious diseases, and the role of the UPS therein. PMID- 28646426 TI - Eftrenonacog Alfa: A Review in Haemophilia B. AB - Eftrenonacog alfa (AlprolixTM) is a recombinant fusion protein comprising human factor IX (FIX) covalently linked to the constant region (Fc) domain of human IgG1 (i.e. rFIXFc). The presence of the Fc domain extends the terminal half-life (t1/2) of rFIXFc, permitting prolonged treatment intervals. rFIXFc is available for intravenous use for the prophylaxis and treatment of bleeding in patients with haemophilia B. In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, rFIXFc prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens. Preliminary data from an extension of both studies indicated sustained efficacy, as demonstrated by low median ABRs, with longer term rFIXFc prophylaxis. rFIXFc was also effective in the treatment of bleeding episodes and when used in the perioperative setting in all age groups. rFIXFc was well tolerated in clinical studies in previously treated patients, with the majority of treatment-emergent adverse events considered to be unrelated to rFIXFc; there were no reports of inhibitor development. In conclusion, rFIXFc provides an effective alternative to plasma-derived and recombinant FIX products for the management of patients with haemophilia B, with its extended t1/2 permitting a less frequent administration schedule and potentially providing a prolonged protective haemostatic effect, which eases the treatment burden on the patient. PMID- 28646425 TI - Hydroxylamine-induced oxidation of ferrous carbonylated truncated hemoglobins from Mycobacterium tuberculosis and Campylobacter jejuni is limited by carbon monoxide dissociation. AB - Hydroxylamine (HA) is an oxidant of ferrous globins and its action has been reported to be inhibited by CO, even though this mechanism has not been clarified. Here, kinetics of the HA-mediated oxidation of ferrous carbonylated Mycobacterium tuberculosis truncated hemoglobin N and O (Mt-trHbN(II)-CO and Mt trHbO(II)-CO, respectively) and Campylobacter jejuni truncated hemoglobin P (Cj trHbP(II)-CO), at pH 7.2 and 20.0 degrees C, are reported. Mixing Mt-trHbN(II) CO, Mt-trHbO(II)-CO, and Cj-trHbP(II)-CO solution with the HA solution brings about absorption spectral changes reflecting the disappearance of the ferrous carbonylated derivatives with the concomitant formation of the ferric species. HA oxidizes irreversibly Mt-trHbN(II)-CO, Mt-trHbO(II)-CO, and Cj-trHbP(II)-CO with the 1:2 stoichiometry. The dissociation of CO turns out to be the rate-limiting step for the oxidation of Mt-trHbN(II)-CO, Mt-trHbO(II)-CO, and Cj-trHbP(II)-CO by HA. Values of the second-order rate constant for HA-mediated oxidation of Mt trHbN(II)-CO, Mt-trHbO(II)-CO, and Cj-trHbP(II)-CO range between 8.8 * 104 and 8.6 * 107 M-1 s-1, reflecting different structural features of the heme distal pocket. This study (1) demonstrates that the inhibitory effect of CO is linked to the dissociation of this ligand, giving a functional basis to previous studies, (2) represents the first comparative investigation of the oxidation of ferrous carbonylated bacterial 2/2 globins belonging to the N, O, and P groups by HA, (3) casts light on the correlation between kinetics of HA-mediated oxidation and carbonylation of globins, and (4) focuses on structural determinants modulating the HA-induced oxidation process. PMID- 28646427 TI - Tanshinone IIA Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice Infected with Porphyromonas gingivalis. AB - Tanshinone IIA (TSA), a pharmacologically active component isolated from Danshen, may prevent cardiovascular diseases due to its anti-inflammatory, anti-oxidative, and anti-adipogenic effects. Porphyromonas gingivalis, a major periodontal pathogen, may contribute to the progression of atherosclerosis. Here, we studied the effects of TSA on atherosclerosis in ApoE-/- mice with P. gingivalis infection. Eight-week-old ApoE-/- mice were randomized to (a) phosphate-buffered saline (PBS), (b) P. gingivalis, and (c) P. gingivalis + TSA (60 mg kg-1 day-1). The mice were injected with (a) PBS, or (b) and (c) P. gingivalis 3 times per week for a total of 10 times. After 8 weeks, atherosclerotic risk factors in serum and in heart, aorta, and liver tissues were analyzed in all mice using Oil Red O, atherosclerosis cytokine antibody arrays, enzyme-linked immunosorbent assay (ELISA), real-time PCR, and microRNA array. CD40, G-CSF, IFN-gamma, interleukin (IL)-1beta, IL-6, MCP-1, MIP-3alpha, tumor necrosis factor-alpha (TNF alpha), and VEGF were attenuated by TSA in atherosclerosis cytokine antibody arrays. TSA-treated mice showed a significant reduction of C-reactive protein (CRP), ox-LDL, IL-1beta, IL-6, IL-12, and TNF-alpha in ELISA data. Real-time PCR analyses showed that TSA decreased the expression of CCL-2, CD40, IL-1beta, IL-6, TNF-alpha, and MMP-2 in heart and aorta tissues. Moreover, hepatic CRP was downregulated by TSA, although FASN and HMG-CoA were not. The relative expressions of miR-146b and miR-155 were elevated by P. gingivalis infection and were downregulated by TSA treatment. These results suggest that TSA was a potential therapeutic agent that may have the ability to prevent P. gingivalis induced atherosclerosis associated with anti-inflammatory and anti-oxidative effects. PMID- 28646428 TI - Effects of Carvacrol on Survival, Mesenteric Blood Flow, Aortic Function and Multiple Organ Injury in a Murine Model of Polymicrobial Sepsis. AB - Carvacrol (CRV) has strong cytoprotective, antioxidant, and anti-inflammatory properties. We aimed to demonstrate the possible protective effects of CRV on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wistar rats were allocated into the following four groups: Sham, CLP, Sham + CRV, and CLP + CRV. The animals were orally administered with CRV (80 mg/kg/day) or vehicle (corn oil; 1 mL/kg/day) for 7 days. At the eighth day, Sham or CLP procedure was applied. Twenty hours after the operations, MBF and contractile responses of isolated aortic preparations to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological assessments. Additionally, survival rates were recorded throughout 96 h. CRV administration improved the mesenteric perfusion, contractile function of aorta, and survival after CLP. CRV substantially prevented the elevations in the levels of LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) but could not prevent the elevations of AST and ALT after CLP. The decreased liver, kidney, and spleen glutathione levels and increased liver, kidney, lung, and spleen malondialdehyde levels induced by CLP were substantially restored by CRV. Also, histopathological protective effects of CRV on multiple organ damage due to CLP were observed. CRV possesses strong ameliorative effects on sepsis due to its protective effects on mesenteric perfusion and aortic function and its antioxidative and anti-inflammatory effects. PMID- 28646429 TI - Decoupled side chain and backbone dynamics for proton translocation - M2 of influenza A. AB - The 97 amino acid bitopic membrane protein M2 of influenza A forms a tetrameric bundle in which two of the monomers are covalently linked via a cysteine bridge. In its tetrameric assembly the protein conducts protons across the viral envelope and within intracellular compartments during the infectivity cycle of the virus. A key residue in the translocation of the protons is His-37 which forms a planar tetrad in the configuration of the bundle accepting and translocating the incoming protons from the N terminal side, exterior of the virus, to the C terminal side, inside the virus. With experimentally available data from NMR spectroscopy of the transmembrane domains of the tetrameric M2 bundle classical MD simulations are conducted with the protein bundle in different protonation stages in respect to His-37. A full correlation analysis (FCA) of the data sets with the His-37 tetrad either in a fully four times unprotonated or protonated state, assumed to mimic high and low pH in vivo, respectively, in both cases reveal asymmetric backbone dynamics. His-37 side chain rotation dynamics is increased at full protonation of the tetrad compared to the dynamics in the fully unprotonated state. The data suggest that proton translocation can be achieved by decoupled side chain or backbone dynamics. Graphical abstract Visualization of the tetrameric bundle of the transmembrane domains of M2 of influenza A after 200 ns of MD simulations (upper left). The four histidine residues 37 are either not protonated as in M20 or fully protonated is in M24+. The asymmetric dynamics of the backbones are shown after a full correlation analysis (FCA) in blue (lower left). The rotational dynamics of the chi2 dihedral angles of the histidines in M20 (upper right) are less than those in M24+ (lower right). PMID- 28646430 TI - Mechanical strength assessment of a drilled hole in the contralateral cortex at the end of the open wedge for high tibial osteotomy. AB - BACKGROUND: This study aimed to investigate, by means of finite element analysis, the effect of a drill hole at the end of a horizontal osteotomy to reduce the risk of lateral cortex fracture while performing an opening wedge high tibial osteotomy (OWHTO). The question was whether drilling a hole relieves stress and increases the maximum correction angle without fracture of the lateral cortex depending on the ductility of the cortical bone. METHODS: Two different types of osteotomy cuts were considered; one with a drill hole (diameter 5 mm) and the other without the hole. The drill holes were located about 20 mm distally to the tibial plateau and 6 mm medially to the lateral cortex, such that the minimal thickness of the contralateral cortical bone was 5 mm. Based on finite element calculations, two approaches were used to compare the two types of osteotomy cuts considered: (1) Assessing the static strength using local stresses following the idea of the FKM-guideline, subsequently referred to as the "FKM approach" and (2) limiting the total strain during the opening of the osteotomy wedge, subsequently referred to as "strain approach". A critical opening angle leading to crack initiation in the opposite lateral cortex was determined for each approach and was defined as comparative parameter. The relation to bone aging was investigated by considering the material parameters of cortical bones from young and old subjects. RESULTS: The maximum equivalent (von-Mises) stress was smaller for the cases with a drill hole at the end of the osteotomy cut. The critical angle was approximately 1.5 times higher for the specimens with a drill hole compared to those without. This corresponds to an average increase of 50%. The calculated critical angle for all approaches is below 5 degrees . The critical angle depends on the used approach, on patient's age and assumed ductility of the cortical bone. CONCLUSIONS: Drilling a hole at the end of the osteotomy reduces the stresses in the lateral cortex and increases the critical opening angle prior to cracking of the opposite cortex in specimen with small correction angles. But the difference from having a drill hole or not is not so significant, especially for older patients. The ductility of the cortical bone is the decisive parameter for the critical opening angle. PMID- 28646431 TI - A protracted infectious swelling on the neck. PMID- 28646432 TI - Asynchronus bilateral ovarian torsions in girls-systematic review. AB - BACKGROUND: Bilateral ovarian torsions with complete loss of ovaries is devastating. This study analyzed the literature on bilateral ovarian torsions in girls to evaluate surgical options and outcomes. METHODS: Literature was searched on Pubmed(r) (1987-2014) using terms "bilateral", "adnexal", "ovary", "torsion" and "children". Data were collected on age, surgical preference, pathology and outcomes. RESULTS: Thirteen articles were identified, and 9 met the inclusion criteria (5 case reports, 4 original articles); and analyzed 17 girls (mean age: 8.75 years, range: 1-16). Bilateral oophorectomies (n=4), ipsilateral oophorectomy of severely affected ovary and contralateral oophoropexy (n=10), and detorsion of bilateral ovaries and bilateral oophoropexy (n=3) were performed. One torsion recurrence occurred after two oophoropexies. Laparoscopy and open surgery was done in 2 and 15 girls, respectively. Considering etiology, there were simple tubo-ovarian torsions (n=8), polycystic ovary (n=1), polycystic ovary associated with Down syndrome (n=1) and corpus luteum cyst (n=1). No tumors were reported. Serial ultrasound follow-ups of ipsilateral oophorectomy and contralateral oophoropexy (n=5) confirmed follicular function (n=4) and viability and position of the ovary (n=1). CONCLUSIONS: Though extremely rare, school age girls present bilateral ovarian torsion. Ipsilateral oophorectomy and contralateral detorsion with oophoropexy has been the preferred approach. PMID- 28646433 TI - Oxcarbazepine oral suspension in pediatric patients with partial seizures and/or generalized tonic-clonic seizures: a multi-center, single arm, observational study in China. AB - BACKGROUND: To assess efficacy and safety of oxcarbazepine (OXC) oral suspension in pediatric patients aged 2-16 years with partial seizures (PS) and/or generalized tonic-clonic seizures (GTCS) in real-world clinical practice in China. METHODS: This 26-week, single arm, multicenter and observational study recruited patients aged 2-16 years with PS or GTCS suitable for OXC oral suspension treatment. Enrolled patients received OXC oral suspension treatment for 26 weeks. Primary endpoints included mean seizure frequency at the end of the treatment and mean seizure frequency reduction at the end of the treatment vs. baseline. Secondary efficacy-related endpoints and safety parameters were also assessed. RESULTS: Nine hundred and eighty-seven pediatric patients were enrolled and 912 (92.4%) completed the study. The mean seizure frequencies at baseline and the end of week 26 were 13.40+/-64.92 and 1.62+/-19.47 times/ month, respectively. The mean seizure frequency reduction was 10.03+/-63.67 times/month and the mean seizure frequency reduction percentage was 90.02%+/-5127.0% (P<0.0001). After 26 weeks of treatment, 82.36%, 7.24% and 3.86% of the patients became controlled, significantly improved and improved, respectively. Adverse events (AEs) were reported in 74 (7.65%) patients. Rash was the most common AE. The efficacy of OXC was not affected by seizure types, age or gender. CONCLUSIONS: This study confirms the efficacy and good safety profile of OXC oral suspension in Chinese pediatric patients aged 2-16 years with PS and/or GTCS. PMID- 28646434 TI - Performance of QuantiFERON(r)-TB Gold In-Tube assay in children receiving disease modifying anti-rheumatic drugs. AB - BACKGROUND: To evaluate the performance of the Quantiferon(r)-TB Gold In-Tube (QFT-IT) interferon (IFN)-gamma assay for the detection of latent tuberculosis infection (LTBI) in children receiving anti-rheumatic treatment in a tertiary referral hospital of Northern Greece. METHODS: A total of 79 consecutive children receiving anti-rheumatic treatment [of which 18 screened prior to antitumor necrosis factor (TNF)-alpha treatment] were tested using Mantoux tuberculin skin test (TST) and QFT-IT. Association of both tests with risk factors for latent tuberculosis and Bacillus Calmette-Guerin immunization was determined. Influence of age, TNF-alpha inhibitors, systemic corticosteroids, conventional disease modifying anti-rheumatic drugs (DMARDs) and total duration of therapy on the QFT IT mitogen-induced response was evaluated. RESULTS: Agreement between TST and QFT IT results was moderate (k=0.38). Frequency of QFT-IT indeterminate results was low (2.5%). In patients with risk factors for LTBI, the odds of a positive IFN gamma assay was increased by a factor of 27.6 (P=0.002), whereas there was no positive TST. There was a significant difference in the mitogen-induced IFN-gamma secretion among various treatments (P=0.038). TNF-alpha inhibitors were associated with increased mitogen-induced IFN-gamma secretion compared to monotherapy with conventional DMARDs (P=0.008). All children screened prior to anti-TNF-alpha treatment exhibited a negative QFT-IT and no active TB disease was detected during a 2-year follow-up. CONCLUSIONS: QFT-IT may be a more reliable test than TST for detection of LTBI in children with rheumatic diseases receiving anti-rheumatic treatment. Drug regimen might influence the mitogen-induced IFN gamma secretion and the effect of TNF-alpha inhibitors might vary according to the specific agent administered. PMID- 28646435 TI - Eco-friendly synthesis of silver nanoparticles using green algae (Caulerpa serrulata): reaction optimization, catalytic and antibacterial activities. AB - Stable colloidal silver nanoparticles (AgNPs) were synthesized using Caulerpa serrulata (green marine algae) aqueous extract as an efficient reducing and stabilizing agent. This method is considered to be a sustainable alternate to the more complicated chemical procedures. To achieve the optimization synthesis of AgNPs, several effects such as extract concentration, contact time, pH values, and temperature were examined. The synthesized AgNPs were characterized by UV-Vis spectroscopy, FT-IR, XRD, and HR-TEM. The synthesized AgNPs showed an intense surface plasmon resonance band at 412 nm at the optimal conditions (20% (v/v) extract and 95 degrees C). TEM reveal that higher extract concentration and higher temperature leading to the formation of spherical AgNPs with an average particle size of 10 +/- 2 nm. The synthesized AgNPs showed excellent catalytic reduction activity of Congo red (CR) dye from aqueous solutions. The degradation percentage of CR with AgNPs accelerated by increasing either NaBH4 concentration or catalytic dosage. The AgNPs synthesized at higher temperature (e.g., 10Ag-95) exhibited the highest catalytic activity. The reaction kinetics was found to be pseudo first order with respect to the dye concentration. Moreover, the AgNPs displayed antibacterial activity at lower concentration against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella sp., Salmonella typhi, and Escherichia coli and may be a good alternative therapeutic approach. The outcomes of the current study confirmed that the synthesized AgNPs had an awesome guarantee for application in catalysis and wastewater treatment. PMID- 28646436 TI - Behavior of fluopyram and tebuconazole and some selected pesticides in ripe apples and consumer exposure assessment in the applied crop protection framework. AB - The supervised field trials were conducted in a commercial apple orchard in 2016. The trials were an attempt to determine a model for dissipation and toxicological evaluation of fluopyram, tebuconazole, captan, tetrahydrophthalimide (THPI), pirimicarb, spirodiclofen, and boscalid residues detected in fruit of Red Jonaprince, Lobo, and Gala varieties immediately before harvest. The analysis also covered amounts of pesticides still present in remnants of calyx in Lobo and Gala varieties immediately before harvest. Laboratory samples of ripe apples were collected within 14 days of the treatment. Levels of pesticide residues detected in the samples changed at a constant exponential rate, and the residue levels found in ripe apples of Red Jonaprince, Gala, and Lobo varieties immediately before harvest were below maximum residue levels (MRL). Overall, captan residues in remnants of calyx were at a level of 22.3% for the Gala variety and 9.3% for the Lobo variety. Likewise, the long-term daily intake of the detected substances by a Polish adult consumer was low, ranging from 0.02% ADI for pirimicarb to 0.72% ADI for captan. PMID- 28646437 TI - Cytotoxic and genotoxic effects of silver nanoparticle/carboxymethyl cellulose on Allium cepa. AB - Several mutagenic agents may be present in substances released in the environment, which may cause serious environmental impacts. Among these substances, there is a special concern regarding the widespread use of silver nanoparticles (AgNP) in several products due to their widely known bactericidal properties, including in the medical field and the food industry (e.g., active packaging). The assessment of the effects of AgNP released in the environment, having different concentrations, sizes, and being associated or not to other types of materials, including polymers, is therefore essential. In this research, the objective was to evaluate the genotoxic and cytotoxic effects of AgNP (size range between 2 and 8 nm) on root meristematic cells of Allium cepa (A. cepa). Tests were carried out in the presence of colloidal solution of AgNP and AgNP mixed with carboxymethylcellulose (CMC), using distinct concentrations of AgNP. As a result, when compared to control samples, AgNP induced a mitotic index decrease and an increase of chromosomal aberration number for two studied concentrations. When AgNP was in the presence of CMC, no cytotoxic potential was verified, but only the genotoxic potential for AgNP dispersion having concentration of 12.4 ppm. PMID- 28646438 TI - Noctiluca and copepods grazing on the phytoplankton community in a nutrient enriched coastal environment along the southwest coast of India. AB - The relative grazing impact of Noctiluca scintillans (hereafter referred only Noctiluca) and copepods (Acrocalanus gracilis, Paracalanus parvus, Acartia danae and Oithona similis) on the phytoplankton community in an upwelling-mudbank environment along the southwest coast India is presented here. This study was carried out during the Pre-Southwest Monsoon (April-May) to the Late Southwest Monsoon (August) period in 2014. During the sampling period, large hydrographical transformation was evident in the study area (off Alappuzha, Southwest coast of India); warmer Pre-Southwest Monsoon water column condition got transformed into cooler and nitrate-rich hypoxic waters during the Southwest Monsoon (June-August) due to intense coastal upwelling. Copepods were present in the study area throughout the sampling period with a noticeable increase in their abundance during the Southwest Monsoon. On the other hand, the first appearance of Noctiluca in the sampling location was during the Early Southwest Monsoon (mid June) and thereafter their abundance increased towards the Peak Southwest Monsoon. The grazing experiments carried out as per the food removal method showed noticeable differences in the feeding preferences of Noctiluca and copepods, especially on the different size fractions of phytoplankton. Noctiluca showed the highest positive electivity for the phytoplankton micro-fraction (av. 0.49 +/- 0.04), followed by nano-fraction (av. 0.17 +/- 0.04) and a negative electivity for the pico-fraction (av. -0.66 +/- 0.06). In total ingestion of Noctiluca, micro-fraction contribution (83.7%) was significantly higher compared to the nano- (15.7%) and pico-fractions (0.58%). On the other hand, copepods showed the highest positive electivity for the phytoplankton nano-fraction (av. 0.38 +/- 0.04) followed by micro- (av. -0.17 +/- 0.05) and pico-fractions (av. 0.35 +/- 0.05). Similarly, in total ingestion of copepods, nano-fraction (69.7%) was the highest followed by micro- (28.9%) and pico-fractions (1.37%). The grazing pressure of Noctiluca on the total phytoplankton was found to be 27.7% of the standing stock and 45.6% of the production, whereas in the case of copepods, it was 9.95% of the standing stock and 16.6% of the production. The study showed that the grazing pressure of Noctiluca on the total phytoplankton as well as larger phytoplankton fraction was 2.8- and 8-folds higher than that of the copepods. This suggests the leading role of Noctiluca as an effective grazer of larger phytoplankton along the southwest west coast of India, especially during the Peak/Late Southwest Monsoon. PMID- 28646439 TI - Alterations in contact lens fitting parameters following cross-linking in keratoconus patients of Indian ethnicity. AB - BACKGROUND: Most studies have either excluded patients using contact lens or not taken their effect while analyzing post-collagen cross-linkage (CXL) changes. This study aims to study impact of CXL on lens fit in both quantitative and qualitative manner. OBJECTIVE: To evaluate changes in CL fit post-CXL and to correlate these changes with alterations in corneal topographic parameters. STUDY DESIGN: Prospective intervention study on 20 keratoconic eyes of 14 patients (age > 18 years), with mean follow-up of 6 months. METHODS: Preoperative evaluation included UCVA, BCVA, corneal topography, AS-OCT and contact lens fit. Patients were evaluated at 2 weeks, 1, 3, 4 and 6 months post-CXL; contact lens trial with standard rigid gas permeable (RGP) lens performed at 3 and 6 months. MAIN OUTCOME MEASURE: Changes in objective and subjective parameters of lens fit. RESULTS: Over 6-month follow-up post-CXL, improvement in visual acuity by one Snellen line, both UCVA and BCVA, and decrease in flat/mean/apical K by 0.8 D, 0.8 D and 1.3 D, respectively, resulted in significant improvement in RGPCL fit. Almost 20% increase in near-ideal fit, 100% acceptable fit, 65% improved subjective comfort with 8 h/day increase in duration of comfortable CL wear were observed. CONCLUSION: Despite no statistically significant change in objective parameters of lens fit, a tendency for flatter lens fit along with contact lens induced further flattening of the ectatic cornea which resulted in marked improvement in both objective and subjective contact lens fit. PMID- 28646440 TI - A comparison of three different intravitreal treatment modalities of macular edema due to branch retinal vein occlusion. AB - PURPOSE: To compare the efficacy of intravitreal injection of ranibizumab, dexamethasone implant and aflibercept for the management of macular edema (ME) related to branch retinal vein occlusion (BRVO). METHODS: This retrospective and comparative study included 62 eyes of 62 patients with BRVO and ME. Patients received one of the following treatments: 0.5 mg ranibizumab (group 1, n = 22), 0.7 mg dexamethasone implant (group 2, n = 20) and 2 mg aflibercept (group 3, n = 20). The 6-month treatment protocol in groups 1 and 3 consisted of 3-dose loading treatment for the first 3 months and followed by repeat injections based on clinical necessity. Group 2 received only single dose of 0.7 mg dexamethasone implant for 6 months. Visual acuity (VA), central macular thickness (CMT), serous retinal detachment (SRD) height and intraocular pressure (IOP) measurements were done at baseline and first 6 months of follow-up. RESULTS: At baseline, the groups did not differ in age, gender, duration of ME, VA, CMT, IOP and SRD height (p > 0.05). Mean number of injections per eye within six months were 3.64 +/- 0.49 (range 3-4) in group 1, only 1 in group 2 and 3.35 +/- 0.49 (range 3-4) in group 3.VA was significantly better in group 2 in first 3 months but it became the worst among three groups in sixth month. CMT did not differ between groups in first 3 months, but it was significantly higher in group 2 at sixth month. SRD height was significantly lower in group 2 in first 3 months, but there was no difference between the groups at the end of the sixth month. IOP was significantly higher in group 2 in third and sixth months. CONCLUSION: In the treatment of ME associated with BRVO, dexamethasone implant appears to be more advantageous in terms of VA and SRD height for the first 3 months. However, at the end of the sixth month of treatment, anti-VEGF drugs were more efficient in maintaining the increased visual acuity and reduced CMT. A dexamethasone implant may be the first treatment option in BRVO cases with high SRD. PMID- 28646441 TI - Safety, efficacy and refractive outcomes of LASIK surgery in patients aged 65 or older. AB - PURPOSE: Report on the safety, efficiency and refractive outcomes of LASIK surgery in patients aged 65 or older. METHODS: This study includes a case series of patients >=65 years that underwent corneal refractive surgery during the period June 2010 to June 2015 at Hospital Zambrano Hellion, Monterrey, Mexico. Inclusion criteria were normal topography, central corneal thickness >500 MUm, preoperative manifest refraction spherical equivalent (MRSE) up to -8.5 D and +6.0 D, cylinder up to -6.0 D, CDVA of 20/25 or better and with no other ocular pathology. RESULTS: A total of 44 eyes (24 patients) were included. Mean age was 67.2 +/- 2.1 years (range 65-80), with mean follow-up of 12.2 +/- 1.3 months. Conventional LASIK was performed in 20 patients (group 1, 36 eyes) to improve UDVA (10 eyes myopic LASIK and 26 eyes hyperopic LASIK) and presbyopic LASIK (monovision) in 4 patients (group 2, 8 eyes) to restore near-vision performance. Preoperative MRSE group 1 was myopic: -2.79 +/- 1.88 D; hyperopic +2.19 +/- 1.88 D; and +2.10 +/- 0.87 D in group 2. Preoperative UDVA in group 1 was 0.67 +/- 0.30 LogMAR; 0.46 +/- 0.18 LogMAR; and Jaeger >=4 in 90% in group 2. Postoperative MRSE: -0.29 +/- 0.86 D (myopic LASIK) (p < 0.001), +0.34 +/- 0.62 D (hyperopic LASIK) (p < 0.001) and -1.25 +/- 0.59 D (non-dominant eye) in presbyopic LASIK. Postoperative UDVA in myopic LASIK was 0.15 +/- 0.30 (p = 0.001) and 0.11 +/- 0.11 (p < 0.001) for hyperopic LASIK. In group 2, binocular UDVA was 0.16 +/- 0.17 (p = 0.12) and UNVA was >=J2 in 100% of the patients. CONCLUSION: Even though elder patients may present greater LASIK restrictions due to lens and other ocular age-related changes, patients >=65 years that were candidates for conventional and presbyopic LASIK showed satisfactory and safe refractive and visual outcomes. PMID- 28646442 TI - Variability of adverse events in the public health-care service of the Tuscany region. AB - The objective of the study is to analyze the variation of adverse events (AEs) according to the different structure of hospitals. The study is a multicenter, retrospective study. It involves 4 teaching hospitals (THs) and 32 community hospitals, distributed in 12 local trusts (LTs), of the Tuscany Regional Healthcare Service (RHS). A random sample of the clinical records of patients admitted in LTs and THs in 2008 was selected from the database of the hospital discharge records of the centers. Among 11,293 clinical records included, a total of 354 adverse events were identified. There was a significant higher incidence of AEs in the male and elderly (>65 years) population, and the incidence of AEs was more relevant in the THs (5.3, 95% CI 4.7-6.1) than in the LTs (1.8, 95% CI 1.5-2.2). AEs related to falls were significantly more preventable in THs (OR 19.22, 95% CI 2.45-151.02), while in LTs, AEs related to infections were the most preventable (OR 6.22, 95% CI 1.35-28.67). Concerning the consequence of AE, death is significantly more probable for AEs related to unexpected cardiac arrest in LTs, while disability and prolongation of the stay are significantly more probable consequences associated with re-admission in THs, and to transfer to ICU or HDU in LTs. Re-interventions, surgical complications and falls are the factors more correlated with AEs. In conclusion, the study shows a higher risk of incurring adverse events for the THs compared to the LTs, presumably connected with a major complexity of the clinical cases. Furthermore, the preventability of AEs is higher in the LTs (56.1 vs 42.2%), and this might be associated with lower expertise in managing complications in these settings. Concerning specialties, there are no significant differences in AEs distribution. PMID- 28646443 TI - Recent Discoveries in Monogenic Disorders of Childhood Bone Fragility. AB - PURPOSE OF REVIEW: This review summarizes our current knowledge on primary osteoporosis in children with focus on recent genetic findings. RECENT FINDINGS: Advances in genetic research, particularly next-generation sequencing, have found several genetic loci that associate with monogenic forms of inherited osteoporosis, widening the scope of primary osteoporosis beyond classical osteogenesis imperfecta. New forms of primary osteoporosis, such as those related to WNT1, PLS3, and XYLT2, have identified defects outside the extracellular matrix components and collagen-related pathways, in intracellular cascades directly affecting bone cell function. Primary osteoporosis can lead to severe skeletal morbidity, including abnormal longitudinal growth, compromised bone mass gain, and noticeable fracture tendency beginning at childhood. Early diagnosis and timely care are warranted to ensure the best achievable bone health. Future research will most likely broaden the spectrum of primary osteoporosis, hopefully provide more insight into the genetics governing bone health, and offer new targets for treatment. PMID- 28646444 TI - Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments. AB - PURPOSE OF REVIEW: Bone is a structurally unique microenvironment that presents many challenges for the development of 3D models for studying bone physiology and diseases, including cancer. As researchers continue to investigate the interactions within the bone microenvironment, the development of 3D models of bone has become critical. RECENT FINDINGS: 3D models have been developed that replicate some properties of bone, but have not fully reproduced the complex structural and cellular composition of the bone microenvironment. This review will discuss 3D models including polyurethane, silk, and collagen scaffolds that have been developed to study tumor-induced bone disease. In addition, we discuss 3D printing techniques used to better replicate the structure of bone. 3D models that better replicate the bone microenvironment will help researchers better understand the dynamic interactions between tumors and the bone microenvironment, ultimately leading to better models for testing therapeutics and predicting patient outcomes. PMID- 28646446 TI - Innovations in the Endovascular Management of Critical Limb Ischemia: Retrograde Tibiopedal Access and Advanced Percutaneous Techniques. AB - PURPOSE OF REVIEW: Retrograde tibiopedal access and interventions have contributed to advance of endovascular techniques to treat critical limb ischemia (CLI) patients. This review encompasses the spectrum from advanced diagnostic imaging and technical therapeutic approaches for infrapopliteal occlusions, to a discussion of current standards and future directions. RECENT FINDINGS: Contemporary studies of infrapopliteal angioplasty show suboptimal short-term and 1-year clinical outcomes. Comparative data is needed to shift the focus from PTA to disruptive treatment modalities that can further improve outcomes. Retrograde pedal access has emerged as an important tool to facilitate successfully percutaneous revascularization and limb salvage in patients with CLI. To efficiently approach the complexity of CLI, new thought processes are needed to change the reigning paradigms. Retrograde tibial-pedal access has shown improvement in the rate of successful revascularizations and is an important tool in the amputation-prevention armamentarium. Additional technologies may further improve success rates. Drug-eluting stents have shown better outcomes than PTA in patients with focal infrapopliteal lesions. Registry data have demonstrated the advantage of several atherectomy devices in the tibial arteries. More recently, bioresorbable vascular scaffolds have been used successfully, and further studies with drug-coated balloons are underway. Interventional operators are now even working in the inframalleolar space to reconstitute the plantar arch. Well conducted studies are needed to generate high-quality evidence in the field of critical limb ischemia management. PMID- 28646445 TI - Update on Neurocritical Care of Stroke. AB - PURPOSE OF REVIEW: This review will highlight the recent advancements in acute ischemic stroke diagnosis and treatment, with special attention to new features and recommendations of stroke care in the neurocritical care unit. RECENT FINDINGS: New studies suggest that pre-hospital treatment of stroke with mobile stroke units and telestroke technology may lead to earlier stroke therapy with intravenous tissue plasminogen activator (tPA), and recent studies show tPA can be given in previously contraindicated situations. More rapid automated CT perfusion and angiography may demonstrate a vascular penumbra for neuroendovascular intervention. Further, the greatest advance in acute stroke treatment since 2014 is the demonstration that neuroendovascular catheter-based thrombectomy with stent retrievers recanalizing intracranial large vessel occlusion (LVO) improves both recanalization and long-term outcomes in several trials. Hemorrhagic transformation and severe large infarct cerebral edema remain serious post-stroke challenges, with new guidelines describing who and when patients should get medical or surgical intervention. The adage "time is brain" directs the most evidence-based approach for rapid stroke diagnosis for tPA eligible and LVO recanalization using an orchestrated team approach. The neurocritical care unit is the appropriate location to optimize stroke outcomes for the most severely affected stroke patients. PMID- 28646447 TI - Microbial transformations of selenite by methane-oxidizing bacteria. AB - Methane-oxidizing bacteria are well known for their role in the global methane cycle and their potential for microbial transformation of wide range of hydrocarbon and chlorinated hydrocarbon pollution. Recently, it has also emerged that methane-oxidizing bacteria interact with inorganic pollutants in the environment. Here, we report what we believe to be the first study of the interaction of pure strains of methane-oxidizing bacteria with selenite. Results indicate that the commonly used laboratory model strains of methane-oxidizing bacteria, Methylococcus capsulatus (Bath) and Methylosinus trichosporium OB3b, are both able to reduce the toxic selenite (SeO32-) but not selenate (SeO42-) to red spherical nanoparticulate elemental selenium (Se0), which was characterized via energy-dispersive X-ray spectroscopy (EDXS), X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS). The cultures also produced volatile selenium-containing species, which suggests that both strains may have an additional activity that can transform either Se0 or selenite into volatile methylated forms of selenium. Transmission electron microscopy (TEM) measurements and experiments with the cell fractions cytoplasm, cell wall and cell membrane show that the nanoparticles are formed mainly on the cell wall. Collectively, these results are promising for the use of methane oxidizing bacteria for bioremediation or suggest possible uses in the production of selenium nanoparticles for biotechnology. PMID- 28646448 TI - Purification of the exopolysaccharide produced by Alteromonas infernus: identification of endotoxins and effective process to remove them. AB - Alteromonas infernus bacterium isolated from deep-sea hydrothermal vents can produce by fermentation a high molecular weight exopolysaccharide (EPS) called GY785. This EPS described as a new source of glycosaminoglycan-like molecule presents a great potential for pharmaceutical and biotechnological applications. However, this unusual EPS is secreted by a Gram-negative bacterium and can be therefore contaminated by endotoxins, in particular the lipopolysaccharides (LPS). Biochemical and chemical analyses of the LPS extracted from A. infernus membranes have shown the lack of the typical LPS architecture since 3-deoxy-D manno-oct-2-ulopyranosonic acid (Kdo), glucosamine (GlcN), and phosphorylated monosaccharides were not present. Unlike for other Gram-negative bacteria, the results revealed that the outer membrane of A. infernus bacterium is most likely composed of peculiar glycolipids. Furthermore, the presence of these glycolipids was also detected in the EPS batches produced by fermentation. Different purification and chemical detoxification methods were evaluated to efficiently purify the EPS. Only the method based on a differential solubility of EPS and glycolipids in deoxycholate detergent showed the highest decrease in the endotoxin content. In contrast to the other tested methods, this new protocol can provide an effective method for obtaining endotoxin-free EPS without any important modification of its molecular weight, monosaccharide composition, and sulfate content. PMID- 28646449 TI - Occurrence of Pepper Mild Mottle Virus (PMMoV) in Groundwater from a Karst Aquifer System in the Yucatan Peninsula, Mexico. AB - The Yucatan Peninsula of Mexico hosts a karst aquifer system that is the only source of freshwater for the area; however, it is vulnerable to human-mediated contamination. Pepper mild mottle virus (PMMoV) is one of the most abundant RNA viruses associated with human feces, making it a viable indicator for tracking fecal pollution in aquatic environments, including groundwater. In this study, groundwater samples collected from a karst aquifer from fresh and brackish water locations were analyzed for fecal indicator bacteria, somatic and male F+ specific coliphages, and PMMoV during the rainy and dry seasons. Total coliform bacteria were detected at all sites, whereas Escherichia coli were found at relatively low levels <40 MPN/100 ml. The highest average concentrations of somatic and male F+ specific coliphages were 920 and 330 plaque forming units per 100 ml, respectively, detected in freshwater during the rainy season. PMMoV RNA was detected in 85% of the samples with gene sequences sharing 99-100% of nucleotide identity with PMMoV sequences available in GenBank. Quantification of PMMoV genome copies (GC) by quantitative real-time PCR indicated concentrations ranging from 1.7 * 101 to 1.0 * 104 GC/L, with the highest number of GC detected during the rainy season. No significant correlation was observed between PMMoV occurrence by season or water type (p > 0.05). Physicochemical and indicator bacteria were not correlated with PMMoV concentrations. The abundance and prevalence of PMMoV in the karst aquifer may reflect its environmental persistence and its potential as a fecal indicator in this karst aquifer system. PMID- 28646450 TI - MicroRNA Changes in Preconditioning-Induced Neuroprotection. AB - Preconditioning is a paradigm in which sublethal stress-prior to a more injurious insult-induces protection against injury. In the central nervous system (CNS), preconditioning against ischemic stroke is induced by short durations of ischemia, brief seizures, exposure to anesthetics, and other stresses. Increasing evidence supports the contribution of microRNAs (miRNAs) to the pathogenesis of cerebral ischemia and ischemic tolerance induced by preconditioning. Studies investigating miRNA changes induced by preconditioning have to date identified 562 miRNAs that change expression levels after preconditioning, and 15% of these changes were reproduced in at least one additional study. Of miRNAs assessed as changed by preconditioning in more than one study, about 40% changed in the same direction in more than one study. Most of the studies to assess the role of specific miRNAs in the neuroprotective mechanism of preconditioning were performed in vitro, with fewer studies manipulating individual miRNAs in vivo. Thus, while many miRNAs change in response to preconditioning stimuli, the mechanisms underlying their effects are not well understood. The data does suggest that miRNAs may play significant roles in preconditioning-induced neuroprotection. This review focuses on the current state of knowledge of the possible role of miRNAs in preconditioning-induced cerebral protection. PMID- 28646451 TI - Regulation of sustained attention, false alarm responding and implementation of conditional rules by prefrontal GABAA transmission: comparison with NMDA transmission. AB - RATIONALE: Both prefrontal cortex (PFC) GABAA and NMDA transmission regulate attentional processes, yet how they may differentially regulate signal detection or other aspects of attention is unclear. OBJECTIVES: We examined PFC GABAA and NMDA receptor regulation of attention using a sustained attention task (SAT) permitting identification of distinct forms of impairments. As this task requires implementation of conditional rules, we also investigated how reducing PFC GABA transmission affected performance of visual and auditory conditional discriminations. METHODS: Male rats were well-trained on the SAT that required identifying whether a brief visual stimulus (500-50 ms) was present/absent by pressing one of two levers. They then received intra-PFC infusions of the GABAA antagonist bicuculline (12.5-50 ng), the NMDA antagonist MK-801 (6 MUg), and i.p. injections of MK-801 (0.1-0.3 mg/kg) prior to testing. Separate groups were trained either on a similar task where the visual stimulus was presented for 2.5 s, or a task where presentation of one of two auditory cues required responding on a left or right lever. RESULTS: Both doses of bicuculline impaired vigilance, selectively increasing errors during nonsignal trials. Intra-PFC MK-801 induced subtle impairments at short signal durations. Systemic MK-801 impaired performance and increased response latencies. Visual and auditory conditional discrimination was impaired by 50 ng, but not 12.5 ng of bicuculline. CONCLUSIONS: These findings highlight a key role for PFC GABA transmission in reducing sensitivity to distractors during attentional performance. Furthermore, they reveal that disruption of GABA signaling can interfere with the ability to implement conditional rules. PMID- 28646453 TI - Answer to the Letter to the Editor of A. Piazzolla et al. concerning, "The Surgical Algorithm for the AOSpine, Thoracolumbar Spine Injury Classification System" by A. R. Vaccaro et al.; Eur Spine J (2016); 25(4):1087-1094. PMID- 28646452 TI - Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility. AB - The zona pellucida (ZP) is an extracellular matrix universally surrounding mammalian eggs, which is essential for oogenesis, fertilization, and pre implantation embryo development. Here, we identified two novel heritable mutations of ZP2 and ZP3, both occurring in an infertile female patient with ZP abnormal eggs. Mouse models with the same mutations were generated by CRISPR/Cas9 gene editing system, and oocytes obtained from female mice with either single heterozygous mutation showed approximately half of the normal ZP thickness compared to wild-type oocytes. Importantly, oocytes with both heterozygous mutations showed a much thinner or even missing ZP that could not avoid polyspermy fertilization, following the patient's pedigree. Further analysis confirmed that precursor proteins produced from either mutated ZP2 or ZP3 could not anchor to oocyte membranes. From these, we conclude that ZP mutations have dosage effects which can cause female infertility in humans. Finally, this patient was treated by intracytoplasmic sperm injection (ICSI) with an improved culture system and successfully delivered a healthy baby. PMID- 28646454 TI - The Oswestry Disability Index, confirmatory factor analysis in a sample of 35,263 verifies a one-factor structure but practicality issues remain. AB - PURPOSE: To analyze the factor structure of the Oswestry Disability Index (ODI) in a large symptomatic low back pain (LBP) population using exploratory (EFA) and confirmatory factor analysis (CFA). METHODS: Analysis of pooled baseline ODI LBP patient data from the international Spine Tango registry of EUROSPINE, the Spine Society of Europe. The sample, with n = 35,263 (55.2% female; age 15-99, median 59 years), included 76.1% of patients with a degenerative disease, and 23.9% of the patients with various other spinal conditions. The initial EFA provided a hypothetical construct for consideration. Subsequent CFA was considered in three scenarios: the full sample and separate genders. Models were compared empirically for best fit. RESULTS: The EFA indicated a one-factor solution accounting for 54% of the total variance. The CFA analysis based on the full sample confirmed this one-factor structure. Sub-group analyses by gender achieved good model fit for configural and partial metric invariance, but not scalar invariance. A possible two-construct model solution as outlined by previous researchers: dynamic activities (personal care, lifting, walking, sex and social) and static activities (pain, sleep, standing, travelling and sitting) was not preferred. CONCLUSIONS: The ODI demonstrated a one-factor structure in a large LBP sample. A potential two-factor model was considered, but not found appropriate for constructs of dynamic and static activity. The use of the single summary score for the ODI is psychometrically supported. However, practicality limitations were reported for use in the clinical and research settings. Researchers are encouraged to consider a shift towards newer, more sensitive and robustly developed instruments. PMID- 28646455 TI - Human nucleus pulposus intervertebral disc cells becoming senescent using different treatments exhibit a similar transcriptional profile of catabolic and inflammatory genes. AB - PURPOSE: Chronic low back pain has been associated with intervertebral disc (IVD) degeneration, which is characterized by the accumulation of extracellular matrix (ECM)-degrading proteases and inflammatory molecules in the degenerate tissue. IVD degeneration could be the outcome of natural organismal ageing and/or of the exposure of the disc to cumulative stressful environmental stimuli and is accompanied by an increased population of senescent cells in the tissue. On the other hand, senescent cells are known to secrete proteolytic enzymes and inflammatory molecules, which can contribute to ECM catabolism. The aim of this study was to investigate the transcriptional profile of selected metalloproteinases (MMPs) and inflammatory mediators in human nucleus pulposus IVD cells that became senescent using three different approaches: serial subculturing, exposure to ionizing radiation and p16INK4a overexpression. METHODS: Gene expression was assessed using quantitative RT-PCR and protein levels were determined by western blot analysis. The proliferative potential of the cells, as well as the percentage of senescent cells in the population were estimated by nuclear BrdU incorporation and by senescence-associated beta galactosidase staining, respectively. RESULTS: All senescent cells showed a similar regulation of MMP-1, -2, -3, -9, interleukin (IL) 6, IL8 and interferon gamma at the level of transcription, with only some quantitative differentiations observed in p16INK4a-overexpressing cells. CONCLUSIONS: Data described here suggest that senescent cells may have similar functions in IVD homeostasis, irrespective of the origin of senescence induction. PMID- 28646456 TI - Using Comics to Promote Colorectal Cancer Screening in the Asian American and Pacific Islander Communities. AB - There are unaesthetic aspects in teaching people about the early detection of colorectal cancer using the fecal immunochemical test. Comics were seen as a way to overcome those unaesthetic aspects. This study used the Asian grocery store based cancer education venue to pilot-test the clarity, cultural acceptability, and alignment of five colorectal cancer education comics intended for publication in Asian American and Pacific Islander (API) community newspapers. After developing the colorectal cancer education comics, API students asked shoppers to review a comic from their collection and provide feedback on how to make the comic clearer and more culturally pertinent to API readers. To evaluate viewers' responses, the students gathered such unobtrusive data as: (1) how many of the predetermined salient information points were discussed as the student educators interacted with shoppers and (2) how many comics the shoppers were willing to review. Shoppers were also asked to evaluate how effective the comics would be at motivating colorectal cancer screening among APIs. The students were able to cover all of the salient information points with the first comic. As evidence of the comics' capacity to engage shoppers' interest, shoppers willingly evaluated all five comics. Using multiple comics enabled the educators to repeatedly address the four salient colorectal cancer information points. Thus, the comics helped student educators to overcome the unesthetic elements of colorectal cancer discussions, while enabling them to engage shoppers in animated discussions, for far more time than with their conventional didactic educational methods. PMID- 28646457 TI - National Survey Among Radiation Oncology Residents Related to Their Needs in Geriatric Oncology. AB - Currently, there is no formal curriculum addressing geriatric oncology within Canadian radiation oncology (RO) residency programs. Knowledge related to geriatric medicine may help radiation oncologists modify RT based on frailty status and geriatric considerations. Understanding specific learning needs allow program coordinators to align the current curriculum with residents' geriatric oncology learning needs. The purpose of this study is to determine the geriatric oncology educational needs of the Canadian RO residents and to inform Canadian RO residency training. A cross-sectional survey, with Likert, multiple choice, and open-ended questions, was pretested and distributed electronically by program directors to Canadian RO residents over 6 weeks. Responses were analyzed with descriptive statistics and common themes. One-hundred and thirty-five Canadian RO residents were contacted and 63 responded (47%). Half (49%) lacked confidence managing the elderly with multiple comorbidities, polypharmacy, functional and cognitive impairment, and challenging social circumstances;73% agreed additional training would be helpful. Forty-four percent lacked confidence regarding psychogeriatric referrals, fall prevention, palliative and hospice care, and community resources preventing re-hospitalization; 63% agreed additional training would be helpful. Seventy-six percent believed discussion groups, continuing education, geriatric oncology electives, and journal clubs would provide learning opportunities. Seventy-one percent agreed integrating geriatric assessment into RO curricula would improve care. Seventy-nine percent believed geriatric oncology principles have not been adequately integrated into radiation oncology curricula. There are significant gaps specific to geriatric assessment and management of older cancer patients in the current Canadian RO curricula. Most residents agreed that it is important to integrate geriatric oncology training to improve and personalize the care of older cancer patients. PMID- 28646458 TI - Ovarian Cancer Knowledge in Women and Providers Following Education with Inside Knowledge Campaign Materials. AB - Because no effective methods for preventing or screening for ovarian cancer exist, symptom recognition is integral to its early detection. The Centers for Disease Control and Prevention's Inside Knowledge: Get the Facts about Gynecologic Cancer campaign was developed to raise awareness and educate women and providers about risk factors, symptoms, recommended screening, and prevention strategies for the five main gynecologic cancers, including ovarian cancer. Inside Knowledge campaign materials were utilized by CDC's National Comprehensive Cancer Control Program grantees to educate women and providers about gynecologic cancer from 2014 to 2015. Grantees recruited participants and held educational sessions using Inside Knowledge materials. Questionnaires were given before and after the sessions to assess changes in awareness, confidence, and behavioral intentions around gynecologic cancer information and analyzed in 2016. This analysis focused on an assessment of changes related to ovarian cancer information. Participants' knowledge increased after educational sessions. Among women, there were increases in correctly identifying that the Papanicolaou (Pap) test does not screen for ovarian cancer (89.2%) and that genetic testing is available (77.9%). There was a lower increase in knowledge that HPV is not a cause of ovarian cancer (56.4%). Providers and women reported significant increases in their confidence in their ability to talk to each other about gynecologic cancer post-session. Ovarian cancer awareness, confidence, and related behaviors increased in participants exposed to Inside Knowledge materials. Using these materials to increase knowledge could lead to more empowered patients, better provider-patient communications, and improved care for gynecologic cancers, including ovarian cancer. PMID- 28646461 TI - Interactive video game built for mask induction in pediatric patients. PMID- 28646459 TI - Silymarin inhibits adipogenesis in the adipocytes in grass carp Ctenopharyngodon idellus in vitro and in vivo. AB - In this study, two experiments were performed to explore the function of silymarin in adipogenesis in grass carp (Ctenopharyngodon idellus) using in vitro and in vivo models. In experiment 1, differentiated grass carp pre-adipocytes were treated with silymarin for 6 days. Treatment with 100 MUg mL-1silymarin (SM100 group) significantly reduced triglyceride accumulation at day 6. The adipogenic gene expression levels of PPARgamma, C/EBPalpha, SREBP1c, FAS, SCD1, and LPL, and the protein expression level of PPARgamma were significantly down regulated in the SM100 group. Additionally, the SM100 group had significantly lower reactive oxygen species production and reduced glutathione contents compared with the control in vitro. In experiment 2, the juvenile grass carp (mean body weight= 27.4 +/- 0.17 g) were fed six isonitrogenous and isocaloric diets in a factorial design containing 0, 100, or 200 mg kg-1 silymarin (SM0, SM100, SM200) associated with either 4 or 8% lipid levels (low lipid, LL, and high lipid, HL, respectively) for 82 days. The results demonstrated that dietary silymarin supplementation significantly reduced the elevated intraperitoneal fat index in grass carp fed with high-lipid diets, and the gene expression of adipogenesis (PPARgamma, FAS) when supplemented with dietary silymarin was notably lower than when no silymarin was supplemented under the high-lipid diets. Thus, our data suggest that silymarin suppressed lipid accumulation in grass carp both in vitro and in vivo, and the effect might be due to an influence on the expression of adipogenesis factors and ROS production partly associated with effects on antioxidant capability. PMID- 28646460 TI - A nationwide survey of aortic valve surgery in Japan: current status of valve preservation in cases with aortic regurgitation. AB - OBJECTIVE: Although aortic valve-sparing operations are performed throughout Japan, the indications, specific repair techniques, and outcomes have not been reported in full. Thus, we conducted the first nationwide survey of aortic valve sparing surgery. METHODS: We mailed a questionnaire to 508 institutions across Japan to obtain information on elective aortic valve and aortic root surgeries performed in 2014. Included in the mailing was a secondary questionnaire that sought further information from institutions reporting aortic valve-sparing surgeries. RESULTS: Two hundred and fifty (49%) institutions responded and reported a total of 7859 aortic valve operations and 771 aortic root operations. Aortic valve operations performed strictly for aortic regurgitation totaled 2080, 156 (8%) of which were aortic valve repairs. Of the 699 aortic root surgeries performed for aortic regurgitation, 236 (34%) were valve-sparing root replacement surgeries. The valve-sparing root replacement surgeries comprised aortic valve reimplantation (n = 173, 73%) and aortic root remodeling (n = 63, 27%). Five of 57 (9%) institutions were responsible for 42% (99/233) of the total aortic valve sparing surgeries performed. Detailed information that was obtained for 233 patients who underwent aortic valve repair or valve-sparing root replacement showed 30-day mortality and reoperation for regurgitation after aortic valve repair (n = 97), aortic root remodeling (n = 37), and aortic valve reimplantation (n = 99) to be 1, 0, and 1% and 3, 3, and 1%, respectively. CONCLUSION: To date, aortic valve-sparing operations have been performed for limited patients at limited institution in Japan, but the early outcomes have been excellent. PMID- 28646462 TI - Diagnostic utility of PET/CT with 18F-DOPA and 18F-FDG in persistent or recurrent medullary thyroid carcinoma: the importance of calcitonin and carcinoembryonic antigen cutoff. AB - PURPOSE: This study sought to evaluate and compare the utility of 18-F fluorodihydroxyphenylalanine (18F-DOPA) and 18-F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for identification of lesions in patients with recurrent medullary thyroid carcinoma (MTC). In addition, we analyzed the correlation between the calcitonin (Ct), carcinoembryonic antigen (CEA) levels, each doubling time (DT), and PET positivity. We evaluated the reliability of the 150 pg/mL Ct cutoff set by the American Thyroid Association guidelines for further imaging (including 18F-DOPA PET/CT). METHODS: We prospectively recruited 18 patients with recurrent MTC, identified by elevation of Ct or CEA. Each patient underwent a 18F-FDG PET/CT and a 18F-DOPA PET/CT. RESULTS: Abnormal uptakes were detected with 18F-DOPA (n=12) and 18F-FDG (n=9), (sensitivity of 66.7% vs. 50%; p<0.01). Twenty-eight lesions were detected with 18F-DOPA vs. 16 lesions with 18F-FDG (1.56+/-1.5 vs. 0.89+/ 1.18 lesions per patient; p=0.01). None of our patients showed additional lesions with 18F-FDG in comparison to 18F-DOPA. Patient-based detection rate increased significantly with Ct levels >=150 pg/mL vs. Ct<150 pg/mL for both 18F-DOPA (sensitivity 90.9% vs. 28.6%; p=0.013) and 18F-FDG PET/CT (sensitivity 72.7% vs. 14.3%; p=0.025). Using a CEA cutoff of >=5 ng/mL, detection rates of 18F-DOPA and 18F-FDG PET/CT were 81.1% and 72.7%, respectively. No correlation between Ct-DT or CEA-DT and PET positivity was found. Histological confirmation was obtained in eight patients. CONCLUSIONS: 18F-DOPA PET/CT appears to be superior to 18F-FDG PET/CT in detecting and locating lesions in patients with recurrent MTC. This technique tends to be especially useful in patients with negative results in other imaging modalities and Ct>=150 pg/mL or CEA>=5 ng/mL. PMID- 28646464 TI - Early retreatment after surgical clipping of ruptured intracranial aneurysms. AB - BACKGROUND: Although a rerupture after surgical clipping of ruptured intracranial aneurysms is rare, it is associated with high morbidity and mortality. The causes for retreatment and rupture after surgical clipping are not clearly defined. METHODS: From a prospectively maintained database of 244 patients who had undergone surgical clipping of ruptured intracranial aneurysms, we selected patients who experienced retreatment or rerupture within 30 days after surgical clipping. Aneurysm occlusions were examined by microvascular Doppler ultrasonography and indocyanine green video-angiography. Indications for retreatment included rerupture and partial occlusion. We analyzed the characteristics and causes of early retreatment. RESULTS: Six patients (2.5%, 95% CI 0.9 to 5.3%) were retreated within 30 days after surgical clipping, including two patients (0.8%, 95% CI 0.1 to 2.9%) who experienced a rerupture. The retreated aneurysms were found in the anterior communicating artery (AcomA) (n = 5) and basilar artery (n = 1). Retreatment of the AcomA (7.5%) was performed significantly more frequently than that of other arteries (0.56%) (p < 0.01). A laterally projected AcomA aneurysm (17.4%) was more frequently retreated than were other aneurysm types (2.3%). Cases of laterally projecting AcomA aneurysms tended to result from an incomplete clip placed using a pterional approach from the opposite side of the aneurysm projection. CONCLUSIONS: Despite developments, the rates of retreatment and rerupture after surgical clipping remain similar to those reported previously. Retreatment of the AcomA was significantly more frequent than was retreatment of other arteries. Patients underwent retreatment more frequently when they were originally treated for lateral type aneurysms using a pterional approach from the opposite side of the aneurysm projection. The treatment method and evaluation modalities should be considered carefully for AcomA aneurysms in particular. PMID- 28646463 TI - Patterns of failure after radical prostatectomy in prostate cancer - implications for radiation therapy planning after 68Ga-PSMA-PET imaging. AB - BACKGROUND: Salvage radiotherapy (SRT) after radical prostatectomy (RPE) and lymphadenectomy (LAE) is the appropriate radiotherapy option for patients with persistent/ recurrent prostate cancer (PC). 68Ga-PSMA-PET imaging has been shown to accurately detect PC lesions in a primary setting as well as for local recurrence or for lymph node (LN) metastases. OBJECTIVE: In this study we evaluated the patterns of recurrence after RPE in patients with PC, putting a highlight on the differentiation between sites that would have been covered by a standard radiation therapy (RT) field in consensus after the RTOG consensus and others that would have not. METHODS AND MATERIALS: Thirty-one out of 83 patients (37%) with high-risk PC were the subject of our study. Information from 68Ga-PSMA PET imaging was used to individualize treatment plans to include suspicious lesions as well as possibly boost sites with tracer uptake in LN or the prostate bed. For evaluation, 68Ga-PSMA-PET-positive LN were contoured in a patient dataset with a standard lymph drainage (RTOG consensus on CTV definition of pelvic lymph nodes) radiation field depicting color-coded nodes that would have been infield or outfield of that standard lymph drainage field and thereby visualizing typical patterns of failure of a "blind" radiation therapy after RPE and LAE. RESULTS: Compared to negative conventional imaging (CT/MRI), lesions suspicious for PC were detected in 27/31 cases (87.1%) by 68Ga-PSMA-PET imaging, which resulted in changes to the radiation concept. There were 16/31 patients (51.6%) that received a simultaneous integrated boost (SIB) to a subarea of the prostate bed (in only three cases this dose escalation would have been planned without the additional knowledge of 68Ga-PSMA-PET imaging) and 18/31 (58.1%) to uncommon (namely presacral, paravesical, pararectal, preacetabular and obturatoric) LN sites. Furthermore, 14 patients (45.2%) had a changed TNM staging result by means of 68Ga-PSMA-PET imaging. CONCLUSION: Compared to conventional CT or MRI staging, 68Ga-PSMA-PET imaging detects more PC lesions and, thus, significantly influences radiation planning in recurrent prostate cancer patients enabling individually tailored treatment. PMID- 28646465 TI - Delayed complications of deep brain stimulation: 16-year experience in 249 patients. AB - BACKGROUND: Over the years, most of the deep brain stimulation (DBS) complications described have been mainly related to the surgery itself or the stimulation. Only a few authors have dealt with chronic complications or complications due to implanted material. METHODS: We retrospectively analyzed complications beyond the 1st month after surgery in 249 patients undergoing DBS at our site for 16 years, with 321 interventions overall. RESULTS: Our results show that infection is the most frequent delayed complication (12.5%), the pulse generator being the most common location. Lead breaks (9.3%) are the second most frequent complication. Symptomatic peri-lead edema and cyst formation were exceptional. CONCLUSIONS: The best knowledge about DBS complications allows for better solutions. In case of infection, conservative treatment or partial removal of the DBS system appears to be safe and reasonable. Intracranial complications related to DBS material such as peri-lead edema and cyst formation have a good prognosis. They may appear long after DBS implantation. PMID- 28646466 TI - Effects of catheter-based renal denervation on heart failure with reduced ejection fraction: a systematic review and meta-analysis. AB - Despite the recent advances in the management of heart failure, the mortality of heart failure patients remains high. It is of urgent need to develop new therapy for heart failure. Heart failure is characterized by increased sympathetic activity, and chronic sympathetic activation is involved in the maintenance of the pathological state. Catheter-based renal denervation (RDN) has emerged as an invasive but safe approach that can reduce sympathetic activation. Studies have reported inconsistent results regarding the effect of RDN in heart failure patients due to limited power with small sample sizes. We aimed to conduct a meta analysis of the effect of RDN on heart failure patients with reduced left ventricular (LV) ejection fraction (EF). An electronic search for studies examining the effect of RDN on LV function in heart failure patients with reduced EF was conducted. Two controlled (80 patients) and 2 uncontrolled studies (21 patients) were included in this meta-analysis. In the pooled analysis, 6 months after RDN, there was a greater increase in EF (weighted mean difference [95% CI] = 8.63 [6.02, 11.24] %) and a greater decrease in LV end-diastolic diameter ( 0.58 [-0.83, -0.34] cm) in RDN group than in control group. No serious adverse events such as acute renal artery stenosis and dissection occurred. Our meta analysis of feasibility studies suggests that RDN may improve LV function in heart failure patients with reduced EF, providing the rationale to conduct next phase trials to confirm the observed potential benefits of RDN. PMID- 28646468 TI - An investigation into the association between demographic and morbidity factors, and sleep disturbance. AB - BACKGROUND: The recognition of sleep disorders is important because in the long term, they are associated with numerous deleterious health outcomes. Despite the high prevalence of sleep disorders, they are widely under-diagnosed at general practice level. AIM: This study aims to investigate the association between demographic and morbidity factors, and self-reported sleep disturbance symptoms. METHODS: A quantitative cross-sectional study design was used. The data collection tool was an anonymous questionnaire consisting of 22 sleep symptoms categorised into four subscales: 1. Insomnia, 2. Daytime Distress, 3. Sleep Disorder, 4. Psychological Distress. Participants were adults >=18 years of age attending their general practitioner. RESULTS: A total of 281 questionnaires were analysed (70.3% response rate). Participants with a diagnosis of depression and those who experienced low mood 'very frequently' had significantly higher median scores on all four subscales. Those with a body mass index (BMI) >30 kg/m2 had a higher median score on subscale 3, compared to those with lower BMIs. Smokers had higher median scores on subscales 1-3 compared to non-smokers. Participants >65 years of age had lower median scores on all subscales compared to younger participants. Married participants had lower median scores on subscales 1-3 compared to unmarried participants. A total of 37% reported that they would be willing to participate in an overnight sleep study, and 5.3% had been formally diagnosed with a sleep disorder. CONCLUSIONS: A number of factors are significantly associated with sleep disturbance, particularly depression, low mood, elevated BMI and smoking. General practitioners should consider these factors to increase recognition of patients who would benefit from sleep disorder investigation. PMID- 28646467 TI - Symptom management challenges in heart failure: pharmacotherapy considerations. AB - Heart failure is a chronic, progressive illness that is increasing in prevalence in the USA. Patients with advanced heart failure experience a high symptom burden that is comparable to patients with advanced cancer. Palliative care, however, is underutilized in patients with heart failure, and symptoms may go untreated as the disease progresses. A combination of pharmacologic and non-pharmacologic interventions should be used to address symptoms and maintain quality of life. While there have been significant advances in evidence-based heart failure treatments in recent years, selection of appropriate palliative medications as symptoms progress is challenging due to limited clinical studies in this patient population. Medications that are commonly used for symptom management in other life-limiting illnesses may have little to no evidence in heart failure, or have undesirable cardiac effects that preclude use. Clinicians must extrapolate available clinical evidence and prescribing considerations relevant to heart failure to palliate symptoms as well as possible. The objectives of this paper are to review the most common and distressing symptoms in heart failure, analyze evidence, or lack thereof, for pharmacologic management of symptoms, and provide prescribing considerations based on side effect profiles and comorbid conditions. PMID- 28646470 TI - APOBEC3B and IL-6 form a positive feedback loop in hepatocellular carcinoma cells. AB - APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma (HCC) and APOBEC3B (A3B) remains unknown. It has been confirmed that interleukin-6 (IL-6) has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3B in HepG2 cells. A3B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3B and IL-6, and thereby promoted the prolonged non-resolving inflammation. Collectively, these findings suggest that A3B is essential for oncogenesis of HCC, and is a potential target for preventive intervention. PMID- 28646469 TI - The Cathinones MDPV and alpha-PVP Elicit Different Behavioral and Molecular Effects Following Acute Exposure. AB - Since the mid-to-late 2000s, synthetic cathinones have gained popularity among drug users due to their psychostimulant effects greater than those produced by cocaine and amphetamine. Among them, 3,4-methylenedioxypyrovalerone (MDPV) and 1 phenyl-2-(pyrrolidin-1-yl)pentan-1-one (alpha-PVP) are ones of the most popular cathinones available in the clandestine market as "bath salts" or "fertilizers." Pre-clinical studies indicate that MDPV and alpha-PVP induced psychomotor stimulation, affected thermoregulation, and promoted reinforcing properties in rodents. However, a direct comparative analysis on the effects caused by MDPV and alpha-PVP on the behavior and neuronal activation in rodents is still lacking. Behavioral analyses revealed that both MDPV and alpha-PVP affect spontaneous and stimulated motor responses. In particular, MDPV showed a greater psychomotor effect than alpha-PVP in line with its higher potency in blocking the dopamine transporter (DAT). Notably, MDPV was found to be more effective than alpha-PVP in facilitating spontaneous locomotion and it displayed a biphasic effect in contrast to the monophasically stimulated locomotion induced by alpha-PVP. In addition to the behavioral results, we also found a different modulation of immediate early genes (IEGs) such as Arc/Arg3.1 and c-Fos in the frontal lobe, striatum, and hippocampus, indicating that these drugs do impact brain homeostasis with changes in neuronal activity that depend on the drug, the brain area analyzed, and the timing after the injection. These results provide the first discrimination between MDPV and alpha-PVP based on behavioral and molecular data that may contribute to explain, at least in part, their toxicity. PMID- 28646471 TI - Decoding early myelopoiesis from dynamics of core endogenous network. AB - A decade ago mainstream molecular biologists regarded it impossible or biologically ill-motivated to understand the dynamics of complex biological phenomena, such as cancer genesis and progression, from a network perspective. Indeed, there are numerical difficulties even for those who were determined to explore along this direction. Undeterred, seven years ago a group of Chinese scientists started a program aiming to obtain quantitative connections between tumors and network dynamics. Many interesting results have been obtained. In this paper we wish to test such idea from a different angle: the connection between a normal biological process and the network dynamics. We have taken early myelopoiesis as our biological model. A standard roadmap for the cell-fate diversification during hematopoiesis has already been well established experimentally, yet little was known for its underpinning dynamical mechanisms. Compounding this difficulty there were additional experimental challenges, such as the seemingly conflicting hematopoietic roadmaps and the cell-fate inter conversion events. With early myeloid cell-fate determination in mind, we constructed a core molecular endogenous network from well-documented gene regulation and signal transduction knowledge. Turning the network into a set of dynamical equations, we found computationally several structurally robust states. Those states nicely correspond to known cell phenotypes. We also found the states connecting those stable states. They reveal the developmental routes-how one stable state would most likely turn into another stable state. Such interconnected network among stable states enabled a natural organization of cell fates into a multi-stable state landscape. Accordingly, both the myeloid cell phenotypes and the standard roadmap were explained mechanistically in a straightforward manner. Furthermore, recent challenging observations were also explained naturally. Moreover, the landscape visually enables a prediction of a pool of additional cell states and developmental routes, including the non sequential and cross-branch transitions, which are testable by future experiments. In summary, the endogenous network dynamics provide an integrated quantitative framework to understand the heterogeneity and lineage commitment in myeloid progenitors. PMID- 28646472 TI - Berry syndrome: a rare cardiac malformation with extra-cardiac findings. PMID- 28646473 TI - Detection of FOXO1 break-apart status by fluorescence in situ hybridization in atypical alveolar rhabdomyosarcoma. AB - The morphologies of alveolar rhabdomyosarcoma (ARMS) are various. Some cases entirely lack an alveolar pattern and instead display a histological pattern that overlaps with embryonal rhabdomyosarcoma (ERMS). The method of pathological diagnosis of ARMS and ERMS has been updated in the 4th edition of the World Health Organization's guidelines for classification of skeletal muscle tumors. Under the new guidelines, there is still no molecular test to distinguish between these two subtypes of rhabdomyosarcoma (RMS). In the present study, we applied fluorescent in situ hybridization (FISH) and found that the Forkhead box O1 (FOXO1) gene broke apart, amplified, and displayed an aneuploid signal that was related to the RMS pathological subtype. Aside from the fact that FOXO1 break apart and its amplification were correlated with atypical ARMS, aneuploidies were usually found in atypical ERMS. In conclusion, our results detail a potential biomarker to improve the accuracy of pathological diagnosis by discriminating between atypical ARMS and atypical ERMS. PMID- 28646474 TI - Correlation between BRAF V600E mutation and clinicopathological features in pediatric papillary thyroid carcinoma. AB - In adults, the presence of the BRAF V600E mutation in papillary thyroid cancer (PTC) has been demonstrated to be strongly associated with aggressive cancer-cell characteristics and poor patient prognosis. In contrast, the frequency of this mutation in pediatric PTC has undergone limited study, and the few available estimates range from 0 to 63%. Furthermore, the role of the BRAF V600E mutation in pediatric PTC is controversial; thus, the present study aimed to investigate the prevalence and role of the BRAF V600E mutation in 48 pediatric patients with PTC, aged 3-13 years. Of these patients, 41 were diagnosed with classic PTC, five were found to have a follicular variant of PTC, and two to exhibit a diffuse sclerosing PTC variant. The BRAF V600E mutation was identified to be present in 35.4% of the 48 analyzed patients, and in 41.5% of the patients diagnosed with classical PTC. Furthermore, the presence of the BRAF V600E mutation was found to be associated with a patient age at diagnosis of less than ten years (P=0.011), the performance of a thyroidectomy (P=0.03), exhibited tumor multifocality (P=0.02) and/or extra-thyroidal invasion (P=0.003), and both a low MACIS (Metastases, Age, Completeness of resection, Invasion, Size)(P=0.036) and AMES (Age, Metastasis, Extent of tumor, Size)(P=0.001) score. Together, these data suggest that the presence of the BRAF V600E mutation may be negatively correlated with partial aggressive clinicopathological features of pediatric PTC. PMID- 28646475 TI - Latero-cervical lymph node metastases (N1b) represent an additional risk factor for papillary thyroid cancer outcome. AB - PURPOSE: Papillary thyroid carcinoma (PTC), the most common thyroid cancer histotype, has a good prognosis even when spread to the neck lymph node (LN). The prognostic role of LN metastases' location is still controversial. The aim of the present study was to evaluate the clinical relevance of the number and location of LN metastases at presentation in PTCs. METHODS: This retrospective study included a consecutive series of 1653 PTC patients followed for a mean period of 5.9 years in a referral thyroid cancer clinic. All patients have undergone thyroidectomy with the dissection of at least six LNs. According to the LN status, patients were subdivided into 569 N0 (34.4%), 644 N1a (39.0%, central compartment) and 440 N1b (26.6%, latero-cervical compartment). RESULTS: Age at diagnosis was significantly lower in N1b (39.8, IQR 30.7-51.6) and N1a (40.1, IQR 31.3-50.1) than in N0 (44.7, IQR 36.6-55.0 yrs). The male gender was more prevalent in N1b than in N1a and N0 (F/M = 1.9/1, 4.0/1 and 5.5/1, respectively). Persistent/recurrent disease at last control was significantly more frequent in N1b (29.8%) than in N1a (14.3%), and in N1a than in N0 (4.2%) (p < 0.01 for all). Also, distant metastases were significantly (p < 0.001) more frequent in N1b (14.1%) than in N1a (4.3%) and N0 (1.6%). LN metastases' number (>5) was a significant risk factor for persistent/recurrent disease only for N1a patients. CONCLUSIONS: These data indicate that persistent/recurrent disease and distant metastases are significantly more frequent in patients with latero-cervical LN (N1b) metastases and that the LN location should be used for a better postsurgical risk stratification. PMID- 28646477 TI - A double-quadratic model for predicting Vibrio species in water environments of Japan. AB - Vibrio spp. are natural inhabitants of marine and estuarine environments. Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus are the major infectious agents for humans. Their densities are affected by environmental factors such as water temperature and salinity. The detailed contribution of each factor still remains to be elucidated. Here we conducted multi-coastal study in a 21-month period to examine relationships between environmental factors and V. cholerae, V. parahaemolyticus and V. vulnificus densities in sea surface water in eight coastal sites of four prefectures in Japan. Vibrio densities were measured by a most-probable-number with PCR method which is highly sensitive and quantitative (3/100 ml of detection limit). Vibrio densities were analyzed with environmental factors including water temperature, salinity, total dissolved substance, and pH, and their quadratics. A linear regression model suited best for prediction of V. cholerae density. A novel double-quadratic model suited best for the prediction of V. parahaemolyticus and V. vulnificus densities. PMID- 28646476 TI - The relationship between circulating adiponectin, leptin and vaspin with bone mineral density (BMD), arterial calcification and stiffness: a cross-sectional study in post-menopausal women. AB - OBJECTIVE: To explore the relationship between circulating adiponectin, leptin and vaspin with bone mineral density (BMD), arterial stiffness and vascular calcification in post-menopausal women. We hypothesised that adipokines produced by adipose tissue may be mediators of bone and cardiovascular disease (CVD) and explain, in part, the observed association between osteoporosis and CVD. DESIGN: We studied 386 ambulant community dwelling postmenopausal women aged (mean [SD] 61 [6.4] years). BMD at the lumbar spine, femoral neck (FN), and total hip (TH), body composition; fat mass (FM) and lean mass (LM) as well as abdominal aortic calcification (AAC) were determined by dual energy X-ray absorptiometry. Pulse wave velocity (PWV) and augmentation index, markers of arterial stiffness were measured. Fasting adiponectin, leptin and vaspin were quantified in serum. RESULTS: A positive independent association was observed between vaspin and BMD at the FN (p = 0.009), TH (p = 0.037) in the whole study population adjusted for confounders including age, FM, LM and lifestyle variables. Using the same model, a negative association was seen between adiponectin and BMD at the FN in women with osteoporosis (p = 0.043). Serum adiponectin was significantly higher in women with fractures (20.8 [9.3] ug/ml compared to those without (18.5 [8.6] ug/ml, p = 0.018) and associated with a significant increased risk of fracture (HR 1.032, 95% CI 1.003-1.063, p = 0.032). Leptin was not associated with BMD or fracture risk after adjustment. Adiponectin was independently associated with AAC (p = 0.007) and significantly higher in women with AAC scores > 1; (19.2[9.2]) compared to those with no or low AAC scores (<1); 16.8 [8.0], p = 0.018). In adjusted analyses, PWV velocity was positively associated with circulating vaspin (p = 0.039) and AI was negatively associated with serum leptin (p = 0.002). CONCLUSION: Adiponectin, leptin, vaspin are related to markers of bone and vascular health and may contribute to the observed association between osteoporosis and CVD. PMID- 28646478 TI - Newborn screening for Fabry disease in the north-west of Spain. AB - : Fabry disease is an X-linked lysosomal storage disorder caused by the impairment of alpha-galactosidase A. Enzyme replacement therapy is available to treat patients, who often experience delayed diagnosis. A newborn screening for Fabry disease was performed to study the prevalence of the pathology and to evaluate the possibility to implement the test in systematic screenings. We collected 14,600 dried blood spot samples (7575 males and 7025 females) and carried out a diagnostic study by fluorometric measurement of alpha-galactosidase A enzymatic activity and GLA gene sequencing. We detected one patient with a mutation in GLA associated with classical Fabry Disease (M290I), ten subjects carrying genetic variants of uncertain diagnosis (S126G, R118C, A143T), and a girl with the non-characterized variant F18Y, which was not previously described. Additional 25 samples presented nucleotide substitutions described as polymorphisms (D313Y, rs2071225, and rs2071397). The estimated prevalence for Fabry disease in north-western Spanish males is of 0.013%. CONCLUSION: These results confirm that the prevalence of Fabry disease is underestimated and systematic screening is feasible; however, further characterization of variants of uncertain clinical significance is necessary to establish protocols of patients' management. What is Known: * Fabry disease is a rare disease of delayed diagnosis, whose prevalence is underestimated. However, early diagnosis is important for better efficiency of the current available treatment. What is New: * This newborn screening for Fabry disease performed on Spanish population reveals a prevalence of genetic alterations in GLA of 0.1% in males (0.013% with classic Fabry disease) and also characterizes these modifications in order to discriminate between pathogenic mutations and genetic variants of unknown significance. PMID- 28646479 TI - Negative Body Attitudes and Sexual Dissatisfaction in Men: The Mediating Role of Body Self-Consciousness During Physical Intimacy. AB - Previous research indicated that negative attitudes about the body and appearance are common among men and demonstrated that negative body attitudes are associated with negative sexual experiences. The present study investigated the association between body attitudes and sexual dissatisfaction and the mediating role of body self-consciousness during physical intimacy. In a cross-sectional design, 201 Dutch men completed an online survey regarding body attitudes toward muscularity, body fat, height, and genitals, body self-consciousness during physical intimacy, and sexual dissatisfaction. Hypotheses were tested using correlation analyses and a mediation analysis with body attitudes as predictors, body self-consciousness as mediator, and sexual dissatisfaction as outcome. Correlation analyses showed that negative body attitudes and body self-consciousness during physical intimacy were significantly related to sexual dissatisfaction. The mediation analysis revealed that negative attitudes toward muscularity, body fat, and genitals had indirect effects on sexual dissatisfaction through body self-consciousness during physical intimacy. Negative attitudes toward genitals additionally had a direct effect on sexual dissatisfaction. These findings indicate that body image interventions focused on male body attitudes may be beneficial in improving men's body image, which may ultimately increase sexual satisfaction. PMID- 28646480 TI - Preschool Gender-Typed Play Behavior at Age 3.5 Years Predicts Physical Aggression at Age 13 Years. AB - Gender differences in play behavior and physical aggression have been consistently reported. Theoretical perspectives concerning evolutionary, social, and social-cognitive mechanisms suggest that male-typical play behavior during childhood increases subsequent physical aggression. The evidence supporting these connections is limited, however. The present study investigated the association between gender-typed play behavior in early childhood and physical aggression in early adolescence using a sample drawn from a longitudinal, population study, the Avon Longitudinal Study of Parents and Children. Based on gender-typed play behavior as measured by the Pre-School Activities Inventory at age 3.5 years, samples of masculine (64 boys, 60 girls), feminine (80 boys, 66 girls), and randomly selected control children (55 boys, 67 girls) were recruited at age 13 years and administered the Reinisch Aggression Inventory. After controlling for a range of sociodemographic variables, maternal characteristics, and behavioral problems, including hyperactivity and conduct problems at age 3.5, significant group differences in physical aggression at age 13 were found among children classified as masculine, control, and feminine at age 3.5. Masculine children exhibited significantly more physical aggression than control children or feminine children, and control children exhibited significantly more physical aggression than feminine children. The association between gender-typed play behavior and physical aggression was not moderated by sex. These results suggest that the degree of childhood gender-typed play behavior independently predicts the degree of physical aggression at adolescence in boys and in girls. PMID- 28646481 TI - Effects of Geography on Mental Health Disparities on Sexual Minorities in New York City. AB - Gay and lesbian individuals have higher rates of psychological distress than do heterosexual individuals. The minority stress hypothesis attributes this disparity to adversity-related stress experienced by sexual minorities. In support of this idea, research in the U.S. has generally found that mental health disparities between sexual minorities and others are narrower in places where tolerance is relatively high. However, few studies have examined disparities between sexual minorities and others in neighborhoods where sexual minorities are most highly concentrated. Likewise, little research attention has been given to disparities for people who move to more tolerant places from less tolerant states and countries. Using data from the New York City Community Health Survey, we found some evidence that disparities between sexual minorities and others were lower in areas with higher concentrations of sexual minorities. However, disparities did not vary by the tolerance level of the state of birth among those born in the U.S. and were actually lower among those born in the least tolerant nations. These results complicate the idea that there is a dose-response relationship between tolerance and psychological distress among sexual minorities. PMID- 28646482 TI - Clinical, serological and histological determinants of patient and renal outcome in ANCA-associated vasculitis with renal involvement: an analysis from a referral centre. AB - PURPOSE: To evaluate significance of clinical and histopathological prognostic factors for renal and patient outcome in AAV patient cohort. METHODS: Retrospective study included consecutive patients diagnosed with pauci-immune crescentic glomerulonephritis from January 2003 to December 2013. Primary outcome was combined endpoint patient death or progression to end-stage renal disease (ESRD). Secondary outcomes were patient survival and progression to ESRD (renal survival) singularly and disease relapse. Kaplan-Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between phenotypes and finding significant predictors regarding outcomes. RESULTS: Out of 81 patients, 40.7% patients reached primary endpoint, 22.2% died, 29.6% reached ESRD and 16% relapsed during follow-up. Multivariate Cox proportional hazards regression-adjusted analysis found higher BVAS (HR 1.08, 95% CI 1.01-1.17, p = 0.042), higher baseline maximal serum creatinine (HR 1.02, 95% CI 1.01-1.03, p = 0.04) and lower haemoglobin (HR 0.97, 95% CI 0.95-0.99, p = 0.011) significantly associated with primary endpoint. Higher BVAS (HR 1.25, 95% CI 1.01-1.43, p = 0.001) and lower haemoglobin (HR 0.95, 95% CI 0.91-0.99, p = 0.008) were significantly associated with patient survival, while for renal survival, lower haemoglobin (HR 0.97, 95% CI 0.94-0.99, p = 0.041) and the need for acute haemodialysis (HR 3.15, 95% CI 1.20-8.26, p = 0.02) were significant predictors. On multivariate-adjusted analysis, no significant predictors for disease relapse were found. Kaplan-Meier survival analysis found no difference between clinical, serological and pathohistological phenotypes for all of the endpoints. CONCLUSIONS: Renal function at presentation, anaemia and BVAS should be included in prediction models for the outcomes for the AAV patients. PMID- 28646483 TI - From novice to expert: analyzing the learning curve for MRI-transrectal ultrasonography fusion-guided transrectal prostate biopsy. AB - PURPOSE: To investigate the learning curve of a novice in MRI/TRUS software fusion biopsy and to compare his results with the expert standard at our institution. METHODS: Overall 126 MRI/TRUS fusion-guided transrectal biopsies were performed using an electromagnetic tracking ultrasonography platform. The learning progress of the novice was evaluated comparing his initial 42 procedures (group A) with his following 42 (group B). The institution's expert standard (group C), which was compared to the novice's groups, was defined by the expert's experience of 42 MRI/TRUS fusion biopsies. Primary learning curve parameters were targeted biopsy detection quotient and biopsy time. RESULTS: Overall detection of prostate cancer was 64% (27/42), 62% (26/42) and 62% (26/42) in groups A, B and C, respectively. The median target biopsy detection quotient significantly increased (p = 0.04) in group B (0.75, interquartile range (IQR) 0.25-1.0) compared to group A. (0.33, IQR 0.2-0.5). Group C revealed a median detection quotient of 0.5 (IQR 0.25-0.76) that did not differ significantly from the novice's groups (p = 0.2). Median biopsy time was significantly higher in group A (45 min, IQR 33-50 min) compared to groups B (25 min, IQR 23-29 min) and C (24 min, IQR 16-46 min) (p < 0.01). CONCLUSIONS: The present study revealed the individual learning curve of a novice in MRI/TRUS fusion biopsy and demonstrated significant learning progress regarding targeted biopsy detection quotient and biopsy time. PMID- 28646484 TI - A practical approach to generate suitable de novo synthesis RNA template for a flavivirus RNA-dependent RNA polymerase. PMID- 28646485 TI - Findings from the Harvard Medical School Cambridge Integrated Clerkship, a Year Long Longitudinal Psychiatry Experience. AB - OBJECTIVE: The Harvard Medical School Cambridge Integrated Clerkship is a longitudinal integrated clerkship that has provided an alternative clinical model for medical education in psychiatry since its inception in 2004. This study was undertaken in an effort to better understand the student experience of the Cambridge Integrated Clerkship and how it may have impacted students' perceptions of and interest in psychiatry, as well as performance. METHODS: Qualitative surveys were sent via e-mail to the first 11 student cohorts who had completed the Cambridge Integrated Clerkship (from 2004 to 2014) and for whom we had e-mail addresses (N = 100), and the free-text responses were coded thematically. All available standardized scoring data and residency match data for Cambridge Integrated Clerkship graduates were obtained. RESULTS: From 2006 to 2014, 12 out of 73 Cambridge Integrated Clerkship students who entered the match chose a psychiatry residency (16.4%), four times more than students in traditional clerkships at Harvard Medical School (3.8% of 1355 students) or the national average (4.1% of 146,066 US applicants). Thirty of the 100 surveyed Cambridge Integrated Clerkship graduates (30%) responded to the qualitative survey with free-text remarks on a number of themes. CONCLUSIONS: Cambridge Integrated Clerkship students compared positively to their classmates in terms of standardized test performance. Their fourfold higher match rate into psychiatry compared to other students raises intriguing questions as to what role a longitudinal clerkship might have played in developing interest in psychiatry as a career. PMID- 28646486 TI - Diagnosing neuralgic amyotrophy: Choosing the right test at the right time. PMID- 28646487 TI - Immunotoxic effects of thymus in mice following exposure to nanoparticulate TiO2. AB - Titanium dioxide nanoparticles (TiO2 NPs) have been extensively used in industry, medicine, and daily life, and have shown potential toxic effects for animals or humans. We noted that the effects of TiO2 NPs on the immune system and its mechanism of action in animals or humans have not been elucidated. Thus, mice were exposed to the TiO2 NPs (0, 1.25, 2.5, or 5 mg kg-1 body weight) for 9 consecutive months. Exposure to TiO2 NPs was accumulated in the thymus, leading to a decrease in body weight and increases in the weight of the thymus or thymus indices. In the blood, exposure to TiO2 NPs significantly decreased white blood cell, red blood cell, reticulocyte, haemoglobin, and mean corpuscular haemoglobin concentration; and increased mean corpuscular volume, mean corpuscular haemoglobin, platelets, and mean platelet volume. The reductions of lymphocyte subsets, including CD3+, CD4+, CD8+, B cell, and natural killer cell, were observed in the TiO2 NP-treated mouse thymus. Appearance of starry-sky aspect of the cortex that is given by the body of macrophages, bleeding, severe hemolysis or congestion, fatty degeneration, and cell apoptosis or necrosis were observed in the thymus following TiO2 NPs exposure. Importantly, TiO2 NPs increased expression of nucleic factor-kappaB(NF-kappaB), IkappaB kinase1/2, interleukin 1beta, interleukin -4, regulated upon activation normal T-cell expressed and secreted, cyclooxygenase 2, neutrophil gelatinase-associated lipocalin, purinergic receptors-7, interferon-inducible protein 10, hypoxia inducible factor 1-alpha, p-c-Jun N-terminal kinase, p-p38, and p-extracellular signal-regulated kinase 1/2 protein, respectively; whereas suppressed expression of IkappaB, peroxisome proliferater-activated receptor-gamma, trefoil factor 1, peroxisome proliferator activated receptor gamma coactivator-1alpha, and prostaglandin E2 proteins in the thymus, respectively. Taken together, these results suggest that TiO2 NPs exerts toxic effects on lymphoid organs and T cell and innate immune cell homeostasis in mice and that these immunotoxic potential effects may result from the activation of NF-kappaB-mediated mitogen-activated protein kinases (MAPKs) pathway. PMID- 28646489 TI - Functional analysis of p.Ala253_Leu254insAsn mutation in PLS3 responsible for X linked osteoporosis. AB - Mutations in Plastin-3 (PLS3) have been identified as a cause of X-linked osteoporosis. To reveal the molecular mechanism of PLS3 on osteoporosis, we characterized the p.Ala253_Leu254insAsn mutation in PLS3. We first identified Lymphocyte cytosolic protein 1 (LCP1) as a binding partner of PLS3 and the mutation disrupted the interaction between them. We then confirmed the roles of PLS3 and LCP1 in the regulation of intracellular Ca2+ , which was weakened by the mutant PLS3. Moreover, the interaction between PLS3 and LCP1 was enhanced under a low concentration of extracellular Ca2+ . However, the mutation in PLS3 weakened the responsiveness. The reduced regulation on Ca2+ caused by p.Ala253_Leu254insAsn may be the possible molecular mechanism of osteoporosis. PMID- 28646488 TI - Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas. AB - Stem cell leukemia/lymphoma syndrome (SCLL) is driven by constitutive activation of chimeric FGFR1 kinases generated by chromosome translocations. We have shown that FGFR inhibitors significantly suppress leukemia and lymphoma development in vivo, and cell viability in vitro. Since resistance to targeted therapies is a major reason for relapse, we developed FGFR1-overexpressing mouse and human cell lines that are resistant to the specific FGFR inhibitors AZD4547 and BGJ398, as well as non-specific inhibitors, such as ponatinib, TKI258 and E3810. Two mutually exclusive mechanisms for resistance were demonstrated; an activating V561M mutation in the FGFR1 kinase domain and mutational inactivation of PTEN resulting in increased PI3K/AKT activity. Ectopic expression of PTEN in the PTEN mutant cells resensitizes them to FGFR inhibitors. Treatment of resistant cells with BGJ398, in combination with the BEZ235 PI3K inhibitor, shows an additive effect on growth in vitro and prolongs survival in xenograft models in vivo. These studies provide the first direct evidence for both the involvement of the FGFR1 V561M mutation and PTEN inactivation in the development of resistance in leukemias overexpressing chimeric FGFR1. These studies also provide a potential strategy to treat leukemias and lymphomas driven by FGFR1 activation that become resistant to FGFR1 inhibitors. PMID- 28646490 TI - Manganese-Catalyzed C-H Functionalizations: Hydroarylations and Alkenylations Involving an Unexpected Heteroaryl Shift. AB - A manganese-catalyzed regio- and stereoselective hydroarylation of allenes is reported. The C-H functionalization method provides access to various alkenylated indoles in excellent yields. Moreover, a hydroarylation/cyclization cascade involving an unexpected C-N bond cleavage and aryl shift has been developed, which provides a new synthetic approach to substituted pyrroloindolones. PMID- 28646491 TI - Sickle cells produce functional immune modulators and cytotoxics. AB - Sickle erythrocytes' (SSRBCs) unique physical adaptation to hypoxic conditions renders them able to home to hypoxic tumor niches in vivo, shut down tumor blood flow and induce tumoricidal responses. SSRBCs are also useful vehicles for transport of encapsulated drugs and oncolytic virus into hypoxic tumors with enhanced anti-tumor effects. In search of additional modes for arming sickle cells with cytotoxics, we turned to a lentiviral beta-globin vector with optimized Locus Control Region/beta-globin coding region/promoter/enhancers. We partially replaced the beta-globin coding region of this vector with genes encoding T cell cytolytics, perforin and granzyme or immune modulating superantigens SEG and SEI. These modified vectors efficiently transduced Sca+ ckit- Lin- hematopoietic stem cells (HSCs) from humanized sickle cell knockin mice. Irradiated mice reconstituted with these HSCs displayed robust expression of transgenic RNAs and proteins in host sickle cells that was sustained for more than 10 months. SSRBCs from reconstituted mice harboring SEG/SEI transgenes induced robust proliferation and a prototypical superantigen-induced cytokine reaction when exposed to human CD4+/CD8+ cells. The beta-globin lentiviral vector therefore produces a high level of functional, erythroid-specific immune modulators and cytotoxics that circulate without toxicity. Coupled with their unique ability to target and occlude hypoxic tumor vessels these armed SSRBCs constitute a potentially useful tool for treatment of solid tumors. PMID- 28646492 TI - Prenatal, perinatal and neonatal risk factors for perinatal arterial ischaemic stroke: a systematic review and meta-analysis. AB - The aim of the present study was to perform a meta-analysis of published data to determine the significance of clinical factors and exposures to the risk of perinatal arterial ischaemic stroke (PAIS) and provide guidance for clinical diagnosis and treatment. A comprehensive literature search of the PubMed, Embase, MEDLINE and Cochrane Library databases for relevant observational studies (cohort/case-control) from March 1984 to March 2016 was undertaken. Two review authors independently examined the full text records to determine which studies met the inclusion criteria and evaluated risk factors for PAIS. Risk ratios, odds ratios and 95% confidence intervals were estimated. A total of 11 studies were included in the analyses. Intrapartum fever >38 degrees C, pre-eclampsia, oligohydramnios, primiparity, forceps delivery, vacuum delivery, fetal heart rate abnormalities, abnormal cardiotocography tracing, cord abnormalities, birth asphyxia, emergency caesarean section, tight nuchal cord, meconium-stained amniotic fluid, umbilical arterial pH <7.10, Apgar score at 5 min <7, resuscitation at birth, hypoglycaemia, male gender and small for gestational age were identified as risk factors for PAIS. This systemic review and meta-analysis provides a preliminary evidence-based assessment of the risk factors for PAIS. Patients with any of the risk factors identified in this analysis should be given careful consideration to ensure the prevention of PAIS. Future studies focusing on the combined effects of multiple prenatal, perinatal and neonatal risk factors for PAIS are warranted. PMID- 28646494 TI - Topiramate as an adjunct to amantadine in the treatment of dyskinesia in parkinson's disease: A randomized, double-blind, placebo-controlled multicenter study. PMID- 28646495 TI - Nursing Philosophy of community mental health nurses in Japan: A qualitative, descriptive study. AB - The present study reports the findings of a qualitative, descriptive study that sought to clarify nursing philosophy for community mental health nurses (CMHN) working at independent psychiatric home-visit nursing agencies in Japan. We carried out participant observation and semistructured interviews with 13 CMHN in rural and urban areas. We identified eight subthemes and three higher-order themes based on these subthemes. CMHN embraced a nursing philosophy in which they: (i) have respect for consumers' ways of life and their self-realization; (ii) find harmony between view of life and work; and (iii) build communities where residents support each other beyond their roles. Together, these themes constitute a valuable nursing philosophy that supports the recovery of people with mental illness. The themes could also help educate professionals about principles and meanings relevant to recovery, which are regarded as key to changing the professional's care paradigm from a biomedical model to a recovery model. PMID- 28646493 TI - Src family kinase phosphorylation of the motor domain of the human kinesin-5, Eg5. AB - Spindle formation in mammalian cells requires precise spatial and temporal regulation of the kinesin-5, Eg5, which generates outward force to establish spindle bipolarity. Our results demonstrate that Eg5 is phosphorylated in cultured cells by Src family kinases (SFKs) at three sites in the motor head: Y125, Y211, and Y231. Mutation of these sites diminishes motor activity in vitro, and replacement of endogenous Eg5 with phosphomimetic Y211 in LLC-Pk1 cells results in monopolar spindles, consistent with loss of Eg5 activity. Cells treated with SFK inhibitors show defects in spindle formation, similar to those in cells expressing the nonphosphorylatable Y211 mutant, and distinct from inhibition of other mitotic kinases. We propose that this phosphoregulatory mechanism tunes Eg5 enzymatic activity for optimal spindle morphology. PMID- 28646496 TI - Unmet belongingness needs but not high belongingness needs alone predict adverse well-being: A response surface modeling approach. AB - OBJECTIVE: Previous work has linked high levels of belongingness needs to low well-being, suggesting that high desire for social connection causes problems. Against that view, we hypothesized that problems stem especially from unmet belongingness needs. To examine this, discrepancies between belongingness needs and relationship satisfaction were measured. METHOD: A total of 1,342 adolescents (Mage = 13.94 years, 48.6% boys) completed questionnaires about belongingness needs, relationship satisfaction, loneliness, depressive symptoms, and self esteem. A combination of polynomial regression analyses with response surface modeling examined the effects of both fulfilled and unmet belongingness needs on well-being. RESULTS: Fulfilled belongingness needs did not affect adolescents' well-being. However, larger discrepancies between high belongingness needs and low relationship satisfaction were related to higher loneliness, more depressive symptoms, and lower self-esteem. Thus, well-being was most strongly affected among adolescents reporting an unmet need to belong. CONCLUSIONS: We add to the current knowledge by emphasizing that especially belongingness needs that exceed relationship satisfaction, regardless of the actual levels of both, contribute to actual health outcomes. Thus, high need to belong is not detrimental per se, but only in combination with low relationship satisfaction. Implications for clinical practice could be to prevent unmet belongingness needs to ultimately alleviate negative affect and self-esteem. PMID- 28646497 TI - Geometrical principles of homomeric beta-barrels and beta-helices: Application to modeling amyloid protofilaments. AB - Examples of homomeric beta-helices and beta-barrels have recently emerged. Here we generalize the theory for the shear number in beta-barrels to encompass beta helices and homomeric structures. We introduce the concept of the "beta-strip," the set of parallel or antiparallel neighboring strands, from which the whole helix can be generated giving it n-fold rotational symmetry. In this context, the shear number is interpreted as the sum around the helix of the fixed register shift between neighboring identical beta-strips. Using this approach, we have derived relationships between helical width, pitch, angle between strand direction and helical axis, mass per length, register shift, and number of strands. The validity and unifying power of the method is demonstrated with known structures including alpha-hemolysin, T4 phage spike, cylindrin, and the HET s(218-289) prion. From reported dimensions measured by X-ray fiber diffraction on amyloid fibrils, the relationships can be used to predict the register shift and the number of strands within amyloid protofilaments. This was used to construct models of transthyretin and Alzheimer beta(40) amyloid protofilaments that comprise a single strip of in-register beta-strands folded into a "beta-strip helix." Results suggest both stabilization of an individual beta-strip helix and growth by addition of further beta-strip helices can involve the same pair of sequence segments associating with beta-sheet hydrogen bonding at the same register shift. This process would be aided by a repeat sequence. Hence, understanding how the register shift (as the distance between repeat sequences) relates to helical dimensions will be useful for nanotube design. PMID- 28646498 TI - Introducing solution-focussed brief therapy to mental health nurses across a local health district in Australia. AB - Solution-focussed brief therapy (SFBT) can be applied to effectively address a broad range of mental health-, alcohol-, and substance-related challenges. The compatibility that SFBT has with mental health nursing practice has been widely recognized. The aim of the present mixed-methods study was to introduce and evaluate the utility of SFBT principles, strategies, and techniques to the clinical work of mental health nurses from a local health district in Sydney, Australia. Following a 4-hour introductory SFBT workshop, participants were invited to complete a one-page evaluation and undertake a follow-up individual telephone interview with a research assistant. Participants (n = 65) were positive about the workshop content and recognized the potential benefits of SFBT in clinical practice. Interviewed participants (n = 14) were enthusiastic about SFBT. However, they also identified that using SFBT was challenging, particularly as the approach was considered different to current practices in mental health services. A lack of confidence with incorporating SFBT in their clinical work was also acknowledged, and participants expressed interest in additional training, including more time to practise SFBT strategies and techniques. Widespread training for mental health nurses in SFBT is indicated, including opportunities for supervision and to observe SFBT being employed by experienced clinicians. PMID- 28646500 TI - Ending preventable stillbirth: A gift for all women. PMID- 28646499 TI - The association between oral hygiene and periodontitis: a systematic review and meta-analysis. AB - OBJECTIVE: Dental plaque accumulation and inadequate personal oral hygiene (OH) are known major risk factors of periodontitis. Nevertheless, the magnitude of their effects has not yet been the subject of a meta-analysis. MATERIAL AND METHODS: The Medline and Scopus databases were searched up to May 2016. Observational studies were eligible if they assessed associations between OH and periodontitis in adult subjects. A multivariate random-effects meta-analysis was used to pool the effects of fair/poor OH versus good OH on periodontitis across studies. The associations between oral care habits and periodontitis were also assessed. RESULTS: A total of 50 studies were eligible; 15 were used for pooling the effect of fair OH versus good OH and poor OH versus good OH on periodontitis, with pooled odds ratios (ORs) of 2.04 [95% confidence interval (CI): 1.65-2.53] and 5.01 (95% CI: 3.40-7.39), respectively. Eleven studies examined oral care habits measured according to toothbrushing regularity and dental visit frequency; pooled ORs of 0.66 (95% CI: 0.47-0.94) and 0.68 (95% CI: 0.47-0.98) were obtained, respectively. CONCLUSIONS: Fair to poor OH increases the risk of periodontitis by two- to five-fold. This risk can be reduced by regular toothbrushing and dental visits. PMID- 28646501 TI - Progressive aortic root dilatation in pediatric heart transplant recipients. AB - BACKGROUND: To determine prevalence, clinical implication, and risk factors for aortic root dilation (ARD) in pediatric heart transplant recipients. METHODS: Serial echocardiograms were reviewed in all pediatric heart transplant recipients from 1999 to 2014 to assess maximal systolic diameter at the aortic annulus, aortic sinus, aortic sino-tubular (ST) junction, and ascending aorta. ARD was defined by a sinus/annulus ratio >1.56, ST junction/annulus ratio >1.28, and/or ascending aorta/annulus ratio >1.35. RESULTS: A total of 147 subjects (53% male) were evaluated; 50% had congenital heart disease (CHD). Of the 74 with CHD, 38 had prior aortic arch reconstruction. The median age at transplant was 3 years (7 days-20.3 years) with a median duration of follow-up of 3.88 years (3 months-15 years). Prevalence of ARD significantly increased in the cohort from 15.6% at the initial echocardiogram to 49.6% at later follow-up (P<.0001). The median duration to development of ARD was 7.6 months. There were no significant differences in prevalence of ARD or days to maximum ratio based on the pretransplant diagnosis. Aortic regurgitation was very rare (7 with <=mild) and did not correlate with ARD or require any interventions. CONCLUSION: During intermediate follow-up, ARD commonly develops in children post-heart transplant, and prevalence increases with time after transplant. Within 1 year after transplant, almost 50% had developed abnormalities in aortic root size that were not apparent at the initial posttransplant echocardiogram. Preexisting CHD or need for prior arch reconstruction did not increase the risk of ARD. PMID- 28646502 TI - The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat. AB - : The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher beta-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral beta glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. CONCLUSION: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295). PMID- 28646503 TI - Personality change across the life span: Insights from a cross-cultural, longitudinal study. AB - OBJECTIVE: Personality traits are characterized by both stability and change across the life span. Many of the mechanisms hypothesized to cause personality change (e.g., the timing of various social roles, physical health, and cultural values) differ considerably across culture. Moreover, personality consistency is valued highly in Western societies, but less so in non-Western societies. Few studies have examined how personality changes differently across cultures. METHOD: We employed a multilevel modeling approach to examine age-related changes in Big Five personality traits in two large panel studies of Americans (n = 6,259; Mage = 46.85; 52.5% female) and Japanese (n = 1,021; Mage = 54.28; 50.9% female). Participants filled out personality measures twice, over either a 9-year interval (for Americans) or a 4-year period (for Japanese). RESULTS: Changes in Agreeableness and Openness to Experience did not systematically vary across cultures; changes in Extraversion, Neuroticism, and Conscientiousness did vary across cultures. Further, Japanese show significantly greater fluctuation in the level of all the traits tested over time than Americans. CONCLUSIONS: The culture specific social, ecological, and life-course factors that are associated with personality change are discussed. PMID- 28646504 TI - Views of mental health consumers about being involved in nursing handover on acute inpatient units. AB - The involvement of consumers in handover with nurses has been identified as reducing miscommunication and a reduction in adverse events in generalist nursing settings. Mental health (MH) care is complex, and handover practices need to fit with the philosophy of recovery-focussed practice. Recovery-focussed practice recognizes the person at the centre of care as an expert in their own treatment and decision-making. The aim of the present study was to explore the views of consumers with a mental illness, without prior involvement in nursing handover, about their need to be involved in nursing handover on an acute mental health inpatient unit. Using an exploratory descriptive, qualitative design (n = 11), participants who were receiving care in an acute inpatient unit were recruited using purposive convenience sampling. Data were collected using semistructured interviews and analysed using thematic analysis. Participants' diagnoses were schizophrenia (n = 6), bipolar affective disorder (n = 4), and depression (n = 1). Two themes emerged from the interviews: (i) behind closed doors; and (ii) being involved. Several subthemes were also identified. The first theme, behind closed doors, had two subthemes: (i) it is about us; and (ii) knowing their thoughts. The second theme had three subthemes: (i) clarifying issues; (ii) setting expectations; and (iii) when and how. Nursing handover on the acute inpatient unit offers a good opportunity for consumers to take an active role in the delivery of nursing care. There is a need to rethink the way nursing handover occurs to include consumers. PMID- 28646505 TI - Hypomethylation and decreased expression of BRG1 in the myocardium of patients with congenital heart disease. AB - BACKGROUND: BRG1, an ATPase subunit of the SWItch/Sucrose Non-Fermentable complex, is tightly associated with cardiac development. However, little is known about the association between the pathogenesis of CHD and BRG1. METHODS: The methylation of a BRG1 promoter and a novel CpG island in the second intron was analyzed in the myocardium of congenital heart disease (CHD) patients (n = 24) and normal controls (n = 11) using pyrosequencing and the MassARRAY platform. BRG1 expression was sketched in the normal fetal and postnatal heart using real time PCR. BRG1 mRNA and protein expression was detected by means of real-time PCR and immunohistochemistry. The expression of GATA4 was analyzed with real-time PCR. RESULTS: The CpG shore in the second intron of BRG1 was hypomethylated in the myocardium of patients (p < 0.05). BRG1 showed a high level of expression in the normal fetal heart in the second trimester (p < 0.01). Compared with that of the normal subjects, BRG1 expression was decreased by 70% in the myocardium of patients (n = 92; p < 0.05). Of note, the expression of GATA4 was significantly correlated with BRG1 expression (r = 0.7475; p = 0.0082) in the myocardium, and it was also decreased by 70% in these patients (n = 92; p < 0.05). CONCLUSION: These results suggested that the early high expression of BRG1 in fetal hearts maintained normal cardiac development and that the abnormal hypomethylation and decreased expression of BRG1 in human hearts probably affect the expression of GATA4, which affects the pathogenesis of CHD. Birth Defects Research 109:1183 1195, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28646506 TI - Three lessons for genetic toxicology from baseball analytics. AB - In many respects the evolution of baseball statistics mirrors advances made in the field of genetic toxicology. From its inception, baseball and statistics have been inextricably linked. Generations of players and fans have used a number of relatively simple measurements to describe team and individual player's current performance, as well as for historical record-keeping purposes. Over the years, baseball analytics has progressed in several important ways. Early advances were based on deriving more meaningful metrics from simpler forerunners. Now, technological innovations are delivering much deeper insights. Videography, radar, and other advances that include automatic player recognition capabilities provide the means to measure more complex and useful factors. Fielders' reaction times, efficiency of the route taken to reach a batted ball, and pitch-framing effectiveness come to mind. With the current availability of complex measurements from multiple data streams, multifactorial analyses occurring via machine learning algorithms have become necessary to make sense of the terabytes of data that are now being captured in every Major League Baseball game. Collectively, these advances have transformed baseball statistics from being largely descriptive in nature to serving data-driven, predictive roles. Whereas genetic toxicology has charted a somewhat parallel course, a case can be made that greater utilization of baseball's mindset and strategies would serve our scientific field well. This paper describes three useful lessons for genetic toxicology, courtesy of the field of baseball analytics: seek objective knowledge; incorporate multiple data streams; and embrace machine learning. Environ. Mol. Mutagen. 58:390-397, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28646507 TI - Influences of placental growth factor on mouse retinal vascular development. AB - BACKGROUND: Placental growth factor (PGF) is important for wound-healing and vascular collaterogenesis. PGF deficiency is associated with preeclampsia, a hypertensive disease of human pregnancy. Offspring born to preeclamptic mothers display cognitive impairments and brain vascular and neurostructural deviations. Low PGF production during development may contribute to alterations in offspring cerebrovascular beds. Retina is a readily accessible part of the central nervous system with a well-described pattern of vascular development in mice. Impacts of PGF deficiency were addressed during mouse retinal vascularization. RESULTS: Retinal vessels were compared between Pgf-/- and congenic C57BL/6 (B6) mice. PGF deficiency altered neonatal retinal vascularization patterns. Some anatomic alterations persisted into adulthood, particularly in males. Greater arterial wall collagen IV expression was found in adult Pgf-/- females. Pregnancy (studied in adult females at gestational days 11.5 or 18.5) induced subtle changes upon the mother's retinal vasculature but these pregnancy-induced changes did not differ between genotypes. Significant sex-related differences occurred between adult male and female B6 although sexually dimorphic retinal vascular differences were absent in B6 neonates. CONCLUSIONS: Overall, PGF has a role in retinal vascular angiogenesis and vessel organization during development but does not affect retinal vessel adaptations in adult females during pregnancy. Developmental Dynamics 246:700-712, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28646508 TI - Hepatic stimulator substance resists hepatic ischemia/reperfusion injury by regulating Drp1 translocation and activation. AB - : Ischemia/reperfusion injury, induced by abnormal mitochondrial fission-related apoptosis, is a major concern in liver transplantation settings. Our previous studies have demonstrated that hepatic stimulator substance (HSS) is an antiapoptotic effector and could protect liver from ischemia/reperfusion injury. However, the underlying mechanism remains unclear. In the present study, we report that in vitro and in vivo HSS could regulate mitochondrial fission and hepatocyte apoptosis during liver ischemia/reperfusion injury by orchestrating the translocation and activation of dynamin-related protein 1 (Drp1). Using a mouse model of ischemia/reperfusion-induced liver injury, we found that HSS haploinsufficient (HSS+/- ) mice displayed exacerbated liver damage based on their increased serum aminotransferase levels, cell structural destruction, and apoptosis levels compared to wild-type (HSS+/+ ) littermates. Disruption of HSS markedly increased cyclin-dependent kinase 1 (CDK1) and Bax expression, accompanied by elevated phosphorylated Drp1 and release of cytochrome c. In parallel in vitro studies, we found that HSS could inhibit the expression of CDK1 and that HSS inhibits hepatocyte apoptosis through its suppression of CDK1/cyclin B-mediated phosphorylation at Ser-616 of Drp1, thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. On the contrary, knockdown of HSS increased CDK1 as well as Drp1 phosphorylation and aggravated hepatocellular apoptosis. Mechanistic investigation showed that HSS was able to reduce the stability and translation of CDK1 mRNA by modulating the expression of several microRNAs (miRs), including miR 410-3p, miR-490-3p, and miR-582-5p. CONCLUSION: Our data reveal a novel mechanism for HSS in regulating the mitochondrial fission machinery and further suggest that modulation of HSS may provide a therapeutic approach for combating liver damage. (Hepatology 2017;66:1989-2001). PMID- 28646509 TI - Resistance to group clinical supervision: A semistructured interview study of non participating mental health nursing staff members. AB - This present study is a report of an interview study exploring personal views on participating in group clinical supervision among mental health nursing staff members who do not participate in supervision. There is a paucity of empirical research on resistance to supervision, which has traditionally been theorized as a supervisee's maladaptive coping with anxiety in the supervision process. The aim of the present study was to examine resistance to group clinical supervision by interviewing nurses who did not participate in supervision. In 2015, we conducted semistructured interviews with 24 Danish mental health nursing staff members who had been observed not to participate in supervision in two periods of 3 months. Interviews were audio-recorded and subjected to discourse analysis. We constructed two discursive positions taken by the informants: (i) 'forced non participation', where an informant was in favour of supervision, but presented practical reasons for not participating; and (ii) 'deliberate rejection', where an informant intentionally chose to not to participate in supervision. Furthermore, we described two typical themes drawn upon by informants in their positioning: 'difficulties related to participating in supervision' and 'limited need for and benefits from supervision'. The findings indicated that group clinical supervision extended a space for group discussion that generated or accentuated anxiety because of already-existing conflicts and a fundamental lack of trust between group members. Many informants perceived group clinical supervision as an unacceptable intrusion, which could indicate a need for developing more acceptable types of post-registration clinical education and reflective practice for this group. PMID- 28646510 TI - Compound muscle action potential duration in critical illness neuromyopathy. AB - INTRODUCTION: We sought to determine the specificity of compound muscle action potential (CMAP) durations and amplitudes in a large critical illness neuromyopathy (CINM) cohort relative to controls with other neuromuscular conditions. METHODS: Fifty-eight patients with CINM who had been seen over a 17 year period were retrospectively studied. Electrodiagnostic findings of the CINM cohort were compared with patients with axonal peripheral neuropathy and myopathy due to other causes. RESULTS: Mean CMAP durations were prolonged, and mean CMAP amplitudes were severely reduced both proximally and distally in all nerves studied in the CINM cohort relative to the control groups. The specificity of prolonged CMAP durations for CINM approached 100% if they were encountered in more than 1 nerve. DISCUSSION: Prolonged, low-amplitude CMAPs occur more frequently and with greater severity in CINM patients than in neuromuscular controls with myopathy and axonal neuropathy and are highly specific for the diagnosis of CINM. Muscle Nerve 57: 395-400, 2018. PMID- 28646511 TI - Control of autoimmune inflammation using liposomes to deliver positive allosteric modulators of metabotropic glutamate receptors. AB - Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation. The therapeutic potential of PHCCC, however, is hindered by dose-limiting toxicity, poor solubility, and the need for frequent dosing. We hypothesized liposomal delivery of PHCCC might enable safe, effective delivery of this hydrophobic drug to exploit metabolism as a means of controlling inflammation in self-reactive immune cells. PHCCC was readily encapsulated in liposomes modified with polyethylene glycol. Under sink conditions, controlled release resulted in 58% of drug released into media over 18 hours. Culture of primary DCs with PHCCC liposomes reduced pro-inflammatory cytokine secretion while reducing toxicity four-fold compared with soluble PHCCC. During co-culture of DCs with myelin-reactive T cells from transgenic mice, PHCCC liposomes reduced T cell proliferation and interferon gamma secretion. These results support the potential of using liposomes to promote tolerance through biocompatible delivery of metabolic modulators. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2977-2985, 2017. PMID- 28646513 TI - Long-term outcomes of Group D retinoblastoma eyes during the intravitreal melphalan era. AB - BACKGROUND: To evaluate outcomes of Group D retinoblastoma (Rb) eyes during the intravitreal melphalan era. PROCEDURE: Retrospective chart review of patients diagnosed with Group D Rb from 2011 to 2016 was done. Overall, 76 Group D eyes of 68 patients were included; salvage therapy included systemic chemoreduction with vincristine, etoposide, and carboplatin with local consolidation, followed by intravitreal injection of melphalan for recurrent or persistent seeding. External beam radiation was not used as a treatment modality. Primary outcome measurement was globe salvage. RESULTS: Of 76 Group D eyes, 24 were enucleated primarily and 52 were treated with intent to salvage the globe. Systemic chemoreduction salvaged 25 of 52 eyes (48%). Tumor recurrences were diagnosed in 27 eyes (52%); five with massive retinal recurrences underwent enucleation and 22 were treated with intravitreal melphalan injection. Of the 22 injected eyes, 14 (64%) were salvaged and eight required enucleation primarily for retinal recurrences. Success in eradicating vitreous seeds was 100%. The Kaplan-Meier 3-year survival estimate for treated eyes is 76.5% (95% CI: 61.4-86.3). Median follow-up for the group of 76 Group D eyes was 29.5 months (SD 17.9 months). CONCLUSION: During a 6 year period that included the initiation of intravitreal melphalan at our institution, the salvage rate of treated Group D eyes was 75% (39/52 eyes). Intravitreal melphalan was utilized for ocular salvage in 42% (22/52 eyes). Systemic chemoreduction combined with intravitreal melphalan for seeding demonstrated a high overall salvage rate for Group D eyes in this cohort. PMID- 28646514 TI - Incidental pulmonary arterial dilatation and coronary calcifications in patients with hypertension and normal findings on myocardial perfusion technetium-99m sestamibi single-photon emission computed tomography. PMID- 28646512 TI - WMJ-8-B, a novel hydroxamate derivative, induces MDA-MB-231 breast cancer cell death via the SHP-1-STAT3-survivin cascade. AB - BACKGROUND AND PURPOSE: Histone deacetylase (HDAC) inhibitors have been demonstrate to have broad-spectrum anti-tumour properties and have attracted lots of attention in the field of drug discovery. However, the underlying anti-tumour mechanisms of HDAC inhibitors remain incompletely understood. In this study, we aimed to characterize the underlying mechanisms through which the novel hydroxamate-based HDAC inhibitor, WMJ-8-B, induces the death of MDA-MB-231 breast cancer cells. EXPERIMENTAL APPROACH: Effects of WMJ-8-B on cell viability, cell cycle distribution, apoptosis and signalling molecules were analysed by the MTT assay, flowcytometric analysis, immunoblotting, reporter assay, chromatin immunoprecipitation analysis and use of siRNAs. A xenograft model was used to determine anti-tumour effects of WMJ-8-B in vivo. KEY RESULTS: WMJ-8-B induced survivin reduction, G2/M cell cycle arrest and apoptosis in MDA-MB-231 cells. STAT3 phosphorylation, transactivity and its binding to the survivin promoter region were reduced in WMJ-8-B-treated cells. WMJ-8-B activated the protein phosphatase SHP-1 and when SHP-1 signalling was blocked, the effects of WMJ-8-B on STAT3 phosphorylation and survivin levels were abolished. However, WMJ-8-B increased the transcription factor Sp1 binding to the p21 promoter region and enhanced p21 levels. Moreover, WMJ-8-B induced alpha-tubulin acetylation and disrupted microtubule assembly. Inhibition of HDACs was shown to contribute to WMJ-8-B's actions. Furthermore, WMJ-8-B suppressed the growth of MDA-MB-231 xenografts in mammary fat pads in vivo. CONCLUSIONS AND IMPLICATIONS: The SHP-1 STAT3-survivin and Sp1-p21 cascades are involved in WMJ-8-B-induced MDA-MB-231 breast cancer cell death. These results also indicate the potential of WMJ-8-B as a lead compound for treatment of breast cancer and warrant its clinical development. PMID- 28646515 TI - Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival. AB - : Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short-term prognosis, whereas factors associated with long-term survival are largely unknown. The aims of our study were to (1) determine the impact of complete abstinence from alcohol on long-term survival and (2) identify prognostic factors at admission capable of predicting abstinence during long-term follow-up in patients with AH. One hundred forty-two patients with biopsy-proven AH that survived the first episode were included. Demographic, psychiatric, and biochemical variables at admission and drinking status during follow-up were obtained. Cox regression, logistic regression, and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow-up of 55 months. During follow-up, complete abstinence was reported in 39% and was associated with better long-term survival (hazard ratio, 0.53; P = 0.03). After adjustment for baseline prognostic scoring systems (Model for End-Stage Liver Disease and age, bilirubin, international normalized ratio, creatinine scores), complete abstinence was independently associated with survival (P < 0.05). Age and lack of past alcoholism treatments were independently associated with complete abstinence (P < 0.001 and P = 0.02, respectively) during follow-up. CART analysis generated a simple and practical algorithm based on the combination of past alcoholism treatments and age. Using CART analysis, we stratified 2 subgroups of patients with high (65%) and low (26%-29%) rates of complete abstinence after an episode of AH. CONCLUSION: Complete abstinence after an episode of AH positively impacts long-term survival. The combination of 2 variables easily obtained at admission might be useful to predict long-term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842-1853). PMID- 28646517 TI - Clinical characteristics and outcomes of previously untreated patients with adult onset T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma with hyper-CVAD based regimens. PMID- 28646516 TI - Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis. AB - BACKGROUND AND PURPOSE: Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation. EXPERIMENTAL APPROACH: CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg.kg-1 .day 1 ) for 2 weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations and then stimulated with IFNgamma in the presence or absence of tofacitinib in order to study mediators of RCT. KEY RESULTS: Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNgamma further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor alpha and ATP-binding cassette transporter (ABCA1) synthesis. CONCLUSIONS AND IMPLICATIONS: Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients. PMID- 28646518 TI - Comparative proteomics and protein profile related to phenolic compounds and antioxidant activity in germinated Oryza sativa 'KDML105' and Thai brown rice 'Mali Daeng' for better nutritional value. AB - BACKGROUND: Brown rice (BR) and germinated brown rice (GBR) are considered as prime sources of carbohydrate and bioactive compounds for more than half of the populations worldwide. Several studies have reported on the proteomics of BR and GBR; however, the proteomic profiles related to the synthesis of bioactive compounds are less well documented. In the present study, BR and GBR were used in a comparative analysis of the proteomic and bioactive compound profiles for two famous Thai rice varieties: Khao Dawk Mali 105 (KDML) and Mali Daeng (MD). RESULTS: The proteomes of KDML and MD revealed differences in the expression patterns of proteins after germination. Total phenolic compound content, anthocyanin contents and antioxidant activity of red rice MD was approximately 2.6-, 2.2- and 9.2-fold higher, respectively, compared to that of the white rice KDML. Moreover, GBR of MD showed higher total anthocyanin content and greater antioxidant activity, which is consistent with the increase expression of several proteins involved in the biosynthesis of phenolic compounds and protection against oxidative stress. CONCLUSION: Red rice MD exhibits higher nutrient values compared to white rice KDML and the appropriate germination of brown rice could represent a method for improving health-related benefits. (c) 2017 Society of Chemical Industry. PMID- 28646519 TI - The Association of Health Literacy With Preventable Emergency Department Visits: A Cross-sectional Study. AB - BACKGROUND: Policymakers argue that emergency department (ED) visits for conditions preventable with high-quality outpatient care contribute to waste in the healthcare system. However, access to ambulatory care is uneven, especially for vulnerable populations like minorities, the poor, and those with limited health literacy. The impact of limited health literacy on ED visits that are preventable with timely, high-quality ambulatory care is unknown. OBJECTIVE: The objective was to determine the association of health literacy with preventable ED visits. METHODS: We conducted an observational cross-sectional study of potentially preventable ED visits (outcome) among adults (>=18 years old) in an ED serving an urban community. We assessed health literacy (predictor) through structured interviews with the Rapid Estimate of Adult Literacy in Medicine (REALM). We recorded age, sex, race, employment, payer, marital and health status, and number of comorbidities through structured interviews or electronic record review. We identified potentially preventable ED visits in the 2 years before the index ED visit by applying Agency for Healthcare Research and Quality technical specifications to identify ambulatory care sensitive conditions using ED discharge diagnoses in hospital administrative data. We used Poisson regression to evaluate the number of preventable ED visits among patients with limited (REALM < 61) versus adequate (REALM >= 61) health literacy after adjusting for covariates. RESULTS: Of 1,201 participants, 709 (59%) were female, 370 (31%) were African American, mean age was 41.6 years, and 394 (33%) had limited health literacy. Of 4,444 total ED visits, 423 (9.5%) were potentially preventable. Of these, 260 (61%) resulted in hospital admission and 163 (39%) were treat and release. After covariates were adjusted for, patients with limited literacy had 2.3 (95% confidence interval [CI] = 1.7-3.1) times the number of potentially preventable ED visits resulting in hospital admission compared to individuals with adequate health literacy, 1.4 (95% CI = 1.0-2.0) times the number of treat-and-release visits, and 1.9 (95% CI = 1.5-2.4) times the number of total preventable ED visits. CONCLUSIONS: Our results suggest that the ED may be an important site to deploy universal literacy-sensitive precautions and to test literacy-sensitive interventions with the goal of reducing the burden of potentially preventable ED visits on patients and the healthcare system. PMID- 28646520 TI - Shape analysis of the cervical spinous process. AB - Most textbooks describe the bifid spinous process as a shape associated with the typical cervical vertebra. Somewhere later they may acknowledge that cervical vertebrae are not always bifid, and that its appearance may be asymmetric. A high incidence of bifid cervical spinous processes may be a human characteristic, but because of known racial/geographic variation it may not be a very good one. Rarely can one find a satisfactory explanation of the functional or developmental basis for this shape variation. This article explores the distinctive shape of the cervical spinous process. Analysis is based upon the spinous processes of the third through seventh cervical vertebrae from fifty individuals. Shape differences were evaluated using the techniques of geometric morphometrics. Statistical comparisons were based upon 1000 permutations of a MANOVA based analysis. Significant shape differences were identified among the cervical vertebrae. However, post hoc analysis failed to identify significant differences between the C3 and C4 and between the C4 and C5 spinous process shapes. Primary shape differences were due to the depth of the bifid separation and the length of the process. Vertebrae with shorter spinous processes tended to display a more pronounced bifid condition. Combined observations from this and several other investigations suggest that a combination of variation in the spinalis cervicis muscle and behavioral patterns associated with cervical load may provide the best explanation for the shape variation in the cervical spinous process. Clin. Anat. 30:894-900, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28646521 TI - Enhancing Perovskite Electrocatalysis of Solid Oxide Cells Through Controlled Exsolution of Nanoparticles. AB - Perovskite oxides have received a great deal of attention as promising electrodes in both solid oxide fuel cells (SOFCs) and solid oxide electrolyzer cells (SOECs) because of their reasonable reactivity, impurity tolerance, and tunable properties. In particular, exploration is still required for improving perovskite electrodes, which normally suffer from slow kinetics in electrocatalysis. Experimental studies have led to the development of new classes of perovskites with advanced characteristics and electrode kinetics at technical levels. In parallel with those developments, achievements in theoretical and computational studies have led to substantial understanding, at the atomic level, of their physicochemical properties and electrocatalytic behaviors. Their chemical and structural flexibilities enable perovskites to accommodate most metallic elements without destroying their complex matrix structures, thereby delivering a pathway to engineer their catalytic properties. In this Minireview, recent advances in perovskite electrodes are introduced, and perovskites with exsolved nanoparticles are discussed as enhanced electrocatalytic materials. PMID- 28646522 TI - Pericarditis during infliximab therapy in paediatric ulcerative colitis. AB - WHAT IS KNOWN AND STUDY OBJECTIVE: Infliximab is a widely used drug for treating inflammatory bowel disease (IBD). This drug is known to rarely cause pericarditis in adult populations. CASE SUMMARY: This report details the case of a 14-year-old boy with ulcerative colitis who developed pericarditis after a second infliximab infusion. After discontinuation of therapy, the patient's symptoms were resolved. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first reported paediatric case of pericarditis as a possible complication of infliximab therapy in IBD. Among infliximab-related delayed adverse reactions, cardiac complications should be monitored in the paediatric population. PMID- 28646523 TI - Does clinical placement in a community alcohol and other drugs rehabilitation centre influence students' career intention? AB - Due to an ageing workforce, there is a growing need for greater numbers of nurses to work in areas, such as mental health and alcohol and other drugs (AOD) rehabilitation. These practitioners need to approach their work as 'recovery oriented practitioners'. Positive experiences and preceptorship during clinical placement in AOD rehabilitation settings might influence students' later career choices and address some of the workforce shortage issues. The aim of the present concurrent, mixed-methods study was to explore students' perceptions of their clinical placement experience in a community-based AOD rehabilitation setting, and to examine attitude, career intention, and satisfaction with the placement. Fifty-eight students completed pre-post-test surveys, with closed and open-ended questions, which included standardized measures. A small sample of survey respondents also agreed to participate in a semistructured interview. The quantitative results revealed two predictors for higher intention to pursue a career in AOD: (i) a high satisfaction with their clinical placement (beta = 0.29, P = 0.008); and (ii) a high baseline attitude to recovery-oriented practice (beta = 0.28, P = 0.013). The qualitative findings identified five factors influencing placement experience: (i) educational factors; (ii) students' background factors; (iii) placement factors; (iv) client factors; and (v) staff factors. A model that synthesizes the quantitative and qualitative findings was also developed. In conclusion, clinical placement in a community-based AOD rehabilitation centre improved students' intention to work in that setting. PMID- 28646524 TI - Risk factors for severe respiratory depression from prescription opioid overdose. AB - BACKGROUND AND AIMS: Prescription opioid overdose is a leading cause of injury related morbidity and mortality in the United States. We aimed to identify characteristics associated with clinical severity in emergency department patients with prescription opioid overdose. DESIGN: This was a secondary data analysis of adult prescription opioid overdoses from a large prospective cohort of acute overdoses. We examined elements of a typical emergency department evaluation using a multivariable model to determine which characteristics were associated with clinical severity, specifically severe respiratory depression (SRD). SETTING: This study was conducted at two urban academic emergency departments in New York City, USA. PARTICIPANTS: Adult patients who presented with acute prescription opioid overdose between 2009 and 2013 were included in the current study. We analyzed 307 patients (mean age = 44.7, 42% female, 2.0% mortality). MEASUREMENTS: Patient demographics, reported substances ingested, suspected intent for ingesting the substance, vital signs, laboratory data, treatments including antidotes and intubation and outcome of death were recorded by trained research assistants. Intent was categorized into four mutually exclusive categories: suicide, misuse, therapeutic error and undetermined. The primary outcome was SRD, defined as administration of either (a) naloxone or (b) endotracheal intubation (ETI). FINDINGS: A total of 109 patients suffered SRD with 90 patients receiving naloxone alone, nine ETI alone and 10 both naloxone and ETI. The most common opioids were oxycodone (n = 124) and methadone (n = 116). Mean age was higher in patients with SRD (51.1 versus 41.1, P < 0.001). Opioid misuse was associated with SRD in the multivariable analysis [odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.21-3.55]. The unadjusted relative risk of SRD was high for fentanyl (83.3% SRD) and lowest for codeine (3.6% SRD). CONCLUSION: In emergency department patients in the United States with prescription opioid overdose, worse clinical severity was associated with opioid misuse, increased with age and was widely variable, depending on the specific opioid medication involved. PMID- 28646525 TI - Preliminary characterization of putative structural cuticular proteins in the malaria vector Anopheles sinensis. AB - BACKGROUND: The insect cuticle protects against environmental stresses such as insecticides, physical injury, dehydration and pathogenic microorganisms. Structural cuticular proteins (CPs) are the primary components of the cuticle, and are of interest for physiology-based pest management methods. Anopheles sinensis CPs are poorly characterised at present, and therefore we performed whole-genome sequence analysis and re-analysed available transcriptome data to identify potential insecticide resistance-associated CPs. RESULTS: Genome analysis revealed 238 putative CPs belonging to 11 different families; 136 proteins possessing a Rebers and Riddiford motif (CPR), 12 CPs analogous to peritrophins with a single chitin-binding domain (CPAP1), eight CPs analogous to peritrophins with three chitin-binding domains (CPAP3), four proteins with a 44 amino acid motif (CPF), five CPF-like (CPFL) proteins, nine Tweedle proteins, three proteins of low complexity with alanine residues (CPLCA), 26 proteins of low complexity with conserved glycine residues (CPLCG), seven proteins of low complexity with invariant W residues (CPLCW), 27 proteins of low complexity with proline residues (CPLCP), and one protein with two or three copies of a C-X -C motif (CPCFC). Two CPs belonging to the CPR and CPAP3 families were over expressed in a deltamethrin-resistant strain. CONCLUSION: These results establish an information framework for An. sinensis CPs that provides a basis for further molecular research. (c) 2017 Society of Chemical Industry. PMID- 28646526 TI - ADAMTS13 test and/or PLASMIC clinical score in management of acquired thrombotic thrombocytopenic purpura: a cost-effective analysis. AB - BACKGROUND: The ADAMTS13 test distinguishes thrombotic thrombocytopenic purpura (TTP) from other thrombotic microangiopathies (TMAs). The PLASMIC score helps determine the pretest probability of ADAMTS13 deficiency. Due to inherent limitations of both tests, and potential adverse effects and cost of unnecessary treatments, we performed a cost-effectiveness analysis (CEA) investigating the benefits of incorporating an in-hospital ADAMTS13 test and/or PLASMIC score into our clinical practice. STUDY DESIGN AND METHODS: A CEA model was created to compare four scenarios for patients with TMAs, utilizing either an in-house or a send-out ADAMTS13 assay with or without prior risk stratification using PLASMIC scoring. Model variables, including probabilities and costs, were gathered from the medical literature, except for the ADAMTS13 send-out and in-house tests, which were obtained from our institutional data. RESULTS: If only the cost is considered, in-house ADAMTS13 test for patients with intermediate- to high-risk PLASMIC score is the least expensive option ($4,732/patient). If effectiveness is assessed as measured by the number of averted deaths, send-out ADAMTS13 test is the most effective. Considering the cost/effectiveness ratio, the in-house ADAMTS13 test in patients with intermediate- to high-risk PLASMIC score is the best option, followed by the in-house ADAMTS13 test without the PLASMIC score. CONCLUSIONS: In patients with clinical presentations of TMAs, having an in hospital ADAMTS13 test to promptly establish the diagnosis of TTP appears to be cost-effective. Utilizing the PLASMIC score further increases the cost effectiveness of the in-house ADAMTS13 test. Our findings indicate the benefit of having a rapid and reliable in-house ADAMTS13 test, especially in the tertiary medical center. PMID- 28646527 TI - A randomized clinical trial to compare pain levels during three types of oral anesthetic injections and the effect of Dentalvibe(r) on injection pain in children. AB - BACKGROUND: Pain control is of great importance particularly in pediatric dentistry. The Dentalvibe(r) is a device that delivers vibration to the injection site in order to reduce intraoral injections' pain. AIMS: The purpose of this study was to compare pain levels caused by three types of anesthesia injections and the effect of the Dentalvibe(r) on reducing the injection pain. DESIGN: The study included 40 children, and each one received six injections. The injections were divided randomly into two methods: experimental (DV): buccal and palatal infiltration on the maxilla and inferior alveolar nerve block (IANB) with vibration and traditional (TR): receiving the same previous injections without vibration. Moreover, pain was assessed using the FLACC(r) and Wong-Baker faces(r) pain scales. Then after, patients were asked about their favorite method. RESULTS: No statistically significant differences were observed regardless of the injection site in subjective and objective evaluation in the (TR) method. Although the pain scores in (DV) method were less than the traditional in most injections, the differences were not statistically significant. CONCLUSIONS: Children experienced similar levels of pain in all sites of injection using the traditional method. The Dentalvibe(r) did not decrease discomfort and was not accepted more by children. PMID- 28646528 TI - Genetic variants in microRNA-binding sites of DNA repair genes as predictors of recurrence in patients with squamous cell carcinoma of the oropharynx. AB - The incidence of squamous cell carcinoma of the oropharynx (SCCOP) continues to rise because of increasing rates of human papillomavirus (HPV) infection. Inherited polymorphisms in DNA repair pathways may influence the risk of SCCOP development and the prognosis of SCCOP. We sought to determine whether polymorphisms in microRNA (miRNA)-binding sites within 3'-untranslated regions (3'UTRs) of genes in DNA repair pathways modulate the risk of SCCOP recurrence. We evaluated the associations between nine such polymorphisms and SCCOP recurrence in 1,008 patients with incident SCCOP using the log-rank test and multivariable Cox models. In an analysis of all the patients, patients with variant genotypes of BRCA1 rs12516 and RAD51 rs7180135 had better disease-free survival (log-rank, p = 0.0002 and p = 0.0003, respectively) and lower risk of SCCOP recurrence (hazard ratio [HR], 0.5, 95% confidence interval [CI], 0.2-0.8, and HR, 0.5, 95% CI, 0.3-0.9, respectively) than patients with common homozygous genotypes of the two polymorphisms after multivariable adjustment. Moreover, in tumor HPV16-positive patients, patients with variant genotypes of the same two polymorphisms also had better disease-free survival (log-rank, p = 0.004 and p = 0.003, respectively) and lower recurrence risk (HR, 0.2, 95% CI, 0.1-0.6, and HR, 0.2, 95% CI, 0.0-0.7, respectively) than patients with common homozygous genotypes of the two polymorphisms. No such significant associations were found for other polymorphisms. These findings support significant roles of BRCA1 rs12516 and RAD51 rs7180135 in modifying the risk of recurrence of SCCOP, particularly HPV16-positive SCCOP. However, these results must be validated in larger studies. PMID- 28646529 TI - Notalgia paresthetica: factors associated with its perceived severity, duration, side, and localization. AB - BACKGROUND: Notalgia paresthetica (NP) is a disorder characterized by pruritus localized to the patient's back. Little is known about predictors of severity, duration, side, and localization. OBJECTIVE: To identify factors associated with perceived severity, duration, side, and localization of NP. METHODS: In a cross sectional study, disease severity, duration, side, and localization were compared among the considered variables. Multivariate analysis was used to assess each variable contribution in predicting disease severity and its duration. RESULTS: Sixty-five patients were recruited. Disease involved more female than male patients (Female/Male: 1.6) and after adjusting for all potential confounders, it was perceived as more severe in females (OR = 7.3, 95% CI = 2-26.3, P < 0.01). NP was reported more frequently on the right side among patients sleeping on the left side and conversely (P < 0.05). A higher disease duration was significantly linked to a higher body mass index (OR = 4.8, 95% CI = 1.3-17.1, P < 0.05). CONCLUSION: Our study linked female gender to worse disease severity, a higher body mass index to longer disease duration, and prevailing sleep position to NP side expression. The sleeping position should be considered a possible target for treating the disease. PMID- 28646530 TI - Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury. AB - Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1-/- ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1-/- mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1-/- mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018. PMID- 28646532 TI - Acquired bilateral telangiectasia macularis eruptiva perstans: A unique clinical feature of photodamaging rather than a subtype of cutaneous mastocytosis. AB - Telangiectasia macularis eruptiva perstans (TMEP) is a rare subtype of cutaneous mastocytosis, characterized by telangiectatic tan to brown macules on the trunk and extremities. Although TMEP has been descried as an uncommon disease in the literature, we often encounter patients with TMEP lesions in the outpatient clinic. We aimed to assess the clinical and histopathological characteristics of acquired bilateral TMEP, and the pathophysiological mechanism of acquired bilateral TMEP among these patients. We retrospectively reviewed 30 patients (28 men and 2 women) with acquired bilateral TMEP; multiple telangiectatic dark red to brown macules that were symmetrically distributed. The clinical characteristics and general histopathological findings of lesional skin were investigated. The number of mast cells was evaluated using immunohistochemical analysis with an antibody directed against c-kit (CD117). Acquired bilateral TMEP was predominantly localized on the sun-exposed area: the upper arm in 30 patients (100%), forearm in 19 patients (63.3%) and anterior chest in 15 patients (50%). A total of 16 patients (53.3%) showed at least one aggravating factor, including UV irradiation, alcohol use and heat exposure. Compared with the mast cell numbers in 19 age- and biopsy site-matched healthy controls (91 +/- 29.0/mm2 ), the number of mast cells in the papillary dermal skin of acquired bilateral TMEP patients was significantly increased (159 +/- 37.2/mm2 , P < 0.01). In addition, a significant difference in vessel numbers in the papillary dermis was observed between acquired bilateral TMEP patients and healthy controls (10.5 +/- 1.9 vs 5.4 +/- 1.0/mm2 , P < 0.01). Acquired bilateral TMEP is a relatively common disorder in middle-aged Asian men. An increased number of mast cells and dilated vessels might be a photoaging-related reactive process of chronic sun-exposure, which consequently leads to the formation of characteristic telangiectatic hyperpigmentary macules through certain melanogenic mediators. PMID- 28646531 TI - Morin, a novel liver X receptor alpha/beta dual antagonist, has potent therapeutic efficacy for nonalcoholic fatty liver diseases. AB - BACKGROUND AND PURPOSE: Morin is a natural occurring flavonoid in many dietary plants and has a wide range of beneficial effects on metabolism; however, the mechanism underlying its action remains elusive. EXPERIMENTAL APPROACH: A reporter assay and the time-resolved FRET assay were used to identify morin as a dual antagonist of liver X receptor (LXR)-alpha and -beta. Morin (100 mg. 100 g-1 diet) was administered to high-fat diet-induced obese or LXRbeta-/- mice. The pharmacological effects and mechanism of action of morin were evaluated by Western blot and RT-PCR analyses. KEY RESULTS: From the in vitro assays, morin was shown to be a dual antagonist of LXRalpha and LXRbeta. In vivo, morin blunted the development of liver hepatic steatosis, reduced body weight gains, lowered triglyceride levels and improved glucose and insulin tolerance in mice fed a high fat diet. Mechanistically, morin inhibited 3T3-L1 adipocyte differentiation and lipid formation in human hepatic HepG2 cells and suppressed the mRNA expression of genes downstream of LXR. Consistently, the effects of morin on metabolic disorders were attenuated in LXRbeta-/- mice. CONCLUSION AND IMPLICATIONS: Our data reveal that morin is a dual antagonist of LXRalpha and LXRbeta and suggest that morin may alleviate hepatic steatosis and other associated metabolic disorders via the suppression of LXR signalling and, therefore, shows promise as a novel therapy or nutraceutical for nonalcoholic fatty liver disease. PMID- 28646533 TI - Palladium-Catalyzed Fluoroarylation of gem-Difluoroalkenes. AB - A Pd-catalyzed fluoroarylation of gem-difluoroalkenes with aryl halides is reported. By taking advantage of the in situ generated alpha-CF3 -benzylsilver intermediates derived from the nucleophilic addition of silver fluoride to gem difluoroalkenes, this strategy bypasses the use of a strong base, thus enabling a mild and general synthetic method for ready access to non-symmetric alpha,alpha disubstituted trifluoroethane derivatives. PMID- 28646534 TI - History of consolidation is prognostic in acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplantation in minimal residual disease-negative first complete remission. AB - BACKGROUND: Prognostic factors among acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in minimal residual disease (MRD)-negative first complete remission (CR1) are unknown. We retrospectively attempted to answer the following question: In AML patients undergoing allo-HCT in MRD-negative CR1, does a history of prior consolidation provide additional prognostic information? METHODS: The inclusion criteria were: (i) Age > 18 years, (ii) AML in CR1 after 1-2 cycles of intensive induction chemotherapy, with or without consolidation, (iii) Allo-HCT between 1/2003 and 4/2016 at our institution, (iv) Available standard-sensitivity 4-color flow cytometry results from a bone marrow aspiration at diagnosis and after completion of all previous chemotherapy within one month prior to HCT, (v) Flow cytometry based MRD-negative status at the time of HCT. RESULTS: A history of prior consolidation was associated with favorable overall survival (Hazard Ratio [95% Confidence Interval]: 0.59 [0.35-0.99], P = .046), relapse-free survival (0.60 [0.37-0.96], P = .036), and relapse (0.50 [0.27-0.92], P = .025). Analysis of potential sources of bias was unrevealing. CONCLUSIONS: In AML patients undergoing allo-HCT in MRD-negative CR1, a history of prior consolidation was associated with favorable outcomes. If the path to pre-HCT MRD negativity includes consolidation, it may identify patients with improved prognosis following HCT in MRD-negative state. These results warrant validation in larger cohorts. PMID- 28646535 TI - Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma. AB - Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. Signal transducer and activator of transcription 3(STAT3) expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO 3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl 2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of human umbilical vein endothelial cells capillary-like structures and invasion at both 5 and 10 uM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens. PMID- 28646536 TI - Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon. AB - Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in 2 genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon (HEC) has been reported in some patients as a non-pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a HEC (HEC group) and 39 with a classical postnatal form (CC group). SLC3A1 and SLC7A9 were sequenced. All patients were fully genotyped, and the relationship between the genotype and clinical features was analyzed. We identified mutations in SLC3A1 in 80% of the HEC group and in only 49% of the CC group. The SLC3A1 p.Thr216Met mutation was found in 21% of the alleles in the HEC group but was never found in the CC group. Most of the mutations found in the HEC group were considered severe mutations in contrast with the CC group. Twenty-five novel mutations were reported. This study shows a relationship between genotype and the clinical form of cystinuria, suggesting that only the patients with the most severe mutations presented with an HEC. These results emphasized the need for prenatal cystinuria screening using classical third-trimester ultrasound scan and the early management of suspected newborns. PMID- 28646537 TI - Explaining infant feeding: The role of previous personal and vicarious experience on attitudes, subjective norms, self-efficacy, and breastfeeding outcomes. AB - OBJECTIVES: Breastfeeding confers important health benefits to both infants and their mothers, but rates are low in the United Kingdom and other developed countries despite widespread promotion. This study examined the relationships between personal and vicarious experience of infant feeding, self-efficacy, the theory of planned behaviour variables of attitudes and subjective norm, and the likelihood of breastfeeding at 6-8 weeks post-natally. DESIGN: A prospective questionnaire study of both first-time mothers (n = 77) and experienced breastfeeders (n = 72) recruited at an antenatal clinic in South East England. METHODS: Participants completed a questionnaire at 32 weeks pregnant assessing personal and vicarious experience of infant feeding (breastfeeding, formula feeding, and maternal grandmother's experience of breastfeeding), perceived control, self-efficacy, intentions, attitudes (to breastfeeding and formula feeding), and subjective norm. Infant feeding behaviour was recorded at 6-8 weeks post-natally. Multiple linear regression modelled the influence of vicarious experience on attitudes, subjective norm, and self-efficacy (but not perceived control) and modelled the influence of attitude, subjective norm, self-efficacy, and past experience on intentions to breastfeed. Logistic regression modelled the likelihood of breastfeeding at 6-8 weeks. RESULTS: Previous experience (particularly personal experience of breastfeeding) explained a significant amount of variance in attitudes, subjective norm, and self-efficacy. Intentions to breastfeed were predicted by subjective norm and attitude to formula-feeding and, in experienced mothers, self-efficacy. Breastfeeding at 6 weeks was predicted by intentions and vicarious experience of formula-feeding. CONCLUSION: Vicarious experience, particularly of formula-feeding, has been shown to influence the behaviour of first-time and experienced mothers both directly and indirectly via attitudes and subjective norm. Interventions that reduce exposure to formula-feeding (perhaps by limiting advertising) or cushion mothers from its effects may enable more mothers to meet their breastfeeding goals. Statement of contribution What is already known on this subject? Rates of breastfeeding in the United Kingdom are low and resistant to change. Self-efficacy may be an important and modifiable factor for breastfeeding initiation and maintenance. What does this study add? Self-efficacy may only be a relevant factor among mothers who already have personal experience of breastfeeding. Vicarious experience of formula-feeding has been shown to be related to a lower rate of breastfeeding at 6 weeks. PMID- 28646538 TI - A novel ATTR L32V mutation causes familial amyloid polyneuropathy in a Bolivian family. AB - We report a new transthyretin (ATTR) gene c.272C>G mutation and variant protein, p.Leu32Val, in a kindred of Bolivian origin with a rapid progressive peripheral neuropathy and cardiomyopathy. Three individuals from a kindred with peripheral nerve and cardiac amyloidosis were examined. Analysis of the TTR gene was performed by Sanger direct sequencing. Neuropathologic examination was obtained on the index patient with mass spectrometry study of the ATTR deposition. Direct DNA sequence analysis of exons 2, 3, and 4 of the TTR gene demonstrated a c.272 C>G mutation in exon 2 (p.L32V). Sural nerve biopsy revealed massive amyloid deposition in the perineurium, endoneurium and vasa nervorum. Mass spectrometric analyses of ATTR immunoprecipitated from nerve biopsy showed the presence of both wild-type and variant proteins. The observed mass results for the wild-type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. The ATTR L32V is associated with a severe course. This has implications for treatment of affected individuals and counseling of family members. PMID- 28646539 TI - Elevated soluble alpha-hemoglobin pool in sickle cell anemia. PMID- 28646540 TI - Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester. AB - The World Health Organization currently recommends quinine+clindamycin for use against malaria in the first trimester. This may soon change to recommending artemisinin-based combination therapies (standard duration of dosing = 3 days). The non-artemisinin partner drugs include amodiaquine, lumefantrine, mefloquine, piperaquine, sulfadoxine+pyrimethamine, and pyronaridine. For quinine, clindamycin, and mefloquine and the combinations of sulfadoxine+pyrimethamine and artemether+lumefantrine, there are reports (including studies without internal comparison groups) that combined describe 304 to >1100 exposures of women in the first trimester for each drug with no conclusive evidence of adverse effects on pregnancy at therapeutic doses. This is despite the fact that all of these drugs or drug combinations caused embryo deaths and/or malformations in at least one animal species and all except lumefantrine had at least one exposure ratio <1. It now seems that these animal studies overestimated the risk of developmental toxicity in women with malaria. Three other non-artemisinins (amodiaquine, piperaquine, and pyronaridine) have few or no reported exposures in women in the first trimester and have exposure ratios <=2 based on studies in pregnant rats and rabbits with dosing throughout organogenesis. However, none of these drugs caused embryo deaths or malformations in pregnant rats and rabbits with the exception of pyronaridine, which caused embryo deaths only at a dose that was excessively toxic to the mothers. Thus, for amodiaquine, piperaquine, and pyronaridine, the testing in animals did not reveal findings of concern and the exposure ratios were in the range of the other non-artemisinin antimalarials described above. Birth Defects Research 109:1075-1126, 2017. (c) 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. PMID- 28646541 TI - Health Care Quality: Measuring Obesity in Performance Frameworks. AB - OBJECTIVE: Obesity affects over one-third of Americans and leads to several chronic and costly comorbid conditions. The national movement toward value-based care calls for a refocusing of efforts to address the US obesity epidemic. To help set the stage, the current landscape of obesity-specific quality measures was evaluated. METHODS: Seven quality measure databases and nine professional societies were searched. Inclusion and exclusion criteria were applied. Measures were then classified by domain and by implementation in national public programs. RESULTS: Eleven obesity-specific quality measures in adults were identified (nine process and two outcome). Three measures received National Quality Forum (NQF) endorsement. Two measures were actively used within Centers for Medicare and Medicaid Services (CMS) programs. Only one measure was both NQF-endorsed and used by CMS. CONCLUSIONS: Limitations exist with respect to obesity-specific quality metrics. Such gaps provide opportunities for obesity care specialists to engage and offer valuable insights and pragmatic approaches toward quality measurement. PMID- 28646542 TI - Reconstitution of Low-Density Lipoproteins with Fatty Acids for the Targeted Delivery of Drugs into Cancer Cells. AB - Low-density lipoproteins (LDLs) are a class of nanocarriers for the targeted delivery of therapeutics into aberrant cells that overexpress the LDL receptor. A facile procedure is used for reconstituting the hydrophobic core of LDLs with a binary fatty acid mixture. Facilitated by the tumor targeting capability of the apolipoprotein, the reconstituted, drug-loaded LDLs can effectively target cancer cells that overexpress the LDL receptor while showing minor adverse impact on normal fibroblasts. According to a hypothesized mechanism, the reconstituted LDLs can also enable metabolism-triggered drug release while preventing the payloads from lysosomal degradation. This study demonstrates that LDLs reconstructed with fatty acids hold great promise to serve as effective and versatile nanocarriers for targeted cancer therapy. PMID- 28646543 TI - Hepatic bile acid uptake in humans and mice: Multiple pathways and expanding potential role for gut-liver signaling. PMID- 28646544 TI - Pure intraductal carcinoma of the parotid gland: Cytologic findings on FNA sample. Report of one case. AB - One case of intraductal carcinoma of the parotid gland in a 67-year-old male patient is here introduced. The patient, who had a one-year history of a parotid mass, had undergone ultrasound and MRI examination that disclosed a 13x4x3 mm well delimited nodular mass of the accessory lobe of his left parotid gland. Ultrasound-guided Fine Needle Aspiration (FNA) had been performed by the clinician. The obtained smears showed widespread cellular necrosis in which cellular clusters with moderate and focally severe atypias displayed papillary and cribriform architecture and were admixed with sheets of epithelial cells with less striking nuclear atypias, squamous, or apocrine metaplasia. Histopathological examination disclosed a pure intraductal carcinoma of the parotid gland with classical morphology, which was radically excised. The differential cytological diagnosis of pure intraductal carcinoma of salivary glands may be difficult and comprises mucoepidermoid carcinoma as well as "in situ" carcinomas developping in the context of sclerosing polycystic adenosis, mammary analogue secretory carcinoma (MASC) of the salivary glands and cystic variants of salivary adenocarcinoma NOS (formerly called cystadenocarcinomas). PMID- 28646546 TI - Community mental health work: Negotiating support of users' recovery. AB - Mental health services have changed over the past decades through an increased emphasis on deinstitutionalization and normalization, and with recovery processes situated in everyday life as a new locus of support. These changes have led to a need for new knowledge and methods concerning the provision of community mental health services. The aim of the present study was to explore how community mental health workers provide support to users, by investigating professionals' own narratives of how they work. Seven community mental health workers participated in narrative interviews, which were subject to a qualitative, interpretive analysis. A primary finding was that community mental health workers provide flexible and individually-adjusted support through engaging in negotiations with users, management, and others. Our findings show both opportunities and challenges of negotiating support, raising the following question for discussion: How and when are negotiations a valuable way for professionals and users to collaborate? PMID- 28646545 TI - Disruptions in Emotion Regulation as a Mechanism Linking Community Violence Exposure to Adolescent Internalizing Problems. AB - Although community violence is an established risk factor for youth aggression, less research has examined its relation with internalizing psychopathology. This study examined associations of community violence exposure with internalizing symptoms, and state and trait emotion dysregulation as mechanisms underlying these associations, in 287 adolescents aged 16-17 (45.6% male; 40.8% White). Community violence exposure was associated with internalizing symptoms, negative affect during peer evaluation, trait emotional reactivity, and infrequent problem solving. Multiple emotion dysregulation indices were also associated with internalizing symptoms. In simultaneous multiple mediator models, indirect effects of community violence on internalizing problems were significantly explained by state and trait emotion dysregulation. Findings implicate emotion dysregulation as one mechanism linking community violence exposure to adolescent internalizing symptoms. PMID- 28646547 TI - A dual-fluorescence reporter in the Eomes locus for live imaging and medium-term lineage tracing. AB - The T-box transcription factor Eomes (also known as Tbr2) shows short-lived expression in various localized domains of the embryo, including epiblast cells during gastrulation and intermediate progenitor cells in the cerebral cortex. In these tissues Eomes fulfills crucial roles for lineage specification of progenitors. To directly observe Eomes-dependent cell lineages in the living embryo, we generated a novel dual-fluorescence reporter allele that expresses a membrane-bound tdTomato protein for investigation of cell morphology and a nuclear GFP for cell tracing. This allele recapitulates endogenous EOMES protein expression and is suitable for live imaging. We found that the allele can also be used as a short-to-medium-term lineage tracer, as GFP persists in cells longer than EOMES protein and marks Eomes-dependent lineages with a timeframe of days to weeks depending on the proliferation rate. In summary, we present a novel genetic tool for investigation of Eomes-dependent cell types by live imaging and lineage tracing. PMID- 28646548 TI - Targeted Calorie Message Promotes Healthy Beverage Consumption Better than Charity Incentive. AB - OBJECTIVE: Sugar-sweetened beverage (SSB) consumption is cited as a major contributor to the U.S. obesity epidemic. The objective of this paper was to leverage insights from behavioral economics to examine whether nudges would entice college students to save meal calories by choosing water over SSBs. METHODS: Three message-based nudge interventions, with washout periods between, were used during the 7-week study. Calorie savings (self-interest), charity (prosocial), or charity-plus-calorie message posters were displayed in a college based food franchise. Multilevel logistic regressions compared the proportions of students choosing water during three experimental conditions. This study assessed whether the frequency of dining establishment visits over the study period moderated effects of the experimental conditions on beverage choices. Multiple data points from the same customer were treated as repeated measures. RESULTS: A total of 2,393 unique students purchased 6,730 meals. Posters displaying calorie information increased water choice relative to washout periods, while the poster without calorie information (charity only) had no effect. Controlling for fixed effects produced the same results. The calorie message poster influenced less frequent diners more than frequent diners. CONCLUSIONS: Food-service operations can nudge college students to substitute water for SSBs with a simple calorie based message to save hundreds of calories per meal. PMID- 28646550 TI - Healthy controls in nonalcoholic fatty liver disease management: A biomedical research perspective. PMID- 28646549 TI - Inhibition of JNK signalling mediates PPARalpha-dependent protection against intrahepatic cholestasis by fenofibrate. AB - BACKGROUND AND PURPOSE: Fenofibrate, a PPARalpha agonist, is the most widely prescribed drug for treating hyperlipidaemia. Although fibrate drugs are reported to be beneficial for cholestasis, their underlying mechanism has not been determined. EXPERIMENTAL APPROACH: Wild-type mice and Pparalpha-null mice were pretreated orally with fenofibrate for 3 days, following which alpha naphthylisothiocyanate (ANIT) was administered to induce cholestasis. The PPARalpha agonist WY14643 and JNK inhibitor SP600125 were used to determine the role of PPARalpha and the JNK pathway, respectively, in cholestatic liver injury. The same fenofibrate regimen was applied to investigate its beneficial effects on sclerosing cholangitis in a DDC-induced cholestatic model. KEY RESULTS: Fenofibrate, 25 mg.kg-1 twice a day, totally attenuated ANIT-induced cholestasis and liver injury as indicated by biochemical and histological analyses. This protection occurred in wild-type, but not in Pparalpha-null, mice. Alterations in bile acid synthesis and transport were found to be an adaptive response rather than a direct effect of fenofibrate. WY14643 attenuated ANIT-induced cholestasis and liver injury coincident with inhibition of JNK signalling. Although SP600125 did not affect cholestasis, it inhibited liver injury in the ANIT model when the dose of fenofibrate used was ineffective. Fenofibrate was also revealed to have a beneficial effect in the sclerosing cholangitis model. CONCLUSIONS AND IMPLICATIONS: These data suggest that the protective effects of fenofibrate against cholestasis-induced hepatic injury are dependent on PPARalpha and fenofibrate dose, and are mediated through inhibition of JNK signalling. This mechanism of fenofibrate protection against intrahepatic cholestasis may offer additional therapeutic opportunities for cholestatic liver diseases. PMID- 28646551 TI - Prospero-related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating interleukin-8 expression. AB - : Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor kappaB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor kappaB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. CONCLUSIONS: We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894-1909). PMID- 28646552 TI - Targeting histone deacetylase 4/ubiquitin-conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice. AB - : Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5-10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; gammaH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin-conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation-induced cell death and reduced homologous recombination repair of DNA double-strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation-treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4-dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. CONCLUSION: HDAC4 signaling blockade enhances radiation induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2017). PMID- 28646553 TI - Epithelial-mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease. AB - Epithelial-mesenchymal transition (EMT) plays key roles during lung development and many lung diseases such as chronic obstructive pulmonary disease (COPD), lung cancer, and pulmonary fibrosis. Here, integrating morphological observations with underlying molecular mechanisms, we highlight the functional role of EMT in lung development and injury repair, and discuss how it can contribute to pathogenesis of chronic lung disease. We discuss the evidence of manifestation of EMT and its potential driving role in COPD, idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans syndrome (BOS), and lung cancer, while noting that all cells need not display a full EMT in any of these contexts, i.e., often cells co express epithelial and mesenchymal markers but do not fully convert to extracellular matrix (ECM) -producing fibroblasts. Finally, we discuss recent therapeutic attempts to restrict EMT in chronic lung disease. Developmental Dynamics 247:346-358, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28646554 TI - THESEUS1 positively modulates plant defense responses against Botrytis cinerea through GUANINE EXCHANGE FACTOR4 signaling. AB - The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses. THESEUS1 (THE1) acts as a sensor of cell wall integrity that controls cell elongation during plant growth. However, no specific role for THE1 in plant defense responses has been reported. Here, we found that THE1 interacts with GUANINE EXCHANGE FACTOR4 (GEF4) and that both proteins play regulatory roles in plant resistance to the necrotrophic fungus Botrytis cinerea. Genetic analysis showed that THE1 and GEF4 function in the same genetic pathway to mediate plant defense responses. In addition, using transcriptome analysis, we identified various genes (such as defense-related, secondary metabolite-related, and transcription factor genes) that are likely downstream targets in the THE1-GEF4 signaling pathway. Our results suggest that THE1 functions as an upstream regulator of GEF4 signaling to positively regulate defense responses against B. cinerea in Arabidopsis. PMID- 28646555 TI - Low-thrombogenic fibrin-heparin coating promotes in vitro endothelialization. AB - Long-term performance of implanted cardiovascular grafts can be ensured if living endothelium overgrows their surface. Surface modifications to implants are therefore being sought that can encourage endothelialization while preventing thrombus formation until the natural endothelium is formed. In the present study, heparin was covalently attached to a fibrin mesh grown from a polyvinyl chloride (PVC) substrate surface by the catalytic action of surface immobilized thrombin on a fibrinogen solution. The coating prevented platelet activation, thrombin generation and clot formation, and reduced inflammatory reactions when exposed to fresh human whole blood circulating in a Chandler loop model. In addition, in vitro seeded human umbilical vein and human saphenous vein endothelial cells showed considerably enhanced attachment and proliferation on the coating. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2995-3005, 2017. PMID- 28646558 TI - Neurology Concepts: Young Women and Ischemic Stroke-Evaluation and Management in the Emergency Department. AB - OBJECTIVE: Ischemic stroke is a leading cause of morbidity and mortality worldwide. While the incidence of ischemic stroke is highest in older populations, incidence of ischemic stroke in adults has been rising particularly rapidly among young (e.g., premenopausal) women. The evaluation and timely diagnosis of ischemic stroke in young women presents a challenging situation in the emergency department, due to a range of sex-specific risk factors and to broad differentials. The goals of this concepts paper are to summarize existing knowledge regarding the evaluation and management of young women with ischemic stroke in the acute setting. METHODS: A panel of six board-certified emergency physicians, one with fellowship training in stroke and one with training in sex- and sex-based medicine, along with one vascular neurologist were coauthors involved in the paper. Each author used various search strategies (e.g., PubMed, PsycINFO, and Google Scholar) for primary research and reviewed articles related to their section. The references were reviewed and evaluated for relevancy and included based on review by the lead authors. RESULTS: Estimates on the incidence of ischemic stroke in premenopausal women range from 3.65 to 8.9 per 100,000 in the United States. Several risk factors for ischemic stroke exist for young women including oral contraceptive (OCP) use and migraine with aura. Pregnancy and the postpartum period (up to 12 weeks) is also an important transient state during which risks for both ischemic stroke and cerebral hemorrhage are elevated, accounting for 18% of strokes in women under 35. Current evidence regarding the management of acute ischemic stroke in young women is also summarized including use of thrombolytic agents (e.g., tissue plasminogen activator) in both pregnant and nonpregnant individuals. CONCLUSION: Unique challenges exist in the evaluation and diagnosis of ischemic stroke in young women. There are still many opportunities for future research aimed at improving detection and treatment of this population. PMID- 28646556 TI - Injury-induced maladaptation and dysregulation of calcium channel alpha2 delta subunit proteins and its contribution to neuropathic pain development. AB - : Voltage-gated calcium channels (VGCCs) play important roles in physiological functions including the modulation of neurotransmitter release, neuronal network activities, intracellular signalling pathways and gene expression. Some pathological conditions, including nerve injuries, can cause the dysregulation of VGCCs and their subunits. This in turn can lead to a functional maladaptation of VGCCs and their subunits, which can contribute to the development of disorders such as pain sensations. This review has summarized recent findings related to maladaptive changes in the dysregulated VGCC alpha2 delta1 subunit (Cav alpha2 delta1 ) with a focus on exploring the mechanisms underlying the contribution of Cav alpha2 delta1 to pain signal transduction. At least under neuropathic pain conditions, the dysregulated Cav alpha2 delta1 can modulate VGCC functions as well as other plasticity changes. The latter includes abnormal excitatory synaptogenesis resulting from its interactions with injury-induced extracellular matrix glycoprotein molecule thrombospondins, which is independent of the VGCC functions. Blocking Cav alpha2 delta1 with gabapentinoids can reverse neuropathic pain significantly with relatively mild side effects, but only in a small population of neuropathic pain patients due to reasons yet to be explored. There are emerging data suggesting that early preventive treatment with gabapentinoids can prevent aberrant excitatory synapse formation and the development of chronic pain. If these findings are confirmed clinically, this could be an attractive approach for neuropathic pain management. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 28646559 TI - Pandemic (H1N1) 2009 influenza A virus infection associated with respiratory signs in sloth bears (Melursus ursinus). AB - In 2009, a pandemic influenza A virus (pH1N1) spread globally in humans and infected a broad range of captive animals with close human contact. In February 2014, a pH1N1 virus was isolated from a sloth bear with respiratory signs at a US zoo, demonstrating that recurring epidemics present an ongoing threat to animals, including threatened species. This is the first report of pH1N1 infection in sloth bears. To understand the sloth bear virus within the global context of pH1N1, phylogenetic trees were inferred including full-length sequences from available non-human, non-swine hosts, representing four families in the order Carnivora and one order of birds. A combination of phylogenetic and epidemiological evidence strongly suggests the sloth bear was infected with a human-origin pH1N1 virus, supporting the implementation of biosecurity measures to protect human and animal health. PMID- 28646560 TI - Reply. PMID- 28646561 TI - Pathways to arithmetic fact retrieval and percentage calculation in adolescents. AB - BACKGROUND: Developing sufficient mathematical skills is a prerequisite to function adequately in society today. Given this, an important task is to increase our understanding regarding the cognitive mechanisms underlying young people's acquisition of early number skills and formal mathematical knowledge. AIMS: The purpose was to examine whether the pathways to mathematics model provides a valid account of the cognitive mechanisms underlying symbolic-number processing and mathematics in adolescents. The pathways model states that the three pathways should provide independent support to symbolic-number skill. Each pathway's unique contribution to formal mathematics varies depending on the complexity and demand of the tasks. SAMPLE: The study used a sample of 114 adolescents (71 girls). Their mean age was 14.60 years (SD = 1.00). METHODS: The adolescents were assessed on tests tapping the three pathways and general cognitive abilities (e.g., working memory). A structural equation path analysis was computed. RESULTS: Symbolic-number comparison was predicted by the linguistic pathway, the quantitative pathway, and processing speed. The linguistic pathway, quantitative pathways, and symbolic-number comparison predicted arithmetic fact retrieval. The linguistic pathway, working memory, visual analogies, and symbolic number comparison predicted percentage calculation. CONCLUSIONS: There are both similarities and differences in the cognitive mechanisms underlying arithmetic fact retrieval and percentage calculation in adolescents. Adolescents' symbolic number processing, arithmetic fact retrieval, and percentage calculation continue to rely on the linguistic pathways, whereas the reliance upon the spatial pathway has ceased. The reliance upon the quantitative pathway varies depending on the task. PMID- 28646562 TI - Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk. AB - : Hepatocellular adenomas (HCAs) are rare benign tumors divided into three main subgroups defined by pathomolecular features, HNF1A (H-HCA), mutated beta-catenin (b-HCA), and inflammatory (IHCA). In the case of unclassified HCAs (UHCAs), which are currently identified by default, a high risk of bleeding remains a clinical issue. The objective of this study was to explore UHCA proteome with the aim to identify specific biomarkers. Following dissection of the tumoral (T) and nontumoral (NT) tissue on formalin-fixed, paraffin-embedded HCA tissue sections using laser capture methodology, we performed mass spectrometry analysis to compare T and NT protein expression levels in H-HCA, IHCA, b-HCA, UHCA, and focal nodular hyperplasia. Using this methodology, we searched for proteins which are specifically deregulated in UHCA. We demonstrate that proteomic profiles allow for discriminating known HCA subtypes through identification of classical biomarkers in each HCA subgroup. We observed specific up-regulation of the arginine synthesis pathway associated with overexpression of argininosuccinate synthase (ASS1) and arginosuccinate lyase in UHCA. ASS1 immunohistochemistry identified all the UHCA, of which 64.7% presented clinical bleeding manifestations. Interestingly, we demonstrated that the significance of ASS1 was not restricted to UHCA, but also encompassed certain hemorrhagic cases in other HCA subtypes, particularly IHCA. CONCLUSION: ASS1 + HCA combined with a typical hematoxylin and eosin stain aspect defined a new HCA subgroup at a high risk of bleeding. (Hepatology 2017;66:2016-2028). PMID- 28646564 TI - The interference of genetic associations in establishing the prognostic value of the immunophenotype in acute myeloid leukemia. AB - BACKGROUND: In acute myeloid leukemia controversy exists about the role of immunophenotyping of the blasts at diagnosis as a potential prognostic factor. METHODS: We retrospectively analyzed immunophenotypic marker expression on blasts in relation to genetic aberrancies and survival data of 684 patients. All patients were included in different studies from the HOVON/SAKK Consortium. RESULTS: Markers CD2, CD7, CD11b, CD19, CD22, and CD56 all appeared to be associated with one or more established prognostic genetic aberrancies. In the overall population, differences in univariate survival analyses were observed for CD2, CD11b, and CD22. After correcting these survival differences for currently used risk profile data, only CD11b expression remained of prognostic value for poor overall survival (OS) and event-free survival (EFS). CD11b expression turned out to be an independent factor for poor OS and EFS in the subgroup of patients who lacked cytogenetic and molecular aberrancies. CONCLUSIONS: In this study, we demonstrate that associations between immunophenotypic markers and genetic aberrancies interfere with the prognostic properties of immunophenotypic markers. Such may account for most of the previously reported prognostic impact of these markers. Only CD11b expression remained as an independent prognostic marker. (c) 2017 International Clinical Cytometry Society. PMID- 28646563 TI - Cohesive network reconfiguration accompanies extended training. AB - Human behavior is supported by flexible neurophysiological processes that enable the fine-scale manipulation of information across distributed neural circuits. Yet, approaches for understanding the dynamics of these circuit interactions have been limited. One promising avenue for quantifying and describing these dynamics lies in multilayer network models. Here, networks are composed of nodes (which represent brain regions) and time-dependent edges (which represent statistical similarities in activity time series). We use this approach to examine functional connectivity measured by non-invasive neuroimaging techniques. These multilayer network models facilitate the examination of changes in the pattern of statistical interactions between large-scale brain regions that might facilitate behavior. In this study, we define and exercise two novel measures of network reconfiguration, and demonstrate their utility in neuroimaging data acquired as healthy adult human subjects learn a new motor skill. In particular, we identify putative functional modules in multilayer networks and characterize the degree to which nodes switch between modules. Next, we define cohesive switches, in which a set of nodes moves between modules together as a group, and we define disjoint switches, in which a single node moves between modules independently from other nodes. Together, these two concepts offer complementary yet distinct insights into the changes in functional connectivity that accompany motor learning. More generally, our work offers statistical tools that other researchers can use to better understand the reconfiguration patterns of functional connectivity over time. Hum Brain Mapp 38:4744-4759, 2017. (c) 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID- 28646565 TI - Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy. AB - WHAT IS KNOWN AND OBJECTIVE: The mixed lineage leukaemia (MLL) gene translocations are found in approximately 10% of adults with acute myeloid leukaemia (AML) and are markers of poor prognosis. As the best reported response in relapsed and refractory MLL-rearranged AML is around 40%, reinduction treatment is very challenging for those patients. CASE DESCRIPTION: We report a case of relapsed and refractory AML with MLL-AF9, who did not respond to FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) regimen reinduction treatment, but achieved complete response and molecular remission after chidamide-based chemotherapy. WHAT IS NEW AND CONCLUSION: Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor that is clinically active in relapsed and refractory peripheral T-cell lymphomas. To the best of our knowledge, successful reinduction treatment on relapsed MLL-AF9 by chidamide based regimen has not been previously reported. PMID- 28646567 TI - Severe menses-associated hypertension successfully treated with gonadotropin releasing hormone agonist. AB - A case of a 32-year-old nulliparous white woman referred for a 5-year history of severe hypertension, hypokalemia, and resultant systolic dysfunction is presented. She additionally had a left ventricular ejection fraction of 30% including left ventricular dilation and normal left ventricular mass index, as measured by cardiac magnetic resonance imaging when she initially presented to us. Her history revealed that her severe hypertension episodes were monthly and would occur around the catamenial (menses-associated) time. Two weeks following her menses, blood pressure decreased significantly but remained elevated above 140/90 mm Hg. This cycle repeated monthly and required multiple hospitalizations for hypertensive emergency in the form of acute decompensated heart failure and severe headaches. She required potassium supplementation. This prompted a complete evaluation for secondary causes of hypertension, which was negative. Female and male sex hormone levels, including testosterone, were also within normal limits. She received an injection of leuprolide acetate depot (11.25 mg every 3 months), a gonadotropin-releasing hormone agonist. This significantly reduced the magnitude of these episodes. PMID- 28646568 TI - Blink R1 latency utility in diagnosis and treatment assessment of polyradiculoneuropathy-organomegaly-endocrinopathy-monoclonal protein-skin changes and chronic inflammatory demyelinating polyradiculoneuropathy. AB - INTRODUCTION: In polyradiculoneuropathy-organomegaly-endocrinopathy-monoclonal protein-skin changes (POEMS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), limb nerve conduction studies (NCSs) are limited in identifying demyelination and in detecting treatment effects in severely affected patients. Blink R1 latency may improve these assessments. METHODS: POEMS and CIDP patients who had undergone NCS and blink reflex were identified. Correlations among R1 latency, limb NCS, and neuropathy impairment scores (NIS) were compared. RESULTS: Among 182 patients (124 POEMS, 58 CIDP) who were identified, R1 prolongation (>13 ms) occurred in 64.3% (65.3% POEMS, 62.1% CIDP). R1 prolongation correlated with more severely affected NCS in both POEMS (ulnar CMAP 2.6 mV vs. 4.5 mV, P = 0.001) and CIDP (2.0 mV vs. 6.1 mV, P < 0.001). In severely affected patients (ulnar CMAP <=0.5 mV [10%:18/182]), R1 (>13 ms) helped establish demyelination. In 31 patients (16 POEMS, 15 CIDP), the R1 latency changes were concordant with NIS changes in 94% of patients with POEMS and 60% of patients with CIDP. DISCUSSION: Blink R1 latencies are valuable in defining demyelination and detecting improvement in severely affected POEMS and CIDP patients. Muscle Nerve 57: E8-E13, 2018. PMID- 28646566 TI - Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults. AB - BACKGROUND AND AIMS: Chronic alcohol use is associated with lower gray matter volume, and we reported recently that alcohol use showed negative associations with widespread gray matter (GM) volume even among young adults. The current study aimed to test the strength of association between (1) alcohol use and GM volume; (2) alcohol use and white matter (WM) integrity; (3) cannabis use and GM volume; and (4) cannabis use and WM integrity among adults and adolescents. DESIGN AND SETTING: General linear models within large pooled cross-sectional samples of adolescents and adults who had participated in studies collecting substance use and neuroimaging data in the southwestern United States. PARTICIPANTS: The current analysis included adults aged 18-55 years (n = 853) and adolescents aged 14-18 years (n = 439) with a range of alcohol and cannabis use. MEASUREMENTS: The dependent variable was GM volume or WM integrity, with key predictors of alcohol use [Alcohol Use Disorders Identification Test (AUDIT) score] and cannabis use (past 30-day use). FINDINGS: Alcohol use showed large clusters of negative associations (etap2 = 0.028-0.145, P < 0.001) with GM volume among adults and to a lesser extent (one cluster; etap2 = 0.070, P < 0.05) among adolescents. Large clusters showed significant associations (etap2 = 0.050-0.124, P < 0.001) of higher alcohol use with poorer WM integrity, whereas adolescents showed no significant associations between alcohol use and WM. No associations were observed between structural measures and past 30-day cannabis use in adults or adolescents. CONCLUSIONS: Alcohol use severity is associated with widespread lower gray matter volume and white matter integrity in adults, and with lower gray matter volume in adolescents. PMID- 28646569 TI - Nanosilver particles increase follicular atresia: Correlation with oxidative stress and aromatization. AB - Present study was performed in order to update the possible mechanism(s), involving in nanosilver particles (NSPs)-induced detrimental impacts in ovarian tissue. For this purpose, 24 mature female rats were divided into control and 0.5, 1, 5 mg/kg NSPs-received groups (intraperitoneally, for 35 days). Follicular growth and atresia, ovarian total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD) contents, serum estrogen (E2 ) level and macrophages infiltration were investigated. Moreover, ovarian angiogenesis, cellular mRNA damage and cytochrome aromatase CYP19 expression were analyzed. The NSPs enhanced follicular atresia diminished E2, reduced TAC and SOD level, elevated MDA content and up-regulated macrophages infiltration. Cellular mRNA damage, impaired angiogenesis and diminished CYP19 expression were revealed in NSPs-received groups. Therefore NSPs by down-regulating aromatization, reduce E2 synthesis which then it leads to impaired angiogenesis. The impaired angiogenesis in turn down-regulates ovarian antioxidant status, which partially enhances follicular atresia by triggering lipid peroxidation and mRNA damage. PMID- 28646570 TI - Inactivation of Bacillus Spores in Wash Waters Using Dilute Chlorine Bleach Solutions at Different Temperatures and pH Levels. AB - Inactivation of Bacillus globigii spores in wash water was studied to simulate chlorine inactivation of Bacillus anthracis spores in water generated during biological cleanups. Eight waters were studied, with six containing detergent. Chlorine levels were approximately 3000 mg/L. Results across different waters showed decreasing inactivation with increasing pH. Inactivation did not appear to be influenced by chemical oxygen demand, suspended solids, turbidity, or dissolved solids. Inactivation efficacy was expressed as the time calculated to yield 6 log10 inactivation at 3000 mg NaOCl/L. This time ranged from 5 to 51 minutes at ~21 degrees C and from 11 to 209 minutes at ~5 degrees C. For one wash water, inactivation was conducted when there was no pH adjustment, and when the pH was buffered at 7 and 8. Inactivation in these buffered waters was rapid, but inactivation decreased sharply at a pH above ~9.3. PMID- 28646571 TI - Comparison of Reed and Water Lettuce in Constructed Wetlands for Wastewater Treatment. AB - In the present study two designs, vertical and horizontal systems, were used and two different plant species, Water Lettuce (Pistia stratiotes) and Reed plant (Phragmites karka), compared for their removal efficiency. The vertical system appeared to be more stable and efficient for almost all the parameters. The vertical system, planted with Water Lettuce, showed percentage removal efficiency for BOD, phosphate and chloride as 82, 95.4, and 51, respectively, whereas turbidity and total suspended solids removal efficiencies were almost the same. However, fecal coliform removal by the Water Lettuce was 98.8% for both designs (vertical and horizontal), showing the ability of the plant to uptake nutrients and release toxins for pathogen disinfection. It appears that the vertical system could be the better option, planted with Water Lettuce, or with both plants in a co-culture environment. PMID- 28646572 TI - General Fate Model for Microconstituents in an Activated Sludge System. AB - Nine laboratory-scale continuous flow porous-pot bioreactors, operating at various solids retention times (SRT) and hydraulic retention times, were used to simulate activated sludge systems, and to evaluate biodegradation kinetic models for the fate of 17alpha-ethinylestradiol (EE2), bisphenol-A (BPA), and triclosan (TCS) at the MUg/L range. Mathematical models were applied to describe the degradation mechanism of selected microconstituents and the pseudo-second-order model was found to best fit the results when active microconstituent degraders (XC) were used (r2 = 0.99). The result of XC estimation showed that SRT plays an important role in formation of the biomass capable of degrading selected microconstituents. It is also observed that microconstituent degraders are naturally present in an activated sludge system, even at low SRTs; however, the concentration of XC is dependent on SRT. It seems that biodegradation studies should incorporate XC, and not mixed liquor suspended solids concentration, in their kinetic formulations. PMID- 28646575 TI - Malignancies and ustekinumab: an analysis of the U.S. Food and Drug Administration Adverse Event Reporting System and the European Union Drug Regulating Authorities Pharmacovigilance database. PMID- 28646574 TI - A habitat-based approach to predict impacts of marine protected areas on fishers. AB - Although marine protected areas can simultaneously contribute to biodiversity conservation and fisheries management, the global network is biased toward particular ecosystem types because they have been established primarily in an ad hoc fashion. The optimization of trade-offs between biodiversity benefits and socioeconomic values increases success of protected areas and minimizes enforcement costs in the long run, but it is often neglected in marine spatial planning (MSP). Although the acquisition of spatially explicit socioeconomic data is perceived as a costly or secondary step in MSP, it is critical to account for lost opportunities by people whose activities will be restricted, especially fishers. We developed an easily reproduced habitat-based approach to estimate the spatial distribution of opportunity cost to fishers in data-poor regions. We assumed the most accessible areas have higher economic and conservation values than less accessible areas and their designation as no-take zones represents a loss of fishing opportunities. We estimated potential distribution of fishing resources from bathymetric ranges and benthic habitat distribution and the relative importance of the different resources for each port of total catches, revenues, and stakeholder perception. In our model, we combined different cost layers to produce a comprehensive cost layer so that we could evaluate of trade offs. Our approach directly supports conservation planning, can be applied generally, and is expected to facilitate stakeholder input and community acceptance of conservation. PMID- 28646573 TI - Interferon-beta regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis. AB - CD11c+ dendritic cells (DCs) exert a critical role as antigen-presenting cells in regulating pathogenic T cells in multiple sclerosis (MS). To determine whether the therapeutic benefit of interferon-beta (IFN-beta) treatment for MS is in part influenced by IFN regulation of DC function, we examined the immunophenotype of DCs derived from IFN-beta+/+ and IFN-beta-/- mice using a myelin oligodendrocyte glycoprotein (MOG) peptide-induced mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our earlier work identified that IFN-beta-/- mice exhibit earlier onset and more rapid progression of neurological impairment compared with IFN-beta+/+ mice. In this study we show that lipopolysaccharide /MOG peptide-stimulated IFN-beta-/- DCs secrete cytokines associated with pathological T helper type 17 rather than regulatory T-cell polarization and exhibit increased CD80 and MHCII expression when compared with stimulated IFN beta+/+ DCs. IFN-beta-/- DCs from mice immunized to develop EAE induce greater proliferation of MOG-transgenic CD4+ T cells and promote interleukin-17 production by these T cells. Adoptive transfer of MOG peptide-primed IFN-beta-/- DCs into IFN-beta+/+ and IFN-beta-/- mice immunized to develop EAE resulted in their rapid migration into the central nervous system of recipient mice, before onset of disease, which we attribute to failed signal transducer and activator of transcription 1-mediated inhibition of CCR7. Taken together, our data support immunoregulatory roles for IFN-beta in the activation and migration of DCs during EAE. PMID- 28646576 TI - Accuracy of visual cervical screening: verification bias revisited. PMID- 28646577 TI - Clinical experience with infliximab biosimilar in psoriasis. PMID- 28646578 TI - The impact of a novel transendometrial approach for caesarean myomectomy on obstetric outcomes of subsequent pregnancy: a longitudinal panel study. AB - OBJECTIVE: To evaluate the obstetric and surgical outcomes of a novel transendometrial approach for myomectomy during caesarean section in subsequent pregnancies. DESIGN: Longitudinal panel study. SETTING: Chang Gung Memorial Hospital, Taiwan, with approximately 5000 births per annum. POPULATION: Pregnant women complicated with uterine myoma. METHOD: Sixty-three pregnant women who received transendometrial myomectomy during the first caesarean delivery reported a subsequent live pregnancy and planned an elective repeat caesarean delivery. MAIN OUTCOME MEASURES: Obstetric outcomes consisted of gestational age at birth, newborn weight, Apgar score, birthweight adequacy, uterine rupture, placental abruption, placenta praevia, placenta accreta, spontaneous preterm birth and preterm premature rupture of membranes. Surgical outcomes consisted of surgical time, blood loss, blood transfusion, postoperative fever, length of hospital stay and mean adhesion score. RESULT: The mean gestational age at birth and newborn weight at the subsequent caesarean section were superior to those at the first caesarean delivery. Spontaneous preterm birth, small-for-gestational-age infants and preterm premature rupture of membranes occurred more often in the first pregnancy than in the subsequent pregnancy. The mean surgical time was shorter for the subsequent caesarean delivery than for the first caesarean delivery combined with myomectomy. The other surgical composite outcomes of blood loss, blood transfusion, postoperative fever, length of hospital stay and mean adhesion score were similar across the two stages of caesarean deliveries. CONCLUSION: The novel transendometrial approach for caesarean myomectomy may improve the obstetric outcomes of subsequent pregnancy without causing any additional immediate and long-term adverse surgical outcomes. TWEETABLE ABSTRACT: Transendometrial caesarean myomectomy may improve future obstetric outcomes. PMID- 28646579 TI - Enantioseparations 2017. PMID- 28646580 TI - Biosimilars for psoriasis: worldwide overview of regulatory guidelines, uptake and implications for dermatology clinical practice. AB - The introduction of biological drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologics for patients with psoriasis. For approval of biosimilars, different regulatory agencies use highly variable methods for definition, production, approval, marketing and postmarketing surveillance. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in patients with psoriasis; spontaneous reporting, registries and use of 'big data' should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biological therapy treatment decisions may become more physician independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and government agencies. PMID- 28646581 TI - A systematic review of pharmacogenetic studies on the response to biologics in patients with psoriasis. AB - BACKGROUND: Biologics are indicated for treating moderate-to-severe psoriasis. As the number of biologics registered for the treatment of psoriasis increases, so does the need for biomarkers to guide personalized therapeutic decisions. Genetic variants might serve as predictors for treatment response, a field of research known as pharmacogenetics. OBJECTIVES: To assess which genetic variants are associated with response to biologics in patients with psoriasis according to current literature. METHODS: A systematic search was performed in Embase, MEDLINE, the Cochrane Library and Web of Science. In total, 26 papers were included in this systematic review; 24 original studies and two meta-analyses. Quality was assessed using a predesigned form and risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: The majority of studies reported a candidate gene approach, focusing on polymorphisms in genes related to the therapeutic target or to psoriasis susceptibility. Studied populations were small and results were divergent, especially for studies investigating tumour necrosis factor inhibitors. The evidence for the role of HLA-Cw6 in ustekinumab efficacy shows minimal heterogeneity, with a higher response rate among patients who were positive for HLA-Cw6 reported across three of five studies. CONCLUSIONS: Pharmacogenetic studies in psoriasis have generated divergent results. Replication of findings in larger cohorts is required. Large-scale hypothesis free searches for genetic biomarkers are needed to uncover the complete genetic background of outcomes for treatment with biologics. PMID- 28646582 TI - Comprehensive mathematical model of oxidative phosphorylation valid for physiological and pathological conditions. AB - We developed a mathematical model of oxidative phosphorylation (OXPHOS) that allows for a precise description of mitochondrial function with respect to the respiratory flux and the ATP production. The model reproduced flux-force relationships under various experimental conditions (state 3 and 4, uncoupling, and shortage of respiratory substrate) as well as time courses, exhibiting correct P/O ratios. The model was able to reproduce experimental threshold curves for perturbations of the respiratory chain complexes, the F1 F0 -ATP synthase, the ADP/ATP carrier, the phosphate/OH carrier, and the proton leak. Thus, the model is well suited to study complex interactions within the OXPHOS system, especially with respect to physiological adaptations or pathological modifications, influencing substrate and product affinities or maximal catalytic rates. Moreover, it could be a useful tool to study the role of OXPHOS and its capacity to compensate or enhance physiopathologies of the mitochondrial and cellular energy metabolism. PMID- 28646583 TI - Sebum lipids influence macrophage polarization and activation. AB - BACKGROUND: As lipids are known to regulate macrophage functions, it is reasonable to suppose that a sebocyte-macrophage axis mediated by sebum lipids may exist. OBJECTIVES: To investigate if sebocytes could contribute to the differentiation, polarization and function of macrophages with their secreted lipids. METHODS: Oil Red O lipid staining and Raman spectroscopy were used to assess the dermal lipid content and penetration. Immunohistochemistry was used to analyse the macrophage subsets. Human peripheral blood monocytes were differentiated in the presence of either supernatant from human SZ95 sebocytes or major sebum lipid components and activated with Propionibacterium acnes. Macrophage surface markers and their capacity to uptake fluorescein isothiocyanate-conjugated P. acnes were detected by fluorescence-activated cell sorting measurements. Cytokine protein levels were evaluated by enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: Sebaceous gland-rich skin had an increased dermal lipid content vs. sebaceous gland-poor skin to which all the tested sebum component lipids could contribute by penetrating the dermoepidermal barrier. Of the lipids, oleic acid and linoleic acid promoted monocyte differentiation into alternatively activated macrophages. Moreover, linoleic acid also had an anti-inflammatory effect in P. acnes-activated macrophages, inhibiting the secretion of interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha. Squalene, palmitic acid, stearic acid and oleic acid augmented the secretion of IL-1beta, even in the absence of P. acnes, whereas oleic acid had a selective effect of inducing IL-1beta but downregulating IL-6 and TNF-alpha secretion. CONCLUSIONS: Our results suggest a role for sebaceous glands in modulating innate immune responses via their secreted lipids that are of possible pathological and therapeutic relevance. PMID- 28646584 TI - Prehospital Advanced Cardiac Life Support for Out-of-hospital Cardiac Arrest: A Cohort Study. AB - OBJECTIVES: Out-of-hospital advanced cardiac life support (ACLS) has not consistently shown a positive impact on survival. Extracorporeal cardiopulmonary resuscitation (E-CPR) could render prolonged on-site resuscitation (ACLS or basic cardiac life support [BCLS]) undesirable in selected cases. The objectives of this study were to evaluate, in patients suffering from out-of-hospital cardiac arrest (OHCA) and in a subgroup of potential E-CPR candidates, the association between the addition of prehospital ACLS to BCLS and survival to hospital discharge, prehospital return of spontaneous circulation (ROSC), and delay from call to hospital arrival. METHODS: This cohort study targets adult patients treated for OHCA between April 2010 and December 2015 in the city of Montreal, Canada. We defined potential E-CPR candidates using clinical criteria previously described in the literature (65 years of age or younger, initial shockable rhythm, absence of ROSC after 15 minutes of prehospital resuscitation, and emergency medical services-witnessed collapse or witnessed collapse with bystander cardiopulmonary resuscitation). Associations were evaluated using multivariate regression models. RESULTS: A total of 7,134 patients with OHCA were included, 761 (10.7%) of whom survived to discharge. No independent association between survival to hospital discharge and the addition of prehospital ACLS to BCLS was found in either the entire cohort (adjusted odds ratio [AOR] = 1.05 [95% confidence interval {CI} = 0.84-1.32], p = 0.68) or among the 246 potential E-CPR candidates (AOR = 0.82 [95% CI = 0.36-1.84], p = 0.63). The addition of prehospital ACLS to BCLS was associated with a significant increase in the rate of prehospital ROSC in all patients experiencing OHCA (AOR = 3.92 [95% CI = 3.38 4.55], p < 0.001) and in potential E-CPR candidates (AOR = 3.48 [95% CI = 1. 76 6.88], p < 0.001) compared to isolated prehospital BCLS. Delay from call to hospital arrival was longer in the ACLS group than in the BCLS group (difference = 16 minutes [95% CI = 15-16 minutes], p < 0.001). CONCLUSIONS: In a tiered response urban emergency medical service setting, prehospital ACLS is not associated with an improvement in survival to hospital discharge in patients suffering from OHCA and in potential E-CPR candidates, but with an improvement in prehospital ROSC and with longer delay to hospital arrival. PMID- 28646585 TI - Prognostic value of cell cycle arrest biomarkers in patients at high risk for acute kidney injury: A systematic review and meta-analysis. AB - Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are G1 cell cycle arrest biomarkers. This systematic review aimed to evaluate the prognostic value of urinary [TIMP 2].[IGFBP7] in patients at high risk for AKI. The MEDLINE (via PubMed), Ovid, EMBASE and Cochrane Library databases were systematically searched from inception to December 25, 2016. Original clinical studies which met the eligibility criteria were included in this study. The prognostic accuracy of urinary [TIMP 2].[IGFBP7] for assessing the need for renal replacement therapy (RRT) and mortality was evaluated by pooled sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curves. A total of four prospective cohort studies evaluating 277 patients were included. The estimated area under the receiver operating characteristic curve (AUC) of urinary [TIMP 2].[IGFBP7] for predicting the need for RRT in patients at high risk for AKI was 0.915 (standard error [SE] = 0.040). Pooled sensitivity and specificity with corresponding 95% confidence intervals (CI) were 0.69 (95% CI 0.53-0.82) and 0.81 (95% CI 0.75-0.86), respectively. Urinary [TIMP-2].[IGFBP7] for mortality prediction in patients at high risk for AKI was assessed by qualitative description. Based on the above data, urinary [TIMP-2].[IGFBP7] performs well in predicting the need for RRT and mortality in patients at high risk for AKI. However, further meta-analyses are warranted as more data become available. PMID- 28646587 TI - Perioperative pain management after fibular free flap harvesting for head-and neck reconstruction using mini-catheters to inject local anesthetic: A pilot study. AB - BACKGROUND: Fibular donor site pain management in the early postoperative period can help minimize complications, patient discomfort, and agitation. Traditional management of postoperative pain consists of systemic administration of opioids and NSAIDS. The use of local anesthetics in addition to systemic analgesics has the potential to improve pain control. Purpose of the study is to evaluate the efficacy of mini-catheters used to inject local anesthetic into the fibular donor site after flap harvesting for reconstruction of the head-and-neck area. METHODS: Prospective study on 31 patients (mean age 52 years) treated for head and neck reconstruction with fibula free flap using minicatheter for local anesthetic injection in the early postoperative time. A bolus of chirochaine (0.125% w/v; 20 mL) was injected through the catheter before the patient regained consciousness. Postoperatively, three consecutive injections (20 mL each) were administered 8, 16, and 24 h after surgery. Pain evaluation before and after local anesthetic injection is used to assess efficacy and overall pain control. RESULTS: No major or minor complication occurred. Mean pain value was 1.69. At 8 h, the pain scores before injection ranged from 0 to 10 (mean 4.13 +/- 3.06). After injection, the pain scores ranged from 0 to 5 (mean 1 +/- 1.34). Similarly, at 16 h, the pain scores ranged from 0 to 8 (mean 2.77 +/- 2.42) before injection and from 0 to 6 (mean 0.42 +/- 1.2) thereafter. At 24 h, the initial pain score ranged from 0 to 6 (mean 1.71 +/- 1.74) and from 0 to 1 (mean 0.1 +/- 0.3) after drug administration. Pre and postinjection pain scores differences were statistically significant after all three injections (P < .001). CONCLUSIONS: Minicatheter seems to be easy, safe, and efficient when used to control pain after fibular free-flap harvesting. PMID- 28646588 TI - Duration and cessation characteristics of heparinization after finger replantation: A retrospective analysis of outcomes. AB - BACKGROUND: To prevent postoperative thrombosis, indications for anticoagulation in finger replantation have been described, but no consensus has yet been found for cessation protocols. The aim of this study is to investigate cessation methods of intravenous anticoagulation after finger replantation. METHODS: A retrospective review of all patients treated for a finger replantation between December 2014 and July 2016 was performed. Only those who required postoperative treatment with intravenous heparin were extracted. Primary outcome was survival of finger at hospital discharge and data collection focused on postoperative anticoagulation regimens. RESULTS: 108 patients with replantation were treated with intravenous heparin and included in the analysis. When anticoagulated, survival rate was 60% (n = 65) at hospital discharge, wherein arterial and venous thrombosis accounted for 60 and 40% respectively. Descriptive analysis failed to demonstrate an increase in failure rates when tested for duration of intravenous heparin, fixed or variable infusion rates of anticoagulation and need for vascular grafts. However, there was a 2.8-fold (P = .009) increase in the survival rate with progressive weaning of anticoagulation rather than abrupt discontinuation. Subgroup analysis demonstrated similar findings when considering arterial thrombosis alone (OR 5.2, P = .012), but did not show any significant difference for venous thrombosis (OR 1.7, P = .344). CONCLUSIONS: Progressive tapering of intravenous heparin is associated with an increased survival rate after finger replantation, particularly for arterial thrombosis. Further prospective and randomized trials are necessary to elucidate the optimal duration, method of infusion and indications for vascular grafts. PMID- 28646586 TI - Vaccine candidate discovery for the next generation of malaria vaccines. AB - Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre- to post genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody-guided vaccine design spanned both eras but currently benefits from technological advances facilitating high-throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen-specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines. PMID- 28646589 TI - Synthesis of 5-Acyl-2-Amino-3-Cyanothiophenes: Chemistry and Fluorescent Properties. AB - Independent of the substrate structure and reaction conditions, 3-amino-2 cyanothioacrylamides, which contain two active electrophilic centers, were shown to interact with various active halo methylene compounds under mild conditions to afford 5-acyl-2-amino-3-cyanothiophenes as the only products. A series of new polyfunctional thiophene derivatives with a rare combination of functionalities were synthesized, and their photophysical properties were experimentally and computationally investigated. The calculated electronic characteristics of the ground and excited states were compared to the experimental results, which provided a good understanding of the relationship between the optoelectronic properties and the molecular structures. After absorption of light quanta, the systems populate an intramolecular charge-transfer (ICT) Franck-Condon state, and emission occurs from a twisted ICT minimum. PMID- 28646590 TI - Randomized Controlled Double-blind Trial Comparing Haloperidol Combined With Conventional Therapy to Conventional Therapy Alone in Patients With Symptomatic Gastroparesis. AB - OBJECTIVE: Gastroparesis is a debilitating condition that causes nausea, vomiting, and abdominal pain. Management includes analgesics and antiemetics, but symptoms are often refractory. Haloperidol has been utilized in the palliative care setting for similar symptoms. The study objective was to determine whether haloperidol as an adjunct to conventional therapy would improve symptoms in gastroparesis patients presenting to the emergency department (ED). STUDY DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled trial of adult ED patients with acute exacerbation of previously diagnosed gastroparesis. The treatment group received 5 mg of haloperidol plus conventional therapy (determined by the treating physician). The control group received a placebo plus conventional therapy. The severity of each subject's abdominal pain and nausea were assessed before intervention and every 15 minutes thereafter for 1 hour using a 10-point scale for pain and a 5-point scale for nausea. Primary outcomes were decreased pain and nausea 1 hour after treatment. RESULTS: Of the 33 study patients, 15 were randomized to receive haloperidol. Before treatment, the mean intensity of pain was 8.5 in the haloperidol group and 8.28 in the placebo group; mean pretreatment nausea scores were 4.53 and 4.11, respectively. One hour after therapy, the mean pain and nausea scores in the haloperidol group were 3.13 and 1.83 compared to 7.17 and 3.39 in the placebo group. The reduction in mean pain intensity therapy was 5.37 in the haloperidol group (p <= 0.001) compared to 1.11 in the placebo group (p = 0.11). The reduction in mean nausea score was 2.70 in the haloperidol group (p <= 0.001) and 0.72 in the placebo group (p = 0.05). Therefore, the reductions in symptom scores were statistically significant in the haloperidol group but not in the placebo group. No adverse events were reported. CONCLUSIONS: Haloperidol as an adjunctive therapy is superior to placebo for acute gastroparesis symptoms. PMID- 28646591 TI - Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts. AB - BACKGROUND: Cutaneous warts have a cure rate after therapy of no more than approximately 50%. Recently, we developed and validated a standard assessment tool for warts (Cutaneous WARTS diagnostic tool, CWARTS) based on phenotypical characteristics. OBJECTIVES: To assess whether patient and morphological wart characteristics predict the human papillomavirus (HPV) type in a specific wart and whether these characteristics as well as the HPV type predict a favourable treatment response. METHODS: Photographs were used to score nine morphological wart characteristics using the newly developed CWARTS tool. Genotyping of 23 wart associated HPV types was performed using the hyperkeratotic skin lesion polymerase chain reaction/multiplex genotyping assay. The results were correlated with a favourable response to treatment with monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. Odds ratios were calculated using logistic regression in a generalized estimating equations model. RESULTS: Black dots (capillary thrombosis) strongly predicted the presence of any HPV type in a wart. From all characteristics tested, the HPV type most strongly predicted the treatment response when the warts were treated with monochloroacetic acid or a combination of cryotherapy and salicylic acid with a significantly decreased treatment response if the warts contained HPVs of the alpha genus (HPV2, HPV27 or HPV57). When cryotherapy alone was used for common warts, HPV type did not play a role, but cryotherapy was less effective in the presence of callus and when the wart was located deeper in the skin. CONCLUSIONS: Morphological characteristics of the warts and the HPV genotype influence treatment outcome and thus potentially influence future treatment decisions for common and plantar warts. PMID- 28646592 TI - Influence of inspiratory resistive loading on expiratory muscle fatigue in healthy humans. AB - NEW FINDINGS: What is the central question of this study? This study is the first to measure objectively both inspiratory and expiratory muscle fatigue after inspiratory resistive loading to determine whether the expiratory muscles are activated to the point of fatigue when specifically loading the inspiratory muscles. What is the main finding and its importance? The absence of abdominal muscle fatigue suggests that future studies attempting to understand the neural and circulatory consequences of diaphragm fatigue can use inspiratory resistive loading without considering the confounding effects of abdominal muscle fatigue. Expiratory resistive loading elicits inspiratory as well as expiratory muscle fatigue, suggesting parallel coactivation of the inspiratory muscles during expiration. It is unknown whether the expiratory muscles are likewise coactivated to the point of fatigue during inspiratory resistive loading (IRL). The purpose of this study was to determine whether IRL elicits expiratory as well as inspiratory muscle fatigue. Healthy male subjects (n = 9) underwent isocapnic IRL (60% maximal inspiratory pressure, 15 breaths min-1 , 0.7 inspiratory duty cycle) to task failure. Abdominal and diaphragm contractile function was assessed at baseline and at 3, 15 and 30 min post-IRL by measuring gastric twitch pressure (Pga,tw ) and transdiaphragmatic twitch pressure (Pdi,tw ) in response to potentiated magnetic stimulation of the thoracic and phrenic nerves, respectively. Fatigue was defined as a significant reduction from baseline in Pga,tw or Pdi,tw . Throughout IRL, there was a time-dependent increase in cardiac frequency and mean arterial blood pressure, suggesting activation of the respiratory muscle metaboreflex. The Pdi,tw was significantly lower than baseline (34.3 +/- 9.6 cmH2 O) at 3 (23.2 +/- 5.7 cmH2 O, P < 0.001), 15 (24.2 +/- 5.1 cmH2 O, P < 0.001) and 30 min post-IRL (26.3 +/- 6.0 cmH2 O, P < 0.001). The Pga,tw was not significantly different from baseline (37.6 +/- 17.1 cmH2 O) at 3 (36.5 +/- 14.6 cmH2 O), 15 (33.7 +/- 12.4 cmH2 O) and 30 min post-IRL (32.9 +/- 11.3 cmH2 O). Inspiratory resistive loading elicits objective evidence of diaphragm, but not abdominal, muscle fatigue. Agonist-antagonist interactions for the respiratory muscles appear to be more important during expiratory versus inspiratory loading. PMID- 28646593 TI - MRI-assisted dual motion correction for myocardial perfusion defect detection in PET imaging. AB - PURPOSE: Myocardial perfusion (MP) PET imaging is a powerful tool in risk assessment and stratification of patients with coronary artery disease. Involuntary organ motion degrades cardiac PET image resolution, while respiratory and/or cardiac gating to freeze the motion leads to noisier reconstructed images due to reduced counts in the gated frames. In this work, we propose an MRI assisted dual motion correction method to compensate for respiratory and cardiac motion in MP PET data and study the impact of dual motion correction on MP defect detection using systematically designed experiments. METHODS: The proposed dual motion correction method addresses the respiratory motion before correcting the cardiac motion among the respiratory motion corrected cardiac gates. The respiratory motion is estimated from the respiratory-gated only PET images and compensated within a 4D motion-incorporated image reconstruction algorithm. The cardiac motion is then corrected using the motion vector fields estimated from the corresponding cardiac-gated MR images. To evaluate the proposed method, we performed experiments using the standard XCAT phantom and two individual-specific volunteer XCAT phantoms. For each of the three phantoms, we simulated four dual gated Rb-82 MP PET imaging datasets, one with normal perfusion and the other three with 50% nontransmural, 75% nontransmural, and transmural regionally reduced perfusion. The corresponding cardiac-gated MR images were simulated by the SIMRI simulator, with the sequence specified to be 3D T1-weighted as used in a protocol of a clinical PET/MRI scanner. We quantitatively evaluated the reconstructed images with no motion correction, only respiratory motion correction and dual motion correction, in terms of the myocardium to blood pool contrast and the trade-off between the noise and the normal to defect contrast. Using the channelized Hotelling observer, we performed receiver operating characteristic analysis for the task of detecting perfusion abnormalities with various myocardial coverages. RESULTS: Compared with no motion correction, the respiratory motion correction was demonstrated to improve the myocardium to blood pool contrast as well as the trade-off between the noise and the normal to defect contrast, on top of which the cardiac motion correction furthered the improvement. In the task of detecting regional perfusion defects, transmural or different levels of nontransmural, the respiratory motion correction significantly increased the defect detectability compared with no motion correction. Additionally, the respiratory and cardiac motion correction significantly improved the defect detection compared with the respiratory motion correction alone. Furthermore, the separability of the transmural and nontransmural defects was also improved by the proposed MRI assisted dual motion correction method. CONCLUSIONS: The proposed dual respiratory and cardiac motion correction technique improves the accuracy of PET quantification and MP defect detection and classification, which shows its promise for clinical applications especially in cardiac PET/MR imaging. PMID- 28646594 TI - Prevalence and prognosis of low-volume, oligorecurrent, hormone-sensitive prostate cancer amenable to lesion ablative therapy. AB - OBJECTIVES: To describe the anatomical patterns of prostate cancer (PCa) recurrence after primary therapy and to investigate if patients with low-volume disease have a better prognosis as compared with their counterparts. MATERIALS AND METHODS: Patients eligible for an 18-F choline positron-emission tomography (PET)-computed tomography (CT) were enrolled in a prospective cohort study. Eligible patients had asymptomatic biochemical recurrence after primary PCa treatment and testosterone levels >50 ng/mL. The number of lesions was counted per scan. Patients with isolated local recurrence (LR) or with <=3 metastases (with or without LR) were considered to have low-volume disease and patients with >3 metastases to have high-volume disease. Descriptive statistics were used to report recurrences. Cox regression analysis was used to investigate the influence of prognostic variables on the time to developing castration-resistant PCa (CRPC). RESULTS: In 208 patients, 625 sites of recurrence were detected in the lymph nodes (N1/M1a: 30%), the bone (18%), the prostate (bed; 11%), viscera (4%), or a combination of any of the previous (37%). In total, 153 patients (74%) had low-volume recurrence and 55 patients (26%) had high-volume recurrence. The 3 year CRPC-free survival rate for the whole cohort was 79% (95% confidence interval 43-55), 88% for low-volume recurrences and 50% for high-volume recurrences (P < 0.001). Longer PSA doubling time at time of recurrence and low volume disease were associated with a longer time to CRPC. CONCLUSIONS: Three out of four patients with PCa with a 18-F choline PET-CT-detected recurrence have low volume disease, potentially amenable to local therapy. Patients with low-volume disease have a better prognosis as compared with their counterparts. Lymph node recurrence was the most dominant failure pattern. PMID- 28646595 TI - Point-of-Care Ultrasound Work Flow Innovation: Impact on Documentation and Billing. AB - OBJECTIVES: To evaluate the impact that an innovative automated ultrasound (US) work flow, which allows for bedside performance of examination documentation and order placement, has on point-of-care US billing compared to ordering US examinations through an electronic medical record. METHODS: We conducted a retrospective review of point-of-care US billing data (March 2014-February 2016) for adult and pediatric emergency departments with an emergency medicine residency and a US fellowship. An innovative work flow with the ability to automate US billing and selectively transfer the images and reports for patient care examinations to an electronic medical record and picture archiving and communication system using the QPath US work flow solution (Telexy Healthcare, Maple Ridge, British Columbia, Canada) was implemented. The total number of examinations billed and percent increase in technical and professional revenue, excluding examinations performed by US fellows, before and after implementation of the automated work flow innovation were determined. RESULTS: After implementation of our automated US work flow process, the number of patient care US examinations billed increased significantly due to completing documentation and immediate billing determination at the bedside. The increase in percent billing relative to total examinations was noted in both technical (32% to 61%; P < .0001) and professional (37% to 65%; P < .0001) billing components. In addition, there was a net increase in technical and professional fee revenue to 96% and 78%, respectively. CONCLUSIONS: The implementation of an innovative automated work flow to include bedside point-of-care US documentation, order placement, and the automated transfer of images and reports led to a significant increase in US billing revenue, documentation, and compliance. PMID- 28646596 TI - The course and distribution of the buccal nerve: clinical relevance in dentistry. AB - BACKGROUND: The buccal branch of the mandibular division of the trigeminal nerve is commonly anaesthetized for dental procedures and may be damaged during surgery. Descriptions of the distribution of the buccal nerve (BN) in anatomical texts are generally lacking in detail and do not provide information about the extent of its variation between individuals. There are also commonly-held clinical beliefs about the BN that lack support from anatomical dissections. METHODS: Detailed dissections of the course and distribution of the BN were performed in a sample of 12 hemi-heads from 11 edentulous and partially dentate human adult cadavers. RESULTS: A broader distribution of the BN was found than described previously, with innervation extending to the lips in all cases. Approximately half of the lateral sides of the lips were innervated by the BN in two cases and approximately one-third of their lateral sides in the other 10 cases. Distribution of the BN to the lower lips was wider than to the upper lips. CONCLUSIONS: Our findings provide a stronger anatomical basis to underpin clinical procedures involving the BN and indicate that some commonly-held clinical views about this nerve are not supported by anatomical evidence. PMID- 28646598 TI - Local anaesthesia and nerve damage. PMID- 28646597 TI - A Contrast-Enhanced Ultrasonographic Study About the Impact of Long-term Exercise Training on Mammary Tumor Vascularization. AB - OBJECTIVES: This study aimed to evaluate the impact of long-term exercise training on the vascularization of rat mammary tumors. METHODS: Female rats were divided into 4 groups: N-methyl-N-nitrosourea (MNU) treated sedentary, MNU treated exercised, control sedentary, and control exercised. Tumor development was induced in the MNU groups by MNU administration. Exercised groups were trained for 35 weeks. Tumor vascularization was evaluated by pulsed Doppler and contrast-enhanced ultrasonography. RESULTS: The pulsatility and resistive indices were slightly higher in the MNU sedentary group (P > .05). Mammary tumors mainly had centripetal and heterogeneous enhancement of the contrast, clear margins, and the presence of penetrating vessels. The MNU exercised group had a lower arrival time and time to peak and higher peak intensity, wash-in, and wash-out (P > .05). The area under the curve was similar between groups (P > .05). CONCLUSIONS: The contrast-enhanced ultrasonographic study did not detect differences in mammary tumor vascularization between MNU sedentary and MNU exercised groups previously detected by power Doppler imaging, B-flow imaging, and immunohistochemistry. PMID- 28646600 TI - Intranasal ketamine proved feasible for pain control in paediatric care and parental support was high. PMID- 28646599 TI - Boldness predicts an individual's position along an exploration-exploitation foraging trade-off. AB - Individuals do not have complete information about the environment and therefore they face a trade-off between gathering information (exploration) and gathering resources (exploitation). Studies have shown individual differences in components of this trade-off but how stable these strategies are in a population and the intrinsic drivers of these differences is not well understood. Top marine predators are expected to experience a particularly strong trade-off as many species have large foraging ranges and their prey often have a patchy distribution. This environment leads these species to exhibit pronounced exploration and exploitation phases but differences between individuals are poorly resolved. Personality differences are known to be important in foraging behaviour but also in the trade-off between exploration and exploitation. Here we test whether personality predicts an individual exploration-exploitation strategy using wide ranging wandering albatrosses (Diomedea exulans) as a model system. Using GPS tracking data from 276 wandering albatrosses, we extract foraging parameters indicative of exploration (searching) and exploitation (foraging) and show that foraging effort, time in patch and size of patch are strongly correlated, demonstrating these are indicative of an exploration-exploitation (EE) strategy. Furthermore, we show these are consistent within individuals and appear stable in the population, with no reproductive advantage. The searching and foraging behaviour of bolder birds placed them towards the exploration end of the trade-off, whereas shy birds showed greater exploitation. This result provides a mechanism through which individual foraging strategies may emerge. Age and sex affected components of the trade-off, but not the trade-off itself, suggesting these factors may drive behavioural compensation to maintain resource acquisition and this was supported by the evidence that there were no fitness consequence of any EE trait nor the trade-off itself. These results demonstrate a clear trade-off between information gathering and exploitation of prey patches, and reveals for the first time that boldness may drive these differences. This provides a mechanism through which widely reported links between personality and foraging may emerge. PMID- 28646601 TI - Autophagy activation is required for myofibroblast differentiation during healing of oral mucosa. AB - AIM: It is known that periodontal tissues heal faster that skin, and gingiva in particular heal without scar formation. The mechanisms regulating this behaviour are still unclear. The aim of our work was to compare wound healing in oral mucosa and gingiva, investigating the role of alpha-smooth muscle actin (alphaSMA)-expressing myofibroblasts and autophagy. MATERIALS AND METHODS: Biopsies were obtained from seven patients immediately before and 24 hr after vertical releasing incision in oral mucosa and attached gingiva. Both whole biopsies and primary cultures of fibroblasts derived from the same tissues were subjected to immunofluorescence, Western blot and quantitative real-time PCR analyses. RESULTS: We demonstrated that in oral mucosa, characterized by partially fibrotic outcome during repair, the activation of autophagy determined an increase in alphaSMA and collagen 1a1 production. Conversely, wound healing did not stimulate autophagy in attached gingiva, and subsequently, no increase in myofibroblast differentiation and collagen deposition could be seen, thus justifying its scarless outcome. CONCLUSIONS: The elucidation of the differential regulation of autophagy in periodontal tissues and its correlation with myofibroblast differentiation and fibrotic outcome could allow the identification of new molecules involved in periodontal healing and the development of new surgical approaches for periodontal treatment that could improve the outcome of postoperative wounds. PMID- 28646602 TI - Comparison of Acoustic Radiation Force Impulse Imaging and Strain Elastography in Differentiating Malignant From Benign Thyroid Nodules. AB - OBJECTIVES: This study aimed to evaluate the diagnostic value of acoustic radiation force impulse (ARFI) imaging and strain elastography in differentiating malignant from benign thyroid nodules. METHODS: This study included 128 patients (104 female and 24 male; mean age +/- standard deviation, 48 +/- 11 years; range, 23-76 years) with 152 pathologically proven thyroid nodules. Conventional sonography, strain ratio (SR) of strain elastography, virtual touch tissue imaging (VTI) grade, and virtual touch tissue quantification (shear wave velocity [SWV]) from ARFI imaging data were generated for each nodule. The diagnostic performance of the three elastography analysis methods was analyzed and compared by multiple receiver operating characteristic curve analysis. The interobserver agreement for VTI grade was also assessed. RESULTS: The best cutoff values for VTI grade, mean SWV, and mean SR for predicting malignant thyroid nodules were greater than or equal to grade chi, 2.87 m/s and 2.37, respectively. The area under the receiver operating characteristic curve for VTI grade, mean SWV, and mean SR was 0.854, 0.869 and 0.849, respectively (P > .05), and the accuracy was 83.55, 81.58 and 80.26%, respectively (P > .05). The accuracy of the combined use of conventional sonography and ARFI imaging for VTI grade, mean SWV, and mean SR was 98.03, 95.39 and 96.71%, respectively, which was slightly higher than that of conventional sonography (P > .05). The interobserver agreement produced a kappa value of 0.98 (95% confidence interval, 0.959-1.000). CONCLUSIONS: Both strain elastography and ARFI imaging have high sensitivity and specificity for differentiating malignant from benign thyroid nodules. Combined with sonography, these techniques can improve the accuracy of thyroid nodule diagnosis. PMID- 28646604 TI - Melanoma mortality is rising in susceptible Australians. PMID- 28646603 TI - Comparison of Oral Contrast-Enhanced Transabdominal Ultrasound Imaging With Transverse Contrast-Enhanced Computed Tomography in Preoperative Tumor Staging of Advanced Gastric Carcinoma. AB - OBJECTIVES: This study assessed the diagnostic performance of transabdominal oral contrast-enhanced ultrasound (US) imaging for preoperative tumor staging of advanced gastric carcinoma by comparing it with transverse contrast-enhanced computed tomography (CT). METHODS: This retrospective study included 42 patients with advanced gastric cancer who underwent laparoscopy, radical surgery, or palliative surgery because of serious complications and had a body mass index of less than 25 kg/m2 . A cereal-based oral contrast agent was used for transabdominal oral contrast-enhanced US. Retrospective analyses were conducted using preoperative tumor staging data acquired by either transabdominal oral contrast-enhanced US or transverse contrast-enhanced CT. Both contrast-enhanced US and contrast-enhanced CT examinations were reviewed by 2 experienced radiologists independently for preoperative tumor staging according to the seventh edition of the TNM classification. The accuracy, sensitivity, and specificity were calculated by comparing the results of contrast-enhanced US and contrast-enhanced CT with pathologic findings. The overall accuracies of the imaging modalities were compared by the McNemar test. RESULTS: No significant difference was noted in the overall accuracy of transabdominal oral contrast enhanced US (86% [36 of 42]) and transverse contrast-enhanced CT (83% [35 of 42] P > .999). For stage T2 to T4 gastric cancer, the accuracies of transabdominal oral contrast-enhanced US were 88%, 86%, and 98%, respectively, and those of transverse contrast-enhanced CT were 93%, 83%, and 90%. CONCLUSIONS: The overall accuracy of transabdominal oral contrast-enhanced US was comparable with that of transverse contrast-enhanced CT for preoperative tumor staging of advanced gastric cancer. PMID- 28646605 TI - Observations and impacts of bleach washing on indoor chlorine chemistry. AB - Ambient levels of chlorinated gases and aerosol components were measured by online chemical ionization and aerosol mass spectrometers after an indoor floor were repeatedly washed with a commercial bleach solution. Gaseous chlorine (Cl2 , 10's of ppbv) and hypochlorous acid (HOCl, 100's of ppbv) arise after floor washing, along with nitryl chloride (ClNO2 ), dichlorine monoxide (Cl2 O), and chloramines (NHCl2 , NCl3 ). Much higher mixing ratios would prevail in a room with lower and more commonly encountered air exchange rates than that observed in the study (12.7 h-1 ). Coincident with the formation of gas-phase species, particulate chlorine levels also rise. Cl2 , ClNO2 , NHCl2 , and NCl3 exist in the headspace of the bleach solution, whereas HOCl was only observed after floor washing. HOCl decays away 1.4 times faster than the air exchange rate, indicative of uptake onto room surfaces, and consistent with the well-known chlorinating ability of HOCl. Photochemical box modeling captures the temporal profiles of Cl2 and HOCl very well and indicates that the OH, Cl, and ClO gas-phase radical concentrations in the indoor environment could be greatly enhanced (>106 and 105 cm-3 for OH and Cl, respectively) in such washing conditions, dependent on the amount of indoor illumination. PMID- 28646606 TI - Vismodegib for recurrent locally destructive basal cell carcinoma in a renal transplant patient. PMID- 28646607 TI - More pieces of the fructose puzzle. PMID- 28646608 TI - Fluid filling of the digestive tract for improved proton resonance frequency shift-based MR thermometry in the pancreas. AB - PURPOSE: To demonstrate that fluid filling of the digestive tract improves the performance of respiratory motion-compensated proton resonance frequency shift (PRFS)-based magnetic resonance (MR) thermometry in the pancreas. MATERIALS AND METHODS: In seven volunteers (without heating), we evaluated PRFS thermometry in the pancreas with and without filling of the surrounding digestive tract. All data acquisition was performed at 1.5T, then all datasets were analyzed and compared with three different PRFS respiratory motion-compensated thermometry methods: gating, multibaseline, and referenceless. The temperature precision of the different methods was evaluated by assessing temperature standard deviation over time, while a simulation experiment was used to study the accuracy of the methods. RESULTS: Without fluid intake, errors in temperature precision in the pancreas up to 10 degrees C were observed for all evaluated methods. After liquid intake, temperature precision improved to median values between 1.8 and 2.9 degrees C. The simulations showed that gating had the lowest accuracy, with errors up to 7 degrees C. Multibaseline and referenceless thermometry performed better, with a median error in the pancreas between -3 and +3 degrees C after fluid intake, for all volunteers. CONCLUSION: Preparation of the digestive tract near the pancreas by filling it with fluid improved MR thermometry precision and accuracy for all common respiratory motion-compensated methods evaluated. These improvements are attributed to reducing field inhomogeneity in the pancreas. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:692-701. PMID- 28646609 TI - Validation of psoriasis severity classification based on use of topical or systemic treatment. PMID- 28646610 TI - Measuring the societal impact of psoriasis in the United Kingdom through a non interventional study of patients. PMID- 28646611 TI - Prediction in ecology: a first-principles framework. AB - Quantitative predictions are ubiquitous in ecology, yet there is limited discussion on the nature of prediction in this field. Herein I derive a general quantitative framework for analyzing and partitioning the sources of uncertainty that control predictability. The implications of this framework are assessed conceptually and linked to classic questions in ecology, such as the relative importance of endogenous (density-dependent) vs. exogenous factors, stability vs. drift, and the spatial scaling of processes. The framework is used to make a number of novel predictions and reframe approaches to experimental design, model selection, and hypothesis testing. Next, the quantitative application of the framework to partitioning uncertainties is illustrated using a short-term forecast of net ecosystem exchange. Finally, I advocate for a new comparative approach to studying predictability across different ecological systems and processes and lay out a number of hypotheses about what limits predictability and how these limits should scale in space and time. PMID- 28646612 TI - Dowling-Degos disease with mutation in the exon 1 of the keratin 5 gene. PMID- 28646613 TI - Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease. AB - BACKGROUND: Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. OBJECTIVE: The aim of this study was to report EV causing mutations in four patients with EV and to give an overview of all described patients with EV. PATIENTS AND METHODS: We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and beta-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. RESULTS: Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While beta-HPVs were identified in the majority of cases, alpha-HPVs were detected in several individuals. CONCLUSION: The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV 20 were unexpectedly identified more frequently than HPV-8. PMID- 28646614 TI - Does breast MRI background parenchymal enhancement indicate metabolic activity? Qualitative and 3D quantitative computer imaging analysis. AB - PURPOSE: To investigate whether the degree of breast magnetic resonance imaging (MRI) background parenchymal enhancement (BPE) is associated with the amount of breast metabolic activity measured by breast parenchymal uptake (BPU) of 18F-FDG on positron emission tomography / computed tomography (PET/CT). MATERIALS AND METHODS: An Institutional Review Board (IRB)-approved retrospective study was performed. Of 327 patients who underwent preoperative breast MRI from 1/1/12 to 12/31/15, 73 patients had 18F-FDG PET/CT evaluation performed within 1 week of breast MRI and no suspicious findings in the contralateral breast. MRI was performed on a 1.5T or 3.0T system. The imaging sequence included a triplane localizing sequence followed by sagittal fat-suppressed T2 -weighted sequence, and a bilateral sagittal T1 -weighted fat-suppressed fast spoiled gradient-echo sequence, which was performed before and three times after a rapid bolus injection (gadobenate dimeglumine, Multihance; Bracco Imaging; 0.1 mmol/kg) delivered through an IV catheter. The unaffected contralateral breast in these 73 patients underwent BPE and BPU assessments. For PET/CT BPU calculation, a 3D region of interest (ROI) was drawn around the glandular breast tissue and the maximum standardized uptake value (SUVmax ) was determined. Qualitative MRI BPE assessments were performed on a 4-point scale, in accordance with BI-RADS categories. Additional 3D quantitative MRI BPE analysis was performed using a previously published in-house technique. Spearman's correlation test and linear regression analysis was performed (SPSS, v. 24). RESULT: The median time interval between breast MRI and 18F-FDG PET/CT evaluation was 3 days (range, 0-6 days). BPU SUVmax mean value was 1.6 (SD, 0.53). Minimum and maximum BPU SUVmax values were 0.71 and 4.0. The BPU SUVmax values significantly correlated with both the qualitative and quantitative measurements of BPE, respectively (r(71) = 0.59, P < 0.001 and r(71) = 0.54, P < 0.001). Qualitatively assessed high BPE group (BI RADS 3/4) had significantly higher BPU SUVmax of 1.9 (SD = 0.44) compared to low BPE group (BI-RADS 1/2) with an average BPU SUVmax of 1.17 (SD = 0.32) (P < 0.001). On linear regression analysis, BPU SUVmax significantly predicted qualitative and quantitative measurements of BPE (beta = 1.29, t(71) = 3.88, P < 0.001 and beta = 19.52, t(71) = 3.88, P < 0.001). CONCLUSION: There is a significant association between breast BPU and BPE, measured both qualitatively and quantitatively. Increased breast cancer risk in patients with high MRI BPE could be due to elevated basal metabolic activity of the normal breast tissue, which may provide a susceptible environment for tumor growth. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:753-759. PMID- 28646615 TI - Definition of healthcare-associated influenza: A review and results from an international survey. AB - AIM: To describe definitions of healthcare-associated influenza (HAI) in recent literature and in hospitals participating in a survey of Society for Healthcare Epidemiology of America (SHEA) Research Network (SRN) members. METHOD: A review with PubMed search was undertaken to retrieve articles published between 2008 and 2016, focusing on the subject headings "influenza, human" and "cross infection." Definitions of clinical influenza-like illness (ILI) and HAI were identified. An invitation to participate in the survey was sent to 218 SRN members via email. RESULTS: Of 75 articles on HAI included in the review, 30 presented a standardized definition of clinical ILI based on fever (100%), cough (80%), and sore throat (70%). Forty studies (53%) contained a standardized HAI definition, grounded on threshold delay from admission in 29 of them, this delay ranging from 48 to 196 hour (median: 72 hour). Fifty-five SRN members responded to the survey, with a standardized definition of HAI adopted by 76% of them. This definition was based on clinical features for 24%, virological features for 31%, and both for 45%. Fever (mean threshold: 38.0 degrees C) was part of the definition for 82%. The features required most frequently in the clinical definition were cough (46%) and sore throat (26%). Median threshold delay between admission and symptoms onset adopted for HAI definition was 48 hour (range: 24-96 hour). CONCLUSION: This work underlined the heterogeneity of HAI definitions in different countries. A standardized definition would be helpful to evaluate HAI spread, outcomes in patients and healthcare systems, and the impact of prevention measures, including vaccination. PMID- 28646617 TI - Melanoma-associated GRM3 variants dysregulate melanosome trafficking and cAMP signaling. AB - Large-scale sequencing studies have revealed several genes that are recurrently mutated in melanomas. To annotate the melanoma genome, we have expressed tumor associated variants of these genes in zebrafish and characterized their effects on melanocyte development and function. Here, we describe expression of tumor associated variants of the recurrently mutated metabotropic glutamate receptor 3 (GRM3) gene. Unlike wild-type GRM3, tumor-associated GRM3 variants disrupted trafficking of melanosomes, causing their aggregation in the cell body. Melanosomes are trafficked in a cAMP-dependent manner, and drugs that directly or indirectly increased cAMP levels were able to suppress melanosome aggregation in mutant GRM3-expressing melanocytes. Our data show that oncogenic GRM3 variants dysregulate cAMP signaling, a heretofore unknown role for these oncogenes. cAMP signaling has been implicated in melanoma progression and drug resistance, and our data show that oncogenic properties of GRM3 could be mediated, at least in part, by alterations in cAMP signaling. PMID- 28646616 TI - Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-kappaB signaling pathway. AB - BACKGROUND: Influenza A viruses (IAV) result in severe public health problems with worldwide each year. Overresponse of immune system to IAV infection leads to complications, and ultimately causing morbidity and mortality. OBJECTIVE: Curcumin has been reported to have anti-inflammatory ability. However, its molecular mechanism in immune responses remains unclear. METHODS: We detected the pro-inflammatory cytokine secretion and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB)-related protein expression in human macrophages or mice infected by IAV with or without curcumin treatment. RESULTS: We found that the IAV infection caused a dramatic enhancement of pro-inflammatory cytokine productions of human macrophages and mice immune cells. However, curcumin treatment after IAV infection downregulated these cytokines production in a dose dependent manner. Moreover, the NF-kappaB has been activated in human macrophages after IAV infection, while administration of curcumin inhibited NF-kappaB signaling pathway via promoting the expression of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaBalpha), and inhibiting the translocation of p65 from cytoplasm to nucleus. CONCLUSIONS: In summary, IAV infection could result in the inflammatory responses of immune cells, especially macrophages. Curcumin has the therapeutic potentials to relieve these inflammatory responses through inhibiting the NF-kappaB signaling pathway. PMID- 28646618 TI - Tryptophan as a surrogate prognostic marker for diabetic nephropathy. AB - AIMS/INTRODUCTION: Diabetic nephropathy is one of the leading causes of end-stage renal disease. Unfortunately, reliable surrogate markers for predicting the prognostic outcome of diabetic nephropathy are as yet absent. In order to find new markers in predicting the progression of diabetic nephropathy, we carried out a prospective study by investigating the correlation between serum metabolites and the annual change of estimated glomerular filtration rate (eGFR). MATERIALS AND METHODS: From September 2013 to September 2015, 52 diabetes patients at various stages of chronic kidney disease were enrolled. While serum levels of 175 metabolites were measured by AbsoluteIDQTM p180 kit, only those with a significant difference in advancing chronic kidney disease stages were selected. After then, serial renal function change of these patients was followed up for 12 months, the outcome of renal function with each selected metabolite was compared according to the occurrence of a rapid decline (sustained annual decrement rate >=5%) of eGFR. RESULTS: A total of 26 metabolites were found to be significantly associated with the severity of chronic kidney disease. Tryptophan (Trp) showed a significant association with the event of rapid decline in eGFR (P = 0.036). Serum concentration of Trp <44.20 MUmol/L showed the most valuable predictive value with 55.6% sensitivity and 87% specificity. CONCLUSIONS: A lower level of Trp, especially <44.20 MUmol/L, was related to a rapid decline in eGFR. Accordingly, Trp might be regarded as a potential prognostic marker for diabetic nephropathy. PMID- 28646619 TI - Early insights into Zika's microcephaly physiopathology from the epicenter of the outbreak: teratogenic apoptosis in the central nervous system. AB - Fetal infection by the Zika virus has been implicated in the exceptional rise in the number of microcephalic newborns recorded by the end of 2015 in Brazil. The mechanism by which this teratogenic effect is produced in the developing brain has not been fully established. Very early in the outbreak, we addressed this question by evaluating available initial data from a gestational and postnatal clinical investigation in the Brazilian state of Pernambuco. The present study was undertaken to test the hypothesis that the subtractive dysmorphic brain malformations observed in Zika-related microcephaly are primarily due to the massive induction of apoptosis of neuroprogenitor cells. We designed a physiopathological algorithm based on the examination of the following medical findings: epidemiological data, ultrasound images, computed tomography scans, placental tissue, cerebral fluid analysis, eye fundoscopy, neurological examination and necroscopy findings. PMID- 28646620 TI - Atopic dermatitis is inversely associated with hepatitis B antigen positivity: a population-based cohort study. AB - BACKGROUND: No clear association between hepatitis B virus (HBV) infection and atopic dermatitis (AD) has been established. Some studies have reported that subjects with HBV had an increased risk of atopy; other studies reported an inverse association between HBV seropositivity and allergic diseases. OBJECTIVE: We evaluated the association between AD and hepatitis B antigen (HBsAg) positivity using Korean National Health and Nutrition Examination Survey data. METHODS: In total, 14 776 participants aged >19 years were included in the analysis. Multiple logistic regression analyses were used to evaluate the odds ratio of HBsAg positivity in association with AD and asthma. RESULTS: The prevalence of HBsAg positivity was lower in individuals with AD than in those without AD (mean [SE], 0.7% [0.4] vs. 3.7% [0.2]; P < 0.001). However, HBsAg positivity was not significantly associated with asthma (3.7% [0.2] vs. 2.8% [0.8]; P < 0.001). HBsAg positivity decreased the risk of AD significantly (OR = 0.223; 95% CI = 0.069-0.72). CONCLUSIONS: This study demonstrates an inverse association between AD and HBsAg positivity using a nationwide, population-based, cross-sectional health examination and survey. PMID- 28646621 TI - The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors. AB - Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure-activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC50 = 0.1 +/- 0.04 MUm, H3N2 IC50 = 0.26 +/- 0.18 MUm) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors. PMID- 28646622 TI - Dormancy cycles in buried seeds of three perennial Xyris (Xyridaceae) species from the Brazilian campo rupestre. AB - Dormancy cycles are an important mechanism for avoiding seed germination under unfavourable periods for seedling establishment. This mechanism has been scarcely studied in tropical species. Here, we studied three tropical and perennial species of Xyris, X. asperula, X. subsetigera and X. trachyphylla, to investigate in situ longevity and the existence of seasonal seed dormancy cycles. Seeds of three species of Xyris were buried in their natural habitat, with samples exhumed bimonthly for 18 months. Germination of exhumed seeds was assessed under a 12-h photoperiod over a broad range of temperatures. Seeds of X. trachyphylla were also subjected to treatments to overcome secondary dormancy. Seeds of all species are able to form a persistent seed bank and exhibit seasonal changes in germinability. Secondary dormancy was acquired during the rainy summer and was overcome during the subsequent dry season (autumn/winter). Desiccation partially overcomes secondary dormancy in X. trachyphylla seeds. Soil seed bank persistence and synchronisation of seed germination under favourable conditions for seedling establishment contribute to the persistence and regeneration of X. asperula, X. subsetigera and X. trachyphylla in their natural environment. PMID- 28646623 TI - Pregnancy outcome in women with cystic fibrosis-related diabetes. AB - INTRODUCTION: With increasing life expectancy, more women with cystic fibrosis and diabetes mellitus become pregnant. We investigated how pre-gestational diabetes (cystic fibrosis-related diabetes) influenced pregnancy outcome and the clinical status of these women. MATERIAL AND METHODS: We analyzed all pregnancies reported to the French cystic fibrosis registry between 2001 and 2012, and compared forced expiratory volume (FEV1 ) and body mass index before and after pregnancy in women with and without pre-gestational diabetes having a first delivery. RESULTS: A total 249 women delivered 314 infants. Among these, 189 women had a first delivery and 29 of these had pre-gestational diabetes. There was a trend towards a higher rate of assisted conception among diabetic women (53.8%) than non-diabetic women (34.5%, p = 0.06), and the rate of cesarean section was significantly higher in diabetic women (48% vs. 21.4%, p = 0.005). The rate of preterm birth and mean infant birthweight did not differ significantly between diabetic and non-diabetic women. Forced expiratory volume before pregnancy was significantly lower in the diabetic group. The decline in forced expiratory volume and body mass index following pregnancy did not differ between the women with and those without pre-gestational diabetes. CONCLUSION: Pre-gestational diabetes in women with cystic fibrosis is associated with a higher rate of cesarean section but does not seem to have a clinically significant impact on fetal growth or preterm delivery. The changes in maternal pulmonary and nutritional status following pregnancy in women with cystic fibrosis were not influenced by pre-gestational diabetes. PMID- 28646624 TI - Prognostic relevance of oxidative stress measurement in chronic lymphocytic leukaemia. AB - OBJECTIVE: To evaluate the prognostic significance of oxidative stress (OS) and antioxidant defence status measurement in patients with chronic lymphocytic leukaemia (CLL). METHODS: d-ROMs test and BAP test were evaluated at diagnosis of 165 patients with CLL and correlated with clinical-biological features and prognosis. RESULTS: An increased oxidative damage (d-ROMs test) and a reduced antioxidant potential (BAP test) were found in CLL patients than normal controls (P<.0001). CLL patients with higher d-ROMs values had higher number of circulating white blood cells and lymphocytes, and higher values of beta2 microglobulin. Higher d-ROMs values were found in female (P=.0003), in patients with unmutated IgVH (P=.04), unfavourable cytogenetics (P=.002) and more advanced clinical stage (P=.002). Higher BAP test values were found in patients expressing CD49d (P=.01) and with more advanced clinical stage (P=.004). At a median follow up of 48 months, CLL patients with d-ROMs >=418 CARR U were found to have a shorter time to first treatment (TFT) (P=.0002), and a reduced survival (P=.006) than others. CLL patients with BAP test values >=2155 MUmol/L had a shorter TFT (P=.008) and a shorter survival (P=.003). CONCLUSIONS: OS can affect CLL patients by concomitantly increasing reactive oxygen metabolites production and decreasing antioxidant defences. PMID- 28646625 TI - Fluctuating effects of genetic and plastic changes in body mass on population dynamics in a large herbivore. AB - Recent studies suggest that evolutionary changes can occur on a contemporary time scale. Hence, evolution can influence ecology and vice-versa. To understand the importance of eco-evolutionary dynamics in population dynamics, we must quantify the relative contribution of ecological and evolutionary changes to population growth and other ecological processes. To date, however, most eco-evolutionary dynamics studies have not partitioned the relative contribution of plastic and evolutionary changes in traits on population, community, and ecosystem processes. Here, we quantify the effects of heritable and non-heritable changes in body mass distribution on survival, recruitment, and population growth in wild bighorn sheep (Ovis canadensis) and compare their importance to the effects of changes in age structure, population density, and weather. We applied a combination of a pedigree-based quantitative genetics model, statistical analyses of demography, and a new statistical decomposition technique, the Geber method, to a long-term data set of bighorn sheep on Ram Mountain (Canada), monitored individually from 1975 to 2012. We show three main results: (1) The relative importance of heritable change in mass, non-heritable change in mass, age structure, density, and climate on population growth rate changed substantially over time. (2) An increase in body mass was accompanied by an increase in population growth through higher survival and recruitment rate. (3) Over the entire study period, changes in the body mass distribution of ewes, mostly through non-heritable changes, affected population growth to a similar extent as changes in age structure or in density. The importance of evolutionary changes was small compared to that of other drivers of changes in population growth but increased with time as evolutionary changes accumulated. Evolutionary changes became increasingly important for population growth as the length of the study period considered increased. Our results highlight the complex ways in which ecological and evolutionary changes can affect population dynamics and illustrate the large potential effect of trait changes on population processes. PMID- 28646626 TI - Sexual Dimorphism in Umbilical Vein Blood Flow During the Second Half of Pregnancy: A Longitudinal Study. AB - OBJECTIVES: To investigate gestational age-specific serial changes in umbilical vein (UV) volume blood flow during the second half of normal pregnancy and establish sex-specific reference ranges. METHODS: This work was a prospective longitudinal study of singleton low-risk pregnancies. The UV diameter and maximum blood flow velocity were serially measured by sonography at the intra-abdominal portion of the UV over 19 to 41 weeks. Umbilical vein volume blood flow was calculated and normalized for estimated fetal weight. RESULTS: One hundred seventy-nine women and their fetuses (87 male and 92 female) were included in the final analysis, and a total of 746 observations were used to construct sex specific reference intervals. We found no statistically significant sex-specific differences in the UV parameters examined. However, the temporal development patterns of normalized UV volume blood flow appeared to differ between male and female fetuses during the second half of pregnancy, with crossovers at 24 and 32 weeks' gestation. CONCLUSIONS: Umbilical vein volume blood flow is similar among male and female fetuses in quantitative terms, but the pattern of gestational age dependent temporal changes may be different, which may have important physiologic implications with regard to in utero development and maturation of the fetoplacental unit. PMID- 28646627 TI - Collecting Validity Evidence for Simulation-Based Assessment of Point-of-Care Ultrasound Skills. AB - OBJECTIVES: The aim of this study was to examine the validity of a simulator test designed to evaluate focused assessment with sonography for trauma (FAST) skills. METHODS: Participants included a group of ultrasound novices (n = 25) and ultrasound experts (n = 10). All participants had their FAST skills assessed using a virtual reality ultrasound simulator. Procedural performance on the 4 FAST windows was assessed by automated simulator metrics, which received a passing or failing score. The validity evidence for these simulator metrics was examined by a stepwise approach according to the Standards for Educational and Psychological Testing. Metrics with validity evidence were included in a simulator test, and the reliability of test scores was determined. Finally, a pass/fail level for procedural performance was established. RESULTS: Of the initial 55 metrics, 34 (61.8%) had validity evidence (P < .01). A simulator test was constructed based on the 34 metrics with established validity evidence, and test scores were calculated as percentages of the maximum score. The median simulator test scores were 14.7% (range, 0%-47.1%) and 94.1% (range, 94.1%-100%) for novices and experts, respectively (P < .001). The pass/fail level was determined to be 79.7%. CONCLUSIONS: The performance of FAST examinations can be assessed in a simulated setting using defensible performance standards, which have both good reliability and validity. PMID- 28646628 TI - Focal Liver Lesions: Real-time 3-Dimensional Contrast-Enhanced Ultrasonography Compared With 2-Dimensional Contrast-Enhanced Ultrasonography and Magnetic Resonance Imaging. AB - OBJECTIVES: This study sought to evaluate the application of real-time 3 dimensional (3D) contrast-enhanced ultrasonography (US) to diagnose focal liver lesions and to compare these results with those from 2-dimensional (2D) contrast enhanced US and contrast-enhanced magnetic resonance imaging (MRI). METHODS: Patients with focal liver lesions were examined by 2D contrast-enhanced US, 3D contrast-enhanced US, and contrast-enhanced MRI for lesion characterization, and biopsies and comprehensive clinical diagnoses served as reference standards. The sensitivity, specificity, area under the receiver operating characteristic curve, and intermodality agreement were assessed. The number of contrast agent injections and lesions observed per injection were calculated for 3D and 2D contrast-enhanced US. The number and display quality of the feeding arteries observed with 3D and 2D contrast-enhanced US were assessed. RESULTS: A total of 117 patients with 151 focal liver lesions were enrolled, including 67 cases of hepatocellular carcinoma, 51 cases of liver metastasis, and 33 cases of benign liver lesions. No significant differences were found among the modalities. The sensitivity values for 3D contrast-enhanced US, 2D contrast-enhanced US, and contrast-enhanced MRI were 96%, 95%, and 93%, respectively; the specificity values were 87%, 84%, and 89%; and the area under the receiver operating characteristic curve values were 0.92, 0.90, and 0.92. The intermodality agreement was excellent (kappa > 0.77). Fewer contrast agent injections were needed, and more lesions and feeding arteries were more clearly displayed on 3D than 2D contrast-enhanced US (P < .001). CONCLUSIONS: Real-time 3D contrast enhanced US is useful for diagnosing focal liver lesions and for observing feeding arteries with fewer contrast agent injections. PMID- 28646629 TI - Mechanisms of inhibitory effects of polycyclic aromatic hydrocarbons in photosynthetic primary processes in pea leaves and thylakoid preparations. AB - Inhibitory effects of polycyclic aromatic hydrocarbons (PAHs) on plants were studied in pea leaves in order to elucidate the mechanisms of action of PAHs such as naphthalene (Naph) and phenanthrene (Phen) on activity of photosystem II (PSII). The changes in different Chl fluorescence parameters were calculated on the basis of Chl fluorescence induction curves. H2 O2 content was measured in leaf homogenates with the luminol-dependent chemiluminescence method. We demonstrated that following PAH treatment, total energy dissipation (DI0 /ABS) and amount of QB -non-reducing complexes of PSII significantly increased. Non photochemical quenching (NPQ) also increased, when weak oxidative stress after PAH application developed. In leaves, a two-step increase in H2 O2 was found with time of incubation in the presence of PAHs, which may be associated with damage to the lipid bilayer of the plasma membrane and then violation of lipid bilayer membranes of cell organelles. A hypothesis for the mode of action of PAHs is provided that involves the role of ROS, membrane permeability and associated functional changes in PSII. PMID- 28646630 TI - Characteristics of systemic inflammation in hepatitis B-precipitated ACLF: Differentiate it from No-ACLF. AB - BACKGROUND & AIMS: Patients with severe exacerbation of chronic hepatitis B (SE CHB) are at risk of developing acute-on-chronic liver failure (ACLF). Systemic inflammation (SI) is a major driver of ACLF. The aim of this study was to identify characteristics of SI in hepatitis B-precipitated-ACLF (HB-ACLF), which may be distinct from No-ACLF patients with SE-CHB. METHODS: Two cohorts of patients with SE-CHB were enrolled in two tertiary hospitals. The associations between circulating leucocyte counts/subsets and ACLF progression and prognoses were analysed in Cohort A. Cytokine measurements, leucocyte phenotyping and whole blood transcriptomic analyses were performed using peripheral blood samples obtained from patients in Cohort B. RESULTS: Circulating leucocyte counts were higher in the HB-ACLF patients than in the No-ACLF patients (P < .001). Peripheral neutrophilic leucocytosis and monocytosis were associated with lymphopenia. The neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) were correlated with risk of death in patients with SE-CHB. NLR independently predicted progression to ACLF in patients without ACLF at enrolment and short-term mortality in ACLF patients. Plasma IL-6, IL-10, G-CSF and GM-CSF levels were higher in ACLF patients (P < .05). Blood transcriptome analyses showed that genes associated with cell migration and mobility and responses to wounding and bacteria were expressed at higher levels while genes involved in lymphocyte-mediated immunity were expressed at lower levels in HB-ACLF patients than in No-ACLF patients. CONCLUSIONS: Systemic inflammation in HB-ACLF was characterized by an excessive innate immune response, which was associated with disease progression and mortality. PMID- 28646631 TI - Synthesis of novel and functionally selective non-competitive muscarinic antagonists as chemical probes. AB - Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site. These compounds were found to be non-competitive antagonists that completely abolished carbachol activation in functional assays. Several of these compounds antagonized functional response to carbachol with great potency at M1 and M4 than at the rest of receptor subtypes. PMID- 28646632 TI - Publication output target for ophthalmology subspecialty fellows in Australia. PMID- 28646633 TI - Reclassification of Flexibacter tractuosus NBRC 15981T as Marivirga harenae sp. nov. in the family Flammeovirgaceae. AB - Flexibacter tractuosa [Lewin, 1969] was reclassified as Marivirga tractuosa. Flexibacter tractuosus NBRC 15981T was reclassified herein by using a polyphasic taxonomic approach. Cells of the strain were strictly aerobic, Gram-stain negative, slender rods, which were motile by gliding. The major respiratory quinone was menaquinone-7 and the predominant (>5 %) cellular fatty acids were iso-C15 : 0, iso-G-C15 : 1, C16 : 1omega7c and iso-C17 : 0 3-OH. The polar lipid pattern indicated the presence of a phosphatidylethanolamine, several unidentified aminolipids, glycolipids and five unidentified polar lipids. The G+C content of the genomic DNA was 35.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain NBRC 15981T clustered with members of the genus Marivirga in the family Flammeovirgaceae of the phylum Bacteroidetes. Levels of DNA-DNA relatedness were less than 16 % between strain NBRC 15981T and the two closely related species, Marivirga sericea NBRC 15983T and Marivirga tractuosa NBRC 15989T. Strain NBRC 15981T could be differentiated from these type strains in the genus Marivirga based on the polar lipid pattern and the activity of alpha chymotrypsin, as well as by alpha-glucosidase and beta-glucosidase activity. On the basis of these results, NBRC 15981T is proposed as representing a novel species of the genus Marivirga, named Marivirga harenae sp. nov. The type strain is JK11T (=NBRC 15981T=NCIMB 1429T). PMID- 28646635 TI - Postprandial Endotoxemia: A Significant Contributor to Chronic Diseases. AB - The increase of chronic diseases in the world's population continues unabated. Cardiovascular disease (CVD), type 2 diabetes (T2D), obesity, arthritis, autoimmunity, and gastrointestinal disorders are all too common and costly, and most have as their source inflammation. T2D is now considered a pandemic, and there is one commonality to many of these: They are, for the most part, preventable. PMID- 28646634 TI - Marinisporobacter balticus gen. nov., sp. nov., Desulfosporosinus nitroreducens sp. nov. and Desulfosporosinus fructosivorans sp. nov., new spore-forming bacteria isolated from subsurface sediments of the Baltic Sea. AB - Four novel Gram-stain-positive, endospore-forming bacteria of the order Clostridiales were isolated from subsurface sediments sampled during International Ocean Discovery Program Expedition 347 to the Baltic Sea. One strain (59.4MT) grew as an obligate heterotroph by aerobic respiration and anaerobically by fermentation. Optimum growth was observed with 0.5 % NaCl at 25 degrees C and pH 7.0-7.3. Analysis of 16S rRNA gene sequences of 59.4MT revealed Alkaliphilus transvaalensis (92.3 % identity), Candidatus Geosporobacter ferrireducens (92.2 %), Geosporobacter subterraneus (91.9 %) and Alkaliphilus peptidifermentans (91.7 %) to be the closest relatives. On the basis of the results of phenotypic and genotypic analyses, we propose that strain 59.4MT represents a novel species within a novel genus, Marinisporobacter balticus gen. nov., sp. nov., with the type strain 59.4MT (=DSM 102940T=JCM 31103T). Three other strains, 59.4F, 59.4BT and 63.6FT, were affiliated with the genus Desulfosporosinus and grew as strictly anaerobic sulfate reducers. These strains additionally used thiosulfate, elemental sulfur, sulfite and DMSO as electron acceptors and hydrogen as an electron donor. Strains 59.4F and 59.4BT had identical 16S rRNA gene sequences, which were most similar to those of Desulfosporosinus lacus (97.8 %), Desulfosporosinus hippei (97.3 %) and Desulfosporosinus orientis (97.3 %). Strain 63.6FT was closely related to D. lacus (97.7 %), Desulfosporosinus meridiei (96.6 %) and D. hippei (96.5 %). The similarity of 16S rRNA gene sequences of strains 59.4BT and 63.6FT was 96.6 %. We propose the new names Desulfosporosinus nitroreducens sp. nov., incorporating strain 59.4F (=DSM 101562=JCM 31104) and the type strain 59.4BT (=DSM 101608T=JCM 31105T), and Desulfosporosinus fructosivorans sp. nov., with the type strain 63.6FT (=DSM 101609T=JCM 31106T). PMID- 28646636 TI - Holly Lucille, ND, RN: The Mind as the Root of a Healing Art. AB - No Abstract Available. PMID- 28646637 TI - TS Gene Polymorphisms Correlate with Susceptibility to Acute Lymphocytic Leukemia in Children. AB - BACKGROUND Acute lymphocytic leukemia (ALL) in children is a clonal disease of bone marrow hematopoietic stem cells. This study aimed to explore the associations between MTHFR or TS genetic polymorphisms and susceptibility to acute lymphocytic leukemia (ALL) in children. MATERIAL AND METHODS This case control study included 79 ALL patients (case group) and 102 non-ALL patients (control group). Post-PCR genomic DNA sequencing revealed MTHFR C677T and MTHFR A1298C genotypes and TS polymorphisms. The chi2 test was used to compare differences in MTHFR and TS polymorphisms (including genotypic and allelic distributions) between groups. Logistic regression analysis was used to determine genetic polymorphisms and ALL risk associations. RESULTS The results indicated that TS 3R allele frequency was significantly higher in the case group than in the control group (chi2=7.45, P<0.05). The MTHFR C677T and MTHFR A1298C polymorphisms were not associated with ALL risk. Compared to the TS 2R/2R genotype, subjects carrying TS 2R/3R were twice as likely to develop ALL, and the TS 3R/3R+3R/4R genotype carried a 4-fold higher risk of developing ALL (OR=1.96, CI: 1.14-3.36). CONCLUSIONS The TS genetic polymorphisms increase the ALL risk. The TS 3R allele was a risk factor for ALL. There were no associations between MTHFR C677T or MTHFR A1298C polymorphisms and ALL susceptibility. PMID- 28646638 TI - Corrigendum to "Oncolytic adenovirus expressing relaxin (YDC002) enhances therapeutic efficacy of gemcitabine against pancreatic cancer" [Cancer Lett. 396 (2017) 155-166]. PMID- 28646639 TI - Corrigendum to "Molecular phylogenetic relationships reveal contrasting evolutionary patterns in Gorgoniidae (Octocorallia) in the Eastern Pacific" [Molec. Phylogenet. Evol. 111 (2017) 219-230]. PMID- 28646640 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 28646641 TI - Do large mergers increase or decrease the productivity of pharmaceutical R&D? AB - There is current uncertainty regarding the effects of mergers on pharmaceutical R&D productivity, with various mechanisms reported by which mergers could either help or harm R&D, and mixed empirical findings in prior analyses. Here, we present an analysis that is novel in several ways: we use downstream measures of R&D productivity, account for both inputs and outputs in our calculations, and use a self-controlled design. We find that recent large pharmaceutical mergers are associated with statistically significant increases in R&D productivity. These results are perhaps not surprising in light of the broader literature on R&D productivity that points to two factors as instrumental in driving higher R&D productivity (depth of scientific information, and objectivity of decision-making based on that information), both of which could be expected to increase because of a merger. PMID- 28646642 TI - Universal Postpartum Mental Health Screening for Parents of Newborns With Prenatally Diagnosed Birth Defects. AB - OBJECTIVE: To describe the implementation of a nurse-led project to screen parents for depression and traumatic stress in the postpartum period after visiting their newborns in the NICU. DESIGN: A standardized universal mental health postpartum screening and referral protocol was developed for parents of high-risk neonates. SETTING/LOCAL PROBLEM: The project occurred at the Garbose Family Special Delivery Unit, the world's first obstetrics unit housed within a pediatric hospital serving healthy women who give birth to newborns with prenatally diagnosed fetal anomalies. Parents of neonates admitted to the NICU are at greater risk to develop postpartum psychological distress; therefore, early identification is critical. PATIENTS: A total of 1,327 participants were screened, including 725 women who gave birth to live newborns at the Garbose Family Special Delivery Unit and 602 fathers. INTERVENTION/MEASUREMENTS: Obstetric nurses asked parents to complete a screening tool that assessed their psychological risk in the postpartum period. A system for mental health triage and referral was available for parents with elevated scores. RESULTS: Overall monthly screening procedure compliance rates were high (96.5% mothers and 79.6% fathers). Women (5.5%, n = 40) and men (5.5%, n = 33) showed high risk for traumatic stress, and 35.9% (n = 260) of women and 9.5% (n = 57) of men showed elevated risk for major depression in the imediate postpartum period. CONCLUSION: Incorporating the screening process into routine nursing practice with immediate mental health triage and referral made the program feasible. The risk factors identified add to the growing knowledge about parents of newborns in the NICU. PMID- 28646643 TI - Pathways to Competence in Sexual and Reproductive Health Care for Advanced Practice Nurses. AB - Sexual and reproductive health (SRH) care is often overlooked in advanced practice nursing educational programs, but advanced practice registered nurses are expected to provide care in this sensitive area. Competencies for SRH care were developed by the World Health Organization, and individual countries including the United States have adapted them to their unique health systems and populations. In this article, we discuss extant and future pathways for advanced practice registered nurses to develop competence in SRH care. PMID- 28646644 TI - A Systematic Review to Uncover a Universal Protocol for Accuracy Assessment of 3 Dimensional Virtually Planned Orthognathic Surgery. AB - PURPOSE: The aim of this study was to systematically review methods used for assessing the accuracy of 3-dimensional virtually planned orthognathic surgery in an attempt to reach an objective assessment protocol that could be universally used. MATERIALS AND METHODS: A systematic review of the currently available literature, published until September 12, 2016, was conducted using PubMed as the primary search engine. We performed secondary searches using the Cochrane Database, clinical trial registries, Google Scholar, and Embase, as well as a bibliography search. Included articles were required to have stated clearly that 3-dimensional virtual planning was used and accuracy assessment performed, along with validation of the planning and/or assessment method. Descriptive statistics and quality assessment of included articles were performed. RESULTS: The initial search yielded 1,461 studies. Only 7 studies were included in our review. An important variability was found regarding methods used for 1) accuracy assessment of virtually planned orthognathic surgery or 2) validation of the tools used. Included studies were of moderate quality; reviewers' agreement regarding quality was calculated to be 0.5 using the Cohen kappa test. CONCLUSIONS: On the basis of the findings of this review, it is evident that the literature lacks consensus regarding accuracy assessment. Hence, a protocol is suggested for accuracy assessment of virtually planned orthognathic surgery with the lowest margin of error. PMID- 28646645 TI - Comorbidity Assessment in Patients With Oral Squamous Cell Carcinoma: Can Imaging Techniques (Fludeoxyglucose Positron-Emission Tomographic Computed Tomography and Contrast-Enhanced Computed tomography) Provide Additional Information? AB - PURPOSE: This study evaluated the role of imaging staging examinations (positron emission tomographic computed tomography [PET/CT] and contrast-enhanced computed tomography [ceCT]) for the assessment of the comorbidity status of patients with oral squamous cell carcinoma (OSCC). A binary null hypothesis was drafted: 1) imaging staging examinations do not augment knowledge about the comorbidity status of patients with OSCC and 2) there is no difference between PET/CT and ceCT in this regard. MATERIALS AND METHODS: A retrospective cohort study design was selected to address the research question. Patients with histologically confirmed OSCC who underwent whole-body staging by PET/CT or ceCT from 2012 through 2015 were considered for inclusion according to predefined criteria. Data collection was performed by the review of patient charts and histology, radiology, and nuclear medicine reports. The Charlson Comorbidity Index (CCI) was chosen to quantify comorbidity and was calculated before and after staging and then compared. The type of imaging staging examination (PET/CT or ceCT) served as the predictor variable and the CCI was determined as the primary outcome variable. Descriptive and inferential statistics were computed for the variable scale. The significance level was set at a P value less than or equal to .05. RESULTS: The sample was composed of 178 patients (71 women, 107 men; average age, 64.2 yr) of whom 109 (61%) underwent PET/CT and 69 (39%) underwent ceCT staging. The pre- and post-staging CCI notably differed. Neither imaging technique showed superior results. CONCLUSION: Relevant and otherwise covert comorbidities can be found by the performance of imaging staging examinations. This enables clinicians to better assess the peri-therapeutic risk and prognosis of patients with OSCC. Therefore, a detailed evaluation of incidental findings on imaging studies is warranted and recommended. PMID- 28646646 TI - Antileukemic activity and cellular effects of the antimalarial agent artesunate in acute myeloid leukemia. AB - The artimisinins are a class of antimalarial compounds whose antiparasitic activity is mediated by induction of reactive oxygen species (ROS). Herein, we report that among the artimisinins, artesunate (ARTS), an orally bioavailable compound has the most potent antileukemic activity in AML models and primary patients' blasts. ARTS was most cytotoxic to the FLT3-ITD+ AML MV4-11 and MOLM-13 cells (IC50 values of 1.1 and 0.82MUM respectively), inhibited colony formation in primary AML and MDS cells and augmented cytotoxicity of chemotherapeutics. ARTS lowered cellular BCL-2 level via ROS induction and increased the cytotoxicity of the BCL-2 inhibitor venetoclax (ABT-199). ARTS treatment led to cellular and mitochondrial ROS accumulation, double stranded DNA damage, loss of mitochondrial membrane potential and induction of the intrinsic mitochondrial apoptotic cascade in AML cell lines. The antileukemic activity of ARTS was further confirmed in MV4-11 and FLT3-ITD+ primary AML cell xenografts as well as MLL-AF9 syngeneic murine AML model where ARTS treatment resulted in significant survival prolongation of treated mice compared to control. Our results demonstrate the potent preclinical antileukemic activity of ARTS as well as its potential for a rapid transition to a clinical trial either alone or in combination with conventional chemotherapy or BCL-2 inhibitor, for treatment of AML. PMID- 28646647 TI - Successful maintenance of key physiological parameters in preterm lambs treated with ex vivo uterine environment therapy for a period of 1 week. AB - BACKGROUND: Extremely preterm infants born at the border of viability (22-24 weeks' gestation) have high rates of death and lasting disability. Ex vivo uterine environment therapy is an experimental neonatal intensive care strategy that provides gas exchange using parallel membranous oxygenators connected to the umbilical vessels, sparing the extremely preterm cardiopulmonary system from ventilation-derived injury. OBJECTIVE: In this study, we aimed to refine our ex vivo uterine environment therapy platform to eliminate fetal infection and inflammation, while simultaneously extending the duration of hemodynamically stable ex vivo uterine environment therapy to 1 week. STUDY DESIGN: Merino-cross ewes with timed, singleton pregnancies were surgically delivered at 112-115 days of gestation (term is ~150 days) and adapted to ex vivo uterine environment therapy (treatment group; n = 6). Physiological variables were continuously monitored; humerus and femur length, ductus arteriosus directional flow, and patency were estimated with ultrasound; serial blood samples were collected for hematology and microbiology studies; weight was recorded at the end of the experiment. Control group animals (n = 7) were euthanized at 122 days of gestation and analyzed accordingly. Bacteremia was defined by positive blood culture. Infection and fetal inflammation was assessed with white blood cell counts (including differential leukocyte counts), plasma and lung proinflammatory cytokine measurements, and lung histopathology. RESULTS: Five of 6 fetuses in the treatment group completed the 1-week study period with key physiological parameters, blood counts remaining within normal ranges, and no bacteremia detected. There were no significant differences (P > .05) in arterial blood oxygen content or lactate levels between ex vivo uterine environment therapy and control groups at delivery. There was no significant difference (P > .05) in birthweight between control and ex vivo uterine environment groups. In the ex vivo uterine environment group, we observed growth of fetal humerus (P < .05) and femur (P < .001) over the course of the 7-day experimental period. There was no difference in airway or airspace morphology or consolidation between control and ex vivo uterine environment animals, and there was no increase in the number of lung cells staining positive for T-cell marker CD3+. CONCLUSION: Five preterm lambs were maintained in a physiologically stable condition for 1 week with significant growth and without clinically significant bacteremia or systemic inflammation. Although substantial further refinement is required, a life support platform based around ex vivo uterine environment therapy may provide an avenue to improve outcomes for extremely preterm infants. PMID- 28646648 TI - Natural history of a viral cohesive end site: cosN of the lambda-like phages. AB - The base pairs of cosN, the site where the 12 base-long cohesive ends are generated in lambda-like phages, show partial-two fold rotational symmetry. In a bioinformatic survey, we found that the cosN changes in 12 natural cosN variants are restricted to bp 6-to-12 of the cohesive end sequence. In contrast, bp 1-5 of the cohesive end sequence are strictly conserved (13/13), as are the two bp flanking the left nicking site (bp -2 and -1). The bp flanking the right nick site (bp 13 and 14) are conserved in 12 of 13 variants. Five cosN variants differing by as many as five bp were used to replace lambda's cosN. No significant effects of the cosN changes on lambda's virus yield were found. In sum, bp -2 to 5 are critical cosN function, and bp 6-12 of the cohesive end sequence are not critical for terminase recognition or virus fitness. PMID- 28646649 TI - Two single mutations in the fusion protein of Newcastle disease virus confer hemagglutinin-neuraminidase independent fusion promotion and attenuate the pathogenicity in chickens. AB - The fusion (F) protein of Newcastle disease virus (NDV) affects viral infection and pathogenicity through mediating membrane fusion. Previously, we found NDV with increased fusogenic activity in which contained T458D or G459D mutation in the F protein. Here, we investigated the effects of these two mutations on viral infection, fusogenicity and pathogenicity. Syncytium formation assays indicated that T458D or G459D increased the F protein cleavage activity and enhanced cell fusion with or without the presence of HN protein. The T458D- or G459D-mutated NDV resulted in a decrease in virus replication or release from cells. The animal study showed that the pathogenicity of the mutated NDVs was attenuated in chickens. These results indicate that these two single mutations in F altered or diminished the requirement of HN for promoting membrane fusion. The increased fusogenic activity may disrupt the cellular machinery and consequently decrease the virus replication and pathogenicity in chickens. PMID- 28646650 TI - Requirement for eukaryotic translation initiation factors in cap-independent translation differs between bipartite genomic RNAs of red clover necrotic mosaic virus. AB - The bipartite genomic RNAs of red clover necrotic mosaic virus (RCNMV) lack a 5' cap and a 3' poly(A) tail. RNA1 encodes viral replication proteins, and RNA2 encodes a movement protein (MP). These proteins are translated in a cap independent manner. We previously identified two cis-acting RNA elements that cooperatively recruit eukaryotic translation initiation factor (eIF) complex eIF4F or eIFiso4F to RNA1. Such cis-acting RNA elements and host factors have not been identified in RNA2. Here we found that translation of RNA1 was significantly compromised in Arabidopsis thaliana carrying eif4f mutation. RNA1 replicated efficiently in eifiso4f1 mutants, suggesting vigorous translation of the replication proteins from RNA1 in the plants. In contrast, MP accumulation was decreased in eifiso4f1 mutants but not in eif4f mutants. Collectively, these results suggest that RCNMV uses different eIF complexes for translation of its bipartite genomic RNAs, which may contribute to fine-tuning viral gene expression during infection. PMID- 28646651 TI - Use of Sequence-Independent, Single-Primer-Amplification (SISPA) for rapid detection, identification, and characterization of avian RNA viruses. AB - Current technologies with next generation sequencing have revolutionized metagenomics analysis of clinical samples. To achieve the non-selective amplification and recovery of low abundance genetic sequences, a simplified Sequence-Independent, Single-Primer Amplification (SISPA) technique in combination with MiSeq platform was applied to target negative- and positive sense single-stranded RNA viral sequences. This method allowed successful sequence assembly of full or near full length avian influenza virus (AIV), infectious bronchitis virus (IBV), and Newcastle disease virus (NDV) viral genome. Moreover, SISPA analysis applied to unknown clinical cases of mixed viral infections produced genome assemblies comprising 98% NDV and 99% of IBV genomes. Complete or near complete virus genome sequence was obtained with titers at or above 104.5 EID50/ml (50% embryo infectious dose), and virus identification could be detected with titers at or above 103 EID50/ml. Taken together, these studies demonstrate a simple template enrichment protocol for rapid detection and accurate characterization of avian RNA viruses. PMID- 28646652 TI - Influenza A virus cap-snatches host RNAs based on their abundance early after infection. AB - The influenza A virus RNA polymerase cleaves the 5' ends of host RNAs and uses these RNA fragments as primers for viral mRNA synthesis. We performed deep sequencing of the 5' host-derived ends of the eight viral mRNAs of influenza A/Puerto Rico/8/1934 (H1N1) virus in infected A549 cells, and compared the population to those of A/Hong Kong/1/1968 (H3N2) and A/WSN/1933 (H1N1). In the three strains, the viral RNAs target different populations of host RNAs. Host RNAs are cap-snatched based on their abundance, and we found that RNAs encoding proteins involved in metabolism are overrepresented in the cap-snatched populations. Because this overrepresentation could be a reflection of the host response early after infection, and thus of the increased availability of these transcripts, our results suggest that host RNAs are cap-snatched mainly based on their abundance without preferential targeting. PMID- 28646654 TI - Inducing asymmetrical switch costs in bilingual language comprehension by language practice. AB - The most widely discussed observation in the language control literature is the larger cost found when switching into the first than the second language (i.e., asymmetrical switch costs), which has been determined as a marker of persisting, reactive inhibition. While this is a common effect in bilingual language production, it generally does not occur in bilingual language comprehension. In this bilingual language comprehension study, we manipulated the relative activation of languages by letting participants practice in pure language blocks prior to a mixed language block. While no effect was found of practicing second language words, asymmetrical switch costs were observed when practicing the same (Experiments 1 and 2) or different first-language words (Experiment 3) as in the following mixed language block. These findings indicate that, similar to bilingual production, bilingual comprehension relies on persisting, reactive language control. PMID- 28646653 TI - Cryo-EM: beyond the microscope. AB - The pace at which cryo-EM is being adopted as a mainstream tool in structural biology has continued unabated over the past year. Initial successes in obtaining near-atomic resolution structures with cryo-EM were enabled to a large extent by advances in microscope and detector technology. Here, we review some of the complementary technical improvements that are helping sustain the cryo-EM revolution. We highlight advances in image processing that permit high resolution structure determination even in the presence of structural and conformational heterogeneity. We also review selected examples where biochemical strategies for membrane protein stabilization facilitate cryo-EM structure determination, and discuss emerging approaches for further improving the preparation of reliable plunge-frozen specimens. PMID- 28646655 TI - Syntheses, toxicities and anti-inflammation of H2S-donors based on non-steroidal anti-inflammatory drugs. AB - Three series of H2S donors based on NSAIDs were synthesized and characterized by 1H-NMR, IR and ESI-HRMS. The H2S-release abilities of all compounds were evaluated in the presence of TECP or cysteine. The results show all compounds were fast H2S-releasers, and their half-lives were in range of 0-20 min. Under the same condition, H2S released from compound 9 was more than any other compounds. In cytotoxicity aspect, all compounds but 1 and 2 displayed much lower toxicities to both LO2 and HepG2 cell lines, and the IC50 values of most compounds were over 800 MUM. Compounds 1 and 2 had a stronger anti-proliferative activity to both cell lines, but they displayed lower toxicities to LO2 than to HepG2. Based on the cytotoxicity, the developmental toxicities of the compounds were assessed using zebrafish embryos. The results show all tested compounds 2, 9 and 15 had effects on the mortality, hatching rate and spontaneous movements of zebrafish embryos, and caused embryos teratogenesis; and the compounds had dose dependent toxicities to both embryonic and larval zebrafish. In addition, all compounds had a better anti-inflammatory activity. In the test of anti inflammatory activities, the tested compounds all reduced the levels of intracellular nitrite and pro-inflammatory cytokines (TNF-alpha, COX-2), increased the levels of anti-inflammatory cytokines (IL-10, HO-1). All these suggest these H2S donors based on NSAIDs have a potential to be a candidate medicine. PMID- 28646656 TI - Azide-alkyne cycloaddition towards 1H-1,2,3-triazole-tethered gatifloxacin and isatin conjugates: Design, synthesis and in vitro anti-mycobacterial evaluation. AB - Twelve novel 1H-1,2,3-triazole-tethered gatifloxacin (GTFX) isatin conjugates 5a l with greater lipophilicity compared with GTFX were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H37Rv and MDR-TB as well as cytotoxicity. The preliminary results showed that all the targets (MIC: 0.10-8 MUg/mL) exhibited excellent inhibitory activity against MTB H37Rv and MDR-TB, but eight of them (CC50: 7.8 62.5 MUg/mL) were much more toxic than the parent GTFX (CC50: 125 MUg/mL). Among them, 5g (MIC: 0.10 MUg/mL) was 4-8 times more potent in vitro than the references GTFX (MIC: 0.78 MUg/mL) and RIF (MIC: 0.39 MUg/mL) against MTB H37Rv, but less active than INH (MIC: 0.05 MUg/mL). The most potent 5g and 5h (MIC: 0.25 MUg/mL) were 4->512 times more active than the three references (MIC: 1.0->128 MUg/mL) against MDR-TB. Unfortunately, both of the two hybrids (CC50: 7.8 MUg/mL) were much more cytotoxic than the other derivatives, need to be further optimized. PMID- 28646657 TI - "Half-sandwich" Schiff-base Ir(III) complexes as anticancer agents. AB - A series of "half-sandwich" Schiff-base Ir(III) complexes were synthesized and investigated for their in vitro activities against the leukemia K562 cell line. These compounds demonstrated antiproliferative activities against K562 cells with IC50 values of 0.26-4.77 MUM. In particular, compound 10c showed cytotoxicity against five cancer cell lines/sublines and stronger activities than cisplatin in K562, K562/A02, MCF-7, MCF-7/ADM, and A549 cells. Mechanism studies illustrated that compound 10c increased the level of reactive oxygen species and induced apoptosis of K562 cells. This compound effectively decreased the mitochondrial membrane potential and the protein level of Bcl-2. It also increased the protein levels of Bax, caspase-3, and caspase-9, and led to release of cytochrome c in K562 cells, indicating that the apoptosis induced by compound 10c was mediated by the intrinsic mitochondria apoptosis pathway. PMID- 28646658 TI - Investigation and structural elucidation of a new impurity in bulk drug of cilostazol by LC/MS/MS, FT-IR and NMR. AB - A new impurity was detected in bulk cilostazol (CIL) crude during routine analysis. The impurity (~4%, the specification for unknown impurity in crude is not more than 0.20%) has a relative retention time of 1.46. Based on MS, NMR and IR spectral data, the impurity was identified as 6,6'-bis(4-(1-cyclohexyl-1H tetrazol-5-yl) butoxy)-3,3',4,4'-tetrahydro-[7,7'-biquinoline]-2,2'(1H,1'H) dione(CIL-dimer). The precursor of CIL-dimer is an oxidative product of starting material 6-Hydroxy-3,4-dyhydro-1H-quinolin-2-one(6-HQ), CIL-dimer was formed in the following reaction with 5-(3-Chloro-propyl)-1-cyclohexyl-1H-tetrazol(CHCBT). PMID- 28646659 TI - Analysis of recombinant monoclonal antibodies in hydrophilic interaction chromatography: A generic method development approach. AB - Hydrophilic interaction liquid chromatography (HILIC) is a well-established technique for the separation and analysis of small polar compounds. A recently introduced widepore stationary phase expanded HILIC applications to larger molecules, such as therapeutic proteins. In this paper, we present some generic HILIC conditions adapted for a wide range of FDA and EMA approved recombinant monoclonal antibody (mAb) species and for an antibody-drug conjugate (ADC). Seven approved mAbs possessing various isoelectric point (pI) and hydrophobicity as well as a cysteine conjugated ADC were used in this study. Samples were digested by IdeS enzyme and digests were further fragmented by chemical reduction. The resulting fragments were separated by HILIC. The main benefit of HILIC was the separation of polar variants (glycovariants) in a reasonable analysis time at the protein level, which is not feasible with other chromatographic modes. Three samples were selected and chromatographic conditions were further optimized to maximize resolution. A commercial software was used to build up retention models. Experimental and predicted chromatograms showed good agreement and the average error of retention time prediction was less than 2%. Recovery of various species and sample stability under the applied conditions were also discussed. PMID- 28646660 TI - Towards understanding transcriptional networks in cellular reprogramming. AB - Most of the knowledge we have on the molecular mechanisms of transcription factor mediated reprogramming comes from studies conducted in induced pluripotency. Recently however, a few studies investigated the mechanisms of cellular reprogramming in direct and indirect transdifferentiation, which allows us to explore whether shared parallel mechanisms can be drawn. Moreover, there are currently several computational tools that have been developed to predict and enhance the reprogramming process by reconstructing the transcriptional networks of reprogramming cells. These new tools have the potential to greatly benefit the field of reprogramming, providing us with new approaches that can transform our understanding of the initiation, progression and successful completion of cellular fate transition. PMID- 28646661 TI - Congruent bodily arousal promotes the constructive recognition of emotional words. AB - Considerable research has shown that bodily states shape affect and cognition. Here, we examined whether transient states of bodily arousal influence the categorization speed of high arousal, low arousal, and neutral words. Participants realized two blocks of a constructive recognition task, once after a cycling session (increased arousal), and once after a relaxation session (reduced arousal). Results revealed overall faster response times for high arousal compared to low arousal words, and for positive compared to negative words. Importantly, low arousal words were categorized significantly faster after the relaxation than after the cycling, suggesting that a decrease in bodily arousal promotes the recognition of stimuli matching one's current arousal state. These findings highlight the importance of the arousal dimension in emotional processing, and suggest the presence of arousal-congruency effects. PMID- 28646662 TI - Estimation of the molar absorption coefficient of copper salicylate within the spectral range 300-350nm. AB - Additional absorption was detected in absorption spectra within the range 300 350nm after addition of copper sulfate CuSO4(aq) to a solution of sodium salicylate NaNSal (rN=7.8). The additional maximum absorption was observed at 320nm. Assuming that the additional absorption depends on the formation of copper salicylate CuSal, the molar absorption coefficient epsilonCuSal of this complex was determined to be (3.8+/-0.02).103M-1sm-1. This value is almost equal to that of monoanion HSal-, epsilonHSal-=(3.6+/-0.04).103M-1sm-1, and is 2.5 times as much as epsilonFe3+HSal-=(1.55+/-0.05).103M-1sm-1 for iron salicylate. The difference in epsilonCuSal and epsilonFe3+HSal- is due to the difference in the initial electron states of Cu2+ and Fe3+ ions that have the d9 and d5 configurations, respectively. PMID- 28646663 TI - Experimental determination of the absolute infrared absorption intensities of formyl radical HCO. AB - Formyl radical HCO is an important reactive intermediate in combustion, atmospheric and extraterrestrial chemistry. Like in the case of other transients, the lack of knowledge of the absolute IR intensities limits the quantitative spectroscopic studies on this species. We report the first experimental determination of the absorption intensities for the fundamental vibrational bands of HCO. The measurements have been performed using matrix-isolation FTIR spectroscopy. Determination of the values was based on the repeated photodissociation and thermal recovery of the HCO radical using the known value of the absorption coefficient of CO. The experimentally determined values (93.2+/ 6.0, 67.2+/-4.5, and 109.2+/-6.6kmmol-1 for the nu1, nu2, and nu3 modes, respectively) have been compared to the calculated IR intensities obtained by DFT and UCCSD(T) computations. PMID- 28646664 TI - Wogonin attenuates inflammation by activating PPAR-gamma in alcoholic liver disease. AB - Alcoholic liver disease (ALD) is one of the predominant causes of liver-related morbidity and mortality worldwide. However, effective therapy for ALD is still lacking. Wogonin, a major flavonoid compound, is found in Scutellaria baicalensis Georgi. Accumulating studies have revealed that wogonin possesses anti inflammatory and anti-tumour activities in various models. However, the hepatoprotective activity of wogonin in ALD is still obscure. In this study, we found that wogonin significantly attenuated inflammatory response in EtOH-fed mice, and reduced the expression of inflammatory cytokines such as TNF-alpha and IL-6 in EtOH-induced RAW264.7 cells. Furthermore, our findings showed that wogonin remarkably induced the expression of PPAR-gamma in vivo and in vitro. Compared with the wogonin-treated group, blockade of PPAR-gamma with inhibitor (T0070907) or PPAR-gamma small interfering (si)-RNA were applied in RAW264.7 cells to evaluate the involvement of wogonin in alleviating EtOH-induced inflammation. Moreover, forced expression of PPAR-gamma further suppressed the expression of TNF-alpha and IL-6 when treated with wogonin on EtOH-induced RAW264.7 cells. In addition, it was demonstrated that wogonin remarkably suppressed PPAR-gamma-meditated phosphorylation and activation of NF-kappaB-P65. In conclusion, our results indicated that wogonin may serve as an effective modulator of PPAR-gamma by down-regulating NF-kappaB pathway, thereby attenuated inflammatory response in ALD. PMID- 28646665 TI - The N400 in processing repeated name and pronoun anaphors in sentences and discourse. AB - We report two EEG/ERP experiments that examined processing of repeated name (e.g., Bill; Experiment 1) and pronoun (e.g., he; Experiment 2) subject anaphors to single antecedents (e.g., Bill) and to antecedents embedded in a conjunction (e.g., Bill and Mary) within sentences and discourses. Experiment 1 replicated previous reports of repeated references to single antecedents eliciting greater N400 negativity than repeated references to conjoined antecedents within sentences, and extended these results to cross-sentence (discourse) references. Experiment 2 found that pronouns also elicited greater N400 negativity following single than conjoined antecedents. In both experiments, references to conjoined antecedents elicited greater frontal negativity than references to single antecedents in both sentences and discourse. Our results indicate that, in processing subject anaphors, the N400 is an index of reference predictability rather than a marker of the fit between antecedent salience and reference form, and that frontal negativity marks referential ambiguity elicited by conjoined phrases. PMID- 28646666 TI - Detection of Mycobacterium avium subspecies paratuberculosis in powdered infant formula using IS900 quantitative PCR and liquid culture media. AB - Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated in Crohn's disease in humans resulting in public concern over the presence of MAP in powdered infant formula, which could contribute towards early human exposure to MAP or MAP components. Testing of representative powdered infant formula samples using effective tests is required to provide information on contamination of infant formula with MAP, so that consumers can make informed decisions. This study aimed to test representative powdered infant formula samples for the presence of MAP using a quantitative PCR and liquid culture method. For this purpose, an efficient DNA extraction method was developed and an optimum decontamination protocol for culture method was identified. A total of 122 powdered infant formula samples were tested, comprising 72 brands produced by 12 manufacturers from 9 countries. Powdered infant formula samples were reconstituted and centrifuged to separate the casein pellet, cream layer and whey fraction. A sensitive qPCR test was performed on DNA extracted from the casein pellet. In addition, the cream layer and casein pellet were cultured in liquid media, following decontamination with the optimum protocol. Of the 122 samples tested, 6 were positive for MAP DNA but none were positive for growth in culture at 12 and 20 weeks. The limit of detection of the quantitative PCR was less than 5 MAP organisms per 1.5g milk powder. The methods developed in the study could be used for quality assurance testing for infant formula and calf milk replacers. The low contamination level of MAP and absence of viable forms in our study suggests a relatively low risk of exposure of infants to MAP components. PMID- 28646667 TI - Prevalence and characterization of extended-spectrum beta-lactamase (ESBL) and AmpC beta-lactamase producing Enterobacteriaceae in fresh pork meat at processing level in Germany. AB - ESBL or AmpC beta-lactamase producing Enterobacteriaceae is an increasing concern in human medicine. A distribution via the food chain is discussed, but less is known about these bacteria on fresh pork meat. The aim of this study was to investigate the prevalence of ESBL/AmpC Enterobacteriaceae bacteria in fresh pork meat at processing level in Germany. The analysis comprised microbiological hygiene parameters and further pheno- and genotypical characterization of ESBL/AmpC isolates. The examination included three pools of meat and one corresponding meat juice sample from each of the tested pork meat batches (n=63). ESBL/AmpC producers were found in 42.9% (36.5% confirmed by genotype, gt) of the investigated batches, either in meat or meat juice. Meat juice was more often (28.6%) contaminated with ESBL/AmpC bacteria than meat (20.6%). Hygiene parameters were satisfactory in all samples and were thus not a suitable tool for predicting the presence of ESBL/AmpC producers. Most of the 37 confirmed ESBL/AmpC bacteria were identified as Escherichia coli (n=18) or Serratia fonticola (n=13). Susceptibility testing identified 32 of the 37 isolates to be multidrug-resistant. The most common resistance genes TEM, SHV, and CTX-M were found in 19 of the ESBL/AmpC isolates, mostly E. coli. A single detected AmpC beta-lactamase producing E. coli carried a CMY-2 gene. Multilocus sequence typing (MLST) investigations of the ESBL/AmpC E. coli revealed 11 different sequence types. In conclusion, fresh pork meat can harbor highly diverse multidrug resistant ESBL Enterobacteriaceae, even though at low rates. The study suggests that fresh pork meat might be a source for multidrug-resistant ESBL/AmpC Enterobacteriaceae of various origins. Therefore these data contribute to the epidemiological understanding of the distribution of resistant bacteria and the impact of the food chain on public health. PMID- 28646668 TI - beta-galactosidase from Aspergillus lacticoffeatus: A promising biocatalyst for the synthesis of novel prebiotics. AB - beta-galactosidase (EC 3.2.1.23) are interesting enzymes able to catalyze lactose hydrolysis and transfer reactions to produce lactose-based prebiotics with potential application in the pharmaceutical and food industry. In this work, Aspergillus lacticoffeatus is described, for the first time, as an effective beta galactosidase producer. The extracellular enzyme production was evaluated in synthetic and alternative media containing cheese whey and corn steep liquor. Although beta-galactosidase production occurred in all media (expect for the one composed solely by cheese whey), the highest enzymatic activity values (460U/mL) were obtained for the synthetic medium. Ochratoxin A production in synthetic medium was also evaluated and 9days of fermentation was identified as a suitable fermentation time to obtain a crude extract enzyme with mycotoxin concentration below the legal comparable value established for wine and grape juices (2ng/mL). The optimal pH and temperature for the crude extract enzyme was found in the range of 3.5-4.5 and 50-60 degrees C, respectively. The beta-galactosidase activity was reduced in the presence of Ba2+, Fe2+, Li+, K+ and galactose, while additives (except for ascorbic acid) and detergents exhibited a positive effect on enzymatic activity. This enzyme was able to catalyze the synthesis of prebiotics, namely lactulose (2.5g/L) and a galacto-oligosaccharide (trisaccharide, 6.3g/L), either when whole cells or crude enzyme was used as biocatalyst. The lactulose production using fungal whole cells is herein reported for the first time. Additionally, A. lacticoffeatus was also found to produce an enzyme with fructosyltransferase activity and other prebiotics, namely fructo oligosaccharide 1-kestose (2.4g/L). PMID- 28646669 TI - Validation of a commercial kit aimed to the detection of pathogenic anisakid nematodes in fish products. AB - Anisakids are parasitic nematodes responsible for a zoonosis that occurs following the ingestion of fish and fish products infected with larvae belonging to the genera Anisakis and Pseudoterranova. Rarely Contracaecum is found in association with gastric/intestinal illness, while Hysterothylacium is commonly considered not pathogenic. Although Real Time PCR assays have been recently used with the aim to detect and quantify these parasites in food products, methods applied did not undergo through extensive validation process, a feature highly desirable or mandatory in the case of testing laboratories accredited for the ISO EN 17025:2005. Here, a comprehensive study has been performed to validate a commercial kit based on multiplex real time PCR for the qualitative detection of Anisakis and Pseudoterranova. Inclusivity/exclusivity trials were carried out on DNA from species of the genera Anisakis, Pseudoterranova, Contracaecum, Hysterothylacium and Ascaris, on fish intentionally contaminated with Anisakis spp. and Pseudoterranova spp. and on marine organisms as fish, crustacean and squid to test the commercial kit on a large sample. The assay gave positive amplification for several Anisakis and Pseudoterranova species, while providing no signal for the members of the remaining genera. Each sample was correctly assigned either to Anisakis or Pseudoterranova, thus indicating that no cross reaction occurred. The LOD was determined using two independent standard curves. Robustness was assayed by using two different thermocyclers in three distinct laboratories with different operators. The establishment of a validation dossier will permit the use of the commercial kit for the detection of Anisakis and Pseudoterranova DNA in fish and fish products intended for human consumption by public or private laboratories, following the requirements regarding the quality assurance processes described in the ISO EN 17025:2005. PMID- 28646670 TI - A metagenomic assessment of viral contamination on fresh parsley plants irrigated with fecally tainted river water. AB - Microbial food-borne diseases are still frequently reported despite the implementation of microbial quality legislation to improve food safety. Among all the microbial agents, viruses are the most important causative agents of food borne outbreaks. The development and application of a new generation of sequencing techniques to test for viral contaminants in fresh produce is an unexplored field that allows for the study of the viral populations that might be transmitted by the fecal-oral route through the consumption of contaminated food. To advance this promising field, parsley was planted and grown under controlled conditions and irrigated using contaminated river water. Viruses polluting the irrigation water and the parsley leaves were studied by using metagenomics. To address possible contamination due to sample manipulation, library preparation, and other sources, parsley plants irrigated with nutritive solution were used as a negative control. In parallel, viruses present in the river water used for plant irrigation were analyzed using the same methodology. It was possible to assign viral taxons from 2.4 to 74.88% of the total reads sequenced depending on the sample. Most of the viral reads detected in the river water were related to the plant viral families Tymoviridae (66.13%) and Virgaviridae (14.45%) and the phage viral families Myoviridae (5.70%), Siphoviridae (5.06%), and Microviridae (2.89%). Less than 1% of the viral reads were related to viral families that infect humans, including members of the Adenoviridae, Reoviridae, Picornaviridae and Astroviridae families. On the surface of the parsley plants, most of the viral reads that were detected were assigned to the Dicistroviridae family (41.52%). Sequences related to important viral pathogens, such as the hepatitis E virus, several picornaviruses from species A and B as well as human sapoviruses and GIV noroviruses were detected. The high diversity of viral sequences found in the parsley plants suggests that irrigation on fecally-tainted food may have a role in the transmission of a wide diversity of viral families. This finding reinforces the idea that the best way to avoid food-borne viral diseases is to introduce good field irrigation and production practices. New strains have been identified that are related to the Picornaviridae and distantly related to the Hepeviridae family. However, the detection of a viral genome alone does not necessarily indicate there is a risk of infection or disease development. Thus, further investigation is crucial for correlating the detection of viral metagenomes in samples with the risk of infection. There is also an urgent need to develop new methods to improve the sensitivity of current Next Generation Sequencing (NGS) techniques in the food safety area. PMID- 28646671 TI - Frontotemporal lobar degeneration and social behaviour: Dissociation between the knowledge of its consequences and its conceptual meaning. AB - Inappropriate social behaviour is an early symptom of frontotemporal lobar degeneration (FTLD) in both behavioural variant frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Knowledge of social behaviour is essential for appropriate social conduct. The superior anterior temporal lobe (ATL) has been identified as one key neural component for the conceptual knowledge of social behaviour, but it is unknown whether this is dissociable from knowledge of the consequences of social behaviour. Here, we used a newly-developed test of knowledge about long-term and short-term consequences of social behaviour to investigate its impairment in patients with FTLD relative to a previously developed test of social conceptual knowledge. We included 19 healthy elderly control participants and 19 consecutive patients with features of bvFTD or SD and defined dissociations as performance differences between tasks for each patient (Bonferroni-corrected p < .05). Knowledge of long-term consequences was selectively impaired relative to short-term consequences in five patients and the reverse dissociation occurred in one patient. Six patients showed a selective impairment of social concepts relative to long-term consequences with the reverse dissociation occurring in one patient. These results corroborate the hypothesis that knowledge of long-term consequences of social behaviour is dissociable from knowledge of short-term consequences, as well as of social conceptual knowledge. Confirming our hypothesis, we found that patients with more marked grey matter (GM) volume loss in frontopolar relative to right superior ATL regions of interest exhibited poorer knowledge of the long-term consequences of social behaviour relative to the knowledge of its conceptual meaning and vice versa (n = 15). These findings support the hypothesis that frontopolar and ATL regions represent distinct aspects of social knowledge. This suggests that rather than being unable to suppress urges to behave inappropriately, FTLD patients often lose the knowledge of what appropriate social behaviour is and can therefore not be expected to behave accordingly. PMID- 28646673 TI - Quantification of evaporation induced error in atom probe tomography using molecular dynamics simulation. AB - Non-equilibrium molecular dynamics was used to simulate the dynamics of atoms at the atom probe surface and five objective functions were used to quantify errors. The results suggested that before ionization, thermal vibration and collision caused the atoms to displace up to 1A and 25A respectively. The average atom displacements were found to vary between 0.2 and 0.5A. About 9 to 17% of the atoms were affected by collision. Due to the effects of collision and ion-ion repulsion, the back-calculated positions were on average 0.3-0.5A different from the pre-ionized positions of the atoms when the number of ions generated per pulse was minimal. This difference could increase up to 8-10A when 1.5ion/nm2 were evaporated per pulse. On the basis of the results, surface ion density was considered an important factor that needed to be controlled to minimize error in the evaporation process. PMID- 28646672 TI - Transcranial magnetic stimulation to visual cortex induces suboptimal introspection. AB - Blindsight patients with damage to the visual cortex can discriminate objects but report no conscious visual experience. This provides an intriguing opportunity to allow the study of subjective awareness in isolation from objective performance capacity. However, blindsight is rare, so one promising way to induce the effect in neurologically intact observers is to apply transcranial magnetic stimulation (TMS) to the visual cortex. Here, we used a recently-developed criterion-free method to conclusively rule out an important alternative interpretation of TMS induced performance without awareness: that TMS-induced blindsight may be just due to conservative reporting biases for conscious perception. Critically, using this criterion-free paradigm we have previously shown that introspective judgments were optimal even under visual masking. However, here under TMS, observers were suboptimal, as if they were metacognitively blind to the visual disturbances caused by TMS. We argue that metacognitive judgments depend on observers' internal statistical models of their own perceptual systems, and introspective suboptimality arises when external perturbations abruptly make those models invalid - a phenomenon that may also be happening in actual blindsight. PMID- 28646674 TI - A multimodal spatiotemporal cardiac motion atlas from MR and ultrasound data. AB - Cardiac motion atlases provide a space of reference in which the motions of a cohort of subjects can be directly compared. Motion atlases can be used to learn descriptors that are linked to different pathologies and which can subsequently be used for diagnosis. To date, all such atlases have been formed and applied using data from the same modality. In this work we propose a framework to build a multimodal cardiac motion atlas from 3D magnetic resonance (MR) and 3D ultrasound (US) data. Such an atlas will benefit from the complementary motion features derived from the two modalities, and furthermore, it could be applied in clinics to detect cardiovascular disease using US data alone. The processing pipeline for the formation of the multimodal motion atlas initially involves spatial and temporal normalisation of subjects' cardiac geometry and motion. This step was accomplished following a similar pipeline to that proposed for single modality atlas formation. The main novelty of this paper lies in the use of a multi-view algorithm to simultaneously reduce the dimensionality of both the MR and US derived motion data in order to find a common space between both modalities to model their variability. Three different dimensionality reduction algorithms were investigated: principal component analysis, canonical correlation analysis and partial least squares regression (PLS). A leave-one-out cross validation on a multimodal data set of 50 volunteers was employed to quantify the accuracy of the three algorithms. Results show that PLS resulted in the lowest errors, with a reconstruction error of less than 2.3 mm for MR-derived motion data, and less than 2.5 mm for US-derived motion data. In addition, 1000 subjects from the UK Biobank database were used to build a large scale monomodal data set for a systematic validation of the proposed algorithms. Our results demonstrate the feasibility of using US data alone to analyse cardiac function based on a multimodal motion atlas. PMID- 28646676 TI - Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. AB - Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naive patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful. PMID- 28646675 TI - Conformational regulation of CRISPR-associated nucleases. AB - Adaptive immune systems in bacteria and archaea rely on small CRISPR-derived RNAs (crRNAs) to guide specialized nucleases to foreign nucleic acids. The activation of these nucleases is controlled by a series of molecular checkpoints that ensure precise cleavage of nucleic acid targets, while minimizing toxic off-target cleavage events. In this review, we highlight recent advances in understanding regulatory mechanisms responsible for controlling the activation of these nucleases and identify emerging regulatory themes conserved across diverse CRISPR systems. PMID- 28646677 TI - "Should I or shouldn't I?" Imitation of undesired versus allowed actions from peer and adult models by 18- and 24-month-old toddlers. AB - Imitation is a common way of acquiring novel behaviors in toddlers. However, little is known about toddlers' imitation of undesired actions. Here we investigated 18- and 24-month-olds' (N=110) imitation of undesired and allowed actions from televised peer and adult models. Permissiveness of the demonstrated actions was indicated by the experimenter's response to their execution (angry or neutral). Analyses revealed that toddlers' imitation scores were higher after demonstrations of allowed versus undesired actions, regardless of the age of the model. In agreement with prior research, these results suggest that third-party reactions to a model's actions can be a powerful cue for toddlers to engage in or refrain from imitation. In the context of the present study, third-party reactions were more influential on imitation than the model's age. Considering the relative influence of different social cues for imitation can help to gain a fuller understanding of early observational learning. PMID- 28646678 TI - Bioengineering for intestinal organoid cultures. AB - Recent advances allow access to human cell-based intestinal organoids that recreate human physiology to levels not possible with conventional 2D cell cultures. Despite their huge potential, there are many challenges that remain. This review will cover recent bioengineering approaches to improve organoid maturation, scale up, reproducibility and analysis. The first section covers the advances in engineering the culture environment, followed by the section on tools for micro-manipulation and analysis of organoids. The last section reviews the computational models developed to guide the use of engineered materials and tools, and to interpret observed results as well. The ability to use organoids for discovery research, and the need to both exert exquisite experimental control and obtain quantitative measurements from organoid models means that the field is ripe for collaborative efforts between biologists, engineers, clinicians and industry. PMID- 28646679 TI - Hypoxia-induced ADAM 17 expression is mediated by RSK1-dependent C/EBPbeta activation in human lung fibroblasts. AB - Hypoxia was identified as a mediator of lung fibrosis in patients with chronic obstructive asthma (COA). Overexpression of a disintegrin and metalloproteinase 17 (ADAM 17) and connective tissue growth factor (CTGF) leads to development of tissue fibrosis. However, the signaling pathway in hypoxia-induced ADAM 17 expression remains poorly defined. In this study, we investigated the roles that ribosomal S-6 kinase 1 (RSK1)/CCAAT/enhancer-binding protein beta (C/EBPbeta) dependent ADAM 17 expression plays in hypoxia-induced CTGF expression in human lung fibroblasts. We observed that hypoxia caused increases in ADAM 17 expression and ADAM 17-luciferase activity in WI-38 cells. Hypoxia-induced CTGF-luciferase activity and CTGF expression were reduced in cells transfected with small interfering (si)RNA of ADAM 17 in WI-38 cells. Moreover, hypoxia-induced ADAM 17 expression was reduced by RSK1 siRNA and C/EBPbeta siRNA. Hypoxia caused time dependent increases in RSK1 phosphorylation at Thr359/Ser363. Exposure of cells to hypoxia resulted in increased C/EBPbeta phosphorylation at Thr266 and C/EBPbeta-luciferase activity in time-dependent manners, and these effects were suppressed by RSK1 siRNA. Hypoxia induced recruitment of C/EBPbeta to the ADAM 17 promoter. Furthermore, CTGF-luciferase activity induced by hypoxia was attenuated by RSK1 siRNA and C/EBPbeta siRNA. These results suggest that hypoxia instigates the RSK1-dependent C/EBPbeta signaling pathway, which in turn initiates binding of C/EBPbeta to the ADAM 17 promoter and ultimately induces ADAM 17 expression in human lung fibroblasts. Moreover, RSK1/C/EBPbeta-dependent ADAM 17 expression is involved in hypoxia-induced CTGF expression. Our results suggest possible therapeutic approaches for treating hypoxia-mediated lung fibrosis in COA. PMID- 28646680 TI - The experiences of supporting learning in pairs of nursing students in clinical practice. AB - The purpose of this study is to describe how supervisors experience supporting nursing students' learning in pairs on a Developing and Learning Care Unit in Sweden. The present study has been carried out with a Reflective Lifeworld Research (RLR) approach founded on phenomenology. A total of 25 lifeworld interviews were conducted with supervisors who had supervised pairs of students. The findings reveal how supervisors support students' learning in pairs through a reflective approach creating learning space in the encounter with patients, students and supervisors. Supervisors experience a movement that resembles balancing between providing support in learning together and individual learning. The findings also highlight the challenge in supporting both the pairs of students and being present in the reality of caring. In conclusion, the learning space has the potential of creating a relative level of independency in the interaction between pairs of students and their supervisor when the supervisor strives towards a reflective approach. PMID- 28646681 TI - Proteomic analysis of developing wheat grains infected by powdery mildew (Blumeria graminis f.sp. tritici). AB - Blumeria graminis f.sp. tritici (Bgt) infection greatly interferes with the normal source-sink relationships and always causes tremendous loss of yield and quality in wheat. To better understand the impact of this pathogen on grain development, proteome characterization during grain development in susceptible wheat cultivar Xinong 979 infected by powdery mildew was investigated by 2-DE and tandem MALDI-TOF/TOF-MS. Identification of 111 differentially expressed protein spots representing 85 unique proteins and six expression patterns showed a chronological description of wheat grain formation. Comparative proteome profiles indicated that 43 protein spots displayed significant abundance change, which is mainly involved in stress/defense responses, primary metabolism, and storage protein. The down-regulation of defense response-related proteins including alpha purothionin, lactoylglutathione lyase, and alpha-amylase inhibitor CM16 in infected grains compared to control during seed filling might be related to the susceptibility of wheat to Bgt, while the enhanced expression of beta-amylase and glyceraldehyde-3-phosphate dehydrogenase and the down-regulation of ADP glucose pyrophosphorylase in infected grains probably resulted in the negative effects on yield formation. Our data reveal the complex grain metabolism mechanisms and defense responses during compatible interactions of wheat and Bgt, and provide valuable information for further understanding of the underlying molecular processes which can possibly yield novel strategies for breeding resistant cultivars and protection strategies in the field. PMID- 28646682 TI - Sensing NADH conformation using phasor analysis on fluorescence spectra. AB - Phasor analysis on fluorescence signals is a sensitive approach for analyzing multicomponent systems. Initially developed for time-resolved measurements, a spectral version has been used for the rapid identification of regions during the spectral imaging of biological systems. Here we show that quantitative information regarding conformation can be obtained from phasor analysis of fluorescence spectrum shape. Methanol denaturation of NADH and NADH binding to various dehydrogenase proteins are used as model reactions. Thermodynamic constants are calculated and compared with previous studies based on more direct measures of conformation. Next, the quantitative monitoring of UV-excited autofluorescence spectrum shape during chemically-induced metabolic transitions is presented and discussed in terms of NADH-utilizing pathways. Results show how phasor analysis is useful in assessing two-state behavior, and in interpreting autofluorescence as emission from an ensemble of cellular NADH forms. PMID- 28646683 TI - Fabrication of low-fire-hazard flexible poly (vinyl chloride) via reutilization of heavy metal biosorbents. AB - As a naturally abundant biopolymer, chitosan is considered to be a suitable adsorbent for stannate (SnO32-) in tin plating wastewater. However, mass transfer of the adsorbent and its recycling remain challenging problems. Though flexible poly(vinyl chloride) (PVC) is highly flammable due to the addition of plasticizers, the traditional flame retardant, antimony trioxide (Sb2O3), is potentially harmful. In this study, chitosan was anchored onto the surface of PVC resin to adsorb SnO32- from wastewater. Thereafter, tin-doped chitosan-coated PVC resin was readily recycled and processed into a flexible PVC composite (modified fPVC). The limiting oxygen index value of the modified fPVC increased to 33.1%, and the peak heat release rate decreased to 161kW/m2. In addition to reducing fire hazards, this approach also decreased the content of harmful hydrogen chloride gas released during the combustion of modified fPVC. Meanwhile, the tensile properties of modified fPVC were enhanced compared with those of the Sb2O3-treated sample. These results indicated the synthesis of an eco-friendly Sb2O3-free flexible PVC composite that poses a low fire hazard. PMID- 28646684 TI - The relationship between non-suicidal self-injury and alexithymia in borderline personality disorder: "Actions instead of words". AB - INTRODUCTION: Borderline personality disorder (BPD) is a serious mental illness that centers on the inability to effectively regulate emotions. A large amount of BPD patients engage in non-suicidal self-injury (NSSI). Given the NSSI contributes to serious health risks, it is important to know why some BPD patients engage in NSSI and others do not. A possible associated factor of NSSI in BPD may be alexithymia, which reflects difficulties in identifying and communicating feelings. Therefore the aim of the present study was to investigate whether NSSI was associated with alexithymia and whether this association still stood when controlling for gender and depression. METHODS: The current study explored the relationship between NSSI and alexithymia in 185 BPD patients by means of the Self-Injury Questionnaire-Treatment Related and the Toronto Alexithymia Scale-20 (TAS). RESULTS: Of the 185 BPD inpatients, 82.7% reported life-time NSSI, of whom 52.9% were still engaging in current NSSI; and 71.3% scored in the alexithymic range (cut-off score>=61). Current NSSI was significantly associated with TAS-total. Additionally, when considering the separate TAS subscales Difficulties Describing Feelings (DDF), Difficulties Identifying Feelings (DIF) and Externally Oriented Thinking (EOT), only DDF was significantly associated with NSSI, even after controlling for gender and depression. CONCLUSION: These results suggest that NSSI in BPD patients is associated with alexithymia. More specific, difficulties describing feelings can lead to NSSI, independently of the depressive status of the BPD patient. The implications for clinical treatment of self-injurious BPD patients will be discussed. PMID- 28646686 TI - EEG spectral analysis as a putative early prognostic biomarker in nondemented, amyloid positive subjects. AB - We studied whether electroencephalography (EEG)-derived measures of brain oscillatory activity are related to clinical progression in nondemented, amyloid positive subjects. We included 205 nondemented amyloid positive subjects (63 subjective cognitive decline [SCD]; 142 mild cognitive impairment [MCI]) with a baseline resting-state EEG data and >=1-year follow-up. Peak frequency and relative power of 4 frequency bands were calculated. Relationships between normalized EEG measures and time to clinical progression (conversion from SCD to MCI/dementia or from MCI to dementia) were analyzed using Cox proportional hazard models. One hundred eight (53%) subjects clinically progressed after 2.1 (IQR 1.3 3.0) years. In the total sample, none of the EEG spectral measures were significant predictors. Stratified for baseline diagnosis, we found that in SCD patients higher delta and theta power (HR [95% CI] = 1.7 [1.0-2.7] resp. 2.3 [1.2 4.4]), and lower alpha power and peak frequency (HR [95% CI] = 0.5 [0.3-1.0] resp. 0.6 [0.4-1.0]) were associated with clinical progression over time. In amyloid positive subjects with normal cognition, slowing of oscillatory brain activity is related to clinical progression. PMID- 28646685 TI - A highly adhesive and naturally derived sealant. AB - Conventional surgical techniques to seal and repair defects in highly stressed elastic tissues are insufficient. Therefore, this study aimed to engineer an inexpensive, highly adhesive, biocompatible, and biodegradable sealant based on a modified and naturally derived biopolymer, gelatin methacryloyl (GelMA). We tuned the degree of gelatin modification, prepolymer concentration, photoinitiator concentration, and crosslinking conditions to optimize the physical properties and adhesion of the photocrosslinked GelMA sealants. Following ASTM standard tests that target wound closure strength, shear resistance, and burst pressure, GelMA sealant was shown to exhibit adhesive properties that were superior to clinically used fibrin- and poly(ethylene glycol)-based glues. Chronic in vivo experiments in small as well as translational large animal models proved GelMA to effectively seal large lung leakages without the need for sutures or staples, presenting improved performance as compared to fibrin glue, poly(ethylene glycol) glue and sutures only. Furthermore, high biocompatibility of GelMA sealant was observed, as evidenced by a low inflammatory host response and fast in vivo degradation while allowing for adequate wound healing at the same time. Combining these results with the low costs, ease of synthesis and application of the material, GelMA sealant is envisioned to be commercialized not only as a sealant to stop air leakages, but also as a biocompatible and biodegradable hydrogel to support lung tissue regeneration. PMID- 28646688 TI - Solar radiation and out-of-hospital cardiac arrest in Japan. AB - BACKGROUND: Although several studies have estimated the effects of temperature on mortality and morbidity, little is known regarding the burden of out-of-hospital cardiac arrest (OHCA) attributable to solar radiation. METHODS: We obtained data for all cases of OHCA and meteorological data reported between 2011 and 2014 in 3 Japanese prefectures: Hokkaido, Ibaraki, and Fukuoka. We first examined the relationship between daily solar radiation and OHCA risk for each prefecture using time-varying distributed lag non-linear models and then pooled the results in a multivariate random-effects meta-analysis. The attributable fractions of OHCA were calculated for low and high solar radiation, defined as solar radiation below and above the minimum morbidity solar radiation, respectively. The minimum morbidity solar radiation was defined as the specific solar radiation associated with the lowest morbidity risk. RESULTS: A total of 49,892 cases of OHCA occurred during the study period. The minimum morbidity solar radiation for each prefecture was the 100th percentile (72.5 MJ/m2) in Hokkaido, the 83rd percentile (59.7 MJ/m2) in Ibaraki, and the 70th percentile (53.8 MJ/m2) in Fukuoka. Overall, 20.00% (95% empirical confidence interval [eCI]: 10.97-27.04) of the OHCA cases were attributable to daily solar radiation. The attributable fraction for low solar radiation was 19.50% (95% eCI: 10.00-26.92), whereas that for high solar radiation was 0.50% (95% eCI: -0.07-1.01). CONCLUSIONS: Low solar radiation was associated with a substantial attributable risk for OHCA. Our findings suggest that public health efforts to reduce OHCA burden should consider the solar radiation level. Large prospective studies with longitudinal collection of individual data is required to more conclusively assess the impact of solar radiation on OHCA. PMID- 28646687 TI - Cortical amyloid accumulation is associated with alterations of structural integrity in older people with subjective memory complaints. AB - We determined the effect of cortical amyloid load using 18F-florbetapir PET on cognitive performance and gray matter structural integrity derived from MRI in 318 cognitively normally performing older people with subjective memory impairment from the INSIGHT-preAD cohort using multivariate partial least squares regression. Amyloid uptake was associated with reduced gray matter structural integrity in hippocampus, entorhinal and cingulate cortex, middle temporal gyrus, prefrontal cortex, and lentiform nucleus (p < 0.01, permutation test). Higher amyloid load was associated with poorer global cognitive performance, delayed recall and attention (p < 0.05), independently of its effects on gray matter connectivity. These findings agree with the assumption of a two-stage effect of amyloid on cognition, (1) an early direct effect in the preclinical stages of Alzheimer's disease and (2) a delayed effect mediated by downstream effects of amyloid accumulation, such as gray matter connectivity decline. PMID- 28646689 TI - Association between maternal urinary chromium and premature rupture of membranes in the Healthy Baby Cohort study in China. AB - Chromium exposure from increasing industrial releases has become a threat for pregnant women due to the potential health effects on vulnerable embryos. Previous studies have suggested that maternal chromium exposure is associated with adverse birth outcomes, but no epidemiological research has been conducted to examine the relationship between chromium exposure and premature rupture of membranes (PROM). This study aimed at investigating the association of maternal urinary chromium exposure levels with PROM and was performed with 5408 pregnant women recruited from 2012 to 2014 in the city of Wuhan, China. Maternal urinary chromium collected before labor was adjusted with creatinine, and its association with PROM was evaluated using logistic regression. Each one unit increase in the natural logarithm transformed maternal urinary chromium concentration (MUg/g creatinine), an odds ratio (OR) of 1.47 [95% confidence interval (CI): 1.36, 1.58] for PROM was observed. Compared to the lowest tertile of maternal urinary chromium, PROM was positively correlated with increased urinary levels of chromium (adjusted OR = 1.42; 95% CI: 1.09, 1.84 for the medium tertile; adjusted OR = 2.77; 95% CI: 2.18, 3.52 for the highest tertile). Additionally, the association of chromium with PROM appeared to be more significant among male infants (adjusted OR = 3.52; 95% CI: 2.51, 4.94 for the highest tertile) than female infants (adjusted OR = 2.16; 95% CI: 1.52, 3.06 for the highest tertile) (p for interaction = 0.05). Our large birth cohort showed an association between maternal urinary chromium levels and PROM, and the association may differ by infant gender. Further studies from different populations are needed to confirm the observed association. PMID- 28646690 TI - Polycyclic aromatic hydrocarbons in the water-SPM-sediment system from the middle reaches of Huai River, China: Distribution, partitioning, origin tracing and ecological risk assessment. AB - The polycyclic aromatic hydrocarbons (PAHs) concentrations in the water, suspended particulate matter (SPM) and sediment from the middle reaches of Huai River were analyzed by a gas chromatograph-mass spectrometer (GC-MS). The mean concentrations for the sum of 16 PAHs (?16 PAHs) in the water, SPM and sediment were 1204 ng/L, 3192 ng/g (dry weight; dw), and 7955 ng/g (dw), respectively. Along the vertical profiles of water columns, higher ?16 PAHs levels were seen in surface and bottom water layers and co-located SPM. The PAHs distribution in water and SPM is found to be controlled by organic carbon. Based on the statistic correlations of the organic carbon normalized partition coefficients (lgKOC) and octanol-water partition coefficient (lgKOW), we observed that the calculated partition coefficients do not increase as large as that would be expected from the increase of hydrophobicity. The principal component analysis suggests that coal combustion and the petroleum refinery were the primary PAHs contributors in the studied water-SPM-sediment system. The high ecological risks of PAHs in studied system highlight the urgent needs for remedial actions. PMID- 28646691 TI - What housing features should inform the development of housing solutions for adults with neurological disability?: A systematic review of the literature. AB - Despite the recent emphasis in Australian political, academic, and legislative narratives to more actively promote real housing choice for people with high healthcare and support needs, there is a lack of understanding regarding the specific housing features that might constitute better housing solutions for this population. Inclusive housing provision in Australia rightly emphasises safety and accessibility issues but often fails to incorporate factors related to broader psychosocial elements of housing such as dwelling location, neighbourhood quality, and overall design. While the importance of these broader elements appears obvious, it is not yet clear what specific housing features relate to these elements and how they might contribute to housing solutions for people with high healthcare and support needs. For individuals with complex neurological conditions such as brain injury or cerebral palsy, who require maximum support on a daily basis yet want to live independently and away from a primary care hospital or health facility, a more detailed understanding of the housing features that might influence design and development is needed. Thus, in order to clarify the broader factors related to housing solutions for this population, a systematic review was conducted to identify and synthesise the current research evidence (post-2003) and guide future housing design and development opportunities. From the included studies (n=26), 198 unique housing features were identified. From the 198 features, 142 related to housing design (i.e., internal or external characteristics of the dwelling and its land), 12 related to the dwelling's location (i.e., its proximity to available resources), and 54 related to the nature of the surrounding neighbourhood (i.e., the physical, social, and economic conditions of the area). The findings of this review contribute significantly to the literature by reporting a broader scope of relevant housing features for people with neurological disability, presenting preliminary guiding principles for housing design and development for this population, and identifying opportunities for future research. PMID- 28646692 TI - Specific subcortical structures are activated during seizure-induced death in a model of sudden unexpected death in epilepsy (SUDEP): A manganese-enhanced magnetic resonance imaging study. AB - Sudden unexpected death in epilepsy (SUDEP) is a major concern for patients with epilepsy. In most witnessed cases of SUDEP generalized seizures and respiratory failure preceded death, and pre-mortem neuroimaging studies in SUDEP patients observed changes in specific subcortical structures. Our study examined the role of subcortical structures in the DBA/1 mouse model of SUDEP using manganese enhanced magnetic resonance imaging (MEMRI). These mice exhibit acoustically evoked generalized seizures leading to seizure-induced respiratory arrest (S-IRA) that results in sudden death unless resuscitation is rapidly instituted. MEMRI data in the DBA/1 mouse brain immediately after acoustically-induced S-IRA were compared to data in C57 (control) mice that were exposed to the same acoustic stimulus that did not trigger seizures. The animals were anesthetized and decapitated immediately after seizure in DBA/1 mice and after an equivalent time in control mice. Comparative T1 weighted MEMRI images were evaluated using a 14T MRI scanner and quantified. We observed significant increases in activity in DBA/1 mice as compared to controls at previously-implicated auditory (superior olivary complex) and sensorimotor-limbic [periaqueductal gray (PAG) and amygdala] networks and also in structures in the respiratory network. The activity at certain raphe nuclei was also increased, suggesting activation of serotonergic mechanisms. These data are consistent with previous findings that enhancing the action of serotonin prevents S-IRA in this SUDEP model. Increased activity in the PAG and the respiratory and raphe nuclei suggest that compensatory mechanisms for apnea may have been activated by S-IRA, but they were not sufficient to prevent death. The present findings indicate that changes induced by S-IRA in specific subcortical structures in DBA/1 mice are consistent with human SUDEP findings. Understanding the changes in brain activity during seizure-induced death in animals may lead to improved approaches directed at prevention of human SUDEP. PMID- 28646694 TI - Elimination of signals tilting caused by B0 field inhomogeneity using 2D lineshape reference deconvolution. AB - An efficient approach for reference deconvolution of two-dimensional spectra aiming at the correction of static field inhomogeneity was established. In comparison to known techniques, a great improvement was achieved using the cross section along the diagonal of the reference peak instead of its full 2D line shape. The method is termed pseudo-2D diagonal deconvolution. The approach developed allows suppressing the two-dimensional peaks tilting caused by the magnetic field inhomogeneity, while keeping the signal-to-noise ratio constant. Long-known method of 2D reference deconvolution (true-2D reference deconvolution) was also applied for comparison. The neutral and resolution-enhancing pseudo-2D deconvolutions were successfully applied for the resolution of complex overlapping multiplets and for measuring small scalar coupling constants. The new algorithm for the elimination of shape distortion of two-dimensional peaks showed to be promising in the perspective of an automated analysis of 2D correlation NMR spectra. PMID- 28646693 TI - Antibacterial effect of genetically-engineered bacteriophage phiEf11/phiFL1C(Delta36)PnisA on dentin infected with antibiotic-resistant Enterococcus faecalis. AB - OBJECTIVE: Enterococcus faecalis is a gram-positive facultative anaerobic bacterium, which is present in 30-89% of teeth with postendodontic treatment failures. E. faecalis is capable of penetrating dentinal tubules and surviving as a monoculture after conventional endodontic therapy, indicating that it is resistant to commonly used endodontic disinfection protocols. Different E. faecalis strains have shown resistance to several antibiotics, and have been associated with both dental pathology and systemic infections. The aim of this study was to evaluate the efficacy of a genetically engineered bacteriophage to disinfect dentin infected with antibiotic resistant strains of E. faecalis. METHODS: Extracted human dentin root segments were cemented into sealable two chamber devices, fabricated from syringe needle caps to form in vitro infected dentin models. The models were inoculated with an overnight suspension of either E. faecalis V583 (vancomycin resistant strain) or E. faecalis JH2-2 (fusidic acid and rifampin resistant, vancomycin sensitive strain). After 7days of incubation at 37 degrees C, a suspension of a genetically engineered phage, phiEf11/phiFL1C(Delta36)PnisA, was added to the root canal of each infected dentin segment, and the incubation was continued for an additional 72-h. Dentin was harvested from the walls of each root canal and assayed for the residual titer of E. faecalis cells. RESULTS: The recovered E. faecalis titer was reduced by 18% for the JH2-2 infected models, and by 99% for the V583 infected models. CONCLUSION: Treatment: of E. faecalis-infected dentin with bacteriophage phiEf11/phiFL1C(Delta36)PnisA consistently resulted in a decrease in the residual bacterial population of both vancomycin-sensitive and resistant strains. PMID- 28646695 TI - Pre-polarization fields for earth's field NMR: Fast discharge for use with short T1 and large coils. AB - The sensitivity of earth's field NMR is greatly increased by the use of a pre polarizing field Bp. When used with short T1 samples, the field must be decreased rapidly to avoid loss of the pre-polarized magnetization by relaxation. Such a rapid decrease in the field requires rapid discharge (~10ms) of a large stored magnetic field energy (~700J). In addition, in order that the full pre-polarized magnetization be available for the subsequent pulse sequence, the field discharge should be adiabatic. This requirement is difficult to fulfill in cases where Bp is not everywhere parallel to the earth's field, such as with a large surface coil. Circuitry for rapid and controlled discharge is presented. Simulations and experiments confirm the importance of both of these conditions. PMID- 28646696 TI - Occurrence of the most common helminth infections among children in the Eastern Slovak Republic. AB - OBJECTIVES: Ascariasis, trichuriasis and hymenolepiasis occur primarily within poor communities with low hygiene standards. This study examined the occurrence of intestinal helminth infections among children living in two counties (Kosice and Presov) in the Eastern Slovak Republic. STUDY DESIGN: Four hundred and twenty six children were divided into groups according to ethnicity (non-Roma and Roma), age, sex, urban/rural residency and county of residence. METHODS: Stool samples collected from participants were processed by formalin-ethyl acetate sedimentation and examined microscopically. RESULTS: The overall prevalence of infection was 16.90% and the most prevalent species was Ascaris lumbricoides (14.32%). This was followed by Trichuris trichiura (3.76%), Hymenolepis nana (0.94%) and Hymenolepis diminuta (0.23%). The odds ratio for infection was 52 times higher among Roma children compared with non-Roma children. Among Roma children, the lowest prevalence of infection was reported in adolescents aged >=16 years. No significant differences in the prevalence of helminths were found between different sexes, or between hospitalized and non-hospitalized participants. Roma children living in urban areas had a 3.36 higher probability of infection than those living in rural areas. Among Roma children, helminth ova were found in 31.76% of the specimens from Kosice County and 19.69% of the specimens from Presov County. Among non-Roma children, there was only one positive finding in Presov County, and no cases in Kosice County. CONCLUSIONS: Important risk factors associated with helminth infections are ethnicity, county of residence and urban/rural residency. Ascariasis, trichuriasis and hymenolepiasis still occur in children with low hygiene standards, and this needs to be addressed by local authorities. PMID- 28646697 TI - Seroepidemiology of whooping cough in the Czech Republic: estimates of incidence of infection in adults. AB - OBJECTIVES: Despite widespread vaccination programmes, pertussis remains a significant health burden in many countries. Low awareness of the disease, the high rate of asymptomatic cases in adults and difficulties with diagnosis could explain the under-reporting of pertussis. The lack of data on actual incidence constitutes an obstacle for public health authorities for the implementation of a vaccination strategy against pertussis in adults. The aim of this study was to evaluate the seroprevalence of antibodies against Bordetella pertussis infection in adults and to estimate the actual incidence of the disease compared with the reported incidence. STUDY DESIGN: Prospective, multicentre seroprevalence study. METHODS: The study was conducted in 2000 adult subjects aged >=18 years who had not received pertussis vaccination within the last 5 years. All enrolled subjects provided a blood sample for serum testing of IgG antibodies against pertussis toxin, performed by enzyme-linked immunosorbent assay, to indicate if they had an acute infection or if they had been infected with pertussis within the last 12 months or earlier. Results were validated in accordance with the guidelines of the European Sero-epidemiology Network 2 and were expressed in ESEN units/ml. RESULTS: A positive concentration of anti-pertussis toxin antibodies, indicating previous pertussis infection, was demonstrated in 39.9% (n = 799) of all study subjects, and 0.40% (n = 8) of subjects had a concentration suggestive of a recent infection (within the last 12 months). The highest antibody seroprevalence was observed in subjects aged 18-29 years (1.46%). No cases of acute infection were detected. CONCLUSIONS: During the study period, the reported incidence of pertussis in the adult population was 0.84/100,000 inhabitants. Based on the seroprevalence results from this study, it is estimated that the actual incidence of pertussis could be as much as 699/100,000 inhabitants. The actual incidence of pertussis in adults in the Czech Republic could therefore be at least 200-fold higher than the reported incidence. These findings support the need for pertussis vaccination in the adult population. PMID- 28646698 TI - HPV vaccine hesitancy among parents of female adolescents: a pre-post interventional study. PMID- 28646699 TI - Insulin and the polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy among women during reproductive age. PCOS is characterised by hyperandrogenaemia, hyperinsulinaemia, and deranged adipokines secretion from the adipose tissue. In addition to the reduced insulin sensitivity, PCOS women exhibit beta-cell dysfunction as well. Low birth weight and foetal exposure to androgens may contribute to the development of the PCOS phenotype during life. Further metabolic complications lead to dyslipidaemia, worsening obesity and glucose tolerance, high prevalence of metabolic syndrome, and greater susceptibility to diabetes. PCOS women show age-related existence of hypertension, and subtle endothelial and vascular changes. Adverse reproductive outcomes include anovulatory infertility, and unrecognised potentiation of the hormone-dependent endometrial cancer. The main therapeutic approach is lifestyle modification. Metformin is the primary insulin-sensitising drug to be used as an adjuvant therapy to lifestyle modification in patients with insulin resistance and impaired glucose tolerance, as well as in those referred to infertility treatment. Thiazolidinediones should be reserved for women intolerant of or refractory to metformin, while glucagon-like peptide 1 analogues has a potential therapeutic use in obese PCOS women. Randomised clinical trials and repetitive studies on different PCOS phenotypes for the preventive actions and therapeutic options are still lacking, though. PMID- 28646700 TI - Increased serum miR-7 is a promising biomarker for type 2 diabetes mellitus and its microvascular complications. AB - AIMS: To investigate the alteration pattern and physiologic state of islet specific miR-7 in the serum of patients with type 2 diabetes mellitus (T2DM) and T2DM-associated microvascular complications (T2DMC) and to evaluate its clinical significance. METHODS: The levels of serum miR-7 were firstly examined and compared in 76 T2DM patients, 76 T2DMC patients and 74 age-gender matched controls using RT-qPCR. Subsequently, the physiologic state of serum miR-7 was characterized by determining its concentrations in isolated exosomes and corresponding exosome-free samples from the same three cohorts' samples. Moreover, statistical analyzes were performed to evaluate the associations of serum miR-7 with T2DM and T2DMC. RESULTS: Serum miR-7 was significantly elevated in the T2DM patients [(401.0+/-34.37) fmol/L, P<0.001] and in the T2DMC patients [(501.4+/-81.69) fmol/L, P<0.001] when compared with the controls [(175.7+/ 16.59) fmol/L]. Circulating miR-7 was mainly existed as exosome-free form rather than in membrane-bound exosomes. The concentrations of exosome-free miR-7 were markedly higher in the T2DM group [(107.2+/-9.63) fmol/L, P<0.001] and in the T2DMC group [(122.1+/-10.80) fmol/L, P<0.001] compared to the control group [(54.18+/-2.37) fmol/L]. Logistic regression and ROC curve analyses revealed the serum miR-7 was significantly associated with T2DM and microvascular complications (P<0.05). CONCLUSION: Increased serum miR-7 might have the potential as a promising marker for T2DM and its microvascular complications. PMID- 28646701 TI - Use of SGLT2 inhibitors for diabetes and risk of infection: Analysis using general practice records from the NPS MedicineWise MedicineInsight program. AB - AIMS: To explore the feasibility of MedicineInsight data to support risk management plan evaluation, focusing on sodium glucose co-transporter 2 (SGLT2) inhibitors for type 2 diabetes. METHODS: A retrospective study using de identified electronic general practitioner records. Patients who initiated SGLT2 inhibitor between 1 Jan 2012 to 1 Sep 2015 were compared to patients who initiated dipeptidyl peptidase 4 (DPP-4) inhibitors. The two cohorts were followed-up for six months. Risk of urinary-tract (UT) and genital infections was evaluated. The indication for use of SGLT2 inhibitors, recommended prior diabetes therapies and recommended monitoring were investigates. RESULTS: There were 1977 people in the SGLT2 cohort (with 93% initiated on dapagliflozin) and 1964 people in the DPP-4 cohort. Of the SGLT2 initiators, 54% had a documented indication for use as type 2 diabetes; 86% had used metformin and/or a sulfonylurea in the prior 12months. Renal function monitoring was documented for only 25% in the 6months initiation. The frequency of UTI in the 6months post SGLT2 initiation was not significantly increased compared to the DPP-4 cohort (3.6%vs 4.9%; aHR=0.90, 95% CI 0.66-1.24). Genital infection were more frequent in the SGLT2 than in the DPP 4 cohort (2.9% vs 0.9%, aHR=3.50, 95% CI 1.95-5.89). CONCLUSIONS: Similar to existing evidence, we found a higher risk of genital infection associated with SGLT2 inhibitors (primarily dapagliflozin) but no increased risk of UTIs compared to DPP-4 use. PMID- 28646702 TI - Alcohol and recreational drug use in young adults with type 1 diabetes. AB - Alcohol and other recreational drug use reaches peak prevalence in young adulthood, including for those with chronic medical conditions such as type 1 diabetes. This review summarises the current literature on the patterns of substance use amongst young adults with type 1 diabetes and the mechanisms through which alcohol and recreational drugs may affect diabetes related health outcomes. These include the direct physical effect of intoxication, as well as the effects of alcohol and drugs on mental health and glucose metabolism. Evidence for increased associated mortality and morbidity is also presented, and current guidelines, management strategies and directions for further research are discussed. PMID- 28646703 TI - Comparison of type 2 diabetes prevalence in Chinese migrants vs Caucasians and new perspectives for screening of cerebrovascular disease in Chinese: A proof of concept study. AB - AIMS: Type 2 diabetes (T2DM) is a recognized risk factor for intracranial stenosis (ICS) in China where ischemic stroke is a health priority. In Europe little information is available on T2DM prevalence among Chinese minority groups and vascular screening is commonly limited to extracranial vessels. Feasibility of community-based T2DM screening, differences in T2DM prevalence between Chinese migrants and Italians, and prevalence of ICS among Chinese patients with newly diagnosed T2DM were investigated. METHODS: Chinese first generation migrants (n=1200) and native Italians (n=291) aged 35-59years were enrolled in a cross sectional survey. Diagnosis of T2DM was based on fasting plasma glucose and/or current treatment with glucose-lowering drugs. Newly diagnosed Chinese patients were screened for ICS using Doppler ultrasound. RESULTS: T2DM was more prevalent among Chinese (n=168, 14.0%) than Italians (n=21, 7.3%) (age- and gender adjusted OR 2.29; 95% C.L. 1.41-3.72). Prevalence of ICS among newly diagnosed Chinese was 18.2%. Nine out of the 17 patients with any ICS (52%) had >1 intracranial lesion. CONCLUSIONS: T2DM screening within the Chinese community was feasible revealing prevalence twice as much as in the Italian cohort; the 18% prevalence of ICS in newly diagnosed Chinese patients stresses the need of implementing appropriate vascular screening strategies. PMID- 28646704 TI - Location and characterization of lignin in tracheid cell walls of radiata pine (Pinus radiata D. Don) compression woods. AB - Tilted stems of softwoods form compression wood (CW) and opposite wood (OW) on their lower and upper sides, respectively. More is known about the most severe form of CW, severe CW (SCW), but mild CWs (MCWs) also occur widely. Two grades of MCWs, MCW1 and MCW2, as well as SCW and OW were identified in the stems of radiata pine (Pinus radiata) that had been slightly tilted. The four wood types were identified by the distribution of lignin in the tracheid walls determined by fluorescence microscopy. A solution of the fluorescent dye acridine orange (AO) (0.02% at pH 6 or 7) was shown to metachromatically stain the tracheid walls and can also be used to determine lignin distribution. The lignified walls fluoresced orange to yellow depending on the lignin concentration. Microscopically well characterized discs (0.5 mm diameter) of the wood types were used to determine lignin concentrations and lignin monomer compositions using the acetyl bromide method and thioacidolysis, respectively. Lignin concentration and the proportion of p-hydroxyphenyl units (H-units) relative to guaiacyl (G-units) increased with CW severity, with <1% H-units in OW and up to 14% in SCW. Lignin H-units can be used as a marker for CW and CW severity. Similar discs were also examined by Raman and FTIR micro-spectroscopies coupled with principal component analysis (PCA) to determine if these techniques can be used to differentiate the four different wood types. Both techniques were able to do this, particularly Raman micro-spectroscopy. PMID- 28646705 TI - Identification and in vitro characterization of novel nanobodies against human granulocyte colony-stimulating factor receptor to provide inhibition of G-CSF function. AB - It has been shown that Granulocyte colony-stimulating factor (G-CSF) has a higher expression in malignant tumors, and anti-G-CSF therapy considerably decreases tumor growth, tumor vascularization and metastasis. Thus, blocking the signaling pathway of G-CSF could be beneficial in cancer therapy. This study is aimed at designing and producing a monoclonal nanobody that could act as an antagonist of G-CSF receptor. Nanobodies are the antigen binding fragments of camelid single chain antibodies, also known as VHH. These fragments have exceptional properties which makes them ideal for tumor imaging and therapeutic applications. We have used our previously built nanobody phage libraries to isolate specific nanobodies to the G-CSF receptor. After a series of cross-reactivity and affinity experiments, two unique nanobodies were selected for functional analysis. Proliferation assay, real-time PCR and immunofluorescence assays were used to characterize these nanobodies. Finally, VHH26 nanobody that was able to specifically bind G-CSF receptor (G-CSF-R) on the surface of NFS60 cells and efficiently block G-CSF-R downstream signaling pathway in a dose-dependent manner was selected. This nanobody could be further developed into a valuable tool in tumor therapy and it forms a basis for additional studies in preclinical animal models. PMID- 28646706 TI - Corn silk maysin ameliorates obesity in vitro and in vivo via suppression of lipogenesis, differentiation, and function of adipocytes. AB - Present study was aimed to investigate the potential anti-obesity effects of maysin, a major flavonoid of corn silk, in vitro and in vivo using 3T3-L1 preadipocyte cells and C57BL/6 mice. Maysin decreased the levels of intracellular lipid droplets and triglycerides (TG), and down-regulated the protein expression levels of C/EBP-beta, C/EBP-alpha, PPAR-gamma, and aP2 in 3T3-L1 preadipocyte cells, suggesting that maysin inhibits lipid accumulation and adipocyte differentiation. In addition, maysin was shown to induce the apoptotic cell death in 3T3-L1 preadipocyte cells via activation of caspase cascades and mitochondrial dysfunction, which may ultimately lead to reduction of adipose tissue mass. Furthermore, oral administration of maysin (25mg/kg body weight) decreased weight gain and epididymal fat weight in high-fat diet (HFD)-fed C57BL/6 mice. Administration of maysin also reduced serum levels of TG, total-cholesterol, LDL cholesterol, and glucose. Taken collectively, these results suggest for the first time that the purified maysin exerts an anti-obesity effect in vitro and in vivo. These observations may support the applicability of maysin as a potent functional ingredient in health-beneficial foods or as a therapeutic agent to prevent or treat obesity. PMID- 28646707 TI - Use of research in undergraduate nursing students' theses: A mixed methods study. AB - BACKGROUND: Health care personnel are expected to be familiar with evidence-based practice (EBP). Asking clinical questions, conducting systematic literature searches and conducting critical appraisal of research findings have been some of the barriers to EBP. To improve undergraduate nurses' research skills, a collaborative library-faculty teaching intervention was established in 2012. OBJECTIVES: The aim of this study was to evaluate how the collaborative library faculty teaching intervention affected the nursing students' research skills when writing their final theses. DESIGN AND SETTING: Both quantitative and qualitative data collection and analysis were used. The study focused on a final year undergraduate nurse training programme in Norway. PARTICIPANTS: 194 theses submitted between 2013 and 2015 were collected and assessed. The students were exposed to the intervention for respectively one, two and three years during this period. METHODS: Descriptive statistics were used to compare each year's output over the three-year period and to examine the frequency of the use of various databases, types of information and EBP-tools. Qualitative data was used to capture the students' reasoning behind their selection processes in their research. RESULTS: The research skills with regard to EBP have clearly improved over the three years. There was an increase in employing most EBP-tools and the justifications were connected to important EBP principles. The grades in the upper half of the grading scale increased from 66.7 to 82.1% over the period 2013 to 2015, and a correlation was found between grades and critical appraisal skills. CONCLUSIONS: The collaborative library-faculty teaching intervention employed has been successful in the promotion of nursing student research skills as far as the EBP principles are concerned. Writing a thesis in the undergraduate nursing programme is important to develop and practice these research skills. PMID- 28646708 TI - Piezoelectric parametric effects on wave vibration and contact mechanics of traveling wave ultrasonic motor. AB - Elastic wave quality determines the operating performance of traveling wave ultrasonic motor (TWUM). The time-variant circumferential force from the shrink of piezoelectric ceramic is one of the factors that distort the elastic wave. The distorted waveshape deviates from the ideal standard sinusoidal fashion and affects the contact mechanics and driving performance. An analytical dynamic model of ring ultrasonic motor is developed. Based on this model, the piezoelectric parametric effects on the wave distortion and contact mechanics are examined. Multi-scale method is employed to obtain unstable regions and distorted wave response. The unstable region is verified by Floquet theory. Since the waveshape affects the contact mechanism, a contact model involving the distorted waveshape and normal stiffness of the contact layer is established. The contact model is solved by numerical calculation. The results verify that the deformation of the contact layer deviates from sinusoidal waveshape and the pressure distribution is changed, which influences the output characteristics directly. The surface speed within the contact region is averaged such that the rotor speed decreases for lower torque and increases for larger torque. The effects from different parametric strengths, excitation frequencies and pre-pressures on pressure distribution and torque-speed relation are compared. PMID- 28646709 TI - Association between father involvement and attitudes in early child-rearing and depressive symptoms in the pre-adolescent period in a UK birth cohort. AB - BACKGROUND: Much of the research on parenting and its influence on child development has emphasised the mother's role. However, increasing evidence highlights the important role of fathers in the development, health and well being of their children. We sought to explore the association between paternal involvement in early child-rearing and depressive symptoms in 9 and 11 year-old children. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited in the southwest of England. The outcome was depressive symptoms measured using the short Moods and Feelings Questionnaire (sMFQ) score. The main exposure was father involvement measured through factor analysis of fathers' responses on their participation in, understanding of, and feelings about their child's early upbringing. Scores on factor 1 measured fathers' emotional response to the child; scores on factor 2 measured the frequency of father involvement in domestic and childcare activities; scores on factor 3 measured fathers' feelings of security in their role as parent and partner. RESULTS: Children of fathers with high scores on factors 1 and 3 had 13% (OR 0.87, 95%CI 0.77-0.98, p = 0.024) and 9% (OR 0.91, 95%CI 0.80-1.03, p = 0.129) respectively lower adjusted odds of depressive symptoms at 9 and 11 years. For factor 2, there was weak evidence of a 17% increase in odds of depressive symptoms associated with 1 unit higher factor scores at both ages (OR 1.17, 95%CI 1.00-1.37, p = 0.050). LIMITATIONS: In these observational data, the possibility of residual confounding in the association between the exposure and the outcome cannot be ruled out. CONCLUSION: Positive psychological and emotional aspects of father involvement in children's early upbringing, but not the quantity of direct involvement in childcare, may protect children against developing symptoms of depression in their pre-teen years. PMID- 28646710 TI - Psychological distress and the incident risk of functional disability in elderly survivors after the Great East Japan Earthquake. AB - BACKGROUND: We conducted a prospective cohort study to investigate whether psychological distress would have increased the incident risk of functional disability after the 2011 Great East Japan Earthquake. METHODS: First phase data pertaining to psychological distress and other lifestyle factors were collected from 1037 subjects aged >= 65 years, from June to December 2011, in four affected areas of Miyagi prefecture in Japan. Psychological distress was measured by the Kessler 6-item psychological distress scale (K6), and classified into three categories (K6 score <= 9, 10-12, >= 13). Outcome data on functional disability were collected from the public Long-term Care Insurance database. Participants were followed up for about 2.6 years. The Cox model was used to calculate the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During the follow-up period, 118 participants were certified as incident disability (43.8 disability events per 1000 person-years). Compared with the lowest category (K6 score <= 9), participants in the highest category (K6 score >= 13) had a significantly higher risk of functional disability (HR = 2.65, 95% CI = 1.35-5.18, p = 0.002). In order to consider reverse causality, we conducted analysis excluding all incidents and deaths that occurred within the first year of follow-up, but our findings remained unchanged. LIMITATIONS: We did not consider all potential confounders and use of appropriate medication. CONCLUSIONS: The present study has demonstrated that psychological distress was associated with an increased risk of functional disability among elderly survivors of a natural disaster. PMID- 28646711 TI - Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder. AB - BACKGROUND: Balance in the immune system plays roles in bipolar disorder (BD) and its metabolic co-morbidities. Memantine is an NMDA receptor antagonist with anti inflammatory effects. However, the effects of memantine adjunct treatment on metabolic status of BD are unclear. METHODS: During the 12 weeks period, a total of 191 BD patients were enrolled and split into valproate (VPA) + placebo and VPA + memantine (5mg/day) arms. The fasting plasma levels of high-sensitivity C reactive protein (CRP) and metabolic indices were assessed. BD patients were stratified according to their initial CRP level. RESULTS: A cut-off value of initial CRP level of 2322ng/mL discriminated the waist circumference in these BD patients after 12-week VPA treatment. In the high CRP (> 2322ng/mL) group, patients in the VPA + memantine arm had a significantly decreased in their CRP (p= 0.009), total cholesterol (p= 0.002), LDL (p= 0.002) levels, BMI (p= 0.001), and waist circumference (p< 0.001), compared to those in the VPA + placebo arm. However, analysis of the low CRP group did not showed the effect. LIMITATIONS: We recruited BD patients in depressed states and the sample size was relative small. The effects of the fixed dose of memantine on metabolic indices were 12-week follow up in BD patients treated with VPA. CONCLUSIONS: BD patients with high initial CRP levels receiving memantine adjunct treatment have a reduced risk of inflammation and metabolic imbalance. Prospective studies are needed to confirm the long-term outcome for memantine adjunct therapy in BD patients. PMID- 28646712 TI - Prediction of vocational participation and global role functioning in help seeking young adults, from neurocognitive, demographic and clinical variables. AB - BACKGROUND: The purpose of this study was to investigate neurocognitive, demographic and clinical correlates of vocational participation among a sample of young help-seeking adults. METHODS: Young people (18-25 years) accessing an early intervention youth health service participated. The Global Functioning: Role scale and level of vocational participation, participant characteristics (age, gender, socioeconomic background and family history of serious mental illness), distress, psychotic-like experiences, substance use, and mental health diagnoses were recorded. The Cambridge Neuropsychological Testing Automated Battery was used to assess sustained attention, visual memory and executive function. RESULTS: Of the 107 participants, 33 (31%) were not working or studying and 52 (49%) had a diagnosis of affective disorder. Impairments in neurocognitive tests were evidenced in attention shift, sustained attention target sensitivity, impulsivity and spatial working memory errors. Univariate analyses indicated that information processing and target impulsivity were associated with both vocational participation and global functioning, and that spatial working memory strategy was also associated with vocational participation. After controlling for significant demographic and clinical predictors, strategy formation remained a significant correlate of vocational participation (coefficient (95%CI) = -0.08 ( 0.17, -0.01)), but no neurocognitive measures remained significant in the multivariate prediction of global functioning. LIMITATIONS: Neurocognitive outcomes were assessed at a single time point, factors such as fluctuations in motivation could impact on test results. CONCLUSIONS: Interventions targeting work and education participation should consider the capacity of vulnerable young people to develop appropriate plans for role success and provide support accordingly. The study also emphasised the importance of high school completion and avoidance of cannabis use, especially in males. PMID- 28646713 TI - Substance use among HIV-infected patients in Rio de Janeiro, Brazil: Agreement between medical records and the ASSIST questionnaire. AB - BACKGROUND: Substance use assessment is a challenge in busy clinical settings that may adversely affect HIV-infected persons. This study aimed to evaluate agreement between the medical chart and a standardized substance use screening questionnaire. METHODS: Of adults (n=1050) in HIV care in Rio de Janeiro who completed the World Health Organization's Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), we randomly selected 200 participants for medical chart review. Lifetime use of tobacco, alcohol, marijuana, and cocaine agreement between the medical record and ASSIST was evaluated using Kappa statistics. Sensitivity and specificity of chart information were also calculated. RESULTS: The median age was 42.4 years, 60.3% were male and 49.5% were white. Prevalence of lifetime use reported in ASSIST was 55.3% (tobacco), 79.4% (alcohol), 23.1% (marijuana), and 20.7% (cocaine). Any information on lifetime use was found in the medical chart for tobacco (n=180, 90.5%), alcohol (n=183, 92.0%), marijuana (n=143, 71.8%), and cocaine (n=151, 75.9%). The Kappa statistic, sensitivity and specificity of the medical chart accurately identifying lifetime substance users per ASSIST were respectively 0.60, 0.71, and 0.91 for tobacco; 0.22, 0.75, and 0.51 for alcohol; 0.58, 0.51, and 0.98 for marijuana; and 0.73, 0.75, and 0.96 for cocaine. CONCLUSION: Considering inaccuracies in the medical chart, the implementation of brief, standardized substance use screening is recommended in HIV care settings. PMID- 28646715 TI - Understanding the prevalence of lifetime abstinence from alcohol: An ecological study. AB - BACKGROUND: The level of alcohol consumption and related burden in a country are strongly impacted by the prevalence of abstinence from alcohol use. The objective of this study was to characterize the association of lifetime abstinence from alcohol use with economic wealth (as measured in the gross domestic product [GDP]) and Muslim religion on a country level. METHODS: An ecological study was performed using aggregate data of 183 countries for the year 2010. Lifetime abstinence among men and women was predicted using fractional response regression models with the natural logarithm of GDP-PPP (purchasing power parity) and the proportion of Muslim population as predictors. The models were further adjusted by the country's median age and World Health Organization region. Precision of prediction was investigated. RESULTS: Descriptive analyses showed a strong negative association between GDP-PPP and lifetime abstinence in countries without a Muslim majority and a GDP-PPP up to 20,000 international dollars. Regression models confirmed the negative association with GDP-PPP and showed a strong positive association between lifetime abstinence and the proportion of Muslim population. Stratified sensitivity analyses showed that in countries without a Muslim majority only GDP-PPP showed a statistically significant association whereas in Muslim majority countries only the proportion of Muslims was associated with the prevalence of lifetime abstinence. CONCLUSIONS: Particularly in countries with a lower GDP and without Muslim majority the prevalence of lifetime abstinence from alcohol use is strongly negatively associated with GDP PPP. Future research should analyze the accordance in trends of GDP and lifetime abstinence over time. PMID- 28646714 TI - Synthetic cathinones and stereochemistry: S enantiomer of mephedrone reduces anxiety- and depressant-like effects in cocaine- or MDPV-abstinent rats. AB - BACKGROUND AND PURPOSE: The neuropharmacological profile of the synthetic cathinone mephedrone (MEPH) is influenced by stereochemistry. Both MEPH enantiomers are monoamine transporter substrates, but R-MEPH is primarily responsible for rewarding effects of MEPH as it produces greater locomotor activation and intracranial self-stimulation than S-MEPH. S-MEPH is a 50-fold more potent 5-HT releaser than R-MEPH and does not place preference in rats. MEPH is also structurally similar to the cathinone derivative bupropion, an antidepressant and smoking cessation medication, suggesting MEPH has therapeutic and addictive properties. METHODS: We tested the hypothesis that S-MEPH reduces anxiety- and depression-like behaviors in rats withdrawn from chronic cocaine or methylenedioxypyrovalerone (MDPV) using the elevated plus maze (EPM) and forced swim test (FST), respectively. Rats were tested 48-h after a binge-like paradigm (3*/day for 10days in 1-h intervals) of cocaine (10mg/kg), MDPV (1mg/kg) or saline. In vitro studies assessed the receptor binding and activity of S-MEPH. KEY RESULTS: Rats withdrawn from chronic cocaine or MDPV displayed an increase in anxiety- and depression-like behaviors that was antagonized by treatment with S MEPH (10, 30mg/kg). S-MEPH displayed affinity, but not agonist activity, for 5 HT2 receptors (2A-2C) and showed negligible affinity for dopaminergic, adrenergic and nicotinic receptors. CONCLUSION AND IMPLICATION: S-MEPH attenuated withdrawal behaviors following chronic cocaine or MDPV, perhaps through 5-HT release and/or 5-HT2 receptor interactions. The present data suggest S-MEPH may be a possible structural and pharmacological template to develop maintenance therapy for acute anxiety and depression during early withdrawal from psychostimulant abuse. PMID- 28646716 TI - Histopathologic differences partially distinguish syndromic aortic diseases. AB - A variety of syndromic diseases such as Marfan syndrome, Loeys-Dietz syndrome, and bicuspid aortic valve with aneurysm along with risk factors of smoking and hypertension result in ascending aortic aneurysms and dissections. Historically, a complicated variety of terms have been used to describe a range of histopathologies that are present in resected specimens. As a result, no consistent patterns of histopathology have been reported. We used the recent Society for Cardiovascular Pathology/Association for European Cardiovascular Pathology consensus statement on nomenclature and diagnostic criteria for noninflammatory aortic disease to blindly evaluate 148 surgically resected specimens. We found that overall patterns of histopathologic changes could separately cluster bicuspid aortic valve and nonsyndromic subjects from Marfan and Loeys-Dietz subjects. Marfan syndrome cases significantly had more overall medial degeneration and mucoid extracellular matrix accumulation than other syndromes. Smooth muscle cell nuclei loss was a feature of aging and not a feature of Marfan or Loeys-Dietz syndrome subjects. We conclude that a consistent use of histologic and histopathologic descriptors can help discriminate different etiologies of ascending aortic aneurysms. PMID- 28646717 TI - Comprehending the multiple 'values' of green infrastructure - Valuing nature based solutions for urban water management from multiple perspectives. AB - The valuation of urban water management practices and associated nature-based solutions (NBS) is highly contested, and is becoming increasingly important to cities seeking to increase their resilience to climate change whilst at the same time facing budgetary pressures. Different conceptions of 'values' exist, each being accompanied by a set of potential measures ranging from calculative practices (closely linked to established market valuation techniques) - through to holistic assessments that seek to address wider concerns of sustainability. Each has the potential to offer important insights that often go well beyond questions of balancing the costs and benefits of the schemes concerned. However, the need to address - and go beyond - economic considerations presents policy makers, practitioners and researchers with difficult methodological, ethical and practical challenges, especially when considered without the benefit of a broader theoretical framework or in the absence of well-established tools (as might apply within more traditional infrastructural planning contexts, such as the analysis of transport interventions). Drawing on empirical studies undertaken in Sheffield over a period of 10 years, and delivered in partnership with several other European cities and regions, we compare and examine different attempts to evaluate the benefits of urban greening options and future development scenarios. Comparing these different approaches to the valuation of nature-based solutions alongside other, more conventional forms of infrastructure - and indeed integrating both 'green and grey' interventions within a broader framework of infrastructures - throws up some surprising results and conclusions, as well as providing important sign-posts for future research in this rapidly emerging field. PMID- 28646718 TI - Reduced graphene oxide-functionalized FeOOH for signal-on photoelectrochemical sensing of prostate-specific antigen with bioresponsive controlled release system. AB - A new and signal-on photoelectrochemical (PEC) sensing platform was successfully designed for the sensitive detection of prostate-specific antigen (PSA), using reduced graphene oxide- functionalized iron oxyhydroxide (FeOOH-rGO) as the photoactive material, accompanying target-responsive controlled release system to achieve the signal amplification. Introduction of rGO as electron mediator greatly facilitated the electron transfer from FeOOH to electrode under visible light, which inhibited the electron-hole recombination to enhance the photo activity of FeOOH-rGO. Additionally, the bioresponsive release system was controlled via the reaction of target PSA with the aptamer capped glucose-loading mesoporous silica nanoparticle (MSN) to release numerous glucose molecules (as the electron donors) for the amplification of the photocurrent generated from FeOOH-rGO. Thus, more glucose molecules could be released and enhanced photocurrents could be obtained with the increasing PSA concentrations. Experimental results showed that the photocurrents of the PEC sensing platform were linearly dependent on the logarithm of PSA concentrations from 1.0pg/mL to 100ng/mL. Moreover, the PEC sensing system afforded good stability and specificity, and its accuracy matched well with the commercial PSA enzyme-linked immunosorbent assay (ELISA) kit. The excellent performance of the PEC sensing platform indicated its promising prospect as a useful tool for PSA detection in practical application. PMID- 28646719 TI - DNA aptamer-based colorimetric detection platform for Salmonella Enteritidis. AB - Food safety is a major issue to protect public health and a key challenge is to find detection methods for identification of hazards in food. Food borne infections affects millions of people each year and among pathogens, Salmonella Enteritidis is most widely found bacteria causing food borne diseases. Therefore, simple, rapid, and specific detection methods are needed for food safety. In this study, we demonstrated the selection of DNA aptamers with high affinity and specificity against S. Enteritidis via Cell Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX) and development of sandwich type aptamer based colorimetric platforms for its detection. Two highly specific aptamers, crn 1 and crn-2, were developed through 12 rounds of selection with Kd of 0.971uM and 0.309uM, respectively. Both aptamers were used to construct sandwich type capillary detection platforms. With the detection limit of 103 CFU/mL, crn-1 and crn-2 based platforms detected target bacteria specifically based on color change. This platform is also suitable for detection of S. Enteritidis in complex food matrix. Thus, this is the first to demonstrate use of Salmonella aptamers for development of the colorimetric aptamer-based detection platform in its identification and detection with naked eye in point-of-care. PMID- 28646720 TI - Nanoporous gold-based microbial biosensor for direct determination of sulfide. AB - Environmental pollution caused by sulfide compounds has become a major problem for public health. Hence, there is an urgent need to explore a sensitive, selective, and simple sulfide detection method for environmental monitoring and protection. Here, a novel microbial biosensor was developed using recombinant Escherichia coli BL21 (E. coli BL21) expressing sulfide:quinone oxidoreductase (SQR) for sulfide detection. As an important enzyme involved in the initial step of sulfide metabolism, SQR oxidizes sulfides to polysulfides and transfers electrons to the electron transport chain. Nanoporous gold (NPG) with its unique properties was selected for recombinant E. coli BL21 cells immobilization, and then glassy carbon electrode (GCE) was modified by the resulting E. coli/NPG biocomposites to construct an E. coli/NPG/GCE bioelectrode. Due to the catalytic oxidation properties of NPG for sulfide, the electrochemical reaction of the E. coli/NPG/GCE bioelectrode is attributed to the co-catalysis of SQR and NPG. For sulfide detection, the E. coli/NPG/GCE bioelectrode showed a good linear response ranging from 50MUM to 5mM, with a high sensitivity of 18.35MUAmM-1cm-2 and a low detection limit of 2.55MUM. The anti-interference ability of the E. coli/NPG/GCE bioelectrode is better than that of enzyme-based inhibitive biosensors. Further, the E. coli/NPG/GCE bioelectrode was successfully applied to the detection of sulfide in wastewater. These unique properties potentially make the E. coli/NPG/GCE bioelectrode an excellent choice for reliable sulfide detection. PMID- 28646721 TI - Biochemical-immunological hybrid biosensor based on two-dimensional chromatography for on-site sepsis diagnosis. AB - A hybrid-biosensor system that can simultaneously fulfill the immunoassay for protein markers (e.g., C-reactive protein (CRP) and procalcitonin (PCT)) and the enzyme assay for metabolic substances (e.g., lactate) in the same sepsis-based sample has been devised. Such a challenge was pursued through the installation of an enzyme-reaction zone on the signal pad of the typical immuno-strip for the rapid two-dimensional (2-D)-chromatography test. To minimize the mutual interference in the hybrid assays, a pre-determined membrane site was etched in a pattern and mounted with a biochemical-reaction pad, thereby allowing a loaded sample to enter and then stay in the pad for a colored-signal production over the course of an immunoassay. By employing such a constructed system, a serum sample was analyzed according to the vertical direction flowing along the strip, which supplied lactate to the biochemical-reaction zone and then protein markers to the immunological-binding area that was pre-coated with capture antibodies. Thereafter, the enzyme-signal tracers for the immunoassay and the substrate solution were sequentially furnished using a horizontal path for the tracing of the immune complexes that were formed with CRP or PCT. The color signal that was produced from each assay was detected at a pre-determined time and quantified on a smartphone-based detector. Under the optimal conditions, the dynamic ranges for the analytes covered the respective clinical ranges, and the total coefficient of variation was between 8.6% and 13.3%. The hybrid biosensor further showed a high correlation (R2 > 0.95) with the reference systems for the target markers. PMID- 28646722 TI - Radiation therapy utilization and outcomes for older women with breast cancer: Impact of molecular subtype and tumor grade. AB - BACKGROUND: Radiation therapy (RT) utilization for elderly women with respect to human epidermal growth factor receptor 2 (HER2) receptor status has not been evaluated. Our purpose was to determine differences in RT utilization and breast cancer specific survival (BCSS) for elderly breast cancer patients with distinct molecular biomarkers. METHODS: The Surveillance, Epidemiology, and End Results database was queried for women >=70 years of age diagnosed with T1N0M0 breast cancer between 2010 and 2013 receiving breast conservation. Chi-squared analysis was performed to determine the difference in RT utilization between groups. Multivariable logistic regression analysis was performed to determine predictors for RT use. Kaplan-Meier curves were created and the log-rank test done to compare differences in breast cancer specific survival (BCSS) between groups. RESULTS: A total of 12,312 patients met the inclusion criteria. Receipt of RT for patients with distinct tumor biomarkers was as follows: 55.7% for patients with Estrogen Receptor (ER) +/HER2+; 57.1% for patients with ER+/HER2-; 65.6% for patients with ER-/HER2+; and 69.2% for ER-/HER2- patients (p < 0.001). Factors associated with RT use included ER-/HER2- status, 70-74 years of age, and high grade disease, while adjuvant RT was associated with improve BCSS in ER+/HER2- and ER-/HER2- patients. CONCLUSIONS: Patients 70-74 years old and those with ER /HER2- are more likely to receive adjuvant RT. Moreover, adjuvant RT is associated with improvements in BCSS in ER+/HER2- and ER-/HER2- patients. Given possible poor compliance with hormonal therapy, the omission of RT in ER + patients, without consideration of HER2 status, should be undertaken with care. PMID- 28646723 TI - Vacuum-assisted complete excision of solid intraductal/intracystic masses and complex cysts: Is follow-up necessary? AB - INTRODUCTION: Management of complex cysts and benign intraductal/intracystic masses is controversial. The aim of this study was to determine if the complete removal of the complex cyst lesions with ultrasound-guided vacuum-assisted excision (US-VAE) is sufficient for their safe management when the histological diagnosis obtained at biopsy is benign. SUBJECTS AND METHODS: This is a single institution retrospective study performed on patients who underwent breast biopsy between April 2007 and September 2013. Patients with complete removal of complex cyst lesion of a BIRADS 4 lesion by US-VAE that obtained a benign diagnosis were included. Size, morphology, histological diagnosis, and surgical or imaging follow-up of the lesions were analyzed. RESULTS: During the study period, 131 lesions met the inclusion criteria. Benign papilloma represented 32% (42/131) of the lesions; the remaining lesions had various benign diagnoses. Mean size of the solid mass or the cysts' thickest septum was 7 mm (range, 2-24). Mean imaging follow-up was 34.9 months (24-99 months) in 115 lesions. No recurrence or malignancy in the post-biopsy bed were observed during follow-up. Eleven lesions (8.4%) underwent surgery as follow-up: no cancer was found, but two lesions demonstrated atypia. CONCLUSIONS: Complex cyst lesion image completely excised with US-VAE and with a benign histology at biopsy might not require further imaging follow-up or surgery and a return to routine screening can be safely recommended. In a world where healthcare delivery and accessibility is important, elimination of unnecessary follow-ups is pertinent given its lower cost and lesser social impact. PMID- 28646724 TI - Zinc and calcium alter the relationship between mitochondrial respiration, ROS and membrane potential in rainbow trout (Oncorhynchus mykiss) liver mitochondria. AB - At excess levels, zinc (Zn) disrupts mitochondrial functional integrity and induces oxidative stress in aquatic organisms. Although much is known about the modulation of Zn toxicity by calcium (Ca) in fish, their interactions at the mitochondrial level have scarcely been investigated. Here we assessed the individual and combined effects of Zn and Ca on the relationship between mitochondrial respiration, ROS and membrane potential (DeltaPsimt) in rainbow trout liver mitochondria. We tested if cation uptake through the mitochondrial calcium uniporter (MCU) is a prerequisite for Zn- and/or Ca-induced alteration of mitochondrial function. Furthermore, using our recently developed real-time multi parametric method, we investigated the changes in respiration, DeltaPsimt, and reactive oxygen species (ROS, as hydrogen peroxide (H2O2)) release associated with Ca-induced mitochondrial depolarization imposed by transient and permanent openings of the mitochondrial permeability transition pore (mPTP). We found that independent of the MCU, Zn precipitated an immediate depolarization of the DeltaPsimt that was associated with relatively slow enhancement of H2O2 release, inhibition of respiration and reversal of the positive correlation between ROS and DeltaPsimt. In contrast, an equitoxic dose of Ca caused transient depolarization, and stimulation of both respiration and H2O2 release, effects that were completely abolished when the MCU was blocked. Contrary to our expectation that mitochondrial transition ROS Spike (mTRS) would be sensitive to both Zn and Ca, only Ca suppressed it. Moreover, Zn and Ca in combination immediately depolarized the DeltaPsimt, and caused transient and sustained stimulation of respiration and H2O2 release, respectively. Lastly, we uncovered and characterized an mPTP-independent Ca-induced depolarization spike that was associated with exposure to moderately elevated levels of Ca. Importantly, we showed the stimulation of ROS release associated with highly elevated but not unrealistic Ca loads was not the cause but a result of mPTP opening in the high conductance mode. PMID- 28646725 TI - Eculizumab decreases the procoagulant activity of extracellular vesicles in paroxysmal nocturnal hemoglobinuria: A pilot prospective longitudinal clinical study. AB - INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by the susceptibility of blood cells to attack by the complement system, inducing extracellular vesicle (EV) production. Thromboembolism is the leading cause of death in this condition. Eculizumab, a humanized monoclonal antibody which inhibits the C5 protein of the complement, reduces the thrombotic risk in PNH. MATERIALS AND METHOD: We conducted a pilot, prospective, open-label, longitudinal clinical study with six PNH patients treated with eculizumab. The aim was to measure, by flow cytometry, the EVs' production in the patients' platelet-free plasma (PFP) before and during the treatment. We also assessed the procoagulant activity in PFP using STA(r)-Procoag-PPL and thrombin generation assays (TGA). A high-sensitive version of TGA was also used to study the procoagulant profile induced by the EVs using EVs pelleted from PFP. RESULTS: We observed a decrease in platelet EV count with eculizumab treatment (p<0.05). STA(r)-Procoag-PPL assay showed a decrease of the procoagulant profile induced by procoagulant phospholipids (PL) during treatment. These results were not confirmed by TGA on PFP, due to a lack of sensitivity. Thus, we used a high sensitive version of TGA that enabled us to observe variation in the procoagulant profile induced by the EVs with eculizumab (p<0.05). CONCLUSIONS: Eculizumab has an impact on the extent of EV production and on the procoagulant profile induced by the procoagulant PL and the EVs. One factor in the antithrombotic action of eculizumab is its ability to decrease EV production and the procoagulant profile induced by PL and EVs. PMID- 28646726 TI - Trends in admission rates and in-hospital stay for venous thromboembolism. AB - BACKGROUND: Acute venous thromboembolism leads to significant morbidity and mortality. Advances in pharmacotherapy facilitate outpatient care in low-risk acute venous thromboembolism. The proportion of hospitalized acute venous thromboembolism cases and the average length of stay are not known. We sought to identify predictors of hospitalization, changes in hospitalization rates and length of stay of acute venous thromboembolism over a decade in Alberta, Canada. METHODS: Using linked administrative health databases, we identified adult patients diagnosed primarily with acute venous thromboembolism between April 2002 and March 2012. We measured trends using Poisson regression, adjusted length of stay using analysis of covariance. We identified predictors of hospitalization using multivariate logistic regression. RESULTS: 8198 out of 31,656 acute venous thromboembolism cases were hospitalized. The overall venous thromboembolism admission rates ranged between 23.7% and 27.8% with no evident temporal trend (P=0.10). The average admission rate was 51.9% for pulmonary embolism and 16.1% for deep vein thrombosis. The mean length of stay for deep vein thrombosis and pulmonary embolism remained unchanged with an adjusted mean for venous thromboembolism of 6.9+/-1.0days. Higher Charlson index, older age, male gender, pulmonary embolism at presentation and multiple comorbidities were associated with hospitalization. Hospitalization was associated with 30-day mortality (odds ratio:2.8, 95% CI: 2.2-3.5) whereas the length of stay was not (odds ratio:1.0, 95% CI: 0.99-1.0). CONCLUSION: Hospitalization rates and mean length of stay for acute venous thromboembolism did not change significantly between 2002 and 2012. Advances in pharmacotherapy have not yet reduced hospitalization rates or length of stay for venous thromboembolism. PMID- 28646727 TI - Pulmonary embolism prognostic factors and length of hospital stay: A cohort study. AB - INTRODUCTION: Patients with pulmonary embolism (PE) are commonly admitted to hospital for their initial treatment. We aimed to assess the association of length of hospital stay with commonly available clinical variables and their combinations. METHODS: A retrospective multicenter cohort study was conducted on consecutive PE patients admitted to eight Italian centers. Logistic regression analysis was performed to evaluate the association between the length of hospital stay and the Pulmonary Embolism Severity Index (PESI) parameters, National Early Warning Score (NEWS) and other possible determinants. RESULTS: We enrolled 391 patients, with a median hospital stay of 10days (IQR 7-14). Among PESI parameters, only oxygen saturation <90% was significantly associated with length of hospital stay at univariable analysis (OR 1.99; 95% CI 1.3-3.2). At multivariable analysis, NEWS >=5 was associated with prolonged hospitalization (OR 3.14; 95% CI 1.2-8.3). A difference of median hospital stay was found between simplified PESI high and low risk groups (10 and 9days, respectively, p=0.027). DISCUSSION: The median duration of hospital stay was generally long and not influenced by single parameters of PESI or common prognostic factors. The difference of one day between the low- and high-risk groups according to simplified PESI was not clinically significant. PMID- 28646728 TI - Evaluation of the impact of vasa previa on feto-placental hormonal synthesis and fetal growth. AB - INTRODUCTION: A vasa previa (VP) refers to aberrant chorionic vessels which can either connect the chorionic plate to a velamentous cord (type I) or a succenturiate or accessory lobe to the main placental mass (type II). METHODS: We performed retrospective cohort study of 32 singleton pregnancies diagnosed with VP. The levels of maternal serum alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and unconjugated estriol (uE3) were measured at 15-18 weeks as part of the triple test screening for Trisomy 21. The data were subdivided according to the type of VP and compared with those of a control group with central cord insertion and no succenturiate or accessory placental lobe. RESULTS: Twenty one (65.6%) parturient women presented with VP type I and 11 (34.4%) with VP type II. The mean birthweight and placental weight was significantly higher in pregnancies with VP type II than in pregnancies with VP with VP type I (3037.3+/ 400.9 gr vs 2493.5+/-491.6 gr; p=0.004 and 511.0+/-47.2 gr vs 367.1+/-64.3 gr; p<0.0001; respectively). The mean hCG level in VP type II was significantly (p<0.001) higher than those with type I (2.38MoM vs 1.17MoM) and compared to controls (2.38MoM vs 0.99MoM). CONCLUSIONS: There is no obvious impact on both placental and fetal growth in VP type II. By contrast, VP type I is associated with slower feto-placental growth secondary to impaired development and biological functions of the placenta during the first half of pregnancy. PMID- 28646729 TI - The structure of PTSD symptoms according to DSM-5 and IDC-11 proposal: A multi sample analysis. AB - Posttraumatic stress disorder (PTSD) symptoms structure is a subject of ongoing debate since its inclusion in DSM-III classification in 1980. Different research on PTSD symptoms structure proved the better fit of four-factor and five-factor models comparing to the one proposed by DSM-IV. With the publication of DSM-5 classification, which introduced significant changes to PTSD diagnosis, the question arises about the adequacy of the proposed criteria to the real structure of disorder symptoms. Recent analyses suggest that seven-factor hybrid model is the best reflection of symptoms structure proposed to date. At the same time, some researchers and ICD-11 classification postulate a simplification of PTSD diagnosis restricting it to only three core criteria and adding additional diagnostic unit of complex-PTSD. This research aimed at checking symptoms' structure according to well-known and supported four-, five-, six- and seven factor models based on DSM-5 symptoms and the conceptualization proposed by the ICD-11 as well as examining the relation between PTSD symptoms categories with borderline personality disorder. Four different trauma populations were examined with self-reported Posttraumatic Diagnostic Scale for DSM-5 (PDS-5) measure. The results suggest that six- and seven-factor hybrid model as well as three-factor ICD-11 concept fits the data better than other models. The core PTSD symptoms were less related to borderline personality disorder than other, broader, symptoms categories only in one sample. Combination of ICD-11 simplified PTSD diagnosis with the more complex approach (e.g. basing on a seven-factor model) may be an attractive proposal for both scientists and practitioners, however does not necessarily lower its comorbidity with borderline personality disorder. PMID- 28646730 TI - Behavioural addictions: Classification and consequences. PMID- 28646731 TI - The adaptive decision-making, risky decision, and decision-making style of Internet gaming disorder. AB - BACKGROUND: Persistent gaming, despite acknowledgment of its negative consequences, is a major criterion for individuals with Internet gaming disorder (IGD). This study evaluated the adaptive decision-making, risky decision, and decision-making style of individuals with IGD. METHODS: We recruited 87 individuals with IGD and 87 without IGD (matched controls). All participants underwent an interview based on the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) diagnostic criteria for IGD and completed an adaptive decision-making task; the Preference for Intuition and Deliberation Scale, Chen Internet Addiction Scale, and Barratt Impulsivity Scale were also assessed on the basis of the information from the diagnostic interviews. RESULTS: The results demonstrated that the participants in both groups tend to make more risky choices in advantage trials where their expected value (EV) was more favorable than those of the riskless choice. The tendency to make a risky choice in advantage trials was stronger among IGD group than that among controls. Participants of both groups made more risky choices in the loss domain, a risky option to loss more versus sure loss option, than they did in the gain domain, a risky option to gain more versus sure gain. Furthermore, the participants with IGD made more risky choices in the gain domain than did the controls. Participants with IGD showed higher and lower preferences for intuitive and deliberative decision-making styles, respectively, than controls and their preferences for intuition and deliberation were positively and negatively associated with IGD severity, respectively. CONCLUSIONS: These results suggested that individuals with IGD have elevated EV sensitivity for decision-making. However, they demonstrated risky preferences in the gain domain and preferred an intuitive rather than deliberative decision-making style. This might explain why they continue Internet gaming despite negative consequences. Thus, therapists should focus more on decision-making styles and promote deliberative thinking processes to mitigate the long-term negative consequences of IGD. PMID- 28646733 TI - Walls and laws: Structural barriers to forensic psychiatric research. PMID- 28646732 TI - Effects of stimulants and atomoxetine on emotional lability in adults: A systematic review and meta-analysis. AB - BACKGROUND: Emotional lability (EL) is an associated feature of attention deficit/hyperactivity disorder (ADHD) in adults, contributing to functional impairment. Yet the effect of pharmacological treatments for ADHD on EL symptoms is unknown. We conducted a systematic review and meta-analysis to examine the effects of stimulants and atomoxetine on symptoms of EL and compare these with the effects on core ADHD symptoms. METHODS: A systematic search was conducted on the databases Embase, PsychInfo, and Ovid Medline(r) and the clinicaltrials.gov website. We included randomised, double-blind, placebo-controlled trials of stimulants and atomoxetine in adults aged 18-60 years, with any mental health diagnosis characterised by emotional or mood instability, with at least one outcome measure of EL. All identified trials were on adults with ADHD. A random effects meta-analysis with standardised mean difference and 95% confidence intervals was used to investigate the effect size on EL and compare this to the effect on core ADHD symptoms. RESULTS: Of the 3,864 publications identified, nine trials met the inclusion criteria for the meta-analysis. Stimulants and atomoxetine led to large mean weighted effect-sizes for on ADHD symptoms (n=9, SMD=-0.8, 95% CI:-1.07 to -0.53). EL outcomes showed more moderate but definite effects (n=9, SMD=-0.41, 95% CI:-0.57 to -0.25). CONCLUSIONS: In this meta analysis, stimulants and atomoxetine were moderately effective for EL symptoms, while effect size on core ADHD symptoms was twice as large. Methodological issues may partially explain the difference in effect size. Reduced average effect size could also reflect heterogeneity of EL with ADHD pharmacotherapy responsive and non-responsive sub-types. Our findings indicate that EL may be less responsive than ADHD symptoms overall, perhaps indicating the need for adjunctive psychotherapy in some cases. To clarify these questions, our findings need replication in studies selecting subjects for high EL and targeting EL as the primary outcome. PMID- 28646734 TI - Investigating articulated heavy-vehicle crashes in Western Australia using a spatial approach. AB - BACKGROUND: Recent developments in Western Australia's economy including widespread traffic congestion as well as road safety issues are increasingly becoming prominent. Previous studies relied on traditional statistical methods to investigate patterns and characteristics of motor vehicle crashes. Although useful, statistical analysis alone is incapable of providing a spatial context and is therefore unable to associate existing crash characteristics with a spatial distribution. AIMS: To identify concentrations or "hotspots" of articulated heavy vehicle crashes in WA between the years 2001-2013, by using a spatial analysis approach. METHODS: Spatial modelling and spatio-temporal analytical methods such as Emerging Hotspots were used to identify emerging hotspots on specific roads in Western Australia using the Integrated Road Information System (IRIS). RESULTS: The results suggest that the majority of articulated heavy vehicles crashes occurred in the vicinity or within the Perth metropolitan area. Based on spatial-temporal trend analyses, our findings highlight some regions that are emerging as areas of interest. DISCUSSION: This study was one of the first attempts to adopt a spatial analysis approach in studying heavy-vehicle crashes in Western Australia. Applying spatial methodologies to road safety data has the potential of obtaining previously undiscovered insights, which can be extended further, and provide future avenues to research in this field. PMID- 28646735 TI - Hyperpolarized helium-3 magnetic resonance lung imaging of non-sedated infants and young children: a proof-of-concept study. AB - PURPOSE: To develop and evaluate a protocol for hyperpolarized helium-3 (HHe) ventilation magnetic resonance imaging (MRI) of the lungs of non-sedated infants and children. MATERIALS AND METHODS: HHe ventilation MRI was performed on seven children <=4years old. Contiguous 2D-spiral helium-3 images were acquired sequentially with a scan time of <=0.2s/slice. RESULTS: Motion-artifact-free, high signal-to-noise ratio (SNR) images of lung ventilation were obtained. Gas was homogeneously distributed in healthy individuals; focal ventilation defects were found in patients with respiratory diseases. CONCLUSION: HHe ventilation MRI can aid assessment of pediatric lung disease even at a young age. PMID- 28646736 TI - Cell damage caused by ultraviolet B radiation in the desert cyanobacterium Phormidium tenue and its recovery process. AB - Phormidium tenue, a cyanobacterium that grows in the topsoil of biological soil crusts (BSCs), has the highest recovery rate among desert crust cyanobacteria after exposure to ultraviolet B (UV-B) radiation. However, the mechanism underlying its recovery process is unclear. To address this issue, we measured chlorophyll a fluorescence, generation of reactive oxygen species (ROS), lipid peroxidation, and repair of DNA breakage in P. tenue following exposure to UV-B. We found that UV-B radiation at all doses tested reduced photosynthesis and induced cell damage in P. tenue. However, P. tenue responded to UV-B radiation by rapidly reducing photosynthetic activity, which protects the cell by leaking less ROS. Antioxidant enzymes, DNA damage repair systems, and UV absorbing pigments were then induced to mitigate the damage caused by UV-B radiation. The addition of exogenous antioxidant chemicals ascorbate and N-acetylcysteine also mitigated the harmful effects caused by UV-B radiation and enhanced the recovery process. These chemicals could aid in the resistance of P. tenue to the exposure of intense UV-B radiation in desertified areas when inoculated onto the sand surface to form artificial algal crusts. PMID- 28646737 TI - Pollution characteristics and source identification of trace metals in riparian soils of Miyun Reservoir, China. AB - The South-to-North Water Diversion Project, one of China's largest water diversion projects, has aroused widespread concerns about its potential ecological impacts, especially the potential release of trace metals from shoreline soils into Miyun Reservoir (MYR). Here, riparian soil samples from three elevations and four types of land use were collected. Soil particle size distributions, contents and chemical fractionations of trace metals and lead (Pb) isotopic compositions were analyzed. Results showed that soil texture was basically similar in four types of land use, being mainly composed of sand, with minor portions of clay and silt, while recreational land contained more abundant chromium (Cr), copper (Cu), zinc (Zn) and cadmium (Cd), suggesting a possible anthropogenic source for this soil pollution. The potential ecological risk assessment revealed considerable contamination of recreational land, with Cd being the predominant contaminant. Chemical fractionations showed that Cu, arsenic (As), Pb and Cd had potential release risks. Additionally, the 206Pb/207Pb and 208Pb/207Pb values of soils were similar to those of coal combustion. By combining principal component analysis (PCA) with Pb isotopic results, coal combustion was identified as the major anthropogenic source of Zn, Cr, Cu, Cd and Pb. Moreover, isotope ratios of Pb fell in the scope of aerosols, indicating that atmospheric deposition may be the primary input pathway of anthropogenic Zn, Cr, Cu, Cd and Pb. Therefore, controlling coal combustion should be a priority to reduce effectively the introduction of additional Zn, Cu, Cd, and Pb to the area in the future. PMID- 28646738 TI - The effect of soil properties on the toxicity and bioaccumulation of Ag nanoparticles and Ag ions in Enchytraeus crypticus. AB - Standard natural Lufa soils (2.2, 2.3 and 5M) with different organic carbon contents (0.67-1.61%) and pHCaCl2 (5.5-7.3) were spiked with ionic Ag (AgNO3) and polyvinyl pyrrolidone (AgNP-PVP) and citrate (AgNP-Cit) coated Ag nanoparticles (NPs). Enchytraeus crypticus were exposed for 21 days to assess effects on survival and reproduction. Soil, pore water and animals were analyzed for Ag. AgNP-Cit had a strong increasing effect on soil pH, leading to high enchytraeid mortality at concentrations higher than 60-100mg Ag/kg dry soil which made it impossible to determine the influence of soil properties on its toxicity. LC50s were lower for AgNO3 than for AgNP-PVP (92-112 and 335-425mg Ag/kg dry soil, respectively) and were not affected by soil properties. AgNO3 and AgNP-PVP had comparable reproductive toxicity with EC50s of 26.9-75.2 and 28.2-92.3mg Ag/kg dry soil, respectively; toxicity linearly increased with decreasing organic carbon content of the soils but did not show a clear effect of soil pH. Ag uptake in the enchytraeids was higher at higher organic carbon content, but could not explain differences in toxicity between soils. This study indicates that the bioavailability of both ionic and nanoparticulate Ag is mainly affected by soil organic carbon, with little effect of soil pH. PMID- 28646739 TI - Contribution of pharmaceuticals and personal care products (PPCPs) to whole toxicity of water samples collected in effluent-dominated urban streams. AB - Water samples were collected from effluent-dominated urban streams in Tokushima, Kyoto, and Saitama in Japan to roughly determine the contribution of pharmaceuticals and personal care products (PPCPs) and surfactants to whole toxicity of the water. Approximately 100 PPCPs including anionic surfactants such as linear alkylbenzene sulfonate (LAS), were chemically analyzed. Using 14 water samples, chronic or sub-chronic toxicity tests were conducted on three aquatic species, the green alga Raphidocelis subcapitata, the cladoceran Ceriodaphnia dubia, and the zebrafish Danio rerio. Bioassays for the selected individual PPCPs were conducted using the three species. Assuming the concentration addition (CA) model, the contribution of each PPCP to the whole toxicity of the riverwater was estimated based on toxicity unit (TU). The contribution of PPCPs, which primarily consists of a few antibiotic agents such as triclosan and clarithromycin, ranged from 0.9% to 69% of the whole toxicity of the water samples for algae, whereas the selected LAS congeners accounted for at most 5.3%. In contrast, the contribution of LAS ranged from 0.067% to 86% and from 0.021% to 27% of the whole toxicity for cladoceran and zebrafish, respectively, whereas that of PPCPs for these species was at most 2.1% at all sampling points. Our results suggest a limited contribution of PPCPs except for antimicrobial agents and the possible substantial contribution of LAS to toxicity in cladocerans and zebrafish. PMID- 28646740 TI - Epigallocatechin-3-gallate promotes apoptosis in human breast cancer T47D cells through down-regulation of PI3K/AKT and Telomerase. AB - BACKGROUND: Green tea has antioxidant, anti-tumor and anti-bacterial properties. Epigallocatechin-3-gallate (EGCG) in green tea is highly active as a cancer chemopreventive agent. In this study, we designed a series of experiments to examine the effects of EGCG on proliferation and apoptosis of estrogen receptor alpha-positive breast cancer (T47D) cells. METHODS: Cells were treated with EGCG (0-80MUM) and tamoxifen (0-20MUM), as the positive control, up to 72h. Cell viability was determined by MTT assay. Apoptosis investigated by real time PCR of apoptosis and survival (Bax, Bcl-2, p21, p53, PTEN, PI3K, AKT, caspase3 and caspase9 and hTERT) genes and by western blot of Bax/Bcl-2 proteins expressions. RESULTS: The results showed that EGCG decreased cell viability as concentration- and time-dependently. IC50 values were 14.17MUM for T47D and 193.10MUM for HFF cells, as compared with 3.39MUM and 32.75MUM for tamoxifen after 72h treatment, respectively. Also, EGCG (80MUM) significantly increased the genes of PTEN, CASP3, CASP9 and decreased AKT approximately equal to tamoxifen. In gene expression, EGCG (80MUM) significantly increased Bax/Bcl-2 ratio to 8-fold vise 15-fold in tamoxifen (20MUM)-treated T47D cells during 72h. In protein expression of Bax/Bcl-2, EGCG significantly increased 6-fold while this ratio augmented 10 fold in tamoxifen group. EGCG significantly decreased 0.8, 0.4 and 0.3 gene expression of hTERT in 24, 48 and 72h, respectively. CONCLUSIONS: This study suggests that EGCG may be a useful adjuvant therapeutic agent for the treatment of breast cancer. PMID- 28646741 TI - In vitro and in vivo antihydatid activity of a nano emulsion of Zataria multiflora essential oil. AB - In in vitro process of this study, protoscoleces of the hydatid cysts were exposed to two concentrations of nano emulsion (NE) of Zataria multiflora essential oil (ZMEO) (1 and 2mg/mL) for 10 and 20min. Viability of protoscoleces was confirmed using 0.1% eosin staining. For in vivo studies, sixteen laboratory mice were infected intraperitoneally by 1500 live protoscoleces. Five months after infection, the infected mice were divided into treatment and control groups. The mice of treatment group received the NE of ZMEO (20mg/kg) orally via their drinking water while the mice of control group received no treatment. Two months after the start of treatment, all of the mice were necropsied and the hydatid cysts were collected. Subsequently, the numbers, sizes and weights of the collected cysts were compared between the mice of two groups. The results of in vitro scolicidal assays showed that the scolicidal power of NE of a ZMEO at concentration of 1mg/mL was 88.01%, and 100% after 10 and 20min respectively. NE of ZMEO showed 100% scolicidal power at a concentration of 2mg/mL after 10min (comparing to 4.46% for the control group). The results of in vivo studies revealed that the size of the largest cysts as well as the total number of the cysts were significantly lower in the mice treated with NE of ZMEO (P<0.05). In conclusion, NE of ZMEO may be considered as a natural scolicidal agent and a potential therapeutic tool for treatment of hydatid disease. PMID- 28646742 TI - Image analysis for TSH mRNA in situ hybridization in pituitary glands from rats with thyroid follicular cell hypertrophy after treatment with three different test compounds. AB - The goal of this in situ hybridization and image analysis technique is to study the effects of new pharmacological/chemical entities on the thyroid and pituitary gland in rats, reveal the pathogenesis of thyroid follicular cell hypertrophy and to retrospectively exclude the risk of thyroid tumor development in humans. In the present study, we describe the increase of thyroid-stimulating hormone- (TSH ) beta subunit mRNA in the pars distalis of the pituitary gland and the quantitative measurement of TSH mRNA positive cells from rats of three 4-week toxicity studies treated with three different test compounds inducing thyroid follicular cell and hepatocellular hypertrophy in rats. Compared to immunohistochemistry (IHC), in situ hybridization (ISH) for TSH was found to be more sensitive. With this technique we are able to exclude a direct effect of the test compound on the thyroid gland by showing the activation of thyrotrope cells from the pituitary gland and therefore this technique retrospectively enables us to exclude a possible risk for humans at an early stage of drug development. Also in case blood serum samples for evaluation of TSH are not available anymore or hepatocellular hypertrophy is not present (close metabolic relationship between thyroid gland and liver in rodents), the described method allows retrospective investigations on thyroid follicular cell hypertrophy or hyperplasia. This can be of high relevance in human safety assessment for certain drugs in order to exclude a primary effect on the thyroid gland especially when it comes to thyroid neoplasia in rodents as previously described. PMID- 28646743 TI - Analysis of ictal magnetoencephalography using gradient magnetic-field topography (GMFT) in patients with neocortical epilepsy. AB - OBJECTIVE: We aimed to validate the usefulness of gradient magnetic-field topography (GMFT) for analysis of ictal magnetoencephalography (MEG) in patients with neocortical epilepsy. METHODS: We identified 13 patients presenting with an ictal event during preoperative MEG. We applied equivalent current dipole (ECD) estimation and GMFT to detect and localize the ictal MEG onset, and compared these methods with the ictal onset zone (IOZ) derived from chronic intracranial electroencephalography. The surgical resection areas and outcomes were also evaluated. RESULTS: GMFT detected and localized the ictal MEG onset in all patients, whereas ECD estimation showed localized ECDs in only 2. The delineation of GMFT was concordant with the IOZ at the gyral-unit level in 10 of 12 patients (83.3%). The detectability and precision of delineation of ictal MEG activity by GMFT were significantly superior to those of ECD (p<0.05 and p<0.01, respectively). Complete resection of the IOZ in the concordant group provided seizure freedom in 3 patients, whereas seizures remained in 9 patients who had incomplete resections. CONCLUSIONS: Because of its higher spatial resolution, GMFT of ictal MEG is superior to conventional ECD estimation in patients with neocortical epilepsy. SIGNIFICANCE: Ictal MEG study is a useful tool to estimate the seizure onset in patients with neocortical epilepsy. PMID- 28646745 TI - Automatic postural responses are generated according to feet orientation and perturbation magnitude. AB - This investigation aimed to assess the effect of feet orientation angle in upright stance on automatic postural responses (APRs) to mechanical perturbations of different magnitudes. Perturbation was produced by releasing suddenly a load attached to the participant's trunk, leading to forward body sway. We evaluated APRs to loads corresponding to 5% (low) and 10% (high) of the participant's body weight, comparing the following feet orientations: parallel, preferred (M=10.46 degrees ), 15 degrees and 30 degrees for each foot regarding the body midline. Results showed that APRs were sensitive to perturbation magnitude, with the high load leading to increased amplitudes of center of pressure displacement and joints rotation, in addition to stronger and earlier muscular responses. Feet orientation at 30 degrees led to a greater amplitude of center of pressure displacement than the other feet orientations. The low perturbation magnitude led to similar responses both at the hip and ankle across feet orientations, whereas the high load induced increased rotation amplitudes in both joints for feet orientation at 30 degrees . Our results suggest that APRs are generated by the nervous system taking into consideration the biomechanical constraints in the response production. Relevant for standardization of feet placement in evaluations of balance recovery, our results indicated that a moderate range of outward feet orientation angles in stance lead to comparable APRs, while increased outward feet orientation angles lead to distinct postural responses. PMID- 28646744 TI - Systematic biobanking, novel imaging techniques, and advanced molecular analysis for precise tumor diagnosis and therapy: The Polish MOBIT project. AB - Personalized and precision medicine is gaining recognition due to the limitations by standard diagnosis and treatment; many areas of medicine, from cancer to psychiatry, are moving towards tailored and individualized treatment for patients based on their clinical characteristics and genetic signatures as well as novel imaging techniques. Advances in whole genome sequencing have led to identification of genes involved in a variety of diseases. Moreover, biomarkers indicating severity of disease or susceptibility to treatment are increasingly being characterized. The continued identification of new genes and biomarkers specific to disease subtypes and individual patients is essential and inevitable for translation into personalized medicine, in estimating both, disease risk and response to therapy. Taking into consideration the mostly unsolved necessity of tailored therapy in oncology the innovative project MOBIT (molecular biomarkers for individualized therapy) was designed. The aims of the project are: (i) establishing integrative management of precise tumor diagnosis and therapy including systematic biobanking, novel imaging techniques, and advanced molecular analysis by collecting comprehensive tumor tissues, liquid biopsies (whole blood, serum, plasma), and urine specimens (supernatant; sediment) as well as (ii) developing personalized lung cancer diagnostics based on tumor heterogeneity and integrated genomics, transcriptomics, metabolomics, and radiomics PET/MRI analysis. It will consist of 5 work packages. In this paper the rationale of the Polish MOBIT project as well as its design is presented. (iii) The project is to draw interest in and to invite national and international, private and public, preclinical and clinical initiatives to establish individualized and precise procedures for integrating novel targeted therapies and advanced imaging techniques. PMID- 28646746 TI - Variable spontaneous mutation rate in clinical strains of multidrug-resistant Acinetobacter baumannii and differentially expressed proteins in a hypermutator strain. AB - BACKGROUND: The emergence of multidrug resistant Acinetobacter baumannii within hospitals poses a significant threat to patients. The inherent rate of mutation of these strains has not been described nor has the mechanism by which drug resistance arises. METHODS: Here, we determined the spontaneous mutation rates in 93 clinical strains of A. baumannii using fluctuation analysis. To rule out the clonal relatedness of hypermutator strains, pulsed-field gel electrophoresis (PFGE) was conducted. Using a combination of two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry, the differentially expressed proteins of a hypermutator and a reference strain were identified. RESULTS: The spontaneous mutation rate of multi-drug resistant A. baumannii strains varied broadly from 0 to 2.1*10-6 mutation per cell division. The mutation rate in three multidrug resistant A. baumannii (MDR-AB) strains was found to be 1.63*10-6 (95% confidence interval (CI): 1*10-6-2*10-6), 2.1*10-6 (95% CI: 2*10-6 - 3*10-6), and 1.78*10-8 (95% CI: 9.29*10-9 2.95*10-8), consistent with a hypermutator phenotype. This rate is approximately 1000-fold higher than the average mutation rate in other MDR-ABs. PFGE of the three hypermutator strains indicate that they belong to distinct clones. Proteomic analysis of one hypermutator strain revealed 31 differentially expressed proteins including three with sizes of 51.2, 20.9, and 11.9kDa, which corresponded to a serine protease, a polyisoprenoid-binding protein, and the peptidoglycan binding protein, LysM. The serine protease was expressed only in the hypermutator strain, whereas the polyisoprenoid-binding protein and the peptidoglycan binding protein LysM were down-regulated 1.6 and 3 fold, respectively, in the hypermutators strain. CONCLUSION: Hypermutator A. baumannii strains occur with a low, but appreciable frequency among clinical multi-drug resistant isolates. The presence of hypermutator clinical isolates raises concerns that they may contribute to the failure of antibiotic treatment in infected patients and confound the interpretation of in vitro antibiotic susceptibility testing. The differentially expressed proteins involved in biofilm suppression and oxidative stress response, may represent adaptations derived from the hypermutator phenotype, a hypothesis that needs further testing. PMID- 28646747 TI - Nickel toxicity to cardinal tetra (Paracheirodon axelrodi) differs seasonally and among the black, white and clear river waters of the Amazon basin. AB - This study investigated the acute toxicity of nickel (Ni) to cardinal tetra (Paracheirodon axelrodi), within the three main water types of the Amazon basin: black (Rio Negro), white (Rio Solimoes) and clear (Rio Tapajos) during the wet and dry season at pH 7 (representative of white and clear rivers) and pH 4 (representative of black waters). The influence of dissolved organic carbon (DOC) quality on Ni toxicity within the three waters was also explored via the use of DOC isolates. Differences in water chemistry, DOC quality and ion concentrations were shown between waters and between seasons. Toxicity of Ni was shown to vary between river waters, seasons, and pHs. Ni was significantly less toxic during the dry season at pH 4 in all three river waters; for example, black water during the wet season had an LC50 of 9.72 mg Ni/L compared to 41.5 mg Ni/L during the dry season. At pH 7, contrasting effects in toxicity between seasons were shown between black and clear waters (black: wet = 28.9 mg/L, dry = 17.3 mg/L; clear: wet = 13.8 mg/L, dry = 24.1 mg/L). There were no significant differences in Ni toxicity for white waters at pH 7 (white: wet = 22.2 mg/L, dry = 21.8). Overall, Ni was shown to be more toxic at pH 7 than at pH 4 except in black water during the wet season. Toxicity of Ni at pH 4 was positively related to DOC concentration and amount of humic-like and fulvic-like DOC and negatively related to fluorescence index. Therefore, at pH 4, Ni is more toxic in waters containing more allochthonous DOC, consisting of higher amounts of humic-like and fulvic like components. LC50 values for the different DOC concentrates at the same DOC concentration of 4.5 mg/L (black: 26.8 mg/L; white: 73.3 mg/L; clear: 49.2) support the river water findings at pH 4 (Ni more toxic in presence of black DOC) indicating that DOC quality alone can influence Ni toxicity at this pH. PMID- 28646748 TI - The influence of iron oxide nanoparticles upon the adsorption of organic matter on magnetic powdered activated carbon. AB - Combining powdered activated carbon (PAC) with magnetic iron oxides has been proposed in the past to produce adsorbents for natural organic matter (NOM) removal that can be easily separated using a magnetic field. However, the trade off between the iron oxides' benefits and the reduced carbon content, porosity, and surface area has not yet been investigated systematically. We produced 3 magnetic powdered activated carbons (MPAC) with mass fractions of 10%, 38% and 54% maghemite nanoparticles and compared them to bare PAC and pure nanoparticles with respect to NOM adsorption kinetics and isotherms. While adsorption kinetics were not influenced by the presence of the iron oxide nanoparticles (IONP), as shown by calculated diffusion coefficients from the homogeneous surface diffusion model, nanoparticles reduced the adsorption capacity of NOM due to their lower adsorption capacity. Although the nanoparticles added mesoporosity to the composite materials they blocked intrinsic PAC mesopores at mass fractions >38% as measured by N2-adsorption isotherms. Below this mass fraction, the adsorption capacity was mainly dependent on the carbon content in MPAC and mesopore blocking was negligible. If NOM adsorption with MPAC is desired, a highly mesoporous PAC and a low IONP mass fraction should be chosen during MPAC synthesis. PMID- 28646749 TI - Mutually facilitated co-transport of two different viruses through reactive porous media. AB - In this study, we quantified transport and retention behaviors of a human pathogenic virus (Adenovirus 41, abbreviated as Ad-41) and a model bacteriophage (phiX174) through metal oxide-removed and goethite-coated sand under saturated flow conditions. Two sets of bench scale column experiments were conducted: transport of each type of viruses alone and co-transport of both viruses. All experiments were conducted at pH 7.5 using 2 mM artificial ground water (AGW) buffer as background solution. Experimental results revealed that goethite-coated sand (i.e., reactive sand) retained much more viruses relative to metal oxide removed sand (i.e., non-reactive sand), with the difference more pronounced for phiX174 (effluent concentration decreased by 92.1%) than for Ad-41 (effluent concentration decreased by 59.7%). Interestingly, lower retention of both viruses on goethite-coated sand was observed when they co-existed in the influent. The mutual promotion to the transport of the two viruses may be attributed to attachment site competition and steric hindrance effect (illustrated in the graphical abstract). Mass recovery results revealed that phiX174 was largely reversibly attached, whereas Ad-41 was mostly irreversibly bound or inactivated. Force measurements using atomic force microscopy (AFM) demonstrated that phiX174 had doubled affinity to goethite-coated sand compared with Ad-41, consistent with the transport behavior of each type of viruses when they existed alone. As expected, the extended DLVO theory cannot accurately estimate interfacial energy profiles for viruses and reactive sand that have heterogeneous surface properties (i.e., roughness and charge heterogeneity). The results of this study clearly demonstrate that caution must be taken when applying laboratory results, which are generally obtained from experiments employing a single virus species, to predict the mobility and environmental risks in natural systems where multiple agents are present. PMID- 28646750 TI - Phonological and orthographic coding in deaf skilled readers. AB - Written language is very important in daily life. However, most deaf people do not achieve good reading levels compared to their hearing peers. Previous research has mainly focused on their difficulties when reading in a language with an opaque orthography such as English. In the present study, we investigated visual word recognition of deaf adult skilled readers while reading in Spanish, a language with a transparent orthography, for which obligatory phonological mediation has been claimed. Experiment 1 showed a pseudohomophone inhibitory effect in hearing but not in deaf people. Experiment 2 showed similar orthographic sensitivity, as measured by the transposed-letter effect, for both groups. These results suggest that deaf skilled readers do not rely on phonological mediation, while maintaining the same level of orthographic sensitivity as hearing readers, thus suggesting that the use of phonological coding is not required to access the lexicon and meaning in a language with a transparent orthography. PMID- 28646751 TI - An attentional drift diffusion model over binary-attribute choice. AB - In order to make good decisions, individuals need to identify and properly integrate information about various attributes associated with a choice. Since choices are often complex and made rapidly, they are typically affected by contextual variables that are thought to influence how much attention is paid to different attributes. I propose a modification of the attentional drift-diffusion model, the binary-attribute attentional drift diffusion model (baDDM), which describes the choice process over simple binary-attribute choices and how it is affected by fluctuations in visual attention. Using an eye-tracking experiment, I find the baDDM makes accurate quantitative predictions about several key variables including choices, reaction times, and how these variables are correlated with attention to two attributes in an accept-reject decision. Furthermore, I estimate an attribute-based fixation bias that suggests attention to an attribute increases its subjective weight by 5%, while the unattended attribute's weight is decreased by 10%. PMID- 28646752 TI - An image-processing methodology for extracting bloodstain pattern features. AB - There is a growing trend in forensic science to develop methods to make forensic pattern comparison tasks more objective. This has generally involved the application of suitable image-processing methods to provide numerical data for identification or comparison. This paper outlines a unique image-processing methodology that can be utilised by analysts to generate reliable pattern data that will assist them in forming objective conclusions about a pattern. A range of features were defined and extracted from a laboratory-generated impact spatter pattern. These features were based in part on bloodstain properties commonly used in the analysis of spatter bloodstain patterns. The values of these features were consistent with properties reported qualitatively for such patterns. The image processing method developed shows considerable promise as a way to establish measurable discriminating pattern criteria that are lacking in current bloodstain pattern taxonomies. PMID- 28646753 TI - Mechanical properties and molecular structure analysis of subsurface dentin after Er:YAG laser irradiation. AB - : The purpose of this study was to evaluate the chemical and mechanical modifications in subsurface dentin layer after Er: YAG (Erbium-Yttrium Aluminium Garnet) laser irradiation, as the guidance of new dental restorative materials specific for laser irradiated dentin. MATERIALS AND METHODS: Dentin disks obtained from extracted human molars were prepared and exposed to a single pulse Er:YAG laser irradiation at 80mJ/pulse. After laser irradiation the mechanical and chemical characteristics of intertubular dentin in subsurface layer were studied using nanoindentation tester and micro-Raman spectromy (MU-RS). The dentin 5-50um depth beneath the lased surface was determined as testing area. Two way analysis of variance (ANOVA) were used to compare the mechanical values between lased and untreated subsurface dentin (P = 0.05). RESULTS: A laser affected subsurface dentin layer after Er:YAG laser treatment is present. The laser irradiation is considered to decrease the mechanical properties in the superficial subsurface layer (<15um deep). There was no significant difference in nanohardness and Young's modulus between lased subsurface dentin and untreated dentin (p > 0.05) under the depth of 15um. However, the dentin at 5um and 10um depth beneath the lased surface exhibited significantly lower (~ 47.8% and ~ 33.6% respectively) hardness (p < 0.05). Er:YAG laser irradiation affected both mineral and organic components in subsurface dentin layer, a higher degree of crystallinity and reduced organic compounds occurred in the lased subsurface dentin. CONCLUSION: Under the tested laser parameters, Er:YAG laser irradiation causes lower mechanical values and reduction of organic components in subsurface dentin, which has deleterious effects on resin adhesion to this area. PMID- 28646754 TI - Free energy analysis of cell spreading. AB - In this study we present a steady-state adaptation of the thermodynamically motivated stress fiber (SF) model of Vigliotti et al. (2015). We implement this steady-state formulation in a non-local finite element setting where we also consider global conservation of the total number of cytoskeletal proteins within the cell, global conservation of the number of binding integrins on the cell membrane, and adhesion limiting ligand density on the substrate surface. We present a number of simulations of cell spreading in which we consider a limited subset of the possible deformed spread-states assumed by the cell in order to examine the hypothesis that free energy minimization drives the process of cell spreading. Simulations suggest that cell spreading can be viewed as a competition between (i) decreasing cytoskeletal free energy due to strain induced assembly of cytoskeletal proteins into contractile SFs, and (ii) increasing elastic free energy due to stretching of the mechanically passive components of the cell. The computed minimum free energy spread area is shown to be lower for a cell on a compliant substrate than on a rigid substrate. Furthermore, a low substrate ligand density is found to limit cell spreading. The predicted dependence of cell spread area on substrate stiffness and ligand density is in agreement with the experiments of Engler et al. (2003). We also simulate the experiments of Thery et al. (2006), whereby initially circular cells deform and adhere to "V-shaped" and "Y-shaped" ligand patches. Analysis of a number of different spread states reveals that deformed configurations with the lowest free energy exhibit a SF distribution that corresponds to experimental observations, i.e. a high concentration of highly aligned SFs occurs along free edges, with lower SF concentrations in the interior of the cell. In summary, the results of this study suggest that cell spreading is driven by free energy minimization based on a competition between decreasing cytoskeletal free energy and increasing passive elastic free energy. PMID- 28646755 TI - Bio-fabrication of catalytic platinum nanoparticles and their in vitro efficacy against lungs cancer cells line (A549). AB - Platinum based drugs are considered as effective agents against various types of carcinoma; however, the severe toxicity associated with the chemically prepared platinum complexes limit their practical applications. Similarly, water pollution caused by various organic moieties is another serious health problem worldwide. Hence, an intense need exists to develop new, effective and biocompatible materials with catalytic and biomedical applications. In the present contribution, we prepared platinum nanoparticles (PtNPs) by a green route using phytochemicals as a source of reducing and stabilizing agents. Well dispersed and crystalline PtNPs of spherical shapes were prepared and characterized. The bio fabricated PtNPs were used as catalyst and anticancer agents. Catalytic performance of the PtNPs showed that 84% of the methylene blue can be reduced in 32min under visible light irradiation (K=0.078min-1). Similarly the catalytic conversion of 4-nitrophenol to 4-aminophenol was achieved in <20min (K=0.124min 1). The in vitro anticancer study revealed that biogenic PtNPs are the efficient nano-agents possessing strong anticancer activity against the lungs cancer cells line (A549). Interestingly, the as prepared PtNPs were well tolerated by normal human cells, and therefore, could be effective and biocompatible agents in the treatment of different cancer cells. PMID- 28646756 TI - Protein functionalization of ZnO nanostructure exhibits selective and enhanced toxicity to breast cancer cells through oxidative stress-based cell death mechanism. AB - Zinc oxide nanostructure (ZnONS) was chemically synthesized and functionalized (FZnONSBLA) with a small protein bovine alpha-lactalbumin (BLA) by chemical cross linking methods. Both nano-structures were characterized using various techniques such as electron microscopy, dynamic light scattering (DLS), UV-Vis spectroscopy, FT-IR, photo-luminescence and X-ray diffraction. Electron microscopy and DLS analysis revealed their (ZnONS and FZnONSBLA) average size of 200nm and 450nm, respectively. When cytotoxicity of both the nanostructures were assessed in breast cancer cells MCF-7 and MDAMB231 by MTT assay and PI/Annexin V staining (FACS), FZnONSBLA demonstrated higher cell death than ZnONS primarily due to generation of intracellular reactive oxygen species (ROS). Our experimental results also suggested that such enhanced toxicity was due to the lethal structural variant of BLA in FZnONSBLA as well as higher cellular uptake than ZnONS by cancer cells. The death kinetics study with time in cancer cells further proved that FZnONSBLA caused toxicity much faster than ZnONS, thus suggested a strong role of lethal variant of BLA in FZnONSBLA as a cytotoxic agent in cancer cells. Furthermore, FZnONSBLA demonstrated excellent cytocompatibility (normal cells) and hemocompatibility compared to ZnONS. Hence, considering the biodegradable nature of ZnO nonmaterial, our results demonstrated that BLA functionalized ZnONS could be used to develop a suitable therapeutic strategy in cancer. PMID- 28646757 TI - Discovery and structure-activity relationship studies of 2-benzylidene-2,3 dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives as a novel class of potential therapeutics for inflammatory bowel disease. AB - To develop effective therapeutics for inflammatory bowel disease (IBD), 2 benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives, were designed and synthesized and their structure-activity relationships (SAR) were investigated. Compounds 7, 25, 26, 32, 39, 41, 52, 54, and 55 showed potent inhibitory effect (>70%) on the TNF-alpha-induced adhesion of monocytes to colon epithelial cells, which is one of the hallmark events leading to IBD. Such inhibitory activity of the compounds correlated with their suppressive activities against the TNF-alpha-induced production of ROS; ICAM-1 and MCP-1 expression, critical molecules involved in monocyte-epithelial adhesion; and NF-kappaB transcriptional activity. In addition, compounds 41 and 55 significantly suppressed the lipopolysaccharide (LPS)-induced expression of the TNF-alpha gene, with compound 55 showing better efficacy. This inhibition of TNF-alpha expression by compounds 41 and 55 corresponded to their additional inhibitory activity against AP-1 transcriptional activity, which is another transcription factor required for high level TNF-alpha expression. The strong inhibitory activity of compound 55 against an in vivo colitis model was confirmed by its dose-dependent inhibitory activity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis, demonstrating compound 55 as a new potential candidate for the development of therapeutics against IBD. PMID- 28646758 TI - Thermo-responsive diblock and triblock cationic copolymers at the silica/aqueous interface: A QCM-D and AFM study. AB - The properties of synthesized diblock poly(N-isopropylacrylamide)-poly((3 acrylamidopropyl)trimethylammonium chloride) and triblock methoxy-poly(ethylene glycol)-poly(N-isopropylacrylamide)-poly((3-acrylamidopropyl)trimethylammonium chloride) cationic copolymers at the silica/aqueous interface are investigated using quartz crystal microbalance with dissipation monitoring (QCM-D) and atomic force microscopy (AFM). Moreover, dynamic light scattering is employed to assess the copolymers in terms of the hydrodynamic size and interchain aggregation. Although viscoelastic Voigt modeling of the QCM-D data suggests a comparable layer thickness for the copolymers on the silica surface, the AFM imaging and colloidal probe measurements reveal significant differences in surface coverage and thickness of the layers, which are discussed and compared with respect to the stabilization effect by the hydrophilic poly(ethylene glycol) block. PMID- 28646759 TI - Free-standing graphene/vanadium oxide composite as binder-free electrode for asymmetrical supercapacitor. AB - Preparation of free-standing electrode materials with three-dimensional network architecture has emerged as an effective strategy for acquiring advanced portable and wearable power sources. Herein, graphene/vanadium oxide (GR/V2O5) free standing monolith composite has been prepared via a simple hydrothermal process. Flexible GR sheets acted as binder to connect the belt-like V2O5 for assembling three-dimensional network architecture. The obtained GR/V2O5 composite can be reshaped into GR/V2O5 flexible film which exhibits more compact structure by ultrasonication and vacuum filtration. A high specific capacitance of 358Fg-1 for GR/V2O5 monolith compared with that of GR/V2O5 flexible film (272Fg-1) has been achieved in 0.5molL-1K2SO4 solution when used as binder free electrodes in three electrode system. An asymmetrical supercapacitor has been assembled using GR/V2O5 monolith as positive electrode and GR monolith as negative electrode, and it can be reversibly charged-discharged at a cell voltage of 1.7V in 0.5molL-1 K2SO4 electrolyte. The asymmetrical capacitor can deliver an energy density of 26.22Whkg-1 at a power density of 425Wkg-1, much higher than that of the symmetrical supercapacitor based on GR/V2O5 monolith electrode. Moreover, the asymmetrical supercapacitor preserves 90% of its initial capacitance over 1000 cycles at a current density of 5Ag-1. PMID- 28646760 TI - Transparent gel composite films with multiple functionalities: Long-lasting anti fogging, underwater superoleophobicity and anti-bacterial activity. AB - Transparent gel-based composite films with multiple functionalities, showing long lasting anti-fogging properties, underwater superoleophobicity, and anti bacterial activity were successfully prepared from polyvinylpyrrolidone (PVP) and aminopropyl-functionalized clay (AMP-clay). Due to the addition of glutaraldehyde (GA, cross-linker) into the PVP matrices, and AMP-functionalities to the substrate surfaces, both the adhesion properties in water and durability of the anti-fogging properties were significantly improved. In addition, this durability was also found to be markedly improved by increasing the film thickness via deposition of several PVP/AMP/GA layers, while still retaining excellent transparency. PMID- 28646761 TI - Regulation on the aggregation-induced emission (AIE) of DNA-templated silver nanoclusters by BSA and its hydrolysates. AB - The aggregation-induced emission (AIE) phenomenon of the metal nanoclusters (NCs) has been discovered quite recently, which is considered to be creative to improve the optical properties of NCs upon ligand aggregation. In the present study, we report an AIE system for double-stranded DNA-templated silver nanoclusters (AgNCs dsDNA) by using bovine serum albumin (BSA) in solution, which induce a moderate emission enhancement of AgNCs (5-fold) and a blue-shift through a loosen interaction. In addition, significant luminescence enhancement (30-fold) is further stimulated by the addition of digestive enzyme to the system by altering the surface structure of the aggregated particles. The processes are observed directly through transmission electron microscopy (TEM), where the dispersed AgNCs spheres are aggregated in a large incompact sheet-like film by BSA; while further trypsin addition lead them into larger particles (>50nm) with higher density. And the intrinsic mechanism is explained well by UV-vis absorption and time-resolved luminescence spectra. The observed luminescence enhancement in step II is attributed to the AIE through stronger interaction between the hydrolysates of BSA and the ligand dsDNA. Therefore, the optical properties of AgNCs-dsDNA are regulated well by the addition of BSA and trypsin in different amounts, which relates directly to the degree of aggregation and can be extended to other metal nanoclusters by employing the pairs of protein and related enzyme. PMID- 28646762 TI - Hybrid impulsive and switching Hopfield neural networks with state-dependent impulses. AB - We discuss the global stability of switching Hopfield neural networks (HNN) with state-dependent impulses using B-equivalence method. Under certain conditions, we show that the state-dependent impulsive switching systems can be reduced to the fixed-time ones, and that the global stability of corresponding comparison system implies the same stability of the considered system. On this basis, a novel stability criterion for the considered HNN is established. Finally, two numerical examples are given to demonstrate the effectiveness of our results. PMID- 28646763 TI - Deep neural mapping support vector machines. AB - The choice of kernel has an important effect on the performance of a support vector machine (SVM). The effect could be reduced by NEUROSVM, an architecture using multilayer perceptron for feature extraction and SVM for classification. In binary classification, a general linear kernel NEUROSVM can be theoretically simplified as an input layer, many hidden layers, and an SVM output layer. As a feature extractor, the sub-network composed of the input and hidden layers is first trained together with a virtual ordinary output layer by backpropagation, then with the output of its last hidden layer taken as input of the SVM classifier for further training separately. By taking the sub-network as a kernel mapping from the original input space into a feature space, we present a novel model, called deep neural mapping support vector machine (DNMSVM), from the viewpoint of deep learning. This model is also a new and general kernel learning method, where the kernel mapping is indeed an explicit function expressed as a sub-network, different from an implicit function induced by a kernel function traditionally. Moreover, we exploit a two-stage procedure of contrastive divergence learning and gradient descent for DNMSVM to jointly training an adaptive kernel mapping instead of a kernel function, without requirement of kernel tricks. As a whole of the sub-network and the SVM classifier, the joint training of DNMSVM is done by using gradient descent to optimize the objective function with the sub-network layer-wise pre-trained via contrastive divergence learning of restricted Boltzmann machines. Compared to the separate training of NEUROSVM, the joint training is a new algorithm for DNMSVM to have advantages over NEUROSVM. Experimental results show that DNMSVM can outperform NEUROSVM and RBFSVM (i.e., SVM with the kernel of radial basis function), demonstrating its effectiveness. PMID- 28646764 TI - Adaptive near-optimal neuro controller for continuous-time nonaffine nonlinear systems with constrained input. AB - In this paper, an identifier-critic structure is introduced to find an online near-optimal controller for continuous-time nonaffine nonlinear systems having saturated control signal. By employing two Neural Networks (NNs), the solution of Hamilton-Jacobi-Bellman (HJB) equation associated with the cost function is derived without requiring a priori knowledge about system dynamics. Weights of the identifier and critic NNs are tuned online and simultaneously such that unknown terms are approximated accurately and the control signal is kept between the saturation bounds. The convergence of NNs' weights, identification error, and system states is guaranteed using Lyapunov's direct method. Finally, simulation results are performed on two nonlinear systems to confirm the effectiveness of the proposed control strategy. PMID- 28646765 TI - Historical record of polychlorinated biphenyls (PCBs) and special occurrence of PCB 209 in a shallow fresh-water lake from eastern China. AB - Concentrations of polychlorinated biphenyls (PCBs) were measured in dated sediment cores collected from the fifth largest freshwater lake in China, Lake Chaohu, to investigate PCB temporal trends, accumulation, and environmental fate. Total PCB concentrations in Lake Choahu sediments ranged from 0.03 to 24.11 ng g 1 (d.w.). PCB 209 was the dominant congener, accounting for 45.5%-83.9% of total PCBs detected after the mid-20th century. All PCB congeners were positively correlated with total organic carbon (TOC) concentrations. TOC-normalized PCB concentrations exhibited three stages of variation over time: a slight increase from their emergence in the early 20th century, followed by a rapid increase since the late 1950s (peaking in the late 1980s), before a general decrease to the present. Both compositional PCB patterns and principal component analysis (PCA) indicated a source switch from commercial PCBs to other sources. Major contributions of PCB209 to total PCBs in Lake Chaohu sediments is a highlight of this study, with results showing that PCB209 was derived from the upstream city of Hefei, and the production of phthalocyanine-type pigments is the likely source of PCB209. PMID- 28646766 TI - Gaps in aquatic toxicological studies of microplastics. AB - The contamination of aquatic environments with microplastics (MPs) has spurred an unprecedented interest among scientific communities to investigate their impacts on biota. Despite the rapid growth in the number of studies on the aquatic toxicology of MPs, controversy over the fate and biological impacts of MPs is increasingly growing mainly due to the absence of standardized laboratory bioassays. Given the complex features of MPs, such as the diversity of constituent polymers, additives, shapes and sizes, as well as continuous changes in the particle buoyancy as a result of fouling and defouling processes, it is necessary to modify conventional bioassay protocols before employing them for MP toxicity testings. Moreover, several considerations including quantification of chemicals on/in the MP particles, choice of test organisms, approaches for renewing the test solution, aggregation prevention, stock solution preparation, and units used to report MP concentration in the test solution should be taken into account. This critical review suggests some important strategies to help conduct environmentally-relevant MP bioassays. PMID- 28646767 TI - Enhanced photodegradation of 2,4-dichlorophenoxyacetic acid using a novel TiO2@MgFe2O4 core@shell structure. AB - A novel TiO2@MgO-Fe2O3 core-shell structure has been synthesized via a hydrolysis and co-precipitation method followed by calcination at 500 degrees C and has proven to be an efficient photocatalyst. The obtained TiO2@MgO-Fe2O3 core-shell was characterized by scanning electron microscopy, X-ray diffraction, and UV-Vis diffused reflectance techniques. Its photocatalytic activity toward 2,4 dichlorophenoxyacetic acid (2,4-D) was investigated in aqueous solutions with and without visible light irradiation in the presence and absence of hydrogen peroxide. It was revealed that a strong electronic coupling exists between two components within the TiO2@MgO-Fe2O3 core-shell structure. The present findings clearly highlight that TiO2@MgO-Fe2O3 exhibits excellent photocatalytic activity under visible light irradiation in the presence of H2O2. More than 83% degradation of 2,4-D was observed within 240 min, at an initial concentration of 100 mg L-1 with 0.5 g of catalyst per liter. Moreover, the material showed high chemical stability after four consecutive experiments with no significant difference in the rate of photocatalytic degradation. Therefore, the results reported herein offer a green, low cost and highly efficient photocatalyst for environmental remediation. PMID- 28646768 TI - Source profiling of arsenic and heavy metals in the Selangor River basin and their maternal and cord blood levels in Selangor State, Malaysia. AB - Arsenic and 5 heavy metals (nickel, copper, zinc, cadmium and lead) were quantitated in surface water (n = 18) and soil/ore samples (n = 45) collected from 5 land uses (oil palm converted from forest, oil palm in peat swamp, bare land, quarry and forest) in the Selangor River basin by inductively coupled plasma mass spectrometry (ICP-MS). Geographic information system (GIS) was used as a spatial analytical tool to classify 4 land uses (forest, agriculture/peat, urban and bare land) from a satellite image taken by Landsat 8. Source profiling of the 6 elements was conducted to identify their occurrence, their distribution and the pollution source associated with the land use. The concentrations of arsenic, cadmium and lead were also analyzed in maternal blood (n = 99) and cord blood (n = 87) specimens from 136 pregnant women collected at the University of Malaya Medical Center for elucidating maternal exposure as well as maternal-to fetal transfer. The source profiling identified that nickel and zinc were discharged from sewage and/or industrial effluents, and that lead was discharged from mining sites. Arsenic showed a site-specific pollution in tin-tungsten deposit areas, and the pollution source could be associated with arsenopyrite. The maternal blood levels of arsenic (0.82 +/- 0.61 MUg/dL), cadmium (0.15 +/- 0.2 MUg/dL) and lead (2.6 +/- 2.1 MUg/dL) were not significantly high compared to their acute toxicity levels, but could have attributable risks of chronic toxicity. Those in cord blood were significantly decreased in cadmium (0.06 +/- 0.07 MUg/dL) and lead (0.99 +/- 1.2 MUg/dL) but were equivalent in arsenic (0.82 +/- 1.1 MUg/dL) because of the different kinetics of maternal-to-fetal transfer. PMID- 28646769 TI - Health benefit from decreasing exposure to heavy metals and metalloid after strict pollution control measures near a typical river basin area in China. AB - The metal(loid) pollution still is a great concern due to the effects from urbanization and industrialization. While, the health risks from the toxic metal(loid)s could decrease if strict pollution control measures were adopted. However, few studies to date investigate the health risks of heavy metal(loid)s in a systematic river basin for the dependent residents, after taking pollution control measures. Thus, the contents of metal(loid)s (Cu, Pb, Zn, Cd, Mn, As) in surface water along a typical river basin were investigated in this study, and the potential non-carcinogenic and carcinogenic health risks posed to the residents were assessed. Although the soluble contents of Cu, Pb, Zn and Cd exceeded the respective thresholds in two sites located downstream the mine area, they were greatly decreased in comparison with previous contamination levels, and the soluble concentrations of all the metal(loid)s were within the relevant thresholds in the sites far away from the mining area. Moreover, the closer to the mining area, the higher the pollution levels of metal(loid)s. The total hazard index for non-carcinogenic risks of metal(loid)s were basically lower than the threshold (1) for the local population. Whereas, although the content of metal(loid)s were low (such as As), they could pose relative higher non carcinogenic health risks. The result illustrated that pollution levels, toxicity of the contaminants and exposure behavior patterns all could contribute to the potential detrimental health risks. Additionally, the non-carcinogenic and carcinogenic risks from ingestion exposure were ~2-~4 orders of magnitude higher than those from dermal contact. The total carcinogenic risks were basically lower than the maximum tolerable levels (1.0 * 10-4), indicating carcinogenic risks from most areas of the river could also be accepted. Among different population groups, heavy metal(loid)s posed relative higher non-carcinogenic and carcinogenic risks to the children in 0-5 years old. Fortunately, the surface water in most area of this basin is safe in usage for the local population and the health risks were basically acceptable in case exposed to the target metal(loid)s, after the river basin was in the charge of strict pollution control measures. PMID- 28646770 TI - Successful re-challenge with anti-BRAF and anti-MEK in a patient with symptomatic melanoma flare. PMID- 28646771 TI - Efficacy of alectinib in central nervous system metastases in crizotinib resistant ALK-positive non-small-cell lung cancer: Comparison of RECIST 1.1 and RANO-HGG criteria. AB - BACKGROUND: Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria. METHODS: Both studies enrolled patients aged >=18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee. RESULTS: Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate). CONCLUSION: Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used. PMID- 28646773 TI - Survival outcomes of patients with lobular carcinoma in situ who underwent bilateral mastectomy or partial mastectomy. AB - AIM: To compare the survival outcomes between patients treated with bilateral mastectomy and partial mastectomy alone as the initial surgical management for primary lobular carcinoma in situ (LCIS). PATIENTS AND METHODS: Patients with histologically confirmed LCIS underwent partial mastectomy alone or bilateral mastectomy were identified by the SEER*Stat database (version 8.3.2) released in 2016. The primary outcome measure was all-cause mortality and the secondary outcome measure was breast cancer-specific mortality. RESULTS: Of the 5964 cases included in the analysis, 208 cases underwent bilateral mastectomy and 5756 cases underwent partial mastectomy alone. The 1-, 5- and 10-year estimated overall survival rates were 99.7%, 96.7% and 91.7%, respectively. Univariate and multivariate proportional hazards regression (Cox) analyses showed no significant difference between the risk of all-cause mortality in the bilateral mastectomy group compared with the partial mastectomy group (HR = 1.106, 95% confidence interval [CI] 0.350-3.500, P = 0.86). In propensity score-matched model, bilateral mastectomy still did not show benefit to overall mortality (HR = 2.248, 95% CI 0.451-11.200). Patients older than 60 years of age showed a higher risk of all-cause mortality (HR = 7.593, 95% CI 5.357-10.764, P < 0.0001). No risk factors, including surgery type, were identified for breast cancer-specific survival. CONCLUSIONS: Survival outcomes of patients with LCIS who underwent partial mastectomy without radiotherapy were not inferior to patients who underwent bilateral prophylactic mastectomy. Breast cancer-specific mortality in patients with LCIS was extremely low; aggressive prophylactic surgery like bilateral prophylactic mastectomy should not be advocated for most patients with LCIS. PMID- 28646772 TI - Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single centre pharmacovigilance database analysis. AB - AIM: The growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence. PATIENTS AND METHODS: Participants were recruited via Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie (REISAMIC)1 a French registry of grade >=2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia. RESULTS: Out of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjogren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjogren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both). We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57 degrees days (interquartile range (IQR) 24-117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%). CONCLUSION: Although systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted. PMID- 28646774 TI - Observations of black carbon aerosols characteristics over an urban environment: Radiative forcing and related implications. AB - With observations of black carbon (BC) aerosol concentrations, optical and radiative properties were obtained over the urban city of Karachi during the period of March 2006-December 2008. BC concentrations were continuously measured using an Aethalometer, while optical and radiative properties were estimated through the Optical Properties of Aerosols and Clouds (OPAC) and Santa Barbra DISORT Atmospheric Radiative Transfer (SBDART) models, respectively. For the study period, the measured BC concentrations were higher during January, February and November, while lower during May, June, July and August. A maximum peak value was observed during January 2007 while the minimum value was observed during June 2006. The Short Wave (SW) BC Aerosol Radiative Forcing (ARF) both at Top of the Atmosphere (ToA) and within ATMOSphere (ATMOS) were positive during all the months, whereas negative SW BC ARF was found at the SurFaCe (SFC). Overall, SW BC ARF was higher during January, February and November, while relatively lower ARF was found during May, June, July and August. Conversely, the Long Wave (LW) BC ARF at ToA and SFC remained positive, whereas within ATMOS it shifted towards positive values (heating effect) during June-August. Finally, the net (SW+LW) BC ARF were found to be positive at ToA and in ATMOS, while negative at SFC. Moreover, a systematic increase in Atmospheric Heating Rate (AHR) was found during October to January. Additionally, we found highest correlation between Absorption Aerosol Optical Depth (AODabs) and SW BC ARF within ATMOS followed by SFC and ToA. Overall, the contribution of BC to the total ARF was found to greater than 84% for the whole observational period while contributing up to 93% during January 2007. PMID- 28646775 TI - Consequences of intensive forest harvesting on the recovery of Swedish lakes from acidification and on critical load exceedances. AB - Across much of the northern hemisphere, lakes are at risk of re-acidification due to incomplete recovery from historical acidification and pressures associated with more intensive forest biomass harvesting. Critical load (CL) calculations aimed at estimating the amount of pollutants an ecosystem can receive without suffering adverse consequences are dependent on these factors. Here, we present a modelling study of the potential effects of intensified forest harvesting on re acidification of a set of 3239 Swedish lakes based on scenarios with varying intensities of forest biomass harvest and acid deposition. There is some evidence that forestry would have caused a certain level of acidification even if deposition remained at 1860 levels. We show that all plausible harvest scenarios delay recovery due to increased rates of base cation removal. Scenario results were used to estimate critical loads for the entire population of lakes in Sweden. The forestry intensity included in critical load calculations is a political decision. After scaling calculations to the national level, it was apparent that a high but plausible forest harvest intensity would lead to an increase in the area of CL exceedances and that even after significant reductions in forest harvest intensity, there would still be areas with CL exceedances. Our results show that forest harvest intensity and regional environmental change must be carefully considered in future CL calculations. PMID- 28646776 TI - Characterizing the PAHs in surface waters and snow in the Athabasca region: Implications for identifying hydrological pathways of atmospheric deposition. AB - The composition of polycyclic aromatic hydrocarbons present in snow and surface waters in the Athabasca Oil Sands Region (AOSR) was characterized in order to identify major contributors to the organics detected in rivers and lakes in the region. PAH concentrations, measured by three monitoring programs in 2011, were used to compare the PAH compositions of snow and surface waters across the AOSR. The 2011 dataset includes total (dissolved+particulate) concentrations of thirty four parent and alkylated PAH compounds in 105 snow, 272 river, and 3 lake samples. The concentration of PAHs in rivers varies seasonally, with the highest values observed in July. The timing of increases in PAH concentrations in rivers coincides with the high river discharge during the spring freshet, indicating that this major hydrological event may play an important role in delivering PAHs to rivers. However, the composition of PAHs present in rivers during this period differs from the composition of PAHs present in snow, suggesting that direct runoff and release of PAHs accumulated on snow may not be the major source of PAHs to the Athabasca River and its tributaries. Instead, snowmelt may contribute indirectly to increases in PAHs due to hydrological processes such as erosion of stream channels, remobilization of PAH-containing sediments, increased catchment runoff, and snowmelt-induced groundwater inputs during this dynamic hydrologic period. Better understanding of transformations of PAH profiles during transport along surface and subsurface flow paths in wetland-dominated boreal catchments would improve identification of potential sources and pathways in the region. The compositional differences highlight the challenges in identifying the origins of PAHs in a region with multiple potential natural and anthropogenic sources particularly when the potential transport pathways include air, soil and water. PMID- 28646777 TI - Predicting improved optical water quality in rivers resulting from soil conservation actions on land. AB - Deforestation in New Zealand has led to increased soil erosion and sediment loads in rivers. Increased suspended fine sediment in water reduces visual clarity for humans and aquatic animals and reduces penetration of photosynthetically available radiation to aquatic plants. To mitigate fine-sediment impacts in rivers, catchment-wide approaches to reducing soil erosion are required. Targeting soil conservation for reducing sediment loads in rivers is possible through existing models; however, relationships between sediment loads and sediment-related attributes of water that affect both ecology and human uses of water are poorly understood. We present methods for relating sediment loads to sediment concentration, visual clarity, and euphotic depth. The methods require upwards of twenty concurrent samples of sediment concentration, visual clarity, and euphotic depth at a river site where discharge is measured continuously. The sediment-related attributes are related to sediment concentration through regressions. When sediment loads are reduced by soil conservation action, percentiles of sediment concentration are necessarily reduced, and the corresponding percentiles of visual clarity and euphotic depth are increased. The approach is demonstrated on the Wairua River in the Northland region of New Zealand. For this river we show that visual clarity would increase relatively by approximately 1.4 times the relative reduction of sediment load. Median visual clarity would increase from 0.75m to 1.25m (making the river more often suitable for swimming) after a sediment load reduction of 50% associated with widespread soil conservation on pastoral land. Likewise euphotic depth would increase relatively by approximately 0.7 times the relative reduction of sediment load, and the median euphotic depth would increase from 1.5m to 2.0m with a 50% sediment load reduction. PMID- 28646778 TI - The hydrological functioning of a constructed fen wetland watershed. AB - Mine reclamation requires the reconstruction of entire landforms and drainage systems. The hydrological regime of reclaimed landscapes will be a manifestation of the processes operating within the individual landforms that comprise it. Hydrology is the most important process regulating wetland function and development, via strong controls on chemical and biotic processes. Accordingly, this research addresses the growing and immediate need to understand the hydrological processes that operate within reconstructed landscapes following resource extraction. In this study, the function of a constructed fen watershed (the Nikanotee Fen watershed) is evaluated for the first two years following construction (2013-2014) and is assessed and discussed within the context of the construction-level design. The system design was capable of sustaining wet conditions within the Nikanotee Fen during the snow-free period in 2013 and 2014, with persistent ponded water in some areas. Evapotranspiration dominated the water fluxes from the system. These losses were partially offset by groundwater discharge from the upland aquifer, which demonstrated strong hydrologic connectivity with the fen in spite of most construction materials having lower than targeted saturated hydraulic conductivities. However, the variable surface infiltration rates and thick placement of a soil-capping layer constrained recharge to the upland aquifer, which remained below designed water contents in much of the upland. These findings indicate that it is possible to engineer the landscape to accommodate the hydrological functions of a fen peatland following surface oil sands extraction. Future research priorities should include understanding the storage and release of water within coarse-grained reclaimed landforms as well as evaluating the relative importance of external water sources and internal water conservation mechanisms for the viability of fen ecosystems over the longer-term. PMID- 28646779 TI - Polychlorinated biphenyls in the surrounding of an e-waste recycling facility in North-Rhine Westphalia: Levels in plants and dusts, spatial distribution, homologue pattern and source identification using the combination of plants and wind direction data. AB - During this study the occurrence of polychlorinated biphenyls (PCBs) in the surrounding of an e-waste recycling facility in North-Rhine Westphalia was analysed. PCB levels were analysed in curly kale, spruce needles, street dusts and dusts. Conspicuously high PCB concentrations in curly kale and spruce needles were found directly northwards of the industrial premises. Furthermore a concentration gradient originating from the industrial premises to the residential areas in direction southwest to northeast was evident. Homologue patterns of highly PCB contaminated dusts and street dusts were comparable to the homologue patterns of PCB in curly kale and spruce needles. This corroborates the suspicion that the activities at the e-waste recycling facility were responsible for the elevated PCB levels in curly kale and spruce needles. The utilization of multiple linear regression of wind direction data and analysed PCB concentrations in spruce needles proved that the e-waste recycling facility caused the PCB emissions to the surrounding. Additionally, this evaluation enabled the calculation of source specific accumulation constants for certain parts of the facility. Consequently the different facility parts contribute with different impacts to the PCB levels in bioindicators. PMID- 28646780 TI - SEM/EDS and optical microscopy analyses of microplastics in ocean trawl and fish guts. AB - Microplastic particles from Atlantic and Pacific Ocean trawls, lab-fed fish guts and ocean fish guts have been characterized using optical microscopy and SEM/EDS in terms of size, morphology, and chemistry. We assessed whether these measurements could serve as a rapid screening process for subsequent identification of the likely microplastic candidates by micro-spectroscopy. Optical microscopy enabled morphological classification of the types of particles or fibers present in the sample, as well as the quantification of particle size ranges and fiber lengths. SEM/EDS analysis was used to rule out non-plastic particles and screen the prepared samples for potential microplastic, based on their element signatures and surface characteristics. Chlorinated plastics such as polyvinyl chloride (PVC) could be easily identified with SEM/EDS due to their unique elemental signatures including chlorine, as could mineral species that are falsely identified as plastics by optical microscopy. Particle morphology determined by optical microscopy and SEM suggests the fish ingested particles contained both degradation fragments from larger plastic pieces and also manufactured microplastics. SEM images of microplastic particle surfaces revealed characteristic cracks consistent with environmental exposure, as well as pigment particles consistent with manufactured materials. Most of the microplastic surfaces in the fish guts and ocean trawls were covered with biofilms, radiolarians, and crustaceans. Many of the fish stomachs contained micro-shell pieces which visually resembled microplastics. PMID- 28646781 TI - Zeta potential evidences silanol heterogeneity induced by metal contaminants at the quartz surface: Implications in membrane damage. AB - Among the physico-chemical features responsible for the so-called "variability of quartz hazard", a key role has been assigned to the silica surface charge, evaluated by means of zeta potential measurement. The zeta potential of silica describes the protonation state of silanols which, in turn, determine interactions with cell membranes. To gain a molecular understanding of the role of silanols in silica pathogenicity, we conducted a systematic investigation of the variation of the zeta potential as a function of pH (zeta plot titration curve) on a large set of respirable quartz particles with different levels of metal contaminants. The membranolytic activity of the particles on red blood cells, used as a readout of pathogenic activity, was assessed in parallel. Pure quartz surfaces showed sigmoid-shaped zeta plots suggesting the presence of silanol families with similar acidity, whereas contaminated dusts exhibited convex-shaped zeta plots, indicating a higher silanol heterogeneity on contaminated surfaces with respect to the pure ones. The quartz particles with a higher surface heterogeneity related to metal contamination showed a higher membranolytic activity. By removing structural defects and chemical heterogeneity, the zeta plot shifted towards the typical shape of pure quartz and the membranolytic activity was reduced. We conclude that the zeta plot is a useful readout to measure the acid-base behavior of quartz surfaces and to describe the chemical heterogeneity of quartz silanols. Surface heterogeneity, here induced by metal contamination, is proposed as the main cause of quartz membranolytic activity, further supporting the hypothesis that surface silanol disorganization determines silica pathogenicity. PMID- 28646782 TI - Emotional dysregulation in borderline personality disorder and its influence on communication behavior and feelings in romantic relationships. AB - Dysfunction in romantic relationships constitutes one of the most burdensome symptoms of borderline personality disorder (BPD). The aim of this study was to ascertain how emotional dysregulation affects behavior and relationship related feelings of women with BPD in threatening conversations with their own romantic partner. Thirty couples in which the women were diagnosed with BPD and 34 healthy control (HC) couples were videotaped while discussing personally threatening (i.e., personal failure) and relationship-threatening (i.e., separation) themes. Third party raters evaluated stress and communication behaviors during the conversations. Relationship related feelings, i.e., closeness and relationship insecurity, were assessed by self-report. Overall, women with BPD were rated as more stressed in threatening situations than HC women and their partners, but not more stressed in relationship-threatening than personally threatening situations. A heightened stress response of women with BPD predicted more negative and less positive communication behaviors and a stronger decline in self-rated closeness to the partner compared to HC. Stress-induced increases in relationship insecurity were specific to women with BPD. Our results highlight the central role of emotional dysregulation in interpersonal dysfunctions of persons with BPD and the need to address individual emotion regulation strategies more explicitly in dyadic contexts. PMID- 28646783 TI - Heart rate variability in patients with major depression disorder during a clinical autonomic test. AB - Major depression disorder (MDD) patients express dysfunction autonomic nervous system (ANS) and reduced heart rate variability (HRV). However, previous researches mainly focused on examining resting state without considering a series of stimulation tests of ANS between MDD patients and healthy people. For this purpose, 40 healthy people and 40 MDD patients participated and finished 10min clinical autonomic test-Ewing test. Parameters of HRV such as time domain, frequency domain, and nonlinear dynamical parameters were calculated. Most of HRV parameters during Ewing test of MDD patients are lower than healthy people, and inversely, the ratio of low frequency to high frequency is higher when standing up. In addition, heart rate of healthy people in deep breathing and Valsalva test states are higher than that in resting state, nonlinear dynamical parameter (RCMSE1) of healthy people in standing up state is higher than that in Valsalva test state. The experimental results suggest that parasympathetic nervous system of MDD patients is influenced by mental state and become dysfunction under long term depression, it cannot exert normal physiological functions when it is activated. Sympathetic activity increases on MDD patients, and this enhancement is more obvious which expresses higher complexity of HRV time series. PMID- 28646784 TI - Premenstrual mood and empathy after a single light therapy session. AB - To examine whether acute changes in cognitive empathy might mediate the impact of light therapy on mood, we assessed the effects of a single light-therapy session on mood and cognitive empathy in 48 premenstrual women, including 17 who met Premenstrual Symptoms Screening Tool criteria for moderate-to-severe premenstrual syndrome / premenstrual dysphoric disorder (PMS/PMDD). Using a participant-blind between-groups design, 23 women underwent 30min of morning light therapy (5,000lx; blue-enriched polychromatic light, 17,000K) while 25 women had a sham session (200lx, polychromatic light, 5,000K). We administered the Positive Affect and Negative Affect Schedule and the Affect Grid right before and after the intervention, and 60min later upon completion of a computerized empathic accuracy task. There were no significant effects of light condition on cognitive empathy as assessed using the computer task. Nonetheless, bright light reduced negative affect, specifically in women not using hormonal contraceptives. No effects of bright light on mood were observed in women who were using contraceptives. If a single light-therapy session does not alter cognitive empathy, then cognitive empathy may not mediate the impact of light therapy on mood in premenstrual women. PMID- 28646785 TI - Higher cardio-respiratory fitness is associated with increased mental and physical quality of life in people with bipolar disorder: A controlled pilot study. AB - The aim of this study was to investigate whether cardiorespiratory fitness among outpatients with bipolar disorder is associated with health related quality of life (HRQL) and explore differences versus healthy controls. Outpatients with bipolar disorder and healthy controls matched for age, sex and body mass index completed the 36-item Short Form Health Survey, the Positive-and-Negative-Affect Schedule (PANAS), a maximal cardiorespiratory fitness test, and wore a Sensewear Armband to measure physical activity and sedentary behavior for eight days. Unpaired t-tests, Pearson correlations and backward regression analyses were performed. Outpatients with bipolar disorder (n = 20; 14?; 47.9 +/- 7.9 years) had a significantly lower physical and mental HRQL than healthy controls (n = 20; 14?; 47.8 +/- 7.6 years), a lower maximum oxygen uptake (VO2max) and were more sedentary. While no significant correlates were found for HRQL in controls, higher VO2max values and lower PANAS negative affect scores predicted better physical and mental HRQL in people with bipolar disorder. The final regression model explained 68% and 58% of the variability in physical and mental HRQL respectively. Cardiorespiratory fitness is associated with mental and physical HRQL among people with bipolar disorder. The current study offers novel targets for scientific investigation and clinical interventions to increase HRQL in people with bipolar disorder. PMID- 28646786 TI - Preliminary study of visual perspective in mental time travel in schizophrenia. AB - This study explored specificity and visual perspective of mental time travel in schizophrenia. Fifteen patients with schizophrenia and 18 controls were recruited. Participants were asked to recall or imagine specific events according to cue words. Results showed that schizophrenia patients generated fewer specific events than controls, the recalled events were more specific than imagined events. Schizophrenia adopted less field perspective and more observer perspective than controls. These results suggested that patients with schizophrenia were impaired in mental time travel both in specificity and visual perspective. Further studies are needed to identify the underlying mechanisms. PMID- 28646787 TI - Parental self-efficacy mitigates the association between low spousal support and stress. AB - This study examined the moderating role of parental self-efficacy of the association between spousal support and stress. Recruited through online survey, 445 Israeli parents filled out self-reported questionnaires. The moderation model explained 36.4% of the variance in parents' stress. The findings confirmed that in the presence of high parental self-efficacy, the effect of spousal support on stress was non-significant. However, the less parental self-efficacy reported, the stronger the association between spousal support and stress was found. These findings have implications for professionals working with families as they emphasize the importance of parents' inner resource in the absence of spousal support. PMID- 28646788 TI - Muscle dysmorphia and psychopathology: Findings from an Italian sample of male bodybuilders. AB - : The aim of this study is to investigate the relationship between the risk of muscle dysmorphia and psychopathological symptoms in an Italian sample of male bodybuilders. METHOD: The sample was recruited online (145 men with a mean age of 30.0 years) and participants were asked to fill out the Muscle Dysmorphic Disorder Inventory (MDDI), Symptom Cheklist-90-R (SCL-90-R), Dissociative Experiences Scale (DES-II), and to provide other socio-demographic data. Bodybuilders at risk of muscle dysmorphia display greater global psychopathology and present higher scores on all SCL-90-R dimensions when compared to bodybuilders not at risk of muscle dysmorphia. Furthermore, risk of muscle dysmorphia is positively associated to dissociative symptoms. The Competitiveness dimension and anabolic steroid intake were not related to muscle dysmorphia, while age appeared to be more significant. Findings are discussed based upon previous studies and directions for future research are suggested. PMID- 28646789 TI - Data-mining for detecting signals of adverse drug reactions of fluoxetine using the Korea Adverse Event Reporting System (KAERS) database. AB - Selective serotonin reuptake inhibitors (SSRIs) have become one of the most broadly used medications in psychiatry. Fluoxetine is the first representative antidepressant SSRI drug approved by the Food and Drug Administration (FDA) in 1987. Safety information on fluoxetine use alone was less reported than its combined use with other drugs. There were no published papers on adverse drug reactions (ADRs) of fluoxetine analyzing spontaneous adverse events reports. We detected signals of the adverse drug reactions of fluoxetine by data mining using the Korea Adverse Events Reporting System (KAERS) database. We defined signals in this study by the reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) indices. The KAERS database included 860,224 AE reports, among which 866 reports contained fluoxetine. We compared the labels of fluoxetine among the United States, UK, Germany, France, China, and Korea. Some of the signals, including emotional lability, myositis, spinal stenosis, paradoxical drug reaction, drug dependence, extrapyramidal disorder, adrenal insufficiency, and intracranial hemorrhage, were not labeled in the six countries. In conclusion, we identified new signals that were not known at the time of market approval. However, certain factors should be required for signal evaluation, such as clinical significance, preventability, and causality of the detected signals. PMID- 28646790 TI - The effects of individual biological rhythm differences on sleep quality, daytime sleepiness, and dissociative experiences. AB - Individuals who differ markedly by sleep chronotype, i.e., morning-type or evening-type also differ on a number of psychological, behavioral, and biological variables. Among several other psychological functions, dissociation may also lead to disruption and alteration of consciousness, which may facilitate dream like experiences. Our study was aimed at an inquiry into the effects of individual biological rhythm differences on sleep quality and daytime sleepiness in conjunction with dissociative experiences. Participants were 372 undergraduate college students, completed a package of psychological instruments, including the Morningness-Eveningness Questionnaire, Dissociative Experiences Scale, Insomnia Severity Index, and Epworth Sleepiness Scale. Using logistic regression models, direct relations of pathological dissociation with sleepiness, sleep quality and circadian preferences were investigated. Poor sleep quality and sleepiness significantly contributed to the variance of dissociative symptomatology. Although there was no substantial linear association between circadian preferences and pathological dissociation, having evening-type preferences of sleep was indirectly associated with higher dissociation mediated by poor sleep quality. Poor sleep quality and daytime sleepiness seems to be significant antecedents of pathological dissociation. Sleep chronotype preferences underlie this relational pattern that chronobiological characteristics seem to influence indirectly on dissociative tendency via sleep quality. PMID- 28646791 TI - Disorganised schizotypy is selectively associated with poorer semantic processing in non-clinical individuals. AB - The nature and severity of semantic memory (SM) impairments in schizophrenia has been related to symptoms, mainly formal thought disorder (FTD), and other clinical factors like length of illness. Symptom-related studies in schizophrenia are often confounded by clinical factors, for example medication and hospitalisations. We completed a schizotypy analogue study to examine the relationship between SM processing and FTD using an analogue schizotypy score referred to as cognitive disorganisation. Sixty individuals without a history of mental illness (M=22.92, SD=2.70) completed a schizotypy questionnaire and three semantic tasks - naming pictures, category fluency and semantic priming. Only decreasing fluency was associated with increasing cognitive disorganisation scores (p=0.029). In line with the prevailing dyssemantic theories, the results highlight that cognitive disorganisation is associated with some difficulties in SM processes, though not all. The observed differential relationships of SM processes to disorganised schizotypy are discussed in relation to previous work, and in terms of potential developmental trajectories for SM impairment in schizophrenia. PMID- 28646792 TI - Bacterial profile in human atherosclerotic plaques. AB - BACKGROUND AND AIMS: Several studies have confirmed the presence of bacterial DNA in atherosclerotic plaques, but its contribution to plaque stability and vulnerability is unclear. In this study, we investigated whether the bacterial plaque-profile differed between patients that were asymptomatic or symptomatic and whether there were local differences in the microbial composition within the plaque. METHODS: Plaques were removed by endarterectomy from asymptomatic and symptomatic patients and divided into three different regions known to show different histological vulnerability: A, upstream of the maximum stenosis; B, site for maximum stenosis; C, downstream of the maximum stenosis. Bacterial DNA composition in the plaques was determined by performing 454 pyrosequencing of the 16S rRNA genes, and total bacterial load was determined by qPCR. RESULTS: We confirmed the presence of bacterial DNA in the atherosclerotic plaque by qPCR analysis of the 16S rRNA gene but observed no difference (n.s.) in the amount between either asymptomatic and symptomatic patients or different plaque regions A, B and C. Unweighted UniFrac distance metric analysis revealed no distinct clustering of samples by patient group or plaque region. Operational taxonomic units (OTUs) from 5 different phyla were identified, with the majority of the OTUs belonging to Proteobacteria (48.3%) and Actinobacteria (40.2%). There was no difference between asymptomatic and symptomatic patients, or plaque regions, when analyzing the origin of DNA at phylum, family or OTU level (n.s.). CONCLUSIONS: There were no major differences in bacterial DNA amount or microbial composition between plaques from asymptomatic and symptomatic patients or between different plaque regions, suggesting that other factors are more important in determining plaque vulnerability. PMID- 28646793 TI - Shexiang Baoxin pills promotes angiogenesis in myocardial infarction rats via up regulation of 20-HETE-mediated endothelial progenitor cells mobilization. AB - BACKGROUND AND AIMS: Therapeutic angiogenesis is a pivotal strategy for ischemic heart disease. The aim of the present study was to determine the effect and molecular mechanism of Shexiang Baoxin pills, a widely-used traditional Chinese medicine for ischemic heart disease, on angiogenesis in a rat model of myocardial infarction (MI). METHODS: We used the occlusion of left anterior descending coronary artery of Sprague-Dawley rats as a model of MI. The MI rats were treated with distilled water, Shexiang Baoxin pills, or Shexiang Baoxin pills + HET0016 (a selective blocker of the biosynthesis of 20-hydroxyeicosatetraenoic acid (20 HETE) at 10 mg/kg/day), respectively. Sham-operated rats were used as controls. RESULTS: Treatment with Shexiang Baoxin pills increases the level of serum 20 HETE in MI rats, which can be suppressed by HET0016 treatment. Shexiang Baoxin pills shows cardio-protective effects on MI rats, including improving cardiac function, decreasing infarction area, and promoting angiogenesis in peri-infarct area. The protective effects of Shexiang Baoxin pills are partly inhibited by HET0016. Furthermore, Shexiang Baoxin pills enhances the number of circulating endothelial progenitor cells (EPCs) and the expression of the vascular endothelial growth factor (VEGF), based on immunohistochemical analysis, in peri infarct area of MI rats, which is partly suppressed by HET0016. CONCLUSIONS: Shexiang Baoxin pills may partially participate in angiogenesis in MI rats. The protective mechanism of Shexiang Baoxin pills may be mediated via up-regulation of 20-HETE, which promotes EPCs mobilization and VEGF expression. PMID- 28646794 TI - Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways. AB - The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFalpha. Moreover, DXI reduced soluble beta-amyloid (Abeta1-42) plaque deposition by decreasing APP, BACE1 and facilitating Abeta degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks. PMID- 28646796 TI - Organic matter drives high interannual variability in methylmercury concentrations in a subarctic coastal sea. AB - Levels of neurotoxic methylmercury (MeHg) in phytoplankton are strongly associated with water MeHg concentrations. Because uptake by phytoplankton is the first and largest step of bioaccumulation in aquatic food webs many studies have investigated factors driving seasonal changes in water MeHg concentrations. Organic matter (OM) is widely accepted as an important driver of MeHg production and uptake by phytoplankton but is also known for strong interannual variability in concentration and composition within systems. In this study, we explore the role of OM on spatial and interannual variability of MeHg in a subarctic coastal sea, the northern Baltic Sea. Using MeHg (2014: 80 +/- 25 fM; 2015: 250 mg/L) can reduce DBP formation by removing halides and organic precursors. However, we show that in a case where reverse osmosis permeate is blended with a separate raw groundwater, the residual bromide level in the permeate could still exceed that in the raw groundwater, and thereby induce DBP formation in the blend. DBP-associated calculated toxicity increased for certain blends in this system due to the DBPs resulting from the combination of the elevated bromide concentration in the permeate and the organic precursors from the raw coastal groundwater. PMID- 28646801 TI - The Effects of Exposure to Low Frequency Electromagnetic Fields on Male Fertility. AB - Context * People are increasingly exposed to low frequency (LF) electromagnetic fields (EMFs), mainly from electricity distribution networks and electronic devices. Critics of this widespread exposure believe that it can have detrimental effects on the human body. On the other hand, many in vivo and in vitro studies have claimed that low frequency electromagnetic therapy can function as a form of alternative medicine and that therapists can treat disease by applying electromagnetic radiation or pulsed EMFs to the body or cells. It is not yet entirely clear, however, whether LF-EMF is beneficial or harmful. Objectives * This study aimed to examine the effects of LF-EMFs on men's reproductive functions, according to the types of waveform and the frequency and duration of exposure. Design * The study reviewed all available research, both human and animal, on the effects of LF-EMFs on male reproductive functions, covering the literature from January 1978 to June 2016. The documents were obtained from PubMed, Science Direct, and Google Scholar, and any article that was irrelevant or a duplicate was excluded. A total of 61 articles were found, and 27 articles were reviewed. Setting * This project was performed at the Avicenna Research Center (Tehran, Iran). Participants * Literature included human and animal studies conducted on rabbits, mice, rats, and boars. Intervention * Among these studies, any article that was irrelevant, a duplicate, or published with duplicate data was excluded. At the end, 27 articles were checked. Outcome Measures * Outcome measures included testing related to reproductive organ weights, reproductive endocrinal hormones, fetal development, and spermatogenesis as well as sperm motility, morphology, and vitality. Results * The reviewed studies provided contradictory results that were highly dependent on the exposure parameters, such as the shape and frequency of wave, intensity, duration, and timing of the exposure. Conclusions * LF-EMF at 15 Hz with a peak intensity of 8 Gauss, with a square waveform of 50 Hz frequency and a duration of a few hours or less can have a positive effect on sperm quality, motility, and fertility. Exposures at other frequencies either had no effects on the sperm's performance and quality or held biological hazard for cells. It appears that there is still little understanding of how EMF affects cellular functions. Therefore, more standardized and controlled studies should be carried out to understand the effects of EMF on the body. PMID- 28646802 TI - Dampness Can Promote the Influenza A Virus and Worsen Its Prognosis by Upregulating the TLR7 Signaling Pathway. AB - Context * Outbreaks of the influenza A virus (IAV) are increasingly recognized as a global public health issue, affecting a large proportion of the world's population. A number of studies have provided epidemiologic evidence that dampness and mold are consistently associated with multiple allergic and respiratory effects, but they focused on dampness-related pathogenic microorganisms leading to allergy rather than the dampness itself. Objective * The current study intended to examine the effects of a damp environment on the promotion of the IAV and determine the adverse effects on its prognosis through upregulation of the toll-like receptor 7 (TLR7)-signaling pathway in the lung. Design * The research team performed an animal study. Setting * The study was performed at Jinan University (Guangzhou, China). Animals * A total of 144 specific-pathogen-free, C57BL/6j mice were included in the study, divided into 6 groups with 24 mice in each group. Intervention * The mice were randomly divided into the 6 groups, with 24 mice in each group: (1) group A: normal mice, a control group; (2) group B: normal mice living in a damp environment, a second control group; (3) group C: virally infected mice living in a normal environment; (4) group D: virally infected mice living in a damp environment; (5) group E: virally infected mice living in a normal environment and receiving treatment with 0.2 mL/d of 0.78 mg/mL oseltamivir; and (6) group F: virally infected mice living in a damp environment and receiving treatment with 0.2 mL/d of 0.78 mg/mL oseltamivir. Outcome Measures * Real-time quantitative polymerase chain reaction was used to measure the mRNA expression of TLR7, myeloid differentiation primary response gene 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), interleukin 1 receptor-associated kinase 4 (IRAK4), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) in the TLR7 signaling pathway and the viral replication level in the lung. Results * The mice began to lose weight after being infected with IAV, especially those mice in groups D and F, where the mice were lost weight more quickly than those in groups C and E. The damages in group F were more serious than for mice in group E. In groups C and D, the mRNA TLR7, MyD88, TRAF6, IRAK4, and NF-kappaB were upregulated after viral infection (P < .01). After the IAV infection, the expression of TLR7, MyD88, TRAF6, and NF-kappaB mRNA in group D was higher (P < .01) than in group C. The oseltamivir treatment reduced the mRNA expression in the TLR7 signaling pathways (P < .01), both in the damp environment and normal environment. The expression of mRNA in the TLR7 signaling pathways was lower in group F than in group E (P < .01). Conclusions * The study suggests that dampness can promote the IAV infection and worsen its prognosis by upregulating the TLR7 signaling pathway. PMID- 28646803 TI - Effects of Balneotherapy on Serum Levels of Shingosine-1-Phosphate in Patients With Osteoarthritis. AB - Context * Balneotherapy is one of the most commonly used nonpharmacological interventions for osteoarthritis (OA), but its mechanism of action in relieving pain and stiffness and in improving physical function is not well understood. Studies have found that therapy provokes a series of neuroendocrinal reactions with anti-inflammatory and analgesic effects. Sphingosine-1-phosphate (S1P), a bioactive lipid, has been implicated as an important mediator in the maintenance of physiological processes (eg, vascular barrier integrity) and in pathophysiologic processes such as inflammatory conditions. Accordingly, targeting S1P and S1P receptors may offer a potential therapy for arthritis. Objective * The aims of the present study were to determine whether (1) balneotherapy modified the circulating levels of S1P as well as some inflammatory parameters and stress markers, in patients with OA; and (2) to assess the relationship of those parameters to therapeutic efficacy. Design * This study was designed as an uncontrolled longitudinal study. Setting * The study took place at the Bolu Physical Therapy and Rehabilitation Hospital (Bolu, Turkey). Participants * Forty patients who suffered from general OA in at least 3 positions on the body, one of which could be the vertebral column, and who fulfilled the American College of Rheumatology Classification criteria and the Kellgren-Moore radiologic criteria, were enrolled in the intervention group in the study. Intervention * During balneotherapy, the participants were fully immersed in warm thermo-mineral water for 20 min at a temperature of 38 degrees C to 40 degrees C. A total of 15 immersions were performed in a period of 15 d. Outcome Measures * A baseline clinical evaluation of participants' pain, stiffness, and physical function was carried out using the Western Ontario and McMaster Universities questionnaire. Baseline serum levels of S1P, cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and heat shock protein 70 (HSP-70) were measured using enzyme-linked immunosorbent assays and high-sensitivity C reactive protein, with an immunoturbidimetric assay. The clinical evaluations and the biochemical measurements were repeated after completion of the balneotherapy period. Results * Balneotherapy caused a significant reduction in circulating levels of S1P and high-density lipoprotein and a limited increase in HSP-70 levels, in addition to a reduction in pain and stiffness and an improvement in physical function. In the Spearman's correlation analysis, S1P was found to be positively associated with serum levels of HSP-70, COX-2, and MMP-3. Conclusion * Balneotherapy modulated serum S1P levels in patients with OA. The effect of S1P modulation on the clinical outcome of patients with OA should be further investigated. PMID- 28646804 TI - Pilot Investigation of 2 Nondiet Approaches to Improve Weight and Health. AB - Context * Weight loss and maintenance are associated with many health benefits, but long-term maintenance of weight loss remains elusive for many people. Overweight individuals are at higher risk than normal-weight individuals for stress-induced overeating. The use of stress-management tools in a weight loss program might decrease the physiological stress that fuels overeating and improve posttreatment maintenance of weight loss Objective * The study intended to compare the differences in outcomes between 2 approaches to achieving weight loss and changes in health-stress reduction and intuitive eating (IE)-during a 14-wk period. Design * The research team designed a small, randomized, controlled pilot study. Setting * The study took place at the University of Kentucky (Lexington, KY, USA). Participants * Men and women, aged 25 to 65 y, with a body mass index >=30 but <=40 kg/m2, were recruited through various outlets on a large college campus, and 33 enrolled in the study. Intervention * Participants were randomly assigned either to an IE or to a stress-reduction program (EBT) for a 7 wk intervention and a 7-wk follow-up period. Outcome Measures * Weight, blood pressure, stress, depression, and eating behaviors were measured at baseline, postintervention at week 7, and postintervention at week 14. Results * Participants were 69.7% female and 93.9% Caucasian. An intent-to-treat analysis was conducted on the main outcome of weight. At 14 wk, the EBT group had lost 4.4 +/- 6.7 lb (1.99 +/- 3.04 kg), and the IE group had lost 1.03 +/- 6.10 lb (0.48 +/- 2.77 kg). A repeated measures analysis of variance did not find any significant difference between groups for weight change (P = .36). Completers in the EBT group significantly improved blood pressure, perceived stress, and food addiction symptoms from baseline to 7 wk (P < .05). Only the changes in weight were maintained at 14 wk. Conclusions * The study suggested that the stress reduction approach may be viable as an approach to weight loss and improvements in health-related outcomes in the short term. A longer investigation of the program is warranted. PMID- 28646805 TI - Natural Cancer Therapy and Prevention Targeted on Cancer Cells and Cancer Stem Cells Based on the Cytochrome P45O Enzyme CYP1B1: A Commentary. AB - The importance of the P450 enzyme CYP1B1 in both cancer therapy and prevention are reviewed and evidence is discussed, which provides strong biological plausibility for the therapeutic merits of this approach. The significant resistance to chemotherapy among common cancers, and the realization that in many cases chemotherapy leaves behind drug-resistant cancer cells that eventually cause recurrence and metastatic disease, has recently prompted the search for natural compounds that would circumvent this problem. There is also the important question of therapies that will kill cancer stem cells (CSCs) because they appear, in many cases, to be resistant to conventional therapy. The repeated observation that resveratrol has the ability kill CSCs in a variety of cancers suggests that this natural product may act through a mechanism that is cancer type independent. There are a few other natural products that have this property and all act through a well-understood mechanism involving CYP1B1, which is known to be overexpressed at the protein level in ordinary cancer cells but not in noncancer cells. These natural products toxic to ordinary cancer cells serve as substrates for this enzyme and the metabolites cause apoptosis or cell cycle arrest. This small group includes resveratrol. The observation that resveratrol also has this same action on CSCs independent of cancer type suggests the hypothesis that these cells also overexpress CYP1B1 and offer the same target as ordinary cancer cells. A number of case histories are reviewed that involve a variety of cancers from different sites and grades or stages treated with a proprietary mixture of CYP1B1 substrates extracted from fruit. They illustrate therapeutic effectiveness with even late-stage cancers put into durable remission. This implies combined ordinary cancer cell and CSC toxicity. In addition, a recent proposed mechanism for CYP1B1 overexpression only in cancer cells are described. Recently developed blood tests for CYP1B1, its cancer active substrates, and the resultant metabolites are reviewed as they add significantly to the biological plausibility of the CYP1B1 mechanism. Thus, a targeted therapy many researchers are actively seeking already exists with evidence of human efficacy and compelling biological plausibility. PMID- 28646807 TI - Manual Therapy With Cryotherapy Versus Manual Therapy With Kinesio Taping for Males With Lumbar Discopathy: A Pilot Randomized Trial. AB - Context * Numerous modalities of therapeutic interventions exist for lumbar discopathy. Manual therapy is one option, although its effectiveness remains controversial. The addition of cryotherapy to manual therapy may enhance the health benefits in patients with lumbar discopathy. Objective * The study intended to evaluate the efficacy of manual therapy combined with cryotherapy vs manual therapy combined with Kinesio taping for males with lumbar discopathy. Design * The research team designed a pilot randomized trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Setting * The study occurred in the Physiotherapy Outpatient Department of the Regional Hospital (Zywiec, Poland). Participants * The participants were 40 males with lumbar discopathy, aged 30-75 y, who were patients in the department at the hospital. Intervention * The participants were randomly assigned to an intervention group that received Kaltenborn-Evjenth orthopedic manual therapy (KEOMT) combined with cryotherapy, the KEOMT-C group (n = 20), or to a control group that received KEOMT combined with Kinesio taping, the KEOMT-K group (n = 20). The participants in both groups received 10 treatments, 2 per wk for 5 wk. Outcome Measures * The primary outcome was measured using a visual analog scale and the Laitinen scale pain ratings. The secondary outcome measured the quality of life using the short form-36 questionnaire. The participants completed the tests at baseline and postintervention. Results * After the treatments, the intervention group had significantly lower scores than the control group for pain as well as significantly higher scores for quality of life. Conclusions * Patients achieved better health benefits from manual therapy when it was combined with cryotherapy. PMID- 28646806 TI - Potential of Probiotics in Hypercholesterolemia: A Review of In Vitro and In Vivo Findings. AB - Context * Coronary heart disease (CHD) is a major public health problem in developing and developed countries. Elevated cholesterol levels, especially low density lipoprotein (LDL) cholesterol, and the emergence of CHD, have been positively correlated in many clinical and epidemiological studies. The health benefits of probiotics have received a great deal of attention, including their blood cholesterol-lowering effects on humans. Objective * The research team intended to determine the current state of research examining the effects of various probiotic strains on lipid profiles, including measures in serum of total cholesterol, LDL cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol. Design * The review examined studies, in both animal and human models and focused on the potential of various probiotic strains to be dietary adjuncts in lowering levels of serum cholesterol with the aim of reducing the risk of cardiovascular disease (CVD) and CHD. Articles were reviewed systematically from Web search bases including PubMed and Cochrane Clinical Trial Registry. Articles meeting the inclusion search criteria were selected for further review and analysis. Only randomized controlled trials evaluating the effects of probiotics on lipid profiles in animals or humans were considered for inclusion in the review. Setting * The selection of articles and further inclusion in the review was performed in Institute of Home Economics, University of Delhi (New Delhi, India). Results * Some of the studies, in both animal and human models, have revealed that several strains were able to improve at least 1 lipid fraction. Although the results from animal studies have been fairly consistent, the findings from studies on humans have varied. Some strains when evaluated in human studies have shown insignificant effects on lipid fractions. Conclusions * Although several mechanisms for cholesterol removal by probiotics have been proposed, they need further investigation to be validated. PMID- 28646808 TI - Traditional Uyghur Medicine: Concepts, Historical Perspective, and Modernization. AB - Context * Traditional Uyghur medicine (TUM) is rooted in ancient Uyghur medical theory that was developed with the combined essence of different traditional medicines, such as Han Chinese, Egyptian, ancient Greek, Arabian, Persian, and Indian medicines. Modern experimental methods and technologies for disease diagnoses have accelerated the modernization of Uyghur medicine. Objective * The research team intended to compile a comprehensive introduction to TUM and to determine the current state of research in the field to establish a basis for future modernization of Uygur medicine. Design * The research team collected information from several databases-the China National Knowledge Infrastructure, the Wanfang Databases, and PubMed-as well as from Uyghur medical books. They also interviewed Uyghur medical scholars to ensure the authenticity of the Uyghur medical theory presented. The registry database of the China Food and Drug Administration was also used to search for and screen registered TUMs. Setting * The selection of articles and further inclusion in the review was performed in the College of Veterinary Medicine, Northwest A&F University (Yangling, China). Results * TUM has been developed to a unique, comprehensive theoretical system with the concepts and theories for clinical diagnosis, treatment, and medication. Advancements of modern experimental methods and disease diagnoses have accelerated the modernization of Uyghur medicine. The establishments of a series of standards/regulations legalize Uyghur drug production, supervision, and management. Conclusions * The future development of Uygur medicine should begin with the standardization of planting, production, and laboratory and clinical practices to form a complete system with the support and participation of the government to realize the modernization of TUM finally worldwide. One pressing matter is a full analysis of the requirements and standards of the dominant international pharmaceutical markets as applied to natural medicinal preparations, including TUM preparations. Knowledge of the exact curative effects of Uygur medicine and the development of TUM preparations that conform to international standards would enable them to be better accepted by the mainstream market. PMID- 28646809 TI - Efficacy of Fascial Distortion Model Treatment for Acute, Nonspecific Low-Back Pain in Primary Care: A Prospective Controlled Trial. AB - Context * Low-back pain (LBP) is a prevalent and potentially crippling condition for which treatment is often unsatisfactory from the perspectives of physicians, patients, and payers. The application of the fascial distortion model (FDM), an integrated concept for the diagnosis and manipulative treatment of musculoskeletal disorders, is conceptually promising for LBP but has not been investigated systematically. Objective * The study intended to provide proof of concept to establish the noninferiority of the FDM treatment as opposed to the therapy recommended by the German National Disease Management Guideline (NDMG) for acute LBP. Design * The study was a prospective, nonrandomized, controlled, parallel-group trial. Setting * The study took place in a private practice for surgery and orthopedics. Participants * Seventy-seven outpatients with acute LBP with an average age of 42.6 +/- 13.5 y, 50.6% of whom were male, took part in the study. Intervention * Participants in the intervention group (FDM group) received osteopathic manipulative treatments according to the FDM, whereas the control group (NDMG group) received an active control treatment following the NDMG. Outcome Measures * Comparing the FDM group (n = 39) and the NDMG group (n = 38), the study measured pain (visual analog scale, patient diary), functional (FFbH-R) and self-reported vocational status, and use of medication (patient diary) at baseline and after 1, 4 and 12 wk of treatment. Results * The study found marked improvements of the symptoms in both groups, with a faster onset of efficacy and significantly less medication under the FDM treatment. Conclusions * FDM appears to be effective with regard to pain relief and functional improvement for LBP. PMID- 28646810 TI - Synergistic Anti-Breast-Cancer Effects of Combined Treatment With Oleuropein and Doxorubicin In Vivo. AB - : Context * Breast cancer is a leading cause of cancer fatalities among women worldwide. Of the more than 80% of patients who receive adjuvant chemotherapy, approximately 40% relapse. The majority of these patients die of disseminated metastatic disease, which emphasizes the need for new therapeutic strategies Objective * The study intended to investigate the anticancer effects of oleuropein (OL) and doxorubicin (DOX) individually and in combination on breast tumor xenografts and also to evaluate the molecular pathways involved. Design * The research team designed in vivo (animal) and in vitro (cell culture) studies. SETTING: The study was performed in the College of Science of King Saud University in the University Center for Women Students (Riyadh, Saudi Arabia). Animals * The study involved 40 female, nude mice (BALB/c OlaHsd-foxn1). Intervention * The mice were injected subcutaneously with MDA-MB-231 human breast cancer cells. After the growth of tumors, the animals were randomly divided into 4 groups to receive intraperitoneal injections: (1) group 1 (control group) dimethyl sulfoxide, (2) group 2 (intervention group)-50 mg/kg of OL, (3) group 3 (intervention group)-2.5 mg/kg of DOX, and (4) group 4 (intervention group)-1.5 mg/kg of DOX, immediately followed by 50 mg/kg of OL. The OL was extracted from Manzanillo olive trees (Olea europaea) grown in Tabouk, Saudi Arabia. Outcome Measures * The measures included the isolation and primary culture of the tumor xenografts, apoptosis analysis by annexin V, cellular lysate preparation, and immunoblotting. RESULTS: The volume of the tumor increased aggressively, reaching 173 mm3 in the control animals in a time-dependent manner. On the other hand, a sharp drop, to 48.7 mm3, in the volume of the tumor was observed with the 2 drugs combined, a more than 3-fold decrease. The effect was mediated through the induction of apoptosis via the mitochondrial pathway. The combined treatment downregulated the antiapoptosis and proproliferation protein, nuclear factor kappa Beta, and its main oncogenic target cyclin D1. Furthermore, it inhibited the expression of BCL-2 and survivin. This inhibition could explain the cooperative suppression of the proliferation of breast tumor xenografts and the induction of apoptosis by the combined effect of the compounds used. Conclusions * The key findings clearly indicate the synergistic efficacy of DOX with natural and nontoxic OL against breast tumor xenografts. PMID- 28646811 TI - Alternative Therapy for Patients With Obstructive Sleep Apnea/Hypopnea Syndrome: A 1-year, Single-blind, Randomized Trial of Tui Na. AB - Context * Obstructive sleep apnea/hypopnea syndrome (OSAHS) is among the most prevalent of sleep-related breathing disorders. No long-term follow-up studies have documented the continued success of lifestyle changes in treatment; oral appliances have an approximate 50% success rate; compliance with continuous positive airway pressure is poor, ranging from 50% to 89%; and the success rate of upper-airway surgery is only 66.4%. Therefore, some OSAHS patients seek alternative treatments. Objectives * The study intended to examine the efficacy of traditional Chinese therapeutic massage (tui na) for patients with OSAHS. Design * The research team designed a prospective study. Setting * The study took place at the outpatient clinic of the sleep center at the Kaohsiung Chang Gung Memorial Hospital (Kaohsiung, Taiwan), an academic tertiary medical center. Participants * Participants were 31 patients with moderate to severe OSAHS. Intervention * Each participant received a tui na treatment at multiple acupoints 2 */wk for 10 wk for approximately 15 min/session. Outcome Measures * At baseline and 3 mo after treatment, participants completed subjective measures, including (1) quality of life using a 36-item, short-form health survey (SF-36); (2) subjective snoring intensity indicated by bed-partners using a 0-10 visual analog scale (VAS); and (3) excessive daytime sleepiness (EDS) status, using a Chinese version of the Epworth Sleepiness Scale (CESS). The research team completed objective measures, including (1) polysomnography, (2) body mass index, and (3) neck circumference. Results * Twenty patients completed the full course of treatment. The apnea/hypopnea index per hour decreased from 43.8 +/- 26.9 to 37.8 +/- 31.7 after the treatments, with P = .049 (paired t test). The arousal index and rapid eye movement stage of sleep improved significantly. Statistically significant improvements were observed for the SF-36 on the score for the physical component summary, for its subscale for general health, for the mental component summary, and for 2 of its subscales: vitality and mental health. The VAS and the CESS showed that snoring intensity and EDS decreased significantly, respectively. No major complications occurred. Conclusions * Tui na is a feasible and safe treatment for patients with OSAHS. It can improve the quality of life, sleep architecture, snoring intensity, and EDS in patients with moderate-to severe OSAHS. In the future, a controlled study should be considered to further investigate the effects of tui na for OSAHS. PMID- 28646812 TI - Oral Consumption of Vitamin K2 for 8 Weeks Associated With Increased Maximal Cardiac Output During Exercise. AB - Background * Vitamin K1 and K2 are not typically common in a Western diet because they are found in a variety of fermented foods. Vitamin K2 in particular has been demonstrated to restore mitochondrial function and has a key role in production of mitochondrial adenosine triphosphate. Thus, it is reasonable to speculate that dietary supplementation with vitamin K2 could increase the function of muscle with high mitochondrial content (ie, skeletal and cardiac muscle). Objective * The purpose of this study was to determine if 8 wk of dietary supplementation with Vitamin K2 could alter cardiovascular responses to a graded cycle ergometer test. Design * The study was a randomized controlled trial. Setting * The study took place in the Applied Physiology Laboratory of the Department of Biological Sciences at the University of North Texas (Denton, TX, USA). Participants * Participants were aerobically trained males and female athletes (N = 26). Intervention * Participants were randomly assigned either to a control group that received a rice flour placebo or to an intervention group that received vitamin K2. For weeks 1 to 4, participants received 300 mg/d; for weeks 5 to 8, they received 150 mg/d. Subjects assigned to the control group received similar doses to mirror the intervention group. Subjects consumed the supplements during an 8 wk period while they maintained their typical exercise habits. Outcome Measures * At baseline and postintervention, participants completed a standard, graded exercise test on an electronically braked cycle ergometer. Before the test, participants were fitted with a mouth piece, and their oxygen consumption, carbon dioxide production, respiratory rate, and respiratory exchange ratio were measured. In addition, participants were fitted with skin-mounted electrodes that measured noninvasive cardiac output, stroke volume, and heart rate. To assess the cumulative exercise change, an area-under-the-curve (AUC) value was calculated separately for each outcome variable at each treatment time point. Results * Vitamin K2 supplementation was associated with a 12% increase in maximal cardiac output, with P = .031, with a trend toward an increase in heart-rate AUC, with P = .070. No significant changes occurred in stroke volume. Conclusions * Although vitamin K2 supplementation has previously been reported to improve cardiovascular function in diseased patients, to the research team's knowledge, the current study is the first to report its potential in active individuals. More research is needed to fully evaluate the potential effects of the observed effects. PMID- 28646813 TI - Hepatoprotective Activity of Satwa, an Ayurvedic Formulation, Against Alcohol induced Liver Injury in Rats. AB - Context * Guduchi Satwa is an Ayurvedic formulation prepared from Tinospora species. It has been used since ancient times to treat liver disorders. Objectives * The study intended to assess the hepatoprotective potential of Satwa prepared from 3 forms of Tinospora against alcohol-induced hepatotoxicity. Design * Male, albino Wistar rats were divided into 6 groups, with 6 rats each: 3 control groups-healthy controls, negative controls, and positive controls-and 3 intervention groups-Tinospora cordifolia, Tinospora sinensis, and Neem-Guduchi. Setting * The study was carried out at the Animal House facility of Bharati Vidyapeeth Deemed University's Medical College (Maharashtra, India). Intervention * Hepatotoxicity was induced by repeated dosing with alcohol for 15 d for all groups except for the healthy controls. To induce hepatotoxicity, the 5 groups received 1 mL of 30% alcohol PO per 100 g of body weight per day. The healthy controls and the negative controls received no hepatoprotective treatments. The other 4 groups received the dosing with alcohol 30 min after the hepatoprotective treatment, which they also received for 15 d: (1) positive controls-100 mg of silymarin per kg of body weight per day PO; (2) intervention group 1 (T cordifolia group)-200 mg of T cordifolia per kg of body weight per day PO; (3) intervention group 2 (T sinensis group)-200 mg of T sinensis per kg of body weight per day PO; and (4) intervention group 3 (Neem-Guduchi group)-200 mg of Neem-Guduchi per kg of body weight per day PO. Outcome Measures * Serum and liver tissue were used for biochemical analysis. Results * For the negative and positive control groups and the 3 intervention groups, the repeated dosing with alcohol produced elevations in the levels of liver-marker enzymes and changes in the lipid-profile status of the animals. Satwa from T cordifolia had a specific action in maintaining the lipid profile: total cholesterol, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein. Improvement in the hepatic function, normalization of the lipid profile in the serum and liver, and improvements in the levels of antioxidant enzymes and oxidative-stress markers were observed in the animals treated with T sinensis Satwa. Neem-Guduchi Satwa was found to have a specific action in maintaining the lipid profile. The differential hepatoprotective effect of that Satwa was also evident from the liver histology. Conclusions * The data suggest that the 3 Satwa might be used in combination as a liver tonic that can help restore and strengthen the liver functions. The current study shows that the combination has the potential to be an effective liver tonic in animals. Scientific data from clinical trials of the 3 Satwa are not available. Systematic clinical trials are required that can yield information on their effects in humans. PMID- 28646814 TI - Nutritional Management of Metabolic Endotoxemia: A Clinical Review. AB - Context * Diet-induced, metabolic endotoxemia is emerging as an important contributory factor to the development of a wide range of chronic diseases, including cardiometabolic, autoimmune, psychiatric, and neurodegenerative illnesses. Emerging human clinical studies have demonstrated that diet and dietary components are potent modifiers of circulating endotoxins and can be used to reduce plasma levels significantly and improve metabolic health. Objective * The aim of the current study was to explore briefly the concept of metabolic endotoxemia and its relationship to disease development, to examine the influence of diet and dietary components on circulating endotoxins, and, finally, discuss the clinical relevance of nutritional interventions for management of metabolic endotoxemia. Design * The researcher performed a literature review of dietary and nutritional interactions with metabolic endotoxemia with a focus on studies relevant to clinical practice. Setting * The study took place at the UK College of Nutrition and Health (London, England). Results * Improving dietary quality, optimizing the intake of phytonutrient-rich foods, improving micronutrient status, consuming fermented foods, manipulating the gut microflora with prebiotics and probiotics, and using specific nutritional supplements, such as glutamine, lactoferrin, resveratrol, and berberine, have been shown to be effective in targeting metabolic endotoxemia. Conclusions * Diet, dietary components, and nutritional supplements, including prebiotics and probiotics, have demonstrated the ability to provide clinically important reductions in circulating endotoxins and improve related sequels, such as inflammation and other negative health markers. The development of personalized nutritional interventions for the management of metabolic endotoxemia is a promising area for future research due to the potential of such interventions to improve multiple aspects of human health and mitigate a wide range of chronic diseases. PMID- 28646816 TI - The Devil and the Details. PMID- 28646815 TI - Integrative Treatment of Chronic Abdominal Bloating and Pain Associated With Overgrowth of Small Intestinal Bacteria: A Case Report. AB - Context * Small intestinal bacterial overgrowth (SIBO) is commonly defined as an increased number of bacteria and/or an abnormal type of bacteria in the small intestine. Conventional treatment for SIBO is typically focused on antibiotics to eradicate the bacterial overgrowth. Numerous studies have demonstrated the antimicrobial activity of herbs, and a diet low in fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) has been shown to enhance antibiotic therapy. Objective * The current case study intended to evaluate the benefits of an alternative, multifaceted approach-including botanical and homeopathic therapies in conjunction with a low-FODMAP diet-in the treatment of SIBO and its associated symptoms. Design * The research team performed a case study. Setting * The study was conducted at SCNM Medical Center (Tempe, AZ, USA). Participant * The participant was a female patient at the SCNM Medical Center with chronic, daily, severe abdominal bloating and pain that particularly worsened after meals and by the end of the day. The patient also had a significant history of chronic constipation that had begun approximately 10 y prior to her experiencing the daily abdominal pain. Intervention * Based on a lactulose breath test for hydrogen and methane, the research team diagnosed the patient with a case of mild SIBO. The treatment approach was multifaceted, involving a low-FODMAP diet, antimicrobial botanical therapy, and homeopathic medicine. Results * The patient's abdominal pain and bloating resolved with the treatment of the SIBO, although her underlying constipation, which was likely associated with other factors, remained. Conclusions * This case study supports an alternative, multifaceted approach to the treatment of SIBO and commonly associated symptoms. PMID- 28646818 TI - Bracket Positioning for Smile Arc Protection. PMID- 28646819 TI - Invisalign with Photobiomodulation: Optimizing Tooth Movement and Treatment Efficacy with a Novel Self-Assessment Algorithm. PMID- 28646820 TI - Practice Profile: Jeremy Fry, DDS, MS, Fry Orthodontic Specialists. PMID- 28646821 TI - Treatment of an Impacted and Inverted Upper Premolar. PMID- 28646822 TI - An Efficient and Effective Technique for Uprighting Mesially Erupting Lower Second Molars. PMID- 28646823 TI - Does the Surgical Correction of Tibial Torsion with Genu Varum Produce Outcomes Similar to Those in Varus Correction Alone? AB - The aim of this article is to study the relationship between tibia vara and external tibial torsion in adults. The following questions were asked: (1) what is the incidence of rotational deformity in patients with genu varum and (2) do patients who undergo correction of tibial torsion with genu varum have similar outcomes to those who undergo simple tibia vara correction? In this study, 69 patients (138 limbs) underwent bilateral proximal tibial osteotomy for the correction of genu varum. Patients with simple coronal plane deformity (varus alone) were treated with either a monolateral external fixator or a hexapod frame. Those with concomitant external tibial torsion were treated with circular external fixation. The primary outcome was the ability to achieve the desired correction of alignment in the coronal, sagittal, and axial planes. Secondary outcomes included a postoperative Knee Injury and Osteoarthritis Outcome Score (KOOS) and a routine patient satisfaction questionnaire. The incidence of tibial torsion among the entire group of patients with bilateral tibia vara was 46% and overwhelmingly external in direction. The two groups had some significant differences in demographics with torsion patients tending to be younger and thinner. The final mechanical axis deviation and medial proximal tibial angle values for both groups did not differ significantly (p = 0.956). The postcorrection thigh-foot axis was not significantly different between the two groups (p = 0.666). Time to union was not significant (p > 0.999). KOOS was not different between the two groups in symptoms, pain, activities of daily living, and return to sport. There was a difference in the quality of life score between the two groups (p = 0.044). There was no difference between the two groups regarding the patient questionnaire. Based on the finding of this analysis, the incidence of rotational malalignment with genu varum is close to 50%. The recognition of this close association with external tibial torsion deformity may allow for further insights into the role of rotation in varus deformity-related knee pathology and treatment. Patients can expect nearly identical outcomes from this surgery. PMID- 28646824 TI - Bone Marrow Aspirate Concentrate versus Platelet Rich Plasma to Enhance Osseous Integration Potential for Osteochondral Allografts. AB - Fresh osteochondral allograft (OCA) transplantation is an attractive treatment option for symptomatic articular cartilage lesions in young, healthy patients. Since a lack of OCA bone integration can be a cause of treatment failure, methods for speeding and enhancing OCA bone integration to mitigate this potential complication are highly desirable. This study sought to determine and compare the potential of bone marrow aspirate concentrate (BMC) and leukoreduced platelet rich plasma (PRP) to repopulate the osseous portion of an OCA with cells and deliver osteogenic proteins. It was hypothesized that BMC would have significantly higher colony forming units (CFUs)/mL and seed the osseous portion of OCA with more cells than PRP. Finally, we hypothesized that the media of BMC and PRP treated OCAs would have significantly higher concentrations of osteogenic proteins compared with negative control OCAs. Cylindrical OCAs (n = 36) created from tissue stored for 21 days were treated with BMC (n = 12) or PRP (n = 12) obtained for 6 dogs, or left untreated as a negative control (n = 12). After treatment, OCAs were cultured for 7 or 14 days. Media were collected for analysis of osteogenic biomarker concentration. Samples of each BMC and PRP were tested for CFU concentration. On day 7 or 14, the grafts were assessed for cell surface adhesion and penetration using fluorescent microscopy. Significant differences in CFU and media biomarker concentration between the groups were determined using one-way analysis of variance (ANOVA) and Tukey's post-hoc test with the significance set at p < 0.05. Only OCAs saturated with BMC had viable cells detectable on the osseous portion of the allografts at day 7 and 14 of culture. BMC samples had a significantly higher (p = 0.029) CFU/mL compared with PRP samples. At day 3 and/or 7 of culture, the concentration of several osteogenic proteins was significantly higher in both BMC and PRP samples. Autogenous BMC can be used to deliver both a cell population and osteogenic proteins that may improve healing of the osseous portion of the OCA clinically. PMID- 28646825 TI - Early Outpatient Physical Therapy May Improve Range-of-Motion in Primary Total Knee Arthroplasty. PMID- 28646826 TI - Comparison of BRCA1 Expression between Triple-Negative and Luminal Breast Tumors AB - Background: Previous studies have suggested that BRCA1 dysregulation has a role in triple-negative phenotypic manifestation. However, differences of BRCA1 expression, as a tumor suppressor gene, have rarely been investigated between luminal and triple-negative breast tumors. Therefore, the present study attempted to compare the BRCA1 expression in triple-negative with luminal breast tumors and its association with the clinicopathologic characteristics of patients. Methods: BRCA1 expression was evaluated by real-time PCR in 26 triple-negative and 27 luminal breast tumors. Results: The results revealed that there is a high frequency of BRCA1 underexpression in both triple-negative and luminal breast tumors. The BRCA1 underexpression was related to young age at diagnosis, lymph node involvement, and grade III tumors. Conclusion: The observations suggest that decreased BRCA1 expression, regardless of tumor subtype, has a general role in breast malignancy and associated with poor prognostic features in breast tumors. PMID- 28646828 TI - Spent yeast as natural source of functional food additives AB - Spent yeasts are by-products arising from beer and wine production which over many years have been chiefly used as feed additives for livestock. They contain many valuable and bioactive substances which has thereby generated much interest in their exploitation. Up till now, the main products obtained from beer-brewing yeasts are beta-glucans and yeast extracts. Other like foodstuffs include dried brewer's yeast, where this is dried and the bitterness removed to be fit for human consumption as well as mannan-oligosaccharides hitherto used in the feed industry. beta-glucans constitute the building blocks of yeast cell walls and can thus be used in human nutrition as dietary supplements or serving as food additives in functional foods. beta-glucans products obtained via post fermentation of beer also exhibit a high and multi-faceted biological activity where they improve the blood's lipid profile, enhance immunological status and have both prebiotic and anti-oxidant properties. Yeast extracts are currently being used more and more to enhance flavour in foodstuffs, particularly for meat and its products. Depending on how autolysis is carried out, it is possible to design extracts of various meat flavours characteristic of specific meats. Many different flavour profiles can be created which may be additionally increased in combination with vegetable extracts. Within the food market, yeast extracts can appear in various guises such as liquids, pastes or powders. They all contain significant amounts of glutamic acid, 5'-GMP and 5'-IMP nucleotides together with various amino acids and peptides that act synergistically for enhancing the flavour of foodstuff products. Recent studies have demonstrated additional benefits of yeast extracts as valuable sources of amino acids and peptides which can be used in functional foods and dietary supplements. These products possess GRAS status (Generally Recognised As Safe) which thereby also adds further as to why they should be used as natural food additives that are functional. PMID- 28646827 TI - Immunization of C57BL/6 Mice with GRA2 Combined with MPL Conferred Partial Immune Protection against Toxoplasma gondii AB - Background: We have previously reported that immunization with GRA2 antigen of Toxoplasma gondii induces protective immunity in CBA/J (H2k) and BALB/c mice (H2d). We aimed to examine whether immunization of a distinct strain of rodent with recombinant dense granule antigens (GRA2) combined with monophosphorryl lipid A (MPL) adjuvant elicits protective immune response against T. gondii. Methods: C57BL/6 (H2b haplotype) mice were immunized with GRA2, formulated in MPL adjuvant. Results: Strong humoral response, predominantly of IgG1 subclass and cellular response, IFN-gamma, was detected at three weeks post immunization. Mice immunized with GRA2 had significantly (p < 0.01) fewer brain cysts than those in the adjuvant group, upon challenge infection. Despite the production of a strong antibody response, IFN-gamma production and brain cyst reduction were not significant when the immunized mice were infected four months after the immunization. Conclusion: We can conclude that GRA2 immunization partially protects against T. gondii infection in C57BL/6 mice, though the potency and longevity of this antigen as a standalone vaccine may vary in distinct genetic backgrounds. This observation further emphasizes the utility of GRA2 for incorporation into a multi-antigenic vaccine against T. gondii. PMID- 28646829 TI - Chia seeds (Salvia hispanica): health promoting properties and therapeutic applications - a review AB - Chia has been known for over 5,500 years. Chia seeds were one of the most important components of the diet of Mayas and Aztecs. The chemical composition and technological properties of chia give the plant a high nutritional potential. Chia is a good source of polyunsaturated fatty acids: omega-3 and omega-6, soluble dietary fiber. It also contains appreciable amount of proteins and phytochemicals. Nutritional value of chia is the reason why it is used in prophylaxis of several non-infectious diseases such as obesity, hypertension, cardiovascular diseases (CVDs), cancer and diabetes. Nutritional and therapeutic aspects of chia are currently being researched by many scientific centres. The aim of this article is to present the nutritional and therapeutic values of chia. PMID- 28646830 TI - Dietary fiber sources consumption and overweight among Polish male students. A cross-sectional study AB - Background: There has been an increase in the prevalence of overweight and obesity in adolescents and young adults, especially in men than women. Many adolescents have a sedentary lifestyle and consume more processed, low-fiber foods. Objective: The aim of this study was to assess the frequency of fiber intake and its selected dietary source consumption in relation to the overweight among Polish male students. Material and Methods: This cross-sectional study involved 1,233 male students aged 13.0-24.9 years from northern, eastern and central Poland. The respondents completed a self-administered Block Screening Questionnaire for Fruit/Vegetable/Fiber Intake and measurements of their body mass and height were performed. The overweight and obesity prevalence was assessed using international standards. Results: The most frequently consumed foods by students included: white bread and potatoes, fruit and fruit or vegetable juices. The odds of overweight (including obesity) were lower from 28% (OR=0.72; 95%CI:0.56-0.93) to 31% (OR=0.69; 95%CI:0.50-0.95) with a daily consumption of white bread compared to non-daily consumption of white bread. Consumption >=4 times/week of prepared vegetables (cooked, preserved or marinated) was associated with 51% lower odds of overweight (OR=0.49; 95%CI:0.27 0.97) compared to consumption less than 4 times/week of these foods. The odds of overweight for the level of fiber intake was insignificant. Conclusions: This study provides surprising insights regarding high-fiber and low-fiber food consumption and overweightin Polish male students. A lower odds of overweight was associated with a higher frequency consumption of relatively low in fiber foods as white bread and cooked, preserved or marinated vegetables. Most of the students consumed fiber at an unacceptable level, so a beneficial impact of high fiber foods on overweight prevalence was not shown. PMID- 28646831 TI - Assessment of differences in nutrients consumption in women diagnosed with osteoporosis as compared to a healthy control group AB - Background: Osteoporosis is a condition that has been much more frequent for women, which is related to menopause and to their lower bone mineral density (BMD). Inappropriate diet is among the development factors of the disease. Objective: To assess differences in consumption of particular nutrients among women with and without osteoporosis diagnosed. Material and Methods: The study was conducted in 2013 in a group of 100 women aged 51-70, using a questionnaire, including a 24-hour recall related to a participant's nutrients consumptions. Results: Women suffering from osteoporosis were found to consume significantly lower amounts of fat (by 16%) andenergy (by 13%), as well as vitamins: A (by 16%), E (by 20%), B6 (by 20%), niacin (by 16%) and C (by 19%). Differencesin the consumption of minerals have been observed in the cases of calcium, phosphorus, sodium and potassium. The women with osteoporosis were fund to consume lower amounts of those elements, by 14%, 13%, 21% and 19% respectively. On the average, participants of the study in both groups consumed amounts of calcium at a half of the recommended level, and substantially exceeded the recommended values of phosphorus, as well as displaying an inappropriate calcium to phosphorus ratio (0.5:1). As little as 8% of the participants with osteoporosis declared a considerable change in their diet, with increased consumption of dairy products. Conclusions: The observed nutrition deficiencies in osteoporosis patients may be conducive to a worsened condition, andmay lead to an onset of the disease in participants from the control group. PMID- 28646832 TI - Diet for women with irritable bowel syndrome - a preliminary study AB - Background: Irritable Bowel Syndrome (IBS) is one of the most frequent digestive system diseases, of various medical signs. It is assumed that proper life style, including appropriate, rational diet is a factor helpful for treating such a disorder. Objective: The purpose of this paper was to assess the selected dietary habits, and to evaluate the nutritional value of daily food rations for patients with a mixed type of Irritable Bowel Syndrome. Material and Methods: The questionnaire survey involved a group of 32 women suffering from a mixed type of Irritable Bowel Syndrome (The Rome III Diagnostic Criteria were used to diagnose the disease). The control group was comprised of 32 healthy women. The methods used to assess the diet were divided into quantitative and qualitative ones. Results: The most frequent dietary mistakes among patients with IBS were associated with snacking sweets (83.0% of the subjects) and fruit (17.0% of the subjects) between the meals. A higher intake of sucrose was found amongst women with IBS, than in the case of the control group (p=0.0169). The analysis of the results demonstrated a significantly higher intake of water (derived from drinks and foods) amongst patients with IBS, than in the case of women of the control group (p=0.0267). An insufficient intake of plant proteins and polyunsaturated fatty acids was recorded in both groups. The supply of protein in general, animal protein, fat in general, saturated fatty acids and sodium, exceeded the recommended norm, both amongst women with IBS and women of the control group. Conclusions: The obtained examination results showed that there are significant dietary improprieties in the diet of women suffering from IBS. In order to eliminate these mistakes in the future, it seems justified to extend the knowledge on rational nutrition amongst patients with IBS. PMID- 28646833 TI - The use of fruit extracts for production of apple chips with enhanced antioxidant activity AB - Background: Style and pace of life make consumers more willing to reach for snack products. This group of processed food includes, among others, fruit chips. Due to the increasing incidence of diseases associated with the excessive exposure to free radicals foods enriched with antioxidant compounds, eg. polyphenols, can be introduced into the sale. Objective: The aim of the study was to use the fruit extracts for the production of apple chips with enhanced antioxidant activity. Material and methods: 'Golden Delicious' variety of apple fruit was used to produce chips. Apple chips were prepared by slicing, soaking in a sugar solution and pre-drying in a microwave oven. Chips were enriched with extracts prepared from fruits of chokeberry, five-flavor berry, Cornelian cherry, woodland hawthorn, goji berry, Japanese quince and cranberry microcarpa. For this purpose, pre-dried apple slices were soaked (5 min) in ethanolic extract of fruits and then dried to achieve a 5% moisture content. Chips were sensory evaluated and their antioxidant activity and total polyphenols content were determined. Results: All enriched apple chips were characterized by high antioxidant activity and a relatively high value of total polyphenols content. Chips soaked in extracts of five-flavor berry, cranberry and goji berry were characterized by the highest antioxidant potential. Samples obtained by using chokeberry and Cornelian cherry extracts showed the highest content of polyphenols. High sensory attractiveness of enriched chips was also showed. The chips with the addition of fiveflavor berry extract were exceptions. Their taste was not acceptable. Conclusions: Fruit extracts are a valuable material for chips enrichment. Taking into account all the analyzed differentiators, extracts of Japanese quince, goji berry and woodland hawthorn were found to be the best enriching additives. The chips soaked in extract of five-flavor berry, despite their high antioxidant activity, were disqualified due to very low score of sensory evaluation. PMID- 28646834 TI - Beverage osmolality as a marker for maintaining appropriate body hydration. AB - Background: Osmolalities can be useful markers for determining whether given beverages are suited for maintaining an adequate hydration of the body. Losing 2% of body water relative to body mass reduces the efficiency of body function when undertaking physical effort by around 20%. Deficiencies in water intakes approaching 5-8% of body mass, double the impairment to the body's physical and mental functioning, whereas at a level of 10% the body becomes incapable of performing any sort of physical effort. For such reasons the body's hydration status is vital to its functioning. Objectives: To asses osmolalities as measured in various types of commercially available mineral waters and non-alcoholic beverages containing different amounts of extracts. Materials and Methods: Test materials were commercially available mineral waters (of low, medium and high mineral content) along with juices, nectars and drinks that are isotonic, energising and those described as being 'light' and sparkling. Osmolality was measured by the 800CL Osmometer instrument from TridentMed whilst the RL-type refractometer was used for determining extract values. Results: Isotonic drinks were found to have the same osmotic pressures as bodily fluids at 275 - 295 mOsm/kg water. The osmotic pressure in mineral waters depended on the extent of mineralisation and ranged from 13 mOsm / kg water (low mineral content) to 119 mOsm/kg water (high mineral content). Low osmolalities were also found in 'light' drinks (from 29.3 to 34 mOsm/kg water). Juices, nectars, energising drinks and colas typically have high sugar contents and have high osmolalities ranging 492 - 784 mOsm / kg water. Statistical analysis demonstrated significant associations (p < 0.05) between osmolalities and extract content in beverages as well as between osmolalities and mineral content in mineral waters. Upon factor analysis, it was possible to group the tested drinks according to similar osmolalities and extract content. Conclusions: Osmolalities measured in beverages are a marker that permits drinks to be classified into groups according to their tonicity and their ability to ensure that the body is properly hydrated; this becoming vital in cases when the body requires rapid body fluid replenishment. PMID- 28646835 TI - Association between blood cholinesterase activity, organophosphate pesticide residues on hands, and health effects among chili farmers in Ubon Ratchathani Province, northeastern Thailand AB - Background: Use of pesticides has been documented to lead to several adverse health effects. Farmers are likely to be exposed to pesticides through dermal exposure as a result of mixing, loading, and spraying. Organophosphate pesticides (OPs) are widely used in most of the agricultural areas throughout Thailand. OPs are cholinesterase inhibitors and blood cholinesterase activity is used as a biomarker of OP effects. Objective: This study aims to determine the association between blood cholinesterase activity and organophosphate pesticide residues on chili farmer's hands and their adverse health effects. Materials and Methods: Ninety chili farmers directly involved with pesticide applications (e.g. mixing, loading, spraying) were recruited and were interviewed face to face. Both enzymes, erythrocyte acetylcholinesterase (AChE) and plasma cholinesterase (PChE), were tested with the EQM Test-mate Cholinesterase Test System (Model 400). Hand wipe samples were used for collecting residues on both hands and OP residues for chlorpyrifos and profenofos were quantified using gas chromatography equipped with a flame photometric detector (GC-FPD). Results: The average activity (+/-SD) of AChE and PChE was 2.73 (+/-0.88) and 1.58 (+/-0.56) U/mL, respectively. About 80.0% of the participants had detectable OP residues on hands. The median residues of chlorpyrifos and profenofos were found to be 0.02 and 0.03 mg/kg/two hands, respectively. Half of participants reported having some acute health symptoms within 48 hours after applying pesticides. When adjusted for gender, number of years working in chili farming, and frequency of pesticide use, AChE activity (Adjusted OR = 0.03, 95%CI: 0.01-0.13) and detected OP residues on hands (Adjusted OR = 0.15, 95%CI: 0.02-0.95) were significantly associated with having health effects, but no significant association was found in PChE activity (Adjusted OR = 2.09, 95%CI: 0.63-6.99). Conclusions: This study suggests that regular monitoring for blood cholinesterase and effective interventions to reduce pesticide exposure to prevent health effects should be provided to chili farmers. PMID- 28646836 TI - Biochemical parameters as monitoring markers of the inflammatory reaction by patients with chronic obstructive pulmonary disease (COPD) AB - Background: Chronic obstructive pulmonary disease (COPD) is an airway inflammatory disease caused by inhalation of toxic particles, mainly cigarette smoking, and now is accepted as a disease associated with systemic characteristics. Objective: The aim of this work was to investigate and compare selected biochemical parameters in patients with and without COPD. Material and Methods: Observation group consisted of clinically stable patients with COPD (n = 60). The control group was healthy persons from the general population, without COPD, who were divided into two subgroups - smokers (n = 30) and non-smokers (n = 30). Laboratory parameters were investigated by automated clinical chemistry analyzer LISA 200th. Results: Albumin in our measurements showed an average value of 39.55 g.l-1 in the patient population; 38.89 g.l-1 in smokers and in non smokers group 44.65 g.l-1. The average value of pre-albumin in the group of patients was 0.28 +/- 0.28 g.l-1 and 0.30 +/- 0.04 g.l-1 in smokers group. The average value of the orosomucoid in patients was about 1.11 +/- 0.90 mg.ml-1. In the group of smokers, the mean value of orosomucoid was 0.60 +/- 0.13 mg.ml-1. The level of C-reactive protein (CRP) in the patient group reached an average value of 15.31 +/- 22.04 mg.l-1, in the group of smokers was 5.18 +/- 4.58 mg. l 1. Prognostic inflammatory and nutritional index (PINI) in the group of patients showed a mean value of 4.65 +/- 10.77 and 0.026 +/- 0.025 in smokers. Conclusions: The results of this work show, that the values of index PINI in COPD patients are significantly higher than in smokers (P <0.001). This along with other monitored parameters indicative inflammation as well as a catabolic process that occurs in the organism of patients with COPD. PMID- 28646837 TI - Microbiological purity assessment of cosmetics used by one and several persons and cosmetics after their expiry date AB - Background: Microbiological purity of cosmetics provides safety of users during their use, prevents physicochemical changes of a preparation, infections and diseases of the skin. Objective: The aim of this study was to assess the level of microbiological contamination of cosmetics used by one person and by several people and cosmetics after their expiry date in relations to standards for marketed cosmetics, ensuring safety of their use. Material and Methods: This study was conducted using 55 samples representing 19 types of cosmetics, divided into three groups: used by one person, used by several people and after the expiry date. In cosmetic samples the general numbers of aerobic mesophilic bacteria were determined with the spread plate method on tryptic-soy agar. The presence of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans were also checked. Results: The number of aerobic mesophylic bacteria in the tested cosmetics ranged from the level below the method detectability to 1.3*107 cfu/g or ml. The presence of Staphylococcus spp. was found in 11 (20.0%) tested cosmetic samples and of P. aeruginosa in one tested preparation. Yeasts C. albicans were not detected, whereas contamination with fungi Aspergillus spp. and Penicillium spp. ranging from 0.5*101 to 1.5*101 cfu/g or ml was recorded in four cosmetics. The level of microbiological contamination of cosmetics used by several people was higher than that of cosmetics used by one person. Cosmetics after the expiry date showed the highest microbiological contamination. Conclusions: The number of users of cosmetic and it expiry date exceeding influenced the level of microbial contamination of preparations. PMID- 28646838 TI - Immune response cytokines as potential biomarkers for DDT induced neurodegeneration AB - Background: The world incidence rate of Alzheimer's Disease (AD) is 64 cases per 1,000 individuals. Due to the aging population, the prevalence of AD is however increasing and yet, little remains known about the etiology of AD. Objective: Previous studies suggested relationships between AD, neuro-inflammation and organochloride pesticide exposures, therefore, we aimed to study the association between DDT and possible biomarkers of AD. Materials and Methods: We explored literature on inflammation, pesticide exposure and biomarkers associated with AD. We measured eligible markers in adult C57BL/6J mice treated with DDT for 4 months (dose=3 mg/kg/day); Hippocampi tissue gene expression was quantified by qPCR. IL 1beta expression was compared in test vs. control mice using t-tests. Furthermore, we studied population data to: explore the immunological markers, identify gaps and possible approaches for addressing them. Results: Average serum levels of IL-1beta were significantly higher (p<0.05) in the DDT treated mice compared to controls. IL-1beta stimulates APP and Abeta41 syntheses, which may be associated with AD pathogenesis. Gaps identified included: (1) Parallel analysis of genetic and environmental risk factors; (2) Definition of toxin-induced neuro inflammation focusing on microglial physiology. Studies focusing on the physiological effects of DDT, focusing on epigenetic aberrations may aid in the description of the effect of DDT on gene expression; (3) The blood-brain-barrier limits comparisons between peripheral and brain-localized IL-1beta and DDT concentrations, suggesting the need for robust measurement schemes. We report that there is still much uncertainty regarding biomarkers associated with AD pathogenesis. Conclusions: Currently, we cannot confidently report that DDT has a causal role in AD incidence. However, by first quantifying the cytokine concentrations post-exposure to DDT, by measuring the metabolite DDE, we can further explore potential drifts in immune marker concentrations that could provide a platform for future studies. PMID- 28646839 TI - In memoriam: Professor Marcello Spano (1954-2017) PMID- 28646840 TI - Screening for Lynch Syndrome in Cases with Colorectal Carcinoma from Mashhad. AB - INTRODUCTION: Lynch Syndrome (LS) is a genetically inherited autosomal disorder that increases the risk of many types of cancer, especially colorectal cancer (CRC). Identifying these subjects improves morbidity and mortality. We aimed to assess the prevalence of LS with both clinical criteria and universal strategy in Mashhad, Iran. METHODS: In this retrospective study, we screened 322 patients with CRC between 2013 and 2016 in Mashhad, Iran. CRCs were screened based on Amsterdam II criteria, revised Bethesda guideline, and universal strategy. Information regarding the clinical criteria was obtained by interviewing the patients or, their families. Tumors were screened by pathologists with IHC staining of four Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2). Tumors with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs. RESULTS: Of 322 CRCs, 33 cases were found to be deficient-MMR; 22 of these had concurrent loss of MLH1 and PMS2, followed by concurrent loss of MSH2 and MSH6 in 8 CRCs. Twenty-two cases with a loss of MLH1 underwent testing for the BRAF mutation, 4 of which were recognized as a positive BRAF mutation. Finally, 29 CRCs were found as being positive screen for LS. Poor sensitivity (21.74%) was found for the Amsterdam II criteria and a poor positive predictive value (15.39%) for the revised Bethesda. CONCLUSION: Application of clinical criteria may not be effective enough to identify LS and at least 2-antibody panel (PMS2, MSH6) should be conducted for newly diagnosed CRCs. PMID- 28646841 TI - Effect of Extracorporeal Shock Wave Therapy on Lower Limb Spasticity in Stroke Patients. AB - BACKGROUND: This study aims to evaluate the effect of extracorporeal shock wave therapy (ESWT) on lower limb spasticity in stroke patients. METHODS: Twenty-eight eligible patients with ankle plantar flexor spasticity were randomly assigned to two groups. ESWT group received 1 session per week for 3 weeks of ESWT along with oral anti-spastic medications and stretching exercises. The control group received only oral anti-spastic medications and stretching exercises similar to ESWT group. At baseline, weeks 1, 3 and 12, spasticity was assessed and compared between the two groups using Modified Ashworth Scale (MAS), clonus score, passive range of motion (ROM) of joint, pain score, 3-m walk duration and lower extremity functional score (LEFS). Three patients were lost during follow-up; 25 patients completed the study and were analyzed. RESULTS: After one session of ESWT treatment, MAS, pain, ROM and LEFS improved significantly compared to baseline. After three weeks of ESWT treatment, MAS, pain and 3-m walk duration improved significantly compared to week 1. At week 12, MAS, pain, ROM, 3-m walk duration and LEFS improved significantly compared to the control group after controlling baseline values. The trend of decrease in pain score and MAS was significantly different between the groups. The trend of increase in ROM and LEFS was significantly different between the groups. CONCLUSION: ESWT significantly improved lower limb spasticity, pain, passive ROM, 3-m walk duration and LEFS immediately and 12 weeks after treatment. So, ESWT in combination with oral anti spastic medications and stretching exercises could be useful for improvement of spasticity in stroke patients. PMID- 28646842 TI - Fruit and Vegetable Consumption in High School Students in Bandar Abbas, Iran: An Application of the Trans-theoretical Model. AB - BACKGROUND: A diet rich in fruits and vegetables is of a great importance, especially to adolescents due to their need for nutrients and their rapid growth. The aim of this study was to investigate the relationship between decisional balance and self-efficacy with stages of change for fruit and vegetable consumption in high school students in Bandar Abbas, Iran. METHODS: In this descriptive-analytical study, data were collected from 345 students studying in eight high schools of Bandar Abbas who were selected through multistage sampling. To collect data, separate questionnaires were designed for evaluating each of the variables, including the stages of change, perceived benefits, perceived barriers, and self-efficacy of fruit and vegetable consumption. Decisional balance was estimated by subtracting the perceived benefits and barriers. The data were analyzed with one-way ANOVA using SPSS 19. RESULTS: The results of this study indicated that the individuals' progress along the stages of change from pre-contemplation to maintenance level was associated with a significant increase in their decisional balance and self-efficacy for fruit and vegetable consumption (P < 0.001). The lowest level of decisional balance and self-efficacy regarding fruit showed up in the pre-contemplation stage, and the highest level of decisional balance and self-efficacy was in the maintenance stage. Similar trends were observed for vegetable consumption. CONCLUSION: Decisional balance and self efficacy should be considered in designing interventions to increase consumption of fruits and vegetables. There needs to be more emphasis on educational programs based on the Trans-theoretical Model (TTM) for the enhancement of perceived benefits and elimination of perceived barriers regarding consumption of fruits and vegetables. PMID- 28646843 TI - Household Food Insecurity is Associated with Health-Related Quality of Life in Rural Type 2 Diabetic Patients. AB - BACKGROUND: Health-related quality of life (HRQOL) is associated with household food insecurity (HFI). However, the studies examining the relationship between HFI and HRQOL in patients with type 2 diabetes are scarce. Thus, this study was designed to examine the relationship between HFI and HRQOL in rural type 2 diabetic patients. METHODS: In this cross-sectional study, we included 1847 rural patients with type 2 diabetes in Neyshabur from April to July 2012. HRQOL and HFI were measured with 36-item HRQOL (SF-36) and 6-item version of Household Food Security questionnaires, respectively. HRQOL was divided into eight dimensions and two summary components. We categorized households as high food secure (HFS), low food secure (LFS), and very low food secure (VLFS). Multiple linear regression model was applied to assess the independent effect of food insecurity on HRQOL. RESULTS: The mean age of participants was 59.65 +/- 12.3 years (range: 30-97) with 69.8% women. The overall prevalence of HFI was 46.1%, and the total mean score of HRQOL was 51.11. Multiple linear regression model showed that HFI was significantly associated with the total mean score of HRQOL and its eight dimensions. One-way ANOVA test also showed that HRQOL (in all dimensions) was significantly different between 3 groups of household food security status (HFS, LFS, and VLFS) (P < 0.05). CONCLUSIONS: The results of this study showed that HFI was associated with all dimensions of HRQOL and it is one of the strongest variables, in association with HRQOL among rural patients with type 2 diabetes. PMID- 28646844 TI - Prevalence and Associated Factors of HIV Infection among Male Prisoners in Tehran, Iran. AB - BACKGROUND: This is a cross-sectional survey conducted on 6900 male prisoners in Great Tehran Prison from October 2013 to May 2014. METHODS: In order to find HIV positive prisoners in the prison's quarantine and two housing units, we used HIV active case finding (ACF) strategy by rapid screening test. In ACF, healthcare staff and trained prisoners asked inmates to answer relevant questions about history of risky behaviors related to HIV as well as to be tested voluntarily by HIV rapid test. A positive result was confirmed by ELISA screening and Western blot tests. Furthermore, to find the prevalence of specific HIV risk factors among prisoners were assessed using a questionnaire, and the results were analyzed by STATA software, providing univariate and multivariate modeling. RESULTS: There were 85 HIV positive patients. The prevalence of HIV was 1.23%. The risk factors independently associated with HIV infection were age (adjusted odds ratio of 3.46 for 35-44 yrs., 95% CI:1.01-11.92), duration of imprisonment (adjusted odds ratio of 4.22 for >=10 yr., 95% CI: 1.92-9.24 ), history of injection drug use (adjusted odds ratio of 5.01, 95% CI: 2.24-11.18), history of needle sharing (adjusted odds ratio of 2.28, 95% CI: 1.25-4.16) and tattooing (adjusted odds ratio of 1.84, 95% CI: 1.05-3.24). CONCLUSIONS: The prevalence and risk factors of HIV infection should be recognized by policy makers for intensifying harm reduction programs and reforming the HIV guidelines in prisons. PMID- 28646845 TI - An Explanation for Variation in Age at Menopause in Developing Countries Based on the Second National Integrated Micronutrient Survey in Iran. AB - BACKGROUND: It is reported that women in developing countries reach menopause earlier compared to developed countries. This seems to be due to underestimation of age at menopause as pre-menopause women who will reach menopause at older ages are commonly excluded in cross-sectional settings. In this study, we propose an estimation method which can deal with this bias. We also assessed major determinants of menopause. METHODS: The second national integrated micronutrient survey in Iran completed in 2015 is a population-based study with a nationally representative sample of 4,898 Iranian women aged 50 to 60 years. We used data on menopause status and menopausal age (asked retrospectively) to estimate the median survival time. We also used Logistic regression to model menopausal status on the current age and to estimate the median age, at which 50% of women will experience menopause. Demographic, lifestyle, and anthropometric determinants were also examined. RESULTS: The estimated age at menopause was 51.2 (51.0-51.3) years in the logistic model and 50.5 (48.1, 53.7) years in survival analysis. In both models, the age at menopause was significantly lower among rural and underweight women. In addition, survival analysis showed that smokers and women with smaller family size had significantly lower age at menopause. CONCLUSION: While many studies stress a gap in age at menopause between developed and developing countries, this study with a reliable estimation method showed that such a gap might originate from an underestimation of age at menopause in developing countries rather than a real difference. PMID- 28646846 TI - Molecular Epidemiology of Human Respiratory Syncytial Virus in Iranian >=60 Years Old Hospitalized Patients with Acute Respiratory Symptoms. AB - BACKGROUND: Human respiratory syncytial virus (HRSV) is an important cause of acute respiratory infection (ARI) and mortality in >=60 years old population around the world. The aim of this study was to determine the frequency and circulating genotypes of HRSV in Iranian patients >= 60 years old. METHODS: In this cross-sectional molecular epidemiology study, we examined the C-terminal located hypervariable domain of G glycoprotein of HRSV in throat swabs from Tehran, Hormozgan, Boushehr, West Azarbayjan, Ghom and Alborz provinces of Iran which were addressed to national influenza center between October 2013 and March 2015. During these two consecutive years, a total of 225 samples collected from patients older than 60 years were tested using RT hemi-nested PCR and sequencing and the acquired sequences were phylogenetically analyzed. RESULTS: Sixteen out of 225 samples (7.1%) yielded a positive result. Among the positive samples, 13 cases (81%) pertained to antigenic group A and the remaining 3 cases (19%) belonged to group B. Three genotypes including GA1, GA2 and BA9 were identified in the first year of survey whereas during the second year, only GA1 and GA2 genotypes were detected. CONCLUSION: Our study indicates that HRSV genotypes from both A and B antigenic groups which were discovered in pediatric population previously, are circulating among Iranian >=60 years old population. PMID- 28646847 TI - Prevalence of Birth Defects in Iran: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Birth defects are a series of disorders that occur during embryonic life. In Iran, no national situation analysis is available to show the rate of congenital disorders. We aimed to estimate the prevalence of structural birth defects in Iran. METHODS: We searched for English studies on PubMed, Scopus and Google Scholar from January 1990 to July 2016. The search for Persian articles was performed in Scientific Information Database and Magiran. Two reviewers assessed the identified articles independently. The relevant studies were selected based on predefined criteria. Data were analyzed using the Comprehensive Meta-Analysis software. Random effect method was used for meta-analysis. RESULTS: In total, 42 studies were included. The prevalence of congenital anomalies was as follows: orofacial clefts, 1.4 per 1,000 births (95% confidence interval [CI]: 1.2-1.6); neural tube defects, 3.2 per 1,000 births (95% CI: 2.5-4.3); urogenital anomalies, 3.9 per 1,000 births (95% CI: 1.2-12.9); musculoskeletal malformations, 3.3 per 1,000 births (95% CI: 2.3-4.9); cardiovascular anomalies, 3.3 per 1,000 births (95% CI: 2.2-5.1); Down syndrome, 0.9 per 1,000 births (95% CI: 0.7-1.2); gastrointestinal disorders, 1.4 per 1,000 births (95% CI: 0.9-2.1). CONCLUSION: Our results show that urogenital disorders are the most prevalent births defects in Iran, followed by musculoskeletal and cardiovascular malformations. PMID- 28646848 TI - An Analysis of Historical Vignettes by Ibn Sina in the Canon of Medicine on the Structure and Function of the Cardiorespiratory Apparatus. AB - Ibn Sina is regarded as one of the greatest physicians, thinkers and medical scholars in the history of medicine. Ibn Sina, a Persian scholar in the medieval era, wrote a famous book of medicine, the Canon of Medicine. The book was adopted as the main textbook of medicine in most Western and Persian universities. In the present critique, we analyzed the functional and anatomic descriptions of the heart, airways and the lungs as viewed by Ibn Sina in volume three of the Canon of Medicine textbook, and compared them to modern anatomy texts. PMID- 28646849 TI - Screening for Dysglycemia: A Comment on Classification and Diagnosis of Diabetes in American Diabetes Association Standards of Medical Care in Diabetes-2016. PMID- 28646850 TI - The Writing of Iranian Medical History. PMID- 28646852 TI - The facial expression of schizophrenic patients applied with infrared thermal facial image sequence. AB - BACKGROUND: Schizophrenia is a neurological disease characterized by alterations to patients' cognitive functions and emotional expressions. Relevant studies often use magnetic resonance imaging (MRI) of the brain to explore structural differences and responsiveness within brain regions. However, as this technique is expensive and commonly induces claustrophobia, it is frequently refused by patients. Thus, this study used non-contact infrared thermal facial images (ITFIs) to analyze facial temperature changes evoked by different emotions in moderately and markedly ill schizophrenia patients. METHODS: Schizophrenia is an emotion-related disorder, and images eliciting different types of emotions were selected from the international affective picture system (IAPS) and presented to subjects during ITFI collection. ITFIs were aligned using affine registration, and the changes induced by small irregular head movements were corrected. The average temperatures from the forehead, nose, mouth, left cheek, and right cheek were calculated, and continuous temperature changes were used as features. After performing dimensionality reduction and noise removal using the component analysis method, multivariate analysis of variance and the Support Vector Machine (SVM) classification algorithm were used to identify moderately and markedly ill schizophrenia patients. RESULTS: Analysis of five facial areas indicated significant temperature changes in the forehead and nose upon exposure to various emotional stimuli and in the right cheek upon evocation of high valence low arousal (HVLA) stimuli. The most significant P-value (lower than 0.001) was obtained in the forehead area upon evocation of disgust. Finally, when the features of forehead temperature changes in response to low valence high arousal (LVHA) were reduced to 9 using dimensionality reduction and noise removal, the identification rate was as high as 94.3%. CONCLUSIONS: Our results show that features obtained in the forehead, nose, and right cheek significantly differed between moderately and markedly ill schizophrenia patients. We then chose the features that most effectively distinguish between moderately and markedly ill schizophrenia patients using the SVM. These results demonstrate that the ITFI analysis protocol proposed in this study can effectively provide reference information regarding the phase of the disease in patients with schizophrenia. PMID- 28646851 TI - Development of an education campaign to reduce delays in pre-hospital response to stroke. AB - BACKGROUND: Systematic reviews call for well-designed trials with clearly described intervention components to support the effectiveness of educational campaigns to reduce patient delay in stroke presentation. We herein describe the systematic development process of a campaign aimed to increase stroke awareness and preparedness. METHODS: Campaign development followed Intervention Mapping (IM), a theory- and evidence-based tool, and was articulated in two phases: needs assessment and intervention development. In phase 1, two cross-sectional surveys were performed, one aiming to measure stroke awareness in the target population and the other to analyze the behavioral determinants of prehospital delay. In phase 2, a matrix of proximal program objectives was developed, theory-based intervention methods and practical strategies were selected and program components and materials produced. RESULTS: In phase 1, the survey on 202 citizens highlighted underestimation of symptom severity, as in only 44% of stroke situations respondents would choose to call the emergency service (EMS). In the survey on 393 consecutive patients, 55% presented over 2 hours after symptom onset; major determinants were deciding to call the general practitioner first and the reaction of the first person the patient called. In phase 2, adult individuals were identified as the target of the intervention, both as potential "patients" and witnesses of stroke. The low educational level found in the patient survey called for a narrative approach in cartoon form. The family setting was chosen for the message because 42% of patients who presented within 2 hours had been advised by a family member to call EMS. To act on people's tendency to view stroke as an untreatable disease, it was decided to avoid fear arousal appeals and use a positive message providing instructions and hope. Focus groups were used to test educational products and identify the most suitable sites for message dissemination. CONCLUSIONS: The IM approach allowed to develop a stroke campaign integrating theories, scientific evidence and information collected from the target population, and enabled to provide clear explanations for the reasons behind key decisions during the intervention development process. TRIAL REGISTRATION: NCT01881152 . Retrospectively registered June 7 2013. PMID- 28646853 TI - Immunogenicity and protective efficacy of a Salmonella Enteritidis sptP mutant as a live attenuated vaccine candidate. AB - BACKGROUND: Salmonella enterica serovar Enteritidis (S. Enteritidis) is a highly adaptive pathogen in both humans and animals. As a Salmonella Type III secretion system (T3SS) effector, Salmonella protein tyrosine phosphatase (SptP) is critical for virulence in this genus. To investigate the feasibility of using C50336DeltasptP as a live attenuated oral vaccine in mice, we generated the sptP gene deletion mutant C50336DeltasptP in S. Enteritidis strain C50336 by lambda Red mediated recombination and evaluated the protective ability of the S. Enteritidis sptP mutant strain C50336DeltasptP against mice salmonellosis. RESULTS: We found that C50336DeltasptP was a highly immunogenic, effective, and safe vaccine in mice. Compared to wild-type C50336, C50336DeltasptP showed reduced virulence as confirmed by the 50% lethal dose (LD50) in orally infected mice. C50336DeltasptP also showed decreased bacterial colonization both in vivo and in vitro. Immunization with C50336DeltasptP had no significant effect on body weight and did not result in obvious clinical symptoms relative to control animals treated with phosphate-buffered saline (PBS), but induced humoral and cellular immune responses at 12 and 26 days post inoculation. Immunization with 1 * 108 colony-forming units (CFU) C50336DeltasptP per mouse provided 100% protection against subsequent challenge with the wild-type C50336 strain, and immunized mice showed mild and temporary clinical symptoms as compared to those of control group. CONCLUSIONS: These results demonstrate that C50336DeltasptP can be a live attenuated oral vaccine for salmonellosis. PMID- 28646854 TI - Treatment delay and fatal outcomes of pulmonary tuberculosis in advanced age: a retrospective nationwide cohort study. AB - BACKGROUND AND OBJECTIVE: Studies focusing on pulmonary tuberculosis in advanced age (>=80 years) are lacking. This study aimed to explore treatment delay, outcomes and their predictors in this group. METHODS: Adult (>=20 years) patients with pulmonary tuberculosis were identified from the National Health Insurance Research Database of Taiwan from 2004 to 2009. Treatment completion and mortality rates were noted at one year after treatment. RESULTS: Among the 81,081 patients with pulmonary tuberculosis identified, 13,923 (17.2%) were aged >=80 years, and 26,897 (33.2%) were aged 65-79 years. The treatment completion, mortality rates and treatment delay were 54.8%, 34.7% and 61 (12-128) [median, (1st-3rd quartiles)] days in patients aged >=80 years, 68.3%, 18.5% and 53 (8-122) days in patients aged 65-79 years, and 78.9%, 6.5% and 21 (1-84) days in patients aged <65 years, respectively. The elder patients were more likely to receive second line anti-tuberculosis agents. The treatment completion rate decreased with older age, female sex, comorbidities, low income, requiring second-line anti tuberculosis agents, severity of pulmonary tuberculosis and longer treatment delay. Older age, female sex, comorbidities, low income, and not undergoing rapid molecular diagnostic tests were independently associated with longer treatment delays. CONCLUSIONS: Pulmonary tuberculosis in advanced age has a longer treatment delay and a higher mortality rate. Applying rapid molecular diagnostic tools may reduce treatment delay and should be integrated into the diagnostic algorithm for pulmonary tuberculosis, particularly in elderly patients. PMID- 28646855 TI - The neutrophil-to-lymphocyte ratio on admission is a good predictor for all-cause mortality in hypertensive patients over 80 years of age. AB - BACKGROUND: Immuno-inflammation plays a major role in the process of hypertension. We aimed to evaluate the association between inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and all cause mortality in elderly patients with hypertension. METHODS: A total of 341 hypertensive patients over 80 years of age were included to this study. The NLR and RDW were measured on admission and all the selected patients were followed up for up to 90 days. Kaplan-Meier curves were plotted to evaluate the association between the NLR and the all-cause mortality at follow-up. Using Cox regression models, we investigated the prognostic value of NLR and RDW for all-cause mortality. RESULTS: Patients with higher quartile of NLR linked to high mortality in hypertensive patients at 90 day after admission (16.47%,13.25%,1.14%,1.17% respectively; chi2 = 20.581,P = 0.000). Surviving patients had lower RDW (13.61 +/- 1.37 VS 14.18 +/- 1.38, p = 0.041) and NLR (4.97 +/- 5.72 VS 7.95 +/- 6.88,p = 0.011). The receiver operating curve (ROC) of the NLR for all-cause mortality had an area under the curve (AUC) =0.714 (95%CI: 0.629-0.798, P = 0.000), with acritical value of 2.97, with sensitivity of 92.6%, and a specificity of 52.5%. The ROC of the RDW to predict all-cause mortality, had an AUC =0.654 (95%CI:0.548 0.761, P = 0.008), with acritical value of 13.2%.The Kaplan-Meier curve showed a significant difference between different NLR levels (p = 0.002). Multivariate Cox proportional hazard analysis shown 3rd quartile of NLR(RR = 9.646, 95% CI 1.302 34.457, P = 0.041) and 4th quartiles(RR = 16.451, 95% CI 2.137-66.643, P = 0.007) were found to independently predict all-cause death in hypertensive patients over 80 years of age. Higher rank of NLR was link to higher incidence of all-cause death for such patients. CONCLUSION: The findings of the present study demonstrate the potential utility of NLR in risk stratification of elderly patients with hypertension to provide information for clinical treatment strategies. PMID- 28646856 TI - The imbalance of Th17/Treg cells is involved in the progression of nonalcoholic fatty liver disease in mice. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common, chronic liver disease worldwide. Recent studies have shown that T helper (Th) 17 and regulatory T (Treg) cells play critical roles in various disorders of liver inflammation. Here, we explored the value of polyene phosphatidylcholine capsules (PPC) for regulating the imbalance of Th17/Treg cells in the pathogenesis of mice with NAFLD. METHODS: C57BL/6 mice were randomly divided into three groups as follows:normal diet (ND), high-fat diet (HF),and HF plus PPC(HF + PPC). The frequencies of splenic Th17 and Treg cells were measured by flow cytometry, and their related cytokines were analyzed by CBA and real-time PCR. RESULTS: At the end of 24 weeks, mice in the HF group had a higher frequency of intrahepatic Th17 cells,and a lower proportion of Treg cells compared with the ND group. The levels of Th17 cell-related cytokines (IL-6, IL-17 and IL-23) in serum and in liver tisse were increased,and the hepatic mRNA levels of RORgammat, STAT3 and IL-6 were also increased. By contrast,the FoxP3 mRNA level was decreased in the HF group. Moreover, significant pathological and biochemical changes in the liver, as well as serum biochemical changes, were found in mice with NAFLD. Interestingly, following treatment with PPC, the levels of liver inflammation,frequencies of Th17/Treg cells and associated cytokines,and biochemical data were significantly altered. CONCLUSION: These findings demonstrate a critical role for PPC in partially attenuating liver inflammatory responses in mice with NAFLD that involves the imbalance of Treg/Th17 cells and associated cytokines. PMID- 28646858 TI - Reasons for encounter by different levels of urgency in out-of-hours emergency primary health care in Norway: a cross sectional study. AB - BACKGROUND: Frequencies of reasons for encounter (RFEs) in emergency primary care out-of-hours (OOH) services are relevant for planning of capacities as well as to target the training of staff at casualty clinics. We aimed to present frequencies of RFEs in the different organ systems, and to identify the most frequent RFEs at different urgency levels. METHODS: We analyzed data on RFEs in Norwegian OOH services. International Classification of Primary Care (ICPC-2) RFE codes were recorded in all contacts to eight representative OOH casualty clinics in 2014 and 2015 covering 20 municipalities with a total population of 260 196. Frequencies of each ICPC-2 chapters and groups of ICPC-2 codes were calculated at different urgency levels. RESULTS: Musculoskeletal, respiratory, skin, digestive and general and unspecified issues were the most frequent RFE groups. Fever was the most frequent single ICPC-2 RFE code, but was less common among the most urgent cases. Abdominal pain was the most common RFE in patients with yellow urgency level (urgent), and chest pain dominated the potentially red (potentially life threatening) cases. There was less variation in the use of ICPC-2 with increasing urgency level. CONCLUSIONS: This study identifies important differences in RFEs between urgency levels in the Norwegian OOH services. The findings provide new insight into the function of the primary health care emergency services in the Norwegian health care system, and should have implications for staffing, training and equipment in the OOH services. PMID- 28646857 TI - Overview of post-discharge predictors for psychiatric re-hospitalisations: a systematic review of the literature. AB - BACKGROUND: High levels of hospital readmission (rehospitalisation rates) is widely used as indicator of a poor quality of care. This is sometimes also referred to as recidivism or heavy utilization. Previous studies have examined a number of factors likely to influence readmission, although a systematic review of research on post-discharge factors and readmissions has not been conducted so far. The main objective of this review was to identify frequently reported post discharge factors and their effects on readmission rates. METHODS: Studies on the association between post-discharge variables and readmission after an index discharge with a main psychiatric diagnosis were searched in the bibliographic databases Ovid Medline, PsycINFO, ProQuest Health Management, OpenGrey and Google Scholar. Relevant articles published between January 1990 and June 2014 were included. A systematic approach was used to extract and organize in categories the information about post-discharge factors associated with readmission rates. RESULTS: Of the 760 articles identified by the initial search, 80 were selected for this review which included a total number of 59 different predictors of psychiatric readmission. Subsequently these were grouped into four categories: 1) individual vulnerability factors, 2) aftercare related factors, 3) community care and service responsiveness, and 4) contextual factors and social support. Individual factors were addressed in 58 papers and were found to be significant in 37 of these, aftercare factors were significant in 30 out of the 45 papers, community care and social support factors were significant in 21 out of 31 papers addressing these while contextual factors and social support were significant in all seven papers which studied them. CONCLUSIONS: This review represents a first attempt at providing an overview of post-discharge factors previously studied in association with readmission. Hence, by mapping out the current research in the area, it highlights the gaps in research and it provides guidance future studies in the area. PMID- 28646859 TI - Comparison of different NAT assays for the detection of microorganisms belonging to the class Mollicutes. AB - BACKGROUND: Mollicutes detection can be cumbersome due to their slow growth in vitro. For this reason, the use of DNA based on generic molecular tests represents an alternative for rapid, sensitive and specific detection of these microorganism. For this reason, six previously described nucleic acid testing assays were compared to evaluate their ability to detect microorganisms belonging to the class Mollicutes. METHODS: A panel of 61 mollicutes, including representatives from the Mycoplasma, Acholeplasma, Mesoplasma, Spiroplasma and Ureaplasma genus, were selected to evaluate the sensitivity and specificity of these assays. A total of 21 non-mollicutes, including closely related non mollicutes species, were used to evaluate specificity. Limits of detection were calculated to determine the analytical sensitivity of the assays. The two best performing assays were subsequently adapted into real-time PCR format, followed by melting curve analysis. RESULTS: Both assays performed satisfactorily, with a 100% specificity described for both assays. The detection limits were found to be between 10-4 and 10-5 dilutions, equivalent to 15 to 150 genome copies approximately. Based on our work, both van Kuppeveld and Botes real-time PCR assays were found to be the best performing tests in terms of sensitivity and specificity. Furthermore, Botes real-time PCR assay could detect phytoplasmas as well. CONCLUSIONS: These assays can be very useful for the rapid, specific and sensitive screening cell line contaminants, clinical samples as well as detecting non-culturable, unknown species of mollicutes or mollicutes whose growth is slow or difficult. PMID- 28646860 TI - Effect of exercising at minimum recommendations of the multiple sclerosis exercise guideline combined with structured education or attention control education - secondary results of the step it up randomised controlled trial. AB - BACKGROUND: Recent exercise guidelines for people with multiple sclerosis (MS) recommend a minimum of 30 min moderate intensity aerobic exercise and resistance exercise twice per week. This trial compared the secondary outcomes of a combined 10-week guideline based intervention and a Social Cognitive Theory (SCT) education programme with the same exercise intervention involving an attention control education. METHODS: Physically inactive people with MS, scoring 0-3 on Patient Determined Disease Steps Scale, with no MS relapse or change in MS medication, were randomised to 10-week exercise plus SCT education or exercise plus attention control education conditions. Outcomes included fatigue, depression, anxiety, strength, physical activity, SCT constructs and impact of MS and were measured by a blinded assessor pre and post-intervention and 3 and 6 month follow up. RESULTS: One hundred and seventy-four expressed interest, 92 were eligible and 65 enrolled. Using linear mixed effects models, the differences between groups on all secondary measures post-intervention and at follow-up were not significant. Post-hoc, exploratory, within group analysis identified improvements in both groups post intervention in fatigue (mean ?(95% CI) SCT 4.99(-9.87, -0.21), p = 0.04, Control -7.68(-12.13, -3.23), p = 0.00), strength (SCT -1.51(-2.41, -0.60), p < 0.01, Control -1.55(-2.30, -0.79), p < 0.01), physical activity (SCT 9.85(5.45, 14.23), p < 0.01, Control 12.92(4.69, 20.89), goal setting (SCT 7.30(4.19, 10.4), p < 0.01, Control 5.96(2.92, 9.01), p < 0.01) and exercise planning (SCT 5.88(3.37, 8.39), p < 0.01, Control 3.76(1.27, 6.25), p < 0.01) that were maintained above baseline at 3 and 6 month follow up (all p < 0.05). Only the SCT group improved at 3 and 6 month follow up in physical impact of MS(-4.45(-8.68, -0.22), -4.12(-8.25, 0.01), anxiety(-1.76(-3.20, -0.31), 1.99(-3.28, -0.71), depression(-1.51(-2.89, -0.13), -1.02(-2.05, 0.01)) and cognition(5.04(2.51, 7.57), 3.05(0.81, 5.28), with a medium effect for cognition and fitness (Hedges' g 0.75(0.24, 1.25), 0.51(0.01, 1.00) at 3 month follow up. CONCLUSIONS: There were no statistically significant differences between groups for the secondary outcomes once age, gender, time since diagnosis and type of MS were accounted for. However, within the SCT group only there were improvements in anxiety, depression, cognition and physical impact of MS. Exercising at the minimum guideline amount has a positive effect on fatigue, strength and PA that is sustained at 3 and 6 months following the cessation of the program. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02301442 , retrospectively registered on November 13th 2014. PMID- 28646861 TI - C-terminal fragment of agrin (CAF) levels predict acute kidney injury after acute myocardial infarction. AB - BACKGROUND: Patients with acute myocardial infarction are at high risk for acute kidney injury. Novel biomarkers that can predict acute kidney injury in AMI may allow timely interventions. C-terminal fragment of agrin (CAF), a proteoglycan of the glomerular and tubular basement membrane, have been recently associated with rapid renal function deterioration and proximal tubular dysfunction. It is unknown whether elevated CAF levels may serve as a novel AKI biomarker in patients presenting with AMI. METHODS: In 436 persons enrolled in a multicenter prospective observational cohort study of patients with acute myocardial infarction, we measured plasma and urine levels of several kidney injury biomarkers including CAF, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin-C.The relationship between biomarker levels at baseline and the development of AKI and long-term mortality were analyzed after adjustment for demographic and clinical variables. RESULTS: AKI incidence was up to 15% during hospitalization. The predictive accuracy for AKI of urinary CAF was similar to NGAL and superior to other tested kidney injury biomarkers. In a multivariate model that included all possible confounding variables only urinary CAF continued to be an independent marker for AKI (OR 1.35 95%CI 1.05 1.74). During the 2 years follow-up, only plasma CAF levels remained a significant independent predictor of mortality (OR 2.5 95%CI 1.02-6.2; P = 0.04). CONCLUSIONS: Elevated CAF levels are associated with AKI in patients with acute myocardial infarction. Our study provides preliminary evidence that CAF levels may predict AKI and mortality after AMI in low risk patients with relative preserved kidney function at baseline. PMID- 28646862 TI - A clinical utility assessment of the automatic measurement method of the quality of Meibomian glands. AB - BACKGROUND: Meibomian gland dysfunction (MGD) is one of the most common diseases observed in clinics and is the leading cause of evaporative dry eye. Today, diagnostics of MGD is not fully automatic yet and is based on a qualitative assessment made by an ophthalmologist. Therefore, an automatic analysis method was developed to assess MGD quantiatively. MATERIALS: The analysis made use of 228 images of 57 patients recorded by OCULUS Keratograph(r) 5 M with a resolution of 1024 * 1360 pixels concern 30 eyes of healthy individuals (14 women and 16 men) and 27 eyes of sick patients (10 women and 17 men). The diagnosis of dry eye was made according to the consensus of DED in China (2013). METHODS: The presented method of analysis is a new, developed method enabling an automatic, reproducible and quantitative assessment of Meibomian glands. The analysis relates to employing the methods of analysis and image processing. The analysis was conducted in the Matlab environment Version 7.11.0.584, R2010b, Java VM Version: Java 1.6.0_17-b04 with Sun Microsystems Inc. with toolboxes: Statistical, Signal Processing and Image Processing. RESULTS: The presented, new method of analysis of Meibomian glands is fully automatic, does not require operator's intervention, allows obtaining reproducible results and enables a quantitative assessment of Meibomian glands. Compared to the other known methods, particularly with the method described in literature it allows obtaining better sensitivity (98%) and specificity (100%) results by 2%. PMID- 28646863 TI - Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows. AB - BACKGROUND: Susceptibility to Mycobacterium bovis infection in cattle is governed in part by host genetics. However, cattle diagnosed as infected with M. bovis display varying signs of pathology. The variation in host response to infection could represent a continuum since time of exposure or distinct outcomes due to differing pathogen handling. The relationships between host genetics and variation in host response and pathological sequelae following M. bovis infection were explored by genotyping 1966 Holstein-Friesian dairy cows at 538,231 SNPs with three distinct phenotypes. These were: single intradermal cervical comparative tuberculin (SICCT) test positives with visible lesions (VLs), SICCT positives with undetected visible lesions (NVLs) and matched controls SICCT negative on multiple occasions. RESULTS: Regional heritability mapping identified three loci associated with the NVL phenotype on chromosomes 17, 22 and 23, distinct to the region on chromosome 13 associated with the VL phenotype. The region on chromosome 23 was at genome-wide significance and candidate genes overlapping the mapped window included members of the bovine leukocyte antigen class IIb region, a complex known for its role in immunity and disease resistance. Chromosome heritability analysis attributed variance to six and thirteen chromosomes for the VL and NVL phenotypes, respectively, and four of these chromosomes were found to explain a proportion of the phenotypic variation for both the VL and NVL phenotype. By grouping the M. bovis outcomes (VLs and NVLs) variance was attributed to nine chromosomes. When contrasting the two M. bovis infection outcomes (VLs vs NVLs) nine chromosomes were found to harbour heritable variation. Regardless of the case phenotype under investigation, chromosome heritability did not exceed 8% indicating that the genetic control of bTB resistance consists of variants of small to moderate effect situated across many chromosomes of the bovine genome. CONCLUSIONS: These findings suggest the host genetics of M. bovis infection outcomes is governed by distinct and overlapping genetic variants. Thus, variation in the pathology of M. bovis infected cattle may be partly genetically determined and indicative of different host responses or pathogen handling. There may be at least three distinct outcomes following M. bovis exposure in dairy cattle: resistance to infection, infection resulting in pathology or no detectable pathology. PMID- 28646864 TI - Femtosecond laser-assisted cataract surgery after penetrating keratoplasty: a case report. AB - BACKGROUND: Cataract surgery after penetratingkeratoplasty (PKP) is often challenging due to changes in the integrity of the cornea caused by PKP. For example, corneal endothelial cell (CEC) loss and corneal edema commonly occur after traditional phacoemulsification cataract surgery in patients that previously had successful PKP. Recent studies have reported that femtosecond laser-assisted cataract surgery (FLACS) significantly reduces the need for ultrasound energy minimizing mechanical damage to the cornea and results in a reduction of CEC loss and corneal edema. CASE PRESENTATION: We report a case in which FLACS was used in a patient with previous PKP. CONCLUSION: This case supports the suggestion that the use of the femtosecond laser improves the surgical outcome of cataract surgery after PKP. This improvement may be result of the precise incision, controlled capsulorhexis, and reduced lens fragmentation experienced with the femtosecond laser which helps to reduce potential complications of cataract surgery after PKP. PMID- 28646865 TI - Development of stereo endoscope system with its innovative master interface for continuous surgical operation. AB - BACKGROUND: Although robotic laparoscopic surgery has various benefits when compared with conventional open surgery and minimally invasive surgery, it also has issues to overcome and one of the issues is the discontinuous surgical flow that occurs whenever control is swapped between the endoscope system and the operating robot arm system. This can lead to problems such as collision between surgical instruments, injury to patients, and increased operation time. To achieve continuous surgical operation, a wireless controllable stereo endoscope system is proposed which enables the simultaneous control of the operating robot arm system and the endoscope system. METHODS: The proposed system consists of two improved novel master interfaces (iNMIs), a four-degrees of freedom (4-DOFs) endoscope control system (ECS), and a simple three-dimensional (3D) endoscope. In order to simultaneously control the proposed system and patient side manipulators of da Vinci research kit (dVRK), the iNMIs are installed to the master tool manipulators of dVRK system. The 4-DOFs ECS consists of four servo motors and employs a two-parallel link structure to provide translational and fulcrum point motion to the simple 3D endoscope. The images acquired by the endoscope undergo stereo calibration and rectification to provide a clear 3D vision to the surgeon as available in clinically used da Vinci surgical robot systems. Tests designed to verify the accuracy, data transfer time, and power consumption of the iNMIs were performed. The workspace was calculated to estimate clinical applicability and a modified peg transfer task was conducted with three novice volunteers. RESULTS: The iNMIs operated for 317 min and moved in accordance with the surgeon's desire with a mean latency of 5 ms. The workspace was calculated to be 20378.3 cm3, which exceeds the reference workspace of 549.5 cm3. The novice volunteers were able to successfully execute the modified peg transfer task designed to evaluate the proposed system's overall performance. CONCLUSIONS: The experimental results verify that the proposed 3D endoscope system enables continuous surgical flow. The workspace is suitable for the performance of numerous types of surgeries. Therefore, the proposed system is expected to provide much higher safety and efficacy for current surgical robot systems. PMID- 28646866 TI - Engineering redox homeostasis to develop efficient alcohol-producing microbial cell factories. AB - The biosynthetic pathways of most alcohols are linked to intracellular redox homeostasis, which is crucial for life. This crucial balance is primarily controlled by the generation of reducing equivalents, as well as the (reduction) oxidation metabolic cycle and the thiol redox homeostasis system. As a main oxidation pathway of reducing equivalents, the biosynthesis of most alcohols includes redox reactions, which are dependent on cofactors such as NADH or NADPH. Thus, when engineering alcohol-producing strains, the availability of cofactors and redox homeostasis must be considered. In this review, recent advances on the engineering of cellular redox homeostasis systems to accelerate alcohol biosynthesis are summarized. Recent approaches include improving cofactor availability, manipulating the affinity of redox enzymes to specific cofactors, as well as globally controlling redox reactions, indicating the power of these approaches, and opening a path towards improving the production of a number of different industrially-relevant alcohols in the near future. PMID- 28646867 TI - A high-quality annotated transcriptome of swine peripheral blood. AB - BACKGROUND: High throughput gene expression profiling assays of peripheral blood are widely used in biomedicine, as well as in animal genetics and physiology research. Accurate, comprehensive, and precise interpretation of such high throughput assays relies on well-characterized reference genomes and/or transcriptomes. However, neither the reference genome nor the peripheral blood transcriptome of the pig have been sufficiently assembled and annotated to support such profiling assays in this emerging biomedical model organism. We aimed to assemble published and novel RNA-seq data to provide a comprehensive, well-annotated blood transcriptome for pigs by integrating a de novo assembly with a genome-guided assembly. RESULTS: A de novo and a genome-guided transcriptome of porcine whole peripheral blood was assembled with ~162 million pairs of paired-end and ~183 million single-end, trimmed and normalized Illumina RNA-seq reads (~6 billion initial reads from 146 RNA-seq libraries) from five independent studies by using the Trinity and Cufflinks software, respectively. We then removed putative transcripts (PTs) of low confidence from both assemblies and merged the remaining PTs into an integrated transcriptome consisting of 132,928 PTs, with 126,225 (~95%) PTs from the de novo assembly and more than 91% of PTs spliced. In the integrated transcriptome, ~90% and 63% of PTs had significant sequence similarity to sequences in the NCBI NT and NR databases, respectively; 68,754 (~52%) PTs were annotated with 15,965 unique gene ontology (GO) terms; and 7618 PTs annotated with Enzyme Commission codes were assigned to 134 pathways curated by the Kyoto Encyclopedia of Genes and Genomes (KEGG). Full exon-intron junctions of 17,528 PTs were validated by PacBio IsoSeq full-length cDNA reads from 3 other porcine tissues, NCBI pig RefSeq mRNAs and transcripts from Ensembl Sscrofa10.2 annotation. Completeness of the 5' termini of 37,569 PTs was validated by public cap analysis of gene expression (CAGE) data. By comparison to the Ensembl transcripts, we found that (1) the deduced precursors of 54,402 PTs shared at least one intron or exon with those of 18,437 Ensembl transcripts; (2) 12,262 PTs had both longer 5' and 3' termini than their maximally overlapping Ensembl transcripts; and (3) 41,838 spliced PTs were totally missing from the Sscrofa10.2 annotation. Similar results were obtained when the PTs were compared to the pig NCBI RefSeq mRNA collection. CONCLUSIONS: We built, validated and annotated a comprehensive porcine blood transcriptome with significant improvement over the annotation of Ensembl Sscrofa10.2 and the pig NCBI RefSeq mRNAs, and laid a foundation for blood-based high throughput transcriptomic assays in pigs and for advancing annotation of the pig genome. PMID- 28646868 TI - Comprehensive benchmarking of Markov chain Monte Carlo methods for dynamical systems. AB - BACKGROUND: In quantitative biology, mathematical models are used to describe and analyze biological processes. The parameters of these models are usually unknown and need to be estimated from experimental data using statistical methods. In particular, Markov chain Monte Carlo (MCMC) methods have become increasingly popular as they allow for a rigorous analysis of parameter and prediction uncertainties without the need for assuming parameter identifiability or removing non-identifiable parameters. A broad spectrum of MCMC algorithms have been proposed, including single- and multi-chain approaches. However, selecting and tuning sampling algorithms suited for a given problem remains challenging and a comprehensive comparison of different methods is so far not available. RESULTS: We present the results of a thorough benchmarking of state-of-the-art single- and multi-chain sampling methods, including Adaptive Metropolis, Delayed Rejection Adaptive Metropolis, Metropolis adjusted Langevin algorithm, Parallel Tempering and Parallel Hierarchical Sampling. Different initialization and adaptation schemes are considered. To ensure a comprehensive and fair comparison, we consider problems with a range of features such as bifurcations, periodical orbits, multistability of steady-state solutions and chaotic regimes. These problem properties give rise to various posterior distributions including uni- and multi-modal distributions and non-normally distributed mode tails. For an objective comparison, we developed a pipeline for the semi-automatic comparison of sampling results. CONCLUSION: The comparison of MCMC algorithms, initialization and adaptation schemes revealed that overall multi-chain algorithms perform better than single-chain algorithms. In some cases this performance can be further increased by using a preceding multi-start local optimization scheme. These results can inform the selection of sampling methods and the benchmark collection can serve for the evaluation of new algorithms. Furthermore, our results confirm the need to address exploration quality of MCMC chains before applying the commonly used quality measure of effective sample size to prevent false analysis conclusions. PMID- 28646869 TI - Long-term outcomes after combined arthroscopic medial reefing and lateral release in patients with recurrent patellar instability - a retrospective analysis. AB - BACKGROUND: There is currently no consensus regarding the optimal surgical treatment method for patients with recurrent patella instability. Our goal was to evaluate the long-term results of combined arthroscopic medial reefing and lateral release, to identify possible risk factors for recurrent dislocations and residual complaints after surgical treatment and to assess functional outcome. METHODS: We performed a retrospective study of 38 patients (43 knees) treated with all-inside technique between 2001 and 2010. The functional outcome was evaluated with the Kujala score, while pain intensity was scored on a visual analogue scale (VAS). Contingency tables were analysed with Fisher's exact test. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The median age at surgery was 16 years (range, 9-44 years) and the median follow-up amounted to 9.7 years (range, 4.7-14.7 years). Residual complaints were present in 34 cases (79%). Patients with residual complaints had a trend for a higher body mass index (BMI) at surgery (25.7 vs. 21.6, P = .086). Twenty-two cases had recurrent dislocation after a median interval of 30 months. The probability of recurrent dislocations amounted to 16% after 1 year and 52% after 10 years. There were no significant differences in the presence of residual complaints (P = .721) and median VAS score (P = .313) between patients with or without recurrent dislocation. Patients with recurrent dislocations had a trend towards younger age at surgery (15 vs. 18 years, P = .076). The median Kujala score of the affected knee was 81. Patients with recurrent dislocations had a significantly lower score compared to patients without recurrent dislocations (67 vs. 91, P < .001). CONCLUSIONS: The combined arthroscopic lateral release with medial reefing does not appear to be an adequate treatment for patients with chronic patellar instability in long-term follow-up. Younger patients might be at a higher risk for recurrent dislocations, while a higher BMI at surgery might be associated with residual complaints. PMID- 28646870 TI - Incidence and diagnosis of Acute kidney injury in hospitalized adult patients: a retrospective observational study in a tertiary teaching Hospital in Southeast China. AB - BACKGROUND: Acute kidney injury (AKI) places a heavy burden on the healthcare system in China and is usually misdiagnosed. However, there are limited studies that have described the epidemiology and diagnosis of AKI in China. The aim of this study was to describe the incidence and diagnosis of AKI in hospitalized adult patients in a tertiary teaching hospital in southeast China. METHODS: All adult patients hospitalized from October 1, 2013 to September 30, 2014 in the First Affiliated Hospital of Nanjing Medical University were screened using the Lab Administration Network. AKI definition and staging were based on the KDIGO AKI criteria. Demographic characteristics, laboratory examination, clinical data, and clinical outcomes of AKI patients were recorded and analyzed. RESULTS: The incidence of AKI was 1.6% (1401/87196). The 30-day mortality was 35.3%. AKI stage 1, 2, 3 and RRT accounted for 38.0% (532/1401), 22.0% (309/1401), 40.0% (560/1401), and 16.3% (228/1401) of patients, respectively. The Renal, other Internal Medicine, Surgery, and ICU Departments accounted for 7.4%, 37.1%, 30.1%, and 25.4% of AKI patients, respectively. The timely diagnosis rate, delayed diagnosis rate, and missed diagnosis rate were 44% (616/1401), 3.3% (46/1401), and 52.7% (739/1401), respectively. Patients hospitalized in the Renal Department had the highest AKI diagnosis rate (89.3%, 88/103), while missed diagnosis rate of the surgical patients was as high as 75.1% (317/422). Multivariable logistic regression analysis indicated that presence of tumors, higher serum albumin, and AKI stage 1 were associated with failure to timely diagnose AKI, whereas presence of chronic kidney disease, oliguria, higher blood urea nitrogen, and greater number of organ failures correlated with earlier diagnosis. CONCLUSIONS: AKI was characterized by a high incidence, high short-term mortality, and high missed diagnosis rate in hospitalized adult patients in our hospital. Interventions for improving diagnosis of AKI are urgently needed. PMID- 28646871 TI - Coffee and caffeine intake and male infertility: a systematic review. AB - BACKGROUND: Semen quality, a predictor of male fertility, has been suggested declining worldwide. Among other life style factors, male coffee/caffeine consumption was hypothesized to influence semen parameters, but also sperm DNA integrity. To summarize available evidence, we performed a systematic review of observational studies on the relation between coffee/caffeine intake and parameters of male fertility including sperm ploidy, sperm DNA integrity, semen quality and time to pregnancy. METHODS: A systematic literature search was performed up to November 2016 (MEDLINE and EMBASE). We included all observational papers that reported the relation between male coffee/caffeine intake and reproductive outcomes: 1. semen parameters, 2. sperm DNA characteristics, 3. fecundability. All pertinent reports were retrieved and the relative reference lists were systematically searched in order to identify any potential additional studies that could be included. RESULTS: We retrieved 28 papers reporting observational information on coffee/caffeine intake and reproductive outcomes. Overall, they included 19,967 men. 1. Semen parameters did not seem affected by caffeine intake, at least caffeine from coffee, tea and cocoa drinks, in most studies. Conversely, other contributions suggested a negative effect of cola containing beverages and caffeine-containing soft drinks on semen volume, count and concentration. 2. As regards sperm DNA defects, caffeine intake seemed associated with aneuploidy and DNA breaks, but not with other markers of DNA damage. 3. Finally, male coffee drinking was associated to prolonged time to pregnancy in some, but not all, studies. CONCLUSIONS: The literature suggests that caffeine intake, possibly through sperm DNA damage, may negatively affect male reproductive function. Evidence from epidemiological studies on semen parameters and fertility is however inconsistent and inconclusive. Well-designed studies with predefined criteria for semen analysis, subject selection, and life style habits definition, are essential to reach a consistent evidence on the effect of caffeine on semen parameters and male fertility. PMID- 28646873 TI - Labelling effects and adolescent responses to peers with depression: an experimental investigation. AB - BACKGROUND: The impact of illness labels on the stigma experiences of individuals with mental health problems is a matter of ongoing debate. Some argue that labels have a negative influence on judgments and should be avoided in favour of information emphasising the existence of a continuum of mental health/illness. Others believe that behavioral symptoms are more powerful influencers of stigma than labels. The phenomenon has received little attention in adolescent research, despite the critical importance of the peer group at this developmental stage. This study employs a novel experimental design to examine the impact of the depression label and continuum information on adolescents' responses to peers with depression. METHODS: Participants were 156 adolescents, 76 male, 80 female (M = 16.25 years; SD = .361), assigned to one of three conditions (Control, Label, Continuum). Participants respond to four audio-visual vignette characters (two clinically depressed) on three occasions. Outcome measures included judgment of the mental health of the vignette characters and emotional responses to them. RESULTS: Neither the provision of a depression label or continuum information influenced perceptions of the mental health of the characters in the audio-visual vignettes or participants' emotional responses to them. CONCLUSION: The findings have implications for the design of interventions to combat depression stigma with adolescents. Interventions should not necessarily target perceptions of psychiatric labels, but rather perceptions of symptomatic behaviour. PMID- 28646872 TI - Role of P2X7R in the development and progression of pulmonary hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease that lacks sufficient treatment. Studies have shown that the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome contributes to PAH pathogenesis, but the role of the upstream molecular P2X7 receptor (P2X7R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH. METHODS AND RESULTS: PH was induced by a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) on left pneumonectomised Sprague-Dawley rats, as validated by significant increases in pulmonary artery pressure and vessel wall thickness. Marked P2X7R was detected by predominant PA immunostaining in lungs from PH rats. Western blot revealed a significant increase in the protein levels of P2X7R as well as NLRP3 and caspase-1 in the diseased lung tissue compared with normal tissue. The rats received A-740003 (a selective P2X7 receptor antagonist, 30 mg/kg) daily starting from 1 week before or 2 weeks after MCT injection. Consequently, A-740003 reversed the NLRP3 inflammasome upregulation, significantly decreased the mean right ventricular (RV) pressure and RV hypertrophy, and reversed pulmonary arterial remodelling 4 weeks after MCT injection, as both a pretreatment and rescue intervention. Notably, A-740003 significantly reduced macrophage and pro-inflammatory cytokine levels, as measured via bronchoalveolar lavage. The recruitment of macrophages as well as collagen fibre deposition in the perivascular areas were also reduced, as confirmed by histological staining. CONCLUSIONS: P2X7R contributes to the pathogenesis of PH, probably in association with activation of the NLRP3 inflammasome. Blockade of P2X7R might be applied as a novel therapeutic approach for the treatment of PAH. PMID- 28646874 TI - CMSA: a heterogeneous CPU/GPU computing system for multiple similar RNA/DNA sequence alignment. AB - BACKGROUND: The multiple sequence alignment (MSA) is a classic and powerful technique for sequence analysis in bioinformatics. With the rapid growth of biological datasets, MSA parallelization becomes necessary to keep its running time in an acceptable level. Although there are a lot of work on MSA problems, their approaches are either insufficient or contain some implicit assumptions that limit the generality of usage. First, the information of users' sequences, including the sizes of datasets and the lengths of sequences, can be of arbitrary values and are generally unknown before submitted, which are unfortunately ignored by previous work. Second, the center star strategy is suited for aligning similar sequences. But its first stage, center sequence selection, is highly time consuming and requires further optimization. Moreover, given the heterogeneous CPU/GPU platform, prior studies consider the MSA parallelization on GPU devices only, making the CPUs idle during the computation. Co-run computation, however, can maximize the utilization of the computing resources by enabling the workload computation on both CPU and GPU simultaneously. RESULTS: This paper presents CMSA, a robust and efficient MSA system for large-scale datasets on the heterogeneous CPU/GPU platform. It performs and optimizes multiple sequence alignment automatically for users' submitted sequences without any assumptions. CMSA adopts the co-run computation model so that both CPU and GPU devices are fully utilized. Moreover, CMSA proposes an improved center star strategy that reduces the time complexity of its center sequence selection process from O(mn 2) to O(mn). The experimental results show that CMSA achieves an up to 11* speedup and outperforms the state-of-the-art software. CONCLUSION: CMSA focuses on the multiple similar RNA/DNA sequence alignment and proposes a novel bitmap based algorithm to improve the center star strategy. We can conclude that harvesting the high performance of modern GPU is a promising approach to accelerate multiple sequence alignment. Besides, adopting the co-run computation model can maximize the entire system utilization significantly. The source code is available at https://github.com/wangvsa/CMSA . PMID- 28646876 TI - Not all waits are equal: an exploratory investigation of emergency care patient pathways. AB - BACKGROUND: Increasing pressure in the United Kingdom (UK) urgent care system has led to Emergency Departments (EDs) failing to meet the national requirement that 95% of patients are admitted, discharged or transferred within 4-h of arrival. Despite the target being the same for all acute hospitals, individual Trusts organise their services in different ways. The impact of this variation on patient journey time and waiting is unknown. Our study aimed to apply the Lean technique of Value Stream Mapping (VSM) to investigate care processes and delays in patient journeys at four contrasting hospitals. METHODS: VSM timing data were collected for patients accessing acute care at four hospitals in South West England. Data were categorised according to waits and activities, which were compared across sites to identify variations in practice from the patient viewpoint. We included Public and Patient Involvement (PPI) to fully interpret our findings; observations and initial findings were considered in a PPI workshop. RESULTS: One hundred eight patients were recruited, comprising 25,432 min of patient time containing 4098 episodes of care or waiting. The median patient journey was 223 min (3 h, 43 min); just within the 4-h target. Although total patient journey times were similar between sites, the stage where the greatest proportion of waiting occurred varied. Reasons for waiting were dominated by waits for beds, investigations or results to be available. From our sample we observed that EDs without a discharge/clinical decision area exhibited a greater proportion of waiting time following an admission or discharge decision. PPI interpretation indicated that patients who experience waits at the beginning of their journey feel more anxious because they are 'not in the system yet'. CONCLUSIONS: The novel application of VSM analysis across different hospitals, coupled with PPI interpretation, provides important insight into the impact of care provision on patient experience. Measures that could reduce patient waiting include automatic notification of test results, and the option of discharge/clinical decision areas for patients awaiting results or departure. To enhance patient experience, good communication with patients and relatives about reasons for waits is essential. PMID- 28646875 TI - Genome analysis of Diploscapter coronatus: insights into molecular peculiarities of a nematode with parthenogenetic reproduction. AB - BACKGROUND: Sexual reproduction involving the fusion of egg and sperm is prevailing among eukaryotes. In contrast, the nematode Diploscapter coronatus, a close relative of the model Caenorhabditis elegans, reproduces parthenogenetically. Neither males nor sperm have been observed and some steps of meiosis are apparently skipped in this species. To uncover the genomic changes associated with the evolution of parthenogenesis in this nematode, we carried out a genome analysis. RESULTS: We obtained a 170 Mbp draft genome in only 511 scaffolds with a N50 length of 1 Mbp. Nearly 90% of these scaffolds constitute homologous pairs with a 5.7% heterozygosity on average and inversions and translocations, meaning that the 170 Mbp sequences correspond to the diploid genome. Fluorescent staining shows that the D. coronatus genome consists of two chromosomes (2n = 2). In our genome annotation, we found orthologs of 59% of the C. elegans genes. However, a number of genes were missing or very divergent. These include genes involved in sex determination (e.g. xol-1, tra-2) and meiosis (e.g. the kleisins rec-8 and coh-3/4) giving a possible explanation for the absence of males and the second meiotic division. The high degree of heterozygosity allowed us to analyze the expression level of individual alleles. Most of the homologous pairs show very similar expression levels but others exhibit a 2-5-fold difference. CONCLUSIONS: Our high-quality draft genome of D. coronatus reveals the peculiarities of the genome of parthenogenesis and provides some clues to the genetic basis for parthenogenetic reproduction. This draft genome should be the basis to elucidate fundamental questions related to parthenogenesis such as its origin and mechanisms through comparative analyses with other nematodes. Furthermore, being the closest outgroup to the genus Caenorhabditis, the draft genome will help to disclose many idiosyncrasies of the model C. elegans and its congeners in future studies. PMID- 28646877 TI - SBMLmod: a Python-based web application and web service for efficient data integration and model simulation. AB - BACKGROUND: Systems Biology Markup Language (SBML) is the standard model representation and description language in systems biology. Enriching and analysing systems biology models by integrating the multitude of available data, increases the predictive power of these models. This may be a daunting task, which commonly requires bioinformatic competence and scripting. RESULTS: We present SBMLmod, a Python-based web application and service, that automates integration of high throughput data into SBML models. Subsequent steady state analysis is readily accessible via the web service COPASIWS. We illustrate the utility of SBMLmod by integrating gene expression data from different healthy tissues as well as from a cancer dataset into a previously published model of mammalian tryptophan metabolism. CONCLUSION: SBMLmod is a user-friendly platform for model modification and simulation. The web application is available at http://sbmlmod.uit.no , whereas the WSDL definition file for the web service is accessible via http://sbmlmod.uit.no/SBMLmod.wsdl . Furthermore, the entire package can be downloaded from https://github.com/MolecularBioinformatics/sbml mod-ws . We envision that SBMLmod will make automated model modification and simulation available to a broader research community. PMID- 28646878 TI - Achieving sustainability in health information systems: a field tested measure of country ownership. AB - BACKGROUND: A country will trust, value, and use, its health information system (HIS) to the extent it has had a role in its creation and maintenance. A sense of ownership contributes in turn to the long-term sustainability of the HIS, and thus the country's ability to monitor and evaluate population health and health services. To facilitate progress toward greater ownership, we developed and tested a tool to measure the country's ownership of its monitoring and evaluation (M&E) system. METHODS: Through a systematic review of the literature, we identified four dimensions of country ownership of an M&E system: partnership, commitment and responsibility, capacity, and accountability. We identified relevant indicators of the dimensions already in use in other tools used to assess M&E systems. We tested the data collection tool with 95 stakeholders of the Tanzanian HIS for HIV/AIDS control. RESULTS: We identified 56 items that addressed elements of the four dimensions. The respondents found our tool for assessing country ownership of an HIS to be clear and relevant, leading to the identification of important issues to be discussed. For example, all stakeholder groups affirmed that the Tanzanian Commission for AIDS is "playing a leadership role in addressing HIV through collaborative partnerships and work across borders to achieve greater impact." While many respondents disagreed with the statement, "There is an adequate number of government monitoring and evaluation posts at the sub-national level." CONCLUSIONS: Stakeholders found the M&E country ownership tool to address relevant questions clearly. It enabled them to identify successes and challenges within four dimensions of country ownership. It thus holds the potential to lead to an agenda for strengthening country ownership. If implemented every few years, the tool can provide a means of monitoring progress through a set of standardized indicators. As country ownership of M&E increases, so will the long-term sustainability of the HIS. PMID- 28646879 TI - Discovery of a single male Aedes aegypti (L.) in Merseyside, England. AB - BACKGROUND: The mosquito Aedes aegypti (L.) is found in tropical and sub-tropical regions where it is the major vector of dengue fever, yellow fever, chikungunya and more recently Zika virus. Given its importance as a vector of arboviruses and its propensity to be transported to new regions, the European Centre for Disease Prevention and Control (ECDC) has placed Ae. aegypti on a list of potentially invasive mosquito species. It was previously reported in the United Kingdom (UK) in 1865 and 1919 but did not establish on either occasion. It is now beginning to reappear in European countries and has been recorded in the Netherlands (not established) and Madeira (Portugal), as well as southern Russia, Georgia and Turkey. RESULTS: During summer 2014, a single male Ae. aegypti was captured during mosquito collections in north-western England using a sweep net. Morphological identification complimented by sequencing of the ITS2 rDNA, and cox1 mtDNA regions, confirmed the species. Following confirmation, a programme of targeted surveillance was implemented around the collection site by first identifying potential larval habitats in greenhouses, a cemetery, a farm and industrial units. Despite intensive surveillance around the location, no other Ae. aegypti specimens were collected using a combination of sweep netting, larval dipping, mosquito magnets, BG sentinel traps and ovitraps. All species collected were native to the UK. CONCLUSION: The finding of the single male Ae. aegypti, while significant, presents no apparent disease risk to public health, and the follow-up survey suggests that there was no established population. However, this report does highlight the need for vigilance and robust surveillance, and the requirement for procedures to be in place to investigate such findings. PMID- 28646880 TI - 6-shogaol, a neuroactive compound of ginger (jahe gajah) induced neuritogenic activity via NGF responsive pathways in PC-12 cells. AB - BACKGROUND: Ginger is a popular spice and food preservative. The rhizomes of the common ginger have been used as traditional medicine to treat various ailments. 6 Shogaol, a pungent compound isolated from the rhizomes of jahe gajah (Zingiber officinale var officinale) has shown numerous pharmacological activities, including neuroprotective and anti-neuroinflammatory activities. The aim of this study was to investigate the potential of 6-shogaol to mimic the neuritogenic activity of nerve growth factor (NGF) in rat pheochromocytoma (PC-12) cells. METHODS: The cytotoxic effect of 6-shogaol was determined by 3-(4,5 dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The neuritogenic activity was assessed by neurite outgrowth stimulation assay while the concentration of extracellular NGF in cell culture supernatant was assessed by enzyme-linked immunosorbent assay (ELISA). Involvement of cellular signaling pathways, mitogen-activated protein kinase kinase/extracellular signal-regulated kinase1/2 (MEK/ERK1/2) and phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) in 6-shogaol-stimulated neuritogenesis were examined by using specific pharmacological inhibitors. RESULTS: 6-Shogaol (500 ng/ml) induced neuritogenesis that was comparable to NGF (50 ng/ml) and was not cytotoxic towards PC-12 cells. 6-Shogaol induced low level of NGF biosynthesis in PC-12 cells, showing that 6 shogaol stimulated neuritogenesis possibly by inducing NGF biosynthesis, and also acting as a substitute for NGF (NGF mimic) in PC-12 cells. The inhibitors of Trk receptor (K252a), MEK/ERK1/2 (U0126 and PD98059) and PI3K/AKT (LY294002) attenuated the neuritogenic activity of both NGF and 6-shogaol, respectively. CONCLUSIONS: The present findings demonstrated that 6-shogaol induced neuritogenic activity in PC-12 cells via the activation MEK/ERK1/2 and PI3K/AKT signaling pathways. This study suggests that 6-shogaol could act as an NGF mimic, which may be beneficial for preventive and therapeutic uses in neurodegenerative diseases. PMID- 28646881 TI - Heme molecule functions as an endogenous agonist of astrocyte TLR2 to contribute to secondary brain damage after intracerebral hemorrhage. AB - Toll-like receptor 2 (TLR2) was recently shown to contribute to secondary brain damage after intracerebral hemorrhage (ICH), although the molecular mechanisms of this contribution are elusive. In this study, we tested the hypothesis that hemin functions as a TLR2 endogenous agonist, causing proinflammatory astrocyte activation and secondary brain damage after ICH. Hemin administration to the mouse brain striatum induced ICH injury and neurological deficits, however, the brain injury volume and neurological deficits due to hemin injection were significantly reduced in TLR2 knock-out (KO) mice. Hemin administration induced neutrophil infiltration and upregulated neutrophil-attracting chemokine and proinflammatory cytokine expression in wild-type (WT) mice; these effects were ameliorated in TLR2 KO mice. Likewise, ICH-induced blood-brain barrier (BBB) damage was also decreased in TLR2 KO mice. This effect was most likely due to reduced matrix metalloproteinase 9 (MMP9) activity in the TLR2 KO mice compared to WT mice. In primary astrocytes, hemin directly induced MMP9 activity as well as proinflammatory cytokine and chemokine expression in a TLR2-dependent manner. Finally, hemin-induced MMP9 activity and proinflammatory gene expression were almost completely blocked by TLR2-neutralizing antibodies. Taken together, our data propose that heme released to the brain parenchyma after ICH injury activates TLR2 in astrocytes and induces inflammatory gene expression and BBB damage, which contribute to secondary brain damage after ICH. PMID- 28646882 TI - Magnetic foreign body ingestion in pediatric patients: report of three cases. AB - BACKGROUND: Although foreign bodies (FBs) typically pass spontaneously and uneventfully through the digestive tract, a subset of such bodies may become trapped, eventually leading to significant injury. In particular, the ingestion of magnetic materials can cause serious morbidity due to proximate attraction through the intestinal wall. CASE PRESENTATION: We recently treated three pediatric patients who had ingested several magnetic foreign materials. None of these patients exhibited any clinical symptoms or signs suggestive of surgical abdomen. Moreover, it was difficult to determine a definite diagnosis and a treatment plan due to limitations in history taking and radiologic examination. After admission to the hospital, these patients underwent surgery for the following reasons: (1) failure to spontaneously pass ingested foreign materials; (2) sudden-onset abdominal pain and vomiting during hospitalization; and (3) gastric perforation incidentally discovered during gastroduodenoscopy. Subsequently, all patients were discharged without complications; however, their conditions might have been fatal without surgery at an appropriate time. CONCLUSIONS: As the clear identification about the number and characteristics of ingested magnets via radiographic examination or patient history appears to be difficult in pediatric patients, close inpatient observation would be required in any case of undetermined metallic FB ingestion. Patients who are confirmed to have ingested multiple magnets should be regarded as conditional surgical patients, although their clinical conditions are stable. PMID- 28646883 TI - IOEASMA: an integrated clinical and educational pathway for managing asthma in children and adolescents. AB - BACKGROUND: Due to the lack of real life clinical and educational studies, "Io e l'Asma" Centre performed this implementation research (IR). Evaluate long-term effectiveness on bronchial asthma control of an integrated clinical and educational pathway for asthmatic children and adolescents. METHODS: An observational retrospective pre-post intervention IR study was conducted among 262 children with asthma, ages 6-15 yrs. The intervention protocol included three clinical visits 8 weeks apart; an educational course at visit 1, post intervention consisted in two follow-up visits 6 months apart. The primary outcome was to verify the percentage of children who achieved bronchial asthma control at each visit. Secondary outcomes were based on daily therapy modulation, hospital admissions and the number of school days missed. An economic assessment was also included. RESULTS: Two hundred sixty two children with bronchial asthma completed the pathway and were included in the analysis. The percentage of children who obtained disease control increased from 44% at visit 1 to 79% at visit 3 and at 1-year follow-up was 83%. Hospital admissions represent 11% of children: 8% before the intervention, 2% during the intervention, and 1% before and during the intervention; no hospitalizations related to bronchial asthma exacerbations were reported during the 2 follow-up visits. CONCLUSIONS: The therapeutic-educational pathway was adapted according to the international guidelines and the primary performance indicators. Our findings confirmed that the clinical plus educational approach, shared between specialists and family physicians, is an effective template for asthma management. These findings also demonstrated a strong economic advantage. PMID- 28646884 TI - The increased concentration of macrophage migration inhibitory factor in serum and cerebrospinal fluid of patients with tick-borne encephalitis. AB - BACKGROUND: Host factors determining the clinical presentation of tick-borne encephalitis (TBE) are not fully elucidated. The peripheral inflammatory response to TBE virus is hypothesized to facilitate its entry into central nervous system by disrupting the blood-brain barrier with the involvement of a signaling route including Toll-like receptor 3 (TLR3) and pro-inflammatory cytokines macrophage migration inhibitory factor (MIF), tumor necrosis factor-alpha (TNFalpha), and interleukin-1 beta (IL-1beta). METHODS: Concentrations of MIF, TNFalpha, and IL 1beta were measured with commercial ELISA in serum and cerebrospinal fluid (CSF) from 36 hospitalized TBE patients, 7 patients with non-TBE meningitis, and 6 controls. The CSF albumin quotient (AQ) was used as a marker of blood-brain barrier permeability. Single nucleotide polymorphisms rs3775291, rs5743305 (associated with TLR3 expression), and rs755622 (associated with MIF expression) were assessed in blood samples from 108 TBE patients and 72 non-TBE controls. The data were analyzed with non-parametric tests, and p < 0.05 was considered significant. RESULTS: The median serum and CSF concentrations of MIF and IL-1beta were significantly increased in TBE group compared to controls. MIF concentration in serum tended to correlate with AQ in TBE, but not in non-TBE meningitis. The serum concentration of TNFalpha was increased in TBE patients bearing a high expression TLR3 rs5743305 TT genotype, which also associated with the increased risk of TBE. The low-expression rs3775291 TLR3 genotype TT associated with a prolonged increase of CSF protein concentration. The high-expression MIF rs755622 genotype CC tended to correlate with an increased risk of TBE, and within TBE group, it was associated with a mild presentation. CONCLUSIONS: The results point to the signaling route involving TLR3, MIF, and TNFalpha being active in TBE virus infection and contributing to the risk of an overt neuroinvasive disease. The same factors may play a protective role intrathecally contributing to the milder course of neuroinfection. This suggests that the individual variability of the risk and clinical presentation of TBE might be traced to the variable peripheral and intrathecal expression of the mediators of the inflammatory response, which in turn associates with the host genetic background. PMID- 28646885 TI - Comparison of the protective efficacy between single and combination of recombinant adenoviruses expressing complete and truncated glycoprotein, and nucleoprotein of the pathogenic street rabies virus in mice. AB - BACKGROUND: Rabies is an important viral zoonosis that causes acute encephalitis and death in mammals. To date, several recombinant vaccines have been developed based on G protein, which is considered to be the main antigen, and these vaccines are used for rabies control in many countries. Most recombinant viruses expressing RABV G protein retain the G gene from attenuated RABV. Not enough is currently known about the protective effect against RABV of a combination of recombinant adenoviruses expressing the G and N proteins of pathogenic street RABV. METHODS: We constructed a recombinant adenovirus (Ad-0910Gsped) expressing the signal peptide and ectodomain (sped) of G protein of the Korean street strain, and evaluated the immunological protection conferred by a single and combination of three kinds of recombinant adenoviruses (Ad-0910Gsped and Ad-0910G with or without Ad-0910 N) in mice. RESULTS: A combination of Ad-0910G and Ad 0910 N conferred improved immunity against intracranial challenge compared to single administration of Ad-0910G. The Ad-0910G virus, expressing the complete G protein, was more immunogenic than Ad-0910Gsped, which expressed a truncated G protein with the transmembrane and cytoplasmic domains removed. Additionally, oral vaccination using a combination of viruses led to complete protection. CONCLUSIONS: Our results suggest that this combination of viruses is a viable new intramuscular and oral vaccine candidate. PMID- 28646886 TI - Implementation science for ambulatory care safety: a novel method to develop context-sensitive interventions to reduce quality gaps in monitoring high-risk patients. AB - BACKGROUND: Missed evidence-based monitoring in high-risk conditions (e.g., cancer) leads to delayed diagnosis. Current technological solutions fail to close this safety gap. In response, we aim to demonstrate a novel method to identify common vulnerabilities across clinics and generate attributes for context flexible population-level monitoring solutions for widespread implementation to improve quality. METHODS: Based on interviews with staff in otolaryngology, pulmonary, urology, breast, and gastroenterology clinics at a large urban publicly funded health system, we applied journey mapping to co-develop a visual representation of how patients are monitored for high-risk conditions. Using a National Academies framework and context-sensitivity theory, we identified common systems vulnerabilities and developed preliminary concepts for improving the robustness for monitoring patients with high-risk conditions ("design seeds" for potential solutions). Finally, we conducted a face validity and prioritization assessment of the design seeds with the original interviewees. RESULTS: We identified five high-risk situations for potentially consequential diagnostic delays arising from suboptimal patient monitoring. All situations related to detection of cancer (head and neck, lung, prostate, breast, and colorectal). With clinic participants we created 5 journey maps, each representing specialty clinic workflow directed at evidence-based monitoring. System vulnerabilities common to the different clinics included challenges with: data systems, communications handoffs, population-level tracking, and patient activities. Clinic staff ranked 13 design seeds (e.g., keep patient list up to date, use triggered notifications) addressing these vulnerabilities. Each design seed has unique evaluation criteria for the usefulness of potential solutions developed from the seed. CONCLUSIONS: We identified and ranked 13 design seeds that characterize situations that clinicians described 'wake them up at night', and thus could reduce their anxiety, save time, and improve monitoring of high-risk patients. We anticipate that the design seed approach promotes robust and context-sensitive solutions to safety and quality problems because it provides a human-centered link between the experienced problem and various solutions that can be tested for viability. The study also demonstrates a novel integration of industrial and human factors methods (journey mapping, process tracing and design seeds) linked to implementation theory for use in designing interventions that anticipate and reduce implementation challenges. PMID- 28646888 TI - Utilization of HIV testing services among pregnant mothers in low income primary care settings in northern Ethiopia: a cross sectional study. AB - BACKGROUND: HIV testing of women in child bearing age is an entry point for preventing mother-to-child transmission of HIV (MTCT). This study aims to identify the proportion of women tested for HIV and to determine factors associated with utilization of HIV testing services among pregnant mothers in primary care settings in northern Ethiopia. METHODS: A cross sectional study was conducted in 416 pregnant women from four primary care centers between October 2, 2012 and May 31, 2013 in East Gojjam, Ethiopia. RESULTS: The proportion of mothers who tested for HIV was 277(67%). Among mothers who were not tested for HIV, lack of HIV risk perception (n = 68, 49%) was a major self-reported barrier for HIV testing. A multivariable logistic regression analysis showed that those pregnant women who had comprehensive knowledge about MTCT had an Adjusted Odd Ratio (AOR) of 3.73 (95% CI: 1.56, 8.94), having comprehensive knowledge on prevention of mother to child transmission (PMTCT) of HIV an AOR of 2.56 (95% CI: 1.26, 5.19), and a favorable attitude towards persons living with HIV an AOR of 2.42 (95%CI, 1.20, 4.86) were more likely to be tested for HIV. CONCLUSION: One third of pregnant women had never been tested for HIV until the time of the study. Efforts should be made to improve mother's knowledge about MTCT and PMTCT to increase uptake of HIV testing. Enhancing mother's HIV risk perception to scale up HIV testing in resource limited setting is highly recommended. PMID- 28646887 TI - Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for a randomized controlled trial. AB - BACKGROUND: A randomized controlled trial of adults with empyema recently demonstrated decreased length of stay in hospital in patients treated with intrapleurally administered dornase alfa and fibrinolytics compared to fibrinolytics alone. Whether this treatment strategy is safe and effective in children remains unknown. METHODS/DESIGN: This study protocol is for a superiority, placebo-controlled, parallel-design, multicenter randomized controlled trial. The participants are previously well children admitted to a children's hospital with a diagnosis of empyema requiring chest tube insertion and fibrinolytics administered intrapleurally. Children will be randomized after the treating physician has decided that pleural drainage is required but prior to chest tube insertion. After chest tube insertion, participants in the treatment group will receive intrapleurally administered tissue plasminogen activator (tPA) 4 mg followed by dornase alfa 5 mg. Participants in the placebo group will receive tPA 4 mg followed by normal saline. Study treatments will be administered once daily for 3 days. All participants, parents or caregivers, clinicians, and research personnel will remain blinded. The primary outcome is length of stay from chest tube insertion to discharge from hospital. Secondary outcomes include time to meeting discharge criteria, chest tube duration, fever duration, need for additional procedures, adverse events, hospital readmission, cost of hospitalization, and mortality. DISCUSSION: This multicenter randomized controlled trial will assess the safety, effectiveness, and cost-effectiveness of combined treatment with dornase alfa and fibrinolytics compared to fibrinolytics alone for the treatment of empyema in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01717742 . Registered on 8 October 2012. PMID- 28646889 TI - Apps to improve diet, physical activity and sedentary behaviour in children and adolescents: a review of quality, features and behaviour change techniques. AB - BACKGROUND: The number of commercial apps to improve health behaviours in children is growing rapidly. While this provides opportunities for promoting health, the content and quality of apps targeting children and adolescents is largely unexplored. This review systematically evaluated the content and quality of apps to improve diet, physical activity and sedentary behaviour in children and adolescents, and examined relationships of app quality ratings with number of app features and behaviour change techniques (BCTs) used. METHODS: Systematic literature searches were conducted in iTunes and Google Play stores between May November 2016. Apps were included if they targeted children or adolescents, focused on improving diet, physical activity and/or sedentary behaviour, had a user rating of at least 4+ based on at least 20 ratings, and were available in English. App inclusion, downloading and user-testing for quality assessment and content analysis were conducted independently by two reviewers. Spearman correlations were used to examine relationships between app quality, and number of technical app features and BCTs included. RESULTS: Twenty-five apps were included targeting diet (n = 12), physical activity (n = 18) and sedentary behaviour (n = 7). On a 5-point Mobile App Rating Scale (MARS), overall app quality was moderate (total MARS score: 3.6). Functionality was the highest scoring domain (mean: 4.1, SD: 0.6), followed by aesthetics (mean: 3.8, SD: 0.8), and lower scoring for engagement (mean: 3.6, SD: 0.7) and information quality (mean: 2.8, SD: 0.8). On average, 6 BCTs were identified per app (range: 1-14); the most frequently used BCTs were providing 'instructions' (n = 19), 'general encouragement' (n = 18), 'contingent rewards' (n = 17), and 'feedback on performance' (n = 13). App quality ratings correlated positively with numbers of technical app features (rho = 0.42, p < 0.05) and BCTs included (rho = 0.54, p < 0.01). CONCLUSIONS: Popular commercial apps to improve diet, physical activity and sedentary behaviour in children and adolescents had moderate quality overall, scored higher in terms of functionality. Most apps incorporated some BCTs and higher quality apps included more app features and BCTs. Future app development should identify factors that promote users' app engagement, be tailored to specific population groups, and be informed by health behaviour theories. PMID- 28646890 TI - Influence of type I IFN signaling on anti-MOG antibody-mediated demyelination. AB - BACKGROUND: Antibodies with specificity for myelin oligodendrocyte glycoprotein (MOG) are implicated in multiple sclerosis and related diseases. The pathogenic importance of anti-MOG antibody in primary demyelinating pathology remains poorly characterized. OBJECTIVE: The objective of this study is to investigate whether administration of anti-MOG antibody would be sufficient for demyelination and to determine if type I interferon (IFN) signaling plays a similar role in anti-MOG antibody-mediated pathology, as has been shown for neuromyelitis optica-like pathology. METHODS: Purified IgG2a monoclonal anti-MOG antibody and mouse complement were stereotactically injected into the corpus callosum of wild-type and type I IFN receptor deficient mice (IFNAR1-KO) with and without pre established experimental autoimmune encephalomyelitis (EAE). RESULTS: Anti-MOG induced complement-dependent demyelination in the corpus callosum of wild-type mice and did not occur in mice that received control IgG2a. Deposition of activated complement coincided with demyelination, and this was significantly reduced in IFNAR1-KO mice. Co-injection of anti-MOG and complement at onset of symptoms of EAE induced similar levels of callosal demyelination in wild-type and IFNAR1-KO mice. CONCLUSIONS: Anti-MOG antibody and complement was sufficient to induce callosal demyelination, and pathology was dependent on type I IFN. Induction of EAE in IFNAR1-KO mice overcame the dependence on type I IFN for anti MOG and complement-mediated demyelination. PMID- 28646891 TI - Absence of Batf3 results in reduced liver pathology in mice infected with Schistosoma japonicum. AB - BACKGROUND: The involvement of CD8+T cells in schistosomiasis is being increasingly appreciated, but the underlying mechanism is not well defined. RESULTS: In this study, we showed that the absence of Batf3 alleviated liver damage in Batf3 -/- mice infected with S. japonicum. We found alleviated liver granulomatous inflammation in Batf3 -/- mice with schistosomiasis japonica could not be attributed to the difference in schistosome egg or worm burden. The stronger Tc1 cell responses observed in Batf3 -/- mice suggested that the deletion of Batf3 resulted in more activation of CD8+T cells unexpectedly during the natural infection of schistosomes. We detected a small amount of CD8alpha+ DCs in the spleen of Batf3 -/- mice at 9w post-infection. This small amount of newly generated CD8alpha+ DCs might contribute to enhanced activation of CD8+T cells via cross-presentation and activation which then attenuate hepatic pathological damage found in Batf3 -/- mice. CONCLUSIONS: Our study provides evidence that Batf3 is associated with the immunoregulation of the liver granuloma formation, which may confer a new options for schistosomiasis treatment. PMID- 28646892 TI - Effect of acupuncture on cerebrovascular reserve in patients with acute cerebral infarction: protocol for a randomized controlled pilot study. AB - BACKGROUND: The incidence of cerebral infarction has been growing year by year in China and around the world. According to clinical observation, acupuncture utilizing the "waking up the spirit" needling method is widely used in patients with cerebral infarction, though the underlying mechanisms remain unclear. Additionally, a number of studies have begun to focus on the relationship between cerebrovascular reserve (CVR) and cerebral infarction. The present study aims to investigate whether CVR is one of potential mechanisms underpinning this effect of acupuncture on patients with cerebral infarction. METHODS: This is a single centre, prospective, single-blinded, randomized controlled pilot study. Sixty eligible patients will be randomized into an intervention group (waking up the spirit acupuncture) and a control group (hand and foot 12-meridian acupuncture) in a 1:1 ratio. All treatments will be conducted once a day on weekdays followed by a 2-day rest period on the weekend, over a total treatment course of 2 weeks. The primary outcome measures are cerebrovascular reserve (CVR) capacity and Breath-holding Index (BHI) which will be evaluated at baseline and 2 weeks after the first acupuncture treatment, and the secondary outcome measures are National Institutes of Health Stroke Scale (NIHSS) and Barthel Index scores which will be used to further evaluate the efficacy of the intervention. DISCUSSION: Cerebrovascular reserve is an independent risk factor for the occurrence, progression, and recurrence of cerebral infarction that requires attention. This trial aims to investigate whether acupuncture utilizing the waking up the spirit needling method can improve CVR capacity in patients with acute cerebral infarction, thus reducing NIHSS scores and preventing further progression of the disease. Furthermore, data and evidence gained from this study will be utilized in the development of future research projects regarding the effects of acupuncture in patients with acute cerebral infarction. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN99117074 . Registered on 20 April 2016. PMID- 28646893 TI - Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study. AB - BACKGROUND: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600-mutated melanoma treated in the Phase III coBRIM study. METHODS: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms. RESULTS: Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014). CONCLUSIONS: Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600-mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012. PMID- 28646894 TI - Changes in the food environment over time: examining 40 years of data in the Framingham Heart Study. AB - BACKGROUND: Research has explored associations between diet, body weight, and the food environment; however, few studies have examined historical trends in food environments. METHODS: In the Framingham Heart Study Offspring (N = 3321) and Omni (N = 447) cohorts, we created food environment metrics in four Massachusetts towns utilizing geocoded residential, workplace, and food establishment addresses from 1971 to 2008. We created multilevel models adjusted for age, sex, education, and census tract poverty to examine trends in home, workplace, and commuting food environments. RESULTS: Proximity to and density of supermarkets, fast-food, full service restaurants, convenience stores, and bakeries increased over time for residential, workplace, and commuting environments; exposure to grocery stores decreased. The greatest increase in access was for supermarkets, with residential distance to the closest supermarket 1406 m closer (95% CI 1303 m, 1508 m) by 2005 2008 than in 1971-1975. Although poorer census tracts had higher access to fast food restaurants consistently across follow-up, this disparity dissipated over time, due to larger increases in proximity to fast-food in wealthier neighborhoods. CONCLUSIONS: Access to most food establishment types increased over time, with similar trends across home, workplace, and commuter environments. PMID- 28646895 TI - Stereotactic radiosurgery versus whole-brain radiotherapy after intracranial metastasis resection: a systematic review and meta-analysis. AB - BACKGROUND: In patients with one to three brain metastases who undergo resection, options for post-operative treatments include whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) of the resection cavity. In this meta-analysis, we sought to compare the efficacy of each post-operative radiation modality with respect to tumor recurrence and survival. METHODS: Pubmed, Embase and Cochrane databases were searched through June 2016 for cohort studies reporting outcomes of SRS or WBRT after metastasis resection. Pooled effect estimates were calculated using fixed-effect and random-effect models for local recurrence, distant recurrence, and overall survival. RESULTS: Eight retrospective cohort studies with 646 patients (238 with SRS versus 408 with WBRT) were included in the analysis. Comparing SRS to WBRT, the overall crude risk ratio using the fixed effect model was 0.59 for local recurrence (95%-CI: 0.32-1.09, I2: 3.35%, P heterogeneity = 0.36, 3 studies), 1.09 for distant recurrence (95%-CI: 0.74-1.60, I2: 50.5%, P-heterogeneity = 0.13; 3 studies), and 2.99 for leptomeningeal disease (95% CI 1.55-5.76; I2: 14.4% p-heterogeneity: 0.28; 2 studies). For the same comparison, the risk ratio for median overall survival was 0.47 (95% CI: 0.41-0.54; I2: 79.1%, P-heterogeneity < 0.01; 4 studies) in a fixed-effect model, but was no longer significant (0.63; 95%-CI: 0.40-1.00) in a random-effect model. SRS was associated with a lower risk of leukoencephalopathy (RR: 0.15, 95% CI: 0.07-0.33, 1 study), yet with a higher risk of radiation-necrosis (RR: 19.4, 95% CI: 1.21-310, 1 study). CONCLUSION: Based on retrospective cohort studies, the results of this study suggest that SRS of the resection cavity may offer comparable survival and similar local and distant control as adjuvant WBRT, yet may be associated with a higher risk for developing leptomeningeal disease. Future research on SRS should focus on achieving a better understanding of the various factors that may favor SRS over WBRT. PMID- 28646896 TI - Detection of the Plasmodium falciparum Kelch-13 gene P553L mutation in sporozoites isolated from mosquito salivary glands in South-Central Vietnam. AB - BACKGROUND: Plasmodium falciparum has developed resistance against artemisinin in Southeast Asia. Mutations in the P. falciparum Kelch-13 (Pfk13) gene are associated with artemisinin resistance in vitro and in vivo. We investigated the prevalence of mutations in PfK13 from sporozoite-stage parasites isolated from the salivary glands of Anopheles dirus mosquitoes. METHODS: Mosquitoes were caught by human-landing catches at two locations within the Khanh Phu commune, South-Central Vietnam. Identification of Anopheles species was performed based on morphological features and nucleotide sequence analysis. Sporozoite-infected salivary glands were stored on filter paper and at 4-6 degrees C. A nested-PCR targeting the small subunit ribosomal RNA gene was used for Plasmodium species identification. Pfk13 was amplified by nested PCR, and subjected to nucleotide sequencing. RESULTS: Five of 33 P. falciparum sporozoite samples carried the P553L mutation at the PfK13 locus. This mutation has been recorded previously in Vietnam, but not in Khanh Hoa province, were surveys of K13 polymorphism have not previously been carried out. CONCLUSION: These results demonstrate the utility of mosquito-stage malaria parasite samples for studies on the molecular epidemiology of drug resistance. PMID- 28646897 TI - An exploration of facilitators and challenges in the scale-up of a national, public sector community health worker cadre in Zambia: a qualitative study. AB - BACKGROUND: In 2010 a public sector cadre of community health workers called Community Health Assistants (CHAs) was created in Zambia through the National Community Health Worker Strategy to expand access to health services. This cadre continues to be scaled up to meet the growing demands of Zambia's rural population. We summarize factors that have facilitated the scale-up of the CHA program into a nationwide CHW cadre and the challenges of introducing and institutionalizing the cadre within the Zambian health system. METHODS: Semi structured, individual interviews were held across 5 districts with 16 CHAs and 6 CHA supervisors, and 10 focus group discussions were held with 93 community members. Audio recordings of interviews and focus group discussions were transcribed and thematically coded using Dedoose web-based software. RESULTS: The study showed that the CHAs play a critical role in providing a wide range of services at the community level, as described by supervisors and community members. Some challenges still remain, that may inhibit the CHAs ability to provide health services effectively. In particular, the respondents highlighted infrequent supervision, lack of medical and non-medical supplies for outreach services, and challenges with the mobile data reporting system. CONCLUSIONS: The study shows that in order to optimize the impact of CHAs or other community health workers, key health-system support structures need to be functioning effectively, such as supervision, community surveillance systems, supplies, and reporting. The Ministry of Health with support from partners are currently addressing these challenges through nationwide supervisor and community data trainings, as well as advocating for adding primary health care as a specific focus area in the new National Health Strategy Plan 2017-2021. This study contributes to the evidence base on the introduction of formalized community health worker cadres in developing countries. PMID- 28646898 TI - Prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Ureaplasma urealyticum infections using a novel isothermal simultaneous RNA amplification testing method in infertile males. AB - BACKGROUND: The purpose of this study was to evaluate the prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Ureaplasma urealyticum infections in infertile men that consulted our outpatient departments using a novel simultaneous amplification testing (SAT) that is RNA-detection based. The possible impact of C. trachomatis, N. gonorrhoeae, M. genitalium and U. urealyticum infections on semen parameters was also noted in the present study. METHODS: A total of 2607 males that were diagnosed with infertility were included in this study. C. trachomatis, N. gonorrhoeae, M. genitalium and U. urealyticum infections were detected in the urine samples using SAT method. Related data, including semen parameters and age as well as C. trachomatis, N. gonorrhoeae, M. genitalium and U. urealyticum infections were collected and analyzed. RESULTS: A total of 51 and 1418 urine samples were found positive for M. genitalium RNA and U. urealyticum RNA, respectively, while the prevalence of C. trachomatis and N. gonorrhoeae was relatively lower. Men with positive M. genitalium RNA and U. urealyticum RNA had higher sperm DNA fragmentation index (DFI) while the comparisons of other semen parameters yielded nonsignificant results between the RNA positive and negative group. A multivariate linear regression analysis revealed that U. urealyticum and M. genitalium infections posed significant factors of DFI (adjusted R2 = 46.2%). CONCLUSIONS: Our study suggested a relative high prevalence of U. urealyticum and M. genitalium infection based on this novel SAT detection method. U. urealyticum and M. genitalium infection could possibly impair male fertility potential through promoting sperm DNA damage. PMID- 28646899 TI - Immunoproteasome deficiency alters microglial cytokine response and improves cognitive deficits in Alzheimer's disease-like APPPS1 mice. AB - The immunoproteasome (iP) represents a specialized type of proteasomes, which plays an important role in the clearance of oxidant-damaged proteins under inflammatory and pathological conditions determining the outcome of various diseases. In Alzheimer's disease (AD)-like APPPS1 mice Abeta-deposition is paralleled by iP upregulation, most likely mediated through type I interferon induction. To define the impact of increased iP expression we crossed APPPS1 mice with mice deficient in the iP subunit LMP7 resulting in impaired iP function. While LMP7 deficient APPPS1 mice showed no major change in cerebral Abeta pathology, we observed an altered cytokine response in microglia isolated from LMP7 deficient APPPS1 mice compared to LMP7 expressing APPPS1 control mice. The altered microglial cytokine profile upon iP deficiency in the presence of extracellular Abeta-pathology was associated with an improvement of Abeta associated cognitive deficits typically present in APPPS1 mice. Our findings suggest a role for iP in the regulation of the innate immune response towards extracellular Abeta-pathology and indicate that inhibition of iP function can modulate the cognitive phenotype upon overexpression of Abeta. PMID- 28646900 TI - Human umbilical cord stem cell conditioned medium versus serum-free culture medium in the treatment of cryopreserved human ovarian tissues in in-vitro culture: a randomized controlled trial. AB - BACKGROUND: To reduce young female fertility loss, the in-vitro culture of cryopreserved ovarian cortical tissues (OCTs) is considered an effective approach without delaying treatment and undergoing stimulation medicine. However, ischemic damage and follicular loss during the in-vitro culture of OCTs are major technical challenges. Human umbilical cord stem cells (HUMSCs) and their conditioned medium (HUMSC-CM) have been considered to be potential resources for regeneration medicine because they secrete cytokines and enhance cell survival and function. The aim of this study was to determine whether HUMSC-CM improves the development of frozen-thawed in-vitro cultured ovarian tissues compared with a serum-free culture medium (SF-CM). METHODS: The thawed OCTs (n = 68) were cultivated in HUMSC-CM and SF-CM in vitro for 8 days, and the ovarian tissues were processed and analyzed by a classical histological evaluation. The microvessel density (MVD) and apotosis detection during in-vitro culture of OCTs were also performed. RESULTS: A significant difference in the rate of morphologically normal primordial follicles in the HUMSC-CM group was observed compared to that in the SF-CM group (group C) from days 2 to 4 (day 2: group B 58.0 +/- 2.45% vs group C 32.0 +/- 5.83%, p = 0.002; day 3: group B 55.5 +/- 4.20% vs group C 21.0 +/- 9.80%, p = 0.048; day 4: group B 52.0 +/- 4.08% vs group C 21.5 +/- 8.19%, p = 0.019). The microvessel density (MVD) detection showed a time-dependent increase and peaked on day 4. There was a significant difference between groups B (49.33 +/- 0.58) and C (24.33 +/- 3.79) (p = 0.036). The percentage of apoptotic follicles in group B was lower than that in group C on day 1 (13.75 +/- 2.50% vs 27.0 +/- 10.10%, p = 0.003), day 5 (11.75 +/- 1.50% vs 51.0 +/- 10.5%, p = 0.019) and day 7 (15.0 +/- 5.10% vs 46.5 +/- 21.75%, p = 0.018). CONCLUSIONS: These data have provided the first experimental evidence of the effect of HUMSC-CM on frozen-thawed OCTs in vitro. The results showed that the HUMSC-CM group provided a better protecting effect on the in-vitro culture of the cryopreserved OCTs compared to the SF-CM group. PMID- 28646901 TI - Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects. AB - BACKGROUND: Lowering cholesterol levels decreases the risk of atherosclerotic diseases. Effective ways to stably reduce LDL-C level are warranted in type 2 diabetic patients, a high-risk population for CVD, with various anti-diabetic therapeutic background. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles. We evaluated long-term ezetimibe add-on therapy in T2DM patients with hypercholesterolemia. METHODS: In a randomized, multicenter, open-label, prospective study, a total of 109 T2DM patients not attaining LDL-C target value despite first-line dose statin (10 mg of atorvastatin or 1 mg of pitavastatin) therapy in Japan were recruited. We investigated the difference in cholesterol lowering effect between ezetimibe (10 mg) add-on statin (EAT) group and double-dose statin (DST) group. Changes of parameters related to atherosclerotic event risks were assessed. RESULTS: The reduction of LDL-C was larger in the EAT group (28.3%) than in the DST group (9.2%) at 52 weeks as well as the primary endpoint of 12 weeks. EAT achieved significant lower levels of TC and apo B, respectively. Both treatments attained significant reduction in sd-LDL-C or hsCRP on this long-term basis. Notably, sd LDL-C in EAT reduced as low as 36.1 +/- 14.9 mg/dl to reach near the threshold (35.0 mg/dl) for atherosclerosis with significantly higher achievement rate (55.6%) than DST treatment. Simultaneously, hsCRP reduction by EAT attained as low value as 0.52 +/- 0.43 mg/l. CONCLUSIONS: In the present 52-week long-term period, ezetimibe add-on therapy showed a robust advantage in lowering LDL-C and in attaining target LDL-C values compared with the doubling of statin dose. Moreover, it's meaningful that sd-LDL, powerfully atherogenic lipoprotein, exhibited prominent decrease consistently prominently by ezetimibe add-on therapy. DM patients with hypercholesterolemia are at high risk for CAD, and adding ezetimibe onto usual-dose statin treatment in Japan has been suggested as the first-line therapy for those DM patients who failed to attain the target LDL C value (UMIN000002593). PMID- 28646902 TI - How holobionts get sick-toward a unifying scheme of disease. AB - All humans, animals, and plants are holobionts. Holobionts comprise the host and a myriad of interacting microorganisms-the microbiota. The hologenome encompasses the genome of the host plus the composite of all microbial genomes (the microbiome). In health, there is a fine-tuned and resilient equilibrium within the members of the microbiota and between them and the host. This relative stability is maintained by a high level of microbial diversity, a delicate bio geographic distribution of microorganisms, and a sophisticated and intricate molecular crosstalk among the multiple components of the holobiont. Pathobionts are temporarily benign microbes with the potential, under modified ecosystem conditions, to become key players in disease. Pathobionts may be endogenous, living for prolonged periods of time inside or on the host, or exogenous, invading the host during opportunistic situations. In both cases, the end result is the transformation of the beneficial microbiome into a health-perturbing pathobiome. We hypothesize that probably all diseases of holobionts, acute or chronic, infectious or non-infectious, and regional or systemic, are characterized by a perturbation of the healthy microbiome into a diseased pathobiome. PMID- 28646903 TI - Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. AB - BACKGROUND: Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma. METHODS: C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 105 human AD-MSCs, or EVs (released by 105 AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated. RESULTS: In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3+CD4+ T cells, and pro-inflammatory mediators (interleukin [IL]-4, IL-5, IL 13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-beta in lung tissue, and CD3+CD4+ T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3+CD4+ T cells in the mediastinal lymph nodes. CONCLUSIONS: In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different mechanisms of action of AD-MSCs versus their EVs. PMID- 28646904 TI - CT findings in patients with Cabazitaxel induced pelvic pain and haematuria: a case series. AB - BACKGROUND: Haematuria and pelvic pain are recognized and documented adverse reactions related to Cabazitaxel use. To date there has not been any documentation of imaging findings in patients with this presentation. CASES: We report a case series of five patients who experienced these symptoms while on Cabazitaxel and were all found to have very similar urothelial changes on CT. The patients were noted to have ureteric and renal pelvic dilatation along with urothelial enhancement (in those who had post contrast imaging). All of these changes were noted to be reversible in those who had follow up imaging after cessation of Cabazitaxel and initiation of a short course of steroids. CONCLUSION: This case series helps demonstrate the pathological reversible urothelial inflammatory changes that may be occurring in patients experiencing haematuria and pelvic pain on Cabazitaxel therapy. These changes may relate to direct toxic effect of drug metabolites, a radiation recall type phenomenon or a combination of both. PMID- 28646906 TI - Modulation of oxidative phosphorylation and redox homeostasis in mitochondrial NDUFS4 deficiency via mesenchymal stem cells. AB - BACKGROUND: Disorders of the oxidative phosphorylation (OXPHOS) system represent a large group among the inborn errors of metabolism. The most frequently observed biochemical defect is isolated deficiency of mitochondrial complex I (CI). No effective treatment strategies for CI deficiency are so far available. The purpose of this study was to investigate whether and how mesenchymal stem cells (MSCs) are able to modulate metabolic function in fibroblast cell models of CI deficiency. METHODS: We used human and murine fibroblasts with a defect in the nuclear DNA encoded NDUFS4 subunit of CI. Fibroblasts were co-cultured with MSCs under different stress conditions and intercellular mitochondrial transfer was assessed by flow cytometry and fluorescence microscopy. Reactive oxygen species (ROS) levels were measured using MitoSOX-Red. Protein levels of CI were analysed by blue native polyacrylamide gel electrophoresis (BN-PAGE). RESULTS: Direct cellular interactions and mitochondrial transfer between MSCs and human as well as mouse fibroblast cell lines were demonstrated. Mitochondrial transfer was visible in 13.2% and 6% of fibroblasts (e.g. fibroblasts containing MSC mitochondria) for human and mouse cell lines, respectively. The transfer rate could be further stimulated via treatment of cells with TNF-alpha. MSCs effectively lowered cellular ROS production in NDUFS4-deficient fibroblast cell lines (either directly via co-culture or indirectly via incubation of cell lines with cell-free MSC supernatant). However, CI protein expression and activity were not rescued by MSC treatment. CONCLUSION: This study demonstrates the interplay between MSCs and fibroblast cell models of isolated CI deficiency including transfer of mitochondria as well as modulation of cellular ROS levels. Further exploration of these cellular interactions might help to develop MSC-based treatment strategies for human CI deficiency. PMID- 28646907 TI - Dimensions of social capital of families with thalassemia in an indigenous population in Tamil Nadu, India - a qualitative study. AB - BACKGROUND: Studies have shown that social capital is positively associated with health, and the association is context-based. Indigenous populations with poor access to health care largely depend on social capital for their health care needs. This study was conducted to explore the dimensions and types of social capital and its utilization by families with thalassemia for their health and well-being in an indigenous population in Tamil Nadu, India. METHODS: The participants in the study were parents who had children with thalassemia, belonged to an indigenous community in Tamil Nadu, were poor and marginalized, and had poor access to health care. Different dimensions and types of social capital were examined with the help of qualitative in-depth interviews using a phenomenological approach. A total of 8 in-depth interviews were conducted and transcribed. Thematic analysis of the data was performed. RESULTS: The social capital identified through the in-depth interviews consisted of various levels of family support, financial support from relatives and neighbors, the provision of information from formal and informal networks, and trust in the physician. Indigenous communities are close-knit due to their geographical remoteness and limited accessibility. Family ties were a form of social capital that encouraged bonding, and provided support and care to the children affected by thalassemia. The bonding also helped to meet the regular requirement of blood donation for the children. Relatives and neighbors were an asset that served as a bridge for the families affected, helping them in times of immediate and urgent financial need, making it easier to sustain long-term treatment and providing emotional support. There were informal networks that bridged parents belonging to indigenous and non indigenous communities, with the latter providing the former with information to help them choose better health care at an affordable cost. The other formal links were the ties between the parents and nongovernmental organizations, such as the local thalassemia association, which connected members belonging to different areas. It was these ties that were of the greatest assistance to the families affected in coping with the disease, enabling them to sustain the treatment, and assisting them to choose and carry out the complicated bone marrow transplantation, which is the definitive treatment for this condition. CONCLUSION: The bonding, bridging, and linking dimensions of social capital help communities cope with thalassemia, the more so in indigenous and marginalized communities. PMID- 28646905 TI - Mechanistic understanding of nanoparticles' interactions with extracellular matrix: the cell and immune system. AB - Extracellular matrix (ECM) is an extraordinarily complex and unique meshwork composed of structural proteins and glycosaminoglycans. The ECM provides essential physical scaffolding for the cellular constituents, as well as contributes to crucial biochemical signaling. Importantly, ECM is an indispensable part of all biological barriers and substantially modulates the interchange of the nanotechnology products through these barriers. The interactions of the ECM with nanoparticles (NPs) depend on the morphological characteristics of intercellular matrix and on the physical characteristics of the NPs and may be either deleterious or beneficial. Importantly, an altered expression of ECM molecules ultimately affects all biological processes including inflammation. This review critically discusses the specific behavior of NPs that are within the ECM domain, and passing through the biological barriers. Furthermore, regenerative and toxicological aspects of nanomaterials are debated in terms of the immune cells-NPs interactions. PMID- 28646908 TI - Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. AB - BACKGROUND: Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. METHODS: The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660) versus unrelated donors (n = 381), for patients with PRF AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. RESULTS: HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant >=90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. CONCLUSIONS: HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients' outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated. PMID- 28646909 TI - The morphological regeneration and functional restoration of bladder defects by a novel scaffold and adipose-derived stem cells in a rat augmentation model. AB - BACKGROUND: Due to the multilineage differentiation ability and paracrine role of adipose-derived stem cells (ASCs) for bladder defect repair, various scaffolds have been applied in combination with ASCs to promote bladder regeneration and restore bladder function. However, the low survival rate of ASCs and the difficulty of promoting bladder functional recovery are still unsolved. To explore these problems, we investigated the feasibility of a novel scaffold seeded with ASCs in a rat model of bladder augmentation. METHODS: A novel autologous myofibroblast (AM)-silk fibroin (SF) scaffold was harvested after subcutaneously prefabricating the bladder acellular matrix grafts (BAMG) and SF by removing the BAMG. The AM-SF scaffolds were then seeded with ASCs (AM-SF ASCs). Fifty percent supratrigonal cystectomies were performed followed by augmenting the cystectomized defects with AM-SF scaffolds or AM-SF-ASCs. The histological and functional assessments of bladders were performed 2, 4, and 12 weeks after surgery while the ASCs were tracked in vivo. RESULTS: For bladder tissue regeneration, immunofluorescence analysis revealed that AM-SF-ASCs (the experimental group) promoted better morphological regeneration of the urothelium, vessels, bladder smooth muscle, and nerve than AM-SF scaffolds (the control group). Regarding functional restoration, the AM-SF-ASC group exhibited higher bladder compliance and relatively normal micturition pattern compared to the AM SF group. In addition, a certain number of surviving ASCs could be found in vivo 12 weeks after implantation, and some of them had differentiated into smooth muscle cells. CONCLUSIONS: The AM-SF scaffolds with ASCs could rapidly promote bladder morphological regeneration and improved bladder urinary function. In addition, the bag-shaped structure of the AM-SF scaffold can improve the survival of ASCs for at least 12 weeks. This strategy of AM-SF-ASCs has a potential to repair large-scale bladder defects in the clinic in the future. PMID- 28646911 TI - Autophagy and multidrug resistance in cancer. AB - Multidrug resistance (MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence. Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells. PMID- 28646910 TI - The role of 5-HT receptors in depression. AB - Depression is a polygenic and highly complex psychiatric disorder that remains a major burden on society. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are some of the most commonly prescribed drugs worldwide. In this review, we will discuss the evidence that links serotonin and serotonin receptors to the etiology of depression and the mechanisms underlying response to antidepressant treatment. We will then revisit the role of serotonin in three distinct hypotheses that have been proposed over the last several decades to explain the pathophysiology of depression: the monoamine, neurotrophic, and neurogenic hypotheses. Finally, we will discuss how recent studies into serotonin receptors have implicated specific neural circuitry in mediating the antidepressant response, with a focus being placed on the hippocampus. PMID- 28646912 TI - Influences of age-related changes in mesenchymal stem cells on macrophages during in-vitro culture. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have been widely used in cytotherapy and tissue engineering due to their immunosuppressive ability and regenerative potential. Recently, the immunomodulatory influence of MSCs has been gaining increasing attention because their functional roles in modulating immune responses likely have high clinical significance. METHODS: In this study, we investigated the influence of MSCs on macrophages (Mphis) in in-vitro cell culture systems. Given evidence that aged MSCs are functionally compromised, bone marrow-derived MSCs (BMSCs) isolated from both young and aged mice (YMSCs and AMSCs) were evaluated and contrasted. RESULTS: We found that YMSCs exhibited greater proliferative and osteo-differentiation potential compared to AMSCs. When cocultured with RAW264.7 cells (an Mphi cell line), both YMSCs and AMSCs coaxed polarization of Mphis toward an M2 phenotype and induced secretion of anti inflammatory and immunomodulatory cytokines. Compared to AMSCs, YMSCs exhibited a more potent immunomodulatory effect. While Mphis cocultured with either YMSCs or AMSCs displayed similar phagocytic ability, AMSC coculture was found to enhance Mphi migration in Transwell systems. When BMSCs were prestimulated with interferon gamma before coculture with RAW264.7 cells, their regulatory effects on Mphis appeared to be modified. Here, compared to stimulated AMSCs, stimulated YMSCs also exhibited enhanced cellular influence on cocultured RAW264.7 cells. CONCLUSIONS: Our data suggest that BMSCs exert an age-related regulatory effect on Mphis with respect to their phenotype and functions but an optimized stimulation to enhance MSC immunomodulation is in need of further investigation. PMID- 28646913 TI - Interplay between craniofacial stem cells and immune stimulus. AB - Craniofacial mesenchymal stem cells (MSCs), isolated from an abundant and accessible source of craniofacial tissues, possess self-renewal and multilineage differentiation potential. It has been reported that craniofacial MSCs show elevated proliferation and regeneration capacities compared to bone marrow mesenchymal stem cells (BMMSCs). Furthermore, the immunomodulatory property has generated an emerging multidisciplinary research field that translates MSC-based therapies to the clinic for the treatment of inflammatory and autoimmune diseases. Due to tremendous unmet clinical needs, it was extensively investigated how craniofacial MSCs impose their therapeutic effects, especially by interacting with immune cells. Mechanically, MSCs take advantage of a variety of pathways to regulate immune cells, including paracrine signaling such as transforming growth factor (TGF)-beta and hepatocyte growth factor (HGF) pathways, and cell-cell contact Fas/FasL signaling-induced apoptosis. In return, immune cells attenuate MSC function by secreting inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. This perspective review critically discusses the interaction of craniofacial MSCs with the immune milieu, as well as the underlying molecular mechanism contributing to the future improved therapeutic effects of craniofacial MSCs. PMID- 28646914 TI - Markerless motion capture systems as training device in neurological rehabilitation: a systematic review of their use, application, target population and efficacy. AB - BACKGROUND: Client-centred task-oriented training is important in neurological rehabilitation but is time consuming and costly in clinical practice. The use of technology, especially motion capture systems (MCS) which are low cost and easy to apply in clinical practice, may be used to support this kind of training, but knowledge and evidence of their use for training is scarce. The present review aims to investigate 1) which motion capture systems are used as training devices in neurological rehabilitation, 2) how they are applied, 3) in which target population, 4) what the content of the training and 5) efficacy of training with MCS is. METHODS: A computerised systematic literature review was conducted in four databases (PubMed, Cinahl, Cochrane Database and IEEE). The following MeSH terms and key words were used: Motion, Movement, Detection, Capture, Kinect, Rehabilitation, Nervous System Diseases, Multiple Sclerosis, Stroke, Spinal Cord, Parkinson Disease, Cerebral Palsy and Traumatic Brain Injury. The Van Tulder's Quality assessment was used to score the methodological quality of the selected studies. The descriptive analysis is reported by MCS, target population, training parameters and training efficacy. RESULTS: Eighteen studies were selected (mean Van Tulder score = 8.06 +/- 3.67). Based on methodological quality, six studies were selected for analysis of training efficacy. Most commonly used MCS was Microsoft Kinect, training was mostly conducted in upper limb stroke rehabilitation. Training programs varied in intensity, frequency and content. None of the studies reported an individualised training program based on client centred approach. CONCLUSION: Motion capture systems are training devices with potential in neurological rehabilitation to increase the motivation during training and may assist improvement on one or more International Classification of Functioning, Disability and Health (ICF) levels. Although client-centred task oriented training is important in neurological rehabilitation, the client-centred approach was not included. Future technological developments should take up the challenge to combine MCS with the principles of a client-centred task-oriented approach and prove efficacy using randomised controlled trials with long-term follow-up. TRIAL REGISTRATION: Prospero registration number 42016035582 . PMID- 28646915 TI - Isolation, speciation and antifungal susceptibility testing of Candida isolates from various clinical specimens at a tertiary care hospital, Nepal. AB - BACKGROUND: Candida species are responsible for various clinical infections ranging from mucocutaneous infection to life threatening invasive diseases along with increased resistance to antifungal drugs has made a serious concern. Resistance to antifungal agents has increased during the last decade. Thus, identification of Candida up to species level and its antifungal susceptibility testing has a paramount significance in the management of Candidal infections. The aim of the study was to speciate Candida species and to determine antifungal susceptibility pattern of Candida species to antifungal agents. METHODS: A total of 100 consecutive Candida species were isolated from 1248 clinical specimens over 7 months period. Growths on Sabouraud dextrose agar were evaluated for colony appearance, macroscopic examination, Gram staining, germ tube test and urea hydrolysis test. Further, they were processed for Candida speciation on CHROMagar. Antifungal susceptibility testing was performed as recommended by Clinical and Laboratory Standards Institute (CLSI) M44-A document. RESULTS: Out of 100 Candida isolates, Candida albicans (56%) was the most common species. Among the non-albicans Candida species, Candida tropicalis (20%) was the predominant isolate followed by Candida glabrata (14%). Regarding antifungal susceptibility pattern, Candida species were more susceptible to clotrimazole (82%) followed by fluconazole (64%) and miconazole (44%). CONCLUSIONS: Candida albicans was the predominant species responsible for various Candidal infections. Among commonly used antifungal drugs clotrimazole, miconazole and fluconazole were most effective. PMID- 28646916 TI - PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Protein regulator of cytokinesis-1 (PRC1) belongs to the microtubule associated proteins (MAPs) family, and is involved in cytokinesis. Recent investigations suggest PRC1 involvement in human carcinogenesis, including breast carcinoma, hepatocellular carcinoma and etc. However, whether PRC1 contributes to lung adenocarcinoma tumorigenesis remains unknown. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting and Immunohistochemical staining (IHC) were used to evaluate and contrast the PRC1 expression profile in lung adenocarcinoma and adjacent normal lung tissues. We examined the clinical use of PRC1 in lung adenocarcinoma prognosis. Additionally, the tumorigenesis impact of PRC1 in lung adenocarcinoma cells was verified via in vitro and in vivo metastasis and tumorigenesis assays. Notably, Next Generation Sequencing (NGS) was performed to investigate the molecular mechanism underlying the oncogenic role of PRC1 in lung adenocarcinoma. RESULTS: PRC1 mRNA and protein expressions were upregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues. PRC1 protein overexpression correlated with lymph node metastasis and was an independent poor prognostic factor for lung adenocarcinoma patients. Our data implied that PRC1 depletion limited the proliferation and invasion of lung adenocarcinoma cells in vitro and lowered tumor development and lung metastasis in vivo. Remarkably, limiting PRC1 substantially prompted G2/M phase cell cycle arrest and apoptosis. Mechanistically, by conducting NGS on PRC1 depleted A549 cells and control cells, we discovered that PRC1 expression was significantly correlated with the Wnt signaling pathway. CONCLUSIONS: This investigation offers confirmation that PRC1 is a prognostic and promising therapeutic biomarker for people with lung adenocarcinoma and takes on a key part in the activation of the Wnt/beta-catenin pathway in lung adenocarcinoma development. PMID- 28646917 TI - Polycaprolactone nanofiber scaffold enhances the osteogenic differentiation potency of various human tissue-derived mesenchymal stem cells. AB - BACKGROUND: Polycaprolactone (PCL) has been regarded as a promising synthetic material for bone tissue engineering application. Owing to its unique biochemical properties and great compatibility, PCL fibers have come to be explored as a potential delivering scaffold for stem cells to support bone regeneration during clinical application. METHODS: The human derived mesenchymal stem cells (MSCs) were obtained from umbilical cord (UC), bone marrow (BM), and adipose tissue (AD), respectively. The osteogenic differentiation potency of various human MSCs on this novel synthetic biomaterial was also investigated in vitro. RESULTS: Here, we illustrated that those human UC-, BM-, and AD-derived MSCs exhibited fibroblast-like morphology and expressed characteristic markers. Impressively, PCL nanofiber scaffold could support those MSC adhesion and proliferation. Long term culture on PCL nanofiber scaffold maintained the viability as well as accelerated the proliferation of those three different kinds of human MSCs. More importantly, the osteogenic differentiation potency of those human MSCs was increased significantly by culturing on PCL nanofiber scaffold. Of note, BM derived MSCs demonstrated greater differentiation potency among the three kinds of MSCs. The Wnt/beta-catenin and Smad3 signaling pathways contributed to the enhanced osteogenesis of human MSCs, which was activated consistently by PCL nanofiber scaffold. CONCLUSIONS: The utilization of PCL nanofiber scaffold would provide a great application potential for MSC-based bone tissue repair by enhancing the osteogenic differentiation of human MSCs. PMID- 28646918 TI - Diurnal cycling of rhizosphere bacterial communities is associated with shifts in carbon metabolism. AB - BACKGROUND: The circadian clock regulates plant metabolic functions and is an important component in plant health and productivity. Rhizosphere bacteria play critical roles in plant growth, health, and development and are shaped primarily by soil communities. Using Illumina next-generation sequencing and high resolution mass spectrometry, we characterized bacterial communities of wild-type (Col-0) Arabidopsis thaliana and an acyclic line (OX34) ectopically expressing the circadian clock-associated cca1 transcription factor, relative to a soil control, to determine how cycling dynamics affected the microbial community. Microbial communities associated with Brachypodium distachyon (BD21) were also evaluated. RESULTS: Significantly different bacterial community structures (P = 0.031) were observed in the rhizosphere of wild-type plants between light and dark cycle samples. Furthermore, 13% of the community showed cycling, with abundances of several families, including Burkholderiaceae, Rhodospirillaceae, Planctomycetaceae, and Gaiellaceae, exhibiting fluctuation in abundances relative to the light cycle. However, limited-to-no cycling was observed in the acyclic CCAox34 line or in soil controls. Significant cycling was also observed, to a lesser extent, in Brachypodium. Functional gene inference revealed that genes involved in carbohydrate metabolism were likely more abundant in near-dawn, dark samples. Additionally, the composition of organic matter in the rhizosphere showed a significant variation between dark and light cycles. CONCLUSIONS: The results of this study suggest that the rhizosphere bacterial community is regulated, to some extent, by the circadian clock and is likely influenced by, and exerts influences, on plant metabolism and productivity. The timing of bacterial cycling in relation to that of Arabidopsis further suggests that diurnal dynamics influence plant-microbe carbon metabolism and exchange. Equally important, our results suggest that previous studies done without relevance to time of day may need to be reevaluated with regard to the impact of diurnal cycles on the rhizosphere microbial community. PMID- 28646919 TI - Determinants of modern contraceptive practice in Yaounde-Cameroon: a community based cross sectional study. AB - BACKGROUND: Despite numerous efforts put in place to increase modern contraceptive use in Cameroon as a means to fight maternal and infant mortality, the prevalence of modern contraception has shown only a slow increase and maternal mortality is constantly rising. This paper attempts to identify barriers to contraceptive use in Biyem-Assi, Yaounde-Cameroon so as to clearly define in which domain and how to intervene concerning contraceptive use in Cameroon. METHODS: It was a community-based cross sectional study involving a two-steps cluster sampling. Data were collected from November 2014 to April 2015 and analysis done with Epi-Info version 3.5.4. Association between contraceptive use and independent factors was estimated by calculating odds ratio (OR) and confidence interval at 95%. Significance of association in univariate analysis was estimated by calculating the p value with chi2 test. Potential confounder (pregnancy intention) controlled in a multiple logistic regression. RESULTS: A total of 613 sexually active women were enrolled into the study with a mean age of 27.2 (delta +/- 6.2) years. Among the women, 293 (47.8%) were in a union and 530 (86.8%) of them had attended at least a secondary education. Also, 107 (17.5%) responded that their beliefs do not approve contraceptive use and 101 (16.6%) said their partners do not approve contraception. At the moment of data collection, 361 (58.9 [54.9-62.8] %) were currently using a modern contraceptive method. The rate of use of modern contraception was significantly lower in women in a union (OR 0.57, p = 0.0002) and in those with age greater than 30 years (OR 0.45, p = 0.0004). Conversely, the rate of use was significantly higher in women whose partners approved contraception (OR 4.14, p = 0.0000) or when family planning was discussed within the couple (OR 1.93, p = 0.0028). CONCLUSION: The rate of use of modern contraception in Biyem-Assi Health District is relatively high. Women in a union and those aged greater than 30 years turn to be less likely to use a contraceptive method than the rest of the population meanwhile women whose partner approve contraceptive-use or who discuss about family planning with their partners, are most likely to use a contraceptive method than others. To increase the rate of use of modern contraception in Yaounde-Cameroon, interventions should target more of couples and not women alone. PMID- 28646920 TI - Dynamics of Th9 cells and their potential role in immunopathogenesis of murine schistosomiasis. AB - BACKGROUND: Th1, Th2, Th17, Treg and Tfh cells play important roles in schistosomiasis. Th9 cells secrete IL-9 as a signature cytokine and contribute to several classes of inflammatory disease. However, the effects of Th9 cells in schistosomiasis are unknown. We aimed to explore the dynamic changes and potential roles of Th9 cells in the pathogenesis of hepatic egg granulomatous inflammation in mice infected with Schistosoma japonicum. METHODS: Twenty mice with S. japonicum infection and five normal controls (NC) were used as models. The average areas of egg granulomas were estimated by hematoxylin-eosin (H & E) staining. Hepatic IL-9 and transcription factor PU.1 levels were detected by immunohistochemistry. Flow cytometry techniques were used to analyze the proportions of Th9 cells. With the help of ELISA, serum levels of IL-9 were examined. RESULTS: The egg granulomas began to form from four weeks after infection and continued to develop. In parallel with the development of egg granulomas, the hepatic levels of IL-9 and PU.1 increased very slowly during the first four weeks post-infection and increased rapidly thereafter. Moreover, the proportions of splenic Th9 cells and levels of serum IL-9 had similar developmental trends with the egg granulomas. CONCLUSION: The proliferation of Th9 cells and levels of IL-9 were significantly higher in S. japonicum-infected mice compared to NC. In addition, dynamic changes of Th9 and IL-9 were synchronous with the developmental trend of hepatic egg granulomatous inflammation, suggesting that Th9 cells might be a new subset in the pathogenesis of schistosomiasis. PMID- 28646921 TI - Factors associated with intimate partner physical violence among women attending antenatal care in Shire Endaselassie town, Tigray, northern Ethiopia: a cross sectional study, July 2015. AB - BACKGROUND: Intimate partner physical violence is a common global phenomenon. About 30.00% and 38.83% of women in the world and in sub-Saharan Africa experienced physical violence by their partner respectively in 2013. Though intimate partner violence has serious adverse health consequences, there is limited information about partner violence during pregnancy in Ethiopia. Therefore, the aim of this study was to assess the prevalnce of physical intimate partner violence during pregnancy and associated factors among women attending antenatal care in Shire Endaselassie town, Tigray, northen Ethiopia METHODS: A facility based cross-sectional study was conducted from May 3 to July 6, 2015. Four hundred and twenty-two pregnant women attending three public health facilities were included using systematic sampling technique. In addition, twenty two purposely selected key informants were interviewed. The data collectors and supervisors were trained on all data collection processes. Data were entered to Epi-Info version 7.1.2.00 and exported to SPSS version 20.00. Logistic regression was used to identify factors associated with intimate partner physical violence. Statistical significance was declared at p < 0.05. Qualitative data were categorized into themes and triangulated with the quantitative results. RESULTS: The prevalence of intimate partner physical violence in pregnancy was 20.6% (CI = 16.70, 24.90). Age at first marriage greater than or equal to 17 years (AOR = 4.42, CI = 2.07, 9.42), women with no formal education (AOR = 2.78 CI = 1.10, 7.08), rural dwellers (AOR = 2.63 CI = 1.24, 5.58), intimate partners with no formal education (AOR = 2.78 CI = 1.10, 7.08) and intimate partner alcohol consumption (AOR = 3.8 CI = 1.85, 7.82) were factors associated with intimate partner physical violence towards pregnant women. CONCLUSION: Nearly one fifth of women surveyed experienced intimate partner physical violence during pregnancy. Early marriage, rural dwelling, intimate partner alcohol consumption, and educational status were associated with intimate partner physical violence during pregnancy. Urgent attention to women's rights and health is essential at all levels to alleviate the problem and its risk factors in Tigray regional state of Ethiopia. PMID- 28646922 TI - An investigation of the impact of using different methods for network meta analysis: a protocol for an empirical evaluation. AB - BACKGROUND: Network meta-analysis, a method to synthesise evidence from multiple treatments, has increased in popularity in the past decade. Two broad approaches are available to synthesise data across networks, namely, arm- and contrast synthesis models, with a range of models that can be fitted within each. There has been recent debate about the validity of the arm-synthesis models, but to date, there has been limited empirical evaluation comparing results using the methods applied to a large number of networks. We aim to address this gap through the re-analysis of a large cohort of published networks of interventions using a range of network meta-analysis methods. METHODS: We will include a subset of networks from a database of network meta-analyses of randomised trials that have been identified and curated from the published literature. The subset of networks will include those where the primary outcome is binary, the number of events and participants are reported for each direct comparison, and there is no evidence of inconsistency in the network. We will re-analyse the networks using three contrast-synthesis methods and two arm-synthesis methods. We will compare the estimated treatment effects, their standard errors, treatment hierarchy based on the surface under the cumulative ranking (SUCRA) curve, the SUCRA value, and the between-trial heterogeneity variance across the network meta-analysis methods. We will investigate whether differences in the results are affected by network characteristics and baseline risk. DISCUSSION: The results of this study will inform whether, in practice, the choice of network meta-analysis method matters, and if it does, in what situations differences in the results between methods might arise. The results from this research might also inform future simulation studies. PMID- 28646923 TI - Predictive value of body mass index to metabolic syndrome risk factors in Syrian adolescents. AB - BACKGROUND: Obesity has become a serious epidemic health problem in both developing and developed countries. There is much evidence that obesity among adolescents contributed significantly to the development of type 2 diabetes and coronary heart disease in adulthood. Very limited information exists on the prevalence of overweight, obesity, and associated metabolic risk factors among Syrian adolescents. Therefore, the purpose of this study was to determine the relationship between obesity determined by body mass index and the major metabolic risk factors among Syrian adolescents. METHODS: A cross-sectional study of a randomly selected sample of 2064 apparently healthy Syrian adolescents aged 18 to 19 years from Damascus city, in Syria, was performed. Body mass index and blood pressure were measured. Serum concentrations of glucose, triglycerides, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol were determined. Metabolic syndrome was defined using the national criteria for each determined metabolic risk factor. Individuals with a body mass index 25 to 29.9 were classified as overweight, whereas individuals with a body mass index >=30 were classified as obese. A receiver operating characteristics curve was drawn to determine appropriate cut-off points of the body mass index for defining overweight and obesity, and to indicate the performance of body mass index as a predictor of risk factors. RESULTS: The obtained data showed that blood pressure and the overall mean concentrations of fasting blood sugar, triglycerides, cholesterol, low-density lipoprotein cholesterol, and triglycerides/high-density lipoprotein-cholesterol were significantly higher in overweight and obese adolescent groups (p <0.0001) in comparison with the normal group. Based on receiver operating characteristics calculation for body mass index and some metabolic risks, the data suggest the best body mass index cut-offs ranged between 23.25 and 24.35 kg/m2. CONCLUSIONS: A strong association between overweight and obesity as determined by body mass index and high concentrations of metabolic syndrome components has been demonstrated. Although body mass index values were lower than the international cut-offs, these values were good predictors of some metabolic abnormalities in Syrian adolescents; body mass index is a good predictor of these abnormalities in this population. PMID- 28646924 TI - Ciprofloxacin for contacts of cases of meningococcal meningitis as an epidemic response: study protocol for a cluster-randomized trial. AB - BACKGROUND: Epidemics of meningococcal meningitis are common in the "African meningitis belt." Current response strategies include reactive vaccination campaigns, which are often organized too late to have maximal impact. A novel strain of Neisseria meningitidis serogroup C has been circulating in recent years, and vaccine supplies are limited. An evaluation of chemoprophylaxis with single-dose ciprofloxacin for household contacts of meningitis cases has therefore been recommended. METHODS/DESIGN: A three-arm cluster-randomized trial has been designed for implementation during a meningococcal meningitis epidemic in a health district in Niger in which at least two Health Zones (HZs) have met the weekly epidemic threshold. The primary outcome is the incidence (attack rate) of meningitis during the epidemic. Villages will be randomized in a 1:1:1 ratio to one of three different arms: standard care, household-level prophylaxis, or village-wide prophylaxis. After study launch, when a case of meningococcal meningitis is identified in an HZ, the first reported case from a village will trigger the inclusion and randomization of the village. Household-level prophylaxis with single-dose ciprofloxacin will be offered in the home to all household members within 24 hours of the notification of the case, and village wide distributions will occur within 72 hours of the notification of the case. The sample size necessary to detect differences between each of the two intervention arms and the standard care arm will be set after 4 weeks of data collection, in order to quantify multiple variables that could be particular to a given area. The primary analysis will compare attack rates at the end of the epidemic in each of the three arms. A nested sub-study will assess the effects of ciprofloxacin prophylaxis on the prevalence of ciprofloxacin-resistant enterobacteriaceae. A total of 200 participants in the standard care arm and 200 in the village-wide prophylaxis arm will provide stool samples at days 0, 7, and 28 following their village's inclusion in the study. DISCUSSION: An innovative trial is proposed for implementation during an epidemic that will assess the impact of a novel strategy for meningitis outbreak response. In parallel, we will describe potential negative effects of the intervention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02724046 . Registered on 15 March 2016. Last updated on 13 June 2017. PMID- 28646925 TI - Stress ulcer prophylaxis versus placebo or no prophylaxis in adult hospitalised acutely ill patients-protocol for a systematic review with meta-analysis and trial sequential analysis. AB - BACKGROUND: Stress ulcer prophylaxis is considered standard of care in many critically ill patients in the intensive care unit (ICU). However, the quality of evidence supporting this has recently been questioned, and clinical equipoise exists. Whether there is overall benefit or harm of stress ulcer prophylaxis in adult hospitalised acutely ill patients is unknown. Accordingly, we aim to assess patient-important benefits and harms of stress ulcer prophylaxis versus placebo or no treatment in adult hospitalised acutely ill patients with high risk of gastrointestinal bleeding irrespective of hospital setting. METHODS/DESIGN: We will conduct a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis and assess use of proton pump inhibitors (PPIs) or histamine-2-receptor antagonists (H2RAs) in any dose, formulation and duration. We will accept placebo or no prophylaxis as control interventions. The participants will be adult hospitalised acutely ill patients with high risk of gastrointestinal bleeding. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: There is a need for a high-quality systematic review to summarise the benefits and harms of stress ulcer prophylaxis in hospitalised patients to inform practice and future research. Although stress ulcer prophylaxis is used worldwide, no firm evidence for benefit or harm as compared to placebo or no treatments has been established. Critical illness is a continuum not limited to the ICU setting, which is why it is important to assess the benefits and harms of stress ulcer prophylaxis in a wider perspective than exclusively in ICU patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055676. PMID- 28646926 TI - High burden of Schistosoma mansoni infection in school-aged children in Marolambo District, Madagascar. AB - BACKGROUND: A school-based survey was undertaken to assess prevalence and infection intensity of schistosomiasis in school-aged children in the Marolambo District of Madagascar. METHODS: School-aged children from six purposively selected schools were tested for Schistosoma haematobium by urine filtration and Schistosoma mansoni using circulating cathodic antigen (CCA) and Kato-Katz stool analysis. The investigators did not address soil-transmitted helminths (STH) in this study. RESULTS: Of 399 school-aged children screened, 93.7% were infected with S. mansoni based on CCA analysis. Kato-Katz analysis of stool revealed S. mansoni infection in 73.6% (215/ 292). Heavy infections (> 400 eggs per gram) were common (32.1%; 69/ 215), with a mean of 482 eggs per gram of stool. Moderate infection intensities were detected in 31.2% (67/ 215) and light infection intensities in 36.7% (79/ 215) of infected participants. No infection with S. haematobium was detected by urine filtration. CONCLUSIONS: Intestinal schistosomiasis appears a considerable public health issue in this remote area of Madagascar where there is a pressing need for mass drug administration. PMID- 28646927 TI - HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial-mesenchymal transition. AB - BACKGROUND: Homeobox B7 (HOXB7) has been identified associated with poor prognosis of hepatocellular carcinoma (HCC). However, the specific mechanism by which HOXB7 promotes the malignant progression of HCC remains to be determined. METHODS: Immunohistochemistry (IHC) was used to detect the expression level of HOXB7 in 77-paired HCC tissue samples, and the correlation between HOXB7 and HCC prognosis was assessed. The location of HOXB7 was confirmed by immunofluorescence. Cell Titer-Blue assay was used to assess the proliferation of hepatoma cells. The stem-like properties of hepatoma cells were analysed by sphere formation and clone formation assays. The effect of HOXB7 on expression of cancer stem cell markers was evaluated. Transwell and wound-healing assays were performed to estimate the invasion and migration abilities of hepatoma cells. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Bioluminescence imaging was used to survey the effect of HOXB7 on the metastatic ability of hepatoma cells in vivo. RESULTS: Higher expression of HOXB7 was detected in HCC tissues compared with noncancerous tissues and significantly associated with poor prognosis of HCC. In addition, HOXB7 knockdown suppressed the cell proliferation, clone formation, sphere formation, invasion and migration of hepatoma cells in vitro; conversely, these biological abilities of hepatoma cells were enhanced by HOXB7 overexpression. Moreover, the cancer stem cell markers EPCAM and NANOG were up-regulated by HOXB7. The role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that c-Myc and Slug expression was elevated by HOXB7 and the AKT pathway was activated. CONCLUSION: Overexpression of HOXB7 was significantly correlated with poor prognosis of HCC. HOXB7 up-regulated c-Myc and Slug expression via the AKT pathway to promote the acquisition of stem-like properties and facilitate epithelial-mesenchymal transition of hepatoma cells, accelerating the malignant progression of HCC. PMID- 28646928 TI - The association between ambient fine particulate matter and incident adenocarcinoma subtype of lung cancer. AB - BACKGROUND: Adenocarcinoma (AC) is the most common lung cancer among non-smokers, but few studies have assessed the effect of PM2.5 on AC among never smokers. The purpose of this study was to assess the association between ambient PM2.5 and incident lung AC in the Adventist Health and Smog Study-2 (AHSMOG-2), a cohort of 80,044 non-smokers (81% never smokers) followed for 7.5 years (597,177 person years) (2002-2011). METHODS: Incident lung AC was identified through linkage with U.S. state cancer registries. Ambient PM2.5 levels at subjects' residences were estimated for the years 2000 and 2001, immediately prior to study start. RESULTS: A total of 164 incident lung AC occurred during follow-up. Each 10 MUg/m3 increment in PM2.5 was associated with an increase in the hazard rate of lung AC [HR = 1.31 (95% confidence interval (CI) 0.87-1.97)] in the single-pollutant model. Excluding those with prevalent non-melanoma skin cancer (NMSC) strengthened the association with lung AC (HR = 1.62 (95% CI, 1.11-2.36) for each 10 MUg/m3 PM2.5 increment. Also, limiting the analyses to subjects who spent more than 1 h/day outdoors, increased the estimate (HR = 1.55, 95% CI: 1.05, 2.30). CONCLUSIONS: Increased risk of AC was observed for each 10 MUg/m3 increment in ambient PM2.5 concentrations. The risk was higher among those without prevalent NMSC and those who spent more than 1 h/day outdoors. PMID- 28646930 TI - The Urology Guide to Coffee and Tea. PMID- 28646929 TI - Maternal serum anti-Mullerian hormone in Sudanese women with preeclampsia. AB - OBJECTIVES: A case-control study was conducted at Omdurman Maternity Tertiary Hospital, Sudan, during the period from May to August 2014 to investigate AMH level in women with preeclampsia compared to healthy controls. The cases were women with preeclampsia and healthy pregnant women were the controls. The obstetrics and medical history was gathered using a questionnaire. AMH level was measured using ELISA. RESULTS: There was no significant difference between the two groups (40 in each arm of the study) in the age, parity and gestational age. Thirty-three of the 40 cases were patients with severe preeclampsia. There was no significant difference in median inter-quartile of the AMH level between the women with preeclampsia and the controls [0.700 (0.225-1.500) vs. 0.700 (0.400 1.275) ng/ml, P = 0.967]. In a linear regression model there was no association between the log of AMH and age, parity, gestational age, BMI, hemoglobin level and preeclampsia. PMID- 28646931 TI - Legends in Urology. PMID- 28646932 TI - BCG: A throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy. AB - INTRODUCTION: It is 40 years since the initial documentation of the efficacy of bacille Calmette-Guerin (BCG) in the management of non-muscle invasive bladder cancer (NMIBC) and probably an opportune a time as any to retrace the origins of this development and to reflect on the progress that has occurred on the use of immune modifiers in the treatment of NMIBC. MATERIALS AND METHODS: A PubMed search for publications on the history of BCG was conducted, and those related to the development of the vaccine for protection against tuberculosis as well as those published in the last 40 years related to its use for treatment for NMIBC were selected for review. A manual search was also carried out for recent articles on immunotherapy for NMIBC failing to respond to BCG. Publications were selected for their usefulness in exemplifying the development of BCG as an antineoplastic agent, elucidating its mechanisms of action of BCG or introducing significant modifications in treatment regimens resulting in enhancement of its efficacy. Alternative innovative immunotherapeutic approaches were chosen to illustrate current trends in the management of this disease. RESULTS: Well thought-out modifications of the original protocol resulted in enhanced efficacy of the vaccine, which currently ranks as the best-known and most-used and investigated agent for high risk NMIBC. Despite its efficacy, a considerable number (30%-40%) of these tumors fail to respond to BCG. In addition, as a live bacterium it carries the potential for serious adverse effects and some patients are unable to tolerate it. These shortcomings have created the need for new agents. These range from other mycobacteria and viruses to monoclonal antibodies alone or in combination with other agents currently at various stages of development. CONCLUSION: After 4 decades of use, BCG remains the most effective agent against high risk NMIBC, but it still holds substantial drawbacks. The enduring use of immunotherapy for NMIBC has created a propitious environment to search for better alternatives. There are an increasing number of promising in vitro, animal and early human clinical trials to anticipate a significant therapeutic alternative in the foreseeable future. PMID- 28646933 TI - BCG for high grade NMIBC - Lessons learned over 40 years. PMID- 28646934 TI - Timing interval from peri-prostatic block to biopsy impacts procedural pain. AB - INTRODUCTION: To compare visual analog scale (VAS) pain scores between patients with a 2-minute versus 10-minute delay of peri-prostatic lidocaine injection prior to transrectal ultrasound-guided prostate biopsies (TRUS-bx). MATERIALS AND METHODS: Eighty patients who underwent standard 12-core TRUS-bx by a single surgeon were prospectively randomized into four different treatment arms: bibasilar injection with a 2-minute delay, bibasilar injection plus a single apical injection with a 2-minute delay, bibasilar injection with a 10-minute delay, and bibasilar injection plus a single apical injection with a 10-minute delay. Patients were asked to report their level of pain on the VAS (0-10, with 10 indicating unbearable pain) at the following intervals: probe insertion (baseline), after each core, and post-procedure. The primary outcome measure was mean VAS score across all 12 cores minus baseline VAS score, which we refer to baseline-adjusted mean VAS score. RESULTS: Baseline-adjusted mean VAS score was significantly higher for the 2-minute delay group compared to the 10-minute delay group (mean: -0.7 versus -1.6, p = 0.025). Subset analysis of biopsies 1-3, 4-6, 7-9 and 10-12 also demonstrated higher baseline-adjusted mean VAS scores in the 2 minute delay group (all p <= 0.043). CONCLUSIONS: Lower TRUS-bx VAS scores can be achieved by extending the time from lidocaine injection to onset of prostate biopsy from 2 to 10 minutes. PMID- 28646935 TI - Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. AB - INTRODUCTION: To report the five year results of a prospective, multi-center, randomized, blinded sham control trial of the Prostatic Urethral Lift (PUL) in men with bothersome lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: At 19 centers in North America and Australia, 206 subjects >= 50 years old with International Prostate Symptom Score (IPSS ) > 12, peak flow rate (Qmax) <= 12 mL/s, and prostate volume 30 cc-80 cc were randomized 2:1 to the PUL procedure or blinded sham control. In PUL permanent UroLift implants are placed to hold open the lateral lobes of the prostate to reduce urinary obstruction. After randomized comparison at 3 months and the only opportunity to add more PUL implants, PUL patients were followed to 5 years. LUTS severity (IPSS), quality of life (QOL), BPH Impact Index (BPHII), Qmax, sexual function, and adverse events were assessed throughout follow up. RESULTS: IPSS improvement after PUL was 88% greater than that of sham at 3 months. LUTS and QOL were significantly improved by 2 weeks with return to preoperative physical activity within 8.6 days. Improvement in IPSS, QOL, BPHII, and Qmax were durable through 5 years with improvements of 36%, 50%, 52%, and 44% respectively. No difference was seen between Intent to Treat and Per Protocol populations. Surgical retreatment was 13.6% over 5 years. Adverse events were mild to moderate and transient. Sexual function was stable over 5 years with no de novo, sustained erectile or ejaculatory dysfunction. CONCLUSIONS: PUL offers rapid improvement in symptoms, QOL and flow rate that is durable to 5 years. These improvements were achieved with minimal use of a postoperative urinary catheter, rapid return to normal, and preservation of both erectile and ejaculatory function. Symptom improvement was commensurate with patient satisfaction. PUL offers a minimally invasive option in the treatment of LUTS due to BPH. PMID- 28646936 TI - Surgical flow disruptions during robotic-assisted radical prostatectomy. AB - INTRODUCTION: We sought to apply the principles of human factors research to robotic-assisted radical prostatectomy to understand where training and integration challenges lead to suboptimal and inefficient care. MATERIALS AND METHODS: Thirty-four robotic-assisted radical prostatectomy and bilateral pelvic lymph node dissections over a 20 week period were observed for flow disruptions (FD) - deviations from optimal care that can compromise safety or efficiency. Other variables - physician experience, trainee involvement, robot model (S versus Si), age, body mass index (BMI), and American Society of Anesthesiologists (ASA) physical status - were used to stratify the data and understand the effect of context. Effects were studied across four operative phases - entry to insufflations, robot docking, surgical intervention, and undocking. FDs were classified into one of nine categories. RESULTS: An average of 9.2 (SD = 3.7) FD/hr were recorded, with the highest rates during robot docking (14.7 [SD = 4.3] FDs/hr). The three most common flow disruptions were disruptions of communication, coordination, and equipment. Physicians with more robotic experience were faster during docking (p < 0.003). Training cases had a greater FD rate (8.5 versus 10.6, p < 0.001), as did the Si model robot (8.2 versus 9.8, p = 0.002). Patient BMI and ASA classification yielded no difference in operative duration, but had phase-specific differences in FD. CONCLUSIONS: Our data reflects the demands placed on the OR team by the patient, equipment, environment and context of a robotic surgical intervention, and suggests opportunities to enhance safety, quality, efficiency, and learning in robotic surgery. PMID- 28646937 TI - Comparison of external beam radiotherapy versus permanent seed brachytherapy as monotherapy for intermediate-risk prostate cancer - a single center Canadian experience. AB - INTRODUCTION: We tested different classification systems in order to separate intermediate-risk prostate cancers into prognostic groups. We then examined which groups were most suited for either prostate seed brachytherapy (PB) or external beam radiotherapy (EBRT). MATERIALS AND METHODS: We selected patients with D'Amico intermediate-risk prostate cancer who were treated exclusively with either PB or EBRT. Patients were excluded if they had received androgen deprivation therapy in combination with EBRT or a follow up of < 30 months without recurrence. The Kaplan-Meier method was used to compare groups. RESULTS: Our sample consisted of 475 patients treated from July 2002-September 2013. Median follow up for patients without biochemical failure (BF) was 56 months (interquartile range 44-78); 222 patients (47%) were treated with PB exclusively (D90 interquartile range 145-176 Gy) and 253 (53%) with EBRT exclusively (dose interquartile range 76-80 Gy). The rate of BF was significantly lower in patients treated with PB (5.4%) than in patients treated with EBRT (14.2%) (p = 0.036, log rank test). Upon univariate analysis, significant predictors of BF included the number of unfavorable intermediate-risk factors (0, 1, 2, 3) (p = 0.024) as well as the Cancer of the Prostate Risk Assessment (CAPRA) score (p = 0.002). After adjusting for the type of treatment, only the CAPRA score remained predictive (p = 0.025). For patients with a CAPRA score of 0-2, those with PB fared better than those treated with EBRT (p = 0.042). This difference disappeared in patients with a CAPRA score of 3-5 (p = 0.5). CONCLUSIONS: Using our current selection criteria for monotherapy, we found that PB or EBRT as monotherapy are equally effective treatment options for intermediate-risk prostate cancer. PMID- 28646938 TI - A survey of patient preferences regarding medical expulsive therapy following the SUSPEND trial. AB - INTRODUCTION: Several recent trials have reported limited benefit for medical expulsive therapy (MET) in terms of stone passage rates, analgesic requirements, or need for intervention. We evaluated patient attitudes regarding MET after explaining these new findings. MATERIALS AND METHODS: Over a 12 week period, an investigator-designed survey was offered to sequential patients during routine appointments in our urologic clinic. A brief summary of the conflicting data for MET was provided. Patients then answered questions about their attitudes toward using MET. RESULTS: Patients (n = 200; 103 M, 97 F) were 56 +/- 14 years old (range 20-103 years) and were mostly being seen for management of kidney stones (88%). Forty-nine percent reported they would try tamsulosin despite the new data; 26% said they would not, and 25% were unsure. Of patients indicating they would take tamsulosin, 35% stated they would also be willing to take steroids. Thirty-five percent of patients said they were willing to pay the full price of tamsulosin if needed. Seventy-one percent said they would prefer to try medical therapy prior to pursuing surgical therapy, again, despite new evidence regarding the efficacy of MET. CONCLUSION: In this initial report of patient attitudes about MET after SUSPEND trial results, we found that nearly half of patients would still try MET and that the vast majority of patients prioritize medical over surgical therapy when possible. As new research emerges, ways to translate this information to patients and to assess their attitudes and perceptions should be developed. PMID- 28646939 TI - Hounsfield Units for nephrolithiasis: predictive power for the clinical urologist. AB - INTRODUCTION: We aim to determine the optimal method for measuring Hounsfield Units (HU) of calculi for the clinical urologist. MATERIALS AND METHODS: We present a single institution prospective study from 2014-2015 for 125 consecutive patients. Demographics, baseline characteristics, imaging, and stone analysis were collected. CT scanners and settings were heterogeneous. Hounsfield units were measured by use of ellipsoid tool and free hand outline by two independent urology graders using Philips iSite PACs. RESULTS: Stone analysis demonstrated 26 pure calcium oxalate (CaOx) stones, 15 pure calcium phosphate (CaP) stones, and 7 uric acid stones, among other mixed types. Excellent agreement was notable amongst the two graders for ellipsoid and free hand grading, and values were consistent with those previously published with other methods. Mean grades for free-hand versus ellipse differed overall (p = 0.006) as ellipsoid HU measurement was consistently higher than free-hand measurement by an average of 107 units. Either method could differentiate between uric acid stones and any calcium containing stone (p <= 0.05). The free-hand method demonstrated statistical difference between pure calcium oxalate and calcium phosphate stones (p = 0.03). Applying either method took less than 6 seconds. CONCLUSIONS: For urologists lacking HU on their radiology reports, free hand or ellipsoid measurement may quickly provide an additional tool to guide management. Both methods differentiate between any calcium containing stone and uric acid stones. PMID- 28646940 TI - Management of refractory idiopathic overactive bladder: intradetrusor injection of botulinum toxin type A versus posterior tibial nerve stimulation. AB - INTRODUCTION: To compare the safety and efficacy of posterior tibial nerve stimulation (PTNS) versus an intradetrusor injection of botulinum toxin type-A (BTX-A) 100 U in the management of refractory idiopathic overactive bladder (OAB). MATERIALS AND METHODS: We randomized 60 patients with refractory idiopathic OAB to receive an intradetrusor injection of BTX-A 100 U or PTNS. We assessed the patients at baseline, 6 weeks, 3 months, 6 months, and 9 months, and determined their clinical symptoms, overall OAB symptom score, urgency score, quality-of-life score, and urodynamic study parameters. RESULTS: The two patient groups had similar baseline characteristics. After treatment, the patients in the BTX-A group had significant improvements in all parameters compared to their baseline values. Patients in the PTNS group initially had significant improvements in all parameters, but by 9 months, this was no longer true for most parameters. In general, the improvements were more significant in the BTX group, especially at 9 months. In the BTX-A group, two patients (6.6%) needed clean intermittent catheterization; 3 patients (2 women and 1 man; 10% of patients) had mild hematuria, and 2 patients (6.6%) had urinary tract infections (UTIs). In the PTNS group, local adverse effects included minor bleeding spots and temporary pain. CONCLUSIONS: Intradetrusor injection of BTX-A and PTNS are both effective to manage refractory idiopathic OAB. BTX-A is more effective than PTNS and is also durable, minimally invasive, reversible, and safe, but it also has more side effects. PMID- 28646941 TI - Postwash total motile sperm count: should it be included as a standard male infertility work up. AB - INTRODUCTION: Pregnancy rates after intrauterine insemination (IUI) varies greatly. We aimed to identify pre and post processing semen analysis parameters that may be predictive of successful pregnancy in couples undergoing IUI. MATERIALS AND METHODS: A retrospective study of the records of all couples underwent IUI for a 2 year period at our infertility center. Different characteristics of female subjects, pre and post processing semen parameters and treatment parameters were compared statistically. RESULTS: Thirty-two clinical pregnancies followed 526 IUI cycles in 294 couples, for a clinical pregnancy rate of 6.1% per cycle and a 10.9% per couple. The mean age of the women at IUI was 31.14 +/- 6 years (range 19-45 years). Neither maternal age, body mass index, number of mature follicles, maximum day 3 follicle stimulating hormone level, presence or absence of previous children, number of previous miscarriages, nor prewash semen parameters had any impact on pregnancy rate post IUI. Postwash total motile sperm count (TMSC) (p = .027) and number of cycles (p = .042) were independent predictors of successful pregnancy after IUI. CONCLUSIONS: A postwash TMSC of 5 million sperm or more is significantly associated with a high pregnancy rate. After ruling out medically or surgically correctable male factors that may contribute to infertility, we recommend including a pretreatment sperm processing during routine male fertility work up for proper patient counseling and direction to the suitable assisted reproduction technique. PMID- 28646942 TI - Endoscopic placement of double-J ureteric stents in children as a treatment for primary hydronephrosis. AB - INTRODUCTION: The aim of this study was to determine the efficacy and potential complications of double-J ureteric stents in the treatment of primary hydronephrosis in pediatric patients. MATERIALS AND METHODS: A retrospective case records review of 133 patients (45 girls and 88 boys) treated because of primary hydronephrosis with double-J ureteric stents, in Department of Pediatric Surgery, Split University Hospital, between December 1997 and December 2014, was performed. Success of treatment, results of follow up investigations and complications were recorded. Patients were followed up clinically and radiologically for a minimum of 2 years following stent insertion. RESULTS: In all, 133 endoscopic double-J ureteric stents insertions were performed. Of the total number of patients, left-sided hydronephrosis was found in 82 patients, right-sided in 38, and bilateral in 13 patients. The median age of children was 2 years (range 0-17 years). Mean hospital stay was 2 days (range 1-10 days). In primary hydronephrosis, double-J ureteric stenting alone was effective with resolution of hydronephrosis in 73% of cases (97/133 insertions). Regarding the age of the patients the highest success of 83.5% was achieved in age group 0-4 years. Success in groups 5-9 years; 10-14 years and 15-17 years were 47%; 33.5% and 0%, respectively. Several complications have been recorded: symptomatic infections, migration in the renal pelvis and bladder, progression of hydronephrosis, spontaneously prolapse of prosthesis, bleeding and perforation of the renal pelvis. A significant, decreasing trend in success rates by age of participants was observed (p < 0.001). CONCLUSIONS: Ureteric stenting is minimally invasive procedure that provides an alternative to open surgery in patients with primary hydronephrosis. Endoscopic placement of ureteric double-J stents should be considered as a first-line treatment in the management of primary hydronephrosis especially in children till 4 years of age, with success rate of 83.5% and without the need for conventional surgery. In a case of failure we are time-consuming to definitive surgery. PMID- 28646943 TI - State of the art: Advanced techniques for prostatic urethral lift for the relief of prostate obstruction under local anesthesia. AB - Benign prostatic hypertrophy (BPH) affects an estimated 60% of men over the age of 50 and 90% of men over the age of 80. The prostatic urethral lift (PUL) is a safe and effective office-based procedure that is used worldwide for the treatment of BPH in men who are dissatisfied with medications due to side effects or lack of efficacy or don't want to have a transurethral resection of the prostate due to the side effects and invasiveness of the procedure. In 2012 Barkin et al, published the standard technique for the delivery of the Urolift implant. The objective of this article is to describe the current state of the art advanced techniques for the delivery of the UroLift implant. PMID- 28646944 TI - Oncocytic adrenocortical carcinoma: a rare adrenal tumor subtype. AB - Oncocytic tumors arising from the adrenal gland are rare. Oncocytic adrenal neoplasms (OAN) may mimic adrenocortical carcinoma (ACC) at presentation, and can only be definitively diagnosed histologically. Most OANs are benign, and carry a favorable prognosis. We report on an 83-year-old female who, while being investigated for anemia and weight loss, was found to have a 23 cm adrenal mass concerning for ACC. Adrenalectomy and histopathology confirmed a malignant OAN, based on the Lin-Weiss-Bisceglia criteria. We report on the largest non functional, malignant OAN cited in the literature to date. OAN's, though rare, can be considered in the differential diagnosis of large adrenal tumors. PMID- 28646945 TI - Primary amyloidosis of the bladder; a mimicker of bladder cancer. AB - Amyloidosis is a protein folding disorder characterized by the deposition of fibrillar proteins into solid organs or tissues. Primary localized amyloidosis of the bladder is very rare and can mimic bladder cancer in its presentation with hematuria, lower urinary tract symptoms or a mass on imaging. A case of localized amyloidosis of the bladder in a 48-year-old man with painless gross hematuria and evidence of bladder mass on ultrasound is presented. Amyloidosis is a rare but important non-malignant process of the bladder. We present a review of the literature and suggestions for management of this rare bladder disease. PMID- 28646946 TI - Preface. PMID- 28646947 TI - Measles, immune suppression and vaccination: direct and indirect nonspecific vaccine benefits. AB - The measles virus is among the most transmissible viruses known to infect humans. Prior to measles vaccination programs, measles infected over 95% of all children and was responsible for over 4 million deaths each year. Measles vaccination programs have been among the greatest public health achievements reducing, eliminating endemic measles in the whole of the Americas and across much of the globe. Where measles vaccines are introduced, unexpectedly large reductions in all-cause childhood mortality have been observed. These gains appear to derive in part from direct heterologous benefits of measles vaccines that enhance innate and adaptive immune responses. Additionally, by preventing measles infections, vaccination prevents measles-associated short- and long-term immunomodulating effects. Before vaccination, these invisible hallmarks of measles infections increased vulnerability to non-measles infections in nearly all children for weeks, months, or years following acute infections. By depleting measles incidence, vaccination has had important indirect benefits to reduce non-measles mortality. Delineating the relative importance of these two modes of survival benefits following measles vaccine introduction is of critical public health importance. While both support continued unwavering global commitments to measles vaccination programs until measles eradication is complete, direct heterologous benefits of measles vaccination further support continued commitment to measles vaccination programs indefinitely. We discuss what is known about direct and indirect nonspecific measles vaccine benefits, and their implications for continued measles vaccination programs. PMID- 28646948 TI - Generalized herd effects and vaccine evaluation: impact of live influenza vaccine on off-target bacterial colonisation. AB - Interactions between pathogens and commensal microbes are major contributors to health and disease. Infectious diseases however are most often considered independent, viewed within a one-host one-pathogen paradigm and, by extension, the interventions used to treat and prevent them are measured and evaluated within this same paradigm. Vaccines, especially live vaccines, by stimulating immune responses or directly interacting with other microbes can alter the environment in which they act, with effects that span across pathogen species. Live attenuated infl uenza vaccines for example, while safe, increase upper respiratory tract bacterial carriage density of important human commensal pathogens like Streptococcus pneumoniae and Staphylococcus aureus. Further, by altering the ecological niche and dynamics of phylogenetically distinct microbes within the host, vaccines may unintentionally affect transmission of non-vaccine targeted pathogens. Thus, vaccine effects may span across species and across scales, from the individual to the population level. In keeping with traditional vaccine herd-effects that indirectly protect even unvaccinated individuals by reducing population prevalence of vaccine-targeted pathogens, we call these cross species cross-scale effects "generalized herd-effects". As opposed to traditional herd-effects, "generalized" relaxes the assumption that the effect occurs at the level of the vaccine-target pathogen and "herd effect" implies, as usual, that the effects indirectly impact the population at large, including unvaccinated bystanders. Unlike traditional herd-effects that decrease population prevalence of the vaccine-target, generalized herd-effects may decrease or increase prevalence and disease by the off-target pathogen. LAIV, for example, by increasing pneumococcal density in the upper respiratory tract of vaccine recipients, especially children, may increase pneumococcal transmission and prevalence, leading to excess pneumococcal invasive disease in the population, especially among the elderly and others most susceptible to pneumococcal disease. However, these effects may also be beneficial, for example the large reductions in all-cause mortality noted following measles vaccines. Here we discuss evidence for these novel vaccine effects and suggest that vaccine monitoring and evaluation programs should consider generalized herd effects to appreciate the full impacts of vaccines, beneficial or detrimental, across species and scales that are inevitably hiding in plain sight, affecting human health and disease. PMID- 28646949 TI - Recognition and diagnosis of invasive fungal infections in neonates. AB - Fungal infections largely caused by Candida species are responsible for a significant disease burden in neonates and invasive candidiasis in hospitalised neonates has high associated morbidity and mortality. Early initiation of antifungal treatment improves outcome but the recognition and diagnosis of systemic fungal infection in this population is difficult due to the non-specific clinical presentation and the high false negative rate of cultures. There is a need for a practical, sensitive and rapid diagnostic test to enhance identification and early treatment. Serum detection of (1,3)-beta-d-glucan and Candida PCR are promising candidates but at present limited data exists for their use in the neonatal intensive care setting. Until such investigations are validated, early initiation of antifungal treatment on the basis of risk factor profile and clinical features remains the safest practical approach. PMID- 28646950 TI - Pertussis disease and transmission and host responses: insights from the baboon model of pertussis. AB - Whooping cough is a highly contagious, acute respiratory disease, caused by the Gram-negative bacterium Bordetella pertussis (Bp). Despite the introduction and widespread use of vaccines starting in the 1950s pertussis cases continue to be reported, with a significant global impact. The role of specific virulence factors in disease and the immune mechanisms associated with protection following natural infection or vaccination are still not completely understood. The recently-developed baboon model of clinical pertussis provides a valuable tool for the study of pertussis. Baboons infected with B. pertussis exhibit all of the manifestations of human pertussis including paroxysmal coughing, mucus production, leukocytosis and transmission. The establishment of this model provides the opportunity to address unanswered questions about the natural progression of this disease and host responses to infection and vaccination in a very relevant model. In this review, we present an overview of our knowledge of pertussis along with recent advances resulting from use of the baboon model. Remaining questions and future research directions are discussed. We hope that the knowledge gained through use of the baboon model of pertussis and clinical studies will allow the development of more efficacious vaccines, conferring long lasting protection against disease and transmission. PMID- 28646951 TI - Fecal microbiota transplantation for recurrent clostridium difficile infection in children. AB - Fecal microbiota transplantation (FMT) is a relatively simple, promising treatment for recurrent Clostridium difficile infection. While there are a wide variety of approaches including mode of delivery, the results are nonetheless encouraging, even amongst younger children. Experience with FMT in the pediatric population is increasing, showing similar success compared to adults. This article will provide an overview of C. difficile infection along with review of the rationale, methods and complications of FMT including the current experience of FMT in children. PMID- 28646952 TI - Drug-Resistant tuberculosis - primary transmission and management. AB - The DOTS strategy assisted global tuberculosis (TB) control, but was unable to prevent the emergence and spread of drug-resistant strains. Genomic evidence confirms the transmission of drug-resistant Mycobacterium tuberculosis strains in many different settings, indicative of epidemic spread. These findings emphasise the need for enhanced infection control measures in health care and congregate settings. Young children in TB endemic areas are particularly vulnerable. Although advances in TB drug and vaccine development are urgently needed, improved access to currently available preventive therapy and treatment for drug resistant TB could reduce the disease burden and adverse outcomes experienced by children. We review new insights into the transmission dynamics of drug resistant TB, the estimated disease burden in children and optimal management strategies to consider. PMID- 28646953 TI - Nontuberculous mycobacterial disease in childhood - update on diagnostic approaches and treatment. AB - Recent studies suggest that the incidence of nontuberculous mycobacterial infections in children may be increasing. Nontuberculous mycobacterial lymphadenitis, skin and soft tissue infection, and pulmonary disease each present unique challenges in relation to diagnosis and treatment. In this update, we critically review the recent literature on the epidemiology, clinical features, diagnostic approaches and treatment of nontuberculous mycobacterial disease in children. In addition, we outline key areas warranting further research. PMID- 28646954 TI - Development of respiratory syncytial virus (RSV) vaccines for infants. AB - 2017 will mark the 60th anniversary since the first isolation of RSV in children. In spite of concerted efforts over all these years, the goal of developing an effective vaccine against paediatric RSV disease has remained elusive. One of the main hurdles standing in the way of an effective vaccine is the fact that the age incidence of severe disease peaks within the first 3 months of life, providing limited opportunity for intervention. In addition to this complexity, the spectre of failed historical vaccines, which increased the risk of illness and death upon subsequent natural infection, has substantially increased the safety criteria against which modern vaccines will be assessed. This review traces the history of RSV vaccine development for young infants and analyses the potential reasons for the failure of historic vaccines. It also discusses recent breakthroughs in vaccine antigen design and the progressive evolution of platforms for the delivery of these antigens to seronegative infants. PMID- 28646955 TI - Toxic shock syndrome - the seven Rs of management and treatment. AB - Staphylococcal and streptococcal toxic shock syndrome (TSS) are associated with significant morbidity and mortality. There has been considerable progress in understanding the pathophysiology and delineating optimal management and treatment. This article reviews the management of TSS, outlining the 'Seven Rs of Managing and Treating TSS': Recognition, Resuscitation, Removal of source of infection, Rational choice of antibiotics, Role of adjunctive treatment (clindamycin and intravenous immunoglobulin), Review of progress and Reduce risk of secondary cases in close contacts. PMID- 28646956 TI - Clean water, clean hands or new vaccines? AB - Throughout human history, pathogens transmitted through feces from person to person have caused substantial mortality. Over a century ago civil engineers in high income countries developed approaches to collect and remove feces from the environment that in communities with high incomes and strong governments markedly reduced the burden of enteric disease. These approaches, however, have not been successfully extended to impoverished communities in low income countries. Water/sanitation/hygiene professionals have attempted, with only limited success, to reduce fecal exposure and human disease in the absence of definitive civil engineering approaches. Medical professionals have worked to develop vaccines against some of the most important fecal oral pathogens. Each of these approaches needs further development and adaptation to optimally address the burden of fecally transmitted diseases in impoverished communities. PMID- 28646957 TI - Whither vaccines? AB - Currently used vaccines have had major effects on eliminating common infections, largely by duplicating the immune responses induced by natural infections. Now vaccinology faces more complex problems, such as waning antibody, immunosenescence, evasion of immunity by the pathogen, deviation of immunity by the microbiome, induction of inhibitory responses, and complexity of the antigens required for protection. Fortunately, vaccine development is now incorporating knowledge from immunology, structural biology, systems biology and synthetic chemistry to meet these challenges. In addition, international organisations are developing new funding and licensing pathways for vaccines aimed at pathogens with epidemic potential that emerge from tropical areas. PMID- 28646958 TI - New tools for malaria control - using them wisely. AB - The incidence of malaria in sub-Saharan Africa is falling and in many countries on the continent the pattern of malaria infection within the country is becoming more heterogeneous. National malaria control programmes need to take this into account and the 'one size fits all' approach to malaria control may no longer be appropriate, with individual approaches being needed in different parts of a country. This applies particularly to decisions on the introduction of new control tools. Recent experience with Seasonal Malaria Chemoprevention and with the RTS,S/AS01 malaria vaccine provides examples of interventions which need to be deployed on a restricted rather than a national basis, taking account of differences in climate and the intensity of malaria infection between regions within a country. Designing, implementing and monitoring more complex national malaria control programmes will require staff skilled in many disciplines, and substantial funding will be needed to sustain these more complex control programmes, even though the burden of the disease is falling. PMID- 28646960 TI - The controversial role of breast milk in GBS late-onset disease. AB - Group B streptococcus (GBS) is one of the most common causes of neonatal sepsis and meningitis. Intra-partum antibiotic prophylaxis does not play a significant role in reducing the risk of GBS late-onset disease. One of the proposed mechanisms for GBS late-onset disease is infection through contaminated breast milk. Infants in whom breast milk is thought to be the source for GBS late-onset disease are more heavily colonised and reports suggest they have a higher recurrence rate compared to infants with other potential sources. There is no consensus whether the breast milk of mothers of infants with GBS late-onset disease, especially those with recurrent episodes, should be tested for GBS. In addition, recommendations differ on whether breast-feeding should be interrupted or breast milk pasteurised, or whether the mother and infant should be treated for colonisation. In this review we discuss these different approaches. PMID- 28646961 TI - Rhinovirus - not just the common cold. AB - Rhinoviruses (RV) are ubiquitous respiratory tract pathogens. They affect both the upper and lower respiratory tract and cause colds but have also been associated with wheezing, asthma exacerbations and pneumonia. New blood transcription profiling techniques of the host immune response are becoming available to characterise the pathogenesis of RV in humans. This review will outline the clinical impact of RVs in children. PMID- 28646959 TI - Is chickenpox so bad, what do we know about immunity to varicella zoster virus, and what does it tell us about the future? AB - Varicella and zoster continue to cause significant morbidity and even mortality in children and adults. Complications include bacterial superinfection, central nervous system manifestations such as meningitis, encephalitis, and cerebellar ataxia, and pain syndromes especially post herpetic neuralgia. Many developed countries but not all, are now administering live attenuated varicella vaccine routinely, with a decrease in the incidence of disease, providing personal and herd immunity. There is some controversy, however, in some countries concerning whether a decrease in the circulation of wild type virus will result in loss of immunity to VZV in persons who have already had varicella. This manuscript reviews the complications of varicella and zoster in detail, the reasons for development of vaccines against these diseases, complications of vaccinations, and mechanisms by which immunity to this virus develops and is maintained. There are strong indications that the best way to control disease and spread of this virus is by vaccination against both. PMID- 28646962 TI - The long shadow of lemierre's syndrome. AB - Lemierre's syndrome is a rare and feared complication of pharyngitis, occurring most commonly in adolescents and young adults. It is typically defined by the constellation of septic internal jugular vein thrombophlebitis, pulmonary and other septic emboli, and sterilesite infection by Fusobacterium necrophorum. The rarity and severity of Lemierre's syndrome has made it an attractive subject for case reports but there is a paucity of evidence to inform areas of persistent uncertainty. In recent years, heightened attention and controversy has focused upon speculation that a purported rise in the incidence of Lemierre's syndrome is due to reduced antibiotic prescribing for respiratory tract infections, that F. necrophorum is an under-appreciated cause of acute tonsillopharyngitis and that testing and targeted treatment would prevent cases of Lemierre's syndrome. PMID- 28646963 TI - Spectrum and burden of dermatophytes in children. AB - Tinea capitis is the most important superficial fungal condition in children. It is often unrecognised but the presence of alopecia, scale and lymphadenopathy, especially in inner-city children should prompt investigation. An understanding of changing epidemiology and prevalence of causative organisms is important in deciding appropriate therapy. The use of diagnostic aids including dermoscopy is increasing and is reported to be helpful in identifying subtle signs. Trichophyton tonsurans accounts for the majority of cases in the UK and terbinafine is increasingly advocated as a safe and effective therapy. Exclusion from school is unnecessary provided the child is receiving appropriate systemic and topical therapy, but family members should be screened and carriers should receive treatment. Steroids and surgical treatments should be avoided. Treatment failure is common and may be multifactorial. Mycological cure after completing treatment should be sought and therefore follow up is necessary for Tinea capitis cases. Development of molecular diagnostic methods may improve our ability to diagnose Tinea capitis accurately and quickly in the future. Emerging new dermatophytoses affecting other anatomical sites are discussed which, although not common in the UK, may be seen due to increasing travel worldwide. PMID- 28646964 TI - Global advocacy needed for sepsis in children. AB - Sepsis in children is a complex syndrome that develops from various infections and results in 15-30% mortality in high-income countries and up to 50% or higher in low-income countries. Worldwide, this represents an annual burden of 30 million cases resulting in 8 million deaths. Not surprisingly, there is a significantly higher burden in low-income countries with children there being 18 times more likely to die before the age of 5 years compared to high-income countries. Factors such as commercial air travel, climate change, and unchecked population growth have contributed to the growing burden of infectious diseases and ensuing sepsis. In this article, we review the important role of global advocacy to improve public awareness of sepsis; increase access to essential medicines and vaccines; improve use of evidence-based treatment guidelines; raise awareness of antimicrobial resistance and encourage antibiotic stewardship; and, develop resilient health systems that can cope with health crises. Advocacy in these areas can assist nations in reaching the United Nations sustainable development goals (UN SDGs) of low rates of neonatal and under-5 mortality. PMID- 28646965 TI - Cholera - management and prevention. AB - Cholera is an acute secretory diarrhoeal infection caused by the bacterium Vibrio cholerae. It is likely to have originated in the Indian sub-continent; however, it spread to cause six worldwide pandemics between 1817-1923. The ongoing seventh worldwide pandemic of cholera began in 1961. The intensity, duration and severity of cholera epidemics have been increasing, signaling the need for more effective control and prevention measures. The response to the cholera pandemics of the 19th century led to the development of safe and effective sanitation and water systems which have effectively removed the risk of cholera in many settings. However, such systems are not in place to protect billions of people worldwide. Although some progress has been made in expanding access to water in recent years, achieving optimal infrastructure will, in the most optimistic scenario, take decades. Climate change, extreme weather events and rapid urbanisation suggests that alternatives to the current paradigm of providing large centralised water and sanitation systems should be considered, including smaller decentralised systems. The aim of this review paper is to provide an overview of current knowledge regarding management of cholera with a focus on prevention measures including vaccination and water and sanitation interventions. PMID- 28646966 TI - A systematic approach to diagnosing intra-thoracic tuberculosis in children. AB - Children suffer a huge and often underappreciated burden of disease in tuberculosis (TB) endemic countries. Major hurdles include limited awareness among health care workers, poor integration of TB into maternal and child health approaches, diagnostic difficulties and a lack of child-friendly treatment options. Accurate disease diagnosis is particularly difficult in young and vulnerable children who tend to develop paucibacillary disease and are unable to produce an expectorated sputum sample. In addition, access to chest radiography is problematic in resource-limited settings. Differentiating between TB exposure and M. tuberculosis infection, and especially between M. tuberculosis infection and TB disease is crucial to guide clinical management. TB represents a dynamic continuum from well-contained "latent" infection to incipient and ultimately severe disease. The clinical spectrum of disease in children is broad and can be confused with a myriad of common infections. We provide a pragmatic 4-step approach to diagnose intra-thoracic TB in children and demonstrate how classifying clinical, radiological and laboratory findings into recognised clinical syndromes may provide a more refined diagnostic approach, even in resource-limited settings. PMID- 28646967 TI - The respiratory microbiome and respiratory infections. AB - Despite advances over the past ten years lower respiratory tract infections still comprise around a fifth of all deaths worldwide in children under five years of age with the majority in low- and middle-income countries. Known risk factors for severe respiratory infections and poor chronic respiratory health do not fully explain why some children become sick and others do not. The respiratory tract hosts bacteria that can cause respiratory infections but also normal commensal bacteria. Together, this microbial population is called the microbiome. The composition of the respiratory microbiome in the first few months of life is likely influenced by external factors such as environment, mode of delivery and infant feeding practices, which are also associated with susceptibility to respiratory infections and wheezing illness/asthma. Recently, multiple studies have shown that respiratory microbiota profiles early in life are associated with an increased risk and frequency of subsequent respiratory infections, disease severity and occurrence of wheeze in later childhood. Early interactions between infectious agents such as viruses and the respiratory microbiome have shown to modulate host immune responses potentially affecting the course of the disease and future respiratory health. Deeper understanding of these interactions will help the development of new therapeutic agents or preventive measures that may modify respiratory health outcomes and help us to stratify at risk populations to better target our current interventional approaches. PMID- 28646968 TI - Congenital cytomegalovirus - who, when, what-with and why to treat? AB - Congenital cytomegalovirus (CMV) is the commonest cause of congenital infection worldwide and the leading non-genetic cause of sensorineural hearing loss in children. Appropriate investigations and timely decision on treatment is required as studies have shown that treatment with antiviral therapy leads to improved hearing and neurodevelopmental outcomes in the long term when started in the first month of life. This paper outlines the epidemiology, investigations in the diagnosis of congenital CMV infection and current evidence surrounding treatment. PMID- 28646970 TI - Introduction. PMID- 28646971 TI - Family engagement in education and intervention: Implementation and evaluation to maximize family, school, and student outcomes. PMID- 28646969 TI - Things that could be Mycoplasma pneumoniae. AB - M. pneumoniae infection gives rise to a wide variety of manifestations. The pathogenesis of secondary manifestations is not always known. Some depend on the direct invasion of M. pneumoniae and others on the indirect effect of M. pneumoniae through pathological immune responses, for instance autoreactive antibodies in Guillain-Barre Syndrome. Diagnosis remains challenging with currently available diagnostic tests, because they do not demonstrate a causal relation due to M. pneumoniae asymptomatic carriage or previous infection. The mainstay of treatment is macrolide antibiotics, but the role of additional immunomodulation therapy is unclear. Knowledge of the pathogenesis of the different manifestations should guide strategies for diagnosis and treatment. PMID- 28646972 TI - Effectiveness evaluation of the Positive Family Support intervention: A three tiered public health delivery model for middle schools. AB - This article presents the results of an evaluation of Positive Family Support, an ecological family intervention and treatment approach to parent supports and family management training developed from a history of basic and translational research. This effectiveness trial, with 41 public middle schools randomly assigned to intervention or control, examined student-, teacher-, and parent reported outcomes, as well as math and reading scores and school attendance. Multilevel analyses suggested that for students at risk for behavior problems, immediate-intervention schools outperformed control schools on parent-reported negative school contacts for students at risk for behavior problems. Implementation, however, was hampered by several challenges, including school funding cuts, lack of staff time to provide parenting supports, and staff turnover. Given that preventive interventions are generally cost effective, it is critical that researchers continue their efforts to refine these interventions and find ways to support schools' implementation of evidence-based programs that can reduce problem behavior. This article is part of a special issue "Parental Engagement in School-Based Interventions". PMID- 28646973 TI - Parent involvement in beginning primary school: Correlates and changes in involvement across the first two years of school in a New Zealand sample. AB - This study described the relations of parents' and teachers' beliefs and attitudes to forms of parents' involvement in children's first two years of primary school. Parents of children in their first year of primary school (age 5) were recruited from 12 classrooms within four schools in New Zealand; 196 families participated in their child's first year, and 124 families continued to participate in their child's second school year. Parents completed the Family Involvement Questionnaire, New Zealand, and we archivally collected parent documented children's oral reading homework. Teachers' rated helpfulness of parents' involvement at school (level 2) and parents' rated teacher invitations to be involved and their perceived time and energy (level 1) contributed to school-based involvement in Year 1 in multilevel models, with parents' rated teacher invitations for involvement also found to predict Year 1 home-school communication in regression analyses. Contributors to Year 1 child-parent reading in multilevel models included level 1 predictors of two or more adults in the home and parents' perceived time and energy. Longitudinal analyses suggested both consistency and change in each form of involvement from Year 1 to Year 2, with increases in each form of involvement found to be associated with increases in parents' and/or teachers' views about involvement in Year 2 in cross-sectional time-series analyses. Implications for schools wanting to engage families are that parents' involvement in children's schooling may be influenced by parents' perceptions of their capacity, teachers' engagement efforts, and the school's climate for involvement. This is a special issue paper "Family Engagement in Education and Intervention". PMID- 28646975 TI - Impact of Incredible Years(r) on teacher perceptions of parental involvement: A latent transition analysis. AB - The purpose of the present study was to examine the impact of the Incredible Years(r) Teacher Classroom Management (IY TCM) training on teacher perceptions of parental involvement. A cluster randomized design was used to assign 42 classroom teachers to either an IY TCM training (n=19) or a control condition (n=23). Teachers rated parental involvement (i.e., bonding with teacher, parental involvement at school) for the families of 805 low income students (IY TCM=504, control=301). A latent profile transition analysis framework was used to model the effect of IY TCM on teacher perceptions of parental involvement from pre to posttest. Four profiles consisting of various patterns of high, medium, and low teacher perceptions of bonding with and involvement of parents emerged. Analyses of teacher profiles at baseline revealed teachers who felt parental involvement and bonding was low were also likely to rate students as having more externalizing behaviors, fewer social competencies, more attention deficit symptoms, and disruptive behaviors towards adults and peers compared to teachers with more adaptive profiles. Further analysis revealed that parents of teachers randomly assigned to IY TCM were more likely to transition to a more adaptive view of parental involvement at follow-up compared to teachers in the control condition. Because teacher perceptions of parental involvement may adversely impact teacher attitudes towards difficult students, findings from the present study support the promise of teacher training as an avenue for conferring protections for struggling students. PMID- 28646974 TI - Testing the feasibility of a briefer school-based preventive intervention with aggressive children: A hybrid intervention with face-to-face and internet components. AB - This study describes the results from a feasibility study of an innovative indicated prevention intervention with hybrid face-to-face and web-based components for preadolescent youth. This intervention includes a considerably briefer set of face-to-face sessions from the evidence-based Coping Power program and a carefully integrated internet component with practice and teaching activities and cartoon videos for children and for parents. The Coping Power - Internet Enhanced (CP-IE) program introduces a set of cognitive-behavioral skills in 12 small group sessions for children delivered during the school day and 7 group sessions for parents. Eight elementary schools were randomly assigned to CP IE or to Control, and six children at each school were identified each year based on 4th grade teacher ratings of aggressive behavior. Path analyses of teacher rated disruptive behavior outcomes for 91 fifth grade children, across two annual cohorts, indicated Control children had significantly greater increases in conduct problem behaviors across the 5th grade year than did CP-IE children. This much briefer version of Coping Power provided beneficial preventive effects on children's behavior in the school setting similar to the effects of the longer version of Coping Power. The website materials appeared to successfully engage children, and parents' use of the website predicted children's changes in conduct problems across the year. PMID- 28646976 TI - Promoting parent academic expectations predicts improved school outcomes for low income children entering kindergarten. AB - This study explored patterns of change in the REDI (Research-based Developmentally Informed) Parent program (REDI-P), designed to help parents support child learning at the transition into kindergarten. Participants were 200 prekindergarten children attending Head Start (55% European-American, 26% African American, 19% Latino, 56% male, Mage=4.45years, SD=0.29) and their primary caregivers, who were randomized to a 16-session home-visiting intervention (REDI P) or a control group. Extending beyond a prior study documenting intervention effects on parenting behaviors and child kindergarten outcomes, this study assessed the impact of REDI-P on parent academic expectations, and then explored the degree to which intervention gains in three areas of parenting (parent-child interactive reading, parent-child conversations, parent academic expectations) predicted child outcomes in kindergarten (controlling for baseline values and a set of child and family characteristics). Results showed that REDI-P promoted significant gains in parent academic expectations, which in turn mediated intervention gains in child emergent literacy skills and self-directed learning. Results suggest a need to attend to the beliefs parents hold about their child's academic potential, as well as their behavioral support for child learning, when designing interventions to enhance the school success of children in low-income families. PMID- 28646977 TI - The efficacy of conjoint behavioral consultation in the home setting: Outcomes and mechanisms in rural communities. AB - This study reports the results of a randomized controlled trial examining the effect of Conjoint Behavioral Consultation (CBC), a family-school partnership intervention, on children's behaviors, parents' skills, and parent-teacher relationships in rural community and town settings. Participants were 267 children, 267 parents, and 152 teachers in 45 Midwestern schools. Using an Intent to Treat approach and data analyzed within a multilevel modeling framework, CBC yielded promising results for some but not all outcomes. Specifically, children participating in CBC experienced decreases in daily reports of aggressiveness, noncompliance, and temper tantrums; and increases in parent-reported adaptive skills and social skills at a significantly greater pace than those in a control group. Other outcomes (e.g., parent reports of internalizing and externalizing behaviors) suggested a nonsignificant effect at post-test. CBC parents reported using more effective parenting strategies, gaining more competence in their problem-solving practices, and feeling more efficacious for helping their child succeed in school than parents in the control group. Parents participating in CBC also reported significant improvements in the parent-teacher relationship, and the parent-teacher relationship mediated the effect of CBC on children's adaptive skills. Implications for practice in rural communities, study limitations, and directions for future research are discussed. PMID- 28646978 TI - Medical Education in Electrocardiography. PMID- 28646980 TI - Binocular vision in the twenty-first century. PMID- 28646979 TI - Inhibition of rapid delayed rectifier potassium current (IKr) by ischemia/reperfusion and its recovery by vitamin E in ventricular myocytes. AB - Ischemia/reperfusion (I/R) induces prolongation of QT interval and action potential duration (APD), which is a major cardiac electrical disorder in patients with arrhythmias. However, the mechanism of QT interval prolongation induced by I/R remains unclear. In the present study, we hypothesized that the rapid component of delayed rectifier potassium (IKr) channel plays an important role in I/R-induced QT interval prolongation. We observed a marked attenuation of IKr and a significant prolongation of action potential duration (APD) in a simulated I/R system with sodium dithionite (Na2S2O4) in ventricular myocytes of guinea pigs. The IKr current density was inhibited by 64% and APD increased by 87% respectively. Moreover, the inhibition of IKr is primarily ascribed to overproduction of reactive oxygen species (ROS) by I/R, which can be partly reversed by antioxidant vitamin E (100MUmol/L). The value of IKr tail current density increased from 0.516+/-0.040 pA/pF in I/R to 0.939+/-0.091 pA/pF when treated with vitamin E. Moreover, we also demonstrated that QTc interval was increased by I/R and reversed by Vitamin E in isolated guinea pig hearts. In conclusion, the inhibition of IKr is one of the underlying mechanisms of prolongation of QT interval and APD in I/R. Vitamin E might have a benefit in coronary reperfusion therapy. PMID- 28646981 TI - Home Alone: Does Modality Matter? Revisiting Hospital Readmissions in Dialysis. PMID- 28646982 TI - Serum Potassium and the Long Interdialytic Interval: Minding the Gap. PMID- 28646983 TI - Quiz Page July 2017: An Unusual Cause of Hypokalemia. PMID- 28646984 TI - AJKD Atlas of Renal Pathology: Chronic Interstitial Nephritis. PMID- 28646985 TI - AJKD Atlas of Renal Pathology: Anti-Tubular Basement Membrane Antibody Disease. PMID- 28646986 TI - AJKD Atlas of Renal Pathology: Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency. PMID- 28646987 TI - State-based perinatal quality collaboratives: Pursuing improvements in perinatal health outcomes for all mothers and newborns. AB - State-based perinatal quality collaboratives (SPQC) have become increasingly widespread in the United States. Whereas the first was launched in 1997, today over 40 states have SPQCs that are actively working or are in development. Despite great variability in the structure and function of SPQCs among states, many have seen their efforts lead to significant improvements in the care of mothers and newborns. Clinical topics targeted by SPQCs have included nosocomial infection in newborns, human milk use, neonatal abstinence syndrome, early term deliveries without a medical indication, maternal hemorrhage, and maternal hypertension, among others. While each SPQC uses approaches suited to its own context, several themes are common to the goals of all SPQCs, including developing obstetric and neonatal partnerships; including families as partners; striving for participation by all providers; utilizing rigorous quality improvement science; maintaining close partnerships with public health departments; and seeking population-level improvements in health outcomes. PMID- 28646989 TI - Neutrophils in cisplatin AKI-mediator or marker? AB - Inflammation is an important mediator of most forms of acute kidney injury (AKI). Although neutrophils are prominent components of the inflammatory cascade, the precise role of neutrophils in AKI and the mechanisms by which they contribute to AKI remain controversial. In this issue, Deng et al. identify an important cross talk between renal epithelial cells and neutrophils involving the production and action of leukotriene B4 in mediating cisplatin AKI. We discuss the possible explanations for the discrepant findings that have been reported for neutrophils in cisplatin AKI. PMID- 28646990 TI - beta2-adrenergic receptors in inflammation and vascular complications of diabetes. AB - The cross talk between the immune and nervous systems is critical not only for maintaining normal homeostasis but also for the progression of a variety of inflammatory diseases. Macrophage activation and beta2-adrenergic receptors are known to play important roles in facilitating this communication between these 2 systems. Using an integrated in vitro and in vivo study, Noh et al. reveal that beta2-adrenergic receptor agonists exhibit protective effects against the vascular complications of diabetes. The protective effects of beta2-adrenergic receptor agonists seem to be dependent on a beta-arrestin2/inhibitor of kappa B/nuclear factor-kappaB signaling pathway. PMID- 28646991 TI - Understanding the immune signature fingerprint of peritoneal dialysis-related peritonitis. AB - Although acute peritonitis is a common and severe complication associated with peritoneal dialysis, the culture-based test used as the diagnostic criterion for this disease is often too slow to allow appropriate point-of-care diagnosis of specific bacterial infection. To address this problem, Zhang et al. report the efficacy of a novel set of immune biomarkers derived from a machine-learning algorithm applied to patient data. This fingerprint could predict major pathogenic causes of peritonitis. PMID- 28646992 TI - Preventive nephrology in the era of "I" evidence: should we screen for chronic kidney disease? AB - In this issue, Ferguson and colleagues demonstrate that chronic kidney disease (CKD) screening in populations burdened with CKD may be cost effective. Whether we should screen for CKD, however, continues to be debated despite the availability of effective clinical strategies that mitigate the risks of CKD progression. This study highlights the need for pragmatic trials to test the effectiveness of early CKD detection combined with optimization of clinical management and calls for innovation to tackle CKD. PMID- 28646993 TI - Improving the evidence for the management of childhood nephrotic syndrome. AB - Management of idiopathic nephrotic syndrome in children is based on a series of clinical trials. The trial by Sinha and colleagues in this issue is 1 of many needed to improve the evidence base for induction and maintenance therapies in this population. While key questions remain about identifying the appropriate therapy for each patient, clinical trials provide an opportunity to extend evidence-based practice that minimizes toxicity and optimizes patient health. PMID- 28646994 TI - Reading the tree leaves-how to enrich clinical trials of diabetic kidney disease. AB - Most participants selected for clinical trials of renoprotective drugs do not reach approved endpoints; thus, large trials or prolonged follow-up are needed to achieve adequate statistical power. Yamanouchi et al. used a classification and regression trees analysis to enrich enrollment criterion for patients at the highest risk of reaching these outcomes. Their findings suggest a greater role for newly identified biomarkers of diabetic kidney disease in the selection of participants for clinical trials. PMID- 28646996 TI - The perfect storm. PMID- 28646995 TI - Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. AB - The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease. PMID- 28646997 TI - The Authors Reply. PMID- 28646998 TI - Skin rash in a patient with antineutrophil cytoplasmic antibody vasculitis. PMID- 28646999 TI - Endophthalmitis complicating dialysis access infection. PMID- 28647000 TI - The Case | Myeloid bodies in the kidney biopsy of a patient with systemic lupus erythematosus. PMID- 28647001 TI - Gastric bypass surgery stimulates the dormant gut-brain axis in obesity. AB - To truly reduce the rates of chronic kidney disease, a root cause of kidney damage, obesity, must be targeted. Weight loss is often unsustainable because imbalances in satiety regulators are frequently not addressed to ensure maintenance of weight loss. In a recent study, gastric bypass surgery rebalanced satiety signals through resensitization of the gut-brain axis in obesity. This research may lead to noninvasive strategies to reduce obesity and obesity-related kidney disease. PMID- 28647002 TI - Natural killers: the bad guys in fibrosis? AB - Immune cells infiltrating the tubulointerstitium critically contribute to the progression of chronic kidney disease. In this issue of Kidney international, Law et al. provide first evidence for a role of natural killer cells in the perpetuation of tubulointerstitial fibrosis in human renal disease. By detailed flow cytometric characterization of leukocytes isolated from kidney biopsies of chronic kidney disease patients, they define accumulation of natural killer cells as a feature of fibrotic kidney tissue and provide insight into potential mechanisms of how these cells might promote chronic kidney inflammation. PMID- 28647003 TI - Here/In This Issue and There/Abstract Thinking: Neighborhoods. PMID- 28647004 TI - The Opioid Epidemic: What Is a Child Psychiatrist to Do? PMID- 28647005 TI - Individual Variability and Medications to Treat Attention-Deficit/Hyperactivity Disorder: The World According to the Caudate. PMID- 28647006 TI - A Meta-Analysis of Gaze Differences to Social and Nonsocial Information Between Individuals With and Without Autism. AB - OBJECTIVE: Numerous studies have identified abnormal gaze in individuals with autism. However, only some findings have been replicated, the magnitude of effects is unclear, and the pattern of gaze differences across stimuli remains poorly understood. To address these gaps, a comprehensive meta-analysis of autism eye-tracking studies was conducted. METHOD: PubMed and a manual search of 1,132 publications were used to identify studies comparing looking behavior to social and/or nonsocial stimuli between individuals with autism and controls. Sample characteristics, eye-tracking methods, stimulus features, and regions of interest (ROIs) were coded for each comparison within each study. Multivariate mixed effects meta-regression analyses examined the impact of study methodology, stimulus features, and ROI on effect sizes derived from comparisons using gaze fixation metrics. RESULTS: The search yielded 122 independent studies with 1,155 comparisons. Estimated effect sizes tended to be small to medium but varied substantially across stimuli and ROIs. Overall, nonsocial ROIs yielded larger effect sizes than social ROIs; however, eye and whole-face regions from stimuli with human interaction produced the largest effects (Hedges g = 0.47 and 0.50, respectively). Studies with weaker study designs or reporting yielded larger effects, but key effects remained significant and medium in size, even for high rigor designs. CONCLUSION: Individuals with autism show a reliable pattern of gaze abnormalities that suggests a basic problem with selecting socially relevant versus irrelevant information for attention and that persists across ages and worsens during perception of human interactions. Aggregation of gaze abnormalities across stimuli and ROIs could yield clinically useful risk assessment and quantitative, objective outcome measurements. PMID- 28647007 TI - Childhood Psychiatric Disorders as Risk Factor for Subsequent Substance Abuse: A Meta-Analysis. AB - OBJECTIVE: To assess the prospective risk of developing substance-related disorders after childhood mental health disorders (i.e., attention deficit/hyperactivity disorder [ADHD], oppositional defiant disorder [ODD] or conduct disorder [CD], anxiety disorder, and depression) using meta-analysis. METHOD: PubMed, Embase, and PsycInfo were searched for relevant longitudinal studies that described childhood (<18 years old) ADHD, ODD or CD, anxiety, or depression in relation to later alcohol-, nicotine-, or drug-related disorders or substance use disorders (SUDs) published in peer-reviewed journals in the English language from 1986 to May 2016. Two researchers conducted all review stages. Meta analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. RESULTS: Thirty-seven studies including more than 762,187 participants were identified for quantitative analyses. These studies included 22,029 participants with ADHD, 434 participants with ODD or CD, 1,433 participants with anxiety disorder, and 2,451 participants with depression. Ninety-seven effects sizes were extracted for analyses. Meta-analysis showed a significantly increased risk for addiction in ADHD (n = 23, odds ratio [OR] 2.27, 95% CI 1.98-3.67; OR alcohol 2.15, 95% CI 1.56-2.97; OR drugs 1.52, 95% CI 1.52-5.27; OR nicotine 2.52, 95% CI 2.01-3.15; OR SUDs 2.61, 95% CI 1.77-3.84), ODD or CD (n = 8, OR 3.18, 95% CI 1.97-5.80; OR alcohol 1.73, 95% CI 1.51-2.00; OR drugs 4.24, 95% CI 1.3.21.5.59; OR nicotine 4.22, 95% CI 3.21-5.55; OR SUDs 4.86, 95% CI 3.09-7.56), and depression (n = 13, OR 2.03, 95% CI 1.47-2.81; OR alcohol 1.10, 95% CI 1.02 1.19; OR nicotine 2.56, 95% CI 1.89-3.48; OR SUDs 2.20, 95% CI 1.41-3.43), but not for anxiety disorders (n = 15, OR 1.34, 95% CI 0.90-1.55, not significant). CONCLUSION: Childhood ADHD, ODD, CD, and depression increase the risk of developing substance-related disorders. Anxiety disorders do not seem to increase the risk for future substance-related disorders, although the findings are highly heterogeneous. These findings emphasize the need for early detection and intervention to prevent debilitating substance-related disorders in later life. PMID- 28647008 TI - Trajectories of Neighborhood Cohesion in Childhood, and Psychotic and Depressive Symptoms at Age 13 and 18 Years. AB - OBJECTIVE: Exposure to adverse social environments has been associated with psychotic and depressive symptoms in adolescence in cross-sectional studies, but the longitudinal relation is unclear. This study examined whether longitudinal trajectories of exposure to adverse social environments across childhood are associated with psychotic experiences and depressive symptoms in adolescence. METHOD: Data on participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to estimate longitudinal trajectories of childhood exposure to neighborhood cohesion (NC), discord (ND), and stress (NS) using latent class growth modeling. Logistic regression was used to examine the association between these trajectories and psychotic experiences and depressive symptoms at 13 and 18 years of age, adjusting for maternal psychopathology, participant sociodemographic and socioeconomic characteristics, and area-level deprivation. RESULTS: A dose-response association was observed between higher NS and the odds of psychotic experiences at 13 years (medium NS, adjusted odds ratio [aOR] 1.25, 95% CI 1.05-1.49; high NS, aOR 1.77, 95% CI 1.30-2.40), whereas high levels of ND predicted psychotic experiences at 18 years (aOR 1.50, 95% CI 1.10 2.07). High levels of NC (aOR 1.43, 95% CI 1.02-1.71) and NS (aOR 1.55, 95% CI 1.07-2.26) were associated with increased odds of high depressive symptoms at 18 years in a dose-response fashion. CONCLUSION: Prolonged and more severe exposure to adverse social environments is associated with greater odds of developing psychotic and depressive symptoms in late adolescence. PMID- 28647009 TI - Teenage Parenthood and Birth Rates for Individuals With and Without Attention Deficit/Hyperactivity Disorder: A Nationwide Cohort Study. AB - OBJECTIVE: Prior studies have established that attention-deficit/hyperactivity disorder (ADHD) is associated with risky sexual behavior, but it remains unknown whether individuals with ADHD also are more likely to become parents while being teenagers. This aspect is clinically relevant because teenage parenthood is associated with adverse outcomes for parents and children. Therefore, the main aim of this study was to investigate whether individuals with ADHD would be more likely to become teenage parents compared with individuals without ADHD. METHOD: This is a historical prospective cohort study based on nationwide data from Danish registers. The cohort consisted of all individuals (N = 2,698,052) born in Denmark from January 1, 1960 through December 31, 2001. The association between ADHD (n = 27,479 cases) and parenthood (first child) in age intervals of 12 to 16, 17 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, and 40 years and above was investigated by Poisson regression and expressed as incidence rate ratios (IRRs) with accompanying 95% CIs. IRRs can be interpreted as relative risks. RESULTS: Compared with individuals without ADHD, those with ADHD were significantly more likely to become parents at 12 to 16 years of age (IRR for females 3.62, 95% CI 2.14-6.13; IRR for males 2.30, 95% CI 1.27-4.17) and at 17 to 19 years of age (IRR for females 1.94, 95% CI 1.62-2.33; IRR for males 2.27, 95% CI 1.90-2.70). CONCLUSION: Individuals with ADHD are significantly more likely to become teenage parents compared with individuals without ADHD. Therefore, it might be appropriate to target this group with an intervention program that includes sexual education and contraceptive counseling. PMID- 28647010 TI - Social Skills Training for Children and Adolescents With Autism Spectrum Disorder: A Randomized Controlled Trial. AB - OBJECTIVE: Social skills group training (SSGT) for children and adolescents with autism spectrum disorder (ASD) is widely applied, but effectiveness in real-world practice has not yet been properly evaluated. This study sought to bridge this gap. METHOD: This 12-week pragmatic randomized controlled trial of SSGT compared to standard care alone was conducted at 13 child and adolescent psychiatry outpatient units in Sweden. Twelve sessions of manualized SSGT ("KONTAKT") were delivered by regular clinical staff. Participants (N = 296; 88 females and 208 males) were children (n = 172) and adolescents (n = 124) aged 8 to 17 years with ASD without intellectual disability. The primary outcome was the Social Responsiveness Scale rating by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and 3-month follow-up. Moderator analyses were conducted for age and gender. RESULTS: Significant treatment effects on the primary outcome were limited to parent ratings for the adolescent subgroup (posttreatment: -8.3; 95% CI = -14.2 to -1.9; p = .012, effect size [ES] = 0.32; follow-up: -8.6; 95% CI = -15.4 to -1.8; p = .015, ES = 0.33) and females (posttreatment: -8.9; 95% CI = -16.2 to -1.6; p = .019, ES = 0.40). Secondary outcomes indicated moderate effects on adaptive functioning and clinical severity. CONCLUSION: SSGT for children and adolescents with ASD in regular mental health services is feasible and safe. However, the modest and inconsistent effects underscore the importance of continued efforts to improve SSGT beyond current standards. CLINICAL TRIAL REGISTRATION INFORMATION: Social Skills Group Training ("KONTAKT") for Children and Adolescent With High functioning Autism Spectrum Disorders; https://clinicaltrials.gov/; NCT01854346. PMID- 28647011 TI - Brain Structural Signatures of Adolescent Depressive Symptom Trajectories: A Longitudinal Magnetic Resonance Imaging Study. AB - OBJECTIVE: Most evidence for structural brain abnormalities associated with adolescent depression is based on cross-sectional study designs that do not take into account the dynamic course of depressive symptoms and brain maturation across adolescence. In this study, a longitudinal design was used to investigate the association between different trajectories of depressive symptoms and longitudinal changes in brain structure throughout adolescence. METHOD: One hundred forty-nine adolescents were assessed on depressive symptoms and underwent structural magnetic resonance imaging at 12 years of age and were followed up multiple times until 19 years. Three depressive symptom trajectories (low-stable [n = 97], early-decreasing [n = 33], late-increasing [n = 19]) were identified, and effects of group and group by time on hippocampus and amygdala volume and prefrontal cortical thickness and surface area were evaluated. RESULTS: The early decreasing symptoms group exhibited differences in cortical surface area compared to the low-stable and late-increasing symptoms groups, moderated by sex. Specifically, females in the early-decreasing symptoms group showed lower anterior cingulate and orbitofrontal cortex surface areas across adolescence compared to females in the other groups. Males in the early-decreasing symptoms group showed lower right orbitofrontal cortex surface area expansion over time compared to males in the low-stable and late-increasing symptoms groups. No effects were found for cortical thickness or for hippocampus and amygdala volume. CONCLUSION: Alterations in cortical surface area were specifically observed in young people experiencing depressive symptoms in early adolescence. These findings suggest that early adolescence is a particularly sensitive period for cortical surface area abnormalities associated with depressive symptoms and could provide a critical window for treatment of (subthreshold) depressive symptoms. PMID- 28647012 TI - Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine. AB - OBJECTIVE: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention deficit/hyperactivity disorder (ADHD). METHOD: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response. RESULTS: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F1,30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31 3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F1,30 = 14.99; p < .001). CONCLUSION: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach. CLINICAL TRIAL REGISTRATION INFORMATION: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391. PMID- 28647014 TI - The Context of Symptom Measures: Interpretation and Clinical Diagnosis of Autism Spectrum Disorders in Intellectual Disabilities. PMID- 28647015 TI - Dr. Havdahl et al. reply. PMID- 28647013 TI - Autism Spectrum Symptoms in a Tourette's Disorder Sample. AB - OBJECTIVE: Tourette's disorder (TD) and autism spectrum disorder (ASD) share clinical features and possibly an overlapping etiology. The aims of this study were to examine ASD symptom rates in participants with TD, and to characterize the relationships between ASD symptom patterns and TD, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). METHOD: Participants with TD (n = 535) and their family members (n =234) recruited for genetic studies reported TD, OCD, and ADHD symptoms and completed the Social Responsiveness Scale Second Edition (SRS), which was used to characterize ASD symptoms. RESULTS: SRS scores in participants with TD were similar to those observed in other clinical samples but lower than in ASD samples (mean SRS total raw score = 51; SD = 32.4). More children with TD met cut-off criteria for ASD (22.8%) than adults with TD (8.7%). The elevated rate in children was primarily due to high scores on the SRS Repetitive and Restricted Behaviors (RRB) subscale. Total SRS scores were correlated with TD (r = 0.27), OCD (r = 0.37), and ADHD (r = 0.44) and were higher among individuals with OCD symptom-based phenotypes than for those with tics alone. CONCLUSION: Higher observed rates of ASD among children affected by TD may in part be due to difficulty in discriminating complex tics and OCD symptoms from ASD symptoms. Careful examination of ASD specific symptom patterns (social communication vs. repetitive behaviors) is essential. Independent of ASD, the SRS may be a useful tool for identifying patients with TD with impairments in social communication that potentially place them at risk for bullying and other negative sequelae. PMID- 28647017 TI - Corrigendum. PMID- 28647016 TI - Summer Reading. PMID- 28647018 TI - Corrigendum. PMID- 28647019 TI - Corrigendum. PMID- 28647020 TI - Reprint of 'A Comprehensive review of group level model performance in the presence of heteroscedasticity: Can a single model control Type I errors in the presence of outliers?' AB - Even after thorough preprocessing and a careful time series analysis of functional magnetic resonance imaging (fMRI) data, artifact and other issues can lead to violations of the assumption that the variance is constant across subjects in the group level model. This is especially concerning when modeling a continuous covariate at the group level, as the slope is easily biased by outliers. Various models have been proposed to deal with outliers including models that use the first level variance or that use the group level residual magnitude to differentially weight subjects. The most typically used robust regression, implementing a robust estimator of the regression slope, has been previously studied in the context of fMRI studies and was found to perform well in some scenarios, but a loss of Type I error control can occur for some outlier settings. A second type of robust regression using a heteroscedastic autocorrelation consistent (HAC) estimator, which produces robust slope and variance estimates has been shown to perform well, with better Type I error control, but with large sample sizes (500-1000 subjects). The Type I error control with smaller sample sizes has not been studied in this model and has not been compared to other modeling approaches that handle outliers such as FSL's Flame 1 and FSL's outlier de-weighting. Focusing on group level inference with a continuous covariate over a range of sample sizes and degree of heteroscedasticity, which can be driven either by the within- or between-subject variability, both styles of robust regression are compared to ordinary least squares (OLS), FSL's Flame 1, Flame 1 with outlier de-weighting algorithm and Kendall's Tau. Additionally, subject omission using the Cook's Distance measure with OLS and nonparametric inference with the OLS statistic are studied. Pros and cons of these models as well as general strategies for detecting outliers in data and taking precaution to avoid inflated Type I error rates are discussed. PMID- 28647021 TI - Reprint of: Minimizing noise in pediatric task-based functional MRI; Adolescents with developmental disabilities and typical development. AB - Functional Magnetic Resonance Imaging (fMRI) represents a powerful tool with which to examine brain functioning and development in typically developing pediatric groups as well as children and adolescents with clinical disorders. However, fMRI data can be highly susceptible to misinterpretation due to the effects of excessive levels of noise, often related to head motion. Imaging children, especially with developmental disorders, requires extra considerations related to hyperactivity, anxiety and the ability to perform and maintain attention to the fMRI paradigm. We discuss a number of methods that can be employed to minimize noise, in particular movement-related noise. To this end we focus on strategies prior to, during and following the data acquisition phase employed primarily within our own laboratory. We discuss the impact of factors such as experimental design, screening of potential participants and pre-scan training on head motion in our adolescents with developmental disorders and typical development. We make some suggestions that may minimize noise during data acquisition itself and finally we briefly discuss some current processing techniques that may help to identify and remove noise in the data. Many advances have been made in the field of pediatric imaging, particularly with regard to research involving children with developmental disorders. Mindfulness of issues such as those discussed here will ensure continued progress and greater consistency across studies. PMID- 28647022 TI - Reprint of 'Noise contributions to the fMRI signal: An Overview'. AB - The ability to discriminate signal from noise plays a key role in the analysis and interpretation of functional magnetic resonance imaging (fMRI) measures of brain activity. Over the past two decades, a number of major sources of noise have been identified, including system-related instabilities, subject motion, and physiological fluctuations. This article reviews the characteristics of the various noise sources as well as the mechanisms through which they affect the fMRI signal. Approaches for distinguishing signal from noise and the associated challenges are also reviewed. These challenges reflect the fact that some noise sources, such as respiratory activity, are generated by the same underlying brain networks that give rise to functional signals that are of interest. PMID- 28647023 TI - How I Became a Clinician Scientist in Dermatology-A Tale of Serendipity, Wise Mentors, and a Good Pinch of Tenacity. PMID- 28647024 TI - Montagna Symposium 2016-The Skin: Our Sensory Organ for Itch, Pain, Touch, and Pleasure. PMID- 28647025 TI - Olumacostat Glasaretil, a Promising Topical Sebum-Suppressing Agent that Affects All Major Pathogenic Factors of Acne Vulgaris. AB - Hunt et al. show that olumacostat glasaretil, an inhibitor of acetyl coenzyme A carboxylase, reduces saturated and monounsaturated fatty acyl chains in sebaceous lipids. Topical olumacostat glasaretil application decreases hamster ear sebaceous gland size and shows efficacy in treating patients with acne vulgaris. Olumacostat glasaretil-mediated sebum suppression may reduce Propionibacterium acnes growth and biofilm formation, comedogenesis, and inflammation. PMID- 28647026 TI - S100B: Correlation with Active Vitiligo Depigmentation. AB - Vitiligo, the most common depigmenting disorder, is caused by immune destruction of melanocytes by cytotoxic CD8+ T cells. One weakness in vitiligo management is the lack of an assessment method for active depigmentation. Beginning with reports about increased S100B levels in different inflammatory and tissue damage processes, Speeckaert et al. explored correlations between the S100B dynamics and vitiligo activity, identifying high circulating S100B levels in patients with active depigmentation which were strongly correlated with the extent of affected skin surface. These authors have proposed S100B as a potential disease activity marker in vitiligo. PMID- 28647027 TI - Targeting of Stem Cell Niches Using Unconventional Genetic Tools. AB - Maintenance of hair follicle (HF) stem cell quiescence and self-renewal are key functions of a specific cellular niche represented by the HF bulge and adjacent cell populations. The unique context of this niche is crucial for normal HF functioning, but mechanisms implicated in its maintenance are still not quite clear. The Letter to the Editor by Sada et al. introduces a novel Slc1a3-CreER genetic mouse model which, in contrast to previously reported marking tools, selectively and highly efficiently demarcates the telogen bulge inner layer, one of the critical structural components of the bulge stem cell niche. The successful use of this tool identified the inner root sheath as a cellular source of telogen bulge inner layer and suggested its potential for further endeavors into fundamental and applied aspects of HF stem cell biology and club hair formation. PMID- 28647028 TI - Research Techniques Made Simple: Cost-Effectiveness Analysis. AB - Cost-effectiveness analysis (CEA) is a research method used to determine the clinical benefit-to-cost ratio of a given intervention. CEA offers a standardized means of comparing cost-effectiveness among interventions. Changes in quality adjusted life-years, disability-adjusted life-years, or survival and mortality are some of the common clinical benefit measures incorporated into CEA. Because accounting for all associated costs and benefits of an intervention is complex and potentially introduces uncertainty into the analysis, sensitivity analyses can be performed to test the analytic model under varying conditions. CEA informs the identification of high-value clinical practices and can be used to evaluate preventative, diagnostic, and therapeutic interventions in dermatology. PMID- 28647029 TI - SnapshotDx Quiz: July 2017. PMID- 28647030 TI - Cells to Surgery Quiz: July 2017. PMID- 28647031 TI - Cover Story: Towards a preventive treatment of Alzheimer's disease with multi functional liposomes. PMID- 28647032 TI - Endovascular treatment for claudication still awaits long-term results. PMID- 28647033 TI - Invited commentary. PMID- 28647035 TI - Percutaneous treatment of adult aortic coarctation with multiple intrathoracic aneurysms. PMID- 28647034 TI - Muscle strength and control characteristics are altered by peripheral artery disease. AB - OBJECTIVE: Peripheral artery disease (PAD), a common manifestation of atherosclerosis, is characterized by lower leg ischemia and myopathy in association with leg dysfunction. Patients with PAD have impaired gait from the first step they take with consistent defects in the movement around the ankle joint, especially in plantar flexion. Our goal was to develop muscle strength profiles to better understand the problems in motor control responsible for the walking impairment in patients with PAD. METHODS: Ninety-four claudicating PAD patients performed maximal isometric plantar flexion contractions lasting 10 seconds in two conditions: pain free (patient is well rested and has no claudication symptoms) and pain induced (patient has walked and has claudication symptoms). Sixteen matched healthy controls performed the pain-free condition only. Torque curves were analyzed for dependent variables of muscle strength and motor control. Independent t-tests were used to compare variables between groups, and dependent t-tests determined differences between conditions. RESULTS: Patients with PAD had significantly reduced peak torque and area under the curve compared with controls. Measures of control differed between PAD conditions only. Load rate and linear region duration were greater in the pain condition. Time to peak torque was shorter in the pain condition. CONCLUSIONS: This study conclusively demonstrates that the plantar flexor muscles of the PAD patient at baseline and without pain are weaker in patients with PAD compared with controls. With the onset of claudication pain, patients with PAD exhibit altered muscle control strategies and further strength deficits are manifest compared to baseline levels. The myopathy of PAD legs appears to have a central role in the functional deterioration of the calf muscles, as it is evident both before and after onset of ischemic pain. PMID- 28647036 TI - Supra-aortic interventions for endovascular exclusion of the entire aortic arch. AB - OBJECTIVE: Our aim was to analyze the outcomes of endovascular exclusion of the entire aortic arch (proximal landing in zone 0, distal landing in zone III or beyond, after Ishimaru) in which complete surgical debranching of the supra aortic vessels (I), endovascular supra-aortic revascularization (chimney, fenestrated, or branched grafts) with partial surgical debranching (II), or total endovascular supra-aortic revascularization (III) was additionally performed. METHODS: Publications describing endovascular repair of the aortic arch (2000 2016) were systematically searched and reviewed. RESULTS: From a total of 53 relevant studies including 1853 patients, only 1021 patients undergoing 35 different total aortic arch procedures were found eligible for further evaluation and included in group I, II, or III (429, 190, and 402 patients, respectively). Overall early mortality was higher in group I vs groups II and III (P = .001; 1 - beta = 95.6%) but exceeded in group III (18.6%) and group II (14.0%) vs group I (8.0%; P = .044; 1 - beta = 57.4%) for diseases involving zone 0. Mortality was higher in all subgroups treated for zone 0 disease compared with corresponding subgroups treated for zone I to zone III disease. The incidence of cerebral ischemic events was increased in groups I and II vs group III (7.5% and 11% vs 1.7%; P = .0001) and correlated with early mortality (R2 = .20; P = .033). The incidence of type II endoleaks and endovascular reintervention was similar between groups and correlated with each other (R2 = .37; P = .004). Type Ia endoleak occurred more often in groups II and III than in group I (7.1% and 12.1% vs 5.8%; P = .023) and correlated with midterm mortality (R2 = .53; P = .005). Retrograde type A dissection was low in all groups, whereas aneurysm growth was higher in group III (2.6%, 4.2%, 10.7%; P = .002), correlating with midterm mortality (R2 = .311; P = .009). Surgical revision slightly correlated with surgical complications (R2 = .18; P = .044) but not with mortality (R2 = .10; P = .214). CONCLUSIONS: Because early mortality was significantly higher in patients receiving endovascular treatment for proximal aortic disease, endovascular-based approaches proved to be feasible alternatives to hybrid surgical procedures, especially when they were performed for aneurysms located in the distal aortic arch. Whereas cerebral ischemia accompanies both surgical and endovascular involvement of the supra-aortic vessels, endoleaks and aneurysm growth remain hallmarks of endovascular supra-aortic repair. Because surgical revision had no impact on mortality, complete surgical debranching may become the option of choice for patients with good life expectancy suffering from proximal aortic arch disease, whereas total endovascular procedures could be particularly advantageous in patients with short life expectancy and distal aortic arch disease. PMID- 28647037 TI - Invited commentary. PMID- 28647038 TI - MIPS: Clinical practice improvement activities. PMID- 28647039 TI - Corrigendum to "Facile cellulose dissolution without heating in [C4mim][CH3COO]/DMF solvent" [Carbohydr. Polym. (2015) 249-254]. PMID- 28647040 TI - Synthesis of some transition metal (M: 25Mn, 27Co, 28Ni, 29Cu, 30Zn, 47Ag, 48Cd) sulfide nanostructures by hydrothermal method. AB - The design of nanostructures with favored shape, particle size and structure is one of the most important fields of nanoscience. To reach this target hydrothermal method is one of the most applicable methods which allow us to obtain favored structures by changing some parameters. This review focuses on synthesis of some transition metal sulfides by hydrothermal method because of technological importance of this group of material. The common sulfides of Mn, Co, Ni, Cu, Zn, Ag and Cd are introduced and a mechanism proposed for their synthesis. The effects of temperature and time reaction, surfactant, reactants concentration, metal and sulfur sources and etc. on the morphology, particle size and some properties of the products are investigated. SEM and TEM images show the morphology and size of the as-synthesized samples. Chemical composition of the samples is characterized by XRD, EDS and etc. The magnetic, optical and thermoelectric properties of the metal sulfides are investigated. PMID- 28647041 TI - To drain or not to drain the infraperitoneal anastomosis after rectal excision for cancer. PMID- 28647042 TI - Transanal endoscopic microsurgery for the treatment of uncommon rectal lesions. AB - INTRODUCTION: Transanal endoscopic microsurgery (TEM) was developed as a less aggressive alternative treatment for rectal lesions (mainly adenomas and adenocarcinomas). However, its use for other rectal lesions has become more frequent, trying to reduce the morbidity associated with more invasive techniques. The aim of this study is to describe our experience in the use of TEM in other rectal lesions. METHODS: Retrospective and descriptive study including patients operated with TEM (from June 2008 to December 2016) for the treatment of rectal lesions different from adenomas or adenocarcinomas. RESULTS: Among the 138 patients treated by TEM in our department, 10 patients were operated on for rectal lesions other than adenomas or adenocarcinomas. Rectal lesions were 3neuroendocrine tumours, a neuroendocrine tumour metastasis, a rectal stenosis, a cloacogenic polyp, an endometrioma, a retrorrectal tumour, a presacral abscess and a lesion in the rectovaginal septum. Mean operative time was 72min and postoperative stay was 4.2 days. Only one patient needed a reoperation, due to rectal bleeding. CONCLUSIONS: TEM could be a useful tool for the treatment of rectal lesions different from adenomas or adenocarcinomas, potentially decreasing the morbidity associated with more aggressive surgical techniques. PMID- 28647044 TI - Chest pain of recent onset: assessment and diagnosis (CG95). A step change in the requirement for cardiovascular CT. PMID- 28647045 TI - Cardiovascular Risk in Psoriasis. PMID- 28647046 TI - Assessment of emergency general surgery care based on formally developed quality indicators. AB - BACKGROUND: Emergency general surgery outcomes vary widely across the United States. The utilization of quality indicators can reduce variation and assist providers in administering care aligned with established recommendations. Previous quality indicators have not focused on emergency general surgery patients. We identified indicators of high-quality emergency general surgery care and assessed patient- and hospital-level compliance with these indicators. METHODS: We utilized a modified Delphi technique (RAND Appropriateness Methodology) to develop quality indicators. Through 2 rankings, an expert panel ranked potential quality indicators for validity. We then examined historic compliance with select quality indicators after 4 nonelective procedures (cholecystectomy, appendectomy, colectomy, small bowel resection) at 4 academic centers. RESULTS: Of 25 indicators rated as valid, 13 addressed patient-level quality and 12 addressed hospital-level quality. Adherence with 18 indicators was assessed. Compliance with performing a cholecystectomy for acute cholecystitis within 72 hours of symptom onset ranged from 45% to 76%. Compliance with surgery start times within 3 hours from the decision to operate for uncontained perforated viscus ranged from 20% to 100%. Compliance with exploration of patients with small bowel obstructions with ischemia/impending perforation within 3 hours of the decision to operate was 0% to 88%. For 3 quality indicators (auditing 30-day unplanned readmissions/operations for patients previously managed nonoperatively, monitoring time to source control for intra-abdominal infections, and having protocols for bypass/transfer), none of the hospitals were compliant. CONCLUSION: Developing indicators for providers to assess their performance provides a foundation for specific initiatives. Adherence to quality indicators may improve the quality of emergency general surgery care provided for which current outcomes are potentially modifiable. PMID- 28647047 TI - Hemobilia as unusual complication of liver biopsy, magnetic resonance findings. PMID- 28647048 TI - "Resident as teacher" in pediatric surgery: Innovation is overdue in Central Europe. AB - PURPOSE: We set out to evaluate how residents in pediatric surgery learn and how they teach. We hypnotized that European residents learn as much from their peers and teach as much as their fellows worldwide, but that they receive comparably less educational training. METHODS: An online questionnaire was distributed to the participants of the combined annual meeting for German, Swiss and Austrian residents in pediatric surgery. Participants were asked whom they learn from in different workplace environments (ward, operating room, emergency department), how, when and why they adopt the role of teacher and how they were prepared for this role. RESULTS: Response rate was 48%. 65 questionnaires were analyzed. Residents stated that they predominantly learn from each other on wards and in the emergency department, less frequently in the operating room. They ranked fellow residents as first or second most important source of instruction. 53% of participants have never had any educational training, for another 33% the instruction was being done by fellow residents without any set curriculum. 93% of the participating residents had no or did not know about any resident as teacher training program available to them. Nevertheless, motivation to teach was stated to be high and interest in educational training was assured. CONCLUSIONS: Our data delivers evidence that peer teaching during residency is the rule rather than the exception in Central Europe. Educational training however is scarce. Resident as teacher-training programs need to be introduced. Next to local initiatives, we strongly recommend national initiatives powered by regulatory authorities and surgical associations. TYPE OF STUDY: Research paper. LEVEL OF EVIDENCE: II. PMID- 28647050 TI - Public health masking mandates improve hospital healthcare personnel vaccination rates. PMID- 28647049 TI - Targeting of regulated necrosis in kidney disease. AB - The term acute tubular necrosis was thought to represent a misnomer derived from morphological studies of human necropsies and necrosis was thought to represent an unregulated passive form of cell death which was not amenable to therapeutic manipulation. Recent advances have improved our understanding of cell death in acute kidney injury. First, apoptosis results in cell loss, but does not trigger an inflammatory response. However, clumsy attempts at interfering with apoptosis (e.g. certain caspase inhibitors) may trigger necrosis and, thus, inflammation mediated kidney injury. Second, and most revolutionary, the concept of regulated necrosis emerged. Several modalities of regulated necrosis were described, such as necroptosis, ferroptosis, pyroptosis and mitochondria permeability transition regulated necrosis. Similar to apoptosis, regulated necrosis is modulated by specific molecules that behave as therapeutic targets. Contrary to apoptosis, regulated necrosis may be extremely pro-inflammatory and, importantly for kidney transplantation, immunogenic. Furthermore, regulated necrosis may trigger synchronized necrosis, in which all cells within a given tubule die in a synchronized manner. We now review the different modalities of regulated necrosis, the evidence for a role in diverse forms of kidney injury and the new opportunities for therapeutic intervention. PMID- 28647051 TI - Longitudinal nosocomial outbreak of Pseudomonas fluorescens bloodstream infection of 2 years' duration in a coronary care unit. AB - BACKGROUND: Outbreaks of bloodstream infections (BSI) of nonfermenting bacteria are a critical issue and often associated with hospital environments. We experienced a long-lasting outbreak of Pseudomonas fluorescens BSI limited to a coronary care unit (CCU). METHODS: We conducted a retrospective epidemiologic investigation and a case-control study for Pseudomonas fluorescens BSI from April 2011-July 2014. Environmental sample culture was conducted to detect the specific environmental source of transmission. RESULTS: Hospital-wide microbiology data from the term identified 13 case patients with P fluorescens BSI and 32 control patients with BSI due to organisms other than P fluorescens in the CCU. The case control study revealed that the case group had significantly higher odds of exposure to only cardiac output (CO) measurement with thermodilution method (odds ratio, 22.0; 95% confidence interval, 2.4-202.3). The organism was identified only from an ice bath used for CO measurement. The susceptibility patterns were identical among all strains derived from the cases and the environment. CONCLUSIONS: The nosocomial outbreak of P fluorescens BSI in our CCU over 2 years was associated with a contaminated ice bath used for CO measurement within the unit. Detection and elimination of the specific source was essential to stop the outbreak. PMID- 28647052 TI - Outbreaks of health care-associated influenza-like illness in France: Impact of electronic notification. AB - BACKGROUND: Mandatory notification of health care-associated (HA) infections, including influenza-like illness (ILI) outbreaks, has been implemented in France since 2001. In 2012, the system moved to online electronic notification of HA infections (e-SIN). The objectives of this study are to describe ILI outbreak notifications to Sante publique France (SPF), the French national public health agency, and to evaluate the impact of notification dematerialization. METHODS: All notifications of HA ILI outbreaks between July 2001 and June 2015 were included. Notifications before and after e-SIN implementation were compared regarding notification delay and information exhaustiveness. RESULTS: Overall, 506 HA ILI outbreaks were reported, accounting for 7,861 patients and health care professionals. Median delay between occurrence of the first case and notification was, respectively, 32 and 13 days before and after e-SIN utilization (P < .001). Information exhaustiveness was improved by electronic notification regarding HA status (8.5% of missing data before and 2.3% after e-SIN, P = .003), hypotheses of cause (25.4% of missing data before vs 8.0% after e-SIN, P < .001), and level of event control (23.7% of missing data before vs 7.5% after e-SIN, P < .001). CONCLUSIONS: HA influenza notifications, including HA ILI or influenza, to health authorities are essential to guide decisional instances and health care practices. Electronic notifications have improved the timeliness and quality of information transmitted. PMID- 28647053 TI - Resistance to hepatitis C virus. Implications and therapeutic options. AB - We are currently living in an unprecedented era of hepatitis C treatment with the availability of highly effective drugs yielding minimal side effects. The problem we currently face is the retreatment of patients refractory to these drugs. Although several factors can influence treatment failure, this review focuses on antiviral resistance. Resistance-associated substitutions may be identified at baseline or be treatment-emergent. The latter seem to be more clinically relevant and must be studied in the event of treatment failure (no virological response). In this article, we present the latest data from clinical trials and studies in real-life clinical practice. Finally, based on this current evidence, we propose some recommendations for the management and retreatment of these patients. PMID- 28647054 TI - Saving resources in relation to ultrafast urease test. PMID- 28647056 TI - [Pharmaceutical interviews in case of high blood pressure]. PMID- 28647055 TI - Uncovering Gene Regulatory Networks Controlling Plant Cell Differentiation. AB - The development of multicellular organisms relies on the precise regulation of cellular differentiation. As such, there has been significant effort invested to understand the process through which an immature cell undergoes differentiation. In this review, we highlight key discoveries and advances that have contributed to our understanding of the transcriptional networks underlying Arabidopsis root endodermal differentiation. To conclude, we propose perspectives on how advances in molecular biology, microscopy, and nucleotide sequencing will provide the tools to test the biological significance of these gene regulatory networks (GRN). PMID- 28647057 TI - Prevalence of obstructive sleep apnoea in acute coronary syndrome: Routine screening in intensive coronary care units. AB - INTRODUCTION: Increased evidence has shown that, despite the maximum care afforded to patients admitted with acute coronary syndromes (ACS), a residual risk of mortality remains, in which obstructive sleep apnoea (OSA) appears to be a largely undiagnosed factor, particularly in the intensive cardiac care unit (ICCU). The purpose of this study is to determine whether the systematic screening for sleep-disordered breathing (SDB) is feasible and may be recommended. The aims of our study are to determine: (1) The estimated prevalence of OSA in patients admitted to the ICCU for ACS determined by a validated, user friendly portable screening device; (2) The feasibility of the screening in this context; (3) To assess any negative impact of OSA on the severity of ACS. PATIENTS AND METHODS: This is an observational study of 101 patients admitted to the ICCU for ACS showing no clinical evidence of heart failure (HF). In the 24 72hours following admission, they underwent an overnight sleep study using a 3 channel portable screening device with automatic analysis. RESULTS: Sixty-two out of the 101 patients proved positive to the screening test, and its feasibility was acceptable. OSA patients tended to have greater peak levels of hs-cTnT (3685+/-3576ng/L versus 2830+/-3333ng/L, P=0.08) than the non-OSA group. Compared with the non-OSA group, OSA patients presented more severe ACS, with a greater average GRACE score at admission of 112.2+/-26.3 (versus 98.4+/-19.2, P<0.001). In the OSA group, we found a statistically significant inverse correlation between the apnoea-hypopnea index (AHI) and the left ventricular ejection fraction (LVEF) in the linear regression analysis (r=-0.26; P=0.037). CONCLUSIONS: A systematic screening of patients in the ICCU is acceptable. OSA is frequently found in the acute phase of ischaemic heart disease and its presence is associated with more severe ACS and a poorer left ventricle systolic function. PMID- 28647058 TI - [Management of multiple valve disease]. AB - Polyvalvular disease is not a rare condition, the lack of specific data for each situation does not allow perfoming standardized management and guidelines. We want to present by this review available data on the management of polyvalvular disease, taking into account different possible associations between the valve lesions. PMID- 28647059 TI - [Silhouettes at different age of life: Retrospective appreciation of corpulence and his impact on prevalence of hypertension at 60years]. AB - PURPOSE OF THE STUDY: In epidemiological studies, recall of weight and height are not readily available at different ages of life. In order to improve the knowledge of the weight history, Sorensen et al. in 1983, developed a tool from silhouettes allowing an individual to evaluate his corpulence at different ages of life. Validity studies showed that measured weight and size were correlated to 80% in the reported silhouette. Studies have also shown that silhouettes are a good way to trace the weight history in an individual's life. Very few epidemiological studies have used this tool. A French study revealed a decrease of the risk of breast cancer in obese girls between the age of 8 and adolescence. Another study showed that a low birth weight or a thin silhouette before adulthood was associated with an increased risk of diabetes. On the basis of these findings, it was interesting to evaluate the relationship between the silhouette at 20years and the risk of hypertension at the age of 60years. RESULTS: It was shown that the prevalence of hypertension at age 60 was higher among obese subjects at 20years than among thin subjects (45.3% vs 36.7% (P<0.05). CONCLUSION: The classification between slimness and obesity is relevant using this tool. The history of corpulence is an important element to consider in the determinants of pathology, especially in hypertension. PMID- 28647060 TI - Lipid Droplets Can Spontaneously Bud Off from a Symmetric Bilayer. AB - Lipid droplets (LDs) are cytosolic organelles that protrude from the endoplasmic reticulum membrane under energy-rich conditions. How an LD buds off from the endoplasmic reticulum bilayer is still elusive. By using a continuous media description, we computed the morphology of a lipid droplet embedded in between two identical monolayers of a bilayer. We found that beyond a critical volume, the droplet morphology abruptly transits from a symmetrical elongated lens to a spherical protrusion. This budding transition does not require any energy consuming machinery, or curvature-inducing agent, or intrinsic asymmetry of the bilayer; it is solely driven by the large interfacial energy of the LD, as opposed to the bilayer surface tension. This spontaneous budding mechanism gives key insights on cellular LD formation. PMID- 28647061 TI - Vesicle Fusion Mediated by Solanesol-Anchored DNA. AB - Fusion between two lipid bilayers is one of the central processes in cell biology, playing a key role in endocytosis, exocytosis, and vesicle transport. We have previously developed a model system that uses the hybridization of complementary DNA strands to model the formation of the SNARE four-helix bundle that mediates synaptic vesicle fusion and used it to study vesicle fusion to a tethered lipid bilayer. Using single vesicle assays, 70% of observed fusion events in the DNA-lipid system are arrested at the hemifusion stage, whereas only 5% eventually go to full fusion. This may be because the diglycerol ether that anchors the DNA in the membrane spans only half the bilayer: upon hemifusion and mixing of the outer leaflets, the DNA-lipid is free to diffuse into the target membrane and away from the vesicle. Here, we test the hypothesis that the length of the membrane anchor may impact the outcome by comparing single leaflet spanning DNA-lipid mediated vesicle fusion with fusion mediated by DNA anchored by solanesol, a C45 isoprenoid of sufficient length to span the bilayer. When the solanesol anchor was present on the incoming vesicles, target membrane, or both, ~2-3 times as much full fusion was observed as in the DNA-lipid mediated system, as measured by lipid mixing or content transfer. These results indicate that a transmembrane anchor increases the efficiency of full fusion. PMID- 28647062 TI - High-Resolution Computed Tomography Imaging in Conductive Hearing Loss: What to Look for? AB - Conductive hearing loss (CHL) is caused by the disruption of the sound conductive chain that, in turn, may be due to diseases of the external and middle ear. High resolution computed tomography (CT) is the imaging modality of choice to evaluate CHL because of its excellent spatial resolution. Along with clinical and otoscopic findings, CT also helps in the diagnosis and preoperative planning. This pictorial review aims to illustrate the CT features of common conditions causing CHL that may arise from the external and middle ear, as well as highlights some of the key imaging features that are helpful in management. PMID- 28647063 TI - Parent being a physician: Any influence upon job stress in young physicians? A Norwegian prospective and longitudinal cohort study. AB - OBJECTIVE: To investigate whether being the child of a physician would be of importance for how young physicians experience job stress. METHOD: In a national representative prospective and longitudinal study with five assessment points (NORDOC), young physicians were followed over twenty year after graduation from medical school. RESULTS: Female physicians with a physician parent reported higher levels of job stress over the whole period compared with males with a physician parent. This gender difference did not occur within the group without a physician parent. Male young physicians showed a trend (not quite significant) to be less stressed than their peers without a physician parent. Women physicians were overrepresented in a group with persisting high stress level over the period. CONCLUSIONS: Male physicians with physician parent reporting lower stress levels than their female peers can be interpreted as a consequence of male physicians having more male models during their first working years as the main proportion of older physicians still are men. A father-son relationship may also promote an easier way to lower stress and achieve an identification with the role of doctor than for the females with a father-daughter relationship. With the increasing number of female physician, this gender difference may be prone to changes over time. PMID- 28647064 TI - Efficacy of the doktormitSDM training module in supporting shared decision making - Results from a multicenter double-blind randomized controlled trial. AB - OBJECTIVE: Training to improve physicians' shared decision making (SDM) competencies with proven effectiveness and efficiency is rare. This study evaluated the brief in situ training module 'doktormitSDM'. METHODS: In a multicenter RCT, each physician recorded four consultations, each of which included a diagnostic or treatment decision (N=152 consultations from seven medical specialties). The doktormitSDM training module included two video-based individual coaching sessions (15min) at the physicians' workplaces, supplemented by a manual and a video tutorial. Primary endpoint was the compound measure SDMmass (based on the MAPPIN'SDM system) which incorporates patient and observer perceptions of involvement and doctor-patient concordance on perceived involvement. RESULTS: SDMmass increased significantly in the intervention group compared to the controls (effect size 0.58; p=0.05; t-test). This effect tended to persist at follow-up (effect size 0.63; p=0.06). Patients' perceived involvement increased accordingly (effect sizes 0.9/.58; p=0.01/.07). CONCLUSION: The doktormitSDM training module is effective and efficient at improving SDM competencies. This is the first SDM training to be evaluated with a compound measure simultaneously considering doctor, patient and observer ratings. PRACTICE IMPLICATIONS: Owing to its very brief form and its reference to the doctors' own consultation videos, the doktormitSDM training module meets clinicians' needs and time constraints. PMID- 28647065 TI - Preanalytic process linked to spuriously elevated HIV viral loads: improvement on an FDA-approved process. AB - The processing of specimens often occurs in a central processing area within laboratories. We demonstrated that plasma centrifuged in the central laboratory but allowed to remain within the primary tube following centrifugation was associated with spuriously elevated HIV viral loads compared with recentrifugation of the plasma just prior to testing. PMID- 28647066 TI - Large-scale evaluation of a rapid diagnostic test for human cystic echinococcosis. AB - Cystic echinococcosis (CE) is a neglected zoonotic disease, diagnosed through clinical findings, imaging techniques, and serology, for which many serological tests are available. Here we report a rapid unit assay, the immunochromatographic VIRapid(r) HYDATIDOSIS test (Vircell, Granada, Spain), potentially suitable for laboratories in low-prevalence or poorly equipped areas. This test was evaluated with a large retrospective cohort (224 sera), including patients suffering from CE or from other parasitic or liver diseases. The test was also assessed in routine conditions with a prospective cohort (115 sera) in areas where both cystic and alveolar echinococcoses have been diagnosed. Its performance (in terms of sensitivity, specificity, and both positive and negative likelihood ratios) was similar to an ELISA based on a crude antigen. Our study shows that this test performs adequately in the diagnostic process, when used with caution, especially regarding cross-reactivity with other parasitic diseases. PMID- 28647067 TI - Risk Adjustment and Performance Measurement for Lung Cancer Resection. AB - Comparative audit is an essential tool for multicenter quality efforts. The components include a rigorously defined and collected data source, carefully selected and defined preintervention patient variables that may impact outcome, appropriate risk stratification to aid in comparing varying populations, meticulous outcome selection and analysis, and independent audit to ensure the veracity of the data. PMID- 28647068 TI - Risk Adjustment and Performance Measurement for Esophageal Cancer Resection. AB - Achieving high-quality care for all patients undergoing esophageal cancer requires identifying and modifying risk factors associated with poor outcomes. These factors occur at different time points from the preoperative to the postoperative periods. A straightforward model for predicting outcomes has proved difficult to identify. This article reviews the current studies addressing risk adjustment and performance measurement for esophageal cancer resection. PMID- 28647070 TI - National Quality Forum Metrics for Thoracic Surgery. AB - The National Quality Forum (NQF) is a multistakeholder, nonprofit, membership based organization improving health care through preferential use of valid performance measures. NQF-endorsed measures are considered the gold standard for health care measurement in the United States. The Society of Thoracic Surgeons is the steward of the only six NQF-endorsed general thoracic surgery measures. These measures include one structure measure (participation in a national general thoracic surgery database), two process measures (recording of clinical stage and recording performance status before lung and esophageal resections), and three outcome measures (risk-adjusted morbidity and mortality after lung and esophageal resections and risk-adjusted length of stay greater than 14 days after lobectomy). PMID- 28647071 TI - Volume-Outcome Relationships in Thoracic Surgery. AB - Most thoracic surgery studies indicate that hospital and surgeon procedure volume are inversely associated with mortality. However, controversy exists regarding the strength and validity of this volume-outcome association. Because thresholds of procedure volume are used to recommend the regionalization of care, investigation of the volume-outcome relationship is imperative. This article examines the methodology used in the volume-outcome relationship literature and highlights important areas of concern. Careful examination of the literature demonstrates that lung and esophageal cancer resection volume is not strongly associated with mortality and should not be used as a proxy measure for quality. PMID- 28647069 TI - Oncologic Quality Indicators in Thoracic Surgery. AB - This article outlines a structure for assessing thoracic surgical quality and provides an overview of evidence-based quality metrics for surgical care in both lung cancer and esophageal cancer, with a focus on process and outcome measures in the preoperative, intraoperative, and postoperative setting. PMID- 28647072 TI - Failure-to-Rescue in Thoracic Surgery. AB - Variability in outcomes not attributable to case mix or chance is an indicator of low-quality care. Failure-to-rescue is an outcome measure defined as death during a hospitalization among patients who experience a complication. Researchers have used this measure to better understand the determinants of an untimely death preventing complications, rescue, or both. Studies repeatedly find that complication rates vary little, if at all, across hospitals ranked by risk adjusted mortality rates, suggesting that hospitals are equally capable (or incapable) of preventing complications. In contrast, variation in failure-to rescue rates seems to explain much of the variation in risk-adjusted hospital level mortality rates. These findings suggest that system-level interventions that allow for the early detection and treatment of complications (ie, rescue) may reduce variability in hospital-level outcomes and improve the quality of thoracic surgical care. PMID- 28647073 TI - Quality and Cost in Thoracic Surgery. AB - The value of health care is defined as health outcomes (quality) achieved per dollars spent (cost). The current national health care landscape is focused on minimizing spending while optimizing patient outcomes. With the introduction of minimally invasive thoracic surgery, there has been concern about added cost relative to improved outcomes. Moreover, differences in postoperative hospital care further drive patient outcomes and health care costs. This article presents a comprehensive literature review on quality and cost in thoracic surgery and aims to investigate current challenges with regard to achieving the greatest value for our patients. PMID- 28647074 TI - Patient-Reported Outcomes in Thoracic Surgery. AB - The existing thoracic surgical literature contains several retrospective and observational studies that include patient-reported outcomes. To deliver true patient-centered care, it will be necessary to universally gather patient reported outcomes prospectively, including them in routine patient care, clinical registries, and clinical trials. PMID- 28647075 TI - Database Audit in Thoracic Surgery. AB - Administrative data are less accurate and relevant than specialty-specific, procedure-specific, risk-adjusted data collected in voluntary registries such as the Society of Thoracic Surgeons-General Thoracic Surgery Database (GTSD). Voluntary clinical databases must be proven accurate and complete before they are accepted as credible information sources. With substantial growth of the GTSD, an annual audit was initiated in 2010 to assess the completeness, accuracy, and quality of the data collected. The audit process is essential in validating data quality and adding credibility and value to volunteer clinical registries. It serves as an important tool for improvement of patient care. PMID- 28647076 TI - European Society of Thoracic Surgeons Risk Scores. AB - Risk-adjusted outcome analysis is pivotal for monitoring and improving quality of care. The European Society of Thoracic Surgeons established an online database more than 15 years ago. Several risk models and a composite score have been generated from the data included in the database. This report reviews the methods and applications of these risk scores. PMID- 28647077 TI - International General Thoracic Surgery Database Collaboration. AB - One of the recent goals of the Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD) Task Force has been an increased focus on international database collaboration. To date, such collaboration has primarily been with the European Society of Thoracic Surgeons (ESTS) Registry Task Force. This article provides an overview of the STS GTSD and ESTS registry, recent collaborative projects, obstacles encountered, and future directions for the databases. PMID- 28647079 TI - Quality in Thoracic Surgery. PMID- 28647078 TI - Hospital Readmission Following Thoracic Surgery. AB - Hospital readmission costs the health care system in excess of 1 billion dollars a year. The Hospital Readmission Reduction Program was instituted as part of the Affordable Care Act in 2012 and penalizes hospitals with high rates of readmission. Strategies exist to minimize hospital readmissions and should be implemented by thoracic surgeons. PMID- 28647080 TI - Are capillary and arterial lactates interchangeable? PMID- 28647081 TI - Empirical drug discovery: a view from the proteome. PMID- 28647082 TI - Targeting neuronal function for CNS drug discovery. AB - There is a pressing need for new and more effective treatments for central nervous system (CNS) disorders. A large body of evidence now suggests that alterations in synaptic transmission and neuronal excitability represent underlying factors for many neurological and psychiatric diseases. However, it has been challenging to target these complex functional domains for therapeutic discovery using traditional neuronal assay methods. Here we review advances in neuronal screening technologies and cellular model systems that enable phenotypic screening of neuronal function as a basis for novel CNS drug discovery approaches. PMID- 28647084 TI - Bioprinted three dimensional human tissues for toxicology and disease modeling. AB - The high rate of attrition among clinical-stage therapies, due largely to an inability to predict human toxicity and/or efficacy, underscores the need for in vitro models that better recapitulate in vivo human biology. In much the same way that additive manufacturing has revolutionized the production of solid objects, three-dimensional (3D) bioprinting is enabling the automated production of more architecturally and functionally accurate in vitro tissue culture models. Here, we provide an overview of the most commonly used bioprinting approaches and how they are being used to generate complex in vitro tissues for use in toxicology and disease modeling research. PMID- 28647083 TI - The production of 3D tumor spheroids for cancer drug discovery. AB - New cancer drug approval rates are <=5% despite significant investments in cancer research, drug discovery and development. One strategy to improve the rate of success of new cancer drugs transitioning into the clinic would be to more closely align the cellular models used in the early lead discovery with pre clinical animal models and patient tumors. For solid tumors, this would mandate the development and implementation of three dimensional (3D) in vitro tumor models that more accurately recapitulate human solid tumor architecture and biology. Recent advances in tissue engineering and regenerative medicine have provided new techniques for 3D spheroid generation and a variety of in vitro 3D cancer models are being explored for cancer drug discovery. Although homogeneous assay methods and high content imaging approaches to assess tumor spheroid morphology, growth and viability have been developed, the implementation of 3D models in HTS remains challenging due to reasons that we discuss in this review. Perhaps the biggest obstacle to achieve acceptable HTS assay performance metrics occurs in 3D tumor models that produce spheroids with highly variable morphologies and/or sizes. We highlight two methods that produce uniform size controlled 3D multicellular tumor spheroids that are compatible with cancer drug research and HTS; tumor spheroids formed in ultra-low attachment microplates, or in polyethylene glycol dimethacrylate hydrogel microwell arrays. PMID- 28647085 TI - In vivo phenotypic screening: clinical proof of concept for a drug repositioning approach. AB - In vivo phenotypic screening and drug repositioning are strategies developed as alternatives to underperforming hypothesis-driven molecular target based drug discovery efforts. This article reviews examples of drugs identified by phenotypic observations and describes the use of the theraTRACE(r)in vivo screening platform for finding and developing new indications for discontinued clinical compounds. Clinical proof-of-concept for the platform is exemplified by MLR-1023, a repositioned compound that has recently shown significant clinical efficacy in Type 2 diabetes patients. These findings validate an in vivo screening approach for drug development and underscore the importance of alternatives to target and mechanism based strategies that have failed to produce adequate numbers of new medicines. PMID- 28647086 TI - Phenotypic chemical biology for predicting safety and efficacy. AB - Phenotypic assays using in vitro cell cultures to forecast compound effects in people are transforming pharmaceutical research and contribute to alternative methods for chemical safety testing. How these assays are validated for human disease relevance is a critical factor for developing more predictive assays. Chemical biology, using drugs as well as target-selective chemical probes, is a direct and efficient approach for establishing disease relevance. Chemical probes can connect information across assays and associate targets to clinical effects. When applied at scale, phenotypic chemical biology advances our understanding of drug and toxicity mechanisms enabling construction of disease outcome pathways. To improve the physiological relevance of phenotypic assays, standardized testing of a curated set of phenotypic pathway probes can provide a higher level of validation for phenotypic assay best practices. PMID- 28647087 TI - The evolution of library design: crafting smart compound collections for phenotypic screens. AB - The (re)emergence of phenotypic drug discovery has been marked by a growing interest in screening campaigns that utilize phenotypic assays. The key objectives of phenotypic screens are different from those of target-based screens and can require alternate library-design strategies. Designing a library that is appropriate to the selected assay increases the likelihood of identifying better quality hits, which can reduce both timelines and overall cost of the drug discovery process. Here, we provide an overview of small-molecule library design principles as applied to phenotypic screening. PMID- 28647088 TI - Deorphanization strategies for dark chemical matter. AB - The term dark chemical matter (DCM) was recently introduced for those molecules in a screening collection that have never shown any substantial biological activity despite having been tested in hundreds of high-throughput assays. It was suggested that, if hits emerge from this compound pool in future screening campaigns, they should be prioritized due to their exquisite selectivity profile. In this article we define DCM at our company and describe on-going efforts to shed light on the bioactivity of these apparently silent compounds, with an emphasis on multi-parametric profiling methods. It is also demonstrated that compounds that are dark within one institution might be found active in another, but typically show the foretold selectivity. PMID- 28647089 TI - Reverse Phase Protein Arrays elucidate mechanisms-of-action and phenotypic response in 2D and 3D models. AB - The development of new 2D and 3D phenotypic screening assays combined with high throughput genomic and proteomic technologies are well placed to advance a new era of molecular pathway informed Phenotypic Drug Discovery. We describe the application of Reverse Phase Protein Array (RPPA) technology to elucidate the mechanism-of-action of small molecules at the post-translational pathway level. We propose that profiling of phenotypic hits and lead molecules in increasingly more complex 3D in vitro and ex vivo models at the post-translational pathway network level represents an effective strategy to both triage and progress the preclinical development of phenotypic screening hits. PMID- 28647090 TI - Natural product inspired compound collections: evolutionary principle, chemical synthesis, phenotypic screening, and target identification. AB - Natural products have been an excellent and abundant source of therapeutics for many decades. To expand on their success, and explore areas of chemical space not covered by biosynthesis, the synthesis of natural product-inspired compound collections has emerged as a viable strategy. Herein we describe the principles behind biology-oriented synthesis and related approaches, the requirements for development of novel chemistry and how phenotypic screens are a very fruitful way to explore the bioactivity of compounds made using these approaches. Finally, we summarize state-of-the-art techniques to identify the biological targets of any hits identified. PMID- 28647091 TI - Phenotypic screening-the fast track to novel antibody discovery. AB - The majority of antibody therapeutics have been isolated from target-led drug discovery, where many years of target research preceded drug program initiation. However, as the search for validated targets becomes more challenging and target space becomes increasingly competitive, alternative strategies, such as phenotypic drug discovery, are gaining favour. This review highlights successful examples of antibody phenotypic screens that have led to clinical drug candidates. We also review the requirements for performing an effective antibody phenotypic screen, including antibody enrichment and target identification strategies. Finally, the future impact of phenotypic drug discovery on antibody drug pipelines will be discussed. PMID- 28647093 TI - Hypertrophic olivary degeneration after cerebellar hemorrhage. AB - We present a striking example of hypertrophic olivary degeneration after cerebellar hemorrhage. This case highlights some important teaching points: unique response of the inferior olivary nucleus to de-afferentation, anatomy of Mollaret's triangle and clinical manifestations of disruption in Mollaret's triangle. The purpose of this teaching case is to highlight a rare but important post-stroke complication. PMID- 28647094 TI - Long-term prognosis of hematogenous vertebral osteomyelitis: Mortality, quality of life, and pain. AB - BACKGROUND: Hematogenous vertebral osteomyelitis (HVO) has a generally favorable prognosis if appropriate treatment is initiated in its early phase; however, some intractable cases with HVO can develop neurological impairment as well as spinal deformity during the course of treatment and these sequelae may lead to impaired quality of life (QOL). In this study, we aimed to evaluate the long-term relapse rate, mortality, and QOL of patients with HVO. METHODS: In this retrospective case series study, medical records of 60 patients with HVO with a mean follow-up period of 8 years (5-23 years) were reviewed to assess demographic data, details of infection, and clinical course. Mortality rate was assessed using a Kaplan Meier plot. QOL was measured using the EuroQol 5 Dimension (EQ-5D) questionnaire and residual pain using a numeric rating scale (NRS). RESULTS: HVO relapsed in 4 of 60 patients (7%). Overall 5-year survival rate in 60 patients with HVO was 85%. The factors associated with increased mortality were malignant tumor, diabetes mellitus, chronic use of glucocorticoids, and drug-resistant strains of staphylococcus. Female-to-male ratio, NRS, prevalence of neurological impairment were significantly higher in patients with low EQ-5D score (poor health) compared to those with high EQ-5D score (good health). CONCLUSIONS: Patients with HVO have shorter life expectancy if they have malignancy, diabetes mellitus, chronic use of glucocorticoids, and a history of drug-resistant strains of staphylococcus infection. Female gender, residual neurological defects and persistent back pain are associated with impaired QOL in patients with HVO. PMID- 28647092 TI - Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy. AB - Imbalances in secretory proteostasis induced by genetic, environmental, or aging related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) unfolded protein response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well defined, the impact of UPR activation on secretory proteostasis is only now becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases. PMID- 28647095 TI - Increased detection of blunt carotid and vertebral artery injury after implementation of diagnostic imaging pathway in level 1 trauma centre in Western Australia. AB - BACKGROUND: The incidence of Blunt Carotid Artery and Vertebral Artery Injury (BCVI) is relatively low in modern trauma practice. However, these injuries may be associated with severe neurological consequences. Following the introduction of a Diagnostic Imaging Pathway in Department of Health of Western Australia, we hypothesized that this injury would be less likely to be missed, and accordingly diagnosed more frequently. METHOD: A review of all major trauma (Injury Severity Scale>15) admissions at the State Major Trauma Centre in Royal Perth Hospital was undertaken from 1995 until 2013. BCVI was identified from the hospital's trauma registry. The medical records of these patients were then reviewed. RESULT: 58 of 7451 (0.78%) major trauma patients were diagnosed of BCVI during the study period. An increased incidence, from 0.52% (20/3880) to 1.06% (38/3571), was seen after the introduction of the Diagnostic Imaging Pathway in 2007 (p=0.010). The majority of the cases were caused by motor vehicle crashes, with 66% (n=38) of the cases sustaining concomitant head or cervical spine injury. Other commonly associated injuries included chest, extremity and thoracic spine injury. CONCLUSION: Our study reports a significant increase in the diagnosis of BCVI among major traumas after the introduction of a Diagnostic Imaging Pathway for the screening of this injury in 2007. The previously low incidence of BCVI compared with other centres' reports indicated possible previous under-screening and diagnosis of this injury. PMID- 28647096 TI - Corrigendum to "What infants know about the unsaid: Phonological categorization in the absence of auditory input" [Cognition 152 (2016) 53-60]. PMID- 28647097 TI - Type A dissections in patients with Marfan syndrome: When less is not more. PMID- 28647098 TI - Endoscopy after esophagectomy: Doctors' dilemma. PMID- 28647099 TI - [Effect size in regression analysis in geriatric research: Comments on Rubio et al.] PMID- 28647100 TI - Assessment of DNA Ploidy in the ProMisE molecular subgroups of endometrial cancer. AB - OBJECTIVE: We sought to determine whether DNA ploidy correlates with the four molecular subgroups of endometrial carcinoma (EC) as determined using ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). METHODS: 90 cases of EC previously characterized by clinicopathological parameters, outcomes, and ProMisE molecular subgroup (POLE EDM, MMR-D, p53 wt or p53 abn) were assessed for DNA ploidy using image cytometry. Associations of ploidy with traditional clinicopathological parameters were also tested. RESULTS: Abnormal DNA ploidy status differed amongst the ProMisE groups (p<0.001) and was found in 80.9% (17/21) of p53 abn, 37.0% (10/27) of p53 wt, 28.6% (4/14) of POLE EDM and 14.3% (4/28) of MMR-D. Abnormal DNA content was significantly associated with lower BMI (p=0.034) and grade 3 tumors (p=0.001). In the entire cohort, abnormal DNA content was significantly associated with worse progression free survival (p=0.0094) but not disease specific survival (p=0.249) or overall survival (p=0.187). When examining ploidy within each of the ProMisE groups, abnormal DNA content correlated with worse overall survival (p=0.041) and progression free survival (p=0.011) in the MMR-D group. No statistically significant relationship was seen in the remaining 3 groups. CONCLUSION: Abnormal DNA ploidy status did correlate with the molecular subgroups of EC; abnormal DNA content was seen in the large majority of p53 abn cases. Abnormal ploidy however was also seen in smaller numbers in the p53 wt, POLE EDM and MMR-D groups; therefore abnormal DNA content was not a specific marker for any one molecular group. The addition of ploidy to the ProMisE molecular categories conferred additional prognostic value within the MMR-D group, which merits further study. PMID- 28647101 TI - The role of hypertriglyceridemia for acute kidney injury in the course of acute pancreatitis and an animal model. AB - OBJECTIVE: The aim of this study was to investigate the role of hypertriglyceridemia for acute kidney injury (AKI) in the course of acute pancreatitis. METHODS: Patients with acute pancreatitis were retrospectively divided into four groups according to admission triglyceride: normal group, mild HTG group, moderate HTG group and severe HTG group. Clinical characteristics were compared among these groups. Wild type (WT) mice and Human ApoC III transgenic (ApoCIIItg) mice were used in the next animal experiments. Severe acute pancreatitis (SAP) model was established by retrograde injection of 0.5% sodium taurocholate (0.1 ml/100 g) from duodenum to pancreatic duct. Histological scores, serum amylase, creatinine, usea nitrogen were compared between WT mice and ApoCIIItg mice. RESULTS: Two hundred and sixty-two patients were classified into 4 groups: normal TG (104, 39.7%), mild HTG (72, 27.5%), moderate HTG (47, 17.9%), and severe HTG (39, 14.9%) groups. The proportions of AKI were 13.5% (14/104, normal), 13.9% (10/72, mild), 21.3% (10/47, moderate), and 38.5% (15/39, severe), respectively. After establishing SAP model, the levels of serum amylase (P < 0.05) and pancreatic histological score (P < 0.05) of ApoCIII-SAP-9h group were significantly higher than that of WT-SAP-9h group, respectively. ApoCIII-SAP 9h group had significantly higher levels of serum creatinine (P < 0.001), usea nitrogen (P < 0.001), and kidney histological score (P < 0.05) than that of WT SAP-9h group, respectively. CONCLUSIONS: Mild HTG has little adverse impact on disease severity of acute pancreatitis; severe HTG can aggravate kidney injury in the course of acute pancreatitis. ApoCIII-SAP mice have more serious pancreatic damage and kidney injury than WT-SAP mice. PMID- 28647102 TI - Boosting Rice Yield by Fine-Tuning SPL Gene Expression. AB - Plant architecture is an important determinant of crop yield. Recent studies showed that SPL family genes regulate the architecture of rice plants. SPLs inhibit tillering in general, but promote panicle branching at optimal expression levels to increase grain number. Fine-tuning the expression of SPL genes may provide useful strategies for crop improvement. PMID- 28647103 TI - Reaffirming 'Ethnobotanical Convergence'. PMID- 28647104 TI - [French haemovigilance from 1994 to nowadays: Evolution and prospects]. AB - Born in France in 1993, haemovigilance aims at monitoring the blood transfusion chain from the donor to the recipient, receiving labile blood products. It differs from the other vigilances due to its organization and its completeness dealing with the collected information. Prior to the European directive, the French agency created a new gravity level: grade 0, aiming at reporting and analyzing the blood transfusion chain dysfunction. Thus, haemovigilance gradually integrates the management of the risks and is given new missions in hospitals and private hospitals. One of its first actions will be to achieve an a-priori analysis, preventing the risks throughout the blood transfusion chain. Such crosscutting missions will be used to manage the coordination of vigilance and in some cases identity monitoring. Haemovigilance may be a key player in identity monitoring because patients' immunology-hematological data base can make it possible to confirm or deny a patient's identity (misused identity or homonyms). Haemovigilance is going to meet other challenges such as the training of health professionals', the implementation of patients' blood management and the periodic revision of the blood transfusions bulletin. A new crosscutting medical profession appears in some countries: blood transfusion practitioner. It combines vigilance, risk management, support for the therapeutic blood transfusions, health professionals training and the evaluation of practices and results. A final mission would be for haemovigilance to be responsible for medicinal products derived from human blood to allow a better monitoring of plasma transfusions. PMID- 28647105 TI - [Sarcoidosis occurring after chemotherapy for breast cancer: Difficulty of drug causality assessment]. PMID- 28647106 TI - [Outpatient consumption of antibiotics with a bacterial resistance risk in 2014 in France]. AB - AIM: This article proposes a description of French regional consumption of antibiotics with a bacterial resistance risk (amoxicillin+clavulanic acid, third generation cephalosporins [C3G] and fluoroquinolones). METHODS: Antibiotics reimbursements data were obtained by Open Medic website. The antibiotic consumption profile has been established using some indicators of the European Surveillance of Antimicrobial Consumption (ESAC) in daily-defined dose per 1000 inhabitants per day (DID) or in percentage. RESULTS: Provence-Alpes-Cote d'Azur Corse (34.4 DID) and Midi-Pyrenees-Languedoc-Roussillon (33.5 DID) consume the most of both, systemic antibiotics and antibiotics with a bacterial resistance risk. Pays-de-la-Loire (26.7 DID), Bretagne (29.1 DID), Centre-Val-de-Loire (29.7 DID) et Auvergne-Rhone-Alpes (29.7 DID) consume the less of both, systemic antibiotics and antibiotics with a bacterial resistance risk. CONCLUSION: Even if some environmental and socioeconomic factors could explain variabilities between regions, a link between consumption intensity and misuse is not excluded. PMID- 28647107 TI - [Justification of off-label antibiotics uses in hospitalized children]. AB - : Unlicensed and off-label (UL/OL) drugs are commonly used in pediatrics wards, especially the antibiotics. It remains unclear if this strategy is justified by randomized controlled trials of good quality? OBJECTIVE: The aim of this study was to compare the level of evidence of UL/OL antibiotics prescription in hospitalized children. The initial hypothesis was that the UL/OL antibiotics prescriptions had a lower level of evidence than licensed antibiotics. METHOD: This observational study assessed the antibiotics prescription in the children mother and women hospital of Lyon. Each antibiotic medicine courses was classified depending on: (i) they were licensed, UL or OL, (ii) their level of evidence for efficiency (sufficient evidence, insufficient evidence, no evidence) and (iii) the existence or not of randomized controlled trials (RCT) or not. The antibiotics medicine courses in atypical cases were excluded (rare disease, lack of diagnosis, comorbidities modifying antibiotic use). Data were collected with computerized patient file data. The data were compared using Fisher exact test and chi2. RESULTS: One hundred and eight medicine courses were identified, corresponding to 72 mono, bi or tri-antibiotic therapies administered to 62 patients; 34% were OL and 66% were licensed. No prescriptions were UL. Thirty-two prescriptions were excluded from the evidence assessment. No proof of efficiency was found for any of the 76 analyzed medicine courses. RCTs were found for 36 of the analyzed medicine courses (47%); licensed medicine courses were significantly more justified by RCTs than UL/OL medicine courses (63% vs. 16%, P<0.001). DISCUSSION: This study has shown the absence of RCTs of good quality to justify the prescriptions of antibiotics in pediatrics, regardless their license status. Nevertheless, the licensed prescriptions have shown more data of efficiency than OL prescriptions. Still, even when data were found, no antibiotics prescriptions reach the threshold of good quality studies. New clinical trials should respond to the patient needs. PMID- 28647108 TI - [Alimemazine-induced restless legs syndrome: About two cases]. PMID- 28647109 TI - [MEOPA use practices in a university hospital: Which conformity?] AB - INTRODUCTION: MEOPA (equimolar mixture of oxygen and nitrous oxide) is used for its analgesic and anxiolytic properties in order to obtain conscious sedation of the patient when performing painful care. It is subject to an enhanced pharmacovigilance and addictovigilance monitoring. In this context, it is important to dispose of hospital utilization data. This work aims to assess the compliance of the use of nitrous oxide regarding the recommendations of the summary of product characteristics, in a French university hospital (Nantes) and consider possible improvements. MATERIALS AND METHODS: Transversal descriptive study, conducted in 2014 with all health professionals using MEOPA. RESULTS: Two thousand thirty-four health professionals answered the questionnaire ; durations of administrations are in conformity and the premises are generally appropriate but almost 60% of professionals have the feeling of inhaling the drug. The systematization of the prescription (always or almost always prescribed for 67% of professionals) and traceability of use (always or almost always in the patient's file for 71% of professionals) are potential source of improvement, particularly since 18% of professional health reported "abuse demands" from patients. CONCLUSION: The formation and information of health professionals are major issues of good use of nitrous oxide. PMID- 28647110 TI - Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation. AB - We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management. PMID- 28647111 TI - Right Ventricular Function: Imaging Techniques. AB - Functional assessment of the right ventricle (RV) is challenging and has been understudied compared with the left ventricle. However, advances in echocardiographic assessment of RV function permit the quantitative assessment of RV performance via numerous modalities. Many RV function indices have now been studied in large samples of healthy dogs, and studies suggest a clinical benefit to echocardiographic RV function assessment in dogs and cats. This article reviews relevant RV anatomy and physiology and highlights numerous indices of RV function assessment for dogs and cats. Imaging techniques, advantages and disadvantages, and clinical impact of these indices are discussed. PMID- 28647112 TI - Arrhythmogenic Right Ventricular Cardiomyopathy in the Boxer Dog: An Update. AB - Arrhythmogenic right ventricular cardiomyopathy is an inheritable form of myocardial disease characterized most commonly by ventricular tachycardias, syncope, and sometimes systolic dysfunction and heart failure. A genetic mutation in the striatin gene has been identified in many affected dogs. Dogs with only one copy of the mutation (heterozygous) have a variable prognosis, with many dogs remaining asymptomatic or being successfully managed on antiarrhythmic drugs for years. Dogs that are homozygous for the mutation seem to have a worse prognosis. PMID- 28647113 TI - Feline Congestive Heart Failure: Current Diagnosis and Management. AB - Congestive heart failure (CHF) is a well-known disorder in feline practice, having been recognized as the most common clinical syndrome in cats with hypertrophic cardiomyopathy, for example. This article identifies the reasons why an accurate diagnosis of CHF is important and the means by which to obtain one; pharmacologic and nonpharmacologic methods for controlling signs of CHF; and recommendations for follow-up evaluations, monitoring, and troubleshooting. PMID- 28647114 TI - Status of Therapeutic Gene Transfer to Treat Cardiovascular Disease in Dogs and Cats. AB - Gene therapy is a procedure resulting in the transfer of a gene into an individual's cells to treat a disease. One goal of gene transfer is to express a functional gene when the endogenous gene is inactive. However, because heart failure is a complex disease characterized by multiple abnormalities at the cellular level, an alternate gene delivery approach is to alter myocardial protein levels to improve function. This article discusses background information on gene delivery, including packaging, administration, and a brief discussion of some of the candidate transgenes likely to alter the progression of naturally occurring heart disease in dogs and cats. PMID- 28647115 TI - When noise is beneficial for sensory encoding: Noise adaptation can improve face processing. AB - The presence of noise usually impairs the processing of a stimulus. Here, we studied the effects of noise on face processing and show, for the first time, that adaptation to noise patterns has beneficial effects on face perception. We used noiseless faces that were either surrounded by random noise or presented on a uniform background as stimuli. In addition, the faces were either preceded by noise adaptors or not. Moreover, we varied the statistics of the noise so that its spectral slope either matched that of the faces or it was steeper or shallower. Results of parallel ERP recordings showed that the background noise reduces the amplitude of the face-evoked N170, indicating less intensive face processing. Adaptation to a noise pattern, however, led to reduced P1 and enhanced N170 amplitudes as well as to a better behavioral performance in two of the three noise conditions. This effect was also augmented by the presence of background noise around the target stimuli. Additionally, the spectral slope of the noise pattern affected the size of the P1, N170 and P2 amplitudes. We reason that the observed effects are due to the selective adaptation of noise-sensitive neurons present in the face-processing cortical areas, which may enhance the signal-to-noise-ratio. PMID- 28647116 TI - Peripheral nerve sheath tumors of the breast. AB - Benign and malignant peripheral nerve sheath tumors can involve the breast, presenting as masses in the dermis, deep breast parenchyma or axillary soft tissue. Although the histologic features are frequently characteristic, diagnosis can be challenging on core needle biopsy, and the differential diagnosis includes a variety of other benign and malignant spindle cell lesions of the breast. Here, we review the key clinical and pathological features of breast schwannoma, neurofibroma, granular cell tumor, and malignant peripheral nerve sheath tumor. PMID- 28647117 TI - Isolation of a potential biocontrol agent Paenibacillus polymyxa NSY50 from vinegar waste compost and its induction of host defense responses against Fusarium wilt of cucumber. AB - Fusarium wilt caused by Fusarium oxysporum f. sp. cucumerinum (FOC) is one of the major destructive soil-borne diseases infecting cucumber. In this study, we screened 60 target strains isolated from vinegar waste compost, from which 10 antagonistic strains were identified to have the disease suppression capacity of bio-control agents. The 16S rDNA gene demonstrated that the biocontrol agents were Paenibacillus polymyxa (P. polymyxa), Bacillus amyloliquefaciens (B. amyloliquefaciens) and Bacillus licheniformis (B. licheniformis). Based on the results of antagonistic activity experiments and pot experiment, an interesting strain of P. polymyxa (named NSY50) was selected for further research. Morphological, physiological and biochemical characteristics indicated that this strain was positive for protease and cellulase and produced indole acetic acid (22.21+/-1.27MUg mL-1) and 1-aminocyclopropane-1-carboxylate deaminase (ACCD). NSY50 can significantly up-regulate the expression level of defense related genes PR1 and PR5 in cucumber roots at the early stages upon challenge with FOC. However, the gene expression levels of a set of defense-related genes, such as the plant nucleotide-binding site (NBS)-leucine-rich repeat (LRR) gene family (e.g., Csa001236, Csa09775, Csa018159), 26kDa phloem protein (Csa001568, Csa003306), glutathione-S-transferase (Csa017734) and phenylalanine ammonia-lyase (Csa002864) were suppressed by pretreatment with NSY50 compared with the single challenge with FOC after nine days of inoculation. Of particular interest was the reduced expression of these genes at disease progression stages, which may be required for F. oxysporum dependent necrotrophic disease development. PMID- 28647118 TI - Screening of wheat endophytes as biological control agents against Fusarium head blight using two different in vitro tests. AB - In order to find biological control agents (BCAs) for the management of Fusarium head blight (FHB), a major disease on wheat crops worldwide, 86 microorganisms isolated from inner tissues of wheat plants were discriminated for their ability to inhibit the growth of Fusarium graminearum and Fusarium culmorum by in vitro dual culture assays. A group of 22 strains appeared very effective to inhibit F. graminearum (inhibition of 30-51%) and they were also globally effective in controlling F. culmorum (inhibition of 15-53%). Further evaluation of a subselection of strains by screening on detached spikelets in vitro confirmed three species, namely Phoma glomerata, Aureobasidium proteae and Sarocladium kiliense, that have not yet been reported for their efficacy against Fusarium spp., indicating that looking for BCAs toward FHB among wheat endophytes proved to be promising. The efficacy of some strains turned out different between both in vitro screening approaches, raising the importance of finding the most appropriate screening approach for the search of BCAs. This study pointed out the interest of the test on detached wheat spikelets that provided information about a potential pathogenicity, the growth capacity and efficacy of the endophyte strains on the targeted plant, before testing them on whole plants. PMID- 28647119 TI - In vitro PGPR properties and osmotic tolerance of different Azospirillum native strains and their effects on growth of maize under drought stress. AB - Osmotic variations in the soil can affect bacterial growth diminishing the number of inoculated bacteria. In a scenario of water deficit having tolerant bacteria would be beneficial to achieve a better response of the plant to stress. Thus, selection of more resistant bacteria could be useful to design new inoculants to be used in arid zones. In this sense, a group of Azospirillum isolates deposited in INTA collection was characterized in order to select strains tolerant to osmotic stress. The results obtained demonstrated that Az19 strain has similar in vitro PGPR characteristics to Az39, the most used strain in Argentina for inoculants industries, with the advantage of a better tolerance to osmotic and salt stress. Inoculation of maize plants with this strain resulted in a better response against water deficit compared to Az39 strain, encouraging us to further study the behavior of this strain in greenhouse and field trials in view of developing new inoculants suitable for areas with water deficit. PMID- 28647120 TI - DrrC protein of Streptomyces peucetius removes daunorubicin from intercalated dnrI promoter. AB - DrrC is a DNA-binding protein of Streptomyces peucetius that provides self resistance against daunorubicin, the antibiotic produced by the organism. DrrC was expressed in E.coli and purified by using N-terminal MBP-tag which retained DNA-binding property in spite of the tag. Mobility shift assay confirmed the interaction of 313bp DNA that has the dnrI promoter, daunorubicin and MBP-DrrC in the presence of ATP. Biotinylated and immobilized 313bp DNA was intercalated with daunorubicin to observe the release of the drug when MBP-DrrC is allowed to act on the DNA. The release of daunorubicin was recorded by absorption and fluorescence spectroscopy. The experiments proved that daunorubicin was released from DNA in the presence of MBP-DrrC. Fluorescence emission of daunorubicin had a maximum peak at 591nm. However, emission spectrum of released daunorubicin showed hypochromism with a maximum peak at 584nm that is possibly because it is in complex with MBP-DrrC. We propose that DrrC naturally binds at intercalated sites to eject daunorubicin; in the process both drug and protein are dislodged from DNA. Like UvrA, DrrC possibly scans the DNA for intercalated daunorubicin. When it encounters daunorubicin, DrrC dislodges it, thereby allowing DNA replication and transcription to go on unhindered. Thus a novel self resistance mechanism by DNA repair is mediated by DrrC. PMID- 28647121 TI - DNA-based stable isotope probing identifies formate-metabolizing methanogenic archaea in paddy soil. AB - Paddy methane (CH4) production is biologically dominated by methanogenic archaea that metabolize a variety of organic and/or inorganic carbon sources. Though formate is easily dissimilated into H2/CO2, formate-metabolizing methanogenic archaea are distinct from CO2-utilizing methanogen taxa. The identity of formate metabolizing methanogenic archaea in paddy soil remains elusive. In this investigation, molecular approaches based on stable isotope probing (SIP) technique were conducted to identify the formate-metabolizing methanogenic archaea in paddy soil. CH4 emission monitor, real-time quantitative PCR (qPCR) and Denaturing Gradient Gel Electrophoresis (DGGE) analyses consistently indicated that some methanogenic archaea metabolized 13C-labeled formate in microcosm and accounted for a large portion of formate-metabolizing archaea in anoxic paddy soil. Phylogenetic identification further found that this guild was affiliated to Methanobacteriaceae. Taken together Methanobacteriaceae could be the dominant formate-metabolizing methanogenic archaea and play an important role in the CH4 production in paddy soil. These findings would extend the extant knowledge on paddy methanogenic archaea and microbial-driven paddy CH4 emission. PMID- 28647122 TI - Effect of succinate on phosphate solubilization in nitrogen fixing bacteria harbouring chick pea and their effect on plant growth. AB - Diverse nitrogen fixing bacteria harbouring chick pea rhizosphere and root nodules were tested for multiple plant growth promoting traits like tricalcium phosphate (TCP) and rock phosphate (RP) solubilization, production of ammonia, indole 3-acetic acid, chitinase, phytase and alkaline phosphatase. Isolates belonged to diverse genus like Enterobacter, Acinetobacter, Erwinia, Pseudomonas, Rhizobium, Sinorhizobium, Ensifer, Klebsiella, etc. Most isolates solubilized TCP and RP along with the lowering of media pH, indicating acidification to be the chief mechanism behind this solubilization. However, lowering of media pH and P release decreased by 32-100% when media was supplemented with succinate, a major component of plant root exudates indicating succinate mediated repression of P solubilization. Maximum TCP and RP solubilization with P release of 850MUg/mL and 2088MUg/mL was obtained with lowering of media pH up to 2.8 and 3.3 for isolate E43 and PSB1 respectively. This pH drop changed to 4.4 and 4.8 with 80% and 87% decrease in P solubilization in the presence of succinate. Maximum 246MUg/mL indole 3-acetic acid production in Lh3, 44.8U/mL chitinase activity in MB3, 11.3U/mL phytase activity in I91 and 9.4U/mL alkaline phosphatase activity in SM1 were also obtained. Most isolates showed multiple PGP traits which resulted in significant plant growth promotion of chick pea plants. Present study shows repression of P solubilization by succinate for various bacterial groups which might be one of the reasons why phosphate solubilizing bacteria which perform well in vitro often fail in vivo. Studying this repression mechanism might be critical in understanding the in vivo efficacy. PMID- 28647123 TI - Zinc solubilizing Bacillus spp. potential candidates for biofortification in maize. AB - Bioaugmentation of Zn solubilizing rhizobacteria could be a sustainable intervention to increase bioavailability of Zn in soil which can be helpful in mitigation of yield loss and malnutrition of zinc. In present study, a number of pure rhizobacterial colonies were isolated from maize rhizosphere and screened for their ability to solubilize zinc oxide. These isolates were screened on the basis of zinc and phosphate solubilization, IAA production, protease production, catalase activity and starch hydrolysis. All the selected isolates were also positive for oxidase activity (except ZM22), HCN production (except ZM27) and utilization of citrate. More than 70% of isolates produces ammonia, hydrogen cyanide, siderophores, exopolysaccharides and cellulase. More than half of isolates also showed potential for urease activity and production of lipase. The ZM31 and S10 were the only isolates which showed the chitinase activity. All these isolates were evaluated in a jar trial for their ability to promote growth of maize under axenic conditions. Results revealed that inoculation of selected zinc solubilizing rhizobacterial isolates improved the growth of maize. In comparison, isolates ZM20, ZM31, ZM63 and S10 were best compared to other tested isolates in stimulating the growth attributes of maize like shoot length, root length, plant fresh and dry biomass. These strains were identified as Bacillus sp. (ZM20), Bacillus aryabhattai (ZM31 and S10) and Bacillus subtilis (ZM63) through 16S rRNA sequencing. This study indicated that inoculation of Zn solubilizing strains have potential to promote growth and can be the potential bio-inoculants for biofortification of maize to overcome the problems of malnutrition. PMID- 28647124 TI - Putative protein VC0395_0300 from Vibrio cholerae is a diguanylate cyclase with a role in biofilm formation. AB - The hallmark of the lifecycle of Vibrio cholerae is its ability to switch between two lifestyles - the sessile, non-pathogenic form and the motile, infectious form in human hosts. One of these changes is in the formation of surface biofilms, when in sessile aquatic habitats. The cell-cell interactions within a V. cholerae biofilm are stabilized by the production of an exopolysachharide (EPS) matrix, which in turn is regulated by the ubiquitous secondary messenger, cyclic di-GMP (c-di-GMP), synthesized by proteins containing GGD(/E)EF domains in all prokaryotic systems. Here, we report the functional role of the VC0395_0300 protein (Sebox3) encoded by the chromosome I of V. cholerae, with a GGEEF signature sequence, in the formation of surface biofilms. In our study, we have shown that Escherichia coli containing the full-length Sebox3 displays enhanced biofilm forming ability with cellulose production as quantified and visualized by multiple assays, most notably using FEG-SEM. This has also been corroborated with the lack of motility of host containing Sebox3 in semi-solid media. Searching for the reasons for this biofilm formation, we have demonstrated in vitro that Sebox3 can synthesize c-di-GMP from GTP. The homology derived model of Sebox3 displayed significant conservation of the GGD(/E)EF architecture as well. Hence, we propose that the putative protein VC0395_0300 from V. cholerae is a diguanylate cyclase which has an active role in biofilm formation. PMID- 28647125 TI - Isogenic mutations in the Moraxella catarrhalis CydDC system display pleiotropic phenotypes and reveal the role of a palindrome sequence in its transcriptional regulation. AB - Moraxella catarrhalis is becoming an important human respiratory tract pathogen affecting significant proportions from the population. However, still little is known about its physiology and molecular regulation. To this end, the CydDC, which is a heterodimeric ATP binding cassette transporter that has been shown to contribute to the maintenance of the redox homeostasis across the periplasm in other Gram-negative bacteria, is studied here. Amino acids multiple sequence alignments indicated that M. catarrhalis CydC is different from the CydC proteins of the bacterial species in which this system has been previously studied. These findings prompted further interest in studying this system in M. catarrhalis. Isogenic mutant in the CydDC system showed suppression in growth rate, hypersensitivity to oxidative and reductive stress and increased accumulation of intracellular cysteine levels. In addition, the growth of cydC- mutant exhibited hypersensitivity to exogenous cysteine; however, it did not display a significant difference from its wild-type counterpart in the murine pulmonary clearance model. Moreover, a palindrome was detected 94bp upstream of the cydD ORF suggesting it might act as a potential regulatory element. Real-time reverse transcription-PCR analysis showed that deletion/change in the palindrome resulted into alterations in the transcription levels of cydC. A better understanding of such system and its regulation helps in developing better ways to combat M. catarrhalis infections. PMID- 28647126 TI - MERS-CoV infection: Mind the public knowledge gap. AB - In August 2015, the Corona outbreak caused by Middle East respiratory syndrome coronavirus (MERS-CoV) was the 9th episode since June 2012 in Saudi Arabia. Little is known about the public awareness toward the nature or prevention of the disease. The aim of this work was to assess the knowledge of the adult population in Riyadh toward the MERS-CoV. In this cross-sectional survey, a self administrated questionnaire was distributed to randomly selected participants visiting malls in Riyadh. The questionnaire contained measurable epidemiological and clinical MERS-CoV knowledge level variables and relevant source of information. The study included 676 participants. Mean age was 32.5 (+/-SD 8.6) years and 353 (47.8%) were males. Almost all participants heard about the corona disease and causative agent. The study showed a fair overall knowledge (66.0%), less knowledge on epidemiological features of the disease (58.3%), and good knowledge (90.7%) on the clinical manifestation of the MERS-CoV. Internet was the major (89.0%) source of disease information, and other sources including health care providers, SMS, television, magazines and books were low rated (all <25%). In a multivariate logistic regression analysis age <=30 years (Odds Ratio (OR)=1.647, 95%CI 1.048-2.584, P=0.030), male gender (OR=1.536, 95%CI 1.105 2.134, P=0.01), and no tertiary education (OR=1.957, 95%CI 1.264-3.030, P=0.003) were independent significant predictors of poor epidemiological knowledge. This study concludes that there was inadequate epidemiological knowledge received by the public and the reliance mostly on the clinical manifestations to recognizing the MERS-CoV disease. Comprehensive public health education programs is important to increase awareness of simple epidemiological determinants of the disease is warranted. PMID- 28647127 TI - Infrared light detection by the haller's organ of adult american dog ticks, Dermacentor variabilis (Ixodida: Ixodidae). AB - The Haller's organ (HO), unique to ticks and mites, is found only on the first tarsus of the front pair of legs. The organ has an unusual morphology consisting of an anterior pit (AP) with protruding sensilla and a posterior capsule (Cp). The current thinking is that the HO's main function is chemosensation analogous to the insect antennae, but the functionality of its atypical structure (exclusive to the Acari) is unexplained. We provide the first evidence that the HO allows the American dog tick, Dermacentor variabilis, to respond to infrared (IR) light. Unfed D. variabilis adults with their HOs present were positively phototactic to IR. However, when the HOs were removed, no IR response was detected. Ticks in these experiments were also attracted to white light with and without the HOs, but were only positively phototactic to white light when the ocelli (primitive eyes) were unobstructed. Covering the eyes did not prevent IR attraction. A putative TRPA1 receptor was characterized from a D. variabilis specific HO transcriptome we constructed. This receptor was homologous to transient receptor potential cation channel, subfamily A, member 1 (TRPA1) from the pit organ of the pit viper, python, and boa families of snakes, the only receptor identified so far for IR detection. HO scanning electron microscopy (SEM) studies in the American dog tick showed the AP and Cp but also novel structures not previously described; the potential role of these structures in IR detection is discussed. The ability of ticks to use IR for host finding is consistent with their obligatory hematophagy and has practical applications in tick trapping and the development of new repellents. PMID- 28647128 TI - Seasonal dynamics of adult Dermacentor reticulatus in a peri-urban park in southern Europe. AB - Studies on the human-biting pathogen vectors Dermacentor reticulatus and Ixodes ricinus have been scarce in southern Europe. The aims of the present study were to determine the abundance of these ticks in a peri-urban park in northern Italy, describe the seasonal activity of D. reticulatus and examine the correlation between tick occurrence and environmental factors. Ticks were collected monthly from April 2015 to May 2016 using both dragging and flagging techniques. Various climatic variables (mean temperature, relative humidity and evapotranspiration for the collection dates; and 30-day moving averages preceding each collection date were calculated for rainfall, temperature, relative humidity and saturation deficit) also were recorded. Overall, 444 adults of D. reticulatus and 10 adults of I. ricinus were collected. Males of D. reticulatus appeared earlier in the year than females, but overall females were collected more frequently than males (1:1.25). Statistical analysis showed significant differences in the density of D. reticulatus among sampling transects and among months. The seasonal dynamic of D. reticulatus was characterized by a single peak of activity in the early spring. Tick density was associated with climatic variables: the 30-day moving average saturation deficit was particularly significant as most ticks (83%) were collected at values below 5.2mmHg. At the level of individual sampling transects, seasonal dynamics could be influenced by habitat type and host availability. We found D. reticulatus to be most abundant in mixed forests dominated by oaks and rich in ponds. As to I. ricinus, though found in a small number, its presence can be confirmed by our investigation. In light of the results of this study, the risk for encounters with D. reticulatus and I. ricinus may be higher than previously thought in northern Italy. PMID- 28647129 TI - Decisions after irreversible cardiopulmonary arrest: ends and opportunities. PMID- 28647130 TI - Fever-Induced Paroxysmal Weakness and Encephalopathy, a New Phenotype of ATP1A3 Mutation. AB - BACKGROUND: We identified a group of patients with ATP1A3 mutations at residue 756 who display a new phenotype, distinct from alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndromes. METHODS: Four patients with c.2267G>A (R756H) mutations from two families and two patients with c.2267G>T (R756L) mutations from one family are described and compared with the previously reported patients with mutations resulting in R756H and R756C protein variants. RESULTS: Patients with ATP1A3 R756H have onset in childhood of infrequent, fever-triggered paroxysms of encephalopathy and weakness with slowly improving but persistent deficits. Motor findings of weakness are mostly generalized, and patients may also have bulbar or oculomotor problems. Longer term outcomes range from mild motor apraxia with near-normal function to persistent dysphagia, dysarthria, cognitive deficit, motor apraxia, and inability to walk because of ataxia. Patients with ATP1A3 R756L have a similar phenotype that includes paroxysmal, stepwise progression of ataxia associated with infections. CONCLUSIONS: ATP1A3 mutations affecting residue 756 result in a clinical syndrome, separate from those associated with previously described ATP1A3 mutations, which consists chiefly of fever-induced paroxysmal weakness and encephalopathy (FIPWE). Patients with R756L and R756C protein variants display more prominent ataxia, overlapping with the relapsing encephalopathy with cerebellar ataxia syndrome previously described in a patient with the c.2266C>T (R756C) mutation. All patients reported with mutations at residue 756 to date have had a similar episodic course and clinical features. Patients with mutations of ATP1A3 residue 756 appear to have a distinct clinical phenotype compared with patients with other ATP1A3 mutations, with fever-induced encephalopathy as key differentiating feature. PMID- 28647131 TI - Congenital Mydriasis With Aortic and Cerebrovascular Disease. PMID- 28647132 TI - Mutations in S-adenosylhomocysteine hydrolase (AHCY) affect its nucleocytoplasmic distribution and capability to interact with S-adenosylhomocysteine hydrolase like 1 protein. AB - S-adenosylhomocysteine hydrolase (AHCY) is thought to be located at the sites of ongoing AdoMet-dependent methylation, presumably in the cell nucleus. Endogenous AHCY is located both in cytoplasm and the nucleus. Little is known regarding mechanisms that drive its subcellular distribution, and even less is known on how mutations causing AHCY deficiency affect its intracellular dynamics. Using fluorescence microscopy and GFP-tagged AHCY constructs we show significant differences in the intensity ratio between nuclei and cytoplasm for mutant proteins when compared with wild type AHCY. Interestingly, nuclear export of AHCY is not affected by leptomycin B. Systematic deletions showed that AHCY has two regions, located at both sides of the protein, that contribute to its nuclear localization, implying the interaction with various proteins. In order to evaluate protein interactions in vivo we engaged in bimolecular fluorescence complementation (BiFC) based studies. We investigated previously assumed interaction with AHCY-like-1 protein (AHCYL1), a paralog of AHCY. Indeed, significant interaction between both proteins exists. Additionally, silencing AHCYL1 leads to moderate inhibition of nuclear export of endogenous AHCY. PMID- 28647133 TI - [Men who have sex with men and human immunodeficiency virus testing in dental practice]. AB - OBJECTIVE: To explore the attitudes of men who have sex with men (MSM) towards the implementation of rapid HIV-1/2 testing in the dental practice, and to evaluate MSM's perceptions of stigma and discrimination related to sexual orientation by dental care professionals. METHODS: Cross-sectional study using a self-administered, anonymous, structured analytical questionnaire answered by 185 MSM in Mexico. The survey included sociodemographic variables, MSM's perceptions towards public and private dental providers, and dental services, as well as their perception towards rapid HIV-1/2 testing in the dental practice. In addition, the perception of stigma and discrimination associated with their sexual orientation was explored by designing a psychometric Likert-type scale. The statistical analysis included factor analysis and non-hierarchical cluster analysis. RESULTS: 86.5% of the respondents expressed their willingness to take a rapid HIV-1/2 screening test during their dental visit. Nevertheless, 91.9% of them considered it important that dental professionals must be well-trained before administering any rapid HIV-1/2 tests. Factor analysis revealed two factors: experiences of sexual orientation stigma and discrimination in dental settings, and feelings of concern about the attitude of the dentist and dental staff towards their sexual orientation. Based on these factors and cluster analysis, three user profiles were identified: users who have not experienced stigma and discrimination (90.3%); users who have not experienced stigma and discrimination, but feel a slight concern (8.1%), and users who have experienced some form of discrimination and feel concern (1.6%). CONCLUSION: The dental practice may represent a potential location for rapid HIV-1/2 testing contributing to early HIV infection diagnosis. PMID- 28647134 TI - Autoimmune necrotising myopathy: A case report. PMID- 28647135 TI - Ultrasound-dependent cytoplasmic internalization of a peptide-sonosensitizer conjugate. AB - A method to induce cytoplasmic peptide delivery, using ultrasound, was demonstrated using a molecular conjugate of a cell-penetrating peptide (CPP), a functional peptide, and a sonosensitizer. As a model of such molecular conjugates, TatBim-RB, consisting of the Tat CPP, the Bim apoptosis inducing peptide, and the sonosensitizer rose bengal was synthesized. CPPs have been widely used for intracellular delivery of various cargos; however, CPP-fused molecules tend to become entrapped in endosomes, as was observed for TatBim-RB molecules applied to cells. To promote escape of the entrapped TatBim-RB molecules, cells were irradiated with ultrasound, which successfully induced endosomal escape and cytoplasmic dispersion of TatBim-RB, and subsequently apoptosis. Our results suggest that this peptide-sonosensitizer conjugate strategy may facilitate numerous kinds of medicinal chemistry studies, and furthermore, this specific conjugate may exhibit potential as a novel therapeutic agent for the promotion of apoptosis. PMID- 28647136 TI - Polypectomy for complete endoscopic resection of small colorectal polyps. AB - BACKGROUND AND AIMS: Small colorectal polyps are encountered frequently and may be incompletely removed during colonoscopy. The optimal technique for removal of small colorectal polyps is uncertain. The aim of this study was to compare the incomplete resection rate (IRR) by using EMR or cold snare polypectomy (CSP) for the removal of small adenomatous polyps. METHODS: This was a prospective randomized controlled study from a tertiary-care referral center. A total of 358 patients who satisfied the inclusion criteria (polyp sized 6-9 mm) were randomized to the EMR (n =179) and CSP (n =179) groups, and their polyps were treated with conventional EMR or CSP, respectively. After polypectomy, an additional 5 forceps biopsies were performed at the base and margins of polypectomy sites to assess the presence of residual polyp tissue. The EMR and CSP samples were compared to assess the IRR. RESULTS: Among a total of 525 polyps, 415 (79.0%) were adenomatous polyps, and 41 (16.4%) were advanced adenomas. The overall IRR for adenomatous polyps was significantly higher in the CSP group compared with the EMR group (18/212, 8.5% vs 3/203, 1.5%; P = .001). Logistic regression analysis revealed that the CSP procedure was a stronger risk factor for the IRR (odds ratio [OR] 6.924; 95% confidence interval [CI], 2.098 24.393; P = .003). In addition, piecemeal resection was the most important risk factor for the IRR (OR 28.696; 95% CI, 3.620-227.497; P = .001). The mean procedure time for polypectomy was not significantly different between the EMR and CSP groups (5.5 +/- 2.7 vs 4.7 +/- 3.4 minutes; P = .410). None of these patients presented with delayed bleeding. There were no severe adverse events related to the biopsies. CONCLUSIONS: EMR was significantly superior to CSP for achieving complete endoscopic resection of small colorectal polyps. Patients with piecemeal resection of polyps had a higher risk for incomplete resection. (Clinical trial registration number: Hongwei-1102-12.). PMID- 28647137 TI - Apneic oxygenation reduces the incidence of hypoxemia during emergency intubation: A systematic review and meta-analysis. AB - STUDY OBJECTIVE: Apneic oxygenation has been advocated for the prevention of hypoxemia during emergency endotracheal intubation. Because of conflicting results from recent trials, the efficacy of apneic oxygenation remains unclear. We performed a systematic review and meta-analysis to investigate the effect of apneic oxygenation on the incidence of clinically significant hypoxemia during emergency endotracheal intubation. METHODS: MEDLINE, EMBASE, and PubMed databases were searched without language and time restrictions for studies of apneic oxygenation performed in a critical care setting. Meta-analysis was conducted with a random-effect model, and according to intention-to-treat allocation wherever applicable. Subgroup analyses were performed to ensure the robustness of findings across various clinical outcomes. RESULTS: Eight studies (n=1953) were included in the meta-analysis. The pooled absolute risk of clinically significant hypoxemia was 27.6% in the usual care group and 19.1% in the apneic oxygenation group, without any heterogeneity across studies (I2=0%; p=0.42). Apneic oxygenation reduced the relative risk of hypoxemia by 30% (95% confidence interval 0.59 to 0.82). There was a trend toward lower mortality in the apneic oxygenation group (relative risk of death 0.77; 95% confidence interval 0.59 to 1.02). CONCLUSION: Apneic oxygenation significantly reduces the incidence of hypoxemia during emergency endotracheal intubation. These findings support the inclusion of apneic oxygenation in everyday clinical practice. PMID- 28647138 TI - Think like a sponge: The genetic signal of sensory cells in sponges. AB - A complex genetic repertoire underlies the apparently simple body plan of sponges. Among the genes present in poriferans are those fundamental to the sensory and nervous systems of other animals. Sponges are dynamic and sensitive animals and it is intuitive to link these genes to behaviour. The proposal that ctenophores are the earliest diverging metazoan has led to the question of whether sponges possess a 'pre-nervous' system or have undergone nervous system loss. Both lines of thought generally assume that the last common ancestor of sponges and eumetazoans possessed the genetic modules that underlie sensory abilities. By corollary extant sponges may possess a sensory cell homologous to one present in the last common ancestor, a hypothesis that has been studied by gene expression. We have performed a meta-analysis of all gene expression studies published to date to explore whether gene expression is indicative of a feature's sensory function. In sponges we find that eumetazoan sensory-neural markers are not particularly expressed in structures with known sensory functions. Instead it is common for these genes to be expressed in cells with no known or uncharacterized sensory function. Indeed, many sensory-neural markers so far studied are expressed during development, perhaps because many are transcription factors. This suggests that the genetic signal of a sponge sensory cell is dissimilar enough to be unrecognizable when compared to a bilaterian sensory or neural cell. It is possible that sensory-neural markers have as yet unknown functions in sponge cells, such as assembling an immunological synapse in the larval globular cell. Furthermore, the expression of sensory-neural markers in non-sensory cells, such as adult and larval epithelial cells, suggest that these cells may have uncharacterized sensory functions. While this does not rule out the co-option of ancestral sensory modules in later evolving groups, a distinct genetic foundation may underlie the sponge sensory system. PMID- 28647139 TI - Impact of Raised Serum Cobalt Levels From Recalled Articular Surface Replacement Hip Prostheses on the Visual Pathway. AB - BACKGROUND: The articular surface replacement (ASR) was recalled in 2010 because of higher than expected revision rates. Patients reported symptoms of neurologic dysfunction including poor vision. This cohort study, using objective measurements, aimed to establish whether a higher incidence of visual function defects exists in ASR patients. METHODS: Thirty-three ASR patients and 33 non-ASR controls (control 1) were recruited. Data were compared with normative population data from the visual electrophysiology database (control 2). Patients underwent investigations for serum cobalt levels, psychophysical visual tests, and extensive electrophysiological visual testing. RESULTS: After excluding 2 subjects with pre-existing eye disease, data from 33 ASR patients were compared with the 2 control cohorts. The median serum cobalt level in the ASR group (median, 52 nmol/L [interquartile range, 14-151 nmol/L]) was significantly higher than that in the control 1 cohort (median, 7 nmol/L [interquartile range, 5-14 nmol/L]; P < .0001). The photoreceptor function of patients with an ASR of the hip showed significantly larger electroretinography mixed rod-cone b-wave amplitudes than both control 1 and control 2 cohorts (P = .0294 and .0410, respectively). Abnormalities in macular function as reflected by multifocal and scotopic electroretinography were more prevalent in control 1 (P = .0445 and .0275, respectively). Optic nerve pathway measurements using visual-evoked potential latency was significantly longer in the ASR group compared with those in the control 2 cohort (P = .0201). There were no statistical differences in visual acuity. CONCLUSION: A statistically significant disturbance in visual electrophysiology was found in the ASR group when compared with the control groups. These differences did not translate to identifiable clinical visual deficits. Orthopedic surgeons need to be aware of the possibility of visual dysfunction in patients with ASR and other metal-on-metal hip arthroplasties; however, routine visual testing is not recommended. PMID- 28647140 TI - Improve artificial neural network for medical analysis, diagnosis and prediction. PMID- 28647141 TI - Sepsis in Haiti: Prevalence, treatment, and outcomes in a Port-au-Prince referral hospital: Methodological issues. PMID- 28647142 TI - Better methodology and research index are needed. PMID- 28647143 TI - A tertiary center experience with velopharyngeal surgical techniques for treatment of snoring and obstructive sleep apnea. AB - OBJECTIVES: The aim of this study was to assess the outcomes of patients who treated with the relatively new surgical procedures; anterior palatoplasty (AP), Cahali lateral pharyngoplasty (CLP), and expansion sphincter pharyngoplasty (ESP) for habitual snoring or obstructive sleep apnea (OSA). METHODS: Prospective series of 93 patients were evaluated. The performed surgical techniques, polysomnographic outcomes, pre- and postoperative clinical parameters, and complication rates were assessed. RESULTS: There were 14 snorers and 79 OSA patients. The mean age was 40.7 years, mean BMI was 27.67kg/m2, and the mean follow-up time was 5.90 months. There were 30 subjects in AP, 30 subjects in CLP, and 33 subjects in ESP groups. Apnea hypopnea index (AHI) improved from 16.90 to 14.27 (p=0.135) in AP, from 17.69 to 12.05 in CLP (p=0.004), and from 26.83 to 9.08 in ESP groups (p<0.001). When surgical success criteria is defined as more than 50% reduction in AHI to final AHI <15events/h, success rates were 45%, 64%, and 74% in AP, CLP, and ESP groups, respectively. Epworth Sleepiness Scale and visual analog scale for snoring significantly decreased after all procedures (p<0.05). The minimum oxygen saturation significantly increased after all procedures, however, only ESP caused statistically significant improvements in oxygen desaturation index, mean SaO2 and the percentage of sleep time with SaO2 below 90%. During the follow-up period, 61 of 93 patients (65.6%) indicated one or more complaints, but none of them was persistent. CONCLUSION: We suggest that these relatively new velopharyngeal surgical techniques are effective in the management of snoring and OSA without causing persistent side-effects, and ESP is one step ahead of the other two techniques. PMID- 28647144 TI - Simultaneous determination of UV-filters and estrogens in aquatic invertebrates by modified quick, easy, cheap, effective, rugged, and safe extraction and liquid chromatography tandem mass spectrometry. AB - Ultraviolet-filters (UV-filters) and estrogens have attracted increased attention as contaminants of emerging concern (CECs) due to their widespread occurrence in the environment. Most of these CECs are hydrophobic and have the potential to accumulate in aquatic organisms. To date, co-analysis of UV-filters and estrogens has not been reported due, in part, to the complex environmental matrices. Here, a multi-residue method has been developed for simultaneous determination of five UV-filters and three estrogens in tissue from aquatic and marine organisms. The procedure involved a modified Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction with a novel reverse-solid-phase extraction (reverse-SPE) cleanup in place of dispersive-SPE, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. The tissue mass, acetonitrile content, and salt conditions for QuEChERS extraction, along with the reverse-SPE cartridge material and elution conditions, were thoroughly investigated and optimized. Five UV filters (i.e., 3-(4-methylbenzylidene) camphor, benzophenone-3, ethylhexylmethoxycinnamate, homosalate, and octocrylene) and three estrogens (i.e., estrone, 17beta-estradiol, and 17alpha-ethinylestradiol) were simultaneously analyzed by taking advantage of wrong-way-round ionization in LC MS/MS. The optimized analytical protocol exhibited good recoveries (>80%) for target compounds and enabled their detection at concentrations as low as 0.2ng/g in 50mg tissue samples. The method was applied to determine concentrations of target analytes in four invertebrates (i.e., Orconectes virilis, Procambarus clarkii, Crassostrea virginica, and Ischadium recurvum). All eight target analytes were detected at least once in the tissue samples, with the highest concentration being 399ng/g of homosalate in O. virilis. These results highlight the ubiquitous bioaccumulation of CECs in aquatic and marine invertebrates. PMID- 28647145 TI - Total peak shape analysis: detection and quantitation of concurrent fronting, tailing, and their effect on asymmetry measurements. AB - Most peak shapes obtained in separation science depart from linearity for various reasons such as thermodynamic, kinetic, or flow based effects. An indication of the nature of asymmetry often helps in problem solving e.g. in column overloading, slurry packing, buffer mismatch, and extra-column band broadening. However, existing tests for symmetry/asymmetry only indicate the skewness in excess (tail or front) and not the presence of both. Two simple graphical approaches are presented to analyze peak shapes typically observed in gas, liquid, and supercritical fluid chromatography as well as capillary electrophoresis. The derivative test relies on the symmetry of the inflection points and the maximum and minimum values of the derivative. The Gaussian test is a constrained curve fitting approach and determines the residuals. The residual pattern graphically allows the user to assess the problematic regions in a given peak, e.g., concurrent tailing or fronting, something which cannot be easily done with other current methods. The template provided in MS Excel automates this process. The total peak shape analysis extracts the peak parameters from the upper sections (>80% height) of the peak rather than the half height as is done conventionally. A number of situations are presented and the utility of this approach in solving practical problems is demonstrated. PMID- 28647146 TI - Analysis of oxidised heavy paraffininc products by high temperature comprehensive two-dimensional gas chromatography. AB - Heavy petroleum fractions are produced during crude and synthetic crude oil refining processes and they need to be upgraded to useable products to increase their market value. Usually these fractions are upgraded to fuel products by hydrocracking, hydroisomerization and hydrogenation processes. These fractions are also upgraded to other high value commercial products like lubricant oils and waxes by distillation, hydrogenation, and oxidation and/or blending. Oxidation of hydrogenated heavy paraffinic fractions produces high value products that contain a variety of oxygenates and the characterization of these heavy oxygenates is very important for the control of oxidation processes. Traditionally titrimetric procedures are used to monitor oxygenate formation, however, these titrimetric procedures are tedious and lack selectivity toward specific oxygenate classes in complex matrices. Comprehensive two-dimensional gas chromatography (GC*GC) is a way of increasing peak capacity for the comprehensive analysis of complex samples. Other groups have used HT-GC*GC to extend the carbon number range attainable by GC*GC and have optimised HT-GC*GC parameters for the separation of aromatics, nitrogen-containing compounds as well as sulphur-containing compounds in heavy petroleum fractions. HT-GC*GC column combinations for the separation of oxygenates in oxidised heavy paraffinic fractions are optimised in this study. The advantages of the HT-GC*GC method in the monitoring of the oxidation reactions of heavy paraffinic fraction samples are illustrated. PMID- 28647147 TI - Capillary electrophoresis with stationary nanogel zones of galactosidase and Erythrina cristagalli lectin for the determination of beta(1-3)-linked galactose in glycans. AB - A thermally responsive nanogel is used to create stationary zones of enzyme and lectin in a separation capillary. Once patterned in the capillary, analyte is driven through the zone, where it is converted to a specific product if an enzyme is used or captured if a lectin is used. These stationary zones are easily expelled after the analysis and then re-patterned in the capillary. The nanogel is compatible with enzymes and lectins and improves the stability of galactosidase, enabling more cost-effective use of biological reagents that provide insight into glycan structure. A feature of using stationary zones is that the reaction time can be controlled by the length of the zone, the applied field controlling the analyte mobility, or the use of electrophoretic mixing by switching the polarity of the applied voltage while the analyte is located in the zone. The temperature, applied voltage, and length of the stationary zone, which are factors that enhance the performance of the enzyme, are characterized. The combined use of enzymes and lectins in capillary electrophoresis is a new strategy to advance rapid and automated analyses of glycans using nanoliter volumes of enzymes and lectins. The applicability of this use of stationary zones of enzyme and lectin in capillary electrophoresis is demonstrated with the identification of beta(1-3)-linked galactose in N-glycan. PMID- 28647148 TI - Monolithic capillary column with an integrated electrochemical detector. AB - The carbon fiber and silver microwire were used as working and pseudoreference electrode, respectively, and inserted into the ending of capillary to prepare monolithic capillary column with an integrated electrochemical detector. Prepared capillary devices offered stable and robust results with relative standard deviations of retention, resolution, and detection signal lower than 1.5, 5.5, and 5.0%, respectively. To further increase sensitivity of developed electrochemical microdetector, multiple pulse amperometry detection mode has been used. Optimized integrated device provided reliable chromatographic separation of mixture of neurotransmitters with calibration curve for dopamine linear from 0.5 to 20.0mgL-1 and an instrumental limit of detection as low as 24pg of injected dopamine. Finally, developed capillary column was applied to successful determination of dopamine in a human urine. By using both calibration curve and standard addition method, the dopamine level was determined to be 0.74+/-0.03mgL 1 and 0.71+/-0.02mgL-1, respectively. Triplicates of dopamine analysis provided relative standard deviations lower than 2.7% for intraday analyses, while interday relative standard deviations were lower than 3.6% for five consecutive days. PMID- 28647149 TI - Argentation gas chromatography revisited: Separation of light olefin/paraffin mixtures using silver-based ionic liquid stationary phases. AB - Silver ion or argentation chromatography utilizes stationary phases containing silver ions for the separation of unsaturated compounds. In this study, a mixed ligand silver-based ionic liquid (IL) was evaluated for the first time as a gas chromatographic (GC) stationary phase for the separation of light olefin/paraffin mixtures. The selectivity of the stationary phase toward olefins can be tuned by adjusting the ratio of silver ion and the mixed ligands. The maximum allowable operating temperature of these stationary phases was determined to be between 125 degrees C and 150 degrees C. Nuclear magnetic resonance (NMR) spectroscopy was used to characterize the coordination behavior of the silver-based IL as well as provide an understanding into the retention mechanism of light olefins. PMID- 28647150 TI - OSPAR standard method and software for statistical analysis of beach litter data. AB - The aim of this study is to develop standard statistical methods and software for the analysis of beach litter data. The optimal ensemble of statistical methods comprises the Mann-Kendall trend test, the Theil-Sen slope estimation, the Wilcoxon step trend test and basic descriptive statistics. The application of Litter Analyst, a tailor-made software for analysing the results of beach litter surveys, to OSPAR beach litter data from seven beaches bordering on the south eastern North Sea, revealed 23 significant trends in the abundances of beach litter types for the period 2009-2014. Litter Analyst revealed a large variation in the abundance of litter types between beaches. To reduce the effects of spatial variation, trend analysis of beach litter data can most effectively be performed at the beach or national level. Spatial aggregation of beach litter data within a region is possible, but resulted in a considerable reduction in the number of significant trends. PMID- 28647151 TI - Effect of low concentrations of Irgarol 1051 on RGB (R, red; G, green; B, blue) colour values of the hard-coral Acropora tenuis. AB - Colour change in Acropora tenuis, a representative species of Indo-Pacific hard coral, in response to low concentrations of Irgarol 1051 was examined in the laboratory. Branches of A. tenuis were exposed to 0, 1, and 10MUgIrgarol1051/L for 14days, and photographed daily using digital camera. These Irgarol 1051 concentrations were similar to those recorded at a number of sea ports. Red, green and blue (RGB) coral colour values were quantified from the photographs, with black represented by R=G=B=0 and white as R=G=B=255. Exposure to Irgarol 1051 caused RGB values to increase, moving towards the 'white' end of the spectrum as Irgarol 1051 concentration increased. These results suggest that the ambient levels of Irgarol 1051 recorded from port environments could be implicated in coral bleaching, if concentrations over nearby reef ecosystems are similar. PMID- 28647152 TI - A first report of rare earth elements in northwestern Mediterranean seaweeds. AB - : The concentrations of rare earth elements (REE) were determined by ICP-MS in dominant seaweed species, collected from three locations of the northwestern Mediterranean Sea. This is the first study to define levels and patterns of REE in macro algae from these coastal areas. Rare elements are becoming emerging inorganic contaminants in marine ecosystems, due to their worldwide increasing applications in industry, technology, medicine and agriculture. Significant inter site and interspecies differences were registered, with higher levels of REE in brown and green macro algae than in red seaweeds. Levels of light REE were also observed to be greater compared to heavy REE in all samples. One of the investigated locations (Bergeggi, SV) had higher REE and SigmaREE concentrations, probably due to its proximity to an important commercial and touristic harbor, while the other two sites were less affected by anthropogenic contaminations, and showed comparable REE patterns and lower concentrations. CAPSULE: Rare earth elements in seaweeds. PMID- 28647153 TI - Organic matter properties of Fennoscandian ecosystems: Potential oxidation of northern environments under future change? AB - The oxidative ratio (OR) of an ecosystem, which reflects the ratio of O2:CO2 associated with ecosystem gas exchanges, is an important parameter in understanding the sink of CO2 represented by the terrestrial biosphere. There is a growing body of ecosystem-based approaches to understand OR; however, there are still a number of unknowns. This study addressed two gaps in our understanding of the oxidation of the terrestrial biosphere: (1) What is the oxidation state of Arctic ecosystems, and in particular permafrost soils? (2) Will coupled climate and land use change cause the terrestrial organic matter oxidation state to change? The study considered eight locations along a transect from southern Sweden to northern Norway and sampled different organic matter types (soil, litter, trees, and herbaceous vegetation) as well as different soil orders (Inceptisols, Spodosols, Histosols, and Gelisols). The study showed that although there was no difference between soil orders, there was a significant effect due to location with OR increasing from 1.03 at the southernmost location to 1.09 in the northernmost location; this increase is independent of soil order or type of organic matter. The pattern of post hoc differences in the OR with latitude suggests that the increase in OR is correlated with the northern limit of arable agriculture. The study suggests that the combined effects of climate and land use change could lead to a decrease in terrestrial organic matter OR and an increase in its oxidation state. PMID- 28647154 TI - Synergistic negative effects of small-sized benthivorous fish and nitrogen loading on the growth of submerged macrophytes - Relevance for shallow lake restoration. AB - Rapid recruitment of small fish after biomanipulation in warm lakes may delay the reestablishment of submerged macrophytes, not least at high nutrient concentrations. Success has recently been obtained in controlling phosphorus (P) loading to many lakes, but nitrogen (N) inputs often remain high. To determine the interactive effects of N loading and the abundance of small-sized fish on the growth of the submerged macrophyte Vallisneria natans, we conducted an outdoor mesocosm experiment with a factorial design on the north shore of Lake Taihu, China. The experiment involved two densities of small crucian carp - low (10gm-2) and high (40gm-2) - crossed with two levels of N loading - present-day external nutrient loading (P: 5MUgL-1day-1, N: 130MUgL-1day-1) and P: 5MUgL-1day-1 with a three times higher N loading (N: 390MUgL-1day-1). The results showed that nitrogen-fish interactions significantly hindered the growth of V. natans, particularly at the high N loading. At low N loading, high densities of fish decreased the relative growth rate, mean leaf length, leaf mass and root mass of V. natans by 16%, 5%, 8%, and 23%, respectively, compared with these measures at low fish densities. The effect of fish was even stronger when N loading was high, with decreases of 232%, 32%, 57%, and 47% for the respective plant growth measures. The stronger effect at high N loading was attributed to higher turbidity due to enhanced phytoplankton biomass and to increased consumption or damage of plants by the fish in response to the more nutrient-enriched plant tissue. Our results indicate that high abundance of small crucian carp in warm lakes may reduce the resilience of submerged macrophytes to external N loading, thereby lowering the chances of successful restoration by biomanipulation. PMID- 28647155 TI - Quantifying trade-offs between future yield levels, food availability and forest and woodland conservation in Benin. AB - Meeting the dual objectives of food security and ecosystem protection is a major challenge in sub-Saharan Africa (SSA). To this end agricultural intensification is considered desirable, yet, there remain uncertainties regarding the impact of climate change on opportunities for agricultural intensification and the adequacy of intensification options given the rapid population growth. We quantify trade offs between levels of yield gap closure, food availability and forest and woodland conservation under different scenarios. Each scenario is made up of a combination of variants of four parameters i.e. (1) climate change based on Representative Concentration Pathways (RCPs); (2) population growth based on Shared Socioeconomic Pathways (SSPs); (3) cropland expansion with varying degrees of deforestation; and (4) different degrees of yield gap closure. We carry out these analyses for three major food crops, i.e. maize, cassava and yam, in Benin. Our analyses show that in most of the scenarios, the required levels of yield gap closures required to maintain the current levels of food availability can be achieved by 2050 by maintaining the average rate of yield increases recorded over the past two and half decades in addition to the current cropping intensity. However, yields will have to increase at a faster rate than has been recorded over the past two and half decades in order to achieve the required levels of yield gap closures by 2100. Our analyses also show that without the stated levels of yield gap closure, the areas under maize, cassava and yam cultivation will have to increase by 95%, 102% and 250% respectively in order to maintain the current levels of per capita food availability. Our study shows that food security outcomes and forest and woodland conservation goals in Benin and likely the larger SSA region are inextricably linked together and require holistic management strategies that considers trade-offs and co-benefits. PMID- 28647156 TI - Corrections. PMID- 28647157 TI - Veneered zirconia inlay-retained fixed dental prostheses: 10-Year results from a prospective clinical study. AB - OBJECTIVE: The purpose of this study was to evaluate the 10-year clinical performance of zirconia-based inlay-retained fixed dental prostheses (IRFDP). METHODS: For replacement of a molar in 27 patients, 30 IRFDP were luted by use of different cements, Panavia F (Kuraray Europe GmbH) or Multilink Automix (Ivoclar Vivadent GmbH), with use of inlay/inlay, inlay/full-crown, or inlay/partial-crown retainers for anchorage. Frameworks were milled from yttria-stabilized zirconia (IPS e.maxZirCAD; Ivoclar Vivadent GmbH) and fully veneered with pressable ceramic (IPS e.max ZirPress; Ivoclar Vivadent GmbH). Before luting, the IRFDP were silica-coated (Rocatec; 3M Espe) and silanized (Monobond S; Ivoclar Vivadent GmbH). Complications (for example, chipping or delamination of the veneering ceramic, debonding, secondary caries, endodontic treatment, and abutment tooth fracture) and failure were reported, by use of standardized report forms, 2 weeks, 6 months, and 1, 2, and 10 years after cementation. Statistical analysis included Kaplan-Meier survival and success (complication-free survival) and Cox regression analysis (alpha=0.05 for all). RESULTS: During the 10-year observation period, the complications most often observed were chipping of the veneer and debonding. Twenty-five restorations failed and one participant dropped out. Cumulative 10-year survival and success were 12.1% and 0%, respectively. The design of the retainer, use of a dental dam, choice of cement, and location in the dental arch had no statistically significant effect on the occurrence of complications. CONCLUSIONS: Use of fully veneered zirconia-based IRFDP with this technique cannot be recommended. CLINICAL SIGNIFICANCE: A large incidence of complications and poor survival were observed for fully veneered zirconia-based IRFDP, revealing an urgent need for further design improvements for this type of restoration. This, again, emphasizes the need for testing of new restoration designs in clinical trials before implementation in general dental practice. PMID- 28647158 TI - A systematic review of unilateral versus bilateral percutaneous vertebroplasty/percutaneous kyphoplasty for osteoporotic vertebral compression fractures. AB - OBJECTIVE: The aim of this study was to compare the unilateral and bilateral approaches in treating osteoporotic vertebral compression fractures. METHODS: Based on the principles and methods of the Cochrane systematic reviews, the records of the Cochrane Library, PubMed, Web of Science, Chinese Bio-medicine database, China Journal Full-text Database, VIP database, and Wanfang database were reviewed until October 2014. The randomized controlled trials on unilateral and bilateral approaches to percutaneous vertebroplasty (PVP)/percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures were included. The risk of bias of included trials was assessed based on the Cochrane Handbook for Systematic Reviews of Interventions Version. The RevMan Software 5.0 was used for meta-analysis. RESULTS: Fifteen randomized controlled trials with a total of 850 patients were included. Risk of bias in the included studies was inevitable. There was no statistically significant difference in visual analog scale, vertebral height, kyphotic angular, and quality of life. The main operative complications were bone cement leakage and adjacent vertebral fracture, without difference between the two groups. CONCLUSIONS: In view of the current evidence, there is insufficient evidence to show any difference between the unilateral and bilateral approaches in both the PVP and PKP treatment in osteoporotic vertebral compression fractures. LEVEL OF EVIDENCE: Level I, Therapeutic study. PMID- 28647159 TI - Risk factors for lymph node metastases of facial cutaneous squamous cell carcinoma. AB - PURPOSE: Determining the risk factors for lymph node metastases of facial cutaneous squamous cell carcinoma and identifying their value for predicting nodal spread. MATERIAL AND METHODS: Data on 99 patients were examined retrospectively. Conditions such as tumor staging, tumor thickness, location, histological grading, R1-resection, local recurrence, lymph node metastases, and neurovascular and lymphovascular invasion were evaluated. Statistical analysis was performed using a logistic regression analysis and Fisher's test. RESULTS: Logistic regression analysis indicates that poor differentiation, R1-resection, and periorbital location are high risk factors for nodal spread in facial cutaneous squamous cell carcinoma. CONCLUSION: Patients who show poorly differentiated facial cutaneous squamous cell carcinoma and/or have had previous R1-resection might benefit from treatment of regional lymph nodes. PMID- 28647160 TI - A clinical decision rule to predict zygomatico-maxillary fractures. AB - Patients presenting with periorbital trauma require clinical assessment to exclude zygomatico-maxillary fractures. A single-centre pilot investigation was undertaken at a general hospital in the United Kingdom. The sample was composed of 229 adult patients attending our emergency department with periorbital injuries. Findings from 17 signs or symptoms of facial injury were recorded on a validated tool. The relationship between clinical presentation and displaced zygomatico-maxillary fracture was assessed using diagnostic test parameters and tests for correlation. A decision-making rule was derived. The presence of a) palpable bony step, b) bony asymmetry, c) lateral sub-conjunctival haemorrhage with no posterior limit, d) anaesthesia or paraesthesia to lip/cheek or side of nose and e) palpable emphysema were all specific features of radiographically displaced zygomatico-maxillary fracture (specificity all >75.0 %, p value for correlation all <0.001). A decision-making rule based on the presence of any one of features (a),(c),(d) or (e) identified all patients with displaced zygomatico maxillary fractures in this sample (sensitivity 100% (95% CI 93.4%-100.0%), specificity 72.6% (95% CI 65.3%-79.0%). Implementation of this clinical decision making rule would identify all patients with displaced fractures at the triage stage whilst reducing radiographic exposures by 55% in this sample. PMID- 28647161 TI - DOT-C: A cluster randomised feasibility trial evaluating directly observed anti HCV therapy in a population receiving opioid substitute therapy from community pharmacy. AB - BACKGROUND: Direct-acting antiviral therapy (DAAs) for hepatitis C infection (HCV) have a much smaller burden of treatment than interferon-based regimes, require less monitoring and are very effective. New pathways are required to increase access to treatment amongst people prescribed opioid substitution therapy (OST). METHODS: An exploratory cluster randomised controlled trial with mixed methods evaluation was undertaken to compare the uptake of dried blood spot testing (DBST) and treatment of people with genotype 1 HCV infection in a conventional service pathway versus a pharmacist-led pathway in a population receiving OST. RESULTS: Pharmacies randomised to the conventional pathway obtained 58 DBST from 244 patients (24%):15 new reactive tests and 33 new negative tests were identified. Within the pharmacist-led pathway, 94 DBST were obtained from 262 patients (36%): 26 new reactive tests and 54 new negative tests were identified. Participants in the pharmacist-led pathway were more likely to take a DBST (p<0.003). Of participants referred for treatment through the conventional pathway, 4 patients from 15 with new reactive tests (27%) attended clinic for assessment. In the pharmacist-led treatment pathway, 20 patients from 26 with new reactive tests (77%) attended for assessment blood tests. Participants in the pharmacist-led pathway were more likely to proceed through the assessment for treatment (p<0.002). One participant completed treatment through the conventional pathway and three patients completed treatment through the pharmacist-led pathway. The process evaluation identified key themes important to service user completers and staff participants. CONCLUSION: The study provides evidence that testing and treatment for HCV in a pharmacist led pathway is a feasible treatment pathway for people who receive supervised OST consumption through community pharmacies. This feasibility trial therefore provides sufficient confirmation to justify proceeding to a full trial. PMID- 28647162 TI - Response to the letter to the editor regarding ''Evaluation of vitamin D levels in children with primary epistaxis''. PMID- 28647163 TI - Observer-based distributed adaptive fault-tolerant containment control of multi agent systems with general linear dynamics. AB - In this paper, we consider the distributed containment control problem of multi agent systems with actuator bias faults based on observer method. The objective is to drive the followers into the convex hull spanned by the dynamic leaders, where the input is unknown but bounded. By constructing an observer to estimate the states and bias faults, an effective distributed adaptive fault-tolerant controller is developed. Different from the traditional method, an auxiliary controller gain is designed to deal with the unknown inputs and bias faults together. Moreover, the coupling gain can be adjusted online through the adaptive mechanism without using the global information. Furthermore, the proposed control protocol can guarantee that all the signals of the closed-loop systems are bounded and all the followers converge to the convex hull with bounded residual errors formed by the dynamic leaders. Finally, a decoupled linearized longitudinal motion model of the F-18 aircraft is used to demonstrate the effectiveness. PMID- 28647164 TI - Liver transplantation in New Orleans: parity in a world of disparity? AB - BACKGROUND: Racial disparity in access to liver transplantation among African Americans (AA) compared to Caucasians (CA) has been well described. The aim of this investigation was to examine the presentation of AA liver transplant recipients in a socioeconomically challenged region. METHODS: 680 adult liver transplant candidates and 233 resultant recipients between 2007 and 2015 were analyzed using univariate and multivariate analyses to evaluate factors significant for transplantation. RESULTS: Percentages of wait list patients transplanted were similar between CA and AA (34.9% vs. 32.2%, p = 0.5205). AA were younger (50.4 +/- 1.8 vs. 56.3 +/- 0.7 yrs, p = 0.0003) with higher average MELD scores (22.9 +/- 1.6 vs. 19.4 +/- 0.7, p = 0.0230). Overall patient mortality was similar (AA 22.7% vs. CA 26.3%, p = 0.5931). A multiple linear regression showed that male gender was strongly associated with transplantation. CONCLUSIONS: Equal access to liver transplantation remains challenging for racial minorities. At our institution, AA were accepted and transplanted at an equivalent rate as CA despite a higher AA population, HCV rate and diagnosed HCC. AA were younger and sicker at the time of transplant, but overall had similar outcomes compared to CA. Our study highlights the need for studies to delineate the underpinnings of disparity in transplantation access. PMID- 28647165 TI - Modelling efforts needed to advance herpes simplex virus (HSV) vaccine development: Key findings from the World Health Organization Consultation on HSV Vaccine Impact Modelling. AB - Development of a vaccine against herpes simplex virus (HSV) is an important goal for global sexual and reproductive health. In order to more precisely define the health and economic burden of HSV infection and the theoretical impact and cost effectiveness of an HSV vaccine, in 2015 the World Health Organization convened an expert consultation meeting on HSV vaccine impact modelling. The experts reviewed existing model-based estimates and dynamic models of HSV infection to outline critical future modelling needs to inform development of a comprehensive business case and preferred product characteristics for an HSV vaccine. This article summarizes key findings and discussions from the meeting on modelling needs related to HSV burden, costs, and vaccine impact, essential data needs to carry out those models, and important model components and parameters. PMID- 28647166 TI - Clinical development of a recombinant Ebola vaccine in the midst of an unprecedented epidemic. AB - The 2014-2016 Ebola outbreak caused over 28,000 cases and 11,000 deaths. Merck & Co. Inc., Kenilworth, NJ USA and NewLink Genetics are working with private and public partners to develop and license an Ebola vaccine that was evaluated extensively during the outbreak. The vaccine referred to as V920 is a recombinant vesicular stomatitis virus (rVSV) in which the VSV-G envelope glycoprotein (GP) is completely replaced by the Zaire ebolavirus GP (rVSVDeltaG-ZEBOV-GP). Eight Phase I and four Phase II/III clinical trials enrolling approximately 17,000 subjects were conducted in parallel to the outbreak to assess the safety, immunogenicity, and/or efficacy of V920. Immunogenicity data demonstrate that anti-GP antibodies are generally detectable by ELISA by 14days postvaccination with up to 100% seroconversion observed by 28days post dose. In addition, the results of a ring vaccination trial conducted by the WHO and their partners in Guinea suggest robust vaccine efficacy within 10days of receipt of a single dose of vaccine. The vaccine is generally well-tolerated when administered to healthy, non-pregnant adults. The development of this vaccine candidate in the context of this unprecedented epidemic has involved the close cooperation of large number of international partners and highlights what we as a public health community can accomplish when working together towards a common goal. Study identification: V920-001 to V920-012. CLINICALTRIALS.GOV identifiers: NCT02269423; NCT02280408; NCT02374385; NCT02314923; NCT02287480; NCT02283099; NCT02296983; NCT02344407; NCT02378753; NCT02503202. PMID- 28647167 TI - Adolescent meningococcal serogroup A, W and Y immune responses following immunization with quadrivalent meningococcal A, C, W and Y conjugate vaccine: Optimal age for vaccination. AB - BACKGROUND: Recently the incidence of meningococcal serogroup Y (MenY) and in particular serogroup W (MenW) invasive disease has risen in several European countries, including the Netherlands. Adolescents are a target group for primary prevention through vaccination to protect against disease and reduce carriage and induce herd protection in the population. The present study assessed MenA, MenW and MenY antibody levels in adolescents up to one year following primary vaccination with quadrivalent MenACWY-PS conjugated to tetanus toxoid (MenACWY TT). METHODS: In this phase IV, open-label study, healthy 10-, 12- and 15-year olds received the MenACWY-TT vaccine. Blood samples were collected before, 1month and 1year after the vaccination. Functional antibody levels against MenA, MenW and MenY were measured with serum bactericidal assay using baby rabbit complement (rSBA). MenA-, MenW-, and MenY-PS specific IgG, IgG1 and IgG2 levels were measured using fluorescent-bead-based multiplex immunoassay. RESULTS: The quadrivalent MenACWY-TT vaccine elicited robust antibody responses against MenA, MenW and MenY, and the majority (94%) of the participants maintained rSBA titers >=128 one year after the vaccination against all three serogroups. After one year, higher MenW rSBA GMTs were observed in the 12- and 15-year-olds compared to the 10-year-olds, while rSBA GMTs against MenA and MenY were similar between age groups. Furthermore, those participant who showed SBA titer >=8 at baseline, also had higher antibody levels one year after vaccination as compared to participants with rSBA titer <8 at baseline. CONCLUSION: The MenACWY-TT vaccine induces robust protective primary immune responses up to one year after vaccination. Our results suggest that persistence of individual protection increases with the age at which a primary quadrivalent MenACWY-TT vaccination is administered. Our results indicate that 12 or 15years seems a more optimal age for a primary quadrivalent MenACWY-TT vaccination to protect against the rapid increase of MenW disease. PMID- 28647168 TI - Communicating infectious disease prevalence through graphics: Results from an international survey. AB - BACKGROUND: Graphics are increasingly used to represent the spread of infectious diseases (e.g., influenza, Zika, Ebola); however, the impact of using graphics to adequately inform the general population is unknown. OBJECTIVE: To examine whether three ways of visually presenting data (heat map, dot map, or picto trendline)-all depicting the same information regarding the spread of a hypothetical outbreak of influenza-influence intent to vaccinate, risk perception, and knowledge. DESIGN: Survey with participants randomized to receive a simulated news article accompanied by one of the three graphics that communicated prevalence of influenza and number of influenza-related deaths. SETTING: International online survey. PARTICIPANTS: 16,510 adults living in 11 countries selected using stratified random sampling based on age and gender. MEASUREMENTS: After reading the article and viewing the presented graphic, participants completed a survey that measured interest in vaccination, perceived risk of contracting disease, knowledge gained, interest in additional information about the disease, and perception of the graphic. RESULTS: Heat maps and picto trendlines were evaluated more positively than dot maps. Heat maps were more effective than picto-trendlines and no different from dot maps at increasing interest in vaccination, perceived risk of contracting disease, and interest in additional information about the disease. Heat maps and picto-trendlines were more successful at conveying knowledge than dot maps. Overall, heat maps were the only graphic to be superior in every outcome. LIMITATIONS: Results are based on a hypothetical scenario. CONCLUSION: Heat maps are a viable option to promote interest in and concern about infectious diseases. PMID- 28647170 TI - The complexity and cost of vaccine manufacturing - An overview. AB - As companies, countries, and governments consider investments in vaccine production for routine immunization and outbreak response, understanding the complexity and cost drivers associated with vaccine production will help to inform business decisions. Leading multinational corporations have good understanding of the complex manufacturing processes, high technological and R&D barriers to entry, and the costs associated with vaccine production. However, decision makers in developing countries, donors and investors may not be aware of the factors that continue to limit the number of new manufacturers and have caused attrition and consolidation among existing manufacturers. This paper describes the processes and cost drivers in acquiring and maintaining licensure of childhood vaccines. In addition, when export is the goal, we describe the requirements to supply those vaccines at affordable prices to low-resource markets, including the process of World Health Organization (WHO) prequalification and supporting policy recommendation. By providing a generalized and consolidated view of these requirements we seek to build awareness in the global community of the benefits and costs associated with vaccine manufacturing and the challenges associated with maintaining consistent supply. We show that while vaccine manufacture may prima facie seem an economic growth opportunity, the complexity and high fixed costs of vaccine manufacturing limit potential profit. Further, for most lower and middle income countries a large majority of the equipment, personnel and consumables will need to be imported for years, further limiting benefits to the local economy. PMID- 28647169 TI - The number of injected same-day preschool vaccines relates to preadolescent needle fear and HPV uptake. AB - PURPOSE: Fear of needles develops at approximately five years of age, and decreases compliance with healthcare. We sought to examine the relationship of preschool vaccine history, parent and preadolescent needle fear, and subsequent compliance with optional vaccines. METHODS: As part of a private practice randomized controlled trial, parents and 10-12year olds rated needle anxiety on a 100mm visual analog scale. This follow-up cohort study compared their needle anxiety to previous vaccination records, including number of vaccinations between ages four and six years (total and same-day maximum), and subsequent initiation of the HPV vaccine through age 13. RESULTS: Of the 120 preadolescents enrolled between 4.28.09 and 1.19.2010, 117 received preschool vaccinations between ages four and six years. The likelihood of being in the upper quartile of fear (VAS>=83) five years later increased with each additional same-day injection (OR=3.108, p=0.0100 95%CI=1.311, 7.367), but was not related to total lifetime or total four-to-six year injections. Only 12.5% (15) of parents reported anxiety about their preadolescents' vaccines (VAS>50). Parent and child anxiety was weakly correlated (r=0.15). Eight children in the upper fear quartile began their HPV series (26.67%) compared to 14 in the lower quartile (48.28% VAS<32) (OR 2.57, p=0.0889, 95%CI 0.864-7.621); there was no difference in HPV uptake between upper and lower quartile of parent anxiety. CONCLUSIONS: The more same-day preschool injections between 4 and 6years of age, the more likely a child was to fear needles five years later. Preadolescent needle fear was a stronger predictor than parent vaccine anxiety of subsequent HPV vaccine uptake. PMID- 28647171 TI - Worm Control in Livestock: Bringing Science to the Field. AB - Parasitic roundworm infections are ubiquitous in grazing livestock. Chemical control through the frequent 'blanket' administration of anthelmintics (wormers) has been, and remains, the cornerstone in controlling these infections, but this practice is unsustainable. Alternative strategies are available but, even with the plethora of best practice advice available, have yet to be integrated into routine farming practice. This is probably due to a range of factors, including contradictory advice from different sources, changes to advice following increased scientific understanding, and top-down knowledge exchange patterns. In this article, we discuss the worm control options available, the translation of new best practice advice from science bench to field, and ideas for future work and directions. PMID- 28647172 TI - Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. AB - BACKGROUND: On Nov 11, 2015, the Brazilian Ministry of Health declared a Public Health Emergency of National Concern in response to an increased number of microcephaly cases, possibly related to previous Zika virus outbreaks. We describe the course of the dual epidemics of the Zika virus infection during pregnancy and microcephaly in Brazil up to Nov 12, 2016, the first anniversary of this declaration. METHODS: We used secondary data for Zika virus and microcephaly cases obtained through the Brazilian Ministry of Health's surveillance systems from Jan 1, 2015, to Nov 12, 2016. We deemed possible Zika virus infections during pregnancy as all suspected cases of Zika virus disease and all initially suspected, but later discarded, cases of dengue and chikungunya fever. We defined confirmed infection-related microcephaly in liveborn infants as the presence of a head circumference of at least 2 SDs below the mean for their age and sex, accompanied by diagnostic imaging consistent with an infectious cause, or laboratory, clinical, or epidemiological results positive for Zika virus or STORCH (infectious agents known to cause congenital infection, mainly syphilis, toxoplasmosis, cytomegalovirus, and herpes simplex virus). We excluded cases of congenital anomalies or death without microcephaly. We analyse the spatial clustering of these diseases in Brazil to obtain the kernel density estimation. FINDINGS: Two distinct waves of possible Zika virus infection extended across all Brazilian regions in 2015 and 2016. 1 673 272 notified cases were reported, of which 41 473 (2.5%) were in pregnant women. During this period, 1950 cases of infection-related microcephaly were confirmed. Most cases (1373 [70.4%]) occurred in the northeast region after the first wave of Zika virus infection, with peak monthly occurrence estimated at 49.9 cases per 10 000 livebirths. After a major, well documented second wave of Zika virus infection in all regions of Brazil from September, 2015, to September, 2016, occurrence of microcephaly was much lower than that following the first wave of Zika virus infection, reaching epidemic levels in all but the south of Brazil, with estimated monthly peaks varying from 3.2 cases to 15 cases per 10 000 livebirths. INTERPRETATION: The distribution of infection-related microcephaly after Zika virus outbreaks has varied across time and Brazilian regions. Reasons for these apparent differences remain to be elucidated. FUNDING: None. PMID- 28647173 TI - An update on Zika virus infection. AB - The epidemic history of Zika virus began in 2007, with its emergence in Yap Island in the western Pacific, followed in 2013-14 by a larger epidemic in French Polynesia, south Pacific, where the first severe complications and non-vector borne transmission of the virus were reported. Zika virus emerged in Brazil in 2015 and was declared a national public health emergency after local researchers and physicians reported an increase in microcephaly cases. In 2016, WHO declared the recent cluster of microcephaly cases and other neurological disorders reported in Brazil a global public health emergency. Similar clusters of microcephaly cases were also observed retrospectively in French Polynesia in 2014. In 2015-16, Zika virus continued its spread to cause outbreaks in the Americas and the Pacific, and the first outbreaks were reported in continental USA, Africa, and southeast Asia. Non-vector-borne transmission was confirmed and Zika virus was established as a cause of severe neurological complications in fetuses, neonates, and adults. This Review focuses on important updates and gaps in the knowledge of Zika virus as of early 2017. PMID- 28647174 TI - Risk of Zika-related microcephaly: stable or variable? PMID- 28647175 TI - Neuropsychological and psychiatric outcome of GPi-deep brain stimulation in dystonia. AB - BACKGROUND: Previous investigators have observed changes in cognitive and psychiatric domains after GPi-DBS for dystonia, such as declines in semantic verbal fluency and set shifting or increased suicidality. Others have reported stability or improvements in select areas, such as graphomotor speed and mood. Interpretation of these findings is limited by inclusion of select patient populations or limited neuropsychological testing. OBJECTIVE: To describe cognitive and neuropsychiatric outcomes in a cohort of patients with primary and secondary dystonia undergoing Globus Pallidus pars interna deep brain stimulation (GPi-DBS). METHODS: Patients with primary and secondary dystonia were evaluated at baseline and post-operatively with a comprehensive battery of neuropsychological tests and mood inventories including anxiety, depression and hopelessness scales. Statistical significance was calculated with one-tailed student t-test, defined as p value < 0.05. RESULTS: Twelve patients were included in the study. Nine were male (75%) and the mean age at baseline assessment was 42.3 years (range 13-68; SD 18.0). The majority had focal or segmental dystonia (8/12, 66%), 4 patients had generalized dystonia. Three patients had monogenic dystonias (DYT 1 and DYT 3), and two patients had acquired (tardive) dystonia. Mean time between surgery and follow-up was 13.1 months (SD 3.1). Subjects demonstrated stable performance on most tests, with statistically significant improvements noted in working memory (letter-number sequencing), executive function (trail-making B), anxiety and depression. CONCLUSIONS: In an etiologically and clinically diverse patient population, administration of comprehensive battery of cognitive tests pre and post-operatively suggests that GPi-DBS is safe from cognitive and psychiatric perspectives. PMID- 28647176 TI - Mitochondrial oxidative phosphorylation efficiency is upregulated during fasting in two major oxidative tissues of ducklings. AB - Fasted endothermic vertebrates must develop physiological responses to maximize energy conservation and survival. The aim of this study was to determine the effect of 1-wk. fasting in 5-wk. old ducklings (Cairina moschata) from whole-body resting metabolic rate and body temperature to metabolic phenotype of tissues and mitochondrial coupling efficiency. At the level of whole organism, the mass specific metabolic rate of ducklings was decreased by 40% after 1-wk. of fasting, which was associated with nocturnal Tb declines and shallow diurnal hypothermia during fasting. At the cellular level, fasting induced a large reduction in liver, gastrocnemius (oxidative) and pectoralis (glycolytic) muscle masses together with a fuel selection towards lipid oxidation and ketone body production in liver and a lower glycolytic phenotype in skeletal muscles. At the level of mitochondria, fasting induced a reduction of oxidative phosphorylation activities and an up-regulation of coupling efficiency (+30% on average) in liver and skeletal muscles. The present integrative study shows that energy conservation in fasted ducklings is mainly achieved by an overall reduction in mitochondrial activity and an increase in mitochondrial coupling efficiency, which would, in association with shallow hypothermia, increase the conservation of endogenous fuel stores during fasting. PMID- 28647177 TI - Infectious diseases in solid organ transplant recipients: Analysis of autopsied cases in Japan. AB - BACKGROUND: With the improvements in immunosuppressive agents and graft survival, infections such as mycoses have become major complications after solid organ transplantation (SOT). METHODS: Our group has continuously updated an epidemiological database of visceral mycoses (VM) among autopsy cases in Japan since 1989. Data on infectious agents and clinical information were complied using similar procedures. RESULTS: Among the all autopsied cases studied, 356 undergone SOT. Of these, 214 (60.1%) suffered from one or more types of infections, including 51 (14.3%) with VM. Thus, the incidence of VM was higher in SOT recipients than in non-transplanted cases (P < 0.0001). Aspergillus spp. (Asp) was the most predominant agent and Candida spp. was second. Specifically, among SOT recipients, Asp was the most predominant in liver and lung transplant recipients. Among the 217 autopsied liver transplants cases, the incidence of VM was highest in those with fulminant hepatitis (FH, P = 0.01). The incidence of cytomegalovirus infection tended to be higher in cases with mycosis (P = 0.06). Multivariate logistic regression analysis identified FH (odds ratio, 3.61, 95% confidence interval 1.34-9.75; P = 0.03) as an independent risk factor for mycosis in liver transplant recipients. CONCLUSION: This epidemiological analysis of autopsied cases provides a strong incentive to intensify efforts to diagnose and treat post-SOT infectious diseases. PMID- 28647178 TI - Traditional usage, phytochemistry and pharmacology of Croton sylvaticus Hochst. ex C. Krauss. AB - Croton sylvaticus (C. sylvaticus) is widely used as herbal medicine by the indigenous people of tropical Africa. The potential of C. sylvaticus as herbal medicine, the phytochemistry and pharmacological properties of its parts used as herbal medicines are reviewed. The extensive literature survey revealed that C. sylvaticus is traditionally used to treat or manage at least 24 human and animal diseases and ailments. The species is used as herbal medicine for diseases and ailments such as abdominal pains, boils, fever, inflammation, malaria, rheumatism, swellings and tuberculosis and as ethnoveterinary medicine. Multiple classes of phytochemicals such as alkaloids, anthraquinones, essential oils, flavonoids, lignan, phenolics, sterols, tannins and terpenoids have been isolated from the species. Scientific studies on C. sylvaticus indicate that it has a wide range of pharmacological activities which include antibacterial, antifungal, anti inflammatory, antioxidant, larvicidal and effects on the central nervous system. Although studies have confirmed that C. sylvaticus has a wide range of bioactives, further research on the exact bioactive molecules and mechanisms of action are required. PMID- 28647179 TI - Euphorbia neriifolia L.: Review on botany, ethnomedicinal uses, phytochemistry and biological activities. AB - The present review is intended to provide information on botany, ethnomedicinal uses, phytochemistry and biological activities of various parts of Euphorbia neriifolia (E. neriifolia). E. neriifolia has several ethnomedicinal uses. The latex of E. neriifolia is used as laxative, purgative, rubefacient, carminative and expectorant as well as in treatment of whooping cough, gonorrhoea, leprosy, asthma, dyspepsia, jaundice, enlargement of the spleen, tumours, stone in the bladder, abdominal troubles and leucoderma. Leaves are brittle, heating, carminative, and good for improving the appetite and treatment of tumours, pains, inflammations, abdominal swellings and bronchial infections. Roots are used as symptomatic treatment of snake bite, scorpion sting and antispasmodic. Various plant parts or whole E. neriifolia extract and its isolates have been reported scientifically using various in-vivo and in-vitro experimental methods for anaesthetic, analgesic, anti-anxiety, anti-convulsant, anti-psychotic, anti arthritis, anti-carcinogenic, antidiabetic, anti-diarrhoeal, anti-inflammatory, anti-thrombotic, antimicrobial, antioxidant, antiulcer, cytotoxic, death-receptor expression enhancing, dermal irritation, diuretic, haemolytic, immunomodulatory, radioprotective, scorpion venom and wound healing properties. It is reported to have chemical constituents like, neriifolin-S, neriifolin, neriifoliene, euphol, neriifolione, cycloartenol, nerifoliol, lectin, euphonerins A-G, 3-O-acetyl-8-O tigloylingol, taraxerol, antiquorin, etc. Identified chemical constituents are still required to be explored for their advanced isolation techniques and biological activities. PMID- 28647180 TI - Helianthus tuberosus (Jerusalem artichoke) tubers improve glucose tolerance and hepatic lipid profile in rats fed a high-fat diet. AB - OBJECTIVES: To analyze the effects of feeding Helianthus tuberosus (HT) tubers on glucose tolerance and lipid profile in rats fed a high-fat diet (HFD). METHODS: A normal HFD or HFD including 10 w/w% HT tubers (HFD + HT) was fed to F334/Jcl rats. After 10 weeks, organ weights, glucose tolerance, and lipid profile were analyzed. RESULTS: The body weight, liver weight, and epidermal fat content in the HFD group were higher than those of the normal group, and similar to those of the HFD + HT group. The oral glucose tolerance test at 10 weeks revealed that the blood glucose level 30 min after beginning the test in the HFD + HT group was significantly lower than that in the HFD group. Liver triglyceride and total cholesterol levels in the HFD + HT group were significantly lower than those in the HFD group. Fecal triglyceride and total cholesterol levels in the HFD + HT group were higher than those in the HFD group. Histological analyses revealed that fat and glycogen accumulation increased in the HFD group, but decreased in the HFD + HT group. CONCLUSIONS: These results indicate that HT tubers have anti fatty liver effects based on improvements in glucose tolerance and the hepatic lipid profile. PMID- 28647181 TI - Rosmarinic acid attenuates hepatic fibrogenesis via suppression of hepatic stellate cell activation/proliferation and induction of apoptosis. AB - OBJECTIVE: To investigate the antifibrotic role of rosmarinic acid (RA), a natural polyphenolic compound, on HSCs activation/proliferation and apoptosis in vitro and in vivo. METHODS: The impact of RA on stellate cell line (HSC-T6) proliferation, activation and apoptosis was assessed along with its safety on primary hepatocytes. In vivo, rats were divided into: (i) normal; (ii) thioacetamide (TAA)-intoxicated rats for 12 weeks; (iii) TAA + silymarin or (iv) TAA + RA. At the end of experiment, liver functions, oxidative stress, inflammatory and profibrogenic markers, tissue inhibitor metalloproteinases type 1 (TIMP-1) and hydroxyproline (HP) levels were evaluated. Additionally, liver histopathology and immunohistochemical examinations of alpha-smooth muscle actin (alpha-SMA), caspase-3 and proliferation cellular nuclear antigen (PCNA) were determined. RESULTS: RA exhibited anti-proliferative effects on cultured HSCs in a time and concentration dependent manner showing an IC50 of 276 MUg/mL and 171 MUg/mL for 24 h and 48 h, respectively, with morphological reversion of activated stellate cell morphology to quiescent form. It significantly improved ALT, AST, oxidative stress markers and reduced TIMP-1, HP levels, inflammatory markers and fibrosis score (S1 vs S4). Furthermore, reduction in alpha-SMA plus elevation in caspase-3 expressions of HSCs in vitro and in vivo associated with an inhibition in proliferation of damaged hepatocytes were recorded. CONCLUSIONS: RA impeded the progression of liver fibrosis through inhibition of HSCs activation/proliferation and induction of apoptosis with preservation of hepatic architecture. PMID- 28647182 TI - Preoperative application of combination of portal venous injection of donor spleen cells and intraperitoneal injection of rapamycin prolongs the survival of cardiac allografts in mice. AB - OBJECTIVE: To investigate the effects of preoperative portal venous injection of donor spleen cells (PVIDSC) and intraperitoneal injection of rapamycin in the acute rejection of cardiac allograft in mice and the underlying mechanisms. METHODS: Homogenous female B6 mice and BALB/c mice were used as recipients and donors of heart transplantation. These mice were randomly divided into different groups and received PVIDSC alone, rapamycin alone, or PVIDSC and rapamycin combined therapy. In addition, the underlying mechanism was studied by measuring a number of cytokines. RESULTS: Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin significantly prolonged the survival of heterotopic cardiac allograft in mice, but had no effects on the survival time of cardiac allografts in mice pre-sensitized by skin grafting. Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin increased the expression of IL-10 and Foxp3 and reduced the expression of INF-. Short-term preoperative administration of rapamycin promotes the expression of CD4+CD25+Foxp3+ regulator T cells. However, preoperative using alone of rapamycin, or combination of PVIDSC and rapamycin had no effects on the inhibition of proliferation of memory T cells. CONCLUSIONS: Preoperative application of combination of PVIDSC and rapamycin significantly prolonged the survival time of cardiac allografts in mice but not in mice pre-sensitized by skin grafting. This may be explained by the fact that combination of PVIDSC and rapamycin inhibited the cellular immune response and induced the expression of IL 10 from Tr1 cells and CD4+CD25+FoxP3+ regulatory T cells. PMID- 28647183 TI - Activity of Tagetes minuta Linnaeus (Asteraceae) essential oil against L3 Anisakis larvae type 1. AB - OBJECTIVE: To evaluate in vitro effects of Tagetes minuta L. essential oil (TEO) on L3 Anisakis larvae type 1. METHODS: In order to evaluate the potential use of Tagetes minuta essential oil against L3 Anisakis larvae three different media were tested: 1) a saline solution (SS); 2) an industrial marinating solution (MS); 3) sunflower seeds oil (SO). For each media and concentrations of TEO (0.1%, 0.5%, 1.0% and 5.0% v/v), 20 parasites were introduced into plastic Petri dishes (diameter 90 mm) and maintained at room temperature. As controls, larvae were maintained without TEO under identical experimental conditions in SS, MS and SO. A total of 900 larvae were tested. The normalized mean viability, LT100, LT50 and the percentage of inactivation at 24 h were calculated. RESULTS: In vitro tests revealed a complete inactivation of parasites in saline solution after 2 h with 5% and 1% of TEO. In marinating solution, a complete inactivation of parasites was observed after 4 h at all concentrations used. A slower activity for all TEO concentration was reported in SO. CONCLUSIONS: The results obtained, showing a strong activity against Anisakis larvae, confirm TEO as a larvicidal agent in the treatment of human anisakidosis and in the industrial marinating process. PMID- 28647184 TI - Identification of novel biomarkers for adult-onset-immunodeficiency (AOID) syndrome using serum proteomics. AB - OBJECTIVE: To identify the candidate protein biomarkers of adult-onset immunodeficiency (AOID) syndrome using serum proteomics. METHODS: Screening and verification phases were performed in the study. A total of 97 serum samples were classified into three groups: AOID patients with opportunistic infections (active AOID), AOID patients without opportunistic infections (inactive AOID), and healthy control. In the screening phase, pooled sera collected from patients and healthy control in each group were separated by 2D-gel electrophoresis, analyzed for differentially expressed proteins and identified for biomarkers using LC/MS. In the verification phase, the protein candidates were selected for confirmation by western blotting. RESULTS: The analysis revealed 35 differentially expressed proteins. Three proteins including haptoglobin, gelsolin, and transthyretin, were selected for verification. The results showed that the levels of haptoglobin in both active and inactive AOID groups were significantly higher than that in the control group, while the levels of gelsolin in the active AOID group were significantly lower than that in the inactive AOID group. The level of transthyretin in the active AOID group was also significantly lower than that in the control group. CONCLUSIONS: The comparison of serum proteins between the three groups revealed three candidates which are related to chronic inflammatory diseases. Haptoglobin and transthyretin biomarkers could be applied in clinical assessment for monitor of disease outcome, including for the study of AOID pathogenesis. PMID- 28647185 TI - Relationship between catecholamine level and gene polymorphism of beta1 adrenergic receptor G1165C in children with EV71 infection in hand foot and mouth disease. AB - OBJECTIVE: To investigate the relationship between the levels of plasma adrenaline and norepinephrine and gene polymorphism of beta1 adrenergic receptor G1165C in children with enterovirus 71 (EV71) infection in hand foot and mouth disease (HFMD). METHODS: The polymerase chain reaction (PCR) was used to detect the expression of gene polymorphism of beta1 adrenergic receptor G1165C in vitro. The levels of plasma adrenaline and norepinephrine were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The plasma norepinephrine level of severe group was significantly higher than the mild group in children with EV71 infection in HFMD (P < 0.05); however, the levels of plasma adrenaline in two groups had no statistical differences (P > 0.05); There was no significant difference in the distribution of beta1 adrenergic receptor G1165C genotype and allele between EV71 infection group and healthy control group (P > 0.05). Further analysis of EV71 infection group by dividing it into mild and severe groups showed that there was no significant difference in the distribution of genotype and allele between these two groups as well (P > 0.05). There was no significant difference in the levels of epinephrine and norepinephrine in different genotypes of EV71 infection group (P > 0.05), and in the levels of plasma epinephrine and norepinephrine in the mild and severe groups (P > 0.05). CONCLUSIONS: As the disease gets worse, the plasma norepinephrine level has a rising trend in children with EV71 infection in HFMD, which is an important indicator to evaluate the progress of the disease. However, the gene polymorphism of beta1 adrenergic receptor G1165C have no significant correlation, not only with the susceptibility and severity of EV71 infection in hand, foot and mouth disease, but also with the levels of catecholamine. PMID- 28647186 TI - Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity. AB - OBJECTIVE: To investigate the effect of two extracts of Bougainvillea spectabilis (B. spectabilis) flowers with yellow and pink/purple on brain oxidative stress and neuronal damage caused in rats by systemic rotenone injection. METHODS: Rotenone 1.5 mg/kg was given three times per week alone or in combination with B. spectabilis flowers extracts (25 mg or 50 mg) via the subcutaneous route for 2 weeks. Brain concentrations of the lipid peroxidation marker malondialdehyde (MDA), reduced glutathione, nitric oxide (nitrite), the pro-inflammatory cytokine interleukin-1beta (Il-1beta) as well as butyrylcholinesterase, and paraoxonase-1 (PON-1) activities, were determined. Histopathology and caspase-3 immunohistochemistry were also performed. RESULTS: Rotenone resulted in significant increases of brain MDA (the product of lipid peroxidation), and nitric oxide content along with decreased brain reduced glutathione. There were also marked and significant inhibition of brain PON-1 and BChE activities and increased Il-1beta in brain of rotenone-treated rats. B. spectabilis flowers extract itself resulted in brain oxidative stress increasing both lipid peroxidation and nitrite content whilst inhibiting PON-1 activity. The yellow flowers extract inhibited BChE activity and increased brain Il-1beta. When given to rotenone-treated rats, B. spectabilis extracts, however, decreased lipid peroxidation while their low administered doses increased brain GSH. Brain nitrite decreased by the pink extract but showed further increase by the yellow extract. Either extract, however, caused further inhibition of PON-1 activity while the yellow extract resulted in further inhibition of BChE activity. Histopathological studies indicated that both extracts protected against brain, liver and kidney damage caused by the toxicant. CONCLUSIONS: These data indicate that B. spectabilis flowers extracts exert protective effect against the toxic effects of rotenone on brain, liver and kidney. B. spectabilis flowers extracts decreased brain lipid peroxidation and prevented neuronal death due to rotenone and might thus prove the value in treatment of Parkinson's disease. PMID- 28647187 TI - Prevalence and risk factors of Blastocystis infection among underprivileged communities in rural Malaysia. AB - OBJECTIVES: To determine the prevalence and risk factors of Blastocystis among underprivileged communities living in rural Malaysia. METHODS: This cross sectional study was conducted among 253 participants aged between 1 and 85 years. Stool samples were examined using Wheatley's trichrome stain after in-vitro cultivation in Jones' medium to detect the presence of Blastocystis. Information pertaining to the demography, socioeconomic and environment were collected using pre-validated questionnaires. RESULTS: The total prevalence of Blastocystis infection was 40.7%. The multiple logistic regression analysis revealed that age >=15 years (OR = 2.72; 95% CI = 1.47-5.04) and presence of infected family members (OR = 8.56; 95% CI = 4.47-16.38) were the significant risk factors associated with blastocystosis in these communities. CONCLUSIONS: Blastocystosis is revealed through this study to be still prevalent among Orang Asli communities in rural Malaysia. The two main approaches that should be implemented by the public health authority in battling this infection would be the screening of other family members and giving treatment to the infected individuals. Moreover, it is imperative for health education on good personal and food hygiene practices are provided in order to reduce the morbidity and transmission of Blastocystis infection among the Orang Asli in their communities meaningfully. PMID- 28647188 TI - MiR-200a and miR-200b target PTEN to regulate the endometrial cancer cell growth in vitro. AB - OBJECTIVE: To study whether miR-200a and miR-200b target PTEN gene expression to regulate the endometrial cancer cell growth in vitro. METHODS: Endometrial cancer cells ECC-1 were cultured and transfected with the miR-200a and miR-200b mimics and inhibitors as well as the negative control mimics and inhibitors, and then the cell proliferation activity as well as the expression of PTEN and downstream genes in cells was determined; after transfection of miR-200a and miR-200b mimics as well as PTEN-3'UTR luciferase report gene plasmids, the fluorescence activity of luciferase reporter gene was determined. RESULTS: 12 h, 24 h and 48 h after transfection, the cell proliferation activity of miR-200a mimics group and miR 200b mimics group were significantly higher than those of NC mimics group while the cell proliferation activity of miR-200a inhibitor group and miR-200b inhibitor group were significantly lower than those of NC inhibitor group; 48 h after transfection, PTEN expression in cells and PTEN-3'UTR luciferase reporter gene fluorescence activity of miR-200a mimics group and miR-200b mimics group were significantly lower than those of NC mimics group while p-PI3K and p-Akt expression were significantly higher than those of NC mimics group; PTEN expression in cells and PTEN-3'UTR luciferase reporter gene fluorescence activity of miR-200a inhibitor group and miR-200b inhibitor group were significantly higher than those of NC inhibitor group while p-PI3K and p-Akt expression were significantly lower than those of NC inhibitor group. CONCLUSION: miR-200a and miR-200b can promote the endometrial cancer cell growth in vitro by targeted inhibition of PTEN gene expression. PMID- 28647189 TI - Ethnobotanical profiling of the medicinal flora of Kotli, Azad Jammu and Kashmir, Pakistan: Empirical reflections on multinomial logit specifications. AB - OBJECTIVE: To report the indigenous people's uses of plants from a multidimensional perspective in a remote area where strong ethnobotanical cultural practices prevail. METHODS: An ethnobotanical survey was conducted in the field during 2014-2016. Ethnobotanical data were gathered from 182 informants through oral interviews and semi-structured questionnaires. The distribution of plants was explored using both descriptive and graphical methods. Further, a Multinomial Logit Specification was applied to find out the probability of the occurrence of diverse utilization of plants in multipurpose domains. RESULTS: The study identified 202 plant species distributed among 71 families and 156 genera. Ethnobotanical data indicate that there are more medicinal (36.96%) uses of plants as compared to all other use categories. The output from the Multinomial Logit Specifications (MLS) model reveals that perennial and non-woody plants are exploited more for medicinal and food uses than annual and woody plants. In the context of ethnomedicinal uses, aerial plant parts particularly leaves are more extensively used for the preparation of herbal recipes as compared to underground parts. CONCLUSIONS: The results of the study emphasize the need to create awareness among the local communities about the conservation status of plant species in order to maintain a sustainable resource of plant-derived materials into the future. The novel econometric approach employed in this study adds a new insightful methodology to the existing body of literature in the field of ethnobotany. We strongly recommend conservation measures, alongside phytochemical and pharmacological studies on the useful plant species identified in this study in order to ensure their sustainable and effective utilization. PMID- 28647190 TI - Matrine inhibits bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway: An experimental study. AB - OBJECTIVE: To study the inhibitory effect of matrine on bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway. METHODS: Human T24 bladder cancer cell lines were cultured and treated with different doses of matrine (0.25 mg/mL, 0.5 mg/mL and 1.0 mg/mL) as well as 20 MUmol/L PI3K inhibitor LY294002 for 24 h, and the cell proliferation activity, the number of invasive cells as well as the expression of p-PI3K, p-AKT, proliferation genes and invasion genes were determined. RESULTS: Different doses of matrine could decrease the cell viability value, the number of invasive cells as well as the expression of p-PI3K, p-AKT, MMP2 and MMP9, and increase the expression of p16, p21 and p27 in dose-dependent manner; p16, p21 and p27 expression in cells of 20 MUmol/L LY29002 group were significantly higher than those of 0 MUmol/L LY29002 group while MMP2 and MMP9 expression were significantly lower than those of 0 MUmol/L LY29002 group (P < 0.05). CONCLUSIONS: Matrine can inhibit bladder cancer cell proliferation and invasion in vitro and regulate the expression of cell cycle-inhibiting molecules and invasion-related genes through PI3K/AKT signaling pathway. PMID- 28647191 TI - Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway: An experimental study. AB - OBJECTIVE: To study the effect of pyrrolidine dithiocarbamate (PDTC) on the anti tuberculosis drug-induced liver injury and the molecular mechanism. METHODS: Clean male SD rats were selected as experimental animals and randomly divided into normal group, model group, PDTC group and AG490 group. Animal model of anti tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC, and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention, the rats were executed, and the liver injury indexes, inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression, liver injury indexes, inflammation indexes and oxidative stress indexes in liver tissue were determined. RESULTS: p-JAK2, p STAT3, TNF-alpha, IL-1beta, IL-6, ROS, 8-OHdG and MDA expression in liver tissue as well as TBIL, ALT, AST, gamma-GT, TNF-alpha, IL-1beta, IL-6, 8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2, p-STAT3, TNF-alpha, IL-1beta, IL-6, ROS, 8-OHdG and MDA expression in liver tissue as well as TBIL, ALT, AST, gamma-GT, TNF-alpha, IL 1beta, IL-6, 8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. CONCLUSIONS: PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury. PMID- 28647192 TI - Genetic diversity and phylogenetic analysis of EG95 sequences of Echinococcus granulosus: Implications for EG95 vaccine application. AB - OBJECTIVE: To analyse the genetic variability of EG95 sequences and provide guidance for EG95 vaccine application against Echinococcus granulosus (E. granulosus). METHODS: We analysed EG95 polymorphism by collecting total 97 different E. granulosus isolates from 12 different host species that originated from 10 different countries. Multiple sequence alignments and the homology were performed by Lasergene 1 (DNASTAR Inc., Madison, WI), and the phylogenetic analysis was performed by using MEGA5.1 (CEMI, Tempe, AZ, USA). In addition, linear and conformational epitopes were analysed, including secondary structure, NXT/S glycosylation, fibronectin type III (FnIII) domain and glycosylphosphatidylinositol anchor signal (GPI-anchor). The secondary structure was predicted by PSIPRED method. RESULTS: Our results indicated that most isolates overall shared 72.6-100% identity in EG95 gene sequence with the published standard EG95 sequence, X90928. However, EG95 gene indeed has polymorphism in different isolates. Phylogenetic analysis showed that different isolates could be divided into three subgroups. Subgroup 1 contained 87 isolates while Subgroup 2 and Subgroup 3 consisted of 3 and 7 isolates, respectively. Four sequences cloned from oncosphere shared a high identity with the parental sequence of the current vaccine, X90928, and they belonged to Subgroup 1. However, in comparison to X90928, several amino acid mutations occurred in most isolates besides oncosphere, which potentially altered the immunodominant linear epitopes, glycosylation sites and secondary structures in EG95 genes. All these variations might change their previous antigenicity and thereby affecting the efficacy of current EG95 vaccine. CONCLUSIONS: This study reveals the genetic variability of EG95 sequences in different E. granulosus isolates, and proposed that more vaccination trials would be needed to test the effectiveness of current EG95 vaccine against distinct isolates in different countries. PMID- 28647193 TI - Cryopreserved venous allograft is an acceptable conduit in patients with current or prior angioaccess graft infection. AB - OBJECTIVE: The durability of cryopreserved allograft has been previously demonstrated in the setting of infection. The objective of this study was to examine the safety, efficacy, patency, and cost per day of graft patency associated with using cryopreserved allograft (vein and artery) for hemodialysis access in patients with no autogenous tissue for native fistula creation and with arteriovenous graft infection or in patients at high risk for infection. METHODS: Patients implanted with cryopreserved allograft for hemodialysis access between January 2004 and January 2014 were reviewed using a standardized, multi institutional database that evaluated demographic, comorbidity, procedural, and outcomes data. RESULTS: There were 457 patients who underwent placement of cryopreserved vein (femoral: n = 337, saphenous: n = 11) or artery (femoral: n = 109) for hemodialysis access at 20 hospitals. Primary indications for allograft use included high risk of infection in 191 patients (42%), history of infected prosthetic graft in 169 (37%), and current infection in 97 (21%). Grafts were placed more frequently in the arm (78%) than in the groin, with no difference in allograft conduit used. Mean time from placement to first hemodialysis use was 46 days (median, 34 days). Duration of functional graft use was 40 +/- 7 months for cryopreserved vein and 21 +/- 8 months for cryopreserved artery (P < .05), and mean number of procedures required to maintain patency at follow-up of 58 +/- 21 months was 1.6 for artery and 0.9 for vein (P < .05). Local access complications occurred in 32% of patients and included late thrombosis (14%), graft stenosis (9%), late infection (9%), arteriovenous access malfunction (7%), early thrombosis (3%), and early infection (3%). Early and late infections both occurred more frequently in the groin (P = .030, P = .017, respectively), and late thrombosis occurred more frequently with cryopreserved artery (P < .001). Of the 82 patients (18%) in whom the cryopreserved allograft was placed in the same location as the excised infected prosthetic graft, 13 had infection of the allograft during the study period (early: n = 4; late: n = 9), with no significant difference in infection rate (P = .312) compared with the remainder of the study population. The 1-, 3-, and 5-year primary patency was 58%, 35%, and 17% for cryopreserved femoral vein and 49%, 17%, and 8% for artery, respectively (P < .001). Secondary patency at 1, 3, and 5 years was 90%, 78%, and 58% for cryopreserved femoral vein and 75%, 53%, and 42% for artery, respectively (P < .001). Mean allograft fee per day of graft patency was $4.78 for cryopreserved vein and $6.97 for artery (P < .05), excluding interventional costs to maintain patency. CONCLUSIONS: Cryopreserved allograft provides an excellent conduit for angioaccess when autogenous tissue is not available in patients with current or past conduit infection. Cryopreserved vein was associated with higher patency and a lower cost per day of graft patency. Cryopreserved allograft allows for immediate reconstruction through areas of infection, reduces the need for staged procedures, and allows early use for dialysis. PMID- 28647195 TI - Adapting to a total endovascular approach for complex aortic aneurysm repair: Outcomes after fenestrated and branched endovascular aortic repair. AB - OBJECTIVE: This study reports the feasibility of adopting a total endovascular approach for the treatment of complex abdominal aortic aneurysms (AAAs) at a European aortic center and compares the short- and midterm results against those from large and multicenter studies. METHODS: All patients treated endovascular aortic repair (EVAR) for juxta/pararenal AAAs or thoracoabdominal aortic aneurysms (TAAAs), both elective and acute, as well as reoperations, from 2010 to 2015 were included. Treatment was fenestrated (FEVAR) or branched (BEVAR), and outcomes were analyzed for technical success and mortality at 30 and 90 days and by Kaplan-Meier curve estimates at 3 years. Outcomes on target vessels were reported as freedom from branch instability in the follow-up period. Reinterventions, endoleaks and perioperative and postoperative morbidities were analyzed. RESULTS: A total of 71 patients were treated for juxta/pararenal AAA (n = 40) or TAAA (n = 31): 14 type II, 4 type III, and 13 type IV. There were 47 FEVAR (including 2 physician-modified fenestrated grafts) and 24 BEVAR procedures performed. Four TAAAs were ruptured. No open repairs were performed for these pathologies in this period. Mortality was 2.8% (n = 2) at 30 days and 9.9% at 90 days (n = 7). One late rupture occurred in a patient whose treatment was a technical failure. Survival at 3 years was 77.9% +/- 5.6% overall, 90.9% +/- 5.2% for juxta/pararenal AAAs, and 60.7% +/- 10.3% for TAAAs. Graft deployment was successful in 69 of 71 patients. Revascularization was successful in 205 of 208 target vessels (98.6%): 51 of 51 superior mesenteric arteries, 27 of 27 celiac arteries, and 127 of 130 renal arteries. There were 131 fenestrated bridging stent grafts and 74 branched bridging stent grafts. Technical success was 68 of 71 (95.7%). There were nine cases of branch instability (5 BEVARs, 4 FEVARs) in five patients (7.0%). Seven vessels (5 renal arteries and 2 superior mesenteric arteries) underwent reintervention: 5 for stenoses, 1 for occlusion, and 1 for stent migration. Freedom from branch instability at 3 years was 92.7% +/- 2.5% overall, 88.6% +/- 6.4% for BEVAR, and 94.6% for FEVAR. CONCLUSIONS: The short- and midterm results obtained here indicate that the benefits of a total endovascular treatment for complex aortic aneurysms, as demonstrated by large and multicenter studies, can be adapted and replicated at other centers with a dedicated aortic service. This may help guide future considerations of how to refer or treat this complex patient group. PMID- 28647194 TI - Prediction of 6-minute walk performance in patients with peripheral artery disease. AB - BACKGROUND: Peripheral artery disease (PAD) is a highly prevalent disease that impairs walking ability. Walking tests, such as the 6-minute walk test (6MWT) and 4-meter walk test, are commonly used to assess exercise endurance and ambulatory function over a short distance, respectively. The 6MWT performance is predictive of PAD severity and disease outcomes, but it is not feasible in many clinical settings because it requires a long walkway to serve as the test route and lengthens clinic visits. As an alternative, the 4-meter walk test is convenient, inexpensive, and repeatable, but whether it accurately predicts endurance performance in the long-distance 6MWT is not known. The goal of this study was to develop a statistical model to predict 6MWT gait speed from 4-meter walk test results and clinical characteristics among patients with PAD. METHODS: Measures of 6MWT gait speed were derived from 183 patients with symptomatic PAD who were evaluated at the University of Oklahoma Health Sciences Center (2004-2012). The testing procedures and research personnel remained constant throughout the duration of the study. Independent variables included demographic and clinical information and 4-meter walk test gait speed. Fivefold cross validation and manual backward selection were used for model selection. Adjusted R2 and corrected Akaike information criterion were applied to quantify the predictive performance of the regression models. RESULTS: A total of 183 people (54% male; mean age, 65 [standard deviation (SD), 10] years) with moderate PAD severity (ankle-brachial index [ABI]; mean, 0.72 [SD, 0.24]) performed the walking tests. Participants covered an average distance of 335 (SD, 97) m distance in the 6MWT. The 4-meter walk gait speed, ABI, and dyspnea were independent predictors of 6MWT speed in the multivariate model (adjusted R2 = 0.55). The model resulted in 95% prediction interval widths of 30 m for mean and 260 m for individual predicted 6MWT distance measures. CONCLUSIONS: Slower 4-meter walking speed, lower ABI, and presence of dyspnea all predict slower 6MWT gait speed, which corresponds to shorter 6MWT distance. Prediction of group means is reasonably precise; however, prediction of individual patient 6MWT performance is imprecise relative to between-group differences that are clinically important. PMID- 28647197 TI - Characterizing tissue perfusion after lower extremity intervention using two dimensional color-coded digital subtraction angiography. AB - OBJECTIVE: Digital subtraction angiography (DSA) of the peripheral arterial vasculature provides lumenographic information but only a qualitative assessment of blood flow. The ability to quantify adequate tissue perfusion of the lower extremities would enable real-time perfusion assessment during DSA of patients with peripheral arterial disease (PAD). In this study, we used a novel real-time imaging software to delineate tissue perfusion parameters in the foot in PAD patients. METHODS: Between March 2015 and June 2016, patients (N = 31) underwent lower extremity angiography using a two-dimensional perfusion (2DP) imaging protocol (Philips Healthcare, Andover, Mass). Of the 31 enrolled patients, 16 patients received preintervention and postintervention DSA images (18 angiograms), while contrast agent injection settings and the position of the foot, catheter, and C-arm were kept constant. The region of interest for perfusion measurements was taken at the level of the medial malleolus. Perfusion parameters included arrival time (AT) of contrast material, wash-in rate (WIR), time to peak (TTP) contrast intensity, and area under the curve (AUC). RESULTS: Patients (mean age, 67 years; male, 61%) undergoing 2DP had limbs classified as Rutherford class 3 (n = 9 limbs), class 4 (n = 11), and class 5 (n = 14) ischemia with a mean ankle-brachial index of 0.63. For the whole cohort, median (interquartile range) AT measured 5.20 (3.10-7.25) seconds; WIR, 61.95 (43.53 86.43) signal intensity (SI)/s; TTP, 3.80 (2.88-4.50) seconds; peak intensity, 725.00 (613.75-1138.00) SI; and AUC, 12,084.00 (6742.80-17,059.70) SI*s. A subset of patients had 2DP performed before and after intervention (n = 18 cases). A detectable improvement in SI and two-dimensional flow parameters was seen after intervention. Average AT of contrast material to the region of interest shortened after intervention with percentage decrease of 30.1% +/- 49.1%, corresponding decrease in TTP of 17.6% +/- 24.7%, increase in WIR of 68.8% +/- 94.2% and in AUC of 10.5% +/- 37.6%, decrease in mean transit time of 18.7% +/- 28.1%, and increase in peak of 34.4% +/- 42.2%. CONCLUSIONS: The 2DP imaging allows measurement of blood flow in real time as an adjunct to DSA. The AT may be the most sensitive marker of perfusion change in the lower extremity. Quantitative thresholds based on 2DP hold promise for immediate treatment effectiveness assessment in patients with PAD. PMID- 28647196 TI - Smooth muscle cells of human veins show an increased response to injury at valve sites. AB - OBJECTIVE: Venous valves are essential but are prone to injury, thrombosis, and fibrosis. We compared the behavior and gene expression of smooth muscle cells (SMCs) in the valve sinus vs nonvalve sites to elucidate biologic differences associated with vein valves. METHODS: Tissue explants of fresh human saphenous veins were prepared, and the migration of SMCs from explants of valve sinus vs nonvalve sinus areas was measured. Proliferation and death of SMCs were determined by staining for Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling. Proliferation and migration of passaged valve vs nonvalve SMCs were determined by cell counts and using microchemotaxis chambers. Global gene expression in valve vs nonvalve intima-media was determined by RNA sequencing. RESULTS: Valve SMCs demonstrated greater proliferation in tissue explants compared with nonvalve SMCs (19.3% +/- 5.4% vs 6.8% +/- 2.0% Ki67-positive nuclei at 4 days, respectively; mean +/- standard error of the mean, five veins; P < .05). This was also true for migration (18.2 +/- 2.7 vs 7.5 +/- 3.0 migrated SMCs/explant at 6 days, respectively; 24 veins, 15 explants/vein; P < .0001). Cell death was not different (39.6% +/- 16.1% vs 41.5% +/- 16.0% terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, respectively, at 4 days, five veins). Cultured valve SMCs also proliferated faster than nonvalve SMCs in response to platelet-derived growth factor subunit BB (2.9 +/- 0.2-fold vs 2.1 +/- 0.2-fold of control, respectively; P < .001; n = 5 pairs of cells). This was also true for migration (6.5 +/- 1.2-fold vs 4.4 +/- 0.8-fold of control, respectively; P < .001; n = 7 pairs of cells). Blockade of fibroblast growth factor 2 (FGF2) inhibited the increased responses of valve SMCs but had no effect on nonvalve SMCs. Exogenous FGF2 increased migration of valve but not of nonvalve SMCs. Unlike in the isolated, cultured cells, blockade of FGF2 in the tissue explants did not block migration of valve or nonvalve SMCs from the explants. Thirty-seven genes were differentially expressed by valve compared with nonvalve intimal-medial tissue (11 veins). Peptide-mediated inhibition of SEMA3A, one of the differentially expressed genes, increased the number of migrated SMCs of valve but not of nonvalve explants. CONCLUSIONS: Valve compared with nonvalve SMCs have greater rates of migration and proliferation, which may in part explain the propensity for pathologic lesion formation in valves. Whereas FGF2 mediates these effects in cultured SMCs, the mediators of these stimulatory effects in the valve wall tissue remain unclear but may be among the differentially expressed genes discovered in this study. One of these genes, SEMA3A, mediates a valve specific inhibitory effect on the injury response of valve SMCs. PMID- 28647198 TI - Trends in open abdominal exposure among vascular surgery trainees. AB - BACKGROUND: This retrospective study evaluates the trends in open abdominal surgery cases among integrated vascular surgery residents compared with their 5 + 2 counterparts. METHODS: The Accreditation Council for Graduate Medical Education (ACGME) case logs between 2007 and 2016 were collected from a pool of 9861 residents and fellows from 371 institutions. Trainees were grouped into three categories: general surgery residency (GSR), integrated vascular surgery residency (IVSR), and vascular surgery fellowship in the United States. Inclusion criteria were specific to open abdominal cases of or including the anatomy adjacent to the aorta performed by the surgeon chief. RESULTS: The 5 + 2 graduates have obtained significantly more open vascular surgery training experience than their IVSR graduate counterparts (P < .01). GSR chief residents performed significantly more open abdomen cases than IVSR chief residents (P < .01). IVSR chiefs performed significantly more open vascular procedures than GSR chiefs (P < .01). On the completion of vascular surgery fellowship, 5 + 2 graduates had significantly more open abdominal aortic aneurysm (AAA) exposure during training than IVSR graduates did (P < .01); however, IVSR trainees had performed significantly more open AAA procedures than their GSR counterparts (P < .01). CONCLUSIONS: Up to 2016, graduates of the 5 + 2 vascular training pathway had significantly higher open abdominal exposure than those of the IVSR track. However, graduates of the IVSR track had significantly higher open AAA exposure than GSR graduates. PMID- 28647199 TI - Influence of frailty on treatment outcomes after revascularization in patients with critical limb ischemia. AB - OBJECTIVE: It is unclear whether frailty adversely affects treatment outcomes in patients with critical limb ischemia (CLI). The aim of this study was to investigate the influence of frailty on CLI patients after revascularization. METHODS: Patients undergoing infrapopliteal revascularization between 2007 and 2015 were retrospectively analyzed. The patient was defined as CLI frail when two or more of the following were present: low Geriatric Nutritional Risk Index, low skeletal muscle mass index, or nonambulatory status. The primary study end point was 2-year amputation-free survival (AFS). To analyze the diagnostic criteria of frailty, the CLI Frailty Index was compared with a modified Frailty Index using a receiver operating characteristic area under the curve. The secondary end points were occurrence of Clavien-Dindo class IV complications and 30-day or hospital mortality. RESULTS: During the study period, 266 patients and 325 limbs underwent infrapopliteal revascularization. The AFS rate 1 year and 2 years after revascularization was 81.8% and 72.9% for the CLI frail- group vs 45.8% and 34.0% for the CLI frail+ group (P < .001), respectively. Multivariate analysis revealed that the CLI Frailty Index (hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.78-4.32; P < .001) and hemodialysis (HR, 1.72; 95% CI, 1.11-2.69; P = .02) were risk factors for AFS 2 years after revascularization. The CLI Frailty Index area under the curve was 0.72 compared with 0.63 for the modified Frailty Index (P = .01). Only the CLI Frailty Index was found to be a risk factor for morbidity (HR, 3.21; 95% CI, 1.45-7.27; P = .004) and 30-day or hospital mortality (HR, 6.32; 95% CI, 1.43-43.7; P = .01). CONCLUSIONS: The CLI Frailty Index is a risk factor for 2-year AFS in CLI patients after revascularization. This result could prove useful for prognostic prediction and decision-making in selection of bypass surgery or endovascular therapy as a first treatment strategy. PMID- 28647200 TI - Racial disparities after infrainguinal bypass surgery in hemodialysis patients. AB - BACKGROUND: Peripheral arterial disease poses a significant burden in the hemodialysis (HD)-dependent population. Race is a known modifier of outcomes after surgical treatment of peripheral arterial disease. A comprehensive evaluation of the effect of race on infrainguinal bypass surgery (IBS) outcomes in HD patients is lacking. In this study, we evaluated the effects of race on long-term IBS outcomes in a large, nationally representative cohort of HD patients. METHODS: We studied all HD patients who underwent IBS between January 2007 and December 2011 in the United States Renal Disease System-Medicare matched database. Univariate methods were used to compare patients' demographic and medical characteristics. Kaplan-Meier, univariate and multivariable logistic, and Cox regression analyses were used to evaluate long-term graft patency, limb salvage, and mortality. RESULTS: There were 9305 IBSs performed in 5188 white (56%), 3354 black (36%), and 763 Hispanic (8%) patients. Of these, 4531 (49%) were femoral-popliteal, 3173 (34%) were femoral-tibial, and 1601 (17%) were popliteal-tibial bypasses. Comparing whites vs blacks vs Hispanics, acute graft failure was 14% vs 16% vs 15% (P = .03), with no statistical difference on multivariate analyses. Primary patency was 52% vs 45% vs 48% at 1 year and 24% vs 21% vs 26% at 4 years (P < .001). Primary assisted patency was 56% vs 48% vs 53% at 1 year and 29% vs 25% vs 32% at 4 years (P < .001); secondary patency was 65% vs 56% vs 60% at 1 year and 40% vs 33% vs 40% at 4 years (P < .001). Limb salvage was 68% vs 60% vs 62% at 1 year and 45% vs 42% vs 40% at 4 years (P < .001). Black patients had higher long-term graft failure (adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 1.05-1.24; P = .001) and limb loss (aHR, 1.27; 95% CI, 1.15-1.40; P < .001) compared with white patients. No differences in graft failure (aHR, 0.99; 95% CI, 0.89-1.11; P = .89) and limb loss (aHR, 1.08; 95% CI, 0.94-1.23; P = .28) were found in Hispanics vs whites. All-cause mortality was lower among blacks (aHR, 0.65; 95% CI, 0.60-0.71; P < .001) and Hispanics (aHR, 0.67; 95% CI, 0.59-0.75; P < .001) compared with whites. CONCLUSIONS: This large study confirms the presence of multidirectional racial disparities in graft durability, limb salvage, and mortality after IBS in HD patients. Black patients had lower graft patency and higher limb loss than white and Hispanic patients, whereas perioperative and long-term mortality was higher in white patients. These results should inform further granular root cause analyses and subsequent action to eliminate these disparities. PMID- 28647201 TI - Axis Misalignment of Toric Intraocular Lens: Placement Error and Postoperative Rotation. PMID- 28647202 TI - The Current State of Teleophthalmology in the United States. AB - Telemedicine services facilitate the evaluation, diagnosis, and management of the remote patient. Telemedicine has rapidly flourished in the United States and has improved access to care, outcomes, and patient satisfaction. However, the use of telemedicine in ophthalmology is currently in its infancy and has yet to gain wide acceptance. Current models of telemedicine in ophthalmology are largely performed via "store and forward" methods, but remote monitoring and interactive modalities exist. Although studies have examined the effects of telemedicine, few reports have characterized its current status. We perform a descriptive analysis of the current state of teleophthalmology in the United States. We describe the use of teleophthalmology in the hospital and outpatient settings. We also review the applications to retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and glaucoma, as well as anticipated barriers and hurdles for the future adoption of teleophthalmology. With ongoing advances in teleophthalmology, these models may provide earlier detection and more reliable monitoring of vision-threatening diseases. PMID- 28647204 TI - Return to competition after an Achilles tendon rupture using both on and off the field load monitoring as guidance: A case report of a top-level soccer player. AB - OBJECTIVES: To describe the Return to competition after Achilles Tendon rupture (ATR) in an elite soccer player. DESIGN: Case report. SETTING: Return to sport (RTS) of a professional soccer player who suffered an ATR during a match. The RTS phase started 15 weeks after surgery and specific on-field activities were gradually introduced. Criteria used to monitor the transition through the different phases were strength and endurance of the calf muscle and ability to sustain specific on-field training loads (TL) monitored with Global Positioning System and heart-rate system. TLs were weekly compared to pre-injury values to evaluate recovery and to prescribe future sessions. PARTICIPANT: A 39-year-old (height 178 cm, weight 75 kg) elite soccer defender player, playing in Italian Serie-A league. RESULTS: Days of absence were lower compared to a cohort presented in UEFA study (119 versus 161 +/- 65 days, respectively). External-TL and Internal-TL were organized to gradually increase during RTS and resulted in higher values prior to return to competition compared to pre-injury values. Concentric plantar flexion peak torque increased till 9th months after surgery. CONCLUSIONS: Monitoring of the field activities allowed comparison with pre injury values and provided a useful and functional criteria to pass return to team activity and competition. PMID- 28647203 TI - Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results. AB - PURPOSE: To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). DESIGN: Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. PARTICIPANTS: Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. METHODS: Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 months (group 2), and 2 participants with unilateral visual loss (group 3) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included visual acuity, visual fields, optical coherence tomography, pattern electroretinography, and neuro-ophthalmic examinations. Generalized estimating equation methods were used for longitudinal analyses. MAIN OUTCOME MEASURE: Loss of visual acuity. RESULTS: For groups 1 and 2, month 12 average acuity improvements with treatment relative to baseline were 0.24 logarithm of the minimum angle of resolution (logMAR). Fellow eyes had a 0.09-logMAR improvement. A post hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in group 2 patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (P = 0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute group 2 gene therapy patients of 0.96 was more than that observed in our prior acute natural history patients (0.17 logMAR; P < 0.001). Two patients demonstrated asymptomatic uveitis that resolved without treatment. Optical coherence tomography of treated eyes showed an average temporal retinal nerve fiber layer thickness of 54 MUm before injection and 55 MUm at month 12. For fellow eyes before injection, it was 56 MUm, decreasing to 50 MUm at month 12 (P = 0.013). Generalized estimating equations suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by approximately 0.05 MUV (P = 0.009 exchangeable). No difference between eyes in outcomes of other visual function measures was evident. CONCLUSIONS: Allotopic gene therapy for LHON at low and medium doses seems to be safe and does not damage the temporal retinal nerve fiber layer, opening the door next for testing of the high dose. PMID- 28647205 TI - Measurement properties of visual rating of postural orientation errors of the lower extremity - A systematic review and meta-analysis. AB - OBJECTIVES: To systematically review measurement properties of visual assessment and rating of Postural Orientation Errors (POEs) in participants with or without lower extremity musculoskeletal disorders. METHODS: A systematic review according to the PRISMA guidelines was conducted. The search was performed in Medline (Pubmed), CINAHL and EMBASE (OVID) databases until August 2016. Studies reporting measurement properties for visual rating of postural orientation during the performance of weight-bearing functional tasks were included. No limits were placed on participant age, sex or whether they had a musculoskeletal disorder affecting the lower extremity. RESULTS: Twenty-eight articles were included, 5 of which included populations with a musculoskeletal disorder. Visual rating of the knee-medial-to-foot position (KMFP) was reliable within and between raters, and meta-analyses showed that this POE was valid against 2D and 3D kinematics in asymptomatic populations. Other segment-specific POEs showed either poor to moderate reliability or there were too few studies to permit synthesis. Intra rater reliability was at least moderate for POEs within a task whereas inter rater reliability was at most moderate. CONCLUSIONS: Visual rating of KMFP appears to be valid and reliable in asymptomatic adult populations. Measurement properties remain to be determined for POEs other than KMPF. PMID- 28647206 TI - CT at onset of chronic lung allograft dysfunction in lung transplant patients predicts development of the restrictive phenotype and survival. AB - PURPOSE: To describe early signs for restrictive subtype of chronic lung allograft dysfunction (CLAD) after lung transplantation in computed tomography (CT) and to evaluate the predictive value for disease progression and survival. MATERIAL AND METHODS: 52 CT examinations in lung transplant patients at CLAD onset were scored for CT features referring to airways disease, parenchymal or pleural abnormality. Patients with and without later development of restrictive CLAD (TLC<=80%) were compared. A radiological score for inflammation including pleural effusion, central and peripheral ground glass opacities and consolidations was calculated and used for survival analysis. RESULTS: CT of patients with later development of restrictive CLAD showed significantly more often abnormalities at CLAD onset, in particular consolidations (57% vs. 4%; p<0.001) and ground glass attenuations (71% vs. 7%; p<0.001) than those of patients without the restrictive phenotype. CT score for inflammation was significantly higher in patients with than without later restrictive CLAD (3.4 vs. 0.6; p<0.001). Survival of patients with a high score (>2) for inflammation in CT at CLAD onset was significantly lower than of those with a low score (443 vs. 2415 days; p=0.019). CONCLUSIONS: CT at CLAD onset differs in patients with/without later development of the restrictive phenotype. It is therefore an indicator for future development of restrictive CLAD and predictor for survival. It should be implemented in the diagnostic work-up at diagnosis of CLAD. PMID- 28647207 TI - Clinical value of miR-425-5p detection and its association with cell proliferation and apoptosis of gastric cancer. AB - Researches have shown that miR-425-5p expression altered in lung, esophageal, and glial cancer. Similarly, in our previous study, we found miR-425-5p expression was up-regulated in GC cells and could promote gastric cancer (GC) cell invasion and metastasis. However, the functional mechanism and the prognostic significance of miR-425-5p in GC remain unclear. Therefore, the present study examined miR-425 5p expression in GC tissues and also evaluated miR-425-5p of the therapeutic and prognostic value. Moreover, with interference of miR-425-5p expression in cell lines, we investigated the molecular mechanism of miR-425-5p and the expression level was higher in GC tissues comparing with that in gastric tumor-adjacent mucosa. These results suggested that miR-425-5p over-expression may be associated with depth of invasion and TNM stages and can be a prognostic marker of poor outcome. After inhibition of miR-425-5p expression in MKN45 cells, the cell activity was weakened. The number of G0/G1 cells increased while G2/M and S cells decreased, and the cell apoptotic rates elevated (P<0.05). Some proliferation and apoptosis related genes were altered (P<0.05). Consequently, miR-425-5p can be considered as a marker of poor prognosis and it is probably involved in GC cell proliferation and apoptosis by regulating some of the genes which participate these processes. PMID- 28647208 TI - MAGE-A family is involved in gastric cancer progression and indicates poor prognosis of gastric cancer patients. AB - BACKGROUND: As the best characterized CTA family members, melanoma-associated antigens (MAGE) have been reported to express in various malignant tumors. However, the expression pattern of MAGE-A family in gastric cancer (GC) specimens and their prognostic and therapeutic significance for GC patients is still unclear. MATERIALS AND METHODS: Tissue microarray - based immunohistochemistry analysis was used to examine the expression of MAGE-A family members (including MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12) in 86 cases of GC specimens, 20 cases of the corresponding adjacent normal gastric specimens, and 9 cases of intraepithelial neoplasia specimens. The association between MAGE-A expression and the clinicopathological parameters as well as the 5-year overall survival of GC patients was analyzed. RESULTS: 54.7% of GC specimens showed positive MAGE-A expression. In the adjacent normal gastric specimens, MAGE-A was not expressed in the normal surface mucous cells, but expressed in some normal fundic glands. In addition, MAGE-A expression was also detected in intraepithelial neoplasia specimens. In GC specimens, MAGE-A expression was associated with lymph node metastasis, poor differentiation, and high clinical TNM stage. MAGE-A expression was also correlated with the poor 5-year overall survival of GC patients. However, MAGE-A expression is not an independent prognostic factor for GC patients. CONCLUSIONS: MAGE-A family may be involved in the gastric cancer progression, and their expression could be considered to improve the prognostic evaluation for GC patients. PMID- 28647209 TI - Decreased expression of the ATM gene linked to poor prognosis for gastric cancer of different nationalities in Xinjiang. AB - OBJECTIVE: To explore the clinicopathological significance of ATM gene in the occurrence and prognosis of gastric cancer (GC) from different nationalities in Xinjiang. METHOD: The expression of ATM in 385 patients with GC (including 98 Uygurs, 231 Hans and 56 Kazaks) and its corresponding adjacent tissues were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry assay to, analyze its correlations with clinicopathological features and prognosis of GC. RESULTS: The ATM expression in GC tissues was significantly decreased when compared to that in adjacent normal tissues of Uygur, Han and Kazak patients in Xinjiang, while Uygurs and Kazaks were much lower than Hans in the ATM expression of GC tissues (all P<0.05). Kaplan-Meier analysis showed that Uygur and Kazak patients with ATM-negative tumors had a markedly lower survival rate than patients in Hans (P=0.028), and GC patients with ATM negative expression presented more unfavorable overall survival rate than those with positive expression among the three different nationalities (all P<0.05). Multivariate Cox regression analysis revealed that nationality, ATM expression, TNM staging, depth of invasion, and lymph node metastasis were independent factors affecting the prognosis of GC patients in Xinjiang (all P<0.05). CONCLUSION: ATM was downregulated in GC patients in Xinjiang, especially for Uygurs and Kazaks, which suggested ATM to be an independent indicator of prognosis for GC therapy. PMID- 28647210 TI - High expression levels of Cyr61 and VEGF are associated with poor prognosis in osteosarcoma. AB - Cysteine Rich Angiogenic Inducer 61 (Cyr61) and Vascular Endothelial Growth Factor (VEGF) are signaling proteins involved in the regulation of tumor angiogenesis and progression. The purpose of this study was to investigate the clinicopathological and prognostic significance of Cyr61 and VEGF expressions in osteosarcoma. Immunohistochemical staining was performed to evaluate the expression of both the proteins in 84 osteosarcoma samples. Correlation between Cyr61/VEGF expressions and clinicopathological parameters was determined using Rank sum test and Spearman's rank correlation coefficient. Prognostic factors were identified using univariate and multivariate Cox regression analysis. The expressions of Cyr61 and VEGF were weak in 26.2% and 17.9%, moderate in 26.2% and 23.8%, and strong in 47.6% and 58.3% of osteosarcoma samples, respectively. Cyr61 and VEGF expressions moderately correlated with each other in osteosarcoma, and exhibited significant association with Enneking stage and distant metastasis. In addition, the high expression of both proteins significantly correlated with short overall survival time in these patients. The key finding in this study was that both Cyr61 and VEGF expressions were independent prognostic indicators of overall survival. In summary, our results indicate that expression of Cyr61 and VEGF may serve as important prognostic predictors in patients with osteosarcoma. PMID- 28647211 TI - Tubuloreticular inclusions in peritubular capillaries of renal allografts. AB - BACKGROUND: Tubuloreticular inclusions (TRIs) are anastomosing networks of microtubules that are frequently found in autoimmune diseases and viral infections. In renal allografts, TRIs have been reported in glomerular endothelial cells in association with viral infections and donor specific antibodies (DSAs), but their presence in peritubular capillaries has not been explored. METHODS: We collected seven cases with TRIs out of 148 consecutive renal allograft biopsies taken from Dec. 2015 to Dec. 2016. RESULTS: TRIs were present in peritubular capillaries in seven cases and were concomitantly present in glomerular endothelial cells in two cases. The diagnoses included polyomavirus nephropathy (n=2), acute T cell-mediated rejection (ACR) (n=1), combined ACR and antibody-mediated rejection (AMR) (n=1), suspicious for ACR (n=1), chronic active AMR (n=1), and moderate tubular atrophy and interstitial fibrosis (n=1). Six patients had recent or current viral infections (BK polyomavirus, hepatitis B virus, herpes simplex virus, and cytomegalovirus in two, two, one, and one case, respectively). DSA was positive in one case. Five cases had moderate to severe interstitial inflammation and four cases had peritubular capillaritis. CONCLUSION: TRIs are not rare in peritubular capillaries. They are associated with various viral infections and their appearance seems to be related to peritubular capillary injury. PMID- 28647212 TI - Combined primary hepatic neuroendocrine carcinoma and hepatocellular carcinoma with aggressive biological behavior (adverse clinical course): A case report. AB - Combined primary hepatic neuroendocrine carcinoma (PHNEC) and hepatocellular carcinoma (HCC) is a very rare malignant hepatic tumor. Its prognosis and histological features are uncertain. Here we report the case of such a tumor in a 70-year-old male Japanese patient with adverse prognosis. The patient underwent a right hepatic lobectomy for a tumor mass that measured 11*10cm in diameter located in the right lobe of the liver, treated with transcatheter arterial chemoembolization (TACE) and percutaneous transhepatic portal vein embolization (PTPE) therapy five weeks before the operation. Histologically, the hepatic tumor was composed of predominantly HCC and admixed with a small part of neuroendocrine carcinoma (NEC). The NEC component was distributed as a collision-type tumor separated by fibrous bands from HCC and the combined-type tumor, focally intermingling with HCC. One month after the surgery, metastasis to abdominal lymph nodes and the lumbar vertebra was detected. Although the additional treatments of systematic chemotherapy and radiation therapy were performed, the patient died 3 months after the initial surgery. PMID- 28647213 TI - Evaluating a medical directive for nurse-initiated analgesia in the Emergency Department. AB - OBJECTIVES: Although acute pain is a common presentation in the Emergency Department (ED), analgesics are often delayed until the patient is seen by a physician. We assessed the effect of a medical directive for nurse-initiated analgesia on time to first dose of analgesics, proportion of patients receiving analgesics in less than 30min, and total length of stay in the ED. METHODS: A medical directive for nurse-initiated analgesia was introduced in our ED in October 2011. This before-after health record review included all patients presenting to the ED with musculoskeletal back pain in 4month periods before and after implementation of the medical directive. RESULTS: A total of 524 cases were reviewed, of which 401 were included - 201 and 200 in the before and after implementation groups respectively. After implementation there was a shorter time to first dose of analgesic (mean of 118 vs 160min, p<0.001), and a higher proportion of patients receiving analgesics in the first 30min (20% vs 4%, p<0.001). However there was no difference in total proportion of patients receiving analgesics (71% vs 67%, p=0.46) or total length of stay in the ED (337 vs 323min, p=0.51). CONCLUSIONS: A medical directive for nurse-initiated analgesia in the ED was associated with significantly reduced time to the first dose of analgesic, and increased the proportion of patients receiving analgesics within 30min. We can conclude that medical directives for nurse-initiated analgesia effectively improve the timeliness and quality of care for patients with acute pain. PMID- 28647214 TI - Development and in vivo evaluation of functionalized ritonavir proliposomes for lymphatic targeting. AB - AIMS: The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4+ T cells in the lymphatic system. MATERIALS AND METHODS: The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies. KEY FINDINGS: The mean particle size was found to be in the range of 126.6 to 306.2nm with PDI of 0.340-1.00. The entrapment efficiency was found to be in the range of 18.9 to 86.2%. The formulations showed a zeta potential in the range of -18.1 to -20.2mv. Biotinylated proliposomes (LIP-5B) were in the size of 149.8+/-6.8nm with entrapment efficiency 61.6%. The % CDR of pure drug, conventional, biotinylated proliposome in 3h was found to be 58.3, 82.04, and 95.9% respectively. In vitro drug release and in vivo pharmacokinetics of the pure drug, optimized conventional proliposomes (LIP-5) and biotin proliposomes (LIP-5B) were executed. SIGNIFICANCE: The AUC for the liposomes were found to be much higher in the spleen and thymus compared to that in the plasma which indicated that the developed formulations enhance the bioavailability and target specificity compared to that of the pure drug thereby enhancing bioavailability at target site. PMID- 28647215 TI - Reply to Eugenio Ventimiglia, Paolo Capogrosso, Walter Cazzaniga, Francesco Montorsi, and Andrea Salonia's Letter to the Editor re: Giovanni Corona, Giulia Rastrelli, Abraham Morgentaler, Alessandra Sforza, Edoardo Mannucci, Mario Maggi. Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. Eur Urol 2017;72:1000-11. PMID- 28647216 TI - Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging? AB - BACKGROUND: The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged >=70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio. OBJECTIVE: To assess the potential of a risk-based strategy including MRI to selectively identify men aged >=70 yr with high-grade PCa. DESIGN, SETTING, AND PARTICIPANTS: Three hundred and thirty-seven men with prostate-specific antigen >=3.0 ng/ml at a fifth screening (71-75 yr) in the European Randomized study of Screening for Prostate Cancer Rotterdam were biopsied. One hundred and seventy nine men received six-core transrectal ultrasound biopsy (TRUS-Bx), while 158 men received MRI, 12-core TRUS-Bx, and fusion TBx in case of Prostate Imaging Reporting and Data System >=3 lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the overall, low-grade (Gleason Score 3+3) and high-grade (Gleason Score >= 3+4) PCa rate. Secondary outcome was the low- and high-grade PCa rate detected by six-core TRUS-Bx, 12-core TRUS-Bx, and MRI +/- TBx. Tertiary outcome was the reduction of biopsies and low-grade PCa detection by upfront risk stratification with the Rotterdam Prostate Cancer Risk Calculator 4. RESULTS AND LIMITATIONS: Fifty-five percent of men were previously biopsied. The overall, low-grade, and high-grade PCa rates in biopsy naive men were 48%, 27%, and 22%, respectively. In previously biopsied men these PCa rates were 25%, 20%, and 5%. Sextant TRUS-Bx, 12-core TRUS-Bx, and MRI +/- TBx had a similar high grade PCa rate (11%, 12%, and 11%) but a significantly different low-grade PCa rate (17%, 28%, and 7%). Rotterdam Prostate Cancer Risk Calculator 4-based stratification combined with 12-core TRUS-Bx +/- MRI-TBx would have avoided 65% of biopsies and 68% of low-grade PCa while detecting an equal percentage of high grade PCa (83%) compared with a TRUS-Bx all men approach (79%). CONCLUSIONS: After four repeated screens and >=1 previous biopsies in half of men, a significant proportion of men aged >=70 yr still harbor high-grade PCa. Upfront risk stratification and the combination of MRI and TRUS-Bx would have avoided two thirds of biopsies and low-grade PCa diagnoses in our cohort, while maintaining the high-grade PCa detection of a TRUS-Bx all men approach. Further studies are needed to verify these results. PATIENT SUMMARY: Prostate cancer screening reduces mortality but is accompanied by unnecessary biopsies and overdiagnosis of nonaggressive tumors, especially in repeatedly screened elderly men. To tackle these drawbacks screening should consist of an upfront risk-assessment followed by magnetic resonance imaging and transrectal ultrasound-guided biopsy. PMID- 28647217 TI - Recognition and Management of Hemostatic Disorders in Critically Ill Patients Needing to Undergo an Invasive Procedure. AB - Abnormal laboratory coagulation test results are frequently documented in critically ill patients, and these patients often also need to undergo invasive procedures. Clinicians have an understandable desire to minimize any perceived heightened risk of bleeding complications in those patients who require invasive procedures. In this setting, prophylactic administration of platelets or plasma is commonplace. This review explores the nature of these sequential statements and the degree to which these statements are supported by evidence. We discuss the complexity of managing the low risk of procedure-related bleeding in a setting where coagulation tests fail to reliably predict this risk. The role of prophylactic transfusion of platelets and plasma and correction of medication induced coagulopathy is also reviewed. New strategies are required to improve the evidence base, including novel methodological approaches or the use of a clinical scoring system. PMID- 28647218 TI - The environmental performance of SMEs in the Brazilian textile industry and the relationship with their financial performance. AB - Currently, the concern with the environment is increasing and organizations seek solutions to preserve nature and at the same time earn higher profits or competitiveness. For this, they make frequent use of structured procedures in order to reduce their costs and expenses. However, it has not been always considered the environmental performance related to the financial performance of these processes. Therefore, this study aimed to investigate the relationship between environmental performance measured by eco-efficiency level with the financial performance of small and medium textile manufacturing companies. This study was done through a survey conducted in the interest of research companies in the state of Parana in Brazil, where financial and environmental performance indicators were measured. The data analysis and validation of the hypotheses proposed, to some extent showed a surprising result because the larger the size of the company, the worst its environmental performance measured by their eco efficiency level. On the other hand, it was not possible to identify a statistically significant relationship between environmental and financial performances of the companies surveyed. Therefore, it is concluded that this study is in line with those authors who claim not to be possible to establish a direct relationship between environmental and financial performances of companies, in opposition of another group of authors who claim contrariwise. PMID- 28647219 TI - Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections. AB - BACKGROUND/PURPOSE: Aspergillus-associated infection might comprise up to 23-29% of severe influenza patients from the community throughout stay in an intensive care unit (ICU). In Taiwan, cases of severe influenza with aspergillosis are increasingly reported. Therefore, we describe the relative risk of mortality among severe influenza patients with aspergillosis and other coinfections compared to severe influenza patients without Aspergillus coinfections. METHODS: We retrospectively reviewed 124 adult patients with severe influenza in a tertiary medical center in southern Taiwan from January 2015 through March 2016. The definition of probable aspergillosis required abnormal radiological findings and positive Aspergillus galactomannan (GM) antigen and/or Aspergillus isolation. RESULTS: Probable aspergillosis (detected throughout the whole course) and other coinfections (only community-acquired) were diagnosed in 21 (17%) and 38 (31%) of all patients respectively. Klebsiella pneumoniae (36.8%), Pseudomonas aeruginosa (31.6%) and Staphylococcus aureus (31.6%) were the most frequent isolates of other coinfections. In-ICU mortality of Aspergillus group (66.7%) was significantly higher than other coinfections (23.7%, p = 0.001) or control group without coinfections (15.4%, p < 0.001), with significant odds ratios after adjusting for important variables. The factor of GM index >=0.6 had a 19.82 (95% CI, 4.91 to 80.07, p < 0.0001) odds of expiring in an ICU among the Aspergillus group. CONCLUSION: Dual Aspergillus and influenza infection is emerging in southern Taiwan. Meanwhile, community-acquired P. aeruginosa should be listed in the common copathogens with severe influenza. The 67% mortality linked to aspergillosis highlights the need for physicians to focus attention on patients with GM >= 0.6. PMID- 28647220 TI - Investigation of zinc recovery by hydrogen reduction assisted pyrolysis of alkaline and zinc-carbon battery waste. AB - Zinc (Zn) recovery from alkaline and zinc-carbon (Zn-C) battery waste were studied by a laboratory scale pyrolysis process at a reaction temperature of 950 degrees C for 15-60min residence time using 5%H2(g)-N2(g) mixture at 1.0L/min gas flow rate. The effect of different cooling rates on the properties of pyrolysis residue, manganese oxide particles, were also investigated. Morphological and structural characterization of the produced Zn particles were performed. The battery black mass was characterized with respect to the properties and chemical composition of the waste battery particles. The thermodynamics of the pyrolysis process was studied using the HSC Chemistry 5.11 software. A hydrogen reduction reaction of the battery black mass (washed with Milli-Q water) takes place at the chosen temperature and makes it possible to produce fine Zn particles by rapid condensation following the evaporation of Zn from the pyrolysis batch. The amount of Zn that can be separated from the black mass increases by extending the residence time. Recovery of 99.8% of the Zn was achieved at 950 degrees C for 60min residence time using 1.0L/min gas flow rate. The pyrolysis residue contains MnO and Mn2O3 compounds, and the oxidation state of manganese can be controlled by cooling rate and atmosphere. The Zn particles exhibit spherical and hexagonal particle morphology with a particle size varying between 200nm and 3um. However the particles were formed by aggregation of nanoparticles which are primarily nucleated from the gas phase. PMID- 28647221 TI - Effect of thermo-tolerant actinomycetes inoculation on cellulose degradation and the formation of humic substances during composting. AB - The inoculum containing four cellulolytic thermophilic actinomycetes was screened from compost samples, and was inoculated into co-composting during different inoculation phases. The effect of different inoculation phases on cellulose degradation, humic substances formation and the relationship between inoculation and physical-chemical parameters was determined. The results revealed that inoculation at different phases of composting improved cellulase activities, accelerated the degradation of cellulose, increased the content of humic substances and influenced the structure of actinomycetic community, but there were significant differences between different inoculation phases. Redundancy analysis showed that the different inoculation phases had different impacts on the relationship between exogenous actinobacteria and physical-chemical parameters. Therefore, based on the promoting effort of inoculation in thermophilic phase of composting for the formation of humic substances, we suggested an optimized inoculation strategy to increase the content of humic substances, alleviate CO2 emission during composting. PMID- 28647222 TI - Soil application of sewage sludge stabilized with steelmaking slag and its effect on soil properties and wheat growth. AB - The effect of sewage sludge, stabilized with steelmaking slag, on soil chemical properties and fertility and on wheat (Triticum aestivum L.) growth was evaluated. Dewatered sewage sludge [75% (wet weight basis)] stabilized with steelmaking slag (25%) and three soils with different pH values were used in a pot experiment with winter wheat. The following treatments were applied: (i) sludge addition of 30gkg-1 (~ 120Mgha-1, rate equivalent to the common inorganic N fertilization for wheat, based on sludge's water soluble NO3-N), (ii) sludge addition of 10gkg-1 (~ 40Mgha-1, rate equivalent to the common inorganic N fertilization for wheat, based on sludge's Kjeldahl-N), (iii) addition of the common inorganic N fertilization for wheat (120kgNha-1) as NH4NO3, (iv) control (no fertilizer, no sludge). Sludge application at both rates to all soils resulted in a significant increase of pH, electrical conductivity of the saturation extract (ECse) and soil available NO3-N and P, in comparison to the other two treatments and this increase remained constant till the end of the pot experiment. In sludge treatments pH did not exceed the critical value of 8.5, whereas ECse, although it did not reach the limit of 4dSm-1, exceeded the value of 2dSm-1 at the rate of 30gkg-1. Concentrations of heavy metals, which regulate the agronomic use of sewage sludge according to the established legislation, ranged from not detectable to lower than the respective permissible levels. Both rates of sludge's addition in all soils improved wheat's growth, as judged by the significant increase of the aboveground biomass yield and the total plant uptake of almost all nutrients, compared to the other two treatments. It was concluded that sewage sludge stabilized with steelmaking slag could be used in agriculture, applied at rates based on sludge's Kjeldahl-N content and crop's demand for N. However, potential environmental impacts must also be considered. PMID- 28647223 TI - Fluid dynamics model on fluidized bed gasifier using agro-industrial biomass as fuel. AB - The present study shows the experimental and numerical results of thermal gasification of biomass, on the energy potential of agro-industrial waste from the Portalegre region. Gasification tests were performed in a pilot-scale fluidized bed gasifier, in order to study the behavior of peach stones and miscanthus to investigate the effect of gasification temperatures at 750 degrees C, 800 degrees C and 850 degrees C at a constant biomass flow rate of 45kg/h. In order to optimize the operating conditions of the biomass gasification process, a numerical model is developed namely COMMENT code. This model is a computer model of two dimensions describing the biomass gasification processes in a fluidized bed gasifier using peach stone and miscanthus as fuel. Both phases, solid and gaseous, were described using an Eulerian-Eulerian approach exchanging mass, energy, and momentum. The numerical model results are then compared with experimental results. The produced results show the impact of the increased temperature in the calorific value of the syngas. The tests carried out at 750 degrees C shown an increase in CO2 and N2 and a decrease of CO in the range of 5% comparing to the tests carried out at 850 degrees C. In addition, increased temperature favors a decrease in tar production in thermal gasification process. Numerical results shows to be in good agreement with the experimental data. PMID- 28647224 TI - Does artificial aging affect mechanical properties of CAD/CAM composite materials. AB - PURPOSE: The purpose of this study was to determine the flexural strength and Weibull characteristics of different CAD/CAM materials after different in vitro aging conditions. METHODS: The specimens were randomly assigned to one of the six in vitro aging conditions: (1) water storage (37 degrees C, 3 weeks), (2) boiling water (24h), (3) hydrochloric acid exposure (pH: 1.2, 24h), (4) autoclave treatment (134 degrees C, 200kPa, 12h), (5) thermal cycling (5000 times, 5-55 degrees C), (6) cyclic loading (100N, 50,000 cycles). No treatment was applied to the specimens in control group. Three-point bending test was used for the calculation of flexural strength. The reliability of the strength was assessed by Weibull distribution. Surface roughness and topography was examined by coherence scanning interferometry. Evaluated parameters were compared using the Kruskall Wallis or Mann-Whitney U test. RESULTS: Water storage, autoclave treatment and thermal cycling significantly decreased the flexural strength of all materials (p<0.05), whereas HCl exposure or cyclic loading did not affect the properties (p>0.05). Weibull moduli of CerasmartTM and LavaTM Ultimate were similar with control. Vita Enamic(r) exhibited similar Weibull moduli in all aging groups except the HCl treated group (p>0.05). Ra values of CerasmartTM and LavaTM Ultimate were in the range of 0.053-0.088MUm in the aged groups. However Ra results of Vita Enamic(r) were larger than 0.2MUm. CONCLUSIONS: Flexural strength of newly developed restorative CAD/CAM materials was significantly decreased by artificial aging. Cyclic loading or HCl exposure does not affect to the flexural strength and structural reliability of CerasmartTM and LavaTM Ultimate. PMID- 28647225 TI - 57-Year-Old Woman With Abdominal Pain. PMID- 28647226 TI - Inhalation of nanoplatelets - Theoretical deposition simulations. AB - Primary objective of the contribution was the theoretical prediction of nanoplatelet deposition in the human respiratory tract. Modeling was founded on the hypothetical inhalation of graphene nanoplatelets (GNP) measuring 0.01 and 0.1MUm in thickness and adopting a projected area diameter of 1-30MUm. Particle uptake was assumed to take place with inhalation flow rates of 250, 500, 750, and 1000cm3s-1, respectively. For an appropriate description of pulmonary particle behavior, transport of GNP in a stochastic lung structure and deposition formulae based on analytical and numerical studies were presupposed. The results obtained from the theoretical approach clearly demonstrate that GNP with a thickness of 0.01MUm deposit in the respiratory tract by 20-50%, whereas GNP with a thickness of 0.1MUm exhibit a deposition of 20-90%. Larger platelets deposit with higher probability than small ones. Increase of inhalation flow rate is accompanied by decreased deposition in the case of thin GNP, whilst thicker GNP are preferably accumulated in the extrathoracic region. Generation-specific deposition ranges from 0.05 to 7% (0.01MUm) and from 0.05 to 9%, with maximum values being obtained in airway generation 20. In proximal airway generations (0-10), deposition is increased with inhalation flow rate, whereas in intermediate to distal generations a reverse effect may be observed. Health consequences of GNP deposition in different lung compartments are subjected to an intense debate. PMID- 28647227 TI - In vivo cellular reactions to different biomaterials-Physiological and pathological aspects and their consequences. AB - Biomaterials are widely used in guided bone regeneration (GBR) and guided tissue regeneration (GTR). After application, there is an interaction between the host immune system and the implanted biomaterial, leading to a biomaterial-specific cellular reaction. The present review focuses on cellular reactions to numerous biomaterials in vivo with consideration of different implantation models and microenvironments in different species, such as subcutaneous implantation in mice and rats, a muscle model in goats and a femur model in rabbits. Additionally, cellular reactions to different biomaterials in various clinical indications within the oro-maxillofacial surgical field were considered. Two types of cellular reactions were observed. There was a physiological reaction with the induction of only mononuclear cells and a pathological reaction with the induction of multinucleated giant cells (MNGCs). Attention was directed to the frequently observed MNGCs and consequences of their appearance within the implantation region. MNGCs have different subtypes. Therefore, the present review addresses the different morphological phenotypes observed within the biomaterial implantation bed and discusses the critical role of MNGCs, their subtypes and their precursors as well as comparing the characteristics and differences between biomaterial-related MNGCs and osteoclasts. Polymeric biomaterials that only induced mononuclear cells underwent integration and maintained their integrity, while polymeric biomaterials that induced MNGCs underwent disintegration with material breakdown and loss of integrity. Hence, there is a question regarding whether our attention should be directed to alternative biological concepts, in combination with biomaterials that induce a physiological mononuclear cellular reaction to optimize biomaterial-based tissue regeneration. PMID- 28647228 TI - Chloramine demand estimation using surrogate chemical and microbiological parameters. AB - A model is developed to enable estimation of chloramine demand in full scale drinking water supplies based on chemical and microbiological factors that affect chloramine decay rate via nonlinear regression analysis method. The model is based on organic character (specific ultraviolet absorbance (SUVA)) of the water samples and a laboratory measure of the microbiological (Fm) decay of chloramine. The applicability of the model for estimation of chloramine residual (and hence chloramine demand) was tested on several waters from different water treatment plants in Australia through statistical test analysis between the experimental and predicted data. Results showed that the model was able to simulate and estimate chloramine demand at various times in real drinking water systems. To elucidate the loss of chloramine over the wide variation of water quality used in this study, the model incorporates both the fast and slow chloramine decay pathways. The significance of estimated fast and slow decay rate constants as the kinetic parameters of the model for three water sources in Australia was discussed. It was found that with the same water source, the kinetic parameters remain the same. This modelling approach has the potential to be used by water treatment operators as a decision support tool in order to manage chloramine disinfection. PMID- 28647229 TI - A combined process coupling phytoremediation and in situ flushing for removal of arsenic in contaminated soil. AB - Phytoremediation and soil washing are both potentially useful for remediating arsenic (As)-contaminated soils. We evaluated the effectiveness of a combined process coupling phytoremediation and in situ soil flushing for removal of As in contaminated soil through a pilot study. The results showed that growing Pteris vittata L. (P.v.) accompanied by soil flushing of phosphate (P.v./Flushing treatment) could significantly decrease the total As concentration of soil over a 37day flushing period compared with the single flushing (Flushing treatment). The P.v./Flushing treatment removed 54.04% of soil As from contaminated soil compared to 47.16% in Flushing treatment, suggesting that the growth of P. vittata was beneficial for promoting the removal efficiency. We analyzed the As fractionation in soil and As concentration in soil solution to reveal the mechanism behind this combined process. Results showed that comparing with the control treatment, the percent of labile arsenate fraction significantly increased by 17% under P.v./Flushing treatment. As concentration in soil solution remained a high lever during the middle and later periods (51.26-56.22mg/L), which was significantly higher than the Flushing treatment. Although soil flushing of phosphate for more than a month, P. vittata still had good accumulation and transfer capacity of As of the soil. The results of the research revealed that combination of phytoremediation and in situ soil flushing is available to remediate As contaminated soils. PMID- 28647230 TI - Effect of barium sulfate modification on the SO2 tolerance of V2O5/TiO2 catalyst for NH3-SCR reaction. AB - Sulfur poisoning of V2O5/BaSO4-TiO2 (VBT), V2O5/WO3-TiO2 (VWT) and V2O5/BaSO4-WO3 TiO2 (VBWT) catalysts was performed in wet air at 350 degrees C for 3hr, and activities for the selective catalytic reduction of NOx with NH3 were evaluated for 200-500 degrees C. The VBT catalyst showed higher NOx conversions after sulfur poisoning than the other two catalysts. The introduction of barium sulfate contributed to strong acid sites for the as-received catalyst, and eliminated the redox cycle of active vanadium oxide to some extent, which resulted in a certain loss of activity. Readily decomposable sulfate species formed on VBT-S instead of inactive sulfates on VWT-S. These decomposable sulfates increased the number of strong acid sites significantly. Some sulfate species escaped during catalyst preparation and barium sulfate was reproduced during sulfur poisoning, which protects vanadia from sulfur oxide attachment to a great extent. Consequently, the VBT catalyst exhibited the best resistance to sulfur poisoning. PMID- 28647231 TI - Simultaneous elimination of cyanotoxins and PCBs via mechanical collection of cyanobacterial blooms: An application of "green-bioadsorption concept". AB - In this study, the distribution, transfer and fate of both polychlorinated biphenyls (PCBs) and cyanotoxins via phytoplankton routes were systematically investigated in two Chinese lakes. Results indicated that PCB adsorption/bioaccumulation dynamics has significantly positive correlations with the biomass of green alga and diatoms. Total lipid content of phytoplankton is the major factor that influences PCB adsorption/bioaccumulation. Cyanobacterial blooms with relatively lower lipid content could also absorb high amount of PCBs due to their high cell density in the water columns, and this process was proposed as major route for the transfer of PCBs in Chinese eutrophic freshwater. According to these findings, a novel route on fates of PCBs via phytoplankton and a green bioadsorption concept were proposed and confirmed. In the practice of mechanical collections of bloom biomass from Lake Taihu, cyanotoxin/cyanobacteria and PCBs were found to be removed simultaneously very efficiently followed this theory. PMID- 28647232 TI - Determination of water environment standards based on water quality criteria in China: Limitations and feasibilities. AB - There is a need to formulate water environment standards (WESs) from the current water quality criteria (WQC) in China. To this end, we briefly summarize typical mechanisms applied in several countries with longer histories of developing WESs, and three limitations to formulating WESs in China were identified. After analyzing the feasibility factors including economic development, scientific support capability and environmental policies, we realized that China is still not ready for a complete change from its current nation-wide unified WES system to a local-standard-based system. Thus, we proposed a framework for transformation from WQC to WESs in China. The framework consists of three parts, including responsibilities, processes and policies. The responsibilities include research authorization, development of guidelines, and collection of information, at both national and local levels; the processes include four steps and an impact factor system to establish water quality standards; and the policies include seven specific proposals. PMID- 28647233 TI - Evaluation of bacterial pathogen diversity, abundance and health risks in urban recreational water by amplicon next-generation sequencing and quantitative PCR. AB - The microbial quality of urban recreational water is of great concern to public health. The monitoring of indicator organisms and several pathogens alone is not sufficient to accurately and comprehensively identify microbial risks. To assess the levels of bacterial pathogens and health risks in urban recreational water, we analyzed pathogen diversity and quantified four pathogens in 46 water samples collected from waterbodies in Beijing Olympic Forest Park in one year. The pathogen diversity revealed by 16S rRNA gene targeted next-generation sequencing (NGS) showed that 16 of 40 genera and 13 of 76 reference species were present. The most abundant species were Acinetobacter johnsonii, Mycobacterium avium and Aeromonas spp. Quantitative polymerase chain reaction (qPCR) of Escherichia coli (uidA), Aeromonas (aerA), M. avium (16S rRNA), Pseudomonas aeruginosa (oaa) and Salmonella (invA) showed that the aerA genes were the most abundant, occurring in all samples with concentrations of 104-6 genome copies/100mL, followed by oaa, invA and M. avium. In total, 34.8% of the samples harbored all genes, indicating the prevalence of these pathogens in this recreational waterbody. Based on the qPCR results, a quantitative microbial risk assessment (QMRA) showed that the annual infection risks of Salmonella, M. avium and P. aeruginosa in five activities were mostly greater than the U.S. EPA risk limit for recreational contacts, and children playing with water may be exposed to the greatest infection risk. Our findings provide a comprehensive understanding of bacterial pathogen diversity and pathogen abundance in urban recreational water by applying both NGS and qPCR. PMID- 28647234 TI - Local PM10 and PM2.5 emission inventories from agricultural tillage and harvest in northeastern China. AB - Mineral particles or particulate matters (PMs) emitted during agricultural activities are major recurring sources of atmospheric aerosol loading. However, precise PM inventory from agricultural tillage and harvest in agricultural regions is challenged by infrequent local emission factor (EF) measurements. To understand PM emissions from these practices in northeastern China, we measured EFs of PM10 and PM2.5 from three field operations (i.e., tilling, planting and harvesting) in major crop production (i.e., corn and soybean), using portable real-time PM analyzers and weather station data. County-level PM10 and PM2.5 emissions from agricultural tillage and harvest were estimated, based on local EFs, crop areas and crop calendars. The EFs averaged (107+/-27), (17+/-5) and 26mg/m2 for field tilling, planting and harvesting under relatively dry conditions (i.e., soil moisture <15%), respectively. The EFs of PM from field tillage and planting operations were negatively affected by topsoil moisture. The magnitude of PM10 and PM2.5 emissions from these three activities were estimated to be 35.1 and 9.8 kilotons/yr in northeastern China, respectively, of which Heilongjiang Province accounted for approximately 45%. Spatiotemporal distribution showed that most PM10 emission occurred in April, May and October and were concentrated in the central regions of the northeastern plain, which is dominated by dryland crops. Further work is needed to estimate the contribution of agricultural dust emissions to regional air quality in northeastern China. PMID- 28647235 TI - Selective elimination of chromophoric and fluorescent dissolved organic matter in a full-scale municipal wastewater treatment plant. AB - Effluent organic matter (EfOM) from municipal wastewater treatment plants potentially has a detrimental effect on both aquatic organisms and humans. This study evaluated the removal and transformation of chromophoric dissolved organic matter (CDOM) and fluorescent dissolved organic matter (FDOM) in a full-scale wastewater treatment plant under different seasons. The results showed that bio treatment was found to be more efficient in removing bulk DOM (in term of dissolved organic carbon, DOC) than CDOM and FDOM, which was contrary to the disinfection process. CDOM and FDOM were selectively removed at various stages during the treatment. Typically, the low molecular weight fractions of CDOM and protein-like FDOM were more efficiently removed during bio-treatment process, whereas the humic-like FDOM exhibited comparable decreases in both bio-treatment and disinfection processes. Overall, the performance of the WWTP was weak in terms of CDOM and FDOM removal, resulting in enrichment of CDOM and FDOM in effluent. Moreover, the total removal of the bulk DOM (P<0.05) and the protein like FDOM (P<0.05) displayed a significant seasonal variation, with higher removal efficiencies in summer, whereas removal of CDOM and the humic-like FDOM showed little differences between summer and winter. In all, the results provide useful information for understanding the fate and transformation of DOM, illustrating that sub-fractions of DOM could be selectively removed depending on treatment processes and seasonality. PMID- 28647236 TI - Hydrolysis of polyaluminum chloride prior to coagulation: Effects on coagulation behavior and implications for improving coagulation performance. AB - The effects of polyaluminum chloride (PACl) hydrolysis prior to coagulation on both the coagulation zone and coagulation performance of a kaolin suspension were investigated by a novel jar test named the "reversed coagulation test". The tests showed that PACl hydrolysis prior to coagulation decreased the performance of charge neutralization coagulation in the case of short-time slow mixing (10min; G=15sec-1) and increased the optimal dosage for charge neutralization and sweep coagulation. Moreover, the hydrolysis time had insignificant effects on the size and zeta potential of PACl precipitates and the residual turbidity of the raw water. However, PACl hydrolysis prior to coagulation and the size of PACl precipitates had a negligible effect on the performance of sweep coagulation. The results imply that, in practice, preparing a PACl solution with deionized water, rather than tap water or the outlet water from a wastewater treatment unit, can significantly save PACl consumption and improve the performance of charge neutralization coagulation, while preparing the PACl solution with tap or outlet water would not affect the performance of sweep coagulation. In addition, the optimal rapid mixing intensity appears to be determined by a balance between the degree of coagulant hydrolysis before contacting the primary particles and the average size of flocs in the rapid mixing period. These results provide new insights into the role of PACl hydrolysis and will be useful for improving coagulation efficiency. PMID- 28647237 TI - Developing a chloramine decay index to understand nitrification: A case study of two chloraminated drinking water distribution systems. AB - The management of chloramine decay and the prevention of nitrification are some of the critical issues faced by water utilities that use chloramine as a disinfectant. In this study, potential association between high performance size exclusion chromatography (HPSEC) data obtained with multiple wavelength Ultraviolet (UV) detection from two drinking water distribution systems in Australia and nitrification occurrence was investigated. An increase in the absorbance signal of HPSEC profiles with UV detection at lambda=230nm between apparent molecular weights of 200 to 1000Da was observed at sampling sites that experienced rapid chloramine decay and nitrification while its absorbance signal at lambda=254nm decreased. A chloramine decay index (C.D.I) defined as the ratio of area beneath the HPSEC spectra at two different wavelengths of 230 and 254nm, was used in assessing chloramine decay occurrences. The C.D.Is of waters at locations that experienced nitrification were consistently higher than locations not experiencing nitrification. A simulated laboratory study showed that the formation of nitrite/nitrate and/or soluble microbial products and/or the release of extracellular polymeric substances (EPS) during nitrification may contribute to the C.D.I. increase. These findings suggest that C.D.I derived from HPSEC with multiple wavelength UV detection could be an informative index to track the occurrence of rapid chloramine decay and nitrification. PMID- 28647238 TI - Adsorption-desorption behavior of atrazine on agricultural soils in China. AB - Adsorption and desorption are important processes that affect atrazine transport, transformation, and bioavailability in soils. In this study, the adsorption desorption characteristics of atrazine in three soils (laterite, paddy soil and alluvial soil) were evaluated using the batch equilibrium method. The results showed that the kinetics of atrazine in soils was completed in two steps: a "fast" adsorption and a "slow" adsorption and could be well described by pseudo second-order model. In addition, the adsorption equilibrium isotherms were nonlinear and were well fitted by Freundlich and Langmuir models. It was found that the adsorption data on laterite, and paddy soil were better fitted by the Freundlich model; as for alluvial soil, the Langmuir model described it better. The maximum atrazine sorption capacities ranked as follows: paddy soil>alluvial soil>laterite. Results of thermodynamic calculations indicated that atrazine adsorption on three tested soils was spontaneous and endothermic. The desorption data showed that negative hysteresis occurred. Furthermore, lower solution pH value was conducive to the adsorption of atrazine in soils. The atrazine adsorption in these three tested soils was controlled by physical adsorption, including partition and surface adsorption. At lower equilibrium concentration, the atrazine adsorption process in soils was dominated by surface adsorption; while with the increase of equilibrium concentration, partition was predominant. PMID- 28647239 TI - Fluoride removal by Al, Ti, and Fe hydroxides and coexisting ion effect. AB - Batch experiments were conducted to evaluate fluoride removal by Al, Fe, and Ti based coagulants and adsorbents, as well as the effects of coexisting ions and formation of aluminum-fluoride complexes on fluoride removal by co-precipitation with alum (Al2(SO4)3.18H2O). Aluminum sulfate was more efficient than the other coagulants for fluoride removal in the pH range between 6 and 8. Nano-crystalline TiO2 was more effective for fluoride removal than Al and Fe hydroxides in a pH range of 3-5. Coexisting anions in water decreased the removal of fluoride in the order: phosphate (2.5mg/L)>arsenate (0.1mg/L)>bicarbonate (200mg/L)>sulfate (100mg/L)=nitrate (100mg/L)>silicate (10mg/L) at a pH of 6.0. The effect of silicate became more significant at pH>7.0. Calcium and magnesium improved the removal of fluoride. Zeta-potential measurements determined that the adsorption of fluoride shifted the PZC of Al(OH)3 precipitates from 8.9 to 8.4, indicating the chemical adsorption of fluoride at the surface. The presence of fluoride in solution significantly increased the soluble aluminum concentration at pH<6.5. A Visual MINTEQ modeling study indicated that the increased aluminum solubility was caused by the formation of AlF2+, AlF2+, and AlF3 complexes. The AlFx complexes decreased the removal of fluoride during co-precipitation with aluminum sulfate. PMID- 28647240 TI - Ammonia and greenhouse gas emissions from a subtropical wheat field under different nitrogen fertilization strategies. AB - Minimizing soil ammonia (NH3) and nitrous oxide (N2O) emission factors (EFs) has significant implications in regional air quality and greenhouse gas (GHG) emissions besides nitrogen (N) nutrient loss. The aim of this study was to investigate the impacts of different N fertilizer treatments of conventional urea, polymer-coated urea, ammonia sulfate, urease inhibitor (NBPT, N-(n-butyl) thiophosphoric triamide)-treated urea, and nitrification inhibitor (DCD, dicyandiamide)-treated urea on emissions of NH3 and GHGs from subtropical wheat cultivation. A field study was established in a Cancienne silt loam soil. During growth season, NH3 emission following N fertilization was characterized using active chamber method whereas GHG emissions of N2O, carbon dioxide (CO2), and methane (CH4) were by passive chamber method. The results showed that coated urea exhibited the largest reduction (49%) in the EF of NH3-N followed by NBPT-treated urea (39%) and DCD-treated urea (24%) over conventional urea, whereas DCD-treated urea had the greatest suppression on N2O-N (87%) followed by coated urea (76%) and NBPT-treated urea (69%). Split fertilization of ammonium sulfate-urea significantly lowered both NH3-N and N2O-N EF values but split urea treatment had no impact over one-time application of urea. Both NBPT and DCD-treated urea treatments lowered CO2-C flux but had no effect on CH4-C flux. Overall, application of coated urea or urea with NPBT or DCD could be used as a mitigation strategy for reducing NH3 and N2O emissions in subtropical wheat production in Southern USA. PMID- 28647241 TI - Biodegradation of 3,5-dimethyl-2,4-dichlorophenol in saline wastewater by newly isolated Penicillium sp. yz11-22N2. AB - In this study, the performance of 3,5-dimethyl-2,4-dichlorophenol (DCMX) degradation by a screened strain was investigated. 18S rDNA and the neighbor joining method were used for identification of the isolated strain. The results of phylogenetic analysis and scanning electron micrographs showed that the most probable identity of the screened strain should be Penicillium sp. Growth characteristics of Penicillium sp. and degradation processes of DCMX were examined. Fourier transform infrared spectroscopy of the inoculated DCMX solution was recorded, which supported the capacity of DCMX degradation by the screened Penicillium sp. Under different salinity conditions, the highest growth rate and removal efficiency for DCMX were obtained at pH6.0. The removal efficiency decreased from 100% to 66% when the DCMX concentration increased from 5 to 60mg/L, respectively. Using a Box-Behnken design, the maximum DCMX removal efficiency was determined to be 98.4%. With acclimation to salinity, higher removal efficiency could be achieved. The results demonstrate that the screened Penicillium sp. has the capability for degradation of DCMX. PMID- 28647242 TI - Effect of oxide nanoparticles on the morphology and fluidity of phospholipid membranes and the role of hydrogen bonds. AB - Engineered oxide nanoparticles (NPs) are widely applied in insulators, catalyzers, paints, cosmetic products, textiles and semiconductors. Their attachment on cell membrane may lead to cytotoxicity. The effects of Al2O3, Fe2O3, SiO2, TiO2 and ZnO NPs on membrane integrity and fluidity were studied using giant or small unilamellar vesicles in this study. Al2O3 and SiO2 NPs disrupted the oppositely charged membrane, indicating the important role of electrostatic attraction. However, Fe2O3, TiO2 and ZnO NPs did not cause serious membrane disruption as Al2O3 and SiO2 NPs. Membrane fluidity was evaluated by the generalized polarity (GP) values of Laurdan fluorescent emission. SiO2 NPs induce the membrane gelation of both positively and negatively charged membrane. Al2O3 and ZnO NPs induced the gelation of the oppositely charged membrane, but did not cause obvious membrane gelation to the like charged membrane. The phospholipid molecular structural changes after NP exposure were analyzed by Fourier transform infrared (FT-IR) spectroscopy. FT-IR spectra revealed the hydrogen bond formation between NPs and the carbonyl/phosphate groups of phospholipids. Al2O3 and SiO2 NPs showed strongest evidence of hydrogen bonding on their FT-IR spectra. It was consistent with the microscopic observation and fluorescent data that Al2O3 and SiO2 NPs caused more serious membrane disruption and gelation. This study on membrane damage provides further knowledge on the cytotoxicity of nanomaterials and the safety of NP application. PMID- 28647243 TI - Quantification of hookworm ova from wastewater matrices using quantitative PCR. AB - A quantitative PCR (qPCR) assay was used to quantify Ancylostoma caninum ova in wastewater and sludge samples. We estimated the average gene copy numbers for a single ovum using a mixed population of ova. The average gene copy numbers derived from the mixed population were used to estimate numbers of hookworm ova in A. caninum seeded and unseeded wastewater and sludge samples. The newly developed qPCR assay estimated an average of 3.7*103 gene copies per ovum, which was then validated by seeding known numbers of hookworm ova into treated wastewater. The qPCR estimated an average of (1.1+/-0.1), (8.6+/-2.9) and (67.3+/ 10.4) ova for treated wastewater that was seeded with (1+/-0), (10+/-2) and (100+/-21) ova, respectively. The further application of the qPCR assay for the quantification of A. caninum ova was determined by seeding a known numbers of ova into the wastewater matrices. The qPCR results indicated that 50%, 90% and 67% of treated wastewater (1L), raw wastewater (1L) and sludge (~4g) samples had variable numbers of A. caninum gene copies. After conversion of the qPCR estimated gene copy numbers to ova for treated wastewater, raw wastewater, and sludge samples, had an average of 0.02, 1.24 and 67 ova, respectively. The result of this study indicated that qPCR can be used for the quantification of hookworm ova from wastewater and sludge samples; however, caution is advised in interpreting qPCR generated data for health risk assessment. PMID- 28647244 TI - On-board measurement of particle numbers and their size distribution from a light duty diesel vehicle: Influences of VSP and altitude. AB - In this study, the particle size-resolved distribution from a China-3 certificated light-duty diesel vehicle was measured by using a portable emission measurement system (PEMS). In order to examine the influences of vehicle specific power (VSP) and high-altitude operation, measurements were conducted at 8 constant speeds, which ranged from 10 to 80km/hr at 10km/hr intervals, and two different high altitudes, namely 2200 and 3200m. The results demonstrated that the numbers of particles in all size ranges decreased significantly as VSP increased when the test vehicle was running at lower speeds (<20km/hr), while at a moderate speed (between 30 and 60km/hr), the particle number was statistically insensitive to increase VSP. Under high-speed cruising conditions, the numbers of ultrafine particles and PM2.5 were insensitive to changes in VSP, but the numbers of nanoparticles and PM10 surged considerably. An increase in the operational altitude of the test vehicle resulted in increased particle number emissions at low and high driving speeds; however, particle numbers obtained at moderate speeds decreased as altitude rose. When the test vehicle was running at moderate speeds, particle numbers measured at the two altitudes were very close, except for comparatively higher number concentrations of nanoparticles measured at 2200m. PMID- 28647245 TI - Transport and humification of dissolved organic matter within a semi-arid floodplain. AB - In order to understand the transport and humification processes of dissolved organic matter (DOM) within sediments of a semi-arid floodplain at Rifle, Colorado, fluorescence excitation-emission matrix (EEM) spectroscopy, humification index (HIX) and specific UV absorbance (SUVA) at 254nm were applied for characterizing depth and seasonal variations of DOM composition. Results revealed that late spring snowmelt leached relatively fresh DOM from plant residue and soil organic matter down into the deeper vadose zone (VZ). More humified DOM is preferentially adsorbed by upper VZ sediments, while non- or less humified DOM was transported into the deeper VZ. Interestingly, DOM at all depths undergoes rapid biological humification process evidenced by the products of microbial by-product-like (i.e., tyrosine-like and tryptophan-like) matter in late spring and early summer, particularly in the deeper VZ, resulting in more humified DOM (e.g., fulvic-acid-like and humic-acid-like substances) at the end of year. This indicates that DOM transport is dominated by spring snowmelt, and DOM humification is controlled by microbial degradation, with seasonal variations. It is expected that these relatively simple spectroscopic measurements (e.g., EEM spectroscopy, HIX and SUVA) applied to depth- and temporally-distributed pore-water samples can provide useful insights into transport and humification of DOM in other subsurface environments as well. PMID- 28647246 TI - Environmentally relevant concentrations of aminopolycarboxylate chelating agents mobilize Cd from humic acid. AB - Although Cd is a pollutant of public health relevance, many dietary sources from which it can be absorbed into human tissues remain unknown. While it is well established that the biogeochemical cycle of Cd involves its complexation with environment-derived ligands (e.g., humic acids, HAs) and anthropogenic ones (e.g., chelating agents, CAs), the interaction of Cd with both of these ligands is less well understood. To gain insight, a HA-Cd complex was injected on a size exclusion chromatography (SEC) column coupled on-line with a flame atomic absorption spectrometer (FAAS) using 10mmol/L Tris buffer (pH8.0) as the mobile phase. This approach allowed us to observe the intact HA-Cd complex and the retention behavior of Cd as a function of 2-20MUmol/L concentrations of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or methylglycinediacetic acid (MGDA) that were added to the mobile phase. An increase of the retention time of Cd was indicative of a partial or complete abstraction of Cd from HA. Our results revealed that all CAs abstracted Cd from the HA-Cd complex at concentrations of 5MUmol/L, while MGDA and DTPA were effective at 2MUmol/L. The bioavailability of some of the on-column formed CA-Cd complexes explains the previously reported increased accumulation of Cd in periphyton in the ecosystem downstream of wastewater treatment plants. In addition, our results imply that the use of effluents which contain CAs and Cd for the irrigation of food crops can introduce Cd into the food supply and compromise food safety. PMID- 28647247 TI - Spatial variability and possible sources of acetate and formate in the surface snow of East Antarctica. AB - Spatial trends of acetate (Ac-) and formate (Fo-) were determined in surface snow samples along a coastal-inland transect (180km) in the ice cap region at Princess Elizabeth Land and along a coastal transect in the Amery Ice Shelf (130km), East Antarctica. Variations in both Ac- and Fo- seem to be unrelated to the acidity of snow. Ionic balance determined for the snow samples indicate the availability of HNO3 that could undergo photolysis to produce hydroxyl radical (OH), one of the major reactants involved in oxidation reactions with organic matter. The strong positive correlations between Ac- and NO3- in snow from both regions indicate that NO3- mediated OH-oxidation of organic compounds in snow could be an important source of Ac- within the snowpack. On the other hand, negative correlation between Fo- and NO3- might indicate that sources other than OH oxidation of organic matter may be dominant in the case of Fo-. Higher Ac- concentrations in the ice cap compared to the ice shelf correspond with long range transport of biomass burning emissions to the ice cap region. Interaction of Ac- and Fo- with alkaline minerals could lead to their stability in the snowpack and minimize their loss from the snow surface. Resident microbial communities could also influence the budget of the carboxylic acids in snow. PMID- 28647248 TI - Synergetic analysis of springtime air pollution episodes over Gwangju, Korea. AB - The characteristics of springtime aerosols, including their optical and microphysical properties, were analyzed for the months of March to May of 2009 in Gwangju (35.23 degrees N, 126.84 degrees E), Korea. A high Light Detection and Ranging (LIDAR)-derived aerosol depolarization ratio (delta) of 0.25+/-0.04 was determined on dust particles during the observation period. The Angstrom exponent values of the 440-870nm wavelength pair (A440-870) and single-scattering albedo at 675nm (Omega675) measured by a CIMEL sun/sky radiometer were 0.77+/-0.19 and 0.95+/-0.01, respectively. The elevated dust layers reached a maximum elevation of 4km above sea level. Anthropogenic/smoke particles that originated from highly populated/industrialized regions could be distinguished by their relatively smaller particle size (A440-870 ranged between 1.33 and 1.36) and higher light absorbing (Omega675 of 0.92+/-0.01) characteristics. These aerosols are mostly distributed at altitudes <1.2km. The root-mean-square deviation (RMSD) between the aerosol optical depth (AOD, tau) derived from LIDAR (tauLIDAR) and from the CIMEL sun/sky radiometer (tauCIMEL) varied with respect to the surface PM10 concentration. The RMSD between tauLIDAR and tauCIMEL was as low as 13% under lower PM10 concentration levels (<100MUg/m3). In contrast, the RMSD between tauLIDAR and tauCIMEL increased three times (~31%) under high surface PM10 concentration levels (>100MUg/m3). These results suggest that the accuracy of tauLIDAR is influenced by specific atmospheric conditions, regardless of its uncertainty. PMID- 28647249 TI - Potential acute effects of suspended aluminum nitride (AlN) nanoparticles on soluble microbial products (SMP) of activated sludge. AB - The study aims to identify the potential acute effects of suspended aluminum nitride (AlN) nanoparticles (NPs) on soluble microbial products (SMP) of activated sludge. Cultured activated sludge loaded with 1, 10, 50, 100, 150 and 200mg/L of AlN NPs were carried out in this study. As results showed, AlN NPs had a highly inverse proportionality to bacterial dehydrogenase and OUR, indicating its direct toxicity to the activated sludge viability. The toxicity of AlN NPs was mainly due to the nano-scale of AlN NPs. In SMP, AlN NPs led to the decrease of polysaccharide and humic compounds, but had slight effects on protein. The decrease of tryptophan-like substances in SMP indicated the inhibition of AlN NPs on the bacterial metabolism. Additionally, AlN NPs reduced obviously the molecular weight of SMP, which might be due to the nano-scale of AlN. PMID- 28647250 TI - Constructed wetlands for wastewater treatment in cold climate - A review. AB - Constructed wetlands (CWs) have been successfully used for treating various wastewaters for decades and have been identified as a sustainable wastewater management option worldwide. However, the application of CW for wastewater treatment in frigid climate presents special challenges. Wetland treatment of wastewater relies largely on biological processes, and reliable treatment is often a function of climate conditions. To date, the rate of adoption of wetland technology for wastewater treatment in cold regions has been slow and there are relatively few published reports on CW applications in cold climate. This paper therefore highlights the practice and applications of treatment wetlands in cold climate. A comprehensive review of the effectiveness of contaminant removal in different wetland systems including: (1) free water surface (FWS) CWs; (2) subsurface flow (SSF) CWs; and (3) hybrid wetland systems, is presented. The emphasis of this review is also placed on the influence of cold weather conditions on the removal efficacies of different contaminants. The strategies of wetland design and operation for performance intensification, such as the presence of plant, operational mode, effluent recirculation, artificial aeration and in-series design, which are crucial to achieve the sustainable treatment performance in cold climate, are also discussed. This study is conducive to further research for the understanding of CW design and treatment performance in cold climate. PMID- 28647251 TI - PET-modified red mud as catalysts for oxidative desulfurization reactions. AB - This work describes the synthesis of catalysts based on red mud/polyethylene terephthalate (PET) composites and their subsequent heat treatment under N2 atmosphere. The materials were characterized by scanning electron microscopy (SEM), temperature programmed reduction (TPR), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric (TG) analysis and N2 adsorption/desorption. The catalysts were evaluated in the oxidative desulfurization reaction of dibenzothiophene (DBT) in a biphasic system. The results indicated that the PET impregnation on red mud increased the affinity of the catalyst with the nonpolar phase (fuel), in which the contaminant was dissolved, allowing a higher conversion (up to 80%) and selectivity to the corresponding dibenzothiophene sulfone. The sulfone compound is more polar than DBT and diffused into the polar solvent as indicated by the data obtained via gas chromatography-mass spectrometry (GC-MS). PMID- 28647252 TI - Source apportionment of perfluoroalkyl substances in surface sediments from lakes in Jiangsu Province, China: Comparison of three receptor models. AB - Receptor models have been proved as useful tools to identify source categories and quantitatively calculate the contributions of extracted sources. In this study, sixty surface sediment samples were collected from fourteen lakes in Jiangsu Province, China. The total concentrations of C4-C14-perfluoroalkyl carboxylic acids and perfluorooctane sulfonic acid (?12PFASs) in sediments ranged from 0.264 to 4.44ng/gdw (dry weight), with an average of 1.76ng/gdw. Three commonly-applied receptor models, namely principal component analysis-multiple linear regression (PCA-MLR), positive matrix factorization (PMF) and Unmix models, were employed to apportion PFAS sources in sediments. Overall, these three models all could well track the ?12PFASs concentrations as well as the concentrations explained in sediments. These three models identified consistently four PFAS sources: the textile treatment sources, the fluoropolymer processing aid/fluororesin coating sources, the textile treatment/metal plating sources and the precious metal sources, contributing 28.1%, 37.0%, 29.7% and 5.3% by PCA-MLR model, 30.60%, 39.3%, 22.4% and 7.7% by PMF model, and 20.6%, 52.4%, 20.2% and 6.8% by Unmix model to the ?12PFASs, respectively. Comparative statistics of multiple analytical methods could minimize individual-method weaknesses and provide convergent results to enhance the persuasiveness of the conclusions. The findings could give us a better knowledge of PFAS sources in aquatic environments. PMID- 28647253 TI - Nano-sized Fe2O3/Fe3O4 facilitate anaerobic transformation of hexavalent chromium in soil-water systems. AB - The purpose of this study is to investigate the effects of nano-sized or submicro Fe2O3/Fe3O4 on the bioreduction of hexavalent chromium (Cr(VI)) and to evaluate the effects of nano-sized Fe2O3/Fe3O4 on the microbial communities from the anaerobic flooding soil. The results indicated that the net decreases upon Cr(VI) concentration from biotic soil samples amended with nano-sized Fe2O3 (317.1+/ 2.1mg/L) and Fe3O4 (324.0+/-22.2mg/L) within 21days, which were approximately 2 fold of Cr(VI) concentration released from blank control assays (117.1+/ 5.6mg/L). Furthermore, the results of denaturing gradient gel electrophoresis (DGGE) and high-throughput sequencing indicated a greater variety of microbes within the microbial community in amendments with nano-sized Fe2O3/Fe3O4 than the control assays. Especially, Proteobacteria occupied a predominant status on the phylum level within the indigenous microbial communities from chromium contaminated soils. Besides, some partial decrease of soluble Cr(VI) in abiotic nano-sized Fe2O3/Fe3O4 amendments was responsible for the adsorption of nano sized Fe2O3/Fe3O4 to soluble Cr(VI). Hence, the presence of nano-sized Fe2O3/Fe3O4 could largely facilitate the mobilization and biotransformation of Cr(VI) from flooding soils by adsorption and bio-mediated processes. PMID- 28647254 TI - Quantifying public health benefits of environmental strategy of PM2.5 air quality management in Beijing-Tianjin-Hebei region, China. AB - In 2013, China issued "Air Pollution Prevention and Control Action Plan (Action Plan)" to improve air quality. To assess the benefits of this program in Beijing Tianjin-Hebei (BTH) region, where the density of population and emissions vary greatly, we simulated the air quality benefit based on BenMAP to satisfy the Action Plan. In this study, we estimate PM2.5 concentration using Voronoi spatial interpolation method on a grid with a spatial resolution of 1*1km2. Combined with the exposure-response function between PM2.5 concentration and health endpoints, health effects of PM2.5 exposure are analyzed. The economic loss is assessed by using the willingness to pay (WTP) method and human capital (HC) method. When the PM2.5 concentration falls by 25% in BTH and reached 60MUg/m3 in Beijing, the avoiding deaths will be in the range of 3175 to 14051 based on different functions each year. Of the estimated mortality attributable to all causes, 3117 annual deaths were due to lung cancer, 1924 - 6318 annual deaths were due to cardiovascular, and 343 - 1697 annual deaths were due to respiratory. Based on WTP, the estimated monetary values for the avoided cases of all cause mortality, cardiovascular mortality, respiratory mortality and lung cancer ranged from 1110 to 29632, 673 to 13325, 120 to 3579, 1091 to 6574 million yuan, respectively. Based on HC, the corresponding values for the avoided cases of these four mortalities were 267 to 1178, 161 to 529, 29 to 143 and 261 million yuan, respectively. PMID- 28647255 TI - Influence of coagulation mechanisms and floc formation on filterability. AB - Minimizing particles in water is a key goal for improving drinking water quality and safety. The media filtration process, as the last step of the solid-liquid separation process, is largely influenced by the characteristics of flocs, which are formed and controlled within the coagulation process. In a laboratory-based study, the impacts of the physical characteristics of flocs formed using aluminum sulfate on the filtration treatment of two comparative water samples were investigated using a photometric dispersion analyzer and a filterability apparatus. In general, the optimum dosage for maximizing filterability was higher than that for minimizing turbidity under neutral pH conditions. For a monomeric aluminum-based coagulant, the charge neutralization mechanism produced better floc characteristics, including floc growth speed and size, than the sweep flocculation mechanism. In addition, the charge neutralization mechanism showed better performance compared to sweep flocculation in terms of DOC removal and floc filterability improvement for both waters, and showed superiority in turbidity removal only when the raw water had high turbidity. For the different mechanisms, the ways that floc characteristics impacted on floc filterability also differed. The low variation in floc size distribution obtained under the charge neutralization mechanism resulted in the flocs being amenable to removal by filtration processes. For the sweep flocculation mechanism, increasing the floc size improved the settling ability of flocs, resulting in higher filter efficiency. PMID- 28647256 TI - Bioavailability of wastewater derived dissolved organic nitrogen to green microalgae Selenastrum capricornutum, Chlamydomonas reinhardtii, and Chlorella vulgaris with/without presence of bacteria. AB - Effluent dissolved organic nitrogen (DON) is problematic in nutrient sensitive surface waters and needs to be reduced to meet demanding total dissolved nitrogen discharge limits. Bioavailable DON (ABDON) is a portion of DON utilized by algae or algae+bacteria, while biodegradable DON (BDON) is a portion of DON decomposable by bacteria. ABDON and BDON in a two-stage trickling filter (TF) wastewater treatment plant was evaluated using three different microalgal species, Selenastrum capricornutum, Chlamydomonas reinhardtii and Chlorella vulgaris and mixed cultured bacteria. Results showed that up to 80% of DON was bioavailable to algae or algae+bacteria inoculum while up to 60% of DON was biodegradable in all the samples. Results showed that C. reinhardtii and C. vulgaris can be used as a test species the same as S. capricornutum since there were no significant differences among these three algae species based on their ability to remove nitrogen species. PMID- 28647257 TI - Performance of CH4MODwetland for the case study of different regions of natural Chinese wetland. AB - Reliable national estimates of CH4 emissions from natural wetlands depend on model validation based on site observations. We therefore evaluated the performance of the CH4MODwetland model in simulating CH4 emissions from 11 representative wetland sites in five regions of China. Model performance analysis showed that this method effectively simulates differences in the CH4 fluxes between different sites and regions. The model efficiency for estimating the daily CH4 fluxes in the northeastern China (NE), Inner Mongolia and northwestern China (NW), the North China plain and the Middle-Lower Yangtze Plain (E) and the Qinghai Tibetan Plateau (SW) was 0.51, 0.20, 0.52 and 0.65, respectively. The efficiency for estimating the annual mean CH4 fluxes in southern China (S) was 0.99. Systematic negative deviation between the simulated and observed CH4 emissions existed in all regions, especially in the NW region, which had a mean deviation (RMD) value of -36.7%. On the national scale, the root mean square error (RMSE), the RMD, the model efficiency (EF) between the simulated and observed seasonal values were 28.7%, -7.8% and 0.93, respectively. The CH4 emissions showed the highest sensitivity to air temperature in the NE and SW regions, and to water table depth in the E region. Based on the sensitivity analysis, future climate warming and wetting are likely to increase the wetland CH4 emissions at different levels in all regions of China. PMID- 28647258 TI - Influence of haze pollution on water-soluble chemical species in PM2.5 and size resolved particles at an urban site during fall. AB - To investigate the influence of haze on the chemical composition and formation processes of ambient aerosol particles, PM2.5 and size-segregated aerosol particles were collected daily during fall at an urban site of Gwangju, Korea. During the study period, the total concentration of secondary ionic species (SIS) contributed an average of 43.9% to the PM2.5, whereas the contribution of SIS to the PM2.5 during the haze period was 62.3%. The NO3- and SO42- concentrations in PM2.5 during the haze period were highly elevated, being 13.4 and 5.0 times higher than those during non-haze period, respectively. The PM, NO3-, SO42-, oxalate, water-soluble organic carbon (WSOC), and humic-like substances (HULIS) had tri-modal size distributions peaks at 0.32, 1.0, and 5.2MUm during the non haze and haze periods. However, during the non-haze period they exhibited dominant size distributions at the condensation mode peaking at 0.32MUm, while on October 21 when the heaviest haze event occurred, they had predominant droplet mode size distributions peaking at 1.00MUm. Moreover, strong correlations of WSOC and HULIS with SO42-, oxalate, and K+ at particle sizes of <1.8MUm indicate that secondary processes and emissions from biomass burning could be responsible for WSOC and HULIS formations. It was found that the factors affecting haze formation could be the local stable synoptic conditions, including the weak surface winds and high surface pressures, the long-range transportation of haze from eastern China and upwind regions of the Korean peninsula, as well as the locally emitted and produced aerosol particles. PMID- 28647259 TI - Effect of current emission abatement strategies on air quality improvement in China: A case study of Baotou, a typical industrial city in Inner Mongolia. AB - The national Air Pollution Prevention and Control Action Plan required significant decreases in PM2.5 levels over China. To explore more effective emission abatement strategies in industrial cities, a case study was conducted in Baotou to evaluate the current national control measures. The total emissions of SO2, NOX, PM2.5 and NMVOC (non-methane volatile organic compounds) in Baotou were 211.2Gg, 156.1Gg, 28.8Gg, and 48.5Gg, respectively in 2013, and they would experience a reduction of 30.4%, 26.6%, 15.1%, and 8.7%, respectively in 2017 and 39.0%, 32.0%, 24.4%, and 12.9%, respectively in 2020. The SO2, NOX and PM2.5 emissions from the industrial sector would experience a greater decrease, with reductions of 37%, 32.7 and 24.3%, respectively. From 2013 to 2020, the concentrations of SO2, NO2, and PM2.5 are expected to decline by approximately 30%, 10% and 14.5%, respectively. The reduction rate of SNA (sulfate, nitrate and ammonium) concentrations was significantly higher than that of PM2.5 in 2017, implying that the current key strategy toward controlling air pollutants from the industrial sector is more powerful for SNA. Although air pollution control measures implemented in the industrial sector could greatly reduce total emissions, constraining the emissions from lower sources such as residential coal combustion would be more effective in decreasing the concentration of PM2.5 from 2017 to 2020. These results suggest that even for a typical industrial city, the reduction of PM2.5 concentrations not only requires decreases in emissions from the industrial sector, but also from the low emission sources. The seasonal variation in sulfate concentration also showed that emission from coal-burning is the key factor to control during the heating season. PMID- 28647260 TI - Numerical simulation of flow hydrodynamics of struvite pellets in a liquid-solid fluidized bed. AB - Phosphorus recovery in the form of struvite has been aroused in recent decades for its dual advantages in eutrophication control and resource protection. The usage of the struvite products is normally determined by the size which is largely depended on the hydrodynamics. In this study, flow behavior of struvite pellets was simulated by means of Eulerian-Eulerian two-fluid model combining with kinetic theory of granular flow in a liquid-solid fluidized bed reactor (FBR). A parametric study including the mesh size, time step, discretization strategy, turbulent model and drag model was first developed, followed by the evaluations of crucial operational conditions, particle characteristics and reactor shapes. The results showed that a cold model with the mesh resolution of 16*240, default time step of 0.001sec and first order discretization scheme was accurate enough to describe the fluidization. The struvite holdup profile using Syamlal-O'Brien drag model was best fitted to the experimental data as compared with other drag models and the empirical Richardson-Zaki equation. Regarding the model evaluation, it showed that liquid velocity and particle size played important roles on both solid holdups and velocities. The reactor diameter only influenced the solid velocity while the static bed height almost took no effect. These results are direct and can be applied to guide the operation and process control of the struvite fluidization. Moreover, the model parameters can also be used as the basic settings in further crystallization simulations. PMID- 28647261 TI - Removal of ammonium ion from water by Na-rich birnessite: Performance and mechanisms. AB - Na-rich birnessite (NRB) was synthesized by a simple synthesis method and used as a high-efficiency adsorbent for the removal of ammonium ion (NH4+) from aqueous solution. In order to demonstrate the adsorption performance of the synthesized material, the effects of contact time, pH, initial ammonium ion concentration, and temperature were investigated. Adsorption kinetics showed that the adsorption behavior followed the pseudo second-order kinetic model. The equilibrium adsorption data were fitted to Langmuir and Freundlich adsorption models and the model parameters were evaluated. The monolayer adsorption capacity of the adsorbent, as obtained from the Langmuir isotherm, was 22.61mg NH4+-N/g at 283K. Thermodynamic analyses showed that the adsorption was spontaneous and that it was also a physisorption process. Our data revealed that the higher NH4+ adsorption capacity could be primarily attributed to the water absorption process and electrostatic interaction. Particularly, the high surface hydroxyl-content of NRB enables strong interactions with ammonium ion. The results obtained in this study illustrate that the NRB is expected to be an effective and economically viable adsorbent for ammonium ion removal from aqueous system. PMID- 28647262 TI - Development of a hybrid photo-bioreactor and nanoparticle adsorbent system for the removal of CO2, and selected organic and metal co-pollutants. AB - Fossil fuel combustion and many industrial processes generate gaseous emissions that contain a number of toxic organic pollutants and carbon dioxide (CO2) which contribute to climate change and atmospheric pollution. There is a need for green and sustainable solutions to remove air pollutants, as opposed to conventional techniques which can be expensive, consume additional energy and generate further waste. We developed a novel integrated bioreactor combined with recyclable iron oxide nano/micro-particle adsorption interfaces, to remove CO2, and undesired organic air pollutants using natural particles, while generating oxygen. This semi-continuous bench-scale photo-bioreactor was shown to successfully clean up simulated emission streams of up to 45% CO2 with a conversion rate of approximately 4% CO2 per hour, generating a steady supply of oxygen (6mmol/hr), while nanoparticles effectively remove several undesired organic by-products. We also showed algal waste of the bioreactor can be used for mercury remediation. We estimated the potential CO2 emissions that could be captured from our new method for three industrial cases in which, coal, oil and natural gas were used. With a 30% carbon capture system, the reduction of CO2 was estimated to decrease by about 420,000, 320,000 and 240,000 metric tonnes, respectively for a typical 500MW power plant. The cost analysis we conducted showed potential to scale-up, and the entire system is recyclable and sustainable. We further discuss the implications of usage of this complete system, or as individual units, that could provide a hybrid option to existing industrial setups. PMID- 28647263 TI - A zero-valent iron and organic matter mixture enhances herbicide and herbicide degradation product removal in subsurface waters. AB - The pesticide atrazine, its degradation products, and 2,6-dichlorobenzamide (BAM) are persistent in groundwater environment. We studied whether their dissipation can be enhanced with a mixture of a complex carbon source and zero-valent iron (ZVI) called EHC(r). The application rates were 1.0% and 2.0% (by weight) in subsurface sediments slurries (atrazine 30mg/L), and 2.0% in 1.5m pilot-scale sediment columns with groundwater flowing through (atrazine 0.08, desethylatrazine DEA 0.03, BAM 0.02MUg/L). In the slurries under aerobic conditions, atrazine of 0.88+/-0.14mg/g of EHC(r) was dissipated chemically, as concentrations did not differ significantly between the slurries and their sterilized controls. No degradation occurred in the slurries under anaerobic conditions. In the pilot-scale columns under water-saturated conditions, atrazine, DEA and BAM were not detected in effluents during 33, 64 and 64days from the beginning of the water flow through EHC(r) columns, respectively, but thereafter traces of compounds could be detected. No atrazine or degradation products (BAM, DEA, deisopropylatrazine, desethyldeisopropylatrazine) could be extracted from the column sediments at the end of the experiment. As a result, the sum of dissipated pesticides was about 7.6MUg/g of EHC(r) in columns under water-saturated conditions, and 0.88mg/g of EHC(r) in slurries under aerobic conditions. EHC(r) can be used to enhance the dissipation of studied pesticides in small quantities, preferentially under aerobic conditions. PMID- 28647264 TI - MgO-based adsorbents for CO2 adsorption: Influence of structural and textural properties on the CO2 adsorption performance. AB - A series of MgO-based adsorbents were prepared through solution-combustion synthesis and ball-milling process. The prepared MgO-based powders were characterized using X-ray diffraction, scanning electron microscopy, N2 physisorption measurements, and employed as potential adsorbents for CO2 adsorption. The influence of structural and textural properties of these adsorbents over the CO2 adsorption behaviour was also investigated. The results showed that MgO-based products prepared by solution-combustion and ball-milling processes, were highly porous, fluffy, nanocrystalline structures in nature, which are unique physico-chemical properties that significantly contribute to enhance their CO2 adsorption. It was found that the MgO synthesized by solution combustion process, using a molar ratio of urea to magnesium nitrate (2:1), and treated by ball-milling during 2.5hr (MgO-BM2.5h), exhibited the maximum CO2adsorption capacity of 1.611mmol/g at 25 degrees C and 1atm, mainly via chemisorption. The CO2 adsorption behaviour on the MgO-based adsorbents was correlated to their improved specific surface area, total pore volume, pore size distribution and crystallinity. The reusability of synthesized MgO-BM2.5h was confirmed by five consecutive CO2 adsorption-desorption times, without any significant loss of performance, that supports the potential of MgO-based adsorbent. The results confirmed that the special features of MgO prepared by solution-combustion and treated by ball-milling during 2.5hr are favorable to be used as effective MgO-based adsorbent in post-combustion CO2 capture technologies. PMID- 28647265 TI - Evaluation of co-metabolic removal of trichloroethylene in a biotrickling filter under acidic conditions. AB - This study investigated the removal of hydrophobic trichloroethylene (TCE) in the presence of methanol (co-metabolite) in a biotrickling filter, which was seeded with fungi at pH4. Starvation was chosen as the biomass control strategy. Two systems, Biofilter I (methanol:TCE 70:30) and Biofilter II (methanol:TCE 80:20) were run in parallel, each with varying composition ratios. The TCE loading rates for both biofilters ranged from 3.22 to 12.88g/m3/hr. Depending on the ratio, methanol concentrations varied from 4.08 to 27.95g/m3/hr. The performance of the systems was evaluated and compared by calculating removal kinetics, carbon mass balance, efficiencies and elimination capacities. Methanol was observed to enhance TCE removal during the initial loading rate. However, methanol later inhibited TCE degradation above 6.44g TCE/m3/hr (Biofilter I) and 3.22g TCE/m3/hr (Biofilter II). Conversely, TCE did not impede methanol removal because over 95% methanol elimination was consistently achieved. Overall, Biofilter I was able to outperform Biofilter II due to its greater resistance towards methanol competition. PMID- 28647266 TI - Synthesis of a novel illite@carbon nanocomposite adsorbent for removal of Cr(VI) from wastewater. AB - A novel illite@carbon (I@C) nanocomposite adsorbent has been synthesized via a facile hydrothermal carbonization process (HTC) using glucose as carbonaceous source and illite as the carrier. The morphology, microstructure and surface properties of the prepared nanocomposite adsorbent were analyzed by FESEM, TGA, XRD, FT-IR and Zeta potential measurements. Batch experiments were carried out on the adsorption of Cr(VI) to determine the adsorption properties of the composite. The adsorption of Cr(VI) onto the I@C nanocomposite was well described by the pseudo-second-order kinetic model and Langmuir isotherm. Compared with the illite and carbon material (SC) separately, the prepared I@C nanocomposite adsorbent exhibited enhanced adsorption performance for Cr(VI) with a maximum adsorption capacity of 149.25mg/g, which was higher than that of most reported adsorbents. In addition, the adsorption process was spontaneous and endothermic based on the adsorption thermodynamics study. The adsorption of Cr(VI) by I@C was highly pH dependent and the optimum adsorption occurred at pH2.0. The Zeta potential analysis results indicated that the electrostatic interactions between anionic Cr(VI) and the positively charged surface of the adsorbent might be critical to the adsorption mechanism. This study demonstrated that the I@C nanocomposite should be a promising candidate for a low-cost, environmental friendly and highly efficient adsorbent for the removal of toxic Cr(VI) from wastewater. PMID- 28647267 TI - Relationship between nutrients and plankton biomass in the turbidity maximum zone of the Pearl River Estuary. AB - Nutrients, dissolved and particulate organic carbon and plankton (bacterio-, phyto- and zoo-) were compared in the turbidity maximum zone (TMZ) and adjacent areas (non-TMZ) in the Pearl River estuary. Our results showed that high levels of suspended substances had marked effect on dynamics of nutrients and plankton in the TMZ. Based on the cluster analysis of total suspended solids (TSS) concentrations, all stations were divided into two groups, TMZ with average TSS of 171mg/L and non-TMZ of 45mg/L. Suspended substances adsorbed PO43- and dissolved organic carbon, resulting in higher particulate phosphorus and organic carbon (POC) and lower PO43- and DOC in the TMZ, compared to the non-TMZ. However, suspended substances had limited effect on nitrogenous nutrients. Phytoplankton growth was light-limited due to high concentrations of suspended substances in the TMZ and a peak of phytoplankton abundance appeared in the non TMZ. In contrast, the highest bacterial abundance occurred in the TMZ, which was likely partly responsible for low DOC levels. Two peaks of zooplankton abundance observed in the TMZ and non-TMZ in the Pearl River estuary were primarily supported by bacteria and phytoplankton, respectively. Our finding implied that high levels of suspended solids in the TMZ affect the trophic balance. PMID- 28647268 TI - Adsorption of Ca2+ on single layer graphene oxide. AB - Graphene oxide (GO) holds great promise for a broad array of applications in many fields, but also poses serious potential risks to human health and the environment. In this study, the adsorptive properties of GO toward Ca2+ and Na+ were investigated using batch adsorption experiments, zeta potential measurements, and spectroscopic analysis. When pH increased from 4 to 9, Ca2+ adsorption by GO and the zeta potential of GO increased significantly. Raman spectra suggest that Ca2+ was strongly adsorbed on the GO via -COOCa+ formation. On the other hand, Na+ was adsorbed into the electrical diffuse layer as an inert counterion to increase the diffuse layer zeta potential. While the GO suspension became unstable with increasing pH from 4 to 10 in the presence of Ca2+, it was more stable at higher pH in the NaCl solution. The findings of this research provide insights in the adsorption of Ca2+ on GO and fundamental basis for prediction of its effect on the colloidal stability of GO in the environment. PMID- 28647269 TI - Quantum chemical investigation on photodegradation mechanisms of sulfamethoxypyridazine with dissolved inorganic matter and hydroxyl radical. AB - Sulfamethoxypyridazine (SMP) is one of the commonly used sulfonamide antibiotics (SAs). SAs are mainly studied to undergo triplet-sensitized photodegradation in water under natural sunlight with other coexisting aquatic environmental organic pollutants. In this work, SMP was selected as a representative of SAs. We studied the mechanisms of triplet-sensitized photodegradation of SMP and the influence of selected dissolved inorganic matter, i.e., anions (Br-, Cl-, and NO3-) and cations ions (Ca2+, Mg2+, and Zn2+) on SMP photodegradation mechanism by quantum chemical methods. In addition, the degradation mechanisms of SMP by hydroxyl radical (OH) were also investigated. The creation of SO2 extrusion product was accessed with two different energy pathways (pathway-1 and pathway-2) by following two steps (step-I and step-II) in the triplet-sensitized photodegradation of SMP. Due to low activation energy, the pathway-1 was considered as the main pathway to obtain SO2 extrusion product. Step-II of pathway-1 was measured to be the rate-limiting step (RLS) of SMP photodegradation mechanism and the effect of the selected anions and cations was estimated for this step. All selected anions and cations promoted photodegradation of SMP by dropping the activation energy of pathway-1. The estimated low activation energies of different degradation pathways of SMP with OH radical indicate that OH radical is a very powerful oxidizing agent for SMP degradation via attack through benzene derivative and pyridazine derivative ring. PMID- 28647270 TI - Polycyclic aromatic hydrocarbons in ambient air, surface soil and wheat grain near a large steel-smelting manufacturer in northern China. AB - The total concentrations and component profiles of polycyclic aromatic hydrocarbons (PAHs) in ambient air, surface soil and wheat grain collected from wheat fields near a large steel-smelting manufacturer in Northern China were determined. Based on the specific isomeric ratios of paired species in ambient air, principle component analysis and multivariate linear regression, the main emission source of local PAHs was identified as a mixture of industrial and domestic coal combustion, biomass burning and traffic exhaust. The total organic carbon (TOC) fraction was considerably correlated with the total and individual PAH concentrations in surface soil. The total concentrations of PAHs in wheat grain were relatively low, with dominant low molecular weight constituents, and the compositional profile was more similar to that in ambient air than in topsoil. Combined with more significant results from partial correlation and linear regression models, the contribution from air PAHs to grain PAHs may be greater than that from soil PAHs. PMID- 28647271 TI - Relationship between Measures of Neonatal Glycemia, Neonatal Illness, and 2-Year Outcomes in Very Preterm Infants. AB - OBJECTIVES: To investigate relationships between early neonatal glycemia, neonatal characteristics, neonatal illness, and developmental outcomes in very preterm infants. STUDY DESIGN: A retrospective, observational cohort study of 443 infants born weighing <1500 g or <30 weeks of gestation, and admitted within 24 hours to National Women's Hospital, Auckland, New Zealand. Glucose variability was defined as the standard deviation around the mean after log transformation of all blood glucose concentrations. Absolute glycemic excursions in the first week were used to divide the infants into 4 groups: normoglycemic; hypoglycemic; hyperglycemic, and unstable. RESULTS: Compared with normoglycemic infants, hypoglycemic and unstable infants had lower birth weight z-scores, and hyperglycemic and unstable infants were of lower birth weight. Hypoglycemic infants had similar outcomes to normoglycemic infants. Hyperglycemic and unstable infants were less likely to survive without neonatal morbidity and less likely to survive without neurodevelopmental impairment at 2 years of age. Higher mean blood glucose concentration was seen in the hyperglycemic and unstable groups, and was associated with worse neonatal and 2-year outcomes. Greater glucose variability was seen in the hypoglycemic and unstable groups, and was associated with worse neonatal illness but not outcome at 2 years. No associations between measures of neonatal glycemia and neonatal or 2-year outcomes remained after correction for gestation, birth weight z-score, and socioeconomic status. CONCLUSIONS: In very preterm infants, measures of neonatal glycemia are markers of gestational age and intrauterine growth, and are not independent predictors of neonatal illness or outcomes at 2 years of age. PMID- 28647273 TI - The effect of miR-30d on apoptosis and autophagy in cultured astrocytes under oxygen-glucose deprivation. AB - MiR-30d has been demonstrated to regulate autophagy in human cancer cells. However, the role of miR-30d in astrocytes exposed to hypoxia-ischemia is not clear. In this study, we established model of oxygen and glucose deprivation (OGD) with rat primary astrocytes and evaluated the role of miR-30d in the cross talk between autophagy and apoptosis in astrocytes after OGD. We found that miR 30d inhibited Beclin1 expression in astrocytes. Inhibition of miR-30d by antagomir significantly increased cell autophagy but decreased cell apoptosis in astrocytes exposed to OGD. Knockdown of Beclin1 reversed the upregulation of autophagy and downregulation of apoptosis induced by miR-30d inhibition in astrocytes subjected to OGD. These results strongly indicated that miR-30d played critical roles in the cross-talk between autophagy and apoptosis of astrocytes subjected to OGD by targeting Beclin1. MiR-30d is a novel target to attenuate cell injury under hypoxia-ischemia condition. PMID- 28647274 TI - Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells. AB - BACKGROUND AIMS: Sonic hedgehog (Shh) is an intercellular signaling molecule that regulates pancreas development in mammals. Manipulation of Shh signaling pathway can be used as reliable approach to improve the generation of functional insulin producing cells (IPCs) from mesenchymal stromal cells (MSCs). METHODS: In the present study, a novel differentiation protocol was used to produce IPCs from adipose tissue-derived MSCs (ATDMSCs) based on sequential inhibition and reactivation of Shh pathway. ATDMSCs were differentiated into IPCs via a 14-day basic protocol using 1% insulin transferrin selenium (ITS) and 1% nicotinamide in Dulbecco's Modified Eagle's Medium medium. A mixture of 0.25 umol/L cyclopamine + 64 ng/mL basic fibroblast growth factor at day 3 of differentiation and 150 ng/mL recombinant Shh at day 11 of differentiation were used, respectively, to promote sequential inhibition and reactivation of Shh pathway. Insulin granule formation, glucose-stimulated insulin secretion and gene expression pattern related to the pancreatic endocrine development and function were analyzed in manipulated and unmanipulated IPCs. RESULTS: IPCs obtained after Shh manipulation secreted higher amounts of insulin in vitro. This phenotype was accompanied by increased expression of both genes critical for beta-cell function and transcription factors associated with their mature phenotype including Pdx1, MafA, Nkx2.2, Nkx6.1, Ngn3, Isl1 and insulin at day 14 of differentiation. CONCLUSIONS: Our findings indicated that the early inhibition and late reactivation of Shh signaling pathway during the differentiation of ATDMSCs improved the functional properties of IPCs, a novel method that could be considered as an alternative approach for cell-based therapy for type 1 diabetes. PMID- 28647275 TI - When fatigue symptoms are associated with ... fatigue symptoms. PMID- 28647276 TI - Reply. PMID- 28647278 TI - The ruptured hydatid cyst of the right kidney; demonstration with multidetector computed tomography. PMID- 28647279 TI - Pulmonar plombage. PMID- 28647277 TI - Risk factors for nosocomial infections in patients receiving extracorporeal membrane oxygenation supportive therapy. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to analyze risk factors for nosocomial infection (NI) in patients receiving extracorporeal membrane oxygenation (ECMO) support. PATIENTS AND METHODS: Clinical NI data were collected from patients who received ECMO support therapy, and analyzed retrospectively. RESULTS: Among 75 ECMO patients, 20 were found to have developed NI (infection rate 26.7%); a total of 58 pathogens were isolated, including 43 strains of gram negative bacteria (74.1%) and 15 strains of gram-positive bacteria (25.9%). Multi drug resistant strains were highly concentrated and were mainly shown to be Acinetobacter baumannii, Pseudomonas aeruginosa, and coagulase-negative staphylococci. Incidence of NI was related to the duration of ECMO support therapy and the total length of hospital stay, and the differences were statistically significant (P<.05). A prolonged period of ECMO support extended the hospital stay, but it did not increase the mortality rate. However, an elevated level of lactic acid increased the mortality rate in this study population. CONCLUSIONS: ECMO-associated secondary NIs correlated significantly with the length of hospital stay and with the duration of ECMO support. Therefore, to reduce the incidence of ECMO-associated NIs, preventive strategies that aim to shorten the duration of ECMO support therapy and avoid lengthy hospitalization should be applied, wherever possible. PMID- 28647280 TI - Renal involvement in MELAS. PMID- 28647281 TI - Serotonergic modulation of nicotine-induced kinetic tremor in mice. AB - We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via alpha7 nicotinic acetylcholine (nACh) receptors. Since alpha7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT1A agonist, 8 hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT1A antagonist). In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT2 agonist, 2,5-dimethoxy-4 iodoamphetamine (DOI), significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT2 antagonist). The 5-HT3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5 HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT3 antagonist) or SB-258585 (5-HT6 antagonist). These results suggest that postsynaptic 5-HT1A receptors are involved in induction of nicotine tremor mediated by alpha7 nACh receptors. In addition, 5 HT2 receptors have an inhibitory modulatory role in induction of nicotine tremor. PMID- 28647282 TI - CXCL16/CXCR6-mediated adhesion of human peripheral blood mononuclear cells to inflamed endothelium. AB - The endothelial chemokine CXC motif ligand 16 (CXCL16) is involved in the recruitment and firm adhesion of CXCR6+ cells to the atherosclerosis-prone aortic vessel wall. Recently we showed that CXCR6+ platelets from flowing blood attach to CXCL16 expressed by activated endothelium on the luminal side of the blood vessel. With this study we supplement these findings with the observation that platelets bound to the inflamed endothelium are presenting CXCR6 to CXCL16 positive peripheral blood mononuclear cells (PBMCs) and, thus, are mediating an increased adhesion of PBMCs to the arterial wall. Furthermore we identified endothelial CXCL16 as an important adhesion molecule promoting the firm adhesion of CXCR6-positive PBMCs to inflamed endothelium. Our results demonstrate that endothelial CXCL16 as well as platelet CXCR6 are acting as potent PBMC-adhesion ligands, inducing PBMC-adhesion to the atherosclerosis-prone vessel wall and thus promoting the progression of atherosclerosis. PMID- 28647272 TI - Outcomes of Preterm Infants following Discussions about Withdrawal or Withholding of Life Support. AB - OBJECTIVES: To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. STUDY DESIGN: This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated. RESULTS: WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of <=24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. CONCLUSIONS: Wide center variations in WWLST discussions occur, especially at <=24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063. PMID- 28647283 TI - Optimal cooling strategies for players in Australian Tennis Open conditions. AB - OBJECTIVES: We compared the utility of four cooling interventions for reducing heat strain during simulated tennis match-play in an environment representative of the peak conditions possible at the Australian Open (45 degrees C, <10% RH, 475W/m2 solar radiation). DESIGN: Nine trained males undertook four trials in a climate chamber, each time completing 4 sets of simulated match-play. METHODS: During ITF-mandated breaks (90-s between odd-numbered games; 120-s between sets), either iced towels (ICE), an electric fan (FANdry), a fan with moisture applied to the skin (FANwet), or ad libitum 10 degrees C water ingestion only (CON) was administered. Rectal temperature (Tre), mean skin temperature (Tsk), heart rate (HR), thermal sensation (TS), perceived exertion (RPE) and whole body sweating (WBSR) were measured. RESULTS: After set 3, Tre was lower in ICE (38.2+/-0.3 degrees C) compared to FANdry (38.7+/-0.5 degrees C; p=0.02) and CON (38.5+/-0.5 degrees C; p=0.05), while Tre in FANwet (38.2+/-0.3 degrees C) was lower than FANdry (p=0.05). End-exercise Tre was lower in ICE (38.1+/-0.3 degrees C) and FANwet (38.2+/-0.4 degrees C) than FANdry (38.9+/-0.7 degrees C; p<0.04) and CON (38.8+/-0.5 degrees C; p<0.04).Tsk for ICE (35.3+/-0.8 degrees C) was lower than all conditions, and Tsk for FANwet (36.6+/-1.1 degrees C) was lower than FANdry (38.1+/-1.3 degrees C; p<0.05). TS for ICE and FANwet were lower than CON and FANdry (p<0.05). HR was suppressed in ICE and FANwet relative to CON and FANdry (p<0.05). WBSR was greater in FANdry compared to FANwet (p<0.01) and ICE (p<0.001). CONCLUSIONS: Fan use must be used with skin wetting to be effective in hot/dry conditions. This strategy and the currently recommended ICE intervention both reduced Tre by ~0.5-0.6 degrees C and Tsk by ~1.0-1.5 degrees C while mitigating rises in HR and TS. PMID- 28647284 TI - The effects of high intensity interval training on muscle size and quality in overweight and obese adults. AB - OBJECTIVES: Despite growing popularity of high intensity interval training (HIIT) for improving health and fitness, limited data exist identifying the effects of HIIT on muscle characteristics. The purpose of the current study was to investigate the effects of a 3-week HIIT intervention on muscle size and quality in overweight and obese men and women. DESIGN: Randomized controlled trial. METHODS: Forty-four overweight and obese men and women (mean+/-SD; age: 35.4+/ 12.3years; height: 174.9+/-9.7cm; weight: 94.6+/-17.0kg; %fat: 32.7+/-6.5%) completed the current study. During baseline and post testing, muscle cross sectional area (mCSA) and echo intensity (EI) were determined from a panoramic scan of the vastus lateralis obtained by B-mode ultrasonography. Body composition variables were measured using dual energy X-ray absorptiometry. Participants were randomized into either a 1:1 work-to-rest ratio HIIT group (SIT; n=16), a 2:1 work-to-rest ratio HIIT group (LIT; n=19), or control (CON; n=9). HIIT participants performed five, 2-min bouts (LIT) or 10, 1-min bouts (SIT) at 85 100% VO2peak for 9 sessions over three weeks. RESULTS: Analysis of covariance demonstrated a significant increase in mCSA for SIT (p=0.038; change (Delta)=3.17+/-3.36cm2) compared to CON (Delta=-0.34+/-2.36cm2). There was no significant difference in EI across groups (p=0.672). CONCLUSIONS: HIIT may be an effective exercise modality to influence muscle size in overweight and obese individuals. Future studies should investigate muscle characteristics and remodeling in an overweight population following interventions of longer duration and varying work-to-rest protocols. PMID- 28647285 TI - Contrasting patterns of energy metabolism in northern vs southern peripheral European flounder populations exposed to temperature rising and hypoxia. AB - A two months common garden experiment was carried out to explore the potential differences of energy metabolism in northern core (France, 50 degrees N and 47 degrees N) vs southern peripheral (Portugal, 41 degrees N) populations of European flounder Platichthys flesus, submitted to cold condition (CC: water temperature = 10 degrees C) and to warm and hypoxic condition (WHC: water temperature = 22 degrees C, and moderate hypoxia with O2 saturation = 40% during the last 6 days). Convergent growth rates (in length) were observed in the different populations and conditions, when the southern peripheral population of Portugal did not grow under cold conditions. A general reduction in liver lipid storage was observed in all populations subjected to WHC when compared to CC, whereas muscle lipid storage was unaffected. The thermal and hypoxia treatment induced changes in muscle phospholipids (PL) ratios: phosphatidylserine/PL, phosphatidylinositol/PL, between northern and southern populations. Fish from northern estuaries displayed marked anaerobiosis in WHC (increased liver LDH activity) vs marked aerobiosis under CC (higher muscle CS and CCO activities). Contrariwise, fish from the southern estuary displayed equilibrium between anaerobiosis and aerobiosis activities in WHC. Flounders from the southern population exhibited generally lower G6PDH activity (proxy for anabolism and for defense against oxidative damage), tissue-specific anaerobiosis response (muscle LDH activity) and lower CS and CCO muscle activities (aerobiosis markers) when compared to northern populations. Globally, these inter-population differences in bioenergetics suggest that southern peripheral vs northern core populations have developed differential capacity to cope with interacting stressors and that much of this variation is more likely due to local adaptation. PMID- 28647286 TI - The taper corrosion pattern observed for one bi-modular stem design is related to geometry-determined taper mechanics. AB - Bi-modular primary hip stems exhibit high revision rates owing to corrosion at the stem-neck taper, and are associated with local adverse tissue reactions. The aim of this study was to relate the wear patterns observed for one bi-modular design to its design-specific stem-neck taper geometry. Wear patterns and initial geometry of the taper junctions were determined for 27 retrieved bi-modular primary hip arthroplasty stems (Rejuvenate, Stryker Orthopaedics) using a tactile coordinate-measuring device. Regions of high-gradient wear patterns were additionally analyzed via optical and electron microscopy. The determined geometry of the taper junction revealed design-related engagement at its opening (angle mismatch), concentrated at the medial and lateral apexes (axes mismatch). A patch of retained topography on the proximal medial neck-piece taper apex was observed, surrounded by regions of high wear. On the patch, a deposit from the opposing female stem taper-containing Ti, Mo, Zr, and O-was observed. High stress concentrations were focused at the taper apexes owing to the specific geometry. A medial canting of the components may have augmented the inhomogeneous stress distributions in vivo. In the regions with high normal loads interfacial slip and consequently fretting was inhibited, which explains the observed pattern of wear. PMID- 28647287 TI - Microwave thermal ablation: Effects of tissue properties variations on predictive models for treatment planning. AB - Microwave thermal ablation (MTA) therapy for cancer treatments relies on the absorption of electromagnetic energy at microwave frequencies to induce a very high and localized temperature increase, which causes an irreversible thermal damage in the target zone. Treatment planning in MTA is based on experimental observations of ablation zones in ex vivo tissue, while predicting the treatment outcomes could be greatly improved by reliable numerical models. In this work, a fully dynamical simulation model is exploited to look at effects of temperature dependent variations in the dielectric and thermal properties of the targeted tissue on the prediction of the temperature increase and the extension of the thermally coagulated zone. In particular, the influence of measurement uncertainty of tissue parameters on the numerical results is investigated. Numerical data were compared with data from MTA experiments performed on ex vivo bovine liver tissue at 2.45GHz, with a power of 60W applied for 10min. By including in the simulation model an uncertainty budget (CI=95%) of +/-25% in the properties of the tissue due to inaccuracy of measurements, numerical results were achieved in the range of experimental data. Obtained results also showed that the specific heat especially influences the extension of the thermally coagulated zone, with an increase of 27% in length and 7% in diameter when a variation of -25% is considered with respect to the value of the reference simulation model. PMID- 28647288 TI - Gap junctions, pannexins and pain. AB - Enhanced expression and function of gap junctions and pannexin (Panx) channels have been associated with both peripheral and central mechanisms of pain sensitization. At the level of the sensory ganglia, evidence includes augmented gap junction and pannexin1 expression in glial cells and neurons in inflammatory and neuropathic pain models and increased synchrony and enhanced cross-excitation among sensory neurons by gap junction-mediated coupling. In spinal cord and in suprapinal areas, evidence is largely limited to increased expression of relevant proteins, although in several rodent pain models, hypersensitivity is reduced by treatment with gap junction/Panx1 channel blocking compounds. Moreover, targeted modulation of Cx43 expression was shown to modulate pain thresholds, albeit in somewhat contradictory ways, and mice lacking Panx1 expression globally or in specific cell types show depressed hyperalgesia. We here review the evidence for involvement of gap junctions and Panx channels in a variety of animal pain studies and then discuss ways in which gap junctions and Panx channels may mediate their action in pain processing. This discussion focusses on spread of signals among satellite glial cells, in particular intercellular Ca2+ waves, which are propagated through both gap junction and Panx1-dependent routes and have been associated with the phenomenon of spreading depression and the malady of migraine headache with aura. PMID- 28647289 TI - Dysregulation of miR-499, miR-708 and miR-1908 during a depression episode in bipolar disorders. AB - Affective disorders include unipolar disorder (UP) (depression episodes) and bipolar disorder (BP) (depression and mania episodes). Currently, no biological markers are known that can help to differentiate these disorders. However, recent studies have suggested that psychiatric disorders can be connected with small, non-coding RNA, like microRNA. The objective of this study was to analyse the expression level of three microRNAs (miR-499, miR-708, miR-1908) in bipolar and unipolar disorder during depression episodes and after entering the remission state. The group consisted of adult women only, 17 UP (age: 50+/-17) and 15 BP (age: 33+/-13) patients. The expression level of miRNAs was investigated by RT qPCR with the TaqMan assay. Our study has shown a lower expression level of miR 499 (p=0.008), miR-708 (p=0.02) and miR-1908 (p=0.004) in depression episodes of the bipolar disorder patients in comparison to remission state. We have not found similar differences in unipolar disorder and between those types in acute phase of depression and during remission. Obtained results indicate that miRNAs: miR 499, miR-708 and miR-1908 are the most promising candidates for biomarkers of depression episodes of bipolar disorder. PMID- 28647290 TI - Effect of professional expertise and exposure to everyday life decision-making on moral choices. AB - Moral sense is defined as a feeling of fairness or unfairness of an action that knowingly causes harm to people other than the subject. It is crucial in determining human behavior and becomes pivotal in operational environments. Here we assessed whether professional daily life experience in an operational environment affects moral judgment by asking 41 military pilots of the Italian Air Force (P) and 69 controls (C) to solve 40 moral dilemmas. We found that P gave more morally acceptable utilitarian responses to moral dilemmas. Interestingly, men and women in P equally accepted utilitarian resolutions of moral dilemmas, whereas in C women were less prone than men to accept utilitarian responses. We conclude that professional daily life experience of P, in an operational environment, affects moral judgment and mitigates gender predisposition towards moral dilemmas. PMID- 28647291 TI - Genistein supplementation improves insulin resistance and inflammatory state in non-alcoholic fatty liver patients: A randomized, controlled trial. AB - BACKGROUND & AIMS: The beneficial effect of genistein has indicated on metabolic disorders and inflammatory state. The aim of this study was to investigate the effect of genistein supplementation on non-alcoholic fatty liver disease (NAFLD) as the hepatic manifest of metabolic syndrome. METHODS: In the present randomized double-blind controlled trial, patients with NAFLD were daily supplemented with either 250 mg genistein (n = 41) or placebo (n = 41) for 8-weeks. Both groups were instructed to follow an energy-balanced diet and physical activity recommendations. And their anthropometric and biochemical indices were assessed before and after the intervention. RESULTS: At the end of the study, the genistein group had lower level of serum insulin (p = 0.001) and homeostasis model assessment for insulin resistance (HOMA-IR) (p = 0.041) compare to the placebo group. In addition serum malondialdehyde (MDA) (p = 0.004), tumor necrosis factor-alpha (TNF-alpha) (p = 0.045) and interleukin (IL)-6 (p = 0.018) also were lower in the genistein group. Compare with placebo, genistein supplementation significantly reduced waist to hip ratio (p = 0.021), body fat percentage (p = 0.015) and triglyceride (p = 0.018). However, there were no significant changes in BMI, fasting blood glucose (p = 0.122), alanine aminotransferase (ALT) (p = 0.536), aspartate aminotransferase (AST) (p = 0.265) between the two groups. CONCLUSIONS: Oral supplementation with 250 mg genistein for 8-weeks can reduce insulin resistance, oxidative and inflammatory indices along with improvement in fat metabolism in patients with NAFLD. Studies with longer duration and larger samples might be needed to reveal other beneficial effects of genistein. PMID- 28647292 TI - Risk factors of refeeding syndrome in malnourished older hospitalized patients. AB - BACKGROUND & AIMS: Despite the high prevalence of malnutrition among older hospitalized persons, it is unknown how many of these malnourished patients are at risk of developing the refeeding syndrome (RFS). In this study, we sought to compare the prevalence and severity of malnutrition among older hospitalized patients with prevalence of known risk factors of RFS. METHODS: This cross sectional multicenter-study investigated older participants who were consecutively admitted to the geriatric acute care ward. Malnutrition screening was conducted using Nutritional Risk Screening (NRS-2002), Malnutrition Universal Screening Tool (MUST) and Mini Nutritional Assessment-Short Form (MNA-SF). The National Institute for Health and Clinical Excellence (NICE) criteria were applied for assessing patients at risk of RFS. Weight and height were measured. Degree of weight loss (WL) was obtained by interview. Serum phosphate, magnesium, potassium, sodium, calcium, creatinine and urea were analyzed according to standard procedures. RESULTS: The study group comprised 342 participants (222 females) with a mean age of 83.1 +/- 6.8 and BMI range of 14.7-43.6 kg/m2. More participants were assessed at risk of malnutrition using NRS-2002 (n = 253, 74.0%) compared to MUST (n = 170, 49.7%) and MNA-SF (n = 191, 55.8%). Of total participants, 239 (69.9%; 157 females) were considered to be at risk of RFS. Based on NRS-2002, 75.9% (n = 192) of patients at risk of malnutrition are at risk of RFS whereas according to MUST and MNA-SF, 85.9% (n = 146) and 69.1% (n = 132) of patients at risk of malnutrition are exposed to high risk of RFS, respectively. In addition, the prevalence of risk of RFS is significantly increased with higher score of NRS-2002 and MUST and lower score of MNA-SF. In a stepwise multiple regression analysis, disease severity (38.2%), WL in 3 months (20.3%) and BMI (33.3%) mainly explained variance in NRS-2002, MUST and MNA-SF scores, respectively, in patients with risk of RFS. CONCLUSION: Nearly three quarters of geriatric hospitalized patients with risk of malnutrition demonstrated significant risk of RFS. Therefore, additional screening for risk of RFS in patients screened for malnutrition appears to be abdicable among this population. PMID- 28647293 TI - Dynapenic obesity as an associated factor to lipid and glucose metabolism disorders and metabolic syndrome in older adults - Findings from SABE Study. AB - BACKGROUND & AIMS: There is little evidence showing that dynapenic obesity is associated with lipid and glucose metabolism disorders, high blood pressure, chronic disease and metabolic syndrome. Our aim was to analyze whether dynapenic abdominal obesity can be associated with lipid and glucose metabolism disorders, high blood pressure, metabolic syndrome and cardiovascular diseases in older adults living in Sao Paulo. METHODS: This cross-sectional study included 833 older adults who took part of the third wave of the Health, Well-being and Aging Study in 2010. Based on waist circumference (>88 cm women and >102 cm men) and handgrip strength (<16 kg women and <26 kg men), four groups were identified: non dynapenic/non-abdominal obese (ND/NAO), abdominal obese alone (AOA), dynapenic alone (DA) and dynapenic/abdominal obese (D/AO). Dependent variables were blood pressure, lipid profile, fasting glucose and glycated-haemoglobin, metabolic syndrome and cardiovascular diseases. Logistic regression was used to analyze the associations between dynapenia and abdominal obesity status and lipid and glucose metabolic profiles, blood pressure, cardiovascular diseases and metabolic syndrome. RESULTS: The fully adjusted models showed that D/AO individuals had higher prevalence of low HDL plasma concentrations (OR = 2.51, 95%CI: 1.40-4.48), hypertriglyceridemia (OR = 2.53, 95%CI: 1.43-4.47), hyperglycemia (OR = 2.05, 95%CI: 1.14-3.69), high glycated-haemoglobin concentrations (OR = 1.84, 95%CI: 1.03-3.30) and metabolic syndrome (OR = 12.39, 95%CI: 7.38-20.79) than ND/NAO. Dynapenic and D/AO individuals had higher prevalence of heart disease (OR = 2.05, 95%CI: 1.17-3.59 and OR = 1.92, 95%CI: 1.06-3.48, respectively) than ND/NAO. CONCLUSION: D/AO was associated with high prevalence of lipid and glucose metabolism disorders and metabolic syndrome while dynapenia and D/AO were associated with high prevalence of heart disease. PMID- 28647294 TI - The UN Convention on the Rights of Persons with Disabilities: 'Rights, will and preferences' in relation to mental health disabilities. AB - The UN Convention on the Rights of Persons with Disabilities spells out in the most up-to-date and specific manner the rights of persons with disabilities. In doing so the Convention presents serious challenges to many conventional practices in respect of people with disabilities, especially those with mental health disabilities. According to a number of authorities, most notably the UN Committee on the Rights of Persons with Disabilities, 'substitute decision making' is not consistent with the Convention. 'Respect for the rights, will and preferences' is to be regarded as the touchstone for compliance with the Convention. However 'will and preferences' is nowhere defined. This paper examines the meaning of these terms, and draws attention to instances where a contemporaneous 'preference' may be at variance with a person's 'will'. In such cases, it is argued, that 'substitute decision-making' - or giving effect to the person's 'will' - may be justified. PMID- 28647295 TI - Associations Between Sleep Habits and Dysglycemia in Adults in the United States: A Cross-Sectional Analysis. AB - OBJECTIVES: To examine the independent and joint associations between sleep duration and quality with glycated hemoglobin (A1C) levels and dysglycemia in non institutionalized adults living in the United States. METHODS: Data from the United States National Health and Nutrition Examination Survey (2005-2008) were used (N=9478; >=20 years). Information on sleep quantity and quality were derived from the Sleep Disorders Questionnaire and used to classify sleep quality as good, fair, poor, or very poor. RESULTS: Overall, sleep quantity and quality were related to A1C levels in our unadjusted models. In general, a U-shaped relationship between sleep quantity and A1C levels was observed. Compared to those who slept for 7 to 8 hours per night, sleeping for 4 hours or fewer was associated with higher A1C levels (mean, 95% CI; 5.49%, 5.45 to 5.53 vs. 5.69%, 5.60 to 5.77; p<0.05), whereas only those reporting good and very poor sleep quality had higher A1C levels than poor sleepers (mean, 95% CI: 5.63%, 5.57 to 5.69; 5.56%, 5.52 to 5.60 vs. 5.46%, 5.42 to 5.50; p<0.05). The relationships among sleep duration and quality and the joint effects of sleep quality and quantity and dysglycemia were not significant after multivariable adjustment. CONCLUSIONS: Between 7 and 8 hours of sleep and fair/poor sleep quality were associated with optimal A1C levels, while sleeping for fewer or more hours appeared to increase dysglycemia, without adjustment for covariates. These relationships were attenuated following multivariable adjustment. Future research is necessary to refine our understanding of the sleep/glycemic-control relationship to provide a context for the clinical significance of these findings for longer-term A1C control in adults with diabetes. PMID- 28647296 TI - Multiple stressors including contaminant exposure and parasite infection predict spleen mass and energy expenditure in breeding ring-billed gulls. AB - Daily energy expenditure (DEE) in animals is influenced by many factors although the impact of stressors remains largely unknown. The objective of this study was to determine how multiple physiological stressors (parasite infection and contaminant exposure) and natural challenges (energy-demanding activities and weather conditions) may affect DEE in nesting ring-billed gulls (Larus delawarensis) exposed to high concentrations of persistent organic contaminants (POPs). Physical activity, temperature, gastrointestinal parasitic worm abundance, relative spleen mass, plasma thyroid hormone levels and liver concentrations of POPs were determined; field metabolic rate (FMR) was used as a measure of DEE. For females, FMR was best explained by the percent of time spent in nest-site attendance and exposure to temperatures below their lower critical limit (65% of variation); 32% was also explained by relative spleen mass. In males, FMR was best explained by the number of hours spent in nest site attendance and either relative spleen mass or liver concentrations of tetra brominated diphenyl ethers (tetra-BDEs) (55% of variation). Relative spleen mass, as an important factor relating to FMR, was best explained by models with a combination of parasite abundance (Diplostomum for females and Eucoleus for males) in a negative relationship, and liver POP concentrations (p,p'-DDE for females and tetra-BDEs for males) in a positive relationship (34%, 55% of variation for females and males, respectively). This study demonstrates that immune activity may be an important factor affecting energy expenditure in ring billed gulls, and that contaminants and parasite abundance may have both a direct and/or indirect influence on FMR. PMID- 28647297 TI - Use of gonadotropins in infertile patients. AB - A new era in the history of gonadotropins. PMID- 28647298 TI - Vital signs: when twin bliss doesn't measure up. PMID- 28647299 TI - Otolaryngology consultation tracheostomies and complex patient population. AB - PURPOSE: To assess for the differences in patients undergoing tracheostomy by the otolaryngology consult service versus other specialties. MATERIALS AND METHODS: A series of 1035 tracheostomies performed at our institution from January 2013 through November 2015 was retrospectively reviewed. Patient-related factors that contribute to procedural difficulty were reviewed. RESULTS: 805 consecutive tracheostomies were included. Otolaryngology performed 176/805 (21.8%) tracheostomies as a consulting service. Morbidly obese patients were three times as likely to be referred to otolaryngology as other services (adjusted OR: 3.23; 95% CI: 2.21-4.72). Mean BMI was 36.38kg/m2 for Consults vs. 28.69kg/m2 for Others and morbidly obese patients had a mean BMI of 49.84kg/m2 vs. 42.68kg/m2 for Consults and Others respectively (p<0.001). Patients with upper airway compromise (8.5% of Consults vs. 1.6% for Others) had 5.5 times higher odds to be performed by otolaryngology (adjusted OR: 5.46; 95% CI: 2.24-13.28). Otolaryngology performed 81.8% of awake tracheostomies (n=9/11). There were significantly higher proportions of patients with diabetes, renal, pulmonary and cardiovascular disease in the Consults groups vs. Others (p<0.05). CONCLUSIONS: More complex tracheostomies are being referred to and performed by otolaryngology at our institution. Difficult and challenging tracheostomies seem to be the "standard" for otolaryngologists. PMID- 28647300 TI - Retrograde Parotidectomy and facial nerve outcomes: A case series of 44 patients. AB - PURPOSE: The most common surgical method to remove benign parotid tumors remains the prograde approach. We examined if a retrograde surgical technique offers better outcomes than historical prograde controls. MATERIALS AND METHODS: A retrospective chart review at Stanford Hospital was conducted to identify retrograde parotidectomies between February 2012 and October 2014 that were staffed by the senior author (DS) with resident involvement. Facial nerve (FN) outcomes and other post-surgical parameters were recorded. RESULTS: We identified 44 consecutive cases and found that 18.2% (n=8) of patients experienced temporary paresis and 2.3% (n=1) experienced minor (HB 2) permanent paresis limited to one branch. The average hospital length of stay was 0.64 days and complication rate was 6.8%. CONCLUSION: The retrograde technique has complication rates comparable to historical rates for the prograde technique and is amenable to minimally invasive outpatient superficial parotidectomy. PMID- 28647301 TI - Factors affecting hematopoietic stem cell mobilization and apheresis in allogeneic donors: The role of iron status. AB - Infused CD34 cell count has a significant impact on transplant outcome. In this retrospective study, we aimed to analyze the impact of donor iron parameters on peripheral blood stem cell (PBSC) collection. A total of 303 related donors were included in the study. The mobilization regimen, recombinant G-CSF, was given for four consecutive days. A CD34+ cell count below 2*106/kg was defined as mobilization failure which was demonstrated in 23 donors (7.6%). Mobilization failure was more frequent in female donors than male donors (13.7% vs 3.4%). Body mass index, mean corpuscular volume, hemoglobin and ferritin levels were found to be lower in donors with mobilization failure. Body mass index was significantly correlated with PBSC count on the 4th day of G-CSF. Body mass index, male gender, mean corpuscular volume and ferritin levels had significant impact on PBSC count. Although PBSC count was found to be similar between female and male donors, female gender was shown to have an adverse impact on PBSC collection, which may be attributed to lower body weight and concurrent iron deficiency. PMID- 28647302 TI - Variable validity of computer extracted problem lists for complications of diabetes mellitus within the VA Greater Los Angeles Health System. AB - PURPOSE: Electronic health data in the form of International Classification of Disease, Ninth Revision (ICD-9) codes is routinely used for clinical research, yet the accuracy of specific diagnoses is largely unknown. The purpose of this study is to assess the validity of computer extracted problem lists for diabetic retinopathy (DR) and other complications of diabetes mellitus (DM) within the VA Greater Los Angeles Health Administration (VHAGLA). METHODS: The study population consisted of patients at the VHAGLA with an ICD-9 diagnosis of DM between Jan 1st 1999 and March 22nd 2016 with visits to the eye clinic. Fifty patients either with or without an ICD-9 diagnosis of DR were randomly selected. The accuracy of ICD-9 codes for DR, as well as related co-morbidities such as hypertension, hyperlipidemia, coronary artery disease (CAD), and cerebrovascular accident (CVA), were assessed through chart review. RESULTS: A total of 3193 patients met our inclusion criteria. Of the 50 patients with an ICD-9 diagnosis of DR, the positive predictive value (PPV) was 0.7. For 50 patients without a ICD-9 diagnosis of DR, the negative predictive value (NPV) was 0.9. Of the other co morbid medical conditions, NPV ranged from a low of 63% for obesity to a high of 98% for CVA and CAD. CONCLUSION: Validity of ICD-9 diagnoses of diabetic complications in this VA population varied considerably, with DR demonstrating moderate agreement, obesity being more under-documented, and CVA and CAD being more consistently documented. These discrepancies should be considered when using billing codes for research purposes. PMID- 28647303 TI - The predictors of metabolic syndrome based on Walker Health-Promoting lifestyle in Iran 2016. AB - BACKGROUND: Understanding the metabolic syndrome has been the center of attention in recent years as a major risk factor of many diseases. Given the rising incidence of this disease and as the patient can compete against this disease with choosing healthy lifestyle, in the present study, we investigated the predictors of metabolic syndrome, based on Walker's health-promoting lifestyle in two large cities in Iran, in 2016. METHODS: This cross-sectional study used two stage cluster sampling to select 1128 patients, among patients who referred to health centers in Isfahan and Yazd. Data were gathered by Walker lifestyle questionnaire that evaluates health-promoting behavior (nutrition, physical activity, health responsibility, spiritual growth, interpersonal relations, and stress management) by self-report that were completed by interviews for illiterate and semi-literate individuals. Data analysis was performed by SPSS statistical software. RESULTS: In this study, 576 women and 454 men participated with mean age of 56.19+/-12.11years and mean weight of 73.90+/-14.45kg. RESULTS: showed that the highest mean score for different health-promoting behaviors was related to social responsibility (25.53+/-5.65) and the lowest was related to nutritional status (15.18+/-5.79). Regarding the strongest predictor of lifestyle, the results of regression analysis showed that the most direct impact was related to stress management (R2=0.343) and the least direct impact was related to social responsibility (R2=0.243). Among the structures, physical activity with overall effect of R2=0.621 was the strongest predictor of lifestyle based on Walker's pattern. CONCLUSION: Considering the results of this study, the greater emphasis in planning and interventions to reduce the risk of metabolic syndrome should be spotted on physical activity and stress management in patients with the metabolic syndrome. PMID- 28647304 TI - Phylogenies of symbiotic genes of Bradyrhizobium symbionts of legumes of economic and environmental importance in Brazil support the definition of the new symbiovars pachyrhizi and sojae. AB - Bradyrhizobium comprises most tropical symbiotic nitrogen-fixing strains, but the correlation between symbiotic and core genes with host specificity is still unclear. In this study, the phylogenies of the nodY/K and nifH genes of 45 Bradyrhizobium strains isolated from legumes of economic and environmental importance in Brazil (Arachis hypogaea, Acacia auriculiformis, Glycine max, Lespedeza striata, Lupinus albus, Stylosanthes sp. and Vigna unguiculata) were compared to 16S rRNA gene phylogeny and genetic diversity by rep-PCR. In the 16S rRNA tree, strains were distributed into two superclades-B. japonicum and B. elkanii-with several strains being very similar within each clade. The rep-PCR analysis also revealed high intra-species diversity. Clustering of strains in the nodY/K and nifH trees was identical: 39 strains isolated from soybean grouped with Bradyrhizobium type species symbionts of soybean, whereas five others occupied isolated positions. Only one strain isolated from Stylosanthes sp. showed similar nodY/K and nifH sequences to soybean strains, and it also nodulated soybean. Twenty-one representative strains of the 16S rRNA phylogram were selected and taxonomically classified using a concatenated glnII-recA phylogeny; nodC sequences were also compared and revealed the same clusters as observed in the nodY/K and nifH phylograms. The analyses of symbiotic genes indicated that a large group of strains from the B. elkanii superclade comprised the novel symbiovar sojae, whereas for another group, including B. pachyrhizi, the symbiovar pachyrhizi could be proposed. Other potential new symbiovars were also detected. The co-evolution hypotheses is discussed and it is suggested that nodY/K analysis would be useful for investigating the symbiotic diversity of the genus Bradyrhizobium. PMID- 28647305 TI - Impact of Asthma on the Sexual Functioning of Patients. A Case-Control Study. AB - INTRODUCTION: Sexual limitations play an important role in the quality of life of patients with chronic diseases. Very limited information is available on the impact of asthma on the sexual functioning of these individuals. MATERIALS AND METHODS: Cross-sectional, observational, multicenter study. Asthma patients and healthy individuals were recruited. All subjects participated in an interview in which demographic and clinical data were recorded, and completed the Goldberg Anxiety-Depression Scale (GADS) to evaluate the presence of concomitant psychiatric disease. Men also completed the International Index of Erectile Function (IIEF), and women, the Female Sexual Function Index (FSFI). RESULTS: A total of 276cases were included, comprising 172asthma patients (63 men and 109 women) with a mean age of 42 (+/-14) years, and 104 controls (52men and 51women) with a mean age of 39 (+/-12) years. Time since onset of asthma was 15 years and severity distribution was: 6.4% intermittent, 17.9% mild persistent, 47.4% moderate, and 28.2% severe. Disease was considered controlled in 57.7%, partially controlled in 28.2%, and uncontrolled in 14.1%. Women with asthma had greater sexual limitations than women in the control group, with a total FSFI score of 22.1 (+/-9) compared to 26.5 (+/-6.8), respectively (P<.005). Men with asthma had significantly more severe erectile dysfunction with a total IIEF score of 59.5 (+/-12.5) compared to 64.3 (+/-8.2) in male controls (P<.05). An association was also observed between sexual problems and poorer asthma control. CONCLUSIONS: Asthma is associated with a poorer sexual quality of life among patients. These results should arouse the interest of healthcare professionals in detecting and alleviating possible sexual limitations among their asthma patients in routine clinical practice. PMID- 28647307 TI - Results of a national survey on the management of patients with macular disease. PMID- 28647306 TI - Complete genome sequence of a phthalic acid esters degrading Mycobacterium sp. YC RL4. AB - Mycobacterium sp. YC-RL4 is capable of utilizing a broad range of phthalic acid esters (PAEs) as sole source of carbon and energy for growth. The preliminary studies demonstrated its high degrading efficiency and good performance during the bioprocess with environmental samples. Here, we present the complete genome of Mycobacterium sp. YC-RL4, which consists of one circular chromosome (5,801,417bp) and one plasmid (252,568bp). The genomic analysis and gene annotation were performed and many potential genes responsible for the biodegradation of PAEs were identified from the genome. These results may advance the investigation of bioremediation of PAEs-contaminated environments by strain YC-RL4. PMID- 28647308 TI - Playing with future sight. Choroidal neovascularisation due to hand-held laser pointers. PMID- 28647309 TI - Optic nerve metastasis caused by lung adenocarcinoma. AB - INTRODUCTION: Isolated optic nerve metastases are extremely uncommon. Many cases are associated with involvement from locations such as the choroid, orbit, or central nervous system. Optic nerve metastases often have their origin in primary tumours of the breast, lung, and stomach, in adults. CASE REPORT: The case is presented of a 57 year-old woman with a diagnosis of lung adenocarcinoma. Her first complaint was a sudden loss of visual acuity in her right eye. The diagnosis of optic nerve metastases was made based on her history, and the results of the MRI scan. DISCUSSION: Isolated optic nerve metastases are an uncommon condition, but should be suspected in any patient with a history of oncology who has deteriorated visual acuity. PMID- 28647310 TI - Effect of a web-based positive psychology intervention on prenatal well-being: A case series study. AB - BACKGROUND: Detrimental effects of women's negative feelings during pregnancy have been extensively examined and documented, but research on the influence of positive feelings and protective factors on their prenatal mental health is scarce. Evidence from the positive psychology field has shown that practicing some brief positive exercises, called positive psychology interventions, can maximize well-being by increasing positive emotions, engagement, and meaning. AIM: The aim of this study is to examine the effect of a positive psychology web based intervention on indices of women's prenatal well-being. METHODS: Specifically, a case series design was adopted, and data from six women are presented. Participants were involved in a 5-week online positive psychology intervention that includes a set of positive psychology interventions specifically adapted for pregnant women. Measures of women's mental well-being, depression, pregnancy-related anxiety, life satisfaction, and social support were measured at pre- and post-intervention. Compliance with the intervention and exercise preferences were assessed at post-test. Single-item related well-being measures were assessed weekly. FINDINGS AND DISCUSSION: The findings of this case series study indicate potential effects of the intervention on supporting mental well-being and decreasing depressive symptomatology in these pregnant women. Furthermore, this study provides some suggestions for developing future online based positive interventions addressed to pregnant women. However, these findings are preliminary, and future studies are needed in order to assess the effects of the intervention in a wider population of pregnant women. PMID- 28647311 TI - A Collection of Brain Sections of "Euthanasia" Victims: The Series H of Julius Hallervorden. AB - Julius Hallervorden, a distinguished German neuropathologist, admitted on several occasions that he had received some five hundred brains of "euthanasia" victims from the Nazi killing centres for the insane. He investigated the brains in the summer of 1942; however, their traces were subsequently lost. The present study shows, that the Series H, which was part of the Hallervorden collection of brain sections in the Max Planck Institute for Brain Research, comprises the brain sections of the above mentioned five hundred euthanasia victims. The provenance of 105 patients could be reconstructed and 84 are for sure euthanasia victims. Most of them were killed in Bernburg or in Sonnenstein-Pirna. Hallervorden used the brain sections of Series H until 1956 for his studies and never publicly regretted this abuse of the brains of euthanasia victims. PMID- 28647312 TI - Comparison of the PI3K-AKT-mTOR Pathway Expression Profile in Tumoral Versus Nontumoral Tissue Samples From Heart Transplant Recipients. PMID- 28647313 TI - Ruptured Sinus of Valsalva Aneurysm Causing Myocardial Infarction. PMID- 28647314 TI - Out-of-working-hours Primary Percutaneous Coronary Intervention in STEACS: Does It Worsen Clinical Outcomes? PMID- 28647315 TI - Safety and Efficacy of New Biodegradable Polymer-based Sirolimus-Eluting Stents in a Preclinical Model. AB - INTRODUCTION AND OBJECTIVES: New drug-eluting stents (DES) designed to overcome the limitations of existing devices should initially be tested in preclinical studies. Our objective was to analyze the safety and efficacy of new biodegradable polymer-based DES compared with bare-metal stents (BMS) and commercially available DES in a model of normal porcine coronary arteries. METHODS: We randomly implanted 101 stents (BMS and biodegradable polymer-based sirolimus-eluting stents: 3 test stent iterations [BD1, BD2, and BD3], Orsiro, Biomime and Biomatrix) in the coronary arteries of 34 domestic pigs. Angiographic and histomorphometric studies were conducted 1 month (n = 83) and 3 months (n = 18) later. RESULTS: The stents were implanted at a stent/artery ratio of 1.31 +/- 0.21, with no significant differences between groups. At 1 month, the new test stents (BD1, BD2 and BD3) showed less late loss and angiographic restenosis, as well as lower histologic restenosis and neointimal area (P < .0005), than the BMS. There were no differences in endothelialization, vascular injury, or inflammation between the new test stents and BMS, although the new stents showed higher fibrin deposition (P = .0006). At 3 months, all these differences disappeared, except for a lower neointimal area with the new BD1 stent (P = .027). No differences at any time point were observed between the new test stents and commercially available controls. CONCLUSIONS: In this preclinical model, the new biodegradable polymer-based DES studied showed less restenosis than BMS and no significant differences in safety or efficacy vs commercially available DES. PMID- 28647316 TI - Advanced strategies for quality control of Chinese medicines. AB - Quality control is always the critical issue for Chinese medicines (CMs) with their worldwide increasing use. Different from western medicine, CMs are usually considered that multiple constituents are responsible for the therapeutic effects. Therefore, quality control of CMs is a challenge. In 2011, the strategies for quantification, related to the markers, reference compounds and approaches, in quality control of CMs were reviewed (Li, et al., J. Pharm. Biomed. Anal., 2011, 55, 802-809). Since then, some new strategies have been proposed in these fields. Therefore, the review on the strategies for quality control of CMs should be updated to improve the safety and efficacy of CMs. Herein, novel strategies related to quality marker discovery, reference compound development and advanced approaches (focused on glyco-analysis) for quality control, during 2011-2016, were summarized and discussed. PMID- 28647317 TI - Associations of systemic sphingolipids with measures of hepatic function in liver cirrhosis are related to cholesterol. AB - Lipoprotein particles are composed of various lipid classes including cholesterol and sphingolipids, and are low in serum of patients with liver cirrhosis. Hepatic decompensation is associated with a further decline of lipoproteins. Aim of the present work was to evaluate whether ceramide and sphingomyelin species are similarly changed in patients with liver cirrhosis and whether these variations are related to systemic cholesterol levels. In a cohort of 45 patients suffering from liver cirrhosis, cholesteryl ester species and subsequently total cholesterol were identified to be negatively associated with model of end stage liver disease (MELD) score. Indeed, the negative correlations of ceramide (Cer) and sphingomyelin (SM) species with MELD score, bilirubin and anti-thrombin 3 were non-significant after adjustment for cholesterol. Cer/SM ratios of species with identical acyl chains were not related to Child-Pugh or MELD score indicating that both lipids are comparably changed. Further, cholesterol levels and concentrations of all sphingolipids measured were similar in systemic, hepatic vein and portal vein blood. Cholesterol and distinct sphingolipids were similar before and 3 months after insertion of a transjugular intrahepatic portosystemic shunt while hexosylceramide 24:1 was significantly induced. It is concluded that analysis of distinct systemic sphingolipid species is not superior to measurement of cholesterol as non-invasive marker of hepatic injury in patients with liver cirrhosis. PMID- 28647318 TI - Expression of genes for melanotropic peptides and their receptors for morphological color change in goldfish Carassius auratus. AB - To evaluate the association of the melanotropic peptides and their receptors for morphological color change, we investigated the effects of changes in background color, between white and black, on xanthophore density in the scales and expression levels of genes for hormonal peptides and corresponding receptors (MCH R2, MC1R, and MC5R) in goldfish (Carassius auratus). The xanthophore density in both dorsal and ventral scales increased after transfer from a white to black background. However, xanthophore density in dorsal scales increased after transfer from a black to white background, and that of ventral scales decreased after transfer from a black to black background, which served as the control. In the white-reared fish, melanin-concentrating hormone (mch) mRNA content in the brain was higher than that in black-reared fish, whereas proopiomelanocortin a (pomc-a) mRNA content in the pituitary was lower than that in the black-reared fish. Agouti-signaling protein (asp) mRNA was detected in the ventral skin but not in the dorsal skin. No difference was observed in the asp mRNA content between fish reared in white or black background, suggesting that ASP might not be associated with background color adaptation. In situ hybridization revealed that both mc1r and mc5r were expressed in the xanthophores in scales. The mRNA content of mc1r in scales did not always follow the background color change, whereas those of mc5r decreased in the white background and increased in the black background, suggesting that mc5r might be a major factor reinforcing the function of MSH in morphological color changes. White backgrounds increased mch mRNA content in the brain, but decreased mch-r2 mRNA content in the scales. These altered expression levels of melanotropin receptors might affect reactivity to melanotropins through long-term adaptation to background color. PMID- 28647319 TI - In vitro stimulation of vitellogenin expression by insulin in the mud crab, Scylla paramamosain, mediated through PI3K/Akt/TOR pathway. AB - Vitellogenin (vtg) synthesis, known as vitellogenesis, is one of most important processes in the ovarian development of oviparous animals. Recently, multiple insulin-like peptides (ILPs) have been reported in crustacean species due to the application of transcriptome sequencing. In this context, the present study reports that the addition of an exogenous ILP, bovine insulin, stimulates vtg (termed Sp-vtg) expression in hepatopancreatic explants from the mud crab, Scylla paramamosain, by in vitro experiments. Homologous genes of key factors in ILP signaling, Sp-PI3K, Sp-Akt, Sp-Rheb and Sp-TOR, have been isolated in S. paramamosain based on a transcriptome database. Further experiments reveal that the RNAi-mediated Sp-Akt gene knockdown and the inhibitors of Sp-PI3K and Sp-TOR block the stimulation of Sp-vtg expression by insulin. The combined results implicate the endogenous ILP and its corresponding signaling in the regulation of Sp-vtg synthesis in S. paramamosain. PMID- 28647320 TI - An integrated aerobic-anaerobic strategy for performance enhancement of Pseudomonas aeruginosa-inoculated microbial fuel cell. AB - Microbial fuel cell (MFC) is a promising device for energy generation and organic waste treatment simultaneously by electrochemically active bacteria (EAB). In this study, an integrated aerobic-anaerobic strategy was developed to improve the performance of P. aeruginosa-inoculated MFC. With an aerobic start-up and following an anaerobic discharge process, the current density of MFC reached a maximum of 99.80uA/cm2, which was 91.6% higher than the MFC with conventional constant-anaerobic operation. Cyclic voltammetry and HPLC analysis showed that aerobic start-up significantly increased electron shuttle (pyocyanin) production (76% higher than the constant-anaerobic MFC). Additionally, enhanced anode biofilm formation was also observed in the integrated aerobic-anaerobic MFC. The increased pyocyanin production and biofilm formation promoted extracellular electron transfer from EAB to the anode and were the underlying mechanism for the MFC performance enhancement. This work demonstrated the integrated aerobic anaerobic strategy would be a practical strategy to enhance the electricity generation of MFC. PMID- 28647321 TI - Development of large-scale and economic pH control system for outdoor cultivation of microalgae Haematococcus pluvialis using industrial flue gas. AB - The aim of this study was to develop the economic and effective buffer system for microalgae mass cultivation using industrial flue gas. Due to the continuous flue gas supplement, culture media acidified, therefore cell growth inhibited. Although buffering agent was added, this result increase in cost for overall culture process. Therefore combined buffer system of bicarbonate and phosphate (BP) for large-scale use was investigated. The bicarbonate buffer system generated from CO2 dissolution, additionally phosphate buffer system improves the buffer performance under the continuous CO2 supplementation from flue gas. The microalgae Haematococcus pluvialis was cultivated under autotrophic outdoor conditions using these buffer solutions. As a result, the autotrophic BP buffer system enhanced the biomass and astaxanthin productivity of H. pluvialis to 105% and 103%, respectively. The results confirm that the BP buffer system reduces the cost of microalgal CO2 conversion process, particularly for the outdoor mass cultivation. PMID- 28647322 TI - Hand therapy interventions, outcomes, and diagnoses evaluated over the last 10 years: A mapping review linking research to practice. AB - STUDY DESIGN: Mapping review. INTRODUCTION: Although published literature and evidence to support medical practice is becoming more abundant, it is not known how well available evidence supports the full spectrum of hand therapy practice. PURPOSE OF THE STUDY: The aim of this mapping review was to identify strengths and/or gaps in the available literature as compared with the hand therapy scope of practice to guide future research. METHODS: A systematic search and screening was conducted to identify evidence published from 2006 to 2015. Descriptive data from 191 studies were extracted, and the diagnoses, interventions, and outcomes used in the literature were compared with the hand therapy scope of practice. RESULTS: Osteoarthritis, tendon surgeries, and carpal tunnel syndrome were most frequently studied. Exercise, education, and orthotic interventions were most common, each used in more than 100 studies; only 12 studies used activity-based interventions. Primary outcome measures included range of motion, pain/symptoms, strength, and functional status. DISCUSSION: Abundant high-quality research exists for a portion of the hand therapy scope of practice; however, there is a paucity of evidence for numerous diagnoses and interventions. CONCLUSIONS: More evidence is needed for complex diagnoses and activity-based interventions as well as behavioral and quality-of-care outcomes. LEVEL OF EVIDENCE: Not applicable. PMID- 28647323 TI - Mechanism of plant-mediated synthesis of silver nanoparticles - A review on biomolecules involved, characterisation and antibacterial activity. AB - Engineering a reliable and eco-accommodating methodology for the synthesis of metal nanoparticles is a crucial step in the field of nanotechnology. Plant mediated synthesis of metal nanoparticles has been developed as a substitute to defeat the limitations of conventional synthesis approaches such as physical and chemical methods. Biomolecules, such as proteins, amino acids, enzymes, flavonoids, and terpenoids from several plant extracts have been used as a stabilising and reducing agents for the synthesis of AgNPs. Regardless of an extensive range of biomolecules assistance in the synthesis procedure, researchers are facing a significant challenge to synthesise stable and geometrically controlled AgNPs. In the past decade, several efforts were made to develop Plant-mediated synthesis methods to produce stable, cost effective and eco-friendly AgNPs. More than hundred different plants extract sources for synthesising AgNPs were described in the last decade by several researchers. Most of the reviews were focused on various plant sources for synthesis, various characterization techniques for characteristic analysis, and antibacterial activity against bacterial. There are many reviews are available for the plant mediated synthesis of AgNPs as well as antibacterial activity of AgNPs but this is the first review article mainly focused on biomolecules of plants and its various parts and operating conditions involved in the synthesis. Apart from, this review includes the characterisation of AgNPs and antibacterial activity of such nanoparticles with size, shape and method used for this study. PMID- 28647324 TI - AMPK as a Therapeutic Target for Treating Metabolic Diseases. AB - The AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways and may have therapeutic importance for treating obesity, insulin resistance, type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Given the ubiquitous expression of AMPK, it has been a challenge to evaluate which tissue types may be most beneficially poised for mediating the positive metabolic effects of AMPK-centered treatments. In this review we evaluate the metabolic phenotypes of transgenic mouse models in which AMPK expression and function have been manipulated, and the impact this has on controlling lipid metabolism, glucose homeostasis, and inflammation. This information may be useful for guiding the development of AMPK targeted therapeutics to treat chronic metabolic diseases. PMID- 28647325 TI - The processing of semantic relatedness in the brain: Evidence from associative and categorical false recognition effects following transcranial direct current stimulation of the left anterior temporal lobe. AB - A dominant view of the role of the anterior temporal lobe (ATL) in semantic memory is that it serves as an integration hub, specialized in the processing of semantic relatedness by way of mechanisms that bind together information from different brain areas to form coherent amodal representations of concepts. Two recent experiments, using brain stimulation techniques along with the Deese Roediger-McDermott (DRM) paradigm, have found a consistent false memory reduction effect following stimulation of the ATL, pointing to the importance of the ATL in semantic/conceptual processing. To more precisely identify the specific process being involved, we conducted a DRM experiment in which transcranial direct current stimulation (anode/cathode/sham) was applied over the participants' left ATL during the study of lists of words that were associatively related to their non-presented critical words (e.g., rotten, worm, red, tree, liqueur, unripe, cake, food, eden, peel, for the critical item apple) or categorically related (e.g., pear, banana, peach, orange, cantaloupe, watermelon, strawberry, cherry, kiwi, plum, for the same critical item apple). The results showed that correct recognition was not affected by stimulation. However, an interaction between stimulation condition and type of relation for false memories was found, explained by a significant false recognition reduction effect in the anodal condition for associative lists that was not observed for categorical lists. Results are congruent with previous findings and, more importantly, they help to clarify the nature and locus of false memory reduction effects, suggesting a differential role of the left ATL, and providing critical evidence for understanding the creation of semantic relatedness-based memory illusions. PMID- 28647326 TI - Effect of prepartum energy balance on neutrophil function following pegbovigrastim treatment in periparturient cows. AB - Treatment with granulocyte colony-stimulating factor (G-CSF) increases polymorphonuclear cell (neutrophil) count and enhances neutrophil function in the periparturient cow. Prepartum undernutrition was hypothesized to reduce the effect of a commercially available recombinant bovine G-CSF product (pegbovigrastim) on neutrophil count and function. Hence this study was undertaken to test the effect of undernutrition for approximately 1 mo before calving on the innate immune response to pegbovigrastim. Cows (n = 99) on pasture were blocked by expected calving date and body condition score and randomly assigned in a 2 * 2 factorial design. The first factor was that cows were fed to exceed energy requirements prepartum (full feeding) or restricted to approximately 85% of prepartum energy requirements (restricted feeding). The second factor was that at approximately 7 d before expected calving date, half the cows in each feed group were injected with pegbovigrastim and the remaining half were injected with saline. Treatments were repeated on the day of calving. Blood samples were collected pre- and postcalving for complete blood count, biochemistry, and in vitro assessment of neutrophil function including phagocytosis, myeloperoxidase release, and oxidative burst. Prepartum energy restriction resulted in lower body weight, a higher proportion of cows with elevated concentrations (i.e., >0.4 mmol/L) of fatty acids, and higher average beta-hydroxybutyrate concentrations before calving relative to fully fed cows. Treatment with pegbovigrastim increased the total white cell, neutrophil, lymphocyte, and monocyte counts. Pegbovigrastim treatment resulted in increased release of myeloperoxidase by neutrophils. Prepartum feeding group did not have an effect, and no feeding group * treatment interaction was observed for any of the white cell counts or functional tests. We concluded that pegbovigrastim treatment results in significant increases in neutrophil count and enhances neutrophil function as indicated by increased myeloperoxidase release. The response to pegbovigrastim was not affected by restricted prepartum energy intake. PMID- 28647327 TI - Genomic analysis of cow mortality and milk production using a threshold-linear model. AB - The objective of this study was to investigate the feasibility of genomic evaluation for cow mortality and milk production using a single-step methodology. Genomic relationships between cow mortality and milk production were also analyzed. Data included 883,887 (866,700) first-parity, 733,904 (711,211) second parity, and 516,256 (492,026) third-parity records on cow mortality (305-d milk yields) of Holsteins from Northeast states in the United States. The pedigree consisted of up to 1,690,481 animals including 34,481 bulls genotyped with 36,951 SNP markers. Analyses were conducted with a bivariate threshold-linear model for each parity separately. Genomic information was incorporated as a genomic relationship matrix in the single-step BLUP. Traditional and genomic estimated breeding values (GEBV) were obtained with Gibbs sampling using fixed variances, whereas reliabilities were calculated from variances of GEBV samples. Genomic EBV were then converted into single nucleotide polymorphism (SNP) marker effects. Those SNP effects were categorized according to values corresponding to 1 to 4 standard deviations. Moving averages and variances of SNP effects were calculated for windows of 30 adjacent SNP, and Manhattan plots were created for SNP variances with the same window size. Using Gibbs sampling, the reliability for genotyped bulls for cow mortality was 28 to 30% in EBV and 70 to 72% in GEBV. The reliability for genotyped bulls for 305-d milk yields was 53 to 65% to 81 to 85% in GEBV. Correlations of SNP effects between mortality and 305-d milk yields within categories were the highest with the largest SNP effects and reached >0.7 at 4 standard deviations. All SNP regions explained less than 0.6% of the genetic variance for both traits, except regions close to the DGAT1 gene, which explained up to 2.5% for cow mortality and 4% for 305-d milk yields. Reliability for GEBV with a moderate number of genotyped animals can be calculated by Gibbs samples. Genomic information can greatly increase the reliability of predictions not only for milk but also for mortality. The existence of a common region on Bos taurus autosome 14 affecting both traits may indicate a major gene with a pleiotropic effect on milk and mortality. PMID- 28647328 TI - Effects of feeding an immunomodulatory supplement to heat-stressed or actively cooled cows during late gestation on postnatal immunity, health, and growth of calves. AB - Heat stress during late gestation negatively affects the physiology, health, and productivity of dairy cows as well as the calves developing in utero. Providing cows with active cooling devices, such as fans and soakers, and supplementing cows with an immunomodulating feed additive, OmniGen-AF (OG; Phibro Animal Health Corporation), improves immune function and milk yield of cows. It is unknown if maternal supplementation of OG combined with active cooling during late gestation might benefit the developing calf as well. Herein we evaluated markers of innate immune function, including immune cell counts, acute phase proteins, and neutrophil function, of calves born to multiparous dams in a 2 * 2 factorial design. Dams were supplemented with OG or a bentonite control (NO) beginning at 60 d before dry off and exposed to heat stress with cooling (CL) or without active cooling (HT) during the dry period (~46 d). At birth, calves were separated from their dams and fed 6.6 L of their dams' colostrum in 2 meals. Calf body weight and rectal temperature were recorded, and blood samples were collected at birth (before colostrum feeding) and at 10, 28, and 49 d of age. Calves born to either CL dams or OG dams were heavier at birth than calves born to HT or NO dams, respectively. Concentrations of serum amyloid A were higher in the blood of calves born to OG dams relative to NO and for HT calves relative to CL calves. In addition, calves born to cooled OG dams had greater concentrations of plasma haptoglobin than calves born to cooled control dams. Neutrophil function at 10 d of age was enhanced in calves born to cooled OG dams and lymphocyte counts were higher in calves born to OG dams. Together these results suggest that adding OG to maternal feed in combination with active cooling of cows during late gestation is effective in mitigating the negative effects of in utero heat stress on postnatal calf growth and immune competence. PMID- 28647329 TI - Structural changes induced by high-pressure processing in micellar casein and milk protein concentrates. AB - Reconstituted micellar casein concentrates and milk protein concentrates of 2.5 and 10% (wt/vol) protein concentration were subjected to high-pressure processing at pressures from 150 to 450 MPa, for 15 min, at ambient temperature. The structural changes induced in milk proteins by high-pressure processing were investigated using a range of physical, physicochemical, and chemical methods, including dynamic light scattering, rheology, mid-infrared spectroscopy, scanning electron microscopy, proteomics, and soluble mineral analyses. The experimental data clearly indicate pressure-induced changes of casein micelles, as well as denaturation of serum proteins. Calcium-binding alphaS1- and alphaS2-casein levels increased in the soluble phase after all pressure treatments. Pressurization up to 350 MPa also increased levels of soluble calcium and phosphorus, in all samples and concentrations, whereas treatment at 450 MPa reduced the levels of soluble Ca and P. Experimental data suggest dissociation of calcium phosphate and subsequent casein micelle destabilization as a result of pressure treatment. Treatment of 10% micellar casein concentrate and 10% milk protein concentrate samples at 450 MPa resulted in weak, physical gels, which featured aggregates of uniformly distributed, casein substructures of 15 to 20 nm in diameter. Serum proteins were significantly denatured by pressures above 250 MPa. These results provide information on pressure-induced changes in high concentration protein systems, and may inform the development on new milk protein based foods with novel textures and potentially high nutritional quality, of particular interest being the soft gel structures formed at high pressure levels. PMID- 28647330 TI - Effect of skim milk treated with high hydrostatic pressure on permeate flux and fouling during ultrafiltration. AB - Ultrafiltration (UF) is largely used in the dairy industry to generate milk and whey protein concentrate for standardization of milk or production of dairy ingredients. Recently, it was demonstrated that high hydrostatic pressure (HHP) extended the shelf life of milk and improved rennet coagulation and cheese yield. Pressurization also modified casein micelle size distribution and promoted aggregation of whey proteins. These changes are likely to affect UF performance. Consequently, this study determined the effect of skim milk pressurization (300 and 600 MPa, 5 min) on UF performance in terms of permeate flux decline and fouling. The effect of HHP on milk proteins was first studied and UF was performed in total recycle mode at different transmembrane pressures to determine optimal UF operational parameters and to evaluate the effect of pressurization on critical and limiting fluxes. Ultrafiltration was also performed in concentration mode at a transmembrane pressure of 345 kPa for 130 or 140 min to evaluate the decline of permeate flux and to determine fouling resistances. It was observed that average casein micelle size decreased by 32 and 38%, whereas beta lactoglobulin denaturation reached 30 and 70% at 300 and 600 MPa, respectively. These results were directly related to UF performance because initial permeate fluxes in total recycle mode decreased by 25% at 300 and 600 MPa compared with nonpressurized milk, critical flux, and limiting flux, which were lower during UF of milk treated with HHP. During UF in concentration mode, initial permeate fluxes were 30% lower at 300 and 600 MPa compared with the control, but the total flux decline was higher for nonpressurized milk (62%) compared with pressure treated milk (30%). Fouling resistances were similar, whatever the treatment, except at 600 MPa where irreversible fouling was higher. Characterization of the fouling layer showed that caseins and beta-lactoglobulin were mainly involved in membrane fouling after UF of pressure-treated milk. Our results demonstrate that HHP treatment of skim milk drastically decreased UF performance. PMID- 28647331 TI - Combination of histidine, lysine, methionine, and leucine promotes beta-casein synthesis via the mechanistic target of rapamycin signaling pathway in bovine mammary epithelial cells. AB - The ratio of different AA in the diets of cows is vital to improve milk protein yield. beta-Casein is one of the important milk proteins with high nutritive value. However, the suitable ratio of essential amino acids (EAA) for the expression of beta-casein in the immortalized bovine mammary epithelial cell line is not fully characterized. This study employed response surface methodology to determine the optimal ratio of His, Lys, Met, and Leu on beta-casein expression level in vitro and clarified the effect of the 4 EAA on beta-casein via the mechanistic target of rapamycin (mTOR) signaling pathway. A central composite design containing 5 axial points per EAA and 28 combinations of the 4 EAA was used in our study. The results of response surface methodology and the changes of the mTOR-related signaling proteins were determined by western blot. The results showed that beta-casein level was significantly affected by all 4 EAA (R2 = 0.71). The optimum conditions for beta-casein expression are found to be 5.47 mM of His, 7.48 mM of Lys, 1.17 mM of Met, and 8.21 mM of Leu (His:Lys:Met:Leu = 5:6:1:7) in the designed scope of concentration. The interaction of Leu and Met significantly affected beta-casein expression (P < 0.01). The phosphorylation of mTOR (Ser2481), regulatory associated protein of target of rapamycin (Ser792), ribosomal protein S6 kinase 1 (Thr389), ribosomal protein S6 (Ser235/236), and eukaryotic elongation factor 2 (Thr56) was increased with the supplementation of either single EAA or an optimal combination of EAA. However, the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (Thr37) was decreased with the addition of Lys, Met, or Leu alone. Furthermore, the phosphorylation (P) of eIF2alpha (Ser51) was decreased when Met was supplemented alone. Under the optimal mixture of 4 EAA, the phosphorylation of mechanistic target of rapamycin complex 1 signaling proteins was significantly greater than the single EAA supplementations and the expression of beta-casein was 98% as high as the positive control (i.e., medium with all AA). A similar trend was found with P ribosomal protein S6 kinase 1 and P-ribosomal protein S6. In conclusion, the extracellular concentrations of His, Lys, Met, and Leu at a ratio of 5:6:1:7 maximized beta-casein expression in the immortalized bovine mammary epithelial cell line may occur via activation of the mechanistic target of rapamycin complex 1 signaling pathway. PMID- 28647332 TI - Longitudinal relationship between fecal culture, fecal quantitative PCR, and milk ELISA in Mycobacterium avium ssp. paratuberculosis-infected cows from low prevalence dairy herds. AB - Mycobacterium avium ssp. paratuberculosis (MAP), the causative agent of ruminant Johne's disease, presents a particular challenge with regard to infection mitigation on dairy farms. Diagnostic testing strategies to identify and quantify MAP and associated antibodies are imperfect, and certain facets of the relationship between diagnostic tests remain to be explored. Additional repeated measures data from known infected animals are needed to complement the body of cross-sectional research on Johne's disease-testing methods. Statistical models that accurately account for multiple diagnostic results while adjusting for the effects of individual animals and herds over time can provide a more detailed understanding of the interplay between diagnostic outcomes. Further, test results may be considered as continuous wherever possible so as to avoid the information loss associated with dichotomization. To achieve a broader understanding of the relationship between diagnostic tests, we collected a large number of repeated fecal and milk samples from 14 infected cows, in addition to bulk milk samples, from 2 low-prevalence dairy herds in the northeast United States. Predominately through the use of mixed linear modeling, we identified strong associations between milk ELISA optical density, fecal quantitative PCR, and fecal culture in individual animals while concurrently adjusting for variables that could alter these relationships. Notably, we uncovered subtleties in the predictive abilities of fecal shedding level on milk ELISA results, with animals categorized as disease progressors reaching higher ELISA optical density levels. Moreover, we observed that spikes in fecal shedding could predict subsequent high ELISA values up to 2 mo later. We also investigated the presence of MAP in individual milk samples via PCR and noted an association between poor udder hygiene and MAP positivity in milk, suggesting some level of environmental contamination. The paucity of positive milk samples and the complete absence of detectable MAP in the bulk tank throughout the study period indicate that contamination of milk with MAP may not be of chief concern in low-prevalence herds. An enhanced understanding of the interrelationships between diagnostic tests can only benefit the development of testing strategies and objectives, which in turn may lessen MAP infection prevalence in dairy herds. PMID- 28647333 TI - Effects of bedding with recycled sand on lying behaviors, udder hygiene, and preference of lactating Holstein dairy cows. AB - Effects of bedding with recycled sand and season on lying behaviors, hygiene, and preferences of late-lactation Holstein cows were studied. It was hypothesized that recycled sand will decrease lying time and increase hygiene scores due to increased moisture content and organic matter, and thus a preference for the control sand will be evident. Cows (n = 64) were divided into 4 groups (n = 8 per group) per season. In summer (August to September), cows were balanced by days in milk (268.1 +/- 11.9 d) and parity (2.0 +/- 0.2). In winter (January to February), mean DIM was 265.5 +/- 34.1 d. Cows were assigned to 1 of 2 treatments using a crossover design with each treatment lasting 7 d (no-choice phase): bedding with recycled sand (RS; n = 32) or control (CO; clean sand; n = 32). Stocking density was maintained at 100%. The choice phase allowed cows to have access to either treatment with stocking density at 50%. Accelerometers recorded daily lying time, number of lying bouts per day, lying bout duration (min/bout), and total steps per day. Teat swabs, milk, sand samples, and udder hygiene scores were collected on d 0, 3, and 7 of each experimental week. Samples were cultured for streptococci, staphylococci, and gram-negative bacteria. Video data were used to assess bedding preferences. All data were analyzed using the MIXED and GLIMMIX procedures of SAS 9.4 (SAS Institute Inc., Cary, NC). Lying time was not affected by treatment, but cows did take more steps during winter. Bacterial counts were elevated for cows on recycled sand. A preference was observed for clean sand during the summer, but no preference was observed for sand during the winter. Regardless of bedding, the most commonly observed behavior was lying in the stalls, which suggested either bedding might be suitable. Caution should be used with this interpretation of preference, as sand was recycled only once. This limited reclamation was still sufficient to potentially alter the composition of sand, driving the observed preference. If these changes in composition continue, then the strength of the preference may also change. However, considering all variables within the current study, recycled sand is a viable bedding source to use for dairy cows. PMID- 28647334 TI - Test characteristics of milk amyloid A ELISA, somatic cell count, and bacteriological culture for detection of intramammary pathogens that cause subclinical mastitis. AB - Bovine mastitis is an important disease in the dairy industry, causing economic losses as a result of withheld milk and treatment costs. Several studies have suggested milk amyloid A (MAA) as a promising biomarker in the diagnosis of mastitis. In the absence of a gold standard for diagnosis of subclinical mastitis, we estimated the diagnostic test accuracy of a commercial MAA-ELISA, somatic cell count (SCC), and bacteriological culture using Bayesian latent class modeling. We divided intramammary infections into 2 classes: those caused by major pathogens (e.g., Escherichia coli, Staphylococcus aureus, streptococci, and lacto-/enterococci) and those caused by all pathogens (major pathogens plus Corynebacterium bovis, coagulase-negative staphylococci, Bacillus spp., Streptomyces spp.). We applied the 3 diagnostic tests to all samples. Of 433 composite milk samples included in this study, 275 (63.5%) contained at least 1 colony of any bacterial species; of those, 56 contained major pathogens and 219 contained minor pathogens. The remaining 158 samples (36.5%) were sterile. We determined 2 different thresholds for the MAA-ELISA using Bayesian latent class modeling: 3.9 ug/mL to detect mastitis caused by major pathogens and 1.6 ug/mL to detect mastitis caused by all pathogens. The optimal SCC threshold for identification of subclinical mastitis was 150,000 cells/mL; this threshold led to higher specificity (Sp) than 100,000 cells/mL. Test accuracy for major pathogen intramammary infections was as follows: SCC, sensitivity (Se) 92.6% and Sp 72.9%; MAA-ELISA, Se 81.4% and Sp 93.4%; bacteriological culture, Se 23.8% and Sp 95.2%. Test accuracy for all-pathogen intramammary infections was as follows: SCC, sensitivity 90.3% and Sp 71.8%; MAA-ELISA, Se 88.0% and Sp 65.2%; bacteriological culture, Se 83.8% and Sp 54.8%. We suggest the use of SCC and MAA ELISA as a combined screening procedure for situations such as a Staphylococcus aureus control program. With Bayesian latent class analysis, we were able to identify a more differentiated use of the 3 diagnostic tools. The MAA-ELISA is a valuable addition to existing tools for the diagnosis of subclinical mastitis. PMID- 28647335 TI - Incidence and duration of increased somatic cell count in Swedish dairy cows and associations with milking system type. AB - Mastitis is one of the most costly diseases in dairy cows worldwide. Increased somatic cell count (SCC) is an indication of mastitis, often subclinical, which implies bacterial infection without clinical signs of inflammation. The aim was to investigate the occurrence of elevated udder SCC (defined as >=200,000 cells/mL) over the lactation period, and before and after the dry period, for cows of different parity. The aim was also to analyze the association between prevalence and incidence of increased udder SCC and information on cow and herd level, such as breed and milking system type. Data were extracted from the Swedish Official Milk Recording Scheme between January 1, 2008, and December 31, 2011, including all herds with a yearly average of >60 cows. The data include descriptive information on herd and cow level and the results from the systematic test milking. The data included the following: for 2009, 239,182 cows in 1,633 herds; for 2010, 251,852 cows in 1,680 herds; and for 2011, 247,746 cows in 1,596 herds. The results show a peak in elevated udder SCC during the late summer season and that the highest proportion of cases occurs during the first lactation month; the latter was most prominent for primiparous cows. Forty-seven percent of all cows with elevated SCC recovered during dry period (went from high to low SCC), whereas 34% of all cows with low SCC before the dry period had an elevated SCC at first testing after calving. For first lactation cows, 19% had an elevated SCC at first test milking. When the outcomes for the 3 consecutive years were reanalyzed, it was confirmed that the effect of fixed factors such as breed, milk yield, and parity did not change over time, whereas the effect of milking system type did. For the incidence of becoming a new case and the prevalence of cows with elevated udder SCC, automatic milking system (AMS) was associated with reduced SCC in 2009 but associated with increased SCC in 2011. Regarding the proportion of new cases of elevated SCC per cow and year, AMS appeared to be a risk factor for all 3 yr, but the effect decreased over time. The shift for AMS from protective to risk factor regarding incidence of new cases and number of recordings with elevated SCC might reflect a change of the AMS population over these years. The findings indicate the need for appropriate udder health management customized to the system. PMID- 28647336 TI - Milk composition and health status from mammary gland quarters adjacent to glands affected with naturally occurring clinical mastitis. AB - Mammary gland quarters have usually been considered to be anatomically and physiologically independent, but some recent research has indicated more interdependence than previously reported. The objective of this study was to compare milk composition (fat, total protein, lactose, solids-not-fat, and chloride) and health status (somatic cell count, differential leukocyte count, and lactate dehydrogenase) of milk samples from unaffected mammary glands of an udder with a single clinically inflamed quarter to results of milk samples from healthy mammary glands of healthy cows. The study was designed as a prospective case control study with case and control cows matched by parity and days in milk. Cases were defined as cows (n = 59) experiencing clinical mastitis in a single mammary gland, and controls (n = 59) were defined as cows that had not experienced clinical mastitis during the current lactation. Quarter milk samples were collected from all mammary glands adjacent to clinically affected quarters of cases and from the same mammary glands of controls. Samples were used to assess concentration of chloride and lactate dehydrogenase, fat, total protein, solids-not-fat, somatic cell count, and differential leukocyte count. Microbiological analysis was also performed on milk samples obtained from clinically affected mammary glands (n = 59). Logistic regression models were used to assess possible associations among quarter somatic cell count (>=150,000 cells/mL) and quarter type (adjacent to case or control). Multivariate linear models were used to compare milk composition and health status between quarter types. A total of 170 quarters were enrolled per group. Milk obtained from adjacent quarters of cases contained a lesser concentration of total protein, lactose, and solids-not-fat, but had a greater concentration of fat and chloride. The somatic cell count, total leukocyte count, and absolute numbers of neutrophils, lymphocytes, and macrophages were all increased in milk obtained from adjacent quarters of case cows compared with milk obtained from quarters of control cows. The relative proportion of neutrophils was increased, whereas the proportion of macrophages was decreased in milk obtained from cases. Approximately 30% of milk samples obtained from adjacent quarters of cases had a somatic cell count >=150,000 cells/mL compared with 12% of milk samples obtained from quarters of control cows. The position of the mammary gland was not associated with any outcomes. In conclusion, our results support previous research that indicates the immune response to intramammary infection in a single mammary gland quarter alters milk composition and health status throughout the udder. PMID- 28647337 TI - Comparison of Bayesian regression models and partial least squares regression for the development of infrared prediction equations. AB - The objective of this study was to compare the prediction accuracy of 92 infrared prediction equations obtained by different statistical approaches. The predicted traits included fatty acid composition (n = 1,040); detailed protein composition (n = 1,137); lactoferrin (n = 558); pH and coagulation properties (n = 1,296); curd yield and composition obtained by a micro-cheese making procedure (n = 1,177); and Ca, P, Mg, and K contents (n = 689). The statistical methods used to develop the prediction equations were partial least squares regression (PLSR), Bayesian ridge regression, Bayes A, Bayes B, Bayes C, and Bayesian least absolute shrinkage and selection operator. Model performances were assessed, for each trait and model, in training and validation sets over 10 replicates. In validation sets, Bayesian regression models performed significantly better than PLSR for the prediction of 33 out of 92 traits, especially fatty acids, whereas they yielded a significantly lower prediction accuracy than PLSR in the prediction of 8 traits: the percentage of C18:1n-7 trans-9 in fat; the content of unglycosylated kappa-casein and its percentage in protein; the content of alpha lactalbumin; the percentage of alphaS2-casein in protein; and the contents of Ca, P, and Mg. Even though Bayesian methods produced a significant enhancement of model accuracy in many traits compared with PLSR, most variations in the coefficient of determination in validation sets were smaller than 1 percentage point. Over traits, the highest predictive ability was obtained by Bayes C even though most of the significant differences in accuracy between Bayesian regression models were negligible. PMID- 28647338 TI - Hepatitis B virus reactivation recurred after the cessation of entecavir in an allogenetic hematopoietic stem cell transplantation patient. PMID- 28647339 TI - The effects of amoxicillin and vancomycin on parameters reflecting cholesterol metabolism. AB - BACKGROUND: Changes in the microbiota composition have been implicated in the development of obesity and type 2 diabetes. However, not much is known on the involvement of gut microbiota in lipid and cholesterol metabolism. In addition, the gut microbiota might also be a potential source of plasma oxyphytosterol and oxycholesterol concentrations (oxidation products of plant sterols and cholesterol). Therefore, the aim of this study was to modulate the gut microbiota by antibiotic therapy to investigate effects on parameters reflecting cholesterol metabolism and oxyphytosterol concentrations. DESIGN: A randomized, double blind, placebo-controlled trial was performed in which 55 obese, pre-diabetic men received oral amoxicillin (broad-spectrum antibiotic), vancomycin (antibiotic directed against Gram-positive bacteria) or placebo (microcrystalline cellulose) capsules for 7days (1500mg/day). Plasma lipid and lipoprotein, non-cholesterol sterol, bile acid and oxy(phyto)sterol concentrations were determined at baseline and after 1-week intervention. RESULTS: Plasma secondary bile acids correlated negatively with cholestanol (marker for cholesterol absorption, r=-0.367; P<0.05) and positively with lathosterol concentrations (marker for cholesterol synthesis, r=0.430; P<0.05). Fasting plasma secondary bile acid concentrations were reduced after vancomycin treatment as compared to placebo treatment (-0.24+/-0.22MUmol/L vs. -0.08+/-0.29MUmol/L; P<0.01). Vancomycin and amoxicillin treatment did not affect markers for cholesterol metabolism, plasma TAG, total cholesterol, LDL-C or HDL-C concentrations as compared to placebo. In addition, both antibiotic treatments did not affect individual isoforms or total plasma oxyphytosterol or oxycholesterol concentrations. CONCLUSION: Despite strong correlations between plasma bile acid concentrations and cholesterol metabolism (synthesis and absorption), amoxicillin and vancomycin treatment for 7days did not affect plasma lipid and lipoprotein, plasma non-cholesterol sterol and oxy(phyto)sterol concentrations in obese, pre-diabetic men. PMID- 28647340 TI - A simulator for training in endovascular aneurysm repair: The use of three dimensional printers. AB - OBJECTIVES: To develop an endovascular aneurysm repair (EVAR) simulation system using three dimensional (3D) printed aneurysms, and to evaluate the impact of patient specific training prior to EVAR on the surgical performance of vascular surgery residents in a university hospital in Brazil. METHODS: This was a prospective, controlled, single centre study. During 2015, the aneurysms of patients undergoing elective EVAR at Sao Paulo University Medical School were 3D printed and used in training sessions with vascular surgery residents. The 3D printers Stratasys-Connex 350, Formlabs-Form1+, and Makerbot were tested. Ten residents were enrolled in the control group (five residents and 30 patients in 2014) or the training group (five residents and 25 patients in 2015). The control group performed the surgery under the supervision of a senior vascular surgeon (routine procedure, without simulator training). The training group practised the surgery in a patient specific simulator prior to the routine procedure. Objective parameters were analysed, and a subjective questionnaire addressing training utility and realism was answered. RESULTS: Patient specific training reduced fluoroscopy time by 30% (mean 48 min, 95% confidence interval [CI] 40-58 vs. 33 min, 95% CI 26-42 [p < .01]), total procedure time by 29% (mean 292 min [95% CI 235-336] vs. 207 [95% CI 173-247]; p < .01), and volume of contrast used by 25% (mean 87 mL [95% CI 73-103] vs. 65 mL [95% CI 52-81]; p = .02). The residents considered the training useful and realistic, and reported that it increased their self confidence. The 3D printers Form1+ (using flexible resin) and Makerbot (using silicone) provided the best performance based on simulator quality and cost. CONCLUSION: An EVAR simulation system using 3D printed aneurysms was feasible. The best results were obtained with the 3D printers Form1+ (using flexible resin) and Makerbot (using silicone). Patient specific training prior to EVAR at a university hospital in Brazil improved residents' surgical performance (based on fluoroscopy time, surgery time, and volume of contrast used) and increased their self confidence. PMID- 28647341 TI - Suppression of autophagic flux contributes to cardiomyocyte death by activation of necroptotic pathways. AB - BACKGROUND: The role of necroptosis in myocardial injury has not been fully characterized. Here we examined roles of mitochondrial permeability transition pore (mPTP) and autophagy in necroptosis of cardiomyocytes. METHODS AND RESULTS: In H9c2 cells, necroptosis was induced by treatment with TNF-alpha (TNF) and z VAD-fmk (zVAD) for 24h, and necroptotic death was determined by LDH release (as % of total). TNF/zVAD increased LDH release from 16.6+/-4.3% to 60.6+/-2.7%, and the LDH release was suppressed by necrostatin-1 (29.4+/-4.0%), a RIP1 inhibitor, and by siRNA-mediated knockdown of RIP3 (27.7+/-2.0%), confirming RIP1-RIP3 dependent necroptosis. TNF/zVAD-induced necroptosis was not attenuated by mPTP inhibitors or GSK-3beta inhibitors. TNF/zVAD increased LC3-II level, but the change was not further enhanced by bafilomycin A1. The increase of LC3-II by TNF/zVAD was associated with suppression of both autophagic flux and LC3-LAMP1 co localization. TNF/zVAD did not modify phosphorylation of Akt, p70s6K, AMPK, ULK1 or VASP but significantly increased RIP1-p62 binding and conversely reduced p62 LC3 binding. Rapamycin inhibited RIP1-p62 and RIP1-RIP3 interactions induced by TNF/zVAD and partly restored autophagic flux and suppressed LDH release in TNF/zVAD-treated cells. The effect of rapamycin on LDH release was reduced by knockdown of Atg5 expression. Knockdown of p62 by siRNA augmented LDH release by TNF/zVAD. CONCLUSION: Suppression of autophagic flux contributes to RIP1-RIP3 interaction and necroptosis of cardiomyocytes, and sequestration of p62 from its interaction with LC3-II by p62-RIP1 interaction possibly underlies the suppressed autophagy. The mPTP is unlikely to play a major role in execution of necroptosis in cardiomyocytes. PMID- 28647342 TI - Association between hospitalization for acute medical illness and VTE risk: A lower efficacy of thromboprophylaxis in elderly patients? Results from the EDITH case-control study. AB - INTRODUCTION: Whether the association between hospitalization and venous thromboembolism (VTE) is modified by the use of thromboprophylaxis in older patients remains insufficiently evaluated. Our objective was to estimate VTE risk associated with hospitalization for acute medical illness depending on prescription of pharmacological thromboprophylaxis, in two different age categories using a 75years cutoff. METHODS: Using a case-control design, we estimated the risk for symptomatic VTE associated with hospitalization for acute medical illness depending on prescription of pharmacological thromboprophylaxis in two different age categories using a 75 years cut-off. RESULTS: 750 symptomatic VTE cases and their 750 age and sex-matched controls were analyzed. A total of 145 cases (19.3%) and 91 controls (12.1%) were hospitalized for acute medical illness in the preceding 3months prior to inclusion in the study (p<0.001). Hospitalization for acute medical illness was associated with a 75% increase in VTE risk: OR 1.75 (95% CI: 1.32-2.33). In patients <75years, there was a 2-fold increase in VTE risk associated with hospitalization when thromboprophylaxis was not prescribed: OR 2.01 (95% CI: 1.11-3.62), whereas no association was found when thromboprophylaxis was prescribed: OR 0.93 (95% CI: 0.44-1.95). In patients >=75years, VTE risk associated with hospitalization remained significant whether or not thromboprophylaxis was prescribed: OR 2.69 (95% CI 1.28-5.66) and OR 2.02 (95% CI: 1.01-4.03) respectively. CONCLUSION: Our results suggest that VTE prevention in acutely ill medical patients may be less effective in patients >=75years. This finding needs to be addressed in further studies. PMID- 28647343 TI - Alcoholic cardiomyopathy: What is known and what is not known. AB - Excessive alcohol consumption represents one of the main causes of non-ischemic dilated cardiomyopathy. Alcoholic cardiomyopathy is characterized by dilation and impaired contraction of one or both myocardial ventricles. It represents the final effect of alcohol-induced toxicity to the heart. Several pathophysiological mechanisms have been proposed at the basis of alcohol-induced damage, most of which are still object of research. Unfortunately, symptoms of alcoholic cardiomyopathy are not specific and common to other forms of heart failure and appear when dilatation and systolic dysfunction are consolidated. Thus, early diagnosis is mandatory to prevent the development and progression to heart failure. Although physicians are aware of this disease, several pitfalls in the diagnosis, natural history, prognosis and treatment are still present. The aim of this narrative review is to describe clinical characteristics of alcoholic cardiomyopathy, highlighting the areas of uncertainty. PMID- 28647344 TI - Oncogene-Expressing Senescent Melanocytes Up-Regulate MHC Class II, a Candidate Melanoma Suppressor Function. AB - On acquisition of an oncogenic mutation, primary human and mouse cells can enter oncogene-induced senescence (OIS). OIS is characterized by a stable proliferation arrest and secretion of proinflammatory cytokines and chemokines, the senescence associated secretory phenotype. Proliferation arrest and the senescence associated secretory phenotype collaborate to enact tumor suppression, the former by blocking cell proliferation and the latter by recruiting immune cells to clear damaged cells. However, the interactions of OIS cells with the immune system are still poorly defined. Here, we show that engagement of OIS in primary human melanocytes, specifically by melanoma driver mutations NRASQ61K and BRAFV600E, causes expression of the major histocompatibility class II antigen presentation apparatus, via secreted IL-1beta signaling and expression of CIITA, a master regulator of major histocompatibility class II gene transcription. In vitro, OIS melanocytes activate T-cell proliferation. In vivo, nonproliferating oncogene expressing melanocytes localize to skin-draining lymph nodes, where they induce T cell proliferation and an antigen presentation gene expression signature. In patients, expression of major histocompatibility class II in melanoma is linked to favorable disease outcome. We propose that OIS in melanocytes is accompanied by an antigen presentation phenotype, likely to promote tumor suppression via activation of the adaptive immune system. PMID- 28647345 TI - Cutaneous Nod2 Expression Regulates the Skin Microbiome and Wound Healing in a Murine Model. AB - The skin microbiome exists in dynamic equilibrium with the host, but when the skin is compromised, bacteria can colonize the wound and impair wound healing. Thus, the interplay between normal skin microbial interactions versus pathogenic microbial interactions in wound repair is important. Bacteria are recognized by innate host pattern recognition receptors, and we previously showed an important role for the pattern recognition receptor NOD2 in skin wound repair. NOD2 is implicated in changes in the composition of the intestinal microbiota in Crohn's disease, but its role on skin microbiota is unknown. Nod2-deficient (Nod2-/-) mice had an inherently altered skin microbiome compared with wild-type controls. Furthermore, we found that Nod2-/- skin microbiome dominated and caused impaired healing, shown in cross-fostering experiments of wild-type pups with Nod2-/- pups, which then acquired altered cutaneous bacteria and delayed healing. High throughput sequencing and quantitative real-time PCR showed a significant compositional shift, specifically in the genus Pseudomonas in Nod2-/- mice. To confirm whether Pseudomonas species directly impair wound healing, wild-type mice were infected with Pseudomonas aeruginosa biofilms and, akin to Nod2-/- mice, were found to exhibit a significant delay in wound repair. Collectively, these studies show the importance of the microbial communities in skin wound healing outcome. PMID- 28647346 TI - STING Is Involved in Antiviral Immune Response against VZV Infection via the Induction of Type I and III IFN Pathways. AB - Varicella zoster virus (VZV) is a human-restricted alpha-herpesvirus that exhibits tropism for the skin. The VZV host receptors and downstream signaling pathways responsible for the antiviral innate immune response in the skin are not completely understood. Here, we show that STING mediates an important host defense against VZV infection in dermal cells including human dermal fibroblasts and HaCaT keratinocytes. Inhibition of STING using small interfering-RNA or short hairpin RNA-mediated gene disruption resulted in enhanced viral replication but diminished IRF3 phosphorylation and induction of IFNs and proinflammatory cytokines. Pretreatment with STING agonists resulted in reduced VZV glycoprotein E expression and viral replication. Additionally, using RNA sequencing to analyze dual host and VZV transcriptomes, we identified several host immune genes significantly induced by VZV infection. Furthermore, significant up-regulation of IFN-lambda secretion was observed after VZV infection, partly through a STING dependent pathway; IFN-lambda was shown to be crucial for antiviral defense against VZV in human dermal cells. In conclusion, our data provide an important insight into STING-mediated induction of type I and III IFNs and subsequent antiviral signaling pathways that regulate VZV replication in human dermal cells. PMID- 28647347 TI - Differential Activation of Human Keratinocytes by Leishmania Species Causing Localized or Disseminated Disease. AB - All Leishmania species parasites are introduced into mammalian skin through a sand fly bite, but different species cause distinct clinical outcomes. Mouse studies suggest that early responses are critical determinants of subsequent adaptive immunity in leishmaniasis, yet few studies address the role of keratinocytes, the most abundant cell in the epidermis. We hypothesized that Leishmania infection causes keratinocytes to produce immunomodulatory factors that influence the outcome of infection. Incubation of primary or immortalized human keratinocytes with Leishmania infantum or Leishmania major, which cause visceral or cutaneous leishmaniasis, respectively, elicited dramatically different responses. Keratinocytes incubated with L. infantum significantly increased expression of proinflammatory genes for IL-6, IL-8, tumor necrosis factor, and IL-1B, whereas keratinocytes exposed to several L. major isolates did not. Furthermore, keratinocyte-monocyte co-incubation studies across a 4 uM semipermeable membrane suggested that L. infantum-exposed keratinocytes release soluble factors that enhance monocyte control of intracellular L. infantum replication (P < 0.01). L. major-exposed keratinocytes had no comparable effect. These data suggest that L. infantum and L. major differentially activate keratinocytes to release factors that limit infection in monocytes. We propose that keratinocytes initiate or withhold a proinflammatory response at the site of infection, generating a microenvironment uniquely tailored to each Leishmania species that may affect the course of disease. PMID- 28647348 TI - Pivotal Role of Lesional and Perilesional T/B Lymphocytes in Pemphigus Pathogenesis. AB - Pemphigus is a skin and mucosal membrane-targeting autoimmune bullous disease. Previous studies have shown that circulating anti-desmoglein1/3 antibodies are pathogenic and mediate blister formation. However, the role of infiltrating immune cells in lesional skin has not been fully investigated. In this study we showed that there existed a large number of B and T lymphocytes and plasma cells in the skin lesions by immunohistochemistry and immunofluorescence staining. In addition, a significantly increased number of Dsg1- and Dsg3-specific B cells could be identified by flow cytometric analysis or enzyme-linked immunospot technique (i.e., ELISPOT) assay. Furthermore, anti-Dsg1 and Dsg3 antibodies could be detected from the supernatant of in vitro cultures with isolated lymphocytes from lesional skin. We found that most T lymphocytes infiltrating pemphigus vulgaris lesions were CD4+ T helper cells expressing IL-21 and IL-17a but not typical T follicular helper cells expressing CXCR5. Additionally, our microarray assay showed that the level of chemokine CCL19 was significantly elevated, suggesting active T-/B-lymphocyte trafficking and aggregation in the pemphigus vulgaris lesions. Collectively, our results suggest a critical role of locally infiltrating lymphocytes in pemphigus pathogenesis. PMID- 28647349 TI - Inhibitor of Apoptosis Proteins (IAPs) Limit RIPK1-Mediated Skin Inflammation. AB - Inhibitor of apoptosis proteins (IAPs) are critical regulators of cell death and survival pathways. Mice lacking cIAP1 and either cIAP2 or XIAP die in utero, and myeloid lineage-specific deletion of all IAPs causes sterile inflammation, but their role in the skin is unknown. We generated epidermal-specific IAP-deficient mice and found that combined genetic deletion of cIAP1 (epidermal knockout [EKO]) in keratinocytes and ubiquitous cIAP2 deletion (cIap1EKO/EKO.cIap2-/-) caused profound skin inflammation and keratinocyte death, lethal by postpartum day 10. To investigate their role in skin homeostasis, we injected an IAP antagonist compound subcutaneously into wild-type and knockout mice. This induced a toxic epidermal necrolysis-like local inflammation, which mirrored the phenotype seen in cIap1EKO/EKO.cIap2-/- mice. Loss of one Ripk1 allele limited lesion formation and significantly extended the lifespan of cIap1EKO/EKO.cIap2-/- mice. cIAP activities are important for recruitment of LUBAC to signaling complexes, and loss of LUBAC component SHARPIN, induces dermatitis in mice. Consistent with this relationship between cIAPs and LUBAC, Ripk1 heterozygosity also protected against development of dermatitis in Sharpin-deficient mice. This work therefore refines our molecular understanding of inflammatory signaling in the skin and defines potential targets for treating skin inflammation. PMID- 28647350 TI - Antitumor activity of resveratrol is independent of Cu(II) complex formation in MCF-7 cell line. AB - Resveratrol (Rsv) is widely reported to possess anticarcinogenic properties in a plethora of cellular and animal models having limited toxicity toward normal cells. In the molecular level, Rsv can act as a suppressive agent for several impaired signaling pathways on cancer cells. However, Fukuhara and Miyata have shown a non-proteic reaction of Rsv, which can act as a prooxidant agent in the presence of copper (Cu), causing cellular oxidative stress accompanied of DNA damage. After this discovery, the complex Rsv-Cu was broadly explored as an antitumor mechanism in multiples tumor cell lines. The aim of the study is to explore the anticarcinogenic behavior of resveratrol-Cu(II) complex in MCF-7 cell line. Selectivity of Rsv binding to Cu ions was analyzed by HPLC and UV-VIS. The cells were enriched with concentrations of 10 and 50uM CuSO4 solution and treated with 25uM of Rsv. Copper uptake after enrichment of cells, as its intracellular distribution in MCF-7 line, was scanned by ICP-MS and TEM-EDS. Cell death and intracellular ROS production were determined by flow cytometry. Different from the extracellular model, no relationship of synergy between Rsv-Cu(II) and reactive oxidative species (ROS) production was detected in vitro. ICP-MS revealed intracellular copper accumulation to both chosen concentrations (0.33+/ 0.09 and 1.18+/-0.13ppb) but there is no promotion of cell death by Rsv-Cu(II) complex. In addition, significant attenuation of ROS production was detected when cells were exposed to CuSO4 after Rsv treatment, falling from 7.54% of ROS production when treated only with Rsv to 3.07 and 2.72% with CuSO4. Based on these findings antitumor activity of resveratrol when in copper ions presence, is not mediated by Rsv-Cu complex formation in MCF-7 human cell line, suggesting that the antitumoral reaction is dependent of a cancer cellular model. PMID- 28647351 TI - Development of an ON/OFF switchable fluorescent probe targeting His tag fused proteins in living cells. AB - The fluorescent labeling of target proteins is useful for analyzing their functions and localization in cells, and several fluorescent probes have been developed. However, the fusion of tags such as green fluorescent protein (GFP) to target proteins occasionally affects their functions and/or localization in living cells. Therefore, an imaging method that uses short peptide tags such as hexa-histidine (the His tag) has been attracting increasing attention. Few studies have investigated ON/OFF switchable fluorescent probes for intracellular His-tagged proteins. We herein developed a novel ON/OFF switchable probe for imaging targeted intracellular proteins fused with a CH6 tag, which is composed of one cysteine residue and six histidine residues. PMID- 28647352 TI - How to Approach a Patient With Nonalcoholic Fatty Liver Disease. PMID- 28647353 TI - Recent Advances in Endoscopy. AB - In this narrative review, invited by the Editors of Gastroenterology, we summarize recent advances in the field of gastrointestinal endoscopy. We have chosen articles published primarily in the past 2-3 years. Although a thorough literature review was performed for each topic, the nature of the article is subjective and systematic and is based on the authors' experience and expertise regarding articles we believed were most likely to be of high clinical and scientific importance. PMID- 28647354 TI - The Future of Endoscopic Retrograde Cholangiopancreatography. PMID- 28647355 TI - Random-start ovarian stimulation in women desiring elective cryopreservation of oocytes. AB - The current study investigates the utility of random-start ovarian stimulation in women desiring elective oocyte cryopreservation. Women in the study cohort underwent random-start ovarian stimulation, and were subdivided based on the phase of the menstrual cycle that ovarian stimulation began, i.e. early follicular, late follicular or luteal phase. Women undergoing conventional cycle day (CD) 2/3 ovarian stimulation start were controls. A total of 1302 women were included - 859 (66.0%) conventional CD 2/3, 342 (26.3%) early follicular, 42 (3.2%) late follicular and 59 (4.5%) luteal ovarian stimulation starts. There was no difference in the demographics or baseline ovarian stimulation characteristics. The duration of ovarian stimulation (11 versus 9 days; P < 0.001) and total dosage of gonadotrophins administered (4095.5 versus 3155 IU; P < 0.001) was higher in the random-start group. The number of total and MII oocytes in the control and random-start groups was similar. A non-significant trend towards increased cycle cancellation was noted in the late follicular start group (7.1%). Study findings indicate the number of total and MII oocytes derived from random-start protocols initiated during any phase of the menstrual cycle is similar to conventional CD 2/3 ovarian stimulation start protocols in women desiring elective oocyte cryopreservation. PMID- 28647356 TI - Optimizing bone morphogenic protein 4-mediated human embryonic stem cell differentiation into trophoblast-like cells using fibroblast growth factor 2 and transforming growth factor-beta/activin/nodal signalling inhibition. AB - Several studies have demonstrated that human embryonic stem cells (hESC) can be differentiated into trophoblast-like cells if exposed to bone morphogenic protein 4 (BMP4) and/or inhibitors of fibroblast growth factor 2 (FGF2) and the transforming growth factor beta (TGF-beta)/activin/nodal signalling pathways. The goal of this study was to investigate how the inhibitors of these pathways improve the efficiency of hESC differentiation when compared with basic BMP4 treatment. RNA sequencing was used to analyse the effects of all possible inhibitor combinations on the differentiation of hESC into trophoblast-like cells over 12 days. Genes differentially expressed compared with untreated cells were identified at seven time points. Additionally, expression of total human chorionic gonadotrophin (HCG) and its hyperglycosylated form (HCG-H) were determined by immunoassay from cell culture media. We showed that FGF2 inhibition with BMP4 activation up-regulates syncytiotrophoblast-specific genes (CGA, CGB and LGALS16), induces several molecular pathways involved in embryo implantation and triggers HCG-H production. In contrast, inhibition of the TGF beta/activin/nodal pathway decreases the ability of hESC to form trophoblast-like cells. Information about the conditions needed for hESC differentiation toward trophoblast-like cells helps us to find an optimal model for studying the early development of human trophoblasts in normal and in complicated pregnancy. PMID- 28647357 TI - Biophysical characterization of histone H3.3 K27M point mutation. AB - Lysine 27 to methionine (K27 M) mutation of the histone variant H3.3 drives the formation of an aggressive glioblastoma multiforme tumor in infants. Here we analyzed how the methionine substitution alters the stability of H3.3 nucleosomes in vitro and modifies its kinetic properties in live cells. We also determined whether the presence of mutant nucleosomes perturbed the mobility of the PRC2 subunit Ezh2 (enhancer-of-zeste homolog 2). We found that K27 M nucleosomes maintained the wild-type molecular architecture both at the level of bulk histones and single nucleosomes and followed similar diffusion kinetics to wild type histones in live cells. Nevertheless, we observed a remarkable differential recovery of Ezh2 in response to transcriptional stress that was accompanied by a faster diffusion rate of the mobile fraction of Ezh2 and a significantly increased immobile fraction, suggesting tighter chromatin binding of Ezh2 upon transcription inhibition. The differential recovery of Ezh2 was dependent on transcription, however, it was independent from K27 M mutation status. These biophysical characteristics shed more light on the mechanism of histone H3.3 K27M in glioma genesis in relation to the kinetic properties of Ezh2. PMID- 28647358 TI - Mitochondria-associated membranes (MAMs): An emerging platform connecting energy and immune sensing to metabolic flexibility. AB - Living organisms have the capacity to sense both nutrients and immune signals in order to adapt their metabolism to the needs, and both metabolic inflexibility and exacerbated immune responses are associated with metabolic diseases. Over the past decade, mitochondria emerged as key nutrient and immune sensors regulating numerous signalling pathways, and mitochondria dysfunction has been extensively implicated in metabolic diseases. Interestingly, mitochondria interact physically and functionally with the endoplasmic reticulum (ER, in contact sites named mitochondria-associated membranes (MAMs), in order to exchange metabolites and calcium and regulate cellular homeostasis. Emerging evidences suggest that MAMs provide a platform for hormone and nutrient signalling pathways and for innate immune responses, then regulating mitochondrial bioenergetics and apoptosis. Here, I thus propose the concept that MAMs could be attractive nutrient and immune sensors that regulate mitochondria physiology in order to adapt metabolism and cell fate, and that organelle miscommunication could be involved in the metabolic inflexibility and the pro-inflammatory status associated with metabolic diseases. PMID- 28647359 TI - Mild hypothermia ameliorates muscle wasting in septic rats associated with hypothalamic AMPK-induced autophagy and neuropeptides. AB - Sepsis, always developing muscle wasting, contributes to serious complications and mortality. Mild hypothermia has been reported to have protective effects on the prognosis of septic patients. However, the underlying mechanisms remain unclear. We therefore hypothesized that mild hypothermia could ameliorate muscle wasting during sepsis and whether it was associated with hypothalamus AMPK induced autophagy and neuropeptides. Adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline. Mild hypothermia was instantly induced at 33 degrees C for 3h after LPS injected. Meanwhile, the control and sepsis groups were simultaneously placed on the thermal mattress to maintain the a normal temperature in control group whatever the changes induced by anesthesia. Twenty-four hours after injection, skeletal muscle and hypothalamus tissues were obtained. Muscle wasting was measured by the mRNA expression of two muscle atrophic genes, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that LPS administration significantly decreased hypothalamic AMPK-induced autophagy together with muscle wasting. Also, increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuro-peptides Y (NPY) and decreased agouti-related protein (AgRP) were observed. Mild hypothermia significantly increased hypothalamic AMPK-induced autophagy and ameliorated LPS-induced muscle wasting, and attenuated the alteration of neuropeptides, POMC, CART and NPY. In conclusion, mild hypothermia could alleviate muscle wasting by LPS injection, which was associated with reversing the level of hypothalamic AMPK-induced autophagy and the alteration of neuropeptides. These results suggested that mild hypothermia could be a potential treatment concept and a novel mechanism in management of muscle wasting in critically ill patients. PMID- 28647360 TI - Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution. AB - The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from Shank3 at sub-atomic resolution. While the structure presents the canonical SH3 domain fold, the binding site for proline rich peptides is not conserved. In line with this, no binding of Pro-rich sequences by the Shank3 SH3 domain was observed. Sequence comparisons indicate that all Shank isoforms have similarly lost the classical Pro-rich peptide binding site from the SH3 domain. Whether the corresponding site in the Shank SH3 domains has evolved to bind a non-poly-Pro target sequence is currently not known. Our work provides an intriguing example of the evolution of a well characterized protein-protein interaction domain within the context of multi domain protein scaffolds, allowing the conservation of structural features, but losing canonical functional sites. The data are further discussed in light of known mutations in the SH3 domain or its vicinity in the different Shank isoforms. PMID- 28647361 TI - Apolipoprotein O expression in mouse liver enhances hepatic lipid accumulation by impairing mitochondrial function. AB - Apolipoprotein O (ApoO) was recently observed in the cellular mitochondrial inner membrane, which plays a role in mitochondrial function and is associated with myocardiopathy. Empirical information on the physiological functions of apoO is therefore limited. In this study, we aimed to elucidate the effect of apoO on hepatic fatty acid metabolism. An adenoviral vector expressing hApoO was constructed and introduced into chow diet and high-fat diet induced mice and the L02 human hepatoma cell line. High levels of hApoO mRNA and protein were detected in the liver, and the expression of lipid metabolism genes was significantly altered compared with negative controls. The liver function indices (serum ALT and AST) were clearly elevated, and the ultrastructure of cellular mitochondria was distinctly altered in the liver after apoO overexpression. Further, mitochondrial membrane potential decreased with hApoO treatment in L02 cells. These results establish a link between apoO and lipid accumulation and could suggest a new pathway for regulating non-alcoholic fatty liver disease progression. PMID- 28647362 TI - Farnesoid X receptor agonist GW4064 ameliorates lipopolysaccharide-induced ileocolitis through TLR4/MyD88 pathway related mitochondrial dysfunction in mice. AB - Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory condition of the gastro intestinal tract characterized by diarrhoea and abdominal pain. Farnesoid X receptor (FXR) plays an important role in enteroprotection and mucosal injury by regulating inflammatory responses and barrier function in the intestinal tract. Here we show the mechanisms of FXR agonist, GW4064, inhibits mucosal injury in ileum caused by lipopolysaccharides (LPS). Ileum injury was induced by intraperitoneal injection of LPS in Wild-type (WT) and FXR knockout (KO) mice. GW4064 alleviates LPS-mediated tight junction dysfunction as well as macrophage infiltration in WT mice, but not in FXR KO mice. Interesting, GW4064 suppresses NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome mediates tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL 1beta, as well as mitochondrial respiratory complexes mRNA expression in WT and FXR KO mice treated with LPS. This results demonstrated that central roles of FXR in coordinating regulation of both inflammation and mitochondrial dysfunction. We propose that GW4064 is promising therapeutic agent for treatment of ileocolitis. PMID- 28647363 TI - CADPS2 gene expression is oppositely regulated by LRRK2 and alpha-synuclein. AB - The Ca2+-dependent activator protein for secretion 2 (CADPS2) is a member of the CAPS/CADPS protein family that plays crucial roles in synaptic vesicle dynamics. Genomic variability in the CADPS2 gene has been associated to autism spectrum disorders and Alzheimer's disease, both characterized by altered neurotransmission. Biological evidence also linked CADPS2 to Parkinson's disease (PD), as a disease-causing mutation in leucine-rich repeat kinase 2 (LRRK2) was reported to increase CADPS2 gene and protein expression. Furthermore, restoration of CADPS2 physiologic levels was able to provide neuroprotection in patient derived neurons, consistent with the synaptic dysfunction postulated to underlie PD. However, little is known about the influence of PD-related proteins on transcriptional regulation of critical synaptic genes such as CADPS2. Here we aimed at investigating the transcriptional effects of LRRK2 and alpha-synuclein (aSyn) on CADPS2 gene expression, using a combination of in silico analyses and cell biology techniques. First, we identified a predicted promoter in the human CADPS2 genomic sequence, which we then utilized in a luciferase-based gene reporter assay. This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells. Our results indicate that LRRK2 and aSyn participate in the dysregulation of CADPS2 by altering transcription and support the hypothesis that synaptic dysfunctions, through different mechanisms, might contribute to the neuronal defects of diseases such as PD. PMID- 28647364 TI - Crystal structures of the isochorismatase domains from Vibrio anguillarum. AB - Antibiotic resistance is becoming a global threat and overuse of antibiotics in aquaculture disease control worsens the situation. To reduce the risk of drug resistance developed in aquaculture, safer biocontrol programs are needed. Antivirulence therapy, with less chance for developing drug resistance, is a promising approach. To facilitate antivirulence inhibitor design against Vibrio anguillarum, a serious aquaculture pathogen, we present crystal structures for isochorismatase domains of AngB and VabB, which are required to synthesize siderophore, a critical virulence factor. Both structures are highly similar to known isochorismatases in fold and active site, therefore we conclude inhibitors for isochorismatases can be developed in a common framework. The structural information will improve design of virulence inhibitors against Vibrio anguillarum. We also firstly report that isochorismatase family could bind endogenous metabolite during the hetero-expression process, which is likely nicotinic acid, nicotinamide or pyrazinic acid, based on structural analysis and affinity prediction. Taken together, our results provide precise structural information of isochorismatase domains for antivirulence inhibitor design against Vibrio anguillarum. PMID- 28647365 TI - Conjugated linoleic acid prevents age-induced bone loss in mice by regulating both osteoblastogenesis and adipogenesis. AB - Osteoporosis (OP) can increase the risk of bone fracture and other complications, which is a major clinical problem. Previous researches have revealed that conjugated linoleic acid (CLA) can promote the bone formation. But the mechanisms are not clear. Thus, we tested the hypothesis that CLA acts on bone formation might be via mTOR Complex1 (mTORC 1) pathway by in vitro and vivo assays. We studied the effect of CLA mix on MC3T3-E1 pre-osteoblasts differentiation into osteoblasts, and bone formation under osteoporotic conditions. At the same time, 3T3-L1 pre-adipocyte with the same CLA mix concentration gradient for 8 days with adipogenic differentiation medium. We found that Alkaline phosphatase (ALP), runt related transcription factor 2 (RUNX2) and osteocalcin (OCN) expressions of pre osteoblasts were up-regulated. Moreover in presence of CLA, peroxisome proliferators-activated receptor gamma(PPARgamma) and CCAAT/enhancer-binding protein (C/EBPalpha) were down-regulated. Osteoporosis mice bone parameters in the distal femoral meraphysis were significantly increased compared with placebo mice. Furthermore, the phosphor-S6 (P-S6) was suppressed and phosphor-AKT (P-AKT) was up-regulated. Consistently, CLA can stimulate differentiation of osteoblasts and inhibited pre-adipocytes differentiated into adipocytes via AKT/mTORC1 signal pathway. Overall CLA thus be a suitable candidate for the treatment of patients with postmenopausal osteoporosis and obesity. PMID- 28647366 TI - Crystal structure of the crenarchaeal ExoIII AP endonuclease SisExoIII reveals a conserved disulfide bond endowing the protein with thermostability. AB - AP endonuclease recognizes and cleaves apurinic/apyrimidinic (AP) sites and plays a critical role in base excision repair. Many ExoIII and EndoIV family AP endonucleases have been characterized both biochemically and structurally in Eukaryote and Bacteria. However, relatively fewer have been studied in Euryarchaeota and there is no such report on an AP endonuclease from Crenarchaeota. Here we report, for the first time, the crystal structure of a crenarchaeal ExoIII AP endonuclease, SisExoIII, from Sulfolobus islandicus REY15A. SisExoIII comprises a two-layer core formed by 10 beta-sheets and a shell formed by 9 surrounding alpha-helices. A disulfide bond connecting beta8 and beta9 is formed by Cys142 and Cys215. This intra-molecular linkage is conserved among crenarchaeal ExoIII homologs and site-directed mutagenesis revealed that it endows the protein with thermostability, however, disruption of the disulfide bond only has a slight effect on the AP endonuclease activity. We also observed that several key residues within the catalytic center including conserved Glu35 and Asn9 show different conformation compared with known ExoIII proteins and form various intra-molecular salt bridges. The protein possesses three putative DNA binding loops with higher flexibility and hydrophobicity than those of ExoIIIs from other organisms. These features may result in low AP endonuclease activity and defect of exonuclease activity of SisExoIII. The study has deepened our understanding in the structural basis of crenarchaeal ExoIII catalysis and clarified a role of the disulfide bond in maintaining protein thermostability. PMID- 28647367 TI - Mitochondrial quality control pathways: PINK1 acts as a gatekeeper. AB - Mitochondria have a pivotal role in the maintenance of cell homeostasis and survival. Mitochondria are involved in processes such as ATP production, reactive oxygen species production, apoptosis induction, calcium homeostasis and protein degradation. Thus, mechanisms that regulate the intrinsic quality of mitochondria have a crucial role in dictating overall cell fate. The importance of these well regulated mechanisms is highlighted in disease scenarios such as neurodegeneration, cancer and neuromuscular atrophy. How mitochondria senses and regulates their intrinsic quality control, and consequently cell survival, is still not fully understood. In this review, we discuss the pathways that are at present considered as state-of-the-art for mitochondria quality control regulation, and highlight a mitochondrial protein-PINK1-that has revealed to act as a mitochondrial gatekeeper able to sense the presence of healthy or damaged mitochondria. PMID- 28647368 TI - Identification and characterization of the leaf specific networks of inner and rosette leaves in Brassica rapa. AB - Inner and rosette leaves of Chinese cabbage (Brassica rapa) have different characteristics in terms of nutritional value, appearance, taste, color and texture. Many researchers have utilized differentially expressed genes for exploring the difference between inner and rosette leaves of Brassica rapa. The functional characteristics of a gene, however, is determined by complex interactions between genes. Hence, a noble network approach is required for elucidating such functional difference that is not captured by gene expression profiles alone. In this study, we measured gene expression in the standard cabbage genome by RNA-Sequencing and constructed rosette and inner leaf networks based on the gene expression profiles. Furthermore, we compared the topological and functional characteristics of these networks. We found significant functional difference between the rosette and inner leaf networks. Specifically, we found that the genes in the rosette leaf network were associated with homeostasis and response to external stimuli whereas the genes in the inner leaf network were mainly related to the glutamine biosynthesis processes and developmental processes with hormones. Overall, the network approach provides an insight into the functional difference of the two leaves. PMID- 28647369 TI - Synthesis of cytochrome c oxidase 1 (SCO1) inhibits insulin sensitivity by decreasing copper levels in adipocytes. AB - Dysregulation of insulin signaling leads to type 2 diabetes mellitus (T2DM) and other metabolic disorders. Obesity is an important contributor to insulin resistance, and although the understanding of this relationship has improved in recent years, the mechanism of obesity-induced insulin resistance is not completely understood. Disorders of copper metabolism tend to accompany the development of obesity, which increases the risk of insulin resistance. Synthesis of cytochrome c oxidase 1 (SCO1) functions in the assembly of cytochrome c oxidase (COX) and cellular copper homeostasis. However, the role of SCO1 in the regulation of metabolism remains unknown. Here, we found that obese mice had higher expression of SCO1 and lower levels of copper in white adipose tissue (WAT) than did the control mice. Overexpression of SCO1 in adipocytes was associated with copper deficiency. Copper increased insulin sensitivity by decreasing the level of phosphatase and tensin homolog (PTEN) protein. Ectopic expression of SCO1 led to insulin resistance and was accompanied by a decrease in intracellular copper level, and addition of copper abolished the inhibitory effect of SCO1 on insulin sensitivity. Our results demonstrated a novel role of SCO1 in modulating insulin sensitivity via the regulation of copper concentration in WAT and suggested a potential therapeutic target for T2DM. PMID- 28647370 TI - Oleanolic acid prevents cartilage degeneration in diabetic mice via PPARgamma associated mitochondrial stabilization. AB - Hyperglycemia-induced cartilage degeneration induces osteoarthritis (OA). Since oleanolic acid (OLA) have several pharmacological effects such as anti inflammatory, anti-oxidant, we hypothesized it possesses protection against high glucose injured cartilage. We now report that OLA decreased type X collagen and reversed the cartilage degeneration in growth plate from db/db mice. OLA increased type II collagen expression in a concentration-dependent manner (10-50 MUMU) in high glucose-treated chondrocytes. OLA prevented the high glucose induced cell injury and decreased the level of MMP-13, PGE2 and IL-6 due to decreasing mitochondrial membrane potential and stimulated the ATP production. Moreover, OLA treatment inhibited apoptosis. And the reversed SOD2 expression and activity may be ascribed to decreased SOD2 protein degradation by OLA treatment, via PPPAgamma. In conclusion, OLA protected against the high-glucose-induced cartilage injury via PPARgamma/SOD2 pathway. PMID- 28647371 TI - Triglyceride synthesis in hepatocytes isolated from rats fed a low-protein diet is enhanced independently of upregulation of insulin signaling. AB - It is known that protein malnutrition develops fatty liver in rats. However, the mechanisms by which protein malnutrition enhances lipid accumulation in the liver are not fully understood. Our previous studies have demonstrated that protein malnutrition upregulates insulin signaling with an increase in TG levels in rat livers. Here, we examined whether the upregulated insulin signaling contributes to an enhancement of TG accumulation under protein malnutrition. As it is difficult to analyze insulin-induced hepatic TG synthesis in vivo, the isolated hepatocytes derived from rats fed a low-protein diet were used. The hepatocytes were isolated from rats fed a 15% casein diet (15C) as a control diet or a 5% casein diet (5C) as a low-protein diet and then treated with insulin. As shown in vivo, insulin signaling was upregulated in isolated hepatocytes from 5C-fed rats (5C hepatocytes). However, the insulin-induced increase in the mRNA levels of lipogenic enzymes, including acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS), was similar in both groups. The amounts of TG synthesized from both glucose and palmitate, as well as ACC1 and FAS protein levels, were increased at the basal state in 5C hepatocytes, but were not further increased by insulin. These results indicate that TG synthesis via both de novo fatty acid synthesis and esterification is enhanced in 5C hepatocytes, which is independent of the upregulation of insulin signaling. PMID- 28647372 TI - Delta opioid receptor agonist attenuates lipopolysaccharide-induced myocardial injury by regulating autophagy. AB - BACKGROUND: Previous studies have described the protective effects of DADLE on myocardial injury in sepsis. Recently, autophagy has been shown to be an innate defense mechanism in sepsis-related myocardial injury. However, whether DADLE has an pro-autophagic effect is yet to be elucidated. The present study aimed to investigate the effect of DADLE on the regulation of autophagy during sepsis. METHODS: Male mice were subjected to LPS or vehicle intraperitoneal injection. After LPS injection, mice received either DADLE, Naltrindole or vehicle. ELISA and JC-1 were used to evaluate the level cTnI and Mitochondrial membrane potential. Cardiac ultrastructural and autophagosomes were visualized by transmission electron microscopy. The relative protein levels were analyzed by Western blot. RESULTS: The results showed that treatment with DADLE both immediately or 4 h after LPS intraperitoneal injection could improve the survival rate of mice with endotoxemic. DADLE could ease myocardium ultrastructure injury induced by LPS, this cardioprotective effect was also seen in increased MMP levels, and decreased cTnI levels. Through observation of transmission electron microscopy and Western blot we have discovered that the amount of autophagosome and the expression of autophagy related protein LC3II, Beclin1 were significantly increased with DADLE treatment. DADLE promoted LPS-induced autophagosome maturation as indicated by the increased LAMP-1 protein level and decreased SQSTM1/p62 protein level. The selective delta-opioid receptor antagonist Naltrindole play an opposite effects. CONCLUSIONS: DADLE could improve the survival and protect myocardial dysfunction in mice with LPS-induced endotoxemia. This effect was related to the increase of autophagy. PMID- 28647373 TI - Salusin-beta mediates high glucose-induced endothelial injury via disruption of AMPK signaling pathway. AB - The dysregulated proliferation, migration, apoptosis and angiogenesis of endothelial cells are involved in diabetic endothelial dysfunction. The circulating salusin-beta levels were increased in diabetic patients, and salusin beta contributes to diabetic cardiomyopathy in rats. However, the roles of salusin-beta in diabetes mellitus-induced endothelial dysfunction are not fully understood. Herein, we demonstrated the increased expressions of salusin-beta in human umbilical vein endothelial cells (HUVECs) cultured in HG medium. Exposure of HUVECs to HG inhibited the proliferation, migration, and angiogenesis, retarded cell cycle progression of endothelial cells, which were rescued by knockdown of salusin-beta. We also established that silencing of salusin-beta with adenoviruse-mediated shRNA reduced high glucose-induced apoptosis by up regulating Bcl-2 expression and down-regulating Bax and caspase-3 expressions. Blockade of salusin-beta ameliorated HG-induced suppression of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Of note, pretreatment with AMPK inhibitor Compound C abolished salusin-beta silencing mediated endothelial protective effects. In summary, our results highlighted the involvement of salusin-beta in HG-related endothelial dysfunction, and salusin beta contributed high glucose-induced endothelial injury via inactivation of AMPK signaling pathway. PMID- 28647374 TI - Overexpression of Dentin matrix protein 1 in Nestin+ cells causes bone loss in mouse long bone. AB - The well-known matrix protein Dentin matrix protein 1 (DMP1) is expressed by osteoblasts and osteocytes in bone, and it controls bone mineralization. Recently, it has been found that DMP1 is also expressed in other cell types, such as chondrocytes. Nestin+ cells are one important type of progenitor cell in bone marrow and are associated with bone remodeling. In our preliminary experiment, DMP1 could also be detected in Nestin+ cells in bone marrow. This study was designed to explore the effect on bone of DMP1 in Nestin+ cells. A transgenic mouse model with DMP1 expression driven by the Nestin promoter was generated. In vivo and in vitro experiments revealed that overexpression of DMP1 in Nestin+ cells could limit the proliferation and osteogenic differentiation of BMMSCs, subsequently leading to decreased bone mass. Lower expression of bone matrix protein and a lower bone deposition rate were also observed. Meanwhile, overexpression of DMP1 in Nestin+ cells had no influence on osteoclast activity. These data indicate that DMP1 plays negative roles in differentiation of Nestin+ cells and bone formation. PMID- 28647375 TI - Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke. AB - Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro inflammatory environment. Wild-type and IFNAR1-/- primary murine neurons and glia were exposed to oxygen glucose deprivation (OGD) and cell viability was assessed. Transient cerebral ischemia/reperfusion injury was induced by mid-cerebral artery occlusion (MCAO) in wild-type and IFNAR1-/- and IFNAR2-/- mice in vivo, and infarct size, and molecular parameters measured. To block IFNAR1 signalling, wild type mice were treated with a blocking monoclonal antibody directed to IFNAR1 (MAR-1) and MCAO was performed. Quantitative PCR confirmed MCAO in wild-type mice induced a robust type-I interferon gene regulatory signature. Primary cultured IFNAR1-deficient neurons were found to be protected from cell death when exposed to OGD in contrast to primary cultured IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 +/- 7.1 mm3 n = 8) compared to wild-type controls (65.1 +/- 4.8 mm3 n = 8). Western blot and immunohistochemistry showed alterations in Akt and Stat-3 phosphorylation profiles in the IFNAR1-/- brain. MAR-1 injection into WT mice (i.v. 0.5 mg 60 min prior to MCAO) resulted in a 60% decrease in infarct size when compared to the IgG control. IFNAR2-/- mice failed to display the neuroprotective phenotype seen in IFNAR1-/- mice after MCAO. Our data proposes that central nervous system signalling through IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke. PMID- 28647376 TI - Mitochondrial permeability transition pore: Back to the drawing board. AB - Current models theorizing on what the mitochondrial permeability transition (mPT) pore is made of, implicate the c-subunit rings of ATP synthase complex. However, two very recent studies, one on atomistic simulations and in the other disrupting all genes coding for the c subunit disproved those models. As a consequence of this, the structural elements of the pore remain unknown. The purpose of the present short-review is to (i) briefly review the latest findings, (ii) serve as an index for more comprehensive reviews regarding mPT specifics, (iii) reiterate on the potential pitfalls while investigating mPT in conjunction to bioenergetics, and most importantly (iv) suggest to those in search of mPT pore identity, to also look elsewhere. PMID- 28647377 TI - Establishing rarity in the context of orphan medicinal product designation in the European Union. AB - In the European Union (EU) legislative framework for orphan medicinal product designation, establishing that a condition affects not more than five in 10,000 people is a prerequisite for applications based on rarity. Demonstrating this requirement to the Committee of Orphan Medicinal Products (COMP) can be a particularly challenging task for sponsors. Here, we identify and examine three common issues with the estimation of prevalence in orphan drug applications in the EU (the discernment between diagnosed and undiagnosed cases; the duration of the disease; and the need for an explicit contemporary conclusion) as critical factors for acceptable prevalence estimation. These concerns are discussed in detail based on recent examples of applications, which are reflected in published European Medicines Agency (EMA) documents. PMID- 28647378 TI - Leishmaniasis drug discovery: recent progress and challenges in assay development. AB - Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates. It is therefore imperative that more physiologically relevant assays are developed to identify anti-leishmanial compounds. This review provides an overview of the disease, current treatment options and compares the various technologies and assay formats currently available for leishmanial drug discovery. PMID- 28647379 TI - [Impetigoid secondary syphilis]. PMID- 28647380 TI - [Lymphedema of the lower limbs: Initial manifestation of gastric linitis plastica]. AB - BACKGROUND: Primary lymphedemas are constitutional abnormalities of the lymphatic system. Secondary lymphedemas occur after damage to the lymphatic system, mainly after cancer treatments or tumour mass compression. There are many other causes, including filariasis, which is nonetheless very rare in France. PATIENTS AND METHODS: A 52-year-old man presented with a two-month history of increased size of the left leg. He was asymptomatic and in good general condition. Clinical examination revealed non-pitting lymphedema and ipsilateral hydrocele without loco-regional compressive lymph node. Initial extensive explorations were unremarkable. Lymphoscintigraphy revealed low tracer fixation in the left leg. The symptoms continued to worsen, with exacerbation and bilateralization of the lymphedema. Two months later, axillary lymph nodes appeared corresponding to metastasis from a signet-ring cell carcinoma. Despite two lines of chemotherapy, the patient died 8 months later due to multiple metastatic disease. DISCUSSION: Our case is remarkable because the lymphedema was not related to extrinsic compression and was the first symptom of gastric cancer. In the absence of compression, endo-lymphatic micro-metastases could constitute the causative process. Acquired lymphedema of the lower limbs must be recognized as a potential early symptom of gastric carcinoma and should therefore prompt further investigations. PMID- 28647381 TI - Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model. AB - BACKGROUND: Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. METHODS: A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. RESULTS: Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. CONCLUSIONS: This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target. PMID- 28647382 TI - IL-17A gene polymorphism rs2275913 is associated with the development of asthma after bronchiolitis in infancy. AB - BACKGROUND: Interleukin-17 (IL-17A) is a mainly pro-inflammatory cytokine, and IL 17 signaling implicates in the development of allergic asthma. The polymorphism rs2275913 in the promoter region of the IL-17A gene has in previous studies been associated with asthma susceptibility. The objective was to evaluate the association between IL-17A rs2275913 (-197G>A) polymorphism and post bronchiolitis asthma and/or allergic rhinitis in a prospective 11-13 years post bronchiolitis follow-up. METHODS: 166 previously healthy full-term infants, hospitalized for bronchiolitis at age less than 6 months, were invited to follow up visits at the ages of 5-7 years and 11-13 years. Asthma diagnoses and presumptive symptoms, allergic rhinitis and use of inhaled corticosteroids (ICS) were registered. Blood samples for IL-17A rs2275913 (-197G>A) polymorphism were obtained during hospitalization or at the 5-7 years control visit. RESULTS: There were no significant differences between children with the wild GG and variant GA or AA genotype in the severity of bronchiolitis during hospitalization or in the outcomes until the age 5-7 years. At 11-13 years of age, children with the variant GA or AA genotype had significantly less often current asthma, use of ICSs during last 12 months or allergic rhinitis than those with the wild GG genotype. The ICS use during last 12 months retained the statistical significance in adjusted analyses (adjusted OR 0.25), whereas current asthma and allergic rhinitis marginally lost it. CONCLUSIONS: The IL-17A rs2275913 (-197G>A) polymorphism decreased the risk of post-bronchiolitis asthma at 11-13 years of age, but not earlier in life, in the present prospective, long-term follow-up study. PMID- 28647383 TI - Impact of Agaricus bisporus mushroom consumption on satiety and food intake. AB - Previous studies on mushrooms suggest that they can be more satiating than meat, but this effect has not been studied with protein-matched amounts. The objective of this study was to assess the differences with satiety and ten-day food intake between A. bisporus mushrooms (226 g) and meat (28 g) in a randomized open-label crossover study. Thirty-two healthy participants (17 women, 15 men) consumed two servings of mushrooms or meat for ten days. On the first day, fasted participants consumed protein-matched breakfasts. Participants rated their satiety using visual analogue scales (VAS) at baseline and at regular intervals after the meal. Three hours later, participants were served an ad libitum lunch. Participants were given mushrooms or meat to consume at home for the following nine days. Energy intake was assessed at the ad libitum lunch, and participants also completed diet diaries on the day of the study, day 2, and day 10. Participants reported less hunger (p = 0.045), greater fullness (p = 0.05), and decreased prospective consumption (p = 0.03) after the mushroom breakfast. There were no significant differences in participant ratings of satisfaction (p = 0.10). There were also no statistically significant differences in energy intake at the ad libitum lunch or with the diet diaries from days 1 (p = 0.61), 2 (p = 0.77), or 10 (p = 0.69). Mushroom consumption did increase fiber intake on days 1, 2, and 10 but the difference in fiber consumption was only statistically significant on day 2 (p = 0.0001). The mushroom intervention also did not affect energy intake over the ten day feeding period. PMID- 28647384 TI - Impulsivity moderates the effect of approach bias modification on healthy food consumption. AB - The study aimed to modify approach bias for healthy and unhealthy food and to determine its effect on subsequent food consumption. In addition, we investigated the potential moderating role of impulsivity in the effect of approach bias re training on food consumption. Participants were 200 undergraduate women (17-26 years) who were randomly allocated to one of five conditions of an approach avoidance task varying in the training of an approach bias for healthy food, unhealthy food, and non-food cues in a single session of 10 min. Outcome variables were approach bias for healthy and unhealthy food and the proportion of healthy relative to unhealthy snack food consumed. As predicted, approach bias for healthy food significantly increased in the 'avoid unhealthy food/approach healthy food' condition. Importantly, the effect of training on snack consumption was moderated by trait impulsivity. Participants high in impulsivity consumed a greater proportion of healthy snack food following the 'avoid unhealthy food/approach healthy food' training. This finding supports the suggestion that automatic processing of appetitive cues has a greater influence on consumption behaviour in individuals with poor self-regulatory control. PMID- 28647386 TI - The Importance of Combined Teaching Methods in Radiology Resident Education. PMID- 28647385 TI - Hunger and disinhibition but not cognitive restraint are associated with central norepinephrine transporter availability. AB - The relationship between food-intake related behaviours measured by the Three Factor Eating Questionnaire (TFEQ) and in vivo norepinephrine transporter (NET) availability has not been explored yet. We investigated ten obese individuals (body mass index (BMI) 42.4 +/- 3.7 kg/m2) and ten normal-weight healthy controls (HC, BMI 23.9 +/- 2.5 kg/m2) with (S,S)-[11C]-O-methylreboxetine ([11C]MRB) positron emission tomography (PET). All participants completed the TFEQ, which measures cognitive restraint, disinhibition and hunger. Image analysis required magnetic resonance imaging data sets onto which volumes-of-interests were drawn. Tissue time activity curves (TACs) were obtained from the dynamic PET data followed by kinetic modeling of these regional brain TACs applying the multilinear reference tissue model (2 parameters) with the occipital cortex as reference region. Obese individuals scored significantly higher on the hunger subscale of the TFEQ. Correlative data analysis showed that a higher degree of hunger correlated negatively with the NET availability of the insular cortex in both obese individuals and HC; however, this finding was more pronounced in obesity. Further, for obese individuals, a negative correlation between disinhibition and NET BPND of the locus coeruleus was detected. In conclusion, these initial data provide in vivo imaging support for the involvement of the central NE system in maladaptive eating behaviors such as susceptibility to hunger. PMID- 28647387 TI - Practical Considerations for the Use of Breast MRI for Breast Cancer Evaluation in the Preoperative Setting. AB - Preoperative contrast-enhanced (CE) breast magnetic resonance imaging (MRI) remains controversial in the newly diagnosed breast cancer patient. Additional lesions are frequently discovered in these patients with CE breast MRI. As staging and treatment planning evolve to include more information on tumor biology and aggression, so should our consideration of extent of disease. Directing CE breast MRI to those patients most likely to have additional disease may be beneficial. We sought to develop practical guidance for the use of preoperative CE breast MRI in the newly diagnosed breast cancer patient based on recent scientific data. Our review suggests several populations for whom preoperative breast MRI is most likely to find additional disease beyond that seen on conventional imaging. These can be viewed in three categories: (1) tumor biology-patients with invasive lobular carcinoma or aggressive tumors such as triple negative breast cancer (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative) and HER2 positive tumors; (2) patient characteristics-dense breast tissue or younger age, especially those age <60; and (3) clinical scenarios-patients with more sonographic disease than expected or those who are node positive at initial diagnosis. Focusing breast MRI on patients with any of the aforementioned characteristics may help utilize preoperative breast MRI where it is likely to have the most impact. PMID- 28647389 TI - Improving Abnormality Detection on Chest Radiography Using Game-Like Reinforcement Mechanics. AB - RATIONALE AND OBJECTIVES: Despite their increasing prevalence, online textbooks, question banks, and digital references focus primarily on explicit knowledge. Implicit skills such as abnormality detection require repeated practice on clinical service and have few digital substitutes. Using mechanics traditionally deployed in video games such as clearly defined goals, rapid-fire levels, and narrow time constraints may be an effective way to teach implicit skills. MATERIALS AND METHODS: We created a freely available, online module to evaluate the ability of individuals to differentiate between normal and abnormal chest radiographs by implementing mechanics, including instantaneous feedback, rapid fire cases, and 15-second timers. Volunteer subjects completed the modules and were separated based on formal experience with chest radiography. Performance between training and testing sets were measured for each group, and a survey was administered after each session. RESULTS: The module contained 74 cases and took approximately 20 minutes to complete. Thirty-two cases were normal radiographs and 56 cases were abnormal. Of the 60 volunteers recruited, 25 were "never trained" and 35 were "previously trained." "Never trained" users scored 21.9 out of 37 during training and 24.0 out of 37 during testing (59.1% vs 64.9%, P value <.001). "Previously trained" users scored 28.0 out of 37 during training and 28.3 out of 37 during testing phases (75.6% vs 76.4%, P value = .56). Survey results showed that 87% of all subjects agreed the module is an efficient way of learning, and 83% agreed the rapid-fire module is valuable for medical students. CONCLUSIONS: A gamified online module may improve the abnormality detection rates of novice interpreters of chest radiography, although experienced interpreters are less likely to derive similar benefits. Users reviewed the educational module favorably. PMID- 28647388 TI - Characterization of Breast Masses in Digital Breast Tomosynthesis and Digital Mammograms: An Observer Performance Study. AB - RATIONALE AND OBJECTIVES: This study aimed to compare Breast Imaging Reporting and Data System (BI-RADS) assessment of lesions in two-view digital mammogram (DM) to two-view wide-angle digital breast tomosynthesis (DBT) without DM. MATERIALS AND METHODS: With Institutional Review Board approval and written informed consent, two-view DBTs were acquired from 134 subjects and the corresponding DMs were collected retrospectively. The study included 125 subjects with 61 malignant (size: 3.9-36.9 mm, median: 13.4 mm) and 81 benign lesions (size: 4.8-43.8 mm, median: 12.0 mm), and 9 normal subjects. The cases in the two modalities were read independently by six experienced Mammography Quality Standards Act radiologists in a fully crossed counterbalanced manner. The readers were blinded to the prevalence of malignant, benign, or normal cases and were asked to assess the lesions based on the BI-RADS lexicon. The ratings were analyzed by the receiver operating characteristic methodology. RESULTS: Lesion conspicuity was significantly higher (P << .0001) and fewer lesion margins were considered obscured in DBT. The mean area under the receiver operating characteristic curve for the six readers increased significantly (P = .0001) from 0.783 (range: 0.723-0.886) for DM to 0.911 (range: 0.884-0.936) for DBT. Of the 366 ratings for malignant lesions, 343 on DBT and 278 on DM were rated as BI-RADS 4a and above. Of the 486 ratings for benign lesions, 220 on DBT and 206 on DM were rated as BI-RADS 4a and above. On average, 17.8% (65 of 366) more malignant lesions and 2.9% (14 of 486) more benign lesions would be recommended for biopsy using DBT. The inter-radiologist variability was reduced significantly. CONCLUSION: With DBT alone, the BI-RADS assessment of breast lesions and inter radiologist reliability were significantly improved compared to DM. PMID- 28647390 TI - Neural synergies for controlling reach and grasp movement in macaques. AB - It has been suggested that the brain adopts a simplified strategy to coordinate a large number of degrees of freedom in motor control. Synergies have been proposed as a strategy to produce movements by recruitment of a small number of fixed modular patterns. However, there is no direct support for a synergistic organization of the brain itself. In this study, we recorded neural activities from the dorsal premotor cortex (PMd) of monkeys trained to reach and grasp differently shaped objects (grasping task) or the same object in different positions (reaching task). Non-negative matrix factorization (NNMF) was applied to the neural data to extract neural synergies, whose functional roles were verified in several ways. We found that motor cortex used similar neural synergies for grasping different objects; combining only a few of the synergies accounted for most of the variance in the original data. When used for single trial task decoding, the synergy coefficients performed as well and robustly as the original data in both tasks. The synergy amplitudes for each unit were significantly correlated with the corresponding neuron's firing rate. In addition, we also observed synergies shared between tasks and task-specific synergies, as shown before for muscle synergies. Altogether, we demonstrated that neural synergies are effective in describing neural population activity during reach to grasp movements and provide a new tool for interpreting neural data for movement control. PMID- 28647391 TI - Addressing low participant in colorectal cancer screening: Respect for individual freedom versus the community good. PMID- 28647392 TI - A novel dual inhibitor of microtubule and Bruton's tyrosine kinase inhibits survival of multiple myeloma and osteoclastogenesis. AB - Bruton's tyrosine kinase (BTK) regulates many vital signaling pathways and plays a critical role in cell proliferation, survival, migration, and resistance. Previously, we reported that a small molecule, KS99, is an inhibitor of tubulin polymerization. In the present study, we explored whether KS99 is a dual inhibitor of BTK and tubulin polymerization. Although it is known that BTK is required for clonogenic growth and resistance, and microtubules are essential for cancer cell growth, dual targeting of these two components has not been explored previously. Through docking studies, we predicted that KS99 interacts directly with the catalytic domain of BTK and inhibits phosphorylation at the Y223 residue and kinase activities. Treatment of KS99 reduces the cell viability of multiple myeloma (MM) and CD138+ cells, with an IC50 of between 0.5 and 1.0 MUmol/L. We found that KS99 is able to induce apoptosis in MM cells in a caspase-dependent manner. KS99 suppressed the receptor activator of NF-kappaB ligand (RANKL) induced differentiation of macrophages to osteoclasts in a dose-dependent manner and, importantly, inhibited the expression of cytokines associated with bone loss. Finally, we found that KS99 inhibits the in vivo tumor growth of MM cells through the inhibition of BTK and tubulin. Overall, our results show that dual inhibition of BTK and tubulin polymerization by KS99 is a viable option in MM treatment, particularly in the inhibition of refraction and relapse. PMID- 28647393 TI - The Effect and Use of Milestones in the Assessment of Neurological Surgery Residents and Residency Programs. AB - OBJECTIVES: The purpose of this study was to determine the effect of the Accreditation Council for Graduate Medical Education Milestones on the assessment of neurological surgery residents. The authors sought to determine the feasibility, acceptability, and utility of this new framework in making judgments of progressive competence, its implementation within programs, and the influence on curricula. Residents were also surveyed to elicit the effect of Milestones on their educational experience and professional development. DESIGN, SETTING, AND PARTICIPANTS: In 2015, program leadership and residents from 21 neurological surgery residency programs participated in an online survey and telephone interview in which they reflected on their experiences with the Milestones. Survey data were analyzed using descriptive statistics. Interview transcripts were analyzed using grounded theory. RESULTS: Response themes were categorized into 2 groups: outcomes of the Milestones implementation process, and facilitators and barriers. Because of Milestones implementation, participants reported changes to the quality of the assessment process, including the ability to identify struggling residents earlier and design individualized improvement plans. Some programs revised their curricula based on training gaps identified using the Milestones. Barriers to implementation included limitations to the adoption of a developmental progression model in the context of rotation block schedules and misalignment between progression targets and clinical experience. The shift from time-based to competency-based evaluation presented an ongoing adjustment for many programs. Organized preparation before clinical competency committee meetings and diverse clinical competency committee composition led to more productive meetings and perceived improvement in promotion decisions. CONCLUSIONS: The results of this study can be used by program leadership to help guide further implementation of the Milestones and program improvement. These results also help to guide the evolution of Milestones language and their implementation across specialties. PMID- 28647394 TI - Whole-genome gene expression analysis in urine samples of patients with prostate cancer and benign prostate hyperplasia. AB - OBJECTIVE: There is an urgent need to find new biomarkers with higher specificity and sensitivity for using early detection of prostate cancer (PrCa) and reducing recurrent unnecessary biopsy rates, psychological and physical stress on the patient, and costs. Being noninvasive, urine-based tests might be suitable in routine practice. The aim of this study was to report the first whole-genome gene expression analysis in urine samples, as noninvasive method, that were obtained from PrCa, benign prostate hyperplasia (BPH), and control groups by using the microarray system from Turkey, to our knowledge. METHODS: Whole-genome gene expression profiling was conducted in urine samples of 25 patients with PrCa, 24 patients with BPH, and 11 healthy males by using the Illumina Hi Scan microarray system. RESULTS: The number of probes showing a significant change at the level of expression were 101 and 75 in PrCa-control and BPH-control comparison groups, respectively. Further, 51 of them were the same in both comparison groups. There was no significant change at the level of expression in PrCa-BPH comparison group. CONCLUSION: This study revealed several candidate biomarkers for early diagnosis of PrCa and contributed to the literature by detecting the differences of gene expression profiles in urine samples of PrCa-control and BPH-control comparison groups using the microarray. However, further studies are needed in larger groups. PMID- 28647395 TI - Survival differences among patients with bladder cancer according to sex: Critical evaluation of radical cystectomy use and delay to treatment. AB - OBJECTIVE: Sex differences in bladder cancer survival are well known. However, the effect of type of treatment, timing to surgery when rendered, and survival outcomes according to sex have not been extensively examined. Given the relatively low incidence of bladder cancer in females, large multicenter and population-based studies are required to elucidate sex differences in survival. In this study, we sought to characterize the effect of use and timing of radical cystectomy (RC) according to sex and survival outcomes. METHODS: A total of 9,907 patients aged 66 years or older diagnosed with clinical stage II to IV N0M0 bladder cancer from January 1, 2001 to December 31, 2011 from Surveillance, Epidemiology, and End Results-Medicare data were analyzed. We used multivariable regression analyses to identify factors predicting the use and delay of RC. Cox proportional hazards models were used to analyze survival outcomes. RESULTS: Of the 9,907 patients diagnosed with bladder cancer, 3,256 (32.9%) were females. Women were significantly more likely to undergo RC across all stages compared to their male counterparts (stage II: relative risk [RR] = 1.48, 95% CI: 1.33-1.65, P<0.001; stage III: RR = 1.24, 95% CI: 1.13-1.37, P<0.001; and stage IV: RR = 1.33, 95% CI: 1.19-1.49, P<0.001). Moreover, there was no significant difference in delay to RC according to sex across all clinical stages. Using propensity score matching, women had worse overall (hazard ratio = 1.07; CI: 1.01-1.14; P = 0.024), and worse cancer-specific survival (hazard ratio = 1.26; CI: 1.17-1.36, P<0.001) than men. CONCLUSION: Sex differences persist with women who are significantly more likely to undergo RC independent of clinical stage. However, women have significantly worse survival than men. Delay from diagnosis to surgery did not account for this decreased survival among women. PMID- 28647396 TI - Testicular cancer: The usage of central review for pathology diagnosis of orchiectomy specimens. AB - BACKGROUND: Radical orchiectomy specimens present a unique set of challenges for pathology assessment owing to their rarity and complexity. This study compares second opinion pathology reports generated at a single, large academic institution to primary reports from outside hospitals. METHODS: A database search was conducted for orchiectomy cases that were sent to our institution for management of testicular cancer from 2014 to 2015. Cases sent for consultation without a finalized diagnosis from the outside hospitals were excluded. A total of 221 consecutive cases were evaluated for comparison of final diagnoses between the outside institution and central pathology review. RESULTS: This study revealed significant discrepancy involving multiple parameters between original and second opinion pathology reports. Of 221 cases of germ cell tumors assessed, 31% showed some discrepancy of histologic subtype. Overall, reporting of lymphovascular invasion changed in 22% of cases; of those, initially called positive 23% were changed to negative and of those initially called negative 12% were changed to positive. Although the overall discrepancy for spermatic cord invasion was 9%, an initial positive diagnosis was negated 35% of the time. The pathologic stage was altered in 23% of cases, mostly secondary to differences interpreting lymphovascular and spermatic cord invasion. CONCLUSION: Pathologists evaluating orchiectomy specimens should be aware of the major pitfalls in classification and staging, many of which may affect patient management. PMID- 28647397 TI - Actinomyces radicidentis and Actinomyces haliotis, coccoid Actinomyces species isolated from the human oral cavity. AB - There are few reports on the bacterial species Actinomyces radicidentis in the literature. In this study, putative A. radicidentis isolates were collected from 16 root canal samples from 601 examined patients. The isolates were examined by biochemical tests, 16S rRNA gene sequencing, Arbitrarily-primed (AP-) PCR, antibiotic susceptibility testing, and MALDI-TOF analyses. In parallel, two A. radicidentis reference strains and two putative A. radicidentis isolates from United Kingdom were tested. Sixteen of the 18 isolates were confirmed as A. radicidentis. The remaining two isolates, both of which were isolated from root canals (one from Sweden and the other from the UK), but were identified as Actinomyces haliotis by sequencing ~ 1300 base pairs of the 16S rRNA-gene. This isolates had a divergent, but between them similar, AP-PCR pattern, and a common distribution of sequence signatures in the 16S rRNA gene, but were not identified by MALDI-TOF. A. haliotis is a close relative to A. radicidentis, hitherto only been described from a sea-snail. The identity of A. haliotis was confirmed by a phylogenetic tree based on 16S rRNA gene sequences with species specific sequences included, and by additional biochemical tests. The examined bacteria exhibited similar antibiotic susceptibility patterns when tested for 10 separate antibiotic classes with E-tests (bioMerieux). The MIC90 for beta-lactams (benzylpenicillin and cefuroxime) and vancomycin was 0.5 mg/L, for colistin and ciprofloxacin 8 mg/mL and for the other antibiotic classes <= 25 mg/mL The isolation of A. haliotis from infected dental root canals cast doubt on the accepted opinion that all Actinomyces infections have an endogenous source. PMID- 28647398 TI - Immune-modulatory effects of syncytiotrophoblast extracellular vesicles in pregnancy and preeclampsia. AB - Unique immunologic adaptations exist to successfully establish and maintain pregnancy and to avoid an immune attack against the semi allogenic fetus. These adaptations occur both locally at the maternofetal interface and in the peripheral circulation and affect the innate as well as the adaptive immune system. Pregnancy is characterized by a general inflammatory state with activation of monocytes and granulocytes, but also with suppressive lymphocytes (regulatory T cells), and skewing towards T helper 2 immunity. The pregnancy complication preeclampsia is associated with an exaggerated inflammatory state and predominance of T helper 1 and 17 immunity. The syncytiotrophoblast has been found to secrete extracellular vesicles as communication factors into the maternal circulation. Syncytiotrophoblast extracellular vesicles from normal pregnancy have been shown to interact with monocytes, granulocytes, T cells and natural killer cells and influence the function of these cells. In doing so, they may support the inflammatory state of normal pregnancy as well as the suppressive lymphocyte phenotype. During preeclampsia, syncytiotrophoblast extracellular vesicles are not only increased in numbers but also showed an altered molecular load. Based on data from in vitro studies, it can be suggested that syncytiotrophoblast extracellular vesicles from preeclamptic pregnancies may support the exaggerated inflammatory state during preeclampsia. In this review, we discuss the immunological functions of syncytiotrophoblast extracellular vesicles and their involvement in adapting the maternal peripheral immunological adaptations to pregnancy. PMID- 28647399 TI - Quantitative imaging outperforms molecular markers when predicting response to chemoradiotherapy for rectal cancer. AB - BACKGROUND AND PURPOSE: To explore the integration of imaging and molecular data for response prediction to chemoradiotherapy (CRT) for rectal cancer. MATERIAL AND METHODS: Eighty-five rectal cancer patients underwent preoperative CRT. 18F FDG PET/CT and diffusion-weighted imaging (DWI) were acquired before (TP1) and during CRT (TP2) and prior to surgery (TP3). Inflammatory cytokines and gene expression were analysed. Tumour response was defined as ypT0-1N0. Multivariate models were built combining the obtained parameters. Final models were calculated on the data combination with the highest AUC. RESULTS: Twenty-two patients (26%) achieved ypT0-1N0 response. 18F-FDG PET/CT had worse predictive performance than DWI and T2-volumetry (AUC 0.61+/-0.04, 0.72+/-0.03, and 0.72+/-0.02, respectively). Combining all imaging parameters increased the AUC to 0.81+/-0.03. Adding cytokines or gene expression did not improve the AUC (AUC of 0.72+/-0.06 and 0.79+/-0.04 respectively). Final models combining 18F-FDG PET/CT, DWI, and T2 weighted volumetry at all TPs and using only TP1 and TP3, allowed ypT0-1N0 prediction with a 75% sensitivity, 94% specificity and PPV of 80%. CONCLUSIONS: Combining 18F-FDG PET/CT, DWI, and T2-weighted MRI volumetry obtained before CRT and prior to surgery may help physicians in selecting rectal cancer patients for organ-preservation. PMID- 28647400 TI - Intraoperative Registered Ultrasound and Fluoroscopy (iRUF) for dose calculation during prostate brachytherapy: Improved accuracy compared to standard ultrasound based dosimetry. AB - BACKGROUND AND PURPOSE: Intraoperative transrectal ultrasound dosimetry during low-dose-rate prostate brachytherapy is imprecise due to sonographic distortion caused by seed echoes and needle tracks that obscure seed positions or create false signals as well as traumatic edema. Here we report the results of a pilot study comparing a combined ultrasound and fluoroscopy-based seed localization method (iRUF) to standard ultrasound-based dosimetry (USD). MATERIAL AND METHODS: Eighty patients undergoing permanent Pd-103 seed implantation for prostate cancer were prospectively enrolled. Seed implantation was performed using standard USD for intraoperative dose tracking. Upon implant completion, six X-ray images were intraoperatively acquired using a mobile C-arm and transverse ultrasound images of the implanted prostate were also acquired. Three-dimensional seed locations were reconstructed from X-ray images and registered to the ultrasound for iRUF dosimetry. Day 1 CT/MRI scans were performed for post-implant dosimetry. Prostate and urethral dosimetric parameters were separately calculated for analysis on iRUF, USD, and CT/MRI data sets. Differences and similarities between dosimetric values measured by iRUF, USD, and CT/MRI were assessed based on root mean squared differences, intraclass correlation coefficients (ICC), and Wilcoxon signed rank test. RESULTS: Data from 66 eligible patients were analyzed. Compared to CT/MRI, iRUF dosimetry showed higher correlation with overall ICC of 0.42 (0.01 for USD) and significantly smaller root mean squared differences (overall 16.5 vs 21.5 for iRUF and USD) than USD for all prostate and urethral dosimetric parameters examined. USD demonstrated a tendency to overestimate dose to the prostate when compared to iRUF. CONCLUSIONS: iRUF approximated post-implant CT/MRI prostate and urethral dosimetry to a greater degree than USD. A phase II trial utilizing iRUF for intraoperative dynamic plan modification is underway, with the goal to confirm capability to minimize and correct for prostate underdosage not otherwise detected. PMID- 28647401 TI - Human papillomavirus infection increases the chemoradiation response of esophageal squamous cell carcinoma based on P53 mutation. AB - BACKGROUND AND PURPOSE: A retrospective study was carried out to analyze multiple prognostic predictors, including human papillomavirus (HPV) infection for chemoradiation treatment of esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: DNA extracted from a total of 192 patients treated with chemoradiation for locally advanced ESCC was examined to determine HPV status by polymerase chain reaction (PCR) and P53 gene mutation by genetic sequencing. The relationships between the chemoradiation response (CRR) and overall survival (OS) rate with HPV status and P53 gene mutation were analyzed. RESULTS: Thirty-two of the 108 patients with P53 mutated tumors were stained positive for HPV, while thirty-five of the 84 P53 wild-type tumors were HPV positive. P53 mutation and HPV infection were two independent events (p=0.083, Kappa=0.083). HPV infection increased the CRR (p=0.017) and 3-year OS (p=0.047) compared with the HPV negative group. This difference was more significant in the P53 mutation subgroup (CRR p=0.019; OS p=0.025). However, HPV infection led to no difference in the P53 wild-type subgroup (CRR p=0.802; OS p=0.468). The P53 mutation status was an independent prognostic factor (CRR p=0.034; OS p<0.001). Age was another significant prognostic factor for OS (p=0.001). CONCLUSIONS: Depending on P53 mutation status, HPV infection can contribute to a higher tumor response and better prognosis of ESCC treated with chemoradiation therapy. PMID- 28647402 TI - Autologous Stem Cell Transplantation in Patients With Multiple Myeloma: An Activity-based Costing Analysis, Comparing a Total Inpatient Model Versus an Early Discharge Model. AB - BACKGROUND: Activity-based costing (ABC) was developed and advocated as a means of overcoming the systematic distortions of traditional cost accounting. MATERIALS AND METHODS: We calculated the cost of high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients with multiple myeloma using the ABC method, through 2 different care models: the total inpatient model (TIM) and the early-discharge outpatient model (EDOM) and compared this with the approved diagnosis related-groups (DRG) Italian tariffs. RESULTS: The TIM and EDOM models involved a total cost of ?28,615.15 and ?16,499.43, respectively. In the TIM model, the phase with the greatest economic impact was the posttransplant (recovery and hematologic engraftment) with 36.4% of the total cost, whereas in the EDOM model, the phase with the greatest economic impact was the pretransplant (chemo-mobilization, apheresis procedure, cryopreservation, and storage) phase, with 60.4% of total expenses. In an analysis of each episode, the TIM model comprised a higher absorption than the EDOM. In particular, the posttransplant represented 36.4% of the total costs in the TIM and 17.7% in EDOM model, respectively. The estimated reduction in cost per patient using an EDOM model was over ?12,115.72. The repayment of the DRG in Calabrian Region for the ASCT procedure is ?59,806. Given the real cost of the transplant, the estimated cost saving per patient is ?31,190.85 in the TIM model and ?43,306.57 in the EDOM model. CONCLUSION: In conclusion, the actual repayment of the DRG does not correspond to the real cost of the ASCT procedure in Italy. Moreover, using the EDOM, the cost of ASCT is approximately the half of the TIM model. PMID- 28647403 TI - Prognostic Factors and Outcomes of Adult Lymphoblastic Lymphoma in the United States. AB - BACKGROUND: T-lymphoblastic lymphoma (T-LL) and B-lymphoblastic lymphoma (B-LL) are aggressive lymphoid neoplasms accounting for 2% to 4% of adult non-Hodgkin lymphoma. The aim of the present analysis was to characterize the clinical features and histologic subtypes and to assess the clinical prognostic factors for 696 adult patients with LL, the largest epidemiologic sample to date. PATIENTS AND METHODS: The present retrospective cohort study used the Surveillance, Epidemiology, and End Results database to identify adult patients (age, > 18 years) with LL with data recorded from 2001 to 2012. We used multivariate Cox regression models to test the clinical prognostic factors, stratified by the histologic subtype. RESULTS: Of 696 patients with LL (median age, 39 years), 367 (53%) had T-LL and 131 (19%) had B-LL. Patients with T-LL tended to be younger (33 years vs. 48 years), male (66% vs. 50.4%), and less likely to have extranodal involvement (6% vs. 32%) compared with those with B-LL. The 5-year survival rate for those with B-LL versus those with T-LL was not significantly different (45% vs. 48%; P = .58), even in a model adjusted for clinical features, disease stage, primary site, radiotherapy, and year of diagnosis (adjusted hazard ratio, 0.93; 95% confidence interval, 0.69-1.25; P = .63). Multivariate analysis identified age, race, and radiotherapy as independent prognostic factors for outcome in T-LL. Limited tumor stage and the most recent year of diagnosis were favorable prognostic factors for B-LL. CONCLUSION: Adult patients with LL have poor long-term outcomes and novel therapies are needed. Radiotherapy had a positive effect on T-LL outcomes. PMID- 28647404 TI - Patient-Centered Outcomes and Treatment Preferences Regarding Sexual Problems: A Qualitative Study Among Midlife Women. AB - BACKGROUND: Sexual dysfunction is common in midlife women and can have a significant negative impact on quality of life. Although treatments exist, there is little research on which sexual function outcomes and treatments midlife women prefer. AIM: To better understand the sexual function outcomes that were most important to sexually active women 45 to 60 years old and the types of treatments they would prefer from individual interviews and focus groups. METHODS: Twenty individual interviews and three focus groups (N = 39) were led by a trained facilitator, audio recorded, and transcribed. Two investigators developed a codebook, and the primary investigator coded all data. A second investigator coded five randomly selected interviews to ensure intercoder reliability. Codes relating to outcomes and treatment preferences were examined to identify central themes. RESULTS: The mean age was 52.8 years (range = 45-59). When asked what they would want a sexual dysfunction treatment to do, women sought solutions to specific sexual problems: low desire, vaginal pain and dryness, and decreased arousal or ability to achieve orgasm. However, when asked about the most important aspect of their sex life, most women indicated emotional outcomes, such as enhanced intimacy with their partner, were most important to them. Most women preferred behavioral over pharmaceutical treatments, citing concerns about side effects. These women felt that behavioral treatments might be better equipped to address physical and psychological aspects of sexual problems. CLINICAL IMPLICATIONS: This study highlights the importance of considering not only physical but also emotional outcomes when evaluating and treating sexual dysfunction in midlife women. It also emphasizes the importance of developing behavioral treatments in addition to pharmaceutical treatments. STRENGTHS AND LIMITATIONS: By using a qualitative approach, this study allowed women the time and space to speak their own words about their experiences with sexuality at midlife. In addition, different racial and ethnic groups and menopausal statuses were represented. Limitations include limited generalizability, as is true for most qualitative research. In addition, although most women did endorse sexual problems, we did not exclude women with no sexual complaints. CONCLUSIONS: Midlife women value physical and emotional outcomes with regard to sexual function. Many midlife women in this sample expressed a preference for behavioral approaches over pharmaceutical approaches for the treatment of sexual dysfunction. Thomas HN, Hamm M, Hess R, et al. Patient-Centered Outcomes and Treatment Preferences Regarding Sexual Problems: A Qualitative Study Among Midlife Women. J Sex Med 2017;14:1011-1017. PMID- 28647405 TI - Docosahexaenoic acid promotes oligodendrocyte differentiation via PPAR-gamma signalling and prevents tumor necrosis factor-alpha-dependent maturational arrest. AB - Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid known to be neuroprotective in several models of human diseases, including multiple sclerosis. The protective effects of DHA are largely attributed to its ability to interfere with the activity of transcription factors controlling immune and inflammatory responses, including the agonist-dependent transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). In this study, we used primary oligodendrocyte progenitor (OP) cultures from neonatal rat brain to investigate whether DHA could influence OP maturation and directly promote myelination, as previously reported for selective PPAR-gamma agonists. We show that, similarly to the selective PPAR-gamma agonist pioglitazone (PGZ), DHA promotes OP maturation and counteracts the maturational arrest induced by TNF alpha, used to mimic inflammatory conditions. The PPAR-gamma antagonist GW9662 prevented both DHA-induced OP maturation and PPAR-gamma nuclear translocation, supporting the hypothesis that DHA acts through the activation of PPAR-gamma. In addition, both PGZ and DHA induced the phosphorylation of extracellular signal regulated-kinase 1-2 (ERK1/2), in a PPAR-gamma-dependent manner. ERK1/2 activity is known to regulate the transition from OPs to immature oligodendrocytes and the presence of specific inhibitors of ERK1/2 phosphorylation (U0126 or PD98059) prevented the differentiating effects of both DHA and PGZ. These results indicate that DHA might influence the process of OP maturation through its PPAR-gamma agonistic activity and provide novel molecular mechanisms for the action of this dietary fatty acid, further supporting the nutritional intervention in demyelinating diseases such as multiple sclerosis. PMID- 28647406 TI - Unstable Angina in the Era of Cardiac Troponin Assays with Improved Sensitivity-A Clinical Dilemma. AB - BACKGROUND: There is an expectation that with the adoption of more sensitive cardiac troponin (cTn) assays, unstable angina would become a rarity. However, recent data from the SWEDEHEART registry demonstrated that 15% of patients admitted with non-ST-elevation acute coronary syndrome still were regarded as having unstable angina. We aimed to further investigate the clinical characteristics and outcome of these patients. METHODS: This was a retrospective, registry-based analysis (SWEDEHEART) including 3204 unstable patients, 18,194 non ST-elevation myocardial infarction (NSTEMI) patients, and 977 controls without acute cardiovascular disease. All patients had available data on peak cTnT levels (more sensitive assay) and 1-year outcome. RESULTS: The annual proportions of patients with unstable angina (2009-2013) among those with non-ST-elevation acute coronary syndrome ranged from 9.4% to 15.3%. Only 1239 unstable angina patients (39.7%) had a peak cTnT level <=14 ng/L. Patients with unstable angina tended to be younger than those with NSTEMI but had higher prevalence of most cardiovascular risk factors and more advanced coronary artery disease. Compared with controls, the adjusted hazard ratios (95% confidence interval) regarding major cardiovascular events were 2.97 (1.30-6.78) and 5.44 (2.54-11.65) in unstable angina patients with peak cTnT <=14 ng/L and >14 ng/L, respectively. CONCLUSION: The diagnosis of unstable angina is still commonly used, even in the era of more sensitive cTn assays. Minor cTnT elevation is common, which makes unstable angina difficult to distinguish from NSTEMI. Patients with unstable angina have a nonneglectable cardiovascular risk. We suggest that the clinical management of patients presenting with unstable symptoms should depend on their estimated cardiovascular risk rather than on strictly applied diagnostic criteria. PMID- 28647407 TI - External Validation of the Simple NULL-PLEASE Clinical Score in Predicting Outcome of Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Rapid clinical decision-making on further management of patients with out-of-hospital cardiac arrest may be challenging. Recently, a "futility" score (NULL-PLEASE) incorporating multiple adverse resuscitation features (Nonshockable rhythm, Unwitnessed arrest, Long no-flow or Long low-flow period, blood PH <7.2, Lactate >7.0 mmol/L, End-stage chronic kidney disease on dialysis, Age >=85 years, Still resuscitation, and Extracardiac cause) has been proposed to help identify patients with out-of-hospital cardiac arrest unlikely to survive; however, external independent score validation is lacking. METHODS: We retrospectively validated the NULL-PLEASE predictive ability for early in hospital outcome of out-of-hospital cardiac arrest in a single-center cohort of 547 consecutive patients with out-of-hospital cardiac arrest who were admitted from April 2013 to October 2016 (mean age, 66.3 +/- 13.2 years); 227 patients (41.5%) died. Because pH and lactate were inconsistently measured, a modified NULL-PLEASE score excluding both variables was calculated as the principal analysis. A sensitivity analysis included the subgroup with pH data available (n = 177). RESULTS: Long low-flow period and age >=85 years were independently associated with fatal outcome (both P < .001). Patients with a modified NULL PLEASE score of >=5 had a 3.3-fold greater risk of fatal outcome compared with a score of 0 to 4 (odds ratio, 3.34; 95% confidence interval [CI], 2.29-4.89; P < .001); 77% of nonsurvivors had a score >=5; NULL-PLEASE showed a modest predictive ability for fatal outcome (c-statistic 0.658; 95% CI, 0.613-0.704; P < .001). Sensitivity analysis yielded similar results, with 88% of nonsurvivors having a score >=5. CONCLUSIONS: The NULL-PLEASE score was predictive for early in-hospital outcome of out-of-hospital cardiac arrest, with a 3.3-fold greater odds for fatal outcome at the score values of >=5. PMID- 28647408 TI - Identification and expression characterization of WntA during intestinal regeneration in the sea cucumber Apostichopus japonicus. AB - Wnt genes encode secreted glycoproteins that act as signaling molecules; these molecules direct cell proliferation, migration, differentiation and survival during animal development, maintenance of homeostasis and regeneration. At present, although the regeneration mechanism in Apostichopus japonicus has been studied, there is a little research on the Wnt signaling pathway in A. japonicus. To understand the potential role of the Wnt signaling pathway in A. japonicus, we cloned and sequenced the WntA gene in A. japonicus. Protein localization analysis showed that WntA protein was ubiquitously expressed in epidermal cells, the muscle and submucosa of the intestinal tissue. After stimulation and evisceration, the dynamic changes in expression of the WntA gene and protein showed that WntA was constitutively expressed during different stages of intestine regeneration in A. japonicus, with higher levels during the early wound healing stage and late lumen formation in the residual and nascent intestinal tissues, indicating its response to intestinal regeneration. Simultaneously, cell proliferation and apoptosis analysis showed that the patterns of cell proliferation were similar to the patterns of WntA protein expression during different intestinal regeneration stages in this organism. Taken together, these results suggested that WntA might participate in intestinal regeneration and may be connected with cell proliferation, apoptosis in different intestinal layers. This research could establish a basis for further examination of WntA functions in A. japonicus and Wnt genes in other echinoderms. PMID- 28647409 TI - A Residue Specific Insight into the Arkadia E3 Ubiquitin Ligase Activity and Conformational Plasticity. AB - Arkadia (Rnf111) is an E3 ubiquitin ligase that plays a central role in the amplification of transforming growth factor beta (TGF-beta) signaling responses by targeting for degradation the negative regulators of the pathway, Smad6 and Smad7, and the nuclear co-repressors Ski and Skil (SnoN). Arkadia's function in vivo depends on the really interesting new gene (RING)-H2 interaction with the E2 enzyme UbcH5b in order to ligate ubiquitin chains on its substrates. A conserved tryptophan (W972) in the C-terminal alpha-helix is widely accepted as essential for E2 recruitment and interaction and thus also for E3 enzymatic activity. The present NMR-driven study provides an atomic-level investigation of the structural and dynamical properties of two W972 Arkadia RING mutants, attempting to illuminate for the first time the differences between a functional and a nonfunctional mutant W972A and W972R, respectively. A TGF-beta-responsive promoter driving luciferase was used to assay for Arkadia function in vivo. These experiments showed that the Arkadia W972A mutant has the same activity as wild type (WT) Arkadia in enhancing TGF-beta signaling responses, while W972R does not. Only minor structural differences exist between the W972A RING domain and WT RING. In contrast, the W972R mutant hardly interacts with E2. The loss of function correlates with structural changes in the C-terminal alpha-helix and an increase in the distance between the Zn(II) ions. Our data show that the position occupied by W972 within WT Arkadia is critical for the function of RING and that it depends on the nature of the residue at this position. PMID- 28647410 TI - Reoperative bariatric surgery for treatment of type 2 diabetes mellitus. AB - Primary bariatric surgery has been proven to be effective in weight loss and improvement of weight-related metabolic co-morbidities. However, a small proportion of patients after bariatric surgery either have persistent hyperglycemia or relapse after initial remission of their metabolic disease. Revisional bariatric surgery has been evaluated extensively for weight recidivism and postoperative complications. However, there has not been any high-level evidence validating the utility of revisional bariatric surgery on recurrent metabolic diseases, especially diabetes. In this review of 30 studies, we aimed to summarize the evidence and determine whether revisional surgery can have a positive impact on metabolic diseases that were not reversed by initial bariatric intervention. Overall, 14-38% of patients had residual diabetes at the time of revisional surgery. Depending on the index surgery and subsequent reconstruction, revisions induced 20-80% additional excess weight loss, or further decrease of body mass index by 10-30%. Improvement of diabetes was seen in 65-100% of patients. Specifically, conversion to Roux-en-Y gastric bypass (RYGB) yielded improvement of diabetes in 79%, 72%, and 62% of patients who previously had vertical banded gastroplasty (VBG), adjustable gastric banding (AGB), or sleeve gastrectomy (SG), respectively. Converting AGB to SG improved diabetes in 65% of patients, and SG to duodenal switch improved diabetes in 79% of patients. Revision of the gastric pouch or stoma in RYGB yielded improvement of diabetes in 79% of patients. Further clinical and mechanistic research is needed to better delineate the role of revisional bariatric surgery in patients with residual metabolic disease. PMID- 28647411 TI - Hippocampal 5-HT1A receptor expression changes in prodromal stages of Alzheimer's disease: Beneficial or deleterious? AB - There is increasing evidence that the serotonergic system is highly dysfunctional in Alzheimer's disease (AD), and this could be related to cognitive impairments associated with dementia. Of the various serotonin receptors, 5-HT1A receptors are relevant to AD as they are highly expressed in the human hippocampus and are known to be involved in the regulation of memory processes. This review will discuss the involvement of 5-HT1A receptors in AD at several levels (post-mortem, in-vivo imaging, animal models). The involvement of this receptor subtype in AD pathophysiology will be reviewed particularly in terms of the modulation of its expression in the hippocampal region. Hypotheses involving 5-HT1A receptors will be developed, from two points of view: 5-HT1A receptors expression regulation as being beneficial and needing to be pharmacologically stimulated; and 5-HT1A receptors expression modulation as deleterious and needing to be limited. Finally, we will propose perspectives for future experiments that should weigh in favor of one or the other of the two hypotheses. PMID- 28647412 TI - Real-world data to assess changes in low-density lipoprotein cholesterol and predicted cardiovascular risk after ezetimibe discontinuation post reporting of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial. AB - BACKGROUND: The 2008 Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study demonstrated ezetimibe + simvastatin vs simvastatin alone had a neutral effect on the surrogate endpoint of carotid intima-media thickness. Subsequent media portrayal of the study prompted ezetimibe discontinuation in many patients. OBJECTIVE: The objective of the study was to assess the impact of ENHANCE reporting on ezetimibe discontinuation, low density lipoprotein cholesterol (LDL-C) changes, and potential cardiovascular disease (CVD) risk. METHODS: This analysis used claims data in a retrospective, observational study of patients receiving ezetimibe + statin and compared LDL-C for patients who discontinued ezetimibe (n = 970) vs those who continued ezetimibe + statins (n = 3706) after ENHANCE results disclosure. Change in relative CVD risk was estimated from the absolute LDL-C difference between groups per the Cholesterol Treatment Trialists' meta-analysis of statin trials. RESULTS: The rate of ezetimibe discontinuation was 2% in the 6 months before and 21% in the 6 months after reporting of ENHANCE results. Among patients who ultimately discontinued vs continued ezetimibe, respective mean LDL-C levels were 79.8 and 78.3 mg/dL 6 months before reporting of the ENHANCE results and 93.5 and 78.1 mg/dL 6 months after reporting of ENHANCE. Predictive application of the Cholesterol Treatment Trialists' meta-analysis suggested the 13.9 mg/dL increase in mean LDL-C translated to a 9.4% increase in relative CVD risk for those who discontinued ezetimibe. CONCLUSION: After reporting of the neutral ENHANCE results, ezetimibe discontinuation rate increased, LDL-C levels increased, and predicted CVD risk increased among those who discontinued ezetimibe. Characterization of clinical outcomes regarding lipid-altering agents based on surrogate biomarker studies not designed to assess CVD outcomes may be misleading, potentially placing patients at increased CVD risk. PMID- 28647413 TI - Omega-6 fatty acids: Opposing associations with risk-The Ludwigshafen Risk and Cardiovascular Health Study. AB - BACKGROUND: Omega-6 polyunsaturated fatty acids (omega-6 PUFA) are recommended in European cardiovascular prevention guidelines. However, individual fatty acids have distinct biological functions, and there have been conflicting reports about the association of omega-6 PUFA with cardiovascular risk. OBJECTIVE: The aim of our study was to investigate the association of individual omega-6 fatty acids with mortality in a cohort of patients referred for coronary angiography. METHODS: Omega-6 PUFA proportions were measured in erythrocytes at baseline in a total of 3259 patients participating in the Ludwigshafen Risk and Cardiovascular Health Study using the HS-Omega-3 Index method. Associations of omega-6 PUFA with mortality were analyzed by Cox regression with adjustment for conventional risk factors. RESULTS: During a median follow-up of 10.0 years, 975 patients (29.9%) died, 614 patients (18.8%) from cardiovascular causes. gamma-Linolenic acid was inversely associated with all-cause and cardiovascular mortalities in models adjusted for cardiovascular risk factors with hazard ratios of 0.88 (0.82-0.95) and 0.86 (0.79-0.95) per 1-standard deviation increase, respectively. Adrenic acid and docosapentaenoic acid omega-6 were both directly associated with risk with hazard ratio of 1.10 (1.30-1.18) and 1.12 (1.05-1.19) for all-cause mortality, respectively. No association was found for arachidonic acid. CONCLUSIONS: We observed opposing associations of individual omega-6 PUFA with mortality risk. While LA and gamma-linolenic acid were associated with reduced risk, there was a direct association for adrenic acid and docosapentaenoic acid. These differences do not support the use of omega-6 PUFA concentrations as a single combined metric, and the prognostic value of each individual member should be examined separately. PMID- 28647414 TI - Effect of different packaging materials containing poly-[2-(tert-butylamino) methylstyrene] on the growth of spoilage and pathogenic bacteria on fresh meat. AB - The objective of this study was to investigate the effect of novel antimicrobial packaging materials containing poly-[2-(tertbutylamino) methylstyrene] (poly(TBAMS)) on the growth of typical spoilage and pathogenic bacteria present on meat. The antimicrobial activity of materials containing different poly(TBAMS) concentrations was determined by comparing the bacterial counts on reference and sample materials at different temperatures and times and in the presence of meat components. Storage tests with poultry fillets and veal cutlets were conducted with samples vacuum packaged in the reference foil and foil containing 10% poly(TBAMS). After specific time intervals, typical spoilage microorganisms, total viable count (TVC), sensory changes and pH value were analysed. The results of the different poly(TBAMS) containing packaging materials showed an increase of the antimicrobial activity with an increasing amount of poly(TBAMS) in the base polymer. A high antimicrobial activity against inoculum of spoilage and pathogenic organisms typical for meat products was detected of a multilayer foil containing 10% poly(TBAMS) in the inner layer after 24h at 7 degrees C. Gram positive-bacteria were more sensitive to poly(TBAMS) foil than gram-negative bacteria. In storage tests however, over the entire storage, a significant effect of this poly(TBAMS) foil on microbial growth on chicken breast fillets and veal cutlets could not be identified. Poly(TBAMS) packaging materials showed very good antimicrobial properties against a wide range of bacteria. However, for a significant inhibition of microbial growth on fresh meat, a higher amount of poly(TBAMS) was necessary to prolong the shelf life of meat. PMID- 28647415 TI - Restrictive Arteriopathy in Late-Onset Pompe Disease: Case Report and Review of the Literature. AB - Late-onset Pompe disease (LOPD) is an adult type of classical Pompe disease and presents without cardiomyopathy. Neuroimaging in LOPD is typically limited to posterior circulation and involves dilative arteriopathy, especially dolichoectasia and intracranial aneurysms. We report an interesting case of an established diagnosis of asymptomatic LOPD in a young man with a restrictive variant pattern in posterior vasculature. We discuss the clinical presentation, neuroimaging, existing literature, and prognosis in vascular variants of LOPD. PMID- 28647416 TI - Related Factors of Asymmetrical Vein Sign in Acute Middle Cerebral Artery Stroke and Correlation with Clinical Outcome. AB - OBJECTIVE: The aim of our study was to analyze the related factors of asymmetrical cortical vein sign (ACVS) and asymmetrical medullary vein sign (AMVS) on susceptibility-weighted imaging (SWI) in patients with acute middle cerebral artery (MCA) stroke and whether their presence can be used as an independent predictor for clinical outcome. METHODS: According to the presence of ACVS and AMVS on SWI, 124 patients with acute MCA stroke within 3 days were divided into several different groups. In addition, those patients were also divided into good and poor outcome group by using the modified Rankin Scale at 3 months after stroke. We investigated respectively the differences in magnetic resonance imaging findings and the clinical data among those different groups. RESULTS: The ACVS was demonstrated in 90 of 124 patients. Of the 90 patients, 47 were accompanied with the AMVS. The rest of 34 patients showed no ACVS and AMVS. The infarct size and MCA status showed significant differences among the ACVS+, AMVS+ group; ACVS+, AMVS- group; and ACVS-, AMVS- group (all P < .001). Moreover, the ACVS, AMVS, and MCA occlusion were more common in the poor outcome group (all P< .001). In the multivariate logistic regression, AMVS (P = .027; odds ratio, 2.37; 95% confidence interval, 1.23-8.73) was associated with poor outcome. CONCLUSIONS: The ACVS and AMVS were correlated to the status of MCA steno occlusion and infarct size, whereas the AMVS was proved to be independently related to the stroke severity and poor outcome rather than the ACVS. PMID- 28647417 TI - Recurrent Thromboembolic Events after Ischemic Stroke in Patients with Primary Brain Tumors. AB - BACKGROUND: Stroke mechanisms and the risk of recurrent thromboembolism are incompletely understood in patients with primary brain tumors. We sought to better delineate these important clinical features. METHODS: We performed a retrospective cohort study of adults with primary brain tumors diagnosed with magnetic resonance imaging-confirmed acute ischemic stroke at the Memorial Sloan Kettering Cancer Center from 2005 to 2015. Study neurologists collected data on patients' cancer history, stroke risk factors, treatments, and outcomes. Stroke mechanisms were adjudicated by consensus. The primary outcome was recurrent thromboembolism (arterial or venous) and the secondary outcome was recurrent ischemic stroke. Kaplan-Meier statistics were used to calculate cumulative outcome rates, and Cox hazards analysis was used to evaluate the association between potential risk factors and outcomes. RESULTS: We identified 83 patients with primary brain tumors and symptomatic acute ischemic stroke. Median survival after index stroke was 2.2 years (interquartile range, .5-7.0). Tumors were mostly gliomas (72%) and meningiomas (13%). Most strokes were from unconventional mechanisms, particularly radiation vasculopathy (36%) and surgical manipulation (18%). Small- or large-vessel disease or cardioembolism caused 13% of strokes, whereas 29% were cryptogenic. Cumulative recurrent thromboembolism rates were 11% at 30 days, 17% at 180 days, and 27% at 365 days, whereas cumulative recurrent stroke rates were 5% at 30 days, 11% at 180 days, and 13% at 365 days. We found no significant predictors of outcomes. CONCLUSION: Patients with primary brain tumors generally develop strokes from rare mechanisms, and their risk of recurrent thromboembolism, including stroke, is high. PMID- 28647418 TI - Comparison of Stroke Prediction Accuracy of ABCD2 and ABCD3-I in Patients with Transient Ischemic Attack: A Meta-Analysis. AB - BACKGROUND: A direct comparison of the stroke prediction utility of the ABCD2 and ABCD3-I scores has not been performed. Thus, we conducted a diagnostic meta analysis and applied the results to a hypothetical cohort of 1000 patients with transient ischemic attack (TIA) to assess the power of stroke prediction by ABCD2 and ABCD3-I scores. METHODS: Medline, PubMed, Embase, and manuscript references were searched to identify studies that directly compared the stroke predictive powers of ABCD2 and ABCD3-I scores. We conducted a diagnostic meta-analysis using bivariate random effects models, and the predictive powers of ABCD2 and ABCD3-I scores were assessed by their summary sensitivity and specificity. Then, we applied the results to a hypothetical cohort of 1000 patients with TIA to calculate the effect per 1000 patients triaged for stroke prevention in a virtual setting. RESULTS: Of the 35 identified studies on ABCD2 and ABCD3-I, 6 studies (7364 participants) directly compared the diagnostic accuracies of ABCD2 and ABCD3-I scores for occurrence of a future stroke. The pooled sensitivities of ABCD2 versus ABCD3-I were 79.9% (62.2%-90.6%) versus 96.1% (90.2%-98.5%) at 7 days (P = .022), and 76.6% (63.8%-85.8%) versus 94.6% (88.9%-97.5%) at 90 days (P = .001). The pooled specificities of ABCD2 versus ABCD3-I were 29.2% (18.2% 43.3%) versus 17.7% (8.5%-33.3%) at 7 days (P = .214), and 40.3% (25.0%-57.7%) versus 20.2% (12.6%-30.6%) at 90 days (P = .032). CONCLUSIONS: ABCD3-I scores had a better sensitivity but poorer specificity than ABCD2 scores. However, in community-based referring settings, it is more suitable to use ABCD2 at initial triage and deciding on urgency of specialist assessment. The prognostic utility of each of the components of the scores should be carefully considered rather than dichotomized scores during clinical triage. PMID- 28647419 TI - Intracerebral Hemorrhagic Expansion Occurs in Patients Using Non-Vitamin K Antagonist Oral Anticoagulants Comparable with Patients Using Warfarin. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulant (NOAC) use has significantly reduced intracerebral hemorrhagic (ICH) risk compared with standard anticoagulant treatment. Hematoma expansion (HE) is a known predictor of mortality in warfarin-associated ICH. Little is known about HE in patients using NOACs. METHODS: We conducted a retrospective chart review of patients with ICH admitted to Cedars-Sinai Medical Center from October 2010 to June 2016. We identified patients with concomitant administration of an oral anticoagulant and collected data including evidence of HE on imaging and modified Rankin Scale (mRS) at discharge. We defined HE as relative (>=33% increase) or absolute expansion (>=12 mL). We compared outcomes of patients with and without HE. RESULTS: Out of 814 patients with ICH who were admitted, we identified 9 patients with recent NOAC use and 18 intentionally matched controls on warfarin. We found no significant differences in National Institutes of Health Stroke Scale or ICH score on presentation (median [interquartile range] 15 [5,21] versus 7 [1.25,19.5] [P = .41] and 2 [1,4] versus 1 [1,3] [P = .33]) between patients on NOACs and those on warfarin. Four out of the 9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated HE, with no significant difference (P = .42). There were no significant differences in mRS on discharge between groups (P = .52). CONCLUSIONS: In our coagulopathic NOAC patient population, HE occurs within 6 hours in 44% of patients. This case series did not have sufficient statistical power to detect significant differences between the groups. To our knowledge, this is one of the largest case series reporting on HE with concomitant NOAC use. PMID- 28647420 TI - Increased Prevalence of Cerebrovascular Disease in Hospitalized Patients with Ehlers-Danlos Syndrome. AB - BACKGROUND AND PURPOSE: Small studies have suggested that Ehlers-Danlos syndrome (EDS) is associated with a number of cerebrovascular complications. We sought to determine whether a clinical diagnosis of EDS is associated with a higher prevalence of cerebrovascular diseases than the general population by performing a case-control study of hospitalized patients in the Nationwide Inpatient Sample (NIS). METHODS: Using the 2000-2012 NIS, we performed a case-control study matching cases of EDS to controls without such a diagnosis. The prevalence of various cerebrovascular diseases between the 2 groups was compared, and multivariate logistic regression was used to adjust for suspected comorbidities. RESULTS: Between 2000 and 2012, there were a total of 9067 discharges carrying a diagnosis of EDS. On univariate analysis, patients with EDS were more likely to be hospitalized for carotid dissection (.2% versus .01%, odds ratio [OR] = 18.0, confidence interval [CI] = 2.41-135.12, P < .0001), vertebral dissection (.1% versus 0%, P = .008), cervical artery aneurysm (.1% versus .01%, OR = 9.01, CI = 1.14-71.11, P < .0001), cerebral aneurysm (.4% versus .09%, OR = 4.89, CI = 2.28 10.47, P < .0001), and cerebrovascular malformation (.1% versus .02%, OR = 5, CI = 1.10-22.85, P = .021), compared to the controls. On multivariate analysis adjusted for age, race, and comorbidities, EDS patients had significantly higher odds of carotid dissection (OR = 15.02, CI = 3.08-270.87, P < .0001), vertebral dissection (OR = 2406539.5, P = .0037), cervical artery aneurysm (OR = 11.75, CI = 2.11-220.71, P = .0026), cerebral aneurysm (OR = 5.59, CI = 2.69-13.18, P < .0001), and cerebrovascular malformation (OR = 4.67, CI = 1.20-30.87, P = .0243). CONCLUSIONS: Carotid and vertebral dissections, cervical and cerebral aneurysms, as well as other cerebrovascular malformations are more common in hospitalized patients with EDS compared to controls. PMID- 28647421 TI - Evaluation of Respiratory Muscle Strength in the Acute Phase of Stroke: The Role of Aging and Anthropometric Variables. AB - BACKGROUND: During hospitalization, stroke patients are bedridden due to neurologic impairment, leading to loss of muscle mass, weakness, and functional limitation. There have been few studies examining respiratory muscle strength (RMS) in the acute phase of stroke. OBJECTIVE: This study aimed to evaluate the RMS of patients with acute stroke compared with predicted values and to relate this to anthropometric variables, risk factors, and neurologic severity. METHODS: This is a cross-sectional study in the acute phase of stroke. After admission, RMS was evaluated by maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP); anthropometric data were collected; and neurologic severity was evaluated by the National Institutes of Health Stroke Scale. The analysis of MIP and MEP with predicted values was performed by chi-square test, and the relationship between anthropometric variables, risk factors, and neurologic severity was determined through multiple linear regression followed by residue analysis by the Shapiro-Wilk test; P < .05 was considered statistically significant. RESULTS: In the 32 patients studied, MIP and MEP were reduced when compared with the predicted values. MIP declined significantly by 4.39 points for each 1 kg/m2 increase in body mass index (BMI), and MEP declined significantly by an average of 3.89 points for each 1 kg/m2 increase in BMI. There was no statistically significant relationship between MIP or MEP and risk factors, and between MIP or MIP and neurologic severity in acute phase of stroke. CONCLUSION: There is a reduction of RMS in the acute phase of stroke, and RMS was lower in individuals with increased age and BMI. PMID- 28647422 TI - Hand hygiene compliance monitoring: we need to stop kidding ourselves. PMID- 28647423 TI - Effect of hand hygiene and glove use on cleanliness of reusable surgical instruments. AB - BACKGROUND: During functionality testing and packaging of reusable surgical instruments (RSI) for sterilization, instruments are frequently touched. There is a lack of standards relating to hand hygiene frequency and use of gloves in the sterilizing service unit packing area. AIM: To determine the effect of hand hygiene and glove use on maintenance of RSI cleanliness. METHODS: Following manual and automated cleaning, Halsted-mosquito forceps were assessed for adenosine triphosphate (ATP), protein and microbial contamination after handling with gloved and ungloved but washed hands using an ATP surface swab test, bicinchoninic acid assay, and standard culture plate/broth, respectively. Gram's stain was used to classify the isolates. RSI contamination was assessed immediately following and 1, 2, and 4 h after washing hands. FINDINGS: Packing instruments with hands that had been unwashed for 2 or 4 h resulted in a significant increase in contaminating ATP when compared with all other treatment groups (P < 0.05). There was a significant correlation between the time since washing hands, the amount of ATP (r = 0.93; P <= 0.001), and the microbial load (r = 0.83; P <= 0.001) contaminating the forceps, where the longer the time the hands remained unwashed the higher the contamination. Significantly more contaminating protein was found on forceps handled with ungloved hands that had not been washed for 2 or 4 h (P < 0.001). CONCLUSION: Critical RSI inspection, assembling, lubricating and packing should be performed using either gloves or within 1 h of washing hands. PMID- 28647424 TI - Self-disinfecting surfaces and activity against Staphyloccocus aureus ATCC 6538 under real-life conditions. AB - Environmental surface contamination provides a potential reservoir for pathogens to cause infections. As such, self-disinfecting surfaces have been developed to possibly reduce exogenous transmission. Five different self-disinfecting surfaces were evaluated for activity against Staphylococcus aureus ATCC 6538 under real life conditions using the dry inoculation method. Various antimicrobial effects were detected. However, following disinfection with alcoholic wipes, these effects disappeared. Further development is necessary to produce self disinfecting surfaces that are stable in the presence of hospital disinfectants, as it is impossible to guarantee that self-disinfecting surfaces in healthcare settings will not be exposed to disinfectants. PMID- 28647425 TI - Use of antibiotics and the prevalence of antibiotic-associated diarrhoea in patients with spinal cord injuries: an international, multi-centre study. AB - BACKGROUND: Little is known about the use of antibiotics and the extent of antibiotic-associated diarrhoea (AAD) in patients with spinal cord injuries (SCIs). AIMS: To record the use of antibiotics, establish the prevalence of AAD and Clostridium difficile infection (CDI), and assess if there was any seasonal variation in antibiotic use and incidence of AAD in patients with SCIs. METHODS: A retrospective study was conducted in six European SCI centres between October 2014 and June 2015. AAD was defined as two or more watery stools (Bristol Stool Scale type 5, 6 or 7) over 24 h. FINDINGS: In total, 1267 adults (median age 54 years, 30.7% female) with SCIs (52.7% tetraplegia, 59% complete SCI) were included in this study. Among the 215 (17%) patients on antibiotics, the top three indications for antibiotics were urinary tract infections (UTIs), infected pressure ulcers and other skin infections. Thirty-two of these 215 (14.9%) patients developed AAD and two patients out of the total study population (2/1267; 0.16%) developed CDI. AAD was more common in summer than in spring, autumn or winter (30.3% vs 3.8%, 7.4% and 16.9%, respectively; P<0.01). AAD was associated with age >=65 years, tetraplegia, higher body mass index, hypoalbuminaemia, polypharmacy, multiple antibiotic use and high-risk antibiotic use. Summer and winter seasons and male sex were identified as independent predictors for the development of AAD. CONCLUSION: This survey found that AAD is common in patients with SCIs, and UTI is the most common cause of infection. Summer and winter seasons and male sex are unique predictors for AAD. Both AAD and UTIs are potentially preventable; therefore, further work should focus on preventing the over-use of antibiotics, and developing strategies to improve hospital infection control measures. PMID- 28647426 TI - Age-related changes in structural connectivity are improved using subject specific thresholding. AB - BACKGROUND: Deterministic diffusion tractography obtained from high angular resolution diffusion imaging (HARDI) requires user-defined quantitative anisotropy (QA) thresholds. Most studies employ a common threshold across all subjects even though there is a strong degree of individual variation within groups. We sought to explore whether it would be beneficial to use individual thresholds in order to accommodate individual variance. To do this, we conducted two independent experiments. METHOD: First, tractography of the arcuate fasciculus and network connectivity measures were examined in a sample of 14 healthy participants. Second, we assessed the effects of QA threshold on group differences in network connectivity measures between healthy young (n=19) and old (n=14) individuals. RESULTS: The results of both experiments were significantly influenced by QA threshold. Common thresholds set too high failed to produce sufficient reconstructions in most subjects, thus decreasing the likelihood of detecting meaningful group differences. On the other hand, common thresholds set too low resulted in spurious reconstructions, providing deleterious results. COMPARISON WITH EXISTING METHODS: Subject specific thresholds acquired using our QA threshold selection method (QATS) appeared to provide the most meaningful networks while ensuring that data from all subjects contributed to the analyses. CONCLUSIONS: Together, these results support the use of a subject-specific threshold to ensure that data from all subjects are included in the analyses being conducted. PMID- 28647427 TI - First molecular detection of Leishmania infantum in Sergentomyia minuta (Diptera, Psychodidae) in Alentejo, southern Portugal. AB - Protozoan parasites, such as Leishmania spp., are the causative agents of many insect-borne infectious diseases with medical and veterinary importance. Leishmaniasis, caused by Leishmania spp., is transmitted by female phlebotomine sand flies. In the Alentejo region of Portugal, located at the north of Algarve, cases of human and canine leishmaniasis caused by Leishmania infantum have been notified. However, no recent studies regarding the sand fly fauna in the region are available. We therefore aimed to explore the phlebotomine sand fly species found in both, Evora and Beja Districts, to gain an insight about the leishmaniasis epidemiology in these areas. After the identification of the insect species, PCR molecular tests were used to assess L. infantum infection rate in the sand fly captured females, together with the analysis of blood meal sources of the insect vectors. One Sergentomyia minuta female was positive for L. infantum infection and another for human blood as a meal source. The occurrence of this phlebotomine species infected with L. infantum may suggest that, in the Mediterranean basin, leishmaniasis epidemiology is changing. Also, if the importance of S. minuta for the zoonotic and anthroponotic cycle of leishmaniasis is later proven, the strategies to control its vector will inevitably to be rethought. PMID- 28647428 TI - Reproducibility of Automated Voice Range Profiles, a Systematic Literature Review. AB - OBJECTIVE: Reliable voice range profiles are of great importance when measuring effects and side effects from surgery affecting voice capacity. Automated recording systems are increasingly used, but the reproducibility of results is uncertain. Our objective was to identify and review the existing literature on test-retest accuracy of the automated voice range profile assessment. STUDY DESIGN: Systematic review. DATA SOURCES: PubMed, Scopus, Cochrane Library, ComDisDome, Embase, and CINAHL (EBSCO). METHODS: We conducted a systematic literature search of six databases from 1983 to 2016. The following keywords were used: phonetogram, voice range profile, and acoustic voice analysis. Inclusion criteria were automated recording procedure, healthy voices, and no intervention between test and retest. Test-retest values concerning fundamental frequency and voice intensity were reviewed. RESULTS: Of 483 abstracts, 231 full-text articles were read, resulting in six articles included in the final results. The studies found high reliability, but data are few and heterogeneous. CONCLUSION: The reviewed articles generally reported high reliability of the voice range profile, and thus clinical usefulness, but uncertainty remains because of low sample sizes and different procedures for selecting, collecting, and analyzing data. More data are needed, and clinical conclusions must be drawn with caution. PMID- 28647429 TI - Musculoskeletal Pain and Voice-related Quality of Life in Dysphonic and Non dysphonic Subjects. AB - PURPOSE: This study aimed to compare and correlate musculoskeletal pain and voice related quality of life of dysphonic and non-dysphonic individuals. METHOD: This is a retrospective case-control study. A total of 74 adults were divided into two groups: the experimental group (EG) comprising 37 individuals with vocal complaints and hyperfunctional dysphonia, and the control group (CG) comprising 37 individuals without vocal complaints and with healthy voices. Both groups presented similar gender and age (28 females and 9 males for each group; average age = 31.5). All the participants answered the protocols: Voice-Related Quality of Life and Musculoskeletal Pain Questionnaire. Statistical data were analyzed by Mann-Whitney U test (P <= 0.05) and Spearman correlation test (P <= 0.05). RESULTS: It was observed that the EG presented significantly lower scores of voice-related quality of life in the social-emotional (P < 0.001), physical (P < 0.001), and total (P < 0.001) fields. Concerning musculoskeletal pain, it was observed in the EG that there was a higher intensity in pain in the region of the larynx (P < 0.001), and a higher frequency of pain in the submandibular (P = 0.013), larynx (P < 0.001), and front of the neck (P = 0.002) regions, when compared with the CG. CONCLUSION: In the group of individuals studied, worst indexes of voice-related quality of life and higher frequency and intensity of pain in the larynx were observed, in addition to higher frequency of pain in regions near the larynx in dysphonic subjects. There was correlation between voice-related quality of life and the frequency and intensity of musculoskeletal pain. PMID- 28647430 TI - Determining the Relevant Criteria for Three-dimensional Vocal Tract Characterization. AB - OBJECTIVE: Soprano singers face a number of specific challenges when singing vowels at high frequencies, due to the wide spacing of harmonics in the voice source. The varied and complex techniques used to overcome these are still not fully understood. Magnetic resonance imaging (MRI) has become increasingly popular in recent years for singing voice analysis. This study proposes a new protocol using three-dimensional MRI to investigate the articulatory parameters relevant to resonance tuning, a technique whereby singers alter their vocal tract to shift its resonances nearer to a voice source harmonic, increasing the amplitude of the sound produced. METHODS: The protocol was tested with a single soprano opera singer. Drawing on previous MRI studies, articulatory measurements from three-dimensional MRI images were compared to vocal tract resonances measured directly using broadband noise excitation. The suitability of the protocol was assessed using statistical analysis. RESULTS: No clear linear relationships were apparent between articulatory characteristics and vocal tract resonances. The results were highly vowel dependent, showing different patterns of resonance tuning and interactions between variables. This potentially indicates a complex interaction between the vocal tract and sung vowels in soprano voices, meriting further investigation. CONCLUSIONS: The effective interpretation of MRI data is essential for a deeper understanding of soprano voice production and, in particular, the phenomenon of resonance tuning. This paper presents a new protocol that contributes toward this aim, and the results suggest that a more vowel-specific approach is necessary in the wider investigation of resonance tuning in female voices. PMID- 28647431 TI - Temporal Segmentation for Laryngeal High-Speed Videoendoscopy in Connected Speech. AB - OBJECTIVE: This study proposes a gradient-based method for temporal segmentation of laryngeal high-speed videoendoscopy (HSV) data obtained during connected speech. METHODS: A custom-developed HSV system coupled with a flexible fiberoptic nasolaryngoscope was used to record one vocally normal female participant during reading of the "Rainbow Passage." A gradient-based algorithm was developed to generate a motion window. When applied to the HSV data, the motion window acted as a filter tracking the location of the vibrating vocal folds. The glottal area waveform was estimated using a statistical-based image-processing approach. The vocal fold vibratory frequency was computed by an autocorrelation-based extraction of the fundamental frequency (f0) from the glottal area waveform. Temporal segmentation was then performed based on the f0 contour and automatic detection of the epiglottic obstructions. Additionally, visual temporal segmentation was performed by viewing the HSV images frame by frame to determine the time points of the vocalization onsets and offsets, and the epiglottic obstructions of the glottis. RESULTS: The time points resulting from the automatic and visual temporal segmentation methods were cross-validated. The f0 contour patterns of rise and fall resulting from the automatic algorithm were found to be in agreement with the visual inspection of the vibratory frequency change in the HSV data. CONCLUSIONS: This study demonstrated the feasibility of automatic temporal segmentation of HSV imaging of connected speech, which allows for mapping the video content into onsets, offsets, and epiglottic obstructions for each vocalization. Automated analysis of HSV imaging of connected speech has significant clinical potential for advancing instrumental voice assessment protocols. PMID- 28647432 TI - Peer-assisted Learning: Intensity-modulated Radiotherapy Transition in Developing Countries. AB - Intensity-modulated radiotherapy (IMRT) is not widely used in developing countries due to technical challenges and a lack of expertise and resources. We outline head and neck cancer IMRT implementation challenges and highlight how improvised solutions allowed successful IMRT transition in Jordan. This article showcases a 'peer-assisted learning' model, promoting IMRT transition in other developing countries. Unlike the 'top-down' approach, this model is uncommonly addressed in oncology journals. Developing countries could benefit from this article to enhance the adoption of modern radiotherapy technology. PMID- 28647433 TI - Targeted release of transcription factors for human cell reprogramming by ZEBRA cell-penetrating peptide. AB - Transcription factors (TFs) are key actors of the control of gene expression and consequently of every major process within cells, ranging from cell fate determination, cell cycle control and response to environment. Their ectopic expression has proven high potential in reprogramming cells for regenerative medicine; ontogenesis studies and cell based modelling. Direct delivery of proteins could represent an alternative to current reprogramming methods using gene transfer but still needs technological improvements. Herein, we set-up an efficient cellular penetration of recombinant TFs fused to the minimal transduction domain (MD) from the ZEBRA protein. We show that ZEBRA MD-fused TFs applied on primary human fibroblasts and cord blood CD34+ hematopoietic stem cells route through the cytoplasm to the nucleus. The delivery of Oct4, Sox2 and Nanog by MD leads to the activation of mRNA transcripts from genes regulated by these TFs. Moreover, the expression of genes involved in the pluripotency network but not directly bound by these TFs, is also induced. Overall, the repeated application of MD-Oct4, MD-Sox2, MD-Nanog TFs and the post-transcriptional regulator RNA-binding protein MD-Lin28a, triggers the rejuvenation of human fibroblasts and CD34+ cells. This study provides powerful tools for cell fate reprogramming without genetic interferences. PMID- 28647434 TI - Hyperechogenicity of substantia nigra for differential diagnosis of Parkinson's disease: A meta-analysis. AB - Studies have suggested that the majority of patients with Parkinson's disease have abnormal ultrasound hyperechogenicity of the substantia nigra, and that this may be useful in diagnosis. We performed a systematic review and meta-analysis to evaluate diagnostic value of substantia nigra ultrasound to differentiate Parkinson's disease from atypical parkinsonism and from essential tremor. We systematically searched PubMed and EMBASE for relevant studies published until November 2016. Eligible articles were screened, data were extracted and study quality was scored by two independent reviewers. We applied random effect models to calculate pooled estimates for the prevalence of hyperechogenicity in each condition. For final meta-analysis, 71 articles with a total number of 5730 participants (idiopathic Parkinson's disease: 4494, atypical parkinsonism: 594, essential tremor: 642) were included. The pooled prevalence rate of hyperechogenicity was 84% (95 %CI 80-87%) in idiopathic Parkinson's disease, 28% (95% CI 20-36%) in atypical parkinsonism and 15% (95% CI 7-23%) in essential tremor. Based on our meta-analysis, substantia nigra hyperechogenecity has 75% (95% CI: 60-86%) sensitivity and 70% (95% CI: 55-81%) specificity to differentiate idiopathic Parkinson's disease from atypical parkinsonism. Sensitivity and specificity to distinguish idiopathic Parkinson's disease from essential tremor was calculated as 78% (95% CI: 69-85%) and 85% (95% CI: 77-91%), respectively. Findings from our meta-analysis showed that transcranial sonography can provide useful information to differentiate idiopathic Parkinson's disease from mimicking movement disorders, although sensitivity and specificity are suboptimal, particularly for differentiating from atypical parkinsonism. PMID- 28647435 TI - Dietary habits in Parkinson's disease: Adherence to Mediterranean diet. AB - INTRODUCTION: Our objective is to describe the dietary habits, food preferences and adherence to Mediterranean diet (MeDi) of a large sample of Italian Parkinson's Disease (PD) patients compared to a group of controls. METHODS: Dietary habits of 600 PD patients from throughout Italy and 600 controls matched by gender, age, education, physical activity level and geographical residence, were collected using the ON-GP Food Frequency Questionnaire. Then, we compared patients by disease duration and the presence of swallowing disturbances. RESULTS: Overall, adherence of PD patients (males, 53.8%; mean disease duration, 9.2 +/- 7.0 years) to MeDi was similar to controls (score, 4.8 +/- 1.7 vs. 4.9 +/ 1.6; P = 0.294). Patients consumed less alcohol and fish and drank significantly less water, coffee, and milk which resulted also in lower total fluids intake. On the contrary, they ate more fruit, cooked vegetables, cereals and baked items, more dressings and more sweets in general. Disease duration was associated with increased intake of several food groups but it was not associated with changes in MeDi score (P = 0.721). Patients with swallowing disturbances (n = 72) preferred softer and more viscous food but preferences did not result in differences in dietary pattern. However, patients with dysphagia drank less fluids (P = 0.043). DISCUSSION: PD patients presented different dietary habits and food preferences compared to the general population and adherence to MeDi was not associated with disease duration. Self-reported dysphagia was associated with reduced intake of fluids. These aspects may be amenable to change in order to improve the management of nutritional issues in this patient population. PMID- 28647436 TI - Social judgments, frontal asymmetry, and aggressive behavior in young children: A replication study using EEG. AB - Early in their lives young children are confronted with social judgments by peers. Previous studies have shown that in adults negative social judgments are associated with more aggressive behavior. However, little is known about the relation between social judgments and aggressive behavior, or the underlying neurocognitive mechanisms, in early childhood. We developed the Social Network Aggression Task - Early Childhood (SNAT-EC) to examine the mediating role of frontal EEG asymmetry in the relation between social judgment and aggressive behavior in 4-6 year old children. To replicate our findings, we included three samples: a pilot sample, test sample 1 and test sample 2 (total N = 78). In the SNAT-EC, children receive positive, negative and neutral social judgments about their chosen cuddly animal by same-aged unfamiliar peers. EEG was acquired to measure frontal asymmetry during the processing of social judgments. Aggressive behavior was measured as the duration of a button press with which children could destroy balloons of the judging peer, thus reducing the number of remaining balloons for that peer. We used a within-subject mediation model to test whether frontal asymmetry mediated the effect of social judgment (negative vs. positive) on aggressive behavior. Results show that the SNAT-EC robustly elicits more aggressive behavior in response to negative social judgments about the cuddly animal compared to positive judgments. Meta-analysis revealed a large combined effect size (r = .42) for the relation between negative (vs. positive) social judgments and aggressive behavior. However, frontal asymmetry in response to the social judgments did not mediate the relation between social judgment and aggressive behavior. Future studies should search for other neural mediators to bridge the brain-behavior gap between social judgments and aggressive behavior, in particular in early childhood. PMID- 28647437 TI - Inhibitory control is not lateralized in Parkinson's patients. AB - Parkinson's disease (PD) is often characterized by asymmetrical symptoms, which are more prominent on the side of the body contralateral to the most extensively affected brain hemisphere. Therefore, lateralized PD presents an opportunity to examine the effects of asymmetric subcortical dopamine deficiencies on cognitive functioning. As it has been hypothesized that inhibitory control relies upon a right-lateralized pathway, we tested whether left-dominant PD (LPD) patients suffered from a more severe deficit in this key executive function than right dominant PD patients (RPD). To this end, via a countermanding task, we assessed both proactive and reactive inhibition in 20 LPD and 20 RPD patients, and in 20 age-matched healthy subjects. As expected, we found that PD patients were significantly more impaired in both forms of inhibitory control than healthy subjects. However, there were no differences either in reactive or proactive inhibition between LPD and RPD patients. All in all, these data support the idea that brain regions affected by PD play a fundamental role in subserving inhibitory function, but do not sustain the hypothesis according to which this executive function is predominantly or solely computed by the brain regions of the right hemisphere. PMID- 28647438 TI - Attention is allocated closely ahead of the target during smooth pursuit eye movements: Evidence from EEG frequency tagging. AB - It is under debate whether attention during smooth pursuit is centered right on the pursuit target or allocated preferentially ahead of it. Attentional deployment was previously probed using a secondary task, which might have altered attention allocation and led to inconsistent findings. We measured frequency tagged steady-state visual evoked potentials (SSVEP) to measure attention allocation in the absence of any secondary probing task. The observers pursued a moving dot while stimuli flickering at different frequencies were presented at various locations ahead or behind the pursuit target. We observed a significant increase in EEG power at the flicker frequency of the stimulus in front of the pursuit target, compared to the frequency of the stimulus behind. When testing many different locations, we found that the enhancement was detectable up to about 1.5 degrees ahead during pursuit, but vanished by 3.5 degrees . In a control condition using attentional cueing during fixation, we did observe an enhanced EEG response to stimuli at this eccentricity, indicating that the focus of attention during pursuit is narrower than allowed for by the resolution of the attentional system. In a third experiment, we ruled out the possibility that the SSVEP enhancement was a byproduct of the catch-up saccades occurring during pursuit. Overall, we showed that attention is on average allocated ahead of the pursuit target during smooth pursuit. EEG frequency tagging seems to be a powerful technique that allows for the investigation of attention/perception implicitly when an overt task would be confounding. PMID- 28647439 TI - Testing the effects of expression, intensity and age on emotional face processing in ASD. AB - Individuals with autism spectrum disorder (ASD) commonly show global deficits in the processing of facial emotion, including impairments in emotion recognition and slowed processing of emotional faces. Growing evidence has suggested that these challenges may increase with age, perhaps due to minimal improvement with age in individuals with ASD. In the present study, we explored the role of age, emotion type and emotion intensity in face processing for individuals with and without ASD. Twelve- and 18-22- year-old children with and without ASD participated. No significant diagnostic group differences were observed on behavioral measures of emotion processing for younger versus older individuals with and without ASD. However, there were significant group differences in neural responses to emotional faces. Relative to TD, at 12 years of age and during adulthood, individuals with ASD showed slower N170 to emotional faces. While the TD groups' P1 latency was significantly shorter in adults when compared to 12 year olds, there was no significant age-related difference in P1 latency among individuals with ASD. Findings point to potential differences in the maturation of cortical networks that support visual processing (whether of faces or stimuli more broadly), among individuals with and without ASD between late childhood and adulthood. Finally, associations between ERP amplitudes and behavioral responses on emotion processing tasks suggest possible neural markers for emotional and behavioral deficits among individuals with ASD. PMID- 28647440 TI - Optimal percutaneous coronary intervention in patients with ST-elevation myocardial infarction and multivessel disease: An updated, large-scale systematic review and meta-analysis. AB - BACKGROUND: Our study aimed to compare three different percutaneous coronary intervention (PCI) approaches: culprit-only (COR) and complete (CR) revascularization - categorizing into immediate (ICR) or staged (SCR). METHODS: We searched 13 databases for randomized controlled trials. Articles were included if they compared at least two strategies. To have more studies in each analysis, an adjusted analysis was performed using person-years to incorporate follow-up durations and obtain pooled rate ratios (RR), with their corresponding 95% confidence interval. RESULTS: Thirteen trials were included with a population of 2830 patients. COR significantly increased major adverse cardiac event (MACE) (adjusted RR 1.67, 95% CI: 1.27-2.19) and repeat revascularization (2.12, 1.67 2.69), which was driven by repeat PCI, without any difference in all-cause mortality and myocardial infarction (MI) compared to CR. When categorizing CR into SCR and ICR, the trend repeated with COR increased MACE (1.99, 1.53-2.6 for ICR), cardiovascular mortality (2.06, 1.07-3.96 for ICR), MI for ICR (1.72, 1.04 2.86), repeat revascularization and repeat PCI for both ICR and SCR. Non cardiovascular mortality, stroke, nephropathy, re-hospitalization, stent thrombosis and bleeding were similar among all approaches. CONCLUSIONS: In MVD STEMI patients, CR is better than COR in terms of MACE, cardiovascular mortality, repeat revascularization with no difference in safety outcomes. There was a trend towards to a reduction of cardiovascular mortality and MI in ICR compared to SCR when each matched with COR; even though there is no statistically significant difference between ICR and SCR when compared together. PMID- 28647441 TI - Prevention of epilepsy: Should we be avoiding clinical trials? AB - Epilepsy prevention is one of the great unmet needs in epilepsy. Approximately 15% of all epilepsy is caused by an acute acquired CNS insult such as traumatic brain injury (TBI), stroke or encephalitis. There is a latent period between the insult and epilepsy onset that presents an opportunity to intervene with preventive treatment that is unique in neurology. Yet no phase 3 epilepsy prevention studies, and only 2 phase 2 studies have been initiated in the last 16years. Current prevailing opinion is that the research community is not ready for clinical preventive epilepsy studies, and that animal models should first be refined and biomarkers of epileptogenesis and of epilepsy discovered before clinical studies are embarked upon. We review data to suggest that there is basis to do epilepsy prevention studies now with the current knowledge and available drugs, and that those studies are feasible with currently available tools. We suggest that a different approach is needed from the past in order to maximize chances of success, minimize the cost, and set up platform for future preventive treatment development. That approach should include close coordination of preclinical and clinical development programs in a combined PTE prevention strategy, consideration of polytherapy, and simultaneous, combined clinical development of preventive treatment and of biomarker discovery. We argue that the currently favored approach of eschewing clinical studies until biomarkers are available will delay the discovery of epilepsy prevention treatment by at least 10 years and significantly increase the cost of such discovery. PMID- 28647442 TI - The Impact of the Transition From Volume to Value on Heart Failure Care: Implications of Novel Payment Models and Quality Improvement Initiatives. AB - In response to wide variation in quality and outcomes as well as escalating health care costs, the U.S. health care system is moving away from a volume-based payment system to a quality- and value-based system. Medicare, the largest insurer and payer of health care, has accelerated the movement toward value-based care with the development and implementation of myriad alternate payment models and pay-for-performance programs as part of the Affordable Care Act. Given that heart failure affects a significant number of Medicare patients and that these patients account for a disproportionate amount of health care utilization and spending, heart failure has become a focal point for these initiatives. In this article, we highlight 4 such programs beyond the Hospital Readmission Reduction Program (HRRP) which financially penalizes hospitals for excess readmissions. Specifically, we focus on Hospital Value-Based Purchasing (HVBP), Bundled Payments for Care Improvement (BPCI), the Merit-Based Incentive Payment System (MIPS), and Accountable Care Organizations (ACOs). The HVBP and BPCI programs aim to improve quality and cost efficiency primarily among patients who are hospitalized, and the MIPS program has taken similar aim in the ambulatory setting. Finally, ACOs encourage active population health management across the continuum of care as providers bear financial risk for enrolled patients. Given broader discussions about health care reform, the specific policies and programs meant to accelerate the transition from volume to value may be altered. However, the underlying drivers for reform will persist, and heart failure is a clinical condition that by comparison will be subject to greater scrutiny. PMID- 28647443 TI - Dermal and transdermal delivery of pharmaceutically relevant macromolecules. AB - The skin offers an attractive way for dermal and transdermal drug delivery that is why the drug still needs certain qualities to transcend the outermost layer of the skin, the stratum corneum. The requirements are: drugs with a maximum molecular weight of 1kDa, high lipophilicity and a certain polarity. This would restrict the use of a transdermal delivery of macromolecules, which would make the drug more effective in therapeutic administration. Various studies have shown that macromolecules without support do not penetrate the human skin. This effect can be achieved using physical and chemical methods, as well as biological peptides. The most popular physical method is the use of microneedles to create micropores in the skin and release the active agent in different sections. But also, other methods have been tested. Microjets, lasers, electroporation, sonophoresis and iontophoresis are also promising methods to successfully deliver dermal and transdermal macromolecules. Additionally, there are different penetration enhancer groups and biological peptides, which are also considered to be interesting approaches of enabling macromolecules to travel along the skin. All these methods will be described and evaluated in this review article. PMID- 28647444 TI - Spot Urine Protein-to-Creatinine Ratio to Predict the Magnitude of 24-Hour Total Proteinuria in Preeclampsia of Varying Severity. AB - OBJECTIVE: The predictive value of spot urine protein-to-creatinine ratio (PCR) for estimating total 24-hour proteinuria in severe preeclampsia is unclear. This study aimed to assess the diagnostic accuracy of spot urine PCR for ascertaining the magnitude of proteinuria in women with preeclampsia of varying severity. METHODS: A total of 205 patients with prediagnosed preeclampsia were included in this prospective cohort study. Patients were allocated into one of the three groups categorized by severity of disease, as follows: gestational hypertension, group 1 (n = 41); preeclampsia, group 2 (n = 88); and severe preeclampsia, group 3 (n = 76). We assessed the spot urine PCRs to determine significant proteinuria and the magnitude of proteinuria in these groups. RESULTS: The spot urine PCR was 0.53, with 81% sensitivity and 93% specificity to detect significant proteinuria. A significant correlation was found between PCR and 24-hour total proteinuria in group 1 (r = 0.473, P = 0.002). There were also significant correlations in group 2 (r = 0.814, P < 0.001) and group 3 (r = 0.912, P < 0.001). The established formula using spot urine PCR to estimate 24-hour total proteinuria in severe preeclampsia was Y = 832.02X + 378.74 mg (r2 = 0.8304). CONCLUSION: Although 24 hour urine collection remains a merely reliable test to determine the degree of total proteinuria, our findings suggest that it is likely to assess the magnitude of proteinuria by the spot urine PCR, especially in severe preeclampsia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.govNCT01623791. PMID- 28647445 TI - The Value of Anti-Mullerian Hormone in Predicting Clinical Pregnancy After Intrauterine Insemination. AB - OBJECTIVES: To evaluate the utility of anti-Mullerian hormone (AMH) in predicting clinical pregnancy with intrauterine insemination (IUI) and compare it to other markers of quantitative ovarian reserve. METHODS: Retrospective cohort study of women undergoing natural and stimulated IUI cycles. All patients achieved a clinical pregnancy within three IUI cycles or completed three IUI cycles without pregnancy. Receiver operating curves were generated to determine the ability of AMH, antral follicle count, age, BMI, and day 3 FSH to predict clinical pregnancy with IUI. Characteristics of those with and without pregnancy were compared using Mann-Whitney U, chi-square, and Fisher exact tests. RESULTS: Of 209 women included, 49% achieved clinical pregnancy. Pregnant patients were more likely to have a higher AMH (2.76 vs. 1.55 ng/mL, P = 0.0004). The area under the curve was 0.642 in predicting clinical pregnancy within three IUI cycles using AMH (0.608 if excluding polycystic ovarian syndrome patients); 0.639 using antral follicle count; 0.549 using age; 0.599 using day 3 FSH; and 0.639 using BMI. CONCLUSION: Although serum AMH appears significantly higher in women achieving clinical pregnancy, the predictive value of AMH alone was no better than that for other markers of quantitative ovarian reserve in a patient who clinically qualifies for IUI. PMID- 28647446 TI - Social and Geographic Determinants of Hysterectomy in Ontario: A Population-Based Retrospective Cross-Sectional Analysis. AB - OBJECTIVES: This study sought to determine whether social factors (neighbourhood education and income) and geographic factors (urban or rural dwelling and local service area) are associated with hysterectomy rates, proportion of hysterectomies performed minimally invasively, and hysterectomy complication and readmission rates in Ontario. METHODS: The Canadian Institute for Health Information Discharge Abstract Database was used to perform a population-based retrospective cross-sectional study on women who had an abdominal, vaginal, and laparoscopic hysterectomy in 2007 for benign gynaecologic conditions in hospitals in Ontario, Canada. Crude and age-standardized rates of hysterectomy, proportion of hysterectomy performed minimally invasively (vaginal or laparoscopic), and rates of surgical complications were analyzed by neighbourhood educational attainment, neighbourhood income, rural or urban residency, and health service delivery area (Canadian Task Force Classification of Study Design II). RESULTS: A total of 13 511 women who underwent hysterectomy were included. Age-standardized hysterectomy rates were higher for the lowest neighbourhood educational quartile compared with the highest (relative risk [RR] 1.49; 95% CI 1.39-1.60), higher with rural compared with urban dwelling (RR 1.54; 95% CI 1.47-1.61), varied with local health service delivery area (Local Health Integration Network [LHIN]) (range 133.4-439.5 per 100 000 women), and also varied non-linearly with neighbourhood income quintile. Proportion of hysterectomies performed minimally invasively did not vary with neighbourhood education or income, were higher for rural compared with urban areas (RR 1.10; 95% CI 1.03-1.19), and varied with LHIN (range 30.0-62.9 per 100 hysterectomies). Surgical complications varied with neighbourhood educational quartile, but not with income or urban or rural residence. CONCLUSIONS: Considerable social and geographic variation exists in rates of hysterectomy in Ontario, whereas only geographic variation is seen in use of minimally invasive routes. Surgical complication rates vary only by neighbourhood education. Such findings suggest inequities in hysterectomy practice in Ontario, and there is a need to evaluate factors influencing patients' decision making, physicians' clinical and surgical practice, and health system policies to help address the observed disparities. PMID- 28647447 TI - Dienogest Therapy as a Treatment for Catamenial Pneumothorax: Case Report and Review of Hormonal Options. AB - BACKGROUND: Catamenial pneumothorax is a rare but serious condition for women of reproductive age. We describe a trial of dienogest as hormonal therapy for catamenial pneumothorax and review the literature on hormonal suppressive therapy for this condition. CASE: A 39-year-old female, gravida 0 para 0, presented with recurrent pneumothoraces coinciding with her menses. After surgical therapy, she was started on leuprolide acetate injections for 6 months to reduce recurrence. To reduce long-term side effects of leuprolide acetate, the patient was started on dienogest 4 mg orally once daily instead of leuprolide acetate for hormonal suppression and experienced resolution of recurrent pneumothoraces. CONCLUSION: For women with recurrent catamenial pneumothorax, dienogest may be an effective hormonal treatment option and alternative to long-term GnRH agonist therapy for long-term suppression. PMID- 28647448 TI - Simulation of images of CDMAM phantom and the estimation of measurement uncertainties of threshold gold thickness. AB - PURPOSE: To demonstrate a method of simulating mammography images of the CDMAM phantom and to investigate the coefficient of variation (CoV) in the threshold gold thickness (tT) measurements associated with use of the phantom. METHODS: The noise and sharpness of Hologic Dimensions and GE Essential mammography systems were characterized to provide data for the simulation. The simulation method was validated by comparing the tT results of real and simulated images of the CDMAM phantom for three different doses and the two systems. The detection matrices produced from each of 64 images using CDCOM software were randomly resampled to create 512 sets of 8, 16 and 32 images to estimate the CoV of tT. Sets of simulated images for a range of doses were used to estimate the CoVs for a range of diameters and threshold thicknesses. RESULTS: No significant differences were found for tT or the CoV between real and simulated CDMAM images. It was shown that resampling from 256 images was required for estimating the CoV. The CoV was around 4% using 16 images for most of the phantom but is over double that for details near the edge of the phantom. CONCLUSIONS: We have demonstrated a method to simulate images of the CDMAM phantom for different systems at a range of doses. We provide data for calculating uncertainties in tT. Any future review of the European guidelines should take into consideration the calculated uncertainties for the 0.1mm detail. PMID- 28647449 TI - IGRT and motion management during lung SBRT delivery. AB - Patient motion can cause misalignment of the tumour and toxicities to the healthy lung tissue during lung stereotactic body radiation therapy (SBRT). Any deviations from the reference setup can miss the target and have acute toxic effects on the patient with consequences onto its quality of life and survival outcomes. Correction for motion, either immediately prior to treatment or intra treatment, can be realized with image-guided radiation therapy (IGRT) and motion management devices. The use of these techniques has demonstrated the feasibility of integrating complex technology with clinical linear accelerator to provide a higher standard of care for the patients and increase their quality of life. PMID- 28647450 TI - Central administration of ghrelin induces conditioned avoidance in rodents. AB - Feelings of hunger carry a negative-valence (emotion) signal that appears to be conveyed through agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus. The circulating hunger hormone, ghrelin, activates these neurons although it remains unclear whether it also carries a negative-valence signal. Given that ghrelin also activates pathways in the midbrain that are important for reward, it remains possible that ghrelin could act as a positive reinforcer and hence, carry a positive-valence signal. Here we used condition preference/avoidance tests to explore the reinforcing/aversive properties of ghrelin, delivered by intracerebroventricular (ICV) injection (2ug/injection once a day for 4 days). We found that ICV ghrelin produces conditioned avoidance, both in a conditioned place preference/avoidance test (CPP/CPA, in which the animals avoid a chamber previously paired to ghrelin injection) and in a conditioned flavor preference/avoidance test (CFP/CFA, in which the animals consume/avoid a taste previously paired to ghrelin injection). These effects of ghrelin to induce a CPA were observed when conditioning to ghrelin occurred in the absence or presence of food. We did not find evidence, however, that brain ghrelin delivery to rats induces malaise (in the pica test). Our data indicate that ICV ghrelin carries a negative-valence signal consistent with its role as a circulating hunger hormone and with its effects to activate AgRP neurones. PMID- 28647451 TI - Association of mitochondrial DNA in peripheral blood with depression, anxiety and stress- and adjustment disorders in primary health care patients. AB - Mitochondrial dysfunction may result in a variety of diseases. The objectives here were to examine possible differences in mtDNA copy number between healthy controls and patients with depression, anxiety or stress- and adjustment disorders; the association between mtDNA copy number and disease severity at baseline; and the association between mtDNA copy number and response after an 8 week treatment (mindfulness, cognitive based therapy). A total of 179 patients in primary health care (age 20-64 years) with depression, anxiety and stress- and adjustment disorders, and 320 healthy controls (aged 19-70 years) were included in the study. Relative mtDNA copy number was measured using quantitative real time PCR on peripheral blood samples. We found that the mean mtDNA copy number was significantly higher in patients compared to controls (84.9 vs 75.9, p<0.0001) at baseline. The difference in mtDNA copy number between patients and controls remained significant after controlling for age and sex (beta=8.13, p<0.0001; linear regression analysis). The mtDNA copy number was significantly associated with Patient Health Questionnaire (PHQ-9) scores (beta=0.57, p=0.02) at baseline. After treatment, the change in mtDNA copy number was significantly associated with the treatment response, i.e., change in Hospital Anxiety and Depression Scale (HADS-D) and PHQ-9 scores (beta=1.00, p=0.03 and beta=0.65, p=0.04, respectively), after controlling for baseline scores, age, sex, BMI, smoking status, alcohol drinking and medication. Our findings show that mtDNA copy number is associated with symptoms of depression, anxiety and stress- and adjustment disorders and treatment response in these disorders. PMID- 28647452 TI - Differential roles of the infralimbic and prelimbic areas of the prefrontal cortex in reconsolidation of a traumatic memory. AB - Studies about reconsolidation of conditioned fear memories have shown that pharmacological manipulation at memory reactivation can attenuate or enhance the subsequent expression of the conditioned fear response. Here we examined the effects of a single injection of the mTOR inhibitor rapamycin (Rap) into the infralimbic (IL) and prelimbic (PL) areas [which compose the ventromedial prefrontal cortex (PFC)] on reconsolidation and extinction of a traumatic fear memory. We found opposite effects of Rap infused into the PL and IL on reconsolidation and extinction: intra-PL Rap and systemic Rap impaired reconsolidation and facilitated extinction whereas intra-IL Rap enhanced reconsolidation and impaired extinction. These effects persisted at least 10 days after reactivation. Shock exposure induced anxiety-like behavior and impaired working memory and intra-IL and -PL Rap normalized these effects. Finally, when measured after fear retrieval, shocked rats exhibited reduced and increased phosphorylated p70s6K levels in the IL and basolateral amygdala, respectively. No effect on phosphorylated p70s6K levels was observed in the PL. The study points to the differential roles of the IL and PL in memory reconsolidation and extinction. Moreover, inhibiting mTOR via rapamycin following reactivation of a fear memory may be a novel approach in attenuating enhanced fear memories. PMID- 28647453 TI - National funding for mental health research in Finland, France, Spain and the United Kingdom. AB - As part of the Roamer project, we aimed at revealing the share of health research budgets dedicated to mental health, as well as on the amounts allocated to such research for four European countries. Finland, France, Spain and the United Kingdom national public and non-profit funding allocated to mental health research in 2011 were investigated using, when possible, bottom-up approaches. Specifics of the data collection varied from country to country. The total amount of public and private not for profit mental health research funding for Finland, France, Spain and the UK was ?10.2, ?84.8, ?16.8, and ?127.6 million, respectively. Charities accounted for a quarter of the funding in the UK and less than six per cent elsewhere. The share of health research dedicated to mental health ranged from 4.0% in the UK to 9.7% in Finland. When compared to the DALY attributable to mental disorders, Spain, France, Finland, and the UK invested respectively ?12.5, ?31.2, ?39.5, and ?48.7 per DALY. Among these European countries, there is an important gap between the level of mental health research funding and the economic and epidemiologic burden of mental disorders. PMID- 28647454 TI - Elevated serum [Met5]-enkephalin levels correlate with improved clinical and behavioral outcomes in experimental autoimmune encephalomyelitis. AB - Methionine enkephalin ([Met5]-enkephalin, Opioid growth factor (OGF)) is a small neuropeptide with growth-related as well as immunomodulatory properties. OGF is distributed widely throughout the body, is both autocrine and paracrine produced, and has a very short half-life in serum. In addition to its neurotransmitter functions, OGF inhibits cell replication of a wide variety of cells involved in the autoimmune process. In this preclinical study, mice were immunized with myelin oligodendrocytic glycoprotein (MOG35-55) to establish a chronic progressive form of autoimmune encephalomyelitis (EAE), and serum enkephalin levels were assessed throughout the disease as well as in response to OGF therapy in order to determine whether OGF may be a biological marker for EAE and multiple sclerosis. Immunized mice were randomly assigned to groups receiving daily 10mg/kg OGF (n=24) or saline (n=25) beginning at the time of established disease and clinical behavior. Open field activity, rearing, forced swimming, and novel object tests were monitored. Serum levels of peptide were measured prior to immunization, before clinical symptoms were observed, and at the onset and peak period of disease. Spinal cord neuropathology was evaluated 40days after immunization. EAE disease onset occurred on day 9 post immunization when the mean clinical score was 1.5. Peak disease scores for saline-injected EAE mice reached a mean of 5.7 on day 18, whereas mice receiving OGF had a peak clinical score of 2.5. Behavioral tests conducted 5days post-immunization (and before clinical signs of EAE) revealed that EAE mice had reduced serum enkephalin levels related to elevated clinical disease scores. Serum levels of enkephalin collected at peak disease and after 40days correlated with clinical scores. Disease status was associated with activity in the open field, rearing, time associating with a novel object, and pain sensitivity. Clinical signs of EAE correlated with levels of enkephalins such that as behavioral scores increased, serum [Met5]-enkephalin levels decreased. Thus, [Met5]-enkephalin is a novel biomarker that is associated with disease onset and progression, as well as response to therapy in a mouse model of EAE, and may provide new insight into MS. PMID- 28647455 TI - Comparison of mucosal lining fluid sampling methods and influenza-specific IgA detection assays for use in human studies of influenza immunity. AB - We need greater understanding of the mechanisms underlying protection against influenza virus to develop more effective vaccines. To do this, we need better, more reproducible methods of sampling the nasal mucosa. The aim of the current study was to compare levels of influenza virus A subtype-specific IgA collected using three different methods of nasal sampling. Samples were collected from healthy adult volunteers before and after LAIV immunization by nasal wash, flocked swabs and Synthetic Absorptive Matrix (SAM) strips. Influenza A virus subtype-specific IgA levels were measured by haemagglutinin binding ELISA or haemagglutinin binding microarray and the functional response was assessed by microneutralization. Nasosorption using SAM strips lead to the recovery of a more concentrated sample of material, with a significantly higher level of total and influenza H1-specific IgA. However, an equivalent percentage of specific IgA was observed with all sampling methods when normalized to the total IgA. Responses measured using a recently developed antibody microarray platform, which allows evaluation of binding to multiple influenza strains simultaneously with small sample volumes, were compared to ELISA. There was a good correlation between ELISA and microarray values. Material recovered from SAM strips was weakly neutralizing when used in an in vitro assay, with a modest correlation between the level of IgA measured by ELISA and neutralization, but a greater correlation between microarray-measured IgA and neutralizing activity. In conclusion we have tested three different methods of nasal sampling and show that flocked swabs and novel SAM strips are appropriate alternatives to traditional nasal washes for assessment of mucosal influenza humoral immunity. PMID- 28647456 TI - Improved recovery of functionally active eosinophils and neutrophils using novel immunomagnetic technology. AB - Clinically relevant and reliable reports derived from in vitro research are dependent on the choice of cell isolation protocols adopted between different laboratories. Peripheral blood eosinophils are conventionally isolated using density-gradient centrifugation followed by immunomagnetic selection (positive/negative) while neutrophils follow a more simplified dextran sedimentation methodology. With the increasing sophistication of molecular techniques, methods are now available that promise protocols with reduced user manipulations, improved efficiency, and better yield without compromising the purity of enriched cell populations. These recent techniques utilize immunomagnetic particles with multiple specificities against differential cell surface markers to negatively select non-target cells from whole blood, greatly reducing the cost/time taken to isolate granulocytes. Herein, we compare the yield efficiencies, purity and baseline activation states of eosinophils/neutrophils isolated using one of these newer protocols that use immunomagnetic beads (MACSxpress isolation) vs. the standard isolation procedures. The study shows that the MACSxpress method consistently allowed higher yields per mL of peripheral blood compared to conventional methods (P<0.001, n=8, Wilcoxon paired test), with high isolation purities for both eosinophils (95.0+/-1.7%) and neutrophils (94.2+/-10.1%) assessed by two methods: Wright's staining and flow cytometry. In addition, enumeration of CD63+ (marker for eosinophil activation) and CD66b+ (marker for neutrophil activation) cells within freshly isolated granulocytes, respectively, confirmed that conventional protocols using density-gradient centrifugation caused cellular activation of the granulocytes at baseline compared to the MACSxpress method. In conclusion, MACSxpress isolation kits were found to be superior to conventional techniques for consistent purifications of eosinophils and neutrophils that were suitable for activation assays involving degranulation markers. PMID- 28647457 TI - Quantitative in vitro and in vivo models to assess human IgE B cell receptor crosslinking by IgE and EMPD IgE targeting antibodies. AB - Targeting plasma IgE by therapeutic mABs like Omalizumab (Xolair(r)) is current clinical practice for severe allergic conditions or other IgE related diseases like chronic urticaria. As an alternative to soluble IgE targeting, IgE supply can be lowered by targeting the Extracellular Membrane Proximal Domain (EMPD) of the IgE B cell receptor (BCR) present on IgE switched B cells. This ultimately leads to apoptosis of these cells upon IgE BCR crosslinking. Since tools to selectively assess the efficacy of IgE BCR crosslinking by IgE targeting antibodies are limited, a readily quantifiable cell model was developed that allows to specifically address IgE BCR crosslinking activity in vitro. The new cell model allowed for a direct quantitative comparison of anti-EMPD IgE therapeutic prototype antibody 47H4 with anti-IgE(Ce3) directed therapeutic antibody Omalizumab and with a newly selected anti-human EMPD IgE monoclonal antibody, designated mAB 15cl12. Furthermore, a complementing mouse model was developed that allows for in vivo validation of antibodies addressing human EMPD IgE. It carries a targetable humanized EMPD IgE sequence that has been introduced by seamless genomic replacement of the endogenous EMPD encoding sequence. The model allowed to directly compare IgE lowering activity of two anti-human EMPD IgE therapeutic antibodies in vivo. Our tools provide the means for quantitative assessment of IgE BCR crosslinking activity which is increasingly gaining attention with respect to forthcoming second generation anti-IgE clinical candidates such as Ligelizumab or other clinical candidates featuring additional effector functions such as IgE BCR crosslinking activity. PMID- 28647458 TI - Factors Associated With Efficacy of Percutaneous Tibial Nerve Stimulation for Fecal Incontinence, Based on Post-Hoc Analysis of Data From a Randomized Trial. AB - BACKGROUND & AIMS: A recent randomized, multi-center, phase 3 trial, performed in the United Kingdom (Control of Fecal Incontinence using Distal Neuromodulation Trial), demonstrated no significant clinical benefit of percutaneous tibial nerve stimulation (PTNS) compared to sham stimulation in patients with fecal incontinence (FI). However, this study did not analyze predictors of response. We used data from this trial to identify factors that predict the efficacy of PTNS in adults with FI. METHODS: The study population comprised 205 patients from the CONtrol of Fecal Incontinence using Distal NeuromodulaTion Trial. The primary outcome was a binary indicator of success (>=50% reduction in weekly FI episodes after 12 weeks of treatment) or failure, as per the original trial characteristics including baseline FI symptom type, defecatory urgency, and co existent symptoms of baseline liquid stool consistency and obstructive defecation (OD) were defined a priori. Univariable and multivariable analyses were performed to explore these factors as predictors of response to PTNS and sham. RESULTS: In both univariable and multivariable analysis, the presence of OD symptoms negatively predicted outcome in patients who received PTNS (OR, 0.38; 95% CI, 0.16-0.91; P = .029), and positively predicted sham response (OR, 3.45; 95% CI, 1.31-9.21; P = .012). No other tested variable affected outcome. Re-analysis of the primary outcome excluding patients with OD symptoms (n = 112) resulted in a significant clinical effect of PTNS compared to sham (48.9% vs 18.2% response, P = .002; multivariable OR, 4.71; 95% CI, 1.71-12.93; P = .003). CONCLUSIONS: Concomitant OD symptoms negatively affected the clinical outcome of PTNS vs sham in a major randomized controlled trial. Future appropriately designed studies could further explore this observation with potential for future stratified patient selection. PMID- 28647459 TI - Treatment of Aseptic Liver Abscess Due to Crohn's Disease Using Infliximab. PMID- 28647460 TI - A prospective study evaluating tobramycin pharmacokinetics and optimal once daily dosing in burn patients. AB - BACKGROUND: Once-daily aminoglycoside dosing (ODA) is used in most patient populations to optimize antibacterial activity and reduce toxicity. Unfortunately, burn patients are excluded from ODA due to concerns over altered pharmacokinetics resulting in a shortened half-life and low peak aminoglycoside concentrations. Retrospective studies suggest that ODA may be appropriate if higher milligram/kilogram doses are used. However, no prospective clinical trials in burn patients exist to confirm these findings. OBJECTIVE: To determine the adequacy of once daily tobramycin dosed at 10mg/kg in adult burn patients. METHODS: This prospective single dose pharmacokinetic clinical trial was conducted at the Ross Tilley Burn Centre. Patients with a total burn surface area (TBSA) of <20% and creatinine clearance >=50mL/min were eligible. A first-order one compartment model was used to determine the pharmacokinetic profile from 3 or 5 tobramycin levels over a 24h period per patient. Monte Carlo simulation (MCS) was performed to determine the probability of target level attainment. RESULTS: The mean percent TBSA, partial, and full thickness burn were 10%, 6%, and 4%, respectively. Nine of the ten patients recruited achieved peak concentrations of >=20mg/L (mean of 29.4+/-5.7mg/L) and all patients had a trough level <=0.5mg/L. The mean half-life, volume of distribution, and clearance were 2.58h, 0.33L/kg, and 7.40L/h, respectively. The MCS determined probability of attaining target peak concentrations with the 10mg/kg dose was 97%, which almost doubled that predicted with the usual 7mg/kg dose. CONCLUSION: Burn patients with adequate renal function and <20% TBSA are candidates for ODA. Tobramycin half-life was similar to healthy, non-burn patients. The larger than normal volume of distribution supports the use of the higher empiric dose of 10mg/kg total body or adjusted weight in non-obese and obese patients, respectively, with further dose adjustment based on therapeutic drug monitoring. PMID- 28647461 TI - Toric Intraocular Lenses Versus Peripheral Corneal Relaxing Incisions for Astigmatism Between 0.75 and 2.5 Diopters During Cataract Surgery. AB - PURPOSE: To compare the outcomes after toric intraocular lens (tIOL) or peripheral corneal relaxing incisions (PCRI) for keratometric astigmatism (KA) between 0.75 and 2.5 diopters (D) during cataract surgery. DESIGN: Prospective randomized clinical trial. METHODS: Eighty eyes (80 participants) received either tIOL or PCRI and were assessed preoperatively, 1, 3, 6, and 12 months postoperatively. PRIMARY OUTCOME MEASURE: Uncorrected (UCDVA) and best-corrected distance logMAR visual acuity (BCDVA) at 12 months. SECONDARY OUTCOME MEASURES: Uncorrected near visual acuity (UCNVA), manifest refraction, KA and mean keratometry (KM), corneal aberrometry, tIOL rotation, and quality-of-life questionnaire. RESULTS: Comparing tIOLs vs PCRIs, there was no significant difference in the UCDVA, BCDVA, and UCNVA. At 12 months, 61% vs 53% had UDCVA of 20/25 or better, 100% vs 76% gained >=1 lines, and 59% vs 43% were within +/-0.13 D spherical equivalent. In the PCRI group, anterior KA decreased at 1 month and remained stable thereafter; there was a nonsignificant trend toward a flatter posterior KA and steeper posterior KM and the total corneal Z2-2 was low at 1 and 12 months. Over 12 months, there were changes in posterior corneal tilt, coma, and hexafoil in the PCRI group. The mean rotation of the tIOLs at 12 months was 1.8 +/- 1.4 degrees. tIOL patients were happier and were glad to use the nonprescription sunglasses. CONCLUSION: There was no difference in visual acuity, although more tIOL patients gained >=1 line and were within +/-0.13 D. After PCRIs, the anterior KA decreased in the early postoperative period and remained stable thereafter and posterior corneal aberrations changed constantly over 12 months. PMID- 28647462 TI - Optical Coherence Tomography Angiography of Macular Features After Proton Beam Radiotherapy for Small Choroidal Melanoma. AB - PURPOSE: To describe the macular features of patients treated with proton beam therapy for choroidal melanoma (CM), using optical coherence tomography angiography (OCTA). DESIGN: Retrospective case-control study. METHODS: This study included patients treated with proton beam radiotherapy (PBR) for a small CM. Only patients who had received 100% of the dose of 60 Gy external beam radiation to the macular area were included in the analysis. All the patients had undergone a full ophthalmologic examination, including visual acuity, optical coherence tomography B-scan, and OCTA. Qualitative and quantitative vascular features of the retinal plexus and the choriocapillaris were analyzed on OCTA and compared with those in healthy subjects matched on age and sex. RESULTS: Thirty-seven patients had undergone an OCTA after PBR for a small CM. Seventeen patients (9 men and 8 women) were included. The mean age of the patients was 56.6 years (range, 28-86). At presentation, the mean tumor thickness was 3.39 mm (range, 1.3 7.0 mm). The mean follow-up duration was 35.8 months (range, 11-72 months). Thirteen patients (76.5%) had a clinical radiation maculopathy; 8 patients (47.1%) had macular cysts on OCT-B scan. All patients (100%) had abnormalities on OCTA. Some "signal void" spots were detected at the level of the choriocapillaris in 15 patients (88.2%). The mean vascular density (regarding the full retina) was significantly lower in the patients treated with PBR than in healthy subjects (P < .0001). CONCLUSION: Patients treated with PBR for CM (with 100% of the dose given to the macula) present major changes at both plexuses but also a vascular rarefaction of the choriocapillaris. PMID- 28647463 TI - The structurally unique photosynthetic Chlorella variabilis NC64A hydrogenase does not interact with plant-type ferredoxins. AB - Hydrogenases from green algae are linked to the photosynthetic electron transfer chain via the plant-type ferredoxin PetF. In this work the [FeFe]-hydrogenase from the Trebouxiophycean alga Chlorella variabilis NC64A (CvHydA1), which in contrast to other green algal hydrogenases contains additional FeS-cluster binding domains, was purified and specific enzyme activities for both hydrogen (H2) production and H2 oxidation were determined. Interestingly, although C. variabilis NC64A, like many Chlorophycean algal strains, exhibited light dependent H2 production activity upon sulfur deprivation, CvHydA1 did not interact in vitro with several plant-type [2Fe-2S]-ferredoxins, but only with a bacterial2[4Fe4S]-ferredoxin. In an electrochemical characterization, the enzyme exhibited features typical of bacterial [FeFe]-hydrogenases (e.g. minor anaerobic oxidative inactivation), as well as of algal enzymes (very high oxygen sensitivity). PMID- 28647464 TI - Data against a Common Assumption: Xenogeneic Mouse Models Can Be Used to Assay Suppression of Immunity by Human MSCs. AB - Much of what we know about immunology suggests that little is to be gained from experiments in which human cells are administered to immunocompetent mice. Multiple reports have demonstrated that this common assumption does not hold for experiments with human mesenchymal stem/stromal cells (hMSCs). The data demonstrate that hMSCs can suppress immune responses to a variety of stimuli in immunocompetent mice by a range of different mechanisms that are similar to those employed by mouse MSCs. Therefore, further experiments with hMSCs in mice will make it possible to generate preclinical data that will improve both the efficacy and safety of the clinical trials with the cells that are now in progress. PMID- 28647465 TI - French Registry on Acute ST-elevation and non-ST-elevation Myocardial Infarction 2015 (FAST-MI 2015). Design and baseline data. AB - BACKGROUND: The FAST-MI programme, consisting of 1-month surveys of patients admitted to hospital for acute myocardial infarction (AMI) in France, has run since 2005. AIM: To gather data on the characteristics, management and outcomes of patients hospitalized for AMI at the end of 2015 in France and to provide comparisons with the previous surveys. METHODS: Consecutive adults with ST segment elevation myocardial infarction (STEMI) or non-ST-segment-elevation myocardial infarction (NSTEMI) with symptom onset<=48hours were included over a 1 month period, with a possible extension of recruitment for 1 additional month. Patients with AMI following cardiovascular procedures were excluded. In all, 204 centres participated in the survey (114 community hospitals, 40 academic, 48 private clinics, 2 army hospitals), representing 78% of French centres managing AMI patients. Inclusion started from 5 October 2015. Data were collected on-site from source files by external research technicians, using an electronic case record form with automatic quality checks. Centralized biology was organized in voluntary centres to collect RNA and DNA samples, serum and stools. Long-term follow-up was organized centrally with interrogation of municipal registry offices, physicians and by direct contact with the patients or their families. RESULTS: A total of 5291 patients were included over the entire recruitment period, with 3813 included during the first month (STEMI: 49%, NSTEMI: 51%). Mean age was 66+/-14 years, 29% were>=75 years of age, 28% were women; 80% presented with typical chest pain. In STEMI patients, 6% received intravenous fibrinolysis and 71% underwent primary PCI. The hospital death rate was 2.7% (STEMI: 2.8%, NSTEMI: 2.5%). CONCLUSIONS: Recruitment was in line with expectations and the first data show that management has continued to evolve since the 2010 survey, with continued improvement in hospital outcomes. PMID- 28647466 TI - Incidence, indications and predicting factors of permanent pacemaker implantation after transcatheter aortic valve implantation: A retrospective study. AB - BACKGROUND: As the number of transcatheter aortic valve implantation (TAVI) procedures is constantly increasing, it is important to consider common complications, such as pacemaker (PM) implantation, and their specific risk factors. AIMS: Echocardiographic, computed tomography and electrocardiographic data were analysed to determine the predicting factors, if any, associated with PM implantation. METHODS: This retrospective study included patients referred to Nancy University Hospital for a TAVI procedure from January 2013 to December 2015. Both Medtronic CoreValve and Edwards SAPIEN valves were implanted. Patients with preprocedurally implanted PMs and/or referred from another institution were excluded. RESULTS: Of 208 TAVI patients, 23 had a pre-existing PM and were excluded. A new PM was required in 38 patients (20.5%). Pre-existing right bundle branch block (RBBB), the use of the Medtronic CoreValve and large prostheses were identified as predictors of PM implantation (P=0.0361, P=0.0004 and P=0.0019, respectively). Using logistic regression, predictors of PM implantation included first-degree atrioventricular block (odds ratio 3.7, 95% confidence interval 1.5 9.1; P=0.0054) and large aortic annulus diameter in echocardiography (odds ratio 1.2, 95% confidence interval 1-1.4; P=0.0447), with a threshold of 24.1mm. For the combination of preTAVI PR duration >220ms and QRS duration >120ms, the positive predictive value for PM implantation reached 80%. CONCLUSION: Use of the Medtronic CoreValve, RBBB and first-degree atrioventricular block are major risk factors for post-TAVI PM implantation. In addition, large aortic annulus and large valvular prosthesis are independent risk factors for PM implantation. The combination of preTAVI prolonged PR interval and increased QRS duration could be used as a marker for periprocedural PM implantation. PMID- 28647467 TI - Reliability and measurement error of the Osteoarthritis Research Society International (OARSI) recommended performance-based tests of physical function in people with hip and knee osteoarthritis. AB - OBJECTIVE: To estimate the reliability and measurement error of performance-based tests of physical function recommended by the Osteoarthritis Research Society International (OARSI) in people with hip and/or knee osteoarthritis (OA). DESIGN: Prospective repeated measures between independent raters within a session and within-rater over a week interval. Relative reliability was estimated for 51 people with hip and/or knee OA (mean age 64.5 years, standard deviation (SD) 6.21 years; 47% females; 36 (70%) primary knee OA) on the 30s Chair Stand Test (30sCST), 40m Fast-Paced Walk Test (40mFPWT), 11-Stair Climb Test (11-step SCT), Timed Up and Go (TUG), Six-Minute Walk Test (6MWT), 10m Fast-Paced Walk Test (10mFPWT) and 20s Stair Climb Test (20sSCT) using intra-class correlation coefficients (ICC). Absolute reliability was calculated using standard error of measurement (SEM) and minimal detectable change (MDC). RESULTS: Measurement error was acceptable (SEM < 10%) for all tests. Between-rater reliability was: optimal (ICC > 0.9, lower 1-sided 95% CI > 0.7) for the 40mFPWT, 6MWT and 10mFPWT; sufficient (ICC >0.8, lower 1-sided 95% CI > 0.7) for 30sCST, 20sSCT; unacceptable (lower 1-side 95% CI < 0.7) for 11-step SCT and TUG. Within-rater reliability was optimal for 40mFPWT, and 6MWT; sufficient for 30sCST and 10mFPWT and unacceptable for 11-step SCT, TUG and 20sSCT. CONCLUSIONS: The 30sCST, 40mFPWT, 6MWT and 10mFPWT, demonstrated, at minimum, acceptable levels of both between and within-rater reliability and measurement error. All tests demonstrated sufficiently small measurement error indicating they are adequate for measuring change over time in individuals with knee/hip OA. PMID- 28647468 TI - Influence of rabbit notochordal cells on symptomatic intervertebral disc degeneration: anti-angiogenic capacity on human endothelial cell proliferation under hypoxia. AB - OBJECTIVES: Symptomatic degenerative disc disease (DDD) is associated with neovascularization and nerve ingrowth into intervertebral discs (IVDs). Notochordal cells (NCs) are key cells that may lead to regeneration of IVDs. However, their activities under conditions of hypoxia, the real environment of IVD, are not well known. We hypothesized that NCs may inhibit neovascularization by interacting with endothelial cells (ECs) under hypoxia. DESIGN: Human IVDs were isolated and cultured to produce nucleus pulposus (NP) cell conditioned medium (NPCM). Immortalized human microvascular ECs were cultured in NPCM with notochordal cell-rich rabbit nucleus pulposus cells (rNC) under hypoxia. Vascular endothelial growth factor (VEGF), vascular cell adhesion molecule (VCAM), and interleukin-8 (IL-8) were analyzed by ELISA. Focal adhesion kinase (FAK), filamentous actin (F-actin), and platelet-derived growth factor (PDGF) were evaluated to investigate EC activity. Wound-healing migration assays were performed to examine EC migration. RESULTS: The VEGF level of EC cells cultured in NPCM was significantly higher under hypoxia compared to normoxia. VEGF expression was significantly decreased, and FAK, F-actin, PDGF expression were inhibited when ECs were cocultured with rNCs under hypoxia. ECs cocultured with rNC in NPCM showed significantly decreased migratory activity compared to those without rNC under hypoxia. CONCLUSIONS: The angiogenic capacity of ECs was significantly inhibited by NCs under hypoxia via a VEGF-related pathway. Our results suggest that NCs may play a key role in the development of IVDs by inhibiting vascular growth within the disc, and this may be a promising novel therapeutic strategy for targeting vascular ingrowth in symptomatic DDD. PMID- 28647469 TI - Intra-articular injection of microRNA-140 (miRNA-140) alleviates osteoarthritis (OA) progression by modulating extracellular matrix (ECM) homeostasis in rats. AB - OBJECTIVE: Disruptions of extracellular matrix (ECM) homeostasis are key events in the pathogenesis of osteoarthritis (OA). MicroRNA-140 (miRNA-140) is expressed specifically in cartilage and regulates ECM-degrading enzymes. Our objective in this study was to determine if intra-articular injection of miRNA-140 can attenuate OA progression in rats. DESIGN: miRNA-140 levels in human normal and OA cartilage derived chondrocytes and synovial fluid were assessed by polymerase chain reaction (PCR). After primary human chondrocytes were transfected with miRNA-140 mimic or inhibitor, PCR and western blotting were performed to quantify Collagen II, MMP-13, and ADAMTS-5 expression. An OA model was induced surgically in rats, and subsequently treated with one single intra-articular injection of miRNA-140 agomir. At 4, 8, and 12 weeks after surgery, OA progression were evaluated macroscopically, histologically, and immunohistochemically in these rats. RESULTS: miRNA-140 levels were significantly reduced in human OA cartilage derived chondrocytes and synovial fluid compared with normal chondrocytes and synovial fluid. Overexpressing miRNA-140 in primary human chondrocytes promoted Collagen II expression and inhibited MMP-13 and ADAMTS-5 expression. miRNA-140 levels in rat cartilage were significantly higher in the miRNA-140 agomir group than in the control group. Moreover, behavioural scores, chondrocyte numbers, cartilage thickness and Collagen II expression levels in cartilage were significantly higher, while pathological scores and MMP-13 and ADAMTS-5 expression levels were significantly lower in the miRNA-140 agomir group than in the control group. CONCLUSION: Intra-articular injection of miRNA-140 can alleviate OA progression by modulating ECM homeostasis in rats, and may have potential as a new therapy for OA. PMID- 28647470 TI - BCL2: A promising cancer therapeutic target. AB - A remarkable characteristic of majority of cancer cells is that, they fail to undergo apoptosis, which in turn confers them a survival advantage over normal cells. Targeted cancer therapy aims at disrupting the functions of proteins that play an important role during cancer progression. Antiapoptotic protein, BCL2, is one such protein that is highly upregulated in many cancers as compared to normal cells, making it an ideal target for cancer therapy. Although, several BCL2 targeting agents have been investigated over the past 30 years, very few have exhibited any clinical significance. This mini-review outlines a road map of existing BCL2 inhibitors and their relevance in treating cancer, and discusses potential strategies for future research with respect to BCL2 specific cancer therapy. PMID- 28647471 TI - Evaluation of the scientific production on HIV in indigenous people, from 1989 to 2016. PMID- 28647472 TI - [Acute fatty liver of pregnancy and mitochondrial fatty acid oxidation. Consequences for the offspring]. AB - Acute fatty liver of pregnancy (AFLP) is a rare liver disease unique to pregnancy that can lead to acute liver failure. The prognosis, initially often fatal for both mother and child, has been improved by prompt delivery. The diagnosis should be highly suspected if the mother presents epigastric pain, nausea and/or vomiting, or polyuria-polydipsia in the third trimester of pregnancy. AFLP has been found associated with a genetic deficiency of fatty acid beta-oxidation, which may cause sudden death in infancy. Consequently, the mother and her newborn should undergo screening for this deficiency. PMID- 28647473 TI - [Rotavirus-Salmonella coinfection due to turtles: Two cases with exotic pets]. AB - Salmonellosis is a leading cause of bacterial gastroenteritis, responsible for invasive infections especially in young children. Reptiles are salmonella reservoirs, and the indirect contact via parents' hands may be responsible for contamination. We report on two cases of Salmonella-rotavirus coinfection secondary to the presence of turtles in the home. PMID- 28647474 TI - Antiviral profiling of the capsid assembly modulator BAY41-4109 on full-length HBV genotype A-H clinical isolates and core site-directed mutants in vitro. AB - The HBV core protein represents an attractive target for new antiviral therapies due to its multiple functions within the viral life-cycle. Here, we report the antiviral activity of the capsid assembly modulator (CAM) BAY41-4109 and two nucleos(t)ide analogues (NAs) on a diverse panel of 54 HBV clinical isolates from genotype (GT) A-H and assessed the impact of core amino acid (aa) substitutions using site-directed mutants (SDMs). The median EC50 values of BAY41-4109 across genotypes ranged from 26 nM in GT G to 215 nM in GT F irrespective of the presence of NA resistance mutations compared to 43 nM for the GT D reference construct. Combined analyses of clinical isolates and SDMs identified aa changes at positions 29, 33 and 118 led to reduced antiviral activity of BAY41-4109 with fold changes in EC50 values of 6, 46, and 9 for D29G, T33N, and Y118F, respectively. These aa substitutions are located within the CAM binding pocket, and are expected to have an effect on CAM binding based on structural modeling. Importantly aa variations at these positions were rarely (<0.3%) observed as naturally occurring in public sequence databases. NA's remained fully active against these variants. Our study demonstrated that BAY41-4109 generally remained fully active across GT A-H clinical isolates. In addition, core aa substitutions within the CAM-binding pocket replicated in vitro and variants at positions 29, 33, and 118 were identified to reduce antiviral activity. PMID- 28647475 TI - Advanced Cell Classifier: User-Friendly Machine-Learning-Based Software for Discovering Phenotypes in High-Content Imaging Data. AB - High-content, imaging-based screens now routinely generate data on a scale that precludes manual verification and interrogation. Software applying machine learning has become an essential tool to automate analysis, but these methods require annotated examples to learn from. Efficiently exploring large datasets to find relevant examples remains a challenging bottleneck. Here, we present Advanced Cell Classifier (ACC), a graphical software package for phenotypic analysis that addresses these difficulties. ACC applies machine-learning and image-analysis methods to high-content data generated by large-scale, cell-based experiments. It features methods to mine microscopic image data, discover new phenotypes, and improve recognition performance. We demonstrate that these features substantially expedite the training process, successfully uncover rare phenotypes, and improve the accuracy of the analysis. ACC is extensively documented, designed to be user-friendly for researchers without machine-learning expertise, and distributed as a free open-source tool at www.cellclassifier.org. PMID- 28647476 TI - Substance P promotes hepatic stellate cell proliferation and activation via the TGF-beta1/Smad-3 signaling pathway. AB - Prolonged activation and proliferation of hepatic stellate cells (HSCs) usually results in the initiation and progression of liver fibrosis following injury. Recent studies have shown that Substance P (SP) participates in the development of fibrosis. However, whether SP is involved in liver fibrosis, especially in the activation and proliferation of HSCs, is largely unknown. In the present study, we measured the effects of a series of concentrations of SP on the cell viability and activation of HSC-T6 cells and LX2 cells. The underlying mechanism was also investigated. We found that SP effectively increased cell viability, both in an MTT assay (p<0.05) and in a lactate dehydrogenase activity assay (LDH) (p<0.05). Moreover, SP upregulated the protein expression of alpha-SMA and Collagen I (both p<0.05) and decreased the release of lipid droplets (LDs) (p<0.05), all of which are associated with HSC activation. Apoptosis analysis revealed that SP can attenuate the increase of cell apoptosis induced by serum withdrawal (p<0.05). Furthermore, these effects were all blocked by an SP receptor antagonist, L732138. More importantly, L732138 decreased the activation of the TGF beta1/Smad3 signaling pathway, which is highly associated with liver fibrosis. Taken together, our results demonstrate that SP can promote HSC proliferation and induce HSC activation via the TGF-beta1/Smad3 signaling pathway. PMID- 28647478 TI - Embolization of ovarian vein for pelvic congestion syndrome with ethylene vinyl alcohol copolymer (Onyx(r)). AB - PURPOSE: To evaluate the safety and efficacy of pelvic embolization using ethylene vinyl alcohol copolymer (Onyx(r)) for pelvic congestion syndrome. MATERIAL AND METHODS: Between March 2012 to September 2016, 17 women (mean age, 44.7+/- 12.2 (SD) years; range: 34-71years) presenting with pelvic congestion syndrome were evaluated for transvenous embolization with Onyx(r). Pelvic congestion syndrome was initially diagnosed by clinical examination and the results of transvaginal Doppler ultrasound and further confirmed by pelvic venography. Primary and secondary clinical efficacy was defined respectively by the resolution of the symptoms after embolization and at the end of the follow up, irrespective to the number of embolization procedures. RESULTS: Technical efficacy of embolization was 100% with no significant complications during and after embolization. After a mean follow-up time of 24.2 months (range: 6 69months) a primary and secondary clinical efficacy of 76.4% (13/17 women) and 94.1% (16/17 women) respectively were observed. Four women (23.5%) underwent a second embolization procedure with one woman requiring a third embolization procedure. These additional embolization procedures were associated with direct puncture of vulvar varices for sclerotherapy in two women. Five women (29%) had recurrent symptoms 21 months post-treatment (7-42months). CONCLUSION: Pelvic embolization using ethylene vinyl alcohol copolymer (Onyx(r)) has a favorable clinical success for pelvic congestion syndrome. PMID- 28647477 TI - Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma. AB - We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondrial uncoupling in vitro due to the increased mitochondrial transmembrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP+C8, TPP+C10 and TPP+C12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP+C10 increased the cytosolic ADP/ATP ratio and significantly increased the AMP levels in a concentration-dependent manner in TA3/Ha murine mammary adenocarcinoma cells. Interestingly, TPP+C10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP+C10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30days of intraperitoneal (i.p.) administration of the combination of TPP+C10 (10mg/kg/48h) and the antibiotic doxycycline (10mg/kg/24h) completely eliminated the subcutaneous tumor burden in mice (n=6), without any relapses at 60days post-treatment. This enhancement of the individual activities of TPP+C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP+C10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-alpha as an adaptive response. Moreover, i.p. administration of TPP+C10 (10mg/kg/24h) to healthy mice did not produce toxicity or damage in organs important for drug metabolism and excretion, as indicated by hematological, biochemical and histological assessments. These findings suggest that the combination of TPP+C10 with doxycycline is a valuable candidate therapy for breast cancer management. PMID- 28647479 TI - Scurvy in a 3-year-old autistic girl: Whole-body magnetic resonance imaging findings. PMID- 28647480 TI - Phytochemical profile and alpha-glucosidase inhibitory activity of Sardinian Hypericum scruglii and Hypericum hircinum. AB - The phytochemical profile, antioxidant activity and alpha-glucosidase inhibitory activity of Hypericum scruglii Bacchetta, Brullo et Salmeri and Hypericum hircinum L. were analyzed and compared to those of the best-known Hypericum perforatum L. Samples were prepared using three different extraction methods (maceration in 70% ethanol, extraction in MeOH/phosphate buffer and decoction), the influence of which on the metabolic profile and bioactivities are discussed. H. scruglii and H. hircinum extracted in 70% ethanol strongly inhibited alpha glucosidase (IC50 7.25 and 14.05MUg/ml, respectively), which is a valuable enzymatic target for treating metabolic disorders, while H. perforatum was found to be less powerful than the other two species in all the performed biological tests. The phytochemical profile was analyzed by NMR, HPLC-DAD and HPLC-FLD, revealing remarkable differences among the species. In particular, H. scruglii, which is a species endemic to Sardinia Island (Italy), was particularly enriched in two phloroglucinol-derivatives identified by means of 2D NMR and LC/MS/MS experiments as 3-geranyl-1-(2'-methylbutanoyl)-phloroglucinol and 3-geranyl-1-(2' methylpropanoyl)-phloroglucinol. PMID- 28647481 TI - New depsides from the roots of Salvia miltiorrhiza and their radical-scavenging capacity and protective effects against H2O2-induced H9c2 cells. AB - Phytochemical investigation of the roots of Salvia miltiorrhiza led to isolations of two new depsides (1-2), along with thirteen known compounds (3-15). Their structures and relative stereochemistry were elucidated by NMR spectral (1H and 13C NMR, HSQC, HMBC), CD and HR-ESIMS data analyses. The absolute configuration of 1 was determined by comparison of the experimental and calculated ECD spectra. All the depsides (1-10) were found to exhibit stronger free radical scavenging capacity (ranging from 2.62 to 22.05MUM) than diterpenoids (11-15, IC50>100MUM), among which Salvianolic acid A and Salvianolic acid B were the most potent compounds. Additionally, most of depsides (1, 3, 5, 7, 8, 9, 10) possessed significant protective effects against H2O2-induced H9c2 apoptosis in low concentrations. The negative mode collision-induced dissociations of compound 1 and 2 were featured by the alpha-cleavage and beta-cleavage to lose danshensu (198Da) and caffeic acid (180Da), respectively, while alpha,beta dihydroxybenzenes depsides (8-hydroxy) showed characteristic neutral elimination of H2O. PMID- 28647482 TI - Isolation and structural characterization of dihydrobenzofuran congeners of licochalcone A. AB - In an effort to explore the residual complexity of naturally occurring chalcones from the roots of Glycyrrhiza inflata (Fabaceae), two new licochalcone A (LicA) derivatives were isolated as trace metabolites from enriched fractions. Both constituents contain a dihydrofuran moiety linked to carbons C-4 and C-5 of the retrochalcone core. Compound 1 (LicAF1) represents a new chemical entity, whereas compound 2 (LicAF2) has previously been reported as a Lewis acid catalyzed rearrangement of LicA. Evaluation of chirality revealed that both dihydrofuran derivatives existed as a mixture of R and S enantiomers. Interestingly, when solutions were exposed to sunlight, both dihydrofuran retrochalcones, initially isolated as trans isomers, were found to rapidly isomerize yielding trans and cis isomers. Analysis of the 1D 1H NMR spectra of the photolysis products revealed the presence of two sets of proton resonances ascribed to each of the geometric isomers. An up-field shift of all proton resonances arising from the cis isomer was observed, suggesting that anisotropic shielding effects were introduced through an overall perturbation of the 3-dimensional structure upon photoisomerization. Similar up-field shifts were observed in the 13C spectrum of the cis isomer, except for the CO, C-alpha, and C-6 carbons, which experienced downfield shifts. Analogous NMR results were observed for LicA. Hence, the results presented herein encompass the isolation and full characterization of LicAF analogs 1 and 2, and observations of their trans-to-cis photoisomerization through the systematic analysis of their NMR spectra. PMID- 28647483 TI - Demands on response inhibition processes determine modulations of theta band activity in superior frontal areas and correlations with pupillometry - Implications for the norepinephrine system during inhibitory control. AB - Response inhibition processes are important for goal-directed behavior and particularly demanded when it is unlikely to inhibit automatically executed responses. It has been suggested that the norepinephrine (NE) system is important to consider for such likelihood effects. As an indirect measure of the NE system activity we used the pupil diameter and integrated this data with neurophysiological (EEG) data and beamforming analyses. The study shows that inhibitory control processes reflected by theta oscillations are strongly modulated by the likelihood to employ these processes and that these mechanisms were related to neural processes in the SMA and SFG. Probably, the modulations observed for theta band activity may reflect modulations in the encoding of a surprise, or conflict signal. Interestingly, correlation analyses of neuronal activity at the sensor and the source level with pupil diameter data revealed strong correlations that were only seen in the condition where inhibitory control processes were rarely demanded. On the basis of findings and theoretical models suggesting that the pupil diameter can be interpreted as a proximate of NE system activity the results may be interpreted that the NE system modulates inhibitory control processes via theta band activity in the SFB when the likelihood to inhibit a prepotent response tendency is low. From this it may be speculated that the NE system dynamically gains and loses relevance to modulate inhibitory control depending on boundary conditions that determine the mode of responding. PMID- 28647484 TI - Neural representation of geometry and surface properties in object and scene perception. AB - Multiple cortical regions are crucial for perceiving the visual world, yet the processes shaping representations in these regions are unclear. To address this issue, we must elucidate how perceptual features shape representations of the environment. Here, we explore how the weighting of different visual features affects neural representations of objects and scenes, focusing on the scene selective parahippocampal place area (PPA), but additionally including the retrosplenial complex (RSC), occipital place area (OPA), lateral occipital (LO) area, fusiform face area (FFA) and occipital face area (OFA). Across three experiments, we examined functional magnetic resonance imaging (fMRI) activity while human observers viewed scenes and objects that varied in geometry (shape/layout) and surface properties (texture/material). Interestingly, we found equal sensitivity in the PPA for these properties within a scene, revealing that spatial-selectivity alone does not drive activation within this cortical region. We also observed sensitivity to object texture in PPA, but not to the same degree as scene texture, and representations in PPA varied when objects were placed within scenes. We conclude that PPA may process surface properties in a domain specific manner, and that the processing of scene texture and geometry is equally weighted in PPA and may be mediated by similar underlying neuronal mechanisms. PMID- 28647485 TI - Dynamic network model with continuous valued nodes for longitudinal brain morphometry. AB - Longitudinal brain morphometry probes time-related brain morphometric patterns. We propose a method called dynamic network modeling with continuous valued nodes to generate a dynamic brain network from continuous valued longitudinal morphometric data. The mathematical framework of this method is based on state space modeling. We use a bootstrap-enhanced least absolute shrinkage operator to solve the network-structure generation problem. In contrast to discrete dynamic Bayesian network modeling, the proposed method enables network generation directly from continuous valued high-dimensional short sequence data, being free from any discretization process. We applied the proposed method to a study of normal brain development. PMID- 28647486 TI - Geographically weighted negative binomial regression applied to zonal level safety performance models. AB - Generalized Linear Models (GLM) with negative binomial distribution for errors, have been widely used to estimate safety at the level of transportation planning. The limited ability of this technique to take spatial effects into account can be overcome through the use of local models from spatial regression techniques, such as Geographically Weighted Poisson Regression (GWPR). Although GWPR is a system that deals with spatial dependency and heterogeneity and has already been used in some road safety studies at the planning level, it fails to account for the possible overdispersion that can be found in the observations on road-traffic crashes. Two approaches were adopted for the Geographically Weighted Negative Binomial Regression (GWNBR) model to allow discrete data to be modeled in a non stationary form and to take note of the overdispersion of the data: the first examines the constant overdispersion for all the traffic zones and the second includes the variable for each spatial unit. This research conducts a comparative analysis between non-spatial global crash prediction models and spatial local GWPR and GWNBR at the level of traffic zones in Fortaleza/Brazil. A geographic database of 126 traffic zones was compiled from the available data on exposure, network characteristics, socioeconomic factors and land use. The models were calibrated by using the frequency of injury crashes as a dependent variable and the results showed that GWPR and GWNBR achieved a better performance than GLM for the average residuals and likelihood as well as reducing the spatial autocorrelation of the residuals, and the GWNBR model was more able to capture the spatial heterogeneity of the crash frequency. PMID- 28647487 TI - Does pregnancy have any impact on long term damage accrual and on the outcome of lupus nephritis? AB - No data are available about the impact of pregnancy on the long-term outcome of lupus nephritis. Thirty-two women with lupus nephritis with a 10-year follow-up after their first pregnancy ("women who gave birth") and 64 matched controls with the same follow-up and who never had pregnancies ("controls") were compared for the occurrence of SLE flares, chronic kidney disease (CKD), and SLICC/ACR Damage Index (SDI) in the post pregnancy period. The same evaluations were done before and after pregnancy in women who gave birth. The predictors of CKD and damage accrual in the whole population were studied. All patients were Caucasians and had biopsy proven LN. At conception and after 10 years, in both groups, less than 10% of patients had active renal disease (p = ns). Controls had more frequent arterial hypertension (p = 0.025). Between the two groups there was no difference in SLE flares and in CKD free survival curves (p = 0.6 and p = 0.37) during the 10-year follow-up. In both groups, the temporal trend, based on annual evaluation, of glomerular filtration rate and serum creatinine shows a significant decrease and increase respectively. However, the women who gave birth persistently maintained better values of renal function than controls during the whole follow-up (P = 0.00001). There was no difference in the CKD-free survival curves. SDI did not increase significantly in women who gave birth in comparison to controls. All the above mentioned clinical parameters were comparable before and after pregnancy in the women who gave birth. Among the basal clinical characteristics, high serum creatinine and occurrence of SLE flares predicted CKD, whereas low levels of C3, pre-existing damage score, and occurrence of SLE flares predicted SDI increase. Pregnancy was not a predictor of CKD or SDI increase. Carrying a pregnancy during inactive lupus nephritis does not seem to increase the rate of SLE flares, worsen renal prognosis or increase SDI significantly in the very long-term. PMID- 28647488 TI - Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis. AB - Oxidation-associated malondialdehyde (MDA) modification of proteins can generate immunogenic neo-epitopes that are recognized by autoantibodies. In health, IgM antibodies to MDA-adducts are part of the natural antibody pool, while elevated levels of IgG anti-MDA antibodies are associated with inflammatory and autoimmune conditions. Yet, in human autoimmune disease IgG anti-MDA responses have not been well characterized and their potential contribution to disease pathogenesis is not known. Here, we investigate MDA-modifications and anti-MDA-modified protein autoreactivity in rheumatoid arthritis (RA). While RA is primarily associated with autoreactivity to citrullinated antigens, we also observed increases in serum IgG anti-MDA in RA patients compared to controls. IgG anti-MDA levels significantly correlated with disease activity by DAS28-ESR and serum TNF-alpha, IL-6, and CRP. Mass spectrometry analysis of RA synovial tissue identified MDA modified proteins and revealed shared peptides between MDA-modified and citrullinated actin and vimentin. Furthermore, anti-MDA autoreactivity among synovial B cells was discovered when investigating recombinant monoclonal antibodies (mAbs) cloned from single B cells, and 3.5% of memory B cells and 2.3% of plasma cells were found to be anti-MDA positive. Several clones were highly specific for MDA-modification with no cross-reactivity to other antigen modifications such as citrullination, carbamylation or 4-HNE-carbonylation. The mAbs recognized MDA-adducts in a variety of proteins including albumin, histone 2B, fibrinogen and vimentin. Interestingly, the most reactive clone, originated from an IgG1-bearing memory B cell, was encoded by near germline variable genes, and showed similarity to previously reported natural IgM. Other anti-MDA clones display somatic hypermutations and lower reactivity. Importantly, these anti-MDA antibodies had significant in vitro functional properties and induced enhanced osteoclastogenesis, while the natural antibody related high-reactivity clone did not. We postulate that these may represent distinctly different facets of anti MDA autoreactive responses. PMID- 28647490 TI - Sex-biased eicosanoid biology: Impact for sex differences in inflammation and consequences for pharmacotherapy. AB - The incidence, severity and progression of autoimmune diseases (e.g. scleroderma, multiple sclerosis, rheumatoid arthritis) and certain inflammatory diseases (e.g. asthma) are sex-biased where these pathologies dominate in women. However, other immune disorders such as sepsis, post-surgery infections and gout display higher incidence and severity in men. The molecular and cellular basis underlying this sex dimorphism remains incompletely elucidated but may provide important insights for sex-specific pharmacotherapy. Nevertheless, the sex as a variable in biochemical and preclinical research on inflammation is often neglected. Thus, respective animal studies are routinely performed with males, and experiments with isolated cells rarely report the sex of the donor. However, sex differences on the cellular level do exist, in particular related to inflammatory processes that prompt for sex-specific appreciation of inflammation research. For instance, the biosynthesis of pro-inflammatory eicosanoids is sex-biased where leukotriene (LT) formation is under control of testosterone that regulates the subcellular localization of the key enzyme 5-lipoxygenase, with possible implications for gender-tailored pharmacotherapy of LT-related disorders (i.e. asthma). Moreover, prostaglandin (PG) production is sex-biased, and sex-dependent efficacy of aspirin was evident in several clinical trials. Here, we highlight the sex bias in eicosanoid biology possibly underlying the obvious sex disparities in inflammation, stimulating scientists to take sex into account when studying the pathophysiology and pharmacotherapy of inflammatory diseases. PMID- 28647489 TI - A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases. AB - Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities. Here, we describe an assay suitable for high throughput screening to discover substrate selective ERK1/2 inhibitors, which may have a larger therapeutic window than conventional inhibitors. Specifically, we aim to target a substrate-binding pocket within the ERK1/2 catalytic domain outside of the catalytic cleft. The assay uses an AlphaScreen format to detect phosphorylation of a high-efficiency substrate harboring an essential docking site motif. Pilot screening established that the assay is suitably robust for high-throughput screening. Importantly, the assay can be conducted at high ATP concentrations, which we show reduces the discovery of conventional ATP-competitive inhibitors. These studies provide the basis for high-throughput screens to discover new classes of non-conventional ERK1/2 inhibitors. PMID- 28647491 TI - Emerging pharmacological approaches to promote neurogenesis from endogenous glial cells. AB - Neurodegenerative disorders are emerging as leading contributors to the global disease burden. While some drug-based approaches have been designed to limit or prevent neuronal loss following acute damage or chronic neurodegeneration, regeneration of functional neurons in the adult Central Nervous System (CNS) still remains an unmet need. In this context, the exploitation of endogenous cell sources has recently gained an unprecedented attention, thanks to the demonstration that, in some CNS regions or under specific circumstances, glial cells can activate spontaneous neurogenesis or can be instructed to produce neurons in the adult mammalian CNS parenchyma. This field of research has greatly advanced in the last years and identified interesting molecular and cellular mechanisms guiding the neurogenic activation/conversion of glia. In this review, we summarize the evolution of the research devoted to understand how resident glia can be directed to produce neurons. We paid particular attention to pharmacologically-relevant approaches exploiting the modulation of niche associated factors and the application of selected small molecules. PMID- 28647492 TI - Eszopiclone for persistent negative symptoms in schizophrenia - An unintended N of-1 study. AB - Persistent negative and cognitive symptoms in patients with schizophrenia pose a significant challenge to clinicians. Being a heterogeneous cluster of symptoms with potentially distinct underlying pathogenesis, it is important to examine novel therapies based on emerging neurobiological evidence. Eszopiclone is known to enhance the deficient sleep spindles that are related to impairments in learning and memory in schizophrenia. In this report we highlight the potential utility of eszopiclone in treating persistent negative symptoms in a patient with chronic schizophrenia. The unintended N-of-1 design that spanned out over a period of 24weeks demonstrated improvements in negative symptoms while the patient was on eszopiclone and worsening of these symptoms while unintentionally being off eszopiclone treatment. These observations suggest a reasonable degree of specificity of our patient's response to eszopiclone, thus warranting future sleep-EEG guided systematic studies. PMID- 28647493 TI - Associations between the DBH gene, plasma dopamine beta-hydroxylase activity and cognitive measures in Han Chinese patients with schizophrenia. AB - The dopamine (DA) and norepinephrine (NE) systems modulate cognitive function. Dopamine beta-hydroxylase (DbetaH) converts DA to NE, and its activity is under strong genetic control. This study examines the association of plasma DbetaH (pDbetaH) activity, DBH gene polymorphisms (-1021C>T, rs1611115 and 444G>A, rs1108580) and cognitive deficits in Han Chinese patients with schizophrenia. We assessed pDbetaH activity and cognitive function using the Verbal Fluency Test (VFT), Trail Making Test (TMT) A-B, Stroop color-word test and Wisconsin Card Sorting Test (WCST) in 200 patients with schizophrenia before and after 8weeks of antipsychotic treatment (96 patients completed assessments at baseline and post treatment). We found that rs1611115 was significantly associated with pDbetaH activity, and there was strong LD between rs1611115 and rs1108580 polymorphisms. Correlation analysis indicated that pDbetaH activity correlated nominally with improvement in VFT score after 8weeks antipsychotic treatment. Moreover, there was a significant genotype effect of the rs1108580 on VFT: the VFT score of patients with AA genotype was higher than that of patients with AG/GG genotype either at baseline or the end of 8 weeks after treatment. However, this difference was not observed for rs1611115. Our findings confirm a strong association between genotype at rs1611115 and pDbetaH activity in Chinese patients with schizophrenia. Our data also suggest the rs1108580 polymorphism may influence some aspects of cognitive function in schizophrenia. PMID- 28647494 TI - Association between familiarity disorders and serious violence among inmates with schizophrenia. PMID- 28647495 TI - Ecological monitoring in a discrete-time prey-predator model. AB - The paper is aimed at the methodological development of ecological monitoring in discrete-time dynamic models. In earlier papers, in the framework of continuous time models, we have shown how a systems-theoretical methodology can be applied to the monitoring of the state process of a system of interacting populations, also estimating certain abiotic environmental changes such as pollution, climatic or seasonal changes. In practice, however, there may be good reasons to use discrete-time models. (For instance, there may be discrete cycles in the development of the populations, or observations can be made only at discrete time steps.) Therefore the present paper is devoted to the development of the monitoring methodology in the framework of discrete-time models of population ecology. By monitoring we mean that, observing only certain component(s) of the system, we reconstruct the whole state process. This may be necessary, e.g., when in a complex ecosystem the observation of the densities of certain species is impossible, or too expensive. For the first presentation of the offered methodology, we have chosen a discrete-time version of the classical Lotka Volterra prey-predator model. This is a minimal but not trivial system where the methodology can still be presented. We also show how this methodology can be applied to estimate the effect of an abiotic environmental change, using a component of the population system as an environmental indicator. Although this approach is illustrated in a simplest possible case, it can be easily extended to larger ecosystems with several interacting populations and different types of abiotic environmental effects. PMID- 28647496 TI - A comprehensive complex systems approach to the study and analysis of mammalian cell cycle control system in the presence of DNA damage stress. AB - Not many models of mammalian cell cycle system exist due to its complexity. Some models are too complex and hard to understand, while some others are too simple and not comprehensive enough. Moreover, some essential aspects, such as the response of G1-S and G2-M checkpoints to DNA damage as well as the growth factor signalling, have not been investigated from a systems point of view in current mammalian cell cycle models. To address these issues, we bring a holistic perspective to cell cycle by mathematically modelling it as a complex system consisting of important sub-systems that interact with each other. This retains the functionality of the system and provides a clearer interpretation to the processes within it while reducing the complexity in comprehending these processes. To achieve this, we first update a published ODE mathematical model of cell cycle with current knowledge. Then the part of the mathematical model relevant to each sub-system is shown separately in conjunction with a diagram of the sub-system as part of this representation. The model sub-systems are Growth Factor, DNA damage, G1-S, and G2-M checkpoint signalling. To further simplify the model and better explore the function of sub-systems, they are further divided into modules. Here we also add important new modules of: chk-related rapid cell cycle arrest, p53 modules expanded to seamlessly integrate with the rapid arrest module, Tyrosine phosphatase modules that activate Cyc_Cdk complexes and play a crucial role in rapid and delay arrest at both G1-S and G2-M, Tyrosine Kinase module that is important for inactivating nuclear transport of CycB_cdk1 through Wee1 to resist M phase entry, Plk1-Related module that is crucial in activating Tyrosine phosphatases and inactivating Tyrosine kinase, and APC-Related module to show steps in CycB degradation. This multi-level systems approach incorporating all known aspects of cell cycle allowed us to (i) study, through dynamic simulation of an ODE model, comprehensive details of cell cycle dynamics under normal and DNA damage conditions revealing the role and value of the added new modules and elements, (ii) assess, through a global sensitivity analysis, the most influential sub-systems, modules and parameters on system response, such as G1-S and G2-M transitions, and (iii) probe deeply into the relationship between DNA damage and cell cycle progression and test the biological evidence that G1-S is relatively inefficient in arresting damaged cells compared to G2-M checkpoint. To perform sensitivity analysis, Self-Organizing Map with Correlation Coefficient Analysis (SOMCCA) is developed which shows that Growth Factor and G1-S Checkpoint sub-systems and 13 parameters in the modules within them are crucial for G1-S and G2-M transitions. To study the relative efficiency of DNA damage checkpoints, a Checkpoint Efficiency Evaluator (CEE) is developed based on perturbation studies and statistical Type II error. Accordingly, cell cycle is about 96% efficient in arresting damaged cells with G2-M checkpoint being more efficient than G1-S. Further, both checkpoint systems are near perfect (98.6%) in passing healthy cells. Thus this study has shown the efficacy of the proposed systems approach to gain a better understanding of different aspects of mammalian cell cycle system separately and as an integrated system that will also be useful in investigating targeted therapy in future cancer treatments. PMID- 28647497 TI - Prediction of metastasis in advanced colorectal carcinomas using CGH data. AB - Logistic Regression Model (LRM) and artificial neural networks (ANNs) as two nonlinear models have been used to establish a novel two-stage hybrid modeling procedure for prediction of metastasis in advanced colorectal carcinomas. Two different datasets were used in training and testing procedures. For the first stage of hybrid modeling procedure, LRM was used to evaluate the contribution of DNA sequence copy number aberrations detected by Comparative Genomic Hybridization in advanced colorectal carcinoma and its metastasis. Then, the most effective parameters were selected by the LRM. Selected effective parameters among 565 detected chromosomal gains and losses were as follows: gain of 20q11.2, loss of 1q42, loss of 13q34, gain of 5q12, gain of 17p13, loss of 2q22, loss of 11q24 and gain of 2p11.2. Consequently, neural network models were constructed and fed by the parameters selected by LRM to build hybrid predictors on the two databases during self-consistency and jackknife tests, and performance of the hybrid model was verified. The results showed that our two-stage hybrid model approach is very promising for prediction of metastasis in advanced colorectal carcinomas. PMID- 28647498 TI - The role of the peptides at the origin of life. AB - The peptides in biosystems are polymers of L-amino acids, but they racemize slowly by an active isomerization kinetics. The chemical reactions in biosystems are, however, reversible and here we show by a thermodynamics analysis and by comprehensive Molecular Dynamics simulations of models of peptides, that the isomerization kinetics racemizes the peptides at high water activity, in agreement with experimental observations of aging of peptides, but enhances homochirality at a smaller water activity. The main conclusion of the simulations is that it is only possible to obtain and maintain homochirality in the presence of a hydrophobic compact core in a peptide of hundreds of chiral units and at a low water activity, and thus the establishment of homochirality at the origin of life and aging of proteins in biosystems might be strongly connected. PMID- 28647499 TI - Complete sequence and characterization of the mitochondrial genome of Diphyllobothrium stemmacephalum, the type species of genus Diphyllobothrium (Cestoda: Diphyllobothriidae), using next generation sequencing. AB - We first constructed and characterized the complete mitochondrial genome (mitogenome) sequence of Diphyllobothrium stemmacephalum, the type species of genus Diphyllobothrium, using next generation sequencing (NGS). The mitogenome of D. stemmacephalum was 13,716bp, including 12 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 2 longer intergenic non-coding regions, and has features common to mitogenomes of other cestodes. Although it has been accepted that tRNA for serine (trnS2(UCN)) in Platyhelminthes lacks a D arm, the trnS2(UCN) of D. stemmacephalum was predicted to have a paired D arm as in Diplogonoporus balaenopterae. The non-coding region 2 contained eight tandem repeat units (34nucleotides/unit). This study also corroborated that D. stemmacephalum is phylogenetically more closely related to Dip. balaenopterae than to Diphyllobothrium latum and Diphyllobothrium nihonkaiense. As demonstrated here, mitogenome sequence data obtained using NGS is useful for gaining a better understanding of the systematics, phylogeny and taxonomic revisions involving valuable specimens preserved in museums, universities or research institutes for which sequence data are not yet available, and also for making diagnoses based on clinical samples. PMID- 28647500 TI - Acceptability of the community-level provision of Sayana(r) Press by medical and nursing students in Kinshasa, Democratic Republic of the Congo. AB - OBJECTIVES: The objectives were to assess acceptors' attitudes toward Sayana(r) Press as a method and toward the mechanism of community-based distribution by medical and nursing (M/N) students, known locally as "DBCs," in Kinshasa, Democratic Republic of the Congo, and to evaluate the experience of these DBCs. STUDY DESIGN: In 2015, surveys were conducted among (1) acceptors of Sayana(r) Press on the day of the initial injection, (2) these same acceptors 3 months later and (3) the DBCs providing community-based services. The analysis was descriptive and involved no significance testing. RESULTS: Acceptors of Sayana(r) Press expressed high levels of satisfaction with the method, despite some pain experienced at injection and subsequent side effects. Although most were satisfied with the counseling and services received from the DBCs, less than one third realized that the providers were M/N students. The DBCs expressed satisfaction in serving as community-based distributors; more than 95% would recommend it to others. Their primary complaints were lack of remuneration, stockouts and need for greater supervision. CONCLUSIONS: Consistent with results from previous pilot introductions of Sayana(r) Press in three African countries, clients were highly satisfied with Sayana(r) Press as a method. The reported preference for resupply at health centers may reflect a lack of client awareness that the DBCs administering methods near the health center were not in fact staff from the health center. The pilot served to gain acceptance for the use of M/N students in community-based distribution, paving the way for additional task shifting pilots in Kinshasa. IMPLICATIONS: Sayana(r) Press represents a promising new method for increasing access to modern contraception in low-income countries. The Kinshasa experience is the first to test the use of medical and nursing students as providers at the community level. The study reports high levels of satisfaction on three counts: acceptors of the contraceptive method, acceptors of the mode of service delivery, and DBCs in their role as providers of contraception at the community level. However, many clients were not aware that the DBCs were students. The study represents an important contribution to the literature on task-shifting, especially in a country with chronic shortages of healthcare personnel. PMID- 28647501 TI - Driving simulators in the clinical assessment of fitness to drive in sleepy individuals: A systematic review. AB - Road traffic injuries are projected to be the leading cause of death for those aged between 15 and 29 years by the year 2030, and sleepiness is estimated to be the underlying cause in up to 15-20% of all motor vehicle accidents. Sleepiness at the wheel is most often caused by socially induced sleep deprivation or poor sleep hygiene in otherwise healthy individuals, medical disorders, or the intake of drugs. Validated methods for objectifying sleepiness are urgently sought, particularly in the context of driving. Based on the assumption that the identification and treatment of sleepiness, and its causes, may prevent motor vehicle accidents, driving simulators are a seemingly promising diagnostic tool. Despite the rising use of these in research, the reliability of their conclusions in healthy sleepy individuals and patients is still unclear. This systematic review aims to evaluate the practical value of driving simulators in a clinical environment when judging fitness to drive in sleepy individuals. From the 1674 records screened, 12 studies in sleepy individuals containing both simulated and real driving data were included. In general, simulated driving did not reliably predict real-life motor vehicle accidents, and especially not on an individual level, despite the moderate relationship between simulated and real-road test driving performance. The severity of sleepiness is most likely not the critical factor leading to motor vehicle accidents, but rather the perception of sleepiness. The self-perception of sleepiness related impairment, and risky behaviour while at the wheel should also be considered as key influencing factors. PMID- 28647502 TI - Alternative complement pathway hemolytic assays reveal incomplete complement blockade in patients treated with eculizumab. AB - Eculizumab is a monoclonal anti-C5 antibody used in the treatment of atypical hemolytic uremic syndrome (aHUS). We monitored complement inhibition in 16 eculizumab-treated patients suffering from HUS or transplant rejection (not aHUS patients). Blood samples were obtained one to four weeks after the last eculizumab injection. We observed that eculizumab efficiently blocked the terminal pathway (TP) through classical pathway (CP) activation measured by kinetic hemolytic assay (HA) (<10%) but incompletely blocked the TP through alternative pathway (AP) activation measured by rabbit (APH50>23%) or chicken erythrocytes HA (AP100>15%). Conversely, functional ELISA revealed a complete blockade of TP through AP activation in all patients (<10%). C5a and sC5b9 levels were not correlated with residual APH50 or AP100. Similar results were obtained after in vitro addition of increasing amounts of eculizumab to a control serum (in vitro APH50>60% and AP100>20%). We also showed that ELISA was less sensitive than HA. PMID- 28647503 TI - Exogenous glucagon-like peptide-1 reduces body weight and cholecystokinin-8 enhances this reduction in diet-induced obese male rats. AB - The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP 1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24 h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action. PMID- 28647504 TI - Antimicrobial investigation of selected soil actinomycetes isolated from unexplored regions of Kashmir Himalayas, India. AB - The aim of the present study was to isolate and evaluate the antimicrobial potential of soil actinomycetes of Kashmir Himalayas. The secondary metabolites of actinomycetes are the prominent source of antibiotics. A total of 121 morphologically different actinomycete strains were isolated and screened for antimicrobial activity against various human pathogens. The ethyl acetate extract of fermented broth an actinomycete strain, identified as Streptomyces pratensis exhibited significant antimicrobial activity against Staphylococcus aureus ATCC 29213 with MIC 0.25 MUg/ml and Mycobacterium tuberculosis Strain H37Rv with MIC 0.062 MUg/ml. The strain S. pratensis IIIM06 was grown on large scale and their broth was extracted with ethyl acetate. The extract was subjected to various chromatography techniques which led to the isolation of four compounds whose structures were established as actinomycin C1, actinomycin C2, actinomycin C3 and actiphenol on the basis of spectral data analysis. Actinomycin C1, C2 and C3 exhibited potent antimicrobial activity against S. aureus as well as M. tuberculosis. The isolated indigenous actinomycetes exhibited good antibacterial activity and the study reveals that IIIM06 is a promising strain and could be of great potential for industrial applications. PMID- 28647505 TI - Identification of MAPKs as signal transduction components required for the cell death response during compatible infection by the synergistic pair Potato virus X Potato virus Y. AB - Systemic necrosis is one of the most severe symptoms caused in compatible plant virus interactions and shares common features with the hypersensitive response (HR). Mitogen-activated protein kinase (MAPK) cascades are associated with responses to compatible and incompatible host-virus interactions. Here, we show that virus-induced gene silencing of the Nicotiana benthamiana MAPK genes salicylic acid-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK), and the MAPK kinase (MAPKK) genes MEK1 and MKK1, partially compromised the HR-like response induced by the synergistic interaction of Potato virus X with Potato virus Y (PVX-PVY). Nevertheless, ameliorated cell death induced by PVX-PVY in the MAPK(K)-silenced plants did not facilitate virus accumulation in systemically infected leaves. Dual silencing of SIPK and of the oxylipin biosynthetic gene 9-Lipoxygenase showed that the latter was epistatic to SIPK in response to PVX-PVY infection. These findings demonstrate that SIPK, WIPK, MEK1 and MKK1 function as positive regulators of PVX-PVY-induced cell death. PMID- 28647506 TI - The S2 glycoprotein subunit of porcine epidemic diarrhea virus contains immunodominant neutralizing epitopes. AB - The porcine epidemic diarrhea virus (PEDV) spike (S) protein is the major target of neutralizing antibodies against PEDV. Here immunodominant neutralizing epitopes of PEDV were identified using a panel of S-specific monoclonal antibodies (mAbs). Ten of eleven S-specific mAbs successfully neutralized PEDV infectivity in vitro. Notably, epitope mapping by peptide ELISAs revealed that nine of these mAbs recognized linear neutralizing epitopes located in the N terminus of the S2 glycoprotein subunit (amino acids [aa] 744-759, 747-774 and/or 756-771). Additionally, one mAb recognized a neutralizing epitope located in the C-terminus of S2 (aa 1371-1377), while only one neutralizing mAb reacted against a region of the S1 glycoprotein subunit (aa 499-600). Notably, mAbs that recognized epitopes within the S2 subunit presented the highest neutralizing activity against PEDV. Together these results indicate that the S2 glycoprotein subunit contains major antigenic determinants and, perhaps, the immunodominant neutralizing epitopes of PEDV. PMID- 28647507 TI - Differential replication of Foot-and-mouth disease viruses in mice determine lethality. AB - Adult C57BL/6J mice have been used to study Foot-and-mouth disease virus (FMDV) biology. In this work, two variants of an FMDV A/Arg/01 strain exhibiting differential pathogenicity in adult mice were identified and characterized: a non lethal virus (A01NL) caused mild signs of disease, whereas a lethal virus (A01L) caused death within 24-48h independently of the dose used. Both viruses caused a systemic infection with pathological changes in the exocrine pancreas. Virus A01L reached higher viral loads in plasma and organs of inoculated mice as well as increased replication in an ovine kidney cell line. Complete consensus sequences revealed 6 non-synonymous changes between A01L and A10NL genomes that might be linked to replication differences, as suggested by in silico prediction studies. Our results highlight the biological significance of discrete genomic variations and reinforce the usefulness of this animal model to study viral determinants of lethality. PMID- 28647508 TI - Fingerprint-efficacy study of the quaternary alkaloids in Corydalis yanhusuo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis yanhusuo is a well-known Chinese herbal medicine that is commonly applied as an analgesic agent in clinic using for thousands of years. Resent research showed that the quaternary ammonium alkaloids from Corydalis yanhusuo have a significant effect on myocardial ischemia. However, the corresponding anti-myocardial ischemia components that represent the efficacy of the quaternary ammonium alkaloids have not been elucidated. AIM OF THE STUDY: Explore the anti-myocardial ischemia components of Corydalis yanhusuo and develop a method of quality control for Corydalis yanhusuo. Chemical fingerprints of quaternary ammonium alkaloids extracted from Corydalis yanhusuo samples from 37 different sources were identified using UPLC-Q-TOF MS. The protective effects of the 37 samples with respect to H9C2 cell hypoxia reoxygenation were detected by MTT assays. The fingerprint-efficacy relationship between the chemical fingerprints and cardioprotection afforded by Corydalis yanhusuo was investigated using three chemometric methods. RESULTS: Because of their inherent differences in chemical compositions, the protective effects to H9C2 cell hypoxia-reoxygenation were different. The results of three chemometric methods showed that the source of the Corydalis yanhusuo has an important influence on both the chemical fingerprint and efficacy. In particular, dehydrocorybulbine, 13-methyldehydrocorydalmine, dehydrocorydaline, columbamine, and palmatine appear to be the main effective components for quality control of this TCM. CONCLUSION: This work provides a general model of combination of UPLC and cardioprotection efficiency to study the fingerprint-efficacy relationship of Corydalis yanhusuo which can offer some references for detecting principal components of Corydalis yanhusuo on cardioprotection efficiency. Fingerprint efficacy studies also provide a powerful method of quality control in Corydalis yanhusuo and other TCMs. PMID- 28647509 TI - A review of Acalypha indica L. (Euphorbiaceae) as traditional medicinal plant and its therapeutic potential. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha indica is an herbal plant that grows in wet, temperate and tropical region, primarily along the earth's equator line. This plant is considered by most people as a weed and can easily be found in these regions. Although this plant is a weed, Acalypha indica has been acknowledged by local people as a useful source of medicine for several therapeutic treatments. They consume parts of the plant for many therapeutics purposes such as anthelmintic, anti-ulcer, bronchitis, asthma, wound healing, anti-bacterial and other applications. As this review was being conducted, most of the reports related to ethnomedicinal practices were from Asian and African regions. THE AIM OF THE REVIEW: The aim of this review is to summarize the current studies on ethnomedicinal practices, phytochemistry, pharmacological studies and a potential study of Acalypha indica in different locations around the world. This review updates related information regarding the potential therapeutic treatments and also discusses the toxicity issue of Acalypha indica. MATERIALS AND METHODS: This review was performed through a systematic search related to Acalypha indica including the ethnomedicinal practices, phytochemistry and pharmacological studies around the world. The data was collected from online journals, magazines, and books, all of which were published in English, Malay and Indonesian. Search engine websites such as Google, Google Scholar, PubMed, Science Direct, Researchgate and other online collections were utilized in this review to obtain information. RESULTS: The links between ethnomedicinal practices and scientific studies have been discussed with a fair justification. Several pharmacological properties exhibited certain potentials based on the obtained results that came from different related studies. Based on literature studies, Acalypha indica has the capability to serve as anthelmintic, anti-inflammation, anti-bacterial, anti-cancer, anti-diabetes, anti-hyperlipidemic, anti-obesity, anti-venom, hepatoprotective, hypoxia, and wound healing medicine. For the traditional practices, the authors also mentioned several benefits of consuming the raw plant and decoction. CONCLUSION: This review summarizes the current studies of Acalypha indica collected from many regions. This review hopefully will provide a useful and basic knowledge platform for anyone interested in gaining information regarding Acalypha indica. PMID- 28647511 TI - The futile cycle of hospital readmission in patients with diabetes. PMID- 28647510 TI - Hepatoprotective effect of Gan Kang Yuan against chronic liver injury induced by alcohol. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gan Kang Yuan (GKY) is a compound medicine formulated on the basis of traditional Chinese medicine (TCM). It was composed of Herba Cistanchis (Roucongrong), Radix Puerariae (Gegen), Radix Astragali (Huangqi), Fructus Schisandrae (Wuweizi) and Radix Glycyrrhizae (Gancao). AIM: The purpose of this study is to research the hepatoprotective effect of GKY against liver injury induced by alcohol, and to elucidate the mechanism of hepatopretective effect. MATERIALS AND METHODS: Hepatoprotective activity of GKY was researched both in vivo and vitro. In vitro, effect of GKY on the survival rates of HepG2 cells were assessed. In vivo research, ICR mice were oral administrated with alcohol (Er Guo-tou white spirit, 56%, 6mL/kg, once per day) for 31 days to establish liver injury model. Meanwhile, positive group or experimental groups were treated with bicyclol (300mg/kg) or GKY (200, 600, 1800mg/kg). Serological indexes including aspartate and alanine transaminases (AST, ALT), gamma-glutamyl transpeptidase (gamma-GTP), total bilirubin (TBil), total cholesterol (TCHO) and serum triglyceride (STG) were estimated. Hepatic indicators including superoxide dismutase (SOD), glutathione S-transferase (GST), glutathione (GSH), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and liver triglyceride (LTG) were analyzed. Histopathologic changes of liver tissue were observed. RESULTS: The survival rates of HepG2 cell were observably promoted by GKY. Alcoholic treatment drastically altered the serum indexes and liver indicators of model animals, while these alteration were significantly ameliorated by GKY (p < 0.05, 0.01 or 0.001) in experimental group. The microvesicular steatosis and necrosis in hepatic histopathology induced by alcoholic treatment also were notably attenuated by GKY administration. CONCLUSIONS: These findings indicated that GKY possessed hepatoprotective property against liver injury induced by ethanol. GKY significantly promoted activities of relative enzymes and suppressed the contents of MDA and LTG, which might be the mechanism of hepatoprotective effect of GKY. PMID- 28647512 TI - Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor alpha concentrations: A systematic review and meta-analysis of controlled trials. AB - OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor alpha (TNF-alpha) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-alpha levels in T2DM patients. METHODS: A systematic review and a meta-analysis were undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-alpha. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. RESULTS: Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-alpha concentrations following treatment with DPP-4 inhibitors (SMD: -1.84, 95% CI: -2.88, -0.80, p=0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-alpha-lowering activity of sitagliptin (SMD: -1.49, 95% CI: -2.89, -0.10) and vildagliptin (SMD: -2.80, 95% CI: -4.98, -0.61) (p=0.326). CONCLUSION: This meta analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-alpha levels with no apparent difference between sitagliptin and vildagliptin. PMID- 28647513 TI - Respiratory syncytial virus bronchiolitis, weather conditions and air pollution in an Italian urban area: An observational study. AB - BACKGROUND: In this study we sought to evaluate the association between viral bronchiolitis, weather conditions, and air pollution in an urban area in Italy. METHODS: We included infants hospitalized for acute bronchiolitis from 2004 to 2014. All infants underwent a nasal washing for virus detection. A regional agency network collected meteorological data (mean temperature, relative humidity and wind velocity) and the following air pollutants: sulfur dioxide, nitrogen oxide, carbon monoxide, ozone, benzene and suspended particulate matter measuring less than 10um (PM10) and less than 2.5um (PM2.5) in aerodynamic diameter. We obtained mean weekly concentration data for the day of admission, from the urban background monitoring sites nearest to each child's home address. Overdispersed Poisson regression model was fitted and adjusted for seasonality of the respiratory syncytial virus (RSV) infection, to evaluate the impact of individual characteristics and environmental factors on the probability of a being positive RSV. RESULTS: Of the 723 nasal washings from the infants enrolled, 266 (68%) contained RSV, 63 (16.1%) rhinovirus, 26 (6.6%) human bocavirus, 20 (5.1%) human metapneumovirus, and 16 (2.2%) other viruses. The number of RSV-positive infants correlated negatively with temperature (p < 0.001), and positively with relative humidity (p < 0.001). Air pollutant concentrations differed significantly during the peak RSV months and the other months. Benzene concentration was independently associated with RSV incidence (p = 0.0124). CONCLUSIONS: Seasonal weather conditions and concentration of air pollutants seem to influence RSV-related bronchiolitis epidemics in an Italian urban area. PMID- 28647514 TI - Aqueous cigarette tar extracts disrupt corticogenesis from human embryonic stem cells in vitro. AB - BACKGROUND: Cigarette butts are the most common form of litter in the world, and approximately 4.5 trillion smoked cigarettes are discarded every year worldwide. Cigarette butts contain over 4000 chemicals, many of which are known to have neurotoxic effects. Stem cell neuronal differentiation provides an excellent cellular model with which to examine the impact of aqueous cigarette tar extracts (ACTEs) on neurodevelopment. METHODS: We have developed a neurosphere-based stem cell neuronal differentiation protocol that can recapitulate corticogenesis and produce cell types that are similar to upper and lower layer cortical projection neurons found in the germinal zone of the developing human cortex. In this study, ACTEs were generated from smoked cigarette butts and then applied at different concentrations to neuronal progenitors and cortical neurons derived from human embryonic stem cells. RESULTS: ACTEs reduced the expression of the cortical neuronal progenitor markers pax6, tbr2, and neuroD and decreased the number of cortical layer neurons (tbr1, satb2, foxp2, and brn2) after exposure to as low as 1.87% of the extract from one smoked cigarette butt. Furthermore, our results showed that ACTEs increased reactive oxygen species (ROS) production in cortical neurons, which caused a substantial loss of the synaptic proteins PSD95, synaptophysin, vesicular glutamate transporter1 (vGlut1), and the extracellular matrix molecule reelin; all of those molecules are important for the maintenance of cortical neuron identity and activity. CONCLUSION: ACTEs from smoked cigarettes have significant effects on cortical neuron development and neurodegeneration. The stem cell neuronal differentiation model holds great promise as a potentially powerful tool for the assessment of ACTEs on neurotoxicity. PMID- 28647515 TI - A phytoestrogen supplement prevents the altered gene expression associated with pregnancy implantation induced by IL-1beta in endometrial epithelial cells. AB - Phytoestrogens stimulate expression of the uterine estrogen receptor and regulate uterine functions in reproductive tissues. However, comprehensive understanding of the beneficial impacts of phytoestrogens on uterine biology at the molecular level remains unexplored. Interleukin-1beta (IL-1beta) expression is increased in the inflamed decidua and is associated with first trimester pregnancy loss. AglyMax-Sup has the same composition as that of the phytoestrogen supplement AglyMax but with added vitamins and other components. Expression of genes associated with implantation may be enhanced by AglyMax-Sup compared with AglyMax. We tested the hypothesis that AglyMax-Sup has greater effects on implantation compared with AglyMax, using RT-PCR and Western blotting in the endometrial epithelial cell line. Furthermore, we investigated the protective effect of AglyMax-Sup on IL-1betainduced changes in estrogen-responsive gene expression in endometrial epithelial cells. The purpose of this study was to compare the effects of the phytoestrogen supplement AglyMax-Sup with those of AglyMax on estrogen-responsive gene expression. AglyMax and AglyMax-Sup significantly (p<0.05) induced gene expression of glycodelin-A, HoxA10, IL-11, LIF, MEG-E8 and TGFbeta1. AglyMax-Sup induced high levels of these genes compared with the levels induced by AglyMax. The enhanced expression of LIF, IL-11, integrin alphaV, and HOXA10 induced by AglyMax-Sup was abolished by the ER antagonist fulvestrant and the ERK inhibitor PD98059. Meanwhile, IL-1beta inhibited progesterone plus estrogen-induced TGFbeta1, glycodelin-A, HOXA10, and integrin alphaV expression. IL-1beta-induced suppression of these expression was reversed by AglyMax-Sup. These results indicate that expression of genes associated with implantation may be increased by AglyMax-Sup compared with AglyMax. AglyMax-Sup might abrogate IL-1beta-mediated changes that can affect embryo implantation via the MAPK pathway. PMID- 28647516 TI - Health risk assessment of heavy metals via dietary intake of five pistachio (Pistacia vera L.) cultivars collected from different geographical sites of Iran. AB - Pistachio is an important horticultural product and Iran is considered as a main pistachio producing country. Assessment of heavy metals in this export fruit is crucial for protecting public health against toxic heavy metals. The concentration of selected heavy metals in soil, water and five pistachio cultivars from four geographical regions of Iran were measured. Although none of the elements were detected in water irrigation, infield metal content in the soil had good correlation with that of pistachio. The highest amounts of Al, As, Co, Ni and Se were reported in samples collected from Sarakhs, Iran. Considering both cultivar and region effects on selected heavy metals concentration, Kaleghoochi cultivar from Sarakhs site showed the highest amount of Al, As, Ni and Se. The maximum concentration of Hg was found in Akbari cultivar collected from Damghan. In the Akbari and the Ahmad aghaei cultivars collected from Sarakhs and Damghan cultivation zones, respectively, the highest amount of Co were observed. Based on our results, the HI value for the consumers of Iranian pistachio was 0.066. It seems that the levels of heavy metals in these pistachio samples pose no risk to consumers. PMID- 28647517 TI - Proteomics to study macrophage response to viral infection. AB - : Viral infections are a major burden to human and animal health. Immune response against viruses consists of innate and adaptive immunity which are both critical for the eradication of the viral infection. The innate immune system is the first line of defense against viral infections. Proper innate immune response is required for the activation of adaptive, humoral and cell-mediated immunity. Macrophages are innate immune cells which have a central role in detecting viral infections including influenza A and human immunodeficiency viruses. Macrophages and other host cells respond to viral infection by modulating their protein expression levels, proteins' posttranslational modifications, as well as proteins' intracellular localization and secretion. Therefore the detailed characterization how viruses dynamically manipulate host proteome is needed for understanding the molecular mechanisms of viral infection. It is critical to identify cellular host factors which are exploited by different viruses, and which are less prone for mutations and could serve as potential targets for novel antiviral compounds. Here, we review how proteomics studies have enhanced our understanding of macrophage response to viral infection with special focus on Influenza A and Human immunodeficiency viruses, and virus infections of swine. SIGNIFICANCE: Influenza A viruses (IAVs) and human immunodeficiency viruses (HIV) infect annually millions of people worldwide and they form a severe threat to human health. Both IAVs and HIV-1 can efficiently antagonize host response and develop drug-resistant variants. Most current antiviral drugs are directed against viral proteins, and there is a constant need to develop new next generation drugs targeting host proteins that are essential for viral replication. Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are economically important swine pathogens. Both PRRSV and PCV2 cause severe respiratory tract illnesses in swine. IAVs, HIV-1, and swine viruses infect macrophages activating antiviral response against these viruses. Macrophages also have a central role in the replication and spread of these viruses. However, macrophage response to these viruses is incompletely understood. Current proteomics methods can provide a global view of host-response to viral infection which is needed for in-depth understanding the molecular mechanisms of viral infection. Here we review the current proteomics studies on macrophage response to viral infection and provide insight into the global host proteome changes upon viral infection. PMID- 28647518 TI - Increasing the accuracy of proteomic typing by decellularisation of amyloid tissue biopsies. AB - : Diagnosis and treatment of systemic amyloidosis depend on accurate identification of the specific amyloid fibril protein forming the tissue deposits. Confirmation of monoclonal immunoglobulin light chain amyloidosis (AL), requiring cytotoxic chemotherapy, and avoidance of such treatment in non-AL amyloidosis, are particularly important. Proteomic analysis characterises amyloid proteins directly. It complements immunohistochemical staining of amyloid to identify fibril proteins and gene sequencing to identify mutations in the fibril precursors. However, proteomics sometimes detects more than one potentially amyloidogenic protein, especially immunoglobulins and transthyretin which are abundant plasma proteins. Ambiguous results are most challenging in the elderly as both AL and transthyretin (ATTR) amyloidosis are usually present in this group. We have lately described a procedure for tissue decellularisation which retains the structure, integrity and composition of amyloid but removes proteins that are not integrated within the deposits. Here we show that use of this procedure before proteomic analysis eliminates ambiguity and improves diagnostic accuracy. SIGNIFICANCE: Unequivocal identification of the protein causing amyloidosis disease is crucial for correct diagnosis and treatment. As a proof of principle, we selected a number of cardiac and fat tissue biopsies from patients with various types of amyloidosis and show that a classical procedure of decellularisation enhances the specificity of the identification of the culprit protein reducing ambiguity and the risk of misdiagnosis. PMID- 28647519 TI - Is sarcopenia associated with an increased risk of all-cause mortality and functional disability? AB - BACKGROUND: While a recent meta-analysis of observational studies reported a statistically significant association between sarcopenia and both all-cause mortality and functional decline, a recently developed inverse heterogeneity (IVhet) model has been shown to be more valid than the traditional random-effects model used. OBJECTIVE: The objective of this short report was to use a previous meta-analysis to compare the two approaches. METHODS: Aggregate data meta analysis of prospective observational studies conducted in any setting. Men and women 60years of age and older in which all-cause mortality (12 studies, 14,169 participants) or functional decline (6 studies, 8561 participants) was assessed. Using the IVhet model, pooling of previous studies regarding the association between sarcopenia and all-cause mortality as well as functional decline. Absolute and relative differences between IVhet and random-effects results were also calculated as well as influence analysis with each study deleted once. Non overlapping 95% confidence intervals (CI) for odds ratios (OR) were considered statistically significant. RESULTS: Sarcopenia was associated with an increased risk for all-cause mortality (OR=3.64, 95% CI=2.94 to 4.51) and functional decline (OR=2.58, 95% CI=1.33 to 4.99). Compared to the random-effects model, the OR was slightly higher (0.04 or 1.1%) but with wider CI (0.16 or 11.3%) for all cause mortality and 0.45 (14.9%) lower with a CI that was 0.34 (10.2%) wider for functional decline. With each study deleted from the model once, results remained statistically significant for both all-cause mortality and functional decline. CONCLUSION: These results provide additional and more accurate evidence in support of an association between sarcopenia and an increased risk for both all cause mortality and functional decline. PMID- 28647520 TI - Percutaneous Intramedullary Screw Fixation of Distal Fibula Fractures: A Case Series and Systematic Review. AB - The current reference standard for unstable ankle fractures is open reduction and internal fixation using a plate and lag screws. This approach requires extensive dissection and wound complications are not uncommon. The use of intramedullary screw fixation might overcome these issues. The aim of our study was to provide an overview of the published data regarding intramedullary screw fixation of fibula fractures combined with a small consecutive case series. We performed a search of published studies to identify the studies in which fibula fractures were treated with percutaneous intramedullary screw fixation. Additionally, all consecutive patients treated for an unstable ankle fracture in a level 1 trauma center using an intramedullary screw were retrospectively included. The literature search identified 6 studies with a total of 180 patients. Wound infection was seen in 1 patient (0.6%), anatomic reduction was achieved in 168 patients (93.3%), and a loss of reduction was seen in 2 patients (1.1%). Implant removal was deemed necessary in 3 patients (1.7%) and nonunion was seen is 2 patients (1.1%). A total of 11 patients, in whom no wound complications occurred, were included in our study. The follow-up duration was a minimum of 12 months. A secondary dislocation was seen in 1 patient, and delayed union was observed after 7.5 months in 1 other patient. In conclusion, intramedullary screw fixation is a safe and adequate method to use for fibula fractures, with a low risk of wound complications. Additional research regarding functional outcome is warranted. PMID- 28647521 TI - Heterotopic Ossification of the Peroneus Brevis Tendon in a Pediatric Patient. AB - Heterotopic ossification (HO) is abnormal formation of mature lamellar bone in soft tissues. HO is most commonly diagnosed in the setting of localized trauma, which results in improper differentiation of progenitor cells, leading to aberrant tissue formation. In the pediatric population, nongenetic causes of HO have rarely been reported, especially HO involving the tendons of the ankle. We present a case of HO of the peroneus brevis tendon without systemic disease in a pediatric patient. The patient was a 7-year-old female with a normal birth and developmental history who first presented 6 weeks after a right ankle sprain with pain localized to the lateral calcaneus. Prominent swelling and tenderness to palpation were noted over the peroneal tubercle. Radiographic imaging showed dystrophic calcification within the peroneus brevis tendon. After failed conservative management, the heterotopic ossified mass (1.5 * 0.3 cm) was excised from the peroneus brevis tendon. The tendon was primarily repaired. The patient was followed up for 12 weeks postoperatively and achieved full resolution of her pain with a return to normal activity. HO has been theorized to be the result of an imbalance between bone mineralization and demineralization. In the setting of localized trauma, inductive agents have been implicated in pathologic bone formation. In the pediatric population, HO has rarely been diagnosed in the absence of genetic causes. In patients presenting with lateral foot and ankle pain, HO of the peroneal tendons should be considered in the differential diagnosis. In a patient with pain secondary to HO, surgical excision of the heterotopic mass can achieve symptom resolution. PMID- 28647522 TI - Functional Medium-Term Results After Autologous Matrix-Induced Chondrogenesis for Osteochondral Lesions of the Talus: A 5-Year Prospective Cohort Study. AB - Autologous matrix-induced chondrogenesis (AMIC) has gained popularity in the treatment of osteochondral lesions of the talus. Previous studies have presented promising short-term results for AMIC talar osteochondral lesion repair, a 1-step technique using a collagen type I/III bilayer matrix. The aim of the present study was to investigate the mid-term effects. The 5-year results of a prospective cohort study are presented. All patients underwent an open AMIC procedure for a talar osteochondral lesion. Data analysis included general demographic data, preoperative magnetic resonance imaging findings, intraoperative details, and German version of the Foot Function Index (FFI-D) scores preoperatively and at 1 and 5 years after surgery. The primary outcome variable was the longitudinal effect of the procedure, and the influence of various variables on the outcome was tested. Of 47 consecutive patients, 21 (45%) were included. Of the 21 patients, 8 were female (38%) and 13 were male (62%), with a mean age of 37 +/- 15 (range 15 to 62) years and a body mass index of 26 +/- 5 (range 20 to 38) kg/m2. The defect size was 1.4 +/- 0.9 (range 0.2 to 4.0) cm2. The FFI-D decreased significantly from preoperatively to 1 year postoperatively (56 +/- 18 versus 33 +/- 25; p = .003), with a further, nonsignificant decrease between the 1- and 5-year follow-up examination (33 +/- 25 versus 24 +/- 21; p = .457). Similar results were found for the FFI-D subscales of function and pain. The body mass index and lesion size showed a positive correlation with the preoperative FFI-D overall and subscale scores. These results showed a significant improvement in pain and function after the AMIC procedure, with a significant return to sports by the 5-year follow-up point. The greatest improvement overall was seen within the first year; however, further clinical satisfaction among the patients was noticeable after 5 years. PMID- 28647523 TI - Thermal aggregation of human immunoglobulin G in arginine solutions: Contrasting effects of stabilizers and destabilizers. AB - Arginine is widely used as aggregation suppressor of proteins in biotechnology and pharmaceutics. However, why the effect of arginine depends on the types of proteins and stresses, including monoclonal antibodies, is still unclear. Here we investigated the precise processes of the thermal aggregation of human immunoglobulin G (IgG) in the presence of additives. As expected, arginine was the best additive to suppress the formation of insoluble aggregates during heat treatment, though it was unable to preserve the monomer content. A systematic analysis of the additives showed that sugars and kosmotropic ion inhibit the formation of soluble oligomers. These behaviors indicate that the thermal aggregation of IgG occurs by (i) the formation of soluble oligomers, which is triggered by the unfolding process that can be stabilized by typical osmolytes, and (ii) the formation of insoluble aggregates through weak cluster-cluster interactions, which can be suppressed by arginine. Understanding the detailed mechanism of arginine will provide useful information for the rational formulation design of antibodies. PMID- 28647524 TI - Preparation and evaluation of BSA-based hydrosol nanoparticles cross-linked with genipin for oral administration of poorly water-soluble curcumin. AB - One of the most interesting functions of albumin is the ability to interact with bioactive compounds. This study describes preparation of protein-based nanoparticles (NPs) for the preparation of solid dispersion of curcumin (CN). Fabrication of hydrosol system of dispersed CN in bovine serum albumin (BSA) was approached, followed by cross-linking with glutaraldehyde (Gta). Response surface methodology (RSM) was used to investigate the influence of input factors (pH, CN content and organic phase ratio (r)), on the particle size and CN entrapment efficiency (EE). Particle size, EE and CN loading efficiency (LE) at optimum condition (pH 7, r 10% and 3.4mg of CN content), were found to be in the range of 153-184.4nm, 72.54%, and 14.508MUg/mg, respectively. In the optimum formulation, genipin (Gnp) was used at three different levels (0.1-0.2 and 0.3% w/w of BSA), as a safe, natural cross-linker instead of toxic Gta, to address the limitation of oral delivery purpose. AFM and SEM analysis revealed the spherical and smooth surface of Nps. Ninhydrin (NHD) assay and FT-IR analysis confirmed the cross linking between BSA and Gnp. In vitro release studies ensure the efficiency of the formulation for sustained release of soluble CN. PMID- 28647525 TI - Catalytic hydrolysis of starch for biohydrogen production by using a newly identified amylase from a marine bacterium Catenovulum sp. X3. AB - An identified cold-adaptive, organic solvents-tolerant alkaline alpha-amylase (HP664) from Catenovulum sp. strain X3 was heterologously expressed and characterized in E. coli, and it was further applied to starch saccharification for biohydrogen production. The recombinant HP664 belongs to a member of glycoside hydrolase family 13 (GH13), with a molecular weight of 69.6kDa without signal peptides, and also shares a relatively low similarity (49%) to other reported amylases. Biochemical characterization demonstrated that the maximal enzymatic activity of HP664 was observed at 35 degrees C and pH 9.0. Most metal ions inhibited its activity; however, low polar organic solvents (e.g., benzene and n-hexane) could enhance the activity by 35-50%. Additionally, HP664 also exhibited the catalytic capability on various polysaccharides, including potato starch, amylopectin, dextrin and agar. In order to increase the bioavailability of starch for H2 production, HP664 was utilized to elevate fermentable oligosaccharide level, and the results revealed that the maximal hydrolytic percentage of starch was up to 44% with 12h of hydrolysis using 5.63U of HP664. Biohydrogen fermentation of the starch hydrolysate by Clostridium sp. strain G1 yielded 297.7mL of H2 after 84h of fermentation, which is 3.73-fold higher than the control without enzymatic treatment of HP664. PMID- 28647526 TI - National Survey of Adult and Pediatric Reference Intervals in Clinical Laboratories across Canada: A Report of the CSCC Working Group on Reference Interval Harmonization. AB - OBJECTIVE: Reference intervals are widely used decision-making tools in laboratory medicine, serving as health-associated standards to interpret laboratory test results. Numerous studies have shown wide variation in reference intervals, even between laboratories using assays from the same manufacturer. Lack of consistency in either sample measurement or reference intervals across laboratories challenges the expectation of standardized patient care regardless of testing location. Here, we present data from a national survey conducted by the Canadian Society of Clinical Chemists (CSCC) Reference Interval Harmonization (hRI) Working Group that examines variation in laboratory reference sample measurements, as well as pediatric and adult reference intervals currently used in clinical practice across Canada. DESIGN AND METHODS: Data on reference intervals currently used by 37 laboratories were collected through a national survey to examine the variation in reference intervals for seven common laboratory tests. Additionally, 40 clinical laboratories participated in a baseline assessment by measuring six analytes in a reference sample. RESULTS: Of the seven analytes examined, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatinine reference intervals were most variable. As expected, reference interval variation was more substantial in the pediatric population and varied between laboratories using the same instrumentation. Reference sample results differed between laboratories, particularly for ALT and free thyroxine (FT4). Reference interval variation was greater than test result variation for the majority of analytes. CONCLUSION: It is evident that there is a critical lack of harmonization in laboratory reference intervals, particularly for the pediatric population. Furthermore, the observed variation in reference intervals across instruments cannot be explained by the bias between the results obtained on instruments by different manufacturers. PMID- 28647527 TI - Delayed shock after lead extraction: Unrecognized or underappreciated? PMID- 28647528 TI - The linkage between nutrient supply, intracellular enzyme abundances and bacterial growth: New evidences from the central carbon metabolism of Corynebacterium glutamicum. AB - Corynebacterium glutamicum serves as important production host for small molecular compounds that are derived from precursor molecules of the central carbon metabolism. It is therefore a well-studied model organism of industrial biotechnology. However, a deeper understanding of the regulatory principles underlying the synthesis of central metabolic enzymes under different environmental conditions as well as its impact on cell growth is still missing. We studied enzyme abundances in C. glutamicum in response to growth on: (i) one limiting carbon source by sampling chemostat and fed-batch cultivations and (ii) changing carbon sources provided in excess by sampling batch cultivations. The targeted quantification of 20 central metabolic enzymes by isotope dilution mass spectrometry revealed that cells maintain stable enzyme concentrations when grown on d-glucose as single carbon and energy source and, most importantly, independent of its availability. By contrast, switching from d-glucose to d fructose, d-mannose, d-arabitol, acetate, l-lactate or l-glutamate results in highly specific enzyme regulation patterns that can partly be explained by the activity of known transcriptional regulators. Based on these experimental results we propose a simple framework for modeling cell population growth as a nested function of nutrient supply and intracellular enzyme abundances. In summary, our study extends the basis for the formulation of predictive mechanistic models of bacterial growth, applicable in industrial bioprocess development. PMID- 28647529 TI - Linking secondary metabolites to biosynthesis genes in the fungal endophyte Cyanodermella asteris: The anti-cancer bisanthraquinone skyrin. AB - Fungal aromatic polyketides display a very diverse and widespread group of natural products. Due to their excellent light absorption properties and widely studied biological activities, they offer numerous application for food, textile and pharmaceutical industry. The biosynthetic pathways of fungal aromatic polyketides usually involve a set of successive enzymes, in which a non-reductive polyketide synthase iteratively catalyzes the essential assembly of simple building blocks into (often polycyclic) aromatic compounds. However, only a limited number of such pathways have been described so far and further elucidation of the individual biosynthetic steps is needed to fully exploit the biotechnological and medicinal potential of these compounds. Here, we identified the bisanthraquinone skyrin as the main pigment of the fungus Cyanodermella asteris, an endophyte that has recently been isolated from the traditional Chinese medicinal plant Aster tataricus. The genome of C. asteris was sequenced, assembled and annotated, which enables first insights into a genome from a non lichenized member of the class Lecanoromycetes. Genetic and in silico analyses led to the identification of a gene cluster of five genes suggested to encode the enzymatic pathway for skyrin. Our study is a starting point for rational pathway engineering in order to drive the production towards higher yields or more active derivatives. Moreover, our investigations revealed a large potential of secondary metabolite production in C. asteris as well as in all Lecanoromycetes of which genomes were available. These findings convincingly emphasize that Lecanoromycetes are prolific producers of secondary metabolites. PMID- 28647530 TI - Measuring kinetic rate constants of multiple-component reactions with optical biosensors. AB - One may measure the kinetic rate constants associated with biochemical reactions using an optical biosensor: an instrument in which ligand molecules are convected through a flow cell over a surface to which receptors are immobilized. If there are multiple reactants, one is faced with the problem of fitting multiple kinetic rate constants to one signal, since data from all of the reacting species is lumped together. Even in the presence of ambiguous data, one may use a series of experiments to accurately determine the rate constants. Moreover, the true set of rate constants may be identified by either postprocessing the signals or adjusting the ligand inflow concentrations. PMID- 28647531 TI - A rapid mass spectrometric method for the measurement of catalytic activity of ten-eleven translocation enzymes. AB - Enzymatic methylation at carbon five on cytosine (5mC) in DNA is a hallmark of mammalian epigenetic programming and is critical to gene regulation during early embryonic development. It has recently been shown that dynamic erasure of 5mC by three members of the ten-eleven translocation (TET) family plays a key role in cellular differentiation. TET enzymes belong to Fe (II)- and 2-ketoglutarate (2KG) dependent dioxygenases that successively oxidize 5mC to 5-hydroxymethyl cytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5CaC), thus providing a chemical basis for the removal of 5mC which once was thought to be a permanent mark in mammalian genome. Since then a wide range of biochemical assays have been developed to characterize TET activity. Majority of these methods require multi-step processing to detect and quantify the TET-mediated oxidized products. In this study, we have developed a MALDI mass spectrometry based method that directly measures the TET activity with high sensitivity while eliminating the need for any intermediate processing steps. We applied this method to the measurement of enzymatic activity of TET2 and 3, Michaleis-Menten parameters (KM and kcat) of TET-2KG pairs and inhibitory concentration (IC50) of known small molecule inhibitors of TETs. We further demonstrated the suitability of the assay to analyze chemoenzymatic labeling of 5hmC by beta-glucosyltransferase, highlighting the potential for broad application of our method in deconvoluting the functions of novel DNA demethylases. PMID- 28647533 TI - Transport properties and regulatory roles of nitrogen in arbuscular mycorrhizal symbiosis. AB - Many terrestrial plants can form root symbiosis with beneficial microorganisms for enhancing uptake of mineral nutrients or increasing fitness to adverse environmental challenges. Arbuscular mycorrhizal (AM) symbiosis that is formed by AM fungi and the roots of vascular flowering plants is the most widespread mutualistic associations in nature. As a typical endosymbiosis, AM interactions involves the differentiation of both symbionts to create novel symbiotic interfaces within the root cells, and requires a continuous nutrient exchange between the two partners. AM plants have two pathways for nutrient uptake, either direct uptake via the root hairs and root epidermis at the plant-soil interface, or indirectly through the AM fungal hyphae at the plant-fungus interface. Over the last few years, great progress has been made in deciphering the mechanisms underlying the AM-mediated modulation of nutrient uptake processes, and an increasing number of plant and fungal genes responsible for transporting nutrients from the soil or across the intraradical symbiotic interfaces have been identified and functionally characterized. Here, we summarize the recent advances in the nitrogen uptake, assimilation and translocation in the AM symbiosis, and also explore the current understanding of how the N status and interplay with C and P in modulating the development of AM associations. PMID- 28647532 TI - Carbapenem-resistant Enterobacteriaceae in the community: a scoping review. AB - Carbapenem antibiotics are used as a last resort to treat serious Gram-negative bacteria (GNB) infections; however, carbapenemase-producing strains of GNB have emerged as a major source of resistance. Owing to the highly transmissible nature of plasmid-borne carbapenemases, numerous reports have warned about the likely spread into the community from healthcare settings. Since the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in the community is largely unknown, we conducted a scoping review of the literature to assess the percentage of CRE isolates that could be associated with the community. Initially, 361 studies were assessed and 15 met the inclusion criteria. Although 5 studies (33.3%) found no community-associated CRE, the remaining 10 studies identified percentages ranging from 0.04% to 29.5% of either community-associated or community-onset CRE among their samples, with US-based studies alone ranging from 5.6 to 10.8%. The presence of CRE in the community poses an urgent public health threat. PMID- 28647534 TI - Molecular cell biology of complement membrane attack. AB - The membrane attack complex (MAC) is the pore-forming toxin of the complement system, a relatively early evolutionary acquisition that confers upon complement the capacity to directly kill pathogens. The MAC is more than just a bactericidal missile, having the capacity when formed on self-cells to initiate a host of cell activation events that can have profound consequences for tissue homeostasis in the face of infection or injury. Although the capacity of complement to directly kill pathogens has been recognised for over a century, and the pore-forming killing mechanism for at least 50 years, there remains considerable uncertainty regarding precisely how MAC mediates its killing and cell activation activities. A recent burst of new information on MAC structure provides context and opportunity to re-assess the ways in which MAC kills bacteria and modulates cell functions. In this brief review we will describe key aspects of MAC evolution, function and structure and seek to use the new structural information to better explain how the MAC works. PMID- 28647535 TI - The involvement of monoaminergic neurotransmission in the antidepressant-like action of scopolamine in the tail suspension test. AB - Some clinical studies indicate that scopolamine may induce a rapid antidepressant effect. Although scopolamine is a muscarinic antagonist, it seems that not only cholinergic but also glutamatergic and GABAergic systems might be involved in the mechanism of its antidepressant activity in animal models of depression. Here, we present a set of behavioral data aimed at investigating the role of monoaminergic system activity in the mechanism of the antidepressant-like action of scopolamine in an animal model based on behavioral despair, namely, the tail suspension test (TST). It was found that AMPT induced a partial reduction in the antidepressant like effect of scopolamine (0.3mg/kg) in the TST in C57BL/6 mice and that the effect of scopolamine was comparable to the effect of reboxetine (10mg/kg), which was used in this study as a reference drug. The attenuated antidepressant-like effect of scopolamine in AMPT-treated mice was observed in both its immediate (30min after administration) and prolonged (24h after administration) action in the TST. On the other hand, serotonin depletion by PCPA-pretreatment had no effect on the antidepressant effect of scopolamine (0.3mg/kg) either 30min or 24h after administration. Furthermore, a dose-dependent decrease in the immobility time of mice treated with a non-active dose of reboxetine (2mg/kg) together with non-active doses of scopolamine (0.03 and 0.1mg/kg) was found, suggesting a synergistic interaction between reboxetine and scopolamine in the TST. In contrast, a subeffective dose of the SSRI citalopram co-administered with subeffective doses of scopolamine did not induce significant changes in the behavior of mice in this test. Altogether, these data suggest that activation of the noradrenergic system might be involved in the antidepressant-like effect of scopolamine in the TST. PMID- 28647536 TI - CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery. AB - This study examined the impact of corticotropin-releasing hormone type 1 receptor (CRHR1) blockade using Antalarmin (ANT) on the expression of markers of neuroplasticity and inflammation, as well as neuroprotection and behavioral recovery following global cerebral ischemia. Male Wistar rats (N=50) were treated with ANT (2MUg/2MUl; icv) or a vehicle solution prior to a sham or four vessel (4VO) occlusion. Seven days post ischemia, anxiety was assessed in the Elevated Plus Maze and Open Field tests, and fear and spatial learning in a Y-Maze Passive Avoidance Task and the Barnes Maze. Thirty days post ischemia, brain derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor expression, hippocampal neuronal death and inflammation were determined by analyzing immunoreactivity (ir) of neuron-specific nuclear protein (NeuN), microglia (IBA1, ionized calcium binding adaptor molecule 1), astrocytes (GFAP, glial fibrillary acidic protein) and TNFalpha (tumor necrosis factor alpha) a pro inflammatory cytokine. Our findings revealed that ANT improved behavioral impairments, while conferring neuroprotection and blunting neuroinflammation in all hippocampal sub-regions post ischemia. We also observed reduced BDNF and TrkB mRNA and protein levels at the hippocampus, and increased expression at the hypothalamus and amygdala post ischemia, site-specific alterations which were regularized by pre-ischemic CRHR1 blockade. These findings support that CRHR1 actively contributes to altered brain plasticity, neuronal inflammation and injury and recovery of function following ischemic brain insults. PMID- 28647537 TI - Variation in compulsory psychiatric inpatient admission in England: a cross classified, multilevel analysis. AB - BACKGROUND: The increasing rate of compulsory admission to psychiatric inpatient beds in England is worrying. Studying variation between places and services could be key to identifying targets for interventions to reverse this trend. We modelled spatial variation in compulsory admissions in England using national patient-level data and quantified the extent to which patient, local-area, and service-setting characteristics accounted for this variation. METHODS: This study is a cross-sectional, multilevel analysis of the 2010-11 Mental Health Minimum Data Set (MHMDS). Data from eight provider trusts were excluded, including three independent provider trusts that lacked spatial identification codes. We excluded patients detained under sections of the Mental Health Act concerned only with conveyance to, or assessment in, a registered Place of Safety, or for short-term (<=72 h) assessment only, as these do not in themselves necessarily mean that the person will be admitted to an inpatient mental health bed. MHMDS contained reasonably complete data for a limited number of patient characteristics, namely age, sex, and ethnicity; however, several patient-level variables could not be included in our analysis because of high levels of missing data. Multilevel models were applied with MLwiN to estimate variation in compulsory admission, starting with null (unconditional) models that partitioned total variance in compulsory admission between each level in the model. The primary outcome was compulsory admission to a psychiatric inpatient bed, compared with people admitted voluntarily or receiving only community-based care. FINDINGS: Data were available for 1 238 188 patients, covering 64 National Health Service provider trusts (93%) and 31 865 census lower super output areas (LSOAs; 98%). 7.5% and 5.6% of the variance in compulsory admission occurred at LSOA level and provider trust levels, respectively, after adjusting for patient characteristics. Black patients were almost three times more likely to be admitted compulsorily than were white patients (odds ratio [OR] 2.94, 95% CI 2.90-2.98). Compulsory admission was greater in more deprived areas (OR 1.22, 1.18-1.27) and in areas with more non-white residents (OR 1.51, 1.43-1.59), after adjusting for confounders. INTERPRETATION: Rates of compulsory admission to inpatient psychiatric beds vary significantly between local areas and services, independent of patient, area, and service characteristics. Compulsory admission rates seem to reflect local factors, especially socioeconomic and ethnic population composition. Understanding how these factors condition access to, and use of, mental health care is likely to be important for developing interventions to reduce compulsion. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme. PMID- 28647538 TI - Why we need to understand service variation in compulsion. PMID- 28647539 TI - Chemical addressability of potato virus X for its applications in bio/nanotechnology. AB - Potato virus X (PVX), a type member of the plant virus potexvirus group, offers a unique nanotechnology platform based on its high aspect ratio and flexible filamentous shape. The PVX platform has already been engineered and studied for its uses in imaging, drug delivery, and immunotherapies. While genetic engineering procedures are well established for PVX, there is limited information about chemical conjugation strategies for functionalizing PVX, partly due to the lack of structural information of PVX at high resolution. To overcome these challenges, we built a structural model of the PVX particle based on the available structures from pepino mosaic virus (PepMV), a close cousin of PVX. Using the model and a series of chemical conjugation experiments, we identified and probed the addressability of cysteine side chains. Chemical reactivity of cysteines was confirmed using Michael-addition and thiol-selective probes, including fluorescent dyes and biotin tags. LC/MS/MS was used to map Cys 121 as having the highest selectivity for modification. Finally, building on the availability of two reactive groups, the newly identified Cys and previously established Lys side chains, we prepared multifunctional PVX nanoparticles by conjugating Gd-DOTA for magnetic resonance imaging (MRI) to lysines and fluorescent dyes for optical imaging to cysteines. The resulting functionalized nanofilament could have applications in dual-modal optical-MRI imaging applications. These results further extend the understanding of the chemical properties of PVX and enable development of novel multifunctional platforms in bio/nanotechnology. PMID- 28647540 TI - Reversible swelling of SBMV is associated with reversible disordering. AB - The structures of the compact and swollen southern bean mosaic virus (SBMV) particles have been compared by X-ray diffraction and proton magnetic resonance (PMR). Small-angle X-ray scattering showed that removal of divalent cations at alkaline pH causes the particle diameter to increase from 289A in the native SBMV by 12% in solution and by 9% in microcrystals. The swelling is fully reversible upon re-addition of Ca2+ and Mg2+ ions, as shown by the X-ray patterns at 6A resolution and by the 270MHz PMR spectra. Beyond 30A resolution, X-ray patterns from the compact SBMV in solution and in microcrystals show fine fringes of ~1/225A-1 width extending to 6A resolution, whereas patterns from the swollen SBMV in solution and in microcrystals show only broader fringes of ~1/90A-1 width, Model calculations demonstrate that the fine fringes from compact SBMV arise from regular packing of the protein subunits on the icosahedral surface lattice; the smearing of fine fringes in the swollen virus pattern can be simulated by uncorrelated displacements of pentamers and hexamers of protein subunits, with a standard deviation of 6A from their mean locations. The PMR spectrum of compact SBMV is poorly resolved, whereas PMR spectrum of swollen SBMV shows sharp resonances in the methyl proton region. The line-narrowing for a fraction of the aliphatic protons upon swelling cannot be accounted for by rotational relaxation of the particle of 6*106MW, but must be attributed to internal motion in small regions of the protein subunits. PMID- 28647541 TI - Response Tailored Protocol Versus the Fixed 12Weeks Course of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection: A Randomized, Open-label, Non-inferiority Trial. AB - BACKGROUND: The most recent European Association for the Study of the Liver (EASL) 2016 Guidelines on treatment of hepatitis C (HCV), allowed for shortening the course of treatment for some subsets of patients with sofosbuvir/ledipasvir and with grazoprevir/elbasvir based on cutoff baseline HCV RNA values. We hypothesized that it would be prudent to also consider an objectively assuring very rapid, on-treatment, virologic response to therapy at week 2 (vRVR) before taking the decision of shortening the treatment duration. So we planned this study to test whether a dual sofosbuvir/daclatasvir (SOF/DCV) treatment duration tailored according to achieving vRVR to 8 or 12weeks is non-inferior to the recommended fixed 12weeks course in non-cirrhotic Egyptian chronic HCV genotype-4 patients. METHODS: The study was conducted in an outpatient setting according to a prospective, randomized, open-label, comparative, non-inferiority study design. A hundred twenty eligible, non-cirrhotic, chronic HCV patients were randomly assigned (1:1) to receive daily doses in the form of one Gratisovir 400mg table (generic sofosbuvir produced by Pharco Pharmaceuticals, Alexandria, Egypt) plus one Daktavira 60mg tablet (generic daclatasvir produced by Dawood Pharm, Egypt) for either a fixed 12weeks duration (reference group) or a response tailored duration (test group). In the test group the treatment duration was tailored according to the virus load tested by real time PCR into 8weeks for patients who had undetectable HCV RNA level in their serum by the end of the second week of treatment (vRVR)), or 12weeks for those who did not show vRVR. The primary outcome of the trial was the proportions of patients achieving SVR12 (HCV RNA below lower level of quantification at week 12 after end of treatment). The comparison between groups was based on testing the null hypothesis of inferiority of the response-tailored group with a pre-specified margin of non-inferiority (NI m) of 0.1 (10%). The protocol was registered with a WHO Clinical Trial Registration ID: ACTRN12617000263392. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372041 FINDINGS: Starting from Jun, 5 2016, a hundred twenty eligible patients from 4 outpatient clinics in Alexandria, Egypt were randomized to either a fixed duration group (reference group: n=60 patients) or a response tailored duration group (test group: n=60 patients). During the whole period of the study, only 1 patient dropped-out from each group. Both were lost to follow-up after the 4th week's visit. Baseline characteristics in both groups were almost matching. Fifty eight out of the total 60 intention-to-treat (ITT) patients in the reference group achieved SVR12 (96.67% (95% confidence interval (CI): 88.64-99%). Whereas, 59 out of the total 60 (ITT) patients in the test group achieved SVR12 (98.33% (CI: 91.14-99.71%). The per-protocol (PP) analysis, excluding patients who dropped-out before collecting their final result, showed that 58/59 (98.31% (CI: 91-99.7%)) of patients in the reference group and 59/59 (100% (CI: 93.89-100%) of the test group achieved SVR12. Non-inferiority was declared since the upper bound of the two-sided 95% CI for the difference in proportions of SVR12 between groups (P(reference)-P(test)) did not exceed the specified non-inferiority margin of +0.1 (10%), both in ITT population (-1.67%, CI: -9.8%-+5.9%), and in the PP population (-1.69%, CI: -9%-+4.58%). No fatalities or serious adverse events were reported during the period of the study. Similar rates of non-serious adverse events were reported in both groups with a trend of higher incidence rate in the fixed 12weeks group; all were mild in severity. INTERPRETATION: Shortening the duration of therapy based on observed vRVR could provide a prudent basis to avoid unnecessary long treatment courses. This could not only reduce the drug exposure and the risk of adverse drug reactions, but also cut the cost of full treatment course with such expensive medications by one third. This could economize the treatment budget at the individual out-of-pocket level as well as the public health services and insurance levels and allow for better utilization of public health resources. PMID- 28647542 TI - Parallel interactive retrieval of item and associative information from event memory. AB - Memory contains information about individual events (items) and combinations of events (associations). Despite the fundamental importance of this distinction, it remains unclear exactly how these two kinds of information are stored and whether different processes are used to retrieve them. We use both model-independent qualitative properties of response dynamics and quantitative modeling of individuals to address these issues. Item and associative information are not independent and they are retrieved concurrently via interacting processes. During retrieval, matching item and associative information mutually facilitate one another to yield an amplified holistic signal. Modeling of individuals suggests that this kind of facilitation between item and associative retrieval is a ubiquitous feature of human memory. PMID- 28647543 TI - Healthy Eating and Activity Across the Lifespan (HEAL): A call to action to integrate research, clinical practice, policy, and community resources to address weight-related health disparities. AB - Despite intense nationwide efforts to improve healthy eating and physical activity across the lifespan, progress has plateaued. Moreover, health inequities remain. Frameworks that integrate research, clinical practice, policy, and community resources to address weight-related behaviors are needed. Implementation and evaluation of integration efforts also remain a challenge. The purpose of this paper is to: (1) Describe the planning and development process of an integrator entity, HEAL (Healthy Eating and Activity across the Lifespan); (2) present outcomes of the HEAL development process including the HEAL vision, mission, and values statements; (3) define the planned integrator functions of HEAL; and (4) describe the ongoing evaluation of the integration process. HEAL team members used a theoretically-driven, evidence-based, systemic, twelve-month planning process to guide the development of HEAL and to lay the foundation for short- and long-term integration initiatives. Key development activities included a review of the literature and case studies, identifying guiding principles and infrastructure needs, conducting stakeholder/key informant interviews, and continuous capacity building among team members. Outcomes/deliverables of the first year of HEAL included a mission, vision, and values statements; definitions of integration and integrator functions and roles; a set of long-range plans; and an integration evaluation plan. Application of the HEAL integration model is currently underway through community solicited initiatives. Overall, HEAL aims to lead real world integrative work that coalesce across research, clinical practice, and policy with community resources to inspire a culture of health equity aimed at improving healthy eating and physical activity across the lifespan. PMID- 28647544 TI - Racial and ethnic disparities among state Medicaid programs for breast cancer screening. AB - Breast cancer screening by mammography has been shown to reduce breast cancer morbidity and mortality. The use of mammography screening though varies by race, ethnicity, and, sociodemographic characteristics. Medicaid is an important source of insurance in the US for low-income beneficiaries, who are disproportionately members of racial or ethnic minorities, and who are less likely to be screened than women with higher socioeconomic statuses. We used 2006-2008 data from Medicaid claims and enrollment files to assess racial or ethnic and geographic disparities in the use of breast cancer screening among Medicaid-insured women at the state level. There were disparities in the use of mammography among racial or ethnic groups relative to white women, and the use of mammography varied across the 44 states studied. African American and American Indian women were significantly less likely than white women to use mammography in 30% and 39% of the 44 states analyzed, respectively, whereas Hispanic and Asian American women were the minority groups most likely to receive screening compared with white women. There are racial or ethnic disparities in breast cancer screening at the state level, which indicates that analyses conducted by only using national data not stratified by insurance coverage are insufficient to identify vulnerable populations for interventions to increase the use of mammography, as recommended. PMID- 28647545 TI - Workplace interventions to improve sitting posture: A systematic review. AB - PURPOSE: Evaluate the effectiveness of workplace interventions to improve sitting posture of workers that spend long periods of time seated at a visual display terminal. METHODS: A systematic review of randomised controlled trials, non randomised controlled trials and single-group intervention trials featuring workplace interventions with pre- and follow-up measurements of sitting posture was conducted (registered in PROSPERO, CRD#42015027648). Nine databases were searched for studies available between January 2005 and February 2016. RESULTS: 2519 articles were screened with 12 studies meeting the inclusion criteria. The included studies featured various ergonomic workplace interventions and comprised 4 randomised controlled trial (n=457), 2 non-randomised controlled trials (n=416) and 6 single-group intervention trials (n=328). Due to clinical and methodological heterogeneity, pooling of data was not completed and a narrative summary of findings was developed using the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework. The evidence for four review outcomes was assessed with medium to large positive improvements obtained for the majority of studies investigating changes to gross sitting posture, whereas mixed findings were obtained for more specific local segment assessments of sitting posture. The overall evidence quality for all review outcomes were identified as either 'low' or 'very low'. CONCLUSION: There is evidence which is limited in quality to indicate that ergonomic workplace interventions can improve gross sitting posture. More high quality research across a range of intervention types is required with longer follow-up durations and more advanced methods to assess sitting posture with greater frequency and less bias. PMID- 28647546 TI - A review of the effects of very low nicotine content cigarettes on behavioral and cognitive performance. AB - The present systematic review examines whether very low nicotine content (VLNC) cigarettes ameliorate withdrawal-induced impairments in behavioral/cognitive performance. PubMed, PsycInfo, and Web of Science were searched for performance effects of VLNC cigarettes. For inclusion, reports had to be in English, published in a peer-reviewed journal through June 2017, examine VLNC cigarettes (<0.2mg nicotine yield), include >=2hour smoking abstinence or reduced nicotine exposure, and examine performance. 19 of 1243 articles reviewed met inclusion criteria. Poorer performance after smoking VLNC versus normal nicotine content (NNC) cigarettes was observed across 7 of 10 domains, including reaction time (8/11), short-term memory (3/10), sustained attention (4/6), inhibitory control (1/4), long-term memory (3/3 studies), and response variability (2/2). In two studies, combining VLNC smoking with nicotine replacement therapy (NRT) resulted in performance that was comparable to performance after NNC smoking. VLNC versus NNC differences were not discerned in motor control/functioning (0/2), visuospatial processing (0/2), learning (0/1), or verbal fluency (0/1). Eleven of nineteen (58%) studies were rated of Good or Excellent quality. Overall, VLNC cigarettes may not fully ameliorate withdrawal-induced disruptions in performance, although this varies by domain, with the strongest evidence for reaction time. Importantly, combining VLNC cigarettes with NRT appears to ameliorate withdrawal that is not reduced by VLNC cigarettes alone. As only 19 studies were identified, many domains are under-investigated. A more thorough evaluation of the extent to which VLNC cigarettes affect withdrawal-impaired performance may be warranted. PMID- 28647547 TI - Beyond education and income: Identifying novel socioeconomic correlates of cigarette use in U.S. young adults. AB - Young adulthood is defined by transitions in family life, living situations, educational settings, and employment. As a result, education and income may not be appropriate measures of socioeconomic status (SES) in young people. Using a national sample of young adults aged 18-34 (n=3364; collected February 2016), we explored novel socioeconomic correlates of ever cigarette use, past 30-day cigarette use, and daily cigarette use, weighted to account for non-response. Measures of SES assessed current education, household income, employment status, and subjective financial situation (SFS) and childhood SES (maternal and paternal education, SFS during childhood, parental divorce before age 18). Parental smoking during childhood was examined in sensitivity analyses. The highest prevalence of ever cigarette use was in young adults whose parents divorced before age 18 (57% vs. 47% overall). In general, current education, subjective financial status, and parental education were inversely correlated with past 30 day and daily cigarette use in bivariate analyses. In multivariable Poisson regression models controlling for age, gender, race/ethnicity, and other SES measures, lower education and poorer SFS were most strongly correlated with ever and past 30-day cigarette use. Lower maternal education emerged as the strongest correlate of daily smoking, conferring a twofold higher prevalence of daily smoking compared to maternal education of a Bachelor's degree or greater. Current household income was not a strong predictor of any cigarette use outcome. Novel measures like SFS may improve estimates of socioeconomic disadvantage during this developmental stage. PMID- 28647548 TI - The bioeconomy in Poland within the context of the European Union. AB - This article outlines the potential of the development of bioeconomy in Poland in the context of the European Union (EU). The analyses take into account the concept of bioeconomy, the overview of documents referring to the bioeconomy in the EU, including policy frameworks and agendas. Many countries including Poland emphasise the importance of bioeconomy, but have not yet developed a complex strategy. The state of bioeconomy in Poland is characterised by the sectors of agriculture, forestry and food production, as well as parts of the chemical, biotechnology and energy industries. In 2014 the global production volume in the Polish bioeconomy amounted to PLN 343 billion with the sector employing almost 3 million staff. However, the structure of the bioeconomy is dominated by traditional sectors, such as agriculture and agro-food industries. This article presents the analysis of research and development activity in Poland from 2009 to 2015. It reports the position of Poland on GMOs and their future development potential. It is worth mentioning that many EU states including Poland have declared themselves as being "GMO-free countries". PMID- 28647549 TI - Motivational Interviewing Improves Sustainable Return to Work in Injured Workers After Rehabilitation: A Cluster Randomized Controlled Trial. AB - OBJECTIVE: To examine whether motivational interviewing (MI) leads to more sustainable return-to-work outcomes for injured workers undergoing rehabilitation. DESIGN: Cluster randomized controlled trial. SETTING: Workers' compensation rehabilitation facility. PARTICIPANTS: Claimants (N=728) undergoing rehabilitation for musculoskeletal conditions, who were predominantly employed (529, 72.7%) men (460, 63.2%) with chronic conditions (mean duration, 234d). INTERVENTIONS: MI is a goal-oriented, client-centered counseling approach that facilitates behavioral change through identifying and resolving ambivalence. Treating clinicians at the facility were randomized into 2 groups. One group included 6 clinicians who were trained to conduct MI interventions during rehabilitation, while the control group included 6 clinicians who continued standard procedures. MAIN OUTCOME MEASURES: Outcomes included compensation outcomes over 1 year after discharge. This included reception of disability benefits and recurrence rates. Analysis was stratified by admission employment status and included chi-square test, t test, and multivariable regression. RESULTS: Participants included 728 claimants, of whom 367 (50.4%) were treated with MI. Unemployed claimants in the MI group received significantly more partial temporary disability benefits (mean, 8.2d vs 0.2d; P=.02), indicating return to modified work duties. Employed claimants in the control group had a higher recurrence rate (9.1% vs 4.5%; P=.04). The adjusted odds ratio for benefit recurrence was 2.7 (95% confidence interval, 1.1-6.5) after controlling for age, sex, and number of previous claims. CONCLUSIONS: Use of MI appears to lead to more sustainable return to work after rehabilitation and facilitates transition to modified work duties. PMID- 28647550 TI - Longitudinal Prediction of Quality-of-Life Scores and Locomotion in Individuals With Traumatic Spinal Cord Injury. AB - OBJECTIVES: To examine (1) differences in quality-of-life scores for groups based on transitions in locomotion status at 1, 5, and 10 years postdischarge in a sample of people with spinal cord injury (SCI); and (2) whether demographic factors and transitions in locomotion status can predict quality-of-life measures at these time points. DESIGN: Retrospective case study of the National SCI Database. SETTING: Model SCI Systems Centers. PARTICIPANTS: Individuals with SCI (N=10,190) from 21 SCI Model Systems Centers, identified through the National SCI Model Systems Centers database between the years 1985 and 2012. Subjects had FIM (locomotion mode) data at discharge and at least 1 of the following: 1, 5, or 10 years postdischarge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM locomotion mode; Severity of Depression Scale; Satisfaction With Life Scale; and Craig Handicap Assessment and Reporting Technique. RESULTS: Participants who transitioned from ambulation to wheelchair use reported lower participation and life satisfaction, and higher depression levels (P<.05) than those who maintained their ambulatory status. Participants who transitioned from ambulation to wheelchair use reported higher depression levels (P<.05) and no difference for participation (P>.05) or life satisfaction (P>.05) compared with those who transitioned from wheelchair to ambulation. Demographic factors and locomotion transitions predicted quality-of-life scores at all time points (P<.05). CONCLUSIONS: The results of this study indicate that transitioning from ambulation to wheelchair use can negatively impact psychosocial health 10 years after SCI. Clinicians should be aware of this when deciding on ambulation training. Further work to characterize who may be at risk for these transitions is needed. PMID- 28647551 TI - Factors Predicting Falls and Mobility Outcomes in Patients With Stroke Returning Home After Rehabilitation Who Are at Risk of Falling. AB - OBJECTIVE: To identify factors predicting falls and limited mobility in people with stroke at 12 months after returning home from rehabilitation. DESIGN: Observational cohort study with 12-month follow-up. SETTING: Community. PARTICIPANTS: People with stroke (N=144) and increased falls risk discharged home from rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Falls were measured using monthly calendars completed by participants, and mobility was assessed using gait speed over 5m (high mobility: >0.8m/s vs low mobility: <=0.8m/s). Both measures were assessed at 12 months postdischarge. Demographics and functional measures, including balance, strength, visual or spatial deficits, disability, physical activity level, executive function, functional independence, and falls risk, were analyzed to determine factors significantly predicting falls and mobility levels after 12 months. RESULTS: Those assessed as being at high falls risk (Falls Risk for Older People in the Community [FROP-Com] score>=19) were 4.5 times more likely to fall by 12 months (odds ratio [OR], 4.506; 95% confidence interval [CI], 1.71-11.86; P=.002). Factors significantly associated with lower usual gait speed (<=0.8m/s) at 12 months in the multivariable analysis were age (OR, 1.07; 95% CI, 1.01-1.14; P=.033), physical activity (OR, 1.09; 95% CI, 1.03-1.17, P=.007), and functional mobility (OR, .83; 95% CI, .75-.93; P=.001). CONCLUSIONS: Several factors predicted falls and limited mobility for patients with stroke 12 months after rehabilitation discharge. These results suggest that clinicians should include assessment of falls risk (FROP-Com), physical activity, and dual-task Timed Up and Go test during rehabilitation to identify those most at risk of falling and experiencing limited mobility outcomes at 12 months, and target these areas during inpatient and outpatient rehabilitation to optimize long-term outcomes. PMID- 28647552 TI - Clinical Utility of the Patient Health Questionnaire-9 in the Assessment of Major Depression After Broad-Spectrum Traumatic Brain Injury. AB - OBJECTIVE: To determine the predictive validity of the Patient Health Questionnaire-9 (PHQ-9) when screening for symptoms of depression after traumatic brain injury. DESIGN: Retrospective analysis of data collected as part of routine clinical outpatient care over a period of 30 months. SETTING: Regional rehabilitation facility. PARTICIPANTS: Persons (N=137) with mild to severe traumatic brain injury who were referred for neuropsychological evaluation within 1 to 12 months. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PHQ-9 and Minnesota Multiphasic Personality Inventory-2-Restructured Form. RESULTS: PHQ-9 scores >=10 had a sensitivity of 91.7 and a specificity of 60.2 for predicting a diagnosis of major depression. Correlations between scores of PHQ-9 and Minnesota Multiphasic Personality Inventory-2-Restructured Form Demoralization (.64) and Low Positive Emotions (.48) scales ranged from large to medium. Premorbid outpatient psychiatric treatment was the most consistent predictor of PHQ-9 elevations as well as final diagnoses of major depression. CONCLUSIONS: The PHQ-9 has adequate clinical utility as a screening instrument for depression in outpatients with traumatic brain injury. Elevations on this instrument cannot, however, be automatically attributed to neuropathology, especially not in the context of premorbid psychiatric dysfunction. Clinicians should conduct more thorough follow-up assessment in those with highly elevated PHQ-9 scores. PMID- 28647553 TI - Morphosyntactic correctness of written language production in adults with moderate to severe congenital hearing loss. AB - OBJECTIVE: To examine whether moderate to severe congenital hearing loss (MSCHL) leads to persistent morphosyntactic problems in the written language production of adults, as it does in their spoken language production. DESIGN: Samples of written language in Dutch were analysed for morphosyntactic correctness and syntactic complexity. STUDY SAMPLE: 20 adults with MSCHL and 10 adults with normal hearing (NH). RESULTS: Adults with MSCHL did not differ from adults with NH in the morphosyntactic correctness and syntactic complexity of their written utterances. Within the MSCHL group, the number of morphosyntactic errors in writing was related to the degree of hearing loss in childhood. CONCLUSIONS: At the group level, MSCHL does not affect the morphosyntactic correctness of language produced in the written modality, in contrast to earlier observed effects on spoken language production. However, at the individual level, our data suggest that adults who acquired their language with more severe auditory limitations are more at risk of persistent problems with morphosyntax in written language production than adults with a lower degree of hearing loss in childhood. PMID- 28647554 TI - Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice. AB - Progranulin deficiency due to heterozygous null mutations in the GRN gene is a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations cause neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. Progranulin is a secreted glycoprotein expressed in both neurons and microglia, but not astrocytes, in the brain. We generated conditional progranulin knockout mice that lack progranulin in nestin-expressing cells (Nes-cKO mice), which include most neurons as well as astrocytes. We confirmed near complete knockout of progranulin in neurons in Nes-cKO mice, while microglial progranulin levels remained similar to that of wild-type animals. Overall brain progranulin levels were reduced by about 50% in Nes-cKO, and no Grn was detected in primary Nes-cKO neurons. Nes-cKO mice aged to 12months did not display any increase in lipofuscin deposition, microgliosis, or astrogliosis in the four brain regions examined, though increases were observed for most of these measures in Grn-null animals. We conclude that neuron-specific loss of progranulin is not sufficient to cause similar neuropathological changes to those seen in constitutive Grn-null animals. Our results suggest that increased lipofuscinosis and gliosis in Grn null animals are not caused by intrinsic progranulin deficiency in neurons, and that microglia-derived progranulin may be sufficient to maintain neuronal health and homeostasis in the brain. PMID- 28647555 TI - Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes. AB - The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Abeta, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Abeta load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS. PMID- 28647556 TI - Synapsin I phosphorylation is dysregulated by beta-amyloid oligomers and restored by valproic acid. AB - Alzheimer's disease is the most prevalent form of dementia in the elderly but the precise causal mechanisms are still not fully understood. Growing evidence supports a significant role for Abeta42 oligomers in the development and progression of Alzheimer's. For example, intracellular soluble Abeta oligomers are thought to contribute to the early synaptic dysfunction associated with Alzheimer's disease, but the molecular mechanisms underlying this effect are still unclear. Here, we identify a novel mechanism that contributes to our understanding of the reported synaptic dysfunction. Using primary rat hippocampal neurons exposed for a short period of time to Abeta42 oligomers, we show a disruption in the activity-dependent phosphorylation cycle of SynapsinI at Ser9. SynapsinI is a pre-synaptic protein that responds to neuronal activity and regulates the availability of synaptic vesicles to participate in neurotransmitter release. Phosphorylation of SynapsinI at Ser9, modulates its distribution and interaction with synaptic vesicles. Our results show that in neurons exposed to Abeta42 oligomers, the levels of phosphorylated Ser9 of SynapsinI remain elevated during the recovery period following neuronal activity. We then investigated if this effect could be targeted by a putative therapeutic regime using valproic acid (a short branch-chained fatty acid) that has been proposed as a treatment for Alzheimer's disease. Exposure of Abeta42 treated neurons to valproic acid, showed that it restores the physiological regulation of SynapsinI after depolarisation. Our data provide a new insight on Abeta42 mediated pathology in Alzheimer's disease and supports the use of Valproic acid as a possible pharmaceutical intervention for the treatment of Alzheimer's disease. PMID- 28647557 TI - KCC3 loss-of-function contributes to Andermann syndrome by inducing activity dependent neuromuscular junction defects. AB - Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na+/K+-ATPase alpha1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na+/K+ ATPase alpha1 localization and reduces NMJ denervation in Slc12a6-/- mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome. PMID- 28647558 TI - Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea +/- thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 * 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 * 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor. PMID- 28647559 TI - miRNA-146a, miRNA-155 and JNK expression levels in peripheral blood mononuclear cells according to grade of knee osteoarthritis. AB - Osteoarthritis (OA) is the most common joint disease characterized by joint pain and a progressive loss of articular cartilage. OA known as a non-inflammatory disease. Despite this the recent studies are shown synovitis and low inflammation to have a role in OA pathophysiology. The aim of this study to determine the roles of a potential therapeutic targets miRNA-146a, miRNA-155 and JNK expression levels in OA patients. Peripheral mononuclear blood cells (PBMCs) were extracted from OA patients and healthy subjects. The expression levels of miRNA-146a, miRNA 155 and JNK were quantified using by real-time PCR assay. According to study results a statistically significant increase was observed only in miRNA-155 expression level (p=0,039). However, miRNA-146a and miRNA-155 expressions increased in the progressive stages (grade 3 and grade 4) in OA patients. Our data suggests that correlation of miRNAs regulating and signal pathways can play an important role in OA pathogenesis and disease progression. PMID- 28647560 TI - Transcript expression bias of phosphatidylethanolamine binding protein gene in bumblebee, Bombus lantschouensis (Hymenoptera: Apidae). AB - The phosphatidylethanolamine-binding protein (PEBP) family is a highly conserved group of proteins found in a wide range of organism. It plays an important role in innate immunity of insects. Little is known on the expression characteristic and function of PEBP in bees. In the current study, we cloned the pebp gene and investigated its expression profiles at different developmental stages and reproductive status from bumblebee, Bombus lantschouensis (Vogt), which is one of the most abundant pollinators for wild plants and crops in Northern China. Two transcripts (PEBPX1 and PEBPX2) of the pebp gene were cloned for the first time. The transcript PEBPX2 lacked a signal peptide sequence compared to PEBPX1. The full-length cDNA of these two PEBP transcripts is 1005bp and 915bp, with an open reading frame of 627bp and 549bp, respectively. Transcript PEBPX2 was one order of magnitude more expressed than transcript PEBPX1 at most of the developmental stages and different reproductive status (egg-laying versus non- egg-laying females). Both of the PEBP transcripts were highly expressed in brown-eyed with light and dark pigmented cuticle pupae stages. Quantitative PCR and Western Blot demonstrated that PEBP was significantly up-regulated in egg-laying females. In summary, we suggest that levels of these two PEBPs could be related to the regulation of reproduction in bumblebees. In addition, both transcripts likely play an important role in the metamorphosis developmental stage of bumblebee pupae. PMID- 28647561 TI - Identification of a novel splicing mutation within SLC17A8 in a Korean family with hearing loss by whole-exome sequencing. AB - Hereditary hearing loss (HHL) is a common genetically heterogeneous disorder, which follows Mendelian inheritance in humans. Because of this heterogeneity, the identification of the causative gene of HHL by linkage analysis or Sanger sequencing have shown economic and temporal limitations. With recent advances in next-generation sequencing (NGS) techniques, rapid identification of a causative gene via massively parallel sequencing is now possible. We recruited a Korean family with three generations exhibiting autosomal dominant inheritance of hearing loss (HL), and the clinical information about this family revealed that there are no other symptoms accompanied with HL. To identify a causative mutation of HL in this family, we performed whole-exome sequencing of 4 family members, 3 affected and an unaffected. As the result, A novel splicing mutation, c.763+1G>T, in the solute carrier family 17, member 8 (SLC17A8) gene was identified in the patients, and the genotypes of the mutation were co-segregated with the phenotype of HL. Additionally, this mutation was not detected in 100 Koreans with normal hearing. Via NGS, we detected a novel splicing mutation that might influence the hearing ability within the patients with autosomal dominant non-syndromic HL. Our data suggests that this technique is a powerful tool to discover causative genetic factors of HL and facilitate diagnoses of the primary cause of HHL. PMID- 28647562 TI - Postoperative Complications of Patients With Spina Bifida Undergoing Urologic Laparotomy: A Multi-institutional Analysis. AB - OBJECTIVE: To characterize perioperative morbidity and mortality in adult patients with spina bifida undergoing laparotomy. PATIENTS AND METHODS: We retrospectively studied the postoperative complications of 59 operations of patients with spina bifida undergoing abdominal laparotomies for urologic indications at 3 institutions. We evaluated postoperative complications using the Clavien-Dindo classification scale. RESULTS: The overall complication rate was 91.5%. The most common complications were ileus, pressure ulcers, urinary tract infection, and wound infection. Over 40% of the patients developed a class 3 or 4 complication requiring subsequent surgery or intensive care unit admission. The hospital readmission rate was 42% and was correlated with higher-grade complications. On multivariable analysis, only older age was significantly associated with grade of complication. CONCLUSION: These data demonstrate that adult patients with spina bifida comprise a unique population that faces an extremely high surgical risk even in centers of excellence. As patients with spina bifida live longer lives, thanks to modern medicine, there is a timely opportunity for research on perioperative management in these patients to improve postsurgical outcomes. PMID- 28647563 TI - In Vitro Comparison of Holmium Lasers: Evidence for Shorter Fragmentation Time and Decreased Retropulsion Using a Modern Variable-pulse Laser. AB - OBJECTIVE: To compare the performance of variable- and fixed-pulse lasers on stone phantoms in vitro. MATERIALS AND METHODS: Seven-millimeter stone phantoms were made to simulate calcium oxalate monohydrate stones using BegoStone plus. The in vitro setting was created with a clear polyvinyl chloride tube. For each trial, a stone phantom was placed at the open end of the tubing. The Cook Rhapsody H-30 variable-pulse laser was tested on both long- and short-pulse settings and was compared to the Dornier H-20 fixed-pulse laser; 5 trials were conducted for each trial arm. Fragmentation was accomplished with the use of a flexible ureteroscope and a 273-micron holmium laser fiber using settings of 1 J * 12 Hz. The treatment time (in minute) for complete fragmentation was recorded as was the total retropulsion distance (in centimeter) during treatment. Laser fibers were standardized for all repetitions. RESULTS: The treatment time was significantly shorter with the H-30 vs the H-20 laser (14.3 +/- 2.5 vs 33.1 +/- 8.9 minutes, P = .008). There was no difference between the treatment times using the long vs short pulse widths of the H-30 laser (14.4 +/- 3.4 vs 14.3 +/- 1.7 minutes, P = .93). Retropulsion differed by laser type and pulse width, H-30 long pulse (15.8 +/- 5.7 cm), H-30 short pulse (54.8 +/- 7.1 cm), and H-20 (33.2 +/- 12.5 cm) (P <.05). CONCLUSION: The H-30 laser fragmented stone phantoms in half the time of the H-20 laser regardless of the pulse width. Retropulsion effects differed between the lasers, with the H-30 causing the least retropulsion. Longer pulse widths result in less stone retropulsion. PMID- 28647564 TI - Effects of chronic forced-swim stress on behavioral properties in rats with neonatal repeated MK-801 treatment. AB - The two-hit hypothesis has been used to explain the onset mechanism of schizophrenia. It assumes that predisposition to schizophrenia is originally attributed to vulnerability in the brain which stems from genetic or early developmental factors, and that onset is triggered by exposure to later detrimental factors such as stress in adolescence or adulthood. Based on this hypothesis, the present study examined whether rats that had received neonatal repeated treatment with an N-methyl-d-aspartate (NMDA) receptor antagonist (MK 801), an animal model of schizophrenia, were vulnerable to chronic stress. Rats were treated with MK-801 (0.2mg/kg) or saline twice daily on postnatal days 7-20, and animals in the stress subgroups were subjected to 20days (5days/week*4weeks) of forced-swim stress in adulthood. Following this, behavioral tests (prepulse inhibition, spontaneous alternation, open-field, and forced-swim tests) were carried out. The results indicate that neonatal repeated MK-801 treatment in rats inhibits an increase in immobility in the forced-swim test after they have experienced chronic forced-swim stress. This suggests that rats that have undergone chronic neonatal repeated NMDA receptor blockade could have a reduced ability to habituate or adapt to a stressful situation, and supports the hypothesis that these rats are sensitive or vulnerable to stress. PMID- 28647566 TI - Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection. PMID- 28647567 TI - Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation. AB - BACKGROUND & AIMS: We investigated the functional role and clinical significance of stearoyl-CoA desaturase-1 (SCD1) mediated endoplasmic reticulum (ER) stress in regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing a novel therapeutic strategy against hepatocellular carcinomas (HCCs). METHODS: We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize the functional roles of SCD1 in regulating liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations were identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of SCD1 inhibition and sorafenib was tested using a patient-derived tumor xenograft (PDTX) model. RESULTS: SCD1 overexpression was found in HCC, which was associated with shorter disease-free survival (p = 0.008, log rank test). SCD1 was found to regulate the populations of liver T-ICs; while its suppression by a SCD1 inhibitor suppressed liver T-ICs and sorafenib resistance. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant PDTX model, and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Suppression of SCD1 forces liver T-ICs to differentiate via ER stress-induced unfolded protein response, resulting in an enhanced sensitivity to sorafenib. The PDTX#1 model, combined with sorafenib treatment and a novel SCD1 inhibitor (SSI-4), showed a maximal growth suppressive effect. CONCLUSIONS: SCD1-mediated ER stress regulates liver T-ICs and sorafenib sensitivity. Targeting SCD1 alone or in combination with sorafenib might be a novel personalized medicine against HCC. Lay summary: In this study, SCD1 was found to play a critical role in regulating liver tumor-initiating cells and sorafenib resistance through the regulation of ER stress-mediated differentiation. Targeting SCD1 in combination with sorafenib may be a novel therapeutic strategy against liver cancer. PMID- 28647569 TI - Sepsis in alcohol-related liver disease. AB - Alcohol-related liver disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well designed trials before clinical implementation. PMID- 28647568 TI - Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol induced liver injury in mice and patients. AB - BACKGROUND & AIMS: Macrophage migration inhibitory factor (MIF) is a multi-potent cytokine that contributes to the inflammatory response to injury. MIF is expressed by multiple cell types; however, the cellular source and actions of MIF in alcoholic liver disease (ALD) are not well known. Here we tested the hypothesis that non-myeloid cells, specifically hepatocytes, are an important cellular source of MIF in ALD. METHODS: MIF expression was measured in HuH7 and differentiated THP-1 cells in response to ethanol. Ethanol-induced liver injury was assessed in C57BL/6 (WT) and Mif-/- bone marrow chimeras. MIF was measured in peripheral and suprahepatic serum, as well as visualized by immunohistochemistry in liver biopsies, from patients with alcoholic hepatitis (AH). RESULTS: HuH7 hepatocytes, but not THP-1 macrophages, released MIF in response to ethanol challenge in culture. In chimeric mice expressing MIF in non-myeloid cells (Mif-/ ->WT), chronic ethanol feeding increased ALT/AST, hepatic steatosis, and expression of cytokine/chemokine mRNA. In contrast, chimeric mice not expressing MIF in non-myeloid cells (WT->Mif-/-) were protected from ethanol-induced liver injury. Immunohistochemical staining of liver biopsies from patients with AH revealed a predominant localization of MIF to hepatocytes. Interestingly, the concentration of MIF in suprahepatic serum, but not peripheral serum, was positively correlated with clinical indicators of disease severity and with an increased risk of mortality in patients with AH. CONCLUSIONS: Taken together, these data provide evidence that hepatocyte-derived MIF is critical in the pathogenesis of ALD in mice and likely contributes to liver injury in patients with AH. Lay summary: Alcoholic liver disease is a major cause of preventable mortality worldwide, and lacks specific pharmacological therapies. Recent studies have recognized that macrophage migration inhibitor factor (MIF) has a critical role in the inflammatory response to liver damage. However, the cells that produce this protein are still unknown. Our present findings reveal that hepatocytes, the main cell type in the liver, are primarily responsible for MIF production in response to alcohol, which promotes liver injury. Our study suggests that drugs inhibiting MIF production could be beneficial in treating patients with liver disease due to excessive alcohol consumption. PMID- 28647570 TI - Young children's attributions of causal power to novel invisible entities. AB - In two studies, we investigated the development of children's reasoning about potent invisible entities. In Study 1, children aged 2.2-5.5years (N=48) were briefly told about a novel invisible substance that could produce a novel outcome make a novel box turn green. During this introduction, children watched as one container was inverted over a box and the box lit up green, and then another identical container was inverted over the box and the box did not light up. On test trials, the experimenter inserted a spoon in novel (actually empty) containers and inverted the spoon over the box, which turned green in one trial and did not light up in the other trial. For both trials, children were asked whether there was anything in each container. Children across this age range appropriately reported that an invisible substance was present only when the box lit up. In Study 2, children aged 2.4-4.5years (N=48) watched similar demonstrations but were not explicitly provided information about the invisible substance. Children as young as 3years spontaneously inferred that an invisible substance was present when the box lit up and was absent when the box did not light up. A final task tested children's ability to use their causal knowledge of invisible substances to produce an effect-making the box light up. The youngest children had difficulty with this task, but many children aged 3.5-4.5years performed capably. These results indicate an early-emerging understanding of potent invisible entities that develops rapidly during early childhood. PMID- 28647571 TI - Adsorption of p-chlorophenol on three amino-modified hyper-cross-linked resins. AB - Three amino-modified hyper-cross-linked resins (HCP-M, HCP-E, and HCP-D) were synthesized, and they were evaluated for adsorption of p-chlorophenol from aqueous solution. The results indicated that the uploading amounts of the amino groups on the three resins followed an order of HCP-M 65 years), community-dwelling adults admitted to a safety net hospital in the Midwest for 3 or more nights and discharged home after an SNF stay (n = 1543). MEASUREMENTS: The primary outcome was hospital readmission within 30 days of SNF discharge. The primary independent variables were either a home health visit or an outpatient provider visit within a week of SNF discharge. RESULTS: Out of 8754 community-dwelling, hospitalized older adults, 3025 (34.6%) were discharged to an SNF, of whom 1543 (51.0%) returned home. Among the SNF to home group, a home health visit within a week of SNF discharge was associated with reduced hazard of 30-day hospital readmission [adjusted hazard ratio (aHR) 0.61, P < .001] but outpatient provider visits were not associated with reduced risk of hospital readmission (aHR = 0.67, P = .821). CONCLUSION: For patients discharged from an SNF to home, the finding that a home health visit within a week of discharge is associated with reduced hazard of 30 day hospital readmissions suggests a potential avenue for intervention. PMID- 28647578 TI - Regular Source of Care for the Elderly: A Cross-National Comparative Study of Hong Kong With 11 Developed Countries. AB - OBJECTIVE: This study aimed to give an international perspective of health service gaps for caring for elderly individuals and explore the role of primary care for caring for elderly individuals with chronic conditions in Hong Kong. DESIGN: Cross-sectional, telephone survey. SETTING: Hong Kong. PARTICIPANT: A sample of 1000 Chinese participants in Hong Kong aged 60 or older. MEASUREMENTS: Questionnaire extracted from the Commonwealth Fund 2014 International Health Policy Survey of Older Adults. RESULTS: Similar to the 11 countries, more than half (about 65%) of Hong Kong respondents suffered from chronic conditions, whereas approximately one-third of them had at least 2 chronic conditions. US respondents had highest rate of having chronic conditions. Only 65% of Hong Kong respondents reported having a regular source of care and a higher proportion of elderly reported having poor self-rated health when compared with overseas counterparts. However, the proportion of elderly individuals who could access same-day or next-day medical care was higher compared with findings of other countries. Both Hong Kong and US respondents were more likely to report cost related problems when accessing care. Waiting time for specialists in Hong Kong was much longer and coordination between regular doctors was poorer than in all other countries. Although half of Hong Kong respondents had a management plan for chronic conditions, a smaller proportion of them considered it helpful. CONCLUSIONS: Hong Kong has the lowest rate of regular source of care when compared with 11 developed countries, although people in Hong Kong were more likely to be able to access same-day or next-day medical care. To cope with increasing needs of chronic disease care, there may be a need to further develop the provision of regular source of care for elderly individuals, including the development of quality primary care in Hong Kong. PMID- 28647579 TI - Frailty Is Associated With Lower Expression of Genes Involved in Cellular Response to Stress: Results From the Toledo Study for Healthy Aging. AB - BACKGROUND: Specific mechanisms underlying frailty syndrome are not well known. Frailty can be viewed as a loss of functional reserve resulting in increased vulnerability to stressors. We hypothesize that pathways regulating cellular response to stress are potential players in the development of frailty. The aim of this study was to evaluate the association of the expression of certain genes related to cellular response to stress with the presence of frailty in older patients. METHODS: A sample of 350 individuals aged 65 years or older (22% frail) was selected from the Toledo Study of Healthy Aging. RNA was extracted from blood and retro-transcribed into complementary DNA. TaqMan Low density Arrays were used for the measurement of expression of genes implicated in cellular response to oxidative stress, genes implicated in inflammation, genes implicated in vascular physiology, and genes related to hypoxia. For data analysis, a logistic regression model was used to assess the relationship of gene expression and frailty. RESULTS: Among the analyzed genes, lower expression of genes related to cellular response to hypoxia (hypoxia inducible factor-1alpha) or to cellular response to oxidative stress (nuclear factor erythroid 2-related factor 2 and its target genes heme oxygenase-2, thioredoxin reductase-1, and superoxide dismutase 2), but not to those related to inflammation or vascular physiology, were significantly associated with the presence of frailty after adjustment for age and sex. These associations remained significant after adjustment by type 2 diabetes and Charlson index of comorbidities. Lower expressions of genes involved in cellular response to stress were also associated with increased risk of functional impairment. CONCLUSIONS: Reduced expression of several genes implicated in cellular response to oxidative stress or hypoxia is significantly associated with the presence of frailty. These results help to fill the gap of knowledge of this evolving field and provide targets for intervention to promote health and independence in the elderly. PMID- 28647581 TI - Development of field-applicable tests for rapid and sensitive detection of Candidatus Phytoplasma oryzae. AB - Napier grass Stunt Disease (NSD) is a severe disease of Napier grass (Pennisetum purpureum) in Eastern Africa, caused by the leafhopper-transmitted bacterium Candidatus Phytoplasma oryzae. The pathogen severely impairs the growth of Napier grass, the major fodder for dairy cattle in Eastern Africa. NSD is associated with biomass losses of up to 70% of infected plants. Diagnosis of NSD is done by nested PCR targeting the phytoplasma DNA, which is difficult to perform in developing countries with little infrastructure. We report the development of an easy to use, rapid, sensitive and specific molecular assay for field diagnosis of NSD. The procedure is based on recombinase polymerase amplification and targets the imp gene encoding a pathogen-specific immunodominant membrane protein. Therefore we followed a two-step process. First we developed an isothermal DNA amplification method for real time fluorescence application and then transferred this assay to a lateral flow format. The limit of detection for both procedures was estimated to be 10 organisms. We simplified the template preparation procedure by using freshly squeezed phloem sap from Napier grass. Additionally, we developed a laboratory serological assay with the potential to be converted to a lateral flow assay. Two murine monoclonal antibodies with high affinity and specificity to the immunodominant membrane protein IMP of Candidatus Phytoplasma oryzae were generated. Both antibodies specifically reacted with the denatured or native 17 kDa IMP protein. In dot blot experiments of extracts from infected plant, phytoplasmas were detected in as little as 12,5 MUg of fresh plant material. PMID- 28647580 TI - One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study. AB - OBJECTIVES: Although the biological rationale for the association between folate, vitamin B12, and homocysteine with cognitive function seems plausible, conflicting results have been reported. This study aimed to determine the associations between 1-carbon (1-C) metabolism biomarkers (folate, vitamin B12, and homocysteine), and cognitive impairment at baseline and the rate of cognitive decline over 5 years in the very old. DESIGN: The Newcastle 85+ Study was a prospective longitudinal study of people 85 years old and followed over 5 years in Northeast England. SETTING: Community-dwelling and institutionalized. PARTICIPANTS: The analytical sample included 765 very old participants with 1-C metabolism biomarkers and cognitive measures. MEASUREMENTS: Global cognition was measured by the Standardized Mini-Mental State Examination (SMMSE) at baseline, and at 3 and 5 years of follow-up and, attention-specific cognition with the Cognitive Drug Research (CDR) System at baseline, and at 1.5 and 3.0 years of follow-up. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were determined by immunoassay. Linear mixed models were used to estimate the associations between quartiles of 1-C metabolism biomarkers and cognition over 3 (CDR) and 5 years (SMMSE). RESULTS: Compared with participants in the lowest quartile of RBC folate concentrations (<612 nmol/L), those in the highest quartile of RBC folate concentrations (>1280 nmol/L) had 1 more point on the SMMSE at baseline (beta = +1.02, SE = 0.43, P = .02). Those in quartile 4 of tHcy (>21.4 MUmol/L) had 1 point less in the SMMSE at baseline than those in the lowest quartile (<13.5 MUmol/L) (beta = -1.05, SE = 0.46, P = .02). Plasma vitamin B12 was not predictive of global or attention specific cognition at baseline and at follow-up. None of the 1-C metabolism biomarkers except tHcy was associated with the rate of decline in attention scores over 3 years. CONCLUSION: RBC folate and tHcy, but not plasma vitamin B12, were associated with better global cognition in the very old at baseline but were not predictive of rate of decline over 5 years. PMID- 28647582 TI - Comparison of sequencing the D2 region of the large subunit ribosomal RNA gene (MicroSEQ(r)) versus the internal transcribed spacer (ITS) regions using two public databases for identification of common and uncommon clinically relevant fungal species. AB - CONTEXT: Fungal infections cause considerable morbidity and mortality in immunocompromised patients. Rapid and accurate identification of fungi is essential to guide accurately targeted antifungal therapy. With the advent of molecular methods, clinical laboratories can use new technologies to supplement traditional phenotypic identification of fungi. OBJECTIVE: The aims of the study were to evaluate the sole commercially available MicroSEQ(r) D2 LSU rDNA Fungal Identification Kit compared to the in-house developed internal transcribed spacer (ITS) regions assay in identifying moulds, using two well-known online public databases to analyze sequenced data. DESIGN: 85 common and uncommon clinically relevant fungi isolated from clinical specimens were sequenced for the D2 region of the large subunit (LSU) of ribosomal RNA (rRNA) gene with the MicroSEQ(r) Kit and the ITS regions with the in house developed assay. The generated sequenced data were analyzed with the online GenBank and MycoBank public databases. RESULTS: The D2 region of the LSU rRNA gene identified 89.4% or 92.9% of the 85 isolates to the genus level and the full ITS region (f-ITS) 96.5% or 100%, using GenBank or MycoBank, respectively, when compared to the consensus ID. When comparing species-level designations to the consensus ID, D2 region of the LSU rRNA gene aligned with 44.7% (38/85) or 52.9% (45/85) of these isolates in GenBank or MycoBank, respectively. By comparison, f-ITS possessed greater specificity, followed by ITS1, then ITS2 regions using GenBank or MycoBank. Using GenBank or MycoBank, D2 region of the LSU rRNA gene outperformed phenotypic based ID at the genus level. Comparing rates of ID between D2 region of the LSU rRNA gene and the ITS regions in GenBank or MycoBank at the species level against the consensus ID, f-ITS and ITS2 exceeded performance of the D2 region of the LSU rRNA gene, but ITS1 had similar performance to the D2 region of the LSU rRNA gene using MycoBank. CONCLUSION: Our results indicated that the MicroSEQ(r) D2 LSU rDNA Fungal Identification Kit was equivalent to the in-house developed ITS regions assay to identify fungi at the genus level. The MycoBank database gave a better curated database and thus allowed a better genus and species identification for both D2 region of the LSU rRNA gene and ITS regions. PMID- 28647583 TI - The temporal expression of adipokines during spinal fusion. AB - BACKGROUND CONTEXT: Adipokines are secreted by white adipose tissue and have been associated with fracture healing. Our goal was to report the temporal expression of adipokines during spinal fusion in an established rabbit model. PURPOSE: Our goal was to report the temporal expression of adipokines during spinal fusion in an established rabbit model. STUDY DESIGN: The study design included a laboratory animal model. METHODS: New Zealand white rabbits were assigned to either sham surgery (n=2), unilateral posterior spinal fusion (n=14), or bilateral posterior spinal fusion (n=14). Rabbits were euthanized 1-6 and 10 weeks out from surgery. Fusion was evaluated by radiographs, manual palpation, and histology. Reverse transcription-polymerase chain reaction on the bone fusion mass catalogued the gene expression of leptin, adiponectin, resistin, and vascular endothelial growth factor (VEGF) at each time point. Results were normalized to the internal control gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (2^DeltaCt), and control bone sites (2^DeltaDeltaCt). Quantitative data were analyzed by two-factor analysis of variance (p<.05). RESULTS: Manual palpation scores, radiograph scores, and histologic findings showed progression of boney fusion over time (p<.0003). The frequency of fusion by palpation after 4 weeks was 68.75%. Leptin expression in decortication and bone graft sites peaked at 5 weeks after the fusion procedure (p=.0143), adiponectin expression was greatest 1 week after surgery (p<.001), VEGF expression peaked at 4 weeks just after initial increases in leptin expression (p<.001), and resistin decreased precipitously 1 week after the fusion procedure (p<.001). CONCLUSIONS: Leptin expression is likely associated with the maturation phase of bone fusion. Adiponectin and resistin may play a role early on during the fusion process. Our results suggest that leptin expression may be upstream of VEGF expression during spinal fusion, and both appear to play an important role in bone spinal fusion. PMID- 28647584 TI - Transforaminal lumbar interbody fusion (TLIF) versus posterior lumbar interbody fusion (PLIF) in lumbar spondylolisthesis: a systematic review and meta-analysis. AB - BACKGROUND CONTEXT: Transforaminal lumbar interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF) are both frequently used as a surgical treatment for lumbar spondylolisthesis. Because of the unilateral transforaminal route to the intervertebral space used in TLIF, as opposed to the bilateral route used in PLIF, TLIF could be associated with fewer complications, shorter duration of surgery, and less blood loss, whereas the effectiveness of both techniques on back or leg pain is equal. PURPOSE: The objective of this study was to compare the effectiveness of both TLIF and PLIF in reducing disability, and to compare the intra- and postoperative complications of both techniques in patients with lumbar spondylolisthesis. STUDY DESIGN/SETTING: A systematic literature review and meta-analysis were carried out. METHODS: We conducted a Medline (using PubMed), Embase (using Ovid), Cochrane Library, Current Controlled Trials, ClinicalTrials.gov and NHS Centre for Review and Dissemination search for studies reporting TLIF, PLIF, lumbar spondylolisthesis and disability, pain, complications, duration of surgery, and estimated blood loss. A meta-analysis was performed to compute pooled estimates of the differences between TLIF and PLIF. Forest plots were constructed for each analysis group. RESULTS: A total of 192 studies were identified; nine studies were included (one randomized controlled trial and eight case series), including 990 patients (450 TLIF and 540 PLIF). The pooled mean difference in postoperative Oswestry Disability Index (ODI) scores between TLIF and PLIF was -3.46 (95% confidence interval [CI] -4.72 to -2.20, p<=.001). The pooled mean difference in the postoperative VAS scores was -0.05 (95% CI -0.18 to 0.09, p=.480). The overall complication rate was 8.7% (range 0% 25%) for TLIF and 17.0% (range 4.7-28.8%) for PLIF; the pooled odds ratio was 0.47 (95% CI 0.28-0.81, p=.006). The average duration of surgery was 169 minutes for TLIF and 190 minutes for PLIF (mean difference -20.1, 95% CI -33.5 to -6.6, p=.003). The estimated blood loss was 350 mL for TLIF and 418 mL for PLIF (mean difference -43.9 mL, 95% CI -71.2 to -16.6, p=.002). CONCLUSIONS: TLIF has advantages over PLIF in the complication rate, blood loss, and operation duration. The clinical outcome is similar, with a slightly lower postoperative ODI score for TLIF. PMID- 28647585 TI - Distribution of peanut protein in school and home environments of inner-city children. PMID- 28647586 TI - Graphic depiction of bioinformatics data. PMID- 28647587 TI - Sampling frequency for water quality variables in streams: Systems analysis to quantify minimum monitoring rates. AB - Insufficient temporal monitoring of water quality in streams or engineered drains alters the apparent shape of storm chemographs, resulting in shifted model parameterisations and changed interpretations of solute sources that have produced episodes of poor water quality. This so-called 'aliasing' phenomenon is poorly recognised in water research. Using advances in in-situ sensor technology it is now possible to monitor sufficiently frequently to avoid the onset of aliasing. A systems modelling procedure is presented allowing objective identification of sampling rates needed to avoid aliasing within strongly rainfall-driven chemical dynamics. In this study aliasing of storm chemograph shapes was quantified by changes in the time constant parameter (TC) of transfer functions. As a proportion of the original TC, the onset of aliasing varied between watersheds, ranging from 3.9-7.7 to 54-79 %TC (or 110-160 to 300-600 min). However, a minimum monitoring rate could be identified for all datasets if the modelling results were presented in the form of a new statistic, DeltaTC. For the eight H+, DOC and NO3-N datasets examined from a range of watershed settings, an empirically-derived threshold of 1.3(DeltaTC) could be used to quantify minimum monitoring rates within sampling protocols to avoid artefacts in subsequent data analysis. PMID- 28647588 TI - Environmentally-relevant concentrations of Al(III) and Fe(III) cations induce aggregation of free DNA by complexation with phosphate group. AB - Environmental persistence of free DNA is influenced by its complexation with other chemical species and its aggregation mechanisms. However, it is not well known how naturally-abundant metal ions, e.g., Al(III) and Fe(III), influence DNA aggregation. This study investigated aggregation behaviors of model DNA from salmon testes as influenced by metal cations, and elucidated the predominant mechanism responsible for DNA aggregation. Compared to monovalent (K+ and Na+) and divalent (Ca2+ and Mg2+) cations, Al(III) and Fe(III) species in aqueous solution caused rapid DNA aggregations. The maximal DNA aggregation occurred at 0.05 mmol/L Al(III) or 0.075 mmol/L Fe(III), respectively. A combination of atomic force microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy revealed that Al(III) and Fe(III) complexed with negatively charged phosphate groups to neutralize DNA charges, resulting in decreased electrostatic repulsion and subsequent DNA aggregation. Zeta potential measurements and molecular computation further support this mechanism. Furthermore, DNA aggregation was enhanced at higher temperature and near neutral pH. Therefore, DNA aggregation is collectively determined by many environmental factors such as ion species, temperature, and solution pH. PMID- 28647589 TI - Mannose-conjugated layered double hydroxide nanocomposite for targeted siRNA delivery to enhance cancer therapy. AB - Sheet-like layered double hydroxide nanoparticles (LDH NPs) have showed great potentials in biomedical applications such as nanocarriers for drug and gene delivery, biosensors and imaging agents. However, target delivery of drugs and genes using LDH NPs to the desired tumor sites is a major challenge in cancer therapy. The aim of this study is to develop a functional LDH-based nanocomposite for target delivery of siRNA to cancer cells. Mannose as a targeting moiety was firstly conjugated onto SiO2-coated LDH nanocomposite. Cellular uptake data have demonstrated that siRNA is more efficiently delivered to osteosarcoma (U2OS) cells by mannose-conjugated SiO2 coated LDH nanocomposite (Man-SiO2@LDH) compared to unmodified LDH NP. A commercial cell death-siRNA (CD-siRNA) delivered by Man SiO2@LDH can kill cancer cells more effectively. These results reveal that the Man-SiO2@LDH nanocomposite is capable of target-delivering siRNA or drugs to tumor cells for more effective cancer treatment, which provides great potentials in cancer therapy. PMID- 28647590 TI - Differences in the coronal proteome acquired by particles depositing in the lungs of asthmatic versus healthy humans. AB - Most inhaled nanomedicines in development are for the treatment of lung disease, yet little is known about their interaction with the respiratory tract lining fluids (RTLFs). Here we combined the use of nano-silica, as a protein concentrator, with label-free snapshot proteomics (LC-MS/MS; key findings confirmed by ELISA) to generate a quantitative profile of the RTLF proteome and provided insight into the evolved corona; information that may be used in future to improve drug targeting to the lungs by inhaled medicines. The asthmatic coronal proteome displayed a reduced contribution of surfactant proteins (SP-A and B) and a higher contribution of alpha1-antitrypsin. Pathway analysis suggested that asthmatic RTLFs may also be deficient in proteins related to metal handling (e.g. lactoferrin). This study demonstrates how the composition of the corona acquired by inhaled nanoparticles is modified in asthma and suggests depressed mucosal immunity even in mild airway disease. PMID- 28647591 TI - Chitosan-based nanocomposites for the repair of bone defects. AB - Chitosan scaffolds of different deacetylation degrees, average molecular weights and concentrations reinforced with silica nanoparticles were prepared for bone tissue regeneration. The resulting nanocomposites showed similar pore sizes (<300 MUm) regardless the deacetylation degree and concentration used in their formulation. Their mechanical compression resistance was increased by a 30% with the addition of silica nanoparticles as nanofillers. The biocompatibility of the three-dimensional chitosan scaffolds was confirmed by the Alamar Blue assay in human primary osteoblasts as well as the formation of cell spheroids indicative of their great potential for bone regeneration. In vivo implantation of the scaffolds in a mice calvaria defect model provided substantial evidences of the suitability of these nanocomposites for bone tissue engineering showing a mature and dense collagenous tissue with small foci of mineralization, vascularized areas and the infiltration of osteoblasts and osteoclasts. Nevertheless, mature bone tissue formation was not observed after eight weeks of implantation. PMID- 28647592 TI - Liposphere mediated topical delivery of thymoquinone in the treatment of psoriasis. AB - Thymoquinone (TMQ) is reported with good anti-psoriatic activity; however, the hydrophobicity, poor aqueous solubility, light and pH sensitive nature of TMQ hinder its delivery to target site. To address these delivery challenges of TMQ, lipospheres were explored. The topical use of lipospheres offers an effective mean of penetration along with stability and scalability. TMQ lipospheres of particle size below 70 nm were prepared and evaluated. These lipospheres resulted in deeper skin penetration, slow release and skin compatibility. Anti inflammatory and anti-psoriatic potential of lipospheres was determined using in vitro cell lines and imiquimod induced psoriatic plaque model. Cell lines studies indicated reduction in the level of nitric oxide and IL-2, IL-6, IL-1beta, TNF alpha, whereas in vivo results indicated improvement in the phenotypic, histopathological features and reduced level of IL-17 and TNF-alpha in psoriatic skin. These results suggest the potential of TMQ lipospheres in the management of psoriasis. PMID- 28647593 TI - Features of emotional and social behavioral phenotypes of calsyntenin2 knockout mice. AB - Calsyntenin-2 (Clstn2) is the synaptic protein that belongs to the super family of cadherins, playing an important role in learning and memory. We recently reported that Clstn2 knockout mice (Clstn2-KO) have a deficit of GABAergic interneurons coupled with hyperactivity and deficient spatial memory. Given, that impaired functioning of GABA receptors is linked to several psychopathologies, including anxiety and autism, we sought to further characterize Clstn2-KO mice with respect to emotional and social behavior. Clstn2-KO males and females were tested in the elevated plus-maze (EPM), open field (OF), forced swim test, social affiliation and recognition test, social transmission of food preference (STFP), dyadic social interactions and marble burying test. Clstn2-KO mice demonstrated high exploration and hyperactivity in the dimly lit EPM that affect anxiety parameters. In contrast, in a more adverse situation in the OF have increased emotionality in Clstn2-KO males, not females. Assessment of hyperactivity for prolong period in the OF showed that Clstn2-KO animals were able to decline their hyperactivity, but their ambulation still remained higher than in WT littermates. Additionally, Clstn2-KO mice expressed stereotyped behavior. Strikingly, analysis of social behavior identified deficient social motivation and social recognition only in Clstn2-KO males, but not in females. Further analysis of social communication in the STFP and direct observation of agonistic interactions confirmed the reduced social behavior in Clstn2-KO males. Altogether, current results showed Clstn2 gene and sex interactions on socio-emotional performance in mice, suggesting a possible role of calsyntenin2 in psychopathological mechanisms of autism. PMID- 28647595 TI - Intermittent hypoxia caused cognitive dysfunction relate to miRNAs dysregulation in hippocampus. AB - Intermittent hypoxia (IH) is a characteristic pathophysiological change of obstructive sleep apnea (OSA), a commonly diagnosed chronic sleep disorder. With the process of OSA, patients will suffer from the nervous system damage and appear to multiple cognitive dysfunction. The mechanism that how IH causes cognitive impairment is still unknown. Both control and experimental rats were placed in conditions absence and presence of intermittent hypoxia (IH) for 8h a day for a week, two weeks and four weeks, and then followed by behavioral assessments with Morris Water Maze (MWM) test. The results showed that the escape latency of the tested animals to IH significantly increased the escape latency on the last four training days in comparison to the control group. Consistent with this, the expressions of apoptosis/anti-apoptosis proteins were both changed in the hippocampus. Then we utilized the miRNA microarray assay to investigate the level of miRNA expression in rat hippocampus which suffered from intermittent hypoxia. It is noteworthy that the expressions of miR-26b and miR-207 were consistently dysregulated in all the experimental groups post IH. And we utilized qRT-PCR methods to verify the microarray results. Our results showed that microarray based analysis of microRNA expression in rat hippocampus after IH has shown that some microRNAs such as miR-26b and miR-207 could be involved in the OSA-induced cognitive impairments. PMID- 28647596 TI - Testing the physiological plausibility of conflicting psychological models of response inhibition: A forward inference fMRI study. AB - The neural mechanisms underlying response inhibition and related disorders are unclear and controversial for several reasons. First, it is a major challenge to assess the psychological bases of behaviour, and ultimately brain-behaviour relationships, of a function which is precisely intended to suppress overt measurable behaviours. Second, response inhibition is difficult to disentangle from other parallel processes involved in more general aspects of cognitive control. Consequently, different psychological and anatomo-functional models coexist, which often appear in conflict with each other even though they are not necessarily mutually exclusive. The standard model of response inhibition in go/no-go tasks assumes that inhibitory processes are reactively and selectively triggered by the stimulus that participants must refrain from reacting to. Recent alternative models suggest that action restraint could instead rely on reactive but non-selective mechanisms (all automatic responses are automatically inhibited in uncertain contexts) or on proactive and non-selective mechanisms (a gating function by which reaction to any stimulus is prevented in anticipation of stimulation when the situation is unpredictable). Here, we assessed the physiological plausibility of these different models by testing their respective predictions regarding event-related BOLD modulations (forward inference using fMRI). We set up a single fMRI design which allowed for us to record simultaneously the different possible forms of inhibition while limiting confounds between response inhibition and parallel cognitive processes. We found BOLD dynamics consistent with non-selective models. These results provide new theoretical and methodological lines of inquiry for the study of basic functions involved in behavioural control and related disorders. PMID- 28647594 TI - Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia. AB - Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the 'two-hit' theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a 'two-hit' (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments. PMID- 28647597 TI - Hypoxic postconditioning improves behavioural deficits at 6 weeks following hypoxic-ischemic brain injury in neonatal rats. AB - Hypoxic-ischemic (HI) brain injury in newborns is associated with high morbidity and mortality, with many babies suffering neurological deficits. Recently, we showed that hypoxic postconditioning (PostC) immediately post injury can protect against HI up to one week in neonatal rats. Here, we aimed to examine whether long term functional deficits were also improved by PostC. Sprague-Dawley rats were assigned to control (C) or HI group on postnatal day 7 (P7). The HI group underwent unilateral carotid artery occlusion followed by hypoxia (7% oxygen, 3h). Half of each group were randomly assigned to the PostC group (8% oxygen, 1h/day for 5days post-injury), or normoxic group, where animals were kept under ambient conditions. Righting reflex and negative geotaxis tests were performed on P8 and P14. On P42, rats underwent further behavioural tests of motor function and memory (forelimb grip strength, grid walking and novel object recognition tasks). Brain injury was assessed using histological scoring of brain sections. At P14, PostC reduced the righting reflex deficit compared to HI alone. Long-term (6 weeks) behavioural deficits were observed in grid walking and novel object recognition tests after HI alone, with both functions improved following PostC. Following HI, there was an increase in brain injury assessed by histological scoring compared to control, and this damage was reduced by PostC. This novel finding of long-term histological neuroprotection accompanied by functional improvements by PostC further demonstrates the clinical potential of mild hypoxia for the treatment of HI brain injury. PMID- 28647598 TI - Functional brain networks during picture encoding and recognition in different odor contexts. AB - Contextual odors can serve as retrieval cues when applied during encoding and recall/recognition of information. To investigate the neuronal basis of these observations, we collected functional MRI data while participants (n=51) performed an encoding and recognition memory task during which odors (congruent: CO or incongruent: IO) were presented as contextual cues. Recognition performance was not influenced by odor, but there was increased activation in the piriform cortex during successful encoding in the CO group, possibly indicating enhanced retrieval of information previously integrated with an olfactory percept. Moreover, group-independent component analysis revealed a stronger task modulation of subcortical networks for IO versus CO during the recognition task, pointing to differences in olfactory processing. These observations provide a deeper understanding of the involvement of functional neuronal networks in memory tasks and a basis for further evaluation of the impact of odor contexts. PMID- 28647599 TI - PCR-SSCP analysis of MDGI gene and its association with milk production traits in river buffalo (Bubalus bubalis). AB - In this study, we investigated the genetic variation within 3'UTR of Mammary Derived Growth Inhibitor (MDGI) gene of buffalo using PCR-SSCP and sequencing; and also analyzed association of polymorphism with the milk production traits. The study revealed two conformational patterns, 'A' and 'B' among 234 Mehsana buffaloes maintained with their records in the field and at farm. The frequency of SSCP variant 'A' was found to be invariably high in the buffalo population under study. Further, association analysis of SSCP variants with various milk production and milk quality traits indicated no significant effect on any of the traits investigated. Sequencing of SSCP variant 'A' showed homozygous G/G and A/A and 'B' had heterozygous G/C and A/G at positions +124 and +140 respectively, in the 3'UTR of buffalo MDGI. The preliminary results showed the substantial variations in the distribution of SSCP variants' frequencies within Mehsana buffaloes, however these variants had non-significant association with milk yield, fat yield and fat percentage in Mehsana buffaloes. PMID- 28647600 TI - The in vitro biocompatibility of d-(+) raffinose modified chitosan: Two dimensional and three-dimensional systems for culturing of horse articular chondrocytes. AB - The present study investigated the biocompatibility of chitosan films and scaffolds modified with d-(+)raffinose and their capability to support the growth and maintenance of the differentiation of articular chondrocytes in vitro. Primary equine articular chondrocytes were cultured on films and scaffolds of modified d-(+) raffinose chitosan. Their behavior was compared to that of chondrocytes grown in conventional bi- and three-dimensional culture systems, such as micromasses and alginate beads. Chitosan films maintained the phenotype of differentiated chondrocytes (typical round morphology) and sustained the synthesis of cartilaginous extracellular matrix (ECM), even at 4weeks of culture. Indeed, starting from 2weeks of culture, chondrocytes seeded on chitosan scaffolds were able to penetrate the surface pores and to colonize the internal matrix. Moreover they produced ECM expressing the genes of typical chondrocytes differentiation markers such as collagen II and aggrecan. In conclusion, chitosan modified with d-raffinose represents an ideal support for chondrocyte adhesion, proliferation and for the maintenance of cellular phenotypic and genotypic differentiation. This novel biomaterial could potentially be a reliable support for the re-differentiation of dedifferentiated chondrocytes. PMID- 28647601 TI - Benzaldehyde dehydrogenase-driven phytoalexin biosynthesis in elicitor-treated Pyrus pyrifolia cell cultures. AB - Pyrus pyrifolia (Asian pear) cell cultures respond to yeast extract (YE) treatment by accumulating benzoate-derived biphenyl phytoalexins, namely, noraucuparin and aucuparin. Biphenyl phytoalexins are defense-marker metabolites of the sub-tribe Malinae of the family Rosaceae. The substrates for biphenyl biosynthesis are benzoyl-CoA and malonyl-CoA, which combine in the presence of biphenyl synthase (BIS) to produce 3,5-dihydroxybiphneyl. In the non-beta oxidative pathway, benzoyl-CoA is directly derived from benzoic acid in a reaction catalyzed by benzoate-CoA ligase (BZL). Although the core beta-oxidative pathway of benzoic acid biosynthesis is well-understood, the complete cascade of enzymes and genes involved in the non-beta-oxidative pathway at the molecular level is poorly understood. In this study, we report the detection of benzaldehyde dehydrogenase (BD) activity in YE-treated cell cultures of P. pyrifolia. BD catalyzes the conversion of benzaldehyde to benzoic acid. BD and BIS activities were coordinately induced by elicitor treatment, suggesting their involvement in biphenyl metabolism. Changes in phenylalanine ammonia-lyase (PAL) activity preceded the increases in BD and BIS activities. Benzaldehyde was the preferred substrate for BD (Km=52.0MUM), with NAD+ being the preferred co-factor (Km=64MUM). Our observations indicate the contribution of BD towards biphenyl phytoalexin biosynthesis in the Asian pear. PMID- 28647602 TI - Improvement of lindane removal by Streptomyces sp. M7 by using stable microemulsions. AB - Lindane is an organochlorine pesticide which persists in the environment and can cause serious health problems due to its chlorinated and hydrophobic nature. Microemulsions are isotropic and macroscopically homogeneous systems with high solubilization capacity of hydrophilic and hydrophobic compounds. The aim of this study was to evaluate the removal of high concentrations of lindane by the actinobacterium Streptomyces sp. M7 in aqueous and soil systems in the presence of stable microemulsions. Three stable microemulsions were successfully formed with Tween 80, 1-pentanol and three vegetable oils. In most cases, an increase in the cosurfactant/surfactant ratio in the microemulsions favored the solubilization of lindane, while an increase in the oil/surfactant ratio negatively affected the stability of the system. The microemulsion prepared with soybean oil allowed the solubilization of 66% of lindane added to the aqueous medium and 4.5 times more than the surfactant solution at the same concentration. This microemulsion increased the bioavailability of lindane in the aqueous medium and hence enhanced its removal by Streptomyces sp. M7 almost two times respect to the achieved with the surfactant solution. In loam soil system, the addition of the microemulsion allowed an 87% of lindane removal by Streptomyces sp. M7, increasing almost 50% the removal respect to the obtained without the addition of surfactant agents, although it did not present significant difference respect to the obtained with the surfactant solution. This is the first report on enhanced lindane removal by actinobacteria by using direct microemulsions as bioremediation tools. PMID- 28647603 TI - Effects of the herbicide glyphosate on non-target plant native species from Chaco forest (Argentina). AB - Agriculture based on transgenic crops has expanded in Argentina into areas formerly occupied by Chaco forest. Even though glyphosate is the herbicide most widely used in the world, increasing evidence indicates severe ecotoxicological effects on non-target organisms as native plants. The aim of this work is to determine glyphosate effects on 23 native species present in the remaining Chaco forests immersed in agricultural matrices. This is a laboratory/greenhouse approach studying acute effects on seedlings after 21 days. A gradient of glyphosate rates (525, 1050, 2100, 4200, and 8400g ai/Ha; recommended field application rate (RFAR) = 2100g ai/Ha) was applied on four-week seedlings cultivated in a greenhouse and response variables (phytotoxicity, growth reduction, and sensitivity to the herbicide) were measured. This gradient of herbicide rates covers realistic rates of glyphosate applications in the crop field and also those that can reach vegetation of forest relicts by off-target drift and overspray. Testing was performed following guidelines for vegetative vigour (post-germination spray). All species showed lethal or sublethal effects after the application of the 25% of RFAR (50% of species showed severe phytotoxicity or death and 70% of species showed growth reduction). The results showed a gradient of sensitivity to glyphosate by which some of the studied species are very sensitive to glyphosate and seedlings died with 25% of RFAR while other species can be classified as herbicide-tolerant. Thus, the vegetation present in the forest relicts could be strongly affected by glyphosate application on crops. Lethal and sublethal effects of glyphosate on non-target plants could promote both the loss of biodiversity in native forest relicts immersed in the agroecosystems and the selection of new crop weeds considering that some biotypes are continuously exposed to low doses of glyphosate. PMID- 28647604 TI - Hydrogen-rich water induces aluminum tolerance in maize seedlings by enhancing antioxidant capacities and nutrient homeostasis. AB - The ameliorative effect of H2 on aluminum (Al)-induced stress remains poorly understood. We treated maize seedlings with Al and hydrogen-rich water (HRW) to determine the roles of H2 in the alleviation of Al toxicity. Our results demonstrated that Al stress triggered damage to the photosynthetic apparatus, plant growth inhibition, and reactive oxygen species (ROS) production, and boosted lipid peroxidation. However, the addition of HRW at 75% saturation markedly alleviated Al toxicity symptoms through the promotion of root elongation. These responses were related to the significantly increased activities of typical antioxidant enzymes (CAT, APX, SOD, and POD). In vivo imaging of plasma membrane integrity, lipid peroxidation, and the level of ROS provided further evidence that HRW could improve Al tolerance. Our results also indicate that 100% HRW mitigated Al toxicity less than 75% HRW. Moreover, different concentrations of HRW significantly improved photosynthesis and increased nutrient uptake. We conclude that exogenous H2 supplementation could enhance Al tolerance by reestablishing redox homeostasis and maintaining nutrient homeostasis. PMID- 28647605 TI - Will heavy metals in the soils of newly submerged areas threaten the water quality of Danjiangkou Reservoir, China? AB - Soil heavy metal contents were measured in newly submerged areas of the Danjiangkou Reservoir, China. We aimed to determine the heavy metal distribution in this area and the associated ecological risk. Most of these heavy metal contents (except Pb and Mn) suggest enrichment compared with the background values of soils from Henan Province, especially As and Cd with mean geo accumulation index (Igeo) values of 0.84 and 0.54. The spatial analysis results indicated that the highest heavy metal contents were distributed in the arable soils above 160m elevation, whereas low heavy metal contents were observed under other land-use types above 160m elevation. According to Igeo and EF values, Cd was the major heavy metal contaminant in the newly submerged area, Cr, Pb and Mn mainly originated from natural geochemical sources. In contrast, Ni, Cd, As, Cu, and Zn mainly originated from anthropogenic sources. Evaluation using the potential ecological risk (PER) method indicated that PER of individual elements were low in the studied soils, and the comprehensive PER index was at a moderate level, indicating heavy metals in the soils of newly submerged areas may not threaten the water quality of Danjiangkou Reservoir, especially in winter. PMID- 28647606 TI - Role of Streptomyces pactum in phytoremediation of trace elements by Brassica juncea in mine polluted soils. AB - The industrial expansion, smelting, mining and agricultural practices have increased the release of toxic trace elements (TEs) in the environment and threaten living organisms. The microbe-assisted phytoremediation is environmentally safe and provide an effective approach to remediate TEs contaminated soils. A pot experiment was conducted to test the potential of an Actinomycete, subspecies Streptomyces pactum (Act12) along with medical stone compost (MSC) by growing Brassica juncea in smelter and mines polluted soils of Feng County (FC) and Tongguan (TG, China), respectively. Results showed that Zn (7, 28%), Pb (54, 21%), Cd (16, 17%) and Cu (8, 10%) uptake in shoot and root of Brassica juncea was pronounced in FC soil. Meanwhile, the Zn (40, 14%) and Pb (82, 15%) uptake in the shoot and root were also increased in TG soil. Shoot Cd uptake remained below detection, while Cu decreased by 52% in TG soil. The Cd and Cu root uptake were increased by 17% and 33%, respectively. Results showed that TEs uptake in shoot increased with increasing Act12 dose. Shoot/root dry biomass, chlorophyll and carotenoid content in Brassica juncea were significantly influenced by the application of Act12 in FC and TG soil. The antioxidant enzymatic activities (POD, PAL, PPO and CAT) in Brassica juncea implicated enhancement in the plant defense mechanism against the TEs induced stress in contaminated soils. The extraction potential of Brasssica was further evaluated by TF (translocation factor) and MEA (metal extraction amount). Based on our findings, further investigation of Act12 assisted phytoremediation of TEs in the smelter and mines polluted soil and hyperaccumulator species are suggested for future studies. PMID- 28647607 TI - Bioaccessibility and risk assessment of essential and non-essential elements in vegetables commonly consumed in Swaziland. AB - The green leafy vegetables (Mormodica involucrate, Bidens pilosa and Amaranthus spinosus) are economic; seasonal; locally grown and easily available; easy to propagate and store; highly nutritious food substances that form an important component of diets. This study applies a physiology based extraction technique (PBET) to mimic digestion of these vegetables to determine the fraction of essential (Fe and Zn) and non-essential elements (Cd, Cr and Pb) that are made available for absorption after ingestion. Prior to the application of the PBET, the vegetables were cooked adopting indigenous Swazi cooking methods. Cooking mobilized most of the metals out of the vegetable mass, and the final substrate concentrations are: raw > cooked > supernatant for all the metals, and the order of average metal leaching was: Pb (82.2%) >Cr (70.6%) >Zn (67.5%) >Fe (60.2%) >Cd (53.6%). This meant that the bioavailable concentrations are significantly lower than in the original vegetable mass, if only the solid mass is consumed. Bioaccessibility was higher in the gastric tract than in the intestinal phases of the PBET for all the metals in all the vegetables. Risk assessment protocols employed on the non-essential elements (Cr, Cd and Pb) showed that the associated risks of ingesting metal contaminated vegetables are higher for children, than they are for adults, based on the target hazard quotient (THQ) index. However, the overall health risk associated with ingestion of these metals is low, for both children and adults, based on the HR index. Conclusively, this study expounds on the nutritional and risk benefits associated with ingesting naturally grown vegetables. PMID- 28647608 TI - A route-based pathway analysis framework integrating mutation information and gene expression data. AB - We propose a new way of analyzing biological pathways in which the analysis combines both transcriptome data and mutation information and uses the outcome to identify "routes" of aberrant pathways potentially responsible for the etiology of disease. Each pathway route is encoded as a Bayesian Network which is initialized with a sequence of conditional probabilities which are designed to encode directionality of regulatory relationships encoded in the pathways, i.e. activation and inhibition relationships. First, we demonstrate the effectiveness of our model through simulation in which the model was able to easily separate Test samples from Control samples using fictitiously perturbed pathway routes. Second, we apply our model to analyze the Breast Cancer data set, available from TCGA, against many cancer pathways available from KEGG and rank the significance of identified pathways. The outcome is consistent with what have already been reported in the literature. Third, survival analysis has been carried out on the same data set by using pathway routes as features. Overall, we envision that our model of using pathway routes for analysis can further refine the conventional ways of subtyping cancer patients as it can discover additional characteristics specific to individual's tumor. PMID- 28647609 TI - A machine learning approach for automated wide-range frequency tagging analysis in embedded neuromonitoring systems. AB - EEG is a standard non-invasive technique used in neural disease diagnostics and neurosciences. Frequency-tagging is an increasingly popular experimental paradigm that efficiently tests brain function by measuring EEG responses to periodic stimulation. Recently, frequency-tagging paradigms have proven successful with low stimulation frequencies (0.5-6Hz), but the EEG signal is intrinsically noisy in this frequency range, requiring heavy signal processing and significant human intervention for response estimation. This limits the possibility to process the EEG on resource-constrained systems and to design smart EEG based devices for automated diagnostic. We propose an algorithm for artifact removal and automated detection of frequency tagging responses in a wide range of stimulation frequencies, which we test on a visual stimulation protocol. The algorithm is rooted on machine learning based pattern recognition techniques and it is tailored for a new generation parallel ultra low power processing platform (PULP), reaching performance of more that 90% accuracy in the frequency detection even for very low stimulation frequencies (<1Hz) with a power budget of 56mW. PMID- 28647610 TI - The JAK/STAT3 axis: A comprehensive drug target for solid malignancies. AB - Intercellular communication between tumor cells, immune cells and the stroma characterises the tumor microenvironment, which is instrumental for establishing the ecological niche that fosters tumor growth and metastasis. While tumor cell intrinsic STAT3 signaling provides a crucial axis to support cell proliferation and survival, it also regulates many activities of the non-transformed cells that collectively make up the tumor microenvironment. Accordingly, excessive activation of STAT3 is a hallmark of many malignancies, and often occurs in response to cytokines of the IL-6 and IL-10 families. However, tumor extrinsic STAT3 signaling also regulates the effector function of tumor-associated immune and stromal cells, which support the growth of tumors by suppressing the host's anti-tumor immune response. Given that STAT3 mediates tumorigenic effects in many cell types, the molecular players of STAT3 signaling and its upstream JAK kinases provide viable therapeutic targets for the treatment of cancer. Here we provide an update on novel insights into the role of STAT3 in immune suppression and describe current therapeutic strategies that target the JAK/STAT3 signaling axis for the treatment of malignancies. PMID- 28647612 TI - Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors. AB - Apolipoprotein E (APOE) is a member of the vertebrate protein family of exchangeable apolipoproteins that is characterized by amphipathic alpha-helices encoded by multiple nucleotide tandem repeats. Its equivalent in flying insects - apolipophorin-III - shares structural and functional commonalities with APOE, suggesting the possibility of an evolutionary relationship between the proteins. In contrast to all other known species, human APOE is functionally polymorphic and possesses three major allelic variants (epsilon4, epsilon3 and epsilon2). The present review examines the current knowledge on APOE gene structure, phylogeny and APOE protein topology as well as its human isoforms. The epsilon4 allele is associated with an increased age-related disease risk but is also the ancestral form. Despite increased mortality in the elderly, epsilon4 has not become extinct and is the second-most common allele worldwide after epsilon3. APOE epsilon4, moreover, shows a non-random geographical distribution, and similarly, the epsilon2 allele is not homogenously distributed among ethnic populations. This likely suggests the existence of selective forces that are driving the evolution of human APOE isoforms, which may include differential interactions with dietary factors. To that effect, micronutrients such as vitamin D and carotenoids or dietary macronutrient composition are elucidated with respect to APOE evolution. PMID- 28647611 TI - Autophagy suppresses isoprenaline-induced M2 macrophage polarization via the ROS/ERK and mTOR signaling pathway. AB - The objective of this study was to examine the effect of autophagy on stress induced M2 macrophage polarization in the tumor microenvironment of breast cancer and to determine whether the underlying mechanism was related to the reactive oxygen species (ROS)/ERK and mTOR pathway. In vitro, we found that the basal autophagy level in mouse RAW 264.7 macrophages decreased with the incubation of tumor cell culture supernatant. Similarly, the polarization of RAW 264.7 to M2 macrophages was inhibited by the autophagy inducer rapamycin and increased by the autophagy inhibitor 3-MA or by siBeclin1. In addition, we found that not only was M2 molecule expression down-regulated but intracellular ROS generation was also blocked by autophagy induction. In vivo, we observed that mice that received an isoprenaline injection as a stress agent exhibited augmented implanted breast tumor growth, lung metastasis, intratumoral mRNA expression of M2 molecules and serum ROS generation. In contrast, the intratumoral expression of LC3-II and Beclin1 was decreased. In addition, we observed that isoprenaline induced the up regulation of the intratumoral expression of phosphorylated mTOR, phosphorylated ERK1/2, phosphorylated Tyr705-STAT3 and HIF-1alpha, whereas rapamycin induced an opposite effect on the same molecules and could abolish the effects of isoprenaline. These results suggest that autophagy might suppress M2 macrophage polarization induced by isoprenaline via the ROS/ERK and mTOR signaling pathway. Our findings provide a theoretical basis for why high levels of stress hormones accelerate the progression of breast cancer, and autophagy may play a role in determining the outcomes of cancer therapy. PMID- 28647613 TI - Validating a two-dimensional bipolar spectrum model integrating DSM-5's mixed features specifier for Major Depressive Disorder. AB - INTRODUCTION: The literature on DSM-5's 'Major Depressive Disorder with lifetime mixed features' (MDD-MF) is limited. This study investigated MDD-MF's potential inclusion into a bipolar spectrum. METHODS: We recruited 287 patients with Bipolar I disorder (BD-I), BD-II, MDD-MF or 'MDD without lifetime mixed features' (MDD-noMF); most (N=280) were stabilized for at least one year on medication. Sixteen validators (clinical features, psychiatric family history, temperament, stabilizing treatment) were compared across groups and subjected to trend analyses. Two discriminant function analyses (DFA; primary and secondary), excluding or including, respectively, treatment-related predictors, explored latent dimensions maximizing between-group discrimination; mahalanobis distances between group 'centroids' were calculated. RESULTS: Eleven validators differed significantly across groups; nine varied monotonically along a bipolar diathesis gradient with significant linear trends; two peaked at MDD-MF and displayed significant quadratic trends. In the primary DFA, apart from a classic bipolarity dimension, correlating with hospitalizations, early age at onset, lifetime psychosis and lower anxious temperament scores, on which groups ranked along a bipolar propensity gradient, a second dimension was also significant, peaking at BD-II and MDD-MF (challenging the classic bipolar ranking), which correlated with lifetime psychiatric comorbidities, suicidality, lower lifetime psychosis rates, female gender, higher cyclothymic and lower depressive temperament scores; MDD-MF was equipoised amidst BD-II and MDD-noMF. After including treatment-related predictors (secondary DFA), discrimination improved overall but BD-II and MDD-MF were closest than any other pair, suggesting similar treatment patterns for these two groups at this naturalistic setting. CONCLUSIONS: To our knowledge, this is the first time a two-dimensional bipolar spectrum based on classic external validators is proposed, fitting the data better than a unidimensional model. Additional predictors are warranted to improve BD-II/MDD-MF discrimination. PMID- 28647614 TI - Inefficiency of ulipristal acetate on uterus leiomyomas as an additional sign to suspect leiomyosarcoma. AB - The unexpected diagnosis of a leiomyosarcoma from a surgical specimen of a presumed leiomyoma is rare, but with deleterious consequences, especially if morcellation techniques are used. There are currently no effective methods for such a preoperative diagnosis. Ulipristal acetate has demonstrated efficacy for the preoperative treatment of leiomyomas, but not for all patients. We report two cases of leiomyosarcomas in patients treated with ulipristal acetate for a presumed leiomyoma. We propose that ineffective ulipristal acetate treatment may indicate a population in which uterine leiomyosarcoma is more prevalent. Attention should be given to any features of clinical and imaging examinations which raise the suspicion of a leiomyosarcomas in this population. Such suspicion should guide appropriate measures to avoid seeding the tumor, postponing the diagnosis, upstaging the patient and delaying the treatment (SPUD). PMID- 28647615 TI - Prevalence and associative factors of orthostatic hypotension in older adults: Results from the Well-being of the Singapore Elderly (WiSE) study. AB - BACKGROUND: Orthostatic hypotension (OH) is commonly reported among older adults and is associated with an increased risk of mortality. This study aimed to describe the prevalence and investigate the possible associations between OH with sociodemographic variables, chronic medical conditions, health service utilisation, dementia and cognitive status among older adults residing in Singapore. METHODS: Data was collected from 2266 participants aged 60 years and older who participated in the Well-being of the Singapore Elderly (WiSE) study in 2013. Face-to-face interviews were conducted and data collected includes sociodemographic information, blood pressure measurements, medical history, health services utilisation, and cognitive status. RESULTS: The prevalence of OH among older adults in Singapore was 7.8%. OH was highest in participants aged 85 years and above (OR: 2.33; 1.26-4.30; p=0.007) compared to those aged 75-84 years (OR: 1.76; 1.08-2.85; p=0.023). Participants with hypertension were more likely to have OH (OR: 3.03; 1.56-5.88, p=0.001) than those without hypertension. Those with dementia were also more likely to have OH than those with normal cognitive status (p=0.007). CONCLUSIONS: Older age, hypertension, and dementia were independently associated with OH in the older adult population in Singapore. Interventions such as home safety assessment and preventive measures should be implemented to improve older adult's functional capacity and quality of life to prevent injury. PMID- 28647617 TI - Photodynamic therapy with epidermal ablation using fractional CO2 laser for treating superficial basal cell carcinoma: A case series. PMID- 28647618 TI - Genetic and ecological processes promoting early diversification in the lowland Mesoamerican bat Sturnira parvidens (Chiroptera: Phyllostomidae). AB - With 22 species, Sturnira is the most speciose genus of frugivorous Neotropical bats. Sturnira parvidens inhabits lowland tropical areas from Mexico to Central America. The elevation of this taxon to species level was recent, and discrepancies with respect to its geographic limits and phylogenetic position continue to exist. In order to identify genetic and ecological processes likely involved in the diversification and current distribution of S. parvidens, we evaluated relationships, researched phylogeographic and demographic history, and tested the divergence/conservatism of the climatic niche of this bat. We used data from mitochondrial loci (cytochrome b and the hypervariable D-loop region I) and the nuclear recombination activating gene 1, in 173 samples of S. parvidens and 77 samples of related species. We performed Bayesian analyses to infer phylogenetic relationships and analyzed phylogeographic structure, genetic diversity, divergence times and historical demography. Sturnira bakeri is the sister group of S. parvidens, and inhabits Western Ecuador. The two species diverged c. 1.84Ma, and their distributions are disjunct and separated by Sturnira luisi. Within S. parvidens there are two haplogroups with nearly allopatric distributions that are limited to the Sierra Madre del Sur, on the Mexican Pacific Slope. The divergence time between haplogroups was c. 0.423Ma and we detected signals of demographic expansion. We also analyzed 526 occurrence data of S. parvidens to test for changes in environmental niche of this species. We detected signals of divergence of climatic niche, mainly in temperature and seasonality variables. Likely, both genetic and ecological processes have shaped the evolutionary history of S. parvidens. Despite many climatic fluctuations during the Pleistocene, only the most intense oscillations had an impact on these bats. In addition, ecological differentiation prevents admixture of genetic lineages that are in contact and lack apparent geographical barriers at the southern Sierra Madre del Sur. We concluded that speciation in Sturnira was promoted by this taxon's ability to colonize new geographical and environmental spaces and form genetically structured groups when populations become isolated. PMID- 28647616 TI - Photodynamic therapy in dermatology beyond non-melanoma cancer: An update. AB - Photodynamic therapy (PDT) employs a photosensitizer (PS) and visible light in the presence of oxygen, leading to production of cytotoxic reactive oxygen species, which can damage the cellular organelles and cause cell death. In dermatology, PDT has usually taken the form of topical application of a precursor in the heme biosynthesis pathway, called 5-aminolevulinic acid (or its methyl ester), so that an active PS, protoporphyrin IX accumulates in the skin. As PDT enhances dermal remodeling and resolves chronic inflamation, it has been used to treat cutaneous disorders include actinic keratoses, acne, viral warts, skin rejuvenation, psoriasis, localized scleroderma, some non-melanoma skin cancers and port-wine stains. Efforts are still needed to mitigate the side effects (principally pain) and improve the overall procedure. PMID- 28647619 TI - Molecular phylogeny of the Achatinoidea (Mollusca: Gastropoda). AB - This study presents a multi-gene phylogenetic analysis of the Achatinoidea and provides an initial basis for a taxonomic re-evaluation of family level groups within the superfamily. A total of 5028 nucleotides from the nuclear rRNA, actin and histone 3 genes and the 1st and 2nd codon positions of the mitochondrial cytochrome c oxidase subunit I gene were sequenced from 24 species, representing six currently recognised families. Results from maximum likelihood, neighbour joining, maximum parsimony and Bayesian inference trees revealed that, of currently recognised families, only the Achatinidae are monophyletic. For the Ferussaciidae, Ferussacia folliculus fell separately to Cecilioides gokweanus and formed a sister taxon to the rest of the Achatinoidea. For the Coeliaxidae, Coeliaxis blandii and Pyrgina umbilicata did not group together. The Subulinidae was not resolved, with some subulinids clustering with the Coeliaxidae and Thyrophorellidae. Three subfamilies currently included within the Subulinidae based on current taxonomy likewise did not form monophyletic groups. PMID- 28647620 TI - The mitogenome phylogeny of Adephaga (Coleoptera). AB - The beetle suborder Adephaga consists of several aquatic ('Hydradephaga') and terrestrial ('Geadephaga') families whose relationships remain poorly known. In particular, the position of Cicindelidae (tiger beetles) appears problematic, as recent studies have found them either within the Hydradephaga based on mitogenomes, or together with several unlikely relatives in Geadephaga based on 18S rRNA genes. We newly sequenced nine mitogenomes of representatives of Cicindelidae and three ground beetles (Carabidae), and conducted phylogenetic analyses together with 29 existing mitogenomes of Adephaga. Our results support a basal split of Geadephaga and Hydradephaga, and reveal Cicindelidae, together with Trachypachidae, as sister to all other Geadephaga, supporting their status as Family. We show that alternative arrangements of basal adephagan relationships coincide with increased rates of evolutionary change and with nucleotide compositional bias, but these confounding factors were overcome by the CAT Poisson model of PhyloBayes. The mitogenome + 18S rRNA combined matrix supports the same topology only after removal of the hypervariable expansion segments. Densely sampled mitogenomes, analyzed with site heterogeneous mixture models, support a plausible hypothesis of basal relationships in the Adephaga. PMID- 28647621 TI - Hemi-arthroplasty for distal radius fracture in the independent elderly. AB - INTRODUCTION: The authors report their experience with hemi-arthroplasty in irreparable fresh distal radius fracture in independent elderly patients as first line treatment (12 fractures in 11 women; mean age, 74 years) or in second line after clinically disabling primary failure (4 fractures in 4 women; mean age, 78 years). RESULTS: In the 12 primary surgeries, at a mean 32 months' follow-up, there were no complications requiring implant ablation; mean pain score was 1/10, flexion-extension 62 degrees , Lyon Wrist score 75%, and Patient-Related Wrist Evaluation (PRWE) 22 points. In 2 of the 4 secondary surgeries, at a mean 24 months' follow-up, there were no complications requiring implant ablation; mean pain score was 2.5/10, flexion-extension 62 degrees , Lyon Wrist score 58%, and PRWE 50 points: i.e., slightly poorer results than in primary surgery. CONCLUSION: Salvage of complex fracture in independent elderly patients by hemi arthroplasty, whether primary or secondary to failure, seems to be a considerable progress, to be confirmed in larger series. PMID- 28647622 TI - Risk factors for unsuccessful acetabular press-fit fixation at primary total hip arthroplasty. AB - BACKGROUND: Surgeon at primary total hip arthroplasty sometimes cannot achieve sufficient cementless acetabular press-fit fixation and must resort to other fixation methods. Despite a predominant use of cementless cups, this issue is not fully clarified, therefore we performed a large retrospective study to: (1) identify risk factors related to patient or implant or surgeon for unsuccessful intraoperative press-fit; (2) check for correlation between surgeons' volume of operated cases and the press-fit success rate. HYPOTHESIS: Unsuccessful intra operative press-fit more often occurs in older female patients, particular implants, due to learning curve and low-volume surgeons. MATERIALS AND METHODS: Retrospective observational cohort of prospectively collected intraoperative data (2009-2016) included all primary total hip arthroplasty patients with implant brands that offered acetabular press-fit fixation only. Press-fit was considered successful if acetabulum was of the same implant brand as the femoral component without additional screws or cement. Logistic regression models for unsuccessful acetabular press-fit included patients' gender/age/operated side, implant, surgeon, approach (posterior n=1206, direct-lateral n=871) and surgery date (i.e. learning curve). RESULTS: In 2077 patients (mean 65.5 years, 1093 females, 1163 right hips), three different implant brands (973 ABG-IITM-Stryker, 646 EcoFitTM Implantcast, 458 ProcotylTM L-Wright) were implanted by eight surgeons. Their unsuccessful press-fit fixation rates ranged from 3.5% to 23.7%. Older age (odds ratio 1.01 [95% CI: 0.99-1.02]), female gender (2.87 [95% CI: 2.11-3.91]), right side (1.44 [95% CI: 1.08-1.92]), surgery date (0.90 [95% CI: 1.08-1.92]) and particular implants were significant risk factors only in three surgeons with less successful surgical technique (higher rates of unsuccessful press-fit with ProcotylTM-L and EcoFitTM [P=0.01]). Direct-lateral hip approach had a lower rate of unsuccessful press-fit than posterior hip approach (P<0.01), but there was no correlation between surgeons' volume and rate of successful press-fit (Spearman's rho=0.10, P=0.82). Subcohort of 961 patients with 5-7-years follow-up indicated higher early/late cup revision rates with unsuccessful press-fit. DISCUSSION: Success of press-fit fixation depends entirely on the surgeon and surgical approach. With proper operative technique, the unsuccessful press-fit fixation rate should be below 5% and the impact of patients' characteristics or implants on press-fit fixation is then insignificant. Findings of huge variability in operative technique between surgeons of the presented study emphasize the need for surgeon-specific data stratification in arthroplasty studies and indicate the possibility of false attribution of clinically observed phenomena to patient related factors in pooled data of large centers or hip arthroplasty registers. LEVEL OF EVIDENCE: Level III, retrospective observational case control study. PMID- 28647623 TI - Proximal femoral osteosarcoma: Diagnostic challenges translate into delayed and inappropriate management. AB - BACKGROUND: The proximal femuris is an uncommon site of osteosarcoma. The unusual manifestations at this site may lead to diagnostic and therapeutic mistakes. We therefore performed a retrospective study to estimate the proportions of patients with imaging study findings and/or clinical manifestations typical for osteosarcoma and/or inappropriate treatment decisions. HYPOTHESIS: Proximal femoral osteosarcoma often produces atypical clinical and radiological presentations. MATERIAL AND METHODS: Consecutive patients who underwent surgery at our center to treat proximal femoral osteosarcoma were included. For each patient, we collected the epidemiological characteristics, clinical symptoms, imaging study findings, treatment, and tumor outcome. Proportions were computed with their confidence intervals. RESULTS: Twelve patients had surgery for proximal femoral osteosarcoma between 1986 and 2015. Imaging findings were typical in 1 (8%) patient; they consisted of ill-defined osteolysis in 11/12 (92%) patients, a periosteal reaction in 1/12 (8%) patient, soft tissue involvement in 7/12 (58%) patients, and immature osteoid matrix in 11/12 (92%) patients. No patient had the typical combination of pain with a soft tissue swelling. Management was inappropriate in 2/12 (17%) patients, who did not undergo all the recommended imaging studies before surgery and were treated in another center before the correct diagnosis was established. At last follow-up, 4 patients had died (after a mean of 7 years) and 8 were alive (after a mean of 4 years). CONCLUSION: Proximal femoral osteosarcoma is uncommon and rarely produces the typical clinical and imaging study findings. The atypical presentation often results in diagnostic errors and inappropriate treatments. Ill-defined osteolysis on standard radiographs should prompt computed tomography or magnetic resonance imaging of the proximal femur. Treatment in a specialized center is imperative. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 28647625 TI - Thermoresponsive poly(glycidyl ether) brushes on gold: Surface engineering parameters and their implication for cell sheet fabrication. AB - : Thermoresponsive polymer coatings, optimized for cell adhesion and thermally triggered cell detachment, allow the fabrication of confluent cell sheets with intact extracellular matrix. However, rational design guidelines for such coatings are rare, since temperature-triggered cell adhesion and detachment from thermoresponsive surfaces are mechanistically not well understood. Herein, we investigated the impact of molecular weight (2, 9, 24kDa), grafting density (0.04 1.4 chains nm-2), morphology, and roughness of well-characterized thermoresponsive poly(glycidyl ether) brushes on the cell response at 37 and 20 degrees C. NIH 3T3 mouse fibroblasts served as a model cell line for adhesion, proliferation, and cell sheet detachment. The cell response was correlated with serum protein adsorption from cell culture medium containing 10% fetal bovine serum. Intact cell sheets could be harvested from all the studied poly(glycidyl ether) coated surfaces, irrespective of the molecular weight, provided that the morphology of the coating was homogenous and the surface was fully shielded by the hydrated brush. The degree of chain overlap was estimated by the ratio of twice the polymer's Flory radius in a theta solvent to its interchain distance, which should be located in the strongly overlapping brush regime (2 Rf/l>1.4). In contrast, dense PNIPAM (2.5kDa) control monolayers did not induce protein adsorption from cell culture medium at 37 degrees C and, as a result, did not allow a significant cell adhesion. These structural design parameters of functional poly(glycidyl ether) coatings on gold will contribute to future engineering of these thermoresponsive coatings on more common, cell culture relevant substrates. STATEMENT OF SIGNIFICANCE: Cell sheet engineering as a scaffold-free approach towards tissue engineering resembles a milestone in regenerative medicine. The fabrication of confluent cell sheets maintains the extracellular matrix of cells which serves as the physiological cell scaffold. Thermoresponsive poly(glycidyl ether)s are highly cell-compatible and brushes thereof promote cell adhesion and growth without modification with additional cell adhesive ligands. Thus, a direct correlation of temperature-dependent serum protein adsorption and cell response with surface design parameters such as grafting density and molecular weight became accessible. Hence, surface engineering parameters of well-defined poly(glycidyl ether) monolayers for reproducible cell sheet fabrication have been identified. These design guidelines may also prove beneficial in the development of other brush-like thermoresponsive coatings for cell sheet engineering. PMID- 28647624 TI - Shape memory polyurethanes with oxidation-induced degradation: In vivo and in vitro correlations for endovascular material applications. AB - : The synthesis of thermoset shape memory polymer (SMP) polyurethanes from symmetric, aliphatic alcohols and diisocyanates has previously demonstrated excellent biocompatibility in short term in vitro and in vivo studies, although long term stability has not been investigated. Here we demonstrate that while rapid oxidation occurs in these thermoset SMPs, facilitated by the incorporation of multi-functional, branching amino groups, byproduct analysis does not indicate toxicological concern for these materials. Through complex multi-step chemical reactions, chain scission begins from the amines in the monomeric repeat units, and results, ultimately, in the formation of carboxylic acids, secondary and primary amines; the degradation rate and product concentrations were confirmed using liquid chromatography mass spectrometry, in model compound studies, yielding a previously unexamined degradation mechanism for these biomaterials. The rate of degradation is dependent on the hydrogen peroxide concentration, and comparison of explanted samples reveals a much slower rate in vivo compared to the widely accepted literature in vitro real-time equivalent of 3% H2O2. Cytotoxicity studies of the material surface, and examination of the degradation product accumulations, indicate that degradation has negligible impact on cytotoxicity of these materials. STATEMENT OF SIGNIFICANCE: This paper presents an in-depth analysis on the degradation of porous, shape memory polyurethanes (SMPs), including traditional surface characterization as well as model degradation compounds with absolute quantification. This combination of techniques allows for determination of rates of degradation as well as accumulation of individual degradation products. These behaviors are used for in vivo-in vitro comparisons for determination of real time degradation rates. Previous studies have primarily been limited to surface characterization without examination of degradation products and accumulation rates. To our knowledge, our work presents a unique example where a range of material scales (atomistic-scale model compounds along with macroscopic porous SMPs) are used in conjunction with ex planted samples for calculation of degradation rates and toxicological risk. PMID- 28647626 TI - Smoking Cessation Rates among Patients Undergoing Vascular Surgery in a Canadian Center. AB - BACKGROUND: Smoking is the single most important modifiable risk factor for patients with vascular disease. The aim of this study was to determine the prevalence of smoking and cessation rates among patients undergoing vascular surgery in a Canadian center. METHODS: As part of the Vascular Quality Initiative, a prospectively maintained database was used to identify the patients undergoing vascular surgery between 2010 and 2013. Smoking prevalence data were collated preprocedure, postprocedure, and at year follow-up after intervention at a median of 13 months (mean = 14.4 +/- 7.8 months). Cessation rates at 13-month follow-up were assessed to determine any statistically significant univariate factors. These factors were then used to build a model through backwards logistic regression. Multicollinearity was tested by assessing both variance inflation factors and tolerance. RESULTS: Overall, 624 patients had complete follow-up data. Of these, 209 (33.5%) were smokers presurgically. At 1-year follow-up, of those 209 patients who were smokers preoperatively, 87 (41.6%) had stopped smoking while 122 (58.4%) had not. Patients who were male and aged >70 years were more likely to be smokers preoperatively (P = 0.001 and P < 0.001, respectively). Cessation rates were increased in those aged >70 years (P = 0.005) and in those with chronic obstructive pulmonary disease (P = 0.016). Gender was also statistically associated, with cessation rates higher in females (P = 0.011). CONCLUSIONS: More than one-third of patients who underwent surgery in a Canadian vascular center continue to smoke. Uniquely, we report a statistically significant association between gender and postoperative cessation rates. PMID- 28647627 TI - Endovascular Retrieval of Migrated Distal End of Ventriculoperitoneal Shunt from Bilateral Pulmonary Arteries: A Technical Note. AB - Ventriculoperitoneal (VP) shunting of cerebrospinal fluid is one of the most common procedures performed by neurosurgeons around the world. Migration of distal VP shunt catheter into bilateral segmental pulmonary arteries is an extremely rare complication of VP shunt placement. In the present case, a 30-year old male underwent VP shunting complicated by migration of distal VP shunt catheter into the bilateral pulmonary arteries. Despite manual attempt at externalizing the distal VP shunt catheter at the level of the clavicle, a small piece of distal VP shunt catheter in bilateral pulmonary arteries was noted on computed tomography of the chest obtained after manual externalization. This persistent distal VP shunt catheter was likely left behind after a break in the distal VP shunt catheter during manual externalization procedure. Given the small size of the segmental pulmonary arteries, a novel endovascular technique was used to move the distal VP shunt catheter from the bilateral segmental pulmonary arteries to the main pulmonary trunk. Once in the main pulmonary trunk, a snare device was used to retrieve the distal shunt catheter through the femoral vein. In this technical note, the authors highlight the relevant endovascular technical details to first move the VP shunt catheter from the bilateral segmental arteries followed by successful catheter retrieval using snare device. PMID- 28647628 TI - Nontraumatic Proximal Ulnar Artery Pseudoaneurysm Mimicking a Soft Tissue Tumor in Image Modality. AB - Aneurysm of the proximal ulnar artery is extremely rare. Ultrasonography, computed tomography, and magnetic resonance imaging generally provide accurate diagnosis of aneurysm. A 29-year-old woman who had undergone an excision biopsy of a mass in her right arm by an orthopedic surgeon was referred to our department. We resected the mass and interposed it with a reversed great saphenous vein. Histopathological examination suggested that the mass was a pseudoaneurysm consisting of organized thrombi with recanalization. Clinicians should be aware of the possibility of misdiagnosis of soft tissue tumor in cases of pseudoaneurysm, especially if imaging examination reveals a density consistent with organized thrombus with recanalization. PMID- 28647629 TI - Histological Analysis of a New Route after Subintimal Crural Angioplasty. AB - BACKGROUND: Subintimal angioplasty is an alternative approach in treating critical limb ischemia with crural artery disease. However, route or location of the newly created channel is not understood. CASE PRESENTATION: A 68-year-old man was referred to our hospital with ischemic gangrene of the right big toe. We performed endovascular treatment because he was a poor candidate for bypass surgery. The posterior tibial artery was treated using subintimal angioplasty, although it resulted in early occlusion. We decided that he was not able to receive any further limb salvage treatment and performed amputation below the knee 7 days after treatment. The specimen from the origin of posterior tibial artery to plantar artery bifurcation was resected and the formalin-fixed vessel was cut into 39 segments. Histological analysis showed that the newly formed lumen was comparatively well dilated and created in the media by tearing internal elastic lamina in almost the whole of its length. The severely poor runoff vessels below the ankle were thought to be a main cause of early occlusion. CONCLUSIONS: The newly formed lumen by subintimal crural angioplasty could be well dilated and created in the media. PMID- 28647630 TI - Endovascular Repair of Iatrogenic Iliocaval Fistula Causing High-Output Cardiac Failure after Spine Fusion. AB - The case being presented is a 35-year-old female with a 3-year history of progressive dyspnea and right-sided heart failure following spine surgery. Physical examination identified a continuous bruit in the lower abdomen radiating to her back which prompted further evaluation. Echocardiography showed normal left ventricle systolic function, enlarged right ventricle, functional tricuspid regurgitation, and moderate pulmonary hypertension. A computed tomography (CT) scan of the abdomen and pelvis demonstrated findings consistent with an arteriovenous fistula (AVF) between the right common iliac artery and the inferior vena cava. She underwent an uneventful endovascular repair without perioperative complication. The patient's symptoms resolved a few hours after the procedure and she continued to be symptom free at 3-month follow-up. This case illustrates an iatrogenic iliocaval fistula causing high-output cardiac failure which was successfully treated endovascularly with excellent clinical result. PMID- 28647631 TI - A Prospective, Randomized, Multicenter Clinical Trial on the Safety and Efficacy of a Ready-to-Use Fibrin Sealant as an Adjunct to Hemostasis during Vascular Surgery. AB - BACKGROUND: Anastomotic or "stitch hole" bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene. Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety and the hemostatic effectiveness of a ready-to-use human plasma-derived FS in vascular surgery. METHODS: Patients with mild/moderate suture line bleeding during elective, open, vascular surgery using synthetic grafts or patches were studied. In an initial Exploratory Study, all patients were treated with FS Grifols, and in a subsequent Primary Study were randomized in a 2:1 ratio to FS Grifols or manual compression (MC). The primary efficacy end point was time to hemostasis (TTH), assessed at defined intervals from the start of treatment application, during a 10-min observational period. Safety end points (in Exploratory + Primary Studies) included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests (coagulation, complete blood count, serum clinical chemistry parameters, microscopic urinalysis), viral markers, and immunogenicity. RESULTS: In the Primary Study, the proportion of patients who achieved hemostasis at the 3 min time point was higher in the FS Grifols group (46.4%, n = 51/110) than in the MC group (26.3%, n = 15/57) (P < 0.05). The benefit was maintained at successive time intervals: 69 FS Grifols patients (62.7%) and 18 MC patients (31.6%) at 4 min; 82 FS Grifols patients (74.5%) and 28 MC patients (49.1%) at 5 min. The differences between the groups persisted for TTH <= 7 min and TTH <= 10 min. Treatment failure was reported for 13 FS Grifols patients (11.8%) and 16 MC patients (28.1%). TTH was shorter after FS Grifols application than after MC application. Differences were statistically significant in favor of FS Grifols for each TTH category and for the overall comparison (P < 0.001) as well as for each TTH category (cumulative) and for treatment failure (P = 0.016). Overall, AE experience and types of AEs reported were those expected in this patient population and were similar between the 2 treatment groups. The most frequently reported AEs were procedural pain (59.9% and 69.2% of patients in the FS Grifols [n = 72 + 111] and MC [n = 57] groups, respectively) and nausea (23.5% and 19.2% of patients, respectively). CONCLUSIONS: FS Grifols was efficacious and safe as an adjunct to anastomotic hemostasis in patients undergoing arterial surgery using prosthetic material with mild to moderate bleeding. PMID- 28647632 TI - Axillary Artery to Right Atrial Graft for Dialysis Access Using an Autologous Femoropopliteal Vein. AB - Patients with prolonged history of central venous catheters can develop central venous occlusion. We report the creation of an axillary artery to right atrial graft using the femoropopliteal vein (FPV) for dialysis access in a patient with end-stage renal disease on hemodialysis with history of central venous occlusion. The patient had previously developed steal syndrome following a right brachial artery to right atrial polytetrafluoroethylene graft requiring revision to a left axillary artery inflow which subsequently thrombosed. This is the first report of using an autologous FPV conduit to the right atrium for dialysis. PMID- 28647633 TI - Nicotine Dependence and Willingness to Quit Smoking in Vascular Surgery Patients. AB - BACKGROUND: Smoking rates have declined; however, it remains the primary modifiable risk factor for vascular disease. While vascular surgeons often advise patients to quit, few provide assistance. We sought to understand patients' interest in quitting and determine factors that influence this willingness to quit. METHODS: Anonymous surveys were given to vascular surgery clinic patients in a single institution over a 5-month period. Demographic information, smoking status, cessation attempts, and barriers to quitting were obtained. Nicotine dependence was determined using the Fagerstrom Test, and willingness to quit was assessed using a contemplation ladder. Patient's willingness to quit was evaluated in relation to symptomatic status, previous/planned operation, and nicotine dependence levels. RESULTS: A total of 490 patients (92%) completed the survey with 109 (22%) current smokers, 195 (40%) former smokers, and 186 (38%) never smokers. Never smokers were more likely to be female and employed while smokers were more likely to be disabled. Although 51% of smokers displayed moderate/high nicotine dependence, 54% demonstrated willingness to consider quitting within 6 months. The primary barrier to cessation identified was previous failed attempt(s) to quit in 44%. Most (90%) had previously attempted quitting, 63% attempted 3 or more times, and the most common technique used was "quitting cold turkey". Fifty-nine percent of patients reported physicians' had offered assistance in cessation, but only 2% had been in a cessation program. There was no correlation between willingness to consider quitting and symptomatic status, previous/planned operation, or nicotine dependence. Smokers of less than 10 cigarettes/day had a lower nicotine dependence level (P = 0.0001) and higher willingness to consider quitting (P = 0.0015), as did those who had fewer failed prior attempts to quit and who did not believe it was too late to quit. CONCLUSIONS: Most of our vascular patients self-report as nonsmokers. Over half of those who smoke demonstrate willingness to consider quitting within 6 months, which is not dependent on nicotine dependence, previous/planned operation, or symptomatic status. Those who smoke less than 10 cigarettes per day, have fewer past failed attempts to quit, and believe that it is not too late to quit are more likely to consider quitting. Vascular surgeons should be more aware of previous quit attempts and patterns of smoking and be proactive in assisting patients in cessation attempts. PMID- 28647634 TI - More Successful Results with Less Energy in Endovenous Laser Ablation Treatment: Long-term Comparison of Bare-tip Fiber 980 nm Laser and Radial-tip Fiber 1470 nm Laser Application. AB - BACKGROUND: Varices and venous insufficiency are common and serious health problems in the general population which affect the quality of life. Endothermal treatment of the great saphenous vein has become the first line of treatment for superficial venous reflux, and the endovenous laser ablation (EVLA) method has been widely accepted all over the world. In this method, ablation is provided by a laser fiber inserted into the lumen of the vein. Initially, the fibers were 810 nm, but today the fibers are usually 940, 980, or 1470 nm. METHODS: The study included 400 patients (419 procedures) who were diagnosed with venous insufficiency and underwent 980 and 1470 nm EVLA. Patients were followed up for 48 months. A 980-nm bare-tip laser catheter in Group A and a 1470-nm radial-tip laser catheter in Group B were inserted until they were 2 cm below the saphenofemoral junction. An EVLA catheter was drawn slowly at the rate of 1-3 cm/sec (2.08 +/- 0.6). The energy applied to the saphenous vein was 60-120 J/cm (84.65 +/- 13.03) and 45-120 J/cm (76.95 +/- 15.06) in Group A and Group B, respectively (P < 0.001), with 15 W in the continuous mode. Follow-up visits included a physical examination and Doppler ultrasonography performed at the following time points: day 1, week 1, and months 1, 6, 12, 24, 36, and 48. Saphenous vein occlusion rates and postprocedure saphenous vein diameters were evaluated at each follow-up visit. Pain levels were evaluated using the Wong Baker FACES(r) pain scale (0-10). Postoperative complications were recorded. RESULTS: Group A (980 nm laser) consisted of 200 patients with a mean age of 37.84 +/- 12.2 years. Group B (1470 nm laser) consisted of 200 patients with a mean age of 38.38 +/- 12.1 years. The mean duration of the procedure was 32.2 +/- 9.7 min in Group A and 31.7 +/- 8.8 min in Group B, respectively (P = 0.47). Induration, ecchymosis, and paresthesia rates were significantly higher in the bare-tip laser group. The most important complication, deep vein thrombosis, was observed in 4 patients in Group A. Recanalization rates were found to be increased by prolonged follow-up periods. At the 48-month follow-up, this rate was 15.9% in Group A and 8.3% in Group B (P = 0.017). This rate showed that the 1470-nm wavelength laser treatment was more successful in Group B than in Group A over the long term. CONCLUSIONS: Both the 980 and 1470 nm wavelength laser assisted EVLA procedures appear to be effective in treating saphenous vein insufficiency. The 1470-nm radial-tip fiber is preferred due to lower energy levels, lower complication rates, early return to daily life, and the successful long-term occlusion rate. PMID- 28647635 TI - New Vein Compression Entities in Patients with Unexplained Leg Swelling. AB - BACKGROUND: This retrospective study identifies often overlooked anatomical sites for nonthrombotic venous outflow obstruction (NTVO) in patients with unexplained lower extremity edema and pain. METHODS: We reviewed the charts of 75 consecutive patients experiencing symptoms of unexplained lower extremity edema with pain that were unexplained by ultrasound, computed tomography angiography (CTA), and magnetic resonance imaging (MRI), who subsequently underwent venography in an outpatient medical office from 2010 to 2014. We categorized venograms based on the presence or absence of NTVO lesions and calculated prevalence of each at specific sites. The patients with NTVO lesions showing >50% stenosis on venography were then treated with angioplasty and/or stenting. After intervention, we documented subjective levels of pain and edema. RESULTS: Of the 75 venograms reviewed, physicians classified 52 as normal and 23 as showing evidence of compression, including 9 with May-Thurner syndrome and 14 with anatomical compressions at previously underreported sites. These 14 compression sites occurred at the following: iliofemoral vein at the inguinal ligament region (n = 7, 50%), external iliac vein at the iliac artery bifurcation (n = 1, 7.1%), both inguinal ligament region and iliac artery bifurcation (n = 4, 28.6%), and popliteal vein at the popliteal fossa (n = 2, 14.3%). Nine of the 14 patients (64.3%) reported total or near total resolution of lower extremity pain and edema at follow-up between 1 and 7 months (mean = 5.3 +/- 2 months, median = 6 months) after balloon angioplasty and/or stent. Five with failed primary interventions underwent subsequent stenting and/or angioplasty and reported total or near total resolution of pain and clinical resolution of edema. CONCLUSIONS: This study provides evidence to broaden the disease profile of venous compression syndromes to other sites such as the hypogastric artery, inguinal ligament, and popliteal fossa. The results support previous research that suggests increased incidence of NTVO exists among patients with unexplained lower extremity edema and pain. In an effort to encourage further exploration, we developed a diagnostic algorithm to support a critical and systematic review of patients with lower extremity edema and pain that may go unexplained using traditional diagnostic measures, including ultrasound, CTA, and MRI alone. PMID- 28647636 TI - Transcatheter Arterial Embolization of a Lumbar Artery Injury with Traumatic Aortic Dissection. AB - Whole-body-enhanced computed tomography of a septuagenarian woman hit by a truck revealed a traumatic aortic dissection (Stanford B) and arterial bleeding from the right lumbar artery in the right iliopsoas muscle. Angiography revealed an active arterial extravasation from a false lumen of the left lumbar artery. We performed a transcatheter arterial embolization (TAE) of the right lumbar artery. After fenestration of the intimal flap, the left lumbar artery was successfully selected and embolized; the patient's clinical condition subsequently stabilized. This is the first report of successful treatment of a lumbar artery injury with a traumatic aortic dissection by a TAE. PMID- 28647637 TI - Transcervical Carotid Artery Stenting Using a Prosthetic Arterial Conduit: Case Series of a Novel Surgical Technique. AB - We present a series of 4 patients with carotid restenosis following carotid endarterectomy (CEA) who underwent transcervical carotid artery stenting (CAS) using a novel prosthetic conduit technique. The patients were high risk for repeat CEA (short and obese necks) and had contraindications to transfemoral CAS (bovine arch, prior dissection). CAS was thus performed via a transcervical approach with a polytetrafluoroethylene conduit anastomosed to the proximal common carotid artery. The addition of a conduit allowed stent placement via a secure, stable platform. All patients recovered from their procedure without incident and are free from restenosis at follow-up. PMID- 28647638 TI - Evolution of Practices in Carotid Surgery: Observational Study in France from 2006 to 2015. AB - BACKGROUND: The principal objective of this study is to determine the evolution of surgical management of stenosis of carotid bifurcation over a period of 10 years in France. The secondary objective is to ascertain the impact of recommendations and of the literature on the evolution of these practices. METHODS: From the registry of the "Agence Technique de l'Information sur l'Hospitalisation" we collected all the data for carotid surgery procedures carried out in French healthcare establishments between 2006 and 2015. The search was conducted using the common classification of medical procedures for open surgery and endovascular treatment, and diagnosis-related groups corresponding to neurovascular disease. We conducted a descriptive analysis of data year-by-year and analyzed the number of procedures, the evolution of the type of surgery according to the type of establishment, and the mean duration of hospital stays. RESULTS: During the study period, 165,276 classical procedures (95.8%) and 7319 endovascular procedures (4.2%) of carotid bifurcation were performed. The overall number of procedures was stable over time at a mean of approximately 17,000 procedures per year. Concerning conventional surgery, eversion endarterectomy became the main technique from 2008 onwards, superseding open endarterectomy with patch closure, whereas direct primary closure of the carotid bifurcation has been declining steadily ever since. The use of a shunt declined steadily from 16.3% in 2006 to 13.3% in 2015. Endovascular treatment progressed steadily during the study period from 455 procedures (2.7% of procedures) in 2006 to 943 procedures (5.7%) in 2015. The mean hospital length of stay for patients without associated severe comorbidity was constant for classical surgery (mean of 5.4 days). CONCLUSION: This observational analysis showed stability in the number of carotid procedures performed during the period and a progressive modification of carotid surgery practices in France, in accordance with the recommendations of learned societies and major publications. PMID- 28647639 TI - Flow Reduction-Aided Thrombin Injection for Complex Femoral Pseudoaneurysms: Case Series and Review of the Literature. AB - BACKGROUND: Peripheral pseudoaneurysms are a known complication of vascular access procedures. Complex lesions-those with short, wide necks or other complex arrangements-would conventionally require open repair, but we believe that even these lesions could be managed with an endovascular approach. METHODS: Four patients with complex pseudoaneurysms were offered an open repair or thrombin injection with the use of flow-reducing balloons. RESULTS: In our series of 4 patients with complex pseudoaneurysms, all were safely treated with percutaneous thrombin injection in conjunction with endovascular flow reduction. All patients recovered from their procedures without incident and are free from recurrence at follow-up. CONCLUSIONS: Flow reduction-aided thrombin injection may have particular utility in complex femoral pseudoaneurysms, especially in a patient population that may not tolerate open repair. High-risk lesions may merit special consideration for this technique, and further study is warranted. PMID- 28647640 TI - Bypass Surgery after Endovascular Therapy for Infrapopliteal Lesion Is Not a Poor Outcome Compared with Initial Bypass Surgery by Vascular Surgeons. AB - BACKGROUND: It is unclear whether prior endovascular therapy (EVT) adversely affects bypass surgery. The aim of this study is to investigate treatment outcomes between initial bypass (bypass-first) and bypass surgery after EVT (EVT first). METHODS: We conducted a retrospective analysis of critical limb ischemia patients undergoing infrapopliteal bypass between November 2006 and December 2015. Graft patency, limb salvage (LS), amputation-free survival (AFS), and overall survival (OS) were examined between bypass-first and EVT-first groups. RESULTS: The subjects in this study were 75 patients and 82 limbs in the bypass first group and 24 patients and 24 limbs in the EVT-first group. The average age was higher in EVT-first group (P = 0.03). The percentage of inframalleolar bypass was higher in the EVT-first group (P = 0.002). Primary patency at 1 and 2 years was 72.0% and 67.5% for the bypass-first group and 53.1% and 47.2% for the EVT first group, respectively (P = 0.04). Inframalleolar bypass was a risk factor for lower primary patency (hazard ratio 3.07, 95% confidence interval 1.18-8.51, P = 0.02) in multivariate analysis, while there were no differences in secondary patency, LS, AFS, and OS. CONCLUSIONS: Bypass surgery after EVT has lower primary patency rates in comparison with primary bypass in patients submitted to infrapopliteal revascularization. Although very heterogeneous study population with a lot of bias in the indication of the revascularization, LS, OS and AFS are not affected by previous EVT. PMID- 28647641 TI - Impact of Left Subclavian Artery Revascularization before Thoracic Endovascular Aortic Repair on Postoperative Cerebrovascular Hemodynamics. AB - BACKGROUND: The impact of left subclavian artery (LSA) revascularization before thoracic endovascular aortic repair (TEVAR) on cerebrovascular flow is not well described. We studied bilateral vertebral and carotid artery flow characteristics before and after TEVAR to evaluate the hemodynamic effects of LSA revascularization. METHODS: Seventy-four patients with mixed etiologies (mean age 70.9 +/- 10.5 years) underwent LSA revascularization and TEVAR (2006-2016) and had available preoperative and postoperative carotid duplex study available. Data from patient demographics, procedures, preoperative, and postoperative carotid duplex studies were gathered. Revascularization was by left common carotid artery (LCCA) to LSA bypass (n = 70, 94.6%) or LSA to LCCA transposition (n = 4, 5.4%). RESULTS: Duplex confirmation of antegrade left vertebral artery (LVA) flow decreased significantly after TEVAR with LSA revascularization (100.0% vs. 77.9%, P < 0.001). Incidence of retrograde LVA flow increased from 0.0% to 8.3% (P = 0.063). Postoperatively, LVA bidirectional flow was observed in 3 patients (4.4%). Flow directions in the right vertebral artery (RVA) did not change significantly. Peak systolic velocity (PSV) in the LVA decreased significantly after TEVAR from 55.1 +/- 22.0 cm/s to 35.9 +/- 26.3 cm/s (P < 0.001). In contrast, PSV increased in the RVA and the right internal carotid artery (ICA; 52.2 +/- 21.7 cm/s to 63.2 +/- 23.3 cm/s, P = 0.012 and 95.3 +/- 46.8 cm/s to 102.8 +/- 42.9 cm/s, P = 0.011). PSV did not change significantly in the left ICA. At mean follow-up of 36.6 +/- 26.8 months, primary bypass patency was 100.0%. Postoperatively, one case of temporary spinal cord ischemia was seen (1.4%). Stroke rate was 6.9% (n = 5, 100.0% embolic), all without permanent disabilities. Stroke circulation distribution was 60.0% posterior, 20.0% anterior, and 20.0% mixed. Location of stroke was left sided (n = 2) or in both hemispheres (n = 3). There were no deaths at 30 days. Neurological events during follow-up included 3 new strokes. All-cause mortality rate during follow-up was 12.2% (n = 9). CONCLUSIONS: Adjunctive LSA revascularization in the setting of zone 2 TEVAR coverage is associated with hemodynamic vertebral artery changes. Future studies in larger sample sizes should evaluate whether these novel findings are an important determinant of postoperative neurologic events. PMID- 28647642 TI - A model of how targeted and universal welfare entitlements impact on material, psycho-social and structural determinants of health in older adults. AB - A growing body of research attests to the impact of welfare regimes on health and health equity. However, the mechanisms that link different kinds of welfare entitlement to health outcomes are less well understood. This study analysed the accounts of 29 older adults in England to delineate how the form of entitlement to welfare and other resources (specifically, whether this was understood as a universal entitlement or as targeted to those in need) impacts on the determinants of health. Mechanisms directly affecting access to material resources (through deterring uptake of benefits) have been well documented, but those that operate through psychosocial and more structural pathways less so, in part because they are more challenging to identify. Entitlement that was understood collectively, or as arising from financial or other contributions to a social body, had positive impacts on wellbeing beyond material gains, including facilitating access to important health determinants: social contact, recognition and integration. Entitlement understood as targeted in terms of individualised concepts of need or vulnerability deterred access to material resources, but also fostered debate about legitimacy, thus contributing to negative impacts on individual wellbeing and the public health through the erosion of social integration. This has important implications for both policy and evaluation. Calls to target welfare benefits at those in most need emphasise direct material pathways to health impact. We suggest a model for considering policy change and evaluation which also takes into account how psychosocial and structural pathways are affected by the nature of entitlement. PMID- 28647643 TI - Cognitive functioning among Dutch older adults: Do neighborhood socioeconomic status and urbanity matter? AB - Positive associations of neighborhood socioeconomic characteristics and older adults' cognitive functioning have been demonstrated in previous studies, but overall results have been mixed and evidence from European countries and particularly the Netherlands is scarce. We investigated the effects of socioeconomic status (SES) and urbanity of neighborhoods on four domains of cognitive functioning in a sample of 985 Dutch older adults aged 65-88 years from the Longitudinal Aging Study Amsterdam. Besides cross-sectional level differences in general cognitive functioning, processing speed, problem solving and memory, we examined cognitive decline over a period of six years. Growth models in a multilevel framework were used to simultaneously assess levels and decline of cognitive functioning. In models not adjusting for individual SES, we found some evidence of higher levels of cognitive functioning in neighborhoods with a higher SES. In the same models, urbanity generally showed positive or inversely U-shaped associations with levels of cognitive functioning. Overall, effects of neighborhood urbanity remained significant when adjusting for individual SES. In contrast, level differences by neighborhood SES were largely explained by the respondents' individual SES. This suggests that neighborhood SES does not influence levels of cognitive functioning beyond the fact that individuals with a similar SES tend to self-select into neighborhoods with a corresponding SES. No evidence of systematically faster decline in neighborhoods with lower SES or lower degrees of urbanity was found. The findings suggest that neighborhood SES has no independent effect on older adults cognitive functioning in the Netherlands. Furthermore, the study reveals that neighborhood urbanity should be considered a determinant of cognitive functioning. This finding is in line with theoretical approaches that assume beneficial effects of exposure to complex environments on cognitive functioning. We encourage further investigations into the effect of urbanity in other contexts before drawing firm conclusions. PMID- 28647644 TI - From quantum measurement to biology via retrocausality. AB - A reaction cycle in general or a metabolic cycle in particular owes its evolutionary emergence to the covering reaction environment acting as a measurement apparatus of a natural origin. The quantum measurement of the environmental origin underlying the molecular processes observed in the biological realm is operative cohesively between the measuring and the measured. The measuring part comes to pull in a quantum as an indivisible lump available from an arbitrary material body to be measured. The inevitable difference between the impinging quantum upon the receiving end on the part of the environment and the actual quantum pulled into the receiving end comes to effectively be nullified through the retrocausative propagation of the corresponding wave function proceeding backwards in time. The retrocausal regulation applied to the interface between the measuring and the measured is to function as the organizational agency supporting biology, and is sought in the act for the present in the immediate future within the realm of quantum phenomena. Molecular dynamics in biology owes both the evolutionary buildup and maintenance of its organization to the retrocausal operation of the unitary transformation applied to quantum phenomena proceeding backwards in time. Quantum measurement provides the cohesive agency that is pivotal for implementing the retrocausal regulation. In particular, the physical origin of Darwinian natural selection can be seen in the retrocausal regulation applied to the unitary transformation of a quantum origin. PMID- 28647645 TI - Adding dimension to cellular mechanotransduction: Advances in biomedical engineering of multiaxial cell-stretch systems and their application to cardiovascular biomechanics and mechano-signaling. AB - Hollow organs (e.g. heart) experience pressure-induced mechanical wall stress sensed by molecular mechano-biosensors, including mechanosensitive ion channels, to translate into intracellular signaling. For direct mechanistic studies, stretch devices to apply defined extensions to cells adhered to elastomeric membranes have stimulated mechanotransduction research. However, most engineered systems only exploit unilateral cellular stretch. In addition, it is often taken for granted that stretch applied by hardware translates 1:1 to the cell membrane. However, the latter crucially depends on the tightness of the cell-substrate junction by focal adhesion complexes and is often not calibrated for. In the heart, (increased) hemodynamic volume/pressure load is associated with (increased) multiaxial wall tension, stretching individual cardiomyocytes in multiple directions. To adequately study cellular models of chronic organ distension on a cellular level, biomedical engineering faces challenges to implement multiaxial cell stretch systems that allow observing cell reactions to stretch during live-cell imaging, and to calibrate for hardware-to-cell membrane stretch translation. Here, we review mechanotransduction, cell stretch technologies from uni-to multiaxial designs in cardio-vascular research, and the importance of the stretch substrate-cell membrane junction. We also present new results using our IsoStretcher to demonstrate mechanosensitivity of Piezo1 in HEK293 cells and stretch-induced Ca2+ entry in 3D-hydrogel-embedded cardiomyocytes. PMID- 28647646 TI - The secreted protein WNT5A regulates condylar chondrocyte proliferation, hypertrophy and migration. AB - OBJECTIVE: Our previous study showed that WNT5A, a member of the noncanonical WNT pathway, is involved in interleukin-1beta induced matrix metalloproteinase expression in temporomandibular joint (TMJ) condylar chondrocytes. The purpose of this study is to further explore the roles of WNT5A in cartilage biology of the TMJ. METHODS: An early TMJ osteoarthritis-like rat model was constructed by a mechanical method (steady mouth-opening). The gene and protein levels of WNT5A during the condylar cartilage changes were measured. Effects of WNT5A on chondrocyte proliferation, hypertrophy and migration were analyzed after WNT5A gain or loss of function in vitro. A c-Jun N-terminal kinase (JNK) inhibitor SP600125 was used to evaluate the involvement of JNK pathway in these effects of WNT5A. The expression and transcription activity of cell cycle regulators c-MYC and Cyclin D1 were examined to determine the mechanism behind WNT5A regulation of chondrocyte proliferation. RESULTS: WNT5A was significantly upregulated in the condylar cartilage of rats in the early TMJ osteoarthritis-like model. Activating WNT5A facilitated condylar chondrocyte proliferation, hypertrophy and migration. Conversely, inhibiting WNT5A activity in chondrocytes decreased their proliferation, hypertrophy and migration. Blockage of the JNK pathway by its inhibitor, SP600125, impaired these effects of WNT5A on chondrocytes. WNT5A regulated both the expression and transcriptional activity of c-MYC and Cyclin D1 in chondrocytes, both of which were upregulated in condylar cartilage of the rat early TMJ osteoarthritis. CONCLUSION: WNT5A regulates condylar chondrocyte proliferation, hypertrophy and migration. These findings provide new insights into the role of WNT5A signaling in TMJ cartilage biology and its potential in future therapy for TMJ degenerative diseases. PMID- 28647647 TI - iTRAQ-based quantitative analysis of alveolar bone resorption in rats with experimental periodontitis. AB - OBJECTIVE: Periapical periodontitis results in alveolar bone resorption around the root apex. During the progression of inflammation, host cells release various inflammatory mediators and pro-inflammatory cytokines through immune responses. However, the pathological mechanisms associated with periapical bone destruction remain unclear. This study was objected to identify differentially regulated proteins in periapical periodontitis via a quantitative proteomics approach using isobaric tags for relative and absolute quantification (iTRAQ) labelling of peptides. METHODS: A model of periapical periodontitis by sealing LPS into the pulp chambers of rats was established. iTRAQ was employed to screen differentially expressed proteins in alveolar bone between periapical lesions and healthy controls. These proteins were further analysed by bioinformatics. And four proteins were validated by western bolt. RESULTS: We identified 4398 proteins, of which 7 were up-regulated and 151 were down-regulated in periapical periodontitis compared to normal tissue. Using bioinformatics tools such as GO and KEGG pathway analysis, we found that our proteomics strategy could identify and quantify differentially expressed proteins that were not described in previous studies examining periapical periodontitis; these proteins included hexokinase, legumain and members of the keratin family. CONCLUSION: In summary, our results represent potential biomarkers for the detection of periapical periodontitis and demonstrate that quantitative proteomics is a robust discovery tool for the identification of differentially regulated proteins in periapical periodontitis. PMID- 28647648 TI - Establishment of a primary culture of polymorphous low grade adenocarcinoma cells. AB - OBJECTIVE: The aim of the present study was to establish a primary cell culture derived from polymorphous low grade adenocarcinoma (PLGA). DESIGN: The neoplastic cells were derived from a 57-year-old female patient diagnosed with PLGA. A fragment of the tumor was collected and submitted to enzymatic digestion followed by centrifugation on a Percoll gradient. The cell population was characterized by means of immunofluorescence and detection of PRKD1 gene mutations. RESULTS: Epifluorescence analysis of the primary culture revealed that the malignant epithelial cells were predominantly polygonal in shape and positive for cytokeratin 7, vimentin, and S100. The doubling time of the cell culture was 86.73h. The restriction digestion assay showed that the neoplastic cells possess PRKD1 gene mutations. CONCLUSION: The establishment of primary cell culture derived from PLGA should be considered a useful tool for molecular analysis of this salivary gland tumor. PMID- 28647649 TI - Recovery after PILP remineralization of dentin lesions created with two cariogenic acids. AB - OBJECTIVES: Acetate and lactate are important cariogenic acids produced by oral bacteria. They produced different residual dentin structures in artificial lesions of similar depth. We evaluated if such lesions responded in the same way to a polymer-induced-liquid-precursor (PILP) remineralization. DESIGN: Dentin blocks obtained from human third molars, divided into 6 groups (n=3). Blocks were demineralized with acetate (66h) or lactate (168h) buffer at pH 5.0 to create 140MUm target lesion depths. A-DEM and L-DEM groups received no remineralization. Other groups were remineralized for 14days. 100MUg/mL polyaspartate was added into the remineralizing buffer for A-PIL and L-PIL, whereas A-CAP and L-CAP were treated with the same solution but without polyaspartate. Cross-sectioned blocks were examined for shrinkage and AFM-topography. Line profiles of reduced elastic modulus (Er) were obtained by AFM-based nanoindentation across the lesion. Ultrastructures were examined with TEM. RESULTS: A-PIL and L-PIL recovered in shrinkage to the original height of the dentin and it appeared normal with tubules, with increases in Er at both outer flat and inner sloped zones. At the sloped zone, acetate lesions lost more Er but recovery rate after PILP was not statistically different from lactate lesions. A-CAP and L-CAP showed surface precipitates, significantly less recovery in shrinkage or Er as compared to PILP groups. TEM-ultrastructure of PILP groups showed similar structural and mineral components in the sloped zone for lesions produced by either acid. CONCLUSIONS: The PILP process provided significant recovery of both structure and mechanical properties for artificial lesions produced with acetate or lactate. PMID- 28647650 TI - Quick sequential organ failure assessment compared to systemic inflammatory response syndrome for predicting sepsis in emergency department. AB - PURPOSE: It is unclear whether quick sequential (sepsis-related) organ failure assessment (qSOFA) also has prognostic value for organ failure in patients with a suspected infection. The aim of this study was to determine whether qSOFA has prognostic value when compared to systemic inflammatory response syndrome (SIRS) in predicting organ failure in patients with a suspected infection in an emergency department (ED). METHODS: A retrospective observational study was conducted in an ED during a 9-year period. We analyzed the ability of qSOFA compared to SIRS to predict the development of organ failure in patients (defined as an increase in the SOFA score of 2 points or more) using the area under receiver operating characteristic (AUROC) curve. RESULTS: A total of 1009 patients with suspected infection were finally included in the study. The predictive validity of qSOFA for organ failure was higher than that of SIRS (AUROC=0.814 vs. AUROC=0.662, p=0.02). qSOFA was also superior to SIRS in predicting in-hospital mortality (AUROC=0.733 vs. AUROC=0.599, p=0.04). When the qSOFA score was equal to or >1, its sensitivity and specificity to predict organ failure was 75% and 82%, respectively. CONCLUSIONS: qSOFA has a superior ability compared to SIRS in predicting the occurrence of organ failure in patients with a suspected infection. However, given the low sensitivity of qSOFA, further confirmatory tests for organ failure are needed. PMID- 28647651 TI - Concomitant vasopressin and hydrocortisone therapy on short-term hemodynamic effects and vasopressor requirements in refractory septic shock. AB - PURPOSE: The objective of this study was to evaluate the short-term hemodynamic effects as well as vasopressor requirements with concomitant vasopressin (AVP) and hydrocortisone (HCT) compared to either agent alone in refractory septic shock. MATERIALS AND METHODS: This was a retrospective, cohort study conducted in adult septic shock patients. Patients received continuous infusion AVP at 0.04units/min and/or HCT 200-300mg intravenous daily in divided doses for refractory septic shock. Refractory septic shock was defined as systolic or mean blood pressure (MAP) of <90mmHg or <70mmHg, respectively, despite fluid resuscitation and requiring norepinephrine. RESULTS: A total of 300 patients were evaluated. The rate of achieving a "response" (norepinephrine dose reduction by >=50% without any decrease in MAP) at 4h from baseline was significantly higher in patients receiving concomitant AVP/HCT (88.5%) compared to HCT alone (62.3%) or AVP alone (72.9%) (p=0.0005). The AVP/HCT group had higher "response" rates over the HCT and AVP monotherapy groups at 12 (p=0.052) and 24h (p=0.036). Multivariate regression showed combination therapy to be independently associated with response at 4h. CONCLUSIONS: Concomitant AVP and HCT was associated with an immediate, additive catecholamine-sparing effect over either agent alone in patients with refractory septic shock. PMID- 28647653 TI - Privacy, Confidentiality, and Security of Health Care Information: Lessons from the Recent WannaCry Cyberattack. PMID- 28647652 TI - Kinase Activity in Recurring Primary Skull Base Chordomas and Chondrosarcomas: Identification of Novel Pathways of Oncogenesis and Potential Drug Targets. AB - BACKGROUND: Chordomas and chondrosarcomas can occur in the skull base. Currently, 45% of chordomas and 56% of chondrosarcomas recur within 5 years of surgery. The role of adjuvant therapy is highly debated. No pharmacotherapies have been approved by the U.S. Food and Drug Administration for chordomas or chondrosarcomas. High propensity for recurrence and lack of definitive adjuvant therapy necessitate additional basic science research to identify molecular anomalies associated with recurrent disease. METHODS: We pooled tumor lysates from patients based on clinical criteria into 4 groups: primary chordomas, primary chordomas that recurred, primary chondrosarcomas, and primary chondrosarcomas that recurred. We used a peptide labeling method, isobaric tags for relative and absolute quantitation, to uniquely identify each tumor group. Phosphorylated peptides were identified and quantified via mass spectroscopy to determine and predict active kinases. RESULTS: Six groups of phosphorylated peptides were associated with primary tumors that later recurred. Specific kinases associated with primary chordomas that recurred were FES and FER. Specific kinases associated with primary chondrosarcomas that recurred were FES, FER, SRC family kinases, PKC, ROCK, and mitogen-activated protein kinase signaling (JNK, ERK1, p38). CONCLUSIONS: These data provide clinicians with a means to screen skull base chordomas and chondrosarcomas to help identify tumors with a propensity to recur. Many of these kinases can be efficaciously inhibited by Food and Drug Administration-approved drugs that have not yet been used in clinical trials for treatment of skull base chordomas or chondrosarcomas. Validation of kinases identified in this study may advance treatment options for patients with these tumors. PMID- 28647654 TI - The Clinical Features and Surgical Outcomes of Spinal Cord Tanycytic Ependymomas: A Report of 40 Cases. AB - OBJECTIVE: Spinal cord tanycytic ependymomas (TEs) rarely are reported because of extremely low incidence. Understanding of this disease is therefore poor. The aim of this study was to analyze the incidence and clinical, radiologic, pathologic, and prognostic features of spinal cord TEs. METHODS: Approximately 4000 spinal cord tumors were resected surgically in Beijing Tiantan Hospital between April 2009 and May 2016. We identified all cases of pathologically proved TEs among these patients. RESULTS: TEs accounted for approximately 1% of spinal cord tumors (40 of an estimated 4000). Patients with TE were a mean age of 40.0 years and had no significant sex preference (21 male and 19 female). The median diameter of the maximal tumor was 54.2 mm (range, 16-153 mm). The mean preoperative Japanese Orthopedic Association (JOA) score was 13.0. Radiologically, 47.5% (19/40) cases showed poorly defined tumor border, and 40% (16/40) of them showed preoperative syringomyelia. Gross total resection was achieved in 30 cases, subtotal resection in 8, and partial resection in 2. At the time of discharge, JOA score and neurologic function showed improvement in 26 cases (65%), no change in 12 cases (30%), and worsening in 2 cases (5%). At a median follow-up of 43 months (range, 7-101 months), 1- and 5-year progression-free survival rates were 100.0% and 97.5%, respectively. Only one patient had tumor recurrence which was found 30 months after surgery. No patient died of tumor recurrence. At the latest follow up, JOA score showed improvement in 30 cases (75%), no change in 8 cases (20%), and worsening in 2 cases (5%). Univariate analysis revealed that tumor size and preoperative JOA score were significantly associated with the short-term outcomes. Meanwhile, age >=40 years, tumor size >=50 mm, non-gross total resection, and preoperative JOA score <14 were significantly associated with an increased risk of worsened long-term outcomes. Poorly defined tumor border and preoperative JOA score <14 significantly limited the extent of tumor resection. CONCLUSIONS: Spinal cord TE is a rare subtype of ependymomas with low recurrence. Long-term survival can be expected, although poorly defined tumor border is an independent predictor of long-term outcomes. Microsurgical treatment of spinal cord TEs remains a formidable challenge due to the poorly defined border and critical neurovascular structures encasement. It is unnecessary for radical tumor resection at the cost of severe neurologic deficits. PMID- 28647655 TI - Face, Content, and Construct Validity of an Aneurysm Clipping Model Using Human Placenta. AB - OBJECTIVE: Proficient open surgical treatment of cerebral aneurysms requires extensive training and practice. This study tested the validity of a human placenta aneurysm model for surgical simulation training of aneurysm clipping. METHODS: There were 30 participants divided into 3 groups (n = 10 per group) according to their neurosurgical experience: low experience, intermediate experience, and attending. Subjective measures were collected using the Aneurysm Clipping Participant Survey (n = 27). Objective measures were collected by observing the participants (n = 30) work through a series of aneurysm clipping tasks while 2 independent raters evaluated them using a newly developed standardized tool, the Objective Structured Assessment of Aneurysm Clipping Skills. RESULTS: In terms of the subjective measures of face validity, most of the attending group (7/10; 70%) rated the models as "somewhat" to "very well" replicating real surgery. Content validity assessment of the model showed that it could improve the following skills: microdissection technique (27/27; 100%), use of clip appliers for aneurysm clipping (27/27; 100%), and surgical technique when applied to patients (25/27; 93%). The objective measure for construct validity demonstrated that mean Objective Structured Assessment of Aneurysm Clipping Skills scores between the 3 groups (low-experience group, 22.9 +/- 5.4; intermediate-experience group, 32.8 +/- 4.0; attending group, 43.3 +/- 1.3) differed significantly (P < 0.001). CONCLUSIONS: The human placenta aneurysm clipping model is a useful training tool for teaching residents, with evidence of internal consistency and face, content, and construct validities. The Objective Structured Assessment of Aneurysm Clipping Skills scale is a feasible tool to assess aneurysm clipping skills quantitatively. PMID- 28647656 TI - Delayed Retroclival and Cervical Spinal Subdural Hematoma Complicated by Preexisting Chiari Malformation in Adult Trauma Patient. AB - INTRODUCTION: Traumatic spinal subdural hematoma involving the retroclival region and upper cervical spine is a rare pathology. To our knowledge, there have only been 2 prior cases in an adult trauma patient. We describe a patient with preexisting Chiari 1 malformation, who recently sustained a unilateral type 1 occipital condyle fracture with associated disruption of the tectorial membrane and transverse ligament, which returned with a retroclival subdural hematoma extending down to C7, causing spinal cord compression and symptomatic obstructive hydrocephalus. CASE PRESENTATION: A 30-year-old female sustained a motor vehicle collision. Computed tomography C spine revealed a type I occipital condyle fracture. Magnetic resonance imaging C spine demonstrated disruption of the tectorial membrane and avulsion of the transverse ligament at its attachment to the left C1 tubercle; moreover, there was a Chiari 1 malformation. The patient was neurologically intact. A halo was recommended, but the patient opted for an aspen collar with close management. She was discharged but returned 3 days later with apneic episodes, along with bradycardia and hypertension. She was promptly intubated. Computed tomography head showed interval ventricular enlargement. Magnetic resonance imaging C spine revealed a new ventral hematoma spanning the retroclival region to C7, most pronounced at C2-C3. On examination, she opened her eyes to pain, her pupils were equal and reactive, and she withdrew in all extremities. An external ventricular drain was emergently placed. She underwent a suboccipital craniectomy, C1-3 laminectomies, and occiput-C4 instrumented fusion. The dura was significantly tense, and no epidural hematoma was observed during lateral exploration. Postoperatively, she woke up well, exhibiting a nonfocal neurologic examination. A diagnostic angiogram was negative. She was extubated uneventfully, and the external ventricular drain was weaned off in 4 days. CONCLUSION: Traumatic spinal subdural hematoma involving both the retroclival region and upper cervical spine can lead to bulbar signs and symptomatic obstructive hydrocephalus. There should be vigilance for this pathology in patients with high-energy craniocervical trauma. Disruption of the tectorial membrane and therapeutic anticoagulation may be risk factors. The clinical scenario can be complicated in the setting of a preexisting Chiari 1 malformation. PMID- 28647657 TI - Distribution and Network of Basal Temporal Language Areas: A Study of the Combination of Electric Cortical Stimulation and Diffusion Tensor Imaging. AB - OBJECTIVE: The basal temporal language area (BTLA) is considered to have several functions in language processing; however, its brain network is still unknown. This study investigated the distribution and networks of the BTLA using a combination of electric cortical stimulation and diffusion tensor imaging (DTI). METHOD: 10 patients with intractable focal epilepsy who underwent presurgical evaluation with subdural electrodes were enrolled in this study (language dominant side: 6 patients, language nondominant side: 4 patients). Electric stimulation at 50 Hz was applied to the electrodes during Japanese sentence reading, morphograms (kanji) reading, and syllabograms (kana) reading tasks to identify the BTLA. DTI was used to identify the subcortical fibers originating from the BTLA found by electric stimulation. RESULTS: The BTLA was found in 6 patients who underwent implantation of the subdural electrodes in the dominant hemisphere. The BTLA was located anywhere between 20 mm and 56 mm posterior to the temporal tips. In 3 patients, electric stimulation of some or all areas within the BTLA induced disturbance in reading of kanji words only. DTI detected the inferior longitudinal fasciculus (ILF) in all patients and the uncinate fasciculus (UF) in 1 patient, originating from the BTLA. ILF was detected from both kanji-specific areas and kanji-nonspecific areas. CONCLUSION: This study indicates that the network of the BTLA is a part of a ventral stream and is mainly composed of the ILF, which acts as a critical structure for lexical retrieval. ILF is also associated with the specific processing of kanji words. PMID- 28647658 TI - Is It Feasible to Treat Odontoid Fractures via Primary Posterior Reduction and Fixation without Fusion? AB - OBJECTIVE: To evaluate results and feasibility of primary posterior reduction and fixation without fusion using C1-C2 screw-rod system for odontoid fractures. METHODS: This study comprised a consecutive series of 46 patients with odontoid fractures. Posterior reduction and fixation without fusion using the C1-C2 screw rod system was performed, and instrumentation was not removed. Radiologic outcomes were assessed on follow-up computed tomography or plain radiographs. Visual analog scale of neck pain, American Spinal Injury Association impairment scale, patient satisfaction, neck disability index, and range of motion of flexion extension and rotation of the cervical spine were recorded and analyzed. RESULTS: Mean follow-up time was 4.1 years (range, 12 months to 8 years). Radiographic evaluation indicated solid fusion of odontoid fractures in all cases and no implant failures. No patient reported severe neck pain at follow-up. Neurologicl evaluation showed there was 1- to 2-grade improvement in patients with neurologic deficit. Of patients, 31 reported acceptable outcomes, and 15 reported good outcomes. Range of motion of rotation of the cervical spine and neck disability index score gradually improved significantly during 1 year of follow-up with no obvious change after that. Rate of neck disability index score improvement was 85%. CONCLUSIONS: Posterior reduction and fixation without fusion can be successfully performed for healing of odontoid fractures with acceptable results and minimal morbidity. PMID- 28647659 TI - Flow Diverters as Useful Adjunct to Traditional Endovascular Techniques in Treatment of Direct Carotid-Cavernous Fistulas. AB - BACKGROUND: Direct carotid-cavernous sinus fistulas (CCFs) are high-flow arteriovenous shunts that are typically the result of a severe head injury. The endovascular treatment of these lesions includes the use of detachable balloons, coils, liquid embolic agents, and covered stents. To minimize the chance of treatment failure and subsequent complications, endoluminal reconstruction using a flow-diverting stent may be added to the treatment construct. METHODS: We present 3 cases and review the existing literature. RESULTS: Three patients with direct traumatic CCFs were treated with either coils, coils and Onyx, or a detachable balloon, followed by placement of a flow-diverting stent for endoluminal reconstruction. All 3 cases had complete angiographic occlusion of the CCFs and recovered clinically. No complications were observed. CONCLUSIONS: We believe that endovascular coil or balloon occlusion of the fistula from either a transvenous or transarterial approach followed by flow diversion may be an appropriate treatment for direct CCFs. This addition of a flow diverter may facilitate endothelialization of the injury to the internal carotid artery. PMID- 28647660 TI - Novel Oral Anticoagulants in Patients Undergoing Cranial Surgery. AB - BACKGROUND: The number of patients treated with novel oral anticoagulants (NOACs) is increasing. Despite growing clinical relevance, guidelines on the perioperative management of neurosurgical patients treated with NOACs are still lacking. The aim of this study was to analyze the occurrence of postoperative bleeding events and factors that might influence bleeding rates in these patients. METHODS: Out of 1353 consecutive patients undergoing cranial neurosurgical procedures, 30 (2.2%) received NOACs preoperatively. The rates of perioperative and postoperative intracranial bleeding events, rate of postoperative thromboembolic events, hematologic findings, morbidity, and mortality were reviewed. A subanalysis of factors influencing the bleeding risk of these patients and the bleeding rate depending on the preoperative discontinuation time of NOACS, with cutoff of 24 and 48 hours, was performed as well. RESULTS: The rate of perioperative bleeding was 13.3% (n = 4 of 30). Postoperative bleeding led to death in 2 patients. The median discontinuation time was significantly shorter in the patients experiencing a bleeding event compared to those without a bleeding event (1.5 days [range 0-3 days] vs. 11 days [range, 0-120 days]). The rate of perioperative thromboembolic events was 3.3% (n = 1), and overall mortality was 13.3% (n = 4). CONCLUSIONS: The postoperative bleeding rate in patients undergoing cranial surgery treated with NOACs was 13.3%. A shorter preoperative discontinuation time seems to have a significant effect on bleeding rate. Further studies evaluating the management and postsurgical outcomes of these patients are warranted. PMID- 28647661 TI - Can We Make Simple In Situ Decompression of the Ulnar Nerve at the Elbow Still Easier? AB - BACKGROUND: In situ decompression and transposition are equally effective in cubital tunnel syndrome treatment. Both are traditionally performed in the supine position. OBJECTIVE: To validate our surgical technique for in situ decompression in the lateral decubitus position, comparing results with other techniques used in our institutions. METHODS: A retrospective study was performed from January 2009 to February 2016, of 188 patients with cubital tunnel syndrome 115 males, 73 females; mean age, 53.44 +/- 12.12 years standard deviation (range, 18-84 years) treated with in situ decompression in the lateral or supine positions or transposition (subcutaneous or submuscular). The lateral decubitus group received local anesthesia and the remainder received a brachial plexus block. Clinical and electrophysiologic results between these 4 groups were compared. RESULTS: There were no statistically significant demographic differences between groups. Results were better in in situ decompression groups compared with transpositions. Mean follow-up was 1511.1 +/- 770.57 days standard deviation (range, 310-4203 days). There were no recurrences or residual elbow pain/dysesthesia/anesthetic scar/hyperesthesia/neuroma in the lateral decubitus group. Complication and recurrence rates were in direct correlation to incision size. The worst results were seen in transpositions, particularly in the submuscular group. In situ decompression in the supine position had better results than transpositions but worse than those performed in lateral decubitus. Smaller surgical wound correlates with a reduction in operating time, costs, complication rates, and time out of work. CONCLUSIONS: In situ decompression is equally as effective as ulnar nerve transpositions but with fewer complications and recurrences. In the lateral decubitus position, the retroepicondylar tunnel is more accessible, allowing smaller incisions and better results. PMID- 28647662 TI - Microsurgical Bypass Training Rat Model, Part 1: Technical Nuances of Exposure of the Aorta and Iliac Arteries. AB - BACKGROUND: Animal models using rodents are frequently used for practicing microvascular anastomosis-an essential technique in cerebrovascular surgery. However, safely and efficiently exposing rat's target vessels is technically difficult. Such difficulty may lead to excessive hemorrhage and shorten animal survival. This limits the ability to perform multiple anastomoses on a single animal and may increase the overall training time and costs. We report our model for microsurgical bypass training in rodents in 2 consecutive articles. In part 1, we describe the technical nuances for a safe and efficient exposure of the rat abdominal aorta and common iliac arteries (CIAs) for bypass. METHODS: Over a 2 year period, 50 Sprague-Dawley rats underwent inhalant anesthesia for practicing microvascular anastomosis on the abdominal aorta and CIAs. Lessons learned regarding the technical nuances of vessel exposure were recorded. RESULTS: Several technical nuances were important for avoiding intraoperative bleeding and preventing animal demise while preparing an adequate length of vessels for bypass. The most relevant technical nuances include (1) generous subcutaneous dissection; (2) use of cotton swabs for the blunt dissection of the retroperitoneal fat; (3) combination of sharp and blunt dissection to isolate the aorta and iliac arteries from the accompanying veins; (4) proper control of the posterior branches of the aorta; and (5) efficient division and mobilization of the left renal pedicle. CONCLUSIONS: Applying the aforementioned technical nuances enables safe and efficient preparation of the rat abdominal aorta and CIAs for microvascular anastomosis. PMID- 28647663 TI - Management of Residual Tumor After Limited Subtotal Resection of Large Vestibular Schwannomas: Lessons Learned and Rationale for Specialized Care. AB - BACKGROUND: In an era where subtotal resection (STR) is increasingly used, we have encountered a growing number of patients referred to our institution with limited resection of large vestibular schwannomas (VSs), sometimes associated with grave complications. Our aim was to highlight lessons learned in the management of large VSs and provide a rationale for specialized care. METHODS: A prospectively maintained database of >2000 patients with VSs evaluated at our institution between 2000 and 2016 was reviewed. Details of 10 patients with residual tumor after limited subtotal resection were reviewed, with 3 presented in detail to illustrate key aspects of management. RESULTS: All but 1 patient underwent initial surgery at private hospitals without a designated skull base team. The median posterior fossa tumor diameter at the time of initial operation was 4.0 cm, whereas median diameter of residual tumor at the time of our evaluation was 3.5 cm. Before referral, 3 patients had undergone fractionated radiation therapy after their initial operation; 1 had undergone stereotactic radiosurgery. Four patients had moderate to severe facial weakness; 2 had permanent sequelae from stroke, including hemiparesis and blindness; and 7 had ongoing symptomatic brainstem compression and/or hydrocephalus. CONCLUSIONS: Management of large VSs remains challenging, including treating presenting hydrocephalus, maximizing extent of resection while optimizing facial nerve outcome, and avoiding complications. Most cases should be approached with the intent of complete resection, realizing that subtotal resection may become necessary based on intraoperative findings. PMID- 28647664 TI - Patient-perceived responsiveness of primary care systems across Europe and the relationship with the health expenditure and remuneration systems of primary care doctors. AB - BACKGROUND: Health systems are expected to be responsive, that is to provide services that are user-oriented and respectful of people. Several surveys have tried to measure all or some of the dimensions of the responsiveness (e.g. autonomy, choice, clarity of communication, confidentiality, dignity, prompt attention, quality of basic amenities, and access to family and community support), however there is little evidence regarding the level of responsiveness of primary care (PC) systems. METHODS: This work analyses the capacity of primary care systems to be responsive. Data collected from 32 PC systems were used to investigate whether a relationship exists between the responsiveness of PC systems and the PC doctor remuneration systems and domestic health expenditure. RESULTS: There appears to be a higher responsiveness of PC when doctors are paid via capitation than when they only receive a fee for services or a mixed payment method. In addition, countries that spend more on health services are associated with higher levels of dignity and autonomy. CONCLUSION: Quality, as measured from the patient's perspective, does not necessarily overlap with PC performance based on structure and process indicators. The results could also stimulate a new debate on the role of economic resources and PC workforce payment mechanisms in the achievement of quality goals, in this case related to the capacity of PC systems to be responsive. PMID- 28647665 TI - Comparative metabolism of DDAO benzoate in liver microsomes from various species. AB - DDAB (6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate) is a newly developed near-infrared fluorescent probe for human carboxylesterase 2 (hCE2), exhibiting high specificity and good reactivity for real-time monitoring the enzymatic activities of hCE2 in complex biological systems. In order to explore the applicability of DDAB in commonly used animal species, the interspecies difference in DDAB hydrolysis was carefully investigated by using liver microsomes from human and five experimental animals including mouse, rat, dog, minipig and monkey. Metabolite profiling demonstrated that DDAB hydrolysis could be catalyzed by all tested liver microsomes from different animals but displayed significant difference in the reaction rate. Chemical inhibition assays demonstrated that carboxylesterases (CEs) were the major enzymes involved in DDAB hydrolysis in all tested liver microsomes, indicating that DDAB was a selective substrate of CEs in a variety of mammals. However, the differential effects of loperamide (LPA, a specific inhibitor against hCE2) on DDAB hydrolysis among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (CLmax) for DDAB hydrolysis in liver microsomes from different animals were determined, and the order of CLmax values for the formation of DDAO was CyLM>MLM~PLM>RLM>HLM~DLM. These findings were helpful for the rational use of DDAB as an imaging tool for CE2 in different mammals, as well as for translational researches on the function of mammalian CEs and CE2 associated drug-drug interactions. PMID- 28647666 TI - Brain-derived neurotrophic factor levels and depression during methamphetamine withdrawal. AB - BACKGROUND: Depression symptoms is highly comorbid with methamphetamine (METH) dependence. Except for the role in the pathophysiology of depression symptoms, brain-derived neurotrophic factor (BDNF) is also involved in the METH dependence. The present study aims to explore whether BDNF plays a role in the development of depression symptoms during METH withdrawal. METHODS: We recruited 179 patients with METH dependence who were followed up for two weeks. Ultimately, 131 (73.2%) patients finished the follow-up. Besides, 90 healthy controls were also recruited. Serum BDNF levels were measured by DuoSet ELISA Development System upon admission. The short form (13 items) of the Beck Depression Inventory (BDI) and Amphetamine Withdrawal Questionnaire (AWQ) were used to measure the depression and withdrawal symptoms. Patients with BDI score >= 8 were identified to have depression symptoms. RESULTS: Of the 131 patients, 64 (48.9%) were identified to have depression symptoms at the two-week endpoint. Patients with depression symptoms showed significantly lower BDNF levels than those with no depression symptoms. Serum BDNF levels (<= 1251.0pg/ml) were independently associated with the development of depression symptoms during METH withdrawal (OR = 3.50, 95% CI, 1.14-10.73, p = 0.028). LIMITATIONS: BDNF levels were tested in serum but not in brain and the baseline BDI and AWQ scores between the depression and non-depression groups were not matched. Besides, the follow-up time was relatively short. CONCLUSIONS: Our study demonstrated that patients with serum BDNF levels <= 1251.0pg/ml had higher risk of depression symptoms during METH withdrawal. PMID- 28647667 TI - Self-esteem and non-suicidal self-injury in adulthood: A systematic review. AB - BACKGROUND: Non-suicidal self-injury (NSSI) is a self-destructive act that represents a considerable burden on the individual and society. Low self-esteem may be a psychological variable that is related to NSSI. However, little is known about the nature of this relationship in adulthood. This systematic review therefore aimed to provide a synthesis of the available literature on the relationship between self-esteem and NSSI. METHODS: Articles were independently identified and risk of bias assessed by two reviewers searching PsycINFO, CINAHL, Medline and Web of Science databases. Inclusion criteria were: (1) a mean sample age of eighteen years or over (2) full manuscripts available in English (3) assessment of NSSI (4) assessment(s) of self-esteem. A narrative synthesis of results was undertaken. A random-effects meta-analysis of differences in self esteem between NSSI and non-NSSI groups was also undertaken. RESULTS: Seventeen studies were identified and indicated a significant negative relationship between self-esteem and NSSI. The meta-analysis indicated lower self-esteem in those with experiences of NSSI versus those without, d = 0.59 - 1.17. Results suggested that although low self-esteem and NSSI are related in both clinical and non-clinical populations, there are a number of factors which also influence this relationship. LIMITATIONS: The absence of longitudinal research is a major limitation of this literature. CONCLUSIONS: It will be important for clinicians to consider the impact of self-esteem in those seeking support for NSSI. Further research should undertake longitudinal research to better understand the self esteem and NSSI relationship. PMID- 28647668 TI - A combined marker of early non-improvement and the occurrence of melancholic features improve the treatment prediction in patients with Major Depressive Disorders. AB - BACKGROUND: Early Improvement of depressive symptoms within two weeks of antidepressant treatment is a highly sensitive but less specific predictor of later treatment outcome. The aim of this study was to identify clinical features at treatment initiation which are associated with early improvement and non improvement as well as to identify variables predicting non-remission in patients showing an early improvement. METHODS: 889 patients with a major depressive episode according to DSM-IV who had participated in an antidepressant treatment trial served as study sample. Clinical predictors (demographic variables, psychopathology, comorbid disorders) were analysed in 698 (79%) early improver (Hamilton Depression Rating Scale reduction > 20% after 14 days of treatment) compared to 191 (21%) non-improver. Furthermore, clinical predictors for later remission and non-remission were analysed in the 698 patients showing an early improvement. RESULTS: Patients with more severe depression and suicidality were more likely to become non-improver, and also non-remitter after 8 weeks of treatment in case of early improvement. Early improver with melancholic, anxious or atypical depression as well as with comorbid social phobia or avoidant personality disorder had an increased risk for non-remission at study end. The combined marker of early non-improvement and the occurrence of melancholic features increased the specificity of treatment prediction from 30% to 90%. LIMITATIONS: Comorbid disorders were only assessed at baseline. CONCLUSIONS: Patients with early non-improvement and melancholic features at treatment initiation have a particularly high risk of later non-remission. This group of patients should be considered more attention in treatment decisions. PMID- 28647670 TI - Temperament and character profile of college students who have suicidal ideas or have attempted suicide. AB - OBJECTIVE: Suicide is a major cause of death in university students. Personality traits have been suggested as possible risk factors for suicidal behaviors. This study looked at the relationship between the personality dimensions of the Temperament and Character Inventory (TCI) and suicidal behaviors. METHOD: A total of 5644 college students took the TCI test and the suicidality module of the M.I.N.I. The students were divided into the suicidal ideation group (n = 302; 5.4%) and the suicide attempt group (n = 301; 5.3%). Each group's TCI dimension and sub-dimension scores were compared with one another. To find out which TCI dimension affects suicide risk when depressed, regression analysis and mediation analysis were conducted. RESULTS: First, we adjusted for age, sex and depressive mood and compared the TCI scores of the participants based on their suicide risk. After the adjustment, self-directedness decreased in the suicidal ideation group while novelty seeking and persistence increased in the suicide attempt group. It turned out that self-directedness has a partial mediating effect between depressive symptom and suicide risk (beta = -0.068 P < 0.001). CONCLUSION: We adjusted for depressive mood and it turned out that the suicidal ideation group is affected by character whereas the suicide attempt group is affected by temperament. Among the character dimensions, self-directedness was found to reduce the effect of depressive mood on suicide risk. Therefore, when evaluating suicide risk, assessing character dimensions, especially self-directedness along with depressive mood, a risk factor, will be helpful. PMID- 28647669 TI - "Engage" therapy: Prediction of change of late-life major depression. AB - OBJECTIVE: Engage grew out of the need for streamlined psychotherapies that can be accurately used by community therapists in late-life depression. Engage was based on the view that dysfunction of reward networks is the principal mechanism mediating depressive symptoms. Accordingly, Engage uses "reward exposure" (exposure to meaningful activities) and assumes that repeated activation of reward networks will normalize these systems. This study examined whether change in a behavioral activation scale, an index of reward system function, predicts change in depressive symptomatology. METHODS: The participants (N = 48) were older adults with major depression treated with 9 weekly sessions of Engage and assessed 27 weeks after treatment. Depression was assessed with the 24-item Hamilton Depression Rating Scale (HAM-D) and behavioral activation with the four subscales of Behavioral Activation for Depression Scale (activation, avoidance/rumination, work impairment, social impairment) at baseline, 6 weeks (mid-treatment), 9 weeks (end of treatment), and 36 weeks. RESULTS: Change only in the Activation subscale during successive periods of assessment predicted depression severity (HAM-D) at the end of each period (F1, 47 = 21.05, p<0.0001). An increase of one standard deviation in the Activation score resulted in a 2.04 (95% CI: 1.17-2.92) point decrease in HAM-D. For every one point increase in the Activation score, HAM-D was decreased by 0.22 points (95% CI: 0.12-0.31). LIMITATIONS: No comparison group. Partial overlap of Activation Subscale with HAM D, lack of detailed neurocognitive assessment and social support. CONCLUSION: Change in behavioral activation predicts improvement of depressive symptoms and signs in depressed older adults treated with Engage. PMID- 28647671 TI - Use of Oncogenic Driver Mutations in Staging of Multiple Primary Lung Carcinomas: A Single-Center Experience. AB - OBJECTIVE: The staging of multiple pulmonary adenocarcinomas requires the distinction of intrapulmonary metastasis (IPM) from multiple primary lung cancers (MPLCs). This can be challenging in some patients, and the addition of data from oncogenic driver mutations in these tumors may be helpful in this determination. METHODS: As a proof of principle, molecular driver results from primary tumors and their metastases in 45 patients were compared (cohort 1). Then, 69 patients with a total of 154 synchronous or metachronous lung carcinomas were identified, and the pathologic findings were compared with oncogenic driver mutation. Each patient was assigned a highest potential T or M category on the basis of clinical, histopathologic, and molecular findings (cohort 2). RESULTS: The concordance rate of EGFR, KRAS, BRAF, and ALK receptor tyrosine kinase gene (ALK) mutations was 96% in cohort 1. In cohort 2, 36% of multiple same-lobe nodules were MPLCs, 40% were IPM, and 24% were noninformative by molecular findings. Of nodules with multiple lobe involvement, 81.5% were MPLCs and 7.4% were IPM, with 11% noninformative. Of metachronous tumors, 52.9% were MPLCs. Overall survival was 100% at 2 years, 95% at 3 years, and 80% at 4 years in patients with available follow-up. CONCLUSIONS: Oncogenic driver mutations are concordant between primary tumors and metastasis. The largest proportion of MPLCs was seen in tumors of multiple lobes, but with a substantial proportion of MPLCs among single-lobe nodules and with metachronous tumors. Overall survival was higher than expected for the respective highest T or M category, which is in support of the high frequency of MPLC. PMID- 28647672 TI - Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer. AB - Intracellular compartmentalization and trafficking of molecules plays a critical role in complex and essential cellular processes. In lung cancer and other malignancies, aberrant nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators results in tumorigenesis and inactivation of apoptosis. Pharmacologic agents targeting this process, termed selective inhibitors of nuclear export (SINE), have demonstrated antitumor efficacy in preclinical models and human clinical trials. Exportin-1 (XPO1), which serves as the sole exporter of several tumor suppressor proteins and cell cycle regulators, including retinoblastoma, adenomatous polyposis coli, p53, p73, p21, p27, forkhead box O, signal transducer and activator of transcription 3, inhibitor of kappaB, topoisomerase II, and protease activated receptor 4-is the principal focus of development of SINE. The most extensively studied of the SINE to date, the exportin-1 inhibitor selinexor (KPT-330 [Karyopharm Therapeutics, Inc., Newton Centre, MA]), has demonstrated single-agent anticancer activity and synergistic effects in combination regimens against multiple cancer types, with principal toxicities of low-grade cytopenias and gastrointestinal effects. SINE may have particular relevance in KRAS-driven tumors, for which this treatment strategy demonstrates significant synthetic lethality. A multicenter phase 1/2 clinical trial of selinexor in previously treated advanced KRAS-mutant NSCLC is under way. PMID- 28647673 TI - Constitutive differences in glucocorticoid responsiveness to stress are related to variation in aggression and anxiety-related behaviors. AB - Glucocorticoids coordinate responses that enable an individual to cope with stressful challenges and, additionally, mediate adaptation following cessation of a stressor. There are important individual differences in the magnitude of glucocorticoid responsiveness to stressors. However, whether individual differences in glucocorticoid responsiveness to stress are linked to different behavioral strategies in coping with social and non-social challenges is not easily studied, owing to the lack of appropriate animal models. To address this, we generated three lines of Wistar rats selectively bred for the magnitude of their glucocorticoid responses following exposure to a variety of stressors over three consecutive days at juvenility. Here, we present findings following observations of a high level of variation in glucocorticoid responsiveness to stress in outbred Wistar rats, and the strong response to selection for this trait over a few generations. When challenged with different stressful challenges, rats from the three lines differed in their coping behaviors. Strikingly, the line with high glucocorticoid responsiveness to stress displayed enhanced aggression and anxiety-like behaviors. In addition, these rats also showed alterations in the expression of genes within both central and peripheral nodes of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced reactivity to acute stress exposure. Together, these findings strongly link differences in glucocorticoid responsiveness to stress with marked differences in coping styles. The developed rat lines are thus a promising model with which to examine the relationship between variation in reactivity of the HPA axis and stress-related pathophysiology and could be employed to assess the therapeutic potential of treatments modulating stress habituation to ameliorate psychopathology. PMID- 28647674 TI - In pregnancy increased maternal STAI trait stress score shows decreased insulin sensitivity and increased stress hormones. AB - INTRODUCTION: Chronic or acute stressors influence maternal and fetal Hypothalamus-Pituitary-Adrenal Axes (HPA) during pregnancy. In this study, the effect of maternal stress into maternal insulin sensitivity was investigated during pregnancy. MATERIALS AND METHODS: Eighty-two pregnant women [aged 27.1+/ 2.5 (mean+/-SD) yrs; BMI=25+/-2.2kg/m2] had at the 2nd and 3rd trimesters anthropometry, fasting blood samples (cortisol, Corticotropin Releasing Hormone (CRH), active amylin, Interleukin (IL6)), Oral Glucose Tolerance Test (OGTT) for glucose and insulin, state-trait anxiety inventory (STAI) trait and state questionnaires (for stress assessment). RESULTS: Maternal cortisol, CRH and STAI state score increased significantly from 2nd to 3rd trimester. At these trimesters women with STAI trait scores >=40 had greater serum cortisol and CRH concentrations and lower insulin sensitivity index (ISI) values than those with scores <40 while STAI trait score predicted negatively ISI. At the 2nd trimester maternal CRH concentrations correlated positively with maternal STAI state, Homeostatic Model Assessment Insulin Resistance (HOMAR), 1st and 2nd phase insulin secretion and negatively with ISI. STAI trait correlated negatively with ISI. STAI state correlated positively with maternal systolic blood pressure and HOMAR. At the 3rd trimester STAI trait correlated negatively and positively with ISI and STAI state, respectively, while STAI state correlated positively with HOMAR. In women with STAI state scores >=40, these scores correlated positively with maternal CRH. CONCLUSIONS: In normal pregnant women, enhanced long-term stress is associated with decreased insulin sensitivity. Both long- and short- term stress are associated with enhanced maternal HPA axis and increased placental CRH secretion. PMID- 28647676 TI - A safe strategy to rule out pulmonary embolism: The combination of the Wells score and D-dimer test: One prospective study. PMID- 28647677 TI - Buprenorphine augmentation improved symptoms of OCD, compared to placebo - Results from a randomized, double-blind and placebo-controlled clinical trial. AB - BACKGROUND: In the search for new psychopharmacologic options in the treatment of obsessive-compulsive disorders (OCD), some findings suggested that augmentation with buprenorphine, a partial-opioid agonist used to treat opioid addiction, moderate acute pain and moderate chronic pain, is worthy of consideration. Accordingly, to explore this possibility further, a double-blinded, placebo controlled clinical trial was performed. METHOD: A total of 43 patients (mean age: 34.41 years; SD = 6.58; 53.5% males) with refractory OCD and treated with SSRIs or clomipramine at therapeutic dosages were randomly assigned either to an adjuvant buprenorphine or to an adjuvant placebo condition. Patients completed the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) at baseline, weeks 3, 9 and 12 (study completion). Buprenorphine (2-4 mg; sublingual) and placebo (tablets with identical shape, color, consistency, and scent) were given daily. RESULTS: Symptoms of obsessive-compulsive disorders decreased over time, but more so in the buprenorphine than in the placebo condition. Substantial improvements were observed up to week 3 and then 9. Response and partial response were observed in the buprenorphine at week 9 more than in the placebo condition. The advantage had disappeared by week 12. CONCLUSIONS: The pattern of results suggests that adjuvant buprenorphine augmentation can reduce symptoms of obsessive-compulsive disorders after only three weeks, compared to a placebo. Adjuvant buprenorphine seems to accelerate symptom improvement. PMID- 28647675 TI - Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors. AB - Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary adrenal axis. Here, we investigated effects of repeated ethanol intoxication withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h 28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naive (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse. PMID- 28647678 TI - Methyl jasmonate attenuated lipopolysaccharide-induced depressive-like behaviour in mice. AB - Depression is a recurrent neuropsychiatric disorder that affects millions of individuals worldwide and impact negatively on the patients' social functions and quality of life. Studies have shown that i.p injection of lipopolysaccharide (LPS) induces depressive-like behavior in rodents via induction of oxidative stress and neuroinflammation. Methyl jasmonate (MJ), an isolated compound from jasmine plant has gained reputation in aromatherapy for treatment of depression, nervousness and memory deficits. This study was designed to evaluate the effects of MJ on LPS-induced depressive-like behavior in mice. Mice were given MJ (5-20 mg/kg), imipramine (10 mg/kg) or vehicle (10 mL/kg) intraperitoneally for 7 consecutive days. On day 7, treatment was carried out 30 min prior to i.p injection of LPS (830 MUg/kg). Twenty four hours after LPS administration, tail suspension, forced swim and sucrose preference tests were carried out. Thereafter, serum corticosterone levels were determined using ELISA. The levels of malondialdehyde (MDA), glutathione (GSH) and tumor necrosis factor-alpha (TNF alpha) were determined in brain tissue homogenates. LPS significantly increased immobility time in the tail suspension and forced swim tests when compared with vehicle (p < 0.05), which indicates depressive-like syndromes. However, the increased immobility time was significantly reduced by MJ (5-20 mg/kg) when compared with LPS-treated group. LPS administration also altered the levels of MDA, GSH, corticosterone and TNF alpha in mice, which was significantly reversed by MJ. These findings suggest that attenuation of LPS-induced depressive-like behavior by MJ may be related to suppression of oxidative stress and release of TNF alpha. PMID- 28647679 TI - Factors impacting on psychological wellbeing of international students in the health professions: A scoping review. AB - BACKGROUND: There are increasing numbers of international students undertaking health professional courses, particularly in Western countries. These courses not only expose students to the usual stresses and strains of academic learning, but also require students to undertake clinical placements and practice-based learning. While much is known about general issues facing international students, less is known about factors that impact on those studying in the health professions. OBJECTIVES: To explore what is known about factors that influence the psychological wellbeing of international students in the health professions. DESIGN: A scoping review. DATA SOURCES: A range of databases were searched, including CINAHL, Medline, Scopus, Proquest and ERIC, as well as grey literature, reference lists and Google Scholar. REVIEW METHODS: The review included qualitative or quantitative primary peer reviewed research studies that focused on international undergraduate or postgraduate students in the health professions. The core concept underpinning the review was psychological issues, with the outcome being psychological and/or social wellbeing. Thematic analysis across studies was used to identify key themes emerging. RESULTS: A total of 13 studies were included in the review, from the disciplines of nursing, medicine and speech-language pathology. Four key factor groups emerged from the review: negotiating structures and systems, communication and learning, quality of life and self-care, and facing discrimination and social isolation. CONCLUSIONS: International health professional students face similar issues to other international students. The nature of their courses, however, also requires negotiating different health care systems, and managing a range of clinical practice issues including with communication, and isolation and discrimination from clinical staff and patients. Further research is needed to specifically explore factors impacting on student well-being and how international students can be appropriately prepared and supported for their encounters. PMID- 28647680 TI - A retrospective review of unintentional opioid overdose risk and mitigating factors among acutely injured trauma patients. AB - BACKGROUND: Opioid medication to treat acutely injured patients is usual care in trauma settings. A higher prevalence of alcohol and other substance misuse in this population compared to the general population increases the vulnerability of such patients to both misuse of their prescribed opioids, and also unintentional opioid overdose. The primary purpose of this study was to assess the prevalence of substance use and unintentional opioid overdose risk among acutely injured trauma patients, and to examine the frequency and predictors of high opioid dose at discharge. METHODS: A retrospective electronic medical record (EMR) review of three-months of data from two Level 1 trauma centers. We assessed the prevalence of substance misuse, unintentional opioid overdose risk, and presence of documentation of clinical strategies to mitigate these risks, such as co prescription of the opioid agonist naloxone. RESULTS: In total, 352 patient EMRs were examined. Over 40% of the patients reviewed had at least one indication of substance misuse (42.5% [95%CI: 37.3, 47.7]); at least 1 unintentional opioid overdose risk factor was identified in 240 EMR reviewed (68.2% [95%CI: 63.3, 73.1]). Dose of opioid medication was not significantly different for patients with substance misuse versus those without. There was no co-prescription of naloxone for any of the discharged patients. CONCLUSIONS: Our results indicate that despite the high rates of substance misuse, the potential for misuse, dependence and unintentional overdose risk from prescribed opioid medications are prevalent among acutely injured trauma patients. Prescribing after acute trauma care should address these risk factors. PMID- 28647681 TI - Daily associations between cannabis motives and consumption in emerging adults. AB - BACKGROUND: Increasing rates of cannabis use among emerging adults is a growing public health problem. Intensive longitudinal data can provide information on proximal motives for cannabis use, which can inform interventions to reduce use among emerging adults. METHOD: As part of a larger longitudinal study, patients aged 18-25 years (N=95) recruited from an urban Emergency Department completed daily text message assessments of risk behaviors for 28days, including daily cannabis quantity and motives. Using a mixed effects linear regression model, we examined the relationships between daily quantity of cannabis consumed and motives (i.e., enhancement, social, conformity, coping, and expansion). RESULTS: Participants were, on average, 22.0 years old (SD=2.2); 48.4% were male, 45.3% were African American, and 56.8% received public assistance. Results from the multi-level analysis (clustering day within individual), controlling for gender, race, and receipt of public assistance, indicated daily use of cannabis use for enhancement (beta=0.27), coping (beta=0.15), and/or social motives (beta=0.34) was significantly associated with higher quantities of daily cannabis use; whereas expansion and conformity motives were not. CONCLUSIONS: Daily data show that emerging adults who use cannabis for enhancement, social, and coping motives reported using greater quantities of cannabis. Future research should examine more comprehensive cannabis motives (e.g., boredom, social anxiety, sleep) and test tailored interventions focusing on alternative cognitive/behavioral strategies to address cannabis motives. PMID- 28647682 TI - Body mass index, body dissatisfaction and adolescent smoking initiation. AB - BACKGROUND: Smoking influences body weight, but there is little evidence as to whether body mass index (BMI) and body dissatisfaction increase smoking initiation in adolescents. METHODS: We evaluated the association between measured BMI, body dissatisfaction and latent classes of smoking initiation (never smokers, experimenters, late onset regular smokers, early onset regular smokers) in the Avon Longitudinal Study of Parents and Children. In observational analyses we used BMI (N=3754) and body dissatisfaction at age 10.5 years (N=3349). In Mendelian randomisation (MR) analysis, we used a BMI genetic risk score of 76 single nucleotide polymorphisms (N=4017). RESULTS: In females, higher BMI was associated with increased odds of early onset regular smoking (OR: 1.11, 95% CI: 1.04, 1.18) compared to being a never smoker, but not clearly associated with experimenting with smoking (OR: 1.04, 95% CI: 0.99, 1.10) or late onset regular smoking (OR: 1.01, 95% CI: 0.94, 1.09). No clear evidence was found for associations between BMI and smoking initiation classes in males (p-value for sex interaction<=0.001). Body dissatisfaction was associated with increased odds of late-onset regular smoking (OR: 1.71, 95% CI: 1.32, 1.99) in males and females combined (P-value for sex interaction=0.32). There was no clear evidence for an association between the BMI genetic risk score and smoking latent classes in males or females but estimates were imprecise. CONCLUSIONS: BMI in females and body dissatisfaction in males and females are associated with increased odds of smoking initiation, highlighting these as potentially important factors for consideration in smoking prevention strategies. PMID- 28647683 TI - Artery tertiary lymphoid organs in giant cell arteritis are not exclusively located in the media of temporal arteries. PMID- 28647685 TI - IRTKS is correlated with progression and survival time of patients with gastric cancer. AB - BACKGROUND AND OBJECTIVES: IRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear. DESIGN: We used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS-deficient and p53-deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53. RESULTS: IRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous p53+/- mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/- MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21. Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation. CONCLUSION: IRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway. PMID- 28647684 TI - Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. AB - OBJECTIVE: To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. DESIGN: 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). The score difference between baseline and 16 years was modelled by generalised linear models. RESULTS: Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). CONCLUSIONS: Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer. PMID- 28647686 TI - Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study. AB - OBJECTIVE: Magnitude and independent drivers of the risk of acute arterial events in IBD are still unclear. We addressed this question in patients with IBD compared with the general population at a nationwide level. DESIGN: Using the French National Hospital Discharge Database from 2008 to 2013, all patients aged 15 years or older and diagnosed with IBD were identified and followed up until 31 December 2013. The rates of incident acute arterial events were calculated and the impact of time with active disease (period around hospitalisation for IBD flare or IBD-related surgery) on the risk was assessed by Cox regression adjusted for traditional cardiovascular risk factors. RESULTS: Among 210 162 individuals with IBD (Crohn's disease (CD), n=97 708; UC, n=112 454), 5554 incident acute arterial events were identified. Both patients with CD and UC had a statistically significant overall increased risk of acute arterial events (standardised incidence ratio (SIR) 1.35; 95% CI 1.30 to 1.41 and SIR 1.10; 95 CI 1.06 to 1.13, respectively). The highest risk was observed in patients under the age of 55 years, both in CD and UC. The 3-month periods before and after IBD-related hospitalisation were associated with an increased risk of acute arterial events in both CD and UC (HR 1.74; 95 CI 1.44 to 2.09 and 1.87; 95% CI 1.58 to 2.22, respectively). CONCLUSION: Patients with IBD are at increased risk of acute arterial events, with the highest risk in young patients. Disease activity may also have an independent impact on the risk. PMID- 28647687 TI - Overweight, Obesity, and Survival After Stroke in the Framingham Heart Study. AB - BACKGROUND: We investigated how body weight affects survival after stroke, leveraging the availability of multiple prestroke body mass index (BMI) measurements and using a nested case-control design in a community-based sample. METHODS AND RESULTS: We compared all-cause mortality in participants stratified by prestroke weight. Separate analyses were performed for ischemic stroke and all stroke and for age-, sex-, and BMI category-matched stroke-free controls. Participants were grouped into BMI categories and followed for up to 10 years. Differences in survival were tested for interaction by case status. In sensitivity analysis, to exclude those with prestroke weight loss, we restricted the reference group to participants with 2 consistently normal BMI measurements within 10 years before stroke/matching. There were 782 stroke cases (age 71+/-9, 51% female participants, 87% ischemic stroke) and 2346 controls (age 72+/-9, 51% female participants). Overweight participants with ischemic stroke had a lower mortality compared with those with normal weight (hazard ratio [HR]=0.70, 95%CI 0.55-0.90, P=0.005). The association of reduced mortality with BMI >=25, compared with normal-weight BMI 18.5 to <25, was pronounced among ischemic stroke cases but diminished with inclusion of hemorrhagic strokes (case-control interaction P=0.051 and P=0.130, respectively). Compared with participants with stable normal weight, moderately increased weight was protective after ischemic stroke (overweight HR=0.72, 95%CI 0.53-0.99, P=0.041). CONCLUSIONS: Overweight and mildly obese participants had better 10-year survival after ischemic stroke compared with normal-weight participants, even after excluding persons with recent prestroke weight loss. There may be unknown protective factors associated with a moderately increased body weight before stroke. PMID- 28647688 TI - Antihypertensive Medication Adherence and Risk of Cardiovascular Disease Among Older Adults: A Population-Based Cohort Study. AB - BACKGROUND: Antihypertension medication (antihypertensive) adherence lowers risk of cardiovascular disease (CVD); few studies have examined this association among older adults. METHODS AND RESULTS: We assessed this association among Medicare fee-for-service beneficiaries aged 66 to 79 years who were newly diagnosed with hypertension and initiated on antihypertensives in 2008-2009 (n=155 597). We calculated proportion of days covered (PDC) during follow-up, using proportional subdistribution hazard models, to examine association between antihypertensive adherence and a composite CVD outcomes, including first incident of fatal/nonfatal acute myocardial infarction, ischemic heart disease, stroke/transient ischemic attack, and heart failure. During follow-up (median 5.8 years and 798 621 person-years), we documented 47 198 CVD events. Among beneficiaries, 60.8%, 30.3%, and 8.9% had PDC >=80%, 40% to 79%, and <40%. Crude incidence of CVD events were 40.1 (95% CI, 40.0-40.1), 93.9 (93.8-93.9), and 98.1 (98.1-98.2) per 1000 person-years for PDC >=80%, 40% to 79%, and <40%, respectively. Adjusted hazard ratios for CVD events were 1.0 (<40% as reference), 1.0 (0.97-1.03) for 40% to 79%, and 0.44 (0.42-0.45) for >=80% (P<0.001). Dose response analysis suggested a nonlinear relationship between PDC and risk for CVD events with a protective effect of >=80%. The pattern of associations between PDC and ischemic heart disease, stroke/transient ischemic attack, and heart failure were largely consistent as for CVD events and across different groups. CONCLUSIONS: Antihypertensive adherence was associated with a significantly lower risk of CVD events among older adults. There appeared to be a threshold effect in reducing CVD events at around PDC 80%, above which the risk for CVD reduced substantially. PMID- 28647689 TI - Associations of Cigarette Smoking With Subclinical Inflammation and Atherosclerosis: ELSA-Brasil (The Brazilian Longitudinal Study of Adult Health). AB - BACKGROUND: There is a need to identify sensitive biomarkers of early tobacco related cardiovascular disease. We examined the association of smoking status, burden, time since quitting, and intensity, with markers of inflammation and subclinical atherosclerosis. METHODS AND RESULTS: We studied 14 103 participants without clinical cardiovascular disease in ELSA-Brasil (Brazilian Longitudinal Study of Adult Health). We evaluated baseline cross-sectional associations between smoking parameters and inflammation (high-sensitivity C-reactive protein [hsCRP]) and measures of subclinical atherosclerosis (carotid intima-media thickness, ankle-brachial index, and coronary artery calcium [CAC]). The cohort included 1844 current smokers, 4121 former smokers, and 8138 never smokers. Mean age was 51.7+/-8.9 years; 44.8% were male. After multivariable adjustment, compared with never smokers, current smokers had significantly higher levels of hsCRP (beta=0.24, 0.19-0.29 mg/L; P<0.001) and carotid intima-media thickness (beta=0.03, 0.02-0.04 mm; P<0.001) and odds of ankle-brachial index <=1.0 (odds ratio: 2.52; 95% confidence interval, 2.06-3.08; P<0.001) and CAC >0 (odds ratio: 1.83; 95% confidence interval, 1.46-2.30; P<0.001). Among former and current smokers, pack-years of smoking (burden) were significantly associated with hsCRP (P<0.001 and P=0.006, respectively) and CAC (P<0.001 and P=0.002, respectively). Among former smokers, hsCRP and carotid intima-media thickness levels and odds of ankle-brachial index <=1.0 and CAC >0 were lower with increasing time since quitting (P<0.01). Among current smokers, number of cigarettes per day (intensity) was positively associated with hsCRP (P<0.001) and CAC >0 (P=0.03) after adjusting for duration of smoking. CONCLUSIONS: Strong associations were observed between smoking status, burden, and intensity with inflammation (hsCRP) and subclinical atherosclerosis (carotid intima-media thickness, ankle-brachial index, CAC). These markers of early cardiovascular disease injury may be used for the further study and regulation of traditional and novel tobacco products. PMID- 28647691 TI - Prevention Pays-Lessons from the Chief Medical Officer's Annual Report: five years on. PMID- 28647692 TI - Female genital mutilation: the law as it relates to children. PMID- 28647690 TI - Acute Kidney Injury After Primary Angioplasty: Is Contrast-Induced Nephropathy the Culprit? AB - BACKGROUND: Acute kidney injury (AKI) following primary percutaneous coronary intervention (pPCI) is frequently interpreted as contrast-induced AKI but may result from other insults. We aimed to determine the causal association of contrast material exposure and the incidence of AKI following pPCI using a control group of propensity score-matched patients with ST-segment-elevation myocardial infarction who were not exposed to contrast material. METHODS AND RESULTS: We studied 2025 patients with ST-segment-elevation myocardial infarction who underwent pPCI and 1025 patients receiving fibrinolysis or no reperfusion who were not exposed to contrast material during the first 72 hours of hospital stay (control group). AKI was defined as creatinine of >=0.5 mg/dL or >25% rise within 72 hours. AKI rates were similar in the pPCI and control groups (10.3% versus 12.1%, respectively; P=0.38). Propensity score matching resulted in 931 matched pairs with PCI and no PCI, with balanced baseline covariates (standardized difference <0.1). Among propensity score-matched patients, AKI rates were not significantly different with and without PCI (8.6% versus 10.9%, P=0.12). In the pPCI cohort, independent predictors of AKI included age >=70 years, insulin treated diabetes mellitus, diuretic therapy, anterior infarction, baseline estimated glomerular filtration rate, and variables related to the presence of pump failure (higher Killip class, intra-aortic balloon pump use) and reduced left ventricular ejection fraction but not contrast material dose. A risk score based on the PCI cohort had similar discriminatory capacity for AKI in the control group (C statistic 0.81+/-0.02 and 0.78+/-0.02, respectively; P=0.26). CONCLUSIONS: The development of AKI in patients with ST-segment-elevation myocardial infarction undergoing pPCI is mainly related to older age, baseline estimated glomerular filtration rate, heart failure, and hemodynamic instability. Risk for AKI is similar among ST-segment-elevation myocardial infarction patients with and without contrast material exposure. PMID- 28647693 TI - Recognition, investigation and management of mitochondrial disease. AB - Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of cell apoptosis and numerous biochemical catabolic and synthetic pathways that are critical for cellular health. Primary mitochondrial disorders are a group of greater than 200 single gene defects arising from two genomes (nuclear and mitochondrial) leading to mitochondrial dysfunction, and are associated with extremely heterogeneous phenotypes. Neuromuscular features predominate, but often with multisystem involvement. Clinical suspicion of a mitochondrial disorder should prompt multipronged investigation with biochemical and molecular genetic studies. Recent wide-scale adoption of next-generation sequencing approaches has led to a rapid increase in the number of disease genes. The advances in unravelling the genetic landscape of mitochondrial diseases have not yet been matched by progress in developing effective therapies, and the mainstay of care remains supportive therapies in a multidisciplinary team setting. PMID- 28647695 TI - The Warburg Effect and Mass Spectrometry-based Proteomic Analysis. AB - Compared to normal cells, cancer cells have a unique metabolism by performing lactic acid fermentation in the presence of oxygen, also known as the Warburg effect. Researchers have proposed several hypotheses to elucidate the phenomenon, but the mechanism is still an enigma. In this review, we discuss three typical models, such as "damaged mitochondria", "adaptation to hypoxia", and "cell proliferation requirement", as well as contributions from mass spectrometry analysis toward our understanding of the Warburg effect. Mass spectrometry analysis supports the "adaptation to hypoxia" model that cancer cells are using quasi-anaerobic fermentation to reduce oxygen consumption in vivo. We further propose that hypoxia is an early event and it plays a crucial role in carcinoma initiation and development. PMID- 28647696 TI - Cytokeratin 18-associated Histone 3 Modulation in Hepatocellular Carcinoma: A Mini Review. AB - Unstable cytokeratins are associated with tumor transformation in the development of human hepatocellular carcinoma. We previously demonstrated that the cytokeratin 18 was modulated and that a histone H3-specific modification occured, among members of the histone family, during the development of human hepatocellular carcinoma. Evidence suggested that the modification of histone H3 was highly correlated with the modulation of cytokeratin 18 and probably plays an important role in tumorigenesis of hepatocytes. Aberrant expression of histone deacetylase leading to imbalance between acetylation and deacetylation of histones may exhibit regulatory roles in tumor transformation. Recently we found that overexpression of histone deacetylase-1 and hypoacetylation of histone H3 were associated with hepatocellular carcinoma. The underlying roles of histone H3 modulation are discussed in this mini-review article. PMID- 28647698 TI - Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival. AB - BACKGROUND/AIM: Activin and its antagonist follistatin (FST) have been implicated in several solid tumours. This study investigated the role of FST in breast cancer. MATERIALS AND METHODS: FST expression was examined using reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry in a cohort of breast cancer samples. Expression was correlated to pathological and prognostic parameters in our patient cohort. FST was overexpressed in MCF-7 cells and assays for growth and invasion were performed. RESULTS: FST is expressed in breast tissue, in the cytoplasm of mammary epithelial cells. Expression was decreased in breast cancer tissue in comparison to normal mammary tissue. Over-expression of FST in vitro led to significantly increased growth rate and reduced invasion. Higher FST associates with lower-grade tumours and better survival. CONCLUSION: Our results suggest a role for FST as a suppressor of invasion and metastasis in breast cancer. PMID- 28647697 TI - Analysis of K-Ras Interactions by Biotin Ligase Tagging. AB - BACKGROUND: Mutations of the human K-Ras 4B (K-Ras) G protein are associated with a significant proportion of all human cancers. Despite this fact, a comprehensive analysis of K-Ras interactions is lacking. Our investigations focus on characterization of the K-Ras interaction network. MATERIALS AND METHODS: We employed a biotin ligase-tagging approach, in which tagged K-Ras proteins biotinylate neighbor proteins in a proximity-dependent fashion, and proteins are identified via mass spectrometry (MS) sequencing. RESULTS: In transfected cells, a total of 748 biotinylated proteins were identified from cells expressing biotin ligase-tagged K-Ras variants. Significant differences were observed between membrane-associated variants and a farnesylation-defective mutant. In pancreatic cancer cells, 56 K-Ras interaction partners were identified. Most of these were cytoskeletal or plasma membrane proteins, and many have been identified previously as potential cancer biomarkers. CONCLUSION: Biotin ligase tagging offers a rapid and convenient approach to the characterization of K-Ras interaction networks. PMID- 28647699 TI - Proteomic Analysis of Normal and Cancer Cervical Cell Lines Reveals Deregulation of Cytoskeleton-associated Proteins. AB - BACKGROUND: Both HPV-positive and -negative cervical cancers are primarily associated with features of cell cycle and cytoskeletal disruption; however, the actual biological processes affected remain elusive. To this end, we systematically characterized the intracellular proteomic profiles of four distinct and informative cervical cell lines. MATERIALS AND METHODS: Cell extracts from a normal cervical (HCK1T) and three cervical cancer cell lines, one HPV-negative (C33A), and two HPV-positive, SiHa (HPV16+) and HeLa (HPV18+), were analyzed by 2-dimensional electrophoresis and differentially expressed proteins were identified by MALDI-TOF mass spectrometry, while differential expression was confirmed by western blot analysis. RESULTS: In total, 113 proteins were found differentially expressed between the normal and the cervical cancer lines. Bioinformatics analysis revealed the actin cytoskeleton signaling pathway to be significantly affected, while up-regulation of cofilin-1, an actin depolymerizing factor, was documented and further validated by western blotting. Furthermore, two-way comparisons among the four cell lines, revealed a set of 18 informative differentially expressed proteins. CONCLUSION: These novel identified proteins provide the impetus for further functional studies to dissect the mechanisms operating in the two distinct pathways of cervical carcinogenesis. PMID- 28647700 TI - Molecular Proteomic Characterization of a Pediatric Medulloblastoma Xenograft. AB - BACKGROUND/AIM: Medulloblastoma (MBL), an archetypal primitive neuroectodermal tumor of the cerebellum, is the most common pediatric central nervous system malignancy representing approximately 20% of all childhood brain tumors. Herein, we report on a new xenotransplantable tumor cell line, derived from a 6-year-old female patient with cerebellar medulloblastoma, and the completele proteome molecular characterization of subsequent tumors from MBL xenotrasplanted mice. MATERIALS AND METHODS: Tumors were grown in nude mice as subcutaneous xenografts (MBLX) composed of small round cells with hyperchromatic nuclei and scant cytoplasm. Tumor specimen were extracted from animals upon their sacrifice and their molecular proteomic content was analyzed by 2-DE coupled to MALDI-TOF MS analysis. RESULTS: Altogether 350 single-gene products were identified through the current approach, reported as the MBLX database. CONCLUSION: This new xenotransplantable tumor model, offers the scientific community valuable insight on the validity of xenografts altogether, while providing the means for a novel experimental model towards the study of human MBL. PMID- 28647701 TI - Aberrant Methylation of T-cadherin Can Be a Diagnostic Biomarker for Colorectal Cancer. AB - BACKGROUND/AIM: T-cadherin is a tumor suppressor gene, its predictive value in colorectal cancer (CRC) still remains controversial. In this study, we aimed to evaluate the association between T-cadherin promoter methylation and CRC by performing a meta-analysis. MATERIALS AND METHODS: The relevant literature was searched using the PubMed, Cochrane Library, Web of Science and Google Scholar databases for articles published until December 2016. The effect sizes were estimated by measuring an odds ratio (OR) with a 95% confidence interval (CI). Sensitivity analysis was performed to examine the heterogeneity and funnel plots were constructed to evaluate publication bias. RESULTS: Nine studies, including 488 samples were included in this meta-analysis. The pooled OR of T-cadherin promoter methylation in cancer tissues was 16.73 (95%CI=6.24-44.87), 19.48 (95%CI=5.64-67.31) and 2.23 (95%CI=1.05-4.75) compared to normal tissues, adjacent tissues and premalignant tissues, respectively. The relationship between T-cadherin promoter methylation and clinicopathological features were also analyzed. However, a significant association was not observed between T-cadherin promoter methylation status and gender, tumor stage, and lymph node status (p>0.05). CONCLUSION: The methylation status of T-cadherin promoter was strongly associated with CRC risk. However, T-cadherin promoter methylation may have a limited prognostic value for CRC patients. PMID- 28647703 TI - Selling a gun to a stranger without a background check: acceptable behaviour? AB - OBJECTIVE: One way that guns get into the wrong hands is via gun sales without a background check. While the large majority of Americans support laws requiring universal background checks, no prior study has assessed whether Americans think it is acceptable behaviour to sell a gun to a stranger without a background check, whether or not there is a law against it. METHODS: We sponsored a nationally representative survey of over 3900 American adults, oversampling gun owners, using an online panel provided by the survey firm Growth for Knowledge. RESULTS: Over 72% of American adults agree or strongly agree with the statement that 'whether it is legal or not, it is NOT acceptable to sell a gun to a stranger without a background check' and 11% disagree or strongly disagree. Subgroups less likely to agree are young adults, men, conservatives, those with less than a high school education and gun owners. CONCLUSION: Reducing the number of guns sold without a background check could help reduce the flow of guns to felons. Changes in normative attitudes and behaviours, as well as changes in law, could help accomplish this goal. Most Americans, including gun owners, believe selling a gun to a stranger without a background check is not acceptable behaviour. PMID- 28647702 TI - Comparative miRNA Expression Profile Analysis of Squamous Cell Carcinoma and Peritumoral Mucosa from the Meso- and Hypopharynx. AB - BACKGROUND/AIM: The role of microRNAs (miRNA) in carcinogenesis is related to their genome-regulatory function. The aim of the present study was to identify and compare miRNA expression signatures of meso- and hypopharynx squamous cell cancers in consideration of the cancer field hypothesis. PATIENTS AND METHODS: Thirteen snap-frozen biopsy series of tumors and peritumoral tissues from the meso- and hypopharynx were analyzed regarding their miRNA expression with quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Significant miRNA expression changes of miR-21, -27a, -34a, -143 and -146a were found in peritumoral tissues that were dependent from the tumor location and the distance from the primary tumor site. CONCLUSION: miRNA expression analysis was found to be appropriate for molecular segregation of tumor location and peritumoral tissue segments, and appears to be a promising marker for cancer field characterization. PMID- 28647704 TI - The impact of policies regulating alcohol trading hours and days on specific alcohol-related harms: a systematic review. AB - BACKGROUND: Evidence supports the expectation that changes in time of alcohol sales associate with changes in alcohol-related harm in both directions. However, to the best of our knowledge, no comprehensive systematic reviews had examined the effect of policies restricting time of alcohol trading on specific alcohol related harms. OBJECTIVE: To compile existing evidence related to the impact of policies regulating alcohol trading hours/days of on specific harm outcomes such as: assault/violence, motor vehicle crashes/fatalities, injury, visits to the emergency department/hospital, murder/homicides and crime. METHODS: Systematic review of literature studying the impact of policies regulation alcohol trading times in alcohol-related harm, published between January 2000 and October 2016 in English language. RESULTS: Results support the premise that policies regulating times of alcohol trading and consumption can contribute to reduce injuries, alcohol-related hospitalisations/emergency department visits, homicides and crime. Although the impact of alcohol trading policies in assault/violence and motor vehicle crashes/fatalities is also positive, these associations seem to be more complex and require further study. CONCLUSION: Evidence suggests a potential direct effect of policies that regulate alcohol trading times in the prevention of injuries, alcohol-related hospitalisations, homicides and crime. The impact of these alcohol trading policies in assault/violence and motor vehicle crashes/fatalities is less compelling. PMID- 28647706 TI - Testing joint-position sense: does it matter how you hold the toe? PMID- 28647707 TI - Hepatitis E virus and neurological disorders. AB - Hepatitis E is the most common cause of hepatitis worldwide. While originally considered a disease of developing countries, it is increasingly recognised in developed countries, probably related to contaminated pork meat, and where infection is often asymptomatic. However, several non-liver manifestations have become apparent, the most important of which are neurological, including Guillain Barre syndrome (acute inflammatory demyelinating polyradiculoneuropathy (AIDP)), neuralgic amyotrophy and meningoencephalitis. We recommend testing all patients with AIDP and neuralgic amyotrophy for hepatitis E and consider testing any patient with an unexplained neurological illness and abnormal liver function tests for the virus. PMID- 28647708 TI - Relapsing cerebral amyloid angiopathy-related inflammation: the wax and the wane. AB - Cerebral amyloid angiopathy-related inflammation (CAA-I) is a rare variant of cerebral amyloid angiopathy (CAA). Its precise pathophysiology remains uncertain and we currently have limited evidence on which immunosuppressive agents are the most effective in its treatment. The disease course of CAA-I disorders can vary from an isolated clinical event to recurrent episodes. We present a case of biopsy-confirmed CAA-I that gives insight into its potential relapsing nature and the challenges of its long-term management. PMID- 28647705 TI - Revolution in acute ischaemic stroke care: a practical guide to mechanical thrombectomy. AB - Rapid, safe and effective arterial recanalisation to restore blood flow and improve functional outcome remains the primary goal of hyperacute ischaemic stroke management. The benefit of intravenous thrombolysis with recombinant tissue-type plasminogen activator for patients with severe stroke due to large artery occlusion is limited; early recanalisation is generally less than 30% for carotid, proximal middle cerebral artery or basilar artery occlusion. Since November 2014, nine positive randomised controlled trials of mechanical thrombectomy for large vessel occlusion in the anterior circulation have led to a revolution in the care of patients with acute ischaemic stroke. Its efficacy is unmatched by any previous therapy in stroke medicine, with a number needed to treat of less than 3 for improved functional outcome. With effectiveness shown beyond any reasonable doubt, the key challenge now is how to implement accessible, safe and effective mechanical thrombectomy services. This review aims to provide neurologists and other stroke physicians with a summary of the evidence base, a discussion of practical aspects of delivering the treatment and future challenges. We aim to give guidance on some of the areas not clearly described in the clinical trials (based on evidence where available, but if not, on our own experience and practice) and highlight areas of uncertainty requiring further research. PMID- 28647709 TI - Mechanical thrombectomy services: can the UK meet the challenge? PMID- 28647710 TI - Perforated duodenal diverticulum: a rare complication in a common condition. AB - The authors present a rare case of perforated duodenal diverticulum diagnosed in an 80-year-old Caucasian woman with vomiting and abdominal pain localised to the epigastrium. CT scan showed thickening of the second portion of the duodenum with retroperitoneal fat stranding and perihepatic free fluid, with a presumptive diagnosis of a duodenal perforation. A laparotomy was performed which showed a perforated diverticulum in the second portion of the duodenum. A diverticulectomy with single-layer closure was performed, without complications. The postoperative course was uneventful. PMID- 28647711 TI - Down syndrome and Moyamoya disease: unusual cause of stroke. AB - Down syndrome is a frequent clinical entity, being considered one of the most frequent chromosomal aberrations. It is characterised by a typical clinical phenotype and is associated with a heterogeneous group of organ and system specific abnormalities. The cardiovascular system is commonly affected and if so, it may be associated with an increased morbidity and mortality. Cerebrovascular events in patients with Down syndrome are multifactorial, being possibly related to congenital heart disease, vascular malformations and traditional cardiovascular risk factors. Moyamoya disease is a rare chronic occlusive vascular disease causing stenosis of the distal portion of the internal carotid artery, which has been associated with Down syndrome. The authors report the case of a 26-year-old woman with Down syndrome who presented with an acute stroke secondary to Moyamoya disease. The case is noteworthy for the rarity of this clinicopathological entity, and serves as a reminder for the possible association between these two conditions. PMID- 28647712 TI - Disseminated histoplasmosis in a patient with HIV diagnosed by simple bedside investigations. PMID- 28647713 TI - Microcephaly in infantile Sandhoff's disease. PMID- 28647714 TI - The burden of multiple sclerosis and patients' coping strategies. AB - OBJECTIVES: Multiple sclerosis (MS) is a chronic disease that mainly affects young people. Patients with MS experience several emotional responses to changed perceptions of themselves and manage this situation in ways focused on controlling the overall burden of disease. This present study aimed to evaluate differences between patients with MS and healthy controls (HCs) in coping styles, identifying the MS clinical features that influence adaptive responses. METHODS: Patients with MS, according to the McDonald 2010 criteria, and HCs were recruited. Coping strategies were assessed using the Coping Orientation to the Problems Experienced (COPE-NVI; Italian version) questionnaire. RESULTS: A cohort of 135 patients with MS (female: 89/135, 65.9%) and 94 HCs (female: 64/94, 68%) were enrolled. Impaired social support and problem solving was noted for MS group (p=0.005). In the MS group, the social support worsened with increasing disease duration (p=0.002) independently of the level of disability. Associations between a higher Expanded Disability Status Scale score and avoidance strategies (p<0.01), as well between avoidance strategies and a previous depression diagnosis (p<0.001) were reported. CONCLUSION: Our findings highlight the negative impact of MS on various aspects of patients' life. Therefore, psychosocial interventions are needed to increase adaptive coping mechanisms aimed to manage the burden of MS. PMID- 28647715 TI - Finding meaning: a personal reflection on Adem Crosby. PMID- 28647716 TI - Bilateral recurrent pyosalpinx in a sexually inactive 12-year-old girl secondary to rare variant of Mullerian duct anomaly. AB - Pyosalpinx is a severe sequel of chronic pelvic inflammatory disease, whereby the fallopian tubes become filled with pus.1 2 Pyosalpinx often affects sexually active women and rarely is seen in celibate adolescent girls.3 We report a case of a 12-year-old girl with no prior sexual history who presented to our emergency department with complaints of severe right lower quadrant pain of 1-day duration. Ultrasonography and CT scan of the abdomen and pelvis revealed free fluid collections in the pelvis without visualisation of the appendix. A preoperative diagnosis of acute ruptured appendicitis was given and she was taken to the operating room. Peroperative findings included bilaterally distended, pus-filled pyosalpinges. A definitive diagnosis of bilateral pyosalpinx was then made. Two week antibiotic therapy was successful but the patient returned with recurrent pyosalpinx and a pelvic abscess 9 weeks later. PMID- 28647717 TI - A large choledochocystolithiasis mimicking Mirizzi syndrome. AB - An 18-year-old man presented with spontaneous severe epigastric pain, progressing and radiating to back since 3 days. It was associated with epigastric tenderness, bilious vomiting and jaundice. He had been intermittently experiencing these symptoms for the last 1 year. No known comorbid. Ultrasound showed a poorly visualised heterogeneous focus at porta hepatis; considering poor visualisation, this might represent an enlarged calcified lymph node or cystic duct calculus causing extrinsic compression or a large sludge ball within the common bile duct (CBD), leading to dilatation of common hepatic duct and intrahepatic biliary system. Subsequent magnetic resonance cholangiopancreatography revealed a focal saccular dilatation of middle part of CBD, a type I-B choledochal cyst, large heterogeneous focus seen within it representing choledochocystolithiasis. Later, CT was performed for further characterisation of surrounding anatomy and pathology, which confused the appearance of choledochocystolithiasis for Mirizzi syndrome. Later, surgery and histopathology confirmed type I-B choledochocystolithiasis and chronic cholecystitis. PMID- 28647718 TI - New meniscal tears after ACL injury: what is the risk? A systematic review protocol. AB - BACKGROUND: Secondary meniscal tears after ACL injuries increase the risk of knee osteoarthritis. The current literature on secondary meniscal injuries after ACL injury is not consistent and may have methodological shortcomings. This protocol describes the methods of a systematic review investigating the rate of secondary meniscal injuries in children and adults after treatment (operative or non operative) for ACL injury. METHODS: We will search electronic databases (Embase, Ovid Medline, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature), SPORTDiscus, PEDro and Google Scholar) from database inception. Extracted data will include demographic data, methodology, intervention details and patient outcomes. Risk of bias will be assessed using the Newcastle Ottawa checklist for cohort studies. Article screening, eligibility assessment, risk of bias assessment and data extraction will be performed in duplicate by independent reviewers. A proportion meta-analysis will be performed if studies are homogeneous (I2<75%). If meta-analysis is precluded, data will be synthesised descriptively using best-evidence synthesis. The strength of recommendations and quality of evidence will be assessed using the Grading of Recommendations Assessment Development and Evaluation working group methodology. ETHICS AND DISSEMINATION: This protocol is written according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses, and was registered in the International Prospective Register of Systematic Reviews on 22 March 2016. TRIAL REGISTRATION NUMBER: CRD42016036788. PMID- 28647719 TI - A cross-sectional study on the prevalence and associated risk factors for workplace violence against Chinese nurses. AB - OBJECTIVES: The purpose of the present study was to explore the characteristics of workplace violence that Chinese nurses at tertiary and county-level hospitals encountered in the 12 months from December 2014 to January 2016, to identify and analyse risk factors for workplace violence, and to establish the basis for future preventive strategies. DESIGN: A cross-sectional study. SETTING: A total of 44 tertiary hospitals and 90 county-level hospitals in 16 provinces (municipalities or autonomous regions) in China. METHODS: We used stratified random sampling to collect data from December 2014 to January 2016. We distributed 21 360 questionnaires, and 15 970 participants provided valid data (effective response rate=74.77%). We conducted binary logistic regression analyses on the risk factors for workplace violence among the nurses in our sample and analysed the reasons for aggression. RESULTS: The prevalence of workplace violence was 65.8%; of this, 64.9% was verbal violence, and physical violence and sexual harassment accounted for 11.8% and 3.9%, respectively. Frequent workplace violence occurred primarily in emergency and paediatric departments. Respondents reported that patients' relatives were the main perpetrators in tertiary and county-level hospitals. Logistic regression analysis showed that respondents' age, department, years of experience and direct contact with patients were common risk factors at different levels of hospitals. CONCLUSIONS: Workplace violence is frequent in China's tertiary and county-level hospitals; its occurrence is especially frequent in the emergency and paediatric departments. It is necessary to cope with workplace violence by developing effective control strategies at individual, hospital and national levels. PMID- 28647720 TI - Thinker, Soldier, Scribe: cross-sectional study of researchers' roles and author order in the Annals of Internal Medicine. AB - OBJECTIVE: How researchers' contributions relate to author order on the byline remains unclear. We sought to identify researchers' contributions associated with author order, and to explore the existence of author profiles. DESIGN: Observational study. SETTING: Published record. PARTICIPANTS: 1139 authors of 119 research articles published in 2015 in the Annals of Internal Medicine. PRIMARY OUTCOMES: Presence or absence of 10 contributions, reported by each author, published in the journal. RESULTS: On average, first authors reported 7.1 contributions, second authors 5.2, middle authors 4.0, penultimate authors 4.5 and last authors 6.4 (p<0.001). The first author made the greatest contributions to drafting the article, designing the study, analysing and interpreting the data, and providing study materials or patients. The second author contributed to data analysis as well and to drafting the article. The last author was most involved in obtaining the funding, critically revising the article, designing the study and providing support. Factor analysis yielded three author profiles Thinker (study design, revision of article, obtaining funding), Soldier (providing material or patients, providing administrative and logistical support, collecting data) and Scribe (analysis and interpretation of data, drafting the article, statistical expertise). These profiles do not strictly correspond to byline position. CONCLUSIONS: First, second and last authors of research articles made distinct contributions to published research. Three authorship profiles can be used to summarise author contributions. These findings shed light on the organisation of clinical research teams and may help researchers discuss, plan and report authorship in a more transparent way. PMID- 28647721 TI - Effects of a peer support programme for youth social services employees experiencing potentially traumatic events: a protocol for a prospective cohort study. AB - INTRODUCTION: The use of peer support programmes to help workers experiencing potentially traumatic events (PTE) has increased in high-risk organisations in the last decades. However, the scientific evidence of its effectiveness is still very limited. This paper aims to describe the protocol of a prospective cohort study that assesses the efficacy of a peer support programme among youth social services employees exposed to a PTE at work on psychological well-being, work functioning and needs of support. METHODS AND ANALYSIS: This is a mixed-methods prospective study that will examine workers' evolution four times over a 12-month period in Canada. This study involves: (1) quantitative data obtained through self-administrated questionnaires among 222 workers, and (2) qualitative in-depth interviews with a subsample of 45 workers. This study will compare findings from a cohort who received the support of a peer following a PTE (peer support experimental protocol) as part of the experimental protocol of the Montreal Youth Social Services-University Institute (MYSS-UI), the second group of workers did not ask for the peer support (no peer support-experimental protocol) but was part of MYSS-UI, and the third group received standard organisational support from the Monteregie Youth Social Services (MYSS) (standard organisational protocol). ETHICS AND DISSEMINATION: The protocol and informed consent form complied with the ethics guidelines of the MYSS-UI. The Research Ethics Board of MYSS-UI and MYSS reviewed and accepted the protocol as required. The results of the study will be published in peer-reviewed journals, presented at research and general public conferences, disseminated via a public report for the institute that funded the project and for all workers. Results of this study will influence decision making regarding intervention policies following PTE and peer support interventions may be expanded throughout the youth social services in Canada and worldwide. PMID- 28647722 TI - Developing implementation strategies for firearm safety promotion in paediatric primary care for suicide prevention in two large US health systems: a study protocol for a mixed-methods implementation study. AB - INTRODUCTION: The promotion of safe firearm practices, or firearms means restriction, is a promising but infrequently used suicide prevention strategy in the USA. Safety Check is an evidence-based practice for improving parental firearm safety behaviour in paediatric primary care. However, providers rarely discuss firearm safety during visits, suggesting the need to better understand barriers and facilitators to promoting this approach. This study, Adolescent Suicide Prevention In Routine clinical Encounters, aims to engender a better understanding of how to implement the three firearm components of Safety Check as a suicide prevention strategy in paediatric primary care. METHODS AND ANALYSIS: The National Institute of Mental Health-funded Mental Health Research Network (MHRN), a consortium of 13 healthcare systems across the USA, affords a unique opportunity to better understand how to implement a firearm safety intervention in paediatric primary care from a system-level perspective. We will collaboratively develop implementation strategies in partnership with MHRN stakeholders. First, we will survey leadership of 82 primary care practices (ie, practices serving children, adolescents and young adults) within two MHRN systems to understand acceptability and use of the three firearm components of Safety Check (ie, screening, brief counselling around firearm safety and provision of firearm locks). Then, in collaboration with MHRN stakeholders, we will use intervention mapping and the Consolidated Framework for Implementation Research to systematically develop and evaluate a multilevel menu of implementation strategies for promoting firearm safety as a suicide prevention strategy in paediatric primary care. ETHICS AND DISSEMINATION: Study procedures have been approved by the University of Pennsylvania. Henry Ford Health System and Baylor Scott & White institutional review boards (IRBs) have ceded IRB review to the University of Pennsylvania IRB. Results will be submitted for publication in peer reviewed journals. PMID- 28647723 TI - A retrospective cohort study of high-impact users among patients with cerebrovascular conditions. AB - OBJECTIVE: To apply group-based trajectory modelling (GBTM) to the hospital administrative data to evaluate, model and visualise trends and changes in the frequency of long-term hospital care use of the subgroups of patients with cerebrovascular conditions. DESIGN: A retrospective cohort study of patients with cerebrovascular conditions. SETTINGS: Secondary care of all patients with cerebrovascular conditions admitted to English National Hospital Service hospitals. PARTICIPANTS: All patients with cerebrovascular conditions identified through national administrative data (Hospital Episode Statistics) and subsequent emergency hospital admissions followed up for 4 years. MAIN OUTCOME MEASURE: Annual number of emergency hospital readmissions. RESULTS: GBTM model classified patients with intracranial haemorrhage (n=2605) into five subgroups, whereas ischaemic stroke (n=34 208) and transient ischaemic attack (TIA) (n=20 549) patients were shown to have two conventional groups, low and high impact. The covariates with significant association with high-impact users (17.1%) among ischaemic stroke were epilepsy (OR 2.29), previous stroke (OR 2.18), anxiety/depression (OR 1.63), procedural complication (OR 1.43), admission to intensive therapy unit (ITU) or high dependency unit (HDU) (OR 1.42), comorbidity score (OR 1.36), urinary tract infections (OR 1.32), vision loss (OR 1.32), chest infections (OR 1.25), living alone (OR 1.25), diabetes (OR 1.23), socioeconomic index (OR 1.20), older age (OR 1.03) and prolonged length of stay (OR 1.00). The covariates associated with high-impact users among TIA (20.0%) were thromboembolic event (OR 3.67), previous stroke (OR 2.51), epilepsy (OR 2.25), hypotension (OR 1.86), anxiety/depression (OR 1.63), amnesia (OR 1.62), diabetes (OR 1.58), anaemia (OR 1.55), comorbidity score (OR 1.39), atrial fibrillation (OR 1.27), living alone (OR 1.25), socioeconomic index (OR 1.13), older age (OR 1.04) and prolonged length of stay (OR 1.02). The high-impact users (0.5%) among intracranial haemorrhage were strongly associated with thromboembolic event (OR 20.3) and inversely related to older age (OR 0.58). CONCLUSION: GBTM effectively assessed trends in the use of hospital care by the subgroups of patients with cerebrovascular conditions. High-impact users persistently had higher annual readmission during the follow-up period. PMID- 28647724 TI - Observed and projected trends in paediatric health resources and services in China between 2003 and 2030: a time-series study. AB - OBJECTIVES: The two-child policy took effect in China on 1 January 2016, thus officially ending the one-child policy. The resultant growth in the population will create a considerable demand for public services such as paediatric healthcare, even while there are limited paediatric resources. We estimated the relationship between paediatric health resources and services and child mortality to determine the degree of the deficiency of such resources in China. Projecting the quantity of paediatric health resource allocation and service supply through 2030 will help provide data reference for future policy decision making. DESIGN: Time-series study. SETTING: The People's Republic of China. PARTICIPANTS: Paediatric patients whose data were recorded between 2003 and 2012 from the National Health and Family Planning Commission of the People's Republic of China. PRIMARY AND SECONDARY OUTCOME MEASURES: Child mortality and paediatric health resources and services data were entered into a cubic polynomial regression model to project paediatric health resources and services to 2030. RESULTS: Child mortality decreased throughout the past decade. Furthermore, the number of paediatric beds, paediatricians and nurses increased between 2003 and 2012, although the proportions increased rather slowly. Both the number and proportion of paediatric outpatients and inpatients increased rapidly. The observed and model-predicted values matched well (adjusted R2=93.8% for paediatric beds; adjusted R2=96.6% for paediatric outpatient visits). Overall, the projection indicated that paediatric beds, paediatricians and nurses will reach 460 148, 233 884 and 184 059 by 2030, respectively. Regarding paediatric services, the number of paediatric outpatient visits and inpatients is expected to reach upwards of 449.95 million and 21.83 million by 2030, respectively. CONCLUSIONS: Despite implementation of the two-child policy, resource allocation in paediatrics has many deficiencies. Proper measures should be taken to actively respond to the demand for paediatric health services. PMID- 28647725 TI - Percutaneous coronary intervention patients' and cardiologists' experiences of the informed consent process in Northern England: a qualitative study. AB - OBJECTIVE: Informed consent is central to ethical medical practice, but little is known about how the process takes place in clinical practice. Percutaneous coronary intervention (PCI) is a common revascularisation procedure. Studies report that patients overestimate benefits, forget the risks and are unaware of alternative treatments. The aim of this study was to describe PCI patients' and cardiologists' experiences of the informed consent process in acute care settings. DESIGN/SETTING/PARTICIPANTS: A qualitative study with a maximum variation sample of elective and acute PCI patients and cardiologists taking their consent, recruited from a district general hospital and tertiary centre. In depth interviews were conducted, and consent discussions were audio recorded. Data collection, coding and theorising occurred simultaneously. FINDINGS: Forty one (26 male) patients scheduled for elective (20) or urgent (21) PCI and 19 cardiologists (5 female) participated. Despite diversity in patients' experiences of informed consent, elective and acute patients experienced a common four-stage process of consent. Most patients made the decision to have treatment at PCI referral and took a passive role in the discussions we recorded. They recognised cardiologists as experts, trusted the medical system to 'fix' their health problem and were unaware of their role in the informed consent process. Informed consent discussions functioned as a formal 'event',enabling cardiologists to check patients' understanding and enabling patients to access treatment. CONCLUSIONS: The configuration of services and patients' perceptions of their role in informed consent underpin a mismatch between legal and ethical principles of informed consent and current practice. The variation in patients' experiences of the current place of informed consent in service delivery represents a missed opportunity for cardiologists to work in decision-making partnerships with patients. In light of recent changes in the law, a new approach to informed consent is required. PMID- 28647728 TI - Impact of five tobacco endgame strategies on future smoking prevalence, population health and health system costs: two modelling studies to inform the tobacco endgame. AB - OBJECTIVE: There is growing international interest in advancing 'the tobacco endgame'. We use New Zealand (Smokefree goal for 2025) as a case study to model the impacts on smoking prevalence (SP), health gains (quality-adjusted life-years (QALYs)) and cost savings of (1) 10% annual tobacco tax increases, (2) a tobacco free generation (TFG), (3) a substantial outlet reduction strategy, (4) a sinking lid on tobacco supply and (5) a combination of 1, 2 and 3. METHODS: Two models were used: (1) a dynamic population forecasting model for SP and (2) a closed cohort (population alive in 2011) multistate life table model (including 16 tobacco-related diseases) for health gains and costs. RESULTS: All selected tobacco endgame strategies were associated with reductions in SP by 2025, down from 34.7%/14.1% for Maori (indigenous population)/non-Maori in 2011 to 16.0%/6.8% for tax increases; 11.2%/5.6% for the TFG; 17.8%/7.3% for the outlet reduction; 0% for the sinking lid; and 9.3%/4.8% for the combined strategy. Major health gains accrued over the remainder of the 2011 population's lives ranging from 28 900 QALYs (95% Uncertainty Interval (UI)): 16 500 to 48 200; outlet reduction) to 282 000 QALYs (95%UI: 189 000 to 405 000; sinking lid) compared with business-as-usual (3% discounting). The timing of health gain and cost savings greatly differed for the various strategies (with accumulated health gain peaking in 2040 for the sinking lid and 2070 for the TFG). CONCLUSIONS: Implementing endgame strategies is needed to achieve tobacco endgame targets and reduce inequalities in smoking. Given such strategies are new, modelling studies provide provisional information on what approaches may be best. PMID- 28647726 TI - Treatments for gestational diabetes: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the effectiveness of different treatments for gestational diabetes mellitus (GDM). DESIGN: Systematic review, meta-analysis and network meta-analysis. METHODS: Data sources were searched up to July 2016 and included MEDLINE and Embase. Randomised trials comparing treatments for GDM (packages of care (dietary and lifestyle interventions with pharmacological treatments as required), insulin, metformin, glibenclamide (glyburide)) were selected by two authors and double checked for accuracy. Outcomes included large for gestational age, shoulder dystocia, neonatal hypoglycaemia, caesarean section and pre-eclampsia. We pooled data using random-effects meta-analyses and used Bayesian network meta-analysis to compare pharmacological treatments (ie, including treatments not directly compared within a trial). RESULTS: Forty-two trials were included, the reporting of which was generally poor with unclear or high risk of bias. Packages of care varied in their composition and reduced the risk of most adverse perinatal outcomes compared with routine care (eg, large for gestational age: relative risk0.58 (95% CI 0.49 to 0.68; I2=0%; trials 8; participants 3462). Network meta-analyses suggest that metformin had the highest probability of being the most effective treatment in reducing the risk of most outcomes compared with insulin or glibenclamide. CONCLUSIONS: Evidence shows that packages of care are effective in reducing the risk of most adverse perinatal outcomes. However, trials often include few women, are poorly reported with unclear or high risk of bias and report few outcomes. The contribution of each treatment within the packages of care remains unclear. Large well-designed and well-conducted trials are urgently needed. TRIAL REGISTRATION NUMBER: PROSPERO CRD42013004608. PMID- 28647727 TI - Patients as partners in Enhanced Recovery After Surgery: A qualitative patient led study. AB - OBJECTIVES: Explore the experience of patients undergoing colorectal surgery within an Enhanced Recovery After Surgery (ERAS) programme. Use these experiential data to inform the development of a framework to support ongoing, meaningful patient engagement in ERAS. DESIGN: Qualitative patient-led study using focus groups and narrative interviews. Data were analysed iteratively using a Participatory Grounded Theory approach. SETTING: Five tertiary care centres in Alberta, Canada, following the ERAS programme. PARTICIPANTS: Twenty-seven patients who had undergone colorectal surgery in the last 12 months were recruited through purposive sampling. Seven patients participated in a codesign focus group to set and prioritise the research direction. Narrative interviews were conducted with 20 patients. RESULTS: Patients perceived that an ERAS programme should not be limited to the perioperative period, but should encompass the journey from diagnosis to recovery. Practical recommendations to improve the patient experience across the surgical continuum, and enhance patient engagement within ERAS included: (1) fully explain every protocol, and the purpose of the protocol, both before surgery and while in-hospital, so that patients can become knowledgeable partners in their recovery; (2) extend ERAS guidelines to the presurgery phase, so that patients can be ready emotionally, psychologically and physically for surgery; (3) extend ERAS guidelines to the recovery period at home to avoid stressful situations for patients and families; (4) consider activating a programme where experienced patients can provide peer support; (5) one size does not fit all; personalised adaptations within the standardised pathway are required.Drawing upon these data, and through consultation with ERAS Alberta stakeholders, the ERAS team developed a matrix to guide sustained patient involvement and action throughout the surgical care continuum at three levels: individual, unit and ERAS system. CONCLUSION: This patient-led study generated new insights into the needs of ERAS patients and informed the development of a framework to improve patient experiences and outcomes. PMID- 28647729 TI - Analgesic Effects of Diluted Bee Venom Acupuncture Mediated by delta-Opioid and alpha2-Adrenergic Receptors in Osteoarthritic Rats. AB - Context * Pain from osteoarthritis is associated with peripheral nociception and central pain processing. Given the unmet need for innovative, effective, and well tolerated therapies, many patients, after looking for more satisfactory alternatives, decide to use complementary and alternative modalities. The analgesic mechanism of subcutaneous injections of diluted bee venom into an acupoint is thought to be part of an anti-inflammatory effect and the central modulation of pain processing. Objectives * Using the rat model of collagenase induced osteoarthritis (CIOA), the study intended to investigate the analgesic effects of bee venom acupuncture (BVA) as they are related to the acupuncture points and dosage used and to determine whether the analgesic mechanisms of BVA for pain were mediated by opioid or adrenergic receptors. Design * Male Sprague Dawley rats were randomly assigned to one of 19 groups, with n = 10 for each group. Setting * The study was conducted at the East-West Bone and Joint Research Institute at Kyung Hee University (Seoul, South Korea). Intervention * All rats were intra-articularly injected with collagenase solution in the left knee, followed by a booster injection performed 4 d after the first injection. For the groups receiving BVA treatments, the treatment was administered into the ST-36 acupoint, except for 1 group that received the treatment into a nonacupoint. Three BVA intervention groups received no pretreatment with agonists or antagonists; 1 of them received a dose of 1 mg/kg of bee venom into acupoint ST 36, 1 received a dose of 2 mg/kg into acupoint ST-36, and 1 received a dose of 1 mg/kg into a nonacupoint location. For the intervention groups receiving pretreatments, the opioid-receptor or adrenergic-receptor agonists or antagonists were injected 20 min before the 1-mg/kg BVA treatments. Outcome Measures * Changes in the rats' pain thresholds were assessed by evaluation of pain-related behavior, using a tail flick latency unit. Results * The pain reached its maximum value after 4 wk of CIOA induction. The 1-mg/kg ST-36 BVA treatment resulted in a more significant analgesic effect than nonacupoint BVA. Pain-related behavior was more effectively improved by treatment with 1 mg/kg of BVA than with 2 mg/kg of BVA. The analgesic effects of the BVA were not synergistic with the agonist pretreatments with the MU-, delta-, or kappa-opioid receptors or with the alpha1 , alpha2-, and beta-adrenergic receptors. The analgesic effects of the BVA were not decreased by the antagonist pretreatments for the MU- or kappa-opioid receptors or for the alpha1- or beta-adrenergic receptors. The ST-36-BVA-induced analgesia was inhibited by the antagonist pretreatments for the delta-opioid receptor and the alpha2-adrenergic receptor. Conclusion * The ST-36 BVA treatment exerted an analgesic effect on CIOA-induced pain through the partial involvement of the delta-opioid and alpha2-adrenergic receptors. PMID- 28647730 TI - Qiliqiangxin Attenuates Adverse Cardiac Remodeling after Myocardial Infarction in Ovariectomized Mice via Activation of PPARgamma. AB - BACKGROUND/AIMS: This study was designed to investigate the therapeutic effect of traditional Chinese medication Qiliqiangxin (QLQX) on adverse cardiac remodeling after myocardial infarction (MI) in bilateral ovariectomized (OVX) female mice. METHODS: Eight-week old female C57BL/6 mice were operated to ligate the left anterior descending coronary artery seven days after bilateral ovariectomy and were orally administered either QLQX or vehicle. 21 days after ligation, echocardiography was performed to evaluate the heart function of all mice. Masson's Trichrome staining was applied to evaluate myocardial fibrosis. Collagen deposition was determined by the mRNA level of Collagen I, Collagen III and alpha SMA using real-time quantitative polymerase chain reaction (qPCR). Myocardial apoptosis was examined by the protein level of Bax, Bcl2 and the Bcl2/Bax ratio using western blotting. RESULTS: These mice displayed a significant reduction in heart function, increased myocardial fibrosis and apoptosis, and decreased expression of peroxisome proliferator activated receptor gamma (PPARgamma) in the heart tissue, which could be reversed by QLQX treatment. Inhibition of PPAR reduced QLQX-mediated cardio-protective effects, while PPARgamma activation did not further enhance the beneficial effect of QLQX. Furthermore, QLQX upregulated 9 genes (Cd36, Fatp, Pdk4, Acadm, Acadl, Acadvl, Cpt1a, Cpt1b and Cpt2) facilitating energy metabolism in the MI hearts of the OVX mice and 5 (Acadm, Acadl, Cpt1a, Cpt1b, Cpt2) of the 9 genes were the downstream targets of PPARgamma. CONCLUSION: The present study indicates that QLQX has a treatment effect on pathological remodeling post MI in bilateral OVX female mice via activation of PPARgamma, suggesting that QLQX may be a promising prescription for the treatment of postmenopausal women suffering from MI. PMID- 28647731 TI - Recovery of Vocal Fold Epithelium after Acute Phonotrauma. AB - We investigated the timeline of tissue repair of vocal fold epithelium after acute vibration exposure using an in vivo rabbit model. Sixty-five New Zealand white breeder rabbits were randomized to 120 min of modal- or raised-intensity phonation. After the larynges were harvested at 0, 4, 8, and 24 h, and at 3 and 7 days, the vocal fold tissue was evaluated using electron microscopy and quantitative real-time polymerase chain reaction. There was an immediate decrease in the microprojection depth and height following raised-intensity phonation, paired with upregulation of cyclooxygenase-2. This initial 24-h period was also characterized by the significant downregulation of junction proteins. Interleukin 1beta and transforming growth factor beta1 were upregulated for 3 and 7 days, respectively, followed by an increase in epithelial cell surface depth at 3 and 7 days. These data appear to demonstrate a shift from inflammatory response to the initiation of a restorative process in the vocal fold epithelium between 24 h and 3 days. Despite the initial damage from raised-intensity phonation, the vocal fold epithelium demonstrates a remarkable capacity for the expeditious recovery of structural changes from transient episodes of acute phonotrauma. While structurally intact, the return of functional barrier integrity may be delayed by repeated episodes of phonotrauma and may also play an important role in the pathophysiology of vocal fold lesions. PMID- 28647732 TI - Perioperative Strokes Following Surgical Correction of Mitral Valves: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The primary aim of this meta-analysis was to quantify the impact of perioperative strokes on stroke-related mortality after open mitral valve (MV) procedures were performed. METHODS: An electronic search of the PubMed, Embase, and the Web of Science databases was performed to retrieve articles published up to December 2015, relevant to patients undergoing MV procedures. Data were extracted from the final list of 25 studies to calculate a summary OR for 30-day stroke-related mortality. RESULTS: The stroke rate in the total sample population was 1.62% (73/4,498). The 30-day all-cause mortality rate was 3.51% (158/4,498). The percentage of total deaths caused by stroke was 6.87%. The summary OR of stroke-related mortality following MV procedures was estimated to be 7.22 (95% CI 4.13-12.63, p < 0.0001). A subgroup analysis was done for studies involving concomitant MV surgery and coronary artery bypass grafting. The summary estimate of the subgroup showed an OR of 8.508 (95% CI 1.552-46.622, p = 0.0136). CONCLUSION: Perioperative strokes following open MV procedures may be associated with more than 7 times greater odds of 30-day stroke-related mortality. They appear to be more commonly occurring than what is reported by current literature, making further studies investigating possible mechanisms and preventive measures a priority. PMID- 28647733 TI - Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence? AB - Healing and regeneration of bone injuries, particularly those that are associated with large bone defects, are a complicated process. There is growing interest in the application of osteoinductive and osteogenic growth factors and mesenchymal stem cells (MSCs) in order to significantly improve bone repair and regeneration. MSCs are multipotent stromal stem cells that can be harvested from many different sources and differentiated into a variety of cell types, such as preosteogenic chondroblasts and osteoblasts. The effectiveness of MSC therapy is dependent on several factors, including the differentiating state of the MSCs at the time of application, the method of their delivery, the concentration of MSCs per injection, the vehicle used, and the nature and extent of injury, for example. Tissue engineering and regenerative medicine, together with genetic engineering and gene therapy, are advanced options that may have the potential to improve the outcome of cell therapy. Although several in vitro and in vivo investigations have suggested the potential roles of MSCs in bone repair and regeneration, the mechanism of MSC therapy in bone repair has not been fully elucidated, the efficacy of MSC therapy has not been strongly proven in clinical trials, and several controversies exist, making it difficult to draw conclusions from the results. In this review, we update the recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine. We will also review the most recent clinical trials to find out how MSCs may be beneficial for treating bone defects. PMID- 28647734 TI - MiR-4673 Modulates Paclitaxel-Induced Oxidative Stress and Loss of Mitochondrial Membrane Potential by Targeting 8-Oxoguanine-DNA Glycosylase-1. AB - BACKGROUND: Our previous study identified a novel microRNA, miR-4673, which is upregulated in A549 cells exposed to paclitaxel (PTX). In this study, we investigated the role of miR-4673 in PTX-induced cytotoxicity. METHODS: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, apoptosis assay, 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide (JC-1) staining and 2',7'-Dichlorofluorescein (DCFH) staining were used to evaluate cell viability, apoptosis, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis and Luciferase reporter assay were used to explore whether 8-oxoguanine-DNA glycosylase-1 (OGG1) is a target gene of miR-4673. RESULTS: Enforced expression of miR-4673 decreased cell viability and increased PTX-induced apoptosis, MMP loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis, which was used to identify potential target of miR-4673, revealed a binding site of miR-4673 in 3'UTR of OGG1. Luciferase reporters assays showed that miR-4673 specifically binds to 'CUGUUGA' in 3'UTR of OGG1. Enforced expression of miR-4673 decreased accumulation of OGG1. In addition, silencing OGG1 enhanced inhibitory effects of PTX on apoptosis, MMP loss and ROS generation, which is similar to effects of miR-4673. Moreover, enforced expression of OGG1 compromised promoting effects of miR-4673 on PTX-induced apoptosis, MMP loss and ROS generation. CONCLUSION: miR-4673 modulates PTX induced apoptosis, MMP loss and ROS generation by targeting OGG1. PMID- 28647735 TI - Uniparental Disomy of Chromosome 15 in Two Cases by Chromosome Microarray: A Lesson Worth Thinking. AB - Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurogenetic disorders caused by loss of function of the imprinted genes at 15q11q13. A 5-7 Mb paternal/maternal deletion of chromosomal region 15q11.2q13 is the major genetic cause of PWS/AS, but in a small group of patients, the PWS/AS phenotype can result from maternal/paternal uniparental disomy (UPD) of chromosome 15. Various mechanisms leading to UPD include gametic complementation, trisomy rescue, and compensatory UPD, which can be inferred from the pattern of uniparental heterodisomy (heteroUPD) or uniparental isodisomy (isoUPD). However, heteroUPD and isoUPD, especially mixed heteroUPD and isoUPD, are very rare in patients with PWS/AS. Here, we report 2 children with PWS/AS caused by mixed segmental heteroUPD 15 and isoUPD 15 which failed to be identified by chromosome microarray (CMA) but could be detected by other molecular genetic methods. The present report unravels the mechanism of mixed iso/heteroUPD 15 in PWS/AS and phenotype genotype correlations. Moreover, our study suggests that CMA is prone to misdiagnosis for imprinting disorders such as PWS/AS, though it is considered a highly useful tool for copy number variations. As a result, other molecular detection methods, such as methylation analysis and STR marker analysis for UPD, should be supplementary used in this situation. PMID- 28647736 TI - No Severe Hypercalcemia with Daily Vitamin D3 Supplementation of up to 30 ug during the First Year of Life. AB - BACKGROUND: Vitamin D supplementation is widely recommended for infants, but the optimal dose remains unclear. High intake may result in hypercalcemia. METHODS: We evaluated the incidence of hypercalcemia during the first year of life in a cohort of 987 healthy children who received 10 or 30 MUg of vitamin D3 supplementation daily. Ionized calcium (Ca-ion) was analyzed at 6 and 12 months, and serum 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentration at 12 months. Severe hypercalcemia was defined as Ca-ion exceeding the reference limit (1.16-1.39 mmol/L) by 10%. RESULTS: No severe hypercalcemia occurred. Mild hypercalcemia (1.40-1.52 mmol/L) was present at 6 months in 28% and at 12 months in 2% of infants. At 12 months, 25-OHD ranged between 23 and 241 nmol/L (median 97), and PTH was between undetectable and 104 pg/mL (median 24) and was below the reference range (11.5-78.4 pg/mL) in 11%. 25-OHD and Ca-ion correlated positively (r = 0.149), and 25-OHD was slightly higher in the 12 infants with mild hypercalcemia (median 97 vs. 110 nmol/L, p = 0.046). CONCLUSIONS: Vitamin D3 supplementation of 10 or 30 ug did not cause severe hypercalcemia. Mild hypercalcemia was more prevalent at 6 months than at 12 months, and was associated weakly with 25-OHD at 12 months. PMID- 28647737 TI - Trends in the Management of Acute Appendicitis in a Single-Center Quality Register Cohort of 5,614 Patients. AB - Acute appendicitis is one of the most common reasons for emergency surgery. At Stockholm South General Hospital, information on all patients - 15 years or older - undergoing surgery for acute appendicitis is included in a quality register. Data on surgical method, preoperative imaging, hospital stay, intraoperative findings, and 30-day complications were recorded for each patient. From January 2004 to December 2014, 5,614 consecutive patients were registered. The percentage of patients examined with preoperative imaging increased from 30% in 2004 to 93% in 2014. The use of laparoscopic appendectomy increased from 6 to 79%. Negative appendectomies decreased from 7.5-10 to 1.7%. The mean perforation rate was 28.6%. Some form of postoperative complication occurred in 6.6% of those on whom laparoscopy was performed and 10.5% of those who underwent an open surgery, with a significant difference (p < 0.001) in the rate of surgical site infections (surgical site infections, higher in open cases) but with no difference in the number of deep postoperative abscesses. The overall hospital stay decreased from 2004 to 2014 for perforated and non-perforated appendicitis. The overall 30-day mortality rate was 0.12%. Changes in preoperative imaging and treatment strategy for appendicitis during this period resulted in a lower rate of negative appendectomies with acceptable complication rates and shortened hospital stay. PMID- 28647738 TI - Outcome and Treatment of Antenatally Diagnosed Nonimmune Hydrops Fetalis. AB - INTRODUCTION: The objectives of this study were to evaluate the outcome of nonimmune hydrops fetalis in an attempt to identify independent predictors of perinatal mortality. MATERIAL AND METHODS: A retrospective cohort study was conducted including all cases of nonimmune hydrops from two tertiary care centers. Perinatal outcome was evaluated after classifying nonimmune hydrops into ten etiological groups. We examined the effect of etiology, site of fluid accumulation, and gestational age at delivery on postnatal survival. Neonatal mortality and hospital discharge survival were compared between the expectant management and fetal intervention groups among those with idiopathic etiology. RESULTS: A total of 142 subjects were available for analysis. Generally, nonimmune hydrops carried 37% risk of neonatal mortality and 50% chance of survival to discharge, which varies markedly based on the underlying etiology. Ascites was an independent predictor of perinatal mortality (p value = 0.003). There was nonsignificant difference in neonatal mortality and hospital discharge survival among idiopathic cases that were managed expectantly versus those in whom fetal intervention was carried out. DISCUSSION: The outcome of nonimmune hydrops varies largely according to the underlying etiology and the presence of ascites is an independent risk factor for perinatal mortality. In our series, fetal intervention did not offer survival advantage among fetuses with idiopathic nonimmune hydrops. PMID- 28647739 TI - Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. AB - The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP. PMID- 28647740 TI - Integrative Assessment of Pretreatment Inflammation-, Nutrition-, and Muscle Based Prognostic Markers in Patients with Muscle-Invasive Bladder Cancer Undergoing Radical Cystectomy. AB - OBJECTIVE: The present study evaluated the clinical relevance of an integrative preoperative assessment of inflammation-, nutrition-, and muscle-based markers for patients with muscle-invasive bladder cancer (MIBC) undergoing curative radical cystectomy (RC). METHODS: The analysis enrolled 117 patients and the variables included age, body mass index (BMI), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), Controlling Nutritional Status score, psoas muscle index (PMI), and peak expiratory flow (PEF). The correlations among the variables were evaluated and their prognostic values after RC were tested. RESULTS: Three inflammation markers (ratios of blood cell counts) were positively correlated (p < 0.0001). The PNI and the BMI were positively correlated (p = 0.04), although they were inversely correlated with the three inflammation markers (p < 0.0001). Age was not significantly correlated with the inflammation markers and PMI, although older age was associated with lower PNI and lower PEF. The disease-specific survival was independently predicted by T4 tumor, positive N status, and decreased PNI. Overall survival was independently predicted by T4 tumor, mGPS, and pretreatment sarcopenia status. CONCLUSIONS: The inflammation-, nutrition-, and muscle-based markers would be useful risk assessment tools for MIBC. PMID- 28647741 TI - Plasma Dipeptidyl Peptidase-4 Activity, a Novel Biomarker or Even a Possible Therapeutic Target for Depression in Type 2 Diabetic Patients: Results from a Cross-Sectional Study in China. PMID- 28647742 TI - Interprofessional Collaborative Learning Experience. PMID- 28647743 TI - Predictive Accuracy of Calf Circumference Measurements to Detect Decreased Skeletal Muscle Mass and European Society for Clinical Nutrition and Metabolism Defined Malnutrition in Hospitalized Older Patients. AB - BACKGROUND/AIMS: The ability to readily diagnose sarcopenia and malnutrition in a clinical setting is essential. This study is aimed at clarifying the calf circumference (CC) cut-off values for decreased skeletal muscle mass (SMM), according to the Asian Work Group for Sarcopenia's criteria definition of sarcopenia, and those for European Society for Clinical Nutrition and Metabolism defined malnutrition, in hospitalized Japanese patients. METHODS: The study involved 1,164 patients aged >=65 years. Predictive CC cut-off values were determined using receiver operating curve (ROC) analyses. The predictive validity of the cut-off values was confirmed against in-hospital mortality. RESULTS: There were 654 females and 510 males (mean age, 83.5 +/- 8.2 years). Decreased SMM and malnutrition were observed in 80.4 and 32.8% of all patients, respectively. ROC analyses identified CCs of <=29 cm (female, area under the curve [AUC] 0.791) and <=30 cm (male, AUC 0.832) as cut-off values for decreased SMM, and CCs of <=26 cm (female, AUC 0.798) and <=28 cm (male, AUC 0.837) for malnutrition. CC cut-off values for SMM and malnutrition were independently correlated with in-hospital mortality. CONCLUSIONS: The study determined appropriate cut-off values for CC to identify decreased SMM and malnutrition according to the relevant guidelines. PMID- 28647744 TI - Effectiveness of Supported Self-Help in Recurrent Depression: A Randomized Controlled Trial in Primary Care. AB - BACKGROUND: The burden and economic consequences of depression are high, mostly due to its recurrent nature. Due to current budget and time restraints, a preventive, low- cost, accessible minimal intervention is much needed. In this study, we evaluated the effectiveness of a supported self-help preventive cognitive therapy (S-PCT) added to treatment as usual (TAU) in primary care, compared to TAU alone. METHODS: We conducted a randomized controlled trial among 248 patients with a history of depression, currently in full or partial remission or recovery. Participants were randomized to TAU augmented with S-PCT (n = 124) or TAU alone (n = 124). S-PCT consisted of an 8-week self-help intervention, supported by weekly telephone guidance by a counselor. The intervention included a self-help book that could be read at home. The primary outcome was the incidence of relapse or recurrence and was assessed over the telephone by the Structured Clinical Interview for DSM-IV axis 1 disorders. Participants were observed for 12 months. Secondary outcomes were depressive symptoms, quality of life (EQ-5D and SF-12), comorbid psychopathology, and self-efficacy. These secondary outcomes were assessed by digital questionnaires. RESULTS: In the S-PCT group, 44 participants (35.5%) experienced a relapse or recurrence, compared to 62 participants (50.0%) in the TAU group (incidence rate ratio = 0.71, 95% CI 0.52-0.97; risk difference = 14, 95% CI 2-24, number needed to treat = 7). Compared to the TAU group, the S-PCT group showed a significant reduction in depressive symptoms over 12 months (mean difference -2.18; 95% CI -3.09 to -1.27) and a significant increase in quality of life (EQ-5D) (mean difference 0.04; 95% CI 0.004-0.08). S-PCT had no effect on comorbid psychopathology, self-efficacy, and quality of life based on the SF-12. CONCLUSIONS: A supported self-help preventive cognitive therapy, guided by a counselor in primary care, proved to be effective in reducing the burden of recurrent depression. PMID- 28647745 TI - Early Halt of a Randomized Controlled Study with 3% Hypertonic Saline in Acute Bronchiolitis. AB - BACKGROUND: Albeit not recommended because of contradictory results, nebulized 3% hypertonic saline is widely used for treating acute viral bronchiolitis. Whether clinical differences may be attributed to the type of nebulizer used has never been studied. OBJECTIVES: By modifying the amount of salt deposited into the airways, the nebulizer characteristics might influence clinical response. METHODS: A prospective, randomized, controlled trial included infants hospitalized in a French university hospital for a first episode of bronchiolitis. Each child received 6 nebulizations of 3% hypertonic saline during 48 h delivered with 1 of the 3 following nebulizers: 2 jet nebulizers delivering large or small particles, with a low aerosol output, and 1 mesh nebulizer delivering small particles, with a high aerosol output. The primary endpoint was the difference in the Wang score at 48 h. RESULTS: Only 61 children of 168 were recruited before stopping this study because of severe adverse events (n = 4) or parental requests for discontinuation due to discomfort to their child during nebulization (n = 2). One minor adverse event was noted in 91.8% (n = 56/61) of children. A high aerosol output induced 75% of the severe adverse events; it was significantly associated with the nebulization-induced cough between 24 and 48 h (p = 0.036). Decreases in Wang scores were not significantly different between the groups at 48 h, 9 recoveries out of 10 being obtained with small particles. CONCLUSION: No beneficial effects and possibly severe adverse events are observed with 3% hypertonic saline in the treatment of bronchiolitis. PMID- 28647746 TI - The Effects of an Internet-Based Imagery Rehearsal Intervention: A Randomized Controlled Trial. AB - BACKGROUND: Nightmares are extremely dysphoric dreams, which are prevalent and associated with psychological strain. This study investigated (a) the efficacy of an internet-based imagery rehearsal therapy (IRT), (b) the role of imagery rescription, and (c) the role of guidance during internet-based IRT. METHODS: A total of 127 patients suffering from mainly idiopathic nightmares were randomly assigned to 1 of 2 IRT internet-based groups (guided IRT; unguided IRT) or to 1 of 2 active control groups (frequency control group; narrative control group). RESULTS: IRT was more effective than a nightmare frequency control condition with respect to nightmare frequency and nightmare distress. Compared to the narrative control group, IRT was only superior in improving nightmare distress but not in nightmare frequency because the narrative control group also improved regarding nightmare frequency. Guidance by a nightmare coach did not affect efficacy, compliance, or dropout. CONCLUSION: Internet-based IRT seems to be an effective treatment even when offered with minimal guidance by a nightmare coach. Describing the nightmare narrative in detail already decreased nightmare frequency. However, with regard to inducing decreases in nightmare frequency and nightmare distress, IRT was superior to the narrative control group. The results are discussed with reference to the mastery hypothesis. PMID- 28647747 TI - Comparing the Effects of Mindfulness-Based Cognitive Therapy and Sleep Psycho Education with Exercise on Chronic Insomnia: A Randomised Controlled Trial. AB - BACKGROUND: Mindfulness-based cognitive therapy (MBCT) is a potential treatment for chronic insomnia. We evaluated the efficacy of MBCT for insomnia (MBCT-I) by comparing it with a sleep psycho-education with exercise control (PEEC) group. METHODS: Adults with chronic primary insomnia (n = 216) were randomly allocated to the MBCT-I or PEEC group. The MBCT-I included mindfulness and psycho-education with cognitive and behavioural components under cognitive behavioural therapy for insomnia. PEEC included psycho-education of sleep hygiene and stimulus control, and exercises. Any change in insomnia severity was measured by the Insomnia Severity Index (ISI). Secondary outcomes included sleep parameters measured by a sleep diary, health service utilisation, absence from work and mindfulness measured by the Five Facet Mindfulness Questionnaire. RESULTS: The ISI score significantly decreased in the MBCT-I group compared with the PEEC group at 2 months (i.e., post-intervention) (p = 0.023, effect size [95% CI] -0.360 [-0.675, -0.046]) but not at 5 or 8 months. Treatment response rates and remission rates based on the ISI cut-off scores were not significantly different between groups. Wake time after sleep onset (WASO) was less in the MBCT-I group at 2 and 5 months. At 8 months, both groups showed a reduced ISI score, sleep onset latency and WASO, and increased sleep efficiency and total sleep time; however, no group differences were seen. Other outcome measures did not significantly improve in either group. CONCLUSIONS: Long-term benefits were not seen in MBCT-I when compared with PEEC, although short-term benefits were seen. PMID- 28647748 TI - Single-Level Anterior Cervical Corpectomy and Fusion Using a New 3D-Printed Anatomy-Adaptive Titanium Mesh Cage for Treatment of Cervical Spondylotic Myelopathy and Ossification of the Posterior Longitudinal Ligament: A Retrospective Case Series Study. AB - BACKGROUND The aim of this study was to evaluate the clinical and radiological outcomes of the use of a new 3D-printed anatomy-adaptive titanium mesh cage (AA TMC) for single-level anterior cervical corpectomy and fusion (ACCF) in patients with cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL). MATERIAL AND METHODS We retrospectively reviewed the records of 15 consecutive patients who underwent ACCF surgeries with AA-TMC implantation. The Japanese Orthopedic Association (JOA) scoring system, a visual analogue scale (VAS), the mean intervertebral height (MIBH) of the surgical segments, and the surgical segmental angle (SSA) were recorded preoperatively, immediately after surgery and at the final follow-up visit. The outcomes of these parameters at different time points were compared. RESULTS Six months after ACCF surgery, solid bony fusions of the surgical level were achieved in all patients. The mean MIBH was 21.05+/-1.99 mm preoperatively, 27.51+/-1.44 mm immediately after surgery (P<0.05), and 26.85+/-1.25 mm at the last follow-up visit (P<0.05). At the last follow-up visit, none of the AA-TMCs exhibited severe subsidence (>3 mm). The mean SSA was 6.66+/-7.08 degrees preoperatively, 14.03+/-2.3 degrees immediately after surgery (P<0.05), and 15.09+/-2.1 degrees at the final follow up visit (P>0.05). The mean VAS and JOA scores were 6.6+/-1.26 and 10.47+/-2.07, respectively, preoperatively and 2.47+/-1.3 and 13.6+/-1.96 immediately after surgery, respectively (P<0.05). At the last follow-up visit, the mean VAS and JOA were further restored to 1.67+/-1.18 and 14.9+/-1.39, respectively (P<0.05). CONCLUSIONS The application of the AA-TMC in single-level ACCF significantly relieved symptoms of CSM and OPLL. The rational design of the AA-TMC restores the surgical segmental curvature, maintains the intervertebral height, and prevents postoperative subsidence-related complications. PMID- 28647749 TI - Expression of High-Mobility Group Box 1 Protein (HMGB1) and Toll-Like Receptor 9 (TLR9) in Retinas of Diabetic Rats. AB - BACKGROUND Diabetic retinopathy (DR) and diabetic optic neuropathy are important complications of diabetes mellitus (DM) which can lead to blindness in diabetic patients. Recent studies showed that chronic low-grade inflammation is thought to be one of the important pathophysiological mechanisms in the occurrence and development of DR and diabetes optic neuropathy. This study explored the expressions of inflammatory factors HMGB-1 and TLR9. MATERIAL AND METHODS SD rats were randomly divided into a diabetic mellitus group and a control group. A DM rat model was produced by intraperitoneal injection of 1% STZ with 60 mg/Kg weight. At 4, 8, and 16 weeks after injection, the rats were sacrificed and eyeballs were enucleated for HE staining, immunohistochemistry, Western blot, and RT-PCR. RESULTS We found that, compared with the control group, levels of HMGB1 and TLR9 in retinas were significantly increased in DM groups of different time courses. Furthermore, a significant correlation was found between HMGB1 and TLR9 (all P<0.05). CONCLUSIONS Our results demonstrated that the HMGB1-TLR9 signaling pathway may be involved in the pathogenesis of diabetic retinopathy. Blockage of HMGB1 and/or TLR9 may represent a novel approach to treating diabetic retinopathy and diabetic optic neuropathy. PMID- 28647750 TI - Misdiagnosed paranasal gossypiboma: a 10-year experience with 21 cases at a tertiary center. AB - BACKGROUND: Different from rhinoliths, the paranasal gossypiboma is a foreign body, such as a surgical sponge, left in the nasal cavity. It is a rare, frequently misdiagnosed disease that has rarely been reported. We summarize its clinical characteristics, management, and possible risk factors. METHODOLOGY: We reviewed medical records of confirmed paranasal gossypibomas at a tertiary medical center between 2005 and 2015. Clinical symptoms, age, sex, anatomic sites, endoscopic photography, computed tomography, intraoperative findings, and past medical history were reviewed. RESULTS: The study included 21 patients, each of whom had ultimately undergone two operations. Among them, 20 underwent endoscopic nasal surgery in primary hospitals, and 15 had been misdiagnosed during the second surgery. The average interval to discovery of a retained foreign body was 200 days. Predominant occurrence sites were the maxillary and ethmoid sinuses. Computed tomography showed paranasal gossypiboma as a heterogeneous cystic lesion with a thin calcified shell. CONCLUSIONS: A history of endoscopic nasal surgery, especially performed at a primary hospital, is a warning sign for clinicians. Computed tomography can add to the warning by showing a heterogeneous cystic lesion with a thin calcified shell. Clinicians should be aware of these characteristics to avoid misdiagnosing paranasal gossypiboma. PMID- 28647751 TI - Chronic rhinosinusitis severity is associated with need for asthma-related systemic corticosteroids. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is highly prevalent in patients with asthma. However, no study has evaluated the effect of CRS severity on asthma related oral corticosteroid use - a marker of poor asthma control and prognosis. We therefore sought to evaluate the association between CRS severity and asthma related oral corticosteroid use. METHODOLOGY: Prospective cross-sectional study of 110 adult asthmatic CRS patients. CRS severity was measured using the 22-item Sinonasal Outcomes Test (SNOT-22) and Lund-Kennedy endoscopy score. Number of asthma-related courses of oral corticosteroids in the past year was queried at enrollment. Association was sought between metrics for CRS severity and asthma related oral corticosteroids use in the last year. Receiver operating characteristic (ROC) curves defined whether SNOT-22 or endoscopy scores could be used for detecting asthma-related oral corticosteroid use. RESULTS: The mean SNOT 22 score was 44.9 (standard deviation [SD] : 23.3) and mean endoscopy score was 4.1 (SD: 3.0). The mean number of asthma-related oral corticosteroid courses taken in the last year was 1.1 (SD: 1.9). SNOT-22, but not endoscopy score, was associated with requiring at least one course of asthma-related oral corticosteroids in the last year (odds ratio = 1.03, 95%CI: 1.02 - 1.06, p=0.003), which translates to an odds ratio of 2.0 for a 21-point increase in SNOT-22. ROC analysis identified equally optimal SNOT-22 scores of greater than 32 (sensitivity: 88.1%, specificity: 41.2%) or greater than 65 (sensitivity: 38.1%, specificity: 91.2%) for detecting the need for at least one course of oral corticosteroids within the past year. CONCLUSIONS: CRS symptom severity is associated with past asthma-related oral corticosteroid use. SNOT-22 scores may be used as a versatile tool to screen for past asthma-related oral corticosteroid use in asthmatic CRS patients - i.e. those at greatest risk from their asthma - with either high sensitivity or high specificity. PMID- 28647752 TI - Possible Effects of Electric Fields on a Pair of Spherical Cells. AB - Electric fields (EF) can induce some physiological or biological effects in neural tissues, which have been explored in many applications such as electroporation. The key to understand the possible underlying mechanisms of such effects tend to be the induced transmembrane potential. Although transmembrane potentials have already been the subject of many theoretical studies, most previous works concerning this topic are mainly focused on the situations of isolated cells. In previous studies, cells are often considered to be three compartment models with different electroconductivities in different regions (the three compartments are often intracellular regions, membrane, and extracellular regions). In the present paper, we utilize a finite element method (FSM) (with the help of COMSOL(r)) to calculate the induced transmembrane potential by the applied EF for a model of two neurons, which may have significant difference on electroporation. PMID- 28647753 TI - The bee, the flower, and the electric field: electric ecology and aerial electroreception. AB - Bees and flowering plants have a long-standing and remarkable co-evolutionary history. Flowers and bees evolved traits that enable pollination, a process that is as important to plants as it is for pollinating insects. From the sensory ecological viewpoint, bee-flower interactions rely on senses such as vision, olfaction, humidity sensing, and touch. Recently, another sensory modality has been unveiled; the detection of the weak electrostatic field that arises between a flower and a bee. Here, we present our latest understanding of how these electric interactions arise and how they contribute to pollination and electroreception. Finite-element modelling and experimental evidence offer new insights into how these interactions are organised and how they can be further studied. Focussing on pollen transfer, we deconstruct some of the salient features of the three ingredients that enable electrostatic interactions, namely the atmospheric electric field, the capacity of bees to accumulate positive charge, and the propensity of plants to be relatively negatively charged. This article also aims at highlighting areas in need of further investigation, where more research is required to better understand the mechanisms of electrostatic interactions and aerial electroreception. PMID- 28647755 TI - Namib Desert Soil Microbial Community Diversity, Assembly, and Function Along a Natural Xeric Gradient. AB - The hyperarid Namib desert is a coastal desert in southwestern Africa and one of the oldest and driest deserts on the planet. It is characterized by a west/east increasing precipitation gradient and by regular coastal fog events (extending up to 75 km inland) that can also provide soil moisture. In this study, we evaluated the role of this natural aridity and xeric gradient on edaphic microbial community structure and function in the Namib desert. A total of 80 individual soil samples were collected at 10-km intervals along a 190-km transect from the fog-dominated western coastal region to the eastern desert boundary. Seventeen physicochemical parameters were measured for each soil sample. Soil parameters reflected the three a priori defined climatic/xeric zones along the transect ("fog," "low rain," and "high rain"). Microbial community structures were characterized by terminal restriction fragment length polymorphism fingerprinting and shotgun metaviromics, and their functional capacities were determined by extracellular enzyme activity assays. Both microbial community structures and activities differed significantly between the three xeric zones. The deep sequencing of surface soil metavirome libraries also showed shifts in viral composition along the xeric transect. While bacterial community assembly was influenced by soil chemistry and stochasticity along the transect, variations in community "function" were apparently tuned by xeric stress. PMID- 28647756 TI - Role of coronal high-resolution diffusion-weighted imaging in acute optic neuritis: a comparison with axial orientation. AB - PURPOSE: Through a comparison with the axial orientation, we aimed to evaluate the role of coronal high-resolution diffusion-weighted imaging (DWI) in acute optic neuritis based on diagnostic accuracy and the reproducibility of apparent diffusion coefficient (ADC) measurements. METHODS: Orbital DWI, using readout segmented, parallel imaging, and 2D navigator-based reacquisition (RESOLVE-DWI), was performed on 49 patients with acute vision loss. The coronal (thickness = 3 mm) and axial (thickness = 2 mm) diffusion images were evaluated by two neuroradiologists retrospectively. The sensitivity, specificity, and accuracy were calculated through diagnostic test; the inter- and intra-observer reliabilities were assessed with a weighted Cohen's kappa test. In addition, the agreement of ADC measurement among observers was evaluated by the intra-class correlation coefficient (ICC), coefficient of variation (CV), and Bland-Altman plots. Comparison of ADC values was also performed by unpaired t test. RESULTS: Among the 49 patients, 47 clinically positive optic nerves and 51 clinically negative optic nerves were found. The sensitivity, specificity, and accuracy were 85.1/87.2%, 90.2/94.12%, and 87.8/90.8%, respectively, for coronal RESOLVE-DWI and 83.0/85.1%, 66.7/76.5%, and 75.5/79.6%, respectively, for axial RESOLVE-DWI. The inter-observer kappa values were 0.710 and 0.806 for axial and coronal RESOLVE-DWI, respectively, and the intra-observer kappa values were 0.822 and 0.909, respectively (each P < 0.0001). Regarding the reproducibility of ADC measurements on axial and coronal RESOLVE-DWI, the ICCs among observers were 0.846 and 0.941, respectively, and the CV values were 7.046 and 4.810%, respectively. Bland-Altman plots revealed smaller inter-observer variability on coronal RESOLVE-DWI. ADC values were significantly lower in positive group (each P < 0.0001). CONCLUSION: Higher specificity and better reproducibility of ADC measurements were found for coronal RESOLVE-DWI, which demonstrated the feasibility of the use of coronal RESOLVE-DWI to examine acute optic neuritis patients. PMID- 28647758 TI - A meta-analysis of quantitative trait loci for abiotic and biotic stress resistance in tetraploid cotton. AB - The number and location of mapped quantitative trait loci (QTL) depend on genetic populations and testing environments. The identification of consistent QTL across genetic backgrounds and environments is a pre-requisite to marker-assisted selection. This study analyzed a total of 661 abiotic and biotic stress resistance QTL based on our previous work and other publications using the meta analysis software Biomercator. It identified chromosomal regions containing QTL clusters for different resistance traits and hotspots for a particular resistance trait in cotton from 98 QTL for drought tolerance under greenhouse (DT) and 150 QTL in field conditions (FDT), 80 QTL for salt tolerance in the greenhouse conditions (ST), 201 QTL for resistance to Verticillium wilt (VW, Verticillium dahliae), 47 QTL for resistance to Fusarium wilt (FW, Fusarium oxysporum f. sp. vasinfectum), and 85 QTL for resistance to root-knot nematodes (RKN, Meloiodogyne incognita) and reniform nematodes (RN, Rotylenchulus reniformis). The traits used in QTL mapping for abiotic stress tolerance included morphological traits-plant height and fresh and dry shoot and root weights, physiological traits-chlorophyll content, osmotic potential, carbon isotope ratio, stomatal conductance, photosynthetic rate, transpiration, canopy temperature, and leaf area index, agronomic traits-seedcotton yield, lint yield, boll weight, and lint percent, and fiber quality traits-fiber length, uniformity, strength, elongation, and micronaire. The results showed that resistance QTL are not uniformly distributed across the cotton genome; some chromosomes carried disproportionally more QTL, QTL clusters, or hotspots. Twenty-three QTL clusters were found on 15 chromosomes (c3, c4, c5, c6, c7, c11, c14, c15, c16, c19, c20, c23, c24, c25, and c26). Moreover, 28 QTL hotshots were associated with different resistance traits including one hotspot on c4 for Verticillium wilt resistance, two QTL hotspots on c24 for chlorophyll content measured under both drought and salt stress conditions, and three other hotspots on c19 for the resistance to Verticillium wilt and Fusarium wilt, and micronaire under drought stress conditions. This meta analysis of stress tolerance QTL provides an important foundation for cotton breeding and further studies on the genetic mechanisms of abiotic and biotic stress resistance in cotton. PMID- 28647757 TI - Arbuscular mycorrhiza effects on plant performance under osmotic stress. AB - At present, drought and soil salinity are among the most severe environmental stresses that affect the growth of plants through marked reduction of water uptake which lowers water potential, leading to osmotic stress. In general, osmotic stress causes a series of morphological, physiological, biochemical, and molecular changes that affect plant performance. Several studies have found that diverse types of soil microorganisms improve plant growth, especially when plants are under stressful conditions. Most important are the arbuscular mycorrhizal fungi (AMF) which form arbuscular mycorrhizas (AM) with approximately 80% of plant species and are present in almost all terrestrial ecosystems. Beyond the well-known role of AM in improving plant nutrient uptake, the contributions of AM to plants coping with osmotic stress merit analysis. With this review, we describe the principal direct and indirect mechanisms by which AM modify plant responses to osmotic stress, highlighting the role of AM in photosynthetic activity, water use efficiency, osmoprotectant production, antioxidant activities, and gene expression. We also discuss the potential for using AMF to improve plant performance under osmotic stress conditions and the lines of research needed to optimize AM use in plant production. PMID- 28647760 TI - Dr. Solco Tromp and the Tromp Award. AB - The Tromp Award is the highest honor awarded by the International Society of Biometeorology (ISB). The award acknowledges outstanding research in biometeorology by a scientist under the age of 35 and was established in conjunction with the Tromp Foundation and the ISB. In honor of the 60th anniversary of the ISB, this article will provide a brief summary of the life of Dr. Solco Tromp and of the six awardees of the Tromp Award since the inaugural issuance of the award in 1999. The Tromp Award was established in part to recognize and support the efforts of young biometeorological professionals. As the brief summary of the awardees and a few of their selected subsequent publications have shown, the ISB and the Tromp Award has proven effective at identifying and supporting promising young scientists. PMID- 28647759 TI - A community-based randomized controlled trial of Mom Power parenting intervention for mothers with interpersonal trauma histories and their young children. AB - We conducted a study to evaluate the effectiveness of Mom Power, a multifamily parenting intervention to improve mental health and parenting among high-risk mothers with young children in a community-based randomized controlled trial (CB RCT) design. Participants (N = 122) were high-risk mothers (e.g., interpersonal trauma histories, mental health problems, poverty) and their young children (age <6 years), randomized either to Mom Power, a parenting intervention (treatment condition), or weekly mailings of parenting information (control condition). In this study, the 13-session intervention was delivered by community clinicians trained to fidelity. Pre- and post-trial assessments included mothers' mental health symptoms, parenting stress and helplessness, and connection to care. Mom Power was delivered in the community with fidelity and had good uptake (>65%) despite the risk nature of the sample. Overall, we found improvements in mental health and parenting stress for Mom Power participants but not for controls; in contrast, control mothers increased in parent-child role reversal across the trial period. The benefits of Mom Power treatment (vs. control) were accentuated for mothers with interpersonal trauma histories. Results of this CB-RCT confirm the effectiveness of Mom Power for improving mental health and parenting outcomes for high-risk, trauma-exposed women with young children. ClinicalTrials.gov Identifier: NCT01554215. PMID- 28647761 TI - Tourism climatology past and present: A review of the role of the ISB Commission on Climate, Tourism and Recreation. AB - The Executive Board of the International Society of Biometeorology (ISB) founded the Commission on Climate, Tourism and Recreation (CCTR) at the 15th International Congress of Biometeorology in Sydney, Australia in 1999. The aims of the CCTR are to bring together researchers from around the world to critically review the current state of knowledge in tourism and recreation climatology and explore possibilities for future research. Almost two decades on, research in tourism climatology has developed and expanded due in large part to the initiatives and activities of the CCTR and several collaborative research projects run under the auspices of the CCTR. This work is reviewed here. Recent CCTR meeting highlighted the fact that, although climate is an essential part of the resource base for tourism, which is one of the world's biggest and fastest growing industries, relatively little is known about the effects of climate on tourist choices and broad demand patterns or the influence climate has on the commercial prospects and sustainability of tourism operators and destinations. The work here reviews what has been done, its conceptual underpinnings and current research frontiers. PMID- 28647762 TI - Association between bone scan index and activities of daily living in patients with advanced non-small cell lung cancer: methodological issues in cross sectional study. PMID- 28647764 TI - Editorial. PMID- 28647765 TI - Epidemiology of hepatocellular carcinoma: target population for surveillance and diagnosis. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer mortality worldwide. Incidence rates of liver cancer vary widely between geographic regions and are highest in Eastern Asia and sub-Saharan Africa. In the United States, the incidence of HCC has increased since the 1980s. HCC detection at an early stage through surveillance and curative therapy has considerably improved the 5-year survival. Therefore, medical societies advocate systematic screening and surveillance of target populations at particularly high risk for developing HCC to facilitate early-stage detection. Risk factors for HCC include cirrhosis, chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), excess alcohol consumption, non-alcoholic fatty liver disease, family history of HCC, obesity, type 2 diabetes mellitus, and smoking. Medical societies utilize risk estimates to define target patient populations in which imaging surveillance is recommended (risk above threshold) or in which the benefits of surveillance are uncertain (risk unknown or below threshold). All medical societies currently recommend screening and surveillance in patients with cirrhosis and subsets of patients with chronic HBV; some societies also include patients with stage 3 fibrosis due to HCV as well as additional groups. Thus, target population definitions vary between regions, reflecting cultural, demographic, economic, healthcare priority, and biological differences. The Liver Imaging Reporting and Data System (LI-RADS) defines different patient populations for surveillance and for diagnosis and staging. We also discuss general trends pertaining to geographic region, age, gender, ethnicity, impact of surveillance on survival, mortality, and future trends. PMID- 28647763 TI - Decompression plus fusion versus decompression alone for degenerative lumbar spondylolisthesis: a systematic review and meta-analysis. AB - PURPOSE: To compare the clinical effectiveness of decompression plus fusion and decompression alone for patients with degenerative lumbar spondylolisthesis, a systematic review and meta-analysis of all available evidence was performed. METHODS: A search of the literature was conducted on PubMed/MEDLINE, EMBASE, and the Cochrane Collaboration Library. Relevant studies comparing decompression plus fusion and decompression alone were selected according to eligibility criteria. Predefined endpoints were extracted and meta-analyzed from the identified studies. RESULTS: Four randomized controlled trials and 13 observational studies were eligible. The pooled data revealed that fusion was associated with significantly higher rates of satisfaction and lower leg pain scores when compared with decompression alone. However, fusion significantly increased the intraoperative blood loss, operative time and hospital stay. Both techniques had similar ODI, back pain scores, complication rate, and reoperation rate. CONCLUSIONS: Based on the available evidence, decompression plus fusion maybe be better than decompression alone in the treatment of degenerative spondylolisthesis. Fusion had advantages of improvement of clinical satisfaction, as well as reduction of postoperative leg pain, with similar complication rate to decompression alone. PMID- 28647766 TI - Impact of patient questionnaires on completeness of clinical information and identification of causes of pain during outpatient abdominopelvic CT interpretation. AB - PURPOSE: To evaluate the impact of questionnaires completed by patients at the time of abdominopelvic CT performed for abdominal pain on the completeness of clinical information and the identification of potential causes of pain, compared with order requisitions alone. METHODS: 100 outpatient CT examinations performed for the evaluation of abdominal pain were retrospectively reviewed. The specificity of the location of pain was compared between the order requisition and patient questionnaire. An abdominal imaging fellow (Reader 1) and abdominal radiologist (Reader 2) reviewed the examinations independently in two sessions 6 weeks apart (one with only the order requisition and one also with the questionnaire). Readers recorded identified causes of pain and rated their confidence in interpretation (1-5 scale; least to greatest confidence). RESULTS: In 30% of patients, the questionnaire provided a more specific location for pain. Among these, the pain was localized to a specific quadrant in 40%. With having access to the questionnaire, both readers identified additional causes for pain not identified in session 1 (Reader 1, 8.6% [7/81]; Reader 2 5.3% [4/75]). Additional identified causes of pain included diverticulitis, cystitis, peritoneal implants, epiploic appendagitis, osseous metastatic disease, umbilical hernia, gastritis, and SMA syndrome. Confidence in interpretation was significantly greater using the questionnaire for both readers (Reader 1: 4.8 +/- 0.6 vs. 4.0 +/- 0.5; Reader 2: 4.9 +/- 0.3 vs. 4.7 +/- 0.5, p < 0.001). CONCLUSION: Patient questionnaires provide additional relevant clinical history, increased diagnostic yield, and improve radiologists' confidence. Radiology practices are encouraged to implement questionnaires and make these readily available to radiologists at the time of interpretation. PMID- 28647767 TI - Inferno sign in epididymo-orchitis. PMID- 28647768 TI - LI-RADS(r) ancillary features on CT and MRI. AB - The Liver Imaging Reporting and Data System (LI-RADS) uses an algorithm to assign categories that reflect the probability of hepatocellular carcinoma (HCC), non HCC malignancy, or benignity. Unlike other imaging algorithms, LI-RADS utilizes ancillary features (AFs) to refine the final category. AFs in LI-RADS v2017 are divided into those favoring malignancy in general, those favoring HCC specifically, and those favoring benignity. Additionally, LI-RADS v2017 provides new rules regarding application of AFs. The purpose of this review is to discuss ancillary features included in LI-RADS v2017, the rationale for their use, potential pitfalls encountered in their interpretation, and tips on their application. PMID- 28647769 TI - A "hanging" bladder stone. PMID- 28647770 TI - CT value of the intestine is useful predictor for differentiate irreversible ischaemic changes in strangulated ileus. AB - PURPOSE: To determine the differential points of strangulated ileus with and without irreversible ischaemic changes, especially on preoperative computed tomography (CT) images. METHODS: Seventy patients with strangulated ileus underwent emergency operations between January 2009 and July 2016 in our department. Of these patients, 57 met the study requirements, including 30 patients who had irreversible ischaemic changes (ischaemic group; n = 30) and 27 patients who had reversible ischaemic changes during laparotomy (non-ischaemic group; n = 27). We compared the preoperative clinical and radiographic factors between the ischaemic and non-ischaemic groups. RESULTS: Univariate analysis revealed that a mean CT value of the intestine in an unenhanced image >=16.5 HU (p < 0.001), a mean CT value ratio of the intestine (enhanced/unenhanced image) <1.5 (p < 0.001), presence of mesenteric fluid (p = 0.002) and presence of free peritoneal fluid (p = 0.009) were associated with the ischaemic group. CONCLUSIONS: Calculation of the mean CT value of a strangulated intestine may be a useful method for predicting irreversible ischaemic changes in addition to the presence of mesenteric fluid or free peritoneal fluid. PMID- 28647771 TI - Detection of potentially relevant extracolonic and colorectal findings at CT colonography in a low-risk symptomatic patient population. AB - PURPOSE: CT colonography (CTC) is a widely accepted examination tool for detection of colorectal lesions but evidence of the proportions of relevant extracolonic findings (ECF) in a large symptomatic but still relatively low-risk cohort is lacking, as well as their relationship to symptoms, age, and sex. METHODS: All patients (n = 3208) with colorectal symptoms, imaged between January 2007 and September 2016 with first-time CTC, were retrospectively selected. The majority (96.7%) was examined with low-dose unenhanced protocol. The most relevant ECF and colorectal lesions (>=6 mm) were prospectively assessed according to C-RADS classifications. Follow-up was elaborated based on the electronic record review. Chi-square test was utilized for evaluating the associations between relevant findings and symptoms, age, and sex. RESULTS: A total of 270 (8.4%) patients were classified as C-RADS E3, 63 (2.0%) patients as C-RADS E4, and 437 (13.6%) patients were assessed with colorectal lesions (C-RADS C2-4). At follow-up, two thirds of ECF turned out to be a malignancy or relevant disease that required further medical attention. The proportion of ECF was not related to specific colorectal symptoms. Patients aged >=65 years and men had significantly higher proportions of ECF than younger patients (C-RADS E3 p = 0.005; C-RADS E4 p < 0.001) and women (C-RADS E3 p = 0.013; C-RADS E4 p = 0.009), respectively. CONCLUSION: Proportions of relevant ECF and colorectal findings are relatively low in symptomatic low-risk patients. By use of CTC as a singular examination, especially in elderly patients, most colonoscopies can be avoided with the benefit of diagnosing relevant ECF without introducing substantial over diagnosis. PMID- 28647772 TI - Diseases of the esophagus: a pattern approach. AB - The esophagus may be involved by a variety of morphologic abnormalities, including nodules and plaques, ulceration, distal esophageal strictures and rings, upper or midesophageal strictures, and diffuse narrowing (also known as a small-caliber esophagus). The use of a pattern approach for evaluating esophageal disease on barium studies facilitates diagnosis of a host of pathologic conditions associated with these morphologic abnormalities. This article therefore presents an approach for diagnosing esophageal disease on barium studies that emphasizes the radiographic and clinical features used to differentiate the underlying causes of disease and the diagnostic pitfalls associated with performing and interpreting these studies. PMID- 28647773 TI - CTHRC1 promotes osteogenic differentiation of periodontal ligament stem cells by regulating TAZ. AB - Collagen triple helix repeat containing 1 (CTHRC1) is associated with bone metabolism. Alveolar bone has an ability to rapidly remodel itself to adapt its biomechanical environment and function. However, whether CTHRC1 is expressed in alveolar bone tissue and the role of CTHRC1 in alveolar bone remodeling remain unclear. We used orthodontic tooth movement (OTM) rat model to study the effects of CHTRC1 in alveolar bone remodeling in vivo. We found that CTHRC1 was expressed in normal physiological condition of osteocytes, bone matrix, and periodontal ligament cells in rat. During the OTM, the expression of CTHRC1, Runx2 and TAZ were increased. We further studied the effects of CTHRC1 on osteogenic differentiation of human periodontal ligament stem cells in vitro. CTHRC1 can positively regulate the expression of TAZ and osteogenic differentiation markers like Col1, ALP, Runx2 and OCN. Overexpression of CHTRC1 increased osteogenic differentiation of PDLSCs, which could be abolished by TAZ siRNA. Our results suggest that CTHRC1 plays an important role in alveolar bone remodeling and osteogenic differentiation of PDLSCs. PMID- 28647774 TI - Automatic identification of coronary tree anatomy in coronary computed tomography angiography. AB - An automatic coronary artery tree labeling algorithm is described to identify the anatomical segments of the extracted centerlines from coronary computed tomography angiography (CCTA) images. This method will facilitate the automatic lesion reporting and risk stratification of cardiovascular disease. Three dimensional (3D) models for both right dominant (RD) and left dominant (LD) coronary circulations were built. All labels in the model were matched with their possible candidates in the extracted tree to find the optimal labeling result. In total, 83 CCTA datasets with 1149 segments were included in the testing of the algorithm. The results of the automatic labeling were compared with those by two experts. In all cases, the proximal parts of main branches including LM were labeled correctly. The automatic labeling algorithm was able to identify and assign labels to 89.2% RD and 83.6% LD coronary tree segments in comparison with the agreements of the two experts (97.6% RD, 87.6% LD). The average precision of start and end points of segments was 92.0% for RD and 90.7% for LD in comparison with the manual identification by two experts while average differences in experts is 1.0% in RD and 2.2% in LD cases. All cases got similar clinical risk scores as the two experts. The presented fully automatic labeling algorithm can identify and assign labels to the extracted coronary centerlines for both RD and LD circulations. PMID- 28647775 TI - A Natural, Calcium-Rich Marine Multi-mineral Complex Preserves Bone Structure, Composition and Strength in an Ovariectomised Rat Model of Osteoporosis. AB - Calcium supplements are used as an aid in the prevention of osteopenia and osteoporosis and also for the treatment of patients when used along with medication. Many of these supplements are calcium carbonate based. This study compared a calcium-rich, marine multi-mineral complex (Aquamin) to calcium carbonate in an ovariectomised rat model of osteoporosis in order to assess Aquamin's efficacy in preventing the onset of bone loss. Animals were randomly assigned to either non-ovariectomy control (Control), ovariectomy (OVX) plus calcium carbonate, ovariectomy plus Aquamin or ovariectomy plus Aquamin delay where Aquamin treatment started 8 weeks post OVX. At the end of the 20-week study, the trabecular architecture was measured using micro computed tomography, bone composition was assessed using Fourier transform infrared spectroscopy and the mechanical properties were assessed using nanoindentation and three-point bend testing. The study demonstrates that oral ingestion of Aquamin results in less deterioration of trabecular bone structure, mineral composition and tissue level biomechanical properties in the tibia of rats following ovariectomy than calcium carbonate. This study has shown that in an animal model of osteoporosis, Aquamin is superior to calcium carbonate at slowing down the onset of bone loss. PMID- 28647776 TI - Sentinel node biopsy for axillary management after neoadjuvant therapy for breast cancer: a single-center retrospective analysis with long follow-up. AB - PURPOSE: Sentinel node biopsy (SNB) after neoadjuvant therapy (NAT) for breast cancer remains controversial. We conducted a retrospective study of patients who underwent SNB after NAT to evaluate the effectiveness of this procedure. METHODS: A consecutive 105 women with locally advanced breast cancer (cT1-4, cN0-3, M0) were treated with NAT between 2006 and 2015. The subjects were 80 of these patients who became or remained clinically node-negative after NAT, 53 of whom had axillary management determined by SNB (group A) and the other 27 underwent axillary lymph node dissection (ALND) without SNB (group B). SNB was performed using a modified dye method. RESULTS: The sentinel node (SN) identification rate was 94.3% and the mean number of removed SNs was 2.4. ALND was avoided in 33 patients, who were confirmed as SN-negative. There was no difference in recurrence-free and overall survival rates between groups A and B (p = 0.71 and p = 0.46, respectively) during the median follow-up time of 63 months. Of the 33 patients who did not undergo ALND, 10 suffered recurrence (33%). One patient (3%) had recurrence in an axillary lymph node and four had recurrence in a supraclavicular lymph node. CONCLUSION: Axillary SNB after NAT did not affect the axillary failure rate or the prognosis. SNB may be a reliable procedure, even after NAT. PMID- 28647777 TI - The effect of low- and high-power microwave irradiation on in vitro grown Sequoia plants and their recovery after cryostorage. AB - Two distinct microwave power levels and techniques have been studied in two cases: low-power microwave (LPM) irradiation on in vitro Sequoia plants and high power microwave (HPM) exposure on recovery rates of cryostored (-196 degrees C) Sequoia shoot apices. Experimental variants for LPM exposure included: (a) in vitro plants grown in regular conditions (at 24 +/- 1 degrees C during a 16-h light photoperiod with a light intensity of 39.06 MUEm-2 s-1 photosynthetically active radiation), (b) in vitro plants grown in the anechoic chamber with controlled environment without microwave irradiation, and (c) in vitro plants grown in the anechoic chamber with LPM irradiation for various times (5, 15, 30, 40 days). In comparison to control plants, significant differences in shoot multiplication and growth parameters (length of shoots and roots) were observed after 40 days of LPM exposure. An opposite effect was achieved regarding the content of total soluble proteins, which decreased with increasing exposure time to LPM. HPM irradiation was tested as a novel rewarming method following storage in liquid nitrogen. To our knowledge, this is the first report using this type of rewarming method. Although, shoot tips subjected to HPM exposure showed 28% recovery following cryostorage compared to 44% for shoot tips rewarmed in liquid medium at 22 +/- 1 degrees C, we consider that the method represent a basis and can be further improved. The results lead to the overall conclusion that LPM had a stimulating effect on growth and multiplication of in vitro Sequoia plants, while the HPM used for rewarming of cryopreserved apices was not effective to achieve high rates of regrowth after liquid nitrogen exposure. PMID- 28647778 TI - A correlation between secondary structure and rheological properties of low density lipoproteins at air/water interfaces. AB - The secondary structure of apolipoprotein B-100 is studied within the bulk phase and at the air/water interface. In these "in viro" experiments, infrared reflection absorption spectroscopy (IRRAS) study was performed at the air/water interface while circular dichroism (CD) was conducted in the bulk phase. In the bulk phase, the conformational structure containing a significant amount of beta structure, whereas varying amount of alpha-helix, unordered structures, and beta sheet were observed at the air/water interface depending on the low-density lipoprotein (LDL) film interfacial pressure. The present IRRAS results demonstrate the importance of interfacial pressure-induced structural conformations on the apoB-100. A correlation between the secondary structure of the apoB-100 protein and the monomolecular film elasticity at the air/water interface was also established. The orientation of apoB-100 with respect to the LDL film-normal was found to depend on the interfacial pressure exhibited by the monomolecular film. These results may shed light on LDL's pivotal role in the progression of atherosclerotic coronary artery disease as demonstrated previously by clinical trials. PMID- 28647779 TI - Transcriptome profiling and digital gene expression analysis of the skin of Dybowski's frog (Rana dybowskii) exposed to Aeromonas hydrophila. AB - Recently, populations of Rana dybowskii, an important amphibian species in Northeast China, have decreased, mainly owing to the disease caused by Aeromonas hydrophila. However, effective control methods have not yet been developed. In order to explore the immune responses of R. dybowskii upon exposure to A. hydrophila infection, Illumina high-throughput transcriptome sequencing and digital gene expression (DGE) technology were employed to investigate transcriptomic changes in the skin of R. dybowskii exposed to A. hydrophila. In this work, a total of 26,244,446 transcriptome sequencing reads were obtained and assembled into 109,089 unique unigenes using de novo assembly, and a total of 37,105 unigenes (34.0%) were functionally annotated against the non-redundant (Nr), Swiss-Prot, Cluster of Orthologous Groups of Proteins (COG), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases. Gene expression changes in the skin tissue of R. dybowskii exposed to A. hydrophila were investigated by a tag-based DGE system, and a total of 1435 significantly differentially expressed genes were identified, including 460 that were up regulated and 975 that were down-regulated, indicating a large change in the host transcriptome profile exposed to A. hydrophila. Among these, 478 genes were associated with immune-relevant pathways, metabolic pathways, cellular components, growth, migration, and muscle and hormone signaling pathways. We confirmed the differential expression of 106 immune-relevant genes associated with innate and adaptive immune responses. Our data provide a fairly comprehensive molecular biology background for the deeper understanding of the amphibian immune system following A. hydrophila infection. PMID- 28647781 TI - Computer navigation-assisted surgery for musculoskeletal tumors: a closer look into the learning curve. AB - BACKGROUND: Computer navigation-assisted surgery for musculoskeletal tumors has shown to reduce the risk of intra-lesional margins in resection. Experiences with this method are still limited to smaller case series. METHOD: We reviewed our first experiences in 24 patients in whom computer navigation-assisted surgery had been performed. In 7 of these patients (6 male and 1 female), this has influenced the surgical treatment plan and navigation was used for both tumor resection and reconstruction. Three of the patients suffered from a chondrosarcoma, 2 from an osteosarcoma, 1 from a fibrosarcoma and 1 from an Ewing's sarcoma. Tumors were localized in the femur (n = 2), the tibia (n = 1), the sacrum (n = 1), the humerus (n = 1), the ilium (n = 1) and in the gluteal region (n = 1). RESULTS: The mean registration error was 0.9 mm. No intra-operative complications occurred. Two postoperative complications were observed which required revision surgery. Except for one marginal resection, all tumors were excised with wide margins. One patient suffered from a local recurrence, and one patient died of disease after distant metastatic dissemination. CONCLUSION: Computer navigation assisted surgery represents a safe and helpful tool for the resection of musculoskeletal tumors and may influence surgical treatment plans in selected cases to provide more limited resections. Surgeons should be aware of risks considering biomechanical and oncological consequences in doing so. Further investigations and the evaluation of newer techniques (e.g., computed tomography guided navigation) are needed to assess long-term outcomes of computer navigation assistance in musculoskeletal tumor surgery. PMID- 28647780 TI - Analysis of Newly Identified and Rare Synonymous Genetic Variants in the RET Gene in Patients with Medullary Thyroid Carcinoma in Polish Population. AB - Gain-of-function germline mutations of the RET proto-oncogene are responsible for initiation of carcinogenesis within the thyroid gland and development of hereditary form of medullary thyroid carcinoma and MEN2 syndrome. Genotype phenotype correlations are established for most RET mutations, but the importance of the synonymous changes in this gene remains debatable. We aimed to analyze RET gene variants in Polish population. Genetic testing for the RET gene variants was performed with standard methods in 585 people aged 1-85, including 448 patients with medullary thyroid carcinoma and 131 of their first- and second-degree relatives, as well as six patients suspected of MTC/MEN2. Besides the most frequent synonymous changes, p.Leu769Leu, p.Ser836Ser, and p.Ser904Ser, four rare changes-c.1827C>T (p.Cys609Cys), c.2364C>T (p.Ile788Ile), c.2418C>T (p.Tyr806Tyr), and c.2673G>A (p.Ser891Ser)-were found in the RET gene, in the Polish population. Two of the rare changes, p.Cys609Cys and p.Ile788Ile, had not been previously described. The frequency of molecular synonymous variants in the general population was evaluated by testing 400 anonymous blood samples of neonates. Our findings may contribute to a better understanding of the genetic diversity of the RET gene and the involvement of synonymous variants in this diversity. PMID- 28647782 TI - Ocular, corneal, and internal aberrations in eyes with keratoconus, forme fruste keratoconus, and healthy eyes. AB - PURPOSE: The purpose of this study is to evaluate ocular, corneal, and internal aberration parameters in eyes with keratoconus (KC), forme fruste keratoconus (FFKC), and normal eyes. METHOD: In a prospective study, one eye of 110 patients with KC, 60 FFKC patients, and 150 healthy participants was evaluated using OPD Scan II. Ocular, corneal, and internal higher-order aberrations were measured through a sixth-order Zernike polynomial decomposition. Receiver operating characteristic analysis was performed to evaluate the diagnostic ability of the aberration parameters in discriminating KC and FFKC from normal eyes. RESULTS: The root mean square of the all ocular aberration measurements was significantly higher in the KC and FFKC patients than that of normal participants (p < 0.05). All of the corneal aberration measurements were significantly higher in KC patients than those of normal patients (p < 0.05); however, only corneal total higher-order aberration (HOA), vertical and total coma, and higher-order astigmatism were significantly higher in the FFKC patients than normal participants (p < 0.05). The results also showed that internal aberration lower order astigmatism, total trefoil, and total higher-order spherical aberration were significantly different between KC and normal groups (p < 0.05). In comparison, internal total HOA, lower and higher-order astigmatism, total trefoil, and vertical coma were significantly different between FFKC and normal groups (p < 0.05). Ocular vertical and total coma had the highest ability in discriminating keratoconic from normal eyes. Ocular total higher aberration and total coma had the highest diagnostic ability in discriminating FFKC from normal eyes. The diagnostic ability of internal aberration, on the other hand, was moderate to poor in discriminating KC and FFKC from normal eyes. CONCLUSION: Ocular aberration especially vertical and total coma and total HOA were found to be suitable parameters to discriminate KC and FFKC from normal patients. These two parameters could be used as discriminating factors in evaluating the patient for refractive surgery in an attempt to avoid iatrogenic ectasia. PMID- 28647783 TI - A sample predictive model for intraocular pressure following laser in situ keratomileusis for myopia and an "intraocular pressure constant". AB - PURPOSE: To describe a sample predictive model for intraocular pressure (IOP) following laser in situ keratomileusis (LASIK) for myopia and an IOP constant. METHODS: The records of patients that underwent LASIK for myopia and myopic astigmatism via WaveLight Allegretto Wave Eye-Q 400 Hz excimer laser and Hansatome XP microkeratome were retrospectively reviewed. Patients with no systemic or ocular disease other than myopia or myopic astigmatism were included in the study. Preoperative and postoperative month 1 data and intraoperative data were used to build the predictive model for IOP after LASIK. The IOP constant was calculated by subtracting the predicted IOP from preoperative IOP. The paired samples t test, Pearson's correlation analysis, curve estimation analysis, and linear regression analysis were used to evaluate the study data. RESULTS: The study included 425 eyes in 214 patients with a mean age of 32 +/- 7.8 years. Mean spherical equivalent of the attempted correction (SE-ac) was -3.7 +/- 1.7 diopters. Mean post-LASIK decrease in IOP was 4.6 +/- 2.3 mmHg. The difference between preoperative and postoperative IOP was statistically significant (P < 0.001). SE-ac, preoperative IOP, and central corneal thickness had highly significant effects on postoperative IOP, based on linear regression analysis (P < 0.001 and R 2 = 0.043, P < 0.001 and R 2 = 0.370, and P < 0.001 and R 2 = 0.132, respectively). Regression model was created (F = 127.733, P < 0.001), and the adjusted R 2 value was 0.548. CONCLUSIONS: Evaluation of IOP after LASIK is important in myopic patients. The present study described a practical formula for predicting the true IOP with the aid of an IOP constant value in myopic eyes following LASIK. PMID- 28647784 TI - Replacing single frozen-thawed euploid embryos in a natural cycle in ovulatory women may increase live birth rates compared to medicated cycles in anovulatory women. AB - PURPOSE: The goal of this study was to compare pregnancy outcomes between natural frozen embryo transfer (FET) cycles in ovulatory women and programmed FET cycles in anovulatory women after undergoing in vitro fertilization with preimplantation genetic screening (IVF-PGS). METHODS: This was a retrospective cohort study performed at an academic medical center. Patients undergoing single FET IVF-PGS cycles between October 2011 and December 2014 were included. Patients were stratified by type of endometrial replacement: programmed cycles with estrogen/progesterone replacement and natural cycles. IVF-PGS with 24-chromosome screening was performed on all included patients. Those patients with euploid embryos had single embryo transfer in a subsequent FET. The primary study outcome was live birth/ongoing pregnancy rate. Secondary outcomes included implantation, biochemical pregnancy, and miscarriage rates. RESULTS: One hundred thirteen cycles met inclusion criteria: 65 natural cycles and 48 programmed cycles. The programmed FET group was younger (35.9 +/- 4.5 vs. 37.5 +/- 3.7, P = 0.03) and had a higher AMH (3.95 +/- 4.2 vs. 2.37 +/- 2.4, P = 0.045). The groups were similar for BMI, gravidity, parity, history of uterine surgery, and incidence of Asherman's syndrome. There was also no difference in embryo grade at biopsy or transfer, and proportion of day 5 and day 6 transfers. Implantation rates were higher in the natural FET group (0.66 +/- 0.48 vs. 0.44 +/- 0.50, P = 0.02). There was no difference in the rates of biochemical pregnancy or miscarriage. After controlling for age, live birth/ongoing pregnancy rate was higher in natural FETs with an adjusted odds ratio of 2.68 (95% CI 1.22-5.87). CONCLUSIONS: Natural FET in ovulatory women after IVF-PGS is associated with increased implantation and live birth rates compared to programmed FET in anovulatory women. Further investigation is needed to determine whether these findings hold true in other patient cohorts. PMID- 28647785 TI - Fertility preservation for trans men: frozen-thawed in vitro matured oocytes collected at the time of ovarian tissue processing exhibit normal meiotic spindles. AB - PURPOSES: At the moment of sex reassignment surgery (SRS), the ovarian tissue is sometimes cryopreserved as fertility preservation option for female-to-male trans men, also called trans men. During this preparation, cumulus-oocyte-complexes (COCs) can be found and in vitro matured. It is not known if these oocytes are developmentally competent. In order to use these oocytes for fertility preservation and subsequent fertilization, a normal spindle structure before and after vitrification is necessary. METHODS: A total of 680 COCs were collected from trans men (n = 16) at the time of SRS and after testosterone treatment. The COCs were subjected to in vitro maturation and those that reached the metaphase II stage (MII) were collected and split into two groups; group 1 was immediately fixed for spindle staining and group 2 was first vitrified and warmed followed by spindle staining. Statistical analysis was performed by Fisher's exact test. RESULTS: After 48 h in vitro maturation, 38.1% of COCs were at MII stage. Those oocytes were split in two groups: (1) 126 MII oocytes in the noncryopreservation group and (2) 133 MII oocytes underwent cryopreservation through vitrification. The oocyte survival rate, after 2 h warming, was 67.7%. Both the noncryopreserved and the vitrified group showed comparable results concerning normal spindle structure and chromosomes alignment, 85.7% vs. 92.2% (P = 0.27). CONCLUSIONS: Spindle structure analysis and chromosomal alignment after vitrification seem normal in in vitro matured COCs collected during the tissue processing of ovaries in trans men at the time of SRS. The MII oocytes do not seem to be morphologically affected by prolonged testosterone treatment. PMID- 28647786 TI - Mosaic embryo transfer after oocyte in vitro maturation in combination with non invasive prenatal testing (NIPT)-first report of a euploid live birth. AB - PURPOSES: The purpose of this study is to describe a healthy life birth after a mosaic embryo transfer in oocyte in vitro maturation (IVM). METHODS: Patient received minimal stimulation, starting on day 3 after menstrual period. No hCG trigger was administered. Oocyte retrieval was performed and oocytes were matured for 30 h. After denuding, mature oocytes were inseminated by ICSI. Embryos were cultured until blastocyst stage and biopsied. RESULTS: One euploid embryo after array comprehensive genome hybridization (aCGH) was diagnostic. However, the next generation sequencing (NGS) re-analysis showed that embryo was a mosaic for chromosome 13 and 21. Nevertheless, pregnancy ultrasound scans and non-invasive prenatal test (NIPT-Verifi-Illumina) indicated a normal fetus development. Finally, a healthy baby was born after 38 weeks. Its weight was 4480 g, head circumference 36 cm, and total length of 51 cm. To confirm that the baby was chromosomically normal, an NGS test was performed in buccal cells, a normal profile was obtained. CONCLUSIONS: Our finding confirmed that mosaic embryo transfer would bring a healthy offspring. PMID- 28647787 TI - Using stem cell oxygen physiology to optimize blastocyst culture while minimizing hypoxic stress. AB - This review is a response to the Fellows Forum on testing 2% oxygen for best culture of human blastocysts (J Ass Reprod Gen 34:303-8, 1; J Ass Reprod Gen 34:309-14, 2) prior to embryo transfer. It is a general analysis in support of the position that an understanding of stem cell physiology and responses to oxygen are necessary for optimization of blastocyst culture in IVF and to enhance reproductive success in fertile women. PMID- 28647788 TI - The efficacy and safety of two low-dose peri-operative dexamethasone on pain and recovery following total hip arthroplasty: a randomized controlled trial. AB - PURPOSE: To evalute the efficacy and safety of two low-dose peri-operative dexamethasone on pain and recovery following total hip arthroplasty (THA). METHODS: One hundred ten patients received two-dose of 10 mg IV-dexamethasone (group dexa) or IV-isotonic saline (group placebo). The level of C-reactive protein (CRP) and interleukin-6 (IL-6), pain at rest and during mobilization, incidence of post-operative nausea and vomiting (PONV), intensity of nausea, post operative fatigue, consumption of analgesic and antiemetic rescue, range of motion (ROM), post-operative length of stay (post-operative LOS), wound problems and complications were recorded and compared. RESULTS: The level of inflammation markers (CRP, IL-6) in group dexa was lower than group placebo at 24, 48, 72 hours post-operatively. Dynamic pain VAS score at 24 hours was lower in group dexa (P = 0.002), however, there was no significant effect on pain at rest. In group dexa, patients had a lower incidence of PONV (P = 0.003), as well as a lower VAS score of nausea (P = 0.044). The post-operative fatigue (P < 0.001) was relieved and the consumption of analgesic and antiemetic rescues were reduced. Furthermore, patients had better maximum hip flexion (P < 0.001) and abduction (P = 0.017), with shorter post-operative LOS (P = 0.006). There is no difference between groups in wound problems. No surgical site infection or gastrointestinal haemorrhage was detected in both groups. CONCLUSIONS: The administration of two low-dose peri-operative dexamethasone can effectively reduce the post-operative level of CRP and IL-6, provide additional pain and nausea control, ameliorate post-operative fatigue, enhance mobility, and shorten post-operative LOS following THA, without increasing the risk of infection and gastrointestinal hemorrhage. LEVEL OF EVIDENCE: I. PMID- 28647789 TI - Probing slow timescale dynamics in proteins using methyl 1H CEST. AB - Although 15N- and 13C-based chemical exchange saturation transfer (CEST) experiments have assumed an important role in studies of biomolecular conformational exchange, 1H CEST experiments are only beginning to emerge. We present a methyl-TROSY 1H CEST experiment that eliminates deleterious 1H-1H NOE dips so that CEST profiles can be analyzed robustly to extract methyl proton chemical shifts of rare protein conformers. The utility of the experiment, along with a version that is optimized for 13CHD2 labeled proteins, is established through studies of exchanging protein systems. A comparison between methyl 1H CEST and methyl 1H CPMG approaches is presented to highlight the complementarity of the two experiments. PMID- 28647790 TI - Should Degree Programs in Biomedical and Health Informatics be Dedicated or Integrated? : Reflections and Recommendations after more than 40 Years of Medical Informatics Education at TU Braunschweig, including 10 Years of B.Sc. and 15 Years of M.Sc. Integrated Degree Curricula. AB - Education in biomedical and health informatics (BMHI) has been established in many countries throughout the world. For degree programs in BMHI we can distinguish between those that are completely stand-alone or dedicated to the discipline vs. those that are integrated within another program. After running integrated degree medical informatics programs at TU Braunschweig for 10 years at the B.Sc. and for 15 years at the M.Sc level, we (1) report about this educational approach, (2) analyze recommendations on, implementations of, and experiences with degree educational programs in BMHI worldwide, (3) summarize our lessons learned with the integrated approach at TU Braunschweig, and (4) suggest an answer to the question, whether degree programs in biomedical and health informatics should be dedicated or integrated. According to our experience at TU Braunschweig and based on our analysis of publications, there is a clear dominance of dedicated degree programs in BMHI. The specialization in medical informatics within a computer science program, as offered at TU Braunschweig, may be a good way of implementing an integrated, informatics-based approach to medical informatics, in particular if a dual degree option can be chosen. The option of curricula leading to double degrees, i.e. in this case to two separate degrees in computer science and in medical informatics might, however, be a better solution. PMID- 28647791 TI - Premonitory Symptoms of Migraine in Childhood and Adolescence. AB - PURPOSE OF REVIEW: Premonitory symptoms in migraine; symptoms occurring before the onset of migraine pain or aura, are an increasingly recognised area of interest within headache research. It has been recently documented in the literature that these symptoms also occur in children and adolescents, with a comparable phenotype to adults. This review discusses the wide presentation of premonitory symptoms in migraine in children and adolescents, and the importance of understanding how these early symptoms are mediated in order to ensure that targeted abortive therapies are developed in the future. Recognition of these symptoms by parents, guardians, teachers and carers is of importance in ensuring early and effective attack treatment. RECENT FINDINGS: A previous clinic-based questionnaire study in 103 children found a prevalence of premonitory symptoms in paediatric migraine of 67%, with a mean number of reported symptoms of two. A recent study found that in a clinic population of 100 children or adolescents with a migraine diagnosis who were preselected as having at least one premonitory symptom associated with their attacks, two or more premonitory symptoms were reported by 85% of patients. The most common symptoms were fatigue, mood change and neck stiffness. Although the population prevalence of premonitory symptoms in migraine within the paediatric population, or their ability to predict accurately the onset of an impending headache cannot be deduced from the retrospective studies performed to date, premonitory symptoms occur in children as young as 18 months old. Understanding the biological basis of these, and their heterogeneous phenotype may help future targeted therapeutic research, helping the development of drugs that act before the onset of pain, limiting the morbidity associated with the migraine attack. PMID- 28647794 TI - An Update on the Risk of Lymph Node Metastasis for the Follicular Variant of Papillary Thyroid Carcinoma with the New Diagnostic Paradigm. AB - Previous data has shown that the risk of nodal metastases is significantly greater for classical papillary thyroid carcinoma (PTC) as compared to the follicular variant (FVPTC). Given a recent change in diagnostic paradigm and definition of the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) we intended to investigate if there remains a significant difference in nodal involvement between classical PTC and FVPTC. A 6 year retrospective review of all cases with FVPTC in the diagnostic line from the University of Utah/ARUP Laboratories was conducted. Two pathologists reviewed the remaining cases using the recently described histologic criteria of NIFTP to determine the total number the FVPTCs fitting the new classification paradigm. Histologic and clinical follow-up was tracked for all patients to determine the rate of nodal disease for all groups. 127 cases were identified using the above listed criteria. Forty-seven cases (37%) were classified as NIFTPs. None of the 47 patients had nodal disease either at the time of surgery or on follow-up. Twenty-eight cases met the current criteria for FVPTC (21%); of these 7/28 (25%) had evidence of nodal disease. By comparison, 17/45 (38%) of patients with mixed classical and FVPTC had nodal disease. Overall, there was no statistically significant difference in the risk of nodal metastasis between the pure FVPTC and mixed classical/FVPTC groups (p = 0.43). Our data indicates that implementing new definition for FVPTC will narrow the gap in the risk of nodal metastases between the classical PTC and FVPTC histologic subtypes. PMID- 28647792 TI - Regeneration of hyaline cartilage promoted by xenogeneic mesenchymal stromal cells embedded within elastin-like recombinamer-based bioactive hydrogels. AB - Over the last decades, novel therapeutic tools for osteochondral regeneration have arisen from the combination of mesenchymal stromal cells (MSCs) and highly specialized smart biomaterials, such as hydrogel-forming elastin-like recombinamers (ELRs), which could serve as cell-carriers. Herein, we evaluate the delivery of xenogeneic human MSCs (hMSCs) within an injectable ELR-based hydrogel carrier for osteochondral regeneration in rabbits. First, a critical-size osteochondral defect was created in the femora of the animals and subsequently filled with the ELR-based hydrogel alone or with embedded hMSCs. Regeneration outcomes were evaluated after three months by gross assessment, magnetic resonance imaging and computed tomography, showing complete filling of the defect and the de novo formation of hyaline-like cartilage and subchondral bone in the hMSC-treated knees. Furthermore, histological sectioning and staining of every sample confirmed regeneration of the full cartilage thickness and early subchondral bone repair, which was more similar to the native cartilage in the case of the cell-loaded ELR-based hydrogel. Overall histological differences between the two groups were assessed semi-quantitatively using the Wakitani scale and found to be statistically significant (p < 0.05). Immunofluorescence against a human mitochondrial antibody three months post-implantation showed that the hMSCs were integrated into the de novo formed tissue, thus suggesting their ability to overcome the interspecies barrier. Hence, we conclude that the use of xenogeneic MSCs embedded in an ELR-based hydrogel leads to the successful regeneration of hyaline cartilage in osteochondral lesions. PMID- 28647793 TI - Training in Robotic Surgery-an Overview. AB - PURPOSE OF REVIEW: There has been a rapid and widespread adoption of the robotic surgical system with a lag in the development of a comprehensive training and credentialing framework. A literature search on robotic surgical training techniques and benchmarks was conducted to provide an evidence-based road map for the development of a robotic surgical skills for the novice robotic surgeon. RECENT FINDINGS: A structured training curriculum is suggested incorporating evidence-based training techniques and benchmarks for progress. This usually involves sequential progression from observation, case assisting, acquisition of basic robotic skills in the dry and wet lab setting along with achievement of individual and team-based non-technical skills, modular console training under supervision, and finally independent practice. Robotic surgical training must be based on demonstration of proficiency and safety in executing basic robotic skills and procedural tasks prior to independent practice. PMID- 28647795 TI - Investigation of Chlorella vulgaris UTEX 265 Cultivation under Light and Low Temperature Stressed Conditions for Lutein Production in Flasks and the Coiled Tree Photo-Bioreactor (CTPBR). AB - Lutein has an increasing share in the pharmaceutical and nutraceutical market due to its benefits to eye health. Microalgae may be a potential source for lutein production while the expense limits the commercialization. In this study, a coiled tubular tree photobioreactor (CTPBR) design was investigated for cultivating the cold tolerant microalgae Chlorella vulgaris UTEX 265 under various conditions for lutein production. The influence and interaction of light irradiance strength, lighting cycle, and temperature on microalgae and lutein production efficiency at low temperature range were also studied in flasks via response surface method (RSM). The results demonstrated that 14 h day-light, 120 MUmol photons m-2 s-1, and 10 degrees C was the optimal condition for algae growth and lutein production at low temperature experimental ranges. C. vulgaris UTEX 265 showed good potential to produce lutein in cold weather, and the optimum lutein production was contrary to the specific lutein content but corresponds to the trend of optimum growth. Additionally, fast growth (MU = 1.50 day-1) and good lutein recovery (11.98 mg g-1 day-1) in CTPBR were also achieved at the low irradiance stress condition and the low temperature photo-inhibition conditions. PMID- 28647796 TI - Large suprasellar craniopharyngioma surgery in adults through the trans-eyebrow supraorbital approach. PMID- 28647797 TI - Overdrainage of cerebrospinal fluid and hydrocephalus shunts. PMID- 28647798 TI - A new model for biofilm formation and inflammatory tissue reaction: intraoperative infection of a cranial implant with Staphylococcus aureus in rats. AB - BACKGROUND: Implant failure is a severe and frequent adverse event in all areas of neurosurgery. It often involves infection with biofilm formation, accompanied by inflammation of surrounding tissue, including the brain, and bone loss. The most common bacteria involved are Staphylococcus aureus. We here test whether intraoperative infection of intracranial screws with Staphylococcus aureus would lead to biofilm formation and inflammatory tissue reaction in rats. METHODS: Two titanium screws were implanted in the cranium of Sprague-Dawley rats, anesthetized with xylazine (4 mg/kg) and ketamine (75 mg/kg). Prior to the implantation of the screws, Staphylococcus aureus was given in the drill holes; controls received phosphate-buffered saline (PBS). Rats were euthanized 2, 10 and 21 days after surgery to remove the screws for analysis of biofilm formation with a confocal laser scanning microscope. The surrounding tissue composed of soft tissue and bone, as well as the underlying brain tissue, was evaluated for inflammation, bone remodeling, foreign body reaction and fibrosis after H&E staining. RESULTS: Intraoperative application of Staphylococcus aureus leads to robust and stable biofilm formation on the titanium implants on days 10 and 21 after surgery, while no bacteria were found in controls. This was accompanied by a substantial inflammatory response of peri-implant tissue after infection, also affecting the underlying brain tissue. CONCLUSIONS: Intraoperative infection of implants with Staphylococcus aureus in rats may be useful as a tool to model new implant materials and surfaces on biofilm formation and inflammatory tissue reaction in vivo. PMID- 28647799 TI - A case of atypical type A thymoma with vascular invasion and lung metastasis. AB - We present a case of type A thymoma with invasion of the left brachiocephalic vein and lung metastases. An 84-year-old man underwent extended thymectomy combined with left brachiocephalic vein reconstruction and resection of a lung metastasis. Histological examination showed vascular invasion by the tumor. The lung metastasis had high mitotic activity and slight nuclear enlargement, the so called "atypical" features, but the main part of the primary tumor did not. However, the intravascular portion of the tumor had "atypical" histological features like the lung metastasis. It seems that "atypical" histological features are related to clinically malignant behavior. PMID- 28647800 TI - Safety and effectiveness of tolvaptan for fluid management after pediatric cardiovascular surgery. AB - BACKGROUND: Postoperative fluid management is important after open heart surgery, because cardiopulmonary bypass evokes an abnormal inflammatory response and increases vascular permeability, especially in pediatric patients. We assessed the safety and effectiveness of tolvaptan for management of postoperative fluid retention after congenital heart surgery. METHODS AND RESULTS: This retrospective study analyzed data from 43 children with uncomplicated congenital heart disease who underwent open heart surgery between September 2013 and August 2016. The patients were divided into two groups. Group N (n = 18; September 2013 through May 2014) received the conventional oral diuretics alone, and Group T (n = 25; June 2014 through August 2016) received a single dose of tolvaptan (0.45 mg/kg) in addition to the conventional oral diuretic therapy. Data were collected, while patients who received intensive care were assessed and compared between groups. Add-on tolvaptan use was associated with increased urinary output standardized by body weight (54.3 +/- 4.5 vs 47.3 +/- 19.1 mL/kg; p = 0.043), decreased additional intravenous diuretic dose standardized by body weight (0.26 +/- 0.23 vs 0.62 +/- 0.48 mg/kg; p = 0.001), and a smaller decrease in central venous pressure (1.3 +/- 2.7 vs 1.9 +/- 3.8 mmHg; p = 0.019). Laboratory analysis showed that electrolyte concentrations in blood and urine did not significantly differ between groups. CONCLUSIONS: Tolvaptan appears to be effective and safe for management of postoperative fluid retention after congenital heart surgery. PMID- 28647801 TI - Prognostic factors of atrial fibrillation following coronary artery bypass graft surgery. AB - OBJECTIVE: Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery. To prevent this complication, routine pharmacological prophylactic drugs could be administered. Our study aimed to analyze the various perioperative factors associated with the development of POAF after coronary artery bypass graft (CABG) surgery. METHODS: This prospective study included 617 patients, who received CABG surgery in the year 2014. RESULTS: There were 429 (69.5%) male and 188 (30.5%) female patients. Mean patient age was 67.2 (9.4) years, and 365 patients (59.2%) were more than 65 years. Incidence of POAF was 24.1% (N = 149). Multivariable analysis showed that independent predictors of POAF after CABG surgery were: age >65 (P = 0.008; OR 2.089; 95% CI 1.208-3.613), AF in the past (P < 0.001; OR 10.838; 95% CI 5.28-22.247), preoperative hypertrophy or dilation of left atrium (P = 0.002; OR 4.996; 95% CI 1.823-13.691), CABG surgery using 4 or more bypass grafts (P = 0.042; OR 1.669; 95% CI 0.972-2.866), preoperative hypokalemia (P = 0.001; OR 3.317; 95% CI 1.678 6.559), >trivial mitral (P = 0.024; OR 7.556; 95% CI 0.964-20.376), and aortic (P = 0.009; OR 1.937; 95% CI 1.178-3.187) valve regurgitation. CONCLUSIONS: The profile of patients affected by POAF was considerably different with regard to the demographics, preoperative heart condition, history of previous heart rhythm disorders, and operative data. The most important independent factors that predicted POAF after CABG surgery were associated with structural heart defects, advanced age, history of previous AF, and preoperative hypokalemia. PMID- 28647802 TI - A case of SAPIEN XT valve fallen into left ventricle during valve-in-valve transcatheter aortic valve implantation. AB - Late transcatheter heart valve embolization is a rare but life-threatening complication of transcatheter aortic valve implantation. Surgical intervention is performed for most cases, but some cases were treated by valve-in-valve transcatheter aortic valve implantation. We describe a patient in whom a 29-mm Edwards SAPIEN XT valve migrated into the left ventricular outflow tract 41 days after the initial implantation. We tried to perform valve-in-valve transcatheter aortic valve implantation using a transfemoral approach. As soon as the second transcatheter heart valve touched the first implanted valve, it fell into the left ventricle. Immediate surgical intervention was required. The first valve was removed, and surgical aortic valve replacement was successfully performed. In conclusion, we should choose surgical aortic valve replacement for late transcatheter heart valve embolization. Even if we need to treat by catheter intervention, transapical approach may be better. PMID- 28647804 TI - Estimating the long-term functional burden of osteoporosis-related fractures. AB - : Although fractures are associated with short-term reductions in functional status, there is limited information on longer-term burden of fracture. This study documents evidence of an association between fractures and significant declines and functional health and activities that persist but attenuate beyond two years. INTRODUCTION: Although fractures are associated with short-term reductions in functional status and may have other short-term effects on healthcare utilization (hospitalization and follow-up care), there is limited information on long-term burden of fracture beyond 12 to 24 months post-fracture. Analysis of the long-term health burden can inform policymakers, health care practitioners, and payers. METHODS: We acquired a data set containing the 1992 2012 Health and Retirement Survey data linked to the same individuals' Medicare claims. Fracture cases (n = 745) were matched to non-fracture controls using propensity scores matching. A regression-adjusted difference-in-difference (DD) approach was used to compare the change in functional status measures from baseline to two post-fracture periods for fracture cases relative to the change over the same time periods for matched controls. Self-reported measures of functional status were examined: limitations to activities of daily living (ADLs), limitations to instrumental activities of daily living (IADLs), a mobility index, a gross motor skills index, a fine motor skills index, and self reported general health status. RESULTS: Fracture cases reported increases in limitations to ADLs, difficulties with mobility, difficulties with gross motor skills, and difficulties with fine motor skills in each HRS collection period (the survey is administered every 2 years) following the fracture or index date (thus up to two years later) than matched controls (all p values < 0.05). The magnitude of these effects diminished in the second post-fracture wave (two to four years after fracture/index date), but they were still statistically significant. CONCLUSIONS: Results suggest that fractures are associated with significant declines in some measures of functional activities up to two years following the fracture. The effects persist beyond two years but are smaller in magnitude. PMID- 28647803 TI - Chronic joint pain and handgrip strength correlates with osteoporosis in mid-life women: a Singaporean cohort. AB - : This study aimed to identify novel correlates which may relate to low bone mass at lumbar spine in mid-life Asian women. The possibility of developing a prediction model for osteoporosis (OP) was explored which resulted in a risk assessment tool that performed better than currently available tools. INTRODUCTION: In order to identify novel correlates associated with low spinal bone mineral density (BMD) in mid-life women, we examined a large number of lifestyle and medical and performance measurements and developed a prediction model for triage to BMD scanning. METHODS: Women (n = 512) aged 45-69 years (mean 57.0 +/- 6.3) attending gynecology clinics for "well woman" visits were recruited for this cross-sectional study from 2014 to 2015. We assessed symptoms, medical history, anthropometry, and physical performance. Stepwise multinomial logistic regressions were performed to examine significant associated covariates for pre specified outcomes (normal [T-score >= -1.0], low bone mass [T-score between -1 and -2.5], and OP [T-score <= -2.5] at the lumbar spine). A new screening model was developed, and its performance was compared with the OP Screening Tool for Asians (OSTA) and Fracture Risk Assessment Tool (FRAX(r)). RESULTS: Spinal OP was found in 6.8%. Multivariate analysis indicated that chronic joint pain, the most common symptom reported by 37.5% of the women, was significantly associated with OP. Only age (Relative Risk Ratio [RRR] 1.63; 95%CI, 1.03-2.60), weight (RRR 0.14; 95% CI, 0.07-0.27), postmenopausal status (RRR 11.59, 95%CI, 1.15-116.73), chronic joint pain (RRR, 4.12; 95% CI, 1.53-11.07), and right handgrip strength (RRR 0.50; 95% CI, 0.31-0.80) were independently associated with spinal OP. Combining these five variables, our final model's area under curve (AUC) was significantly higher at 84% than both the OSTA [AUC; 79% (p value < 0.0231 'c' statistics)] and FRAX(r) [AUC 58% (p value < 0.0001 'c' statistic)]. CONCLUSION: A novel screening tool that combines age, weight, and menopausal status with chronic joint pain and right handgrip strength more reliably predicts spinal OP in mid-life Singaporean women. PMID- 28647805 TI - A Comprehensive Health Profile of Guyanese Immigrants Aged 18-64 in Schenectady, New York. AB - Guyanese immigrants are the 5th largest foreign-born group in NY State, but sparse literature is available on their health status and health needs. A community-based health interview survey of Schenectady NY residents aged 18-64 (N = 1861) was analyzed. Bivariate comparisons between Guyanese respondents and White, Black, and Hispanic respondents were made for each variable to identify disparities. As predominantly low SES immigrants, Guyanese adults were less likely to be covered by health insurance, have a usual place for care, and receive cancer screenings. They were more likely to engage in alcohol binge drinking, but generally in good overall physical and mental health and less likely to smoke or report disability. Stable family structure and supportive interpersonal relationships are major assets of this group. Improved access to affordable health insurance, linkages to primary care, targeted cancer screening programs, and culturally-sensitive behavioral health services are recommended for Guyanese immigrants. PMID- 28647806 TI - Pre-anesthetic stroke volume variation can predict cardiac output decrease and hypotension during induction of general anesthesia. AB - This study aimed to assess the reliability of stroke volume variation (SVV) in predicting cardiac output (CO) decrease and hypotension during induction of general anesthesia. Forty-five patients undergoing abdominal surgery under general anesthesia were enrolled. Before induction of anesthesia, patients were required to maintain deep breathing (6-8 times/min), and pre-anesthetic SVV was measured for 1 min by electrical cardiometry. General anesthesia was induced with propofol, remifentanil, rocuronium, and sevoflurane. Study duration was defined from the start of fluid administration till 5 min after tracheal intubation. Blood pressure (BP) was measured every minute. Cardiac output was measured continuously by electrical cardiometry. Receiver operating characteristics (ROC) curves were made regarding the incidence of decreased CO (less than 70% of the baseline) and hypotension (mean BP <65 mmHg). The risk of developing decreased CO and hypotension was evaluated by multivariate logistic regression analysis. The time from the start of the procedure to onset of decreased CO was analyzed by the Kaplan-Meier method. The area under the ROC curve and optimal threshold value of pre-anesthetic SVV for predicting decreased CO and hypotension were 0.857 and 0.693. Patients with lower SVV exhibited a significantly slower onset and lower incidence of decreased CO than those with higher SVV (p = 0.003). Multivariate logistic regression analysis indicated high pre-anesthetic SVV as being an independent risk factor for decreased CO and hypotension (odds ratio, 1.43 and 1.16, respectively). In conclusions, pre-anesthetic SVV can predict incidence of decreased CO and hypotension during induction of general anesthesia. PMID- 28647807 TI - Preoperative nutritional status and its impact on cholangitis after Kasai portoenterostomy in biliary atresia patients. AB - OBJECTIVE: To explore the preoperative nutrition status in patients with biliary atresia (BA) and its effect on the cholangitis of Kasai portoenterostomy (KPE). METHODS: 106 patients who had been diagnosed with BA type III and were undergoing KPE were divided into two groups according to the score obtained using STRONGkids. Preoperative and postoperative data were collected to compare general characteristics and postoperative outcomes between the different groups. RESULTS: Forty-nine (46.2%) patients were at moderate nutritional risk (MNR) and fifty seven (53.8%) patients were at high nutritional risk (HNR) preoperatively. The MNR group had shorter postoperative hospitalization times than the HNR group (P = 0.023). The initial postoperative cholangitis occurred later (P = 0.002) and the incidence of early cholangitis was lower (P = 0.029) in patients at MNR than in those at HNR. The ratio of jaundice clearance (P = 0.02) and 2-year native liver survival (P = 0.0109) were significantly higher in MNR group than in HNR group. CONCLUSIONS: Patients with BA presented the greatest nutritional deficiencies and patients at HNR are more vulnerable to the early cholangitis and the rate of jaundice clearance is lower than those at MNR. The occurrence of initial postoperative cholangitis in MNR group was later than in HNR group. PMID- 28647808 TI - Characterization of Arabidopsis thaliana regrowth patterns suggests a trade-off between undamaged fitness and damage tolerance. AB - Herbivory is a fundamental type of plant-animal interaction that presents substantial selection pressure on plants to replace lost tissues and to prevent subsequent losses in fitness. Apical herbivory, which entails removal or damage to the apical meristem, causes a change in plant architecture by disrupting the balance of hormones produced in part by the apical meristem. Therefore, for an annual semelparous plant, the ability to preserve reproductive success following damage (i.e., to tolerate damage) is largely dependent on the plant's pre-damage investment into fitness and its regrowth pattern following damage. Using multiple regression analyses, we assessed the relationship of developmental and architectural traits of experimentally damaged plants relative to undamaged plants of 33 Arabidopsis thaliana genotypes that display a wide range of undamaged fitness and damage tolerance. Our analyses revealed evidence for an evolutionary bet-hedging strategy within a subset of genotypes to presumably maximize fitness under natural herbivory-genotypes with the greatest seed production when undamaged exhibited a significant reduction in seed yield when damaged, while genotypes with low undamaged seed production were the only genotypes whose seed yield increased when damaged. Patterns of endopolyploidy paralleled those of seed production, such that the increase in whole-plant ploidy by genome re-replication during growth/regrowth contributes to undamaged fitness, damage tolerance, and their trade-off. Overall, this study provides the first large-scale characterization of A. thaliana regrowth patterns and suggests that investment into fitness and endopolyploidy when undamaged may come at a cost to tolerance ability once damaged. PMID- 28647809 TI - Left ventricles of aging athletes: better untwisters but not more relaxed during exercise. AB - OBJECTIVE: With an aging population and the increasing prevalence of heart failure with preserved ejection fraction, developing strategies to prevent diastolic dysfunction is crucial. Regular endurance training has been suggested to be one such strategy. However, the underlying mechanisms of training, including the effect on left ventricular (LV) untwist, which promotes LV filling, are unclear and studies exploring the heart during exercise in the aging heart are lacking. METHODS: Cardiopulmonary exercise testing with speckle tracking echocardiography was realized in male subjects: 16 young athletes (YA), 19 young controls (YC), 22 middle-aged athletes (MA) with a lifelong history of endurance training, and 20 middle-aged controls (MC). RESULTS: During exercise, the early filling was lower in MC compared to YC, whereas it was preserved between YA and MA. At exercise, peak untwisting rate/peak twist ratio and the percentage of untwist during isovolumic relaxation time were decreased in senior groups but higher in YA and MA compared to age-matched controls. Early diastolic filling reserve correlated with untwisting rate/peak twist reserve in YA and MA (R 2 = 0.22, p < 0.05) but not in controls. LV relaxation indices in athletes at rest and during exercise were not improved compared to age-matched controls. CONCLUSION: LV intrinsic relaxation was similarly lower with age, independently of training, while the age-related decrease of untwist during exercise was lower with lifelong exercise training. The preservation of untwist mechanics in MA could thus sustain the early filling during exercise. Further studies are needed to confirm the role of exercise training as a preventive strategy for diastolic dysfunction and heart failure. PMID- 28647810 TI - Distal nerve transfer versus supraclavicular nerve grafting: comparison of elbow flexion outcome in neonatal brachial plexus palsy with C5-C7 involvement. AB - PURPOSE: Ulnar and median nerve transfers to arm muscles have been used to recover elbow flexion in infants with neonatal brachial plexus palsy, but there is no direct outcome comparison with the classical supraclavicular nerve grafting approach. METHODS: We retrospectively analyzed patients with C5-C7 neonatal brachial plexus palsy submitted to nerve surgery and recorded elbow flexion recovery using the active movement scale (0-7) at 12 and 24 months after surgery. We compared 13 patients submitted to supraclavicular nerve grafting with 21 patients submitted to distal ulnar or median nerve transfer to biceps motor branch. We considered elbow flexion scores of 6 or 7 as good results. RESULTS: The mean elbow flexion score and the proportion of good results were better using distal nerve transfers than supraclavicular grafting at 12 months (p < 0.01), but not at 24 months. Two patients with failed supraclavicular nerve grafting at 12 months showed good elbow flexion recovery after ulnar nerve transfers. CONCLUSION: Distal nerve transfers provided faster elbow flexion recovery than supraclavicular nerve grafting, but there was no significant difference in the outcome after 24 months of surgery. Patients with failed supraclavicular grafting operated early can still benefit from late distal nerve transfers. Supraclavicular nerve grafting should remain as the first line surgical treatment for children with neonatal brachial plexus palsy. PMID- 28647811 TI - Is it possible to detect PEth 16:0/18:1 and PEth 18:1/18:1 in red blood cells after 20 years of storage in liquid nitrogen? AB - INTRODUCTION: Phosphatidylethanol (PEth), as measured in freshly drawn blood samples, could be a promising new biomarker for habitual alcohol consumption, but it is still unknown whether PEth can also be determined from blood samples having been stored frozen for a longer period. MATERIALS AND METHODS: PEth 16:0/18:1 and PEth 18:1/18:1 were determined by LC-MS/MS from red blood cells (RBC) derived from blood samples of (I) 20 healthy volunteers (after 1 month of storage at -80 degrees C) and (II) 232 participants of the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg study (after 20 years of storage at -196 degrees C). Analyses involved liquid-liquid extraction from 100 MUl aliquots with phosphatidylpropanol (PProp 18:1/18:1) as the internal standard. Extracts were subjected to a 10-min LC gradient separation, using multiple reaction monitoring of deprotonated molecules for quantification. RESULTS: After 1 month of storage at -80 degrees C, PEth was detectable in all samples at mean concentrations of 393.6 +/- 12.4 ng/ml (PEth 16:0/18:1) and 43.3 +/- 1.1 ng/ml (PEth 18:1/18:1). In samples stored for 20 years at -196 degrees C, PEth was detectable in 23.7% of all samples at mean concentrations of 412.2 +/ 655.5 ng/ml (PEth 16:0/18:1) and 38.0 +/- 74.8 ng/ml (PEth 18:1/18:1). DISCUSSION AND CONCLUSION: PEth can be determined reliably from samples of moderate habitual alcohol consumers after 1 month of storage at -80 degrees C. Our data suggest that PEth is generally also detectable in samples after 20 years of storage at -196 degrees C. Further studies are needed to assess the still unknown impact of storage duration and temperature on different PEth specimen concentrations. PMID- 28647812 TI - Genetically engineered orange petunias on the market. AB - MAIN CONCLUSION: Unauthorized genetically engineered orange petunias were found on the market. Genetic engineering of petunia was shown to lead to novel flower color some 20 years ago. Here we show that petunia lines with orange flowers, generated for scientific purposes, apparently found their way to petunia breeding programmes, intentionally or unintentionally. Today they are widely available, but have not been registered for commerce. PMID- 28647813 TI - GhVLN4 is involved in cell elongation via regulation of actin organization. AB - MAIN CONCLUSION: GhVLN4 exhibited activity of cross-linking actin filaments into bundles. Overexpression of GhVLN4 increased the abundance of thick actin bundles and resulted in longer cell phenotypes. Actin bundle is a dynamic, higher-order cytoskeleton structure that is essential for cell expansion. Villin is one of the major proteins responsible for crosslinking actin filaments into bundles. However, this kind of actin binding protein has rarely been investigated in cotton. In the present work, a cotton villin gene was molecularly cloned from Upland cotton and denominated as GhVLN4. This gene was more highly expressed in fiber-bearing wild-type cotton TM-1 (Texas Marker-1) than in Ligon lintless-1 mutant (Li-1). Biochemical analysis combined with subcellular localization revealed that GhVLN4 is an actin-binding protein performing actin filament bundling activity in vitro. In line with these findings, a greater abundance of thick actin filament bundles were observed in GhVLN4-overexpressing transgenic plants compared with those in wild-type control. Moreover, ectopic expression of GhVLN4 significantly enhanced the cell length-width ratio of Schizosaccharomyces pombe yeast and increased the length of various Arabidopsis cells, including root cells, root hairs and pollen tubes. Taken together, our results demonstrate that GhVLN4 is involved in the generation of actin filament bundles, suggesting that GhVLN4 may play important roles in regulating plant cell morphogenesis and expansion by remodeling actin cytoskeleton. PMID- 28647814 TI - The effects of variable practice on locomotor adaptation to a novel asymmetric gait. AB - Very little is known about the effects of specific practice on motor learning of predictive balance control during novel bipedal gait. This information could provide an insight into how the direction and magnitude of predictive errors during acquisition of a novel gait task influence transfer of balance control, as well as yield a practice protocol for the restoration of balance for those with locomotor impairments. This study examined the effect of a variable practice paradigm on transfer of a novel asymmetric gait pattern in able-bodied individuals. Using a split-belt treadmill, one limb was driven at a constant velocity (constant limb) and the other underwent specific changes in velocity (variable limb) during practice according to one of three prescribed practice paradigms: serial, where the variable limb velocity increased linearly; random blocked, where variable limb underwent random belt velocity changes every 20 strides; and random practice, where the variable limb underwent random step-to step changes in velocity. Random practice showed the highest balance control variability during acquisition compared to serial and random blocked practice which demonstrated the best transfer of balance control on one transfer test. Both random and random blocked practices showed significantly less balance control variability during a second transfer test compared to serial practice. These results indicate that random blocked practice may be best for generalizability of balance control while learning a novel gait, perhaps, indicating that individuals who underwent this practice paradigm were able to find the most optimal balance control solution during practice. PMID- 28647816 TI - Effect of routine rapid insertion of Bakri balloon tamponade on reducing hemorrhage from placenta previa during and after cesarean section. AB - PURPOSE: To evaluate the effectiveness of routine rapid insertion of a Bakri balloon during cesarean section for placenta previa based on a retrospective control study. METHODS: Women with singleton pregnancies who underwent cesarean section for placenta previa at our institution between 2003 and 2016 were enrolled. Between 2015 and 2016, women who routinely underwent balloon tamponade during cesarean section were defined as the balloon group. Between 2003 and 2014, women who underwent no hemostatic procedures except balloon tamponade were defined as the non-balloon group. The clinical outcomes of the two groups were retrospectively analyzed. RESULTS: Of the 266 women with placenta previa, 50 were in the balloon group and 216 were in the non-balloon group. The bleeding amounts were significantly smaller in the balloon group than in the non-balloon group: intraoperative bleeding (991 vs. 1250 g, p < 0.01), postoperative bleeding (62 vs. 150 g, p < 0.01), and total bleeding (1066 vs. 1451 g, p < 0.01). Furthermore, the mean surgical duration was shorter in the balloon group than the non-balloon group (30 vs. 50 min, p < 0.01). In the balloon group, five patients suffered from increasing hemorrhage due to prolapse of the balloon from the uterus after the operation, but the hemorrhage was controlled by balloon re insertion without additional hemostatic procedures. CONCLUSIONS: This study demonstrated that the routine rapid insertion of Bakri balloon tamponade during cesarean section significantly decreased intra- and postoperative hemorrhage and shortened the surgical duration in women with placenta previa. PMID- 28647815 TI - Update on the Epidemiology, Diagnosis, and Treatment of Mania in Older-Age Bipolar Disorder. AB - PURPOSE OF REVIEW: The population over age 60 is growing more rapidly than the general population. Given the projected increase and need for data that can inform treatment, this review provides a brief description of newer publications focused on mania in older-age bipolar disorder (OABD), including epidemiology, diagnosis, and treatments. RECENT FINDINGS: Age cutoffs to define OABD range from 50 to 65 years. OABD clinical presentation and course of illness is highly variable, often characterized by mood episode recurrence, medical comorbidity, cognitive deficits, and impaired functioning. There is little pharmacotherapy data on mania in OABD. Lithium and valproate have been tested in a single randomized controlled trial and there is data of more limited quality with other compounds. Treating OABD is challenging due to medical complexity, comorbidity, diminished tolerance to treatment, and a limited evidence base. More data is needed to keep pace with clinical demand. PMID- 28647817 TI - Molecular characterization of the CD79a and CD79b and its role against Aeromonas hydrophila infection in Chinese sucker (Myxocyprinus asiaticus). AB - CD79a and CD79b heterodimers are the important signaling components of B cell receptor (BCR) complex which plays a crucial role in B cell development and antibody production. In the present study, CD79a and CD79b homologues from Chinese sucker (Myxocyprinus asiaticus), namely MaCD79a and MaCD79b, were identified and their expression at early developmental stages and under constitutive and stimulated conditions were investigated. The cDNA sequences for MaCD79a and MaCD79b contained open reading frame of 678 and 636 bp in length for 225 and 211 amino acid residues, respectively. The conserved features and important functional residues were found by sequence analysis. RT-PCR analysis revealed that transcripts of MaCD79s were detected in eggs and hatchling at 1-3 and 5-11 days post hatching (dph), but not detected at 13-17 and 19-27 dph, and constantly detected from 30 dph. Tissue distribution analysis showed that MaCD79s was most highly expressed in immune tissues, such as the spleen, head kidney, and kidney; the relatively low levels were detected in the heart, gill, and liver. Results of in situ hybridization also confirmed that MaCD79s is mainly expressed in systematic immune organs. Meanwhile, similar to IgM, MaCD79s-expressing cells in mucosal immune organ including the digestive track and gill were observed. Additionally, significant upregulation of MaCD79s was seen in the head kidney and spleen of Chinese sucker injected with Aeromonas hydrophila by quantitative real time PCR. Taken together, our findings provided further information regarding fish CD79s gene and its role in adaptive immunity, which will contribute to the preservation and aquaculture of Chinese sucker. PMID- 28647819 TI - The Italian Version of the Opening Minds Stigma Scale for Healthcare Providers: Validation and Study on a Sample of Bachelor Students. AB - Prejudices on psychiatric disorders frequently turn into stigmatizating attitudes, also among health care providers. The Opening Minds Stigma Scale for Health Care Providers (OMS-HC) was introduced in 2012 to measure stigma. No Italian versions of this tool exist so far. We wanted to investigate stigma among healthcare students in Italy, and to prepare an Italian version of the scale. A multicentric, cross-sectional study was conducted on a sample of Nursing, Physiotherapy, Occupational therapy, and Dietistics students. The Italian version of the scale was obtained through back-translation.?561 students were enrolled, median age 21 years, IQR [20;23], 62.22% females (n = 349). 262 students declared having met subjetcs affected by psychiatric disorders during their training; 50 had one or more psychiatric disorders in their lives. The Italian version proved valid and reliable. Older students had lower stigma scores. No differences existed between stigma scores according to gender and personal experience of mental illness. PMID- 28647820 TI - Liver Transplantation for Hepatocellular Carcinoma: "Experience of Memorial Sisli Hospital". PMID- 28647818 TI - Assessment of the effect of systemic delivery of sclerostin antibodies on Wnt signaling in distraction osteogenesis. AB - Sclerostin is a known inhibitor of the Wnt signaling pathway which is involved in osteogenesis and, when inactivated, stimulates bone formation. To our knowledge, this effect has not been studied in the context of distraction osteogenesis (DO). Tibial DO was conducted on a total of 24 wild-type mice, which were then divided into 2 groups-a saline injection group (control) and an anti-sclerostin (Scl-Ab) injection group (treatment). The mice in the treatment group received 100 mg/kg intravenous injections of the antibody weekly until killing. The 12 mice in each group were subdivided into four time points according to post-osteotomy time of killing-11 days (mid-distraction), 17 days (late distraction), 34 days (mid consolidation) and 51 days (late consolidation), with 3 mice per subgroup. After killing, the tibia specimens were collected for immunohistochemical analysis. Our results show that the group injected with anti-sclerostin had an earlier peak (day 11) in the distraction phase of the osteogenic molecules involved in the Wnt signaling pathway in comparison to the placebo group. In addition, downregulation of the inhibitors of this pathway was noted in the treatment group when compared with the placebo group. Furthermore, LRP-5 showed a significant increase in expression in the treatment group. Sclerostin inhibition has a significant effect on the DO process through its effect on the Wnt pathway. This effect was evident through the decreased effect of sclerostin on LRP-5 and earlier upregulation of the osteogenic molecules involved in this pathway. PMID- 28647821 TI - Hepatocellular Cancer: Is Recurrence Inevitable? PMID- 28647822 TI - Devosia nitraria sp. nov., a novel species isolated from the roots of Nitraria sibirica in China. AB - An aerobic, Gram-stain negative, short rod-shaped and motile strain, 36-5-1T, was isolated from the roots of Nitraria sibirica in Zhangye city, Gansu province, north-west of China. Phylogenetic analysis based on the 16S rRNA gene sequence and two housekeeping genes (glnA and atpD) indicated that the strain represents a novel species closely related to the Devosia, Rhizobium and Devosia genera with 98.3, 96.2 and 91.1% similarities, respectively. The strain 36-5-1T contained Q 10 as the predominant ubiquinone and 16:0 (36.8%) as the major fatty acid; a large amount of unidentified glycolipid, diphosphatidylglycerol, phosphatidylglycerol and a small amount of unidentified polar lipids were present as polar lipids. In addition, the G+C content of the genomic DNA was 61.7 mol% and the DNA-DNA hybridization with type strains Devosia geojensis BD-c194T and Devosia pacifica NH131T 44.1 +/- 1.1 and 40.2 +/- 1.7, respectively. Based on chemotaxonomic data and molecular properties, strain 36-5-1T represents a novel species within the genus Devosia, for which the name Devosia nitraria sp. nov. is proposed. The type strain is 36-5-1T (=CGMCC1.15704T=NBRC112416T). PMID- 28647824 TI - Preservation of vaginal elasticity is essential for avoiding mesh complications after prolapse surgery. PMID- 28647823 TI - High risk of lower urinary tract symptoms in patients with irritable bowel syndrome. AB - BACKGROUND: The aim of the present study was to investigate the prevalence of urinary tract infection (UTI) and the risk of lower urinary tract symptoms (LUTS) in women with irritable bowel syndrome (IBS) (including each subtype: constipation, diarrhea, and mixed) compared to women in the general population. METHODS: Between January 2014 and December 2015, consecutive adult female patients diagnosed with IBS at the outpatient clinic of the University of Salerno and healthy women with regular bowel habits were enrolled in the study. At baseline, we checked for UTI with a dipstick test and questioned patients about the presence of LUTS in the previous 24 h. RESULTS: We enrolled 141 IBS patients and 91 healthy controls in the study. There was no difference in the prevalence of UTI between IBS patients and healthy controls (4.9 vs 3.3%, p = 0.5). When we excluded patients with UTI, we found a 2.79 higher risk of increased urinary frequency [odds ratio (OR) 2.79, 95% confidence interval (CI) 1.37-5.68], a 2.68 higher risk of urinary urgency (OR 2.68, 95% CI 1.04-6.91), and more than three times the risk of having dysuria (OR 3.25, 95% CI 1.06-9.97) in IBS women compared to healthy controls. The risk of having at least one urinary symptom was independent of IBS subtype and IBS severity. CONCLUSIONS: Our study shows that IBS women have a similar risk of UTI compared to healthy women even if they complain more of LUTS, independently of IBS subtype and severity. PMID- 28647825 TI - Contribution characteristics of the in situ extracellular polymeric substances (EPS) in Phanerochaete chrysosporium to Pb immobilization. AB - White rot fungi have been extensively reported to have strong adsorption capacity to heavy metal ions, whereas the knowledge of extracellular polymeric substances (EPS) from the fungus has been rarely involved. In this study, the contribution characteristics of 'the in situ EPS in Phanerochaete chrysosporium to Pb immobilization were investigated. First of all, the component and amount of EPS were investigated. It was found that the main component of EPS was carbohydrates, and highest EPS amount was produced at 5 days. In the Pb2+ immobilization experiments, EPS was demonstrated to play a more important role in immobilizing Pb2+ at lower initial Pb concentration. pH increase was beneficial for EPS to immobilize Pb. Higher EPS amount increased the Pb removal efficiency at a certain extent, while the specific uptake decreased. The Pb2+ immobilization by EPS produced at 7 days was most successful. PMID- 28647826 TI - Numerical simulation of a glucose sensitive composite membrane closed-loop insulin delivery system. AB - Closed-loop insulin delivery system works on pH modulation by gluconic acid production from glucose, which in turn allows regulation of insulin release across membrane. Typically, the concentration variation of gluconic acid can be numerically modeled by a set of non-linear, non-steady state reaction diffusion equations. Here, we report a simpler numerical approach to time and position dependent diffusivity of species using finite difference and differential quadrature (DQ) method. The results are comparable to that obtained by analytical method. The membrane thickness directly determines the concentrations of the glucose and oxygen in the system, and inversely to the gluconic acid. The advantage with the DQ method is that its parameter values need not be altered throughout the analysis to obtain the concentration profiles of the glucose, oxygen and gluconic acid. Our work would be useful for modeling diabetes and other systems governed by such non-linear and non-steady state reaction diffusion equations. PMID- 28647828 TI - 3D printing of severe hypertrophic cardiomyopathy in a child with Rasopathy. AB - We describe the use of 3D printing in conjunction with echocardiography in assessing hypertrophic cardiomyopathy in a boy with Rasopathy. 3D printing may supplement conventional imaging including echocardiography and MRI in the evaluation of hypertrophic cardiomyopathy. PMID- 28647827 TI - Association Between CD4+, Viral Load, and Pulmonary Function in HIV. AB - PURPOSE: The antiretroviral therapy era has shifted the epidemiology of HIV associated diseases, increasing the recognition of non-infectious pulmonary complications secondary to HIV. We aimed to determine the association between CD4+, viral load, and pulmonary function in individuals with uncontrolled HIV, and determine how changes in these parameters are associated with pulmonary function longitudinally. METHODS: This is a retrospective observational study of individuals with HIV who underwent pulmonary function testing in an urban medical center between August 1997 and November 2015. RESULTS: Of the 146 participants (mean age 52 +/- 10 years), 49% were Hispanic, 56% were men, and 44% were current smokers. CD4+ <200 cells/MUl was associated with significant diffusion impairment compared to CD4+ >=200 cells/MUl (DLCO 56 vs. 70%, p = <0.01). VL (viral load) >=75 copies/ml was associated with significant diffusion impairment compared to VL <75 copies/ml (DLCO 60 vs. 71%, p = <0.01). No difference in FEV1, FEV1/FVC, or TLC was noted between groups. In univariate analysis, CD4+ and VL correlated with DLCO (r = +0.33; p = <0.01; r = -0.26; p = <0.01) and no correlation was noted with FEV1, FEV1/FVC, or TLC. Current smoking and history of AIDS correlated with DLCO (r = -0.20; p = 0.03; r = -0.20; p = 0.04). After adjusting for smoking and other confounders, VL >=75 copies/ml correlated with a 11.2 (CI 95% [3.03 19.4], p = <0.01) decrease in DLCO. In Spearman's Rank correlation, there was a negative correlation between change in VL and change in DLCO over time (rho = 0.47; p = <0.01). CONCLUSION: The presence of viremia in individuals with HIV is independently associated with impaired DLCO. Suppression of VL may allow for recovery in diffusing capacity over time, though the degree to which this occurs requires further investigation. PMID- 28647829 TI - Extra central nervous system metastases from glioblastoma: a new possible trigger event? AB - Extra-cranial metastases of glioblastoma (GBM) represent a rare event, and the biological-genetic mechanisms involved in the pathogenesis have not yet been determined. We report the case of a young patient with multiple visceral and osseous metastases occurred after 4 years after first diagnosis of GBM. The strangeness as well as the rarity of this event does not allow to identify an effective treatment for GBM metastases, making the management of this ominous tumor an even greater challenge. PMID- 28647830 TI - The Comprehension of Syntactic and Affective Prosody by Adults with Autism Spectrum Disorder Without Accompanying Cognitive Deficits. AB - The present study investigates the comprehension of syntactic and affective prosody in adults with autism spectrum disorder without accompanying cognitive deficits (ASD w/o cognitive deficits) as well as age-, education- and gender matched unimpaired adults, while processing orally presented sentences. Two experiments were conducted: (a) an on-line sentence completion task containing local subject/object ambiguities and (b) an affective prosody task exploring the comprehension of six emotions. The syntactic prosody task revealed that the experimental group performed similar to the control group on the fillers and the object condition. On the other hand, the ASD w/o cognitive deficits group manifested lower accuracy compared to the unimpaired controls in the subject reading condition, as well as slower reaction times in all conditions. In the affective prosody task, the experimental group performed significantly worse than the controls in the recognition of the emotion of surprise, whereas no differences between the experimental and the control group were attested in the recognition of all other emotions. A positive correlation was found between the two tasks in the ASD w/o cognitive deficits group. Thus, individuals with ASD w/o cognitive deficits face slight difficulties with the decoding of prosody, both the syntactic and the affective one. More specifically, these difficulties are attested in the most difficult conditions, i.e. the subject reading and the emotion of surprise. PMID- 28647831 TI - Alterations in regional homogeneity of resting-state brain activity in fatigue of Parkinson's disease. AB - Fatigue is a common complaint in patients with Parkinson's disease (PD). However, the neural bases of fatigue in PD remain uncertain. In this cross-sectional study, our aim was to study the change of the local brain function in PD patients with fatigue. Among 49 patients with PD, 17 of them had fatigue and the remaining 32 patients without fatigue, and 25 age- and gender-matched healthy controls were enrolled. All subjects were evaluated with Fatigue Severity Scale (FSS) and had a resting-state functional magnetic resonance imaging (rs-fMRI) scan. The fMRI images were analyzed using regional homogeneity (ReHo) to study the change of the local brain function. ReHo analysis controlling for gray matter volume, age, gender, and education showed decreased ReHo in the left anterior cingulate cortex (ACC) and the right superior frontal gyrus (dorsolateral part), and increased ReHo in the left postcentral gyrus and the right inferior frontal gyrus (orbital and triangular part), compared PD-F with PD-NF; In PD patients, the regional activity in the left ACC and the right superior frontal gyrus (dorsolateral part) was negatively correlated with the FSS scores, while that in the left postcentral gyrus, the right inferior frontal gyrus (orbital and triangular part) was positively correlated with the FSS scores. This study demonstrates that brain areas including frontal, postcentral and ACC regions indicative of sensory, motor, and cognitive systems are involved in fatigue in PD patients. PMID- 28647832 TI - Genetic dissection of adventitious shoot regeneration in roses by employing genome-wide association studies. AB - KEY MESSAGE: We analysed the capacity to regenerate adventitious shoots in 96 rose genotypes and found 88 SNP markers associated with QTLs, some of which are derived from candidate genes for shoot regeneration. In an association panel of 96 rose genotypes previously analysed for petal colour, we conducted a genome wide association study on the capacity of leaf petioles for direct shoot regeneration. Shoot regeneration rate and shoot ratio (number of shoots/total number of explants) were used as phenotypic descriptors for regeneration capacity. Two independent experiments were carried out with six replicates of ten explants each. We found significant variation between the genotypes ranging from 0.88 to 88.33% for the regeneration rate and from 0.008 to 1.2 for the shoot ratio, which exceeded the rates reported so far. Furthermore, we found 88 SNP markers associated with either the shoot regeneration rate or the shoot ratio. In this association analysis, we found 12 SNP markers from ESTs (expressed sequence tags) matching known candidate genes that are involved in shoot morphogenesis. The best markers explained more than 51% of the variance in the shoot regeneration rate and more than 0.65 of the variance in the shoot regeneration ratio between the homozygote marker classes. The genes underlying some of the best markers such as a GT-transcription factor or an LRR receptor-like protein kinase are novel candidate genes putatively involved in the observed phenotypic differences. The associated markers were mapped to the closely related genome of Fragaria vesca and revealed many distinct clusters, which also comprised the known candidate genes that functioned in the organogenesis of plant shoots. However, the validation of candidate genes and their functional relationship to shoot regeneration require further analysis in independent rose populations and functional analyses. PMID- 28647833 TI - The evaluation of the right inferior phrenic artery diameter in cirrhotic patients. AB - PURPOSE: The purpose of this study is to evaluate the relationship between right inferior phrenic artery diameter and portal hypertension in cirrhotic patients. METHODS: CT examinations of 38 patients with chronic liver disease (patient group) and 40 patients without any liver disease (control group) were evaluated. The right inferior phrenic artery diameter of the patient and control group were measured. CT findings of portal hypertension, which were accepted as ascites, collaterals, splenomegaly and portal vein diameter greater than 13 mm, were determined and scored in the patient group. Patients obtained scores between one and four with respect to portal hypertension findings, and the scores were compared with phrenic artery diameters. Child-Pugh and MELD scores of the patients were also calculated. RESULTS: The mean diameter of the right inferior phrenic artery in the patient group was larger than that in the control group (p < 0.001). The mean phrenic artery diameter of the patients with score 1 was significantly different from those with score 2 (p = 0.028), score 3 (p = 0.001) and score 4 (p = 0.005). We found a linear and moderate relationship between phrenic artery diameter values and Child-Pugh scores (p = 0.012, r = 0.405). CONCLUSION: Dilatation of the right inferior phrenic artery in cirrhotic patients may be a nonspecific sign of developing portal hypertension. PMID- 28647834 TI - Influence of multi-leaf collimator leaf transmission on head and neck intensity modulated radiation therapy and volumetric-modulated arc therapy planning. AB - The aim of this study was to quantify the effect of multi-leaf collimators (MLCs) with different leaf widths on the planning of intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). Toward this objective, dose transmission through a high-definition 120-leaf MLC (HD120MLC) and 120-leaf Millennium MLC (M120MLC) was investigated, using it with a test case and clinical case studies. In test case, studies with IMRT and VMAT plans, the difference in MLC leaf width had a limited effect on planning target volumes (PTVs). Organs at risk (OARs) were more affected by a reduction in dose transmission through the MLC than by a reduction in MLC leaf width. The results of the test case studies and clinical case studies were mostly similar. In the latter, the different MLCs had no effect on the PTV regardless of the treatment method; however, the HD120MLC plans achieved dose reductions to OARs similar to or larger than the dose reduction of the M120MLC plans. The similar results of the test case and clinical case studies showed that despite a limitation of the irradiation field size, the HD120MLC plans were superior. PMID- 28647835 TI - Resveratrol alleviates inflammatory hyperalgesia by modulation of reactive oxygen species (ROS), antioxidant enzymes and ERK activation. AB - OBJECTIVES: Impact of ROS in development of hyperalgesia has recently motivated scientists to focus on ROS as novel target of anti-hyperalgesic interventions. However, role of ROS in molecular signaling of hyperalgesia is still poorly understood. The present study is aimed to analyze the effect of dietary antioxidant resveratrol on antioxidant defense system, ROS level and TNFR1-ERK signaling pathway during early and late phase of inflammatory hyperalgesia. METHODS AND MATERIALS: Hyperalgesia was assessed by paw withdrawal latency test in complete Freund's adjuvant-induced hyperalgesic rats. Activities of antioxidant enzymes were measured by in-gel assays, ROS level was measured by DCFH2DA, and expression of pERK, ERK and TNFR1 was estimated by Western blotting. RESULTS: Anti-hyperalgesic effect of resveratrol was observed by paw withdrawal latency test. ROS level was increased in paw skin as well as spinal cord during early phase which was further increased in paw skin, but remained constant in spinal cord up to late phase. Resveratrol differentially regulated the activities of SOD, catalase and GPx in paw skin as well as spinal cord of hyperalgesic rats in both phases. Activities were normalized back showing anti-hyperalgesic effect of resveratrol. Upregulated ERK signaling was modulated by resveratrol, whereas TNFR1 level remained unchanged. CONCLUSION: Overall results suggest that resveratrol alleviates inflammatory hyperalgesia by downregulation of ERK activation, modulation of ROS and differential regulation of antioxidant enzymes during early and late phases. PMID- 28647836 TI - From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation. AB - OBJECTIVES: The aim was to evaluate the activity of seven medicinal, anti inflammatory plants at the hH4R with focus on defined chemical compounds from Curcuma longa. MATERIALS: Activities were analyzed with membrane preparations from Sf9 cells, transiently expressing the hH4R, Galphai2 and Gbeta1gamma2 subunits. METHODS: From the methanolic extract of C. longa curcumin (1), demethoxycurcumin (2) and bis(4-hydroxy-cinnamoyl)methane (3) were isolated, purified with HPLC (elution-time 10.20, 9.66, 9.20 min, respectively) and together with six additional extracts, were characterized via radioligand binding studies at the hH4R. RESULTS: Compounds from C. longa were the most potent ligands at the hH4R. They exhibited estimated K i values of 4.26-6.26 uM (1.57 2.31 ug/mL) (1); 6.66--8.97 uM (2.26-3.04 ug/mL) (2) and 10.24-14.57 uM (3.16 4.49 ug/mL) (3) (95% CI). The estimated K i value of the crude extract of curcuma was 0.50-0.81 ug/mL. Fractionated curcumin and the crude extract surpassed the effect of pure curcumin with a K i value of 5.54 uM or 2.04 ug/mL [95% CI (4.47 6.86 uM), (1.65-2.53 ug/mL)]. CONCLUSION: Within this study, defined compounds of C. longa were recognized as potential ligands and reasonable lead structures at the hH4R. The mode of anti-inflammatory action of curcumin was further elucidated and the role of extracts in traditional phytomedicine was strengthened. PMID- 28647837 TI - Targeting metabolic reprogramming in KRAS-driven cancers. AB - Mutations of KRAS are found in a variety of human malignancies, including in pancreatic cancer, colorectal cancer, and non-small cell lung cancer at high frequency. To date, no effective treatments that target mutant variants of KRAS have been introduced into clinical practice. In recent years, a number of studies have shown that the oncogene KRAS plays a critical role in controlling cancer metabolism by orchestrating multiple metabolic changes. One of the metabolic hallmarks of malignant tumor cells is their dependency on aerobic glycolysis, known as the Warburg effect. The role of KRAS signaling in the regulation of aerobic glycolysis has been reported in several types of cancer. KRAS-driven cancers are characterized by altered metabolic pathways involving enhanced nutrients uptake, enhanced glycolysis, enhanced glutaminolysis, and elevated synthesis of fatty acids and nucleotides. However, Just how mutated KRAS can coordinate the metabolic shift to promote tumor growth and whether specific metabolic pathways are essential for the tumorigenesis of KRAS-driven cancers are questions which remain to be answered. In this context, the aim of this review is to summarize current data on KRAS-related metabolic alterations in cancer cells. Given that cancer cells rely on changes in metabolism to support their growth and survival, the targeting of metabolic processes may be a potential strategy for treating KRAS-driven cancers. PMID- 28647838 TI - Preoperative Education for Hip and Knee Replacement: Never Stop Learning. AB - PURPOSE OF REVIEW: Participation in alternative payment models has focused efforts to improve outcomes and patient satisfaction while also lowering cost for elective hip and knee replacement. The purpose of this review is to determine if preoperative education classes for elective hip and knee replacement achieve these goals. RECENT FINDINGS: Recent literature demonstrates that patients who attend education classes prior to surgery have decreased anxiety, better post operative pain control, more realistic expectations of surgery, and a better understanding of their surgery. As a result, comprehensive clinical pathways incorporating a preoperative education program for elective hip and knee replacement lead to lower hospital length of stay, higher home discharge, lower readmission, and improved cost. In summary, we report convincing evidence that preoperative education classes are an essential element to successful participation in alternative payment models such as the Bundle Payment Care Initiative. PMID- 28647839 TI - Do Bumble Bee, Bombus impatiens, Queens Signal their Reproductive and Mating Status to their Workers? AB - Reproduction in social insect societies reflects a delicate balance between cooperation and conflict over offspring production, and worker reproduction is widespread even in species showing strong reproductive skew in favor of the queen. To navigate these conflicts, workers are predicted to develop the means to estimate the queen's fecundity - potentially through behavioral and/or chemical cues - and to adjust their reproduction to maximize their fitness. Here, we introduced bumble bee, Bombus impatiens, workers to queens of different mating and reproductive status and examined worker reproduction and expression levels of two genes which were previously shown to be sensitive to the presence of the queen, vitellogenin and Kruppel-homolog 1. We further explored whether the queen's chemical secretion alone is sufficient to regulate worker reproduction, aggression and gene expression. We found that worker ovary activation was inhibited only in the presence of egg-laying queens, regardless of their mating status. Workers reared in the presence of newly-mated queens showed intermediate vitellogenin expression levels relative to workers reared with mated egg-laying and virgin queens. However, none of the whole-body chemical extracts of any of the queen treatment groups affected ovary activation, aggressive behavior, or gene expression in workers. Our findings indicate that only the presence of a freely-behaving, egg-laying queen can fully inhibit worker reproduction. It remains to be determined if workers detect differences in queen mating status and fecundity through differences in the queens' behavior alone or through the queen's behavior in concert with fertility signals. PMID- 28647840 TI - Interaction of Ferulic Acid with Glutathione S-Transferase and Carboxylesterase Genes in the Brown Planthopper, Nilaparvata lugens. AB - Plant phenolics are crucial defense phytochemicals against herbivores and glutathione S-transferase (GST) and carboxylesterase (CarE) in herbivorous insects are well-known detoxification enzymes for such xenobiotics. To understand relationship between a plant phenolic and herbivore GST or CarE genes, we evaluated the relationship between a rice phenolic ferulic acid and resistance to brown planthopper (BPH, Nilaparvata lugens), and investigated the interaction of ferulic acid with GST or CarE genes in BPH. The results indicate that ferulic acid content in tested rice varieties was highly associated with resistance to BPH. Bioassays using artificial diets show that the phenolic acid toxicity to BPH was dose dependent and the LC25 and LC50 were 5.81 and 23.30 MUg/ml at 72 hr, respectively. Activities of the enzymes BPH GST and CarE were increased at concentrations below the LC50 of ferulic acid. Moreover, low ferulic acid concentrations (< LC25) upregulated the transcriptional levels of NlGSTD1 and NlGSTE1 of the GST family and NlCE of the CarE family. By using dsRNA-induced gene silencing (DIGS) of GST or CarE, it was shown that suppressed expression levels of NlGSTD1, NlGSTE1 and NlCE were 14.6%-21.2%, 27.8%-34.2%, and 10.5% 19.8%, respectively. Combination of NlGSTD1, NlGSTE1 or NlCE knockdown with ferulic acid increased nymph mortality by 92.9%, 119.9%, or 124.6%, respectively. These results suggest that depletion of detoxification genes in herbivorous insects by plant-mediated RNAi technology might be a new potential resource for improving rice resistance to BPH. PMID- 28647841 TI - Anterior cruciate ligament tibial insertion site is elliptical or triangular shaped in healthy young adults: high-resolution 3-T MRI analysis. AB - PURPOSE: To clarify the morphology of anterior cruciate ligament (ACL) tibial insertion site in healthy young knees using high-resolution 3-T MRI. METHODS: Subjects were 50 ACL-reconstructed patients with a mean age of 21.4 +/- 6.8 years. The contralateral healthy knees were scanned using high-resolution 3-T MRI. The tibial insertion sites of the anteromedial (AM) and posterolateral (PL) bundle fibres, and the ACL attachment on the anterior horn of lateral meniscus (AHLM) were segmented from the MR images, and 3D models were reconstructed to evaluate the morphology. The shape of ACL footprint was qualitatively analysed, and the size of AM and PL attachments and AHLM overlapped area was measured digitally. RESULTS: Tibial AM and PL bundles were clearly identified in 42 of 50 knees (84.0%). Morphology of the whole ACL tibial insertion site was elliptical in 23 knees (54.8%) and triangular in 19 knees (45.2%), but not classified as C shape in any knees. However, the AM bundle attachment was of C-shape in 29 knees (69.0%) and band-like in 13 knees (31.0%). Overlap of ACL on AHLM was found in 26 knees (61.9%), and the size of the overlapped area was 4.8 +/- 4.7% of the whole ACL insertion site. CONCLUSION: 3D morphology of the intact ACL tibial insertion site analysed by high-resolution 3-T MRI was elliptical or triangular in healthy young knees. However, the AM bundle insertion site was of C-shape or band-like. A small lateral portion of the ACL was overlapped with the AHLM. As for clinical relevance, these findings should be considered in order to reproduce the native ACL insertion site sufficiently. LEVEL OF EVIDENCE: III. PMID- 28647842 TI - Excellent healing rates and patient satisfaction after arthroscopic repair of medium to large rotator cuff tears with a single-row technique augmented with bone marrow vents. AB - PURPOSE: This study evaluated the repair integrity and patient clinical outcomes following arthroscopic rotator cuff repair of medium to large rotator cuff tears using a single-row technique consisting of medially based, triple-loaded anchors augmented with bone marrow vents in the rotator cuff footprint lateral to the repair. METHODS: This is a retrospective study of 52 patients (53 shoulders) comprising 36 males and 16 females with a median age of 62 (range 44-82) with more than 24-month follow-up, tears between 2 and 4 cm in the anterior-posterior dimension and utilizing triple-loaded anchors. Mann-Whitney test compared Western Ontario Rotator Cuff (WORC) outcome scores between patients with healed and re torn cuff repairs. Multivariate logistic regression analysed association of variables with healing status and WORC score. Cuff integrity was assessed on MRI, read by a musculoskeletal fellowship-trained radiologist. RESULTS: Magnetic resonance imaging (MRI) demonstrated an intact repair in 48 of 53 shoulders (91%). The overall median WORC score was 95.7 (range 27.6-100.0). A significant difference in WORC scores were seen between patients with healed repairs 96.7 (range 56.7-100.0) compared with a re-tear 64.6 (27.6-73.8), p < 0.00056. CONCLUSIONS: Arthroscopic repair of medium to large rotator cuff tears using a triple-loaded single-row repair augmented with bone marrow vents resulted in a 91% healing rate by MRI and excellent patient reported clinical outcomes comparable to similar reported results in the literature. LEVEL OF EVIDENCE: IV. PMID- 28647843 TI - Alarming increase in the registration of degenerative rotator cuff-related lesions a nationwide epidemiological study investigating 244,519 patients. AB - PURPOSE AND HYPOTHESIS: Shoulder lesions are common and a challenge to diagnose. They often result in significant disability for the patient and are an economic burden to society. From recent studies, an increasing incidence has been reported. The purpose of this study was to investigate and map the incidence of shoulder lesions in Denmark from 1996 to 2013 with focus on sex, age and geographical area. METHODS: The Danish National Patient Registry was searched retrospectively to find the number of shoulder lesions in Denmark during the period 1996-2013. Regional population data were retrieved from the services of Statistics Denmark. Incidence rates were analysed using Poisson regression models, and all analyses were done in R 3.2.2, and p values less than 0.05 were considered statistically significant. RESULTS: During the 18-year period, 244,519 patients with a DM 75 diagnosis were registered. Male-to-female ratio was 51:49, and median age was 51. Most frequent were rotator cuff syndrome with a mean incidence rate of 313.3 (confidence interval 241.8-384.8) per 105 person-years at risk (PYRS). A statistically significant increase in overall incidence rate from 149.4 per 105 PYRS in 1996 to 715.3 per 105 PYRS in 2013 was found (p < 0.01). Incidence was highest for men aged 51-70 (1085.1 per 105 PYRS in 2013). There was no significant difference in incidence between sexes. Rural areas had a 1.4-fold higher mean incidence rate than urban areas. CONCLUSION: The incidence of shoulder lesions rapidly increased mainly due to an increase among people of working age (31-70 years). There were no significant differences in incidence between sexes. Rural areas had a 1.4-fold higher incidence rate than urban areas. As shoulder lesions impose a huge socioeconomic burden on society, not to mention a great distress to the patient, the present findings is highly relevant for political decision-making regarding preventive and health promoting initiatives. PMID- 28647844 TI - Digital Health Technologies to Promote Lifestyle Change and Adherence. AB - OPINION STATEMENT: Cardiovascular disease is the leading cause of morbidity and mortality worldwide with an estimated 17.5 million deaths annually, or 31% of all global deaths, according to the World Health Organization. The majority of these deaths are preventable by addressing lifestyle modification (i.e., smoking cessation, diet, obesity, and physical inactivity) and promoting medication adherence. At present, initiatives to develop cost-effective modalities to support self-management, lifestyle modification, and medication adherence are a leading priority. Digital health has rapidly emerged as technology with the potential to address this gap in cardiovascular disease self-management and transform the way healthcare has been traditionally delivered. However, limited evidence exists about the type of technologies available and how they differ in functionality, effectiveness, and application. We aimed to review the most important and relevant recent studies addressing health technologies to promote lifestyle change and medication adherence including text messaging, applications ("apps"), and wearable devices. The current literature indicates that digital health technologies will likely play a prominent role in future cardiovascular disease management, risk reduction, and delivery of care in both resource-rich and resource-limited settings. However, there is limited large-scale evidence to support adoption of existing interventions. Further clinical research and healthcare policy change are needed to move the promise of new digital health technologies towards reality. PMID- 28647845 TI - Recent progress in the development of white spot syndrome virus vaccines for protecting shrimp against viral infection. AB - White spot syndrome virus (WSSV) has been extensively investigated since the white spot disease outbreak in shrimp in 1990. These investigations have mainly focused on determining the function of viral structural proteins, and on utilizing the envelope proteins as subunit vaccines to protect the host. These studies have shown that a WSSV vaccine can be a practical and effective approach for controlling WSSV infection. The development of such a vaccine has become an intense focus of research in the field. This research has resulted in significant progress in the development of WSSV vaccines. However, because of the progress of this work, periodic summaries are needed to facilitate further research on the development of effective WSSV vaccines. This paper provides a comprehensive summary on the status of WSSV vaccines with regard to the following aspects: subunit vaccines, inactivated whole virus vaccines, DNA vaccines, protective antibodies, and the application of RNAi technology. Current limitations in this area of research are also described, as well as prospects for the development and application of improved WSSV vaccines in the future, and for investigating other important aquatic diseases. PMID- 28647847 TI - The processing of price comparison is not holistic but componential. AB - In three experiments, we evaluate whether the processing of prices is holistic or componential. When participants receive two prices and they select the higher price, distance effects are found when the distances between the two prices are defined holistically but not when they are defined in terms of digits (Experiment 1). This result suggests that prices are processed holistically. However, we show that the holistic distance effect can be explained by the compatibility between the digits and the monetary category of prices (euro and cent). After controlling for the holistic distance, compatible trials (e.g., 8 euro-4 cent, 8 > 4, and euro > cent) are processed faster than incompatible trials (e.g., 8 cent-4 euro, 8 > 4 but cent < euro) with simultaneous and sequential presentation of prices (Experiment 2). Moreover, the compatibility effect is modulated by the ratio of intra monetary category comparisons (8 euro-6 euro) and inter monetary category comparisons (8 euro-4 cents) (Experiment 3). The existence of compatibility effects between the digits and the monetary category of prices suggests that cognitive processing of prices is not holistic but componential. PMID- 28647846 TI - Attentional processing of itch. AB - Itch is a prevalent somatosensory symptom that can be highly disabling, because it is likely to draw attention and, as a result, may interfere with the performance of daily activities. Yet, research experimentally investigating attention to itch is lacking. In this study we aimed to investigate attentional processing of itch using multiple behavioral attention tasks. Forty-one healthy participants performed (1) a modified Stroop task with itch-related words, (2) a dot-probe task with itch-related pictures, and (3) a recently developed somatosensory attention task in which the effect of experimentally induced itch on the localization of visual targets was examined. Additionally, a number of self-report questionnaires related to somatosensory attentional processing were administered. Results indicated that participants' attention was biased toward itch-related words and pictures assessed by means of the dot-probe and modified Stroop task, respectively. For the somatosensory attention task, results showed that itch did not significantly influence the allocation of attention. However, when taking into account the time course of attention during the itch stimulus, data suggested that participants tended to disengage attention away during the itch stimulus. This is the first study that indicates an attentional bias for itch, using methods that have previously been validated for other sensations such as pain. In addition, the newly developed somatosensory attention task may reflect the time course of attention toward a tonic itch stimulus. PMID- 28647848 TI - The utilization of round window membrane surface tension in facilitating slim electrodes insertion during cochlear implantation. AB - This is a prospective randomized study aimed to evaluate the round window membrane (RWM) surface tension in facilitating slim electrodes insertion during cochlear implantation. A total number of (118) children were included in this study (118 implantations). Mean age was 36.72 months (range from 18 to 60 months). This study was conducted from January 2015 to September 2016 at a cochlear implant centre in a tertiary referral hospital. Slit incision in the anterosuperior quadrant of the RWM was done in 70 cases, While RWM cruciate incision was done in 48 cases. Of the 48 patients who underwent RWM cruciate incision, 13 cases had no problem, while in 35 cases, we faced difficult insertion. When slit incision of the RWM was done (70 cases), 68 cases showed smooth insertion, meanwhile, we faced increased operative time due to flopping of the electrode in 2 cases only. Moreover, residual low-frequency hearing preservation was more achieved when slit incision of the RWM was done. Tensile strength of the round window membrane after slit incision of the RWM offers support to slim electrodes during introduction, decreasing incidence of kinking and floppiness, hence shortening the maneuver time and minimizing the number of trials. This facilitates easy smooth slim electrodes introduction, decreasing intracochlear trauma. Moreover, slit incision of the RWM may offer better residual hearing preservations than cruciate incision of the RWM during slim electrodes introduction. PMID- 28647849 TI - The clinical outcomes of using a new cross-linked hyaluronan gel in endoscopic frontal sinus surgery. AB - In endoscopic sinus surgery (ESS) synechiae formation and ostial stenosis are frequently encountered. This is not uncommon after frontal recess and ostium interventions due to the narrow recess and difficult anatomy of the region. The goal of this study is to evaluate the efficacy of the new cross-linked hyaluronan gel-PureRegen(r) Gel Sinus-on wound healing and synechiae prevention in endoscopic frontal sinus surgery. The study consists of two groups of patients who underwent ESS, including frontal sinus surgery. In the study group of 37 patients, PureRegen(r) Gel Sinus was applied to both the frontal recess and ostium at the end of the procedure. The control group consisted of 28 patients. In this group, nasal dressing material was not applied at the end of surgery neither to the frontal recess nor to the ostium. Postoperatively, epithelization was found to be significantly better at 2 and 4 weeks in the study group when compared with the findings in patients where no postoperative dressing was applied. In the eighth week, there was no significant difference found between the two groups in terms of epithelization. Synechiae formation was significantly lower in the PureRegen(r) Gel Sinus group than the control group at all 2, 4 and 8 weeks postoperative evaluations. The effects of PureRegen(r) Gel Sinus on wound healing, especially in reepithelization, have shown to occur earlier in the postoperative period. Rapid reepithelization and control of infection related granulation tissue formation with antibiotics in the early postoperative period may explain the low stenosis rate in frontal sinus ostia in PureRegen(r) Gel Sinus applied patients. PMID- 28647850 TI - Wound healing protein profiles in the postoperative exudate of bisphosphonate related osteonecrosis of mandible. AB - Recurrent bacterial infections in cases of bisphosphonate-related osteonecrosis of jaw (BRONJ) frequently occur. Therefore, BRONJ are usually treated by radical saucerization followed by intensive antibiotic medications without bisphosphonate therapy. The postoperative exudate (POE) from BRONJ lesions may directly indicate the inflammatory status of osteomyelitis in patients, but so far, the POE has rarely been examined for its expression of various cytokines and wound healing proteins. A total of 27 cases of BRONJ, which involved the mandible, were selected and their individual POE collected 6 h, 1 day, and 2 days after surgical intervention was analyzed by immunoprecipitation high performance liquid chromatography (IP-HPLC). The different protein expressions in the BRONJ POE were compared with findings from ten cases of chronic mandibular osteomyelitis (CMO) exudate as the control group. For the protein expressions for inflammation, osteogenesis, and angiogenesis, in the 6 h POE sample, the BRONJ exudate exhibited more expression of IL-10, IL-28, OPG, and osteocalcin, but less expression of TNFalpha and LL-37 than the control. In the 1 day POE sample, the BRONJ exudate showed more expression of TNFalpha, IL-6, 8, 12, 28, alpha1 antitrypsin, VEGF-A, and VEGF-C, but less expression of CD68, lysozyme, bFGF, RANKL, bFGF, and ALP than the control. In the 2 day POE sample, the BRONJ exudate consistently showed more expression of LL-37, beta-defensin-1, and VEGF-A than the control. The present BRONJ POE revealed the rapid progress of bony wound healing through increased molecular signaling for inflammation, angiogenesis, and osteogenesis compared to the control. Therefore, it was suggested that the POE obtained from the postoperative bony lesions should be collected and analyzed by the IP-HPLC method to predict the prognosis of seriously complicated inflammatory bony diseases such as BRONJ. PMID- 28647851 TI - A questionnaire survey of radiological diagnosis and management of renal dysplasia in children. AB - BACKGROUND: The condition called renal dysplasia is considered to be a frequent cause of chronic kidney disease in children. Formally, it is defined by histological parameters. In current nephrology practice, however, the appearance of the kidneys on ultrasound scanning is often used as a basis for the diagnosis. METHODS: The European Society for Pediatric Nephrology Working Group on Congenital Anomalies of the Kidney and Urinary Tract hypothesized that the current diagnostic approach with regard to renal dysplasia was not homogeneous. Accordingly, we here report the results of a survey targeting pediatric nephrologists with 12 questions regarding their perceptions of the ultrasonographic characteristics of renal dysplasia and further tests that they might undertake. RESULTS: Of almost 1200 physicians who successfully received the invitation, 248 from 54 countries completed the survey. There was a notable lack of homogeneity regarding the ultrasonographic diagnosis of renal dysplasia and also of follow-up tests, including genetic testing and further radiology. CONCLUSIONS: Based on the responses to this large survey, a picture emerges of nephrologists' current clinical practice with regard to renal dysplasia. The Working Group considers that these results serve as an important sounding board which can provide the basis for more definitive recommendations regarding the challenges to clinical diagnosis and diagnostic follow-up of this important condition. PMID- 28647852 TI - From tubular sublimate nephropathy via urinary concentrating mechanism to glomerular disease-Wilhelm Kriz's contribution to modern nephrology : On the occasion of a symposium honoring Wilhelm Kriz on his 80th birthday. PMID- 28647853 TI - Are podocytes motile? AB - Podocytes, the postmitotic and highly branched epithelial cells of the glomerulus, play a pivotal role for the function of the glomerular filtration barrier and the development of chronic kidney disease. It has long been discussed whether podocytes in vivo are motile and can laterally migrate in a coordinated way along the capillaries until they reach the position of naked glomerular basement membrane often found in podocytopathies. Such motility would also be the prerequisite for the replacement of lost podocytes by progenitor cells. Additionally, the change of the podocyte foot processes from a normal to an effaced morphology, like it is found in many kidney diseases, would require a dynamic behavior of podocytes. Since the actin cytoskeleton is expressed in podocytes in vitro and in vivo and the morphology of podocytes is highly dependent on actin, actin-associated, and actin-regulating proteins, it was assumed that podocytes are dynamic and motile. After earlier technical limitations had been overcome and novel microscopic techniques like multiphoton microscopy had been developed, it became possible to continuously study the behavior of podocytes in living rodents and zebrafish larvae under physiological and pathological conditions. Recent in vivo microscopic studies in different model organisms suggest that lateral migration of podocytes in situ is a very unlikely event and only dynamic apical cell protrusions can be observed under pathological conditions. This review discusses recent findings concerning different forms of motility (like lateral translocative (LTM), apical translocative (ATM), and stationary motility (SM)) and their role for podocytopathies. PMID- 28647854 TI - The influence of head-of-bed elevation in patients with obstructive sleep apnea. AB - PURPOSE: The purpose of this study is to test the effects of a mild degree of head-of-bed elevation (HOBE) (7.5 degrees ) on obstructive sleep apnea (OSA) severity and sleep quality. METHODS: OSA patients were recruited from a single sleep clinic (Criciuma, Santa Catarina, Brazil). Following a baseline polysomnography (PSG), all patients underwent a PSG with HOBE (within 2 weeks). In addition, a subset of patients performed a third PSG without HOBE. RESULTS: Fifty-two patients were included in the study (age 53.2 +/- 9.1 years; BMI 29.6 +/- 4.8 kg/m2, neck circumference 38.9 +/- 3.8 cm, and Epworth Sleepiness Scale 15 +/- 7). Compared to baseline, HOBE significantly decreased the apnea-hypopnea index (AHI) from 15.7 [11.3-22.5] to 10.7 [6.6-16.5] events/h; p < 0.001 and increased minimum oxygen saturation from 83.5 [77.5-87] to 87 [81-90]%; p = 0.003. The sleep architecture at baseline and HOBE were similar. However, sleep efficiency increased slightly but significantly with HOBE (87.2 [76.7-90.7] vs 88.8 [81.6-93.3]; p = 0.005). The AHI obtained at the third PSG without HOBE (n = 7) returned to baseline values. CONCLUSIONS: Mild HOBE significantly improves OSA severity without interfering in sleep architecture and therefore is a simple alternative treatment to ameliorate OSA. PMID- 28647855 TI - Short-term annoyance from nocturnal aircraft noise exposure: results of the NORAH and STRAIN sleep studies. AB - PURPOSE: The German Aerospace Center (DLR) investigated in the NORAH sleep study the association between a distinct change in nocturnal aircraft noise exposure due to the introduction of a night curfew (11:00 p.m.-5:00 a.m.) at Frankfurt Airport and short-term annoyance reactions of residents in the surrounding community. Exposure-response curves were calculated by random effects logistic regression to evaluate the aircraft noise-related parameters (1) number of overflights and (2) energy equivalent noise level LASeq for the prediction of short-term annoyance. Data of the NORAH sleep study were compared with the STRAIN sleep study which was conducted by DLR near Cologne-Bonn Airport in 2001/2002 (N = 64), representing a steady-state/low-rate change. METHODS: The NORAH sleep study was based on questionnaire surveys with 187 residents living in the vicinity of Frankfurt Airport. Noise-induced short-term annoyance and related non acoustical variables were assessed. Nocturnal aircraft noise exposure was measured inside the residents' home. RESULTS: A statistically significant rise in the portion of annoyed residents with increasing number of overflights was found. Similarly, the portion of annoyed subjects increased with rising LASeq. Importance of the frequency of fly-overs for the prediction of annoyance reactions was emphasized. The annoyance probability was significantly higher in the NORAH than in the STRAIN sleep study. CONCLUSIONS: Results confirm the importance of both acoustical parameters for the prediction of short-term annoyance due to nocturnal aircraft noise. Quantitative annoyance models that were derived at steady-state/low-rate change airports cannot be directly applied to airports that underwent a distinct change in operational and noise exposure patterns. PMID- 28647856 TI - Glial and Neuronal Protein Tyrosine Phosphatase Alpha (PTPalpha) Regulate Oligodendrocyte Differentiation and Myelination. AB - CNS myelination defects occur in mice deficient in receptor-like protein tyrosine phosphatase alpha (PTPalpha). Here, we investigated the role of PTPalpha in oligodendrocyte differentiation and myelination using cells and tissues from wild type (WT) and PTPalpha knockout (KO) mice. PTPalpha promoted the timely differentiation of neural stem cell-derived oligodendrocyte progenitor cells (OPCs). Compared to WT OPCs, KO OPC cultures had more NG2+ progenitors, fewer myelin basic protein (MBP)+ oligodendrocytes, and reduced morphological complexity. In longer co-cultures with WT neurons, more KO than WT OPCs remained NG2+ and while equivalent MBP+ populations of WT and KO cells formed, the reduced area occupied by the MBP+ KO cells suggested that their morphological maturation was impeded. These defects were associated with reduced myelin formation in KO OPC/WT neuron co-cultures. Myelin formation was also impaired when WT OPCs were co-cultured with KO neurons, revealing a novel role for neuronal PTPalpha in myelination. Canonical Wnt/beta-catenin signaling is an important regulator of OPC differentiation and myelination. Wnt signaling activity was not dysregulated in OPCs lacking PTPalpha, but suppression of Wnt signaling by the small molecule XAV939 remediated defects in KO oligodendrocyte differentiation and enhanced myelin formation by KO oligodendrocytes. However, the myelin segments that formed were significantly shorter than those produced by WT oligodendrocytes, raising the possibility of a role for glial PTPalpha in myelin extension distinct from its pro-differentiating actions. Altogether, this study reveals PTPalpha as a molecular coordinator of oligodendroglial and neuronal signals that controls multiple aspects of oligodendrocyte development and myelination. PMID- 28647860 TI - Sub-optimal Testing and Awareness of HCV and HBV Among High Risk Individuals at an Underserved Safety-Net Hospital. AB - Sub-optimal screening for chronic hepatitis C virus (HCV) and chronic hepatitis B virus (HBV) among high risk groups delays diagnosis and treatment. We aimed to evaluate overall rates of HCV and HBV screening and patient knowledge of their testing result. Adults age >=18 years undergoing elective outpatient endoscopy at a large, urban safety-net hospital from July 2015 to July 2016 were prospectively evaluated to determine rates of HCV and HBV testing, the results of those completed tests, and patient knowledge of test results among high risk individuals (as determined by U.S. Preventative Services Task Force). Among 1125 patients (52.3% male, 70.4% foreign-born), 66.5% were high risk for chronic HCV; only 30.9% received prior testing. 14.7% had positive chronic HCV infection. Patients born in the 1945-1965 cohort were more likely to have received prior HCV testing compared to those born outside of this cohort (32.7 vs. 16.9%, p = 0.01). Among patients who received HCV screening, 29.3% were aware of test results. Overall, 61.6% were high risk for chronic HBV; only 25.1% received prior testing. 4.1% were positive for chronic HBV. Compared to Caucasians, Asians (19.0 vs. 44.4%, p < 0.001) and Hispanics (20.0 vs. 44.4%, p < 0.001) were less likely to have previous HBV testing. Among patients who received prior HBV screening, 18.4% were aware of test results. Less than one-third of high risk patients received HCV and HBV screening among an ethnically diverse safety-net population. Equally low rates of patient knowledge of testing results were observed. PMID- 28647858 TI - Counter-intuitive plasma vitamin D and zinc status in HIV-1-infected adults with persistent low-level viraemia after treatment initiation: a pilot case-control study. AB - Determinants of persistent low-level viraemia [PLLV, a viral load (VL) of between 50 and 500 copies/mL] have not been elucidated. In a case-control study, we evaluated the influence of micronutrients on PLLV in a population of 454 HIV-1 adults having initiated antiretroviral therapy (ART) between January 2007 and December 2011. Plasma levels of retinol (vitamin A), 25-OH vitamin D2 + D3, vitamin E and zinc were measured at ART initiation in cases (PLLV after 6 months of ART) and in controls (VL <50 copies/mL after 6 months). Cases and controls were matched for the CD4 cell count (+/-50/mm3) and ethnic origin. Intergroup differences in demographic, biological and treatment parameters and sunshine intensity at ART initiation were adjusted using a propensity score. A receiver operating characteristic (ROC) curve was used to assess intergroup differences in plasma micronutrient levels. Thirty-three of the 454 patients (7.3%) displayed PLLV (median VL: 92 copies/mL). Patients were predominantly male (89%), Caucasian (64%) and CDC stage C (25%). The median age was 38 years, the median initial VL was 5.2 log10 copies/mL and the median CD4 count was 74/mm3. The 22 cases and matched controls were balanced in these respects, and had similar vitamin A/E levels. Two cases (9%) and 9 controls (41%) had a vitamin D level <10.3 ng/mL (p = 0.0015), and 2 cases (9%) and 10 controls (48%) had a zinc level <74.6 MUg/dL (p = 0.04). Our results support in vitro studies suggesting that vitamin D favours HIV-1 replication and that HIV-1 is zinc-dependent. Wide-scale, prospective studies are required. PMID- 28647861 TI - Qualitative spatial logic descriptors from 3D indoor scenes to generate explanations in natural language. AB - The challenge of describing 3D real scenes is tackled in this paper using qualitative spatial descriptors. A key point to study is which qualitative descriptors to use and how these qualitative descriptors must be organized to produce a suitable cognitive explanation. In order to find answers, a survey test was carried out with human participants which openly described a scene containing some pieces of furniture. The data obtained in this survey are analysed, and taking this into account, the QSn3D computational approach was developed which uses a XBox 360 Kinect to obtain 3D data from a real indoor scene. Object features are computed on these 3D data to identify objects in indoor scenes. The object orientation is computed, and qualitative spatial relations between the objects are extracted. These qualitative spatial relations are the input to a grammar which applies saliency rules obtained from the survey study and generates cognitive natural language descriptions of scenes. Moreover, these qualitative descriptors can be expressed as first-order logical facts in Prolog for further reasoning. Finally, a validation study is carried out to test whether the descriptions provided by QSn3D approach are human readable. The obtained results show that their acceptability is higher than 82%. PMID- 28647859 TI - High-touch surfaces: microbial neighbours at hand. AB - Despite considerable efforts, healthcare-associated infections (HAIs) continue to be globally responsible for serious morbidity, increased costs and prolonged length of stay. Among potentially preventable sources of microbial pathogens causing HAIs, patient care items and environmental surfaces frequently touched play an important role in the chain of transmission. Microorganisms contaminating such high-touch surfaces include Gram-positive and Gram-negative bacteria, viruses, yeasts and parasites, with improved cleaning and disinfection effectively decreasing the rate of HAIs. Manual and automated surface cleaning strategies used in the control of infectious outbreaks are discussed and current trends concerning the prevention of contamination by the use of antimicrobial surfaces are taken into consideration in this manuscript. PMID- 28647857 TI - ROS-modulated therapeutic approaches in cancer treatment. AB - PURPOSE: Reactive oxygen species (ROS) are produced in cancer cells as a result of increased metabolic rate, dysfunction of mitochondria, elevated cell signaling, expression of oncogenes and increased peroxisome activities. Certain level of ROS is required by cancer cells, above or below which lead to cytotoxicity in cancer cells. This biochemical aspect can be exploited to develop novel therapeutic agents to preferentially and selectively target cancer cells. METHODS: We searched various electronic databases including PubMed, Web of Science, and Google Scholar for peer-reviewed english-language articles. Selected articles ranging from research papers, clinical studies, and review articles on the ROS production in living systems, its role in cancer development and cancer treatment, and the role of microbiota in ROS-dependent cancer therapy were analyzed. RESULTS: This review highlights oxidative stress in tumors, underlying mechanisms of different relationships of ROS and cancer cells, different ROS mediated therapeutic strategies and the emerging role of microbiota in cancer therapy. CONCLUSION: Cancer cells exhibit increased ROS stress and disturbed redox homeostasis which lead to ROS adaptations. ROS-dependent anticancer therapies including ROS scavenging anticancer therapy and ROS boosting anticancer therapy have shown promising results in vitro as well as in vivo. In addition, response to cancer therapy is modulated by the human microbiota which plays a critical role in systemic body functions. PMID- 28647862 TI - Investigating the relationship between costs and outcomes for English mental health providers: a bi-variate multi-level regression analysis. AB - Provider payment systems for mental health care that incentivize cost control and quality improvement have been a policy focus in a number of countries. In England, a new prospective provider payment system is being introduced to mental health that should encourage providers to control costs and improve outcomes. The aim of this research is to investigate the relationship between costs and outcomes to ascertain whether there is a trade-off between controlling costs and improving outcomes. The main data source is the Mental Health Minimum Data Set (MHMDS) for the years 2011/12 and 2012/13. Costs are calculated using NHS reference cost data while outcomes are measured using the Health of the Nation Outcome Scales (HoNOS). We estimate a bivariate multi-level model with costs and outcomes simultaneously. We calculate the correlation and plot the pairwise relationship between residual costs and outcomes at the provider level. After controlling for a range of demographic, need, social, and treatment variables, residual variation in costs and outcomes remains at the provider level. The correlation between residual costs and outcomes is negative, but very small, suggesting that cost-containment efforts by providers should not undermine outcome-improving efforts under the new payment system. PMID- 28647863 TI - Evaluation of cortical mandibular bone in patients with oral squamous cell carcinoma. AB - OBJECTIVES: The aim of the study was to evaluate the mandible cortical bone changes in patients with oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: Twenty patients who underwent some mandibular bone removal as part of the treatment of OSCC had bone samples collected in two parts: in the proximity of the tumor (BPT) and in the surgical margin (BEP). Cortical microarchitecture was analyzed trough micro-computed tomography, together with texture analysis, followed by microcrack evaluation in histological sections and gene expression of RANK, RANKL, OPG, and sclerostin by quantitative polymerase chain reaction. RESULTS: Bone surface was higher in BPT (0.005 +/- 0.002 vs 0.004 +/- 0.002, p = 0.01) compared with BEP. In BPT, the subset of patients without bone invasion presented higher anisotropy (0.83 +/- 0.07) compared with the ones with bone invasion (0.70 +/- 0.14) (p = 0.04). RANK, RANKL, OPG, and sclerostin were found to be downregulated in the majority of cases in both parts. There were significant correlations between the parameters of microarchitecture and gene expression analysis (p < 0.001 to p < 0.05), most of them related with OPG levels. CONCLUSION: The cortex in the mandible in the proximity of the tumor reveals more bone surface than the bone in the surgical margin, and the tumor invasion causes a decrease in anisotropy. RANK, RANKL, OPG, and sclerostin are downregulated in mandible, in both parts analyzed. Correlation tests revealed the association between cortical thickness, bone surface, anisotropy, porosity, bone mineral density, and OPG levels. CLINICAL RELEVANCE: The mandible cortical bone microarchitecture changes in the proximity of the squamous cell carcinoma lesion. PMID- 28647865 TI - Response to: systematic review of dietary, nutritional, and physical activity interventions for the prevention of prostate cancer progression and mortality by Hackshaw-McGeagh and Colleagues. PMID- 28647864 TI - Bonding of composite resins to PEEK: the influence of adhesive systems and air abrasion parameters. AB - OBJECTIVE: The objective of the study was to investigate the tensile bond strength (TBS) to polyaryletheretherketone (PEEK) after different pretreatment and conditioning methods. METHODS: Four hundred PEEK specimens were fabricated and allocated to the following air-abrasion methods (n 1 = 80/pretreatment): (i) 50 MUm Al2O3 (0.05 MPa); (ii) 50 MUm Al2O3 (0.35 MPa); (iii) 110 MUm Al2O3 (0.05 MPa); (iv) 110 MUm Al2O3 (0.35 MPa); and (v) Rocatec 110 MUm (0.28 MPa). These pretreatments were combined with the following conditioning methods (n 2 = 20/pretreatment/conditioning): (a) visio.link (VL); (b) Monobond Plus/Heliobond (MH); (c) Scotchbond Universal (SU); and (d) dialog bonding fluid (DB). After veneering of all specimens with dialog occlusal and aging (28 days H2O, 37 degrees C + 20,000 thermal cycles, 5/55 degrees C), TBS was measured. Data was analysed using Kaplan-Meier survival analysis with Breslow-Gehan test and Cox regressions. RESULTS: The major impact on TBS showed the conditioning, followed by the air-abrasion-pressure, while the grain size of the air-abrasion powder did not show any effect. Specimens air-abraded at 0.35 MPa showed the highest survival rates. However, within VL groups, this observation was not statistically significant. Within MH groups, pretreatment using 110 MUm Al2O3 and 0.05 MPa resulted in higher survival rates compared to groups treated with 50 and 110 MUm Al2O3 using a pressure of 0.35 MPa. The use of VL showed the highest survival rates between the adhesive systems and the TBS values higher than 25 MPa independent of the pretreatment method. As an exception, only VL showed significantly higher survival rates when compared to MH. CONCLUSIONS: The adequate choice of the adhesive system and higher pressures improved the TBS between PEEK and veneering resin composite. The particle size had no major impact. CLINICAL RELEVANCE: According to this study, best veneering of PEEK with dialog occlusal can be achieved by conditioning with visio.link in combination with the pretreatment of airborne particle abrasion at a pressure of 0.35 MPa. PMID- 28647866 TI - Coffee consumption and risk of renal cell carcinoma. AB - BACKGROUND: Studies have suggested an inverse association between coffee consumption and risk of renal cell carcinoma (RCC); however, data regarding decaffeinated coffee are limited. METHODS: We conducted a case-control study of 669 incident RCC cases and 1,001 frequency-matched controls. Participants completed identical risk factor questionnaires that solicited information about usual coffee consumption habits. The study participants were categorized as non coffee, caffeinated coffee, decaffeinated coffee, or both caffeinated and decaffeinated coffee drinkers. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusting for multiple risk factors for RCC. RESULTS: Compared with no coffee consumption, we found an inverse association between caffeinated coffee consumption and RCC risk (OR 0.74; 95% CI 0.57-0.99), whereas we observed a trend toward increased risk of RCC for consumption of decaffeinated coffee (OR 1.47; 95% CI 0.98-2.19). Decaffeinated coffee consumption was associated also with increased risk of the clear cell RCC (ccRCC) subtype, particularly the aggressive form of ccRCC (OR 1.80; 95% CI 1.01 3.22). CONCLUSIONS: Consumption of caffeinated coffee is associated with reduced risk of RCC, while decaffeinated coffee consumption is associated with an increase in risk of aggressive ccRCC. Further inquiry is warranted in large prospective studies and should include assessment of dose-response associations. PMID- 28647867 TI - The effects of 4 weeks stretching training to the point of pain on flexibility and muscle tendon unit properties. AB - PURPOSE: The purpose of this study was to compare the benefits and possible problems of 4 weeks stretching when taken to the point of pain (POP) and to the point of discomfort (POD). METHODS: Twenty-six physically active women (20 +/- 1.1 years) took part in group-based stretching classes of the hamstring muscles, 4 times per week for 4 weeks, one group one stretching to POD, the other to POP. Passive stiffness, joint range of motion (ROM), maximal isometric torque and concentric knee flexion torque, were measured before training and 2 days after the last training session. RESULTS: Hip flexion ROM increased by 14.1 degrees (10.1 degrees -18.1 degrees ) and 19.8 degrees (15.1 degrees -24.5 degrees ) and sit-and-reach by 7.6 (5.2-10.0) cm and 7.5 (5.0-10.0) cm for POD and POP, respectively (Mean and 95% CI; p < 0.001 within group; NS between groups), with no evidence of damage in either group. Despite the large increases in flexibility there were no changes in either compliance or viscoelastic properties of the muscle tendon unit (MTU). CONCLUSION: Hamstrings stretching to POP increased flexibility and had no detrimental effects on muscle function but the benefits were no better than when stretching to POD so there is no justification for recommending painful stretching. The improvements in flexibility over 4 weeks of stretching training appear to be largely due to changes in the perception of pain rather than physical properties of the MTU although less flexible individuals benefited more from the training and increased hamstring muscle length. PMID- 28647868 TI - Effects of high-altitude exposure on supraspinal fatigue and corticospinal excitability and inhibition. AB - PURPOSE: While acute hypoxic exposure enhances exercise-induced central fatigue and can alter corticospinal excitability and inhibition, the effect of prolonged hypoxic exposure on these parameters remains to be clarified. We hypothesized that 5 days of altitude exposure would (i) normalize exercise-induced supraspinal fatigue during isolated muscle exercise to sea level (SL) values and (ii) increase corticospinal excitability and inhibition. METHODS: Eleven male subjects performed intermittent isometric elbow flexions at 50% of maximal voluntary contraction to task failure at SL and after 1 (D1) and 5 (D5) days at 4350 m. Transcranial magnetic stimulation and peripheral electrical stimulation were used to assess supraspinal and peripheral fatigues. Pre-frontal cortex and biceps brachii oxygenation was monitored by near-infrared spectroscopy. RESULTS: Exercise duration was not statistically different between SL (1095 +/- 562 s), D1 (1132 +/- 516 s), and D5 (1440 +/- 689 s). No significant differences were found between the three experimental conditions in maximal voluntary activation declines at task failure (SL -16.8 +/- 9.5%; D1 -25.5 +/- 11.2%; D5 -21.8 +/- 7.0%; p > 0.05). Exercise-induced peripheral fatigue was larger at D5 versus SL (100 Hz doublet at task failure: -58.8 +/- 16.6 versus -41.8 +/- 20.1%; p < 0.05). Corticospinal excitability at 50% maximal voluntary contraction was lower at D5 versus SL (brachioradialis p < 0.05, biceps brachii p = 0.055). Cortical silent periods were shorter at SL versus D1 and D5 (p < 0.05). CONCLUSIONS: The present results show similar patterns of supraspinal fatigue development during isometric elbow flexions at SL and after 1 and 5 days at high altitude, despite larger amount of peripheral fatigue at D5, lowered corticospinal excitability and enhanced corticospinal inhibition at altitude. PMID- 28647869 TI - Muscular viscoelastic characteristics of athletes participating in the European Master Indoor Athletics Championship. AB - PURPOSE: To investigate how the viscoelastic characteristics of muscles (non neural tone, elasticity and stiffness) vary as a function of age and gender in a sample of track and field master athletes. To compare these findings with data on related sedentary subjects in literature. METHODS: A total of 390 athletes (aged 35-99) were assessed during the European Master Athletics Indoor Championship 2016. A non-invasive measurement device called MyotonPro was used to measure tone, stiffness, and elasticity in the biceps brachii and rectus femoris muscles at rest. Linear regression analysis was used to assess the correlation between age and the measured parameters. To compare our results with previously reported data, we stratified participants according to gender and age. RESULTS: Tone was found to not be dependent on age, whereas stiffness was found to be age dependent. Elasticity was found to be both physical activity and age dependent. Tone (only for men), elasticity, and stiffness were lower in master athletes than in sedentary subjects. CONCLUSIONS: Tone, elasticity, and stiffness change with aging; nevertheless, our findings suggest that physical activity can delay the effects of muscular aging, improving fitness in older people. PMID- 28647870 TI - Prothrombotic genetic risk factors in patients with very early ST-segment elevation myocardial infarction. AB - The contribution of prothrombotic genetic risk factors in the pathogenesis of premature acute myocardial infarction (MI) is controversial. We examined the prevalence of prothrombotic polymorphisms (G1691A of factor V gene [FV Leiden] and G20210A of prothrombin [FII] gene), deficiencies of natural anticoagulants (protein C, protein S and antithrombin III) and antiphospholipid syndrome (APS) in patients with early ST-segment elevation MI (STEMI). We recruited 255 consecutive patients who had survived a STEMI <= 35 years of age (224 men). The control group consisted of 400 healthy individuals matched with cases for age and sex. G20210A polymorphism of FII gene was more frequent in young patients than in controls (7.4 vs. 3.5%, p = 0.023). The odds ratio (OR) for STEMI for carriers versus non-carriers was 2.239 (95% CI 1.102-4.250). The adjusted OR for major cardiovascular risk factors was 2.569 (95% CI 1.086-6.074). The risk was increased by 22-fold (95% CI 9.192-66.517) when G20210A polymorphism was present in combination with smoking. There was no difference in the prevalence of FV Leiden between patients and controls (7.8 vs. 6.5%, p = 0.512). There was only one patient (0.4%) with protein C deficiency and one with APS (0.4%). G20210A polymorphism of FII gene may be associated with increased risk of premature STEMI and the risk increases substantially when smoking is present. The contribution of other prothrombotic disorders such as deficiencies of protein C, protein S and antithrombin III and APS was minimal in this cohort. PMID- 28647872 TI - Identification and characterization of intramolecular gamma-halo interaction in d0 complexes: a theoretical approach. AB - A mechanistic investigation to detect intramolecular M?X-C type interactions in d0 neutral and cationic complexes was carried out through a benchmark study employing different density functional methods. As gamma-halogen is involved in M?X-C type interactions, it is denoted as a gamma-halo interaction and the respective conformers are designated as halo-conformers. By analyzing the geometrical parameters of halo-conformers, it was observed that, irrespective of the nature of the metal and the halogen, the Cgamma-X bond distance increases compared to the usual C-X bond, which brings the M and X centers close enough to generate a weak interaction. Generation of the M?X-C interaction was confirmed by performing NBO, AIM and Wiberg bond index analyses, from which the persistence of gamma-halo interaction was seen to be prominent. Moreover, for each neutral and cationic complex, the values of Wiberg bond order are in good agreement with the AIM results. The effect of the metal center, as well as gamma-halogen substitution, on gamma-halo interaction was also studied in the present work. To justify the practical subsistence of the halo-conformers, we checked the stability of the conformers with respect to their beta-conformers by comparing the zero-point-corrected electronic energies. Therefore, the entire study was designed in such a way that it can provide evidence in support of intramolecular M?X-C interactions, where, instead of the C-H bond, the Cgamma-X bond will interact with the central transition metal. PMID- 28647871 TI - Cytoskeleton as a Target of Quinolinic Acid Neurotoxicity: Insight from Animal Models. AB - Cytoskeletal proteins are increasingly recognized as having important roles as a target of the action of different neurotoxins. In the last years, several works of our group have shown that quinolinic acid (QUIN) was able to disrupt the homeostasis of the cytoskeleton of neural cells and this was associated with cell dysfunction and neurodegeneration. QUIN is an excitotoxic metabolite of tryptophan metabolism and its accumulation is associated with several neurodegenerative diseases. In the present review, we provide a comprehensive view of the actions of QUIN upstream of glutamate receptors, eliciting kinase/phosphatase signaling cascades that disrupt the homeostasis of the phosphorylation system associated with intermediate filament proteins of astrocytes and neurons. We emphasize the critical role of calcium in these actions and the evidence that misregulated cytoskeleton takes part of the cell response to the injury resulting in neurodegeneration in different brain regions, disrupted cell signaling in acute tissue slices, and disorganized cytoskeleton with altered cell morphology in primary cultures. We also discuss the interplay among misregulated cytoskeleton, oxidative stress, and cell-cell contact through gap junctions mediating the quinolinic acid injury in rat brain. The increasing amount of cross talks identified between cytoskeletal proteins and cellular signaling cascades reinforces the exciting possibility that cytoskeleton could be a new target in the neurotoxicity of QUIN and further studies will be necessary to develop strategies to protect the cytoskeleton and counteracts the cytotoxicity of this metabolite. PMID- 28647873 TI - Degradation of 3,4-dichlorobenzotrifluoride by the Fenton-like process using zirconia-coated magnetite magnetic nanoparticles as an effective heterogeneous catalyst. AB - In this study, zirconia-coated magnetite magnetic nanoparticles (ZrO2/Fe3O4 MNPs) were prepared, characterized, and used as an effective and reusable heterogeneous catalyst for 3,4-dichlorobenzotrifluoride (3,4-DCBTE) degradation. The catalytic potential of the Fe3O4/ZrO2-H2O2 system for the removal of 3,4-DCBTE was tested in comparison with several other systems, and the effects of various operating parameters, including initial solution pH, catalyst addition, H2O2 concentrations, and reaction temperature, were also evaluated with respect to the degradation efficiency of 3,4-DCBTE. Results showed that the Fe3O4/ZrO2 composite could effectively enhance the oxidation of 3,4-DCBTE by the Fenton-like process, and there might be a synergetic effect in the Fe3O4/ZrO2 composite. When the mass ratio of Fe3O4 and ZrO2 was 1:1, the Fe3O4/ZrO2 exhibited the best catalytic activity, and the catalyst-driven Fenton process achieved high removal of 3,4 DCBTE (98.5%) and total organic carbon (TOC) (52.7%) at the operating conditions: pH 3.0, catalyst 2.0 g/L, H2O2 30 mM, temperature 30 degrees C, and reaction time 1 h. Furthermore, five successive runs of the Fenton oxidation using the same Fe3O4/ZrO2 composite resulted in the steady removal of 3,4-DCBTE, further confirming the high stability of the catalyst. In addition, the possible catalytic mechanism and degradation pathways of 3,4-DCBTE were also investigated. PMID- 28647875 TI - Evaluating the efficiency of nuclear energy policies: an empirical examination for 26 countries. AB - The decarbonization of the global economy is an urgent concern. As a potential solution, it can be important to understand the efficiency of nuclear energy policies. For this purpose, the paper analyzes whether there is a unit root in nuclear energy consumption in 26 countries and it uses the unit root tests with two endogenous (unknown) structural breaks. The paper finds that nuclear energy consumption is stationary around a level and the time trend in 25 of 26 countries and nuclear energy consumption contains a unit root only in France. The paper also discusses the potential implications of the findings. PMID- 28647874 TI - Alleviative effect of licorice on copper chloride-induced oxidative stress in the brain: biochemical, histopathological, immunohistochemical, and genotoxic study. AB - Although copper is an essential micronutrient involved in a variety of biological processes indispensable for sustaining life, it can be toxic when administered in excess. Licorice (Glycyrrhizaglabra) has been used in Chinese folk medicine for the treatment of various disorders. Licorice has the biological capabilities of detoxication, antioxidation, and antiinfection. Here, we test the hypothesis that licorice could ameliorate copper-induced neurotoxic and genotoxic effects in adult male albino rats. For this purpose, 48 adult male albino rats were randomized into five groups: group I (8 rats), untreated control; group II (16 rats), subdivided into; vehicle control IIa (8 rats) which received 1 mL saline twice weekly intraperitoneally for 8 weeks and vehicle control IIb (8 rats) received 0.5 mL distilled water/day orally gavaged for 8 weeks; group III (8 rats), treated with licorice dissolved in 0.5 mL of distilled water, 50 mg/kg b.w./day orally gavaged for 8 weeks; group IV (8 rats), copper chloride (CuCl2) dissolved in 0.5 mL saline, 7 mg/kg b.w. twice weekly intraperitoneal for 8 weeks; and group V (8 rats), CuCl2 + licorice (the same previously mentioned doses) licorice extract were orally given for 10 days before treatment was initiated then followed by CuCl2 intraperitoneally for 8 weeks. We found that CuCl2 exposure significantly increased brain oxidative stress as manifested by elevated malondialdehyde levels, decreased reduced glutathione content, and depressed antioxidant enzyme activities in brain tissues when compared with control groups. This was accompanied by histopathological changes in the form of increased cellularity and swelling of astrocytes that showed dense eosinophilic cytoplasm, pyknotic nuclei, and multiple apoptotic bodies that associated with degenerated neurons with deep eosinophilic cytoplasm. Also, strong Bax immunoreactions in the brain were detected. Furthermore, comet assay results confirmed CuCl2-related oxidative DNA damage. Notably, all these changes were partially ameliorated in rats treated concomitantly with licorice and CuCl2. Our results showed that licorice exerts protective effects against CuCl2-induced neuro- and genotoxicities. These effects may be attributed to the antioxidative property of licorice. PMID- 28647876 TI - Characteristics and effects of dissolved organic phosphorus from different sources on the water quality of Erhai Lake in Southwest China. AB - To establish the influence of dissolved organic phosphorus (DOP) from different sources on the water quality of Erhai Lake in August 2014, enzymatic hydrolysis technology was used to characterize enzymatically hydrolyzable phosphorus (EHP). The results indicate that the DOP represents a significant source of the bioavailable P in the lake water and its different sources of Erhai Lake, and the bioavailability of the P pool may be underestimated by up to 55% if DOP is ignored and only the soluble-reactive phosphorus (SRP) is considered. The significant differences in DOP characteristics from the different sources may be related to the origin of the DOP, regional pollution, and environmental factors. The DOP from the sediment porewater can act as an important source of DOP in the lake water based on its high DOP content and high DOP loads from the sediment release. In addition, the highest EHP loads from the sediment release can threaten the water quality of Erhai Lake and sustain the algal blooms when they occur. Therefore, for the protection of Erhai Lake, the contributions of not only the SRP but also the DOP to the bioavailable P pool should be considered, emphasizing the eutrophication risk caused by DOP from sediments, especially in the middle section of Erhai Lake. The effects of DOP from the inflowing rivers on the water quality should also not be ignored, due to its high bioavailability. PMID- 28647877 TI - Volatile organic compounds (VOCs) during non-haze and haze days in Shanghai: characterization and secondary organic aerosol (SOA) formation. AB - To better understand the characterization and secondary organic aerosol (SOA) formation of volatile organic compounds (VOCs) during non-haze and haze days, ambient VOCs were continuously measured by a vehicle-mounted online thermal desorption system coupled with a gas chromatography-mass spectrometry (TD-GC/MS) system in Shanghai, China. The average concentrations of VOCs in haze episodes (193.2 MUg m-3) were almost 50% higher than in non-haze periods (130.8 MUg m-3). VOC concentrations exhibited a bi-modal pattern in the morning and evening rush hour periods on both non-haze and haze days. The ratios of toluene to benzene (T/B) and m,p-xylene to ethylbenzene (X/E) indicated that VOCs were aged air mass transported from nearby areas. The estimated SOA yields were 12.6 +/- 5.3 and 16.7 +/- 6.7 MUg m-3 for non-haze and haze days, respectively, accounting for 9.6 and 8.7% of the corresponding PM2.5 concentrations, which were slightly underestimated. VOCs-sensitivity (VOCs-S) based on a PM2.5-dependent model was used to investigate the variation between VOCs and PM2.5 concentrations in the morning rush hour. It was found that VOCs were more sensitive to PM2.5 on clean days than during periods of heavy particulate pollution. VOCs-sensitivity was significantly correlated with the ratio of specific PM2.5 to background PM2.5, with a simulated equation of y = 0.84x-0.62 (r 2 = 0.93, p < 0.001). Our findings suggest that strategies to mitigate VOC emissions and further alleviate haze episodes in Shanghai based on reducing gasoline vehicle-related sources would be very efficient. PMID- 28647878 TI - Selection of Zygosaccharomyces rouxii strains resistant to cadmium with improved removal abilities through ultraviolet-diethyl sulfate cooperative mutagenesis. AB - Cd2+ resistance and bioaccumulation capacity were selected from parental Zygosaccharomyces rouxii (CRZ-0) while maintaining NaCl tolerance using protoplast mutagenesis technology. Ultraviolet-diethyl sulfate (UV-DES) cooperative mutagenesis, followed by preliminary screening and rescreening, was used to select the mutant strain CRZ-9. CRZ-9 grew better than CRZ-0 in YPD medium with 20 or 50 mg L-1 of Cd2+. Scanning electron microscopy observations and flow cytometry tests indicated that CRZ-9 was more effective at eliminating reactive oxygen species (ROS) generated by Cd2+, which led to less cellular structural damage and lower lethality. Furthermore, compared with CRZ-0, CRZ-9 exhibited increased potential for application with higher Cd2+ removal ratio, wider working pH range, and lower biomass dosage in Cd2+ bioaccumulation. The mutant strain CRZ-9 possessed improved Cd2+ resistance and bioaccumulation capacity and therefore is a promising strain to remove Cd2+ from wastewater. PMID- 28647879 TI - Disposal of household pharmaceuticals in insular communities: social attitude, behaviour evaluation and prevention activities. AB - The increase in medicine and drug consumption have resulted in identifying these emerging pollutants in all aquatic compartments, ranging from surface water and groundwater resources to the marine environment. Pharmaceuticals are an indispensable part of life today. A large number of pharmaceuticals are used in a daily basis in the treatment, prevention, cure or diagnosis of diseases or to otherwise enhance people's physical or mental well-being. This paper focuses on the evaluation of the attitude of citizens in Cyprus regarding the disposal of pharmaceuticals as well as to identify the main reasons why pharmaceutical wastes are produced. The result indicted that in Cyprus, there is lack of data regarding the amount of pharmaceutical wastes that are discarded into household waste and sinks. The survey audit showed that 86.6% of men's and 83.3% of women's used pharmacy with or without doctor's recipe. Social behaviour is considered to be the most significant reason that pharmaceutical are produced. The results indicated that, citizens mainly keep unused medicines and drugs at home in case they are needed again as well as patients use to cut-off or to reduce their treatment in case that on the first 3-6 days they feel better. The survey indicated that the main disposal method of unused or expired medicines and drugs is in household waste followed from the sink and the toilet. Furthermore, the main disposal solution of unused or expired medicines and drugs remain the household bin as well as the sewage system (sink or toilet), while a percentage more than 55% of the participants indicated that they will follow a specific waste management program if existing in place. Moreover, in order to reduce the production of pharmaceutical wastes, specific prevention activities must be considered. PMID- 28647880 TI - Selective removal and preconcentration of triclosan using a water-compatible imprinted nano-magnetic chitosan particles. AB - A water-compatible magnetic triclosan (TCS) imprinted material (TCS-CTS-Fe0-MIPs) was synthesized for selective enrichment and detection of TCS in real complex water samples. The material was synthesized by using chitosan (CTS) as functional monomer, which has rich surface O- and N-containing functional groups. The TCS imprinted CTS was coated on Fe0 surface and then cross-linked with glutaraldehyde. Scanning electron microscopy suggested that the imprinted material was covered with a layer of imprinted film, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirmed that the imprinted material had more functional groups (amino and hydroxyl groups) than that of non imprinted material. The TCS imprinted and non-imprinted materials used in each adsorption experiments were 0.1 mg mL-1. The maximum adsorption capacity of the TCS imprinted material and non-TCS imprinted material were 20.86 and 15.11 mg g 1, respectively. The adsorption results showed that selectivity coefficient was 10.151, 1.353, and 8.271 in the presence of p-chlorophenol, 2,4,6 trichlorophenol, and bisphenol-A, respectively. The recoveries of river water and lake water samples were 92.8, 91.3, 92.4, and 81.4, 82.3, 82.1%, respectively, when the samples were spiked with 4, 6, and 8 MUg L-1 of TCS with the imprinted material. The adsorption capacity of the TCS imprinted material and non-TCS imprinted material lost 5.2 and 6.2% after six times of recycling. The high selectivity and excellent adsorption capacity of the imprinted material can be attributed to the presence of sterically complementary imprinted sites and high surface, which would also made it more accessible to TCS than that of non imprinted material. The present study would provide an environmental friendly and convenient method for the removal and the monitoring of TCS in environmental water samples. PMID- 28647881 TI - Alterations in soil microbial communities caused by treatments with penicillin or neomycin. AB - Antibiotic residues in soils can lead to serious health risk and ecological hazards. In this study, the effects of penicillin and neomycin, two antibiotics widely used in animal production, were investigated on soil bacterial communities. Changes in the community structure were monitored using three 16S ribosomal DNA (rDNA) polymerase chain reaction-based approaches, including denaturing gradient gel electrophoresis (DGGE), amplified rDNA restriction analysis (ARDRA), and terminal-restriction fragment length polymorphism (T-RFLP) analysis. The prominent DGGE bands were excised from gels and sequenced, and the data indicated the prevalence of Gammaproteobacteria in the soils. The total soil bacterial community, including uncultured bacteria, exhibited a higher diversity than that of cultured bacteria. Some microbial strains were capable of surviving and even subsisting on penicillin or neomycin. We also observed toxic effects of the antibiotics on the indigenous soil bacterial communities since some genotypes disappeared after the treatments (e.g., Pseudomonas sp., Stenotrophomonas sp., Salinimonas, and uncultured Acinetobacter sp.). The implications of these findings are that the functions of soil bacterial communities may be negatively affected if key microbial community members are lost. PMID- 28647882 TI - Leaching of phthalate esters from different drinking stuffs and their subsequent biodegradation. AB - Phthalate esters (PAEs) are mainly used as plasticizers, and their release in the environment during the manufacturing, use, and disposal has caused serious environmental health concerns, since some of them are suspected to be mutagens, hepatotoxic agents, and carcinogens. In the present study, leaching of PAEs from different drinking stuffs (water cooler, mineral water bottles) exposed to sunlight and baby feeders subjected to different heating treatments (boiling, autoclave and oven) was studied. Results showed that a total of 10 PAEs were leached and identified. Among them, dimethyl phthalate, bis(2-methoxyethyl) phthalate, diethyl phthalate, and dibutyl phthalate were the major leached PAEs found in the range 9-112.50 MUg L-1. Boiling treatment was found safer for baby feeders as PAE leaching was ~26-54% less as compared to other two treatments. The leached PAEs in water samples were then subjected to biodegradation experiment with Bacillus thuringiensis strain at optimized conditions (time 72 h and 30 degrees C). Hence, leaching of hazardous PAEs from different water stuffs is alarming and needs immediate attention. Moreover, B. thuringiensis strain was found effective for PAE remediation (75-96% degradation) at neutral pH. Graphical abstract ?. PMID- 28647883 TI - CASPER: computer-aided segmentation of imperceptible motion-a learning-based tracking of an invisible needle in ultrasound. AB - PURPOSE: This paper presents a new micro-motion-based approach to track a needle in ultrasound images captured by a handheld transducer. METHODS: We propose a novel learning-based framework to track a handheld needle by detecting microscale variations of motion dynamics over time. The current state of the art on using motion analysis for needle detection uses absolute motion and hence work well only when the transducer is static. We have introduced and evaluated novel spatiotemporal and spectral features, obtained from the phase image, in a self supervised tracking framework to improve the detection accuracy in the subsequent frames using incremental training. Our proposed tracking method involves volumetric feature selection and differential flow analysis to incorporate the neighboring pixels and mitigate the effects of the subtle tremor motion of a handheld transducer. To evaluate the detection accuracy, the method is tested on porcine tissue in-vivo, during the needle insertion in the biceps femoris muscle. RESULTS: Experimental results show the mean, standard deviation and root-mean square errors of [Formula: see text], [Formula: see text] and [Formula: see text] in the insertion angle, and 0.82, 1.21, 1.47 mm, in the needle tip, respectively. CONCLUSIONS: Compared to the appearance-based detection approaches, the proposed method is especially suitable for needles with ultrasonic characteristics that are imperceptible in the static image and to the naked eye. PMID- 28647884 TI - Fluoxetine induces apoptosis through endoplasmic reticulum stress via mitogen activated protein kinase activation and histone hyperacetylation in SK-N-BE(2) M17 human neuroblastoma cells. AB - Fluoxetine (FLX) is an antidepressant drug that belongs to the class of selective serotonin reuptake inhibitors. FLX is known to induce apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti cancer effects of FLX were investigated in SK-N-BE(2)-M17 human neuroblastoma cells. FLX induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid or CHOP siRNA transfection reduced FLX-induced cell death. FLX induced phosphorylation of mitogen-activated protein kinases (MAPKs) family, p38, JNK, and ERK, and an upstream kinase apoptosis signal kinase 1 (ASK1). Inhibition of MAPKs and ASK1 reduced FLX induced cell death and CHOP expression. We then showed that FLX reduced mitochondrial membrane potential (MMP) and ER stress inhibitors as well as MAPK inhibitors ameliorated FLX-induced loss of MMP. Interestingly, FLX induced hyperacetylation of histone H3 and H4, upregulation of p300 histone acetyltransferase (HAT), and downregulation of histone deacetylases (HDACs). Treatment with a HAT inhibitor anacardic acid or p300 HAT siRNA transfection blocked FLX-induced apoptosis in SK-N-BE(2)-M17 cells. However, FLX did not induce histone acetylation and anacardic acid had no protective effect on FLX induced cell death and CHOP expression in MYCN non-amplified SH-SY5Y human neuroblastoma and MYCN knockdowned SK-N-BE(2)-M17 cells. These findings suggest that FLX induces apoptosis in neuroblastoma through ER stress and mitochondrial dysfunction via the ASK1 and MAPK pathways and through histone hyperacetylation in a MYCN-dependent manner. PMID- 28647885 TI - Osteomacs and Bone Regeneration. AB - PURPOSE OF REVIEW: Mounting evidence supporting the critical contribution of macrophages, in particular osteal macrophages, to bone regeneration is reviewed. We specifically examine the potential role of macrophages in the basic multicellular units coordinating lifelong bone regeneration via remodelling and bone regeneration in response to injury. We review and discuss the distinctions between macrophage and osteoclast contributions to bone homeostasis, particularly the dichotomous role of the colony-stimulating factor 1-colony-stimulating factor 1 receptor axis. RECENT FINDINGS: The impact of inflammation associated with aging and other hallmarks of aging, including senescence, on macrophage function is addressed in the context of osteoporosis and delayed fracture repair. Resident macrophages versus recruited macrophage contributions to fracture healing are also discussed. We identify some of the remaining knowledge gaps that will need to be closed in order to maximise benefits from therapeutically modulating or mimicking the function of macrophages to improve bone health and regeneration over a lifetime. PMID- 28647886 TI - Wnt Signaling in Ewing Sarcoma, Osteosarcoma, and Malignant Peripheral Nerve Sheath Tumors. AB - PURPOSE OF REVIEW: Wnt signaling plays a central role in development and homeostasis, and its dysregulation is a common event in many types of human cancer. Here we explore in detail the contributions of Wnt signaling to the initiation and maintenance of three types of saroma: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. This review provides an overview of the Wnt signaling pathway and explores in detail the current knowledge about its role in the initiation or maintenance of three tumor types: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. RECENT FINDINGS: Recent work has assessed the role(s) of Wnt signaling within these cell types. This review provides an overview of the mechanistic insights that have been gained from a number of recent studies to set the foundation for potential therapeutic applications. Wnt signaling has emerged as a potentially critical pathway in maintaining the growth of these types of tumors. Given the fact that many new inhibitors of the pathway have recently or will soon enter Phase 1 clinical trials, it is likely that assessment of their activity in these tumor types will occur in human patients. PMID- 28647887 TI - Connexins and Pannexins in Bone and Skeletal Muscle. AB - PURPOSE OF REVIEW: To discuss current knowledge on the role of connexins and pannexins in the musculoskeletal system. RECENT FINDINGS: Connexins and pannexins are crucial for the development and maintenance of both bone and skeletal muscle. In bone, the presence of connexin and more recently of pannexin channels in osteoblasts, osteoclasts, and osteocytes has been described and shown to be essential for normal skeletal development and bone adaptation. In skeletal muscles, connexins and pannexins play important roles during development and regeneration through coordinated regulation of metabolic functions via cell-to cell communication. Further, under pathological conditions, altered expression of these proteins can promote muscle atrophy and degeneration by stimulating inflammasome activity. In this review, we highlight the important roles of connexins and pannexins in the development, maintenance, and regeneration of musculoskeletal tissues, with emphasis on the mechanisms by which these molecules mediate chemical (e.g., ATP and prostaglandin E2) and physical (e.g., mechanical stimulation) stimuli that target the musculoskeletal system and their involvement in the pathophysiological changes in both genetic and acquired diseases. PMID- 28647888 TI - Osteoimmunology in Bone Fracture Healing. AB - PURPOSE OF REVIEW: In the process of bone fracture healing, inflammation is thought to be an essential process that precedes bone formation and remodeling. We review recent studies on bone fracture healing from an osteoimmunological point of view. RECENT FINDINGS: Based on previous observations that many types of immune cells infiltrate into the bone injury site and release a variety of molecules, recent studies have addressed the roles of specific immune cell subsets. Macrophages and interleukin (IL)-17-producing gammadelta T cells enhance bone healing, whereas CD8+ T cells impair bone repair. Additionally, IL-10 producing B cells may contribute to bone healing by suppressing excessive and/or prolonged inflammation. Although the involvement of other cells and molecules has been suggested, the precise underlying mechanisms remain elusive. Accumulating evidence has begun to reveal the deeper picture of bone fracture healing. Further studies are required for the development of novel therapeutic strategies for bone fracture. PMID- 28647889 TI - Viability of the World Health Organization quality of life measure to assess changes in quality of life following treatment for alcohol use disorder. AB - PURPOSE: Quality of life is an outcome often examined in treatment research contexts such as biomedical trials, but has been studied less often in alcohol use disorder (AUD) treatment. The importance of considering QoL in substance use treatment research has recently been voiced, and measures of QoL have been administered in large AUD treatment trials. Yet, the viability of popular QoL measures has never been evaluated in AUD treatment samples. Accordingly, the present manuscript describes a psychometric examination of and prospective changes in the World Health Organization Quality of Life measure (WHOQOL-BREF) in a large sample (N = 1383) of patients with AUD recruited for the COMBINE Study. METHODS: Specifically, we examined the construct validity (via confirmatory factor analyses), measurement invariance across time, internal consistency reliability, convergent validity, and effect sizes of post-treatment changes in the WHOQOL-BREF. RESULTS: Confirmatory factor analyses of the WHOQOL-BREF provided acceptable fit to the current data and this model was invariant across time. Internal consistency reliability was excellent (alpha > .9) for the full WHOQOL-BREF for each timepoint; the WHOQOL-BREF had good convergent validity, and medium effect size improvements were found in the full COMBINE sample across time. CONCLUSIONS: These findings suggest that the WHOQOL-BREF is an appropriate measure to use in samples with AUD, that the WHOQOL-BREF scores may be examined over time (e.g., from pre- to post-treatment), and the WHOQOL-BREF may be used to assess improvements in quality of life in AUD research. PMID- 28647890 TI - Comparison of lercanidipine plus hydrochlorothiazide vs. lercanidipine plus enalapril on micro and macrocirculation in patients with mild essential hypertension. AB - Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4 weeks with lercanidipine 20 mg per day orally. Then, they were treated for 6 months with lercanidipine + enalapril (n = 15) or lercanidipine + hydrochlorothiazide (n = 15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, while after treatment with lercanidipine + hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine + enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations. PMID- 28647891 TI - Is it reasonable to use a lower DOACs dose in some patients with VTE? Yes. AB - In the Hokusai-VTE trial, 733 patients were treated with the reduced dose edoxaban regimen, which maintained efficacy and safety compared with the 60 mg dose, and was safer than warfarin. The prophylactic doses of apixaban and rivaroxaban reduced the risk of recurrent venous thromboembolism (VTE) in the extended treatment trials. Dabigatran 110 mg was approved by the European Medicine Agency for VTE treatment. Further data from registries and real-world studies will help to clarify whether patients, with other specific characteristics, can benefit from the reduced dose of direct oral anticoagulants. PMID- 28647892 TI - Postprandial hypotension in neurological disorders: systematic review and meta analysis. AB - PURPOSE: Postprandial hypotension (PPH) has been associated with increased risk of syncope, falls, stroke, angina and mortality. As the majority of patients with PPH are asymptomatic, the diagnosis is often overlooked. The aim of this study was to perform a systematic review and meta-analysis of available scientific evidence on the likelihood of PPH in neurological diseases. METHODS: A systematic review of the literature (PubMed library, Cochrane Database for Systematic Reviews and Cochrane Central Register of Controlled Trials for results up to January 2017) identified 327 studies, of which 11 reported the frequency of PPH in patients with neurological diseases compared to healthy controls. These 11 studies were on patients with Parkinson's disease (PD; n = 6 studies), multiple system atrophy (MSA; n = 1), Alzheimer's disease (AD; n = 1) and diabetic neuropathy (DN; n = 2). RESULTS: The meta-analysis revealed that patients with neurological diseases had a significantly higher frequency of PPH than healthy controls [147/289 patients vs. 41/217 controls; odd ratio (OR) 5.23, 95% confidence interval (CI) 2.90-9.45, p < 0.00001]. For each of the four diseases, the respective patients had a significantly higher frequency of PPH than healthy controls (PD: 107/201 patients vs. 32/136 controls; OR 3.49, 95% CI 2.09-5.83, p < 0.0001; MSA: 19/27 patients vs. 0/24 controls; OR 89.55, 95% CI 2.65-3030.33, p = 0.01; AD: 7/10 patients vs. 6/23 controls; OR 6.61, 95% CI 1.28-34.14, p = 0.02; DN: 14/51 patients vs. 3/34 controls; OR 4.83, 95%CI 1.20-19.41, p = 0.03). CONCLUSION: The likelihood of having PPH is higher in patients with neurological diseases than in healthy controls. These findings should prompt further research focusing on the epidemiology and pathophysiology of PPH in different neurological diseases. PMID- 28647893 TI - The overdiagnosis of what? On the relationship between the concepts of overdiagnosis, disease, and diagnosis. AB - Overdiagnosis and disease are related concepts. Widened conceptions of disease increase overdiagnosis and vice versa. This is partly because there is a close and complex relationship between disease and overdiagnosis. In order to address the problems with overdiagnosis, we may benefit from a closer understanding this relationship. Accordingly, the objective of this article is to elucidate the relationship between disease and overdiagnosis. To do so, the article starts with scrutinizing how overdiagnosis can explain the expansion of the concept of disease. Then it investigates how definitions of disease address various challenges of overdiagnosis. The article specifically investigates recent attempts to clarify the relationship between the concepts of disease and overdiagnosis. Several shortcomings are identified and lead to a closer analysis of overdiagnosis in the diagnostic process. Contrary to recent contributions to the field, it is argued that cases of overdiagnosis are not cases of disease. They are non-verified labelling of disease. It is revealed how overdiagnosis establishes an unwarranted link between indicative phenomena, such as polyps or cell changes, and harm, and thereby generates a link to disease. One implication of this study is that we should stop attributing disease language to indicative phenomena. That is, we should stop calling it "cancer screening" when we are actually searching for polyps. Another implications is that we should strive for scientific progress in differentiating phenomena that are of negative value to us from those that are not. In overdiagnosis we diagnose something that is not disease: it is over-diagnosis. PMID- 28647894 TI - Keratin gene mutations influence the keratinocyte response to DNA damage and cytokine induced apoptosis. AB - The keratin filament cytoskeleton is vital to the normal function of epithelial cells. It provides structural support and regulates different aspects of cell metabolism. Mutations in keratins 5 and 14 cause a skin fragility disorder, epidermolysis bullosa simplex (EBS). Patients with severe EBS have an increased cumulative risk for basal cell carcinoma. In this study, we tested how keratin 5 and 14 mutant EBS patient-derived keratinocytes behave in the face of two different types of stressors that are able to induce cell death: ionizing radiation and cytokines TNF-alpha and TRAIL. The data point out to a substantial difference between how normal and keratin mutant keratinocytes deal with such stresses. When case of DNA damage, the ATM/Chk2-pathway is one of the two main tracks that can prevent the progression of mitosis and so allow repair. This was altered in all investigated keratin mutants with a particular down-regulation of the activated form of checkpoint kinase 2 (pChk2). Keratin mutants also appear less sensitive than normal cells to treatment with TNF-alpha or TRAIL, and this may be linked to the up-regulation of two pro-survival proteins, Bcl-2 and FLIP. Such changes are likely to have a profound effect on mutant keratinocytes ability to survive and withstand stress, and in theory this may be also a contributing factor to cell transformation. PMID- 28647895 TI - Systematic design for trait introgression projects. AB - KEY MESSAGE: Using an Operations Research approach, we demonstrate design of optimal trait introgression projects with respect to competing objectives. We demonstrate an innovative approach for designing Trait Introgression (TI) projects based on optimization principles from Operations Research. If the designs of TI projects are based on clear and measurable objectives, they can be translated into mathematical models with decision variables and constraints that can be translated into Pareto optimality plots associated with any arbitrary selection strategy. The Pareto plots can be used to make rational decisions concerning the trade-offs between maximizing the probability of success while minimizing costs and time. The systematic rigor associated with a cost, time and probability of success (CTP) framework is well suited to designing TI projects that require dynamic decision making. The CTP framework also revealed that previously identified 'best' strategies can be improved to be at least twice as effective without increasing time or expenses. PMID- 28647896 TI - Omics-based hybrid prediction in maize. AB - KEY MESSAGE: Complementing genomic data with other "omics" predictors can increase the probability of success for predicting the best hybrid combinations using complex agronomic traits. Accurate prediction of traits with complex genetic architecture is crucial for selecting superior candidates in animal and plant breeding and for guiding decisions in personalized medicine. Whole-genome prediction has revolutionized these areas but has inherent limitations in incorporating intricate epistatic interactions. Downstream "omics" data are expected to integrate interactions within and between different biological strata and provide the opportunity to improve trait prediction. Yet, predicting traits from parents to progeny has not been addressed by a combination of "omics" data. Here, we evaluate several "omics" predictors-genomic, transcriptomic and metabolic data-measured on parent lines at early developmental stages and demonstrate that the integration of transcriptomic with genomic data leads to higher success rates in the correct prediction of untested hybrid combinations in maize. Despite the high predictive ability of genomic data, transcriptomic data alone outperformed them and other predictors for the most complex heterotic trait, dry matter yield. An eQTL analysis revealed that transcriptomic data integrate genomic information from both, adjacent and distant sites relative to the expressed genes. Together, these findings suggest that downstream predictors capture physiological epistasis that is transmitted from parents to their hybrid offspring. We conclude that the use of downstream "omics" data in prediction can exploit important information beyond structural genomics for leveraging the efficiency of hybrid breeding. PMID- 28647897 TI - Varicocele and semen quality: a retrospective case-control study of 4230 patients from a single centre. AB - PURPOSE: The aim of the present study is to assess impairment of spermatogenesis induced by varicocele in, to our knowledge, the largest single-centre caseload available to date. MATERIALS AND METHODS: We conducted a retrospective study on 4230 consecutive patients attending our Department for andrological outpatient assessment and preconception check-ups between 2011 and 2014. A total of 2113 patients had varicocele (Group V), while the remaining 2117 were selected as the control group (Group C). All patients were divided into age classes (<17, 18-28, 29-39 and >=40 years), and Group V patients were classified as "low" (I-II) or "high" (III-IV) grade. RESULTS: Varicocele patients had a higher mean height than controls, as well as lower BMI. There was also a statistically significant reduction in the concentration/mL and the total sperm number in Group V against Group C. When stratified by age, values for all semen parameters were significantly worse in the older than in the younger age classes in both Group V and Group C, except for concentration/mL and total sperm number in the 29-39 and >=40 age classes in both groups. A multivariable logistic regression analysis showed that factors independently predicting the presence of varicocele were older age, higher BMI and smoking for more than 10 years. CONCLUSIONS: Varicocele patients show worse semen parameters compared to controls, although their values were still within WHO reference limits. Semen quality is further worsened by increased age, grade and chronic smoking. PMID- 28647898 TI - Respiratory diphtheria due to Corynebacterium ulcerans transmitted by a companion dog, Italy 2014. AB - A serious respiratory tract infection due to Corynebacterium ulcerans was observed in a 70-year-old woman. Clinical presentation included pseudomembranes in the upper respiratory tract and lung involvement. C. ulcerans was recovered from the nose of the patient's dog. Both dog's and patient's isolates belonged to Sequence Type 331. PMID- 28647899 TI - Value of contrast-enhanced MRI in the differentiation between nasopharyngeal lymphoid hyperplasia and T1 stage nasopharyngeal carcinoma. AB - OBJECTIVES: To investigate the value of contrast-enhanced MRI in differentiation between benign nasopharyngeal lymphoid hyperplasia (NPLH) and T1 stage nasopharyngeal carcinoma (NPC). METHODS: Eighty-six NPLH patients and 38 T1 stage NPC patients who underwent a contrast-enhanced MRI and an endoscopic biopsy were included. The patients' symptoms and MRI features of nasopharyngeal mucosal thickening like location, symmetry, nasopharyngeal bubble, superficial mucus, nasopharyngeal retention cysts, serrated protrusions, contrast-enhancement type were documented. Accompanying signs such as sinus mucosal thickening, middle ear effusion, and cervical lymph nodes enlargement were also recorded. These MRI features were compared by Chi-square tests. Logistic regression analysis was done to identify the most predictive MRI features of malignancy. RESULTS: NPLH patients had more symptoms of pharynx discomfort or pain, while T1 stage NPC patients had more symptom of neck mass (P < 0.05). The most common pattern of nasopharyngeal mucosal thickening in NPLH was diffuse wall thickening (38.37%), while unilateral posterolateral wall thickening (39.47%) was more in T1 stage NPC. Nasopharyngeal bubble, retention cysts, serrated protrusions, symmetry, homogeneous enhancement, slight enhancement and vertical stripes were more common in NPLH, while nasopharyngeal wall asymmetry, inhomogeneous enhancement, moderated or marked enhancement and cervical lymph nodes enlargement were more in T1 stage NPC (P < 0.05). Logistic regression analysis identified unilateral posterolateral wall thickening, nasopharyngeal wall asymmetry, inhomogeneous enhancement and cervical lymph nodes enlargement were the most predictive MRI features for malignancy. CONCLUSIONS: Careful analysis of contrast-enhanced MRI features of the nasopharynx and neck is helpful in differentiating benign NPLH from T1 stage NPC. PMID- 28647900 TI - Breast Cancer Risk Associated with Genotype Polymorphisms of the Aurora Kinase a Gene (AURKA): a Case-Control Study in a High Altitude Ecuadorian Mestizo Population. AB - Breast cancer (BC) is the leading cause of cancer related death among women in 2014. The AURKA gene that encodes the protein called Aurora kinase A plays an important role in the progression of the cell cycle, by controlling and promoting the entry into the phase of mitosis. The single nucleotide polymorphism AURKA T91A (rs2273535) (Phe21Ile) has been identified as functional alternator of this kinase, the Ile allele is associated with the occurrence of chromosome segregation errors and tumor progression. Therefore, it is essential to know how BC risk is associated with histopathological characteristics, immunohistochemical characteristics, and genotype polymorphism in a high altitude Ecuadorian mestizo population. In this retrospective case-control study 200 individuals were analyzed. DNA was extracted from 100 healthy and 100 affected women. Genotypes were determined by genomic sequencing. We found significant association between the AURKA T91A (rs2273535) (Phe21Ile) genotype and an increased risk of BC development: Phe/Ile (odds ratio [OR] = 2.6; 95% confidence interval [CI] = 1.4 4.9; P = 0.004), Ile/Ile (OR = 3.8; 95% CI = 1.6-9.0; P = 0.002), and Phe/Ile + Ile/Ile (OR = 2.9; 95% CI = 1.6-5.2; P = 0.001). Additionally, the rs2273535 variant was associated with the tumor grade SBR III (OR = 9.6; 95% CI = 1.0-91.9; P = 0.048) and the Ki-67 >= 20 (OR = 16.5; 95% CI = 2.7-101.3; P = 0.002). In brief, this study provides the first evidence where the Ile allele of the AURKA gene could act as potentially predictive biomarker of BC in the high altitude Ecuadorian mestizo population that lives at 2800 m above sea level (masl). PMID- 28647901 TI - In vivo visualization of the locus coeruleus in humans: quantifying the test retest reliability. AB - The locus coeruleus (LC) is a brainstem nucleus involved in important cognitive functions. Recent developments in neuroimaging methods and scanning protocols have made it possible to visualize the human LC in vivo by utilizing a T1 weighted turbo spin echo (TSE) scan. Despite its frequent use and its application as a biomarker for tracking the progress of monoaminergic-related neurodegenerative diseases, no study to date has investigated the reproducibility and inter-observer variability of LC identification using this TSE scan sequence. In this paper, we aim to quantify the test-retest reliability of LC imaging by assessing stability of the TSE contrast of the LC across two independent scan sessions and by quantifying the intra- and inter-rater reliability of the TSE scan. Additionally, we created a probabilistic LC atlas which can facilitate the spatial localization of the LC in standardized (MNI) space. Seventeen healthy volunteers participated in two scanning sessions with a mean intersession interval of 2.8 months. We found that for intra-rater reliability the mean Dice coefficient ranged between 0.65 and 0.74, and inter-rater reliability ranged between 0.54 and 0.64, showing moderate reproducibility. The mean LC contrast was 13.9% (SD 3.8) and showed scan-rescan stability (ROI approach: ICC = 0.63; maximum intensity approach: ICC = 0.53). We conclude that localization and segmentation of the LC in vivo are a challenging but reliable enterprise although clinical or longitudinal studies should be carried out carefully. PMID- 28647902 TI - Ultrasonography assessment of heel entheses in patients with spondyloarthritis: a comparative study with magnetic resonance imaging and conventional radiography. AB - The aim of the present study was to determine the agreement between ultrasonography (US), magnetic resonance imaging (MRI), and conventional radiography (CR) in the detection of findings indicative of enthesopathy in spondyloarthritis (SpA) patients. A cross-sectional study was performed in 40 SpA patients. Heel entheses (Achilles tendon and plantar fascia) were bilaterally examined by US, MRI, and CR. The three imaging modalities were carried out by three independent operators blinded to the other imaging modality data. Soft tissue abnormalities indicative of enthesopathy as thickening, structural changes, and bursitis were assessed by both US and MRI, and cortical bone abnormalities indicative of enthesopathy as erosions and enthesophytes were assessed by the three imaging modalities. The unweighted kappa values between US and MRI were 0.80, 0.66, 0.69, 0.70, and 0.70 for thickening, structural changes, bursitis, enthesophytes, and bone erosions, respectively. With respect to the detection of enthesophytes, the unweighted kappa values between CR and both US and MRI were 0.78 and 0.76, respectively. At last, for the recognition of bone erosions, the unweighted kappa values between CR and both US and MRI were 0.38 and 0.45, respectively. Using MRI as standard reference method, US was more sensitive with respect to CR revealing bone erosions. The present study provides evidence about the high overall agreement between US and MRI for all abnormal comparable findings at entheseal level and between US, MRI, and CR for the detection of enthesophytes in SpA patients. PMID- 28647903 TI - Farmers' attitude toward treated sludge use in the villages of West Bank, Palestine. AB - An application of treated sewage sludge on agricultural land has been widely accepted, as this method is simple and economical for disposal of wastewater residues. When applied properly on an agricultural land, sludge can replenish organic matter and nutrients in soil. Although sewage sludge has been used in agriculture in many parts of the world, its acceptability varies with different cultures and beliefs among farmers. Farmers' concerns on sludge use are primarily due to its anthropogenic origin, pollutants that it carries, a general perception of sewage being dirty, and its offensive odor. This paper aims to investigate farmers' perceptions on land application of treated sewage sludge on their farm. This study targeted two farming communities, namely, Anza and Beit Dajan villages, located in Jenin and Nablus districts in the West Bank, Palestine. In this study, a sample of 106 farmers were randomly selected and surveyed through a mixture of structured and open-ended questions. Results indicated that, overall, farmers have positive perceptions on land application of sludge. A majority of the farmers are in favor of the concept of sludge use when a planned wastewater treatment plant is constructed and it becomes operational. Results also indicate that a majority of the farmers are in favor of using sludge for fertilizing fruit trees, rather than growing vegetables and other plants in a greenhouse, and that many of them have knowledge of sludge properties and advantages and disadvantages of sludge use in agriculture. Despite the positive perceptions by the majority of farmers, a small fraction of the farmers are in disfavor of the use of sludge for the following reasons: psychological and social concerns, potential health risks, and their religious beliefs. Results further suggest that the land application of treated sewage sludge can be accepted by more farmers if the consumers are willing to buy agricultural products fertilized by sludge, sludge meets the public health requirements, and sludge is available at low costs. To improve farmers' perceptions on the land application of sludge, several measures are recommended. PMID- 28647904 TI - A cost-precision model for marine environmental monitoring, based on time integrated averages. AB - Ongoing marine monitoring programs are seldom designed to detect changes in the environment between different years, mainly due to the high number of samples required for a sufficient statistical precision. We here show that pooling over time (time integration) of seasonal measurements provides an efficient method of reducing variability, thereby improving the precision and power in detecting inter-annual differences. Such data from weekly environmental sensor profiles at 21 stations in the northern Bothnian Sea was used in a cost-precision spatio temporal allocation model. Time-integrated averages for six different variables over 6 months from a rather heterogeneous area showed low variability between stations (coefficient of variation, CV, range of 0.6-12.4%) compared to variability between stations in a single day (CV range 2.4-88.6%), or variability over time for a single station (CV range 0.4-110.7%). Reduced sampling frequency from weekly to approximately monthly sampling did not change the results markedly, whereas lower frequency differed more from results with weekly sampling. With monthly sampling, high precision and power of estimates could therefore be achieved with a low number of stations. With input of cost factors like ship time, labor, and analyses, the model can predict the cost for a given required precision in the time-integrated average of each variable by optimizing sampling allocation. A following power analysis can provide information on minimum sample size to detect differences between years with a required power. Alternatively, the model can predict the precision of annual means for the included variables when the program has a pre-defined budget. Use of time integrated results from sampling stations with different areal coverage and environmental heterogeneity can thus be an efficient strategy to detect environmental differences between single years, as well as a long-term temporal trend. Use of the presented allocation model will then help to minimize the cost and effort of a monitoring program. PMID- 28647905 TI - Time-dependent leaf proteome alterations of Brachypodium distachyon in response to drought stress. AB - KEY MESSAGE: For the first time, a comprehensive proteome analysis was conducted on Brachypodium leaves under drought stress. Gradual changes in response to drought stress were monitored. Drought is one of the major stress factors that dramatically affect the agricultural productivity worldwide. Improving the yield under drought is an urgent challenge in agriculture. Brachypodium distachyon is a model species for monocot plants such as wheat, barley and several potential biofuel grasses. In the current study, a comprehensive proteome analysis was conducted on Brachypodium leaves under different levels of drought application. To screen gradual changes upon drought, Brachypodium leaves subjected to drought for 4, 8 and 12 days were collected for each treatment day and relative water content of the leaves was measured for each time point. Cellular responses of Brachypodium were investigated through a proteomic approach involving two dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry (MS). Among 497 distinct spots in Brachypodium protein repertoire, a total of 13 differentially expressed proteins (DEPs) were identified as responsive to drought by mass spectrometry and classified according to their functions using bioinformatics tools. The biological functions of DEPs included roles in photosynthesis, protein folding, antioxidant mechanism and metabolic processes, which responded differentially at each time point of drought treatment. To examine further transcriptional expression of the genes that code identified protein, quantitative real time PCR (qRT-PCR) was performed. Identified proteins will contribute to the studies involving development of drought-resistant crop species and lead to the delineation of molecular mechanisms in drought response. PMID- 28647906 TI - Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. AB - Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function. PMID- 28647907 TI - A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. AB - Approximately 50% of individuals aged 6-49 years in the United States are infected with cytomegalovirus (CMV), with seroprevalence increasing with age, reaching 85-90% by 75-80 years according to Bate et al. (Clin Infect Dis 50 (11): 1439-1447, 2010) and Pawelec et al. (Curr Opin Immunol 24:507-511, 2012). Following primary infection, CMV establishes lifelong latency with periodic reactivation. Immunocompetent hosts experience largely asymptomatic infection, but CMV can cause serious illness in immunocompromised populations, such as transplant patients and the elderly. Control of CMV requires constant immune surveillance, and recent discoveries suggest this demand alters general features of the immune system in infected individuals. Here, we review recent advances in the understanding of the immune response to CMV and the role of CMV in immune aging and fitness, while highlighting the importance of potential confounding factors that influence CMV studies. Understanding how CMV contributes to shaping "baseline" immunity has important implications for a host's ability to mount effective responses to diverse infections and vaccination. PMID- 28647909 TI - Organic matter export to the seafloor in the Baltic Sea: Drivers of change and future projections. AB - The impact of environmental change and anthropogenic stressors on coastal marine systems will strongly depend on changes in the magnitude and composition of organic matter exported from the water column to the seafloor. Knowledge of vertical export in the Baltic Sea is synthesised to illustrate how organic matter deposition will respond to climate warming, climate-related changes in freshwater runoff, and ocean acidification. Pelagic heterotrophic processes are suggested to become more important in a future warmer climate, with negative feedbacks to organic matter deposition to the seafloor. This is an important step towards improved oxygen conditions in the near-bottom layer that will reduce the release of inorganic nutrients from the sediment and hence counteract further eutrophication. The evaluation of these processes in ecosystem models, validated by field observations, will significantly advance the understanding of the system's response to environmental change and will improve the use of such models in management of coastal areas. PMID- 28647910 TI - Perception of Spirituality and Spiritual Care among Muslim Nurses in Indonesia. AB - This cross-sectional study was conducted to examine 256 Muslim nurses' perception of spirituality and spiritual care in Indonesia. The Spirituality and Spiritual Care Rating Scale (SSCRS) was translated and culturally adapted. Moderately high degrees in five domains and total SSCRS were found. Specialty, education level, clinical seniority, having spiritual training, and previous spiritual caring experience could impact on the SSCRS. Most nurses have cared for patients with spiritual needs, but denied having any formal training in providing spiritual care. Providing adequate curriculum and on-job training to equip nurses' knowledge and competence of spiritual care is urgent in Muslim healthcare environment. PMID- 28647908 TI - CMV immune evasion and manipulation of the immune system with aging. AB - Human cytomegalovirus (HCMV) encodes numerous proteins and microRNAs that function to evade the immune response and allow the virus to replicate and disseminate in the face of a competent innate and acquired immune system. The establishment of a latent infection by CMV, which if completely quiescent at the level of viral gene expression would represent an ultimate in immune evasion strategies, is not sufficient for lifelong persistence and dissemination of the virus. CMV needs to reactivate and replicate in a lytic cycle of infection in order to disseminate further, which occurs in the face of a fully primed secondary immune response. Without reactivation, latency itself would be redundant for the virus. It is also becoming clear that latency is not a totally quiescent state, but is characterized by limited viral gene expression. Therefore, the virus also needs immune evasion strategies during latency. An effective immune response to CMV is required or viral replication will cause morbidity and ultimately mortality in the host. There is clearly a complex balance between virus immune evasion and host immune recognition over a lifetime. This poses the important question of whether long-term evasion or manipulation of the immune response driven by CMV is detrimental to health. In this meeting report, three groups used the murine model of CMV (MCMV) to examine if the contribution of the virus to immune senescence is set by the (i) initial viral inoculum, (ii) inflation of T cell responses, (iii) or the balance between functionally distinct effector CD4+ T cells. The work of other groups studying the CMV response in humans is discussed. Their work asks whether the ability to make immune responses to new antigens is compromised by (i) age and HCMV carriage, (ii) long-term exposure to HCMV giving rise to an overall immunosuppressive environment and increased levels of latent virus, or (iii) adapted virus mutants (used as potential vaccines) that have the capacity to elicit conventional and unconventional T cell responses. PMID- 28647911 TI - Religiosity and Healthy Lifestyle Behaviours in Malaysian Muslims: The Mediating Role of Subjective Well-Being and Self-Regulation. AB - Past research on healthy lifestyle behaviours has been primarily conducted within Western or Judeo-Christian contexts, while non-Western or Muslim contexts remain under-represented. This study examined predictors of healthy lifestyle behaviours (religiosity, goal-setting, impulse control, and subjective well-being) in Malaysian Muslims and explored the mechanisms underlying the relationship between religiosity and healthy lifestyle behaviours. Self-report survey responses from 183 healthy adults (M age = 28.63 years, 18-50 years) were analysed using regression and multiple mediation analyses. The results indicated that subjective well-being emerged as the strongest predictor, followed by goal-setting. Furthermore, subjective well-being and goal-setting mediated the religiosity healthy lifestyle behaviour relationship. The findings provide guidance for future health-promoting interventions. PMID- 28647913 TI - How Adaptation Makes Low Firing Rates Robust. AB - Low frequency firing is modeled by Type 1 neurons with a SNIC, but, because of the vertical slope of the square-root-like f-I curve, low f only occurs over a narrow range of I. When an adaptive current is added, however, the f-I curve is linearized, and low f occurs robustly over a large I range. Ermentrout (Neural Comput. 10(7):1721-1729, 1998) showed that this feature of adaptation paradoxically arises from the SNIC that is responsible for the vertical slope. We show, using a simplified Hindmarsh-Rose neuron with negative feedback acting directly on the adaptation current, that whereas a SNIC contributes to linearization, in practice linearization over a large interval may require strong adaptation strength. We also find that a type 2 neuron with threshold generated by a Hopf bifurcation can also show linearization if adaptation strength is strong. Thus, a SNIC is not necessary. More fundamental than a SNIC is stretching the steep region near threshold, which stems from sufficiently strong adaptation, though a SNIC contributes if present. In a more realistic conductance-based model, Morris-Lecar, with negative feedback acting on the adaptation conductance, an additional assumption that the driving force of the adaptation current is independent of I is needed. If this holds, strong adaptive conductance is both necessary and sufficient for linearization of f-I curves of type 2 f-I curves. PMID- 28647912 TI - Chemiluminescent immunoassay technology: what does it change in autoantibody detection? AB - Diagnostic technology is rapidly evolving, and over the last decade, substantial progress has been made even for the identification of antibodies, increasingly approaching this type of diagnostic to that of automated clinical chemistry laboratory. In this review, we describe the analytical and diagnostic characteristics of chemiluminescence technology in its strength and in its applicability for a more rapid and accurate diagnosis of autoimmune diseases. The wide dynamic range, greater than that of immunoenzymatic methods, the high sensitivity and specificity of the results expressed in quantitative form, the high degree of automation and the clinical implications related to the reduction in the turnaround time, and the ability to run a large number of antibody tests (even of different isotypes), directed towards large antigenic panels in random access mode, make this technology the most advanced in the clinical laboratory, with enormous repercussions on the workflow and on the autoimmunology laboratory organisation. Further improvements are expected in the coming years with the development of new analytical platforms such as the flow-injection chemiluminescent immunoassay, the two-dimensional resolution for chemiluminescence multiplex immunoassay and the magnetic nanoparticles chemiluminescence immunoassay, which will likely result in additional increases in the clinical efficacy of antibody tests. PMID- 28647914 TI - Shifting the Physical Inactivity Curve Worldwide by Closing the Gender Gap. AB - PURPOSE: The aims of this study were to (i) examine gender differences in physical inactivity in countries with different levels of Human Development Index (HDI); and (ii) assess whether small changes in the prevalence of inactivity in women could achieve the World Health Organization's (WHO) global inactivity target. METHODS: Data on inactivity were extracted for 142 countries for the year 2010 from the WHO Data Repository. Data for HDI were obtained for the year 2010 from the United Nations Development Program. Absolute and relative gender differences were calculated for countries according to four HDI categories. The potential effects of increasing women's activity levels on achievement of the WHO physical inactivity target were computed. RESULTS: Overall inactivity prevalence was higher in women (27%) than in men (20%). Women were more inactive than men in all except eight countries. Absolute gender differences [median 7.5% (range -10.1 to 33.2)] did not vary by HDI category, but there was a small negative correlation between relative gender difference in inactivity and HDI (rho -0.19; p = 0.02), which was mostly influenced by three outlier countries with low HDI. A decrease in inactivity levels of 4.8% points among women across the world would achieve the WHO target of reducing global levels of inactivity by 10%. CONCLUSION: Gender differences in the prevalence of physical inactivity were highly variable, both within and across categories of HDI. Interventions which result in small changes in inactivity prevalence in women would achieve the 2025 WHO global target for inactivity, without any change to the prevalence in men. PMID- 28647915 TI - Impact of the 21-gene recurrence score on outcome in patients with invasive lobular carcinoma of the breast. AB - PURPOSE: Invasive lobular carcinoma (ILC) of the breast has unique clinicopathologic characteristics, compared to invasive ductal carcinoma. The role of the 21-gene Recurrence Score (RS) has not been clearly defined for ILC. We sought to determine the prognostic value of RS and the impact of adjuvant chemotherapy on long-term survival in patients with ILC. METHODS: Utilizing the Surveillance, Epidemiology and End Results database from 2004 to 2013, we identified records of women aged 18-74 years, diagnosed with estrogen receptor (ER)-positive ILC (stage I to III) with RS available. We categorized patients into risk groups based on the traditional RS cutoffs and into those of the Trial Assigning Individualized Options for Treatment (TAILORx). Five-year breast cancer specific survival (BCSS) was analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Of the 7316 women included, 21% were in the low-risk; 71%, intermediate-risk; and 8%, high-risk groups as per TAILORx RS cutoffs. The 5-year BCSS was 99% in the low-risk, 99% in the intermediate-risk, and 96% in the high-risk groups. A high-risk RS as per TAILORx cutoff was independently associated with increased mortality (hazard ratio [HR] of death 2.37, 95% confidence interval [CI] 1.14-4.95) when compared to a low-risk RS. In both the high-risk and intermediate-risk groups, adjuvant chemotherapy was not significantly associated with the HR of death (high-risk, HR 1.14, 95% CI 0.55 2.38; intermediate-risk, HR 1.08, 95% CI 0.62-1.87). CONCLUSION: For patients with ER-positive ILC, 8% were in the high-risk and 72% were in the intermediate risk groups as per the TAILORx RS cutoffs. In the high-risk group, the RS predicted a lower 5-year BCSS. Adjuvant chemotherapy did not seem to confer a survival benefit for either the intermediate- or the high-risk cohorts. PMID- 28647916 TI - Impact of Site Selection and Study Conduct on Outcomes in Global Clinical Trials. AB - PURPOSE OF REVIEW: There are over 25 million patients living with heart failure globally. Overall, and especially post-discharge, clinical outcomes have remained poor in heart failure despite multiple trials, with both successes and failures over the last two decades. Matching therapies to the right patient population, identifying high-quality sites, and ensuring optimal trial design and execution represent important considerations in the development of novel therapeutics in this space. RECENT FINDINGS: While clinical trials have undergone rapid globalization, this has come with regional variation in comorbidities, clinical parameters, and even clinical outcomes and treatment effects across international sites. These issues have now highlighted knowledge gaps about the conduct of trials, selection of study sites, and an unmet need to develop and identify "ideal" sites. There is a need for all stakeholders, including academia, investigators, healthcare organizations, patient advocacy groups, industry sponsors, research organizations, and regulatory authorities, to work as a multidisciplinary group to address these problems and develop practical solutions to improve trial conduct, efficiency, and execution. We review these trial-level issues using examples from contemporary studies to inform and optimize the design of future global clinical trials in heart failure. PMID- 28647917 TI - Novel Endpoints for Heart Failure Clinical Trials. AB - PURPOSE OF REVIEW: With the growing prevalence of heart failure, there is a particular need to develop new pharmacologic treatments that can improve outcomes. While there are several approved therapies for heart failure with reduced ejection fraction, there is currently no approved agent for those with preserved ejection fraction. The current review aimed to explore the utility of alternate endpoints to mortality and hospitalization. RECENT FINDINGS: There is increased interest in the use of alternative endpoints such as functional status and quality of life for heart failure drug development to focus on patients feeling better in addition to improving outcomes. This should ideally be measured using objective as well as subjective parameters. While mortality and hospitalization remain important endpoints for clinical trials in heart failure, other more patient-centered outcomes are attractive alternatives yet how to best incorporate these in a trial setting remains to be elucidated. PMID- 28647918 TI - Designing Future Clinical Trials in Heart Failure With Preserved Ejection Fraction: Lessons From TOPCAT. AB - PURPOSE OF REVIEW: Spironolactone did not demonstrate benefit with respect to the primary composite endpoint in the global TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial in patients with chronic heart failure with preserved ejection fraction (HFpEF). We identify key lessons from the TOPCAT experience that can be applied to future HFpEF trials. RECENT FINDINGS: Subsequent analyses of TOPCAT have revealed marked regional heterogeneity in patient profiles, event rates, drug adherence, and treatment effects. Significant regional variation may impact the success of global HFpEF trials. Given potential benefits in the Americas subgroup in TOPCAT, mineralocorticoid receptor antagonists can be considered in appropriately selected patients with HFpEF to reduce risk of heart failure hospitalization. A planned registry-based trial should provide additional evidence regarding the role of spironolactone in HFpEF. The overall design, execution, and study oversight of TOPCAT have provided key insights into the conduct of future HFpEF trials. PMID- 28647919 TI - Role of SGLT2 Inhibitors in Patients with Diabetes Mellitus and Heart Failure. AB - PURPOSE OF REVIEW: This review aims to summarize the evidence on cardiovascular risks and benefits of glucose-lowering drugs in diabetic patients, with a particular focus on the role of sodium-glucose transporter-2 (SGLT-2) inhibitors and their promising potential as a heart failure treatment. RECENT FINDINGS: The SGLT-2 inhibitor empagliflozin has emerged as the first glucose-lowering drug to lower cardiovascular mortality in diabetes with an unprecedented 38% relative risk reduction. In addition, empagliflozin significantly reduced the rate of heart failure admissions with 35% when compared to placebo in diabetic patients with established atherosclerosis. SGLT-2 inhibitors should be considered as a first-line drug to achieve glycemic control in diabetic patients at high risk for cardiovascular diseases and heart failure in particular. As SGLT-2 inhibitors target different pathophysiological pathways in heart failure, they might even be considered in the broader population without diabetes, but this remains the topic of further study. PMID- 28647920 TI - Predictive Value of C-Reactive Protein for Complications Post-laparoscopic Roux En-Y Gastric Bypass-Author Reply. PMID- 28647921 TI - Proteome Profile of Aspergillus terreus Conidia at Germinating Stage: Identification of Probable Virulent Factors and Enzymes from Mycotoxin Pathways. AB - Aspergillus terreus is an emerging opportunistic fungal pathogen that causes invasive aspergillosis in immunocompromised individuals. The main risk group of individuals for this organism is leukopenic patients, individuals having cancers, bone marrow transplant persons and those who have immunological disorders. The lack of early diagnostic marker for A. terreus and intrinsic resistance to Amphotericin B, further limits the successful therapy of A. terreus-associated infections. The germination of inhaled conidia is the key step to establish successful invasion in host tissues or organs. Thus, profiling of expressed proteins during germination of conidia not only shed light on proteins that are involved in invasion or virulence but may also provide early diagnostic markers. We used nanoLC-Q-TOF to study the proteome of germinating conidia (at 16 h time points) of A. terreus. We observed expression of 373 proteins in germinating conidia of A. terreus. A total of 74 proteins were uncharacterized in the database. The expressed proteins were associated with various processes like cell wall modulation, virulence factors and secondary metabolite biosynthesis. The most abundant proteins were associated with protein biosynthesis, carbohydrate metabolism and unknown functions. Among virulent proteins, mitogen-activated protein kinase (hog1) and mitogen-activated protein kinase (mpkC) are key virulent proteins observed in our study. We observed 7 enzymes from terretonin and 10 enzymes from geodin mycotoxin biosynthesis pathway. Interestingly, we observed expression of terrelysin protein, associated with blood cell lysis. Quantitative RT-PCR analysis showed 26-fold increase in transcripts encoding for dihydrogeodin oxidase and 885-fold for terrelysin gene in germinating conidia in comparison to conidia. Further, we propose that terrelysin protein and secondary metabolite such as geodin could be explored as diagnostic marker for A. terreus associated infections. PMID- 28647922 TI - Comparison of quality of chest compressions during training of laypersons using Push Heart and Little Anne manikins using blinded CPRcards. AB - BACKGROUND: Mass Cardio-Pulmonary Resuscitation (CPR) training using less expensive and easily portable manikins is one way to increase the number of trained laypeople in a short time. The easy-to-carry, low-cost CPR training model called Push Heart (PH) is widely used in Japan. The aim of this study was to examine if PH can achieve chest compression quality that is similar to that using more conventional Little Anne (LA) manikins for training laypersons. METHODS: This prospective randomized crossover study was done during routine community CPR training of laypersons in Singapore. The participants were randomly allocated into two groups, using the PH and LA models respectively. They crossed over during the training so that both groups had measurements using both models. Chest compression data were collected using blinded CPRcards, which are credit card sized devices with accelerometers and data capture. Participants did not receive any CPR feedback during measurement. RESULTS: Forty-two people had data captured for the study with 15 males. The median compression depth was 41.5 mm on LA and 38.0 mm on PH (p = 0.0664), and median compression rate was 105 cpm on LA and 103 cpm on PH (p = 0.2429). Overall, only 1.5% of compressions performed on the PH achieved adequate depth of between 50-70 mm compared to 5.5% achieved on LA (p = 0.049). In contrast, 84% of all compressions performed on the PH were within the adequate rate of 100-120 cpm compared to 79.5% on LA (p = 0.457). Only the under 20-year-old group was able to achieve adequate median compression depth (50.5 mm) on LA, while the older age groups did not (p = 0.0024). The other age groups performed similar quality of chest compression regardless of the model used. 73.8% of participants preferred the LA for training. After the training, participants felt similarly well-prepared with either model with a median score of 8/10 on LA compared to 7/10 on PH (p = 0.0011). CONCLUSIONS: The PH can be an alternative mass CPR training model. Both models achieved satisfactory chest compression rates, but the majority of participants, especially the elderly, had difficulty achieving adequate depth. PMID- 28647923 TI - Foodborne Illness Outbreak Investigation in a High-Profile Sports Club. AB - A foodborne illness outbreak involving an elite sports team was investigated by a public health unit in Sydney, Australia. An epidemiological association was established between gastrointestinal illness and the consumption of food supplied by an external caterer, with a lamb meal most strongly associated with illness. Genetically identical Salmonella isolates were identified from clinical specimens, residual food items, and an environmental swab taken from the catering premises. The training schedule and other club operations were significantly affected by this outbreak. Increased susceptibility due to regular shared activities and the potential for significant impact upon performance indicates that sports clubs must ensure that food suppliers comply with the highest standards of hygiene. Collaboration with public health authorities assists in source identification and prevention of further transmission. PMID- 28647925 TI - Psychobehavioral Effects of Meditation. AB - Meditation is an increasingly popular psychobehavioral therapy. Various meditation techniques in use make it hard to objectively scrutinize the psychological benefits. Therefore, in this study we set out to examine the effects of two fundamentally different meditative techniques, Zazen, 'seated meditation', in which the body and mind are calmed, and Tai Chi, 'meditation in motion', based on energetic martial art performance. The aim was to compare the effects of both techniques on personality structure, emotional intelligence, mood, and coping with stress. The study was conducted in 48 healthy volunteers, aged 39-50, divided into those practicing Zazen, Tai Chi, and the non-meditating controls, each group consisting of 16 persons. The psychometric tools consisted of Coping Inventory for Stressful Situations (CISS), the University of Wales Institute of Science and Technology Mood Adjective Checklist (UMACL), Emotional Intelligence Inventory (INTE), and the NEO Five-Factor Inventory (NEO-FFI). We found that both Zazen and Tai Chi meditations significantly enhanced openness to experience, one of the personality dimensions of the Big Five Model. The enhanced openness was associated with improved strategies for coping with stress. The meditators had less avoidance-oriented approaches to perceived stress. They also had improved mood compared with non-meditating controls. The findings suggest that enhanced openness to experience could shape one's desire to hold onto the meditation regimen. We conclude that both, diametrically different types of meditation, are conducive to mental health by improving the general well-being, counteracting stress, and leading to a better vigor of spirit. Meditation may thus be considered a complimentary, albeit rather modestly acting, adjunct to psychotherapy. PMID- 28647924 TI - Comparative Expression Analysis of Rice and Arabidopsis Peroxiredoxin Genes Suggests Conserved or Diversified Roles Between the Two Species and Leads to the Identification of Tandemly Duplicated Rice Peroxiredoxin Genes Differentially Expressed in Seeds. AB - BACKGROUND: Peroxiredoxins (PRXs) have recently been identified as plant antioxidants. Completion of various genome sequencing projects has provided genome-wide information about PRX genes in major plant species. Two of these -- Oryza sativa (rice) and Arabidopsis -- each have 10 PRX members. Although significant progress has been made in understanding their biological roles in Arabidopsis, those functions in rice, a model crop plant, have not been well studied. RESULTS: We performed a comparative expression analysis of rice and Arabidopsis PRXs. Our phylogenetic analysis revealed that one subgroup contains three rice and three Arabidopsis Type-II PRXs that are expressed ubiquitously. This suggests that they are involved in housekeeping functions to process reactive oxygen species (ROS). Within the second subgroup, expression of Os1 CysPrxA (LOC_Os7g44430) and AtOs1-CysPrx is conserved in seeds while Os1-CysPrxB (LOC_Os7g44440) shows a root-preferential pattern of expression. We used transgenic plants expressing the GUS reporter gene under the control of the promoters of these two tandem duplicates to confirm their meta-expression patterns. Our GUS expression data from developing seeds and those that were germinating indicated that Os1-CysPrxB is involved in root development, as initiated from the embryo, while Os1-CysPrxA has roles in regulating endosperm development near the aleurone layer. For the third and fourth subgroups, the rice PRXs are more likely to show leaf/shoot-preferential expression, while those from Arabidopsis are significantly expressed in the flowers and seeds in addition to the leaf/shoot. To determine the biological meaning of those expression patterns that were dominantly identified in rice PRXs, we analyzed three rice genes showing leaf/shoot-preferential expression in a mutant of the light-responsive 1 deoxy-D-xylulose 5-phosphate reductoisomerase (dxr) gene and found that two of them were significantly down-regulated in the mutant. CONCLUSION: A global expression analysis of the PRX family in rice identified tandem duplicates, Os1 CysPrxA and Os1-CysPrxB, in the 1-CysPrx subgroup that are differentially expressed in developing seeds and germinating seeds. Analysis of the cis-acting regulatory elements (CREs) revealed unique CREs responsible for embryo and root or endosperm-preferential expression. In addition, the presence of leaf/shoot preferential PRXs in rice suggests that they are required in that crop because those plants must tolerate a higher light intensity in their normal growth environment when compared with that of Arabidopsis. Downregulation of two PRXs in the dxr mutant causing an albino phenotype, implying that those genes have roles in processing ROS produced during photosynthesis. Network analysis of four PRXs allowed us to model regulatory pathways that explain the underlying protein interaction network. This will be a useful hypothetical model for further study. PMID- 28647926 TI - Importance of GOLD Guidelines for Chronic Obstructive Pulmonary Disease. AB - In December 2011, a major revision of GOLD 2011 guidelines was published based on the evidence-based medicine. The goal of GOLD 2011 is to determine the severity of the disease, its impact on the patient's health, and the risk of future events; all of which eventually guide therapy. A combined COPD assessment according to GOLD 2011 considers the patient's level of symptoms, spirometry abnormalities, risk of exacerbation, and the presence of comorbidities. GOLD 2011 stratifies patients into four basic groups labeled A, B, C, and D. The aim of the present study was to assess the importance of updated GOLD guidelines for the diagnosis, treatment, and prevention of COPD. We found that the multicomponent 2011 guidelines offer a significant advantage over the previous mono-component COPD assessment according to GOLD 2006 in terms of disease control and therapy management, with patients enjoying better spirometry values and a higher arterial oxygen content considered the primary outcomes of interest. PMID- 28647927 TI - The Impact of Eid Al-Fitr on Serum Uric Acid and Arthritis among Patients with Gout. PMID- 28647928 TI - Pre-procedural Ultrasonography for Tracheostomy in Critically Ill Patients: A Prospective Study. AB - BACKGROUND: Percutaneous dilatational tracheostomy (PDT) has become a standard technique for critically ill patients who require long-term ventilation. The most common early post-operative complication is bleeding related to anatomical variation in vasculature. The procedure is performed at the patient's bedside unless this is deemed unsafe and then the accepted alternative is open tracheostomy in the operating room. OBJECTIVES: To evaluate the use of pre procedural ultrasound to aid in the decision of whether PDT in critical care patients should be performed at the patient's bedside or by open surgical tracheostomy. METHODS: Patients were jointly evaluated by a critical care physician and a head and neck surgeon. Based on this evaluation, the method of tracheostomy was determined. Subsequently, pre-procedural ultrasound examination of the anterior neck was performed. The final decision whether to perform PDT or open surgical tracheostomy was based on the ultrasound findings. Changes in management decisions following ultrasound were recorded. RESULTS: We included 36 patients in this prospective study. Following ultrasound examination, the management decision was changed in nine patients (25%). CONCLUSIONS: Pre procedural ultrasound for critically ill patients undergoing tracheostomy can influence management decisions regarding the performance of tracheostomy. PMID- 28647929 TI - Vitamin D Status among Israeli Medical Residents. AB - BACKGROUND: Israel is a country with a sunny climate; however, vitamin D deficiency and insufficiency are common findings in certain populations whose exposure to sunlight is limited. Medical residency is known for long indoor working hours, thus theoretically limiting the opportunities for sun exposure. OBJECTIVES: To evaluate whether the vitamin D status among residents in a single medical center in Tel Aviv is below the normal range. METHODS: Forty-six residents (28 females, 18 males, average age 33.9 +/- 2.8 years) in three residency programs (internal medicine, general surgery/obstetrics and gynecology, pediatrics) were recruited. Demographic data, personal lifestyle, physical activity details and sun exposure duration were obtained by a questionnaire. Serum levels for 25(OH)D were analyzed by a radioimmunoassay. RESULTS: The mean serum 25(OH)D concentration was 29.8 +/- 5.8 ng/ml. According to Institute of Medicine definitions, none of the residents were vitamin D deficient and only two residents (4%) were vitamin D insufficient (15 ng/ml each). The level of 25(OH)D was similar among the various medical specialties. The 25(OH)D levels correlated with the duration of sun exposure and the number of offspring (regression analysis: R2 = 9.2%, P < 0.04 and R2 = 8.9%, P < 0.04, respectively), but not with nutritional data, blood chemistry, or extent of physical activity. CONCLUSIONS: Most of the residents maintained normal or near normal 25(OH)D levels, indicating that the residency program itself did not pose a significant risk for vitamin D deficiency. PMID- 28647930 TI - Primary Percutaneous Coronary Intervention Versus In-hospital thrombolysis as Reperfusion Therapy in Early-Arriving Low-risk STEMI Patients. AB - BACKGROUND: Trials have shown superiority of primary percutaneous intervention (PPCI) over in-hospital thrombolysis in ST-elevation myocardial infarction (STEMI) patients treated within 6-12 hours from symptom onset. These studies also included high-risk patients not all of whom underwent a therapeutic intervention. OBJECTIVES: To compare the outcome of early-arriving stable STEMI patients treated by thrombolysis with or without coronary angiography to the outcome of PPCI-treated STEMI patients. METHODS: Based on six biannual Acute Coronary Syndrome Israeli Surveys comprising 5474 STEMI patients, we analyzed the outcome of 1464 hemodynamically stable STEMI patients treated within 3 hours of onset. Of these, 899 patients underwent PPCI, 383 received in-hospital thrombolysis followed by angiography (TFA), and 182 were treated by thrombolysis only. RESULTS: Median time intervals from symptom onset to admission were similar while door-to-reperfusion intervals were 63, 45 and 52.5 minutes for PPCI, TFA and thrombolysis only, respectively (P < 0.001). The 30-day composite endpoint of death, post-infarction angina and myocardial infarction occurred in 77 patients of the PPCI group (8.6%), 64 patients treated by TFA (16.7%), and 36 patients of the thrombolysis only group (19.8%, P < 0.001), with differences mostly due to post-infarction angina. One-year mortality rate was 27 (3%), 13 (3.4%) and 11 (6.1%) for PPCI, TFA and thrombolysis only, respectively (P = 0.12). CONCLUSIONS: PPCI was superior to thrombolysis in early-arriving stable STEMI patients with regard to 30-day composite endpoint driven by a decreased incidence of post infarction angina. No 1 year survival benefit for PPCI over thrombolysis was observed in early-arriving stable STEMI patients. PMID- 28647931 TI - Correct Evaluation of Gastric Wall Thickness May Support a Change in Staplers' Size When Performing Sleeve Gastrectomy. AB - BACKGROUND: Leakage from the staple line is the most serious complication encountered after sleeve gastrectomy, occurring in 2.4% of surgeries. The use of inappropriately sized staplers, because of variability in stomach wall thickness, is a major cause of leakage. OBJECTIVES: To measure stomach wall thickness across different stomach zones to identify variables correlating with thickness. METHODS: The study comprised 100 patients (52 females). Stomach wall thickness was measured immediately after surgery using a digital caliper at the antrum, body, and fundus. Results were correlated with body mass index (BMI), age, gender, and pre-surgical diagnosis of diabetes, hypertension, hyperlipidemia and fatty liver. RESULTS: Stomach thickness was found to be 5.1 +/- 0.6 mm at the antrum, 4.1 +/- 0.6 mm at the body, and 2. 6 +/- 0.5 mm at the fundus. No correlation was found between stomach wall thickness and BMI, gender, or co morbidities. CONCLUSIONS: Stomach wall thickness increases gradually from the fundus toward the antrum. Application of the correct staple height during sleeve gastrectomy is important and may, theoretically, prevent leaks. Staplers should be chosen according to the thickness of the tissue. PMID- 28647932 TI - Prospective Comparison between Remnant-Preserving Augmentation and Double-Bundle Reconstruction in Anterior Cruciate Ligament Tears. AB - BACKGROUND: The debate continues regarding the best way to manage partial anterior cruciate ligament (ACL) tears. OBJECTIVES: To prospectively compare the clinical outcomes of remnant-preserving augmentation (RPA) and double-bundle reconstruction (DBR) in patients with ACL tears. METHODS: In this prospective study, we included 13 cases of RPA and 30 cases of DBR with a follow-up period of 6 months, 12 months and 24 months. We clinically compared the preoperative and postoperative range of motion, Knee Society Score (KSS), Visual Analog Scale (VAS), Lysholm score, Tegner activity score, Short Form Health Survey (SF-36), thigh and calf circumference and anterior translation (Using the KT-1000 knee arthrometer). RESULTS: There were no significant differences in Lysholm score, Tegner score, VAS or KSS within the two groups at any time. The KT-1000 arthrometer results were higher in the RPA group at 6 months than in the DBR group; however, it did not reach statistical significance. CONCLUSIONS: We found no significant differences between the two specific groups leading us to believe that RPA may play a role in reconstruction when only a single bundle is injured. PMID- 28647933 TI - A New System of Documentation to Improve Dietitian-Physician Crosstalk. AB - BACKGROUND: Standardization of the dietetic care process allows for early identification of malnutrition and metabolic disorders, interdisciplinary collaboration among the medical team, and improved quality of patient care. Globally, dietitians are adopting a nutrition care model that integrates national regulations with professional scope of practice. Currently, Israel lacks a standardized dietetic care process and documentation terminology. OBJECTIVES: To assess the utilization of a novel sectoral documentation system for nutrition care in Israel. METHODS: Seventy dietitians working in 63 geriatric facilities completed an online training program presenting the proposed patient-sectoral model. Training was followed by submission of sample case studies from clinical practice or completion of a case simulation. Application of the proposed model was assessed by measuring the frequency participants implemented different sections of the model and responses to an approval questionnaire. RESULTS: Fifty four participants (77%) provided completed cases. Over 80% of participants reported each step of the proposed dietary care process with 100% reporting the "nutrition diagnosis". Fifty-one dietitians (72.8%) completed the approval survey with the section on nutrition diagnosis receiving a highly favorable response (95%), indicating that the new documentation system was beneficial. Over 80% of participants rated the model useful in clinical practice. CONCLUSIONS: A sectoral approach for documenting dietetic care may be the ideal model for dietitians working in specific patient populations with the potential for improving interdisciplinary collaboration in patient care. PMID- 28647934 TI - Colorectal and Endometrial Cancer Risk and Age at Diagnosis in BLMAsh Mutation Carriers. AB - BACKGROUND: Biallelic BLM gene mutation carriers are at an increased risk for cancer, including colorectal cancer (CRC). Whether heterozygous BLM gene mutations confer an increased cancer risk remains controversial. OBJECTIVES: To evaluate CRC and endometrial cancer risk in BLM heterozygous mutation carriers. METHODS: Jewish Ashkenazim at high risk for colon or endometrial cancer and endometrial cancer cases unselected for family history were genotyped for the BLMAsh predominant mutation. RESULTS: Overall, 243 high-risk individuals were included: 97 men CRC patients (55.12 +/- 12.3 years at diagnosis), 109 women with CRC (56.5 +/- 13.7 years), 32 women with endometrial cancer (58.25 +/- 13.4 years) and 5 women with both CRC and endometrial cancer. In addition, 120 unselected Ashkenazi women with endometrial cancer (64.2 +/- 11.58 years) were genotyped. The BLMAsh mutation was present in 4/243 (1.65%) high-risk patients; 2 CRC (0.97%) 2 endometrial cancer (5.4%), and 1/120 unselected endometrial cancer patients (0.84%). Notably, in high-risk cases, BLMAsh mutation carriers were diagnosed at a younger age (for CRC 47.5 +/- 7.8 years; P = 0.32 ; endometrial cancer 49.5 +/- 7.7 years; P = 0.36) compared with non-carriers. CONCLUSIONS: Ashkenazi high risk CRC/endometrial cancer, and women with endometrial cancer have a higher rate of BLMAsh heterozygous mutation compared with the general population. BLMAsh heterozygous mutation carriers are diagnosed with CRC and endometrial cancer at a younger age compared with non-carriers. These observations should be validated and the possible clinical implications assessed. PMID- 28647935 TI - Evaluation of Patients with Acute Chest Pain Using SPECT Myocardial Perfusion Imaging: Prognostic Implications of Mildly Abnormal Scans. AB - BACKGROUND: While patients presenting to emergency departments (ER) with chest pain are increasingly managed in chest pain units (CPU) that utilize accelerated diagnostic protocols for risk stratification, such as single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), data are lacking regarding the prognostic implications of mildly abnormal scans in this population. OBJECTIVES: To evaluate the prognostic implications of mildly abnormal SPECT MPI results in patients with acute chest pain. METHODS: Of the 3753 chest pain patients admitted to the CPU at the Leviev Heart Center, Sheba Medical Center 1593 were further evaluated by SPECT MPI. Scans were scored by extent and severity of stress-induced perfusion defects, with 1221 patients classified as normal, 82 with myocardial infarction without ischemia, 236 with mild ischemia, and 54 with more than mild ischemia. Mild ischemia patients were further classified to those who did and did not undergo coronary angiography within 7 days. RESULTS: Mild ischemia patients who underwent coronary angiography were more likely to be male (92% vs. 81%, P = 0.01) and to have left anterior descending ischemia (67% vs. 42%, P = 0.004). After 50 months, these patients returned less often to the ER with chest pain (53% vs. 87%, P < 0.001) and had a lower combined endpoint of acute coronary syndrome and death (8% vs. 16%, P < 0.001). CONCLUSIONS: Compared to patients with chronic stable angina, patients presenting with acute chest pain exhibiting mildly abnormal SPECT MPI findings should perhaps undergo a more aggressive diagnostic and therapeutic approach. PMID- 28647936 TI - 18F-FDG-PET/CT Pulmonary Infiltrates in Non-Hodgkin Lymphoma Patients Treated with Combined Immunochemotherapy: Incidence and Clinical Characteristics. AB - BACKGROUND: Pulmonary infiltrates (PIs) detected in patients with non-Hodgkin lymphoma (NHL) may present a diagnostic challenge due to their wide differential diagnosis, including infection, pulmonary lymphoma and immunochemotherapy associated pulmonary toxicity. OBJECTIVES: To characterize therapy-associated PIs by positron emission tomography/computed tomography (PET/CT) imaging. METHODS: We conducted a historical analysis of fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT) PIs in NHL patients treated with combined immunochemotherapy including rituximab. Incidence of PIs, radiological features, patients' characteristics, underlying NHL type, rituximab/chemotherapy dosing schedules, and symptoms were recorded. Therapy-associated PIs were defined as new or worsening PIs appearing after treatment onset, without evidence of active pulmonary lymphoma or infection. RESULTS: Among 80 patients who met the pre-specified criteria, therapy-associated PIs were identified in 17 (21%), 6 of whom had accompanying symptoms. Increased FDG uptake was observed in nine, and PI resolution in six. The incidence of PIs was higher in females and in patients with aggressive lymphoma, at advanced stages, and in those who had received treatment consisting of a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 14 days (R-CHOP-14). CONCLUSIONS: This characterization of therapy-associated PIs may support the clinician managing NHL patients. Further prospective studies are needed to establish the role of each therapeutic component and the natural history of this phenomenon. PMID- 28647937 TI - The Impact of Fasting on Rheumatic Diseases. PMID- 28647938 TI - The Dark Side of Beauty: About Breast Implants and Lymphoma. PMID- 28647940 TI - Non-surgical Treatment of Retroperitoneal Hemorrhage and Urinary Bladder Perforation. PMID- 28647939 TI - Non-Criteria or Seronegative Obstetric Antiphospholipid Syndrome? AB - BACKGROUND: Obstetric antiphospholipid syndrome (Obs-APS) is one of the most commonly identified causes of recurrent pregnancy loss and its accurate diagnosis is a requirement for optimal treatment. Some patients do not fulfill the revised Sapporo classification criteria, the original APS classification criteria, and are considered to be non-criteria Obs-APS. In these patients with non-criteria, there is controversy about their inclusion within the spectrum of APS and eventually their treatment as having Obs-APS. A subset of patients may also have clinical characteristics of Obs-APS even though lupus anticoagulant (LA), anticardiolipin antibodies, and anti-beta2-glycoprotein I (abeta2GPI) antibodies are consistently negative. These patients are recognized as seronegative Obs-APS. We reviewed evidence of non-criteria Obs-APS and discuss a case of a woman with a diagnosis of active systemic lupus erythematosus (SLE) and non-criteria Obs-APS with four consecutive pregnancy losses. After an accurate diagnosis the patient received prenatal counseling and benefited from the optimal treatment of Obs-APS that led to a successful pregnancy. The applicability of this successful experience about outcomes in women with non-criteria, or seronegative, Obs-APS is also evaluated. PMID- 28647941 TI - Anaplastic Large T-Cell Lymphoma Associated with Breast Implants - Rare Disease. PMID- 28647942 TI - Lungs in White Induced by Docetaxel. AB - BACKGROUND: Taxanes are often used in the treatment of many types of cancers. Side effects of docetaxel are not as well documented as paclitaxel, but both can cause pulmonary injury. We present a dramatic case of a patient being treated for prostatic adenocarcinoma with docetaxel who presented with interstitial pneumonitis and responded dramatically to the early treatment with corticosteroids. This case is important as it reveals the side effects of docetaxel administration without administration of other chemotherapeutic agents, and it illustrates the importance of early diagnosis and treatment of docetaxel induced interstitial pneumonitis. Further research into the mechanism of the side effects of docetaxel is warranted. PMID- 28647943 TI - Meeting Report: The 2015-USFQ Biennial Meeting on Growth Hormone Research. PMID- 28647944 TI - Management of Type 1 Diabetes in Children in the First 5 Years of Life. AB - A significant increase in children <6 years of age being diagnosed with type 1 diabetes (T1D) is occurring. The parents (caregivers) of these children have full responsibility for the complex and individualized management while having to deal with the emotional stress of caring for a child with a chronic condition. This article will provide a summary of the diagnosis and recommended medical treatment for this special age group of children. Also presented will be common day-to-day family management issues for health care providers to consider as they provide care for this most common endocrine chronic condition. PMID- 28647945 TI - The Emerging Adult with Diabetes: Transitioning from Pediatric to Adult Care. AB - Transfer from pediatric to adult health care is a significant life event for youth with chronic medical conditions. Unfortunately, youth may not be well prepared to navigate the shift in health care services, increasing their risk for loss to follow up and poor health outcomes. This review explores transition in care through the lens of type 1 diabetes, highlighting current practices and guidelines and offering recommendations for future consideration. Limited evidence suggests that transition programs that focus on strategies to prepare youth developmentally and equip the health care system appropriately have positive impact on the hand off of care, and health outcomes. Advanced practice nurses are well positioned to play a key role in helping youth with chronic conditions with the transition process. PMID- 28647946 TI - Current Strategies in Nutrition Education to Optimize Glycemic Management for Children with Diabetes. AB - Recent developments in the understanding of the impact of dietary quality and meal composition are driving changes in the education provided to children and young people about nutrition and lifestyle management of Type 1 Diabetes (T1D). Nutrition education is moving beyond carbohydrate counting and insulin adjustment to acknowledging the influence of whole food choices on glycemic outcomes. PMID- 28647947 TI - Continuous Glucose Monitoring in Pediatrics: The Gap between Potential Benefits and the Reality of Utility. AB - Continuous Glucose Monitoring (CGM) is rapidly becoming a standard of care in the management of Type 1 diabetes (T1D). Today's devices are nearly as accurate as home glucose meters. They provide glucose data every 5 minutes, alert to high and low blood glucose levels, and allow for remote monitoring of a user's glucose data and patterns. Use of CGM has many benefits including support for tighter glycemic control without increasing the risk for hypoglycemia. There is however emerging evidence of some negative aspects associated with using CGM, which may result in decreased utilization of the device as well as a decline in quality of life, especially in the pediatric population. This article explores some of the challenges to successful CGM use and offers guidelines for helping patients/families minimize the negative impact of these revolutionary devices. PMID- 28647948 TI - Gender Creative or Transgender Youth and Advanced Nursing Practice. AB - The World Professional Association for Transgender Health (WPATH) defines gender dysphoria as "Discomfort or distress that is caused by a discrepancy between a person's gender identity and that person's sex assigned at birth (and the associated gender role and/or primary and secondary sex characteristics)" (WPATH, 2016). Gender creative (GC) and transgender (TG) youth are at high risk for severe mental health disparities if they don't receive competent and timely gender transitioning care. Although awareness and early care of TG youth in specialty clinics is improving and increasing, there is still much effort that is required to eliminate barriers to care at many levels and thus improve outcomes. Nurses, particularly advanced practice nurses, are poised to lead the way in creating safe, inclusive, family centered spaces for TG and GC children, youth and their families as well as acting as vital mentors for other nurses. The purpose of this paper is to discuss the increasing prevalence of GC and TG youth, the significance of inclusive care for GC and TG youth, treatment guidelines, and the impact parents and advanced practice nurses can have on the journey of these youth as they explore and find their place on the gender spectrum. PMID- 28647949 TI - The Key to Adrenal Insufficiency Education: Repetition, Repetition, Repetition. AB - Described more than 150 years ago by Thomas Addison, adrenal gland dysfunction, while treatable, remains a clinically significant and potentially fatal disease. Vague and non-specific symptomatology can delay diagnosis of adrenal insufficiency and lead to adrenal crisis. Affected individuals may delay self management due to knowledge deficits or lack of required therapies. Advanced practice nurses must remain vigilant for signs and symptoms of adrenal insufficiency and prevention of crisis. Education of patients and their caregivers/family members must emphasize early intervention with regards to adrenal insufficiency in order to prevent adrenal crisis. Repetition of education about sick day rules and demonstration of intramuscular injections should be incorporated as part of the routine follow-up care of all individuals to enhance their confidence and self-efficacy in self-management of adrenal insufficiency. PMID- 28647950 TI - Turner Syndrome: Care of the Patient: Birth to Late Adolescence. AB - Turner syndrome (TS) is a genetic condition occurring in females resulting from the loss of part or all of one of the X chromosomes. The two hallmark features of Turner syndrome include short stature and primary ovarian insufficiency. In addition, Turner syndrome can involve multiple healthcare issues including cardiac and renal anomalies, autoimmune disorders, hearing loss, ophthalmologic issues, bone anomalies, dermatologic issues and psychosocial and educational concerns. The presenting signs of Turner syndrome can vary markedly, leading to delayed or even missed diagnosis. Early identification of TS allows for appropriate screening and surveillance evaluations and more timely treatment intervention. This article will provide an overview of the healthcare issues common to patients with TS, treatments available and the screening and surveillance testing that is recommended. PMID- 28647951 TI - Complexities of Care in Klinefelter Syndrome: An APRN Perspective. AB - 47,XXY (Klinefelter Syndrome) is associated with a spectrum of complex clinical needs that are associated with variable physical, neurocognitive and psychosocial aspects. For patients and families affected by this sex chromosome trisomy, navigation of health care services is difficult due to lack of 47,XXY awareness among many health care providers and little evidence to support endocrine and additional treatment plans. While endocrine management of androgen deficiency has been the mainstay of treatment for patients from puberty through adulthood, testosterone replacement, alone, fails to mitigate many symptoms and issues. Prior to the onset of puberty, boys with 47,XXY often do not receive interdisciplinary evaluations and treatment. Since multiple health and ancillary therapeutic services are required for the management of 47,XXY, patients and families often experience disjointed and uncoordinated care. We discuss complexities of caring for patients with 47,XXY and the benefit of integrating advanced practice nursing and medical perspectives to improve care delivery. PMID- 28647952 TI - Children with Short Stature and Growth Failure: Heightism, Gender and Racial Disparities. AB - Growth is the single most important indication of the health of a child. Identification of growth disorders in all children is crucial as growth failure can be the first sign of a number of acute and chronic conditions. However, gender and racial biases have resulted in inequities in the identification, referral and treatment of children with growth disorders. In addition, short children have been impacted by a number of psychosocial issues. Heightism is prejudice or discrimination against individuals based on height, and refers to discrimination against individuals whose height is not within the normal acceptable range. Studies have shown that short children have been affected by juvenilization, teasing, bullying, victimization, loss of independence/ overprotection, and exclusion. The role of the advanced practice nurse is critical in addressing heightism and racial and gender disparities in children with growth failure/short stature. PMID- 28647953 TI - Depressive Symptoms and Quality of Life in the Patients of Inflammatory Bowel Disease. PMID- 28647954 TI - Does Single Balloon Enteroscopy Have Similar Efficacy and Endoscopic Performance Compared with Double Balloon Enteroscopy? PMID- 28647955 TI - Which Is Crucial, Strengthen the Foundation or Building the Dream House? PMID- 28647956 TI - [Problem demanding prompt solution for standardized evaluation in prolapsed surgery]. PMID- 28647957 TI - [Long-term effectiveness of transvaginal high uterosacral ligament suspension]. AB - Objective: To assess the long-term effectiveness of the transvaginal high uterosacral ligament suspension (HUS) in women suffering from advanced pelvic organ prolapse (POP). Methods: A retrospective review of records identified 118 women who underwent transvaginal HUS with or without additional concomitant anterior and (or) posterior repairs from June 2003 to August 2009 in the First Affiliated Hospital, General Hospital of People's Liberation Army. Of 118 women, 104 women completed the follow-up during study period; these 104 women were analysed. Follow-up visits were performed 2, 6 and 12 months after surgery and then annually. Anatomic results of POP was established by pelvic examination using pelvic organ prolapse quantitation system (POP-Q) staging. Funtional results were obtained by patient global impression of improvement (PGI-I), pelvic floor distress inventory-short form 20 (PFDI-20) and pelvic floor impact questionnaire short form (PFIQ-7). Surgical success required the fulfillment of all 3 criteria: (1) prolapse leading edge of 0 cm or less and apex of 1/2 total vaginal length or less; (2) the absence of pelvic organ prolapse symptoms as reported on the PFDI-20 question No. 3 ( "Do you usually have a bulge or something falling out that you can see or feel in your vaginal area?" ); and (3) no prolapse reoperations or pessary use during the study period. Results: The mean follow-up time was (9.1+/-1.5) years. The overall surgery success rate was 91.3% (95/104) according to above all 3 criteria. Prolapse recurrence rates were isolated anterior 6.7% (7/104), isolated apical 0, isolated posterior 2.9% (3/104) and multiple compartments 1.0% (1/104). Five women (4.8%, 5/104) developed bothersome vaginal bulge symptoms. None of recurrent women underwent retreatment, including either surgery or use of a pessary at last follow-up. The subjective satisfaction rate was 90.4% (94/104). PFDI-20 and PFIQ-7 scores showed a statistically significant improvement from preoperative 72 and 65 points to postoperative 17 and 9 points respectively (all P<0.01). There was a 2.9% (3/104) rate of intraoperative ureteral kinking and 3.8% (4/104) rate of postoperative morbidity. Conclusions: The transvaginal HUS for vault prolapse offers good long term anatomical results with excellent vault suspension. With additional concomitant anterior and (or) posterior repairs, it will be a reconstructive surgery for the majority of advanced POP. It is minimal traumatic and appropriate for different type of POP, especially for the eldly patients. It is worthy of being popularized for clinical application. PMID- 28647958 TI - [Prospective cohort study on the outcomes of sacrospinous ligament fixation using conventional instruments in treating stage III-IV pelvic organ prolapse]. AB - Objective: To evaluate the medium and long term safety and efficacy of sacrospinous ligament fixation (SSLF) performed with conventional instruments in treating stage III-IV pelvic organ prolapse (POP). Methods: A prospective cohort analysis was conducted in the Peking Union Medical College Hospital, between May 2007 and June 2015, enrolling 55 women with stage III-IV POP who intended to receive SSLF. Primary end points were objective success rates using pelvic organ prolapse quantitation system (POP-Q) and subjective satisfaction rates with questionnaires after surgery according to vaginal examination and related questionnaires for all patients who received SSLF eventually. Exploratory outcomes included perioperative parameters and complications. Results: Of these 55 POP patients enrolled, 52 (95%, 52/55) received SSLF using conventional surgical instruments, the other 3 cases converted to ischial spinous fascia fixation due to difficulty exposing. Medium blood loss during operation was 100 ml (20-300 ml) and operative time 60 minutes (20-165 minutes). Pelvic hematoma with diameters of 5 cm and 7 cm were observed in two patients, both recovered fully with conservative methods. All patients were able to micturate spontaneously after catheter withdrawal. One patient reported right thigh pain after operation which remained till 3-month follow-up and relieved after physiotherapy. The objective success rate was 100% (52/52) at 3 months. With a medium follow-up time of 23.7 months, the objective success rate was 98% (51/52), the recurrence rate was 2% (1/52) and the satisfactory rate was 94% (49/52). De novo urinary incontinence occurred in 6% (3/52) of patients. Conclusion: Most POP could be corrected with SSLF using conventional instruments which is a feasible, economic and effective procedure for Asian patients with medium compartment prolapse. PMID- 28647960 TI - [Quality analysis of observational studies on pelvic organ prolapse in China]. AB - Objective: To evaluate the quality of observational studies on pelvic organ prolapse in China. Methods: The checklist of strengthening the reporting of observational studies in epidemiology (STROBE) statement was applied to evaluate the observational studies. The articles were searched in the SinoMed database using the terms: prolapse, uterine prolapse, cystocele, rectal prolapse and pelvic floor; limited to Chinese core journals in obstetrics and gynecology from January 1996 to December 2015. With two 10-year groups (1996-2005 and 2006-2015), the chi(2) test was used to evaluate inter-group differences. Results: (1) A total of 386 observational studies were selected, including 15.5%(60/386) of case control studies, 80.6%(311/386) of cohort studies and 3.9% (15/386) of cross sectional studies. (2) There were totally 22 items including 34 sub-items in the checklist. There were 17 sub-items (50.0%, 17/34) had a reporting ratio less than 50% in all of aticles, including: 1a (study's design) 3.9% (15/386), 6a (participants) 24.6% (95/386), 6b (matched studies) 0 (0/386), 9 (bias) 8.3% (32/386), 10 (study size) 3.9%, 11 (quantitative variables) 41.2% (159/386), 12b 12e (statistical methods in detail) 0-2.6% (10/386), 13a (numbers of individuals at each stage of study) 18.9% (73/386), 13b (reasons for non-participation at each stage) 18.9%, 13c (flow diagram) 0, 16b and 16c (results of category boundaries and relative risk) 9.6% (37/386) and 0, 19 (limitations) 31.6% (122/386), 22 (funding) 20.5% (79/386). (3) The quality of articles published in the two decades (1996-2005 and 2006-2015) were compared, and 38.2%(13/34) of sub items had been significantly improved in the second 10-year (all P<0.05). The improved items were as follows: 1b (integrity of abstract), 2 (background/rationale), 6a (participants), 7 (variables), 8 (data sources/measurement), 9 (bias), 11 (quantitative variables), 12a (statistical methods), 17 (other analyses), 18 (key results), 19 (limitations), 21 (generalisability), 22 (funding). Conclusions: The quality of observational studies on POP in China is suboptimal in half of evaluation items. However, the quality of articles published in the second 10-year have significantly improved. PMID- 28647959 TI - [Re-treatments of recurrence after pelvic floor repair surgery]. AB - Objective: To analyze re-treatments of recurrence after the pelvic floor repair surgery. Methods: The protocol and the effect of re-treatments were investigated by reviewing and analyzing the clinical data of 81 recurrent patients (grade II and above), who had received the pelvic floor repair surgery from January 2011 to January 2016. Pelvic organ prolapse quantitation system (POP-Q) and two questionnaires about quality of life [pelvic floor distress inventory-short form 20 (PFDI-20) and pelvic floor impact questionnaire short form (PFIQ-7)] were used to evaluate objective and subjective efficacy, respectively. Results: Among 81 recurrent patients who were followed up for a median of 35 months (10- 69 months), 78 cases (with prolapse up to grade III or IV) were treated by surgical operation with both objective cure rate and subjective satisfaction being 100% (78/78); 3 cases (with grade II prolapse) were treated by pelvic floor electrical stimulation biofeedback, and 1 case among the three cases had the vaginal foreign body sensation, the subjective satisfaction was 2/3. The methods of surgical operation for the 78 recurrent patients included: total pelvic floor reconstructive surgery (55 cases; 3 of which involve trachelectomy), anterior pelvic reconstructive surgery (2 cases), posterior pelvic reconstructive surgery (3 cases), Y-mesh sacral colpopexy (2 cases), colpocleisis (11 cases), vaginal hysterectomy combined posterior fornix forming (3 cases), and vaginal hysterectomy combined posterior pelvic reconstructive surgery(2 cases). Conclusion: The extent of recurrence, the recurrent site and complications must be carefully considered and evaluated for re-treatments of recurrence after pelvic floor repair surgery, and then an appropriately individualized re treatment protocol could be designed for each of the patients. PMID- 28647961 TI - [Analysis of maternal deaths in Shanghai from 1996 to 2015]. AB - Objective: To analyze the trend of maternal mortality ratio (MMR) and cause of death in Shanghai from 1996 to 2015. Methods: To collect the material about the maternal death and the maternal death audit from 1996 to 2015, and to analyze the MMR, the cause of death and the result of the maternal death audit of Shanghai from 1996 to 2015 retrospectively. Results: (1) The change of MMR: the MMR in Shanghai decreased from 28.84 per 100 000 live births in 1996 to 6.66 per 100 000 live births in 2015. (2) The characteristic of maternal death: the proportion of Shanghai citizens was 27.4%(121/441) and the proportion of migrant women was 72.6%(320/441). The women with advanced maternal age was 8.2% (20/243) since 1996 to 2005, and increased to 16.7% (33/198) since 2006 to 2015. Maternal deaths during pregnancy increased from 27.6%(67/243) in the first 10 years (1996-2005) to 35.4%(70/198) in the recent 10 years (2006-2015) . The intrapartum maternal deaths was 6.2%(15/243) in the first 10 years and in the recent 10 years it was zero. The proportion of postpartum deaths in the first 10 years and in the recent 10 years were 66.3% (161/243) and 64.6%(128/198) respectively. (3) The cause of maternal death: During the recent 10 years, indirect obstetric causes [63.1%(125/198)] was more than direct obstetric causes [36.9% (73/198) ] for the first time. The death causes changed significantly. Postpartum hemorrhage remained the leading cause of maternal deaths, but the specific mortality rate (SMR) of postpartum hemorrhage decreased significantly from 7.42 per 100 000 live births in the first 10 years to 1.51 per 100 000 live births in the recent 10 years. The maternal deaths because of heart disease and cerebrovascular disease rose to the second and the forth reasons. (4) Maternal death audit: the avoidable maternal death ratio decreased from 3.66 per 100 000 live births in the first 10 years to 1.86 per 100 000 live births in the recent 10 years. Conclusions: During the past 20 years, the MMR of Shanghai decreased significantly and was close to the level of developed countries. In recent years, the causes of maternal death become more complicated. With the implementation of the second child policy, women with high risk factors increase, so government investment, policy support should be strengthened to optimize the management. PMID- 28647962 TI - [Effect of endoplasmic reticulum stress in trophocytes on the pathogenesis of intrahepatic cholestasis of pregnancy]. AB - Objective: To evaluate the effect of endoplasmic reticulum stress in trophocytes, in patients with intrahepatic cholestasis of pregnancy (ICP). Methods: Sixty-one pregnant women who were hospitalized in Women's Hospital, School of Medicine, Zhejiang University from January to December 2015 were recruited. Thirty-one women who were diagnosed as ICP were defined as the ICP group and 30 healthy pregnant women were defined as the control group. The localization and expression intensity of glucose regulated protein 78 (GRP-78) in placental tissues were detected by immunohistochemistry technique. Electronic microscope was used to observe ultra-microstructure change of the endoplasmic reticulum in trophocytes and cell line Swan71. Reverse transcription (RT)-PCR and western blot were used to investigate the expression of GRP-78 mRNA and protein in Swan 71 cell. Results: (1) GRP-78 protein was mainly expressed in the cytoplasm of cytotrophoblasts and syncytiotrophoblasts. The protein expression of GRP-78 in placentas of the ICP group (13.2+/-2.4) was significantly higher than that in the control group (7.8+/-1.3, P<0.01). (2) The volume of endoplasmie reticulum did not increase and the microvilli developed well, with no swelling and no expansion of endoplasmic reticulum in the control group.In the ICP group, microvilli injury, endoplasmic reticulum edema were found; the volume of endoplasmic reticulum increased, with dilation, vacuolation and significant degranulation. After treated with 100 MUmol/L cholyglycine for 24 hours, universal dilatation of the endoplasmic reticulum were seen in the Swan71 cells. (3) In Swan71 cells, cholylglycine displayed a concentration-dependent up-regulation on the expression of GRP-78. The expressions of GRP-78 mRNA in 0, 25, 50, 100 MUmol/L cholylglycine experimental group were 1.01+/-0.17, 2.17+/-0.16, 5.47+/-0.36, 5.65+/-0.82, respectively. The expression of GRP-78 protein in 0, 25, 50, 100 MUmol/L cholylglycine experimental group were 1.01+/-0.04, 1.17+/-0.15, 1.33+/-0.13, 1.73+/-0.13, respectively. The expression of GRP-78 mRNA and protein in 100 and 50 MUmol/L cholylglycine experimental group were significantly higher than 0 MUmol/L (all P<0.01). Conclusion: The obvious expansion of endoplasmic reticulum and the increased expression of GRP-78 in trophocytes indicated that endoplasmic reticulum stress of trophocytes may be involved in the pathogenesis of ICP. PMID- 28647963 TI - [Effects of prophylactic chemotherapy on outcomes and prognosis of patients older than 40 years with invasive mole]. AB - Objective: To discuss the effects of prophylactic chemotherapy on the outcomes and prognosis of invasive mole patients. Methods: One hundred and fifteen invasive mole (IM) patients older than 40 years were registered in Peking Union Medical Collage Hospital.Eleven of them were treated with prophylactic chemotherapy before diagnosed as IM prophylactic chemotherapy group, while the other 104 cases received therapeutic chemotherapy after diagnosed as IM (non prophylactic chemotherapy group). The general clinical data (including age, clinical stage, risk factor score), treatment, outcomes and relapse of patients were retrospectively compared between two groups. Results: (1) The age of prophylactic chemotherapy group and non-prophylactic chemotherapy group were (47+/-5) versus (46+/-4) years old. Ratio of clinical stageI-II were 3/11 versus 29.8% (31/104), clinical stage III-IV were 8/11 versus 70.2% (73/104). Ratio of risk factor score 0-6 were 11/11 versus 84.6% (88/104), risk factor score >6 were 0 versus 15.4% (16/104). There were no significant statistical differences between two groups in age, clinical stage or risk factor score (all P>0.05). (2) Treatment: the total chemotherapy courses between prophylactic chemotherapy group and non-prophylactic chemotherapy group (median 7 versus 5) were significantly different (Z=3.071,P=0.002). There were no significant statistical differences between two groups in the chemotherapy courses until negative conversion of beta hCG, consolidation chemotherapy courses, total therapeutic chemotherapy courses or ratio of hysterectomy (all P>0.05). (3) Outcomes and relapse: between the prophylactic chemotherapy group and the non-prophylactic chemotherapy group, the complete remission rate were 11/11 versus 98.1%(102/104), the relapse rate were 0 versus 1.0%(1/102). There were no significant difference between the two groups in outcomes or relapse rate (P>0.05). Conclusions: Prophylactic chemotherapy does not substantially benefit the IM patients older than 40 years. Prophylactic chemotherapy may not significantly improve patients' prognosis, in which increased sample size is required in further study. PMID- 28647964 TI - [Association between single nucleotide polymorphism of BARD1 gene and BRCA1 gene mutation in epithelial ovarian cancer]. AB - Objective: To investigate the relationship between single nucleotide polymorphism (SNP) of BARD1 gene and BRCA1 gene in epithelial ovarian cancer (EOC). Methods: Nineteen EOC patients with BRCA1 gene mutation and 50 EOC cases without BRCA1 gene mutation between January 2016 and October 2016 were collected, and all EOC were diagnosed by pathological method. BARD1 gene variants were detected by next generation sequencing (NGS). The SNP of BARD1 gene was analyzed by Pearson linear correlation. Logistic regression analysis was used to research the clinicopathologic features and BRCA1 gene mutation associated with BARD1 gene SNP. Pearson's chi-square test was used to analyze the association between BARD1 gene Val507Met, Arg378Ser and Pro24Ser with different clinicopathologic features and BRCA1 gene mutation risk. Results: (1) Eight BARD1 gene variants were found in 69 ovarian cancer patients, in which Val507Met, Arg378Ser and Pro24Ser were common variants, and the rate of mutation were all 54% (37/69). (2) There was a significant linear correlation among Val507Met, Arg378Ser and Pro24Ser (all P<0.01). (3) Obvious differences were found in Val507Met, Arg378Ser and Pro24Ser of BARD1 gene between BRCA1(+) and BRCA1(-) (all P<0.05) . (4) No differences were found between BARD1 gene Val507Met, Arg378Ser and Pro24Ser and the clinicopathologic features (all P>0.05), while obvious differences were found in BRCA1 gene mutation compared to the controls group. The risk of BRCA1 mutation in Val507Met and Arg378Ser were more evident in subjects with negative family history, positive menopause history, negative tubal ligation, onset age (<=60 years old) and sensitivity to platinum-based chemotherapy in EOC (all P<0.05), while Pro24Ser was only more evident in positive menopause history of EOC (P<0.05). Conclusions: BARD1 Val507Met, Arg378Ser and Pro24Ser are the common genotypes, which are associated with BRCA1 mutation in EOC. The family history, menopause history, tubal ligation, onset age and sensitivity to platinum-based chemotherapy have effects on BARD1 SNP in the risk of BRCA1 gene mutation. PMID- 28647965 TI - [Paying attention to different health needs of different ethnic groups in process health for all program]. AB - In recent years, great effort has been made in the promotion of health for all in China. Articles on column on chronic and non-communicable disease risk factors in Uighur population, analysis based on the investigation results of Uygur population health status in the Kashi area of Xinjiang of China and similar domestic and foreign studies showed that the health data in different countries are different. The differences in health related data exist in different ethnic groups even in same country or same ethnic group in different areas. Only by fully understanding the differences in disease and related factors among different ethnic groups, developing individualized health indicators and conducting targeted intervention, the goal of health for all can be achieved. PMID- 28647966 TI - [Prevalence of diabetes mellitus and associated risk factors in Uygur population in Kashgar area of Xinjiang Uygur Autonomous Region]. AB - Objective: To investigate the epidemiologic characteristics of diabetes mellitus (DM) in Uygur residents in Kashgar of Xinjiang. Methods: The survey was conducted among the Uygur residents aged >=18 years selected through stratified cluster sampling in Kashgar by means of questionnaire survey, physical examination and basic laboratory test. The prevalence of different groups were calculated and risk factors of DM was analyzed by logistic vegression model. Results: A total of 4 608 adults were surveyed. The prevalence of DM was 11.31% (standardized prevalence: 10.59%) and the prevalence was 13.65% (standardized prevalence: 12.34%) in males and 10.04% (standardized prevalence: 9.83%) in females. The prevalence increased with age. The prevalence of DM was higher than the prevalence of impaired fasting glucose (IFG) in people aged >60 years, especially in females. The rates of awareness, treatment and control of DM were 28.02%, 21.31% and 5.57%, respectively. Multivariate logistic regression analysis indicated that people aged 45-55, 55-65 and >65 years had higher risk of DM and the odds ratio were 2.08 (95%CI: 1.24-3.48), 2.73 (95%CI: 1.63-4.56) and 3.90 (95%CI: 2.24-6.78) for men and 2.63 (95% CI: 1.71-4.02), 3.14 (95%CI: 2.00-4.94) and 5.56 (95%CI: 3.47-8.92) for woman, respectively. Family history of DM (OR=2.88 for men, 95% CI: 1.45-5.72; OR=2.52 for women, 95% CI: 1.49-4.26) and BMI>=28.0 kg/m(2) (OR=1.77 for men, 95% CI: 1.19-2.64, OR=1.80 for women, 95% CI: 1.30-2.50) were also risk factors for DM. Conclusion: The prevalence of DM was high in Uygur residents in Kashgar, but the rate of awareness, treatment and control of DM were low. It is necessary to improve the detection rate of DM and conduct targeted prevention and control of DM. PMID- 28647967 TI - [Prevalence of dyslipidemia and normal blood lipids level in Uygur population in Kashgar area of Xinjiang Uygur Autonomous Region]. AB - Objective: To understand the prevalence of dyslipidemia and normal blood lipids level in Uygur diabetes patients in Kashgar prefecture in southern area of Xinjiang. Methods: A total of 5 078 local residents aged >=18 years (42.56% were men) selected through cluster random sampling in Kashgar were surveyed by means of questionnaire survey, physical examination and laboratory test, and 521 diabetes patients were screened. Results: The overall prevalence of dyslipidemia in diabetes patients was 59.50% (310/521) with adjusted rate as 49.39%. Age >=65 years, overweight, obesity and abdominal obesity increased the risk for dyslipidemia by 0.771 times (95% CI: 1.015-3.088), 1.132 times (95% CI: 1.290 3.523), 1.688 times (95% CI: 1.573-4.592) and 0.801 times (95% CI: 1.028-3.155) respectively. Compared with males, female was a protective factor for dyslipidemia (OR=0.507, 95%CI: 0.334-0.769). The overall normal rate of blood lipids level including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) for type 2 diabetes patients was 11.13%. Female, higher BMI and abdominal obesity were the factors influencing the overall normal blood lipids level. The normal rate of LDL-C level decreased with increase of age, BMI and waist circumferences (trend test chi(2)=18.049, P<0.001; trend test chi(2)=10.582, P=0.001; chi(2)=19.081, P<0.001), but increased with educational level (trend test chi(2)=9.764, P=0.002). Conclusion: The prevalence of dyslipidemia in Uygur diabetes patients in Kashgar was high, however, the overall normal rate of blood lipid level was relatively low. Obesity was the most important risk factor for dyslipidemia in this area. More attention should be paid to dyslipidemia prevention in women. PMID- 28647968 TI - [Prevalence of hypertension and risk factors in Uygur population in Kashgar area of Xinjiang Uygur Autonomous Region]. AB - Objective: To investigate the prevalence of hypertension and risk factors in Uygur adults in Kashgar of Xinjiang. Methods: A total of 4 748 Uygur adults aged >=18 years selected through cluster random sampling in Shufu county of Kashgar prefecture were surveyed by means of questionnaire survey, physical examination and laboratory test. The prevalence, awareness, treatment and control rate of hypertension of different groups were calculated and risk factors of hypertension was analyzed by using non-conditional logistic regression model. Results: The overall prevalence of hypertension was 15.73% (age-adjusted prevalence was 13.75%). The prevalence rates of hypertension in men and women were 16.36% (age adjusted prevalence was 12.96%), 15.39% (age-adjusted prevalence was 14.34%), respectively. The rates of awareness, treatment and control of hypertension were 59.57%, 52.74%, 21.29%, respectively. The prevalence of hypertension increased with age. Compared with age group 18-34 years, the age groups 55-64, >=65 years had higher risk of hypertension and the OR values were 10.53, 20.96 for men and 16.27, 33.20 for women. The overweight (OR=1.47 for men, OR=1.82 for women, P<0.05) and obesity (OR=1.88 for men, OR=2.66 for women, P<0.05) also increased the risk of hypertension. The groups with family history of hypertension (OR=3.85 for men, OR=2.34 for women, P<0.05) also had higher risk of hypertension. Hypertriglyceridemia was positively correlated with the prevalence of hypertension in men (OR=1.62, 95%CI: 1.09-2.41). Conclusions: The prevalence of hypertension in Uygur adults in Kashgar area of Xinjiang was at relatively low level. The related risk factors were age, overweight, obesity, family history and hypertriglyceridemia in men and the risk factors were similar in women except hypertriglyceridemia. PMID- 28647969 TI - [Knowledge, attitude and practice to chronic diseases and associated influencing factors in Uygur population in Kashgar area of Xinjiang Uygur Autonomous Region]. AB - Objective: To investigate the knowledge, attitude and practice (KAP) to chronic diseases and associated influencing factors in Uygur adults in Kashgar of southern Xinjiang, and provide basic information for developing ethnic specific prevention and control strategies for chronic diseases. Methods: With stratified cluster random sampling, investigations, including questionnaire survey, physical examination and laboratory tests were performed among local residents who were aged >=18 years and selected in Shufu county in southern Xinjiang. KAP scores were calculated and unconditional logistic regression models were used to analyze influencing factors. Results: A total of 4 772 Uygur adults were surveyed. The awareness rate of chronic disease related knowledge ranged from 4.32% to 56.04%, while the awareness rate of preventive measures were from 1.76% to 85.18% and the participation rate of prevention program varied from 4.00% to 97.99%. The average KAP score was 15.90+/-4.20 and the rate of total KAP was 47.86%. Multi-factor analysis suggested the pass rate of total KAP score increased with educational level. Other factors positively associated with 'KAP score pass rate' were commercial insurance investment, hypertension, family history of common chronic diseases, female and abdominal obesity, while overweight was negatively associated with the KAP score pass rate. Conclusions: The KAP level on chronic diseases was low in Uygur adults in Kashgar. It is necessary to continuously implement ethnic targeted health education and health promotion campaigns, especially in low education level, low income level, overweight and male groups. PMID- 28647970 TI - [Association between the types of obesity and the 10-year-coronary heart disease risk, in Tibet Autonomous Region and Xinjiang Uygur Autonomous Region]. AB - Objective: To investigate the association between types of obesity and the 10 year-coronary heart disease risk in Tibet and Xinjiang of China. Methods: Using the multi-stage random sampling method, 7 631 participants aged 35 or older were examined under the International Standardized Examination process but with only 5 802 were eligible for analysis, in the 2015-2016 season. Results: The prevalence rates of general obesity, central obesity, visceral obesity and compound obesity were 0.53%, 12.62%, 10.08% and 42.35%, respectively. Out of all the compound obesity cases, 58.65% (1 441/2 457) of them appeared as having all types of obesity in our study. Risk related to the 10-year-coronary heart disease was higher in men than in women [(3.05+/-4.14)% vs. (1.42+/-2.37) %, P<0.000 1. Compound obesity (30.16%) showed the highest proportion on the risk of 10-year coronary heart disease than central obesity (28.01%), visceral obesity (18.46%) or the general obesity (19.35%). After adjustment for confounding factors, results from the multivariate analysis showed the risk in compound obesity was higher than central obesity, visceral obesity or general obesity and was associated with the highest risk on the 10-year-coronary heart disease (OR=2.889, 95%CI: 2.525-3.305). People with anomalous BMI and WC seemed to have had the higher risk (OR=3.168, 95%CI: 2.730-3.677). Conclusions: Obesity was popular in the residents of Tibet and Xinjiang areas of China. Men and people with compound obesity (especially both BMI and WC were abnormal) seemed to carry greater risk on the 10-year-coronary heart disease. PMID- 28647971 TI - [Association between body fat percentage, visceral fat index and cardiometabolic risk factor clustering among population aged 35 year old or over, in Tibet Autonomous Region and Xinjiang Uygur Autonomous Region]. AB - Objective: To investigate the association between body fat percentage (BFP), visceral fat index (VFI) and Cardiometabolic Risk Factor Clustering (CRFC), among population aged 35 or older in Tibet and Xinjiang areas. Methods: Using the stratified multi-stage random sampling method, 7 571 residents aged 35 or above were examined with international standardized examination between 2015 and 2016. Of the eligible 5 643 participants, association of BFP and VFI with CRFC was defined as having two or more of the four risk factors: hypertension, diabetes mellitus, high TG and low HDL-C, at the same time. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were employed to further explore the relationships. Results: The overall prevalence of CRFC among aged 35 and older population in Tibet and Xinjiang areas was 9.78%. BFP and VFI were divided into four groups by quartile. After adjustment for age, gender, race, cigarette smoking, alcohol consumption, education attainments, and altitude of residence, ORs of CRFC seemed to have increased with BFP and VFI. Compared with people having BFP of 5.0%-27.0%, the OR(95% CI) were 1.15(0.86-1.54), 1.48(1.05-2.07) and 1.72(1.10-2.68) for the ones who presented 27.1%-31.7%, 31.8% 36.6% and 36.7%-50.0% of BFP. Compared to people of having 1-6 of VFI, with OR (95%CI) as 1.20(0.81-1.79), 1.91(1.30-2.80) and 3.91(2.64-5.77) for the ones having 7-9, 10-13 and 14-30 of VFI. Areas under the curve (AUC) of CRFC appeared as 0.55 for BFP and 0.70 for VFI, respectively, with statistically significant difference (P<0.01). Conclusion: Both BFP and VFI levels were closely associated with CRFC while VFI seemed to have a better predictive value than the BFP. PMID- 28647973 TI - [Study on the immunization status and its influencing factors among workers from the polio network laboratories in China]. AB - Objective: To Investigate the immune status and influencing factors of provincial polio network laboratory (PNL) workers in China so as to provide evidence for the development of related strategies to protect personnel working at the PNLs. Methods: All the practitioners from the PNLs at the provincial centers for disease control, were selected as objects for this study, from October to December, 2016, under a questionnaire survey. Information on status of immunity and influencing factors was collected, with SAS software, trend chi-square used for statistics analysis. Results: A total of 77 workers were involved in this survey, with 60 (78%) of them completed the polio-based immune program but the rest 17 (22%) remained records unclear. 66 people (about 86%) remembered clearly that they had received vaccination when engaging in the polio-lab work, but the rest 11 (14%) with only partial vaccination records. We also noticed that the Influencing factors realted to vaccination status were: age (chi(2)=2.48, P<0.05), title (chi(2)=2.51, P<0.05), years of employment (P<0.000 1), education (chi(2)=0.74, P=0.46) and gender (chi(2)=0.46, P=0.50). Conclusion: Immune status of the Chinese provincial PNL practitioners appeared fairly good as 86% of all the workers had received polio-related vaccination, with 41% of them completed a 3-time inoculation program, when started working in this field. PMID- 28647972 TI - [Relationship between pesticide exposure and adverse pregnancy outcomes among reproductive couples in rural areas of China]. AB - Objective: To analyze the association between pesticide exposure and adverse pregnancy outcomes in women from the rural areas of China. Methods: Data of "National Free Preconception Health Examination Project (NFPHEP)" from January 2010 to December 2012 was used for analysis. A total of 248 501 families that were planning to deliver a baby in the next 6 months were enrolled. Data on paternal exposure to pesticides before or during pregnancy was collected through questionnaires, with related outcomes on pregnancy recorded by doctors. Results: Among all the 248 501 participants, 1 806 (0.74%) women and 2 653 (1.09%) men reported to have been exposed to pesticide before pregnancy, with 505 (0.21%) reported of having been exposed to pesticide during the period of pregnancy. Maternal exposure to pesticide was found a risk factor related to stillbirth (OR=3.37, 95%CI: 2.05-5.55), peculiar smell pregnancy (OR=3.17, 95%CI:1.18-8.55) and low birth weight (OR=7.56, 95% CI: 5.36-10.66). Paternal exposure to pesticide was also found related to miscarriage (OR=1.37, 95% CI: 1.03-1.80), low birth weight (OR=3.65, 95% CI:1.51-8.84), or giant infant (OR=0.64, 95%CI: 0.44 0.93). Maternal exposure to pesticide during pregnancy appeared a risk factor on miscarriage (OR=4.65, 95% CI: 3.47-6.24). Other adverse outcomes on pregnancy would include premature birth and high birth weight. Conclusion: Parental pesticide exposure appeared a risk factor on stillbirth, peculiar smell pregnancy, low birth weight and miscarriage. PMID- 28647974 TI - [CD(4+) T lymphocyte responses to anti-retroviral therapy, among HIV/AIDS patients aged 18 and over]. AB - Objective: To compare the differences of CD(4) (+) T lymphocyte (CD(4)) counts between patients aged 18 and over, to explore the effect of age on treatment, 36 months after having received the China National Free AIDS Antiretroviral Treatment on HIV/AIDS. Methods: Through the National ART Information Ssystem, we selected those HIV/AIDS patients who initiated the ART 36 months after the ART, between January 1, 2010 and December 31, 2012 in Guangzhou, Liuzhou and Kunming. Patients were divided into age groups as 18-49, 50-59 and 60 or over year olds, at the baseline of treatment. Under different levels of baseline CD(4) counts, we chose the baseline and different time-point of CD(4) counts as dependent variables, applied mixed linear model to analyze the effects of age, viral suppression, gender, baseline CD(4)/CD(8) ratio and initial treatment regimen. Results: A total of 5 331 HIV/AIDS patients were recruited. No differences were found on age group ratios between different levels of baseline CD(4) counts. At the level of baseline CD(4)<200 cells/MUl, both the 50-59 and 60 or above years old groups had lower CD(4) counts than the 18-49 year-old group, within 36 months after the initiation of ART. However, at the baseline CD(4) level of 200-350 cells/MUl, no significant differences on CD(4) counts between the 50-59 year-old and 18-49 year-old groups were noticed. CD(4) counts seemed lower in the 60 and above year-old group than in the 18-49 year-old group. Conclusion: Age might serve as an influencing factor on CD(4) counts within 36 months after the initiation of ART, suggesting that earlier initiation of ART might be of help to the recovery of immune function in the 50-59 year-old group. PMID- 28647975 TI - [One-night-stand behavior and associated factors among young men who have sex with men in Wuhan, China]. AB - Objective: This present study was to examine the prevalence and determinants of one-night-stand behavior among young men who have sex with men (YMSM). Methods: A total of 403 YMSM aged 16 to 25 were recruited through internet promotion, extending activity and HIV VCT in Wuhan. Data was gathered through anonymous questionnaire. Binary logistic regression was used to examine factors associated with one-night-stand behavior. Results: Of the 398 YMSM, 48.99% (195/398) reported having had casual sex in the last 6 months. Of the ones having had casual sex, 34.29% (60/175) and 28.65% (49/171) reported using condoms consistently during anal or oral sexual contacts, respectively. These figures were lower than those of YMSM not having casual sexual contacts [with anal sex as 49.08% (80/163) and oral sex as 38.85% (61/157)]. 76.80% (149/194) of the YMSM reported having had multiple sexual partners, with the figure higher than those without [33.15% (60/181)] (P<0.01). Results from the logistic regression analysis showed that the following factors seemed to be associated with casual sex activities among YMSM, including: often using internet, (OR=4.89, 95%CI: 1.90 12.54), taking illegal drugs (OR=2.72, 95%CI: 1.60-4.63). Conclusions: YMSM who had engaged in casual sex, practicing unprotected sex or having multiple sexual partners, were recognized as high risk population. Targeted intervention programs are needed to decrease the one-night-stand behavior. Internet intervention strategy seemed an important method to serve the purpose. PMID- 28647976 TI - [Status of marriage and HIV transmission between couples in newly reported HIV cases before diagnosis was made, among men who have sex with men in China, 2014]. AB - Objective: To analyze the status of marriage and HIV transmission between couples in newly reported HIV cases before diagnoses were made, among men who have sex with men (MSM) in China. Methods: Baseline and follow-up information related to newly reported cases in 2014 were collected from the Chinese HIV/AIDS Comprehensive Response Information Management System. Infected MSM who were older than 22 years of age were included in this study. HIV cases were divided into sero-concordant or sero-discordant group, according to the HIV status of the couple who were tested 180 days post-diagnosis. Multivariate logistic regression method was used to analyze the potential factors associated with HIV transmission between couples before diagnosis was made. Results: A total of 5 081 (22.7%) of the HIV infected MSM who had couples, were included in this study. A total of 3 715 cases had their couples tested 180 days after the diagnosis was made. 7.6% (282) had positive couples. Results from the multivariate logistic regression analysis showed that factors as: older than 60 (OR=2.64, 95% CI: 1.50-4.65) years of age, being minorities (OR=1.93, 95% CI: 1.13-3.29), having CD(4)(+)T cells less than 500 cells/MUl (<200: OR=2.91, 95%CI: 1.82-4.65; 200-349: OR=1.98, 95%CI: 1.22-3.23; 350-500: OR=1.69, 95%CI: 1.00-2.86), with self-reported unsafe behaviors (OR=1.92, 95% CI: 1.44-2.58) etc., were more likely to transmit HIV to their couples before the diagnosis was made. Conclusion: Behavior interventions and early HIV testing should be promoted, especially among those MSM who had couples, to avoid inter-spousal transmission. PMID- 28647977 TI - [Surveillance data on typhoid fever and paratyphoid fever in 2015, China]. AB - Objective: Through analyzing the surveillance data on typhoid fever and paratyphoid fever in 2015 to understand the related epidemiological features and most possible clustering areas of high incidence. Methods: Individual data was collected from the passive surveillance program and analyzed by descriptive statistic method. Characteristics on seasonal, regional and distribution of the diseases were described. Spatial-temporal clustering characteristics were estimated, under the retrospective space-time method. Results: A total of 8 850 typhoid fever cases were reported from the surveillance system, with incidence rate as 0.65/100 000. The number of paratyphoid fever cases was 2 794, with incidence rate as 0.21/100 000. Both cases of typhoid fever and paratyphoid fever occurred all year round, with high epidemic season from May to October. Most cases involved farmers (39.68%), children (15.89%) and students (12.01%). Children under 5 years showed the highest incidence rate. Retrospective space time analysis for provinces with high incidence rates would include Yunnan, Guangxi, Guizhou, Hunan and Guangdong, indicating the first and second class clusters were mainly distributed near the bordering adjacent districts and counties among the provinces. Conclusion: In 2015, the prevalence rates of typhoid fever and paratyphoid fever were low, however with regional high prevalence areas. Cross regional transmission existed among provinces with high incidence rates which might be responsible for the clusters to appear in these areas. PMID- 28647978 TI - [Severe cases with hand, foot and mouth disease: data based on national pilot hand, foot and mouth disease surveillance system]. AB - Objective: To investigate the clinical severity, etiological classification and risk factors of severe cases with hand, foot and mouth disease (HFMD). Methods: A total of 1 489 records on severe and fatal HFMD cases reported to the national pilot surveillance system of HFMD were used to analyze the demographic, medical treatment, etiological classification of the cases. Treatment outcome related risk factors were also studied with multi-variable stepwise logistic regression method. Results: Seven out of the 1 489 severe HFMD cases died of this disease. A total of 960 (72.9%) were under three years old and 62.9% were male and most of the cases (937, 62.9%) resided in rural areas. Among all the cases, 494 (33.2%) went to seek the first medical assistance at the institutions of village or township level. Durations between disease onset and first medical attendance, being diagnosed as the disease or diagnosed as severe cases were 0(0-1) d, 1 (0 2) d and 2 (1-4) d, respectively. In total, 773 (51.9%) of the severe HFMD cases were diagnosed as with aseptic meningitis, 260 (17.5%) with brainstem encephalitis, 377 (25.3%) with non-brainstem encephalitis, 6 (0.4%) with encephalomyelitis, 1 (0.1%) with acute flaccid paralysis, 4 (0.3%) with pulmonary hemorrhage/pulmonary edema and 68 (4.6%) with cardiopulmonary failure. Of the etiologically diagnosed 1 217 severe and fatal HFMD cases, 642 (52.8%) were with EV71, other enterovirus 261 (21.5%), Cox A16 36 (3.0%), 1 (0.1%) with both EV71 and Cox A16. However, 277 (22.8%) showed negative on any pathogenic virus. Complication (Z=3.15, P=0.002) and duration between onset and diagnosed as severe cases (Z=3.95, P<0.001) were shown as key factors related to treatment outcomes. Conclusions: Most severe HFMD cases appeared in boys, especially living in the rural areas. Frequently seen complications would include aseptic meningitis, non brainstem encephalitis and brainstem encephalitis. EV71 was the dominant etiology for severe and fatal cases. Early diagnosis and complication control were crucial, related to the treatment outcome of HFMD. PMID- 28647979 TI - [Study on seasonal characteristics and pathogenic distribution of influenza in Gansu province of China]. AB - Objective: To study the epidemiologic characteristics of influenza in Gansu province of China and to optimize the related vaccination program. Methods: Weekly influenza surveillance data from the first week of 2010 to the fortieth week of 2016 were collected, in Gansu province. chi(2) test was used to compare the differences of nucleic acid positive rate and the virus types in the four seasons. Time series seasonal decomposition (TSSD) was used to explore seasonal patterns and characteristics of influenza epidemics in Gansu. Results: 59 791 specimens were tested, with 8 501 positive for influenza virus and positive rates as 14.22%. Types A(H1N1)pdm09, A(H3N2) and type B were accounted for 98.76% of all the positive specimens. Proportions of the positive rate of influenza virus appeared in spring, summer, autumn and winter were 15.12%, 0.98%, 4.02% and 24.26% respectively. The predominant type of virus in autumn and winter was A(H3N2), with B mainly in spring. Influenza in Gansu province showed typical single-peak type distribution, with epidemic peak appeared from December to next January. The type A(H3N2) related peak appeared the earliest, followed by A(H1N1) pdm09, with type B the latest. Conclusions: Peaks and the duration of influenza seasonal epidemics were related to the types of dominant strains. Annual influenza vaccination campaigns should start in October, to provide effective protection during the epidemic period. PMID- 28647980 TI - [Burn-related burden among Chinese population from 1990 to 2013]. AB - Objective: To analyze the burden and changes caused by burns among Chinese population, from 1990 to 2013. Methods: Using the G20 data and the China national and subnational data from GBD2013, this study deemed to comprehensively show the burden caused by burns and the change from 1990 to 2013, using the indicators of death and DALY. Results: In 2013, the standardized mortality of burns in Chinese was 0.88/100 000, with the standardized DALY rate of burn as 30.58/100 000. The ratio of DALY between males and females was 1.85 ? 1. Among the G20 countries, China ranked 16 for the standardized DALY rate, according to the top down order. The highest death rate was seen in the age group of 70 and over, followed by age group of 5, which had the highest DALY rate and followed by the 70 or older age group. In different provinces, Guizhou presented the highest DALY rate (50.24/100 000), with Aomen area the lowest (6.16/100 000). From 1990 to 2013, the burden of burn reduced generally. Both the standardized rates on death and DALY reduced by 68.10% and 76.95% respectively, more in females than in males. Standardized rates on death and DALY reduced among all the age groups, with the rates of reduction increasing by age. From 1990 to 2013, the DALY rate decreased in all the provinces. Conclusions: The burden of burn decreased in Chinese population during 1990-2013. However, the burden of burn among children, elderly and males were still relatively high that called for closer attention. PMID- 28647981 TI - [Disparities of sex on cancer incidence and mortality in Jiashan county, Zhejiang province,1990-2014]. AB - Objective: This study aimed to describe the sex disparities on cancer incidence and mortality in Jiashan population. Methods: All data concerning incident and death cases of cancers were gathered from the database of Cancer Registry in Jiashan county. Data from the 2010 China census was used as the standard population. Sex-specific age-standardized incidence rates (ASIRs), mortality rates (ASMRs) per 100 000 persons for all cancers and types of each cancer were calculated for the years of 1990 to 1999, 2000 to 2009, 2010 to 2014, and 1990 to 2014. In addition, the corresponding male-to-female incidence rate ratios (IRRs) and mortality rate ratios (MRRs) were also calculated. Results: The ASIR of all cancers was 226.13/10(5) for the whole period of 1990 to 2014, with 266.04/10(5) for males and 187.22/10(5) for females, respectively. The corresponding IRR was 1.42 (95%CI: 1.39-1.46), with significant difference noticed in the incidence rates between males and females (P<0.05). The ASMR of all cancers was 155.39/10(5), with 206.55/10(5) for males and 104.98/10(5) for females, respectively. The corresponding MRR was 1.97 (95% CI: 1.91-2.03), with significant difference between males and females (P<0.05). Among all the cancer types, only gallbladder cancer and thyroid cancer showed female predominance in both incidence and mortality, with male predominance in all the remaining cancers. Conclusion: Finding from our study suggested that a male predominance in both incidence and mortality for a majority of cancers in Jiashan population. PMID- 28647982 TI - [Impact of diabetes prevalence and mortality on health life expectancy among residents in Zhejiang province]. AB - Objective: To evaluate the impact of diabetes prevalence and mortality on health life expectancy (HLE). Methods: A cause-excluded health adjusted life expectancy method was used to quantitatively analyze the impact of diabetes on HLE and the composition of health life losses (HLL), using the integrated data on population mortality, self-assessed health status and diabetes prevalence. Results: The HLE for people aged 15 was 55.80 in Zhejiang, in 2013. After removing the diabetes morbidity and mortality, the HLE for men aged 15 increased by 0.86 and 1.13, respectively, with an increase of 1.04 and 0.66 for urban and rural residents. Substantial increase of HLE was observed in women and urban residents than those for men and rural residents. HLL caused by diabetes mortality and morbidity appeared as 0.10 and 0.79, with a ratio of 7.92. Conclusion: HLL caused by diabetes mortality was much greater than those caused by diabetes mortality, suggesting the most effective measure in reducing the diabetes-related HLL is to promote the healthy lifestyle in urban areas and especially for women. PMID- 28647983 TI - [Spectrum and case fatality of inpatients with malignant tumors from 1995 to 2014 in Shenzhen city]. AB - Objective: To analyze the epidemiological features, spectrum and case fatality of malignant tumor patients in Shenzhen city, to provide evidence for the development of prevention and treatment strategies on malignant tumor in Shenzhen. Methods: All the hospitalized malignant tumor patients including deaths, were monitored from 1995 to 2014 in Shenzhen, and data was analyzed by SPSS 20.0 software. Results: There were 160 988 inpatients of malignant tumors between 1995 and 2014 in Shenzhen. The top three hospitalized tumors were lung (13.64%), liver (11.13%) and breast (7.86%) cancers. Numbers of the malignant tumor inpatients had been rapidly increasing during the past 20 years, 12.3 times in 2014 higher than in 1995. The total number of deaths due to malignant tumors was 19 460. Deaths of the top three malignant tumors were lung (24.40%), liver (19.84%) and colorectal (8.63%) cancers and the number of deaths was increasing, 12.5 times higher in 2014 than in 1995. The overall case fatality rate was 12.09%. The annual percent change (APC) of malignant tumors case fatality rate was 9.7%(95%CI: 2.0%-18.0%), during 1995-2003, with an increasing trend (t=2.72, P<0.05). The APC of case fatality rate during 2003-2014 was -3.4%(95%CI: -7.6% 1.1%), but the decreasing trend (t=-1.63, P>0.05) was not statistically significant. The top three major malignant tumors related to case fatality rate were lung cancer (21.62%), liver cancer (21.39%), and esophageal cancer (16.50%). The case fatality rates of leukemia and liver cancer had decreased during the past 20 years. The case fatality rates of cancers in lung, esophagus, stomach, breast, colorectal and nasopharyngeal, had all increased. The number of male patients was significantly exceeding the females (chi(2)=41.691, P<0.01), with sex ratio as 1.65?1. From age 35 and on, the number of deaths due to malignant tumors increased significantly, with the peak after 60 years of age. Conclusions: The number of malignant tumor inpatients had an annual increase as well as the case fatality rate. Cancers in lung, liver appeared the leading causes of death among the malignant tumor patients, with elderly in particular. Strategies related to the prevention and treatment of cancers in lung, liver should be strengthened. PMID- 28647984 TI - [Screening on key techniques used for surveillance and disposal of public health emergencies]. AB - Objective: To explore the key techniques used for surveillance and disposal of infectious diseases, food poisoning and hospital infection to improve the ability of surveillance and disposal on public health emergency. Methods: Framework on surveillance and disposal of infectious diseases, food poisoning and hospital infection was set up, based on literature review and expert group discussion. Delphi method and technique for order preference by similarity to ideal solution comprehensive evaluation method were used for ordering preference by similarity, to screen key techniques set for surveillance and disposal of the above said events. Results: Framework to be used for selecting key techniques was designed, based on the classification of emergency events, processing cycle of emergency events and level of techniques. Twenty six public health experts were selected for a 2-round consultation, with their authority as 0.796. Ten key techniques with important significance for surveillance and disposal of infectious diseases, food poisoning and hospital infection were selected from each event. Among these key techniques, the early-warning system was recognized as the key technique, important for the surveillance and disposal of all three emergency events. Items as technology used for unknown pathogenic microorganism detection, personal protection, gene sequencing and tracing technology, microorganism molecular typing technology, nucleic acid detection technology etc. were the key techniques and need to develop for the surveillance and disposal of infectious diseases and iatrogenic infection. Data regarding key technologies on security and privacy, early warning and forecasting, field rapid detection were sorted out that all in need to improve the surveillance programs on disposal of infectious diseases and food poisoning. Data exchange appeared another key technique on infectious diseases, with toxin detection and other 5 techniques the key techniques for food poisoning. Data collection, standardization and other 3 techniques appeared as the key techniques on iatrogenic infection. Conclusions: Key techniques were selected in this study to meet the requirements of surveillance, disposal of infectious disease, food poisoning and iatrogenic infection. Authority of the experts got improved in the two-round consultation, ensuring the reliability of the results of screening and providing a scientific basis for the further research and priority development of the key techniques. PMID- 28647985 TI - [Discriminatory power of variable number on tandem repeats loci for genotyping Mycobacterium tuberculosis strains in China]. AB - Objective: Using the standard genotype method, variable number of tandem repeats (VNTR), we constructed a VNTR database to cover all provinces and proposed a set of optimized VNTR loci combinations for each province, in order to improve the preventive and control programs on tuberculosis, in China. Methods: A total of 15 loci VNTR was used to analyze 4 116 Mycobacterium tuberculosis strains, isolated from national survey of Drug Resistant Tuberculosis, in 2007. Hunter-Gaston Index (HGI) was also used to analyze the discriminatory power of each VNTR site. A set combination of 12-VNTR, 10-VNTR, 8-VNTR and 5-VNTR was respectively constructed for each province, based on 1) epidemic characteristics of M. tuberculosis lineages in China, with high discriminatory power and genetic stability. Results: Through the completed 15 loci VNTR patterns of 3 966 strains under 96.36% (3 966/4 116) coverage, we found seven high HGI loci (including QUB11b and MIRU26) as well as low stable loci (including QUB26, MIRU16, Mtub21 and QUB11b) in several areas. In all the 31 provinces, we found an optimization VNTR combination as 10-VNTR loci in Inner Mongolia, Chongqing and Heilongjiang, but with 8-VNTR combination shared in other provinces. Conclusions: It is necessary to not only use the VNTR database for tracing the source of infection and cluster of M. tuberculosis in the nation but also using the set of optimized VNTR combinations in monitoring those local epidemics and M. tuberculosis (genetics in local) population. PMID- 28647986 TI - [Studies on the serum types and identification efficiency on Diarrheagenic Escherichia coli isolated from diarrhea patients, in Zhejiang province]. AB - Objective: To investigate the serotypes of Diarrheagenic Escherichia coli (DEC) isolated from diarrheal patients in Zhejiang province and to explore the identification efficiency of serological screening methods. Methods: Serological agglutination tests were carried out in 696 strains of DEC (through the identification of virulence genes) which were selected from the Infectious Diarrhea Pathogen Monitoring Network Strain Bank of Zhejiang province, from July 2009 to June 2013. Results of virulence genes, serological identification and classification were compared. Results: Among the 696 isolates of DEC, O antigen type was identified in 288 (41.4%) isolates which belonging to 35 different 'O' serum types. H antigen was seen in 171 (24.6%) isolates and determined as having 21 types. The agglutination rates of EAEC, ETEC, EPEC and EHEC isolates were 31.9% (130/408), 70.6% (127/180), 31.5% (29/92) and 14.3% (2/14), respectively and belonged to 30, 18, 15 kinds of 'O' sero-groups, respectively. One EHEC isolate was identified as O157?H7. Serum groups were diverse for EAEC and EPEC, while relatively concentrated on ETEC. Different types of DEC might belong to the same sero-group or type. Among the 74 strains of DEC available for classification serologically, 41 isolates were in consistent with virulence gene identification and another 33 strains were not. Conclusions: The sero-group/type of DEC strains in Zhejiang were varied. Based on the serological screening method alone, DEC classification might end in getting the wrong answer, thus we would recommend the use of virulence gene for the purpose of identification. PMID- 28647987 TI - [Distribution of HIV-1 subtypes among foreign patients, in Guangzhou, between 2008 and 2010, and in 2015]. AB - Objective: To understand the characteristic of subtype distribution among foreigners who were living with HIV-1, in Guangzhou. Methods: HIV-1 RNAs were extracted from 114 serum specimens in foreigners diagnosed with HIV-1 infections between 2008 and 2010, and in 2015. Partial pol gene of HIV-1 genome from these RNA samples were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) with nucleotide sequenced. Subsequently, phylogenetic tree was reconstructed using the pol sequences of samples and references. Results: Among all the 114 samples, 57.9% were from males and 42.1% from females, with an average age as 35.21 years old and the standard deviation as 9.63 years. A total of 6.8% of the samples were from Africans. The top three subtypes were identified as CRF02_AG, subtype G and subtype C, accounted for 30.7%, 14.9% and 12.3% respectively. Compared with samples gathered from 2008 to 2010, the proportions of subtype A1 and CRF01_AE significantly increased, while the other subtypes significantly decreased in 2015 (chi(2)=37.570; P=0.013, 99% CI: 0.010-0.016). Proportions of CRF01_AE and subtype G among males outnumbered the females but the proportions of subtype A1, CRF02_AG and URF among females appeared the other way round (chi(2)=15.528; P=0.029, 99%CI: 0.024-0.033). Proportions of CRF02_AG and subtype G among HIV-1 positive Africans were larger than those from other Southeast Asian countries or areas, However, the proportion of CRF01_AE among HIV 1 positive patients from Southeast Asian countries was higher than those patients from other areas (chi(2)=39.399; P=0.009, 99% CI: 0.006-0.011). The rates of resistance to any drug of protease inhibitors (PIs), reverse transcriptase inhibitors (RTIs), as well as to PIs, NRTIs, and NNRTIs alone, were 21.9%, 12.3%, 6.1% and 7.0%, respectively. One of nine CRF01_AEs from the HIV-1 positive patients were found closely clustered in those phylogenetic tree (bootstrap=0.855) samples, collected from local patients in Guangzhou. Conclusions: Our findings showed that these foreign subtypes had been spread to the natives, more from the Africans than from the other areas, in Guangzhou. These types of viruses were different from the strains identified locally, suggesting that they might have been brought in by foreigners living with HIV-1, in Guangzhou. Programs related to care, support and behavioral intervention for HIV positive foreigners living in Guangzhou, should be strengthened. PMID- 28647988 TI - [Bibliometric analysis on relations between cardiovascular disease and erectile dysfunction]. AB - Objective: To understand the current situation and trend on the relations between erectile dysfunction (ED) and cardiovascular disease (CVD) through analyzing the epidemiologic research data. Methods: We conducted a literature search on the Scopus for potentially relevant epidemiologic studies on ED and CVD published from 1957 to October, 28, 2016. Age of the article, types, regions, citation, and co-authorship of the documents were recorded. Results: A total number of 412 pieces of literature were published in the past six decades, with original articles the most common types of ED and CVD. ED and CVD associated epidemiologic topics had an annual increase in number, and remained stable in the past decade, with occident countries as the United States and Italy taking the lead in this area. Clinical and epidemiological studies were the hottest areas, with most authors sharing a co-authorship. Conclusion: Our results suggested that inter disciplinary cooperation with emphasize on clinical application were the effective starting points for ED and CVD associated epidemiologic studies. PMID- 28647989 TI - [Accuracy of CT colonography for the detection of colorectal neoplasm: a subgroup Meta-analysis]. AB - Objective: To assess the accuracy of computed tomographic colonography (CTC) for detection of colorectal neoplasm. Methods: Publications prior to January 2016 from the Medline, Embase, CNKI, WANFANG, and VIP literature databases were systematically reviewed. A QUADAS checklist was used to assess the quality of the studies. According to the sizes of tumor (>=6 mm or >=10 mm), diagnostic test accuracy indexes (area under the curve, sensitivity and specific) were pooled and stratified. Spearman correlation and curve of summary receiver operating characteristic (SROC) were applied to comprehensively assess the threshold effect. A bi-variate mixed-effects model was used for testing the overall merging value and heterogeneity. Results: A total of 19 articles (n=11 540) were included in the analysis. A total of 18 studies were from Europe and Unite States, with 1 from Asia. Numbers of studies regarding information on general population, high risk groups and clinical symptoms were 9, 5 and 5, respectively. In 19 articles, data on the accuracy of CTC diagnosis (>=6 mm group) was recorded, with another 17 on the group >=10 mm. Area under the SROC curve in the >=6 mm group was 0.92 (95% CI: 0.92-0.94). It was estimated that the pooled sensitivity and specificity were 0.80 (95% CI: 0.73-0.86) and 0.89 (95% CI: 0.86-0.92) respectively. In area under the SROC curve, the pooled sensitivity and specificity in >=10 mm group were 0.87(95%CI:0.80-0.92), 0.97(95%CI:0.95-0.98), respectively. Results from the subgroup showed that the sensitivity of with or without the fecal tagging groups were 0.84 and 0.67 in the >=6 mm group, 0.92 and 0.76 in the >=10 mm group. It was also found that in the experienced or less experienced readers, rates of sensitivity were 0.83 and 0.75 in the >=6 mm group, 0.91 and 0.79 in the >=10 mm group. Conclusions: CTC had high diagnostic efficiency for colorectal neoplasm, especially in the >=10 mm group. Fecal tagging and experience of the reasers can improve the diagnostic sensitivity. PMID- 28647990 TI - [Adverse reaction caused by rabies vaccine in China: a Meta-analysis]. AB - Objective: To conduct a Meta-analysis on the rate of adverse reaction related to rabies vaccine, so as to provide reference for rabies vaccine immunization in China. Methods: We electronically searched databases including CNKI, VIP information resource integration service platform, WanFang Data, CBM, PubMed and The Cochrane Library, to collect studies on Chinese people who had received full rabies vaccination and recording all the adverse reactions, from January 2000 to July 2016. Inclusion and exclusion criteria were strictly followed. Meta-analysis for the adverse reaction rate was performed using the R software. Results: A total of 29 related papers had met the inclusion criteria, with no publication bias noticed. A total number of 11 020 cases had adverse reactions, among all the 94 222 respondents, with an incidence of adverse reactions as 1.04%-47.78%. The overall incidence rate of adverse reaction was 9.82% (95%CI: 7.58%-12.72%). A combined local adverse reaction rate appeared as 12.05% (95% CI: 9.26%-15.69%). The systemic adverse reaction rate was 9.06% (95%CI: 7.07%-11.61%). The overall adverse reaction rate on aqueous vaccine was 32.39% (95%CI: 21.88%-47.94%). Combined adverse reaction rate of freeze dried vaccine appeared as 8.65% (95%CI: 4.54%-16.51%). Significant differences were seen between both groups (P<0.05). Conclusions: The local adverse reaction rate caused by rabies vaccination was higher than the systemic adverse reaction rate. The adverse reaction rate of aqueous rabies vaccine was higher than that of freeze dried rabies vaccine. Our results suggested that the aqueous vaccine should gradually be eliminated. PMID- 28647991 TI - [The Chinese national twin cohort: an update]. AB - The importance of large cohort studies in China has been increasingly emphasized. As special group in the population, twins provide excellent natural resources since they share the same birthday, maternal intrauterine environment and early family environment. Twin cohorts are unique for and benefit on controlling the confounding factors as age, gender (same-sex twins), genetic background (monozygotic twins) or early environment (being raised together) in the etiological studies on complex diseases. In this review, we briefly introduce the objectives, current situation, challenges and opportunities related to the Chinese national twin cohort, focusing on the characteristics of twins that are different from other groups in the general population. PMID- 28647993 TI - [Impact of HIV/HBV infection and HIV/HBV co-infection on outcomes of pregnancy]. AB - Both HIV and HBV infection have become major health problems, of global concern, due to the high prevalence in the past few decades. Data from cumulated epidemiological surveys have shown the links between maternal HIV or HBV infection and adverse outcomes on pregnancy. Maternal HIV or HBV infection may also increase the mother-to-child (MTCT) transmission of the two diseases. However, association between HIV-HBV co-infection and adverse pregnancy is still inconclusive. Does maternal HIV-HBV co-infection have an impact on mother-to child transmission on either HIV or HBV? Study on effective precautionary measures to promote both maternal and child's health is deemed necessary. PMID- 28647992 TI - [Progress of research in relation to the impact of climate change on children's health status]. AB - Along with global warming, climate change has become one of the biggest public health challenges. The unique metabolism, behavior, physiology and development in children, will make them suffer more from the climate change. In the present review, we summarized the progress and situation of studies on the associations between climate change and children's health also trying to provide adaptation and mitigation strategies. The purpose of this study was to offer scientific evidence for prevention and control on the adverse effects as injuries, diseases and deaths among children that resulted from the changes of climate. PMID- 28647994 TI - [Brief comment on the present and future of interventional medicine]. PMID- 28647995 TI - [The risk factors analysis and optimal timing for drainage of lymphocele infection after pelvic lymphadenectomy in patients with endometrial cancer]. AB - Objcetive: To investigate the incidence and risk factors of Lymphocele infection and the optimal timing for drainage after pelvic lymphadenectomy. Methods: This retrospective study was carried out on 397 patients who received a pelvic lymphadenectomy with or without a para-aortic lymphadenectomy between January 2009 and April 2016, due to endometrial cancer in General hospital of Tianjin medical university.A total of 76 patients developed lymphocele and 20 patients developed lymphocele infection. Results: (1)The incidence of lymphocele infection was 5.04% (20/397). Single factor analysis indicated diameter of lymphocele >=5 cm and postoperative anemia were associated with lymphocele formation (P<0.001, P=0.023). Multiple factors Logistic analysis through the adjustment of the factors showed diameter of lymphocele >=5 cm was the independent risk factors for lymphocyst infection (P<0.001). (2)The total treatment period of cases treated only with antibiotics tended to be shorter than that of cases treated with combined antibiotics and drainage (P=0.008). However, for severe cases which needed drainage, initiating the drainage by day 3 significantly shortened the total treatment period compared with cases started on or after day 4 (P=0.048). Conclusion: To identify the risk factors of the lymphocele infection is useful to help reduce the incidence of them with effective measurement.When drainage is required in addition to antibiotics, the earlier the drainage is performed, the shorter the treatment period is. PMID- 28647996 TI - [Curative effects and influenced factors of primary chemotherapy with single agent methotrexate on low-risk gestational trophoblastic neoplasia]. AB - Objective: To evaluate the efficacy of primary chemotherapy with single-agent methotrexate (MTX) for low-risk gestational trophoblastic neoplasia and to analysis the influenced factors. Methods: We retrospectively reviewed 259 cases with low-risk gestational trophoblastic neoplasia whose primary chemotherapies were MTX 0.4 mg.kg(-1) (maximum 25 mg) daily for 5 days every other week. Patients' data between January 2001 and June 2015 was collected and the relationships of different factors to outcomes of chemotherapy were also evaluated. Results: 183 of the 259 patients (70.66%, 183/259) achieved complete primary remission and all patients achieved complete remission after salvage chemotherapy. Univariate analysis showed that FIGO score, serum level of HCG before treatment and interval months from previous pregnancy were significantly associated with outcome of chemotherapy (P=0.001, 0.018, 0.014 respectively). Logistic regression analysis showed that the FIGO score (OR=4.094) and antecedent pregnancy (OR=0.268) were two independent factors predictive for the outcome of chemotherapy. Conclusions: Primary chemotherapy with single-agent MTX may still be one of the options for patients with low risk GTN. The FIGO score and antecedent pregnancy are two independent risk factors of outcome of single-agent MTX chemotherapy. PMID- 28647997 TI - [Endovascular management and classification of the dissecting aneurysms of the vertebral artery]. AB - Objective: To summarize the classifications and optimize endovascular treatment of the dissecting aneurysms of the vertebral artery (DAVA). Methods: The clinical information of 39 cases of DAVA treated with endovascular methods in our department between January 2007 and September 2016 were analyzed retrospectively.According to the location of the aneurysm in relation to the posterior inferior cerebellar artery (PICA), the aneurysms were classified into three types: type pre-PICA, located proximally to the PICA; type in-PICA, located at the PICA origin; and type post-PICA located distally to the PICA.According to the hemodynamics of the contralateral vertebral artery, the aneurysms were classified into two types: compensatory type: including well-developed contralateral vertebral arteries and a guaranteed posterior circulation blood supply following the occlusion of the ipsilateral vertebral artery; and non compensatory type: including contralateral vertebral arteries that were hypoplastic and provided an inadequate posterior circulation blood supply following ipsilateral vertebral artery occlusion.The choices of reconstructive or destructive methods were made according to the above-mentioned classification, combined with the consideration of morphological features and onset styles.Reconstructive surgery included stent-assisted coil embolization and the placement of multiple overlapping stents (6 patients). Destructive surgery referred to coil embolization combined with proximal coil trapping of the dissected segment of the parent artery (CE+ PT). Results: A total of 16 patients were type pre-PICA, of which 9 patients were compensatory type and 7 were non compensatory type.In compensatory type, 4 underwent coil embolization combined with proximal coil trapping of the dissected segment of the parent artery (CE+ PT) and 5 underwent stent-assisted coil embolization (stent/coils). In non compensatory type, 6 underwent stent/coils and 1 underwent multiple overlapping stents placement (stents). Nine patients were type in-PICA, of which 5 patients were compensatory type and 4 were non-compensatory type. In compensatory type, all patients underwent stent/coils.In non-compensatory type, 2 underwent stent/coils and 2 underwent multiple overlapping stents placement (stents). Fourteen patients were type post-PICA, of which 8 patients were compensatory type and 6 were non-compensatory type.In compensatory type, 6 underwent CE+ PT, 1 underwent stent/coils and 1 underwent stents. In non-compensatory type, 4 underwent stent/coils and 2 underwent stents.Totally, there were 10 underwent CE+ PT, 23 underwent stent/coils and 6 underwent stents.The incidence of perioperative complications was 7.7% (3/39), and the death rate associated with these complications was 5.1% (2/39). Of the 36 patients followed with long-term repeated angiographic examinations, 28(77.8%) patients had complete occlusion.Clinical outcome evaluations were performed using the Modified Rankin Scale and resulted in the following scores: 0-2 for 36 patients, 3-6 for 3 patients. Conclusions: The classifications based on location, hemodynamics, morphological features and onset styles of the DAVA is safe and effective for the choice of the endovascular methods. PMID- 28647998 TI - [Analysis of optical coherence tomography of early and very late stent restenosis after drug-eluting stent implantation]. AB - Objective: Using optical coherence tomography (OCT) to analyze the morphological characteristics of lesions between early in-stent restenosis (E-ISR) and very late in-stent restenosis (VL-ISR) after drug-eluting stents (DES) implantation. Methods: In 25 patients (DES) with ISR, OCT images were acquired before percutaneous coronary intervention (PCI), the morphological characteristics of E ISR (<1 years, n=14) and VL-ISR (>3 years, n=11) were compared.The quantitative and qualitative analysis of the entire stent and the minimum lumen area (MLA) site were carried out respectively. OCT quantitative restenotic tissue analysis included the assessment of mean lumen area, mean stent area, mean neointimal area and mean neointimal burden.OCT qualitative restenotic tissue analysis included the assessment of tissue structure [homogeneous or heterogeneous intima (lipid rich neoitima, thin-cap fibroatheroma (TCFA)-like intima)], presence of microvessels, intraluminal material (red thrombus, pale thrombus), disrupted intima with cavity and tissue prolapse and was performed at every 1-mm slice of the entire stent. Results: Compared with the E-ISR group, the proportion of cross sections with heterogeneous intima in the entire stent was significantly higher in the VL-ISR group (60.57% vs 32.93%, P=0.005), and both peristent and intraintimal microvessels were more frequently observed in the VL-ISR group (P<0.05). In addition, lipid-rich neointima (72.7% vs 21.4%, P=0.017), TCFA-like intima (54.5% vs 7.1%, P=0.021), disrupted intima with visible cavity (63.6% vs 7.1%, P=0.007) and red thrombus (63.6% vs 7.1%, P=0.007) were observed more frequently in the VL-ISR group compared with E-ISR group for the entire stent.The heterogeneous intima was observed more frequently in the VL-ISR group (90.9% vs 35.7%, P=0.012) at the MLA sites.Intraintimal microvessels and disrupted intima with visible cavity were observed only in the VL-ISR group. Conclusions: OCT imaging indicates that the morphological characteristics of restenosis lesions in VL-ISR are different from those in E-ISR.The atherosclerotic changes of neointima, such as lipid-rich neointima, disrupted intima with cavity and microvessels are more often observed in VL-ISR lesions after DES implantation compared with E-ISR.Progression of the atherosclerosis within neointima after DES implantation may be associated with VL-ISR. PMID- 28647999 TI - [Relationship between the ratio of neutrophil/lymphocyte and risk stratification, prognosis in patients with non-ST-elevation acute coronary syndrome]. AB - Objective: To investigate the value of neutrophil to lymphocyte ratio (NLR) in predicting risk stratification and prognosis in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Methods: A total of 227 NSTE-ACS patients after percutaneous coronary intervention (PCI) were collected from September 2012 to September 2014 in Beijing Anzhen Hospital.Groups: (1)According to NLR, the patients were divided into 3 groups: NLR<2.20 group; 2.2<=NLR<3.33 group; NLR>=3.33 group.(2)According to the global registry of acute coronary events (GRACE) score, the patients were divided into 3 groups: Low-risk group, Medium risk group and High-risk group.(3)According to the occurrence of major adverse cardiac events (MACE), the patients were divided into 2 groups: MACE group and non MACE group.Receiver operator characteristic curve (ROC) was used to assess value of NLR for high risk NSTE-ACS patients.Then COX regression analysis was used to analyze correlation between NLR and MACE. Results: A total of 227 NSTE ACS patients after PCI were collected and the ratio of MACE was 32.2% (73/227). The GRACE score and the incidence of MACE in NLR>=3.33 group were higher than those in 2.2<=NLR<3.33 group and NLR<2.20 group (all P<0.01). The level of NLR and the incidence of MACE in High-risk group were higher than those in Low-risk group and Medium-risk group (all P<0.05). The level of NLR and the GRACE score in MACE group were higher than those in non MACE group (all P<0.05). COX regression analysis indicated that NLR was independent risk factor for MACE occurrence in NSTE-ACS patients at 1 year after PCI (OR=1.214, 95%CI: 1.114-1.323, P=0.000). Conclusion: The level of NLR has significant correlation with High-risk NSTE-ACS patients, and NLR is an independent risk factor for poor prognosis in patients with NSTE-ACS. PMID- 28648000 TI - [Study on feasibility of enhanced recovery after surgery combined with mobile microendoscopic discectomy-transforaminal lumbar interbody fusion in the treatment of lumbar spondylolisthesis]. AB - Objective: To explore the feasibility of enhanced recovery after surgery (ERAS) combined with mobile microendoscopic discectomy-transforaminal lumbar interbody fusion (MMED-TLIF) in the treatment of lumbar spondylolisthesis and its influence on postoperative rehabilitation. Methods: From October 1 2014 to July 1 2016 , a cohort of 52 patients with lumbar spondylolisthesis who received the program of ERAS-MMED-TLIF were retrospectively reviewed in Department of Minimally Invasive Spine Surgery, Tianjin Hospital.The primary outcomes include the operation time, intraoperative blood loss, length of hospital stay, VAS score (low back pain and leg pain) and Oswestry Disability Index (ODI) at different follow-up time and complication.The height of intervertebral space and fusion rate were also recorded as radiographic indicators. Results: All cases had an average follow-up of 12 months. The mean operative time was (115+/-30) min with a mean blood loss of (100+/-35) ml.Compared with preoperative condition, VAS score of low back pain (6.3+/-3.3 vs 3.5+/-2.3, P<0.05), VAS score of leg pain (7.1 +/- 4.2 vs 3.1 +/- 2.6, P<0.05) and the ODI disability index score (43.5+/-9.6 vs 20.9+/-7.3, P<0.05) at the postoperative 24 h were decreased and the difference was statistically significant.The mean hospitalized time were (4.9+/-1.3) days with mean postoperative hospital stay (2.1+/-1.2) days.Fusion rate was 92.31% (48/52) at the last follow-up time. Conclusion: ERAS combined with MMED-TLIF is feasible in the treatment of lumbar spondylolisthesis, which can significantly reduce intraoperative bleeding, shorten the total length of stay and postoperative hospital stay, improve postoperative pain and promote rapid rehabilitation of patients after operation without increasing the operation time and influencing the long-term effect, it can be applied in clinical practice. PMID- 28648001 TI - [CT findings and clinical features of Takayasu's arteritis with pulmonary artery involvement]. AB - Objective: To explore the CT findings of the Takayasu's arteritis (TA)with pulmonary artery (PA) involvement and its clinical significance. Methods: A total of 35 patients with TA involving the PA in Xijing Hospital from November 2007 to November 2016, 6 male cases, 29 female cases, the age was 15-52 (28+/-9) years old, were retrospectively collected and included in the study group (TA+ P group), meanwhile 40 patients with TA but not involving the pulmonary artery in this hospital from January 2015 to November 2016 were collected as control group, 5 male cases, 35 female cases, the age was 7-67 (28+/-12) years old.The clinical and laboratory data, the pulmonary artery and right heart measurement data of the two groups were compared by using t test, chi(2) test , and rank sum test.The CT signs of pulmonary artery involvement in the TA+ P group were analyzed. Results: TA+ P group patients had shortness of breath, wheezing(54.3% vs 10.0%), cough(31.4% vs 12.5%)and palpitations(11.4% vs 0)mostly, and there were statistical difference between TA+ P group and TA group (all P<0.05), However, there was no difference between the two groups in the activity and duration of disease (all P>0.05). In TA+ P group, a total of 312 pulmonary artery segments were involved in 35 patients.The lumen stenosis of PA was more common(35 cases, 211 segments), followed by occlusion(14 cases, 94 segments), bilateral PA (23 cases, 217 segments) and multiple branches of PA involvement(34 cases, 311 segments) were more common.The PA systolic pressure, the diameter of main pulmonary artery, right atrium and right ventricular width of the TA+ P group patients were significantly higher than those of the TA group (all P<0.05). Conclusions: There are some CT certain characteristics in TA pulmonary arterial involvement, and they are not related to the activity and duration of the disease.Most patients with PA involvement present pulmonary hypertension and a series of special clinical manifestations. PMID- 28648002 TI - [Application value of whole brain 3D artery spin labeling in diagnosis of intracranial tumors]. AB - Objective: To investigate the perfusion characteristics of arterial spin labeling (ASL) in intracranial tumor and its application value in classification. Methods: The clinical, pathological and imaging data of 44 patients with gliomas confirmed by pathology were analyzed retrospectively, including 9 low grade gliomas, 15 high grade gliomas, 11 cases of meningiomas, 6 cases of neurilemmoma, 3 cases of metastatic tumors.Conventional plain scan, 3D- ASL and MRI dynamic enhanced imaging (DSC-MRI) were performed.The mean maximal cerebral blood flow (CBF) of the solid component of tumor was obtained based on the region of interest.Immunohistochemical staining was performed in 24 patients with glioma.The differences of cerebral blood flow map (CBF) and relative cerebral blood flow (rCBF) in 44 patients with intracranial tumors were compared. The results of paired t test between the tumor area and the contralateral mirror area were measured by the two methods. Results: Taken the normal control-lateral grey matter(GM) as reference to normalize the CBF of tumor, three normalized tumor blood flow (nTBF) acquired by ASL showed statistical difference between low grade and high grade gliomas respectively (P<0.05). While taken the mirror region (M) and normal control-lateral white matter (WM) as reference to normalize the CBF of tumor, it showed no statistical difference (P>0.05). There was no 1p deletion in the cases of ASL perfusion in low-grade glioma group.In the case of 1p deletion in high grade glioma group, ASL was low perfusion, and there was no 1p deletion in the cases of ASL perfusion. Conclusion: 3D ASL can be used to identify high grade and low-grade gliomas which has important reference value in the qualitative diagnosis of brain tumors and preoperative grading of gliomas.A separate use of 3D-ASL might cause over-or underestimation of tumor diagnosis, therefore a comprehensive analysis is needed. PMID- 28648003 TI - [Curative effect analysis of 15 cases of cervical intra-and extra-spinal tumors by microsurgical resection]. AB - Objective: To explore the curative effect of microsurgical treatment of cervical intra- and extra-spinal tumors. Methods: The clinical data of 15 patients with cervical intra-and extra-spinal tumors in Department of Neurosurgery, the First Affiliated Hospital of Bengbu Medical College from January 2013 to February 2017 were retrospectively analyzed. According to Shaw's tumor stage: 6 cases in stage I, 5 cases in stage II, 3 cases in stage III, and 1 case in stage IV. About the surgical methods: 9 cases were treated via posterior median semi-laminectomy approach, of which were internal fixation in 2 cases, and via posterior median approach spinous process and vertebral plate complex orthotopic replantation to spinal canal plasty in 3 cases, other 3 cases were operated via anterior cervical approach, including internal fixation in 1 case. After the surgery, vertebral canal MRI was adopted to evaluate the tumor, and CT three-dimensional reconstruction or X-ray of the spine was used for assessing the stability of spinal column, and Frankel grading standard was employed to evaluate the recovery of spinal cord function. Results: The tumors were totally resected in the first stage with the help of a microscope. Histological types of the tumors included schwannoma in 14 cases, gangliocytoma in 1 case. There was no leakage of cerebrospinal fluid and infection of incisional wound after operations. After the surgery, Frankel grading standard was adopted to assess the recovery of the spinal cord function, and the results showed grade D in 4 patients and grade E in 11 patients. All patients were followed-up for 1 to 24 months with an average of 13 months without tumor recurrence and spinal instability. Conclusion: Appropriate surgical approach should be selected to treat the cervical intra- and extra-spinal tumors, totally resection of the tumor could be achieved under the microscope, and the corresponding vertebral reconstruction and spinal fixation should be used to maintain spinal stability if necessary. PMID- 28648004 TI - [Effects of botulinum toxin type A injection for pathological characteristic of calf in rats with spinal cord injure]. AB - Objective: To explore the effect of BoTN-A on pathological characteristics of calf (GM) and motor function of ankle dorsiflexors in SCI model rats. Methods: Thirty-six SD male rats (weight 260-280 g) were randomly allocated into normal control group and 12w-control group, NS-injection group and BT-injection group in this study.NS/BT-injection groups were divided into two subgroups separately (2w NS, 2w-BT, 8w-NS, 8w-BT). No injection was applied in normal control group or 12w control group.Saline/BoTN-A was injected in right GM in NS/BT-injection group at two different time points(2w, 8w). GM and Sol on right side of rats would be forwarded for pathologicalexaminations, such as muscle weight, myosin heavy chain (MyHC) electrophoretic analysisat the 12th week. Results: Compared with the other three groups, the muscle weights of GM and Sol in the BT-injection group significantly decreased.MyHC type ratioof GM and Sol on the right side in the BT injection group also significantlychanged.According to subgroup comparisons, MyHC type ratio of GM and Sol on the injectedside in the 2w-BT subgroup was significant different from that of the 8w-BT subgroup.MyHC type ratios of GM on the non-injected side in the BT injection group also changed more than normal control group.The change of MyHC type ratio of non-injected GM was significantly higher in the 2 week-BT subgroup than that in the 8-week subgroup. Conclusions: BoNT-A intervention resulted in pathological changes not only in the injected GM in SCI rats, but also in non-injected GM and non-injected Sol.The effects of earlier (2 weeks) BoTN-A intervention on pathologic characteristicsof GM and Sol were larger than that of later intervention. PMID- 28648005 TI - [Components of human placental extract and its protective effect to rat from D GalN induced acute liver injury]. AB - Objective: To evaluate the effect of human placental extracts (HPE) on the protection from acute liver injury (ALI) induced by D-GalN and analyze the components of HPE. Methods: (1)Fourty male mice were randomly divided into five groups (Blank, Model, MgIG, HPE and HPE+ MgIG) for the ALI model and treatments.The serum alanine aminotransferase (ALT) and aspartate transaminase (AST) were determined by biochemical assays.Nitric monoxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) in serum and hepatic tissue were detected by assay kits.The extent of liver damage was evaluated by histological examination.(2)Relative molecular mass of HPE was determined by SDS-PAGE.(3) Component identification was performed by using LCMS TOF.(4)Selected functional molecules in HPE were detected by protein array. Results: (1) A lower level of NO and MDA and a higher SOD and T-AOC were observed in rats treated with HPE compared to the non-treated rats in an acute liver failure disease model.(2) The size of HPE was about 1 200-4 600 by electrophores.(3) 7 peaks of HPE were identified, including uracil, hypoxanthine, tyrosine, phenylalanine, tryptophan, xanthine and thymine.(4) Comparable high concentrations of TGF-beta, IGF-1, IL-9, IL-29 and TNF-alpha of HPE were revealed by protein array. Conclusions: (1) HPE protects rat from liver damage induced by D-GalN. (2) HPE contains Uracil, hypoxanthine, xanthine, thymine, and functional proteins as TGF-beta, IGF-1, IL-9, IL-29 and TNF-alpha. PMID- 28648007 TI - [Current status and prospect of colorectal cancer in precision medical model]. PMID- 28648006 TI - [0.5 Gy X-ray radiation promotes osteoblast differentiation by Wnt/beta-Catenin signaling]. AB - Objective: To investigate the important roles of Wnt signaling in the processes of 0.5Gy X-ray promoting osteoblast differentiation, and make clear the molecular mechanisms involved. Methods: Flow cytometry was employed to detect the apoptosis after osteoblast exposure to 0.5 Gy X-ray radiation.The protein level of osteoblast differentiation markers, such as collagen Ialpha (Col1alpha), alkaline phosphatase (ALP), osteocalcin (OCN), were detected by Western-blot and ALP activity staining was performed. Real-time PCR and Western-blot were utilized to evaluate the variations of key factors in Wnt signaling pathways, while specific inhibitor of Wnt/beta-Catenin, XAV939 was used to block the Wnt signaling. Results: Low-dose (0.5 Gy) X-ray induced significant decline in MC3T3-E1 osteoblast apoptosis at three days after radiation.The dynamic variations in the expression of osteoblast differentiation markers, including Col1alpha, ALP, OCN, were observed after 0.5 Gy X-ray irradiation by Western blot analysis.The protein levels of Col1alpha have a reduction temporarily at 4 days of radiation (34.5%+/ 5.8%, t=9.912, P<0.001), then a significant increase is detected at 10 day after radiation (162.5%+/-6.5%, t=2.673, P<0.05). OCN levels dropped by 83% (t=3.968, P<0.01) at 4 day after 0.5 Gy X-ray radiation, and raised at 10 day (39.5%+/ 4.1%, t=3.219, P<0.05) and 14 day (79.4%+/-7.5%, t=6.708, P<0.001), respectively. ALP levels increased at 7 day (79.7%+/-22.3%, t=6.257, P<0.001) and 10 day(128.3%+/-6.1%, t=4.340, P<0.01)after radiation. At the same time, 0.5 Gy X ray radiation can activate Wnt/GSK-3/beta-Catenin signaling.The mRNA levels of Wnt3a,LPR5 and TCF-4 increased by 1.7 fold (t=6.573, P<0.001), 1.1 fold (t=5.323, P<0.05) and 1.4 fold (t=3.054, P<0.05) at 7 day after radiation.In addition, p GSK-3beta level reduced by 42.1% (t=4.460, P<0.01), and active beta-Catenin increased by 1.9 fold (t=3.528, P<0.05). However, the specific inhibitor of Wnt/beta-Catenin, XAV939 completely abrogated Wnt/beta-Catenin signaling and the increase in ALP expression and activity induced by 0.5 Gy X-ray radiation. Conclusion: These results demonstrated that low dose X-ray radiation promoted osteoblast survival at early differentiation, and promoted differentiation at middle and late stage, in which Wnt signaling participated the regulation processes. PMID- 28648008 TI - [Circulating tumor cells in patients with breast tumors were detected by a novel device: a multicenter, clinical trial in China]. AB - Objective: Circulating tumor cells (CTC) have become an important part of liquid biopsy, which have underwent a process from simple counting to molecular typing and genotyping. To this end, we used Cellcollector to verify the effectiveness and safety of CTC detection in patients with breast tumor, and to conduct the following analysis. Methods: One hundred and ninety patients who received treatment in six leading Chinese cancer centers were involved from April to August in 2016. Among which, 127 patients were diagnosed as metastatic breast cancer, and the other 63 patients as benign breast tumors. Results: In metastatic breast cancer group, 74.8%(95/127) were CTC positive. While in benign tumor group, they were all CTC negative patients. The area under the Receiver Operating Characteristic curve were 0.832(95%CI: 0.784-0.879). The sensitivity of Cellcollector was 74.8%, specificity was 100% (Youden index 0.748). A total of 117 patients in MBC groups received a second detection of Cellcollector after 3-4 weeks, among which 44.4% (52/117) were CTC positive patients. The incidence of adverse events and severe adverse events in MBC was 66.9%(85/127) and 39.8% (53/127). Furthermore, we used Cellcollector to perform the HER2 testing and gene sequencing. Conclusions:In vivo isolation of CTCs overcomes blood volume limitations compared to other approaches. The further application of molecular typing and gene typing might help to implement CTC-based "liquid biopsies" into clinical decision making. PMID- 28648009 TI - [Diagnostic performance of T-SPOT.TB on peripheral blood in combination with adenosine deaminase on pleural fluid for the diagnosis of tuberculous pleurisy within different age group]. AB - Objective: To evaluate the performance of T cell enzyme-linked immuno-spot assay (T-SPOT) on peripheral blood in combination with adenosine deaminase (ADA) on pleural fluid for diagnosis of tuberculous (TB) pleurisy within different age groups. Methods: The data of patients with pleural effusion from the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Wenzhou Medical University from April 2012 to November 2016 were retrospectively analyzed, and the diagnoses of these patients were histopathologically confirmed through medical thoracoscopy. The cases who had confirmed diagnosis, in the same time, received peripheral blood T-SPOT.TB were enrolled. The performance of peripheral blood T-SPOT.TB in combination with pleural fluid ADA on diagnosing TB pleurisy in the younger patients (16-59 years old) and elderly patients (>=60 years old) were analyzed respectively. The sensitivity, specificity and the receiver operating characteristic (ROC) curve were adopted for statistical analysis. Results: A total of 448 cases were finally enrolled, 341(76.1%) confirmed with TB pleurisy, 224 males, 117 females, (47+/-19) years old; and 107 (23.9%) classified as non-TB pleurisy, 65 males, 42 females, (61+/-14) years old. There were 285 cases who were classified as younger group, and the other 163 cases were classified as elderly group. The sensitivity and specificity of peripheral blood T-SPOT.TB were 85.4% (204/239) and 71.7% (33/46) in the younger patients, 76.5% (78/102) and 59.0% (36/61) respectively in the elderly patients. The sensitivity of peripheral blood T-SPOT.TB in the younger patients was significantly higher than that in the elderly patients (P=0.047). The sensitivity and specificity were 99.2% and 95.7% in combination with peripheral blood T SPOT.TB and pleural fluid ADA respectively in the younger patients. The area under ROC curve (AUC) of T-SPOT.TB in the younger patients was 0.833, AUC of T SPOT.TB combined with ADA was 0.911. The combination test of 2 tests had the sensitivity of 96.1% and the specificity of 90.2% respectively in the elderly patients. The AUC of T-SPOT.TB in the elderly patients was 0.747, AUC of T SPOT.TB combined with ADA was 0.911. Conclusion: Peripheral blood T-SPOT.TB combined with pleural fluid ADA can improve the diagnostic performance for TB pleurisy with different ages, especially for elderly patients who can't tolerate pleural biopsy. PMID- 28648010 TI - [Experience of Sun's procedure for chronic type B dissection with aortic arch involvement]. AB - Objective: To study the surgical treatment of chronic type B dissection with aortic arch involvement using Sun's procedure. Methods: Between February 2009 and December 2015, 29 patients [20 males, 9 females, with a mean age of (41+/-12) years, range 24-64 years] with type B dissection with aortic arch involvement underwent Sun's procedure. Sixteen patient had a history of hypertension. Marfan syndrome was observed in 9 cases, coronary artery disease in 3 cases, mitral regurgitation in 3 patients, cerebrovascular disease in one patient. Twenty-two patients suffered proximal aortic arch disease, 4 cases experienced history of aortic root procedure and 2 subjects had history of pregnancy. Four patients had aortic arch malformation. Results: One case suffered from massive cerebral infarction after surgery and died in another hospital. Concomitant procedures included mitral valve replacement in 3 cases, coronary artery bypass grafting in 3 patients, reconstruction of the right aberrant subclavian artery in one patient. Ventilator support exceeding 24 hours obseved in 2 patients. One of them recieved continuous renal replacement therapy and recovered before discharge. Spinal cord injury was obseved in one case, brain infarction in one patient and pericardial drainage in one case. Two patients required tracheotomy. During 12-94 (43+/-23) months' follow-up, thoracoabdominal aortic replacment was performed in 4 patients, thoracic endovascular aortic repair (TEVAR) in 2 subjects and repair of perivalvular leakage in one patient. Conclusions: Sun's procedure obtained satisfactory results in patients with chronic type B dissection with aortic arch involvement. Concomitant repair of proximal aortic arch lesions and distal type B dissection can be adopted using Sun's procedure. PMID- 28648011 TI - [Relationship between carotid plaque and diabetic retinopathy in type 2 diabetes mellitus patients]. AB - Objective: To analyze the relevant factors for diabetic retinopathy. Methods: The data of type 2 diabetes mellitus patients undergoing general examination and ophthalmology specialist consultation were collected from the inpatients of Department of Endocrinology in Beijing Airport Hospital between 2013 and 2016, and the relevant factors of diabetic retinopathy were retrospectively analyzed. Results: A total of 432 cases were analyzed, including 168 cases of non-diabetic retinopathy and 264 cases of diabetic retinopathy. In the non-diabetic retinopathy group, there were 88 cases of male and 80 cases of female, with an mean age of (57.0+/- 13.6) years old. Meanwhile, the diabetic group had 142 cases of male and 122 cases of female, with an mean age of (62.7+/-10.4) years old. Univariate logistic regression analysis showed that age and glycosylated hemoglobin value were significantly higher in the diabetic retinopathy group than those of the non-diabetic retinopathy group, and the incidence of diabetic peripheral neuropathy, carotid plaque and central retinal thickness was significantly higher than that of the non-diabetic retinopathy group. Multivariate logistic regression analysis displayed that carotid plaque (OR=9.922, 95%CI: 3.700-26.603, P<0.001) and thinning of central retinal thickness (OR=9.639, 95%CI: 3.604-25.781, P<0.001) were independently associated with diabetic retinopathy. Conclusions: Carotid plaque is an independent risk factor for diabetic retinopathy, and thinning of central retinal thickness may indicate the progression of retinopathy. Therefore, patients with these two signs need to be observed more closely in clinical practice. PMID- 28648012 TI - [Validation of the Caprini risk assessment model for venous thromboembolism in Chinese hospitalized patients in a general hospital]. AB - Objective: To assess the validity of Caprini risk assessment model in prediction of venous thromboembolism in Chinese hospitalized patients in a general hospital. Methods: Medical record review was performed in Beijing Shijitan Hosital for all eligible hospitalized patients who underwent screening for venous thromboembolism between January and December 2015. The Caprini score of patients with or without venous thromboemboilism and incidence of venous thromboembolism in patients with various Caprini risk levels, surgery and medical patients was compared. Results: A total of 6 966 inpatients were enrolled. Three hundred and ninety-six patients developed venous thromboembolism. The Caprini median score of patients with venous thromboemboilism was 5 (3-7), which higher than 3(2-5) of patients without venous thromboembolism(Z=-13.68, P<0.01). Incidence of venous thromboembolism of patients in low, moderate, high, highest risk level was 1.0%, 1.8%, 5.7%, 10.6%, respectively. There was no statistically significant difference of incidence between low and moderate risk patients (OR=1.88, 95%CI: 0.89-3.99, P>0.05), but significant difference between moderate and high risk (OR=3.23, 95%CI: 2.06-5.06, P<0.01), high and highest risk patients (OR=1.97, 95%CI: 1.59-2.45, P<0.01). There was no incidence difference of venous thromboembolism between surgery and medical patients in the same Caprini level of low (chi(2)=3.58 , P>0.05), moderate(chi(2)=2.89, P>0.05), high(chi(2)=0.46, P>0.05), highest risk(chi(2)=1.61, P>0.05). Conclusion: Caprini risk assessment model can effectively predict the occurence of venous thromboembolism in Chinese hospitalized patients with high risk of VTE(Caprini score >2)in a general hospital. PMID- 28648013 TI - [Retrospective analysis of anesthetic and perioperative management in patients of acute fatty liver of pregnancy]. AB - Objective: To retrospectively analyze the clinical characteristics of patients with acute fatty liver of pregnancy (AFLP), and to discuss perioperative and anesthetic management. Methods: A retrospective review was conducted on the records of pregnant patients with a diagnosis of acute fatty liver of pregnancy in Peking University Third Hospital from January 2007 to December 2015. 12 cases were identified. The clinical features, preoperative laboratory findings, types of delivery, anesthetic techniques for cesarean section, and the outcomes of parturients and fetus were collected and analyzed. Results: Among the 12 cases, 91.7% were primigravid, 50% had twin pregnancies, and one was diagnosed with concomitant preeclampsia. The common clinical features included nausea (6 cases, 54.5%), vomiting (5 cases, 45.5%), jaundice (5 cases, 45.5%), malaise (3 cases, 27.3%), epigastric discomfort (2 cases, 18.2%), anorexia (2 cases, 18.2%) and regurgitation (1 case, 9.1%). Laboratory tests mainly showed impaired hepatic function and hypoglycemia. Cesarean deliveries were performed in 10 of the 11 patients diagnosed antepartum. Cesarean section was performed under neuraxial anesthesia (1 case) or general anesthesia (9 cases). The patient transferred to our center after delivery and diagnosed postpartum died. All the patients diagnosed antepartum survived. 6 out of the 18 fetuses were transferred to the pediatric department due to preterm, low birth weight, intrauterine restriction or asphyxiation, and were all survived. Conclusions: AFLP is one of the most severe complications in parturients. Prognosis can be improved with early diagnosis and prompt termination of pregnancy. Hepatic function, coagulation status and urgency of delivery should be well considered to choose the appropriate anesthetic method, and anesthetic management should be individualized. PMID- 28648014 TI - [Clinical efficacy observation of atomization inhalation combined with oral administration of oseltamivir in 4 cases with H7N9 avian influenza]. AB - Objective: To investigate the clinical efficacy of atomization inhalation combined with oral administration of oseltamivir in treatment of human infection with H7N9 avian influenza. Methods: To analyze the clinical data of 4 patients hospitalized from Mar 6th 2017 to Apr 12th 2017 with avian influenza(H7N9) infection treated by conventional therapy(oseltamivir, 150 mg, po, Bid) plus with oseltamivir inhalation(75 mg dissolved in 20 ml N. S, Bid) and administered with antibacterial treatment, blood purification and immunomodulators. Results: Undergoing these comprehensive therapies, Bronchial lavage fluid and pharynx of 1 case was negative for H7N9 RNA after 24 h, 2 cases negative for H7N9 after 3 d and 1 case negative for H7N9 RNA after 4 d. All patients were cured and discharged without any complications. Conclusions: Aseltamivir inhalation combined with oral treatment can significantly shorten the time of virus nucleic acid turning negative, improve the efficacy of anti avian influenza virus H7N9, and increase the cure rate of avian influenza H7N9 infection patients. PMID- 28648015 TI - [Therapeutic effects of Tubastatin A Hcl on airway inflammation in acute mice asthma model]. AB - Objective: To investigated the therapeutic effects of Tubastatin A Hcl, a selective HDAC6 inhibitor, on airway inflammation in acute mice bronchial asthma (asthma) model. Methods: A total of 48 BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and Tubastatin A Hcl group with 12 mice in each group. Then the airway hyperresponsiveness was assessed in each group; total cell number, different cell number, levels of Interleukin (IL)-4, IL 5 and Interferon-gamma (IFN-gamma) in the bronchoalveolar lavage fluid (BALF) were detected; the lung tissues of each group were stained with HE to observe the inflammatory cells infiltration. AB-PAS was used to observe the goblet cell metaplasia in tracheal epithelium. Masson staining was used to observe the collagen deposition in lung tissue. Results: The airway reactivity in Tubastatin A Hcl group was significantly lower than that in asthma group [(4.18+/-0.94) vs (6.02+/-0.47), P<0.05]; in the Tubastatin A Hcl group, the total inflammatory cells [(57.0+/-5.7)*10(4)/ml vs (87.0+/-5.6)*10(4)/ml], eosinophil cells [(6.8+/ 1.7)*10(4)/ml vs (12.3+/-3.5)*10(4)/ml] and levels of IL-4 [(19.3+/-2.7) vs (26.2+/-3.2)ng/ml] in BALF were obviously lower than those of asthma group (all P<0.05); IL-5 in Tubastatin A Hcl group was lower and IFN-gamma was higher than that of asthma group, while there were no significant differences (both P>0.05). The degree of inflammatory cells infiltrations around the airway and vascular, number of inflammatory cells [(9.80+/-2.42) vs (20.67+/-7.53)], score of inflammation [(2.20+/-0.70) vs (3.60+/-0.68) points, ], and percentage of goblet cell metaplasia [(50.46+/-5.03)% vs (71.06+/-5.38)%] in the lung tissue of Tubastatin A Hcl group were lower than that of asthma group (all P<0.05). Although collagen deposition in the lung tissue of Tubastatin A Hcl group was lower than asthma group, there were no significant differences (P>0.05). However, all of the above results in the dexamethasone group were slightly better than Tubastatin A Hcl group, which had no significant differences (P>0.05). Conclusion: Tubastatin A Hcl can effectively alleviate the level of airway inflammation in acute asthma, but its anti-inflammatory effect is limited, which is not as significant as dexamethasone. PMID- 28648016 TI - [Mechanisms of cytoskeleton and PI3Kdelta-RhoA in fine particulate matter deteriorating phagocytosis defect of alveolar macrophage in mice with chronic obstructive pulmonary disease]. AB - Objective: To explore the mechanism of cytoskeleton and PI3Kdelta-RhoA in fine particulate matter deteriorating phagocytosis defect of alveolar macrophage (AM) in chronic obstructive pulmonary disease (COPD) mice. Methods: Forty mice were randomly divided into four groups: health control group, COPD group, health PM2.5 group, COPD PM2.5 group and with ten in each group. A mouse model of COPD was established by cigarette smoke exposure, and health PM2.5 group and COPD PM2.5 group mice were given PM2.5 (588 MUg/m(3)) aerosol inhalation for 90 days. AM were isolated from lung tissue by discontinuous density gradient centrifugation. Mean fluorescence intensity (MFI) and the percent of alveolar macrophage engulfing flurescein isothiocyanate-labeled Escherichia coli (FITC-E.coli) AM (AM%) were detected by flow cytometry. The mRNA and protein expression were measured by real time polymerase chain reaction (RT-PCR) and Western blot. The activity of RhoA was measured by GTPase linked immunosorbent assay (G-LISA) Kit. Cytoskeleton was observed by laser scanning confocal microscopy. Results: The MFI and the AM% in COPD group [4 512+/-517, (32.19+/-4.57)%] and health PM2.5 group [7 631+/-585, (50.78+/-4.58)%] were significantly lower than those in health control group [9 857+/-1 042, (68.53+/-2.88)%], while those in COPD PM2.5 group [3 121+/-393, (21.90+/-2.58)%] were lower than those in COPD group (all P<0.01). The mRNA and protein of PI3Kdelta in COPD group (3.41+/-0.54, 0.84+/-0.08)and health PM2.5 group (1.52+/-0.35, 0.71+/-0.11) were higher than those in health control group (1.00+/-0.00, 0.57+/-0.07) (all P<0.05), and in COPD PM2.5 group (5.53+/-0.42, 1.17+/-0.25), the above parameters were remarkably increased as compared to those in COPD group (all P<0.01). The mRNA, protein and activity of RhoA in COPD group (0.70+/-0.07, 0.41+/-0.10, 0.70+/-0.06) and health PM2.5 group (0.84+/-0.06, 0.46+/-0.11, 0.87+/-0.07) were lower than those in health control group (1.00+/-0.00, 0.56+/-0.09, 1.19+/-0.09) (all P<0.05), and above parameters of COPD PM2.5 group (0.42+/-0.05, 0.31+/-0.06, 0.44+/-0.04) were significantly lower than COPD group (all P<0.01). Cytoskeleton of AM: long and dense filopodia and membrane fold could been seen clearly around the AM of health control group; in COPD group and health PM2.5 group, short and sparse filopodia and slightly deformed AM can been seen. Filopodia remarkably decreased and rigid cells with impaired capacity of engulfing FITC-E.coli can be generally observed in COPD PM2.5 group. Negative correlations were existed between PI3Kdelta mRNA, protein and RhoA mRNA, protein, activity in all groups (all P<0.01). Negative correlations were existed between PI3Kdelta mRNA, protein and MFI, and positive correlations were existed between RhoA mRNA, protein, activity and MFI in all groups (all P<0.05). Conclusion: Fine particulate matter (PM2.5) can deteriorate the phagocytosis of AM from COPD mice through over activating PI3Kdelta and inhibiting the activity of RhoA then causing cytoskeleton abnormal rearrangement. PMID- 28648017 TI - [Precision medicine and its practice in China]. PMID- 28648018 TI - [Is the heart failure with preserved ejection fraction and isolated]. PMID- 28648019 TI - [Update on cardiovascular precision medicine]. PMID- 28648020 TI - [Precision cardiovascular medicine: is the new era already here?] PMID- 28648021 TI - [Twenty years experiences on the therapy of pulmonary artery hypertension: from classical diagnostics and treatment strategies to precision medicine]. PMID- 28648022 TI - [Heart failure with preserved ejection fraction might be the early-stage of heart failure with reduced ejection fraction]. PMID- 28648023 TI - [heart failure with preserved ejection fraction is a special type of heart failure]. PMID- 28648024 TI - [Comparison on the efficacy and safety of different occlusion devices for the treatment of patients with patent foramen ovale]. AB - Objective: To compare the efficacy and safety of Cardi-O-fix patent foramen ovale (PFO) occluder and Amplatzer PFO occluder for the treatment of patients with PFO. Methods: A total of 246 consecutive patients (105 males and 141 females) with PFO were prospectively enrolled from May 30, 2013 to March 30, 2015 in our hospital. PFO interventional closure was applied according to the anatomical structure of the disease and patients' wishes.Cardi-O-fix PFO occluder was used in 180 cases (COF group), Amplatzer PFO occluder was used in the remaining 66 cases (Amp group). Post-procedure safety including recurrent stroke, transient ischemic attack, death, and complete closure rate, and efficacy including procedure related complications of different devices were compared during the 12 months follow-up. Results: (1) Rate of transient ischemic attack was similar between COF group and Amp group at 12 months after procedure(1.1%(2/180) vs. 1.5%(1/66), P=1.000). There was no recurrent stroke and death during the 12 months follow-up period.Complete closure rate was similar between COF group and Amp group at 12 months after the procedure(90.6%(163/180)vs. 86.4%(57/66), P=0.355). (2) Three cases(1.7%) of paroxysmal atrial fibrillation were observed in COF group during the 12 months follow-up period, 1 patient converted spontaneously to sinus rhythm and 2 patients received successful pharmacologic conversion and converted to sinus rhythm. One patient(1.5%)developed paroxysmal atrial fibrillation and was pharmacologically converted to sinus rhythm in the Amp group. There was no significant difference in rate of paroxysmal atrial fibrillation between the two groups(P=1.000). There was no complications such as occluder translocation, erosion, pericardial effusion and puncture site bleeding in the 2 groups during the 12 months follow-up. Conclusion: Efficacy and safety are similar for PFO treatment with Cardi-O-fix PFO occluder or Amplatzer PFO occluder in this patient cohort. PMID- 28648025 TI - [Comparison of aortic valve dysfunction and ascending aorta dimension between patients with different bicuspid aortic valve morphology]. AB - Objective: To compare the characteristics of aortic valve dysfunction and ascending aorta dimension in patients with different bicuspid aortic valve (BAV) morphology. Methods: A total of 197 patients who underwent aortic valve replacement between April 2014 and March 2015 and were diagnosed with BAV by pathology were included, and their clinical data were retrospectively analyzed. Patients were divided into raphe(+) group(109 cases) and raphe(-) group(88 cases) according to the presence or absence of raphe, and L-R group(fusion of left and right cusp, 125 cases) and L/R-N group(fusion of left or right and noncoronary cusp, 72 cases) according to fusion type of the cusps. The characteristics of aortic valve dysfunction and ascending aorta dimension in patients with different BAV morphology were compared. Results: (1) Aortic stenosis incidence was lower in raphe(+) group than in raphe(-) group(22.9%(25/109) vs. 69.3%(61/88), P<0.001). Aortic regurgitation incidence was higher in raphe(+) group than in raphe(-) group (61.5%(67/109) vs. 22.7%(20/88), P<0.001). Incidence of type 1 of aortic root dilation was higher in raphe(+) group than in raphe(-) group (23.9%(26/109)vs.10.2%(9/88), P=0.024). (2) Aortic stenosis incidence was lower in L-R group than in L/R-N group(29.6%(37/125) vs. 68.1%(49/72), P<0.001). Aortic regurgitation incidence was higher in L-R group than in L/R-N group (59.2%(74/125) vs. 18.1%(13/72), P<0.001). Incidence of type 3 of aortic root dilation was lower in L-R group than in L/R-N group(10.4%(13/125) vs. 37.5%(27/72), P=0.006). (3) Aortic stenosis incidence was lower in L-R patients than in L/R-N patients(15.1%(13/86)vs. 52.2%(12/23), P=0.001), and aortic regurgitation incidence was higher in L-R patients than in L/R-N patients in raphe(+) group(73.3%(63/86)vs. 17.4%(4/23), P<0.001). Conclusion: There is significant difference in the type of valvular dysfunction and ascending aorta dilatation in patients with different morphological characteristics of BAV. PMID- 28648026 TI - [Serum uric acid is associated with disease severity and an important predictor for clinical outcome in patients with pulmonary hypertension]. AB - Objective: The growing body of literature showed a link between uric acid and pulmonary hypertension (PH), but the impact of hyperuremia on outcome of patients with PH has not been well defined. Therefore, the present study was performed to analyze the impact of uric acid on outcome of PH patients. Methods: One hundred seventy-three PH patients (112 females, mean age 38 years old), who were hospitalized in our department between January 2010 and December 2015, were included in our study, the PH diagnosis was made based on right heart catheterization examination result (mean pulmonary artery pressure>=25 mmHg(1 mmHg=0.133 kPa)). PH patients were divided into mild to moderate PH group (Rp/Rs<=0.6, n=97) and severe PH group (Rp/Rs>0.6, n=76). Fifty-one patients (33 females, mean age 45 years old) without PH based on right heart catheterization were included as control subjects. All participants were followed up for a median of 24 months(6-71 months). Clinical endpoints were defined as cardiogenic death or heart-and-lung transplantation. Results: Uric acid was positively correlated with pulmonary vascular resistance(r=0.398, P<0.01), systemic vascular resistance(r=0.244, P<0.01) and mean right atrial pressure (r=0.26, P<0.01), and was negatively correlated with cardiac index(r=-0.278, P<0.01)and mixed venous oxygen saturation (r=-0.322, P<0.01)in PH patients. Serum uric acid level was significantly higher in patients with severe PH than in patients with mild-to moderate PH and the control subjects (both P<0.05). According to the receiver operating characteristic curve (ROC), 425.5 MUmol/L was found to be the best cut off value of serum uric acid level to predict the outcome of PH patients (sensitivity 50%, specificity 72%). During follow-up, patients with higher level of uric acid (>425.5 MUmol/L) were linked with poorer clinical outcome compared to patients with uric acid <425.5 MUmol/L(P=0.027). Conclusion: Our findings suggests that uric acid is associated with the severity of PH and higher uric acid level serves as an important predictor for poor clinical outcome of PH patients. PMID- 28648027 TI - [SIRT1 signaling pathway mediated the protective effects on myocardium of rats after endurance training and acute exhaustive exercise]. AB - Objective: To detect the expression of SIRT1 and Ac-FOXO1 in rats after endurance training and acute exhaustive exercise, and explicit the myocardial protective effect of SIRT1. Methods: Rats were randomly divided into four groups: control group(n=20), exhaustive exercise group (E group, n=20), exhaustive exercise group + endurance training (TE group, n=18), exhaustive exercise group + endurance training + selective SIRT1 inhibitor (TSE group, n=17). The Control and E groups were fed routinely for 5 weeks. The TE and TSE groups were subjected to swimming exercise for 5 weeks for endurance exercising. The TSE group was intraperitoneally injected with selective SIRT1 inhibitor Sirtinol(2 mg/kg) at 30 minutes before endurance exercising. The E, TE and TSE groups were subjected to exhaustive exercise. The myocardial tissues of rats were collected after exhaustive exercise. Real-time polymerase chain reaction (PCR) and Western blot analysis were performed to detect the myocardial mRNA and protein expressions of SIRT1 and Ac-FOXO1. The myocardial protein expression of Bax and Bcl-2 was also detected by Western blot. Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay was used to assess the apoptosis of myocardial cells. Results: Compared with Control group, the SIRT1 and Bcl-2 expression in the myocardial tissue was obviously decreased, while the Ac-FOXO1, Bax, and the myocardial cell apoptosis were significantly increased in E group (all P<0.01). Compared with E group, the expression of SIRT1 and Bcl-2 was obviously up regulated (both P<0.01), while the Ac-FOXO, Bax and the myocardial cell apoptosis was significantly reduced in TE group (all P<0.01). Compared with TE group, the SIRT1 and Bcl-2 expression was obviously lower (both P<0.01), while Ac-FOXO1, Bax, and the cell apoptosis were significantly higher in group TSE (all P<0.01). Conclusion: Endurance training could protect myocardium by reducing the myocardial oxidative stress injury and apoptosis via activating SIRT1 signaling pathway, up-regulating the myocardial expression of SIRT1 and regulating the deacetylation of FOXO1. PMID- 28648028 TI - [Expression changes of Notch and nuclear factor-kappaB signaling pathways in the rat heart with myocardial infarction]. AB - Objective: To observe the expression changes of Notch and nuclear factor-kappaB (NF-kappaB) signaling pathways in rat myocardium post myocardial infarction. Methods: Myocardial infarction was established by ligation of the left anterior descending coronary artery(MI group), sham rats (similar surgical procedure without coronary artery ligation) served as control, the rats were sacrificed at first week, 4th and 8th week after operation, the non-infarct myocardial tissue in both groups was obtained to detect the mRNA expression of Notch1, Dll4 and Hes1 by RT-PCR, the protein expression of NICD1 was detected by Western blot, the nuclear protein p65 content was detected to reflect the activation degree of NF kappaB signaling in the cardiomyocytes. Results: The myocardial mRNA expression of Notch1 in MI group was significantly higher than in control group (1.68+/-0.35 vs. 0.47+/-0.12, P<0.05) at first week, and tended to be higher at the 4th week and 8th week (P>0.05). The mRNA expression of Dll4 and Hes1 was similar between the two groups at the three time points. NICD1 protein level was increased at the first week in MI group as compared with control group (1.31+/-0.33 vs.0.45+/ 0.11, P<0.05), which tended also to be higher at the 4th week and 8th week post operation (P>0.05). For NF-kappaB activation study, the nuclear protein p65 content was higher at first week, 4th week and 8th week in MI group as compared with respective control groups (0.286+/-0.052 vs.0.049+/-0.016 (P<0.01), 0.247+/ 0.056 vs. 0.043+/-0.018 (P<0.01), 0.120+/-0.033 vs. 0.044+/-0.009 (P<0.05)), the most significant increase was found in the first week. Conclusions: Notch and NF kappaB signaling pathways are actively involved in the process of ventricular remodeling after myocardial infarction. Notch1 and NF-kappaB signaling pathways are both activated at the first week after myocardial infarction, NF-kappaB signaling pathway activation after myocardial infarction continues up to 8 weeks. These two signal transduction pathways may thus serve as new targets for future intervention studies to prevent heart failure. PMID- 28648029 TI - [Effects of overexpression of human tissue inhibitor of metalloproteinase-1 on the inflammatory response in rats with myocardial infarction and related mechanisms]. AB - Objective: To observe the effects of recombinant adenovirus with human tissue inhibitor of metalloproteinase-1(Ad-hTIMP-1) on the inflammatory response in rats with myocardial infarction (MI) and explore the related mechanisms. Methods: The male Wistar rats were randomly divided into sham-operated group, saline group, Ad Track group and Ad-hTIMP-1 group according to the random number table (n=8 each group). MI was induced by ligation of the left anterior descending coronary artery and MI rats were injected with saline, Ad-Track and Ad-hTIMP-1, respectively. Sham-operated rats received similar surgical procedure without ligation of the left anterior descending coronary artery. After 4 weeks, the cardiac function was measured by echocardiography, then rats were sacrificed and hearts were removed for morphological and biological analysis. The morphology of myocardial tissue in each group was detected by HE staining and Masson staining. The mRNA expressions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL 10 and C-reactive protein(CRP) were detected by real-time PCR. Immune histochemical staining was performed to observe the protein expression levels of IL-6 and CRP. Results: (1) Left ventricular end systolic dimension derived from echocardiography was increased in saline group ((5.10+/-0.72) mm) and Ad-Track group ((4.88+/-0.64) mm) compared to sham-operated group ((4.25+/-0.46) mm), which was reduced in Ad-hTIMP-1 group ((4.13+/-0.35) mm, all P<0.05). The left ventricular ejection fraction was (72.46+/-5.74)%, (64.27+/-8.52)%, (64.65+/ 3.90)%, and (71.55+/-6.95)%, the fractional shortening was (36.90+/-4.97)%, (29.03+/-3.40)%, (30.95+/-2.51)%, and (36.31+/-5.68)% in sham-operated group, saline group, Ad-Track group and Ad-hTIMP-1 group, respectively. The left ventricular ejection fraction and fractional shortening in saline group and Ad Track group were lower than those in sham-operated group and Ad-hTIMP-1 group (all P<0.05). (2) Necrosis of myocardial cells was not found and a small amount of immune cell infiltration and interstitial fibrosis were observed on HE and Masson stained myocardial sections of Ad-hTIMP-1 group. (3) Real-time PCR showed that mRNA expressions of TNF-alpha, IL-6, IL-10 and CRP were lower in Ad-hTIMP-1 group than in saline group. mRNA expressions of TNF-alpha, IL-10 and CRP were lower in Ad-hTIMP-1 group than in Ad-Track group (all P<0.05). (4) Immune histochemical staining showed that protein expressions of IL-6 and CRP were higher in saline group and Ad-Track group than those in Ad-hTIMP-1 group (all P<0.05). Conclusion: Recombinant adenovirus Ad-hTIMP-1 can improve cardiac function in rats with myocardial infarction via inhibiting the inflammatory response and downregulating the expression of TNF-alpha, IL-6 and CRP. PMID- 28648030 TI - [Effect and mechanism of intermittent alkaline stimulation on high phosphorus induced calcification in vascular smooth muscle cells of rats]. AB - Objective: To explore the effect and possible mechanisms of intermittent alkaline on rat vascular smooth muscle cells (VSMCs) calcification induced by high phosphorus. Methods: VSMCs were isolated from rat thoracic aorta and cultured in vitro. The fourth generation VSMCs were randomly divided into control group, high phosphorus+ pH7.4, high phosphorus+ pH7.5, high phosphorus+ pH7.6 and high phosphorus+ pH7.7 group with random number table. The control group was cultured in DMEM with 10% fetal bovine serum. Other groups were cultured in DMEM with 10 mmol/L beta-glycerophosphate and alkalized by 7.4% NaHCO(3) to adjust the pH respectively. After the intervention of 4 hours, the control group was replaced with the normal medium containing 10% fetal bovine serum, the other 4 groups were replaced with high phosphorus based on the pH value of the culture medium, and then replaced the culture medium every other day. After 4 days intervention, the mRNA and protein expression of L type calcium channel beta(3) subunit(LTCC beta(3)) and Runt related transcription factor 2 (Runx2) were detected by RT-PCR and Western blot. After 4 days intervention, the level of VSMC calcium ion was detected by Fluo-3/AM. After 14 days intervention, alkaline phosphatase (ALP) activity was measured by enzyme linked immunosorbent assay (ELISA) and the calcification was observed by measuring calcium content. Results: (1) Compared with control group, the gene and protein expressions of LTCC beta(3) were higher in high phosphorus+ pH7.4 group (0.49+/-0.03 vs. 0.23+/-0.02 and 0.45+/-0.03 vs. 0.26+/-0.02 respectively, all P<0.05). Compared with high phosphorus+ pH7.4 group, the mRNA(0.86+/-0.05) and protein(0.62+/-0.04) expressions of LTCC beta(3) were higher in high phosphorus+ pH7.5 group (P<0.05). Compared with high phosphorus+ pH7.5 group, the mRNA(0.99+/-0.05) and protein(0.80+/-0.03) expressions of LTCC beta(3) were higher in high phosphorus+ pH7.5 group (all P<0.05). Compared with high phosphorus+ pH7.6 group, the mRNA(1.16+/-0.05) and protein(0.93+/-0.03) expressions of LTCC beta(3) were higher in high phosphorus+ pH7.7 group (all P<0.05). (2) Compared with control group, calcium ion influx were higher in high phosphorus+ pH7.4 group (124.61+/-6.06 vs. 75.68+/-7.82, P<0.05). Compared with high phosphorus+ pH7.4 group, calcium ion influx was higher in high phosphorus+ pH7.5 group(210.85+/-9.75, P<0.05). Compared with high phosphorus+ pH7.5 group, calcium ion influx was higher in high phosphorus+ pH7.6 group(298.44+/-11.42, P<0.05). Compared with high phosphorus+ pH7.6 group, calcium ion influx was higher in high phosphorus+ pH7.7 group(401.13+/-11.41, P<0.05). (3) Compared with control group, the mRNA and protein expressions of Runx2 and ALP were higher in high phosphorus+ pH7.4 group (0.60+/-0.04 vs. 0.34+/ 0.03, 0.42+/-0.04 vs. 0.21+/-0.02, 67.2+/-4.3 vs. 23.2+/-2.3 respectively, all P<0.05). Compared with high phosphorus+ pH7.4 group, the mRNA(0.76+/-0.05) and protein(0.68+/-0.03) expressions of Runx2 and ALP(102.1+/-5.4) were higher in high phosphorus+ pH7.5 group (all P<0.05). Compared with high phosphorus+ pH7.5 group, the mRNA(0.90+/-0.05) and protein(0.90+/-0.05) expressions of Runx2 and ALP(139.3+/-4.9) were higher in high phosphorus+ pH7.6 group (all P<0.05). Compared with high phosphorus+ pH7.6 group, the mRNA(1.11+/-0.05) and protein(1.08+/-0.06) expressions of Runx2 and ALP(197.0+/-6.7) were higher in high phosphorus+ pH7.7 group (all P<0.05). (4) Compared with control group, the calcium content were higher in high phosphorus+ pH7.4 group ((75.4+/-4.3)mg/g pro vs.(25.2+/-2.1)mg/g pro, P<0.05). Compared with high phosphorus+ pH7.4 group, the calcium content were higher in high phosphorus+ pH7.5 group ((100.8+/-5.7) mg/g pro, P<0.05). Compared with high phosphorus+ pH7.5 group, the calcium content were higher in high phosphorus+ pH7.6 group ((143.5+/-6.1) mg/g pro, P<0.05). Compared with high phosphorus+ pH7.6 group, the calcium content were higher in high phosphorus+ pH7.7 group ((205.1+/-8.2) mg/g pro, P<0.05). Conclusion: Intermittent alkaline stimulation can promote high phosphorus induced rat VSMCs calcification possibly through upregulating LTCC beta(3) subunit gene and protein expression, increasing calcium ion influx and enhancing VSMCs phenotypic transformation. PMID- 28648032 TI - [Interentional therapy in apatient with congenital hepatic arteriovenous fistula]. PMID- 28648031 TI - [Impact of different antithrombotic therapy strategy on prognosis in coronary heart disease patients combining with atrial fibrillation: a meta analysis]. AB - Objective: To evaluate the impact of various anticoagulation antiplatelet therapy strategies on the prognosis of patients with coronary heart disease combining with atrial fibrillation. Methods: Present meta analysis was performed according to search results on English EMBASE database by computer retrieval, Pubmed, the Cochrane Central Register of Controlled Trials, Medline, Chinese CBM database, CNKI database, Wan Fang database, China science and technology papers online electronic databases, manual retrieval for important international conference proceedings up to April 30 2016. Trials published in English and Chinese language, which met the Cochrane system evaluation requirements were included and the inclusion and exclusion criteria were made based on Cochrane system evaluation requirements. The end point is the incident of major adverse cardiac events (MACE), ischemic stroke and major bleeding events. The patients were randomly assigned into triple antithrombotic therapy (aspirin+ clopidogrel+ warfarin) group and dual antiplatelet therapy (aspirin+ clopidogrel) group.The collected full-text literatures underwent further quality assessment of the risks of bias using RevMan 5.3 software. Impact of various antithrombotic therapeutic strategies on the outcome of coronary heart disease patients combining with atrial fibrillation were evaluated. Results: In this meta analysis, 12 randomized controlled trials with 11 353 patients were included. Among these patients, 3 486 patients received triple antithrombotic therapy and 7 867 patients received dual anti-platelet therapy. There was no significant difference in incidence rate of MACE (OR=0.93, 95%CI 0.74-1.18, P>0.05) and the incidence rate of ischemic stroke (OR=0.88, 95%CI 0.70-1.10, P=0.27) between the two patients groups. However, the incidence rate of major bleeding events in triple antithrombotic therapy group was twice higher than that in dual anti-platelet therapy (OR=1.94, 95%CI 1.33 2.82, P=0.000 6). Conclusion: Compared with dual anti-platelet therapy strategy, coronary heart disease patients combining with atrial fibrillation who were treated by triple antithrombotic therapy strategy have the similar outcome on risk of ischemic stroke, but higher risk of major bleeding events. PMID- 28648034 TI - [Research update on the impacts of depression on patients with chronic heart failure]. PMID- 28648033 TI - [Update on the clinical application of valsartan/sacubitril in patients with heart failure]. PMID- 28648035 TI - [Research progress on detection of chemotherapy induced myocardial injury by cardiovascular magnetic respnance]. PMID- 28648036 TI - [Research progress on the correlation between hmocysteine and atrial fibrilation]. PMID- 28648037 TI - [Effects of activating silent information regulator 1 on early kidney damage in rats with severe burn]. AB - Objective: To investigate the effects of activating silent information regulator 1 (SIRT1) on the early kidney damage in rats with severe burn. Methods: Thirty healthy male SD rats were divided into sham injury group (SI), pure burn group (PB), and SIRT1 activator group (SA) according to the random number table, with 10 rats in each group. Rats in groups PB and SA were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burn) on the back. Immediately after injury, rats in group PB were intraperitoneally injected with normal saline in the dosage of 50 mL/kg, and those in group SA with 1 mg/mL (final mass concentration) resveratrol in the dosage of 50 mL/kg. Rats in group SI were sham injured and intraperitoneally injected with normal saline in the dosage of 50 mL/kg immediately after injury. Kidney tissue and abdominal aorta blood of rats in the three groups were collected at 24 hours after injury. The morphology of kidney tissue was observed after HE staining. The serum content of creatinine and urea nitrogen was determined with enzyme-linked immunosorbent assay. Protein expressions of SIRT1, Bax, and Bcl-2 in kidney tissue were determined with Western blotting. mRNA expressions of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and IL-10 in kidney tissue were determined with real-time fluorescent quantitative reverse transcription polymerase chain reaction. Data were processed with one-way analysis of variance and LSD-t test. Results: (1) In rats of group SI, structures of kidney tubules and glomeruli were intact. In rats of group PB, structures of kidney tubules were not clear with casts in them, and glomeruli showed pyknosis. In rats of group SA, structures of kidney tubules were relatively intact, and the pyknosis of glomeruli were slighter as compared with that of group PB with fewer glomeruli showing pyknosis. (2) The serum content of creatinine and urea nitrogen in rats of group PB was (67+/-14) MUmol/L and (22.0+/-4.4) mmol/L, respectively, which was significantly higher than that of group SI [(28+/-7) MUmol/L and (5.5+/-1.2) mmol/L respectively, with t values respectively 6.07 and 11.53, P values below 0.01]. The serum content of creatinine and urea nitrogen in rats of group SA was (39+/-9) MUmol/L and (14.1+/-1.7) mmol/L, respectively, significantly lower than that of group PB (with t values respectively 4.09 and 4.17, P values below 0.01). (3) Compared with those of group SI, protein expressions of SIRT1 and Bcl-2 in kidney tissue of rats in group PB were significantly decreased (with t values respectively 16.32 and 19.58, P values below 0.01), while the protein expression of Bax was significantly increased (t=5.98, P<0.01). Compared with those of group PB, protein expressions of SIRT1 and Bcl-2 in kidney tissue of rats in group SA were significantly increased (with t values respectively 6.94 and 5.37, P values below 0.01), while the protein expression of Bax was significantly decreased (t=3.44, P<0.01). (4) mRNA expressions of TNF-alpha, IL-1beta, and IL-10 in kidney tissue of rats in group PB were 17.0+/-4.0, 2.27+/-0.59, and 2.5+/-0.9, respectively, significantly higher than those of group SI (1.0, 1.00, and 1.0, respectively, with t values from 3.27 to 8.93, P<0.05 or P<0.01). mRNA expressions of TNF-alpha and IL-1beta in kidney tissue of rats in group SA were 6.8+/-1.2 and 1.18+/-0.26, respectively, significantly lower than those of group PB (with t values respectively 4.59 and 4.32, P values below 0.01). mRNA expression of IL-10 in kidney tissue of rats in group SA was 5.0+/-1.0, significantly higher than that of group PB (t=5.51, P<0.01). Conclusions: Activating SIRT1 on early stage of severe burn in rats can decrease levels of creatinine and urea nitrogen, thus improving the kidney function. It can down regulate the protein expression of Bax and up-regulate the protein expression of Bcl-2, thus reducing the apoptosis in kidney tissue. Meanwhile, it can inhibit expressions of TNF-alpha and IL-1beta and promote the expression of IL-10, thus alleviating the inflammatory response in kidney. PMID- 28648038 TI - [Effects of Na(+) /H(+) exchanger 1 inhibitor on intestinal injury of rats with burn sepsis and the mechanism]. AB - Objective: To observe the effects of Na(+) /H(+) exchanger 1 (NHE1) inhibitor on intestinal injury of rats with burn sepsis, and to explore the possible mechanism preliminarily. Methods: Ninety SD rats were divided into control group, pure sepsis group, and NHE1 inhibitor group according to the random number table, with 30 rats in each group. Full-thickness scald (hereinafter referred to as burn) model with 20% total body surface area were reproduced on the back of rats in pure sepsis and NHE1 inhibitor groups, and then 50 MUL liquid of Pseudomonas aeruginosa ATCC 27853 (2*10(5) colony forming unit/mL) were injected into the center of wounds on the back. Rats in NHE1 inhibitor group were intraperitoneally injected with 0.1 mmol/L NHE1 inhibitor cariporide (0.4 mg/kg) rapidly after the successful establishment of burn sepsis model, while rats in pure sepsis group were injected with the same volume of normal saline. Except for not being made burn wounds nor receiving bacterination, rats in control group were treated the same as those in pure sepsis group. Rats with burn sepsis in each group were laparotomized and injected with 200 mL fluorescein isothiocyanate (FITC)-dextran in the concentration of 0.1 mol/L in terminal ileum at 12 hours post injury, and their left ventricular blood and terminal ileum were collected 30 minutes later. The serum content of FITC-dextran was detected with fluorescence spectrophotometer (n=10); the morphology of intestinal tissue was observed with HE staining (n=10); the content of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in serum and intestinal tissue was determined with enzyme linked immunosorbent assay (n=20); the activity of myeloperoxidase (MPO) in serum and intestinal tissue was detected with colorimetric method (n=20); the protein expression of nuclear factor-kappa B-p65 (NF-kappaB-p65) and phosphorylation levels of mitogen-activated protein kinase (MAPK) signal pathway related proteins p38MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase 1/2 (JNK1/2) were determined by Western blotting (n=4). The same samples of rats in control group were collected for related detection at the same time point as above. Data were processed with one-way analysis of variance and SNK test. Results: (1) The serum content of FITC-dextran of rats in pure sepsis group was significantly higher than that in control group (P<0.01), while the serum content of FITC-dextran of rats in NHE1 inhibitor group was significantly lower than that in pure sepsis group (P<0.01). Compared with that in control group, infiltration of a large number of inflammatory cells, ulcer and necrosis of intestinal mucosa of rats in pure sepsis group were observed. The injury condition of intestine of rats in NHE1 inhibitor group was better than that in pure sepsis group. (2) The serum content of IL-6, TNF-alpha, and MPO of rats in pure sepsis group was (387+/-42) and (164.7+/-10.1) ng/mL, and (7.5+/-1.5) U/mL, respectively, significantly higher than that in control group [(75+/-17) and (13.1+/-6.5) ng/mL, and (2.3+/-0.7) U/mL, respectively, with P values below 0.01]. The serum content of IL-6, TNF-alpha, and MPO of rats in NHE1 inhibitor group was (176+/-37) and (64.9+/-9.3) ng/mL, and (5.9+/-0.8) U/mL, respectively, which was significantly lower than that in pure sepsis group (with P values below 0.01). (3) The content of IL-6, TNF-alpha, and MPO in intestinal tissue of rats in pure sepsis group was (190+/-13) and (172.8+/-29.7) ng/mL, and (8.7+/-1.5) U/mL, respectively, significantly higher than that in control group [respectively (20+/-3) and (11.9+/-2.3) ng/mL, and (2.9+/-0.3) U/mL, with P values below 0.01]. The content of IL-6, TNF-alpha, and MPO of intestinal tissue of rats in NHE1 inhibitor group was (35+/-6) and (45.2+/-6.1) ng/mL, and (5.3+/-0.6) U/mL, respectively, significantly lower than that in pure sepsis group (with P values below 0.01). (4) The protein expression of NF-kappaB-p65 and phosphorylation levels of p38MAPK and ERK1/2 in intestinal tissue of rats in pure sepsis group were significantly higher than those in control group (with P values below 0.01); the protein expression of NF-kappaB-p65 and the phosphorylation level of p38MAPK in intestinal tissue of rats in NHE1 inhibitor group were significantly lower than those in pure sepsis group (with P values below 0.01); phosphorylation levels of JNK1/2 in intestinal tissue of rats in the three groups were similar (with P values above 0.05). Conclusions: The inhibition of NHE1 can significantly alleviate the intestinal injury, and the mechanisms may be attributed to the regulation of NF-kappaB and p38MAPK signal pathway, resulting in inhibition of the inflammatory response of intestinal tract. PMID- 28648039 TI - [Effects of combined application of culture supernatant of human umbilical cord mesenchymal stem cells and ciprofloxacin on Staphylococcus aureus in vitro]. AB - Objective: To explore the effects of combined application of culture supernatant of human umbilical cord mesenchymal stem cells (hUCMSCs) and ciprofloxacin on Staphylococcus aureus (SA) in vitro. Methods: hUCMSCs were isolated from umbilical cord tissue of full-term healthy fetus after cesarean section and cultured. Cells in the third passage were used in the experiments after identification. SA strains isolated from wounds of burn patients in our burn wards were used in the experiments. Cells were divided into 0, 10, 100, and 1 000 ng/mL lipopolysaccharide (LPS) groups according to the random number table (the same dividing method below). Cells were cultured with culture medium of mesenchymal stem cells (MSCs) after being treated with medium containing the corresponding mass concentrations of LPS for 12 h. At post culture hour (PCH) 6, 12, and 24, 6 wells of culture supernatant of cells in each group were obtained to measure the content of LL-37 with enzyme-linked immunosorbent assay. Ninety blood agar plates were divided into ciprofloxacin control group (CC), ciprofloxacin+ supernatant group (CS), and ciprofloxacin+ supernatant+ LL-37 antibody group (CSL), with 30 blood agar plates in each group. Blood agar plates in group CC were coated with 1.5*10(8) colony forming unit (CFU)/mL bacteria solution prepared with normal saline. Blood agar plates in group CS were coated with 1.5*10(8) CFU/mL bacteria solution prepared with normal saline and culture supernatant of hUCMSCs (cultured by culture medium of MSCs, the same below) in double volume of normal saline. Blood agar plates in group CSL were coated with 1.5*10(8) CFU/mL bacteria solution prepared with normal saline, culture supernatant of hUCMSCs in double volume of normal saline, and 2.6 MUL LL-37 antibody in the concentration of 2 MUg/mL. At PCH 12, 24, and 48, 10 blood agar plates of each group were harvested to observe the distribution of SA colony on blood agar plate and to measure the diameter of bacterial inhibition ring of ciprofloxacin. The minimum inhibitory concentration (MIC) of ciprofloxacin against SA of each group was recorded. Fractional inhibitory concentration (FIC) indexes of ciprofloxacin in groups CS and CSL at PCH 12, 24, and 48 were calculated, and the effect of synergy was evaluated. Data were processed with analysis of variance of factorial design, one-way analysis of variance, LSD-t test, Kruskal-Wallis test, and Mann-Whitney U test. Results: (1) At each PCH, the content of LL-37 in culture supernatant of cells in 10, 100, and 1 000 ng/mL LPS groups was higher than that in 0 ng/mL LPS group (with t values from 11.22 to 33.36, P values below 0.01); the content of LL-37 in culture supernatant of cells in 100 and 1 000 ng/mL LPS groups was higher than that in 10 ng/mL LPS group (with t values from 2.24 to 18.73, P<0.05 or P<0.01); the content of LL-37 in culture supernatant of cells in 1 000 ng/mL LPS group was higher than that in 100 ng/mL LPS group (with t values from 12.46 to 14.70, P values below 0.01). (2) At PCH 12, 24, and 48, the bacterial colonies in groups CC, CS, and CSL began to integrate over time. At PCH 12, 24, and 48, the diameters of bacterial inhibition ring of ciprofloxacin in group CC were 26, 24, and 23 mm, respectively, with no obvious change. At PCH 12, 24, and 48, the diameters of bacterial inhibition ring of ciprofloxacin in groups CS and CSL were 82, 71, 68 mm, and 74, 59, 56 mm, respectively, significantly longer than those of group CC. (3) At each PCH, the MIC of ciprofloxacin against SA was significantly higher in group CC than in groups CS and CSL (with Z values from 6.22 to 6.71, P values below 0.01); the MIC of ciprofloxacin against SA was significantly higher in group CSL than in group CS (with Z values all equal to 6.72, P values below 0.01). (4) FIC indexes of ciprofloxacin in groups CS and CSL at PCH 12, 24, and 48 were 0.011, 0.032, 0.032, and 0.122, 0.350, 0.350, respectively. The results indicated that culture supernatant of hUCMSCs had synergistically antibacterial effect on ciprofloxacin. Conclusions: hUCMSCs can secrete LL-37, and the secretion level is increased with increase of LPS concentration. Combination of culture supernatant of hUCMSCs and ciprofloxacin can decrease the dosage of ciprofloxacin in resisting SA. Once LL 37 is neutralized, the synergistically antibacterial effect of culture supernatant of hUCMSCs is decreased. PMID- 28648040 TI - [Effects of seawater immersion on the inflammatory response and oxygen free radical injury of rats with superficial partial-thickness scald at early stage]. AB - Objective: To study the effects of seawater immersion on the inflammatory response and oxygen free radical injury of rats with superficial-thickness scald at early stage. Methods: Seventy Wistar rats were divided into healthy control group (HC, n=7), pure scald group (PS, n=21), scald+ fresh water immersion group (SF, n=21), and scald+ seawater immersion group (SS, n=21) according to the random number table. Rats in group HC did not receive any treatment, while 5% total body surface area superficial partial-thickness scald was made on the back of rats in the latter three groups. Rats in group PS lived freely immediately post burn, while wounds on the back of rats in groups SF and SS were immersed into fresh water and seawater, respectively. Serum and full-thickness skin tissue in the center of wounds on the back of 7 rats in groups PS, SF, and SS at post immersion (injury) hour (PIH) 2, 4, and 6 were collected, respectively, while serum and full-thickness skin tissue at the same position of the 7 rats in group HC were collected at PIH 6 of rats in other groups. Morphology of skin tissue was observed with HE staining; tumor necrosis factor-alpha (TNF-alpha) content in serum and skin tissue was determined by enzyme-linked immunosorbent assay; superoxide dismutase (SOD) content in serum and skin tissue was determined by hydroxylamine method; malondialdehyde content in serum and skin tissue was determined by thiobarbituric acid method. Data were processed with analysis of variance of factorial design, one-way analysis of variance, Welch test, LSD test, and Tamhane test. Results: (1) Epidermal cells of skin tissue of rats in group HC arranged in order and continuously, and the dermis tissue and accessory structures were clear and complete. The skin layer and epidermis of wounds of rats in group PS had no significant change, but the edema of epidermis and dermis and infiltration of inflammatory cells enhanced over time at PIH 2, 4, and 6. The horny layer of epidermis of wounds of rats in group SF reduced, and the edema of epidermis and dermis and infiltration of inflammatory cells enhanced over time at PIH 2, 4, and 6; some epidermal cells disintegrated at PIH 6. The horny layer of epidermis of wounds of rats in group SS significantly reduced, along with the increase in disintegration of epidermal cells, the significant enhancement of edema of epidermis and dermis, and infiltration of a large number of inflammatory cells over time at PIH 2, 4, and 6. (2) Compared with (247+/-27) pg/mL in group HC, the serum content of TNF-alpha of rats in group PS significantly increased at PIH 2 and 4 [respectively (675+/-122) and (367+/-54) pg/mL, P<0.05 or P<0.01] but significantly decreased at PIH 6 [(147+/-27) pg/mL, P<0.01]; the serum content of TNF-alpha of rats in group SF significantly decreased at PIH 6 [(90+/-24) pg/mL, P<0.01]; the serum content of TNF-alpha of rats in group SS significantly increased at PIH 2, 4, and 6 [respectively (1 646+/-58), (2 086+/-114), and (2 951+/-58) pg/mL, with P values below 0.01]. Compared with (364+/-123) U/mL in group HC, the serum content of SOD of rats in group PS significantly increased at PIH 2 and 4 [respectively (489+/-13) and (447+/-14) U/mL, with P values below 0.05]; the serum content of SOD of rats in group SF significantly decreased at PIH 6 [(282+/-13) U/mL, P<0.05]; the serum content of SOD of rats in group SS significantly increased at PIH 2 [(461+/-23) U/mL, P<0.05] but significantly decreased at PIH 4 and 6 [respectively (226+/-8) and (205+/-10) U/mL, with P values below 0.01]. Compared with that in group HC, the serum content of malondialdehyde of rats in groups PS, SF, and SS significantly increased at PIH 2, 4, and 6 (with P values below 0.01). (3) Compared with that in group HC, the TNF-alpha content in wound tissue of rats in groups PS and SS significantly increased at PIH 2, 4, and 6 (P<0.05 or P<0.01), and the TNF-alpha content in wound tissue of rats in group SF significantly increased at PIH 2 and 4 (with P values below 0.01). Compared with that in group HC, the SOD content in wound tissue of rats in groups PS and SF significantly increased at PIH 2, 4, and 6 (P<0.05 or P<0.01), and the SOD content in wound tissue of rats in group SS significantly increased at PIH 2 and 4 (with P values below 0.01). Compared with that in group HC, the malondialdehyde content in wound tissue of rats in groups PS, SF, and SS significantly increased at PIH 2, 4, and 6 (with P values below 0.01). Conclusions: Seawater immersion can enhance the inflammatory response and oxygen free radical injury of wounds and the whole body of rats with superficial partial-thickness scald at early stage. PMID- 28648041 TI - [Effects of hypoxia on the phenotype transformation of human dermal fibroblasts to myofibroblasts and the mechanism]. AB - Objective: To investigate the effects of hypoxia on the phenotype transformation of human dermal fibroblasts to myofibroblasts and the mechanism. Methods: The third passage of healthy adult human dermal fibroblasts in logarithmic phase were cultured in DMEM medium containing 10% fetal bovine serum for the following five experiments. (1) In experiments 1, 2, and 3, cells were divided into normoxia group and hypoxia group according to the random number table, with 10 dishes in each group. Cells of normoxia group were cultured in incubator containing 21% oxygen, while those of hypoxia group with 1% oxygen. At post culture hour (PCH) 0 and 48, 5 dishes of cells were collected from each group, respectively. mRNA expressions of markers of myofibroblasts including alpha smooth muscle actin (alpha-SMA), type I collagen, and type III collagen of cells were determined with real time fluorescent quantitative reverse transcription polymerase chain reaction in experiment 1. Protein expressions of alpha-SMA, type I collagen, and type III collagen of cells were determined with Western blotting in experiment 2. The protein expression of nuclear factor-kappa B (NF-kappaB) of cells was determined with Western blotting in experiment 3. (2) In experiment 4, cells were divided into normoxia group, hypoxia group, and hypoxia+ pyrrolidine dithiocarbamate (PDTC) group according to the random number table, with 5 dishes in each group. Cells in the former two groups were treated the same as those in experiment 1. Cells in hypoxia+ PDTC group were treated the same as those in hypoxia group plus adding 4 mL PDTC with a final molarity of 10 MUmol/L in the culture medium. At PCH 48, the protein expression of NF-kappaB of cells was determined with Western blotting. (3) In experiment 5, cells were divided into normoxia group, hypoxia group, hypoxia+ PDTC group, and normoxia+ PDTC group according to the random number table, with 5 dishes in each group. Cells in the former three groups were treated the same as those in experiment 4. Cells in normoxia+ PDTC group were treated the same as those in normoxia group plus adding 4 mL PDTC with a final molarity of 10 MUmol/L in the culture medium. At PCH 48, protein expressions of alpha-SMA, type I collagen, and type III collagen of cells were determined with Western blotting. Data were processed with analysis of variance of factorial design, one-way analysis of variance, and LSD-t test. Results: (1) Compared with those of normoxia group at corresponding time point, mRNA expressions and protein expressions of alpha-SMA, type I collagen, and type III collagen and the protein expression of NF-kappaB in fibroblasts of hypoxia group were not changed obviously at PCH 0 (with t values from -1.21 to 2.04, P values above 0.05), while mRNA expressions and protein expressions of alpha-SMA, type I collagen, and type III collagen and the protein expression of NF-kappaB significantly increased at PCH 48 (with t values from -12.57 to -3.44, P values below 0.01). (2) At PCH 48, the protein expression of NF-kappaB in fibroblasts of hypoxia group was 0.83+/-0.12, significantly higher than that of normoxia group (0.17+/-0.06, t=-16.96, P<0.001). The protein expression of NF-kappaB in fibroblasts of hypoxia+ PDTC group was 0.31+/-0.08, significantly lower than that of hypoxia group (t=12.73, P<0.001). (3) At PCH 48, protein expressions of alpha SMA, type I collagen, and type III collagen in fibroblasts of hypoxia group were 0.73+/-0.09, 1.25+/-0.10, and 1.16+/-0.07, respectively, significantly higher than those of normoxia group (0.14+/-0.06, 0.87+/-0.08, and 0.77+/-0.13, respectively, with t values from 9.24 to 11.24, P values below 0.001). The protein expression of alpha-SMA in fibroblasts of normoxia+ PDTC group was 0.24+/ 0.07, significantly higher than that of normoxia group (t=4.22, P<0.01). Protein expressions of type I collagen and type III collagen in fibroblasts of normoxia+ PDTC group were 0.25+/-0.06 and 0.32+/-0.11, respectively, significantly lower than those of normoxia group (with t values respectively -4.31 and -3.88, P values below 0.01). Protein expressions of alpha-SMA, type I collagen, and type III collagen in fibroblasts of hypoxia+ PDTC group were 0.09+/-0.08, 0.38+/-0.12, and 0.47+/-0.08, respectively, significantly lower than those of hypoxia group (with t values from 11.78 to 22.98, P values below 0.001). Conclusions: Hypoxia can significantly up-regulate the expressions of alpha-SMA, type I collagen, and type III collagen in human dermal fibroblasts, which may promote the phenotype transformation of fibroblasts to myofibroblasts, and this is likely to be associated with the activation of NF-kappaB signal pathway. PMID- 28648042 TI - [Effects of lappaconitine on pain and inflammatory response of severely burned rats and the mechanism]. AB - Objective: To explore the effects of lappaconitine (LA) on pain and inflammatory response of severely burned rats and the mechanism. Methods: Forty SD rats were divided into healthy+ normal saline group, sham injury+ normal saline group, pure burn group, burn+ LA group, and healthy+ LA group according to the random number table (the same dividing method below), with 8 rats in each group. Rats in pure burn and burn+ LA groups were inflicted with about 32% total body surface area deep partial-thickness scald (hereinafter referred to as burn) on the back and right hind. Rats in sham injury+ normal saline group were sham injured. Rats in burn+ LA group were intraperitoneally injected with 1 g/L LA solution in the dosage of 4 mL/kg at 2.0 h before injury and post injury hour (PIH) 0 (immediately), 24.0, 48.0, and 72.0. Rats in healthy+ LA group were intraperitoneally injected with LA solution in the same dose at the same time points as above, and rats in healthy+ normal saline and sham injury+ normal saline groups were intraperitoneally injected with normal saline in the dose of 4 mL/kg at the same time points as above. At 1.5 h before injury and PIH 12.5, 24.5, 36.5, 48.5, and 72.5, the paw withdrawal mechanical threshold (PWMT) of injured rats was detected, and their pain behaviors were observed. The same observation and detection were conducted in rats without injury in the two groups at the same time points as above. Another 32 SD rats were divided into normal saline group, trinitrophenyl (TNP)-ATP group, minocyline group, pyridoxal phosphate-6-azophenyl-2', 4'-disulfonic acid (PPADS) group, with 8 rats in each group, and all the rats were inflicted with the same burn injury as above. At PIH 48.0, rats in normal saline group were intrathecally injected with 10 MUL normal saline; rats in TNP-ATP group were intrathecally injected with 10 MUL TNP-ATP in the concentration of 30 nmol/MUL; rats in minocyline group were intrathecally injected with 10 MUL minocyline in the concentration of 5 g/L; rats in PPADS group were intrathecally injected with 10 MUL PPADS in the concentration of 10 nmol/MUL. The PWMT of rats was detected at 0.5 h before injection and 0.5 h after. At PIH 72.5, the tissue in the dorsal horn of spinal cord of rats in sham injury+ normal saline, pure burn, and burn+ LA groups was harvested to observe the co-expression of P2X(4) receptor and OX42 receptor with immunofluorescent staining and to observe the expression of P2X(4) receptor and count the positive cells with immunohistochemical staining. The venous blood was harvested for determination of serum content of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) with enzyme-linked immunosorbent assay. The same observation and determination were conducted in rats without injury in the two groups at the same time point as above. Data were processed with one-way analysis of variance, analysis of variance for repeated measurement, SNK test, paired t test, and Bonferroni correction. Results: (1) There were no abnormal activity in rats of healthy+ normal saline, sham injury+ normal saline, healthy+ LA groups at all time points. Until PIH 72.5, rats in pure burn group were in poor mental state; red and swollen manifestation and blister were observed in burn wounds on the back and right hind; imbalance in gait, lick, bite, and scratch were observed occasionally. Fewer behaviors such as lick, bite, and limp were observed in rats in burn+ LA group than in pure burn group, and the red and swollen manifestation in wounds of rats in burn+ LA group dissipated faster than that in pure burn group. (2) At 1.5 h before injury, there were no significant differences in the PWMT values of rats in healthy+ normal saline, sham injury+ normal saline, pure burn, burn+ LA, and healthy+ LA groups (F=0.106, P>0.05). PWMT values of rats in pure burn group were significantly lower than those in the other 4 groups at all post injury time points (with P values below 0.05). PWMT values of rats in burn+ LA group were significantly lower than those in healthy+ normal saline, sham injury+ normal saline, and healthy+ LA groups at all post injury time points (with P values below 0.05). (3) At 0.5 h before injection, PWMT values of rats in normal saline, TNP-ATP, PPADS, and minocyline groups were close, respectively 15.3+/-0.8, 15.1+/-1.0, 15.3+/-0.9, and 15.6+/-1.1 (F=0.343, P>0.05). At 0.5 h after injection, PWMT values of rats in normal saline group and PPADS group were respectively 15.2+/-1.2 and 14.8+/-1.0, which were significantly lower than 20.8+/-1.4 and 26.3+/-1.0 in TNP-ATP group and minocyline group respectively (with P values below 0.05). PWMT values of rats in normal saline and PPADS groups were similar before and after injection (with t values respectively 0.073 and 0.772, P values above 0.05), while those of rats in TNP-ATP and minocyline groups were higher after injection than before injection (with t values respectively 10.180 and -20.813, P values below 0.01). (4) At PIH 72.5, co-expression of P2X(4) receptor and OX42 receptor was observed in a few microglias of rats in healthy+ normal saline, sham injury+ normal saline, and healthy+ LA groups, while co-expression of P2X(4) receptor and OX42 receptor was observed in a large number of microglias of rats in pure burn and burn+ LA groups. At PIH 72.5, more P2X(4) receptor positive cells were observed in rats in pure burn group than in the other 4 groups (with P values below 0.05), and more P2X(4) receptor positive cells were observed in rats in burn+ LA group than in healthy+ normal saline, sham injury+ normal saline, and healthy+ LA groups (with P values below 0.05). (5) At PIH 72.5, the serum content of TNF-alpha and IL-1beta of rats in pure burn group was significantly higher than that in the other 4 groups (with P values below 0.001). The serum content of TNF-alpha and IL-1beta of rats in burn+ LA group was significantly lower than that in healthy+ normal saline, sham injury+ normal saline, and healthy+ LA groups (with P values below 0.001). Conclusions: LA has significant analgesic effects on severely burned rats, and it can ameliorate the excessive inflammational situation. The mechanism may be related to its inhibition of expression of P2X(4) receptor in microglias in the dorsal horn of spinal cord and reduction in the release of inflammatory factors TNF alpha and IL-1beta. PMID- 28648043 TI - [Advances in the research of application of vacuum-assisted closure in wound healing and its mechanism]. AB - As a new generation of negative pressure drainage technology, vacuum-assisted closure (VAC) can provide stable and persistent negative pressure, and there are several modes to choose from. VAC plays an important role in closing wounds quickly, controlling infection, promoting angiogenesis, increasing blood flow, and promoting granulation tissue growth of wounds. It is now widely applied in all kinds of acute, chronic, and special wounds in clinic with good therapeutic results. However, we need to pay attention to contraindications and complications of VAC when it is used, avoiding secondary damage due to improper treatment. In this review, we summarize VAC dressings, treating pressure and mode choice, mechanism in promoting wound healing, and clinical application of VAC. PMID- 28648044 TI - Dendrons and Multiarm Polymers with Thiol-Exchangeable Cores: A Reversible Conjugation Platform for Delivery. AB - Disulfide exchange reaction has emerged as a powerful tool for reversible conjugation of proteins, peptides and thiol containing molecules to polymeric supports. In particular, the pyridyl disulfide group provides an efficient handle for the site-specific conjugation of therapeutic peptides and proteins bearing cysteine moieties. In this study, novel biodegradable dendritic platforms containing a pyridyl disulfide unit at their focal point were designed. Presence of hydroxyl groups at the periphery of these dendrons allows their elaboration to multivalent initiators that yield poly(ethylene glycol) based multiarm star polymers via controlled radical polymerization. The pyridyl disulfide unit at the core of these star polymers undergoes efficient reaction with thiol functional group containing molecules such as a hydrophobic dye, namely, Bodipy-SH, glutathione, and KLAK sequence containing peptide. While conjugation of the hydrophobic fluorescent dye to the PEG-based multiarm polymer renders it water soluble, it can be cleaved off the construct through thiol-disulfide exchange in the presence of an external thiol such as dithiothreitol. The multiarm polymer was conjugated with a thiol group containing apoptotic peptide to increase its solubility and cellular transport. In vitro cytotoxicity and apoptosis assays demonstrated that the resultant peptide-polymer conjugate had almost five times more apoptotic potential primarily through triggering apoptosis by disrupting mitochondrial membranes of human breast cancer cell line (MDA-MB-231) compared to naked peptide. The novel dendritic platform disclosed here offers an attractive template that can be modified to multiarm polymeric constructs bearing a "tag and release" characteristic. PMID- 28648045 TI - First Identification of Palytoxin-Like Molecules in the Atlantic Coral Species Palythoa canariensis. AB - Palytoxin (PLTX) is a complex marine toxin produced by Zoanthids (Palyhtoa), dinoflagellates (Ostreopsis), and cyanobacteria (Trichodesmium). Contact with PLTX-like compounds present in aerosols or marine organisms has been associated with adverse effects on humans. The worldwide distribution of producer species and seafood contaminated with PLTX-like molecules illustrates the global threat to human health. The identification of species capable of palytoxin production is critical for human safety. We studied the presence of PLTX analogues in Palythoa canariensis, a coral species collected in the Atlantic Ocean never described as a PLTX-producer before. Two methodologies were used for the detection of these toxins: a microsphere-based immunoassay that offered an estimation of the content of PLTX-like molecules in a Palythoa canariensis extract and an ultrahigh pressure liquid chromatography coupled to an ion trap with a time-of-flight mass spectrometer (UPLC-IT-TOF-MS) that allowed the characterization of the toxin profile. The results demonstrated the presence of PLTX, hydroxy-PLTX and, at least, two additional compounds with PLTX-like profile in the Palythoa canariensis sample. The PLTX content was estimated in 0.27 mg/g of lyophilized coral using UPLC-IT-TOF-MS. Therefore, this work demonstrates that Palythoa canariensis produces a mixture of PLTX-like molecules. This is of special relevance to safeguard human health considering Palythoa species are commonly used for decoration by aquarium hobbyists. PMID- 28648046 TI - A Printed Equilibrium Dialysis Device with Integrated Membranes for Improved Binding Affinity Measurements. AB - Equilibrium dialysis is a simple and effective technique used for investigating the binding of small molecules and ions to proteins. A three-dimensional (3D) printer was used to create a device capable of measuring binding constants between a protein and a small ion based on equilibrium dialysis. Specifically, the technology described here enables the user to customize an equilibrium dialysis device to fit their own experiments by choosing membranes of various material and molecular-weight cutoff values. The device has dimensions similar to that of a standard 96-well plate, thus being amenable to automated sample handlers and multichannel pipettes. The device consists of a printed base that hosts multiple windows containing a porous regenerated-cellulose membrane with a molecular-weight cutoff of ~3500 Da. A key step in the fabrication process is a print-pause-print approach for integrating membranes directly into the windows subsequently inserted into the base. The integrated membranes display no leaking upon placement into the base. After characterizing the system's requirements for reaching equilibrium, the device was used to successfully measure an equilibrium dissociation constant for Zn2+ and human serum albumin (Kd = (5.62 +/- 0.93) * 10 7 M) under physiological conditions that is statistically equal to the constants reported in the literature. PMID- 28648047 TI - High Contribution of Nonfossil Sources to Submicrometer Organic Aerosols in Beijing, China. AB - Source apportionment of organic carbon (OC) and elemental carbon (EC) from PM1 (particulate matter with a diameter equal to or smaller than 1 MUm) in Beijing, China was carried out using radiocarbon (14C) measurement. Despite a dominant fossil-fuel contribution to EC due to large emissions from traffic and coal combustion, nonfossil sources are dominant contributors of OC in Beijing throughout the year except during the winter. Primary emission was the most important contributor to fossil-fuel derived OC for all seasons. A clear seasonal trend was found for biomass-burning contribution to OC with the highest in autumn and spring, followed by winter and summer. 14C results were also integrated with those from positive matrix factorization (PMF) of organic aerosols from aerosol mass spectrometer (AMS) measurements during winter and spring. The results suggest that the fossil-derived primary OC was dominated by coal combustion emissions whereas secondary OC was mostly from fossil-fuel emissions. Taken together with previous 14C studies in Asia, Europe and USA, a ubiquity and dominance of nonfossil contribution to OC aerosols is identified not only in rural/background/remote regions but also in urban regions, which may be explained by cooking contributions, regional transportation or local emissions of seasonal dependent biomass burning emission. In addition, biogenic and biomass burning derived SOA may be further enhanced by unresolved atmospheric processes. PMID- 28648048 TI - Pressure Impact on the Stability and Distortion of the Crystal Structure of CeScO3. AB - The effects of high pressure on the crystal structure of orthorhombic (Pnma) perovskite-type cerium scandate were studied in situ under high pressure by means of synchrotron X-ray powder diffraction, using a diamond-anvil cell. We found that the perovskite-type crystal structure remains stable up to 40 GPa, the highest pressure reached in the experiments. The evolution of unit-cell parameters with pressure indicated an anisotropic compression. The room temperature pressure-volume equation of state (EOS) obtained from the experiments indicated the EOS parameters V0 = 262.5(3) A3, B0 = 165(7) GPa, and B0' = 6.3(5). From the evolution of microscopic structural parameters like bond distances and coordination polyhedra of cerium and scandium, the macroscopic behavior of CeScO3 under compression was explained and reasoned for its large pressure stability. The reported results are discussed in comparison with high-pressure results from other perovskites. PMID- 28648049 TI - Analysis of Liquid Chromatography-Mass Spectrometry Data with an Elastic Net Multivariate Curve Resolution Strategy for Sparse Spectral Recovery. AB - Analysis of liquid chromatography-mass spectrometry (LC-MS) data requires the differentiation between a small number of relevant chemical signals and a larger amount of noise. This is often done based, at least partially, on a threshold which assumes that low intensity m/z signals arise from the noise. This eliminates low-intensity fragments, isotopes, and adducts and may exclude relevant low-intensity compounds all together. This work describes the use of multivariate curve resolution-alternating least-squares with an additional sparse regression step using elastic net (MCR-ENALS) to distinguish relevant m/z signals without the use of a harsh thresholding step, thus allowing for discovery of low intensity m/z signals corresponding to the analytes. This strategy is demonstrated first on a unit mass analysis of amphetamines in which relevant m/z signals are found at as low as a 0.1% intensity relative to the molecular m/z peak. The incorporation of MCR-ENALS into our previously reported data reduction strategy for analysis of high-resolution LC-MS is also demonstrated. Analysis based on only 0.3% of the original data set, while retaining low-intensity isotope peaks, was accomplished without the use of thresholding, allowing for the application of MCR-ENALS to the high-resolution LC-MS data. PMID- 28648050 TI - Ruthenium Nanoparticles Mediated Electrocatalytic Reduction of UO22+ Ions for Its Rapid and Sensitive Detection in Natural Waters. AB - Reduction of UO22+ ions to U4+ ions is difficult due to involvement of two axially bonded oxygen atoms, and often requires a catalyst to lower the activation barrier. The noble metal nanoparticles (NPs) exhibit high electrocatalytic activity, and could be employed for the sensitive and rapid quantifications of U022+ ions in the aqueous matrix. Therefore, the Pd, Ru, and Rh NPs decorated glassy carbon electrode were examined for their efficacy toward electrocatalytic reduction of UO22+ ions and observed that Ru NPs mediate efficiently the electro-reduction of UO22+ ions. The mechanism of the electroreduction of UO22+ by the RuNPs/GC was studied using density functional theory calculations which pointed different approach of 5f metal ions electroreduction unlike 4p metal ions such as As(III). RuNP decorated on the glassy carbon would be hydrated, which in turn assist to adsorb the uranyl sulfates through hydrogen bonding thus facilitated electro-reduction. Differential pulse voltammetric (DPV) technique, was used for rapid and sensitive quantification of UO22+ ions. The RuNPs/GC based DPV technique could be used to determine the concentration of uranyl in a few minutes with a detection limit of 1.95 ppb. The RuNPs/GC based DPV was evaluated for its analytical performance using seawater as well lake water and groundwater spiked with known amounts of UO22+. PMID- 28648051 TI - Community Biological Ammonium Demand: A Conceptual Model for Cyanobacteria Blooms in Eutrophic Lakes. AB - Cyanobacterial harmful algal blooms (CyanoHABs) are enhanced by anthropogenic pressures, including excessive nutrient (nitrogen, N, and phosphorus, P) inputs and a warming climate. Severe eutrophication in aquatic systems is often manifested as non-N2-fixing CyanoHABs (e.g., Microcystis spp.), but the biogeochemical relationship between N inputs/dynamics and CyanoHABs needs definition. Community biological ammonium (NH4+) demand (CBAD) relates N dynamics to total microbial productivity and NH4+ deprivation in aquatic systems. A mechanistic conceptual model was constructed by combining nutrient cycling and CBAD observations from a spectrum of lakes to assess N cycling interactions with CyanoHABs. Model predictions were supported with CBAD data from a Microcystis bloom in Maumee Bay, Lake Erie, during summer 2015. Nitrogen compounds are transformed to reduced, more bioavailable forms (e.g., NH4+ and urea) favored by CyanoHABs. During blooms, algal biomass increases faster than internal NH4+ regeneration rates, causing high CBAD values. High turnover rates from cell death and remineralization of labile organic matter consume oxygen and enhance denitrification. These processes drive eutrophic systems to NH4+ limitation or colimitation under warm, shallow conditions and support the need for dual nutrient (N and P) control. PMID- 28648053 TI - Separation of Ellagitannin-Rich Phenolics from U.S. Pecans and Chinese Hickory Nuts Using Fused-Core HPLC Columns and Their Characterization. AB - U.S. pecans and Chinese hickory nuts possess a wide array of phenolic constituents with potential health benefits including phenolic acids and proanthocyanidins. Only limited information is available, however, on their compositions. The present study optimized the separation performance and characterized the low-molecular-weight phenolic fractions of these nuts with C18 and pentafluorophenyl (PFP) fused-core LC columns by employing a kinetic approach. Although both types of reversed-phase columns demonstrated similar performance in general, the PFP column furnished greater plate numbers and superior peak shapes for the low-molecular-weight fractions as well as overall separations of ellagic acid derivatives. The high-molecular-weight fraction of pecans, analyzed by a 3-MUm HILIC column, possessed more proanthocyanidins than the Chinese hickory nuts with dimers and trimers (31.4 and 18.34 mg/g crude extract, respectively) being present at the greatest levels. Chinese hickory nuts had lower proanthocyanidin content but possessed tetramers and pentamers at 4.46 and 4.01 mg/g crude extract, respectively. PMID- 28648052 TI - Anticancer Therapeutic Alginate-Based Tissue Sealants for Lung Repair. AB - Injury to the connective tissue that lines the lung, the pleura, or the lung itself can occur from many causes including trauma or surgery, as well as lung diseases or cancers. To address current limitations for patching lung injuries, to stop air or fluid leaks, an adherent hydrogel sealant patch system was developed, based on methacrylated alginate (AMA) and AMA dialdehyde (AMA-DA) blends, which is capable of sealing damaged tissues and sustaining physiological pressures. Methacrylation of alginate hydroxyl groups rendered the polysaccharide capable of photo-cross-linking when mixed with an eosin Y-based photoinitiator system and exposed to visible green light. Oxidation of alginate yields functional aldehyde groups capable of imine bond formation with proteins found in many tissues. The alginate-based patch system was rigorously tested on a custom burst pressure testing device. Blending of nonoxidized material with oxidized (aldehyde modified) alginates yielded patches with improved burst pressure performance and decreased delamination as compared with pure AMA. Human mesothelial cell (MeT-5A) viability and cytotoxicity were retained when cultured with the hydrogel patches. The release and bioactivity of doxorubicin encapsulated submicrospheres enabled the fabrication of drug-eluting adhesive patches and were effective in decreasing human lung cancer cell (A549) viability. PMID- 28648054 TI - Practical Singly and Doubly Electrophilic Aminating Agents: A New, More Sustainable Platform for Carbon-Nitrogen Bond Formation. AB - Given the importance of amines in a large number of biologically active natural products, active pharmaceutical ingredients, agrochemicals, and functional materials, the development of efficient C-N bond-forming methods with wide substrate scope continues to be at the frontier of research in synthetic organic chemistry. Here, we present a general and fundamentally new synthetic approach for the direct, transition-metal-free preparation of symmetrical and unsymmetrical diaryl-, arylalkyl-, and dialkylamines that relies on the facile single or double addition of readily available C-nucleophiles to the nitrogen atom of bench-stable electrophilic aminating agents. Practical single and double polarity reversal (i.e., umpolung) of the nitrogen atom is achieved using sterically and electronically tunable ketomalonate-derived imines and oximes. Overall, this novel approach represents an operationally simple, scalable, and environmentally friendly alternative to transition-metal-catalyzed C-N cross coupling methods that are currently used to access structurally diverse secondary amines. PMID- 28648055 TI - Poly(ethylene glycol)-Mediated Collagen Gel Mechanics Regulates Cellular Phenotypes in a Microchanneled Matrix. AB - For the past few decades, efforts have been extensively made to reproduce tissue of interests for various uses including fundamental bioscience studies, clinical treatments, and even soft robotic systems. In these studies, cells are often cultured in micropores introduced in a provisional matrix despite that bulk rigidity may negatively affect cellular differentiation involved in tissue formation. To this end, we hypothesized that suspending cells within a soft fibrous matrix that is encapsulated within the microchannels of a provisional matrix would allow us to mediate effects of the matrix rigidity on cells and, in turn, to increase the cell differentiation level. We examined this hypothesis by filling microchannels interpenetrating alginate matrices with collagen gels of controlled elastic moduli (i.e., 125 to 1 Pa). Myoblasts used as a model predifferentiated cell were suspended within the collagen gels. The elastic modulus of the collagen gels was decreased through the addition of poly(ethylene glycol) during the gel preparation. Myoblasts loaded in the collagen gel exhibited a higher myogenic differentiation level than those adhered to the collagen-coated microchannel wall. Furthermore, the collagen gel softened by poly(ethylene glycol) further increased the volume of the multinucleated myofibers. The role of collagen gel softness on cell differentiation became more significant when the bulk elastic modulus of the alginate matrix was tuned to be close to that of muscle tissue (i.e., 11 kPa). We believe that the results of this study would be useful to understanding phenotypic activities of a wide array of cells involved in tissue development and regeneration. PMID- 28648056 TI - Anamorsin/Ndor1 Complex Reduces [2Fe-2S]-MitoNEET via a Transient Protein-Protein Interaction. AB - Human mitoNEET is a homodimeric protein anchored to the outer mitochondrial membrane and has a C-terminal [2Fe-2S] binding domain located in the cytosol. Recently, human mitoNEET has been shown to be implicated in Fe/S cluster repair of cytosolic iron regulatory protein 1 (IRP1), a key regulator of cellular iron homeostasis in mammalian cells. The Fe/S cluster repair function of mitoNEET is based on an Fe/S redox switch mechanism: under normal cellular conditions, reduced [2Fe-2S]+-mitoNEET is present and is inactive as an Fe/S cluster transfer protein; under conditions of oxidative cellular stress, the clusters of mitoNEET become oxidized, and the formed [2Fe-2S]2+-mitoNEET species reacts promptly to initiate Fe/S cluster transfer to IRP1, recycling the cytosolic apo-IRP1 into holo-aconitase. Until now, no clear data have been available on which is the system that reduces the mitoNEET clusters back once oxidative stress is not present anymore. In the present work, we used UV-vis and NMR spectroscopies to investigate the electron transfer process between mitoNEET and the cytosolic electron-donor Ndor1/anamorsin complex, a component of the cytosolic iron-sulfur protein assembly (CIA) machinery. The [2Fe-2S] clusters of mitoNEET are reduced via the formation of a transient complex that brings the [2Fe-2S] clusters of mitoNEET close to the redox-active [2Fe-2S] cluster of anamorsin. Our data provide in vitro evidence of a possible direct link between the CIA machinery and the mitoNEET cluster transfer repair pathway. This link might contribute to recovery of CIA machinery efficiency to mature cytosolic and nuclear Fe/S proteins. PMID- 28648057 TI - Magnetic Anisotropy along a Series of Lanthanide Polyoxometalates with Pentagonal Bipyramidal Symmetry. AB - Magneto-structural correlations in a series of lanthanide polyoxometalates (POMs) with pentagonal bipyramidal symmetry, namely, [Ln2(NMP)12(PW12O40)][PW12O40] (NMP is N-methyl pyrrolidone), were studied in detail experimentally combined with theoretical calculations. Furthermore, two types of Dy-based complexes with pentagonal bipyramidal symmetry were built to discuss the dependence of the theoretical energy barriers with the axial Dy-O bond lengths when the magnetic axes in ground Kramers doublet are along the axial orientation or on the equatorial plane. A meaningful conclusion was put forward for designing such Dy based SIMs with high performance. PMID- 28648058 TI - Effect of Exogenous Nitro Oxide on Chilling Tolerance, Polyamine, Proline, and gamma-Aminobutyric Acid in Bamboo Shoots (Phyllostachys praecox f. prevernalis). AB - The effects of exogenous nitro oxide (NO) on chilling resistance and the metabolism of polyamine, proline, and gamma-aminobutyric acid of bamboo shoots were investigated. Bamboo shoots were dipped in 0.07 mM sodium nitroprusside (SNP) and stored at 1 degrees C for 56 days. During the storage, the development of chilling injury of SNP treated bamboo shoots was inhibited with decreased accumulation of malonaldehyde and electrical leakage. At the end of storage, the chilling injury incidence of treated bamboo shoots decreased by 37.9% while their malonaldehyde content and electrical leakage were 8.8% and 18.6% lower than that of the control, respectively. Interestingly, the endogenous NO, polyamines, gamma aminobutyric acid, and proline contents of treated bamboo shoot also significantly increased. Consistently, the metabolisms of these nitrogenous compounds were stimulated in treated bamboo shoots, according to their higher (20.2%-49.8%) related enzyme activities, including nitric oxide synthase, arginine decarboxylase, ornithine decarboxylase, glutamate decarboxylase, orn delta-aminotransferase, and Delta1-pyrroline-5-carboxylate synthetase. The results indicated that the SNP treatment enhanced chilling tolerance of bamboo shoots, which might associate with the activated metabolism of polyamines, gamma aminobutyric acid, and proline. SNP treatment might be an alternative technology to avoid chill injury during cold storage of bamboo shoots. PMID- 28648059 TI - Polyoxometalate-Incorporated Metallapillararene/Metallacalixarene Metal-Organic Frameworks as Anode Materials for Lithium Ion Batteries. AB - A series of remarkable crystalline compounds containing metallapillararene/metallacalixarene metal-organic frameworks (MOFs), [Ag5(pyttz)3.Cl.(H2O)][H3SiMo12O40].3H2O (1), [Ag5(trz)6][H5SiMo12O40] (2), [Ag5(trz)6][H5GeMo12O40] (3), and [Ag5(trz)6][H4PW12O40] (4) (pyttz = 3-(pyrid-4 yl)-5-(1H-1,2,4-triazol-3-yl)-1,2,4-triazolyl, trz = 1,2,4-triazole), have been obtained by using a simple one-step hydrothermal reaction of silver nitrate, pyttz for 1 and trz for 2-4, and Keggin type polyoxometalates (POMs). Crystal analysis reveals that Keggin POMs have been successfully incorporated in the windows of the metallapillararene/metallacalixarene MOFs in compounds 1-4. In addition, the Keggin silicomolybdenate-based hybrid compounds 1 and 2 were used as anode materials in lithium ion batteries (LIBs), which exhibited promising electrochemical performance with the first discharge capacities of 1344 mAh g-1 for 1 and 1452 mAh g-1 for 2, and this stabilized at 520 mAh g-1 for 1 and 570 mAh g-1 for 2 after 100 cycles at a current density of 100 mA g-1. The performances are better than that of (NBu4)4[SiMo12O40] matrix and commercial graphite anodes. PMID- 28648060 TI - Synthesis and Spectroscopy of Silver-Doped PbSe Quantum Dots. AB - Electronic impurity doping of bulk semiconductors is an essential component of semiconductor science and technology. Yet there are only a handful of studies demonstrating control of electronic impurities in semiconductor nanocrystals. Here, we studied electronic impurity doping of colloidal PbSe quantum dots (QDs) using a postsynthetic cation exchange reaction in which Pb is exchanged for Ag. We found that varying the concentration of dopants exposed to the as-synthesized PbSe QDs controls the extent of exchange. The electronic impurity doped QDs exhibit the fundamental spectroscopic signatures associated with injecting a free charge carrier into a QD under equilibrium conditions, including a bleach of the first exciton transition and the appearance of a quantum-confined, low-energy intraband absorption feature. Photoelectron spectroscopy confirms that Ag acts as a p-type dopant for PbSe QDs and infrared spectroscopy is consistent with k.p calculations of the size-dependent intraband transition energy. We find that to bleach the first exciton transition by an average of 1 carrier per QD requires that approximately 10% of the Pb be replaced by Ag. We hypothesize that the majority of incorporated Ag remains at the QD surface and does not interact with the core electronic states of the QD. Instead, the excess Ag at the surface promotes the incorporation of <1% Ag into the QD core where it causes p-type doping behavior. PMID- 28648061 TI - Development of a Comprehensive Flavonoid Analysis Computational Tool for Ultrahigh-Performance Liquid Chromatography-Diode Array Detection-High-Resolution Accurate Mass-Mass Spectrometry Data. AB - Liquid chromatography and mass spectrometry methods, especially ultrahigh performance liquid chromatography coupled with diode array detection and high resolution accurate-mass multistage mass spectrometry (UHPLC-DAD-HRAM/MSn), have become the tool-of-the-trade for profiling flavonoids in foods. However, manually processing acquired UHPLC-DAD-HRAM/MSn data for flavonoid analysis is very challenging and highly expertise-dependent due to the complexities of the chemical structures of the flavonoids and the food matrixes. A computational expert data analysis program, FlavonQ-2.0v, has been developed to facilitate this process. The program first uses UV-vis spectra for an initial stepwise classification of flavonoids into classes and then identifies individual flavonoids in each class based on their mass spectra. Step-wise identification of flavonoid classes is based on a UV-vis spectral library compiled from 146 flavonoid reference standards and a novel chemometric model that uses stepwise strategy and projected distance resolution (PDR) method. Further identification of the flavonoids in each class is based on an in-house database that contains 5686 flavonoids analyzed in-house or previously reported in the literature. Quantitation is based on the UV-vis spectra. The stepwise classification strategy to identify classes significantly improved the performance of the program and resulted in more accurate and reliable classification results. The program was validated by analyzing data from a variety of samples, including mixed flavonoid standards, blueberry, mizuna, purple mustard, red cabbage, and red mustard green. Accuracies of identification for all samples were above 88%. FlavonQ-2.0v greatly facilitates the identification and quantitation of flavonoids from UHPLC-HRAM-MSn data. It saves time and resources and allows less experienced people to analyze the data. PMID- 28648062 TI - Resveratrol Improved the Progression of Chronic Prostatitis via the Downregulation of c-kit/SCF by Activating Sirt1. AB - The regulation mechanism of inflammation inducing prostate carcinogenesis remains largely unknown. Therefore, we investigated the role of the c-kit/SCF pathway, which has been associated with the control of prostate carcinogenesis, in chronic prostatitis (CP) rats and evaluated the anti-prostatitis effect of resveratrol. We performed hemolysin and eosin staining to evaluate the histopathological changes in prostates. Multiple approaches evaluated the expression levels of c kit, stem cell factor (SCF), Sirt1, and carcinogenesis-associated proteins. The CP group exhibited severe diffuse chronic inflammation. Meanwhile, the prostate cells appeared atypia; the activity of c-kit/SCF was upregulated, and carcinogenesis-associated proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. In summary, CP could further cause prostate carcinogenesis, which may be associated with activated c-kit/SCF signaling. Resveratrol treatment could improve the progression of CP via the downregulation of c-kit/SCF by activating Sirt1. PMID- 28648063 TI - Chiral Discrimination of Diamines by a Binaphthalene-Bridged Porphyrin Dimer. AB - A pair of 1,1'-binaphthalene-bridged bisporphyrins, (R)- and (S)-H1, were designed to examine their chiral discrimination abilities toward a range of model diamines by using UV-vis absorption, CD, and 1H NMR spectroscopy with the assistance of DFT molecular modeling. The spectroscopic titrations revealed that (R)-/(S)-H1 could encapsulate (R)-/(S)-DACH and (R)-/(S)-PPDA in the chiral bisporphyrin cavities, leading to the selective formation of sandwich-type 1:1 complexes via dual Zn-N coordination interactions. In particular, the chiral recognition energy (DeltaDeltaG degrees ) toward (R)-/(S)-DACH was evaluated to be -4.02 kJ mol-1. The binding processes afforded sensitive CD spectral changes in response to the stereostructure of chiral diamines. Remarkable enantiodiscrimination effects were also detected in the NMR titrations of (R) /(S)-H1, in which the nonequivalent chemical shift (DeltaDeltadelta) can reach up to 0.57 ppm for (R)-/(S)-DACH. However, due to the large steric effect, another chiral diamine ((R)-/(S)-DPEA) could not be sandwiched in the chiral bisporphyrin cavity; therefore, (R)-/(S)-DPEA could hardly be discriminated by (R)-/(S)-H1. The present results demonstrate a chiral bisporphyrin host with integrated CD and NMR chiral sensing functions and also highlight the binding-mode-dependent character of its enantiodiscrimination performance for different chiral guests. PMID- 28648064 TI - Unraveling the Magnesium-Ion Intercalation Mechanism in Vanadium Pentoxide in a Wet Organic Electrolyte by Structural Determination. AB - Magnesium batteries have received attention as a type of post-lithium-ion battery because of their potential advantages in cost and capacity. Among the host candidates for magnesium batteries, orthorhombic alpha-V2O5 is one of the most studied materials, and it shows a reversible magnesium intercalation with a high capacity especially in a wet organic electrolyte. Studies by several groups during the last two decades have demonstrated that water plays some important roles in getting higher capacity. Very recently, proton intercalation was evidenced mainly using nuclear resonance spectroscopy. Nonetheless, the chemical species inserted into the host structure during the reduction reaction are still unclear (i.e., Mg(H2O)n2+, Mg(solvent, H2O)n2+, H+, H3O+, H2O, or any combination of these). To characterize the intercalated phase, the crystal structure of the magnesium-inserted phase of alpha-V2O5, electrochemically reduced in 0.5 M Mg(ClO4)2 + 2.0 M H2O in acetonitrile, was solved for the first time by the ab initio method using powder synchrotron X-ray diffraction data. The structure was tripled along the b-axis from that of the pristine V2O5 structure. No appreciable densities of elements were observed other than vanadium and oxygen atoms in the electron density maps, suggesting that the inserted species have very low occupancies in the three large cavity sites of the structure. Examination of the interatomic distances around the cavity sites suggested that H2O, H3O+, or solvated magnesium ions are too big for the cavities, leading us to confirm that the intercalated species are single Mg2+ ions or protons. The general formula of magnesium-inserted V2O5 is Mg0.17HxV2O5, (0.66 <= x <= 1.16). Finally, density functional theory calculations were carried out to locate the most plausible atomic sites of the magnesium and protons, enabling us to complete the structure modeling. This work provides an explicit answer to the question about Mg intercalation into alpha-V2O5. PMID- 28648065 TI - Membrane Alterations in Pseudomonas putida F1 Exposed to Nanoscale Zerovalent Iron: Effects of Short-Term and Repetitive nZVI Exposure. AB - In this study, we report the effect of the commercial nanoscale zerovalent iron (nZVI) on environmental bacteria, emphasizing the importance of nZVI-bacterial membrane interaction on nZVI toxicity as well as the adaptability of bacteria to nZVI. Exposure of Pseudomonas putida F1 to 0.1, 1.0, and 5.0 g/L of nZVI caused the reduction in colony forming units (CFUs) substantially for almost 3 orders of magnitude. However, a rebound in the cell number was observed after the prolonged exposure except for 5.0 g/L nZVI at which bacterial viability was completely inhibited. Upon exposure, nZVI accumulated on and penetrated into the bacterial cell membrane. Cell membrane composition analysis revealed the conversion of the cis to trans isomer of unsaturated fatty acid upon short-term nZVI exposure, resulting in a more rigid membrane counteracting the membrane-fluidizing effect of nZVI. Several cycles of repetitive exposure of cells to 0.1 g/L nZVI induced a persistent phenotype of P. putida F1 as indicated by smaller colony morphology, a more rigid membrane, and higher tolerance to nZVI. A low interaction between nZVI particles and the surface of the nZVI-persistent phenotypic cells reduced the nZVI-induced membrane damage. This study unveils the significance of nZVI membrane interaction on toxicity of nZVI toward bacteria. PMID- 28648067 TI - Synthesis, Crystal Structure, and Magnetic Properties of R2Mg3SiPn6 (R = La, Ce; Pn = P, As). AB - Four new quaternary pnictides, R2Mg3SiPn6 (R = La, Ce; Pn = P, As), were synthesized via high-temperature solid-state reactions and gas-phase transport reactions with iodine. Their crystal structures were determined by single crystal X-ray diffraction. All four compounds are isostructural and crystallize in a new structure type in the orthorhombic space group Pnma (No. 62, Z = 4), Pearson symbol oP48. The crystal structures of R2Mg3SiPn6 are composed of two-dimensional puckered MgP3 layers, which are connected in a three-dimensional framework by P-P dimers and MgSiP4 double-tetrahedral chains. Rare-earth cations are encapsulated inside the channels of the framework running along [010]. Quantum-chemical calculations predict that La2Mg3SiP6 is an indirect narrow bandgap semiconductor. The Mg-P bonding in MgP4 tetrahedra and MgP6 octahedra was analyzed by means of crystal orbital Hamilton population (COHP) analysis. Magnetic characterization of Ce-containing compounds confirmed the trivalent nature of cerium atoms and revealed complex ferrimagnetic ordering at low temperatures. PMID- 28648066 TI - Effects of Topography-Related Puff Parameters on Carbonyl Delivery in Mainstream Cigarette Smoke. AB - Smoking topography parameters differ substantially between individual smokers and may lead to significant variation in tobacco smoke exposure and risk for tobacco caused diseases. However, to date, little is known regarding the impact of individual puff parameters on the delivery of many harmful smoke constituents including carbonyls. To examine this, we determined the effect of altering individual puff parameters on mainstream smoke carbonyl levels in machine-smoked reference cigarettes. Carbonyls including formaldehyde, acetaldehyde, crotonaldehyde, propionaldehyde, methyl ethyl ketone (MEK), acrolein, and acetone were determined in cigarette smoke by HPLC after derivatization with 2,4 dinitrophenylhydrazine (DNPH). Deliveries of all carbonyls were nearly two-fold greater when cigarettes were smoked according to the more intense Health Canada Intense (HCI) protocol compared to the International Organization of Standardization (ISO) method, consistent with the two-fold difference in total puff volume between methods (ISO: 280-315 mL; CI: 495-605 mL). When individual topography parameters were assessed, changes in puff volume alone had the greatest effect on carbonyl delivery as predicted with total carbonyls being strongly correlated with overall puff volume (r2: 0.52-0.99) regardless of how the differences in volume were achieved. All seven of the carbonyls examined showed a similar relationship with puff volume. Minor effects on carbonyl levels were observed from vent blocking and changing the interpuff interval, while effects of changing puff duration and peak flow rate were minimal. Overall, these results highlight the importance of considering topography, especially puff volume, when the toxicant delivery and potential exposure smokers receive are assessed. The lack of an impact of other behaviors, including puff intensity and duration independent of volume, indicate that factors such as temperature and peak flow rate may have minimal overall effects on carbonyl production and delivery. PMID- 28648068 TI - Redox Activity of Oxo-Bridged Iridium Dimers in an N,O-Donor Environment: Characterization of Remarkably Stable Ir(IV,V) Complexes. AB - Chemical and electrochemical oxidation or reduction of our recently reported Ir(IV,IV) mono-MU-oxo dimers results in the formation of fully characterized Ir(IV,V) and Ir(III,III) complexes. The Ir(IV,V) dimers are unprecedented and exhibit remarkable stability under ambient conditions. This stability and modest reduction potential of 0.99 V vs NHE is in part attributed to complete charge delocalization across both Ir centers. Trends in crystallographic bond lengths and angles shed light on the structural changes accompanying oxidation and reduction. The similarity of these mono-MU-oxo dimers to our Ir "blue solution" water-oxidation catalyst gives insight into potential reactive intermediates of this structurally elusive catalyst. Additionally, a highly reactive material, proposed to be a Ir(V,V) MU-oxo species, is formed on electrochemical oxidation of the Ir(IV,V) complex in organic solvents at 1.9 V vs NHE. Spectroelectrochemistry shows reversible conversion between the Ir(IV,V) and proposed Ir(V,V) species without any degradation, highlighting the exceptional oxidation resistance of the 2-(2-pyridinyl)-2-propanolate (pyalk) ligand and robustness of these dimers. The Ir(III,III), Ir(IV,IV) and Ir(IV,V) redox states have been computationally studied both with DFT and multiconfigurational calculations. The calculations support the stability of these complexes and provide further insight into their electronic structures. PMID- 28648069 TI - Carbon-Nitrogen and Nitrogen-Nitrogen Bond Formation from Nucleophilic Attack at Coordinated Nitrosyls in Fe and Ru Heme Models. AB - The conversion of inorganic NOx species to organo-N compounds is an important component of the global N-cycle. Reaction of a C-based nucleophile, namely the phenyl anion, with the ferric heme nitrosyl [(OEP)Fe(NO)(5-MeIm)]+ generates a mixture of the C-nitroso derivative (OEP)Fe(PhNO)(5-MeIm) and (OEP)Fe(Ph). The related reaction with [(OEP)Ru(NO)(5-MeIm)]+ generates the (OEP)Ru(PhNO)(5-MeIm) product. Reactions with the N-based nucleophile diethylamide results in the formation of free diethylnitrosamine, whereas the reaction with azide results in N2O formation; these products derive from attack of the nucleophiles on the bound NO groups. These results provide the first demonstrations of C-N and N-N bond formation from attack of C-based and N-based nucleophiles on synthetic ferric-NO hemes. PMID- 28648070 TI - Magnetic Resonance Imaging Quantification of Fasted State Colonic Liquid Pockets in Healthy Humans. AB - The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (~8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean +/- SEM) 11 +/- 5 pockets of resting liquid with a total volume of 2 +/- 1 mL (average). The colonic fluid peaked at 7 +/- 4 mL 30 min after the water drink. This peak fluid was distributed in 17 +/- 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment. PMID- 28648072 TI - Nucleation of Salt Crystals in Clay Minerals: Molecular Dynamics Simulation. AB - Nucleation of salt crystals in confined media occurs in many processes of high importance, such as injection of CO2 in geological formations for its sequestration. In particular, salt precipitation in clays, a main component of sedimentary rock, is an important phenomenon. The crystals precipitate on the pores' surface, modify the pore space morphology, and reduce its flow and transport properties. Despite numerous efforts to understand the mechanisms of nucleation of salt crystals in confined media, the effect of the clay's chemistry on the growth, distribution, and properties of the crystals is not well understood. We report the results of extensive molecular dynamics simulation of nucleation and growth of NaCl crystals in a clay pore using molecular models of two types of clay minerals, Na-montmorillonite and kaolinite. Clear evidence is presented for the nucleation of the salt crystals that indicates that the molecular structure of clay minerals affects their spatial distribution, although the nucleation mechanism is the same in both types of clays. PMID- 28648071 TI - Elucidation of the Catalytic Mechanism of a Miniature Zinc Finger Hydrolase. AB - To improve our mechanistic understanding of zinc metalloenzymes, we report a joint computational and experimental study of a minimal carbonic anhydrase (CA) mimic, a 22-residue Zn-finger hydrolase. We combine classical molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) geometry optimizations, and QM/MM free energy simulations with ambient and high-pressure kinetic measurements to investigate the mechanism of the hydrolysis of the substrate p-nitrophenylacetate (pNPA). The zinc center of the hydrolase prefers a pentacoordinated geometry, as found in most naturally occurring CAs and CA-like enzymes. Two possible mechanisms for the catalytic reaction are investigated. The first one is analogous to the commonly accepted mechanism for CA-like enzymes: a sequential pathway, in which a Zn2+-bound hydroxide acts as a nucleophile and the hydrolysis proceeds through a tetrahedral intermediate. The initial rate-limiting step of this reaction is the nucleophilic attack of the hydroxide on pNPA to form the tetrahedral intermediate. The computed free energy barrier of 18.5 kcal/mol is consistent with the experimental value of 20.5 kcal/mol obtained from our kinetics experiments. We also explore an alternative reverse protonation pathway for the hydrolase, in which a nearby hydroxide ion from the bulk acts as the nucleophile (instead of a zinc-bound hydroxide). According to QM/MM MD simulations, hydrolysis occurs spontaneously along this pathway. However, this second scenario is not viable in our system, as the tertiary structure of the hydrolase lacks a suitably positioned residue that would act as a general base and generate a hydroxide ion from a nearby bulk water molecule. Hence, our combined theoretical and experimental study indicates that the investigated minimal CA mimic retains the essential mechanistic features of CA-like enzyme catalysis. The high-pressure experiments show that its catalytic efficiency can be enhanced by applying hydrostatic pressure. According to the simulations, more drastic improvements might be afforded by mutations that make the reverse protonation pathway accessible. PMID- 28648073 TI - Effects of Molecular Structure and Solvent Polarity on Adsorption of Carboxylic Anchoring Dyes onto TiO2 Particles in Aprotic Solvents. AB - Interactions of molecules with the surface of TiO2 particles are of fundamental and technological importance. One example is that the adsorption density and energy of the dye molecules on TiO2 particles affect the efficiency of dye sensitized solar cells (DSSC). In this work, we present measurements characterizing the adsorption of the two isomers, para-ethyl red (p-ER) and ortho ethyl red (o-ER), of a dye molecule potentially applicable for DSSC onto TiO2 particles by second harmonic scattering (SHS). It is found that while at the wavelengths used here o-ER has a much bigger molecular hyperpolarizability, p-ER exhibits strong SHS responses but o-ER gives no detectable SHS when the dyes are added to the TiO2 colloids, respectively. This observation indicates that o-ER does not adsorb onto TiO2, likely due to steric hindrance. Furthermore, we investigate how solvents affect the surface adsorption strength and density of p ER onto TiO2 in four aprotic solvents with varying polarity. The absolute magnitude of the adsorption free energy was found to increase with the specific solvation energy that represents the ability of accepting electrons and solvent polarity. It is likely that resolvation of the solvent molecules displaced by the adsorption of the dye molecule at the surface in stronger electron-accepting and more polar solvents results in a larger adsorption free energy for the dye adsorption. PMID- 28648074 TI - Boronic Acid-Functionalized Oxide-Free Silicon Surfaces for the Electrochemical Sensing of Dopamine. AB - Boronic acid monolayers covalently bound to hydrogen-terminated Si(111) surfaces have been prepared from the UV-directed hydrosilylation reaction of 4 vinylbenzeneboronic acid. X-ray photoelectron spectroscopy (XPS) analysis of the modified surface revealed characteristic peaks from the attached organic molecule with the expected molecular composition and without the oxidation of underlying silicon. From XPS data, the surface coverage was estimated to be ca. 0.34 +/- 0.04 ethylbenzene boronic acid chain per surface silicon atom (i.e., (4.4 +/- 0.5) * 10-10 mol cm-2), which is consistent with a densely packed monolayer. The electrochemical impedance spectroscopy measurements performed at pH 7.4 in the presence of the Fe(CN)63-/Fe(CN)64- reporter couple showed specific dopamine induced changes as a result of the binding of the guest molecule to the immobilized boronate species. The charge-transfer resistance (Rct) was found to decrease from 4.9 MOmega to 14 kOmega upon increasing the dopamine concentration in the range of 10 MUM-1 mM. Furthermore, the presence of the interfering ascorbic acid until a concentration of 10 mM did not significantly change the electrochemical response of the functionalized surface. Comparative electrochemical data obtained at the reference ethylbenzene monolayer provided clear evidence that the immobilized boronic acid units were responsible for the observed changes. PMID- 28648075 TI - Synergistic Effects of Gold-Palladium Nanoalloys and Reducible Supports on the Catalytic Reduction of 4-Nitrophenol. AB - Herein we report on the catalytic activity of mesoporous nickel, iron, cerium, cobalt, and manganese oxides prepared using KIT-6 as a hard template via evaporation-assisted precipitation. The mesoporous metal oxides (MMOs) were characterized and used as heterogeneous catalysts in the reduction of 4 nitrophenol (4-Nip) by sodium borohydride (BH4-). Furthermore, polyamidoamide (PAMAM) dendrimers were used to synthesize gold-palladium nanoalloy particles. The size of AuPd/PAMAM was found to be 3.5 +/- 0.8 nm in diameter before being immobilized on the aforementioned mesoporous metal oxides and used as catalysts in the reduction of 4-Nip. Prior to catalytic evaluation, the reduction profiles of the mesoporous metal oxides were investigated by hydrogen-temperature programmed reduction (H2-TPR) and showed that mesoporous metal oxides can be easily reduced at lower temperatures and that the immobilization of gold palladium nanoalloy particles lowers their reduction temperatures. Mesoporous cobalt and manganese oxides showed catalytic activity toward 4-Nip reduction, and the activity was enhanced after immobilization of the gold-palladium nanoalloys. Isolation of nanoparticles activity was achieved by immobilization of the gold palladium nanoalloys on the inert silica support. From this we postulated an electron relay mechanism for the reduction of 4-nitrophenol. With the use of power rate law we showed that 4-Nip reduction follows pseudo-first-order kinetics. PMID- 28648076 TI - Asymmetric Dipyrrin and F-BODIPYs Conjugated to Terminal Alkynes and Alkenes. AB - An asymmetric meso-H dipyrrin featuring a conjugated terminal alkyne substituent was converted to its corresponding difluoro boron complex, and the extent of pi conjugation was extended using Sonogashira cross-coupling. Treatment of the alkyne-substituted dipyrrin with BF3.OEt2 and NEt3 revealed the reactivity of the conjugated terminal alkyne toward Lewis-activated electrophilic substitution and led to the isolation of F-BODIPYs bearing terminal bromovinyl and enol substituents. PMID- 28648077 TI - Stable and Functionalizable Quantum Dots with a Thin Zwitterionic Carboxybetaine Layer. AB - A new type of ligand chemistry, with a zwitterionic carboxybetaine headgroup and a bidentate thiol end group (CBSS), is introduced to promote the stability of quantum dots (QDs) with targeting capability. Results show that QDs are stable over a broad range of pH values after surface modification. Surface binding assays and cellular internalization studies show that QDs capped with CBSS exhibit low nonspecific adsorption. The CBSS ligand also allows the conjugation of highly specific targeting ligands while effectively maintaining the nonfouling background. This QD chemistry offers a unique approach to presenting abundant functional groups for ligand immobilization in a thin layer with an ultralow background and holds significant potential for imaging applications. PMID- 28648078 TI - Controllable Synthesis of Mesoporous Sulfur-Doped Carbon Nitride Materials for Enhanced Visible Light Photocatalytic Degradation. AB - Mesoporous sulfur-doped graphitic carbon nitride (MCNS) materials were successfully synthesized using thiourea as a low-cost precursor and SiO2 gel solution as a template through a simple thermal condensation method. The effects of three synthesis key factors, namely, the reaction temperature, the reaction time, and the weight ratio of SiO2/thiourea, and also their interactions on the removal rate of methyl orange (MO) were investigated using response surface methodology, and the samples were subjected to several characterization techniques. Results showed that the optimized physicochemical properties could be achieved for the MCNS samples by controlling the synthesis key factors, and it was found that the reaction temperature and the reaction time had significant influences on the MO photocatalytic removal. Among bulk graphitic carbon nitride (g-C3N4), CN (undoped g-C3N4), CNS (sulfur-doped g-C3N4 without template), and TiO2 (Degussa P25) samples, the optimized MCNS-4 illustrated the highest photocatalytic activity toward the removal of MO under visible light irradiation. The enhanced performance originated from the synergistic effects of high surface area, mesoporous texture, sulfur doping, and high visible light absorption, which were helpful for the separation and transportation of the photogenerated electron hole pairs. Furthermore, MCNS-4 revealed high reusability and stability without any significant decrease in its efficiency. Our findings not only confirm the importance of simultaneous sulfur doping and mesoporous structure to synthesize highly active photocatalysts but also might provide a new insight into textural engineering of carbon nitride materials only by the optimization of the synthesis key variables, considering their interactions without relying on extra metal oxides. PMID- 28648079 TI - Mass Spectrometry Imaging, Laser Capture Microdissection, and LC-MS/MS of the Same Tissue Section. AB - Mass spectrometry imaging (MSI) is able to simultaneously record the distributions of hundreds of molecules directly from tissue. Rapid direct tissue analysis is essential for MSI in order to maintain spatial localization and acceptable measurement times. The absence of an explicit analyte separation/purification step means MSI lacks the depth of coverage of LC-MS/MS. In this work, we demonstrate how atmospheric pressure MALDI-MSI enables the same tissue section to be first analyzed by MSI, to identify regions of interest that exhibit distinct molecular signatures, followed by localized proteomics analysis using laser capture microdissection isolation and LC-MS/MS. PMID- 28648080 TI - Sensitive Detection of Competitive Molecular Adsorption by Surface-Enhanced Raman Spectroscopy. AB - Surface adsorption plays a critical role in a wide variety of fields from surface catalysis to molecular separation. Despite the importance, limited access to simultaneously sensitive and selective detection mechanisms has hampered the acquisition of comprehensive and versatile experimental data needed to understand the complex aspects of mixture adsorption, calling for a molecular detection method capable of obtaining the surface adsorption isotherms over a wide range of concentrations as well as distinguishing the competitive adsorption of different adsorbates. Here, we test surface-enhanced Raman spectroscopy (SERS) as an effective analysis tool of surface adsorption phenomena. Using a sensitive SERS substrate, we characterize the adsorption isotherms of chemical species of various binding energies. We obtained the isotherms for strongly binding species in a concentration range from subpicomolar to micromolar. A log-sigmoidal dependency of the SERS signals to the analyte concentration could be modeled by surface binding theories accurately using molecular dynamics simulations, thereby bringing out the potential capability of sensitive SERS for describing a single compound adsorption process. SERS also enabled the determination of competitive adsorption isotherms from a multiple-compound solution for the first time. The successful demonstration of the sensitive and selective characterization of surface adsorption lends SERS adaptability to a cheap, facile, and effective solution for chemical analysis. PMID- 28648081 TI - In Silico and in Vitro Screening for P-Glycoprotein Interaction with Tenofovir, Darunavir, and Dapivirine: An Antiretroviral Drug Combination for Topical Prevention of Colorectal HIV Transmission. AB - The aim of the study was to use in silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (Papp), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a DeltaGPB value -38.24 kcal/mol, darunavir a DeltaGPB value -36.84 kcal/mol. The rank order of permeability of the compounds in vitro was tenofovir < darunavir < dapivirine. The Papp for tenofovir in Caco-2 cell monolayers was 0.10 +/- 0.02 * 10-6 cm/s, ER = 1. For dapivirine, Papp was 32.2 +/- 3.7 * 10-6 cm/s, but the ER = 1.3 was lower than anticipated based on the in silico findings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (Papp = 6.4 +/- 0.9 * 10-6 cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silico modeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silico modeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that in silico modeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly different permeability, but was not interdependent. PMID- 28648082 TI - Width-Tuned Magnetic Order Oscillation on Zigzag Edges of Honeycomb Nanoribbons. AB - Quantum confinement and interference often generate exotic properties in nanostructures. One recent highlight is the experimental indication of a magnetic phase transition in zigzag-edged graphene nanoribbons at the critical ribbon width of about 7 nm [ Magda , G. Z. et al. Nature 2014 , 514 , 608 ]. Here we show theoretically that with further increase in the ribbon width, the magnetic correlation of the two edges can exhibit an intriguing oscillatory behavior between antiferromagnetic and ferromagnetic, driven by acquiring the positive coherence between the two edges to lower the free energy. The oscillation effect is readily tunable in applied magnetic fields. These novel properties suggest new experimental manifestation of the edge magnetic orders in graphene nanoribbons and enhance the hopes of graphene-like spintronic nanodevices functioning at room temperature. PMID- 28648083 TI - Temporal Signal Pattern Recognition in Mass Spectrometry: A Method for Rapid Identification and Accurate Quantification of Biomarkers for Inborn Errors of Metabolism with Quality Assurance. AB - Mass spectrometry (MS)-based metabolomic initiatives that use conventional separation techniques are limited by low sample throughput and complicated data processing that contribute to false discoveries. Herein, we introduce a new strategy for unambiguous identification and accurate quantification of biomarkers for inborn errors of metabolism (IEM) from dried blood spots (DBS) with quality assurance. A multiplexed separation platform based on multisegment injection capillary electrophoresis-mass spectrometry (MSI-CE-MS) was developed to provide comparable sample throughput to flow injection analysis-tandem MS (FIA-MS/MS) but with greater selectivity as required for confirmatory testing and discovery-based metabolite profiling of volume-restricted biospecimens. Mass spectral information is encoded temporally within a separation by serial injection of three or more sample pairs, each having a unique dilution pattern, alongside a quality control (QC) that serves as a reference in every run to facilitate between-sample comparisons and/or batch correction due to system drift. Optimization of whole blood extraction conditions on DBS filter paper cut-outs was first achieved to maximize recovery of a wide range of polar metabolites from DBS extracts. An interlaboratory comparison study was also conducted using a proficiency test and retrospective neonatal DBS that demonstrated good agreement between MSI-CE-MS and validated FIA-MS/MS methods within an accredited facility. Our work demonstrated accurate identification of various IEM based on reliable measurement of a panel of primary or secondary biomarkers above an upper cutoff concentration limit for presumptive screen-positive cases without stable isotope-labeled reagents. Additionally, nontargeted metabolite profiling by MSI-CE-MS with temporal signal pattern recognition revealed new biomarkers for early detection of galactosemia, such as N-galactated amino acids, that are a novel class of pathognomonic marker due to galactose stress in affected neonates. PMID- 28648084 TI - Practical, Broadly Applicable, alpha-Selective, Z-Selective, Diastereoselective, and Enantioselective Addition of Allylboron Compounds to Mono-, Di-, Tri-, and Polyfluoroalkyl Ketones. AB - A practical method for enantioselective synthesis of fluoroalkyl-substituted Z homoallylic tertiary alcohols has been developed. Reactions may be performed with ketones containing a polylfluoro-, trifluoro-, difluoro-, and monofluoroalkyl group along with an aryl, a heteroaryl, an alkenyl, an alkynyl, or an alkyl substituent. Readily accessible unsaturated organoboron compounds serve as reagents. Transformations were performed with 0.5-2.5 mol % of a boron-based catalyst, generated in situ from a readily accessible valine-derived aminophenol and a Z- or an E-gamma-substituted boronic acid pinacol ester. With a Z organoboron reagent, additions to trifluoromethyl and polyfluoroalkyl ketones proceeded in 80-98% yield, 97:3 to >98:2 alpha:gamma selectivity, >95:5 Z:E selectivity, and 81:19 to >99:1 enantiomeric ratio. In notable contrast to reactions with unsubstituted allylboronic acid pinacol ester, additions to ketones with a mono- or a difluoromethyl group were highly enantioselective as well. Transformations were similarly efficient and alpha- and Z-selective when an E-allylboronate compound was used, but enantioselectivities were lower. In certain cases, the opposite enantiomer was favored (up to 4:96 er). With a racemic allylboronate reagent that contains an allylic stereogenic center, additions were exceptionally alpha-selective, affording products expected from gamma-addition of a crotylboron compound, in up to 97% yield, 88:12 diastereomeric ratio, and 94:6 enantiomeric ratio. Utility is highlighted by gram scale preparation of representative products through transformations that were performed without exclusion of air or moisture and through applications in stereoselective olefin metathesis where Z-alkene substrates are required. Mechanistic investigations aided by computational (DFT) studies and offer insight into different selectivity profiles. PMID- 28648086 TI - Lower morbidity and improved outcomes in patients with screen-detected colorectal cancer. AB - Screening for colorectal cancer is now integrated into the fabric of healthcare systems across the world, as a wealth of evidence exists as regards its benefits in reducing cancer-specific mortality through the detection of early-stage disease. Options for screening include both endoscopic and stool-based tests, with a majority of countries opting for repeated faecal occult blood screening tests (FOBt). These can be either guaiac-based, as is the current system across the UK, or immunoglobulin-based, as is the case in the accompanying article from Spain. Patients testing positive for FOBt proceed to colonoscopy, where a relatively small proportion of patients, less than 10% in established screening programmes, will have a colorectal cancer identified. As national programmes have developed, multiple publications have focused on the differing aspects between colorectal cancers diagnosed through screening programmes (SD) and those diagnosed outside the screening pathway (NSD). In particular, patients diagnosed with SD tumours have been noted to be younger, more likely to be male and less socioeconomically deprived. Furthermore, tumour characteristics are different with early-stage disease and an absence of rectal tumours predominating in the SD patient group. PMID- 28648085 TI - Specifying RNA-Binding Regions in Proteins by Peptide Cross-Linking and Affinity Purification. AB - RNA-binding proteins (RBPs) allow cells to carry out pre-RNA processing and post transcriptional regulation of gene expression, and aberrations in RBP functions have been linked to many diseases, including neurological disorders and cancer. Human cells encode thousands of RNA-binding proteins with unique RNA-binding properties. These properties are regulated through modularity of a large variety of RNA-binding domains, rendering RNA-protein interactions difficult to study. Recently, the introduction of proteomics methods has provided novel insights into RNA-binding proteins at a systems level. However, determining the exact protein sequence regions that interact with RNA remains challenging and laborious, especially considering that many RBPs lack canonical RNA-binding domains. Here we describe a streamlined proteomic workflow called peptide cross-linking and affinity purification (pCLAP) that allows rapid characterization of RNA-binding regions in proteins. pCLAP is based upon the combined use of UV cross-linking and enzymatic digestion of RNA-bound proteins followed by single-shot mass spectrometric analysis. To benchmark our method, we identified the binding regions for polyadenylated RNA-binding proteins in HEK293 cells, allowing us to map the mRNA interaction regions of more than 1000 RBPs with very high reproducibility from replicate single-shot analyses. Our results show specific enrichment of many known RNA-binding regions on many known RNA-binding proteins, confirming the specificity of our approach. PMID- 28648088 TI - Idiopathic esophageal ulcer as an initial manifestation of HIV infection. AB - The esophageal ulcer us a common complication in people affected by the acquired human immunodeficiency virus (HIV), especially in the final stages and in patients who develop an acute retroviral syndrome. Although, it can be caused by various infectious agents, such as species of candida, cytomegalovirus (CMV) and herpes simplex virus (HSV), no aetiological agent is successfully identified in a large proportion of patients and it is classified as idiopathic. We report the case of an idiopathic esophageal ulcer associated with the initial diagnosis of HIV-1. PMID- 28648087 TI - Cost-effectiveness of a hepatitis B virus screening strategy to prevent reactivation in patients with hematologic neoplasms. AB - INTRODUCTION: The effectiveness of a screening strategy for the detection of a hepatitis B virus (HBV) infection followed by prophylaxis in order to prevent HBV reactivation was assessed in patients with hematologic neoplasms. MATERIAL AND METHODS: A decision tree was developed to compare the cost and effectiveness (prevented reactivations) over an 18 month period of a screening strategy prior to chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) with a non-screening approach. HBsAg+ (hepatitis B surface antigen) and/or anti-HBc+ (antibodies to hepatitis B core antigen) and HBV-DNA+ patients received oral antiviral prophylaxis with tenofovir disoproxil (245 mg once daily) from chemotherapy baseline until one year after chemotherapy completion. Non-screened patients received tenofovir in case of a reactivation. Model probabilities were obtained from the literature. The total cost (?, 2015) included: antiviral prophylaxis, R-CHOP, screening tests (HBsAg, anti-HBc, HBV DNA) and liver function tests. Drug therapy costs were estimated using ex-factory prices with mandatory deductions. The incremental cost-effectiveness ratio (ICER) was calculated in order to assess the cost-effectiveness of this intervention in terms of cost per reactivation averted versus no screening. RESULTS: In a hypothetical cohort of 1,000 patients, screening prevented 7.36 reactivations when compared to the non-screening approach (14.9 versus 22.3). Total cost/patient (including ?8,282 for R-CHOP) was ?8,584 for the screening strategy and ?8,449 for the non-screening approach. The ICER for screening versus non screening was ?18,376/prevented reactivation. CONCLUSION: HBV screening followed by oral antiviral prophylaxis yielded more health benefits than non-screening, reducing HBV reactivation in patients with hematologic neoplasms on chemotherapy. PMID- 28648089 TI - Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: An electrophysiological study in healthy volunteers. AB - Background Benefits of cervical non-invasive vagus nerve stimulation (nVNS) devices have been shown in episodic cluster headache and preliminarily suggested in migraine, but direct evidence of vagus nerve activation using such devices is lacking. Vagal somatosensory evoked potentials (vSEPs) associated with vagal afferent activation have been reported for invasive vagus nerve stimulation (iVNS) and non-invasive auricular vagal stimulation. Here, we aimed to show and characterise vSEPs for cervical nVNS. Methods vSEPs were recorded for 12 healthy volunteers who received nVNS over the cervical vagus nerve, bipolar electrode/DS7A stimulation over the inner tragus, and nVNS over the sternocleidomastoid (SCM) muscle. We measured peak-to-peak amplitudes (P1-N1), wave latencies, and N1 area under the curve. Results P1-N1 vSEPs were observed for cervical nVNS (11/12) and auricular stimulation (9/12), with latencies similar to those described previously, whereas SCM stimulation revealed only a muscle artefact with a much longer latency. A dose-response analysis showed that cervical nVNS elicited a clear vSEP response in more than 80% of the participants using an intensity of 15 V. Conclusion Cervical nVNS can activate vagal afferent fibres, as evidenced by the recording of far-field vSEPs similar to those seen with iVNS and non-invasive auricular stimulation. PMID- 28648090 TI - Effectiveness of a 10-week group program based on Dialectical Behaviour Therapy skills among patients with personality and mood disorders: findings from a pilot study. AB - OBJECTIVES: Community mental health services are often required to manage people experiencing repeated crises. Personality disorders are not uncommon, accounting for up to one-third of such presentations. These patients are often difficult to treat, leading to a revolving-door phenomenon. This study evaluated the effectiveness of a pilot intervention in reducing psychological symptoms and distress, and examined the impact of the intervention on mental health service utilization. METHODS: A pre- versus post-treatment evaluation was conducted of the effectiveness of a 10-week group psychological intervention based on Dialectical Behaviour Therapy skills, conducted in a regional Australian community mental health service with patients diagnosed with either Cluster B personality disorder or a mood disorder. RESULTS: Of those who completed the program ( N = 38 patients), 84% were female, with an average age of 35.13 years. Participants were active clients of the service for an average of 58.3 weeks prior to the program. They demonstrated significant improvements in quality of life and self-control, and a reduction in hopelessness, cognitive instability and dependence on mental health services. CONCLUSIONS: Limiting the Dialectical Behaviour Therapy program to a short-term skills-based group component was successful with the targeted patient group; however, more research is required to establish the generalizability of these results. PMID- 28648091 TI - Mediators Go Together: High Production of CXCL9, CXCL10, IFN-gamma, and TNF-alpha in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis. AB - HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic demyelinating and disabling syndrome caused by human T lymphotropic virus 1 (HTLV 1). Although the pathogenic mechanisms that lead to HAM/TSP outcome have not been elucidated, genetic and immunological factors may be involved in the myelopathy occurrence. This study aimed to compare cytokines, chemokines, and nitric oxide (NO) levels in asymptomatic and HAM/TSP HTLV-1-infected patients. The study group consisted of 21 HAM/TSP and 48 asymptomatic HTLV-1 patients. Chemokines (CCL5, CCL2, CXCL8, CXCL9, and CXCL10) and cytokines [IL-2, interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF-alpha), IL-4, IL-6, and IL-10] were measured using cytometric bead array, whereas NO production was measured after reaction of supernatants with nitrate reduction solution. CXCL9 and CXCL10 chemokines levels were found to be higher in the HAM/TSP group. CXCL9 was also strongly correlated with CXCL10 and both CXCL9 and CXCL10 were moderately correlated with CCL2 and CCL5 levels, in both HAM/TSP and asymptomatic groups. There was no significant difference related to NO, IL-4, IL-6, and IL-10 levels between the clinical groups but TNF-alpha and IFN-gamma levels were increased in HAM/TSP patients. Thus, factors such as CXCL9, CXCL10, TNF-alpha, and IFN-gamma could be good prognostic biomarker candidates, and further studies may help to clarify their association with HAM/TSP immunopathogenesis. PMID- 28648094 TI - Visualization of Nicotine Adenine Dinucleotide Redox Homeostasis with Genetically Encoded Fluorescent Sensors. AB - SIGNIFICANCE: Beyond their roles as redox currency in living organisms, pyridine dinucleotides (NAD+/NADH and NADP+/NADPH) are also precursors or cosubstrates of great significance in various physiologic and pathologic processes. Recent Advances: For many years, it was challenging to develop methodologies for monitoring pyridine dinucleotides in situ or in vivo. Recent advances in fluorescent protein-based sensors provide a rapid, sensitive, specific, and real time readout of pyridine dinucleotide dynamics in single cells or in vivo, thereby opening a new era of pyridine dinucleotide bioimaging. In this article, we summarize the developments in genetically encoded fluorescent sensors for NAD+/NADH and NADP+/NADPH redox states, as well as their applications in life sciences and drug discovery. The strengths and weaknesses of individual sensors are also discussed. CRITICAL ISSUES: These sensors have the advantages of being specific and organelle targetable, enabling real-time monitoring and subcellular level quantification of targeted molecules in living cells and in vivo. FUTURE DIRECTIONS: NAD+/NADH and NADP+/NADPH have distinct functions in metabolic and redox regulation, and thus, a comprehensive evaluation of metabolic and redox states must be multiplexed with a combination of various metabolite sensors in a single cell. Antioxid. Redox Signal. 28, 213-229. PMID- 28648093 TI - S-Nitrosylation of Ras Mediates Nitric Oxide-Dependent Post-Injury Neurogenesis in a Seizure Model. AB - AIMS: Nitric oxide (NO) is involved in the upregulation of endogenous neurogenesis in the subventricular zone and in the hippocampus after injury. One of the main neurogenic pathways activated by NO is the extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway, downstream of the epidermal growth factor receptor. However, the mechanism by which NO stimulates cell proliferation through activation of the ERK/MAPK pathway remains unknown, although p21Ras seems to be one of the earliest targets of NO. Here, we aimed at studying the possible neurogenic action of NO by post translational modification of p21Ras as a relevant target for early neurogenic events promoted by NO in neural stem cells (NSCs). RESULTS: We show that NO caused S-nitrosylation (SNO) of p21Ras in Cys118, which triggered downstream activation of the ERK/MAPK pathway and proliferation of NSC. Moreover, in cells overexpressing a mutant Ras in which Cys118 was replaced by a serine-C118S-, cells were insensitive to NO, and no increase in SNO, in ERK phosphorylation, or in cell proliferation was observed. We also show that, after seizures, in the presence of NO derived from inducible nitric oxide synthase, there was an increase in p21Ras cysteine modification that was concomitant with the previously described stimulation of proliferation in the dentate gyrus. INNOVATION: Our work identifies p21Ras and its SNO as an early target of NO during signaling events that lead to NSC proliferation and neurogenesis. CONCLUSION: Our data highlight Ras SNO as an early event leading to NSC proliferation, and they may provide a target for NO-induced stimulation of neurogenesis with implications for brain repair. Antioxid. Redox Signal. 28, 15-30. PMID- 28648095 TI - Key performance indicators for Australian mental health court liaison services. AB - OBJECTIVES: The aim of this paper is to describe the development and technical specifications of a framework and national key performance indicators (KPIs) for Australian mental health Court Liaison Services (CLSs) by the National Mental Health Court Liaison Performance Working Group (Working Group). METHODS: Representatives from each Australian State and Territory were invited to form a Working Group. Through a series of national workshops and meetings, a framework and set of performance indicators were developed using a review of literature and expert opinion. RESULTS: A total of six KPIs for CLSs have been identified and a set of technical specifications have been formed. CONCLUSIONS: This paper describes the process and outcomes of a national collaboration to develop a framework and KPIs. The measures have been developed to support future benchmarking activities and to assist services to identify best practice in this area of mental health service delivery. PMID- 28648097 TI - OxyVita(r)C, a next-generation haemoglobin-based oxygen carrier, with coagulation capacity (OVCCC). Modified lyophilization/spray-drying process: proteins protection. AB - Uncontrolled haemorrhage is one of the leading causes of death. This issue is present in controlled environments, such as hospitals, as well as pre-hospital and remote locations. Treatment is more challenging in remote locations where there is a lack of effective products to deliver oxygen and control coagulation. Poorly treated haemorrhage can lead to rapidly deteriorating bodily conditions that can result in organ failure and tissue death. Thus, the availability of products to support oxygen delivery to tissues and coagulation processes within the body is essential for the effective treatment of severe haemorrhage, particularly in out-of-the-hospital settings. The presence of such products would fill the gap that is currently present in emergency treatment. Promising results of an ex-vivo study on a novel haemoglobin-based oxygen carrier OxyVita(r)C with coagulation capacity (OVCCC) are presented in this article. The proprietary protein protection technology allows for the powderization of protein components without changes in their characteristics and physiological activity. This technology was applied to the oxygen carrier OxyVita(r)C, to plasma and to platelets. The functionality of all tested components, as well as a mixture of OxyVita(r)C and platelets, was studied. The results suggest future clinical trials investigating the powderization of OVCCC, plasma and platelets are warranted. The development of this powderization method offers a huge advancement into a field in which no viable products exist. PMID- 28648098 TI - The effect of perceived control on self-reported cardiovascular disease incidence across adulthood and old age. AB - OBJECTIVE: To examine whether rates of change in perceived control are predictive of cardiovascular disease (CVD) incidence across adulthood and old age. DESIGN: We used the PATH Through Life Project (n = 7103, M = 40, SD = 16; 52% women), a longitudinal panel survey that encompasses three cohorts at Time 1, ages 20-24, 40-44 and 60-64, who have been assessed three times at four-year intervals. METHOD: We examined whether rates of change in perceived control were associated with CVD incidence over 8 years of time, over and above that of baseline levels of perceived control and known risk factors for CVD. MAIN OUTCOME MEASURES: Self reported CVD incidence. RESULTS: Increases in perceived control over time were associated with decreased likelihood of 8-year incidence of CVD and these effects were independent of socio-demographics, covariates and baseline levels of perceived control. The effects were consistent across young adulthood, midlife and old age and for men and women. CONCLUSIONS: Findings demonstrate the importance of changes in perceived control as a predictor of CVD incidence across adulthood and old age. We suggest future research using mediation analysis to test reverse causality and mechanisms underlying the effects of perceived control on CVD incidence. PMID- 28648099 TI - Social anxiety and work status: the role of negative metacognitive beliefs, symptom severity and cognitive-behavioural factors. AB - BACKGROUND: Psychological health has a profound effect on personal and occupational functioning with Social Anxiety Symptoms in particular having a major effect on ability to work. Recent initiatives have focused on treating psychological illness with cognitive-behavioural models with a view to increasing return to work. However, the psychological correlates of work status amongst individuals with elevated mental health symptoms such as social anxiety are under explored. AIMS: This study reports a test of unique predictors of work status drawing on variables that have been given centre stage in cognitive-behavioural models and in the metacognitive model of psychological disorder. METHODS: The sample consisted of high socially anxious individuals who reported to be working (n = 102) or receiving disability benefits (n = 102). RESULTS: A comparison of these groups showed that those out of work and receiving benefits had greater symptom severity, higher avoidance and use of safety behaviours, greater self consciousness, and elevated negative metacognitive beliefs and beliefs about the need to control thoughts. However, when the covariance's between these variables were controlled, only negative metacognitive beliefs significantly predicted out of-work status. CONCLUSIONS: Our finding might be important because CBT does not focus on metacognitive beliefs, but targets components that in our analysis had no unique predictive value for work status. PMID- 28648096 TI - NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. AB - SIGNIFICANCE: The nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) and NADP+/reduced NADP+ (NADPH) redox couples are essential for maintaining cellular redox homeostasis and for modulating numerous biological events, including cellular metabolism. Deficiency or imbalance of these two redox couples has been associated with many pathological disorders. Recent Advances: Newly identified biosynthetic enzymes and newly developed genetically encoded biosensors enable us to understand better how cells maintain compartmentalized NAD(H) and NADP(H) pools. The concept of redox stress (oxidative and reductive stress) reflected by changes in NAD(H)/NADP(H) has increasingly gained attention. The emerging roles of NAD+-consuming proteins in regulating cellular redox and metabolic homeostasis are active research topics. CRITICAL ISSUES: The biosynthesis and distribution of cellular NAD(H) and NADP(H) are highly compartmentalized. It is critical to understand how cells maintain the steady levels of these redox couple pools to ensure their normal functions and simultaneously avoid inducing redox stress. In addition, it is essential to understand how NAD(H)- and NADP(H)-utilizing enzymes interact with other signaling pathways, such as those regulated by hypoxia-inducible factor, to maintain cellular redox homeostasis and energy metabolism. FUTURE DIRECTIONS: Additional studies are needed to investigate the inter-relationships among compartmentalized NAD(H)/NADP(H) pools and how these two dinucleotide redox couples collaboratively regulate cellular redox states and cellular metabolism under normal and pathological conditions. Furthermore, recent studies suggest the utility of using pharmacological interventions or nutrient-based bioactive NAD+ precursors as therapeutic interventions for metabolic diseases. Thus, a better understanding of the cellular functions of NAD(H) and NADP(H) may facilitate efforts to address a host of pathological disorders effectively. Antioxid. Redox Signal. 28, 251-272. PMID- 28648100 TI - The replacement of assertive outreach services by reinforcing local community teams: a replication study reporting comparative outcomes and patient reported experience. AB - BACKGROUND: This is the third in a series of papers on patient outcomes and other consequences of the withdrawal of specialist assertive outreach (AO) teams. We previously reported positive outcomes for patients receiving a less intensive service at up to four years, but had not systematically interviewed patients. AIMS: To test the generalizability of earlier findings through replication in another service. To complement the analysis of service utilisation with patient reported experience between the two treatment models. METHODS: Service level evaluation 12 months pre and post service change for 55 eligible AO patients. Thirty three consenting patients answered validated questionnaires. RESULTS: There were no statistically significant changes in hospital bed use comparing the year before and the year after the change (850-712 bed days, median 34-20). No significant change in crisis activity occurred despite a highly significant reduction in face to face contacts from a mean of 90-40. There were no significant changes in patient reported experience. CONCLUSIONS: Results are consistent with earlier studies. Reinforcing community mental health teams can provide an integrated service model that is clinically effective and equally acceptable to patients, making this a viable and affordable alternative to orthodox AO teams. PMID- 28648101 TI - An exploratory study of information sources and key findings on UK cocaine related deaths. AB - Cocaine-related deaths have increased since the early 1990s in Europe, including the UK. Being multi-factorial, they are difficult to define, detect and record. The European Monitoring Centre for Drugs and Drug Addiction commissioned research to: describe trends reported to Special Mortality Registries and General Mortality Registers; provide demographic and drug-use characteristic information of cases; and establish how deaths are identified and classified. A questionnaire was developed and piloted amongst all European Monitoring Centre for Drugs and Drug Addiction Focal Point experts/Special Mortality Registries: 19 (63%) responded; nine countries provided aggregated data. UK General Mortality Registers use cause of death and toxicology to identify cocaine-related deaths. Categorisation is based on International Classification of Diseases codes. Special Mortality Registries use toxicology, autopsy, evidence and cause of death. The cocaine metabolites commonly screened for are: benzoylecgonine, ecgonine methyl ester, cocaethylene and ecgonine. The 2000s saw a generally accelerating upward trend in cases, followed by a decline in 2009. The UK recorded 2700-2900 deaths during 1998-2012. UK Special Mortality Registry data (2005-2009) indicate: 25-44 year-olds account for 74% of deaths; mean age=34 (range 15-81) years; 84% male. Cocaine overdoses account for two-thirds of cases; cocaine alone being mentioned/implicated in 23% in the UK. Opioids are involved in most (58%) cocaine overdose cases. PMID- 28648102 TI - Posterior communicating artery aneurysms demonstrate faster interval growth than other growing aneurysms. AB - Background Posterior communicating artery aneurysms are often associated with a high rupture risk. This study compares the differences in the rate of growth and morphological characteristics between growing posterior communicating artery aneurysms and other types of growing aneurysms. Materials and methods Thirteen patients with growing internal carotid artery aneurysms were scanned using Siemens 64 slice computed tomography scanners. Three patients had ophthalmic aneurysms, three had superior hypophyseal aneurysms and seven had posterior communicating artery aneurysms. Each aneurysm case had three distinct time points, with an average separation time of 1.3 +/- 0.6 years. Annual aneurysm dimensional growth, annual volume growth, annual increase in surface area, size ratio, aspect ratio, and non-sphericity index were analysed. Results Posterior communicating artery aneurysms demonstrated significantly higher annual increases in dimensional growth, volume and surface area when compared to other internal carotid artery aneurysms. Posterior communicating artery aneurysms also demonstrated a significantly higher increase in aspect ratio, size ratio and lower non-sphericity index. Discussion Posterior communicating artery aneurysms had significantly greater growth per year when compared to other types of internal carotid artery aneurysms, and had different morphological characteristics. PMID- 28648103 TI - Association of five-factor score with the mortality in Japanese patients with polyarteritis nodosa. AB - AIM: To determine mortality and its predictive factors in Japanese patients with polyarteritis nodosa (PAN). METHODS: This retrospective single-center study determined the mortality of 18 patients with PAN who were admitted to Juntendo University Hospital from 1994 to 2016. The variables at baseline, including patient demographics, clinical characteristics, and treatment, were analyzed for their association with mortality. RESULTS: The median age of onset was 57.0 years. The 1-year survival rate was 100% (16/16) and the 5-year survival rate was 80.0% (8/10). The relationship between mortality, as defined by the survival rate and each variable was evaluated by Cox univariate analysis. A higher 2009 five factor score (FFS) was associated with increased mortality, with a hazard ratio of 2.34 (p = .04). Analysis of the secondary outcome of relapse-free survival time revealed an association with rapid progressive renal failure, Birmingham Vasculitis Activity Score (BVAS), the 1996 FFS, and the 2009 FFS, with hazard ratios of 7.28 (p = .048), 1.26 (p = .02), 2.32 (p = .03), and 1.82 (p = .04), respectively. CONCLUSION: We investigated mortality, relapse-free survival, and their predictive factors in Japanese patients with PAN. The BVAS and the 1996 FFS at diagnosis may be prognostic factors for relapse-free survival, and the 2009 FFS at diagnosis may be a prognostic factor for both mortality and relapse-free survival. PMID- 28648104 TI - A speculated cause of respiratory inhibition in infants. AB - OBJECTIVE: In our previous studies, we documented that threatened premature labor and asymmetrical intrauterine growth restriction were risk factors for respiratory inhibition. The goal of this study was to determine the cause of respiratory inhibition by considering perinatal risk factors. METHODS: We examined 1497 infants with a gestational age of 36 weeks or greater. All infants were monitored using pulse oximetry and examined via cranial sonography. Respiratory inhibition was defined as severe hypoxemia caused by respiratory inhibition immediately after crying or gastroesophageal reflux or as a respiratory pause during feeding. We examined the relationships between respiratory inhibition and perinatal factors and speculated on the cause of respiratory inhibition. RESULTS: The median gestational age, birth weight, Apgar score at 1 min, and Apgar score at 5 min of the subjects were 38.9 weeks, 2930 g, 8.0 points, and 9.0 points, respectively. Respiratory inhibition was observed in 422 infants. Lateral ventricle enlargement and increased echogenicity in the ganglionic eminence were observed in 417 and 516 infants, respectively. Respiratory inhibition was significantly correlated with shorter gestational periods, twin pregnancies, lateral ventricle enlargement, and increased echogenicity in the ganglionic eminence. CONCLUSIONS: We speculate that umbilical cord compression is a major cause of respiratory inhibition. PMID- 28648105 TI - Abnormal distribution of AQP4 in minor salivary glands of primary Sjogren's syndrome patients. AB - A decreased saliva production occurs in primary Sjogren's syndrome (pSS), an autoimmune disease characterized by oral and ocular dryness due to dysfunction of the lacrimal and salivary glands (SGs). Since water movement is involved in saliva secretion, the expression, localization, and function of the water channels aquaporins (AQPs) have been extensively studied in SGs. To date, the presence of AQP4 remains controversial and ambiguous in human SGs. We investigated by immunohistochemistry, high-resolution confocal microscopy and quantitative image analysis, Western blot and real-time RT-PCR, the presence of the AQP4 gene, and the distribution of AQP4 protein in healthy controls and pSS SG biopsies. Through the immunohistochemical analysis, we demonstrated that AQP4 presence is confined to the basal region of acini, to the lateral and apical membrane of intercalated and striated ducts in both control and pSS glands. The most striking observation was the discovery of AQP4 localization in myoepithelial cells (MECs) that surround acini lobules and intercalated ducts, and the demonstration of AQP4-downregulated immunoreactivity in pSS MECs. Our studies suggest that the capacity for water flow across the membrane of MECs may be altered in pSS, identifying AQP4 as a promising new therapeutic agent to treat xerostomia. PMID- 28648106 TI - Pressure Autoregulation Measurement Techniques in Adult Traumatic Brain Injury, Part I: A Scoping Review of Intermittent/Semi-Intermittent Methods. AB - The purpose of this study was to perform a systematic, scoping review of commonly described intermittent/semi-intermittent autoregulation measurement techniques in adult traumatic brain injury (TBI). Nine separate systematic reviews were conducted for each intermittent technique: computed tomographic perfusion (CTP)/Xenon-CT (Xe-CT), positron emission tomography (PET), magnetic resonance imaging (MRI), arteriovenous difference in oxygen (AVDO2) technique, thigh cuff deflation technique (TCDT), transient hyperemic response test (THRT), orthostatic hypotension test (OHT), mean flow index (Mx), and transfer function autoregulation index (TF-ARI). MEDLINE(r), BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016), and reference lists of relevant articles were searched. A two tier filter of references was conducted. The total number of articles utilizing each of the nine searched techniques for intermittent/semi-intermittent autoregulation techniques in adult TBI were: CTP/Xe-CT (10), PET (6), MRI (0), AVDO2 (10), ARI-based TCDT (9), THRT (6), OHT (3), Mx (17), and TF-ARI (6). The premise behind all of the intermittent techniques is manipulation of systemic blood pressure/blood volume via either chemical (such as vasopressors) or mechanical (such as thigh cuffs or carotid compression) means. Exceptionally, Mx and TF-ARI are based on spontaneous fluctuations of cerebral perfusion pressure (CPP) or mean arterial pressure (MAP). The method for assessing the cerebral circulation during these manipulations varies, with both imaging-based techniques and TCD utilized. Despite the limited literature for intermittent/semi-intermittent techniques in adult TBI (minus Mx), it is important to acknowledge the availability of such tests. They have provided fundamental insight into human autoregulatory capacity, leading to the development of continuous and more commonly applied techniques in the intensive care unit (ICU). Numerous methods of intermittent/semi-intermittent pressure autoregulation assessment in adult TBI exist, including: CTP/Xe-CT, PET, AVDO2 technique, TCDT-based ARI, THRT, OHT, Mx, and TF-ARI. MRI-based techniques in adult TBI are yet to be described, with the main focus of MRI techniques on metabolic-based cerebrovascular reactivity (CVR) and not pressure-based autoregulation. PMID- 28648107 TI - Practitioners' experience of the integration of mental health into primary health care in the West Rand District, South Africa. AB - BACKGROUND: Despite the alarming prevalence of neuropsychiatric disorders in South Africa, mental health care remains under-resourced. The Mental Health Framework Policy of South Africa outlined the objective to integrate mental health into primary health care. The aim is to make mental health care more accessible, affordable and acceptable. Practitioners, however, find the application of the policy challenging. The identification of challenges can guide efforts to create conditions favourable to the implementation of the policy. AIM: To explore and describe primary health practitioners' experience of the integration of mental health into primary health care. METHODS: A mixed-method exploratory descriptive design was used to collect quantitative data by means of a structured questionnaire from a purposive sample consisting of 95 primary health care practitioners and qualitative data from a sub-sample of 12 participants by means of semi-structured interviews. Data were analyzed using mixed-method analysis. RESULTS: The results indicated that though progress has been made in the implementation of the integration of mental health into primary health care, several challenges remain. CONCLUSIONS: The identified challenges may contribute to inconsistent care and difficulties such as unidentified symptoms, defaulting treatment and the revolving-door phenomenon. Recommendations were made based on the findings of the study. PMID- 28648108 TI - An Italian contribution to the study of the validity and reliability of the trait meta-mood scale. AB - BACKGROUND: Emotional intelligence (EI) is a field of study that is receiving increasingly attention in the literature, due to its relevance to a series of aspects of human psychological and social functioning. AIMS: This study used archival data from an Italian sample encompassing 885 nonclinical adults, to contribute to the study of the validity and reliability of the Trait Meta Mood Scale (TMMS), a widely used measure of self-perceived EI. METHOD: Statistical analyses focused on internal consistency, factor structure and concurrent validity of an Italian TMMS version. RESULTS: Results confirmed previous international studies supporting the cross-cultural adaptability of the TMMS, showing adequate reliability and validity indexes for all TMMS scores. CONCLUSIONS: EI may be measured via self-report. Its relationship to psychopathology, however, deserves more research, as certain components of EI correlate positively with psychological suffering. PMID- 28648109 TI - A multi-level examination of the experiences of female sex workers living with HIV along the continuum of care in the Dominican Republic. AB - Female sex workers (FSWs) are disproportionately affected by HIV, but there is limited research on their HIV care experiences. This study explored the experiences of 44 FSWs living with HIV in Santo Domingo, Dominican Republic along the HIV care continuum using in-depth interviews and focus groups. Data were analysed through narrative and thematic analysis. Individual-level factors that facilitated engagement in HIV care were physical and mental health. At the interpersonal level, disclosure of HIV or sex work status and receipt of emotional and economic support were important influences on engagement. Yet, negative reactions to or lack of disclosure of these statuses compromised engagement, further highlighting the role of stigma and discrimination. At the environmental level, FSWs described considerable challenges with the health system including long waits and treatment stock-outs at their clinics, but were generally satisfied with HIV clinic staff. At the structural level, lack of economic resources complicated care and treatment adherence. Findings underscore the need for psychosocial and economic support tailored to the unique needs of FSWs to maximise the individual and public health benefits of HIV care. PMID- 28648111 TI - Reduction of white matter integrity correlates with apathy in Parkinson's disease. AB - BACKGROUND: Apathy is a common non-motor symptom in Parkinson's disease (PD), but little is known about apathy and white matter (WM) change. In this study, we investigated whether fractional anisotropy (FA) of the WM can distinguish apathetic patients from non-apathetic PD patients, and whether the FA value correlates with the severity of apathy in PD. METHODS: Thirty-nine PD patients participated in our study, of which 18 participants were with apathy symptom, and 21 without apathy symptom. Diffusion tensor imaging was performed on all the subjects. RESULTS: Compared to non-apathetic PD patients, the apathetic group had reduced FA values in the genu and body of corpus callosum, bilateral anterior corona radiata, left superior corona radiata and left cingulum. Furthermore, in these WM regions, the FA values were negatively correlated with the Lille Apathy Rating Scale scores in apathetic subjects. CONCLUSION: The WM change is associated with apathy in PD patients. In addition, the FA values of specific regions of WM could be a promising marker to predict the severity of apathy. PMID- 28648110 TI - Response Inhibition Deficits and Altered Motor Network Connectivity in the Chronic Phase of Pediatric Traumatic Brain Injury. AB - Poor response inhibition is a hallmark of pediatric traumatic brain injury (TBI). We assessed motor response inhibition by measuring commission error rates on Simple (minimized cognitive demands) and Motivation (monetary reward) Go/No-Go tasks, comparing 17 children with chronic TBI (>1 year post-injury) and 14 matched, uninjured peers. Using resting state functional magnetic resonance imaging (fMRI), we examined between-group differences in whole-brain intrinsic connectivity of the motor network as derived from the averaged time course of bilateral primary motor cortex seeds, to identify regions of interest (ROIs) for brain-behavior correlations. Independent sample t tests compared Go/No-Go performance and connectivity at the ROI level. Pearson correlations examined relationships between intrinsic connectivity at the ROI level and Go/No-Go performance. Adolescents with TBI showed poorer performance on Simple and Motivation Go/No-Go tasks compared with controls. In whole-brain contrasts, adolescents with TBI showed significantly reduced functional connectivity between the motor network and voxels within the left caudate. Furthermore, in ROI analyses, the group with TBI had significantly lower connectivity between the motor network and left caudate and numerically lower connectivity between the motor network and right caudate. In adolescents with TBI, lower motor network to left caudate connectivity correlated with poorer Simple task performance; lower motor network to right caudate connectivity correlated with poorer Simple and Motivation task performance. No significant brain-behavior relationships existed among controls. These results are consistent with previous pediatric TBI literature and suggest that disrupted intrinsic connectivity of a corticostriatal motor network may contribute to response inhibition deficits. PMID- 28648112 TI - Narrative research on mental health recovery: two sister paradigms. AB - BACKGROUND: Despite the breadth of narrative studies on individuals with severe mental illness, the suitability of narrative inquiry to exploring mental health recovery (MHR) has not been examined. AIMS: (1) Examining the appropriateness of narrative inquiry to studying MHR; (2) assessing the extent to which narrative studies on MHR conform to the unique features of narrative research, as a distinctive form of qualitative inquiry. METHODS: Review of empirical, theoretical and methodological literature on recovery and narrative inquiry. RESULTS: Considering the perspectives of recovery and narrative as paradigms, the similarity between their ontology and epistemology is shown, evident in 10 common emphases: meaning, identity, change and development, agency, holism, culture, uniqueness, context, language and giving voice. The resemblance between these "sister" paradigms makes narrative methodology especially fruitful for accessing the experiences of individuals in recovery. Reviewing narrative studies on MHR suggests that, currently, narrative research's uniqueness, centered on the holistic principle, is blurred on the philosophical, methodological and textual levels. CONCLUSIONS: Well-established narrative research has major implications for practice and policy in recovery-oriented mental health care. The narrative inquiry paradigm offers a possible path to enhancing the distinctive virtues of this research, realizing its potential in understanding and promoting MHR. PMID- 28648113 TI - Mood and mobility: navigating the emotional spaces of digital social networks. PMID- 28648114 TI - Pseudohypoparathyroidism type 1B - a rare cause of tetany: case report. AB - Pseudohypoparathyroidism (PHP) is a rare group of disorders characterised by end organ resistance to the parathyroid hormone (PTH). A 16-year-old boy presented with a 2-year history of involuntary dystonic movements involving mainly the left hand, initially after writing and later during physical exercise. Serum calcium was 1.37 mmol/L (2.20-2.69), phosphate 2.1 mmol/L (0.8-1.45) and PTH 302 ng/L (12 88). CT scan of the head demonstrated multiple subcortical and diffuse basal ganglia calcifications. Genetic analysis confirmed a methylation defect in the GNAS cluster on chromosome 20q13.32 which established the diagnosis. Treatment with calcitriol and calcium carbonate led to complete remission of symptoms. Causes of hypocalcaemia should be considered in evaluating patients with movement disorders. The diagnosis of PHP-1B is challenging but the overall prognosis is excellent. PMID- 28648115 TI - Complete thoracolumbar fracture-dislocation with intact neurologic function: Explanation of a novel cord saving mechanism. AB - BACKGROUND: The thoracolumbar junction from T11 to L2 is a common site of injury in which fracture and dislocations are the most prevalent ones occurring at this location. Fracture dislocation is defined as failure of all three columns of the spine with gross displacement. Considering the significant violence necessary to produce fracture dislocations, these injuries are often associated with major neural deficit, with the majority of casualties becoming paraplegic immediately. Preservation of neurological function following complete fracture dislocation is quite rare entity. OBJECTIVE: To represent the possibility of existence of a preservation mechanism for functional integrity of cord despite spinal gross fracture dislocation by reproducing the injury on a plastic model and simulating a corresponding model using 3DSlicer software, detailed description the pathomechanism of neurologic sparing. CASE REPORT: A 19-year-old female who sustained severe thoracolumbar fracture dislocation but with normal neurology is presented. Despite the severity of the condition, the diagnosis was initially missed due to associated vital injuries. RESULTS: Combined posterior and anterior surgery resulted in optimal coronal and sagittal alignment, as well as proper stabilization without any complication. At 9-year follow-up, the patient was found to be doing well. CONCLUSION: The prognosis for complete recovery with preplanned surgical intervention in thoracolumbar injuries affecting all three columns but with normal neurologic function is promising based on images, plastic models and 3D simulated model based on digital images. PMID- 28648116 TI - Emboli and cognitive state in surgical vs. transcatheter aortic valve replacement. AB - Background Neurologic complications and neurocognitive impairment due to cerebral emboli are common following heart surgery. This study aimed to compare the number of emboli detected in the middle cerebral artery in open aortic valve replacement, apical and femoral transcatheter aortic valve replacement, and also to test for an association between the number of emboli captured in each procedure and changes in the patient's cognitive state. Methods Forty-four patients were enrolled in the study, 36 of whom were included in the final analyses: 14 underwent open aortic valve replacement, 2 had femoral transcatheter aortic valve replacement, and 10 had apical transcatheter aortic valve replacement. The number of emboli was detected by middle cerebral artery intraoperative transcranial Doppler ultrasound. The day before the elective surgery and 6-12 weeks later, all patients underwent neurocognitive evaluations by the Mini-Mental State Examination; the difference was tested for an association with the number of emboli. Results Open aortic valve replacement resulted in a significantly greater number of emboli (8555, range 2999-12489) than apical (1962, range 521-3850) or femoral (1220, range 948-1946) transcatheter approaches ( p = 0.003). Both transcatheter approaches yielded a comparable amount of emboli ( p = 0.798). No significant association was observed between the change in Mini-Mental State Examination score and the mean number of emboli ( r = 0.026; p = 0.907). Conclusions Compared to transcatheter aortic valve replacement, more cerebral emboli are detected during surgical aortic valve replacement; however, this does not appear to adversely affect a patient's cognitive state. PMID- 28648117 TI - Alteration of sarcoplasmic reticulum Ca2+ ATPase expression in lower limb ischemia caused by atherosclerosis obliterans. AB - Atherosclerosis is a disease caused by a build-up of fatty plaques and cholesterol in the arteries. The lumen of the vessels is obliterated resulting in restricted blood supply to tissues. In ischemic conditions, the cytosolic Ca2+ level of skeletal muscle may increase, indicating the alteration of Ca2+ removal mechanisms. Ca2+ is transported from cytosol into the sarcoplasmic reticulum by Ca2+ ATPase (SERCA), with its 1a isoform expressed in adult, while its 1b isoform in neonatal and regenerating fast-twitch skeletal muscle. To investigate the role of these isoforms in ischemic skeletal muscle, biopsies from musculus biceps femoris of patients who underwent amputation due to atherosclerosis were examined. Samples were removed from the visibly healthy and hypoxia-affected tissue. Significantly increased SERCA1a expression was detected under the ischemic conditions (246 +/- 69%; p < 0.05) compared with the healthy tissue. Furthermore, the ratio of SERCA1a-positive fibers was slightly increased (46 +/- 4% in healthy tissue and 60 +/- 5% in ischemic tissue; p > 0.05), whereas SERCA2a did not change. In addition, in primary cultures derived from hypoxia-affected tissue, the diameter and fusion index of myotubes were significantly increased (30 +/- 1.6 um vs. 41 +/- 2.4 um and 31 +/- 4% vs. 45 +/- 3%; p < 0.05). We propose that the increased SERCA1a expression indicates the existence and location of compensating mechanisms in ischemic muscle. PMID- 28648118 TI - Physiological effects of proinsulin-connecting peptide in human subcutaneous adipose tissue. AB - Recent studies suggest that proinsulin-connecting peptide (C-peptide) may exhibit characteristics of a hormone and show physiological functions in various tissues. This study was aimed to determine whether C-peptide could be involved in the regulation of lipolysis, adiponectin release, and function of mesenchymal stem cells (MSCs) in adipose tissue. Human subcutaneous adipose tissue was cultured in the presence of C-peptide. The level of lipolysis was determined by glycerol measurement in the conditioned media. Effect of C-peptide on adiponectin secretion was evaluated in differentiated adipocytes. The adipogenic and osteogenic abilities of adipose MSCs were evaluated using oil red and alizarin red staining, respectively. The tetrazolium bromide test was conducted for evaluating the effect of C-peptide on MSCs proliferation. C-peptide induced a significant decrease in basal lipolysis at concentrations of 8 and 16 nM (p < 0.05). It had no significant effects on isoproterenol-stimulated lipolysis, adiponectin secretion, and adipogenic or osteogenic differentiation of MSCs. At a concentration of 4 nM, this peptide significantly increased the proliferative capability of MSCs (p < 0.05). These results suggest that C-peptide has some physiological effects in human subcutaneous adipose tissue and contributes to the regulation of basal lipolysis and pool of MSCs. PMID- 28648119 TI - Is there a relationship between increased aortic stiffness and segmental left ventricular deformation in elite athletes? (Insights from the MAGYAR-Sport Study). AB - Introduction Myocardial contractility of the left ventricle (LV) is related to arterial distensibility. Sport activity is frequently associated with changes in both LV and arterial functions. This study aimed to find correlations between three-dimensional speckle-tracking echocardiography-derived segmental LV deformation parameters and echocardiographically assessed aortic stiffness index (ASI) in athletes. This study comprised 26 young elite athletes (mean age: 26.7 +/- 8.4 years, nine men). Results Among segmental circumferential strains (CSs), only that of apical anterior (r = 0.40, p = 0.05), septal (r = 0.47, p = 0.01), inferior (r = 0.59, p = 0.001), lateral (r = 0.44, p < 0.05), and midventricular anteroseptal (r = 0.44, p < 0.05) segments correlated with ASI, whereas LV-CS of the midventricular anterior segment showed a correlation tendency. Only longitudinal strain of basal anteroseptal (r = -0.46, p < 0.05) and inferoseptal (r = -0.57, p < 0.01) segments showed correlations with ASI, whereas that of the basal anterior segment had only a tendency to correlate. Some segmental multidirectional strains also correlated with ASI. Conclusions Correlations could be demonstrated between increased aortic stiffness and circular function of the apical and midventricular LV fibers and longitudinal motion of the basal septum and LV anterior wall (part of LV outflow tract) in maintaining circulation in the elite athletes. PMID- 28648120 TI - Long-QT syndrome-associated caveolin-3 mutations differentially regulate the hyperpolarization-activated cyclic nucleotide gated channel 4. AB - Background Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current If. It associates with cav-3 and both form a macromolecular complex. Methods To examine the effects of human LQTS associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole cell patch-clamp technique. Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics. Conclusions Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations. PMID- 28648121 TI - Spontaneous otoacoustic emission recordings during contralateral pure-tone activation of medial olivocochlear reflex. AB - We hypothesized that cochlear frequency discrimination occurs through medial olivocochlear efferent (MOCE)-induced alterations in outer hair cell (OHC) electromotility, which is independent from basilar membrane traveling waves. After obtaining informed consent, volunteers with normal hearing (n = 10; mean age: 20.6 +/- 1.2 years) and patients with unilateral deafness (n = 10; mean age: 30.2 +/- 17.9 years) or bilateral deafness (n = 8; mean age: 30.7 +/- 13.8 years) underwent a complete physical and audiological examination, and audiological tests including transient evoked otoacoustic emission and spontaneous otoacoustic emission (TEOAE and SOAE, respectively). SOAE recordings were performed during contralateral pure-tone stimuli at 1 and 3 kHz. SOAE recordings in the presence of contralateral pure-tone stimuli showed frequency-specific activation out of the initial frequency range of SOAE responses. Basilar membrane motion during pure-tone stimulation results from OHC activation by means of MOCE neurons rather than from a traveling wave. Eventually, frequency-specific responses obtained from SOAEs suggested that OHC electromotility may be responsible for frequency discrimination of the cochlea independently from basilar membrane motion. PMID- 28648122 TI - Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6. AB - 1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF 05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study. 3. The geometric mean (per cent coefficient of variability) area under the concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1662 ngch/mL (26%) and 21.51 ng/mL (27%), respectively, for dacomitinib and 469 ngch/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to Cmax were 8 and 4 h postdose for dacomitinib and PF-05199265, respectively; mean terminal half-life of dacomitinib was 62.7 h. Geometric mean apparent clearance and volume of distribution of dacomitinib were 27.06 L/h and 2415 L, respectively. The metabolite PF-05199265-to-dacomitinib ratios were 0.2907 for AUCinf and 0.2656 for Cmax. 4. Dacomitinib total (AUCinf) and peak exposures (Cmax) were similar among subjects with different CYP2D6 genotypes, whereas both parameters for PF-05199265 were higher in extensive metabolisers (n = 5) versus intermediate metabolisers (n = 8). PMID- 28648123 TI - Value of intravoxel incoherent motion in assessment of pathological grade of clear cell renal cell carcinoma. AB - Background Intravoxel incoherent motion (IVIM) can provide a unique view of tissue perfusion without the use of exogenous contrast agents. Purpose To investigate the value of IVIM in assessing grades of clear cell renal cell carcinoma (CRCC). Material and Methods A total of 107 patients with pathologically proven CRCC were included, 26 with grade I, 27 with grade II, 25 with grade III, and 29 with grade IV. These tumors were divided into low (I + II) and high grades (III + IV). Nine b values (0, 30, 50, 80, 150, 300, 500, 800, and 1500 s/mm2) were used in diffusion-weighted imaging (DWI). The tissue diffusivity (D), pseudodiffusivity (D*), and perfusion fraction (f) were calculated using bi exponential fitting of the diffusion data. Results The D values of the four groups were 1.83 +/- 0.38, 1.23 +/- 0.19, 1.07 +/- 0.26, and 0.37 +/- 0.11 * 10-3 mm2/s ( P < 0.05). The D* values of the four groups were 0.079 +/- 0.021, 0.053 +/- 0.019, 0.047 +/- 0.022, and 0.033 +/- 0.017 ( P < 0.05). The f values of the four groups were 0.208 +/- 0.09, 0.341 +/- 0.12, 0.373 +/- 0.15, and 0.461 +/- 0.17 ( P < 0.05). Both the D and D* values correlated negatively with CRCC grading ( r = -0.677 and -0.693, P < 0.05). The f values correlated positively with CRCC grading (r = 0.699, P < 0.05). The areas of the D, D*, and f values under the ROC curves to diagnose low and high CRCC grades were 0.934, 0.837, and 0.793, respectively. The cutoff values of D, D*, and f were 1.13, 0.056, and 0.376, respectively; the diagnostic performance for low and high CRCC grading had a sensitivity of 82.0%, 80.7%, and 83.2% and a specificity of 90.8%, 86.3%, and 82.6%. Conclusion IVIM may provide information for differentiating CRCC grades. PMID- 28648124 TI - Knowledge-based iterative model reconstruction in coronary computed tomography angiography: comparison with hybrid iterative reconstruction and filtered back projection. AB - Background Knowledge-based iterative model reconstruction (IMR) is known to allow radiation dose reduction while preserving image quality. Purpose To investigate the effect of IMR on coronary computed tomography angiography (CCTA) by comparing it with filtered back projection (FBP) and hybrid iterative reconstruction (HIR). Material and Methods Forty-five patients (group A) who underwent CCTA with prospective electrocardiogram (ECG) triggering at 80 kVp were included. All images were reconstructed using three algorithms: FBP, HIR, and IMR. The control group comprised 45 patients (group B) who underwent CCTA at 100 kVp; their images were reconstructed with HIR alone. Objective and subjective image quality was assessed by two radiologists. Results In group A, the signal-to-noise and contrast-to-noise ratios were significantly higher for images reconstructed with IMR than with HIR or FBP ( P < 0.001). IMR was also superior to HIR and FBP in subjective image quality analyses, including image noise, vessel sharpness, beam hardening artifact, and overall quality ( P < 0.001). Moreover, the images reconstructed using IMR in group A had superior image quality with less radiation exposure than those reconstructed using HIR in group B on both objective and subjective analyses ( P < 0.001). The mean attenuation values were also significantly higher in group A than in group B ( P < 0.001). Conclusion Compared with HIR and FBP, IMR provided higher quality images with less radiation exposure in CCTA, using low kilovoltage and prospective ECG triggering. PMID- 28648125 TI - Accuracy of the diagnostic evaluation of hepatocellular carcinoma with LI-RADS. AB - Background There are few studies about the Liver Imaging Reporting and Data System (LI-RADS), which was developed with the purpose of standardizing the interpretation and reporting of liver imaging examinations in patients at risk for hepatocellular carcinoma (HCC). Purpose To evaluate the diagnostic accuracy of HCC diagnosis using LI-RADS. Material and Methods The computed tomography (CT), magnetic resonance imaging (MRI), and clinical data of 297 lesions in 249 patients between June 2012 and August 2013 were retrospectively analyzed. Using LI-RADS 2014, two radiologists evaluated the lesions and a LI-RADS category was retrospectively assigned to each nodule. Results The final diagnoses of 297 nodules in 249 patients consisted of 191 malignant and 106 benign lesions. Out of 44 LI-RADS category 1 lesions, none were HCCs. However, 2/25 category 2 lesions, 3/35 category 3 lesions, 16/25 category 4 lesions, 151/156 category 5 lesions, and 3/12 category LRM/OM (probable malignancy, not specific for HCC/other malignancy) lesions were HCCs. The Kappa value was 0.44 (95% confidence interval [CI] = 0.39-0.49) between two observers during LI-RADS grading. Conclusion The negative predictive value of LI-RADS category 1 was 100%. In addition, a relevant proportion of lesions categorized as category 2 or 3, or even as other malignancies, were HCCs. LI-RADS category 5 had a high specificity for HCC. LI RADS was not able to give a differential diagnosis for the false-positive lesions of LI-RADS category 5. PMID- 28648127 TI - Specialist palliative care nurses' management of the needs of patients with depression. AB - BACKGROUND: Depression is an important condition to consider if we are to optimise the care outcomes for patients with palliative care needs. Depression has a high incidence in palliative patients, with up to 15% diagnosed with major depression and 37% expressing some form of depressive symptoms ( O'Connor et al, 2010 ). The challenge is to ensure that palliative care patients with depression are identified in a timely manner and that their depression is effectively managed. AIM: To examine how Australian specialist inpatient palliative care nurses perceive, assess and respond to depression in a patient case study. METHOD: This descriptive pilot study is a replication of a United States study by Little et al (2005) , exploring contemporary Australian specialist palliative care nurses' screening, assessment and management of depression in people with a progressive life-limiting illness. A survey titled 'Specialist palliative care nurses managing patients with complex care needs' questioned the nursing assessment, knowledge and clinical care priorities related to a case vignette of a patient demonstrating signs of depression. RESULTS: A total of 33 nurses completed this survey. Less than half (39.4%) of the participants identified depression as a major issue arising from the case vignette. Depression screening tools were not widely known. Functionality assessments measuring activities of daily living were the most recognised and widely used tools by participants. CONCLUSION: This small sample pilot study demonstrated that specialist palliative care nurses are still not confident in their screening and responding to a patient with depression. The available evidenced based depression screening tools were unfamiliar to these nurses and not widely used which can result in depression remaining undetected and undermanaged. The connections between physical health and mental health need stronger recognition and response within nursing care of palliative patients. PMID- 28648128 TI - HOPES for palliative wounds. PMID- 28648126 TI - Knee Osteoarthritis and Risk of Hypertension: A Longitudinal Cohort Study. AB - Although previous research has indicated an association between osteoarthritis (OA) and cardiovascular disease, it remains unclear whether people with OA are at greater risk of developing hypertension. The aim of this study was to answer this uncertainity. We used the data of the Osteoarthritis Initiative, an ongoing public and private longitudinal study including people at higher risk of OA or having knee OA. Knee OA was defined through radiological and clinical assessment. Incident hypertension was defined as a systolic blood pressure >=140 mmHg and/or a diastolic value >=90 mmHg. Multivariate Cox's regression analyses were constructed considering the presence of knee OA as the exposure and incident hypertension as the outcome during a 96-month follow-up interval. A total of 3558 people with normative blood pressure values at baseline were analyzed (1930 OA/1628 controls). Incidence of hypertension within the follow-up interval was significantly higher in people with knee OA than in those without (60/[1000 person-years] vs. 55/[1000 person-years]; p < 0.0001). After adjusting for 13 confounders, people with knee OA had a 13% higher chance of developing hypertension (hazard ratio = 1.13; 95% confidence interval: 1.01-1.26; p = 0.03). Propensity score analysis did not alter these conclusions. In conclusion, this is the first longitudinal data analysis to demonstrate that people with knee OA have a higher chance of developing hypertension than those without OA. Our data suggest that monitoring blood pressure and prescribing health promotion interventions may be warranted among people with OA to mitigate the potential onset and adverse consequences of hypertension. PMID- 28648129 TI - 'One voice, one vision' A message for palliative care nursing in Europe. PMID- 28648130 TI - Communication in palliative care: the applicability of the SAGE and THYME model in Singapore. AB - BACKGROUND: Majority of the progress and development in palliative care in the last decade has been improvements in physical aspects of treatment, namely pain and symptom management. Psychosocial aspects of care have improved, although not enough to meet the needs of many patients and family members. This is evident in many parts of the world and notably in Singapore, where palliative care is seen as an emerging medical and nursing specialty. AIM: To discuss the implementation of the SAGE and THYME communication model in a palliative care context. The article examines the use of the model and how its implementation can improve communication between patients and nurses. The model works by reviewing contemporary developments made in relation to improving communication in palliative care. These include, highlighting the importance of meeting individual needs, therapeutic relationship building, and advanced communication training within a Singaporean context. RESULTS: The implementation of the SAGE and THYME model can be a useful way of enabling nurses to improve and maintain effective communication in a medically dominated health care system. The challenges and constraints in educating and training nurses with limited skills in palliative care, forms part of the review, including the cultural and attitude constraints specific to Singaporean palliative care. PMID- 28648131 TI - Politics and palliative care: Ghana. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 28648132 TI - Conscientious objection-a way out for assisted suicide or a non-starter? PMID- 28648133 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 28648134 TI - Cognitive behavioural therapy in palliative care: evaluation of staff following a foundation level course. PMID- 28648135 TI - Peer mentoring supports the learning needs of nurses providing palliative care in a rural acute care setting. AB - BACKGROUND: A specific set of assessment scales can underpin the management of distressing symptoms of patients requiring palliative care. A research assistant supported nurses working in a rural hospital setting during the introduction of these scales. AIM: A secondary analysis was conducted to further explore the qualitative data of a previously reported mixed-method study. In particular, the experiences of nurses working alongside a research assistant in the facilitation of using a new assessment form. METHOD: Purposeful sampling was employed: participating nurses were invited to attend one of three focus group meetings. FINDINGS: Data analysis revealed three main themes: a contact person, coach/mentor and extra help initiatives. Three to four subthemes corresponded with each main theme. CONCLUSION: Findings suggest nurses benefit from having someone to assist in learning about new documentation. Nurses respond positively to mentorship and practical guidance when integrating a new assessment form into routine evidence-based practice. PMID- 28648136 TI - Two new alkaloids from the twigs of Trigonostemon filipes. AB - A phytochemical investigation of the alkaloid constituents from Trigonostemon filipes Y. T. Chang et S. L. Mo led to the isolation of two new indole alkaloids, trigonostemine G (1) and trigonostemone J (2), together with two known ones, trigonostemine A (3) and trigonostemine B (4). Their structures were determined by extensive spectroscopic methods. Compounds 1-4 exhibited moderate AChE inhibitory activity with inhibition ratio of 31.6, 31.7, 41.7, and 42.4%, respectively. In addition, compounds 1-2 showed weak cytotoxicity against K562 and BEL-7402 human cancer cell lines. PMID- 28648137 TI - Control strategies and sensitivity analysis of anthroponotic visceral leishmaniasis model. AB - This study proposes a mathematical model of Anthroponotic visceral leishmaniasis epidemic with saturated infection rate and recommends different control strategies to manage the spread of this disease in the community. To do this, first, a model formulation is presented to support these strategies, with quantifications of transmission and intervention parameters. To understand the nature of the initial transmission of the disease, the reproduction number [Formula: see text] is obtained by using the next-generation method. On the basis of sensitivity analysis of the reproduction number [Formula: see text], four different control strategies are proposed for managing disease transmission. For quantification of the prevalence period of the disease, a numerical simulation for each strategy is performed and a detailed summary is presented. Disease-free state is obtained with the help of control strategies. The threshold condition for globally asymptotic stability of the disease-free state is found, and it is ascertained that the state is globally stable. On the basis of sensitivity analysis of the reproduction number, it is shown that the disease can be eradicated by using the proposed strategies. PMID- 28648138 TI - Psychological symptomatology and impaired prepulse inhibition of the startle reflex are associated with cannabis-induced psychosis. AB - BACKGROUND: Cannabis-induced psychotic disorder (CIPD) is a psychiatric disorder induced by cannabis consumption. The psychological and psychophysiological features of this disorder are still unknown. We aimed to examine the psychological, personality and psychophysiological features of patients with CIPD. This study is an analytical extension of our previously published data, which previously found prepulse inhibition (PPI) deficits in the CIPD group used in this current paper. METHODS: We used a sample of 45 patients with CIPD. After 9 months of follow up, these patients were assessed with a Symptom Checklist-90-R (SCL-90-R) questionnaire of psychopathology, with the Eysenck Personality Questionnaire, and with a psychophysiological paradigm of inhibition of the startle reflex (PPI). These results were compared with a group of patients with schizophrenia and cannabis abuse (SCHZ) ( n = 54); patients with cannabis dependence (CD) ( n = 21); and healthy controls ( n = 50). RESULTS: CIPD patients obtained significant higher scores in the SCL-90-R subscale of neuroticism. These patients showed PPI percentages similar to SCHZ patients within early attentional levels (30 ms). The variables with greater correlation, and that appeared in the CIPD group were interpersonal sensitivity, depression and phobia. CONCLUSIONS: Neurotic symptomatology and difficulties in inhibition of the startle reflex might be risk factors for developing CIPD. PMID- 28648139 TI - Mutagenic Analysis of an Adeno-Associated Virus Variant Capable of Simultaneously Promoting Immune Resistance and Robust Gene Delivery. AB - In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated virus (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: (i) efficiently delivering therapeutic genes to many clinically valuable cells (e.g., stem or cancer cells) and (ii) effectively bypassing immunoglobulin (IgG) neutralization. Detailed interpretation of the structural features of AAVr3.45, which was previously engineered from AAV2, demonstrated that the LATQVGQKTA peptide at the heparan sulfate proteoglycan binding domain, especially the presence of cationic lysine on the peptide, served as a key motif for dramatically enhancing its gene delivery capabilities, ultimately broadening its tropisms for many cancer cell lines. Furthermore, the substitution of valine on the AAV2 capsid at the amino acid 719 site to methionine functioned as a coordinator for promoting viral resistance against IgG inactivation. The NAb-resistant characteristics of AAVr3.45 were possibly associated with the LATQVGQKTA sequence itself, indicating that its synergistic cooperation with the point mutation (V719M) is required for maximizing its ability to evade NAb inactivation. The potential of AAVr3.45 as a cancer gene therapy agent was confirmed by provoking apoptosis in breast adenocarcinoma by efficiently delivering a pro-apoptotic gene, BIM (Bcl-2-like protein 11), under high titers of human IgG. Thus, the superior aspects of the NAb-resistant AAVr3.45 as a potential therapeutic agent for systemic injection approaches, especially for cancer gene therapy, were highlighted in this study. PMID- 28648140 TI - Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants. AB - 1. 1-Chloropyrene, one of the major chlorinated polycyclic aromatic hydrocarbon contaminants, was incubated with human cytochrome P450 (P450 or CYP) enzymes including CYP1A1, 1A2, 1B1, 2A6, 2A13, 2B6, 2C9, 2D6, 2E1, 3A4 and 3A5. Catalytic differences in 1-chloropyrene oxidation by polymorphic two CYP1B1 and five CYP2A13 allelic variants were also examined. 2. CYP1A1 oxidized 1-chloropyrene at the 6- and 8-positions more actively than at the 3-position, while both CYP1B1.1 and 1B1.3 preferentially catalyzed 6-hydroxylation. 3. Five CYP2A13 allelic variants oxidized 8-hydroxylation much more than 6- and 3-hydroxylation, and the variant CYP2A13.3 was found to slowly catalyze these reactions with a lower kcat value than other CYP2A13.1 variants. 4. CYP2A6 catalyzed 1-chloropyrene 6 hydroxylation at a higher rate than the CYP2A13 enzymes, but the rate was lower than the CYP1A1 and 1B1 variants. Other human P450 enzymes had low activities towards 1-chloropyrene. 5. Molecular docking analysis suggested differences in the interaction of 1-chloropyrene with active sites of CYP1 and 2 A enzymes. In addition, a naturally occurring Thr134 insertion in CYP2A13.3 was found to affect the orientation of Asn297 in the I-helix in interacting with 1-chloropyrene (and also 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK) and caused changes in the active site of CYP2A13.3 as compared with CYP2A13.1. PMID- 28648141 TI - Anesthetic management of spontaneous cervical epidural hematoma during pregnancy: a case report. AB - BACKGROUND: Spontaneous spinal epidural hematoma during pregnancy is a quite rare event requiring emergent decompressive surgery in the majority of cases to prevent permanent neurological damage. Therefore, there is little data in the literature regarding anesthetic management of cervical localization during pregnancy. The potential for difficult airway management with the patient under general anesthesia is one of the major concerns that needs to be addressed to prevent further cord compression. Anesthetic management should also include measures to maintain the mean arterial pressure to improve spinal cord perfusion. Furthermore, spine surgery in pregnant patients needs special consideration in terms of positioning and in the postoperative period. CASE PRESENTATION: We present a case of a 35-year-old white woman at 21 weeks of gestation with a spontaneous cervical epidural hematoma. Fiberoptic bronchoscope-guided nasal intubation was a safe option to ensure a higher rate of successful endotracheal intubation while minimizing the risk of aggravating the injury. Her care posed other multiples challenges that required a multidisciplinary team approach. CONCLUSIONS: The case of our patient serves as a reminder of this rare condition and its implications regarding anesthesia. PMID- 28648142 TI - Overcoming intratumoural heterogeneity for reproducible molecular risk stratification: a case study in advanced kidney cancer. AB - BACKGROUND: Metastatic clear cell renal cell cancer (mccRCC) portends a poor prognosis and urgently requires better clinical tools for prognostication as well as for prediction of response to treatment. Considerable investment in molecular risk stratification has sought to overcome the performance ceiling encountered by methods restricted to traditional clinical parameters. However, replication of results has proven challenging, and intratumoural heterogeneity (ITH) may confound attempts at tissue-based stratification. METHODS: We investigated the influence of confounding ITH on the performance of a novel molecular prognostic model, enabled by pathologist-guided multiregion sampling (n = 183) of geographically separated mccRCC cohorts from the SuMR trial (development, n = 22) and the SCOTRRCC study (validation, n = 22). Tumour protein levels quantified by reverse phase protein array (RPPA) were investigated alongside clinical variables. Regularised wrapper selection identified features for Cox multivariate analysis with overall survival as the primary endpoint. RESULTS: The optimal subset of variables in the final stratification model consisted of N-cadherin, EPCAM, Age, mTOR (NEAT). Risk groups from NEAT had a markedly different prognosis in the validation cohort (log-rank p = 7.62 * 10-7; hazard ratio (HR) 37.9, 95% confidence interval 4.1-353.8) and 2-year survival rates (accuracy = 82%, Matthews correlation coefficient = 0.62). Comparisons with established clinico pathological scores suggest favourable performance for NEAT (Net reclassification improvement 7.1% vs International Metastatic Database Consortium score, 25.4% vs Memorial Sloan Kettering Cancer Center score). Limitations include the relatively small cohorts and associated wide confidence intervals on predictive performance. Our multiregion sampling approach enabled investigation of NEAT validation when limiting the number of samples analysed per tumour, which significantly degraded performance. Indeed, sample selection could change risk group assignment for 64% of patients, and prognostication with one sample per patient performed only slightly better than random expectation (median logHR = 0.109). Low grade tissue was associated with 3.5-fold greater variation in predicted risk than high grade (p = 0.044). CONCLUSIONS: This case study in mccRCC quantitatively demonstrates the critical importance of tumour sampling for the success of molecular biomarker studies research where ITH is a factor. The NEAT model shows promise for mccRCC prognostication and warrants follow-up in larger cohorts. Our work evidences actionable parameters to guide sample collection (tumour coverage, size, grade) to inform the development of reproducible molecular risk stratification methods. PMID- 28648143 TI - Polymorphism rs547984 on human chromosome 1q43 is not associated with primary open angle glaucoma in a Saudi cohort. AB - BACKGROUND: To investigate the association between polymorphism rs547984, located in close proximity to the Zona Pellucida Glycoprotein 4 (ZP4) gene on human chromosome 1q43 and primary open angle glaucoma (POAG). METHOD: Polymorphism rs547984 was genotyped using Taq-Man(r) assay in 185 subjects comprising of 90 unrelated POAG cases and 95 controls of Saudi origin. RESULTS: Association analysis between cases and controls revealed no significant genotype distribution under additive (p = 0.356), dominant (p = 0.517) and recessive (p = 0.309) models. Besides, the allele frequency distribution was also found to be non significant (p = 0.70). The minor "A" allele frequency was found to be 0.49 and 0.50 among POAG cases and controls, respectively. In addition, specific clinical indices used to assess severity of glaucoma such as intraocular pressure (IOP), cup/disc ratio and number of anti-glaucoma medication also did not show any significant genotype distribution in POAG cases. CONCLUSION: Polymorphism rs547984 is neither associated with any clinical indices important for POAG such as IOP and cup/disc ratio nor is a risk factor for POAG in the Saudi cohort. PMID- 28648144 TI - Repression of the F-box protein Skp2 is essential for actin damage-induced tetraploid G1 arrest. AB - We previously reported that p53 plays a role as a key regulator in the tetraploid G1 checkpoint, which is activated by actin damage-induced cytokinesis blockade and then prevents uncoupled DNA replication and nuclear division without cytokinesis. In this study, we investigated a role of Skp2, which targets CDK2 inhibitor p27/Kip1, in actin damage-induced tetraploid G1 arrest. Expression of Skp2 was reduced, but p27/Kip1 was increased, after actin damage-induced cytokinesis blockade. The role of Skp2 repression in tetraploid G1 arrest was investigated by analyzing the effects of ectopic expression of Skp2. After actin damage, ectopic expression of Skp2 resulted in DNA synthesis and accumulation of multinucleated cells, and ultimately, induction of apoptosis. These results suggest that Skp2 repression is important for sustaining tetraploid G1 arrest after cytokinesis blockade and is required to prevent uncoupled DNA replication and nuclear division without cytokinesis. [BMB Reports 2017; 50(7): 379-383]. PMID- 28648145 TI - ER membrane protein complex subunit 6 (EMC6) is a novel tumor suppressor in gastric cancer. AB - The endoplasmic reticulum (ER) membrane protein complex subunit 6 (EMC6) is a novel human autophagy-related molecule. Here, using tissue microarray and immunohistochemistry, we report that EMC6 protein is lost or reduced in glandular cells of patients with gastric adenocarcinoma, compared to normal stomach mucosa. Overexpression of EMC6 in gastric cancer cells inhibited cell growth, migration, invasion, and induced apoptosis and cell cycle arrest at S-phase. Further investigation suggested that EMC6 overexpression in BGC823 human adenocarcinoma gastric cancer cells reduced tumorigenicity in a xenograft model, demonstrating that EMC6 has the characteristics of a tumor suppressor. This is the first study to show that EMC6 induces cell death in gastric cancer cells. The molecular mechanism of how EMC6 functions as a tumor suppressor needs to be further explored. [BMB Reports 2017; 50(8): 411-416]. PMID- 28648146 TI - Emerging roles of protein disulfide isomerase in cancer. AB - The protein disulfide isomerase (PDI) family is a group of multifunctional endoplasmic reticulum (ER) enzymes that mediate the formation of disulfide bonds, catalyze the cysteine-based redox reactions and assist the quality control of client proteins. Recent structural and functional studies have demonstrated that PDI members not only play an essential role in the proteostasis in the ER but also exert diverse effects in numerous human disorders including cancer and neurodegenerative diseases. Increasing evidence suggests that PDI is actively involved in the proliferation, survival, and metastasis of several types of cancer cells. Although the molecular mechanism by which PDI contributes to tumorigenesis and metastasis remains to be understood, PDI is now emerging as a new therapeutic target for cancer treatment. In fact, several attempts have been made to develop PDI inhibitors as anti-cancer drugs. In this review, we discuss the properties and diverse functions of human PDI proteins and focus on recent findings regarding their roles in the state of diseases including cancer and neurodegeneration. [BMB Reports 2017; 50(8): 401-410]. PMID- 28648147 TI - Functional roles of CTCF in breast cancer. AB - CTCF, Zinc-finger protein, has been identified as a multifunctional transcription factor that regulates gene expression through various mechanisms, including recruitment of other co-activators and binding to promoter regions of target genes. Furthermore, it has been proposed to be an insulator protein that contributes to the establishment of functional threedimensional chromatin structures. It can disrupt transcription through blocking the connection between an enhancer and a promoter. Previous studies revealed that the onset of various diseases, including breast cancer, could be attributed to the aberrant expression of CTCF itself or one or more of its target genes. In this review, we will describe molecular dysfunction involving CTCF that induces tumorigenesis and summarize the functional roles of CTCF in breast cancer. [BMB Reports 2017; 50(9): 445-453]. PMID- 28648149 TI - Attitudes to sexual health in the United States: results from a national survey of youth aged 15-25 years. AB - : Background Several common global definitions of sexual health refer to physical, emotional and social well-being, with respect to sexuality, and also to the need for this well-being to be reflected for all individuals in relationships. How well sexual health definitions fit US youths' attitudes to sexual health, and associations between these attitudes, sexual behaviours and sexual health care were assessed. METHODS: In total, 4017 youth aged between 15 and 25 years via an online survey panel, weighted to be representative of the US population, were surveyed. Respondents reported their attitudes towards seven dimensions of sexual health that we abstracted from existing global definitions (emotional fulfillment, social connectedness, spirituality, overall pleasure, physical intimacy, mental fulfillment, reciprocal benefits). Respondents also reported on sexual health-related discussions with partners, sexual behaviours, and their use of sexual health care. Outcomes through weighted frequency estimates and ordinal regression models were reported. RESULTS: Youth generally construed all seven dimensions as important to sexual health, with the emotional dimension rated most favourably. Attitudes to the dimensions of overall pleasure, physical intimacy and spirituality were most consistently related to sexual health discussions and behaviours. The behaviours most consistently related to sexual health attitudes were going for a sexual health check-up, discussing birth control/pregnancy and discussing risk before sex without a condom. CONCLUSIONS: Youth construal of sexual health fits well with global sexual health definitions. Attitudes to dimensions of sexual health were related to some sexual health related behaviours, especially healthcare use and complex discussions. PMID- 28648148 TI - Debt Counselling for Depression in Primary Care: an adaptive randomised controlled pilot trial (DeCoDer study). AB - BACKGROUND: Depression and debt are common in the UK. Debt Counselling for Depression in Primary Care: an adaptive randomised controlled pilot trial (DeCoDer) aimed to assess the clinical effectiveness and cost-effectiveness of the addition of a primary care debt counselling advice service to usual care for patients with depression and debt. However, the study was terminated early during the internal pilot trial phase because of recruitment delays. This report describes the rationale, methods and findings of the pilot study, and implications for future research. OBJECTIVES: The overarching aim of the internal pilot was to identify and resolve problems, thereby assessing the feasibility of the main trial. The specific objectives were to confirm methods for practice recruitment and the ability to recruit patients via the proposed approaches; to determine the acceptability of the study interventions and outcome measures; to assess contamination; to confirm the randomisation method for main trial and the level of participant attrition; and to check the robustness of data collection systems. DESIGN: An adaptive, parallel, two-group multicentre randomised controlled pilot trial with a nested mixed-methods process and economic evaluation. Both individual- and cluster (general practice)-level were was used in the pilot phase to assign participants to intervention or control groups. SETTING: General practices in England and Wales. PARTICIPANTS: Individuals were included who were aged >= 18 years, scored >= 14 on the Beck Depression Inventory II and self-identified as having debt worries. The main exclusion criteria were being actively suicidal or psychotic and/or severely depressed and unresponsive to treatment; having a severe addiction to alcohol/illicit drugs; being unable/unwilling to give written informed consent; currently participating in other research including follow-up phases; having received Citizens Advice Bureau (CAB) debt advice in the past year; and not wanting debt advice via a general practice. INTERVENTIONS: The participants in the intervention group were given debt advice provided by the CAB and shared biopsychosocial assessment, in addition to treatment as usual (TAU) and two debt advice leaflets. The participants in the control group were given advice leaflets provided by the general practitioner and TAU only. MAIN OUTCOME MEASURES: (1) Outcomes of the pilot trial - the proportion of eligible patients who consented, the number of participants recruited compared with target, assessment of contamination, and assessment of patient satisfaction with intervention and outcome measures. (2) Participant outcomes - primary - Beck Depression Inventory II; secondary - psychological well-being, health and social care utilisation, service satisfaction, substance misuse, record of priority/non-priority debts, life events and difficulties, and explanatory measures. Outcomes were assessed at baseline (pre-randomisation) and at 4 months post randomisation. Other data sources - qualitative interviews were conducted with participants, clinicians and CAB advisors. RESULTS: Of the 238 expressions of interest screened, 61 participants (26%) were recruited and randomised (32 in the intervention group and 29 in the control group). All participants provided baseline outcomes and 52 provided the primary outcome at 4 months' follow-up (14.7% dropout). Seventeen participants allocated to the intervention saw a CAB advisor. Descriptive statistics are reported for participants with complete outcomes at baseline and 4 months' follow-up. Our qualitative findings suggest that the relationship between debt and depression is complex, and the impact of each on the other is compounded by other psychological, social and contextual influences. CONCLUSIONS: As a result of low recruitment, this trial was terminated at the internal pilot phase and was too small for inferential statistical analysis. We recommend ways to reduce this risk when conducting complex trials among vulnerable populations recruited in community settings. These cover trial design, the design and delivery of interventions, recruitment strategies and support for sites. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79705874. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 35. See the NIHR Journals Library website for further project information. Mark Gabbay and Adele Ring are part-funded by NIHR Collaborations for Leadership in Applied Health Research and Care (CLAHRC) North West Coast and Richard Byng and Rod S Taylor, Vashti Berry and Elizabeth Shaw part-funded by NIHR CLAHRC South West Peninsula. PMID- 28648150 TI - Trends in chlamydia and gonorrhoea testing and positivity in Western Australian Aboriginal and non-Aboriginal women 2001-2013: a population-based cohort study. AB - BACKGROUND: This study aimed to examine trends in chlamydia and gonorrhoea testing and positivity in Aboriginal and non-Aboriginal women of reproductive age. METHODS: A cohort of 318002 women, born between 1974 and 1995, residing in Western Australia (WA) was determined from birth registrations and the 2014 electoral roll. This cohort was then probabilistically linked to all records of chlamydia and gonorrhoea nucleic acid amplification tests conducted by two large WA pathology laboratories between 1 January 2001 and 31 December 2013. Trends in chlamydia and gonorrhoea testing and positivity were investigated over time and stratified by Aboriginality and age group. RESULTS: The proportion of women tested annually for chlamydia increased significantly between 2001 and 2013 from 24.5% to 36.6% in Aboriginal and 4.0% to 8.5% in non-Aboriginal women (both P values <0.001). Concurrent testing was high (>80%) and so patterns of gonorrhoea testing were similar. Chlamydia and gonorrhoea positivity were substantially higher in Aboriginal compared with non-Aboriginal women; age-, region- and year adjusted incidence rate ratios were 1.52 (95% confidence interval (CI) 1.50-1.69, P<0.001) and 11.80 (95% CI 10.77-12.91, P<0.001) respectively. Chlamydia positivity increased significantly in non-Aboriginal women aged 15-19 peaking in 2011 at 13.3% (95% CI 12.5-14.2%); trends were less consistent among 15-19-year old Aboriginal women but positivity also peaked in 2011 at 18.5% (95% CI 16.9 20.2%). Gonorrhoea positivity was 9.7% (95% CI 9.3-10.1%), 6.7% (95% CI 6.4 7.0%), 4.7% (4.4-5.0%), and 3.1% (2.8-3.4%) among Aboriginal women aged respectively 15-19, 20-24, 25-29 and >=30 years, compared with <1% in all age groups in non-Aboriginal women. Over time, gonorrhoea positivity declined in all age groups among Aboriginal and non-Aboriginal women. CONCLUSION: Between 2001 and 2013 in WA chlamydia and gonorrhoea positivity remained highest in young Aboriginal women despite chlamydia positivity increasing among young non Aboriginal women. More effective prevention strategies, particularly for young Aboriginal women, are needed to address these disparities. PMID- 28648151 TI - [Bone tumour as differential diagnosis of pain in the extremities in a newborn baby]. AB - Infants are a challenging group of patients: their symptoms can be subtle, and it is difficult to differentiate between pain and normal reaction to their needs. It is important to investigate symptoms by a thorough examination of the physical condition and the history of symptoms and to contact a specialist at an early stage. An X-ray should also be performed early. Infants can also suffer from serious conditions such as bone tumours which need fast and proper treatment, and this case report describes an infant boy with suspected bone tumour, which turned out to be a fracture from the prenatal period or during labour. PMID- 28648152 TI - [Wandering spleen in a patient hospitalized with acute abdomen]. AB - An 11-year-old girl was hospitalized with a two-day history of lower abdominal pain. The patient had a localized peritoneal reaction in the right lower quadrant, an elevated C-reactive protein level, and an increased white blood cell count. On the suspicion of acute appendicitis a diagnostic laparoscopy was performed. This revealed a misplaced spleen in the right side of the pelvis with a partly torsion of a long vascular pedicle. The splenic tissue was vital without any sign of ischaemia. However, splenopexy was not possible, and an uncomplicated elective splenectomy was performed. PMID- 28648154 TI - [The cause of cytopenia of undetermined significance can often be found by using next generation sequencing]. AB - Patients with persistent cytopenia are frequently referred to the haematological departments , and a diagnosis of myelodysplastic syndrome is often suspected. After routine assessment including a broad range of blood tests, bone marrow biopsy, and cytogenetics, a definite diagnosis can still not be found for some patients, although they have symptomatic cytopenia. In these cases, next generation sequencing is a valuable supplement in identifying patients with early stages of myeloid cancer. PMID- 28648153 TI - [Human papillomavirus and oropharyngeal cancer]. AB - The prevalence of oropharyngeal cancer is increasing in the Western world, and human papillomavirus (HPV) is believed to play a role in this development. Patients with HPV-positive oropharyngeal cancer differ significantly from patients with HPV-negative cancer. They may present solely with a small cervical metastasis and thus undergo an extensive diagnostic workup. Treatment modalities include radiotherapy often in combination with chemotherapy. However, new surgical advances are now possible. In this review we discuss the changing epidemiology, virology, symptomatology and different treatment modalities. PMID- 28648156 TI - ? PMID- 28648155 TI - [Ubehandlet idiopatisk skoliose hos en dansk teenager]. PMID- 28648157 TI - ? PMID- 28648158 TI - [Advanced labour pain relief]. AB - Delivery and labour pain is normally the most painful event in a woman's lifetime. Physical and psychological factors may influence the severity of labour pain, and labour pain relief is an important issue for the obstetric anaesthetist. We describe the current most effective pharmacological techniques used for labour analgesia: systemically with remifentanil and regionally with epidural analgesia. PMID- 28648159 TI - [Treating post-operative pain]. AB - Post-operative pain is a problem for many patients and affects recovery, risk of post-operative complications and quality of life. A thorough preoperative evaluation, careful perioperative planning, identification, and individualized treatment of high-risk patients can reduce post-operative pain. Multimodal treatment combines different analgesic techniques in order to utilize synergistic and additive effects of different treatments and has the potential to optimize effects and reduce side effects. Identification and treatment of patients with chronic post-operative pain should be prioritized. PMID- 28648160 TI - [Strategies to avoid the risk of addiction when treating patients with chronic pains]. AB - Addiction is a feared complication of long-term opioid treatment in patients with chronic pains. Strategies to decrease the risk of addiction include estimating of risk factors, establishing treatment goals realistic for pain and function, considering how to discontinue therapy if treatment goals are not achieved, avoiding administration forms with rapid absorption, using validated screening instruments and avoiding high opioid doses. If signs of addiction do occur, precautions to hinder overuse of opioid should be taken. PMID- 28648161 TI - [Potential pharmacological consequences of the development of the opioid consumption in Denmark]. AB - The total consumption of weak opioids (mainly of tramadol) in Denmark was doubled during the period 2001-2013. On the contrary, the total consumption of strong opioids remained almost constant in the same period. The increase in tramadol consumption is not rational, as it has no special benefits with regards to efficacy, side effects and abuse potential. The terms strong- and weak opioids are inappropriate, because it often erroneously is interpreted as if the weak opioids are safer, but it is really just a matter of potency: strong opioids are simply more potent. PMID- 28648162 TI - [Treatment of acute pain in opioid addicts]. AB - The challenge of managing acute pain in opioid-addicted patients is a question of fully understanding the pharmacological effects of the illegal drugs and to prevent overdosing or withdrawal symptoms. It requires a thorough knowledge of the patient's daily consumption of legal and illegal drugs and an understanding obtained through an accepting and empathetic communication with the patient. Substitution management aims to prevent opioid withdrawal symptoms and is not a means of managing pain. When planning the pain management the patient must receive at least 25% of the daily methadone dose, recalculated into equipotent substitute morphine. PMID- 28648163 TI - [Self-injury, converting emotional distress into physical pain]. AB - Self-inflicted pain by cutting, hitting or burning oneself has become a common way to regulate emotions and to serve as coping strategy. 21.5-32% of adolescents in non-clinical populations have a history of non-suicidal self-injury. Non suicidal self-injury has a momentarily relieving effect and is an important predictor of suicidal behaviour; even superficial self-injury should be taken seriously. There is an urgent need for organized treatment programmes for young people who self-harm. PMID- 28648164 TI - [Pharmacological treatment of chronic non-cancer pain]. AB - 19% of the grown-up Danish population suffer from a chronic pain condition. Most patients are treated by general practi-tioners (GPs), and only a smaller group need specialist treatment. This article goes through the pharmacological possibilities available with a special focus on treatment by GPs. For chronic pain as fibromyalgia and low back pain non-steroidal anti-inflammatory drugs and paracetamol are not recommended on a regular basis. The main pharmacological treatment is tricyclic antidepressants and gabapentinoids. If opioids are needed, long acting drugs are preferred. PMID- 28648165 TI - [Psychosocial treatment of pain at general practitioners and in specialist pain treatment units]. AB - Patients with complex chronic pain conditions are often difficult to treat with analgesia alone. Psychosocial intervention is needed to help them gain control and find an appropriate level of activity. This article summarizes the possibilities of psychosocial treatment of pain patients at the general practitioners and in specialist units of multidisciplinary pain treatment. The theoretical frame used is cognitive behavioural therapy. In practice, psychoeducation, mindfulness, and relaxation exercises are introduced to the patients to help them with daily life activity and work. PMID- 28648166 TI - [Pain in the dying patient]. AB - Pain is one of the most frequent symptoms in patients with advanced chronic illnesses. However, knowledge of prevalence and intensity of pain in the last days of life is poor. This review shows that more than half of patients who are dying from either cancer or non-malignant diseases experience pain, but only very few patients have unbearable pain. More knowledge of pain in the last days of life is needed, and teaching symptom management in the dying patient ought to be compulsory at the medical schools in Denmark. PMID- 28648167 TI - [Cardiac arrest induced by vasospastic angina pectoris after vaginally administered misoprostol]. AB - A 41-year-old woman developed cardiac arrest after administration of misoprostol in order to induce an abortion. She was successfully resuscitated. Coronary angiography revealed coronary artery spasm which responded to nitroglycerine. Misoprostol is first-line treatment for medically induced abortion. Reports have described cardiovascular adverse events in women with cardiovascular risk factors, and clinicians should be aware of this. PMID- 28648169 TI - [The incidence of congenital hypothyroidism is increasing]. AB - The prognosis of primary congenital hypothyroidism, which has potentially devastating effects on neurodevelopment, has been almost eradicated after the implementation of the neonatal screening programme. Although early facilitation with substitution of levothyroxine is preventative, caution should still be taken in severe cases, as subtle psychomotor delays may occur. Treatment dose may be indicative of the severity and pathology behind the condition and can be used as guidance when deciding which patients should have a trial of levothyroxine in cases where the thyroid gland remains in situ. PMID- 28648168 TI - [Mitral valve endocarditis diagnosed after panophthalmitis with Enterococcus faecalis]. AB - An 86-year-old man underwent cataract surgery on the left eye, but suddenly he lost his vision three days after surgery. Topical treatments for panophthalmitis were started according to international guidelines. Later, a broad-range polymerase chain reaction showed Enterococcus faecalis in corpus vitreum, and IV antiobiotic treatment was initiated. To exclude endocarditis an echocardiography was performed, and this showed mitral regurgitation with a small mobile vegetation. Uncertainty concerning a possible causality between panophthalmitis and mitral valve endocarditis remains. PMID- 28648170 TI - [Specialized palliative care in Denmark lacks capacity and accessibility]. AB - Specialized palliative care (SPC) has a core task in providing palliative care to patients and the families of patients suffering from life-threatening diseases. SPC-units also support the generalist palliative care level. In spring 2016, Denmark had a capacity of 55 units comprising hospices, palliative care teams and palliative hospital wards, which is an insufficient number according to the European Association for Palliative Care recommendations. Despite many non-cancer deaths, 96% of the patients receiving SPC have cancer. The accessibility to SPC is unequally distributed across the regions. PMID- 28648171 TI - Breaking down hierarchies of decision-making in primates. AB - Possible options in a decision often organize as a hierarchy of subdecisions. A recent study concluded that perceptual processes in primates mimic this hierarchical structure and perform subdecisions in parallel. We argue that a flat model that directly selects between final choices accounts more parsimoniously for the reported behavioral and neural data. Critically, a flat model is characterized by decision signals integrating evidence at different hierarchical levels, in agreement with neural recordings showing this integration in localized neural populations. Our results point to the role of experience for building integrated perceptual categories where sensory evidence is merged prior to decision. PMID- 28648173 TI - abcd. PMID- 28648172 TI - Serial, parallel and hierarchical decision making in primates. AB - The study of decision-making has mainly focused on isolated decisions where choices are associated with motor actions. However, problem-solving often involves considering a hierarchy of sub-decisions. In a recent study (Lorteije et al. 2015), we reported behavioral and neuronal evidence for hierarchical decision making in a task with a small decision tree. We observed a first phase of parallel evidence integration for multiple sub-decisions, followed by a phase in which the overall strategy formed. It has been suggested that a 'flat' competition between the ultimate motor actions might also explain these results. A reanalysis of the data does not support the critical predictions of flat models. We also examined the time-course of decision making in other, related tasks and report conditions where evidence integration for successive decisions is decoupled, which excludes flat models. We conclude that the flexibility of decision-making implies that the strategies are genuinely hierarchical. PMID- 28648174 TI - Functionalization of pectin with laccase-mediated oxidation products of ferulic acid. AB - Pectin is a natural biopolymer extracted mostly from citrus peel, sugar beet and apple pomace. In order to improve its functional properties and then to enlarge the field of its potential applications, functionalization reaction of citrus pectin with ferulic acid (FA)-oxidation products was performed in aqueous medium, at 30 degrees C and pH7.5, in the presence of Myceliophthora thermophila laccase as biocatalyst. The conjugation between FA-oxidation products and pectin was confirmed using FTIR, UV-Vis and LC-MS analyses. The obtained results suggested that covalent bonds were between the pectin carboxyl groups and FA-oxidation products between the pectin carboxyl groups and FA-oxidation products. The determination of the total phenolic content showed that the modified pectin contained 5 times more phenols than the native pectin. In view of these results, this enzymatic procedure appears as a promising way to provide new pectin-based polymers that are expected to present new properties of interest. PMID- 28648175 TI - Enzymatic phosphorylation of mannose by glucomannokinase from Mycobacterium phlei using inorganic polyphosphate. AB - Mannose-6-phosphate is an important phosphor-sugar, which is involved in many physiological functions and it is used to treat many diseases. Its production is however expensive since it requires costly substrate ATP as phosphorylation agent. This study has focused upon the direct synthesis of M6P by glucomannokinase using inorganic polyphosphate without involvement of ATP. The gene cloned for glucomannokinase has been sequenced from Mycobacterium phlei and it is transformed into Escherichia coli for expression. After purification involving affinity chromatography, a band of 30kDa corresponding to the enzyme has been isolated from induced crude supernatant. A total amount of 0.69mg/ml of enzyme has been successively obtained and the purity exceeds 90%. The kinetic assay studies show that this enzyme has more affinity towards polyphosphate and glucose than ATP and mannose respectively. The KM values of the enzyme for glucose, mannose, ATP and hexametaphosphate derived from experiments are 9.5, 203.7, 4.6, 1.7MUM, respectively. The enzyme has shown a maximum production of mannose-6-phosphate at optimized conditions of pH 8.5, 25 degrees C, poly(P)/mannose ratio 3:1 and in the presence of bivalent ion Mg2+. The results reveal that the glucomannokinase from Mycobacterium phlei suitable for further production of mannose-6-phosphate. PMID- 28648176 TI - Action of a GH115 alpha-glucuronidase from Amphibacillus xylanus at alkaline condition promotes release of 4-O-methylglucopyranosyluronic acid from glucuronoxylan and arabinoglucuronoxylan. AB - Glucuronic acid and/or 4-O-methyl-glucuronic acid (GlcA/MeGlcA) are substituents of the main xylans present in hardwoods, conifers, and many cereal grains. alpha Glucuronidases from glycoside hydrolase family GH115 can target GlcA/MeGlcA from both internally and terminally substituted regions of xylans. The current study describes the first GH115 alpha-glucuronidase, AxyAgu115A, from the alkaliphilic organism Amphilbacillus xylanus. AxyAgu115A was active in a wide pH range, and demonstrated better performance in alkaline condition compared to other characterized GH115 alpha-glucuronidases, which generally show optimal activity in acidic conditions. Specifically, its relative activity between pH 5.0 and pH 8.5 was above 80%, and was 35% of maximum at pH 10.5; although the enzyme lost 30% and 80% relative residual activity after 24-h pre-incubation at pH 9 and pH 10, respectively. AxyAgu115A was also similarly active towards glucuronoxylan as well as comparatively complex xylans such as spruce arabinoglucurunoxylan. Accommodation of complex xylans was supported by docking analyses that predicted accessibility of AxyAgu115A to branched xylo-oligosaccharides. MeGlcA release by AxyAgu115A from each xylan sample was increased by up to 30% by performing the reaction at pH 11.0 rather than pH 4.0, revealing applied benefits of AxyAgu115A for xylan recovery and processing. PMID- 28648177 TI - Species specific substrates and products choices of 4-O-acetyltransferase from Trichoderma brevicompactum. AB - Antagonistic species of Trichoderma such as T. harzianum, T. viride, T. virens and T. koningii are well-known biocontrol agents that have been reported to suppress pathogenic soil microbes and enhance the growth of crop plants. Secondary metabolites (SMs) including trichothecenes are responsible for its biocontrol activities. The trichothecenes, trichodermin and harzianum A (HA) are produced in species dependent manner respectively, by Trichoderma brevicompactum (TB) and Trichoderma arundinaceum (TA). The last step in the pathway involves the conversion of trichodermol into trichodermin or HA alternatively, which is catalyzed by 4-O-acetyltransferase (encoded by tri3 gene). Comparative sequence analysis of acetyltransferase enzyme of TB with other chloramphenicol acetyltransferase (CAT) family proteins revealed the conserved motif involved in the catalysis. Multiple substrate binding studies were carried out to explore the mechanism behind the two different outcomes. His188 was found to have a role in initial substrate binding. In the case of trichodermin synthesis, represented by ternary complex 1, the trichodermol and acetic anhydride (AAn), the two substrates come very close to each other during molecular simulation analysis so that interactions become possible between them and acetyl group may get transferred from AAn to trichodermol, and Tyr476 residue mediates this phenomenon resulting in the formation of trichodermin. However, in case of the HA biosynthesis using the TB version of enzyme, represented by ternary complex 2, the two substrates, trichodermol and octa-2Z,4E,6E-trienedioic acid (OCTA) did not show any such interactions. PMID- 28648178 TI - Characterization of Ruminiclostridium josui arabinoxylan arabinofuranohydrolase, RjAxh43B, and RjAxh43B-containing xylanolytic complex. AB - A novel gene (axh43B) from Ruminiclostridium josui encoding a cellulosomal enzyme consisting of a catalytic module of subfamily GH43_10, a family-6 carbohydrate binding module, and a dockerin module, was expressed using Escherichia coli. RjAxh43B released only arabinose from arabinoxylan and 23,33-di-alpha-l arabinofuranosyl xylotriose, but not 32-alpha-l-arabinofuranosyl xylobiose or 23 alpha-l-arabinofuranosyl xylotriose, strongly suggesting that RjAxh43B is an arabinoxylan alpha-l-1,3-arabinofuranohydrolase capable of cleaving alpha-1,3 linked arabinose residues of doubly arabinosylated xylan. When Axh43B was mixed with the recombinant scaffolding protein RjCipA of R. josui at a molar ratio of 6:1, the activity of the RjAxh43B-RjCipA complex (6:1) toward insoluble wheat arabinoxylan was similar to that of RjAxh43B alone, suggesting that RjAxh43B does not show a proximity effect, which is defined as an activity enhancement effect caused by the presence of plural catalytic subunits adjoining each other. When RjAxh43A was mixed with xylanase RjXyn10C, they acted synergistically toward insoluble wheat arabinoxylan and rice straw powder in the absence of RjCipA. Furthermore, the RjAxh43B-RjXyn10C-RjCipA (3:3:3) complex had higher activity toward insoluble wheat arabinoxylan than a mixture of RjAxh43B and RjXyn10C without RjCipA, suggesting that incorporation of a xylanase and an alpha-l arabinofuranosidase into a cellulosome is beneficial for more efficiently degrading arabinoxylan. PMID- 28648179 TI - FT-Raman spectroscopic analysis of enhanced activity of supercritical carbon dioxide treated bacterial alpha-amylase. AB - Our previous investigation on high pressure supercritical carbon dioxide treatment of a bacterial alpha-amylase had revealed enhanced activity of the same. 1H NMR analysis of the activity enhanced enzyme led the authors to hypothesize that the enhancement was possibly owing to alterations in the active site of the enzyme. In the present study, the changes in the active site of the treated enzyme was analysed by Fourier-transform Raman (FT-Raman) spectroscopy. The spectra obtained revealed shifting of bands in the active site of alpha amylase indicating a nudging effect of the bonds in this region consequent to high pressure treatment. Also, shifts in bands in the OH stretching vibration of water were observed in the enzyme spectra. These variations in the spectra confirmed changes in the active site as well as in the water associated with the same that perhaps had a concerted effect on the increased activity of alpha amylase. PMID- 28648180 TI - Kinetic study on anaerobic oxidation of methane coupled to denitrification. AB - Monod kinetic parameters provide information required for kinetic analysis of anaerobic oxidation of methane coupled to denitrification (AOM-D). This information is critical for engineering AOM-D processes in wastewater treatment facilities. We first experimentally determined Monod kinetic parameters for an AOM-D enriched culture and obtained the following values: maximum specific growth rate (MUmax) 0.121/d, maximum substrate-utilization rate (qmax) 28.8mmol CH4/g cells-d, half maximum-rate substrate concentration (Ks) 83MUMU CH4, growth yield (Y) 4.76gcells/mol CH4, decay coefficient (b) 0.031/d, and threshold substrate concentration (Smin) 28.8MUM CH4. Clone library analysis of 16S rRNA and mcrA gene fragments suggested that AOM-D reactions might have occurred via the syntrophic interaction between denitrifying bacteria (e.g., Ignavibacterium, Acidovorax, and Pseudomonas spp.) and hydrogenotrophic methanogens (Methanobacterium spp.), supporting reverse methanogenesis-dependent AOM-D in our culture. High MUmax and qmax, and low Ks for the AOM-D enrichment imply that AOM D could play a significant role in mitigating atmospheric methane efflux. In addition, these high kinetic features suggest that engineered AOM-D systems may provide a sustainable alternative to nitrogen removal in wastewater treatment. PMID- 28648181 TI - A highly sensitive carbapenemase assay using laser desorption/ionization mass spectrometry based on a parylene-matrix chip. AB - A quantitative carbapenemase assay was developed using laser desorption/ionization mass spectrometry (LDI-MS) based on a parylene-matrix chip. As a first step, the reproducibility (spot-to-spot, shot-to-shot, and day-to-day) of LDI-MS based on a parylene-matrix chip and the quantification ranges for four carbapenem antibiotics (doripenem, ertapenem, imipenem, and meropenem) were determined. A carbapenem-susceptibility test was performed using the four carbapenems and 51 bacterial strains that displayed (1) carbapenem resistance with carbapenemase, (2) carbapenem resistance without carbapenemase, or (3) carbapenem susceptibility. The susceptibility test results showed that LDI-MS based on a parylene-matrix chip was more sensitive and selective for detecting the carbapenemase reaction than conventional MALDI-TOF MS based on a 2,5 dihydroxybenzoic acid matrix. PMID- 28648182 TI - Biotransformation of pyridoxal 5'-phosphate from pyridoxal by pyridoxal kinase (pdxY) to support cadaverine production in Escherichia coli. AB - Cadaverine, a five-carbon diamine (1,5-diaminopentane), can be made by fermentation or direct bioconversion and plays an important role as a building block of polyamides. Lysine decarboxylase (CadA) transforms L-lysine to cadaverine and pyridoxal 5'-phosphate (PLP) can increases conversion rate and yield as a cofactor. Biotransformation of cadaverine using whole Escherichia coli cells that overexpress the lysine decarboxylase has many merits, such as the rapid conversion of l-lysine to cadaverine, possible application of high concentration reactions up to the molar level, production of less byproduct and potential reuse of the enzyme by immobilization. However, the supply of PLP, which is a cofactor of lysine decarboxylase, is the major bottleneck in this system. Therefore, we initiated our study on PLP precursors and PLP-related enzymes and discovered that pyridoxal (PL) can be a viable alternative to supply PLP. Among various PLP systems examined, pyridoxal kinase (PdxY) showed the highest conversion of PL to PLP, resulting in more than 60% conversion of l lysine to cadaverine with lysine decarboxylase. When the reaction with 0.4M l lysine, 0.2mM PL and more whole cells was performed, it resulted in an 80% conversion yield. Furthermore, when barium-alginate immobilization was applied, it showed a 90% conversion yield in 1h with PL, suggesting that it is compatible with developed whole-cell systems without a direct supply of exogenous PLP. PMID- 28648183 TI - Stroke Treatment and Prevention. PMID- 28648184 TI - Uterine Fluid in Pregnancy: A Biological and Clinical Outlook. AB - Once considered a simple medium for sperm and embryo transport, the functional spectrum of uterine fluid is now expanding. Novel molecular players, such as extracellular vesicles and mobile RNAs, have been detected in the uterine fluid of livestock, rodents, and humans. These novel molecules, together with previously known ions and proteins, ensure uterine fluid homeostasis and facilitate embryo-maternal interactions. Here, we propose that these molecules may also carry information that mirrors maternal environmental exposure and possibly relay such information to the embryo via uterine fluid, generating long term epigenetic effects on the offspring via embryonic and placental programming. Moreover, the development of systematic profiling of uterine fluid molecular signatures may now hold promise, relying on high-throughput methods and non invasive biomarkers for clinical use. PMID- 28648186 TI - ? PMID- 28648187 TI - [Role of the nurse in the case of complex hand wounds]. AB - The initial assessment and care determine the quality of the secondary surgical treatment of complex hand wounds. The caregiver providing this initial care plays a critical role. The analysis of the management of these traumas in exceptional situations enables the key stages of the initial treatment to be identified: bleeding control, infection prevention and an accurate assessment of the injury. These measures thereby help to optimise the patient's transfer towards a specialised unit. PMID- 28648189 TI - ? PMID- 28648185 TI - Exosomes as Reconfigurable Therapeutic Systems. AB - Historically, small molecules, including steroid hormones and cytokines, have been attributed a role in paracrine and endocrine signaling, and now include a new player: biological nanoparticles, or 'exosomes'. Generated intracellularly, and defined simply as nanoparticulate packages of signaling moieties, exosomes have emerged as vehicles for highly specialized local and distant intercellular communication. Exosomes are increasingly being recognized as contributing factors in many diseases, and their potential as biomarkers and in therapeutics is rapidly emerging. This review highlights recent advances in the exploitation of exosomes in diagnostic and therapeutic applications. We discuss various facets of nanoparticles, namely the isolation and manipulation of exosomes, the construction of synthetic exosome-like particles in vivo, and their potential use in the treatment of various diseases. PMID- 28648188 TI - [The humanistic partnership model in health care]. AB - The humanistic partnership model in health care has been jointly developed by nursing professionals and partner patients. In line with the evolution of our society and nursing thinking, it provides a new implementation of the discipline's core concepts and invites professionals and partner patients to "move together towards" a co-constructed future which is recorded in the patient's life project. PMID- 28648190 TI - [Drug use and addictive practices in France]. AB - In terms of drug use, legal substances, namely tobacco and alcohol, are the most commonly consumed. Cannabis is the most widely consumed illegal substance, followed by cocaine with ten times fewer users, far ahead of other products. This broad overview conceals numerous nuances explored by the French drug and drug addiction watch. PMID- 28648191 TI - [The fight against addictive behaviour in France]. AB - The French inter-ministerial mission for the fight against drugs and addictive behaviour (MILDECA) is responsible for coordinating the campaign against drugs and addictive practices. Thanks to a medical concept of these phenomena which has evolved towards a very broad definition of 'addictive practices', public policies are increasingly orientated towards prevention and health education. Specific structures and tools are available to health professionals to help improve their knowledge and the provision of care in this field. PMID- 28648192 TI - [Contemporary behavioural addictions, an overview and the nursing position]. AB - Behavioural addiction is characterised by thoughts focused on a particular activity and its repetition, with a significant amount of time devoted to this activity at the expense of others. The nurse must adapt to these addicts by treating them as individuals without judging them and by trying to understand how they have tried, through this behaviour, to resolve their issues. The challenge is to reposition the body at the heart of the nursing relationship. PMID- 28648193 TI - [Adolescence and psychoactive substances]. AB - By the age of 17, most young people have tried alcohol, tobacco and cannabis and some of them have already become regular users. While they have partly achieved their objective, clinics for young addicts, created ten years ago and aimed specifically at this section of the population, still struggle to reach out to certain teenagers, notably those with issues relating to alcohol consumption. PMID- 28648194 TI - [Preventing addictive practices in the workplace thanks to occupational health services]. AB - The workplace can be concerned by all types and all levels of addictive practices: consumption of alcohol or psychoactive substances, work addiction, internet addiction and technology addiction. Addictions can be related to multiple factors, both within and outside the workplace. With the employer, responsible for occupational health and safety, the multidisciplinary team of the inter-company occupational health service must today implement a collective and global prevention policy with regard to addictions, in addition to the traditional follow-up. PMID- 28648195 TI - [Addictions in schools, the role of the nurse]. AB - The school nurse, as the health expert, must establish a climate of trust in order to help prevent addictions and implement health education actions. She draws on the experience of the young students with regard to the demands and risks of their daily life. PMID- 28648196 TI - [Support for addictive behaviour among nursing staff]. AB - For the last 10 years the FIDES mission has promoted an addiction prevention policy within the Paris public hospitals group. It raises awareness among all hospital staff, provides the health professionals concerned access to comprehensive training in identifying addictive behaviour, offers support for all difficult situations and carries out studies into substance use practices. PMID- 28648197 TI - [Prevention and understanding of addictive practices in emergency departments]. AB - Nurses must adopt a supportive and caring approach to patients with an addiction during their virtually systematic visit to emergency departments. If they detect symptoms of addiction, nurses can then promote a strategy of prevention and long term treatment. PMID- 28648198 TI - [The nurse in an addiction treatment, support and prevention centre]. AB - The nurse in an addiction treatment, support and prevention centre works within a multidisciplinary team. She is available to listen to the addicts and support them. Thanks to her specific skills and training, she plays a key role in the follow-up. PMID- 28648199 TI - ? PMID- 28648200 TI - [What place does old age hold in our society?] AB - Ageing is often the subject of denial in our societies. In addition to the over medicalisation of elderly people there is also a certain form of exclusion, or even contempt. Elderly people remind us all that life is relative and of our own mortality. What can be done to ensure that old age is considered differently? PMID- 28648201 TI - ? PMID- 28648202 TI - A review on autosomal dominant tubulointerstitial kidney disease. AB - In recent years there has been a reclassification of hereditary tubulointerstitial renal diseases. The old concepts of nephronoptisis or medullary cystic disease have been reordered based on the discovery of new genes. The 2015 KDIGO guidelines proposed a unification of terminology, diagnostic criteria and monitoring. So far 4genes causing autosomal dominant tubulointerstitial kidney disease have been described: MUC1, UMOD, HNF1B and REN. Although the mutation in each of them causes distinctive features in how they present, all have in common the progressive tubulointerstitial damage and renal fibrosis. In this article, we present a review of the guidelines and the literature, and some practical recommendations for dealing with this disease. PMID- 28648203 TI - High levels of both serum gamma-glutamyl transferase and alkaline phosphatase are independent preictors of mortality in patients with stage 4-5 chronic kidney disease. AB - INTRODUCTION: High serum gamma-glutamyl transferase (GGT) levels are associated with increased mortality in the general population. However, this association has scarcely been investigated in patients with chronic kidney disease (CKD). This study aims to investigate the clinical characteristics of CKD patients with abnormally elevated serum GGT, and its value for predicting mortality. MATERIAL AND METHODS: Retrospective observational study in a population cohort of adults with stage 4-5 CKD not yet on dialysis. Demographic, clinical, and biochemical parameters of prognostic interest were recorded and used to characterise CKD patients with high levels of GGT (>36 IU/l). Cox proportional hazard regression models were used to analyse the influence of baseline serum GGT and alkaline phosphatase (ALP) levels on mortality for whatever reason. RESULTS: The study group consisted of 909 patients (mean age 65+/-15 years). Abnormally elevated GGT or ALP levels at baseline were observed in 209 (23%) and 172 (19%) patients, respectively, and concomitant elevations of GGT and ALP in 68 (7%). High GGT levels were associated with higher comorbidity burden, and a biochemical profile characterised by higher serum concentration of uric acid, triglycerides, alanine aminotransferase, ferritin, and C-reactive. During the study period, 365 patients (40%) died (median survival time=74 months). In adjusted Cox regression models, high levels of GGT (hazard ratio [HR]=1.39;CI 95%: 1.09-1.78, P=.009) and ALP (HR=1.31; CI95%: 1.02-1.68, P=.038) were independently associated with mortality. CONCLUSION: High serum levels of GGT are independent predictors of mortality in CKD patients. PMID- 28648204 TI - Long-term prognosis of chronic kidney disease in non-ST elevation acute coronary syndrome treated with invasive strategy. AB - BACKGROUND AND AIM: Patients with chronic kidney disease (CKD) have an increased risk of adverse cardiovascular outcomes after non-ST elevation acute coronary syndrome (NSTEACS). However, the information available on this specific population, is scarce. We evaluate the impact of CKD on long-term prognosis in patients with NSTEACS managed with invasive strategy. METHODS: We conduct a prospective registry of patients with NSTEACS and coronary angiography. CKD was defined as a glomerular filtration rate < 60ml/min/1,73m2. The composite primary end-point was cardiac death and non fatal cardiovascular readmission. We estimated the cumulative probability and hazard rate (HR) of combined primary end point at 3-years according to the presence or absence of CKD. RESULTS: We included 248 p with mean age of 66.9 years, 25% women. CKD was present at baseline in 67 patients (27%). Patients with CKD were older (74.9 vs. 63.9 years; P<.0001) with more prevalence of hypertension (89.6 vs. 66.3%; P<.0001), diabetes (53.7 vs. 35.9%; P=.011), history of heart failure (13.4 vs. 3.9%; P=.006) and anemia (47.8 vs. 16%; P<.0001). No differences in the extent of coronary artery disease. CKD was associated with higher cumulative probability (49.3 vs. 28.2%; log-rank P=.001) and HR of the primary combined end-point (HR: 1.94; CI95%: 1.12 3.27; P=.012). CKD was an independent predictor of adverse cardiovascular outcomes at 3-years (HR: 1.66; CI95%: 1.05-2.61; P=.03). CONCLUSIONS: In NSTEACS patients treated with invasive strategie CKD is associated independently with an increased risk of adverse cardiovascular outcomes at 3years. PMID- 28648205 TI - Cost analysis of integrated renal replacement therapy program in the province of Toledo (2012-2013). AB - BACKGROUND: Renal replacement therapy (RRT) is the object of constant analysis in the search for efficiency and sustainability. OBJECTIVE: To calculate the direct cost of healthcare for the prevalent RRT population in the province of Toledo (2012/2013). METHOD: a) Population: All prevalent patients at some point in RRT in 2012 (669) and in 2013 (682). b) Costs included (?): 1) dialysis procedure; 2) inpatient, outpatient and emergency care, dialysis and non-dialysis related; 3) drug consumption; 4) medical transport. c) Calculation and analysis: The aggregate localized or reconstructed cost of each item was calculated from the individual cost of each patient. Annual cost and cost per patient/year was calculated for the whole RRT and for its subprograms (?). RESULTS: a) Aggregate costs: The total cost of RRT amounted to 15.84 and 15.77 million euros (2012/2013). Dialysis procedures account for 40.2% of the total while the sum of hospital care and drug consumption represents 41.5%. Healthcare for patients on hospital haemodialysis (HHD) and combined haemodialysis (CHD), peritoneal dialysis (PD) and transplant (Tx) accounts for 70.0, 5.0 and 25.0% of the total respectively. b) Patient/year cost: From the number of patients/year provided by each subprogramme, the following values were obtained in 2012/2013: All RRT 26,130/25,379; HHD 49,167/53,289; CHD 44,657/44,971; PD 45,538/51,869 and Tx 10,909/10,984. CONCLUSIONS: Our results are consistent with others published, although our patient/year values are slightly higher, probably because they include elements such as outpatient pharmacy, hospital and medical transport cargo. The growing contribution of Tx to the survival of the whole RRT population contains the overall costs and reduces the patient/year cost, making RRT sustainable. PMID- 28648206 TI - How to assess the efficacy of phosphate binders. AB - BACKGROUND AND AIMS: The efficacy of phosphate binders is difficult to be estimated clinically. This study analyzes the changes in serum phosphate and urinary phosphate excretion after the prescription of phosphate binders (PB) in patients with chronic kidney disease stage 4-5 pre-dialysis, and the usefulness of the ratio between total urinary phosphate and protein catabolic rate (Pu/PCR) for estimating the efficacy of PB. METHODS: This retrospective observational cohort study included adult chronic kidney disease patients. Biochemical parameters were determined baseline and after 45-60 days on a low phosphate diet plus PB ("binder" subgroup=260 patients) or only with dietary advice ("control" subgroup=79 patients). RESULTS: Phosphate load (total urinary excretion) per unit of renal function (Pu/GFR) was the best parameter correlated with serum phosphate levels (R2=0.61). Mean+/-SD level of Pu/PCR was 8.2+/-2.3mg of urinary phosphate per each g of estimated protein intake. After treatment with PB, serum phosphate levels decreased by 11%, urinary phosphate 22%, protein catabolic rate 7%, and Pu/PCR 15%. In the control subgroup, Pu/PCR increased by 20%. Urinary phosphate and urea nitrogen excretion correlated strongly, both baseline and after PB or dietary advice. CONCLUSIONS: The proposed parameter Pu/PCR may reflect the rate of intestinal phosphate absorption, and therefore, its variations after PB prescription may be a useful tool for estimating the pharmacological efficacy of these drugs. PMID- 28648207 TI - Stage progression and need for renal replacement therapy in a renal protection programme in Colombia. A cohort study. AB - BACKGROUND: Due to the global burden represented by chronic kidney disease (CKD), the World Health Organization encouraged the implementation of renal protection programmes (RPP) to affect its incidence through prevention and control measures. OBJECTIVES: To assess the effectiveness of a Colombian RPP in terms of its effect on the stage progression of CKD and the need for renal replacement therapy (RRT). METHODS: An analytical study that monitored 2cohorts of patients diagnosed with CKD. The study compares the behaviour of clinical and renal impairment indicators from patients exposed to a RPP with that of patients following conventional treatment (CT). The population of both intervention groups was considered when determining the sample size. The incidence rate was calculated as well as patient survival (Kaplan Meier). In addition, a multivariate analysis (Cox) was used to calculate the influence that exposure to the RPP had on the outcomes of the patients following the RPP and those following CT. RESULTS: The patients exposed to the RPP took longer to advance to the next CKD stage and require RRT. The incidence rate for progression is higher for the patients following CT (0.050, IC 95%: 0.040-0.064) compared to those in the RPP (0.034, IC 95%: 0.030-0.039). The ratio of incidence rates was 1.480 (IC 95% 1.21-1.90). The hazard of progression was lower for the RPP (HR: 0.855, IC 95%: 0.74- 0.98), as was the hazard of requiring RRT (HR: 0.797, IC 95%: 0.606-1.049). CONCLUSIONS: The RPP is a secondary prevention strategy against CKD which has an effect on the stage progression of CKD and the need for RRT. Early patient detection has a positive effect on the outcomes studied. PMID- 28648208 TI - Diarrhea and malnutrition in kidney transplant recipient: A case of infection by cryptosporidiosis. PMID- 28648209 TI - Cortical necrosis: An uncommon cause of acute renal failure with a very poor outcome. PMID- 28648210 TI - Spontaneous tendon ruptures in chronic renal failure. PMID- 28648211 TI - Prevalence and risk of progression of chronic kidney disease in diabetics and hypertensive patients followed in primary care in Madrid. PMID- 28648212 TI - The use of a quality care program for the management of renal disease in the Aragon region. PMID- 28648213 TI - Pulmonary hemorrhage in a patient with IgA nefropathy. PMID- 28648216 TI - An Interview with Carolyn M. Clancy. PMID- 28648215 TI - Erratum to "Renal graft survival according to Banff 2013 classification in indication biopsies". PMID- 28648214 TI - Hypertensive pulmonary edema related to desmopressin acetate. PMID- 28648218 TI - Innovative Information Technology-Powered Population Health Care Management Improves Outcomes and Reduces Hospital Readmissions and Emergency Department Visits. AB - BACKGROUND: Patients with chronic conditions are often the most frequent users of health care. Moreover, adapting to developments in one's illness, understanding how to self-manage a chronic illness, and sharing information between primary care and specialty providers, can be a full-time job for someone with a chronic illness. In response to these challenges, Christiana Care Health System (Wilmington, Delaware) developed Care Link, an information technology (IT) enhanced care management support to enable populations of patients to achieve better clinical outcomes at lower cost. METHODS: In 2012 Christiana Care received a grant to design a generalizable, scalable, and replicable IT-driven care model that would integrate disparate clinical and registry data generated from routine care to support longitudinal care management for patients with ischemic heart disease. The single-disease care management program was expanded beginning in mid 2015 to serve risk-based models for many diseases and chronic conditions. RESULTS: More than 8,600 patients in several surgical and medical populations, including joint replacement, cervical spine surgery, and congestive heart failure, have been supported by Care Link. For example, preoperative assessment of patients with elective joint replacement to predict post-acute care needs led to an increase in the volume of patients discharged to home with self-care or with home health care by 30%-from 61% to 80%. CONCLUSION: Care Link IT functions can be replicated to address the unique longitudinal care needs of any population. Care Link's next steps are to continue to increase the number of patients served throughout the region and to expand the scope of care management programming. PMID- 28648220 TI - Flying Blind: Don't Manage Warfarin Without a Registry. PMID- 28648219 TI - Primary Care Collaboration to Improve Diagnosis and Screening for Colorectal Cancer. AB - BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death, reducible by screening and early diagnosis, yet many patients fail to receive recommended screening. As part of an academic improvement collaborative, 25 primary care practices worked to improve CRC screening and diagnosis. METHODS: The project featured triannual learning sessions, monthly conference calls, practice coach support, and monthly reporting. The project phases included literature review and interviews with national leaders/organizations, development of driver diagrams to identify key factors and change ideas, project launch and practice team planning, and a practice improvement phase. RESULTS: The project activities included (1) inventory of barriers and best practices, (2) driver diagram to drive improvements, (3) list of changes to try, (4) compilation of lessons learned, and (5) five key changes to optimize screening and follow-up. Practices leveraged prior transformation efforts to track patients for screening and follow-up during and between office visits. By mapping processes, testing changes, and collecting data, sites targeted opportunities to improve quality, safety, efficiency, and patient and care team experience. Successful change interventions centered around partnering with gastroenterology, engaging leadership, leveraging registries and health information technology, promoting alternative screening options, and partnering with and supporting patients. Several practices achieved improvement in screening rates, while others demonstrated no change from baseline during the 10-month testing and implementation phase (July 2014-April 2015). CONCLUSION: The collaborative effectively engaged teams in a broad set of process improvements with key lessons learned related to barriers, information technology challenges, outreach challenges/strategies, and importance of stakeholder and patient engagement. PMID- 28648221 TI - Designing and Implementing an Electronic Patient Registry to Improve Warfarin Monitoring in the Ambulatory Setting. AB - BACKGROUND: Warfarin requires individualized dosing and monitoring in the ambulatory setting for protection against thromboembolic disease. Yet in multiple settings, patients spend upwards of 30% of time outside the therapeutic range, subjecting them to an increased risk of adverse events. At an urban, publicly funded clinic, the electronic health record (EHR) would not support integration with extant warfarin management software, which led to the creation and implementation of an electronic patient registry and a complementary team-based work flow to provide real-time health-system-level data for warfarin patients. METHODS: Creation of the registry, which began in August 2014, entailed use of an existing platform, which could interface with the outpatient EHR. The registry was designed to help ensure regular testing and monitoring of patients while enabling identification of patients and subpopulations with suboptimal management. The work flow used for the clinic's warfarin patients was also redesigned. An assessment indicated that the registry identified 341 (96%) of 357 patients actively seen in the clinic. RESULTS: For the cohort of the 357 patients in the registry, the no-show rate decreased from 31% (preimplementation, August 2014-December 2014) to 21% (postimplementation, January 2015-November 2015). The ratio of visits to no-shows increased from 2.3 to 4.0 visits. CONCLUSION: Design and implementation of an electronic registry in conjunction with a complementary work flow established an active tracking system that improved treatment monitoring for patients on anticoagulation therapy. Registry creation also facilitated assessment of the quality of care and laid the groundwork for ongoing evaluation and quality improvement efforts. PMID- 28648222 TI - Improving Care Teams' Functioning: Recommendations from Team Science. AB - BACKGROUND: Team science has been applied to many sectors including health care. Yet there has been relatively little attention paid to the application of team science to developing and sustaining primary care teams. Application of team science to primary care requires adaptation of core team elements to different types of primary care teams. CORE TEAM ELEMENTS: Six elements of teams are particularly relevant to primary care: practice conditions that support or hinder effective teamwork; team cognition, including shared understanding of team goals, roles, and how members will work together as a team; leadership and coaching, including mutual feedback among members that promotes teamwork and moves the team closer to achieving its goals; cooperation supported by an emotionally safe climate that supports expression and resolution of conflict and builds team trust and cohesion; coordination, including adoption of processes that optimize efficient performance of interdependent activities among team members; and communication, particularly regular, recursive team cycles involving planning, action, and debriefing. These six core elements are adapted to three prototypical primary care teams: teamlets, health coaching, and complex care coordination. CONCLUSION: Implementation of effective team-based models in primary care requires adaptation of core team science elements coupled with relevant, practical training and organizational support, including adequate time to train, plan, and debrief. Training should be based on assessment of needs and tasks and the use of simulations and feedback, and it should extend to live action. Teamlets represent a potential launch point for team development and diffusion of teamwork principles within primary care practices. PMID- 28648223 TI - Clinical Guidelines of the Australasian Sleep Association (ASA). PMID- 28648217 TI - Integrating Research, Quality Improvement, and Medical Education for Better Handoffs and Safer Care: Disseminating, Adapting, and Implementing the I-PASS Program. AB - BACKGROUND: In 2009 the I-PASS Study Group was formed by patient safety, medical education, health services research, and clinical experts from multiple institutions in the United States and Canada. When the I-PASS Handoff Program, which was developed by the I-PASS Study Group, was implemented in nine hospitals, it was associated with a 30% reduction in injuries due to medical errors and significant improvements in handoff processes, without any adverse effects on provider work flow. METHODS: To effectively disseminate and adapt I-PASS for use across specialties and disciplines, a series of federally and privately funded dissemination and implementation projects were carried out following the publication of the initial study. The results of these efforts have informed ongoing initiatives intended to continue adapting and scaling the program. RESULTS: As of this writing, I-PASS Study Group members have directly worked with more than 50 hospitals to facilitate implementation of I-PASS. To further disseminate I-PASS, Study Group members delivered hundreds of academic presentations, including plenaries at scientific meetings, workshops, and institutional Grand Rounds. Some 3,563 individuals, representing more than 500 institutions in the 50 states in the United States, the District of Columbia, Puerto Rico, and 57 other countries, have requested access to I-PASS materials. Most recently, the I-PASSSM Patient Safety Institute has developed a virtual immersion training platform, mobile handoff observational tools, and processes to facilitate further spread of I-PASS. CONCLUSION: Implementation of I-PASS has been associated with substantial improvements in patient safety and can be applied to a variety of disciplines and types of patient handoffs. Widespread implementation of I-PASS has the potential to substantially improve patient safety in the United States and beyond. PMID- 28648224 TI - Guidelines for sleep studies in adults - a position statement of the Australasian Sleep Association. PMID- 28648225 TI - Australasian Sleep Association clinical practice guidelines for performing sleep studies in children. PMID- 28648226 TI - Australasian Sleep Association position statement regarding the use of psychological/behavioral treatments in the management of insomnia in adults. AB - Insomnia disorder is a high prevalence condition with a high disease burden, which, left untreated, can increase risk of poorer health outcomes. Due to Insomnia's tendency towards having a chronic course, long-term treatment approaches are required to reduce the impact of Insomnia over time. After reviewing the available literature, The Australasian Sleep Association (ASA) recommends Cognitive Behavior Therapy for Insomnia (CBT-I) as a first line treatment in the management of Insomnia. The ASA notes that in addition to CBT-I, there is emerging evidence for the use of Mindfulness Based Therapy for Insomnia when used in combination with behavioural techniques (MBT-I). CBT-I should be used whenever possible, and medications should be limited to the lowest necessary dose and shortest necessary duration. CBT-I, whilst the most effective long-term treatment, does not work for everybody across all circumstances, so there will be circumstances in which other treatments are required (e.g., pharmacotherapy). Improving access to CBT-I is an important issue which will involve raising awareness of the effectiveness of CBT-I, increasing the number of trained practitioners, and the development of effective low intensity treatments that can be offered in the first instance. PMID- 28648227 TI - The management, privacy and medico-legal issues of electronic CPAP data in Australia and New Zealand: Electronic CPAP data management in Australia and New Zealand. AB - STUDY OBJECTIVE: Continuous Positive Airway Pressure (CPAP) is considered to be the gold standard treatment for obstructive sleep apnoea (OSA). CPAP monitoring systems allow tracking of patient CPAP adherence and treatment efficacy, by measuring residual sleep-disordered breathing, hours of CPAP use, and mask leak etc. The American Thoracic Society (ATS) published a position paper in 2013 highlighting issues of interpreting CPAP data such as a lack of consistency between CPAP manufacturers data algorithms, legal implications of CPAP data and implications for CPAP adherence. This paper extends on this work by investigating these issues in an Australasian context. METHOD: A review of current literature on CPAP monitoring systems, privacy and security of CPAP data for major Australasian CPAP providers, and CPAP adherence was undertaken. A legal review was also commissioned for issues related to privacy and security of CPAP data. RESULTS: CPAP manufacturers' utilize different algorithms for respiratory event detection and clinicians need to be aware the implications for interpreting CPAP data. Australasian CPAP manufacturers have created security/privacy policies with the intent to follow relevant legislation to protect patients' CPAP data, however they do need to be constantly reviewed and updated to avoid data breaches and changes to agreements. No guarantees can be provided by the Australasian Sleep Association on CPAP manufacturers' compliance with these policies and there is the potential for some degree of liability for physicians and CPAP providers associated with CPAP data. Lastly, providing patients with feedback on their CPAP usage and OSA management appears to have positive influence CPAP adherence. CONCLUSIONS: CPAP data provides many opportunities to increase OSA patient care and to help patients self-manage this chronic condition. However, issues relating to lack of standardization of CPAP parameters, privacy, security, and legal implications will need to be managed in this changing technologic and clinical environment. PMID- 28648228 TI - Great British medalists: Psychosocial biographies of Super-Elite and Elite athletes from Olympic sports. AB - Participants were 32 former GB athletes from Olympic sports, 16 Super-Elite athletes who had won multiple medals at major championships, and 16 matched Elite athletes who had not. In-depth interviews with the athletes, their coaches, and one of their parents explored all psychosocial aspects of their development and careers. Content analyses revealed that there were no differences between Super Elite and Elite athletes with regard to family values, conscientiousness, or commitment to training. However, the two groups were found to be different with regard to: (1) the experience of a foundational negative life event coupled with a foundational positive sport-related event; (2) the experience of a career turning point that enhanced motivation and focus for their sport; (3) need for success; (4) obsessiveness and/or perfectionism with regard to training and performance; (5) ruthlessness and/or selfishness in the pursuit of their sporting goals; (6) dual focus on both mastery and outcome; (7) the use of counterphobic attitudes and/or total preparation to maintain higher levels of performance under pressure; and (8) the relative importance of sport over other aspects of life. The results are discussed within the context of psychodynamic theory, and recommendations are made for both applied implications and future research. PMID- 28648229 TI - On elite and super-elite Great British athletes: Some theoretical implications from findings. AB - We present commentary focused on the theoretical implications of Hardy et al.'s (2017) study of elite (E) and super-elite (SE) UK athletes. Athlete developmental experiences are first discussed, and we consider how Hardy et al.'s findings fit with extant and emerging theory regarding motivation and experiences of adversity. We then focus on athlete characteristics and propose a complementary theory-based interpretation of Hardy et al.'s findings based on the idea that SE athletes may be more focused on agency than E athletes. We consider this proposition in light of theory and empirical research addressing the agency and communion theoretical distinction. PMID- 28648230 TI - The psychosocial development of world-class athletes: Additional considerations for understanding the whole person and salience of adversity. AB - In the target article, Hardy and colleagues provided an incisive analysis of retrospectively reported psychosocial factors associated with the development and careers of 32 former athletes from Olympic sports. They found that Super-Elite athletes ("serial" medal winners at major international championships, i.e., World Championship or Olympic Games) differed from matched Elite performers (won medals at international competitions but not major championships) with regard to several important psychosocial factors (e.g., negative life events, turning point, relative importance of sport). In this commentary, I critique and extend upon these key findings to delineate additional considerations for understanding the whole person (i.e., traits, characteristic adaptations, narrative identity) and salience of adversity (i.e., timing, frequency, and duration) with the goal to stimulate future research and theory on the psychosocial development of Olympic champions. PMID- 28648231 TI - The journey of a thousand miles...: Notes on Hardy et al.'s Great British Medalists Project. AB - The Great British Medalist Project is an exceptional project that is destined to generate much discussion among researchers in psychology, skill acquisition, and expertise. The authors should be congratulated for a project of incredible growth and scope. This brief commentary highlights a range of interesting findings, some novel and some supportive of previous research, but urges caution until their validity, reliability, and generalizability can be determined. Several directions for further research are also briefly discussed. PMID- 28648232 TI - Embedding the psychosocial biographies of Olympic medalists in a (meta )theoretical model of dynamic networks. AB - Based on in-depth interviews, Hardy et al. focused on the role of psychosocial factors in the development of elite and super-elite athletes. They reveal interesting differences and commonalities in the frequencies at which certain aspects related to life events, personality, contextual factors, etc. were reported. Here, we argue that insights in the development of (super-)elite athletes will advance if we go beyond explanations in the frequency-domain, and search for process explanations in the time-domain. This means that we should investigate how athletes develop from one time point to the next, and the next, etc., thereby examining how (psychosocial) factors change and combine across time, as well as how the timing of events can shape an athlete's further developmental trajectory. We therefore present a process-oriented dynamic network model of talent development, assuming that (super-)elite performance develops out of structures of dynamically interacting (psychosocial) factors, which we illustrate using the outcomes of Hardy et al. PMID- 28648233 TI - Assessing risk factors for athletic excellence. AB - Hardy et al. present a qualitative interview study to identify differences between elite and super-elite athletes, but their approach closely parallels the case-control methodology developed and discussed primarily within the epidemiological literature. The strengths and weaknesses of this approach may be less familiar to a psychological or sports-science audience. Here, I comment on this methodological choice and the implications it has for the robustness and value of the inferences that are drawn. I conclude that while Hardy et al. have made valuable progress in dissecting the factors that generate elite athletic performance, their work is best considered as exploratory, and would benefit greatly from confirmation via a prospective cohort approach. PMID- 28648234 TI - In search of the golden skill. AB - Athletes devote their lives to practicing their chosen sport so as to attain the highest level of skilled performance. A perennial question is why are some athletes better than others? Most debates on this issue reduce to genetics (natural abilities) vs differences in accumulated deliberative practice. In contrast, the target article under discussion here reports on a study that identified psychosocial factors (obsessiveness, ruthlessness) and early life experiences (trauma or loss) that distinguished those athletes at the Olympics and World Championships that medaled over those that did not. The interpretation seems to be that other factors and not just skill make true winners. The point will be made here, however, that psychosocial factors might just predict more devotion to practice at the expense of everything else. If this is true then perhaps the most successful athletes really are just the most skilled. PMID- 28648235 TI - Much Ado about...? A response to Hardy et al. AB - Our response to the Great British Medallist (GBM) study focuses on three concerns. First, we discuss the extent to which the findings presented are actually novel and offer practitioners genuine guidance and information about how to structure talent development pathways. Second, we suggest that a lack of critical consideration of the findings against the considerable body of knowledge that already exists in this domain is a significant limitation. Finally, and most pertinently from a practitioner perspective, we highlight our concerns about the extent to which the findings presented may be prematurely adopted by practitioners without a genuinely appropriate evidence base. PMID- 28648236 TI - The stress test: Does what doesn't kill me, make me a super-elite athlete? AB - Super-elite athletes succeed in part because: (a) previous hardship builds resilience, (b) success breeds success, and (c) they can rename anxiety as excitement. It is unlikely that most of their outstanding success is due to psychodynamic compensatory mechanisms. PMID- 28648237 TI - Adversity-related experiences are essential for Olympic success: Additional evidence and considerations. AB - Drawing on Hardy et al.'s study as the target article, in this commentary, we focus on the adversity-related experiences and consequences of the Olympic and/or World champions that they sampled. With this in mind, we divide the narrative into two main sections. In the first section, we explore the association between adversity-related experiences and Olympic success, and provide additional evidence in support of the notion that adversity-related experiences are essential for success at the highest level of sport. In the second section, we discuss the role of adversity-related experiences in Olympic success considering a series of important psychosocial processes that are required for superior performance. In ending, we reflect on the salient (contentious and ethical) issues in the study and practice of adversity-related experiences and sport performance. We hope that our commentary adds to the extant literature and is useful for future study and practice in performance sport. PMID- 28648238 TI - Getting gritty about practice and success: Motivational characteristics of great performers. AB - We consider the data reported in the target article with respect to key motivational frameworks and characteristics, including grit and self-determined forms of motivation. Empirical data are reviewed that highlight the relationships between these concepts and practice and success. We highlight the concept of grit as a defining characteristic of the super-elite athletes, in reference to both their continued perseverance in the face of obstacles, as well as the increased motivation seemingly caused by such obstacles or setbacks. We discuss the dynamic nature of motivation with respect to cross-sectional and longitudinal age-related comparisons in athletes. Such research is necessary to better understand the characteristics that are potentially transitory or that are a consequence of success, rather than being causal in nature. In the final section, we provide evidence consistent with a profile of a super-elite athlete that is best defined with respect to coexisting types of motivations that have traditionally been considered both positive and negative with respect to their outcomes. The between group comparisons of highly successful athletes in the target article, is unusual yet important if we are to better understand the psychosocial profiles necessary to succeed, that are unbiased by age, practice, and competition experience. PMID- 28648239 TI - Great British medalists: A commentary based on a developmental systems theory perspective. AB - In their target article, Hardy and colleagues outline some psychosocial factors that were proposed to underpin the development of serial sporting champions. In this commentary, we suggest that the psychodynamic compensatory mechanisms model described by Hardy et al. is limited by its failure to consider the role of the broader developmental systems in which an individual exists (including funding structure, community, culture, and historical niche). We suggest that any workable talent development model needs to consider the bidirectional relationships between individuals and their contexts, and as such, should be guided by a more dynamic, developmental systems theory approach. PMID- 28648240 TI - Eventual sport performance level: What about the role of type of sport, perception of critical life events, and practice quality? AB - The target article describes an interesting study, which provides some challenging findings regarding athletes' pathway to excellence. The suggested links between critical life events, need for success, personal characteristics, and eventual performance level make sense from a psychodynamic perspective. This commentary will discuss some critical points related to the application of the findings in talent identification and -development programs. These are (1) the possible effect of the selection of participants on the results (including the impact of dependence on others for team sport athletes and the opportunity for multiple medal attainment), (2) a lack of detail in the description of how the athletes approached the critical life events (the perception of an event may contribute more to development than the event itself), and (3) a lack of detail in the description of the practice process throughout development. Some interesting differences were found in the motivation for and approach to practice, but little detail was given about what the athletes exactly were doing at the time. The concept of self-regulated learning may be useful in explaining how super-elite athletes action their goals through quality practice. PMID- 28648241 TI - Is a peaceful mind a winning mind? Comment on. AB - This commentary on Hardy and colleagues' discussion of psychosocial biographies of British super-elite athletes discusses cultural differences from a Chinese perspective. While British super-elite athletes might cope with high pressure by a counter-phobic attitude or total preparation, Chinese super-elite athletes achieve that by "Pingchangxin," a concept originated from Hongzhou Buddhism. This concept is difficult to translate but includes having no evaluation of good and evil, maintaining a peaceful mind in adversity and frustration, letting nature take its course, so as to reach the realm of freedom. While it is necessary to have a fighting spirit to achieve our sporting goals during tough training and competitions, on the other hand, we also need Pingchangxin to deal with high pressure in critical moments, and ups and downs in competitions. This chapter outlines how Chinese athletes and coaches think of ways leading to Pingchangxin and methods used by Chinese sport psychologists to cultivate this mentality; such as psychological education, group discussion, and calligraphy workshops. Finally, this chapter proposes a three-level psychological construction system for Chinese super-elite athletes. PMID- 28648242 TI - Super-elite athletes: Some complimentary observations from Australia and some lessons for sports expertise research: Comment on Hardy et al. AB - This commentary provides an Australian perspective through the lens of former Australian tennis players' reflections of their journey to becoming super/elite tennis players. Their observations are largely supportive of the findings of the target article. Further, the experimental design and terminology used in the target article are contextualized from the perspective of sports expertise research. PMID- 28648243 TI - A culture of striving augments use of working memory? Implications for attention control. AB - : A culture of striving was notable in the developmental background of many of the elite and super elite athletes in the Hardy et al. STUDY: Critically, a culture of striving was credited with a positive influence on a range of issues relevant to elite sports performance, including performance under pressure. Of the six athletes who did not reveal a culture of striving, five reported the greatest difficulty performing in high-pressure situations. We suspect that a culture of striving facilitates the development of attention control ability, which subsequently assists performance under pressure. We discuss attention control from the perspective of working memory and hypothesize that a culture of striving trains individuals to maximize their working memory capacity. PMID- 28648244 TI - The tales athletes tell: Narrative structure and identity in Great British medalists. AB - Using a life story approach, Hardy and colleagues present a study examining the similarities and differences in the psychosocial development of UK-based elite and super-elite athletes. We found this work to be a highly personal account into the lives of these cohorts, which advances knowledge concerning the psychology and influencing events and circumstances that separate the good from the great performers. We make some suggestions for how to enrich the study's findings and approach, by (1) adopting McAdams' multilayer framework of personality, as an overarching structure for assessing the whole person, and (2) encouraging the authors to explore the narrative structure of the presented life stories and go beyond simply an interpretation of their content. PMID- 28648246 TI - Preface. PMID- 28648247 TI - MY APPROACH to the patient with supraventricular tachycardia*. PMID- 28648245 TI - Great British medalists: Response to the commentaries. AB - Hardy et al. (2017) reported the findings of a large-scale, multisource, qualitative study that examined the commonalities of, and discriminators between, a group of super-elite (SE) and a group of elite (E) athletes who were matched on gender, sport, discipline, and era. Fifteen research teams who are actively engaged in research in the domain then provided critical commentaries on the target paper. In our response to these commentaries, we briefly remind the reader of the primary findings of the original paper and then deal with the commentaries under the subheadings: Necessary and Sufficient Conditions for Elite Performance; Mediating and Moderating Variables; Methodological Issues; Omissions; and Alternative Approaches. Finally, we discuss the very small number of disagreements that we have with any of the commentaries. PMID- 28648248 TI - MY APPROACH to frequent ventricular extrasystoles*. PMID- 28648249 TI - Ranaviruses and other members of the family Iridoviridae: Their place in the virosphere. AB - Members of the family Iridoviridae, collectively referred to as iridovirids, are large, double-stranded DNA-containing viruses that infect invertebrates and cold blooded (ectothermic) vertebrates. Infections in the former often lead to massive levels of virus replication resulting in iridescence of the infected animal and ultimately death. Among the latter, infections target a variety of organs and are capable of causing high levels of morbidity and mortality among commercially and ecologically important fish and amphibian species. The viral replication strategy has been elucidated primarily through the study of frog virus 3 (FV3) with additional input from other iridovirids of ecological or commercial importance. Replication occurs within both nuclear and cytoplasmic compartments and involves synthesis of genome length and concatemeric DNA, extensive methylation of the viral genome (among vertebrate viruses only), coordinate expression of three classes of viral gene products, and formation of icosahedral virions within cytoplasmic viral assembly sites. Phylogenetic analyses delineate five genera within the family and suggest that members of the families Iridoviridae, Ascoviridae, and Marseilleviridae compromise a monophyletic lineage in which ascoviruses are most closely related to invertebrate iridoviruses. PMID- 28648250 TI - Re: The accuracy of emergency abdominal CT in adult patients who present with non traumatic abdominal pain: results of a UK national audit. A reply. PMID- 28648251 TI - Immune thrombocytopenia of childhood responsive to tonsillectomy in the setting of chronic tonsillitis: A case report and literature review. AB - OBJECTIVES: Immune thrombocytopenia of childhood (platelet count <100,000/MUL) is the most common cause of thrombocytopenia in children. Patients typically present with bruising and bleeding in the setting of thrombocytopenia. Although it is usually short-lived, some cases persist and are unresponsive to treatment. This can lead to exposure to a variety of treatment regimens including immunosuppressants and splenectomy. The goal of this report is to present a case of chronic ITP of childhood that responded to tonsillectomy addressing the tonsils as a source of chronic infection and inflammation triggering ITP. METHODS: A 4-year-old male with ITP of childhood presented with enlarged tonsils and obstructive sleep apnea. History and physical were consistent with chronic tonsillitis/adenoiditis including malaise, poor oral intake, congestion, rhinorrhea, tonsil hypertrophy, and lymphadenopathy persisting despite antibiotic therapy. Tonsillectomy and adenoidectomy were performed. RESULTS: One, six, and eighteen weeks post-operatively the platelet count was 371, 215, and 205 respectively. Although at 12months two relapses had occurred, during the observed period, he had decreased incidence and severity of disease. CONCLUSION: In around 60% of ITP there is a history of prior infection within the last month but no systemic symptoms at time of diagnosis. Additionally, chronic ITP is characterized by relapses coinciding with infection. This case is unique because the patient had chronic ITP and a clinical history and physical exam concerning for a subclinical, indolent inflammatory process that responded to surgical intervention. Given that chronic ITP exacerbation has been associated with recurrent acute infections it seems probable that chronic tonsillitis could serve as a trigger for relapse or contribute to a prolonged and/or more severe disease course. Therefore, tonsillectomy may result in earlier treatment and/or an altered disease course with avoidance of the expense and morbidity associated with frequent exacerbations and multiple treatment regimens. PMID- 28648252 TI - Active Fault Tolerant Control Based on Interval Type-2 Fuzzy Sliding Mode Controller and Non Linear Adaptive Observer for 3-DOF Laboratory Helicopter. PMID- 28648253 TI - Statistical validation of 1H NMR protocol vs standard biochemical assay in quality control of RBC packed units. AB - BACKGROUND: Time dependent quantification of endogenous metabolites in biological samples (blood, urine, biological tissues extracts) in normal and pathological conditions as well as following therapeutic protocols is well established. In the clinical practice, such a dynamic flux of information allows the physician to identify and appreciate alterations associated to biochemical pathways of specific organs. In the years, many biochemical assays have been developed to detect, selectively, this vast array of molecules. METHODS: The Proton Nuclear Magnetic Resonance (1H NMR) spectrum allows the identification and quantification of more than 30 RBC-associated metabolites with minimum manipulation of the sample. To validate the use of 1H NMR spectroscopy for quality control purposes in transfusion medicine, a series of statistical tools have been employed to analyse and compare accuracy and precision of the 1H NMR results with respect to the ones obtained by standard biochemical assays. RESULTS: Among the many metabolites that can be detected and quantified by 1H NMR spectroscopy we selected creatinine and lactate, since they are routinely quantified by standard biochemical assays and because they are characterized by a wide concentration dynamic range. We show that 1D 1H NMR spectroscopy is an accurate a precise method for metabolite quantification. CONCLUSION: These results validate the use of 1H NMR spectroscopy in transfusion medicine as a method to evaluate the quality of RBC packed units and to develop novel and more efficient RBCs storage protocols. PMID- 28648254 TI - The theft of well-being: a comment on Zunzunegui et al. PMID- 28648255 TI - Assessing gender stereotypes and sexual risk practices in men who have sex with men. AB - OBJECTIVE: To analyze the construct validity and the internal consistency of the 12-item Bem Sex Role Inventory (BSRI-12) questionnaire and to study the association between gender stereotypes and sexual risk practices in men who have sex with men (MSM). METHODS: Cross-sectional study of 601 MSM who voluntarily and anonymously responded to an online survey on risk practices and gender stereotypes. The BSRI-12 was used to obtain gender stereotypes (masculine, feminine, undifferentiated and androgynous). For data analysis, exploratory factor analysis (EFA) of the BSRI-12 and logistic regression were performed. RESULTS: Two main factors (Cronbach alpha 0.95 and 0.81) were obtained from the EFA. Using the androgynous roles as the reference category, we found lower odds of engaging in unprotected anal intercourse (UAI) among those who endorse feminine roles (OR: 0.53; 95%CI: 0.29-0.95). Endorsing masculine roles with alcohol consumption (OR: 1.92; 95%CI: 1.15-3.20) or the undifferentiated when not knowing the partner's serological status (OR: 1.55; 95%CI: 1.02-2.35) were associated with higher odds of UAI compared to those endorsing the androgynous roles. Undifferentiated participants also perform receptive UAI using poppers (OR: 2.19; 95%CI: 1.24-3.87), and insertive UAI not knowing the serological status of the sexual partner (OR: 1.69; 95%CI: 1.04-2.76) compared to androgynous participants. CONCLUSION: The BSRI is a valid and consistent instrument for identifying gender stereotypes in MSM. A greater proportion of participants within the undifferentiated and the masculine category engage in risk practices with the influence of substance consumption and unawareness of their sexual partner's serological status. The information obtained may be useful to define intervention and prevention programs. PMID- 28648256 TI - A comparative analysis of pretreatment strategies on the properties and hydrolysis of brewers' spent grain. AB - In this study, brewer's spent grain (BSG) was subjected to a range pretreatments to study the effect on reducing sugar yield. Glucose and xylose were found to be the predominant sugars in BSG. Brewers spent grain was high in cellulose (19.21g/100g of BSG) and lignin content (30.84g/100g of BSG). Microwave assisted alkali (MAA) pretreatment was found to be the most effective pretreatment for BSG, where the pretreatment was conducted at 400W for 60s. A maximum reducing yield was observed with high biomass loading (1g/10ml), cellulase (158.76MUl/10ml), hemicellulase (153.3MUl/10ml), pH (5.4) and an incubation time (120h). Upon enzymatic hydrolysis, MAA pretreated BSG yielded 228.25mg of reducing sugar/g of BSG which was 2.86-fold higher compared to native BSG (79.67mg/g of BSG); simultaneously BSG was de-lignified significantly. The changes in functional groups, crystallinity and thermal behaviour was studies by means of FTIR, XRD and DSC, respectively. PMID- 28648257 TI - A capillary micellar electrokinetic chromatography method for the stereoselective quantitation of bioallethrin in biotic and abiotic samples. AB - A capillary micellar electrokinetic chromatography (MEKC) method was developed enabling the stereoselective separation of the insecticide bioallethrin. The use of sodium deoxycholate bile salt and acetyl-beta-cyclodextrin (acetyl-beta-CD) made possible the separation of bioallethrin stereoisomers with a high enantioresolution (7.4) in a short analysis time (6.5min). The analytical characteristics of the developed method were evaluated in terms of linearity, accuracy, precision, and limits of detection (LOD) and quantitation (LOQ) showing a good performance for the quantitation of bioallethrin stereoisomers with LODs of 0.2 and 0.3mg/L. The developed method was applied to the stereoselective analysis of a commercial bioallethrin pediculicide formulation and to evaluate the toxicity of bioallethrin stereoisomers on the growth of the unicellular freshwater green alga Pseudokirchneriella subcapitata and on the germination of the higher plant Sorghum bicolor (non-target organisms). The analysis of the commercial pediculicide showed a good agreement between the contents determined for the two stereoisomers and those labelled in the commercial samples. Different toxic responses and biodegradation profiles were found for each stereoisomer in ecotoxicity assays. The mixture of S/R stereoisomers of bioallethrin resulted more toxic than S-bioallethrin for green algae, with EC50 values of 1.10+/-0.06 for the mixture and of 1.73+/-0.05mg/L for the pure S-biallethrin (esbiol). Germination of plants seeds was also affected. PMID- 28648258 TI - Quantitative on-line analysis of sulfur compounds in complex hydrocarbon matrices. AB - An improved method for on-line measurement of sulfur containing compounds in complex matrices is presented. The on-line system consists of a specifically designed sampling system connected to a comprehensive two-dimensional gas chromatograph (GC*GC) equipped with two capillary columns (Rtx(r)-1 PONA*SGE BPX50), a flame ionization detector (FID) and a sulfur chemiluminescence detector (SCD). The result is an unprecedented sensitivity down to ppm level (1 ppm-w) for various sulfur containing compounds in very complex hydrocarbon matrices. In addition to the GC*GC-SCD, the low molecular weight sulfur containing compounds such as hydrogen sulfide (H2S) and carbonyl sulfide (COS) can be analyzed using a thermal conductivity detector of a so-called refinery gas analyzer (RGA). The methodology was extensively tested on a continuous flow pilot plant for steam cracking, in which quantification of sulfur containing compounds in the reactor effluent was carried out using 3-chlorothiophene as internal standard. The GC*GC FID/-SCD settings were optimized for ppm analysis of sulfur compounds in olefin rich (ethylene- and propylene-rich) hydrocarbon matrices produced by steam cracking of petroleum feedstocks. Besides that is primarily used for analysis of the hydrocarbon matrix, FID of the GC*GC-FID/-SCD set-up serves to double check the amount of added sulfur internal standard which is crucial for a proper quantification of sulfur compounds. When vacuum gas oil containing 780 ppm-w of elemental sulfur in the form of benzothiophenes and dibenzothiophenes is subjected to steam cracking, the sulfur balance was closed, with 75% of the sulfur contained in the feed is converted to hydrogen sulfide, 13% to alkyl homologues of thiophene while the remaining 12% is present in the form of alkyl homologues of benzothiophenes. The methodology can be applied for many other conversion processes which use sulfur containing feeds such as hydrocracking, catalytic cracking, kerogen evolution, bio-waste pyrolysis, supercritical water treatment, etc. PMID- 28648259 TI - Semisynthesis and spectral characterization of 5-methylpyranopelargonidin and 4 methylfuropelargonidin and their separation and detection in strawberry fruit wine. AB - Condensation of anthocyanins and their aglycons with small organic molecules yields more stable natural dyes, e.g. pyranoanthocyanins arising spontaneously in various food products. Reaction of pelargonidin with acetone produces two isomeric anthocyanidin dyes - 5-methylpyranopelargonidin and 4 methylfuropelargonidin. A robust semipreparative liquid chromatographic method was developed to isolate both derivatives from a simple aged solution of pelargonidin in methanol: acetone: 37% aqueous hydrochloric acid (1:1:0.008, v/v/v). Detailed interpretation of mass and nuclear magnetic resonance spectra allowed to assign structures of both dyes in isolated fractions. A fast UHPLC-MS method was optimized for the control of their production in the reaction mixture. Use of reversed stationary phase and acidic mobile phases in gradient mode allowed separation of both isomers in less than one minute. Fragmentation of both dyes after collision activated dissociation in collision cell was studied comprehensively and the observed processes were compared with data from quantum calculations (computational chemistry utilizing DFT methods). When comparing both isomers, retro-Diels-Alder fragmentation appears preferred in furo-derivative, while small losses (i.e. methane and water molecules) were more pronounced in pyrano-derivative. Both studied isomeric dyes were found in laboratory prepared strawberry fruit wine and their content was compared with major present anthocyanins and their derivatives. PMID- 28648261 TI - Drug Safety, Climate Change, Causality, and Predictability. PMID- 28648260 TI - Broadening the Perspective on Gun Violence: An Examination of the Firearms Industry, 1990-2015. AB - INTRODUCTION: Firearm violence injures or kills 100,000 Americans each year. This paper applies the Host-Agent-Vector-Environment model to this issue. Research on firearm violence tends to focus on two elements-the host (i.e., victims of firearm violence) and the environment (i.e., gun policies)-but little attention has been paid to the agent (the gun and ammunition) or the vector (firearm manufacturers, dealers, and the industry lobby). METHODS: Using Bureau of Alcohol, Tobacco, Firearms and Explosives data, trends in firearm manufacturing were investigated from 1990 to 2015. Outcome measures included: (1) trends in domestic gun manufacturing by weapon type; (2) trends in production by firearm caliber; and (3) 2015 market share by type of firearm and company. Data were collected and analyzed in 2016. RESULTS: Overall domestic firearms production decreased slightly from 1996 through 2004, and then steadily increased from 1.7% in 2005 to 13.8% in 2013, when >10 million firearms were produced for the domestic market. The increase in total firearm production was driven by the increased production of pistols and rifles. Within the pistol category, increased production was attributable to an increase in higher caliber weapons. Similar trends were observed in gun purchases and recovered and traced crime guns. CONCLUSIONS: Trends in firearm manufacturing reveal a shift toward more-lethal weapons, and this trend is also observed in gun purchases and crime gun traces. This may reflect a societal shift in cultural practices and norms related to guns and could inform strategies to reduce firearm violence. PMID- 28648262 TI - Placebos and Clinical Therapeutics. PMID- 28648263 TI - USDA's Food, Nutrition and Consumer Services Helps Bring Regional and Local Foods to Consumers. PMID- 28648264 TI - Position of the Academy of Nutrition and Dietetics: Interprofessional Education in Nutrition as an Essential Component of Medical Education. AB - It is the position of the Academy of Nutrition and Dietetics that registered dietitian nutritionists (RDNs) should play a significant role in educating medical students, residents, fellows, and physicians in practice. The more physicians learn about the effectiveness of nutrition for the prevention and treatment of noncommunicable diseases, the more likely they are to consult with RDNs and refer patients for medical nutrition therapy. The more interprofessional education that occurs between medical students, other health professional students, and RDNs, the more likely all health care professionals will understand and value the role of the RDN in improving the quality of care provided to patients. The training and experience of RDNs make them uniquely qualified for the role of educating medical students about nutrition as it relates to health and disease. This position paper provides RDNs with the tools and language to emphasize to medical educators, course directors, curriculum committees, medical school deans, residency and fellowship directors, physicians, and other health professionals in training and practice how ongoing nutrition counseling and management, conducted by an RDN, can benefit their patients. Specific teaching settings and examples for RDNs to take a leadership role (paid and unpaid positions) in ensuring that future physicians discuss nutrition, healthy lifestyle, and physical activity with their patients, consult with RDNs, and refer patients for medical nutrition therapy are presented. This position paper supports interprofessional education in nutrition as an essential component of medical education. PMID- 28648265 TI - Should Albumin and Prealbumin Be Used as Indicators for Malnutrition? PMID- 28648266 TI - Serving Those Who Protect Our Nation. PMID- 28648267 TI - Ecological Insights into the Dynamics of Plant Biomass-Degrading Microbial Consortia. AB - Plant biomass (PB) is an important resource for biofuel production. However, the frequent lack of efficiency of PB saccharification is still an industrial bottleneck. The use of enzyme cocktails produced from PB-degrading microbial consortia (PB-dmc) is a promising approach to optimize this process. Nevertheless, the proper use and manipulation of PB-dmc depends on a sound understanding of the ecological processes and mechanisms that exist in these communities. This Opinion article provides an overview of arguments as to how spatiotemporal nutritional fluxes influence the successional dynamics and ecological interactions (synergism versus competition) between populations in PB dmc. The themes of niche occupancy, 'sugar cheaters', minimal effective consortium, and the Black Queen Hypothesis are raised as key subjects that foster our appraisal of such systems. Here we provide a conceptual framework that describes the critical topics underpinning the ecological basis of PB-dmc, giving a solid foundation upon which further prospective experimentation can be developed. PMID- 28648268 TI - Do not lose sight-non-JIA related uveitis. PMID- 28648269 TI - Genetic predisposition to acute recurrent and chronic pancreatitis-more evidence for a role in children. PMID- 28648270 TI - 50 Years Ago in The Journal of Pediatrics: Shigellae with Transferable Drug Resistance: Outbreak in a Nursery for Premature Infants. PMID- 28648271 TI - 50 Years Ago in The Journal of Pediatrics: Primary Atypical Pneumonia: An Epidemic Caused by Mycoplasma pneumoniae. PMID- 28648272 TI - Defining outcomes. PMID- 28648273 TI - No excuse for prescribing combination antifungal/corticosteroid creams. PMID- 28648274 TI - Tight glycemic control may be harmful in hyperglycemic, critically ill children. PMID- 28648275 TI - Vitamin D reduces respiratory tract infections frequency. PMID- 28648276 TI - Amitriptyline and topiramate do not demonstrate benefit in pediatric migraine. PMID- 28648277 TI - Screen time associated with adolescent obesity and obesity risk factors. PMID- 28648278 TI - Tonsillectomy for short-term benefit in obstructive sleep-disordered breathing. PMID- 28648279 TI - Do it yourself. PMID- 28648280 TI - Is more oxygen better for our smallest babies, or maybe just our smallest babies? PMID- 28648281 TI - 50 Years Ago in The Journal of Pediatrics: The Radiographic Diagnosis of Congenital Hypertrophic Pyloric Stenosis. PMID- 28648282 TI - 50 Years Ago in The Journal of Pediatrics: Developmental Changes in Overflow in Normal and Aberrantly Functioning Children. PMID- 28648283 TI - 50 Years Ago in The Journal of Pediatrics: An Assessment of the Creatine Kinase Test in the Detection of Carriers of Duchenne Muscular Dystrophy. PMID- 28648285 TI - Simultaneous learning of two languages from birth positively impacts intrinsic functional connectivity and cognitive control. AB - This study explores the effect of individual differences in the age of acquisition of a second language using resting-state functional magnetic resonance imaging (rs-fMRI) to examine functional connectivity and its relation with cognitive control within bilinguals. We compared simultaneous bilinguals, who learned two languages from birth, to sequential bilinguals, who learned a second language following mastery of their first language. Results show an effect of language experience on the strength of anticorrelation between the default mode network and the task-positive attention network and on cognitive control, with simultaneous bilinguals demonstrating stronger anticorrelations between the two networks, as well as superior cognitive control compared to sequential bilinguals. These findings demonstrate that the timing of language learning may have an impact on cognitive control, with the simultaneous learning of two languages being associated with more optimal brain connectivity for cognitive control compared to sequential language learning. PMID- 28648286 TI - Yeast diversity during the fermentation of Andean chicha: A comparison of high throughput sequencing and culture-dependent approaches. AB - Diversity and dynamics of yeasts associated with the fermentation of Argentinian maize-based beverage chicha was investigated. Samples taken at different stages from two chicha productions were analyzed by culture-dependent and culture independent methods. Five hundred and ninety six yeasts were isolated by classical microbiological methods and 16 species identified by RFLPs and sequencing of D1/D2 26S rRNA gene. Genetic typing of isolates from the dominant species, Saccharomyces cerevisiae, by PCR of delta elements revealed up to 42 different patterns. High-throughput sequencing (HTS) of D1/D2 26S rRNA gene amplicons from chicha samples detected more than one hundred yeast species and almost fifty filamentous fungi taxa. Analysis of the data revealed that yeasts dominated the fermentation, although, a significant percentage of filamentous fungi appeared in the first step of the process. Statistical analysis of results showed that very few taxa were represented by more than 1% of the reads per sample at any step of the process. S. cerevisiae represented more than 90% of the reads in the fermentative samples. Other yeast species dominated the pre fermentative steps and abounded in fermented samples when S. cerevisiae was in percentages below 90%. Most yeasts species detected by pyrosequencing were not recovered by cultivation. In contrast, the cultivation-based methodology detected very few yeast taxa, and most of them corresponded with very few reads in the pyrosequencing analysis. PMID- 28648287 TI - Biodiversity and ochratoxin A profile of Aspergillus section Nigri populations isolated from wine grapes in Cyprus vineyards. AB - The objective of this study was to evaluate the biodiversity of Aspergillus section Nigri populations from Cyprus vineyards by morphological, toxigenic and phylogenetic analysis. Aspergillus section Nigri populations were isolated from grapes of the varieties 'Maratheftiko' and 'Cabernet Sauvignon' originating from six growing regions of Cyprus during 2010 and 2011 years. The isolation frequency of Aspergillus section Nigri from grape samples was 43.3% and a total of 284 isolates were selected for further analyses based on the macroscopic characteristics of black aspergilli. The isolates were characterized by sequencing analysis of the calmodulin gene in order to identify species responsible for ochratoxin A (OTA) production. The phylogenetic analysis showed that the isolates were grouped in three major clusters. The A. tubingensis cluster included 262 isolates (92.25%), the A. niger cluster included 15 isolates identified as A. niger (5.3%) and 6 isolates identified as A. welwitschiae (2.1%). One isolate was classified as A. carbonarius (0.35%) and was grouped in a cluster together with the reference isolates of A. carbonarius, A. sclerotioniger, A. sclerotiocarbonarius and A. ibericus. All the isolates were evaluated for their ochratoxigenic ability by HPLC coupled with a fluorescence detector (HPLC-FLD) and the positive isolates were re-examined using ultra high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). The Aspergillus carbonarius isolate produced an average quantity of 1436.1 ng OTA/g Czapek Yeast Agar (CYA); From the A. niger strains three isolates (20%) produced OTA and only one isolate from A. welwitschiae (16.7%) was proved ochratoxigenic with toxin production average at 23.9 ng/g and 9.1 ng/g CYA respectively. Grape must samples derived from the collected berries were also analyzed for OTA and none of the samples were found contaminated with the mycotoxin. The results showed that the geographic area and the meteorological conditions had no significant effect on the incidence and the distribution of black aspergilli in this 2-year project. However, absence of rainfall and low humidity during the harvesting period were critical for the low incidence of the ochratoxigenic A. carbonarius on grapes. PMID- 28648284 TI - Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integration of genomics, transcriptomics, and metabolomics. While ICC and HCC share recurrently mutated genes, including TP53, ARID1A, and ARID2, mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2, whereas the C2 subtype is linked to obesity, T cell infiltration, and bile acid metabolism. These molecular subtypes are found in 582 Asian, but less so in 265 Caucasian patients. Thus, Asian ICC and HCC, while clinically treated as separate entities, share common molecular subtypes with similar actionable drivers to improve precision therapy. PMID- 28648288 TI - Characterization of Bacillus megaterium, Bacillus pumilus, and Paenibacillus polymyxa isolated from a Pinot noir wine from Western Washington State. AB - This report provides the first confirmed evidence of Bacillus-like bacteria present in a wine from Washington State. These bacteria were isolated from a 2013 Pinot noir wine whose aroma was sensorially described as being 'dirty' or 'pond scum.' Based on physiological traits and genetic sequencing, three bacterial isolates were identified as Bacillus megaterium (strain NHO-1), Bacillus pumilus (strain NHO-2), and Paenibacillus polymyxa (strain NHO-3). These bacteria grew in synthetic media of low pH (pH 3.5) while some survived ethanol concentrations up to 15% v/v. However, none tolerated molecular SO2 concentrations >=0.4 mg/l. Growth of strains NHO-1 and NHO-3 in a Merlot grape juice resulted in increases of titratable and volatile acidities while decreases in titratable acidity were noted for NHO-2. PMID- 28648289 TI - Enteric bacteria of food ice and their survival in alcoholic beverages and soft drinks. AB - This study aimed to evaluate the levels of enteric bacteria in ice cubes produced in different environments (home-made, prepared in bars and pubs with ice machines and produced in industrial plants) and to determine their survival in different alcoholic beverages and soft drinks. Members of the Enterobacteriaceae family were found in almost all samples analysed. All industrial and the majority of home-made samples did not contain coliforms. Enterococci were not identified in domestic samples while they were detected in two industrial and three bar/pub samples. The samples collected from bars and pubs were characterized by the highest levels of enteric bacteria. Fourteen strains representing 11 species of eight bacterial genera were identified, some of which are known agents of human infections. The most numerous groups included Enterococcus and Stenotrophomonas. The survival of Enterococcus faecium ICE41, Pantoea conspicua ICE80 and Stenotrophomonas maltophilia ICE272, that were detected at the highest levels (100-400 CFU/100 mL thawed ice) in the ice cubes, was tested in six drinks and beverages characterized by different levels of alcohol, CO2, pH and the presence of antibacterial ingredients. The results showed a species-specific behaviour and, in general, a reduction of the microbiological risks associated with ice after its transfer to alcoholic or carbonated beverages. PMID- 28648290 TI - Milk-originated Bacillus cereus sensu lato strains harbouring Bacillus anthracis like plasmids are genetically and phenotypically diverse. AB - Bacillus cereus sensu lato is widely distributed in food products, including raw and processed milk. Plasmids often determine bacterial virulence and toxicity, but their role in the evolution of B. cereus sensu lato is only partly known. Here, we observed that nearly 8% of B. cereus sensu lato isolates were positive for pXO1-like plasmids and 12% for pXO2-like plasmids in raw and ultra-heat treated (UHT) milk from one dairy plant. However, pXO1-like plasmids were significantly more frequent in raw milk, while pXO2-like plasmids were more frequent in processed milk. Strains from raw and UHT milk were enterotoxigenic, with up to one-fifth of the isolates being psychrotolerant. Phylogenetic assessment using multi-locus sequence typing revealed a polyphyletic structure for these bacilli, with distinct groups of cold-adapted isolates and pathogenic strains (including emetic B. cereus). Populations corresponding to both sampling sites exhibited significant linkage disequilibrium and the presence of purifying selection. The far-from-clonal population structure indicated the presence of sequence types or ecotypes adapted to specific conditions in the dairy industry. A high recombination-to-mutation ratio suggested an important role for horizontal gene transfer among B. cereus sensu lato isolates in milk. PMID- 28648291 TI - Gene expression as a good indicator of aflatoxin contamination in dry-cured ham. AB - Aspergillus flavus and Aspergillus parasiticus are mould species producers of aflatoxins (AFs) and may grow on dry-cured ham during the ripening process. In this study, the influence of different water activity (aw) and temperatures on the temporal relative expression of three genes involved in AFs biosynthesis and their relationship with AFs production on dry-cured ham-based medium were evaluated. In general, the regulatory aflR and aflS genes showed similar expression patterns, and the expression of the structural aflP gene was much higher than that obtained for aflR and aflS genes. Regarding A. flavus, a decrease of aw regardless of temperature caused an increase of the expression of the regulatory aflR and aflS genes. Concerning A. parasiticus, the highest and lowest expression values of the regulatory aflR and aflS genes were found at 0.95 aw and 0.85 aw, respectively. The expression of the structural aflP gene of both species was stimulated at low temperature and aw. The PCA analysis indicated that both toxigenic species showed a strong correlation between the relative expression of the aflR and aflS genes and the concentration of AFs under conditions which simulate dry-cured ham ripening. This suggests that an early detection of the expression of regulatory genes can be a good indicator of possible AFs contamination of dry-cured ham through ripening. PMID- 28648292 TI - Fusarium proliferatum - Causal agent of garlic bulb rot in Spain: Genetic variability and mycotoxin production. AB - Fusarium proliferatum is a world-wide occurring fungal pathogen affecting several crops included garlic bulbs. In Spain, this is the most frequent pathogenic fungus associated with garlic rot during storage. Moreover, F. proliferatum is an important mycotoxigenic species, producing a broad range of toxins, which may pose a risk for food safety. The aim of this study is to assess the intraspecific variability of the garlic pathogen in Spain implied by analyses of translation elongation factor (tef-1alpha) and FUM1 gene sequences as well as the differences in growth rates. Phylogenetic characterization has been complemented with the characterization of mating type alleles as well as the species potential as a toxin producer. Phylogenetic trees based on the sequence of the translation elongation factor and FUM1 genes from seventy nine isolates from garlic revealed a considerable intraspecific variability as well as high level of diversity in growth speed. Based on the MAT alleles amplified by PCR, F. proliferatum isolates were separated into different groups on both trees. All isolates collected from garlic in Spain proved to be fumonisin B1, B2, and B3 producers. Quantitative analyses of fumonisins, beauvericin and moniliformin (common secondary metabolites of F. proliferatum) showed no correlation with phylogenetic analysis neither mycelial growth. This pathogen presents a high intraspecific variability within the same geographical region and host, which is necessary to be considered in the management of the disease. PMID- 28648293 TI - Light based technologies for microbial inactivation of liquids, bead surfaces and powdered infant formula. AB - This study evaluates the potential of continuous wave Ultraviolet C light (UV-C) and broad-spectrum intense pulsed light (in this study referred to as High Intensity Light Pulses, HILP) for the inactivation of pathogens of public concern in powdered infant formula (PIF) producers. To achieve this goal a sequential set of experiments were performed, firstly in clear liquid media, secondly on the surface of spherical beads under agitation and, finally in PIF. L. innocua was the most sensitive microorganism to both technologies under all conditions studied with reductions exceeding 4 log10 cycles in PIF. In the clear liquid medium, the maximum tolerance to light was observed for C. sakazakii against UV-C light and for B. subtilis spores against HILP, with a fluence of approximately 17 mJ/cm2 required for a 1 log10 cycle inactivation (D value) of each species. In PIF it was possible to inactivate >99% of the vegetative cell populations by HILP with a fluence of 199 mJ/cm2 and of B. subtilis spores by doubling the fluence. By contrast, for UV-C treatments a fluence of 2853 mJ/cm2 was needed for 99.9% reduction of C. sakazakii, which was the most light-resistant microorganism to UV C. Results here obtained clearly show the potential for light-based interventions to improve PIF microbiological safety. PMID- 28648294 TI - Tolerance development in Listeria monocytogenes-Escherichia coli dual-species biofilms after sublethal exposures to pronase-benzalkonium chloride combined treatments. AB - This study was designed to assess the effects that sublethal exposures to pronase (PRN) and benzalkonium chloride (BAC) combined treatments have on Listeria monocytogenes-Escherichia coli dual-species biofilms grown on stainless steel in terms of tolerance development (TD) to these compounds. Additionally, fluorescence microscopy was used to observe the changes of the biofilm structure. PRN-BAC exposure was carried out using three different approaches and TD was evaluated treating biofilms with a final 100 MUg/ml PRN followed by 50 MUg/ml BAC combined treatment. Results showed that exposure to PRN-BAC significantly decreased the number of adhered L. monocytogenes (P < 0.05), while E. coli counts remained generally unaltered. It was also demonstrated that the incorporation of recovery periods during sublethal exposures increased the tolerance of both species of the mixed biofilm to the final PRN-BAC treatment. Moreover, control biofilms became more resistant to PRN-BAC if longer incubation periods were used. Regardless of the treatment used, log reduction values were generally lower in L. monocytogenes compared to E. coli. Additionally, microscopy images showed an altered morphology produced by sublethal PRN-BAC in exposed L. monocytogenes-E. coli dual-species biofilms compared to control samples. Results also demonstrated that L. monocytogenes-E. coli dual-species biofilms are able to develop tolerance to PRN-BAC combined treatments depending on way they have been previously exposed. Moreover, they suggest that the generation of bacterial tolerance should be included as a parameter for sanitation procedures design. PMID- 28648295 TI - Detection and prevalence of protozoan parasites in ready-to-eat packaged salads on sale in Italy. AB - To investigate the prevalence of protozoan contamination by Giardia duodenalis, Cryptosporidium spp., Toxoplasma gondii and Cyclospora cayetanensis, in 'ready to eat' (RTE) salads on sale in Italy, 648 packages were purchased from industrial and local brands. Nine individual packages from each brand were collected per month, pooled and subjected to microscopy and molecular analyses. Microscopic examination of 864 slides detected Cryptosporidium spp. but also Blastocystis hominis and Dientamoeba fragilis. Molecular tools identified G. duodenalis assemblage A, Cryptosporidium parvum and Cryptosporidium ubiquitum, T. gondii Type I and C. cayetanensis. B. hominis and D. fragilis were also molecularly confirmed. The overall prevalence of each protozoan species was 0.6% for G. duodenalis, 0.8% for T. gondii, 0.9% for Cryptosporidium spp., and 1.3% for C. cayetanensis, while prevalence for B. hominis was 0.5% and for D. fragilis 0.2%. Microscopy and/or molecular tools revealed that 4.2% of the samples were contaminated by at least one protozoan species, and 0.6% of samples presented contamination by two protozoan species, with a number of oocysts ranging from 62 to 554 per g of vegetable matter for T. gondii, and 46 to 1.580 for C. cayetanensis. This is Europe's first large-scale study on the presence of protozoans in packaged salads, and shows that RTE sanitation processes do not guarantee a product free from protozoans of fecal origin. PMID- 28648296 TI - Effect of storage temperature on the lag time of Geobacillus stearothermophilus individual spores. AB - The lag times (lambda) of Geobacillus stearothermophilus single spores were studied at different storage temperatures ranging from 45 to 59 degrees C using the Bioscreen C method. A significant variability of lambda was observed among individual spores at all temperatures tested. The storage temperature affected both the position and the spread of the lambda distributions. The minimum mean value of lambda (i.e. 10.87 h) was observed at 55 degrees C, while moving away from this temperature resulted in an increase for both the mean and standard deviation of lambda. A Cardinal Model with Inflection (CMI) was fitted to the reverse mean lambda, and the estimated values for the cardinal parameters Tmin, Tmax, Topt and the optimum mean lambda of G. stearothermophilus were found to be 38.1, 64.2, 53.6 degrees C and 10.3 h, respectively. To interpret the observations, a probabilistic growth model for G. stearothermophilus individual spores, taking into account lambda variability, was developed. The model describes the growth of a population, initially consisting of N0 spores, over time as the sum of cells in each of the N0 imminent subpopulations originating from a single spore. Growth simulations for different initial contamination levels showed that for low N0 the number of cells in the population at any time is highly variable. An increase in N0 to levels exceeding 100 spores results in a significant decrease of the above variability and a shorter lambda of the population. Considering that the number of G. stearothermophilus surviving spores in the final product is usually very low, the data provided in this work can be used to evaluate the probability distribution of the time-to-spoilage and enable decision-making based on the "acceptable level of risk". PMID- 28648297 TI - Modeling the risk of salmonellosis from consumption of pistachios produced and consumed in the United States. AB - The risk of salmonellosis from consumption of pistachios produced and consumed in the U.S. was assessed through quantitative microbial risk assessment. Data on Salmonella prevalence and concentration on pistachios, nut crop volume, storage times and temperatures during processing and handling, and reductions during storage or from roasting were derived from laboratory experiments, published literature, and industry expert opinion. Uncertainty was analyzed via what-if scenarios for Salmonella prevalence, concentration, storage reduction, treatment variability, portion of crop treated, and increased consumption. The estimated U.S. incidence of salmonellosis when 100% of pistachios were exposed to a 4 +/- 0 log reduction treatment averaged 1.4 cases per billion servings, or <1 case/year, without considering Salmonella decline during storage. Including Salmonella decline during storage reduced the salmonellosis estimates approximately 10-fold. The predicted arithmetic mean number of cases associated with individual 500,000 kg storage silos, contaminated at the highest observed levels, ranged from 5 to 530 when the product was consumed untreated, but was reduced to below 1 case per silo when a 4 +/- 0 log reduction treatment was applied. Assuming a uniform 4-log reduction treatment is applied to 100% of the crop and there is no decline of Salmonella during storage, the assessment indicates the following: 10-fold increases in either Salmonella prevalence or concentration, 2-fold increases in both prevalence and concentration, or consumption of >0.05% of untreated product volume yield an arithmetic mean risk of >1 case/year. PMID- 28648298 TI - Slightly acidic electrolyzed water combined with chemical and physical treatments to decontaminate bacteria on fresh fruits. AB - Effect of sequential combination of slightly acidic electrolyzed water (SAEW) with chemical and physical treatments on bacterial decontamination on fruits was investigated in this study. Effect of treatments on microbial and sensory quality was also analyzed after subsequent storage at 4 degrees C and room temperature (RT, 23 +/- 0.15 degrees C). Whole apple and tomato fruits were inoculated with cocktail strains of Escherichia coli O157:H7 and Listeria monocytogenes. Uninoculated and inoculated fruits were washed first with distilled water (DW), calcium oxide (CaO), fumaric acid (FA), and SAEW at RT for 3 min. Combinations were performed by adding treatment one at a time to SAEW as following FA + SAEW, CaO + FA + SAEW, and CaO + FA + SAEW + ultrasonication (US) or microbubbles (MB). All the sanitizer treatments resulted in significant (p < 0.05) bacterial reduction compared to DW used as control. Increasing the treatments in combination from FA + SAEW to CaO + FA + SAEW + US resulted in an increased bacterial decontamination. The cavitation induced by ultrasonication in FA + SAEW solution resulted in a higher additive effect in decontamination of Escherichia coli O157:H7 and Listeria monocytogenes compare to the agitation generated by microbubble generator in FA + SAEW solution. CaO + FA + SAEW and CaO + FA + SAEW + US were effective in improving the microbial safety and quality of apple fruits. However, additional treatment of US impacted on the quality of tomato fruits during storage at RT. Therefore, a combination of SAEW with sanitizers (CaO and FA) and mechanical force (Ultrasonication) has the potential to be used in postharvest sanitation processing in the fresh fruit industry. PMID- 28648299 TI - The intra-articular injection of RANKL-binding peptides inhibits cartilage degeneration in a murine model of osteoarthritis. AB - We recently found that the receptor activator of NF-kappaB ligand (RANKL)-binding peptide, OP3-4 stimulated the differentiation of both chondrocytes and osteoblasts. OP3-4 is also shown to inhibit cartilage degeneration. To clarify whether the peptide can inhibit cartilage degeneration without stimulating bone formation, we first performed a proliferation assay using C3H10T1/2 (the murine mesenchymal stem cell line), which is the common origin of both chondrocytes and osteoblasts. The RANKL-binding peptides, OP3-4 and W9, promoted cellular proliferation at 24 and 48 h, respectively. Next, we injected both peptides into the intra-articular space of the knee joints of mice with monosodium-iodoacetate (MIA)-induced osteoarthritis to clarify the effects of the peptides on cartilage tissue. Twenty-five nine-week-old male C57BL/6J mice received injections of vehicle, or the same molar amount of W9, OP3-4, or a control peptide (which could not stimulate osteoblast differentiation) on days 7, 14, and 21 after the injection of MIA. The mice were sacrificed on day 28. The histomorphometric analyses revealed that both peptides inhibited the degeneration of cartilage without enhancing bone formation activity. Our data suggest that the stimulation of mesenchymal cell proliferation by the RANKL-binding peptides might lead to the inhibition of cartilage degeneration. PMID- 28648300 TI - The effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3 dimercaptosuccinic acid (DMSA) on the nephrotoxicity in the mouse during repeated cisplatin (CDDP) treatments. AB - Previously, we reported that specific lower dose of sodium 2,3-dimercapto-1 propanesulfonic acid (DMPS) which is an antidote to heavy metal intoxication, inversely enhanced cisplatin (CDDP)-induced antitumor activity to S-180 cell bearing mouse. This activity was only weak with meso-2,3-dimercaptosuccinic acid (DMSA), however. This study investigated the effects of lower doses of DMPS or DMSA on the nephrotoxicity and kinetics of CDDP. Kidney and blood isolated from female mice which received CDDP with or without DMPS or DMSA once daily for 4 days were provided for measuring levels of blood urea nitrogen (BUN) and transporter proteins (OCT2: organic cation transporter; MATE1: multidrug and toxin extrusion) mRNA, and CDDP-originated platinum, and TUNEL staining of renal tubular cells. DMPS or DMSA reduced effectively CDDP-induced BUN, and caused a moderate reduction of platinum in kidney. Additionally, both dimercapto-compounds restored the CDDP-reduced mRNA levels of transporter proteins (OCT2 and MATE1), and apparently suppressed the CDDP-induced apoptosis. These results suggest that DMPS, as well as DMSA, at approximate 17-fold dose (MUmol/kg) of CDDP, has an enough potential to reverse the CDDP nephrotoxicity, and concomitant use of DMPS considering both dose and timing for administration is potentially useful for preventing nephrotoxicity and enhancing antitumor activity during CDDP chemotherapy. PMID- 28648302 TI - Nephrotic Syndrome With Cancer Immunotherapies: A Report of 2 Cases. AB - Oncologic immunotherapies use a patient's immune response to eliminate tumor cells by modulation of immune checkpoints, including programmed cell death 1 (PD 1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) proteins. Immune mediated sequelae, including interstitial nephritis, have been reported; however, glomerular disease appears rare. We describe 2 cases of nephrotic syndrome in patients treated with these agents. Patient 1 received the anti-PD-1 antibody pembrolizumab for Hodgkin lymphoma. Following his second dose, he developed nephrotic syndrome and acute kidney injury. Biopsy showed diffuse foot-process effacement consistent with minimal change disease and findings of acute tubular injury. Pembrolizumab therapy cessation and corticosteroid treatment yielded improvement in proteinuria and acute kidney injury. Patient 2 received the CTLA-4 antibody ipilimumab for melanoma. He developed nephrotic syndrome with biopsy changes consistent with minimal change disease. Ipilimumab therapy was stopped and proteinuria resolved following corticosteroid treatment. Ipilimumab rechallenge caused relapse of nephrotic-range proteinuria. These cases suggest an association between therapeutic immune activation and the development of nephrotic syndrome. Given the increasing prevalence of oncologic immunotherapies, monitoring patients for renal sequelae is warranted. PMID- 28648301 TI - Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus. AB - BACKGROUND: Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM). STUDY DESIGN: Cross-sectional associations were assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM. SETTING & PARTICIPANTS: African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American-Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies. PREDICTORS: eGFR (CKD-EPI creatinine equation), spot UACR. MEASUREMENTS: MRI based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A1c concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed. RESULTS: Mean participant age was 60.1+/-7.9 (SD) years; diabetes duration, 12.1+/-7.7 years; hemoglobin A1c concentration, 8.3%+/-1.7%; eGFR, 88.7+/-21.6mL/min/1.73m2; and UACR, 119.2+/ 336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P<0.05), with a trend toward association with higher eGFR. Higher white matter lesion volume was associated with higher UACR (P<0.05) and lower eGFR (P<0.001). WMV was not associated with either kidney parameter. Higher UACR was associated with lower Digit Symbol Coding performance (P<0.001) and a trend toward association with higher Stroop interference; eGFR was not associated with cognitive tests. LIMITATIONS: Cross-sectional; single UACR measurement. CONCLUSIONS: In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory. PMID- 28648304 TI - Foreword. PMID- 28648303 TI - Risk of ESRD and Mortality Associated With Change in Filtration Markers. AB - BACKGROUND: Using change in estimated glomerular filtration rate (eGFR) based on creatinine concentration as a surrogate outcome in clinical trials of chronic kidney disease has been proposed. Risk for end-stage renal disease (ESRD) and all cause mortality associated with change in concentrations of other filtration markers has not been studied in chronic kidney disease populations. STUDY DESIGN: Observational analysis of 2 clinical trials. SETTING & PARTICIPANTS: Participants in the MDRD (Modification of Diet in Renal Disease; n=317) Study and AASK (African American Study of Kidney Disease and Hypertension; n=373). PREDICTORS: Creatinine, cystatin C, beta-trace protein (BTP), and beta2-microglobulin (B2M) were measured in serum samples collected at the 12- and 24-month follow-up visits, along with measured GFR (mGFR) at these time points. OUTCOMES: ESRD and all-cause mortality. MEASUREMENTS: Poisson regression was used to estimate incidence rate ratios and 95% CIs for ESRD and all-cause mortality during long term follow-up (10-16 years) per 30% decline in mGFR or eGFR for each filtration marker and the average of all 4 markers. RESULTS: 1-year decline in mGFR, eGFRcr, eGFRBTP, and the average of the 4 filtration markers was significantly associated with increased risk for incident ESRD in both studies (all P<=0.02). Compared to mGFR, only decline in eGFRBTP was statistically significantly more strongly associated with ESRD risk in both studies (both P<=0.03). Decline in eGFRcr, but not mGFR or the other filtration markers, was significantly associated with risk for all-cause mortality in AASK only (incidence rate ratio per 30% decline, 4.17; 95% CI, 1.78-9.74; P<0.001), but this association was not significantly different from decline in mGFR (P=0.2). LIMITATIONS: Small sample size. CONCLUSIONS: Declines in mGFR, eGFRcr, eGFRBTP, and the average of 4 filtration markers (creatinine, cystatin C, BTP, and B2M) were consistently associated with progression to ESRD. PMID- 28648305 TI - Assessing the Budget Impact and Economic Outcomes of the Introduction of Daclatasvir + Asunaprevir and Sofosbuvir/Ledipasvir for the Treatment of Chronic Hepatitis C Virus Infection in Japan. AB - BACKGROUND: The advent of highly efficacious, well-tolerated, all-oral direct acting antiviral regimens has revolutionized the standard of care for patients chronically infected with hepatitis C virus. As efficacy and safety rates converge, prescribers and payers need to consider value for money. OBJECTIVES: To evaluate the health economic value of daclatasvir + asunaprevir versus sofosbuvir/ledipasvir via a cost-effectiveness analysis, and determine the optimal treatment considering both costs and health outcomes in Japan. METHODS: A previously published Markov model was used to estimate the cost-effectiveness of daclatasvir + asunaprevir compared with sofosbuvir/ledipasvir on the basis of a matching-adjusted indirect comparison of pivotal trials and modeling inputs specific to the Japanese setting. A de novo budget impact model was developed and used to predict the cost implications of differing treatment sequences. RESULTS: Cost-effectiveness results demonstrated minimal difference in terms of benefit (0.037 fewer QALYs and 0.014 fewer life-years with daclatasvir + asunaprevir); nevertheless, a significant difference in cost was predicted (estimated Y2,299,700 [US $21,695] reduction with daclatasvir + asunaprevir). The budget impact analysis estimated that treatment with daclatasvir + asunaprevir is expected to be less expensive than treatment with sofosbuvir/ledipasvir (as the proportion of patients initially treated with sofosbuvir/ledipasvir increased from 0% to 100%, total costs increased from Y206 to Y403 billion [US $1.94 billion to US $3.80 billion]). CONCLUSIONS: On the basis of results from an established cost-effectiveness model and a conventional budget impact analysis, treatment with daclatasvir + asunaprevir is expected to be cost-saving compared with treatment with sofosbuvir/ledipasvir in Japan with similar health outcomes, regardless of treatment sequence. PMID- 28648306 TI - Cost-Benefit Analysis and Assessment of Quality of Care in patients with Hemophilia undergoing treatment at National Rural Health Mission in Maharashtra, India. AB - BACKGROUND: Hemophilia is a genetic disorder with high health care burden. In India, most patients with hemophilia seek care through self-purchasing factor concentrate and incur huge out-of-pocket (OOP) expenditure. In March 2013, the government of India launched a pilot hematology program through the National Rural Health Mission for providing free treatment services to patients with hemophilia in the state of Maharashtra. OBJECTIVES: To estimate the benefit-cost ratio of the program from a patient perspective, to estimate reduction in OOP expenditure of the patients and their families, and to assess the quality of care delivered and the barriers to access care among patients with hemophilia. METHODS: This cross-sectional study evaluated the intervention of free treatment to patients with hemophilia at four district civil hospitals of Maharashtra. The study sample included 232 people with hemophilia (193 with hemophilia A, 31 with hemophilia B, 6 with von Willebrand disease, and 2 others) under four study arms over a 1-year study period. Cost-benefit analysis was performed for patients undergoing treatment at government hospitals and through nongovernmental organizations. RESULTS: The benefit-cost ratio for the government program was 1.89. There was reduction in OOP expenditure by 21% per patient annually for the families. About 98% patients were highly satisfied with the services, whereas a major barrier to access was difficulty in commuting during active bleeding episodes. CONCLUSIONS: The government intervention through the National Rural Health Mission was cost-beneficial to the patients with hemophilia. It helped in reducing the OOP expenditure by 21%. PMID- 28648307 TI - Comparison on Human Resource Requirement between Manual and Automated Dispensing Systems. AB - OBJECTIVE: This study was conducted to compare human resource requirement among manual, automated, and modified automated dispensing systems. METHODS: Data were collected from the pharmacy department at the 2100-bed university hospital (Siriraj Hospital, Bangkok, Thailand). Data regarding the duration of the medication distribution process were collected by using self-reported forms for 1 month. The data on the automated dispensing machine (ADM) system were obtained from 1 piloted inpatient ward, whereas those on the manual system were the average of other wards. Data on dispensing, returned unused medication, and stock management processes under the traditional manual system and the ADM system were from actual activities, whereas the modified ADM system was modeled. The full time equivalent (FTE) of each model was estimated for comparison. RESULTS: The result showed that the manual system required 46.84 FTEs of pharmacists and 132.66 FTEs of pharmacy technicians. By adding pharmacist roles on screening and verification under the ADM system, the ADM system required 117.61 FTEs of pharmacists. Replacing counting and filling medication functions by ADM has decreased the number of pharmacy technicians to 55.38 FTEs. After the modified ADM system canceled the return unused medication process, FTEs requirement for pharmacists and pharmacy technicians decreased to 69.78 and 51.90 FTEs, respectively. CONCLUSIONS: The ADM system decreased the workload of pharmacy technicians, whereas it required more time from pharmacists. However, the increased workload of pharmacists was associated with more comprehensive patient care functions, which resulted from the redesigned work process. PMID- 28648308 TI - Healthy China 2030: A Vision for Health Care. PMID- 28648309 TI - Economic Burden of Community-Acquired Pneumonia Among Pediatric Patients (Aged 3 Months to < 19 Years) in the Philippines. AB - OBJECTIVE: 1) To determine the hospitalization, follow-up and total costs, and the economic burden of community-acquired pneumonia among pediatric patients aged 3 months to <19 years of age; 2) To compare the estimated cost of hospitalization to the pneumonia case rate payments of the Philippine Health Insurance Corporation (PhilHealth). METHODS: Using the societal perspective, both healthcare and non-healthcare costs were estimated. This was done through two tertiary private hospitals in the Philippines. A base-case and sensitivity analyses were performed using 2012 as the reference year. The PhilHealth claims were the basis for the economic burden. RESULTS: The estimated healthcare-related hospitalization cost for PCAP-C was PHP24,332 - 75,409 (US$576 - 1,786). For PCAP D, it was PHP77,460 - 121,301 (US$1,834 - 2,872) without mechanical ventilation and PHP97,993 - 141,834 if mechanical ventilation was used. These amounts are markedly higher than the PhilHealth case rates of PHP15,000 for PCAP C and PHP32,000 for PCAP D. The post-discharge cost was PHP1,175 - 1,531 for PCAP C and PHP1,275 for PCAP D. The total hospitalization cost were PHP 31,332 - 93,609 for PCAP C and PHP117,103 - 160,944 for PCAP D. The exact economic burden due to pneumonia among the pediatric population was not definitely ascertained due to lack of specific number of PhilHealth claims for this age group. CONCLUSIONS: There is a huge disparity between the PhilHealth case rates for PCAP C and PCAP D and the study results. Hence, the estimated economic burden of hospitalization for pneumonia would be markedly higher. PMID- 28648310 TI - Comparative Study on Health-Related Quality of Life of Farmers and Workers. AB - OBJECTIVE: To estimate and compare the health-related quality of life (HRQOL) between Chinese farmers and workers and study the relationships between the sociodemographic factors and HRQOL of the 2 populations. METHODS: We conducted 2 cross-sectional surveys in Zhejiang Province in China by using multistage cluster sampling; we applied the EuroQOL 5-dimensions 3-level (EQ-5D-3L) self-report questionnaire to assess the HRQOL of farmers and workers through face-to-face interviews. The chi2 test, 1-way analysis of variance (ANOVA), and multiple linear regression models were used to compare the HRQOL between farmers and workers and identify the factors that influence HRQOL. RESULTS: We included 3675 farmers and 2836 workers in the analysis. The HRQOL differed between the 2 populations. The most prevalent problems reported were Pain/Discomfort and Anxiety/Depression; workers reported significantly more Pain/Discomfort and Anxiety/Depression compared with farmers (P < 0.001). The mean EQ-5D index scores were 0.987 for farmers and 0.959 for workers (P < 0.001), and the EQ-VAS scores were 83.59 for farmers and 81.11 for workers (P < 0.001), indicating that farmers had better HRQOL compared with workers. Sex, age, marital status, education level, and personal monthly income were reported to influence the HRQOL of farmers, whereas marital status and education level were reported to influence that of workers. CONCLUSIONS: The HRQOL of farmers was better than that of workers. To improve the HRQOL, it is important to pay more attention to mental health, especially in workers. PMID- 28648311 TI - Mapping Sri Lankan EQ-5D-3L to EQ-5D-5L Value Sets. AB - OBJECTIVES: Quality-adjusted life-years are the common outcome measure in contemporary economic evaluations in health care. Due to the limitations of the sensitivity of the EQ-5D-3L in specific disease conditions, the EuroQoL group has developed a new EQ-5D-5L classification system with 3,125 health states. This study estimated the Sri Lankan value set for the EQ-5D-5L using a crosswalk methodology. METHODS: The EuroQoL group had developed a crosswalk methods to obtain interim value set for the EQ-5D-5L health states using available EQ-5D-3L values. This was achieved by mapping EQ-5D-3L and EQ-5D-5L ratings through cross tabulations by each dimension level. Using above official EuroQoL crosswalk probabilities, an interim value set for the Sri Lankan EQ-5D-5L health states were generated based upon the Sri Lankan EQ-5D-3L value set (which was estimated using time trade-off method: n= 780). Comparison were conducted between the Sri Lankan EQ-5D-5L values and other countries. RESULTS: The Sri Lankan EQ-5D-5L recorded utility value of -0.73 for the worst health state and 0.85 for a best possible utility for a health state other than the full health. The UK (mean= 0.4) and Japanese (mean = 0.45) EQ-5D-5L mean utility values were higher than the Sri Lankan values (mean = 0.07). However, Thailand median values (0.21) were closer to the Sri Lankan median values (0.14) than the UK (0.41) or Japan (0.45). CONCLUSIONS: This study produced the Sri Lankan EQ-5D-5L interim value set using crosswalk methods. Currently, this is the only EQ-5D-5L value set available for the South Asian region. PMID- 28648312 TI - The Emerging Role of Patient-Reported Outcomes (PROs) in Clinical Trials: An Indian Perspective. AB - In an attempt to reduce costs of clinical trials and increase recruitments, pharmaceutical companies have been shifting their trials to offshore locations in Asia, Africa, the Middle East, Eastern Europe, and Latin America. Hence, methods for conducting clinical trials need to be adapted to the varying languages, cultures, ethnicities, and socioeconomic groups of these regions. This is of prime importance in the collection of patient-reported outcome (PRO) data. To ensure correct capturing of PRO data from multiregional sites, it is important that the tools for data collection are adapted to the respective cultures, and the data collected have the same interpretation across cultures (cross-cultural equivalence). This article deals with challenges involved in the adaptation of PRO measures to various cultures, especially of those used for multiregional trials being conducted in the developing world. PMID- 28648313 TI - Cost of Osteoporotic Fractures in Singapore. AB - OBJECTIVES: To estimate the 3-month direct and indirect costs associated with osteoporotic fractures from both the hospital's and patient's perspectives in Singapore and to compare the cost between acute and prevalent osteoporotic fractures. METHODS: Resource use and expenditure data were collected using interviewer-administered questionnaires at baseline and at a 3-month follow-up between July 2013 and January 2014. Estimated osteoporotic fracture-related costs included hospitalizations, accident and emergency room visits, outpatient physician visits, laboratory tests, medications, transportation, health care and community services, special equipment and home/car modifications, and productivity loss. RESULTS: A total of 67 patients agreed to participate, giving a response rate of 64.4%. The mean (median) 3-month direct medical cost from the hospital's perspective was found to be SGD 3,886.90 (SGD 413.10), of which 74.2% was accounted for by inpatient services, 25.2% by outpatient services, and 0.6% by accident and emergency services. Moreover, considerable variation (SD = SGD 2,615.40) was observed in the costs of outpatient rehabilitation services. Findings were similar when the patient's perspective was taken. The total costs, with both direct and indirect costs included, were SGD 11,438.70 (acute) and SGD 1,015.40 (prevalent), of which 34.7% and 8.0%, respectively, were accounted for by inpatient services. CONCLUSIONS: Hospitalization was associated with the highest cost borne by both the hospital and the patient, and informal care dominated indirect costs. Better knowledge of the financial consequences of fragility fractures could enable proactive and preventive measures to be undertaken, especially at sites of care with high cost drivers. PMID- 28648314 TI - Direct Cost for Treating Chronic Kidney Disease at an Outpatient Setting of a Tertiary Hospital: Evidence from a Cross-Sectional Study. AB - BACKGROUND: Chronic kidney disease (CKD) has a high morbidity and mortality in developing countries. And this burden is also increasing rapidly in India. Unaffordability due to high cost of medication and hemodialysis remains one of the major barriers in the successful treatment of CKD. OBJECTIVES: To determine the direct cost involved in treating CKD at an outpatient department of a public tertiary care hospital. METHODS: This cross-sectional study was carried out at a public tertiary care hospital. Patients diagnosed with CKD by a physician were included in the study after obtaining a written informed consent. All the relevant data were collected on a predesigned case record form. RESULTS: The results are based on data obtained from 150 patients. The average age of the patients was 55.7 +/- 10.1 years. The average number of drugs per prescription was found to be 6.5 +/- 1.7. The annual average costs of treatment for patients on medication only and for patients on hemodialysis plus medication were Rs 25,836 (US $386) and Rs 2,13,144 (US $3181), respectively (Rs = Indian rupee). Treatment cost was found to be statistically significantly higher in patients on hemodialysis, treatment support by employer, patients with a smoking habit, patients with comorbidities, and patients with end-stage renal disease. Calcium tablets, vitamin D sachets, iron supplements, torsemide, and amlodipine were the top five medications prescribed. CONCLUSIONS: Reimbursement, patient's dialysis status, habits, and comorbidities were found to have a significant effect on the direct cost of treatment. PMID- 28648315 TI - Psychometric Properties of the Patient-Reported Outcomes Measure of Pharmaceutical Therapy for Quality of Life (PROMPT-QOL). AB - OBJECTIVES: To assess the psychometric properties of a novel instrument for medication management, the Patient-Reported Outcomes Measure of Pharmaceutical Therapy for Quality of Life (PROMPT-QOL), using both conventional psychometrics and Rasch analysis in a large sample. METHODS: This study was conducted with 1156 adult outpatients continuously taking any medicines at least 3 months from three university hospitals in Bangkok, Thailand, between July 2014 and March 2015. The psychometric properties were assessed in five steps: 1) assessment of dimensional structure, 2) item selection, 3) assessment of practicality, 4) assessment of reliability, and 5) assessment of criterion and known-groups validity. RESULTS: The PROMPT-QOL contained 43 items including nine domains, and their five-point Likert scale functioning worked well. Most items fulfilled the item selection criteria. The PROMPT-QOL took an average administration time of 13.4 +/- 5.8 minutes. Only two items had missing data of 0.1% to 0.2%. All domains provided good to excellent test-retest reliability with intraclass correlation coefficients between 0.67 and 0.83. All domains of the PROMPT-QOL yielded high Cronbach's alpha values between 0.77 and 0.89, greater than an acceptable level of 0.70, except for the Availability and Accessibility domain (0.58). A multiple regression showed that the Medication Effectiveness domain was the strongest predictor of the overall QOL of the PROMPT-QOL, followed by the Therapeutic Relationships, Psychological Impacts, Convenience, and Availability and Accessibility domains (adjusted R2 ~ 52%). As expected, patients with higher PROMPT-QOL domain scores were associated with being younger, more educated, having a lower number of medicines, patients' perceptions of better disease control, having no adverse drug reactions, and medicine preference. CONCLUSIONS: The PROMPT-QOL was practical, reliable, and valid for Thai patients. PMID- 28648316 TI - Exploring Product-Specific Attributes of a Community Cardiac Rehabilitation Program in an Asian Urban City. AB - BACKGROUND: Cardiac rehabilitation (CR) has been proven to improve long-term outcomes for patients. Despite its benefits, its uptake throughout the world is poor. Factors affecting the motivation and barriers impeding an individual from participating in a CR program have been extensively studied. Nevertheless, knowledge of product-specific factors in affecting participation is lacking. OBJECTIVES: To find out cultural-specific product attributes that are important to those contemplating participation in a community-based CR program using Consolidated criteria for Reporting Qualitative research (COREQ) as an anchor. METHODS: Participants were recruited from attendees of the CR program at the Singapore Heart Foundation. A literature review was done to identify product specific attributes that affected participation in CR programs. An interview guide was developed on the basis of the list of product attributes. The analysis was done by two independent analysts using NVivo version 11 (QSR International, Melbourne, Australia) via an inductive approach. Data analysis was carried out with recruitment and interviews ongoing until thematic saturation was reached. RESULTS: In total, 13 male and 9 female participants (16 Chinese, 4 Indian, 1 Malay, and 1 Eurasian) aged between 47 and 89 years were interviewed. A total of 8 categories (System, Infrastructure, Environment, Monitoring, Activity, Program, Staff, and Companionship) with 30 subcategories were identified. New themes that have not been explored by previous studies were discovered under five different categories: System, Infrastructure, Environment, Program, and Companionship. CONCLUSIONS: This study allows a better understanding of product-specific factors affecting participation in CR programs and serves as a springboard for further research to improve participation in community-based CR programs. PMID- 28648317 TI - Minimal Clinically Important Differences (MCIDs) of the Thai Version of the Leicester Cough Questionnaire for Subacute and Chronic Cough. AB - OBJECTIVES: To investigate the minimal clinically important differences (MCIDs) of the Thai version of the Leicester Cough Questionnaire (LCQ-T) in patients with subacute and chronic cough. METHODS: Patients with cough for 3 or more weeks were recruited from outpatient clinics. They self-completed the LCQ-T at an initial evaluation and repeated the LCQ-T with a Global Rating of Change scale at follow up. For the anchor-based method, the MCID was defined as a change in the LCQ scores that corresponded to the smallest improvement in Global Rating of Change score (+2 to +3). For distribution-based methods, the MCIDs were estimated from the standard error of measurement and a half and one-third of the SD of the LCQ score changes from baseline to follow-up. RESULTS: A total of 107 patients were included. The causes of cough were postinfectious cough/bronchitis (35.5%), asthma (20.6%), rhinosinusitis (16.8%), bronchiectasis (17.8%), and chronic obstructive pulmonary disease (9.3%). The anchor-based method yielded MCIDs of 1.1, 0.4, 0.4, and 0.4 for the total, physical, psychological, and social domains, respectively. The distribution-based method using standard error qof measurement yielded MCIDs of 0.8, 0.3, 0.3, and 0.3, whereas those using a half SD yielded MCIDs of 2.0, 0.6, 0.8, and 0.8 and those using one-third SD yielded MCIDs of 1.4, 0.4, 0.5, and 0.5 for the total, physical, psychological, and social domains, respectively. CONCLUSIONS: The MCIDs of the LCQ-T for subacute and chronic cough are 1.1, 0.4, 0.4, and 0.4 for the total, physical, psychological, and social domains, respectively. These estimates should be useful in making meaningful interpretations of the changes in quality of life because of cough. PMID- 28648318 TI - Translation, Revision, and Validation of the Diabetes Distress Scale for Indonesian Type 2 Diabetic Outpatients with Various Types of Complications. AB - OBJECTIVES: To translate, revise, and validate the Diabetes Distress Scale (DDS) instrument for Indonesian type 2 diabetes mellitus (T2DM) outpatients with various complications. METHODS: Participants were recruited from four hospitals and two primary health care centers. The study was performed with forward and backward translations, an adaptation testing with a small subset of participants, and validation analysis. Factor analysis with maximum likelihood estimation and promax rotation was then used to investigate the instrument structure. Internal consistency among the items was estimated using Cronbach alpha for each domain of the DDS. RESULTS: In total, 324 participants (246 from the hospitals and 78 from the primary health care centers) were involved in this study. To improve participant comprehension of the exact meaning of questions, examples of daily activities for patients with T2DM (e.g., diet, exercise, and adherence to therapy) were added to some questions after the translation and revision procedures. The factor analysis revealed a correlation among the four factors ranging from 0.40 to 0.67. The factor loadings of selected items from the four factors ranged from 0.41 to 0.98. The order of the four factors in the factor analysis was as follows: interpersonal distress, emotional burden, physician distress, and regimen distress. The internal consistency for the four domains ranged from 0.78 to 0.83. The instrument resulting from this study was labeled "DDS17 Bahasa Indonesia." CONCLUSIONS: The DDS17 Bahasa Indonesia provides an initial psychometric validation study, factor structure, and internal consistency for assessing the distress of Indonesian T2DM outpatients. Use of this instrument in future research and clinical trials is recommended for the Indonesian context. PMID- 28648319 TI - Prediction of Change in Prescription Ingredient Costs and Co-payment Rates under a Reference Pricing System in South Korea. AB - BACKGROUND: The reference pricing system (RPS) establishes reference prices within interchangeable reference groupings. For drugs priced higher than the reference point, patients pay the difference between the reference price and the total price. OBJECTIVES: To predict potential changes in prescription ingredient costs and co-payment rates after implementation of an RPS in South Korea. METHODS: Korean National Health Insurance claims data were used as a baseline to develop possible RPS models. Five components of a potential RPS policy were varied: reference groupings, reference pricing methods, co-pay reduction programs, manufacturer price reductions, and increased drug substitutions. The potential changes for prescription ingredient costs and co-payment rates were predicted for the various scenarios. RESULTS: It was predicted that transferring the difference (total price minus reference price) from the insurer to patients would reduce ingredient costs from 1.4% to 22.8% for the third-party payer (government), but patient co-payment rates would increase from a baseline of 20.4% to 22.0% using chemical groupings and to 25.0% using therapeutic groupings. Savings rates in prescription ingredient costs (government and patient combined) were predicted to range from 1.6% to 13.7% depending on various scenarios. Although the co-payment rate would increase, a 15% price reduction by manufacturers coupled with a substitution rate of 30% would result in a decrease in the co-payment amount (change in absolute dollars vs. change in rates). CONCLUSIONS: Our models predicted that the implementation of RPS in South Korea would lead to savings in ingredient costs for the third-party payer and co payments for patients with potential scenarios. PMID- 28648320 TI - Cost-Effectiveness of Edoxaban vs. Warfarin in Patients with Atrial Fibrillation Based on Results of the ENGAGE AF - TIMI 48 Trial: Taiwanese Perspective. AB - BACKGROUND: Novel anticoagulants, such as factor Xa inhibitors, have entered clinical practice as alternatives to warfarin for the prevention of stroke and systemic embolic event (SEE) in patients with atrial fibrillation (AF). It is not known whether edoxaban, the fourth-to-market factor Xa inhibitor approved for this indication, will be cost-effective in Taiwan, where the cost of warfarin monitoring is prohibitive. METHODS: A Markov model projecting lifetime results of edoxaban 60 mg/30 mg dose-reduced versus warfarin in patients with nonvalvular AF, based on the ENGAGE AF - TIMI 48 trial, found edoxaban to be of high value relative to warfarin, from the perspective of the US health care system. We applied Taiwan-specific cost inputs to this model structure to assess the relative cost-effectiveness of edoxaban versus warfarin from the perspective of the Taiwanese health care system. Event rates and hazard ratios from the ENGAGE AF - TIMI 48 East Asian subpopulation were explored in sensitivity analyses. RESULTS: Edoxaban was found to be highly cost-effective compared with warfarin, based on guidelines proposed by the World Health Organization (WHO), with a base case incremental cost-effectiveness ratio of $12,902 per quality-adjusted life year gained. These results were robust to variation of key model parameters, including assumptions regarding the cost and quality-of-life impact of stroke and bleeding events, and assuming East Asian-specific (as opposed to full-trial population) rates for combinations of ischemic stroke, SEE, and major bleeding. CONCLUSIONS: Despite its higher acquisition cost, edoxaban is an economically attractive alternative to warfarin for the prevention of stroke and SEE in patients with AF in Taiwan. PMID- 28648321 TI - Cost-Utility Analysis of Single-Fraction Versus Multiple-Fraction Radiotherapy in Patients with Painful Bone Metastases: An Iranian Patient's Perspective Study. AB - OBJECTIVES: To evaluate two of the various treatment strategies of bone metastasis- single-fraction radiotherapy and multiple-fraction radiotherapy. METHODS: A multistage Markov decision model was applied to assess the incremental costs per quality-adjusted life-year (QALY) gained of single fraction against multiple fractions. The model had a monthly cycle length over a lifetime horizon with 1000 hypothetical cohort samples. The EuroQol five-dimensional questionnaire was used to estimate the health-related quality of life in patients. To cope with parameters of uncertainty, we conducted a probabilistic sensitivity analysis using a Monte-Carlo simulation technique. Both cost and utility variables were discounted by 3% in the base model. Strategies were assessed considering a willingness-to-pay threshold of US $6578 per QALY gained. RESULTS: The expected mean cost and quality-adjusted life-years were, respectively, US $447.28 and 5.95 months for patients receiving single-fraction radiotherapy and US $1269.66 and 7.87 months for those receiving multiple-fraction radiotherapy. The incremental cost-utility ratio was US $428.38 per QALY. Considering the Iranian gross domestic product per capita (US $6578) as the recommended willingness to pay for 1 QALY gained, the multiple-fraction method was found to be a cost-effective strategy. CONCLUSIONS: Policymakers should advocate the multiple-fraction method instead of the single-fraction method in the treatment of patients with painful bone metastases. PMID- 28648323 TI - Is It Time for Joint Health Technology Assessment in Asia? Opportunities and Challenges. PMID- 28648322 TI - Induction of Type 2 Diabetes Mellitus with Antihypertensive Therapy: Is There Any Role of Alpha Adducin, ACE, and IRS-1 Gene? AB - Hypertension and diabetes are related disorders that share common pathophysiological pathways and occur together. Although hypertension itself is a risk factor for developing diabetes, prolonged use of first-line antihypertensive therapy has also been reported to induce diabetes. Genetic polymorphism of genes affecting salt sensitivity and insulin resistance can have a role in antihypertensive therapy-induced diabetes. Polymorphism of the alpha adducin gene, angiotensin-converting enzyme gene, and insulin receptor substrate 1 gene has been found to be associated with new incident diabetes in hypertensive patients via salt sensitivity and insulin resistance. Many studies have, however, revealed a negative correlation with this hypothesis and have shown no role of antihypertensive therapy in diabetes induction. Therefore, more detailed experimental studies are needed to reach a final conclusion. PMID- 28648324 TI - Drug-coated balloon angioplasty for the management of recurring infrapopliteal disease in diabetic patients with critical limb ischemia. AB - OBJECTIVE: To describe the 1-year outcomes of recurring infrapopliteal disease after endovascular revascularization with the Lutonix drug-coated balloons (LDCB) in diabetic patients with critical limb ischemia (CLI), and to benchmark our findings with previously published objective performance goals (OPG) addressing safety and efficacy of new catheter-based therapies for CLI. METHODS: The present study was a retrospective, single-center, and single-arm trial of symptomatic diabetic patients with CLI, who underwent LDCB-angioplasty for recurring infrapopliteal disease. Acute procedural and technical success were recorded. TcPO2 metrics variations at baseline and follow up were analyzed. Freedom from clinically driven target lesion revascularization (CD-TLR) was calculated using Kaplan-Meier analysis, and outcomes compared with previously published OPG for infrapopliteal interventions. RESULTS: 21 patients (15 men; mean age 66,6+/-11,2 years) were followed-up for 356.5+/-159.2 days and 90.47% had 12-months follow up data available for analysis. TcPO2 increased (14.3+/-11.6mmHg to 53.8+/-11.7mmHg; p<0.05). Limb salvage rate was 100%, and 90.4% of patients achieved the combined endpoint of reduction in ulcer size/depth or complete healing. LDCB had superior efficacy (MALE+post-operative death, amputation free survival, freedom from re intervention, limb salvage and survival rates), while attaining superior or equivalent safety (Major Adverse Limb Events, major adverse cardiovascular events and Amputation) endpoints for the overall, modified clinical and anatomical high risk groups. CONCLUSIONS: Lutonix DCB is safe and effective for recurring infrapopliteal disease. It outperforms the OPG for CLI patients with clinical and anatomical high-risk features. PMID- 28648325 TI - Erratum to "Use of ondansetron during pregnancy and congenital malformations in the infant" [Reprod. Toxicol. 50C (2017) 134-137]. PMID- 28648326 TI - The Role for International Outreach in Hand Surgery. AB - Internationally, surgery is making its mark as a necessary priority in Low and Middle Income Countries (LMICs). In 2013, Paul Farmer, MD, and international leaders from 14 countries founded the Lancet Commission of Global Surgery to develop and assemble the best evidence on the state of surgery worldwide, to study the economics of surgical and anesthesia care delivery, and to develop strategies for improving access. Concurrently, there is growing interest in hand surgery. The Journal of Hand Surgery (European Volume) recently called for LMIC research with the goal of using their resources to improve the end product. International outreach was further prioritized at the American Society for Surgery of the Hand, with Scott Kozin, MD, and colleagues subsequently launching the Touching Hands Program (THP). Insight into current models, proven benefits, emphasis on quality, and research in international hand surgery will help invested volunteers provide high-quality, safe, and innovative solutions in the global hand surgery landscape. PMID- 28648327 TI - Incidence of Acute Complications Following Surgery for Syndactyly and Polydactyly: An Analysis of the National Surgical Quality Improvement Program Database from 2012 to 2014. AB - PURPOSE: Congenital hand differences are infrequent phenomena, and their treatment represents a relatively small fraction of cases performed by hand surgeons. Little is known about the incidence of wound complications and acute postoperative problems given the relative rarity of these procedures. This study sought to characterize the incidence of complications within 30 days of surgery for congenital hand differences. METHODS: The National Surgical Quality Improvement Program (NSQIP) contains prospective data regarding 30-day morbidity from 64 pediatric centers across the United States. Data from all available years (2012-2014) were queried for Current Procedural Terminology (CPT) codes pertinent to the treatment of congenital hand differences. Bivariate statistics, Fisher exact tests and Poisson 95% confidence intervals (95% CI) were used to assess the incidence of complications and examine risk factors for these outcomes. RESULTS: We identified a total of 1,656 congenital hand cases that represented 4 different CPT codes, including surgery for simple syndactyly, complex syndactyly, and polydactyly. The overall incidence of complications was 2.2% (95% CI, 1.6%-3.1%; n = 37) with the most common complication being superficial surgical site infection (1.7%; 95% CI, 1.1%-2.4%) followed by related readmission (0.3%; 95% CI, 0.1%-0.7%). There was a higher incidence of complications observed in patients undergoing complex syndactyly repair (5.2% for complex syndactyly repair vs 2.3% for all others). CONCLUSIONS: The rate of acute complications following procedures to correct syndactyly and polydactyly is low, the most common of which is superficial surgical site infection. The incidence of acute complications may be helpful in counseling patients and families. We suggest that further research must prioritize collecting data on long-term functional outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 28648328 TI - Functional Outcomes of Thumb Trapeziometacarpal Arthrodesis With a Locked Plate Versus Ligament Reconstruction and Tendon Interposition. AB - PURPOSE: To compare standardized functional and patient-reported early outcomes following trapeziometacarpal arthrodesis (TMA) using a locking cage plate construct with trapezial excision, ligament reconstruction, and tendon interposition (LRTI). METHODS: This prospective cohort enrolled 50 consecutive patients with trapeziometacarpal osteoarthritis undergoing TMA or LRTI. Demographic data, objective measurements, Sollerman function testing, and patient reported outcomes were collected before surgery and at various time intervals up to 12 months after surgery. The study was powered to detect a minimally clinically important difference on the Michigan Hand Questionnaire between groups at 12 months. To account for selection bias, we performed between-group statistical analysis of the magnitude of change from preoperative to postoperative data. All complications were recorded. RESULTS: There were no significant differences in the amount of change in grip or pinch strength, patient-reported outcomes, or functional hand testing between TMA and LRTI. The TMA group had significantly increased thumb tip opposition distance. The TMA group was complicated by a 26% overall nonunion rate of which 8% were symptomatic. The LRTI group (Wagner incision) had a significantly increased incidence of superficial branch of the radial nerve paresthesia. The incidence of complications was similar between operative groups, but revision surgery was more common after TMA. CONCLUSIONS: Compared with LRTI, TMA failed to demonstrate superior improvement in strength, standardized functional performance, or patient reported function and is associated with an increased likelihood of revision surgery in the first 12 months. Trapeziometacarpal arthrodesis with a locking plate and screw construct does not ensure union, although most radiographic nonunions were asymptomatic. Wagner incisions are associated with a significantly increased incidence of superficial branch of the radial nerve paresthesia compared with dorsal trapeziometacarpal exposure. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 28648329 TI - Biomechanical Properties of 3-Dimensional Printed Volar Locking Distal Radius Plate: Comparison With Conventional Volar Locking Plate. AB - PURPOSE: This study evaluated the biomechanical properties of a new volar locking plate made by 3-dimensional printing using titanium alloy powder and 2 conventional volar locking plates under static and dynamic loading conditions that were designed to replicate those seen during fracture healing and early postoperative rehabilitation. METHODS: For all plate designs, 12 fourth generation synthetic composite radii were fitted with volar locking plates according to the manufacturers' technique after segmental osteotomy. Each specimen was first preloaded 10 N and then was loaded to 100 N, 200 N, and 300 N in phases at a rate of 2 N/s. Each construct was then dynamically loaded for 2,000 cycles of fatigue loading in each phase for a total 10,000 cycles. Finally, the constructs were loaded to a failure at a rate of 5 mm/min. RESULTS: All 3 plates showed increasing stiffness at higher loads. The 3-dimensional printed volar locking plate showed significantly higher stiffness at all dynamic loading tests compared with the 2 conventional volar locking plates. The 3-dimensional printed volar locking plate had the highest yield strength, which was significantly higher than those of 2 conventional volar locking plates. CONCLUSIONS: A 3-dimensional printed volar locking plate has similar stiffness to conventional plates in an experimental model of a severely comminuted distal radius fracture in which the anterior and posterior metaphyseal cortex are involved. CLINICAL RELEVANCE: These results support the potential clinical utility of 3-dimensional printed volar locking plates in which design can be modified according the fracture configuration and the anatomy of the radius. PMID- 28648330 TI - Experience With Patient Referrals for Upper Extremity Transplantation at a U.S. Academic Medical Center. AB - PURPOSE: To date, there have been over 100 upper extremity transplantations (UET) performed worldwide. However, little data are available regarding institutional screening practices or description of the population of patients that seek transplantation as a treatment modality for their upper extremity disabilities. We performed a review of our institutional experience in an attempt to better understand our referral patterns and identify factors that may be associated with successful screening. METHODS: Contact demographic data, injury characteristics, and mode of referral were retrospectively reviewed from 2010 through 2015. Differences in demographic data, injury-related characteristics, and clinical trial outcomes were assessed with the Chi-square test or Fisher exact test. RESULTS: There were a total of 89 UET contacts. The average age was 35.2 years, with most contacts being white (n = 24). The majority were male (n = 66; 75.0%) and the most common indication for referral was trauma (n = 43; 55.8%). Of the 89 contacts, 20 (22.5%) were physician referrals and 69 (77.5%) were self-referrals. Physician referrals led to the most screened and accepted contacts, whereas self referrals more often led to immediate exclusion. CONCLUSIONS: This study gives an overview of the demographic composition of our UET contacts, with a specific emphasis on mode of referral. We have identified that physician referrals have led to more screened and accepted patients versus self-referred individuals. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, Level IV. PMID- 28648331 TI - IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases. AB - IL-35 is a new anti-inflammatory cytokine identified in 2007, which inhibits inflammation and immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. The unique initiator and effector anti-inflammatory properties of IL-35 bring tremendous interest in investigating its role during cardiovascular disease (CVD) development, in which inflammatory processes are firmly established as central to its development and complications. In this review, we update recent understanding of how IL-35 is produced and regulated in the cells. In addition, we outline the signaling pathways affected by IL-35 in different cell types. Furthermore, we summarize the roles of IL-35 in atherosclerosis, diabetes, and sepsis. We propose a new working model that IL-35 and its receptors are novel homeostasis-associated molecular pattern (HAMP) and HAMP receptors, respectively, which explains the complex nature of IL-35 signaling as an anti-inflammatory initiator, effector and blocker. Thorough understanding of this topic is significant towards development of new anti-inflammatory therapies against CVDs and other diseases. (total words: 163). PMID- 28648332 TI - Turn up the pump or fix the leak? PMID- 28648333 TI - Right ventricle-to-pulmonary artery conduit for surgical management of transposition of great arteries with a complex coronary pattern. PMID- 28648334 TI - Catch-22: Management of aortoesophageal fistula after thoracic endovascular aortic repair. PMID- 28648335 TI - Minimalist thoracoscopic resection of thymoma associated with myasthenia gravis. PMID- 28648336 TI - Discussion. PMID- 28648337 TI - Discussion. PMID- 28648338 TI - Discussion. PMID- 28648339 TI - Discussion. PMID- 28648340 TI - Discussion. PMID- 28648341 TI - Discussion. PMID- 28648342 TI - Discussion. PMID- 28648343 TI - July 2017 Featured Articles, Volume 225. PMID- 28648344 TI - Discussion. PMID- 28648345 TI - Discussion. PMID- 28648346 TI - Discussion. PMID- 28648347 TI - Discussion. PMID- 28648348 TI - Discussion. PMID- 28648349 TI - Discussion. PMID- 28648350 TI - Discussion. PMID- 28648351 TI - Discussion. PMID- 28648352 TI - Discussion. PMID- 28648354 TI - Erratum to "Hypofractionated Radiotherapy in pancreatic cancer: lessons from the past in the era of Stereotactic Body Radiation Therapy" [Critical Reviews in Oncology / Hematology 103C (2016) 49-61]. PMID- 28648353 TI - Healthcare contact and treatment uptake following hepatitis C virus screening and counseling among rural Appalachian people who use drugs. AB - BACKGROUND: Hepatitis C virus (HCV) remains a major contributor to morbidity and mortality worldwide. Since 2009, Kentucky has led the United States in cases of acute HCV, driven largely by injection drug use in rural areas. Improved treatment regimens hold promise of mitigating the impact and transmission of HCV, but numerous barriers obstruct people who inject drugs (PWID) from receiving care, particularly in medically underserved settings. METHODS: 503 rural people who use drugs were recruited using respondent-driven sampling and received HCV screening and post-test counseling. Presence of HCV antibodies was assessed using enzyme immunoassay of dried blood samples. Sociodemographic and behavioral data were collected using computer-based questionnaires. Predictors of contacting a healthcare provider for follow-up following HCV-positive serotest and counseling were determined using discrete-time survival analysis. RESULTS: 150 (59%) of 254 participants reported contacting a healthcare provider within 18 months of positive serotest and counseling; the highest probability occurred within six months of serotesting. 35 participants (14%) reported they were seeking treatment, and 21 (8%) reported receiving treatment. In multivariate time dependent modeling, health insurance, internet access, prior substance use treatment, meeting DSM-IV criteria for generalized anxiety disorder, and recent marijuana use increased the odds of making contact for follow-up. Participants meeting criteria for major depressive disorder and reporting prior methadone use, whether legal or illegal, were less likely to contact a provider. CONCLUSION: While only 8% received treatment after HCV-positive screening, contacting a healthcare provider was frequent in this sample of rural PWID, suggesting that the major barriers to care are likely further downstream. These findings offer insight into the determinants of engaging the cascade of medical treatment for HCV and ultimately, treatment-as-prevention. Further study and increased resources to support integrated interventions with effectiveness in other settings are recommended to mitigate the impact of HCV in this resource-deprived setting. PMID- 28648355 TI - Impact of age and sex on survival and causes of death in adults with congenital heart disease. AB - BACKGROUND: The impact of gender and aging on relative survival and causes of death in adults with congenital heart disease (ACHD) are not well known. METHODS: Single center observational longitudinal study of 3311 consecutive ACHD (50.5% males) followed up to 25years. Patients were divided by the age at last follow-up into three groups: <40, 40-65 and >65years old. Their vital status was verified by crosschecking the Spanish National Death Index. Regression model for relative survival from reference population was performed. Cause of death was classified according to the International Classification of Diseases (ICD-10). Patients who died from cardiovascular (CV) causes were further investigated on a case-by-case basis. RESULTS: During a cumulative follow-up time of 37,608 person-years 336 patients died (10%). Age-adjusted relative survival in females was significantly worse than in males (hazard ratio [HR] 1.25; 95% confidence interval [CI] 1.0 1.6; p=0.046), and sex-adjusted relative survival improved across the three group of ages (HR 0.98; 95% CI 0.97-0.99; p<0.001). There was a temporal decline of CV deaths with aging in both genders (p<0.001). The leading cause of CV death was heart failure but sudden death prevailed in subjects <40years (p=0.004). While sudden death progressively declined with aging heart failure significantly increased (p<0.001). CONCLUSIONS: Women with CHD fare worse than men. There are a decline in CV deaths and a major temporal shift in the causes of CV deaths with aging. Heart failure surpasses sudden death as the primary cause of death in survivors over 40years. PMID- 28648356 TI - Effects of high-intensity interval versus continuous exercise training on post exercise heart rate recovery in coronary heart-disease patients. AB - BACKGROUND: Heart rate recovery (HRR) has been considered a prognostic and mortality indicator in both healthy and coronary patients. Physical exercise prescription has shown improvements in VO2peak and HRR, but most of the studies have been carried out applying continuous training at a moderate intensity, being very limited the use of protocols of high intensity interval training in coronary patients. We aimed to compare the effects of a moderate continuous training (MCT) versus a high intensity interval training (HIIT) programme on VO2peak and HRR. METHODS: Seventy three coronary patients were assigned to either HIIT or MCT groups for 8weeks. Incremental exercise tests in a cycloergometer were performed to obtain VO2peak data and heart rate was monitored during and after the exercise test to obtain heart rate recovery data. RESULTS: Both exercise programmes significantly increase VO2peak with a higher increase in the HIIT group (HIIT: 4.5+/-4.46ml/kg/min vs MCT: 2.46+/-3.57ml/kg/min; p=0.039). High intensity interval training resulted in a significantly increase in HRR at the first and second minute of the recovery phase (15,44+/-7,04 vs 21,22+/-6,62, p<0,0001 and 23,73+/-9,64 vs 31,52+/-8,02, p<0,0001, respectively). CONCLUSIONS: The results of our research show that the application of HIIT to patients with chronic ischemic heart disease of low risk resulted in an improvement in VO2peak, and also improvements in post-exercise heart-rate recovery, compared with continuous training. PMID- 28648358 TI - Editorial. PMID- 28648357 TI - Acidic stress enhances CovR/S-dependent gene repression through activation of the covR/S promoter in emm1-type group A Streptococcus. AB - Streptococcus pyogenes (group A Streptococcus) is a clinically important gram positive bacterium that causes severe diseases with high mortality. Spontaneous mutations in genes encoding the CovR/CovS two-component regulatory system have been shown to derepress expression of virulence factors and are significantly associated with invasiveness of infections. Sensor kinase CovS senses environmental signals and then regulates the levels of phosphorylated CovR. In addition, CovS is responsible for survival of group A Streptococcus under acidic stress. How this system regulates the expression of CovR-controlled genes under acidic stress is not clear. This study shows that the expression of CovR controlled genes, including hasA, ska, and slo, is repressed under acidic conditions by a CovS-dependent mechanism. Inactivation of CovS kinase activity or CovR protein phosphorylation derepresses the transcription of these genes under acidic conditions, suggesting that the phosphorylation of CovR is required for the repression of the CovR-controlled genes. Furthermore, the promoter activity of the covR/covS operon (pcov) was upregulated after 15min of incubation under acidic conditions. Replacement of pcov with a constitutively activated promoter abrogated the acidic-stress-dependent repression of the genes, indicating that the pH-dependent pcov activity is directly involved in the repression of CovR controlled genes. In summary, the present study shows that inactivation of CovS not only derepresses CovR-controlled genes but also abrogates the acidic-stress dependent repression of the genes; these phenomena may significantly increase bacterial virulence during infection. PMID- 28648359 TI - Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. AB - Melatonin is a physiological hormone involved in sleep timing and is currently used exogenously in the treatment of primary and secondary sleep disorders with empirical evidence of efficacy, but very little evidence from randomised, controlled studies. The aim of this meta-analysis was to assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders. An electronic literature review search of MEDLINE (1950-present) Embase (1980- present), PsycINFO (1987- present), and Scopus (1990- present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015. This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, non 24-h sleep wake syndrome in people who are blind, and rapid eye movement-behaviour disorder. Meta-analyses were performed to determine the magnitude of effect in studies of melatonin in improving sleep. A total of 5030 studies were identified; of these citations, 12 were included for review based on the inclusion criteria of being: double or single-blind, randomised and controlled. Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p = 0.002), delayed sleep phase syndrome (p < 0.0001), and regulating the sleep-wake patterns in blind patients compared with placebo. These findings highlight the potential importance of melatonin in treating certain first degree sleep disorders. The development of large-scale, randomised, controlled trials is recommended to provide further evidence for therapeutic use of melatonin in a variety of sleep difficulties. PMID- 28648360 TI - Positional patients (PP) and non positional patients (NPP) are two dominant phenotypes that should be included in the phenotypic approaches to obstructive sleep apnea. PMID- 28648361 TI - Gamma radiation increases the risk of radiation-related root dental caries. PMID- 28648362 TI - Formation of an international intergroup to coordinate clinical trials in head and neck cancers: HNCIG. AB - Clinical trials in head and neck cancer (HNC) face multiple challenges including low global incidence, excessive patient comorbidity rate, high treatment-related toxicity and more recently a changing tumor biology landscape. As clinical trials evolve to address new knowledge about HNC biology, the overall pool of eligible patients for each trial becomes smaller, leading to more accrual challenges. These challenges have led to the formation of the Head and Neck Cancer Intergroup (HNCIG) comprised of large HNC international and national cooperative groups and sites with the goal of facilitating the conduct of high quality clinical trials in a timely manner to improve outcomes in HNC. This article describes the objectives, structure, and activities of the HNCIG. PMID- 28648363 TI - Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells. AB - Replicating Lgr5+ stem cells and quiescent Bmi1+ cells behave as intestinal stem cells (ISCs) in vivo. Disrupting Lgr5+ ISCs triggers epithelial renewal from Bmi1+ cells, from secretory or absorptive progenitors, and from Paneth cell precursors, revealing a high degree of plasticity within intestinal crypts. Here, we show that GFP+ cells from Bmi1GFP mice are preterminal enteroendocrine cells and we identify CD69+CD274+ cells as related goblet cell precursors. Upon loss of native Lgr5+ ISCs, both populations revert toward an Lgr5+ cell identity. While active histone marks are distributed similarly between Lgr5+ ISCs and progenitors of both major lineages, thousands of cis elements that control expression of lineage-restricted genes are selectively open in secretory cells. This accessibility signature dynamically converts to that of Lgr5+ ISCs during crypt regeneration. Beyond establishing the nature of Bmi1GFP+ cells, these findings reveal how chromatin status underlies intestinal cell diversity and dedifferentiation to restore ISC function and intestinal homeostasis. PMID- 28648366 TI - [Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy]. AB - Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis. PMID- 28648365 TI - Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State. AB - Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state. PMID- 28648367 TI - Re: Incontinence Medication Response Relates to the Female Urinary Microbiota. PMID- 28648364 TI - Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling. AB - Gastric and small intestinal organoids differentiated from human pluripotent stem cells (hPSCs) have revolutionized the study of gastrointestinal development and disease. Distal gut tissues such as cecum and colon, however, have proved considerably more challenging to derive in vitro. Here we report the differentiation of human colonic organoids (HCOs) from hPSCs. We found that BMP signaling is required to establish a posterior SATB2+ domain in developing and postnatal intestinal epithelium. Brief activation of BMP signaling is sufficient to activate a posterior HOX code and direct hPSC-derived gut tube cultures into HCOs. In vitro, HCOs express colonic markers and contained colon-specific cell populations. Following transplantation into mice, HCOs undergo morphogenesis and maturation to form tissue that exhibits molecular, cellular, and morphologic properties of human colon. Together these data show BMP-dependent patterning of human hindgut into HCOs, which will be valuable for studying diseases including colitis and colon cancer. PMID- 28648368 TI - Re: Nicholas J. Giacalone, William U. Shipley, Rebecca H. Clayman, et al. Long term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience. Eur Urol 2017;71:952-60: Methodological Issues to Avoid Misinterpretation. PMID- 28648369 TI - Water diversion projects negatively impact lake metabolism: A case study in Lake Dazong, China. AB - Water diversion projects are one of the major tools for counteracting water resource shortage in China. Many diversion projects aimed at diverting water from the Yangtze River or other rivers. This study, using one of the lakes receiving Yangtze River water as a case study, illustrated how nutrient, O2, and N2 fluxes across the sediment-water interface (SWI) changed with increasing nitrate loads during in situ benthic chamber incubation. Increasing nitrate loads in the overlying water caused complex changes in the SWI fluxes. Furthermore, responses of the SWI fluxes to increasing nitrate loads were largely driven by season. Dissolved inorganic carbon (DIC), ammonium (NH4+), CO2, and N2 fluxes increased with enhanced nitrate loads, likely induced by stimulated anaerobic mineralization. DIC had a stronger response to nitrate additions in late summer versus in winter. Nitrate influxes were enhanced by increasing nitrate loads in winter and showed a similar but stronger response in summer, with a shift from sediment release to influx. Sediment oxygen consumption decreased with increasing nitrate loads in both late summer and, especially, winter. Nitrate addition may have changed the proportions of aerobic and anaerobic respiration, i.e., nitrate competed with O2 as an electron acceptor. With increasing nitrate loads, anaerobic respiration was strengthened in the dark benthic chamber. Water diversion from the heavily polluted Yangtze River to Lake Dazong may be disadvantageous for controlling eutrophication, especially during the summer. PMID- 28648370 TI - Can nutrient enrichment influence the invasion of Phragmites australis? AB - Plant invasion and nutrient enrichment because of anthropogenic landscape modifications seriously threaten native plant community diversity in aquatic and wetland ecosystems. It is poorly understood, however, whether these two disturbances interact with the functional identity of recipient native plants to drive community change. We performed combined studies in the fields and greenhouse to examine whether nutrient enrichment may trigger the invasion of Phragmites australis in wetlands through competitive advantage over native Melaleuca ericifolia. Chemical characterizations of rhizosphere water were distinguished in two different nutrient enriched wetlands associated with and without Phragmites over the seasons. Significant changes in rhizosphere water were observed in invaded area compared to uninvaded area at both sites. High nitrogen (NO3-), phosphorous (PO43-), dissolved organic carbon, phenolics contents, with low pH were found in invaded areas compared to uninvaded areas. Total biomass of Phragmites was positively regressed with rhizosphere water nitrogen (NO3-) and phosphorous (PO43-) content. Nutrient addition significantly enhanced the growth and competitive ability of Phragmites over Melaleuca. In contrast, Melaleuca was significantly less competitive than Phragmites. There was a significantly positive correlation between the growth of Phragmites grown alone and its competitive ability. The findings in greenhouse studies coupled with characteristics of Phragmites and its' rhizosphere chemistry in the nutrient enriched fields suggest that nutrient enrichment may enhance Phragmites invasion through correspondingly increasing growth and maintaining inherent competitive advantages of Phragmites. Nutrient management could limit the vigorous growth of Phragmites in wetlands and thereby reduce invasion through competitive advantages over natives, which might have important management implications for wetland managers. PMID- 28648371 TI - Impacts of tannery effluent on development and morphological characters in a neotropical tadpole. AB - Previous studies have shown the contamination of rivers and streams caused by tannery effluents (TE). However, the effects of TE on amphibians are still unknown. Thus, we evaluated whether the TE, even at low concentrations (0.2%), could cause asymmetric development (inferred through the fluctuating asymmetry indices (FA)) and changes in morphological characteristics of Physalaemus cuvieri larvae. Accordingly, the tadpoles were distributed in groups non-exposed (n=160) and exposed (n=160) to this TE, for 15days. The TE used presented a complex chemical composition (especially high concentrations of Cr, Cd and Ni and a diverse array of toxic organic compounds). We used three individual FA indices: FA1:=|R-L|, ii) FA2=|R-L|/[(R+L)/2] and FA3=(R-L)2, where "R" are "L" are the right and left sides, respectively. The larvae exposed to the TE had higher FA indexes (FA1, FA2 and FA3) for nostril-snout distance, relative to the control group larvae. Regarding eye-snout distance, asymmetry values were higher for the FA1 and FA2 indices (with no difference for the FA3 index), which were similar to those observed for the eye-width character. For eye length, FA2 was higher in animals of the effluent group. Tadpoles exposed to TE had significantly lower body masses than those in the control group, when controlling for body length and larval development stage. Furthermore, tadpoles in the effluent group had smaller body size and lower interocular distance. The frequency of tadpoles that showed any alteration in tail morphology as well as tail attachment position (dorsal and ventral) was significantly higher in the effluent group than in animals not exposed to the TE. Finally, our data show that exposure to TE delayed larval development of tadpoles. Thus, our pioneering study confirms the hypothesis that exposure of P. cuvieri to TE, at low concentrations, impacts development and morphological characters. PMID- 28648372 TI - Moss bag monitoring as screening technique to estimate the relevance of methylated arsine emission. AB - Volatile arsenic (As) species, like arsine, mono-, di-, and trimethylarsine (AsH3, MeAsH2, Me2AsH, Me3As) are difficult to sample in remote areas without sophisticated equipment. The application of moss bags is an easy-to-apply screening technique which has been used for trapping total (mostly particulate) As from different emission sources before. We evaluated its potential for additional volatile As species screening. We found Me2AsH and Me3As in N2 atmosphere to be quantitatively trapped on the mosses and to be recoverable as their respective pentavalent acids (and/or oxyanions) when ground mosses were heated for 90min at 90 degrees C in 0.1M HNO3/3% H2O2. MeAsH2 was trapped partially while AsH3 was not trapped. The most likely mechanism is covalent bonding to the moss surface. While moss monitoring does not replace more sophisticated techniques for volatile As sampling, it can easily be used as screening technique to determine whether besides particulate As volatile methylated As species could have any relevance in environments with yet unknown As emissions. PMID- 28648373 TI - Economic assessment of wild bird mortality induced by the use of lead gunshot in European wetlands. AB - In European wetlands, at least 40 bird species are exposed to the risk of lead poisoning caused by ingestion of spent lead gunshot. Adopting a methodology developed in North America, we estimated that about 700,000 individuals of 16 waterbird species die annually in the European Union (EU) (6.1% of the wintering population) and one million in whole Europe (7.0%) due to acute effects of lead poisoning. Furthermore, threefold more birds suffer sub-lethal effects. We assessed the economic loss due to this lead-induced mortality of these 16 species by calculating the costs of replacing lethally poisoned wild birds by releasing captive-bred ones. We assessed the cost of buying captive-bred waterbirds for release from market surveys and calculated how many captive-bred birds would have to be released to compensate for the loss, taking into account the high mortality rate of captive birds (72.7%) in the months following release into the wild. Following this approach, the annual cost of waterbird mortality induced by lead shot ingestion is estimated at 105 million euros per year in the EU countries and 142 million euros in the whole of Europe. An alternative method, based upon lost opportunities for hunting caused by deaths due to lead poisoning, gave similar results of 129 million euros per year in the EU countries and 185 million euros per year in the whole of Europe. For several reasons these figures should be regarded as conservative. Inclusion of deaths of species for which there were insufficient data and delayed deaths caused indirectly by lead poisoning and effects on reproduction would probably increase the estimated losses substantially. Nevertheless, our results suggest that the benefits of a restriction on the use of lead gunshot over wetlands could exceed the cost of adapting to non-lead ammunition. PMID- 28648374 TI - Cryptic invasions: A review. AB - Cryptic invasions are defined as the introduction and spread of non-native lineages within the species' native range (intra-specific cryptic invasion) or the invasion of non-native species that goes unnoticed due to misidentification as a native or another invasive species (inter-specific cryptic invasion). While population-specific attributes are acknowledged to play a critical role in the success and impact of biological invasions in general, our knowledge of the causes and consequences of cryptic invasions is largely neglected. Cryptic invasions are inherently difficult to recognize and, despite being likely widespread, often go undetected. In this review, we analyse the sources, mechanisms, and consequences of cryptic invasions. Using a bibliometric survey, we first quantify the relative proportion of study questions, taxa, and geographic regions. We then highlight the value of comparative information from archived specimens in uncovering the occurrence and timing of cryptic invasions. We examine the mechanisms of cryptic invasions and emphasise the role of anthropogenic environmental changes on the arrival of cryptic invaders. We then discuss the role of interspecific biological interactions in the success of cryptic invasions and the role of hybridization between native and non-native lineages in cryptic invasions. We examine the competitive advantage of some invasive lineages in key physiological, ecological or sexually-selected traits. We argue that cryptic invasions, often undetected, may trigger subsequent rapid range expansions. We suggest that cryptic invasions are much more common than currently acknowledged. We highlight the role of coevolved associations (host parasite, mutualism, herbivory), inherently population-specific, in the impacts of cryptic invasions on local communities. Finally, we outline a framework to manage intraspecific cryptic invasions. PMID- 28648375 TI - Classifications of seizures and epilepsies, where are we? - A brief historical review and update. AB - In March 2017, the International League Against Epilepsy (ILAE) announced their new classifications of seizures and epilepsies. Development of these classification systems led by the ILAE is a long and complicated process. Outsiders may find it difficult to understand the arguments behind. We summarize the major developmental milestones of the ILAE classification schemata. An update of the latest classification is also included. It is hope that this review can serve as an outline in learning the taxonomy in epileptology. PMID- 28648377 TI - Chemical Tools for Studying TLR Signaling Dynamics. AB - The detection of infectious pathogens is essential for the induction of antimicrobial immune responses. The innate immune system detects a wide array of microbes using a limited set of pattern-recognition receptors (PRRs). One family of PRRs with a central role in innate immunity are the Toll-like receptors (TLRs). Upon ligation, these receptors initiate signaling pathways culminating in the release of pro-inflammatory cytokines and/or type I interferons (IFN-I). In recent years, it has become evident that the specific subcellular location and timing of TLR activation affect signaling outcome. The subtlety of this signaling has led to a growing demand for chemical tools that provide the ability to conditionally control TLR activation. In this review, we survey current models for TLR signaling in time and space, discuss how chemical tools have contributed to our understanding of TLR ligands, and describe how they can aid further elucidation of the dynamic aspects of TLR signaling. PMID- 28648376 TI - Sam68 Allows Selective Targeting of Human Cancer Stem Cells. AB - Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/beta-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/beta-catenin signaling within CSCs. Disruption of CBP-beta-catenin interaction via ICG-001/CWP induces the formation of a Sam68-CBP complex in CSCs that alters Wnt signaling toward apoptosis and differentiation induction. Our study identifies Sam68 as a regulator of human CSC vulnerability. PMID- 28648378 TI - Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities. AB - Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration resistant prostate cancer (CRPC). The A/B steroid ring (Delta5,3beta-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3beta-hydroxysteroid dehydrogenase (3betaHSD). We found that galeterone is metabolized by 3betaHSD to Delta4 galeterone (D4G), which is further converted by steroid-5alpha-reductase (SRD5A) to 3-keto-5alpha-galeterone (5alphaG), 3alpha-OH-5alpha-galeterone, and 3beta-OH 5alpha-galeterone; in vivo it is also converted to the three corresponding 5beta reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Delta5,3beta-hydroxyl structure. PMID- 28648381 TI - Clinical Phenotypes of Poppers Maculopathy and Their Links to Visual and Anatomic Recovery. PMID- 28648379 TI - Targeted Protein Degradation: from Chemical Biology to Drug Discovery. AB - Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell's own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space. PMID- 28648382 TI - Liver transplantation in adult, from living donor. A valid option. PMID- 28648380 TI - Privileged Electrophile Sensors: A Resource for Covalent Drug Development. AB - This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing. PMID- 28648383 TI - Optical coherence tomography angiography in dry age-related macular degeneration. AB - Optical coherence tomography angiography is a new imaging modality that provides noninvasive characterization and quantification of the microvasculature in different retinal conditions. The purpose of this study was to give an updated review of the features of dry age-related macular degeneration investigated by means of new-generation optical coherence tomography angiography. We searched PubMed and Medline using the terms "optical coherence tomography angiography" associated with "age-related macular degeneration," "drusen," "reticular pseudodrusen," and "geographic atrophy" and reviewed publications up to January 2017. PMID- 28648385 TI - Fluorescence imaging of lymphatic outflow of cerebrospinal fluid in mice. AB - Cerebrospinal fluid (CSF) is known to be reabsorbed by the lymphatic vessels and drain into the lymph nodes (LNs) through peripheral lymphatic vessels. In the peripheral lymphatics, the contractile pumping action of lymphangions mediates lymph drainage; yet it is unknown whether lymphatic vessels draining cranial and spinal CSF show similar function. Herein, we used non-invasive near-infrared fluorescence imaging (NIRFI) to image (i) indocyanine green (ICG) distribution along the neuraxis and (ii) routes of ICG-laden CSF outflow into the lymphatics following intrathecal lumbar administration. We demonstrate lymphatic contractile function in peripheral lymphatics draining from the nasal lymphatics to the mandibular LNs. In addition, we observed afferent sciatic lymphatic vessels, which also show contractile activity and transport spinal CSF into the sciatic LNs. This drainage pattern was also visualized by NIRFI following intrathecal thoracic injection. In situ intravital imaging following intrathecal lumbar injection of blue dye shows similar distributions to that seen in vivo with ICG. NIRFI could be used as a tool to probe CSF pathology including neurological disorders by imaging CSF outflow dynamics to lymphatics. PMID- 28648387 TI - What Women (and Clinicians) Don't Know Hurts Them. PMID- 28648386 TI - Knowledge, Attitudes, and Beliefs Regarding Cardiovascular Disease in Women: The Women's Heart Alliance. AB - BACKGROUND: Cardiovascular disease (CVD) is the number 1 killer of women in the United States, yet few younger women are aware of this fact. CVD campaigns focus little attention on physicians and their roles in assessing risk. OBJECTIVES: In 2014, the Women's Heart Alliance (WHA) conducted a nationwide survey to determine barriers and opportunities for women and physicians with regard to CVD. METHODS: From September 18 to 26, 2014, a total of 1,011 U.S. women (age 25 to 60 years) were interviewed using the GfK ("Gesellschaft fur Konsumforschung" Knowledge Panel). From May 6 to 12, 2014, the e-Rewards Inc. Physician and Healthcare Professional Panel surveyed 200 primary care physicians (PCPs) and 100 cardiologists. RESULTS: Overall, 45% of women were unaware that CVD is the number 1 killer of women; only 11% knew a woman who died from CVD. Overall, 45% of women reported it was common to cancel or postpone a physician appointment until losing weight. CVD was rated as the top concern by only 39% of PCPs, after weight and breast health. Only 22% of PCPs and 42% of cardiologists (p = 0.0477) felt extremely well prepared to assess CVD risk in women, while 42% and 40% felt well prepared (p = NS), respectively. Few comprehensively implemented guidelines. CONCLUSIONS: CVD was rated as the top concern less frequently than weight issues by both women and physicians. Social stigma particularly regarding body weight appeared to be a barrier. Physicians reported limited training and use of guideline assessment, whereas most supported a campaign and improved physician education. Campaigns should make CVD "real" to U.S. women, countering stereotypes with facts and validated assessments. Both community women and physicians endorsed investment in women's CVD research and physician education. PMID- 28648384 TI - A novel and rapid method to quantify Treg mediated suppression of CD4 T cells. AB - Measuring regulatory T cell suppression provides important insight into T cell dysfunction in autoimmune disease. However, to date, suppression assays are limited by the requirement for freshly isolated cells, and significant cell numbers. Here, we present a novel and rapid in vitro assay using effector T cell surface expression of both CD25 and CD134 as a surrogate marker of regulatory T cell-mediated suppression. This surface marker-based suppression assay works for frozen samples and for samples with limited cell numbers. It is also shorter taking two days to complete compared to the four days required for proliferation based assays. Furthermore, this assay works with both in vitro expanded and natural Tregs, as well as anti-CD3/anti-CD28 bead-based and APC stimulation conditions. In conclusion, we have developed and validated a new suppression assay for cryopreserved samples with limited cell numbers that may be helpful to investigate T cell regulation in the context of infection or autoimmune diseases. PMID- 28648388 TI - Heterozygous knockout of cytosolic phospholipase A2alpha attenuates Alzheimer's disease pathology in APP/PS1 transgenic mice. AB - Cytosolic phospholipase A2alpha (cPLA2alpha) is a key enzyme in regulation of inflammation process and neuromembrane homeostasis, both of which are critical in pathogenesis of Alzheimer's diseases. By hybride APP/PS1 Tg-AD mice with cPLA2alpha knockout mice, three lines of APP/PS1 Tg-AD mice were produced with genotypes of cPLA2alpha+/+, cPLA2alpha+/- and cPLA2alpha-/-. Compared to cPLA2alpha+/+ Tg-AD mice, the amyloid plaque formation was significantly downregulated in the brain of cPLA2alpha+/- Tg-AD mice, but not in cPLA2alpha-/- Tg-AD mice. The reactive gliosis were also significantly downregulated in both cPLA2alpha+/- and cPLA2alpha-/- Tg-AD mouse lines. The paradoxical effects of cPLA2alpha on the amyloid plaques reveal a complex role of cPLA2alpha in pathogenesis of AD and could be a potential target for prevention and treatment of AD. PMID- 28648390 TI - Clinical and microbiological characteristics of unusual manifestations of invasive pneumococcal disease. AB - INTRODUCTION: Invasive pneumococcal disease (IPD) typically presents as bacterial pneumonia, meningitis or primary bacteraemia. However, Streptococcus pneumoniae can produce infection at any level of the body (endocarditis, arthritis, spontaneous bacterial peritonitis, etc.), which is also known as unusual IPD (uIPD). There are very limited data available about the clinical and microbiological profile of these uncommon manifestations of pneumococcal disease. Our aim was to analyse clinical forms, microbiological profile, epidemiology and prognosis of a cohort of patients with unusual invasive pneumococcal disease (uIPD). METHODS: We present a retrospective study of 389 patients (all adult and paediatric patients diagnosed during the period) diagnosed with IPD at our hospital (Complejo Hospitalario Universitario de Vigo) between 1992 and 2014. We performed an analysis of clinical, microbiological and demographical characteristics of patients comparing the pre-pneumococcal conjugate vaccine (PCV) period with the post-vaccination phase. IPD and uIPD were defined as follows; IPD: infection confirmed by the isolation of S. pneumoniae from a normally sterile site, which classically presented as bacterial pneumonia, meningitis or primary bacteraemia; uIPD: any case of IPD excluding pneumonia, meningitis, otitis media, rhinosinusitis or primary bacteraemia. RESULTS: A total of 22 patients (6%) met the criteria of uIPD. A Charlson index >2 was more prevalent in uIPD patients than IPD patients (45% vs 24%; p=0.08). The most common clinical presentation of uIPD was osteoarticular infection (8 patients, 36%), followed by gastrointestinal disease (4 patients, 18%). Infection with serotypes included in PCV-13 was significantly higher in IPD patients (65%) than in patients with uIPD, 35% (p=0.018). Conversely, infection with multidrug resistant strains was higher among patient with uIPD (27% vs 9%; p=0.014). The all-cause mortality rate was 15%, 13% in the IPD group and 32% among patients with uIPD (p=0.07). According to the multivariate analysis, a Charlson Index >2 (OR 5.1, 95% CI, 1.8-14.0) and a Pitt Score >2 (OR 1.4, 95% CI, 1.2-1.9) were independent predictors of mortality. CONCLUSION: uIPD is a rare entity that affects patients with more comorbidities than typical IPD and it is usually caused by non-vaccine serotypes with greater antimicrobial resistance. PMID- 28648389 TI - Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone. AB - Despite the fact that stress is associated with increased risk of stroke and worsened outcome, most preclinical studies have ignored this comorbid factor, especially in the context of testing neuroprotective treatments. Preclinical research suggests that stress primes microglia, resulting in an enhanced reactivity to a subsequent insult and potentially increasing vulnerability to stroke. Ischemia-induced activated microglia can be polarized into a harmful phenotype, M1, which produces pro-inflammatory cytokines, or a protective phenotype, M2, which releases anti-inflammatory cytokines and neurotrophic factors. Selective modulation of microglial polarization by inhibiting M1 or stimulating M2 may be a potential therapeutic strategy for treating cerebral ischemia. Our laboratory and others have shown progesterone to be neuroprotective against ischemic stroke in rodents, but it is not known whether it will be as effective under a comorbid condition of chronic stress. Here we evaluated the neuroprotective effect of progesterone on the inflammatory response in the hippocampus after exposure to stress followed by global ischemia. We focused on the effects of microglial M1/M2 polarization and pro- and anti-inflammatory mediators in stressed ischemic animals. Male Sprague-Dawley rats were exposed to 8 consecutive days of social defeat stress and then subjected to global ischemia or sham surgery. The rats received intraperitoneal injections of progesterone (8mg/kg) or vehicle at 2h post-ischemia followed by subcutaneous injections at 6h and once every 24h post-injury for 7days. The animals were killed at 7 and 14days post-ischemia, and brains were removed and processed to assess outcome measures using histological, immunohistochemical and molecular biology techniques. Pre ischemic stress (1) exacerbated neuronal loss and neurodegeneration as well as microglial activation in the selectively vulnerable CA1 hippocampal region, (2) dysregulated microglial polarization, leading to upregulation of both M1 and M2 phenotype markers, (3) increased pro-inflammatory cytokine expression, and (4) reduced anti-inflammatory cytokine and neurotrophic factor expression in the ischemic hippocampus. Treatment with progesterone significantly attenuated stress induced microglia priming by modulating polarized microglia and the inflammatory environment in the hippocampus, the area most vulnerable to ischemic injury. Our findings can be taken to suggest that progesterone holds potential as a candidate for clinical testing in ischemic stroke where high stress may be a contributing factor. PMID- 28648391 TI - Role of Global Longitudinal Strain in the Prediction of Outcome in Patients With Severe Aortic Valve Stenosis. AB - In the present study, we assessed the role of Global Longitudinal Strain (GLS) as a predictor of all-cause mortality in patients with severe aortic valve stenosis (AS), irrespective of their type of treatment. Data of 807 patients with AS receiving complete echocardiographic and clinical examination were retrospectively analyzed. Valve area <1 cm2 and sufficient image quality were inclusion criteria; patients with severe concomitant valvulopathy were excluded. Patients were grouped into treatment (aortic valve replacement [AVR]) and conservative (non-AVR) groups. Multivariable Cox analysis was used to assess predictors of all-cause mortality. Five hundred fourteen patients were included and 53.3% were of male gender. Mean age at inclusion was 76.4 +/- 9.8 years; 326 received AVR. Death from any cause occurred in 72.9% of non-AVR group and 17.8% of AVR group (p <0.001). GLS (expressed as |%|) was found to be an independent predictor of all-cause mortality in non-AVR group (hazard ratio [HR] 0.933, 95% CI 0.854 to 0.987, p = 0.038). In patients receiving AVR, GLS and history of coronary artery bypass graft were found to be independent predictors of all-cause mortality (HR for GLS 0.912, 95% CI 0.730 to 0.999, p = 0.048; HR for coronary artery bypass graft 2.977, 95% CI 1.014 to 6.273, p = 0.013). In non-AVR patients, GLS <9.7% showed a higher 1- and 5-year mortality (log rank p values of 0.002 and 0.010, respectively). In conclusion, GLS is an independent predictor of all-cause mortality in severe AS, irrespective of their type of treatment. GLS <9.7% indicates a significantly higher 1- and 5-year mortality in non-AVR patients. Therefore, GLS should be regularly assessed for enhanced risk stratification and clinical decision-making. PMID- 28648392 TI - Meta-Analysis of Seasonal Incidence of Aortic Dissection. AB - We performed the first meta-analysis to identify in which season incidence of aortic dissection is the most and least frequent. MEDLINE and EMBASE were searched through February 2017. Eligible studies were observational studies enrolling patients with aortic dissection and reporting seasonal or monthly incidence of aortic dissection. Study-specific estimates, incidence of aortic dissection in each season (number of aortic dissection in a season divided by that in a year) and risk ratios (RRs) for incidence of aortic dissection in a season versus another season, were combined using the random-effects model. We identified 18 eligible studies enrolling a total of 101,264 patients with aortic dissection. Pooled incidence was 20.6% in summer, 24.8% in autumn, 28.2% in winter, and 25.5% in spring. Pooled analysis demonstrated a statistically significant increase in incidence of aortic dissection in autumn than in summer (RR 1.18; p <0.0001), in winter than in summer (RR 1.37; p <0.0001), in spring than in summer (RR 1.24; p <0.0001), in winter than in spring (RR 1.11; p = 0.006), and in winter than in autumn (RR 1.17; p <0.001); and no statistically significant difference between spring and autumn (RR 1.04; p = 1.00). In conclusion, the incidence in winter (28.2%) was significantly more frequent than that in other seasons and that in summer (20.6%) was significantly less frequent than that in other seasons (winter > spring ~ autumn > summer). PMID- 28648394 TI - Prevalence, Correlates, and Prognostic Relevance of Myocardial Mechanical Dispersion as Assessed by Feature-Tracking Cardiac Magnetic Resonance After a First ST-Segment Elevation Myocardial Infarction. AB - Postinfarction mechanical dispersion (MD), that is, the regional heterogeneity of myocardial contraction throughout the cardiac cycle, has detrimental effects on left ventricular (LV) function and is related to the occurrence of heart failure and ventricular arrhythmias. However, its prevalence, pathophysiological determinants, and clinical utility are still unknown. The aim of the present study is to clarify these issues. In total, 130 consecutive patients (mean age 60 +/- 12 years, 75% male) with a first ST-segment elevation myocardial infarction (STEMI) were included. Cardiac magnetic resonance (CMR) with late gadolinium enhancement imaging was performed to assess LV function, infarct size, and microvascular obstruction. Feature-tracking analysis was applied to cine-CMR short-axis images to assess MD, defined as the SD of the time-to-peak circumferential strain of the LV segments expressed as percent cardiac cycle. For comparison purpose, 40 control subjects similar in age and gender to the STEMI group were also included. Patients were followed-up for a median of 95 months; the outcome event was defined as a composite of cardiovascular death, aborted sudden cardiac death, and hospitalization for heart failure. STEMI patients had significantly higher MD compared with controls (12.0 +/- 5.35% vs 3.85 +/- 0.99%, p <0.001). At multivariate analysis, heart rate (beta = 0.20, p = 0.008), LV end systolic volume index (beta = 0.37, p <0.001), and infarct size (beta = 0.23, p = 0.017) were significantly and independently related to MD. The outcome event occurred in 26 (20%) patients. At multivariate Cox proportional hazards analysis, MD was significantly and independently related to the outcome event (p <0.001). MD provided significant incremental value over the other clinical and CMR variables in predicting the outcome event (p <0.001 for the chi-square change). In conclusion, MD after STEMI is a marker of the extent of myocardial damage; its assessment by feature-tracking CMR provides significant, independent, and incremental long-term prognostic information. PMID- 28648393 TI - Etiologies, Trends, and Predictors of 30-Day Readmissions in Patients With Diastolic Heart Failure. AB - An estimated half of all heart failure (HF) populations has been categorized to have diastolic HF (DHF), but sparse data are available describing etiologies and predictors of 30-day readmission in DHF population. The study cohort was derived from the National Readmission Database 2013 to 2014, a subset of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. DHF was identified using International Classification of Diseases, 9th Revision code 428.3x in primary diagnosis field. Readmission etiologies were identified by International Classification of Diseases, 9th Revision code in primary diagnosis field. The primary outcome was 30-day readmission. Hierarchical multivariable logistic regression was used to adjust for confounders. In total, 192,394 patients with DHF were included, of which 40,927 (21.27%) patients were readmitted with total readmissions of 47,056 within 30 days. Predictors of increased readmissions were age (odds ratio [OR] 1.002, 95% confidence interval [CI] 1.001 to 1.0003, p <0.001), diabetes (OR 1.08, 95% CI 1.05 to 1.11, p <0.001), chronic pulmonary disease (OR 1.18, 95% CI 1.15 to 1.21, p <0.001), renal failure (OR 1.21, 95% CI 1.17 to 1.25, p <0.001), peripheral vascular disease (OR 1.05, 95% CI 1.02 to 1.09, p = 0.002), anemia (OR 1.12, 95% CI 1.10 to 1.15, p <0.001), transfusion during index admission (OR 1.18, 95% CI 1.13 to 1.23, p <0.001), discharge to the facility (OR 1.13, 95% CI 1.10 to 1.16, p <0.001), length of stay >2 days, and Charlson comorbidity index >=3, whereas obesity (OR 0.82, 95% CI 0.80 to 0.85, p <0.001), elective admissions (OR 0.88, 95% CI 0.83 to 0.94, p <0.001), and non-Medicare/Medicaid primary payer were predictors of lower readmission rate. Most common etiologies of readmission were acute HF (28.01%), infections (9.54%), acute kidney injury (5.35%), acute respiratory failure (4.86%), and pneumonia (3.92%). In conclusion, DHF population with higher comorbidity burden, longer length of stay, and discharge to facility were prone to increased readmissions, with most common etiologies of readmission being HF, infections, and acute kidney injury. PMID- 28648395 TI - The complete genome of the tetrachloroethene-respiring Epsilonproteobacterium Sulfurospirillum halorespirans. AB - Sulfurospirillum halorespirans is a bacterium that couples the reductive dehalogenation of chlorinated ethenes to growth. This process is called organohalide respiration (OHR), which can be of importance for bioremediation. Here, we report the complete genome of S. halorespirans, the second one of an organohalide-respiring Epsilonproteobacterium after that of Sulfurospirillum multivorans. With both genomes at hand, we were able to ascertain that the genomic region encoding OHR proteins in Epsilonproteobacteria differs from that found in organohalide-respiring bacteria (OHRB) affiliated to other phyla and that the production of a unique cobamide, norpseudo-B12, might not be limited to the model organism S. multivorans. The OHR region is virtually identical in both organisms with differences only in the gene sequence of the key enzyme of OHR, the PCE reductive dehalogenase (PceA), and in regulatory regions. This is of interest, since the availability of natural, closely related variants opens an avenue to study the poorly understood OHRB, which withstand systematic genetic manipulation so far. PMID- 28648397 TI - Editorial. PMID- 28648398 TI - Insulin Expressing Pancreatic Neuroendocrine Tumor Associated With Intratumor Amyloidosis. PMID- 28648396 TI - 25 years of serving the community with ribosomal RNA gene reference databases and tools. AB - SILVA (lat. forest) is a comprehensive web resource, providing services around up to date, high-quality datasets of aligned ribosomal RNA gene (rDNA) sequences from the Bacteria, Archaea, and Eukaryota domains. SILVA dates back to the year 1991 when Dr. Wolfgang Ludwig from the Technical University Munich started the integrated software workbench ARB (lat. tree) to support high-quality phylogenetic inference and taxonomy based on the SSU and LSU rDNA marker genes. At that time, the ARB project maintained both, the sequence reference datasets and the software package for data analysis. In 2005, with the massive increase of DNA sequence data, the maintenance of the software system ARB and the corresponding rRNA databases SILVA was split between Munich and the Microbial Genomics and Bioinformatics Research Group in Bremen. ARB has been continuously developed to include new features and improve the usability of the workbench. Thousands of users worldwide appreciate the seamless integration of common analysis tools under a central graphical user interface, in combination with its versatility. The first SILVA release was deployed in February 2007 based on the EMBL-EBI/ENA release 89. Since then, full SILVA releases offering the database content in various flavours are published at least annually, complemented by intermediate web-releases where only the SILVA web dataset is updated. SILVA is the only rDNA database project worldwide where special emphasis is given to the consistent naming of clades of uncultivated (environmental) sequences, where no validly described cultivated representatives are available. Also exclusive for SILVA is the maintenance of both comprehensive aligned 16S/18S rDNA and 23S/28S rDNA sequence datasets. Furthermore, the SILVA alignments and trees were designed to include Eukaryota, another unique feature among rDNA databases. With the termination of the European Ribosomal RNA Database Project in 2007, the SILVA database has become the authoritative rDNA database project for Europe. The application spectrum of ARB and SILVA ranges from biodiversity analysis, medical diagnostics, to biotechnology and quality control for academia and industry. PMID- 28648399 TI - Christiana Figueres joins The Lancet Countdown-delivering on the promise of Paris. PMID- 28648400 TI - Oesophageal cancer. AB - Oesophageal cancer is a clinically challenging disease that requires a multidisciplinary approach. Extensive treatment might be associated with a considerable decline in health-related quality of life and yet still a poor prognosis. In recent decades, prognosis has gradually improved in many countries. Endoscopic procedures have increasingly been used in the treatment of premalignant and early oesophageal tumours. Neoadjuvant therapy with chemotherapy or chemoradiotherapy has supplemented surgery as standard treatment of locally advanced oesophageal cancer. Surgery has become more standardised and centralised. Several therapeutic alternatives are available for palliative treatment. This Seminar aims to provide insights into the current clinical management, ongoing controversies, and future needs in oesophageal cancer. PMID- 28648401 TI - Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. PMID- 28648402 TI - Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. AB - BACKGROUND: Graded exercise therapy is an effective and safe treatment for chronic fatigue syndrome, but it is therapist intensive and availability is limited. We aimed to test the efficacy and safety of graded exercise delivered as guided self-help. METHODS: In this pragmatic randomised controlled trial, we recruited adult patients (18 years and older) who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome from two secondary-care clinics in the UK. Patients were randomly assigned to receive specialist medical care (SMC) alone (control group) or SMC with additional guided graded exercise self-help (GES). Block randomisation (randomly varying block sizes) was done at the level of the individual with a computer-generated sequence and was stratified by centre, depression score, and severity of physical disability. Patients and physiotherapists were necessarily unmasked from intervention assignment; the statistician was masked from intervention assignment. SMC was delivered by specialist doctors but was not standardised; GES consisted of a self-help booklet describing a six-step graded exercise programme that would take roughly 12 weeks to complete, and up to four guidance sessions with a physiotherapist over 8 weeks (maximum 90 min in total). Primary outcomes were fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale); both were self-rated by patients at 12 weeks after randomisation and analysed in all randomised patients with outcome data at follow-up (ie, by modified intention to treat). We recorded adverse events, including serious adverse reactions to trial interventions. We used multiple linear regression analysis to compare SMC with GES, adjusting for baseline and stratification factors. This trial is registered at ISRCTN, number ISRCTN22975026. FINDINGS: Between May 15, 2012, and Dec 24, 2014, we recruited 211 eligible patients, of whom 107 were assigned to the GES group and 104 to the control group. At 12 weeks, compared with the control group, mean fatigue score was 19.1 (SD 7.6) in the GES group and 22.9 (6.9) in the control group (adjusted difference -4.2 points, 95% CI -6.1 to -2.3, p<0.0001; effect size 0.53) and mean physical function score was 55.7 (23.3) in the GES group and 50.8 (25.3) in the control group (adjusted difference 6.3 points, 1.8 to 10.8, p=0.006; 0.20). No serious adverse reactions were recorded and other safety measures did not differ between the groups, after allowing for missing data. INTERPRETATION: GES is a safe intervention that might reduce fatigue and, to a lesser extent, physical disability for patients with chronic fatigue syndrome. These findings need confirmation and extension to other health-care settings. FUNDING: UK National Institute for Health Research Research for Patient Benefit Programme and the Sue Estermann Fund. PMID- 28648403 TI - Genetic determinant of Bacillus pumilus lipase lethality and its application as positive selection cloning vector in Escherichia coli. AB - Positive selection vectors carry genes that upon expression produce proteins that cause host cell deaths. Insertion of foreign DNA fragments within the ORF of the gene disrupts the lethal effect of the expressed protein. This study described the cloning of Family I.4 Bacillus pumilus lipase gene whose expressed protein is toxic and lethal to Escherichia coli JM109 (DE3) cells. The determinant of toxicity was identified through Error-prone PCR to be the nature of amino acid residue resident at position 28 of the mature lipase protein. The presence of Thr/Ser28 within the mature lipases of B. pumilus and B. licheniformis resulted in lethality to E. coli cells. However, the Thr28Ala or Thr28Gly mutations relieved the lethal phenotype of mature Family I.4 Bacillus lipases. The toxic effect of the expressed mature B. pumilus lipase protein was exploited in the development of a positive selection cloning vector. The B. pumilus lipase gene was synthesised to contain 13 unique silent restriction sites within the ORF, and placed under the regulation of T7 promoter of the pET expression system. Insertional inactivation of the gene's toxic protein was achieved by cloning DNA fragments of different sizes within the designed multiple cloning sites. The toxic effect of the lipase protein was disrupted indicating the potential of the gene for application in suicidal positive selection cloning vectors. The results revealed that protein expression and engineering studies aimed at optimal production of mature Family I.4 Bacillus lipases in E. coli should take into consideration the nature of amino acid 28 resident. PMID- 28648404 TI - Osthole inhibits intimal hyperplasia by regulating the NF-kappaB and TGF beta1/Smad2 signalling pathways in the rat carotid artery after balloon injury. AB - Osthole (7-methoxy-8-isopentenoxy-coumarin), a compound extracted from Cnidiummonnieri (L.) Cusson seeds, has been found to exhibit potent therapeutic effects in cancer due to its ability to inhibit inflammation and cell proliferation. However, its effects on arterial wall hypertrophy-related diseases remain unclear. Therefore, in this study, we aimed to investigate the effects of Osthole on intimal hyperplasia in a rat model of carotid artery balloon injury. We established the balloon-induced carotid artery injury rat model in male Sprague-Dawley rats, after which we administered Osthole (20mg/kg/day or 40mg/kg/day) or volume-matched normal saline orally by gavage for 14 consecutive days. Intimal hyperplasia and the degree of vascular smooth muscle cell proliferation were then evaluated by histopathological examination of the changes in the carotid artery, as well as by examination of proliferating cell nuclear antigen (PCNA) expression. Tumour necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), transforming growth factor-beta (TGF-beta1) and PCNA mRNA expression levels were examined by real-time RT-PCR, while nuclear factor-kappaB (NF-kappaB (p65)), IkappaB-alpha, TGF-beta1 and phospho-Smad2 (p-Smad2) protein expression levels were analysed by immunohistochemistry or western blot analysis. We found that Osthole significantly attenuated neointimal thickness and decreased the elevations in PCNA protein expression induced by balloon injury. Moreover, Osthole down-regulated the pro-inflammatory factors TNF-alpha and IL-1beta and NF kappaB (p65), whose expression had been upregulated after balloon injury. Moreover, IkappaB-alpha protein expression levels increased following Osthole treatment. In addition, the elevations in TGF-beta1 and p-Smad2 protein expression induced by balloon injury were both significantly attenuated by Osthole administration. We concluded that Osthole significantly inhibited neointimal hyperplasia in balloon-induced rat carotid artery injury and that the mechanism by which this occurs may involve NF-kappaB, IL-1beta and TNF-alpha down regulation, which alleviates the inflammatory response, and TGF-beta1/Smad2 signalling pathway inhibition. PMID- 28648406 TI - N-(2-morpholin-4-yl-ethyl)-2-(1naphthyloxy)acetamide inhibits the chronic constriction injury-generated hyperalgesia via the antagonism of sigma-1 receptors. AB - The most used therapeutic treatment to relieve neuropathic pain is that of neuromodulators such as anti-epileptics or anti-depressants; however, there are alternatives that may be potentially useful. The sigma-1 receptor is a therapeutic target that has shown favorable results at preclinical levels. The aim of this study was to evaluate the anti-hyperalgesic effect of N-(2-morpholin 4-yl-ethyl)-2-(1-naphthyloxy) acetamide (NMIN) in a chronic constriction injury model (CCI) and compare it both a sigma-1 antagonist (BD-1063) and also Gabapentin, as well as determine its possible role as an antagonist of sigma-1 receptors. The anti-hyperalgesic effects of Gabapentin (10.0, 17.8, 31.6, 56.2 and 100mg/kg, s.c.), BD-1063 (5.6, 10.0, 17.8, 31.6 and 56.2mg/kg, s.c.) and NMIN (31.6, 10.0, 316mg/kg and 562mg/kg, s.c.) were determined after single-doses, using the von Frey test in the CCI model. NMIN had the same efficacy as BD-1063, but both show less efficacy than Gabapentin. In an analysis of pharmacological potency, the ED50 were compared with it being found that BD-1063 is the most potent drug, followed by Gabapentin and NMIN. The anti-hyperalgesic effect of NMIN on CCI rats was reversed by (+)-pentazocine (s.c. route) and by PRE-084 (i.t. route), both sigma-1 agonists. Furthermore, NMIN reversed the hyperalgesic effect of PRE-084 in naive rats. These results suggest that NMIN has an anti hyperalgesic effect on the CCI model, and that one of its mechanisms of action is as a sigma-1 antagonist, being a significant role the blocking of these receptors at the spinal level. PMID- 28648405 TI - Anti-inflammatory activity of coptisine free base in mice through inhibition of NF-kappaB and MAPK signaling pathways. AB - Coptisine is one of the main constituents of Coptis chinensis which has been widely used for the remedy of inflammatory disorders. Although the biological activities of coptisine have been well known, the pharmacological properties of its free base have seldomly been elucidated thus far. The aim of this study was to investigate the potential anti-inflammatory properties of coptisine free base (CFB, 8-hydroxy-7,8-dihydrocoptisine) on three animal models, namely xylene induced ear edema, acetic acid-induced vascular permeability and carrageenan induced paw edema. The results exhibited that CFB exerted a dose-dependent suppression on ear edema induced by xylene, significantly mitigated the aggravation of vascular permeability caused by acetic acid and paw edema induced by carrageenan. Additionally, CFB significantly suppressed the productions of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), prostaglandinE2 (PGE2) and tumor necrosis factor (TNF-alpha) in the drug-treated groups as compared with the vehicle group after treatment with carrageenan. Signaling events of nuclear factor-kappaB (NF-kappaB) translocation, such as p-IKKalpha, p-IKKbeta, p IkappaBalpha and p65 (nucleus) were significantly inactivated, while inhibitor of nuclear factor kappaBalpha (IkappaBalpha) and p65 (cytosolic) were markedly up regulated by CFB. Furthermore, CFB also significantly suppressed the mitogen activated protein kinase (MAPK) pathway by blocking the phosphorylation of p-p38 (phospho-p38 mitogen-activated protein kinases) and p-JNK (phospho-c-jun N terminal kinase) but not p-ERK (phospho-extracellular signal-regulated kinase). Hence, CFB efficiently prevented inflammation, at least partially, via inhibition of NF-kappaB and MAPK pathways. These findings provided a pioneering pharmacological basis for the anti-inflammatory effect of CFB and suggested CFB might be a potential candidate for the therapy of inflammatory disorders. PMID- 28648407 TI - Health-related quality of life, fear of recurrence, and emotional distress in patients treated for thyroid cancer. AB - Diagnosis of differentiated thyroid carcinoma (papillary or follicular) and its treatment may be associated with a poor health-related quality of life (HRQoL), and with fear of recurrence (FoR), and distress. To our knowledge, this is the first time a single FoR screening question (written to complement a HRQoL questionnaire), has been reported with HRQoL and levels of distress in patients treated for the disease. In April 2014 we did a cross-sectional survey of patients who had presented to the Merseyside and Cheshire thyroid cancer network between April 2009 and November 2013. Questionnaires comprised the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, the THYCA-QoL, the Emotion Thermometers, and the new FoR screening item. A total of 249 surveys were sent and 169 patients responded (68%). The most prevalent issues included tiredness, problems with sleep and needing to rest, pain (particularly in muscles and joints), a dry mouth, hot flushes and tolerating heat, gaining weight, and feeling slowed down or weak; also, having trouble taking long walks or doing strenuous activities, feeling tense, worried, irritable, and anxious, and having difficulty remembering things. One in seven patients (95% CI 9% to 21%) responded to the single FoR question that they "had a lot of fears of recurrence that really preoccupied their thoughts" or were "fearful all the time that their cancer might return and that they struggled with this". Distress overall was relatively low. In conclusion, the HRQoL issues reported by these patients were different from those reported by patients with other cancers of the head and neck. It would be helpful to identify FoR in a subgroup of patients with differentiated thyroid cancer so that they could be given additional support. PMID- 28648408 TI - NHSLA litigation in hip fractures: Lessons learnt from NHSLA data. AB - Hip fractures are a major cause of trauma related death, usually occurring in vulnerable elderly patients. There are an estimated 70,000 hip fractures in the UK per year with numbers set to rise. The estimated annual cost to the healthcare economy is in the region of L2 billion. A 17-year review examining litigation related to hip fractures was undertaken. Under a freedom of information request, data was obtained relating to all orthopaedic claims made to the NHS Litigation Authority (NHSLA) between 1995 and 2012. Data was filtered to identify cases involving hip fractures examining litigation trends related to this specific area. 10263 NHSLA orthopaedic cases were identified, of which 13.3% (n=1364) cases related to the hip and femur. Hip fractures made up 16.7% (n=229). The total cost of hip fracture litigation was over L7 million with an average cost per case of L32,700. The commonest reasons for litigation were diagnostic errors (30.6%), issues with care (24.9%) alleged incompetent surgery (15.7%) and development of pressure sores (5.7%). This study highlights the main causes of litigation in patients sustaining hip fractures, with diagnosis in the emergency department and ward presenting a significant problem. In addition, the data identifies a range of care related issues, as well as several surgical factors and highlights the importance of pressure area care. We discuss these and make suggestions on how to improve practice in this area with the aim of improving patient care and reducing litigation. PMID- 28648409 TI - Management of esophageal injuries secondary to trauma. AB - Traumatic esophageal injuries occur less than 10% of the time in the setting of blunt or penetrating trauma. The purpose of this literature review is to provide an update on the most recent changes involving the diagnosis and treatment of esophageal injuries. A literature search was conducted using PubMed, to identify articles written in English language with the terms "non- iatrogenic", "esophageal", "trauma", "diagnosis", "management", and "prognosis". Case reports and articles involving non-traumatic esophageal perforations were excluded. Fifty pertinent articles in English language from 1947 to 2015 were selected for review. Based on the review of all articles, we designed a diagnostic and therapeutic algorithm to facilitate the diagnosis and management of the traumatic esophageal injury. PMID- 28648410 TI - The Great Unknown-A systematic literature review about risk associated with intraoperative imaging during orthopaedic surgeries. AB - INTRODUCTION: Modern techniques in orthopaedic surgery using minimally invasive procedures, and increased use of fluoroscopic imaging present a potential increased risk to surgeons due to ionizing radiation exposure. This article is a systematic review of recent literature on radiation exposure of orthopaedic surgeons. MATERIALS AND METHODS: Pubmed and Cochrane searches were performed on intraoperative radiation exposure covering English and German articles published between 1.1.2000 and 11.8.2014. Inclusion criteria were clinical studies and systematic literature reviews focusing on radiation exposure of orthopaedic surgeons during surgical procedures of the musculoskeletal system reporting either effective dose (whole body) or equivalent dose at the organ level. All included articles were reviewed with focus on the surgical specialty, the procedure type, the imaging system used, the radiation measurement method, the fluoroscopy time, the radiation exposure, the use of radiation protection, and any references to specific safety guidelines. RESULTS: Thirty-four eligible publications were identified. However, the lack of well-designed studies focusing on radiation exposure of surgeons prevents pooling of data. Highest exposure and subsequent equivalent doses were reported from spinal surgery (up to 4.8mSv of equivalent dose to the hand) and intramedullary nailing (up to 0.142mSV of equivalent dose to the thyroid). Radiation exposure was reduced by 96.9% and 94.2% when wearing a thyroid collar and a lead apron. CONCLUSIONS: With the increasing use of intraoperative imaging, there is a growing need for radiation awareness by the operating surgeon. Strict adherence to radiation protection should be enforced to protect in-training surgeons. Strategies to reduce exposure include C-arm position, distance, protective wear, and new imaging technologies. Radiation exposure is harmful and action should be taken to minimize exposure. PMID- 28648411 TI - Visual feedback explains why propointing is better than antipointing in spatial neglect. AB - Rossit et al. (2011) showed that neglect patients perform normally in a propointing task but not in an antipointing task which requires pointing towards the mirrored position of a target. It is assumed that antipointing relies on information from the perceptual pathway of our visual brain. Therefore, this finding supports the notion that neglect is a disorder that primarily affects perceptual spatial representations within the brain leaving spatial maps used for visuomotor guidance intact. Alternatively, performance of patients might be compromised in both tasks, but only obviously so in tasks in which online corrections are made more difficult. It can be argued that online-corrections via visual feedback are less effective in antipointing because a direct comparison between hand and target is not possible in this condition. Secondly, it is also known that neglect patients have a pronounced egocentric bias which is assumed to be associated with a deviation of the perceived body midline. Since the midline is used to compute the end-position in the antipointing task this could also explain why patients are worse in antipointing. We investigated the influence of visual feedback on pro- and antipointing and the effect of providing a visual reference line for the antipointing task in right-brain damaged patients with neglect (n = 20), right-brain damaged patients without neglect (n = 23) and in a group of healthy participants (n = 22). The withdrawal of visual feedback had a stronger effect on propointing compared to antipointing. This effect was stronger in neglect patients than in patients without neglect or healthy controls. The introduction of a reference line reduced errors in antipointing performance, particularly in neglect patients with a strong egocentric bias. The results support our alternative account and challenge the hypothesis that the spatial disorder in neglect affects primarily perceptual maps within the visual system. PMID- 28648412 TI - Renal outcome after radical cystectomy and urinary diversion performed with restrictive hydration and vasopressor administration in the frame of an enhanced recovery program: A follow-up study of a randomized clinical trial. AB - OBJECTIVE: To determine whether a restrictive perioperative fluid management in the context of an enhanced recovery after surgery program for radical cystectomy and urinary diversion affects renal function, as fluid restriction and the use of vasopressors have been linked to impaired tissue perfusion, potentially resulting in renal dysfunction. METHODS: We followed 166 patients initially included in a randomized clinical trial and equally allocated to receive a continuous norepinephrine administration combined with 1ml/kg/h initially, and after cystectomy 3ml/kg/h crystalloid infusion (intervention group, n = 83), or a standard crystalloid infusion of 6ml/kg/h throughout surgery (control group, n = 83). All patients followed our institutional enhanced recovery after surgery program. We prospectively assessed renal function (plasma creatinine values and estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration equation) postoperatively. Decreased renal function was defined as a decrease in glomerular filtration rate is greater than 20% compared to preoperative values. RESULTS: There was no significant difference in renal function between the groups postoperatively at any time point after discharge: diabetes mellitus (HR = 2.81 [95% CI: 1.48-5.36]; P = 0.002), preoperative estimated glomerular filtration rate (HR = 1.02 [95% CI: 1.00-1.03]; P = 0.007), and age (OR = 1.03 [95% CI: 11.00-1.06]; P = 0.038) were negative predictors for renal deterioration. CONCLUSION: Postoperative renal function evolution was similar in patients receiving restrictive hydration with norepinephrine administration when compared to liberal hydration intraoperatively, suggesting that there is no influence of fluid management and administration of vasopressors on mid-term renal function. PMID- 28648413 TI - Neurovascular bundle size measured on 3.0-T magnetic resonance imaging is associated with the recovery of erectile function after robot-assisted radical prostatectomy. AB - BACKGROUND AND OBJECTIVE: Erectile dysfunction is one of the complications occurring after radical prostatectomy (RP), and recovery of erectile function is quantitatively related to the preservation of the neurovascular bundles (NVB).We evaluated the significance of NVB area on functional outcomes after RP. MATERIALS AND METHODS: Preoperative magnetic resonance imaging was performed on 141 patients who underwent bilateral, nerve-sparing, robot-assisted RP for clinically localized prostate cancer (clinically T2N0M0 on magnetic resonance imaging) and were evaluated at least 12 months after surgery. NVB area was measured as a region of interest that coincided with the outline of the maximum area of the posterolateral region of the prostate on T2-weighted axial imaging. Factors associated with functional outcomes were evaluated using logistic regression analysis. RESULTS: Of 141 patients, 36 patients (25.5%) had no preoperative potency (group 1), 66 patients (46.8%) recovered potency (group 2), and 39 patients (27.7%) did not recover potency (group 3). Although the mean age of the entire cohort was 65.4 years, the mean age of group 1 was greater than groups 2 and 3 (P = 0.001). The NVB area of group 2 was larger than those of groups 1 and 3 (P = 0.001). Potency evaluations involved 105 patients (74.5%; groups 2 and 3), and patients with pre-existing erectile dysfunction were excluded. The median time to potency recovery was 3.0 months after surgery. The multivariable analysis revealed that the NVB area was the only significant factor predictive of potency recovery. CONCLUSIONS: The NVB area in the posterolateral region of the prostate is an independent factor for predicting potency recovery. The degree of postoperative erectile function can be predicted based on the preoperative NVB area. PMID- 28648414 TI - Prognostic role of Ki-67 score in localized prostate cancer: A systematic review and meta-analysis. AB - BACKGROUND: Ki-67 for quantifying tumor proliferation is widely used. In localized prostate cancer (PCa), despite a suggested predictive role of Ki-67 for outcomes after therapies, it has not been incorporated into clinical practice. Herein, we conduct a systematic review and meta-analysis of the literature reporting the association of Ki-67 and disease outcomes in PCa treated radically. METHODS: Medline and EMBASE databases were searched without date or language restrictions, using "KI67" and "prostate cancer" MeSH terms. Studies reporting Ki 67 association with clinical outcomes (disease-free survival [DFS], biochemical failure-free survival, rate of distant metastases [DM], disease-specific survival [DSS], or overall survival [OS], or all of these) in patients with PCa managed actively were included, and relevant data extracted by 2 independent reviewers. Odds ratios (OR) were weighted and pooled in a meta-analysis using Mantel Haenszel random-effect modeling. RESULTS: Twenty-one studies comprising 5,419 patients met eligibility for analysis, and 67.6% of patients had low Ki-67. Mean Ki-67 was 6.14%. High Ki-67 was strongly associated with worse clinical outcomes. DFS was better in those patients with low Ki-67 at 5 and 10 years (OR = 0.32, 95% CI: 0.23-0.44, P<0.00001; OR = 0.31, 95% CI: 0.20-0.48, P<0.00001). Similarly, low Ki-67 was related to improved DSS at 5 and 10 years (OR = 0.15, 95% CI: 0.10 0.21, P<0.00001; OR = 0.16, 95% CI: 0.06-0.40, P<0.00001). Association between low Ki-67 scores with improved OS (OR = 0.47; 95% CI: 0.37-0.61; P<0.00001) and high Ki-67 scores with DM at 5 years (OR = 4.07; 95% CI: 2.52-6.58; P<0.00001) was consistently observed. CONCLUSIONS: High Ki-67 expression in localized PCa is a factor of poor prognosis for DSS, biochemical failure-free survival, DFS, DM, and OS after curative-intent treatments. Incorporation into clinical routine of this widely available and standardized biomarker should be strongly considered. PMID- 28648415 TI - Non-invasive cardiac output monitoring - To be or not to be, that is the question! AB - Role of hemodynamic monitoring in critically ill patients is still controversial. While invasive monitoring is accurate, it may be counter-productive in view of its essentially invasive nature. Non-invasive monitoring is less intrusive but has not yet been well validated for accuracy compared with gold standard of invasive monitoring. PMID- 28648416 TI - Primary percutaneous coronary intervention for acute ST elevation myocardial infarction: Outcomes and determinants of outcomes: A tertiary care center study from North India. AB - BACKGROUND: Primary percutaneous coronary intervention (PCI) is the current standard of care for acute ST elevation myocardial infarction (STEMI). Most of the data on primary PCI in acute STEMI is from western countries. We studied the outcomes of primary PCI for acute STEMI at a tertiary care center in North India. METHODS: Consecutive patients undergoing primary PCI for STEMI were prospectively studied during the period from February 2103 to May 2015. The outcomes assessed were all cause in hospital mortality, factors associated with mortality, major adverse cardiac and cerebrovascular event rate (composite of all cause in hospital mortality, non-fatal re infarction and stroke) and procedural complications. RESULTS: 371 patients underwent primary PCI during the study period. The mean age was 54 years and 82.7% were males. The mean total ischemia time and door to balloon times were 6.8h and 51min respectively. 96.4% patients underwent successful primary PCI. The total in hospital mortality was 12.9%. Mortality with cardiogenic shock at presentation was 66.7% while non-shock mortality was 2.6%. In hospital MACCE rate was 13.5%. Factors significantly associated with mortality were KILLIP class (OR: 8.4), door to balloon time (OR 1.02), final TIMI flow (OR 0.44) and severe LV dysfunction (OR 22.0). Procedure related adverse events were rare and there was no non-CABG associated major TIMI bleeding. CONCLUSION: Primary PCI for acute STEMI is feasible in our setup and associated with high success rate, low mortality in non-shock patients and low complication rates. PMID- 28648417 TI - Effect of heart failure reversal treatment as add-on therapy in patients with chronic heart failure: A randomized, open-label study. AB - OBJECTIVES: The present study was designed to evaluate effect of heart failure reversal therapy (HFRT) using herbal procedure (panchakarma) and allied therapies, as add-on to standard CHF treatment (SCT) in chronic heart failure (CHF) patients. METHODS: This open-label, randomized study conducted in CHF patients (aged: 25-65 years, ejection fraction: 30-65%), had 3-phases: 1-week screening, 6-week treatment (randomized [1:1] to HFRT+SCT or SCT-alone) and follow-up (12-week). Twice weekly HFRT (60-75min) consisting of snehana (external oleation), swedana (passive heat therapy), hrudaydhara (concoction dripping treatment) and basti (enema) was administered. Primary endpoints included evaluation of change in metabolic equivalents of task (MET) and peak oxygen uptake (VO2peak) from baseline, at end of 6-week treatment and follow-up at week 18 (non-parametric rank ANCOVA analysis). Safety and quality of life (QoL) was assessed. RESULTS: Seventy CHF patients (n=35, each treatment-arm; mean [SD] age: 53.0 [8.6], 80% men) were enrolled in the study. All patients completed treatment phase. Add-on HFRT caused a significant increase in METs (least square mean difference [LSMD], 6-week: 1.536, p=0.0002; 18-week: -1.254, p=0.0089) and VO2peak (LSMD, 6-week: -5.52, p=0.0002; 18-week: -4.517, p=0.0089) as compared with SCT-alone. Results were suggestive of improved functional capacity in patients with HFRT (QoL; Mean [SD] HFRT+SCT vs. SCT-alone; 6-week: -0.44 [0.34] vs. -0.06 [0.25], p<0.0001 and 18-week: -0.53 [0.35] vs. -0.29 [0.26], p=0.0013). Seven treatment-emergent adverse events (mild severity) were reported in HFRT arm. CONCLUSION: Findings of this study highlight therapeutic efficacy of add-on HFRT vs. SCT-alone in CHF patients. The non-invasive HFRT showed no safety concerns. PMID- 28648418 TI - Longitudinal ventricular systolic dysfunction in patients with very severe obstructive sleep apnea: A case control study using speckle tracking imaging. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is a prevalent condition that is increasingly recognized to be associated with cardiovascular disease. We aimed to investigate the subclinical systolic ventricular dysfunction of patients with OSA using novel speckle tracking echocardiographic (STE) techniques. METHODS: This study included 31 patients of polysomnography proven very severe OSA [Apnea Hypopnea Index(AHI) >40] and an equal number of matched population with no OSA as controls. All the study participants underwent a detailed conventional and tissue Doppler strain echocardiogram in addition to STE. RESULTS: There was no significant difference in conventional ventricular systolic function parameters including left ventricular (LV) ejection fraction, and myocardial performance index of left ventricle. Diastolic function was significantly reduced in patients with OSA as compared to controls. There was no difference in global circumferential strain or time to its peak between the two groups. However global longitudinal LV strain (GLS) was significantly reduced in patients with OSA (p<0.01). Similarly time to peak longitudinal strain was prolonged in the OSA group as compared to controls. Segmental analysis revealed that the longitudinal strain abnormalities were more pronounced in the apical and mid segments of LV. AHI remained the only significant predictor of GLS in these patients. CONCLUSION: Very severe OSA is associated with significant diastolic dysfunction as well as early systolic abnormalities as evidenced by abnormal global longitudinal strain. Sleep apnea severity as measured by AHI was the only significant predictor of abnormal longitudinal strain in these patients. PMID- 28648420 TI - Prevalence and predictors of ventriculo-atrial conduction in structurally normal hearts. AB - BACKGROUND: The prevalence of ventriculo-atrial (VA) conduction varies from 20% to 90%, depending on the population studied (Militianu et al., 1997; Inoue et al., 1985; Kazmierczak et al., 1993; Ciemniewski et al., 1990; Hayes and Furman, 1983; Westveer et al., 1984). This wide range is mostly based on studies done in patients with implanted devices or impaired atrioventricular conduction. However, the prevalence of VA conduction in structurally normal heart has not been well documented till date. OBJECTIVE: To study the prevalence and identify predictors of retrograde conduction via the His-Purkinje system and AV node in structurally normal hearts. METHODS: We included 54 consecutive adults without structural heart disease who underwent electrophysiological (EP) study for various tachycardias. The basic parameters including PR, AH and HV intervals, atrioventricular Wenckebach point (AVWP) and anterograde effective refractory period (ERP) of atrioventricular node (AVNERP), were measured after ablation. The VA conduction was assessed basally and if absent, after isoprenaline. The VA Wenckebach point (VAWP) and retrograde ERP(VAERP) were recorded in patients showing VA conduction. RESULTS: The mean age was 37.1+/-12.6years. Twenty five (46%) of the patients were men. VA conduction was present in 30 (55%) patients at baseline. Of the remaining 24 patients, 18 (34%) showed VA conduction after isoprenaline. Only 6 (11%) patients failed to reveal VA conduction even after adequate response to isoprenaline. Amongst all clinical and EP variables analysed, only the HV interval was shorter (p<0.01) in patients with VA conduction. CONCLUSION: In structurally normal hearts, VA conduction was present at baseline in 55% of patients. Isoprenaline unmasked VA conduction in an additional 34% of the subjects. The HV interval was longer in patients without VA conduction. PMID- 28648419 TI - Diagnostic accuracy of serum cystatin C for early recognition of contrast induced nephropathy in Western Indians undergoing cardiac catheterization. AB - AIMS: We aimed to compare the diagnostic efficacy of serum cystatin C (sCyC) for contrast induced nephropathy (CIN) in Western Indians undergoing cardiac catheterization. We also aimed to propose a clinically applicable cut-off of sCyC for early identification of CIN in this ethnic group. METHODS: In this prospective study, 253 patients undergoing coronary angiography and/or percutaneous coronary intervention were enrolled. The demographic and risk factor details, levels of sCr at baseline, 24 and 48h after the procedure, whereas baseline and 24h levels of sCyC were noted. Increase of 0.5mg/dl or >=25% from baseline sCr was used to define CIN. Optimum cut off of sCyC for CIN diagnosis was obtained using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: After 48h of contrast media (CM) exposure, the incidence of CIN was 12.25% (31 patients) according to sCr definition, where only 3.9% (10 patients) had sCr rise in 24h. Overall significant (p<0.0001) rise in mean levels of sCr (48h) and sCyC (24h) was observed in CIN patients. However, the mean sCr rise at 24h was non-significant. The optimum cut off of sCyC for diagnosing CIN was found to be a rise of >=10% from baseline (AUC - 0.901; sensitivity - 100%, specificity - 77.89%). According to sCyC, 94 (37.15%) patients had CIN. CONCLUSION: We may conclude that a rise of >=10% in sCyC at 24h could be used as a reliable marker for identification of CIN in western Indians undergoing cardiac catheterization. PMID- 28648421 TI - Clinical outcome of various management strategies in coronary artery ectasia. PMID- 28648422 TI - Troponin I elevation after elective percutaneous coronary interventions: Prevalence and risk factors. AB - Troponin elevation after coronary angioplasty is a prognostic marker associated with significant morbidity and mortality, although its prevalence varies according to clinical and procedural characteristics. We analyzed the frequency of post-procedural enzyme elevation among 112 elective interventions between 2013 and 2014 in a private hospital in Brazil. Troponin increase was observed in 62.5% of the procedures, and was related to age, female sex, low pre-procedural hemoglobin, prior angiotensin converting enzyme inhibitor or angiotensin receptor blocker use and multivessel angioplasty. PCI is not a risk free procedure and these results underscore the importance of a careful clinical assessment before its utilization. PMID- 28648423 TI - Evaluation of gamma glutamyl transferase as a marker of cardiovascular risk, in 200 angiographically proven coronary artery disease patients. AB - Gamma glutamyl transferase (GGT) is emerging as a promising marker for assessing cardiovascular risk. GGT predicts cardiovascular mortality in the population and is positively associated with traditional risk factors for coronary artery disease (CAD). This study was undertaken on 200 north Indian CAD patients diagnosed with coronary angiography to study relation of GGT with risk factors for CAD and severity of CAD. GGT values ranged from 5 to 69U/L and were divided in 4 quartiles. GGT was positively associated with triglyceride (p=0.008) and VLDL cholesterol (p=0.002) in our subjects. Also an increase in total cholesterol from GGT quartile I to quartile IV (p=0.28) was noted. PMID- 28648424 TI - Late-onset dynamic outflow tract gradient in the setting of tako-tsubo cardiomyopathy: An interesting phenomenon with potential implications? AB - In clinical practice, dynamic left ventricular outflow tract obstruction (LVOTO) in the setting of tako-tsubo cardiomyopathy (TTC) has been regarded as an early onset complication typically emerging in accordance with wall motion abnormalities. However, dynamic LVOTO has, very rarely, been reported as a late onset phenomenon in the setting of TTC as well (arising in the late stage or after recovery). Accordingly, the present paper aims to highlight clinical relevance and potential implications of late-onset LVOTO in the setting of TTC. PMID- 28648425 TI - Association between electrocardiographic and echocardiographic right ventricular hypertrophy in a military cohort in Taiwan: The CHIEF study: ECG criteria for RVH. AB - We compared electrocardiographic and echocardiographic right ventricular hypertrophy (RVH) in 264 military members in Taiwan. The correlations of the Myers et al. and Sokolow-Lyon criteria with RV wall thickness were low (r<0.1). Our data supported the American guidance that RVH voltage criteria violations should not receive further echocardiographic investigation. PMID- 28648426 TI - Percutaneous closure of symptomatic large tricuspid paravalvular regurgitation using two muscular VSD occluders. AB - Paravalvular leaks are common following valve replacement surgery. Majority are benign and do not require any active intervention. However, occasionally severe paravalvular regurgitation can produce heart failure and/or hemolysis, needing closure of the defect. It is more commonly associated with aortic and mitral prosthesis, symptomatic tricuspid paravalvular regurgitation being a rare entity. In this report we present the successful percutaneous transcatheter closure of a large paravalvular tricuspid regurgitation in a 59-year old lady with history of multiple previous operations. The elongated crescent-shaped defect was closed using two muscular VSD devices without any residual leak and without hampering the bio-prosthetic tricuspid valve function. Patient had transient complete heart block during the procedure which recovered later. There was marked improvement in the symptomatic status of the patient at discharge (NYHA IV to NYHA II), which was sustained at follow-up. PMID- 28648427 TI - Asymptomatic late embolization of Amplatzer septal occluder device. AB - Atrial septal defects of Ostium Secundum type with suitable anatomy and margins are commonly closed with septal occluder devices. With the increasing number of catheterization laboratories and increasing availability of different devices, the device closure procedure is very commonly performed in different institutes. Embolization of the septal occluder is one of the most dreaded complications of this procedure, which usually occurs in the early hours or days after the procedure. We report a case of silent embolization of the Amplatzer septal occluder, detected seven months after its use to close an Ostium Secundum atrial septal defect, which was detected during pre-anaesthetic evaluation and echocardiography for non-cardiac surgery. The patient denied having any symptom in-between. The device was retrieved and the defect was closed surgically. PMID- 28648428 TI - Transcatheter closure of left ventricle to right atrial communication using cera duct occluder. AB - Left ventricle-right atrial communication could be congenital (Gerbode defect) or acquired as a complication of surgery or infective endocarditis and leads to volume overloading of pulmonary circulation. Two types, direct and indirect types are known depending on the involvement of septal tricuspid leaflet. Transcatheter closure of this defect is feasible and appears an attractive alternative to surgical management. Various devices like Amplatzer duct occluder I, II, Muscular ventricular septal defect device etc. have been used to close this defect. We report two patients, a preteen boy with direct left ventricle-right atrial communication as post operative complication and an adult female with indirect communication who underwent transcatheter closure with Cera duct occluder (Lifetech Scientific (Shenzhen), China). PMID- 28648429 TI - DDD pacemaker for severe heart failure-alternate to CRT. AB - Patients with severe systolic Heart Failure continue to have poor quality of life and increased mortality in spite of optimal medical management. Cardiac Resynchronization Therapy [CRT] is promising modality in patients with systolic heart failure and electrocardiographic [ECG] evidence of left bundle branch block [LBBB]. Cost issues continue to elude many deserving cases of this therapy in our society. Relatively cost effective Dual chamber pacing [DDD] with right atrial and isolated left ventricular pacing [RA-LV] can be a good alternative. PMID- 28648430 TI - A case of multiple cardiac calcified amorphous tumours. AB - Cardiac calcified amorphous tumours of the heart are rare non-neoplastic cardiac masses that can present like a malignant mass or an intra-cardiac thrombus. We report an extremely unusual case of a 73year old man who presented to hospital with dyspnoea and subsequent investigations revealed multiple cardiac CATs. PMID- 28648431 TI - An echocardiographic clue for ostial left main coronary artery stenosis. AB - Calcified nodules in human coronary arteries are usually focally distributed. Non invasive imaging of coronary arteries by bedside emergency transthoracic echocardiography in adults is possible and may become a useful adjunct to other methods of coronary artery examination. Coronary artery stenosis can be identified as localized color aliasing and accelerated flow velocities. Complete visualization of individual ostial coronary segments might ease the demonstration of coronary stenosis by bedside transthoracic echocardiography. The left main coronary artery stenosis requires prompt emergency evaluation and treatment because emergency conditions have higher mortality rates. The authors wish to emphasize the usefulness of emergency bedside echo-Doppler for a prompt diagnosis and treatment of this life-threatening condition. PMID- 28648432 TI - Importance of the heart borders as a fluoroscopic clue for cardiac tamponade. AB - Every catheter laboratory is equipped with an X-ray system designed to provide fluoroscopic imaging of the heart. Although cardiac catheters are well visualized in all X-ray imaging, the soft tissue of myocardium is not. Therefore the imaging of the cardiac chambers is indirect through relation to the cardiac silhouette. However, fluoroscopy can be used to detect complications from the invasive procedures in the cardiac catheterization laboratory, such as cardiac tamponade where the excursion of the cardiac silhouette decreases, and visceral and parietal pericardium are seen separated by the blood of accumulation in the pericardial cavity. Even if a transthoracic or intracardiac echocardiography guidance is immediately available, early fluoroscopic detection of tamponade should be remembered during the invasive procedures in the cardiac catheterization laboratory. PMID- 28648433 TI - The importance of recognizing the prominent Eustachian valve in the evaluation of atrial septal defects before percutaneous or surgical closure. AB - Atrial septal defect closure is now routinely performed using a percutaneous approach under echocardiographic guidance. Since some echocardiographic features play an important role in the assessment of the defect and safety of the procedure, the salient features of the anatomical variations seen in adults undergoing transcatheter device closure should be well known to prevent inadvertent adverse effect or complications. It has been reported that the valve of the inferior vena cava, Eustachian valve, could be mistaken as the atrial septum thus ending in a wrong diagnosis and causing inadvertent surgical or percutaneous closure of an Eustachian valve to interatrial septum. We present a concise article that brings out a practical issue encountered during device closure of atrial septal defects. PMID- 28648434 TI - Guidance on reuse of cardio-vascular catheters and devices in India: A consensus document. AB - Reuse of medical device is accepted worldwide. Benefits of reuse include not only cost saving but a favorable impact on environment. However, certain requirements should be met for reuse to be safe and effective. The devices, which can be reused, should be clearly defined, a meticulous process for dis-infection and sterilization followed and its functionality ascertained before use. Further, an appropriate consent should be obtained where necessary and the cost saving entailed should be directly passed on to the patient. PMID- 28648435 TI - Current concepts of diagnosis and management of pericardial cysts. AB - Pericardial cysts are rare with an incidence of about 1 in every 100,000 persons and one in 10 pericardial cysts may actually be a pericardial diverticulum. Pericardial cysts and diverticula share similar developmental origin and may appear as an incidental finding in chest roentgenogram in an asymptomatic patient. CT scan is considered as best modality for diagnosis and delineation of the surrounding anatomy. Cardiac MRI is recommended in the evaluation of the compressive effects caused by the pericardial cysts. The authors recommend echocardiography for serial follow up and image guided aspiration of the pericardial cyst in presence of compressive effects leading to cardiovascular and airway symptoms. A systematic approach is desirable for management of pericardial cysts depending on size, shape and compression effects, symptoms and easy access to serial Echocardiographic follow up. However, pericardial diverticulum may not be differentiated from cysts by the above testing, and only identified at surgery. PMID- 28648436 TI - Angiotensin-converting enzyme inhibitors and receptor blockers in heart failure and chronic kidney disease - Demystifying controversies. AB - In clinical setting, congestive heart failure (CHF) and chronic kidney disease (CKD) often co-exist in patients due to common underlying predisposing factors. An intricate equilibrium between the cardiovascular and renal system is maintained through rennin angiotensin-aldosterone axis and autonomic nervous system. Consequent to favorable hemodynamic modification, angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocking (ARB) therapy have proven to be an indispensable aspect of heart failure management with morbidity and mortality benefit. Additionally, progression to end stage renal failure may be halted by renin angiotensin aldosterone system (RAAS) blockade in patients with preexisting renal dysfunction. However, concern over the safety of RAAS blockade in presence of renal impairment has led to profound underutilization of these drugs in CHF patients with renal insufficiency. This review aims to provide a simplified guide to pathophysiology and management options of this perplexing situation. PMID- 28648437 TI - Utility of adjunctive modalities in Coronary chronic total occlusion intervention. AB - Coronary chronic total occlusion (CTO) intervention remains one of the most challenging domains in interventional cardiology. Due to the technical challenges involved and potential procedural complications, CTO percutaneous coronary intervention (PCI) attempt and success rates remain less than standard PCI. However, the use of several adjunctive tools such as intravascular ultrasound, optical coherence tomography, rotational atherectomy, orbital atherectomy, excimer laser coronary atherectomy and percutaneous left ventricular assist device may contribute to improved CTO PCI success rates or provide better hemodynamic assessment of CTO lesion (i.e., using fractional flow reserve). In this review we present the current literature describing the utility and efficacy of these adjunctive modalities in CTO intervention. PMID- 28648438 TI - Recent trends in epidemiology of dyslipidemias in India. AB - Dyslipidemia is the most important atherosclerotic risk factor. Review of population based studies in India shows increasing mean total cholesterol levels. Recent studies have reported that high cholesterol is present in 25-30% of urban and 15-20% rural subjects. This prevalence is lower than high-income countries. The most common dyslipidemia in India are borderline high LDL cholesterol, low HDL cholesterol and high triglycerides. Studies have reported that over a 20-year period total cholesterol, LDL cholesterol and triglyceride levels have increased among urban populations. Case-control studies have reported that there is significant association of coronary events with raised apolipoproteinB, total cholesterol, LDL cholesterol and non-HDL cholesterol and inverse association with high apolipoproteinA and HDL cholesterol. Prevalence of suspected familial hypercholesterolemia in urban subjects varies from 1:125 to 1:450. Only limited studies exist regarding lipid abnormalities in children. There is low awareness, treatment and control of hypercholesterolemia in India. PMID- 28648440 TI - Disappearing high velocity severe tricuspid regurgitation following Ventricular septal defect device closure. AB - This report describes the disappearance of severe high velocity tricuspid regurgitation following a small ventricular septal defect device closure, in an eight year old girl. PMID- 28648439 TI - Modulation of myocardial energetics: An important category of agents in the multimodal treatment of coronary artery disease and heart failure. AB - The combined and relative contribution of glucose and fatty acid oxidation generates myocardial energy, which regulates the cardiac function and efficiency. Any dysregulation in this metabolic homeostasis can adversely affect the function of heart and contribute to cardiac conditions such as angina and heart failure. Metabolic agents ameliorate this internal metabolic anomaly, by shifting the energy production pathway from free fatty acids to glucose, resulting in a better performance of the heart. Metabolic therapy is relatively a new modality, which functions through optimization of cardiac substrate metabolism. Among the metabolic therapies, trimetazidine and ranolazine are the agents presently available in India. In the present review, we would like to present the metabolic perspective of pathophysiology of coronary artery disease and heart failure, and metabolic therapy by using trimetazidine and ranolazine. PMID- 28648441 TI - Safety and feasibility of 5 French Glidesheath Slender for complex transradial interventions in small diameter radial arteries. PMID- 28648442 TI - Optical coherence tomography is a kid on the block: I would choose intravascular ultrasound. AB - Intravascular imaging has improved our understanding of in vivo pathophysiology of coronary artery disease (CAD) and predicted decision-making in percutaneous coronary intervention (PCI). Intravascular ultrasound (IVUS) has emerged as the first clinical imaging method contributing significantly to modern PCI techniques. This modality has outlived many other intravascular techniques 26 years after its inception. It has assisted us in understanding dynamics of atherosclerosis and provides several unique insights into plaque burden, remodeling, and restenosis. It is useful as an imaging endpoint in large progression-regression trial and as workhorse in many catheterization laboratories. IVUS guidance appears to be most beneficial in complex lesion subsets that are being treated with drug-eluting stents. The recent introduction of optical coherence tomography (OCT), a light based imaging technique, has further expanded this field because of its higher resolution and faster image acquisition. The omnipresence of OCT raises the question: Does IVUS have a role in the era of OCT? Whether OCT is superior to IVUS in routine clinical practice? Even if OCT is currently gaining clinical significance in detailed planning of interventional strategies and stent optimization in complex lesion subsets, it is the much younger technique and has to prove its worth. Nevertheless, undoubtedly IVUS plays significant role in studies on coronary atherosclerosis and for guidance of PCI. In fact, both the methods are complementary rather than competitive. PMID- 28648443 TI - Transradial primary angioplasty of anomalous right coronary artery from the left sinus of Valsalva. AB - Percutaneous coronary intervention (PCI) of congenitally anomalous coronary arteries may be a technically challenging procedure. There is general belief that femoral approach is associated with better chances of coronary engagement and better guide support during PCI of anomalous coronary arteries. The following case supports that radial access is effective for PCI of an aberrant right coronary artery from the left sinus of Valsalva, even in an acute setting. PMID- 28648444 TI - Is left ventricular dimension an accurate and sufficient criteria for timing of severe aortic regurgitation surgery? PMID- 28648445 TI - Anomalous origin of left circumflex artery from aorta and left anterior descending coronary artery myocardial bridge: An unusual association between two coronary artery anomalies. PMID- 28648446 TI - Pathophysiological mechanisms should be taken into account and guide the treatment of essential arterial hypertension. PMID- 28648447 TI - Homan's sign for deep vein thrombosis: A grain of salt? PMID- 28648448 TI - Calculated low density lipoprotein cholesterol: Its relevance in Indian perspective. PMID- 28648449 TI - Eustachian valve-Masquerading ASD rim. PMID- 28648450 TI - Dental considerations in cardiovascular patients: A practical perspective. PMID- 28648451 TI - Making life simple-Letter to the Editor. PMID- 28648453 TI - Tolerance of Pseudomonas aeruginosa in in-vitro biofilms to high-level peracetic acid disinfection. AB - BACKGROUND: Biofilm has been suggested as a cause of disinfection failures in flexible endoscopes where no lapses in the decontamination procedure can be identified. To test this theory, the activity of peracetic acid, one of the widely used disinfectants in the reprocessing of flexible endoscopes, was evaluated against both planktonic and sessile communities of Pseudomonas aeruginosa. AIM: To investigate the ability of P. aeruginosa biofilm to survive high-level peracetic acid disinfection. METHOD: The susceptibility of planktonic cells of P. aeruginosa and biofilms aged 24, 48, 96, and 192 h to peracetic acid was evaluated by estimating their viability using resazurin viability and plate count methods. The biomass of the P. aeruginosa biofilms was also quantified using Crystal Violet assay. Planktonic cells of P. aeruginosa were treated with 5 30 ppm concentration of peracetic acid in the presence of 3.0 g/L of bovine serum albumin (BSA) for 5 min. Biofilms of P. aeruginosa were also treated with various peracetic acid concentrations (100-3000 ppm) for 5 min. FINDINGS: Planktonic cells of P. aeruginosa were eradicated by 20 ppm of peracetic acid, whereas biofilms showed an age-dependent tolerance to peracetic acid, and 96 h biofilm was only eradicated at peracetic acid concentration of 2500 ppm. CONCLUSION: Ninety-six-hour P. aeruginosa biofilm survives 5 min treatment with 2000 ppm of peracetic acid, which is the working concentration used in some endoscope washer disinfectors. This implies that disinfection failure of flexible endoscopes might occur when biofilms build up in the lumens of endoscopes. PMID- 28648454 TI - Disinfection of gloved hands for multiple activities with indicated glove use on the same patient. AB - Most hand hygiene guidelines recommend that gloves should be changed during patient care when an indication for hand disinfection occurs. Observational studies indicate that the majority of healthcare workers (HCWs) do not disinfect their hands at all during continued glove wear. The aim of this narrative review is to assess the potential benefits and risks for disinfecting gloved hands during patient care for multiple activities with indicated glove use on the same patient. Continued glove wear for multiple activities on the same patient often results in performing procedures, including aseptic procedures with contaminated gloves, especially in a setting where there are many indications in a short time, e.g. anaesthetics or accident and emergency departments. Of further note is that hand hygiene compliance is often lower when gloves are worn. To date, three independent studies have shown that decontamination is at least as effective on gloved hands as on bare hands and that puncture rates are usually not higher after up to 10 disinfections. One study on a neonatal intensive care unit showed that promotion of disinfecting gloved hands during care on the same patient resulted in a significant reduction in the incidence of late-onset infections and of necrotizing enterocolitis. We conclude that disinfection of gloved hands by HCWs may substantially reduce the risk of transmission when gloves are indicated for the entire episode of patient care and when performed during multiple activities on the same patient. PMID- 28648452 TI - Advances in Decoding Axolotl Limb Regeneration. AB - Humans and other mammals are limited in their natural abilities to regenerate lost body parts. By contrast, many salamanders are highly regenerative and can spontaneously replace lost limbs even as adults. Because salamander limbs are anatomically similar to human limbs, knowing how they regenerate should provide important clues for regenerative medicine. Although interest in understanding the mechanics of this process has never wavered, until recently researchers have been vexed by seemingly impenetrable logistics of working with these creatures at a molecular level. Chief among the problems has been the very large size of salamander genomes, and not a single salamander genome has been fully sequenced to date. Recently the enormous gap in sequence information has been bridged by approaches that leverage mRNA as the starting point. Together with functional experimentation, these data are rapidly enabling researchers to finally uncover the molecular mechanisms underpinning the astonishing biological process of limb regeneration. PMID- 28648455 TI - Kinetic modelling and meta-analysis of the B. subtilis SigA regulatory network during spore germination and outgrowth. AB - This study describes the meta-analysis and kinetic modelling of gene expression control by sigma factor SigA of Bacillus subtilis during germination and outgrowth based on microarray data from 14 time points. The analysis computationally models the direct interaction among SigA, SigA-controlled sigma factor genes (sigM, sigH, sigD, sigX), and their target genes. Of the >800 known genes in the SigA regulon, as extracted from databases, 311 genes were analysed, and 190 were confirmed by the kinetic model as being controlled by SigA. For the remaining genes, alternative regulators satisfying kinetic constraints were suggested. The kinetic analysis suggested another 214 genes as potential SigA targets. The modelling was able to (i) create a particular SigA-controlled gene expression network that is active under the conditions for which the expression time series was obtained, and where SigA is the dominant regulator, (ii) suggest new potential SigA target genes, and (iii) find other possible regulators of a given gene or suggest a new mechanism of its control by identifying a matching profile of unknown regulator(s). Selected predicted regulatory interactions were experimentally tested, thus validating the model. PMID- 28648456 TI - Brain-derived neurotrophic factor in the infralimbic cortex alleviates inflammatory pain. AB - In chronic pain, it has been reported that the medial prefrontal cortex (mPFC) takes important regulatory roles, and may change functionally and morphologically in result of chronic pain. Brain-derived neurotrophic factor (BDNF) is well known as a critical modulator of neuronal excitability and synaptic transmission in the central nervous system. The aim of the present study is to investigate the role of BDNF in the infralimbic cortex and the prelimbic cortex of the mPFC in complete Freund's adjuvant (CFA)-induced inflammatory pain. We found that the BDNF level decreased in the infralimbic cortex, but not in the prelimbic cortex, 3days after the CFA induction of the inflammatory pain. BDNF infusion into bilateral infralimbic cortices to activate neuronal activities could alleviate inflammatory pain and accelerate long-term recovery from pain. In conclusion, BDNF in the infralimbic cortex of the mPFC could accelerate recovery from inflammatory pain. PMID- 28648457 TI - Enriched environment promotes remyelination and motor function recovery through modulation of HDAC1/2 in mice. AB - Brain structure and functions are significantly affected by enriched environment (EE). Rodent and rhesus monkeys raised in EE will increase myelination in development, and these increase correlate with improved cognitive functions on learning and memory. However, whether and how EE influences remyelination in the adult remained undefined. Here, we used a cuprizone-induced demyelination mouse model demonstrate that EE significantly enhances remyelination. This EE-regulated remyelination is associated with improved motor skills. We found that histone deacetylases 1/2 (HDAC1/2) were drastically increased in EE. EE act mechanistically by inhibition of Wnt signaling pathway during remyelination through promotion of HDAC1/2. Moreover, pharmacological inhibition of HDACs promoted Wnt signaling activation and impaired remyelination in EE. These results suggested that the effect of EE is likely to be mediated, at least in part, by elevating HDAC1/2 expression and inhibiting Wnt signal pathway, which initiates 'rewiring' of the neural network and accelerates remyelination. These findings highlighted the potential of EE as a promising noninvasive strategy to accelerate remyelination and to restore motor functions for demyelination related disease. PMID- 28648458 TI - Peripheral nerve injury induces a transitory microglial reaction in the rat infralimbic cortex. AB - Undeniable evidence shows that microglia in the spinal cord undergo marked reactions following peripheral injuries. However, only rare studies have investigated the possible short and long term microglial reaction in brain regions following peripheral nerve injury and its interspecies specificities. In the present study we examined microglia in subdivisions of the prefrontal cortex in mice and rats, 7days and 42days after spared nerve injury (SNI) of the sciatic nerve. We show that a bilateral increase of microglial density takes place in the infralimbic cortex in rats 7days post-injury (sham vs. SNI, n=5: ipsilateral 35.4% increase of the median, p=0.0317; contralateral 24.9% increase of the median, p=0.0079), without any detectable change in the other investigated regions, namely the anterior cingulate, prelimbic and agranular insular cortices. In mice, no observable difference could be found in any region at both time points, neither using Iba-1 immunostaining nor with CX3CR1-eGFP animals. Our results indicate that a transitory, species-specific and highly regionalized microglial reaction takes place in the prefrontal cortex following peripheral nerve injury. PMID- 28648459 TI - Acute liver failure is associated with altered cerebral expression profiles of long non-coding RNAs. AB - Hepatic encephalopathy (HE) represents a serious complication of acute liver failure (ALF) in which cerebral edema leading to brainstem herniation as a result of increased intracranial hypertension is a major consequence. Long non-coding RNAs (lncRNAs) play a significant role in coordinating gene expression, with recent studies indicating an influence in the pathogenesis of several diseases. To investigate their involvement in the cerebral pathophysiology of ALF, we profiled the expression of lncRNAs in the frontal cortex of mice at coma stage following treatment with the hepatotoxin azoxymethane. Of the 35,923 lncRNAs profiled using microarrays, 868 transcripts were found to be differentially expressed in the ALF-treated group compared to the sham control group. Of these, 382 lncRNAs were upregulated and 486 lncRNAs downregulated. Pathway analysis revealed these lncRNAs target a number of biological and molecular pathways that include cytokine-cytokine receptor interaction, the mitogen activated protein kinase signaling pathway, the insulin signaling pathway, and the nuclear factor kappaB signaling pathway. False discovery rate adjustment identified 9 upregulated lncRNAs, 2 of which are associated with neuroepithelial transforming gene 1 (NET1) and the monocarboxylate transporter 2 (Slc16a7), potential contributors to astrocyte cytoskeletal disruption/swelling and lactate production, respectively. Our findings suggest an important role for lncRNAs in the brain in ALF in relation to inflammation, neuropathology, and in terms of the functional basis of HE. Further work on these non-coding RNAs may lead to new therapeutic approaches for the treatment and management of cerebral dysfunction resulting from this potentially life-threatening disorder. PMID- 28648460 TI - Bioactive new withanolides from the cultured soft coral Sinularia brassica. AB - Continuing study of the ethyl acetate (EtOAc) extract of the cultured soft coral Sinularia brassica afforded five new withanolides, sinubrasolides H-L (1-5). The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxicities of new compounds 1-5 and a known compound sinubrasolide A (6) against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of compounds 1-6 were evaluated by measuring their ability to suppress N-formyl-methionyl-leucyl-phenyl alanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release in human neutrophils. PMID- 28648461 TI - The structural requirements of histone deacetylase inhibitors: SAHA analogs modified at the C5 position display dual HDAC6/8 selectivity. AB - Histone deacetylase (HDAC) proteins have emerged as important targets for anti cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity. C5-modified SAHA analogs displayed dual selectivity to HDAC6 and HDAC8 over HDAC 1, 2, and 3, with only a modest reduction in potency. These findings are consistent with prior work showing that modification of the linker region of SAHA can alter isoform selectivity. The observed HDAC6/8 selectivity of C5-modified SAHA analogs provide guidance toward development of isoform selective HDAC inhibitors and more effective anti-cancer drugs. PMID- 28648462 TI - Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal muscular atrophy: Screening with iPSC-derived neuronal cells. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard. However, clinical trials involving HDACi have been unsatisfactory, possibly because previous efforts to identify HDACi to treat SMA have employed non-neuronal cells as the screening platform. To address this issue, we generated an SMA-patient specific, induced pluripotent stem cell (iPSC) derived neuronal cell line that contains homogenous Tuj1+neurons. We screened a small library of cyclic tetrapeptide HDACi using this SMA neuronal platform and discovered compounds that elevate SMN2 expression by an impressive twofold or higher. These candidates are also capable of forming gems intranuclearly in SMA neurons, demonstrating biological activity. Our study identifies new potential HDACi therapeutics for SMA screened using a disease-relevant SMA neuronal cellular model. PMID- 28648463 TI - Optimization of a novel series of potent and orally bioavailable GPR119 agonists. AB - We describe the discovery and optimization of a novel series of furo[3,2 d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50=129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50=53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50=42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice. PMID- 28648464 TI - Synthesis and biological evaluation of 2-methyl-1H-benzimidazole-5 carbohydrazides derivatives as modifiers of redox homeostasis of Trypanosoma cruzi. AB - Twelve novel benzimidazole derivatives were synthesized and their in vitro activities against epimastigotes of Trypanosoma cruzi were evaluated. Two derivatives (6 and 7), which have 4-hydroxy-3-methoxyphenyl moiety in their structures, proved to be the most active in inhibiting the parasite growth. Compound 6 showed a trypanocidal activity higher than benznidazole (IC50=5uM and 7.5uM, respectively) and less than nifurtimox (IC50=3.6uM). In addition, the ability of 6 and 7 to modify the redox homeostasis in T cruzi epimastigote was studied; cysteine and glutathione increased in parasites exposed to both compounds, whereas trypanothione only increased with 7 treatment. These results suggest that the decrease in viability of T. cruzi may be attributed to the change in cellular redox balance caused by compound 6 or 7. Furthermore, compounds 6 and 7 showed CC50 values of 160.64 and 160.66uM when tested in mouse macrophage cell line J774 and selectivity indexes (macrophage/parasite) of 32 and 20.1, respectively. PMID- 28648465 TI - Planum temporale asymmetry in people who stutter. AB - PURPOSE: Previous studies have reported that the planum temporale - a language related structure that normally shows a leftward asymmetry - had reduced asymmetry in people who stutter (PWS) and reversed asymmetry in those with severe stuttering. These findings are consistent with the theory that altered language lateralization may be a cause or consequence of stuttering. Here, we re-examined these findings in a larger sample of PWS. METHODS: We evaluated planum temporale asymmetry in structural MRI scans obtained from 67 PWS and 63 age-matched controls using: 1) manual measurements of the surface area; 2) voxel-based morphometry to automatically calculate grey matter density. We examined the influences of gender, age, and stuttering severity on planum temporale asymmetry. RESULTS: The size of the planum temporale and its asymmetry were not different in PWS compared with Controls using either the manual or the automated method. Both groups showed a significant leftwards asymmetry on average (about one-third of PWS and Controls showed rightward asymmetry). Importantly, and contrary to previous reports, the degree of asymmetry was not related to stuttering severity. In the manual measurements, women who stutter had a tendency towards rightwards asymmetry but men who stutter showed the same degree of leftwards asymmetry as male Controls. In the automated measurements, Controls showed a significant increase in leftwards asymmetry with age but this relationship was not observed in PWS. CONCLUSIONS: We conclude that reduced planum temporale asymmetry is not a prominent feature of the brain in PWS and that the asymmetry is unrelated to stuttering severity. PMID- 28648467 TI - Differentiating "could" from "should": Developmental changes in modal cognition. AB - Young children have difficulty in distinguishing events that violate physical laws (impossible events) from those that violate mere physical regularities (improbable events). They judge both as "impossible." Young children also have difficulty in distinguishing events that violate moral laws (immoral events) from events that violate mere social regularities (unconventional events). They judge both as "wrong." In this set of studies, we explored the possibility that both difficulties arise from a more general deficit in modal cognition, or the way in which children represent and reason about possibilities. Participants (80 children aged 3-10years and 101 adults) were shown impossible, improbable, unconventional, and immoral events and were asked to judge whether the events could occur in real life and whether they would be okay to do. Preschool-aged children not only had difficulty distinguishing law-violating events from regularity-violating events but also had difficulty distinguishing the two modal questions themselves, judging physically abnormal events (e.g., floating in the air) as immoral and judging socially abnormal events (e.g., lying to a parent) as impossible. These findings were replicated in a second study where participants (74 children and 78 adults) judged whether the events under consideration would require magic (a specific consequence of impossibility) or would require punishment (a specific consequence of impermissibility). Our findings imply that young children's modal representations clearly distinguish abnormal events from ordinary events but do not clearly distinguish different types of abnormal events from each other. That is, the distinction between whether an event could occur and whether an event should occur must be learned. PMID- 28648466 TI - Prevalence of cardiovascular and respiratory complications following trauma in patients with obesity. AB - BACKGROUND: It is generally accepted that obesity puts patients at an increased risk for cardiovascular and respiratory complications after surgical procedures. However, in the setting of trauma, there have been mixed findings in regards to whether obesity increases the risk for additional complications. OBJECTIVE: The aim of this study was to identify whether obese patients suffer an increased risk of cardiac and respiratory complications following traumatic injury. METHODS: A retrospective analysis of 275,393 patients was conducted using the 2012 National Trauma Data Bank. Hierarchical regression modeling was performed to determine the probability of experiencing a cardiac or respiratory complication. RESULTS: Patients with obesity were at a significantly higher risk of cardiac and respiratory complications compared to patients without obesity [OR: 1.81; CI: 1.72-1.91]. Prevalence of cardiovascular and respiratory complications for patients with obesity was 12.6% compared to 5.2% for non-obese patients. CONCLUSIONS: Obesity is predictive of an increased risk for cardiovascular and respiratory complications following trauma. PMID- 28648468 TI - The Joint Commission Ever-Readiness: Understanding Tracer Methodology. AB - The Joint Commission (TJC) evaluates the consistent provision of appropriate and safe access to health care, treatment, and services. Currently, TJC uses the tracer methodology to assess standards compliance and follows a number of patients through an organization's entire health care delivery process. The tracer methodology uses 3 different types of tracers as follows: individual or patient tracers, program-specific, and system tracers, to identify performance issues in one or more steps of the care process or at interfaces between them. This review article describes the different types of tracers used by TJC and provides examples of each tracer in radiology; it outlines how to achieve TJC ever-readiness with the use of mock tracers and provides practical suggestions on how to ensure staff engagement. PMID- 28648469 TI - Long-Term Clinical Outcomes Following Radiofrequency and Microwave Ablation of Renal Cell Carcinoma at a Single VA Medical Center. AB - PURPOSE: Microwave ablation (MWA) is a relatively newer treatment modality for treatment of renal cell carcinoma (RCC), and only a few small studies have examined the short- and long-term outcomes for MWA applied to renal tumors. The purpose of this retrospective review is to assess the initial experience including technical short- and long-term success rates of using radiofrequency ablation (RFA) and MWA for RCC at a single Veterans Affairs (VA) medical center. MATERIALS AND METHODS: Tumor characteristics were recorded using the R.E.N.A.L. nephrometry score. Group comparisons were performed by using univariate logistic regression analysis to determine factors affecting primary treatment success, failure, and effectiveness. Kaplan-Meier local tumor progression-free survival following ablation was calculated. RESULTS: MWA and RFA groups were not significantly different in primary treatment success (P = 0.82). MWA primary treatment success (90.2%) was not associated with R.E.N.A.L criteria, whereas primary success in the RFA group (88.2%) was predicted by smaller tumor size (P = 0.002). Primary treatment effectiveness rates were not significantly different in MWA (88.2%) and RFA (80.3%) groups (P = 0.29). Although overall primary technique effectiveness was associated with size (P = 0.02), univariate analysis showed a significant association between tumor size and primary effectiveness for RFA (P = 0.002) but not MWA. There was no significant association between R.E.N.A.L score or criteria and primary treatment effectiveness in the RFA or MWA groups. CONCLUSION: RFA and MWA both represent effective treatment modalities for RCC; larger tumor size may be associated with decreased efficacy of thermal ablation techniques. PMID- 28648470 TI - Drug-target interaction prediction by integrating multiview network data. AB - Drug-target interaction (DTI) prediction is a challenging step in further drug repositioning, drug discovery and drug design. The advent of high-throughput technologies brings convenience to the development of DTI prediction methods. With the generation of a high number of data sets, many mathematical models and computational algorithms have been developed to identify the potential drug target pairs. However, most existing methods are proposed based on the single view data. By integrating the drug and target data from different views, we aim to get more stable and accurate prediction results. In this paper, a multiview DTI prediction method based on clustering is proposed. We first introduce a model for single view drug-target data. The model is formulated as an optimization problem, which aims to identify the clusters in both drug similarity network and target protein similarity network, and at the same time make the clusters with more known DTIs be connected together. Then the model is extended to multiview network data by maximizing the consistency of the clusters in each view. An approximation method is proposed to solve the optimization problem. We apply the proposed algorithms to two views of data. Comparisons with some existing algorithms show that the multiview DTI prediction algorithm can produce more accurate predictions. For the considered data set, we finally predict 54 possible DTIs. From the similarity analysis of the drugs/targets, enrichment analysis of DTIs and genes in each cluster, it is shown that the predicted DTIs have a high possibility to be true. PMID- 28648471 TI - Optimisation of continuous gas fermentation by immobilisation of acetate producing Acetobacterium woodii. AB - Hydrogen from water electrolysis is often suggested as a way of storing the excess energy from wind and solar power plants. However, unlike natural gas, hydrogen is difficult to store and distribute. One solution is to convert the hydrogen into other fuels or bulk chemicals. In this study we investigated fermentation in which homoacetogenic clostridia apply the Wood-Ljungdahl pathway to generate acetate from H2 and CO2. Acetate can be used as a bulk chemical or further transformed into biofuels. Autotrophic growth with CO2 as the sole carbon source is slow compared to heterotrophic growth, so the aim of this work was to improve continuous gas fermentation by immobilising the acetate-producing clostridia, thus preventing their wash out from the bioreactor. Two homoacetogenic bacterial strains (Acetobacterium woodii and Moorella thermoacetica) were tested for their acetate production potential, with A. woodii proving to be the better strain with maximum acetate concentration of 29.57 g l 1. Due to its stability during fermentation and good bacterial immobilisation, linen was chosen as immobilisation material for continuous fermentation. This study demonstrates the successful continuous fermentation of acetate from H2 and CO2 using A. woodii immobilised on a low-cost surface at high volumetric productivity of 1.21 +/- 0.05 g acetate l-1 d-1. This has great industrial potential and future studies should focus on the scale-up of this process. PMID- 28648472 TI - Oesophageal pleural fistula presenting with Parvimonas micra infection causing cervical and brain abscesses. AB - Parvimonas micra (P. micra) infections causing spinal cord compression are extremely rare. We report an occult oesophageal pleural fistula presenting with spinal epidural and brain abscesses resulting in severe neurological deficits caused by P. micra. Molecular detection proved to be instrumental in identifying the causative pathogen. Essential management with decompression, drainage, antibiotics and fistula repair lead to a good outcome. PMID- 28648473 TI - Qualification of a precision pattern dispenser. AB - In order to automate sample preparation processes, a precision pattern dispenser was designed to reproducibly dispense radioactive solutions at pre-defined positions. It is composed of an automatic liquid sample handling unit coupled to an XYZ table. Qualification tests were conducted to evaluate the performance of the instrument and to assess the compliance with the requirements, in particular trueness (< 2%) and repeatability (< 1%). The instrument allows preparing sources in different source holders and on air filters, in a fast and accurate way. PMID- 28648474 TI - Combining Left Ventricular Volume Reduction Techniques With Cell Therapies: Quo Vadis? PMID- 28648475 TI - Effects of docosahexanoic acid on metabolic and fat parameters in HIV-infected patients on cART: A randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Hypertriglyceridemia is common in HIV-infected patients. Polyunsaturated fatty acids reduce fasting serum triglyceride (TG) levels in HIV infected patients. It is not known whether docosahexanoic acid (DHA) supplementation can reduce hypertriglyceridemia and modify fat distribution in HIV-infected patients. METHODS: We conducted a randomized, double-blind, placebo controlled trial with 84 antiretroviral-treated patients who had fasting TG levels from 2.26 to 5.65 mmol/l and were randomized to receive DHA or placebo for 48 weeks. TG levels were assessed at baseline, week 4 and every 12 weeks. Body composition was assessed at baseline and at week 48. Registered under ClinicalTrials.gov Identifier no. NCT02005900. RESULTS: Patients receiving DHA had a 43.9% median decline in fasting TG levels at week 4 (IQR: -31% to -56%), compared with -2.9% (-18.6% to 16.5%) in the placebo group (P < 0.0001). DHA levels and decrease in TG at week 4 in the DHA arm correlated significantly (r = 0.7110, P < 0.0001). The median reduction in TG levels in the DHA arm was -43.7% (-32.4% to -57.5%), and in the placebo arm +2.9% (-21.3% to +30.1%) at week 12. The difference remained statistically significant at week 48 (P = 0.0253). LDL cholesterol levels significantly increased at week 4 by 7.1% (IQR: -4.8% to +35.3%) in the DHA arm but not in the placebo group. No significant changes were observed in HDL cholesterol, insulin, and HOMA-IR during the study. Limb fat significantly increased in both arms, without statistically significant differences between groups (P = 0.3889). DHA was well tolerated; only 3 patients experienced treatment-limiting toxicity. CONCLUSIONS: Supplementation with DHA reduced fasting TG levels in antiretroviral-treated HIV-infected patients with mild hypertriglyceridemia. DHA was well tolerated with minor GI symptoms. Peripheral fat significantly increased in the DHA group but did not increase significantly compared with placebo. PMID- 28648476 TI - Constraint-based metabolic modelling of marine microbes and communities. AB - Constraint-based metabolic modelling (CBMM) consists in the use of computational methods and tools to perform genome-scale simulations and predict metabolic features at the whole cellular level. This approach is rapidly expanding in microbiology, as it combines reliable predictive abilities with conceptually and technically simple frameworks. Among the possible outcomes of CBMM, the capability to i) guide a focused planning of metabolic engineering experiments and ii) provide a system-level understanding of (single or community-level) microbial metabolic circuits also represent primary aims in present-day marine microbiology. In this work we briefly introduce the theoretical formulation behind CBMM and then review the most recent and effective case studies of CBMM of marine microbes and communities. Also, the emerging challenges and possibilities in the use of such methodologies in the context of marine microbiology/biotechnology are discussed. As the potential applications of CBMM have a very broad range, the topics presented in this review span over a large plethora of fields such as ecology, biotechnology and evolution. PMID- 28648477 TI - Time to antibiotics administration and outcome in community-acquired pneumonia: Secondary analysis of a randomized controlled trial. AB - BACKGROUND: The association between early antibiotic administration and outcomes remains controversial in patients hospitalized for community-acquired pneumonia. METHODS: We performed a secondary analysis of a randomized controlled trial comparing two antibiotic treatment strategies for patients hospitalized for moderately severe CAP. The univariate and multivariate associations between time to antibiotic administration (TTA) and time to clinical stability were assessed using a Cox proportional hazard model. Secondary outcomes were death, intensive care unit admission and hospital readmission up to 90days. RESULTS: 371 patients (mean age 76years, CURB-65 score>=2 in 52%) were included. Mean TTA was 4.35h (SD 3.48), with 58.5% of patients receiving the first antibiotic dose within 4h. In multivariate analysis, number of symptoms and signs (HR 0.876, 95% CI 0.784 0.979, p=0.020), age (HR 0.986, 95% CI 0.975-0.996, p=0.007), initial heart rate (HR 0.992, 95% CI 0.986-0.999, p=0.023), and platelets count (HR 0.998, 95% CI 0.996-0.999, p=0.004) were associated with a reduced probability of reaching clinical stability. The association between TTA and time to clinical stability was not significant (HR 1.009, 95% CI 0.977-1.042, p=0.574). We found no association between TTA and the risk of intensive care unit admission, death or readmission up to 90days after the initial admission. CONCLUSION: In patients hospitalized for moderately severe CAP, a shorter time to antibiotic administration was not associated with a favorable outcome. These findings support the current recommendations that do not assign a specific time frame for antibiotics administration. PMID- 28648478 TI - Imaging vulnerable plaques by targeting inflammation in atherosclerosis using fluorescent-labeled dual-ligand microparticles of iron oxide and magnetic resonance imaging. AB - OBJECTIVE: Identification of patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and a prelude to clinical sequelae. There are currently no clinical imaging tools to assess the inflammatory activity within plaques. This study characterized inflammation in atherosclerosis using dual targeted microparticles of iron oxide (DT-MPIO) as a magnetic resonance imaging (MRI) probe. METHODS: DT-MPIO were used to detect and characterize inflammatory markers, vascular cell adhesion molecule 1 (VCAM-1). and P-selectin on (1) tumor necrosis factor-alpha-treated cells by immunocytochemistry and (2) aortic root plaques of apolipoprotein-E deficient mice by in vivo MRI. Furthermore, apolipoprotein E-deficient mice with focal carotid plaques of different phenotypes were developed by means of periarterial cuff placement to allow in vivo molecular MRI using these probes. The association between biomarkers and the magnetic resonance signal in different contrast groups was assessed longitudinally in these models. RESULTS: Immunocytochemistry confirmed specificity and efficacy of DT-MPIO to VCAM-1 and P-selectin. Using this in vivo molecular MRI strategy, we demonstrated (1) the DT-MPIO-induced magnetic resonance signal tracked with VCAM-1 (r = 0.69; P = .014), P-selectin (r = 0.65; P = .022), and macrophage content (r = 0.59; P = .045) within aortic root plaques and (2) high-risk inflamed plaques were distinguished from noninflamed plaques in the murine carotid artery within a practical clinical imaging time frame. CONCLUSIONS: These molecular MRI probes constitute a novel imaging tool for in vivo characterization of plaque vulnerability and inflammatory activity in atherosclerosis. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid atherosclerotic disease in the future. PMID- 28648479 TI - Discussion. PMID- 28648480 TI - A 10-year institutional experience with open branched graft reconstruction of aortic aneurysms in connective tissue disorders versus degenerative disease. AB - OBJECTIVE: Aortic reconstruction for complex thoracoabdominal aortic aneurysms (TAAAs) can be challenging, especially in patients with connective tissue disorders (CTDs) in whom tissue fragility is a major concern. Branched graft reconstruction is a more complex operation compared with inclusion patch repair of the aorta but is frequently necessary in patients with CTDs or other pathologies because of anatomic reasons. We describe our institutional experience with open branched graft reconstruction of aortic aneurysms and compare outcomes for patients with CTDs vs degenerative pathologies. METHODS: We retrospectively analyzed all patients undergoing open aortic reconstruction using branched grafts at our institution between July 2006 and December 2015. Postoperative outcomes, including perioperative morbidity and mortality, midterm graft patency, and the development of new aneurysms, were compared for patients with CTD vs degenerative disease. RESULTS: During the 10-year study period, 137 patients (CTD, 29; degenerative, 108) underwent aortic repair with branched graft reconstruction. CTD patients were significantly younger (39 +/- 1.9 vs 68 +/- 1.0 years; P < .001) and had fewer comorbidities (hypertension, chronic obstructive pulmonary disease, coronary artery disease; P < .05) but a higher prevalence of aortic dissections (55% vs 16%; P < .001) and aneurysms involving the thoracic aorta (90% vs 60%; P = .003) than patients with degenerative disease. Perioperative mortality (CTD: 10% [n = 3] vs degenerative: 6% [n = 6]; P = .40) and any complication (62% vs 55%; P = .47) were similar between groups. At a median follow-up time of 14.5 months (interquartile range: 6.5, 43.9 months), CTD patients were more likely to develop both new aortic (21%) and nonaortic (14%) aneurysms compared with the degenerative group (7% and 4% for aortic and nonaortic aneurysms, respectively; P = .02). Loss of branch graft patency occurred in 0 of 99 grafts (0%) in CTD patients and in 13 of 167 grafts (7.8%) in degenerative disease patients (P = .005). Loss of branch graft patency occurred most commonly in left renal artery bypass grafts (77%) and was clinically asymptomatic (creatinine: 1.77 +/- 0.13 mg/dL currently vs 1.41 +/- 0.25 preoperatively; P = .22). CONCLUSIONS: CTD patients with aortic aneurysms who undergo open branched graft reconstruction have reasonable outcomes compared with patients with degenerative pathology, including better branched graft patency and a similar risk of perioperative mortality and complications. Open repair of aortic aneurysms with branched graft reconstruction can be performed safely in both populations with low perioperative mortality, but ongoing surveillance is critical for the detection of new aneurysms, especially among patients with CTD. PMID- 28648481 TI - Outcomes of concomitant renal reconstruction during open paravisceral aortic aneurysm repair. AB - OBJECTIVE: The objective of this study was to review the outcomes of renal artery revascularizations during open aortic aneurysm repair. METHODS: Open abdominal aneurysm repairs performed from 2010 to 2015 at a single institution were reviewed, including type IV thoracoabdominal, suprarenal, and juxtarenal aneurysms. Direct renal reconstruction techniques included eversion endarterectomy, bypass, and vessel reimplantation based on the patient's anatomy. Renal loss was defined by artery occlusion. RESULTS: The study included 125 patients; of these, 57 patients (46%) had 76 renal reconstructions (38 single, 19 bilateral) performed. Interventions included endarterectomy (n = 21), transaortic stenting (n = 2), reimplantation with (n = 25) or without (n = 17) endarterectomy, bypass (n = 4), and ligation (n = 7). Mean aneurysm size was 6.4 cm, with 23% (n = 29) urgent/emergent operations and 20% (n = 25) having had a prior open or endovascular repair. Overall complication rate was 50%, with significant increase among the group requiring renal intervention, primarily accounted for by a 33% early or late dialysis requirement compared with 16% in patients with no renal revascularization (P = .01). Overall 30-day mortality was 9%, with no difference between groups. Urgent/emergent operation (P < .001) was associated with increased 30-day mortality (24% vs 4% elective procedures), but prior open or endovascular repair (P = .4) was not. Mean follow-up was 26 months, with directed imaging out to a mean of 18 months. Renal intervention (P = .01) and urgent/emergent status (P = .04) were predictive of dialysis requirement; however, among those undergoing intervention, renal loss was not associated with an increase in dialysis requirement (P = .2). Of the directed intervention techniques, renal reimplantation with or without endarterectomy was associated with increased risk of dialysis requirement (P = .005) and renal loss (P = .04) relative to endarterectomy alone. Mean creatinine concentration on late follow-up was 1.4 mg/dL (from 1.3 mg/dL preoperatively) and was not statistically significantly different between those undergoing renal intervention (1.5 mg/dL) and those who did not (1.4 mg/dL). CONCLUSIONS: Renal artery reconstruction at the time of open repair of paravisceral aneurysms is associated with an increased complication rate, primarily driven by occlusion of reimplanted vessels and increased dialysis requirement. As reported by others, nonelective presentation is the greatest determinant of early death or adverse outcomes. PMID- 28648482 TI - Comparison of intravascular ultrasound- and centerline computed tomography determined aortic diameters during thoracic endovascular aortic repair. AB - BACKGROUND: Accurate sizing of stent grafts during thoracic endovascular aortic repair (TEVAR) is critical for a successful outcome. Centerline measurements using three-dimensional reconstruction of preoperative computed tomography angiography (CTA) is the current standard for stent graft sizing. However, this technique is predicated on an idealized straightened aorta and does not account for the variability in the aortic diameter during the cardiac cycle or the overall status of the patient's volume. Intravascular ultrasound (IVUS) offers real-time cross-sectional imaging of the aorta orthogonal to the support wire, thereby providing an adjunctive method for aortic diameter determination at the time of TEVAR. METHODS: A retrospective review was performed on all patients who underwent TEVAR for nontraumatic aortic pathology from July 2015 to December 2015. Preoperative CTA images were reconstructed on a dedicated three-dimensional workstation. CTA centerline aortic diameter measurements were performed in major and minor axes at 1-cm intervals from the left subclavian origin to 20 cm distally. The IVUS images were acquired intraoperatively through 1-cm stepwise pullback along the aorta from the left subclavian origin to 20 cm. IVUS aortic diameters were measured at the maximum phase during the cardiac cycle. The average values of major and minor axes diameters from both modalities were calculated at each location for comparison. Linear regression analysis was performed to evaluate correlation, and Bland-Altman plots assessed agreement between different imaging modalities. RESULTS: During the study period, 26 patients underwent TEVAR. Of these, 20 patients had adequate CTA and IVUS images, providing 355 paired measurements. There was a high correlation between CTA- and IVUS-determined aortic diameters (R = 0.62; P < .001). However, Bland-Altman analysis showed that, compared with CT, IVUS resulted in larger aortic diameters, with the mean difference of 3.09 mm. There was a significant variability between IVUS and CTA with the standard deviation of difference (SD diff) of 4.56 mm. When stratified by the aortic position, a high degree of agreement was observed at the base of the left subclavian (position 0), with a mean difference of -2.69 mm and an SD diff of 4 mm. The agreement was the lowest at the angulated aortic segments (2 cm to 7 cm distal to the subclavian origin) with a mean difference up to 7.96 mm and an SD diff up to 8.27 mm. CONCLUSIONS: IVUS imaging and centerline CTA may provide significantly different aortic diameter measurements, particularly in angulated aortic segments. Caution must be taken when sizing a stent graft using CTA alone, particularly in an angulated proximal landing zone. PMID- 28648483 TI - Discussion. PMID- 28648484 TI - Confusions in Nomenclature: "Periventricular Leukomalacia" and "White Matter Injury"-Identical, Distinct, or Overlapping? PMID- 28648485 TI - Effects of Straw Phonation Through Tubes of Varied Lengths on Sustained Vowels in Normal-Voiced Participants. AB - OBJECTIVE: To examine the immediate effects of straw phonation exercises in normal subjects while altering the effective length of the vocal tract. STUDY DESIGN: A nonrandomized comparison of semi-occluded vocal tract length during straw phonation exercises was carried out. METHODS: Oral pressure, mean airflow, aerodynamic resistance, and contact quotient were measured in 20 healthy subjects immediately before and after straw phonation exercises. A short- and long duration phonatory task was used to examine the voice parameters during semi occluded vocal tract exercises. These tasks involved repeating a vocalization of the vowel /a/ through a tube. Each subject underwent the protocol using tubes of three different lengths (7.5 cm, 15 cm, and 30 cm) to allow for the effect of moving the outlet of the vocal tract distal to the mouth to be monitored. RESULTS: Oral pressure and aerodynamic resistance decreased significantly, contact quotient showed a decreasing trend, and airflow increased significantly in pre- and postmeasurements 15 minutes after a long-duration phonatory task. Short-duration tasks were found to have no effect on voice parameters. CONCLUSION: The results present and validate a method to isolate the effect that the length of a semi-occluded vocal tract has during straw phonation exercises. PMID- 28648487 TI - Development of novel avenues to overcome challenges facing CAR T cells. AB - There has been dramatic success in treating patients with adoptive transfer of autologous T cells genetically modified to express a chimeric antigen receptor redirecting them to the antigen CD19. Despite this success, the application of chimeric antigen receptor T-cell therapy in solid malignancies has encountered many challenges that need to be overcome if similar success across other cancers is to become a reality. These challenges can be classified into 6 categories: the heterogeneity of tumor cell clones and tumor-associated antigen expression; poor T-cell trafficking into the tumor site; poor T-cell survival and persistence; the presence of suppressive immune cells; the secretion of suppressive soluble factors in the tumor microenvironment; and the upregulation of T-cell intrinsic inhibitory pathways. We outline specific representative hurdles in each of these categories and summarize the progress made in understanding them and developing strategies to overcome them. PMID- 28648486 TI - Focal brachytherapy for localized prostate cancer: Urinary toxicity depends on tumor location. AB - PURPOSE: To evaluate whether patients with prostate cancer have worse functional urinary recovery with focal brachytherapy (FBT) at the base versus the apex of the prostate. METHODS AND MATERIALS: The functional outcomes of patients treated with FBT at the base of the prostate were compared with those of patients treated with FBT at the apex. Urinary symptoms, continence, and erectile dysfunction were measured using the International Prostate Symptom Score (IPSS), International Continence Score (ICS), and International Index of Erectile Function (IIEF-5) questionnaires, respectively, at baseline and at 6, 12, and 24 months after treatment. RESULTS: Twenty-eight and 13 patients were treated with FBT at the apex and the base, respectively, of the prostate. A significant difference between groups was found in the IPSS score at 6 months (mean IPSS: apex 6.4 +/- 4.7, base 10.6 +/- 5.7; p = 0.02), but not at baseline or at 12 and 24 months after treatment. On multivariate analysis, only FBT at the base of the prostate remained an independent predictor of worsening urinary symptoms (odds ratio, 5.8; p = 0.04). CONCLUSIONS: At 6 months after FBT, significantly less urinary toxicity was found in patients who underwent FBT at the apex versus the base of the prostate. Continence and sexual side effects were minimal in all patients. PMID- 28648488 TI - Relationship between the Mental Foramen, Mandibular Canal, and the Surgical Access Line of the Mandibular Posterior Teeth: A Cone-beam Computed Tomographic Analysis. AB - INTRODUCTION: The purpose of this study was to investigate the relationships between the location of the mental foramen (MF) and the mandibular canal (MC) and the surgical access line (SAL) of the mandibular posterior teeth using cone-beam computed tomographic (CBCT) scans. METHODS: CBCT scans of 204 subjects ranging in age from 18-76 years old were evaluated. The vertical and horizontal distances from the MF to the SAL of the mandibular premolars and first molars and the vertical distance from the MC to the SAL of the second premolars and first molars were measured via CBCT scans. RESULTS: The average vertical distance between the MF and the SALs showed significant increases sequentially from the first premolars to the distal roots of the first molars, and the shortest average distance of 2.74 mm was obtained for the first premolars. The SALs of the second premolars were the closest to the MF in the horizontal direction with an average distance of 1.5 mm. In 19.9% of the cases, the vertical and horizontal distances between the MF and the SALs of the second premolars were less than 2 mm. In addition, the MF was located superior to the root apices in 6.62% of the cases. The majority of the SALs were located at a vertical distance from the MC that was more than 2 mm. Men and women exhibited significant differences in both the horizontal distance from the MF to the SALs of the first premolars and the vertical distance from the MC to the SALs of the second premolars. CONCLUSIONS: To improve the success of endodontic microsurgery, adequate knowledge of the anatomic relationships between the location of the MF and MC and the SAL of the mandibular posterior teeth is indispensable to surgeons. PMID- 28648489 TI - Pyrosequencing Analysis of Cryogenically Ground Samples from Primary and Secondary/Persistent Endodontic Infections. AB - INTRODUCTION: This study aimed to characterize the microbial communities of primary and secondary/persistent endodontic infections using high-throughput pyrosequencing from the pulverized samples. METHODS: The roots of 20 extracted human teeth with primary endodontic infection and 20 teeth with secondary/persistent endodontic infection were collected. The outer surfaces of the roots were disinfected, and whole roots were cryopulverized. 16S amplicon pyrosequencing data from the DNA extracted from the pulverized root powders were obtained, and microorganism abundance and diversity were calculated. Data were analyzed using statistical and bioinformatic methods. RESULTS: Pyrosequencing analysis resulted a total of 2,606,128 sequences from 40 samples. A total of 15 phyla, 160 genera, and 368 species were detected. No significant difference between primary and secondary/persistent endodontic infections was found regarding the diversity and richness of operational taxonomic units at the phyla, genera, and species levels (P > .005). CONCLUSIONS: The present study revealed that the microbial diversity of secondary/persistent endodontic infections did not differ than those of primary endodontic infections. A new archaeal species, Candidatus Nitrosoarchaeum limnia, was detected in root canals of 1 patient with primary endodontic infection for the first time. PMID- 28648490 TI - Interface between Physics and Biology: Training a New Generation of Creative Bilingual Scientists. AB - Whereas physics seeks for universal laws underlying natural phenomena, biology accounts for complexity and specificity of molecular details. Contemporary biological physics requires people capable of working at this interface. New programs prepare scientists who transform respective disciplinary views into innovative approaches for solving outstanding problems in the life sciences. PMID- 28648492 TI - Biocatalysis for synthesis of pharmaceuticals. AB - Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates and drugs has become important and state of the art in the pharmaceutical industry. There has been an increasing awareness of the enormous potential of microorganisms and enzymes (biocatalysts) for the transformation of synthetic chemicals with high chemo-, regio- and enatioselectivities providing products in high yields and purity. In this article, biocatalytic processes are described for the synthesis of key chiral intermediates for development pharmaceuticals. PMID- 28648491 TI - Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium. AB - Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2 alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound. Along with 5, two other new and branched compounds 6 and 7 were synthesized as well. Accompanying the five quinolones were two known compounds 2 and 3 which are inactive against Plasmodium falciparum. The isolation, structure elucidation, total synthesis, and biological evaluation of these compounds are discussed in this article. PMID- 28648493 TI - The use of fructosamine in cystic fibrosis-related diabetes (CFRD) screening. AB - OBJECTIVE: To determine whether serum fructosamine correlates with glycemic control and clinical outcomes in patients being screened for cystic fibrosis related diabetes (CFRD). METHODS: Fructosamine and percent predicted forced expiratory volume in 1s (FEV1) were measured in patients undergoing a 2h oral glucose tolerance test (OGTT) for CFRD screening. Fractional serum fructosamine (FSF) was calculated as fructosamine/total protein. RESULTS: FSF exhibited a positive correlation with 2h OGTT results (r2=0.3201, p=0.009), and ROC curve analysis suggested that FSF can identify patients with an abnormal OGTT (AUC=0.840, p=0.0002). FSF also exhibited a negative correlation with FEV1 (r2=0.3732, p=0.035). Patients with FSF>=3.70MUmol/g had significantly lower FEV1 (median 47%) compared to those with FSF<3.70MUmol/g (median 90%; p=0.015). CONCLUSIONS: FSF correlated with both OGTT results and FEV1, and reliably identified patients with abnormal OGTT results. This simple blood test shows potential as an effective tool in CFRD screening. PMID- 28648494 TI - Characteristics and prevalence of Wilson's disease: A 2013 observational population-based study in France. AB - BACKGROUND AND AIMS: Only a few epidemiological studies on the incidence and prevalence of Wilson's disease (WD) have been performed to date, and the results vary widely according to the reports. The aim of the study was to investigate the prevalence, ambulatory care and treatments of patients with WD in France. METHODS: Among the 58 million general health scheme beneficiaries (86% of the French population), people managed for WD in 2013 were identified using hospitalisation diagnosis in 2011-2013 or specific long-term disease status with a 100% reimbursement for specific healthcare in 2013. Data were derived from the Sniiram (National Health Insurance Information System database). Prevalence by age and sex were calculated. RESULTS: In 2013, 906 prevalent cases were identified, yielding a crude prevalence of 1.5 cases per 100,000; 1.65 per 100,000 in males and 1.44 per 100,000 in females. This prevalence is comparable to that reported in other population-based studies in European countries and to a study using a similar method. Almost 40% of patients were treated by D penicillamine and 14.3% were treated by zinc acetate. Trientine, delivered on a compassionate basis, was not available in the reimbursement database. In 2013, 1.3% of patients underwent liver transplantation and 4% had already undergone liver transplantation in previous years. Fifteen per cent of patients received antidepressants, a higher rate than in general population. CONCLUSIONS: This is the first French population-based epidemiological study of WD in a comprehensive population based on administrative data and constitutes an important step to understand the impact of WD and to study quality of care. PMID- 28648495 TI - Comparison of Zika virus (ZIKV) RNA detection in plasma, whole blood and urine - Case series of travel-associated ZIKV infection imported to Italy, 2016. AB - OBJECTIVES: The capability to detect ZIKV RNA is of crucial importance for cases confirmation. However, due to the short-lived viremia, the detection of ZIKV RNA in plasma/serum is challenging for samples collected more than one week after onset of clinical illness. We compared the window time and detection rate of ZIKV RNA in different specimen types (plasma, whole blood and urine) collected simultaneously at several times post-symptom onset. METHODS: We examined the presence of ZIKV RNA in matched specimens of whole blood, plasma and urine collected in the same date (3-28 days after symptom onset) from 10 ZIKV infected patients. RESULTS: ZIKV RNA was found in plasma as late as 10 days after symptoms onset and tested positive in all 5 (100%) and in 2 of 6 (33,3%) plasma samples collected 1-5 and 6-10 days after symptoms onset, respectively. ZIKV RNA was positive in urine through the 21st day after symptom onset; the detection rate of ZIKV RNA in urine samples was 100% (11/11) for samples collected 1-10 days from symptoms onset, decreasing at later times of sampling. The detection rate of ZIKV RNA in whole blood was comparable to that in urine samples but extended the window of detection of ZIKV RNA up to 26 days after symptom onset. CONCLUSIONS: Our results highlight the usefulness of simultaneously testing multiple specimen types in order to extend the rate and the time frame of ZIKV RNA detection, increasing the possibility of cases confirmation through direct diagnosis in convalescence-phase of infection, supplementing serological data which are often difficult to interpret. PMID- 28648496 TI - Fruits as the vehicle of drug resistant pathogenic yeasts. AB - OBJECTIVE: We investigated the diversity and drug susceptibility of pathogenic yeasts on fruit surfaces. METHOD: Fruits were purchased from supermarkets and washed with buffer. The pellets were re-suspended in medium after centrifugation. The cell suspensions were plated onto CHROMagar Candida medium. Yeasts were identified by ribosomal DNA sequencing and their drug susceptibilities were determined by broth microdilution assay. RESULTS: Of 184 isolates, comprised of 55 species, from 22 different types of fruits, 29 species, including Candida famata, Candida fermentati, Candida guilliermondii, Candida intermedia, Candida krusei, Candida orthopsilosis, Candida parapsilosis, Candida pelliculosa, Candida tropicalis, and others have been reported to cause diseases in humans. In addition to C. krusei, intrinsically resistant to fluconazole, all Rhodotorula and Rhodosporidium species were resistant to fluconazole. One each of C. tropicalis isolate was belonged to diploid sequence type (DST)149 and DST225, genotypes also detected in isolates from humans. Furthermore, the DST225 isolate was less susceptible to azole drugs. The susceptibilities to azole drugs for clinical and agricultural usage were associated to each other. CONCLUSION: It is important to be aware of the existence of pathogenic yeasts, especially drug resistant ones, on the fruit surfaces, a potential route for pathogenic yeasts to be transmitted to humans. PMID- 28648498 TI - A Labeled-Line Neural Circuit for Pheromone-Mediated Sexual Behaviors in Mice. AB - In mice, various instinctive behaviors can be triggered by olfactory input. Despite growing knowledge of the brain regions involved in such behaviors, the organization of the neural circuits that convert olfactory input into stereotyped behavioral output remains poorly understood. Here, we mapped the neural circuit responsible for enhancing sexual receptivity of female mice by a male pheromone, exocrine gland-secreting peptide 1 (ESP1). We revealed specific neural types and pathways by which ESP1 information is conveyed from the peripheral receptive organ to the motor-regulating midbrain via the amygdala-hypothalamus axis. In the medial amygdala, a specific type of projection neurons gated ESP1 signals to the ventromedial hypothalamus (VMH) in a sex-dependent manner. In the dorsal VMH, which has been associated with defensive behaviors, a selective neural subpopulation discriminately mediated ESP1 information from a predator cue. Together, our data illuminate a labeled-line organization for controlling pheromone-mediated sexual behavioral output in female mice. PMID- 28648497 TI - Selective Optogenetic Control of Purkinje Cells in Monkey Cerebellum. AB - Purkinje cells of the primate cerebellum play critical but poorly understood roles in the execution of coordinated, accurate movements. Elucidating these roles has been hampered by a lack of techniques for manipulating spiking activity in these cells selectively-a problem common to most cell types in non-transgenic animals. To overcome this obstacle, we constructed AAV vectors carrying the channelrhodopsin-2 (ChR2) gene under the control of a 1 kb L7/Pcp2 promoter. We injected these vectors into the cerebellar cortex of rhesus macaques and tested vector efficacy in three ways. Immunohistochemical analyses confirmed selective ChR2 expression in Purkinje cells. Neurophysiological recordings confirmed robust optogenetic activation. Optical stimulation of the oculomotor vermis caused saccade dysmetria. Our results demonstrate the utility of AAV-L7-ChR2 for revealing the contributions of Purkinje cells to circuit function and behavior, and they attest to the feasibility of promoter-based, targeted, genetic manipulations in primates. PMID- 28648502 TI - Genetics of thyroid disorders. PMID- 28648499 TI - Light-Dependent Regulation of Sleep and Wake States by Prokineticin 2 in Zebrafish. AB - Light affects sleep and wake behaviors by providing an indirect cue that entrains circadian rhythms and also by inducing a direct and rapid regulation of behavior. While circadian entrainment by light is well characterized at the molecular level, mechanisms that underlie the direct effect of light on behavior are largely unknown. In zebrafish, a diurnal vertebrate, we found that both overexpression and mutation of the neuropeptide prokineticin 2 (Prok2) affect sleep and wake behaviors in a light-dependent but circadian-independent manner. In light, Prok2 overexpression increases sleep and induces expression of galanin (galn), a hypothalamic sleep-inducing peptide. We also found that light dependent, Prok2-induced sedation requires prokineticin receptor 2 (prokr2) and is strongly suppressed in galn mutants. These results suggest that Prok2 antagonizes the direct wake-promoting effect of light in zebrafish, in part through the induction of galn expression in the hypothalamus. PMID- 28648501 TI - Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy. AB - Secondary generalized seizure (sGS) is a major source of disability in temporal lobe epilepsy (TLE) with unclear cellular/circuit mechanisms. Here we found that clinical TLE patients with sGS showed reduced volume specifically in the subiculum compared with those without sGS. Further, using optogenetics and extracellular electrophysiological recording in mouse models, we found that photoactivation of subicular GABAergic neurons retarded sGS acquisition by inhibiting the firing of pyramidal neurons. Once sGS had been stably acquired, photoactivation of GABAergic neurons aggravated sGS expression via depolarized GABAergic signaling. Subicular parvalbumin, but not somatostatin subtype GABAergic, neurons were easily depolarized in sGS expression. Finally, photostimulation of subicular pyramidal neurons genetically targeted with proton pump Arch, rather than chloride pump NpHR3.0, alleviated sGS expression. These results demonstrated that depolarized GABAergic signaling in subicular microcircuit mediates sGS in TLE. This may be of therapeutic interest in understanding the pathological neuronal circuitry underlying sGS. VIDEO ABSTRACT. PMID- 28648500 TI - Perineuronal Nets in the Adult Sensory Cortex Are Necessary for Fear Learning. AB - Lattice-like structures known as perineuronal nets (PNNs) are key components of the extracellular matrix (ECM). Once fully crystallized by adulthood, they are largely stable throughout life. Contrary to previous reports that PNNs inhibit processes involving plasticity, here we report that the dynamic regulation of PNN expression in the adult auditory cortex is vital for fear learning and consolidation in response to pure tones. Specifically, after first confirming the necessity of auditory cortical activity for fear learning and consolidation, we observed that mRNA levels of key proteoglycan components of PNNs were enhanced 4 hr after fear conditioning but were no longer different from the control groups 24 hr later. A similar pattern of regulation was observed in numbers of cells surrounded by PNNs and area occupied by them in the auditory cortex. Finally, the removal of auditory cortex PNNs resulted in a deficit in fear learning and consolidation. PMID- 28648503 TI - Genetics of thyroid function. AB - Recent studies show that subtle variations in thyroid function, including subclinical thyroid dysfunction, and even variation in thyroid function within the normal range, are associated with morbidity and mortality. It is estimated that 40-65% of the inter-individual variation in serum TSH and FT4 levels is determined by genetic factors. To identify these factors, various linkage and candidate gene studies have been performed in the past, which have identified only a few genes. In the last decade, genome-wide association studies identified many new genes, while recent whole-genome sequencing efforts have also been proven to be effective. In the current review, we provide a systematic overview of these studies, including strengths and limitations. We discuss new techniques which will further clarify the genetic basis of thyroid function in the near future, as well as the potential use of these genetic markers in personalizing the management of thyroid disease patients. PMID- 28648504 TI - Disorders of thyroid morphogenesis. AB - Developmental anomalies of the thyroid gland, defined as thyroid dysgenesis, underlie the majority of cases of congenital hypothyroidism. Thyroid dysgenesis is predominantly a sporadic disorder although a reported familial enrichment, variation of incidence by ethnicity and the monogenic defects associated mainly with athyreosis or orthotopic thyroid hypoplasia, suggest a genetic contribution. Of note, the most common developmental anomaly, thyroid ectopy, remains unexplained. Ectopy may result from multiple genetic or epigenetic variants in the germline and/or at the somatic level. This review provides a brief overview of the monogenic defects in candidate genes that have been identified so far and of the syndromes which are known to be associated with thyroid dysgenesis. PMID- 28648505 TI - Hypothyroidism associated with parathyroid disorders. AB - Hypothyroidism may occur in association with congenital parathyroid disorders determining parathyroid hormone insufficiency, which is characterized by hypocalcemia and concomitant inappropriately low secretion of parathormone (PTH). The association is often due to loss of function of genes common to thyroid and parathyroid glands embryonic development. Hypothyroidism associated with hypoparathyroidism is generally mild and not associated with goiter; moreover, it is usually part of a multisystemic involvement not restricted to endocrine function as occurs in patients with 22q11 microdeletion/DiGeorge syndrome, the most frequent disorders. Hypothyroidism and hypoparathyroidism may also follow endocrine glands' damages due to autoimmunity or chronic iron overload in thalassemic disorders, both genetically determined conditions. Finally, besides PTH deficiency, hypocalcemia can be due to PTH resistance in pseudohypoparathyroidism; when hormone resistance is generalized, patients can suffer from hypothyroidism due to TSH resistance. In evaluating patients with hypothyroidism and hypocalcemia, physical examination and clinical history are essential to drive the diagnostic process, while routine genetic screening is not recommended. PMID- 28648506 TI - The role of GLIS3 in thyroid disease as part of a multisystem disorder. AB - Congenital hypothyroidism is the most common hereditary endocrine disorder. In a small number of cases, mutations have been identified that are associated with maldevelopment and maldescent of the thyroid. Some of these mutations present as syndromes with a multisystem phenotype such as NKX2-1, PAX8, and FOXE. The association of permanent neonatal diabetes and congenital hypothyroidism was first reported in 2003 and subsequently led to the identification GLIS3 as the mutation responsible for this presentation. GLIS3 is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with five zinc finger domains and maps to chromosome 9p24. Given the role of GLIS3 in transcriptional activation and repression during embryogenesis, in humans, GLIS3 mutations present with multisystem involvement that also includes renal cystic dysplasia, progressive liver fibrosis and osteopenia. Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post mortem, and apparently normal gross thyroid anatomy on ultrasonography but with temporary TSH resistance on treatment. To date no biological mechanism has explained this variable presentation. PMID- 28648508 TI - Iodide handling disorders (NIS, TPO, TG, IYD). AB - Iodide Handling Disorders lead to defects of the biosynthesis of thyroid hormones (thyroid dyshormonogenesis, TD) and thereafter congenital hypothyroidism (CH), the most common endocrine disease characterized by low levels of circulating thyroid hormones. The prevalence of CH is 1 in 2000-3000 live births. Prevention of CH is based on prenatal diagnosis, carrier identification, and genetic counseling. In neonates a complete diagnosis of TD should include clinical examination, biochemical thyroid tests, thyroid ultrasound, radioiodine or technetium scintigraphy and perchlorate discharge test (PDT). Biosynthesis of thyroid hormones requires the presence of iodide, thyroid peroxidase (TPO), a supply of hydrogen peroxide (DUOX system), an iodine acceptor protein, thyroglobulin (TG), and the rescue and recycling of iodide by the action of iodotyrosine deiodinase or iodotyrosine dehalogenase 1 (IYD or DEHAL1). The iodide transport is a two-step process involving transporters located either in the basolateral or apical membranes, sodium iodide symporter (NIS) and pendrin (PDS), respectively. TD has been linked to mutations in the solute carrier family 5, member 5 transporter (SLC5A5, encoding NIS), solute carrier family 26, member 4 transporter (SLC26A4, encoding PDS), TPO, DUOX2, DUOXA2, TG and IYD genes. These mutations produce a heterogeneous spectrum of CH, with an autosomal recessive inheritance. Thereafter, the patients are usually homozygous or compound heterozygous for the gene mutations and the parents, carriers of one mutation. In the last two decades, considerable progress has been made in identifying the genetic and molecular causes of TD. Recent advances in DNA sequencing technology allow the massive screening and facilitate the studies of phenotype variability. In this article we included the most recent data related to disorders caused by mutations in NIS, TPO, TG and IYD. PMID- 28648507 TI - Resistance to thyrotropin. AB - Resistance to thyrotropin (RTSH) is broadly defined as reduced sensitivity of thyroid follicle cells to stimulation by biologically active TSH due to genetic defects. Affected individuals have elevated serum TSH in the absence of goiter, with the severity ranging from nongoitrous isolated hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Conceptually, defects leading to RTSH impair both aspects of TSH-mediated action, namely thyroid hormone synthesis and gland growth. These include inactivating mutations in the genes encoding the TSH receptor and the PAX8 transcription factor. A common third cause has been genetically mapped to a locus on chromosome 15, but the underlying pathophysiology has not yet been elucidated. This review provides a succinct overview of currently defined causes of nonsyndromic RTSH, their differential diagnoses (autoimmune; partial iodine organification defects; syndromic forms of RTSH) and implications for the clinical approach to patients with RTSH. PMID- 28648509 TI - Pendred syndrome. AB - Pendred syndrome is an autosomal recessive disorder that is classically defined by the combination of sensorineural deafness/hearing impairment, goiter, and an abnormal organification of iodide with or without hypothyroidism. The hallmark of the syndrome is the impaired hearing, which is associated with inner ear malformations such as an enlarged vestibular aqueduct (EVA). The thyroid phenotype is variable and may be modified by the nutritional iodine intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes the multifunctional anion exchanger pendrin. Pendrin has affinity for chloride, iodide, and bicarbonate, among other anions. In the inner ear, pendrin functions as a chloride/bicarbonate exchanger that is essential for maintaining the composition and the potential of the endolymph. In the thyroid, pendrin is expressed at the apical membrane of thyroid cells facing the follicular lumen. Functional studies have demonstrated that pendrin can mediate iodide efflux in heterologous cells. This, together with the thyroid phenotype observed in humans (goiter, impaired iodine organification) suggests that pendrin could be involved in iodide efflux into the lumen, one of the steps required for thyroid hormone synthesis. Iodide efflux can, however, also occur in the absence of pendrin suggesting that other exchangers or channels are involved. It has been suggested that Anoctamin 1 (ANO1/TMEM16A), a calcium-activated anion channel, which is also expressed at the apical membrane of thyrocytes, could participate in mediating apical efflux. In the kidney, pendrin is involved in bicarbonate secretion and chloride reabsorption. While there is no renal phenotype under basal conditions, severe metabolic alkalosis has been reported in Pendred syndrome patients exposed to an increased alkali load. This review provides an overview on the clinical spectrum of Pendred syndrome, the functional data on pendrin with a focus on its potential role in the thyroid, as well as the controversy surrounding the relative physiological roles of pendrin and anoctamin. PMID- 28648510 TI - Disorders of H2O2 generation. AB - After the identification of thyroid H2O2 generation system (DUOX) and of its maturation factors (DUOXA), defects in DUOX2 and/or DUOXA2 were rapidly recognized as the possible cause of congenital hypothyroidism (CH) due to thyroid dyshormonogenesis. The present Review reports data on the prevalence of DUOX2 mutations, which is variable among different series but invariably high, pointing to DUOX2 defects as one of the leading causes of dyshormonogenesis. Differently, DUOXA defects seem to be rarely involved in the pathogenesis of CH. Genotype phenotype correlations are also reported, highlighting the great intra- and inter familial phenotype variability which appears to be a constant feature of the defects in the H2O2 generation systems. Finally, the hypotheses to explain the phenotypic variability of the DUOX2/A2 mutations are discussed, such as the existence of other H2O2 generating systems, the age variability in thyroid hormones requirements, the differences in ethnicity, in iodine intake, and in the methodological approaches. PMID- 28648511 TI - Disorder of thyroid hormone transport into the tissues. AB - Transport of thyroid hormone (TH) across the plasma membrane is essential for intracellular TH metabolism and action, and this is mediated by specific transporter proteins. During the last two decades several transporters capable of transporting TH have been identified, including monocarboxylate transporter 8 (MCT8), MCT10 and organic anion transporting polypeptide 1C1 (OATP1C1). In particular MCT8 and OATP1C1 are important for the regulation of local TH activity in the brain and thus for brain development. MCT8 is a protein containing 12 transmembrane domains, and is encoded by the SLC16A2 gene located on the X chromosome. It facilitates both TH uptake and efflux across the cell membrane. Male subjects with hemizygous mutations in MCT8 are afflicted with severe intellectual and motor disability, also known as the Allan-Herndon-Dudley syndrome (AHDS), which goes together with low serum T4 and high T3 levels. This review concerns molecular and clinical aspects of MCT8 function. PMID- 28648512 TI - The multiple genetic causes of central hypothyroidism. AB - An insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland represents the cause of Central Hypothyrodism (CeH). CeH is about 1000 folds rarer than Primary Hypothyroidism and often represents a real challenge for the clinicians, mainly because they cannot rely on adequately sensitive parameters for diagnosis or management, as it occurs with circulating TSH in PH. Therefore, CeH diagnosis can be frequently missed or delayed in patients with a previously unknown pituitary involvement. A series of genetic defects have been described to account for isolated CeH or combined pituitary hormone defects (CPHDs) with variable clinical characteristics and degrees of severity. The recently identified candidate gene IGSF1 appears frequently involved. This review provides an updated illustration of the different genetic defects accounting for CeH. PMID- 28648513 TI - Inheritable and sporadic non-autoimmune hyperthyroidism. AB - Hyperthyroidism is a clinical state that results from high thyroid hormone levels which has multiple etiologies, manifestations, and potential therapies. Excluding the autoimmune Graves disease, autonomic adenomas account for the most import cause of non-autoimmune hyperthyroidism. Activating germline mutations of the TSH receptor are rare etiologies for hyperthyroidism. They can be inherited in an autosomal dominant manner (familial or hereditary, FNAH), or may occur sporadically as a de novo condition, also called: persistent sporadic congenital non-autoimmune hyperthyroidism (PSNAH). These three conditions: autonomic adenoma, FNAH and PSNAH constitute the inheritable and sporadic non-autoimmune hyperthyroidism. Particularities in epidemiology, etiology, molecular and clinical aspects of these three entities will be discussed in this review in order to guide to an accurate diagnosis allowing among others genetic counseling and presymptomatic diagnosis for the affected families. The optimal treatment based on the right diagnosis will avoid consequences of a persistent or relapsing hyperthyroidism. PMID- 28648514 TI - Neurological phenotypes in spinocerebellar ataxia type 2: Role of mitochondrial polymorphism A10398G and other risk factors. AB - BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is due to a CAG expansion (CAGexp) at ATXN2. SCA2 presents great clinical variability, alongside characteristic ataxia with saccadic slowness. AIMS: To study parkinsonism, dementia, dystonia, and amyotrophy as subphenotypes of SCA2, and to explore the effect of CAG repeats at different loci and of mitochondrial polymorphism A10398G as modifiers of phenotype. METHODS: Symptomatic subjects were classified by presence/absence of neurological signs mentioned above; SARA and NESSCA scores were obtained. CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7 and RAI1, and polymorphism A10398G at mtDNA were established. Group characteristics were compared, with a p < 0.05. RESULTS: Forty-eight SCA2 individuals were included. Age at onset, CAGexp, and disease duration explained 53% and 43% of SARA and NESSCA variations, respectively. CAGexp of subjects with and without parkinsonism were different (medians of 42 and 39 repeats) as well as of subjects with and without dystonia (44 and 40 repeats). Amyotrophy was not significantly related to any variable under study. Concerning polymorphism A10398G, 83% of subjects with and 34% of those without cognitive decline carried 10398G at (p = 0.003). DISCUSSION: Treating the four phenotypic subgroups as outcomes was a valid strategy to identify modifiers of disease. Among correlations found, some confirmed previous reports, such as that between dystonia and CAGexp. Of note was the association between cognitive decline and the variant G at mitochondrial polymorphism A10398G, a variant formerly related to earlier ages at onset in SCA2. PMID- 28648515 TI - [History of cutaneous melanoma: From Laennec's melanosis to the end of 20th century]. PMID- 28648516 TI - [Mycosis fungoides in a heart transplant recipient]. AB - BACKGROUND: Skin cancer occurs frequently in organ transplant patients as a result of induced immunosuppression. Most cases involve carcinomas or B-cell lymphomas induced by the Epstein Barr virus (EBV). Cutaneous T-cell lymphomas remain rare. We report a case of cutaneous T-cell lymphoma of the mycosis fungoides type in a heart transplant recipient. PATIENTS AND METHODS: A 68-year old man who had received a heart transplant 21years earlier and was being treated with tacrolimus, mycophenolate mofetil and prednisolone had been presenting a psoriasiform rash on his trunk, limbs and head for 4years. The rash was resistant to both PUVA therapy and topical corticosteroids. Histopathological examination suggested epidermotropic cutaneous T-cell lymphoma. There was no impairment of the patient's general state of health nor any adenopathy. Molecular biology revealed TCR rearrangement in both blood and skin. Screening for circulating Sezary cells was negative, and PET scan revealed no signs of extracutaneous localization. Mechlorethamine showed little efficacy, bexarotene was complicated by dysthyroidism, hypertriglyceridemia was ineffective, methotrexate was contraindicated because of calcineurin inhibitor-related chronic kidney failure, and interferon could not be given due to the context of heart transplantation. Finally, we treated our patient with gemcitabine, which initially proved effective but was later complicated by septic shock that resulted in the patient's death. CONCLUSION: The particularities of our observation are the onset of cutaneous T-cell lymphoma of the mycosis fungoides type in a heart transplant patient, and the therapeutic difficulties encountered in a setting of transplantation with immunodepression. PMID- 28648517 TI - [Umbilical endometriosis mimicking a keloid in a young black woman: A case report]. AB - BACKGROUND: Most umbilical tumors are diagnosed as benign tumors, umbilical metastases of abdominal and pelvic tumors, or Sister Marie Joseph nodule. Herein, we report a case of cutaneous umbilical endometriosis mistaken for a keloid. PATIENTS AND METHODS: A young black woman aged 26 consulted for a painful umbilical tumefaction. She had noted the appearance of a nodule of the umbilicus 10 months ago with bleeding during her menstrual periods. Skin examination revealed a firm and painful umbilical nodule 2.5cm in diameter. She was treated with corticosteroid injections for one month for umbilical keloid. Given that the symptoms recurred regularly at the time of menstruation, we suspected umbilical endometriosis. This diagnosis was finally confirmed by histopathological examination and hormone therapy was instituted on gynecological advice before scheduled surgical excision. CONCLUSION: In a setting of an umbilical tumor simulating a keloid associated with cyclical symptoms in a black woman, the diagnosis of umbilical endometriosis should not be overlooked by the dermatologist. PMID- 28648518 TI - Selective inhibition of BET proteins reduces pancreatic damage and systemic inflammation in bile acid- and fatty acid ethyl ester- but not caerulein-induced acute pancreatitis. AB - OBJECTIVES: To evaluate the therapeutic potential of I-BET-762, an inhibitor of the bromodomain and extra-terminal (BET) protein family, in experimental acute pancreatitis (AP). METHODS: AP was induced by retrograde infusion of taurolithocholic acid sulphate into the biliopancreatic duct (TLCS-AP) or 2 intraperitoneal (i.p.) injections of ethanol and palmitoleic acid 1 h apart (FAEE AP) or 12 hourly i.p. injections of caerulein (CER-AP). In all treatment groups, I-BET-762 (30 mg/kg, i.p.) was administered at the time of disease induction and again 12 h later. AP severity was assessed at 24 h by serum biochemistry, multiple cytokines and histopathology. RESULTS: TLCS-AP, FAEE-AP and CER-AP resulted in characteristic elevations in serum amylase and cytokine levels, increased pancreatic trypsin and myeloperoxidase activity, typical pancreatic histopathological changes and lung injury. Treatment with I-BET-762 significantly reduced biochemical, cytokine and histopathological responses in TLCS-AP and FAEE AP, but not CER-AP. CONCLUSIONS: These results suggest that in different forms of AP there are significant differences in the epigenetic control of gene transcription contributing to the severity of disease responses. There is therapeutic potential in targeting bromodomains for the treatment of gallstone- and alcohol-related pancreatitis. PMID- 28648519 TI - An upregulation of CD8+CD25+Foxp3+ T cells with suppressive function through interleukin 2 pathway in pulmonary arterial hypertension. AB - Accumulating evidence suggests that abnormal inflammation plays a critical role in the pathogenesis of pulmonary arterial hypertension (PAH). CD8+CD25+Foxp3+ T cell is a novel cell subtype, and its role in PAH is not yet investigated. Here, we observed that PAH patients presented a significant upregulation of CD8+CD25+Foxp3+ T cells and a downregulation of CD4+CD25+Foxp3+ T cells compared to healthy controls. Regardless, the total number of CD25+Foxp3+ T cells in PAH patients was still smaller than that in healthy controls. Compared to CD8+CD25- T cells, CD8+CD25+ T cells presented higher Foxp3 expression, lower interferon (IFN)-gamma expression and higher transforming growth factor (TGF)-beta expression, in both healthy and PAH individuals. The CD8+CD25+ T cells in PAH patients also demonstrated regulatory function by suppressing the proliferation of CD4+CD25- and CD8+CD25- effector T cells, albeit at lower efficiency than CD4+CD25+ T cells from PAH patients and healthy volunteers. CD8+CD25+ T cells from PAH responded to interleukin (IL)-2 supplement by expansion and upregulating Foxp3 expression. In PAH patients, IL-2-treated CD8+CD25+ T cells were more potent at inhibiting CD4+CD25- effector T cell proliferation than IL-2-untreated CD8+CD25+ T cells. Together, we found an upregulation of CD8+CD25+Foxp3+ T cells in PAH patients, and this T cell population presented suppressive activity that could be enhanced by IL-2 treatment. PMID- 28648520 TI - PKMYT1 promoted the growth and motility of hepatocellular carcinoma cells by activating beta-catenin/TCF signaling. AB - Over-activation of beta-catenin/TCF signaling has been frequently observed in hepatocellular carcinoma (HCC). Better understanding the molecular mechanism for the aberrant activation of beta-catenin/TCF signaling would provide novel insights into the treatment of this malignancy. In this study, we have shown that the expression of PKMYT1 was up-regulated in HCC. PKMYT1 positively regulated the growth, migration, colony formation, metastasis and epithelia mesenchymal transition (EMT) of HCC cells. Mechanically, PKMTY1 activated the beta catenin/TCF signaling by binding and inactivating GSK3beta. Taken together, our study demonstrated the oncogenic activity of PKMYT1 in the progression of HCC and suggested that PKMYT1 might be a therapeutic target. PMID- 28648521 TI - Ratiometric co-delivery of multiple chemodrugs in a single nanocarrier. AB - Co-delivery of multiple anti-cancer drugs in a single nanoplatform has shown great promise in enhancing therapeutic efficacy and reducing adverse effects. However, the ratiometric dose control is pivotal, but often challenging in combinational nanomedicine. Here, we report the employment of cyclodextrin bearing amphiphilic polymer conjugate micelles for ratiometric, non-covalent loading of three hydrophobic model drugs, curcumin (CUR), camptothecin (CPT), and doxorubicin (DOX) in one single nanocarrier. Each drug was physically encapsulated in the cyclodextrin-bearing polymer conjugate via guest-host complexation. All three drugs displayed a 1:1 complexation behavior with the cyclodextrin, which corresponded to a drug loading of 6.0+/-0.1% (CUR), 7.5+/ 0.1% (CPT), and 9.0+/-0.1% (DOX) (w/w). The apparent association constant between the conjugate and drug was 2803.7+/-87.0 (CUR), 3699.4+/-123.3 (CPT), and 6760.9+/-176.3 (DOX), respectively. Ratiometric co-assembly of three types of drug-loaded conjugates produced mixed micelles in a dose- and ratio-controlled manner. The hydrodynamic diameter of co-assembled spherical micelles was ca. 150nm that was similar to the single-drug loaded micelles. The ratiometric co delivery of three drugs via mixed micelles was demonstrated both in HepG2 cells in vitro and in a mice model in vivo compared to a mixture of free drugs, as evidenced by co-localization analysis. This work provides a facile way to realize ratiometric co-administration of multiple drugs. PMID- 28648522 TI - Are Children Born with Birth Defects at Increased Risk of Injuries in Early Childhood? AB - OBJECTIVE: To investigate the extent to which children with birth defects experience differential likelihood of various injuries and injury-related hospitalizations in early childhood. STUDY DESIGN: The Florida Birth Defects Registry was used to identify infants born 2006-2010 with select birth defects. Injury matrices were used to detect injuries in inpatient, ambulatory, and emergency department admissions for each infant up to their third birthday. chi2tests were used to compare sociodemographic and perinatal characteristics of children, by presence of an injury-related hospital admission. Adjusted multivariable logistic and zero-inflated negative binomial regression models were used to investigate birth defect and injury associations and related hospital use. RESULTS: We observed a 21% (99% CI: 1.16-1.27) increased odds of injury in children with birth defects. All birth defect subgroups had a statistically significantly increased odds of injury (excluding chromosomal defects), with adjusted ORs ranging from 1.19 to 1.40. The combination of birth defects and injuries resulted in 40% (99% CI: 1.36-1.44) more frequent injury-related hospital visits and a 3-fold (99% CI: 2.76-2.96) increase in time spent receiving inpatient medical care. Over 30% of children with critical congenital heart defects had an injury-related hospital admission. CONCLUSIONS: Children born with specific birth defects are at increased likelihood of various injuries during early life. Although the magnitude of this increased likelihood varied by the mechanism by which the injury occurred, the location of the injury, and the type of birth defect, our study findings support a direct association between birth defects and injuries in early life. PMID- 28648523 TI - Functional characterization and crystal structure of thermostable amylase from Thermotoga petrophila, reveals high thermostability and an unusual form of dimerization. AB - Thermostable alpha-amylases have many industrial applications and are therefore continuously explored from novel sources. We present the characterization of a novel putative alpha-amylase gene product (Tp-AmyS) cloned from Thermotoga petrophila. The purified recombinant enzyme is highly thermostable and able to hydrolyze starch into dextrin between 90 and 100 degrees C, with optimum activity at 98 degrees C and pH8.5. The activity increased in the presence of Rb1+, K1+ and Ca2+ ions, whereas other ions inhibited activity. The crystal structure of Tp AmyS at 1.7A resolution showed common features of the GH-13 family, however was apparently found to be a dimer. Several residues from one monomer interacted with a docked acarbose, an inhibitor of Tp-AmyS, in the other monomer, suggesting catalytic cooperativity within the dimer. The most striking feature of the dimer was that it resembled the dimerization of salivary amylase from a previous crystal structure, and thus could be a functional feature of some amylases. PMID- 28648524 TI - Molecular modeling of biomolecules by paramagnetic NMR and computational hybrid methods. AB - The 3D atomic structures of biomolecules and their complexes are key to our understanding of biomolecular function, recognition, and mechanism. However, it is often difficult to obtain structures, particularly for systems that are complex, dynamic, disordered, or exist in environments like cell membranes. In such cases sparse data from a variety of paramagnetic NMR experiments offers one possible source of structural information. These restraints can be incorporated in computer modeling algorithms that can accurately translate the sparse experimental data into full 3D atomic structures. In this review, we discuss various types of paramagnetic NMR/computational hybrid modeling techniques that can be applied to successful modeling of not only the atomic structure of proteins but also their interacting partners. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28648525 TI - 18F-FDG PET/CT in a cardiac metastasis in a patient with history of malignant neuroectodermal tumour of the chest wall: Case report and review of the literature. AB - The case presented is a 25-year-old male with a malignant neuroectodermal tumour on the left chest wall (Askin tumour), treated with surgery after neoadyuvant chemotherapy and followed by consolidation chemotherapy. After 9 years of disease free survival, the patient developed an acute pulmonary embolism. The echocardiogram, thoracic CT, and cardiac MRI scans revealed a mass in the right atrium. Recurrence of an Askin tumour versus an atrium myxoma was suspected. 18F FDG PET/CT showed an intense hypermetabolic right atrium mass with extension to the right ventricle highly suggestive of malignancy. The result of the histopathology examination after biopsy and subsequently exeresis of the right atrium mass was consistent with a metastasis of the primary tumour. PMID- 28648526 TI - Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. AB - Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings. PMID- 28648528 TI - Extracellular vesicles. PMID- 28648527 TI - Targeting the Thioredoxin System for Cancer Therapy. AB - Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. PMID- 28648529 TI - Cellular mechanisms of morphogenesis. PMID- 28648530 TI - Automatic quantification of IHC stain in breast TMA using colour analysis. AB - Immunohistochemical (IHC) biomarkers in breast tissue microarray (TMA) samples are used daily in pathology departments. In recent years, automatic methods to evaluate positive staining have been investigated since they may save time and reduce errors in the diagnosis. These errors are mostly due to subjective evaluation. The aim of this work is to develop a density tool able to automatically quantify the positive brown IHC stain in breast TMA for different biomarkers. To avoid the problem of colour variation and make a robust tool independent of the staining process, several colour standardization methods have been analysed. Four colour standardization methods have been compared against colour model segmentation. The standardization methods have been compared by means of NBS colour distance. The use of colour standardization helps to reduce noise due to stain and histological sample preparation. However, the most reliable and robust results have been obtained by combining the HSV and RGB colour models for segmentation with the HSB channels. The segmentation provides three outputs based on three saturation values for weak, medium and strong staining. Each output image can be combined according to the type of biomarker staining. The results with 12 biomarkers were evaluated and compared to the segmentation and density calculation done by expert pathologists. The Hausdorff distance, sensitivity and specificity have been used to quantitative validate the results. The tests carried out with 8000 TMA images provided an average of 95.94% accuracy applied to the total tissue cylinder area. Colour standardization was used only when the tissue core had blurring and fading stain and the expert could not evaluate them without a pre-processing. PMID- 28648531 TI - Attitudes About Lung Cancer Screening: Primary Care Providers Versus Specialists. AB - BACKGROUND: On the basis of the results of the National Lung Screening Trial, the US Preventive Services Task Force now recommends yearly low-dose computed tomography (LDCT) for lung cancer screening among high-risk individuals. There is limited information regarding physician attitudes toward LDCT screening and whether these vary according to provider specialty. MATERIALS AND METHODS: Primary care providers (PCPs) and specialists were surveyed about their knowledge and attitudes toward lung cancer screening and likelihood to order an LDCT screening. Descriptive and univariate analyses were used to assess differences between PCPs versus specialists. RESULTS: Of the 103 respondents 69% were PCPs, 45% were attending-level physicians, 42% were male, and most (51%) worked in mixed outpatient/inpatient practice settings. Compared with specialists, PCPs were less likely to feel confident in their ability to identify appropriate patients for lung cancer screening (63.8% vs. 93.5%; P < .01) or to decide the workup of patients with positive LDCT findings (52.9% vs. 93.5%; P < .01). PCPs were also less likely to believe that the recommended yearly screening interval is feasible (27.5% vs. 86.7%; P < .01), to feel comfortable counseling patients on LDCT (51.4% vs. 82.8%; P = .01) or have sufficient time for counseling (14.3% vs. 50%; P < .01). Despite these differences, PCPs were equally as likely as specialists to recommend LDCT for their high-risk smokers. CONCLUSION: Despite feeling less confident and knowledgeable about lung cancer screening, PCPs are as likely as specialists to recommend LDCT screening. However, PCPs need further education to ensure the success of lung cancer screening programs. PMID- 28648532 TI - The Stent Is Not to Blame: Lessons Learned With a Simplified US Version of the Frozen Elephant Trunk. AB - BACKGROUND: We analyzed trends, assessed outcomes and lessons learned, and investigated whether using a simplified US version of the frozen elephant trunk (FET) technique to treat complex arch pathology poses additional risk. METHODS: From 2010 to 2015, we performed 129 consecutive ET procedures (traditional ET [t ET], n = 92 [71.3%]; FET, n = 37 [28.7%]) for chronic dissecting (n = 62 [48.1%]) and atherosclerotic aneurysms (n = 67 [51.9%]). A stepwise logistic regression model using preoperative and intraoperative variables was created to analyze the outcomes. RESULTS: Thirty-day mortality was 12.4% (t-ET, n = 9 [9.8%]; FET, n = 7 [18.9%]; p = 0.24). The rate of persistent (at the time of discharge) stroke was 5.4% (t-ET, n = 5 [5.4%]; FET, n = 2 [5.4%]; p =1.00). The rate of persistent spinal cord deficit was 3.9% (t-ET, n = 3 [3.3%]; FET, n = 2 [5.4%]; p = 0.62). In the multivariable analyses, the addition of FET was not an independent predictor of mortality, permanent stroke, or spinal cord deficit. CONCLUSIONS: With the advent of endovascular technology, there is a clinical shift toward increased use of FET to eliminate or facilitate the second surgical stage in treating patients with extensive aortic pathology. The addition of FET to the surgical armamentarium does not seem to pose additional risk (although larger studies are needed), but judicious use is advised nonetheless. A single-piece endoprosthesis for FET instead of a customized one should be considered. PMID- 28648533 TI - Recurrent Laryngeal Nerve Injury and Swallowing Dysfunction in Neonatal Aortic Arch Repair. AB - BACKGROUND: We evaluated the incidence, clinical effect, and recovery rate of vocal cord dysfunction (VCD) and swallowing dysfunction in neonates undergoing aortic arch repair. METHODS: We retrospectively evaluated 101 neonates who underwent aortic arch reconstruction from 2008 to 2015. Direct flexible laryngoscopy was performed in 89 patients before initiation of postoperative oral feeding after Norwood (n = 63) and non-Norwood (n = 26) arch reconstruction. We defined VCD as immobility of vocal cords or their lack of coaptation and poor mobility. RESULTS: The incidence of VCD after aortic arch repair was 48% (n = 43). There was no significant difference between the VCD and non-VCD groups in postoperative length of stay, extubation failure, cardiopulmonary bypass, cross clamp, selective cerebral perfusion time, operative death, and The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) Congenital Heart Surgery Mortality Categories. Placement of gastrostomy (p = 0.03) and documented aspiration (p = 0.01) were significantly more common in VCD patients. The incidence of VCD was 41% (n = 26) after Norwood and 65% (n = 17) after non-Norwood repairs (p = 0.06). Gastrostomy was required in 44 Norwood patients vs 9 non-Norwood patients (p = 0.004). Median length of stay was similar in Norwood patients with or without VCD (p = .28) but was significantly longer in non-Norwood patients with VCD vs those without (p = 0.002). At follow-up direct flexible laryngoscopy, VCD recovery was 74% (14 of 19) in the Norwood group and 86% (12 of 14) in the non-Norwood group. CONCLUSIONS: The incidence of VCD and swallowing dysfunction in neonates undergoing aortic arch reconstruction is high. Patients with VCD have a significantly higher incidence of gastrostomy placement and aspiration. In the Norwood population, length of stay is not associated with presence or absence of VCD. More than 70% of patients in each group who had direct flexible laryngoscopy follow-up recovered vocal cord function. PMID- 28648534 TI - Promising Outcome of Anatomic Correction of Corrected Transposition of the Great Arteries. AB - BACKGROUND: Anatomic correction of corrected transposition of the great arteries with associated lesions, utilizing the morphologic left ventricle as a systemic pumping chamber, is the preferred method in many centers. The purpose of this study was to analyze functional outcome after anatomic correction. METHODS: Between Jan 1997 and May 2016, 63 patients with corrected transposition of the great arteries and associated lesions underwent anatomic correction. Forty-two patients (67%) underwent palliation before correction, including 14 patients (22%) who required training of systemic ventricle. The double switch procedure was performed in 37 patients; 25 patients underwent the Senning-Rastelli operation, and 1 patient underwent the Senning-Nikaidoh procedure. The median age at correction was 1.6 +/- 3.7(SD) years (range, 0.2 to 17.8 years). RESULTS: The survival and freedom from any event was 95% and 71%, respectively, at 15-year follow-up. The combined freedom from death, failure of systemic ventricle, or heart transplant was 93% at 15-year follow-up regardless of procedure type. Sinus rhythm was present in 49 patients, with 14 patients requiring pacemaker (22%)-8 preoperatively, 4 early postoperatively, and 2 late postoperatively. Neurological development is normal in all patients. Fifty-four percent of the patients are not on medication. CONCLUSIONS: Anatomic correction of corrected transposition of the great arteries is a safe procedure that provides encouraging survival and functional benefits. Ninety-three percent preservation of morphological left ventricle function in 15 years of follow-up supports the concept of anatomic correction. Longer follow-up is needed to confirm superiority of this approach over other management strategies. PMID- 28648535 TI - Technical Performance Score: Predictor of Outcomes in Complete Atrioventricular Septal Defect Repair. AB - BACKGROUND: Technical performance score (TPS) has been associated with both early and late outcomes across a wide range of congenital cardiac procedures. We sought to validate TPS as predictor of outcomes for complete atrioventricular septal defect (CAVSD) repair. METHODS: This was a single-center retrospective review of patients after balanced CAVSD repair between January 1, 2000, and March 1, 2016. We assigned TPS (class 1, no residua; class 2, minor residua; class 3, major residua or reintervention before discharge for residua) based on summation of subcomponent scores from discharge echocardiograms. Outcomes of interest were in hospital complications, postoperative days on ventilator, and postdischarge reintervention. RESULTS: Among 350 patients, median age was 3.2 months (interquartile range [IQR], 2.4 to 4.2 months). Fifty-four patients (16%) had class 1 TPS, 218 (62%) class 2, 63 (18%) class 3, and 15 (4%) were unscorable. There were 36 complications (10%), and median postoperative days on ventilator were 2 (IQR, 1 to 3) days. There were 34 postdischarge reinterventions (10%). Median follow-up was 2.6 years (IQR, 0.09 to 7.9) years. On multivariable modeling, class 3 TPS was associated with complications (odds ratio 5.45, 95% confidence interval [CI]: 1.06 to 28.1, p = 0.04), prolonged postoperative ventilator days (hazard ratio [HR] 0.54, 95% CI: 0.37 to 0.80, p = 0.002), and postdischarge reintervention (HR 5.61, 95% CI: 1.28 to 24.5, p = 0.02) after adjusting for covariates such as age, weight, genetic abnormality, concomitant procedure, prematurity, and second bypass run. CONCLUSIONS: At our center, CAVSD repair was associated with low morbidity. TPS may identify patients with complications, prolonged days on ventilator, and who require postdischarge reinterventions; thus, it provides feedback on areas of improvement and allows identification of patients who warrant closer follow-up. PMID- 28648536 TI - Outcomes of Elective Aortic Hemiarch Reconstruction for Aneurysmal Disease in the Elderly. AB - BACKGROUND: This study evaluated outcomes of elective aortic hemiarch reconstruction for aneurysmal disease in the elderly. METHODS: Patients undergoing elective aortic hemiarch reconstruction for aneurysmal disease at a single institution between 2009 and 2014 were retrospectively reviewed. Patients were stratified into nonelderly (aged less than 75 years) versus elderly (aged 75 years or more). Outcomes included operative mortality and morbidity. RESULTS: In all, 629 patients (95 elderly; 15%) were included. Elderly patients had a greater comorbidity burden. Concomitant aortic valve replacement and coronary artery bypass were performed more frequently whereas root replacement was performed less frequently in the elderly. The overall stroke rate was 1.8% and was higher among the elderly (4.2% versus 1.3%, p = 0.05), although this difference no longer persisted after risk adjustment (odds ratio 2.54, p = 0.17). Median length of intensive care unit and hospital stay were longer in the elderly (64 versus 41 hours and 9 versus 7 days, respectively; each p < 0.001). Unadjusted and risk adjusted operative mortality were similar (2.1% elderly versus 0.9% nonelderly, p = 0.32). Elderly patients were less frequently discharged to home (65% versus 95%, p < 0.001). Propensity matched analysis confirmed these findings. Moderate hypothermic circulatory arrest with antegrade cerebral perfusion was a safe strategy for the elderly patients, with stroke and operative mortality rates of 0% each. CONCLUSIONS: Although elderly patients have a more prolonged recovery after elective aortic hemiarch reconstruction for aneurysmal disease, outcomes are acceptable with low operative mortality and with the majority being discharged home. Moderate hypothermic circulatory arrest with antegrade cerebral perfusion is a safe strategy for this cohort. Advanced age alone should not be viewed as a contraindication in these cases. PMID- 28648537 TI - Outcome of Surgical Repair of Pulmonary Artery Aneurysms: A Single-Center Experience With 38 Patients. AB - BACKGROUND: Pulmonary artery (PA) aneurysms are rare and have been reported only in case reports or small series. We reviewed our experience with surgical repair of PA aneurysms. METHODS: We reviewed all patients with a true PA aneurysm undergoing cardiac operations between 1995 and 2015. We excluded aneurysms and pseudoaneurysms related to right ventricular outflow tract patches or previous conduits. RESULTS: There were 38 patients (24 women [63%]; mean age, 46 +/- 15 years), and 14 patients (37%) were asymptomatic. The main PA was involved 35 patients (92%). The mean aneurysm diameter was 5.8 +/- 1.8 cm. The most common associated pathology was pulmonary valve stenosis/regurgitation in 23 patients (64%). High-pressure (right ventricular systolic pressure >35 mm Hg) aneurysms were present in 23 patients. Operative strategies included reduction arterioplasty in 30 patients (79%) and resection with graft interposition in 8 (21%). The average length of stay was 6.0 +/- 2.2 days. There were no early deaths. Late deaths occurred in 3 patients (8%) and were noncardiac related. Late reoperations occurred in 8% and were not related to the PA aneurysm. All high pressure aneurysms and those larger than 8 cm demonstrated advanced medial necrosis on pathologic examination of the specimens. CONCLUSIONS: PA aneurysms are a real entity, and surgical repair can be done with low morbidity and mortality. Aneurysmorrhaphy or aneurysmectomy can be performed, depending on the anatomic location. Regardless of the size of the PA, we recommend intervention on high-pressure aneurysms due to the occurrence of advanced medial necrosis. PMID- 28648538 TI - Survival in Surgical and Nonsurgical Patients With Superior Sulcus Tumors. AB - BACKGROUND: Treatments for superior sulcus tumor (SST) have evolved, with induction chemoradiotherapy providing an improved R0 resection rate. We reviewed the treatment and outcomes of SSTs in a single institution to identify prognostic factors and optimal treatment strategy. METHODS: Details of patients who underwent any type of treatment for SST from 1997 through 2014 were retrospectively collected. Survival was calculated by the Kaplan-Meier method. Proportional hazards regression was used to test the prognostic significance of factors in univariate and multivariate models. RESULTS: Eighty-nine patients were identified, 8 of whom had M1 disease and were excluded from the analysis. Of the 48 surgical patients, 44 received preoperative induction treatments, with 12 (25%) achieving a pathologic complete response (pCR), 23 with minimal residual disease, and 9 with gross residual disease. Complete resection was achieved in 40 surgical cases. As expected, nonsurgical patients had worse survival than did surgical patients (median survival, 2.1 versus 5.8 years; nonsurgical versus surgical hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2-3.7; p = 0.01). By multivariable Cox analysis, smoking status (HR, 4.4; 95% CI, 1.5-13.0; p = 0.01) and previous or concurrent malignancy (HR, 4.73; 95% CI, 1.6-13.9; p = 0.0.005) were prognostic factors for surgical patients. There were no statistically significant prognostic factors for nonsurgical patients. CONCLUSIONS: Chemoradiotherapy followed by surgical treatment is our favored treatment for operable candidates. Preoperative induction treatments were associated with a 25% pCR rate for surgical patients. Candidates for surgical therapy are expected to have longer survival than those who are not candidates for resection. PMID- 28648539 TI - Prothrombin Complex Concentrates in Pediatric Cardiac Surgery: The Current State and the Future. AB - BACKGROUND: After decades of practice of pediatric cardiac surgery, postoperative bleeding due to the immaturity of hemostasis, hemodilution, and hypothermia remains a concern. Recently, a new approach for adult coagulopathy after bypass has emerged. Prothrombin complex concentrates (PCCs), designed to treat bleeding in hemophilia patients, are safely and efficiently used off label for hemorrhage after bypass. However, optimal dosing, indications and contraindications, and laboratory tests to assess the efficacy of PCC use in children have not yet been established. This literature review outlines the challenges of bypass-related coagulopathy, the pharmacology, and the experience in use of PCCs, with a focus on their potential in pediatric cardiac surgery. METHODS: After a thorough literature search of MEDLINE, Scopus, and Ovid databases using the term "prothrombin complex concentrate AND pediatric," 23 relevant articles were selected. RESULTS: The data supporting successful use of PCCs in acquired coagulopathy after cardiac surgery in adults have been increasing. Although small volume, low immunogenicity, efficiency, and speed in correcting coagulopathy are attractive qualities of PCCs for pediatric practice, current evidence is only anecdotal. The main concerns are unknown dosing regimens, the inability to closely monitor the effects of PCCs in real time, and a possibility of thrombotic complications, which can be particularly devastating in young congenital cardiac patients whose lives frequently depend upon the patency of artificial shunts. CONCLUSIONS: Extensive, high-quality research is warranted to fill in the gaps of knowledge regarding using PCCs in pediatric cardiac practice. PMID- 28648540 TI - Pedicled Vein Grafts in Coronary Surgery: Perioperative Data From a Randomized Trial. AB - BACKGROUND: Less-than-optimal long-term patency of the saphenous vein is one of the main obstacles for the success of coronary artery bypass grafting (CABG). Results from the IMPROVE-CABG trial has shown that harvesting the saphenous vein with a pedicle of perivascular tissue less than 5 mm while using manual distention provides comparable occlusion rates but significantly less intimal hyperplasia at early follow-up. The impact of pedicled veins on duration of operations, leg wound infections, and postoperative bleeding is unknown. METHODS: One hundred patients undergoing first-time elective CABG were randomly assigned to conventional or pedicled vein harvesting. Perioperative and postoperative data were collected prospectively during the hospital stay and at follow-up. RESULTS: Duration of extracorporeal circulation was significantly longer in the pedicled vein group (mean: 76 min versus 65 min, p = 0.006); however, no significant difference was found in the cross-clamp time. No significant difference was found in intraoperative vein graft flow, postoperative bleeding, or leg wound infections (4% in each group). No reoperations were due to vein graft bleeding. CONCLUSIONS: Harvesting a pedicled vein provides comparable postoperative bleeding and leg wound infection rates in selected patients. The technique is associated with a slightly longer duration of extracorporeal circulation than harvesting conventional veins. Promising early results using the pedicled vein technique may contribute to a change in standard vein harvesting technique for CABG in selected patients. PMID- 28648541 TI - Coronary Artery Anomalies in Patients With Transposition of the Great Arteries and Their Impact on Postoperative Outcomes. AB - BACKGROUND: Coronary anomalies are frequently present in children with transposition of the great arteries (TGA). Such anomalies significantly increase the complexity of arterial switch operations and may have an effect on postoperative outcomes. In this study, we aimed to assess the frequency of coronary anomalies in children with TGA and describe their effect on postoperative outcomes. METHODS: All patients with TGA who underwent an arterial switch operation between 1991 and 2015 were consecutively enrolled in this study. Patient coronary patterns were obtained from corresponding operative reports and analyzed to determine their associations with adverse postoperative outcomes. RESULTS: The study included 715 patients with isolated and complex TGA. Coronary anomalies were present in 33.7% of patients and were significantly correlated with the side-by-side configuration of the great arteries. Coronary sinuses with more than 1 ostium were associated with a significantly increased risk of postoperative death (hazard ratio [HR], 2.58), and coronary arteries with a single ostium were associated with an increased risk of postoperative reinterventions (HR, 2.49). In contrast, the trap-door technique of coronary artery transplantation was associated with a reduced risk of reinterventions during postoperative follow-up (HR, 0.40). Complex coronary anomalies were significantly associated with postoperative coronary events (HR, 2.12). CONCLUSIONS: With the exception of patients whose circumflex artery branches off of the right coronary artery, an anomaly that clearly has no effect on postoperative follow-up, patients with unusual coronary patterns are at higher risk for adverse postoperative outcomes than patients with normal coronary anatomy and must be monitored carefully. PMID- 28648542 TI - HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. AB - BACKGROUND: Vaccination has been suggested to be involved in the aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). HPV vaccine was introduced in the Norwegian Childhood Immunisation Programme and offered 12year old girls from 2009. We studied the association between HPV vaccination and risk of CFS/ME and also assessed medical history in relation to both risk of CFS/ME and HPV vaccine uptake. METHODS: Individual data from national registries, including the Norwegian Population Registry, the Norwegian Patient Registry and the Norwegian Immunisation Registry were linked using the unique personal identification number. Yearly incidence rates of CFS/ME for 2009-2014 were calculated among the 824,133 boys and girls, aged 10-17 living in Norway during these 6years. A total of 176,453 girls born 1997-2002 were eligible for HPV vaccination and included in further analyses. Hazard ratios (HRs) of CFS/ME were estimated using Cox regression. Risk differences (RDs) of vaccine uptake were estimated with binomial regression. RESULTS: A similar yearly increase in incidence rate of CFS/ME was observed among girls and boys, IRR=1.15 (95% confidence interval (CI) 1.10-1.19) and 1.15 (95% CI 1.09-1.22), respectively. HPV vaccination was not associated with CFS/ME, HR=0.86 (95% CI 0.69-1.08) for the entire follow-up period and 0.96 (95% CI 0.64-1.43) for the first two years after vaccination. The risk of CFS/ME increased with increasing number of previous hospital contacts, HR=5.23 (95% CI 3.66-7.49) for 7 or more contacts as compared to no contacts. Girls with 7 or more hospital contacts were less likely to be vaccinated than girls with no previous hospital contacts, RD=-5.5% (95% CI 6.7% to -4.2%). CONCLUSIONS: No indication of increased risk of CFS/ME following HPV vaccination was observed among girls in the first 6 birth cohorts offered HPV vaccine through the national immunisation programme in Norway. PMID- 28648544 TI - Risk of intussusception following rotavirus vaccination: An evidence based meta analysis of cohort and case-control studies. AB - BACKGROUND: International post-licensure studies on rotavirus vaccines have identified an increased risk of intussusception in infants after administration. The first developed rotavirus vaccine (Rotashield (RRV-TV)) was suspended post licensure in 1999 after an association with intussusception was found. The currently available second-generation rotavirus vaccines (Rotateq (RV5) and Rotarix (RV1)), are recommended as a routine vaccine by the World Health Organisation (WHO). Post-licensure studies of these vaccines have shown a smaller but temporal increased risk for developing intussusception. METHODS: A meta analysis was performed to summarise available evidence and to give an overall risk of developing intussusception from case-control and cohort studies for all rotavirus vaccines that have been manufactured up to date. A search was conducted on MEDLINE, PubMed, EMBASE and Google Scholar up to May 2017. Eligible studies assessed the relationship between the rotavirus vaccine administration and subsequent development of intussusception both after receiving the first dose and after receiving all doses combined. Data was extracted on study characteristics, methods and outcomes. Results were pooled using the random-effect model. RESULTS: Six cohort studies involving 4506265 total first doses and five case-control studies involving a total sample of 9643 children were included in this analysis. The cohort data revealed that there was an associated increased risk of intussusception after the first 7days post first dose of the vaccine (RR:3.71, 95% CI:1.08-12.69) and after receiving all doses of the rotavirus vaccine (RR:3.47, 95% CI:1.23-9.78). Similarly, the case-control data found an increased risk of intussusception following the first dose (OR: 8.45, 95% CI: 4.08-17.50) and following all doses (OR: 1.59, 95% CI: 1.11-2.27). CONCLUSIONS: Findings of this meta-analysis suggest that the rotavirus vaccine is associated with an increased risk on the development of intussusception, principally seen after administration of the first dose of vaccine. PMID- 28648543 TI - Seasonal influenza vaccine effectiveness against laboratory-confirmed influenza hospitalizations - Latin America, 2013. AB - BACKGROUND: Despite widespread utilization of influenza vaccines, effectiveness (VE) has not been routinely measured in Latin America. METHODS: We used a case test-negative control design to estimate trivalent inactivated influenza VE against laboratory-confirmed influenza among hospitalized children aged 6months 5years and adults aged >=60years which are age-groups targeted for vaccination. We sought persons with severe acute respiratory infections (SARI), hospitalized at 71 sentinel hospitals in Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Honduras, Panama, and Paraguay during January-December 2013. Cases had an influenza virus infection confirmed by real-time reverse transcription PCR (rRT-PCR); controls had a negative rRT-PCR result for influenza viruses. We used a two-stage random effects model to estimate pooled VE per target age-group, adjusting for the month of illness onset, age and preexisting medical conditions. RESULTS: We identified 2620 SARI patients across sites: 246 influenza cases and 720 influenza-negative controls aged <=5years and 448 cases and 1206 controls aged >=60years. The most commonly identified subtype among participants (48%) was the influenza A(H1N1)pdm09 virus followed by influenza A(H3N2) (34%) and influenza B (18%) viruses. Among children, the adjusted VE of full vaccination (one dose for previously vaccinated or two if vaccine naive) against any influenza virus SARI was 47% (95% confidence interval [CI]: 14-71%); VE was 58% (95% CI: 16-79%) against influenza A(H1N1)pdm09, and 65% (95% CI: -9; 89%) against influenza A(H3N2) viruses associated SARI. Crude VE of full vaccination against influenza B viruses associated SARI among children was 3% (95% CI: -150; 63). Among adults aged >=60years, adjusted VE against any influenza SARI was 48% (95% CI: 34-60%); VE was 54% (95% CI: 37-69%) against influenza A(H1N1)pdm09, 43% (95% CI: 18-61%) against influenza A(H3N2) and 34% (95% CI: -4; 58%) against B viruses associated SARI. CONCLUSION: Influenza vaccine provided moderate protection against severe influenza illness among fully vaccinated young children and older adults, supporting current vaccination strategies. PMID- 28648545 TI - Application of the revised WHO causality assessment protocol for adverse events following immunization in India. AB - BACKGROUND: In 2013, the World Health Organization (WHO) and CIOMS introduced a revised Causality Assessment Protocol (CAP) for Adverse Events following Immunization (AEFI). India is one of the first countries to adopt the revised CAP. This study describes the application of the revised CAP in India. METHODS: We describe use of CAP by India's AEFI surveillance program to assess reported AEFIs. Using publicly available results of causality assessment for reported AEFIs, we describe the results by demographic characteristics and review the trends for the results of the causality assessment. RESULTS: A total of 771 reports of AEFI between January 2012 and January 2015, completed causality review by August 2016. The cases were reported as belonging to a cluster (54%; n=302), hospitalized or requiring hospitalization (41%; n=270), death (25%; n=195), or resulting in disability (0.4%; n=3). The most common combinations of vaccines leading to report of an AEFI were DTwP, Hepatitis B, and OPV (14%; n=106), followed by Pentavalent and OPV (13%; n=103), and JE vaccine (13%; n=101). Using the WHO Algorithm, most AEFI reports (89%, n=683) were classifiable. Classifiable AEFI reports included those with a consistent causal association (53%; n=407), an inconsistent causal association (29%; n=226) or were indeterminate causal association with implicated vaccine(s) or vaccination process (6.5%; n=50) (Fig. 1); 88 reports remained unclassifiable. CONCLUSIONS: The revised CAP was informative and useful in classifying most of the reviewed AEFIs in India. Unclassifiable reports could be minimized with more complete information from health records. Improvements in causality assessment, and standardization in reporting between countries, can improve public confidence in vaccine system performance and identify important vaccine safety signals. PMID- 28648546 TI - Process intensification for high yield production of influenza H1N1 Gag virus like particles using an inducible HEK-293 stable cell line. AB - Influenza virus dominant antigens presentation using virus like particle (VLP) approach is attractive for the development of new generation of influenza vaccines. Mammalian cell platform offers many advantages for VLP production. However, limited attention has been paid to the processing of mammalian cell produced VLPs. Better understanding of the production system could contribute to increasing the yields and making large-scale VLP vaccine manufacturing feasible. In a previous study, we have generated a human embryonic kidney HEK-293 inducible cell line expressing Hemagglutinin (HA) and Neuraminidase (NA), which was used to produce VLPs upon transient transfection with a plasmid containing HIV-1 Gag. In this work, to streamline the production process, we have developed a new HEK-293 inducible cell line adapted to suspension growth expressing the three proteins HA, NA (H1N1 A/PR/8/1934) and the Gag fused to GFP for monitoring the VLP production. The process was optimized to reach higher volumetric yield of VLPs by increasing the cell density at the time of induction without sacrificing the cell specific productivity. A 5-fold improvement was achieved by doing media evaluation at small scale. Furthermore, a 3-L perfusion bioreactor mirrored the performance of small-scale shake flask cultures with sequential medium replacement. The cell density was increased to 14*106 cells/ml at the time of induction which augmented by 60-fold the volumetric yield to 1.54*1010 Gag-GFP fluorescent events/ml, as measured by flow cytometry. The 9.5-L harvest from the perfusion bioreactor was concentrated by tangential flow filtration at low shear rate. The electron micrographs revealed the presence of VLPs of 100-150nm with the characteristic dense core of HIV-1 particles. The developed process shows the feasibility of producing high quantity of influenza VLPs from an inducible mammalian stable cell line aiming at large scale vaccine manufacturing. PMID- 28648547 TI - Investigations on phosphorus recovery from aqueous solutions by biochars derived from magnesium-pretreated cypress sawdust. AB - The ability of biochars, derived from the pyrolysis at 400 degrees C; 500 degrees C and 600 degrees C of pretreated cypress sawdust with 20 wt% magnesium chloride (MgCl2) solutions, in recovering phosphorus from aqueous solutions was investigated under various experimental conditions in batch mode. The experimental results indicated that cypress sawdust pretreatment with MgCl2 induced important modifications of the physical and chemical biochars' properties favoring phosphorus recovery from the used synthetic solutions. Moreover, phosphorus recovery efficiency increased with the increase of the used pyrolysis temperature. Indeed, for an aqueous pH of 5.2 and a phosphorus concentration of 75 mg L-1, the recovered amounts increased from 19.2 mg g-1 to 33.8 mg g-1 when the used pyrolysis temperature was raised from 400 degrees C to 600 degrees C. For all the tested biochars, the phosphorus recovery kinetics data were well fitted by the pseudo-second-order model, and the equilibrium state was obtained after 180 min of contact time. Furthermore, the phosphorus recovery data at equilibrium were well described by the Langmuir model with a maximal recovery capacity of 66.7 mg g-1 for the magnesium pretreated biochar at 600 degrees C. Phosphorus recovery by the used biochars occurred probably through adsorption onto biochars' active sites as well as precipitation with magnesium ions as magnesium phosphates components. All these results suggested that biochars derived from MgCl2 pretreated cypress sawdust could be considered as promising materials for phosphorus recovery from wastewaters for a possible further subsequent use in agriculture as amendments. PMID- 28648548 TI - 38-Year-Old Man With Asthma and Eosinophilia. PMID- 28648549 TI - Hippocampal spatial mechanisms relate to the development of arithmetic symbol processing in children. AB - Understanding the meaning of abstract mathematical symbols is a cornerstone of arithmetic learning in children. Studies have long focused on the role of spatial intuitions in the processing of numerals. However, it has been argued that such intuitions may also underlie symbols that convey fundamental arithmetic concepts, such as arithmetic operators. In the present cross-sectional study, we used fMRI to investigate how and when associations between arithmetic operators and brain regions processing spatial information emerge in children from 3rd to 10th grade. We found that the mere perception of a '+' sign elicited grade-related increases of spatial activity in the right hippocampus. That is, merely perceiving '+' signs - without any operands - elicited enhanced hippocampal activity after around 7th grade (12-13 years old). In these children, hippocampal activity in response to a '+' sign was further correlated with the degree to which calculation performance was facilitated by the preview of that sign before an addition problem, an effect termed operator-priming. Grade-related increases of hippocampal spatial activity were operation-specific because they were not observed with '*' signs, which might evoke rote retrieval rather than numerical manipulation. Our study raises the possibility that hippocampal spatial mechanisms help build associations between some arithmetic operators and space throughout age and/or education. PMID- 28648550 TI - Individual housing-based socioeconomic status predicts risk of accidental falls among adults. AB - PURPOSE: Accidental falls are a major public health concern among people of all ages. Little is known about whether an individual-level housing-based socioeconomic status measure is associated with the risk of accidental falls. METHODS: Among 12,286 Mayo Clinic Biobank participants residing in Olmsted County, Minnesota, subjects who experienced accidental falls between the biobank enrollment and September 2014 were identified using ICD-9 codes evaluated at emergency departments. HOUSES (HOUsing-based Index of SocioEconomic Status), a socioeconomic status measure based on individual housing features, was also calculated. Cox regression models were utilized to assess the association of the HOUSES (in quartiles) with accidental fall risk. RESULTS: Seven hundred eleven (5.8%) participants had at least one emergency room visit due to an accidental fall during the study period. Subjects with higher HOUSES were less likely to experience falls in a dose-response manner (hazard ratio: 0.58; 95% confidence interval: 0.44-0.76 for comparing the highest to the lowest quartile). In addition, the HOUSES was positively associated with better health behaviors, social support, and functional status. CONCLUSIONS: The HOUSES is inversely associated with accidental fall risk requiring emergency care in a dose-response manner. The HOUSES may capture falls-related risk factors through housing features and socioeconomic status-related psychosocial factors. PMID- 28648551 TI - Science, Politics, and Communication: The Case of Community Water Fluoridation in the US. AB - Community water fluoridation (CWF) and its effect in reducing the burden of dental caries (tooth decay) is considered one of the 10 public health achievements in the 20th century. In the U.S., three-quarters (74.4%) of people on community water supplies have optimally fluoridated water, and each year approximately 90 communities actively consider starting or discontinuing CWF. CWF exists within the policy environment and includes actions taken by local community councils, health and water boards, and groups; state legislatures and health departments; national regulatory and science agencies; independent science entities; and professional and nonprofit organizations. Epidemiologists have been in the forefront of CWF. Experience with the past 70 years reveals that the coming decades will bring additional questions, recommendations, and challenges for CWF. The continued involvement of epidemiologists as part of multidisciplinary teams is needed in research, surveillance, peer review of studies, assessment of systematic review findings, and in the translation and communication of science findings to audiences with limited science/health literacy. This chapter's purpose is to 1) examine how epidemiologic evidence regarding CWF has been translated into practice and policy, 2) examine how recommendations for and challenges to CWF have affected epidemiologic research and community decision-making, and 3) identify lessons learned for epidemiologists. PMID- 28648552 TI - Epigenetic induction of melatonin MT1 receptors by valproate: Neurotherapeutic implications. AB - We have reported that the anticonvulsant/mood stabilizer and histone deacetylase (HDAC) inhibitor valproate (VPA) induces expression of melatonin receptors both in vitro and in vivo, but the mechanisms involved were not known. Here we show that pharmacological inhibition of CREB, PKC, PI3K, or GSK3beta signaling pathways, which are known targets for VPA, do not prevent its upregulation of melatonin MT1 receptors in rat C6 glioma cells. M344, an HDAC inhibitor unrelated to VPA, mimics the effects of VPA on MT1 expression, whereas valpromide, a VPA derivative lacking HDAC inhibitory activity, does not. Furthermore, VPA, at a concentration which upregulates the MT1 receptor, induces histone H3 hyperacetylation along the length of the MT1 receptor promoter. These results show that an epigenetic mechanism involving histone acetylation underlies induction of MT1 receptor expression by VPA. Given the neuropsychiatric effects of melatonin coupled with evidence that VPA upregulates melatonin receptors in the rat brain, these findings suggest that the melatonergic system contributes to the psychotropic effects of VPA. PMID- 28648553 TI - Escitalopram plasma levels and antidepressant response. AB - Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 (p<0.001) and month 3 (p=0.0003), which persists also excluding 3 patients with SCE equal to 0. Interestingly, by excluding patients with SCE < 20ng/mL, i.e. with a SCE lower than the putative therapeutic threshold, these associations disappeared. The curvilinear function AR = a + (SCE SCE2) explained a higher proportion of variance compared to the linear other models (p<0.001). Our results suggest that for escitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings. PMID- 28648554 TI - The isokinetic rotator cuff strength ratios in overhead athletes: Assessment and exercise effect. AB - OBJECTIVE: Muscle strength imbalance in the shoulder region can be considered as a predisposing factor in the development of movement dysfunctions, possibly leading to overuse injuries. Repetitive overhead throwing, performed in sports, may result in muscle imbalance between the external (ER) and internal (IR) rotators. Muscle strength measured with an isokinetic device, is reported as a concentric (CON) or eccentric (ECC) force. The balance between an agonist and an antagonist is mentioned as a ratio (CON/CON or ECC/CON). The aim of this systematic literature review is to provide an overview of the existing evidence considering the isokinetic muscle strength ratios of ER and IR of the shoulder in healthy overhead athletes. In addition, the effect of exercise programs on these ratios was investigated. METHODS: Two online databases (Web of Science and PubMed) were consulted using different search strategies. Articles were selected based on inclusion and exclusion criteria. All included articles were assessed on their methodological quality. RESULTS AND CONCLUSIONS: There is moderate evidence for a lower functional deceleration ratio (ECC ER/CON IR) at the dominant side. This lower ratio is due to a large overweight of CON IR strength on that side. There is no consensus about which exercise program is the most effective in altering the shoulder isokinetic strength ratios. PMID- 28648555 TI - Comparison of plasma pigment epithelium-derived factor (PEDF), retinol binding protein 4 (RBP-4), chitinase-3-like protein 1 (YKL-40) and brain-derived neurotrophic factor (BDNF) for the identification of insulin resistance. AB - AIMS: To evaluate and compare the association of four potential insulin resistance (IR) biomarkers (pigment-epithelium-derived factor [PEDF], retinol binding-protein-4 [RBP-4], chitinase-3-like protein 1 [YKL-40] and brain-derived neurotrophic factor [BDNF]) with objective measures of IR. METHODS: We studied 81 subjects with different metabolic profiles. All participants underwent a 5-point OGTT with calculation of multiple IR indexes. A subgroup of 21 participants additionally underwent a hyperinsulinemic-euglycemic clamp. IR was defined as belonging to the highest quartile of incremental area under the insulin curve (iAUCins), or to the lowest quartile of the insulin sensitivity index (ISI). RESULTS: PEDF was associated with adiposity variables. PEDF and RBP4 increased linearly across quartiles of iAUCins (for PEDF p-trend=0.029; for RBP-4 p trend=0.053). YKL-40 and BDNF were not associated with any adiposity or IR variable. PEDF and RBP-4 levels identified individuals with IR by the iAUCins definition: A PEDF cutoff of 11.9ng/mL had 60% sensitivity and 68% specificity, while a RBP-4 cutoff of 71.6ng/mL had 70% sensitivity and 57% specificity. In multiple regression analyses simultaneously including clinical variables and the studied biomarkers, only BMI, PEDF and RBP-4 remained significant predictors of IR. CONCLUSIONS: Plasma PEDF and RBP4 identified IR in subjects with no prior diagnosis of diabetes. PMID- 28648556 TI - NICE recommends routine NHS funding for Kadcyla. PMID- 28648557 TI - Risk prediction equations for survival in colorectal cancer. PMID- 28648558 TI - Potential drug targets in small-bowel adenocarcinoma. PMID- 28648559 TI - Atezolizumab in advanced non-small-cell lung cancer. PMID- 28648560 TI - Switch-like behavior enables Wnt11 concentration specific response during dorso ventral axis formation in Xenopus laevis. AB - Wnt signaling plays a role in diverse processes such as cell proliferation, differentiation, migration or cell polarity. Dysfunction of Wnt signaling is associated with human diseases and aging. Wnts can activate several interacting intracellular signaling pathways, in particular the so called canonical and non canonical pathways. The canonical Wnt response leads to a stabilization of cytoplasmic beta-catenin whereas non-canonical Wnt signaling can result in the activation of calcium-calmodulin dependent kinase II (CamKII). Earlier data revealed that those signaling pathways can inhibit each other in a concentration dependent manner. During Xenopus laevis dorsal axis formation, Wnt11 has been shown to activate both, beta-catenin signaling as well as CamKII activity. In line, Wnt11 is required for dorsal as well as ventral cell fates. Here, we show that the concentration dependent mutual inhibition of CamKII and beta-catenin signaling is sufficient to obtain a switch-like behavior as opposed to a graded response. We present a model that faithfully recapitulates the activity of Wnt11 during dorso-ventral axis formation in Xenopus laevis on the basis of the Wnt switch behavior. PMID- 28648561 TI - Exact results for the probability and stochastic dynamics of fixation in the Wright-Fisher model. AB - In this work we consider fixation of an allele in a population. Fixation is key to understanding the way long-term evolutionary change occurs at the gene and molecular levels. Two basic aspects of fixation are: (i) the chance it occurs and (ii) the way the gene frequency progresses to fixation. We present exact results for both aspects of fixation for the Wright-Fisher model. We give the exact fixation probability for some different schemes of frequency-dependent selection. We also give the corresponding exact stochastic difference equation that generates frequency trajectories which ultimately fix. Exactness of the results means selection need not be weak. There are possible applications of this work to data analysis, modelling, and tests of approximations. The methodology employed illustrates that knowledge of the fixation probability, for all initial frequencies, fully characterises the dynamics of the Wright-Fisher model. The stochastic equations for fixing trajectories allow insight into the way fixation occurs. They provide the alternative picture that fixation is driven by the injection of one carrier of the fixing allele into the population each generation. The stochastic equations allow explicit calculation of some properties of fixing trajectories and their efficient simulation. The results are illustrated and tested with simulations. PMID- 28648562 TI - A cellular automaton based on plasma membrane turnover accurately recapitulates cell mechanics during epithelial scattering. AB - Epithelial cells can be triggered to actively detach from epithelial tissues and become solitary, migratory and invasive. This process occurs repeatedly in development, where it is termed epithelial-mesenchymal transition (EMT), and can be recapitulated as epithelial scattering in cell culture models. Detachment of cell-cell junctions involves changes in contractile forces, actin cytoskeletal organization, changes in cell-substrate adhesion properties, surface presentation of cell-cell adhesion molecules, and gene expression. That these cellular processes affect each other and share molecular components creates difficulties in generating hypotheses and designing experiments to understand the mechanics of epithelial scattering. Computational modeling is proving a powerful too in such instances. Here we develop a cellular automaton to reveal insights into how cells rupture epithelial cell-cell junctions during scattering. The model is optimized for realistic and stable recapitulation of behavior of single cells, then for realistic simulation of multiple cells forming epithelial colonies. With a workable model of epithelial cell behavior, we then alter model parameters and assess whether we can realistically mimic epithelial scattering. Adjusting model parameters to recapitulate epithelial scattering reveals that induction of cell migration is the major driver of epithelial scattering. PMID- 28648563 TI - Mathematical modeling for meshwork formation of endothelial cells in fibrin gels. AB - Vasculogenesis is the earliest process in development for spontaneous formation of a primitive capillary network from endothelial progenitor cells. When human umbilical vein endothelial cells (HUVECs) are cultured on Matrigel, they spontaneously form a network structure which is widely used as an in vitro model of vasculogenesis. Previous studies indicated that chemotaxis or gel deformation was involved in spontaneous pattern formation. In our study, we analyzed the mechanism of vascular pattern formation using a different system, meshwork formation by HUVECs embedded in fibrin gels. Unlike the others, this experimental system resulted in a perfusable endothelial network in vitro. We quantitatively observed the dynamics of endothelial cell protrusion and developed a mathematical model for one-dimensional dynamics. We then extended the one-dimensional model to two-dimensions. The model showed that random searching by endothelial cells was sufficient to generate the observed network structure in fibrin gels. PMID- 28648564 TI - Optimal management of nutrient reserves in microorganisms under time-varying environmental conditions. AB - Intracellular reserves are a conspicuous feature of many bacteria; such internal stores are often present in the form of inclusions in which polymeric storage compounds are accumulated. Such reserves tend to increase in times of plenty and be used up in times of scarcity. Mathematical models that describe the dynamical nature of reserve build-up and use are known as "cell quota," "dynamic energy/nutrient budget," or "variable-internal-stores" models. Here we present a stoichiometrically consistent macro-chemical model that accounts for variable stores as well as adaptive allocation of building blocks to various types of catalytic machinery. The model posits feedback loops linking expression of assimilatory machinery to reserve density. The precise form of the "regulatory law" at the heart of such a loop expresses how the cell manages internal stores. We demonstrate how this "regulatory law" can be recovered from experimental data using several empirical data sets. We find that stores should be expected to be negligibly small in stable growth-sustaining environments, but prominent in environments characterised by marked fluctuations on time scales commensurate with the inherent dynamic time scale of the organismal system. PMID- 28648565 TI - WITHDRAWN: Corrigendum to "Thiol-ene Michael-type formation of gelatin/poly(ethylene glycol) biomatrices for three-dimensional mesenchymal stromal/stem cell administration to cutaneous wounds" [Acta Biomater. 9(11) (2013) 8802-8814]. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.actbio.2017.06.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28648566 TI - Disrupted implicit motor sequence learning in schizophrenia and bipolar disorder revealed with ambidextrous Serial Reaction Time Task. AB - BACKGROUND: Impairment of implicit motor sequence learning was shown in schizophrenia (SZ) and, most recently, in bipolar disorder (BD), and was connected to cerebellar abnormalities. The goal of this study was to compare implicit motor sequence learning in BD and SZ. METHODS: We examined 33 patients with BD, 33 patients with SZ and 31 healthy controls with a use of ambidextrous Serial Reaction Time Task (SRTT), which allows exploring asymmetries in performance depending on the hand used. RESULTS: BD and SZ patients presented impaired implicit motor sequence learning, although the pattern of their impairments was different. While BD patients showed no signs of implicit motor sequence learning for both hands, the SZ group presented some features of motor learning when performing with the right, but not with the left hand. CONCLUSIONS: To our best knowledge this is the first study comparing implicit motor sequence learning in BD and SZ. We show that both diseases share impairments in this domain, however in the case of SZ this impairment differs dependently on the hand performing SRTT. We propose that implicit motor sequence learning impairments constitute an overlapping symptom in BD and SZ and suggest further neuroimaging studies to verify cerebellar underpinnings as its cause. PMID- 28648567 TI - Eicosapentaenoic and docosahexaenoic acids have different effects on peripheral phospholipase A2 gene expressions in acute depressed patients. AB - INTRODUCTION: Omega-3 polyunsaturated fatty acids (PUFAs) have been proven critical in the development and management of major depressive disorder (MDD) by a number of epidemiological, clinical and preclinical studies, but the molecular mechanisms underlying this therapeutic action are yet to be understood. Although eicosapentaenoic acid (EPA) seems to be the active component of omega-3 PUFAs' antidepressant effects, the biological research about the difference of specific genetic regulations between EPA and docosahexaenoic acid (DHA), the two main components of omega-3 PUFAs, is still lacking in human subjects. METHODS: We conducted a 12-week randomized-controlled trial comparing the effects of EPA and DHA on gene expressions of phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX2), serotonin transporter (5HTT), and Tryptophan hydroxylase 2 (TPH-2) in 27 MDD patients. In addition, the erythrocyte PUFA compositions and the candidate gene expressions were also compared between these 27 MDD patients and 22 healthy controls. RESULTS: EPA was associated with a significant decrease in HAM-D scores (CI: -13 to -21, p<0.001) and significant increases in erythrocyte levels of EPA (CI: +1.0% to +2.9%, p=0.001) and DHA (CI: +2.9% to +5.6%, p=0.007). DHA treatment was associated with a significant decrease in HAM-D scores (CI: -6 to 14, p<0.001) and a significant increase in DHA levels (CI: +0.2% to +2.3%, p=0.047), but not of EPA levels. The cPLA2 gene expression levels were significantly increased in patients received EPA (1.9 folds, p=0.038), but not DHA (1.08 folds, p=0.92). There was a tendency for both EPA and DHA groups to decrease COX-2 gene expressions. The gene expressions of COX-2, cPLA2, TPH-2 and 5-HTT did not differ between MDD cases and healthy controls. CONCLUSIONS: EPA differentiates from DHA in clinical antidepressant efficacy and in upregulating cPLA2 gene regulations, which supports the clinical observation showing the superiority of EPA's antidepressant effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02615405. PMID- 28648568 TI - Application of machine learning classification for structural brain MRI in mood disorders: Critical review from a clinical perspective. AB - Mood disorders are a highly prevalent group of mental disorders causing substantial socioeconomic burden. There are various methodological approaches for identifying the underlying mechanisms of the etiology, symptomatology, and therapeutics of mood disorders; however, neuroimaging studies have provided the most direct evidence for mood disorder neural substrates by visualizing the brains of living individuals. The prefrontal cortex, hippocampus, amygdala, thalamus, ventral striatum, and corpus callosum are associated with depression and bipolar disorder. Identifying the distinct and common contributions of these anatomical regions to depression and bipolar disorder have broadened and deepened our understanding of mood disorders. However, the extent to which neuroimaging research findings contribute to clinical practice in the real-world setting is unclear. As traditional or non-machine learning MRI studies have analyzed group level differences, it is not possible to directly translate findings from research to clinical practice; the knowledge gained pertains to the disorder, but not to individuals. On the other hand, a machine learning approach makes it possible to provide individual-level classifications. For the past two decades, many studies have reported on the classification accuracy of machine learning based neuroimaging studies from the perspective of diagnosis and treatment response. However, for the application of a machine learning-based brain MRI approach in real world clinical settings, several major issues should be considered. Secondary changes due to illness duration and medication, clinical subtypes and heterogeneity, comorbidities, and cost-effectiveness restrict the generalization of the current machine learning findings. Sophisticated classification of clinical and diagnostic subtypes is needed. Additionally, as the approach is inevitably limited by sample size, multi-site participation and data-sharing are needed in the future. PMID- 28648569 TI - Impaired processing of facial happiness, with or without awareness, in developmental prosopagnosia. AB - Developmental prosopagnosia (DP) is associated with severe, lifelong deficits in face recognition, with such cases often cited as support for a dissociation between the processing of facial identity and emotion. Here we examine the evidence against this dissociation and propose that the processing of facial happiness, either with or without awareness, is actually integrated within the same neural network involved in facial identity recognition. We also test this hypothesis on a group of DP cases and neurotypical controls (NT) by adapting them to expressionless neutral faces, intact happy faces and hybrid faces. Despite these hybrid faces being explicitly identified as expressionless due to their higher spatial frequencies taken from a neutral face, their low spatial frequencies convey happy facial expressions that participants are unaware of. After adaptation, participants were asked to judge the facial expressions of face stimuli that were morphed incrementally in varying degrees of sad through to happy. Both groups exhibited emotion adaptation aftereffects to the intact happy faces, although this effect was smaller in DP. Whereas NT produced emotion adaptation aftereffects without awareness of the happy emotion in the hybrid faces; as a group, those with DP did not. Furthermore, our DP cases also exhibited deficits in judging the emotion of the happiest morphed test faces. Our results indicate that the processing of happy facial expressions, with or without awareness, is likely integrated within the face recognition network. We hypothesise that the previously identified abnormalities in the fusiform gyrus in those with DP is the most likely structure responsible for these deficits. PMID- 28648571 TI - The neuro-cognitive representations of symbols: the case of concrete words. AB - We live our lives surrounded by symbols (e.g., road signs, logos, but especially words and numbers), and throughout our life we use them to evoke, communicate and reflect upon ideas and things that are not currently present to our senses. Symbols are represented in our brains at different levels of complexity: at the first and most simple level, as physical entities, in the corresponding primary and secondary sensory cortices. The crucial property of symbols, however, is that, despite the simplicity of their surface forms, they have the power of evoking higher order multifaceted representations that are implemented in distributed neural networks spanning a large portion of the cortex. The rich internal states that reflect our knowledge of the meaning of symbols are what we call semantic representations. In this review paper, we summarize our current knowledge of both the cognitive and neural substrates of semantic representations, focusing on concrete words (i.e., nouns or verbs referring to concrete objects and actions), which, together with numbers, are the most-studied and well defined classes of symbols. Following a systematic descriptive approach, we will organize this literature review around two key questions: what is the content of semantic representations? And, how are semantic representations implemented in the brain, in terms of localization and dynamics? While highlighting the main current opposing perspectives on these topics, we propose that a fruitful way to make substantial progress in this domain would be to adopt a geometrical view of semantic representations as points in high dimensional space, and to operationally partition the space of concrete word meaning into motor-perceptual and conceptual dimensions. By giving concrete examples of the kinds of research that can be done within this perspective, we illustrate how we believe this framework will foster theoretical speculations as well as empirical research. PMID- 28648570 TI - Brain-behavioral adaptability predicts response to cognitive behavioral therapy for emotional disorders: A person-centered event-related potential study. AB - Single-trial-level analyses afford the ability to link neural indices of elaborative attention (such as the late positive potential [LPP], an event related potential) with downstream markers of attentional processing (such as reaction time [RT]). This approach can provide useful information about individual differences in information processing, such as the ability to adapt behavior based on attentional demands ("brain-behavioral adaptability"). Anxiety and depression are associated with maladaptive information processing implicating aberrant cognition-emotion interactions, but whether brain-behavioral adaptability predicts response to psychotherapy is not known. We used a novel person-centered, trial-level analysis approach to link neural indices of stimulus processing to behavioral responses and to predict treatment outcome. Thirty-nine patients with anxiety and/or depression received 12 weeks of cognitive behavioral therapy (CBT). Prior to treatment, patients performed a speeded reaction-time task involving briefly-presented pairs of aversive and neutral pictures while electroencephalography was recorded. Multilevel modeling demonstrated that larger LPPs predicted slower responses on subsequent trials, suggesting that increased attention to the task-irrelevant nature of pictures interfered with reaction time on subsequent trials. Whereas using LPP and RT averages did not distinguish CBT responders from nonresponders, in trial-level analyses individuals who demonstrated greater ability to benefit behaviorally (i.e., faster RT) from smaller LPPs on the previous trial (greater brain-behavioral adaptability) were more likely to respond to treatment and showed greater improvements in depressive symptoms. These results highlight the utility of trial-level analyses to elucidate variability in within-subjects, brain-behavioral attentional coupling in the context of emotion processing, in predicting response to CBT for emotional disorders. PMID- 28648572 TI - Cortical excitability and neuropsychological functioning in healthy adults. AB - Evidence from clinical populations, such as epilepsy and attention deficit/hyperactivity disorder, suggests a relationship between hyperexcitability and cognitive impairment, but this relationship has not been demonstrated in healthy individuals. Here, we investigate the relationship between cortical excitability and cognitive functioning in healthy adults. Single- and paired pulse TMS was applied to 20 healthy adults to measure cortical excitability and long-interval intracortical inhibition (LICI). A neuropsychological battery was administered to assess aspects of attention, executive function, and mood. Participants with primarily excitatory responses to the LICI paradigm performed worse on a composite measure of attention and reported more negative mood states than participants with primarily inhibitory responses. Thus, differences in attention and mood among healthy adults are related to differences in cortical excitability as measured by LICI. This is consistent with a role for GABAB inhibitory circuits in regulating attention and mood, and suggests that individual variability in these domains may reflect variability in cortical excitability. This study demonstrates preliminary evidence that increased cortical excitability is associated with poorer cognition and mood in healthy adults. These findings provide new insight into the presence of cognitive dysfunction in several patient populations with hyperexcitability and support the development of neurostimulation interventions for clinical use. PMID- 28648573 TI - Personalized treatment with immunoadsorption and intravenous immunoglobulin in a case of severe Rh alloimmunization during pregnancy unresponsive to plasma - exchange. AB - INTRODUCTION: Despite prophylaxis, a small proportion of RhD-negative women may develop anti-D antibodies after a sensitizing event occurring during pregnancy or delivery of a D-positive baby. Intrauterine transfusion (IUT) is the treatment of choice in case of fetal anemia, but it cannot be performed early during pregnancy. Combined treatment with therapeutic plasma-exchange (TPE) and intravenous immunoglobulin (IVIG) can avoid or delay IUT. Immunoadsorption (IA) could represent a more effective treatment in selected cases. CASE REPORT: We report a D-negative female with a history of induced abortion and hydrops fetalis, referred at 8 weeks of gestation with a high anti-D titer. Despite implementing a TPE-IVIG protocol, the patient experienced a spontaneous abortion. At the beginning of her fourth pregnancy, only after a partially effective intensive TPE course, cycles of IA-IVIG were performed. Despite a suboptimal response on the anti-D titer, Doppler ultrasonographic measurements of the fetal middle cerebral artery peak systolic velocity first showed evidence of anemia at 30 weeks of gestation and a IUT was required. After the IUT, anemia persisted with a subsequent dramatic rise in titer, requiring an emergent cesarean section. The infant subsequently underwent successful treatment with IVIG, phototherapy and exchange transfusion and was discharged 7 weeks later without neurological deficits. DISCUSSION: The treatment of high titer anti-D antibodies during pregnancy may require a multidisciplinary approach with utilization of different apheresis strategies in order to have a successful pregnancy outcome. PMID- 28648574 TI - Asymptomatic human blood donors carriers of Leishmania infantum: Potential reservoirs for visceral leishmaniasis in northwestern Iran. AB - BACKGROUND: Little is known regarding transfusion-transmitted leishmaniasis (TTL) and the real global incidence of visceral leishmaniasis (VL) among blood donors as carriers of Leishmania spp. in endemic VL foci including Iran. Recent epidemiological evidences indicate that blood donor may be harbor of Leishmania infantum (L. infantum) infection in Iran. METHODS: The aim of the present study was to determine the prevalence of Leishmania infection among blood donors in a main endemic focus of VL in Iran using DAT and polymerase chain reaction (PCR) based methods Between July-September 2016, blood samples were collected from 600 apparently healthy blood donors from six blood donation centers and blood donation mobile unit in Ardabil Province, where VL cases had been recorded. Each of these samples was tested for anti-Leishmania antibodies, in direct agglutination test (DAT), and for L. infantum kDNA, the PCR-based assay. RESULTS: Of 600 blood donors, which were examined, 23 (3.8%) blood donors were seropositive by DAT and of 23 seropositive subjects, 82.6% (19/23) were positive by PCR. All the seropositive cases were males except one of them was female. CONCLUSIONS: Our findings showed that many asymptomatic human carriers of L. infantum live in the endemic regions of northwestern Iran and potentially act as reservoirs of infection; those must be considered carefully by arrangement VL control strategies in the country. PMID- 28648576 TI - Prior gastroscopy and mortality in patients with gastric cancer: a matched retrospective cohort study. AB - BACKGROUND AND AIMS: The role of prior gastroscopy on the outcome of patients with gastric cancer remains unknown. This study determines the association between intervals of prior gastroscopy and mortality in patients with gastric cancer. METHODS: We identified 20,066 newly diagnosed patients with gastric cancer in the National Health Insurance Database of Taiwan between 2002 and 2007. After we excluded patients who had gastroscopies performed <=6 months before the diagnosis of cancer, patients were matched into 3 cohorts according to the intervals of prior gastroscopy: 6 months to 2 years (<2 Y cohort), 2 to 5 years (2-5 Y cohort), and none within the previous 5 years (>5 Y cohort). The 3 cohorts were matched for age, curative treatment for gastric cancer, Helicobacter pylori therapy, and propensity scores comprised of sex, comorbidities, and concomitant medication usage. The primary outcome is the hazard ratio (HR) of all-cause mortality. RESULTS: After matching, we identified 1286, 1286, and 5144 patients for the <2 Y, 2 to 5 Y, and >5 Y cohorts. Compared with the >5 Y cohort, the HR of all-cause mortality for the <2 Y and 2 to 5 Y cohorts was 0.80 (95% confidence interval [CI], 0.72-0.89; P < .001) and 0.83 (95% CI, 0.76-0.91; P < .001), respectively. The HRs of gastric cancer-specific mortality were significantly lower in the <2 Y (0.80; 95% CI, 0.71-0.91; P < .001) and 2 to 5 Y cohorts (0.83; 95% CI, 0.75-0.93; P < .001). CONCLUSIONS: Patients with gastric cancer who had a gastroscopy performed within 5 years before the cancer diagnosis had significantly lower mortality. Our results may support the role of repeat endoscopic examination or surveillance endoscopy in selected patients. PMID- 28648575 TI - Inadequate Boston Bowel Preparation Scale scores predict the risk of missed neoplasia on the next colonoscopy. AB - BACKGROUND AND AIMS: The risks of missed findings after inadequate bowel preparation are not fully characterized in a diverse cohort. We aimed to evaluate the likelihood of missed polyps after an inadequate preparation as assessed by using the Boston Bowel Preparation Scale (BBPS). METHODS: In this observational study of prospectively collected data within a large, national, endoscopic consortium, we identified patients aged 50 to 75 years who underwent average-risk screening colonoscopy (C1) followed by a second colonoscopy for any indication within 3 years (C2). We determined the polyp detection rates (PDRs) and advanced PDRs during C2 stratified by C1 BBPS scores. RESULTS: Among segment pairs without polyps at C1 (N = 601), those with inadequate C1 BBPS segment scores had a higher PDR at C2 (10%) compared with those with adequate bowel preparation at C1 (5%; P = .04). Among segment pairs with polyps at C1 (N = 154), segments with inadequate bowel preparation scores at C1 had higher advanced PDRs at C2 (20%) compared with those with adequate bowel preparation scores at C1 (4%; P = .03). In multivariable analysis, the presence of advanced polyps at C1 (adjusted odds ratio [OR] 3.5; 95% confidence intervals [CIs], 1.1-10.8) but not inadequate BBPS scores at C1 (adjusted OR 1.8; 95% CI, 0.6-5.1) was associated with a significantly increased risk of advanced polyps at C2. CONCLUSIONS: Inadequate BBPS segment scores generally are associated with higher rates of polyps and advanced polyps at subsequent colonoscopy within a short timeframe. The presence of advanced polyps as well as inadequate BBPS segment scores can inform the risk of missed polyps and help triage which patients warrant a timely repeat colonoscopy. PMID- 28648578 TI - Application of aptamers in treatment and diagnosis of leukemia. AB - Leukemia is a cancer of blood cells and bone marrow, leading to death in many patients mainly in children. Over the last several years, aptamers generated by SELEX (Systematic evolution of ligands by exponential enrichment) method, have quickly become a new class of targeting ligands for drug delivery applications and recently have been widely exploited in different biomedical applications, due to several potent properties such as high binding affinity and selectivity, low or no immunogenicity and toxicity, low cost and thermal stability. In this review, we presented in details about aptamers involved in targeting, and treatment of leukemia. Moreover, some analytical approaches such as electrochemical and optical aptasensors were introduced for detection and diagnosis of leukemia. Finally, we discussed about the directions and challenges of aptamer application in this field. PMID- 28648577 TI - Impact of cap-assisted colonoscopy on the learning curve and quality in colonoscopy: a randomized controlled trial. AB - BACKGROUND AND AIMS: Colonoscopy competency assessment in trainees traditionally has been informal. Comprehensive metrics such as the Assessment of Competency in Endoscopy (ACE) tool suggest that competency thresholds are higher than assumed. Cap-assisted colonoscopy (CAC) may improve competency, but data regarding novice trainees are lacking. We compared CAC versus standard colonoscopy (SC) performed by novice trainees in a randomized controlled trial. METHODS: All colonoscopies performed by 3 gastroenterology fellows without prior experience were eligible for the study. Exclusion criteria included patient age <18 or >90 years, pregnancy, prior colon resection, diverticulitis, colon obstruction, severe hematochezia, referral for EMR, or a procedure done without patient sedation. Patients were randomized to either CAC or SC in a 1:1 fashion. The primary outcome was the independent cecal intubation rate (ICIR). Secondary outcomes were cecal intubation time, polyp detection rate, polyp miss rate, adenoma detection rate, ACE tool scores, and cumulative summation learning curves. RESULTS: A total of 203 colonoscopies were analyzed, 101 in CAC and 102 in SC. CAC resulted in a significantly higher cecal intubation rate, at 79.2% in CAC compared with 66.7% in SC (P = .04). Overall cecal intubation time was significantly shorter at 13.7 minutes for CAC versus 16.5 minutes for SC (P =.02). Cecal intubation time in the case of successful independent fellow intubation was not significantly different between CAC and SC (11.6 minutes vs 12.7 minutes; P = .29). Overall ACE tool motor and cognitive scores were higher with CAC. Learning curves for ICIR approached the competency threshold earlier with cap use but reached competency for only 1 fellow. The polyp detection rate, polyp miss rate, and adenoma detection rate were not significantly different between groups. CONCLUSIONS: CAC resulted in significant improvement in ICIR, overall ACE tool scores, and trend toward competency on learning curves when compared with SC in colonoscopy trainees without prior colonoscopy experience. (Clinical trial registration number: NCT02472730.). PMID- 28648579 TI - Release mechanism of doxazosin from carrageenan matrix tablets: Effect of ionic strength and addition of sodium dodecyl sulphate. AB - The polyelectrolyte matrix tablets loaded with an oppositely charged drug exhibit complex drug-release mechanisms. In this study, the release mechanism of a cationic drug doxazosin mesylate (DM) from matrix tablets based on an anionic polyelectrolyte lambda-carrageenan (lambda-CARR) is investigated. The drug release rates from lambda-CARR matrices are correlated with binding results based on potentiometric measurements using the DM ion-sensitive membrane electrode and with molecular characteristics of the DM-lambda-CARR-complex particles through hydrodynamic size measurements. Experiments are performed in solutions with different ionic strength and with the addition of an anionic surfactant sodium dodecyl sulphate (SDS). It is demonstrated that in addition to swelling and erosion of tablets, the release rates depend strongly on cooperative interactions between DM and lambda-CARR. Addition of SDS at concentrations below its critical micelle concentration (CMC) slows down the DM release through hydrophobic binding of SDS to the DM-lambda-CARR complex. On the contrary, at concentrations above the CMC SDS pulls DM from the complex by forming mixed micelles with it and thus accelerates the release. Results involving SDS show that the concentration of surfactants that are naturally present in gastrointestinal environment may have a great impact on the drug release process. PMID- 28648580 TI - Flowmetry evolution in microvascular surgery: A systematic review. AB - This review aims to provide a summary of the flowmeter devices used in microvascular surgery and assesses their contribution to improving the clinical outcomes of free tissue transfer. Flowmeters are widely accepted as the standard method of intraoperative assessment of the patency of coronary vascular anastomoses, providing thresholds that predict outcome. There is limited evidence regarding the use of flow measurements in plastic surgery microvascular anastomoses; however, flowmetry appears to have some role in postoperative free flap monitoring and prevention of complications. Surgeons rely on subjective clinical robust findings (patency test) as proof of immediate flow. The current literature lacks evidence regarding an objective predictor tool used to evaluate adequate flow changes before and after microvascular anastomosis. An electronic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement by using the MEDLINE, EMBASE, and Cochrane databases. A combination of algorithms including "flowmeter," "Doppler ultrasound," "transit volume flow," and "laser Doppler flowmeter" meshed with "microsurgery" was used to search for experimental and clinical studies that assess microvascular anastomoses by using a flowmeter device. A total of 718 peer reviewed publications and 14 full-text articles described the use of microvascular flowmeters to determine anastomotic patency or free flap viability. Flowmeters are currently used to provide the qualitative assessment of microvascular anastomoses. It seems reasonable to expect flowmetry to provide quantitative values that can be used intraoperatively to predict both outcomes and the necessity for an on-table anastomosis revision; this may allow surgeons to better understand the other factors that predict failure by exclusion. PMID- 28648581 TI - Is long-term post-operative monitoring of microsurgical flaps still necessary? AB - Autologous microsurgical flap reconstruction has become commonplace in most plastic surgery units, and the success rates of this procedure have markedly increased over recent years. However, the possibility of flap failure still needs to be considered. A review of the literature reveals that the critical period for flap-threatening complications is the first 24-48 post-operative hours; however, the window for the onset of these complications remains open for up to 7 days post-operatively. In this study, we focus on the timing of flap complications, aiming to elucidate the time period over which meticulous flap monitoring can positively contribute to flap salvage rates. The relevant literature on the study topic was collated and reviewed in conjunction with the senior author's case series, which consisted of a total of 335 free flaps used during a 2-year period for breast and head and neck reconstruction or limb trauma. Patients' series were then divided into groups according to the complications timing. The correlation between the timing of complications and the flap salvage rate was investigated among the groups. Overall analysis of both the literature and our own data on 335 free flaps showed a progressive reduction in flap salvage rate during post operative days; the correlations between the times of complication onset and the flap salvage rates in all groups were significant up to the third post-operative day. The correlations between salvage rates and later complications were not significant. Our results suggest that hourly flap monitoring should be compulsory during the first 48 post-operative hours, but clinical monitoring four times daily should be sufficient thereafter. PMID- 28648582 TI - Molecular mechanisms of phosphate transport and signaling in higher plants. AB - Phosphorus (P) is an essential macronutrient for plant growth and development. To adapt to low inorganic-phosphate (Pi) environments, plants have evolved complex mechanisms and pathways that regulate the acquisition and remobilization of Pi and maintain P homeostasis. These mechanisms are regulated by complex gene regulatory networks through the functions of Pi transporters (PTs) and Pi starvation-induced (PSI) genes. This review summarizes recent progress in determining the molecular regulatory mechanisms of phosphate transporters and the Pi signaling network in the dicot Arabidopsis (Arabidopsis thaliana) and the monocot rice (Oryza sativa L.). Recent advances in this field provide a reference for understanding plant Pi signaling and specific mechanisms that mediate plant adaptation to environments with limited Pi availability. We propose potential biotechnological applications of known genes to develop plant cultivars with improved Pi uptake and use efficiency. PMID- 28648583 TI - Resistance to breastfeeding: A Foucauldian analysis of breastfeeding support from health professionals. AB - BACKGROUND: Despite widespread consensus regarding the health benefits of breastfeeding, the prevalence of six months exclusive breastfeeding is very low in developed countries including New Zealand. AIM: This paper aims to evaluate the role that health professionals play in promoting exclusive breastfeeding in New Zealand. METHODS: Qualitative research involving face to face postpartum interviews conducted four to six weeks after the birth with 30 new mothers who lived in New Zealand and had identified in a short antenatal questionnaire that they intended to practice exclusive breastfeeding for six months. Themes related to exclusive breastfeeding support from health professionals were extracted from the interview transcripts and interpreted using Foucault's ideas about governmentality and bio-power. RESULTS: Four themes related to the quality of health care support were identified in the interview transcripts. 'Breastfeeding self-efficacy support from the community midwives', 'mothers need to know more about breastfeeding during pregnancy', 'experiencing difficulties breastfeeding' as well as 'pressure and resistance to breastfeeding'. DISCUSSION: Most mothers in this research spoke about feeling pressured to breastfeed within the New Zealand health system. However, the participating mothers acknowledged the effective support that they had received from community midwives who respected their autonomy, strengthened their self-esteem and encouraged them to breastfeed. CONCLUSION: Negative historical experiences related to the medicalization of infant feeding in Western countries suggests that health professionals need to provide effective skill support for breastfeeding mothers so that mothers do not consider it a form of "quiet coercion" or as an exercise of "power". PMID- 28648584 TI - Control of lipid droplet fusion and growth by CIDE family proteins. AB - Cell death-inducing DFF45-like effector (CIDE) family proteins including Cidea, Cideb and Cidec/Fsp27 are expressed in many different tissues and are known as lipid droplet (LD)-and ER-associated proteins. Systematic analyses using genetically modified animal models have demonstrated that CIDE proteins play important roles in regulating various aspects of lipid homeostasis, including lipid storage, lipolysis and lipid secretion. Recent research in ours and other laboratories has revealed that CIDE proteins are crucial regulators of LD fusion and growth in the adipose tissue, liver, skin and mammary glands. CIDE-mediated LD fusion and growth is different from other membrane fusions in that it requires CIDE proteins to be enriched and clustered at the LD-LD contact sites (LDCS). The enriched CIDE proteins then allow the recruitment of other proteins to the LDCS and the formation of potential fusion pores. Neutral lipids in the smaller LDs of the contacted pair are transferred to the larger LDs, owing to the internal pressure difference, thus resulting in the fusion and growth of the LDs. This review summarizes the physiological roles of CIDE proteins in controlling lipid homeostasis, insulin sensitivity and the development of metabolic diseases including obesity, diabetes and fatty liver, with a particular focus on the role of CIDE proteins in controlling LD fusion and growth. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28648585 TI - The synthesis and antitumor activity of lithocholic acid and its derivatives. AB - In this paper, a new and concise synthetic route of lithocholic acid (LCA) using commercially available steroid source deoxycholic acid is reported. A series of amide derivatives of LCA were also synthesized and investigated for their activity against the growth of MCF-7 and MCF-7/ADR cells using the sulforhodamine B assay. For MCF-7, the most potent compound 20 showed a 20-fold higher antitumor activity than LCA. For MCF-7/ADR, the most potent compound 24 showed a 22-fold higher antitumor activity than LCA. The transwell migration assay of 20 was evaluated on MDA-MB-231 cells. The colony formation and apoptosis assays of 20 were performed on MCF-7 and MCF-7/ADR cell lines. PMID- 28648586 TI - Synthesis and anticancer activity of bile acid dendrimers with triazole as bridging unit through click chemistry. AB - Triazole-based novel dendrimers with bile acid surface groups have been synthesized through click chemistry by divergent approach and characterized by spectral data. All the dendrimers exhibit excellent anticancer activity. Higher generation dendrimers exhibit better anticancer activity than the lower generation dendrimers. PMID- 28648587 TI - Cyclized 9,11-secosterol enol-ethers from the gorgonian Pseudopterogorgia americana. AB - Chemical investigation of the MeOH extract from the gorgonian Pseudopterogorgia americana afforded two rare sterols, ameristerenol A (1) and B (2), both 9,11 secosterols possesses a seven-membered cyclic enol-ether in ring C, and ameristerol A (3) is the first example of a naturally occurring 9,11-secosterol containing a gorgosterol side chain with a C-24(28) double bond. Ameristerenol A (1) was converted to the sterol derivatives 4-6 to provide additional chemical diversity and comparison for biological screening. The structures of compounds 1 6, along with three related known analogues 7-9, were determined on the basis of extensive spectroscopic analysis and by comparison with literature data. Compound 6 exhibited slight cytotoxicity activity against human breast cancer cell line MDA-MB-231. PMID- 28648588 TI - Right-sided infective endocarditis in cardiac device carriers: Clinical profile and prognosis. AB - BACKGROUND AND OBJECTIVES: Due to the widespread indications for device implants and the population aging, right-sided infective endocarditis (RSIE) epidemiology has dramatically changed, being nowadays, cardiac device carriers the main affected group. The aim of this work is to describe the epidemiology, clinical profile and outcomes of RSIE in cardiac device carriers. PATIENTS AND METHODS: We included definitive infective endocarditis episodes consecutively diagnosed in 3 tertiary centers from March 1995 to September 2014. A retrospective analysis of 85 variables, one-year follow up and univariate analysis of in-hospital mortality was conducted. RESULTS: Among 1,182 episodes, 100 cardiac device carriers presented with RSIE (8.5%). Mean age+/-SD was 67+/-14 years. Staphylococcus spp. were the main causative microorganisms (coagulase-negative 44%, aureus 31%) and 37% were methicillin-resistant. Cardiac devices were removed in 95% of patients. In-hospital mortality was 8% and one-year mortality was 4%. Univariate analysis demonstrated that renal failure at admission (OR 6.2; 95% CI 1.3-30.3), septic shock (OR 8.9; 95% CI 1.7-47.9) and persistent infection during clinical course (OR 19.4; 95% CI 3-125.7) increase in-hospital mortality while device removal is a protective factor (OR 0.08; 95% CI 0.02-0.39). CONCLUSIONS: RSIE have low in hospital and one-year mortality. Coagulase-negative Staphylococci is responsible of almost half of the episodes and methicillin-resistant incidence is high. Device removal is mandatory since it decreases in-hospital mortality. PMID- 28648589 TI - Strongyloides, a dangerous unknown. PMID- 28648590 TI - Venooclussive disease and systemic sclerosis. PMID- 28648591 TI - Alagille syndrome with atypical phenotype diagnosed by molecular tests: unreported JAG1 mutation. PMID- 28648592 TI - PET/CT for evaluation of the response to therapy and follow-up of patients with tuberculosis. PMID- 28648594 TI - Alpha-1 antitrypsin deficiency associated to the variant PI*Mpalermo: Analysis of 8 cases. PMID- 28648593 TI - MYC-rearranged lymphomas other than Burkitt: Comparison between R-CHOP and Burkitt-type immunochemotherapy. AB - BACKGROUND AND OBJECTIVE: MYC-rearranged (MYC-R) lymphomas other than Burkitt lymphoma (BL) are very aggressive, with poor prognosis when treated with standard regimens. We aimed to study the characteristics and outcome of a series of MYC-R lymphomas comparing the treatment results between R-CHOP based and a specific intensive regimen for BL (BURKIMAB). PATIENTS AND METHODS: Retrospective study of patients diagnosed with MYC-R. Translocations of MYC, BCL2 and BCL6 were evaluated by fluorescent in situ hybridization. Patients were treated with either, R-CHOP based immunochemotherapy or the Burkitt type regimen, BURKIMAB. RESULTS: Thirty-four MYC-R lymphoma cases were studied: 21 treated with R-CHOP and 13 treated with BURKIMAB. There were no differences in CR rate; 45% (9/20) for R-CHOP and 42% (5/12) for BURKIMAB (P=.99). Although overall survival (OS) and progression free survival (PFS) of BURKIMAB-treated patients were better than those of R-CHOP-treated (3y-OS: 46 vs. 24%; 3y-PFS: 46 vs. 10%), the differences were not statistically significant. CONCLUSION: MYC-R lymphomas show poor outcomes even when treated with intensive immunochemotherapy for BL. PMID- 28648595 TI - Molecular evidence of offspring liver dysfunction after maternal exposure to zinc oxide nanoparticles. AB - Recently, reproductive, embryonic and developmental toxicity have been considered as one important sector of nanoparticle (NP) toxicology, with some studies already suggesting varying levels of toxicity and possible transgenerational toxic effects. Even though many studies have investigated the toxic effects of zinc oxide nanoparticles (ZnO NPs), little is known of their impact on overall reproductive outcome and transgenerational effects. Previously we found ZnO NPs caused liver dysfunction in lipid synthesis. This investigation, for the first time, explored the liver dysfunction at the molecular level of gene and protein expression in offspring after maternal exposure to ZnO NPs. Three pathways were investigated: lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis at 5 different time points from embryonic day-18 to postnatal day-20. It was found that the expression of 15, 16, and 16 genes in lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis signalling pathway respectively in F1 animal liver were altered by ZnO NPs compared to ZnSO4. The proteins in these signalling pathways (five in each pathways analyzed) in F1 animal liver were also changed by ZnO NPs compared to ZnSO4. The results suggest that ZnO NPs caused maternal liver defects can also be detected in offspring that might result in problems on offspring liver development, mainly on lipid synthesis, growth, and lesions or apoptosis. Along with others, this study suggests that ZnO NPs may pose reproductive, embryonic and developmental toxicity; therefore, precautions should be taken with regard to human exposure during daily life. PMID- 28648596 TI - Erratum. PMID- 28648597 TI - Genotype-phenotype correlation for congenital heart disease in Down syndrome through analysis of partial trisomy 21 cases. AB - Among Down syndrome (DS) children, 40-50% have congenital heart disease (CHD). Although trisomy 21 is not sufficient to cause CHD, three copies of at least part of chromosome 21 (Hsa21) increases the risk for CHD. In order to establish a genotype-phenotype correlation for CHD in DS, we built an integrated Hsa21 map of all described partial trisomy 21 (PT21) cases with sufficient indications regarding presence or absence of CHD (n=107), focusing on DS PT21 cases. We suggest a DS CHD candidate region on 21q22.2 (0.96Mb), being shared by most PT21 cases with CHD and containing three known protein-coding genes (DSCAM, BACE2, PLAC4) and four known non-coding RNAs (DSCAM-AS1, DSCAM-IT1, LINC00323, MIR3197). The characterization of a DS CHD candidate region provides a useful approach to identify specific genes contributing to the pathology and to orient further investigations and possibly more effective therapy in relation to the multifactorial pathogenesis of CHD. PMID- 28648598 TI - Myelin basic protein stimulates plasminogen activation via tissue plasminogen activator following binding to independent l-lysine-containing domains. AB - Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that encases the axons of all neurons. Both plasminogen (Pg) and tissue type plasminogen activator (t-PA) bind to MBP with high affinity. We investigated the kinetics and mechanisms involved in this process using immobilized MBP and found that Pg activation by t-PA is significantly stimulated by MBP. This mechanism involves the binding of t-PA via a lysine-dependent mechanism to the Lys91 residue of the MBP NH2-terminal region Asp82 -Pro99, and the binding of Pg via a lysine-dependent mechanism to the Lys122 residue of the MBP COOH-terminal region Leu109-Gly126. In this context, MBP mimics fibrin and because MBP is a plasmin substrate, our results suggest direct participation of the Pg activation system on MBP physiology. PMID- 28648599 TI - 2,3-Butandione 2-monoxime inhibits skeletal myosin II by accelerating ATP cleavage. AB - 2,3-Butandione 2-monoxime (BDM) is a widely used myosin inhibitor with an unclear mode of action. In this report, we investigated the mechanism of BDM oxime group nucleophilic reactivity on the phosphoester bond of ATP. BDM increased the ATPase activity of skeletal myosin subfragment 1 (S1) under conditions in which ATP cleavage is the rate-limiting step (K+, EDTA-ATPase activity of native S1 and Mg2+-ATPase activity of trinitrophenylated S1 and partially unfolded S1). Furthermore, the effect of BDM on the S1-bound adenosine 5'-(beta,gamma-imido) triphosphate (AMPPNP) 31P NMR spectrum suggests that BDM changes the microenvironment around the phosphorus atoms of myosin-bound nucleotide. A computational search for the BDM-binding site in the adenosine 5'-[gamma-thio] triphosphate (myosin-ATPgammaS) complex predicted that BDM is located adjacent to the nucleotide on myosin. Therefore, we propose that the BDM oxime group catalytically assists in ATP cleavage, thereby enhancing the ATPase activity of myosin in a manner analogous to pralidoxime-mediated reactivation of organophosphate-inactivated acetylcholinesterase. This is the first study suggesting that oxime provides catalytic assistance for ATP cleavage by an ATP hydrolyzing enzyme. PMID- 28648600 TI - Anticancer, antibacterial and pollutant degradation potential of silver nanoparticles from Hyphaene thebaica. AB - We present here the biosynthesis of AgNps from the aqueous extract of H. thebaica fruit, and monitored through UV-Vis spectrophotometer. The functional group were characterized through ATR-FTIR spectroscopy, the particle size, morphologies and elemental composition of the nanoparticles were investigated by using TEM, FESEM and EDS respectively. The anti-proliferation activity of the synthesized AgNps was carried out using MTT assay on human prostate (PC3), breast (MCF7) and liver (HepG2) cancer cell lines. The anti-proliferation assay showed that the AgNps were able to inhibit the proliferation of the cancer cell lines in a dose depending manner. The effect was found more pronounced on prostate (IC50 2.6 mg/mL) followed by breast (IC50 4.8 mg/mL) and then liver cancer cell lines (IC50 6.8 mg/mL). The prepared AgNps were found to inhibit 99% growth of both E. coli and S. aureus after 24 h of incubation. The nanoparticles were used for the degradation of 4-nitrophenol (4-NP) and Congo red dyes (CR), which efficiently degrade CR, but make complex formation with 4-NP. Therefore, the AgNps synthesized from the aqueous fruit extract of H. thebaica have potential application in pharmacology and waste water treatment. PMID- 28648601 TI - Inhibition of PLD1 activity causes ER stress via regulation of COPII vesicle formation. AB - Phospholipase D (PLD) plays a crucial role in the regulation of some cellular processes, including autophagy and apoptosis. Accumulation of protein in the endoplasmic reticulum (ER) lumen causes ER stress. Although ER stress is a principal cause of apoptosis and autophagy, the relationship between PLD activity and ER stress remains unclear. Protein transport from the ER to the Golgi apparatus is conducted by coat complex II (COPII) transport vesicles. Here, we demonstrated that inhibition of PLD1 activity or PLD1 knockdown suppressed COPII vesicle transport in normal rat kidney (NRK) cells. COPII vesicle coat proteins are composed of Sar1 as well as Sec23/24 and Sec13/31 complexes. For COPII vesicle formation on the ER membrane, Sar1, Sec23/24, and Sec13/31 are sequentially recruited from the cytosol to the ER membrane. Using a cell-free COPII coat protein recruitment assay, we demonstrated that inhibition of PLD1 activity suppressed Sec13/31 recruitment from the cytosol to the ER membrane in COPII vesicle formation. PLD1 knockdown in NRK cells was associated with increased expression of the ER stress marker GRP78 and apoptosis. Taken together, these results suggest that PLD1 activity regulates COPII vesicle transport from the ER to the Golgi apparatus by regulating Sec13/31 recruitment from the cytosol to the ER membrane during COPII vesicle formation. PMID- 28648602 TI - Helicobacter pylori does not use spermidine synthase to produce spermidine. AB - Helicobacter pylori is the primary pathogen associated to gastritis and gastric cancer. Growth of H. pylori depends on the availability of spermidine in vivo. Interestingly, the genome of H. pylori contains an incomplete set of genes for the classical pathway of spermidine biosynthesis. It is thus not clear whether some other genes remained in the pathway would have any functions in spermidine biosynthesis. Here, we study spermidine synthase, which is responsible for the final catalytic process in the classical route. Protein sequence alignment reveals that H. pylori SpeE (HpSpeE) lacks key residues for substrate binding. By using isothermal titration calorimetry, we show that purified recombinant HpSpeE does not interact with the putative substrates putrescine and decarboxylated S adenosylmethionine, and the product spermidine. High performance liquid chromatography analysis further demonstrates that HpSpeE has no detectable in vitro enzymatic activity. Additionally, intracellular spermidine level in speE null mutant strain is comparable to that in the wild type strain. Collectively, our results suggest that HpSpeE is functionally distinct from spermidine production. H. pylori may instead employ the alternative pathway for spermidine synthesis which is dominantly exploited by other human gut microbes. PMID- 28648603 TI - Effects of Brn2 overexpression on eccrine sweat gland development in the mouse paw. AB - Eccrine sweat glands regulate body temperature by secreting water and electrolytes. In humans, eccrine sweat glands are ubiquitous in the skin, except in the lips and external genitalia. In mice, eccrine sweat glands are present only in the paw pad. Brn2 is a protein belonging to a large family of transcription factors. A few studies have examined Brn2 in melanoma cells and epidermal keratinocytes. This study investigated changes in the skin in the K5 Brn2 transgenic mouse, which overexpresses Brn2 and contains the keratin 5 promotor. Interestingly, the volume of eccrine sweat glands was reduced markedly in the K5-Brn2 transgenic mouse compared with the wild-type, while the expression of aquaporin 5, important molecule in sweat secretion, was increased in each sweat gland cell, probably to compensate for the reduction in gland development. However, sweating response to a pilocarpine injection in the hind paw was significantly decreased in the K5-Brn2 transgenic mouse compared with the wild type. The paw epidermis was thicker in the K5-Brn2 transgenic mouse compared with the wild-type. Taken together, eccrine sweat gland development and sweat secretion were suppressed markedly in the K5-Brn2 transgenic mouse. These results may be associated with dominant development of the epidermis by Brn2 overexpression in the paw skin. PMID- 28648604 TI - Technological demands of meat processing-An Asian perspective. AB - A rapid increase in the economy, population, industrialization, and urbanization of Asian countries has driven the fast development of their meat industries over recent decades. This consistent increase in meat production and consumption in Asia has been the major cause for the development of the global meat industry. Meat production methods and consumption are very diverse across different regions and countries in Asia, and thus, it is impossible to cover the technological demands of all Asian countries in this review. Here, we have mainly highlighted the differences in meat production methods and consumption in Asia during recent decades and the meat technology demands of three east Asian countries, namely China, Korea, and Japan, and one south Asian country, India. A brief introduction of the meat industry, in particular the production and consumption trend in these countries, is provided in this article. The technology demands for fresh and processed meat products are then reviewed. PMID- 28648605 TI - A semi-supervised approach using label propagation to support citation screening. AB - Citation screening, an integral process within systematic reviews that identifies citations relevant to the underlying research question, is a time-consuming and resource-intensive task. During the screening task, analysts manually assign a label to each citation, to designate whether a citation is eligible for inclusion in the review. Recently, several studies have explored the use of active learning in text classification to reduce the human workload involved in the screening task. However, existing approaches require a significant amount of manually labelled citations for the text classification to achieve a robust performance. In this paper, we propose a semi-supervised method that identifies relevant citations as early as possible in the screening process by exploiting the pairwise similarities between labelled and unlabelled citations to improve the classification performance without additional manual labelling effort. Our approach is based on the hypothesis that similar citations share the same label (e.g., if one citation should be included, then other similar citations should be included also). To calculate the similarity between labelled and unlabelled citations we investigate two different feature spaces, namely a bag-of-words and a spectral embedding based on the bag-of-words. The semi-supervised method propagates the classification codes of manually labelled citations to neighbouring unlabelled citations in the feature space. The automatically labelled citations are combined with the manually labelled citations to form an augmented training set. For evaluation purposes, we apply our method to reviews from clinical and public health. The results show that our semi-supervised method with label propagation achieves statistically significant improvements over two state-of-the-art active learning approaches across both clinical and public health reviews. PMID- 28648606 TI - The Structure of the R2TP Complex Defines a Platform for Recruiting Diverse Client Proteins to the HSP90 Molecular Chaperone System. AB - The R2TP complex, comprising the Rvb1p-Rvb2p AAA-ATPases, Tah1p, and Pih1p in yeast, is a specialized Hsp90 co-chaperone required for the assembly and maturation of multi-subunit complexes. These include the small nucleolar ribonucleoproteins, RNA polymerase II, and complexes containing phosphatidylinositol-3-kinase-like kinases. The structure and stoichiometry of yeast R2TP and how it couples to Hsp90 are currently unknown. Here, we determine the 3D organization of yeast R2TP using sedimentation velocity analysis and cryo electron microscopy. The 359-kDa complex comprises one Rvb1p/Rvb2p hetero-hexamer with domains II (DIIs) forming an open basket that accommodates a single copy of Tah1p-Pih1p. Tah1p-Pih1p binding to multiple DII domains regulates Rvb1p/Rvb2p ATPase activity. Using domain dissection and cross-linking mass spectrometry, we identified a unique region of Pih1p that is essential for interaction with Rvb1p/Rvb2p. These data provide a structural basis for understanding how R2TP couples an Hsp90 dimer to a diverse set of client proteins and complexes. PMID- 28648607 TI - Crystal Structure of Chicken gammaS-Crystallin Reveals Lattice Contacts with Implications for Function in the Lens and the Evolution of the betagamma Crystallins. AB - Previous attempts to crystallize mammalian gammaS-crystallin were unsuccessful. Native L16 chicken gammaS crystallized avidly while the Q16 mutant did not. The X ray structure for chicken gammaS at 2.3 A resolution shows the canonical structure of the superfamily plus a well-ordered N arm aligned with a beta sheet of a neighboring N domain. L16 is also in a lattice contact, partially shielded from solvent. Unexpectedly, the major lattice contact matches a conserved interface (QR) in the multimeric beta-crystallins. QR shows little conservation of residue contacts, except for one between symmetry-related tyrosines, but molecular dipoles for the proteins with QR show striking similarities while other gamma-crystallins differ. In gammaS, QR has few hydrophobic contacts and features a thin layer of tightly bound water. The free energy of QR is slightly repulsive and analytical ultracentrifugation confirms no dimerization in solution. The lattice contacts suggest how gamma-crystallins allow close packing without aggregation in the crowded environment of the lens. PMID- 28648608 TI - Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly. AB - PGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for structural plasticity, dimerization of the catalytic domain, and the assembly into an enzymatically active dodecameric form. Oligomeric states observed in structures were supported by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation experiments in solution. We report that the catalytically important N-terminal WDPNWD motif acts as a structural integrator assembling PGAM5 into a dodecamer, allosterically activating the phosphatase by promoting an ordering of the catalytic loop. Additionally the observed active site plasticity enabled visualization of essential conformational rearrangements of catalytic elements. The comprehensive biophysical characterization offers detailed structural models of this key mitochondrial phosphatase that has been associated with the development of diverse diseases. PMID- 28648609 TI - Critical Role of Water Molecules in Proton Translocation by the Membrane-Bound Transhydrogenase. AB - The nicotinamide nucleotide transhydrogenase (TH) is an integral membrane enzyme that uses the proton-motive force to drive hydride transfer from NADH to NADP+ in bacteria and eukaryotes. Here we solved a 2.2-A crystal structure of the TH transmembrane domain (Thermus thermophilus) at pH 6.5. This structure exhibits conformational changes of helix positions from a previous structure solved at pH 8.5, and reveals internal water molecules interacting with residues implicated in proton translocation. Together with molecular dynamics simulations, we show that transient water flows across a narrow pore and a hydrophobic "dry" region in the middle of the membrane channel, with key residues His42alpha2 (chain A) being protonated and Thr214beta (chain B) displaying a conformational change, respectively, to gate the channel access to both cytoplasmic and periplasmic chambers. Mutation of Thr214beta to Ala deactivated the enzyme. These data provide new insights into the gating mechanism of proton translocation in TH. PMID- 28648611 TI - Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor. AB - Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous "trigger switch" and "transmission switch" amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator. The proposed "trigger switch" for the mGlu2 involves the side chains of F6433.36a.40c, N7355.47a.47c, and W7736.48a.50c, whereas the "transmission switch" involves the Y6473.40a.44c, L7385.50a.50c, and T7696.44a.46c amino acids. The work has wide impact on understanding mGlu GPCR function and for future allosteric modulator drugs. PMID- 28648612 TI - A Spring-Loaded Mechanism Governs the Clamp-like Dynamics of the Skp Chaperone. AB - The trimeric periplasmic holdase chaperone Skp binds and stabilizes unfolded outer membrane proteins (OMPs) as part of bacterial OMP biogenesis. Skp binds client proteins in its central cavity, thereby reducing its backbone dynamics, but the molecular mechanisms that govern Skp dynamics and adaptation to differently sized clients remains unknown. Here, we employ a combination of microsecond timescale molecular dynamics simulation, small-angle X-ray scattering, and nuclear magnetic resonance spectroscopy to reveal that Skp is remarkably flexible, and features a molecular spring-loaded mechanism in its "tentacle" arms that enables switching between two distinct conformations on sub millisecond timescales. The conformational switch is executed around a conserved pivot element within the coiled-coil structures of the tentacles, allowing expansion of the cavity and thus accommodation of differently sized clients. The spring-loaded mechanism shows how a chaperone can efficiently modulate its structure and function in an ATP-independent manner. PMID- 28648610 TI - Glycan Activation of a Sheddase: Electrostatic Recognition between Heparin and proMMP-7. AB - Heparan sulfate proteoglycans activate the matrix metalloproteinase-7 zymogen (proMMP-7) and recruit it in order to shed proteins from cell surfaces. This occurs in uterine and mammary epithelia, bacterial killing, lung healing, and tumor cell signaling. Basic tracks on proMMP-7 recognize polyanionic heparin, according to nuclear magnetic resonance and mutations disruptive of maturation. Contacts and proximity measurements guided docking of a heparin octasaccharide to proMMP-7. The reducing end fits into a basic pocket in the pro-domain while the chain continues toward the catalytic domain. Another oligosaccharide traverses a basic swath remote on the catalytic domain and inserts its reducing end into a slot formed with the basic C terminus. This latter association appears to support allosteric acceleration of proteolysis. The modes of binding account for extended, heterogeneous assemblies of proMMP-7 with heparinoids during maturation and for bridging to pro-alpha-defensins and proteoglycans. These associations support proteolytic release of activities at epithelial cell surfaces. PMID- 28648613 TI - Multiple mechanisms of resistance to pyrethroids in Anopheles gambiae s.l populations in Niger. AB - INTRODUCTION: We performed a transversal study to map resistance of malaria vectors (Anopheles mosquitoes) to insecticides in Niger within the frame of the National Malaria Control Program funded by the World Health Organization (WHO). METHOD: Larvae of Anopheles gambiae s.l were collected from November to December 2013 in seven locations selected on the basis of different patterns of use of insecticides and environment. WHO susceptibility test tubes were used on females Anopheles to detect resistance to insecticides. Eight insecticides were tested. Percentages of knockdown during exposure time to pyrethroids and DDT and mortality after 24hours of observation for all tested insecticides were calculated. PCR and biochemical tests were carried out to identify the species and mechanisms of resistance (Kdr allele frequencies and activity of detoxification enzymes). RESULTS: In all sites, Anopheles gambiae s.l was susceptible to bendiocarb and malathion but resistant to the five pyrethroids and DDT (24-hour mortality rate was <90%). The Kdr mutation was present in the molecular form M of Anopheles gambiae with an average frequency of 58%. Biochemical tests showed the activity of various enzyme families (esterase, oxidase, and glutathione s-transferase). CONCLUSION: This study showed multiple resistance of Anopheles mosquitoes to insecticides in Niger. A rigorous management of this resistance is imperative to preserve the efficacy of pyrethroids as it is the only class of insecticides used for insecticide-treated nets. PMID- 28648614 TI - The effects of retinoic acid on mmp-2 production, proliferation and ultrastructural morphology in rat uterus. AB - AIMS: Retinoic acid (RA) has a vital importance in order to ensure continuity and morphology in many tissues. Matrix metalloproteinases (MMPs) have significant roles in proliferation, the formation of cancers, and metastasis. In this study the effects of RA on MMP-2 production in cells of rat uterus were investigated. METHODS: Twenty-four adult Spraque Dawley rats were divided into two groups, the experimental group was treated with 40mg/kg/day 13-cis RA for 5days by gavage. Uterine tissue sections were treated with BrdU and MMP-2 antibodies, evaluated using light microscopy. Tissues were fixed with 2.5% glutaraldehyde and evaluated using transmission electron miroscopy. RESULTS: MMP-2 immunoreactivity decreased in the stromal cells compared with the control group and no staining of MMP-2 was observed in glandular epithelium in the experimental group. BrDU labeling of cells showed significant decrease in RA-treated group versus control group cells. Based on the electron microscopy evaluation, the surface epithelial cells of the experimental group showed vacuolization, and an accumulation of lipofuscin bodies was also observed in the gland epithelium. Cells involving autophagic vacuoles contained excess lipid granules in the entire uterus layers especially localized at the border of the endometrium and myometrium. CONCLUSION: RA had negative effects on cell proliferation and cell morphology and inhibited MMP-2 expression. PMID- 28648615 TI - Structural Biology and the Design of New Therapeutics: From HIV and Cancer to Mycobacterial Infections: A Paper Dedicated to John Kendrew. AB - Interest in applications of protein crystallography to medicine was evident, as the first high-resolution structures emerged in the 50s and 60s. In Cambridge, Max Perutz and John Kendrew sought to understand mutations in sickle cell and other genetic diseases related to hemoglobin, while in Oxford, the group of Dorothy Hodgkin became interested in long-lasting zinc-insulin crystals for treatment of diabetes and later considered insulin redesign, as synthetic insulins became possible. The use of protein crystallography in structure-guided drug discovery emerged as enzyme structures allowed the identification of potential inhibitor-binding sites and optimization of interactions of hits using the structure of the target protein. Early examples of this approach were the use of the structure of renin to design antihypertensives and the structure of HIV protease in design of AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design and has been used to progress three oncology drugs through clinical trials to FDA approval. We exemplify current developments in structure-guided target identification and fragment-based lead discovery with efforts to develop new antimicrobials for mycobacterial infections. PMID- 28648616 TI - Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling. AB - How structural dynamics affects cytokine signaling is under debate. Here, we investigated the dynamics of the type I interferon (IFN) receptor, IFNAR1, and its effect on signaling upon binding IFN and IFNAR2 using a combination of structure-based mechanistic studies, in situ binding, and gene induction assays. Our study reveals that IFNAR1 flexibility modulates ligand-binding affinity, which, in turn, regulates biological signaling. We identified the hinge sites and key interactions implicated in IFNAR1 inter-subdomain (SD1-SD4) movements. We showed that the predicted cooperative movements are essential to accommodate intermolecular interactions. Engineered disulfide bridges, computationally predicted to interfere with IFNAR1 dynamics, were experimentally confirmed. Notably, introducing disulfide bonds between subdomains SD2 and SD3 modulated IFN binding and activity in accordance with the relative attenuation of cooperative movements with varying distance from the hinge center, whereas locking the SD3 SD4 interface flexibility in favor of an extended conformer increased activity. PMID- 28648618 TI - Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study. AB - : HannaH (NCT00950300) and PrefHer (NCT01401166) studies validated the subcutaneous (H-s.c.) formulation of trastuzumab as effective and safe as intravenous (H-i.v.) and highly preferred by patients in early breast cancer. The present randomised MetaspHer trial (NCT01810393) is the first study assessing patient's preference in metastatic setting. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long-term response lasting more than 3 years were randomised to receive 3 cycles of 600-mg fixed-dose adjuvant H-s.c., followed by 3 cycles of standard H-i.v., or the reverse sequence. Primary end-point was overall preference for H-s.c. or H-i.v. at cycle six, assessed by Patient Preference Questionnaire (PPQ). Secondary end-points included healthcare professional (HCP) satisfaction; safety and tolerability; quality of life. RESULTS: Hundred and thirteen patients were randomised and treated. H-s.c. was preferred by 79/92 evaluable intent-to-treat patients (85.9%, 95% confidence interval [CI; 78.8 93.0]; p < 0.001), 13/92 preferred H-i.v. (14.1%, 95% CI [7.0-21.3]). HCPs were most satisfied with H-s.c. (56/88 available data, 63.6%, [53.6-73.7]). On the safety population, adverse events occurred in 73 (67.6%) and 49 (44.1%) patients during the H-s.c. and H-i.v. periods, respectively; 7 (6.5%) and 4 (3.6%) were grade >= III, 3 (2.8%) and 2 (1.8%) were serious. CONCLUSION: The safety was consistent with the known H-i.v. and H-s.c. profiles without safety concern raised. Definitively, patients preferred H-s.c. as reported in early stage by PrefHer study. PMID- 28648619 TI - Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation. AB - The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal (30LKKVMRR36) in the human enzyme. Substituting the residues KK31,32 and RR35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell. PMID- 28648617 TI - A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus. AB - Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin (HA) glycoprotein, which is the major antigen on the surface of the virus. The HA is composed of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor binding site and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines and novel therapeutics. PMID- 28648620 TI - Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms. AB - INTRODUCTION: Iron overload leads to multiple organ damage including endocrine organ dysfunctions. Hypogonadism is the most common non-diabetic endocrinopathy in primary and secondary iron overload syndromes. AIM: To explore the molecular determinants of iron overload-induced hypogonadism with specific focus on hypothalamic derangements. A dysmetabolic male murine model fed iron-enriched diet (IED) and cell-based models of gonadotropin-releasing hormone (GnRH) neurons were used. RESULTS: Mice fed IED showed severe hypogonadism with a significant reduction of serum levels of testosterone (-83%) and of luteinizing hormone ( 86%), as well as reduced body weight gain, body fat and plasma leptin. IED mice had a significant increment in iron concentration in testes and in the pituitary. Even if iron challenge of in vitro neuronal models (GN-11 and GT1-7 GnRH cells) resulted in 10- and 5-fold iron content increments, respectively, no iron content changes were found in vivo in hypothalamus of IED mice. Conversely, mice placed on IED showed a significant increment in hypothalamic GnRH gene expression (+34%) and in the intensity of GnRH-neuron innervation of the median eminence (+1.5 fold); similar changes were found in the murine model HFE-/-, resembling human hemochromatosis. CONCLUSIONS: IED-fed adult male mice show severe impairment of hypothalamus-pituitary-gonadal axis without a relevant contribution of the hypothalamic compartment, which thus appears sufficiently protected from systemic iron overload. PMID- 28648621 TI - Differential expression of circulating Th1/ Th2/ Th17 cytokines in serum of Chlamydia trachomatis-infected women undergoing incomplete spontaneous abortion. AB - The study aimed to elucidate role of Th1/Th2/Th17 cytokines in the immunopathogenesis of spontaneous abortion in Chlamydia trachomatis (Ct)-positive first-trimester aborters. Endometrial curettage tissue and serum were collected from 145 aborters (spontaneous abortion (SA) group, n = 85; recurrent miscarriage (RM) group, n = 60) and 120 controls attending Department of Obstetrics & Gynecology at Safdarjung hospital, New Delhi (India). Polymerase chain reaction was used to detect Ct plasmid/MOMP, while commercial cytometric bead array kit was utilized to estimate circulating serum cytokines. 13.7% aborters were Ct positive, however, none was found to be infected among controls. IFN-gamma, TNF alpha, IL-2, IL-6 and IL-17A cytokines were significantly increased in SA group/RM group (Ct-infected) versus controls. IL-4 showed no difference between groups, while IL-10 was significantly elevated in controls versus Ct-infected subjects in SA group/RM group. Furthermore, IFN-gamma, TNF-alpha, IL-6, IL-17A cytokines were significantly elevated in Ct-positive RM group versus Chlamydia infected SA group. However, IL-2, IL-4 and IL-10 cytokines showed no significant difference between Ct-positive SA group versus infected RM group. Positive correlation was found between few cytokines (TNF-alpha and IFN-gamma/IL-17A; IL 17A and IFN-gamma/IL-6) in Ct-positive aborters. Our study clearly established the role of Th1/Th2/Th17 cytokines in the pathogenesis of spontaneous abortion in Ct-infected subjects and found that Chlamydia-positive recurrent aborters had a predominant Th1/Th17 bias. PMID- 28648622 TI - A novel antimicrobial therapy for the control of Aeromonas hydrophila infection in aquaculture using marine polysaccharide coated gold nanoparticle. AB - In the present study, we prepared fucoidan coated Au-NPs (Fu-AuNPs), and examined its antimicrobial activity against Aeromonas hydrophila. The green synthesized Fu AuNPs were bio-physically characterized by Ultraviolet-visible (UV-Vis) spectroscopy, X-ray Diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), Higher Transmission Electron Microscopy (HR-TEM), Zeta potential analysis and Energy Dispersive X-ray spectroscopy (EDX). Fu-AuNPs were crystalline in nature, spherical to triangular in shape, with particle size ranging within 10 100 nm. The synthesized Fu-AuNPs at 100 MUg mL-1 showed inhibition zone against A. hydrophila (23.2 mm) which is much higher than that of commercial antibiotic chloramphenicol (17.3 mm). The biofilm inhibitory activity of Fu-AuNPs against Gram negative (Aeromonas hydrophila) was higher. Light and confocal laser scanning microscopic observations showed that the Fu-AuNPs at 100 MUg mL-1 inhibited the biofilm of A. hydrophila. The cytotoxicity study indicated that Fu AuNPs were effective in inhibiting the viability of human cervical cancer cells (HeLa) at 100 MUg mL-1. In another experiment, the antibacterial effect of Fu AuNPs on tilapia, Oreochromis mossambicus were evaluated in vivo. The mortality rate of O. mossambicus infected by A. hydrophila was much higher (90%), whereas, the mortality of O. mossambicus that received Fu-AuNPs followed by challenge with A. hydrophia was reduced to 30%. This study concludes that Fu-AUNPs are effective in the control of A. hydrophila infections in O. mossambicus. PMID- 28648623 TI - Isolation of anticancer and antimicrobial metabolites from Epicoccum nigrum; endophyte of Ferula sumbul. AB - Owing to the importance of endophytes, current research was aimed to purify the secondary metabolites from targeted source. Ferula sumbul, a lipophilic extract of the endophyte was prepared in 10% methanol and partitioned with ethyl acetate and bioassay guided isolation was carried using standard protocols against bacterial, fungal and cancer cells. The active fractions consisted of three new metabolites (2-methyl-3-nonyl prodiginine, Bis (2-ethylhexyl) phthalate, and a meroterpenoid, Preaustinoid A). Their structures were confirmed with LCMS/MS. The purified metabolites showed valuable results against tested activities which concluded that these compounds have great potential and these may be applicable to textile (dyeing), pharmaceutical (drug, infectious agents) and food (preservatives) industries. This study reveals the potential of E. nigrum as an important source of bioactive compounds including 2-methyl-3-nonyl prodiginine, Bis (2-ethylhexyl) phthalate, and Preaustinoid A. This is first report of isolation of prodiginines as well as meroterpenoid and Bis (2-ethylhexyl) phthalate from Epicoccum nigrum. PMID- 28648624 TI - Extended-spectrum beta-lactamases and plasmid-mediated quinolone resistance in enterobacterial clinical isolates from neonates in Tunisia. AB - This study was conducted to investigate extended-spectrum-beta-lactamase (ESBL) producing Enterobacteriaceae isolates from the Center of Maternity and Neonatology of Monastir, Tunisia. Fourty-six strains out of 283 were found to produce ESBL: Klebsiella pneumoniae (n = 37), Escherichia coli (n = 6), Enterobacter cloacae (n = 2), and Citrobacter freundi (n = 1). Genotyping analysis, using ERIC2 and RAPD, showed that strains were clonally unrelated. PCR amplification followed by sequencing revealed that all strains produced CTX-M-15. This enzyme was co-produced with TEM and SHV determinants in 34 and 36 strains respectively. The blaCTXM-15 gene was bracked by ISEcp1 and/or IS26 in 42 out of the 46 ESBL positive strains. The quinolone resistance determinants were associated to the ESBL producing isolates: we identified the qnrB1 gene in six isolates and the aac(6')-Ib-cr gene in five isolates. This epidemiological study shows the widespread of CTX-M-15 and qnr determinants among enterobacterial isolates from neonates hospitalized at the center of Maternity and Neonatology of Monastir suggesting either mother portage or horizontal transmission. PMID- 28648625 TI - Anti-erythrocyte IgG in hamsters with acute experimental infection by Leptospira interrogans serovar Canicola. AB - The aim of this study was to evaluate the behavior of erythrocyte and platelet, as immunological markers, as well as evaluate the involvement of these factors in hemolytic and hemorrhagic reactions in hamsters experimentally infected by Leptospira interrogans Serovar Canicola. Our experimental design was composed by two randomized groups: Infected Group (IG) (n = 12) and control group (CG) (n = 6). Ninety-six hours after the inoculation, the presence of immunoglobulins (IgG and IgM) and complement C3 levels, related to erythrocytes and platelets, was assessed. Platelet's microparticles marked by CD61, reticulocytes and reticulated platelets were also quantified. Additionally, fibrinogen, prothrombin time, partially activated thromboplastin time and sera levels of IgG and IgM were assessed. Our results showed that levels of platelet decreased in IG (P < 0.001); as well as, there was presence of IgG and C3 associated with erythrocyte surface in the infected animals (P < 0.01, P < 0.05, respectively). Levels of prothrombin time and Activated Partial Thromboplastin Time were increased, while fibrinogen level was decreased (P < 0.01) in IG. CD61 microparticles were higher (P < 0.05) in IG due to platelet activation. Thus, it was established a positive correlation (P < 0.01) between platelets count and fibrinogen (Figure 3, R = 0.84, P < 0.001). Therefore, the platelet consumption component was preponderant in relation to autoimmune causes. Finally, regarding the erythrocytes, the autoimmune component played an important role, did not causing hemolytic reaction in this acute experimental time. PMID- 28648626 TI - Mechanosensitivity of microdomain calcium signalling in the heart. AB - In cardiac myocytes, calcium (Ca2+) signalling is tightly controlled in dedicated microdomains. At the dyad, i.e. the narrow cleft between t-tubules and junctional sarcoplasmic reticulum (SR), many signalling pathways combine to control Ca2+ induced Ca2+ release during contraction. Local Ca2+ gradients also exist in regions where SR and mitochondria are in close contact to regulate energetic demands. Loss of microdomain structures, or dysregulation of local Ca2+ fluxes in cardiac disease, is often associated with oxidative stress, contractile dysfunction and arrhythmias. Ca2+ signalling at these microdomains is highly mechanosensitive. Recent work has demonstrated that increasing mechanical load triggers rapid local Ca2+ releases that are not reflected by changes in global Ca2+. Key mechanisms involve rapid mechanotransduction with reactive oxygen species or nitric oxide as primary signalling molecules targeting SR or mitochondria microdomains depending on the nature of the mechanical stimulus. This review summarizes the most recent insights in rapid Ca2+ microdomain mechanosensitivity and re-evaluates its (patho)physiological significance in the context of historical data on the macroscopic role of Ca2+ in acute force adaptation and mechanically-induced arrhythmias. We distinguish between preload and afterload mediated effects on local Ca2+ release, and highlight differences between atrial and ventricular myocytes. Finally, we provide an outlook for further investigation in chronic models of abnormal mechanics (eg post-myocardial infarction, atrial fibrillation), to identify the clinical significance of disturbed Ca2+ mechanosensitivity for arrhythmogenesis. PMID- 28648627 TI - Myofilament protein dynamics modulate EAD formation in human hypertrophic cardiomyopathy. AB - Patients with hypertrophic cardiomyopathy (HCM), a disease associated with sarcomeric protein mutations, often suffer from sudden cardiac death (SCD) resulting from arrhythmia. In order to advance SCD prevention strategies, our understanding of how sarcomeric mutations in HCM patients contribute to enhanced arrhythmogenesis needs to be improved. Early afterdepolarizations (EADs) are an important mechanism underlying arrhythmias associated with HCM-SCD. Although the ionic mechanisms underlying EADs have been studied in general, whether myofilament protein dynamics mechanisms also underlie EADs remains unknown. Thus, our goals were to investigate if myofilament protein dynamics mechanisms underlie EADs and to uncover how those mechanisms are affected by pacing rate, sarcomere length (SL), and different levels of HCM-induced myofilament remodeling. To achieve this, a mechanistically-based bidirectionally coupled human electrophysiology-force myocyte model under the conditions of HCM was constructed. HCM ionic remodeling included a reduced repolarization reserve, while HCM myofilament modeling involved altered thin filament activation. We found that the mechanoelectric feedback (MEF) on calcium dynamics in the bidirectionally coupled model, via Troponin C buffering of cytoplasmic Ca2+, was the myofilament mechanism underlying EADs. Incorporating MEF diminished the degree of repolarization reserve reduction necessary for EADs to emerge and increased the frequency of EAD occurrence, especially at faster pacing rates. Longer SLs and enhanced thin filament activation diminished the effects of MEF on EADs. Together these findings demonstrate that myofilament protein dynamics mechanisms play an important role in EAD formation. PMID- 28648629 TI - Single-molecule FRET studies of ion channels. AB - Different types of fluorescence spectroscopy approaches have over the last two decades become important techniques in studies of ion channel structure and dynamics. Many fluorescence methods have been used to examine a huge variety of ion channels. Any fluorescence study of ion channels requires the presence of fluorophores, which may be intrinsic to the channel protein, attached either extrinsically to the protein, or be simply located nearby the channel to monitor local conditions such as for many of the ion-sensitive dyes. Many ion channel studies utilize protein-bound or intrinsic protein fluorophores. Single-molecule Forster resonance energy transfer (smFRET) spectroscopy has been particularly useful in gaining detailed structural information for multimeric membrane proteins including ion channels. This technique presents a major advancement in studies of structural dynamics of these membrane proteins. Although it has required different approaches to protein labelling, control of the protein state, as well as careful analysis of the orientations, geometries, and number of fluorescent probes, the smFRET methodology provides an excellent tool for studying the structure of ion channels. PMID- 28648628 TI - Impact of titin strain on the cardiac slow force response. AB - Stretch of myocardium, such as occurs upon increased filling of the cardiac chamber, induces two distinct responses: an immediate increase in twitch force followed by a slower increase in twitch force that develops over the course of several minutes. The immediate response is due, in part, to modulation of myofilament Ca2+ sensitivity by sarcomere length (SL). The slowly developing force response, termed the Slow Force Response (SFR), is caused by a slowly developing increase in intracellular Ca2+ upon sustained stretch. A blunted immediate force response was recently reported for myocardium isolated from homozygous giant titin mutant rats (HM) compared to muscle from wild-type littermates (WT). Here, we examined the impact of titin isoform on the SFR. Right ventricular trabeculae were isolated and mounted in an experimental chamber. SL was measured by laser diffraction. The SFR was recorded in response to a 0.2 MUm SL stretch in the presence of [Ca2+]o = 0.4 mM, a bathing concentration reflecting ~50% of maximum twitch force development at 25 degrees C. Presence of the giant titin isoform (HM) was associated with a significant reduction in diastolic passive force upon stretch, and ~50% reduction of the magnitude of the SFR; the rate of SFR development was unaffected. The sustained SL stretch was identical in both muscle groups. Therefore, our data suggest that cytoskeletal strain may underlie directly the cellular mechanisms that lead to the increased intracellular [Ca2+]i that causes the SFR, possibly by involving cardiac myocyte integrin signaling pathways. PMID- 28648630 TI - Resolution of a steroid-resistant, hypereosinophilic immune diathesis with mepolizumab and concomitant amelioration of a mixed thrombotic microangiopathy. AB - The anaphylatoxins produced by an unbridled complement cascade in atypical hemolytic uremic syndrome (aHUS) can alter the leukocyte environment in tissues and peripheral blood, causing clinically significant eosinophilia. While the membrane attack complex and C5a anaphlatoxin can be suppressed with anti-C5 biologics, the production of C3a is still capable of driving a destructive hypereosinophilic syndrome in spite of anticomplement therapy. The side-effects of glucocorticoids in treating hypereosinophilic syndrome limit their therapeutic index in long-term treatment and this behooves the use of alternative strategies. While use of the anti-IL-5 antibody, mepolizumab, has been reported for treatment of primary hypereosinophilic syndromes off-label, its usage in the setting of complement-driven thrombotic microangiopathy has not been attempted. We report mepolizumab's rapid resolution of a glucocorticoid-resistant hypereosinophilic syndrome that caused multi-organ dysfunction in a patient with a complex immune diathesis. The patient's long standing TTP/aHUS disease activity, shown to have direct correlation with his eosinophil count, improved with anti-IL-5 therapy, suggesting a reciprocal enhancement between the conditions. PMID- 28648631 TI - Flavonoids from artificially induced dragon's blood of Dracaena cambodiana. AB - Dragon's blood is a rare traditional medicine used in many countries. Because of its various therapeutic uses, its requirement is increasing dramatically, while formation of dragon's blood need at least several years, so many researchers tried to induce the formation of dragon's blood artificially, but the chemical constituents of artificially induced dragon's blood were rarely studied. In our research, twenty constituents, including three new ones, were isolated from artificially induced dragon's blood of Dracaena cambodiana, five of which are the same with those from natural dragon's blood. In addition, six compounds exhibited cytotoxic activities, and eleven compounds demonstrated antibacterial activities. Artificially induced dragon's blood is expected to be the substituent of natural dragon's blood. PMID- 28648632 TI - Purification, characterization, cloning and structural analysis of Crocodylus siamensis ovotransferrin for insight into functions of iron binding and autocleavage. AB - Ovotransferrin (OTf), the major protein constituent of egg white, is of great interest due to its pivotal role in biological iron transport and storage processes and its spontaneous autocleavage into peptidic fragments with alternative biological properties, such as antibacterial and antioxidant activities. However, despite being well-investigated in avian, a detailed elucidation of the structure-function relationship of ovotransferrins in the closely related order of Crocodilia has not been reported to date. In this study, electron paramagnetic resonance (EPR) confirmed the presence of two spectroscopically distinct ferric iron binding sites in Crocodylus siamensis OTf (cOTf), but implied a five-fold lower quantity of bound iron than in hen OTf (hOTf). In addition, quantitative estimation of free sulfhydryl groups revealed slight differences to hOTf. To gain a better structural understanding of cOTf, we found a cOTf gene consisting of an open reading frame of 2040bp and encoding a protein of 679 amino acids. In silico prediction of the three-dimensional structure of cOTf and comparison with hOTf revealed four evolutionarily conserved iron-binding sites in both N- and C-lobes, as well as the presence of only 13 of the 15 disulfide bonds in hOTf. This evolutionary loss of disulfide linkages in conjunction with the lack of hydrogen bonding from a dilysine trigger in the C lobe are presumed to affect the iron binding and autocleavage character of cOTf. As a result, cOTf may be capable of exerting a more diverse array of functions compared to its avian counterparts; for instance, ion buffering, antioxidant and antimicrobial activities. PMID- 28648633 TI - Identification of evidence for autoimmune pathology of bilateral sudden sensorineural hearing loss using proteomic analysis. AB - Sudden sensorineural hearing loss (S-SNHL) is an inner ear disorder with an abrupt hearing loss occurring <3days. The pathologic mechanism of the disease remains unclear, although autoimmunity has been regarded as one of the suggested causes, especially in bilateral form. In this study, we aimed to provide evidence for the involvement of autoimmunity in bilateral S-SNHL using proteomic approaches such as ProtoArray(r), western blotting, immunoprecipitation, and liquid column mass spectrometry for mass screening of candidate antigens and autoantibodies based on the hypothesis that multiple autoantibodies and target antigens must exist in order for autoimmune bilateral S-SNHL to develop. As the final outcome, we have proven the involvement of autoimmunity in the disease, and investigated the existence of circulating autoantibodies and candidate antigens. These findings could provide basic evidence necessary for the development of diagnostic biomarkers as well as the understanding of the pathological mechanisms underlying bilateral S-SNHL. S-SNHL: sudden sensorineural hearing loss; LC-MS: liquid chromatography-mass spectrometry; MS: mass spectrometry; autoAb: autoantibody; 1-DE: one-dimensional electrophoresis. PMID- 28648634 TI - Impaired ovarian response to exogenous gonadotropins in female rat offspring born to mothers perinatally exposed to Bisphenol A. AB - The ovary is sensitive to disruption by the environmental estrogen Bisphenol A (BPA). Our aim was to investigate whether perinatal exposure to BPA (50MUg/kgday), orally administered, affects ovarian response to exogenous gonadotrophins (PMSG or PMSG+hCG) in prepubertal female offspring. An altered response to gonadotrophins was observed in BPA-exposed rats. Increased proportion of antral follicles, altered levels of ovarian steroidogenic enzymes, gonadotropin receptors, AR and ERbeta were observed in PMSG group. Besides that, in response to PMSG+hCG, a persistent high Fshr mRNA expression and a decreased number of follicles with high expression of PR before ovulation were observed. After ovulation, there was an increase in antral atretic follicles, reduced Lhcgr mRNA expression and high serum levels of E2. Therefore, an early exposure to a low dose of BPA during perinatal period induces ovarian changes leading to an altered response to exogenous gonadotropin treatment later in life. PMID- 28648635 TI - Pro-oxidant/pro-inflammatory alterations in the offspring's heart of mild diabetic rats are regulated by maternal treatments with a mitochondrial antioxidant. AB - Maternal diabetes programs metabolic and cardiovascular diseases in the offspring. Here, we demonstrated increased pro-oxidant/pro-inflammatory markers in the heart of 2-day-old offspring of diabetic rats, previous to the induction of metabolic alterations. At a pre-pubertal stage, sex-dependent changes were evidenced in the diabetic group, as only males showed increased glycemia as well as increased concentrations of nitrated proteins, matrix metalloproteinase-9 and peroxisome proliferator activated receptor alpha (PPARalpha) in the heart. Differently, the heart of male and female offspring of diabetic rats showed increased levels of connective tissue growth factor (CTGF). Maternal treatments with idebenone, a mitochondrial antioxidant, led to reductions in all the pro oxidant and pro-inflammatory markers evaluated and in PPARalpha protein expression in the heart of the offspring of diabetic rats. The results of the present study highlight the gender dependence and the role of oxidative stress in the diabetes-induced intrauterine programming of heart alterations. PMID- 28648636 TI - Contribution of flagella and motility to gut colonisation and pathogenicity of Salmonella Enteritidis in the chicken. AB - Salmonella Enteritidis causes fowl paratyphoid in poultry and is frequently associated to outbreaks of food-borne diseases in humans. The role of flagella and flagella-mediated motility into host-pathogen interplay is not fully understood and requires further investigation. In this study, one-day-old chickens were challenged orally with a wild-type strain Salmonella Enteritidis, a non-motile but fully flagellated (SE DeltamotB) or non-flagellated (SE DeltafliC) strain to evaluate their ability to colonise the intestine and spread systemically and also of eliciting gross and histopathological changes. SE DeltamotB and SE DeltafliC were recovered in significantly lower numbers from caecal contents in comparison with Salmonella Enteritidis at early stages of infection (3 and 5dpi). The SE DeltamotB strain, which synthesises paralysed flagella, showed poorer intestinal colonisation ability than the non-flagellated SE DeltafliC. Histopathological analyses demonstrated that the flagellated strains induced more intense lymphoid reactivity in liver, ileum and caeca. Thus, in the present study the flagellar structure and motility seemed to play a role in the early stages of the intestinal colonisation by Salmonella Enteritidis in the chicken. PMID- 28648637 TI - Xyloglucan: A functional biomacromolecule for drug delivery applications. AB - The near future of drug delivery system would lie in the search of a versatile and innocuous material, based mostly on the natural resources. The tamarind seed xyloglucan (XG) is a natural neutral hemicellulose and a hydrophilic polysaccharide consisting of a main chain of glucan backbone with xylose and galactose side chains. XG is endowed with idiosyncratic mucoadhesive and in situ gelling properties which rated XG as an attractive, functional polymer for numerous drug delivery applications. In milieu of this, the present review is designed to underline the plausible potential of XG or XG-based systems in drug delivery. The feasibility of surface-tailoring, the flexibility of chemical modification, and the possibility as ligand-conjugations grant XG an extraordinary consideration in the scientific territory. The authors are hopeful that the versatility of XG would meet the expectations of regulatory authorities and the XG-based products will serve the therapeutic needs of the community in the future, if sufficiently investigated and promising outcomes are obtained in human subjects. PMID- 28648638 TI - Polymeric pollutant biodegradation through microbial oxidoreductase: A better strategy to safe environment. AB - The detoxification of xenobiotic organic compounds by various microorganisms through oxidative coupling is facilitated with oxidoreductases. With the help of energy yielding biochemical reactions, these microbes extract energy for their metabolic pathway. They promote the transfer of electrons from a reduced organic substrate to another chemical compound. During such oxidation-reduction reactions, the toxic polymeric substance is finally oxidized into harmless compounds. Enzymatic bioremediation of toxic organic pollutant is a very effective strategy in complex environmental conditions. Oxidoreductases enzymes have a significant potential for the bioremediation of the xenobiotic compounds. Various electron donor complex polymeric substrates containing Phenol and aromatic amines are oxidized by peroxidase in the presence of H2O2 while O2 in the case of dioxygenase. This review attempts to present relevant information on the peroxidases and dioxygenase from various microbial isolates involved in the biodegradation of a wide range of pollutants. PMID- 28648639 TI - Thermal degradation kinetics of polylactic acid/acid fabricated cellulose nanocrystal based bionanocomposites. AB - Cellulose nanocrystals (CNC) are fabricated from filter paper (as cellulosic source) by acid hydrolysis using different acids such as sulphuric (H2SO4), phosphoric (H3PO4), hydrochloric (HCl) and nitric (HNO3) acid. The resulting acid derived CNC are melt mixed with Polylactic acid (PLA) using extruder at 180 degrees C. Thermogravimetric (TGA) result shows that increase in 10% and 50% weight loss (T10, T50) temperature for PLA-CNC film fabricated with HNO3, H3PO4 and HCl derived CNC have improved thermal stability in comparison to H2SO4-CNC. Nonisothermal kinetic studies are carried out with modified-Coats-Redfern (C-R), Ozawa-Flynn-Wall (OFW) and Kissinger method to predict the kinetic and thermodynamic parameters. Subsequently prediction of these parameter leads to the proposal of thermal induced degradation mechanism of nanocomposites using Criado method. The distribution of Ea calculated from OFW model are (PLA-H3PO4-CNC: 125 139 kJmol-1), (PLA-HNO3-CNC: 126-145 kJmol-1), (PLA-H2SO4-CNC: 102-123 kJmol-1) and (PLA-HCl-CNC: 140-182 kJmol-1). This difference among Ea for the decomposition of PLA-CNC bionanocomposite is probably due to various acids used in this study. The Ea calculated by these two methods are found in consonance with that observed from Kissinger method. Further, hyphenated TG-Fourier transform infrared spectroscopy (FTIR) result shows that gaseous products such as CO2, CO, lactide, aldehydes and other compounds are given off during the thermal degradation of PLA-CNC nanocomposite. PMID- 28648640 TI - Pulmonary delivery of synergistic combination of fluoroquinolone antibiotic complemented with proteolytic enzyme: A novel antimicrobial and antibiofilm strategy. AB - Bacterial resistance remains a major hindrance in treatment with antimicrobial agents. Therefore, we assessed the improved antimicrobial and antibiofilm activity of Levofloxacin (LFX) and Serratiopeptidase (SRP) combinations in in vitro microbiological studies. Further, pharmacodynamic and pharmacokinetic studies of liposomal LFX in combination with SRP (LFX liposome-SRP) were performed in S. aureus infected rats. LFX at sub-MIC with SRP eradicated >90% of the preformed biofilm. The entrapment efficiency of LFX in liposome was >80% and the co-spray dried product had MMAD <5 MUm. We observed high LFX concentration in the lung (3.39 MUg/ml over 3 h) and AUC/MIC >=100. In a pharmacodynamic study, untreated infected rat lungs demonstrated higher mRNA expression for inflammatory markers, cytokine levels and microbial load compared to control. Conversely, LFX liposome-SRP significantly abated these adverse repercussions. Histological findings were also in agreement with these observations. Furthermore, our findings corroborate exhibited improved antibiofilm and antimicrobial efficacy of LFX liposome-SRP in treating S. aureus infection. PMID- 28648641 TI - Glypican-based drug releasing titania implants to regulate BMP2 bioactivity as a potential approach for craniosynostosis therapy. AB - Advances in molecular biology and nanomedicine based therapies hold promise to obviate the need of multiple surgical interventions (associated with current management) in craniosynostosis by preventing bone re-ossification. One such adjunctive therapy involves application of glypicans 1 and 3 (GPC1 and GPC3) that are BMP inhibitors implicated in downregulating the BMP2 activity in prematurely fusing sutures. Electrochemically anodized Titania nanotube (TNT) arrays have been recognized as a promising localized, long-term drug delivery platform for bone-related therapies. This study presents the application of nanoengineered TNT/Ti implants loaded with recombinant glypicans for craniosynostosis therapy. By using Dual luciferase Reporter assay, we tested the biofunctionality of eluted glypicans from the TNT/Ti implants for BMP2 bioactivity regulation in C2C12 murine myoblast cell line. BMP2 activity was inhibited significantly for up to 15days by the glypicans released from polymer-coated TNT/Ti implants, indicating their potential application in adjunctive craniosynostosis treatment. PMID- 28648642 TI - HPI/AMF inhibition halts the development of the aggressive phenotype of breast cancer stem cells. AB - Cancer stem cells are responsible for tumor recurrence and metastasis. A new highly reproducible procedure for human breast cancer MCF-7 stem cells (BCSC) isolation and selection was developed by using a combination of hypoxia/hypoglycemia plus taxol and adriamycin for 24h. The BCSC enriched fraction (i) expressed (2-15 times) the typical stemness protein markers CD44+, ALDH1A3 and Oct 3/4; (ii) increased its clonogenicity index (20-times), invasiveness profile (>70%), migration capacity (100%) and ability to form mammospheres, compared to its non-metastatic MCF-7 counterpart. This isolation and selection protocol was successful to obtain stem cell enriched fractions from A549, SiHa and medulloblastoma cells. Since the secretion of HPI/AMF cytokine seems involved in metastasis, the effects of erytrose-4-phosphate (E4P) and 6 phosphogluconate (6PG), potent HPI inhibitors, on the acquisition of the breast stem cell-like phenotype were also evaluated. The presence of E4P during the BCSC selection deterred the development of the stemness phenotype, whereas both extracellular E4P (5-250nM) and 6PG (1MUM) as well as siRNA HPI/AMF depressed the BCSC invasiveness ability (>90%), clonogenicity index (>90%) and contents (50 96%) of stemness (CD44, ALDH1A), pluripotency (p38 MAPK, Oct3/4, wnt/beta catenin) and EMT (SNAIL, MMP-1, vimentin) markers. The cytokine inhibitor repertaxin (10nM) or the anti-IL-8 or anti-TGF-beta monoclonal antibodies (10MUg/mL) did not significantly affect the BCSC metastatic phenotype. E4P also diminished (75%) the formation and growth of MCF-7 stem cell mammospheres. These results suggested that E4P by directly interacting with extracellular HPI/AMF may be an effective strategy to deter BCSC growth and progression. PMID- 28648643 TI - Membrane contact sites. PMID- 28648644 TI - Quercetin suppresses the metastatic ability of lung cancer through inhibiting Snail-dependent Akt activation and Snail-independent ADAM9 expression pathways. AB - Metastasis is the major cause of death from lung cancer. Quercetin, a widely distributed bioflavonoid, is well known to induce growth inhibition in a variety of human cancer cells, but how it affects lung cancer cell invasion and metastasis is unclear. Herein, we found that quercetin inhibited the migration/invasion of non-small cell lung cancer (NSCLC) cell lines and bone metastasis in an orthotopic A549 xenograft model by suppressing the Snail mediated epithelial-to-mesenchymal transition (EMT). Moreover, survival times of animals were also prolonged after quercetin treatment. Mechanistic investigations found that quercetin suppressed Snail-dependent Akt activation by upregulating maspin and Snail-independent a disintegrin and metalloproteinase (ADAM) 9 expression pathways to modulate the invasive ability of NSCLC cells. In clinical samples, we observed that patients with Snailhigh/p-Akthigh tumors had the shortest survival times. In addition, a lower survival rate was also found in ADAM9high patients than in ADAM9low patients. Overall, our results provide new insights into the role of quercetin-induced molecular regulation in suppressing NSCLC metastasis and suggest that quercetin has potential therapeutic applications for metastatic NSCLC. PMID- 28648645 TI - Functional interaction of the two-pore domain potassium channel TASK-1 and caveolin-3. AB - The two-pore domain potassium channel TASK-1 is strongly expressed in the heart and has been shown to modulate the resting membrane potential and action potential. However, little is known about the regulation of TASK-1 channels. The present study was designed to determine whether TASK-1 is modulated by caveolin 3, a primary structural protein of cardiac caveolae. Functional studies with the whole-cell voltage clamp technique showed that the expression of caveolin-3 decreased recombinant TASK-1 currents significantly in HEK293T cells, and this effect was prevented by co-expressing the dominant negative mutant caveolin-3 P104L. Immunofluorescence imaging revealed the colocalization of TASK-1 and caveolin-3. Co-immunoprecipitation analysis indicated that caveolin-3 associated with TASK-1. When co-expressed with caveolin-3 P104L, the fluorescence intensity of caveolin-3 on the cell periphery was reduced. This agrees with the functional evidence that caveolin-3 P104L prevented the inhibitory effect of caveolin-3 on TASK-1 currents, possibly via reducing the plasma membrane targeting of caveolin 3. Further, our data from cardiomyocytes suggest that TASK-1 is associated with caveolin-3. In summary, our study indicates that TASK-1 is functionally regulated by caveolin-3, possibly via association with each other on the cell surface. These results point out a novel mechanism in the regulation of TASK-1. PMID- 28648646 TI - Antroduodenectomy with gastro-duodenostomy (Billroth I technique) for perforated duodenal peptic ulcer. PMID- 28648647 TI - In vitro antibacterial activity of fosfomycin combined with other antimicrobials against KPC-producing Klebsiella pneumoniae. AB - The increasing prevalence of KPC-producing Klebsiella pneumoniae (KPC-Kp) strains poses a serious threat to patients. Therapeutic options are limited to colistin, fosfomycin, tigecycline and selected aminoglycosides. Although the combination of fosfomycin with other antimicrobials is recommended, data regarding possible synergistic activity in vitro and in vivo appear inconsistent. Here we report that five drug combinations (fosfomycin combined with imipenem, ertapenem, tigecycline, colistin or amikacin) had a significant additive effect against 136 KPC-Kp strains in an in vitro chequerboard assay. In addition, time-kill assays revealed that fosfomycin enhanced the bactericidal activity of the five other antimicrobial agents. Moreover, owing to its persistent bactericidal effect, the combination of fosfomycin plus amikacin is an effective therapeutic candidate for infections by KPC-producing organisms. PMID- 28648648 TI - Searching for Intermediate Phenotypes in Posttraumatic Stress Disorder. PMID- 28648651 TI - The Impact of Functional Status on the Outcomes of Endovascular Lower Extremity Revascularization for Critical Limb Ischemia in the Elderly. AB - BACKGROUND: Functional status is an important predictor of outcomes after infrainguinal bypass surgery. There are little data on the effect of functional status on the outcomes of endovascular lower extremity interventions, especially in the elderly frail population. METHODS: This is a retrospective analysis of the American College of Surgeons - National Surgical Quality Improvement Program files for the years 2011-2013 to assess the impact of functional status on outcome after endovascular intervention for critical limb ischemia (CLI). Elderly patients (age >=70) undergoing revascularization for CLI were included. The patients were divided into 2 groups based on functional status prior to surgery: independent (IND) or dependent (DEP), which included partially dependent as well as totally dependent patients. The 2 groups were compared with respect to demographics, comorbidities, complications, length of stay, limb loss, and mortality. Statistical analysis was performed using Student's t-test for continuous variables and Fisher's exact test for categorical variables. RESULTS: There were 1,055 patients (DEP = 253, 24%). There was no difference in gender or race but DEP patients were older than IND (P = 0.008). DEP patients were significantly more likely to have history of congestive heart failure (P = 0.003), hypertension (P = 0.042), and diabetes (P <0.001). There was no difference in emergent surgeries between the 2 groups (P = 1.00). DEP patients had more tibial interventions compared with IND (P <0.001). DEP developed more pneumonia (P <0.001) and septic shock (P = 0.016) and had a trend toward more urinary tract infections (P = 0.051) after endovascular revascularization. There was no significant difference in operating time (P = 0.232) or major amputation (P = 0.092). DEP had significantly longer length of hospital stay (P = 0.0068). DEP had significantly higher mortality (5.98% vs. 2.01%, P = 0.002). On multivariate analysis, DEP status, emergency procedure, congestive heart failure, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, sepsis, and septic shock were independently associated with 30 days of mortality. Irrespective of age, DEP functional status was the most significant preoperative predictor of mortality with an odd ratio of 5.16 [1.93-13.83], P = 0.001 (parsimonious model). CONCLUSIONS: Functional status should be carefully assessed when considering endovascular revascularization in the elderly as DEP has significantly higher morbidity and mortality. PMID- 28648650 TI - Planning, Execution, and Follow-up for Endovascular Aortic Aneurysm Repair Using a Highly Restrictive Iodinated Contrast Protocol in Patients with Severe Renal Disease. AB - BACKGROUND: The cumulative amount of iodinated contrast medium necessary for endovascular repair (EVAR) planning, operative procedure, and subsequent follow up is a threat for the onset of end-stage renal disease in patients with preoperative impaired kidney function. The purpose of this study was to describe a mini-invasive approach aimed to minimize the exposure of these patients to iodinated contrast medium and the subsequent risk of renal function worsening. METHODS: From 2012 to 2015, all patients with abdominal aortic aneurysm (AAA) at high surgical risk and fit for standard EVAR (simple aortic-iliac anatomy: proximal and distal neck length >=15 mm, no severe angulation), underwent EVAR through the following "near-zero contrast" approach, if their glomerular filtration rate (GFR) was <30 mL/min: preoperative planning was performed by noncontrast-enhanced computed tomography and duplex ultrasound (DU); the origin of renal/hypogastric arteries and aortic bifurcation was evaluated and matched with vertebral bone landmarks and the endograft deployed accordingly, using <20 cc of isotonic iodinate contrast medium and contrast-enhancement DU (CEUS). Follow-up was by DU/CEUS at 1, 6, and 12 months. Primary end points were technical success (TS: renal/hypogastric artery patency, absence of type I/III endoleaks, iliac stenosis/kinking, intraoperative mortality, and conversion), 30 day mortality, and new onset of permanent dialysis with renal function evaluation at 1, 6, and 12 months. Secondary end points were type II endoleaks, reinterventions, AAA, and renal-related mortality during the follow-up. RESULTS: Eighteen patients (median age: 74 years, interquartile range [IQR]: 6, male: 78%, American Society of Anaesthesiologists [ASA] IV: 100%) were enrolled. The median AAA diameter and preoperative GFR were 66 mm (IQR: 13) and 22 mL/min (IQR: 4), respectively. Infrarenal (n = 10) and suprarenal fixation (n = 8) endografts were implanted, with a mean dose of iodinate contrast medium injection of 18 mL (IQR) and 100% TS rate. Two type II endoleaks were detected at the completion CEUS. The median postoperative GFR was 22 mL/min (IQR: 5). No patients had GFR worsening >=30% at 1 day and 30 days. The 30-day mortality was 11% (2 deaths for heart failure). At a median follow-up of 16 months (IQR: 8), no patients needed hemodialytic treatment and no endoleaks were detected. One patient died at 6 months for cancer and one at 13 months for myocardial infarction. No reinterventions or AAA and renal-related mortality occurred during the follow-up. CONCLUSIONS: A "near-zero contrast" approach is feasible in EVAR for patients with simple aorto-iliac anatomy. Patients with very poor renal function may still undergo to successful procedures, avoiding renal function impairment. PMID- 28648649 TI - Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse. AB - BACKGROUND: Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms. METHODS: In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used tyramide-amplified immunohistochemistry-fluorescence in situ hybridization to examine neural ensembles in the basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus- or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles. RESULTS: Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited subsequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More important, within BLA, distinct neuronal ensembles encoded pavlovian CPP and operant self administration reward memories and nicotine (the UCS) injections in the home cage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles inhibited both nicotine CPP and relapse to nicotine seeking. CONCLUSIONS: Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse. PMID- 28648652 TI - Dialysis-Related Parameters Influence Remodeling in the Venous Part of the Native Arteriovenous Fistula. AB - BACKGROUND: The aim of this study was to evaluate the association of hemodynamic parameters related to hemodialysis and antropometric parameters of patients with changes in the venous part of the arteriovenous fistula (AVF) at points of needling. METHODS: Two hundred forty-two hemodialysis (HD) patients (60.3% men), with median age 65 (interquartile range [IQR] 56-75) years, on HD treatment for a median of 49 (IQR 20-88) months with functioning fistula were recruited for the study. The history of vascular access, comorbidity, antropometric (body mass index, body surface area, and body composition), and dialysis-related parameters were analyzed. The cross-sectional area of upper extremity vessels were measured using ultrasound and included 2 points: A (arterial point for blood aspiration) and V (venous point for returning the blood after purification). The difference between A and V (A-V) was calculated. RESULTS: The median cross-sectional area of A was larger than V (1.04 [IQR 0.58-1.7] vs. 0.74 cm2 [IQR: 0.41-1.39], P <0.0001). The median difference between A and V (A-V) was 0.17 cm2 and positively correlated with mean blood flow (Qb), effective Kt/V, and time of AVF use. Other analyzed factors had no influence on A-V. In the multivariate analysis, the independent factor increasing the difference (A-V) was mean blood flow measured during HD sessions. CONCLUSIONS: The needling and utilization of AVF for hemodialysis may affect vein anatomy, namely causing dilatation at the arterial point and narrowing at venous point of AVF. We suggest that blood pump velocity of the dialysis machine may have an impact on these changes, but practical importance of these findings has to be elucidated. The significance of (A-V) factor in the prognosis of fistula complications should be further studied and confirmed in the prospective trials. PMID- 28648653 TI - Long-term Results of Tapered Stents in Endovascular Treatment of Carotid Stenosis. AB - BACKGROUND: Recent technological developments allowed significant improvements in interventional approach to carotid artery stenosis. Tapered stents were specifically designed for extracranial carotid artery stenting (CAS) to deal with vessels mismatch with the objective of decreasing the risk of thrombosis. Nevertheless, whether the stent geometry may affect the outcomes of CAS is uncertain. This study aims to investigate the impact of stent configuration on perioperative and long-term results of this procedure. METHODS: All CAS procedures performed between 2005 and 2012 at a single high-volume center were reviewed. Primary end points of the study were 30-day mortality and any ipsilateral neurological event. Secondary end points were any late (>30 days) neurological event and restenosis >50%. RESULTS: About 1,368 procedures were performed in the period 2005-2012. 9.1% of the patients were symptomatic for recent focal neurological event. 883 patients were treated with a cylindrical stent while the others underwent a tapered design device implantation. Technical success was achieved in 96% of the procedures. No perioperative mortality was recorded; perioperative stroke occurred in 1.2% vs. 1.6% (P = not significant) in tapered and straight stent group respectively. Stent design did not predict perioperative ipsilateral neurological events neither at bivariate nor at multivariate analysis. At a mean follow-up of 30 months, late neurological events occurred in 26 cases (1.9%); conic stents resulted protective at Kaplan-Meier analysis (P = 0.027). CONCLUSIONS: The use of conic stents appears to be associated with similar perioperative results when compared with straight stents. Late outcomes suggest a lower risk of restenosis and late neurological events in patients with conical shape stents. PMID- 28648654 TI - Gianturco Z-Stent Fixation of a Modified Iliac Limb Stent-Graft Endoprosthesis for the Treatment of Malignant Superior Vena Cava Syndrome. AB - Superior vena cava (SVC) syndrome, characterized by facial and arm swelling, is most frequently caused by intrathoracic malignancies. Decompression may be achieved with endovenous stent placement. Polytetrafluoroethylene-covered stents have shown to have higher long-term cumulative patency rates compared with uncovered stents for the treatment of malignant SVC syndrome. Unfortunately, polytetrafluoroethylene-covered stents are not readily available worldwide. Moreover, the existing armamentarium, including balloon-expandable iCAST stents (maximum diameter 10 mm) and heparin-coated Viabahn stent-graft endoprostheses (maximum diameter 13 mm), is too small to adequately treat malignant obstruction of the SVC. This report describes a patient with SVC syndrome and SVC tumor thrombus secondary to recurrent nonseminomatous germ cell carcinoma of the mediastinum treated with a Gianturco Z-stent-fixed modified EXCLUDER abdominal aortic aneurysm iliac limb endoprosthesis. PMID- 28648655 TI - Outcomes of Foam Sclerotherapy plus Ligation versus Foam Sclerotherapy Alone for Venous Ulcers in Lower Extremities. AB - BACKGROUND: Foam sclerotherapy (FS) is a safe and effective approach for managing patients with varicose veins and venous ulcers in lower extremities. But, recanalization of the ablated varicose veins and phlebitis are common postoperative complications that jeopardize its clinical effects. We hypothesize that ligation of the ablated varicose veins after FS will improve the outcomes of patients with varicose veins and venous ulcer. This study was aimed to evaluate the clinical efficacy of ligation after FS in comparison with FS alone for the management of patients with varicose veins and venous ulcers in lower extremities. METHODS: Eighteen patients underwent FS plus ligation (FSL) and 15 patients received FS alone. Aberdeen varicose veins questionnaire (AVVQ) and the revised venous clinical severity score (rVCSS), venous disability scores (VDSs), duplex sonography, ulcer healing rate, and ulcer healing time were documented to compare the outcomes in both groups. RESULTS: The ulcer healing time in patients treated with FSL was shorter than that in patients who received FS (P = 0.022; log-rank test). The average healing time was significantly shorter in FSL group than in FS group (35.67 +/- 24.62 days vs. 62.86 +/- 47.43, P = 0.042). The mean rVCSS, VDS, and AVVQ at 3 months after treatment in both groups decreased significantly in comparison with baseline, respectively. There were no severe complications or side effects in both groups. CONCLUSIONS: Ligation of the treated varicose veins after FS can improve the outcomes of patients with venous ulcers in comparison with FS alone. FSL is a safe, effective, and technically feasible procedure and can be used as a day surgery. PMID- 28648656 TI - Endovascular Reconstruction for Chronic Infrarenal Aortoiliac Occlusive Disease. AB - According to the 2007 TransAtlantic Inter-Society Consensus (TASC II) guidelines, surgery is the preferred treatment for extensive (TASC II type C and D) aortoiliac occlusive disease (AIOD). Recent studies, however, have shown that endovascular management can be an effective first-line treatment option for TASC II type C and D categories. While endovascular therapy is now commonly performed in patients with TASC II type D lesions, very few studies have investigated the feasibility and effectiveness of extending endovascular therapy to the most severe subcategory of TASC II D lesions, chronic infrarenal aortoiliac occlusion (CIAO). Herein, we present our technique for endovascular treatment of CIAO which relies on bidirectional subintimal aortoiliac dissection, wire snare for true lumen reentry, and combined balloon-expandable and self-expanding covered stent reconstruction of the aortic bifurcation and bilateral iliac arteries. This technique safely extends the reach of endovascular therapy to the most severe subcategory of TASC II D AIOD, CIAO. It is a viable minimally invasive alternative to aortobifemoral bypass surgery. Long-term follow-up of larger cohorts is needed to verify clinical efficacy and durability of therapy. PMID- 28648657 TI - Reproduction of the atopic march in an adult after allogeneic bone marrow transplantation from an atopic sibling. PMID- 28648658 TI - Ultrasound entheseal abnormalities at the distal interphalangeal joints and clinical nail involvement in patients with psoriasis and psoriatic arthritis, supporting the nail-enthesitis theory. AB - OBJECTIVE: It has been shown that nail involvement in psoriasis is associated with systemic enthesopathy. Our objective was to evaluate the association of nail involvement and enthesopathy at distal interphalangeal joint (DIP) level in psoriasis (PsO) and psoriatic arthritis (PsA) patients. METHODS: Consecutive patients (54 PsO and 56 PsA) seen at the outpatients clinic in this cross sectional study were included. All patients underwent both clinical and ultrasound (US) assessment on the same day. RESULTS: US revealed enthesopathy in at least 1 DIP joint in 9 patients with PsO (17%, 95% CI: 8-29%) and in 18 patients with PsA (32%, 95% CI: 20-46%). US extensor tendon enthesopathy was detected in a higher proportion of fingers with clinical nail involvement compared with fingers without clinical nail involvement, both in PsO and PsA patients (61.2% vs 16.8%, p < 0.0001 and 60.1% vs 22%, p < 0.0001, respectively). Among patients with PsO, 20% (95% CI: 7-41%) and 14% (95% CI: 4-32%) of those with and without clinical nail involvement showed enthesopathy on US examination, respectively (p = 0.54). Among PsA patients, the prevalence of enthesopathy was 30% (95% CI: 15-49%) for patients with clinical nail involvement and 35% (95% CI: 17-56%) for those without nail involvement (p = 0.71). CONCLUSION: Nail disease was associated with DIP US enthesopathy. There was a significant increased prevalence of extensor tendon enthesopathy in fingers with involved nails both in PsO and PsA, although no association was found between nail involvement and extensor tendon enthesopathy at patients' level. These features might support the nail-entheseal pathogenesis theory at DIP level. PMID- 28648659 TI - Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways. AB - Dietary, microbial, and inflammatory factors modulate the gut-brain axis and influence physiological processes ranging from metabolism to cognition. The gut epithelium is a principal site for detecting such agents, but precisely how it communicates with neural elements is poorly understood. Serotonergic enterochromaffin (EC) cells are proposed to fulfill this role by acting as chemosensors, but understanding how these rare and unique cell types transduce chemosensory information to the nervous system has been hampered by their paucity and inaccessibility to single-cell measurements. Here, we circumvent this limitation by exploiting cultured intestinal organoids together with single-cell measurements to elucidate intrinsic biophysical, pharmacological, and genetic properties of EC cells. We show that EC cells express specific chemosensory receptors, are electrically excitable, and modulate serotonin-sensitive primary afferent nerve fibers via synaptic connections, enabling them to detect and transduce environmental, metabolic, and homeostatic information from the gut directly to the nervous system. PMID- 28648660 TI - Friction Mediates Scission of Tubular Membranes Scaffolded by BAR Proteins. AB - Membrane scission is essential for intracellular trafficking. While BAR domain proteins such as endophilin have been reported in dynamin-independent scission of tubular membrane necks, the cutting mechanism has yet to be deciphered. Here, we combine a theoretical model, in vitro, and in vivo experiments revealing how protein scaffolds may cut tubular membranes. We demonstrate that the protein scaffold bound to the underlying tube creates a frictional barrier for lipid diffusion; tube elongation thus builds local membrane tension until the membrane undergoes scission through lysis. We call this mechanism friction-driven scission (FDS). In cells, motors pull tubes, particularly during endocytosis. Through reconstitution, we show that motors not only can pull out and extend protein scaffolded tubes but also can cut them by FDS. FDS is generic, operating even in the absence of amphipathic helices in the BAR domain, and could in principle apply to any high-friction protein and membrane assembly. PMID- 28648662 TI - A Sacrifice-for-Survival Mechanism Protects Root Stem Cell Niche from Chilling Stress. AB - Temperature has a profound influence on plant and animal development, but its effects on stem cell behavior and activity remain poorly understood. Here, we characterize the responses of the Arabidopsis root to chilling (low but above freezing) temperature. Chilling stress at 4 degrees C leads to DNA damage predominantly in root stem cells and their early descendants. However, only newly generated/differentiating columella stem cell daughters (CSCDs) preferentially die in a programmed manner. Inhibition of the DNA damage response in these CSCDs prevents their death but makes the stem cell niche more vulnerable to chilling stress. Mathematical modeling and experimental validation indicate that CSCD death results in the re-establishment of the auxin maximum in the quiescent center (QC) and the maintenance of functional stem cell niche activity under chilling stress. This mechanism improves the root's ability to withstand the accompanying environmental stresses and to resume growth when optimal temperatures are restored. PMID- 28648661 TI - De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. AB - Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation. PMID- 28648664 TI - High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM negative infantile Pompe disease patient. AB - Alglucosidase alfa (rhGAA) has altered the course of an otherwise fatal outcome in classic infantile Pompe disease (IPD), which presents with cardiomyopathy and severe musculoskeletal involvement. However, the response to therapy is determined by several factors including the development of high and sustained antibody titers (HSAT) to rhGAA. Cross-reactive immunologic material (CRIM) negative patients are at the highest risk for development of HSAT. Immune tolerance induction (ITI) with methotrexate, rituximab, and intravenous immunoglobulin (IVIG) has been largely successful in preventing the immune response and in achieving tolerance when done in conjunction with enzyme replacement therapy (ERT) initiation. Reducing antibody titers in cases with an entrenched immune response remains a challenge in the field despite the use of multiple immunomodulatory agents. Success has been shown with addition of bortezomib to the ITI regimen, yet the prolonged course and potential risks with the use of such agents' demands caution. We present here a 7-year-old CRIM negative IPD patient who was not successfully tolerized by an ITI regimen with rituximab, methotrexate, and IVIG due to intolerability to the regimen and recurrent infections. She went on to develop HSAT, with significant clinical decline, loss of all motor abilities, and a fragile medical state, which made it challenging to institute the bortezomib based regimen to reduce HSAT. She had severe developmental delay, respiratory failure with invasive ventilation and tracheostomy, persistent hypotonia, ptosis of eyelids, diffuse severe osteopenia, contractures, and was completely G-tube fed. As a rescue mechanism, we treated her with high dose and high frequency IVIG in an attempt to reduce rhGAA IgG antibody titers (antibody titers; titers). Her titers saw a steady decline on weekly IVIG doses at 1g/kg for 20weeks. Subsequently when the IVIG regimen was altered to 1g/kg every month, rising titers were detected and therefore the regimen was changed to a biweekly regimen. High dose IVIG resulted in an eightfold decrease in antibody titers. Clinically, she showed improvement with partial recovery of previously lost motor abilities, especially hand movements and better head and neck control than before. The regimen was safely tolerated with no hospitalizations. The effectiveness of IVIG as a single agent, in this case with multiple comorbidities and fragile clinical status, was lifesaving and may represent an effective, perhaps lifesaving rescue approach to reduce antibody titers. PMID- 28648666 TI - Editor's Perspectives - July 2017. PMID- 28648663 TI - Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme(r)) in 12 patients with advanced late-onset Pompe disease. AB - BACKGROUND: The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. METHODS: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared. RESULTS: Twelve patients (7 males) were identified. Median age at symptom onset was 24years [IQR=15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24h [IQR=21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5years [IQR=35.75; 66.50]. Median treatment duration was 55months [IQR=39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90min and two increased their assisted walking distance, by 80 and 20m. CONCLUSION: Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities. PMID- 28648665 TI - miR-491 Inhibits Osteosarcoma Lung Metastasis and Chemoresistance by Targeting alphaB-crystallin. AB - Dysregulated microRNAs (miRNAs) play an important role in osteosarcoma (OS) progression. In the present study, we investigate the clinical significance of serum miR-491 level and the potential role of miR-491 in OS lung metastasis and chemoresistance. Clinical data show that the level of miR-491 was decreased in serum from OS patients compared with healthy control subjects, and that a decreased serum miR-491 level is correlated with increased metastasis, poor chemoresponse, and lower survival rate in OS patients. In vitro and in vivo experiments show that overexpression of miR-491 suppresses OS cell lung metastasis, whereas it enhances cisplatin (CDDP)-induced tumor growth inhibition and apoptosis. In contrast, inhibition of miR-491 stimulates OS cell lung metastasis and suppresses CDDP-induced tumor growth inhibition and apoptosis. Furthermore, we demonstrate that miR-491 exerts its role by directly targeting alphaB-crystallin (CRYAB) in OS. Our findings suggest that serum level of miR-491 has potential as a biomarker for predicting OS progression and prognosis of OS patients. Additionally, restoration of miR-491 may be a novel strategy for inhibiting OS lung metastasis and overcoming OS cell resistance to chemotherapy. PMID- 28648667 TI - Simultaneous recordings of intrinsic cardiac nerve activity and skin sympathetic nerve activity from human patients during the postoperative period. AB - BACKGROUND: Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs. OBJECTIVE: The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans. METHODS: Eleven patients (mean age 60 +/- 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia burden. RESULTS: We processed 1365 +/- 973 minutes of recording per patient. Low amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P < .01). A patient with the greatest aICNA developed postoperative atrial fibrillation. CONCLUSION: ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation. PMID- 28648668 TI - Catheter ablation in patients with pleomorphic, idiopathic, premature ventricular complexes. AB - BACKGROUND: Premature ventricular complexes (PVCs) often originate from multiple locations. OBJECTIVE: The goals of this study were to assess characteristics of patients with pleomorphic, idiopathic PVCs and to determine the impact of pleomorphic PVCs on outcomes. METHODS: Records were collected from 153 consecutive patients referred for ablation of PVCs. Patients with structural heart disease (n = 34) or inadequate ambulatory electrocardiographic data (n = 19) were excluded. RESULTS: Among 100 consecutive patients (age 52 +/- 15 years, 53% men, 31% pleomorphic vs 69% monomorphic) referred for ablation of idiopathic PVCs, the success rate was lower in patients with pleomorphic PVCs than in those with monomorphic PVCs (71% vs 90%, P = .017, overall 84%). The presence of pleomorphic PVCs was independently associated with unsuccessful ablation. A cutoff of >=156 nonpredominant PVCs over 24 hours best differentiated successful from unsuccessful ablation procedures (area under the curve 0.64, sensitivity 56%, specificity 74%). Pleomorphic PVCs more often had an epicardial origin than did monomorphic PVCs (29% vs 9%, P = .008). Repeat ablation procedures were required in 20 patients (20%; 6 had pleomorphic PVCs). Of these 20 patients, 16 (80%) had recurrence of the former predominant PVC, 3 patients (15%) had an increase of a nonpredominant PVC, and 1 patient (5%) had a newly emerging PVC focus. CONCLUSION: The presence of pleomorphic PVCs affects ablation outcomes. Successful elimination of the predominant PVC often results in successful ablation, even if not all PVCs are targeted. Although pleomorphic PVCs infrequently require repeat ablation procedures, most recurrences are due to reemergence of the originally targeted predominant PVC morphology. PMID- 28648669 TI - EWOLUTION-The next evolution in appendage closure? PMID- 28648670 TI - The application of atherogenic dyslipidaemia consensus recommendations in the primary care setting. DAT-AP study. AB - BACKGROUND AND AIMS: The "DAT-AP" (from the Spanish, "Dislipemia ATerogenica en Atencion Primaria", for Atherogenic Dyslipidaemia in Primary Care) study objective is to determine to what extent published consensus guidelines for the diagnostic and therapeutic management of AD are used in the primary care setting, and to evaluate the approach of the participating physicians towards the detection, diagnosis, and treatment of AD. METHODS: This is descriptive, cross sectional, multicentre study performed between January and May 2015 in primary care centres throughout Spain. Study data were collected in 2 independent blocks, the first addressing theoretical aspects of AD and the second, practical aspects (clinical cases) RESULTS: The theoretical part is in the process of publication. This manuscript depicts the clinical cases block. Although study participants showed good knowledge of the subject, the high prevalence of this disease requires an additional effort to optimise detection and treatment, with the implementation of appropriate lifestyle interventions and the prescription of the best treatment. PMID- 28648671 TI - Late complications of percutaneous tracheostomy using the balloon dilation technique. AB - OBJECTIVE: The purpose of this study was to determine the late complications in critically ill patients requiring percutaneous tracheostomy (PT) using the balloon dilation technique. DESIGN: A prospective, observational cohort study was carried out. SCOPE: Two medical-surgical intensive care units (ICU). PATIENTS: All mechanically ventilated adult patients consecutively admitted to the ICU with an indication of tracheostomy. INTERVENTIONS: All patients underwent PT according to the Ciaglia Blue Dolphin(r) method, with endoscopic guidance. Survivors were interviewed and evaluated by fiberoptic laryngotracheoscopy and tracheal computed tomography at least 6 months after decannulation. VARIABLES: Intraoperative, postoperative and long-term complications and mortality (in-ICU, in-hospital) were recorded. RESULTS: A total of 114 patients were included. The most frequent perioperative complication was minor bleeding (n=20) and difficult cannula insertion (n=19). Two patients had severe perioperative complications (1.7%) (major bleeding and inability to complete de procedure in one case and false passage and desaturation in the other). All survivors (n=52) were evaluated 211+/ 28 days after decannulation. None of the patients had symptoms. Fiberoptic laryngotracheoscopy and computed tomography showed severe tracheal stenosis (>50%) in 2patients (3.7%), both with a cannulation period of over 100 days. CONCLUSIONS: Percutaneous tracheostomy using the Ciaglia Blue Dolphin(r) technique with an endoscopic guide is a safe procedure. Severe tracheal stenosis is a late complication which although infrequent, must be taken into account due to its lack of clinical expressiveness. Evaluation should be considered in those tracheostomized critical patients who have been cannulated for a long time. PMID- 28648672 TI - Prognostic significance of interventricular septal thickness in patients with AL amyloidosis. AB - The major prognostic determinant of immunoglobulin light chain (AL) amyloidosis is cardiac involvement. However, the role of interventricular septal thickness (IVST), which reflects the extent of cardiac involvement, remains unclear. Therefore, we analyzed 77 patients with newly diagnosed AL amyloidosis and evaluated the prognostic role of IVST. Fifty patients (64.9%) had cardiac involvement and 17 patients (22.1%) showed IVST >15mm. Among all patients, the revised Mayo Clinic Stage III-IV and IVST >15mm were independently associated with inferior overall survival (OS) in a multivariable analysis. IVST >15mm was also adversely prognostic for OS in a subgroup of advanced-stage (revised Mayo Clinic stage III-IV) patients in a multivariable analysis (P<0.001). Furthermore, advanced-stage patients with IVST >15mm did not show survival benefit from treatment with bortezomib-based regimens and/or autologous stem-cell transplantation (ASCT). Our study demonstrated that IVST >15mm is adversely prognostic independent of the revised Mayo Clinic staging system in patients with AL amyloidosis. In addition, the degree of IVST might be used as a useful prognostic indicator that can guide the management of patients with AL amyloidosis especially at an advanced stage. PMID- 28648673 TI - Clinical evaluation of active abdominal lifting and compression CPR in patients with cardiac arrest. AB - BACKGROUND: Chest compression is a standard recommendation during cardiopulmonary resuscitation (CPR). However, chest compression cannot be effectively applied under certain situations, such as chest wall deformity, rib fracture, or hemopneumothorax. An alternative method, abdominal compression, was reported to achieve better resuscitation outcomes in these patients. MATERIALS AND METHODS: A prospective study was performed in adult patients with cardiac arrest and anticipated ineffective chest compression (thoracic trauma, chest deformity, rib fracture, and hemopneumothorax). Active abdominal lifting and compression cardiopulmonary resuscitation was used. Primary outcome was success rate of restoration of spontaneous circulation (ROSC). Secondary outcomes included heart rate (HR), mean arterial pressure (MAP), pulse oximetry saturation (SpO2), arterial blood pH value, arterial oxygen pressure (PaO2), and arterial carbon dioxide tension (PaCO2), which were measured during the periods of pre-CPR, CPR, and 30min post-ROSC. RESULTS: A total of 35 patients were enrolled into the study. Five of them had ROSC (14.3%), which was statistically significantly higher than that (0%) reported in the 2015 Advanced Cardiovascular Life Support manual. HR, MAP, and SpO2 during CPR were also statistically significantly higher during CPR when compared to the period of pre-CPR period (HR 58 versus 0 beats/min, P<0.01; MAP 25 versus 0mm Hg, P<0.01; SpO2 0.68 versus 0.48%, P<0.01). In post-ROSC period, HR was statistically significantly higher than that during pre-CPR period (121 versus 0 best/min, P<0.01). CONCLUSIONS: Active abdominal lifting and compression cardiopulmonary resuscitation could reach better resuscitation outcomes in certain cardiac arrest patients. PMID- 28648674 TI - Hemodynamic changes in patients with influenza A after propacetamol infusion in the emergency department. AB - OBJECTIVES: Recently, there has been an emerging clinical data suggesting that intravenous propacetamol may cause iatrogenic hypotension. The primary objective of this study was to evaluate hemodynamic changes after propacetamol infusion in the emergency department (ED) with the patients of influenza A. Secondary objective was to assess the incidence of propacetamol-induced significant hypotension and to evaluate factors associated with this adverse effect by comparing two groups of patients with or without a significant reduction in blood pressure (BP). METHODS: We retrospectively reviewed the medical records of the patients with laboratory-confirmed influenza A who received intravenous propacetamol for the control of fever in the ED during the 2015-16 influenza season. RESULTS: 101 patients of influenza A were included in this study. Overall, all the vital signs including BP, pulse rate and body temperature recorded after propacetamol administration were lower than the pre-infusion values. A significant reduction in BP was observed in 30 (29.7%) patients and 6 (20%) of them required crystalloid infusion. Interestingly, pre-infusion BPs were higher in the group of propacetamol-induced significant hypotension, yet there was no difference in post-infusion BPs between the groups. DISCUSSION: To our knowledge this is the first study on the effect of intravenous propacetamol in the ED patients with influenza A infection. We hypothesized that the group with a significant reduction in BP could have higher sympathetic tone, consequently showing higher pre-infusion BPs and pulse rate. And there was no difference in post-infusion BPs because baroreflex homeostasis could compensate further decrease in BPs. PMID- 28648675 TI - Segregation of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5 bisphosphate into distinct microdomains on the endosome membrane. AB - Phosphatidylinositol 4-phosphate (PtdIns(4)P) is the immediate precursor of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), which is located on the cytoplasmic leaflet of the plasma membrane and has been reported to possess multiple cellular functions. Although PtdIns(4)P and PtdIns(4,5)P2 have been reported to localize to multiple intracellular compartments and to each function as regulatory molecules, their generation, regulation and functions in most intracellular compartments are not well-defined. To analyze PtdIns(4)P and PtdIns(4,5)P2 distributions, at a nanoscale, we employed an electron microscopy technique that specifically labels PtdIns(4)P and PtdIns(4,5)P2 on the freeze fracture replica of intracellular biological membranes. This method minimizes the possibility of artificial perturbation, because molecules in the membrane are physically immobilized in situ. Using this technique, we found that PtdIns(4)P was localized to the cytoplasmic leaflet of Golgi apparatus and vesicular-shaped structures. The PtdIns(4,5)P2 labeling was observed in the cytoplasmic leaflet of the mitochondrial inner membrane and vesicular-shaped structures. Double labeling of PtdIns(4)P and PtdIns(4,5)P2 with endosome markers illustrated that PtdIns(4)P and PtdIns(4,5)P2 were mainly localized to the late endosome/lysosome and early endosome, respectively. PtdIns(4)P and PtdIns(4,5)P2 were colocalized in some endosomes, with the two phospholipids separated into distinct microdomains on the same endosomes. This is the first report showing, at a nanoscale, segregation of PtdIns(4)P- and PtdIns(4,5)P2-enriched microdomains in the endosome, of likely importance for endosome functionality. PMID- 28648677 TI - Cell type-specific transcriptome profiling in C. elegans using the Translating Ribosome Affinity Purification technique. AB - Organs and specific cell types execute specialized functions in multicellular organisms, in large part through customized gene expression signatures. Thus, profiling the transcriptomes of specific cell and tissue types remains an important tool for understanding how cells become specialized. Methodological approaches to detect gene expression differences have utilized samples from whole animals, dissected tissues, and more recently single cells. Despite these advances, there is still a challenge and a need in most laboratories to implement less invasive yet powerful cell-type specific transcriptome profiling methods. Here, we describe the use of the Translating Ribosome Affinity Purification (TRAP) method for C. elegans to detect cell type-specific gene expression patterns at the level of translating mRNAs. In TRAP, a ribosomal protein is fused to a tag (GFP) and is expressed under cell type-specific promoters to mark genetically defined cell types in vivo. Affinity purification of lysates of animals expressing the tag enriches for ribosome-associated mRNAs of the targeted tissue. The purified mRNAs are used for making cDNA libraries subjected to high throughput sequencing to obtain genome-wide profiles of transcripts from the targeted cell type. The ease of exposing C. elegans to diverse stimuli, coupled with available cell type specific promoters, makes TRAP a useful approach to enable the discovery of molecular components in response to external or genetic perturbations. PMID- 28648676 TI - Regulation of GLUT4 activity in myotubes by 3-O-methyl-d-glucose. AB - The rate of glucose influx to skeletal muscles is determined primarily by the number of functional units of glucose transporter-4 (GLUT4) in the myotube plasma membrane. The abundance of GLUT4 in the plasma membrane is tightly regulated by insulin or contractile activity, which employ distinct pathways to translocate GLUT4-rich vesicles from intracellular compartments. Various studies have indicated that GLUT4 intrinsic activity is also regulated by conformational changes and/or interactions with membrane components and intracellular proteins in the vicinity of the plasma membrane. Here we show that the non-metabolizable glucose analog 3-O-methyl-d-glucose (MeGlc) augmented the rate of hexose transport into myotubes by increasing GLUT4 intrinsic activity without altering the content of the transporter in the plasma membrane. This effect was not a consequence of ATP depletion or hyperosmolar stress and did not involve Akt/PKB or AMPK signal transduction pathways. MeGlc reduced the inhibitory potency (increased Ki) of indinavir, a selective inhibitor of GLUT4, in a dose-dependent manner. Kinetic analyses indicate that MeGlc induced changes in GLUT4 or GLUT4 complexes within the plasma membrane, which enhanced the hexose transport activity and reduced the potency of indinavir inhibition. Finally, we present a simple kinetic analysis for screening and discovering low molecular weight compounds that augment GLUT4 activity. PMID- 28648678 TI - Single plane illumination microscopy as a tool for studying nucleome dynamics. AB - Single plane illumination microscopy (SPIM) is a new optical method that has become extremely important in recent years. It is based on the formation of a "light slice" in the specimen in which fluorescently tagged molecules are observed. The spatial resolution is close to that of confocal optics, but without the disadvantages inherent to scanning or high laser irradiation doses. A recent development is light sheet fluctuation microscopy, which exploits the dynamic information contained in the fluorescence intensity fluctuations of each image pixel. Here we review the principles of this method and show some recent applications to the dynamics of transcription factors and chromatin. We show that the dimerization of Fos and Jun proteins is directly linked to their binding to DNA; that nuclear receptor activation changes their intranuclear dynamics; and that the viscoelastic behavior of interphase chromatin strongly depends on the presence of lamin A. PMID- 28648679 TI - Structure determination of group II introns. AB - Group II introns are self-splicing catalytic RNAs that are able to excise themselves from pre-mRNAs using a mechanism identical to that utilized by the spliceosome. Both structural and phylogenetic data support the hypothesis that group II introns and the spliceosome share a common ancestor. Structures of group II introns have given insight into the active site required for the catalysis of RNA splicing. This review outlines crucial aspects of the structure determination of group II introns such as sample preparation and data processing. Given that group II introns are large RNAs that must be synthesized through in vitro transcription, there are special considerations that must be taken into account in terms of purification and crystallization, as compared to the isolation of large intact ribonucleoprotein complexes such as the ribosome. We specifically focus on the methodology used to determine the structure of the eukaryotic group II intron lariat from the brown algae Pylaiella littoralis. The techniques described in this review can also be applied for the structure determination of other large RNAs. PMID- 28648680 TI - Reversibly constraining spliceosome-substrate complexes by engineering disulfide crosslinks. AB - The spliceosome is a highly dynamic mega-Dalton enzyme, formed in part by assembly of U snRNPs onto its pre-mRNA substrate transcripts. Early steps in spliceosome assembly are challenging to study biochemically and structurally due to compositional and conformational dynamics. We detail an approach to covalently and reversibly constrain or trap non-covalent pre-mRNA/protein spliceosome complexes. This approach involves engineering a single disulfide bond between a thiol-bearing cysteine sidechain and a proximal backbone phosphate of the pre mRNA, site-specifically modified with an N-thioalkyl moiety. When distance and angle between reactants is optimal, the sidechain will react with the single N thioalkyl to form a crosslink upon oxidation. We provide protocols detailing how this has been applied successfully to trap an 11-subunit RNA-protein assembly, the human U1 snRNP, in complex with a pre-mRNA. PMID- 28648681 TI - Traumatic Brain Injury Severity, Comorbidity, Social Support, Family Functioning, and Community Reintegration Among Veterans of the Afghanistan and Iraq Wars. AB - OBJECTIVE: To examine the association between traumatic brain injury (TBI) severity; social, family, and community reintegration outcomes; and return to work status among post-9/11 veterans in Department of Veterans Affairs (VA) care. DESIGN: Retrospective observational cohort study. SETTING: Mail/online survey fielded to a national sample of veterans. PARTICIPANTS: Sample of post-9/11 veterans with at least 3 years of VA care stratified according to TBI severity and comorbidities who completed and returned surveys (N=2023). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Deployment Risk and Resilience Inventory-2 family functioning and social support subscales; Military to Civilian Questionnaire; and employment status. RESULTS: Bivariate analyses revealed that veterans with every classification of TBI severity reported significantly more difficulty on social, family, and community reintegration outcomes than those with no TBI. In the fully adjusted model, veterans with unclassified and moderate/severe TBI reported significantly more difficulty with community reintegration and were less likely to be employed relative to those with no TBI; those with unclassified TBI also reported significantly more difficulty with family functioning. Veterans with mild TBI also reported significantly more difficulty with community reintegration. CONCLUSIONS: This study provides insight into long-term outcomes associated with TBI in post-9/11 veterans and suggests that exposure to TBI has a negative effect on social and family functioning, community reintegration, and return to work even after controlling for comorbidity, deployment experiences, and sociodemographic characteristics. Additional research is required to explicate what appears to be complex interactions among TBI severity, psychosocial well-being, combat exposures, and socioeconomic resources in this population. PMID- 28648682 TI - Qualitative Investigation of Exercise Perceptions and Experiences in People With Multiple Sclerosis Before, During, and After Participation in a Personally Tailored Exercise Program. AB - OBJECTIVE: To undertake a qualitative investigation of exercise perceptions and experiences in people with multiple sclerosis (PwMS) before, during, and after participation in a personally tailored program designed to promote long-term maintenance of self-directed exercise. DESIGN: Focus groups and semistructured telephone interviews. SETTING: University exercise science department close to the recruiting hospital. PARTICIPANTS: PwMS (N=33; mean age +/- SD, 47.6+/-7.9y). INTERVENTIONS: Participants were recruited after participation in a randomized controlled exercise trial; all had been allocated to a 12-week exercise program comprising supervised and self-directed exercise sessions. MAIN OUTCOME MEASURES: Exercise perceptions and experiences before, during, and after participation in the program. RESULTS: Four themes emerged from the analysis: (1) the transition to inactivity; (2) lack of knowledge and confidence; (3) positive exercise experiences; and (4) perspectives on exercise adherence. CONCLUSIONS: Lack of confidence and exercise knowledge, coupled with negative perceptions about physical capabilities after an MS diagnosis, are clear barriers to exercise participation in PwMS. These issues are not being adequately addressed as part of the health care pathway or in community settings. Perceptions of improved posture, ability to overcome everyday difficulties, acute mood enhancements during and after exercise, and increased opportunities for social interaction were among the reported benefits of exercise participation. Despite the provision of a personally tailored exercise plan and use of cognitive behavioral strategies, self-directed exercise continued to present challenges to PwMS, and the importance of seeking cost-effective ways to maintain motivational support was implicit in participant responses. PMID- 28648683 TI - Reliability and validity analyses of the North Star Ambulatory Assessment in Brazilian Portuguese. AB - The North Star Ambulatory Assessment measures motor performance in ambulatory boys with Duchenne muscular dystrophy, a hereditary and degenerative muscle disorder. To use the North Star Ambulatory Assessment in Brazilian boys, we performed the cross-cultural adaptation to the Portuguese language spoken in Brazil and evaluated the reliability and validity of the instrument. Cross cultural adaptation included: independent translations, synthesis, committee review, pre-testing in 12 boys, back-translation and comparison with the original instrument. Thirty-five boys with Duchenne muscular dystrophy and 38 healthy age matched controls were recruited for further analyses. Reliability was assessed by internal consistency and reproducibility. Validity studies included face, content, construct and known-groups analyses. Cross-cultural adaptation resulted in an adequate instrument. Reliability studies demonstrated high internal consistency (Cronbach's alpha = 0.935) and adequate intra and inter-rater reproducibility (intraclass correlation coefficient = 0.988 and 0.962). Validation analyses indicated satisfactory content, face and convergent construct validities, with positive correlations with the Motor Function Measure total score (r = 0.863) and the 6-minute walk test (r = 0.433). The known group validity was demonstrated by higher scores in younger boys with Duchenne muscular dystrophy (p = 0.005). North Star Ambulatory Assessment in Brazilian Portuguese is a reliable and valid instrument to measure functional capacity in boys with Duchenne muscular dystrophy. PMID- 28648684 TI - HBK-15 protects mice from stress-induced behavioral disturbances and changes in corticosterone, BDNF, and NGF levels. AB - Unlike majority of current antidepressants, HBK-15-a 5-HT1A and 5-HT7 receptor antagonist - showed memory-enhancing properties. In this study, we aimed to further characterize pharmacological profile of HBK-15 and investigate its antidepressant- and anxiolytic-like activity in the mouse model of unpredictable chronic mild stress. We used sucrose consumption test, forced swim test and elevated plus maze test as behavioral endpoints. We also evaluated the influence of HBK-15 on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus and prefrontal cortex, as well as body weight, relative adrenal glands weight and plasma corticosterone level in the stressed mice. We utilized LC/MS/MS method to determine HBK-15 concentration in plasma and brain. We evaluated pharmacokinetic profile and distribution to brain of HBK-15 (2.5mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration in CD-1 mice. HBK-15 (2.5mg/kg but not 1.25mg/kg) and fluoxetine (10mg/kg) protected stressed mice from anhedonic-, depressive- and anxiety-like behaviors, decreases in the BDNF and NGF levels in the hippocampus and prefrontal cortex, increases in plasma corticosterone levels and relative adrenal glands weight. The pharmacokinetic analysis demonstrated a rapid absorption of HBK-15 after i.p. administration (tmax=5min), a short half-life (t0.5=74min), large volume of distribution (Vss=3.7L/kg) and bioavailability after i.p. administration equal 25%. HBK-15 administered i.v. and i.p. significantly penetrated brain. Our results suggest that the blockade of serotonergic 5-HT1A and 5-HT7 receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction. PMID- 28648686 TI - Circulating microRNAs as potential biomarkers of HBV infection persistence. AB - OBJECTIVES: To investigate different microRNA (miRNA) expression profile in patients of hepatitis B virus (HBV) infection compared with virus spontaneous clearance ones, and try to find new biomarker for diagnosis and treatment assessment. METHODS: miRNA expression profiling was analyzed in patients with HBV infection and patients with virus spontaneous clearance by Affymetrix Gene Chip miRNA 4.0 Arrays. The differently expressed miRNAs, as verified by RT-PCR, were analyzed and compared with each other in the two groups of patients. RESULTS: Significant difference was found in the expression of miR-29b, miR-34, miR-4485, miR-3180, miR-125, miR-330-3p, miR-1468 in spontaneous clearance group and CHB group. miR-29b, miR-34, miR-4485 was significantly increased in CHB group, while miR-125, miR-330-3p, miR-1468, miR-3180 was significantly decreased. Correlation analysis indicate only miR-29b was positive correlation with HBsAg. CONCLUSIONS: These results indicated above miRNAs may be associated with HBV infection persistence, and provided us new ideas for finding potential biomarkers. PMID- 28648685 TI - Proteomic profiling of Pachyonychia congenita plantar callus. AB - : Callus samples from the ball and the arch of the foot, collected on tape circles, were compared by shotgun proteomic profiling. Pachyonychia congenita subjects were sampled who exhibited a mutation in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, and the proteins were digested and analyzed by tandem mass spectrometry. In comparison with samples from unaffected control subjects, those from subjects with KRT6A or KRT16 mutations displayed the most differences in profile from normal, while those from subjects with KRT6C or KRT17 mutations showed few differences from normal. The profiles from subjects with KRT6B mutations were intermediate in protein profile differences. Degree of departure from the normal profile could be estimated by expression of numerous proteins in callus from the ball of the foot that were consistently different. By contrast, the protein profile from the arch of the foot was hardly affected. The results provide a foundation for noninvasive monitoring of the efficacy of treatments with quantitative assessment of departure from the normal phenotype. SIGNIFICANCE: Pachyonychia congenita is an orphan disease in which the connection between the basic defect (keratin mutation) and debilitating symptoms (severe plantar pain) is poorly understood. Present work addresses the degree to which the protein profile is altered in the epidermis where the severe pain originates. The results indicate that the mutated keratins differ greatly in the degree to which they elicit perturbations in protein profile. In those cases with markedly altered protein levels, monitoring the callus profile may provide an objective measure of treatment efficacy. PMID- 28648688 TI - Association of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with lung adenocarcinoma: A radiologist's perspective. PMID- 28648687 TI - NRAMP1 D543N and INT4 polymorphisms in susceptibility to pulmonary tuberculosis: A meta-analysis. AB - The association of natural resistance associated macrophage protein 1 (NRAMP1) polymorphisms (D543N, INT4) with pulmonary tuberculosis (PTB) risk have been widely reported. However, the findings of previous studies were inconsistent. To clarify the role of these polymorphisms in PTB, we performed a meta-analysis of all available and relevant published studies. Based on comprehensive searches of the PubMed, Medline, Embase, Web of Science, Elsevier Science Direct and Cochrane Library database, we identified outcome data from all articles estimating the association between NRAMP1 polymorphisms and PTB risk. For D543NA/G polymorphism, no associations were found in all genetic models. For INT4C/G polymorphism, significant increased PTB risk was observed in recessive model (CC vs. GC+GG: P=0.025, OR=1.35, 95% CI=1.04-1.75). In the subgroup analysis by ethnicity, significantly increased risk were observed for D543NA/G polymorphism in Americans (GA vs. GG: P=0.03, OR=1.31, 95% CI=1.03-1.67; AA+AG vs. GG: P=0.032, OR=1.29, 95% CI=1.02-1.63). Moreover, the INT4C/G polymorphism was also associated with increased risk of TB for Africans in allele model (A vs. G: P=0.012, OR=1.41, 95% CI=1.08-1.85), heterozygous model (GA vs. GG: P=0.004, OR=1.53, 95% CI=1.14-2.04) and dominant model (AA+AG vs. GG: P=0.007, OR=1.49, 95% CI=1.12-1.98). This meta analysis provides evidences that INT4C/G was associated with increased susceptibility to pulmonary tuberculosis in overall population in recessive model. D543NA/G polymorphism was associated with PTB increased risk in Americans, while INT4C/G polymorphism in Africans. Further well-designed, large scale studies are required to confirm this conclusion. PMID- 28648689 TI - Gaining Thermodynamic Insight From Distinct Glass Formation Kinetics of Structurally Similar Organic Compounds. AB - Thermodynamic and kinetic aspects of crystallization of 12 structurally similar organic compounds were investigated from the supercooled liquid state by calorimetric and rheologic measurements. Based on their crystallization behaviors, these compounds were divided into 3 categories: stable glass formers, poor glass formers, and good glass formers with poor stability on reheating. Correlation was sought between thermodynamic quantities and glass formation based on nucleation and crystal growth theories. Larger values of enthalpy of fusion and melting point were found to correlate with poor glass-forming ability. Conversely, lower entropy of fusion was found to correlate with glass formation. Examination of kinetic aspects of glass formation revealed 2 important facets of good glass formers, that is, rapid increase in viscosity on supercooling and high melting point viscosity compared with non-glass formers. A broader relationship was sought between entropy of fusion and glass formation by including several glass formers from literature. Our analysis indicated that good glass formers tend to have an entropy of fusion closer to 0.3 J cm-3 K-1. The structural similarity of the compounds in this study provides insights regarding the nature of intermolecular interactions responsible for the observed effect on entropy of fusion, viscosity, and crystallization kinetics. PMID- 28648690 TI - Tubulointerstitial nephritis and uveitis syndrome (TINU). Treatment with immunosuppressive therapy. AB - CASE REPORT: Two cases of tubulointerstitial nephritis and uveitis are presented. Immunosuppressive therapy was required to control the uveitis. Contrary to that usually described, uveitis became chronic, which made immunosuppressive therapy necessary. Nephritis was successfully treated with steroids. DISCUSSION: Tubulointerstitial nephritis and uveitis syndrome is an under-diagnosed disorder and requires clinical suspicion due to there being no specific laboratory study available. Recurrences and relapses of ocular inflammation are common. Immunosuppressive therapy is not often needed. PMID- 28648692 TI - Incorrect analysis of cesarean skin incision type and wound complications in obese women? PMID- 28648691 TI - Cesarean in the second stage: a possible risk factor for subsequent spontaneous preterm birth. PMID- 28648693 TI - Reply. PMID- 28648694 TI - Removal notice to The relationship between primary cesarean delivery skin incision type and wound complications in women with morbid obesity: Am J Obstet Gynecol 2014;210:319.e1-4. AB - This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been removed at the request of the Editors-in-Chief and Authors. The original publication reported that univariate analysis showed that a vertical skin incision in obese women undergoing Cesarean delivery was associated with a higher odds ratio for wound complications than a transverse skin incision. Multivariable analyses showed a reversal of the association (i.e. the odds of wound complications were lower in women with a vertical skin incision). However, there was an error in the way the variable was entered in the logistic analysis. Re-analysis with the correct coding of the variable indicates that a transverse skin incision is associated with decreased odds of wound complication compared to a vertical skin incision. PMID- 28648695 TI - The usefulness of advanced lipid and oxidative stress testing for diagnosis and management of low HDL-cholesterol phenotype: A case report. AB - OBJECTIVE: Plasma high-density lipoprotein cholesterol (HDL-C) level is a strong inverse predictor of cardiovascular disease (CVD) development. Tangier disease, a consequence of mutations in the ATP binding cassette transporter 1 (ABCA1) gene, is associated with very low HDL-C levels. Still, the relationship between Tangier disease and CVD is not always evident. The study investigates usefulness of lipoprotein subfractions, oxidative stress and paraoxonase 1 (PON1) status assessment for evaluation and management of patient with low HDL-C phenotype. PATIENT AND METHODS: A 12-year-old boy was hospitalised due to hypertension. Laboratory evaluation revealed low HDL-C level, and subsequent molecular diagnostic confirmed Tangier disease. Lipoprotein subfractions were assessed by gradient-gel electrophoresis. Oxidative stress status was estimated by measuring total antioxidative status, total oxidative status, prooxidative-antioxidative balance, malondialdehyde and advanced oxidation protein products levels. Activity of paraoxonase 1 in serum and its distribution within HDL subclasses was also determined (ten healthy boys aged 13.1+/-3.4years served as the reference group). RESULTS: Analysis of oxidative stress status biomarkers revealed a state of prolonged prooxidants activity. In turn, serum PON1 activity was substantially reduced. The majority of PON1 activity was present on HDL 2 particles. CONCLUSION: Impaired antioxidative potential of HDL may point toward hidden cardiovascular risk in isolated low HDL-phenotype. PMID- 28648696 TI - Integrating behaviour into the pace-of-life continuum: Divergent levels of activity and information gathering in fast- and slow-living snakes. AB - An animal's life history, physiology, and behaviour can be shaped by selection in a manner that favours strong associations among these aspects of an integrated phenotype. Recent work combining animal personality and life-history theory proposes that animals with faster life-history strategies (i.e., fast growth, high annual reproductive rate, short lifespan) should exhibit higher general activity levels relative to those with slower life-history strategies, but empirical tests of within-species variation in these traits are lacking. In garter snakes from ecotypes which are known to differ in ecology, life-history strategy, and physiology, we tested for differences in tongue-flick rate as a measure of information gathering and movement patterns as a measure of general activity. Tongue flicks and movement were strongly positively correlated and both behaviours were repeatable across trials. Snakes from the fast-living ecotype were more active and showed evidence of habituation. The slow-living ecotype maintained low levels of activity throughout the trials. We propose that environmental factors, such as high predation, experienced by the fast-living ecotype select for both increased information-gathering and activity levels to facilitate efficient responses to repeated challenges. Thus, we offer evidence that behaviour is an important component of co-evolved suites of traits forming a general pace-of-life continuum in this system. PMID- 28648697 TI - WITHDRAWN: Re: Managing a Pessary Business. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at (http://www.elsevier.com/locate/withdrawalpolicy). PMID- 28648698 TI - Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. AB - AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. METHODS: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. RESULTS: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS >= 6 months. CONCLUSION: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting >=3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow up, factors predicting clinical outcomes with the combination remained consistent with previous analyses. PMID- 28648700 TI - Five years of EMA-approved systemic cancer therapies for solid tumours-a comparison of two thresholds for meaningful clinical benefit. AB - OBJECTIVE: Several societies have proposed frameworks to evaluate the benefit of oncology drugs; one prominent tool is the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Our objectives were to investigate the extent of European Medicines Agency (EMA)-approved cancer drugs that meet the threshold for 'meaningful clinical benefit' (MCB), defined by the framework, and determine the change in the distribution of grades when an adapted version that addresses the scale's limitations is applied. METHODS: We identified cancer drugs approved by the EMA (2011-2016). We previously proposed adaptations to the ESMO-MCBS addressing its main limitations, including the use of the lower limit of the 95% confidence interval in assessing the hazard ratio. To assess the MCB, both the original and adapted ESMO-MCBS were applied to the respective approval studies. RESULTS: In total, we identified 70 approval studies for 38 solid cancer drugs. 21% of therapies met the MCB threshold by the original ESMO MCBS criteria. In contrast, only 11% of therapies met the threshold for MCB when the adapted ESMO-MCBS was applied. Thus 89% and 79% of therapies did not meet the MCB threshold in the adapted and original ESMO-MCBS, respectively. CONCLUSIONS: In most of the cancer drugs, the MCB threshold is not met at the time of approval when measured using both ESMO-MCBS scales. Since approval status does not translate into a MCB, stakeholders and decision makers should focus on the benefit/risk ratio of anticancer drugs to assure an appropriate allocation of resources in health care systems. PMID- 28648699 TI - Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. AB - BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression. RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis. PMID- 28648701 TI - Universal Genomic Testing: The next step in oncological decision-making or a dead end street? AB - The concept of 'personalised medicine' aims at allocating patients to different treatment options based on individual characteristics to optimise treatment benefit and side effects. In oncology, personalised treatments coupled to biomarkers have led to the approval of targeted agents with high anti-tumour activity. However, these therapies are often limited to narrow, molecularly defined subsets of patients with a specific morphomolecular tumour profile. Recently, it became obvious that the same molecular alteration might drive oncogenesis in many different tumours, and it might be beneficial to target the alteration in a histology informed but entity-overarching way. Consequently, Universal Genomic Testing (UGT) of tumours encompassing panel sequencing to whole exome and transcriptome sequencing is propagated to revolutionise oncology. This article will describe the developments leading to identification and application of potential biomarkers using UGT. On this basis, it will review the clinical evidence of this approach and summarise recommendations for the ongoing evaluation of UGT as the next step in oncological decision-making. PMID- 28648702 TI - A Dual-Pivot Pattern Simulating Native Knee Kinematics Optimizes Functional Outcomes After Total Knee Arthroplasty. AB - BACKGROUND: Few studies on kinematics correlate patterns to functional outcomes after total knee arthroplasty (TKA). The purpose of this study was to determine if lateral pivot motion in early flexion and medial pivot in high flexion, simulating native knee kinematics, produces superior clinical outcomes. A second objective was to determine if specific kinematic patterns produce superior outcomes. METHODS: One hundred twenty consecutive TKAs were performed using sensor trials to record intraoperative knee kinematics. Lateral and medial pivot pattern designations were based on the center of rotation within 3 flexion zones: 0 degrees -45 degrees (early), 45 degrees -90 degrees , and 90 degrees to full flexion (late). Knee Society Scores, pain scores, and patient satisfaction were analyzed in relation to kinematic patterns. RESULTS: Knee Society function scores were higher in TKAs with early lateral pivot/late medial pivot intraoperative kinematics compared to all other kinematic patterns (P = .018), and there was a greater decrease in the proportion who reported that their knee never feels normal (P = .011). Early lateral/late medial pivot had greater function scores at 1-year (P < .001) and improvement from preoperative baseline (P = .008) compared to those with the least ideal pattern. All patients with the most ideal pattern compared to none of the least ideal pattern reported they were very satisfied (P = .003). CONCLUSION: Patients with an intraoperative early lateral pivot pattern followed by medial pivot motion in later flexion, reported higher functional outcome scores along with higher overall patient satisfaction. Replicating the dual-pivot kinematic pattern observed in native knees may improve function and satisfaction after TKA. PMID- 28648703 TI - Osteoclasts in Periprosthetic Osteolysis: The Charnley Arthroplasty Revisited. AB - BACKGROUND: Periprosthetic osteolysis by polyethylene wear debris-triggered osteoclasts is viewed as the main pathophysiological pathway in aseptic loosening in total hip arthroplasty. The present aim was to study osteoclast occurrence in osteolytic lesions in early and late revisions of the Charnley low-friction torque arthroplasty (CLFA). METHODS: Biopsies of the soft interface membrane and the adjacent bone were taken from osteolytic lesions during revision of 16 loose CLFA, early (2-6 years) or late (>10 years) after primary surgery. By light microscopy (LM), cell-dense regions with signs of osteoclast-mediated bone resorption were selected for transmission electron microscopy. Three additional patients were studied in LM for osteoclast markers (tartrate-resistant acid phosphatase and Cathepsin K). RESULTS: LM disclosed a low-grade chronic inflammation and birefringent particles in most sections. Multiple conglomerates of tartrate-resistant acid phosphatase positive and Cathepsin K positive mononuclear and multinucleated cells were found deep in the fibrous interface membrane. Transmission electron microscopy showed traces of polyethylene-like particles in 67%-100% of the cells. Osteoclast-like cells exhibiting resorptive activity were few (mean, 0.7%; standard deviation, 0.2%), and multinucleated cells, possibly osteoclast precursor cells, located immediately on the bone were also scarce (mean, 2.7%; standard deviation, 5.3%). Multinucleated (odds ratio, 3.0; 95% confidence interval, 1.7-5.5) and macrophage-like cells (odds ratio, 3.6; 95% confidence interval, 2.2-5.6) were typically located deeper in the inflammatory interface membrane with a pathologic appearance with distension and abundance of phagocytic vacuoles. There were no systematic differences in cell populations between early or late revisions. CONCLUSION: Despite probable ongoing osteoclastogenesis in the osteolytic lesions, there were few sites of osteoclast mediated bone resorption. These findings attach a contributing biological explanation to the longevity of the CLFA. PMID- 28648704 TI - Total Knee Arthroplasty Using Bicruciate-Stabilized or Posterior-Stabilized Knee Implants Provided Comparable Outcomes at 2 Years: A Prospective, Multicenter, Randomized, Controlled, Clinical Trial of Patient Outcomes. AB - BACKGROUND: The bicruciate-stabilized (BCS) knee arthroplasty was developed to replicate normal knee kinematics. We examined the hypothesis that patients with osteoarthritis requiring total knee arthroplasty (TKA) will have better functional outcome and satisfaction with the BCS implant compared with an established posterior cruciate-stabilized implant. METHODS: This multicenter, randomized, controlled trial compared the clinical outcomes of a BCS implant against an established posterior cruciate-stabilized implant with 2-year follow up. Of the patients awaiting primary knee arthroplasty for osteoarthritis, 228 were randomized to receive either a posterior-stabilized or BCS implant. Primary outcomes were knee flexion and Oxford Knee Score. Secondary outcomes were rate of complications and adverse events (AEs). Tertiary outcomes included Knee Society Score, University of California, Los Angeles, activity score, Patella scores, EQ 5D, 6-minute walk time, and patient satisfaction. RESULTS: Complete data were recorded for 98 posterior-stabilized implants and 97 BCS implants. Twelve patients had bilateral knee implants. There was no difference between the groups for any of the measures at either 1 or 2 years. At 2 years, knee flexion was 119 +/- 0.16 and 120 +/- 1.21 degrees for the posterior-stabilized and BCS implants, respectively, (mean, standard error, P = .538) and Oxford Knee Scores were 40.4 +/- 0.69 and 40.0 +/- 0.67 (P = .828), respectively. There were similar device related AEs and revisions in each group (AEs 18 vs 22; P = .732; revisions 3 vs 4; P = .618). CONCLUSION: There was no evidence of clinical superiority of one implant over the other at 2 years. PMID- 28648706 TI - Total Hip Intraoperative Femur Fracture: Do the Design Enhancements of a Second Generation Tapered-Wedge Stem Reduce the Incidence? AB - BACKGROUND: Intraoperative femur fracture (IFF) is a well-known complication in primary uncemented total hip arthroplasty (THA). Variations in implant instrumentation design and operative technique may influence the risk of IFF. This study investigates IFF between a standard uncemented tapered-wedge femoral stem and its second-generation successor with the following design changes: size specific medial curvature, proportional incremental stem growth, modest reduction in stem length, and distal lateral relief. METHODS: A single experienced surgeon's patient database was retrospectively queried for IFF occurring during primary uncemented THA using a standard tapered-wedge femoral stem system or a second-generation stem. All procedures were performed using soft tissue preserving anatomic capsule repair and posterior approach. The primary outcome measure was IFF. A z-test of proportions was performed to determine significant difference between the 2 stems with respect to IFF. Patient demographics, Dorr classification, and implant characteristics were also examined. RESULTS: Forty one of 1510 patients (2.72%) who received a standard tapered-wedge femoral stem sustained an IFF, whereas 5 of 800 patients (0.63%) using the second-generation stem incurred an IFF. No other significant associations were found. CONCLUSION: A standard tapered-wedge femoral stem instrumentation system resulted in greater than 4 times higher incidence of IFF than its second-generation successor used for primary uncemented THA. Identifying risk factors for IFF is necessary to facilitate implant system improvements and thus maximize patient outcomes. PMID- 28648705 TI - An Aprotinin Containing Fibrin Sealant Does Not Reduce Blood Loss in Total Hip Arthroplasty. AB - BACKGROUND: Fibrin sealants are topical agents used to reduce perioperative blood loss; however, their efficacy in total hip arthroplasty (THA) remains uncertain. The purpose of this study was to determine if a fibrin sealant containing aprotinin as an antifibrinolytic agent, TISSEEL (Baxter, Deerfield, IL), reduces postoperative blood loss and transfusion during THA when compared with intravenous (IV) tranexamic acid (TXA) and control groups. METHODS: Three retrospective uniform cohorts of primary THA procedures were identified, from a prospectively maintained database: 1 group who received TISSEEL, 1 group who received 1 g IV TXA, and 1 group who received neither (control). There were 80 patients in each group. Outcome measures included the lowest measured hemoglobin during postoperative hospitalization, greatest decrease in hemoglobin from preoperative to postoperative values, and blood transfusion rates. RESULTS: The minimum postoperative hemoglobin level was significantly lower for TISSEEL patients compared with that of IV TXA patients (P = .021) and no different when compared with that of control patients (P = .134). Patients receiving fibrin sealant had a greater hemoglobin level decrease compared with that of IV TXA (P = .029) and control (P = .036). Postoperative transfusion rates were no different for the group receiving TISSEEL compared with those of control (P = .375) and were statistically greater when compared with those of IV TXA (P = .002). CONCLUSION: TISSEEL fibrin sealant does not reduce postoperative blood loss or transfusions; however, IV TXA reduced postoperative transfusions compared with TISSEEL and control. Therefore, TXA is recommended to reduce perioperative blood loss, while, utilization of a fibrin sealant requires further refinements before being adopted for routine use in THA. PMID- 28648707 TI - Location of the Common Peroneal Nerve in Valgus Knees-Is the Reported Safe Zone for Well-Aligned Knees Applicable? AB - BACKGROUND: Lateral soft-tissue release can jeopardize the common peroneal nerve (CPN) in total knee arthroplasty for valgus knees. Previous studies reporting safe zones to protect the CPN were based on well-aligned knees. We conducted this study to compare the localization of the CPN in well-aligned knees and in valgus knees. METHODS: We conducted a consecutive 3-dimensional radiographic study on magnetic resonance images of 58 well-aligned knees and 39 valgus knees. We measured the distance between the CPN and the tibia, as well as the mediolateral, anteroposterior, and angular location of the CPN. We compared the results between well-aligned knees and valgus knees. RESULTS: We found that there is an increased distance between the CPN and the tibia at the level of the tibial cut, but not at the joint line in valgus knees. It is safer to release the posterolateral capsule at the tibial side than at the level above this. The angular location and the mediolateral or anteroposterior location of the CPN in valgus knees are similar to those of well-aligned knees. CONCLUSION: The location of the CPN in valgus knees is similar to that in well-aligned knees. The previously reported safe zone in well-aligned knees is applicable in valgus knees to protect the CPN. PMID- 28648708 TI - Letter to the Editor on "Randomized Prospective Trial Comparing the Use of Intravenous Versus Oral Acetaminophen in Total Joint Arthroplasty". PMID- 28648709 TI - Optimizing Mechanical Alignment With Modular Stems in Revision TKA. AB - BACKGROUND: Although mechanical alignment is critical for optimal function and long-term implant durability, the role of modular stems in achieving ideal alignment is unclear. METHODS: We identified 319 revision total knee arthroplasty from 2003-2013, for which stem length, stem diameter, and stem fixation method were recorded prospectively. Three-dimensional canal-filling ratio, the product of canal-filling ratio at the stem tip in both the anteroposterior and lateral planes, and alignment were measured radiographically. RESULTS: Ideal alignment of the femur was considered to be 95 degrees in the anteroposterior (AP) plane and from 1 degrees of extension to 4 degrees of flexion in the lateral plane, and ideal tibial alignment was considered to be 90 degrees in the AP plane. Even after accounting for difference in stem size and canal-fill, ideal AP alignment was more reliably achieved with press-fit stems. CONCLUSION: Furthermore, increased engagement of the diaphysis and its anatomical axis with canal-filling stems facilitates accurate alignment. PMID- 28648710 TI - Preoperative Interventions and Charges in the 2-Year Period Before Unicompartmental Knee Arthroplasty: What Happens Before Surgery. AB - BACKGROUND: This study investigated preoperative interventions and their costs in the 2-year period before a patient undergoing a unicompartmental knee arthroplasty (UKA). METHODS: A retrospective cohort analysis of patients undergoing UKA between 2009 and 2011 was conducted using the PearlDiver Patient Record Database to track inpatient and outpatient billing records. RESULTS: One thousand eight hundred forty-one patients from Medicare and 4704 patients from United Healthcare underwent UKA between 2009 and 2011. In the 2 years before UKA, the per patient average charge was $3919.96 for Medicare patients and $5219.14 for United Healthcare patients, with 21.7% of Medicare-associated charges and 28.2% of United Healthcare-associated charges occurring within 3 months of surgery. In the 2-year period before surgery, 65.5% of Medicare patients and 53.6% of United Healthcare patients received an intra-articular injection, with 29.1% (Medicare) and 46.0% (United Healthcare) of these injections occurring within 3 months of surgery. In addition, 15.1% of Medicare patients and 20.7% of United Healthcare patients underwent an arthroscopy, with between 32.4% and 43.8% of these occurring in the final 6 months before UKA. CONCLUSION: Preoperative interventions (ie, imaging, procedures, physical therapy, and injections) occur at a high frequency in close proximity to UKA resulting in substantial costs. The development of algorithms to guide management of these patients is critical in reducing costs before UKA. PMID- 28648711 TI - Patient-Reported Outcomes Can Be Used to Identify Patients at Risk for Total Knee Arthroplasty Revision and Potentially Individualize Postsurgery Follow-Up. AB - BACKGROUND: Patient-reported outcomes are increasingly used as complementary measures to clinical outcomes in total knee arthroplasty (TKA). However, their prognostic importance has yet to be established. We aimed to determine whether the long-term revision risk in TKA relates to pain and Knee Society Score (KSS) measures at baseline, 1, and 2 years. METHODS: This was a registry-based study of primary TKA procedures at a large tertiary care institution between 1995 and 2010. Patients completed pain and KSS questionnaires both preoperatively and at 1 and 2 years of follow-up. Clinical information including revision outcomes and mortality was collected and recorded by trained registry personnel. Age and gender-adjusted Cox regression models were used to assess the association between pain and KSS measures and revisions and mortality as outcomes. RESULTS: Both the 1-year and 2-year pain and KSSs were significantly associated with the risk for revisions (P < .0001 for trend). The risk for revision was 50%-100% higher among individuals reporting poor or fair KSS at 1 year. Similarly, >=10 points worsening on the KSS was associated with about 2-fold higher risk for revision (hazard ratio, 2.50; 95% confidence interval, 1.25-5.47). The predictive power of the 1- and 2-year KSS diminished but persisted for revisions that occurred furthest from the reporting time points. The results with pain scores were similar but stronger than the KSS. CONCLUSION: Patient-reported outcomes in TKA have long-term prognostic importance and should be taken into account when planning frequency of aftercare of TKA patients. PMID- 28648712 TI - Emerging strategies for delivering antiangiogenic therapies to primary and metastatic brain tumors. AB - Five-year survival rates have not increased appreciably for patients with primary and metastatic brain tumors. Nearly 17,000 patients die from primary brain tumors, whereas approximately 200,000 cases are diagnosed with brain metastasis every year in the US alone. At the same time, with improved control of systemic disease, the incidence of brain metastasis is increasing. Thus, novel approaches for improving the treatment outcome for these uniformly fatal diseases are needed urgently. In the review, we summarize the challenges in the treatment of these diseases using antiangiogenic therapies alone or in combination with radio-, chemo- and immuno-therapies. We also discuss the emerging strategies to improve the treatment outcome using both pharmacological approaches to normalize the tumor microenvironment and physical approaches (e.g., focused ultrasound) to modulate the blood-tumor-barrier, along with limitations of each approach. Finally, we offer some new avenues of future research. PMID- 28648713 TI - Zoonotic infection with Onchocerca dewittei japonica in an 11-year-old boy in Kansai Region, Western Honshu, Japan. AB - An 11-year-old boy living in Otsu City, Shiga Prefecture, Kansai Region, Western Honshu, Japan had zoonotic onchocercosis. The patient developed a painful swelling on the little finger of his left hand. The worm detected in the excised mass had external transverse ridges but did not have inner striae in the cuticle. On the basis of the parasite's histopathological characteristics, the causative agent was identified as a female Onchocerca dewittei japonica (Spirurida: Onchocercidae). The species of the filarial parasite was confirmed by sequencing the cox1 gene of the parasite. The Japanese wild boar Sus scrofa leucomystax is a definitive host for O. dewittei japonica, which is then transmitted by blackflies as the vector to humans. The current case described occurred in the Kansai Region, Western Honshu, where such infections were previously not reported. PMID- 28648715 TI - Midbrain stimulation-evoked lumbar spinal activity in the adult decerebrate mouse. AB - BACKGROUND: Genetic techniques rendering murine models a popular choice for neuroscience research has led to important insights on neural networks controlling locomotor function. Using genetically altered mouse models for in vivo, electrophysiological studies in the adult state could validate key principles of locomotor network organization that have been described in neonatal, in vitro preparations. NEW METHOD: The experimental model presented here describes a decerebrate, in vivo adult mouse preparation in which focal, electrical midbrain stimulation was combined with monitoring lumbar neural activity and motor output after pre-collicular decerebration and neuromuscular blockade. RESULTS: Lumbar cord dorsum potentials (in 9/10 animals) and motoneuron output (in 3/5 animals) including fictive locomotion, was achieved by focal midbrain stimulation. The stimulation electrode locations could be reconstructed (in 6/7 animals) thereby allowing anatomical identification of the stimulated supraspinal regions. COMPARISON WITH EXISTING METHODS: This preparation allows for concomitant recording or stimulation in the spinal cord and in the mid/hindbrain of adult mice. It differs from other methods used in the past with adult mice as it does not require pharmacological manipulation of neural excitability in order to generate motor output. CONCLUSIONS: Midbrain stimulation can consistently be used for inducing lumbar neural activity in adult mice under neuromuscular blockade. This model is suited for examination of brain-spinal connectivity and it may benefit a wide range of fields depending on the features of the genetically modified mouse models used in combination with the presented methods. PMID- 28648714 TI - Evaluation of a minimum-norm based beamforming technique, sLORETA, for reducing tonic muscle contamination of EEG at sensor level. AB - BACKGROUND: Cranial and cervical muscle activity (electromyogram, EMG) contaminates the surface electroencephalogram (EEG) from frequencies below 20 through to frequencies above 100Hz. It is not possible to have a reliable measure of cognitive tasks expressed in EEG at gamma-band frequencies until the muscle contamination is removed. NEW METHOD: In the present work, we introduce a new approach of using a minimum-norm based beamforming technique (sLORETA) to reduce tonic muscle contamination at sensor level. Using a generic volume conduction model of the head, which includes three layers (brain, skull, and scalp), and sLORETA, we estimated time-series of sources distributed within the brain and scalp. The sources within the scalp were considered to be muscle and discarded in forward modelling. RESULT: (1) The method reduced EMG contamination, more strongly at peripheral channels; (2) task-induced cortical activity was retained or revealed after removing putative muscle activity. COMPARISON WITH EXISTING METHODS: This approach can decrease tonic muscle contamination in scalp measurements without relying on time-consuming processing of expensive MRI data. In addition, it is competitive to ICA in muscle reduction and can be reliably applied on any length of recorded data that captures the dynamics of the signals of interest. CONCLUSION: This study suggests that sLORETA can be used as a method to quantitate cranial muscle activity and reduce its contamination at sensor level. PMID- 28648716 TI - A new method of isolating spinal motor neurons from fetal mouse. AB - BACKGROUND: Isolating of primary motor neurons from animal embryos is critical for the study of neurological disease including mechanistic discovery and therapeutic development. Density gradient centrifuge taking advantage of the buoyant of motor neuron permits the enrichment of motor neurons. Despite the metrizamide, an OptiPrep medium has been introduced to separate the motor neurons by gradient centrifuge. NEW METHOD: We hereby used single density gradient of OptiPrep medium to isolate the spinal motor neurons from the fetal mouse. RESULTS: Single density gradient of OptiPrep medium is effective to isolate spinal motor neurons from the fetal mouse. The immunofluorescence staining analysis showed that the purity of cultured motor neurons at 72h was between 90% and 95%. COMPARISON WITH EXISTING METHOD: Four gradients of OptiPrep medium have been previously used to isolate the motor neurons from spinal cord of mouse. In this study, the single gradient of OptiPrep medium was demonstrated to effectively isolate spinal motor neurons from the fetal mouse. CONCLUSIONS: The single gradient of OptiPrep medium is enough to produce high purity of spinal motor neurons from the fetal mouse. PMID- 28648717 TI - Automated classification of self-grooming in mice using open-source software. AB - BACKGROUND: Manual analysis of behavior is labor intensive and subject to inter rater variability. Although considerable progress in automation of analysis has been made, complex behavior such as grooming still lacks satisfactory automated quantification. NEW METHOD: We trained a freely available, automated classifier, Janelia Automatic Animal Behavior Annotator (JAABA), to quantify self-grooming duration and number of bouts based on video recordings of SAPAP3 knockout mice (a mouse line that self-grooms excessively) and wild-type animals. RESULTS: We compared the JAABA classifier with human expert observers to test its ability to measure self-grooming in three scenarios: mice in an open field, mice on an elevated plus-maze, and tethered mice in an open field. In each scenario, the classifier identified both grooming and non-grooming with great accuracy and correlated highly with results obtained by human observers. Consistently, the JAABA classifier confirmed previous reports of excessive grooming in SAPAP3 knockout mice. COMPARISON WITH EXISTING METHODS: Thus far, manual analysis was regarded as the only valid quantification method for self-grooming. We demonstrate that the JAABA classifier is a valid and reliable scoring tool, more cost-efficient than manual scoring, easy to use, requires minimal effort, provides high throughput, and prevents inter-rater variability. CONCLUSION: We introduce the JAABA classifier as an efficient analysis tool for the assessment of rodent self-grooming with expert quality. In our "how-to" instructions, we provide all information necessary to implement behavioral classification with JAABA. PMID- 28648718 TI - An implantable two axis micromanipulator made with a 3D printer for recording neural activity in free-swimming fish. AB - BACKGROUND: Chronically implanted electrodes allow monitoring neural activity from free moving animals. While a wide variety of implanted headstages, microdrives and electrodes exist for terrestrial animals, few have been developed for use with aquatic animals. NEW METHOD: A two axis micromanipulator was fabricated with a Formlabs 3D printer for implanting electrodes into free swimming oyster toadfish (Opsanus tau). The five piece manipulator consisted of a base, body, electrode holder, manual screw drive and locking nut. The manipulator measured approximately 25*20*30mm (l*w*h) and weighed 5.28g after hand assembly. RESULTS: Microwire electrodes were inserted successfully with the manipulator to record high fidelity signals from the anterior lateral line nerve of the toadfish. COMPARISON WITH EXISTING METHOD(S): The micromanipulator allowed the chronically implanted electrodes to be repositioned numerous times to record from multiple sites and extended successful recording time in the toadfish by several days. CONCLUSIONS: Three dimensional printing allowed an inexpensive (<$US 5 material), two axis micromanipulator to be printed relatively rapidly (<2h) to successfully record from multiple sites in the anterior lateral line nerve of free-swimming toadfish. PMID- 28648719 TI - Modification to the Rice-Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48hours. AB - BACKGROUND: The Rice-Vannucci model of hypoxic-ischaemic encephalopathy (HIE) has been associated with a high degree of variability with respect to the development of cerebral infarction and infarct lesion volume. For this reason, we examined the occurrence of communicational blood flow within the common carotid (CCA), internal (ICA), and external (ECA) carotid arteries following CCA occlusion as a source of variability in the model. NEW METHOD: We propose a novel modification to the Rice-Vannucci model, whereby both the CCA and ECA are permanently ligated; mitigating communicational blood flow. RESULTS: Using magnetic resonance angiography, phase-contrast velocity encoding, and pulsed arterial spin labelling, the modified Rice-Vannucci model (CCA/ECA occlusion) was demonstrated to mitigate communicational blood flow, whilst significantly reducing ipsilateral hemispherical cerebral blood flow (CBF). Comparatively, the original Rice Vannucci model (CCA occlusion) demonstrated anterograde and retrograde blood flow within the ICA and CCA, respectively, with a non-significant reduction in ipsilateral CBF. Furthermore, CCA/ECA occlusion plus hypoxia (8% O2/92% N2; 2.5h) resulted in 100% of animals presenting with an infarct (vs 87%), significantly larger infarct volume at 48h (18.5% versus 10.0%; p<0.01), reduced standard deviation (+/-10% versus +/-15%), and significantly worsened functional outcomes when compared to CCA occlusion plus hypoxia. COMPARISON WITH EXISTING METHOD: We compared a modified Rice-Vannucci model (CCA/ECA occlusion+/-hypoxia) to the commonly used Rice-Vannucci model (CCA occlusion+/-hypoxia). CONCLUSION: This study demonstrates that CCA/ECA occlusion in the Rice-Vannucci model of HIE reduces infarct volume variability by limiting communicational blood flow. PMID- 28648720 TI - An engineered home environment for untethered data telemetry from nonhuman primates. AB - BACKGROUND: Wireless neural recording technologies now provide untethered access to large populations of neurons in the nonhuman primate brain. Such technologies enable long-term, continuous interrogation of neural circuits and importantly open the door for chronic neurorehabilitation platforms. For example, by providing continuous consistent closed loop feedback from a brain machine interface, the nervous system can leverage plasticity to integrate more effectively into the system than would be possible in short experimental sessions. However, to fully realize this opportunity necessitates the development of experimental environments that do not hinder wireless data transmission. Traditional nonhuman primate metal cage construction, while durable and standardized around the world, prevents data transmission at the frequencies necessary for high-bandwidth data transfer. NEW METHOD: To overcome this limitation, we have engineered and constructed a radio-frequency transparent home environment for nonhuman primates using primarily non-conductive materials. RESULTS: Computational modeling and empirical testing were performed to demonstrate the behavior of transmitted signals passing through the enclosure. In addition, neural data were successfully recorded from a freely behaving nonhuman primate inside the housing system. COMPARISON WITH EXISTING METHODS: Our design outperforms standard metallic home cages by allowing radiation to transmit beyond its boundaries, without significant interference, while simultaneously maintaining the mechanical and operational integrity of existing commercial home cages. CONCLUSIONS: Continuous access to neural signals in combination with other bio-potential and kinematic sensors will empower new insights into unrestrained behavior, aid the development of advanced neural prostheses, and enable neurorehabilitation strategies to be employed outside traditional environments. PMID- 28648722 TI - Google Trends can provide objective data on the impact of radiation oncology related media events and the level of interest in specific types of treatment. PMID- 28648723 TI - A protocol for the simultaneous identification of chitin-containing particles and their associated bacteria. AB - Chitin is the second most abundant polymer on Earth, playing a crucial role in the biogeochemical cycles. A core issue for studying its processing in aquatic systems is the identification and enumeration of chitin-containing particles and organisms, ideally in a manner that can be directly linked to bulk chitin quantification. The aim of this study was the development of such a technique. We successfully combined the methodology of bulk chitin determination using wheat germ agglutinin (FITC-WGA) for staining chitin-containing particles and organisms along with CARD-FISH staining of either chitin-containing eukaryotic cells or bacteria associated with them. Environmental chitin staining was successfully applied to natural water samples. Fungal hyphae, diatoms, and dinoflagellates, sestonic aggregates and chitin-containing structures derived from metazoa were observed. Also, hybridized bacteria attached to chitinaceous debris were clearly visualized. Finally, as proof of principle, cultured yeast cells were simultaneously-targeted by FITC-WGA and the EUK516 probe without exhibiting any interference between both stains. The presented approach appears as a powerful tool to evaluate the contribution of different size classes and organisms to chitin production and consumption, opening the possibility for application of single-cell approaches targeting the ecophysiology of chitin transformations in aquatic systems. PMID- 28648721 TI - Stability metrics for optic radiation tractography: Towards damage prediction after resective surgery. AB - BACKGROUND: An accurate delineation of the optic radiation (OR) using diffusion MR tractography may reduce the risk of a visual field deficit after temporal lobe resection. However, tractography is prone to generate spurious streamlines, which deviate strongly from neighboring streamlines and hinder a reliable distance measurement between the temporal pole and the Meyer's loop (ML-TP distance). NEW METHOD: Stability metrics are introduced for the automated removal of spurious streamlines near the Meyer's loop. Firstly, fiber-to-bundle coherence (FBC) measures can identify spurious streamlines by estimating their alignment with the surrounding streamline bundle. Secondly, robust threshold selection removes spurious streamlines while preventing an underestimation of the extent of the Meyer's loop. Standardized parameter selection is realized through test-retest evaluation of the variability in ML-TP distance. RESULTS: The variability in ML TP distance after parameter selection was below 2mm for each of the healthy volunteers studied (N=8). The importance of the stability metrics is illustrated for epilepsy surgery candidates (N=3) for whom the damage to the Meyer's loop was evaluated by comparing the pre- and post-operative OR reconstruction. The difference between predicted and observed damage is in the order of a few millimeters, which is the error in measured ML-TP distance. COMPARISON WITH EXISTING METHOD(S): The stability metrics are a novel method for the robust estimate of the ML-TP distance. CONCLUSIONS: The stability metrics are a promising tool for clinical trial studies, in which the damage to the OR can be related to the visual field deficit that may occur after epilepsy surgery. PMID- 28648724 TI - Nitrogen-fixing rhizobial strains isolated from Desmodium incanum DC in Argentina: Phylogeny, biodiversity and symbiotic ability. AB - Desmodium spp. are leguminous plants belonging to the tribe Desmodieae of the subfamily Papilionoideae. They are widely distributed in temperated and subtropical regions and are used as forage plants, for biological control, and in traditional folk medicine. The genus includes pioneer species that resist the xerothermic environment and grow in arid, barren sites. Desmodium species that form nitrogen-fixing symbiosis with rhizobia play an important role in sustainable agriculture. In Argentina, 23 native species of this genus have been found, including Desmodium incanum. In this study, a total of 64 D. incanum nodulating rhizobia were obtained from root nodules of four Argentinean plant populations. Rhizobia showed different abiotic-stress tolerances and a remarkable genetic diversity using PCR fingerprinting, with more than 30 different amplification profiles. None of the isolates were found at more than one site, thus indicating a high level of rhizobial diversity associated with D. incanum in Argentinean soils. In selected isolates, 16S rDNA sequencing and whole-cell extract MALDI TOF analysis revealed the presence of isolates related to Bradyrhizobium elkanii, Bradyrhizobium japonicum, Bradyrhizobium yuanmingense, Bradyrhizobium liaoningense, Bradyrhizobium denitrificans and Rhizobium tropici species. In addition, the nodC gene studied in the selected isolates showed different allelic variants. Isolates were phenotypically characterized by assaying their growth under different abiotic stresses. Some of the local isolates were remarkably tolerant to high temperatures, extreme pH and salinity, which are all stressors commonly found in Argentinean soils. One of the isolates showed high tolerance to temperature and extreme pH, and produced higher aerial plant dry weights compared to other inoculated treatments. These results indicated that local isolates could be efficiently used for D. incanum inoculation. PMID- 28648725 TI - Thaumasiovibrio occultus gen. nov. sp. nov. and Thaumasiovibrio subtropicus sp. nov. within the family Vibrionaceae, isolated from coral reef seawater off Ishigaki Island, Japan. AB - Two phylogenetically distinct Vibrionaceae strains C4II189T and C4V358T isolated from reef seawater off Ishigaki Island, Japan, in 2014 were studied with advanced genome-based taxonomy approaches. All aspects of phylogenetic (16S rRNA phylogeny, MLSA), phenotypic and genetic (ANI, DDH, AAI, and the number of core genes) cohesions between the two identified species were high enough to propose them as members of a new genus within the family Vibrionaceae. Consequently, an eighth genus Thaumasiovibrio gen. nov. is proposed that contains two new species Thaumasiovibrio occultus sp. nov. strain C4II189T (=DSM 101554T=JCM 31629T) (type species) and Thaumasiovibrio subtropicus sp. nov. strain C4V358T (=DSM 101555T=JCM 31630T). Thaumasiovibrio species were phylogenetically distinct from the other Vibrionaceae species based on pyrH gene sequences. The combination of catalase negative, sensitivity to vibriostatic agent O/129, and green colony formation on TCBS for the phylogenetically affiliated strains was the diagnostic features for the current tentative identification of this genus. PMID- 28648726 TI - Taking the measure of MicroED. AB - It is now possible to routinely determine atomic resolution structures by electron cryo-microscopy (cryoEM), facilitated in part by the method known as micro electron-diffraction (MicroED). Since its initial demonstration in 2013, MicroED has helped determine a variety of protein structures ranging in molecular weight from a few hundred Daltons to several hundred thousand Daltons. Some of these structures were novel while others were previously known. The resolutions of structures obtained thus far by MicroED range from 3.2A to 1.0A, with most better than 2.5A. Crystals of various sizes and shapes, with different space group symmetries, and with a range of solvent content have all been studied by MicroED. The wide range of crystals explored to date presents the community with a landscape of opportunity for structure determination from nano crystals. Here we summarize the lessons we have learned during the first few years of MicroED, and from our attempts at the first ab initio structure determined by the method. We re-evaluate theoretical considerations in choosing the appropriate crystals for MicroED and for extracting the most meaning out of measured data. With more laboratories worldwide adopting the technique, we speculate what the first decade might hold for MicroED. PMID- 28648727 TI - Detection of okadaic acid (OA) using ELISA and colloidal gold immunoassay based on monoclonal antibody. AB - Okadaic Acid (OA), a small seafood-borne toxin secreted by Dinophysis and Prorocentrum dinoflagellates, is generally distributed in various species of shellfish and has caused diarrhetic shellfish poisoning (DSP). In view of OA toxin threat to humans and animals, it is essential to develop a rapid, accurate and sensitive method for the detection and quantification of OA in real samples. In this study, a monoclonal antibody named 10E8 was screened by cells fusion of Sp2/0 with spleen cells isolated from immunized mouse, and the isotype of McAb 10E8 was belonged to IgG1. The resulted McAb 10E8 displayed higher specificity to OA antigen, with the highest affinity of 2.66*109L/moL until now. Indirect competitive ELISA (ic-ELISA) indicated that the linear range to detect OA was 20 750ng/mL. The limit of detection (LOD) was 12pg/mL, and the recovery average was (84.04+/-5.08)%. The LOD of colloidal gold immunoassay by naked eye and strip reader was 1ng/mL and 100pg/mL, respectively, with an average recovery of (88.0275+/-4.4225)%. Therefore, the developed ELISA and colloidal gold immunoassay based on this McAb can be used for OA detection in real samples. PMID- 28648728 TI - Microstructure characterization of hydrothermally synthesized PANI/V2O5.nH2O heterojunction photocatalyst for visible light induced photodegradation of organic pollutants and non-absorbing colorless molecules. AB - Polyaniline intercalated vanadium oxide xerogel (PV) hybrid nanocomposite (NC) with novel structure has been successfully synthesized through a simple hydrothermal route. Detailed structure and microstructure characterization of PV NC is illustrated through Rietveld refinement of XRD data and FESEM/HRTEM images. Both FTIR and XPS spectra confirm the presence of PANI and water molecules within the NC and partial reduction of V5+ to V4+, corroborating with the results of XRD pattern analysis. Core-shell structure of PV NC, where PANI sheath layer acts as a shell covering around V2O5.nH2O crystalline core is confirmed from HRTEM images. Successive morphological changes of PV NC with different reaction time have been revealed from FESEM images. UV-vis spectra also confirm the formation of PV NC. Intercalation of water and PANI layers into V2O5.nH2O layer leads to a structural phase transition from orthorhombic to monoclinic phase due to substantial increase in interplanar spacing of (00l) of orthorhombic V2O5. The photocatalytic property of the as synthesized PV NC has been reported for the first time, with a promising photocatalytic activity for the degradation of organic dye, Rhodamine B (RhB) under visible light irradiation. It is attributed to a synergic effect in between PANI and V2O5.nH2O xerogel. The photocatalyst also shows remarkable real visible light photocatalytic activity with non absorbing colorless test molecules like phenol and antibiotic kanamycin. PMID- 28648729 TI - Interaction of ciprofloxacin chlorination products with bacteria in drinking water distribution systems. AB - The interaction of ciprofloxacin chlorination products (CIP-CPs) with bacteria in drinking water distribution systems (DWDSs) was investigated. The piperazine ring of CIP was destroyed by chlorination. Among of CIP-CPs, by the bacterial role, 7.63% of the derivative with two carboxylic groups went through decarboxylation to form desethylene ciprofloxacin, and then loss of C2H5N group generated aniline compound. Furthermore, 12.3% of the aniline compound, 7.60% of chlorinated aniline compound and 1.35% of defluorinated product were bio-mineralized. Therefore, the chlorine and bacteria played synergistic effects on transformation of CIP-CPs in DWDSs, contributing to the obvious decrease of genotoxicity in effluents. Correspondingly, the TEQ4-NQO decreased from 667MUg/L to 9.41MUg/L. However, compared with DWDSs without CIP-CPs, the relative abundance of mexA and qnrS increased 1-fold in effluents and the relative abundance of qnrA and qnrB increased 3-fold in biofilms in DWDSs with CIP-CPs. mexA and qnrS positively correlated with Hyphomicrobium, Sphingomonas and Novosphingobium (p<0.05), while qnrA and qnrB positively correlated with Shewanella and Helicobacter (p<0.05), indicating the increase of antibiotic resistance genes (ARGs) came from the growth of these bacterial genera by transformation of CIP-CPs in DWDSs. These results suggested that biotransformation of antibiotics might increase ARGs risk in DWDSs. PMID- 28648730 TI - Removal of Cu(II) ions from contaminated waters using a conducting microfiltration membrane. AB - Efficient removal of toxic metals using low-pressure membrane processes from contaminated waters is an important but challenging task. In the present work, a conducting microfiltration membrane prepared by embedding a stainless steel mesh in the active layer of a polyvinylidene fluoride membrane is developed to remove Cu(II) ions from contaminated waters. Results showed that the conducting membrane had favorable electrochemical properties and stability as cathode. Batch tests showed that Cu(II) removal efficiency increased with the increase of voltages and leveled off with the further enhancement of electric field. The optimal voltages were determined to be 1.0V and 2.0V for the influent Cu(II) concentrations of 5mg/L and 30mg/L, respectively. X-ray photoelectron spectroscopy and X-ray diffraction results demonstrated the presence of Cu(0) and Cu(OH)2 on the membrane surface. The removal mechanisms involved the intrinsic adsorption of membrane, electrosorption of membrane, adsorption of deposited layer, chemical precipitation of Cu(OH)2 and deposition of Cu(0) which were aided by electrophoresis and electrochemical oxidation-reduction. Long-term tests showed that the major contributors for Cu(II) removal were the deposition of Cu(0) by electrochemical reduction-oxidation (47.3%+/-8.5%) and chemical precipitation (41.1%+/-0.2%), followed by electrosorption, adsorption by the fouling layer and membrane intrinsic sorption. PMID- 28648731 TI - Degradation characteristics of dioxin in the fly ash by washing and ball-milling treatment. AB - In this study, samples were taken from different types of municipal waste incineration plants in the Pearl River Delta, China. Analyzing the distributive characters of elements and dioxin congeners in fly ash, the method of washing ball milling was utilized to remove chloride and degrade dioxin in fly ash. The results showed that more than 90% of particles were in the range of 1~50MUm and most of dioxin and metals existed in 0.030~0.075mm of particles. K, Na, Cl and Br in fly ash could be removed by washing efficiently, however dioxin and other metals remained in the solid phase. Washing and Fe/Ni-SiO2 ball-milling method seemed to be the best choice as the dioxin removal rate could reach up to 93.20%. Dioxin could be degraded to low toxic compounds and heterochorides with Fe/Ni as dechlorinating agent. In the process, PCDFs were partly transformed to PCDDs, while too long time of ball-milling was not benefited for dioxin removing. In addition, the phases of calcium such as Ca(OH)2, CaCO3 and CaSO4 in fly ash could transform from crystal to amorphous. PMID- 28648732 TI - [Adoptive transfer of T lymphocytes]. AB - Within a few years, the success of treatments based on the use of T-cells armed with a chimeric T-receptor for the CD19 molecule (CAR-T CD19) has revolutionized the perception of adoptive transfer approaches. The levels of responses observed in acute leukemias, of the order of 70-90 % are indeed unprecedented. The medical and financial enthusiasm aroused by these results has led to the current situation where more than 300 clinical trials are under way, against some thirty different antigens. This enthusiasm, well justified by the first successes, must however be tempered by the difficulties associated with the use of these cells. Indeed, the management of patients is made very complex both for medical reasons, because the toxicities associated with these treatments are important, and for technical reasons, because the preparation of T lymphocytes for therapeutic use requires dedicated structures. During this same period, knowledge of the mechanisms of regulation of T lymphocytes and the possibilities offered by synthetic biology and techniques of genome engineering have progressed considerably. Combined, they allow envisaging a true "programming" of the T lymphocytes, intended to improve the efficiency of the treatments and the safety of the patients. Medical and industrial perspectives and the role of these approaches in the arsenal of cancer therapies will depend largely on two conditions: the emergence of a robust demonstration of their effectiveness in solid tumors, and the establishment of an acceptable production and distribution model 1. PMID- 28648733 TI - [Is transplantation an alternative to the transfusional impasse in sickle cell disease?] AB - Sickle cell disease is the most frequent genetic disease in France, concerning 400 newborns each year. The management of these Afro-Caribbean patients requires frequent transfusions from Caucasian donors. Due to important erythroid antigenic differences between Caucasian and African, the prevalence of allo-immunization is high in this population with a risk of transfusional impasse. Allogeneic stem cell transplantation is the only curative treatment for this disease and the replacement of red cells and lymphocytes of the sickle cell patient by those of the donor can also resolve the transfusional impasse. However, a close consultation between physicians from the blood bank and transplantation unit will be required for the choice of conditioning regimen and GvH prophylaxis in order to ensure the transition from a mixed chimerism to the full donor curative graft. PMID- 28648734 TI - Drug-induced hemolytic anemia: Pharmacological aspects. AB - Drug-induced hemolytic anemia is a very rare but potentially lethal adverse drug reaction, which can take the form of oxidative damage to vulnerable erythrocytes (as in glucose-6-phosphate dehydrogenase deficiency), drug-induced thrombotic microangiopathy, or immune-mediated hemolytic anemia. For each form, distinctive drugs are documented as potential triggers. When a formal diagnosis of hemolytic anemia is made following drug administration, a structured approach is recommended to assess the plausibility of an adverse drug reaction based on chronological sequence, epidemiological data, objective evidence (when available), and ruling out of non-drug causes. For suspicions of immune-mediated hemolytic anemia, investigations by a laboratory with specific expertise are crucial given the complexity of the field. If there is good reason to believe hemolytic anemia is drug-induced, immediate drug discontinuation is necessary and corticosteroid administration can be considered. The clinical pharmacology specialist can support evaluation of drug imputability and report the case to the pharmacovigilance system, an important last step in managing such events. PMID- 28648735 TI - Editorial overview: Host-microbe interactions: Bacteria. PMID- 28648736 TI - Bone morphogenetic protein (BMP-2) usage and cancer correlation: An analysis of 10,416 spine fusion patients from a multi-center spine registry. PMID- 28648737 TI - Orlistat on plasma lipids and body weight reduction: A really effective drug? PMID- 28648738 TI - Current topics in angiotensin II type 1 receptor research: Focus on inverse agonism, receptor dimerization and biased agonism. AB - Although the octapeptide hormone angiotensin II (Ang II) regulates cardiovascular and renal homeostasis through the Ang II type 1 receptor (AT1R), overstimulation of AT1R causes various human diseases, such as hypertension and cardiac hypertrophy. Therefore, AT1R blockers (ARBs) have been widely used as therapeutic drugs for these diseases. Recent basic research and clinical studies have resulted in the discovery of interesting phenomena associated with AT1R function. For example, ligand-independent activation of AT1R by mechanical stress and agonistic autoantibodies, as well as via receptor mutations, has been shown to decrease the inverse agonistic efficacy of ARBs, though the molecular mechanisms of such phenomena had remained elusive until recently. Furthermore, although AT1R is believed to exist as a monomer, recent studies have demonstrated that AT1R can homodimerize and heterodimerize with other G-protein coupled receptors (GPCR), altering the receptor signaling properties. Therefore, formation of both AT1R homodimers and AT1R-GPCR heterodimer may be involved in the pathogenesis of human disease states, such as atherosclerosis and preeclampsia. Finally, biased AT1R ligands that can preferentially activate the beta-arrestin-mediated signaling pathway have been discovered. Such beta-arrestin-biased AT1R ligands may be better therapeutic drugs for cardiovascular diseases. New findings on AT1R described herein could provide a conceptual framework for application of ARBs in the treatment of diseases, as well as for novel drug development. Since AT1R is an extensively studied member of the GPCR superfamily encoded in the human genome, this review is relevant for understanding the functions of other members of this superfamily. PMID- 28648739 TI - G protein-coupled receptor 35 contributes to mucosal repair in mice via migration of colonic epithelial cells. AB - G protein-coupled receptor 35 (GPR35), a receptor for lysophosphatidic acid, is highly expressed in the gastrointestinal tract. Recently, GPR35 has been implicated in the onset of inflammatory bowel disease (IBD), but its role in physiological and pathological processes in the colon remains undefined. In this study, we investigated the contribution of GPR35-mediated signalling to mucosal repair of colonic epithelium in IBD. GPR35 function was examined in a wound healing model, using young adult mouse colon epithelium (YAMC) cells, and in a dextran sulphate sodium (DSS)-induced mouse model of colitis. Cell proliferation, mRNA expression, extracellular signal-regulated kinase (ERK) activation, and protein localization were determined by MTT assay, quantitative RT-PCR, western blotting, and immunohistochemistry, respectively. GPR35 agonists (YE120, zaprinast, and pamoic acid) promoted wound repair in a concentration-dependent manner independently of cell proliferation, whereas a specific GPR35 antagonist CID2745687, forskolin, and pertussis toxin reversed the YE120-induced effect. YE120 increased the mRNA expression of fibronectin and its receptor integrin alpha5, and ERK1/2 phosphorylation, but these responses were attenuated by CID2745687 and forskolin. Furthermore, the severity of DSS-induced colitis was significantly reduced by daily injections of pamoic acid via upregulation of fibronectin and integrin alpha5 in the colonic epithelium. GPR35 signalling promotes mucosal repair by inducing fibronectin and integrin alpha5 expression, coupling to Gi protein, and activating ERK1/2 in colonic epithelial cells. These findings define GPR35 as a candidate therapeutic target in IBD. PMID- 28648740 TI - Patellofemoral morphology and alignment: reference values and dose-response patterns for the relation to MRI features of patellofemoral osteoarthritis. AB - OBJECTIVE: We aimed to (1) determine reference values for trochlear morphology and patellofemoral (PF) alignment in adults without magnetic resonance imaging (MRI)-defined PF full thickness cartilage damage or knee pain; and (2) evaluate dose-response patterns for these measures with prevalent MRI-defined PF structural damage and/or knee pain. DESIGN: The Framingham Community Cohort is a population-based sample of ambulatory adults aged >=50 years. We evaluated six morphology and alignment measures using MRI (n = 985), and reported reference values (mean +/- 2SD) in a subsample without MRI-defined PF full thickness cartilage damage or knee pain (n = 563). With restricted cubic spline Poisson regression, we evaluated dose-response patterns of each of the six measures with prevalent MRI-defined PF structural damage or joint pain. Our primary outcome was full thickness cartilage damage. RESULTS: For dose-response curves, prevalence ratios (PR) increased monotonically for all measures except patellar tilt, which rose with both lateral and medial tilt. Associations were generally strongest in the lateral PF compartment. PR for the strongest predictors of full thickness cartilage damage reached clinical relevance (PR > 1.5) at sulcus angle (SA) >=135.0 degrees ; patellar tilt angle at <=1.0 degrees and >=15.0 degrees ; and bisect offset >=57.0%. Lateral trochlear inclination (LTI) achieved PR > 1.5 at <=23.0 degrees for full thickness cartilage damage with pain. CONCLUSIONS: SA, patellar tilt, and bisect offset were most strongly associated with full thickness cartilage damage. LTI, patellar tilt and bisect offset had stronger associations with the addition of pain. These findings contribute to better identifying a subset of patients who may benefit from mechanically based interventions. PMID- 28648741 TI - The importance of dose in land-based supervised exercise for people with hip osteoarthritis. A systematic review and meta-analysis. AB - PURPOSE: To compare effects of land-based exercise programmes with high vs low or uncertain compliance with dose recommendations among people with hip osteoarthritis (OA). DESIGN: A systematic review with meta-analyses of supervised exercise programmes in people with symptomatic hip OA was conducted. Dose of the exercise interventions was evaluated according to the American College of Sports Medicine's (ACSM) recommendations for developing and maintaining cardiorespiratory fitness, muscular strength and flexibility in healthy adults. Compliance ratios with the recommendations were calculated. Standardized Mean Differences (SMDs) were calculated in meta-analyses for the outcomes pain and self-reported physical function. Outcome effects were compared between the sub groups of studies with interventions with "high" vs "uncertain" compliance with the ACSM recommendations. RESULTS: Twelve studies including 1202 participants were included. Seven were categorized with "high" and five with "uncertain" compliance with the ACSM recommendations. Ten studies had an overall low risk of bias. Comparing exercise with no exercise, the pooled SMD for pain was -0.42 (95% CI -0.58, -0.26) in the high compliance group, favouring exercise. In the uncertain compliance group the pooled SMD was 0.04 (95% CI -0.24, 0.31). For physical function the SMD was -0.41 (95% CI -0.58, -0.24) in the high compliance group and -0.23 (95% CI -0.52, 0.06) in the uncertain compliance group. CONCLUSIONS: The results show that land-based supervised exercise interventions with high compliance to the ACSM recommendations result in significantly larger improvements in pain and non-significantly larger improvement in self-reported physical function compared with land-based supervised exercise interventions with uncertain compliance. PMID- 28648742 TI - Polo-like kinase 2 modulates alpha-synuclein protein levels by regulating its mRNA production. AB - Variations in the alpha-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of alpha-synuclein with the risk of PD, and make lowering alpha-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular alpha-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in alpha-synuclein because a similar reduction is achieved with the non-phosphorable S129A mutant alpha-synuclein. Using a specific PLK-2 inhibitor (compound 37), we demonstrate that endogenous PLK-2 phosphorylates S129 only in some cells, but increases alpha-synuclein protein levels in all tested cell cultures and brain slices. PLK-2 is found to regulate the transcription of alpha-synuclein mRNA from both the endogenous mouse SNCA gene and transgenic vectors that only contain the open reading frame. Moreover, we are the first to show that regulation of alpha synuclein by PLK-2 is of physiological importance since 10days' inhibition of endogenous PLK-2 in wt C57BL/6 mice increases endogenous alpha-synuclein protein levels. Our findings collectively demonstrate that PLK-2 regulates alpha synuclein levels by a previously undescribed transcription-based mechanism. This mechanism is active in cells and brain tissue, opening up for alternative strategies for modulating alpha-synuclein levels and thereby for the possibility of modifying disease progression in synucleinopaties. PMID- 28648744 TI - Safety in Radiotherapy mini-series. PMID- 28648743 TI - Corrigendum to 'A mathematical method for precisely calculating the radiographic angles of the cup after total hip arthroplasty' Medical Engineering & Physics 38 (2016) 1376-1381. PMID- 28648745 TI - Batch anaerobic digestion of deproteinated malt whisky pot ale using different source inocula. AB - A novel process has been developed for the selective removal of protein from pot ale with recovered protein holding potential as a value-added by-product for the whisky industry. The purpose of this work was to assess the effect of deproteination on pot ale physicochemical characterisation and anaerobic digestion (AD) treatment. Pot ales were taken from five malt whisky distilleries and tested untreated, after centrifugation/filtration and after deproteination at laboratory or pilot scale. At laboratory scale, the deproteination process removed around 20% of total chemical oxygen demand (tCOD) from untreated pot ale and at least 30% dissolved copper from centrifuged pot ale. Biochemical methane potential of untreated, filtered and deproteinated pot ale obtained at pilot scale has been determined using two types of inocula from different source. Average methane yield values of 554+/-67, 586+/-24 and 501+/-23 Nl CH4 kg-1 VS were obtained for untreated, filtered and deproteinated pot ale respectively. A significant difference in methane yield was only observed for untreated pot ale using the two types of inocula. Specifically, when using a non-adapted inoculum untreated pot ale biogas yield was significant lower suggesting inhibition of the AD process. As no significant differences were found for treated pot ale (filtered and deproteinated) with the two inocula it suggests, deproteination may have a positive effect on AD start-up. The results present a clear case for continuation of this work and evaluating the effect on continuous AD. PMID- 28648746 TI - Anaerobic digestion of solid agroindustrial waste in semi-continuous mode: Evaluation of mono-digestion and co-digestion systems. AB - The present study aimed at investigating the anaerobic digestion of four agroindustrial waste, namely cotton gin waste, winery waste, olive pomace and juice industry waste, in semi-continuous mode, conducting mono-digestion and co digestion assays, using an artificial organic fraction sample as co-substrate. These assays were divided into two groups, in which different conditions were applied. Group I investigated the variation in two operational parameters, i.e. the organic loading rate (OLR) and the hydraulic retention time (HRT), while in Group II, the assays were fed with different substrates in a sequential order. Results showed more elevated specific methane yields for co-digestion assays compared with mono-digestion assays. Maximum yields were achieved at an OLR of 1.0gVS/(L.d) and a HRT reduced to half of the initial. Further reduction of the HRT coupled to an increase of the OLR generally caused a significant decrease of specific methane yields, as well as one case of severe overloading, i.e. the mono digestion of juice industry waste, which resulted in instability and ultimately system failure. Sequential feeding with different substrates led to a more equilibrated operation, especially for co-digestion systems, with higher specific methane yields being observed during the phases corresponding to winery waste and juice industry waste substrates. Overall more positive results were obtained in the cases in which the latter substrates were fed to the reactors at process startup. PMID- 28648747 TI - Anaerobic co-digestion of chicken manure and microalgae Chlorella sp.: Methane potential, microbial diversity and synergistic impact evaluation. AB - Anaerobic digestion (AD) is a promising alternative for livestock manure management. This paper presents the experimental results obtained through a batch experiment by using chicken manure (CM) and microalgae Chlorella sp. as co substrates. The effect of co-digestion was evaluated by varying CM to Chlorella sp. ratios (0:10, 2:8, 4:6, 6:4, 8:2, 10: 0 based on the volatile solids (VS)). The major objective of this study is to evaluate the feasibility and synergistic impact of co-digestion of CM and Chlorella sp. Enhanced 14.20% and 76.86% methane production than CM and Chlorella sp. mono-digestion respectively was achieved in co-digestion at the ratio 8:2. In addition, the co-digestion at the ratio 8:2 showed significantly higher methane yield than the weighted average of the individual substrates' specific methane yield (WSMY), indicating strong synergy effect. The Illumina Miseq sequencing analysis showed that the AD process suppressed the acetoclastic methanogenesis Methanosaeta content; but partly enhanced hydrogenotrophic methanogenesis Methanosarcina, Methanospirillum and Methanobacterium, which was responsible for the methane production. The pre treated microalgae was then introduced at the optimal ratio 8:2 to estimate the effect of pre-treatment of microalgae on AD process. However, the pre-treatment exhibited no positive effect. PMID- 28648748 TI - Optimized anaerobic-aerobic sequential system for the treatment of food waste and wastewater. AB - Considering that modern wastewater and solid waste processing facilities seek efficient energy recovery methods, this study investigates anaerobic-aerobic sequential systems for combined treatment of raw wastewater with food waste. The optimum loading rate was found to be 1.6mgVSL-1d-1 resulting in a stable operation of the anaerobic compartment. Yet, the increase in ammonia concentration resulted in gradual accumulation of VFA, until reaching a tipping point of 3000mgL-1 beyond which an abrupt increase in VFA to above 6000mgL-1 was observed, with acute stability loss and performance deterioration. The aerobic system was modeled using computational fluid dynamics methods. Optimum performance was achieved at an average strain rate magnitude of 12.7s-1 yielding a DO concentration of 4mgL-1 which have resulted in 74% conversion of ammonia nitrogen. Under optimum conditions, the studied AASS yielded high total removal rates of 93% VS and 94% COD, with a high specific methane yield of 845LkgVS-1 and a CO2-to-CH4 ratio of 0.63. PMID- 28648750 TI - MUC5B and short telomere length in hypersensitivity pneumonitis. PMID- 28648749 TI - Transcriptome profiling of 3D co-cultured cardiomyocytes and endothelial cells under oxidative stress using a photocrosslinkable hydrogel system. AB - : Myocardial infarction (MI) is one of the most common among cardiovascular diseases. Endothelial cells (ECs) are considered to have protective effects on cardiomyocytes (CMs) under stress conditions such as MI; however, the paracrine CM-EC crosstalk and the resulting endogenous cellular responses that could contribute to this protective effect are not thoroughly investigated. Here we created biomimetic synthetic tissues containing CMs and human induced pluripotent stem cell (hiPSC)-derived ECs (iECs), which showed improved cell survival compared to single cultures under conditions mimicking the aftermath of MI, and performed high-throughput RNA-sequencing to identify target pathways that could govern CM-iEC crosstalk and the resulting improvement in cell viability. Our results showed that single cultured CMs had different gene expression profiles compared to CMs co-cultured with iECs. More importantly, this gene expression profile was preserved in response to oxidative stress in co-cultured CMs while single cultured CMs showed a significantly different gene expression pattern under stress, suggesting a stabilizing effect of iECs on CMs under oxidative stress conditions. Furthermore, we have validated the in vivo relevance of our engineered model tissues by comparing the changes in the expression levels of several key genes of the encapsulated CMs and iECs with in vivo rat MI model data and clinical data, respectively. We conclude that iECs have protective effects on CMs under oxidative stress through stabilizing mitochondrial complexes, suppressing oxidative phosphorylation pathway and activating pathways such as the drug metabolism-cytochrome P450 pathway, Rap1 signaling pathway, and adrenergic signaling in cardiomyocytes pathway. STATEMENT OF SIGNIFICANCE: Heart diseases are the leading cause of death worldwide. Oxidative stress is a common unwanted outcome that especially occurs due to the reperfusion following heart attack or heart surgery. Standard methods of in vivo analysis do not allow dissecting various intermingled parameters, while regular 2D cell culture approaches often fail to provide a biomimetic environment for the physiologically relevant cellular phenotypes. In this research, a systematic genome-wide transcriptome profiling was performed on myocardial cells in a biomimetic 3D hydrogel-based synthetic model tissue, for identifying possible target genes and pathways as protecting regulators against oxidative stress. Identification of such pathways would be very valuable for new strategies during heart disease treatment by reducing the cellular damage due to reperfusion injury. PMID- 28648752 TI - Physiological and self-assessed psychological stress induced by a high fidelity simulation course among third year anesthesia and critical care residents: An observational study. AB - INTRODUCTION: The use of high fidelity simulators in Medicine can improve knowledge, behaviour and practice but may be associated with significant stress. Our objective was to measure physiological and psychological self-assessed intensity of stress before and after a planned simulation training session among third year anaesthesia and critical care residents. METHODS: A convenience sample of 27 residents participating in a simulation training course was studied. Stress was evaluated by self-assessment using a numerical scale and by salivary amylase concentration before and after the session. Technical and non-technical (using the Aberdeen Anaesthetists' Non Technical Skills scale) performances were assessed through videotapes analysis. RESULTS: The median stress score was 5 (2 8) before and 7 (2-10) after the simulation session (P<0.001). For 48% of residents studied, the stress score after the session was superior or equal to 8/10. Salivary amylase concentration increased significantly after the session compared to before the session, respectively (1,250,440+/-1,216,667 vs. 727,260+/ 603,787IU/L, P=0.008). There was no significant correlation between stress parameters and non-technical performance. DISCUSSION: Simulation-induced stress, as measured by self-assessment and biological parameter, is high before the session and increases significantly during the course. While this stress did not seem to impact performance negatively, it should be taken into account. PMID- 28648751 TI - The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. AB - BACKGROUND: Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis. METHODS: We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1. FINDINGS: The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24.4% in UCSF and 32.3% in UTSW vs 10.7%, both p<0.0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33.3%, p=0.09; UTSW 32.0%, p=0.95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1.91, 95% CI 1.02-3.59, p=0.045) and short telomere length (adjusted OR per unit change in mean natural logarithm transformed ratio of telomere repeat copy number to single gene copy number 0.23, 0.09-0.59, p=0.002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0.006). INTERPRETATION: The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk. FUNDING: National Institutes of Health and Nina Ireland Program for Lung Health. PMID- 28648753 TI - Association of increased genotypes risk for bipolar disorder with brain white matter integrity investigated with tract-based spatial statistics: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summarise relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders. AB - BACKGROUND: Diffusion tensor imaging (DTI) studies, which allow the in-vivo investigation of brain tissue integrity, have shown that bipolar disorder (BD) patients present signs of white matter dysconnectivity. In parallel, genome-wide association studies (GWAS) identified several risk genetic variants for BD. I METHODS: In this mini-review, we summarized DTI studies coupling tract-based spatial statistics (TBSS), a reliable technique exploring white matter axon bundles, and genetics in BD. We performed a bibliographic search on PUBMED, using the search terms "TBSS", "genetics", "genome", "genes", "polymorphism", "bipolar disorder". RESULTS: Ten studies met these inclusion criteria. ANK3 and ZNF804A polymorphisms have shown the most consistent results, with the risk alleles showing abnormal white matter integrity in patients with BD. LIMITATIONS: Current studies are limited by the investigation of single SNPs in small and chronically treated samples. CONCLUSIONS: Most considered TBSS-DTI studies found associations between decreased white matter integrity and genetic risk variants. These results suggest an involvement of dysmyelination in the pathogenesis of BD. The combination of TBSS with genotyping can be powerful to unveil the role of white matter in BD, in conjunction with risk genes. Future DTI studies should combine TBSS and GWAS in large populations of drug-free or minimally treated patients with BD at the onset of the disease. PMID- 28648754 TI - What Can Human-Guided Simulations Bring to RNA Folding? AB - Inspired by the recent success of scientific-discovery games for predicting protein tertiary and RNA secondary structures, we have developed an open software for coarse-grained RNA folding simulations, guided by human intuition. To determine the extent to which interactive simulations can accurately predict 3D RNA structures of increasing complexity and lengths (four RNAs with 22-47 nucleotides), an interactive experiment was conducted with 141 participants who had very little knowledge of nucleic acids systems and computer simulations, and had received only a brief description of the important forces stabilizing RNA structures. Their structures and full trajectories have been analyzed statistically and compared to standard replica exchange molecular dynamics simulations. Our analyses show that participants gain easily chemical intelligence to fold simple and nontrivial topologies, with little computer time, and this result opens the door for the use of human-guided simulations to RNA folding. Our experiment shows that interactive simulations have better chances of success when the user widely explores the conformational space. Interestingly, providing on-the-fly feedback of the root mean square deviation with respect to the experimental structure did not improve the quality of the proposed models. PMID- 28648755 TI - High Expression of Long Noncoding RNA MALAT1 Indicates a Poor Prognosis and Promotes Clinical Progression and Metastasis in Bladder Cancer. AB - BACKGROUND: Recent studies have demonstrated that the expression of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cancer cell proliferation, invasion, and metastasis in many tumor types, but the association between bladder cancer and MALAT1 remains unknown. MATERIALS: The expression of MALAT1 was tested by in situ hybridization (ISH) in 120 bladder cancer specimens. The association between MALAT1 expression and clinicopathological features and prognosis of the patients with bladder cancer was analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the relationship between the expression of MALAT1 and progression and metastasis of bladder cancer. RESULTS: ISH showed that high MALAT1 expression was associated with advanced histological grade, high tumor stage, and positive lymph nodes. Kaplan-Meier survival analysis and Cox regression analysis indicated that high tumor stage, positive lymph nodes, and high MALAT1 expression were independent prognostic indicators for overall survival (OS) of patients with bladder cancer. qRT-PCR showed that the expression of MALAT1 in bladder cancer tissues was 2.85 times higher than those measured in adjacent normal tissues (P < .001). The expression of MALAT1 was 2.673 +/- 0.254 in non-muscle-invasive bladder cancer and 2.987 +/- 0.381 in muscle-invasive bladder cancer (P = .018). In bladder cancer specimens with positive lymph nodes, MALAT1 expression was 3.167 +/- 0.297 versus 2.896 +/- 0.329 in bladder cancer specimens with negative lymph nodes (P = .020). CONCLUSION: High MALAT1 expression could serve as an independent prognostic factor for OS of patients with bladder cancer and could be considered as a potential therapeutic target of bladder cancer. PMID- 28648756 TI - Clinicopathologic Features and Prognosis of Sporadic Bilateral Renal Cell Carcinoma: A Series of 148 Cases. AB - INTRODUCTION: The purpose of this study was to investigate the clinicopathologic features, treatment, and prognosis of sporadic bilateral renal cell carcinoma (RCC). PATIENTS AND METHODS: A total of 148 patients with sporadic bilateral RCC treated in our center from June 1986 to December 2015 were included in this retrospective study. Their clinicopathologic features and treatments were evaluated. The survival and prognostic factors were assessed based on data from follow-up. RESULTS: The median age was 54 years (range, 31-78 years). There were 88 patients with synchronous bilateral RCC and 60 with metachronous bilateral RCC. The median interval between bilateral tumors of metachronous bilateral RCC was 75.5 months. There was no significant difference in tumor size, nuclear grade, or T stage between metachronous tumors (P = .385, P = .544, and P = .263, respectively). Of 148 patients, 124 patients underwent bilateral surgery, 16 underwent unilateral surgery, and 8 patients did not undergo surgery. Of the 317 tumors with pathologic results, 297 (93.7%) were clear-cell subtype. A total of 136 (91.9%) patients were followed-up, and the median follow-up period was 77 months (range, 2-398 months). During follow-up, 38 (27.9%) patients died. The 5 year overall survival rate was 85.9%. The median survival time of patients with no surgery was 5 months. Older age (P = .001), bilateral nonoperative treatment (P < .001), higher T stage (P < .001), and multifocality (P = .02) were related to worse prognosis in multivariate analysis. CONCLUSION: In metachronous bilateral RCC, the latter occurrence does not bear a significantly worse pathologic biology. The prognosis of sporadic bilateral RCC with no surgery is poor. The overall oncologic results of patients with sporadic bilateral RCC are comparable with that of patients with unilateral RCC. PMID- 28648757 TI - Editor's Choice - Prolonged ICU Length of Stay after AAA Repair: Analysis of Time Trends and Long-term Outcome. AB - OBJECTIVE: The aim of the study was to investigate the frequency and outcome of prolonged intensive care unit (ICU) length of stay (LOS) after abdominal aortic aneurysm (AAA) repair in the endovascular era. METHODS: All patients operated on for AAA between 1999 and 2013 at Uppsala University hospital were identified. Data were retrieved from the Swedish Vascular registry, the Swedish Intensive Care registry, the National Population registry, and case records. Prolonged ICU LOS was defined as >= 48 h during the primary hospital stay. Patients surviving >= 48 h after AAA surgery were included in the analysis. RESULTS: A total of 725 patients were identified, of whom 707 (97.5%) survived >= 48 h; 563 (79.6%) underwent intact AAA repair and 144 (20.4%) ruptured AAA repair. A total of 548 patients (77.5%) required < 48 h of intensive care, 115 (16.3%) 2-6 days and 44 (6.2%) >= 7 days. The rate of prolonged ICU LOS declined considerably over time, from 41.4% of all AAA repairs in 1999 to 7.3% in 2013 (p < .001) whereas the use of endovascular aortic repair (EVAR) increased from 6.9% in 1999 to 78.0% in 2013 (p < .001). The 30 day survival rate was 98.2% for those with < 48 h ICU stay versus 93.0% for 2-6 days versus 81.8% for >= 7 days (p < .001); the corresponding 90 day survival was 97.1% versus 86.1% versus 63.6% (p < .001) respectively. For patients surviving 90 days after repair, there was no difference in long-term survival between the groups. CONCLUSION: During the period of progressively increasing use of EVAR, a simultaneous significant reduction in frequency of prolonged ICU LOS occurred. Although prolonged ICU LOS was associated with a high short-term mortality, long-term outcome among those surviving the initial 90 days was less affected. PMID- 28648758 TI - The time window for successful right-hemispheric language reorganization in children. AB - AIM: To identify, in a retrospective, observational study, the time window during which successful right-hemispheric language reorganization is possible after left hemispheric brain damage. METHOD: 25 patients (10 females; age 6-41 years; >=12 months after insult; age at insult 0;3-15;11 years) with acute, language-relevant left-hemispheric insults acquired during childhood and adolescence completed questionnaires for self-assessment of language problems. 12 patients of those reporting no (n = 8) or only moderate (n = 4) language problems participated in language fMRI. RESULTS: Language outcome of lesions occurring before 5 years of age (n = 7) was always favorable, and language was right-lateralized (2 patients: age at lesion < 2 years) or bilateral (3 patients: age at lesion 2-5 years). Following lesions occurring after 5 years of age, language outcome was often unfavorable (11/18 patients: moderate or severe problems), and of the 7 patients without problems, none showed right-hemispheric reorganization (fMRI available in 4). INTERPRETATION: The combination of normal language outcome and right hemispheric language reorganization after a left-hemispheric lesion sustained after the neonatal period is extremely rare. Functionally sufficient right hemispheric language was documented in only two patients with lesions acquired before two years of age. PMID- 28648760 TI - Corneal endothelial cells activate innate and acquired arm of anti-viral responses after cytomegalovirus infection. AB - Infection of the corneal endothelial cells by human cytomegalovirus (CMV) is an important cause of corneal endotheliitis. CMV endotheliitis is difficult to completely cure and relapses are frequent. This can cause blinding corneal bullous keratopathy. However, the pathogenesis of CMV endotheliitis remains undetermined. To understand the immunopathology of endotheliitis, we examined how corneal endothelial cells prime the anti-viral immunity after CMV infection based on global transcriptional responses. To accomplish this, human corneal endothelial (HCEn) cells were infected with CMV, and the global transcriptional responses were determined by microarray analyses for primary anti-viral responses using network analysis. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and protein array analyses were used to examine whether anti-viral cytokines were induced, i.e., to determine whether innate immune responses were activated. To examine whether priming of acquired immune response was activated, CMV-infected HCEn cells were co-cultured with allogeneic CD8+ T cells from CMV seropositive donors and tested for priming activity for the CD8+ effector T cells by measuring interferon-gamma secretion. The CMV-induced responses of HCEn cells were characterized by type I interferon and pattern recognition receptor pathways which represent innate immune priming. The global transcriptional activation was specifically associated with antigen presentation with the antimicrobial response functions. Protein array analyses indicated a significant increase in the secretion of anti-viral inflammatory cytokines including CXCL10 as innate immune responses. When HCEn cells were examined to determine whether CMV infection activated anti-viral acquired immunity, CMV-infected HCEn cells directly stimulated the proliferation of CD8+ T cells from CMV-seropositive donors, and pp65 viral epitope induced interferon-gamma secretion from the CD8+ T cells. We conclude that CMV-infected HCEn cells induce innate immune priming along with provisions of acquired immune priming of CD8+ effector T cells. This information should help in the development of useful diagnostic procedures and efficacious therapeutic strategy to treat refractory corneal endotheliitis. PMID- 28648761 TI - Improved JPEG anti-forensics with better image visual quality and forensic undetectability. AB - There is an immediate need to validate the authenticity of digital images due to the availability of powerful image processing tools that can easily manipulate the digital image information without leaving any traces. The digital image forensics most often employs the tampering detectors based on JPEG compression. Therefore, to evaluate the competency of the JPEG forensic detectors, an anti forensic technique is required. In this paper, two improved JPEG anti-forensic techniques are proposed to remove the blocking artifacts left by the JPEG compression in both spatial and DCT domain. In the proposed framework, the grainy noise left by the perceptual histogram smoothing in DCT domain can be reduced significantly by applying the proposed de-noising operation. Two types of denoising algorithms are proposed, one is based on the constrained minimization problem of total variation of energy and other on the normalized weighted function. Subsequently, an improved TV based deblocking operation is proposed to eliminate the blocking artifacts in the spatial domain. Then, a decalibration operation is applied to bring the processed image statistics back to its standard position. The experimental results show that the proposed anti-forensic approaches outperform the existing state-of-the-art techniques in achieving enhanced tradeoff between image visual quality and forensic undetectability, but with high computational cost. PMID- 28648759 TI - EphA2 and ephrin-A5 are not a receptor-ligand pair in the ocular lens. AB - Eph-ephrin bidirectional signaling is essential for eye lens transparency in humans and mice. Our previous studies in mouse lenses demonstrate that ephrin-A5 is mainly expressed in the anterior epithelium, where it is required for maintaining the anterior epithelial monolayer. In contrast, EphA2 is localized in equatorial epithelial and fiber cells where it is essential for equatorial epithelial and fiber cell organization and hexagonal cell shape. Immunostaining of lens epithelial and fiber cells reveals that EphA2 and ephrin-A5 are also co expressed in anterior fiber cell tips, equatorial epithelial cells and newly formed lens fibers, although they are not precisely colocalized. Due to this complex expression pattern and the promiscuous interactions between Eph receptors and ephrin ligands, as well as their complex bidirectional signaling pathways, cataracts in ephrin-A5(-/-) or EphA2(-/-) lenses may arise from loss of function or abnormal signaling mechanisms. To test whether abnormal signaling mechanisms may play a role in cataractogenesis in ephrin-A5(-/-) or EphA2(-/-) lenses, we generated EphA2 and ephrin-A5 double knockout (DKO) mice. We compared the phenotypes of EphA2(-/-) and ephrin-A5(-/-) lenses to that of DKO lenses. DKO lenses displayed an additive lens phenotype that was not significantly different from the two single KO lens phenotypes. Similar to ephrin-A5(-/-) lenses, DKO lenses had abnormal anterior epithelial cells leading to a large mass of epithelial cells that invade into the underlying fiber cell layer, directly resulting in anterior cataracts in ephrin-A5(-/-) and DKO lenses. Yet, similar to EphA2(-/-) lenses, DKO lenses also had abnormal packing of equatorial epithelial cells with disorganized meridional rows, lack of a lens fulcrum and disrupted fiber cells. The DKO lens phenotype rules out abnormal signaling by EphA2 in ephrin-A5(-/-) lenses or by ephrin-A5 in EphA2(-/-) lenses as possible cataract mechanisms. Thus, these results indicate that EphA2 and ephrin-A5 do not form a lens receptor-ligand pair, and that EphA2 and ephrin-A5 have other binding partners in the lens to help align differentiating equatorial epithelial cells or maintain the anterior epithelium, respectively. PMID- 28648762 TI - Repetitive deliberate fires: Development and validation of a methodology to detect series. AB - The detection of repetitive deliberate fire events is challenging and still often ineffective due to a case-by-case approach. A previous study provided a critical review of the situation and analysis of the main challenges. This study suggested that the intelligence process, integrating forensic data, could be a valid framework to provide a follow-up and systematic analysis provided it is adapted to the specificities of repetitive deliberate fires. In this current manuscript, a specific methodology to detect deliberate fires series, i.e. set by the same perpetrators, is presented and validated. It is based on case profiles relying on specific elements previously identified. The method was validated using a dataset of approximately 8000 deliberate fire events collected over 12 years in a Swiss state. Twenty possible series were detected, including 6 of 9 known series. These results are very promising and lead the way to a systematic implementation of this methodology in an intelligence framework, whilst demonstrating the need and benefit of increasing the collection of forensic specific information to strengthen the value of links between cases. PMID- 28648763 TI - Technical note: Intra-alveolar morphology assessed in empty dental sockets of teeth missing post-mortem. AB - Dental human identification relies on distinctive traits detected and compared between ante-mortem (AM) and post-mortem (PM) data. Several distinctive traits may be found in dental roots, such as dilacerations and bifurcations. However, teeth are often dislodged during the manipulation of skeletal remains, charred bodies and bodies retrieved from water. In these situations the identification process is hampered. The present study aims to retrieve information of teeth missing PM through the investigation of intra-alveolar morphology in empty dental sockets using different dental impression materials. This study was conducted using a dry human skull and 6 techniques for intra-alveolar impression, namely: (1) alginate using a dental tray; (2) heavy-body condensation silicone (HBCS) using manual compression; (3) HBSC using a blunt tip probe; (4) HBCS using a dental tray; (5) light- and HBCS using a syringe and a dental tray; and (6) polyether using a syringe and a dental tray. These techniques were evaluated based on 5 criteria: (I) intra-alveolar flow; (II) registration of apical morphology; (III) tensile strength; (IV) complexity; and (V) cost. The best outcomes considering the cost and benefit relation of each technique were observed in the following order: techniques #3>#2>#5>#6. Techniques #1 and #4 did not reach satisfactory outcomes for application in the forensic routine. Forensic dentists must be aware of the possibility of retrieving PM dental information even in the absence of teeth. The impression of intra-alveolar morphology may contribute significantly as source of PM dental information for human identifications. PMID- 28648764 TI - The riddle of thrombocytopenia following transcatheter aortic valve implantation. PMID- 28648765 TI - Adherence to Diabetes Dietary Guidelines Assessed Using a Validated Questionnaire Predicts Glucose Control in Adults With Type 2 Diabetes. AB - OBJECTIVES: The purpose of this study was to determine predominant deviations from Canadian Diabetes Association (CDA) nutrition therapy guidelines for Canadians with type 2 diabetes as a prelude to developing relevant interventions. We hypothesized that lack of adherence to these guidelines would be associated with higher glycated hemoglobin (A1C) levels. METHODS: A cross-sectional trial was conducted to evaluate associations between dietary adherence to CDA and Health Canada guidelines and blood glucose control. Diet was assessed using 3-day diet records and a diabetes-specific validated questionnaire, the Perceived Dietary Adherence Questionnaire (PDAQ). A total of 80 adult participants with type 2 diabetes volunteered. The main outcome measures were A1C levels, adherence to dietary guidelines and food sources of nutrients. Simple and multiple linear regressions that tested the effects of adherence to dietary guidelines concerning A1C levels were conducted; p<0.05 was considered significant. RESULTS: Participants: average age, 61.2+/-10.4 (standard deviation) years; 48 females and 32 males had A1C levels of 7.3%+/-1.3% (56+/-6.3 mmol/mol). Participants' reported mean daily intakes of sodium and saturated fat exceeded CDA nutrition therapy guidelines. Cured meats, fast foods and snack foods were all major contributors to intake of sodium and saturated fat. Saturated fat (r=0.341) and sodium intakes (r=0.296) and total PDAQ scores (r=-0.417) were correlated with A1C levels (p<0.05). CONCLUSIONS: This study population had overall good adherence to several CDA nutrition therapy guidelines; however, sodium and saturated fat intakes exceeded these guidelines and should receive particular attention in interventions with patients who have type 2 diabetes. Adherence to diabetes dietary guidelines as assessed by PDAQ is associated with lower A1C levels. PMID- 28648767 TI - Quality indicators for esophagogastroduodenoscopy: A comparative study of outcomes after an improvement programme in a tertiary hospital. AB - INTRODUCTION: There is an opportunity for improvement in the recording and measuring of quality indicators. However, no previous experiences exist in our field in terms of their compliance in esophagogastroduodenoscopy (EGD). OBJECTIVE: To analyse compliance with EGD quality criteria and evaluate improvement after conducting a training programme. PATIENTS AND METHODS: Comparative study of 2 cohorts: one retrospective (control group) and one prospective (intervention group), before and after a training programme consisting of an information session and the report writing improvement programme. The quality indicators proposed by the American Society for Gastrointestinal Endoscopy and the American College of Gastroenterology were used. RESULTS: A total of 1,200 EGDs were included in a sequential manner (600 in each group). Following the training programme, a significant improvement was observed in the following indicators: documented indication (93 vs. 99.8%; P<0.01), documented full examinations (94.7 vs. 97.3%; P<0.01), correct performance (63.7 vs. 87.9%; P<0.01), appropriate biopsies according to protocols (57.9 vs. 83.8%; P<0.01), photo-documentation of described lesions (84.1 vs. 94.9%; P<0.01), photo-documentation per segment (52.9 vs. 70.5%; P<0.01) and correct overall assessment (56,9 vs. 90.5%; P<0.01). Biopsies for coeliac disease, documented indication, full examination and correct performance, if it went ahead, exceeded the recommended standard. CONCLUSION: A very simple training programme improves EGD quality indicators, with the majority reaching the standards recommended by the American Society for Gastrointestinal Endoscopy and the American College of Gastroenterology. PMID- 28648766 TI - Age-, sex-, and diagnosis-specific incidence rate of medically certified long term sick leave among private sector employees: The Japan Epidemiology Collaboration on Occupational Health (J-ECOH) study. AB - BACKGROUND: Long-term sick-leave is a major public health problem, but data on its incidence in Japan are scarce. We aimed to present reference data for long term sick-leave among private sector employees in Japan. METHODS: The study population comprised employees of 12 companies that participated in the Japan Epidemiology Collaboration on Occupational Health Study. Details on medically certified sick-leave lasting >=30 days were collected from each company. Age- and sex-specific incidence rate of sick-leave was calculated for the period of April 2012 to March 2014. RESULTS: A total of 1422 spells in men and 289 in women occurred during 162,989 and 30,645 person-years of observation, respectively. The three leading causes of sick-leave (percentage of total spells) were mental disorders (52%), neoplasms (12%), and injury (8%) for men; and mental disorders (35%), neoplasms (20%), and pregnancy-related disease (14%) for women. Incidence rate of sick-leave due to mental disorders was relatively high among men in their 20s-40s but tended to decrease with age among women. Incidence rate of sick-leave due to neoplasms started to increase after age 50 in men and after age 40 in women, making neoplasms the leading cause of sick-leave after age 50 for women and after age 60 for men and the second leading cause after age 40 for women and after age 50 for men. Pregnancy-related disease was the second leading cause of sick-leave among women aged 20-39 years. CONCLUSIONS: These results suggest that mental disorder, neoplasms, and pregnancy-related disease are the major causes of long-term sick-leave among private sector employees in Japan. PMID- 28648768 TI - Management of ventral hernia during bariatric surgery: a plea for quality data for quality improvement. PMID- 28648769 TI - Editorial review for "systematic review of patient education practices in weight loss surgery". PMID- 28648770 TI - The role of bariatric endoscopy in the management of obesity. PMID- 28648772 TI - Clinical outbreak of babesiosis caused by Babesia capreoli in captive reindeer (Rangifer tarandus tarandus) in the Netherlands. AB - From a herd of captive reindeer (Rangifer tarandus tarandus) consisting of two males and seven females with five calves, three calves were diagnosed on post mortem examination with a Babesia capreoli infection. The diagnosis was indicated by PCR and when the other reindeer were examined two adult females and a one-year old male were Babesia-positive. Molecular characterization of the 18S rDNA of the parasite showed complete identity with known B. capreoli sequences. Ixodes ricinus has been demonstrated to be a competent vector for B. capreoli from infected roe deer (Capreolus capreolus), the natural host of B. capreoli. The B. capreoli infection in these reindeer may have been transmitted by infected ticks (Ixodes ricinus) originating from roe deer living in the forest and meadows surrounding the enclosure. PMID- 28648773 TI - The burden of tick-borne diseases in the Altai region of Russia. AB - This article presents the results of a comprehensive survey of the burden of tick borne infectious diseases (TBIDs) in the Altai region of Russia. Official data for TBID incidence were analyzed and 201 samples from patients with suspected TBID were studied. Furthermore, questing ticks and ticks recovered from humans were examined to estimate prevalence of TBID-causative agents. The Altai region was determined to have a heightened risk for TBIDs in Russia. The most epidemiologically significant tick-borne illness in this area is spotted fever group rickettsiosis, while nationally in Russia, the leading TBID is Lyme borreliosis. The prevalence of mixed infection was 12.4% among the studied cases. Additionally, the prevalence of poorly studied pathogens - Kemerovo virus (KEMV) and Rickettsia tarasevichiae - in ticks from the Altai region was determined. PMID- 28648774 TI - The Carmat Bioprosthetic Total Artificial Heart Is Associated With Early Hemostatic Recovery and no Acquired von Willebrand Syndrome in Calves. AB - OBJECTIVES: To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after implantation of a new bioprosthetic and pulsatile total artificial heart (TAH). DESIGN: Preclinical study SETTING: Single-center biosurgical research laboratory. PARTICIPANTS: Female Charolais calves, 2-to-6 months old, weighing 102-to-122 kg. INTERVENTIONS: Surgical implantation of TAH through a mid-sternotomy approach. MEASUREMENTS AND MAIN RESULTS: Four of 12 calves had a support duration of several days (4, 4, 8, and 10 days), allowing for the exploration of early steps of hemostasis parameters, including prothrombin time; coagulation factor levels (II, V, VII+X, and fibrinogen); and platelet count. Multimeric analysis of VWF was performed to detect a potential loss of high-molecular weight (HMW) multimers, as previously described for continuous flow rotary blood pumps. Despite the absence of anticoagulant treatment administered in the postoperative phase, no signs of coagulation activation were detected. Indeed, after an immediate postsurgery decrease of prothrombin time, platelet count, and coagulation factor levels, most parameters returned to baseline values. HMW multimers of VWF remained stable either after initiation or during days of support. CONCLUSIONS: Coagulation parameters and platelet count recovery in the postoperative phase of the Carmat TAH (Camat SA, Velizy Villacoublay Cedex, France) implantation in calves, in the absence of anticoagulant treatment and associated with the absence of decrease in HMW multimers of VWF, is in line with early hemocompatibility that is currently being validated in human clinical studies. PMID- 28648775 TI - Systolic Anterior Motion of the Mitral Valve With Left Ventricular Outflow Tract Obstruction: A Rare Cause of Hypotension After Lung Transplantation. PMID- 28648776 TI - The Emperor Has No Clothes: Recognizing the Limits of Current Echocardiographic Technology in Perioperative Quantification of Mitral Regurgitation. PMID- 28648777 TI - mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. AB - Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions. PMID- 28648778 TI - DNA Replication Is Required for Circadian Clock Function by Regulating Rhythmic Nucleosome Composition. AB - Although the coupling between circadian and cell cycles allows circadian clocks to gate cell division and DNA replication in many organisms, circadian clocks were thought to function independently of cell cycle. Here, we show that DNA replication is required for circadian clock function in Neurospora. Genetic and pharmacological inhibition of DNA replication abolished both overt and molecular rhythmicities by repressing frequency (frq) gene transcription. DNA replication is essential for the rhythmic changes of nucleosome composition at the frq promoter. The FACT complex, known to be involved in histone disassembly/reassembly, is required for clock function and is recruited to the frq promoter in a replication-dependent manner to promote replacement of histone H2A.Z by H2A. Finally, deletion of H2A.Z uncoupled the dependence of the circadian clock on DNA replication. Together, these results establish circadian clock and cell cycle as interdependent coupled oscillators and identify DNA replication as a critical process in the circadian mechanism. PMID- 28648779 TI - Natural RNA Polymerase Aptamers Regulate Transcription in E. coli. AB - In search for RNA signals that modulate transcription via direct interaction with RNA polymerase (RNAP), we deep sequenced an E. coli genomic library enriched for RNAP-binding RNAs. Many natural RNAP-binding aptamers, termed RAPs, were mapped to the genome. Over 60% of E. coli genes carry RAPs in their mRNA. Combining in vitro and in vivo approaches, we characterized a subset of inhibitory RAPs (iRAPs) that promote Rho-dependent transcription termination. A representative iRAP within the coding region of the essential gene, nadD, greatly reduces its transcriptional output in stationary phase and under oxidative stress, demonstrating that iRAPs control gene expression in response to changing environment. The mechanism of iRAPs involves active uncoupling of transcription and translation, making nascent RNA accessible to Rho. iRAPs encoded in the antisense strand also promote gene expression by reducing transcriptional interference. In essence, our work uncovers a broad class of cis-acting RNA signals that globally control bacterial transcription. PMID- 28648782 TI - Traumatic Thoracic Burst Fracture Associated with Bronchial Rupture. AB - BACKGROUND: Rupture of, or injury to, the tracheobronchial tree is a rare occurrence in blunt chest trauma. CASE REPORT: We present a case of bronchial rupture caused by fragmented bone from a spinal burst fracture after blunt chest trauma. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although tracheobronchial injury is infrequent, clinicians should be aware of this possible complication after blunt chest trauma. Bronchoscopy can help in the diagnosis. PMID- 28648783 TI - An Unusual Cause of Dynamic Airway Obstruction. PMID- 28648780 TI - The Histone Acetyltransferase Mst2 Protects Active Chromatin from Epigenetic Silencing by Acetylating the Ubiquitin Ligase Brl1. AB - Faithful propagation of functionally distinct chromatin states is crucial for maintaining cellular identity, and its breakdown can lead to diseases such as cancer. Whereas mechanisms that sustain repressed states have been intensely studied, regulatory circuits that protect active chromatin from inactivating signals are not well understood. Here we report a positive feedback loop that preserves the transcription-competent state of RNA polymerase II-transcribed genes. We found that Pdp3 recruits the histone acetyltransferase Mst2 to H3K36me3 marked chromatin. Thereby, Mst2 binds to all transcriptionally active regions genome-wide. Besides acetylating histone H3K14, Mst2 also acetylates Brl1, a component of the histone H2B ubiquitin ligase complex. Brl1 acetylation increases histone H2B ubiquitination, which positively feeds back on transcription and prevents ectopic heterochromatin assembly. Our work uncovers a molecular pathway that secures epigenome integrity and highlights the importance of opposing feedback loops for the partitioning of chromatin into transcriptionally active and inactive states. PMID- 28648781 TI - PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response. AB - Mec1ATR mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATR response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs. PMID- 28648784 TI - [Control of cardiovascular risk factors in coronary patients one year after cardiac rehabilitation]. AB - OBJECTIVE: To assess risk factors monitoring in coronary patients one year after cardiac rehabilitation. METHOD: From 2015 to 2015, cardiac morbidity, total mortality and risk factors data were collected from a 4-week ambulatory cardiac rehabilitation program with a control one year later and were compared with the results of Euroaspire and Reach studies. RESULTS: Out of 1091 (87%) coronary patients, 746 (68%) were re-examined 12months later (aged 60years (ranging from 20 to 85years), 15% women, 44% hypertensive, 36% smokers, 17% diabetics, 74% with dyslipidemia). At the end of the program, management of CV risk factors was improved (BP <= 140/90mmHg and BMI > 30: 80 and 20% vs 65 and 25% at the beginning of the program; LDL < 0.7g/L: 42% and smoking: 4% vs 18% when hospitalized for their cardiac event). Unfortunately, this benefit decreased significantly at one year (BP <= 140/90mmHg: 63%, LDL < 0.7g/L: 27%; smoking: 6%) but it remains better than in Euroaspire IV study: 57, 20 et 16% respectively). While 54% had insufficient physical activity before cardiac rehabilitation, they were only 23% at 1-year vs 60% in Euroaspire study. We reported a total mortality of 0.6% vs 2.9% in Reach study and 12% cardiac hospitalization (53% for a new coronary event). CONCLUSION: Participation of coronary patients in a cardiac rehabilitation program significantly improves management of CV risk factors, morbidity and mortality. However, the control obtained at the end of the program decreases at one year. PMID- 28648785 TI - LC-MS bioanalysis of Trastuzumab and released emtansine using nano-surface and molecular-orientation limited (nSMOL) proteolysis and liquid-liquid partition in plasma of Trastuzumab emtansine-treated breast cancer patients. AB - Antibody-drug conjugates (ADCs) consist of monoclonal antibody and cytotoxic drugs covalently attached via stable crosslinkers, and are prospective antibody drugs for cancer therapy. To cover the overall pharmacokinetic understanding of ADCs, both the antibody and the released drugs are necessary for practical clinical observation. The nano-surface and molecular-orientation limited (nSMOL) proteolysis is a universal approach for antibody bioanalysis that enable Fab selective proteolysis, which maintains antibody sequence specificity while decreasing excess analyte peptides. In this study, we describe quantitative assays for ADC in human plasma using nSMOL for the antibody and polarity selective liquid-liquid partition with a methanol/ethyl acetate mixed solvent for the cytotoxic drugs. This approach led to the successful development of LC-MS validated bioanalysis of the antibody and released drugs within 20% for lower limit of quantitation and 15% for another concentration setting of Trastuzumab emtansine (T-DM1), Trastuzumab antibody and emtansine conjugated with crosslinker (DM1-MCC). The validated concentration ranges in human plasma were 0.06-250MUg/mL for T-DM1 and 0.39-200ng/mL for DM1-MCC. These results indicate that LC-MS method with a two-sided approach, using nSMOL and liquid-liquid partition, show potential for the precise pharmacokinetic study for ADC development and treatment. PMID- 28648786 TI - Selective screening of glutaric acid acidurias by capillary electrophoresis-mass spectrometry. AB - A sensitive and selective method for the separation and quantification of the three organic acids 3-hydroxy-3-methylglutaric acid, 3-methylglutaric acid, and glutaric acid in human urine samples by CE with mass spectrometry detection has been developed. This methodology is faster, simpler and less time-consuming, than other methodologies previously described, and requires of reduced amounts of reagents as well. Samples are first filtered and then diluted in water. For the electrophoretic separation, a 20mM ammonium acetate and 10% methanol solution at pH 9.1 was selected as the running electrolyte. With 5-s hydrodynamic injection, detection limits ranging from 15.5 to 39.3MUM and linear responses ranging from the LOQ calculated for each analyte to more than 400MUM were obtained for the analysis of the different organic acids in less than 13min. Remarkable selectivity is achieved by mass spectrometry detection using 0.25% of formic acid in 50% v/v 2-propanol-water solution as sheath liquid, and enough sensitivity without interferences from the matrices was obtained as well. This methodology has revealed as an efficient approach to help the 3-hydroxy-3-methylglutaric aciduria diagnoses in order to discard or confirm the occurrence of the disease as of the presence or absence of the expected increased levels of these analytes in samples of potential patients. PMID- 28648787 TI - Online turbulent flow extraction coupled with liquid chromatography-tandem mass spectrometry for high throughput screening of anabolic steroids in horse urine. AB - A high throughput method for simultaneous screening of anabolic steroids and their metabolites (4-esterendione, trenbolone, boldenone, oxandrolone, nandrolone, methandrostenolone, testosterone, 1-androstendione, ethisterone, normethandrolone, methyltestosterone, 16beta-Hydroxystanozolol, epitestosterone, bolasterone, norethandrolone, danazol, stanozolol and androstadienone) in equine urine by online turbulent flow extraction coupled with liquid chromatography tandem mass spectrometry was developed. The use of turbulent flow chromatography could simplify pretreatment of horse urine, which has complex matrices as well as high viscosity. The urine was extracted by mixed-mode cation exchange solid phase extraction, and hydrolyzed using beta-glucuronidase/arylsulfatase. Then, the sample was automatically loaded on the TurboFlow Cyclone extraction column for removal of further matrix, followed by separation on a fused core C18 column before MS/MS detection. Optimization and validation of the method were discussed in detail. All analytes were rapidly detected within 10min with high sensitivity (picogram to nanogram per milliliter level), and no interference was observed. The linearity range was from 0.1-10ng/mL for nine steroids and 1.0-50ng/mL for the others, with correlation of coefficient values over 0.995. Precision and accuracy ranged from 0.1 to 14.5% and 1.7 to 12.4%, respectively. The developed method was successfully applied to the analysis of anabolic steroids in horse urine after administration of a model drug. PMID- 28648788 TI - Development of a mixed-mode chromatography with tandem mass spectrometry method for the quantitative analysis of 23 underivatized amino acids in human serum. AB - In this study, a robust, selective and simplified method was developed and validated for the simultaneous quantitative analysis of 23 underivatized amino acids in human serum using mixed-mode chromatography with tandem mass spectrometry (LC-MS/MS). Serum samples were deproteinized with acetonitrile and subjected to LC-MS/MS analysis. The chromatographic separation of amino acids was achieved using a mixed-mode column (150*3mm, 3MUm) with a gradient elution system; the mobile phase consisted of 50mM ammonium formate and 0.1% formic acid in acetonitrile. The total run time was 22min. Eluted compounds were detected in the electrospray ionization-positive mode with multiple reaction monitoring. The validation study evaluated linearity, repeatability, intra and inter-day accuracy and precision, and matrix effect. The validation results were satisfactory in all the tested parameters. This method was successfully applied to the analysis of amino acids in the clinical sample of human serum. PMID- 28648789 TI - Detection of West Nile Virus and other common equine viruses in three locations from the Leeward Islands, West Indies. AB - Equines in the West Indies are used for recreational purposes, tourism industry, racing and agriculture or can be found in feral populations. Little is known in the Caribbean basin about the prevalence of some major equine infectious diseases, some with zoonotic potential, listed as reportable by the OIE. Our objective was to study the prevalence of antibodies for West Nile Virus (WNV), Equine Herpes Virus-1 and 4 (EHV-1 and EHV-4), Equine Influenza (EI), Equine Viral Arteritis (EVA) and Equine Infectious Anemia Virus (EIAV) using a retrospective serological convenience study. We used 180 equine serum samples, 140 from horses and 40 from donkeys in St. Kitts, Nevis, and Sint Eustatius, collected between 2006 and 2015 that were tested with ELISA kits and virus neutralization (for WNV and EVA). Combining ELISA with virus neutralization testing, 25 (13.8%) equine sera were WNV positive (a mixture of indigenous and imported equines) and 3 sera (1.6%) showed doubtful results. For EHV-1, 41 equines (23.7%), mean age 6.7 years, were seropositive. For EHV-4, 138 equines were found seropositive (82.8%), mean age 6.3 years. For EI, 49 equines (27.2%), mean age 7.5 years, were seropositive on ELISA, some previously vaccinated horses. No antibodies against EAV were found on virus neutralization testing, although one animal (0.6%), was EAV positive on ELISA. All samples were EIAV negative. The seroprevalence for EHV-1 and EHV-4 is similar to other parts of the world. For the first time in the study location serologic evidence of antibodies against WNV and EI is reported. This was found in both indigenous and imported animals, highlighting the need for developing proper surveillance plans based on complementary methods of virus detection. Further studies will be needed to define the prevalence, rates of transmission, characterize local virus strains, and study their impact on these populations. PMID- 28648791 TI - Drug-eluting stents versus control therapy in the infrapopliteal disease: A meta analysis of eight randomized controlled trials and two cohort studies. AB - BACKGROUD: Drug-eluting stents (DES) have been proposed for the treatment of infrapopliteal arteries disease. However, the long-term clinical impact of DES treatment in the vascular territory still remains uncertain. METHODS AND RESULTS: Pubmed, Embase, Cochrane data, CNKI and Wanfang Data were searched until December 20, 2016 for eligible studies according to identical strategies. Additional data were manually retrieved. STATA ver. 12.0 software were used to Meta-analyze the efficacies of DES and control treatment (BMS or PTA) for infrapopliteal arteries disease. A total of 927 patients from 10 studies (8 randomized controlled trials and 2 cohort studies) were assigned to DESs (n = 484) versus control treatment (n = 443). The results showed that infrapopliteal DES therapy yielded higher primary patency and EFS, while decreased the risk of restenosis at 12-months compared to controls significantly. At 3 years there were no significant differences between two groups, pooled RRs and 95% CI were 1.639 [0.526-5.105], P = 0.394; 1.197 [0.432-3.317], P = 0.729 and 0.992 [0.960-1.024], P = 0.661, respectively. Subgroup analysis showed that infrapopliteal DES therapy using Sirolimus-eluting stents rather than Everolimus-eluting stents provided higher clinic benefits. Infrapopliteal DES therapy yielded no significant difference for TLR, overall survival, Rutherford-Becker class improvement, limb amputation at 12-months and 3 years compared with control treatment. CONCLUSIONS: The results of the present meta-analysis indicate the non-superiority of infrapopliteal DES therapy over control therapies (BMS/PTA) at 3 years, although short-term benefits at 12 months after DES therapy were evident. Further randomized trials with longer follow-up are required to provide the best scientific evidence regarding the preferred endovascular treatment for patients with occlusive disease of infrapopliteal arteries. PMID- 28648790 TI - Larval stress alters dengue virus susceptibility in Aedes aegypti (L.) adult females. AB - In addition to genetic history, environmental conditions during larval stages are critical to the development, success and phenotypic fate of the Aedes aegypti mosquito. In particular, previous studies have shown a strong genotype-by environment component to adult mosquito body size in response to optimal vs stressed larval conditions. Here, we expand upon those results by investigating the effects of larval-stage crowding and nutritional limitation on the susceptibility of a recent field isolate of Aedes aegypti to dengue virus serotype-2. Interestingly, female mosquitoes from larvae subjected to a stressed regime exhibited significantly reduced susceptibility to disseminated dengue infection 14days post infection compared to those subjected to optimal regimes. Short term survivorship post-infected blood feeding was not significantly different. As with body size, dengue virus susceptibility of a mosquito population is determined by a combination of genetic and environmental factors and is likely maintained by balancing selection. Here, we provide evidence that under different environmental conditions, the innate immune response of field reared mosquitoes exhibits a large range of phenotypic variability with regard to dengue virus susceptibility. Further, as with body size, our results suggest that mosquitoes reared under optimal laboratory conditions, as employed in all mosquito-pathogen studies to date, may not always be realistic proxies for natural populations. PMID- 28648792 TI - Do the complications increased in the anterolateral right-side approach to treat the cervical degenerative disorders? PMID- 28648793 TI - Decompression and coflex interlaminar stabilization compared with conventional surgical procedures for lumbar spinal stenosis: A systematic review and meta analysis. PMID- 28648795 TI - Povidone iodine in wound healing: A review of current concepts and practices. AB - BACKGROUND: Of the many antimicrobial agents available, iodophore-based formulations such as povidone iodine have remained popular after decades of use for antisepsis and wound healing applications due to their favorable efficacy and tolerability. Povidone iodine's broad spectrum of activity, ability to penetrate biofilms, lack of associated resistance, anti-inflammatory properties, low cytotoxicity and good tolerability have been cited as important factors, and no negative effect on wound healing has been observed in clinical practice. Over the past few decades, numerous reports on the use of povidone iodine have been published, however, many of these studies are of differing design, endpoints, and quality. More recent data clearly supports its use in wound healing. METHODS: Based on data collected through PubMed using specified search criteria based on above topics and clinical experience of the authors, this article will review preclinical and clinical safety and efficacy data on the use of povidone iodine in wound healing and its implications for the control of infection and inflammation, together with the authors' advice for the successful treatment of acute and chronic wounds. RESULTS AND CONCLUSION: Povidone iodine has many characteristics that position it extraordinarily well for wound healing, including its broad antimicrobial spectrum, lack of resistance, efficacy against biofilms, good tolerability and its effect on excessive inflammation. Due to its rapid, potent, broad-spectrum antimicrobial properties, and favorable risk/benefit profile, povidone iodine is expected to remain a highly effective treatment for acute and chronic wounds in the foreseeable future. PMID- 28648796 TI - Efficacy and safety of programmable shunt valves for hydrocephalus: A meta analysis. AB - OBJECTIVES: Shunt implantation is an option in the treatment of hydrocephalus. However, the benefits and adverse effects of programmable shunt valves have not been well assessed. MATERIALS AND METHODS: Randomized controlled trials (RCTs) and observational studies assessing the efficacy and safety of programmable valves (PV) treatment for hydrocephalus were identified from electronic databases (PubMed, EMBASE, and Cochrane library). The meta-analysis was performed with the fixed-effect model or random-effect model according to heterogeneity. RESULTS: Three RCTs and eight observational studies met the inclusion criteria including 2622 subjects. Compared with non-PV, PV treatment did not have a statistically significant effect on one-year shunt survival rate [relative risk (RR), 1.06; 95% confidence interval (CI), 0.84-1.35], Substantial heterogeneity was observed between studies (P = 0.09; I2 = 65%). PV administration significantly reduced revision rate (RR, 0.56; 95% CI, 0.45-0.69; I2 = 29%; P = 0.23) and over- or under-drainage complications rate (RR, 0.55; 95% CI, 0.32-0.96). PV was not associated with increased rates of other adverse events, including overall complications rate, infection rate and catheter-related complications rate. CONCLUSIONS: PV treatment is safe and may reduce the revision rate and over- or under-drainage complication rate, especially in patients aged less than 18 years with hydrocephalus. PV treatment is not associated with decreased overall complication rates in patients with hydrocephalus, but the trial sequential analysis indicate more studies are needed to confirm this result. PMID- 28648794 TI - In vitro and in vivo evaluation of a small-caliber coaxial electrospun vascular graft loaded with heparin and VEGF. AB - INTRODUCTION: To date, clinically available expanded polytetrafluoro-ethylene (ePTFE) vascular grafts are suboptimal for reconstructing small caliber (D < 6 mm) arteries, owing to thrombosis in early and restenosis in late stage. Our aim in this preliminary study was to fabricate a nano-fibrous vascular graft which was biofunctionalized with VEGF165 and heparin. The short term performance was evaluated both in vitro and in vivo. METHOD: Four-mm caliber grafts were prepared by the coaxial-elctrospun technique, which consisted of poly(l-lactide-co caprolactone) [P(LLA-CL)] collagen and elastin. Heparin and endothelial cell growth factor-165 (VEGF165) were encapsulated in the core of the fibrous. Controlled release of the heparin and VEGF165 were evaluated for 28 days. Endothelial cells were cultured on the electrospun grafts or ePTFE grafts as controls. The cellular adhesion, proliferation and morphology were examined. Electrospun or ePTFE grafts were randomly implanted into a rabbit infrarenal aortic replacement model (n = 30) for 28 days without any antiplatelet therapy. At the termination, all grafts were examined by Doppler ultrasound and then evaluated with histology and scanning electron microscopy. RESULTS: The cumulative release amount of heparin (6.93 +/- 1.03 mg) and VEGF165 (22.17 +/- 5.56 MUg) during 28 days were measured. Endothelial cells cultured on electrospun grafts showed significantly higher attachment efficiency and proliferation compared to the ePTFE ones (P < 0.001). At 2 h more ECs had attached to the P(LLA CL)/Collagen/Elatin grafts (83.26 +/- 8.02%) compared to P(LLA-CL) (67.07 +/- 4.16%) and ePTFE (46.87 +/- 8.85%). ECs proliferated faster on VEGF loaded grafts (O.D = 2.9 +/- 1.2, n = 12) compared to ePTFE (O.D = 1.7 +/- 1.0, n = 12). The patency was significantly higher in electrospun grafts (86.6%) than ePTFE grafts (40.0%) (P = 0.021). Correspondingly, the microscope images of electrospun implants showed little thrombus when compared with the ePTFE implants. CONCLUSION: Biofunctionalized electrospun graft showed surgical properties, hemocompatibility and higher short-term patency compared with the ePTFE grafts. Despite good early performances, profound study should be designed for long-term evaluation. PMID- 28648797 TI - Protocols in contemporary epilepsy surgery-a short communication. PMID- 28648798 TI - Zoonotic Parasites of Sheltered and Stray Dogs in the Era of the Global Economic and Political Crisis. AB - Sheltered and stray dogs, exposed to zoonotic parasites, including protozoa, helminths, and arthropods, may represent a major threat to public health. Resources for addressing health problems in these animals are not on the priority list of veterinary and public health authorities. Thus, dogs continue to represent an important reservoir for zoonotic parasites. In this article, we review the importance of sheltered and stray dogs as reservoirs of zoonotic parasites in different parts of the world, especially in the context of the current global political and economic crisis. PMID- 28648800 TI - An open letter to the Cochrane Collaboration. PMID- 28648801 TI - Clinical effects of antivirals for hepatitis C: context is critical. PMID- 28648799 TI - Fgf8 Expression and Degradation of Retinoic Acid Are Required for Patterning a High-Acuity Area in the Retina. AB - Species that are highly reliant on their visual system have a specialized retinal area subserving high-acuity vision, e.g., the fovea in humans. Although of critical importance for our daily activities, little is known about the mechanisms driving the development of retinal high-acuity areas (HAAs). Using the chick as a model, we found a precise and dynamic expression pattern of fibroblast growth factor 8 (Fgf8) in the HAA anlage, which was regulated by enzymes that degrade retinoic acid (RA). Transient manipulation of RA signaling, or reduction of Fgf8 expression, disrupted several features of HAA patterning, including photoreceptor distribution, ganglion cell density, and organization of interneurons. Notably, patterned expression of RA signaling components was also found in humans, suggesting that RA also plays a role in setting up the human fovea. PMID- 28648802 TI - To TACE or not to TACE? Lessons from a negative trial. PMID- 28648804 TI - The single IGF-1 partial deficiency is responsible for mitochondrial dysfunction and is restored by IGF-1 replacement therapy. AB - BACKGROUND & AIMS: We previously described in cirrhosis and aging, both conditions of IGF-1 deficiency, a clear hepatic mitochondrial dysfunction with increased oxidative damage. In both conditions, the hepatic mitochondrial function was improved with low doses of IGF-1. The aim of this work was to explore if the only mere IGF-1 partial deficiency, without any exogenous insult, is responsible for hepatic mitochondrial dysfunction. METHODS: Heterozygous (igf1+/-) mice were divided into two groups: untreated and treated mice with low doses of IGF-1. WT group was used as controls. Parameters of hepatic mitochondrial function were determined by flow cytometry, antioxidant enzyme activities were determined by spectrophotometry, and electron chain transport enzyme levels were determined by immunohistochemistry and immunofluorescence analyses. Liver expression of genes coding for proteins involved in mitochondrial protection and apoptosis was studied by microarray analysis and RT-qPCR. RESULTS: Hz mice showed a significant reduction in hepatic mitochondrial membrane potential (MMP) and ATPase activity, and an increase in intramitochondrial free radical production and proton leak rates, compared to controls. These parameters were normalized by IGF-1 replacement therapy. No significant differences were found between groups in oxygen consumption and antioxidant enzyme activities, except for catalase, whose activity was increased in both Hz groups. Relevant genes coding for proteins involved in mitochondrial protection and survival were altered in Hz group and were reverted to normal in Hz+IGF-1 group. CONCLUSIONS: The mere IGF-1 partial deficiency is per se associated with hepatic mitochondrial dysfunction sensitive to IGF-1 replacement therapy. Results in this work prove that IGF-1 is involved in hepatic mitochondrial protection, because it is able to reduce free radical production, oxidative damage and apoptosis. All these IGF-1 actions are mediated by the modulation of the expression of genes encoding citoprotective and antiapoptotic proteins. PMID- 28648805 TI - Animal Social Network Theory Can Help Wildlife Conservation. AB - Many animals preferentially associate with certain other individuals. This social structuring can influence how populations respond to changes to their environment, thus making network analysis a promising technique for understanding, predicting, and potentially manipulating population dynamics. Various network statistics can correlate with individual fitness components and key population-level processes, yet the logical role and formal application of animal social network theory for conservation and management have not been well articulated. We outline how understanding of direct and indirect relationships between animals can be profitably applied by wildlife managers and conservationists. By doing so, we aim to stimulate the development and implementation of practical tools for wildlife conservation and management and to inspire novel behavioral research in this field. PMID- 28648803 TI - Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. AB - BACKGROUND: Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. METHODS: We did a multicentre, randomised, placebo controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum alpha-fetoprotein concentration (<400 ng/mL and >=400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. FINDINGS: Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389.2-800.0) sorafenib versus 800 mg (758.2-800.0) placebo, and median duration of therapy was 120.0 days (IQR 43.0-266.0) for sorafenib versus 162.0 days (70.0-323.5) for placebo. There was no evidence of difference in progression free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0.99 [95% CI 0.77-1.27], p=0.94); median progression-free survival was 238.0 days (95% CI 221.0-281.0) in the sorafenib group and 235.0 days (209.0-322.0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. INTERPRETATION: The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. FUNDING: Bayer PLC and BTG PLC. PMID- 28648806 TI - The Evolutionary Consequences of Stepwise Infection Processes. AB - Molecular and cellular studies reveal that the resistance of hosts to parasites and pathogens is a cascade-like process with multiple steps required to be passed for successful infection. By contrast, much of evolutionary reasoning is based on strongly simplified, one- or two-step infection processes with simple genetics or on resistance being a quantitative trait. Here we attempt a conceptual unification of these two perspectives with the aim of cross-fostering research and filling some of the gaps in our concepts of the ecology and evolution of disease. This conceptual unification has a profound impact on the way we understand the genetics and evolution of host resistance, ecological immunity, evolution of virulence, defence portfolios, and host-pathogen coevolution. PMID- 28648807 TI - Dehydration and starvation yield energetic consequences that affect survival of the American dog tick. AB - Ticks are obligate hematophagous arthropods, but may have to endure extended time (1-2years) between feedings. During these off-host periods, ticks must contend with a multitude of environmental stresses including prolonged or repeated exposure to desiccating conditions. In this study, we measured the energetic consequences of single and repeated bouts of dehydration of American dog ticks, Dermacentor variabilis, and examined the impact of energy reserves on tick survival during dehydration. Recently molted ticks exposed to a single period at 0% relative humidity (RH) for 5d lost ~26% of their body water and showed 1.3- and 1.7-fold reductions in protein and lipid, respectively. These reduced energy reserves coincided with increased O2 consumption in dehydrated ticks. Exposure to repeated cycles of dehydration (0% RH, 48h) and rehydration (100% RH, 24h) also reduced energy reserves; however, ticks were able to fully recover their body water after 12 cycles of dehydration/rehydration and endured >20 cycles. Starvation of ticks, in the absence of dehydration, for 18 or 36weeks resulted in the loss of ~20-40% of protein and 60% of lipid reserves. When ticks were exposed to continuous dehydration at 0% RH, their survival after 18weeks of starvation was only minimally impacted; however, individuals starved for 36weeks succumbed to dehydration much more rapidly than recently fed ticks. Both single and repeated dehydration exposures resulted in substantial energetic costs and ticks with limited energy reserves were more susceptible to dehydration-induced mortality, indicating that adequate energy reserves are critical for tolerance to dehydration stress and long-term success of ticks. PMID- 28648808 TI - Are characteristics of hospitals associated with outcome after cardiac arrest? Insights from the Great Paris registry. AB - PURPOSE: As post-cardiac arrest care may influence patients' outcome, characteristics of receiving hospitals should be integrated in the evaluation of survival. We aimed at assessing the influence of care level center on patients' survival at hospital discharge using a regional registry of out-of-hospital cardiac arrest patients (OHCA). METHODS: We retrospectively analysed a Utstein and in-hospital data prospectively collected for all non-traumatic OHCA patients, in whom a successful return of spontaneous circulation (ROSC) had been obtained, from a large metropolitan area (Great Paris). Receiving hospitals were categorized in 3 groups as follows: A centers (High-case volume with cath-lab 24/7), B centers (Intermediate-case volume with cath-lab partly available) and C centers (Low-case volume and no cath-lab) We compared patients' characteristics and outcome in the 3 groups and performed a multivariate logistic regression using survival to discharge as primary endpoint. RESULTS: Between May 2011 and December 2013, 1476 patients were admitted in 48 hospitals (group A: n=917; group B: n=428; group C: n=91). Overall survival rate at discharge was 433/1436 (30%). Patients' baseline characteristics significantly differed, as hospitals from group A received younger patients with a higher rate of shockable cardiac rhythms (p<0.001). Unadjusted survival rate differed significantly among the 3 groups of hospitals (respectively 34%, 25% and 15.4% for A-C, p<0.01). In multivariate analysis, the category of receiving hospital was no longer associated with survival, even in the subgroup of witnessed arrest and shockable patients. CONCLUSION: In this population-based study, characteristics of receiving hospitals are not associated with survival rate at discharge. This might be partially explained by the prehospital triage organization used in France. PMID- 28648809 TI - Improving quality in measuring time to initiation of CPR during in-hospital resuscitation. AB - OBJECTIVE: Time from the onset of "low or no flow" indicators of cardiac failure to initiation of cardiopulmonary resuscitation is an important quality metric thought to improve the likelihood of survival and preservation of end organ function. We hypothesized that delays in initiation of chest compressions were under recognized during in-hospital resuscitation and aimed to develop a system which identifies the actual time of deterioration during cardiac events. METHODS: Retrospective review on prospectively identified resuscitation records and monitor data were compared. Return of spontaneous circulation, survival, and changes in functional status of patients pre- and post-events with chest compressions were collected as outcome measures. RESULTS: Between October 2012 and April 2015, 59 events which met eligibility criteria occurred in either our pediatric cardiac or general pediatric intensive care units. The median time from event onset to initiation of chest compressions was 47s(s) (interquartile range (IQR) 28-80s) as assessed using monitor data, while the resuscitation record reported a median time of 0s (IQR 0-60s), reflecting the time from recognition to initiation of chest compressions. According to the resuscitation record, 81% vs. 63% of events achieved the quality standard of less than one minute depending on which review method was used (p=0.04). CONCLUSIONS: There is a significant difference between time of deterioration to initiation of chest compressions and the time of recognition to initiation of chest compressions. Resuscitation records should be modified to include more information about the actual timing of patient deterioration. PMID- 28648810 TI - Can somatosensory and visual evoked potentials predict neurological outcome during targeted temperature management in post cardiac arrest patients? AB - PURPOSES: In cardiac arrest patients treated with targeted temperature management (TTM), it is not certain if somatosensory evoked potentials (SEPs) and visual evoked potentials (VEPs) can predict neurological outcomes during TTM. The aim of this study was to investigate the prognostic value of SEPs and VEPs during TTM and after rewarming. METHODS: This retrospective cohort study included comatose patients resuscitated from cardiac arrest and treated with TTM between March 2007 and July 2015. SEPs and VEPs were recorded during TTM and after rewarming in these patients. Neurological outcome was assessed at discharge by the Cerebral Performance Category (CPC) Scale. RESULTS: In total, 115 patients were included. A total of 175 SEPs and 150 VEPs were performed. Five SEPs during treated with TTM and nine SEPs after rewarming were excluded from outcome prediction by SEPs due to an indeterminable N20 response because of technical error. Using 80 SEPs and 85 VEPs during treated with TTM, absent SEPs yielded a sensitivity of 58% and a specificity of 100% for poor outcome (CPC 3-5), and absent VEPs predicted poor neurological outcome with a sensitivity of 44% and a specificity of 96%. The AUC of combination of SEPs and VEPs was superior to either test alone (0.788 for absent SEPs and 0.713 for absent VEPs compared with 0.838 for the combination). After rewarming, absent SEPs and absent VEPs predicted poor neurological outcome with a specificity of 100%. When SEPs and VEPs were combined, VEPs slightly increased the prognostic accuracy of SEPs alone. Although one patient with absent VEP during treated with TTM had a good neurological outcome, none of the patients with good neurological outcome had an absent VEP after rewarming. CONCLUSION: Absent SEPs could predict poor neurological outcome during TTM as well as after rewarming. Absent VEPs may predict poor neurological outcome in both periods and VEPs may provide additional prognostic value in outcome prediction. PMID- 28648811 TI - A case of improved hearing with cochlear implantation in Gaucher disease type 1. AB - Gaucher disease is a lysosomal storage disorder that is caused by congenital defective function of the enzyme glucocerebrosidase. Glucocerebroside that is not hydrolyzed by glucocerebrosidase mainly accumulates in the reticular tissue. We describe a Japanese boy with Gaucher disease type 1 who developed bilateral profound sensorineural hearing loss within approximately 4years. We performed cochlear implantation initially on his right ear and again on his left ear 5 months later. The cochlear implants were successfully utilized with a speech discrimination score of 95% on a Japanese sentence recognition test. There are many reports of central hearing loss in Gaucher disease type 2 or 3. However, to the best of our knowledge, this is the first report of profound inner ear hearing loss with Gaucher disease. It also appears to be the first record of cochlear implantation for Gaucher disease. Cochlear implants may be useful for sensorineural hearing loss in patients with Gaucher disease without neurological symptoms other than hearing loss. PMID- 28648812 TI - Neck metastasis in patients with T1-2 supraglottic cancer. AB - OBJECTIVES: Unlike glottic cancer, supraglottic cancer often presents with neck metastases. This different might be attributable to the location of the primary lesion. This study aimed to clarify the relationships between the sublocation of T1-2 supraglottic cancer, human papillomavirus (HPV) infection, neck metastasis, and prognosis of supraglottic cancer. METHODS: This retrospective clinical study investigated 55 Japanese patients with T1-2 supraglottic cancer treated between 1994 and 2015. RESULTS: Of 55 patients with T1-2 supraglottic cancer, neck metastasis was present at initial diagnosis in 14 patients (25.5%). Presence of neck metastasis was the only factor associated with worse prognosis of T1-2 supraglottic cancer (p=0.004). In multivariate analysis, age <70years (p=0.033) and sublocation of the primary lesion in the superior epilaryngeal portion (p=0.017) were significantly associated with presence of neck metastasis in multivariate analysis. Twelve (27.9%) of 43 patients showed positive results for human papillomavirus infection. However, human papillomavirus infection was not associated with prognosis, presence of neck metastasis, or primary lesion sublocation in T1-2 supraglottic cancer. CONCLUSION: Relatively young patients with supraglottic cancer at the superior epilaryngeal portion are more likely to show neck metastasis. Human papillomavirus infection was not associated with frequency of neck metastasis. PMID- 28648813 TI - Rapid spread of an ongoing outbreak of Zika virus disease in pregnant women in a Mexican hospital. AB - In the first nine weeks of implementation of a Zika Virus Preparedness Plan in a Mexican Public Hospital, we cared for 221 pregnant women with any signal or symptom suggesting Zika virus infection and 99 (44.8%) patients were found to be positive for Zika virus. The median age of patients was 25.3 years (range 13-49). Symptoms in PCR-positive patients were rash (91.4%) followed by headache (53.1%), myalgia (46.9%), arthralgia (45.7%), pruritus (35.8%), retroocular pain (29.6%), conjunctivitis (21%), and fever (21%). The women's epidemiologic exposure history indicates local transmission and a community outbreak. PMID- 28648815 TI - Age-dependent changes in autophosphorylation of alpha calcium/calmodulin dependent kinase II in hippocampus and amygdala after contextual fear conditioning. AB - The hippocampus and amygdala are essential brain regions responsible for contextual fear conditioning (CFC). The autophosphorylation of alpha calcium calmodulin kinase II (alphaCaMKII) at threonine-286 (T286) is a critical step implicated in long-term potentiation (LTP), learning and memory. However, the changes in alphaCaMKII levels with aging and training in associated brain regions are not fully understood. Here, we studied how aging and training affect the levels of phosphorylated (T286) and proportion of phosphorylated:total alphaCaMKII in the hippocampus and amygdala. Young and aged mice, naive (untrained) and trained in CFC, were analysed by immunohistochemistry for the levels of total and phosphorylated alphaCaMKII in the hippocampus and amygdala. We found that two hours after CFC training, young mice exhibited a higher level of phosphorylated and increased ratio of phosphorylated:total alphaCaMKII in hippocampal CA3 stratum radiatum. Furthermore, aged untrained mice showed a higher ratio of phosphorylated:total alphaCaMKII in the CA3 region of the hippocampus when compared to the young untrained group. No effect of training or aging were seen in the central, lateral and basolateral amygdala regions, for both phosphorylated and ratio of phosphorylated:total alphaCaMKII. These results show that aging impairs the training-induced upregulation of autophosphorylated (T286) alphaCaMKII in the CA3 stratum radiatum of the hippocampus. This indicates that distinct age-related mechanisms underlie CFC that may rely more heavily on NMDA receptor-dependent plasticity in young age. PMID- 28648816 TI - How light affects the life of Botrytis. AB - Fungi, like other organisms, actively sense the environmental light conditions in order to drive adaptive responses, including protective mechanisms against the light-associated stresses, and to regulate development. Ecological niches are characterized by different light regimes, for instance light is absent underground, and light spectra from the sunlight are changed underwater or under the canopy of foliage due to the absorption of distinct wavelengths by bacterial, algal and plant pigments. Considering the fact that fungi have evolved to adapt to their habitats, the complexities of their 'visual' systems may vary significantly. Fungi that are pathogenic on plants experience a special light regime because the host always seeks the optimum light conditions for photosynthesis - and the pathogen has to cope with this environment. When the pathogen lives under the canopy and is indirectly exposed to sunlight, it is confronted with an altered light spectrum enriched for green and far-red light. Botrytis cinerea, the gray mold fungus, is an aggressive plant pathogen mainly infecting the above-ground parts of the plant. As outlined in this review, the Leotiomycete maintains a highly sophisticated light signaling machinery, integrating (near)-UV, blue, green, red and far-red light signals by use of at least eleven potential photoreceptors to trigger a variety of responses, i.e. protection (pigmentation, enzymatic systems), morphogenesis (conidiation, apothecial development), entrainment of a circadian clock, and positive and negative tropism of multicellular (conidiophores, apothecia) and unicellular structures (conidial germ tubes). In that sense, 'looking through the eyes' of this plant pathogen will expand our knowledge of fungal photobiology. PMID- 28648814 TI - Modulation of gap junction-associated Cx43 in neural stem/progenitor cells following traumatic brain injury. AB - Restoration of learning and memory deficits following traumatic brain injury (TBI) is attributed, in part, to enhanced neural stem/progenitor cell (NSPCs) function. Recent findings suggest gap junction (GJ)-associated connexin 43 (Cx43) plays a key role in the cell cycle regulation and function of NSPCs and is modulated following TBI. Here, we demonstrate that Cx43 is up-regulated in the dentate gyrus following TBI and is expressed on vimentin-positive cells in the subgranular zone. To test the role of Cx43 on NSPCs, we exposed primary cultures to the alpha-connexin Carboxyl Terminal (alphaCT1) peptide which selectively modulates GJ-associated Cx43. Treatment with alphaCT1 substantially reduced proliferation and increased caspase 3/7 expression on NSPCs in a dose-dependent manner. alphaCT1 exposure also reduced overall expression of Cx43 and phospho (p) Serine368. These findings demonstrate that Cx43 positively regulates adult NPSCs; the modulation of which may influence changes in the dentate gyrus following TBI. PMID- 28648817 TI - Modulatory effect of silymarin on nuclear factor-erythroid-2-related factor 2 regulated redox status, nuclear factor-kappaB mediated inflammation and apoptosis in experimental gastric ulcer. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Silymarin (SM) is a flavonoid mixture with anti-oxidant and anti-inflammatory activities which explain its protective role against hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus we went further to investigate the potential protective effects of SM against indomethacin-induced gastric injury in rats. Pretreatment with SM (50 mg/kg orally) attenuated the severity of gastric mucosal damage as evidenced by decreasing ulcer index (UI) and ulcer score, improvement of disturbed histopathologicl features to be insignificant with those induced by the reference anti-ulcer drug. Pretreatment with SM also suppressed gastric inflammation by decreasing myeloperoxidase activity, tumer necrosis factor-alpha (TNF- alpha) and interleukin 6 (IL6) levels along with nuclear factor kappa B p65 (NF-kappaB) expression. Meanwhile, SM prevent gastric oxidative stress via inhibition of lipid peroxides formation, enhancement of glutathione peroxidase, superoxide dismutase activities and up regulation of nuclear factor-erythroid-2-related factor 2 (Nrf2), the redox sensitive master regulator of oxidative stress signaling. In conclusion, the results herein revealed that SM has a gastro-protective effect which is mediated via suppression of gastric inflammation, oxidative stress, increased the anti oxidant and the cyto-protective defense mechanisms. PMID- 28648818 TI - Evaluation of the preimplantation worksheet in determining Calypso eligibility for men prescribed postprostatectomy radiotherapy with electromagnetic transponder guidance. AB - This study aimed to assess the design and performance of the preimplant suitability worksheet in determining Calypso eligibility for prostate cancer patients prescribed postprostatectomy radiotherapy with electromagnetic transponder guidance. The medical records and radiotherapy planning datasets of 75 patients prospectively recruited between June 2015 and September 2016 to a Phase 2 trial evaluating electromagnetic transponder-guided postprostatectomy radiotherapy were retrospectively examined. Correlation and differences between computed tomography (CT)-defined greater trochanter and prostatic fossa landmarks were evaluated. Receiver operating characteristic curves were also generated to assess the expected and observed accuracy of the worksheet in determining Calypso eligibility. Strong correlation was demonstrated between anterior surface to planning CT-defined greater trochanter and prostate bed center distances (r = 0.95, p <0.001), with a mean difference between measurements of 1.1 cm (95% confidence interval [CI]: 0.9 to 1.3). A similar correlation coefficient was found for surface to greater trochanter location and posterior beacon location (r = 0.92, p <0.001) but with a reduced mean difference of 0.4 cm (95% CI: 0.1 to 0.6). Performance of the worksheet as assessed by planning CT data demonstrated excellent accuracy as a test to determine eligibility (area under the curve: 0.97; 95% CI: 0.92 to 1.00); however, this was not replicated using the same data captured clinically (area under the curve 0.83; 95% CI: 0.68 to 0.98). Although the greater trochanter is a good surrogate for the prostate bed center, it is better associated with the posterior beacon location. As a result, the worksheet will underestimate the truly eligible population if performed accurately and according to manufacturer guidelines. Theoretically, the worksheet could be improved if a cut off of 20 cm is used and the greater trochanter is accurately identified; however, the latter appears to be difficult to achieve in practice. PMID- 28648819 TI - Delta9-tetrahydrocannabinol (Delta9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice. AB - The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Delta9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Delta9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Delta9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Delta9 THC, while mice that received Delta9-THC and PCP+Delta9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Delta9 THC during the early adulthood can potentiate the development of schizophrenia related behavioral phenotypes induced by neonatal exposure to PCP in mice. PMID- 28648821 TI - Caveolae Protect Notochord Cells against Catastrophic Mechanical Failure during Development. AB - The embryonic notochord is a flexible structure present during development that serves as scaffold for formation of the vertebrate spine. This rod-like organ is thought to have evolved in non-vertebrate chordates to facilitate locomotion by providing a rigid but flexible midline structure against which the axial muscles can contract. This hydrostatic "skeleton" is exposed to a variety of mechanical forces during oscillation of the body. There is evidence that caveolae, submicroscopic cup-shaped plasma membrane pits, can buffer tension in cells that undergo high levels of mechanical stress. Indeed, caveolae are particularly abundant in the embryonic notochord. In this study, we used the CRISPR/Cas9 system to generate a mutant zebrafish line lacking Cavin1b, a coat protein required for caveola formation. Our cavin1b-/- zebrafish line exhibits reduced locomotor capacity and prominent notochord lesions characterized by necrotic, damaged, and membrane-permeable cells. Notochord diameter and body length are reduced, but remarkably, the mutants recover and are homozygous viable. By manipulating mechanical stress using a number of different assays, we show that progression of lesion severity in the mutant notochord is directly dependent on locomotion. We also demonstrate changes in caveola morphology in vivo in response to mechanical stress. Finally, induction of a catastrophic collapse of live cavin1b-/- mutant notochord cells provides the first real-time observation of caveolae mediating cellular mechanoprotection. PMID- 28648820 TI - Selective Erasure of Distinct Forms of Long-Term Synaptic Plasticity Underlying Different Forms of Memory in the Same Postsynaptic Neuron. AB - Generalization of fear responses to non-threatening stimuli is a feature of anxiety disorders. It has been challenging to target maladaptive generalized memories without affecting adaptive memories. Synapse-specific long-term plasticity underlying memory involves the targeting of plasticity-related proteins (PRPs) to activated synapses. If distinct tags and PRPs are used for different forms of plasticity, one could selectively remove distinct forms of memory. Using a stimulation paradigm in which associative long-term facilitation (LTF) occurs at one input and non-associative LTF at another input to the same postsynaptic neuron in an Aplysia sensorimotor preparation, we found that each form of LTF is reversed by inhibiting distinct isoforms of protein kinase M (PKM), putative PRPs, in the postsynaptic neuron. A dominant-negative (dn) atypical PKM selectively reversed associative LTF, while a dn classical PKM selectively reversed non-associative LTF. Although both PKMs are formed from calpain-mediated cleavage of protein kinase C (PKC) isoforms, each form of LTF is sensitive to a distinct dn calpain expressed in the postsynaptic neuron. Associative LTF is blocked by dn classical calpain, whereas non-associative LTF is blocked by dn small optic lobe (SOL) calpain. Interfering with a putative synaptic tag, the adaptor protein KIBRA, which protects the atypical PKM from degradation, selectively erases associative LTF. Thus, the activity of distinct PRPs and tags in a postsynaptic neuron contribute to the maintenance of different forms of synaptic plasticity at separate inputs, allowing for selective reversal of synaptic plasticity and providing a cellular basis for developing therapeutic strategies for selectively reversing maladaptive memories. PMID- 28648822 TI - Novel Predators Reshape Holozoan Phylogeny and Reveal the Presence of a Two Component Signaling System in the Ancestor of Animals. AB - Our understanding of the origin of animals has been transformed by characterizing their most closely related, unicellular sisters: the choanoflagellates, filastereans, and ichthyosporeans. Together with animals, these lineages make up the Holozoa [1, 2]. Many traits previously considered "animal specific" were subsequently found in other holozoans [3, 4], showing that they evolved before animals, although exactly when is currently uncertain because several key relationships remain unresolved [2, 5]. Here we report the morphology and transcriptome sequencing from three novel unicellular holozoans: Pigoraptor vietnamica and Pigoraptor chileana, which are related to filastereans, and Syssomonas multiformis, which forms a new lineage with Corallochytrium in phylogenomic analyses. All three species are predatory flagellates that feed on large eukaryotic prey, and all three also appear to exhibit complex life histories with several distinct stages, including multicellular clusters. Examination of genes associated with multicellularity in animals showed that the new filastereans contain a cell-adhesion gene repertoire similar to those of other species in this group. Syssomonas multiformis possessed a smaller complement overall but does encode genes absent from the earlier-branching ichthyosporeans. Analysis of the T-box transcription factor domain showed expansion of T-box transcription factors based on combination with a non-T-box domain (a receiver domain), which has not been described outside of vertebrates. This domain and other domains we identified in all unicellular holozoans are part of the two-component signaling system that has been lost in animals, suggesting the continued use of this system in the closest relatives of animals and emphasizing the importance of studying loss of function as well as gain in major evolutionary transitions. PMID- 28648823 TI - The Evolution of Venom by Co-option of Single-Copy Genes. AB - The classic model for the evolution of novel gene function is through gene duplication followed by evolution of a new function by one of the copies (neofunctionalization) [1, 2]. However, other modes have also been found, such as novel genes arising from non-coding DNA, chimeric fusions, and lateral gene transfers from other organisms [3-7]. Here we use the rapid turnover of venom genes in parasitoid wasps to study how new gene functions evolve. In contrast to the classic gene duplication model, we find that a common mode of acquisition of new venom genes in parasitoid wasps is co-option of single-copy genes from non venom progenitors. Transcriptome and proteome sequencing reveal that recruitment and loss of venom genes occur primarily by rapid cis-regulatory expression evolution in the venom gland. Loss of venom genes is primarily due to downregulation of expression in the gland rather than gene death through coding sequence degradation. While the majority of venom genes have specialized expression in the venom gland, recent losses of venom function occur primarily among genes that show broader expression in development, suggesting that they can more readily switch functional roles. We propose that co-option of single-copy genes may be a common but relatively understudied mechanism of evolution for new gene functions, particularly under conditions of rapid evolutionary change. PMID- 28648824 TI - Sheath Cell Invasion and Trans-differentiation Repair Mechanical Damage Caused by Loss of Caveolae in the Zebrafish Notochord. AB - The notochord, a conserved axial structure required for embryonic axis elongation and spine development, consists of giant vacuolated cells surrounded by an epithelial sheath [1-3]. During morphogenesis, vacuolated cells maintain their structural integrity despite being under constant mechanical stress [4]. We hypothesized that the high density of caveolae present in vacuolated cells [5, 6] could buffer mechanical tension. Caveolae are 50- to 80-nm membrane invaginations lined by cage-like polygonal structures [7, 8] formed by caveolin 1 (Cav1) or Cav3 and one of the cavin proteins [6, 9-11]. Recent in vitro work has shown that plasma membrane caveolae constitute a membrane reservoir that can buffer mechanical stresses such as stretching or osmotic swelling [12]. Moreover, mechanical integrity of vascular and muscle cells is partly dependent on caveolae [13-15]. However, the in vivo mechano-protective roles of caveolae have only begun to be explored. Using zebrafish mutants for cav1, cav3, and cavin1b, we show that caveolae are essential for notochord integrity. Upon loss of caveola function, vacuolated cells collapse at discrete positions under the mechanical strain of locomotion. Then, sheath cells invade the inner notochord and differentiate into vacuolated cells, thereby restoring notochord function and allowing normal spine development. Our data further indicate that nucleotides released by dying vacuolated cells promote sheath cell vacuolization and trans differentiation. This work reveals a novel structural role for caveolae in vertebrates and provides unique insights into the mechanisms that safeguard notochord and spine development. PMID- 28648825 TI - Differential Control of Dopaminergic Excitability and Locomotion by Cholinergic Inputs in Mouse Substantia Nigra. AB - Understanding how dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) govern movements requires a detailed knowledge of how different neurotransmitter systems modulate DA neuronal excitability. We report a heterogeneity of electrophysiological properties between medial and lateral SNc neurons modulated by cholinergic neurotransmission. Lateral DA neurons received mainly excitatory (nicotinic or glutamatergic) mediated cholinergic neurotransmission. Medial DA neurons received predominantly GABAergic currents mediated by presynaptic nicotinic receptors or biphasic GABAergic and nicotinic neurotransmission conveyed by GABA and ACh corelease, which inhibited DA neurons. To examine whether cholinergic signaling in the SNc controls mouse behavior, we used optogenetics in awake behaving mice and found that activation of cholinergic terminals in the medial SNc decreased locomotion, whereas activation in the lateral SNc increased locomotion. Our findings provide novel insights on how cholinergic inputs to subregions of the SNc regulate the excitability of DA neurons differentially, resulting in different patterns of motor behavior. PMID- 28648827 TI - Impacts of ocean acidification on sperm develop with exposure time for a polychaete with long lived sperm. AB - The majority of marine invertebrate species release eggs and sperm into seawater for external fertilisation. Seawater conditions are currently changing at an unprecedented rate as a consequence of ocean acidification (OA). Sperm are thought to be particularly vulnerable to these changes and may be exposed to external environmental conditions for variable periods of time between spawning and fertilisation. Here, we undertook a mechanistic investigation of sperm swimming performance in the coastal polychaete Arenicola marina during an extended exposure to OA conditions (pHNBS 7.77, 1000 MUatm pCO2). We found that key fitness-related aspects of sperm functioning declined faster under OA conditions i.e. impacts became apparent with exposure time. Sperm swimming speed (VCL), the number of motile sperm and sperm path linearity all dropped significantly after 4 h under OA conditions whilst remaining constant under ambient conditions at this time point. Our results highlight the importance of sperm exposure duration in ocean acidification experiments and may help towards explaining species specific differences in response. PMID- 28648826 TI - Attentional Modulation of Neuronal Activity Depends on Neuronal Feature Selectivity. AB - Attention exerts a powerful influence on visual perception. The impact of attention on neuronal activity manifests at early visual information processing stages and progressively increases throughout the visual cortical hierarchy. However, the neuronal mechanisms of attention are unresolved. In particular, the rules governing attentional modulation of individual neurons, whether they are facilitated by or suppressed by attention, are not known. To obtain a more granular or neuron- and circuit-level understanding of the mechanisms of attention and to directly test the feature similarity gain model in V1, we compared attentional modulation with neuronal feature selectivity across a large population of V1 neurons in alert and behaving macaque monkeys trained on an attention-demanding contrast-change detection task. We utilized emerging multi electrode array technology to record simultaneously from V1 neurons spanning all six cortical layers so that we could characterize the laminar position and physiological response properties of diverse V1 neuronal populations. We found significant relationships between attentional modulation and neuronal position within the cortical hierarchy, neuronal physiology, and neuronal feature selectivity. Our results support the feature similarity gain model and further suggest that attentional modulation depends critically upon the match between neuronal feature selectivity and the features required for the task. PMID- 28648828 TI - Tidal Energy: The benthic effects of an operational tidal stream turbine. AB - The effect of modified flow on epifaunal boulder reef communities adjacent to the SeaGen, the world's first grid-compliant tidal stream turbine, were assessed. The wake of the SeaGen was modelled and the outputs were used in conjunction with positional and substrate descriptor variables, to relate variation in epifaunal community structure to the modified physical environment. An Artificial Neural Network (ANN) and Generalised Linear Model (GLM) were used to make predictions on the distribution of Ecological Status (ES) of epifaunal communities in relation to the turbulent wake of the SeaGen. ES was assigned using the High Energy Hard Substrate (HEHS) index. ES was largely High throughout the survey area and it was not possible to make predictions on the spatial distribution of ES using an ANN or GLM. Spatial pattern in epifaunal community structure was detected when the study area was partitioned into three treatment areas: area D1; within one rotor diameter (16 m) of the centre of SeaGen, area D2; between one and three rotor diameters, and area D3; outside of three rotor diameters. Area D1 was found to be significantly more variable than D2 and D3 in terms of epifaunal community structure, bare rock distributions and ES. PMID- 28648830 TI - Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases. AB - Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes. In this review, we introduce the functions of P2YRs and possible dimerization with G protein-coupled receptors (GPCRs) in the cardiovascular system. We focus especially on the crosstalk between uridine nucleotide-responsive P2Y6R and angiotensin (Ang) II type1 receptor (AT1R) signaling, and introduce our recent finding that the P2Y6R antagonist MRS2578 interrupts heterodimerization between P2Y6R and AT1R, thereby reducing the risk of AT1R-stimulated hypertension in mice. These results strongly suggest that targeting P2Y6R oligomerization could be an effective new strategy to reduce the risk of cardiovascular diseases. PMID- 28648829 TI - Novel pharmacotherapies for cardiac amyloidosis. AB - Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease. This review will summarize the preclinical and clinical data for these emerging treatments for AL and ATTR amyloidosis. PMID- 28648832 TI - Decisional conflict screening for a diversity of primary care decisions. Are we SURE yet? PMID- 28648831 TI - Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma. AB - Alterations in arginine metabolism and accelerated formation of advanced glycation end-products (AGEs), crucial mechanisms in obesity-related asthma, can be modulated by glucagon-like peptide 1 (GLP-1). l-arginine dysregulation in obesity promotes inflammation and bronchoconstriction. Prolonged hyperglycemia, dyslipidemia, and oxidative stress leads to production of AGEs, that bind to their receptor (RAGE) further potentiating inflammation. By binding to its widely distributed receptor, GLP-1 blunts the effects of RAGE activation and arginine dysregulation. The GLP-1 pathway, while comprehensively studied in the endocrine and cardiovascular literature, is under-recognized in pulmonary research. Insights into GLP-1 and the lung may lead to novel treatments for obesity-related asthma. PMID- 28648833 TI - Patients and primary care providers identify opportunities for personalized (N-of 1) trials in the mobile health era. PMID- 28648834 TI - Combination avelumab and utomilumab immunotherapy can induce diabetic ketoacidosis. PMID- 28648835 TI - Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. AB - AIM: This study evaluated the effects of a glucagon-like peptide-1 receptor agonist on gastrointestinal (GI) tract motility and residue rates by examining GI transit time and lumen using capsule endoscopy. MATERIAL AND METHODS: GI motility and lumen were assessed by capsule endoscopy before and after liraglutide administration in 14 patients with type 2 diabetes mellitus (T2DM). RESULTS: Gastric transit time in the group with diabetic neuropathy (DN) was 1:12:36+/ 1:04:30h before liraglutide administration and 0:48:40+/-0:32:52h after administration (nonsignificant difference, P=0.19). Gastric transit time in the non-DN group was 1:01:30+/-0:52:59h before administration and 2:33:29+/-1:37:24h after administration (significant increase, P=0.03). Duodenal and small intestine transit time in the DN group was 4:10:34+/-0:25:54h before and 6:38:42+/-3:52:42h after administration (not significant, P=0.09) and, in the non-DN group, 3:51:03+/-0:53:47h before and 6:45:31+/-2:41:36h after administration (significant increase, P=0.03). The GI residue rate in the DN group was 32.1+/ 24% before administration and 90.0+/-9.1% after administration (significant increase, P<0.001), and increased in all patients; in the non-DN group, it was 32.1+/-35.3% before and 78.3+/-23.9% after administration (significant increase, P<0.001), and also increased in all patients. CONCLUSION: Liraglutide causes delayed gastric emptying and inhibits duodenal and small intestine motility. However, these GI movement-inhibiting effects may be decreased or absent in patients with DN-associated dysautonomia. PMID- 28648836 TI - Cortical and Trabecular Bone Analysis of Patients With High Bone Mass From the Barcelona Osteoporosis Cohort Using 3-Dimensional Dual-Energy X-ray Absorptiometry: A Case-Control Study. AB - High bone mass (HBM), a rare phenotype, can be detected by dual-energy X-ray absorptiometry (DXA) scanning. Measurements with peripheral quantitative computed tomography at the tibia have found increased trabecular bone mineral density and changes in cortical bone density and structure, all of which lead to increased bone strength. However, no studies on cortical and trabecular bone have been performed at the femur. The recently developed 3-dimensional (3D)-DXA software algorithm quantifies the trabecular and cortical volumetric bone mineral density (vBMD) and the anatomical distribution of cortical thickness using routine hip DXA scans. We analyzed the femurs of 15 women with HBM and 15 controls from the Barcelona Osteoporosis (BARCOS) cohort using the 3D-DXA technique. The mean vBMD of proximal femur was 29.7% higher in HBM cases than in controls for the integral bone, 41.3% higher for the trabecular bone, and 7.3% higher for the cortical bone (p < 0.001). No differences in bone size were detected between cases and controls. Patients with HBM had a thicker cortex and higher trabecular and cortical vBMDs, as measured by 3D-DXA at the femur and compared to controls; bone size was similar in both groups. To the best of our knowledge, this is the first description of trabecular and cortical characteristics of the hip in patients with HBM. PMID- 28648838 TI - Regarding "The Role of Routine Peritoneal and Omental Biopsies at Risk-reducing Salpingo-oophorectomy". PMID- 28648839 TI - Author's Reply. PMID- 28648837 TI - Integrative characterization of chronic cigarette smoke-induced cardiopulmonary comorbidities in a mouse model. AB - Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model. Some respiratory alterations characteristic of emphysema (decreased airway resistance: Rl; end-expiratory work and pause: EEW, EEP; expiration time: Te; increased tidal mid-expiratory flow: EF50) were detected in anaesthetized C57BL/6 mice, unrestrained plethysmography did not show changes. Typical histopathological signs were peribronchial/perivascular (PB/PV) edema at month 1, neutrophil/macrophage infiltration at month 2, interstitial leukocyte accumulation at months 3-4, and emphysema/atelectasis at months 5-6 quantified by mean linear intercept measurement. Emphysema was proven by micro-CT quantification. Leukocyte number in the bronchoalveolar lavage at month 2 and lung matrix metalloproteinases-2 and 9 (MMP-2/MMP-9) activities in months 5-6 significantly increased. Smoking triggered complex cytokine profile change in the lung with one characteristic inflammatory peak of C5a, interleukin-1alpha and its receptor antagonist (IL-1alpha, IL-1ra), monokine induced by gamma interferon (MIG), macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) at months 2-3, and another peak of interferon-gamma (IFN-gamma), IL-4, 7, 13, 17, 27 related to tissue destruction. Transient systolic and diastolic ventricular dysfunction developed after 1-2 months shown by significantly decreased ejection fraction (EF%) and deceleration time, respectively. These parameters together with the tricuspid annular plane systolic excursion (TAPSE) decreased again after 5-6 months. Soluble intercellular adhesion molecule-1 (sICAM-1) significantly increased in the heart homogenates at month 6, while other inflammatory cytokines were undetectable. This is the first study demonstrating smoking duration-dependent, complex cardiopulmonary alterations characteristic to COPD, in which inflammatory cytokine cascades and MMP-2/9 might be responsible for pulmonary destruction and sICAM-1 for heart dysfunction. PMID- 28648840 TI - Reducing Fluid-Related Complications During Operative Hysteroscopy: Use of a New Mandatory Fluid-Balance Form. AB - STUDY OBJECTIVE: To examine whether our new reporting system and mandatory fluid balance form could improve the communication and awareness within the surgical team and therefore the safety of hysteroscopic operations. DESIGN: A case-control study (Canadian Task Force classification II-2). SETTING: An endoscopic gynecology unit at a tertiary-care university hospital. PATIENTS: Women aged 17 to 88 years (median, 43.9) who underwent operative hysteroscopy to treat uterine pathology. INTERVENTIONS: Operative hysteroscopy was performed using bipolar technology and normal saline as an irrigation media with the new fluid-balance form and a mandatory reporting system. The control group was composed of women who underwent the procedure using the same technology, with a previous protocol. MEASUREMENTS AND MAIN RESULTS: Data regarding intraoperative and postoperative short-term complications were prospectively collected during surgery and at the 2 week follow-up visit. About 2000 procedures were investigated (601 in the study group and 1396 in the control group). In the control group there were 20 incidents of fluid deficit over 2 L. In 4 of these cases the procedure was terminated, but in the other 16 cases the procedure was continued, with or without awareness of the surgeons to the deficit. Of these cases, 2 suffered from media-related complications, and in 3 others complications were avoided by diuretics. In contrast, in the study group there were 10 incidents of fluid deficit over 2 L, of which 5 cases were terminated on time and the other 5 continued under the informed decision of the surgeon. In this group, none of the women experienced a media-related complication. The difference between the number of procedures that were terminated on time between the control and study groups was not statistically significant (p = .115). There was a statistically significant reduction in the total complication rate between the study group (1.8%) and the control group (3.9%; p = .019). CONCLUSIONS: The fluid-balance form and mandatory reporting system have been shown to reduce the rate of total complications in hysteroscopic surgeries, in particular media-related complications. This result is achieved by an improvement of the awareness and communication among the operating team, leading to an improvement in procedure safety. PMID- 28648841 TI - Fine Needle Aspiration Combined With Matrix-assisted Laser Desorption Ionization Time-of-Flight/Mass Spectrometry to Characterize Lipid Biomarkers for Diagnosing Accuracy of Breast Cancer. AB - BACKGROUND: Fine needle aspiration (FNA) cytology has been widely used for pathologic assessment of breast lesions. However, the examination suffers a risk of false-negative results owing to insufficient sample volumes, inaccurate sampling positions, nondefinitive cytologic features, or suboptimal cell preservation. One approach to improve its accuracy is using modern mass spectrometry to detect disease biomarkers, of which the tissue samples are collected through FNA. METHODS: The biological compounds in the FNA tissue samples were extracted and characterized by matrix-assisted laser desorption ionization time-of-flight/mass spectrometry (MALDI-TOF/MS). The results were further analyzed by principal component analysis. Distribution of lipid biomarkers on tissues was explored by imaging mass spectrometry. RESULTS: Lipid profiles of the tissue samples collected by FNA were rapidly obtained through MALDI-TOF/MS analysis. Phosphatidylcholines and triacylglycerols were detected as the predominant compounds in cancerous and normal regions, respectively. The samples were clearly classified by principal component analysis, based on the differences in their lipid profiles. Different lipid patterns were clearly viewed through the molecular imaging of normal and tumorous regions of breast tissue samples. CONCLUSION: The FNA-MALDI-TOF/MS approach can provide complementary information for pathological examinations and improve the accuracy of breast cancer diagnoses. Owing to the ease of operation and automation, it is possible to efficiently screen the lipid biomarkers in a large number of tissue samples by means of MALDI-TOF/MS. PMID- 28648842 TI - Pnrc2 regulates 3'UTR-mediated decay of segmentation clock-associated transcripts during zebrafish segmentation. AB - Vertebrate segmentation is controlled by the segmentation clock, a molecular oscillator that regulates gene expression and cycles rapidly. The expression of many genes oscillates during segmentation, including hairy/Enhancer of split related (her or Hes) genes, which encode transcriptional repressors that auto inhibit their own expression, and deltaC (dlc), which encodes a Notch ligand. We previously identified the tortuga (tor) locus in a zebrafish forward genetic screen for genes involved in cyclic transcript regulation and showed that cyclic transcripts accumulate post-splicing in tor mutants. Here we show that cyclic mRNA accumulation in tor mutants is due to loss of pnrc2, which encodes a proline rich nuclear receptor co-activator implicated in mRNA decay. Using an inducible in vivo reporter system to analyze transcript stability, we find that the her1 3'UTR confers Pnrc2-dependent instability to a heterologous transcript. her1 mRNA decay is Dicer-independent and likely employs a Pnrc2-Upf1-containing mRNA decay complex. Surprisingly, despite accumulation of cyclic transcripts in pnrc2 deficient embryos, we find that cyclic protein is expressed normally. Overall, we show that Pnrc2 promotes 3'UTR-mediated decay of developmentally-regulated segmentation clock transcripts and we uncover an additional post-transcriptional regulatory layer that ensures oscillatory protein expression in the absence of cyclic mRNA decay. PMID- 28648845 TI - Substance abuse and gender differences in first episode psychosis: Impact on hospital readmissions. AB - INTRODUCTION: There have been controversial results in the study of gender differences in first episode psychosis (FEP). Substance abuse is the main existing comorbidity in FEP, and has been associated with worse prognosis and greater symptom severity. OBJECTIVES: To explore gender differences in FEP in relation to drug abuse, and their relationship with hospital readmissions. METHODOLOGY: Descriptive and prospective study (18 months). RESULTS: We included 141 patients (31.2% women), aged 26.1 years on average, mostly diagnosed with schizophreniform disorder (32.6%). A percentage of 58.9 had problematic use of drugs. Gender significant differences were found in age of onset, age at entry to the programme, marital status and cohabitation, and percentage differences were revealed in current drug abuse and frequency of consumption. Gender, duration of untreated psychosis, psychiatric history, age of onset and previous drug use were not predictors of re-entry. Hospital readmission rate was 24.8%, with no gender differences. The most common reasons for admission were abandonment of treatment (66.7%) and drug abuse (44.4%). Drug abuse was higher in the men than in the women as a reason for re-admission. CONCLUSIONS: There are gender differences in FEP. Men have an earlier onset of symptoms and have worse functional outcomes. Drug abuse in men is higher and represents a major cause of hospital readmission. Therapeutic interventions to prevent the effects of drug abuse are necessary from the early stages of the illness. PMID- 28648843 TI - Identification of regulators of germ stem cell enwrapment by its niche in C. elegans. AB - Many stem cell niches contain support cells that increase contact with stem cells by enwrapping them in cellular processes. One example is the germ stem cell niche in C. elegans, which is composed of a single niche cell termed the distal tip cell (DTC) that extends cellular processes, constructing an elaborate plexus that enwraps germ stem cells. To identify genes required for plexus formation and to explore the function of this specialized enwrapping behavior, a series of targeted and tissue-specific RNAi screens were performed. Here we identify genes that promote stem cell enwrapment by the DTC plexus, including a set that specifically functions within the DTC, such as the chromatin modifier lin 40/MTA1, and others that act within the germline, such as the 14-3-3 signaling protein par-5. Analysis of genes that function within the germline to mediate plexus development reveal that they are required for expansion of the germ progenitor zone, supporting the emerging idea that germ stem cells signal to the niche to stimulate enwrapping behavior. Examination of wild-type animals with asymmetric plexus formation and animals with reduced DTC plexus elaboration via loss of two candidates including lin-40 indicate that cellular enwrapment promotes GLP-1/Notch signaling and germ stem cell fate. Together, our work identifies novel regulators of cellular enwrapment and suggests that reciprocal signaling between the DTC niche and the germ stem cells promotes enwrapment behavior and stem cell fate. PMID- 28648844 TI - Novel functions for the RNA-binding protein ETR-1 in Caenorhabditis elegans reproduction and engulfment of germline apoptotic cell corpses. AB - RNA-binding proteins (RBPs) are essential regulators of gene expression that act through a variety of mechanisms to ensure the proper post-transcriptional regulation of their target RNAs. RBPs in multiple species have been identified as playing crucial roles during development and as having important functions in various adult organ systems, including the heart, nervous, muscle, and reproductive systems. ETR-1, a highly conserved ELAV-Type RNA-binding protein belonging to the CELF/Bruno protein family, has been previously reported to be involved in C. elegans muscle development. Animals depleted of ETR-1 have been previously characterized as arresting at the two-fold stage of embryogenesis. In this study, we show that ETR-1 is expressed in the hermaphrodite somatic gonad and germ line, and that reduction of ETR-1 via RNA interference (RNAi) results in reduced hermaphrodite fecundity. Detailed characterization of this fertility defect indicates that ETR-1 is required in both the somatic tissue and the germ line to ensure wild-type reproductive levels. Additionally, the ability of ETR-1 depletion to suppress the published WEE-1.3-depletion infertility phenotype is dependent on ETR-1 being reduced in the soma. Within the germline of etr-1(RNAi) hermaphrodite animals, we observe a decrease in average oocyte size and an increase in the number of germline apoptotic cell corpses as evident by an increased number of CED-1::GFP and acridine orange positive apoptotic germ cells. Transmission Electron Microscopy (TEM) studies confirm the significant increase in apoptotic cells in ETR-1-depleted animals, and reveal a failure of the somatic gonadal sheath cells to properly engulf dying germ cells in etr-1(RNAi) animals. Through investigation of an established engulfment pathway in C. elegans, we demonstrate that co-depletion of CED-1 and ETR-1 suppresses both the reduced fecundity and the increase in the number of apoptotic cell corpses observed in etr-1(RNAi) animals. Combined, this data identifies a novel role for ETR-1 in hermaphrodite gametogenesis and in the process of engulfment of germline apoptotic cell corpses. PMID- 28648846 TI - Construct validity or validity based on the construct?: Comments to Soler et al. PMID- 28648847 TI - Study on the change and acculturation of dietary pattern of Southeast Asian workers living in South Korea. AB - This study analyzed the dietary pattern of Southeast Asian workers (Vietnamese, Thais, Cambodians and Myanmar) living in South Korea in order to recognize the dietary changes after they moved to South Korea. Questionnaires were completed by 251 Southeast Asian workers living in South Korea. Using a self-administered questionnaire, we assessed the diets before and after living in the hometown and in South Korea. Significant changes observed in the Southeast Asian workers were decreased in consumption frequency of fresh fruits, cooked vegetables, rice noodles, green tea and glutinous rice, and increase in consumption of Kimchi, seaweed, milk, coffee and pizza. These changes were attributed to rapid dietary acculturation. The frequencies of eating homemade food were significantly decreased after they came to Korea except for Thais. Thais showed the highest frequencies of eating homemade food daily among others. 28.2% of respondents said their health condition had deteriorated after living in South Korea due to difficulties to adapt Korean food, increased frequencies of eating instant food, and lacking exercises. By providing understanding of the dietary patterns of Southeast Asian workers, these results can be used for preliminary data to develop a program for their Korean food adaptation. PMID- 28648848 TI - Baculovirus LEF-11 nuclear localization signal is important for viral DNA replication. AB - Baculovirus LEF-11 is a small nuclear protein that is involved in viral late gene transcription and DNA replication. However, the characteristics of its nuclear localization signal and its impact on viral DNA replication are unknown. In the present study, systemic bioinformatics analysis showed that the baculovirus LEF 11 contains monopartite and bipartite classical nuclear localization signal sequences (cNLSs), which were also detected in a few alphabaculovirus species. Localization of representative LEF-11 proteins of four baculovirus genera indicated that the nuclear localization characteristics of baculovirus LEF-11 coincided with the predicted results. Moreover, Bombyx mori nucleopolyhedrovirus (BmNPV) LEF-11 could be transported into the nucleus during viral infection in the absence of a cNLSs. Further investigations demonstrated that the NLS of BmNPV LEF-11 is important for viral DNA replication. The findings of the present study indicate that the characteristics of the baculovirus LEF-11 protein and the NLS is essential to virus DNA replication and nuclear transport mechanisms. PMID- 28648849 TI - Cellular DEAD-box RNA helicase 18 (DDX18) Promotes the PRRSV Replication via Interaction with Virus nsp2 and nsp10. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an aetiological agent that can lead to reproductive failure and respiratory diseases of pigs. The replication and pathogenesis of PRRSV, although poorly understood, has been associated with the host factors. DDX18 is a member of DEAD-box RNA helicases (DDXs) family which were proved to participate in viral replication. Previously, we found the DDX18 interacts with both nsp2 and nsp10 of PRRSV by Co Immunoprecipitation (Co-IP). In the present study, we demonstrated the interactions of DDX18 with nsp2 and nsp10, and located DDX18's binding regions as the N-terminus of nsp2 and both the N-terminus and C-terminus of nsp10. The expression of the nsp2 or nsp10 in MARC-145 cells and primary PAM cells redistributed DDX18 from the nucleus to the cytoplasm, and promoted the viral replication, but silencing of the DDX18 gene in MARC-145 cells down-regulated the replication of PRRSV. These findings proved that the cellular RNA helicase DDX18 plays a role in the replication of PRRSV, and provides insights into the understanding of PRRSV replication. PMID- 28648851 TI - The influence of mild acidity on lysyl-phosphatidylglycerol biosynthesis and lipid membrane physico-chemical properties in methicillin-resistant Staphylococcus aureus. AB - The increased biosynthesis of lysyl-phosphatidylglycerol in Staphylococcus aureus when cultured under conditions of mild acidity and the resultant increased proportion of this lipid in the plasma membrane of the bacterium, alters the physico-chemical properties of lipid bilayers in a manner which is itself dependent upon environmental pH. Clinically relevant strains of S. aureus, both methicillin susceptible and resistant, all exhibited increased lysyl phosphatidylglycerol biosynthesis in response to mild environmental acidity, albeit to differing degrees, from ~30% to ~55% total phospholipid. Polar lipid extracts from these bacteria were analysed by 31P NMR and reconstituted into vesicles and monolayers, which were characterised by zeta potential measurements and Langmuir isotherms respectively. A combination of increased lysyl phosphatidylglycerol content and mild environmental acidity were found to synergistically neutralise the charge of the membranes, in one instance altering the zeta potential from -56mV to +21mV, and induce closer packing between the lipids. Challenge of reconstituted S. aureus lipid model membranes by the antimicrobial peptide magainin 2 F5W was examined using monolayer subphase injection and neutron diffraction, and revealed that ionisation of the headgroup alpha-amine of lysyl-phosphatidylglycerol at pH 5.5, which reduced the magnitude of the peptide-lipid interaction by 80%, was more important for resisting peptide partitioning than increased lipid content alone. The significance of these results is discussed in relation to how colonising mildly acidic environments such as human mucosa may be facilitated by increased lysyl-phosphatidylglycerol biosynthesis and the implications of this for further biophysical analysis of the role of this lipid in bacterial membranes. PMID- 28648850 TI - Complete genome analysis of dengue virus type 3 isolated from the 2013 dengue outbreak in Yunnan, China. AB - In the past few decades, dengue has spread rapidly and is an emerging disease in China. An unexpected dengue outbreak occurred in Xishuangbanna, Yunnan, China, resulting in 1331 patients in 2013. In order to obtain the complete genome information and perform mutation and evolutionary analysis of causative agent related to this largest outbreak of dengue fever. The viruses were isolated by cell culture and evaluated by genome sequence analysis. Phylogenetic trees were then constructed by Neighbor-Joining methods (MEGA6.0), followed by analysis of nucleotide mutation and amino acid substitution. The analysis of the diversity of secondary structure for E and NS1 protein were also performed. Then selection pressures acting on the coding sequences were estimated by PAML software. The complete genome sequences of two isolated strains (YNSW1, YNSW2) were 10,710 and 10,702 nucleotides in length, respectively. Phylogenetic analysis revealed both strain were classified as genotype II of DENV-3. The results indicated that both isolated strains of Xishuangbanna in 2013 and Laos 2013 stains (KF816161.1, KF816158.1, LC147061.1, LC147059.1, KF816162.1) were most similar to Bangladesh (AY496873.2) in 2002. After comparing with the DENV-3SS (H87) 62 amino acid substitutions were identified in translated regions, and 38 amino acid substitutions were identified in translated regions compared with DENV-3 genotype II stains Bangladesh (AY496873.2). 27(YNSW1) or 28(YNSW2) single nucleotide changes were observed in structural protein sequences with 7(YNSW1) or 8(YNSW2) non-synonymous mutations compared with AY496873.2. Of them, 4 non-synonymous mutations were identified in E protein sequences with (2 in the beta-sheet, 2 in the coil). Meanwhile, 117(YNSW1) or 115 (YNSW2) single nucleotide changes were observed in non-structural protein sequences with 31(YNSW1) or 30 (YNSW2) non synonymous mutations. Particularly, 14 single nucleotide changes were observed in NS1 sequences with 4/14 non-synonymous substitutions (4 in the coil). Selection pressure analysis revealed no positive selection in the amino acid sites of the genes encoding for structural and non-structural proteins. This study may help understand the intrinsic geographical relatedness of dengue virus 3 and contributes further to research on their infectivity, pathogenicity and vaccine development. PMID- 28648852 TI - Barriers to Goals of Care Discussions With Patients Who Have Advanced Heart Failure: Results of a Multicenter Survey of Hospital-Based Cardiology Clinicians. AB - BACKGROUND: Conversations about goals of care in hospital are important to patients who have advanced heart failure (HF). METHODS: We conducted a multicenter survey of cardiology nurses, fellows, and cardiologists at 8 Canadian teaching hospitals. The primary outcome was the importance of barriers to goals of-care discussions in hospital (1 = extremely unimportant; 7 = extremely important). We also elicited perspectives on roles of different practitioners in having these conversations. RESULTS: Questionnaires were returned by 770/1024 (75.2%) eligible clinicians. The most important perceived barriers were: family members' and patients' difficulty in accepting a poor prognosis (mean [SD] score 5.9 [1.1] and 5.7 [1.2], respectively), family members' and patients' lack of understanding about the limitations and harms of life-sustaining treatments (5.8 [1.1] and 5.7 [1.2], respectively), and lack of agreement among family members about goals of care (5.8 [1.2]). Interprofessional team members were viewed as having different but important roles in goals-of-care discussions. CONCLUSIONS: Cardiology clinicians perceive family and patient-related factors as the most important barriers to goals-of-care discussions in hospital. Many members of the interprofessional team were viewed as having important roles in addressing goals of care. These findings can inform the design of future interventions to improve communication about goals of care in advanced HF. PMID- 28648853 TI - Next generation sequencing of oral microbiota in Type 2 diabetes mellitus prior to and after neem stick usage and correlation with serum monocyte chemoattractant 1. AB - INTRODUCTION: Oral microbiome impacts health and disease. T2DM and periodontitis are associated. Neem (Azadiracta indica) has antibacterial activity against oral microbiota. OBJECTIVES: To characterize oral microbiota (OMB) in saliva samples of T2DM patients by Next generation sequencing. To analyze MCP-1 levels among the T2DM patients before and after a month of neem stick usage as a toothbrush. MATERIALS AND METHODS: Blood and saliva samples were collected from adult T2DM patients before and after the neem stick usage. Metagenomic sequencing was performed on saliva samples targeting V6 region of 16s rRNA. Serum MCP-1 levels were determined using a quantitative sandwich Human MCP-1 standard ABTS development kit (Peprotech, USA). RESULTS: The profile of oral microbiota of T2DM patients (n=24) consists of Streptococcus (95.8%) counts ranging from 2644 to 27,214, Veillonella (72.2%, counts 25-19,709, Neisseria (87.5%) 453-33,445), Rothia (63.6%, 233-6734), Actinomycetes (25%, 161-3730), Fusobacterium (21%, 2252 21,334), and Pigmentiphaga (12.5% 3-16,644). Oral microbiota in healthy controls (n=10), consists of Streptococcus (26.1%), Veillonella (21.9%), Neisseria (16.9%), Haemophilus (10.7%), Actinomycetes (2.6%), Rothia (3.1%), Oribacterium (1.7%). Post neem samples showed drastic reduction in the load of bacteria which was statistically significant. The mean serum MCP-1 before the use of neem stick was 265.18+/-79.44 (range 141.6-980.5pg/ml) and dropped to 33.6+/-7.35 after a month of neem stick usage (P value>0.001). CONCLUSION: OMB of T2DM patients and healthy controls were similar, however bacterial loads were significantly higher in T2DM patients. Use of neem stick has a statistically significant reduction on bacterial loads and MCP-1 levels in T2DM patients. PMID- 28648854 TI - Is there a "burnt-out diabetes" phenomenon in patients on hemodialysis? AB - AIMS: In patients with diabetes on hemodialysis (HD), glycemic control improves spontaneously, leading to normal glycated hemoglobin (HbA1c) levels; this phenomenon is known as "burnt-out diabetes." However, glycated albumin (GA) might be a better indicator of glycemic control than HbA1c in HD patients. Therefore, the aim of this study was to identify how many patients experience "burnt-out diabetes" using HbA1c and GA levels and to examine the association between cardiovascular comorbidity risk and GA levels. METHODS: Patients with diabetes on HD whose HbA1c levels were measured and whose antidiabetic therapy was recorded were included. First, the "burnt-out diabetes" phenomenon was investigated in patients whose HbA1c levels were measured (HbA1c cohort). Then, it was investigated in patients who were assessed for both HbA1c and GA levels (GA cohort). Risk of cardiovascular comorbidity was assessed using multivariable logistic regression models. RESULTS: In the HbA1c cohort, 60,019 patients were included. When "burnt-out diabetes" was defined as HbA1c<6.0% without treatment with antidiabetic medication, it was noted in 11,159 patients (18.6%). In the GA cohort, 23,668 patients were included, and it was found in 4899 patients (20.7%). However, when "burnt-out diabetes" was defined as HbA1c<6.0% and GA<16.0% without treatment with antidiabetic medication, it was found in 1286 patients (5.4%). Patients with GA>18% had a higher risk of cardiovascular comorbidity. CONCLUSIONS: Although the "burnt-out diabetes" phenomenon might be present in 20.7% of patients with diabetes on HD in terms of HbA1c, the rate was significantly decreased to 5.4% in terms of GA. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000018641. PMID- 28648855 TI - Decreasing incidence of foot ulcer among patients with type 1 and type 2 diabetes in the period 2001-2014. AB - AIM: Diabetic foot ulcer (DFU) is a serious complication to diabetes. The aim was to study the incidence of first DFU among patients with type 1 (T1DM) and type 2 diabetes (T2DM), stratified according to etiology: neuropathic, neuro-ischemic or ischemic, over a period of 14years (2001-2014). METHODS: DFU incidence rates were calculated from electronic patient record data from patients with T1DM and complicated T2DM from a large specialized diabetes hospital with a multidisciplinary foot clinic in Denmark. Poisson regression was used to model incidence of first DFU according to calendar year, diabetes type and etiology. RESULTS: Among 5640 patients with T1DM 255 developed a DFU, corresponding to an incidence of 5.8 (95% confidence interval (95%CI) 5.1-6.5) per 1000 patient years; this incidence dropped from 8.1 (95%CI 5.4-11.9) per 1000 patient years in 2002 to 2.6 (95%CI 1.3-5.3) in 2014 (p=0.0059). Among 6953 patients with T2DM 310 developed a DFU, corresponding to an incidence of 11.3 (95%CI 10.1-12.6) per 1000 patient years; this incidence dropped from 17.0 (95%CI 12.2-23.8) per 1000 patient years in 2002 to 8.7 (95%CI 5.3-14.1) per 1000 patient year (p=0.0260) in 2014. CONCLUSION: The incidence of DFU has decreased substantially in T1DM as well as in T2DM. This change was driven by a decrease in incidence of neuropathic ulcers. PMID- 28648856 TI - Presentations for hypoglycemia associated with diabetes mellitus to emergency departments in a Canadian province: A database and epidemiological analysis. AB - AIMS: The prevalence of diabetes mellitus was reportedly 9% in 2014, making it one of the most common global chronic conditions. Hypoglycemia is an important complication of diabetes treatment. The objective of this study was to quantify and characterize hypoglycemia presentations associated with type 1 or 2 diabetes made to emergency departments (EDs) by adults in a Canadian province. METHODS: A retrospective cohort study was conducted using reliable administrative data from Alberta for a five-year period (2010/11-2014/15). Records of interest were those with an ICD-10-CA diagnosis of diabetes-associated hypoglycemia (e.g., E10.63). A descriptive analysis was conducted. RESULTS: Data extraction yielded 7835 presentations by 5884 patients. The majority (56.2%) of presentations were made by males, median patient age was 62, and 60.5% had type 2 diabetes. These episodes constituted 0.08% of presentations to Alberta EDs. The annual rate of presentations decreased by 11.8% during the five-year period. Most presentations (63.4%) involved transportation to ED via ambulance. Median length-of-stay was four hours. For 27.5% of presentations, an X-ray was obtained. Most hypoglycemic episodes (65.2%) were considered to be moderate, while 34.3% were considered to be severe. CONCLUSIONS: Diabetes-associated hypoglycemia presentations to Alberta EDs are more commonly made by patients with type 2 diabetes, who are more likely to be transported via ambulance and also admitted. Each year, approximately one percent of Albertans with diabetes presented with a hypoglycemia episode; however, knowledge of the variation across regions can guide a strategy for improved care. PMID- 28648857 TI - Vibrio cholerae O1 with ctxB7 variant genotype acquired qnrVC mediated ciprofloxacin resistance in Yavatmal, India. PMID- 28648858 TI - Evaluation of vancomycin MIC creep in methicillin-resistant Staphylococcus aureus infections-a systematic review and meta-analysis. AB - OBJECTIVES: Vancomycin is currently the primary option treatment for methicillin resistant Staphylococcus aureus (MRSA). However, an increasing number of MRSA isolates with high MICs, within the susceptible range (vancomycin MIC creep), are being reported worldwide. Resorting to a meta-analysis approach, this study aims to assess the evidence of vancomycin MIC creep. METHODS: We searched for studies in the PubMed database. The inclusion criteria for study eligibility included the possibility of retrieving the reported data values of vancomycin MIC and information concerning the applied MIC methodology. RESULTS: The mean values of vancomycin MICs, of all 29 234 S. aureus isolates reported in the 55 studies included in the meta-analysis, were 1.23 mg/L (95% CI 1.13-1.33) and 1.20 mg/L (95% CI 1.13-1.28) determined by Etest and broth microdilution method, respectively. No significant differences were observed between these two methodologies. We found negative correlation between pooled mean/pooled proportion and time strata. CONCLUSIONS: We have found no evidence of the MIC creep phenomenon. PMID- 28648859 TI - Ceftriaxone versus ceftriaxone plus a macrolide for community-acquired pneumonia in hospitalized patients with HIV/AIDS: a randomized controlled trial. AB - OBJECTIVES: To evaluate if treatment with ceftriaxone and a macrolide, improved patient outcome when compared with monotherapy with ceftriaxone, in hospitalized patients with human immunodeficiency virus/acquired immunodeficient syndrome (HIV/AIDS) with community-acquired pneumonia (CAP). METHODS: Adult patients with HIV hospitalized due to suspected CAP were randomized to receive one of two regimens, ceftriaxone plus macrolide or ceftriaxone plus placebo, at a 1:1 proportion (Brazilian Clinical Trials Registry: RBR-8wtq2b). The primary outcome was in-hospital mortality and the secondary outcomes were mortality within 14 days, need for vasoactive drugs, need for mechanical ventilation, time to clinical stability and length of hospitalization. RESULTS: A total of 227 patients were randomized, two were excluded after randomization; 225 patients were analysed (112 receiving ceftriaxone plus placebo and 113 receiving ceftriaxone plus macrolide). The frequency of the primary outcome, in-hospital mortality, was not statistically different between the regimens: 12/112 (11%) patients who received ceftriaxone plus placebo and 17/113 (15%) who received ceftriaxone plus macrolide died during hospitalization (hazard ratio 1.22, 95% CI 0.57-2.59). We did not find differences between the regimens for any of the secondary outcomes, including mortality within 14 days, which occurred in 5/112 (4%) patients with ceftriaxone plus placebo and in 12/113 (11%) patients with ceftriaxone plus macrolide (relative risk 2.38, 95% CI 0.87-6.53). CONCLUSIONS: Among hospitalized patients with HIV/AIDS with CAP, treatment with ceftriaxone and a macrolide did not improve patient outcomes, when compared with ceftriaxone monotherapy. PMID- 28648860 TI - Global emergence of the widespread Pseudomonas aeruginosa ST235 clone. AB - OBJECTIVES: Despite the non-clonal epidemic population structure of Pseudomonas aeruginosa, several multi-locus sequence types are distributed worldwide and are frequently associated with epidemics where multidrug resistance confounds treatment. ST235 is the most prevalent of these widespread clones. In this study we aimed to understand the origin of ST235 and the molecular basis for its success. METHODS: The genomes of 79 P. aeruginosa ST235 isolates collected worldwide over a 27-year period were examined. A phylogenetic network was built, using a Bayesian approach to find the Most Recent Common Ancestor, and we identified antibiotic resistance determinants and ST235-specific genes. RESULTS: Our data suggested that the ST235 sublineage emerged in Europe around 1984, coinciding with the introduction of fluoroquinolones as an antipseudomonal treatment. The ST235 sublineage seemingly spread from Europe via two independent clones. ST235 isolates then appeared to acquire resistance determinants to aminoglycosides, beta-lactams and carbapenems locally. Additionally, we found that all the ST235 genomes contained the exoU-encoded exotoxin and identified 22 ST235-specific genes clustering in blocks and implicated in transmembrane efflux, DNA processing and bacterial transformation. These unique combinations of genes may have contributed to the poor outcome associated with P. aeruginosa ST235 infections and increased the ability of this international clone to acquire mobile resistance elements. CONCLUSION: Our data suggest that P. aeruginosa ST235 (a) has become prevalent across the globe potentially due to the selective pressure of fluoroquinolones and (b) readily became resistant to aminoglycosides, beta-lactams and carbapenems through mutation and acquisition of resistance elements among local populations. PMID- 28648861 TI - Preparing clinicians for (re-)emerging arbovirus infectious diseases in Europe. AB - BACKGROUND: Arthropod-borne virus (Arbovirus) infections are considered an emerging threat for Europe, with an increase in cases in recent decades. The increase in global travel and trade has contributed to the introduction of vectors and viruses into new geographical areas. Tropical arboviruses such as dengue and chikungunya have re-emerged causing local, sporadic outbreaks ignited by travel-imported cases. The recent Zika virus outbreak in the Americas highlighted a need to strengthen preparedness for (re-)emerging arbovirus infections globally. AIMS: To strengthen preparedness for the early identification of (re-)emerging arbovirus outbreaks in Europe and highlight areas for research. SOURCES: An evidence review of published and grey literature together with consultations with European arbovirus experts. CONTENT: This paper presents an overview of endemic and travel-imported arboviruses of clinical significance in Europe. The overview includes syndromic presentation, risk factors for infection and risk of transmission as well as an update on treatments and vaccinations and surveillance notifications and reporting. The paper also presents predictive modelled risks of further geographical expansion of vectors and viruses. IMPLICATIONS: There are a range of arboviruses of clinical significance to Europe. There has been an increase in notifications of endemic and travel-imported arbovirus cases in recent years and an increased geographical range of vectors and viruses. The heterogeneity in surveillance reporting indicates a risk for the early identification of (re-)emerging outbreaks. The data presented show a need to strengthen preparedness for (re-)emerging arbovirus infections and a need for research into neglected arboviruses, risks of non vector transmission and effective therapeutics and vaccinations. PMID- 28648862 TI - Octacosanol educes physico-chemical attributes, release and bioavailability as modified nanocrystals. AB - Octacosanol is a lesser known nutraceutical with the potential for treatment of several inflammatory diseases, high cholesterol, Parkinson's symptoms and tumour growth along with the capacity to improve athletic performance. But its lipophilicity and large structure inhibits extended solubility in water resulting in poor absorption and a low bioavailability. In the present work, sodium salt of octacosyl sulfate was synthesized. It displayed improved water solubility. Its nanocrystals, synthesized by means of nanoprecipitation technique, enhanced diffusion velocity, antioxidant capacity, shelf-life, penetrability and bioavailability. Particle size of the nanocrystals ranged between 197 and 220nm. Both modified octacosanol and its nanocrystals displayed maximum lipid peroxidation activities at a concentration 1000ppm, but nanocrystals demonstrated higher prevention. From freeze-thaw cycles it was evident that normal octacosanol crystals were far more prone to temperature variations than the nanocrystals. A pronounced increase in release/diffusion rate and bioavailability was observed for the nanocrystals of the modified octacosanol. In vitro release kinetics, bioavailability and bioequivalence were studied. Relative bioavailability for gastric passage and pancreatic passage of nanocrystals was 2.58 times and 1.81 times that of normal crystals respectively. Furthermore the nanocrystals displayed a superior in vitro release rate, while following a non-Fickian mode. PMID- 28648863 TI - Two-phase amorphous-amorphous solid drug dispersion with enhanced stability, solubility and bioavailability resulting from ultrasonic dispersion of an immiscible system. AB - Amorphization of active pharmaceutical ingredients (APIs) and the preparation of solid dispersions are strategies that can be synergized to improve the solubility of oral drugs. Immiscibility between an API and a carrier in the molten state that could be perceived as a problem in the preparation of solid dispersions, may actually introduce an advantage. In the present work, a two-phase amorphous amorphous solid dispersion (AASD) was prepared by ultrasonicating a molten immiscible mixture of indomethacin (IND) and glucose (GLU) prior quenching. By introducing this novel ultrasound assisted method, the immiscible API particles were uniformly dispersed as microscopic glassy clusters of the drug in the solid amorphous GLU matrix; particle sizes of IND in the AASD range from 600nm to 1.4MUm. As a result of the amorphization and particle size reduction of IND, its aqueous solubility increased to reach almost 40ppm (8 times more soluble compared to indomethacin in its crystalline state). In addition, the oral bioavailability and its resistance against crystallization were also enhanced; AASD samples have remained amorphous for more than two years of storage. PMID- 28648864 TI - Impact of plasma protein binding on cargo release by thermosensitive liposomes probed by fluorescence correlation spectroscopy. AB - Thermosensitive liposomes (TSLs) whose phase-transition temperature (Tm) lies slightly above body temperature are ideal candidates for controlled drug release via local hyperthermia. Recent studies, however, have revealed disruptive shifts in the release temperature Tr in mouse plasma, which are attributed to undefined interactions with blood proteins. Here, we study the effects of four major plasma proteins - serum albumin (SA), transferrin (Tf), apolipoprotein A1 (ApoA1) and fibrinogen (Fib) - on the temperature-dependent release of fluorescein di-beta-D galactopyranoside (FDG) from TSLs. The amount of fluorescein released was quantified by fluorescence correlation spectroscopy (FCS) after hydrolysis of FDG with beta-galactosidase (beta-Gal). This approach is more sensitive and thus superior to previous release assays, as it is impervious to the confounding effects of Triton on conventional fluorescence measurements. The assay determines the molar release ratio, i.e. the number of molecules released per liposome. We show that shifts in the Tr of release do not reflect protein affinities for the liposomes derived from adsorption isotherms. We confirm a remarkable shift in induced release towards lower temperatures in the presence of mouse plasma. In contrast, exposure to rat or human plasma, or fetal bovine serum (FBS), has no effect on the release profile. PMID- 28648865 TI - Self-assembled amphiphilic core-shell nanocarriers in line with the modern strategies for brain delivery. AB - Disorders of the central nervous system (CNS) represent increasing social and economic problems all over the world which makes the effective transport of drugs to the brain a crucial need. In the last decade, many strategies were introduced to deliver drugs to the brain trying to overcome the challenge of the blood brain barrier (BBB) using both invasive and non-invasive methods. Non-invasive strategy represented in the application of nanocarriers became very common. One of the most hopeful nanoscopic carriers for brain delivery is core-shell nanocarriers or polymeric micelles (PMs). They are more advantageous than other nanocarriers. They offer small size, ease of preparation, ease of sterilization and the possibility of surface modification with various ligands. Hence, the aim of this review is to discuss modern strategies for brain delivery, micelles as a successful delivery system for the brain and how micelles could be modified to act as "magic bullets" for brain delivery. PMID- 28648866 TI - Cytokines in immunogenic cell death: Applications for cancer immunotherapy. AB - Despite advances in treatments like chemotherapy and radiotherapy, metastatic cancer remains a leading cause of death for cancer patients. While many chemotherapeutic agents can efficiently eliminate cancer cells, long-term protection against cancer is not achieved and many patients experience cancer recurrence. Mobilizing and stimulating the immune system against tumor cells is one of the most effective ways to protect against cancers that recur and/or metastasize. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN gamma or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. To this end, a group of anthracyclines or treatments like photodynamic therapy (PDT) exert their effects on cancer cells in a manner that activates the immune system. This process, known as immunogenic cell death (ICD), is characterized by the release of membrane-bound and soluble factors that boost the function of immune cells. This review will explore different types of ICD inducers, some in clinical trials, to demonstrate that optimizing the cytokine response brought about by treatments with ICD-inducing agents is central to promoting anti-cancer immunity that provides long-lasting protection against disease recurrence and metastasis. PMID- 28648867 TI - An initial investigation into endothelial CC chemokine expression in the human rheumatoid synovium. AB - Rheumatoid arthritis (RA) is a destructive and chronic autoimmune inflammatory disease. Synovial inflammation is a major feature of RA and is associated with leukocyte recruitment. Leukocytes cross the endothelial cells (ECs) into the synovial tissue and fluid and this migration is mediated via a range of chemokines and adhesion molecules on the ECs. As important mediators of leukocyte extravasation, a number of chemokines from each of the chemokine families have been established as expressed in the RA joint. However, as little information is available on which chemokines are expressed/presented by the ECs themselves, the purpose of the study was to ascertain which of the CC chemokines were localised in RA ECs. Immunofluoresence was used to assess the presence of the CC-family chemokines in RA synovial ECs using von-Willebrand factor (VWF) as a pan endothelial marker and a range of human chemokine antibodies. The percentage of VWF positive vessels which were positive for the chemokines was determined. The presence of the four most highly expressed novel chemokines were further investigated in non-RA synovial ECs and the sera and synovial fluid (SF) from patients with RA and osteoarthritis (OA). Statistical analysis of immunofluorescence data was carried out by Student's t-test. For analysis of ELISA data, Kruskal-Wallis ANOVA followed by Dunn's multiple comparison test was utilised to analyse differences in sera and SF levels for each chemokine between RA and OA. Spearman rank correlations of sera and SF chemokine levels with a range of clinical variables were also performed. Chemokine detection varied, the least abundant being CCL27 which was present in 8.3% of RA blood vessels and the most abundant being CCL19 which was present in 80%. Of the 26 chemokines studied, 19 have not been previously observed in RA ECs. Four of these novel chemokines, namely CCL7, CCL14, CCL16 and CCL22 were present on >=60% of vessels. CCL14 and CCL22 were shown to be increased in RA ECs compared to non-RA ECs, p=0.0041 and p=0.014 respectively. EC chemokines CCL7, CCL14, CCL16 and CCL22 also occurred in RA synovial fluid and sera as established by ELISA. CCL7 was shown to be significantly increased in sera and SF from RA patients compared to that from osteoarthritis (OA) patients (p<0.01), and to have a highly significant correlation with the level of anti-CCP (R=0.93, p=0.001). Less abundant chemokines shown to be present in RA ECs were CCL1-3, CCL5, CCL10-13, CCL15, CCL17, CCL18, CCL20, CCL21 and CCL23-28. In conclusion, this initial study is the first to show the presence of a number of CC chemokines in RA ECs. It provides evidence that further validation and investigation into the presence and functionality of these novel chemokines expressed at RA synovial ECs may be warranted. PMID- 28648868 TI - Immune-modulating effects in mouse dendritic cells of lactobacilli and bifidobacteria isolated from individuals following omnivorous, vegetarian and vegan diets. AB - Lactobacilli and bifidobacteria play a primary role in modulation of gut immunity. By considering that microbiota composition depends on various factors, including diet, we asked whether functional differences could characterize faecal populations of lactobacilli and bifidobacteria isolated from individuals with different dietary habits. 155 healthy volunteers who followed omnivorous, ovo lacto-vegetarian or vegan diets were recruited at four Italian centres (Turin, Parma, Bologna and Bari). Faecal samples were collected; lactobacilli and bifidobacteria were isolated on selective media and their immunomodulatory activity was tested in mouse dendritic cells (DCs). Pre-incubation with lactobacilli increased LPS-induced expression of the maturation markers CD80 and CD86, whereas pre-incubation with bifidobacteria decreased such expression. Analysis of the cytokine profile indicated that strains of both genera induced down-regulation of IL-12 and up-regulation of IL-10, whereas expression of TNF alpha was not modulated. Notably, analysis of anti-inflammatory potential (IL 10/IL-12 ratio) showed that lactobacilli evoked a greater anti-inflammatory effect than did bifidobacteria in the omnivorous group (P<0.05). We also found significantly reduced anti-inflammatory potential in the bacterial strains isolated from Bari's volunteers in comparison with those from the cognate groups from the other centres. In conclusion, lactobacilli and bifidobacteria showed a genus-specific ability of modulating in vitro innate immunity associated with a specific dietary habit. Furthermore, the geographical area had a significant impact on the anti-inflammatory potential of some components of faecal microbiota. PMID- 28648869 TI - Long-term cytokine and growth factor release from equine platelet-rich fibrin clots obtained with two different centrifugation protocols. AB - OBJECTIVES: To compare the temporal release (over three weeks) of tumor necrosis factor alpha (TNF-alpha), interleukin 4 (IL-4), IL-1 receptor antagonist (IL 1ra), platelet-derived growth factor BB (PDGF-BB) and transforming growth factor beta-1 (TGF-beta1) from two platelet-rich fibrin (PRF) preparations from equine blood obtained at either 240g/8min or 416g/10min. METHODS: Whole blood from 10 horses was used to obtain PRF clots by two different centrifugation protocols. After 1h of rest, PRF clots were deposited in wells with culture medium, which was changed at 6h, 24h and then every 48h to 21days. Cytokines and GFs were measured by ELISA at 1h (serum supernatants from PRF clots) and all time points of culture medium change. A negative control (plasma) and a positive control (blood lysate) were also included. RESULTS: There were no relevant differences between the two protocols for the temporal release of proteins. However, a significant (p=0.01) effect of time was noted. All cytokines were detected after 6h of PRF clot culture until day 21. GF were detected at 1h until day 21. The concentrations for these proteins diminished gradually over time. A highly significant (p=0.01) correlation was noticed between all the proteins evaluated. CONCLUSIONS: Leukocytes enmeshed in PRF clots were able to produce cytokines, TGF beta1 and PDGF-BB. These findings demonstrate a paramount role of leukocytes in wound healing induced or modified by PRF clots in mammals. PMID- 28648870 TI - TLR7 and TLR8 agonist resiquimod (R848) differently regulates MIF expression in cells and organs. AB - Since its first description in 1966, macrophage migration inhibitory factor (MIF) was found to play a critical role in inflammatory and immune responses as well as in disease pathogenesis especially in tumor pathogenesis and cancer progression. MIF is expressed in different cell types and is associated with many disease severity and tumor pathogenesis. Here, we investigated the influence of TLR7 and TLR8 agonist resiquimod (R848), an immune response inducer used as a prophylactic agent for several infectious diseases as well as anticancer agents and vaccine adjuvant on MIF expression in cells and organs. Humans, mice and rats cell lines from different tissues (blood, retinal, nasopharynx, brain and liver) and C57BL/6J mice organs (brain, liver and spleen) were used for this investigation. In vitro, R848 induced MIF gene overexpression except in brain and liver cells. Furthermore, it enhanced cells ability to release soluble MIF and differently regulated mRNA expression of MIF-related receptors (CD74, CXCR4, CXCR2 and CD44). Its influence on MIF gene expression and MIF proteins release was more consistent in cancer cells. In vivo, a strong positive expression of MIF was observed in different regions in brain and spleen in response to R848 treatment; however in liver, increased MIF expression was observed in hepatocytes only. On the other hand, R848 treatment had induced a slight enhancement of MIF concentration in the plasma of C57BL/6J mice. Taken together, these data suggest that R848 differently regulates MIF mRNA expression depending on organ types and could influence MIF concentration in cellular microenvironment. PMID- 28648871 TI - Creation of an Open Framework for Point-of-Care Computer-Assisted Reporting and Decision Support Tools for Radiologists. AB - Decreasing unnecessary variation in radiology reporting and producing guideline concordant reports is fundamental to radiology's success in value-based payment models and good for patient care. In this article, we present an open authoring system for point-of-care clinical decision support tools integrated into the radiologist reporting environment referred to as the computer-assisted reporting and decision support (CAR/DS) framework. The CAR/DS authoring system, described herein, includes: (1) a definition format for representing radiology clinical guidelines as structured, machine-readable Extensible Markup Language documents and (2) a user-friendly reference implementation to test the fidelity of the created definition files with the clinical guideline. The proposed definition format and reference implementation will enable content creators to develop CAR/DS tools that voice recognition software (VRS) vendors can use to extend the commercial tools currently in use. In making the definition format and reference implementation software freely available, we hope to empower individual radiologists, expert groups such as the ACR, and VRS vendors to develop a robust ecosystem of CAR/DS tools that can further improve the quality and efficiency of the patient care that our field provides. We hope that this initial effort can serve as the basis for a community-owned open standard for guideline definition that the imaging informatics and VRS vendor communities will embrace and strengthen. To this end, the ACR AssistTM initiative is intended to make the College's clinical content, including the Incidental Findings Committee White Papers, available for decision support tool creation based upon the herein described CAR/DS framework. PMID- 28648872 TI - Burnout: Redesign the Work Process Rather Than the Person. PMID- 28648874 TI - A Leadership Development Program for Radiology Residents. PMID- 28648873 TI - Breast Cancer Screening for Average-Risk Women: Recommendations From the ACR Commission on Breast Imaging. AB - Breast cancer is the most common non-skin cancer and the second leading cause of cancer death for women in the United States. Before the introduction of widespread mammographic screening in the mid-1980s, the death rate from breast cancer in the US had remained unchanged for more than 4 decades. Since 1990, the death rate has declined by at least 38%. Much of this change is attributed to early detection with mammography. ACR breast cancer screening experts have reviewed data from RCTs, observational studies, US screening data, and other peer reviewed literature to update our recommendations. Mammography screening has consistently been shown to significantly reduce breast cancer mortality over a variety of study designs. The ACR recommends annual mammography screening starting at age 40 for women of average risk of developing breast cancer. Our recommendation is based on maximizing proven benefits, which include a substantial reduction in breast cancer mortality afforded by regular screening and improved treatment options for those diagnosed with breast cancer. The risks associated with mammography screening are also considered to assist women in making an informed choice. PMID- 28648875 TI - Shotha and the Unified Theory of Inflammatory Diseases 2017. PMID- 28648876 TI - Triple negative invasive lobular carcinoma of the breast presents as small bowel obstruction. AB - Metastasis from breast carcinoma to the gastrointestinal tract (GIT) is very uncommon. To date, only a few cases have been described worldwide. Of those which do metastasize to the GIT, only estrogen receptor (ER), progesterone receptor (PR) and HER2-neu receptor positive cancers have been reported and none have been mentioned in the U.S. We report a case of a 70-year-old white female with history of triple negative lobular carcinoma eight years earlier who presented with solitary jejunal mass causing obstruction. PMID- 28648877 TI - A rare presentation: A case report of osseous metaplasia and mature bone formation in a follicular adenoma of the thyroid. AB - INTRODUCTION: Cases of multinodular goiter, thyroid hyperplasia, follicular adenoma, papillary thyroid carcinoma, and anaplastic thyroid carcinoma have been reported with histopathologic findings of osseous metaplasia (OM), bone marrow metaplasia (BMM), ectopic bone formation (EBF), ossification, and extramedullary hematopoiesis (EMH). To date no report of a follicular adenoma with OM and mature EBF in the absence of EMH has been reported in the English language. PRESENTATION OF CASE: 63-year-old woman with an incidental finding of thyroid nodule unable to be biopsied. One area was found to contain OM with mature EBF and without vascular invasion. The surrounding tissue was unremarkable, and no malignancy was found. DISCUSSION: Ectopic bone formation and osseous metaplasia in a thyroid nodule has an extensive differential diagnosis, from thyroid related pathologies to parathyroid causes, congenital syndromes, and hamartomas. A common theory amongst these is the role of basic fibroblast growth factor (bFGF) and bone morphogenetic protein-2 (BMP-2), signaling factors involved in cellular proliferation and growth. CONCLUSION: This is the first case report of a follicular adenoma with OM and EBF in the absence of EMH. In this case, this adenoma was an incidental finding and the patient had no symptoms or accompanying laboratory abnormalities. Her benign presentation underscores the importance of awareness of the more common changes a thyroid nodule can undergo, such as hemorrhagic, cystic, and fibrotic changes, as well as the rarer changes of calcification with eventual ossification. PMID- 28648879 TI - Reply to Letter to the Editor by Crocoli A, et al. PMID- 28648878 TI - An effective and safe surgical approach for a superior sulcus tumor: A case report. AB - INTRODUCTION: Superior sulcus tumors, frequently referred to as Pancoast tumors, are a wide range of tumors invading a section of the apical chest wall called the thoracic inlet. For this reason, a surgical approach and complete resection may be difficult to accomplish. We experienced a locally advanced superior sulcus tumor (SST) located from the anterior to posterior apex thoracic inlet and performed complete resection after definitive chemoradiation. PRESENTATION OF CASE: A 71-year-old Japanese male presented at our hospital due to left back pain and an abnormal chest computed tomography (CT) scan showing 80*70*60-mm tumor located in the left middle apex thoracic inlet. This tumor was located near the subclavian artery, and the subclavian lymph nodes were swollen. The tumor was found to be an adenocarcinoma (clinical-T3N3M0 stage IIIB). Therefore, we performed definitive chemoradiation therapy. Slight reduction in the tumor size was noted after the treatment, and the subclavian lymph nodes were not swollen. We next performed surgical resection for this SST. Regarding the surgical approaches, the anterior approach was a transmanubrial approach, and the posterior approach was a Paulson's thoracotomy. In this manner, we were able to perform complete en-bloc resection of this tumor. DISCUSSION: This surgical approach was effective and safe for treating a SST located from the anterior to posterior apex of the thoracic inlet. The patient remains healthy and recurrence free at 2.5 years after the operation. CONCLUSION: Surgical approach for SST is difficult. Therefore, this approach is effective and safety. PMID- 28648880 TI - Animated versus non-animated biofeedback therapy for dysfunctional voiding treatment: Does it change the outcome? AB - PURPOSE: The aim of this study is to evaluate and compare the effectiveness of animated vs. non-animated biofeedback therapy in the treatment of dysfunctional voiding (DV) in the pediatric age group. METHODS: In this study, children with DV were randomly assigned for animated and non-animated biofeedback therapy. Age, voiding dysfunction symptom scores (VDSS), urinary ultrasound and uroflowmetry parameters such as electromyography (EMG) activity, voided volumes, post voiding residual urine volume (PVR) and maximum flow rate (Qmax) were evaluated. At the end of treatment, clinical success was regarded as the cessation of EMG activity during voiding, resolution of symptoms (reduction in VDSS, frequency, intermittency, urgency and incontinence), and improvements in uroflowmetry parameters. RESULTS: A total of 40 children were included in the study. There were 20 children in the non-animated group (16 girls, 4 boys; mean age: 10.5+/ 3.2years) and 20 children in the animated group (15 girls, 5 boys; mean age: 9.5+/-3.63years). Patients received a mean of 5.2+/-1.9 sessions in both groups. Cessation of pelvic muscle activity on EMG was 75% in the non-animated group and 90% in the animated group (p=0.407). Reduction in VDSS was clinically significant in both groups (p=0.001 for both). There was no significant difference between the clinical success rates of the nonanimated and animated groups (80% vs. 70% respectively, p=0.125). PVR decreased by 68% in the non-animated group (p=0.015) while a 60% decrease was observed in the animated group (p=0.001). CONCLUSION: In our study, there was no difference between animated and non-animated biofeedback therapy in terms of clinical success rates. TYPE OF STUDY: Prospective comparative study LEVEL OF EVIDENCE: Level II. PMID- 28648881 TI - Congenital chylous ascites in infants: another presentation of intestinal malrotation. AB - OBJECTIVE: The cause of the chylous ascites in infants isn't completely clear. The purpose of this study is to discuss our experience of recognition of intestinal malrotation as a cause of congenital chylous ascites in infants. METHODS: Medical information of 10 infants with chylous ascites, who were admitted to the hospital between 2001 and 2014, was retrospective analyzed. Preoperatively, all patients underwent a period of conservative treatment. RESULTS: We found that nine of ten patients with intestinal malrotation, six of them underwent laparoscopic Ladd's procedure and three patients underwent open Ladd's procedure. The remaining one patient suffered from mesenteric lymph nodes rupture and laparoscopic resection was performed. The cylous ascites subsided in all patients after the surgery and no significant recurrence was encountered during follow-up time. CONCLUSIONS: Our study demonstrates that congenital chylous ascites could be caused by intestinal malrotation, causing the obstruction of the lymphatic flow in the mesenteric lymphatic channels. Ladd's procedure maybe a safe and effective treatment for infantile intractable chylous ascites. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level IV. PMID- 28648882 TI - Transcriptome analysis of the hepatopancreas in Exopalaemon carinicauda infected with an AHPND-causing strain of Vibrio parahaemolyticus. AB - Acute hepatopancreatic necrosis disease (AHPND) caused by Vibrio parahaemolyticus carrying toxin-producing plasmid, has led to severe mortalities in multiple shrimp species throughout Asia. In order to understand the immunological response of shrimp to infection by AHPND-causing strain of V. parahaemolyticus (VPAHPND), the transcriptomic profiles of the hepatopancreas from severe AHPND-infected (BS_G), AHPND-survived (KB_G) and non-infected (PBS_G) Exopalaemon carinicauda groups were obtained using HiSeqTM 2500 (Illumina). In total, 525 million high quality clean reads were obtained in nine libraries and de novo assembled into 130,082 unigenes with an average length of 724 bp. Based on sequence similarity, 22.75% unigenes were annotated in the public databases. Comparative analysis revealed that 3733 genes differentially expressed in VPAHPND infection compared with the controls, including 1114 and 3461 unigenes in BS_G vs PBS_G and KB_G vs PBS_G, respectively. A total of 229 differential expressed genes that have high homologies with the known proteins in crustacean species were identified, among which 127 genes are reported potentially related to immune function. We identified relative genes and pathways associated with AHPND pathogenesis and defenses. Our results provide valuable information for further analysis of the mechanisms of shrimp defense against AHPND infection. PMID- 28648883 TI - Molecular cloning and functional analysis of tumor necrosis factor receptor associated factor 6 (TRAF6) in Crossastrea gigas. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been demonstrated to be a key signaling molecule involved in adaptive and innate immunity. In this study, we obtained the full length CgTRAF6 cDNA and analyzed the characteristics of the ORF and the peptide sequence in Crassostrea gigas. The deduced protein sequence of CgTRAF6 includes a conserved C-terminal TRAF domain following the RING and the zinc finger domain. The TRAF domain is composed of coiled-coil TRAF N and MATH (meprin and TRAF-C homology) subdomains. Furthermore, phylogenetic analysis revealed that CgTRAF6 is clustered together with other members TRAF6 family and is placed in a sub-cluster singly which had a close relationship with Drosophila melanogaster. Expression analysis of CgTRAF6 indicated its constitutive expression in all tissues including mantle, adductor muscle, digestive tract, gonads, heart, gill, and hemocyte. Immune challenge with Vibrio alginolyticus and poly I:C resulted in significant up-regulation of CgTRAF6 expression. Dual-luciferase reporter assays showed that CgTRAF6 could activate both pNF-kappaB-Luc and pISRE-Luc expression, suggesting CgTRAF6 is potentially involved in NF-kappaB and the interferon signaling pathway. Furthermore, RNAi mediated knockdown of CgTRAF6 resulted in the down-regulation of several putative anti-viral signaling (IRF) and effector (PKR & Viperin) molecules coding genes, 7 days post-injection. These results collectively indicate that CgTRAF6 is a member of TRAF6 sub-family and is potentially involved in immune defense system against invading bacteria and viruses in Crassostrea gigas. PMID- 28648884 TI - Epigallocatechin-3-gallate inhibit replication of white spot syndrome virus in Scylla paramamosain. AB - Epigallocatechin-3-gallate (EGCG) has exhibited potential antibacterial and anticancer activities. In this study, we tested whether EGCG can protect the mud crab Scylla paramamosain against white spot syndrome virus (WSSV). Treatment with 1.5 mg/kg EGCG killed crab hemocytes but treatment with 1 mg/kg EGCG did not. Results of the virus challenge experiment confirmed that EGCG could enhance the survival rate of WSSV-challenged crabs, and treatment with 1 mg/kg EGCG significantly increased their resistance to WSSV compared with the control. Thus, 1 mg/kg EGCG was used as the experimental dose in subsequent analyses. EGCG treatment may induce certain immune pathways, such as the phenoloxidase and JAK STAT pathways, and it also can enhance the activity of prophenoloxidase. EGCG + WSSV treatment significantly reduced the number of WSSV copies at 24, 48, and 72 h post-challenge compared with the control (WSSV challenge without EGCG treatment). These results demonstrate that EGCG may effectively improve innate immunity and survival of WSSV-challenged S. paramamosain and inhibit WSSV replication by blocking the expression of late stage WSSV genes. Therefore, our study presented that EGCG might represent a new potential therapeutic or preventive approach to control white spot syndrome. PMID- 28648885 TI - Chlorpyrifos exposure in common carp (Cyprinus carpio L.) leads to oxidative stress and immune responses. AB - Chlorpyrifos (CPF) is an environmental pollutant with increasing importance due to its high toxicity to fish and aquatic animals. To understand how CPF impacts immune response and oxidative stress in common carp (Cyprinus carpio L.), we investigated the transcriptomic profiles of the head kidneys from common carp exposed to CPF for 15days. A total of 52, 297, 928 and 52, 273, 784 high quality clean reads were obtained from CPF exposure groups, 44,677,578 and 44,106,696 high quality clean reads were obtained from corresponding control groups. Among them, 456 genes were differentially expressed, including 246 up-regulated genes and 210 down-regulated genes identified and enriched in databases of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Antioxidant systems, and immune response genes and pathways were verified by quantitative real-time RT-PCR. We found that CPF-induced ROS regulates immune response by stimulating the antigen-presenting ability of head kidney in carp. These results provide new insights for unveiling the biological effects of CPF in common carp. PMID- 28648886 TI - Revisiting Pivotal-Differential Genome Evolution in Wheat. AB - An interesting and possibly unique pattern of genome evolution following polyploidy can be observed among allopolyploids of the Triticum and Aegilops genera (wheat group). Most polyploids in this group are presumed to share a common unaltered (pivotal) subgenome (U, D, or A) together with one or two modified (differential) subgenomes, a status that has been referred to as 'pivotal-differential' genome evolution. In this review we discuss various mechanisms that could be responsible for this evolutionary pattern, as well as evidence for and against the putative evolutionary mechanisms involved. We suggest that, in light of recent advances in genome sequencing and related technologies in the wheat group, the time has come to reopen the investigation into pivotal-differential genome evolution. PMID- 28648887 TI - Adult-like processing of naturalistic sounds in auditory cortex by 3- and 9-month old infants. AB - Functional neuroimaging has been used to show that the developing auditory cortex of very young human infants responds, in some way, to sound. However, impoverished stimuli and uncontrolled designs have made it difficult to attribute brain responses to specific auditory features, and thus made it difficult to assess the maturity of feature tuning in auditory cortex. To address this, we used functional magnetic resonance imaging (fMRI) to measure the brain activity evoked by naturalistic sounds (a series of sung lullabies) in two groups of infants (3 and 9 months) and adults. We developed a novel analysis method - inter subject regression (ISR) - to quantify the similarity of cortical responses between infants and adults, and to decompose components of the response due to different auditory features. We found that the temporal pattern of activity in infant auditory cortex shared similarity with adults. Some of this shared response could be attributed to simple acoustic features, such as frequency, pitch, envelope, but other parts were not, suggesting that even more complex adult-like features are represented in auditory cortex in early infancy. PMID- 28648888 TI - Benchmarking laminar fMRI: Neuronal spiking and synaptic activity during top-down and bottom-up processing in the different layers of cortex. AB - High resolution laminar fMRI is beginning to probe responses in the different layers of cortex. What can we expect this exciting new technique to discover about cortical processing and how can we verify that it is producing an accurate picture of the underlying laminar differences in neural processing? This review will address our knowledge of laminar cortical circuitry gained from electrophysiological studies in macaque monkeys with a focus on the primary visual cortex, as this area has been most often targeted in both laminar electrophysiological and fMRI studies. We will review how recent studies are attempting to verify the accuracy of laminar fMRI by recreating the known laminar profiles of various neural tuning properties. Furthermore, we will examine how feedforward and feedback-related neural processes engage different cortical layers, producing canonical patterns of spiking and synaptic activity as estimated by the analysis of current-source density. These results provide a benchmark for recent studies aiming to examine the profiles of bottom-up and top down processes with laminar fMRI. Finally, we will highlight particularly useful paradigms and approaches which may help us to understand processing in the different layers of the human cerebral cortex. PMID- 28648889 TI - Mapping between fMRI responses to movies and their natural language annotations. AB - Several research groups have shown how to map fMRI responses to the meanings of presented stimuli. This paper presents new methods for doing so when only a natural language annotation is available as the description of the stimulus. We study fMRI data gathered from subjects watching an episode of BBCs Sherlock (Chen et al., 2017), and learn bidirectional mappings between fMRI responses and natural language representations. By leveraging data from multiple subjects watching the same movie, we were able to perform scene classification with 72% accuracy (random guessing would give 4%) and scene ranking with average rank in the top 4% (random guessing would give 50%). The key ingredients underlying this high level of performance are (a) the use of the Shared Response Model (SRM) and its variant SRM-ICA (Chen et al., 2015; Zhang et al., 2016) to aggregate fMRI data from multiple subjects, both of which are shown to be superior to standard PCA in producing low-dimensional representations for the tasks in this paper; (b) a sentence embedding technique adapted from the natural language processing (NLP) literature (Arora et al., 2017) that produces semantic vector representation of the annotations; (c) using previous timestep information in the featurization of the predictor data. These optimizations in how we featurize the fMRI data and text annotations provide a substantial improvement in classification performance, relative to standard approaches. PMID- 28648890 TI - Letter to the editor regarding 'Evaluation of vitamin D levels in children with primary epistaxis'. PMID- 28648891 TI - Implications of the Vienna Integrated Model of Art Perception for art-based interventions in clinical populations: Comment on "Move me, astonish me... delight my eyes and brain: The Vienna Integrated Model of top-down and bottom-up processes in Art Perception (VIMAP) and corresponding affective, evaluative, and neurophysiological correlates" by Matthew Pelowski et al. PMID- 28648892 TI - ASCIZ/ATMIN is dispensable for ATM signaling in response to replication stress. AB - The ATM kinase plays critical roles in the response to DNA double-strand breaks, and can also be activated by prolonged DNA replication blocks. It has recently been proposed that replication stress-dependent ATM activation is mediated by ASCIZ (also known as ATMIN, ZNF822), an essential developmental transcription factor. In contrast, we show here that ATM activation, and phosphorylation of its substrates KAP1, p53 and H2AX in response to the replication blocking agent aphidicolin was unaffected in both immortalized and primary ASCIZ/ATMIN-deficient murine embryonic fibroblasts compared to control cells. Similar results were also obtained in human ASCIZ/ATMIN-deleted lymphoma cells. The results demonstrate that ASCIZ/ATMIN is dispensable for ATM activation, and contradict the previously reported dependence of ATM on ASCIZ/ATMIN. PMID- 28648893 TI - Assessment of Self-Determination in Adolescents with Neonatal Brachial Plexus Palsy. AB - BACKGROUND: The term self-determination refers to decision-making, goal setting, and perseverance to achieve those goals. Numerous studies have established the importance of self-determination to enhance learning and improve postschool outcomes. However, most studies evaluate students with learning disabilities, cognitive impairment, or behavioral disabilities. There is an absence of research on self-determination for adolescents with physical disabilities. OBJECTIVE: To assess self-determination of adolescents with neonatal brachial plexus palsy (NBPP) compared with their typically developing peers via self-reported measures of function. DESIGN: Case-control study. SETTING: Brachial plexus clinic. PARTICIPANTS: Twenty adolescents with NBPP (aged 10-17 years) and their parents and 20 age/gender-matched typically developing adolescents and their parents were recruited. Non-English-speaking participants and those with other physical impairments were excluded from study. METHODS: Participants completed demographic and American Institutes for Research (AIR) self-determination surveys. One of two designated occupational therapists evaluated participant physical function. MAIN OUTCOME MEASUREMENTS: A demographic survey and AIR self-determination assessment were administered, and active range of motion measurements in shoulder forward flexion, elbow flexion, elbow extension, forearm pronation, and supination were obtained. Grip/pinch strength, MRC muscle strength, 9-Hole Peg Test, and Mallet scale scores also were evaluated. RESULTS: Despite physical differences, adolescents with NBPP presented similar self-determination levels as their typically developing peers. Adolescents with NBPP rated their opportunities to engage in self-determined behaviors at school significantly lower than at home. Both adolescents with NBPP and those in the control group rated their opportunities to engage in self-determined behaviors at school significantly lower than at home. CONCLUSIONS: Adolescents with NBPP presented similar self determination scores as their age/gender-matched typically developing peers. These results could be a reflection of our program's patient- and family-centered care approach. Therefore, caregivers and providers should encourage personal development and fulfillment in adolescents with NBPP. Teachers and schools should be aware that opportunities for acquiring self-determination skills might be more limited at school than at home in this age group. LEVEL OF EVIDENCE: III. PMID- 28648894 TI - Compositional analysis of endogenous porphyrins from Helicobacter pylori. AB - Bacteria able to accumulate porphyrins can be inactivated by visible light irradiation thanks to the photosensitizing properties of this class of aromatic pigments (photodynamic therapy, PDT). Since the bacterial resistance to antibiotic is growing, PDT is becoming a valid alternative. In this context, the pathogen Helicobacter pylori (Hp) is a suitable target for PDT since it spontaneously produces and accumulates porphyrins. It is then important to understand the spectroscopic behavior of these endogenous species to exploit them as photosensitizers, thus improving the results given by the application of PDT in the treatment of Hp infections. In this work we extracted porphyrins from both a laboratory-adapted and a virulent strain of Hp, and we performed spectroscopic and chromatographic experiments to collect information about the composition and the spectrophotometric features of the extracts. The main components of the porphyrin mixtures were identified and their relative contribution to the global red fluorescence was examined. PMID- 28648895 TI - Nuclear Factor Erythroid 2 Regulates Human HSC Self-Renewal and T Cell Differentiation by Preventing NOTCH1 Activation. AB - Nuclear factor erythroid-derived 2 (NF-E2) has been associated with megakaryocyte maturation and platelet production. Recently, an increased in NF-E2 activity has been implicated in myeloproliferative neoplasms. Here, we investigate the role of NF-E2 in normal human hematopoiesis. Knockdown of NF-E2 in the hematopoietic stem and progenitor cells (HSPCs) not only reduced the formation of megakaryocytes but also drastically impaired hematopoietic stem cell activity, decreasing human engraftment in immunodeficient (NSG) mice. This phenotype is likely to be related to both increased cell proliferation (p21-mediated) and reduced Notch1 protein expression, which favors HSPC differentiation over self-renewal. Strikingly, although NF-E2 silencing in HSPCs did not affect their myeloid and B cell differentiation in vivo, it almost abrogated T cell production in primary hosts, as confirmed by in vitro studies. This effect is at least partly due to Notch1 downregulation in NF-E2-silenced HSPCs. Together these data reveal that NF-E2 is an important driver of human hematopoietic stem cell maintenance and T lineage differentiation. PMID- 28648896 TI - Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome. AB - L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients. PMID- 28648897 TI - Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells. AB - Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [3H]thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, which is useful for identifying these primary progenitors and study their gene regulation. PMID- 28648898 TI - Genome-wide, Single-Cell DNA Methylomics Reveals Increased Non-CpG Methylation during Human Oocyte Maturation. AB - The establishment of DNA methylation patterns in oocytes is a highly dynamic process marking gene-regulatory events during fertilization, embryonic development, and adulthood. However, after epigenetic reprogramming in primordial germ cells, how and when DNA methylation is re-established in developing human oocytes remains to be characterized. Here, using single-cell whole-genome bisulfite sequencing, we describe DNA methylation patterns in three different maturation stages of human oocytes. We found that while broad-scale patterns of CpG methylation have been largely established by the immature germinal vesicle stage, localized changes continue into later development. Non-CpG methylation, on the other hand, undergoes a large-scale, generalized remodeling through the final stage of maturation, with the net overall result being the accumulation of methylation as oocytes mature. The role of the genome-wide, non-CpG methylation remodeling in the final stage of oocyte maturation deserves further investigation. PMID- 28648899 TI - Transient HES5 Activity Instructs Mesodermal Cells toward a Cardiac Fate. AB - Notch signaling plays a role in specifying a cardiac fate but the downstream effectors remain unknown. In this study we implicate the Notch downstream effector HES5 in cardiogenesis. We show transient Hes5 expression in early mesoderm of gastrulating embryos and demonstrate, by loss and gain-of-function experiments in mouse embryonic stem cells, that HES5 favors cardiac over primitive erythroid fate. Hes5 overexpression promotes upregulation of the cardiac gene Isl1, while the hematopoietic regulator Scl is downregulated. Moreover, whereas a pulse of Hes5 instructs cardiac commitment, sustained expression after lineage specification impairs progression of differentiation to contracting cardiomyocytes. These findings establish a role for HES5 in cardiogenesis and provide insights into the early cardiac molecular network. PMID- 28648900 TI - TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors. AB - Understanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC) and hydroxymethylation (5hmC) are highly dynamic during early embryonic development, less is known about their roles at later stages of differentiation. Using an in vitro model of hepatocyte differentiation, we show here that 5hmC precedes the expression of promoter 1 (P1)-dependent isoforms of HNF4A, a master transcription factor of hepatocyte identity. 5hmC and HNF4A expression from P1 are dependent on ten-eleven translocation (TET) dioxygenases. In turn, the liver pioneer factor FOXA2 is necessary for TET1 binding to the P1 locus. Both FOXA2 and TETs are required for the 5hmC-related switch in HNF4A expression. The epigenetic event identified here may be a key step for the establishment of the hepatocyte program by HNF4A. PMID- 28648901 TI - The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty. AB - OBJECTIVE: To develop Clinical Practice Guidelines for the screening, assessment and management of the geriatric condition of frailty. METHODS: An adapted Grading of Recommendations, Assessment, Development, and Evaluation approach was used to develop the guidelines. This process involved detailed evaluation of the current scientific evidence paired with expert panel interpretation. Three categories of Clinical Practice Guidelines recommendations were developed: strong, conditional, and no recommendation. RECOMMENDATIONS: Strong recommendations were (1) use a validated measurement tool to identify frailty; (2) prescribe physical activity with a resistance training component; and (3) address polypharmacy by reducing or deprescribing any inappropriate/superfluous medications. Conditional recommendations were (1) screen for, and address modifiable causes of fatigue; (2) for persons exhibiting unintentional weight loss, screen for reversible causes and consider food fortification and protein/caloric supplementation; and (3) prescribe vitamin D for individuals deficient in vitamin D. No recommendation was given regarding the provision of a patient support and education plan. CONCLUSIONS: The recommendations provided herein are intended for use by healthcare providers in their management of older adults with frailty in the Asia Pacific region. It is proposed that regional guideline support committees be formed to help provide regular updates to these evidence-based guidelines. PMID- 28648902 TI - Self-Reported Unsteadiness Predicts Fear of Falling, Activity Restriction, Falls, and Disability. AB - OBJECTIVE: To determine if self-reported unsteadiness during walking is associated with fear of falling (FOF), fear-related activity restriction, falls, and disability over 2 years in community-dwelling adults. DESIGN: Data were obtained from the first 2 waves of The Irish Longitudinal Study on Ageing, a population-based study. SETTING: Participants completed a home-based interview and a center-based health assessment at baseline and a home-based interview at 2 years follow-up. PARTICIPANTS: Community-dwelling adults aged >=65 years, with Mini-Mental State Examination score >=18 at baseline, and fully observed variables were included in the analyses (N = 1621). MEASUREMENTS: Outcome variables were FOF, fear-related activity restriction, recurrent falls, and disability. RESULTS: Unsteadiness was independently associated with an increased risk of all outcomes at follow-up after adjusting for sociodemographic variables, and physical, mental, and cognitive health (Incidence Rate Ratio [IRR] range 1.49 2.29; P < .05). All associations were attenuated after adjusting for usual gait speed but remained consistent in direction. The association was strongest for fear-related activity restriction [IRR = 1.82 (1.21-2.73); P < .01]. There was also evidence of an association between unsteadiness and an increased risk of activity restriction in adults who did not report FOF at baseline [IRR = 1.99 (1.10-3.61); P < .05]. CONCLUSIONS: Self-reported unsteadiness is independently associated with an increased risk of FOF, fear-related activity restriction, recurrent falls, and disability at follow-up. Self-reported balance/steadiness should be included in routine assessment of older adults especially those at risk of falls. As unsteadiness is modifiable, older adults should be targeted for balance-related training or medication review to minimize future risk of these outcomes. PMID- 28648903 TI - Social Frailty and Functional Disability: Findings From the Singapore Longitudinal Ageing Studies. AB - BACKGROUND/OBJECTIVE: To examine the association between the social frailty (SF) phenotype and functional disability, independently of the physical frailty (PF) phenotype, and compare the abilities of the PF, SF, and combined social and physical (PSF) indexes for predicting functional disability. METHOD: Cross sectional and longitudinal analyses of a population-based cohort (Singapore Longitudinal Ageing Study, SLAS-1) of 2406 community-dwelling older adults with 3 years of follow-up (N = 1254 and N = 1557 for instrumental activity of daily living (IADL) disability and severe disability (>=3 basic ADL) respectively). MEASUREMENTS: Seven-item social frailty index (living arrangements, education, socioeconomic status, and social network and support, 0 = nil SF, 1 = low, 2-7 = high), PF phenotype (Fried criteria), and instrumental activities of daily living (IADLs) disability and severe disability (>=3 basic ADLs). RESULTS: Compared to nil SF, low and high SF were significantly associated with 1.3 to 2.4 fold increased prevalence and incidence of IADL disability, and 6.3 fold increase in severe disability. Frail individuals with and without SF stood out with 5-11 fold increased prevalence and incidence of IADL disability and 21-25 fold increased prevalence and incidence of severe disability, compared to robust individuals without SF. A combined PSF index more accurately identified individuals with increased risk of functional disability (ROC = 64%) and severe disability (ROC = 81%) than either the SF or the PF indexes alone (55% to 68%). CONCLUSION: The SF index alone or in combination with the PF index has clinical relevance and utility for identifying and stratifying older people at risk of disability. The mental frailty construct is closely related to SF and should be further investigated in future studies. PMID- 28648904 TI - Mixture effects of 30 environmental contaminants on incident metabolic syndrome-A prospective study. AB - BACKGROUND: Several cross-sectional studies have linked different environmental contaminants to the metabolic syndrome (MetS). However, mixture effects have not been investigated and no prospective studies exist regarding environmental contaminants and the MetS. OBJECTIVES: To study mixture effects of contaminants on the risk of incident MetS in a prospective fashion. METHODS: Our sample consisted of 452 subjects from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70years) free from the MetS at baseline, being followed for 10years. At baseline, 30 different environmental contaminants were measured; 6 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, one dioxin, one polybrominated diphenyl ether (all in plasma), 8 perfluoroalkyl substances (in plasma) and 11 metals (in whole blood). The MetS was defined by the ATPIII/NCEP criteria. Gradient boosted Classification and Regression Trees (CARTs) was used to evaluate potential synergistic and additive mixture effects on incident MetS. RESULTS: During 10-year follow-up, 92 incident cases of the MetS occurred. PCB126, PCB170, hexachlorobenzene (HCB) and PCB118 levels were all associated with incident MetS in an additive fashion (OR 1.73 for a change from 10th to 90th percentile (95%CI 1.24-3.04) for PCB126, OR 0.63 (0.42 0.78) for PCB170, OR 1.44 (1.09-2.20) for HCB and OR 1.46 (1.13-2.43) for PCB118). No synergistic effects were found. CONCLUSION: A mixture of environmental contaminants, with PCB126, PCB170, HCB and PCB118 being the most important, showed associations with future development of the MetS in an additive fashion in this prospective study. Thus, mixture effects of environmental contaminants could contribute to the development of cardio-metabolic derangements. PMID- 28648906 TI - COMT genotype is differentially associated with single trial variability of ERPs as a function of memory type. AB - Previous research on the association between intra-subject variability (ISV) in reaction times (RTs) and the Val158Met polymorphism of the catechol-o methyltransferase gene (COMT; rs4680) has yielded mixed results. The present study compared the associations between COMT genotype and ISV in P3b latency measured during working and secondary memory tasks using residue iteration decomposition (RIDE) of single trial latencies. We compared the outcome of the present analyses with a previous analysis of the same data (N=70, n-back tasks) using an alternative single-trial method. Additionally, we used RIDE to analyse the association between COMT genotype and ISV in an independent sample performing a different task (N=91, face-recognition task). Analyses reconfirmed previous results from the n-back tasks, showing that Val alleles are associated with lower ISV. In the face recognition tasks, genotype interacted with task conditions, so Val homozygotes had higher ISV to unfamiliar faces than familiar ones but Met carriers showed no effect of familiarity. Moreover, in both datasets trial-by trial RTs were predicted by P3b latencies. Therefore, the present data suggests that associations between COMT genotype and ISV depend on the type of cognitive processes, which may explain heterogeneity in previous results. PMID- 28648905 TI - Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor Infiltrating T Cells in Hepatocellular Carcinomas. AB - BACKGROUND & AIMS: Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4+ and CD8+ T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. METHODS: We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8+ and CD4+ T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. RESULTS: Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8+ and CD4+ T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8+ TIL, compared with other CD8+ TIL. Compared with TIL that did not express these inhibitory receptors, CD8+ and CD4+ TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8+ and CD4+ TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. CONCLUSIONS: The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. PMID- 28648907 TI - Sulfated dehydropolymer of caffeic acid: In vitro anti-lung cell death activity and in vivo intervention in emphysema induced by VEGF receptor blockade. AB - Induced lung cell death and impaired hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) signaling are proposed as a pathobiologic mechanism for alveolar structural destruction and loss in emphysema. We hypothesized that our sulfated dehydropolymer of caffeic acid, CDSO3, exerts anti-cell death activities and therapeutic interventions in emphysema by virtue of Fe2+ chelation-based HIF-1alpha/VEGF stabilization and elevation. The Fe2+ chelating activity was determined in the chromogenic ferrozine-Fe2+ chelation inhibitory assay. The in vitro anti-cell death activities and their Fe2+ and HIF-1alpha dependence were assessed against a range of emphysematous insults in the lung endothelial (HMVEC-L) and epithelial (A549) cells. CDSO3 was spray-dosed to the lung for three weeks (day 1-21) in an in vivo rat model of apoptotic emphysema induced with a VEGF receptor antagonist SU5416. Post-treatment treadmill exercise endurance, airspace enlargement, and several lung biomarkers/proteins were measured. CDSO3 was a potent Fe2+ chelating molecule. At 10 MUM, CDSO3 inhibited HMVEC-L and A549 cell death induced by histone deacetylase inhibition with trichostatin A, VEGF receptor blockade with SU5416, and cigarette smoke extract by 65-99%, which were all significantly opposed by addition of excess Fe2+ or HIF-1alpha inhibitors. As a potent elastase inhibitor and antioxidant, CDSO3 also inhibited elastase- and H2O2-induced cell death by 92 and 95%, respectively. In the rat model of SU5416-induced apoptotic emphysema, CDSO3 treatment at 60 MUg/kg 1) produced 61-77% interventions against exercise endurance impairment, airspace enlargement [mean linear intercept] and oxidative lung damage [malondialdehyde activity]; 2) normalized the apoptotic marker [cleaved caspase-3]; 3) stimulated the VEGF signaling [VEGF receptor 2 phosphorylation] by 1.4-fold; and 4) elevated the HIF-1alpha and VEGF expression by 1.8- and 1.5-fold, respectively. All of these were consistent with CDSO3's Fe2+ chelation-based HIF-1alpha/VEGF stabilization and elevation against their pathobiologic deficiency, inhibiting lung cell death and development of apoptotic emphysema. PMID- 28648908 TI - Intraventricular Cavernomas of the Third Ventricle: Report of 2 Cases and a Systematic Review of the Literature. AB - BACKGROUND: Intraventricular cavernous malformations are relatively rare benign vascular malformations. Patients may be asymptomatic or present with headache, seizure, hemorrhage, or neurologic deficits. We report 2 cases of patients with cavernomas in the third ventricle and at the foramen of Monro. We also performed a systematic review of the literature to examine the clinical features and efficacy of the current standard of care for these lesions. METHODS: We performed the systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Multiple databases were queried; the title/abstract and MeSH keywords used included "cavernous malformation," "cavernoma," "cavernous hemangioma," "cavernous angioma," "foramen of Monro," "third ventricle," and "intraventricular," along with "AND" and "OR" operators. Patient demographic and clinical data were collected for qualitative synthesis. RESULTS: Patients presented at a median age of 38 years; the most common symptom was headaches. Gross total resection was performed in 84.6% of patients, and 81.8% had clinical improvement with intervention. The incidence of intraventricular hemorrhage and hydrocephalus was 15.4% and 59%, respectively. CONCLUSIONS: The specific location of the cavernoma determines clinical features seen and approach used in surgical resection. Ventriculoperitoneal shunting was not required in most cases, as hydrocephalus improved with removal of the obstruction at the foramen of Monro. Gross total resection appears to be the optimal management strategy in symptomatic patients and leads to a good outcome in most cases. PMID- 28648909 TI - Clinical Efficacy and Its Prognostic Factor of Percutaneous Endoscopic Lumbar Annuloplasty and Nucleoplasty for the Treatment of Patients with Discogenic Low Back Pain. AB - OBJECTIVE: The choice of appropriate treatment of discogenic low back pain (DLBP) frequently is difficult. This study sought to identify the clinical efficacy of percutaneous endoscopic lumbar annuloplasty and nucleoplasty (PELAN) to treat patients with DLBP and to investigate prognostic clinical or radiologic variables. METHODS: Eighty-nine patients with a diagnosis of DLBP who underwent PELAN were included. Numeric Rating Scale (NRS) for back pain, Oswestry Disability Index % (ODI%), and modified Macnab criteria were measured at short term (3-4 weeks) and long-term follow-up period (at least 12 months) to investigate clinical efficacy of PELAN. The subjects were defined as successful group in case of 50% or more reduction of NRS, 40% or more reduction of ODI%, and good or excellent response of Macnab criteria. Clinical and radiologic variables were compared between successful and unsuccessful outcomes group to determine prognostic variables. RESULTS: NRS and ODI% were significantly reduced at short- and long-term follow-up after PELAN. Sixty-two (69.7%) and 68 (76.4%) obtained successful NRS reduction and 59 (66.3%) and 68 (76.4%) accomplished successful ODI% reduction at short-term and long-term follow-up, respectively. Successful Mcnab response was found in 61% at short term and 65.2% at long term. Pain during waist flexion among clinical variables was significantly related to good clinical outcomes and Modic change among radiologic variables was significantly related to poor clinical outcomes. CONCLUSIONS: PELAN provided favorable outcomes in patients with DLBP who were refractory to conservative treatments. Flexion pain was good prognostic, and Modic change was a poor prognostic variable. PMID- 28648910 TI - Risk of Aneurysm Residual Regrowth, Recurrence, and de Novo Aneurysm Formation After Microsurgical Clip Occlusion Based on Follow-up with Catheter Angiography. AB - INTRODUCTION: Established guidelines for radiologic surveillance after microsurgical treatment of intracranial aneurysms are lacking in the literature because of small sample sizes, poor definitions, and heterogeneous use of imaging modalities. We aimed to propose clinically meaningful definitions for postoperative aneurysm residual, recurrence, and de novo aneurysm formation and to analyze our long-term follow-up catheter angiography results in patients with microsurgically treated intracranial aneurysms. METHODS: A retrospective review of all aneurysms treated microsurgically in a consecutive, single-surgeon series from 1997 to present identified patients with long-term follow-up catheter angiography (>1 year after surgery). Clinical and radiologic data were collected for analysis. RESULTS: We identified 240 patients harboring 380 aneurysms (mean follow-up time, 6.0 +/- 3.3 years per patient; range, 1.0-16.8 years). Postoperative residuals were present in 16 out of 346 clipped aneurysms (4.6%), of which only 3 were left unintentionally. Two out of 16 residual aneurysms (12.5%) demonstrated regrowth, with a regrowth risk of 2.1% per year from 93.6 patient-years of angiographic follow-up. Of 326 aneurysms with no postoperative residual, 5 (1.5%) demonstrated aneurysm recurrence, with a recurrence risk of 0.26% per year from 1931.9 patient-years of angiographic follow-up. Eight de novo aneurysms were identified in 240 patients (3.3%), with a risk of 0.6% per year from 1441.9 patient-years of angiographic follow-up. CONCLUSIONS: Microsurgically treated aneurysms have a very low risk of postoperative residuals and aneurysm recurrence. Growth of residuals and de novo aneurysm formation justify following up with catheter angiography 3 to 5 years after microsurgical clipping. PMID- 28648911 TI - Influence of Bimaxillary Surgery on Pharyngeal Airway in Class III Deformities and Effect on Sleep Apnea: A STOP-BANG Questionnaire and Cone-Beam Computed Tomography Study. AB - PURPOSE: To evaluate pharyngeal airway space (PAS; nasopharyngeal, oropharyngeal, and total airway) volume and the correlation of an obstructive sleep apnea (OSA) and hypopnea syndrome screening questionnaire (STOP-BANG) with various mandibular setbacks during bimaxillary surgery and compare these findings with an age- and gender-matched skeletal Class I control group. PATIENTS AND METHODS: This retrospective cohort study was composed of patients with skeletal Class III discrepancy who underwent bimaxillary jaw surgery and were assessed with STOP BANG score, cephalometry, and cone-beam computed tomography (of the PAS). The predictor variable was bimaxillary jaw surgery and included 4-, 6-, and 8-mm setbacks. The primary outcome variables were PAS volume, body mass index, and STOP-BANG score evaluated at 1 week before surgery and after comprehensive orthodontic treatment (11.25 +/- 1.95 months). Other variables were grouped into the following categories: demographic and cephalometric parameters. Statistical intragroup and intergroup differences were assessed by paired t and independent t tests (P < .05), respectively. RESULTS: The study sample was composed of 48 patients (18 to 25 yr old); group I received 4-mm setback (n = 16), group II received 6-mm setback (n = 16), and group III received 8-mm setback (n = 16) mandibular surgery, and all test groups received 4-mm maxillary advancement. The entire study group was compared with a skeletal Class I control group (n = 16). The total PAS volume after orthodontic treatment in groups I and II showed a significant decrease compared with the presurgical PAS (P < .001), but the decrease was not less than that in the control group (P > .05). In contrast, the total PAS volume in group III after orthodontic treatment (23,574 +/- 1,394 mm3) was less than that in the control group (23,884 +/- 1,543 mm3). CONCLUSION: After surgery, patients with Class III discrepancy exhibited a decrease in oropharynx volume; however, the STOP-BANG score showed no change in risk factors scores for OSA at 4- to 8-mm setback surgery of the mandible in bimaxillary jaw surgery. PMID- 28648912 TI - Minor Salivary Gland Biopsy-An Important Contributor to the Diagnosis of Sjogren Syndrome. AB - PURPOSE: Sjogren syndrome (SS), although commonly associated with xerostomia and xerophthalmia, can present with extraglandular manifestations that make definitive diagnosis difficult. The 2 leading diagnostic classification systems include a positive minor salivary gland biopsy (MSGB) result as a major inclusion criterion. The purpose of this study was to better define the role of the MSGB in establishing a diagnosis of SS in a cohort of referred patients. MATERIALS AND METHODS: This is a retrospective cohort study of patients referred to the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery (Boston, MA) over a 5-year period to establish a diagnosis of SS. Inclusion criteria were complete information regarding presenting symptoms, reason for referral, and findings at MSGB. Incomplete records and referral for reasons other than presumptive SS resulted in exclusion. The MSGB and its role in definitive diagnosis based on accepted classification systems were evaluated for sensitivity, specificity, and positive and negative predictive values. Other variables of interest (demographics, pattern of referral, and symptomology) are described for the cohort. RESULTS: Eighty-seven patients met the inclusion criteria. The mean age was 48.3 years (range, 19 to 74 yr) and 75 were women (86.2%). Fifteen MSGB results (17.2%) were positive based on the focus score histologic criteria. In 12 of 15 cases, the positive MSGB result allowed for a definitive diagnosis (80%). In 3 cases, other criteria allowed diagnosis without the contribution of the MSGB (sensitivity of MSGB, 80.0%; specificity, 87.5%; positive predictive value, 57.1%; negative predictive value, 95.5%). CONCLUSION: The MSGB is an important contributor to a diagnosis of SS. When serology was negative, the MSGB often was the criterion that allowed the diagnosis to be established. It is the most frequently positive of the major criteria used by the 2 classification systems in current use. PMID- 28648913 TI - The effects of analgesics on central processing of tonic pain: A cross-over placebo controlled study. AB - INTRODUCTION: Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat moderate to severe pain, but the central mechanisms underlying their analgesia remain unclear. This study investigated how brain activity at rest and exposed to tonic pain is modified by oxycodone (opioid) and venlafaxine (SNRI). METHODS: Twenty healthy males were included in this randomized, cross-over, double-blinded study. 61-channel electroencephalogram (EEG) was recorded before and after five days of treatment with placebo, oxycodone (10 mg extended release b.i.d) or venlafaxine (37.5 mg extended release b.i.d) at rest and during tonic pain (hand immersed in 2 degrees C water for 80 s). Subjective pain and unpleasantness scores of tonic pain were recorded. Spectral analysis and sLORETA source localization were done in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-18 Hz) and beta2 (18-32 Hz) frequency bands. RESULTS: Oxycodone decreased pain and unpleasantness scores (P < 0.05), whereas venlafaxine decreased the pain scores (P < 0.05). None of the treatments changed the spectral indices or brain sources underlying resting EEG. Venlafaxine decreased spectral indices in alpha band of the EEG to tonic pain, whereas oxycodone decreased the spectral indices and brain source activity in delta and theta frequency bands (all P < 0.05). The brain source activity predominantly decreased in the insula and inferior frontal gyrus. CONCLUSION: The decrease of activity within insula and inferior frontal gyrus is likely involved in pain inhibition due to oxycodone treatment, whereas the decrease in alpha activity is likely involved in pain inhibition due to venlafaxine treatment. PMID- 28648914 TI - Psychometrics of social cognitive measures for psychosis treatment research. AB - Social cognition represents an important treatment target, closely linked to everyday social function. While a number of social cognitive interventions have recently been developed, measures used to evaluate these treatments are only beginning to receive psychometric scrutiny. Study goals were to replicate recently-published psychometrics for several social cognitive measures, and to provide information for additional social cognitive measures not included in recent reports. Forty-eight outpatients with psychotic-spectrum disorders completed measures of emotion perception, theory of mind, and attributional bias on two occasions, one month apart. Measures were tested for distributional characteristics, test-retest reliability, utility as a repeated measure, and relationship to symptoms and functioning. For a subgroup of participants, information about sensitivity to social cognitive treatment was also available. We replicated aspects of prior work, including largely favorable psychometric characteristics for the Bell-Lysaker Emotion Recognition Task, and promising but weaker characteristics for The Awareness of Social Inferences Test subscales and Reading the Mind in the Eyes Task. The Hinting Task had adequate test-retest statistics but a more pronounced ceiling effect. Ambiguous Intentions and Hostility Questionnaire data showed evidence of validity but were limited by inconsistency over time. Our results strongly support the Davos Assessment of Cognitive Biases Scale for future evaluation as a social cognitive treatment outcome measure. Its scores were adequately distributed, consistent over time, related to symptoms and functioning, and sensitive to treatment effects. Other relatively novel assessments of attributional bias and theory of mind showed some promise, although more work is needed. PMID- 28648915 TI - Long-term course of negative symptom subdomains and relationship with outcome in patients with a psychotic disorder. AB - BACKGROUND: The longitudinal course of the negative symptoms subdomains social amotivation (SA) and expressive deficits (ED) remains largely unknown. We investigated i) the longitudinal course of SA and ED subdomain scores, ii) whether subgroups based on the course of SA and ED subdomain scores could be identified, iii) whether baseline SA and ED subdomain scores were related to functioning and quality of life six years later and iv) the longitudinal relationship between subgroups and outcomes. METHODS: Measurements at baseline, three and six years from 1067 patients participating in the Genetic Risk and Outcome of Psychosis (GROUP) project were used. We applied mixed models analysis, regression analysis and trajectory analyses. RESULTS: SA and ED subdomain scores decreased over time. Within both subdomains, four subgroups were identified: for both SA and ED a steady low course (+/-60%), increased (+/-15%) and decreased course (+/-15%). Within SA only, a higher level decreased course (+/-6%) and within ED only, a course with relatively stable high ED scores (+/-6%) was found. Lower symptom levels at baseline were related to better functioning (SA & ED) and quality of life (SA) at six years. Overall, low SA and low ED subgroups showed better outcomes than the other subgroups. CONCLUSION: In many patients the course of negative symptoms is unstable and related to the course of outcome. Patients who do show steady low negative symptom levels (60%) may complicate the interpretation of treatment evaluation studies, as they may average out possible effects in subgroups with fluctuating symptom levels. PMID- 28648916 TI - Long-term changes in time spent walking and subsequent cognitive and structural brain changes in older adults. AB - Previous studies have shown that more active older adults have better cognition and brain health based on a variety of structural neuroimaging measures. Nevertheless, the effects of maintaining physical activity (PA) over an extended period of time on future changes in older adults' cognition and brain structure are unknown. Participants were 141 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 60% female; 42% black) studied over a 13-year period. PA (self-reported time spent walking) was assessed annually from years 1 to 10. Magnetic resonance imaging with diffusion tensor was performed at years 10 and 13. Time spent walking decreased on average by 8.4% annually from year 1 to year 10. Independent of initial time spent walking, demographics, and APOE e4 status, better maintenance of time spent walking over the decade predicted less reduction in hippocampal volume (p = 0.03), smaller increases in global gray matter mean diffusivity and white matter axial diffusivity (p < 0.01), and maintenance of general cognitive performance (p < 0.01). Maintenance of cognitive performance was associated with smaller increases in white matter axial diffusivity (p < 0.01). PA at baseline and at year 10, as well as changes in PA over a 5-year period, was less predictive of future changes in brain structure and cognition. Thus, how PA levels change over longer periods of aging may be an important contributor to cognitive and neural protection. PMID- 28648917 TI - Neural changes related to motion processing in healthy aging. AB - Behavioral studies have found a striking decline in the processing of low-level motion in healthy aging whereas the processing of more relevant and familiar biological motion is relatively preserved. This functional magnetic resonance imaging (fMRI) study investigated the neural correlates of low-level radial motion processing and biological motion processing in 19 healthy older adults (age range 62-78 years) and in 19 younger adults (age range 20-30 years). Brain regions related to both types of motion stimuli were evaluated and the magnitude and time courses of activation in those regions of interest were calculated. Whole-brain comparisons showed increased temporal and frontal activation in the older group for low-level motion but no differences for biological motion. Time course analyses in regions of interest known to be involved in both types of motion processing likewise did not reveal any age differences for biological motion. Our results show that low-level motion processing in healthy aging requires the recruitment of additional resources, whereas areas related to the processing of biological motion processing seem to be relatively preserved. PMID- 28648918 TI - Acoustic and Elastic Properties of Glycerol in Oil-Based Gel Phantoms. AB - Phantoms are important tools for image quality control and medical training. Many phantom materials have been proposed for ultrasound; most of them use water as the solvent, but these materials have disadvantages such as dehydration and low temporal stability if not properly stored. To overcome these difficulties, copolymer-in-oil gel was proposed as an inert and stable material; however, speed of sound for these materials is still lower than what is described for most biological tissues. Here, we propose the glycerol dispersion in oil-based gels to modify the acoustic and elastic properties of copolymer-in-oil phantoms. We manufactured copolymer-in-oil gels using styrene-ethylene/butylene-styrene (SEBS) in concentrations 8%-15%. We used 2 types of mineral oils with different viscosities. Glycerol was added in a volume fraction 0%-30% of the total amount of liquid. The acoustic (i.e., speed of sound, attenuation and backscattering) and the mechanical (i.e., density and Young's modulus) properties of the samples were within the range of values observed for soft tissues. The acoustic parameters of the samples were dependent on oil viscosity and glycerol concentration. The speed of sound ranged 1423 m/s - 1502 m/s, while the acoustic attenuation and the ultrasonic backscattering increased by adding glycerol. The density and the Young's moduli were less affected by the presence of glycerol. We conclude that glycerol can be used to control the acoustic parameters of copolymer-in-oil gels. Additionally, it opens the possibility of incorporating other oil-insoluble substances to control further properties of the phantom. PMID- 28648919 TI - Myocardial Strain Rate by Anatomic Doppler Spectrum: First Clinical Experience Using Retrospective Spectral Tissue Doppler from Ultra-High Frame Rate Imaging. AB - Strain rate imaging by tissue Doppler (TDI) is vulnerable to stationary reverberations and noise (clutter). Anatomic Doppler spectrum (ADS) presents retrospective spectral Doppler from ultra-high frame rate imaging (UFR-TDI) data for a region of interest, that is, ventricular wall or segment, at one time instance. This enables spectral assessment of strain rate (SR) without the influence of clutter. In this study, we assessed SR with ADS and conventional TDI in 20 patients with a recent myocardial infarction and 10 healthy volunteers. ADS based SR correlated with fraction of scarred myocardium of the left ventricle (r = 0.68, p < 0.001), whereas SR by conventional TDI did not (r = 0.23, p = 0.30). ADS identified scarred myocardium and ADS Visual was the only method that differentiated transmural from non-transmural distribution of myocardial scar on a segmental level (p = 0.002). Finally, analysis of SR by ADS was feasible in a larger number of segments compared with SR by conventional TDI (p < 0.001). PMID- 28648920 TI - Ultrasound Assessment of Human Meniscus. AB - The aim of the present study was to evaluate the applicability of ultrasound imaging to quantitative assessment of human meniscus in vitro. Meniscus samples (n = 26) were harvested from 13 knee joints of non-arthritic human cadavers. Subsequently, three locations (anterior, center and posterior) from each meniscus were imaged with two ultrasound transducers (frequencies 9 and 40 MHz), and quantitative ultrasound parameters were determined. Furthermore, partial-least squares regression analysis was applied for ultrasound signal to determine the relations between ultrasound scattering and meniscus integrity. Significant correlations between measured and predicted meniscus compositions and mechanical properties were obtained (R2 = 0.38-0.69, p < 0.05). The relationship between conventional ultrasound parameters and integrity of the meniscus was weaker. To conclude, ultrasound imaging exhibited a potential for evaluation of meniscus integrity. Higher ultrasound frequency combined with multivariate analysis of ultrasound backscattering was found to be the most sensitive for evaluation of meniscus integrity. PMID- 28648921 TI - Karyomapping: a single centre's experience from application of methodology to ongoing pregnancy and live-birth rates. AB - This study aimed to determine whether karyomapping can be applied to couples requiring preimplantation genetic diagnosis (PGD) for single gene disorder (SGD) and/or chromosomal rearrangement. 75/82 (91.5%) and 6/82 (7.3%) couples were referred for autosomal SGD and X-linked disease, respectively. One couple (1.2%) was referred for SGD and chromosomal rearrangement. Of 608 embryos, 146 (24%, 95% CI 21-28) day-3 and 462 (76%, 95% CI 72-79) blastocyst biopsies were performed. A total of 81 embryo transfers were performed; 16/81 (20%) were following day-3 embryo biopsy, 65/81 (80%) were following blastocyst biopsy and cryopreserved embryo transfer. Of 81 embryo transfers with known pregnancy outcome, 51 (63%, 95% CI 52-73) were on-going pregnancies, 6/81 (7%, 95% CI 3-15) resulted in first trimester miscarriages and 24/81 (30%, 95% CI 21-40) were failed implantations. Of the 51 on-going pregnancies, 15 (29%, 95% CI 19-43) couples had a singleton live birth at the time of write up. There have been no reports of abnormal prenatal, genetic testing or diagnosis of phenotype at birth. Karyomapping is reliable, efficient and accurate for couples requiring PGD for SGD and/or chromosomal rearrangement. Additionally, it provides aneuploidy screening, minimising risks of miscarriage and implantation failure. PMID- 28648922 TI - Oxovanadium(IV) complexes with Knoevenagel Schiff base condensate as impending chemotherapeutic agents: Synthesis, characterization, biological screening and anti-proliferative assay. AB - Two novel oxovanadium(IV) complexes [VOL1]SO4(1) and [VOL2]SO4(2) containing Knoevenagel condensate Schiff base ligand (L1/L2) have been synthesized and characterized by physical, spectral and analytical methods. These complexes are reported as ionic in nature on the basis of elemental composition and molar conductance, and possess square pyramidal geometry around the central metal ions. The binding interactions of (1) and (2) with calf thymus DNA (CT DNA) were explored by absorption spectrophotometric titration, cyclic voltammetry data and viscosity measurements. The calculated intrinsic binding constant values (Kb) for (1) and (2) obtained from UV-Vis absorption studies are 0.4*105 and 5.6*105 (M-1) respectively. These experimental results indicate that (1) and (2) are intercalative binders and avid binder to CT DNA with different affinities. These complexes exhibit significant oxidative cleavage of supercoiled plasmid (pUC18) DNA in the presence of activators. In particular, the in vitro antimicrobial efficacy of oxovanadium(IV) complexes reveal that they are more active than free ligands. Besides, the in vitro cytotoxic effect of the titled complexes were examined on a bundle of human tumor cell lines such as MCF-7 and HeLa cancerous cell lines by the MTT method. Interestingly, complex (2) exhibits more potent cytotoxic activity than the other complex and standard drug (cisplatin). The mode of cell death was assessed by Hoechst 33258 staining morphological studies. PMID- 28648923 TI - Design and environmentally benign synthesis of novel thiophene appended pyrazole analogues as anti-inflammatory and radical scavenging agents: Crystallographic, in silico modeling, docking and SAR characterization. AB - Oxidative-stress induces inflammatory diseases and infections caused by drug resistant microbial strains are on the rise necessitating the discovery of novel small-molecules for intervention therapy. The current study presents an effective and new green protocol for the synthesis of thiophene-appended pyrazoles through 3+2 annulations method. Chalcones 3(a-g) were prepared from 5-chloro-2 acetylthiophene and aromatic aldehydes by Claisen-Schmidt approach. The reaction of chalcones 3(a-g) with phenylhydrazine hydrochlorides 4(a-b) in acetic acid (30%) medium and also with freshly prepared citrus extract medium under reflux conditions produced the thiophene appended pyrazoles 5(a-l) in moderate yields. Structures of synthesized new pyrazoles were confirmed by spectral studies, elemental analysis and single crystal X-ray diffraction studies. Further, preliminary assessment of the anti-inflammatory properties of the compounds showed that, amongst the series, compounds 5d, 5e and 5l have excellent anti inflammatory activities. Further, compounds 5c, 5d, 5g, and 5i exhibited excellent DPPH radical scavenging abilities in comparison with the standard ascorbic acid. Furthermore, using detailed structural modeling and docking efforts, combined with preliminary SAR, we show possible structural and chemical features on both the small-molecules and the protein that might contribute to the binding and inhibition. PMID- 28648924 TI - Synthesis and biological evaluation of indole derivatives as alpha-amylase inhibitor. AB - A series of twenty indole hydrazone analogs (1-21) were synthesized, characterized by different spectroscopic techniques such as 1H NMR and EI-MS, and screened for alpha-amylase inhibitory activity. All analogs showed a variable degree of alpha-amylase inhibition with IC50 values ranging between 1.66 and 2.65MUM. Nine compounds that are 1 (2.23+/-0.01MUM), 8 (2.44+/-0.12MUM), 10 (1.92+/-0.12MUM), 12 (2.49+/-0.17MUM), 13 (1.66+/-0.09MUM), 17 (2.25+/-0.1MUM), 18 (1.87+/-0.25MUM), 20 (1.83+/-0.63MUM), and 19 (1.97+/-0.02MUM) showed potent alpha-amylase inhibition when compared with the standard acarbose (1.05+/ 0.29MUM). Other analogs showed good to moderate alpha-amylase inhibition. The structure activity relationship is mainly focusing on difference of substituents on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds. PMID- 28648925 TI - New imidoyl-indazole platinum (II) complexes as potential anticancer agents: Synthesis, evaluation of cytotoxicity, cell death and experimental-theoretical DNA interaction studies. AB - Four new neutral N,N imidoyl-indazole ligands (L1, L3, L6, L7) and six new Pt(II) based complexes (C1-5 and C7) were synthesized and characterized by spectroscopic and spectrometric techniques. Additionally, compounds L6, L7, C3, C5 and C7 were analyzed using X-ray diffraction. An evaluation of cytotoxicity and cell death in vitro for both ligands and complexes was performed by colorimetric assay and flow cytometry, in four cancer cell lines and VERO cells as the control, respectively. Cytotoxicity and selectivity demonstrated by each compound were dependent on the cancer cell line assayed. IC50 values of complexes C1-5 and C7 were lower than those exhibited for the reference drug cisplatin, and selectivity of these complexes was in general terms greater than cisplatin on three cancer cell lines studied. In HL60 cells, complexes C1 and C5 exhibited the lowest values of IC50 and were almost five times more selective than cisplatin. Flow cytometry results suggest that each complex predominantly induced necrosis, and its variant necroptosis, instead of apoptosis in all cancer cell lines studied. DNA binding assays, using agarose gel electrophoresis and UV-visible spectrophotometry studies, displayed a strong interaction only between C4 and DNA. In fact, theoretical calculations showed that C4-DNA binding complex was the most thermodynamic favorable interaction among the complexes in study. Overall, induction of cell death by dependent and independent-DNA-metal compound interactions were possible using imidoyl-indazole Pt(II) complexes as anticancer agents. PMID- 28648926 TI - Does opening a supermarket in a food desert change the food environment? AB - Improving access to healthy foods in low-income neighborhoods is a national priority. Our study evaluated the impact of opening a supermarket in a 'food desert' on healthy food access, availability and prices in the local food environment. We conducted 30 comprehensive in-store audits collecting information on healthy and unhealthy food availability, food prices and store environment, as well as 746 household surveys in two low-income neighborhoods before and after one of the two neighborhoods received a new supermarket. We found positive and negative changes in food availability, and an even greater influence on food prices in neighborhood stores. The supermarket opening in a 'food desert' caused little improvement in net availability of healthy foods, challenging the underpinnings of policies such as the Healthy Food Financing Initiative. PMID- 28648927 TI - Silibinin Capsules improves high fat diet-induced nonalcoholic fatty liver disease in hamsters through modifying hepatic de novo lipogenesis and fatty acid oxidation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Silibinin Capsules (SC) is a silybin-phospholipid complex with silybin as the bioactive component. Silybin accounts for 50-70% of the seed extract of Silybum marianum (L.) Gaertn.. As a traditional medicine, silybin has been used for treatment of liver diseases and is known to provide a wide range of hepatoprotective effects. AIM OF THE STUDY: High fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) is a worldwide health problem. This study was to investigate the role of SC in NAFLD with focusing on its underlying mechanism and likely target. MATERIALS AND METHODS: Male hamsters (Cricetidae) received HFD for 10 weeks to establish NAFLD model. NAFLD was assessed by biochemical assays, histology and immunohistochemistry. Proton nuclear magnetic resonance spectroscopy and western blot were conducted to gain insight into the mechanism. RESULTS: Hamsters fed HFD for 10 weeks developed fatty liver accompanying with increased triglyceride (TG) accumulation, enhancing de novo lipogenesis, increase in fatty acid (FA) uptake and reducing FA oxidation and TG lipolysis, as well as a decrease in the expression of phospho-adenosine monophosphate activated protein kinase alpha (p-AMPKalpha) and Sirt 1. SC treatment at 50mg/kg silybin and 100mg/kg silybin for 8 weeks protected hamsters from development of fatty liver, reducing de novo lipogenesis and increasing FA oxidation and p-AMPKalpha expression, while having no effect on FA uptake and TG lipolysis. CONCLUSIONS: SC protected against NAFLD in hamsters by inhibition of de novo lipogenesis and promotion of FA oxidation, which was likely mediated by activation of AMPKalpha. PMID- 28648928 TI - PG2, a botanically derived drug extracted from Astragalus membranaceus, promotes proliferation and immunosuppression of umbilical cord-derived mesenchymal stem cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus is used to manage the deficiency of vital energy in traditional Chinese medicine and confirmed to have many biological functions. Mesenchymal stem cells (MSCs) possess immunosuppressive effects, and are widely used for regenerative medicine and immune disorders. AIMS OF STUDY: This study investigated the effects of Astragalus polysaccharides (APS) on umbilical cord-derived MSCs (UCMSCs), including morphology, surface marker expression, proliferation, differentiation, and in-vitro and in-vivo immunosuppressive capacities. MATERIALS AND METHODS: MSCs isolated from umbilical cords were used. PG2 injection, a botanically derived drug containing a mixture of APS, was added into the culture medium to prepare PG2-treated UCMSCs. The morphology, surface marker expression, proliferation, and differentiation of UCMSCs were determined. The in-vitro immunosuppressive effects of UCMSCs were examined by peripheral blood mononuclear cell (PBMC) proliferation assay. The in-vivo effects were evaluated by circulatory inflammation-associated cytokine levels in mice with septic peritonitis induced by cecal ligation and puncture (CLP) operation. RESULTS: Compared with control UCMSCs, UCMSCs had higher population doublings when exposed to PG2-containing medium (P = 0.003). The reduction rates of PBMC proliferation after phytohemagglutinin stimulation increased significantly when UCMSCs were treated with PG2 (P = 0.004). The serum levels of inflammation-associated cytokines, including TNF-alpha, IL-6, MCP-1, IFN-gamma, and IL-1beta, were significantly lower at 6h after CLP in the mice receiving PG2-treated UCMSCs. CONCLUSIONS: Our results demonstrated that PG2 can enhance UCMSC proliferation and their in-vitro and in-vivo immunosuppressive effects. Consequently, UCMSCs can be obtained in earlier passages to avoid senescence, and sufficient cells can be acquired faster for clinical use. With stronger immunosuppressive effects, UCMSCs may treat immune disorders more effectively. Further studies are warranted. PMID- 28648929 TI - Toxicological effects of Nux Vomica in rats urine and serum by means of clinical chemistry, histopathology and 1H NMR-based metabonomics approach. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried ripe seeds of Nux Vomica (Strychnos nux vomica L.), a traditional Chinese medicine, have been used to treat multifarious symptoms. However, the clinical applications of Nux Vomica are limited by its severe toxicity. In this study, Nux Vomica was subjected to nuclear magnetic resonance (NMR) metabonomics and pathological examination to determine relevant biomarkers in target organs and to explain the underlying toxicity mechanism. MATERIALS AND METHOD: Thirty-six male Sprague-Dawley rats were randomly divided into three groups of twelve rats. The control group was oral gavaged with distilled water, and two experiment groups were treated with Nux Vomica at a dose of 0.315 and 0.630g/kg body weight. On days 14 and 21, serum, urine, liver and kidney tissues were collected for histopathological examination, biochemical analysis and 1H-NMR analysis. RESULTS: The metabolites changes of rats treated with Nux Vomica are obviously differ from that of controls. In serum, low-dose group compared with control shows the significantly changes included elevated concentration of glucose, TMAO, and creatine, with decreased lipids, 3-HB, lactate, and unsaturated fatty acid. Change in taurine was only observed in the separation comparison of high-dose group and control. In urine, the variation metabolites included elevations in glucose, creatine, and TMAO as well as decreased lactate, succinate, alpha-ketoglutaric acid, citrate and hippurate in low-dose group compared with control. Only alanine and creatine were decreased significantly in high-dose group compared with control. CONCLUSION: Nux Vomica induced disruptions in glycolysis, lipid and amino acid metabolism, and toxic effects were aggravated in liver and kidney tissues as dosing time was prolonged. 1H NMR-based metabonomics combined with biochemical and histopathological methods can be applied to elucidate the toxicity mechanism of Nux Vomica decoction that caused liver and kidney injuries in rats. PMID- 28648930 TI - Associations between multiple indicators of socio-economic status and muscle strengthening activity participation in a nationally representative population sample of Australian adults. AB - BACKGROUND: Muscle-strengthening activity (MSA) (e.g. weight training), confers unique health benefits. While socioeconomic status (SES) correlates with leisure time physical activity, little is known about its relation with MSA. METHODS: Cross-sectional study of a representative sample of 8993 Australian adults (>18years) who participated in the National Nutrition and Physical Activity Survey 2011-12. Information was collected on SES (income, education, socio economic disadvantage and remoteness) and MSA participation. RESULTS: 17.9% (CI: 16.8-19.0) met the national guidelines for MSA (>=2 sessions/week). Men and younger adults (<35years) met MSA guidelines more than females (19.7%; CI: 18.3 21.1% vs 16.1%; CI: 14.6-17.6%; p<0.001) and older adults respectively (25.0%; CI: 22.4-27.7% vs 10.4%; CI: 8.9-11.8%; p<0.001). All SES indicators were associated with meeting the guidelines in unadjusted analyses. When adjusting for total physical activity and mutually adjusting for each socioeconomic indicator only remoteness (OR for city vs rural=1.65; CI: 1.17-2.32; p<0.001) was associated with MSA participation (education OR=1.09 for high vs low; CI: 0.80 1.47, p=0.748; income OR=1.31 for Q5 vs Q1, CI: 0.93-1.85, p=0.328; social disadvantage OR=1.04 for v.high vs v.low, CI: 0.76-1.43, p=0.855). These associations were further attenuated when adjusting for BMI, smoking status and self-rated health. CONCLUSION: Remoteness, and to a lesser degree, education, income and social disadvantage, were independently associated with MSA participation. Public health interventions should improve access to strength training facilities, and/or increase home-based muscle-strengthening activity in remote areas. PMID- 28648931 TI - An ulcer on the lower lip. PMID- 28648932 TI - Federal travel restrictions to prevent disease transmission in the United States: An analysis of requested travel restrictions. AB - BACKGROUND: Individuals with certain communicable diseases may pose risks to the health of the traveling public; there has been documented transmission on commercial aircraft of tuberculosis (TB), measles, and severe acute respiratory syndrome (SARS). Federal public health travel restrictions (PHTR) prevent commercial air or international travel of persons with communicable diseases that pose a public health threat. METHODS: We described demographics and clinical characteristics of all cases considered for PHTR because of suspected or confirmed communicable disease from May 22, 2007, to December 31, 2015. RESULTS: We reviewed 682 requests for PHTR; 414 (61%) actions were completed to place 396 individuals on PHTR. The majority (>99%) had suspected (n = 27) or confirmed (n = 367) infectious pulmonary TB; 58 (16%) had multidrug-resistant-TB. There were 128 (85%) interceptions that prevented the initiation or continuation of travel. PHTR were removed for 310 (78%) individuals after attaining noninfectious status and 86 (22%) remained on PHTR at the end of the analysis period. CONCLUSIONS: PHTR effectively prevent exposure during commercial air travel to persons with potentially infectious diseases. In addition, they are effective tools available to public health agencies to prevent commercial travel of individuals with certain communicable diseases and possibly reconnect them with public health authorities. PMID- 28648933 TI - Effectiveness and safety of two 18-gauge needle types on native and allograft renal biopsies. AB - Percutaneous biopsy is a key diagnostic tool for both native and allograft kidney diseases. Adequacy criteria vary, but at a minimum, a biopsy should allow the pathologist to reach a diagnosis and provide prognostic information such as the degree of interstitial fibrosis and tubular atrophy (IF/TA) and percentage of glomerulosclerosis. Whereas most studies use glomerular counts as a surrogate for biopsy adequacy, the amount and preservation of tubulointerstitium is equally important, considering IF/TA is a major prognostic parameter for most medical renal diseases. Many studies have compared the diagnostic adequacy of different gauge needles; however few have investigated performance differences between same gauge needles. In this study, we retrospectively analyzed 235 renal biopsies performed at a single center in Canada over 2years to compare the utilization, safety, diagnostic and prognostic performance of two 18-gauge needles in native and allograft kidney biopsies. We found no significant difference in needle utilization between native and allograft kidneys, or between trainees and staff radiologists. The total tissue yielded area, glomerular counts, percentage of inadequate biopsies and number of passes were similar; however the number of cases in which IF/TA evaluation was deemed not possible was higher for biopsies using disposable instrument needles (4.3% vs. 0%; p=0.01). These also showed greater number of tissue fragments (median 4 for reusable vs 3 for disposable; p=0.04). We postulate that the increased tissue fragmentation might have impaired the pathologists ability to accurately assess interstitial fibrosis and tubular atrophy in biopsies obtained with the disposable instrument needles. PMID- 28648934 TI - Molecular alterations in lesions of anogenital mammary-like glands and their mammary counterparts including hidradenoma papilliferum, intraductal papilloma, fibroadenoma and phyllodes tumor. AB - Lesions affecting anogenital mammary-like glands (AGMLG) are histopathologically very similar to those seen in the breast but whether this morphological similarity is also reflected at the genetic level is unknown. To compare the underlying molecular mechanisms in lesions of AGMLG and their mammary counterparts, we analyzed the mutational profile of 16 anogenital neoplasms including 5 hidradenomas papilliferum (HP), 1 lesion with features of HP and fibroadenoma (FA), 7 FA, 3 phyllodes tumors (PhT)) and 18 analogous breast lesions (6 intraductal papillomas (IDP), 9 FA, and 3 PhT) by high-coverage next generation sequencing (NGS) using a panel comprising 50 cancer-related genes. Additionally, all cases were analyzed for the presence of a mutation in the MED12 gene. All detected mutations with allele frequencies over 20% were independently validated by Sanger sequencing (concordance: 100%). Mutations in PIK3CA, AKT1, MET, ABL1 and TP53 genes were found in lesions of AGMLG and also their mammary counterparts. The PI3K-AKT cascade plays a role in tumors arising at both sites. It appears that some histopathologically similar anogenital and breast lesions develop along similar molecular pathways. PMID- 28648935 TI - EWSR1 rearrangement is present in a subset of myoepithelial tumors of salivary glands with variable morphology and does not correlate with clinical behavior. AB - To investigate that whether myoepithelial tumors of salivary glands (MTs) with EWSR1 rearrangement display distinctive morphological characteristics and whether EWSR1 detection aids to distinguish malignant myoepithelial tumors (MMTs) from benign myoepithelial tumors (BMTs) of salivary glands. We examined 37 cases of MTs, including 24 BMTs, 13 MMTs, by histological, immunohistochemical, and molecular analysis. All of 37 cases were immunoreactive for CKpan, and at least one myoepithelial marker. 26 of 37 cases of MTs were available to be analyzed for EWSR1 rearrangement, with the result that EWSR1 gene break was detected in 4 cases of 15 BMTs, and 4 cases of 11 MMTs. In addition, the 8 EWSR1-rearranged cases displayed not exactly similar morphological features, covering 4 clear-cell cases, 1 plasmacytoid-cell case, 1 spindle-cell case, 1 epithelioid-cell case, and 1 chordoid-cell case. Our study proposed that EWSR1 rearrangement was present in a subset of MTs, with variable morphological features. Moreover, the presence of EWSR1 rearrangement could not be a forceful evidence to distinguish MMTs from BBTs. PMID- 28648936 TI - Diagnostic pathology of Alzheimer's disease from routine microscopy to immunohistochemistry and experimental correlations. AB - The absence of any histologic correlate for Alzheimer's disease despite its commonness and severe clinical sequelae may offers clues to its etiology. Recent evidence strongly suggests that the central event of this disease is the hyperphosphorylation of neuronal tau protein and not the beta amyloid precipitates. In each case, essential and soluble neuronal proteins derivatives form insoluble aggregates that can readily be detected by immunohistochemistry using antibodies specific for the misfolded proteins. Immunohistochemistry also demonstrates that neurons with hyperphosphorylated tau protein are viable. Experimental evidence using neuronal cell cultures suggests that the affected neurons in Alzheimer's disease may have undergone molecular changes that include accumulation of anti-apopotic proteins MCL1 and cFLIP that do not allow the cell to undergo programmed cell death but, rather, to "immortalize" and thus accumulate hyperphosphorylated tau protein in the neuronal cell body and beta amyloid in downstream dendrites. We describe a simplified protocol to demonstrate such changes based on tagged LNA modified microRNA/antimicroRNA oligomers and cell cultures. Co-expression showed that the tagged antimiR-512 strongly localized with the markedly up-regulated proteins MCL1 and cFLIP with concomitant accumulation of hyperphosphorylated tau protein. The data underscore to the anatomic pathologist that the diagnosis of Alzheimer's disease is best accomplished by simple immunohistochemistry tests correlated to the clinical history and the key role pathologists can play in understanding the cause of the disease. PMID- 28648937 TI - The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential. AB - BACKGROUND: FISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma. METHOD: 73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010-2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6. RESULTS: The study was composed of 50 females and 23 males with an age range of 1-73 and a mean age of 35years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis. CONCLUSION: Despite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4 probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome. PMID- 28648938 TI - Lymphoid malignancy-associated hemophagocytic lymphohistiocytosis: Search for the hidden source. AB - Secondary hemophagocytic lymphohistiocytosis (HLH) is an uncommon, but life threatening syndrome of highly stimulated and ineffective immune dysregulation. It is not a disease entity by itself and the current diagnosis of secondary (acquired) HLH is based on constellation of nonspecific clinical and laboratory parameters indicative of overactive immune response. The presenting symptoms are often nonspecific and could potentially be missed, leading to a fatal outcome. Patients with malignancy-associated HLH have a relatively unfavorable overall survival compared with non-malignancy-associated HLH. In this retrospective study, nine adult patients with secondary HLH were identified. Of these four cases were associated with a malignancy and despite a high degree of suspicion, the underlying lymphoid malignancy was not initially evident. Three out of four patients with lymphoid malignancy-associated HLH died over a very short course of time following the diagnosis. The outcome was significantly different for the control group of patients with other underlying cause(s) for HLH. These cases emphasize the importance of a thorough search for a hidden malignant source in patients with secondary HLH for prompt diagnosis and institution of malignancy specific treatment. PMID- 28648939 TI - Prognostic impact of EGFR and cytokeratin 5/6 immunohistochemical expression in triple-negative breast cancer. AB - : Triple-negative breast cancer (TNBC) has an aggressive behavior and limited therapeutic options due to lack of targeted therapy. We aimed in this study to assess the immunohistochemical expression of EGFR and cytokeratin 5/6 and their ability to predict survival and response to neoadjuvant chemotherapy (NAC) among triple-negative breast cancer patients. Thirty-five cases with TNBC were studied by immunohistochemistry for EGFR and CK5/6 expression. Data on overall survival (OS), disease-free survival (DFS) and response to NAC were collected. The resulted data were statistically analyzed. Invasive carcinoma of no special type (NST) was the predominant histopathological type (80%). The commonest histological grade was grade II-III (88.6%). About 57.1% of TNBC cases were CK5/6 positive, and 71.4% were EGFR-positive. EGFR expression showed a significant association with tumor grade and axillary lymph node metastasis (p=0.006, 0.016 respectively). EGFR expression was related to unfavorable response to NAC (p=0.036), poor OS (p=0.002) and poor DFS (p=0.003). CK5/6 expression showed a significant association with tumor grade, unfavorable response to NAC, poor OS & DFS (p=0.007, 0.048, <0.001, 0.043 respectively). Immunohistochemical expression of EGFR and/or CK5/6 showed a high significant association with an unfavorable response to NAC, poor DFS &OS (p=0.010, 0.012, 0.030 respectively). CONCLUSIONS: EGFR and CK5/6 are adverse prognostic markers in TNBC. EGFR and CK5/6 expression could serve as biomarkers for identifying TNBC patients with poor survival that are unlikely to benefit from neoadjuvant chemotherapy. So, targeted therapy against EGFR may be a hopeful therapy for TNBC with NAC resistance. PMID- 28648940 TI - Upregulation of inhibitory signaling receptor programmed death marker-1 (PD-1) in disease evolution from cutaneous lymphoid dyscrasias to mycosis fungoides and Sezary's syndrome. AB - BACKGROUND: Negative immunoregulatory checkpoints impede effective immune responses to tumor and reduce the action of anticancer agents. One such example is programmed death marker-1 (PD-1), an inhibitory signaling receptor expressed on activated and regulatory T-cells. PD-1 expression was reported in a few reports, but the expression profile of PD-1 and mycosis fungoides (MF) remains largely to be characterized. DESIGN: In this study, skin biopsies from 42 prelymphomatous T-cell dyscrasias (CLD), 9 Sezary's syndrome (SS), 103 MF, and 20 CD30+ lymphoproliferative diseases (LPD) were examined for PD-1 expression using immunohistochemistry. RESULTS: PD-1 staining was observed amidst many neoplastic T-cells in 6/9(66.7%) and 62/103 (60.2%) cases of SS and MF respectively, while only 6/42 (14.3%) cases of CLD and 0/20 (0%) cases of CD30+ LPD (P<0.001). Three cases are from same patients representing different stages of disease evolution from CLD to MF and SS with a corresponding enrichment of PD-1 positivity. In all cases there was variable staining of PD-1 amidst macrophages. There was no correlation with disease progression among MF cases. Twenty cases of CD30+ LPD did not show any PD-1 positivity. CONCLUSION: PD-1 seems to correlate with disease progression in epitheliotropic T cell dyscrasias ranging from minimal staining in prelymphomatous dyscrasias to significant staining in MF, likely reflecting the effects of PD-1 on inhibiting tumor surveillance regulatory T cell populations. PD-1 was consistently expressed in MF while it was consistently negative in primary CD30+ LPD, suggesting the possibility of using PD-1 as a means of distinguishing CD30+ MF from primary cutaneous ALCL. PMID- 28648942 TI - Dedifferentiated chondrosarcoma of bone with prominent rhabdoid component. AB - Dedifferentiated chondrosarcomas (DDCS) are rare lesions, defined as tumors having a low-grade chondrosarcomatous component with an abrupt transition to a high-grade sarcoma. Although "malignant fibrous histiocytoma" (undifferentiated pleomorphic sarcoma) is the most common high grade saromatous component, many different types of sarcoma have been described. We present a case of dedifferentiated chondrosarcoma with rhabdomyosarcomatous differentiation harboring a prominent rhabdoid tumor component. To our knowledge, rhabdoid morphology in dedifferentiated chondrosarcoma has not been described in the English-language literature. The pathologic and radiologic features of this case are presented. PMID- 28648943 TI - Corrections. PMID- 28648941 TI - Low-grade fibromyxoid sarcoma: Clinical, morphologic and genetic features. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a bland spindle cell neoplasm that typically arises in the deep soft tissues of the proximal extremities or trunk of young adults. The majority of LGFMS are characterized by a recurrent (7;16)(q34;p11) translocation, resulting in the FUS-CREB3L2 fusion gene, which generates a chimeric protein with transcriptional regulatory activity. Small numbers harbor a FUS-CREB3L1 fusion resulting from t(11;16)(p11;p11), whilst rare cases harbor the EWSR1-CREB3L1 fusion. LGFMS is of low to moderate cellularity and consists of bland spindle cells with small, angulated nuclei and scant, wispy cytoplasm, arranged in a whorled growth pattern and typically showing abrupt transition from myxoid to fibrous areas. Immunohistochemical expression of MUC4 is a consistent finding. Hyalinized spindle cell tumor with giant rosettes (HSCTGR) is a morphological variant of LGFMS that shares the same balanced translocation, and is also immunoreactive for MUC4. A potential relationship between LGFMS and sclerosing epithelioid fibrosarcoma (SEF), a rare fibroblastic neoplasm that most commonly arises in the deep soft tissues of the lower extremities, limb girdles or trunk, has also been suggested. SEF is classically composed of nests and cords of epithelioid cells with clear or eosinophilic cytoplasm embedded within densely sclerotic stroma. In some cases, areas indistinguishable from LGFMS are present, and these have been shown to contain FUS-CREB3L2 fusion transcripts. The majority of pure SEF tumors harbor EWSR1 rearrangements, with EWSR1-CREB3L1 and more rarely EWSR1-CREB3L2 gene fusions more common than those involving FUS. MUC4 immunoreactivity is also seen in approximately 70% of SEF. Surgical resection of these tumors with clear margins is the treatment of choice. Correct diagnosis is important because of the significant potential for recurrence and late metastatic spread. We review LGFMS and SEF, discussing morphology and immunohistochemistry, genetics and molecular findings, and the differential diagnosis. PMID- 28648944 TI - Tubulin beta 3 and 4 are involved in the generation of early fibrotic stages. AB - The endothelial-mesenchymal transition (EndMT) is a fundamental cellular mechanism that occurs under both physiological and pathological conditions and includes the fibrotic stages of numerous organs, namely, the skin, kidneys, heart, lungs and liver. Endothelial cells that undergo EndMT are one of the main source of (myo)fibroblasts in fibrotic tissues. A critical step in cellular transdifferentiation is morphological change, which is engineered by the reorganization of cytoskeletal elements such as microtubules. These dynamic structures consist of alphabeta-tubulin heterodimers that are also involved in cellular movement and intracellular trafficking, processes modulated during EndMT. One fundamental mechanism that underlies microtubule stabilization is the regulation of the levels of alpha and beta-tubulin. However, little is known about the roles of specific tubulin isotypes in the development of EndMT-based diseases. This study provides the first evidence that the upregulation of TUBB3 and TUBB4 is coupled with increased cell migration in EndMT-induced HMEC-1 cells. Immunochemical analysis reveals that these tubulins are upregulated in the early stages of EndMT, and siRNA analysis indicates that they are engaged in the generation of mesenchymal behavior via the enhancement of cell migration. This modulation seems to be especially important in wound healing. Finally, cell surface analysis reveals that TUBB3 and TUBB4 are necessary for the transport and proper localization of N-cadherin within the plasma membrane. We believe that our results will be valuable for the development of effective new anti-fibrotic therapies. PMID- 28648945 TI - Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies. AB - Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra(r)) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals. Neuroprotective effects of PDE5i were dependent on the NO-cGMP-PKG pathway. These included reduced neuronal apoptosis (n=3 studies), oxidative stress (n=5), and neuroinflammation (n=2). PDE5i increased angiogenesis and elevated regional cerebral blood flow in the ischemic penumbra, and improved functional recovery. Some studies found that PDE5i treatment reduced lesion volume (n=9), others found no effect (n=9). Treatment was effective when administered within 24h post-ischemia, though treatment delayed to seven days improved outcome in one study. This review demonstrates both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients, hence translation of preclinical results into clinical trials may be warranted. PMID- 28648946 TI - End of therapy minimal residual disease (MRD) measurement in children with ALL does not predict relapse. PMID- 28648947 TI - Hematopoietic stem cell transplantation in the Sultanate of Oman. AB - The Sultanate of Oman is one of the Arabian Gulf countries with a total population of 4,414,051 as of mid 2016, of which 2,427,825 are Omanis. The gross national income per capita was 7327.7 RO (Omani rial; equivalent to US$19,033) in 2014. There are two hematopoietic stem cell transplantation (HSCT) centers in Oman: the Sultan Qaboos University Hospital (SQUH; allogeneic and autologous) and the Royal Hospital (RH; autologous). HSCT activity in Oman started in 1995 at the SQUH center, which had only one bed, and four cases were performed in that year. The number of allogeneic HSCTs at the SQUH ranged between four and 29 cases per year, of which malignancy was the main indication for transplantation (47%). Most of the transplants were performed from identical sibling donor. T-deplete haploidentical and recently T-replete haploidentical HSCT were also performed at the SQUH center. In the allogeneic HSCT cohort transplanted at the SQUH, the risk of acute graft-versus-host disease (Grades II-IV) was 18%, whereas the risk of extensive chronic graft-versus-host disease was 8%. The HSCT unit at the RH, which started in 2014, performs autologous HSCT procedures only. The number of autologous HSCT cases at the RH ranged between three and 16 cases per year. Limited bed availability is a frequent obstacle to HSCT in Oman. Construction of a much larger national HSCT center is about to be completed, which will likely improve access to transplant services in Oman. PMID- 28648948 TI - Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937. AB - INTRODUCTION: NRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1 year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive-disease SCLC. METHODS: Patients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required. RESULTS: A total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2-74.7) for PCI and 50.8% (95% CI: 34.0-65.3) for PCI+cRT (p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32-0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT. CONCLUSIONS: OS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS. PMID- 28648949 TI - Welding-related brain and functional changes in welders with chronic and low level exposure. AB - Although an essential nutrient, manganese (Mn) can be toxic at high doses. There is, however, uncertainty regarding the effects of chronic low-level Mn-exposure. This review provides an overview of Mn-related brain and functional changes based on studies of a cohort of asymptomatic welders who had lower Mn-exposure than in most previous work. In welders with low-level Mn-exposure, we found: 1) Mn may accumulate in the brain in a non-linear fashion: MRI R1 (1/T1) signals significantly increased only after a critical level of exposure was reached (e.g., >=300 welding hours in the past 90days prior to MRI). Moreover, R1 may be a more sensitive marker to capture short-term dynamic changes in Mn accumulation than the pallidal index [T1-weighted intensity ratio of the globus pallidus vs. frontal white matter], a traditional marker for Mn accumulation; 2) Chronic Mn exposure may lead to microstructural changes as indicated by lower diffusion tensor fractional anisotropy values in the basal ganglia (BG), especially when welding years exceeded more than 30 years; 3) Mn-related subtle motor dysfunctions can be captured sensitively by synergy metrics (indices for movement stability), whereas traditional fine motor tasks failed to detect any significant differences; and 4) Iron (Fe) also may play a role in welding-related neurotoxicity, especially at low-level Mn-exposure, evidenced by higher R2* values (an estimate for brain Fe accumulation) in the BG. Moreover, higher R2* values were associated with lower phonemic fluency performance. These findings may guide future studies and the development of occupation- and public health related polices involving Mn-exposure. PMID- 28648951 TI - Physical activity and healthy ageing: A systematic review and meta-analysis of longitudinal cohort studies. AB - BACKGROUND: Older people constitute a significant proportion of the total population and their number is projected to increase by more than half by 2030. This increasing probability of late survival comes with considerable individual, economic and social impact. Physical activity (PA) can influence the ageing process but the specific relationship with healthy ageing (HA) is unclear. METHODS: We conducted a systematic review and meta-analysis of longitudinal studies examining the associations of PA with HA. Studies were identified from a systematic search across major electronic databases from inception as January 2017. Random-effect meta-analysis was performed to calculate a pooled effect size (ES) and 95% CIs. Studies were assessed for methodological quality. RESULTS: Overall, 23 studies were identified including 174,114 participants (30% men) with age ranges from 20 to 87 years old. There was considerable heterogeneity in the definition and measurement of HA and PA. Most of the identified studies reported a significant positive association of PA with HA, six reported a non-significant. Meta-analysis revealed that PA is positively associated with HA (ES: 1.39, 95% CI=1.23-1.57, n=17) even if adjusted for publication bias (ES: 1.27, 95% CI=1.11 1.45, n=20). CONCLUSIONS: There is consistent evidence from longitudinal observational studies that PA is positively associated with HA, regardless of definition and measurement. Future research should focus on the implementation of a single metric of HA, on the use of objective measures for PA assessment and on a full-range of confounding adjustment. In addition, our research indicated the limited research on ageing in low-and-middle income countries. PMID- 28648952 TI - Extracellular Vesicles as Biomarkers and Therapeutics in Dermatology: A Focus on Exosomes. AB - Extracellular vesicles (exosomes, microvesicles, and apoptotic bodies) are ubiquitous in human tissues, circulation, and body fluids. Of these vesicles, exosomes are of growing interest among investigators across multiple fields, including dermatology. The characteristics of exosomes, their associated cargo (nucleic acids, proteins, and lipids), and downstream functions are vastly different, depending on the cell origin. Here, we review concepts in extracellular vesicle biology, with a focus on exosomes, highlighting recent studies in the field of dermatology. Furthermore, we highlight emerging technical issues associated with isolating and measuring exosomes. Extracellular vesicles, including exosomes, have immediate potential for serving as biomarkers and therapeutics in dermatology over the next decade. PMID- 28648950 TI - Mechanisms of cholangiocyte responses to injury. AB - Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28648953 TI - Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors. AB - A series of thiazole linked indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC 3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 13d displayed cytotoxicity of IC50 = 93 nM towards DU145 cancer cell line. The most active compound 13d was also tested on RWPE-1 cells and was found to be safe compared to the DU145 cells. The target compounds were also evaluated for their inhibition activity of tubulin polymerization. Further, the treatment of compound 13d on DU145 cells led to the inhibition of cell migration ability. The detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 13d induced apoptosis in DU145 cells. The influence of the cytotoxic compound 13d on the cell cycle distribution was assessed on the DU145 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, the treatment with compound 13d caused collapse of mitochondrial membrane potential and elevated intracellular ROS levels in DU145 cells. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Thus, this new molecular scaffold could be a new lead for the development of anticancer agents that target tubulin. PMID- 28648954 TI - Fosphenytoin-induced purple glove syndrome: A case report. AB - BACKGROUND: Purple glove syndrome (PGS) is a poorly understood severe adverse drug reaction that is typically associated with intravenous phenytoin administration. Although fosphenytoin is thought to circumvent this risk of PGS, we reveal a rare case of PGS in a patient treated with fosphenytoin therapy. CASE SUMMARY: A 71-year-old male with history of epilepsy was admitted for seizures and traumatic brain injury and intravenous fosphenytoin and levetiracetam were initiated. The patient continued to have seizure activity on continuous electroencephalography for which fosphenytoin dosing was increased with subsequent seizure control. Serum phenytoin levels became elevated with a total level reaching as high as 25.8ug/mL. Three days into fosphenytoin therapy he developed PGS in both hands. Causation was assessed with the Naranjo adverse drug reaction algorithm that suggested fosphenytoin was probably the cause of PGS. Ten days after discontinuing the fosphenytoin and administering a 7-day course of methylprednisolone, the purple glove syndrome completely resolved. CONCLUSION: Early recognition and emergent management of PGS are key for optimal recovery. Although fosphenytoin has a significantly reduced risk of associated PGS compared to phenyotin, increased awareness for fosphenytoin-induce PGS can accelerate intervention and minimize morbidity of this rare yet detrimental adverse reaction. PMID- 28648955 TI - Undergraduate nursing students' attitudes and preparedness toward caring for dying persons - A longitudinal study. AB - Nursing education needs to prepare students for care of dying patients. The aim of this study was to describe the development of nursing students' attitudes toward caring for dying patients and their perceived preparedness to perform end of-life care. A longitudinal study was performed with 117 nursing students at six universities in Sweden. The students completed the Frommelt Attitude Toward Care of the Dying Scale (FATCOD) questionnaire at the beginning of first and second year, and at the end of third year of education. After education, the students completed questions about how prepared they felt by to perform end-of-life care. The total FATCOD increased from 126 to 132 during education. Five weeks' theoretical palliative care education significantly predicted positive changes in attitudes toward caring for dying patients. Students with five weeks' theoretical palliative care training felt more prepared and supported by the education to care for a dying patient than students with shorter education. A minority felt prepared to take care of a dead body or meet relatives. PMID- 28648956 TI - Emotional displays:-Nurse educators engaging and reflecting on their own emotional displays in preparing nursing students for the emotional complexities of nursing practice. AB - In everyday practice nurses including student nurses, face many situations which can trigger a range of their own emotions, but they also deal with a variety of emotions in patients, patients' relatives and colleagues. There is a need for nurses and those involved in nurse education to understand how emotions impact on professional practice. Yet, while nursing practice involves working often in emotional circumstances, there has been little attention by educational institutions and employers on developing the ability of nurses to understand and manage the emotional demands inherent in their role. This paper examines emotions and their relationship to and appropriateness in nursing practice and education. In particular it examines whether self-understanding by attendance to emotions can enhance the role of nurses educators in preparing nursing students for the complexities of modern nursing practice. PMID- 28648957 TI - Teaching psychology to nursing students-a discussion of the potential contribution of psychology towards building resilience to lapses in compassionate caring. AB - Psychology is a required element in nursing education in many countries. It is particularly aimed at teaching nursing students to get a better understanding of patients, colleagues, health care organizations and themselves, and moreover to apply what they learn about psychology to optimise their care. A meaningful integration of psychology within nursing education requires an emphasis on its application in understanding aspects of care and skills development. However, its ultimate value is demonstrated when addressing problem areas in nursing and health care. In this paper the authors outline an approach to psychology education in nursing which emphasises its development as a problem solving support. An example is presented which focuses on the application of psychology to the challenge of care erosion and deficient critical nursing reflection. The discussion includes the organisational context, social pressure, social cognition, reflection and the role of inner conflict (cognitive dissonance). Nursing educators can contribute to the prevention of care erosion by a combined effort to teach awareness of psychological mechanisms, 'critical' reflection, mastery in practice, strong values and standards, and 'inoculation' against justifications of substandard care. PMID- 28648958 TI - Use of a three-dimensional custom-made porous titanium prosthesis for mandibular body reconstruction. AB - The progress made in recent years in the field of head and neck bone reconstruction is directly related to technological advancements made in computer aided design and manufacturing (CAD/CAM) and three-dimensional printing in particular. Today these technologies are mainly used in mandibular reconstruction to manufacture aids for harvesting and shaping bone flaps. However problems remain when addressing patients with a contraindication to microsurgery who need extensive bone reconstruction. For these patients who cannot benefit from vascularized bone grafts, surgeons have to find alternative solutions aimed at maintaining best function and aesthetics. The goal of this article is to present an original method for mandibular body replacement with custom-made porous titanium prostheses in patients ineligible for a bone free flap. This solution has been used for two patients with an intraoral approach, resulting in no visible scars, with simple postoperative care of a short duration. This innovative solution represents an additional option for the treatment of complex mandibular reconstructions. PMID- 28648959 TI - A Study of GWAS-Supported Variants of rs9943582 in a Chinese Han Population with Ischemic Stroke: No Associations with Disease Onset and Clinical Outcomes. AB - BACKGROUND: The variant rs9943582 of APLNR (apelin receptor) was identified by a large-scale study to be associated with an increased risk of ischemic stroke in a Japanese population. We conducted this study to investigate the association between the variant and age of onset and clinical outcomes of ischemic stroke in a Chinese population. METHODS: Improved multiple ligase detection reaction was used to genotype the variant. We compared the mean age at ischemic stroke onset with one-way ANOVA. The Kaplan-Meier method, log-rank test, and Cox proportional hazards regression models were performed to analyze the association between the variant and clinical outcomes (recurrence and death). RESULTS: A total of 916 ischemic stroke patients were recruited for the study. For age at ischemic stroke onset, no significant association was identified with the variant in any genetic model. In addition, the variant was not strongly associated with recurrence and death risk of ischemic stroke, as shown by the results. CONCLUSIONS: The findings indicated that the variant rs9943582 was not associated with age at onset and clinical outcomes of ischemic stroke. However, evidence from well-designed studies with larger and in different ethnic populations are warranted to further explore the effects of APLNR on the ischemic stroke onset and clinical outcomes. PMID- 28648960 TI - Effect of Cholesteryl Ester Transfer Protein Gene TaqIB Polymorphism on the Risk of Ischemic Stroke: A Meta-Analysis. AB - BACKGROUND: The association between cholesteryl ester transfer protein (CETP) TaqIB polymorphism and ischemic stroke (IS) risk has generated conflicting results. To investigate whether the TaqIB polymorphism of the CETP gene was associated with the risk of IS, a meta-analysis was performed. METHODS: Studies were retrieved by searching PubMed, Web of Science, the Chinese National Knowledge Infrastructure, the Chinese Wanfang Database, and the Chinese VIP Database before January 16, 2017. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association. Depending on the heterogeneity the fixed-effects model or the random-effects model was used. RESULTS: A total of 6 case-control studies were identified with 1494 cases and 1370 controls. Overall, an association of CETP TaqIB polymorphism with IS was found in the 4 genetic models (B2B2 versus B1B1: OR = .63, 95% CI = .51-.79, P < .001; B1B2 + B2B2 versus B1B1: OR = .75, 95% CI = .64-.87, P < .001; B2B2 versus B1B2 + B1B1: OR = .70, 95% CI = .57-.85, P < .001; B2 versus B1: OR = .78, 95% CI = .70-.87, P < .001). In the subgroup analysis by ethnicity, similar risks were also observed in Asian population. CONCLUSIONS: This meta-analysis indicates that CETP TaqIB polymorphism is associated with IS risk, and the B2 allele is a protective factor for IS. PMID- 28648963 TI - The association between diabetes, level of glycaemic control and eye infection: Cohort database study. AB - AIM: To examine whether diabetes and the degree of glycaemic control is associated with an increased risk of acute eye infection, and prescribing of ocular antimicrobial agents. DESIGN AND SETTING: A retrospective cohort study was carried out using the Royal College of General Practitioners Research and Surveillance Centre database (RCGP RSC), a large primary care database in the United Kingdom. We compared ocular infection rates in people aged >=15 years without diabetes to those with diabetes, both type 1 and type 2. We developed logistic regression models to assess the excess risk in diabetes of: conjunctivitis, blepharitis, stye/chalzion, periorbital cellulitis, keratitis/keratoconjunctivitis, lacrimal gland infection, endopthalmitis, and ocular antimicrobial prescriptions over a six-year period (2010-2015). We also analysed the impact of glycaemic control on infection rates in those with diabetes. All models were adjusted for potential confounders. RESULTS: We analysed infection risk in 889,856 people without diabetes and 48,584 people with diabetes (3273 type 1, and 45,311 type 2). After adjustment for confounders both type 1 and type 2 were associated with increased incidence of conjunctivitis (OR 1.61; 95% CI 1.38-1.88; p<0.0001 and OR 1.11; 95% CI 1.06-1.16; p<0.0001 respectively). No association was found with blepharitis, stye/chalzion, periorbital cellulitis, keratitis/keratoconjunctivitis, lacrimal gland infection, and endopthalmitis in the whole population. In subgroup analyses blepharitis was more common in those with type 1 diabetes under 50 years old and endopthalmitis in those under 50 with type 2 diabetes. Glycaemic control was not found to be associated with any infection. Diabetes was also associated with an increased incidence of antimicrobial prescriptions (Type 1 OR 1.69; 95% CI 1.51-1.88; p<0.0001 and type 2 OR 1.17; 95% CI 1.13-1.20; p<0.0001). CONCLUSIONS: Conjunctivitis is recorded more frequently in people with diabetes. However, no substantial increase in recording of other ocular infections was noted. Infection risk was not found to be associated with the degree of glycaemic control. PMID- 28648964 TI - Factors associated with Prolonged Inaction in the hypoglycaemic treatment in people with non-insulin dependent Type 2 Diabetes and elevated glycated haemoglobin: A registry-based cohort study. AB - AIMS: To assess factors associated with Prolonged Inaction (PI) in insulin-naive patients with Type 2 Diabetes Mellitus (T2DM). PI was defined as the absence of treatment initiation or intensification for >=12 months despite HbA1c >7% (53mmol/mol). METHODS: A retrospective cohort study was conducted based on data from Intego, a Flemish General Practice registry. The study period ranged from January 1, 2006 to December 31, 2013. Patients with insulin therapy before the start of the study period were excluded from the analysis. A mixed effects logistic regression was used to assess the association of PI with the presence of co-morbidities, co-medications, process parameters and bio-clinical parameters. RESULTS: In a population of 2265 patients with T2DM, 578 insulin-naive patients presented with an HbA1c >7% (53mmol/mol) for >=12 months. Median follow-up was 1.2 years, median age 67 years, 55% were male. PI was present in 340 patients (59%) and associated with moderate to severe Chronic Kidney Disease, absence of a mental health disorder, less frequent HbA1c measurements, lower HbA1c values and a smaller number of co-medications. CONCLUSIONS: PI is highly prevalent in primary care, particularly in patients with less complex disease status and with less intensive follow-up. PMID- 28648965 TI - Corrigendum to "Common cases of improper lipid annotation using high-resolution tandem mass spectrometry data and corresponding limitations in biological interpretation" [Biochim. Biophys. Acta 1862(8) (2017) 766-770]. PMID- 28648966 TI - Ultralow Radiation Exposure During Flexible Ureteroscopy in Patients With Nephrolithiasis-How Far Can We Go? AB - OBJECTIVE: To evaluate the feasibility and clinical performance of a novel surgeon technique and protocol targeting ultralow fluoroscopy usage in retrograde intrarenal surgery (RIRS). MATERIALS AND METHODS: All RIRS procedures between 2009 and 2015 for 10- to 20-mm renal calculi performed by the same 2 experienced urologists were eligible. All procedures were performed using a highly standardized step-by-step RIRS technique. This technique was modified by the ultralow radiation exposure RIRS protocol; herein, as much as possible of the standardized steps were performed without radiation control targeting ultralow fluoroscopy usage. Primary end points were fluoroscopy time and dose area product. Secondary end points were stone-free rate (SFR) and intraoperative complications according to Satava classification. End points were evaluated using scatter plots and linear regression model. RESULTS: Overall, 174 procedures were assessed. Over the study period, fluoroscopy time and dose area product could be reduced from 167.7 s/318.4 cGy/cm2 in 2009 to 7.4 s/6.4 cGy/cm2 in 2015 (P <.001). SFR (66.7% in 2009; 100% in 2015) and complications (Satava 1 and 2: 28.5% and 4.8%, respectively) improved P <.1), and the surgical duration was reduced (91 minutes and 65 minutes, respectively, P <.001). CONCLUSION: Our findings revealed a continuous reduction of the amount of radiation used by the implementation of a novel ultralow X-ray usage protocol. SFR, complications, and surgical duration all improved, demonstrating that the novel protocol is as effective as current methods. Exposure to ionizing radiation can be significantly reduced if the presented protocol is followed strictly. PMID- 28648967 TI - Glans Necrosis Following Penile Prosthesis Implantation: Prevention and Treatment Suggestions. AB - OBJECTIVE: To examine possible etiology and treatment outcomes in 21 patients with glans necrosis following penile prosthesis implantation. METHODS: Glans necrosis typically presented with a dusky glans on the first postoperative day following prosthesis implantation. RESULTS: The blood supply to the glans penis consists of the dorsal arteries and the terminal branches of the spongiosal arteries. Using the cohort in our study, we compiled preoperative comorbidities and adjunctive surgical maneuvers that might compromise glans vascularity, leading to glans necrosis. Preoperative risk factors were arteriosclerotic cardiovascular disease (90%), diabetes mellitus (81%), smoking (81%), previous prosthesis explantation (57%), and previous radiation therapy (48%). The most prevalent intraoperative and postoperative factor was subcoronal incision for reasons as simple as coincident circumcision or as complex as for penile degloving (86%). Other factors detected were penile wrapping with an occlusive elastic bandage (62%), use of a sliding technique for penile lengthening (33%), and coincident distal urethral injury repair (29%). Seventeen patients (81%) managed expectantly with preservation of implanted prosthesis sustained significant glandular loss. Four patients managed with immediate prosthesis removal healed without sequelae. CONCLUSION: Patients with preoperative risk factors undergoing penile prosthesis implantation should avoid high-risk adjunctive surgical maneuvers. Upon development of signs of glans necrosis postoperatively, in the setting of these high-risk factors, immediate implant removal may prevent subsequent glans necrosis. PMID- 28648968 TI - Comparison of unbiased stereological estimation of total number of cresyl violet stained neurons and parvalbumin positive neurons in the adult human spiral ganglion. AB - Estimation of total number of neurons in the spiral ganglion (SG) at various ages and their functional status is important as these neurons are constantly exposed to noise and other environmental factors that may lead to neuronal loss with aging due to excitotoxic damage. Parvalbumin (PV) is a calcium-binding protein (CBP), found in highly metabolically active neurons. It helps in buffering cytosolic calcium, which is essential for neurotransmitter release. The neurons in the adult human SG express PV more strongly than other CBPs like calbindin and calretinin. These CBPs can be used as signatures to recognise neurons. In the present study, we quantified the number of neurons expressing PV by unbiased stereology and compared it to the number of neurons stained by cresyl violet (CV), which is a Nissl stain, in the adult human SG. Five adult human cadaveric temporal bones were obtained from the forensic science mortuary, after due clearance from the institute ethics committee. Independent CV stained and PV immunostained sections were used to estimate the total number of neurons (optical fractionator), with StereoInvestigator (SI) software. The estimated total number of SG neurons was 27,485+/-3251 and 26,705+/-1823 in the PV and CV stained sections, respectively. There was no significant difference between the estimates (p=0.552). Therefore, CV staining is simpler and more cost effective when estimating neuronal number. Although PV stains spiral ganglion neurons (SGNs) with a greater intensity and provides a functional status, its tedious protocol limits its use for quantification. PMID- 28648970 TI - Treating functional non-epileptic attacks - Should we consider acceptance and commitment therapy? AB - Patients who experience functional non-epileptic attacks (FNEA) are frequently seen in Neurology clinics. Diagnosis alone can result in cessation of attacks for some patients, but many patients require further treatment. There is evidence that certain psychological therapies, like cognitive-behavioral therapy (CBT) and psychodynamic interpersonal therapy (PIT) can be beneficial. Acceptance and commitment therapy (ACT) is a type of CBT that has been found to be effective at treating other somatic disorders, like epilepsy and chronic pain. In this paper, we explain what ACT is, the current evidence-base for its use, and the rationale for why it may be a beneficial treatment for patients who experience FNEA. We conclude that ACT is a potential treatment option for FNEA, and further research is required. PMID- 28648969 TI - A randomized controlled trial of a smoking cessation self-help intervention for dual users of tobacco cigarettes and E-cigarettes: Intervention development and research design. AB - Electronic Nicotine Delivery Systems, also called electronic cigarettes or e cigarettes, have been available for over a decade and use has been increasing dramatically. The primary reported reasons for use are to aid smoking cessation or reduction, yet a significant proportion appear to be long-term users of both products ("dual users"). Dual users may be motivated to quit smoking and might benefit from a behavioral intervention for smoking cessation. This paper describes the intervention development, as well as the design, methods, and data analysis plans for an ongoing randomized controlled trial (RCT). Formative research and learner verification were conducted to create a usable, understandable, and acceptable self-help intervention targeting dual users. The efficacy is being tested in an RCT with current dual users (N=2900) recruited nationally and randomized to one of three conditions. The Assessment Only (ASSESS) group only completes assessments. The Generic Self-Help (GENERIC) group receives non-targeted smoking cessation booklets and supplemental materials sent monthly over 18months. The e-cigarette Targeted Self-Help (eTARGET) group receives the newly developed intervention (targeted booklets and supplemental materials) sent over the same period. All participants complete self-report surveys every 3months over 2years. The primary study outcome is self-reported 7 day point prevalence abstinence. Cost-effectiveness metrics for the GENERIC and eTARGET interventions will also be calculated. PMID- 28648971 TI - Persistence with antiepileptic drugs in epilepsy patients treated in neurological practices in Germany. AB - OBJECTIVE: The goal of this study was to analyze the persistence with antiepileptic drugs (AED) and associated factors in patients followed in neurological practices in Germany. METHODS: This study included patients aged 18years or over who received two initial diagnoses of epilepsy and a first prescription of AED between 2007 and 2015 in a neurological practice (index date). The main outcome measure was the rate of AED persistence within five years of the index date. Kaplan-Meier analyses were performed to study treatment persistence as a function of age. A Cox proportional hazards regression model was used to estimate the relationship between non-persistence and demographic/clinical variables. RESULTS: A total of 8192 patients followed in neurological practices were included. After five years of follow-up, 41.1% (<=40years), 45.2%, (41-60years) and 50.1% (>60years) of patients followed in neurological practices were persistent (log-rank p-value<0.001). A negative association was found between discontinuation and age (<=40years vs. >60years: OR=1.19, 95% CI: 1.09-1.31; 41-60years vs. >60years: OR=1.10, 95% CI: 1.01-1.19). Furthermore, patients receiving old AED (OR=1.16, 95% CI: 1.01-1.34) or gabapentin (OR=1.46, 95% CI: 1.16-1.83) and those diagnosed with depression (OR=1.12, 95% CI: 1.03-1.21) were at a higher risk of non-persistence, whereas those receiving levetiracetam (OR=0.69, 95% CI: 0.60-0.80) or lamotrigine (OR=0.88, 95% CI: 0.79-0.97) and those with dementia (OR=0.74, 95% CI: 0.65-0.83) were at a lower risk. CONCLUSIONS: The rate of epilepsy patients persistent with AED was low after five years of treatment. Age, gender, co-morbidities, and drug characteristics were associated with this persistence. PMID- 28648973 TI - Editorial comment. PMID- 28648972 TI - Diallyl trisulfide, a garlic polysulfide protects against As-induced renal oxidative nephrotoxicity, apoptosis and inflammation in rats by activating the Nrf2/ARE signaling pathway. AB - BACKGROUND: Arsenic (As) contamination is an extremely dangerous global environmental problem as it can enter into the food chain and become bio accumulated, endangering human health. Chronic As intoxication leads to undesirable toxic effects in various organ systems of the body, especially the kidney. Diallyl trisulfide (DATS) is an organosulfur compound which has been widely known for its uses as antibacterial, antitumorogenic, antioxidant agent and has been also reported to have anti-apoptotic and anti-inflammatory properties. PURPOSE: In the present work, we intend to investigate the protective role of DATS, a garlic organosulfur compound in preventing the As-induced oxidative stress mediated renal injury in rats. Study design The activity of DATS to antagonize As-induced renal oxidative toxicity was analyzed using rats as an in vivo model. METHODS: We investigated the nephroprotective effect of DATS on As treated rats by performing various serological, biochemical, molecular and histological studies. The activation of Nrf2 was investigated using western blot. RESULTS: The data showed that As exposure significantly increased the serum and urine nephritic, oxidative stress, apoptosis and inflammatory markers in the renal tissue of rats. As intoxication also decreased the antioxidant status of the renal tissue along with the disturbances in the membrane bound ATPases. As nephrotoxicity was further confirmed with the altered morphological and ultrastructural changes in the renal tissue. Conversely, the DATS pre administration effectively recuperate the altered renal variables by As, which has been further supported by the histological and ultrastructural observations. This counteraction was achieved partially via the activation of Nrf2-ARE pathway through the activation of Akt. CONCLUSION: These findings explicate the prospective use of DATS as a promising organosulfur compound against As-induced renal oxidative dysfunction in rats. PMID- 28648974 TI - A set of care quality indicators for stroke management. AB - OBJECTIVE: This study proposes a set of quality indicators for care outcomes in patients with acute cerebral infarction. These indicators are understandable and relevant from a clinical viewpoint, as well as being acceptable and feasible in terms of time required, ease of data capture, and interpretability. METHOD: The method consisted of reaching consensus among doctors after having reviewed the literature on quality indicators in stroke. We then designed and conducted a field study to assess the understandability and feasibility of the set of indicators. RESULTS: Consensus yielded 8 structural indicators, 5 process indicators, and 12 result indicators. Additionally, standards of reference were established for each indicator. CONCLUSION: This set of indicators can be used to monitor the quality care for stroke patients, identify strengths, and potentially to identify areas needing improvement. PMID- 28648975 TI - Effect of extract of Pueraria tuberosa on expression of hypoxia inducible factor 1alpha and vascular endothelial growth factor in kidney of diabetic rats. AB - BACKGROUNDS: Kidney hypoxia represents a unifying mechanism in the pathogenesis of diabetic nephropathy. Hypoxia-induced factor (HIF)-1alpha mediates the metabolic responses of renal hypoxia by modulating the expression of VEGF. In the present study, we investigated the effect of Pueraria tuberosa extract (PTY-2r) on the expression of HIF-1alpha, VEGF and nephrin in streptozotocin (STZ) induced diabetic nephropathy (DN). METHODS: The model of diabetic nephropathy (DN) was produced by intraperitoneal injection of 55mg/kg of STZ and maintained for 60days. These DN-rats were randomly divided into three groups, i.e., DN, DN+PTY 2r (100mg/100g), and DN+PTY-2r (50mg/100g). A normal control (NC) group was administrated with drug vehicle. Expression of HIF-1alpha, VEGF and nephrin were evaluated in the renal tissue. RESULTS: Blood glucose, urine protein, serum creatinine, and urea, level were significantly raised along with decreased creatinine clearance in DN rats. Immunofluorescence and Western blot analysis showed significantly increased expression of HIF-1alpha & VEGF and decreased expression of nephrin in DN control rats. The PTY-2r treatment significantly reversed these changes in a dose-dependent manner. Correlation analysis showed that the expression of VEGF was positively correlated with that of HIF-1alpha and negatively correlated with nephrin. CONCLUSIONS: The PTY-2r can improve the chronic hyperglycemic condition induced kidney damage, and may delay the development of diabetic nephropathy by inhibiting the expression of HIF-1alpha and VEGF, thereby restoring the expression of nephrin. PMID- 28648976 TI - Synergistic combination of murine bone marrow-derived dendritic cells loaded ex vivo with whole tumor lysate and systemic chemotherapy mediates antitumor immune responses in vivo. AB - In order to get mature dendritic cells (DC) that is a crucial prerequisite for success in tumor immunotherapy protocols. Herein, we assumed that administration of murine bone marrow (BM)-derived DC (BM-DC), loaded ex vivo with whole Ehrlich ascites carcinoma (EAC) lysate, in the context of systemic chemotherapy cyclophosphamide (CTX) to induce antitumor immune responses, may be a good strategy to improve the presentation of tumor-specific antigens to the immune system. In the first series of experiments, BM cells generated either from BM of naive mice or from BM of EAC-bearing mice were cultured in the presence of GM-CSF and IL-4 for 6days. At day 7, cells were loaded for 48h with one of the following maturation agents: EAC lysate (1mg/ml), poly-inosinic: polycytidylic acid [poly(I:C)] (25MUg/ml) or mRNA encoding human telomerase reverse transcriptase (hTERT-mRNA) (2MUg/ml). In the second series of experiments, EAC-bearing mice were intraperitoneally (i.p.) injected with CTX followed by i.p. vaccination with DC, loaded ex vivo with EAC lysate. DC yield and the phenotypic expression of maturity-related surface markers of DC (i.e. CD11b and CD11c) in both series of experiments were investigated. As a result, a significant decrease in the number of DC generated from poly(I:C)-supplemented BM culture from EAC-bearing mice has been detected. Loading of BM cells with poly(I:C), EAC lysate or hTERT-mRNA could induce the expression of CD11b and CD11c. Additionally, vaccination of EAC bearing mice with DC loaded ex vivo with EAC lysate following CTX treatment, resulted in increases in the percentage of multiple populations of CD11b+CD11c+ in BM, spleen and peripheral blood (PB). To conclude, further researches to clarify the mechanism involved in DC maturation are crucial not only to comprehend DC biology but also to optimize DC immunotherapy protocols. PMID- 28648977 TI - Prognostic relevance of lymph node status for patients with ampullary adenocarcinoma after radical resection followed by adjuvant treatment. AB - PURPOSE: Attempts have been made to revise the nodal stage due to simplicity of current N staging system in ampullary adenocarcinoma. However, because of the disease rarity, there have only been a few studies assessing the prognostic impact of lymph node (LN) parameters. METHODS: We retrospectively analyzed 120 patients who underwent radical resection followed by adjuvant chemoradiotherapy for ampullary adenocarcinoma. The effect of LN parameters (number of total harvest LNs, number of metastatic LN (MLN), lymph node ratio (LNR), and log odds of positive LNs (LODDS)) on overall survival (OS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival were evaluated. Cutoff points of MLN, LNR and LODDs were determined using maximal chi2 method. RESULTS: Fifty-seven patients (48%) were staged as pN1 and their survival was not significantly decreased compared with pN0 patients. There was also no significant difference between patients with MLN 0 vs. 1. In univariate analyses, MLN (0-1 vs. >=2), LNR (<=17% vs. >17%) and perineural invasion were common prognosticators for OS and LRFS. Distant metastasis-free survival was not influenced by LN status. In addition, multivariate analysis revealed that among the LN parameters, LNR was able to independently predict both OS and LRFS. CONCLUSIONS: LNR performs better than other LN related parameters for predicting survival. After radical resection followed by adjuvant treatment, survival of patients with one positive LN does not seem to differ from patients without LN metastasis. PMID- 28648978 TI - The thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption is a prognostic biomarker of severity of systemic inflammation. AB - BACKGROUND: In severe drug eruptions, precise evaluation of disease severity at an early stage is needed to start appropriate treatment. It is not always easy to diagnose these conditions at their early stage. In addition, there are no reported prognostic biomarkers of disease severity in drug eruptions. The aim of this study was to test whether the thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption can serve as a prognostic biomarker of systemic inflammation. METHODS: Study participants included 76 patients who received a diagnosis of a drug eruption, one of the following: drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, maculopapular exanthema, and erythema multiforme. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) was eliminated in this study because scoring system for evaluating the severity was established. Correlation coefficients between serum TARC levels and indicators of systemic inflammation, including the neutrophil-to-lymphocyte ratio, Glasgow prognostic score, modified systemic inflammatory response syndrome (mSIRS) score, and C reactive protein in serum were evaluated. RESULTS: Serum TARC levels positively correlated with the neutrophil-to-lymphocyte ratio, Glasgow prognostic score, mSIRS score, C-reactive protein, albumin, white blood cell count, body temperature, and pulse rate. TARC levels negatively correlated with systolic blood pressure. Among these parameters, the mSIRS score showed strong correlation (correlation coefficient: 0.68). CONCLUSIONS: Serum TARC levels correlate well with indicators of systemic inflammation and of disease severity among patients with a drug eruption except SJS/TEN. Serum TARC may be a prognostic biomarker of severity of inflammation in drug eruptions. PMID- 28648979 TI - Obesity-related systemic oxidative stress: An important factor of poor asthma control. PMID- 28648980 TI - Pro- versus Anti-inflammatory Actions of HDLs in Innate Immunity. AB - High-density lipoproteins (HDLs) can inhibit inflammatory cytokine expression on innate immune cells, but sometimes they promote cytokine production as suggested in a recent article in Cell Metabolism by van der Vorst et al. (2017). Kopecky et al. point out that the origin, handling, and storage conditions of HDL preparations dictate their functional properties and can specifically affect immune cells to evoke a pro-inflammatory response. PMID- 28648981 TI - Leptin's Physiologic Role: Does the Emperor of Energy Balance Have No Clothes? AB - The discovery of the obese gene and the demonstration that its encoded protein leptin can reverse obesity due to genetic deficiency of the hormone were landmark discoveries in endocrinology and metabolism. Regarding leptin's role in physiology, it is now established that falling leptin levels are a key signal of the starved state in mice and humans. Repleting leptin reverses the starvation signal both in physiologic starvation and in obesity resulting from genetic leptin deficiency. Since its discovery, it has also been hypothesized that rising leptin levels caused by overfeeding provide a physiologic signal that orchestrates resistance to obesity. Although still widely believed, and possibly true in some circumstances, this aspect of leptin physiology has not been experimentally demonstrated. It will be important to determine whether leptin or as yet undiscovered factors are responsible for the well-documented capacity for physiologic resistance to overfeeding. PMID- 28648982 TI - Disease- or Storage-Associated Structural Modifications Are Unlikely to Explain HDL Pro-inflammatory Effects on Macrophages. AB - Van der Vorst et al. underscore the relevance of HDL quality control, considering HDL source and processing, but argue that disease- or storage-associated structural modifications of HDL cannot explain the observed pro-inflammatory effects on macrophages. Discrepancies between reported effects of HDL in macrophages are probably related to methodological differences. PMID- 28648984 TI - Whole-body biodistribution of the cannabinoid type 1 receptor ligand [18F]MK-9470 in the rat. AB - The endocannabinoid system participates in many processes in the body, including memory, reward, pain, motor activity, food intake, energy metabolism, and gastrointestinal functions. [18F]MK-9470 is a positron emission tomography (PET) ligand that binds with high affinity and selectivity to the cannabinoid type 1 receptor. In order to fully characterize ligand behavior, tracer uptake measured using in vivo microPET was compared with results from ex vivo tissue dissection. Twelve male Sprague-Dawley rats were divided into three subgroups and scanned over time periods of 10min, 30min and 90min using PET. Afterwards, a number of the animals' organs were dissected. Uptake of radioactivity was expressed in terms of %ID/ml and %ID/(g tissue). For comparison of in vivo and ex vivo methods, Bland-Altman plots were computed. The highest uptake of [18F]MK-9470 was found in the liver and small intestine; the brain showed less uptake, while low and unspecific binding was observed in tissue of the heart, lung, kidney and bone. In the brain, normalized uptake of [18F]MK-9470 was on average 0.25%ID/ml (range: 0.16 to 0.28%ID/ml). Bland-Altman plots revealed the best agreement between methods for the 90min acquisition protocols. High hepatic accumulation and metabolism of [18F]MK-9470 occur with mainly enteral excretion, which may vary considerably over time - a finding which may be of relevance in metabolite determination in quantitative brain studies. Comparisons between in vivo and ex vivo methods showed that whole-body distribution of [18F]MK-9470 using positron emission tomography is a preferable alternative to ex vivo biodistribution, and requires a significantly smaller number of animals. PMID- 28648983 TI - Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells. AB - Cancer and stem cells appear to share a common metabolic profile that is characterized by high utilization of glucose through aerobic glycolysis. In the presence of sufficient nutrients, this metabolic strategy provides sufficient cellular ATP while additionally providing important metabolites necessary for the biosynthetic demands of continuous cell proliferation. Recent studies indicate that this metabolic profile is dependent on genes that regulate the fusion and fission of mitochondria. High levels of mitochondrial fission activity are associated with high proliferation and invasiveness in some cancer cells and with self-renewal and resistance to differentiation in some stem cells. These observations reveal new ways in which mitochondria regulate cell physiology, through their effects on metabolism and cell signaling. PMID- 28648986 TI - Segmentation of medical images using mean value guided contour. AB - Partial differential equation-based (PDE-based) methods are extensively used in image segmentation, especially in contour models. Difficulties associated with the boundaries, namely troubles with developing initialization, inadequate convergence to boundary concavities, and difficulties connected to saddle points and stationary points of active contours make the contour models suffer from a feeble performance of referring to complex geometries. The present paper is designed to take advantage of mean value theorem rather than minimizing energy function for contours. It is efficiently capable of resolving above-mentioned problems by applying this theorem to the edge map gradient vectors, which is calculated from the image. Since the contour is computed in a straightforward manner from an edge map instead of force balance equation, it varies from other contour-based image segmentation methods. To illustrate the ability of the proposed model in complex geometries and ruptures, several experiments were also provided to validate the model. The experiments' results demonstrated that the proposed method, which is called mean value guided contour (MVGC), is capable of repositioning contours into boundary concavities and has suitable forcefulness in complex geometries. PMID- 28648987 TI - Factors affecting adult trait Neuroticism in a nationally representative sample. AB - This study explores factors in childhood and adulthood that affect adult trait Neuroticism in a large, nationally representative sample. 5785 participants provided information on family social background measured at birth; Intelligence assessed at 11 years; Behavioural problems measured at 11 years; Malaise assessed at 23 years; Educational qualifications obtained at 33 years; Occupational levels at 42 years, and personality trait Neuroticism measured at 50 years. Structural equation modelling showed that sex, childhood Behavioural Problems, childhood Intelligence, Malaise in early adulthood, and Occupation were all significant and independent predictors of adult trait Neuroticism. Parental social status was significantly and negatively associated with Malaise at age 23, but was not a significant predictor of trait Neuroticism at age 50 years. Education predicted Neuroticism mainly through occupation. The strongest predictor of trait Neuroticism at 50 years was Malaise measured at 23 years, with a corrected correlation of r = .42 over the 27 year period. The results suggest some underlying biological/genetic mechanism. PMID- 28648985 TI - Aging and Caloric Restriction Research: A Biological Perspective With Translational Potential. AB - Aging as a research pursuit is fairly new compared with traditional lines of medical research. A growing field of investigators is focused on understanding how changes in tissue biology, physiology, and systemic homeostasis, conspire to create increased vulnerability to disease as a function of age. Aging research as a discipline is necessarily broad; in part because aging itself is multi-faceted and in part because different model systems are employed to define the underlying biology. In this review we outline aspects of aging research that are likely to uncover the pivotal events leading to age-related disease vulnerability. We focus on studies of human aging and discuss the value of research on caloric restriction, an intervention with proven efficacy in delaying aging. We propose that studies such as these will deliver target factors and processes that create vulnerability in human aging, an advance that would potentially be transformative in clinical care. PMID- 28648988 TI - Comparing the mental health literacy of Chinese people in Australia, China, Hong Kong and Taiwan: Implications for mental health promotion. AB - Using data of 200, 522, 572, and 287 Chinese from Australia, China, Hong Kong and Taiwan respectively, this study aimed at comparing the mental health literacy of Chinese people from different communities, and between Chinese communities and the Australian general public. The participants were asked questions that assessed their recognition of depression and schizophrenia. Compared with the Australians, much lower percentages of Chinese in the four Chinese communities could correctly identify depression and early schizophrenia. Commonalities in the preference for 'psychiatrist', 'psychologist', 'Chinese medical doctor', and 'Chinese traditional healer', a lack of knowledge of medications, and a higher likelihood of endorsement of traditional Chinese medicines were found among the four Chinese communities. Differences in the preference for 'general practitioner' and 'social worker', and a higher percentage of endorsement of herbal medicines were observed among the different Chinese communities. Cultural factors such as Chinese perceptions of mental illness, and socio-contextual factors such as differences in mental health care system in the four communities were offered to explain these commonalities and differences. Mental health promotion programmes for Chinese people may need to consider the above-mentioned cultural and socio-contextual factors so that specific promotion programmes can be developed. PMID- 28648989 TI - Thiol-functionalized nanogels as reactive plasticizers for crosslinked polymer networks. AB - Significant efforts have been expended to mitigate plasticizer migration from crosslinked methacrylic and poly(vinyl chloride) polymer networks by synthesizing reactive plasticizers that can blend homogenously within the networks to reduce polymer property change, acute toxicity and downstream environmental effects of plasticizer migration with limited and varying amount of success. We hypothesized that appropriate thiol-functionalized nanogels synthesized using the same monomers as the parent network to generate highly compact, crosslinked structures will form thermally stable, homogenous networks and perform as optimal reactive plasticizers. Nanogels were synthesized via a thiol-Michael addition solution polymerization and incorporated at different mass ratios within a polyethylene glycol 400 urethane dimethacrylic monomer to form photo-crosslinked networks. While maintaining the inherent hydrolytic stability, thermal stability and biocompatibility of the parent matrix at ~99% acrylic group conversion, the PEG400 urethane dimethacrylic -nanogel networks retained optical clarity with >90% visible light transmission at 20wt% nanogel concentration within the matrix. The addition of the nanogels also enhanced the elongation of the parent matrix by up to 320%, while a 37 degrees C reduction in glass transition temperature (?Tg) and >=50% reduction in modulus was observed. A 52% reduction in the shrinkage stress of the material was also noted. The results indicate that the application of thiol-functionalized nanogels as plasticizers to alter the bulk properties of the parent matrix while mitigating plasticizer migration by covalently crosslinking the nanogels within the polymer matrix provides a simple yet efficient technique to generate network-specific plasticizers with the ability to alter targeted properties within polymers. PMID- 28648990 TI - A numerical-experimental protocol to characterize corneal tissue with an application to predict astigmatic keratotomy surgery. AB - Tonometers are intended to determine the intraocular pressure (IOP) and the quality of corneal tissue. In contrast to the physiological state of stress of the cornea, tonometers induce non-physiological bending stress. Recently, the use of a single experiment to calibrate a set of corneal mechanical properties was suggested to be an ill-posed problem. Thus, we propose a numerical-experimental protocol that uses inflation and indentation experiments simultaneously, restricting the optimization space to circumvent the ambiguity of the fitting. For the first time, both corneal behaviors, i.e., biaxial tension (physiological) and bending (non-physiological), are taken into account. The experimental protocol was performed using an animal model (New Zealand rabbit's cornea). The patient-specific geometry and IOP were registered using a MODI topographer (CSO, Italy) and an applanation tonometer, respectively. The mechanical response was evaluated using inflation and indentation experiments. Subsequently, the optimal set of material properties is identified via an inverse finite element method. To validate the methodology, an in vivo incisional refractive surgery (astigmatic keratotomy, AK) is performed on four animals. The optical outcomes showed a good agreement between the real and simulated surgeries, indicating that the protocol can provide a reliable set of mechanical properties that enables further applications and simulations. After a reliable ex vivo database of inflation experiments is built, our protocol could be extended to humans. PMID- 28648991 TI - Longitudinal pathways from unconventional personal attributes in the late 20s to cannabis use prior to sexual intercourse in the late 30s. AB - A quarter of people living with human immunodeficiency virus (HIV) infection in the United States are women. Furthermore, African American and Hispanic/Latina women continue to be disproportionately affected by HIV, compared with women of other races/ethnicities. Cannabis use prior to intercourse may be associated with increased risky sexual behaviors which are highly related to HIV. The ultimate goal of this research is to better understand the relationships between unconventional personal attributes (e.g., risk-taking behaviors) in the late 20s, substance use (e.g., alcohol) in the mid 30s, and cannabis use prior to intercourse in the late 30s using a community sample; such an understanding may inform interventions. This study employing data from the Harlem Longitudinal Development Study includes 343 female participants (50% African Americans, 50% Puerto Ricans). Structural equation modeling indicated that unconventional personal attributes in the late 20s were associated with substance use in the mid 30s (beta=0.32, p<0.001), which in turn, was associated with cannabis use prior to sexual intercourse in the late 30s (beta=0.64, p<0.001). Unconventional personal attributes in the late 20s were also directly related to cannabis use prior to sexual intercourse in the late 30s (beta=0.39, p<0.01). The findings of this study suggest that interventions focused on decreasing unconventional personal attributes as well as substance use may reduce sexual risk behaviors among urban African American and Puerto Rican women. Also, the implications of this study for health care providers and researchers working in HIV prevention are that these precursors may be useful as patient screening tools. PMID- 28648992 TI - The association between indoor smoke-free home rules and the use of cigar and smokeless tobacco: A longitudinal study. AB - INTRODUCTION: The existence of an indoor smoke-free home rule is associated with lower use of cigar and smokeless tobacco. This study aims to use a longitudinal sample to examine the association between smoke-free home rules and the cessation and uptake of these two types of tobacco products. METHOD: The Tobacco Use Supplement of the Current Population Survey surveyed 28,153 adults in May 2010 and then followed them up 12months later. Data from these two surveys and multiple logistic regressions were used to examine the association between overtime smoke-free home rule status and the use of cigar and smokeless tobacco. RESULTS: Among respondents who used cigar in 2010, having an indoor smoke-free home rules consistently (AOR=2.41, 95% CI=1.52-3.83) and adopting one during the 12-month period (AOR=1.92, 95% CI=1.01-3.68) increased the likelihood of not using cigar in 2011, compared to not having or forgoing a home rule over time. Among adults who had never used cigar by 2010, those having a rule consistently (AOR=0.47, 95% CI=0.38-0.71) were less likely to initiate cigar use. Having a smoke-free home rule consistently was also associated with lower likelihood of start using smokeless tobacco (AOR=0.52, 95% CI=0.35-0.78). Nevertheless, there is no evidence indicating that the adoption of a rule is correlated with the cessation of smokeless tobacco. CONCLUSION: The establishment of indoor smoke free home rules may help reduce cigar use and prevent the uptake of cigar and smokeless tobacco. Such findings call for research using experimental design to further examine the impact of home rules on the use of cigar and smokeless tobacco. PMID- 28648993 TI - Relationship of drinking motives with alcohol consumption and alcohol-related problems identified in a representative community-based study from Ningxia, China. AB - BACKGROUND: Drinking motives have been linked to alcohol consumption and drinking related problems in western countries, but evidence about this relationship is largely lacking for Asian countries. We aim to assess the relationship between drinking motives and drinking-related outcomes in China, where alcohol use disorders are an increasingly important contributor to the overall burden of illness. METHODS: Validated Chinese versions of the Drinking Motives Questionnaire-Revised (DMQ-R) and the Alcohol Use Disorder Identification Test (AUDIT) were used to assess drinking motives and drinking-related outcomes among 612 current drinkers identified from a cross-sectional survey of a representative sample of 2425 adults living in Ningxia Province in 2013. Structural equation modeling was used to estimate the relationships linking specific drinking motives ('enhancement', 'conformity', 'social' and 'coping') to drinking-related outcomes ('level of alcohol consumption', 'alcohol dependence' and 'adverse consequences'). FINDINGS: The enhancement motive is significantly associated with the level of alcohol consumption (beta=0.52, 95% CI=0.27, 0.78). The conformity motive is associated with higher levels of alcohol dependence (beta=0.74, 95% CI=0.50, 0.98) and adverse consequences of drinking (beta=0.43, 95% CI=0.04, 0.81). The social motive and drinking to cope motive are not significantly associated with any of the three drinking outcomes. INTERPRETATION: The relationships between drinking motives and drinking-related outcomes in China are quite different from those reported in western countries. This study highlights the need to consider local context when adapting prevention or intervention strategies developed in western countries to address the problem of the harmful use of alcohol in China. PMID- 28648994 TI - Dynamic and differential expression of the gonadal aromatase during the process of sexual differentiation in a novel transgenic cyp19a1a-eGFP zebrafish line. AB - In zebrafish, there exists a clear need for new tools to study sex differentiation dynamic and its perturbation by endocrine disrupting chemicals. In this context, we developed and characterized a novel transgenic zebrafish line expressing green fluorescent protein (GFP) under the control of the zebrafish cyp19a1a (gonadal aromatase) promoter. In most gonochoristic fish species including zebrafish, cyp19a1a, the enzyme responsible for the synthesis of estrogens, has been shown to play a critical role in the processes of reproduction and sexual differentiation. This novel cyp19a1a-eGFP transgenic line allowed a deeper characterization of expression and localization of cyp19a1a gene in zebrafish gonads both at the adult stage and during development. At the adult stage, GFP expression was higher in ovaries than in testis. We showed a perfect co-expression of GFP and endogenous Cyp19a1a protein in gonads that was mainly localized in the cytoplasm of peri-follicular cells in the ovary and of Leydig and germ cells in the testis. During development, GFP was expressed in all immature gonads of 20 dpf-old zebrafish. Then, GFP expression increased in early differentiated female at 30 and 35dpf to reach a high GFP intensity in well differentiated ovaries at 40dpf. On the contrary, males consistently displayed low GFP expression as compared to female whatever their stage of development, resulting in a clear dimorphic expression between both sexes. Interestingly, fish that undergoes ovary-to-testis transition (35 and 40dpf) presented GFP levels similar to males or intermediate between females and males. In this transgenic line our results confirm that cyp19a1a is expressed early during development, before the histological differentiation of the gonads, and that the down regulation of cyp19a1a expression is likely responsible for the testicular differentiation. Moreover, we show that although cyp19a1a expression exhibits a clear dimorphic expression pattern in gonads during sexual differentiation, its expression persists whatever the sex suggesting that estradiol synthesis is important for gonadal development of both sexes. Monitoring the expression of GFP in control and exposed-fish will help determine the sensitivity of this transgenic line to EDCs and to refine mechanistic based-assays for the study of EDCs. In fine, this transgenic zebrafish line will be a useful tool to study physiological processes such as reproduction and sexual differentiation, and their perturbations by EDCs. PMID- 28648995 TI - When the ball is in the female's court: How the scramble-competition mating system of the North American red squirrel has shaped male physiology and testosterone dynamics. AB - Male reproductive success in most mammals is determined by their success in direct inter-male competition through aggression and conflict, resulting in female-defense mating systems being predominant. This is linked to male testosterone levels and its dynamics. However, in certain environments, a scramble-competition mating system has evolved, where female reproductive behavior takes precedence and male testosterone dynamics are unlikely to be related to inter-male competition. We studied the North American red squirrel (Tamiasciurus hudsonicus), a species with a well-established scramble-competition system. Using an ACTH hormonal challenge protocol as a proxy for competitive interactions, we compared the testosterone dynamics in breeding males in late winter with that in nonbreeding males in late spring in the Yukon. To gain an integrated picture of their physiological state, we also assessed changes in their stress response, body mass, energy mobilization, and indices of immune function. Testosterone levels at the base bleed were high in breeding males (2.72ng/mL) and virtually absent in non-breeding males (0.04ng/mL). Breeding males were in better condition (heavier body mass, higher hematocrit, and higher erythrocytes), had higher indices of immune function (neutrophil:lymphocyte ratio), but a similar ability to mobilize energy (glucose) compared with non breeding males. Though total cortisol was higher in non-breeding males, free cortisol was twice as high in breeding males as their corticosteroid binding globulin levels were half as high. In response to the ACTH challenge, testosterone levels in breeding males declined 49% over the first hour and increased 36% over the next hour; in non-breeding males levels showed no change. Free cortisol increased only modestly (26% in breeding males; 23% in non-breeding males). Glucose levels changed similarly in breeding and nonbreeding males, declining for the first 30min and then increasing for the next 60min. Thus, testosterone and components of the stress axis function in a profoundly different manner in male red squirrels than in males of mammals with female-defense mating systems. There are four probable interrelated reasons for these adaptations in male red squirrels: the marginal benefits of each mating, the constraints of mate searching away from their own resource-based territories, energy mobilization in a harsh environment, and a long life span. PMID- 28648996 TI - RNAi knock-down of the Bemisia tabaci Toll gene (BtToll) increases mortality after challenge with destruxin A. AB - Bemisia tabaci (Gennadius) Middle East-Asia Minor 1 (MEAM1) is a well known invasive insect species. Little information is available on immune system of B. tabaci to date. In this study, one of the Toll-like receptors (TLR; namely BtToll) was cloned in MEAM1 B. tabaci which contains an open reading frame of 3153bp, encoding putative 1050 amino acids. Phylogenetic analysis indicated that BtToll is highly identitical with other members of the TLR family. Transcripts of BtToll detected through qRT-PCR were expressed in all developmental stages of B. tabaci and the highest expression level was observed in the 3rd nymphal instar. BtToll was highly expressed in response to immune challenge. RNA interference was used to knockdown the BtToll expression in adults through the oral route which resulted in significant reduction of BtToll transcript. When the adults were challenged with a mycotoxin from entomogenous fungi - destruxin A (DA) and RNAi, the median lethal concentration (LC50) decreased by 70.67% compared to DA treatment only. Our results suggest that BtToll is an important component of the B. tabaci immune system. RNAi technology using dsToll combined with general control methods (using toxin only) can be used as a potential strategy in integrated B. tabaci management programs. PMID- 28648997 TI - Effects, tolerance mechanisms and management of salt stress in grain legumes. AB - Salt stress is an ever-present threat to crop yields, especially in countries with irrigated agriculture. Efforts to improve salt tolerance in crop plants are vital for sustainable crop production on marginal lands to ensure future food supplies. Grain legumes are a fascinating group of plants due to their high grain protein contents and ability to fix biological nitrogen. However, the accumulation of excessive salts in soil and the use of saline groundwater are threatening legume production worldwide. Salt stress disturbs photosynthesis and hormonal regulation and causes nutritional imbalance, specific ion toxicity and osmotic effects in legumes to reduce grain yield and quality. Understanding the responses of grain legumes to salt stress and the associated tolerance mechanisms, as well as assessing management options, may help in the development of strategies to improve the performance of grain legumes under salt stress. In this manuscript, we discuss the effects, tolerance mechanisms and management of salt stress in grain legumes. The principal inferences of the review are: (i) salt stress reduces seed germination (by up to more than 50%) either by inhibiting water uptake and/or the toxic effect of ions in the embryo, (ii) salt stress reduces growth (by more than 70%), mineral uptake, and yield (by 12-100%) due to ion toxicity and reduced photosynthesis, (iii) apoplastic acidification is a good indicator of salt stress tolerance, (iv) tolerance to salt stress in grain legumes may develop through excretion and/or compartmentalization of toxic ions, increased antioxidant capacity, accumulation of compatible osmolytes, and/or hormonal regulation, (v) seed priming and nutrient management may improve salt tolerance in grain legumes, (vi) plant growth promoting rhizobacteria and arbuscular mycorrhizal fungi may help to improve salt tolerance due to better plant nutrient availability, and (vii) the integration of screening, innovative breeding, and the development of transgenics and crop management strategies may enhance salt tolerance and yield in grain legumes on salt-affected soils. PMID- 28648998 TI - Physiological traits and Mn transporter genes expression in ryegrass genotypes under increasing Mn at short-term. AB - We studied physiological traits and Mn transporter genes expression in ryegrass genotypes (One-50, Banquet-II, Halo-AR1 and Nui) under increasing Mn (2.4-750 MUM) at short-term (8-24 h) in nutrient solution. An increment in Mn concentration occurred early in roots of all genotypes at increased Mn doses relative to control. Banquet-II and Nui roots showed the greatest Mn concentration at the highest Mn supply. Net photosynthesis (Pn) of Banquet-II and Halo-AR1 were not perturbed by Mn doses, whereas One-50 and Nui, decayed strongly at the highest Mn dose, concomitant with reduced total chlorophyll concentration. A high accumulation of Mn in roots together the maintained Pn under increased Mn doses in Banquet-II and Halo-AR1 suggest a higher Mn resistance of these genotypes. Stomatal conductance (gs) of all genotypes did not vary in presence of Mn. In roots of Banquet-II an augment of lipid peroxidation (LP) by Mn excess was observed earlier decreasing afterwards, being attenuated by the augment of the radical scavenging activity (RSA) and total phenols (TP) of this genotype. Mn concentration and LP in tissues of One-50 and Nui genotypes rose together, may be due to its Mn sensitivity. Differential expression of Mn transporter genes were found in the studied genotypes grown under increasing supplies of Mn, being MTP8.1 expressed in shoots and NRAMP2-like in roots. We concluded that Banquet-II showed greater Mn concentration associated to high roots NRAMP2-like gene expression, without changes in photosynthetic performance. Despite, this genotype showed an increase of LP at the first hours of Mn-excess, it was decreased by the RSA and TP. Halo-AR1 appears to be Mn-resistant in the short-term due to its photosynthetic performance was unchanged by Mn-toxicity, whilst One-50 and Nui were Mn-sensitive. PMID- 28648999 TI - In vitro protein synthesis of sugar beet (Beta vulgaris) and maize (Zea mays) is differentially inhibited when potassium is substituted by sodium. AB - The substitution of potassium ions (K+) by sodium ions (Na+) in the nutrition of plants is restricted. It was shown earlier that net protein synthesis is the process which is most sensitive to the substitution of K+ by Na+ in young sugar beet. We hypothesized that the activity of ribosomes is inhibited by the substitution. This hypothesis was tested in an in vitro approach. Cytosolic polysomes were isolated from growing leaves of sugar beet and maize by means of differential centrifugation. In vitro systems of both plant species were tested for functionality and comparability. Translation was quantified by the 35S methionine incorporation in TCA-precipitable products. The effect of different substitution levels (0%, 20%, 40%, 60%, and 80% substitution of K+ by Na+) on in vitro translation was measured. Translation by polysomes of both plant species was significantly inhibited by the substitution. However, the translation by maize polysomes was more negatively affected by the substitution. A significant decrease in the translation by maize polysomes was observed already when 20% of K+ were replaced by Na+, whereas in the case of sugar beet, the translation was inhibited firstly at the substitution level of 40%. The in vitro results show that the process of translation itself is disturbed by the substitution and indicate a higher tolerance of sugar beet polysomes to increased Na+ concentrations and Na+/K+ ratios compared to polysomes of maize. We propose that this tolerance contributes to the salt resistance of sugar beet. PMID- 28649000 TI - Suppression of the MADS-box gene SlMBP8 accelerates fruit ripening of tomato (Solanum lycopersicum). AB - MADS-box genes encode important transcription factors that are involved in many biological processes of plants, including fruit ripening. In our research, a MADS box gene, SlMBP8, was identified, and its tissue-specific expression profiles were analysed. SlMBP8 was highly expressed in fruits of the B+4 stage, in senescent leaves and in sepals. To further characterize its function, an RNA interference (RNAi) expression vector of SlMBP8 was constructed and transferred into tomato. In the transgenic plants, the ripening of fruits was shortened by 2 4 days compared to that of wild type. At the same time, carotenoids accumulated to higher levels and the expression of phytone synthase 1 (PSY1), phytoene desaturase (PDS) and sigma-carotene desaturase (ZDS) was enhanced in RNAi fruits. The transgenic fruits and seedlings showed more ethylene production compared with that of the wild type. Furthermore, SlMBP8-silenced seedlings displayed shorter hypocotyls due to higher endogenous ethylene levels, suggesting that SlMBP8 may modulates the ethylene triple response negatively. A yeast two-hybrid assay indicated that SlMBP8 could interact with SlMADS-RIN. Besides, the expression of ethylene-related genes, including ACO1, ACO3, ACS2, ERF1, E4 and E8, was simultaneously up-regulated in transgenic plants. In addition, SlMBP8-silenced fruits showed higher ethylene production, suggesting that suppressed expression of SlMBP8 promotes carotenoid and ethylene biosynthesis. In addition, the fruits of transgenic plants displayed more rapid water loss and decreased storability compared to wild type, which was due to the significantly induced expressions of cell wall metabolism genes such as PG, EXP, HEX, TBG4, XTH5 and XYL. These results suggest that SlMBP8 plays an important role in fruit ripening and softening. PMID- 28649002 TI - cPLA2alpha activates PI3K/AKT and inhibits Smad2/3 during epithelial-mesenchymal transition of hepatocellular carcinoma cells. AB - Cytosolic phospholipase A2alpha (cPLA2alpha), a key phospholipase that regulates lipid metabolism, plays an important role in tumor progression. In the present study of hepatocellular carcinoma (HCC), cPLA2alpha was overexpressed in highly metastatic HCC cell lines. Immunohistochemical staining showed increased levels of cPLA2alpha at the invasive edges of HCC, and a clinicopathological analysis of samples from 111 patients revealed that its expression level was linked with micro-vascular invasion and cirrhosis. Knockdown of cPLA2alpha inhibited migration, probably due to its role in actin polymerization. Overexpression of cPLA2alpha promoted cell migration and invasion. Based on the mechanistic analysis, our data suggested that cPLA2alpha mediate epidermal growth factor (EGF) induced epithelial-mesenchymal transition (EMT) through PI3K/AKT/ERK pathway. cPLA2alpha activity was required for the transforming growth factor (TGF)-beta-induced EMT. However, cPLA2alpha inhibited Smad2/3 activation and promoted the activation of the PI3K/AKT/ERK pathway. A xenograft tumor transplant model confirmed the role of cPLA2alpha in HCC invasion and metastasis. Based on the mechanistic analysis, cPLA2alpha mediated both EGF- and TGF-beta-induced EMT, which are essential for HCC metastasis. cPLA2alpha is a potentially target for novel therapies of HCC. PMID- 28649003 TI - Targeting EGFRvIII for glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most progressive primary brain tumor. Targeting a novel and highly specific tumor antigen is one of the strategies to overcome tumors. EGFR variant III (EGFRvIII) is present in 25%-33% of all patients with GBM and is exclusively expressed on tumor tissue cells. Currently, there are various approaches to target EGFRvIII, including CAR T-cell therapy, therapeutic vaccines, antibodies, and Bi-specific T Cell Engager. In this review, we focus on the preclinical and clinical findings of targeting EGFRvIII for GBM. PMID- 28649004 TI - MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers. AB - MACC1 was identified as a novel player in cancer progression and metastasis, but its role in death receptor-mediated apoptosis is still unexplored. We show that MACC1 knockdown sensitizes cancer cells to death receptor-mediated apoptosis. For the first time, we provide evidence for STAT signaling as a MACC1 target. MACC1 knockdown drastically reduced STAT1/3 activating phosphorylation, thereby regulating the expression of its apoptosis targets Mcl-1 and Fas. STAT signaling inhibition by the JAK1/2 inhibitor ruxolitinib mimicked MACC1 knockdown-mediated molecular signatures and apoptosis sensitization to Fas activation. Despite the increased Fas expression, the reduced Mcl-1 expression was instrumental in apoptosis sensitization. This reduced Mcl-1-mediated apoptosis sensitization was Bax and Bak dependent. MACC1 knockdown also increased TRAIL-induced apoptosis. MACC1 overexpression enhanced STAT1/3 phosphorylation and increased Mcl-1 expression, which was abrogated by ruxolitinib. The central role of Mcl-1 was strengthened by the resistance of Mcl-1 overexpressing cells to apoptosis induction. The clinical relevance of Mcl-1 regulation by MACC1 was supported by their positive expression correlation in patient-derived tumors. Altogether, we reveal a novel death receptor-mediated apoptosis regulatory mechanism by MACC1 in solid cancers through modulation of the STAT1/3-Mcl-1 axis. PMID- 28649005 TI - CRISPR/Cas9-coupled recombineering for metabolic engineering of Corynebacterium glutamicum. AB - Genome engineering of Corynebacterium glutamicum, an important industrial microorganism for amino acids production, currently relies on random mutagenesis and inefficient double crossover events. Here we report a rapid genome engineering strategy to scarlessly knock out one or more genes in C. glutamicum in sequential and iterative manner. Recombinase RecT is used to incorporate synthetic single-stranded oligodeoxyribonucleotides into the genome and CRISPR/Cas9 to counter-select negative mutants. We completed the system by engineering the respective plasmids harboring CRISPR/Cas9 and RecT for efficient curing such that multiple gene targets can be done iteratively and final strains will be free of plasmids. To demonstrate the system, seven different mutants were constructed within two weeks to study the combinatorial deletion effects of three different genes on the production of gamma-aminobutyric acid, an industrially relevant chemical of much interest. This genome engineering strategy will expedite metabolic engineering of C. glutamicum. PMID- 28649001 TI - A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (<=16 years) low grade glioma - A final report. AB - BACKGROUND: The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. METHODS: Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology-Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 * 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02-7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. FINDINGS: No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. INTERPRETATION: The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of 'duration of therapy' and 'age at stopping therapy'. PMID- 28649006 TI - Optimization of hydrogel containing toluidine blue O for photodynamic therapy by response surface methodology. AB - Photodynamic therapy with toluidine blue O (TBO) hydrogel exhibits antibacterial activity against Staphylococcus aureus and Escherichia coli in this paper. The response surface methodology is employed to optimize formulations for antibacterial activity. The optimal formulations are carbomer concentration of 3% (w/v), TBO concentration of 0.1mg/mL and the quality ratio of NaOH and carbomer of 0.4 (w/w). Under the optimized formulations, the log-transformed of CFUmL-1 on the Staphylococcus aureus and Escherichia coli are 0.84 and 1.26 (the log transformed of CFUmL-1 of negative control groups on the Staphylococcus aureus and Escherichia coli are 8.21 and 8.47), respectively. In comparison with photodynamic therapy with TBO aqueous solution, the proposed formulations provide a much stronger antibacterial activity against Staphylococcus aureus and Escherichia coli. TBO hydrogels are stable during 6weeks at three different temperatures (4, 25 and 40 degrees C) with respect to no change of color, transparency, pH and viscosity. 50% and 68.26% of TBO are released from carbomer hydrogel after 4h and 24h, respectively. TBO hydrogel alone or light alone (630nm) treatment is incapable of showing antibacterial activity against Staphylococcus aureus and Escherichia coli. Therefore, photodynamic therapy with the novel optimized TBO hydrogel formulations is a promising treatment strategy for periodontitis. PMID- 28649007 TI - Polypharmacy and sun exposure: Implications for mitochondrial DNA deletions in skin. AB - Most somatic cells contain many copies of mitochondrial DNA (mtDNA). Because of both the high copy number and the lack of repair mechanisms available to mtDNA, damage to it largely goes unrepaired, and can accumulate over time. Large scale deletions are a recognised type of damage sustained by mtDNA as a consequence of exposure to the ultraviolet light in sunlight. A group of patients were identified as having abnormally high levels of either a 4977 base pair deletion (mtDNA4977) or 3895 base pair deletion (mtDNA3895), in mtDNA from sun exposed skin or skin suspected to be a non-melanoma skin cancer, but not in their non-sun exposed skin biopsies. In three of the four cases, skin cancer was ruled out due to histological testing. Additional factors from these patients' medical histories were studied, and it was noted that they shared diagnoses for multiple pathologies common to an older population, and that they were being treated with the same or related pharmaceuticals, including some that had been known to cause dermal side effects. Investigation into the biochemistry underlying the symptoms, the effects of sun exposure and side effects of the prescribed pharmaceuticals revealed a possible synergistic relationship leading to the localised high levels of mtDNA deletions. PMID- 28649008 TI - Environmental traditional knowledge in a natural protected area as the basis for management and conservation policies. AB - Ethnobotany is an adequate tool to identify the most import wild edible plants used by local people and to develop strategies for its sustainable use and policy making. This research records the wild edible plants used by the inhabitants of the Sierra la Laguna Biosphere Reserve, in Mexico, and identified priority species for sustainable development. The employed quantitative approach included the application of a food-oriented index named Food Significance Index (FSI), which integrated cultural, agricultural and food parameters; moreover, it used multivariate analysis to identify priority edible species for use and/or conservation. Fifty taxa were identified as the most important wild edible plants in the reserve, integrated into five priority groups. Foods in priority group 1 had the highest culinary diversity by grouping three fruits (Ficus petiolaris, Stenocereus thurberi, and Cyrtocarpa edulis), one almond-like seed (Cnidoscolus maculatus), one vegetable (Matelea cordifolia), and one condiment (Capsicum annuum). Priority groups 2-5 were selective for one or two types of food, such as fruits, teas, or seeds. Since group 1 was the most diverse, the FSI and the employed strategy permitted to identify the priority wild edible plant species with the highest potential for food security. The selected six species should be included in the future management program of the reserve as the priority wild edible plants to develop strategies for conservation, sustainable use, and improvement of the local population income. General policies to manage the selected six species are outlined. PMID- 28649009 TI - The need for monetary information within corporate water accounting. AB - A conceptual discussion is provided about the need to add monetary data to water accounting initiatives and how best to achieve this if companies are to become aware of the water crisis and to take actions to improve water management. Analysis of current water accounting initiatives reveals the monetary business case for companies to improve water management is rarely considered, there being a focus on physical information about water use. Three possibilities emerge for mainstreaming the integration of monetization into water accounting: add-on to existing water accounting frameworks and tools, develop new tools which include physical and monetary information from the start, and develop environmental management accounting (EMA) into a water-specific application and set of tools. The paper appraises these three alternatives and concludes that development of EMA would be the best way forward. Suggestions for further research include the need to examine the use of a transdisciplinary method to address the complexities of water accounting. PMID- 28649010 TI - Mussels do not directly assimilate fish farm wastes: Shifting the rationale of integrated multi-trophic aquaculture to a broader scale. AB - Pollution is one of the most significant issues that is currently impeding the development of fish farming. Integrated multi-trophic aquaculture (IMTA) has the potential to reduce the accumulation of organic wastes in the environment by using taxa of lower trophic levels such as filter feeders. However, the capacity of filter feeders to assimilate significant quantities of fish farm wastes has not yet been fully tested in situ. We analyzed the stable isotopes delta13C and delta15N in mussels from six fish farms and from six other areas that were not influenced by fish farming, at two water strata (surface and mid-water) across a marked gradient of eutrophication along more than 900 km of coastline in the Western Mediterranean. We found that the mussels did not directly assimilate fish farming wastes. Consequently, fish farming wastes did not constitute a major component of mussel diet, irrespective of local productivity and depth in the water column. These outcomes do not necessarily mean that IMTA is not suitable in other cases, but rather that there should be a shift in the rationale of IMTA by modifying the concept of direct assimilation of wastes to a more general approach of IMTA based on regional budgets of nutrients. PMID- 28649011 TI - Comparison of techniques to determine human skeletal muscle voluntary activation. AB - Determining volitional activation (VA) can provide insights on the cause of muscle weakness in orthopedic and neurological populations. Two electrical stimulation techniques are traditionally used to quantify VA: interpolation (IT) and superimposition (CAR). IT allows for a more accurate VA estimation, however it requires individuals to be stimulated twice, compared to once for CAR, and thus increases stimulation associated discomfort. To date, there is no agreement on what is the best practical technique for calculating quadriceps VA. This paper aims to address this problem by determining what reference force (i.e., using either peak force or force at the time of stimulation) and type of stimulation (train of pulses (burst), doublet, and twitch) is the best technique to use. Our findings showed that the IT with the force at the time of stimulation as a reference should be used to determine VA and that when a burst was used, the VA ratio computations were more accurate. Additionally, using a twitch with a 2ms pulse duration produced reliable VA calculations and may be an acceptable alternative for pain-sensitive subjects. Accurate assessment of VA deficits can help clinicians design rehabilitation programs that are based on subject-specific strength impairments and are more effective. PMID- 28649012 TI - Small molecule probes of protein aggregation. AB - Understanding the mechanisms of amyloid formation and toxicity remain major challenges. Although substantial progress has been made in the development of methods able to identify the species formed during self-assembly and to describe the kinetic mechanisms of aggregation, the structure(s) of non-native species, including potentially toxic oligomers, remain elusive. Moreover, how fibrils contribute to disease remains unclear. Here we review recent advances in the development of small molecules and other reagents that are helping to define the mechanisms of protein aggregation in molecular detail. Such probes form a powerful platform with which to better define the mechanisms of structural conversion into amyloid fibrils and may provide the much-needed stepping stone for future development of successful therapeutic agents. PMID- 28649013 TI - Online quantitative monitoring of live cell engineered cartilage growth using diffuse fiber-optic Raman spectroscopy. AB - Tissue engineering (TE) has the potential to improve the outcome for patients with osteoarthritis (OA). The successful clinical translation of this technique as part of a therapy requires the ability to measure extracellular matrix (ECM) production of engineered tissues in vitro, in order to ensure quality control and improve the likelihood of tissue survival upon implantation. Conventional techniques for assessing the ECM content of engineered cartilage, such as biochemical assays and histological staining are inherently destructive. Raman spectroscopy, on the other hand, represents a non-invasive technique for in situ biochemical characterization. Here, we outline current roadblocks in translational Raman spectroscopy in TE and introduce a comprehensive workflow designed to non-destructively monitor and quantify ECM biomolecules in large (>3 mm), live cell TE constructs online. Diffuse near-infrared fiber-optic Raman spectra were measured from live cell cartilaginous TE constructs over a 56-day culturing period. We developed a multivariate curve resolution model that enabled quantitative biochemical analysis of the TE constructs. Raman spectroscopy was able to non-invasively quantify the ECM components and showed an excellent correlation with biochemical assays for measurement of collagen (R2 = 0.84) and glycosaminoglycans (GAGs) (R2 = 0.86). We further demonstrated the robustness of this technique for online prospective analysis of live cell TE constructs. The fiber-optic Raman spectroscopy strategy developed in this work offers the ability to non-destructively monitor construct growth online and can be adapted to a broad range of TE applications in regenerative medicine toward controlled clinical translation. PMID- 28649014 TI - Apatite nanoparticles strongly improve red blood cell cryopreservation by mediating trehalose delivery via enhanced membrane permeation. AB - Cryopreservation of red blood cells (RBC) is an important method for maintaining an inventory of rare RBC units and managing special transfusion circumstances. Currently, in a clinical setting, glycerol is used as cryoprotectant against freezing damage. After thawing and before transfusion, glycerol must however be removed to avoid intravascular hemolysis, via a complex and time-consuming deglycerolization process which requires specialized equipment. Improved cryopreservation methods using non-toxic agents are required to increase biocompatibility and decrease processing time. Biocompatible cryoprotectants (e.g. trehalose) were proposed, but their low permeation through RBC membranes limits their cryoprotection efficacy. Herein, we report for the first time a glycerol-free cryopreservation approach, using colloidal bioinspired apatite nanoparticles (NP) as bioactive promoters of RBC cryopreservation mediated by trehalose. Addition of apatite NP in the medium tremendously increases RBC cryosurvival, up to 91% (42% improvement compared to a control without NP) which is comparable to FDA-approved cryoprotection protocol employing glycerol. NP concentration and incubation conditions strongly modulate the NP bioactivity. Complementary experimental and computational analyses of the interaction between apatite NP and model lipid bilayers revealed complex events occurring at the NP bilayer interface. Apatite NP do not cross the bilayer but momentarily modulate its physical status. These changes affect the membrane behavior, and promote the permeation of trehalose and a model fluorescent molecule (FITC). This approach is a new alternative to using toxic glycerol for cells cryopreservation, and the identification of this enhancing no-pore permeation mechanism of apatite NP appears as an original delivery pathway for cryoprotectant agents and beyond. PMID- 28649016 TI - Epileptic seizure detection based on imbalanced classification and wavelet packet transform. AB - PURPOSE: Automatic seizure detection is significant for the diagnosis of epilepsy and the reduction of massive workload for reviewing continuous EEG recordings. METHODS: Compared with the long non-seizure periods, the durations of the seizure events are much shorter in the continuous EEG recordings. So the seizure detection task can be regarded as an imbalanced classification problem. In this paper, a novel method based on the weighted extreme learning machine (ELM) is proposed for seizure detection with imbalanced EEG data distribution. Firstly, the wavelet packet transform is employed to analyze the EEG data and obtain the time and frequency domain features, and the pattern match regularity statistic (PMRS) is used as the nonlinear feature to quantify the complexity of the EEG time series. After that, the EEG feature vectors are discriminated by the weighted ELM. It can assign different weights for the EEG feature samples according to the class distribution, so that to effectively moderate the bias in performance caused by imbalanced class distribution. RESULTS: The metric G-mean which takes into account of both the sensitivity and specificity is used to evaluate the performance of this method. The G-mean of 93.96%, event-based sensitivity of 97.73% and false alarm rate of 0.37/h are yielded on the publicly available EEG dataset. CONCLUSION: The comparison with other detection methods shows the superior performance of this method, which indicates its potential for detecting seizure events in clinical practice. Additionally, much larger amounts of true continuous EEG data will be used to test the proposed method further in the future work. PMID- 28649015 TI - On-command on/off switching of progenitor cell and cancer cell polarized motility and aligned morphology via a cytocompatible shape memory polymer scaffold. AB - In vitro biomaterial models have enabled advances in understanding the role of extracellular matrix (ECM) architecture in the control of cell motility and polarity. Most models are, however, static and cannot mimic dynamic aspects of in vivo ECM remodeling and function. To address this limitation, we present an electrospun shape memory polymer scaffold that can change fiber alignment on command under cytocompatible conditions. Cellular response was studied using the human fibrosarcoma cell line HT-1080 and the murine mesenchymal stem cell line C3H/10T1/2. The results demonstrate successful on-command on/off switching of cell polarized motility and alignment. Decrease in fiber alignment causes a change from polarized motility along the direction of fiber alignment to non polarized motility and from aligned to unaligned morphology, while increase in fiber alignment causes a change from non-polarized to polarized motility along the direction of fiber alignment and from unaligned to aligned morphology. In addition, the findings are consistent with the hypothesis that increased fiber alignment causes increased cell velocity, while decreased fiber alignment causes decreased cell velocity. On-command on/off switching of cell polarized motility and alignment is anticipated to enable new study of directed cell motility in tumor metastasis, in cell homing, and in tissue engineering. PMID- 28649017 TI - Chiral alkylated-aniline as a noninvasive fluorescence sensor: Spectroscopic and molecular modeling studies. AB - Aniline, heterocyclic aromatic amines, and arylamines are known carcinogens. Recently aniline mustard has come into prominence as a novel anticancer agent. In this project, microwave irradiation has been used to synthesize an optically active alkylated aniline namely 2,6-dimethyl-4-(1-(p-tolyl)ethyl)aniline (abbreviated DMPA). The presence of quartet and doublet peaks in NMR and a single chromatogram in HPLC verified that the final product DMPA, prepared from the synthesis reactions, had no major impurities. By using a Lux chiral column in HPLC, two peaks have been detected in the chromatogram, which correspond to two enantiomers of the chiral aniline derivative. Fluorescence spectroscopic measurements on DMPA indicated conspicuous dependence of its emission behavior on the polarity (in terms of the empirical polarity parameter ET(30)) of the homogeneous solvents used, a property important for an optical sensor. The nature of the emission profiles, along with the relevant parameter namely wavelength at emission maximum (lambdaemmax) is used to infer the distribution, binding and microenvironment of the DMPA molecules in human serum albumin protein (HSA). DMPA is weakly fluorescent in aqueous buffer medium, with a dramatic enhancement in the fluorescence emission in the presence of HSA. Molecular modeling studies have been carried out on the two enantiomers (R and S) of DMPA with HSA. The implications of these findings are examined in relation to the potentialities of DMPA as a novel fluorescence sensor for biological systems. PMID- 28649018 TI - Rear foot kinematics when wearing lateral wedge insoles and foot alignment influence the effect of knee adduction moment for medial knee osteoarthritis. AB - Lateral wedge insoles (LWIs) are prescribed for patients with medial knee osteoarthritis to reduce the external knee adduction moment (KAM). However, the biomechanical effects of LWIs are limited in some patients. The purpose of this study was to investigate whether the biomechanical effects of LWIs depend on individual foot alignment and to examine the relationship between change in KAM and changes in foot and ankle biomechanics when wearing LWIs. Twenty-one patients participated in this study. They were categorized into normal or abnormal foot groups based on the foot posture index (FPI). All patients were requested to perform a normal gait under barefoot and LWI conditions. A three-dimensional motion analysis system was used to record 1st and 2nd KAM, knee adduction angular impulse (KAAI), center of pressure displacement, and knee-ground reaction force lever arm. Furthermore, the foot and ankle frontal plane kinematic parameters were evaluated. The 1st KAM was significantly reduced under the LWI condition compared to that under the barefoot condition in the normal foot group. In contrast, there was no significant difference in 1st KAM between both conditions in the abnormal foot group. Decreased rear foot eversion strongly correlated with reduction in the 1st KAM in the normal foot group. These findings suggested that it is helpful to assess individual foot alignment to ensure adequate insole treatment for patients with medial knee osteoarthritis and that decreased rear foot eversion during the early stance phase is significantly involved in the reduction of 1st KAM when wearing LWIs with normal feet. PMID- 28649020 TI - Separation of no-carrier-added astatine radionuclides from alpha-particle irradiated lead bismuth eutectic target: A classical method. AB - Possibility of separation of no-carrier-added (NCA) astatine radionuclides from the bulk lead-bismuth-eutectic (LBE) target was explored in a simple way in the laboratory scale. A LBE target was irradiated by 40MeV alpha-particles delivered from a cyclotron facility, India. Quantitative analysis of the irradiated target indicated the production of 210,209At, 207Po radionuclides in the target matrix. The 210,209At radionuclides were separated by precipitation of bulk Pb, Bi and NCA radiotoxic Po radionuclides. PMID- 28649019 TI - A preliminary study for the production of high specific activity radionuclides for nuclear medicine obtained with the isotope separation on line technique. AB - Radiopharmaceuticals represent a fundamental tool for nuclear medicine procedures, both for diagnostic and therapeutic purposes. The present work aims to explore the Isotope Separation On-Line (ISOL) technique for the production of carrier-free radionuclides for nuclear medicine at SPES, a nuclear physics facility under construction at INFN-LNL. Stable ion beams of strontium, yttrium and iodine were produced using the SPES test bench (Front-End) to simulate the production of 89Sr, 90Y, 125I and 131I and collected with good efficiency on suitable targets. PMID- 28649021 TI - K-edge eliminated material decomposition method for dual-energy X-ray CT. AB - In medical dual-energy CT, projection-domain decomposition is typically used to process the acquired two projection datasets. However, when a high atomic-number contrast-agent is introduced, its K-edge discontinuity challenges this method. In this work, we take advantage of the fact that the contrast agent and its solvent are known in advance and propose to first decompose the attenuation coefficient functions of the contrast agent and its solvent to estimate the attenuation contribution of the K-shell photoelectric. Then, the contribution of the K-edge attenuation to the projection data is eliminated and the problem is decomposed to determine the attenuation coefficient functions of the other biological materials. Numerical experiments are shown to verify that the proposed method can give better results with less artifacts than the result of the direct projection domain decomposition. Moreover, the variances of the decomposition coefficients, which is the index of the noise level of the decomposition coefficient image on the contrast regions, are smaller. PMID- 28649022 TI - A portable RGB sensing gadget for sensitive detection of Hg2+ using cysteamine capped QDs as fluorescence probe. AB - A facile one-pot method was proposed to synthesis cysteamine capped CdTe QDs with a high quantum yield 30%. In the synthesis process, nitrogen protection, ultrasonic treatment, and light irradiation were unnecessary. Additionally, potassium tellurite was used instead of Te powder as Te source, avoiding of the time-consuming Te powder dissolution process. The prepared QDs were found to be Hg2+ sensitive. The detection linear range for Hg2+ was from 5 to 300nM, and the detection limit was calculated to be 1nM. The detection mechanism was mainly ascribed to the electron transfer from cysteamine capped QDs to Hg2+, resulting in a fluorescence quenching phenomenon. In addition, we developed a portable RGB sensing gadget with the QDs as fluorescence probe for Hg2+ detection, and the linear range was from 5 to 200nM. Furthermore, the gadget was applied for Hg2+ detection in tap water sample. The results showed that the average recoveries in real tap water sample were in the range from 97.2% to 115.3%, which indicated that accuracy and precision were satisfactory for practical application requirements. PMID- 28649023 TI - Stability enhanced, repeatability improved Parylene-C passivated on QCM sensor for aPTT measurement. AB - Determination of blood clotting time is essential in monitoring therapeutic anticoagulants. In this work, Parylene-C passivated on quartz crystal microbalance (P-QCM) was developed for the activated partial thromboplastin time (aPTT) measurement. Compared with typical QCM, P-QCM possessed a hydrophobic surface and sensitive frequency response to viscoelastic variations on electrode surface. Fibrin could be adsorbed effectively, due to the hydrophobicity of the P QCM surface. Comparing with typical QCM, the peak-to-peak value (PPV) of P-QCM was increased by 1.94% +/- 0.63%, which indicated enhancement of signal-to-noise ratio. For P-QCM, the coefficient of variation (CV) of frequency decrease and aPTT were 2.58% and 1.24% separately, which demonstrated improvement of stability and reproducibility. Moreover, compared with SYSMEX CS 2000i haematology analyzer, clinical coefficient index (R2) was 0.983. In conclusion, P-QCM exhibited potential for improving stability, reproducibility and linearity of piezoelectric sensors, and might be more promising for point of care testing (POCT) applications. PMID- 28649024 TI - Microfluidic platform integrated with graphene-gold nano-composite aptasensor for one-step detection of norovirus. AB - Noroviruses are a foremost cause of gastroenteritis outbreaks throughout the world. On-site sample processing and detection of the viral clinical samples has always been a problem. This study reports an all-polydimethylsiloxane microfluidic chip integrated with screen-printed carbon electrode for the electrochemical detection of norovirus. The microfluidic chip contained packed silica microbeads zones to filter and enrich the norovirus infected clinical sample. Selective detection of norovirus was accomplished by functionalizing the graphene-gold nanoparticles composite modified carbon electrode with the viral capsid-specific aptamer. Norovirus specific aptamer was tagged with a ferrocene molecule, which acts a redox probe. The interaction of aptamer and norovirus resulted in a decrease in the electrochemical signal from ferrocene. The microfluidic chip and functionalized electrodes were characterized using several microscopic and electrochemical techniques. The optimized microfluidic aptasensor was employed to detect a range of norovirus concentration. Using differential pulse voltammetric analysis, a detection limit of 100 pM with a detection range from 100 pM to 3.5nM for norovirus was obtained. The application of aptasensor was also assessed by detecting norovirus in spiked blood samples. The aptasensor could easily discriminate between the target norovirus and other interfering molecules. The developed microfluidic aptasensor has the potential to be used for point-of-care one-step detection of norovirus in clinical samples. PMID- 28649025 TI - Abeta plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies. AB - Selective detection and staining of toxic amyloid plaques, a potential biomarker present in the Alzheimer's disease (AD) brain is crucial for both clinical diagnosis and monitoring AD disease progression. Herein, we report a coumarin quinoline (CQ) conjugate-based turn-on near-infrared (NIR) fluorescence probe for specific detection of beta-amyloid (Abeta) aggregates. CQ probe is highly sensitive and exhibits ~100-fold fluorescence enhancement in vitro upon binding Abeta aggregates with enhanced quantum yield. Furthermore, the probe has ~10-fold higher binding affinity towards Abeta aggregates (86nM) compared to commonly used Thioflavin T. Most importantly, CQ probe displays unambiguous selectivity towards Abeta aggregates compared to other toxic protein aggregates such as tau, alpha synuclein (alpha-Syn) and islet amyloid polypeptide (IAPP). In addition, CQ is nontoxic to neuronal cells and shows significant blood brain barrier permeability. Remarkably, CQ stains Abeta plaques in human brain tissue over co existing tau aggregates and neurofibrillary tangles (NFTs), which are associated in AD and tauopathies. This is a highly desirable attribute to distinguish AD from tau pathology and mixed dementia. PMID- 28649027 TI - Sample preparation for detection of low abundance proteins in human plasma using ultra-high performance liquid chromatography coupled with highly accurate mass spectrometry. AB - Proteomics is a valuable approach to discover biomarkers in human plasma for early diagnosis. However, detection of biomarkers in the plasma is still challenging because of its large protein content. In our study, we established albumin/IgG depletion methods for identification of low abundance proteins using two commercial kits with additional buffer conditions and various concentrations of cold acetone. Trypsin digestion, desalting, and data-dependent acquisition were also optimized. More than 80% depletion of albumin/IgG was achieved with two commercial kits and 98% depletion of albumin was obtained with 70% cold acetone. Recovery of four reference proteins, BNP (47-76), insulin, cytochrome c, and ubiquitin was obtained in all optimized methods. The best recovery of reference proteins was obtained using the ProteoExtract albumin/IgG removal kit with buffer A (61%-106%). After cold acetone precipitation, three reference proteins were recovered more than 48% except ubiquitin (12%). The number of identified proteins by Mascot was 28, 35, 17, and 34 for ProteoExtract, ProteoPrep, 70%, and 50% cold acetone, respectively. Furthermore, optimized methods detected MS/MS fragmentation patterns of elevated BNP in patient samples with cardiac disease. Our study provides the conditions for efficient biomarker discovery by minimal removing of high abundant proteins. PMID- 28649028 TI - The optimization and establishment of QuEChERS-UPLC-MS/MS method for simultaneously detecting various kinds of pesticides residues in fruits and vegetables. AB - OBJECTIVES: The quality safety supervision and test of agricultural products urgently need a very excellent analytical method with simultaneously detecting many components in order to assess, prevent and control pesticide residues. METHODS: In this research, three fruits and three vegetables produced in Shanghai were selected as the materials, 54 pesticide residues were detected with the ultra-high performance liquid chromatography-tandem mass spectrometric (UPLC MS/MS) method on the basis of optimized QuEChERS method according to different materials properties. RESULTS: The results showed that: all samples were directly extracted by acetonitrile containing 1% (v/v) acetic acid; complex matrix samples were purified by a mixed sorbent of 300mg MgSO4+100mg PSA+100mg C18+0.01g Carb, general matrix samples didn't add Carb, simple matrix samples such as watermelon directly filmed; Chromatographic column was ZORBAX Eclipse Plus-C18 column (3.0mm*150mm, 3.5MUm) at 40 degrees C, the methanol-water of mobile phase at a flow rate of 0.45mL/min by a gradient elution contained 0.1% formic acid and 5mmol/L ammonium acetate and the injection volume was 1MUL. With switching electrospray ion source polarity, [M-H]- and high sensitive [M+Na]+were respectively the precursor ions of eight pesticides and avermectin, [M+H]+ was those of the else 45 pesticides. The detection parameters of multi-reactions monitoring (MRM) with simultaneously positive and negative ions (electron multiplier voltage was 200V) scanning were set as follows: the 310.3kPa of nebulizer pressure, the 300 degrees C of drying gas temperature, the 7L/min of drying gas flow, the 3000V and 3500V of respectively capillary positive and negative voltage. With the optimized method, the calibration curves of 54 pesticides were better linear in 15-500MUg/kg (r >=0.988), the average adding standard recovery rates of 54 pesticides were 73.2%-134.3% except pymetrozine and cyromazine with the relative standard deviations (RSD) of 1.0%-13.8%; the limit of detection (LOD) under three times signal-to-noise ratio (S/N) and limit of quantitative (LOQ) under 10 times S/N were respectively confirmed 0.003 2.000MUg/kg and 0.01-6.67MUg/kg. CONCLUSIONS: The results demonstrated that the optimized "QuEChERS-UPLC-MS/MS method" was a simple, rapid, sensitive, accurate, efficient, economical and safe method that simultaneously detected multiple pesticide residues through one time sample treatment; It had some advantages such as more pesticides per detection, simple and convenient pretreatment and less solvent dosage to be suitable for the quick high-throughput quantitative screening and confirmation of pesticide residues in fruits and vegetables. PMID- 28649026 TI - Proximity hybridization-regulated electrogenerated chemiluminescence bioassay of alpha-fetoprotein via target-induced quenching mechanism. AB - A proximity hybridization-regulated electrogenerated chemiluminescence (PLA-ECL) bioassay was developed for the detection of alpha-fetoprotein (AFP) on basis of the sensitization of gold nanoparticles (AuNPs) and target-induced quenching mechanism. Ru(bpy)32+ was used as ECL signal while ferrocene (Fc) was used as ECL quencher. Ru(bpy)32+ was electrostatically adsorbed into the AuNPs/Nafion film prepared by casting the mixture of Nafion and AuNPs onto the surface of glassy carbon electrode (GCE) to form an ECL platform (Ru(bpy)32+/AuNPs/Nafion/GCE), which displayed strong ECL emissions. A recognition platform was fabricated by self-assembling a capture DNA via thiol-gold bond on the surface of Ru(bpy)32+/AuNPs/Nafion/GCE. After sandwich immunoassay and proximity hybridization assay among capture DNA, AFP, a pair of antibody-oligonucleotide conjugates and a signal probe (DNA-Fc), Fc in DNA-Fc was brought close to the surface of electrode in conjunction with target induced ECL quenching. The ECL intensity decreased with the increasing concentration of the AFP and AFP was monitored with a linear range of 0.05-50ng/mL along with a detection limit of 0.04ng/mL. The ECL bioassay is successfully applied to the detection of AFP in serum samples with one-step recognition, short operating time and good accuracy. This method displays great potential for point-of-care testing and commercial application. PMID- 28649029 TI - Determination of chemical oxygen demand (COD) using an alternative wet chemical method free of mercury and dichromate. AB - Worldwide, the standard methods for the determination of the important wastewater parameter chemical oxygen demand (COD) are still based on the use of the hazardous chemicals, mercury sulfate and chromium(VI). However, due to their properties they are meanwhile classified as "priority pollutants" and shall be phased out or banned in the frame of REACH (current European Chemical Law: Registration, Evaluation, Authorization and restriction of Chemicals) by the European Union. Hence, a new wet-chemical method free of mercury and chromium(VI) was developed. Manganese(III) was used as oxidant and silver nitrate for the removal of chloride ions. The quantification was performed by back titration of manganese(III) with iron(II) as done in the standard method. In order to minimize losses of organic substances during the precipitation of silver chloride, suspended and colloid organic matter had to be separated by precipitation of aluminum hydroxide in a first step. In these cases, two fractions, one of the suspended and colloid matters and a second of the dissolved organic substances, are prepared and oxidized separately. The method was tested with potassium hydrogen phthalate (KHP) as conventional COD reference substance and different types of wastewater samples. The oxidation of KHP was reproducible in a COD range of 20-500 mg/L with a mean recovery rate of 88.7% in comparison to the standard COD method (DIN 38409-41). Also in presence of 1000 mg/L chloride a recovery rate of 84.1% was reached. For a series of industrial and municipal wastewater samples a high correlation (R2 = 0.9935) to the standard method with a mean recovery rate of 78.1% (+/-5.2%) was determined. Even though the results of the new method are not 100% of the standard method, its high correlation to the standard method and reproducibility offers an environmentally benign alternative method with no need to purchase new laboratory equipment. PMID- 28649030 TI - Corrigendum to "Next generation sequencing for whole genome analysis and surveillance of influenza A viruses" [J. Clin. Virol. 79 (2016) 44-50]. PMID- 28649031 TI - Noise detection on ECG based on agglomerative clustering of morphological features. AB - Biosignals are usually contaminated with artifacts from limb movements, muscular contraction or electrical interference. Many algorithms of the literature, such as threshold methods and adaptive filters, focus on detecting these noisy patterns. This study introduces a novel method for noise and artifact detection in electrocardiogram based on time series clustering. The algorithm starts with the extraction of features that best characterize the shape and behaviour of the signal over time and groups its samples in separated clusters by means of an agglomerative clustering approach. The method has been tested in numerous datasets to reveal that it is independent on specific records and globally, the algorithm was able to successfully detect noisy patterns and artifacts with a sensitivity of 88%, a specificity of 92% and an accuracy of 91%, demonstrating a good performance in pattern detection based on morphological clustering. This algorithm can be applied to the detection and sectioning of multiple types of noise for more accurate denoising and adapted for signal classification. PMID- 28649032 TI - A standard mastectomy should not be the only recommended breast surgical treatment for non-metastatic inflammatory breast cancer: A large population-based study in the Surveillance, Epidemiology, and End Results database 18. AB - BACKGROUND: Standard mastectomy has long been the recommended breast surgical treatment for non-metastatic inflammatory breast cancer (IBC). The objective of this population-based study was to evaluate the significance of various breast surgical treatments for this highly aggressive subtype. METHODS: The Surveillance, Epidemiology, and End Results program registry was searched to identify women with non-metastatic IBC receiving standard treatment including breast surgery, radiation therapy and chemotherapy diagnosed between 1998 and 2013. Comparisons of the proportions of various breast surgery procedures over the years were performed using Pearson's chi-square test. Breast cancer-specific survival (BCSS) and overall survival (OS) were estimated using the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. Cox models were then fitted to compare the association between various breast surgical procedures and BCSS or OS after adjusting for patient and tumor characteristics. RESULTS: A total of 3374 cases were identified. Over the years, the proportion of contralateral prophylactic mastectomy (CPM), breast reconstruction and both were increasing. The proportion of implant-based reconstruction was also increasing with no difference in survival compared with other types of reconstruction. There was no statistically significant difference in BCSS or OS among various breast surgery treatments, such as breast conserving surgery, CPM, breast reconstruction and standard unilateral mastectomy. CONCLUSIONS: Breast surgery is of great significance to the clinical outcome of IBC. Standard mastectomy should not be the only recommended breast surgical treatment. PMID- 28649033 TI - Danazol alters mitochondria metabolism of fibrocystic breast Mcf10A cells. AB - Fibrocystic Breast Disease (FBD) or Fibrocystic change (FC) affects about 60% of women at some time during their life. Although usually benign, it is often associated with pain and tenderness (mastalgia). The synthetic steroid danazol has been shown to be effective in reducing the pain associated with FBD, but the cellular and molecular mechanisms for its action have not been elucidated. We investigated the hypothesis that danazol acts by affecting energy metabolism. Effects of danazol on Mcf10A cells homeostasis, including mechanisms of oxidative phosphorylation, cytosolic calcium signaling and oxidative stress, were assessed by high-resolution respirometry and flow cytometry. In addition to fast physiological responses the associated genomic modulations were evaluated by Affimetrix microarray analysis. The alterations of mitochondria membrane potential and respiratory activity, downregulation of energy metabolism transcripts result in suppression of energy homeostasis and arrest of Mcf10A cells growth. The data obtained in this study impacts the recognition of direct control of mitochondria by cellular mechanisms associated with altered energy metabolism genes governing the breast tissue susceptibility and response to medication by danazol. PMID- 28649034 TI - Electrohysterography for uterine monitoring during term labour compared to external tocodynamometry and intra-uterine pressure catheter. AB - OBJECTIVE: Current uterine monitoring techniques have major drawbacks that could be avoided when using electrohysterography for uterine monitoring. Recently, a new electrohysterography method has been developed, providing a real-time tocogram on standard cardiotocography monitors. The diagnostic characteristics of this novel method need to be determined and compared to conventional methods We hypothesised that electrohysterography can perform better than external tocodynamometry due to the adhesive properties of the contact electrodes (less motion sensitive), and the improved signal acquisition through subcutaneous tissue (less obesity sensitive). STUDY DESIGN: In this prospective diagnostic accuracy study, uterine contractions of labouring women were simultaneously monitored by three different monitoring techniques: electrohysterography, external tocodynamometry, and intra-uterine pressure catheter as method of reference. We performed a two-hour measurement during first and/or second stage of term labour. The contractions of each method were automatically detected by a computer-based algorithm. As the applied method had not been described in literature before, an interim analysis was performed to minimise exposure to the invasive pressure catheter. The main outcome parameter was the sensitivity of electrohysterography in comparison to external tocodynamometry for uterine contraction detection, tested by the Wilcoxon signed rank test. RESULTS: Uterine contractions of 48 term labouring women were simultaneously monitored by electrohysterography, external tocodynamometry, and intra-uterine pressure catheter. The study was terminated after the interim analysis as the sensitivity of electrohysterography was significantly higher compared to external tocodynamometry: median 89.5% (interquartile range (IQR); 82-93) and 65.3% (IQR; 53-81) respectively, p<0.001. In a subgroup analysis of obese women (n=15), the sensitivity of electrohysterography was significantly higher than external tocodynamometry (median 88.4% (IQR; 79-95) and 45.8% (IQR; 38-61) respectively, p<0.001). Whereas in a subanalysis of second stage of labour (n=8), electrohysterography did not perform better than external tocodynamometry (median 72.8% (IQR; 61-87) and 66.4% (IQR; 46-75) respectively, p=0.225). Electrohysterography registered 0.4 more contractions per 10min than the intra uterine pressure measurement (p<0.001) and 0.5 more contractions per 10min than external tocodynamometry (p<0.001). CONCLUSION: Electrohysterography has a higher sensitivity for uterine contraction detection than external tocodynamometry during first stage of labour, in non-obese and obese women. Electrohysterography identifies more contractions than conventional techniques. PMID- 28649035 TI - Multifaceted intervention to improve obstetric practices: The OPERA cluster randomized controlled trial. AB - OBJECTIVE: Suboptimal care contributes to perinatal morbidity and mortality. We investigated the effects of a multifaceted program designed to improve obstetric practices and outcomes. STUDY DESIGN: A cluster-randomized trial was conducted from October 2008 to November 2010 in 95 French maternity units randomized either to receive an information intervention about published guidelines or left to apply them freely. The intervention combined an outreach visit with a morbidity/mortality conference (MMC) to review perinatal morbidity/mortality cases. Within the intervention group, the units were randomized to have MMCs with or without clinical psychologists. The primary outcome was the rate of suboptimal care among perinatal morbidity/mortality cases. The secondary outcomes included the rate of suboptimal care among cases of morbidity, the rate of suboptimal care among cases of mortality, the rate of avoidable morbidity and/or mortality cases, and the incidence of, morbidity and/or mortality. A mixed logistic regression model with random intercept was used to quantify the effect of the intervention on the main outcome. RESULTS: The study reviewed 2459 cases of morbidity or mortality among 165,353 births. The rate of suboptimal care among morbidity plus mortality cases was not significantly lower in the intervention than in the control group (8.1% vs. 10.6%, OR [95% CI]: 0.75 [0.50-1.12], p=0.15. However, the cases of suboptimal care among morbidity cases were significantly lower in the intervention group (7.6% vs. 11.5%, 0.62 [0.40-0.94], p=0.02); the incidence of perinatal morbidity was also lower (7.0 vs. 8.10/00, p=0.01). No differences were found between psychologist-backed and the other units. CONCLUSIONS: The intervention reduced the rate of suboptimal care mainly in morbidity cases and the incidence of morbidity but did not succeed in improving morbidity plus mortality combined. More clear-cut results regarding mortality require a longer study period and the inclusion of structures that intervene before and after the delivery room. (ClinicalTrials.gov ID: NCT02584166). PMID- 28649036 TI - All for one and one for all: The value of grassroots collaboration in clinical research. AB - Collaboration in health research is common in current practice. Engaging grassroots clinicians in the evidence synthesis and research process can deliver impactful results and reduce research wastage. The UKARCOG is a group of specialty trainees in obstetrics and gynaecology in the UK aiming to promote women's health research by delivering high-quality impactful research and national audit projects. The collaborative enables trainees to develop essential academic skills and roll out multicentre research projects at high cost effectiveness. Collective research work can face a number of challenges such as establishing a joint authorship style, gaining institutional support and acquiring funds to boost networking and deliver large scales studies. PMID- 28649037 TI - The dynamic effects of obesity on the wages of young workers. AB - This paper considers effects of body mass on wages in the years following labor market entry. The preferred models allow current wages to be affected by both past and current body mass, as well as past wages, while also addressing the endogeneity of body mass. I find that a history of severe obesity has a large negative effect on the wages of white men. White women face a penalty for a history of being overweight, with some evidence of additional penalties that begin above the threshold for severe obesity. Furthermore, the effects of past wages on current wages imply that past body mass has additional, indirect effects on wages, especially for white women. PMID- 28649038 TI - Multiple spectroscopic analyses reveal the fate and metabolism of sulfamide herbicide triafamone in agricultural environments. AB - Triafamone, a sulfamide herbicide, has been extensively utilized for weed control in rice paddies in Asia. However, its fate and transformation in the environment have not been established. Through a rice paddy microcosm-based simulation trial combined with multiple spectroscopic analyses, we isolated and identified three novel metabolites of triafamone, including hydroxyl triafamone (HTA), hydroxyl triafamone glycoside (HTAG), and oxazolidinedione triafamone (OTA). When triafamone was applied to rice paddies at a concentration of 34.2 g active ingredient/ha, this was predominantly distributed in the paddy soil and water, and then rapidly dissipated in accordance with the first-order rate model, with half-lives of 4.3-11.0 days. As the main transformation pathway, triafamone was assimilated by the rice plants and was detoxified into HTAG, whereas the rest was reduced into HTA with subsequent formation of OTA. At the senescence stage, brown rice had incurred triafamone at a concentration of 0.0016 mg/kg, but the hazard quotient was <1, suggesting that long-term consumption of the triafamone containing brown rice is relatively safe. The findings of the present study indicate that triafamone is actively metabolized in the agricultural environment, and elucidation of the link between environmental exposure to these triazine or oxazolidinedione moieties that contain metabolites and their potential impacts is warranted. PMID- 28649040 TI - Oxidative potential of particulate matter 2.5 as predictive indicator of cellular stress. AB - Particulate air pollution being recognized to be responsible for short and long term health effects, regulations for particulate matter with an aerodynamic diameter less than 2.5 (PM2.5) are more and more restrictive. PM2.5 regulation is based on mass without taking into account PM2.5 composition that drives toxicity. Measurement of the oxidative potential (OP) of PM could be an additional PM indicator that would encompass the PM components involved in oxidative stress, the main mechanism of PM toxicity. We compared different methods to evaluate the intrinsic oxidative potential of PM2.5 sampled in Paris and their ability to reflect the oxidative and inflammatory response in bronchial epithelial cells used as relevant target organ cells. The dithiothreitol depletion assay, the antioxidant (ascorbic acid and glutathione) depletion assay (OPAO), the plasmid scission assay and the dichlorofluorescein (DCFH) oxidation assay used to characterize the OP of PM2.5 (10-100 MUg/mL) provided positive results of different magnitude with all the PM2.5 samples used with significant correlation with different metals such as Cu and Zn as well as total polyaromatic hydrocarbons and the soluble organic fraction. The OPAO assay showed the best correlation with the production of intracellular reactive oxygen species by NCI H292 cell line assessed by DCFH oxidation and with the expression of anti-oxidant genes (superoxide dismutase 2, heme-oxygenase-1) as well as the proinflammatory response (Interleukin 6) when exposed from 1 to 10 MUg/cm2. The OPAO assay appears as the most prone to predict the biological effect driven by PM2.5 and related to oxidative stress. PMID- 28649039 TI - PM2.5 exposure in utero contributes to neonatal cardiac dysfunction in mice. AB - OBJECTIVE: Exposure of fine particulate matter (PM2.5) to pregnant dams has been shown to be strongly associated with adverse cardiovascular outcomes in offspring at adulthood, however, effects evident during neonatal periods are unclear. We designed this study to examine cardiac function of neonatal mice (14 days old) exposed to in utero PM2.5. METHODS: Pregnant FVB female mice were exposed either to filtered air (FA) or PM2.5 at an average concentration of 91.78 MUg/m3 for 6 h/day, 5 days/wk (similar to exposure in a large industrial area) throughout the gestation period (21 days). After birth, animals were analyzed at day 14 of life. RESULTS: Fourteen day old mice exposed to PM2.5 during the in utero period demonstrated decreased fractional shortening (%FS, 41.1 +/- 1.2% FA, 33.7 +/- 1.2% PM2.5, p < 0.01) and LVEDd (2.87 +/- 0.08 mm FA, 2.58 +/- 0.07 mm PM2.5, p < 0.05) compared to FA exposed mice. Contractile kinetics and calcium transients in isolated cardiomyocytes from PM2.5 exposed mice illustrated reduced peak shortening (%PS, 16.7 +/- 0.5% FA, 14.7 +/- 0.4% PM2.5, p < 0.01), negative contractile velocity (-dL/dT, -6.91 +/- 0.3 MUm/s FA, -5.46 +/- 0.2 MUm/s PM2.5, p < 0.001), increased time to relaxation 90% (TR90, 0.07 +/- 0.003 s FA, 0.08 +/- 0.004 s PM2.5, p < 0.05), decreased calcium transient amplitude (Delta340/380, 33.8 +/- 3.4 FA, 29.5 +/- 2.8 p.m.2.5) and slower fluorescence decay rate (tau, 0.72 +/- 0.1 s FA, 1.16 +/- 0.15 s PM2.5, p < 0.05). Immunoblotting studies demonstrated alterations in expression of Ca2+ handling proteins- SERCA-2A, p PLN, NCX and CaV1.2 in hearts of 14 day old in utero PM2.5 exposed mice compared to FA exposed hearts. CONCLUSION: PM2.5 exposure during the critical in utero period adversely affects the developing mouse fetus leading to functional cardiac changes that were evident during the very early (14 days) stages of adolescence. These data demonstrated that exposure to PM2.5 during the gestation period significantly impacts cardiovascular outcomes early in life. PMID- 28649041 TI - Determination of the vertical profile of particle number concentration adjacent to a motorway using an unmanned aerial vehicle. AB - A quantitative assessment of the vertical profile of traffic pollution, specifically particle number concentration (PNC), in an open space adjacent to a motorway was possible for the first time, to the knowledge of the authors, using an Unmanned Aerial Vehicle (UAV) system. Until now, traffic pollution has only been measured at ground level while the vertical distribution, is limited to studies conducted from buildings or fixed towers and balloons. This new UAV system demonstrated that the PNC sampled during the period form 10 a.m. to 4 p.m., outside the rush hours with a constant traffic flow, increased from a concentration of 2 * 104 p/cm3 near the ground up to 10 m, and then sharply decreased attaining a steady value of 4 * 103 p/cm3 beyond a height of about 40 m. While more comprehensive investigations would be warranted under different conditions, such as topography and vehicle and fuel type, this finding is of great significance, given that it demonstrates the impact of traffic emissions on human exposure, but less so to pollution within the upper part of the boundary layer. PMID- 28649042 TI - Worldwide human daily intakes of bisphenol A (BPA) estimated from global urinary concentration data (2000-2016) and its risk analysis. AB - To evaluate BPA's potential risk to health, it is important to know human daily intake. This study describes a simple but effective method to estimate the levels of human BPA intake among four different populations based on urinary concentration data. Nationally, of the 30 countries examined, the top ten countries for adult intake were Italy, Sweden, Denmark, France, Cyprus, Australia, Israel, Ghana, Jamaica, and Belgium. When the urinary excretion sample size was large enough and over 1000, it was found that the national estimated BPA daily intakes in the child group among countries, showed a good linear relationship with those of their corresponding adult group. Except the infant group with limited data, the global estimated BPA daily intakes for children and pregnant women were 2 and 1.4 times that of the adult group. Although the national and global estimated BPA daily intakes were generally below the temporary tolerable daily intake (tTDI) recommended by the European Food Safety Authority (EFSA), but some normal individuals' daily intakes exceeded the tTDI. PMID- 28649043 TI - The effects of biodiesels on semivolatile and nonvolatile particulate matter emissions from a light-duty diesel engine. AB - Semivolatile organic compounds (SVOCs) represent a dominant category of secondary organic aerosol precursors that are increasingly included in air quality models. In the present study, an experimental system was developed and applied to a light duty diesel engine to determine the emission factors of particulate SVOCs (pSVOCs) and nonvolatile particulate matter (PM) components at dilution ratios representative of ambient conditions. The engine was tested under three steady state operation modes, using ultra-low-sulfur diesel (ULSD), three types of pure biodiesels and their blends with ULSD. For ULSD, the contribution of pSVOCs to total particulate organic matter (POM) mass in the engine exhaust ranged between 21 and 85%. Evaporation of pSVOCs from the diesel particles during dilution led to decreases in the hydrogen to carbon ratio of POM and the PM number emission factor of the particles. Substituting biodiesels for ULSD could increase pSVOCs emissions but brought on large reductions in black carbon (BC) emissions. Among the biodiesels tested, tallow/used cooking oil (UCO) biodiesel showed advantages over soybean and canola biodiesels in terms of both pSVOCs and nonvolatile PM emissions. It is noteworthy that PM properties, such as particle size and BC mass fraction, differed substantially between emissions from conventional diesel and biodiesels. PMID- 28649044 TI - Quantification and speciation of volatile fatty acids in the aqueous phase. AB - This study lays great emphasis on establishing a reliable analytical platform to quantify and specify volatile fatty acids (VFAs) in the aqueous phase by derivatizing VFAs into their corresponding alkyl esters via thermally-induced rapid esterification (only 10 s reaction time). To this end, reaction conditions for the thermally-induced rapid esterification are optimized. A volumetric ratio of 0.5 at 400 degrees C for VFA/methanol is identified as the optimal reaction conditions to give ~90% volatile fatty acid methyl ester (VFAME) yield. To maintain a high yield of VFAMEs, this study suggests that dilution of the sample to an optimum concentration (~500 ppm for each VFA) is required. Derivatization of VFAs into VFAMEs via the thermally-induced rapid esterification is more reliable to quantify and specify VFAs in the aqueous phase than conventional colorimetric method. PMID- 28649045 TI - Roles of phytoplankton- and macrophyte-derived dissolved organic matter in sulfamethazine adsorption on goethite. AB - Phytoplankton-derived dissolved organic matter (PDOM) and macrophyte-derived dissolved organic matter (MDOM) exist ubiquitously in eutrophic freshwater lakes. To understand the heterogeneous roles of individual fluorescent DOM components in the adsorption of antibiotics onto sediment minerals, the adsorptive fractionation of DOM on goethite (alpha-FeOOH) and its interaction with sulfamethazine (SMT) were investigated using fluorescence excitation-emission matrix combined with parallel factor analysis (EEM-PARAFAC). The affinity sequence for goethite of the 4 fluorescent PARAFAC components followed the order of: tryptophan- > tyrosine- > long emission wavelength (LEW) humic- > and short emission wavelength (SEW) humic-like component. This sequence indicated the preferential adsorption of protein-like substances. Meanwhile, tyrosine-like components can strongly form complexes with SMT with a large binding constant, followed by tryptophan- and SEW humic-like components. However, LEW humic-like component did not effectively react with SMT. The main mechanism of fluorescence quenching between DOM and SMT was static quenching. The result indicated that protein-like substances in DOM were favorable to SMT adsorption by acting as a bridge to form complexes with both goethite surface and SMT molecules, whereas humic-like substances played secondary roles in the DOM-goethite-SMT ternary system. Due to its higher content of protein-like substances, PDOM improved the SMT adsorption on goethite more than MDOM. Therefore, the abundant DOM released from phytoplankton and macrophytes affected the transport of antibiotics to sediments and might eventually change their bioavailability and toxicity to organisms. PMID- 28649046 TI - Transgenerational endocrine disruption and neurotoxicity in zebrafish larvae after parental exposure to binary mixtures of decabromodiphenyl ether (BDE-209) and lead. AB - Polybrominated diphenyl ethers (PBDEs) and heavy metals are two key groups of electric and electronic equipment contaminants. Despite their co-occurrence in aquatic environments, their combined effects remain largely unknown, particularly under a chronic exposure regime. In the present study, adult zebrafish (Danio rerio) were exposed to environmentally relevant concentrations of BDE-209 and lead (Pb), or their binary mixtures, for 3 months. After chronic parental exposure, increased transfer of BDE-209 and Pb to the offspring eggs was activated in the coexposure groups, with BDE-197 being the predominant PBDE congener, indicating the dynamic metabolism of BDE-209 in parental zebrafish. In the presence of Pb, culturing the eggs in clean water until 5 days post fertilization (dpf) further accelerated the debromination of BDE-209 towards BDE 197 in the offspring, caused by the preferential removal of bromine atoms at meta positions. BDE-209 and Pb combinations induced reproductive and thyroid endocrine disruption in adults, which resulted in an imbalanced deposition of hormones in the eggs. However, compared with single chemical exposure, the larval offspring at 5 dpf from the coexposure groups had reversed the adverse influences from maternal origin. In addition, the interaction between BDE-209 and Pb led to transgenerational developmental neurotoxicity in the larval offspring, where inhibited neuronal growth and neurotransmitter signaling, disorganized muscular assembly, and impaired visual function contributed to the observed neurobehavioral deficits. Overall, depending on specific biological events, the complex interaction between BDE-209 and Pb under chronic exposure resulted in significant alterations in their environmental fate and toxicological actions, thus complicating the accurate evaluation of ecological risks and constituting an unquantified threat to environmental safety. PMID- 28649047 TI - High pressure processing improves the tenderness and quality of hot-boned beef. AB - Strip loins from different grades of cattle were subjected to two levels of high pressure processing (HPP) within 1h of slaughter at a commercial meat processing plant and chilled for 1day before freezing. The physical and eating quality characteristics of longissimus thoracis (strip loin) steaks from HPP were compared to meat that was chill aged for 1 or 28days. HPP produced meat after 1day with 60% lower shear force and higher sensory eating quality scores than 1day chill aged meat. Extended chill storage for 28days produced steaks of similar tenderness to HPP meat. HPP also increased the ultimate pH and decreased the cooking loss. Chilled storage of the gluteus medius from prime cattle for 28days significantly improved the shear force by 18%, whilst HPP improved both the shear force by 43% and the sensory eating quality scores. HPP can produce high eating quality eye of rump medallions within 1day of slaughter. PMID- 28649048 TI - An old dichotomy in the space(r) age. PMID- 28649049 TI - Suboptimal agreement between optical coherence tomography and near-infrared spectroscopy for identification of lipid-laden plaque. PMID- 28649050 TI - New light on second-generation drug-eluting stent restenosis. PMID- 28649051 TI - The new pricing policy for coronary stents in India: a boon or a bane? PMID- 28649054 TI - Effect of VKORC1 and CYP2C9 polymorphisms on warfarin dose requirement in Bangladeshi population. AB - Warfarin, an oral anticoagulant is one of the most widely prescribed drugs in modern medicine. Large inter-individuals variability due to age, gender, diet, concurrent drug interactions and variations in CYP2C9 and VKORC1 genes make the management of warfarin therapy challenging and yet no study has been conducted on the Bangladeshi population. The aim of the study was to identify the role of VKORC1 and CYP2C9 polymorphisms in Bangladeshi population in dose requirement of warfarin. We studied 87 heart valve replacement patients who were prescribed warfarin for minimum of 6 months with a target International normalized ratio of 2.0-3.5. Genotyping of VKORC1rs9923231 (-1639 G>A), CYP2C9*2 and CYP2C9*3 was performed by Polymerase Chain Reaction- Restriction Fragment Length Polymorphism. The frequencies of GG, AG and AA genotypes of VKORC1rs9923231 in the studied population were 87.4%, 8%, and 4.6% respectively whereas the frequencies of the CYP2C9*1/3 and CYP2C9*3/3 were 4.6% and 3.4% respectively. The CYP2C9*2 was not found in the studied population. The results of this study indicate that comparatively higher daily maintenance doses of warfarin were required to achieve the target INR for patients carrying both GG genotype of VKORC1rs9923231 and wild type variant of CYP2C9*3 whereas minimum dose were required for patient having AA genotype of VKORC1rs9923231 and *3/*3 variant of CYP2C9. PMID- 28649053 TI - Left atrial appendage occlusion with the AMPLATZER Amulet device: periprocedural and early clinical/echocardiographic data from a global prospective observational study. AB - AIMS: The global, prospective AMPLATZER Amulet observational study documents real world periprocedural, transoesophageal echocardiographic (TEE) and clinical outcomes from left atrial appendage occlusion (LAAO) using the AMPLATZER Amulet device. The aim of this report is to describe the periprocedural and early clinical/TEE results from this study. METHODS AND RESULTS: This multicentre prospective real-world registry included 1,088 patients (75+/-8.5 years, 64.5% male, CHA2DS2-VASc: 4.2+/-1.6, HAS-BLED: 3.3+/-1.1) with non-valvular atrial fibrillation; 82.8% of patients were considered to have an absolute or relative contraindication to long-term anticoagulation and 72.4% had had a previous major bleeding. Periprocedural results, clinical outcomes up to the first three months and the available TEE results from the first scheduled follow-up (one to three months post implant) are reported. Successful device implantation was achieved in 99.0% of patients. During the procedure and index hospitalisation, major adverse events occurred in 3.2% of patients. Patients were discharged on a single antiplatelet agent (23.0%), dual antiplatelets (54.3%) or an oral anticoagulant (18.9%). TEE follow-up 67+/-23 days post procedure in 673 patients showed adequate (<3 mm jet) occlusion of the appendage in 98.2% of patients and device thrombus in 10 patients (1.5%), as evaluated by core laboratory analysis. CONCLUSIONS: This large real-world prospective registry of catheter-based LAAO using the AMPLATZER Amulet device reports a high implant success rate and a low periprocedural complication rate in a population with a high risk of stroke and bleeding. Transoesophageal echo data confirm good closure rates during follow-up and low rates of device-associated thrombus. PMID- 28649055 TI - Lonicera quinquelocularis: A rich source of antioxidant for protection against chronic diseases. AB - The purpose of the research work was to examine the in vitro antioxidant activity of the different aqueous and organic fractions of Lonicera quinquelocularis Hardwicke. The methanol extract was dissolved in distilled water and fractioned with n-hexane, chloroform, ethyl acetate and n-butanol, successively. The antioxidant potential of the remaining aqueous and organic fractions was determined by using 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activity, total antioxidant activity, ferric reducing antioxidant power (FRAP) assay, ferric thiocyanate assay and total phenolics method. Among these fractions ethyl acetate fraction displayed the maximum antioxidant activity with IC50 of (11.13+/-0.12ug/ml). It also exhibited the highest total antioxidant activity (0.595+/-0.00), FRAP value (128.2+/-4.54ug/mL) and total phenolic contents (66.89+/-7.73ug/g) as compared to other organic fractions. Phytochemical investigation of the above mentioned fractions showed the presence of flavanoids, phenolics, terpenoids, sugars, alkaloids, tannins, saponins and cardiac glycosides in appreciable amounts, which have major contribution towards antioxidant activity. PMID- 28649056 TI - Formulation and in vitro evaluation of sustained release matrix tablets using cross-linked natural gum. AB - Polysaccharide gums because of their biocompatibility, biodegradability and non immunogenic properties are considered as the best choice for preparing sustained release tablets as compared to their synthetic counterpart. The cross linking of natural gums in matrix tablets increase the sustained release property of matrix tablets. Isoniazid is a first line therapy of tuberculosis, belongs to BCS I with half-life of 3-4 hours. These characteristics make isoniazid a good candidate for sustained release dosage form. Karaya gum crossed linked with trisodium tri metaphosphate was used as release rate retardant for preparing isoniazid cross linked matrix tablet. Total 8 sustained release formulations were prepared. Both granules and tablets were evaluated under in vitro condition against different parameters. Dissolution studies were performed with all eight formulations for 12 hours using USP apparatus I. Four formulations designated as F1, F2, F3, F4 have drug and karaya gum while other four formulations F5, F6, F7, F8 have drug and crossed linked polymer in ratios of 1:1, 1:2, 1:3 and 1:4 respectively. Dissolution data was analyzed by using different kinetic models. Best fit model for most efficient formulation was zero order while release mechanism was super case I. Formulation 8 showed sufficiently slow release kinetics and about 83% of drug was released in 10 hours, indicating that cross-linked karaya gum proved efficient in preparing sustained release tablets. PMID- 28649057 TI - Isolation and characterization of antimicrobial peptides from healthy male urine. AB - A complex of low-molecular cationic peptides, extracted from human urine by a combination membrane ultrafiltration and weak cation exchange chromatography, was characterized in this study. It provides a simpler solution for the development of novel antimicrobial peptides from biological liquid waste. PMID- 28649058 TI - Buspirone attenuates methylphenidate-induced growth inhibition. AB - Methylphenidate is effective in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults, but its long term use can cause potential adverse effect on growth rate and variable effects on appetite. Previous studies have shown that long term administration of psychostimulant drugs increases the effectiveness of somatodendritic 5-hydroxytryptamine (5-HT)-1A receptors. Repeated administration of buspirone attenuates the effectiveness of somatodendritic 5-HT1A receptors. The present study was designed to test the hypothesis that co-administration of buspirone may attenuate methylphenidate induced effects on growth rate and food intake. Growth rate was calculated weekly in terms of change in body weight as percentage of preceding week's body weight and food intake was calculated weekly by subtracting the amount of food left in the hopper from the amount of food placed in the hopper as % in preceding week mg/gm of body weight after long-term administration of methylphenidate, buspirone and their co-administration. Long term oral administration of methylphenidate at a dose of 2.0 mg/kg/day decrease growth rate, but co-administration of buspirone at a dose of 10 mg/kg/day attenuates effect of methylphenidate on growth rate however food intake was significantly greater in all treated groups after 3 weeks of treatment. It is suggested that buspirone may oppose methylphenidate-induced growth inhibition by decreasing the sensitivity of somatodendritic 5-HT1A receptors. These findings may help to extend future therapeutics in ADHD. PMID- 28649059 TI - Prevention of CCl4 induced hypogonadism with Raphanus sativus seeds in rat. AB - Raphanus sativus seeds are used as condiment and to treat hypogonadism, various ailments of liver and kidneys. The aim of this study was to evaluate the potential protective effects of methanol extract of R. sativus seeds (RSME) against hypogonadism induced with carbon tetrachloride (CCl4) in Sprague-Dawley male rats. Thirty six rats were divided in to six groups with six animals in each. Animals of Group I were control and treated with saline, Group II, III and IV were given orally CCl4 (1 ml/kg bw; 10% in corn oil). Rats of Group III and IV were also simultaneously given RSME at 100 mg/kg bw and 200 mg/kg bw respectively. However, Group V and VI received RSME (100; 200 mg/kg bw, respectively) alone. All treatments were given at alternate days for 15 days. Treatment of CCl4 to rats decreased (P < 0.001) the level of CAT, POD, SOD, GST, GSH-Px and GSR antioxidant enzymes in testes of rat. Concentration of lipid peroxides (TBARS) was increased (P < 0.001) whereas concentration of GSH was decreased (P < 0.001) in testes of CCl4 treated animals. Concentration of testosterone, FSH and LH in serum was decreased (P < 0.001) while the level of estradiol and prolactin was increased (P < 0.001) in CCl4 treated rats. Injuries in seminiferous tubules were determined in histopathology of testes. Administration of RSME, dose dependently, markedly ameliorated the oxidative stress of CCl4 thereby restoring the level of antioxidant enzymes, lipid peroxides, reduced glutathione, male hormones and alterations in histopathology. PMID- 28649060 TI - Antiproliferative effects of selected marine organisms collected from Red Sea. AB - Ten selected marine organisms representing different classes of marine fauna and flora were collected from Saudi Arabia territorial water. They were Antipathes dichotoma, Rumphella sp., Dictoyota dichotoma, Hyrtios erectus, Petrosia sp., Heteroxenia fuscescens, Rumphella aggregata, Sinularia polydactyla, Sarcophyton glaucum, Sarcophyton trocheliophorum. Samples were lyophilized and extracted. Their cytotoxic activity was assessed by determining their IC50's against HepG2, A549 and PC-3 cancer cell lines. The extracts showed variable activities against A549 with IC50 in the range 388.3-0.1ug/mL; HepG2 with IC50 in range 382.5 0.1MUg/ml and PC-3 with IC50 in the range 428.6-0.1ug/mL. Dictoyota dichotoma, Hyrtios erectus, Rumphella aggregata and Sarcophyton glaucum exhibited the highest antiproliferative activity. Therefore, their impact on cell cycle was examined by flow cytometry technique. It was concluded that they cause G0/G1, S phase and G2/M cell cycle arrest. PMID- 28649061 TI - Effect of seaweeds occurring at Karachi coast on mosquito larvae and liver function in rats. AB - Seaweeds have been consumed as human food from thousands of years. In this study ethanol extract of 16 different seaweeds were tested for mosquito larvicidal activity against 4th instar larvae of Aedes aegyptii. The ethanol extracts of Padina pavonia and Sargassum ilicifolium caused 50% mortality at 1200ppm concentration. However other seaweeds Halimeda tuna, Ulva lactuca (Chlorophyta), Dictyota dichotoma var intricata, Jolyna laminariodes, Sargassum binderi (Phaeophyta), Melanothamnus afaqhusainii and Solieria robusta (Rhodophyta) showed LC50 at ~1500 ppm concentration. The n-hexane fraction of Padina pavonia was most potent and produced lethality at minimum concentration (LC50 at 250ppm).The effect of ethanol and water extracts of S. binderii was also examined on liver function of healthy rats. The ethanol extract of Sargassum binderi given orally to rats @ 200mg/kg for 14 days slightly increased the concentration of liver enzymes (ALT, AST, ALP and LDH) and urea level as compared with normal control rats, but did not increase bilirubin, glucose, triglycerides, cholesterol and creatinine. Whereas water extract of S. binderi affected ALT while other biochemical parameters were near normal or slightly decreased as compared to normal control. PMID- 28649062 TI - Antibacterial activity of penicillins alone and in combination with different agents against Staphylococcus aureus. AB - Difficulties in the treatment of the resistant strains of Staphylococcus aureus, which is a frequent cause of nosocomial infections in paediatric patients, has prompted this research to empower the usage of various combinations of penicillin. During the study period 17,452 clinical samples were processed for culture. The positive cultures yielded 564 strains of S. aureus. Out of these, 362 (64.2%) isolates were found to be methicillin sensitive S. aureus (MSSA) and 202 (35.8%) methicillin resistant S. aureus (MRSA). The frequency of S. aureus isolates from male patients (355; 63.1%) was found to be higher than female patients (209; 36.9%) and those from indoor wards (441; 78.2%) were more than the outdoor wards (123; 21.8%). Frequency distribution of S. aureus showed to be highest among blood 342 (60.6%) and cerebrospinal fluid 100 (17.8%) samples. The sensitivity pattern of MSSA with piperacillin-tazobactam was 344 (95.0%), ampicillin-sulbactam 340 (93.9%), co-amoxiclav 332 (91.8%) and ampicillin oxacillin 257 (71.0%). MRSA susceptibility to piperacillin-tazobactam was 143 (71.0%), ampicillin-sulbactam 114 (56.6%), co-amoxiclav 61 (30.2%) and ampicillin cloxacillin 18 (9%). The Cochran Mantel Haenszel test showed that the effectiveness for each penicillin was associated significantly (p<0.05) with both the MSSA and MRSA. The combinations of piperacillin-tazobactam, ampicillin sulbactam, co-amoxiclav and ampicillin-cloxacillin exhibited higher efficacy than using them alone to combat Staphylococcal infections. PMID- 28649063 TI - Isolation of phytoconstituents and evaluation of anticancer and Antioxidant potential of Launaea mucronata (Forssk.) Muschl. subsp. AB - Traditional Medicine is widely used in clinical research due to its low toxicity, low number of side effects, and low cost. Many components of common fruits and vegetables play well-documented roles as chemo preventive or chemotherapeutic agents that suppress tumor genesis. The present study was aimed to identify the DPPH (2, 2-diphenyl-1-picrylhydrazyl) free-radical scavenging constituents from methanol extract of Launaea mucronata using bioassay-guided fractionation. The methanolic extract revealed a strong antioxidant activity, the IC50 values (the concentration with scavenging activity of 50%) was 25.94 mg/ml. The fractionation of the active methanol extract by silica gel column chromatography revealed compounds with strong antioxidant activity. The isolated bioactive compound was determined as, apigenin, quercetin, rutin, isorhamnetin-3-O-beta-glucoside, quercetin-3-O-beta-glucoside, apigenin-7-O- beta-diglucoside, kaempferol-3-o rutinoside), by comparing spectral data (UV, IR, 1H NMR, 13C NMR, and MS) with literature reports. The results obtained confirmed that methanol extract of Launaea mucronata or its derived phytocompounds can be used potentially as a bioactive source of natural antioxidants by contributing beneficial health effects. Launaea mucronata was in vitro investigated for cytotoxic activity against HCT116, HepG2, Hella and MCF-7 cell lines, doxorubicin was used as the reference drug. The results show IC50 19, 19.60, 12.60 and 12.70 MUg/ml respectively. PMID- 28649064 TI - Formulation and Dissolution enhancement of Meloxicam tablets using Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and Povidone in combination. AB - Meloxicam is a poor water soluble drug mostly prescribed in various rheumatic diseases. The present research study was design to formulate and increase the solubility of meloxicam in the tablet dosage form. A 32 full factorial design was employed to optimize meloxicam formulations. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG graft copolymer) and Povidone were taken as independent variables while cumulative drug release at 90 minutes was selected as dependent variable. All trial formulations complied with official standards. Multiple regression by Microsoft Excel on cumulative drug release of the selected formulations (F1, F2, F6- F9) showed the positive effect of PVCL-PVA-PEG graft copolymer (alpha = 0.05) and a negative effect of Povidone (alpha = 0.05). Formulation six (F6) (PVCL-PVA-PEG graft copolymer 3 mg and Povidone 22.5 mg / tablet) was considered as the optimal formulation based on its cumulative drug release. Dissolution kinetics by model dependent analysis predicted Weibull (R2=0.99) as the best fit model in describing meloxicam dissolution kinetics. The role of PVCL-PVA-PEG graft copolymer should be explored with other solubilizers in future studies. PMID- 28649065 TI - Poor adherence with ACE inhibitors is a risk factor of CVA with oral hypoglycemic agents in diabetic patients. AB - Poor adherence with medicine declines the clinical outcome of pharmacotherapy. It may carry serious sequelae especially in case of antihypertensive drugs like cerebrovascular accident (CVA). This study has been planned to find the association of poor adherence with anti-hypertensive with CVA in diabetic and non diabetic patients. One hundred CVA patients who were admitted through Emergency in Abbasi Shaheed hospital, a tertiary care hospital in Karachi, were recruited from Jun 2013 till Dec 2013. The criteria of inclusion was, diagnosed case of CVA, with primary hypertension, availability of patient's therapeutic record, consent of the patient or legal successor/heir. The criteria of exclusion was, secondary hypertension, newly diagnosed primary hypertensive patients and complete adherence with medication. Morisky medication adherence scale was applied. Therapeutic record was accessed. The mean age was 62.15 years with 3:1 male to female ratio. Adherence to medicine was graded < 6. Patients with hypertension were 41 and with diabetes and hypertension were 59. Majority of patients were on monotherapy as compared to polytherapy (62% versus 38%).The mode of therapy was significantly different (P<0.05) in the two groups. ACE Inhibitors, Calcium Channel Blockers, Beta Blockers and other agents were used by 45.16%, 35.48%, 16.12% and 03.24% patients respectively. The aforementioned drugs were used by 57.14%, 33.33% and 09.52% respectively in 21 patients who were on anti-hypertensive and oral hypoglycemic agents. A statistical significant difference (P<0.05) was seen in the case of ACE Inhibitors. Similarly they were used by 42.10%, 39.47% and 18.42% in 38 patients respectively, who were on anti hypertensive and insulin. No statistical significant difference (P>0.05) was seen in any combination (p>0.05). Thus it is concluded that poor adherence with ACE inhibitors may be a risk factor of CVA in diabetic patients using oral hypoglycemic agents. PMID- 28649066 TI - Simultaneous determination and pharmacokinetics of eight ginsenosides by LC-MS/MS after intravenously infusion of 'SHENMAI' injection in dogs. AB - SHENMAI injection, a prescription comprised of Panax ginseng and Ophiopogon japonicas, is being extensively applied in the field of cardio-protection and immune-modulation in China. Ginsenosides are the main active components in SHENMAI injection. In order to capture and analyze the pharmacokinetic profile of major ginsenosides of SHENMAI injection in Beagle dogs, liquid chromatography equipped with electro-spray ionization and tandem mass spectrometry method was applied in simultaneous determination for protopanaxatriol type ginsenoside (Re, Rf, Rg1), protopanaxadiol type ginsenoside (Rb2, Rb1, Rd, Rc) and oleanolic acid type ginsenoside (Ro). A C18 column (150 * 2.1mm, 5MUm) and a linear gradient program were used to achieve chromatographic separation, with 0.02% acetic acid solution and acetonitrile. I.S. and ginsenosides were detected by LC-MS/MS in selective reaction mode. Good linearity spanning 5- 1500ng/mL was achieved with the R2 values higher than 0.99 for all analytes. Limit of quantification of all analytes were 3ng/mL. Intra- and inter-day precisions ranges from 0.47 to15.68 % and accuracies were within the range of 85.27-117.57%. Validated analyzing method was then used in the pharmacokinetic experiment for SMI in dogs. The results showed that the pharmacokinetic profile of protopanaxadiol, protopanaxatriol and oleanolic acid type ginsenoside were significant difference in dogs. Protopanaxadiol type ginsenosides exhibited an extremely higher level of exposure and a much slower elimination process. Whereas protopanaxatriol type ginsenosides were quickly eliminated. We concluded that 20 (S) - protopanaxadiol type ginseno sides could be a potential pharmacokinetic marker of SHENMAI injection. PMID- 28649067 TI - Pharmacognostic and phytochemical studies of Zanthoxylum armatum DC. AB - The pharmacognostic and phytochemical investigations on the leaf, stem bark, and fruit of Zanthoxylum armatum were carried out. Macroscopic study of leaf, stem bark, and fruit of Z. armatum revealed some of the characteristic features like size, shape, color, odor and taste of the crude drug. Distinguishing fragments were identified from the powder drug. Leaf, bark, and fruit powder of this plant have higher values of total, acid insoluble, and water soluble ash as compared to the powder of this plant exhausted with ethanol and n- hexane. Extraction values in methanol were highest for leaves (20.10%) and fruit (11%), while bark showed highest value in chloroform (8.5%). The extractive values varied among other parts with different solvents. Fluorescence analysis of the Z. Armatum leaf, stem bark, and fruit powder with various reagents showed characteristic coloration at day and under UV light. Quantitative phytochemical screening revealed the presence of many bioactive constituents in leaves, such as alkaloids (15.60+/ 0.10 mg/g), sterols (71.60+/-0.10mg/g), saponins (21.57+/-0.12mg/g), tannins (34.43+/-0.21mg/g), phenols (11.66+/-0.33mg/g) and flavonoids (13.68+/-0.66mg/g). Alkaloids (19.60+/-0.10mg/g), sterols (33.83+/-0.29mg/g), saponins (14.78+/ 0.10mg/g), tannins (28.62+/-0.13mg/g), phenols (16.48+/-1.33mg/g) and flavonoids (18.33+/-1.22mg/g) were reported form the bark, while fruits were reported to have alkaloids (25.07+/-0.21mg/g), sterols (164.92+/-0.14mg/g), saponins (28.60+/ 0.10mg/g), tannins (35.5+/-0.5mg/g), phenols (21.68+/-0.44mg/g) and flavonoids (22.8+/-1.33mg/g). Z. armatum is an important medicinal plant, traditionally used for various ailments. This study will be helpful in the future pharmacognostic standardization of this important plant. PMID- 28649068 TI - Expression of four S. pneumoniae type 2 polysaccharide biosynthetic enzymes utilising the endogenous Kex2 protease activity in tobacco. AB - In order to express multisubunit proteins, or to manipulate metabolic pathways in plants it is essential to be able to efficiently express multiple proteins within the same plant cell. To increase the efficiency of multi-protein expression, we demonstrate the use of the Golgi localized Kex2 protease activity in tobacco to process a large polyprotein precursor consisting of four individual protein domains into its individual protein constituents. Four genes encoding enzymes involved in the biosynthesis of S. pneumoniae type 2 polysaccharide were assembled into a single expression cassette as a large polyprotein driven by a single cauliflower mosaic virus (CaMV) 35S promoter. Each of the individual protein domains were separated by three sequential Kex2 protease digestion sites. At the N-terminus a Pr1b signal peptide was incorporated for efficient targeting of the polyprotein to the apoplast. Each individual protein domain was tagged with its own immuno-tag. The construct was used for the transformation of Nicotiana tabacum and stable lines were selected. All four processed proteins could be immunologically detected in protein extracts using Western blotting indicating correct expression and Kex2 processing. Utilisation of the Kex2 protease system represents an efficient way of expressing multiple proteins in the same plant. This method simplifies the transformation procedures, and presents a method for expression of multiple proteins within the same plant. PMID- 28649069 TI - Altered antibacterial activity of Curcumin in the presence of serum albumin, plasma and whole blood. AB - Antibacterial effect is one of the major therapeutic activities of plant-derived Curcumin. This work evaluated the effect of serum albumin, human plasma, and whole blood on the in vitro activity of Curcumin against eight clinical bacterial isolates by standard broth microdilution and plate-counting methods. Toxicological effects of Curcumin towards human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) were also investigated. Curcumin exhibited weak activity against gram-negative bacteria, except Escherichia coli and Shigella flexneri were susceptible and was most active against gram-positive bacteria: Staphylococcus aureus, Streptococcus pyogenes and Enterococcus faecalis. The antibacterial activity was impaired in the presence of bovine serum albumin (BSA), human plasma and whole blood. Curcumin was not toxic to PBMCs and RBCs at 200MUg/mL. Furthermore, Curcumin showed synergistic activity in combination with antibiotics: Ciprofloxacin, Gentamicin, Vancomycin and Amikacin against Staphylococcus aureus. This study demonstrated that the interaction of Curcumin with plasma proteins diminishes its in vitro antibacterial activity. Curcumin derivatives with reduced affinity for plasma protein may improve the bioavailability and antibacterial activities. PMID- 28649070 TI - Elemental analysis of ten plant species at three phenological stages. AB - Livestock rearing is a common practice in Tehsil Takht-e-Nasrati by the locals to earn their livelihood. Low productivity due to poor health of livestock is major consideration in the study area. In order to know whether this low productivity and poor health might be due to poor quality of forage, ten plant species were analyzed for micro mineral quantification at three phenological stages. Mineral compositions of plants are used to diagnose probable deficiencies in food and forage and nutritional status of plants. Comparison among at vegetative stage of test species and micro nutrients showed that the amount of manganese was found high (64.4mg & &Kg-1) in Chrozophora obliqua. Comparison among at reproductive and post reproductive stages of test species and micro nutrients pointed out that the amount of nickel was found high (67.24mg & Kg-1) and (80.4mg & Kg-1) respectively in Vitex trifolia. It is concluded that micro-minerals concentrations available in these forage plants to the grazing livestock were very low, hence this may be, one of the causes responsible for the pitiable health and productivity of the grazing animals in investigated area. PMID- 28649071 TI - Phenolic compounds and antioxidant activity of Calligonum polygonoides stem and buds. AB - In the present study we demonstrate the identification of phenolic compounds and the phenolic contents of the methanol extracts from stem and buds of Calligonum polygonoides with antioxidant activity. Eleven and nine phenolic compounds were identified and quantified from stem and buds, respectively by high-performance liquid chromatography (HPLC). p-Coumaric acid was predominant in stem and gallic acid in buds. In general, the samples with the highest phenolic contents had the highest antioxidant activities. Stem and buds sparked attention due to their high phenolic contents and antioxidant activities. The Results from present study reveal that the C. polygonoides could be considered as a promising source of antioxidant phytochemicals. PMID- 28649072 TI - Investigation of composition extracts, biological activities and optimization of Solanum nigrum L. extraction growing in Iran. AB - Raw materials including medicinal plants are gaining popularity for the production of reliable and safe medicines suitable for human. Response Surface Methodology (RSM) is a collection of mathematical and statistical techniques used for solving the optimization problems. Using the RSM method, compounds, extracts, antioxidant and antibacterial agents of methanol, hexane, chloroform and water extracts of black nightshade (Solanum nigrum) found in Iran, had been studied for this research. GC and GC/MS had been used to determine the composition of the extracts from the aerial parts of S. nigrum. The major components of these varieties are alkane and alkane acid derivatives. The research has shown significant results that the maximum antioxidant activity was achieved in the 2,2 diphenyl-1-picrylhydrazyl (DPPH) test, and significant differences were also observed between the extracts and solvents in this respect (P<0.05, R2adj=99.97%). As regards the antibacterial activity, the chloroform extract has the largest zone of growth inhibition diameter in which the gram-positive bacteria were cultured. PMID- 28649073 TI - Analgesic, anti-inflammatory and antipyretic activity of Salvia moorcroftiana. AB - Salvia moorcroftiana is an herbaceous plant commonly known as "Kallijari" in Pakistan and belongs to the family Lamiaceae. This study was carried out to evaluate its scientific base for its traditional use in pain, fever and inflammation. The powdered plant was extracted by the method of cold maceration using aqueous methanol (70:30) as solvents. Hot plate, flick tail and acetic acid induced writhing test were utilized for analgesic assessment. Anti-inflammatory activity was evaluated by carageenan-induced mice paw edema. Brewer's induced pyrexia was used for the evaluation of antipyretic activity. Non-significant (p<0.01) results as compared to the standard were obtained in all experiments. It was evident from acute toxicity study that plant was non-toxic in nature. It is concluded from the study that plant had the potential to be safely used for pain, fever and inflammation. PMID- 28649074 TI - Neurochemical and behavioral effects of green tea (Camellia sinensis) as observed in animals exposed to restraint stress. AB - Clinical studies on psychiatric patients suggest that life events stress precipitates depression. The possible involvement of 5-Hydroxy tryptamine (5-HT; Serotonin) in depression and other behavioral deficits is also suggested by clinical studies. As a natural stimulant, green tea (Camellia Sinensis) diminishes stress, worry and anxiety, allowing the brain to focus and concentrate better. Previously we have reported that beneficial effects of green tea might be associated with altered levels of 5-HT, which in turn may help in coping with stress. Present study therefore deals with monitoring the behavior and neurochemical profile of single restrained stress in animals previously administered (for 5 weeks) with green tea. Activities in light dark activity box were monitored 1hr post restraint stress. Cumulative food intake values were monitored 24hr post restraint stress. 24hr after restrained stress, rats were decapitated to collect plasma and brain samples. Brain samples were kept stored at -70omicronC until neurochemical analysis by HPLC-EC. Findings illustrate that although food intake was decreased in both green tea- as well as water treated rats, stress-induced anxiogenic effects were attenuated in green tea treated rats. Tone of 5-HT was also normalized in restrained animals. Results suggest beneficial effects of green tea in coping the stressful conditions/stimuli are related to altered 5-HT metabolism. PMID- 28649075 TI - Hypouricemic and nephroprotective effects of total flavonoids from the residue of supercritical CO2 extraction of Humulus lupulus in potassium oxonate-induced mice. AB - Total flavonoids of Humulus lupulus (TFHL) were prepared using ethanol extraction, liquid-liquid partition and purification with polyamide resin. Different dose of TFHL were orally administered to normal and hyperuricemic mice for 7 days. The xanthine oxidase (XOD) inhibitory activity and hypouricemic effects of TFHL on potassium oxonate-induced hyperuricemic mice were examined. The TFHL showed very potent XOD inhibitory activity with IC50=66.8 MUg/mL. At a single oral dose of 100mg/kg TFHL, the serum uric acid levels of hyperuricemic mice significantly decreased (P<0.01) compared with a hyperuricemic control group, and the XOD activity was inhibited by 22%. Moreover, TFHL has a protective role against potassium oxonate-induced renal damage in mice. The results suggested that TFHL could be used as a promising drug or ingredient for treatment of hyperuricemia and gout. PMID- 28649076 TI - Renal clearance and urinary excretion of omeprazole in healthy female volunteers in Pakistan. AB - Omeprazole is a widely prescribed proton pump inhibitor to treat various gastric acid hyper secretion disorders. The present study was designed to evaluate the renal clearance and urinary excretion of omeprazole in eight healthy female volunteers to increase the understanding of the contributing factors such as demographics variability in the renal clearance and urinary excretion of omeprazole under indigenous conditions. The urine and blood samples were collected 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours after oral administration of enteric coated omeprazole (20 mg) and drug concentration in the samples was determined by High Performance Liquid Chromatography (HPLC) with C18 column and UV detector. Urinary excretion and renal clearance of omeprazole was calculated and data was statistically analyzed by using regression/correlation technique. Endogenous creatinine was also measured by reagent kit available in the market. The results indicate that mean diuresis was 0.0172+/-0.0029 ml/min/kg. While the mean values of renal clearance of creatinine and omeprazole were 1.315+/-0.103 and 0.066+/ 0.0042 ml/min. kg, respectively. Whereas, clearance ratio was 0.055+/-0.007 which indicates back diffusion. The cumulative percentage of dose excreted was 6.71+/ 0.358. A significant (p<0.05) negative correlation (r= -0.457) between clearance ratio and urine pH of omeprazole reflecting glomerular filtration reabsorption of drug at kidney tubular level while significant (p<0.05) negative correlation (r= 0.681) between clearance ratio and plasma concentration of omeprazole indicates the involvement of active tubular secretion of drug. It can be concluded that during glomerular filtration, omeprazole diffuse back/reabsorption. Therefore, Urinary excretion of omeprazole in indigenous healthy female subjects was observed to be lower than given in the literature values. PMID- 28649077 TI - Hepatoprotective evaluation of aqueous-ethanolic extract of Capparis decidua (Stems) in paracetamol induced hepatotoxicity in experimental rabbits. AB - Liver diseases are the most common ailment all over the world mostly caused by viruses, toxic chemicals, excessive intake of alcohol, high doses of paracetamol, carbon tetrachloride, chemotherapeutic agents and peroxides oil, etc. There is a great need to assess the scientific basis for the medicinal plants that are claimed to have hepatoprotective activity. We investigate the hepatoprotective effects of aqueous-ethanolic extract of Capparis decidua (Stems) against paracetamol induced liver injury in experimental animals. To observe the level of improvement, biochemical parameters such as SGPT, SGOT, ALP and Total bilirubin levels as well as histopathological changes in liver tissues were studied. Silymarin (50mg/kg, p.o.) was used as reference drug. The levels of the biochemical parameters were increased in rabbits which were intoxicate by paracetamol. Capparis decidua extract (750mg/kg, b.w.) treated rabbits showed maximum reduction of biochemical parameters in a significant (p<0.001) manner. Histopathological examination of the liver tissues of control and treated groups also confirmed the hepatoprotective activity. The phytochemical screening of the extracts revealed the presence of tannins, alkaloids, saponins and flavonoids. The results of the present study therefore suggest that the different doses of Capparis decidua possess significant hepatoprotective effect and this effect might be due to the presence of flavonoids and tannins. PMID- 28649078 TI - 3-(4-chlorophenyl)-[1, 2, 3] oxadiazol-3-ium-5-olate and its 4-formyl analog Ultrasound assisted synthesis and in-vitro anticancer evaluation against human tumor cell lines. AB - The title compound, 3-(4-chlorophenyl)-4-formyl-[1, 2, 3] oxadiazol-3-ium-5-olate 5 was synthesized under ultrasonication by formylation of 3-(4-chlorophenyl)-[1, 2, 3] oxadiazol-3-ium-5-olate 4 and characterized by spectral studies. The ultrasonic method of synthesis was found to be simple, ecofriendly, economical, reduces reaction time and gave good yield when compared with traditional methods of synthesis. Anticancer activity of the compounds were tested against 60 human tumor cell lines and compared with standard drug vincristine sulphate. Compound 5 was found to be active against CNS (SNB-75, %GI=46.71), renal (UO-31, %GI=31.52), non small cell lung (NCI-H522, %GI=25.65), leukemia (MOLT-4, %GI=23.02) human tumor cell lines whereas, compound 4 against breast (MDA-MB-231/ATCC, %GI=19.90, T-47D %GI=16.50, MCF-7 15.10) and ovarian (IGROV1 %GI=19.30, OVCAR-4 %GI=17.90) human tumor cell lines. Compound 5 showed higher cytotoxicity against NCI-H23 cells (non small lung cancer cell panel) as compared to standard drug vincristine sulphate. Further structural modification of these compounds may lead to potent anticancer activity. PMID- 28649079 TI - Cytotoxicity and chromosomal aberrations induced by methanolic extract of Cuscuta reflexa and its pure compounds on meristematic cells of Allium species. AB - Cuscuta reflexa (Convolvulaceae), is commonly known as amarbel or akashbel. In Bangladesh and Nepal some of the tribes use C. reflexa against edema, body ache, cancer, skin infections and liver disorders. Despite its traditional uses there is no information regarding genotoxic effects of either the plant extract or its pure compounds. Methanolic extract of C. reflexa (MECR) and pure compounds derived from it namely, odoroside H, neritaloside, and strospeside, were evaluated in Allium cepa L. and A. sativum L. for their effects on root growth, root apical meristem mitotic index (MI) , and chromosomal aberrations (CAs). In this study, we adopted a new method of calculating percent change in root length. MECR caused a concentration- and time- dependent inhibition in root length at 100 - 10000MUg/ml in A. cepa root. It was accompanied by a subsequent decline in MI which is an indicative of its cytotoxic effect. On the contrary, at low concentrations a significant rise in root length was noticeable. In A. sativum, MECR also reduced the root length having IC50 values ~8 x and 4.3 x lower than A. cepa. A variety of CAs were evident in both Allium systems after treatment with MECR, odoroside H and neritaloside. Thus in MECR, cardenolides glycosides, i.e. odoroside H and neritaloside could be accountable for its genotoxicity. PMID- 28649080 TI - Effects of oral administration of black seed (Nigella sativa) oil on histomorphometric dynamics of testes and testosterone profile in rabbits. AB - The present study was conducted to evaluate the influence of oral administration of black seed (Nigella sativa) oil on histomorphometrical characteristics of testes and testosterone profile in adult rabbits. Twenty adult male rabbits aged seven months were divided into two groups: control and treated. Black seed oil was administrated orally for 60 days at 5ml/kg body weight/day on daily basis in addition to the food and water ad lib to the treated group. Biometric parameters of the testes were recorded immediately after their removal. Tissue samples of testes were processed with paraffin tissue preparation technique. Histometrical parameters of testes were measured with the help of automated image analysis software Image J(r). Serum testosterone concentration was determined with Radioimmunoassay technique. Statistical analysis revealed significant (P<0.05) rise in weight, length, circumference and volume of testis in treated group than control group. The values of histometrical parameters studied viz., thickness of spermatogenic epithelium, diameter and area of seminiferous tubules, diameter of lumen of seminiferous tubules, number of spermatogenic layers of testes and serum testosterone concentration were found significantly (P<0.05) higher in treated group than control group. Based on the data it is conceivable that the oral administration of black seed oil has potential to stimulate testicular function in adult rabbits. PMID- 28649081 TI - Soluble transferrin receptor, Ferritin index in Pakistani population. AB - Inflammation affects the reliability of ferritin. The serum level of transferrin receptor protein (sTfR) represents true demand of iron in the body. This study attempts to identify levels of sTfR and correlate the trends of sTfR/ferritin index with BMI in the population of Karachi. 132 gender matched volunteers between the ages of 20-60 years were recruited for this cross-sectional study. BMI was calculated using the formula: (weight in kg / height in m2). Following groups were made according to South Asian criteria of BMI; Group A: normal weight (18.0-22.9 kg/m2), Group B: overweight (23.0-24.9 kg/m2), Group C: obese (>25.0 kg/m2). Serum ferritin, sTfR and CRP levels were determined using ELISA kits. Statistical comparisons were performed using Mann Whitney U and Spearman's rank correlation, where p<0.05 was considered significant. The results identified increased in TIBC, sTfR, ferritin and CRP in obese as compared to normal weight individuals (p<0.001). sTfR/ferritin ratio was 0.822 which signifies increased risk of acute myocardial infarction in group C. Serum iron (r=-0.359,p=0.004) showed negative correlation with BMI while serum ferritin (r=0.237,p< 0.001) and sTfR (r=0.263,p= 0.036) levels were positively associated to BMI. This study highlights a novel finding that sTfR is most likely a better clinical measure of iron status in inflammatory conditions as its expression is effected by erythropoiesis and not by inflammation. Risk of Acute myocardial infarction can also be predicted by increased sTfR/ferritin ratio. PMID- 28649082 TI - Short Communication - Study on quality and efficacy of commercial tylosin and doxycycline products against local isolates of mycoplasma in broilers. AB - The present study was conducted to investigate the quality and efficacy of commercially available preparations of tylosin and doxycycline available in the local market at Peshawar for poultry. In vitro and in vivo, tests were conducted to check the quality of these antimicrobial drugs. In vitro quality control test was performed by High performance liquid chromatographic (HPLC) and micro dilution method. In vivo, efficacy of the test drugs was checked in broilers infected with Mycoplasma gallisepticum. Results of HPLC indicated that test drug 2 contains doxycycline hydrochloride within specified limits but contain high quantity of active ingredient (Tylosin tartrate 120%). Recovery percentage of test drugs (3, 4, 5) were below the pharmacopoeial limit, which contained low quantity of tylosin tartrate (85%, 87.5%, 85%) respectively however, percent recovery of doxycycline were in the appropriate limits. All the tested drugs were effective against Mycoplasma gallisepticum and showed minimum inhibitory concentration (MIC) at 1.9MUg/ml. The in vivo result indicated that all tested drugs decreased morbidity and mortality in infected chicks. The birds treated with test drugs (3 and 5) showed mortality of 9.5%, which was slightly higher than the other test groups. The current study suggested that there are incidences of substandard drugs in Pakistan and the drug regularity authorities should take strict actions against the manufacturing companies. PMID- 28649083 TI - Report - Prevalence of hospital acquired Burkholderia cepacia infection and its antimicrobial susceptibility in a Chinese hospital. AB - This study aimed to investigate antimicrobial susceptibility of hospital acquired Burkholderia cepacia infection in Shanxi (China) during August 2009 and December 2012. To characterize an emerging nocosomial infection. The medical records of 112 patients that were tested positive for B. cepacia were retrospectively analyzed. The K-B disk diffusion method was used to determine the drug susceptibility of the isolated strains. A hundred and fifty strains of B. cepacia were isolated from 112 patients. The sensitivity rates of B. cepacia to meropenem, imipenem, cotrimoxazole, minocycline and ceftazidime were 65.7%, 14.3%, 76.0%, 68.1% and 74.1%, respectively. All patients suffered from more than two underlying diseases, 89 (79.5%) from another bacterial infection and 92 (82.1%) with indwelling catheter. All patients were given antibiotics, including 62 patients that received carbapenem antibiotics. The average duration of hospitalization before detection of B. cepacia was 31+/-24 days, after which 65 patients (58.0%) improved, 22 (19.0%) died, 8 (7.1%) quit the therapy, and 17 (15.2%) were discharged after full recovery. The prevalence of hospital acquired B. cepacia infection and drug-resistance in the hospital is reported and risk factor exploration requires further study. PMID- 28649084 TI - Malignancy rate of focal thyroid incidentaloma detected by FDG PET-CT: results of a prospective cohort study. AB - OBJECTIVE: To evaluate the malignancy rate of focal thyroid incidentaloma (fTI) in a population of patients undergoing a 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) for a non-thyroid purpose. DESIGN: We conducted a prospective cohort study from January 2013 to November 2014. All consecutive patients referred for a FDG PET-CT were prospectively screened. Patients with known neoplastic thyroid disease were excluded from the analysis. All patients presenting one or more fTI and who accepted to benefit from a complementary thyroid ultrasonography (US) were included and managed according to the French endocrine society consensus. Prevalence of fTI in our population and malignancy rate was assessed. RESULTS: During the inclusion period, 10,171 patients were referred for a FDG PET-CT in our center. Fifty-three patients presenting a known thyroid disease were excluded. Among the remaining 10,118 patients, 127 (1.3%) with 131 fTI were individualized. US could not be performed in 37 patients. The remaining 90 patients (92 fTI) were explored by US +/- fine needle aspiration biopsy (FNAB). US results demonstrated a nodule aspect in 80 cases of which 60 benefited from FNAB. Nineteen of 92 fTI underwent surgery with 10 malignant lesions among the 60 patients performing both US and FNAB. CONCLUSION: The prevalence of fTI discovered on FDG PET-CT in our population was 1.3% with 10 malignant lesions among the 60 patients performing both US and FNAB. PMID- 28649085 TI - A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia. AB - Mutation in the insulin-like growth factor-1 receptor (IGF1R) gene is a rare cause for intrauterine and postnatal growth disorders. Patients identified with IGF1R mutations present with either normal or impaired glucose tolerance. None of the cases described so far showed hypoglycemia. We aimed to identify the genetic basis for small for gestational age, short stature and hypoglycemia over three generations in one family. The proband, a 9-year-old male, presented in infancy with recurrent hypoglycemic episodes, symmetric intrauterine growth retardation and postnatal growth retardation. Blood DNA samples from the patient, his parents, a maternal sister and maternal grandmother underwent Sanger sequencing of the IGF1R gene. Primary skin fibroblast cultures of the patient, his mother and age- and sex-matched control donors were used for gene expression and receptor functional analyses. We found a novel heterozygous mutation (c.94 + 1g > a, D1105E) affecting the splicing site of the IGF1R mRNA in the patient, his mother and his grandmother. Primary fibroblast cultures derived from the patient and his mother showed reduced proliferation and impaired activation of the IGF1R, evident by reduced IGF1R and AKT phosphorylation upon ligand binding. In conclusion, the newly identified heterozygous missense mutation in exon 1 of IGF1R (D1105E) results in impaired IGF1R function and is associated with small for gestational age, microcephaly and abnormal glucose metabolism. Further studies are required to understand the mechanisms by which this mutation leads to hypoglycemia. PMID- 28649086 TI - Early Life Risk Factors for Incident Atrial Fibrillation in the Helsinki Birth Cohort Study. AB - BACKGROUND: Early life risk factors are associated with cardiometabolic disease, but have not been fully studied in atrial fibrillation (AF). There are discordant results from existing studies of birth weight and AF, and the impact of maternal body size, gestational age, placental size, and birth length is unknown. METHODS AND RESULTS: The Helsinki Birth Cohort Study includes 13 345 people born as singletons in Helsinki in the years 1934-1944. Follow-up was through national registries, and ended on December 31, 2013, with 907 incident cases. Cox regression analyses stratified on year of birth were constructed for perinatal variables and incident AF, adjusting for offspring sex, gestational age, and socioeconomic status at birth. There was a significant U-shaped association between birth weight and AF (P for quadratic term=0.01). The lowest risk of AF was found among those with a birth weight of 3.4 kg (3.8 kg for women [85th percentile] and 3.0 kg for men [17th percentile]). High maternal body mass index (>=30 kg/m2) predicted offspring AF; hazard ratio 1.36 (95% CI 1.07-1.74, P=0.01) compared with normal body mass index (<25 kg/m2). Maternal height was associated with early-onset AF (<65.3 years), hazard ratio 1.47 (95% CI 1.24-1.74, P<0.0001), but not with later onset AF. Results were independent of incident coronary artery disease, hypertension, or diabetes mellitus. CONCLUSIONS: High maternal body mass index during pregnancy and maternal height are previously undescribed predictors of offspring AF. Efforts to prevent maternal obesity might reduce later AF in offspring. Birth weight has a U-shaped relation to incident AF independent of other perinatal variables. PMID- 28649087 TI - Acute Hemodynamic and Tissue Effects of Cryoballoon Ablation on Pulmonary Vessels: The IVUS-Cryo Study. AB - BACKGROUND: Cryoballoon-based pulmonary vein isolation (CB-PVI) has been widely used for the treatment of atrial fibrillation. Although generally safe and effective, the procedure may be associated with pulmonary vein (PV) stenosis and bronchial or esophageal injury. The mechanisms leading to these complications have not been studied in detail. Our aim was to examine acute effects of cryoballoon on the pulmonary vessel and right heart pressures as well as PV wall morphology. METHODS AND RESULTS: In 8 patients (5 men, mean age 55+/-14 years) undergoing CB-PVI, pressure in each PV was measured by catheter located inside the PV directly before and after CB-PVI. The right atrial, right ventricular, and pulmonary artery pressures as well as pulmonary arterial wedge capillary pressure in the pulmonary artery branch corresponding to target PV were also measured. Morphological changes in PVs were assessed using intravascular ultrasonography.There were no significant differences in PV pressures before and after ablation. The pulmonary arterial wedge capillary pressure significantly increased during cryoapplication (left superior: 20+/-10 versus 29+/-8.5 mm Hg, P=0.004; left inferior: 24+/-10 versus 32+/-6 mm Hg, P=0.012; right superior: 25+/-9 versus 35+/-10 mm Hg, P=0.002; right inferior: 24+/-10 versus 37+/-12 mm Hg, P=0.0036). The right atrial and pulmonary artery pressures increased significantly after CB-PVI (9+/-6 versus 13+/-8 mm Hg, P=0.004, and 20+/-9 versus 24+/-10 mm Hg, P=0.048, respectively). Intravascular ultrasonography showed acute edema and dissection-like changes causing relative lumen narrowing in 90% of PVs. CONCLUSIONS: CB-PVI causes significant rise in pulmonary artery and right atrial pressures as well as PV wall damage. The clinical significance of these findings warrants further investigations. PMID- 28649090 TI - MiRNA-143 mediates the proliferative signaling pathway of FSH and regulates estradiol production. AB - MicroRNAs (MiRNAs) play important regulatory roles in many cellular processes. MiR-143 is highly enriched in the mouse ovary, but its roles and underlying mechanisms are not well understood. In the current study, we show that miR-143 is located in granulosa cells of primary, secondary and antral follicles. To explore the specific functions of miR-143, we transfected miR-143 inhibitor into primary cultured granulosa cells to study the loss of function of miR-143 and the results showed that miR-143 silencing significantly increased estradiol production and steroidogenesis-related gene expression. Moreover, our in vivo and in vitro studies showed that follicular stimulating hormone (FSH) significantly decreased miR-143 expression. This function of miR-143 is accomplished by its binding to the 3'-UTR of KRAS mRNA. Furthermore, our results demonstrated that miR-143 acts as a negative regulating molecule mediating the signaling pathway of FSH and affecting estradiol production by targeting KRAS. MiR-143 also negatively acts in regulating granulosa cells proliferation and cell cycle-related genes expression. These findings indicate that miR-143 plays vital roles in FSH-induced estradiol production and granulosa cell proliferation, providing a novel mechanism that involves miRNA in regulating granulosa cell functions. PMID- 28649089 TI - Prognostic Nutritional Index and the Risk of Mortality in Patients With Acute Heart Failure. AB - BACKGROUND: Nutritional status has been related to clinical outcomes in patients with heart failure. We assessed the association between nutritional status, indexed by prognostic nutritional index (PNI), and survival in patients hospitalized for acute heart failure. METHODS AND RESULTS: A total of 1673 patients (age 76+/-13 years, 68% men) hospitalized for acute heart failure in a tertiary medical center were analyzed. PNI was calculated as 10*serum albumin (g/dL)+0.005*total lymphocyte count (per mm3). National Death Registry was linked to identify the clinical outcomes of all-cause and cardiovascular death. With increasing tertiles of PNI, age and N-terminal probrain natriuretic peptide decreased, and body mass index, estimated glomerular filtration rate, and hemoglobin increased. During a mean follow-up duration of 31.5 months, a higher PNI tertile was related to better survival free from all-cause and cardiovascular mortality in the total study population and in participants with either reduced or preserved left ventricular ejection fraction. After accounting for age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, serum sodium level, and on-admission systolic blood pressure, PNI was independently associated with cardiovascular death and total mortality (hazard ratio per 1 SD of the natural logarithm of the PNI: 0.76 [95% CI, 0.66-0.87] and 0.79 [95% CI, 0.73-0.87], respectively). In subgroup analyses stratified by age, sex, left ventricular ejection fraction, body mass index, or estimated glomerular filtration rate, PNI was consistently related to mortality. CONCLUSIONS: PNI is independently associated with long-term survival in patients hospitalized for acute heart failure with either reduced or preserved left ventricular ejection fraction. PMID- 28649088 TI - Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury. AB - BACKGROUND: Despite recent improvements in angioplasty and placement of drug eluting stents in treatment of atherosclerosis, restenosis and in-stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor AGGF1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury. METHODS AND RESULTS: AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1+/- mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet-derived growth factor BB-induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs to the synthetic phenotype by countering the inhibitory effect of platelet derived growth factor-BB on SRF expression and the formation of the myocardin/SRF/CArG-box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet-derived growth factor-BB-induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1. CONCLUSIONS: AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1-MEK1/2 ERK1/2-Elk-myocardin-SRF/p27 signaling pathway. PMID- 28649091 TI - The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations. PMID- 28649094 TI - Current management of pregnancy-associated breast cancer. AB - Pregnancy-associated breast cancer is the most common malignancy during pregnancy with an expected rise in incidence. The belief in the need for termination of pregnancy and that chemotherapy is contra-indicated during pregnancy is challenged by recent evidence. Patients can consider breast-conserving surgery and sentinel lymph node biopsy with acceptably low fetal risk from radiation exposure. A range of chemotherapeutics is possible in the second trimester in terms of drug class and frequency. Hormonal therapy and monoclonal antibody therapy are contra-indicated during pregnancy and lactation. Fetal outcome after in-utero exposure to chemotherapy appears similar to that in a non-pregnant population. Future pregnancy, in most situations, does not appear to be contra indicated but a multidisciplinary and patient-centred approach is recommended. Fertility preservation techniques are also being developed with reported success and consequent pregnancies. PMID- 28649092 TI - Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas. AB - Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however, its role in pituitary tissue has never been investigated. In order to validate the role of AHR in PA behaviour, further functional studies were undertaken. Over-expression of AHR in GH3 cells revealed a tumour suppressor potential independent of exogenous ligand activation by benzo alpha-pyrene (BalphaP). Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BalphaP-stimulated AHR reduced E2F-driven transcription and altered expression of cell cycle regulator genes, thus increasing the percentage of cells in G0/G1 phase and slowing the proliferation rate of GH3 cells. Co immunoprecipitation confirmed the interaction between AHR and retinoblastoma (Rb1) protein supporting this as a functional mechanism for the observed reduction. Endogenous Ahr reduction using silencing RNA confirmed the tumour suppressive function of the Ahr. These data support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands. PMID- 28649095 TI - The detection of hepatocellular carcinoma (HCC) from patients' breath using canine scent detection: a proof-of-concept study. AB - : Patients with hepatocellular carcinoma (HCC) have poor outcomes as a result of late detection of the disease. We investigated the possibility of using smell detection by dogs for detecting HCC from the breath of patients. Patients whose diagnosis of HCC was confirmed histologically or radiologically according to the American Association for the Study of Liver Diseases criteria had breaths collected using face masks and transported to the study test site. The numbering of the HCC samples was sent in a sealed envelope to blind the dog trainer during testing but allow for correct rewarding of the dog afterwards. One golden retriever was trained to detect HCC with positive feedback using known samples of HCC and healthy controls in a step-wise manner. The controls were selected from hospital staff and relatives of patients who were not involved in the study. They were questioned about the risks of their disease before selection. When the trainer was confident that the dog could recognize the HCC scent, blind testing was performed using 1 HCC : 3 healthy controls per test run. Once the dog signaled on a specimen, it was given a reward. The correct-detection rate was compared to the theoretical detection rate expected based on chance of 25% using the statistical one-sample test of proportions. Thirty-seven HCC patients were tested. The patients had a mean age of 58 years and 21/37 were male. Seventeen patients had hepatitis B and 14 patients had hepatitis C. Twenty-six patients had one HCC lesion; four patients had two lesions in the liver, whilst seven had many lesions. The number of patients in the very early, early, intermediate, advanced, and terminal stages of the Barcelona Clinic Liver Cancer classification was 5, 9, 21, 1, and 1, respectively. The dog detected correctly in 29 runs. The sensitivity for canine detection was 78% (95% CI: 62%-90%). Compared to the 25% correct indication expected based on chance, this was statistically significant (p < 0.001). CONCLUSION: This is the first study to look at the possibility of detecting HCC from breath using canine olfaction. Our results show that this is possible with an accuracy of 78% (p < 0.001 when compared to chance alone), and are thus a proof of concept. Further refinement of the process of detection will be needed before clinical application. PMID- 28649093 TI - NTL8 Regulates Trichome Formation in Arabidopsis by Directly Activating R3 MYB Genes TRY and TCL1. AB - The NAM, ATAF1/2, and CUC (NAC) are plant-specific transcription factors that regulate multiple aspects of plant growth and development and plant response to environmental stimuli. We report here the identification of NTM1-LIKE8 (NTL8), a membrane-associated NAC transcription factor, as a novel regulator of trichome formation in Arabidopsis (Arabidopsis thaliana). From an activation-tagged Arabidopsis population, we identified a dominant, gain-of-function mutant with glabrous inflorescence stem. By using plasmid rescue and RT-PCR analyses, we found that NTL8 was tagged; thus, the mutant was named ntl8-1 Dominant (ntl8-1D). Recapitulation experiment further confirmed that the phenotype observed in the ntl8-1D mutant was caused by elevated expression of NTL8 Quantitative RT-PCR results showed that the expression level of the single-repeat R3 MYB genes TRIPTYCHON (TRY) and TRICHOMELESS1 (TCL1) was elevated in the ntl8-1D mutant. Genetic analyses demonstrated that NTL8 acts upstream of TRY and TCL1 in the regulation of trichome formation. When recruited to the promoter region of the reporter gene Gal4:GUS by a fused GAL4 DNA-binding domain, NTL8 activated the expression of the reporter gene. Chromatin immunoprecipitation results indicated that TRY and TCL1 are direct targets of NTL8. However, NTL8 did not interact with SQUAMOSA PROMOTER BINDING PROTEIN LIKE9, another transcription factor that regulates the expression of TRY and TCL1, in yeast and plant cells. Taken together, our results suggest that NTL8 negatively regulates trichome formation in Arabidopsis by directly activating the expression of TRY and TCL1. PMID- 28649096 TI - [Aging and homeostasis. Aging of bone.] AB - Quantitative as well as qualitative bone loss occurs with aging in both men and women, leading to alterations in skeletal microarchitecture and increased fracture incidence. Sex steroids, primarily estrogen and testosterone, have been shown to play a central role in the aging process of bone. The relationship between diminishing estrogen levels in women caused by ovarian failure and the development of postmenopausal osteoporosis is widely recognized. Unexpectedly, bone mineral density at various skeletal sites in men is also better correlated with circulating levels of bioavailable estrogen than with testosterone. Recently, it is also suggested that senescent osteocytes and their senescence associated secretory phenotype may contribute to age-related bone loss. Osteoporosis should be considered as a disease developing on the basis of the natural aging process which is modified to some degree by various genetic and environmental factors. PMID- 28649097 TI - [Aging and homeostasis. Aging of skeletal muscle.] AB - With aging, insulin resistance and sarcopenia in skeletal muscle are induced, resulting in skeletal muscle aging. It is suggested that the former is one of the reasons that mitochondrial function decreases with aging, and the latter is due to endocrinologic dysfunction, neurological mechanism, nutritional deficiency and inactivity such as waste are complicatedly involved. Also, as sarcopenia progresses, the amount of physical activity further decreases, and it is also assumed that insulin resistance and sarcopenia progress synergistically. It is suggested that exercise enhances the activity and amount of mitochondria and works preventively against insulin resistance in skeletal muscle accompanying aging and it also works for prevention and amelioration of sarcopenia. On the other hand, as for nutritional supplementation, it has been reported that it works for improving sarcopenia by amino acid ingestion. PMID- 28649098 TI - [Aging and homeostasis. Aging of articular cartilage and chondrocytes.] AB - Articular cartilage is an important structure contributing to shock absorption and joint lubrication. Aging and trauma cause loss of function of articular cartilage, resulting in osteoarthritis(OA). Chondrocyte, the only type of the cell that resides in the articular cartilage. Recent studies have revealed that aging-associated changes in chondrocytes are important causative factors of OA. This review describes various mechanism and factors involved in aging of articular cartilage and chondrocytes. PMID- 28649099 TI - [Aging and homeostasis. Calcium metabolism and aging.] AB - About 99% of total body calcium is present in bone. Therefore, negative calcium balance usually means reduction of bone mass. Negative calcium balance is induced by aging from several mechanisms such as reduced renal production of 1,25 dihydroxyvitamin D[1,25(OH)2D], intestinal resistance to 1,25(OH)2D and increased renal excretion of calcium. However, it is largely unknown how calcium balance is physiologically maintained. PMID- 28649100 TI - [Aging and homeostasis. Sex hormones and aging.] AB - The decline in sex hormones along with aging is suggested to be involved in age associated diseases such as cardiovascular diseases, osteoporosis, and dementia. The decrease of estrogen level after menopause is related to osteoporosis in addition to climacteric disturbance in women, while that of testosterone to sarcopenia, osteoporosis and late-onset hypogonadism in men. New treatment strategy is expected for targeting age-associated diseases against the decreased level of sex hormones. PMID- 28649101 TI - [Aging and homeostasis. Circadian rhythms and aging.] AB - Daily rhythms of physiological and behavioral processes such as sleep and arousal are controlled by the circadian clock. The expression of the clock genes oscillate rhythmically in daily manner, and this clock oscillator resides in almost all of the cells in the body. The circadian clock entrains to diurnal environmental changes by using light and food intake as external time cues. Timing of feeding and fasting strongly affects daily rhythms in the expression of circadian clock genes and key regulators of nutrient homeostasis. Understanding roles of the clock oscillator system and feeding-fasting cycles lets us recognize the importance of timing of feeding, ultimately to adjust the aging-related changes in circadian rhythms. PMID- 28649102 TI - [Aging and homeostasis. Chronic inflammation and aging.] AB - Chronic inflammation is one of the common pathological bases underlying aging and aging-related diseases. Recently, it was reported that complement C1q, a crucial regulator of innate immunity, is deeply involved in the pathogenesis of aging related sarcopenia, heart failure, and hypertension-induced aortic remodeling. In this review, the role and function of chronic inflammation in aging and aging related diseases will be summarized. PMID- 28649103 TI - [Aging and homeostasis. Biomedical Peculiarities of Semi-supercentenarians.] AB - Semi-supercentenarians, or people who reach 105 years of age, are regarded as model cases for 'successful ageing'. Semi-supercentenarians maintain capability and cognition for longer than the centenarians who died between 100-104 years of age, together with postponed frailty or age-related diminution of multiple organ reserve. Understanding the biological factors determining extreme longevity and compression of morbidity might help to achieve extended healthy life span for the wider population. PMID- 28649104 TI - [Aging and homeostasis. Development of novel AdipoR-targeted drugs with exercise mimicking and anti-aging properties.] AB - We have so far clarified that adiponectin, an adipocyte-secreted physiologically active substance, is decreased with the onset of obesity and that lifestyle related diseases are primarily accounted for by the systemically decreased action of adiponectin/adiponectin receptors(AdipoRs). The activation of adiponectin/AdipoR has caloric restrictive and exercise-mimicking effects thus prolonging lifespan. We were the first in the world to succeed in identifying small-molecule compounds that serve as seed compounds for candidate AdipoR activating drugs. Moreover, we have also reported the crystal structures of AdipoRs. It is hoped that these milestones will accelerate our efforts at AdipoR structure-based drug discovery leading to the development of novel AdipoR targeted anti-diabetic drugs with promising life-prolonging properties. PMID- 28649105 TI - [Aging and homeostasis. Age-associated diseases and clinical application of NMN(Nicotinamide Mononucleotide).] AB - Sirtuins are NAD+-dependent deacetylase and have drawn much attention as important regulators of aging and longevity. Because NAD+ decline during the aging process, the approach to regulating aging using NAD+ precursor such as nicotinamide mononucleotide (NMN) to replenish cellular NAD+ through the activation of sirtuins have been investigated. In various animal models, NMN has been shown to mitigate age-associated physiological changes in liver, adipose tissue, muscle, pancreas, kidney, retina, and central nerve system. In animal models of metabolic diseases, NMN has been demonstrated to improve obesity, insulin resistance, and muscle mitochondrial dysfunction. In this review, recent findings in the NMN research will be summarized, and the potential of NMN on the regulation of age-associated diseases in humans will be discussed. PMID- 28649106 TI - [Aging and homeostasis. Aging control through cardiac regenerative medicine.] AB - Heart disease is one of the leading causes of death in the developed countries and various physical conditions in heart failure attribute to the impaired physical activities, which promotes aging. The principle cause of heart failure is the loss of self-renewal ability of cardiomyocytes in various injuries such as myocardial infarction. The replacement of injured tissues with the regenerated human myocardial tissues using technologies on tissue engineering and iPS cell will provide us the novel therapeutic strategy for heart failure and the related aging issues. PMID- 28649107 TI - [Aging and homeostasis. Management of disorders in bone and calcium metabolism associated with ageing.] AB - Disorders in bone and calcium metabolism associated with aging are based on secondary hyperparathyroidism due to impaired intestinal calcium absorption caused by insufficient vitamin D actions and augmented bone resorption due to sex hormone deficiency. Both of them are involved in the development of osteoporosis that increases risk of fractures. Therefore, the most important thing for management of disorders in bone and calcium metabolism associated with aging is to prevent fractures with appropriate drugs for osteoporosis. PMID- 28649108 TI - [Aging and homeostasis. Prevention and treatment of sarcopenia and frailty.] AB - Frailty and sarcopenia are geriatrics syndromes that are increasing in the super aged society and are an important risk factor for the outcomes such as disability, falls, falls/fractures, and death. Although aging is a major factor in both syndromes, muscle weakness is accelerated by malnutrition such as protein and vitamin D deficiency and lack of exercise in a sedentary lifestyle. Therefore, nutritional guidance and exercise instruction are extremely important as well as management of diseases in older people. In addition, social factors affect the progression of frailty;thus a more comprehensive approach is needed, including social participation. In this paper, we describe holistic approaches for prevention and treatment of frailty and sarcopenia. PMID- 28649109 TI - [Aging and homeostasis. Prevention and treatment of locomotive syndrome.] AB - Locomotive syndrome is defined as a condition of reduced mobility due to impairment of the locomotive organs. With the increased aging of society, the demand for the prevention and treatment of locomotive syndrome to improve healthy life expectancy is increasing. Studies have shown that exercise programs including balance training and resistance training are effective in preventing falls. Resistance training also improves walking ability(gait speed)in older adults. In Japan, 'locomotion training' consisting of one-leg standing and squatting exercise is recommended to prevent locomotive syndrome. Surgical intervention for the spine and lower extremities is also indicated if conservative management proves ineffective in subjects with progressive walking disability. PMID- 28649110 TI - Bitcoin and Potosi Silver: Historical Perspectives on Cryptocurrency. AB - Bitcoin, the digital cryptocurrency, has been celebrated as the future of money on the Internet. Although Bitcoin does present several forward-looking innovations, it also integrates a very old concept into its digital architecture: the mining of precious metals. Even though Bitcoin explicitly invokes mining as a metaphor and gold as an example for understanding the cryptocurrency, there has been little critical work on the connections between Bitcoin and previous metalist currency regimes. The following essay proposes a historical comparison with colonial South American silver mining and the global currency regime based on the New World silver peso it created as a way to interrogate Bitcoin. The comparison with colonial South America, and specifically the silver mining economy around the Cerro Rico de Potosi, will help to develop a historical and political understanding of Bitcoin's stakes, including questions of resources, labor, energy, and ecology. Mining and the extractive apparatus that accompanies it always imply massive-scale earthworks that reshape the planet itself, a process known as terraforming. The Potosi comparison will reveal Bitcoin to form part of a similar process of digital primitive accumulation we can provisionally name cryptoforming. PMID- 28649111 TI - Welcoming Wind Turbines and the PIMBY ("Please in My Backyard") Phenomenon: The Culture of the Machine in the Rural American Midwest. AB - This article argues that the welcoming of wind turbines in midwestern farming communities, the so-called PIMBY ("Please in My Backyard") phenomenon, constitutes only the most recent expression of a historical process of farmers forming an ultramodern identity, one that still goes largely unappreciated by relatively backward city residents. We conclude that farmers undertook a two-step process to develop a modern identity that incorporated rural values. In the first step, beginning early in the twentieth century, agrarians employed a discourse of rural capitalistic modernity to combat urban yokel stereotypes within the context of a broader rural-urban conflict. This rural capitalistic modernity strengthened during the cold war until it transformed, in the second step, into the current ultramodern discourse. Wind turbines, in addition to providing economic benefits, function ontologically to maintain an identity of rural citizens as savvy producers and users of technology, and to deflect stereotypes imposed by their urban cousins. PMID- 28649112 TI - Exploding the Black Box: Personal Computing, the Notebook Battery Crisis, and Postindustrial Systems Thinking. AB - Historians of science and technology have generally ignored the role of power sources in the development of consumer electronics. In this they have followed the predilections of historical actors. Research, development, and manufacturing of batteries has historically occurred at a social and intellectual distance from the research, development, and manufacturing of the devices they power. Nevertheless, power source technoscience should properly be understood as an allied yet estranged field of electronics. The separation between the fields has had important consequences for the design and manufacturing of mobile consumer electronics. This paper explores these dynamics in the co-construction of notebook batteries and computers. In so doing, it challenges assumptions of historians and industrial engineers and planners about the nature of computer systems in particular and the development of technological systems. The co construction of notebook computers and batteries, and the occasional catastrophic failure of their compatibility, challenges systems thinking more generally. PMID- 28649113 TI - American AV: Edgar Dale and the Information Age Classroom. AB - This article demonstrates how the influential scholar Edgar Dale, alongside a generation of educational technologists, helped build an essential place for AV materials and pedagogical methods in the American classroom. It also shows that, for decades, the Payne Fund philanthropy supported multimedia research agendas that shaped ideas about teaching and technology, far beyond involvement in their famed studies on motion pictures and children in the 1930s. With his writings and research programs, Dale advanced concepts of media experience and systematicity, which came to be understood as common sense to the information society. In so doing he was a leading contributor to the discursive and ideological structure of our age of technological and informational abundance. PMID- 28649114 TI - Technological Nocturne: The Lisbon Industrial Institute and Romantic Engineering (1849-1888). AB - This article explores technology as romantic culture in the second half of the nineteenth century. It details how new urban nocturnal experiences emerged from the Lisbon Industrial Institute (Instituto Industrial) founded in 1852. It combines the interest in the space of science production, typical of history of science and science studies, with the attention to production and consumption of lighting more commonly found in history of technology and urban history literature. Engineers' practices are put in a cultural continuum with poetry, opera, and modern city life at large. Industrial Institute directors Vitorino Damasio and Fonseca Benevides are described as romantic engineers for whom technology overcame differences between humans through the forging of new social bonds, produced new aesthetic experiences and new ways of feeling, expressed nature's harmony, and led to heroic lives. PMID- 28649115 TI - Producing Skills for an Empire: Theory and Practice in the Seville School of Gunners during the Golden Age of the Carrera de Indias. AB - Through the case study of the school of gunners created in Seville in 1576, this article aims to shed light on the emergence of teaching practices which were not only essential to the development of seaborne empires but also allow us to question the relationship between technology and science in the late Renaissance. The Seville school of gunners was established by the Spanish monarchy in the last quarter of the sixteenth century with the purpose of providing the Carrera de Indias-the transatlantic fleets-with technicians capable of using cannons. Changing the scale of apprenticeship, every year this innovative institution trained dozens of seamen, soldiers, and craftsmen in the art of gunnery. Intertwining theoretical lessons and training sessions on a practice ground, the teaching program was completed by a formal "examination" of the candidates with questions. The study of this school, one of many which existed not only in the territories of the Spanish monarchy but also in England and in Venice, reveals how, at the dawn of the "scientific revolution," skills of technicians could progressively merge with more formalized knowledge. PMID- 28649116 TI - Introduction. AB - This forum opens a conversation between the history of technology and the history of capitalism by considering the "paper technologies of capitalism" of the seventeenth, eighteenth, and nineteenth centuries in England and the United States. Seth Rockman offers an overview, connecting a recent exhibition of quotidian business ephemera to scholarly efforts to historicize the economic past, to engage material artifacts as things, and to embed the production of social knowledge in communities of practice. Three essays follow: William Deringer considers the "computational technologies" available in England to calculate future values; Caitlin Rosenthal traces the "rule of three" in the everyday transactions of the "innumerate" in the U.S. Early Republic; Jonathan Senchyne examines the materiality of paper within the emerging "rags to riches" tropes of nineteenth-century capitalist culture. Finally, Barbara Hahn concludes the forum with reflections of the overlapping terrain of the history of technology and the history of capitalism. PMID- 28649117 TI - Pricing the Future in the Seventeenth Century: Calculating Technologies in Competition. AB - Time is money. But how much? What is money in the future worth to you today? This question of "present value" arises in myriad economic activities, from valuing financial securities to real estate transactions to governmental cost-benefit analysis-even the economics of climate change. In modern capitalist practice, one calculation offers the only "rational" way to answer: compound-interest discounting. In the early modern period, though, economic actors used at least two alternative calculating technologies for thinking about present value, including a vernacular technique called years purchase and discounting by simple interest. All of these calculations had different strengths and affordances, and none was unquestionably better or more "rational" than the others at the time. The history of technology offers distinct resources for understanding such technological competitions, and thus for understanding the emergence of modern economic temporality. PMID- 28649118 TI - Numbers for the Innumerate: Everyday Arithmetic and Atlantic Capitalism. AB - In nineteenth-century America and the Atlantic world, the "rule of three" was usually regarded as the endpoint of a basic mathematics education. This essay considers the importance of the rule as a technology that enabled broader access to the calculations necessary to participate in the increasingly global market economy. Used by workmen, women, and even the enslaved, the rule and related tools translated basic literacy into practical numeracy. By doing so, it offered a diverse range of people the ability to negotiate more effectively. At the same time, however, the rule's spread helped to legitimate particular types of exchange and commensuration, and with them the emerging capitalist economy. PMID- 28649119 TI - Rags Make Paper, Paper Makes Money: Material Texts and Metaphors of Capital. AB - Because nineteenth-century paper was made from rags, the materiality of paper money became a likely ground from which to debate the nature of value in modern capitalism. On one hand, if paper money was backed by nothing but itself, then it was worth little more than itself: a gathering of lowly rags. On the other hand, the process of turning trashed rags into valuable paper modeled how capital could seem to grow out of nothing. Two nineteenth-century literary narratives provide examples of how rags performed considerable social and metaphorical work in the construction of an epistemology of capitalism and its "paper technologies." PMID- 28649121 TI - Ann Johnson, 28 May 1965 to 11 December 2016. PMID- 28649120 TI - Must We Embody Context? AB - The essays in this forum brace this meditation on the historiography of technology. Understanding devices incorporates the context of any particular hardware, as John Staudenmaier showed by quantifying the contents of the first decades of Technology and Culture. As contextualist approaches have widened from systems theory through social construction and into the assemblages of actor network theory, the discipline has kept artifacts at the analytical center: it is the history of technology that scholars seek to understand. Even recognizing that the machine only embodies the technology, the discipline has long sought to explain the machine. These essays invite consideration of how the history of technology might apply to non-corporeal things-methods as well as machines, and all the worldly phenomena that function in technological ways even without physicality. Materiality is financial as well as corporeal, the history of capitalism reminds us, and this essay urges scholars to apply history-of technology approaches more broadly. PMID- 28649122 TI - The Flawed "Tools of Empire": Clive Dewey, Steamboats on the Indus. PMID- 28649123 TI - Extraovarian Primary Peritoneal Carcinomatosis: A Case Report. AB - BACKGROUND Extraovarian primary peritoneal carcinoma (EOPPC) is a rare malignant epithelial tumor with an age-adjusted incidence rate of 6.78 per million, which arises from the peritoneal lining with minimal or no ovarian involvement. EOPPC is a diagnosis of exclusion with the absence of other identifiable primary sites and after surgical assessment and consideration of the histological report to evaluate the extent of ovarian invasion. CASE REPORT A 66-year-old woman complained of mild postprandial epigastric pain. Physical exam revealed positive bowel sounds over all 4 quadrants, with a soft, non-tender abdomen. Distension and dullness to percussion were noted. A CT scan revealed peritoneal fluid, and evaluation of the peritoneal fluid showed an elevated white blood cell count, while fulfilling criteria for exudate. There was no bacterial growth from the peritoneal fluid. Serum tumor markers CEA were significantly elevated, suggestive of an underlying malignancy. An exploratory laparoscopy confirmed diffuse carcinomatosis in the omentum, the coloparietal region bilaterally, as well as surrounding small bowel loops, the transverse and sigmoid colon, and the rectum. A bilateral oophorectomy was performed and 2 biopsies from the thickened peritoneum were taken. The histomorphological features from the pathology examination concluded the patient had peritoneal serous carcinoma with uninvolved ovaries. CONCLUSIONS EOPPC may be misdiagnosed as epithelial ovarian cancer, and should be considered in patients with peritoneal carcinomatosis, normal-sized ovaries, and no identifiable primary lesion. Since the common therapeutic strategies achieve comparable survival rates, failed recognition may be without consequences. However, to further improve survival, optimal cytoreductive surgery is essential and should be made a priority in disease management. PMID- 28649124 TI - A Modified Bowel Preparation Regimen for Colonoscopy Providing the Patients' Satisfaction and Convenience. AB - BACKGROUND A complete cleansing of the bowel is a critical factor that impacts the diagnostic accuracy of colonoscopies. However, the common bowel preparation regimen of two 45 mL doses of sodium phosphate (2*NaP) often leads to uncomfortable symptoms and subsequently lower patient adherence. To improve patient adherence and satisfaction, we proposed a modified regimen composed of two sennoside tablets and one bottle of NaP (S+NaP) and we then evaluated bowel preparation quality and patient satisfaction. MATERIAL AND METHODS A total of 531 patients who underwent colonoscopies at the outpatient coloproctology clinic from January 2016 to December 2016 were retrospectively reviewed. Eligible patients were divided into two groups: S+NaP group (n=93) and 2*NaP group (n=60). We compared bowel preparation quality, adenoma detection rate (ADR), self-reported patient satisfaction scores, and adverse events among the two groups. RESULTS Regarding high bowel preparation quality, our results showed that there was no significant difference among the two groups (p=0.775), as well as no significant differences in ADRs (p=0.187). However, a lower proportion of nausea was found in the S+NaP group compared to the 2*NaP group (24.7% versus 41.7%, respectively, p=0.028). In addition, patients in the S+NaP group were more likely to be very satisfied with the regimen compared with patients in the 2*NaP group (odds ratio: 5.58; 95% confidence interval: 2.36-13.213, p<0.001). CONCLUSIONS Our modified bowel preparation regimen, S+NaP, yielded significantly higher patient satisfaction with less nausea while maintaining similar bowel preparation quality. PMID- 28649125 TI - Glomerular filtration rate: CKD risk factors are associated with increased single nephron GFR. PMID- 28649126 TI - Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPAR-gamma. AB - The root of Polygonum multiflorum Thunb (PM) has been used in China to treat a variety of diseases, such as constipation, early graying of the hair and hyperlipemia. Recent evidence shows that PM causes idiosyncratic drug-induced liver injury (IDILI) in humans. In this study, we investigated the molecular basis of PM-induced liver injury in a rat model of IDILI based on a non hepatotoxic dose of LPS. SD rats were orally administered 3 potentially hepatotoxic compounds of PM: cis-stilbene glucoside (cis-SG, 50 mg/kg), trans-SG (50 mg/kg) or emodin (5 mg/kg), followed by injection of LPS (2.8 mg/kg, iv). Serum and liver histology were evaluated 7 h after LPS injection. Among the 3 compounds tested, cis-SG, but not emodin or trans-SG, induced severe liver injury in rats when combined with LPS. The levels of AST and ALT in plasma and inflammatory cytokines in both plasma and liver tissues were markedly elevated. The liver tissues showed increased injury, hepatocyte apoptosis, and macrophage infiltration, and decreased cell proliferation. Microarray analysis revealed a negative correlation between peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and LPS/cis-SG-induced liver injury. Immunohistochemical staining and RT-PCR results further confirmed that cis-SG significantly inhibited activation of the PPAR-gamma pathway in the liver tissues of LPS/cis-SG-treated rats. Pre-treatment with a PPAR-gamma agonist pioglitazone (500 g/kg, ig) reversed LPS/cis-SG-induced liver injury, which was associated with inhibiting the nuclear factor kappa B (NF-kappaB) pathway. These data demonstrate that cis stilbene glucoside induces immunological idiosyncratic hepatotoxicity through suppressing PPAR-gamma in a rat model of IDILI. PMID- 28649127 TI - The novel alpha-glucan YCP improves the survival rates and symptoms in septic mice by regulating myeloid-derived suppressor cells. AB - Sepsis is a life-threatening health condition that is initially characterized by uncontrolled inflammation, followed by the development of persistent immunosuppression. YCP is a novel alpha-glucan purified from the mycelium of the marine fungus Phoma herbarum YS4108, which has displayed strong antitumor activity via enhancing host immune responses. In this study, we investigated whether YCP could influence the development of sepsis in a mouse model. Caecal ligation and puncture (CLP)-induced sepsis was established in mice that were treated with YCP (20 mg/kg, ip or iv) 2 h before, 4 and 24 h after the CLP procedure, and then every other day. YCP administration greatly improved the survival rate (from 39% to 72% on d 10 post-CLP) and ameliorated disease symptoms in the septic mice. Furthermore, YCP administration significantly decreased the percentage of myeloid-derived suppressor cells (MDSCs) in the lungs and livers, which were dramatically elevated during sepsis. In cultured BM-derived cells, addition of YCP (30, 100 MUg/mL) significantly decreased the expansion of MDSCs; YCP dose-dependently decreased the phosphorylation of STAT3 and increased the expression of interferon regulatory factor-8 (IRF-8). When BM-derived MDSCs were co-cultured with T cells, YCP dose-dependently increased the production of arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS), and activated the NF-kappaB pathway. In addition, the effects of YCP on MDSCs appeared to be dependent on toll-like receptor (TLR) 4. These results reveal that YCP inhibits the expansion of MDSCs via STAT3 while enhancing their immunosuppressive function, partially through NF-kappaB. Our findings suggest that YCP protects mice against sepsis by regulating MDSCs. Thus, YCP may be a potential therapeutic agent for sepsis. PMID- 28649128 TI - LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2 methoxy(phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5-20 MUmol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK 3beta inhibitor with IC50 of 1.84+/-0.07 MUmol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg.kg-1.d-1, ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD. PMID- 28649129 TI - C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling. AB - Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 MUmol/L) or ISO (1 MUmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 MUmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg.kg-1.d-1, for 3 consecutive weeks) significantly increased fractional shortening (43.55%+/-3.98%, 54.79%+/-1.95%, 43.98%+/-7.96% vs 32.18%+/-6.28%), ejection fraction (72.97%+/-4.64%, 84.29%+/ 1.56%, 73.41%+/-9.37% vs 49.17%+/-4.20%) and cardiac output (60.01+/-9.11, 69.40+/-11.63, 58.08+/-8.47 mL/min vs 48.97+/-2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases. PMID- 28649130 TI - Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer. AB - Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg.kg-1.d-1) alone did not inhibit the tumor growth in human breast cancer MCF 7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg.kg-1.d-1) and DEX (8 mg.kg-1.d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs. PMID- 28649131 TI - Blocking the utilization of glucose induces the switch from senescence to apoptosis in pseudolaric acid B-treated human lung cancer cells in vitro. AB - Pseudolaric acid B (PAB), a diterpene acid isolated from the root bark of Pseudolarix kaempferi Gordon, exerts anti-tumor effects in several cancer cell lines. Our previous study showed that PAB mainly induced senescence via p53-p21 activation rather than apoptosis in suppression of the growth of human lung cancer A549 cells (p53 wild-type). In p53-null human lung cancer H1299 cells, however, PAB caused apoptosis without senescence. In this study we investigated what mechanism was responsible for the switch from senescence to apoptosis in PAB treated human lung cancer cell lines. Senescent cells were examined by SA-beta gal staining. Glucose uptake and the apoptosis ratio were assessed using a FACScan flow cytometer. Commercial assay kits were used to measure the levels of ATP and lactate. Transfection of siRNA was used to knockdown the expression of p53 or p21. Western blot analysis was applied to measure the protein expression levels. In p53 wild-type A549 cells, PAB (20 MUmol/L) caused senescence, and time dependently increased glucose utilization; knockdown of p53 or p21 significantly decreased the uptake and metabolism of glucose but elevated PAB-induced apoptosis. Inhibition of glucose utilization using a glycolytic inhibitor 2-DG (1 mmol/L) significantly enhanced apoptosis induction. Similar results were observed in another p53 wild-type H460 cells treated with PAB. Opposite results were found in p53-null H1299 cells, where PAB time-dependently decreased glucose utilization, and induced only apoptosis. Our results demonstrate that PAB-induced senescence is associated with enhanced glucose utilization, and lower glucose utilization might contribute to apoptosis induction. Thus, blocking glucose utilization contributes to the switch from senescence to apoptosis, and p53 plays an important role in this process. PMID- 28649133 TI - Disease genetics: Repeat expansion disorders - going through a phase. PMID- 28649132 TI - Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg.kg-1.d-1, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg.kg 1.d-1), pramipexole (3 mg.kg-1.d-1), or medopar (100 mg.kg-1.d-1) for 18 days. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the alpha-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, alpha-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model. PMID- 28649134 TI - Cancer epigenetics: Therapy-induced transcription is cryptically widespread. PMID- 28649137 TI - Bacterial secretion: Shigella sonnei has the edge. PMID- 28649138 TI - Pseudomonas predators: understanding and exploiting phage-host interactions. AB - Species in the genus Pseudomonas thrive in a diverse set of ecological niches and include crucial pathogens, such as the human pathogen Pseudomonas aeruginosa and the plant pathogen Pseudomonas syringae. The bacteriophages that infect Pseudomonas spp. mirror the widespread and diverse nature of their hosts. Therefore, Pseudomonas spp. and their phages are an ideal system to study the molecular mechanisms that govern virus-host interactions. Furthermore, phages are principal catalysts of host evolution and diversity, which directly affects the ecological roles of environmental and pathogenic Pseudomonas spp. Understanding these interactions not only provides novel insights into phage biology but also advances the development of phage therapy, phage-derived antimicrobial strategies and innovative biotechnological tools that may be derived from phage-bacteria interactions. PMID- 28649135 TI - Synthetic lethality and cancer. AB - A synthetic lethal interaction occurs between two genes when the perturbation of either gene alone is viable but the perturbation of both genes simultaneously results in the loss of viability. Key to exploiting synthetic lethality in cancer treatment are the identification and the mechanistic characterization of robust synthetic lethal genetic interactions. Advances in next-generation sequencing technologies are enabling the identification of hundreds of tumour-specific mutations and alterations in gene expression that could be targeted by a synthetic lethality approach. The translation of synthetic lethality to therapy will be assisted by the synthesis of genetic interaction data from model organisms, tumour genomes and human cell lines. PMID- 28649139 TI - Kinetics and Photochemistry of Ruthenium Bisbipyridine Diacetonitrile Complexes: An Interdisciplinary Inorganic and Physical Chemistry Laboratory Exercise. AB - The study of ruthenium polypyridyl complexes can be widely applied across disciplines in the undergraduate curriculum. Ruthenium photochemistry has advanced many fields including dye-sensitized solar cells, photoredox catalysis, light-driven water oxidation, and biological electron transfer. Equally promising are ruthenium polypyridyl complexes that provide a sterically bulky, photolabile moiety for transiently "caging" biologically active molecules. Photouncaging involves the use of visible (1-photon) or near-IR (2-photon) light to break one or more bonds between ruthenium and coordinated ligand(s), which can occur on short time scales and in high quantum yields. In this work we demonstrate the use of a model "caged" acetonitrile complex, Ru(2,2'-bipyridine)2(acetonitrile)2, or RuMeCN in an advanced synthesis and physical chemistry laboratory. Students made RuMeCN in an advanced synthesis laboratory course and performed UV-vis spectroscopy and electrochemistry. The following semester students investigated RuMeCN photolysis kinetics in a physical chemistry laboratory. These two exercises may also be combined to create a 2-week module in an advanced undergraduate laboratory course. PMID- 28649136 TI - Viral effects on the content and function of extracellular vesicles. AB - The release of membrane-bound vesicles from cells is being increasingly recognized as a mechanism of intercellular communication. Extracellular vesicles (EVs) or exosomes are produced by virus-infected cells and are thought to be involved in intercellular communication between infected and uninfected cells. Viruses, in particular oncogenic viruses and viruses that establish chronic infections, have been shown to modulate the production and content of EVs. Viral microRNAs, proteins and even entire virions can be incorporated into EVs, which can affect the immune recognition of viruses or modulate neighbouring cells. In this Review, we discuss the roles that EVs have during viral infection to either promote or restrict viral replication in target cells. We will also discuss our current understanding of the molecular mechanisms that underlie these roles, the potential consequences for the infected host and possible future diagnostic applications. PMID- 28649140 TI - Towards estimates of future rainfall erosivity in Europe based on REDES and WorldClim datasets. AB - The policy requests to develop trends in soil erosion changes can be responded developing modelling scenarios of the two most dynamic factors in soil erosion, i.e. rainfall erosivity and land cover change. The recently developed Rainfall Erosivity Database at European Scale (REDES) and a statistical approach used to spatially interpolate rainfall erosivity data have the potential to become useful knowledge to predict future rainfall erosivity based on climate scenarios. The use of a thorough statistical modelling approach (Gaussian Process Regression), with the selection of the most appropriate covariates (monthly precipitation, temperature datasets and bioclimatic layers), allowed to predict the rainfall erosivity based on climate change scenarios. The mean rainfall erosivity for the European Union and Switzerland is projected to be 857 MJ mm ha-1 h-1 yr-1 till 2050 showing a relative increase of 18% compared to baseline data (2010). The changes are heterogeneous in the European continent depending on the future projections of most erosive months (hot period: April-September). The output results report a pan-European projection of future rainfall erosivity taking into account the uncertainties of the climatic models. PMID- 28649141 TI - The impact of lake and reservoir parameterization on global streamflow simulation. AB - Lakes and reservoirs affect the timing and magnitude of streamflow, and are therefore essential hydrological model components, especially in the context of global flood forecasting. However, the parameterization of lake and reservoir routines on a global scale is subject to considerable uncertainty due to lack of information on lake hydrographic characteristics and reservoir operating rules. In this study we estimated the effect of lakes and reservoirs on global daily streamflow simulations of a spatially-distributed LISFLOOD hydrological model. We applied state-of-the-art global sensitivity and uncertainty analyses for selected catchments to examine the effect of uncertain lake and reservoir parameterization on model performance. Streamflow observations from 390 catchments around the globe and multiple performance measures were used to assess model performance. Results indicate a considerable geographical variability in the lake and reservoir effects on the streamflow simulation. Nash-Sutcliffe Efficiency (NSE) and Kling-Gupta Efficiency (KGE) metrics improved for 65% and 38% of catchments respectively, with median skill score values of 0.16 and 0.2 while scores deteriorated for 28% and 52% of the catchments, with median values -0.09 and 0.16, respectively. The effect of reservoirs on extreme high flows was substantial and widespread in the global domain, while the effect of lakes was spatially limited to a few catchments. As indicated by global sensitivity analysis, parameter uncertainty substantially affected uncertainty of model performance. Reservoir parameters often contributed to this uncertainty, although the effect varied widely among catchments. The effect of reservoir parameters on model performance diminished with distance downstream of reservoirs in favor of other parameters, notably groundwater-related parameters and channel Manning's roughness coefficient. This study underscores the importance of accounting for lakes and, especially, reservoirs and using appropriate parameterization in large scale hydrological simulations. PMID- 28649142 TI - How Early Life Religious Exposure Relates to the Timing of First Birth. AB - This paper examines intermediary processes explaining how religious socialization and involvement early in life are related to the timing of first births for women in the United States. The theory of conjunctural action forms the basis for hypotheses for how religious schema and materials operate to influence birth timing. Using the NLSY79 data and event history methods, the study finds evidence for expected family size, work-family gender ideology, educational attainment and enrollment, cohabitation, and age at marriage as mediators of associations between early life religious exposure (affiliation and attendance) and the timing of nonmaritally and maritally conceived first births. These findings corroborate other research identifying the long reach of religious socialization and involvement in youth, elucidate some of the pathways for these connections, and motivate further work to understand linkages between religion and family behaviors in the United States. PMID- 28649143 TI - Sugar Price Supports and Taxation: A Public Health Policy Paradox. AB - Domestic US sugar production has been protected by government policy for the past 82 years, resulting in elevated domestic prices and an estimated annual (2013) $1.4 billion dollar "tax" on consumers. These elevated prices and the simultaneous federal support for domestic corn production have ensured a strong market for high-fructose corn syrup. Americans have dramatically increased their consumption of caloric sweeteners during the same period. Consumption of "empty" calories (ie, foods with low-nutrient/high-caloric density)-sugar and high fructose corn syrup being the primary sources-is considered by most public health experts to be a key contributing factor to the rise in obesity. There have been substantial efforts to tax sugar-sweetened beverages (SSBs) to both reduce consumption and provide a source of funds for nutrition education, thereby emulating the tobacco tax model. Volume-based SSB taxes levy the tax rate per ounce of liquid, where some are only imposed on beverages with added sugar content exceeding a set threshold. Nonetheless, volume-based taxes have significant limitations in encouraging consumers to reduce their caloric intake due to a lack of transparency at the point of purchase. Thus, it is hypothesized that point-of-purchase, nutrient-specific excise taxes on SSBs would be more effective at reducing sugar consumption. However, all SSB taxes are limited by the possibility that consumers may compensate their decreased intake from SSBs with other high-calorie junk foods. Furthermore, there are no existing studies to provide evidence on how SSB taxes will impact obesity rates in the long term. The paradox of sugar prices is that Americans have paid higher prices for sugar to protect domestic production for more than 80 years, and now, Americans are being asked to pay even more to promote public health. The effective use of sugar taxes should be considered based on their merits in reducing sugar consumption and making available a new source of funds to support nutrition education, not on lobbying efforts by the food industry or sugar and corn producers. PMID- 28649145 TI - Do SSRIs and SNRIs reduce the frequency and/or severity of hot flashes in menopausal women. AB - CLINICAL QUESTION: In menopausal women who experience regular hot flashes, does treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) reduce the frequency and/or severity of hot flashes? ANSWER: Yes. Review of the literature suggests that treatment with SSRIs or SNRIs reduces the frequency and severity of hot flashes in menopausal and post-menopausal women. Studies demonstrated that paroxetine (Paxil), citalopram (Celexa) and escitolapram (Lexapro) were the most effective SSRIs, and venlafaxine (Effexor) was the most effective first line SNRI, with desvenlafaxine as a second option. The most common side effects reported for both SSRIs and SNRIs are nausea and constipation, with most resolving within the first week of treatment. SNRIs have been associated with increased blood pressure in some patients and should be used with caution in women with hypertension. Women with a history of breast cancer and taking tamoxifen should avoid SSRIs, which have been shown to interfere with tamoxifen metabolism. SNRIs are the safest drugs for this population. Treatment choice should be patient-specific and begin with the lowest dose available. LEVEL OF EVIDENCE FOR THE ANSWER: A. SEARCH TERMS: SSRI, SNRI, hot flashes, vasomotor symptoms, menopause. SEARCH CONDUCTED: August 2014, February 2016 and August 2016. INCLUSION CRITERIA: menopausal, perimenopausal or postmenopausal women 18 years of age or older with frequent and/or severe vasomotor symptoms, meta-analyses, systematic reviews, randomized controlled trials, cohort studies. EXCLUSION CRITERIA: pre-menopause, anxiety, depression, panic disorder, bipolar disorder, co-morbid conditions. PMID- 28649146 TI - A Predictive Framework to Elucidate Venous Stenosis: CFD & Shape Optimization. AB - The surgical creation of vascular accesses for renal failure patients provides an abnormally high flow rate conduit in the patient's upper arm vasculature that facilitates the hemodialysis treatment. These vascular accesses, however, are very often associated with complications that lead to access failure and thrombotic incidents, mainly due to excessive neointimal hyperplasia (NH) and subsequently stenosis. Development of a framework to monitor and predict the evolution of the venous system post access creation can greatly contribute to maintaining access patency. Computational fluid dynamics (CFD) has been exploited to inspect the non-homeostatic wall shear stress (WSS) distribution that is speculated to trigger NH in the patient cohort under investigation. Thereafter, CFD in liaison with a gradient-free shape optimization method has been employed to analyze the deformation modes of the venous system enduring non-physiological hemodynamics. It is observed that the optimally evolved shapes and their corresponding hemodynamics strive to restore the homeostatic state of the venous system to a normal, pre-surgery condition. It is concluded that a CFD-shape optimization coupling that seeks to regulate the WSS back to a well-defined physiological WSS target range can accurately predict the mode of patient specific access failure. PMID- 28649147 TI - Multiblock High Order Large Eddy Simulation of Powered Fontan Hemodynamics: Towards Computational Surgery. AB - Children born with only one functional ventricle must typically undergo a series of three surgeries to obtain the so-called Fontan circulation in which the blood coming from the body passively flows from the Vena Cavae (VCs) to the Pulmonary Arteries (PAs) through the Total Cavopulmonary Connection (TCPC). The circulation is inherently inefficient due to the lack of a subpulmonary ventricle. Survivors face the risk of circulatory sequelae and eventual failure for the duration of their lives. Current efforts are focused on improving the outcomes of Fontan palliation, either passively by optimizing the TCPC, or actively by using mechanical support. We are working on a chronic implant that would be placed at the junction of the TCPC, and would provide the necessary pressure augmentation to re-establish a circulation that recapitulates a normal two-ventricle circulation. This implant is based on the Von Karman viscous pump and consists of a vaned impeller that rotates inside the TCPC. To evaluate the performance of such a device, and to study the flow features induced by the presence of the pump, Computational Fluid Dynamics (CFD) is used. CFD has become an important tool to understand hemodynamics owing to the possibility of simulating quickly a large number of designs and flow conditions without any harm for patients. The transitional and unsteady nature of the flow can make accurate simulations challenging. We developed and in-house high order Large Eddy Simulation (LES) solver coupled to a recent Immersed Boundary Method (IBM) to handle complex geometries. Multiblock capability is added to the solver to allow for efficient simulations of complex patient specific geometries. Blood simulations are performed in a complex patient specific TCPC geometry. In this study, simulations without mechanical assist are performed, as well as after virtual implantation of the temporary and chronic implants being developed. Instantaneous flow structures, hepatic factor distribution, and statistical data are presented for all three cases. PMID- 28649148 TI - ORIGINS AND GENETIC DIVERSITY OF INTRODUCED POPULATIONS OF THE PUERTO RICAN RED EYED COQUI, ELEUTHERODACTYLUS ANTILLENSIS, IN SAINT CROIX (U.S. VIRGIN ISLANDS) AND PANAMA. AB - The Red-eyed Coqui, Eleutherodactylus antillensis, is a terrestrial frog endemic to the Puerto Rican Bank (Puerto Rico and numerous islands and cays off its eastern coast), in the eastern Caribbean Sea. The species was likely introduced in Saint Croix, an island c. 100 km southeast of Puerto Rico, in the late 1930s, and in Panama City, Panama, in the late 1950s or early 1960s, but the source(s) of these introductions are unknown. We analyzed sequence data from one mtDNA locus and four nuDNA introns to infer the origin(s) of the Saint Croix and Panama City populations and quantify their genetic diversity. Saint Croix and Panamanian populations do not share any haplotypes, and they cluster with different native populations, suggesting that they are derived from separate sources in the Puerto Rican Bank. Patterns of population structure trace the probable sources of E. antillensis in Saint Croix to islands off Puerto Rico's eastern coast, which include Vieques, Culebra, Saint Thomas, Saint John, Tortola, and Virgin Gorda, and possibly to eastern Puerto Rico as well. In contrast, Panama City E. antillensis probably originated from either western or eastern Puerto Rico. Genetic diversity in the introduced populations is similar to or lower than in populations in the species' native range, indicating that genetic diversity has not increased in the alien frogs. Our findings may facilitate the development of preventive measures to minimize introductions of non-native amphibians in the Caribbean and Central America. PMID- 28649149 TI - Quantitative Imaging of Cell Membrane-associated Effective Mass Density Using Photonic Crystal Enhanced Microscopy (PCEM). AB - Adhesion is a critical cellular process that contributes to migration, apoptosis, differentiation, and division. It is followed by the redistribution of cellular materials at the cell membrane or at the cell-surface interface for cells interacting with surfaces, such as basement membranes. Dynamic and quantitative tracking of changes in cell adhesion mass redistribution is challenging because cells are rapidly moving, inhomogeneous, and nonequilibrium objects, whose physical and mechanical properties are difficult to measure or predict. Here, we report a novel biosensor based microscopy approach termed Photonic Crystal Enhanced Microscopy (PCEM) that enables the movement of cellular materials at the plasma membrane of individual live cells to be dynamically monitored and quantitatively imaged. PCEM utilizes a photonic crystal biosensor surface, which can be coated with arbitrary extracellular matrix materials to facilitate cellular interactions, within a modified brightfield microscope with a low intensity non-coherent light source. Benefiting from the high sensitivity, narrow resonance peak, and tight spatial confinement of the evanescent field atop the photonic crystal biosensor, PCEM enables label-free live cell imaging with high sensitivity and high lateral and axial spatial-resolution, thereby allowing dynamic adhesion phenotyping of single cells without the use of fluorescent tags or stains. We apply PCEM to investigate adhesion and the early stage migration of different types of stem cells and cancer cells. By applying image processing algorithms to analyze the complex spatiotemporal information generated by PCEM, we offer insight into how the plasma membrane of anchorage dependent cells is dynamically organized during cell adhesion. The imaging and analysis results presented here provide a new tool for biologists to gain a deeper understanding of the fundamental mechanisms involved with cell adhesion and concurrent or subsequent migration events. PMID- 28649150 TI - Personality and Frailty: Evidence From Four Samples. AB - Frailty is a prevalent geriatric syndrome. Little is known about the psychological factors associated with this syndrome. Based on four large samples of older adults aged from 65 to 104 years old, the present study examined whether personality traits are related to frailty. High neuroticism, low conscientiousness, low extraversion, low openness and low agreeableness were related to higher frailty across samples. Longitudinal analysis conducted in one sample revealed that high neuroticism was associated with worsening frailty over an 8-year period. Higher frailty at baseline and over time was related to maladaptive personality changes. This study extends existing knowledge on the link between personality and health in older adults, by identifying the personality traits associated with frailty, a complex geriatric syndrome. PMID- 28649151 TI - Quasi-simultaneous acquisition of nine secondary ions with seven detectors on NanoSIMS50L: application to biological samples. AB - We employed a method of electrostatic peak switching allowing for the quasi simultaneous measurement of 16O, 18O, C2H, C2D,12C14N, 13C14N, 12C15N, P, and S with the NanoSIMS 50L instrument to derive ratios for D/H, 13C/12C, 18O/16O, and 15N/14N from biological samples. This approach involves two steps: (i) derivation of the D/H ratio from measurements of C2D and C2H and (ii) switching of the voltage on deflection plates located in front of two detectors. The method is reliable and easy to set up compared with the magnetic peak-switching mode usually used to perform this type of analysis. PMID- 28649152 TI - Health, Disability and Mortality Differences at Older Ages between the US and England. AB - This paper examines health status differences between England and the United States, with an emphasis on the implications of any health disparities for health care cost differences between the two countries. We first document health status differences in disease prevalence, disability, mortality and co-morbidity. We find higher disease prevalence in the US than in England (confirming previous findings) but much smaller differences between the two countries in disability and mortality. We attribute the smaller differences in disability to the fact that disability measures rely primarily on subjective questions on experiencing disabilities, which are reported differently in the two countries. Smaller mortality differences are most likely due to a combination of earlier disease diagnosis and more effective disease treatment in the US. Co-morbidity is a common and important dimension of disease in both countries that is often neglected in scientific papers, especially by economists. We find, however, that disease prevalence has little implication for out-of-pocket health care costs in the US except for relatively few individuals with particular diseases. Instead, costs are more associated with incidence than prevalence and with those who are going to die in the next year or two. Co- morbidity is associated with higher costs but even this association is limited to a relatively small fraction of people who are co-morbid. PMID- 28649155 TI - Evaluation of Methods to Produce an Image Library for Automatic Patient Model Localization for Dose Mapping During Fluoroscopically-Guided Procedures. AB - The purpose of this work is to evaluate methods for producing a library of 2D radiographic images to be correlated to clinical images obtained during a fluoroscopically-guided procedure for automated patient-model localization. The localization algorithm will be used to improve the accuracy of the skin-dose map superimposed on the 3D patient-model of the real-time Dose-Tracking-System (DTS). For the library, 2D images were generated from CT datasets of the SK-150 anthropomorphic phantom using two methods: Schmid's 3D-visualization tool and Plastimatch's digitally-reconstructed-radiograph (DRR) code. Those images, as well as a standard 2D-radiographic image, were correlated to a 2D-fluoroscopic image of a phantom, which represented the clinical-fluoroscopic image, using the Corr2 function in Matlab. The Corr2 function takes two images and outputs the relative correlation between them, which is fed into the localization algorithm. Higher correlation means better alignment of the 3D patient-model with the patient image. In this instance, it was determined that the localization algorithm will succeed when Corr2 returns a correlation of at least 50%. The 3D visualization tool images returned 55-80% correlation relative to the fluoroscopic-image, which was comparable to the correlation for the radiograph. The DRR images returned 61-90% correlation, again comparable to the radiograph. Both methods prove to be sufficient for the localization algorithm and can be produced quickly; however, the DRR method produces more accurate grey-levels. Using the DRR code, a library at varying angles can be produced for the localization algorithm. PMID- 28649154 TI - Skin dose mapping for non-uniform x-ray fields using a backscatter point spread function. AB - Beam shaping devices like ROI attenuators and compensation filters modulate the intensity distribution of the x-ray beam incident on the patient. This results in a spatial variation of skin dose due to the variation of primary radiation and also a variation in backscattered radiation from the patient. To determine the backscatter component, backscatter point spread functions (PSF) are generated using EGS Monte-Carlo software. For this study, PSF's were determined by simulating a 1 mm beam incident on the lateral surface of an anthropomorphic head phantom and a 20 cm thick PMMA block phantom. The backscatter PSF's for the head phantom and PMMA phantom are curve fit with a Lorentzian function after being normalized to the primary dose intensity (PSFn). PSFn is convolved with the primary dose distribution to generate the scatter dose distribution, which is added to the primary to obtain the total dose distribution. The backscatter convolution technique is incorporated in the dose tracking system (DTS), which tracks skin dose during fluoroscopic procedures and provides a color map of the dose distribution on a 3D patient graphic model. A convolution technique is developed for the backscatter dose determination for the non-uniformly spaced graphic-model surface vertices. A Gafchromic film validation was performed for shaped x-ray beams generated with an ROI attenuator and with two compensation filters inserted into the field. The total dose distribution calculated by the backscatter convolution technique closely agreed with that measured with the film. PMID- 28649153 TI - Corynespora, Exosporium and Helminthosporium revisited - New species and generic reclassification. AB - Molecular phylogenetic analyses of a multigene matrix of partial nuSSU-ITS-LSU rDNA, rpb2 and tef1 sequences were performed to investigate the phylogenetic relationships of Corynespora, Exosporium and Helminthosporium species. Based on phylogenetic analyses and morphology, the genus Exosporium is synonymised with Helminthosporium, and the genus Corynespora is revealed as polyphyletic. Corynespora smithii is confirmed to be closely related to the generic type C. cassiicola and its morphology is described and illustrated. Exosporium tiliae, Corynespora caespitosa, C. endiandrae, C. leucadendri and C. olivacea are recognised in Helminthosporium, and Splanchnonema quercicola and S. kalakadense are combined in Helminthosporium. Based on pure culture studies and DNA sequence data, Massaria heterospora and Massarinula italica are shown to be the sexual morphs of Helminthosporium tiliae and H. microsorum, respectively. European accessions of Splanchnonema quercicola are recognised to differ from the North American type and are described as Helminthosporium quercinum. The sexual morph of H. oligosporum is recorded and described for the first time. The generic type of Helminthosporium, H. velutinum, is epitypified with a recent collection from the type host, Fagus sylvatica. Based on sequence data, Helminthosporium genistae is recognised as a distinct species. Several species for which subperidermal stromata have been reported are shown to be fungicolous on Diaporthales, the "stromata" representing aborted and transformed host stromata or conidiomata: H. caespitosum, H. microsorum, H. quercicola and H. quercinum on Coryneum spp.; H. hispanicum on conidiomata of Juglanconis juglandina; H. juglandinum on conidiomata of Diaporthe sp.; H. oligosporum and H. tiliae on Hercospora tiliae. The newly described H. austriacum is fungicolous on Amphisphaeria cf. millepunctata (Xylariales). PMID- 28649157 TI - Use of patient specific 3D printed neurovascular phantoms to evaluate the clinical utility of a high resolution x-ray imager. AB - Modern 3D printing technology can fabricate vascular phantoms based on an actual human patient with a high degree of precision facilitating a realistic simulation environment for an intervention. We present two experimental setups using 3D printed patient-specific neurovasculature to simulate different disease anatomies. To simulate the human neurovasculature in the Circle of Willis, patient-based phantoms with aneurysms were 3D printed using a Objet Eden 260V printer. Anthropomorphic head phantoms and a human skull combined with acrylic plates simulated human head bone anatomy and x-ray attenuation. For dynamic studies the 3D printed phantom was connected to a pulsatile flow loop with the anthropomorphic phantom underneath. By combining different 3D printed phantoms and the anthropomorphic phantoms, different patient pathologies can be simulated. For static studies a 3D printed neurovascular phantom was embedded inside a human skull and used as a positional reference for treatment devices such as stents. To simulate tissue attenuation acrylic layers were added. Different combinations can simulate different patient treatment procedures. The Complementary-Metal-Oxide Semiconductor (CMOS) based High Resolution Fluoroscope (HRF) with 75MUm pixels offers an advantage over the state-of-the-art 200 MUm pixel Flat Panel Detector (FPD) due to higher Nyquist frequency and better DQE performance. Whether this advantage is clinically useful during an actual clinical neurovascular intervention can be addressed by qualitatively evaluating images from a cohort of various cases performed using both detectors. The above-mentioned method can offer a realistic substitute for an actual clinical procedure. Also a large cohort of cases can be generated and used for a HRF clinical utility determination study. PMID- 28649156 TI - Multi-atlas Segmentation Enables Robust Multi-contrast MRI Spleen Segmentation for Splenomegaly. AB - Non-invasive spleen volume estimation is essential in detecting splenomegaly. Magnetic resonance imaging (MRI) has been used to facilitate splenomegaly diagnosis in vivo. However, achieving accurate spleen volume estimation from MR images is challenging given the great inter-subject variance of human abdomens and wide variety of clinical images/modalities. Multi-atlas segmentation has been shown to be a promising approach to handle heterogeneous data and difficult anatomical scenarios. In this paper, we propose to use multi-atlas segmentation frameworks for MRI spleen segmentation for splenomegaly. To the best of our knowledge, this is the first work that integrates multi-atlas segmentation for splenomegaly as seen on MRI. To address the particular concerns of spleen MRI, automated and novel semi-automated atlas selection approaches are introduced. The automated approach interactively selects a subset of atlases using selective and iterative method for performance level estimation (SIMPLE) approach. To further control the outliers, semi-automated craniocaudal length based SIMPLE atlas selection (L-SIMPLE) is proposed to introduce a spatial prior in a fashion to guide the iterative atlas selection. A dataset from a clinical trial containing 55 MRI volumes (28 T1 weighted and 27 T2 weighted) was used to evaluate different methods. Both automated and semi-automated methods achieved median DSC > 0.9. The outliers were alleviated by the L-SIMPLE (~1 min manual efforts per scan), which achieved 0.9713 Pearson correlation compared with the manual segmentation. The results demonstrated that the multi-atlas segmentation is able to achieve accurate spleen segmentation from the multi-contrast splenomegaly MRI scans. PMID- 28649158 TI - Implementation of material decomposition using an EMCCD and CMOS-based micro-CT system. AB - This project assessed the effectiveness of using two different detectors to obtain dual-energy (DE) micro-CT data for the carrying out of material decomposition. A micro-CT coupled to either a complementary metal-oxide semiconductor (CMOS) or an electron multiplying CCD (EMCCD) detector was used to acquire image data of a 3D-printed phantom with channels filled with different materials. At any instance, materials such as iohexol contrast agent, water, and platinum were selected to make up the scanned object. DE micro-CT data was acquired, and slices of the scanned object were differentiated by material makeup. The success of the decomposition was assessed quantitatively through the computation of percentage normalized root-mean-square error (%NRMSE). Our results indicate a successful decomposition of iohexol for both detectors (%NRMSE values of 1.8 for EMCCD, 2.4 for CMOS), as well as platinum (%NRMSE value of 4.7). The CMOS detector performed material decomposition on air and water on average with 7 times more %NRMSE, possibly due to the decreased sensitivity of the CMOS system. Material decomposition showed the potential to differentiate between materials such as the iohexol and platinum, perhaps opening the door for its use in the neurovascular anatomical region. Work supported by Toshiba America Medical Systems, and partially supported by NIH grant 2R01EB002873. PMID- 28649160 TI - Photon-HDF5: Open Data Format and Computational Tools for Timestamp-based Single Molecule Experiments. AB - Archival of experimental data in public databases has increasingly become a requirement for most funding agencies and journals. These data-sharing policies have the potential to maximize data reuse, and to enable confirmatory as well as novel studies. However, the lack of standard data formats can severely hinder data reuse. In photon-counting-based single-molecule fluorescence experiments, data is stored in a variety of vendor-specific or even setup-specific (custom) file formats, making data interchange prohibitively laborious, unless the same hardware-software combination is used. Moreover, the number of available techniques and setup configurations make it difficult to find a common standard. To address this problem, we developed Photon-HDF5 (www.photon-hdf5.org), an open data format for timestamp-based single-molecule fluorescence experiments. Building on the solid foundation of HDF5, Photon-HDF5 provides a platform- and language-independent, easy-to-use file format that is self-describing and supports rich metadata. Photon-HDF5 supports different types of measurements by separating raw data (e.g. photon-timestamps, detectors, etc) from measurement metadata. This approach allows representing several measurement types and setup configurations within the same core structure and makes possible extending the format in backward-compatible way. Complementing the format specifications, we provide open source software to create and convert Photon-HDF5 files, together with code examples in multiple languages showing how to read Photon-HDF5 files. Photon-HDF5 allows sharing data in a format suitable for long term archival, avoiding the effort to document custom binary formats and increasing interoperability with different analysis software. We encourage participation of the single-molecule community to extend interoperability and to help defining future versions of Photon-HDF5. PMID- 28649159 TI - Initial Simulated FFR Investigation Using Flow Measurements in Patient-specific 3D Printed Coronary Phantoms. AB - PURPOSE: Accurate patient-specific phantoms for device testing or endovascular treatment planning can be 3D printed. We expand the applicability of this approach for cardiovascular disease, in particular, for CT-geometry derived benchtop measurements of Fractional Flow Reserve, the reference standard for determination of significant individual coronary artery atherosclerotic lesions. MATERIALS AND METHODS: Coronary CT Angiography (CTA) images during a single heartbeat were acquired with a 320*0.5mm detector row scanner (Toshiba Aquilion ONE). These coronary CTA images were used to create 4 patient-specific cardiovascular models with various grades of stenosis: severe, <75% (n=1); moderate, 50-70% (n=1); and mild, <50% (n=2). DICOM volumetric images were segmented using a 3D workstation (Vitrea, Vital Images); the output was used to generate STL files (using AutoDesk Meshmixer), and further processed to create 3D printable geometries for flow experiments. Multi-material printed models (Stratasys Connex3) were connected to a programmable pulsatile pump, and the pressure was measured proximal and distal to the stenosis using pressure transducers. Compliance chambers were used before and after the model to modulate the pressure wave. A flow sensor was used to ensure flow rates within physiological reported values. RESULTS: 3D model based FFR measurements correlated well with stenosis severity. FFR measurements for each stenosis grade were: 0.8 severe, 0.7 moderate and 0.88 mild. CONCLUSIONS: 3D printed models of patient-specific coronary arteries allows for accurate benchtop diagnosis of FFR. This approach can be used as a future diagnostic tool or for testing CT image based FFR methods. PMID- 28649161 TI - A system to track skin dose for neuro-interventional cone-beam computed tomography (CBCT). AB - The skin-dose tracking system (DTS) provides a color-coded illustration of the cumulative skin-dose distribution on a closely-matching 3D graphic of the patient during fluoroscopic interventions in real-time for immediate feedback to the interventionist. The skin-dose tracking utility of DTS has been extended to include cone-beam computed tomography (CBCT) of neurointerventions. While the DTS was developed to track the entrance skin dose including backscatter, a significant part of the dose in CBCT is contributed by exit primary radiation and scatter due to the many overlapping projections during the rotational scan. The variation of backscatter inside and outside the collimated beam was measured with radiochromic film and a curve was fit to obtain a scatter spread function that could be applied in the DTS. Likewise, the exit dose distribution was measured with radiochromic film for a single projection and a correction factor was determined as a function of path length through the head. Both of these sources of skin dose are added for every projection in the CBCT scan to obtain a total dose mapping over the patient graphic. Results show the backscatter to follow a sigmoidal falloff near the edge of the beam, extending outside the beam as far as 8 cm. The exit dose measured for a cylindrical CTDI phantom was nearly 10 % of the entrance peak skin dose for the central ray. The dose mapping performed by the DTS for a CBCT scan was compared to that measured with radiochromic film and a CTDI-head phantom with good agreement. PMID- 28649162 TI - Scatter estimation and removal of anti-scatter grid-line artifacts from anthropomorphic head phantom images taken with a high resolution image detector. AB - In radiography, one of the best methods to eliminate image-degrading scatter radiation is the use of anti-scatter grids. However, with high-resolution dynamic imaging detectors, stationary anti-scatter grids can leave grid-line shadows and moire patterns on the image, depending upon the line density of the grid and the sampling frequency of the x-ray detector. Such artifacts degrade the image quality and may mask small but important details such as small vessels and interventional device features. Appearance of these artifacts becomes increasingly severe as the detector spatial resolution is improved. We have previously demonstrated that, to remove these artifacts by dividing out a reference grid image, one must first subtract the residual scatter that penetrates the grid; however, for objects with anatomic structure, scatter varies throughout the FOV and a spatially differing amount of scatter must be subtracted. In this study, a standard stationary Smit-Rontgen X-ray grid (line density - 70 lines/cm, grid ratio - 13:1) was used with a high-resolution CMOS detector, the Dexela 1207 (pixel size - 75 micron) to image anthropomorphic head phantoms. For a 15 * 15cm FOV, scatter profiles of the anthropomorphic head phantoms were estimated then iteratively modified to minimize the structured noise due to the varying grid-line artifacts across the FOV. Images of the anthropomorphic head phantoms taken with the grid, before and after the corrections, were compared demonstrating almost total elimination of the artifact over the full FOV. Hence, with proper computational tools, anti-scatter grid artifacts can be corrected, even during dynamic sequences. PMID- 28649163 TI - Sensitivity evaluation of DSA-based parametric imaging using Doppler ultrasound in neurovascular phantoms. AB - An evaluation of the relation between parametric imaging results obtained from Digital Subtraction Angiography (DSA) images and blood-flow velocity measured using Doppler ultrasound in patient-specific neurovascular phantoms is provided. A silicone neurovascular phantom containing internal carotid artery, middle cerebral artery and anterior communicating artery was embedded in a tissue equivalent gel. The gel prevented movement of the vessels when blood mimicking fluid was pumped through it to obtain Colour Doppler images. The phantom was connected to a peristaltic pump, simulating physiological flow conditions. To obtain the parametric images, water was pumped through the phantom at various flow rates (100, 120 and 160 ml/min) and 10 ml contrast boluses were injected. DSA images were obtained at 10 frames/sec from the Toshiba C-arm and DSA image sequences were input into LabVIEW software to get parametric maps from time density curves. The parametric maps were compared with velocities determined by Doppler ultrasound at the internal carotid artery. The velocities measured by the Doppler ultrasound were 38, 48 and 65 cm/s for flow rates of 100, 120 and 160 ml/min, respectively. For the 20% increase in flow rate, the percentage change of blood velocity measured by Doppler ultrasound was 26.3%. Correspondingly, there was a 20% decrease of Bolus Arrival Time (BAT) and 14.3% decrease of Mean Transit Time (MTT), showing strong inverse correlation with Doppler measured velocity. The parametric imaging parameters are quite sensitive to velocity changes and are well correlated to the velocities measured by Doppler ultrasound. PMID- 28649164 TI - Investigation of signal thresholding to reduce the effects of instrument noise of an EMCCD based micro-CT system. AB - This project investigated the signal thresholding effectiveness at reducing the instrument noise of an electron multiplying charged coupled device (EMCCD) based micro-CT system at low x-ray exposure levels. Scans of a mouse spine and an iodine phantom were taken using an EMCCD detector coupled with a micro-CT system. An iodine filter of 4 mg/cm2 area density was placed in the beam. The output signal was thresholded using some multiple of the inherent background noise. For each threshold, 100, 200, and 300 frames were summed for each projection to evaluate the effect on the reconstructed image. The projection images from the scans were compared using line profiles and their SNR. Our results indicate that, as the threshold was increased, the line profiles of the projection images showed less statistical variation, but also lower signal levels, so that the SNR of the projection images decreased as the threshold increased. When the line profile of a projection image obtained using a signal threshold is compared with one obtained using energy integrating mode, the profile obtained using thresholding had less variation than that obtained using energy integration, which indicates less instrument noise. The SNR at the edges of the scan object is higher in the thresholded images when compared with the energy integrated projection images. We conclude that thresholding the output signal from an EMCCD detector at low x-ray exposure levels is an effective method to reduce the instrument noise of an EMCCD detector. PMID- 28649165 TI - Advanced 3D Mesh Manipulation in Stereolithographic Files and Post-Print Processing for the Manufacturing of Patient-Specific Vascular Flow Phantoms. AB - Complex vascular anatomies can cause the failure of image-guided endovascular procedures. 3D printed patient-specific vascular phantoms provide clinicians and medical device companies the ability to preemptively plan surgical treatments, test the likelihood of device success, and determine potential operative setbacks. This research aims to present advanced mesh manipulation techniques of stereolithographic (STL) files segmented from medical imaging and post-print surface optimization to match physiological vascular flow resistance. For phantom design, we developed three mesh manipulation techniques. The first method allows outlet 3D mesh manipulations to merge superfluous vessels into a single junction, decreasing the number of flow outlets and making it feasible to include smaller vessels. Next we introduced Boolean operations to eliminate the need to manually merge mesh layers and eliminate errors of mesh self-intersections that previously occurred. Finally we optimize support addition to preserve the patient anatomical geometry. For post-print surface optimization, we investigated various solutions and methods to remove support material and smooth the inner vessel surface. Solutions of chloroform, alcohol and sodium hydroxide were used to process various phantoms and hydraulic resistance was measured and compared with values reported in literature. The newly mesh manipulation methods decrease the phantom design time by 30 - 80% and allow for rapid development of accurate vascular models. We have created 3D printed vascular models with vessel diameters less than 0.5 mm. The methods presented in this work could lead to shorter design time for patient specific phantoms and better physiological simulations. PMID- 28649166 TI - Probing Charge Transfer and Hot Carrier Dynamics in Organic Solar Cells with Terahertz Spectroscopy. AB - Time-resolved terahertz spectroscopy (TRTS) was used to explore charge generation, transfer, and the role of hot carriers in organic solar cell materials. Two model molecular photovoltaic systems were investigated: with zinc phthalocyanine (ZnPc) or alpha-sexathiophene (alpha-6T) as the electron donors and buckminsterfullerene (C60) as the electron acceptor. TRTS provides charge carrier conductivity dynamics comprised of changes in both population and mobility. By using time-resolved optical spectroscopy in conjunction with TRTS, these two contributions can be disentangled. The sub-picosecond photo-induced conductivity decay dynamics of C60 were revealed to be caused by auto-ionization: the intrinsic process by which charge is generated in molecular solids. In donor acceptor blends, the long-lived photo-induced conductivity is used for weight fraction optimization of the constituents. In nanoscale multilayer films, the photo-induced conductivity identifies optimal layer thicknesses. In films of ZnPc/C60, electron transfer from ZnPc yields hot charges that localize and become less mobile as they thermalize. Excitation of high-lying Franck Condon states in C60 followed by hole-transfer to ZnPc similarly produces hot charge carriers that self-localize; charge transfer clearly precedes carrier cooling. This picture is contrasted to charge transfer in alpha-6T/C60, where hole transfer takes place from a thermalized state and produces equilibrium carriers that do not show characteristic signs of cooling and self-localization. These results illustrate the value of terahertz spectroscopic methods for probing charge transfer reactions. PMID- 28649167 TI - Broadband Radiometric LED Measurements. AB - At present, broadband radiometric measurements of LEDs with uniform and low uncertainty results are not available. Currently, either complicated and expensive spectral radiometric measurements or broadband photometric LED measurements are used. The broadband photometric measurements are based on the CIE standardized V(lambda) function, which cannot be used in the UV range and leads to large errors when blue or red LEDs are measured in its wings, where the realization is always poor. Reference irradiance meters with spectrally constant response and high-intensity LED irradiance sources were developed here to implement the previously suggested broadband radiometric LED measurement procedure [1, 2]. Using a detector with spectrally constant response, the broadband radiometric quantities of any LEDs or LED groups can be simply measured with low uncertainty without using any source standard. The spectral flatness of filtered-Si detectors and low-noise pyroelectric radiometers are compared. Examples are given for integrated irradiance measurement of UV and blue LED sources using the here introduced reference (standard) pyroelectric irradiance meters. For validation, the broadband measured integrated irradiance of several LED-365 sources were compared with the spectrally determined integrated irradiance derived from an FEL spectral irradiance lamp-standard. Integrated responsivity transfer from the reference irradiance meter to transfer standard and field UV irradiance meters is discussed. PMID- 28649168 TI - The Scandinavian Fantasy: The Sources of Intergenerational Mobility in Denmark and the US. AB - This paper examines the sources of differences in social mobility between the U.S. and Denmark. Measured by income mobility, Denmark is a more mobile society, but not when measured by educational mobility. There are pronounced nonlinearities in income and educational mobility in both countries. Greater Danish income mobility is largely a consequence of redistributional tax, transfer, and wage compression policies. While Danish social policies for children produce more favorable cognitive test scores for disadvantaged children, these do not translate into more favorable educational outcomes, partly because of disincentives to acquire education arising from the redistributional policies that increase income mobility. PMID- 28649169 TI - Form Overrides Meaning When Bilinguals Monitor for Errors. AB - Bilinguals rarely produce unintended language switches, which may in part be because switches are detected and corrected by an internal monitor. But are language switches easier or harder to detect than within-language semantic errors? To approximate internal monitoring, bilinguals listened (Experiment 1) or read aloud (Experiment 2) stories, and detected language switches (translation equivalents or semantically unrelated to expected words) and within-language errors (semantically related or unrelated to expected words). Bilinguals detected semantically related within-language errors most slowly and least accurately, language switches more quickly and accurately than within-language errors, and (in Experiment 2), translation equivalents as quickly and accurately as unrelated language switches. These results suggest that internal monitoring of form (which can detect mismatches in language membership) completes earlier than, and is independent of, monitoring of meaning. However, analysis of reading times prior to error detection revealed meaning violations to be more disruptive for processing than language violations. PMID- 28649170 TI - Examination of the Relationship Between PTSD and Distress Tolerance in a Sample of Male Veterans With Comorbid Substance Use Disorders. AB - Distress tolerance (DT), the perceived or actual ability to tolerate negative emotional or physical states, is inversely related to posttraumatic stress disorder (PTSD) symptoms in civilian, community samples. No studies to date have examined the relationship between DT and PTSD in clinical samples of veterans with a comorbid diagnosis of PTSD and a substance use disorder (SUD). Thus, the present study examined the relationship between DT and PTSD in a sample of predominately African American, male veterans (n = 75) diagnosed with comorbid PTSD and SUD (according to a structured clinical interview). Results of hierarchical linear regression models indicated that DT was inversely related to total PTSD symptom severity score, above and beyond depressive symptoms and SUD severity. Of the 4 symptom clusters, DT was inversely associated with intrusions and hyperarousal. These findings are discussed in light of previous work with civilian samples. Determining whether treatment incorporating DT skills would be useful for veterans undergoing PTSD treatment should be evaluated. PMID- 28649172 TI - CONTROL FUNCTION ASSISTED IPW ESTIMATION WITH A SECONDARY OUTCOME IN CASE-CONTROL STUDIES. AB - Case-control studies are designed towards studying associations between risk factors and a single, primary outcome. Information about additional, secondary outcomes is also collected, but association studies targeting such secondary outcomes should account for the case-control sampling scheme, or otherwise results may be biased. Often, one uses inverse probability weighted (IPW) estimators to estimate population effects in such studies. IPW estimators are robust, as they only require correct specification of the mean regression model of the secondary outcome on covariates, and knowledge of the disease prevalence. However, IPW estimators are inefficient relative to estimators that make additional assumptions about the data generating mechanism. We propose a class of estimators for the effect of risk factors on a secondary outcome in case-control studies that combine IPW with an additional modeling assumption: specification of the disease outcome probability model. We incorporate this model via a mean zero control function. We derive the class of all regular and asymptotically linear estimators corresponding to our modeling assumption, when the secondary outcome mean is modeled using either the identity or the log link. We find the efficient estimator in our class of estimators and show that it reduces to standard IPW when the model for the primary disease outcome is unrestricted, and is more efficient than standard IPW when the model is either parametric or semiparametric. PMID- 28649173 TI - Markov Chain Monte Carlo Inference of Parametric Dictionaries for Sparse Bayesian Approximations. AB - Parametric dictionaries can increase the ability of sparse representations to meaningfully capture and interpret the underlying signal information, such as encountered in biomedical problems. Given a mapping function from the atom parameter space to the actual atoms, we propose a sparse Bayesian framework for learning the atom parameters, because of its ability to provide full posterior estimates, take uncertainty into account and generalize on unseen data. Inference is performed with Markov Chain Monte Carlo, that uses block sampling to generate the variables of the Bayesian problem. Since the parameterization of dictionary atoms results in posteriors that cannot be analytically computed, we use a Metropolis-Hastings-within-Gibbs framework, according to which variables with closed-form posteriors are generated with the Gibbs sampler, while the remaining ones with the Metropolis Hastings from appropriate candidate-generating densities. We further show that the corresponding Markov Chain is uniformly ergodic ensuring its convergence to a stationary distribution independently of the initial state. Results on synthetic data and real biomedical signals indicate that our approach offers advantages in terms of signal reconstruction compared to previously proposed Steepest Descent and Equiangular Tight Frame methods. This paper demonstrates the ability of Bayesian learning to generate parametric dictionaries that can reliably represent the exemplar data and provides the foundation towards inferring the entire variable set of the sparse approximation problem for signal denoising, adaptation and other applications. PMID- 28649174 TI - A Multitaper, Causal Decomposition for Stochastic, Multivariate Time Series: Application to High-Frequency Calcium Imaging Data. AB - Neural data analysis has increasingly incorporated causal information to study circuit connectivity. Dimensional reduction forms the basis of most analyses of large multivariate time series. Here, we present a new, multitaper-based decomposition for stochastic, multivariate time series that acts on the covariance of the time series at all lags, C(tau), as opposed to standard methods that decompose the time series, X(t), using only information at zero-lag. In both simulated and neural imaging examples, we demonstrate that methods that neglect the full causal structure may be discarding important dynamical information in a time series. PMID- 28649171 TI - Injectable scaffolds: Preparation and application in dental and craniofacial regeneration. AB - Injectable scaffolds are appealing for tissue regeneration because they offer many advantages over pre-formed scaffolds. This article provides a comprehensive review of the injectable scaffolds currently being investigated for dental and craniofacial tissue regeneration. First, we provide an overview of injectable scaffolding materials, including natural, synthetic, and composite biomaterials. Next, we discuss a variety of characteristic parameters and gelation mechanisms of the injectable scaffolds. The advanced injectable scaffolding systems developed in recent years are then illustrated. Furthermore, we summarize the applications of the injectable scaffolds for the regeneration of dental and craniofacial tissues that include pulp, dentin, periodontal ligament, temporomandibular joint, and alveolar bone. Finally, our perspectives on the injectable scaffolds for dental and craniofacial tissue regeneration are offered as signposts for the future advancement of this field. PMID- 28649175 TI - An efficient methodology to introduce o-(aminomethyl)phenyl-boronic acids into peptides: alkylation of secondary amines. AB - Current approaches for incorporating boronic acids into peptides require one of the following: the synthesis of commercially unavailable pinacol-protected boronate ester amino acid building blocks, amidation of small-molecule amine containing boronic acids, or reductive amination of amine residues with 2 formylphenyl boronic acid. These methods have drawbacks, such as the use of excess starting materials, the lack of reactive-site specificity, or the inability to add multiple boronic acids in solution. In addition, several of these approaches do not allow for incorporation of the critical o-aminomethyl functionality that allows for binding of sacharrides under physiological conditions. In this work, we report three methods to functionalize synthetic peptides with boronic acids using solid-phase and solution-phase chemistries by alkylating a secondary amine with o-(bromomethyl)phenylboronic acid. Solution phase chemistries afforded the highest yields, and were used to synthesize seven complex biotinylated multi-boronic acid peptides. PMID- 28649176 TI - 4-Aminoquinaldine monohydrate polymorphism: Prediction and impurity aided discovery of a difficult to access stable form. AB - Crystal structure prediction studies indicated the existence of an unknown high density monohydrate structure (Hy1B degrees ) as global energy minimum for 4 aminoquinaldine (4-AQ). We thus performed an interdisciplinary experimental and computational study elucidating the crystal structures, solid form inter relationships, kinetic and thermodynamic stabilities of the stable anhydrate (AH I degrees ), the kinetic monohydrate (Hy1A ) and this novel monohydrate polymorph (Hy1B degrees ) of 4-AQ. The crystal structure of Hy1B degrees was determined by combining laboratory powder X-ray diffraction data and ab initio calculations. Dehydration studies with differential scanning calorimetry and solubility measurements confirmed the result of the lattice energy calculations, which identified Hy1B degrees as the thermodynamically most stable hydrate form. At 25 degrees C the equilibrium of the 4-AQ hydrate/anhydrate system was observed at an aw (water activity) of 0.14. The finding of Hy1B degrees was complicated by the fact that the metastable but kinetically stable Hy1A shows a higher nucleation and growth rate. The presence of an impurity in an available 4-AQ sample facilitated the nucleation of Hy1B degrees , whose crystallisation is favored under hydrothermal conditions. The value of combining experimental with theoretical studies in hydrate screening and characterisation, as well as the reasons for hydrate formation in 4-AQ, are discussed. PMID- 28649177 TI - Nucleic acid extraction from formalin-fixed paraffin-embedded cancer cell line samples: a trade off between quantity and quality? AB - BACKGROUND: Advanced genomic techniques such as Next-Generation-Sequencing (NGS) and gene expression profiling, including NanoString, are vital for the development of personalised medicines, as they enable molecular disease classification. This has become increasingly important in the treatment of cancer, aiding patient selection. However, it requires efficient nucleic acid extraction often from formalin-fixed paraffin-embedded tissue (FFPE). METHODS: Here we provide a comparison of several commercially available manual and automated methods for DNA and/or RNA extraction from FFPE cancer cell line samples from Qiagen, life Technologies and Promega. Differing extraction geometric mean yields were evaluated across each of the kits tested, assessing dual DNA/RNA extraction vs. specialised single extraction, manual silica column based extraction techniques vs. automated magnetic bead based methods along with a comparison of subsequent nucleic acid purity methods, providing a full evaluation of nucleic acids isolated. RESULTS: Out of the four RNA extraction kits evaluated the RNeasy FFPE kit, from Qiagen, gave superior geometric mean yields, whilst the Maxwell 16 automated method, from Promega, yielded the highest quality RNA by quantitative real time RT-PCR. Of the DNA extraction kits evaluated the PicoPure DNA kit, from Life Technologies, isolated 2-14* more DNA. A miniaturised qPCR assay was developed for DNA quantification and quality assessment. CONCLUSIONS: Careful consideration of an extraction kit is necessary dependent on quality or quantity of material required. Here we provide a flow diagram on the factors to consider when choosing an extraction kit as well as how to accurately quantify and QC the extracted material. PMID- 28649178 TI - HOTAIR: a key regulator in gynecologic cancers. AB - Long non-coding RNAs (lncRNAs) play critical roles in the initiation and progression of human cancers. HOX transcript antisense RNA (HOTAIR) is an lncRNA localized to the mammalian HOXC gene cluster; it can interact with polycomb repressive complex 2 and the lysine-specific histone demethylase/CoREST/REST complex, and it manipulates the expression of various genes. HOTAIR promotes tumor invasion and metastasis by silencing tumor suppressors, and activating oncogenes and signaling pathways. HOTAIR is deregulated in many human cancers; despite its critical roles in health and disease, the underlying mechanisms governing HOTAIR function are unknown. In this review, we summarize the recent findings on the roles of HOTAIR in gynecologic cancers. PMID- 28649180 TI - Procoagulatory changes induced by head-up tilt test in patients with syncope: observational study. AB - BACKGROUND: Orthostatic hypercoagulability is proposed as a mechanism promoting cardiovascular and thromboembolic events after awakening and during prolonged orthostasis. We evaluated early changes in coagulation biomarkers induced by tilt testing among patients investigated for suspected syncope, aiming to test the hypothesis that orthostatic challenge evokes procoagulatory changes to a different degree according to diagnosis. METHODS: One-hundred-and-seventy-eight consecutive patients (age, 51 +/- 21 years; 46% men) were analysed. Blood samples were collected during supine rest and after 3 min of 70 degrees head-up tilt test (HUT) for determination of fibrinogen, von Willebrand factor antigen (VWF:Ag) and activity (VWF:GP1bA), factor VIII (FVIII:C), lupus anticoagulant (LA1), functional APC-resistance, and activated prothrombin time (APTT) with and without activated protein C (C+/-). Analyses were stratified according to age, sex and diagnosis. RESULTS: After 3 min in the upright position, VWF:Ag (1.28 +/- 0.55 vs. 1.22 +/- 0.54; p < 0.001) and fibrinogen (2.84 +/- 0.60 vs. 2.75 +/- 0.60, p < 0.001) increased, whereas APTT/C+/- (75.1 +/- 18.8 vs. 84.3 +/- 19.6 s; p < 0.001, and 30.8 +/- 3.7 vs. 32.1 +/- 3.8 s; p < 0.001, respectively) and APC resistance (2.42 +/- 0.43 vs. 2.60 +/- 0.41, p < 0.001) decreased compared with supine values. Significant changes in fibrinogen were restricted to women (p < 0.001) who also had lower LA1 during HUT (p = 0.007), indicating increased coagulability. Diagnosis vasovagal syncope was associated with less increase in VWF:Ag during HUT compared to other diagnoses (0.01 +/- 0.16 vs. 0.09 +/- 0.17; p = 0.004). CONCLUSIONS: Procoagulatory changes in haemostatic plasma components are observed early during orthostasis in patients with history of syncope, irrespective of syncope aetiology. These findings may contribute to the understanding of orthostatic hypercoagulability and chronobiology of cardiovascular disease. PMID- 28649179 TI - The hepatocyte proteome in organotypic rat liver models and the influence of the local microenvironment. AB - BACKGROUND: Liver models that closely mimic the in vivo microenvironment are useful for understanding liver functions, capabilities, and intercellular communication processes. Three-dimensional (3D) liver models assembled using hepatocytes and liver sinusoidal endothelial cells (LSECs) separated by a polyelectrolyte multilayer (PEM) provide a functional system while also permitting isolation of individual cell types for proteomic analyses. METHODS: To better understand the mechanisms and processes that underlie liver model function, hepatocytes were maintained as monolayers and 3D PEM-based formats in the presence or absence of primary LSECs. The resulting hepatocyte proteomes, the proteins in the PEM, and extracellular levels of urea, albumin and glucose after three days of culture were compared. RESULTS: All systems were ketogenic and found to release glucose. The presence of the PEM led to increases in proteins associated with both mitochondrial and peroxisomal-based beta-oxidation. The PEMs also limited production of structural and migratory proteins associated with dedifferentiation. The presence of LSECs increased levels of Phase I and Phase II biotransformation enzymes as well as several proteins associated with the endoplasmic reticulum and extracellular matrix remodeling. The proteomic analysis of the PEMs indicated that there was no significant change after three days of culture. These results are discussed in relation to liver model function. CONCLUSIONS: Heterotypic cell-cell and cell-ECM interactions exert different effects on hepatocyte functions and phenotypes. PMID- 28649181 TI - Fast Chemical Exchange Saturation Transfer (CEST) Imaging with Variably accelerated Sensitivity Encoding (vSENSE). AB - CEST imaging has numerous applications, but its widespread clinical use is hampered by relatively long acquisition times. Here, a novel variably-accelerated sensitivity encoding (vSENSE) method is proposed that provides faster CEST acquisitions than conventional SENSE. The vSENSE approach undersamples k-space variably for images acquired at different saturation frequencies to maximize acquisition speed. vSENSE was validated in a phantom and in 8 patients with brain tumors studied at 3T. The vSENSE method provided a 4-fold acceleration, compared to conventional SENSE which permitted only a 2-fold acceleration, with both compared to a full k-space reconstruction. PMID- 28649182 TI - Highly-accelerated CEST Measurements in Three Dimensions with Linear Algebraic Modeling. AB - CEST MRI can provide valuable molecular level information in vivo, but its translation to routine clinics is hindered by long imaging times. Regional average CEST measurements often suffice for quantitative evaluation, diagnosis, and treatment assessment, while allowing much shorter scan times. Recently, the spectroscopy with linear algebraic modeling (SLAM) method was adapted for CEST MRI in two dimensions (2D), directly obtaining compartmental-average measurements manifold faster than conventional CEST. Here, the SLAM CEST method is extended from 2D to 3D, and applied to patients with brain tumors with acceleration factors of up to 98-fold. PMID- 28649183 TI - Highly Accelerated, Intravascular T1, T2, and Proton Density Mapping with Linear Algebraic Modeling and Sensitivity Profile Correction at 3T. AB - Vessel wall MRI with intravascular (IV) detectors can produce superior local signal-to-noise ratios (SNR) and generate high-resolution T1, T2, and proton density (PD) maps that could be used to automatically classify atherosclerotic lesion stage. However, long acquisition times potentially limit multi-parametric mapping. Here, for the first time, spectroscopy with linear algebraic modeling (SLAM) is applied to yield accurate compartment-average T1, T2 and PD measures at least 10 times faster compared to a standard full k-space reconstructed MIX-TSE sequence at 3T. Simple phase and magnitude sensitivity corrections are incorporated into the SLAM reconstruction to compensate for IV detector non uniformity. PMID- 28649184 TI - The role of avoidance in complicated grief: A detailed examination of the Grief Related Avoidance Questionnaire (GRAQ) in a large sample of individuals with complicated grief. PMID- 28649185 TI - A Remarkable Resurgence of Artificial Intelligence and its Impact on Automation and Autonomy. PMID- 28649186 TI - A SAS Macro for Covariate-Constrained Randomization of General Cluster-Randomized and Unstratified Designs. AB - Ivers et al. (2012) have recently stressed the importance to both statistical power and face validity of balancing allocations to study arms on relevant covariates. While several techniques exist (e.g., minimization, pair-matching, stratification), the covariate-constrained randomization (CCR) approach proposed by Moulton (2004) is favored when clusters can be recruited prior to randomization. CCRA V1.0, a macro published by Chaudhary and Moulton (2006), provides a SAS implementation of CCR for a particular subset of possible designs (those with two arms, small numbers of strata and clusters, an equal number of clusters within each stratum, and constraints that can be expressed as absolute mean differences between arms). This paper presents a more comprehensive macro, CCR, that is applicable across a wider variety of designs and provides statistics describing the range of possible allocations meeting the constraints in addition to performing the actual random assignment. PMID- 28649187 TI - Distinct proteome pathology of circulating microparticles in systemic lupus erythematosus. AB - BACKGROUND: The pathogenesis of systemic lupus erythematosus (SLE) is poorly understood but has been linked to defective clearance of subcellular particulate material from the circulation. This study investigates the origin, formation, and specificity of circulating microparticles (MPs) in patients with SLE based on comprehensive MP proteome profiling using patients with systemic sclerosis (SSc) and healthy donors (HC) as controls. METHODS: We purified MPs from platelet-poor plasma using differential centrifugation of samples from SLE (n = 45), SSc (n = 38), and two sets of HC (n = 35, n = 25). MP proteins were identified and quantitated after trypsin digestion by liquid chromatography-tandem mass spectrometry. The abundance of specific proteins was compared between the groups using univariate statistics and false discovery rate correction for multiple comparisons. Specific proteins and protein ratios were explored for diagnostic and disease activity information using receiver-operating characteristic curves and by analysis of correlations of protein abundance with disease activity scores. RESULTS: We identify and quantitate more than 1000 MP proteins and show that a subpopulation of SLE-MPs (which we propose to call luposomes) are highly specific for SLE, i.e. not found in MP preparations from HC or patients with another autoimmune, systemic disease, SSc. In SLE-MPs platelet proteins and mitochondrial proteins are significantly diminished, cytoskeletal proteins deranged, and glycolytic enzymes and apoptotic proteins significantly increased. CONCLUSIONS: Normal MPs are efficiently removed in SLE, but aberrant MPs, derived from non-lymphoid leukocytes, are less efficiently removed and abundantly produced leading to an altered MP proteome in SLE. The data suggest that an abnormal generation of MPs may partake in the pathology of SLE and that new diagnostic, monitoring, and treatment strategies targeting these processes may be advantageous. PMID- 28649189 TI - Intelligence Level Performance Standards Research for Autonomous Vehicles. AB - United States and European safety standards have evolved to protect workers near Automatic Guided Vehicles (AGV's). However, performance standards for AGV's and mobile robots have only recently begun development. Lessons can be learned from research and standards efforts for mobile robots applied to emergency response and military applications. Research challenges, tests and evaluations, and programs to develop higher intelligence levels for vehicles can also used to guide industrial AGV developments towards more adaptable and intelligent systems. These other efforts also provide useful standards development criteria for AGV performance test methods. Current standards areas being considered for AGVs are for docking, navigation, obstacle avoidance, and the ground truth systems that measure performance. This paper provides a look to the future with standards developments in both the performance of vehicles and the dynamic perception systems that measure intelligent vehicle performance. PMID- 28649188 TI - Using Video Conferencing to Deliver a Brief Motivational Intervention for Alcohol and Sex Risk to Emergency Department Patients: A Proof-of-Concept Pilot Study. AB - Brief motivational intervention (MI) is an efficacious approach to reduce heavy drinking and associated sexual risk behavior among Emergency Department (ED) patients, but the intensity of demands placed on ED staff makes the implementation of in-person MIs logistically challenging. This proof-of-concept pilot study examined the acceptability and logistic feasibility of using video conferencing technology to deliver an MI targeting heavy drinking and risky sexual behavior to patients in an ED setting. Rigorous screening procedures were employed to ensure that the pilot sample represents the target portion of ED patients who would benefit from this multi-target MI. Mixed qualitative and quantitative data from a sample of seven ED patients (57% Female; Mage = 35 years) who received MI by video conference consistently demonstrated high levels of satisfaction, engagement, and acceptability. The observed completion rate supports logistic feasibility, and patient feedback identified methods to improve the experience by using high-definition hardware, ensuring stronger network connectivity, and effectively communicating information regarding protection of privacy. Post-intervention patient ratings and independent ratings of the audio recorded sessions (using the Motivational Interviewing Skills Coding system) were very high, suggesting that intervention fidelity and MI adherence was not compromised by delivery modality. Collectively, these data suggest video conferencing is a viable technology that can be employed to implement brief evidence-based MIs in ED settings. PMID- 28649190 TI - Effects of Light and Sound on the Prefrontal Cortex Activation and Emotional Function: A Functional Near-Infrared Spectroscopy Study. AB - We constructed a near infrared spectroscopy-based real-time feedback system to estimate the subjects' emotional states using the changes in oxygenated hemoglobin concentration [Delta(oxy-Hb)] in the prefrontal cortex (PFC). Using this system, we investigated the influences of continual mild and equivocal stimuli consisting of lights and a reconstructed waterfall sound on Delta[oxy-Hb] in the PFC. The visual (light) and auditory (sound) stimuli changed randomly and independently, depending on the emotional states of the individual subjects. The emotional states induced by the stimuli were examined via a questionnaire rated on an 11-point scale, from +5 (pleasant) to -5 (unpleasant), through 0 (neutral), after the 5-min experiments. Results from 757 subjects revealed that Delta[oxy Hb] in the PFC exhibited a weak, but significant, correlation with emotional change, with the given continual and mild stimuli similar to that experienced in response to the intense pleasant/unpleasant stimuli. Based on the results we discuss the generation of pleasant/unpleasant weak emotional change induced by mild and weak stimuli such as light and sound. PMID- 28649191 TI - Editorial: Metabolic Control of Brain Homeostasis. PMID- 28649192 TI - Deleterious Effects of Chronic Folate Deficiency in the Ts65Dn Mouse Model of Down Syndrome. AB - Folate is an important B vitamin naturally found in the human diet and plays a critical role in methylation of nucleic acids. Indeed, abnormalities in this major epigenetic mechanism play a pivotal role in the pathogenesis of cognitive deficit and intellectual disability in humans. The most common cause of cognitive dysfunction in children is Down syndrome (DS). Since folate deficiency is very common among the pediatric population, we questioned whether chronic folate deficiency (CFD) exacerbates cognitive dysfunction in a mouse model of DS. To test this, adult Ts65Dn mice and their disomic littermates were chronically fed a diet free of folic acid while preventing endogenous production of folate in the digestive tract for a period of 8 weeks. Our results show that the Ts65Dn mouse model of DS was significantly more vulnerable to CFD in terms of plasma homocysteine and N5-methyltetrahydrofolate (5-MTHF) levels. Importantly, these changes were linked to degenerative alterations in hippocampal dendritic morphology and impaired nest building behavior in Ts65Dn mice. Based on our results, a rigorous examination of folate intake and its metabolism in individuals with DS is warranted. PMID- 28649193 TI - Repeated Low Intensity Blast Exposure Is Associated with Damaged Endothelial Glycocalyx and Downstream Behavioral Deficits. AB - Current clinical research into mild traumatic brain injury (mTBI) has focused on white matter changes as identified by advanced MRI based imaging techniques. However, perivascular tau accumulation in the brains of individuals diagnosed with mTBI suggests that the vasculature plays a key role in the pathology. This study used a rat model to examine whether the endothelial glycocalyx, a layer of the vasculature responsible for sensing luminal shear forces, is damaged by exposure to repeated low intensity blast, and whether this layer is associated with observed behavioral deficits. The blast exposure used consisted of 12, 40 kPa blast exposures conducted with a minimum of 24 h between blasts. We found that repeated blast exposure reduced glycocalyx length and density in various brain regions indicating damage. This blast exposure paradigm was associated with a mild performance decrement in the Morris water maze (MWM) which assesses learning and memory. Administration of hyaluronidase, an enzyme that binds to and degrades hyaluronan (a major structural component of the glycocalyx) prior to blast exposure reduced the observed behavioral deficits and induced a thickening of the glycocalyx layer. Taken together these findings demonstrate that the endothelial glycocalyx degradation following repeated blast is associated with behavioral decrements which can be prevented by treatment with hyaluronidase. PMID- 28649194 TI - Seeing Double: Exploring the Phenomenology of Self-Reported Absence of Rivalry in Bistable Pictures. AB - Ambiguous images such as Rubin's vase-face can be interpreted in at least two different ways. These interpretations are typically taken to be mutually exclusive, and ambiguous images have thus served as models of perceptual competition. Here, we present data that challenges this view. In an online survey, we found that a large proportion of people within the general population reported that the two percepts were not competing but could be perceived simultaneously. Of those who reported that they could see both percepts simultaneously, we invited 17 participants to take part in a functional magnetic resonance imaging (fMRI) experiment. In the scanner, participants saw images that could be interpreted as either a landscape or a face and reported at every point in time whether they perceived predominantly the face, the landscape, or both simultaneously. We explored behavioral and neurophysiological (with fMRI) correlates of the reported subjective experience of entertaining two percepts simultaneously by comparing them to those of the simple percepts (i.e., face or landscape). First, by comparing percept durations, we found that the simultaneous state was as stable as the two other percepts. Second, by measuring blood-oxygen level-dependent (BOLD) signal levels within the fusiform face area (FFA), occipital face area (OFA) and parahippocampal place area (PPA), we found evidence from objective data that confirmed the subjective reports. While the results in FFA and OFA were not conclusive, in PPA, BOLD signal levels during subjective reports of perceiving both a landscape and a face were lower than the BOLD signal levels associated with reports of perceiving a landscape (and, in turn, reports of seeing a landscape were associated with greater BOLD signal levels than reports of seeing a face, thus suggesting that BOLD signal levels in PPA are a valid correlate of subjective experience in this task). In sum, the objective measures suggest that entertaining two percepts simultaneously in mind can be regarded as a distinct (mixed) perceptual state. We argue with these results that a more central role of subjective report in cognitive neuroscience is sometimes warranted. PMID- 28649195 TI - Modulating STDP Balance Impacts the Dendritic Mosaic. AB - The ability for cortical neurons to adapt their input/output characteristics and information processing capabilities ultimately relies on the interplay between synaptic plasticity, synapse location, and the nonlinear properties of the dendrite. Collectively, they shape both the strengths and spatial arrangements of convergent afferent inputs to neuronal dendrites. Recent experimental and theoretical studies support a clustered plasticity model, a view that synaptic plasticity promotes the formation of clusters or hotspots of synapses sharing similar properties. We have previously shown that spike timing-dependent plasticity (STDP) can lead to synaptic efficacies being arranged into spatially segregated clusters. This effectively partitions the dendritic tree into a tessellated imprint which we have called a dendritic mosaic. Here, using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and STDP learning, we investigated the impact of altered STDP balance on forming such a spatial organization. We show that cluster formation and extend depend on several factors, including the balance between potentiation and depression, the afferents' mean firing rate and crucially on the dendritic morphology. We find that STDP balance has an important role to play for this emergent mode of spatial organization since any imbalances lead to severe degradation- and in some case even destruction- of the mosaic. Our model suggests that, over a broad range of of STDP parameters, synaptic plasticity shapes the spatial arrangement of synapses, favoring the formation of clustered efficacy engrams. PMID- 28649196 TI - Estimation of Time-Varying, Intrinsic and Reflex Dynamic Joint Stiffness during Movement. Application to the Ankle Joint. AB - Dynamic joint stiffness determines the relation between joint position and torque, and plays a vital role in the control of posture and movement. Dynamic joint stiffness can be quantified during quasi-stationary conditions using disturbance experiments, where small position perturbations are applied to the joint and the torque response is recorded. Dynamic joint stiffness is composed of intrinsic and reflex mechanisms that act and change together, so that nonlinear, mathematical models and specialized system identification techniques are necessary to estimate their relative contributions to overall joint stiffness. Quasi-stationary experiments have demonstrated that dynamic joint stiffness is heavily modulated by joint position and voluntary torque. Consequently, during movement, when joint position and torque change rapidly, dynamic joint stiffness will be Time-Varying (TV). This paper introduces a new method to quantify the TV intrinsic and reflex components of dynamic joint stiffness during movement. The algorithm combines ensemble and deterministic approaches for estimation of TV systems; and uses a TV, parallel-cascade, nonlinear system identification technique to separate overall dynamic joint stiffness into intrinsic and reflex components from position and torque records. Simulation studies of a stiffness model, whose parameters varied with time as is expected during walking, demonstrated that the new algorithm accurately tracked the changes in dynamic joint stiffness using as little as 40 gait cycles. The method was also used to estimate the intrinsic and reflex dynamic ankle stiffness from an experiment with a healthy subject during which ankle movements were imposed while the subject maintained a constant muscle contraction. The method identified TV stiffness model parameters that predicted the measured torque very well, accounting for more than 95% of its variance. Moreover, both intrinsic and reflex dynamic stiffness were heavily modulated through the movement in a manner that could not be predicted from quasi-stationary experiments. The new method provides the tool needed to explore the role of dynamic stiffness in the control of movement. PMID- 28649197 TI - A Minimal Model Describing Hexapedal Interlimb Coordination: The Tegotae-Based Approach. AB - Insects exhibit adaptive and versatile locomotion despite their minimal neural computing. Such locomotor patterns are generated via coordination between leg movements, i.e., an interlimb coordination, which is largely controlled in a distributed manner by neural circuits located in thoracic ganglia. However, the mechanism responsible for the interlimb coordination still remains elusive. Understanding this mechanism will help us to elucidate the fundamental control principle of animals' agile locomotion and to realize robots with legs that are truly adaptive and could not be developed solely by conventional control theories. This study aims at providing a "minimal" model of the interlimb coordination mechanism underlying hexapedal locomotion, in the hope that a single control principle could satisfactorily reproduce various aspects of insect locomotion. To this end, we introduce a novel concept we named "Tegotae," a Japanese concept describing the extent to which a perceived reaction matches an expectation. By using the Tegotae-based approach, we show that a surprisingly systematic design of local sensory feedback mechanisms essential for the interlimb coordination can be realized. We also use a hexapod robot we developed to show that our mathematical model of the interlimb coordination mechanism satisfactorily reproduces various insects' gait patterns. PMID- 28649199 TI - GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Attenuates Cerebral Ischemia Injury In Vivo and Vitro by Differential Modulations of NMDA Receptors Subunit Components at Different Post-Ischemia Stage in Mice. AB - Excessive activation of NMDA receptors (NMDARs) is implicated in pathological synaptic plasticity also known as post-ischemic long-term potentiation (i-LTP) which was produced by glutamate mediated excitotoxicity after stroke. In the past decades, many NMDARs inhibitors failed in clinical investigations due to severe psychotomimetic side effects. GLYX-13 is a NMDAR modulator with glycine site partial agonist properties and has potential protective effects on ischemic neuronal death. However, the underlying molecular mechanism of GLYX-13 attenuating the ischemic neuronal damage remains elusive. Our study was conducted to examine the molecular, cellular and behavioral actions of GLYX-13 in stroke, and further characterize the mechanism underlying the neuroprotective actions via modulation of the NMDAR subunit composition. In present study we found that in vitro oxygen-glucose deprivation (OGD) stroke model, GLYX-13 blocked i-LTP and restored the ratio of NR2A/NR2B subunit composition. The glycine site of NMDARs full coagonist D-serine completely blocked the effects of GLYX-13 on i-LTP. Besides, in vivo middle cerebral artery occlusion (MCAO) model, GLYX-13 decreased the cerebral infarct volume and reduced injury of hippocampus. Western analysis showed that GLYX-13 down-regulated the expression of phosphorylated NR2B (Tyr1472) and up-regulated phosphorylated NR2A (Tyr1325). Furthermore, GLYX-13 treatment along with NR2B specific antagonist (Ro256981) failed to exhibit any additional neuro-protective effects, whereas the application of NR2A antagonist (NVP-AAM007) abolished the neuroprotective effects of GLYX-13, which suggested that the protective action of GLYX-13 should be by its regulation of NMDAR subunit components. Our study provides important insights on the potential protective mechanism of GLYX-13 in ischemia and proposes the glycine site of NMDARs as a novel target for developing therapeutic strategies to store synaptic function in stroke. PMID- 28649198 TI - The Role of Retinal Carotenoids and Age on Neuroelectric Indices of Attentional Control among Early to Middle-Aged Adults. AB - One apparent consequence of aging appears to be loss of some aspects of cognitive control. This loss is measurable as early as mid-adulthood. Since, like many aspects of cognition, there is wide variance among individuals, it is possible that behavior, such as one's diet, could drive some of these differences. For instance, past data on older humans and non-human primates have suggested that dietary carotenoids could slow cognitive decline. In this study, we tested how early such protection might manifest by examining a sample (n = 60) of 25-45 year olds. Carotenoid status was assessed by directly measuring macular pigment optical density (MPOD) which has shown to be highly correlated with the primary carotenoid in brain, lutein. Cognitive control was measured using event-related potentials during the performance of cognitive control tasks designed to tap into different aspects of attentional (i.e., selective attention, attentional inhibition, and response inhibition) control. Our results showed that, across participants, MPOD was related to both age and the P3 component of participants' neuroelectric profile (P3 amplitude) for attentional, but not response, inhibition. Although younger adults exhibited larger P3 amplitudes than their older adult counterparts, older subjects with higher MPOD levels displayed P3 indices similar to their younger adult counterparts in amplitude. Furthermore, hierarchical regression analyses showed that age was no longer a significant predictor of P3 amplitude when MPOD was included as a predictor in the model, suggesting that MPOD may partially contribute to the relationship between age and P3 amplitude. In addition, age and MPOD were shown to have independent associations with intraindividual variability of attentional control, such that younger individuals and individuals with higher MPOD showed less intraindividual variability. These results show a relationship between retinal carotenoids and neuroelectric indices underlying cognitive control. The protective role of carotenoids within the CNS may be evident during early and middle adulthood, decades prior to the onset of older age. PMID- 28649200 TI - Cognitive Variability during Middle-Age: Possible Association with Neurodegeneration and Cognitive Reserve. AB - Objective: Increased variability in cognition with age has been argued as an indication of pathological processes. Focusing on early detection of neurodegenerative disorders, we investigated variability in cognition in healthy middle-aged adults. In order to understand possible determinants of this variability, we also investigated associations with cognitive reserve, neuroimaging markers, subjective memory complaints, depressive symptomatology, and gender. Method: Thirty-one 50 +/- 2 years old individuals were investigated as target group and deviation was studied in comparison to a reference younger group of 30 individuals 40 +/- 2 years old. Comprehensive neuropsychological and structural imaging protocols were collected. Brain regional volumes and cortical thickness were calculated with FreeSurfer, white matter hyperintensities with CASCADE, and mean diffusivity with FSL. Results: Across-individuals variability showed greater dispersion in lexical access, processing speed, executive functions, and memory. Variability in global cognition correlated with, reduced cortical thickness in the right parietal-temporal-occipital association cortex, and increased mean diffusivity in the cingulum bundle and right inferior fronto occipital fasciculus. A trend was also observed for the correlation between global cognition and hippocampal volume and female gender. All these associations were influenced by cognitive reserve. No correlations were found with subjective memory complaints, white matter hyperintensities and depressive symptomatology. Across-domains and across-tasks variability was greater in several executive components and cognitive processing speed. Conclusion: Variability in cognition during middle-age is associated with neurodegeneration in the parietal-temporal occipital association cortex and white matter tracts connecting this to the prefrontal dorsolateral cortex and the hippocampus. Moreover, this effect is influenced by cognitive reserve. Studying variability offers valuable information showing that differences do not occur in the same magnitude and direction across individuals, cognitive domains and tasks. These findings may have important implications for early detection of subtle cognitive impairment and clinical interpretation of deviation from normality. PMID- 28649201 TI - Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation. AB - Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2 ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan 2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects. PMID- 28649202 TI - Neuronal Chemosensation and Osmotic Stress Response Converge in the Regulation of aqp-8 in C. elegans. AB - Aquaporins occupy an essential role in sustaining the salt/water balance in various cells types and tissues. Here, we present new insights into aqp-8 expression and regulation in Caenorhabditis elegans. We show, that upon exposure to osmotic stress, aqp-8 exhibits a distinct expression pattern within the excretory cell compared to other C. elegans aquaporins expressed. This expression is correlated to the osmolarity of the surrounding medium and can be activated physiologically by osmotic stress or genetically in mutants with constitutively active osmotic stress response. In addition, we found aqp-8 expression to be constitutively active in the TRPV channel mutant osm-9(ok1677). In a genome-wide RNAi screen we identified additional regulators of aqp-8. Many of these regulators are connected to chemosensation by the amphid neurons, e.g., odr-10 and gpa-6, and act as suppressors of aqp-8 expression. We postulate from our results, that aqp-8 plays an important role in sustaining the salt/water balance during a secondary response to hyper-osmotic stress. Upon its activation aqp-8 promotes vesicle docking to the lumen of the excretory cell and thereby enhances the ability to secrete water and transport osmotic active substances or waste products caused by protein damage. In summary, aqp-8 expression and function is tightly regulated by a network consisting of the osmotic stress response, neuronal chemosensation as well as the response to protein damage. These new insights in maintaining the salt/water balance in C. elegans will help to reveal the complex homeostasis network preserved throughout species. PMID- 28649204 TI - Effects of Dietary Nitrate Supplementation on Physiological Responses, Cognitive Function, and Exercise Performance at Moderate and Very-High Simulated Altitude. AB - Purpose: Nitric oxide (NO) bioavailability is reduced during acute altitude exposure, contributing toward the decline in physiological and cognitive function in this environment. This study evaluated the effects of nitrate ([Formula: see text]) supplementation on NO bioavailability, physiological and cognitive function, and exercise performance at moderate and very-high simulated altitude. Methods:Ten males (mean (SD): [Formula: see text]: 60.9 (10.1) ml.kg-1.min-1) rested and performed exercise twice at moderate (~14.0% O2; ~3,000 m) and twice at very-high (~11.7% O2; ~4,300 m) simulated altitude. Participants ingested either 140 ml concentrated [Formula: see text]-rich (BRJ; ~12.5 mmol [Formula: see text]) or [Formula: see text]-deplete (PLA; 0.01 mmol [Formula: see text]) beetroot juice 2 h before each trial. Participants rested for 45 min in normobaric hypoxia prior to completing an exercise task. Exercise comprised a 45 min walk at 30% [Formula: see text] and a 3 km time-trial (TT), both conducted on a treadmill at a 10% gradient whilst carrying a 10 kg backpack to simulate altitude hiking. Plasma nitrite concentration ([[Formula: see text]]), peripheral oxygen saturation (SpO2), pulmonary oxygen uptake ([Formula: see text]), muscle and cerebral oxygenation, and cognitive function were measured throughout. Results: Pre-exercise plasma [[Formula: see text]] was significantly elevated in BRJ compared with PLA (p = 0.001). Pulmonary [Formula: see text] was reduced (p = 0.020), and SpO2 was elevated (p = 0.005) during steady-state exercise in BRJ compared with PLA, with similar effects at both altitudes. BRJ supplementation enhanced 3 km TT performance relative to PLA by 3.8% [1,653.9 (261.3) vs. 1718.7 (213.0) s] and 4.2% [1,809.8 (262.0) vs. 1,889.1 (203.9) s] at 3,000 and 4,300 m, respectively (p = 0.019). Oxygenation of the gastrocnemius was elevated during the TT consequent to BRJ (p = 0.011). The number of false alarms during the Rapid Visual Information Processing Task tended to be lower with BRJ compared with PLA prior to altitude exposure (p = 0.056). Performance in all other cognitive tasks did not differ significantly between BRJ and PLA at any measurement point (p >= 0.141). Conclusion: This study suggests that BRJ improves physiological function and exercise performance, but not cognitive function, at simulated moderate and very-high altitude. PMID- 28649203 TI - TRPs in Pain Sensation. AB - According to the International Association for the Study of Pain (IASP) pain is characterized as an "unpleasant sensory and emotional experience associated with actual or potential tissue damage". The TRP super-family, compressing up to 28 isoforms in mammals, mediates a myriad of physiological and pathophysiological processes, pain among them. TRP channel might be constituted by similar or different TRP subunits, which will result in the formation of homomeric or heteromeric channels with distinct properties and functions. In this review we will discuss about the function of TRPs in pain, focusing on TRP channles that participate in the transduction of noxious sensation, especially TRPV1 and TRPA1, their expression in nociceptors and their sensitivity to a large number of physical and chemical stimuli. PMID- 28649205 TI - Support Vector Machine Analysis of Functional Magnetic Resonance Imaging of Interoception Does Not Reliably Predict Individual Outcomes of Cognitive Behavioral Therapy in Panic Disorder with Agoraphobia. AB - BACKGROUND: The approach to apply multivariate pattern analyses based on neuro imaging data for outcome prediction holds out the prospect to improve therapeutic decisions in mental disorders. Patients suffering from panic disorder with agoraphobia (PD/AG) often exhibit an increased perception of bodily sensations. The purpose of this investigation was to assess whether multivariate classification applied to a functional magnetic resonance imaging (fMRI) interoception paradigm can predict individual responses to cognitive behavioral therapy (CBT) in PD/AG. METHODS: This analysis is based on pretreatment fMRI data during an interoceptive challenge from a multicenter trial of the German PANIC NET. Patients with DSM-IV PD/AG were dichotomized as responders (n = 30) or non responders (n = 29) based on the primary outcome (Hamilton Anxiety Scale Reduction >=50%) after 6 weeks of CBT (2 h/week). fMRI parametric maps were used as features for response classification with linear support vector machines (SVM) with or without automated feature selection. Predictive accuracies were assessed using cross validation and permutation testing. The influence of methodological parameters and the predictive ability for specific interoception-related symptom reduction were further evaluated. RESULTS: SVM did not reach sufficient overall predictive accuracies (38.0-54.2%) for anxiety reduction in the primary outcome. In the exploratory analyses, better accuracies (66.7%) were achieved for predicting interoception-specific symptom relief as an alternative outcome domain. Subtle information regarding this alternative response criterion but not the primary outcome was revealed by post hoc univariate comparisons. CONCLUSION: In contrast to reports on other neurofunctional probes, SVM based on an interoception paradigm was not able to reliably predict individual response to CBT. Results speak against the clinical applicability of this technique. PMID- 28649206 TI - The Heuristic Value of p in Inductive Statistical Inference. AB - Many statistical methods yield the probability of the observed data - or data more extreme - under the assumption that a particular hypothesis is true. This probability is commonly known as 'the' p-value. (Null Hypothesis) Significance Testing ([NH]ST) is the most prominent of these methods. The p-value has been subjected to much speculation, analysis, and criticism. We explore how well the p value predicts what researchers presumably seek: the probability of the hypothesis being true given the evidence, and the probability of reproducing significant results. We also explore the effect of sample size on inferential accuracy, bias, and error. In a series of simulation experiments, we find that the p-value performs quite well as a heuristic cue in inductive inference, although there are identifiable limits to its usefulness. We conclude that despite its general usefulness, the p-value cannot bear the full burden of inductive inference; it is but one of several heuristic cues available to the data analyst. Depending on the inferential challenge at hand, investigators may supplement their reports with effect size estimates, Bayes factors, or other suitable statistics, to communicate what they think the data say. PMID- 28649207 TI - Commentary: Reproducibility in Psychological Science: When Do Psychological Phenomena Exist? PMID- 28649208 TI - The Four Causes of ADHD: Aristotle in the Classroom. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most well established and at the same time controversial disorders to the extreme of being placed in doubt. In the first of two parts, the established position is critically reviewed, beginning with showing fallacious reasoning on which the diagnosis is based, lacking clinical proof. Similarly, a certain rhetoric and metaphysics in genetic and neurobiological research is highlighted, where, for example, a meager accumulation of data is offered as robust conclusions, and correlates and correlations as causes and bases. However, that may be, the controversy is silenced in a dialog of the deaf between "defenders" and "critics." with no way out in sight in empirical and scientific terms. A new meta scientific position is necessary to analyze the science of ADHD itself and its social uses. In this respect, the second part introduces Aristotle's four causes, material, formal, efficient, final, as an instrument of enquiry. According to this analysis, ADHD is not the pretended clinical entity as presented, but a practical entity providing a variety of functions. The implications would be rather different from the usual. PMID- 28649209 TI - Map Learning with a 3D Printed Interactive Small-Scale Model: Improvement of Space and Text Memorization in Visually Impaired Students. AB - Special education teachers for visually impaired students rely on tools such as raised-line maps (RLMs) to teach spatial knowledge. These tools do not fully and adequately meet the needs of the teachers because they are long to produce, expensive, and not versatile enough to provide rapid updating of the content. For instance, the same RLM can barely be used during different lessons. In addition, those maps do not provide any interactivity, which reduces students' autonomy. With the emergence of 3D printing and low-cost microcontrollers, it is now easy to design affordable interactive small-scale models (SSMs) which are adapted to the needs of special education teachers. However, no study has previously been conducted to evaluate non-visual learning using interactive SSMs. In collaboration with a specialized teacher, we designed a SSM and a RLM representing the evolution of the geography and history of a fictitious kingdom. The two conditions were compared in a study with 24 visually impaired students regarding the memorization of the spatial layout and historical contents. The study showed that the interactive SSM improved both space and text memorization as compared to the RLM with braille legend. In conclusion, we argue that affordable home-made interactive small scale models can improve learning for visually impaired students. Interestingly, they are adaptable to any teaching situation including students with specific needs. PMID- 28649210 TI - The Relationship between Handedness and Mathematics Is Non-linear and Is Moderated by Gender, Age, and Type of Task. AB - The relationship between handedness and mathematical ability is still highly controversial. While some researchers have claimed that left-handers are gifted in mathematics and strong right-handers perform the worst in mathematical tasks, others have more recently proposed that mixed-handers are the most disadvantaged group. However, the studies in the field differ with regard to the ages and the gender of the participants, and the type of mathematical ability assessed. To disentangle these discrepancies, we conducted five studies in several Italian schools (total participants: N = 2,314), involving students of different ages (six to seventeen) and a range of mathematical tasks (e.g., arithmetic and reasoning). The results show that (a) linear and quadratic functions are insufficient for capturing the link between handedness and mathematical ability; (b) the percentage of variance in mathematics scores explained by handedness was larger than in previous studies (between 3 and 10% vs. 1%), and (c) the effect of handedness on mathematical ability depended on age, type of mathematical tasks, and gender. In accordance with previous research, handedness does represent a correlate of achievement in mathematics, but the shape of this relationship is more complicated than has been argued so far. PMID- 28649212 TI - Similarities and Differences between Individuals Seeking Treatment for Gambling Problems vs. Alcohol and Substance Use Problems in Relation to the Progressive Model of Self-stigma. AB - Aims: People with gambling as well as substance use problems who are exposed to public stigmatization may internalize and apply it to themselves through a mechanism known as self-stigma. This study implemented the Progressive Model for Self-Stigma which consists four sequential interrelated stages: awareness, agreement, application and harm on three groups of individuals with gambling, alcohol and other substance use problems. It explored whether the two guiding assumptions of this model (each stage is precondition for the following stage which are trickle-down in nature, and correlations between proximal stages should be larger than correlations between more distant stages) would differentiate people with gambling problems from those with alcohol and other substance use problems in terms of their patterns of self-stigma and in terms of the stages in the model. Method: 37 individuals with gambling problems, 60 with alcohol problems and 51 with drug problems who applied for treatment in rehabilitation centers in Israel in 2015-2016 were recruited. They completed the Self-stigma of Mental Illness Scale-Short Form which was adapted by changing the term "mental health" to gambling, alcohol or drugs, and the DSM-5-diagnostic criteria for gambling, alcohol or drug disorder. Results: The assumptions of the model were broadly confirmed: a repeated measures ANCOVA revealed that in all three groups there was a difference between first two stages (aware and agree) and the latter stages (apply and harm). In addition, the gambling group differed from the drug use and alcohol groups on the awareness stage: individuals with gambling problems were less likely to be aware of stigma than people with substance use or alcohol problems. Conclusion: The internalization of stigma among individuals with gambling problems tends to work in a similar way as for those with alcohol or drug problems. The differences between the gambling group and the alcohol and other substance groups at the aware stage may suggest that public stigma with regard to any given addictive disorder may be a function of the type of addiction (substance versus behavioral). PMID- 28649211 TI - Online and Mobile Interventions for Problem Gambling, Alcohol, and Drugs: A Systematic Review. AB - Online interventions for gambling, alcohol, and illegal drug related problems have been developing at a fast pace over the past decade. Yet, little is known about the content and efficacy of interventions provided entirely online for reducing drug/alcohol use and gambling, or about the characteristics of those who use these interventions. This systematic review aims to describe the characteristics of online interventions, their efficacy, and the profile of their clientele. Documentation was mainly obtained through four scientific databases in psychology, technology, and medical research (PsychINFO, MedLine, Francis, and INSPEC) using three keywords (substances or gambling, intervention, Internet). Of the 4,708 documents initially identified, 18 studies meeting admissibility criteria were retained and analyzed after exclusion of duplicates and non relevant documents. No study in the review related to problem gambling. The majority of interventions were based upon motivational or cognitive-behavioral theoretical approaches and called upon well-established therapeutic components in the field of addictions. The participants in these studies were generally adults between 30 and 46 years old with a high school education and presenting a high risk or problematic use. More than three quarters of the studies showed a short term decrease in use that was maintained 6 months later, but only two studies included a 12 months follow-up. Online interventions seem promising and appear to meet the needs of participants who are in the workforce and seeking help for the first time. Long-term efficacy studies should nonetheless be conducted. PMID- 28649213 TI - Ethorobotics: A New Approach to Human-Robot Relationship. AB - Here we aim to lay the theoretical foundations of human-robot relationship drawing upon insights from disciplines that govern relevant human behaviors: ecology and ethology. We show how the paradox of the so called "uncanny valley hypothesis" can be solved by applying the "niche" concept to social robots, and relying on the natural behavior of humans. Instead of striving to build human like social robots, engineers should construct robots that are able to maximize their performance in their niche (being optimal for some specific functions), and if they are endowed with appropriate form of social competence then humans will eventually interact with them independent of their embodiment. This new discipline, which we call ethorobotics, could change social robotics, giving a boost to new technical approaches and applications. PMID- 28649214 TI - Interactions between Obsessional Symptoms and Interpersonal Ambivalences in Psychodynamic Therapy: An Empirical Case Study. AB - The classical symptom specificity hypothesis (Blatt, 1974) particularly associates obsessional symptoms to interpersonal behavior directed at autonomy and separation from others. Cross-sectional group research, however, has yielded inconsistent findings on this predicted association, and a previous empirical case study (Cornelis et al., in press; see Chapter 2) documented obsessional pathology to be rooted in profound ambivalences between autonomous and dependent interpersonal dynamics. Therefore, in the present empirical case study, concrete operationalizations of the classical symptom specificity hypothesis are contrasted to alternative hypotheses based on the observed complexities in Chapter 2. Dynamic associations between obsessional symptoms and interpersonal functioning is further explored, aiming at further contribution to theory building (i.e., through suggestions for potential hypothesis-refinement; Stiles, 2009). Similar to the first empirical case study (Chapter 1), Consensual Qualitative Research for Case studies is used to quantitatively and qualitatively describe the longitudinal, clinical interplay between obsessional symptoms and interpersonal dynamics throughout the process of supportive-expressive psychodynamic therapy. In line with findings from Chapter 1, findings reveal close associations between obsessions and interpersonal dynamics, and therapist interventions focusing on interpersonal conflicts are documented as related to interpersonal and symptomatic alterations. Observations predominantly accord to the ambivalence-hypothesis rather than to the classical symptom specificity hypothesis. Yet, meaningful differences are observed in concrete manifestations of interpersonal ambivalences within significant relationships. Findings are again discussed in light of conceptual and methodological considerations; and limitations and future research indications are addressed. PMID- 28649215 TI - Does Watching a Play about the Teenage Brain Affect Attitudes toward Young Offenders? AB - Neuroscience is increasingly used to infer the cognitive capacities of offenders from the activity and volume of different brain regions, with the resultant findings receiving great interest in the public eye. This field experiment tested the effects of public engagement in neuroscience on attitudes toward offenders. Brainstorm is a play about teenage brain development. Either before or after watching this play, 728 participants responded to four questions about the age of criminal responsibility, and the moral responsibility and dangerousness of a hypothetical young or adult offender. After watching the play, participants perceived the young offender as less likely to reoffend than the adult offender and the young, but not adult, offender as less morally responsible for his actions, especially on the first offense. Therefore, public engagement in the newest arrival to the criminological scene - neuroscience - may shift support for different youth justice responses. PMID- 28649216 TI - Retrieval and Encoding Interference: Cross-Linguistic Evidence from Anaphor Processing. AB - The main goal of this paper was to disentangle encoding and retrieval interference effects in anaphor processing and thus to evaluate the hypothesis predicting that structurally inaccessible nouns (distractors) are not considered to be potential anaphor antecedents during language processing (Nicol and Swinney, 1989). Three self-paced reading experiments were conducted: one in German, comparing gender-unmarked reflexives and gender-marked pronouns, and two in Russian, comparing gender-marked and -unmarked reflexives. In the German experiment, no interference effects were found. In the first experiment in Russian, an unexpected reading times pattern emerged: in the condition where the distractor matched the gender of the reflexive's antecedent, reading of the gender-unmarked, but not the gender-marked reflexives was slowed down. The same reading times pattern was replicated in a second experiment in Russian where the order of the reflexive and the main verb was inverted. We conclude that the results of the two experiments in Russian are inconsistent with the retrieval interference account, but can be explained by encoding interference and additional semantic processing efforts associated with the processing of gender marked reflexives. In sum, we found no evidence that would allow us to reject the syntax as an early filer account (Nicol and Swinney, 1989). PMID- 28649217 TI - A Novel Computer-Based Set-Up to Study Movement Coordination in Human Ensembles. AB - Existing experimental works on movement coordination in human ensembles mostly investigate situations where each subject is connected to all the others through direct visual and auditory coupling, so that unavoidable social interaction affects their coordination level. Here, we present a novel computer-based set-up to study movement coordination in human groups so as to minimize the influence of social interaction among participants and implement different visual pairings between them. In so doing, players can only take into consideration the motion of a designated subset of the others. This allows the evaluation of the exclusive effects on coordination of the structure of interconnections among the players in the group and their own dynamics. In addition, our set-up enables the deployment of virtual computer players to investigate dyadic interaction between a human and a virtual agent, as well as group synchronization in mixed teams of human and virtual agents. We show how this novel set-up can be employed to study coordination both in dyads and in groups over different structures of interconnections, in the presence as well as in the absence of virtual agents acting as followers or leaders. Finally, in order to illustrate the capabilities of the architecture, we describe some preliminary results. The platform is available to any researcher who wishes to unfold the mechanisms underlying group synchronization in human ensembles and shed light on its socio-psychological aspects. PMID- 28649218 TI - Editorial: Stress and Cognition. PMID- 28649220 TI - A Study Protocol for Testing the Effectiveness of User-Generated Content in Reducing Excessive Consumption. AB - Excessive consumption is on the rise, as is apparent in growing financial debt and global greenhouse gas emissions. Voluntary simplicity, a lifestyle choice of reduced consumption and sustainable consumer behavior, provides a potential solution for excessive consumers. However, voluntary simplicity is unpopular, difficult to adopt, and under researched. The outlined research project will test a method of promoting voluntary simplicity via user-generated content, thus mimicking an existing social media trend (Minimalism) in an empirical research design. The project will test (a) whether the Minimalism trend could benefit consumers interested in reducing their consumption, and (b) whether self transcendence (i.e., biospheric) and self-enhancement (i.e., egoistic and hedonic) values and goals have a similar impact in promoting voluntary simplicity. A one-week intervention program will test the efficacy of watching user-generated voluntary simplicity videos in reducing non-essential consumption. Each of the two intervention conditions will present participants with similar tutorial videos on consumption reduction (e.g., decluttering, donating), while priming the relevant values and goals (self-transcendence or self-enhancement). These interventions will be compared to a control condition, involving no user generated content. Participants will undergo baseline and post-intervention evaluations of: voluntary simplicity attitudes and behaviors, buying and shopping behaviors, values and goals in reducing consumption, and life satisfaction. Experience sampling will monitor affective state during the intervention. We provide a detailed stepwise procedure, materials, and equipment necessary for executing this intervention. The outlined research design is expected to contribute to the limited literature on voluntary simplicity, online behavioral change interventions, and the use of social marketing principles in consumer interventions. PMID- 28649219 TI - Taking the Perfect Selfie: Investigating the Impact of Perspective on the Perception of Higher Cognitive Variables. AB - Taking selfies is now becoming a standard human habit. However, as a social phenomenon, research is still in the fledgling stage and the scientific framework is sparse. Selfies allow us to share social information with others in a compact format. Furthermore, we are able to control important photographic and compositional aspects, such as perspective, which have a strong impact on the assessment of a face (e.g., demonstrated by the height-weight illusion, effects of gaze direction, faceism-index). In Study 1, we focused on the impact of perspective (left/right hemiface, above/below vs. frontal presentation) on higher cognitive variables and let 172 participants rate the perceived attractiveness, helpfulness, sympathy, dominance, distinctiveness, and intelligence, plus important information on health issues (e.g., body weight), on the basis of 14 3D faces. We could show that lateral snapshots yielded higher ratings for attractiveness compared to the classical frontal view. However, this effect was more pronounced for left hemifaces and especially female faces. Compared to the frontal condition, 30 degrees right hemifaces were rated as more helpful, but only for female faces while faces viewed from above were perceived as significant less helpful. Direct comparison between left vs. right hemifaces revealed no effect. Relating to sympathy, we only found a significant effect for 30 degrees right male hemifaces, but only in comparison to the frontal condition. Furthermore, female 30 degrees right hemifaces were perceived as more intelligent. Relating to body weight, we replicated the so-called "height-weight illusion." Other variables remained unaffected. In Study 2, we investigated the impact of a typical selfie-style condition by presenting the respective faces from a lateral (left/right) and tilted (lower/higher) vantage point. Most importantly, depending on what persons wish to express with a selfie, a systematic change of perspective can strongly optimize their message; e.g., increasing their attractiveness by shooting from above left, and in contrast, decreasing their expressed helpfulness by shooting from below. We could further extent past findings relating to the height-weight illusion and showed that an additional rotation of the camera positively affected the perception of body weight (lower body weight). We discuss potential explanations for perspective related effects, especially gender-related ones. PMID- 28649221 TI - NOTCH 1 Mutation in a Patient with Spontaneous and Recurrent Dissections of Extracranial Arteries. AB - Dissections of extracranial arteries are estimated to account for only 2% of all ischemic strokes but for approximately 20% of strokes in patients younger than 45 years old. Most dissections of extracranial arteries involve some trauma stretch, mechanical stress, or connective tissue abnormalities. In the absence of these disorders, determining the etiology of recurrent extracranial dissections is quite challenging because the underlying nature of these cases is poorly understood. We report the case of a 44-year-old female with recurrent dissections of the vertebral and carotid arteries associated with a heterozygous mutation p.Pro2122Leu in the NOTCH 1 gene. Her mother with a thoracic aortic aneurysm was also positive for this variant. PMID- 28649222 TI - Highly Selective Cyclooxygenase-1 Inhibitors P6 and Mofezolac Counteract Inflammatory State both In Vitro and In Vivo Models of Neuroinflammation. AB - Activated microglia secrete an array of pro-inflammatory factors, such as prostaglandins, whose accumulation contributes to neuronal damages. Prostaglandin endoperoxide synthases or cyclooxygenases (COX-1 and COX-2), which play a critical role in the inflammation, are the pharmacological targets of non steroidal anti-inflammatory drugs, used to treat pain and inflammation. Since it was reported that COX-1 is the major player in mediating the brain inflammatory response, the aim of this study was to evaluate the effects of highly selective COX-1 inhibitors, such as P6 and mofezolac, in neuroinflammation models. Lipopolysaccharide (LPS)-activated mouse BV-2 microglial cells and LPS intracerebroventricular-injected mice as in vitro and in vivo neuroinflammation models, respectively, were used to probe the antiinflammatory efficacy of P6 and mofezolac. Both P6 and mofezolac reduce COX-1 expression in LPS-activated BV-2 cells. This reduction was accompanied with PGE2 release reduction and NF-kB activation downregulation. Coextensively, in the in vivo model, both glial fibrillary acidic protein and ionized calcium-binding adapter molecule-1 expression, two markers of inflammation, were reduced by mofezolac to a rank depending on the encephalon area analyzed. The increase of COX-1 expression observed in all the brain sections of LPS-treated mice was selectively downregulated by the in vivo treatment with mofezolac as well as PGE2 release and Ikbetaalpha phosphorylation amount assayed in the brain areas tested. These results indicate the capability of P6 and mofezolac to modulate the NF-kB signaling pathway, emphasizing the neuroprotective effect and therapeutic potential of COX-1 inhibitors in the control of neuroinflammatory diseases. PMID- 28649223 TI - Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein. AB - Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke. PMID- 28649225 TI - Microsurgical vs. Endoscopic Excision of Colloid Cysts: An Analysis of Complications and Costs Using a Longitudinal Administrative Database. AB - OBJECTIVE: Open microsurgical and endoscopic approaches are the two main surgical options for excision of colloid cysts. Controversy remains as to which is superior. Previous studies consist of small cohort sizes. This topic has not been investigated using national administrative claims data which benefits from larger patient numbers. METHODS: Current Procedural Terminology (CPT) and International Classification of Disease version 9 (ICD-9) coding at inpatient visit was used to select for index surgical procedures corresponding to microsurgical or endoscopic excision of colloid cysts. Comorbidities, costs, and complications were collected. RESULTS: We identified a total of 483 patients. In all, 240 were from the microsurgical cohort and 243 were from the endoscopic cohort. The two groups displayed similar demographic and comorbidity profiles. Thirty-day post-operative complications were also similar between groups with the exception of seizures and thirty-day readmissions, both higher in the open surgical cohort. The seizure rates were 14.7 and 5.4% in the microsurgical and endoscopic cohorts, respectively (p = 0.0011). The thirty-day readmission rates were 17.3 and 9.6% in the microsurgical and endoscopic cohorts, respectively (p = 0.0149). Index admission costs and 90-day post discharge payments were higher in patients receiving microsurgical excision. CONCLUSION: An analysis of administrative claims data revealed few differences in surgical complications following colloid cyst excision via microsurgical and endoscopic approaches. Post-operative seizures and thirty-day readmissions were seen at higher frequency in patients who underwent microsurgical resection. Despite similar complication profiles, patients undergoing microsurgical excision experienced higher index admission costs and 90-day aggregated costs suggesting that complications may have been more severe in this group. PMID- 28649226 TI - Commentary: Sleep Changes without Medial Temporal Lobe or Brain Cortical Changes in Community-Dwelling Individuals with Subjective Cognitive Decline. PMID- 28649224 TI - The Video Head Impulse Test. AB - In 1988, we introduced impulsive testing of semicircular canal (SCC) function measured with scleral search coils and showed that it could accurately and reliably detect impaired function even of a single lateral canal. Later we showed that it was also possible to test individual vertical canal function in peripheral and also in central vestibular disorders and proposed a physiological mechanism for why this might be so. For the next 20 years, between 1988 and 2008, impulsive testing of individual SCC function could only be accurately done by a few aficionados with the time and money to support scleral search-coil systems-an expensive, complicated and cumbersome, semi-invasive technique that never made the transition from the research lab to the dizzy clinic. Then, in 2009 and 2013, we introduced a video method of testing function of each of the six canals individually. Since 2009, the method has been taken up by most dizzy clinics around the world, with now close to 100 refereed articles in PubMed. In many dizzy clinics around the world, video Head Impulse Testing has supplanted caloric testing as the initial and in some cases the final test of choice in patients with suspected vestibular disorders. Here, we consider seven current, interesting, and controversial aspects of video Head Impulse Testing: (1) introduction to the test; (2) the progress from the head impulse protocol (HIMPs) to the new variant-suppression head impulse protocol (SHIMPs); (3) the physiological basis for head impulse testing; (4) practical aspects and potential pitfalls of video head impulse testing; (5) problems of vestibulo-ocular reflex gain calculations; (6) head impulse testing in central vestibular disorders; and (7) to stay right up-to-date-new clinical disease patterns emerging from video head impulse testing. With thanks and appreciation we dedicate this article to our friend, colleague, and mentor, Dr Bernard Cohen of Mount Sinai Medical School, New York, who since his first article 55 years ago on compensatory eye movements induced by vertical SCC stimulation has become one of the giants of the vestibular world. PMID- 28649227 TI - Fish Oil Supplementation Reduces Heart Levels of Interleukin-6 in Rats with Chronic Inflammation due to Epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) is a major cause of premature death related to epilepsy. The causes of SUDEP remain unknown, but cardiac arrhythmias and asphyxia have been suggested as a major mechanism of this event. Inflammation has been implicated in the pathogenesis of both epilepsy and ventricular arrhythmia, with interleukin-6 (IL-6) being recognized as a crucial orchestrator of inflammatory states. Our group previously reported that levels of IL-6 were increased in the hearts of epileptic rats. In this scenario, anti-inflammatory actions are among the beneficial effects of fish oil dietary supplementation. This investigation revealed that elevated levels of IL-6 in the heart were markedly reduced in epileptic rats that were treated in the long-term with fish oil, suggesting protective anti-inflammatory actions against dangerously high levels of IL-6. Based on these findings, our results suggest beneficial effects of long-term intake of fish oil in reducing the inflammation associated with chronic epilepsy. PMID- 28649228 TI - Ras Activity Tunes the Period and Modulates the Entrainment of the Suprachiasmatic Clock. AB - The small GTPase Ras is a universal eukaryotic cytoplasmic membrane-anchored protein, which regulates diverse downstream signal transduction pathways that play an important role in the proper functioning of neurons. Ras activity is a central regulator of structural and functional synaptic plasticity in the adult nervous system, where it channels neuronal responses to various extracellular cues allowing the organism to adapt to complex environmental stimuli. The suprachiasmatic nucleus (SCN) is the principle pacemaker of the circadian clock, and the circadian and photic regulation of Ras activity in the SCN is an important modulator of the clockwork. We have generated transgenic mouse expressing constitutively active V12-H-Ras selectively in neurons via a synapsin I promoter (synRas mice), which serves as a suitable model to study the role of neuronal Ras signaling. Modulation of Ras activity affects ERK1,2/CREB signaling and glycogen synthase kinase-3 beta expression in the SCN, which in turn modify the photoentrainment of the clock and the fine tuning the circadian period length. The main focus of this review is to offer an overview of the function of Ras signaling in the circadian rhythm and its potential role in learning and memory consolidation. PMID- 28649229 TI - Cortical and Subcortical Structural Plasticity Associated with the Glioma Volumes in Patients with Cerebral Gliomas Revealed by Surface-Based Morphometry. AB - Postlesional plasticity has been identified in patients with cerebral gliomas by inducing a large functional reshaping of brain networks. Although numerous non invasive functional neuroimaging methods have extensively investigated the mechanisms of this functional redistribution in patients with cerebral gliomas, little effort has been made to investigate the structural plasticity of cortical and subcortical structures associated with the glioma volume. In this study, we aimed to investigate whether the contralateral cortical and subcortical structures are able to actively reorganize by themselves in these patients. The compensation mechanism following contralateral cortical and subcortical structural plasticity is considered. We adopted the surface-based morphometry to investigate the difference of cortical and subcortical gray matter (GM) volumes in a cohort of 14 healthy controls and 13 patients with left-hemisphere cerebral gliomas [including 1 patients with World Health Organization (WHO I), 8 WHO II, and 4 WHO III]. The glioma volume ranges from 5.1633 to 208.165 cm2. Compared to healthy controls, we found significantly increased GM volume of the right cuneus and the left thalamus, as well as a trend toward enlargement in the right globus pallidus in patients with cerebral gliomas. Moreover, the GM volumes of these regions were positively correlated with the glioma volumes of the patients. These results provide evidence of cortical and subcortical enlargement, suggesting the usefulness of surface-based morphometry to investigate the structural plasticity. Moreover, the structural plasticity might be acted as the compensation mechanism to better fulfill its functions in patients with cerebral gliomas as the gliomas get larger. PMID- 28649230 TI - High Compliance with Scheduled Nimodipine Is Associated with Better Outcome in Aneurysmal Subarachnoid Hemorrhage Patients Cotreated with Heparin Infusion. AB - INTRODUCTION: We sought to determine whether compliance with scheduled nimodipine in subarachnoid hemorrhage patients impacted patient outcomes, with the intent of guiding future nimodipine management in patients who experience nimodipine induced hypotension. METHODS: We performed a retrospective analysis of 118 consecutive aneurysmal subarachnoid hemorrhage patients treated with the Maryland Low-Dose IV Heparin Infusion Protocol. Patients were categorized into three independent nimodipine compliance groups: >=1 dose held, >=1 dose split, and no missed or split-doses. A split-dose was defined as 30 mg of nimodipine administered every 2 h. Our primary outcome was discharge to home. Bivariate and multivariable logistic regression analyses were used to assess predictors of discharge disposition as a function of nimodipine compliance. RESULTS: Of the 118 patients, 20 (17%) received all nimodipine doses, 6 (5%) received split-doses but never had a full dose held, and 92 (78%) had >=1 dose held. Forty-five percent of patients were discharged to home, including 75% who received all doses, 67% who received >=1 split-doses, and 37% with >=1 missed doses (p = 0.003). Multivariable analysis showed that, along with age and World Federation of Neurosurgical Societies grade, nimodipine compliance was an independent predictor of clinical outcome; compared to missing one or more nimodipine doses, full dosing compliance was associated with increased odds of discharge to home (odds ratio 5.20; 95% confidence intervals 1.46-18.56). CONCLUSION: In aneurysmal subarachnoid hemorrhage patients with modified Fisher scores 2 through 4 who are cotreated with a low-dose heparin infusion, full compliance with nimodipine dosing was associated with increased odds of discharge to home. PMID- 28649231 TI - Medications Adherence and Associated Factors among Patients with Type 2 Diabetes Mellitus in the Gaza Strip, Palestine. AB - AIM: The aim of this study was to evaluate the adherence to anti-diabetic medications among patients with type 2 diabetes mellitus (DM) seeking medical care in the Gaza Strip, Palestine. METHODS: A cross-sectional study was conducted among 369 primary care patients with type 2 DM from October to December 2016. Adherence to medications was measured using the Morisky Medication Adherence Scale (MMAS-4). Socio-demographic and clinical variables, provider-patient relationship, health literacy, and health belief were examined for each patient. Univariate, binary logistic regression and multiple linear regression were applied to determine the independent factors influencing adherence to anti diabetic medications using SPSS version 22. RESULTS: Of all the respondents, 214 (58%), 146 (39.5%), and nine (2.5%) had high (MMAS score = 0), medium (MMAS score = 1 + 2), and low (MMAS score >= 3) adherence to anti-diabetic medications, respectively. Factors that were independently associated with adherence to anti diabetic medications were as follows: female gender [odds ratio (OR): 1.657, 95% confidence interval (CI): 1.065-2.578] and perception of disease's severity (OR: 1.510, 95% CI: 0.410-5.560). Elderly (t = 1.345) and longer duration of DM (t = 0.899) were also predictors of adherence but showed no statistical significance (p > 0.05). CONCLUSION: The level of complete adherence to anti-diabetic medications was sub-optimal. New strategies that aim to improve patients' adherence to their therapies are necessary taking into consideration the influencing factors and the importance of having diabetes educators in the primary care centers. PMID- 28649233 TI - Microbial Community Response to Terrestrially Derived Dissolved Organic Matter in the Coastal Arctic. AB - Warming at nearly twice the global rate, higher than average air temperatures are the new 'normal' for Arctic ecosystems. This rise in temperature has triggered hydrological and geochemical changes that increasingly release carbon-rich water into the coastal ocean via increased riverine discharge, coastal erosion, and the thawing of the semi-permanent permafrost ubiquitous in the region. To determine the biogeochemical impacts of terrestrially derived dissolved organic matter (tDOM) on marine ecosystems we compared the nutrient stocks and bacterial communities present under ice-covered and ice-free conditions, assessed the lability of Arctic tDOM to coastal microbial communities from the Chukchi Sea, and identified bacterial taxa that respond to rapid increases in tDOM. Once thought to be predominantly refractory, we found that ~7% of dissolved organic carbon and ~38% of dissolved organic nitrogen from tDOM was bioavailable to receiving marine microbial communities on short 4 - 6 day time scales. The addition of tDOM shifted bacterial community structure toward more copiotrophic taxa and away from more oligotrophic taxa. Although no single order was found to respond universally (positively or negatively) to the tDOM addition, this study identified 20 indicator species as possible sentinels for increased tDOM. These data suggest the true ecological impact of tDOM will be widespread across many bacterial taxa and that shifts in coastal microbial community composition should be anticipated. PMID- 28649232 TI - Ion Channels of Pituitary Gonadotrophs and Their Roles in Signaling and Secretion. AB - Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration. These cells fire action potentials (APs) spontaneously, coupled with voltage-gated calcium influx of insufficient amplitude to trigger gonadotropin release. The spontaneous excitability of gonadotrophs reflects the expression of voltage-gated sodium, calcium, potassium, non-selective cation conducting, and chloride channels at their plasma membrane (PM). These cells also express the hyperpolarization-activated and cyclic nucleotide-gated cation channels at the PM, as well as GABAA, nicotinic, and purinergic P2X channels gated by gamma-aminobutyric acid (GABA), acetylcholine (ACh), and ATP, respectively. Activation of these channels leads to initiation or amplification of the pacemaking activity, facilitation of calcium influx, and activation of the exocytic pathway. Gonadotrophs also express calcium-conducting channels at the endoplasmic reticulum membranes gated by inositol trisphosphate and intracellular calcium. These channels are activated potently by hypothalamic gonadotropin releasing hormone (GnRH) and less potently by several paracrine calcium mobilizing agonists, including pituitary adenylate cyclase-activating peptides, endothelins, ACh, vasopressin, and oxytocin. Activation of these channels causes oscillatory calcium release and a rapid gonadotropin release, accompanied with a shift from tonic firing of single APs to periodic bursting type of electrical activity, which accounts for a sustained calcium signaling and gonadotropin secretion. This review summarizes our current understanding of ion channels as signaling molecules in gonadotrophs, the role of GnRH and paracrine agonists in their gating, and the cross talk among channels. PMID- 28649234 TI - Ecological Succession Pattern of Fungal Community in Soil along a Retreating Glacier. AB - Accelerated by global climate changing, retreating glaciers leave behind soil chronosequences of primary succession. Current knowledge of primary succession is mainly from studies of vegetation dynamics, whereas information about belowground microbes remains unclear. Here, we combined shifts in community assembly processes with microbial primary succession to better understand mechanisms governing the stochastic/deterministic balance. We investigated fungal succession and community assembly via high-throughput sequencing along a well-established glacier forefront chronosequence that spans 2-188 years of deglaciation. Shannon diversity and evenness peaked at a distance of 370 m and declined afterwards. The response of fungal diversity to distance varied in different phyla. Basidiomycota Shannon diversity significantly decreased with distance, while the pattern of Rozellomycota Shannon diversity was unimodal. Abundance of most frequencies OTU2 (Cryptococcus terricola) increased with successional distance, whereas that of OTU65 (Tolypocladium tundrense) decreased. Based on null deviation analyses, composition of the fungal community was initially governed by deterministic processes strongly but later less deterministic processes. Our results revealed that distance, altitude, soil microbial biomass carbon, soil microbial biomass nitrogen and [Formula: see text]-N significantly correlated with fungal community composition along the chronosequence. These results suggest that the drivers of fungal community are dynamics in a glacier chronosequence, that may relate to fungal ecophysiological traits and adaptation in an evolving ecosystem. The information will provide understanding the mechanistic underpinnings of microbial community assembly during ecosystem succession under different scales and scenario. PMID- 28649235 TI - Detection of Mycobacteria by Culture and DNA-Based Methods in Animal-Derived Food Products Purchased at Spanish Supermarkets. AB - Mycobacteria include obligate and opportunistic pathogens that cause significant human and animal disease. The burden of tuberculosis has been largely reduced in developed territories but remains a huge problem worldwide. The significance of nontuberculous mycobacteria is growing considerably, especially in developed regions with higher life expectancy and more therapy-related immunosuppressed individuals. Due to their robustness mycobacteria can contaminate animal products by direct transmission from infected individuals or by environmental contamination during processing. The situation at market level is poorly known. Most studies analyzing commercially available foods are limited to a small or local scale and mainly focused on a particular mycobacterial species. There is a need to investigate if animal products that have passed the established controls to be for sale at main supermarkets could represent a route of contact with any mycobacteria. Thus, our goal was to study the prevalence of mycobacteria in these foods to assess if this could represent a source of human exposure. Five stores from the main supermarket chains in Spain were selected. 138 dairy and 119 meat products were purchased. All were processed using culture and multiplex real-time PCR methods. Additional molecular methods were used to specifically identify any positive result. Mycobacterium avium subsp. hominissuis (2), M. avium subsp. avium (1), and M. fortuitum (1) were isolated from powdered infant formula and ground beef, chicken sausage, and mortadella cold cut, respectively. Mycobacterial DNA (M. avium, M. tuberculosis complex and other nontuberculous mycobacteria) was detected in 15% of dairy products and 2% of meat products. These results show that the prevalence of viable mycobacteria in foods of animal origin obtained at the supermarket was not substantial although a considerable proportion of them contained mycobacterial DNA. Contact with mycobacteria through this route could be ensured over time. Further investigation is necessary to determine the real impact of foodborne mycobacterial exposure on human health and identify critical points in the food production system to enable setting up more stringent control measures. PMID- 28649236 TI - The Validation and Implications of Using Whole Genome Sequencing as a Replacement for Traditional Serotyping for a National Salmonella Reference Laboratory. AB - Salmonella serotyping remains the gold-standard tool for the classification of Salmonella isolates and forms the basis of Canada's national surveillance program for this priority foodborne pathogen. Public health officials have been increasingly looking toward whole genome sequencing (WGS) to provide a large set of data from which all the relevant information about an isolate can be mined. However, rigorous validation and careful consideration of potential implications in the replacement of traditional surveillance methodologies with WGS data analysis tools is needed. Two in silico tools for Salmonella serotyping have been developed, the Salmonella in silico Typing Resource (SISTR) and SeqSero, while seven gene MLST for serovar prediction can be adapted for in silico analysis. All three analysis methods were assessed and compared to traditional serotyping techniques using a set of 813 verified clinical and laboratory isolates, including 492 Canadian clinical isolates and 321 isolates of human and non-human sources. Successful results were obtained for 94.8, 88.2, and 88.3% of the isolates tested using SISTR, SeqSero, and MLST, respectively, indicating all would be suitable for maintaining historical records, surveillance systems, and communication structures currently in place and the choice of the platform used will ultimately depend on the users need. Results also pointed to the need to reframe serotyping in the genomic era as a test to understand the genes that are carried by an isolate, one which is not necessarily congruent with what is antigenically expressed. The adoption of WGS for serotyping will provide the simultaneous collection of information that can be used by multiple programs within the current surveillance paradigm; however, this does not negate the importance of the various programs or the role of serotyping going forward. PMID- 28649238 TI - Clostridium chauvoei, an Evolutionary Dead-End Pathogen. AB - Full genome sequences of 20 strains of Clostridium chauvoei, the etiological agent of blackleg of cattle and sheep, isolated from four different continents over a period of 64 years (1951-2015) were determined and analyzed. The study reveals that the genome of the species C. chauvoei is highly homogeneous compared to the closely related species C. perfringens, a widespread pathogen that affects human and many animal species. Analysis of the CRISPR locus is sufficient to differentiate most C. chauvoei strains and is the most heterogenous region in the genome, containing in total 187 different spacer elements that are distributed as 30 - 77 copies in the various strains. Some genetic differences are found in the 3 allelic variants of fliC1, fliC2 and fliC3 genes that encode structural flagellin proteins, and certain strains do only contain one or two alleles. However, the major virulence genes including the highly toxic C.chauvoei toxin A, the sialidase and the two hyaluronidases are fully conserved as are the metabolic and structural genes of C. chauvoei. These data indicate that C. chauvoei is a strict ruminant-associated pathogen that has reached a dead end in its evolution. PMID- 28649239 TI - Insights into the Classical Genetics of Clitopilus passeckerianus - the Pleuromutilin Producing Mushroom. AB - Clitopilus passeckerianus is the fungal species responsible for the production of pleuromutilin, a diterpene antibiotic that is gaining in commercial interest. Production of the antibiotic is constrained by the low titers typically obtained from isolates. We therefore set out to investigate the possibility of using classical breeding techniques coupled with genetic manipulation as a means to develop such fungi. We show that the original production strain of C. passeckerianus is able to fruit under laboratory conditions, giving viable haploid meiotic basidiospores. The derived progeny displayed the typical physiological and genetic characteristics of a tetrapolar mating system. The monokaryon haploids produced pleuromutilin and haploid lines were amenable to genetic manipulation. Together this shows that the basic requirements for a classical breeding approach are present and the tools required to undertake directed genetic engineering on haploid strains are available, demonstrating that strain improvement may be feasible in this fungus. PMID- 28649237 TI - Outer Membrane Vesicles (OMVs) of Gram-negative Bacteria: A Perspective Update. AB - Outer Membrane Vesicles (OMVs) of Gram-negative bacteria are spherical membrane enclosed entities of endocytic origin. Reported in the consortia of different bacterial species, production of OMVs into extracellular milieu seems essential for their survival. Enriched with bioactive proteins, toxins, and virulence factors, OMVs play a critical role in the bacteria-bacteria and bacteria-host interactions. Emergence of OMVs as distinct cellular entities helps bacteria in adaptating to diverse niches, in competing with other bacteria to protect members of producer species and more importantly play a crucial role in host-pathogen interaction. Composition of OMV, their ability to modulate host immune response, along with coordinated secretion of bacterial effector proteins, endows them with the armory, which can withstand hostile environments. Study of the OMV production under natural and diverse stress conditions has broadened the horizons, and also opened new frontiers in delineating the molecular machinery involved in disease pathogenesis. Playing diverse biological and pathophysiological functions, OMVs hold a great promise in enabling resurgence of bacterial diseases, in concomitance with the steep decline in the efficiency of antibiotics. Having multifaceted role, their emergence as a causative agent for a series of infectious diseases increases the probability for their exploitation in the development of effective diagnostic tools and as vaccines against diverse pathogenic species of Gram-negative origin. PMID- 28649240 TI - Decoding the Role of Glycans in Malaria. AB - Complications arising from malaria are a concern for public health authorities worldwide, since the annual caseload in humans usually exceeds millions. Of more than 160 species of Plasmodium, only 4 infect humans, with the most severe cases ascribed to Plasmodium falciparum and the most prevalent to Plasmodium vivax. Over the past 70 years, since World War II, when the first antimalarial drugs were widely used, many efforts have been made to combat this disease, including vectorial control, new drug discoveries and genetic and molecular approaches. Molecular approaches, such as glycobiology, may lead to new therapeutic targets (both in the host and the parasites), since all interactions are mediated by carbohydrates or glycan moieties decorating both cellular surfaces from parasite and host cells. In this review, we address the carbohydrate-mediated glycobiology that directly affects Plasmodium survival or host resistance. PMID- 28649241 TI - Insulin Modulates Cytokine Release, Collagen and Mucus Secretion in Lung Remodeling of Allergic Diabetic Mice. AB - INTRODUCTION: The role of insulin in lung remodeling in a model of asthma in healthy and diabetic mice was evaluated. MATERIAL AND METHODS: Diabetic male BALB/c mice (alloxan, 50 mg/kg, intravenous) and controls were sensitized by subcutaneous (s.c.) injection of ovalbumin (OA, 20 ug) in aluminum hydroxide (Al(OH)3, 2 mg) 10 days after the alloxan injection and received the same dose 12 days later. Six days after the last sensitization, animals were nebulized with OA solution for 7 days. The first set of diabetic and control mice received 2 and 1 IU, respectively, of s.c. neutral protamine Hagedorn (NPH) insulin and were analyzed 8 h later. The second set of diabetic and control mice received 2 and 1 IU, respectively, of insulin 12 h before the OA challenge and half doses of insulin 2 h before each the seven OA challenges. Twenty-four hours after the last challenge, the following analyses were performed: (a) quantification of the cells in the bronchoalveolar lavage fluid (BALF), the white cell count, and blood glucose; (b) morphological analysis of lung tissues by hematoxylin and eosin staining; (c) quantification of collagen deposition in lung tissues and mucus by morphometric analysis of histological sections stained with Masson's trichrome and periodic acid-Schiff (PAS), respectively; and (d) quantification of the cytokine concentrations (IL-4, IL-5, and IL-13) in the BALF supernatant. RESULTS: Compared to controls, diabetic mice had significantly reduced inflammatory cells (81%) in the BALF, no eosinophils in the BALF and peripheral blood and reduced collagen deposition and mucus in the lungs. BALF concentrations of IL-4 (48%) and IL-5 (31%) decreased and IL-13 was absent. A single dose of insulin restored peripheral blood eosinophils and BALF mononuclear cells but not BALF eosinophils, collagen deposition, and mucus levels. However, multiple doses of insulin restored both total cells and eosinophils in the BALF and peripheral blood, BALF cytokines, and collagen deposition and mucus secretion into the lungs. CONCLUSION: The results suggest that insulin modulates the production/release of cytokines, cell migration, deposition of collagen, and mucus secretion in lung remodeling of a mouse model of asthma. PMID- 28649242 TI - An Approach for a Synthetic CTL Vaccine Design against Zika Flavivirus Using Class I and Class II Epitopes Identified by Computer Modeling. AB - The threat posed by severe congenital abnormalities related to Zika virus (ZKV) infection during pregnancy has turned development of a ZKV vaccine into an emergency. Recent work suggests that the cytotoxic T lymphocyte (CTL) response to infection is an important defense mechanism in response to ZKV. Here, we develop the rationale and strategy for a new approach to developing cytotoxic T lymphocyte (CTL) vaccines for ZKV flavivirus infection. The proposed approach is based on recent studies using a protein structure computer model for HIV epitope selection designed to select epitopes for CTL attack optimized for viruses that exhibit antigenic drift. Because naturally processed and presented human ZKV T cell epitopes have not yet been described, we identified predicted class I peptide sequences on ZKV matching previously identified DNV (Dengue) class I epitopes and by using a Major Histocompatibility Complex (MHC) binding prediction tool. A subset of those met the criteria for optimal CD8+ attack based on physical chemistry parameters determined by analysis of the ZKV protein structure encoded in open source Protein Data File (PDB) format files. We also identified candidate ZKV epitopes predicted to bind promiscuously to multiple HLA class II molecules that could provide help to the CTL responses. This work suggests that a CTL vaccine for ZKV may be possible even if ZKV exhibits significant antigenic drift. We have previously described a microsphere-based CTL vaccine platform capable of eliciting an immune response for class I epitopes in mice and are currently working toward in vivo testing of class I and class II epitope delivery directed against ZKV epitopes using the same microsphere-based vaccine. PMID- 28649244 TI - Editorial: Antibody Repertoire and Graft Outcome following Solid Organ Transplantation. PMID- 28649243 TI - Distinct Blood and Visceral Adipose Tissue Regulatory T Cell and Innate Lymphocyte Profiles Characterize Obesity and Colorectal Cancer. AB - Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this association remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (Treg) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like, gammadelta T, and Treg cell populations in VAT and blood of healthy lean subjects revealed that CD56hi NK and OX40+ Treg cells are more abundant in VAT with respect to blood. Conversely, CD56dim NK and total Treg cells are most present in the circulation, while gammadelta T lymphocytes are uniformly distributed in the two compartments. Interestingly, a reduced frequency of circulating activated Treg cells, and a concomitant preferential enrichment of OX40-expressing Treg cells in VAT, were selectively observed in obese (Ob) subjects, and directly correlated with body mass index. Likewise, CRC patients were characterized by a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected individuals shared a significant reduction of the Vgamma9Vdelta2/gammadelta T cell ratio at systemic level. The alterations in the relative proportions of Treg and NKT-like cells in VAT were found to correlate with the content of pro- and anti inflammatory polyunsaturated fatty acids (PUFA), respectively. Overall, these results provide evidence for distinct alterations of the immune cell repertoire in the periphery with respect to the VAT microenvironment that uniquely characterize or are shared by different inflammatory conditions, such as obesity and CRC, and suggest that VAT PUFA composition may represent one of the factors that contribute to shape the immune phenotypes. PMID- 28649245 TI - Camelid Single-Domain Antibodies As an Alternative to Overcome Challenges Related to the Prevention, Detection, and Control of Neglected Tropical Diseases. AB - Due mainly to properties such as high affinity and antigen specificity, antibodies have become important tools for biomedical research, diagnosis, and treatment of several human diseases. When the objective is to administer them for therapy, strategies are used to reduce the heterologous protein immunogenicity and to improve pharmacokinetic and pharmacodynamic characteristics. Size minimization contributes to ameliorate these characteristics, while preserving the antigen-antibody interaction site. Since the discovery that camelids produce functional antibodies devoid of light chains, studies have proposed the use of single domains for biosensors, monitoring and treatment of tumors, therapies for inflammatory and neurodegenerative diseases, drug delivery, or passive immunotherapy. Despite an expected increase in antibody and related products in the pharmaceutical market over the next years, few research initiatives are related to the development of alternatives for helping to manage neglected tropical diseases (NTDs). In this review, we summarize developments of camelid single-domain antibodies (VHH) in the field of NTDs. Particular attention is given to VHH-derived products, i.e., VHHs fused to nanoparticles, constructed for the development of rapid diagnostic kits; fused to oligomeric matrix proteins for viral neutralization; and conjugated with proteins for the treatment of human parasites. Moreover, paratransgenesis technology using VHHs is an interesting approach to control parasite development in vectors. With enormous biotechnological versatility, facility and low cost for heterologous production, and greater ability to recognize different epitopes, VHHs have appeared as an opportunity to overcome challenges related to the prevention, detection, and control of human diseases, especially NTDs. PMID- 28649246 TI - Redirected Primary Human Chimeric Antigen Receptor Natural Killer Cells As an "Off-the-Shelf Immunotherapy" for Improvement in Cancer Treatment. AB - Primary human natural killer (NK) cells recognize and subsequently eliminate virus infected cells, tumor cells, or other aberrant cells. However, cancer cells are able to develop tumor immune escape mechanisms to undermine this immune control. To overcome this obstacle, NK cells can be genetically modified to express chimeric antigen receptors (CARs) in order to improve specific recognition of cancer surface markers (e.g., CD19, CD20, and ErbB2). After target recognition, intracellular CAR domain signaling (CD3zeta, CD28, 4-1BB, and 2B4) leads to activation of PI3K or DNAX proteins (DAP10, DAP12) and finally to enhanced cytotoxicity, proliferation, and/or interferon gamma release. This mini review summarizes both the first preclinical trials with CAR-engineered primary human NK cells and the translational implications for "off-the-shelf immunotherapy" in cancer treatment. Signal transduction in NK cells as well as optimization of CAR signaling will be described, becoming more and more a focal point of interest in addition to redirected T cells. Finally, strategies to overcome off-target effects will be discussed in order to improve future clinical trials and to avoid attacking healthy tissues. PMID- 28649247 TI - An Antigen-Presenting and Apoptosis-Inducing Polymer Microparticle Prolongs Alloskin Graft Survival by Selectively and Markedly Depleting Alloreactive CD8+ T Cells. AB - Selectively depleting the pathogenic T cells is a fundamental strategy for the treatment of allograft rejection and autoimmune disease since it retains the overall immune function of host. The concept of killer artificial antigen presenting cells (KaAPCs) has been developed by co-coupling peptide-major histocompatibility complex (pMHC) multimer and anti-Fas monoclonal antibody (mAb) onto the polymeric microparticles (MPs) to induce the apoptosis of antigen specific T cells. But little information is available about its in vivo therapeutic potential and mechanism. In this study, polyethylenimine (PEI)-coated poly lactic-co-glycolic acid microparticle (PLGA MP) was fabricated as a cell sized scaffold to covalently co-couple H-2Kb-Ig dimer and anti-Fas mAb for the generation of alloantigen-presenting and apoptosis-inducing MPs. Intravenous infusions of the biodegradable KaAPCs prolonged the alloskin graft survival for 43 days in a single MHC-mismatched murine model, depleted the most of H-2Kb alloreactive CD8+ T cells in peripheral blood, spleen, and alloskin graft in an antigen-specific manner and anti-Fas-dependent fashion. The cell-sized KaAPCs circulated throughout vasculature into liver, kidney, spleen, lymph nodes, lung, and heart, but few ones into local allograft at early stage, with a retention time up to 36 h in vivo. They colocalized with CD8+ T cells in secondary lymphoid organs while few ones contacted with CD4+ T cells, B cells, macrophage, and dendritic cells, or internalized by phagocytes. Importantly, the KaAPC treatment did not significantly impair the native T cell repertoire or non-pathogenic immune cells, did not obviously suppress the overall immune function of host, and did not lead to visible organ toxicity. Our results strongly document the high potential of PLGA MP-based KaAPCs as a novel antigen-specific immunotherapy for allograft rejection and autoimmune disorder. The in vivo mechanism of alloinhibition, tissue distribution, and biosafety were also initially characterized, which will facilitate its translational studies from bench to bedside. PMID- 28649248 TI - A Combination of Podophyllotoxin and Rutin Alleviates Radiation-Induced Pneumonitis and Fibrosis through Modulation of Lung Inflammation in Mice. AB - Pneumonitis and pulmonary fibrosis are predominant consequences of radiation exposure, whether planned or accidental. The present study, demonstrates radioprotective potential of a formulation, prepared by combining podophyllotoxin and rutin (G-003M), in mice exposed to 11 Gy thoracic gamma radiation (TGR). Treated mice were observed for survival and other symptomatic features. Formation of reactive oxygen species (ROS)/nitric oxide (NO) was measured in bronchoalveolar lavage cells. DNA damage and cell death were assessed in alveolar cells by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Total protein (TP), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were measured in bronchoalveolar lavage fluid (BALF)/serum of mice to assess lung vascular permeability. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), transforming growth factor-beta1 (TGF-beta1), cluster of differentiation 45, inducible nitric oxide synthase (iNOS), and nitrotyrosine were also estimated in lungs/BALF of differentially treated mice. Our observations revealed 100% survival in G-003M-pretreated mice against 66.50% in 11 Gy TGR exposed. Other symptoms like reduction in graying of hair, weight loss, and breathing rate were also observed in pretreated groups. Significant decline in ROS/NO and cell death in formulation pretreated mice were also observed. Decreased level of TP, LDH, and ALP in BALF/serum samples revealed G-003M-induced inhibition in lung permeability. Level of IL-6, TNF-alpha, and TGF-beta1 in the lungs of these mice was found corresponding to control group at 8 weeks posttreatment. On the contrary, these cytokines raised significantly in 11 Gy TGR-exposed mice. Lung pneumonitis and fibrosis were found significantly countered in these mice. The observations revealed that G-003M could regulate immune system by curtailing radiation-induced oxidative and inflammatory stress, which has helped in minimizing radiation-inflicted pneumonitis and fibrosis. PMID- 28649249 TI - Dscam1 in Pancrustacean Immunity: Current Status and a Look to the Future. AB - The Down syndrome cell adhesion molecule 1 (Dscam1) gene is an extraordinary example of diversity: by combining alternatively spliced exons, thousands of isoforms can be produced from just one gene. So far, such diversity in this gene has only been found in insects and crustaceans, and its essential part in neural wiring has been well-characterized for Drosophila melanogaster. Ten years ago evidence from D. melanogaster showed that the Dscam1 gene is involved in insect immune defense and work on Anopheles gambiae indicated that it is a hypervariable immune receptor. These exciting findings showed that via processes of somatic diversification insects have the possibility to produce unexpected immune molecule diversity, and it was hypothesized that Dscam1 could provide the mechanistic underpinnings of specific immune responses. Since these first publications the quest to understand the function of this gene has uncovered fascinating insights from insects and crustaceans. However, we are still far from a complete understanding of how Dscam1 functions in relation to parasites and pathogens and its full relevance for the immune system. In this Hypothesis and Theory article, we first briefly introduce Dscam1 and what we know so far about how it might function in immunity. By focusing on seven questions, we then share our sometimes contrasting thoughts on what the evidence tells us so far, what essential experiments remain to be done, and the future prospects, with the aim to provide a multiangled view on what this fascinating gene has to do with immune defense. PMID- 28649252 TI - Sexual Dimorphic Responses in Lymphocytes of Healthy Individuals after Carica papaya Consumption. AB - Sexual dimorphism in immune response is widely recognized, but few human studies have observed this distinction. Food with endo-immunomodulatory potential may reveal novel sex-biased in vivo interactions. Immunomodulatory effects of Carica papaya were compared between healthy male and female individuals. Volunteers were given fixed meals supplemented with papaya for 2 days. Changes in blood immune profiles and hormone levels were determined. In females, total natural killer (NK) cell percentages decreased (12.7 +/- 4.4 vs 14.6 +/- 5.8%, p = 0.018, n = 18) while B cells increased (15.2 +/- 5.5 vs 14.5 +/- 5.0, p = 0.037, n = 18) after papaya consumption. Increased 17beta-estradiol (511.1 +/- 579.7 vs 282.7 +/ 165.0 pmol/l, p = 0.036, n = 9) observed in females may be crucial to this change. Differentiation markers (CD45RA, CD69, CD25) analyzed on lymphocytes showed naive (CD45RA+) non-CD4+ lymphocytes were reduced in females (40.7 +/- 8.1 vs 46.8 +/- 5.4%, p = 0.012, n = 8) but not males. A general suppressive effect of papaya on CD69+ cells, and higher percentage of CD69+ populations in females and non-CD4 lymphocytes, may be relevant. CD107a+ NK cells were significantly increased in males (16.8 +/- 7.0 vs 14.7 +/- 4.8, p = 0.038, n = 9) but not females. Effect in females may be disrupted by the action of progesterone, which was significantly correlated with this population (R = 0.771, p = 0.025, n = 8) after papaya consumption. In males, total T helper cells were increased (33.4 +/- 6.4 vs 32.4 +/- 6.1%, p = 0.040, n = 15). Strong significant negative correlation between testosterone and CD25+CD4+ lymphocytes, may play a role in the lower total CD4+ T cells reported in males. Thus, dissimilar immune profiles were elicited in the sexes after papaya consumption and may have sex hormone influence. PMID- 28649250 TI - Immunity in Protochordates: The Tunicate Perspective. AB - Tunicates are the closest relatives of vertebrates, and their peculiar phylogenetic position explains the increasing interest toward tunicate immunobiology. They are filter-feeding organisms, and this greatly influences their defense strategies. The majority of the studies on tunicate immunity were carried out in ascidians. The tunic acts as a first barrier against pathogens and parasites. In addition, the oral siphon and the pharynx represent two major, highly vascularized, immune organs, where circulating hemocytes can sense non self material and trigger immune responses that, usually, lead to inflammation and phagocytosis. Inflammation involves the recruitment of circulating cytotoxic, phenoloxidase (PO)-containing cells in the infected area, where they degranulate as a consequence of non-self recognition and release cytokines, complement factors, and the enzyme PO. The latter, acting on polyphenol substrata, produces cytotoxic quinones, which polymerize to melanin, and reactive oxygen species, which induce oxidative stress. Both the alternative and the lectin pathways of complement activation converge to activate C3: C3a and C3b are involved in the recruitment of hemocytes and in the opsonization of foreign materials, respectively. The interaction of circulating professional phagocytes with potentially pathogenic foreign material can be direct or mediated by opsonins, either complement dependent or complement independent. Together with cytotoxic cells, phagocytes are active in the encapsulation of large materials. Cells involved in immune responses, collectively called immunocytes, represent a large fraction of hemocytes, and the presence of a cross talk between cytotoxic cells and phagocytes, mediated by secreted humoral factors, was reported. Lectins play a pivotal role as pattern-recognition receptors and opsonizing agents. In addition, variable region-containing chitin-binding proteins, identified in the solitary ascidian Ciona intestinalis, control the settlement and colonization of bacteria in the gut. PMID- 28649253 TI - Variable Level of Dominance of Candidate Genes Controlling Drought Functional Traits in Maize Hybrids. AB - Breeding maize for drought tolerance necessitates the knowledge on tolerant genotypes, molecular basis of drought tolerance mechanism, action, and expression pattern of genes. Studying the expression pattern and gene action of candidate genes during drought stress in the hybrids will help in choosing target genes for drought tolerance breeding. In the present investigation, a set of five hybrids and their seven parents with a variable level of tolerance to drought stress was selected to study the magnitude and the direction of 52 drought-responsive candidate genes distributed across various biological functions, viz., stomatal regulation, root development, detoxification, hormone signaling, photosynthesis, and sugar metabolism. The tolerant parents, HKI1105 and CML425, and their hybrid, ADWLH2, were physiologically active under drought stress, since vital parameters viz., chlorophyll, root length and relative water content, were on par with the respective well-watered control. All the genes were up-regulated in ADWLH2, many were down-regulated in HM8 and HM9, and most were down-regulated in PMH1 and PMH3 in the shoots and roots. The nature of the gene action was controlled by the parental combination rather than the parent per se. The differentially expressed genes in all five hybrids explained a mostly non-additive gene action over additivity, which was skewed toward any of the parental lines. Tissue-specific gene action was also noticed in many of the genes. The non-additive gene action is driven by genetic diversity, allele polymorphism, events during gene regulation, and small RNAs under the stress condition. Differential regulation and cross-talk of genes controlling various biological functions explained the basis of drought tolerance in subtropical maize hybrids. The nature of the gene action and the direction of the expression play crucial roles in designing introgression and hybrid breeding programmes to breed drought tolerant maize hybrids. PMID- 28649254 TI - Pattern of Protein Expression in Developing Wheat Grains Identified through Proteomic Analysis. AB - Grain development is one of the biological processes, which contributes to the final grain yield. To understand the molecular changes taking place during the early grain development, we profiled proteomes of two common wheat cultivars P271 and Chinese Spring (CS) with large and small grains, respectively at three grain developmental stages (4, 8, and 12 days post anthesis). An iTRAQ (isobaric tags for relative and absolute quantitation) based proteomics approach was used for this purpose. More than 3,600 proteins were reported to accumulate during early grain development in both wheat cultivars. Of these 3,600 proteins, 130 expressed differentially between two wheat cultivars, and 306 exhibited developmental stage specific accumulation in either or both genotypes. Detailed bioinformatic analyses of differentially expressed proteins (DEPs) from the large- and small grain wheat cultivars underscored the developmental differences observed between them and shed light on the molecular and cellular processes contributing to these differences. In silico localization of either or both sets of DEPs to wheat chromosomes exhibited a biased genomic distribution with chromosome 4D contributing largely to it. These results corresponded well with the earlier studies, performed in common wheat, where chromosome 4D was reported to harbor QTLs for yield contributing traits specifically grain length. Collectively, our results provide insight into the molecular processes taking place during early grain development, a knowledge, which may prove useful in improving wheat grain yield in the future. PMID- 28649251 TI - Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications. AB - It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor kappaB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit. PMID- 28649255 TI - Overexpression of the PeaT1 Elicitor Gene from Alternaria tenuissima Improves Drought Tolerance in Rice Plants via Interaction with a Myo-Inositol Oxygenase. AB - Abiotic stresses, especially drought, seriously threaten cereal crops yields and quality. In this study, we observed that the rice plants of overexpression the Alternariatenuissima PeaT1 gene showed enhanced drought stress tolerance and increased the survival rate following a drought treatment. In PeaT1 overexpressing (PeaT1OE) plants, abscisic acid and chlorophyll content significantly increased, while the malondialdehyde (MDA) content decreased compared with the wild-type plants. Additionally, we confirmed that the transcript levels of drought-responsive genes, including OsAM1, OsLP2, and OsDST, were prominently lower in the PeaT1OE plants. In contrast, expression levels of genes encoding positive drought stress regulators including OsSKIPa, OsCPK9, OsNAC9, OSEREBP1, and OsTPKb were upregulated in PeaT1OE plants. Furthermore, combing the yeast two-hybrid assay, we found that PeaT1 could interact with amyo inositol oxygenase (OsMIOX), which was verified by pull-down assay. Interestingly, OsMIOX was highly expressed in PeaT1OE plants during the drought treatment. Additionally, the OsMIOX-GFP fusion protein co-localized with the endoplasmic reticulum (ER) marker in tobacco protoplasts, suggesting OsMIOX performs its function in ER. Therefore, our results are useful for elucidating the molecular mechanism underlying the improvement of drought tolerance by PeaT1. PMID- 28649256 TI - Evolutionary Insights Based on SNP Haplotypes of Red Pericarp, Grain Size and Starch Synthase Genes in Wild and Cultivated Rice. AB - The origin and domestication of rice has been a subject of considerable debate in the post-genomic era. Rice varieties have been categorized based on isozyme and DNA markers into two broad cultivar groups, Indica and Japonica. Among other well known cultivar groups Aus varieties are closer to Indica and Aromatic varieties including Basmati are closer to Japonica, while deep-water rice varieties share kinship to both Indica and Japonica cultivar groups. Here, we analyzed haplotype networks and phylogenetic relationships in a diverse set of genotypes including Indian Oryza nivara/Oryza rufipogon wild rice accessions and representative varieties of four rice cultivar groups based on pericarp color (Rc), grain size (GS3) and eight different starch synthase genes (GBSSI, SSSI, SSIIa, SSIIb, SSIIIa, SSIIIb, SSIVa, and SSIVb). Aus cultivars appear to have the most ancient origin as they shared the maximum number of haplotypes with the wild rice populations, while Indica, Japonica and Aromatic cultivar groups showed varying phylogenetic origins of these genes. Starch synthase genes showed higher variability in cultivated rice than wild rice populations, suggesting diversified selection during and after domestication. O. nivara/O. rufipogon wild rice accessions belonging to different sub-populations shared common haplotypes for all the 10 genes analyzed. Our results support polyphyletic origin of cultivated rice with a complex pattern of migration of domestication alleles from wild to different rice cultivar groups. The findings provide novel insights into evolutionary and domestication history of rice and will help utilization of wild rice germplasm for genetic improvement of rice cultivars. PMID- 28649258 TI - Editorial: Genomic Approaches for Improvement of Understudied Grasses. PMID- 28649257 TI - MATI, a Novel Protein Involved in the Regulation of Herbivore-Associated Signaling Pathways. AB - The defense response of the plants against herbivores relies on a complex network of interconnected signaling pathways. In this work, we characterized a new key player in the response of Arabidopsis against the two-spotted spider mite Tetranychus urticae, the MATI (Mite Attack Triggered Immunity) gene. This gene was differentially induced in resistant Bla-2 strain relative to susceptible Kon Arabidopsis accessions after mite attack, suggesting a potential role in the control of spider mites. To study the MATI gene function, it has been performed a deep molecular characterization of the gene combined with feeding bioassays using modified Arabidopsis lines and phytophagous arthropods. The MATI gene belongs to a new gene family that had not been previously characterized. Biotic assays showed that it confers a high tolerance not only to T. urticae, but also to the chewing lepidopteran Spodoptera exigua. Biochemical analyses suggest that MATI encodes a protein involved in the accumulation of reducing agents upon herbivore attack to control plant redox homeostasis avoiding oxidative damage and cell death. Besides, molecular analyses demonstrated that MATI is involved in the modulation of different hormonal signaling pathways, affecting the expression of genes involved in biosynthesis and signaling of the jasmonic acid and salicylic acid hormones. The fact that MATI is also involved in defense through the modulation of the levels of photosynthetic pigments highlights the potential of MATI proteins to be exploited as biotechnological tools for pest control. PMID- 28649259 TI - The CBL and CIPK Gene Family in Grapevine (Vitis vinifera): Genome-Wide Analysis and Expression Profiles in Response to Various Abiotic Stresses. AB - Calcium plays a central role in regulating signal transduction pathways. Calcineurin B-like proteins (CBLs), which harbor a crucial region consisting of EF hands that capture Ca2+, interact in a specific manner with CBL-interacting protein kinases (CIPKs). This two gene families or their interacting-complex widely respond to various environment stimuli and development processes. The genome-wide annotation and specific expression patterns of CBLs and CIPKs, however, in grapevine remain unclear. In the present study, eight CBL and 20 CIPK genes were identified in grapevine genome, and divided into four and five subfamilies, respectively, based on phylogenetic analysis, and validated by gene structure and the distribution of conserved protein motifs. Four (50%) out of eight VvCBLs and eight (40%) out of 20 VvCIPKs were found to be derived from tandem duplication, and five (25%) out of 20 VvCIPKs were derived from segmental duplication, indicating that the expansion of grapevine CBL and CIPK gene families were mainly contributed by gene duplication, and all duplication events between VvCIPK genes only detected in intron poor clade. Estimating of synonymous and non-synonymous substitution rates of both gene families suggested that VvCBL genes seems more conserved than VvCIPK genes, and were derived by positive selection pressure, whereas VvCIPK genes were mainly derived by purifying selection pressure. Expressional analyses of VvCBL and VvCIPK genes based on microarray and qRT-PCR data performed diverse expression patterns of VvCBLs and VvCIPKs in response to both various abiotic stimuli and at different development stages. Furthermore, the co-expression analysis of grapevine CBLs and CIPKs suggested that CBL-CIPK complex seems to be more responsive to abiotic stimuli than during different development stages. VvCBLs may play an important and special role in regulating low temperature stress. The protein interaction analysis suggested divergent mechanisms might exist between Arabidopsis and grapevine. Our results will facilitate the future functional characterization of individual VvCBLs and VvCIPKs. PMID- 28649261 TI - The Role of Sink Strength and Nitrogen Availability in the Down-Regulation of Photosynthetic Capacity in Field-Grown Nicotiana tabacum L. at Elevated CO2 Concentration. AB - Down-regulation of photosynthesis is among the most common responses observed in C3 plants grown under elevated atmospheric CO2 concentration ([CO2]). Down regulation is often attributed to an insufficient capacity of sink organs to use or store the increased carbohydrate production that results from the stimulation of photosynthesis by elevated [CO2]. Down-regulation can be accentuated by inadequate nitrogen (N) supply, which may limit sink development. While there is strong evidence for down-regulation of photosynthesis at elevated [CO2] in enclosure studies most often involving potted plants, there is little evidence for this when [CO2] is elevated fully under open-air field treatment conditions. To assess the importance of sink strength on the down-regulation of photosynthesis and on the potential of N to mitigate this down-regulation under agriculturally relevant field conditions, two tobacco cultivars (Nicotiana tabacum L. cv. Petit Havana; cv. Mammoth) of strongly contrasting ability to produce the major sink of this crop, leaves, were grown under ambient and elevated [CO2] and with two different N additions in a free air [CO2] (FACE) facility. Photosynthetic down-regulation at elevated [CO2] reached only 9% in cv. Mammoth late in the season likely reflecting sustained sink strength of the rapidly growing plant whereas down-regulation in cv. Petit Havana reached 25%. Increased N supply partially mitigated down-regulation of photosynthesis in cv. Petit Havana and this mitigation was dependent on plant developmental stage. Overall, these field results were consistent with the hypothesis that sustained sink strength, that is the ability to utilize photosynthate, and adequate N supply will allow C3 crops in the field to maintain enhanced photosynthesis and therefore productivity as [CO2] continues to rise. PMID- 28649260 TI - Tomato UDP-Glucose Sterol Glycosyltransferases: A Family of Developmental and Stress Regulated Genes that Encode Cytosolic and Membrane-Associated Forms of the Enzyme. AB - Sterol glycosyltransferases (SGTs) catalyze the glycosylation of the free hydroxyl group at C-3 position of sterols to produce sterol glycosides. Glycosylated sterols and free sterols are primarily located in cell membranes where in combination with other membrane-bound lipids play a key role in modulating their properties and functioning. In contrast to most plant species, those of the genus Solanum contain very high levels of glycosylated sterols, which in the case of tomato may account for more than 85% of the total sterol content. In this study, we report the identification and functional characterization of the four members of the tomato (Solanum lycopersicum cv. Micro-Tom) SGT gene family. Expression of recombinant SlSGT proteins in E. coli cells and N. benthamiana leaves demonstrated the ability of the four enzymes to glycosylate different sterol species including cholesterol, brassicasterol, campesterol, stigmasterol, and beta-sitosterol, which is consistent with the occurrence in their primary structure of the putative steroid-binding domain found in steroid UDP-glucuronosyltransferases and the UDP-sugar binding domain characteristic for a superfamily of nucleoside diphosphosugar glycosyltransferases. Subcellular localization studies based on fluorescence recovery after photobleaching and cell fractionation analyses revealed that the four tomato SGTs, like the Arabidopsis SGTs UGT80A2 and UGT80B1, localize into the cytosol and the PM, although there are clear differences in their relative distribution between these two cell fractions. The SlSGT genes have specialized but still largely overlapping expression patterns in different organs of tomato plants and throughout the different stages of fruit development and ripening. Moreover, they are differentially regulated in response to biotic and abiotic stress conditions. SlSGT4 expression increases markedly in response to osmotic, salt, and cold stress, as well as upon treatment with abscisic acid and methyl jasmonate. Stress-induced SlSGT2 expression largely parallels that of SlSGT4. On the contrary, SlSGT1 and SlSGT3 expression remains almost unaltered under the tested stress conditions. Overall, this study contributes to broaden the current knowledge on plant SGTs and provides support to the view that tomato SGTs play overlapping but not completely redundant biological functions involved in mediating developmental and stress responses. PMID- 28649262 TI - Multifunctional Roles of Plant Dehydrins in Response to Environmental Stresses. AB - To respond to environmental changes, plants have developed complex mechanisms that allow them to rapidly perceive and respond to abiotic stresses. Late embryogenesis abundant (LEA) proteins are a large and diverse family that play important roles in environmental stress tolerance in plants. Dehydrins belong to group II LEA proteins, which are considered stress proteins involved in the formation of plants' protective reactions to dehydration. Some studies have demonstrated that dehydrins could binding metal ions or lipid vesicles. In vitro experiments revealed that dehydrins could protect the activity of enzyme from damage caused by environmental stress. Although many studies have been conducted to understand their roles in abiotic stresses, the molecular function of dehydrins is still unclear. In this review, to generate new ideas for elucidating dehydrins' functions, we highlight the functional characteristics of dehydrins to understand their roles under environmental stress in plants. PMID- 28649263 TI - Survey of High Throughput RNA-Seq Data Reveals Potential Roles for lncRNAs during Development and Stress Response in Bread Wheat. AB - Long non-coding RNAs (lncRNAs) are a family of regulatory RNAs that play essential role in the various developmental processes and stress responses. Recent advances in sequencing technology and computational methods enabled identification and characterization of lncRNAs in certain plant species, but they are less known in Triticum aestivum (bread wheat). Herein, we analyzed 52 RNA seq data (>30 billion reads) and identified 44,698 lncRNAs in T. aestivum genome, which were characterized in comparison to the coding sequences (mRNAs). Similar to the mRNAs, lncRNAs were also derived from each sub-genome and chromosome, and showed tissue developmental stage specific and differential expression, as well. The modulated expression of lncRNAs during abiotic stresses like heat, drought, and salt indicated their putative role in stress response. The co-expression of lncRNAs with vital mRNAs including various transcription factors and enzymes involved in Abscisic acid (ABA) biosynthesis, and gene ontology mapping inferred their regulatory roles in numerous biological processes. A few lncRNAs were predicted as precursor (19 lncRNAs), while some as target mimics (1,047 lncRNAs) of known miRNAs involved in various regulatory functions. The results suggested numerous functions of lncRNAs in T. aestivum, and unfolded the opportunities for functional characterization of individual lncRNA in future studies. PMID- 28649264 TI - Genome-Wide Analysis of the PvHsp20 Family in Switchgrass: Motif, Genomic Organization, and Identification of Stress or Developmental-Related Hsp20s. AB - Hsp20 proteins exist in all plant species and represent the most abundant small heat shock proteins (sHSPs) in plants. Hsp20s were known as chaperones maintaining cellular homeostasis during heat or other kinds of abiotic stresses. The objective of this study was to understand the phylogenetic relationship, genomic organization, diversification of motif modules, genome localization, expression profiles, and interaction networks of switchgrass (Panicum virgatum L.) Hsp20s (PvHsp20s). A total of 63 PvHsp20s were identified with their consensus as well as unique ACD motifs and gene structures analyzed. Most PvHsp20s (87%) were responsive to heat and other kinds of abiotic stresses. When under optimum growth condition, 38 of them displayed relative higher expression levels in inflorescence and seeds, suggesting their protective roles in the stress-sensitive reproductive organs. An in silico analysis of interaction network of PvHsp20 proteins further revealed potential interactive proteins, including stress-inducible ones in the network. Furthermore, PvHsp20 genes unevenly distributed in two sets of homeologous chromosomes, and only segmental duplication was found among the paralogous gene pairs, reflecting that the allotetraploidization of switchgrass allowed the accumulation of PvHsp20s that in turn facilitated its successful adaptation in hot and dry plateaus of North America. The present results provided an insight into PvHsp20s with an emphasis on the uniqueness of this gene family in switchgrass. Such information shall also be useful in functional studies of PvHsp20 genes and molecular breeding of switchgrass. PMID- 28649265 TI - Model-Free Conditional Independence Feature Screening For Ultrahigh Dimensional Data. AB - Feature screening plays an important role in ultrahigh dimensional data analysis. This paper is concerned with conditional feature screening when one is interested in detecting the association between the response and ultrahigh dimensional predictors (e.g., genetic makers) given a low-dimensional exposure variable (such as clinical variables or environmental variables). To this end, we first propose a new index to measure conditional independence, and further develop a conditional screening procedure based on the newly proposed index. We systematically study the theoretical property of the proposed procedure and establish the sure screening and ranking consistency properties under some very mild conditions. The newly proposed screening procedure enjoys some appealing properties. (a) It is model-free in that its implementation does not require a specification on the model structure; (b) it is robust to heavy-tailed distributions or outliers in both directions of response and predictors; and (c) it can deal with both feature screening and the conditional screening in a unified way. We study the finite sample performance of the proposed procedure by Monte Carlo simulations and further illustrate the proposed method through two real data examples. PMID- 28649266 TI - Exploring the Uncertainty Associated with Satellite-Based Estimates of Premature Mortality due to Exposure to Fine Particulate Matter. AB - The negative impacts of fine particulate matter (PM2.5) exposure on human health are a primary motivator for air quality research. However, estimates of the air pollution health burden vary considerably and strongly depend on the datasets and methodology. Satellite observations of aerosol optical depth (AOD) have been widely used to overcome limited coverage from surface monitoring and to assess the global population exposure to PM2.5 and the associated premature mortality. Here we quantify the uncertainty in determining the burden of disease using this approach, discuss different methods and datasets, and explain sources of discrepancies among values in the literature. For this purpose we primarily use the MODIS satellite observations in concert with the GEOS-Chem chemical transport model. We contrast results in the United States and China for the years 2004 2011. Using the Burnett et al. (2014) integrated exposure response function, we estimate that in the United States, exposure to PM2.5 accounts for approximately 2% of total deaths compared to 14% in China (using satellite-based exposure), which falls within the range of previous estimates. The difference in estimated mortality burden based solely on a global model vs. that derived from satellite is approximately 14% for the U.S. and 2% for China on a nationwide basis, although regionally the differences can be much greater. This difference is overshadowed by the uncertainty in the methodology for deriving PM2.5 burden from satellite observations, which we quantify to be on the order of 20% due to uncertainties in the AOD-to-surface-PM2.5 relationship, 10% due to the satellite observational uncertainty, and 30% or greater uncertainty associated with the application of concentration response functions to estimated exposure. PMID- 28649267 TI - Evidence for a postreproductive phase in female false killer whales Pseudorca crassidens. AB - BACKGROUND: A substantial period of life after reproduction ends, known as postreproductive lifespan (PRLS), is at odds with classical life history theory and its causes and mechanisms have puzzled evolutionary biologists for decades. Prolonged PRLS has been confirmed in only two non-human mammals, both odontocete cetaceans in the family Delphinidae. We investigate the evidence for PRLS in a third species, the false killer whale, Pseudorca crassidens, using a quantitative measure of PRLS and morphological evidence from reproductive tissues. RESULTS: We examined specimens from false killer whales from combined strandings (South Africa, 1981) and harvest (Japan 1979-80) and found morphological evidence of changes in the activity of the ovaries in relation to age. Ovulation had ceased in 50% of whales over 45 years, and all whales over 55 years old had ovaries classified as postreproductive. We also calculated a measure of PRLS, known as postreproductive representation (PrR) as an indication of the effect of inter population demographic variability. PrR for the combined sample was 0.14, whereas the mean of the simulated distribution for PrR under the null hypothesis of no PRLS was 0.02. The 99th percentile of the simulated distribution was 0.08 and no simulated value exceeded 0.13. These results suggest that PrR was convincingly different from the measures simulated under the null hypothesis. CONCLUSIONS: We found morphological and statistical evidence for PRLS in South African and Japanese pods of false killer whales, suggesting that this species is the third non-human mammal in which this phenomenon has been demonstrated in wild populations. Nonetheless, our estimate for PrR in false killer whales (0.14) is lower than the single values available for the short-finned pilot whale (0.28) and the killer whale (0.22) and is more similar to working Asian elephants (0.13). PMID- 28649269 TI - A comprehensive technique for artificial hybridization in Chickpea (Cicer arietinum). AB - BACKGROUND: Two crossing techniques for hybridization of chickpea have been reported and include pollination after emasculation and pollination without emasculation. Success of crossing with emasculation varied from 5 to 17%; while the success rate varied from 20 to 50% by pollination without emasculation. The important reason for the low success rate of the two procedures could be lack of detailed information on the flowering stages chosen for crossing together with the environment where plants grow. RESULTS: We describe a comprehensive method for chickpea crossing where two genotypes, ICCV96029 as female and PI503023 as male parent were used. Leaf shape and seed size were used as morphological markers to select hybrids. For crossing, incision was made along the central line of the keel petal for the removal of anthers and to expose the stigma for placement of pollen from donor parent on its surface. After pollination, style was inserted back gently inside the keel petal and covered by wing petals and standard petals to make a natural sac which prevents drying of internal organs. Alternatively, if the conditions are favorable there is no need to protect the pollinated flower and therefore petal removal method for cross-pollination can be used. Our method showed around 78% crossing success rate which is much higher than the previous results. CONCLUSIONS: We have shown that the crossing by keel petal incision or petal removal is an effective approach which significantly increases the crossing success rate. Furthermore, our detailed method shows that the flowering stage, selection of parents and temperature play crucial roles in crossing success. PMID- 28649268 TI - Muscle development in the shark Scyliorhinus canicula: implications for the evolution of the gnathostome head and paired appendage musculature. AB - BACKGROUND: The origin of jawed vertebrates was marked by profound reconfigurations of the skeleton and muscles of the head and by the acquisition of two sets of paired appendages. Extant cartilaginous fish retained numerous plesiomorphic characters of jawed vertebrates, which include several aspects of their musculature. Therefore, myogenic studies on sharks are essential in yielding clues on the developmental processes involved in the origin of the muscular anatomy. RESULTS: Here we provide a detailed description of the development of specific muscular units integrating the cephalic and appendicular musculature of the shark model, Scyliorhinus canicula. In addition, we analyze the muscle development across gnathostomes by comparing the developmental onset of muscle groups in distinct taxa. Our data reveal that appendicular myogenesis occurs earlier in the pectoral than in the pelvic appendages. Additionally, the pectoral musculature includes muscles that have their primordial developmental origin in the head. This culminates in a tight muscular connection between the pectoral girdle and the cranium, which founds no parallel in the pelvic fins. Moreover, we identified a lateral to ventral pattern of formation of the cephalic muscles, that has been equally documented in osteichthyans but, in contrast with these gnathostomes, the hyoid muscles develop earlier than mandibular muscle in S. canicula. CONCLUSION: Our analyses reveal considerable differences in the formation of the pectoral and pelvic musculatures in S. canicula, reinforcing the idea that head tissues have contributed to the formation of the pectoral appendages in the common ancestor of extant gnathostomes. In addition, temporal differences in the formation of some cranial muscles between chondrichthyans and osteichthyans might support the hypothesis that the similarity between the musculature of the mandibular arch and of the other pharyngeal arches represents a derived feature of jawed vertebrates. PMID- 28649270 TI - Low values of central venous oxygen saturation (ScvO2) during surgery and anastomotic leak of abdominal trauma patients. AB - BACKGROUND: There is a well known relationship between hypoperfusion and postoperative complications like anastomotic leak. No studies have been done addressing this relationship in the context of abdominal trauma surgery. Central venous oxygen saturation is an important hypoperfusion marker of potential use in abdominal trauma surgery for identifying the risk of anastomotic leak development. The purpose of this study was to identify the relationship between low values of central venous oxygen saturation and anastomotic leak of gastrointestinal sutures in the postoperative period in abdominal trauma surgery. METHODS: A cross-sectional prospective study was performed. Patients over 14 years old who required surgical gastrointestinal repair secondary to abdominal trauma were included. Anastomotic leak diagnosis was confirmed through clinical manifestations and diagnostic images or secondary surgery when needed. Central venous oxygen blood saturation was measured at the beginning of surgery through a central catheter. Demographic data, trauma mechanism, anatomic site of trauma, hemoglobin levels, abdominal trauma index, and comorbidities were assessed as secondary variables. RESULTS: Patients who developed anastomotic leak showed lower mean central venous oxygen saturation levels (60.0% +/- 2.94%) than those who did not (69.89% +/- 7.21%) (p = 0.010). CONCLUSIONS: Central venous oxygen saturation <65% was associated with the development of gastrointestinal leak during postoperative time of patients who underwent surgery secondary to abdominal trauma. PMID- 28649271 TI - Effect of electrochemotherapy on human herpesvirus 8 kinetics in classic Kaposi sarcoma. AB - BACKGROUND: Electrochemotherapy (ECT) has shown to be an effective treatment for cutaneous and subcutaneous Kaposi sarcoma (KS) lesions. However, no study has investigated the impact of ECT treatment on the kinetics of human herpesvirus type 8 (HHV8), which is considered the necessary causal agent of KS. We aimed to evaluate HHV8 viral load and expression levels in patients affected by classic KS who received one or more ECT treatments and have been followed semi annually for up to four years. METHODS: A total of 27 classic KS patients were enrolled in this study. Tumour biopsies and blood samples were obtained before ECT treatment. Additional blood samples were collected at six month intervals for 12-48 months. HHV8 viral load and expression profiles of latent (ORF72 and ORF73) and lytic (K2, K8, K8.1, K10/K10.1, K10.5/K10.6 and ORF16) genes were assessed in all samples by real-time PCR. HHV8 ORF26 and K1 regions were amplified and subjected to direct nucleotide sequencing followed by phylogenetic analysis for variant identification. RESULTS: All KS biopsies and 46.4% of peripheral blood mononuclear cells (PBMCs) collected before ECT treatment were positive for HHV8 DNA. Viral load ranged from 0.02 to 2.3 copies per cell in KS lesions and 3.0 * 10-7 to 6.9 * 10-4 copies per cell in PBMCs. Overall, latent ORF72 and ORF73 as well as lytic K2, K8 and K10/K10.1 were expressed in all KS biopsies. ORF16 mRNA was detected in 71.4% and both K8.1 and K10.5/K10.6 mRNAs in 57.1% of KS samples. The ORF72, ORF73 and K2 transcripts were amplified in 37.5%, 25% and 25% of PBMCs collected before ECT, respectively. After the first ECT session, complete response was achieved in 20 out of 27 (74.1%) patients and HHV8 DNA was detected in four out of 27 (14.8%) PBMC samples at six month follow up. Phylogenetic analysis of ORF26 amplimers showed that most viral variants belonged to A/C (82.3%), and few to C2 (5.9%) or C3 (11.8%) subtype. The K1/VR1 variants fell into A (33.3%) and C (66.7%) HHV8 clade. No correlation was found between HHV8 subtypes and ECT complete response. CONCLUSIONS: ECT therapy has a significant effect on HHV8 kinetics in patients with classic KS. The complete remission of patients was accompanied by clearance of circulating virus. PMID- 28649272 TI - Does spending on refugees make a difference? A cross-sectional study of the association between refugee program spending and health outcomes in 70 sites in 17 countries. AB - BACKGROUND: Numerous simultaneous complex humanitarian emergencies strain the ability of local governments and the international community to respond, underscoring the importance of cost-effective use of limited resources. At the end of 2011, 42.5 million people were forcibly displaced, including 10.4 million refugees under the mandate of the United Nations High Commissioner for Refugees (UNHCR). UNHCR spent US$1.65 billion on refugee programs in 2011. We analyze the impact of aggregate-level UNHCR spending on mortality of refugee populations. METHODS: Using 2011 budget data, we calculated purchasing power parity adjusted spending, disaggregated by population planning groups (PPGs) and UNHCR Results Framework objectives. Monthly mortality reported to UNHCR's Health Information System from 2011 to 2012 was used to calculate crude (CMR) and under-5 (U5MR) mortality rates, and expressed as ratios to country of asylum mortality. Log linear regressions were performed to assess correlation between spending and mortality. RESULTS: Mortality data for 70 refugee sites representing 1.6 million refugees in 17 countries were matched to 20 PPGs. Median 2011 spending was $623.27 per person (constant 2011 US$). Median CMR was 2.4 deaths per 1,000 persons per year; median U5MR was 18.1 under-5 deaths per 1,000 live births per year. CMR was negatively correlated with total spending (p = 0.027), and spending for fair protection processes and documentation (p = 0.005), external relations (p = 0.034), logistics and operations support (p = 0.007), and for healthcare (p = 0.046). U5MR ratio was negatively correlated with total spending (p = 0.015), and spending for favorable protection environment (p = 0.024), fair protection processes and documentation (p = 0.003), basic needs and essential services (p = 0.027), and within basic needs, for healthcare services (p = 0.007). CONCLUSION: Increased UNHCR spending on refugee populations is correlated with lower mortality, likely reflecting unique refugee vulnerabilities and dependence on aid. Future analyses using more granular data can further elucidate the health impact of humanitarian sector spending, thereby guiding policy choices. PMID- 28649273 TI - High burden of malaria and anemia among tribal pregnant women in a chronic conflict corridor in India. AB - BACKGROUND: With more than 200 million cases a year, malaria is an important global health concern, especially among pregnant women. The forested tribal areas of Andhra Pradesh, Telangana and Chhattisgarh in India are affected by malaria and by an on-going chronic conflict which seriously limits access to health care. The burden of malaria and anemia among pregnant women in these areas is unknown; moreover there are no specific recommendations for pregnant women in the Indian national malaria policy. The aim of this study is to measure the burden of malaria and anemia among pregnant women presenting in mobile clinics for antenatal care in a conflict-affected corridor in India. METHODS: This is a descriptive study of routine programme data of women presenting at first visit for antenatal care in Medecins sans Frontieres mobile clinics during 1 year (2015). Burden of malaria and anemia were estimated using rapid diagnostic tests (SD BIOLINE(r) and HemoCue(r) respectively). RESULTS: Among 575 pregnant women (median age: 26 years, interquartile range: 25-30) 29% and 22% were in their first and second pregnancies respectively. Mid-Upper Arm Circumference (MUAC) was below 230 mm in 74% of them. The prevalence of anemia was 92.4% (95% Confidence Intervals (CI): 89.9-94.3), while severe anemia was identified in 6.9% of the patients. The prevalence of malaria was 29.3% (95%CI: 25.7-33.2) with 64% caused by isolated P. falciparum, 35% by either P. falciparum or mixed malaria and 1% by either P. vivax, or P.malariae or P. ovale. Malaria test was positive in 20.8% of asymptomatic cases. Malaria was associated with severe anemia (prevalence ratio: 2.56, 95%CI: 1.40-4.66, p < 0.01). CONCLUSIONS: Systematic screening for malaria and anemia should be integrated into maternal and child health services for conflict affected populations in highly endemic tribal areas. Interventions should include the use of rapid diagnostic test for all pregnant women at every visit, regardless of symptoms. Further studies should evaluate the impact of this intervention alone or in combination with intermittent malaria preventive treatment. PMID- 28649274 TI - Erratum to: Anoxic metabolism and biochemical production in Pseudomonas putida F1 driven by a bioelectrochemical system. AB - [This corrects the article DOI: 10.1186/s13068-016-0452-y.]. PMID- 28649275 TI - Management of enzyme diversity in high-performance cellulolytic cocktails. AB - BACKGROUND: Modern biorefineries require enzymatic cocktails of improved efficiency to generate fermentable sugars from lignocellulosic biomass. Cellulolytic fungi, among other microorganisms, have demonstrated the highest potential in terms of enzymatic productivity, complexity and efficiency. On the other hand, under cellulolytic-inducing conditions, they often produce a considerable diversity of carbohydrate-active enzymes which allow them to adapt to changing environmental conditions. However, industrial conditions are fixed and adjusted to the optimum of the whole cocktail, resulting in underperformance of individual enzymes. RESULTS: One of these cellulolytic cocktails from Myceliophthora thermophila has been analyzed here by means of LC-MS/MS. Pure GH6 family members detected have been characterized, confirming previous studies, and added to whole cocktails to compare their contribution in the hydrolysis of industrial substrates. Finally, independent deletions of two GH6 family members, as an example of the enzymatic diversity management, led to the development of a strain producing a more efficient cellulolytic cocktail. CONCLUSIONS: These data indicate that the deletion of noncontributive cellulases (here EG VI) can increase the cellulolytic efficiency of the cocktail, validating the management of cellulase diversity as a strategy to obtain improved fungal cellulolytic cocktails. PMID- 28649276 TI - A comparison of various lignin-extraction methods to enhance the accessibility and ease of enzymatic hydrolysis of the cellulosic component of steam-pretreated poplar. AB - BACKGROUND: Current single-stage delignification-pretreatment technologies to overcome lignocellulosic biomass recalcitrance are usually achieved at the expense of compromising the recovery of the polysaccharide components, particularly the hemicellulose fraction. One way to enhance overall sugar recovery is to tailor an efficient two-stage pretreatment that can pre-extract the more labile hemicellulose component before subjecting the cellulose-rich residual material to a second-stage delignification process. Previous work had shown that a mild steam pretreatment could recover >65% of the hemicellulose from poplar while limiting the acid-catalysed condensation of lignin. This potentially allowed for subsequent lignin extraction using various lignin solvents to produce a more accessible cellulosic substrate. RESULTS: A two-stage approach using steam and/or solvent pretreatment was assessed for its ability to separate hemicellulose and lignin from poplar wood chips while providing a cellulose-rich fraction that could be readily hydrolysed by cellulase enzymes. An initial steam pretreatment stage was performed over a range of temperatures (160-200 degrees C) using an equivalent severity factor of 3.6. A higher steam temperature of 190 degrees C applied over a shorter residence time of 10 min effectively solubilized and recovered 75% of the hemicellulose while enhancing the ability of various solvents [deep eutectic solvent (DES), ethanol organosolv, soda/anthraquinone (soda/AQ) or a hydrotrope] to extract lignin in a second stage. When the second stage treatments were compared, the mild DES treatment (lactic acid and betaine) at 130 degrees C, removed comparable amounts of lignin with higher selectivity than did the soda/AQ and organosolv pretreatments at 170 degrees C. However, the cellulose-rich substrates obtained after the second-stage organosolv and soda/AQ pretreatments showed the highest cellulose accessibility, as measured by the Simon's staining technique. They were also the most susceptible to subsequent enzymatic hydrolysis. CONCLUSIONS: The second-stage pretreatments varied in their ability to solubilize and extract the lignin component of steam-pretreated poplar while enhancing the enzymatic hydrolysis of the resulting cellulose-rich residual fractions. Although DES extraction was more selective in extracting lignin from the steam-pretreated substrates, the organosolv and soda/AQ post treatments disrupted the cellulose structure to a greater extent while enhancing the ease of enzymatic hydrolysis. Graphical abstractEffective hemicellulose removal via steam pretreatment followed by subsequent lignin extraction under acidic, alkaline or solvolytic conditions results in a highly accessible, more readily hydrolysed cellulose fraction. PMID- 28649277 TI - Diversity of microbial carbohydrate-active enzymes in Danish anaerobic digesters fed with wastewater treatment sludge. AB - BACKGROUND: Improved carbohydrate-active enzymes (CAZymes) are needed to fulfill the goal of producing food, feed, fuel, chemicals, and materials from biomass. Little is known about how the diverse microbial communities in anaerobic digesters (ADs) metabolize carbohydrates or which CAZymes that are present, making the ADs a unique niche to look for CAZymes that can potentiate the enzyme blends currently used in industry. RESULTS: Enzymatic assays showed that functional CAZymes were secreted into the AD environments in four full-scale mesophilic Danish ADs fed with primary and surplus sludge from municipal wastewater treatment plants. Metagenomes from the ADs were mined for CAZymes with Homology to Peptide Patterns (HotPep). 19,335 CAZymes were identified of which 30% showed 50% or lower identity to known proteins demonstrating that ADs make up a promising pool for discovery of novel CAZymes. A function was assigned to 54% of all CAZymes identified by HotPep. Many different alpha-glucan-acting CAZymes were identified in the four metagenomes, and the most abundant family was glycoside hydrolase family 13, which contains alpha-glucan-acting CAZymes. Cellulytic and xylanolytic CAZymes were also abundant in the four metagenomes. The cellulytic enzymes were limited almost to endoglucanases and beta glucosidases, which reflect the large amount of partly degraded cellulose in the sludge. No dockerin domains were identified suggesting that the cellulytic enzymes in the ADs studied operate independently. Of xylanolytic CAZymes, especially xylanases and beta-xylosidase, but also a battery of accessory enzymes, were present in the four ADs. CONCLUSIONS: Our findings suggest that the ADs are a good place to look for novel plant biomass degrading and modifying enzymes that can potentiate biological processes and provide basis for production of a range of added-value products from biorefineries. PMID- 28649278 TI - Dynamics of gene expression during development and expansion of vegetative stem internodes of bioenergy sorghum. AB - BACKGROUND: Bioenergy sorghum accumulates 75% of shoot biomass in stem internodes. Grass stem internodes are formed during vegetative growth and elongate in response to developmental and environmental signals. To identify genes and molecular mechanisms that modulate the extent of internode growth, we conducted microscopic and transcriptomic analyses of four successive sub-apical vegetative internodes representing different stages of internode development of the bioenergy sorghum genotype R.07020. RESULTS: Stem internodes of sorghum genotype R.07020 are formed during the vegetative phase and their length is enhanced by environmental signals such as shade and floral induction in short days. During vegetative growth, the first visible and youngest sub-apical internode was ~0.7 cm in length, whereas the fourth fully expanded internode was ~5 cm in length. Microscopic analyses revealed that all internode tissue types including pith parenchyma and vascular bundles are present in the four successive internodes. Growth in the first two sub-apical internodes occurred primarily through an increase in cell number consistent with expression of genes involved in the cell cycle and DNA replication. Growth of the 3rd internode was associated with an increase in cell length and growth cessation in the 4th internode was associated with up-regulation of genes involved in secondary cell wall deposition. The expression of genes involved in hormone metabolism and signaling indicates that GA, BR, and CK activity decreased while ethylene, ABA, and JA increased in the 3rd/4th internodes. While the level of auxin appears to be increasing as indicated by the up-regulation of ARFs, down-regulation of TIR during development indicates that auxin signaling is also modified. The expression patterns of transcription factors are closely associated with their role during the development of the vegetative internodes. CONCLUSIONS: Microscopic and transcriptome analyses of four successive sub-apical internodes characterized the developmental progression of vegetative stem internodes from initiation through full elongation in the sorghum genotype R.07020. Transcriptome profiling indicates that dynamic variation in the levels and action of GA, CK, IAA, BR, ethylene, ABA, and JA modulate gene expression and growth during internode growth and development. This study provides detailed microscopic and transcriptomic data useful for identifying genes and molecular pathways regulating internode elongation in response to various developmental and environmental signals. PMID- 28649279 TI - A simple method to control glycolytic flux for the design of an optimal cell factory. AB - BACKGROUND: A microbial cell factory with high yield and productivity are prerequisites for an economically feasible bio-based chemical industry. However, cell factories that show a kinetic imbalance between glycolysis and product formation pathways are not optimal. Glycolysis activity is highly robust for survival in nature, but is not optimized for chemical production. RESULTS: Here, we propose a novel approach to balance glycolytic activity with the product formation capacity by precisely controlling expression level of ptsG (encoded glucose transporter) through UTR engineering. For various heterologous pathways with different maximum production rates, e.g., n-butanol, butyrate, and 2,3 butanediol, glycolytic fluxes could be successfully modulated to maximize yield and productivity, while minimizing by-product formation in Escherichia coli. CONCLUSIONS: These results support the application of this simple method to explore the maximum yield and productivity when designing optimal cell factories for value-added products in the fields of metabolic engineering and synthetic biology. PMID- 28649280 TI - Differential beta-glucosidase expression as a function of carbon source availability in Talaromyces amestolkiae: a genomic and proteomic approach. AB - BACKGROUND: Genomic and proteomic analysis are potent tools for metabolic characterization of microorganisms. Although cellulose usually triggers cellulase production in cellulolytic fungi, the secretion of the different enzymes involved in polymer conversion is subjected to different factors, depending on growth conditions. These enzymes are key factors in biomass exploitation for second generation bioethanol production. Although highly effective commercial cocktails are available, they are usually deficient for beta-glucosidase activity, and genera like Penicillium and Talaromyces are being explored for its production. RESULTS: This article presents the description of Talaromyces amestolkiae as a cellulase-producer fungus that secretes high levels of beta-glucosidase. beta-1,4 endoglucanase, exoglucanase, and beta-glucosidase activities were quantified in the presence of different carbon sources. Although the two first activities were only induced with cellulosic substrates, beta-glucosidase levels were similar in all carbon sources tested. Sequencing and analysis of the genome of this fungus revealed multiple genes encoding beta-glucosidases. Extracellular proteome analysis showed different induction patterns. In all conditions assayed, glycosyl hydrolases were the most abundant proteins in the supernatants, albeit the ratio of the diverse enzymes from this family depended on the carbon source. At least two different beta-glucosidases have been identified in this work: one is induced by cellulose and the other one is carbon source-independent. The crudes induced by Avicel and glucose were independently used as supplements for saccharification of slurry from acid-catalyzed steam-exploded wheat straw, obtaining the highest yields of fermentable glucose using crudes induced by cellulose. CONCLUSIONS: The genome of T. amestolkiae contains several genes encoding beta-glucosidases and the fungus secretes high levels of this activity, regardless of the carbon source availability, although its production is repressed by glucose. Two main different beta-glucosidases have been identified from proteomic shotgun analysis. One of them is produced under different carbon sources, while the other is induced in cellulosic substrates and is a good supplement to Celluclast in saccharification of pretreated wheat straw. PMID- 28649281 TI - Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review. AB - BACKGROUND: Duplications or deletions in the 12q13.13 region are rare. Only scattered cases with duplications and/or deletions in this region have been reported in the literature or in online databases. Owing to the limited number of patients with genomic alteration within this region and lack of systematic analysis of these patients, the common clinical manifestation of these patients has remained elusive. CASE PRESENTATION: Here we report an 802 kb duplication in the 12q13.13q13.13 region in a 14 year-old male who presented with dysmorphic features, developmental delay (DD), mild intellectual disability (ID) and mild deformity of digits. Comparing the phenotype of our patient with those of reported patients, we find that patients with the 12q13.13 duplication or the deletion share similar phenotypes, including dysmorphic facies, abnormal nails, intellectual disability, and deformity of digits or limbs. However, patients with the deletion appear to have more severe deformity of digits or limbs. CONCLUSIONS: Deletion and duplication of the 12q13.13 region may represent novel contiguous gene alteration syndromes. All seven reported 12q13.13 deletions and three of four duplications are de novo and vary in size. Therefore, these genomic alterations are not due to non-allelic homologous recombination. PMID- 28649282 TI - Asymmetric DNA methylation of CpG dyads is a feature of secondary DMRs associated with the Dlk1/Gtl2 imprinting cluster in mouse. AB - BACKGROUND: Differential DNA methylation plays a critical role in the regulation of imprinted genes. The differentially methylated state of the imprinting control region is inherited via the gametes at fertilization, and is stably maintained in somatic cells throughout development, influencing the expression of genes across the imprinting cluster. In contrast, DNA methylation patterns are more labile at secondary differentially methylated regions which are established at imprinted loci during post-implantation development. To investigate the nature of these more variably methylated secondary differentially methylated regions, we adopted a hairpin linker bisulfite mutagenesis approach to examine CpG dyad methylation at differentially methylated regions associated with the murine Dlk1/Gtl2 imprinting cluster on both complementary strands. RESULTS: We observed homomethylation at greater than 90% of the methylated CpG dyads at the IG-DMR, which serves as the imprinting control element. In contrast, homomethylation was only observed at 67-78% of the methylated CpG dyads at the secondary differentially methylated regions; the remaining 22-33% of methylated CpG dyads exhibited hemimethylation. CONCLUSIONS: We propose that this high degree of hemimethylation could explain the variability in DNA methylation patterns at secondary differentially methylated regions associated with imprinted loci. We further suggest that the presence of 5-hydroxymethylation at secondary differentially methylated regions may result in hemimethylation and methylation variability as a result of passive and/or active demethylation mechanisms. PMID- 28649283 TI - Clinically-evident tophi are associated with reduced muscle force in the foot and ankle in people with gout: a cross-sectional study. AB - BACKGROUND: The foot and ankle represent a common site for tophi in people with gout, yet it is unclear whether the presence of tophi is related to impaired muscle function. This study aimed to determine the association between foot and ankle tophi and muscle force in people with gout. METHODS: Participants with gout were stratified into two groups based on the presence of clinically-evident tophi affecting the foot or ankle on physical examination. Isometric muscle force for plantarflexion, dorsiflexion, inversion and eversion was measured using static dynamometry. Mixed-models regression was used to determine the difference in muscle force between the two groups while adjusting for age, disease duration and foot pain. This model was also used to determine the difference in muscle force between presence and absence of tophi at specific locations within the foot and ankle. In addition, Pearson's correlations were used to determine the association between total foot tophus count and muscle force. RESULTS: Fifty-seven participants were included (22 with foot or ankle tophi and 35 without foot or ankle tophi). Foot and ankle tophi were most often seen at the Achilles tendon. After adjusting for age, disease duration and foot pain, participants with tophi had significantly reduced muscle force during plantarflexion (P < 0.001), dorsiflexion (P = 0.003), inversion (P = 0.003) and eversion (P = 0.001) when compared to participants without tophi. Those with Achilles tophi had significantly reduced force during plantarflexion (P < 0.001), inversion (P = 0.008) and eversion (P = 0.001). No significant differences in muscle force were observed between the presence and absence of tophi at other foot or ankle locations. There were also no significant correlations between total foot tophus count and muscle force (all P > 0.05). CONCLUSION: In people with gout, clinically-evident foot or ankle tophi are associated with muscle force deficits during foot plantarflexion, dorsiflexion, inversion and eversion, which persist despite adjusting for age, disease duration and foot pain. Tophi at the Achilles tendon, which associate with force deficits, may contribute to reduced muscular activation and consequent disuse muscle atrophy. PMID- 28649284 TI - Development and evaluation of a PCR assay for rapid detection of azithromycin resistant Campylobacter isolated from diarrhoeal patients in Kolkata, India. AB - BACKGROUND: Campylobacter is a well-known bacterial pathogen for triggering acute gastroenteritis in humans both in developed and developing countries. This organism is highly resistant to fluoroquinolones. Macrolides are very much useful for the treatment of campylobacteriosis when clinical therapy is necessary. However, increasing resistance to azithromycin, a potent macrolide has been reported in Campylobacter in recent years. Macrolide resistance in Campylobacter is found mainly due to point mutation in V region of 23S rRNA. RESULTS: We have developed a PCR based assay, which can detect the azithromycin resistant and sensitive Campylobacter strains utilizing mutation responsible for the phenotype. This PCR was validated using 359 Campylobacter strains isolated from diarrhoeal patients at Kolkata, India. Antimicrobial resistance through disk diffusion method was also performed on these strains as a gold standard. Studies through sequencing analysis further confirmed the PCR result. CONCLUSION: This study describes a simple and rapid method for detection of mutation conferring macrolide resistance with additional feature of identification of sensitive strains. PMID- 28649285 TI - Introduction of the DiaGene study: clinical characteristics, pathophysiology and determinants of vascular complications of type 2 diabetes. AB - BACKGROUND: Type 2 diabetes is a major healthcare problem. Glucose-, lipid-, and blood pressure-lowering strategies decrease the risk of micro- and macrovascular complications. However, a substantial residual risk remains. To unravel the etiology of type 2 diabetes and its complications, large-scale, well-phenotyped studies with prospective follow-up are needed. This is the goal of the DiaGene study. In this manuscript, we describe the design and baseline characteristics of the study. METHODS: The DiaGene study is a multi-centre, prospective, extensively phenotyped type 2 diabetes cohort study with concurrent inclusion of diabetes free individuals at baseline as controls in the city of Eindhoven, The Netherlands. We collected anthropometry, laboratory measurements, DNA material, and detailed information on medication usage, family history, lifestyle and past medical history. Furthermore, we assessed the prevalence and incidence of retinopathy, nephropathy, neuropathy, and diabetic feet in cases. Using logistic regression models, we analyzed the association of 11 well known genetic risk variants with type 2 diabetes in our study. RESULTS: In total, 1886 patients with type 2 diabetes and 854 controls were included. Cases had worse anthropometric and metabolic profiles than controls. Patients in outpatient clinics had higher prevalence of macrovascular (41.9% vs. 34.8%; P = 0.002) and microvascular disease (63.8% vs. 20.7%) compared to patients from primary care. With the exception of the genetic variant in KCNJ11, all type 2 diabetes susceptibility variants had higher allele frequencies in subjects with type 2 diabetes than in controls. CONCLUSIONS: In our study population, considerable rates of macrovascular and microvascular complications are present despite treatment. These prevalence rates are comparable to other type 2 diabetes populations. While planning genomics, we describe that 11 well-known type 2 diabetes genetic risk variants (in TCF7L2, PPARG-P12A, KCNJ11, FTO, IGF2BP2, DUSP9, CENTD2, THADA, HHEX, CDKAL1, KCNQ1) showed similar associations compared to literature. This study is well-suited for multiple omics analyses to further elucidate disease pathophysiology. Our overall goal is to increase the understanding of the underlying mechanisms of type 2 diabetes and its complications for developing new prediction, prevention, and treatment strategies. PMID- 28649288 TI - A Hybrid Human-Computer Approach to the Extraction of Scientific Facts from the Literature. AB - A wealth of valuable data is locked within the millions of research articles published each year. Reading and extracting pertinent information from those articles has become an unmanageable task for scientists. This problem hinders scientific progress by making it hard to build on results buried in literature. Moreover, these data are loosely structured, encoded in manuscripts of various formats, embedded in different content types, and are, in general, not machine accessible. We present a hybrid human-computer solution for semi-automatically extracting scientific facts from literature. This solution combines an automated discovery, download, and extraction phase with a semi-expert crowd assembled from students to extract specific scientific facts. To evaluate our approach we apply it to a challenging molecular engineering scenario, extraction of a polymer property: the Flory-Huggins interaction parameter. We demonstrate useful contributions to a comprehensive database of polymer properties. PMID- 28649286 TI - Autism spectrum disorder and epileptic encephalopathy: common causes, many questions. AB - Epileptic encephalopathies represent a particularly severe form of epilepsy, associated with cognitive and behavioral deficits, including impaired social communication and restricted, repetitive behaviors that are the hallmarks of autism spectrum disorder (ASD). With the advent of next-generation sequencing, the genetic landscape of epileptic encephalopathies is growing and demonstrates overlap with genes separately implicated in ASD. However, many questions remain about this connection, including whether epileptiform activity itself contributes to the development of ASD symptomatology. In this review, we compiled a database of genes associated with both epileptic encephalopathy and ASD, limiting our purview to Mendelian disorders not including inborn errors of metabolism, and we focused on the connection between ASD and epileptic encephalopathy rather than epilepsy broadly. Our review has four goals: to (1) discuss the overlapping presentations of ASD and monogenic epileptic encephalopathies; (2) examine the impact of the epilepsy itself on neurocognitive features, including ASD, in monogenic epileptic encephalopathies; (3) outline many of the genetic causes responsible for both ASD and epileptic encephalopathy; (4) provide an illustrative example of a final common pathway that may be implicated in both ASD and epileptic encephalopathy. We demonstrate that autistic features are a common association with monogenic epileptic encephalopathies. Certain epileptic encephalopathy syndromes, like infantile spasms, are especially linked to the development of ASD. The connection between seizures themselves and neurobehavioral deficits in these monogenic encephalopathies remains open to debate. Finally, advances in genetics have revealed many genes that overlap in ties to both ASD and epileptic encephalopathy and that play a role in diverse central nervous system processes. Increased attention to the autistic features of monogenic epileptic encephalopathies is warranted for both researchers and clinicians alike. PMID- 28649287 TI - Regulating role of fetal thyroid hormones on placental mitochondrial DNA methylation: epidemiological evidence from the ENVIRONAGE birth cohort study. AB - BACKGROUND: Fetal development largely depends on thyroid hormone availability and proper placental function with an important role played by placental mitochondria. The biological mechanisms by which thyroid hormones exert their effects on mitochondrial function are not well understood. We investigated the role of fetal thyroid hormones on placental mitochondrial DNA (mtDNA) content and mtDNA methylation. We collected placental tissue and cord blood from 305 mother child pairs that were enrolled between February 2010 and June 2014 in the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort (province of Limburg, Belgium). Placental mtDNA content was determined by qPCR and placental mtDNA methylation by bisulfite-pyrosequencing in two regions, i.e., the D-loop control region and 12S ribosomal RNA (MT-RNR1). The levels of free thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) were measured in cord blood. RESULTS: Cord blood FT3 and FT4 were inversely associated with placental mtDNA methylation at the MT-RNR1 (p <= 0.01) and D-loop (p <= 0.05) regions, whereas a positive association was observed for both hormones with placental mtDNA content (p <= 0.04). Assuming causality, we estimated that MT-RNR1 and D loop methylation mediated, respectively, 77% [indirect effect +14.61% (95% CI 2.64 to 27.98%, p = 0.01)] and 47% [indirect effect +8.60% (95% CI 1.23 to 16.50%, p = 0.02] of the positive association between FT3 and placental mtDNA content. Mediation models with FT4 gave similar results but the estimated effect proportions were smaller compared with those of FT3 (54% and 24%, respectively). CONCLUSIONS: We showed that epigenetic modification at specific loci of the mitochondrial genome could intervene with the thyroid-dependent regulation of mitochondrial DNA copy numbers. PMID- 28649289 TI - Effect of cranberry (Vaccinium macrocarpon) oligosaccharides on the formation of advanced glycation end-products. AB - BACKGROUND: The formation and accumulation of advanced glycation end-products (AGEs) are implicated in several chronic human illnesses including type-2 diabetes, renal failure, and neurodegenerative diseases. The cranberry (Vaccinium macrocarpon) fruit has been previously reported to show anti-AGEs effects, attributed primarily to its phenolic constituents. However, there is lack of similar data on the non-phenolic constituents found in the cranberry fruit, in particular, its carbohydrate constituents. Herein, a chemically characterized oligosaccharide-enriched fraction purified from the cranberry fruit was evaluated for its potential anti-AGEs and free radical scavenging effects. OBJECTIVE: The aim of this study was to evaluate the in vitro anti-AGEs and free radical scavenging effects of a chemically characterized oligosaccharide-enriched fraction purified from the North American cranberry (Vaccinium macrocarpon) fruit. METHOD: The cranberry oligosaccharide-enriched fraction was purified from cranberry hull powder and characterized based on spectroscopic and spectrometric (NMR, MALDI-TOF-MS, and HPAEC-PAD) data. The oligosaccharide-enriched fraction was evaluated for its anti-AGEs and free radical scavenging effects by the bovine serum albumin-fructose, and DPPH assays, respectively. RESULTS: Fractionation of cranberry hull material yielded an oligosaccharide-enriched fraction named Cranf1b-CL. The 1H NMR and MALDI-TOF-MS revealed that Cranf1b-CL consists of oligosaccharides ranging primarily from 6-mers to 9-mers. The monosaccharide composition of Cranf1b-CL was arabinose (25%), galactose (5%), glucose (47%) and xylose (23%). In the bovine serum albumin-fructose assay, Cranf1b-CL inhibited AGEs formation in a concentration-dependent manner with comparable activity to the synthetic antiglycating agent, aminoguanidine, used as the positive control (57 vs. 75%; both at 500MUg/mL). In the DPPH free radical scavenging assay, Cranf1b-CL showed superior activity to the synthetic commercial antioxidant, butylated hydroxytoluene, used as the positive control (IC50 = 680 vs. 2200MUg/mL, respectively). CONCLUSION: The in vitro anti-AGEs and free radical scavenging effects of cranberry oligosaccharides support previous data suggesting that these constituents may also contribute to biological effects of the whole fruit beyond its phenolic constituents alone. Also, this is the first study to evaluate a chemically characterized oligosaccharide fraction purified from the North American cranberry fruit for anti-AGEs and free radical scavenging properties. PMID- 28649290 TI - Preface to the Special Issue on Animal Music Perception. PMID- 28649291 TI - Animal Pitch Perception: Melodies and Harmonies. AB - Pitch is a percept of sound that is based in part on fundamental frequency. Although pitch can be defined in a way that is clearly separable from other aspects of musical sounds, such as timbre, the perception of pitch is not a simple topic. Despite this, studying pitch separately from other aspects of sound has led to some interesting conclusions about how humans and other animals process acoustic signals. It turns out that pitch perception in humans is based on an assessment of pitch height, pitch chroma, relative pitch, and grouping principles. How pitch is broken down depends largely on the context. Most, if not all, of these principles appear to also be used by other species, but when and how accurately they are used varies across species and context. Studying how other animals compare to humans in their pitch abilities is partially a reevaluation of what we know about humans by considering ourselves in a biological context. PMID- 28649292 TI - The Effectiveness of Food Insecurity Screening in Pediatric Primary Care. AB - BACKGROUND: Food insecure children are at increased risk for medical and developmental problems. Effective screening and intervention are needed. METHODS: Our purpose was to (1) evaluate the validity and stability of a single item food insecurity (FI) screen. (2) Assess whether use may lead to decreased FI. Part of a larger cluster randomized controlled trial, pediatric residents were assigned to SEEK or control groups. A single FI question (part of a larger questionnaire) was used on SEEK days. SEEK residents learned to screen, assess, and address FI. A subset of SEEK and control clinic parents was recruited for the evaluation. Parents completed the USDA Food Security Scale ("gold standard"), upon recruitment and 6-months later. Validity, positive and negative predictive values (PPV, NPV) was calculated. The proportion of screened families with initial and subsequent FI was measured. Screening effectiveness was evaluated by comparing SEEK and control screening rates and receipt of Supplemental Nutrition Assistance Program (SNAP) benefits between initial and 6-month assessments. RESULTS: FI screen stability indicated substantial agreement (Cohen's kappa =0.69). Sensitivity and specificity was 59% and 87%, respectively. The PPV was 70%; NPV was 81%. SEEK families had a larger increase in screening rates than control families (24% vs. 4.1%, p<0.01). SEEK families were more likely to maintain SNAP enrollment (97% vs. 81%, p=0.05). FI rates remained stable at approximately 30% for both groups. CONCLUSIONS: A single question screen can identify many families with FI, and may help maintain food program enrollment. Screening may not be adequate to alleviate FI. PMID- 28649293 TI - Small airways disease and severe asthma. AB - The small airways of the lungs are commonly affected in pediatric and adult asthma. Small airways disease has been related to asthma control, severity, and risk of exacerbation. Diagnosis of small airways disease can be best made through evaluation of surgical lung specimens. Noninvasive techniques including spirometry, plethysmography, nitrogen washout, impulse oscillometry, and cross sectional imaging have been utilized to assess and infer the extent of small airways disease in asthma and can be used longitudinally to assess response to treatment. Patients with small airways disease seem to benefit from inhaled asthma medications that have improved capacity to reach the distal lung compartment. This is especially important for patients with severe asthma, who rely upon high doses of inhaled corticosteroid and bronchodilators for asthma control. This review will describe the techniques which may be utilized to assess small airways disease, discuss the prevalence and characteristics of small airways disease in severe asthma, and highlight how small airway disease may complicate severe asthma treatment. PMID- 28649294 TI - Randomised controlled trial of a baked egg intervention in young children allergic to raw egg but not baked egg. AB - BACKGROUND: Consumption of baked egg by raw egg allergic children is associated with immune changes suggesting development of tolerance. However, causation has not been tested using a double blind randomized controlled trial (RCT). We aimed to compare clinical and immunological outcomes after baked egg (BE) consumption in young BE tolerant egg allergic children. METHODS: In a double blind RCT, BE tolerant egg allergic children consumed 10 g BE (1.3 g protein) 2 to 3 times per week for 6 months (n = 21 intervention group) or similar egg free baked goods (n = 22 control group) while maintaining an otherwise egg free diet. The final assessment was a raw egg oral food challenge (OFC) 1 month after ceasing the intervention product. Egg specific IgE and IgG4 were assessed at baseline and 7 months. RESULTS: After the intervention there was no difference in raw egg tolerance between groups, (23.5% (4/17) intervention group and 33.3% (6/18) control group). This was independent of age and amount of BE consumed (aOR 0.50 CI 0.11-2.40 p = 0.39). Both groups demonstrated decreased egg specific serum IgE titres and decreased whole egg specific IgE/IgG4 ratios. DISCUSSION: We conducted this trial because inclusion of baked egg protein in the diet of egg allergic children appears to move children towards a more tolerant immune profile. Strengths of our study include design of the blinded intervention, the consistent dosing protocol and the regular monitoring of symptoms and intake. However, the study was limited by small sample size resulting in insufficient power to show statistically significant results. CONCLUSION: Our study suggests that short term, regular consumption of BE by BE tolerant 1 to 5 year old children with IgE mediated raw egg allergy may not induce, accelerate or slow development of tolerance to raw egg in this selected population. Trials with larger sample sizes are required to further test this hypothesis. TRIAL REGISTRATION: The trial was registered on 7th February 2012 with the Australian New Zealand Clinical Trials Registry (ACTRN 12612000173897). PMID- 28649295 TI - Counseling during Maternal and Infant Health Visits and Postpartum Contraceptive use in Uttar Pradesh, India. AB - CONTEXT: Postpartum family planning is a compelling concern of global significance due to its salience to unplanned pregnancies, and to maternal and infant health in developing countries. Yet, women face the highest level of unmet need for contraception in the year following a birth. A cost-effective way to inform women about their risk of becoming pregnant after the birth of a child is to integrate family planning counseling and services with maternal and infant health services. METHODS: We use recently collected survey data from 2733 women from six cities in Uttar Pradesh, India who had a recent birth (since 2011) to examine the role of exposure to family planning information at maternal and infant health visits on (1) any contraceptive use in the postpartum period, and (2) choice of modern method in the postpartum period. We use discrete-time event history multinomial logit models to examine the duration to contraceptive use, and choice of modern method, in the 12 months following the last birth since 2011. RESULTS: We find that receiving counseling in an institution at the time of delivery has the strongest influence on women's subsequent uptake of modern contraception (female sterilization and IUD). Being visited by a CHW in the extended postpartum period was also strongly associated with subsequent uptake of modern contraception (IUD, condom and hormonal contraception). CONCLUSION: Providing postpartum family planning counseling at key junctures during maternal health visits has the potential to increase uptake of modern contraceptive method in urban Uttar Pradesh. PMID- 28649296 TI - Clinical profile and outcome of diabetic foot ulcer, a view from tertiary care hospital in Semarang, Indonesia. AB - Background: This study attempted to determine the disease burden in terms of clinical profile and outcome of diabetic foot ulcer (DFU) admissions at a tertiary care hospital in a developing country. Methods: In this descriptive study, the data were collected from the medical record of diabetic patients with foot ulcer who were treated in Dr. Kariadi General Hospital during a 3-year period. The demographic characteristic, type of foot lesion, etiology, isolated microorganism, treatment, and outcome were reviewed. Results: Foot problems accounted for 16.2% of total diabetic admission (n = 1429). All patients had type 2 diabetes with no gender predominance. The mean age was 54.3 +/- 8.6 years and diabetes control was very poor. Before admission, the ulcers had already developed for 4.7 +/- 2.9 weeks; however, the majority of patients were unaware of the preceding causes. Ulcers were neuropathic in 42.2% of cases, neuroischemic in 29.9%, and pure ischemic at lesser percentage. More than 70% of ulcers were in Wagner grade >=3 with infection event in nearly all patients. The most common isolates from culture were Gram-negative bacteria. A total of 98 (36.3%) lower extremity amputations (LEAs) at various level of the foot were carried out, including major LEA in 24 patients and multiple amputations in seven patients. Mortality rate due to DFU reached 10.7%. Conclusions: Diabetic foot problems constitute a source of morbidity, a reason for LEA surgery as well as being a cause of death among patients with diabetes mellitus. PMID- 28649297 TI - A scoping review of intimate partner violence assistance programmes within health care settings. AB - Background: The lifetime prevalence of intimate partner violence (IPV) for women presenting to health care settings is estimated to be 38-59%. With the goal of providing help to victims of abuse, numerous IPV assistance programmes have been developed and evaluated across multiple health care settings. Objective: Our scoping review provides an overview of this literature to identify key areas for potential evidence-based recommendations and to focus research priorities. Methods: We conducted a search of MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and psycINFO. We used broad eligibility criteria to identify studies that evaluated the effectiveness of IPV assistance programmes delivered within health care settings. We completed all screening and data extraction independently and in duplicate. We used descriptive statistics to summarize all data. Results: Forty-three studies met all eligibility criteria and were included in our scoping review. Nine categories of assistance programmes were identified: counselling/advocacy, safety assessment/planning, referral, providing IPV resources, home visitation, case management, videos, provider cueing, and system changes. Characteristics of programmes amongst studies frequently reporting positive results included those in which one type of active assistance was used (77.8% of studies reported positive results), a counsellor, community worker, or case manager provided the intervention (83.3% of studies reported positive results), and programmes that were delivered over more than five sessions (100.0% of studies reported positive results). Conclusions: IPV assistance programmes are heterogeneous with regards to the types of assistance they include and how they are delivered and evaluated. This heterogeneity creates challenges in identifying which IPV assistance programmes, and which aspects of these programmes, are effective. However, it appears that many different types of IPV assistance programmes can have positive impacts on women. PMID- 28649299 TI - The neurobiology of PTSD. PMID- 28649298 TI - Neuroimaging the traumatized self: fMRI reveals altered response in cortical midline structures and occipital cortex during visual and verbal self- and other referential processing in women with PTSD. AB - Background: Changes to the diagnostic criteria for PTSD in DSM-5 reflect an increased emphasis on negative cognition referring to self and other, including self-blame, and related pervasive negative affective states including for self conscious emotions such as guilt and shame. Objective: Investigate the neural correlates of valenced self-referential processing (SRP) and other-referential processing (ORP) in persons with PTSD. Method: We compared response to the Visual Verbal Self-Other Referential Processing Task in an fMRI study of women with (n = 20) versus without (n = 24) PTSD primarily relating to childhood and interpersonal trauma histories using statistical parametric mapping and group independent component analysis. Results: As compared to women without PTSD, women with PTSD endorsed negative words as more descriptive both of themselves and others, whereas positive words were endorsed as less descriptive both of themselves and others. Women with PTSD also reported a greater experience of negative affect and a lesser experience of positive affect during SRP specifically. Significant differences between groups were observed within independent components defined by ventral- and middle-medial prefrontal corte x, mediolateral parietal cortex, and visual cortex, depending on experimental conditions. Conclusions: This study reveals brain-based disturbances during SRP and ORP in women with PTSD related to interpersonal and developmental trauma. Psychological assessment and treatment should address altered sense of self and affective response to others in PTSD. PMID- 28649300 TI - Negative body experience in women with early childhood trauma: associations with trauma severity and dissociation. AB - Background: A crucial but often overlooked impact of early life exposure to trauma is its far-reaching effect on a person's relationship with their body. Several domains of body experience may be negatively influenced or damaged as a result of early childhood trauma. Objective: The aim of this study was to investigate disturbances in three domains of body experience: body attitude, body satisfaction, and body awareness. Furthermore, associations between domains of body experience and severity of trauma symptoms as well as frequency of dissociation were evaluated. Method: Body attitude was measured with the Dresden Body Image Questionnaire, body satisfaction with the Body Cathexis Scale, and body awareness with the Somatic Awareness Questionnaire in 50 female patients with complex trauma and compared with scores in a non-clinical female sample (n = 216). Patients in the clinical sample also filled out the Davidson Trauma Scale and the Dissociation Experience Scale. Results: In all measured domains, body experience was severely affected in patients with early childhood trauma. Compared with scores in the non-clinical group, effect sizes in Cohen's d were 2.7 for body attitude, 1.7 for body satisfaction, and 0.8 for body awareness. Associations between domains of body experience and severity of trauma symptoms were low, as were the associations with frequency of dissociative symptoms. Conclusions: Early childhood trauma in women is associated with impairments in self-reported body experience that warrant careful assessment in the treatment of women with psychiatric disorders. PMID- 28649301 TI - Assessment of depression in veterans across missions: a validity study using Rasch measurement models. AB - Background: Depression is a common psychopathological outcome following military deployment. Previous studies have reported differing rates of post-deployment depression, indicating that the toll of war differs across missions. However, it is unclear to what degree the varying prevalence is due methodological differences. Studies comparing rates of depression across cohorts using the same methodology and ensuring measurement invariance are rare, leaving us with limited knowledge on the actual depression prevalence variance across missions. Objective: Applying Rasch models (RM), we aim to validate a measure of depression distributed to all personnel deployed with the Danish Defense since 1998. The main focus was establishing a sufficient sum score and measurement invariance relative to deployment cohort. Method: Two cohorts of the International Security Assistance Force (ISAF) deployed to Afghanistan in 2009 (ISAF7, N = 265) and 2013 (ISAF15, N = 271) were included. Participants filled out a questionnaire concerning their Psychological Reactions to International Missions (PRIM) approximately seven months after home-coming. The questionnaire included a 10 item scale of depression symptoms (PRIM-Depression). The validity of the PRIM Depression was tested using RM with specific focus on differential item functioning (DIF) across the two cohorts. Results: The PRIM-Depression scale displayed excellent overall consistency and showed no problems with monotonicity or homogeneity. However, the full PRIM-Depression scale did not fit a pure RM. We therefore tested the fit of items to a graphical log-linear RM and found evidence of DIF for two items relative to cohort. We proceeded without these two items and tested the resulting 8-item version which fitted a pure RM without DIF on any of the exogenous variables. Conclusions: Our results suggest that the 10-item PRIM Depression scale should be used to compare cohorts only with appropriate score equation. The 8-item version provides a sufficient statistic and can as such be applied using the raw score. PMID- 28649303 TI - Introduction and persistence of tularemia in Bulgaria. PMID- 28649302 TI - Differential predictors of DSM-5 PTSD and ICD-11 complex PTSD among African American women. AB - Background: Complex posttraumatic stress disorder (CPTSD) is proposed for inclusion in the ICD-11 as a diagnosis distinct from posttraumatic stress disorder (PTSD), reflecting deficits in affective, self-concept, and relational domains. There remains significant controversy over whether CPTSD provides useful diagnostic information beyond PTSD and other comorbid conditions, such as depression or substance use disorders. Objective: The present study examined differences in psychiatric presentation for three groups: traumatized controls, DSM-5 PTSD subjects, and ICD-11 CPTSD subjects. Method: The sample included 190 African American women recruited from an urban public hospital where rates of trauma exposure are high. PTSD was measured using Clinician Administered PTSD Scale for DSM-5 and CPTSD was measured using clinician administered ICD-Trauma Interview. Psychiatric diagnoses and emotion dysregulation were also assessed. In a subset of women (n = 60), emotion recognition was measured using the Penn Emotion Recognition Task. Results: There were significant differences across groups on current and lifetime major depression (p < .001) and current and lifetime alcohol and substance dependence (p < .05), with CPTSD showing the highest rates of comorbidities. CPTSD women also showed significantly higher levels of childhood abuse and lower rates of adult secure attachment. Multivariate analysis of variance showed significantly more severe PTSD and depression symptoms and, as expected, more severe emotion dysregulation and dissociation, compared to DSM-5 PTSD and traumatized control groups. Individuals with CPTSD also had higher levels of emotion recognition to faces on a computer based behavioural assessment, which may be related to heightened vigilance toward emotional cues from others. CPTSD women had better facial emotion recognition on a computer-based assessment, which may suggest heightened vigilance toward emotional cues. Conclusions: Our results suggest clear, clinically-relevant differences between PTSD and CPTSD, and highlight the need for further research on this topic with other traumatized populations, particularly studies that combine clinical and neurobiological data. PMID- 28649304 TI - A nationwide outbreak of listeriosis associated with cold-cuts, Sweden 2013-2014. AB - In January 2014, the Public Health Agency of Sweden noticed an increase in listeriosis cases. Isolates from 10 cases had identical pulsed field gel electrophoresis (PFGE) profiles, suggesting a common source. We investigated the outbreak to identify the source and stop transmission. We looked for cases in 2013-2014 and also compared cases notified after February 2014 to randomly selected controls. We surveyed food items consumed two weeks prior to symptom onset. Listeria monocytogenes isolates found by food producers were PFGE-typed. Patient and food isolates with the outbreak PFGE profile were whole-genome sequenced and 51 cases with identical PFGE profile were identified; 12/20 cases and 108/186 controls responded to the survey. All cases were exposed to cold cuts, compared with 72% of controls (p = 0.034). Five isolates of L. monocytogenes with the outbreak PFGE profile were found in cold-cuts from a food producer which stopped production in February 2014, but cases appeared until October 2014. Whole-genome sequencing showed that cold-cut and patient isolates differed by eight single nucleotide polymorphisms. Three patient isolates differed more and were probably not part of the outbreak. Epidemiological and microbiological results indicated cold-cuts as a possible source of the outbreak. PMID- 28649305 TI - Emerging microbiota during cold storage and temperature abuse of ready-to-eat salad. AB - Introduction: Ready-to-eat (RTE) leafy vegetables have a natural leaf microbiota that changes during different processing and handling steps from farm to fork. The objectives of this study were (i) to compare the microbiota of RTE baby spinach and mixed-ingredient salad before and after seven days of storage at 8 degrees C or 15 degrees C; (ii) to explore associations between bacterial communities and the foodborne pathogens Listeria monocytogenes, pathogenic Yersinia enterocolitica, and pathogen model organism Escherichia coli O157:H7 gfp+ when experimentally inoculated into the salads before storage; and (iii) to investigate if bacterial pathogens may be detected in the 16S rRNA amplicon dataset. Material and methods: The microbiota was studied by means of Illumina 16S rRNA amplicon sequencing. Subsets of samples were inoculated with low numbers (50-100 CFU g-1) of E. coli O157:H7 gfp+, pathogenic Y. enterocolitica or L. monocytogenes before storage. Results and discussion: The composition of bacterial communities changed during storage of RTE baby spinach and mixed ingredient salad, with Pseudomonadales as the most abundant order across all samples. Although pathogens were present at high viable counts in some samples, they were only detected in the community-wide dataset in samples where they represented approximately 10% of total viable counts. Positive correlations were identified between viable counts of inoculated strains and the abundance of Lactobacillales, Enterobacteriales, and Bacillales, pointing to positive interactions or similar environmental driver variables that may make it feasible to use such bacterial lineages as indicators of microbial health hazards in leafy vegetables. The data from this study contribute to a better understanding of the bacteria present in RTE salads and may help when developing new types of biocontrol agents.. PMID- 28649306 TI - Decreasing prevalence of transmitted drug resistance among ART-naive HIV-1 infected patients in Iceland, 1996-2012. AB - Introduction: Resistance to antiretroviral drugs can complicate the management of HIV-1 infection and impair control of its spread. The aim of the current study was to investigate the prevalence and transmission of HIV-1 drug resistance among 106 antiretroviral therapy (ART)-naive patients diagnosed in Iceland (1996-2012). Methods: HIV-1 polymerase sequences were analysed using the Calibrated Population Resistance tool. Domestic spread of transmitted drug resistance (TDR) was investigated through maximum likelihood and Bayesian approaches. Results: Among ART-naive patients, the prevalence of TDR to any of the following classes (NRTIs, NNRTIs and PIs) was 8.5% (95% CI: 4.5%- 15.4%): 6.6% to NRTIs, 0.9% to NNRTIs, and 1.9% to PIs. The most frequent NRTI mutation detected was T215C/D (n=7, 5.7%). The only NNRTI mutation detected was K103N (n=1, 0.9%). PI mutations detected were M46I (n=1, 0.9%) and L90M (n=1, 0.9%). Six patients harbouring T215C/D, were linked in a supported phylogenetic cluster. No significant association was found between TDR and demographic or risk groups. Trend analysis showed a decrease in the prevalence of TDR (1996-2012, p=0.003). Conclusions: TDR prevalence in Iceland was at a moderate level and decreased during 1996-2012. Screening for TDR is recommended to limit its local spread and to optimize HIV-1 therapy. Abbreviations: ART: Anti-retroviral therapy; ARV: antiretroviral; ATV/r: atazanavir/ritonavir; AZT: azidothymidine; BEAST: Bayesian evolutionary analysis by sampling trees; CI: confidence interval; CPR: calibrated population resistance; CRF: circulating recombinant form; d4T: stavudine; EFV: efavirenz; FET: Fishers' exact test; FPV/r: fosamprenavir/ritonavir; HET: heterosexual; IDU: injection drug use; IDV/r: indinavir/ritonavir; LPV/r: lopinavir/ritonavir; MSM: men who have sex with men; M-W: Mann-Whitney U test; NFV: nelfinavir; NNRTIs: non nucleoside reverse transcriptase inhibitors; NRTIs: nucleoside reverse transcriptase inhibitors; NVP: nevirapine; PIs: protease inhibitors; pol: polymerase gene; SDRM: surveillance drug resistance mutation; SQV/r: saquinavir/ritonavir; TDR: transmitted drug resistance. PMID- 28649307 TI - Authors' reply. PMID- 28649308 TI - Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis. AB - Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: Sixty-four children with CF, median age (range) of 12.7 (6.4-18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4-46.8) with gas trapping of 40.7% (3.7-100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections (N = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% (p < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions: The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with increased scores in lung changes. Further investigation of impact of infections with different microorganisms on extent and progression of structural CF lung disease is needed. PMID- 28649309 TI - Respiratory symptoms among Swedish soldiers after military service abroad: association with time spent in a desert environment. AB - Introduction: The aim of this paper was to study whether Swedish soldiers who have served abroad had a higher prevalence of respiratory symptoms than the general population and, if this was the case, also to study whether this was associated with time spent in a desert environment. Methods:The prevalence of respiratory symptoms among 1,080 veterans from Kosovo and Afghanistan was compared with that in almost 27,000 subjects from a general population sample, using propensity score matching and logistic regression. Results:The prevalence of wheeze (16.3 vs. 12.3%), wheeze without a cold (11.1 vs. 8.0%), nocturnal coughing (26.6 vs. 20.1%) and chronic bronchitis (12.3 vs. 6.8%) was significantly higher among soldiers than controls (p < 0.05). A dose-response related association was found between time spent in a desert environment and wheeze, wheeze with breathlessness and wheeze when not having a cold. Having been exposed to desert storms was related to nocturnal cough and chronic bronchitis. Conclusion:Swedish soldiers who had served abroad had a higher prevalence of wheeze and cough than a control group from the general population. The association between being exposed to a desert environment and respiratory symptoms indicates that further protective measures should be introduced for military personnel serving in a desert environment. PMID- 28649310 TI - Lung ultrasound has limited diagnostic value in rare cystic lung diseases: a cross-sectional study. AB - Background: Lung ultrasound (LUS) used to identify interstitial syndrome (IS) and pleural thickening related to diffuse parenchymal lung disease (DPLD) has shown significant correlations with ground glass opacity (GGO) on high-resolution computed tomography (HRCT). However, the applicability of LUS in patients with DPLD subtypes as rare cystic lung diseases has not previously been investigated. This study aimed to observe if distinctive LUS findings could be found in patients with lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), and Birt-Hogg-Dube syndrome (BHDS). Methods: This single centre case-based cross-sectional study of patients diagnosed with LAM, PCLH and BHDS was conducted at a Danish DPLD specialist centre. Patients underwent clinical examination including LUS. LUS findings were compared to findings scored according to a modified Belmaati score on HRCT and reviewed in consensus between two pulmonologists and one radiologist. Results: Twelve patients with HRCT proven cystic lung disease were included, six with LAM, three with PLCH, two with BHDS, and one with uncharacteristic cystic lung disease. The mean age was 48.7 years (SD +/- 15.8). In general all had normal LUS findings. IS could not be found in any patients despite GGO presentation on HRCT among 75% of the patients with a Belmaati in the highest category of 0.76-1.00. Pleural thickening on LUS was present in three patients, but with inconsistent findings. Conclusion: This study indicates that LUS has limited value as a diagnostic tool in patients with LAM, PLCH, and BHDS as normal LUS findings did not rule out severe cystic lung disease. PMID- 28649311 TI - Screening tools for evaluation of depression in Chronic Obstructive Pulmonary Disease (COPD). A systematic review. AB - Background: Anxiety and depression are common comorbid disorders in patients with chronic obstructive pulmonary disease (COPD), though estimates of their prevalence vary considerably. Depressive symptoms/depression are important comorbidities in COPD and an increasing interest is shown to these disorders. Depression may lead to reduced quality of life and increased morbidity and mortality. These statements underline the importance of implementing the use of screening instruments for depressive symptoms in a clinical setting. This systematic review evaluates four commonly used screening tools for depression in COPD. Furthermore we assess the prevalence of depression in COPD in the evaluated studies. Design: A literature search identified studies dealing with screening for depression in patients with COPD. We focused on the instruments: Beck Depression Inventory, Geriatric depression scale, Centre for Epidemiological Studies scale on Depression and Hospital and Anxiety Depression Scale. Results: Overall prevalence of depression was 30%. Demographic variations and severity of COPD influenced prevalence. The inter-prevalence of the four screening tools was consistent. We found a low variation between studies using the same tool. Few studies used control groups or compared the screening tool to a psychiatrist evaluation. Conclusions: This article calls for further investigation of the association between COPD and depressive symptoms. The subject is highly relevant for everyday life of patients with COPD and attention needs to be drawn to this issue in both an out- and in-patients. PMID- 28649314 TI - Hierarchical cortical transcriptome disorganization in autism. AB - BACKGROUND: Autism spectrum disorders (ASD) are etiologically heterogeneous and complex. Functional genomics work has begun to identify a diverse array of dysregulated transcriptomic programs (e.g., synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning and differentiation) potentially involved in ASD brain abnormalities during childhood and adulthood. However, it remains unclear whether such diverse dysregulated pathways are independent of each other or instead reflect coordinated hierarchical systems-level pathology. METHODS: Two ASD cortical transcriptome datasets were re-analyzed using consensus weighted gene co-expression network analysis (WGCNA) to identify common co expression modules across datasets. Linear mixed-effect models and Bayesian replication statistics were used to identify replicable differentially expressed modules. Eigengene network analysis was then utilized to identify between-group differences in how co-expression modules interact and cluster into hierarchical meta-modular organization. Protein-protein interaction analyses were also used to determine whether dysregulated co-expression modules show enhanced interactions. RESULTS: We find replicable evidence for 10 gene co-expression modules that are differentially expressed in ASD cortex. Rather than being independent non interacting sources of pathology, these dysregulated co-expression modules work in synergy and physically interact at the protein level. These systems-level transcriptional signals are characterized by downregulation of synaptic processes coordinated with upregulation of immune/inflammation, response to other organism, catabolism, viral processes, translation, protein targeting and localization, cell proliferation, and vasculature development. Hierarchical organization of meta-modules (clusters of highly correlated modules) is also highly affected in ASD. CONCLUSIONS: These findings highlight that dysregulation of the ASD cortical transcriptome is characterized by the dysregulation of multiple coordinated transcriptional programs producing synergistic systems-level effects that cannot be fully appreciated by studying the individual component biological processes in isolation. PMID- 28649312 TI - The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders. AB - BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies. PMID- 28649313 TI - The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation. AB - BACKGROUND: The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. METHODS: From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. RESULTS: The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. CONCLUSIONS: The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials. PMID- 28649316 TI - Discovery of Decamidine as a New and Potent PRMT1 Inhibitor. AB - Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine (2j), which possesses the longest linker in the series, displayed 2- and 4- fold increase in PRMT1 inhibition (IC50 = 13 MUM), as compared with furamdine and stilbamidine. The inhibitory activity toward PRMT1 was validated by secondary orthogonal assays. Docking studies showed that the increased activity is due to the extra interaction of the amidine group with the SAM binding pocket, which is absent when the linker is not long enough. These results provide structural insights into developing the amidine type of PRMT1 inhibitors. PMID- 28649317 TI - Inclusion of sex and gender in biomedical research: survey of clinical research proposed at the University of Pennsylvania. AB - BACKGROUND: The 2015 National Institutes of Health (NIH) policy that sex be considered as a biological variable (SABV) is now a critical part of the peer review process for NIH funding as well as publication in several high-impact scientific journals. We sought to determine the degree to which biomedical researchers at the University of Pennsylvania already consider SABV or gender in their research. METHODS: We reviewed 240 research protocols approved by the University of Pennsylvania Investigational Review Board (IRB) consecutively submitted between January and July 2016. Each protocol was searched for the terms sex, gender, male, female, man, and woman and justifications related to the population under study. A PubMed search was conducted to determine the current state of knowledge regarding potential sex and/or gender differences with respect to protocol topic. Data were summarized using descriptive statistics. RESULTS: Of the 165 (68.8%) protocols that included one of the search terms, only 24 (14.5%) provided justification for the choice of the sex/gender of the population studied. Sixty-three percent (n = 151) of the protocols focused on topics for which the extant literature supports at least a moderate degree of sex/gender differences in some aspect of the disorder/condition being studied. Of these, only three (2.0%) indicated that the investigator would consider sex or gender impact on their primary outcomes. CONCLUSIONS: Review of a subset of IRB protocols submitted at a major research institution suggests that very few investigators are considering sex or gender as important variables in their clinical research at the stage of protocol development. IRBs are in an excellent position to encourage investigators to consider SABV and gender in order to enhance the rigor of research design, maximize the importance of the resulting knowledge, and ensure that subject selection is equitable. These findings serve as the basis for developing an intervention at the level of IRB protocol development and submission that will promote consideration of SABV and/or gender, factors with critical import to patient safety and efficacy of interventions. PMID- 28649315 TI - Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome. AB - BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. PMID- 28649318 TI - Zooplankton communities and Bythotrephes longimanus in lakes of the montane region of the northern Alps. AB - Lakes in the Alps represent a considerable fraction of nutrient-poor lakes in Central Europe, with unique biodiversity and ecosystem properties. Although some individual lakes are well-studied, less knowledge is available on large-scale patterns essential to generalise the understanding of their functioning. Here, we aimed to describe crustacean zooplankton communities (Cladocera, Copepoda) and identify their environmental drivers in the pelagic zone of 54 oligotrophic lakes in the montane region of the Alps (400-1200 m) in Austria, Germany, and Switzerland, covering a spatial scale of 650 km. Moreover, we aimed to provide data on the distribution and ecological requirements of the North American invader Bytotrephes longimanus in its Central European native range. Communities were mainly dominated by widespread species typical of lowland habitats, and only a few true specialists of oligotrophic alpine lakes were present. The most frequent taxa were the Daphnia longispina complex and Eudiaptomus gracilis, with 48 and 45 occurrences, respectively. Species richness decreased with altitude and increased with lake area. The main structuring factors of community composition were chlorophyll a concentration and depth, which drove an apparent separation of mesotrophic and oligotrophic communities. Bytotrephes had 13 occurrences, showing a preference for deep oligotrophic lakes. Its presence was not coupled with lower crustacean species richness as it was repeatedly observed in North America. Additionally, it frequently co-occurred with the other large predatory cladoceran, Leptodora kindtii. B. longimanus might be considered a truly montane species in Central Europe, given its absence in lowland and alpine lakes. PMID- 28649319 TI - Erratum to: A new paradigm of DNA synthesis: three-metal-ion catalysis. AB - [This corrects the article DOI: 10.1186/s13578-016-0118-2.]. PMID- 28649320 TI - Food allergy in a child with de novo KAT6A mutation. AB - Crying combined with miscellaneous gastrointestinal symptoms are typical symptoms of infant with food allergy, but are also common among children with abnormal neurological development. Mutations in KAT6A gene is known to cause a syndrome characterized by developmental delay, hypotonia, cardiac defects, microcephaly, specific facial features and early feeding problems. However, these feeding problems have not earlier been specified. We present the first reported case of a DBPCFC confirmed food allergy in a child with KAT6A mutation whose feeding problems resolved with elimination diet. The present case does not establish proof of cause, but highlights the importance of careful clinical diagnostics despite other possible causes for feeding problems. Recognizing that early feeding problems these patients regularly have might be caused by food allergy is important for outcome and quality of life for these patients. PMID- 28649321 TI - Little association of biological trait values with environmental variables in invasive alien round goby (Neogobius melanostomus). AB - The relative importance of species-specific biological trait characteristics and environmental factors in invasions of nonindigenous species remains controversial because both have mostly been studied independently. Thus, the main objective of this study was to examine the correlation of biological traits with environmental variation in the globally invasive round goby Neogobius melanostomus from the upper Danube River. Based on a sample of 653 specimens along a continuous 200 km river pathway, links between nine environmental factors (substrate-type, six water measurements, and the communities of fishes and macroinvertebrates) and seven biological traits (nutritional and energetic status, trade-offs of parasite resistance and resource allocation, and three growth proxies) were analyzed. Biological trait values of N. melanostomus hardly correlated with the environment, could not explain invasion progress and imply a general low overall importance for invasion success. Instead, alternative individual life-history trajectories appear to determine invasion success. This is in line with up to 15% of all specimens having outlying biological trait values of potential adaptive value, suggesting a considerable importance of adaptive trait variation among single individuals for the whole invasion progress. This "individual trait utility hypothesis" gives an alternative explanation for success of invasive species by single individuals carrying particular traits, and it should be specifically targeted and analyzed at currently invaded sites. PMID- 28649322 TI - Similarity of plant functional traits and aggregation pattern in a subtropical forest. AB - The distribution of species and communities in relation to environmental heterogeneity is a central focus in ecology. Co-occurrence of species with similar functional traits is an indication that communities are determined in part by environmental filters. However, few studies have been designed to test how functional traits are selectively filtered by environmental conditions at local scales. Exploring the relationship between soil characteristics and plant traits is a step toward understanding the filtering hypothesis in determining plant distribution at local scale. Toward this end, we mapped all individual trees (diameter >1 cm) in a one-ha subtropical forest of China in 2007 and 2015. We measured topographic and detailed soil properties within the field site, as well as plant leaf functional traits and demographic rates of the seven most common tree species. A second one-ha study plot was established in 2015, to test and validate the general patterns that were drawn from first plot. We found that variation in species distribution at local scale can be explained by soil heterogeneity and plant functional traits. (From first plot). (1) Species dominant in habitats with high soil ammonium nitrogen and total phosphorus tended to have high specific leaf area (SLA) and relative growth rate (RGR). (2) Species dominant in low-fertility habitats tended to have high leaf dry matter content (LDMC), ratio of chlorophyll a and b (ratioab), and leaf thickness (LT). The hypothesis that functional traits are selected in part by environmental filters and determine plant distribution at local scale was confirmed by the data of the first plot and a second regional site showed similar species distribution patterns. PMID- 28649323 TI - Individual-based analysis of hair corticosterone reveals factors influencing chronic stress in the American pika. AB - Glucocorticoids are often measured in wildlife to assess physiological responses to environmental or ecological stress. Hair, blood, saliva, or fecal samples are generally used depending on the timescale of the stress response being investigated and species-specific considerations. Here, we report the first use of hair samples to measure long-term corticosterone levels in the climate sensitive American pika (Ochotona princeps). We validated an immunoassay-based measurement of corticosterone extracted from hair samples and compared corticosterone estimates obtained from plasma, hair, and fecal samples of nine pikas. To demonstrate an ecological application of this technique, we characterized physiological stress in 49 pikas sampled and released at eight sites along two elevational transects. Microclimate variation was measured at each site using both ambient and subsurface temperature sensors. We used an information theoretic approach to compare support for linear, mixed-effects models relating corticosterone estimates to microclimate, body size, and sex. Corticosterone was measured accurately in pika hair samples after correcting for the influence of sample mass on corticosterone extraction efficiency. Hair- and plasma-based estimates of corticosterone were weakly correlated. The best supported model suggested that corticosterone was lower in larger, male pikas, and at locations with higher ambient temperatures in summer. Our results are consistent with a general negative relationship between body mass and glucocorticoid concentration observed across mammalian species, attributed to the higher mass-specific metabolic rates of smaller bodied animals. The higher corticosterone levels in female pikas likely reflected the physiological demands of reproduction, as observed in a wide array of mammalian species. Additionally, we establish the first direct physiological evidence for thermal stress in the American pika through nonlethal sampling of corticosterone. Interestingly, our data suggest evidence for cold stress likely induced during the summer molting period. This technique should provide a useful tool to researchers wishing to assess chronic stress in climate-sensitive mammals. PMID- 28649324 TI - Conceptualising the interactive effects of climate change and biological invasions on subarctic freshwater fish. AB - Climate change and species invasions represent key threats to global biodiversity. Subarctic freshwaters are sentinels for understanding both stressors because the effects of climate change are disproportionately strong at high latitudes and invasion of temperate species is prevalent. Here, we summarize the environmental effects of climate change and illustrate the ecological responses of freshwater fishes to these effects, spanning individual, population, community and ecosystem levels. Climate change is modifying hydrological cycles across atmospheric, terrestrial and aquatic components of subarctic ecosystems, causing increases in ambient water temperature and nutrient availability. These changes affect the individual behavior, habitat use, growth and metabolism, alter population spawning and recruitment dynamics, leading to changes in species abundance and distribution, modify food web structure, trophic interactions and energy flow within communities and change the sources, quantity and quality of energy and nutrients in ecosystems. Increases in temperature and its variability in aquatic environments underpin many ecological responses; however, altered hydrological regimes, increasing nutrient inputs and shortened ice cover are also important drivers of climate change effects and likely contribute to context dependent responses. Species invasions are a complex aspect of the ecology of climate change because the phenomena of invasion are both an effect and a driver of the ecological consequences of climate change. Using subarctic freshwaters as an example, we illustrate how climate change can alter three distinct aspects of species invasions: (1) the vulnerability of ecosystems to be invaded, (2) the potential for species to spread and invade new habitats, and (3) the subsequent ecological effects of invaders. We identify three fundamental knowledge gaps focused on the need to determine (1) how environmental and landscape characteristics influence the ecological impact of climate change, (2) the separate and combined effects of climate and non-native invading species and (3) the underlying ecological processes or mechanisms responsible for changes in patterns of biodiversity. PMID- 28649325 TI - Influence of pollen limitation and inbreeding depression in the maintenance of incomplete dichogamy in Salvia elegans. AB - The widespread presence of incomplete dichogamy (i.e., partial separation in time between male and female phases) in flowering plants is a long-standing question in floral evolution. In this study, we proposed four scenarios in which depending on the particular combination of pollen limitation and inbreeding depression, the presence of complete dichogamy, incomplete dichogamy, or adichogamy may be favored. Moreover, we evaluated the role of pollen limitation and inbreeding depression in a natural population of Salvia elegans to test the validity of our predicted scenarios. Our results indicate that S. elegans is partially protandrous as pollen viability and stigma receptivity overlap in the last days of life of the flower. Furthermore, through pollination treatments, we found no evidence of pollen limitation or inbreeding depression in any of the evaluated fitness components. As expected by one of the proposed scenarios, incomplete dichogamy seems to be favored in plants with absence of inbreeding depression and pollen limitation as a way to diminish interference between male and female functions. PMID- 28649326 TI - Viral gut metagenomics of sympatric wild and domestic canids, and monitoring of viruses: Insights from an endangered wolf population. AB - Animal host-microbe interactions are a relevant concern for wildlife conservation, particularly regarding generalist pathogens, where domestic host species can play a role in the transmission of infectious agents, such as viruses, to wild animals. Knowledge on viral circulation in wild host species is still scarce and can be improved by the recent advent of modern molecular approaches. We aimed to characterize the fecal virome and identify viruses of potential conservation relevance of diarrheic free-ranging wolves and sympatric domestic dogs from Central Portugal, where a small and threatened wolf population persists in a highly anthropogenically modified landscape. Using viral metagenomics, we screened diarrheic stools collected from wolves (n = 8), feral dogs (n = 4), and pet dogs (n = 6), all collected within wolf range. We detected novel highly divergent viruses as well as known viral pathogens with established effects on population dynamics, including canine distemper virus, a novel bocavirus, and canine minute virus. Furthermore, we performed a 4-year survey for the six wolf packs comprising this endangered wolf population, screening 93 fecal samples from 36 genetically identified wolves for canine distemper virus and the novel bocavirus, previously identified using our metagenomics approach. Our novel approach using metagenomics for viral screening in noninvasive samples of wolves and dogs has profound implications on the knowledge of both virology and wildlife diseases, establishing a complementary tool to traditional screening methods for the conservation of threatened species. PMID- 28649328 TI - Spatiotemporal variation in mechanisms driving regional-scale population dynamics of a Threatened grassland bird. AB - To achieve national population targets for migratory birds, landscape-level conservation approaches are increasingly encouraged. However, knowledge of the mechanisms that drive spatiotemporal patterns in population dynamics are needed to inform scale-variant policy development. Using hierarchical Bayesian models and variable selection, we determined by which mechanism(s), and to what extent, changes in quantity and quality of surrogate grassland habitats contributed to regional variation in population trends of an obligatory grassland bird, Bobolink (Dolichonyx oryzivorous). We used North American Breeding Bird Survey data to develop spatially explicit models of regional population trends over 25 years across 35 agricultural census divisions in Ontario, Canada. We measured the strength of evidence for effects of land-use change on population trends over the entire study period and over five subperiods. Over the entire study period, one region (Perth) displayed strong evidence of population decline (95% CI is entirely below 0); four regions displayed strong evidence of population increase (Bruce, Simcoe, Peterborough, and Northumberland). Population trends shifted spatially among subperiods, with more extreme declines later in time (1986-1990: 28% of 35 census divisions, 1991-1995: 46%, 1996-2000: 40%, 2001-2005: 66%, 2006 2010: 82%). Important predictors of spatial patterns in Bobolink population trends over the entire study period were human development and fragmentation. However, factors inferred to drive patterns in population trends were not consistent over space and time. This result underscores that effective threat identification (both spatially and temporally) and implementation of flexible, regionally tailored policies will be critical to realize efficient conservation of Bobolink and similar at-risk species. PMID- 28649327 TI - Are we ready to detect nematode diversity by next generation sequencing? AB - In a Technical Advance article, Porazinska et al. (2009, Molecular Ecology Resources, 9, 1439-1450) assessed next generation sequencing (NGS) as a method for metagenomic analysis of nematode diversity. We agree that NGS has great potential here. However, it is not an easy path to the successful implementation of NGS for environmental DNA analysis of nematodes. Here, we describe the method's limitations and discuss prospective research questions. For instance, only a few direct extraction kits are suitable for nematode DNA extraction from bulk samples without adaptation. They enable the analysis of extracellular nematode DNA. The most crucial and unresolved issue remains the limited availability of suitable primers. PMID- 28649329 TI - Food availability as a major driver in the evolution of life-history strategies of sibling species. AB - Life-history theory predicts trade-offs between reproductive and survival traits such that different strategies or environmental constraints may yield comparable lifetime reproductive success among conspecifics. Food availability is one of the most important environmental factors shaping developmental processes. It notably affects key life-history components such as reproduction and survival prospect. We investigated whether food resource availability could also operate as an ultimate driver of life-history strategy variation between species. During 13 years, we marked and recaptured young and adult sibling mouse-eared bats (Myotis myotis and Myotis blythii) at sympatric colonial sites. We tested whether distinct, species-specific trophic niches and food availability patterns may drive interspecific differences in key life-history components such as age at first reproduction and survival. We took advantage of a quasi-experimental setting in which prey availability for the two species varies between years (pulse vs. nonpulse resource years), modeling mark-recapture data for demographic comparisons. Prey availability dictated both adult survival and age at first reproduction. The bat species facing a more abundant and predictable food supply early in the season started its reproductive life earlier and showed a lower adult survival probability than the species subjected to more limited and less predictable food supply, while lifetime reproductive success was comparable in both species. The observed life-history trade-off indicates that temporal patterns in food availability can drive evolutionary divergence in life-history strategies among sympatric sibling species. PMID- 28649330 TI - Dual-tracer-based isotope turnover rates in a highly invasive mysid Limnomysis benedeni from Lake Constance. AB - Understanding the ecological patterns of invasive species and their habitats require an understanding of the species' foraging ecology. Stable carbon (delta13C) and nitrogen (delta15N) isotope values provide useful information into the study of animal ecology and evolution, since the isotope ratios of consumers reflect consumer's dietary patterns. Nevertheless, the lack of species- and element-specific laboratory-derived turnover rates could limit their application. Using a laboratory-based dual stable isotope tracer approach (Na15 NO 3 and NaH13 CO 3), we evaluated the delta15N and delta13C isotope turnover rates in full grown adult invasive Limnomysis benedeni from Lake Constance. We provide delta15N and delta13C turnover rates based on nonlinear least-squares regression and posterior linear regression models. Model precisions and fit were evaluated using Akaike's information criterion. Within a couple of days, the delta15N and delta13C of mysids began to change. Nevertheless, after about 14 days, L. benedeni did not reach equilibrium with their new isotope values. Since the experiment was conducted on adult subjects, it is evident that turnover was mainly influenced by metabolism (in contrast to growth). Unlike traditional dietary shifts, our laboratory-based dual stable isotope tracer approach does not shift the experimental organisms into a new diet and avoids dietary effects on isotope values. Results confirm the application of isotopic tracers to label mysid subpopulations and could be used to reflect assimilation and turnover from the labeled dietary sources. Field-based stable isotope studies often use isotopic mixing models commonly assuming diet-tissue steady state. Unfortunately, in cases where the isotopic composition of the animal is not in equilibrium with its diet, this can lead to highly misleading conclusions. Thus, our laboratory based isotopic incorporation rates assist interpretation of the isotopic values from the field and provide a foundation for future research into using isotopic tracers to investigate invasion ecology. PMID- 28649331 TI - Novel approach to heritability detection suggests robustness to paternal genotype in a complex morphological trait. AB - Heritable variation is essential for evolution by natural selection. In Neotropical army ants, the ecological role of a given species is linked intimately to the morphological variation within the sterile worker caste. Furthermore, the army ant Eciton burchellii is highly polyandrous, presenting a unique opportunity to explore heritability of morphological traits among related workers sharing the same colonial environment. In order to exploit the features of this organismal system, we generated a large genetic and morphological dataset and applied our new method that employs geometric morphometrics (GM) to detect the heritability of complex morphological traits. After validating our approach with an existing dataset of known heritability, we simulated our ability to detect heritable variation given our sampled genotypes, demonstrating the method can robustly recover heritable variation of small effect size. Using this method, we tested for genetic caste determination and heritable morphological variation using genetic and morphological data on 216 individuals of E. burchellii. Results reveal this ant lineage (1) has the highest mating frequency known in ants, (2) demonstrates no paternal genetic caste determination, and (3) suggests a lack of heritable morphological variation in this complex trait associated with paternal genotype. We recommend this method for leveraging the increased resolution of GM data to explore and understand heritable morphological variation in nonmodel organisms. PMID- 28649333 TI - Assessing the impact of revegetation and weed control on urban sensitive bird species. AB - Nature in cities is concentrated in urban green spaces, which are key areas for urban biodiversity and also important areas to connect people with nature. To conserve urban biodiversity within these natural refugia, habitat restoration such as weed control and revegetation is often implemented. These actions are expected to benefit biodiversity, although species known to be affected by urbanization may not be interacting with restoration in the ways we anticipate. In this study, we use a case study to explore how urban restoration activities impact different bird species. Birds were grouped into urban sensitivity categories and species abundance, and richness was then calculated using a hierarchical species community model for individual species responses, with "urban class" used as the hierarchical parameter. We highlight variable responses of birds to revegetation and weed control based on their level of urban sensitivity. Revegetation of open grassy areas delivers significant bird conservation outcomes, but the effects of weed control are neutral or in some cases negative. Specifically, the species most reliant on remnant vegetation in cities seem to remain stable or decline in abundance in areas with weed control, which we suspect is the result of a simplification of the understorey. The literature reports mixed benefits of weed control between taxa and between locations. We recommend, in our case study site, that weed control be implemented in concert with replanting of native vegetation to provide the understory structure preferred by urban sensitive birds. Understanding the impacts of revegetation and weed control on different bird species is important information for practitioners to make restoration decisions about the allocation of funds for conservation action. This new knowledge can be used both for threatened species and invasive species management. PMID- 28649332 TI - Behavioral evidence of hunting and foraging techniques by a top predator suggests the importance of scavenging for preadults. AB - Scavenging may be a regular feeding behavior for some facultative raptor species occupying low quality habitats and/or with little experience in hunting techniques. However, its importance has been largely underestimated due to methodological limitations in identifying the real proportion in the diet. Here, through direct observations, we assessed the hunting and foraging success of the threatened Spanish imperial eagle Aquila adalberti determining the influence of age, sex, breeding status, habitat quality, prey type, and landscape characteristics. From 465 observations, Spanish imperial eagles used hunting in flight (42%), scavenging (30%), hunting from a perch (16%) and kleptoparasitism (12%). Our model suggests that Prey size and Prey type best explain hunting success, followed by Landscape and Sex. Our findings suggest that Spanish imperial eagles increase hunting success with age, with scavenging and kleptoparasitism regularly used as juveniles. The absence of relationships with any of the variables considered suggests that kleptoparasitism is an opportunistic behavior used sporadically. Scavenging is also independent of habitat quality and landscape characteristics. Accordingly, low prey density is not a driver of carrion use for preadult individuals, suggesting that a lack of hunting ability obliges this age-class to use this alternative feeding technique regularly. As a result, the threatened Spanish imperial eagle population is also prone to mortality related to the illegal use of poison baits and, potentially, veterinary drugs (i.e., diclofenac). PMID- 28649334 TI - Population structure in chicory (Cichorium intybus): A successful U.S. weed since the American revolutionary war. AB - Plant invasions are recognized as major drivers of ecosystem change, yet the precise cause of these invasions remains unknown for many species. Frequency and modes of introductions during the first, transport and colonization, stages of the invasion process as well as phenotypic changes due to plasticity or changing genetic diversity and adaptation during later establishment and expansion stages can all influence the "success" of invasion. Here, we examine some of these factors in, and the origin of, a very successful weed, Cichorium intybus (chicory) which was introduced to North America in the 18th century and which now can be found in all 48 continental U.S. states and much of Canada. We genotyped a Eurasian collection of 11 chicory cultivars, nine native populations and a North American collection of 20 introduced wild populations which span the species range (592 individuals in total). To detect the geographic sources of North American chicory populations and to assess the genetic diversity among cultivars, native, and introduced populations, we used both a sequenced cpDNA region and 12 nuclear simple sequence repeat (SSR), microsatellite loci. Four cpDNA haplotypes were identified and revealed clear geographic subdivisions in the chicory native range and an interspecific hybrid origin of Radicchio group. Nuclear data suggested that domesticated lines deliberately introduced to North America were major contributors to extant weedy populations, although unintended sources such as seed contaminants likely also played important roles. The high private allelic richness and novel genetic groups were detected in some introduced populations, suggesting the potential for local adaptation in natural sites such as deserts and nature reserves. Our findings suggest that the current populations of weedy U.S. chicory have evolved primarily from several sources of domesticated and weedy ancestors and subsequent admixture among escaped lineages. PMID- 28649335 TI - Early events in speciation: Cryptic species of Drosophila aldrichi. AB - Understanding the earliest events in speciation remains a major challenge in evolutionary biology. Thus identifying species whose populations are beginning to diverge can provide useful systems to study the process of speciation. Drosophila aldrichi, a cactophilic fruit fly species with a broad distribution in North America, has long been assumed to be a single species owing to its morphological uniformity. While previous reports either of genetic divergence or reproductive isolation among different D. aldrichi strains have hinted at the existence of cryptic species, the evolutionary relationships of this species across its range have not been thoroughly investigated. Here we show that D. aldrichi actually is paraphyletic with respect to its closest relative, Drosophila wheeleri, and that divergent D. aldrichi lineages show complete hybrid male sterility when crossed. Our data support the interpretation that there are at least two species of D. aldrichi, making these flies particularly attractive for studies of speciation in an ecological and geographical context. PMID- 28649336 TI - Phylogeography of a widespread small carnivore, the western spotted skunk (Spilogale gracilis) reveals temporally variable signatures of isolation across western North America. AB - We analyzed phylogeographic patterns in the western spotted skunk, Spilogale gracilis Merriam, 1890 (Carnivora: Mephitidae) in relation to historical events associated with Pre-Pleistocene Divergence (PPD) and Quaternary climate change (QCC) using mitochondrial DNA from 97 individuals distributed across Western North America. Divergence times were generated using BEAST to estimate when isolation in putative refugia occurred. Patterns and timing of demographic expansion was performed using Bayesian skyline plot. Putative climatic refugia resulting from Quaternary climate change were identified using paleoecological niche modeling and divergence dates compared to major vicariant events associated with Pre-Pleistocene conditions. We recovered three major mitochondrial clades corresponding to western North America (California, Baja, and across the Great Basin), east-central North America (Texas, central Mexico, New Mexico), and southwestern Arizona/northwestern Mexico. Time to most recent common ancestor for S. gracilis occurred ~1.36 Ma. Divergence times for each major clade occurred between 0.25 and 0.12 Ma, with signature of population expansion occurring 0.15 and 0.10 Ma. Ecological niche models identified three potential climatic refugia during the Last Interglacial, (1) west coast of California and Oregon, (2) northwestern Mexico, and (3) southern Texas/northeastern Mexico as well as two refugia during the Last Glacial Maximum, (1) western USA and (2) southern Texas/northeastern Mexico. This study supports PPD in shaping species-level diversity compared to QCC-driven changes at the intraspecific level for Spilogale, similar to the patterns reported for other small mammals (e.g., rodents and bats). Phylogeographic patterns also appear to have been shaped by both habitat and river vicariance, especially across the desert southwest. Further, continuing climate change during the Holocene coupled with anthropogenic modifications during the Anthropocene appears to be removing both of these barriers to current dispersal of western spotted skunks. PMID- 28649337 TI - The role of conservative versus innovative nesting behavior on the 25-year population expansion of an avian predator. AB - Species ranges often change in relation to multiple environmental and demographic factors. Innovative behaviors may affect these changes by facilitating the use of novel habitats, although this idea has been little explored. Here, we investigate the importance of behavior during range change, using a 25-year population expansion of Bonelli's eagle in southern Portugal. This unique population is almost exclusively tree nesting, while all other populations in western Europe are predominantly cliff nesting. During 1991-2014, we surveyed nest sites and estimated the year when each breeding territory was established. We approximated the boundaries of 84 territories using Dirichlet tessellation and mapped topography, land cover, and the density of human infrastructures in buffers (250, 500, and 1,000 m) around nest and random sites. We then compared environmental conditions at matching nest and random sites within territories using conditional logistic regression, and used quantile regression to estimate trends in nesting habitats in relation to the year of territory establishment. Most nests (>85%, n = 197) were in eucalypts, maritime pines, and cork oaks. Nest sites were farther from the nests of neighboring territories than random points, and they were in areas with higher terrain roughness, lower cover by agricultural and built-up areas, and lower road and powerline densities. Nesting habitat selection varied little with year of territory establishment, although nesting in eucalypts increased, while cliff nesting and cork oak nesting, and terrain roughness declined. Our results suggest that the observed expansion of Bonelli's eagles was facilitated by the tree nesting behavior, which allowed the colonization of areas without cliffs. However, all but a very few breeding pairs settled in habitats comparable to those of the initial population nucleus, suggesting that after an initial trigger possibly facilitated by tree nesting, the habitat selection remained largely conservative. Overall, our study supports recent calls to incorporate information on behavior for understanding and predicting species range shifts. PMID- 28649339 TI - Conservation of wildlife populations: factoring in incremental disturbance. AB - Progressive anthropogenic disturbance can alter ecosystem organization potentially causing shifts from one stable state to another. This potential for ecosystem shifts must be considered when establishing targets and objectives for conservation. We ask whether a predator-prey system response to incremental anthropogenic disturbance might shift along a disturbance gradient and, if it does, whether any disturbance thresholds are evident for this system. Development of linear corridors in forested areas increases wolf predation effectiveness, while high density of development provides a safe-haven for their prey. If wolves limit moose population growth, then wolves and moose should respond inversely to land cover disturbance. Using general linear model analysis, we test how the rate of change in moose (Alces alces) density and wolf (Canis lupus) harvest density are influenced by the rate of change in land cover and proportion of land cover disturbed within a 300,000 km2 area in the boreal forest of Alberta, Canada. Using logistic regression, we test how the direction of change in moose density is influenced by measures of land cover change. In response to incremental land cover disturbance, moose declines occurred where <43% of land cover was disturbed; in such landscapes, there were high rates of increase in linear disturbance and wolf density increased. By contrast, moose increases occurred where >43% of land cover was disturbed and wolf density declined. Wolves and moose appeared to respond inversely to incremental disturbance with the balance between moose decline and wolf increase shifting at about 43% of land cover disturbed. Conservation decisions require quantification of disturbance rates and their relationships to predator-prey systems because ecosystem responses to anthropogenic disturbance shift across disturbance gradients. PMID- 28649338 TI - Estimating and interpreting migration of Amazonian forests using spatially implicit and semi-explicit neutral models. AB - With many sophisticated methods available for estimating migration, ecologists face the difficult decision of choosing for their specific line of work. Here we test and compare several methods, performing sanity and robustness tests, applying to large-scale data and discussing the results and interpretation. Five methods were selected to compare for their ability to estimate migration from spatially implicit and semi-explicit simulations based on three large-scale field datasets from South America (Guyana, Suriname, French Guiana and Ecuador). Space was incorporated semi-explicitly by a discrete probability mass function for local recruitment, migration from adjacent plots or from a metacommunity. Most methods were able to accurately estimate migration from spatially implicit simulations. For spatially semi-explicit simulations, estimation was shown to be the additive effect of migration from adjacent plots and the metacommunity. It was only accurate when migration from the metacommunity outweighed that of adjacent plots, discrimination, however, proved to be impossible. We show that migration should be considered more an approximation of the resemblance between communities and the summed regional species pool. Application of migration estimates to simulate field datasets did show reasonably good fits and indicated consistent differences between sets in comparison with earlier studies. We conclude that estimates of migration using these methods are more an approximation of the homogenization among local communities over time rather than a direct measurement of migration and hence have a direct relationship with beta diversity. As betadiversity is the result of many (non)-neutral processes, we have to admit that migration as estimated in a spatial explicit world encompasses not only direct migration but is an ecological aggregate of these processes. The parameter m of neutral models then appears more as an emerging property revealed by neutral theory instead of being an effective mechanistic parameter and spatially implicit models should be rejected as an approximation of forest dynamics. PMID- 28649340 TI - Truffle biogeography-A case study revealing ecological niche separation of different Tuber species. AB - Ecology of hypogeic mycorrhizal fungi, such as truffles, remains largely unknown, both in terms of their geographical distribution and their environmental niches. Occurrence of true truffles (Tuber spp.) was therefore screened using specific polymerase chain reaction (PCR) assays and subsequent PCR amplicon sequencing in tree roots collected at 322 field sites across the Czech Republic. These sites spanned a wide range of climatic and soil conditions. The sampling was a priori restricted to areas thought to be suitable for Tuber spp. inasmuch as they were characterized by weakly acidic to alkaline soils, warmer climate, and with tree species previously known to host true truffles. Eight operational taxonomic units (OTUs) corresponding to Tuber aestivum, T. borchii, T. foetidum, T. rufum, T. indicum, T. huidongense, T. dryophilum, and T. oligospermum were detected. Among these, T. borchii was the OTU encountered most frequently. It was detected at nearly 19% of the sites. Soil pH was the most important predictor of Tuber spp. distribution. Tuber borchii preferred weakly acidic soils, T. foetidum and T. rufum were most abundant in neutral soils, and T. huidongense was restricted to alkaline soils. Distribution of T. aestivum was mainly dictated by climate, with its range restricted to the warmest sites. Host preferences of the individual Tuber spp. were weak compared to soil and climatic predictors, with the notable exception that T. foetidum appeared to avoid oak trees. Our results open the way to better understanding truffle ecology and, through this new knowledge, also to better-informed trufficulture. PMID- 28649341 TI - Costly defense in a fluctuating environment-sensitivity of annual Nothobranchius fishes to predator kairomones. AB - Antipredator strategies increase the chances of survival of prey species but are subject to trade-offs and always come at a cost, one specific category being the "missed opportunity." Some animals that can modulate the timing of life-cycle events can also desynchronize this timing with the occurrence of a predator. In an unpredictable environment, such a modification may result in a mismatch with prevailing conditions, consequently leading to reproductive failure. In eastern Africa, temporary pools existing only during the rainy season are inhabited by annual fish of the genus Nothobranchius. We examined (i) the capability of multiple Nothobranchius populations and species to cease hatching when exposed to chemical cues from native fish predators and adult conspecifics and (ii) the ability of N. furzeri to modulate their growth rate in the presence of a gape limited fish predator. As the tested Nothobranchius spp. originate from regions with extreme environmental fluctuations where the cost of a missed opportunity can be serious, we predicted an inability to cease hatching as well as lack of growth acceleration as both the predator's gape limitation and the environment select for the same adaptation. Our results showed no biologically relevant influence of kairomone on hatching and no influence on growth rate. This suggests that, in an unpredictable environment, the costs of a missed opportunity are substantial enough to prevent the evolution of some antipredator defense strategies. PMID- 28649342 TI - The relative contribution of drift and selection to phenotypic divergence: A test case using the horseshoe bats Rhinolophus simulator and Rhinolophus swinnyi. AB - Natural selection and drift can act on populations individually, simultaneously or in tandem and our understanding of phenotypic divergence depends on our ability to recognize the contribution of each. According to the quantitative theory of evolution, if an organism has diversified through neutral evolutionary processes (mutation and drift), variation of phenotypic characteristics between different geographic localities (B) should be directly proportional to the variation within localities (W), that is, B ? W. Significant deviations from this null model imply that non-neutral forces such as natural selection are acting on a phenotype. We investigated the relative contributions of drift and selection to intraspecific diversity using southern African horseshoe bats as a test case. We characterized phenotypic diversity across the distributional range of Rhinolophus simulator (n = 101) and Rhinolophus swinnyi (n = 125) using several traits associated with flight and echolocation. Our results suggest that geographic variation in both species was predominantly caused by disruptive natural selection (B was not directly proportional to W). Evidence for correlated selection (co-selection) among traits further confirmed that our results were not compatible with drift. Selection rather than drift is likely the predominant evolutionary process shaping intraspecific variation in traits that strongly impact fitness. PMID- 28649343 TI - Locally adapted populations of a copepod can evolve different gene expression patterns under the same environmental pressures. AB - As populations diverge in allopatry, but under similar thermal conditions, do similar thermal performance phenotypes evolve by maintaining similar gene expression patterns, or does genetic divergence lead to divergent patterns of gene expression between these populations? We used genetically divergent populations of the copepod Tigriopus californicus, whose performance at different thermal conditions is well characterized, to investigate transcriptome-wide expression responses under two different thermal regimes: (1) a nonvariable temperature regime and (2) a regime with variable temperature. Our results show the expression profiles of the response to these regimes differed substantially among populations, even for populations that are geographically close. This pattern was accentuated when populations were raised in the variable temperature environment. Less heat-tolerant populations mounted strong but divergent responses to the different thermal regimes, with a large heat-shock response observed in one population, and an apparent reduction in the expression of genes involved in basic cellular processes in the other. Our results suggest that as populations diverge in allopatry, they may evolve starkly different responses to changes in temperature, at the gene expression level, while maintaining similar thermal performance phenotypes. PMID- 28649344 TI - Historical demography and genetic differentiation of the giant freshwater prawn Macrobrachium rosenbergii in Bangladesh based on mitochondrial and ddRAD sequence variation. AB - Macrobrachium rosenbergii, the giant freshwater prawn, is an important source of high quality protein and occurs naturally in rivers as well as commercial farms in South and South-East Asia, including Bangladesh. This study investigated the genetic variation and population structure of M. rosenbergii sampled from four rivers in Bangladesh (sample size ranged from 19 to 20), assessing sequence variation, both in the mitochondrial cytochrome oxidase subunit 1 (CO1) gene and in 106 single nucleotide polymorphisms (SNPs) sampled randomly from the genome with double digest RAD sequencing (ddRADseq). The mitochondrial variation presented a shallow genealogy with high haplotype diversity (h = 0.95), reflecting an expansion in population size for the last ~82 kyr. Based on the CO1 variation the current effective population size (Ne) was 9.7 * 106 (CI: 1.33 * 106 - 35.84 * 106) individuals. A significant population differentiation was observed with the mitochondrial CO1 sequence variation and based on the ddRADseq variation, which could be traced to the divergence of the population in the Naf River in the South-East border with Myanmar from the other populations. A differentiation in mtDNA haplotype frequencies was also observed between the Biskhali River and the Karnaphuli Rivers in eastern Bangladesh. This study demonstrated the use of high-throughput genotyping based on the ddRADseq method to reveal population structure at a small geographical scale for an important freshwater prawn. The information from this study can be utilized for management and conservation of this species in Bangladesh. PMID- 28649345 TI - Body shape differences in a pair of closely related Malawi cichlids and their hybrids: Effects of genetic variation, phenotypic plasticity, and transgressive segregation. AB - Phenotypic differences may have genetic and plastic components. Here, we investigated the contributions of both for differences in body shape in two species of Lake Malawi cichlids using wild-caught specimens and a common garden experiment. We further hybridized the two species to investigate the mode of gene action influencing body shape differences and to examine the potential for transgressive segregation. We found that body shape differences between the two species observed in the field are maintained after more than 10 generations in a standardized environment. Nonetheless, both species experienced similar changes in the laboratory environment. Our hybrid cross experiment confirmed that substantial variation in body shape appears to be genetically determined. The data further suggest that the underlying mode of gene action is complex and cannot be explained by simple additive or additive-dominance models. Transgressive phenotypes were found in the hybrid generations, as hybrids occupied significantly more morphospace than both parentals combined. Further, the body shapes of transgressive individuals resemble the body shapes observed in other Lake Malawi rock-dwelling genera. Our findings indicate that body shape can respond to selection immediately, through plasticity, and over longer timescales through adaptation. In addition, our results suggest that hybridization may have played an important role in the diversification of Lake Malawi cichlids through creating new phenotypic variation. PMID- 28649346 TI - Couch potatoes do better: Delayed dispersal and territory size affect the duration of territory occupancy in a monogamous mammal. AB - In territorial, socially monogamous species, the establishment and defense of a territory are an important strategy to maximize individual fitness, but the factors responsible for the duration of territory occupancy are rarely studied, especially in long-lived mammals. A long-term monitoring program in southeast Norway spanning over 18 years allowed us to follow the individual life histories of Eurasian beavers (Castor fiber) from adolescence in their natal family group to dispersal and territory establishment until the end of territory occupancy. We investigated whether territory size, resource availability, population density, and dispersal age could explain the duration of territory occupancy, which ranged from 1 to 11 years. The duration of territory occupancy was positively related to dispersal age, suggesting that individuals that delayed dispersal had a competitive advantage due to a larger body mass. This is in support with the maturation hypothesis, which states that an animal should await its physical and behavioral maturation before the acquisition of a territory. Further, we found that individuals that established in medium-sized territories occupied them longer as compared to individuals in small or large territories. This suggests that large territories are more costly to defend due to an increased patrolling effort, and small territories might not have sufficient resources. The lifetime reproductive success ranged from zero to six kits and generally increased with an increasing duration of territory occupancy. Our findings show the importance of holding a territory and demonstrate that dispersal decisions and territory selection have important consequences for the fitness of an individual. PMID- 28649347 TI - Factors restricting the range expansion of the invasive green anole Anolis carolinensis on Okinawa Island, Japan. AB - The green anole Anolis carolinensis invaded the Ogasawara Islands in Japan, drove various native species to extinction, and its distribution expanded 14 years after initial establishment. A. carolinensis invaded Okinawa Island, but it has not expanded its distribution in more than 25 years, although its density is extremely high in the southern region. To determine whether A. carolinensis has the potential to expand its distribution on Okinawa Island, we performed phylogenetic analysis of mitochondrial ND2 DNA sequences to study the origin of A. carolinensis that invaded Okinawa Island. We further used a species distribution model (MaxEnt) based on the distribution of native populations in North America to identify ecologically suitable areas on Okinawa Island. Nucleotide sequence analysis shows that the invader A. carolinensis originated in the western part of the Gulf Coast and inland areas of the United States and that a portion of the anoles on Okinawa was not introduced via the Ogasawara Islands. The MaxEnt predictions indicate that most areas in Okinawa Island are suitable for A. carolinensis. Therefore, A. carolinensis may have the potential to expand its distribution in Okinawa Island. The predictions indicate that habitat suitability is high in areas of high annual mean temperature and urbanized areas. The values of precipitation in summer in the northern region of Okinawa Island were higher compared with those of North America, which reduced the habitat suitability in Okinawa Island. Adaptation to low temperatures, an increase in the mean temperature through global warming, and an increase in open environments through land development will likely expand the distribution of A. carolinensis in Okinawa Island. Therefore, we must continue to monitor the introduced populations and be alert to the possibility that city planning that increases open environments may cause their range to expand. PMID- 28649348 TI - No evidence for adaptation to local rhizobial mutualists in the legume Medicago lupulina. AB - Local adaptation is a common but not ubiquitous feature of species interactions, and understanding the circumstances under which it evolves illuminates the factors that influence adaptive population divergence. Antagonistic species interactions dominate the local adaptation literature relative to mutualistic ones, preventing an overall assessment of adaptation within interspecific interactions. Here, we tested whether the legume Medicago lupulina is adapted to the locally abundant species of mutualistic nitrogen-fixing rhizobial bacteria that vary in frequency across its eastern North American range. We reciprocally inoculated northern and southern M. lupulina genotypes with the northern (Ensifer medicae) or southern bacterium (E. meliloti) in a greenhouse experiment. Despite producing different numbers of root nodules (the structures in which the plants house the bacteria), neither northern nor southern plants produced more seeds, flowered earlier, or were more likely to flower when inoculated with their local rhizobia. We then used a pre-existing dataset to perform a genome scan for loci that showed elevated differentiation between field-collected plants that hosted different bacteria. None of the loci we identified belonged to the well characterized suite of legume-rhizobia symbiosis genes, suggesting that the rhizobia do not drive genetic divergence between M. lupulina populations. Our results demonstrate that symbiont local adaptation has not evolved in this mutualism despite large-scale geographic variation in the identity of the interacting species. PMID- 28649349 TI - Stochastic losses of fire-dependent endemic herbs revealed by a 65-year chronosequence of dispersal-limited woody plant encroachment. AB - The factors responsible for maintaining diverse groundcover plant communities of high conservation value in frequently burned wet pine savannas are poorly understood. While most management involves manipulating extrinsic factors important in maintaining species diversity (e.g., fire regimes), most ecological theory (e.g., niche theory and neutral theory) examines how traits exhibited by the species promote species coexistence. Furthermore, although many ecologists focus on processes that maintain local species diversity, conservation biologists have argued that other indices (e.g., phylogenetic diversity) are better for evaluating assemblages in terms of their conservation value. I used a null model that employed beta-diversity calculations based on Raup-Crick distances to test for deterministic herbaceous species losses associated with a 65-year chronosequence of woody species encroachment within each of three localities. I quantified conservation value of assemblages by measuring taxonomic distinctness, endemism, and floristic quality of plots with and without woody encroachment. Reductions in herb species richness per plot attributable to woody encroachment were largely stochastic, as indicated by a lack of change in the mean or variance in beta-diversity caused by woody encroachment in the savannas studied here. Taxonomic distinctness, endemism, and floristic quality (when summed across all species) were all greater in areas that had not experienced woody encroachment. However, when corrected for local species richness, only average endemism and floristic quality of assemblages inclusive of herbs and woody plants were greater in areas that had not experienced woody encroachment, due to the more restricted ranges and habitat requirements of herbs. Results suggest that frequent fires maintain diverse assemblages of fire-dependent herb species endemic to the region. The stochastic loss of plant species, irrespective of their taxonomic distinctness, to woody encroachment suggests that the relevance of niche partitioning or phylogenetic diversity to the management of biodiversity in wet pine savannas is minimal. PMID- 28649350 TI - Driving factors and temporal fluctuation of Collembola communities and reproductive mode across forest types and regions. AB - Despite the major role of Collembola in forest soil animal food webs, ecological and evolutionary determinants of their community composition are not well understood. We investigated abundance, community structure, life forms, and reproductive mode of Collembola in four different forest types (coniferous, young managed beech, old managed beech, and unmanaged beech forests) representing different management intensities. Forest types were replicated within three regions across Germany: the Schorfheide-Chorin, the Hainich, and the Swabian Alb, differing in geology, altitude, and climate. To account for temporal variation, samples were taken twice with an interval of 3 years. To identify driving factors of Collembola community structure, we applied structural equation modeling, including an index of forest management intensity, abiotic and biotic factors such as pH, C-to-N ratio of leaf litter, microbial biomass, and fungal-to bacterial ratio. Collembola abundance, biomass, and community composition differed markedly between years, with most pronounced differences in the Schorfheide, the region with the harshest climatic conditions. There, temporal fluctuations of parthenogenetic Collembola were significantly higher than in the other regions. In the year with the more favorable conditions, parthenogenetic species flourished, with their abundance depending mainly on abiotic, density independent factors. This is in line with the "Structured Resource Theory of Sexual Reproduction," stating that parthenogenetic species are favored if density independent factors, such as desiccation, frost or flooding, prevail. In contrast, sexual species in the same year were mainly influenced by resource quality-related factors such as the fungal-to-bacterial ratio and the C-to-N ratio of leaf litter. The influence of forest management intensity on abundances was low, indicating that disturbance through forest management plays a minor role. Accordingly, differences in community composition were more pronounced between regions than between different forest types, pointing to the importance of regional factors. PMID- 28649351 TI - New insights into the genetic composition and phylogenetic relationship of wolves and dogs in the Iberian Peninsula. AB - This study investigates the gene pool of Portuguese autochthonous dog breeds and their wild counterpart, the Iberian wolf subspecies (Canis lupus signatus), using standard molecular markers. A combination of paternal and maternal molecular markers was used to investigate the genetic composition, genetic differentiation and genetic relationship of native Portuguese dogs and the Iberian wolf. A total of 196 unrelated dogs, including breed and village dogs from Portugal, and other dogs from Spain and North Africa, and 56 Iberian wolves (wild and captive) were analyzed for nuclear markers, namely Y chromosome SNPs, Y chromosome STR loci, autosomal STR loci, and a mitochondrial fragment of the control region I. Our data reveal new variants for the molecular markers and confirm significant genetic differentiation between Iberian wolf and native domestic dogs from Portugal. Based on our sampling, no signs of recent introgression between the two subspecies were detected. Y chromosome data do not reveal genetic differentiation among the analyzed dog breeds, suggesting they share the same patrilineal origin. Moreover, the genetic distinctiveness of the Iberian wolf from other wolf populations is further confirmed with the description of new mtDNA variants for this endemism. Our research also discloses new molecular markers for wolf and dog subspecies assignment, which might become particularly relevant in the case of forensic or noninvasive genetic studies. The Iberian wolf represents a relic of the once widespread wolf population in Europe and our study reveals that it is a reservoir of unique genetic diversity of the grey wolf, Canis lupus. These results stress the need for conservation plans that will guarantee the sustainability of this threatened top predator in Iberia. PMID- 28649352 TI - Tracking a single pigeon using a shadowing filter algorithm. AB - Miniature GPS devices now allow for measurement of the movement of animals in real time and provide high- quality and high-resolution data. While these new data sets are a great improvement, one still encounters some measurement errors as well as device failures. Moreover, these devices only measure position and require further reconstruction techniques to extract the full dynamical state space with the velocity and acceleration. Direct differentiation of position is generally not adequate. We report on the successful implementation of a shadowing filter algorithm that (1) minimizes measurement errors and (2) reconstructs at the same time the full phase-space from a position recording of a flying pigeon. This filter is based on a very simple assumption that the pigeon's dynamics are Newtonian. We explore not only how to choose the filter's parameters but also demonstrate its improvements over other techniques and give minimum data requirements. In contrast to competing filters, the shadowing filter's approach has not been widely implemented for practical problems. This article addresses these practicalities and provides a prototype for such application. PMID- 28649354 TI - The role of landscape characteristics for forage maturation and nutritional benefits of migration in red deer. AB - Large herbivores gain nutritional benefits from following the sequential flush of newly emergent, high-quality forage along environmental gradients in the landscape, termed green wave surfing. Which landscape characteristics underlie the environmental gradient causing the green wave and to what extent landscape characteristics alone explain individual variation in nutritional benefits remain unresolved questions. Here, we combine GPS data from 346 red deer (Cervus elaphus) from four partially migratory populations in Norway with the satellite derived normalized difference vegetation index (NDVI), an index of plant phenology. We quantify whether migratory deer had access to higher quality forage than resident deer, how landscape characteristics within summer home ranges affected nutritional benefits, and whether differences in landscape characteristics could explain differences in nutritional gain between migratory and resident deer. We found that migratory red deer gained access to higher quality forage than resident deer but that this difference persisted even after controlling for landscape characteristics within the summer home ranges. There was a positive effect of elevation on access to high-quality forage, but only for migratory deer. We discuss how the landscape an ungulate inhabits may determine its responses to plant phenology and also highlight how individual behavior may influence nutritional gain beyond the effect of landscape. PMID- 28649353 TI - Genetic identification of source and likely vector of a widespread marine invader. AB - The identification of native sources and vectors of introduced species informs their ecological and evolutionary history and may guide policies that seek to prevent future introductions. Population genetics provides a powerful set of tools to identify origins and vectors. However, these tools can mislead when the native range is poorly sampled or few molecular markers are used. Here, we traced the introduction of the Asian seaweed Gracilaria vermiculophylla (Rhodophyta) into estuaries in coastal western North America, the eastern United States, Europe, and northwestern Africa by genotyping more than 2,500 thalli from 37 native and 53 non-native sites at mitochondrial cox1 and 10 nuclear microsatellite loci. Overall, greater than 90% of introduced thalli had a genetic signature similar to thalli sampled from the coastline of northeastern Japan, strongly indicating this region served as the principal source of the invasion. Notably, northeastern Japan exported the vast majority of the oyster Crassostrea gigas during the 20th century. The preponderance of evidence suggests G. vermiculophylla may have been inadvertently introduced with C. gigas shipments and that northeastern Japan is a common source region for estuarine invaders. Each invaded coastline reflected a complex mix of direct introductions from Japan and secondary introductions from other invaded coastlines. The spread of G. vermiculophylla along each coastline was likely facilitated by aquaculture, fishing, and boating activities. Our ability to document a source region was enabled by a robust sampling of locations and loci that previous studies lacked and strong phylogeographic structure along native coastlines. PMID- 28649355 TI - Resequencing and comparison of whole mitochondrial genome to gain insight into the evolutionary status of the Shennongjia golden snub-nosed monkey (SNJ R. roxellana). AB - Shennongjia Rhinopithecus roxellana (SNJ R. roxellana) is the smallest geographical population of R. roxellana. The phylogenetic relationships among its genera and species and the biogeographic processes leading to their current distribution are largely unclear. To address these issues, we resequenced and obtained a new, complete mitochondrial genome of SNJ R. roxellana by next generation sequencing and standard Sanger sequencing. We analyzed the gene composition, constructed a phylogenetic tree, inferred the divergence ages based on complete mitochondrial genome sequences, and analyzed the genetic divergence of 13 functional mtDNA genes. The phylogenetic tree and divergence ages showed that R. avunculus (the Tonkin snub-nosed monkey) was the first to diverge from the Rhinopithecus genus ca. 2.47 million years ago (Ma). Rhinopithecus bieti and Rhinopithecus strykeri formed sister groups, and the second divergence from the Rhinopithecus genus occurred ca. 1.90 Ma. R. roxellana and R. brelichi diverged from the Rhinopithecus genus third, ca. 1.57 Ma. SNJ R. roxellana was the last to diverge within R. roxellana species in 0.08 Ma, and the most recent common ancestor of R. roxellana is 0.10 Ma. The analyses on gene composition showed SNJ R. roxellana was the newest geographic population of R. roxellana. The work will help to develop a more accurate protection policy for SNJ R. roxellana and facilitate further research on selection and adaptation of R. roxellana. PMID- 28649356 TI - Asymmetric paternal effect on offspring size linked to parent-of-origin expression of an insulin-like growth factor. AB - Sexual reproduction brings together reproductive partners whose long-term interests often differ, raising the possibility of conflict over their reproductive investment. Males that enhance maternal investment in their offspring gain fitness benefits, even if this compromises future reproductive investment by iteroparous females. When the conflict occurs at a genomic level, it may be uncovered by crossing divergent populations, as a mismatch in the coevolved patterns of paternal manipulation and maternal resistance may generate asymmetric embryonic growth. We report such an asymmetry in reciprocal crosses between populations of the fish Girardinichthys multiradiatus. We also show that a fragment of a gene which can influence embryonic growth (Insulin-Like Growth Factor 2; igf2) exhibits a parent-of-origin methylation pattern, where the maternally inherited igf2 allele has much more 5' cytosine methylation than the paternally inherited allele. Our findings suggest that male manipulation of maternal investment may have evolved in fish, while the parent-of-origin methylation pattern appears to be a potential candidate mechanism modulating this antagonistic coevolution process. However, disruption of other coadaptive processes cannot be ruled out, as these can lead to similar effects as conflict. PMID- 28649357 TI - RNA editing by the host ADAR system affects the molecular evolution of the Zika virus. AB - Zika virus (ZIKV) is a mosquito-transmitted flavivirus, linked to microcephaly and fetal death in humans. Here, we investigate whether host-mediated RNA editing of adenosines (ADAR) plays a role in the molecular evolution of ZIKV. Using complete coding sequences for the ZIKV polyprotein, we show that potential ADAR substitutions are underrepresented at the ADAR-resistant GA dinucleotides of both the positive and negative strands, that these changes are spatially and temporally clustered (as expected of ADAR editing) for three branches of the viral phylogeny, and that ADAR mutagenesis can be linked to its codon usage. Furthermore, resistant GA dinucleotides are enriched on the positive (but not negative) strand, indicating that the former is under stronger purifying selection than the latter. ADAR editing also affects the evolution of the rhabdovirus sigma. Our study now documents that host ADAR editing is a mutation and evolutionary force of positive- as well as negative-strand RNA viruses. PMID- 28649358 TI - Postglacial dispersal patterns and mitochondrial genetic structure of the Pyrenean desman (Galemys pyrenaicus) in the northwestern region of the Iberian Peninsula. AB - The genetic structure of small semiaquatic animals may be influenced by dispersal across both rivers and land. The relative importance of these two modes of dispersal may vary across different species and with ecological conditions and evolutionary periods. The Pyrenean desman (Galemys pyrenaicus) is an endemic mammal of the Iberian Peninsula with a strong phylogeographic structure and semiaquatic habits, thus making it an ideal model to study the effects of river and overland dispersal on its genetic structure. Thanks to different types of noninvasive samples, we obtained an extensive sampling of the Pyrenean desman from the northwestern region of the Iberian Peninsula and sequenced two mitochondrial DNA fragments. We then analyzed, using an isolation-by-distance approach, the correlation between phylogenetic distances and geographical distances measured along both river networks and land to infer the relative importance of river and overland dispersal. We found that the correlations in the whole area and in a large basin were consistent with an effect of overland dispersal, which may be due to the postglacial colonization of new territories using terrestrial corridors and, possibly, a more extensive fluvial network that may have been present during the Holocene. However, in a small basin, likely to be less influenced by the impact of ancient postglacial dispersal, the correlations suggested significant overall effects of both overland and river dispersal, as expected for a semiaquatic mammal. Therefore, different scales and geographical regions reflect different aspects of the evolutionary history and ecology of this semiaquatic species using this isolation-by-distance method. The results we obtained may have crucial implications for the conservation of the Pyrenean desman because they reinforce the importance of interbasin dispersal for this species in the studied area and the need to protect the whole riverine ecosystem, including rivers, upland streams and terrestrial corridors between basins. PMID- 28649359 TI - Species traits and interaction rules shape a species-rich seed-dispersal interaction network. AB - Species phenotypic traits affect the interaction patterns and the organization of seed-dispersal interaction networks. Understanding the relationship between species characteristics and network structure help us understand the assembly of natural communities and how communities function. Here, we examine how species traits may affect the rules leading to patterns of interaction among plants and fruit-eating vertebrates. We study a species-rich seed-dispersal system using a model selection approach to examine whether the rules underlying network structure are driven by constraints in fruit resource exploitation, by preferential consumption of fruits by the frugivores, or by a combination of both. We performed analyses for the whole system and for bird and mammal assemblages separately, and identified the animal and plant characteristics shaping interaction rules. The structure of the analyzed interaction network was better explained by constraints in resource exploitation in the case of birds and by preferential consumption of fruits with specific traits for mammals. These contrasting results when looking at bird-plant and mammal-plant interactions suggest that the same type of interaction is organized by different processes depending on the assemblage we focus on. Size-related restrictions of the interacting species (both for mammals and birds) were the most important factors driving the interaction rules. Our results suggest that the structure of seed dispersal interaction networks can be explained using species traits and interaction rules related to simple ecological mechanisms. PMID- 28649360 TI - Competitive success of southern populations of Betula pendula and Sorbus aucuparia under simulated southern climate experiment in the subarctic. AB - Global warming has been commonly accepted to facilitate species' range shifts across latitudes. Cross-latitudinal transplantations support this; many tree species can well adapt to new geographical areas. However, these studies fail to capture species' adaptations to new light environment because the experiments were not designed to explicitly separate species' responses to light and temperature. Here we tested reaction norms of tree seedlings in reciprocal transplantations 1,000 km apart from each other at two latitudes (60 degrees N and 69 degrees N). In contrast to past studies, we exposed our experimental plants to same temperature in both sites (temperature of 60 degrees N growing site is recorded to adjust temperature of 69 degrees N site in real time via Internet connection) while light environment (photoperiod, light quality) remained ambient. Shoot elongation and autumn coloration were studied in seedlings of two deciduous trees (Betula pendula and Sorbus aucuparia), which were expected to respond differently to day length. Sorbus as a member of Rosaceae family was assumed to be indifferent to photoperiod, while Betula responds strongly to day length. We hypothesized that (1) southern and northern populations of both species perform differently; (2) southern populations perform better in both sites; (3) autumn phenology of southern populations may delay in the northern site; (4) and Sorbus aucuparia is less dependent on light environment. According to the hypotheses, shoot elongation of northern population was inherently low in both species. An evolutionary consequence of this may be a competitive success of southern populations under warming climate. Southern population of B. pendula was delayed in autumn coloration, but not in growth cessation. Sorbus aucuparia was less responsive to light environment. The results suggest that light provides selection pressure in range shifts, but the response is species dependent. PMID- 28649361 TI - Control of lice infestation in horses using a 10 mg/mL deltamethrin topical application. AB - BACKGROUND: Two open-controlled studies evaluated the tolerance and the efficacy of a 10 mg/mL deltamethrin-based pour-on solution (Deltanil(r); Virbac, France) in treating (study 1) and preventing (study 2) natural Damalinia equi infestations in horses. In study 1, seven adult horses received 10 mL of the solution from mane to tail head on day 0 (D0). Four adult horses, living separately, served as non-treated controls. All were naturally infected. Lice burden was recorded by counting the number of live parasites, bilaterally, over seven anatomic regions. Lesional score was based on alopecia, crusts, papules/pustules, nodules/plaques, scales and wounds, each assessed on a 0-3 scale. Evaluation was performed on D0 and subsequently weekly until D56 in treated horses and on D0 and D56 in control horses. In study 2, six adult horses free of parasites were similarly treated on D-2 and D30. Two adult horses, naturally infested with D. equi and left untreated, were mixed with the treated horses from D0 to D60. Evaluation was performed similarly to study 1 on all horses, fortnightly until D60. RESULTS: No adverse event was recorded in either study. In study 1, parasite and lesional scores of control horses were maintained on D56. Parasite scores of the treated horses were reduced by 98% on D7 and 100% from D15 to D56 (mean [SD]: D0 44 [58.4]). Lesional score in treated horses was reduced by 24, 82, 47, 91, 96, 93, 93 and 100% on D7, 15, 21, 28, 35, 42, 50 and 56, respectively (mean [SD]: D0 3.1 [1.8]). In study 2, the lice populations remained high in the two control horses throughout the study (max mean [SD]: D0 159 [151.3], min D45 34 [39.6]). On treated animals, all parasite counts were negative except on D15 (one louse found). The protection rate was 99.7% on D15 and 100% from D30 to D60. CONCLUSIONS: A single application of the 10 mg/mL deltamethrin preparation was effective and safe in the treatment and in the prevention of lice infestation in these horses. It was also effective in preventing new infestations for one month. PMID- 28649362 TI - Challenges in implementing the 2015 BASHH guidelines for the appropriate use of post-exposure prophylaxis for HIV following sexual exposure. AB - The use of post exposure prophylaxis for human immunodeficiency virus (HIV) following sexual exposure (PEPSE) was retrospectively audited in an inner city genitourinary clinic against the 2015 national guidelines by the British Association for Sexual Health and HIV (BASHH). One-hundred out of a total of 101 patients (99%) had a baseline HIV test done. 82.1% (n=83) of patients were given PEPSE prescriptions fitting within recommended indications lower than the 90% target set by BASHH. 84.2% (n=85) of patients had PEPSE administered within 72 hours lower than the 90%. 61.4% (n=62) of patients were known to have completed four weeks of PEPSE lower than the 75% target. 61.4% (n=62) of patients were screened for sexually transmitted infections (STIs) lower than the 90% target. 59.4% (n=60%) of patients had post-PEPSE HIV bloods slightly lower than the 60% target. PMID- 28649363 TI - Genetic and epigenetic control of gene expression by CRISPR-Cas systems. AB - The discovery and adaption of bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems has revolutionized the way researchers edit genomes. Engineering of catalytically inactivated Cas variants (nuclease-deficient or nuclease-deactivated [dCas]) combined with transcriptional repressors, activators, or epigenetic modifiers enable sequence specific regulation of gene expression and chromatin state. These CRISPR-Cas based technologies have contributed to the rapid development of disease models and functional genomics screening approaches, which can facilitate genetic target identification and drug discovery. In this short review, we will cover recent advances of CRISPR-dCas9 systems and their use for transcriptional repression and activation, epigenome editing, and engineered synthetic circuits for complex control of the mammalian genome. PMID- 28649364 TI - Immunosurveillance by human gammadelta T lymphocytes: the emerging role of butyrophilins. AB - In contrast to conventional T lymphocytes, which carry an alphabeta T-cell receptor and recognize antigens as peptides presented by major histocompatibility complex class I or class II molecules, human gammadelta T cells recognize different metabolites such as non-peptidic pyrophosphate molecules that are secreted by microbes or overproduced by tumor cells. Hence, gammadelta T cells play a role in immunosurveillance of infection and cellular transformation. Until recently, it has been unknown how the gammadelta T-cell receptor senses such pyrophosphates in the absence of known antigen-presenting molecules. Recent studies from several groups have identified a unique role of butyrophilin (BTN) protein family members in this process, notably of BTN3A1. BTNs are a large family of transmembrane proteins with diverse functions in lipid secretion and innate and adaptive immunity. Here we discuss current models of how BTN molecules regulate gammadelta T-cell activation. We also address the implications of these recent findings on the design of novel immunotherapeutic strategies based on the activation of gammadelta T cells. PMID- 28649365 TI - The impact factor of an open access journal does not contribute to an article's citations. AB - Background Citations of papers are positively influenced by the journal's impact factor (IF). For non-open access (non-OA) journals, this influence may be due to the fact that high-IF journals are more often purchased by libraries, and are therefore more often available to researchers, than low-IF journals. This positive influence has not, however, been shown specifically for papers published in open access (OA) journals, which are universally accessible, and do not need library purchase. It is therefore important to ascertain if the IF influences citations in OA journals too. Methods 203 randomized controlled trials (102 OA and 101 non-OA) published in January 2011 were included in the study. Five-year citations for papers published in OA journals were compared to those for non-OA journals. Source papers were derived from PubMed. Citations were retrieved from Web of Science, Scopus, and Google Scholar databases. The Thompson-Reuter's IF was used. Results OA journals were found to have significantly more citations overall compared to non-OA journals (median 15.5 vs 12, p=0.039). The IF did not correlate with citations for OA journals (Spearman's rho =0.187, p=0.60). The increase in the citations with increasing IF was minimal for OA journals (beta coefficient = 3.346, 95% CI -0.464, 7.156, p=0.084). In contrast, the IF did show moderate correlation with citations for articles published in non-OA journals (Spearman's rho=0.514, p<0.001). The increase in the number of citations was also significant (beta coefficient = 4.347, 95% CI 2.42, 6.274, p<0.001). Conclusion It is better to publish in an OA journal for more citations. It may not be worth paying high publishing fees for higher IF journals, because there is minimal gain in terms of increased number of citations. On the other hand, if one wishes to publish in a non-OA journal, it is better to choose one with a high IF. PMID- 28649366 TI - Pneumocystis jirovecii detection in asymptomatic patients: what does its natural history tell us? AB - Pneumocystis jirovecii is an unusual ascomycetous fungus that can be detected in the lungs of healthy individuals. Transmission from human to human is one of its main characteristics in comparison with other fungi responsible for invasive infections. P. jirovecii is transmitted through the air between healthy individuals, who are considered to be the natural reservoir, at least transiently. In immunocompromised patients, P. jirovecii multiplies, leading to subacute infections and acute life-threatening pneumonia, called Pneumocystis pneumonia [PCP]. PCP is caused by genotypically distinct mixtures of organisms in more than 90% of cases, reinforcing the hypothesis that there is constant inhalation of P. jirovecii from different contacts over time, although reactivation of latent organisms from previous exposures may be possible. Detection of P. jirovecii DNA without any symptoms or related radiological signs has been called "colonization". This situation could be considered as the result of recent exposure to P. jirovecii that could evolve towards PCP, raising the issue of cotrimoxazole prophylaxis for at-risk quantitative polymerase chain reaction (qPCR)-positive immunocompromised patients. The more accurate way to diagnose PCP is the use of real-time quantitative PCR, which prevents amplicon contamination and allows determination of the fungal load that is mandatory to interpret the qPCR results and manage the patient appropriately. The detection of P. jirovecii in respiratory samples of immunocompromised patients should be considered for potential risk of developing PCP. Many challenges still need to be addressed, including a better description of transmission, characterization of organisms present at low level, and prevention of environmental exposure during immunodepression. PMID- 28649367 TI - Nitric oxide signalling and neuronal nitric oxide synthase in the heart under stress. AB - Nitric oxide (NO) is an imperative regulator of the cardiovascular system and is a critical mechanism in preventing the pathogenesis and progression of the diseased heart. The scenario of bioavailable NO in the myocardium is complex: 1) NO is derived from both endogenous NO synthases (endothelial, neuronal, and/or inducible NOSs [eNOS, nNOS, and/or iNOS]) and exogenous sources (entero-salivary NO pathway) and the amount of NO from exogenous sources varies significantly; 2) NOSs are located at discrete compartments of cardiac myocytes and are regulated by distinctive mechanisms under stress; 3) NO regulates diverse target proteins through different modes of post-transcriptional modification (soluble guanylate cyclase [sGC]/cyclic guanosine monophosphate [cGMP]/protein kinase G [PKG] dependent phosphorylation, S-nitrosylation, and transnitrosylation); 4) the downstream effectors of NO are multidimensional and vary from ion channels in the plasma membrane to signalling proteins and enzymes in the mitochondria, cytosol, nucleus, and myofilament; 5) NOS produces several radicals in addition to NO (e.g. superoxide, hydrogen peroxide, peroxynitrite, and different NO-related derivatives) and triggers redox-dependent responses. However, nNOS inhibits cardiac oxidases to reduce the sources of oxidative stress in diseased hearts. Recent consensus indicates the importance of nNOS protein in cardiac protection under pathological stress. In addition, a dietary regime with high nitrate intake from fruit and vegetables together with unsaturated fatty acids is strongly associated with reduced cardiovascular events. Collectively, NO-dependent mechanisms in healthy and diseased hearts are better understood and shed light on the therapeutic prospects for NO and NOSs in clinical applications for fatal human heart diseases. PMID- 28649368 TI - Wnt target genes and where to find them. AB - Wnt/beta-catenin signaling is highly conserved throughout metazoans, is required for numerous essential events in development, and serves as a stem cell niche signal in many contexts. Misregulation of the pathway is linked to several human pathologies, most notably cancer. Wnt stimulation results in stabilization and nuclear import of beta-catenin, which then acts as a transcriptional co activator. Transcription factors of the T-cell family (TCF) are the best characterized nuclear binding partners of beta-catenin and mediators of Wnt gene regulation. This review provides an update on what is known about the transcriptional activation of Wnt target genes, highlighting recent work that modifies the conventional model. Wnt/beta-catenin signaling regulates genes in a highly context-dependent manner, and the role of other signaling pathways and TCF co-factors in this process will be discussed. Understanding Wnt gene regulation has served to elucidate many biological roles of the pathway, and we will use examples from stem cell biology, metabolism, and evolution to illustrate some of the rich Wnt biology that has been uncovered. PMID- 28649369 TI - Recent advances in understanding contextual TGFbeta signaling. AB - The appearance of the first animal species on earth coincides with the emergence of transforming growth factor beta (TGFbeta) pathways. The evolution of these animals into more complex organisms coincides with a progressively increased TGFbeta repertoire through gene duplications and divergence, making secreted TGFbeta molecules the largest family of morphogenetic proteins in humans. It is therefore not surprising that TGFbeta pathways govern numerous aspects of human biology from early embryonic development to regeneration, hematopoiesis, neurogenesis, and immunity. Such heavy reliance on these pathways is reflected in the susceptibility to minor perturbations in pathway components that can lead to dysregulated signaling and a diverse range of human pathologies such as cancer, fibrosis, and developmental disorders. Attempts to comprehensively resolve these signaling cascades are complicated by the long-recognized paradoxical role the pathway plays in cell biology. Recently, several groups have probed examples of the disparate aspects of TGFbeta biology in a variety of animal models and uncovered novel context-dependent regulatory mechanisms. Here, we briefly review recent advancements and discuss their overall impact in directing future TGFbeta research. PMID- 28649370 TI - Leishmaniasis: a review. AB - Leishmaniasis is caused by an intracellular parasite transmitted to humans by the bite of a sand fly. It is endemic in Asia, Africa, the Americas, and the Mediterranean region. Worldwide, 1.5 to 2 million new cases occur each year, 350 million are at risk of acquiring the disease, and leishmaniasis causes 70,000 deaths per year. Clinical features depend on the species of Leishmania involved and the immune response of the host. Manifestations range from the localized cutaneous to the visceral form with potentially fatal outcomes. Many drugs are used in its treatment, but the only effective treatment is achieved with current pentavalent antimonials. PMID- 28649371 TI - Recent advances in microbial fermentation for dairy and health. AB - Microbial fermentation has been used historically for the preservation of foods, the health benefits of which have since come to light. Early dairy fermentations depended on the spontaneous activity of the indigenous microbiota of the milk. Modern fermentations rely on defined starter cultures with desirable characteristics to ensure consistency and commercial viability. The selection of defined starters depends on specific phenotypes that benefit the product by guaranteeing shelf life and ensuring safety, texture, and flavour. Lactic acid bacteria can produce a number of bioactive metabolites during fermentation, such as bacteriocins, biogenic amines, exopolysaccharides, and proteolytically released peptides, among others. Prebiotics are added to food fermentations to improve the performance of probiotics. It has also been found that prebiotics fermented in the gut can have benefits that go beyond helping probiotic growth. Studies are now looking at how the fermentation of prebiotics such as fructo oligosaccharides can help in the prevention of diseases such as osteoporosis, obesity, and colorectal cancer. The potential to prevent or even treat disease through the fermentation of food is a medically and commercially attractive goal and is showing increasing promise. However, the stringent regulation of probiotics is beginning to detrimentally affect the field and limit their application. PMID- 28649372 TI - The use of high-frequency ventilation during general anaesthesia: an update. AB - Various forms of high-frequency ventilation (HFV) have been described. HFV is broadly defined as artificial ventilation of the lungs with sub-deadspace tidal volumes delivered using supra-physiological frequencies. HFV has been used in anaesthesia and intensive care for special procedures and conditions since the 1960s. Clinical interest in the use and the technical evolution of HFV has developed over time. There is a renewed interest in HFV for avoiding parenchymal movement during stereotactic tumour ablation. The present paper aims to give an overview of the fundamental physiology, technical aspects, and clinical challenges of HFV in ablation procedures during general anaesthesia, where HFV is used to minimise the movements of the ablation target. PMID- 28649373 TI - Novel approaches to HIV therapy. AB - There are approximately 35 million people infected by human immunodeficiency virus (HIV), with an estimated 2 million incident infections annually across the globe. While HIV infection was initially associated with high rates of morbidity and mortality, advances in therapy have transformed it into a chronic and manageable disease. In addition, there is very strong evidence that those on antiretroviral therapy are much less likely to transmit infection to their partners. The success rates for maintaining viral suppression in treated patients has dramatically increased owing to the development of agents that are potent and well tolerated and can often be co-formulated into single pills for simplification. This review will outline advances in treatment over the last several years as well as new strategies that may shift the existing treatment paradigm in the near future. PMID- 28649375 TI - RETRACTION: How blockchain-timestamped protocols could improve the trustworthiness of medical science. AB - [This retracts the article DOI: 10.12688/f1000research.8114.1.][This retracts the article DOI: 10.12688/f1000research.8114.2.][This retracts the article DOI: 10.12688/f1000research.8114.3.]. PMID- 28649374 TI - Screening and identification of novel biologically active natural compounds. AB - With the advent of very rapid and cheap genome analyses and the linkage of these plus microbial metabolomics to potential compound structures came the realization that there was an immense sea of novel agents to be mined and tested. In addition, it is now recognized that there is significant microbial involvement in many natural products isolated from "nominally non-microbial sources". This short review covers the current screening methods that have evolved and one might even be tempted to say "devolved" in light of the realization that target-based screens had problems when the products entered clinical testing, with off-target effects being the major ones. Modern systems include, but are not limited to, screening in cell lines utilizing very modern techniques (a high content screen) that are designed to show interactions within cells when treated with an "agent". The underlying principle(s) used in such systems dated back to unpublished attempts in the very early 1980s by the pharmaceutical industry to show toxic interactions within animal cells by using automated light microscopy. Though somewhat successful, the technology was not adequate for any significant commercialization. Somewhat later, mammalian cell lines that were "genetically modified" to alter signal transduction cascades, either up or down, and frequently linked to luciferase readouts, were then employed in a 96-well format. In the case of microbes, specific resistance parameters were induced in isogenic cell lines from approximately the mid-1970s. In the latter two cases, comparisons against parent and sibling cell lines were used in order that a rapid determination of potential natural product "hits" could be made. Obviously, all of these assay systems could also be, and were, used for synthetic molecules. These methods and their results have led to a change in what the term "screening for bioactivity" means. In practice, versions of phenotypic screening are returning, but in a dramatically different scientific environment from the 1970s, as I hope to demonstrate in the short article that follows. PMID- 28649376 TI - Re-designing the pathway to surgery: better care and added value. AB - The case for radical pathway re-design before surgery is in part driven by healthcare system pressures which are in turn the result of continuously rising demand in the face of tightly constrained resources. Such circumstances tend to drive revolutionary, rather than incremental, change. The current approach to preoperative assessment, that typically occurs in the weeks leading up to surgery, but is all too often only a few days before surgery, results in a lost opportunity for perioperative physicians to improve patient care. Re-engineering this process based on a patient-focused, pathway-driven vision of perioperative medicine offers a means of exploiting this opportunity. This review explores drivers for change, the opportunity offered by pathway re-design, and suggests a variety of strategies to add value in the preoperative pathway, each of which is facilitated by early engagement between perioperative physician and patient: collaborative decision-making, collaborative behavioural change, targeted comorbidity management as well as expectation management and psychological preparation for surgery including surgery schools. PMID- 28649377 TI - A bibliometric analysis of the citation classics of acute appendicitis. AB - INTRODUCTION: Acute appendicitis is one of the most commonly encountered emergency surgical conditions. An understanding of the most highly cited research works in this field is key to good evidence based clinical practice. AIMS: To perform a bibliometric analysis on the 100 most frequently cited articles in the field of acute appendicitis. METHODS: The database of the Institute for Scientific Information (ISI) Web of Science Expanded citation index was searched to identify the 100 most frequently cited articles in the field of acute appendicitis. The web of science expanded citation index tracks article citations made since 1946. RESULTS: The top 100 most frequently cited articles were selected for analysis in this series. The most frequently cited article was cited 649 times and the least cited three article 93 times. The average number of citations per article was 167.74. The top 100 cited articles originated from 17 countries. Over half of the papers originated from the USA. Fifty-one of the papers concentrated on diagnostics of acute appendicitis. Thirty-six papers looked at the treatment of acute appendicitis with 30 of these dealing with the surgical management of the disease. There were 6 studies at level 1a, 20 studies at level 1b and 43,5,17 and 9 studies at levels 2, 3, 4 and 5 respectively. CONCLUSIONS: Bibliometric analysis of the citation classics in a given field can provide interesting insights into the relationship between the quality of research outputs and clinical practice. The study of acute appendicitis remains an active field of research with a growing body of higher quality evidence underpinning our clinical practice. PMID- 28649378 TI - Knot free technique for Laparoscopic Ventral Mesh Rectopexy. AB - AIM: The aim of our study was to describe and assess a new method of mesh fixation using clips in Laparoscopic Ventral Mesh Rectopexy (VMR). This technique avoids knots while suturing in pelvis and saves time. METHOD: A systematic search of the literature (PUBMED, EMBASE) was done to find out alternate ways to fix the mesh over the anterior surface of rectum. This technique has not been used before. We performed five operations using this technique. Indication for surgery was full thickness rectal prolapse in all of them. Majority of patients were female (four) and one was male with age range of 32-69 years. Two patients had previous abdominal surgery. Laparoscopic access included four ports and 30 degrees scope in all cases. Biological mesh was used in 4 cases and synthetic in remaining one. Instead of using normal intra-corporeal or extra-corporeal suturing, a novel technique was used to secure the Ethibond 2/0 suture using endo clip. The mesh fixation to sacral promontory was done with tacker. RESULTS: These patients were prospectively followed up to assess the effectiveness of repair and to assess for the recurrence. The median follow up so far is 8 months (range 5 11). None of the patients had any major complication. No patient has reported recurrence either. CONCLUSION: Our study with limitations of small group and relatively shorter follow up has proven to be a safe technique. This technique has a potential of replacing intra or extracorporeal knot with endo clips and requires less time compared to conventional suturing. It also advantage of having a minimal learning curve. PMID- 28649379 TI - Is transoral robotic surgery a safe and effective multilevel treatment for obstructive sleep apnoea in obese patients following failure of conventional treatment(s)? AB - A best evidence topic was written according to a structured protocol. The question addressed was whether TransOral Robotic Surgery (TORS) is a safe and effective multilevel treatment for Obstructive Sleep Apnoea (OSA) in obese patients following failure of conventional treatment(s). A total of 39 papers were identified using the reported searches of which 5 represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Existing treatments for OSA - primarily CPAP - though highly effective are poorly tolerated resulting in an adherence often lower than 50%. As such, surgery is regaining momentum, especially in those patients failing non-surgical treatment (CPAP or oral appliances). TORS represents the latest addition to the armamentarium of Otorhinolaryngologists - Head and Neck Surgeons for the management of OSA. The superior visualisation and ergonomics render TORS ideal for the multilevel treatment of OSA. However, not all patients are suitable candidates for TORS and its suitability is questionable in obese patients. In view of the global obesity pandemic, this is an important question that requires addressing promptly. Despite the drop in success rates with increasing BMI, the success rate of TORS in non-morbidly obese patients (BMI = 30-35kgm-2) exceeds 50%. A 50% success rate may at first seem low, but it is important to realize that this is a patient cohort suffering from a life-threatening disease and no option left other than a tracheostomy. As such, TORS represents an important treatment in non-morbidly obese OSA patients following failure of conventional treatment(s). PMID- 28649380 TI - GITR ligand fusion protein agonist enhances the tumor antigen-specific CD8 T-cell response and leads to long-lasting memory. AB - BACKGROUND: The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations. METHODS: We explored two separate murine tumor models, CT26 and TC 1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy. In TC 1, GITRL-FP was also combined with concurrent administration of an E7-SLP vaccine. We evaluated tumor growth inhibition by tumor volume measurements as well as changes in CD8 T cell populations and function including cytokine production using flow cytometry. Additionally, we interrogated how these therapies resulted in tumor antigen-specific responses using MHC-I dextramer staining and antigen-specific restimulations. RESULTS: In this study, we demonstrate that a GITR ligand fusion protein (GITRL-FP) is an effective modulator of antigen-specific CD8 T cells. In a CT26 mouse tumor model, GITRL-FP promoted expansion of antigen-specific T cells, depletion of regulatory T cells (Tregs), and generation of long-lasting CD8 T cell memory. This memory expansion was dependent on the dose of GITRL-FP and resulted in complete tumor clearance and protection from tumor rechallenge. In contrast, in TC-1 tumor-bearing mice, GITRL-FP monotherapy could not prime an antigen-specific CD8 T cell response and was unable to deplete Tregs. However, when combined with a vaccine targeting E7, treatment with GITRL-FP resulted in an augmentation of the vaccine-induced antigen-specific CD8 T cells, the depletion of Tregs, and a potent antitumor immune response. In both model systems, GITR levels on antigen-specific CD8 T cells were higher than on all other CD8 T cells, and GITRL-FP interacted directly with primed antigen-specific CD8 T cells. CONCLUSIONS: When taken together, our results demonstrate that the delivery of GITRL-FP as a therapeutic can promote anti-tumor responses in the presence of tumor-specific CD8 T cells. These findings support further study into combination partners for GITRL-FP that may augment CD8 T-cell priming as well as provide hypotheses that can be tested in human clinical trials exploring GITR agonists including GITRL-FP. PMID- 28649381 TI - New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016. AB - This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy. PMID- 28649382 TI - Does sperm quality and DNA integrity differ in cryopreserved semen samples from young, adult, and aged Nellore bulls? AB - BACKGROUND: In humans, it is now well documented that rising paternal age is correlated with decreased sperm DNA integrity and embryonic developmental failures. On the other side of the coin, it is also reported that very young fathers such as teenagers carry an increased risk of adverse birth outcomes. These observations suggest that, at least in humans, there is an age window for optimal sperm DNA integrity. In bovine, little is known about sperm DNA quality in young bulls and how it evolves with age. This study aimed to fill in this gap as it may be of importance for the bovine industry to know when exactly a bull is an optimal performer for reproductive programs. METHODS: Forty Nellore bulls were divided into three age groups: 1.8 to 2 years - young bulls; 3.5 to 7 years - adult bulls; and 8 to 14.3 years - aged bulls. Three ejaculates were collected from each bull, cryopreserved and evaluated for various parameters including: computer-assisted sperm analysis (CASA), plasma membrane and acrosome integrity, mitochondrial potential, sperm nuclear protamination, DNA oxidative damage, and Sperm Chromatin Structure Assay (SCSA). RESULTS: We report here that young bulls presented superior values for motility, plasma and acrosomal membrane integrity, and high mitochondrial potential. However, they also presented higher values for sperm morphological abnormalities compared to adult and aged animal groups (p < 0.05). In addition, young bulls exhibited more defective protamination than older animals did. The oldest bulls showed more nuclear oxidative damage than the younger groups of bulls while both the young and aged groups were found more susceptible to DNA denaturation as revealed with the SCSA test (p < 0.05). CONCLUSION: These results indicate that young bulls spermatozoa best survived the freezing procedure, followed by adult and aged bulls. However, young and aged bulls were found to be more susceptible to DNA damage, respectively caused by protamine deficiency and oxidation. Therefore, although young bulls have correct semen parameters according to classical evaluation, our results indicate that they may show some structural nuclear immaturity. PMID- 28649383 TI - Impact of therapist change after initial contact and traumatic burden on dropout in a naturalistic sample of inpatients with borderline pathology receiving dialectical behavior therapy. AB - BACKGROUND: This study focused on the predictors of therapy dropout in a naturalistic sample of patients with borderline pathology receiving dialectical behavior therapy (DBT) in an inpatient setting. We assumed that the change of the therapist between DBT-briefing and start of DBT-treatment as well as comorbid posttraumatic stress disorder (PTSD) and childhood trauma history were associated with elevated dropout. METHODS: Eighty-nine participants with borderline pathology (>= 3 borderline personality disorder criteria) receiving an inpatient DBT program completed a quality assurance questionnaire set assessing demographic information and pretreatment psychopathology during the days of their inpatient stay. Beyond that, changes of therapists were documented. The predictor analyses were investigated with generalized estimating equations. RESULTS: The dropout rate was 24.7%. A change of therapist between DBT-briefing and treatment as well as high childhood emotional abuse was associated with premature termination of treatment. Higher values of physical neglect during childhood were associated with a protective effect on treatment dropout. Surprisingly, this was also true for comorbid PTSD. CONCLUSIONS: This study supports the importance of therapy process variables as predictors of therapy dropout in borderline pathology. A change of therapist between DBT-briefing and treatment was associated with an increased vulnerability for dropping out of treatment and should therefore be avoided if possible. Against our hypotheses, a comorbid PTSD was even protective with regard to DBT dropout. Therefore, this severely suffering patient group should not be rejected from treatment assuming them to be too unstable for psychotherapy. However, results need to be replicated. ClinicalTrials.gov Identifier: NCT03018639, retrospectively registered on January 9, 2017. PMID- 28649384 TI - Association between rapid serum sodium correction and rhabdomyolysis in water intoxication: a retrospective cohort study. AB - BACKGROUND: Patients with water intoxication may develop rhabdomyolysis. Existing studies suggest a relationship between the serum sodium correction rate and rhabdomyolysis. The aim of the present study was to determine the association between the sodium correction rate and rhabdomyolysis in patients with water intoxication. METHODS: Medical records from all cases of water intoxication presenting to the emergency department and admitted to a single tertiary emergency hospital between September 2012 and August 2016 were examined retrospectively. Serum sodium correction rate was defined as the difference in serum sodium levels at admission and approximately 24 h after admission, divided by time. The primary outcome was rhabdomyolysis, defined as peak creatine kinase level >= 1500 IU/L. Logistic regression analysis was used to calculate the adjusted odds ratio of the serum sodium correction rate controlling for age, sex, convulsion, lying down for >8 h before admission to the emergency department, and serum sodium level on admission. RESULTS: A total of 56 cases of water intoxication were included in the study. The median serum sodium correction rate was 1.02 mEq/L/h, and 32 patients (62.5%) had rhabdomyolysis. Logistic regression analysis showed that serum sodium correction rate was an independent risk factor of rhabdomyolysis (adjusted odds ratio, 1.53 per 0.1 mEq/L/h; 95% confidence interval, 1.18-1.97). CONCLUSIONS: Rapid correction of serum sodium was associated with rhabdomyolysis in patients with water intoxication. Therefore, strict control of serum sodium levels might be needed in such patients. PMID- 28649385 TI - The practice of tracheostomy decannulation-a systematic review. AB - Decannulation is an essential step towards liberating tracheostomized patients from mechanical ventilation. However, despite its perceived importance, there is no universally accepted protocol for this vital transition. Presence of an intact sensorium coordinated swallowing and protective coughing are often the minimum requirements for a successful decannulation. Objective criteria for each of these may help better the clinical judgement of decannulation. In this systematic review on decannulation, we focus attention to this important aspect of tracheostomy care. PMID- 28649386 TI - Erratum to: Biodegradation of total petroleum hydrocarbons from acidic sludge produced by re-refinery industries of waste oil using in-vessel composting. AB - [This corrects the article DOI: 10.1186/s40201-017-0267-1.]. PMID- 28649387 TI - Quality and quantity of construction and demolition waste in Tehran. AB - BACKGROUND: In recent years the generation rate of construction and demolition waste (C&D) has significantly augmented. The aim of this study was to assessed the quality and quantity of construction and demolition waste in Tehran (capital of Iran). METHODS: Questionnaire methods were used for estimating the amount of generated C&D wastes national statistical data and typical waste generation data. In order to defining the composition of C&D waste, trucks were randomly selected and their wastes were separated and weighted. RESULTS: According to obtained results, about 82,646,051 m3 of C&D waste (average 16,529,210 m3 per year) were generated during 2011 to 2016 which only about 26% of them has been recycled. Mixing sand and cement, concrete, broken bricks and soil have the highest amount of the composition of C&D waste in Tehran that was 30, 19, 18 and 11%, respectively. Based on the results, about 2,784,158 t of the waste will generate in 2025 and this is approximately 122% higher than wastes generate in 2016. Based on MAPSA's data, 360 teams of personnel cruise and control the illegal disposals, but due to the expansion of Tehran this number of teams is inadequate and can't be effective in controlling the situation. CONCLUSION: In general, the overall condition of C&D waste management in Tehran seems undesirable and needs to be updated based on the experience of successful countries in this field. PMID- 28649388 TI - Systemic sclerosis due to crystalline silica exposure among jewelry workers in Korea: two case reports. AB - BACKGROUND: Occupational exposure to crystalline silica is a potential risk factor for various systemic autoimmune diseases including systemic sclerosis. The etiology of systemic sclerosis is not conclusively known, but there are epidemiological studies that show the relationship between exposure to crystalline silica and risk of systemic sclerosis. Here we report, for the first time, two cases of crystalline silica-related systemic sclerosis in patients who worked in crystal processing in the jewelry-manufacturing field. CASE PRESENTATION: Case 1 is a 57-year-old man who had worked mainly in crystal processing for multiple jewelry-processing companies for 17 years, since the age of 15 years. He contracted tuberculosis at the age of 25 years and showed Raynaud's phenomenon of both the hands and feet at age 32 years. Digital cyanosis and sclerosis developed at approximately age 41 years. The patient was diagnosed with systemic sclerosis at age 48 years. Case 2 is a 52-year-old man who worked in crystal processing for various jewelry-processing companies for 7 years, since the age of 23 years. He first showed signs of cyanosis in the third and fourth digits of both hands at age 32 years, was diagnosed with Raynaud's syndrome at age 37 years, and was diagnosed with systemic sclerosis at age 38 years. Crystal processing is a detailed process that involves slabbing and trimming the selected amethyst and quartz crystals, which requires close proximity of the worker's face with the target area. In the 1980s and 1990s, the working hours were 12 h per day, and the working environment involved 15 workers crowded into a small, 70-m2 space with poor ventilation. CONCLUSION: Two workers who processed crystals with a maximum crystalline silica content of 56.66% developed systemic sclerosis. Considering the epidemiological and experimental evidence, exposure to crystalline silica dust was an important risk factor for systemic sclerosis. An active intervention is necessary to reduce exposure in similar exposure groups in the field of jewelry processing. PMID- 28649389 TI - Cases of acute mercury poisoning by mercury vapor exposure during the demolition of a fluorescent lamp factory. AB - BACKGROUND: In 2015, workers dismantling a fluorescent lamp factory in Korea were affected by mercury poisoning from exposure to mercury vapor. CASE PRESENTATION: Eighteen out of the 21 workers who participated in the demolition project presented with symptoms of poisoning and, of these, 10 had persistent symptoms even at 18 months after the initial exposure to mercury vapor. Early symptoms of 18 workers included a general skin rash, pruritus, myalgia, sleep disturbance, and cough and sputum production. Following alleviation of these initial symptoms, late symptoms, such as easy fatigue, insomnia, bad dreams, and anxiety disorder, began to manifest in 10 out of 18 patients. Seven workers underwent psychiatric care owing to sleep disturbance, anxiety disorder, and depression, and three workers underwent dermatologic treatment for hyperpigmentation, erythematous skin eruption, and chloracne-like skin lesions. Furthermore, three workers developed a coarse jerky movement, two had swan neck deformity of the fingers, and two received care at an anesthesiology clinic for paresthesia, such as burning sensation, cold sensation, and pain. Two workers underwent urologic treatment for dysfunction of the urologic system and impotence. However, symptomatic treatment did not result in satisfactory relief of these symptoms. CONCLUSION: Awareness of the perils of mercury and prevention of mercury exposure are critical for preventing health hazards caused by mercury vapor. Chelation therapy should be performed promptly following mercury poisoning to minimize damage. PMID- 28649390 TI - Erratum to: The current condition of the workers' general health examination in South Korea: a retrospective study. AB - [This corrects the article DOI: 10.1186/s40557-017-0157-0.]. PMID- 28649391 TI - Erratum to: Practice status of specialized agencies for occupational health management of small- to medium-size enterprises and the factors improving their performance: a cross-sectional survey study. AB - [This corrects the article DOI: 10.1186/s40557-017-0161-4.]. PMID- 28649392 TI - Blood cadmium and volume of uterine fibroids in premenopausal women. AB - BACKGROUND: A number of studies have found associations between heavy metals and uterine fibroids, but the results are inconsistent. Here, we conducted this research to demonstrate the relationships between blood heavy metal concentrations and uterine fibroid volume as well as the rate of uterine fibroid presence. METHODS: In a cross-sectional study, we collected data from 308 premenopausal women aged 30-49 years in Seoul; uterine fibroids are ascertained by past history of myomectomy and pelvic ultrasonography. In the analytic phase, we first analyzed the presence of the fibroids and the concentrations of heavy metals via logistic regression. In subgroup analysis, we used simple and multiple linear regression analyses to examine the associations between heavy metals and uterine fibroid volume. RESULTS: There was no connection between the heavy metal concentrations and the presence of uterine fibroids, but the odds of women having fibroids were higher with three particular metals. In subgroup analysis, the association between blood cadmium concentrations and uterine fibroid volume was statistically significant (adjusted beta coefficient = 2.22, 95% confidential interval: 0.06-4.37). In contrast, blood mercury and lead concentrations were not significantly associated with uterine fibroid volume. CONCLUSIONS: Our findings are the first that we know to report the association of blood cadmium concentrations with the volume of uterine fibroids. We expect that our findings will be used as evidence for supporting policies to improve premenopausal Korean women's health. PMID- 28649393 TI - Single-cell transcriptome of early embryos and cultured embryonic stem cells of cynomolgus monkeys. AB - In mammals, the development of pluripotency and specification of primordial germ cells (PGCs) have been studied predominantly using mice as a model organism. However, divergences among mammalian species for such processes have begun to be recognized. Between humans and mice, pre-implantation development appears relatively similar, but the manner and morphology of post-implantation development are significantly different. Nevertheless, the embryogenesis just after implantation in primates, including the specification of PGCs, has been unexplored due to the difficulties in analyzing the embryos at relevant developmental stages. Here, we present a comprehensive single-cell transcriptome dataset of pre- and early post-implantation embryo cells, PGCs and embryonic stem cells (ESCs) of cynomolgus monkeys as a model of higher primates. The identities of each transcriptome were also validated rigorously by other way such as immunofluorescent analysis. The information reported here will serve as a foundation for our understanding of a wide range of processes in the developmental biology of primates, including humans. PMID- 28649394 TI - Functional neuroimaging and chorea: a systematic review. AB - Chorea is a hyperkinetic movement disorder consisting of involuntary irregular, flowing movements of the trunk, neck or face. Although Huntington's disease is the most common cause of chorea in adults, chorea can also result from many other neurodegenerative, metabolic, and autoimmune conditions. While the pathophysiology of these different conditions is quite variable, recent advances in functional imaging have enabled the development of new methods for analysis of brain activity and neuronal dysfunction. In this paper we review the growing body of functional imaging data that has been performed in chorea syndromes and identify particular trends, which can be used to better understand the underlying network changes within the basal ganglia. While it can be challenging to identify whether changes are primary, secondary, or compensatory, identification of these trends can ultimately be useful in diagnostic testing and treatment in many of the conditions that cause chorea. PMID- 28649395 TI - Cellulose effects on morphology and elasticity of Vibrio fischeri biofilms. AB - Cellulose effects on Vibrio fischeri biofilm morphology were tested for the wild type and two of its isogenic mutants that either exhibit increased cellulose production or do not produce cellulose at all. Confocal laser scanning microscopy imaging of each biofilm revealed that total sessile volume increases with cellulose expression, but the size of colonies formed with cellulose was smaller, creating a more diffuse biofilm. These morphological differences were not attributed to variations in bacterial deposition, extracellular polymeric substances affinity to the surface or bacterial growth. A positive correlation was found between cellulose expression, Young's (elastic) modulus of the biofilm analyzed with atomic force microscope and shear modulus of the related extracellular polymeric substances layers analyzed with quartz crystal microbalance with dissipation monitoring. Cellulose production also correlated positively with concentrations of extracellular DNA. A significant negative correlation was observed between cellulose expression and rates of diffusion through the extracellular polymeric substances. The difference observed in biofilm morphology is suggested as a combined result of cellulose and likely extracellular DNA (i) increasing biofilm Young's modulus, making shear removal more difficult, and (ii) decreased diffusion rate of nutrients and wastes into and out of the biofilm, which effectively limits colony size. PMID- 28649396 TI - Eradication of Pseudomonas aeruginosa biofilms and persister cells using an electrochemical scaffold and enhanced antibiotic susceptibility. AB - Biofilms in chronic wounds are known to contain a persister subpopulation that exhibits enhanced multidrug tolerance and can quickly rebound after therapeutic treatment. The presence of these "persister cells" is partly responsible for the failure of antibiotic therapies and incomplete elimination of biofilms. Electrochemical methods combined with antibiotics have been suggested as an effective alternative for biofilm and persister cell elimination, yet the mechanism of action for improved antibiotic efficacy remains unclear. In this work, an electrochemical scaffold (e-scaffold) that electrochemically generates a constant concentration of H2O2 was investigated as a means of enhancing tobramycin susceptibility in pre-grown Pseudomonas aeruginosa PAO1 biofilms and attacking persister cells. Results showed that the e-scaffold enhanced tobramycin susceptibility in P. aeruginosa PAO1 biofilms, which reached a maximum susceptibility at 40 ug/ml tobramycin, with complete elimination (7.8-log reduction vs control biofilm cells, P <= 0.001). Moreover, the e-scaffold eradicated persister cells in biofilms, leaving no viable cells (5-log reduction vs control persister cells, P <= 0.001). It was observed that the e-scaffold induced the intracellular formation of hydroxyl free radicals and improved membrane permeability in e-scaffold treated biofilm cells, which possibly enhanced antibiotic susceptibility and eradicated persister cells. These results demonstrate a promising advantage of the e-scaffold in the treatment of persistent biofilm infections. PMID- 28649397 TI - Microbial biofilms and the human skin microbiome. AB - The human skin microbiome plays an important role in both health and disease. Microbial biofilms are a well-characterized mode of surface-associated growth, which present community-like behaviors. Additionally, biofilms are a critical element in certain skin diseases. We review how the perception of the resident skin microbiota has evolved from the early linkages of certain microbes to disease states, to a more comprehensive and intricate understanding brought on by biofilm and microbiome revelations. Rapidly expanding arsenals of experimental methods are opening new horizons in the study of human-microbe and microbe microbe interactions. Microbial community profiling has largely remained a separate discipline from that of biofilm research, yet the introduction of metatranscriptomics, metabolomics, and the ability to distinguish between dormant and active members of a community have all paved the road toward a convergent cognizance of the encounter between these two microbial disciplines. PMID- 28649399 TI - Revealing region-specific biofilm viscoelastic properties by means of a micro rheological approach. AB - Particle-tracking microrheology is an in situ technique that allows quantification of biofilm material properties. It overcomes the limitations of alternative techniques such as bulk rheology or force spectroscopy by providing data on region specific material properties at any required biofilm location and can be combined with confocal microscopy and associated structural analysis. This article describes single particle tracking microrheology combined with confocal laser scanning microscopy to resolve the biofilm structure in 3 dimensions and calculate the creep compliances locally. Samples were analysed from Pseudomonas fluorescens biofilms that were cultivated over two timescales (24 h and 48 h) and alternate ionic conditions (with and without calcium chloride supplementation). The region-based creep compliance analysis showed that the creep compliance of biofilm void zones is the primary contributor to biofilm mechanical properties, contributing to the overall viscoelastic character. PMID- 28649398 TI - Ecological networking of cystic fibrosis lung infections. AB - In the context of a polymicrobial infection, treating a specific pathogen poses challenges because of unknown consequences on other members of the community. The presence of ecological interactions between microbes can change their physiology and response to treatment. For example, in the cystic fibrosis lung polymicrobial infection, antimicrobial susceptibility testing on clinical isolates is often not predictive of antibiotic efficacy. Novel approaches are needed to identify the interrelationships within the microbial community to better predict treatment outcomes. Here we used an ecological networking approach on the cystic fibrosis lung microbiome characterized using 16S rRNA gene sequencing and metagenomics. This analysis showed that the community is separated into three interaction groups: Gram-positive anaerobes, Pseudomonas aeruginosa, and Staphylococcus aureus. The P. aeruginosa and S. aureus groups both anti-correlate with the anaerobic group, indicating a functional antagonism. When patients are clinically stable, these major groupings were also stable, however, during exacerbation, these communities fragment. Co-occurrence networking of functional modules annotated from metagenomics data supports that the underlying taxonomic structure is driven by differences in the core metabolism of the groups. Topological analysis of the functional network identified the non-mevalonate pathway of isoprenoid biosynthesis as a keystone for the microbial community, which can be targeted with the antibiotic fosmidomycin. This study uses ecological theory to identify novel treatment approaches against a polymicrobial disease with more predictable outcomes. PMID- 28649400 TI - Tracing back ancient oral microbiomes and oral pathogens using dental pulps from ancient teeth. AB - Ancient dental pulps are highly precious samples because they conserve DNA from humans and blood-borne pathogens for ages. However, little is known about the microbial communities present in dental pulps. Here, we analyzed ancient and modern dental pulp samples from different time periods and geographic regions and found that they are colonized by distinct microbial communities, which can be differentiated from other oral cavity samples. We found that despite the presence of environmental bacteria, ancient dental pulps conserve a clear and well conserved record of oral microbes. We were able to detect several different oral pathogens in ancient and modern dental pulps, which are commonly associated with periodontal diseases. We thus showed that ancient dental pulps are not only valuable sources of DNA from humans and systemic infections, but also an open window for the study of ancient oral microbiomes. PMID- 28649401 TI - Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients. AB - Coronary artery disease is an inflammatory disorder characterized by narrowing of coronary arteries due to atherosclerotic plaque formation. To date, the accumulated epidemiological evidence supports an association between oral bacterial diseases and coronary artery disease, but has failed to prove a causal link between the two. Due to the recent surge in microbial identification and analyses techniques, a number of bacteria have been independently found in atherosclerotic plaque samples from coronary artery disease patients. In this study, we present meta-analysis from published studies that have independently investigated the presence of bacteria within atherosclerotic plaque samples in coronary artery disease patients. Data were collated from 63 studies covering 1791 patients spread over a decade. Our analysis confirms the presence of 23 oral commensal bacteria, either individually or in co-existence, within atherosclerotic plaques in patients undergoing carotid endarterectomy, catheter based atherectomy, or similar procedures. Of these 23 bacteria, 5 (Campylobacter rectus, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, Prevotella nigrescens) are unique to coronary plaques, while the other 18 are additionally present in non-cardiac organs, and associate with over 30 non-cardiac disorders. We have cataloged the wide spectrum of proteins secreted by above atherosclerotic plaque-associated bacteria, and discuss their possible roles during microbial migration via the bloodstream. We also highlight the prevalence of specific poly-microbial communities within atherosclerotic plaques. This work provides a resource whose immediate implication is the necessity to systematically catalog landscapes of atherosclerotic plaque associated oral commensal bacteria in human patient populations. PMID- 28649402 TI - Evolutionary adaptations of biofilms infecting cystic fibrosis lungs promote mechanical toughness by adjusting polysaccharide production. AB - Biofilms are communities of microbes embedded in a matrix of extracellular polymeric substances, largely polysaccharides. Multiple types of extracellular polymeric substances can be produced by a single bacterial strain. The distinct polymer components of biofilms are known to provide chemical protection, but little is known about how distinct extracellular polysaccharides may also protect biofilms against mechanical stresses such as shear or phagocytic engulfment. Decades-long infections of Pseudomonas. aeruginosa biofilms in the lungs of cystic fibrosis patients are natural models for studies of biofilm fitness under pressure from antibiotics and the immune system. In cystic fibrosis infections, production of the extracellular polysaccharide alginate has long been known to increase with time and to chemically protect biofilms. More recently, it is being recognized that chronic cystic fibrosis infections also evolve to increase production of another extracellular polysaccharide, Psl; much less is known about Psl's protective benefits to biofilms. We use oscillatory bulk rheology, on biofilms grown from longitudinal clinical isolates and from genetically manipulated lab strains, to show that increased Psl stiffens biofilms and increases biofilm toughness, which is the energy cost to cause the biofilm to yield mechanically. Further, atomic force microscopy measurements reveal greater intercellular cohesion for higher Psl expression. Of the three types of extracellular polysaccharides produced by P. aeruginosa, only Psl increases the stiffness. Stiffening by Psl requires CdrA, a protein that binds to mannose groups on Psl and is a likely cross-linker for the Psl components of the biofilm matrix. We compare the elastic moduli of biofilms to the estimated stresses exerted by neutrophils during phagocytosis, and infer that increased Psl could confer a mechanical protection against phagocytic clearance. PMID- 28649403 TI - Inter-personal diversity and temporal dynamics of dental, tongue, and salivary microbiota in the healthy oral cavity. AB - Oral microbes form a complex and dynamic biofilm community, which is subjected to daily host and environmental challenges. Dysbiosis of the oral biofilm is correlated with local and distal infections and postulating a baseline for the healthy core oral microbiota provides an opportunity to examine such shifts during the onset and recurrence of disease. Here we quantified the daily, weekly, and monthly variability of the oral microbiome by sequencing the largest oral microbiota time-series to date, covering multiple oral sites in ten healthy individuals. Temporal dynamics of salivary, dental, and tongue consortia were examined by high-throughput 16S rRNA gene sequencing over 90 days, with four individuals sampled additionally 1 year later. Distinct communities were observed between dental, tongue, and salivary samples, with high levels of similarity observed between the tongue and salivary communities. Twenty-six core OTUs that classified within Streptococcus, Fusobacterium, Haemophilus, Neisseria, Prevotella, and Rothia genera were present in >=95% samples and accounted for ~65% of the total sequence data. Phylogenetic diversity varied from person to person, but remained relatively stable within individuals over time compared to inter-individual variation. In contrast, the composition of rare microorganisms was highly variable over time, within most individuals. Using machine learning, an individual's oral microbial assemblage could be correctly assigned to them with 88-97% accuracy, depending on the sample site; 83% of samples taken a year after initial sampling could be confidently traced back to the source subject. PMID- 28649404 TI - Comparative transcriptomic analysis of Gardnerella vaginalis biofilms vs. planktonic cultures using RNA-seq. AB - Bacterial vaginosis is the most common gynecological disorder affecting women of reproductive age. Bacterial vaginosis is frequently associated with the development of a Gardnerella vaginalis biofilm. Recent data indicates that G. vaginalis biofilms are more tolerant to antibiotics and are able to incorporate other bacterial vaginosis -associated species, yielding a multi-species biofilm. However, despite its apparent role in bacterial vaginosis, little is known regarding the molecular determinants involved in biofilm formation by G. vaginalis. To gain insight into the role of G. vaginalis in the pathogenesis of bacterial vaginosis, we carried out comparative transcriptomic analysis between planktonic and biofilm phenotypes, using RNA-sequencing. Significant differences were found in the expression levels of 815 genes. A detailed analysis of the results obtained was performed based on direct and functional gene interactions. Similar to other bacterial species, expression of genes involved in antimicrobial resistance were elevated in biofilm cells. In addition, our data indicate that G. vaginalis biofilms assume a characteristic response to stress and starvation conditions. The abundance of transcripts encoding proteins involved in glucose and carbon metabolism was reduced in biofilms. Surprisingly, transcript levels of vaginolysin were reduced in biofilms relative to planktonic cultures. Overall, our data revealed that gene-regulated processes in G. vaginalis biofilms resulted in a protected form of bacterial growth, characterized by low metabolic activity. This phenotype may contribute towards the chronic and recurrent nature of bacterial vaginosis. This suggests that G. vaginalis is capable of drastically adjusting its phenotype through an extensive change of gene expression. PMID- 28649405 TI - Bacillus subtilis biofilm development in the presence of soil clay minerals and iron oxides. AB - Clay minerals and metal oxides, as important parts of the soil matrix, play crucial roles in the development of microbial communities. However, the mechanism underlying such a process, particularly on the formation of soil biofilm, remains poorly understood. Here, we investigated the effects of montmorillonite, kaolinite, and goethite on the biofilm formation of the representative soil bacteria Bacillus subtilis. The bacterial biofilm formation in goethite was found to be impaired in the initial 24 h but burst at 48 h in the liquid-air interface. Confocal laser scanning microscopy showed that the biofilm biomass in goethite was 3-16 times that of the control, montmorillonite, and kaolinite at 48 h. Live/Dead staining showed that cells had the highest death rate of 60% after 4 h of contact with goethite, followed by kaolinite and montmorillonite. Atomic force microscopy showed that the interaction between goethite and bacteria may injure bacterial cells by puncturing cell wall, leading to the swarming of bacteria toward the liquid-air interface. Additionally, the expressions of abrB and sinR, key players in regulating the biofilm formation, were upregulated at 24 h and downregulated at 48 h in goethite, indicating the initial adaptation of the cells to minerals. A model was proposed to describe the effects of goethite on the biofilm formation. Our findings may facilitate a better understanding of the roles of soil clays in biofilm development and the manipulation of bacterial compositions through controlling the biofilm in soils. PMID- 28649406 TI - Architecture, component, and microbiome of biofilm involved in the fouling of membrane bioreactors. AB - Biofilm formation on the filtration membrane and the subsequent clogging of membrane pores (called biofouling) is one of the most persistent problems in membrane bioreactors for wastewater treatment and reclamation. Here, we investigated the structure and microbiome of fouling-related biofilms in the membrane bioreactor using non-destructive confocal reflection microscopy and high throughput Illumina sequencing of 16S rRNA genes. Direct confocal reflection microscopy indicated that the thin biofilms were formed and maintained regardless of the increasing transmembrane pressure, which is a common indicator of membrane fouling, at low organic-loading rates. Their solid components were primarily extracellular polysaccharides and microbial cells. In contrast, high organic loading rates resulted in a rapid increase in the transmembrane pressure and the development of the thick biofilms mainly composed of extracellular lipids. High throughput sequencing revealed that the biofilm microbiomes, including major and minor microorganisms, substantially changed in response to the organic-loading rates and biofilm development. These results demonstrated for the first time that the architectures, chemical components, and microbiomes of the biofilms on fouled membranes were tightly associated with one another and differed considerably depending on the organic-loading conditions in the membrane bioreactor, emphasizing the significance of alternative indicators other than the transmembrane pressure for membrane biofouling. PMID- 28649407 TI - Biofilm disruption by an air bubble reveals heterogeneous age-dependent detachment patterns dictated by initial extracellular matrix distribution. AB - Bacteria often adhere to surfaces, where they form communities known as biofilms. Recently, it has been shown that biofilm formation initiates with the microscopically heterogeneous deposition of a skeleton of extracellular polymeric substances (EPS) by individual cells crawling on the surface, followed by growth of the biofilm into a surface-covering continuum. Here we report microfluidic experiments with Pseudomonas aeruginosa biofilms showing that their "hidden" heterogeneity can affect the later dynamics of their disruption. Using controlled air bubbles as a model for mechanical insult, we demonstrate that biofilm disruption is strongly dependent on biofilm age, and that disruption to early stage biofilms can take the shape of a semi-regular pattern of ~15 um diameter holes from which bacteria have been removed. We explain hole formation in terms of the rupture and retreat of the thin liquid layer created by the long bubble, which scrapes bacteria off the surface and rearranges their distribution. We find that the resulting pattern correlates with the spatial distribution of EPS: holes form where there is less EPS, whereas regions with more EPS act as strongholds against the scraping liquid front. These results show that heterogeneity in the microscale EPS skeleton of biofilms has profound consequences for later dynamics, including disruption. Because few attached cells suffice to regrow a biofilm, these results point to the importance of considering microscale heterogeneity when designing and assessing the effectiveness of biofilm removal strategies by mechanical forces. PMID- 28649408 TI - Ser/Thr protein kinase PrkC-mediated regulation of GroEL is critical for biofilm formation in Bacillus anthracis. AB - PrkC is a conserved Ser/Thr protein kinase encoded in Bacillus anthracis genome. PrkC is shown to be important for B. anthracis pathogenesis, but little is known about its other functions and phosphorylated substrates. Systemic analyses indicate the compelling role of PrkC in phosphorylating multiple substrates, including the essential chaperone GroEL. Through mass spectrometry, we identified that PrkC phosphorylates GroEL on six threonine residues that are distributed in three canonical regions. Phosphorylation facilitates the oligomerization of GroEL to the physiologically active tetradecameric state and increases its affinity toward the co-chaperone GroES. Deletion of prkC in B. anthracis abrogates its ability to form biofilm. Overexpression of native GroEL recovers the biofilm forming ability of prkC deletion strain. Similar overexpression of GroEL phosphorylation site mutants (Thr to Ala) does not augment biofilm formation. Further analyses indicate the phosphorylation of GroEL in diverse bacterial species. Thus, our results suggest that PrkC regulates biofilm formation by modulating the GroEL activity in a phosphorylation-dependent manner. The study deciphers the molecular signaling events that are important for biofilm formation in B. anthracis. PMID- 28649409 TI - Bacillus subtilis utilizes the DNA damage response to manage multicellular development. AB - Bacteria switch between free-living and a multicellular state, known as biofilms, in response to cellular and environmental cues. It is important to understand how these cues influence biofilm development as biofilms are not only ubiquitous in nature but are also causative agents of infectious diseases. It is often believed that any stress triggers biofilm formation as a means of bacterial protection. In this study, we propose a new mechanism for how cellular and environmental DNA damage may influence biofilm formation. We demonstrate that Bacillus subtilis prevents biofilm formation and cell differentiation when stressed by oxidative DNA damage. We show that during B. subtilis biofilm development, a subpopulation of cells accumulates reactive oxygen species, which triggers the DNA damage response. Surprisingly, DNA damage response induction shuts off matrix genes whose products permit individual cells to stick together within a biofilm. We further revealed that DDRON cells and matrix producers are mutually exclusive and spatially separated within the biofilm, and that a developmental checkpoint protein, Sda, mediates the exclusiveness. We believe this represents an alternative survival strategy, ultimately allowing cells to escape the multicellular community when in danger. PMID- 28649410 TI - Komodo dragon-inspired synthetic peptide DRGN-1 promotes wound-healing of a mixed biofilm infected wound. AB - Cationic antimicrobial peptides are multifunctional molecules that have a high potential as therapeutic agents. We have identified a histone H1-derived peptide from the Komodo dragon (Varanus komodoensis), called VK25. Using this peptide as inspiration, we designed a synthetic peptide called DRGN-1. We evaluated the antimicrobial and anti-biofilm activity of both peptides against Pseudomonas aeruginosa and Staphylococcus aureus. DRGN-1, more than VK25, exhibited potent antimicrobial and anti-biofilm activity, and permeabilized bacterial membranes. Wound healing was significantly enhanced by DRGN-1 in both uninfected and mixed biofilm (Pseudomonas aeruginosa and Staphylococcus aureus)-infected murine wounds. In a scratch wound closure assay used to elucidate the wound healing mechanism, the peptide promoted the migration of HEKa keratinocyte cells, which was inhibited by mitomycin C (proliferation inhibitor) and AG1478 (epidermal growth factor receptor inhibitor). DRGN-1 also activated the EGFR-STAT1/3 pathway. Thus, DRGN-1 is a candidate for use as a topical wound treatment. Wound infections are a major concern; made increasingly complicated by the emerging, rapid spread of bacterial resistance. The novel synthetic peptide DRGN-1 (inspired by a peptide identified from Komodo dragon) exhibits pathogen-directed and host-directed activities in promoting the clearance and healing of polymicrobial (Pseudomonas aeruginosa & Staphylococcus aureus) biofilm infected wounds. The effectiveness of this peptide cannot be attributed solely to its ability to act upon the bacteria and disrupt the biofilm, but also reflects the peptide's ability to promsote keratinocyte migration. When applied in a murine model, infected wounds treated with DRGN-1 healed significantly faster than did untreated wounds, or wounds treated with other peptides. The host-directed mechanism of action was determined to be via the EGFR-STAT1/3 pathway. The pathogen-directed mechanism of action was determined to be via anti-biofilm activity and antibacterial activity through membrane permeabilization. This novel peptide may have potential as a future therapeutic for treating infected wounds. PMID- 28649411 TI - The microbiome of glaciers and ice sheets. AB - Glaciers and ice sheets, like other biomes, occupy a significant area of the planet and harbour biological communities with distinct interactions and feedbacks with their physical and chemical environment. In the case of the glacial biome, the biological processes are dominated almost exclusively by microbial communities. Habitats on glaciers and ice sheets with enough liquid water to sustain microbial activity include snow, surface ice, cryoconite holes, englacial systems and the interface between ice and overridden rock/soil. There is a remarkable similarity between the different specific glacial habitats across glaciers and ice sheets worldwide, particularly regarding their main primary producers and ecosystem engineers. At the surface, cyanobacteria dominate the carbon production in aquatic/sediment systems such as cryoconite holes, while eukaryotic Zygnematales and Chlamydomonadales dominate ice surfaces and snow dynamics, respectively. Microbially driven chemolithotrophic processes associated with sulphur and iron cycle and C transformations in subglacial ecosystems provide the basis for chemical transformations at the rock interface under the ice that underpin an important mechanism for the delivery of nutrients to downstream ecosystems. In this review, we focus on the main ecosystem engineers of glaciers and ice sheets and how they interact with their chemical and physical environment. We then discuss the implications of this microbial activity on the icy microbiome to the biogeochemistry of downstream ecosystems. PMID- 28649412 TI - Surface topology affects wetting behavior of Bacillus subtilis biofilms. AB - The colonization of surfaces by bacterial biofilms constitutes a huge problem in healthcare and industry. When attempting biofilm inactivation or removal, it is crucial to sufficiently wet the biofilm surface with antibacterial agents; however, certain biofilms efficiently resist wetting, and the origin of this behavior remains to date unclear. Here, we demonstrate that, depending on the growth medium used, the model bacterium Bacillus subtilis can form biofilm colonies with distinct surface properties: we find either hydrophilic or two variants of hydrophobic behavior. We show that those differences in biofilm wetting correlate with distinct surface topologies which, in turn, give rise to different physical wetting regimes known from lotus leaves or rose petals. Forming biofilms with different wetting properties may help bacteria to survive in both arid and humid conditions. Furthermore, converting the surface polarity of a biofilm could facilitate their removal from surfaces by increasing their wettability. PMID- 28649413 TI - Identification of donor microbe species that colonize and persist long term in the recipient after fecal transplant for recurrent Clostridium difficile. AB - Fecal microbiota transplantation has been shown to be an effective treatment for patients with recurrent C. difficile colitis. Although fecal microbiota transplantation helps to re-establish a normal gut function in patients, the extent of the repopulation of the recipient microbial community varies. To further understand this variation, it is important to determine the fate of donor microbes in the patients following fecal microbiota transplantation. We have developed a new method that utilizes the unique single nucleotide variants of gut microbes to accurately identify microbes in paired fecal samples from the same individual taken at different times. Using this method, we identified transplant donor microbes in seven recipients 3-6 months after fecal microbiota transplantation; in two of these fecal microbiota transplantation, we were able to identify donor microbes that persist in recipients up to 2 years post-fecal microbiota transplantation. Our study provides new insights into the dynamics of the reconstitution of the gastrointestinal microbe community structure following fecal microbiota transplantation. PMID- 28649414 TI - Characterisation and comparison of bacterial communities on reverse osmosis membranes of a full-scale desalination plant by bacterial 16S rRNA gene metabarcoding. AB - Microbiomes of full-scale seawater reverse osmosis membranes are complex and subject to variation within and between membrane units. The pre-existing bacterial communities of unused membranes before operation have been largely ignored in biofouling studies. This study is novel as unused membranes were used as a critical benchmark for comparison. Fouled seawater reverse osmosis membrane biofilm communities from an array of autopsied membrane samples, following a 7 year operational life-span in a full-scale desalination plant in Western Australia, were characterised by 16S rRNA gene metabarcoding using the bacterial primers 515F and 806R. Communities were then compared based on fouling severity and sampling location. Microbiomes of proteobacterial predominance were detected on control unused membranes. However, fouled membrane communities differed significantly from those on unused membranes, reflecting that operational conditions select specific bacteria on the membrane surface. On fouled membranes, Proteobacteria were also predominant but families differed from those on unused membranes, followed by Bacteriodetes and Firmicutes. Betaproteobacteria correlated with stable, mature and thick biofilms such as those in severely fouled membranes or samples from the feed end of the membrane unit, while Alpha and Gammaproteobacteria were predominantly found in biofilms on fouled but visually clean, and moderately fouled samples or those from reject ends of membrane units. Gammaproteobacteria predominated the thin, compact biofilms at the mid-feed end of membrane units. The study also supported the importance of Caulobacterales and glycosphingolipid-producing bacteria, namely Sphingomonadales, Rhizobiales and Sphingobacteriia, in primary attachment and biofilm recalcitrance. Nitrate-and-nitrite-reducing bacteria such as Rhizobiales, Burkholderiales and some Pseudomonadales were also prevalent across all fouled membranes and appeared to be critical for ecological balance and biofilm maturation. PMID- 28649416 TI - Educational intervention to reduce disease related to sub-optimal basic hygiene in Rwanda: initial evaluation and feasibility study. AB - BACKGROUND: Despite a global reduction in morbidity related to sub-optimal water, sanitation and hygiene, the incidence of such diseases remains a significant problem in sub-Saharan Africa. This study aimed to initially assess the potential effectiveness (primarily in terms of impact on morbidity) of a simple educational intervention delivered in Rwanda. Additionally, we sought to explore feasibility relating to the practicality of evaluating and implementing this type of intervention in a low- and middle-income country. METHODS: Two districts in Northern Province were purposively selected; one was randomly allocated to receive the intervention, with the other acting as control. The intervention was based on an interactive DVD about basic hygiene. Baseline and follow-up data for incident cases of relevant morbidities were collected from health centre records. Changes were compared between the two districts using descriptive statistics and chi-squared tests. Qualitative data were obtained through observations, discussions and feedback and were analysed thematically. RESULTS: Cases of infection with intestinal worms and parasites were frequently recorded in both districts. For these morbidities, there was a 39% decrease in cases between baseline and follow-up in the intervention district (4995 reduced to 3069), compared to 13% (5002 reduced to 4356) in the control district (p < 0.001). Numbers of cases recorded as diarrhoea or dysentery, and changes between baseline and follow-up, were much lower (intervention district 1274 cases reduced to 1171; control district 1949 reduced to 1944). Qualitative data indicated a high level of acceptability for the intervention and also feasibility relating to the practicality of evaluation and implementation, whilst also highlighting problems encountered and possible solutions, in particular, the potential advantages of training local personnel to deliver this type of intervention. CONCLUSIONS: This small-scale study has a number of acknowledged limitations which would need to be addressed in a larger study in order to confidently confirm the effectiveness of the intervention. It nevertheless provides evidence suggesting that the educational intervention is promising in terms of a potential impact on health and feasible to deliver and evaluate. These findings indicate that further evaluation and possibly early implementation are warranted. TRIAL REGISTRATION: Research Registry, researchregistry2180. PMID- 28649415 TI - Unexplored diversity and strain-level structure of the skin microbiome associated with psoriasis. AB - Psoriasis is an immune-mediated inflammatory skin disease that has been associated with cutaneous microbial dysbiosis by culture-dependent investigations and rRNA community profiling. We applied, for the first time, high-resolution shotgun metagenomics to characterise the microbiome of psoriatic and unaffected skin from 28 individuals. We demonstrate psoriatic ear sites have a decreased diversity and psoriasis is associated with an increase in Staphylococcus, but overall the microbiomes of psoriatic and unaffected sites display few discriminative features at the species level. Finer strain-level analysis reveals strain heterogeneity colonisation and functional variability providing the intriguing hypothesis of psoriatic niche-specific strain adaptation or selection. Furthermore, we accessed the poorly characterised, but abundant, clades with limited sequence information in public databases, including uncharacterised Malassezia spp. These results highlight the skins hidden diversity and suggests strain-level variations could be key determinants of the psoriatic microbiome. This illustrates the need for high-resolution analyses, particularly when identifying therapeutic targets. This work provides a baseline for microbiome studies in relation to the pathogenesis of psoriasis. PMID- 28649417 TI - Pilot study of a randomized trial to evaluate a Web-based intervention targeting adolescents presenting to the emergency department with acute asthma. AB - BACKGROUND: Low-income African-American adolescents use preventive medical services less frequently than their White counterparts, indicating a need for effective interventions targeting this group. Puff City is a Web-based, asthma management program for urban adolescents that has been evaluated in high school settings with promising results. The objective of this pilot was to assess the feasibility of initiating Puff City (treatment) in an emergency department setting, thereby informing the conduct of an individual randomized trial to evaluate its effectiveness compared to a generic, Web-based program (control) in preventing subsequent emergency department (ED) visits. METHODS: Teens aged 13-19 years presenting with acute asthma to two urban EDs within the study period were eligible. Subsequent ED visits were collected using the electronic medical record. A priori indication of a potential intervention effect was p < 0.20. RESULTS: Of the 121 teens randomized (65 treatment, 56 control), 86.0% were African-American and 44.6% male, with the mean age = 15.4 years. Computer ownership was reported by 76.8% of teens. Overall, 64.5% of teens completed >3 of 4 sessions and 90% completed the 12-month survey. At 12 months, the treatment group showed a trend toward fewer ED visits than controls (33.8 versus 46.4%), p = 0.15. CONCLUSIONS: Results indicate the feasibility of enrolling at-risk adolescents in ED settings and set the stage for a large, pragmatic trial using a technology-based intervention to reduce the burden of pediatric asthma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01695031. PMID- 28649418 TI - Facilitating access to health research through a participatory research register: a feasibility study in outpatient clinics. AB - BACKGROUND: A research register (Reach West) has been established to facilitate recruitment of people and patients to health-related research. We conducted a prospective feasibility study to investigate the practicality of recruiting through outpatient clinics. METHODS: Patients over 18 years of age attending dental, eye or oncology outpatient clinics in an acute hospital in the West of England were provided with the opportunity to participate in Reach West. In Phase I, recruitment packs were handed to clinic attendees who could place completed consent forms in secure drop-box or return them later on-line or by post. In Phase II, recruitment packs were posted directly to patients with consent forms to be returned by post or on-line. Response rates by age, sex, postcode (for level of deprivation), and clinic type were recorded for those agreeing to participate on paper or on-line. RESULTS: In Phase I, 2,314 of 4,500 (51.4%) of recruitment packs were handed out to clinic attendees, and 114 (5%) consented to join Reach West. In Phase II, 7,173 of 9000 packs were posted (79.7%), and 387 (5.4%) consented to participate. The overall consent rate was 6% (580), with the majority doing so on paper (87%) rather than on-line. The sample was balanced by sex, but mostly comprised people over 50 years located in less deprived postcodes. Non-staff costs for postal recruitment were lower than hand-outs in clinic (L6.84 compared with L8.05 per participant). CONCLUSIONS: Recruiting participants to the Reach West register was feasible among those with oncology, dental or eye outpatient appointments by post or with packs given out in the clinic. Response rates were similar to those achieved for other registers. Recruitment of participants can be achieved through outpatient clinics but other strategies will also be required to attract large numbers of participants and more diverse populations. PMID- 28649421 TI - Message from the new Co-Editor-in-Chief. PMID- 28649419 TI - Identification of transcription factors that promote the differentiation of human pluripotent stem cells into lacrimal gland epithelium-like cells. AB - Dry eye disease is the most prevalent pathological condition in aging eyes. One potential therapeutic strategy is the transplantation of lacrimal glands, generated in vitro from pluripotent stem cells such as human embryonic stem cells, into patients. One of the preceding requirements is a method to differentiate human embryonic stem cells into lacrimal gland epithelium cells. As the first step for this approach, this study aims to identify a set of transcription factors whose overexpression can promote the differentiation of human embryonic stem cells into lacrimal gland epithelium-like cells. We performed microarray analyses of lacrimal glands and lacrimal glands-related organs obtained from mouse embryos and adults, and identified transcription factors enriched in lacrimal gland epithelium cells. We then transfected synthetic messenger RNAs encoding human orthologues of these transcription factors into human embryonic stem cells and examined whether the human embryonic stem cells differentiate into lacrimal gland epithelium-like cells by assessing cell morphology and marker gene expression. The microarray analysis of lacrimal glands tissues identified 16 transcription factors that were enriched in lacrimal gland epithelium cells. We focused on three of the transcription factors, because they are expressed in other glands such as salivary glands and are also known to be involved in the development of lacrimal glands. We tested the overexpression of various combinations of the three transcription factors and PAX6, which is an indispensable gene for lacrimal glands development, in human embryonic stem cells. Combining PAX6, SIX1, and FOXC1 caused significant changes in morphology, i.e., elongated cell shape and increased expression (both RNAs and proteins) of epithelial markers such as cytokeratin15, branching morphogenesis markers such as BARX2, and lacrimal glands markers such as aquaporin5 and lactoferrin. We identified a set of transcription factors enriched in lacrimal gland epithelium cells and demonstrated that the simultaneous overexpression of these transcription factors can differentiate human embryonic stem cells into lacrimal gland epithelium-like cells. This study suggests the possibility of lacrimal glands regeneration from human pluripotent stem cells. PMID- 28649420 TI - Functionally and morphologically damaged mitochondria observed in auditory cells under senescence-inducing stress. AB - We aimed at determining the mitochondrial function in premature senescence model of auditory cells. Short exposure to H2O2 (1 h, 0.1 mM) induced premature cellular senescence in House Ear Institute-Organ of Corti 1 auditory cells. The transmission electron microscopy analysis revealed that damaged mitochondria and autophagosomes containing dense organelles appeared in the auditory cells after short exposure to H2O2. The branch and junction parameters of the skeletonized image of the mitochondria were found to decrease significantly in H2O2-treated cells. A branched reticulum of tubules was poorly formed, featuring coexistence of numerous tiny clusters along with few relatively large entities in the H2O2 treated cells. In terms of bioenergetics, H2O2-treatment led to the dose dependent decrease in mitochondrial membrane potential in the auditory cells. The fragmented mitochondria (fusion < fission) were in a low potential. In addition, the potential of hyperfused mitochondria (fusion > fission) was slightly lower than the control cells. The short-time exposure of live auditory cells to H2O2 damaged the mitochondrial respiratory capacity without any effect on the baseline ATP production rates. The vulnerability of the mitochondrial membrane potential to the uncoupling reagent was increased after H2O2 treatment. Our findings indicated that the mitochondrial dysfunction due to the decline in the O2 consumption rate should be the first event of premature senescence process in the auditory cells, resulting in the imbalance of mitochondrial fusion/fission and the collapse of the mitochondrial network. PMID- 28649422 TI - Both overlapping and independent mechanisms determine how diet and insulin-ligand knockouts extend lifespan of Drosophila melanogaster. AB - Lifespan in many organisms, including Drosophila melanogaster, can be increased by reduced insulin-IGF-like signaling (IIS) or by changes in diet. Most studies testing whether IIS is involved in diet-mediated lifespan extension employ only a few diets, but recent data shows that a broad range of nutritional environments is required. Here, we present lifespan data of long-lived Drosophila, lacking three of the eight insulin-like peptides [Drosophila insulin-like peptides 2,3,5 (dilp2-3,5)] on nine different diets that surround the optimum for lifespan. Their nutritional content was varied by manipulating sugar and yeast concentrations independently, and thus incorporated changes in both diet restriction and nutrient balance. The mutants were substantially longer-lived than controls on every diet, but the effects on the lifespan response to sugar and yeast differed. Our data illustrates how a greater coverage of diet balance (DB) and restriction can unify differing interpretations of how IIS might be involved in the response of lifespan to diet. PMID- 28649423 TI - Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span. AB - Mechanisms that ensure and maintain the stability of genetic information are fundamentally important for organismal function and can have a large impact on disease, aging, and life span. While a multi-layered cellular apparatus exists to detect and respond to DNA damage, various insults from environmental and endogenous sources continuously affect DNA integrity. Over time this can lead to the accumulation of somatic mutations, which is thought to be one of the major causes of aging. We have previously found that overexpression of the essential human DNA repair and splicing factor SNEV, also called PRP19 or hPso4, extends replicative life span of cultured human endothelial cells and impedes accumulation of DNA damage. Here, we show that adult-specific overexpression of dPrp19, the D. melanogaster ortholog of human SNEV/PRP19/hPso4, robustly extends life span in female fruit flies. This increase in life span is accompanied by reduced levels of DNA damage and improved resistance to oxidative and genotoxic stress. Our findings suggest that dPrp19 plays an evolutionarily conserved role in aging, life span modulation and stress resistance, and support the notion that superior DNA maintenance is key to longevity. PMID- 28649424 TI - An alanine expanded PABPN1 causes increased utilization of intronic polyadenylation sites. AB - In eukaryote genomes, the polyadenylation site marks termination of mature RNA transcripts by a poly-adenine tail. The polyadenylation site is recognized by a dynamic protein complex, among which the poly-adenine-binding protein nuclear1 plays a key role. Reduced poly-adenine-binding protein nuclear1 levels are found in aged muscles and are even lower in oculopharyngeal muscular dystrophy patients. Oculopharyngeal muscular dystrophy is a rare, late onset autosomal dominant myopathy, and is caused by an alanine expansion mutation in poly-adenine binding protein nuclear1. Mutant poly-adenine-binding protein nuclear1 forms insoluble nuclear aggregates leading to depletion of functional poly-adenine binding protein nuclear1 levels. In oculopharyngeal muscular dystrophy models, increased utilization of proximal polyadenylation sites has been observed in tandem 3'-untranslated regions, and most often cause gene upregulation. However, global alterations in expression profiles canonly partly be explained by polyadenylation site switches within the most distal 3'-untranslated region. Most poly-adenine signals are found at the distal 3'-untranslated region, but a significant part is also found in internal gene regions, like introns, exons, and internal 3'-untranslated regions. Here, we investigated poly-adenine-binding protein nuclear1's role in polyadenylation site utilization in internal gene regions. In the quadriceps muscle of oculopharyngeal muscular dystrophy mice expressing expPABPN1 we found significant polyadenylation site switches between gene regions in 17% of genes with polyadenylation site in multiple regions (N = 574; 5% False Discovery Rate). Polyadenylation site switches between gene regions were associated with differences in transcript expression levels and alterations in open reading frames. Transcripts ending at internal polyadenylation site were confirmed in tibialis anterior muscles from the same mice and in mouse muscle cell cultures overexpressing expPABPN1. The polyadenylation site switches were associated with nuclear accumulation of full-length transcripts. Our results provide further insights into the diverse roles of poly-adenine-binding protein nuclear1 in the post-transcriptional control of muscle gene expression and its relevance for oculopharyngeal muscular dystrophy pathology and muscle aging. PMID- 28649425 TI - Opposing activities of oncogenic MIR17HG and tumor suppressive MIR100HG clusters and their gene targets regulate replicative senescence in human adult stem cells. AB - Growing evidence suggests that many diseases of aging, including diseases associated with robust changes and adipose deports, may be caused by resident adult stem cell exhaustion due to the process called cellular senescence. Understanding how microRNA pathways can regulate cellular senescence is crucial for the development of novel diagnostic and therapeutic strategies to combat these pathologies. Herein, using integrated transcriptomic and semi-quantitative proteomic analysis, we provide a system level view of the regulation of human adipose-derived stem cell senescence by a subset of mature microRNAs (termed senescence-associated-microRNAs) produced by biogenesis of oncogenic MIR17HG and tumor-suppressive MIR100HG clusters. We demonstrate functional significance of these mature senescence-associated-microRNAs in the process of replicative senescence of human adipose-derived stem cells ex-vivo and define a set of senescence-associated-microRNA gene targets that are able to elicit, modulate and, most importantly, balance intimate connections between oncogenic and senescent events. PMID- 28649426 TI - Conserved and species-specific molecular denominators in mammalian skeletal muscle aging. AB - Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process. PMID- 28649427 TI - Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies. AB - Mammals receive light information through the eyes, which perform two major functions: image forming vision to see objects and non-image forming adaptation of physiology and behavior to light. Cone and rod photoreceptors form images and send the information via retinal ganglion cells to the brain for image reconstruction. In contrast, nonimage-forming photoresponses vary widely from adjustment of pupil diameter to adaptation of the circadian clock. nonimage forming responses are mediated by retinal ganglion cells expressing the photopigment melanopsin. Melanopsin-expressing cells constitute 1-2% of retinal ganglion cells in the adult mammalian retina, are intrinsically photosensitive, and integrate photic information from rods and cones to control nonimage-forming adaptation. Action spectra of ipRGCs and of melanopsin photopigment peak around 480 nm blue light. Understanding melanopsin function lets us recognize considerable physiological effects of blue light, which is increasingly important in our modern society that uses light-emitting diode. Misalignment of circadian rhythmicity is observed in numerous conditions, including aging, and is thought to be involved in the development of age-related disorders, such as depression, diabetes, hypertension, obesity, and cancer. The appropriate regulation of circadian rhythmicity by proper lighting is therefore essential. This perspective introduces the potential risks of excessive blue light for human health through circadian rhythm disruption and sleep deprivation. Knowing the positive and negative aspects, this study claims the importance of being exposed to light at optimal times and intensities during the day, based on the concept of the circadian clock, ultimately to improve quality of life to have a healthy and longer life. PMID- 28649428 TI - The UK ME/CFS Biobank for biomedical research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis. AB - The UK ME/CFS Biobank was launched in August 2011 following extensive consultation with professionals and patient representatives. The bioresource aims to enhance research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), related to pathophysiology, biomarkers and therapeutic approaches. The cohort includes 18-60 year olds, encompassing 284 clinically-confirmed ME/CFS cases, 60 neurologist-diagnosed multiple sclerosis (MS) cases, and 135 healthy individuals. The Biobank contains blood samples, aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA (totalling 29,863 aliquots). Extensive dataset (700 clinical and socio-demographic variables/participant) enables comprehensive phenotyping. Potential reuse is conditional to ethical approval. PMID- 28649429 TI - HD Physiology Project-Japanese efforts to promote multilevel integrative systems biology and physiome research. AB - The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research. PMID- 28649430 TI - Predicting growth of the healthy infant using a genome scale metabolic model. AB - An estimated 165 million children globally have stunted growth, and extensive growth data are available. Genome scale metabolic models allow the simulation of molecular flux over each metabolic enzyme, and are well adapted to analyze biological systems. We used a human genome scale metabolic model to simulate the mechanisms of growth and integrate data about breast-milk intake and composition with the infant's biomass and energy expenditure of major organs. The model predicted daily metabolic fluxes from birth to age 6 months, and accurately reproduced standard growth curves and changes in body composition. The model corroborates the finding that essential amino and fatty acids do not limit growth, but that energy is the main growth limiting factor. Disruptions to the supply and demand of energy markedly affected the predicted growth, indicating that elevated energy expenditure may be detrimental. The model was used to simulate the metabolic effect of mineral deficiencies, and showed the greatest growth reduction for deficiencies in copper, iron, and magnesium ions which affect energy production through oxidative phosphorylation. The model and simulation method were integrated to a platform and shared with the research community. The growth model constitutes another step towards the complete representation of human metabolism, and may further help improve the understanding of the mechanisms underlying stunting. PMID- 28649431 TI - Meta-analysis of host response networks identifies a common core in tuberculosis. AB - Tuberculosis remains a major global health challenge worldwide, causing more than a million deaths annually. To determine newer methods for detecting and combating the disease, it is necessary to characterise global host responses to infection. Several high throughput omics studies have provided a rich resource including a list of several genes differentially regulated in tuberculosis. An integrated analysis of these studies is necessary to identify a unified response to the infection. Such data integration is met with several challenges owing to platform dependency, patient heterogeneity, and variability in the extent of infection, resulting in little overlap among different datasets. Network-based approaches offer newer alternatives to integrate and compare diverse data. In this study, we describe a meta-analysis of host's whole blood transcriptomic profiles that were integrated into a genome-scale protein-protein interaction network to generate response networks in active tuberculosis, and monitor their behaviour over treatment. We report the emergence of a highly active common core in disease, showing partial reversals upon treatment. The core comprises 380 genes in which STAT1, phospholipid scramblase 1 (PLSCR1), C1QB, OAS1, GBP2 and PSMB9 are prominent hubs. This network captures the interplay between several biological processes including pro-inflammatory responses, apoptosis, complement signalling, cytoskeletal rearrangement, and enhanced cytokine and chemokine signalling. The common core is specific to tuberculosis, and was validated on an independent dataset from an Indian cohort. A network-based approach thus enables the identification of common regulators that characterise the molecular response to infection, providing a platform-independent foundation to leverage maximum insights from available clinical data. PMID- 28649432 TI - An individual-based model for collective cancer cell migration explains speed dynamics and phenotype variability in response to growth factors. AB - Collective cell migration is a common phenotype in epithelial cancers, which is associated with tumor cell metastasis and poor patient survival. However, the interplay between physiologically relevant pro-migratory stimuli and the underlying mechanical cell-cell interactions are poorly understood. We investigated the migratory behavior of different collectively migrating non-small cell lung cancer cell lines in response to motogenic growth factors (e.g. epidermal growth factor) or clinically relevant small compound inhibitors. Depending on the treatment, we observed distinct behaviors in a classical lateral migration assay involving traveling fronts, finger-shapes or the development of cellular bridges. Particle image velocimetry analysis revealed characteristic speed dynamics (evolution of the average speed of all cells in a frame) in all experiments exhibiting initial acceleration and subsequent deceleration of the cell populations. To better understand the mechanical properties of individual cells leading to the observed speed dynamics and the phenotypic differences we developed a mathematical model based on a Langevin approach. This model describes intercellular forces, random motility, and stimulation of active migration by mechanical interaction between cells. Simulations show that the model is able to reproduce the characteristic spatio-temporal speed distributions as well as most migratory phenotypes of the studied cell lines. A specific strength of the proposed model is that it identifies a small set of mechanical features necessary to explain all phenotypic and dynamical features of the migratory response of non small cell lung cancer cells to chemical stimulation/inhibition. Furthermore, all processes included in the model can be associated with potential molecular components, and are therefore amenable to experimental validation. Thus, the presented mathematical model may help to predict which mechanical aspects involved in non-small cell lung cancer cell migration are affected by the respective therapeutic treatment. PMID- 28649433 TI - On the performance of de novo pathway enrichment. AB - De novo pathway enrichment is a powerful approach to discover previously uncharacterized molecular mechanisms in addition to already known pathways. To achieve this, condition-specific functional modules are extracted from large interaction networks. Here, we give an overview of the state of the art and present the first framework for assessing the performance of existing methods. We identified 19 tools and selected seven representative candidates for a comparative analysis with more than 12,000 runs, spanning different biological networks, molecular profiles, and parameters. Our results show that none of the methods consistently outperforms the others. To mitigate this issue for biomedical researchers, we provide guidelines to choose the appropriate tool for a given dataset. Moreover, our framework is the first attempt for a quantitative evaluation of de novo methods, which will allow the bioinformatics community to objectively compare future tools against the state of the art. PMID- 28649434 TI - A Clb/Cdk1-mediated regulation of Fkh2 synchronizes CLB expression in the budding yeast cell cycle. AB - Precise timing of cell division is achieved by coupling waves of cyclin-dependent kinase (Cdk) activity with a transcriptional oscillator throughout cell cycle progression. Although details of transcription of cyclin genes are known, it is unclear which is the transcriptional cascade that modulates their expression in a timely fashion. Here, we demonstrate that a Clb/Cdk1-mediated regulation of the Fkh2 transcription factor synchronizes the temporal mitotic CLB expression in budding yeast. A simplified kinetic model of the cyclin/Cdk network predicts a linear cascade where a Clb/Cdk1-mediated regulation of an activator molecule drives CLB3 and CLB2 expression. Experimental validation highlights Fkh2 as modulator of CLB3 transcript levels, besides its role in regulating CLB2 expression. A Boolean model based on the minimal number of interactions needed to capture the information flow of the Clb/Cdk1 network supports the role of an activator molecule in the sequential activation, and oscillatory behavior, of mitotic Clb cyclins. This work illustrates how transcription and phosphorylation networks can be coupled by a Clb/Cdk1-mediated regulation that synchronizes them. PMID- 28649436 TI - Using approximate Bayesian computation to quantify cell-cell adhesion parameters in a cell migratory process. AB - In this work, we implement approximate Bayesian computational methods to improve the design of a wound-healing assay used to quantify cell-cell interactions. This is important as cell-cell interactions, such as adhesion and repulsion, have been shown to play a role in cell migration. Initially, we demonstrate with a model of an unrealistic experiment that we are able to identify model parameters that describe agent motility and adhesion, given we choose appropriate summary statistics for our model data. Following this, we replace our model of an unrealistic experiment with a model representative of a practically realisable experiment. We demonstrate that, given the current (and commonly used) experimental set-up, our model parameters cannot be accurately identified using approximate Bayesian computation methods. We compare new experimental designs through simulation, and show more accurate identification of model parameters is possible by expanding the size of the domain upon which the experiment is performed, as opposed to increasing the number of experimental replicates. The results presented in this work, therefore, describe time and cost-saving alterations for a commonly performed experiment for identifying cell motility parameters. Moreover, this work will be of interest to those concerned with performing experiments that allow for the accurate identification of parameters governing cell migratory processes, especially cell migratory processes in which cell-cell adhesion or repulsion are known to play a significant role. PMID- 28649435 TI - Improved prediction of PARP inhibitor response and identification of synergizing agents through use of a novel gene expression signature generation algorithm. AB - Despite rapid advancement in generation of large-scale microarray gene expression datasets, robust multigene expression signatures that are capable of guiding the use of specific therapies have not been routinely implemented into clinical care. We have developed an iterative resampling analysis to predict sensitivity algorithm to generate gene expression sensitivity profiles that predict patient responses to specific therapies. The resultant signatures have a robust capacity to accurately predict drug sensitivity as well as the identification of synergistic combinations. Here, we apply this approach to predict response to PARP inhibitors, and show it can greatly outperforms current clinical biomarkers, including BRCA1/2 mutation status, accurately identifying PARP inhibitor sensitive cancer cell lines, primary patient-derived tumor cells, and patient derived xenografts. These signatures were also capable of predicting patient response, as shown by applying a cisplatin sensitivity signature to ovarian cancer patients. We additionally demonstrate how these drug-sensitivity signatures can be applied to identify novel synergizing agents to improve drug efficacy. Tailoring therapeutic interventions to improve patient prognosis is of utmost importance, and our drug sensitivity prediction signatures may prove highly beneficial for patient management. PMID- 28649437 TI - Integrating personalized gene expression profiles into predictive disease associated gene pools. AB - Gene expression data are routinely used to identify genes that on average exhibit different expression levels between a case and a control group. Yet, very few of such differentially expressed genes are detectably perturbed in individual patients. Here, we develop a framework to construct personalized perturbation profiles for individual subjects, identifying the set of genes that are significantly perturbed in each individual. This allows us to characterize the heterogeneity of the molecular manifestations of complex diseases by quantifying the expression-level similarities and differences among patients with the same phenotype. We show that despite the high heterogeneity of the individual perturbation profiles, patients with asthma, Parkinson and Huntington's disease share a broadpool of sporadically disease-associated genes, and that individuals with statistically significant overlap with this pool have a 80-100% chance of being diagnosed with the disease. The developed framework opens up the possibility to apply gene expression data in the context of precision medicine, with important implications for biomarker identification, drug development, diagnosis and treatment. PMID- 28649438 TI - Translational learning from clinical studies predicts drug pharmacokinetics across patient populations. AB - Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single patient level. Taking into account the acquired knowledge describing (patho )physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies. PMID- 28649439 TI - Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach. AB - Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling. PMID- 28649440 TI - Cross-species gene modules emerge from a systems biology approach to osteoarthritis. AB - Complexities in degenerative disorders, such as osteoarthritis, arise from multiscale biological, environmental, and temporal perturbations. Animal models serve to provide controlled representations of the natural history of degenerative disorders, but in themselves represent an additional layer of complexity. Comparing transcriptomic networks arising from gene co-expression data across species can facilitate an understanding of the preservation of functional gene modules and establish associations with disease phenotypes. This study demonstrates the preservation of osteoarthritis-associated gene modules, described by immune system and system development processes, across human and rat studies. Class prediction analysis establishes a minimal gene signature, including the expression of the Rho GDP dissociation inhibitor ARHGDIB, which consistently defined healthy human cartilage from osteoarthritic cartilage in an independent data set. The age of human clinical samples remains a strong confounder in defining the underlying gene regulatory mechanisms in osteoarthritis; however, defining preserved gene models across species may facilitate standardization of animal models of osteoarthritis to better represent human disease and control for ageing phenomena. PMID- 28649441 TI - Clinical responses to ERK inhibition in BRAFV600E-mutant colorectal cancer predicted using a computational model. AB - Approximately 10% of colorectal cancers harbor BRAFV600E mutations, which constitutively activate the MAPK signaling pathway. We sought to determine whether ERK inhibitor (GDC-0994)-containing regimens may be of clinical benefit to these patients based on data from in vitro (cell line) and in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was used to develop a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling pathway, and tumor growth. Clinical predictions of anti-tumor activity were enabled by the use of tumor response data from three Phase 1 clinical trials testing combinations of EGFR, BRAF, and MEK inhibitors. Simulated responses to GDC-0994 monotherapy (overall response rate = 17%) accurately predicted results from a Phase 1 clinical trial regarding the number of responding patients (2/18) and the distribution of tumor size changes ("waterfall plot"). Prospective simulations were then used to evaluate potential drug combinations and predictive biomarkers for increasing responsiveness to MEK/ERK inhibitors in these patients. PMID- 28649443 TI - A multiscale model of early cell lineage specification including cell division. AB - Embryonic development is a self-organised process during which cells divide, interact, change fate according to a complex gene regulatory network and organise themselves in a three-dimensional space. Here, we model this complex dynamic phenomenon in the context of the acquisition of epiblast and primitive endoderm identities within the inner cell mass of the preimplantation embryo in the mouse. The multiscale model describes cell division and interactions between cells, as well as biochemical reactions inside each individual cell and in the extracellular matrix. The computational results first confirm that the previously proposed mechanism by which extra-cellular signalling allows cells to select the appropriate fate in a tristable regulatory network is robust when considering a realistic framework involving cell division and three-dimensional interactions. The simulations recapitulate a variety of in vivo observations on wild-type and mutant embryos and suggest that the gene regulatory network confers differential plasticity to the different cell fates. A detailed analysis of the specification process emphasizes that developmental transitions and the salt-and-pepper patterning of epiblast and primitive endoderm cells from a homogenous population of inner cell mass cells arise from the interplay between the internal gene regulatory network and extracellular signalling by Fgf4. Importantly, noise is necessary to create some initial heterogeneity in the specification process. The simulations suggest that initial cell-to-cell differences originating from slight inhomogeneities in extracellular Fgf4 signalling, in possible combination with slightly different concentrations of the key transcription factors between daughter cells, are able to break the original symmetry and are amplified in a flexible and self-regulated manner until the blastocyst stage. PMID- 28649444 TI - Reverse engineering highlights potential principles of large gene regulatory network design and learning. AB - Inferring transcriptional gene regulatory networks from transcriptomic datasets is a key challenge of systems biology, with potential impacts ranging from medicine to agronomy. There are several techniques used presently to experimentally assay transcription factors to target relationships, defining important information about real gene regulatory networks connections. These techniques include classical ChIP-seq, yeast one-hybrid, or more recently, DAP seq or target technologies. These techniques are usually used to validate algorithm predictions. Here, we developed a reverse engineering approach based on mathematical and computer simulation to evaluate the impact that this prior knowledge on gene regulatory networks may have on training machine learning algorithms. First, we developed a gene regulatory networks-simulating engine called FRANK (Fast Randomizing Algorithm for Network Knowledge) that is able to simulate large gene regulatory networks (containing 104 genes) with characteristics of gene regulatory networks observed in vivo. FRANK also generates stable or oscillatory gene expression directly produced by the simulated gene regulatory networks. The development of FRANK leads to important general conclusions concerning the design of large and stable gene regulatory networks harboring scale free properties (built ex nihilo). In combination with supervised (accepting prior knowledge) support vector machine algorithm we (i) address biologically oriented questions concerning our capacity to accurately reconstruct gene regulatory networks and in particular we demonstrate that prior knowledge structure is crucial for accurate learning, and (ii) draw conclusions to inform experimental design to performed learning able to solve gene regulatory networks in the future. By demonstrating that our predictions concerning the influence of the prior-knowledge structure on support vector machine learning capacity holds true on real data (Escherichia coli K14 network reconstruction using network and transcriptomic data), we show that the formalism used to build FRANK can to some extent be a reasonable model for gene regulatory networks in real cells. PMID- 28649445 TI - Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes. AB - Autism Spectrum Disorder (ASD) is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to ASD, showing de novo and inherited unbalanced copy number variants (CNVs) and smaller insertions and deletions (indels), more complex structural variants (SVs), as well as single nucleotide variants (SNVs) deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two CNV microdeletions, which affect regions of NRXN1 and MBD5 - each well-established in association with risk of ASD and other neurodevelopmental disorders. Although each CNV would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks. PMID- 28649447 TI - Certification of clinical and translational researchers: An ill-conceived notion. AB - The National Board of Medical Examiners (NBME) has instituted a new multiple choice examination in order to "certify" clinical and translational investigators. As experienced research educators, we argue that this certification process is unnecessary, values knowledge over competency, may be counter-productive, and is unlikely to achieve any worthwhile outcome. We lay out these arguments in the hope of stimulating a robust discussion among leaders, faculty, and learners engaged in clinical research education and training. PMID- 28649442 TI - Next-generation mammalian genetics toward organism-level systems biology. AB - Organism-level systems biology in mammals aims to identify, analyze, control, and design molecular and cellular networks executing various biological functions in mammals. In particular, system-level identification and analysis of molecular and cellular networks can be accelerated by next-generation mammalian genetics. Mammalian genetics without crossing, where all production and phenotyping studies of genome-edited animals are completed within a single generation drastically reduce the time, space, and effort of conducting the systems research. Next generation mammalian genetics is based on recent technological advancements in genome editing and developmental engineering. The process begins with introduction of double-strand breaks into genomic DNA by using site-specific endonucleases, which results in highly efficient genome editing in mammalian zygotes or embryonic stem cells. By using nuclease-mediated genome editing in zygotes, or ~100% embryonic stem cell-derived mouse technology, whole-body knock out and knock-in mice can be produced within a single generation. These emerging technologies allow us to produce multiple knock-out or knock-in strains in high throughput manner. In this review, we discuss the basic concepts and related technologies as well as current challenges and future opportunities for next generation mammalian genetics in organism-level systems biology. PMID- 28649446 TI - Phenotypic profiling of CFTR modulators in patient-derived respiratory epithelia. AB - Pulmonary disease is the major cause of morbidity and mortality in patients with cystic fibrosis, a disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Heterogeneity in CFTR genotype phenotype relationships in affected individuals plus the escalation of drug discovery targeting specific mutations highlights the need to develop robust in vitro platforms with which to stratify therapeutic options using relevant tissue. Toward this goal, we adapted a fluorescence plate reader assay of apical CFTR mediated chloride conductance to enable profiling of a panel of modulators on primary nasal epithelial cultures derived from patients bearing different CFTR mutations. This platform faithfully recapitulated patient-specific responses previously observed in the "gold-standard" but relatively low-throughput Ussing chamber. Moreover, using this approach, we identified a novel strategy with which to augment the response to an approved drug in specific patients. In proof of concept studies, we also validated the use of this platform in measuring drug responses in lung cultures differentiated from cystic fibrosis iPS cells. Taken together, we show that this medium throughput assay of CFTR activity has the potential to stratify cystic fibrosis patient-specific responses to approved drugs and investigational compounds in vitro in primary and iPS cell-derived airway cultures. PMID- 28649448 TI - Junior faculty core curriculum to enhance faculty development. AB - INTRODUCTION: Senior Instructors and Assistant Professors in their first academic appointment may not have all the tools for an efficient start to their careers. Although many institutions provide access to mentoring programs and seminars on faculty development, the timing and format of the offerings often conflict with ongoing responsibilities of the faculty, particularly clinical faculty. METHODS: We established a collaboration between the Clinical and Translational Science Institute (CTSI) and the University of Rochester Medical Center Office for Faculty Development with the goal of developing a week-long Junior Faculty Core Curriculum that would better suit faculty schedules. We convened focus groups and with their help, identified themes for inclusion in the course. Speakers were identified from among local senior faculty. University leadership was enlisted in promoting the course. Individual speakers and course content were evaluated daily, at the end of the week-long course, and 6 months later. Planning for subsequent years incorporated the feedback. Yearly evaluations and subsequent course modification continued. RESULTS: Junior faculty from nearly every department in the Medical Center were represented. There was high learner satisfaction and participation however several limitations were identified and addressed in subsequent years. The focus on principles and available resources, not specific skills or content was appropriate. Daily interactions among participants from a wide variety of departments fostered networking among faculty who may not otherwise have met and discussed common interests. CONCLUSIONS: The ultimate value of such an early, intensive faculty development program will depend on whether it equips junior faculty to organize, develop, and achieve their academic goals better than alternative formats. This will require further study. PMID- 28649449 TI - Creating effective career development programs. AB - This paper is the fourth in a 5-part series that focuses on educating and training the clinical and translational science workforce. The goal of this paper is to delineate components of effective career development programs that go beyond didactic training. All academic health centers with a Clinical and Translational Science Award have a KL2 career development award for junior faculty, and many also have a TL1 training program for predoctoral and postdoctoral fellows. The training across these programs varies, however junior investigators across the United States experience similar challenges. Junior investigators can get overwhelmed with the demands of building their own research program, particularly in academia. 1Often, they are sidetracked by competing demands that can derail their progress. In these situations, junior investigators experience frustration and may search for alternative career paths. By providing them with additional professional skills in the 5 domains of: (1) self-awareness; (2) selecting the right topic and securing funding; (3) getting adequate support; (4) working with others; and (5) managing yourself, your career, and your demands. We will give junior investigators additional tools to manage these demands and facilitate their own career success. PMID- 28649450 TI - The Northwest Participant and Clinical Interactions Network: Increasing opportunities for patients to participate in research across the Northwestern United States. AB - INTRODUCTION: The Institute of Translational Health Sciences (ITHS) promotes and supports translational research collaboration between clinicians, communities, and investigators across the five-state Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region. The ITHS has developed a collaborative regional clinical research network, the Northwest Participant & Clinical Interactions Network (NW PCI), involving 12 diverse clinical health systems and academic institutions. METHODS: This descriptive article details NW PCI's development, infrastructure and governance, tools, characteristics, and initial outcomes. RESULTS: Regional NW PCI sites are conducting largely industry-sponsored studies; they are interested in including more grant-funded research. Regional NW PCI sites had over 1,240 open studies involving over 6700 patients in 2016. NW PCI trials are largely industry-sponsored; NW PCI sites are interested in including more grant funded research. In its first three years, the NW PCI Coordinating Center facilitated regional sites' participation in 34 new grant and contract applications across diverse topics. CONCLUSION: The NW PCI model supports the goals of the developing CTSA Trial Innovation Network by increasing access to cutting-edge research across the Northwestern U.S., by supporting investigators seeking diverse populations, including those with rare diseases, for their research studies, and by providing settings to test implementation and dissemination of effective interventions. PMID- 28649451 TI - Organizational and training factors that promote team science: A qualitative analysis and application of theory to the National Institutes of Health's BIRCWH career development program. AB - INTRODUCTION: Research organizations face challenges in creating infrastructures that cultivates and sustains interdisciplinary team science. The objective of this paper is to identify structural elements of organizations and training that promote team science. METHODS: We qualitatively analyzed the National Institutes of Health's Building Interdisciplinary Research Careers in Women's Health, K12 using organizational psychology and team science theories to identify organizational design factors for successful team science and training. PRINCIPAL RESULTS: Seven key design elements support team science: (1) semiformal meta organizational structure, (2) shared context and goals, (3) formal evaluation processes, (4) meetings to promote communication, (5) role clarity in mentoring, (6) building interpersonal competencies among faculty and trainees, and (7) designing promotion and tenure and other organizational processes to support interdisciplinary team science. CONCLUSION: This application of theory to a long standing and successful program provides important foundational elements for programs and institutions to consider in promoting team science. PMID- 28649452 TI - Glucocorticoid receptor expression on circulating leukocytes differs between healthy male and female adults. AB - INTRODUCTION: The glucocorticoid receptor (GR) is a key receptor involved in inflammatory responses and is influenced by sex steroids. This study measured GR expression on circulating leukocyte subtypes in males and females. METHODS: A total of 23 healthy adults (12 female) participated in this study. GR expression was measured in leukocyte subtypes using flow cytometry. Peripheral blood mononuclear cell (PBMC) gene expression of GR (NR3C1), GR beta, TGF-beta1 and 2, and glucocorticoid-induced leucine zipper (GILZ) were determined by real-time polymerase chain reaction. RESULTS: Leukocyte GR was lower in females, particularly in granulocytes, natural killer cells, and peripheral blood mononuclear cells (p<=0.01). GR protein expression was different across leukocyte subtypes, with higher expression in eosinophils compared with granulocytes, T lymphocytes, and natural killer cells (p<0.05). There was higher gene expression of GR beta in males (p=0.03). CONCLUSIONS: This is the first study to identify sexual dimorphism in GR expression in healthy adults using flow cytometry. These results may begin to explain the sexual dimorphism seen in many diseases and sex differences in glucocorticoid responsiveness. PMID- 28649453 TI - Informed consent for next-generation nucleotide sequencing studies: Aiding communication between participants and investigators. AB - INTRODUCTION: Obtaining informed consent from prospective participants for research studies that include next-generation nucleotide sequencing (NGS) presents significant challenges because of the need to explain all the potential implications of participating, including the possible return of "incidental" findings, in easy-to-understand language. METHODS AND RESULTS: After reviewing the consent processes at other institutions, we decided to supplement the protocol-specific informed consent form with the following: (1) a short pamphlet for the prospective participant that includes a series of questions that she or he is encouraged to ask the investigator, and (2) a more detailed companion guide for investigators to help them develop simple-language answers to the questions. Both documents are available to use or modify. CONCLUSIONS: We propose an approach to obtaining informed consent for NGS studies that encourages discussion of key issues without creating a complex, comprehensive document for participants; it also maximizes investigator flexibility. We also suggest mechanisms to return restricted information to participants. PMID- 28649454 TI - Methods guiding stakeholder engagement in planning a pragmatic study on changing stroke systems of care. AB - BACKGROUND: The Comprehensive Post-Acute Stroke Services (COMPASS) Study is one of the first large pragmatic randomized-controlled clinical trials using comparative effectiveness research methods, funded by the Patient-Centered Outcomes Research Institute. In the COMPASS Study, we compare the effectiveness of a patient-centered, transitional care intervention versus usual care for stroke patients discharged home from acute care. Outcomes include stroke patient post-discharge functional status and caregiver strain 90 days after discharge, and hospital readmissions. A central tenet of Patient-Centered Outcomes Research Institute-funded research is stakeholder engagement throughout the research process. However, evidence on how to successfully implement a pragmatic trial that changes systems of care in combination with robust stakeholder engagement is limited. This combination is not without challenges. METHODS: We present our approach for broad-based stakeholder engagement in the context of a pragmatic trial with the participation of patients, caregivers, community stakeholders, including the North Carolina Stroke Care Collaborative hospital network, and policy makers. To maximize stakeholder engagement throughout the COMPASS Study, we employed a conceptual model with the following components: (1) Patient and Other Stakeholder Identification and Selection; (2) Patient and Other Stakeholder Involvement Across the Spectrum of Research Activities; (3) Dedicated Resources for Patient and Other Stakeholder Involvement; (4) Support for Patient and Other Stakeholder Engagement Through Organizational Processes; (5) Communication with Patients and Other Stakeholders; (6) Transparent Involvement Processes; (7) Tracking of Engagement; and (8) Evaluation of Engagement. CONCLUSION: In this paper, we describe how each component of the model is being implemented and how this approach addresses existing gaps in the literature on strategies for engaging stakeholders in meaningful and useful ways when conducting pragmatic trials. PMID- 28649455 TI - Science Cafes: Transforming citizens to scientific citizens-What influences participants' perceived change in health and scientific literacy? AB - INTRODUCTION: Science Cafes facilitated by the Clinical and Translational Science Institute of Southeast Wisconsin seek to increase health and scientific literacy through informal conversation between researchers and community members. The goal was to understand what factors have the greatest influence on attendees' perceived changes in health and science literacy levels (PCHSL) to increase impact. METHODS: Previous research established the evaluation used in the Science Cafes to measure PCHSL. In this study, comparisons were made between (1) 2 different approaches to Science Cafes (Genomics Science Cafes or Health Science Cafes) and (2) regression models to show which factors best predicted PCHSL. RESULTS: The approach of the Genomics Science Cafes series to Science Cafes showed a larger impact on PCHSL. Regression models suggest SES and education significantly contributes to PCHSL. CONCLUSIONS: Insights for program development to have greater impact on PCHSL were identified. Continuing to optimize dissemination of research findings to the public is essential for improving community health and well-being. PMID- 28649456 TI - Development of a self-directed, online-learning curriculum to increase community engaged research in clinical and translational science. AB - BACKGROUND: Medical research strives to improve health; community-engaged research (CEnR) supports translation to the community. METHODS: This article describes the use of andragogical theory to develop asynchronous CEnR training. RESULTS: A total of 43 researchers and community members completed at least one module. The majority (67%-100%) stated that training met their educational needs and noted a desire for more information. CONCLUSION: The curriculum reinforced CEnR principles to enhance medical research. PMID- 28649457 TI - Scholarly productivity and professional advancement of junior researchers receiving KL2, K23, or K08 awards at a large public research institution. AB - BACKGROUND: How the productivity and careers of KL2 scholars compare with scholars receiving individual K-awards is unknown. METHODS: The productivity of KL2 scholars (n=21) at our institution was compared with that of K08 (n=34) and K23 (n=26) scholars. RESULTS: KL2 and K23 scholars had greater productivity than K08 scholars (p=0.01). Professional advancement was similar among groups. CONCLUSION: At our institution, scholarly productivity and professional advancement did not differ by type of K-award. PMID- 28649459 TI - The study on force, surface integrity, tool life and chip on laser assisted machining of inconel 718 using Nd:YAG laser source. AB - Inconel 718, a high-temperature alloy, is a promising material for high performance aerospace gas turbine engines components. However, the machining of the alloy is difficult owing to immense shear strength, rapid work hardening rate during turning, and less thermal conductivity. Hence, like ceramics and composites, the machining of this alloy is considered as difficult-to-turn materials. Laser assisted turning method has become a promising solution in recent years to lessen cutting stress when materials that are considered difficult-to-turn, such as Inconel 718 is employed. This study investigated the influence of input variables of laser assisted machining on the machinability aspect of the Inconel 718. The comparison of machining characteristics has been carried out to analyze the process benefits with the variation of laser machining variables. The laser assisted machining variables are cutting speeds of 60-150 m/min, feed rates of 0.05-0.125 mm/rev with a laser power between 1200 W and 1300 W. The various output characteristics such as force, roughness, tool life and geometrical characteristic of chip are investigated and compared with conventional machining without application of laser power. From experimental results, at a laser power of 1200 W, laser assisted turning outperforms conventional machining by 2.10 times lessening in cutting force, 46% reduction in surface roughness as well as 66% improvement in tool life when compared that of conventional machining. Compared to conventional machining, with the application of laser, the cutting speed of carbide tool has increased to a cutting condition of 150 m/min, 0.125 mm/rev. Microstructural analysis shows that no damage of the subsurface of the workpiece. PMID- 28649458 TI - Physico-chemical, rheological and antioxidant properties of sweet chestnut (Castanea sativa Mill.) as affected by pan and microwave roasting. AB - Sweet chestnut (Castanea sativa Mill.) belongs to the family Fagaceae and sub family Castaneoideae. Bioactive components such as tannins are present in sweet chestnut in high proportion giving astringent bitter taste and reducing their palatability. Roasting reduces the anti-nutritional factors in chestnut. This study was conducted to compare the effects of pan and microwave roasting on physicochemical, functional, rheological and antioxidant properties of sweet chestnut. Antioxidant activity was determined using DPPH inhibition activity, reducing power, and total phenolic content. Structural analysis was carried out using FT-IR analysis. Protein, fat, and ash contents displayed insignificant (P > 0.05) variations. "L" value decreased from 90.66 to 81.43, whereas, "a" and "b" values increased from 0.02 to 0.90 and 11.99 to 20.5, respectively, upon roasting. Significant (P < 0.05) increase in water absorption capacity (1.32-3.39 g/g), oil absorption capacity (1.22-1.63 g/g), and antioxidant properties was observed following roasting. Flour obtained from roasted chestnuts exhibited a significant decrease in light transmittance, foaming, and pasting properties. Higher gelatinization temperatures and lower enthalpies were reported in microwave and pan roasted chestnut flours. Roasting also reduced the viscoelastic behavior of native sweet chestnut and changed the transmittance of identical functional groups as revealed by FT-IR analysis. PMID- 28649461 TI - Special Issue: Smart Manufacturing PHM. PMID- 28649460 TI - Pulmonary diseases induced by ambient ultrafine and engineered nanoparticles in twenty-first century. AB - Air pollution is a severe threat to public health globally, affecting everyone in developed and developing countries alike. Among different air pollutants, particulate matter (PM), particularly combustion-produced fine PM (PM2.5) has been shown to play a major role in inducing various adverse health effects. Strong associations have been demonstrated by epidemiological and toxicological studies between increases in PM2.5 concentrations and premature mortality, cardiopulmonary diseases, asthma and allergic sensitization, and lung cancer. The mechanisms of PM-induced toxicological effects are related to their size, chemical composition, lung clearance and retention, cellular oxidative stress responses and pro-inflammatory effects locally and systemically. Particles in the ultrafine range (<100 nm), although they have the highest number counts, surface area and organic chemical content, are often overlooked due to insufficient monitoring and risk assessment. Yet, ample studies have demonstrated that ambient ultrafine particles have higher toxic potential compared with PM2.5. In addition, the rapid development of nanotechnology, bringing ever-increasing production of nanomaterials, has raised concerns about the potential human exposure and health impacts. All these add to the complexity of PM-induced health effects that largely remains to be determined, and mechanistic understanding on the toxicological effects of ambient ultrafine particles and nanomaterials will be the focus of studies in the near future. PMID- 28649462 TI - Iridium-Catalyzed Diastereo-, Enantio-, and Regioselective Allylic Alkylation with Prochiral Enolates. PMID- 28649463 TI - Outcomes of Admissions for Preterm Labor. AB - Objective This study aims to quantitate the incidence of preterm labor (PTL) admissions and determine the frequency and predictors of preterm delivery (PTD) during these admissions. Study Design Retrospective cohort of singleton pregnancies within Kaiser Permanente Northern California, 2001 to 2011. PTL admissions were defined as inpatient encounters > 24 hours with an International Classification of Diseases, 9th Revision code for PTL. Results Total study population was 365,897 with PTL admission rate 11%. PTD occurred in 85% of pregnancies with PTL admission. Delivery occurred within 48 hours of admission in 96% >=34 weeks, 67% 31 to 33 weeks, and 51.9% <31 weeks. Predictors of delivery during PTL admission included gestational age 34 to 36 weeks (adjusted odds ratio [aOR], 6.90), chorioamnionitis (aOR, 105.58), and preterm rupture of membranes (aOR 19.29). Conclusion We demonstrate a high rate of PTD per PTL admission in a highly integrated health care system. More work is needed to determine optimal practices for hospitalization and treatment of women diagnosed with PTL. PMID- 28649465 TI - Dietary and cardio-metabolic risk factors in patients with Obstructive Sleep Apnea: cross-sectional study. AB - BACKGROUND: Little is known about the role of dietary intake in obstructive sleep apnea (OSA), which could prove important in improving clinical outcomes for people with obesity and/or cardiovascular disease within these populations. Reduction in energy intake typically results in weight loss, markedly improving metabolic parameters and ameliorating OSA severity. The aim of this study was to evaluate the association of dietary and cardio-metabolic risk factors with OSA severity. METHODS: This was a cross-sectional study. A total of 75 volunteers at risk of OSA were recruited from 153 patients suffering from sleep disturbance at the Department of Pulmonology, Allergology and Respiratory Oncology at the Poznan University of Medical Sciences. Polysomnography was used for OSA diagnosis. Sleep quality was assessed by the Pittsburgh Sleep Quality Index. Blood pressure, parameters of glucose (fasting glucose, glucose tolerance test) and lipid metabolism (TC, LDL-C, HDL-C, TG) were assessed using routine enzymatic methods. Dietary intake was evaluated by 24-hr dietary recalls and Food Frequency Questionnaire. Ordinal logistic regression models were used for association of background characteristics and dietary intake with OSA severity. All analyses were adjusted for age, sex, BMI, smoking and alcohol intake. RESULTS: A higher percentage of smokers were observed in patients with mild OSA, while alcohol intake was the highest in severe OSA patients. Approximately 60% of the studied patients were self-reported poor sleepers. Results from ordinal logistic regression models showed that higher intakes of alcohol intake were associated with increased odds of severe OSA; whereas higher HDL-C levels were associated with lower odds (OR 0.01; 95% CI [0.0003-0.55]). Significantly higher odds of high OSA severity were observed in patients with disturbed sleep stages and obstructive sleep apnea. Moreover, the investigation of nutrient intake in relation to OSA severity showed that a higher intake of dietary fiber was associated with decreased OSA severity (OR 0.84; 95% CI [0.71-0.98]). CONCLUSIONS: The severity of OSA is related to higher alcohol consumption and disturbed sleep. The significantly lower dietary fiber intake in patients with severe OSA is of particular importance for dietary consulting in clinical practice, which may positively influence cardiometabolic outcomes. PMID- 28649466 TI - The Venice specimen of Ouranosaurus nigeriensis (Dinosauria, Ornithopoda). AB - Ouranosaurus nigeriensis is an iconic African dinosaur taxon that has been described on the basis of two nearly complete skeletons from the Lower Cretaceous Gadoufaoua locality of the Tenere desert in Niger. The entire holotype and a few bones attributed to the paratype formed the basis of the original description by Taquet (1976). A mounted skeleton that appears to correspond to O. nigeriensis has been on public display since 1975, exhibited at the Natural History Museum of Venice. It was never explicitly reported whether the Venice specimen represents a paratype and therefore, the second nearly complete skeleton reported in literature or a third unreported skeleton. The purpose of this paper is to disentangle the complex history of the various skeletal remains that have been attributed to Ouranosaurus nigeriensis (aided by an unpublished field map of the paratype) and to describe in detail the osteology of the Venice skeleton. The latter includes the paratype material (found in 1970 and collected in 1972), with the exception of the left femur, the right coracoid and one manus ungual phalanx I, which were replaced with plaster copies, and (possibly) other manus phalanges. Some other elements (e.g., the first two chevrons, the right femur, the right tibia, two dorsal vertebrae and some pelvic bones) were likely added from other individual/s. The vertebral column of the paratype was articulated and provides a better reference for the vertebral count of this taxon than the holotype. Several anatomical differences are observed between the holotype and the Venice specimen. Most of them can be ascribed to intraspecific variability (individual or ontogenetic), but some are probably caused by mistakes in the preparation or assemblage of the skeletal elements in both specimens. The body length of the Venice skeleton is about 90% the linear size of the holotype. Osteohistological analysis (the first for this taxon) of some long bones, a rib and a dorsal neural spine reveals that the Venice specimen is a sub-adult; this conclusion is supported by somatic evidence of immaturity. The dorsal 'sail' formed by the elongated neural spines of the dorsal, sacral and proximal caudal vertebrae characterizes this taxon among ornithopods; a display role is considered to be the most probable function for this bizarre structure. Compared to the mid-1970s, new information from the Venice specimen and many iguanodontian taxa known today allowed for an improved diagnosis of O. nigeriensis. PMID- 28649464 TI - Light in diagnosis, therapy and surgery. AB - Light and optical techniques have made profound impacts on modern medicine, with numerous lasers and optical devices being currently used in clinical practice to assess health and treat disease. Recent advances in biomedical optics have enabled increasingly sophisticated technologies - in particular those that integrate photonics with nanotechnology, biomaterials and genetic engineering. In this Review, we revisit the fundamentals of light-matter interactions, describe the applications of light in imaging, diagnosis, therapy and surgery, overview their clinical use, and discuss the promise of emerging light-based technologies. PMID- 28649467 TI - Larval exposure to field-realistic concentrations of clothianidin has no effect on development rate, over-winter survival or adult metabolic rate in a solitary bee, Osmia bicornis. AB - There is widespread concern regarding the effects of agro-chemical exposure on bee health, of which neonicotinoids, systemic insecticides detected in the pollen and nectar of both crops and wildflowers, have been the most strongly debated. The majority of studies examining the effect of neonicotinoids on bees have focussed on social species, namely honey bees and bumble bees. However, most bee species are solitary, their life histories differing considerably from these social species, and thus it is possible that their susceptibility to pesticides may be quite different. Studies that have included solitary bees have produced mixed results regarding the impact of neonicotinoid exposure on survival and reproductive success. While the majority of studies have focused on the effects of adult exposure, bees are also likely to be exposed as larvae via the consumption of contaminated pollen. Here we examined the effect of exposure of Osmia bicornis larvae to a range of field-realistic concentrations (0-10 ppb) of the neonicotinoid clothianidin, observing no effect on larval development time, overwintering survival or adult weight. Flow-through respirometry was used to test for latent effects of larval exposure on adult physiological function. We observed differences between male and female bees in the propensity to engage in discontinuous gas exchange; however, no effect of larval clothianidin exposure was observed. Our results suggest that previously reported adverse effects of neonicotinoids on O. bicornis are most likely mediated by impacts on adults. PMID- 28649468 TI - Microbial bioenergetics of coral-algal interactions. AB - Human impacts are causing ecosystem phase shifts from coral- to algal-dominated reef systems on a global scale. As these ecosystems undergo transition, there is an increased incidence of coral-macroalgal interactions. Mounting evidence indicates that the outcome of these interaction events is, in part, governed by microbially mediated dynamics. The allocation of available energy through different trophic levels, including the microbial food web, determines the outcome of these interactions and ultimately shapes the benthic community structure. However, little is known about the underlying thermodynamic mechanisms involved in these trophic energy transfers. This study utilizes a novel combination of methods including calorimetry, flow cytometry, and optical oxygen measurements, to provide a bioenergetic analysis of coral-macroalgal interactions in a controlled aquarium setting. We demonstrate that the energetic demands of microbial communities at the coral-algal interaction interface are higher than in the communities associated with either of the macroorganisms alone. This was evident through higher microbial power output (energy use per unit time) and lower oxygen concentrations at interaction zones compared to areas distal from the interface. Increases in microbial power output and lower oxygen concentrations were significantly correlated with the ratio of heterotrophic to autotrophic microbes but not the total microbial abundance. These results suggest that coral-algal interfaces harbor higher proportions of heterotrophic microbes that are optimizing maximal power output, as opposed to yield. This yield to power shift offers a possible thermodynamic mechanism underlying the transition from coral- to algal-dominated reef ecosystems currently being observed worldwide. As changes in the power output of an ecosystem are a significant indicator of the current state of the system, this analysis provides a novel and insightful means to quantify microbial impacts on reef health. PMID- 28649470 TI - Determinants of seasonal changes in availability of food patches for elephants (Loxodonta africana) in a semi-arid African savanna. AB - Loss of biodiversity caused by impact of elephants (Loxodonta africana) on African woodlands may require a management response, but any action should be based on an understanding of why elephants choose to utilise trees destructively. Comprehension of elephant feeding behaviour requires consideration of the relative value of the plant groups they may potentially consume. Profitability of available food is partly determined by the time to locate a food patch and, therefore, as a foundation for understanding the influence of food availability on diet selection, key controls on the density of grass, forb, and browse patches were investigated across space and time in a semi-arid African savanna. Density of food patches changed seasonally because plant life-forms required different volumes of soil water to produce green forage; and woody plants and forbs responded to long-term changes in soil moisture, while grasses responded to short term moisture pulses. Soil texture, structure of woody vegetation and fire added further complexity by altering the soil water thresholds required for production of green forage. Interpolating between regularly-timed, ground-based measurements of food density by using modelled soil water as the predictor in regression equations may be a feasible method of quantifying food available to elephants in complex savanna environments. PMID- 28649471 TI - The biochronology and palaeobiogeography of Baru (Crocodylia: Mekosuchinae) based on new specimens from the Northern Territory and Queensland, Australia. AB - New records of the Oligo-Miocene mekosuchine crocodylian, Baru, from Queensland and the Northern Territory are described. Baru wickeni and Baru darrowi are accepted as valid species in the genus and their diagnoses are revised. Both species are present in Queensland and the Northern Territory but are restricted in time, with B. wickeni known from the late Oligocene and B. darrowi from the middle Miocene. The broad geographic distributions and restricted time spans of these species indicate that this genus is useful for biochronology. The record of B. wickeni from the Pwerte Marnte Marnte Local Fauna in the Northern Territory establishes that the species inhabited the north-western margin of the Lake Eyre Basin (LEB) drainage system. More southerly Oligo-Miocene sites in the LEB contain only one crocodylian species, Australosuchus clarkae. The Pwerte Marnte Marnte occurrence of B. wickeni indicates that the separation of Baru and Australosuchus did not correspond with the boundaries of drainage basins and that palaeolatitude was a more likely segregating factor. PMID- 28649472 TI - A new species of Trite Simon, 1885 (Araneae: Salticidae) from New Zealand, with remarks on Trite relationships and radiation. AB - A species known from earlier behavioural studies as "Holoplatys sp.", is described as Trite pollardi sp. nov. Within the genus Trite, two species groups are distinguished: the planiceps-group (found in New Caledonia, New Zealand, Lord Howe Island and Norfolk Island) and the incognita-group (limited to New Zealand). The three alternative scenarios of the Trite origin, relationships and radiation in New Zealand, New Caledonia and Lord Howe Island are discussed. Three species are considered to be excluded from Trite. PMID- 28649469 TI - Distinct patterns in the gut microbiota after surgical or medical therapy in obese patients. AB - Bariatric surgery is highly successful in improving health compared to conventional dietary treatments. It has been suggested that the gut microbiota is a relevant factor in weight loss after bariatric surgery. Considering that bariatric procedures cause different rearrangements of the digestive tract, they probably have different effects on the gut microbiota. In this study, we compared the impact of medical treatment, sleeve gastrectomy and Roux-en-Y gastric bypass on the gut microbiota from obese subjects. Anthropometric and clinical parameters were registered before, 6 and 12 months after treatment. Fecal samples were collected and microbiota composition was studied before and six months post treatment using 16S rRNA gene sequencing and qPCR. In comparison to dietary treatment, changes in intestinal microbiota were more pronounced in patients subjected to surgery, observing a bloom in Proteobacteria. Interestingly, Bacteroidetes abundance was largely different after six months of each surgical procedure. Furthermore, changes in weight and BMI, or glucose metabolism, correlated positively with changes in these two phyla in these surgical procedures. These results indicate that distinct surgical procedures alter the gut microbiota differently, and changes in gut microbiota might contribute to health improvement. This study contributes to our understanding of the impact of weight loss surgery on the gut microbiota, and could be used to replicate this effect using targeted therapies. PMID- 28649473 TI - Focus expansion and stability of the spread parameter estimate of the power law model for dispersal gradients. AB - Empirical and mechanistic modeling indicate that pathogens transmitted via aerially dispersed inoculum follow a power law, resulting in dispersive epidemic waves. The spread parameter (b) of the power law model, which is an indicator of the distance of the epidemic wave front from an initial focus per unit time, has been found to be approximately 2 for several animal and plant diseases over a wide range of spatial scales under conditions favorable for disease spread. Although disease spread and epidemic expansion can be influenced by several factors, the stability of the parameter b over multiple epidemic years has not been determined. Additionally, the size of the initial epidemic area is expected to be strongly related to the final epidemic extent for epidemics, but the stability of this relationship is also not well established. Here, empirical data of cucurbit downy mildew epidemics collected from 2008 to 2014 were analyzed using a spatio-temporal model of disease spread that incorporates logistic growth in time with a power law function for dispersal. Final epidemic extent ranged from 4.16 *108 km2 in 2012 to 6.44 *108 km2 in 2009. Current epidemic extent became significantly associated (P < 0.0332; 0.56 < R2 < 0.99) with final epidemic area beginning near the end of April, with the association increasing monotonically to 1.0 by the end of the epidemic season in July. The position of the epidemic wave-front became exponentially more distant with time, and epidemic velocity increased linearly with distance. Slopes from the temporal and spatial regression models varied with about a 2.5-fold range across epidemic years. Estimates of b varied substantially ranging from 1.51 to 4.16 across epidemic years. We observed a significant b *time (or distance) interaction (P < 0.05) for epidemic years where data were well described by the power law model. These results suggest that the spread parameter b may not be stable over multiple epidemic years. However, b ~ 2 may be considered the lower limit of the distance traveled by epidemic wave-fronts for aerially transmitted pathogens that follow a power law dispersal function. PMID- 28649474 TI - Using high-throughput sequencing of ITS2 to describe Symbiodinium metacommunities in St. John, US Virgin Islands. AB - Symbiotic microalgae (Symbiodinium spp.) strongly influence the performance and stress-tolerance of their coral hosts, making the analysis of Symbiodinium communities in corals (and metacommunities on reefs) advantageous for many aspects of coral reef research. High-throughput sequencing of ITS2 nrDNA offers unprecedented scale in describing these communities, yet high intragenomic variability at this locus complicates the resolution of biologically meaningful diversity. Here, we demonstrate that generating operational taxonomic units by clustering ITS2 sequences at 97% similarity within, but not across, samples collapses sequence diversity that is more likely to be intragenomic, while preserving diversity that is more likely interspecific. We utilize this 'within sample clustering' to analyze Symbiodinium from ten host taxa on shallow reefs on the north and south shores of St. John, US Virgin Islands. While Symbiodinium communities did not differ between shores, metacommunity network analysis of host symbiont associations revealed Symbiodinium lineages occupying 'dominant' and 'background' niches, and coral hosts that are more 'flexible' or 'specific' in their associations with Symbiodinium. These methods shed new light on important questions in coral symbiosis ecology, and demonstrate how application-specific bioinformatic pipelines can improve the analysis of metabarcoding data in microbial metacommunity studies. PMID- 28649475 TI - Solid Pseudopapillary Tumor of the Pancreas: An Unusual Cause of Abdominal Pain. AB - Solid-pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor that accounts for less than one percent of pancreatic tumors. The diagnosis could be challenging as SPN tend to manifest with nonspecific abdominal symptoms, variable radiological features, and inconsistent morphology. The cellular origin of SPN is unclear and might involve ductal, acinar and endocrine stem cells. We report a rare case of a 27-year-old female who presented with intermittent abdominal pain for two years, associated with a decrease in appetite. Her medical history was significant for abdominoplasty five years ago. Vital signs were stable. Physical examination revealed mild epigastric tenderness. Laboratory tests were unremarkable. Contrast computed tomography (CT) scan of the abdomen showed a 2 x 2 cm indeterminate pancreatic tail lesion. An endoscopic ultrasound (EUS) disclosed a 2.1 x 1.8 cm hypoechoic mass in the tail of the pancreas.Trans gastric fine needle aspiration was obtained to show clusters of uniform neoplastic cells with abundant cytoplasm and oval bean-shaped nuclei. Immunohistochemical stains were positive for beta-catenin, Vimentin, CD10, CD56, cytokeratin-7 (Ck7), Cyclin D1, and negative for chromogranin, epithelial cadherin (E cadherin) which was consistent with a pseudopapillary tumor. The patient underwent a robotic assisted en-bloc distal pancreatectomy and splenectomy. There were no intra-abdominal metastases. SPN is a rare tumor characterized by a specific immunohistological pattern which makes it highly distinct from other pancreatic neoplasms particularly neuroendocrine tumors, acinar carcinomas, and carcinoids. It is important to differentiate SPN from other pancreatic neoplasms because it is characterized as low potential for malignancy and a favorable prognosis after resection, with a five-year survival rate approaching 85%-95%. PMID- 28649476 TI - A Practice Platform for Systematic Development of Microsurgical Instrument Technique. AB - Many surgical disciplines, particularly those specializing in the pediatric age group, use microsurgical instruments with the assistance of either optical loupe or microscope magnification to perform high precision surgical procedures. We developed a course consisting of two parts: Part 1 consists of low fidelity, inanimate exercises or training and practice platform, and part 2 employed a rat model. In this report, we describe and provide templates for the first part of the course, namely the practice platform as an integral set of six low-fidelity exercises, each focusing on a specific aspect of instrument handling required to master the later use of the instruments during actual microsurgery. This platform is made to systematically and efficiently improve the microsurgical skills of junior as well as advanced surgical trainees. PMID- 28649477 TI - The Importance of Catheter Angiography in Computed Tomography Angiography Negative Subarachnoid Hemorrhage. AB - Computed tomography angiography (CTA) has become an effective tool in the evaluation of patients with subarachnoid hemorrhage (SAH), but it still has limitations. Up to 15% of non-traumatic SAH cases are negative on CTA. The benefits of catheter angiography in the evaluation of certain cases of CTA negative SAH have been previously demonstrated. Here, we present the case of a 48 year-old female who presented with headache and right-sided hemiparesis, who later became apneic and required intubation. A computed tomography (CT) scan of the head demonstrated a diffuse SAH. A CTA of the head and neck showed no vascular abnormality. Catheter angiography diagnosed a conical-shaped aneurysm at the left A1-A2 junction of the anterior communicating artery complex measuring 3.5 mm by 1 mm. The aneurysm was successfully treated with a craniotomy and microvascular clipping using a 4.7 mm curved Yasargil miniclip (Aesculap, Tuttlingen, Germany). This case illustrates the importance and benefit of catheter angiography in CTA-negative cases of SAH. PMID- 28649478 TI - Cerebral Air Embolism as Possible Cause of Stroke During Therapeutic Endobronchial Application of Argon Plasma Coagulation. AB - A 68-year-old male was admitted for evaluation of an endobronchial mass obstructing the right middle lobe (RML) and right lower lobe (RLL) of the lung. Flexible bronchoscopy revealed a notable endobronchial lesion in the bronchus intermedius that completely obstructed the RML and the RLL. Argon plasma coagulation (APC) at 30 watts and gas flow at 0.8 liters/minute to 1 liter/minute were applied to the tumor. In the recovery room, the patient was discovered to have a left-sided facial droop and left-sided weakness. The initial computed tomography (CT) scan of the brain and an angiogram of the head and neck were normal, but a repeat CT scan of the head several hours later was remarkable for an area of hypoattenuation in the right frontoparietal lobe concerning for infarct. A magnetic resonance imaging (MRI) brain scan confirmed acute to sub acute cortical infarcts. Given the direct temporal relation between the onset of neurologic symptoms and the usage of APC with bronchoscopy, a cerebral air embolism (CAE) was thought to be the cause of the patient's acute stroke. PMID- 28649479 TI - Functional Outcomes of Childhood Selective Dorsal Rhizotomy 20 to 28 Years Later. AB - BACKGROUND: Selective dorsal rhizotomy (SDR) is a surgical method used to treat childhood spastic cerebral palsy (CP). However, the effects of early SDR on functional outcomes and quality of life decades later in adulthood remains to be elucidated. OBJECTIVES: To evaluate the long-term outcomes in terms of satisfaction and mobility of adult patients who received childhood SDR. METHODS: Adult patients who received SDR in childhood were surveyed. The survey questionnaire asked about demographic information, quality of life, health outcomes, SDR surgical outcomes, ambulation, manual ability, pain, braces/orthotics, post-SDR treatment, living situation, education level, and work status. RESULTS: Our study included 95 patients. The age that patients received SDR was between two and 18 years. The age at the time of survey was between 23 and 37 years (mean +/- S.D., 30.2 +/- 3.6 years). Post-SDR follow-up ranged from 20 to 28 years (mean +/- S.D., 24.3 +/- 2.2 years). Seventy-nine percent of patients had spastic diplegia, 20% had spastic quadriplegia, and one percent had spastic triplegia. Ninety-one percent of patients felt that SDR impacted positively the quality of life and two percent felt that the surgery impacted negatively the quality of life after SDR. Compared to pre-operative ambulatory function, 42% reported higher level of ambulation and 42% ambulated in the same level. Eighty-eight percent of patients would recommend the procedure to others and two percent would not. Thirty-eight percent reported pain, mostly in the back and lower limbs, with mean pain level 4.2 +/- 2.3 on the Numeric Pain Rating Scale (NPRS). Decreased sensation in patchy areas of the lower limbs that did not affect daily life was reported by eight percent of patients. Scoliosis was diagnosed in 31%. The severity of scoliosis is unknown. Only three percent of them underwent spinal fusion. Fifty-seven percent of patients required some orthopedic surgery after SDR. The soft-tissue tendon lengthening procedures included lengthening on hamstrings, Achilles tendons or adductors. Out of all bone procedures, 24% of patients had hip surgery, five percent had knee surgery, and 10% had derotational osteotomies. No late side effects of SDR surgery were reported in this survey. CONCLUSIONS: In our 95 adult patients who received SDR in childhood, the surgery had positive effects on the quality of life and ambulation 20-28 years later. There were no late complications of SDR surgery. PMID- 28649480 TI - The Role of Organizational Culture in Operating Room Turnaround Time. AB - This analysis looks at the application of a robust process improvement methodology to achieve a sustained organizational change. The implementation took place in a safety net hospital's operating suites that had a problem with relatively long, nonproductive turnover times between surgical procedures. Organizational leadership empowered stakeholders to use Lean and Six-Sigma tools to develop more efficient organizational processes. These processes were then implemented in a phased approach with careful attention to the organization's culture. The result was a significant reduction in turnover times leading to greater operational efficiency. PMID- 28649482 TI - The Impact of Tobacco Use on Outcomes and Toxicity in a Predominantly Minority Population of Males with Prostate Cancer Receiving External Beam Radiation. AB - INTRODUCTION: To investigate whether current or prior smoking history had any impact on prostate cancer outcomes and toxicity in our predominantly minority population of males receiving dose-escalated external beam radiation therapy (EBRT). METHODS: Of the 500 patients treated with EBRT between 2003-2011, 444 had smoking histories recorded. Patients were classified as current smoker, former smoker, or never smoker. Biochemical failure-free survival (BFFS) and distant metastatic-free survival (DMFS) endpoints were analyzed. Multivariate Cox regression and multivariate logistic regression were used to assess whether smoking had an impact on outcomes and toxicity respectively. RESULTS : There were 176 males (39.6%) classified as never smokers, 169 (38.1%) as prior smokers, and 99 (22.3%) as current smokers. The median follow-up was 76 months (range nine 146) and 61.9% of patients were African American. The eight-year BFFS for never smokers, prior smokers and current smokers was 73.6%, 80.2%, and 73.4% respectively, p=0.38. Similarly, the eight-year DMFS was 92.8%, 96.8%, and 95.3% respectively, p=0.54. On multivariate analysis, prior smoking (HR 0.72, p=0.19) and current smoking (HR 1.02, p=0.93) were not associated with increased biochemical failure. Similarly, smoking use was not associated with increased distant metastatic disease (hormone receptor (HR) 0.71, p=0.51 for prior smokers, HR 1.41, p=0.52 for current smokers). The presence of intermediate-risk disease (HR 2.87, p=0.002) was associated with an increased likelihood of biochemical failure. The high-risk disease was associated with both a higher risk of biochemical failure (HR 8.02, p <0.001) as well as distant metastatic disease (HR 17.61, p=0.01). On multivariate regression, prior or current smoking use was not associated with an increased likelihood of late grade two genitourinary or gastrointestinal toxicity. CONCLUSION: Current or prior smoking use was not associated with inferior outcomes or increased toxicity in this study comprising a predominantly minority population undergoing dose escalated radiation therapy for prostate cancer. PMID- 28649483 TI - Measurement Equivalence of the Patient Reported Outcomes Measurement Information System(r) (PROMIS(r)) Anxiety Short Forms in Ethnically Diverse Groups. AB - : This is the first study of the measurement equivalence of the Patient Reported Outcomes Measurement Information System(r) (PROMIS(r)) Anxiety short forms in a large ethnically diverse sample. The psychometric properties and differential item functioning (DIF) were examined across different racial/ethnic, educational, age, gender and language groups. METHODS: These data are from individuals selected from cancer registries in the United States. For the analyses of race/ethnicity the reference group was non-Hispanic Whites (n = 2,263), the studied groups were non-Hispanic Blacks (n = 1,117), Hispanics (n = 1,043) and Asians/Pacific Islanders (n = 907). Within the Hispanic subsample, there were 335 interviews conducted in Spanish and 703 in English. The 11 anxiety items were from the PROMIS emotional disturbance item bank. DIF hypotheses were generated by content experts who rated whether or not they expected DIF to be present, and the direction of the DIF with respect to several comparison groups. The primary method used for DIF detection was the Wald test for examination of group differences in item response theory (IRT) item parameters accompanied by magnitude measures. Expected item scores were examined as measures of magnitude. The method used for quantification of the difference in the average expected item scores was the non-compensatory DIF (NCDIF) index. DIF impact was examined using expected scale score functions. Additionally, precision and reliabilities were examined using several methods. RESULTS: Although not hypothesized to show DIF for Asians/Pacific Islanders, every item evidenced DIF by at least one method. Two items showed DIF of higher magnitude for Asians/Pacific Islanders vs. Whites: "Many situations made me worry" and "I felt anxious". However, the magnitude of DIF was small and the NCDIF statistics were not above threshold. The impact of DIF was negligible. For education, six items were identified with consistent DIF across methods: fearful, anxious, worried, hard to focus, uneasy and tense. However, the NCDIF was not above threshold and the impact of DIF on the scale was trivial. No items showed high magnitude DIF for gender. Two items showed slightly higher magnitude for age (although not above the cutoff): worried and fearful. The scale level impact was trivial. Only one item showed DIF with the Wald test after the Bonferroni correction for the language comparisons: "I felt fearful". Two additional items were flagged in sensitivity analyses after Bonferroni correction, anxious and many situations made me worry. The latter item also showed DIF of higher magnitude, with an NCDIF value (0.144) above threshold. Individual impact was relatively small. CONCLUSIONS: Although many items from the PROMIS short form anxiety measures were flagged with DIF, item level magnitude was low and scale level DIF impact was minimal; however, three items: anxious, worried and many situations made me worry might be singled out for further study. It is concluded that the PROMIS Anxiety short form evidenced good psychometric properties, was relatively invariant across the groups studied, and performed well among ethnically diverse subgroups of Blacks, Hispanic, White non-Hispanic and Asians/Pacific Islanders. In general more research with the Asians/Pacific Islanders group is needed. Further study of subgroups within these broad categories is recommended. PMID- 28649481 TI - Cardio-Oncology: Cancer Therapy-related Cardiovascular Complications in a Molecular Targeted Era: New Concepts and Perspectives. AB - Cardio-oncology is a medical discipline that identifies, prevents, and treats the cardiovascular complications related to cancer therapy. Due to the remarkable proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia, we provide an extensive, comprehensive revision of the most up-to-date scientific information available on the cardiovascular complications associated with the use of newer, novel chemotherapeutic agents, including their reported incidence, suggested pathophysiology, clinical manifestations, potential treatment, and prevention. The authors consider this topic to be relevant for the clinicians since cardiovascular complications associated with the administration of recently approved drugs are relatively underappreciated. The purpose of this article is to provide a state-of-the-art review of cardiovascular complications associated with the use of newer, novel chemotherapeutic agents and targeted therapies, including their reported incidence, suggested pathophysiology, clinical manifestations, potential treatment, and prevention. Ongoing efforts are needed to provide a better understanding of the frequency, mechanisms of disease, prevention, and treatment of cardiovascular complications induced by the newer, novel chemotherapeutic agents. Development of a cardio-oncology discipline is warranted in order to promote task forces aimed at the creation of oncology patient centered guidelines for the detection, prevention, and treatment of potential cardiovascular side effects associated with newer cancer therapies. PMID- 28649484 TI - Enhancing the Angular Sensitivity of Plasmonic Sensors Using Hyperbolic Metamaterials. AB - Surface plasmon resonance (SPR) sensors operate mainly on prism and grating coupling techniques, with spectral and angular scans being the two major interrogation schemes. Among them, the angular scan technique has several advantages including higher measurement precision owing to its higher signal-to noise ratio. The currently available SPR sensor arrangements provide a maximum angular sensitivity of 500 degrees -600 degrees per RIU. Here, we report the study of grating coupled-hyperbolic metamaterial (GC-HMM) sensors with high angular sensitivity. The experimental studies show extraordinary angular sensitivities from visible to near infrared (NIR) wavelengths by exciting bulk plasmon polaritons associated with hyperbolic metamaterials, with a maximum of 7000 degrees per RIU. This angular-scan plasmonic biosensor has been used for the detection of low molecular weight biomolecules such as biotin (244 Da) and high molecular weight macromolecules such as Cowpea mosaic virus (CPMV, 5.6 * 106 Da) at ultralow concentrations. The miniaturized sensing device can be integrated with microfluidic systems for the development of next-generation biosensors for lab-on-a-chip and point-of-care applications. PMID- 28649485 TI - Scedosporium apiospermum brain abscesses in a patient after near-drowning - a case report with 10-year follow-up and a review of the literature. AB - Scedosporium apiospermum is known to be a fungal pathogen affecting immunocompromised as well as non-immunodeficient patients. Although this fungus is found rarely, an infection can lead to severe and even fatal disease. Here, we describe the case of a 41-year-old female who developed multiple Scedosporium apiospermum brain abscesses after near-drowning with aspiration of contaminated mud and water. She showed various neurological symptoms. The patient recovered after removal of abscesses in combination with long-term antifungal treatment. PMID- 28649486 TI - Constrictive pericarditis-induced shunting through a PFO: Persistence despite pericardiectomy. AB - A patent foramen ovale (PFO) is found in around 25-30% of patients. The discovery is often made only on autopsy, as most PFOs are clinically silent and any inter atrial blood exchange typically shunts from the left to right heart [1]. Thus, when a patient presents with hypoxic respiratory failure, concern for presence of a PFO is rarely at the top of the differential. However, in the setting of elevated right heart pressures, PFOs can become of great hemodynamic importance and can lead to deadly complications, including right to left shunting and refractory hypoxic respiratory failure. We present an unusual care of constrictive pericarditis leading to significant shunting through a PFO, and resultant hypoxic respiratory failure which only resolved with PFO closure. PMID- 28649487 TI - Rapid decrease of circulating tumor DNA predicted the treatment effect of nivolumab in a lung cancer patient within only 5 days. AB - A 77-year-old Japanese man presented to our hospital with a 1-month history of low back pain and was diagnosed as having stage IV EGFR mutation-positive lung adenocarcinoma. After treatment with EGFR tyrosine kinase inhibitor and cytotoxic chemotherapy, nivolumab was started as fourth-line therapy. Remarkable regression of the primary tumor was observed, suggesting high anti-tumor activity of nivolumab. We retrospectively investigated the change in circulating tumor DNA (ctDNA) variant allele fractions in serial plasma samples before and after the nivolumab therapy. Targeted sequencing analysis showed tumor-derived TP53R249S and EGFRL858R mutations detectable in plasma, and the timing of decrease was only 5 days, much earlier than the appearance of radiological changes. Overall, these results suggest that ctDNA might reflect tumor burden and might be a surrogate marker of the therapeutic efficacy of immune checkpoint therapy. PMID- 28649488 TI - Hemoptysis in a previously healthy elderly patient with an unrecognized tracheal bronchus: A case report. AB - A 83-year-old healthy female with no past medical history presented with persistent hemoptysis and respiratory failure. She was found to have a tracheal bronchus on bronchoscopy. Patient underwent pulmonary lavage and sterile irrigation. Patient was stable, but developed excessive hemoptysis which prompted a repeat, emergent, bronchoscopy was performed to advance the ET tube to isolate the left lung from the bleeding right lung. Despite the effort taken, the patient became pulseless from the hypoxia caused by blood spillover into the entire tracheobronchial field. ACLS protocol initiated without successful ROSC. Tracheal bronchus is uncommon but when present patients usually develop recurrent pulmonary symptoms at a younger age which require extensive workup which can lead to discovery of pulmonary anomalies. In our patient, she has no recurrent pulmonary symptoms as a child nor as an adult. We suspect the reason to this is the normal size diameter of the bronchus that connects the accessary lobe to the trachea. There are a few Medical conditions that may present with hemoptysis. When there is persistent, new onset hemoptysis in an otherwise healthy individual there should be no hesitation in performing the necessary procedural studies to reach a diagnosis. PMID- 28649489 TI - Brain functional connectivity is associated with visceral sensitivity in women with Irritable Bowel Syndrome. AB - Increased perception of visceral stimuli is a key feature of Irritable Bowel Syndrome (IBS). While altered resting-state functional connectivity (rsFC) has been also reported in IBS, the relationship between visceral hypersensitivity and aberrant rsFC is unknown. We therefore assessed rsFC within the salience, sensorimotor and default mode networks in patients with and without visceral hypersensitivity and in healthy controls (HCs). An exploratory resting-state functional magnetic resonance imaging study was performed in 41 women with IBS and 20 HCs. Group independent component analysis was used to derive intrinsic brain networks. Rectal thresholds were determined and patients were subdivided into groups with increased (hypersensitive IBS, N = 21) or normal (normosensitive IBS, N = 20) visceral sensitivity. Between-group comparisons of rsFC were carried out using region-of-interest analyses and peak rsFC values were extracted for correlational analyses. Relative to normosensitive IBS, hypersensitive patients showed increased positive rsFC of pregenual anterior cingulate cortex and thalamus within the salience network and of posterior insula within the sensorimotor network. When compared to both hypersensitive IBS and HCs, normosensitive IBS showed decreased positive rsFC of amygdala and decreased negative rsFC in dorsal anterior insula within the DMN. DMN and sensorimotor network rsFC were associated with rectal perception thresholds, and rsFC in posterior insula was correlated with reported symptom severity in IBS. Our exploratory findings suggest that visceral sensitivity in IBS is related to changes in FC within resting-state networks associated with interoception, salience and sensory processing. These alterations may play an important role in hypervigilance and hyperalgesia in IBS. PMID- 28649490 TI - Frequency-dependent changes in local intrinsic oscillations in chronic primary insomnia: A study of the amplitude of low-frequency fluctuations in the resting state. AB - New neuroimaging techniques have led to significant advancements in our understanding of cerebral mechanisms of primary insomnia. However, the neuronal low-frequency oscillation remains largely uncharacterized in chronic primary insomnia (CPI). In this study, the amplitude of low-frequency fluctuation (ALFF), a data-driven method based on resting-state functional MRI, was used to examine local intrinsic activity in 27 patients with CPI and 27 age-, sex-, and education matched healthy controls. We examined neural activity in two frequency bands, slow-4 (between 0.027 and 0.073 Hz) and slow-5 (0.010-0.027 Hz), because blood oxygen level dependent (BOLD) fluctuations in different low-frequency bands may present different neurophysiological manifestations that pertain to a spatiotemporal organization. The ALFF associated with the primary disease effect was widely distributed in the cerebellum posterior lobe (CPL), dorsal and ventral prefrontal cortex, anterior cingulate cortex, precuneus, somatosensory cortex, and several default-mode sub-regions. Several brain regions (i.e., the right cerebellum, anterior lobe, and left putamen) exhibited an interaction between the frequency band and patient group. In the slow-5 band, increased ALFF of the right postcentral gyrus/inferior parietal lobule (PoCG/IPL) was enhanced in association with the sleep quality (rho = 0.414, P = 0.044) and anxiety index (rho = 0.406, P = 0.049) of the CPI patients. These findings suggest that during chronic insomnia, the intrinsic functional plasticity primarily responds to the hyperarousal state, which is the loss of inhibition in sensory-informational processing. Our findings regarding an abnormal sensory input and intrinsic processing mechanism might provide novel insight into the pathophysiology of CPI. Furthermore, the frequency factor should be taken into consideration when exploring ALFF-related clinical manifestations. PMID- 28649491 TI - Ventricular shape and relative position abnormalities in preterm neonates. AB - Recent neuroimaging findings have highlighted the impact of premature birth on subcortical development and morphological changes in the deep grey nuclei and ventricular system. To help characterize subcortical microstructural changes in preterm neonates, we recently implemented a multivariate tensor-based method (mTBM). This method allows to precisely measure local surface deformation of brain structures in infants. Here, we investigated ventricular abnormalities and their spatial relationships with surrounding subcortical structures in preterm neonates. We performed regional group comparisons on the surface morphometry and relative position of the lateral ventricles between 19 full-term and 17 preterm born neonates at term-equivalent age. Furthermore, a relative pose analysis was used to detect individual differences in translation, rotation, and scale of a given brain structure with respect to an average. Our mTBM results revealed broad areas of alterations on the frontal horn and body of the left ventricle, and narrower areas of differences on the temporal horn of the right ventricle. A significant shift in the rotation of the left ventricle was also found in preterm neonates. Furthermore, we located significant correlations between morphology and pose parameters of the lateral ventricles and that of the putamen and thalamus. These results show that regional abnormalities on the surface and pose of the ventricles are also associated with alterations on the putamen and thalamus. The complementarity of the information provided by the surface and pose analysis may help to identify abnormal white and grey matter growth, hinting toward a pattern of neural and cellular dysmaturation. PMID- 28649494 TI - Editorial. PMID- 28649492 TI - Relationship between brainstem neurodegeneration and clinical impairment in traumatic spinal cord injury. AB - BACKGROUND: Brainstem networks are pivotal in sensory and motor function and in recovery following experimental spinal cord injury (SCI). OBJECTIVE: To quantify neurodegeneration and its relation to clinical impairment in major brainstem pathways and nuclei in traumatic SCI. METHODS: Quantitative MRI data of 30 chronic traumatic SCI patients (15 with tetraplegia and 15 with paraplegia) and 23 controls were acquired. Patients underwent a full neurological examination. We calculated quantitative myelin-sensitive (magnetisation transfer saturation (MT) and longitudinal relaxation rate (R1)) and iron-sensitive (effective transverse relaxation rate (R2*)) maps. We constructed brainstem tissue templates using a multivariate Gaussian mixture model and assessed volume loss, myelin reductions, and iron accumulation across the brainstem pathways (e.g. corticospinal tracts (CSTs) and medial lemniscus), and nuclei (e.g. red nucleus and periaqueductal grey (PAG)). The relationship between structural changes and clinical impairment were assessed using regression analysis. RESULTS: Volume loss was detected in the CSTs and in the medial lemniscus. Myelin-sensitive MT and R1 were reduced in the PAG, the CSTs, the dorsal medulla and pons. No iron-sensitive changes in R2* were detected. Lower pinprick score related to more myelin reductions in the PAG, whereas lower functional independence was related to more myelin reductions in the vestibular and pontine nuclei. CONCLUSION: Neurodegeneration, indicated by volume loss and myelin reductions, is evident in major brainstem pathways and nuclei following traumatic SCI; the magnitude of these changes relating to clinical impairment. Thus, quantitative MRI protocols offer new targets, which may be used as neuroimaging biomarkers in treatment trials. PMID- 28649495 TI - Non-hyperammonaemic valproate encephalopathy after 20 years of treatment. AB - Sodium valproate is a commonly used antiseizure drug with broad indications for different seizuretypes and epilepsy syndromes. Well-recognised side effects include weight gain, tremor, dizziness, and unsteadiness. Non-hyperammonaemic parkinsonism, with or without cognitive impairment, is a rare adverse effect of sodium valproate. We present the case of a sixty year-old lady with a generalized seizure disorder, treated with phenytoin, valproate, lamotrigine and clonazepam. Following withdrawal of phenytoin she developed an akinetic-rigid syndrome, with ataxia and marked cognitive impairment. Extensive investigation failed to identify a cause. Serum ammonia and valproate levels were normal. Hypothesizing this might be valproate encephalopathy, valproate was rapidly substituted with levetiracetam. Her severe motor symptoms resolved within two weeks and cognitive impairment markedly improved. Valproate-induced encephalopathy, with or without hyperammonaemia and liver toxicity are typically recognizable for their temporal relation between the start of therapy with valproate and emergence of the clinical syndrome. Reversible disorders of motor function and cognition attributable to valproate are well described, but few cases have been reported presenting years after starting treatment. Given the insidious progression, delayed onset, lack of association with drug levels or presence of hyperammonaemia, a high index of suspicion is needed to make the diagnosis. PMID- 28649493 TI - Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease. AB - The ability to inhibit automatic versus voluntary saccade commands in demanding situations can be impaired in neurodegenerative diseases such as Huntington's disease (HD). These deficits could result from disruptions in the interaction between basal ganglia and the saccade control system. To investigate voluntary oculomotor control deficits related to the cortico-basal circuitry, we evaluated early HD patients using an interleaved pro- and anti-saccade task that requires flexible executive control to generate either an automatic response (look at a peripheral visual stimulus) or a voluntary response (look away from the stimulus in the opposite direction). The impairments of HD patients in this task are mainly attributed to degeneration in the striatal medium spiny neurons leading to an over-activation of the indirect-pathway thorough the basal ganglia. However, some studies have proposed that damage outside the indirect-pathway also contribute to executive and saccade deficits. We used the interleaved pro- and anti-saccade task to study voluntary saccade inhibition deficits, Voxel-based morphometry and Tract-based spatial statistic to map cortico-basal ganglia circuitry atrophy in HD. HD patients had voluntary saccade inhibition control deficits, including increased regular-latency anti-saccade errors and increased anticipatory saccades. These deficits correlated with white-matter atrophy in the inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior corona radiata and superior longitudinal fasciculus. These findings suggest that cortico-basal ganglia white-matter atrophy in HD, disrupts the normal connectivity in a network controlling voluntary saccade inhibitory behavior beyond the indirect-pathway. This suggests that in vivo measures of white-matter atrophy can be a reliable marker of the progression of cognitive deficits in HD. PMID- 28649496 TI - De novo transcriptome assembly of loggerhead sea turtle nesting of the Colombian Caribbean. AB - Loggerhead sea turtle Caretta caretta is widely distributed in the oceans of tropical and subtropical latitude. This turtle is an endangered species due to anthropic and natural factors that have decreased their population levels. In this study, RNA sequencing and de-novo assembly of genes expressed in blood were performed. The raw FASTQ files have been deposited on NCBI's SRA database with accession number SRX2629512. A total of 5.4 Gb raw sequence data were obtained, corresponding to 48,257,019 raw reads. Trinity pipeline was used to perform a de novo assembly, we were able to identify 64,930 transcripts for female loggerhead turtle transcriptome with an N50 of 1131 bp. The obtained transcriptome data will be useful for further studies of the physiology, biochemistry and evolution in this species. PMID- 28649498 TI - Oversensing of an unexpected atrial flutter. A new tool to improve detection of supraventricular arrhythmias in subcutaneous implantable cardioverter defibrillators. PMID- 28649497 TI - Spectral analysis assisted photoacoustic imaging for lipid composition differentiation. AB - Recent advances in atherosclerotic plaque detection have shown that not only does lipid core size and depth play important roles in plaque rupture and thrombi formation, but lipid composition, especially cholesterol deposition, is equally important in determining lesion vulnerability. Here, we demonstrate a spectral analysis assisted photoacoustic imaging approach to differentiate and map lipid compositions within an artery wall. The approach is based on the classification of spectral curves obtained from the sliding windows along time-of-flight photoacoustic signals via a numerical k-means clustering method. The evaluation result on a vessel-mimicking phantom containing cholesterol and olive oil shows accuracy and efficiency of this method, suggesting the potential to apply this approach in assessment of atherosclerotic plaques. PMID- 28649499 TI - Macroreentrant form of an adenosine 5'-triphosphate-sensitive atrial tachycardia arising from the vicinity of the atrioventricular node involving the tricuspid and mitral annuli as its reentrant circuit. PMID- 28649500 TI - Complete congenital heart block: A case of multilevel block. PMID- 28649501 TI - Efficacy of a pure Ikr blockade with nifekalant in refractory neonatal congenital junctional ectopic tachycardia and careful attention to damaging the atrioventricular conduction during the radiofrequency catheter ablation in infancy. PMID- 28649502 TI - Rise in defibrillation threshold after postoperative cardiac remodeling in a patient with severe Ebstein's anomaly. PMID- 28649503 TI - Subcutaneous implantable cardioverter-defibrillator placement in a patient with a preexisting transvenous implantable cardioverter-defibrillator. PMID- 28649504 TI - Dual intraventricular response after cardiac resynchronization. PMID- 28649505 TI - Wide complex tachycardia in a patient with pre-excitation: What is the mechanism? PMID- 28649506 TI - Vibratory alert in a recalled implantable cardioverter-defibrillator: Is there something wrong with the device? PMID- 28649507 TI - Permanent His bundle pacing at the time of atrioventricular node ablation: A 3 dimensional mapping approach. PMID- 28649508 TI - Isolation of Shewanella putrefaciens in an elderly man with subacute intestinal obstruction & appendicitis. AB - Shewanella is Gram-negative motile bacillus, non fermentative and facultative anaerobe. Its natural habitat is all forms of water and soil, but has also been isolated from fish, dairy products, oils, and carcasses. Often found with microflora of the marine environment. Bacterial infections with Shewanella spp. are rare. The exposure to the marine environment, sea and diary food are considered as a risk factor for Shewanella spp. infection. Clinical infections seen are otitis, soft tissue infection, bacteremia, ear infection, eye infection, infective arthritis, osteomyelitis, infective endocarditis and peritonitis. PMID- 28649509 TI - Fabry disease: Four case reports of meningioma and a review of the literature on other malignancies. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder caused by loss of function mutations in the GLA gene at Xq22 with subsequent functional deficiency of alpha-galactosidase A, resulting in the accumulation of globotriaosylceramide (GL-3 or Gb3) in multiple cells types throughout the body. As with other rare metabolic disorders, little is known about the incidence of malignancies in these populations and the relationship to the underlying disease, if any. We report the occurrence of meningioma in four female patients with Fabry disease. Two of the cases are from the same family and shared the same GLA mutation. All four patients underwent surgical excision of their tumor. High resolution light microscopy and electron microscopy examination of one case revealed extensive involvement of tumor cells and associated blood vessels by GL-3 accumulation. Because of the small number of Fabry-associated cancer cases reported in the literature, questions about a possible link between lysosomal storage disorders and the development of malignancy remain open. PMID- 28649510 TI - Targeted screening of succinic semialdehyde dehydrogenase deficiency (SSADHD) employing an enzymatic assay for gamma-hydroxybutyric acid (GHB) in biofluids. AB - HYPOTHESIS: An enzymatic assay for quantification of gamma-hydroxybutyric acid (GHB) in biofluids can be employed for targeted screening of succinic semialdehyde dehydrogenase deficiency (SSADHD) in selected populations. RATIONALE: We used a two-tiered study approach, in which the first study (proof of concept) examined 7 urine samples derived from patients with SSADHD and 5 controls, and the second study (feasibility study) examined a broader sample population of patients and controls, including plasma. OBJECTIVE: Split samples of urine and plasma (anonymized) were evaluated by enzymatic assay, gas chromatography alone (proof of concept) and gas chromatography-mass spectrometry, and the results compared. METHOD: Multiple detection methods have been developed to detect GHB. We evaluated an enzymatic assay which employs recombinant GHB dehydrogenase coupled to NADH production, the latter quantified on a Cobas Integra 400 Plus. Results: In our proof of concept study, we analyzed 12 urine samples (5 controls, 7 SSADHD), and in the feasibility study we evaluated 33 urine samples (23 controls, 10 SSADHD) and 31 plasma samples (14 controls, 17 SSADHD). The enzymatic assay carried out on a routine clinical chemistry analyzer was robust, revealing excellent agreement with instrumental methods in urine (GC FID: r = 0.997, p <= 0.001; GC-MS: r = 0.99, p <= 0.001); however, the assay slightly over-estimated GHB levels in plasma, especially those in which GHB levels were low. Conversely, correlations for the enzymatic assay with comparator methods for higher plasma GHB levels were excellent (GC-MS; r = 0.993, p <= 0.001). CONCLUSION: We have evaluated the capacity of this enzymatic assay to identify patients with SSADHD via quantitation of GHB. The data suggests that the enzymatic assay may be a suitable screening method to detect SSADHD in selected populations using urine. In addition, the assay can be used in basic research the elucidate the mechanism of the underlying disease or monitor GHB- levels for the evaluation of drug candidates. SYNOPSIS: An enzymatic assay for GHB in biofluids was evaluated as a screening method for SSADHD and found to be reliable in urine, but in need of refinement for application to plasma. PMID- 28649511 TI - Why does Leigh syndrome respond to immunotherapy? PMID- 28649512 TI - Next-generation sequencing corroborates a probable de novo GNPTG variation previously detected by Sanger sequencing. PMID- 28649513 TI - Reply: Low bone mineral density is a common feature of Zellweger spectrum disorders. PMID- 28649514 TI - Early hematopoietic stem cell transplantation in a patient with severe mucopolysaccharidosis II: A 7 years follow-up. AB - Mucopolysaccharidosis type II (MPS II - Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2 sulfatase (I2S), leading to the accumulation of the glycosaminoglycans, affecting multiple organs and systems. Enzyme replacement therapy does not cross the blood brain barrier, limiting results in neurological forms of the disease. Another option of treatment for severe MPS, hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for the severe form of MPS type I, since it can preserve neurocognition when performed early in the course of the disease. To date, only few studies have examined the long-term outcomes of HSCT in patients with MPS II. We describe the seven-year follow-up of a prenatally diagnosed MPS II boy with positive family history of severe MPS form, submitted to HSCT with umbilical cord blood cells at 70 days of age. Engraftment after 30 days revealed mixed chimerism with 79% donor cells; after 7 years engraftment remains at 80%. I2S activity 30 days post-transplant was low in plasma and normal in leukocytes and the same pattern is observed to date. At age 7 years growth charts are normal and he is very healthy, although mild signs of dysostosis multiplex are present, as well as hearing loss. The neuropsychological evaluation (Wechsler Intelligence Scale for Children - Fourth Edition - WISC-IV), disclosed an IQ of 47. Despite this low measured IQ, the patient continues to show improvements in cognitive, language and motor skills, being quite functional. We believe that HSCT is a therapeutic option for MPS II patients with the severe phenotype, as it could preserve neurocognition or even halt neurodegeneration, provided strict selection criteria are followed. PMID- 28649515 TI - Higher oxidative stress in skeletal muscle of McArdle disease patients. AB - McArdle disease (MCD) is an autosomal recessive condition resulting from skeletal muscle glycogen phosphorylase deficiency. The resultant block in glycogenolysis leads to an increased flux through the xanthine oxidase pathway (myogenic hyperuricemia) and could lead to an increase in oxidative stress. We examined markers of oxidative stress (8-isoprostane and protein carbonyls), NAD(P)H oxidase, xanthine oxidase and antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activity in skeletal muscle of MCD patients (N = 12) and controls (N = 12). Eight-isoprostanes and protein carbonyls were higher in MCD patients as compared to controls (p < 0.05). There was a compensatory up regulation of catalase protein content and activity (p < 0.05), mitochondrial superoxide dismutase (MnSOD) protein content (p < 0.01) and activity (p < 0.05) in MCD patients, yet this increase was not sufficient to protect the muscle against elevated oxidative damage. These results suggest that oxidative stress in McArdle patients occurs and future studies should evaluate a potential role for oxidative stress contributing to acute pathology (rhabdomyolysis) and possibly later onset fixed myopathy. PMID- 28649516 TI - Novel frameshift variant in the IDUA gene underlies Mucopolysaccharidoses type I in a consanguineous Yemeni pedigree. AB - Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disorder that result as a consequence of a deficiency in the lysosomal hydrolase, a-L iduronidase enzyme encoded by IDUA gene. Over a hundred causative variants in IDUA have been identified, which result in a progressive multi-systemic disease with a broad range of severity and disease progression reported across affected individuals. The aim of this study was the detection and interpretation of IDUA mutation in a family with two children affected with lethal MPS I. The IDUA gene was sequenced in the parents of two deceased children who had a clinical diagnosis of MPS I, to assess their carrier status and to help inform on risk in future children. The sequencing analysis was performed by PCR and bidirectional Sanger sequencing of the coding region and exon-intron splice junctions at Labor MVZ Westmecklenburg molecular diagnostics laboratory. A heterozygous c.657delA variant in exon 6 was identified in each parent, which is the most likely explanation for disease in their children. This report represents the first Yemeni family to have a molecular diagnosis for MPS I. PMID- 28649517 TI - Comparison of tandem mass spectrometry to fluorimetry for newborn screening of LSDs. PMID- 28649519 TI - ALG11-CDG: Three novel mutations and further characterization of the phenotype. AB - We report on two novel patients with ALG11-CDG. The phenotype was characterized by severe psychomotor disability, progressive microcephaly, sensorineural hearing loss, therapy-resistant epilepsy with burst suppression EEG, cerebral atrophy with, in one of them, neuronal heterotopia, and early lethality. Analysis of ALG11 revealed compound heterozygosity involving three novel mutations: the splice site mutation c.45-2A > T, the c.36dupG duplication, and the missense mutation c.479G > T (p.G160V) that was present in both. PMID- 28649518 TI - Insights in the etiopathology of galactosyltransferase II (GalT-II) deficiency from transcriptome-wide expression profiling of skin fibroblasts of two sisters with compound heterozygosity for two novel B3GALT6 mutations. AB - Mutations in B3GALT6, encoding the galactosyltransferase II (GalT-II) involved in the synthesis of the glycosaminoglycan (GAG) linkage region of proteoglycans (PGs), have recently been associated with a spectrum of connective tissue disorders, including spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) and Ehlers-Danlos-like syndrome. Here, we report on two sisters compound heterozygous for two novel B3GALT6 mutations that presented with severe short stature and progressive kyphoscoliosis, joint hypermobility and laxity, hyperextensible skin, platyspondyly, short ilia, and elbow malalignment. Microarray-based transcriptome analysis revealed the differential expression of several genes encoding extracellular matrix (ECM) structural components, including COMP, SPP1, COL5A1, and COL15A1, enzymes involved in GAG synthesis and in ECM remodeling, such as CSGALNACT1, CHPF, LOXL3, and STEAP4, signaling transduction molecules of the TGFbeta/BMP pathway, i.e., GDF6, GDF15, and BMPER, and transcription factors of the HOX and LIM families implicated in skeletal and limb development. Immunofluorescence analyses confirmed the down-regulated expression of some of these genes, in particular of the cartilage oligomeric matrix protein and osteopontin, encoded by COMP and SPP1, respectively, and showed the predominant reduction and disassembly of the heparan sulfate specific GAGs, as well as of the PG perlecan and type III and V collagens. The key role of GalT-II in GAG synthesis and the crucial biological functions of PGs are consistent with the perturbation of many physiological functions that are critical for the correct architecture and homeostasis of various connective tissues, including skin, bone, cartilage, tendons, and ligaments, and generates the wide phenotypic spectrum of GalT-II-deficient patients. PMID- 28649520 TI - Successful reduction of high-sustained anti-idursulfase antibody titers by immune modulation therapy in a patient with severe mucopolysaccharidosis type II. AB - We report on a 6 year old boy with severe MPS II undergoing immune modulation therapy due to high IgG antibody titers to IV idursulfase and no significant decline in urinary GAG levels since initiating enzyme replacement therapy. He has complete deficiency of iduronate-2-sulfatase activity due to a submicroscopic deletion of the X chromosome involving the entire I2S gene but not including in the fragile X locus. At 19 months of age, IV idursulfase therapy at the recommended dose of 0.5 mg/kg/week was initiated and then increased to 1.0 mg/kg/week after no observed clinical improvement and no decline in urine GAG level. After one year of ERT at the increased dose, he had no significant decline in urinary GAG excretion and increase of anti-idursulfase IgG antibody titers to 102,000 with complete neutralizing antibodies. In light of the evidence of lack of efficacy of idursulfase therapy, the patient was started on an immune modulation regimen consisting of ofatumumab, bortezomib, methotrexate and IVIG for a 12 week period. Only a slight decrease in IgG titers and urine GAG levels was observed, leading to increased intensity of bortezomib administration and addition of dexamethasone to the regimen, while continuing with the current schedule ofatumumab, IVIG and methotrexate. Over 18 month period of immune modulation therapy, we observed a significant reduction in anti-idursulfase IgG titers and a moderate reduction in urine GAG levels compared to baseline. Modest clinical improvements were observed. Our experience suggests that future MPS II patients with a complete gene deletion may be likely to develop persistent anti idursulfase antibody titers and may benefit from immune modulation therapy prior to the development of high titer levels. PMID- 28649522 TI - Obstetric risk in patients with myopathy due to MATR3 mutations. AB - BACKGROUND: The obstetric risk associated with myopathy due to MATR3 mutations is unknown. METHODS: Eight women with the MATR3 p.S85C mutation were recruited. Information on pregnancy, outcome, and effect on muscular function was analysed retrospectively using a pregnancy and delivery questionnaire. The data were compared with information from the German perinatal quality survey. RESULTS: All eight women responded. Their muscular symptoms started between the ages of 36 and 56. Sixteen pregnancies and twelve deliveries could be analysed. Two women had a voluntary abortion after their deliveries for other medical reasons. One woman reported a miscarriage in the first trimester. Five women had pregnancies and deliveries without complications. One woman twice had labour weakness requiring forceps delivery. Another patient twice had a preterm dilatation of the cervical os and forceps deliveries. One of her children had foetal distress and was born preterm and with low birth weight. No perinatal childhood death was reported. No women described muscular symptoms before or during their pregnancies. CONCLUSIONS: Pregnancies in matrin 3 myopathy typically occur several years before the onset of myopathy. No increase in the incidence of foetal distress or miscarriage was found. However, late pregnancies (e.g. in the 5th decade) should be regarded as pregnancies at risk. PMID- 28649521 TI - Pyruvate carboxylase deficiency: An underestimated cause of lactic acidosis. AB - Pyruvate carboxylase (PC) is a biotin-containing mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in gluconeogenesis and in energy production through replenishment of the tricarboxylic acid (TCA) cycle with oxaloacetate. PC deficiency is a very rare metabolic disorder. We report on a new patient affected by the moderate form (the American type A). Diagnosis was nearly fortuitous, resulting from the revision of an initial diagnosis of mitochondrial complex IV (C IV) defect. The patient presented with severe lactic acidosis and pronounced ketonuria, associated with lethargy at age 23 months. Intellectual disability was noted at this time. Amino acids in plasma and organic acids in urine did not show patterns of interest for the diagnostic work-up. In skin fibroblasts PC showed no detectable activity whereas biotinidase activity was normal. We had previously reported another patient with the severe form of PC deficiency and we show that she also had secondary C IV deficiency in fibroblasts. Different anaplerotic treatments in vivo and in vitro were tested using fibroblasts of both patients with 2 different types of PC deficiency, type A (patient 1) and type B (patient 2). Neither clinical nor biological effects in vivo and in vitro were observed using citrate, aspartate, oxoglutarate and bezafibrate. In conclusion, this case report suggests that the moderate form of PC deficiency may be underdiagnosed and illustrates the challenges raised by energetic disorders in terms of diagnostic work-up and therapeutical strategy even in a moderate form. PMID- 28649523 TI - Exome sequencing for mucolipidosis III: Detection of a novel GNPTAB gene mutation in a patient with a very mild phenotype. AB - Mucolipidosis II and III alpha/beta (ML II/III alpha/beta) are rare autosomal recessive lysosomal storage diseases that are caused by a deficiency of UDP GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the enzyme responsible for the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. A Brazilian patient suspected of having a very mild ML III was investigated using whole next-generation sequencing (NGS). Two mutations in the GNPTAB gene were detected and confirmed to be in trans status by parental analysis: c.1208T>C (p.Ile403Thr), previously reported as being pathogenic, and the novel mutation c.1723G>A (p.Gly575Arg). This study demonstrates the effectiveness of using whole NGS for the molecular diagnosis of very mild ML III alpha/beta patients. PMID- 28649524 TI - Serum beta2-microglobulin is frequently elevated in type 1 Gaucher patients. AB - beta2-Microglobulin is the major prognostic factor in multiple myeloma, a known comorbidity of Gaucher disease. We evaluated herein serum beta2-microglobulin levels of 31 type 1 Gaucher patients; for 8/31 patients, pre- and post-treatment comparisons were made. Thirteen patients (on treatment = 6) had high levels of beta2-microglobulin, and showed higher chitotriosidase activity and Severity Score Index, and lower concentration of platelets, than patients with normal levels. Levels of beta2-microglobulin correlated with chitotriosidase activity (rho = 0.65; p < 0.01), platelets (rho = - 0.42; p = 0.02) and alpha1- (rho = 0.43; p = 0.02) and alpha2-protein bands (rho = - 0.40; p = 0.03). Regarding pre- and post-treatment values, median beta2-microglobulin levels decreased after treatment (pre- = 2931 ng/mL; post- = 1970 ng/mL; p < 0.01). Our data suggest that levels of serum beta2-microglobulin are frequently elevated in type 1 Gaucher patients, correlate with severity of the disease and decrease after treatment. PMID- 28649525 TI - Effects of naturally occurring missense mutations and G525V in the hydratase domain of human d-bifunctional protein on hydratase activity. AB - d-bifunctional protein (d-BP) deficiency is thought to lead to severe lipid metabolism disorders. To investigate the effect of naturally occurring missense mutations in the hydratase domain in d-BP, we constructed several d-BP hydratase variants and measured their activities. Missense mutations at sites whose conservation rates among 30 eukaryotes were < 70% did not affect hydratase activity. We predicted that missense mutations of highly conserved amino acids would markedly reduce activity. However, R562H and R562L, naturally occurring missense mutations of highly conserved amino acids, did not reduce activity. This result suggests that a missense mutation in a highly conserved amino acid does not always lead to severe lipid metabolism disorders. We also investigated the effect of G525V, which had been found in a mildly symptomatic patient with d-BP deficiency who was heterozygous for G525 and G658X. G525V markedly reduced hydratase activity. We had predicted that heterozygous G525V and G658X would lead to severely disordered lipid metabolism. However, the symptoms were inconsistent with this prediction. Characterizing mutations in the d-BP gene and the symptoms of d-BP deficiency may require pleiotropy, not only in vitro, studies. PMID- 28649526 TI - Hyperammonemic crisis in a child with ATP synthase deficiency caused by mtDNA mutation m.8851T>C. PMID- 28649527 TI - Lysinuric protein intolerance in a family of Mexican ancestry with a novel SLC7A7 gene deletion. Case report and review of the literature. AB - Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder caused by mutations in the SLC7A7 located on the chromosome 14q11.2. LPI is most prevalent in Finland (1:50,000), Northern Japan (1:60,000) and Italy. Cases have also been reported in Spain and the United States. Here we report two siblings of Mexican descent. The older child was diagnosed at the age of three with severe chronic respiratory insufficiency leading to her demise. In contrast, the younger child was diagnosed soon after birth and dietary therapy has led to a stable life. Genetic analysis revealed a previously unreported deletion in the SLC7A7 gene. Additional research is needed to clarify the role of lysine in the pathophysiology of pulmonary proteinosis and herpes infections. PMID- 28649528 TI - Corrective effects of hepatotoxicity by hepatic Dyrk1a gene delivery in mice with intermediate hyperhomocysteinemia. AB - Hyperhomocysteinemia results from hepatic metabolism dysfunction and is characterized by a high plasma homocysteine level, which is also an independent risk factor for cardiovascular disease. Elevated levels of homocysteine in plasma lead to hepatic lesions and abnormal lipid metabolism. Therefore, lowering homocysteine levels might offer therapeutic benefits. Recently, we were able to lower plasma homocysteine levels in mice with moderate hyperhomocysteinemia using an adenoviral construct designed to restrict the expression of DYRK1A, a serine/threonine kinase involved in methionine metabolism (and therefore homocysteine production), to hepatocytes. Here, we aimed to extend our previous findings by analyzing the effect of hepatocyte-specific Dyrk1a gene transfer on intermediate hyperhomocysteinemia and its associated hepatic toxicity and liver dysfunction. Commensurate with decreased plasma homocysteine and alanine aminotransferase levels, targeted hepatic expression of DYRK1A in mice with intermediate hyperhomocysteinemia resulted in elevated plasma paraoxonase-1 and lecithin:cholesterol acyltransferase activities and apolipoprotein A-I levels. It also rescued hepatic apolipoprotein E, J, and D levels. Further, Akt/GSK3/cyclin D1 signaling pathways in the liver of treated mice were altered, which may help prevent homocysteine-induced cell cycle dysfunction. DYRK1A gene therapy could be useful in the treatment of hyperhomocysteinemia in populations, such as end-stage renal disease patients, who are unresponsive to B-complex vitamin therapy. PMID- 28649529 TI - Compound heterozygosity with a novel S222N GALT mutation leads to atypical galactosemia with loss of GALT activity in erythrocytes but little evidence of clinical disease. AB - Galactosemia is an inborn error of galactose metabolism caused by mutations in the GALT gene. Though early detection and galactose restriction prevent severe liver disease, affected individuals have persistently elevated biomarkers and often neuro-developmental symptoms. We present a teenage compound heterozygote for a known pathogenic mutation (H132Q) and a novel variant of unknown significance (S222N), with nearly absent erythrocyte GALT enzyme activity but normal biomarkers and only mild anxiety despite diet non-adherence. This case is similar to a previously reported S135L mutation. In this report we investigate the novel S222N variant and critically evaluate a clinically puzzling case. PMID- 28649530 TI - Tetrahydrobiopterin responsiveness in a series of 53 cases of phenylketonuria and hyperphenylalaninemia in Iran. AB - : To determine the prevalence of 6R-Tetrahydrobiopterin (BH4) responsive phenylketonuria (PKU) in 53 cases of patients with various classification of hyperphenylalaninemia and PKU Excluding the BH4 deficient type referring to children's medical center in Iran (phenylalanine 360-2420 MUmol/L), the single dose of 20 mg/kg (Kuvan(r)) and duration of 24 h was used. RESULTS: Among the 4 different categories of mild hyperphenylalaninemia requiring treatment, mild, moderate and classic PKU, the BH4 responders were 90%, 35.7%, 5.6% and 0% respectively after 24 h. CONCLUSION: BH4 responsiveness is more prevalent in mild hyperphenylalaninemia and mild PKU patients in Iran. PMID- 28649531 TI - Stormorken syndrome or York platelet syndrome: A clinician's dilemma. PMID- 28649532 TI - First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children. AB - We report three symptomatic children with profound biotinidase deficiency from Sri Lanka. All three children presented with typical clinical features of the disorder. The first is homozygous for a missense mutation in the BTD gene (c.98_104 del7insTCC; p.Cys33PhefsX36) that is commonly seen in the western countries, the second is homozygous for a novel missense mutation (p.Ala439Asp), and the third is the first reported instance of a contiguous gene deletion causing the enzyme deficiency. In addition, this latter finding exemplifies the importance of considering a deletion within the BTD gene for reconciling enzymatic activity with genotype, which can occur in asymptomatic children who are identified by newborn screening. PMID- 28649533 TI - When should social service referral be considered in phenylketonuria? AB - Lifelong low-phenylalanine (Phe) dietary management is the foundation of care in phenylketonuria (PKU). However, strict monitoring of food intake places a burden on patients and their caregivers, and adherence to the required diet frequently decreases in later childhood and adolescence. Rarely, parents of children with PKU refuse to recognise the importance of treatment and follow-up for this chronic condition. Here, two case studies are presented that document consideration of placement of children into foster care or kinship homes as a last resort to improve persistently high Phe concentrations. In the first case, social service referral led to a 3-year-old girl being placed in a kinship home with her grandparents, resulting in excellent Phe control thereafter. In the second case, discussion with the parents of possible placement of a 12-year-old child into foster care was sufficient to have a positive effect on Phe control. A staged approach for managing intractable non-adherence in PKU is proposed. PMID- 28649534 TI - Aberrant DNA methylation of calcitonin receptor in Fabry patients treated with enzyme replacement therapy. PMID- 28649535 TI - Characterization of the MPS I-H knock-in mouse reveals increased femoral biomechanical integrity with compromised material strength and altered bone geometry. AB - Mucopolysaccharidosis type I (MPS I), is an autosomal recessive lysosomal storage disorder caused by a deficiency in the alpha-L-iduronidase enzyme, resulting in decreased enzymatic activity and accumulation of glycosaminoglycans. The disorder phenotypically manifests with increased urine glycosaminoglycan excretion, facial dysmorphology, neuropathology, cardiac manifestations, and bone deformities. While the development of new treatment strategies have shown promise in attenuating many symptoms associated with the disorder, the bone phenotype remains unresponsive. The aim of this study was to investigate and further characterize the skeletal manifestations of the Idua-W392X knock-in mouse model, which carries a nonsense mutation corresponding to the IDUA-W402X mutation found in Hurler syndrome (MPS I-H) patients. MUCT analysis of the microarchitecture demonstrated increased cortical thickness, trabecular number, and trabecular connectivity along with decreased trabecular separation in the tibiae of female homozygous Idua-W392X knock-in (IDUA-/-) mice, and increased cortical thickness in male IDUA-/- tibiae. Cortical density, as determined by MUCT, and bone mineral density distribution, as determined by quantitative backscattered microscopy, were equivalent in IDUA-/- and wildtype (Wt) bone. However, tibial porosity was increased in IDUA-/- cortical bone. Raman spectroscopy results indicated that tibiae from female IDUA-/- had decreased phosphate to matrix ratios and increased carbonate to phosphate ratios compared to Wt female tibiae, whereas these ratios remained equivalent in male IDUA-/- and Wt tibiae. Femora demonstrated altered geometry and upon torsional loading to failure analysis, female IDUA-/- mouse femora exhibited increased torsional ultimate strength, with a decrease in material strength relative to Wt littermates. Taken together, these findings suggest that the IDUA-/- mutation results in increased bone torsional strength by altering the overall bone geometry and the microarchitecture which may be a compensatory response to increased porosity, reduced bone tensile strength and altered physiochemical composition. PMID- 28649536 TI - Urinary phenylacetylglutamine (U-PAGN) concentration as biomarker for adherence in patients with urea cycle disorders (UCD) treated with glycerol phenylbutyrate. AB - Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age- and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (<~9000 MUg/mL for < 2 years old patients, < 7000 MUg/mL for > 2 years with BSA <= 1.3 m2, and <~5000 MUg/mL for > 2 years of age with BSA > 1.3 m2) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed. PMID- 28649537 TI - Mucopolysaccharidosis type VI on enzyme replacement therapy since infancy: Six years follow-up of four children. PMID- 28649538 TI - Metabolic autopsy with next generation sequencing in sudden unexpected death in infancy: Postmortem diagnosis of fatty acid oxidation disorders. AB - The recent introduction of metabolic autopsy in the field of forensic science has made it possible to detect hidden inherited metabolic diseases. Since the next generation sequencing (NGS) has recently become available for use in postmortem examinations, we used NGS to perform metabolic autopsy in 15 sudden unexpected death in infancy cases. Diagnostic results revealed a case of carnitine palmitoyltransferase II deficiency and some cases of fatty acid oxidation-related gene variants. Metabolic autopsy performed with NGS is a useful method, especially when postmortem biochemical testing is not available. PMID- 28649539 TI - Outcomes of oral biotin treatment in patients with biotinidase deficiency - Twenty years follow-up. AB - INTRODUCTION: Biotinidase deficiency (BTD) is an inborn error of biotin metabolism inherited as an autosomal recessive trait. Due to the, biotinidase deficiency, biotin is not recycled. Individuals with BTD usually exhibit neurological and cutaneous abnormalities unless treated with biotin. Supplementation with biotin may either ameliorate or if early introduced even prevent symptoms when introduced presymptomatically. PATIENTS AND METHODS: Since 1991, 22 Polish patients from 19 families have been diagnosed with BTD. In 16 children the diagnosis had been suspected on the basis of clinical signs: skin lesions, hyperventilation, seizures, spasticity, and laboratory investigation (elevated lactate and metabolites on urine organic acids profile). The defect was enzymatically (serum biotinidase activity measurement) and genetically (tested for mutations in the BTD gene) confirmed afterwards. All patients were treated with biotin. Urine organic acids analysis (GC/MS) for 3-hydroxizovaleric acid was used for patients' monitoring. Neurological, audiological and ophthalmological evaluation has been conducted once a year. RESULTS: In 5 symptomatic patients a progressive optic nerve atrophy had already been noted at the time of treatment initiation. In these patients sensorineural hearing loss has also been diagnosed despite biotin supplementation. Asymptomatic patients treated with biotin supplementation presented no signs or symptoms of BTD. Supplementation with biotin slows the progression of BTD in symptomatic patients, but does not reverse nerve atrophy. Nonetheless, introduction of the treatment with biotin during presymptomatic stage of the disease prevents the onset of symptoms including optic atrophy and hearing loss. Homozygosity for the p.Leu215Phe mutation in BTD gene seems to be frequent in patients from the North-Eastern region of Poland and is connected with the hearing loss. CONCLUSION: Since the prognosis for individuals diagnosed with BTD is good, provided they are treated before symptoms occur, it is justified to add this metabolic disorder to the panel of conditions screened under the national newborn screening programme in Poland. PMID- 28649540 TI - Effect of dietary regime on metabolic control in phenylketonuria: Is exact calculation of phenylalanine intake really necessary? AB - BACKGROUND: A phenylalanine (Phe) restricted dietary management is required in phenylketonuria (PKU) to maintain good metabolic control. Nevertheless, five different models of dietary regimes, which differ in their accuracy of Phe documentation, are used. To investigate the effect of the dietary regime on metabolic control, a multicenter evaluation was performed. PATIENTS/METHODS: 149 patients (max. 800 mg Phe-intake/day; 108 children aged 1-9 years and 41 adolescents aged 10-15 years) could be included. They were separated according to age and dietary regime, revealed by a questionnaire on dietary habits. Dietary regimes vary from daily strict calculation of all Phe-intake (group 1) to a rather loose regime only estimating Phe-intake and including high protein food (group 5). Data were analyzed with respect to metabolic control (Phe concentrations, Phe-concentrations above upper recommended limit during 6 months before the interview), Phe-intake (mg/day) and age (years). RESULTS: Median Phe concentrations in children did not differ significantly among diet groups (group 1: 161; 2: 229, 3: 236, 4: 249, 5: 288 MUmol/l, p = 0.175). However, exact daily Phe calculation led to significantly lower percentage of Phe concentrations above the upper recommended limit (group 1: 17, 2: 50, 3: 42, 4: 50, 5: 75%, p = 0.035). All included patients showed good to acceptable metabolic control. Patients on the dietary regime with the least accuracy, consuming also high protein foods, showed the poorest metabolic control. Median Phe concentrations of all other groups remained within recommended ranges, including from groups not calculating special low protein foods, fruit and vegetables and using a simplified system of recording Phe-intake. In adolescents no significant differences among diet groups were revealed. CONCLUSION: Exact calculation of Phe content of all food is not necessary to achieve good metabolic control in children and adolescents with PKU. Excluding special low protein food, as well as fruit and vegetables from calculation of Phe-intake has no impact on metabolic control. However including protein rich food into the diet and simply estimating all Phe-intake appears insufficient. The simplification of dietary regime may be helpful in enhancing acceptability and feasibility. PMID- 28649541 TI - The lactose and galactose content of milk fats and suitability for galactosaemia. AB - INTRODUCTION: Butter oil, ghee and butter are theoretically low in lactose. All three products are high in milk fat; butter oil and ghee contain approximately 99.3% fat and butter around 80% fat. We report the lactose and galactose content of butter, ghee, and butter oil and assess their suitability in a low galactose diet. METHODS: A total of 12 samples (butter oil n = 5, ghee n = 5, butter n = 2) were analysed by High-Performance Anion Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD) technology used to perform lactose and galactose analyses. RESULTS: Butter oil and ghee were consistently low in lactose and galactose. Butter oil analysis: lactose, 0.47 to 3.08 mg/100 g; galactose, < 0.05 to 2.28 mg/100 g. Ghee analysis: lactose, < 0.05 to 2.9 mg/100 g; galactose, < 0.05 mg to < 1.0 mg/100 g. Butter analysis: lactose 685 to 688 mg/100 g; galactose, 1.3 mg to 1.6 mg/100 g. CONCLUSIONS: Butter oil (commonly used in food industry) and ghee contain minimal lactose and galactose and so are permitted in a UK galactosaemia diet. Butter is considered too high in lactose and is unsuitable in a low galactose diet. PMID- 28649542 TI - A novel nine base deletion mutation in NADH-cytochrome b5 reductase gene in an Indian family with recessive congenital methemoglobinemia-type-II. AB - Recessive hereditary methemoglobinemia (RCM) associated with severe neurological abnormalities is a very rare disorder caused by NADH- cytochrome b5 reductase (cb5r) deficiency (Type II). We report a case of 11 month old male child who had severe mental retardation, microcephaly and gross global developmental delay with methemoglobin level of 61.1%. The diagnosis of NADH-CYB5R3 deficiency was made by the demonstration of significantly reduced NADH-CYB5R3 activity in the patient and intermediate enzyme activity in both the parents. Mutation analysis of the CYB5R gene revealed a novel nine nucleotide deletion in exon 6 leading to the elimination of 3 amino acid residues (Lys173, Ser174 and Val 175). To confirm that this mutation was not an artifact, we performed PCR-RFLP analysis using the restriction enzyme Drd I. As the normal sequence has a restriction recognition site for Drd I which was eliminated by the deletion, a single band of 603-bp was seen in the presence of the homozygous mutation. Molecular modeling analysis showed a significant effect of these 3 amino acids deletion on the protein structure and stability leading to a severe clinical presentation. A novel homozygous 9 nucleotide deletion (p.K173-p.V175del3) is shown to be segregated with the disease in this family. Knowing the profile of mutations would allow us to offer prenatal diagnosis in families with severe neurological disorders associated with RCM - Type II. PMID- 28649543 TI - Tyrosinemia type III in an asymptomatic girl. AB - Tyrosinemia type 3 (HT3) is a rare inborn error of tyrosine metabolism caused by mutations in the HPD gene encoding 4-hydroxyphenyl-pyruvate dioxygenase, which is transmitted in an autosomal recessive trait. The disorder is characterized by tyrosine accumulation in body fluids and massive excretion of tyrosine derivatives into urine (www.orpha.net). Since it is the least frequent form of tyrosinemia, only few cases with the variable but rather mild clinical features have been described so far. We report an 11 year old girl presenting with no clinical symptoms and with normal mental development who has been diagnosed with HT3 through metabolic screening on the basis of elevated serum level of tyrosine ranging from 425 to 535 MUmol/L (normal values: 29-86 MUmol/L), and elevated urinary excretion of p-hydroxyphenyl derivatives confirmed genetically with the homozygous c.479A > G (p.Tyr160Cys) missense change in the HPD gene. The girl has been only presenting with recurrent proteinuria of unknown etiology. A phenylalanine- and tyrosine-restricted diet has never been administered. Presented case may suggest that high tyrosine concentration itself does not participate directly in neuronal damage described in patients with tyrosinemia type 3. PMID- 28649545 TI - CTNS mutations in publicly-available human cystinosis cell lines. AB - Patient samples play an important role in the study of inherited metabolic disorders. Open-access biorepositories distribute such samples. Unfortunately, not all clinically-characterized samples come with reliable genotype information. During studies directed toward population frequency assessments of cystinosis, a rare heritable disorder, we sequenced the CTNS gene from 14 cystinosis-related samples obtained from the Coriell Cell Repository. As a result, the disease genotypes of 7 samples were determined for the first time. The reported disease genotypes of 2 additional samples were found to be incorrect. Furthermore, we identified and experimentally confirmed a novel mutation, c.225 + 5G > A, which causes skipping of the 5th exon and is associated with infantile nephropathic cystinosis. PMID- 28649544 TI - Acute exercise in treated phenylketonuria patients: Physical activity and biochemical response. AB - BACKGROUND: In phenylketonuria, dietary treatment prevents most of the severe brain disease. However, patients have to follow a diet restricted in several natural components, what may cause decreased bone density and obesity. Exercise is known to improve both mental functioning and bone density also avoiding obesity, and could optimize aspects of central and peripheral outcome, regardless changes in phenylalanine (Phe) levels. However, the acute effects of exercise on metabolic parameters in phenylketonuria patients are unknown and thereby long term adaptations are unclear. Therefore, this study aimed to evaluate patients' basal metabolic rate (BMR), and their acute response to an aerobic exercise session on plasma concentrations of Phe, tyrosine (Tyr), and branched-chain amino acids (BCAA), as well as metabolic and hormonal responses. METHODS: Five early- and four late diagnosed phenylketonuria patients aged 21 +/- 4 years and 17 sex-, age-, and BMI-matched controls were evaluated for BMR, peak oxygen consumption (VO2peak) and plasma amino acid, glucose, lipid profile and hormonal levels. At least one week later, participants performed a 30-min aerobic exercise session (intensities individually calculated using the VO2peak results). Blood samples were collected in fasted state (moment 1, M1) and immediately after a small breakfast, which included the metabolic formula for patients but not for controls, and the exercise session (moment 2, M2). RESULTS: Phenylketonuria patients and controls showed similar BMR and physical capacities. At M1, patients presented higher Phe concentration and Phe/Tyr ratio; and lower levels of BCAA and total cholesterol than controls. Besides that, poorly controlled patients tended to stay slightly below the prescribed VO2 during exercise. Both patients and controls showed increased levels of total cholesterol and LDL at M2 compared with M1. Only controls showed increased levels of Tyr, lactate, and HDL; and decreased Phe/Tyr ratio and glucose levels at M2 compared to values at M1. CONCLUSIONS: Acute aerobic exercise followed by a Phe-restricted breakfast did not change Phe concentrations in treated phenylketonuria patients, but it was associated with decreased Phe/Tyr only in controls. Further studies are necessary to confirm our results in a higher number of patients. PMID- 28649546 TI - Respiratory muscle training with enzyme replacement therapy improves muscle strength in late - onset Pompe disease. AB - BACKGROUND: Pompe disease is an autosomal recessive metabolic disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. This deficiency leads to glycogen accumulation in the lysosomes of muscle tissue causing progressive muscular weakness particularly of the respiratory system. Enzyme replacement therapy (ERT) has demonstrated efficacy in slowing down disease progression in infants. Despite the large number of studies describing the effects of physical training in juvenile and adult late onset Pompe disease (LOPD). There are very few reports that analyze the benefits of respiratory muscle rehabilitation or training. METHODS: The effectiveness of respiratory muscle training was investigated using a specific appliance with adjustable resistance (Threshold). The primary endpoint was effect on respiratory muscular strength by measurements of MIP and MEP. Eight late-onset Pompe patients (aged 13 to 58 years; 4 female, 4 male) with respiratory muscle deficiency on functional respiratory tests were studied. All patients received ERT at the dosage of 20 mg/kg/every 2 weeks and underwent training with Threshold at specified pressures for 24 months. RESULTS: A significant increase in MIP was observed during the follow-up of 24 month: 39.6 cm H2O (+ 25.0%) at month 3; 39.5 cm H2O (+ 24.9%) at month 6; 39.1 cm H2O (+ 23.7%) at month 9; 37.3 cm H2O (+ 18.2%) at month 12; and 37.3 cm H2O (+ 17.8%) at month 24. Median MEP values also showed a significant increase during the first 9 months: 29.8 cm H2O, (+ 14.3%) at month 3; 31.0 cm H2O (+ 18.6) at month 6; and 29.5 cm H2O (+ 12.9) at month 9. MEP was then shown to be decreased at months 12 and 24; median MEP was 27.2 cm H2O (+ 4.3%) at 12 months and 26.6 cm H2O (+ 1.9%) at 24 months. The FVC remain stable throughout the study. CONCLUSION: An increase in respiratory muscular strength was demonstrated with Threshold training when used in combination with ERT. PMID- 28649547 TI - Cognitive functioning in mild hyperphenylalaninemia. PMID- 28649548 TI - Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family. AB - We report an 8-year-old girl with lower limb weakness since birth in whom mitochondrial trifunctional protein (MTP) deficiency, an autosomal recessive fatty acid oxidation disorder caused by HADHA or HADHB mutations, had not been definitively diagnosed before she was referred to our hospital. Repeated blood acylcarnitine analysis revealed slightly increased long-chain 3-OH-acylcarnitine levels; electromyography (EMG) suggested peripheral nerve injury; muscle biopsy confirmed a neurogenic lesion in muscle fibers, as shown by EMG. Analysis of the HADHB, which encodes long-chain 3-ketoacyl-CoA thiolase, one of the enzymes constituting mitochondrial trifunctional protein, identified homozygous missense mutation c.739C > T (p.R247C). Mitochondrial trifunctional protein deficiency is an extremely rare disorder and has not been reported in Chinese people to date. It is likely that neonatal onset, as seen in our patient, has not been reported for the neuromyopathic phenotype of mitochondrial trifunctional protein deficiency. PMID- 28649549 TI - LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy. AB - Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency. PMID- 28649550 TI - Analysis of six novel flavin-containing monooxygenase 3 (FMO3) gene variants found in a Japanese population suffering from trimethylaminuria. AB - Polymorphic human flavin-containing monooxygenase 3 (FMO3) is associated with the inherited disorder trimethylaminuria. Several FMO3 variants have been observed in a variety of ethnic groups, including a Japanese cohort suffering from trimethylaminuria. The aim of this study was to screen another self-reported Japanese trimethylaminuria cohort for novel FMO3 variants and to investigate these new variants. Subjects with low FMO3 metabolic capacities were identified by measuring the urinary trimethylamine and trimethylamine N-oxide concentrationsin171 Japanese volunteers. The FMO3 genes from these subjects and their family members were then sequenced. Heterozygotes or homozygotes for novel single-nucleotide polymorphisms c.20 T > C p.(Ile7Thr), c.122 G > A p.(Trp41Ter), c.127T > A p.(Phe43Ile), c.488 T > C p.(Leu163Pro), and c.1127G > A p.(Gly376Glu) and a heterozygote for the novel duplication c.850_860dupTTTAACGATGA p.(Glu287AspfsTer17) were identified. In addition, the known (but as yet uncharacterized) single-nucleotide polymorphism c.929 C > T p.(Ser310Leu) was found. Pedigree analysis revealed the p.(Ser310Leu) FMO3 allele in cis configuration with c.929 C > T p.(Glu158Lys). These variant FMO3 proteins recombinantly expressed in Escherichia coli membranes exhibited decreased N oxygenation activities toward trimethylamine and benzydamine. Although the allele frequencies of these seven variants were low, the present results suggest that individuals homozygous or heterozygous for any of these novel missense or duplicationFMO3 variants or known nonsense mutations such as p.(Cys197Ter) may possess abnormal activities toward trimethylamine N-oxygenation. PMID- 28649551 TI - Residual glycosaminoglycan accumulation in mitral and aortic valves of a patient with attenuated MPS I (Scheie syndrome) after 6 years of enzyme replacement therapy: Implications for early diagnosis and therapy. AB - Mucopolysaccharidosis (MPS) is an inherited metabolic disease caused by deficiency of the enzymes needed for glycosaminoglycan (GAG) degradation. MPS type I is caused by the deficiency of the lysosomal enzyme alpha-l-iduronidase and is classified into Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome based on disease severity and onset. Cardiac complications such as left ventricular hypertrophy, cardiac valve disease, and coronary artery disease are often observed in MPS type I. Enzyme replacement therapy (ERT) has been available for MPS type I, but the efficacy of this treatment for cardiac valve disease is unknown. We report on a 56-year-old female patient with attenuated MPS I (Scheie syndrome) who developed aortic and mitral stenosis and coronary artery narrowing. The cardiac valve disease progressed despite ERT and she finally underwent double valve replacement and coronary artery bypass grafting. The pathology of the cardiac valves revealed GAG accumulation and lysosomal enlargement in both the mitral and aortic valves. Zebra body formation was also confirmed using electron microscopy. Our results suggest that ERT had limited efficacy in previously established cardiac valve disease. Early diagnosis and initiation of ERT is crucial to avoid further cardiac complications in MPS type I. PMID- 28649552 TI - A de novo mutation in CYP21A2 gene in a case of in vitro fertilization. AB - Congenital adrenal hyperplasia, one of the most frequent autosome recessive disorders, is caused by defects in steroidogenic enzymes involved in the cortisol biosynthesis. Approximately 95% of the cases are caused by abnormal function of the 21-hydroxylase enzyme. This deficiency leads to androgen excess, consequently, to virilization and rapid somatic growth with accelerated skeletal maturation. Mutations in CYP21A2 are responsible for different forms of 21 hydroxylase deficiency. Mild impairment in the enzymatic activity causes the non classic or late-onset congenital adrenal hyperplasia that is observed with a prevalence of 1 in 1000 subjects in different populations. The present paper describes a de novo mutation that occurred in the paternal meiosis. The child, who was conceived by in vitro fertilization, presented with precocious puberty and diagnosed with non-classical 21-hydroxylase deficiency. DNA sequencing showed the compound heterozygosis for a de novo CYP21A1P/A2 chimeric gene and the p.Val281Leu mutation inherited from her mother, who was heterozygous for the mutation. The chimeric gene showed pseudogene-derived sequence from 5'-end to intron 3 and CYP21A2 sequences from intron 3 to 3'-end of the gene. Sequencing analysis of the father did not show any mutation. The multiplex ligation dependent probe amplification (MLPA) assay did not indicate loss of DNA discarding gene deletion but confirmed the chimeric gene. In addition, supernumerary copies of CYP21A1P were observed for both parents and for the affect child. Since paternity has been confirmed, those results suggest that a de novo large gene conversion in the paternal meiosis could have occurred by misalignment of alleles bearing different copy numbers of genes in CYP21 locus. PMID- 28649553 TI - Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment. AB - In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls. PMID- 28649554 TI - Comments on 'Newborn screening in southeastern Europe' published in Molecular Genetics and Metabolism, 2014 Sept-Oct;113(1-2):42-45 by U. Groselj, M. ZerjavTansek, A. Smon, N. Angelkova, D. Anton, I. Baric, M. Djordjevic, L. Grimci, M. Ivanova, A. Kadam, V. Mulliqi Kotori, H. Maksic, O. Marginean, O. Margineanu, O. Milijanovic, F. Moldovanu, M. Muresan, S. Murko, M. Nanu, B. Repic Lampert, M. Samardzic, V. Sarnavka, A. Savov, M. Stojiljkovic, B. Suzic, R. Tincheva, H. Tahirovic, A. Toromanovic, N. Usurela, T. Battelino. PMID- 28649555 TI - Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe). AB - BACKGROUND: Carvajal syndrome is an autosomal dominant or autosomal recessive disorder, manifesting with dilated cardiomyopathy, woolly hair, and palmoplantar keratoma. Additional manifestations can be occasionally found. Carvajal syndrome may be due to mutations in the desmocollin-2, desmoplakin, or plakophilin-2 gene. METHODS AND RESULTS: We report a family with Carvajal syndrome which additionally presented with hypoacusis, noncompaction, recurrent pharyngeal infections, oligodontia, and recurrent diarrhoea. Father and brother were also affected and had died suddenly, the father despite implantation of a cardioverter defibrillator (ICD). Genetic studies revealed the novel pathogenic mutation c.1678A > T in the desmoplakin gene resulting in the amino acid change Ile to Phe at position 560 in the index case and her brother. The index case underwent ICD implantation recently. CONCLUSION: Phenotypic manifestations of Carvajal syndrome are even broader than so far anticipated, the number of mutations in the desmoplakin gene responsible for Carvajal syndrome is still increasing, and these patients require implantation of an ICD as soon as their diagnosis is established. PMID- 28649556 TI - Successful pregnancy and delivery in a woman with propionic acidemia from the Amish community. AB - Propionic acidemia (PA) is an inborn error of protein metabolism with a variable clinical presentation ranging from neonatal encephalopathy to seemingly asymptomatic individuals who present with cardiomyopathy or sudden death. PA is recognized in the Amish population, often with an early asymptomatic course and eventual cardiac complications. Thus, Amish women with PA may reach reproductive age without clinical sequelae, but are at increased risk for metabolic decompensation during pregnancy, delivery and postpartum period. We describe the care of an Amish woman with PA during her first pregnancy and delivery. PMID- 28649557 TI - Dusquetide: Reduction in oral mucositis associated with enduring ancillary benefits in tumor resolution and decreased mortality in head and neck cancer patients. AB - Innate immunity is a key component in the pathogenesis of oral mucositis, a universal toxicity of chemoradiation therapy (CRT). Dusquetide, a novel Innate Defense Regulator, has demonstrated both nonclinical and clinical efficacy in ameliorating severe oral mucositis (SOM). Long term follow-up studies from the Phase 2 clinical study evaluating dusquetide as a treatment for SOM in head and neck cancer (HNC) patients receiving CRT have now been completed. Extended analysis indicates that dusquetide therapy was well-tolerated and did not contribute to increased infection, tumor growth or mortality. Potential ancillary benefits of duquetide therapy were also identified. PMID- 28649558 TI - Characterization of lepidopteran-specific cry1 and cry2 gene harbouring native Bacillus thuringiensis isolates toxic against Helicoverpa armigera. AB - Bacillus thuringiensis (Bt) based biopesticides are feasible alternatives to chemical pesticides. Here, we present the distribution of lepidopteran-specific cry1 and cry2 genes in native B. thuringiensis. Forty four out of 86 colonies were found to harbour crystals by phase contrast microscopy exhibiting a Bt index of 0.51. PCR analysis resulted in the amplification of cry1 in 24 and cry2 in 14 isolates. Twelve of the isolates showed presence of both cry1 and cry2, while 18 isolates did not show presence of either of the genes. Toxicity screening using spore-crystal mixtures against 2nd instar larvae of Helicoverpa armigera revealed that the isolates (50%) were either mildly toxic or not toxic (36.36%), and only 13.63% were toxic. The results are interesting, particularly so because the same isolates were previously reported to contain lepidopteran specific vip3A genes also, hence can complement the toxicity of the isolates harbouring vip3A genes. PMID- 28649559 TI - Helicobacter pylori vacuolating cytotoxin and gastric cancer risk: reconsidered. PMID- 28649560 TI - Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells. AB - Reactive oxygen species (ROS) are important signaling molecules that act through the oxidation of nucleic acids, proteins, and lipids. Several hallmarks of cancer, including uncontrolled proliferation, angiogenesis, and genomic instability, are promoted by the increased ROS levels commonly found in tumor cells. To counteract excessive ROS accumulation, oxidative stress, and death, cancer cells tightly regulate ROS levels by enhancing scavenging enzymes, which are dependent on the reducing cofactor nicotinamide adenine dinucleotide phosphate (NADPH). This review focuses on mitochondrial ROS homeostasis with a description of six pathways of NADPH production in mitochondria and a discussion of the possible strategies of pharmacological intervention to selectively eliminate cancer cells by increasing their ROS levels. PMID- 28649561 TI - Psd1 Effects on Candida albicans Planktonic Cells and Biofilms. AB - Candida albicans is an important human pathogen, causing opportunistic infections. The adhesion of planktonic cells to a substrate is the first step for biofilm development. The antimicrobial peptide (AMP) Psd1 is a defensin isolated from Pisum sativum seeds. We tested the effects of this AMP on C. albicans biofilms and planktonic cells, comparing its activity with amphotericin B and fluconazole. Three C. albicans variants were studied, one of them a mutant deficient in glucosylceramide synthase, conferring resistance to Psd1 antifungal action. Atomic force microscopy (AFM) was used to assess morphological and biomechanical changes on fungal cells. Surface alterations, with membrane disruption and leakage of cellular contents, were observed. Cytometry assays and confocal microscopy imaging showed that Psd1 causes cell death, in a time and concentration-dependent manner. These results demonstrate Psd1 pleiotropic action against a relevant fungal human pathogen, suggesting its use as natural antimycotic agent. PMID- 28649562 TI - Umbilical Cord Blood NOS1 as a Potential Biomarker of Neonatal Encephalopathy. AB - BACKGROUND: There are no definitive markers to aid in diagnosis of neonatal encephalopathy (NE). The purpose of our study was (1) to identify and evaluate the utility of neuronal nitric oxide synthase (NOS1) in umbilical cord blood as a NE biomarker and (2) to identify the source of NOS1 in umbilical cord blood. METHODS: This was a nested case-control study of neonates >35 weeks of gestation. ELISA for NOS1 in umbilical cord blood was performed. Sources of NOS1 in umbilical cord were investigated by immunohistochemistry, western blot, ELISA, and quantitative PCR. Furthermore, umbilical cords of full-term neonates were subjected to 1% hypoxia ex vivo. RESULTS: NOS1 was present in umbilical cord blood and increased in NE cases compared with controls. NOS1 was expressed in endothelial cells of the umbilical cord vein, but not in artery or blood cells. In ex vivo experiments, hypoxia was associated with increased levels of NOS1 in venous endothelial cells of the umbilical cord as well as in ex vivo culture medium. CONCLUSION: This is the first study to investigate an early marker of NE. NOS1 is elevated with hypoxia, and further studies are needed to investigate it as a valuable tool for early diagnosis of neonatal brain injury. PMID- 28649563 TI - Symptomatic Congenital Cytomegalovirus Infection in Children of Seropositive Women. AB - Cytomegalovirus (CMV) is the most frequent congenital virus infection worldwide. The risk of congenital CMV (cCMV) transmission is highest in seronegative women who acquire primary CMV infection during pregnancy. A growing body of evidence indicates that secondary CMV infections in pregnant women with preconceptual immunity (either through reactivation of latent virus or re-infection with a new strain of CMV) contribute to a much greater proportion of symptomatic cCMV than was previously thought. Here, we describe a case of symptomatic cCMV infection in the newborn of a woman with proven immunity prior to pregnancy. Diagnosis was confirmed by CMV PCR from amniotic fluid and fetal MR imaging. The newborn presented with typical cCMV symptoms including jaundice, hepatosplenomegaly, cholestasis, petechiae, small head circumference, and sensorineural hearing loss, the most common neurologic sequela. CMV was detected in infant blood and urine by PCR, and intravenous ganciclovir was initiated and continued orally for 6 weeks totally. Apart from persisting right-sided deafness, the child exhibited normal neurological development up through the last follow-up at 4.5 years. To date, the most effective strategy to prevent vertical CMV transmission is hygiene counseling for women of childbearing age, which, in our case, and in concordance with recent literature, applies to seronegative, as well as seropositive, women. Once an expecting mother shows seroconversion or signs of an active CMV infection, there are no established procedures to reduce the risk of transmission, or therapeutic options for the fetus with signs of infection. After birth, symptomatic infants can be treated with ganciclovir to inhibit viral replication and improve hearing ability and neurodevelopmental outcome. A comprehensive review of the literature, including our case study, reveals the most current and significant diagnostic and treatment options available. In conclusion, the triad of maternal hygiene counseling, postnatal hearing screening of all newborns, followed by CMV PCR in symptomatic infants, and antiviral therapy of infants with symptomatic cCMV provides an outline of best practice to reduce the burden of CMV transmission sequelae. PMID- 28649565 TI - Increasing Regional Anesthesia Use in a Serbian Teaching Hospital through an International Collaboration. AB - Many low- and middle-income countries (LMICs) report low rates of regional anesthesia (RA) use for cesarean delivery (CD), despite its association with lower maternal major morbidity and mortality. Also, the prevalence of neuraxial analgesia for labor (NAL) is often low in LMICs. We report on the results of a collaboration in clinical education over a multi-year period between Kybele Inc., an international non-profit organization, and Klinicki Centar Vojvodine (CCV), a teaching hospital in Novi Sad, Serbia, to increase RA use for CD and NAL at CCV. From late 2011 through 2015, teams from Kybele participated in annual to biannual didactic conferences and week-long bedside teaching efforts involving obstetric and anesthesia staff from CCV and surrounding hospitals. Ongoing contact occurred at least weekly between Kybele and the host to discuss progress. De-identified quality improvement data on total deliveries, numbers of elective and non elective CDs, number of vaginal deliveries, type of anesthesia for CD, and the number of NALs were collected. RA use for CD increased to 25% in year 2015 versus 14% in base year 2011 [odds ratio (OR): 2.05; 95% confidence interval (CI): 1.73,2.42; p < 0.001]. NAL increased to 10.5% of laboring women in 2015 versus 1.2% in 2011 (OR: 9.6; 95% CI: 7.2, 12.8; p < 0.001). Greater increases for RA use during non-elective CD were observed between 2011 and 2015 (1.4 versus 7.5% of total CD; OR: 5.52; 95% CI: 2.63, 8.41; p < 0.001) relative to elective CD (12.5 versus 17.5% of total CD; OR: 1.48; 95% CI: 1.23, 1.77; p < 0.001). Overall, RA for CD increased during the 4 year collaboration but was not as great as reported in other countries with similar health-care demographics utilizing a similar program. Detailed descriptions of program interventions and barriers to change at CCV are presented. PMID- 28649566 TI - [68Ga]/[188Re] Complexed [CDTMP] Trans-1,2-Cyclohexyldinitrilotetraphosphonic Acid As a Theranostic Agent for Skeletal Metastases. AB - OBJECTIVE: Metastasis of the osseous tissue is one of the frequent and severe aggravations as a result of several neoplastic conditions, such as metabolic disorders, infections, and cancer. The objective of this study was to evaluate the pertinence of [68Ga]-trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid (CDTMP) as a potential bone imaging agent for positron emission tomography (PET) applications as well as to assess [188Re]-CDTMP for bone pain palliation in metastatic skeletal disorders. METHODS: 68Ga complex of CDTMP was prepared at 80 degrees C at pH 3.5, and 188Re complex of CDTMP was prepared at room temperature. [68Ga]-CDTMP complex was investigated as PET tracer while the therapeutic efficacy was assessed for [188Re]-CDTMP. Labeling efficiency, biodistribution, myelotoxicity, and imaging studies were carried out for the complexes synthesized. Both PET and MicroPET imaging studies were performed for [68Ga] CDTMP whereas SPECT acquisitions were acquired for [188Re]-CDTMP. Data were analyzed semiquantitatively for all the scintigraphic scans obtained. RESULTS: The radiolabeling efficiency was observed to be >70% for [68Ga]-CDTMP. High bone uptake of [68Ga]-CDTMP as compared to contralateral tissue was found in PET imaging in Balb/C mice and New Zealand rabbit; the similar result for bone uptake was correlated in the biodistribution study of the compound in BALB/c mice at different time intervals. Biodistribution experiments carried out in mice showed maximum uptake of 6.12 +/- 1.22%ID/g at 45 min postinjection. For [188Re]-CDTMP, total skeletal uptake was 8.12 +/- 1.11%ID/g observed at 1 h postinjection from biodistribution data. High renal uptake confirms renal route of excretion. A good hydroxyapatite binding too was seen for both the complexes. No evidence of destruction or adverse functioning of vital organs was observed for the 188Re complex. CONCLUSION: [68Ga]-CDTMP complex can be used as a promising PET bone imaging agent and [188Re]-CDTMP as a surrogate moiety for therapeutic application. Owing to the short half-life of 68Ga (68 min), cyclotron-independent radiopharmacy, fast clearance, and rapid renal excretion as evidenced in preclinical animal models. Very low myelotoxicity and highly selective bone uptake prove the potential of [188Re]-CDTMP for therapeutic application. PMID- 28649564 TI - Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies. AB - Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ~50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called "gene editing" to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients' outcome. Pediatricians, neonatologists, pulmonologists, and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized center before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients. PMID- 28649567 TI - Effect of Dark Chocolate Extracts on Phorbol 12-Myristate 13-Acetate-Induced Oxidative Burst in Leukocytes Isolated by Normo-Weight and Overweight/Obese Subjects. AB - Oxidative and inflammatory stress represents a major risk factor for cardiovascular disease (CVD) in overweight and obese subjects. Between the different plant foods, chocolate has been shown to decrease CVD risk due to its antioxidant and anti-inflammatory properties. However, as we recently showed in epidemiological studies, meta-analyses, and human trials, dietary antioxidants resulted more effective in subjects characterized by an ongoing oxidative stress, than in healthy people. Aim of this work was to investigate the effect of different concentrations of chocolate phenolic extract (CPE) on in vitro free radical production, stimulated by phorbol 12-myristate 13-acetate (PMA), in leukocytes extracted from blood of normo-weight and overweight/obese subjects. Neutrophils from overweight/obese group had a significantly higher free radical production compared to the normo-weight group. In neutrophils, the lowest CPE concentration significantly reduced free radical production in overweight/obese group only, and higher CPE concentrations were effective in both groups. In monocytes, the CPE concentration that was significantly effective in reducing free radical production was lower in overweight/obese subjects than in normo weight subjects. Chocolate polyphenol extracts inhibit oxidative burst in human neutrophils and monocytes with a higher efficiency in subjects characterized by an unphysiological oxidative/inflammatory stress, such as overweight and obese. Results of this study provide further evidence about a differential role of dietary antioxidant strictly related to the "stress" condition of the subjects. PMID- 28649568 TI - A Prothrombotic Score Based on Genetic Polymorphisms of the Hemostatic System Differs in Patients with Ischemic Stroke, Myocardial Infarction, or Peripheral Arterial Occlusive Disease. AB - BACKGROUND: While twin studies indicate a genetic component in arterial thrombosis such as ischemic stroke, myocardial infarction (MI), or peripheral arterial occlusive disease (PAOD), the clinical relevance of hemostatic polymorphisms in arterial thrombosis is a matter of debate. METHODS: We analyzed the prevalence of 13 hemostatic polymorphisms [PAI-1, PLAT, F5 (including factor V Leiden and HR2 haplotype), F2, F7, F13A, FGB, TFPI, THBD, MTHFR, ACE, and ITGA2] in patients referred to a tertiary referral center. A "prothrombotic score" was calculated by dividing the number of risk-increasing polymorphisms for thrombosis minus the number of risk-lowering polymorphisms (F7 and F13A) by the number of polymorphisms tested. RESULTS: Datasets of 144 patients with prior ischemic stroke (mean age 44 +/- 13 years; 65% female) were compared to 62 patients with MI or PAOD (mean age 54 +/- 14 years; 47% female). The prothrombotic score was lower in MI and PAOD patients compared to stroke patients [odds ratios 2.7 (95% confidence intervals 1.1-6.2)]. Frequencies of individual polymorphisms did not differ between both groups. CONCLUSION: Patients with MI or PAOD had a lower burden of prothrombotic mutations compared to patients with prior stroke, indicating that a prothrombotic state might play a different role in distinct forms of arterial thrombosis. PMID- 28649569 TI - Environmental Enrichment for Broiler Breeders: An Undeveloped Field. AB - Welfare problems, such as hunger, frustration, aggression, and abnormal sexual behavior, are commonly found in broiler breeder production. To prevent or reduce these welfare problems, it has been suggested to provide stimulating enriched environments. We review the effect of the different types of environmental enrichment for broiler breeders, which have been described in the scientific literature, on behavior and welfare. Environmental enrichment is defined as an improvement of the environment of captive animals, which increases the behavioral opportunities of the animal and leads to improvements in biological function. This definition has been broadened to include practical and economic aspects as any enrichment strategy that adversely affects the health of animals (e.g., environmental hygiene), or that has too many economic or practical constraints will never be implemented on commercial farms and thus never benefit animals. Environmental enrichment for broiler breeders often has the purpose of satisfying the behavioral motivations for feeding and foraging, resting, and/or encouraging normal sexual behavior. Potentially successful enrichments for broiler breeders are elevated resting places, cover panels, and substrate (for broiler breeders housed in cage systems). However, most of the ideas for environmental enrichment for broiler breeders need to be further developed and studied with respect to the use, the effect on behavior and welfare, and the interaction with genotype and production system. In addition, information on practical use and the economics of the production system is often lacking although it is important for application in practice. PMID- 28649570 TI - Evaluating Checklist Use in Companion Animal Wellness Visits in a Veterinary Teaching Hospital: A Preliminary Study. AB - The number of companion animal wellness visits in private practice has been decreasing, and one important factor cited is the lack of effective communication between veterinarians and pet owners regarding the importance of preventive care. Checklists have been widely used in many fields and are especially useful in areas where a complex task must be completed with multiple small steps, or when cognitive fatigue is evident. The use of checklists in veterinary medical education has not yet been thoroughly evaluated as a potential strategy to improve communication with pet owners regarding preventive care. The authors explored whether the use of a checklist based on the American Animal Hospital Association/American Veterinary Medical Association canine and feline preventive care guidelines would benefit senior veterinary students in accomplishing more complete canine and feline wellness visits. A group of students using provided checklists was compared to a control group of students who did not use checklists on the basis of their medical record notes from the visits. The students using the checklists were routinely more complete in several areas of a wellness visit vs. those who did not use the checklists. However, neither group of students routinely discussed follow-up care recommendations such as frequency or timing of follow-up visits. The study authors recommend considering checklist use for teaching and implementing wellness in companion animal primary care veterinary clinical teaching settings. PMID- 28649571 TI - Impact of Built-up-Litter and Commercial Antimicrobials on Salmonella and Campylobacter Contamination of Broiler Carcasses Processed at a Pilot Mobile Poultry-Processing Unit. AB - The small-scale mobile poultry-processing unit (MPPU) produced raw poultry products are of particular food safety concern due to exemption of USDA poultry products inspection act. Limited studies reported the microbial quality and safety of MPPU-processed poultry carcasses. This study evaluated the Salmonella and Campylobacter prevalence in broiler ceca and on MPPU-processed carcasses and efficacy of commercial antimicrobials against Campylobacter jejuni on broilers. In study I, straight-run Hubbard * Cobb broilers (147) were reared for 38 days on clean-shavings (CS, 75) or built-up-litter (BUL, 72) and processed at an MPPU. Aerobic plate counts (APCs), coliforms, Escherichia coli, and yeast/molds (Y/M) of carcasses were analyzed on petrifilms. Ceca and carcass samples underwent microbial analyses for Salmonella and Campylobacter spp. using the modified USDA method and confirmed by API-20e test (Salmonella), latex agglutination immunoassay (Campylobacter), and Gram staining (Campylobacter). Quantitative polymerase chain reaction (CadF gene) identified the prevalence of C. jejuni and Campylobacter coli in ceca and on carcasses. In study II, fresh chilled broiler carcasses were spot inoculated with C. jejuni (4.5 log10 CFU/mL) and then undipped, or dipped into peroxyacetic acid (PAA) (1,000 ppm), lactic acid (5%), lactic and citric acid blend (2.5%), sodium hypochlorite (69 ppm), or a H2O2-PAA mix (SaniDate(r) 5.0, 0.25%) for 30 s. Surviving C. jejuni was recovered onto Brucella agar. APCs, coliforms, and E. coli populations were similar (P > 0.05) on CS and BUL carcasses. Carcasses of broilers raised on BUL contained a greater (P < 0.05) Y/M population (2.2 log10 CFU/mL) than those reared on CS (1.8 log10 CFU/mL). Salmonella was not detected in any ceca samples, whereas 2.8% of the carcasses from BUL were present with Salmonella. Prevalence of Campylobacter spp., C. jejuni was lower (P < 0.05), and C. coli was similar (P > 0.05) in CS treated ceca than BUL samples. Prevalence of Campylobacter spp., C. jejuni, and C. coli was not different (P > 0.05) on CS- and BUL-treated carcasses. All antimicrobials reduced C. jejuni by 1.2-2.0 log CFU/mL on carcasses compared with controls. Hence, raising broilers on CS and applying post-chilling antimicrobial treatment can reduce Salmonella and Campylobacter on MPPU-processed broiler carcasses. PMID- 28649572 TI - Correspondence between Simulator and On-Road Drive Performance: Implications for Assessment of Driving Safety. AB - Forty-two younger (Mean age = 35) and 37 older drivers (Mean age = 77) completed four similar simulated drives. In addition, 32 younger and 30 older drivers completed a standard on-road drive in an instrumented vehicle. Performance in the simulated drives was evaluated using both electronic drive data and video-review of errors. Safety errors during the on-road drive were evaluated by a certified driving instructor blind to simulator performance, using state Department of Transportation criteria. We examined the degree of convergence in performance across the two platforms on various driving tasks including lane change, lane keeping, speed control, stopping, turns, and overall performance. Differences based on age group indicated a pattern of strong relative validity for simulator measures. However, relative rank-order in specific metrics of performance suggested a pattern of moderate relative validity. The findings have implications for the use of simulators in assessments of driving safety as well as its use in training and/or rehabilitation settings. PMID- 28649574 TI - Erratum: "User experience analysis of e-TB Manager, a nationwide electronic tuberculosis recording and reporting system in Ukraine" Niranjan Konduri, Kelly Sawyer and Nataliya Nizova. ERJ Open Res 2017; 3: 00002-2017. AB - [This corrects the article DOI: 10.1183/23120541.00002-2017.]. PMID- 28649573 TI - Supramolecular Self-assembly of a Model Hydrogelator: Characterization of Fiber Formation and Morphology. AB - Hydrogels are of intense recent interest in connection with biomedical applications ranging from 3-D cell cultures and stem cell differentiation to regenerative medicine, controlled drug delivery and tissue engineering. This prototypical form of soft matter has many emerging material science applications outside the medical field. The physical processes underlying this type of solidification are incompletely understood and this limits design efforts aimed at optimizing these materials for applications. We address this general problem by applying multiple techniques (e.g., NMR, dynamic light scattering, small angle neutron scattering, rheological measurements) to the case of a peptide derivative hydrogelator (molecule 1, NapFFKYp) over a broad range of concentration and temperature to characterize both the formation of individual nanofibers and the fiber network. We believe that a better understanding of the hierarchical self assembly process and control over the final morphology of this kind of material should have broad significance for biological and medicinal applications utilizing hydrogels. PMID- 28649575 TI - ECMO in major burn patients: feasibility and considerations when multiple modes of mechanical ventilation fail. AB - BACKGROUND: We report two cases of acute respiratory distress syndrome in burn patients who were successfully managed with good outcomes with extra corporeal membrane oxygenation (ECMO) after failing multiple conventional modes of ventilation, and review the relevant literature. CASE PRESENTATION: The two patients were a 39-year-old male and 53-year-old male with modified Baux Scores of 79 and 78, respectively, with no known inhalation injury. After the initial modified Parkland-based fluid resuscitation and partial escharotomy, both patients developed worsening hypoxemia and acute respiratory distress syndrome. The hypoxemia continued to worsen on multiple modes of ventilation including volume control, pressure regulated volume control, pressure control, airway pressure release ventilation and volumetric diffusive ventilation. In both cases, the PaO2 <= 50 mm Hg on a FiO2 100% during the trial of mechanical ventilation. The deterioration was rapid (<12 h since onset of worsening oxygenation) in both cases. A decision was made to trial the patients on ECMO. Veno-Venous ECMO (V-V ECMO) was successfully initiated following cannulation-under transesophgeal echo guidance-with the dual lumen Avalon(r) (Maquet, NJ, USA) cannula. ECMO support was maintained for 4 and 24 days, respectively. Both patients were successfully weaned off ECMO and were discharged to rehabilitation following their complex hospital course. CONCLUSION: Early ECMO for isolated respiratory failure in the setting on maintained hemodynamics resulted in a positive outcome in our two burn patients suffered from acute respiratory distress syndrome. PMID- 28649576 TI - You Fill My Heart: Looking at One's Partner Increases Interoceptive Accuracy. AB - The integration of external and internal bodily signals provides a coherent, multisensory experience of one's own body. The ability to accurately detect internal bodily sensations is referred to as interoceptive accuracy (IAcc). Previous studies found that IAcc can be increased when people with low IAcc engage in self-processing such as when looking in the mirror or at a photograph of one's own face. However, the way the self is represented changes depending on the context. Specifically, in social situations, the self is experienced in relation to significant others and not as an isolated individual. Intriguingly, in a relational context romantic partners can be used as social mirrors for one's self. We here investigated whether directing one's attention to romantic partners would enhance one's IAcc, similar to the effect of self-face observation when the self is processed in isolation. During a heartbeat counting task, both concurrent self-face and partner-face observation improved accuracy in those with initially low IAcc; however, this improvement was significantly greater for the partner's face. These results suggest that significant others may play an important role in determining the quality of one's self-awareness. Given that high interoceptive awareness is linked to better emotion regulation, increased IAcc during partner observation is likely to have an adaptive role in maintaining stable and secure romantic relationships through greater emotion regulation. PMID- 28649577 TI - In Vivo Murine-Matured Human CD3+ Cells as a Preclinical Model for T Cell-Based Immunotherapies. AB - Adoptive cellular immunotherapy is a promising and powerful method for the treatment of a broad range of malignant and infectious diseases. Although the concept of cellular immunotherapy was originally proposed in the 1990s, it has not seen successful clinical application until recent years. Despite significant progress in creating engineered receptors against both malignant and viral epitopes, no efficient preclinical animal models exist for rapidly testing and directly comparing these engineered receptors. The use of matured human T cells in mice usually leads to graft-versus-host disease (GvHD), which severely limits the effectiveness of such studies. Alternatively, adult apheresis CD34+ cells engraft in neonatal non-obese diabetic (NOD)-severe combined immunodeficiency (SCID)-common gamma chain-/- (NSG) mice and lead to the development of CD3+ T cells in peripheral circulation. We demonstrate that these in vivo murine-matured autologous CD3+ T cells from humans (MATCH) can be collected from the mice, engineered with lentiviral vectors, reinfused into the mice, and detected in multiple lymphoid compartments at stable levels over 50 days after injection. Unlike autologous CD3+ cells collected from human donors, these MATCH mice did not exhibit GvHD after T cell administration. This novel mouse model offers the opportunity to screen different immunotherapy-based treatments in a preclinical setting. PMID- 28649579 TI - Computerized vs. Paper-Pencil Assessment of Cognitive Change following Acute Ischemic Stroke. AB - IMPORTANCE: Cognitive impairment is common among patients with stroke and early recognition can optimize patient care. OBJECTIVE: To determine the validity of computerized cognitive testing in an adult population with acute ischemic stroke. DESIGN: Validation study comparing computerized vs paper-pencil assessments at two time points three months apart in a stroke unit. MAIN OUTCOME: Correlation analyses between computerized (using CogState Brief Battery) and paper-pencil testing (using the Montreal Cognitive Assessment) both at study entry and follow up visits. RESULTS: We found moderate to strong significant correlations between the two instruments at study entry and follow-up sessions. Executive dysfunctions were the main cognitive changes. Test-retest correlations were strong. CONCLUSION AND RELEVANCE: The CogState Brief Battery is a valid alternative for clinicians who wish to measure cognitive skills following acute ischemic stroke. Limitations of computerized testing are discussed. PMID- 28649578 TI - Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus Prone Mice. AB - We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4-15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2'-deoxy-2'-[18F]fluoro-beta-D arabinofuranosyl)cytosine ([18F]FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks. Following 4-week treatment, [18F]FAC-PET/CT showed similar accumulation in cervical and axillary lymph nodes at 12 weeks of age. However, anti-HMGB1 monoclonal antibody sufficiently inhibited the increase in albuminuria compared to an isotype control following 15-week treatment. Complement deposition was also improved; however, there were no significant differences in IgG deposition and renal pathological scores between the two groups. Anti-double-stranded DNA (dsDNA) antibody titers and cytokine and chemokine levels were also unaltered. Although there were no significant differences in glomerular macrophage infiltration, neutrophil infiltration was significantly decreased by the anti-HMGB1 monoclonal antibody. Antagonizing HMGB1 treatment suppressed HMGB1 translocation from nuclei in the kidney and suppressed neutrophil extracellular traps. The anti-HMGB1 monoclonal antibody demonstrated therapeutic potential against albuminuria in lupus nephritis by inhibiting neutrophil recruitment and neutrophil extracellular traps. PMID- 28649580 TI - The reconstruction for proximal nail fold mucous cyst using reverse and island flap. AB - We performed nail fold reconstruction after digital mucous cyst (DMC) excision using an island-type lateral finger flap on seven patients (four males and three females). Our procedure is a simple and useful method to repair minor nail fold lesion defects after DMC excision. PMID- 28649581 TI - The 'Welcome Letter': A Useful Tool for Laboratories and Teams. AB - The ability to clearly set expectations is an important leadership characteristic. However it is very common for individuals heading up research laboratories or scientific collaborations to struggle with, or not identify the advantages of, explicitly communicating what they expect of the people working in their lab or participating on their team, not to mention what the participants can expect in return. Here we describe a 'Welcome Letter' as a tool that can be used in the scientific setting to effectively create a framework for working relationships and serve as a scaffold for building trust. The 'Welcome Letter' enables the lab leader to articulate expectations prior to incorporating new members into the group. Scientific teams can use the letter in much the same way, crafting it together to develop a shared vision for the functioning of the collaboration and once crafted, sharing it with new team members. PMID- 28649582 TI - Attachment and Biobehavioral Catch-up: Addressing the Needs of Infants and Toddlers Exposed to Inadequate or Problematic Caregiving. AB - Parental sensitivity is key to the development of brain architecture, self regulatory capabilities, and secure, organized attachments for infants and young children. For a variety of reasons, many parents struggle providing sensitive, responsive care. Attachment and Biobehavioral Catch-up (ABC) is a 10-session home visiting program developed to enhance parental sensitivity. ABC has been shown effective in enhancing parental sensitivity, and enhancing children's attachment security and regulatory capabilities. A key feature of the intervention is providing parents practice and feedback in interacting sensitively with their children. Effectiveness in dissemination sites has been impressive, likely because treatment fidelity is defined well and monitored carefully. PMID- 28649583 TI - Effects of Alcohol on Human Aggression. AB - There is little debate that alcohol is a contributing cause of aggressive behavior. The extreme complexity of this relation, however, has been the focus of extensive theory and research. And, likely due to this complexity, evidence-based programs to prevent or reduce alcohol-facilitated aggression are quite limited. We integrate I3 Theory and Alcohol Myopia Theory to provide a framework that (1) organizes the myriad instigatory and inhibitory factors that moderate the effect of alcohol on aggression, and (2) highlights the mechanisms by which alcohol facilitates aggression among at-risk individuals. This integrative framework provides the basis for understanding the appropriate targets for prevention and intervention efforts and may serve as a catalyst for future research that seeks to inform intervention development. PMID- 28649584 TI - Data for characterization of SALK_084889, a T-DNA insertion line of Arabidopsis thaliana. AB - In this article we report the identification of T-DNA (transfer DNA) insertion sites within two different gene regions in the genome of an Arabidopsis mutant line, SALK_084889. The T-DNA positions are in the 3' UTR (untranslated region) of DREB2A (Dehydration-responsive element-binding protein 2A) (AT5G05410) and promoter of LOX1 (Lipoxygenase 1) (AT1G55020) as determined by DNA-PCR and sanger sequencing. The expression levels of DREB2A and LOX1 were also analyzed using quantitative realtime PCR (qPCR) in SALK_084889 and wild type Arabidopsis (Col, Columbia). Further, the comparison of drought and heat tolerance between Col and SALK_084889 were conducted by stress treatments. The present data indicate that in SALK_084889, the expression of DREB2A is not downregulated under normal growth conditions but can be affected only in roots under drought treatment, while LOX1 is significantly downregulated in both roots and shoots under all tested conditions. These data are original and have not been published elsewhere. PMID- 28649585 TI - Data on the genome-wide identification of CNL R-genes in Setaria italica (L.) P. Beauv. AB - We report data associated with the identification of 242 disease resistance genes (R-genes) in the genome of Setaria italica as presented in "Genetic diversity of disease resistance genes in foxtail millet (Setaria italica L.)" (Andersen and Nepal, 2017) [1]. Our data describe the structure and evolution of the Coiled coil, Nucleotide-binding site, Leucine-rich repeat (CNL) R-genes in foxtail millet. The CNL genes were identified through rigorous extraction and analysis of recently available plant genome sequences using cutting-edge analytical software. Data visualization includes gene structure diagrams, chromosomal syntenic maps, a chromosomal density plot, and a maximum-likelihood phylogenetic tree comparing Sorghum bicolor, Panicum virgatum, Setaria italica, and Arabidopsis thaliana. Compilation of InterProScan annotations, Gene Ontology (GO) annotations, and Basic Local Alignment Search Tool (BLAST) results for the 242 R-genes identified in the foxtail millet genome are also included in tabular format. PMID- 28649586 TI - Data from salivary gland proteome analysis of female Aedes aegypti Linn. AB - Salivary gland proteins from female Aedes aegypti mosquito were extracted and analyzed on high-resolution mass spectrometry. Proteomic data was analysed using two search algorithms SEQUEST and Mascot, which results in acquisition of 83,836 spectra which were assigned to 5417 peptides belonging to 1208 proteins.These proteins were then assigned molecular functions and further analysis revealed biological processes they are involved in using Gene Ontology annotations. Several immunity related pathways were found to be enriched in salivary gland.The data of this study are also related to the research article "Mosquito-Borne Diseases and Omics: Salivary gland proteome of the female Aedes aegypti mosquito" (Dhawan et al., 2017) [1]. These data are deposited in ProteomeXchange in the public dataset PXD002468. In addition,a scientific interpretation of this dataset by Dhawan et al. [1] is available at http://dx.doi.org/10.1089/journal.omi.2016.0160. PMID- 28649587 TI - Dataset of timberland variables used to assess forest conditions in two Southeastern United States' fuelsheds. AB - The data presented in this article are related to the research article entitled "How is wood-based pellet production affecting forest conditions in the southeastern United States?" (Dale et al., 2017) [1]. This article describes how United States Forest Service (USFS) Forest Inventory and Analysis (FIA) data from multiple state inventories were aggregated and used to extract ten annual timberland variables for trend analysis in two case study bioenergy fuelshed areas. This dataset is made publically available to enable critical or extended analyses of changes in forest conditions, either for the fuelshed areas supplying the ports of Savannah, Georgia and Chesapeake, Virginia, or for other southeastern US forested areas contributing biomass to the export wood pellet industry. PMID- 28649588 TI - Dataset on the superabsorbent hydrogel synthesis with SiO2 nanoparticle and role in water restoration capability of agriculture soil. AB - Synthetic polymer was exploited as water-superabsorbent hydrogel and helped to conserve water in the agricultural soil. The hydrogel polymers were synthesized the carboxymethyl cellulose (CMC) and starch in addition to SiO2 nanoparticles. Superabsorbent hydrogel polymer having 35% water retention ability was analyzed with three replicates. Hydrogel increased the water restoration capability of agricultural soil. PMID- 28649590 TI - Enhancing data visualisation to capture the simulator sickness phenomenon: On the usefulness of radar charts. AB - The data presented in this article are related to the research article entitled "The use of transdermal scopolamine to solve methodological issues raised by gender differences in susceptibility to simulator sickness" (Chaumillon et al., 2017) [1]. In an outstanding first demonstration, Kennedy et al. [2] showed that the Simulator Sickness Questionnaire (SSQ) is an appropriate tool to suit the purposes of characterizing motion sickness experienced in virtual environments. This questionnaire has since been used in many scientific studies. Recently, Balk et al. [3] suggested that the proposed segregation of SSQ scores into three subclasses of symptoms might limit the accuracy of simulator sickness assessment. These authors performed a factor analysis based on SSQ scores obtained from nine studies on driving simulators. Although their factor analysis resulted in the same three orthogonal classes of symptoms as Kennedy et al. [2], unlike this pioneering study, no items were attributed to more than one factor and five items were not attributed to any class of symptoms. As a result, they claimed that an exploration of each item score should give additional cues on individual profiles. To gain a better characterization of such item-by-item exploration, data utilised in this research are shown using a radar chart visualisation. PMID- 28649589 TI - Data supporting the anticancer activity of posterior salivary gland (PSG) toxin from the cuttlefish Sepia pharaonis Ehrenberg (1831). AB - The data presented illustrated the in vitro anti-proliferative effect of the PSG toxin from the cuttlefish, Sepia pharaonis. The cytostatic potentials of the PSG toxin were determined by the lymphocyte migration inhibition assay. The PSG toxin (50 MUg/ml) exhibited commendable inhibition of the migration of lymphocytes across the agarose gel matrix under the presence of lipopolysaccharide mitogen, with a mean migration index of 0.625. The cytotoxicity of the PSG toxin against selected cancer cell lines was determined using the MTT assay. The PSG toxin exhibited dose-dependent cytotoxicity against the MCF-7 breast cancer cells followed by KB (oral), HeLa (cervical) and A549 (lung) cancer cell lines. The PSG toxin also exhibited proportional release of LDH leakage by mitochondrial damage with an IC50 of 13.85 MUM against MCF-7 breast cancer cells. The in vitro anticancer activity of the PSG toxin against the selected cell lines was evaluated by Karthik et al. (2017) [1]. PMID- 28649591 TI - Data on nearshore wave process and surficial beach deposits, central Tamil Nadu coast, India. AB - The chronicles of nearshore morphology and surficial beach deposits provide valuable information about the nature of the beach condition and the depositional environment. It imparts an understanding about the spatial and temporal relationship of nearshore waves and its influence over the distribution of beach sediments. This article contains data about wave and sediment dynamics of the ten sandy beaches along the central Tamil Nadu coast, India. This present dataset comprises nearshore wave parameters, breaker wave type, beach morphodynamic state, grain size distribution and weight percentage of heavy and light mineral distribution. The dataset will figure out the beach morphology and hydrodynamic condition with respect to the different monsoonal season. This will act as a field reference to realize the coastal dynamics in an open sea condition. The nearshore entities were obtained from the intensive field survey between January 2011 and December 2011, while characteristics of beach sediments are examined by the chemical process in the laboratory environment. PMID- 28649592 TI - Fluoride concentration level in rural area in Poldasht city and daily fluoride intake based on drinking water consumption with temperature. AB - Long-term exposure to high level of fluoride can caused several adverse effects on human health including dental and skeletal fluorosis. We investigated all the drinking water source located in rural areas of Poldasht city, west Azerbaijan Province, North West Iran between 2014 and 2015. Fluoride concentration of water samples was measured by SPADNS method. We found that in the villages of Poldasht the average of fluoride concentration in drinking water sources (well, and the river) was in the range mg/l 0.28-10.23. The average daily received per 2 l of drinking water is in the range mg/l 0.7-16.6 per day per person. Drinking water demands cause fluorosis in the villages around the area residents and based on the findings of this study writers are announced suggestions below in order to take care of the health of area residents. PMID- 28649593 TI - Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans. AB - BACKGROUND AND AIMS: Mucoid structures that coat the epithelium play an essential role in keeping the intestinal microbiota at a safe distance from host cells. Encroachment of bacteria into the normally almost-sterile inner mucus layer has been observed in inflammatory bowel disease and in mouse models of colitis. Moreover, such microbiota encroachment has also been observed in mouse models of metabolic syndrome, which are associated low-grade intestinal inflammation. Hence, we investigated if microbiota encroachment might correlate with indices of metabolic syndrome in humans. METHODS: Confocal microscopy was used to measure bacterial-epithelial distance of the closest bacteria per high-powered field in colonic biopsies of all willing participants undergoing cancer screening colonoscopies. RESULTS: We observed that, among all subjects, bacterial epithelial distance was inversely correlated with body mass index, fasting glucose levels, and hemoglobin A1C. However, this correlation was driven by dysglycemic subjects, irrespective of body mass index, whereas the difference in bacterial-epithelial distance between obese and nonobese subjects was eliminated by removal of dysglycemic subjects. CONCLUSIONS: We conclude that microbiota encroachment is a feature of insulin resistance-associated dysglycemia in humans. PMID- 28649595 TI - Unusual indolent behavior of leiomyosarcoma of the vagina: Is observation a viable option? AB - *Primary leiomyosarcoma of the vagina is a rare disease.*We identified a case of unanticipated indolent behavior of vaginal leiomyosarcoma.*Observation or hormonal therapy may be viable option for select patients. PMID- 28649594 TI - Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice. AB - BACKGROUND & AIMS: The factors that distinguish metabolically healthy obesity from metabolically unhealthy obesity are not well understood. Diet has been implicated as a determinant of the unhealthy obesity phenotype, but which aspects of the diet induce dysmetabolism are unknown. The goal of this study was to investigate whether specific macronutrients or macronutrient combinations provoke dysmetabolism in the context of isocaloric, high-energy diets. METHODS: Mice were fed 4 high-energy diets identical in calorie and nutrient content but different in nutrient composition for 3 weeks to 6 months. The test diets contained 42% carbohydrate (sucrose or starch) and 42% fat (oleate or palmitate). Weight and glucose tolerance were monitored; blood and tissues were collected for histology, gene expression, and immunophenotyping. RESULTS: Mice gained weight on all 4 test diets but differed significantly in other metabolic outcomes. Animals fed the starch-oleate diet developed more severe hepatic steatosis than those on other formulas. Stable isotope incorporation showed that the excess hepatic steatosis in starch-oleate-fed mice derived from exaggerated adipose tissue lipolysis. In these mice, adipose tissue lipolysis coincided with adipocyte necrosis and inflammation. Notably, the liver and adipose tissue abnormalities provoked by starch-oleate feeding were reproduced when mice were fed a mixed-nutrient Western diet with 42% carbohydrate and 42% fat. CONCLUSIONS: The macronutrient composition of the diet exerts a significant influence on metabolic outcome, independent of calories and nutrient proportions. Starch-oleate appears to cause hepatic steatosis by inducing progressive adipose tissue injury. Starch-oleate phenocopies the effect of a Western diet; consequently, it may provide clues to the mechanism whereby specific nutrients cause metabolically unhealthy obesity. PMID- 28649596 TI - Phenoconversion from probable rapid eye movement sleep behavior disorder to mild cognitive impairment to dementia in a population-based sample. AB - INTRODUCTION: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with synucleinopathies. In 2012, we reported an increased risk of mild cognitive impairment (MCI) and Parkinson disease (PD) in cognitively normal Olmsted County, Minnesota, residents, aged 70 to 89 years with probable RBD. Here, we examine their progression to dementia and other neurodegenerative phenotypes. METHODS: Fifteen participants with RBD who were diagnosed with either MCI or PD were longitudinally followed, and their subsequent clinical courses were reviewed. RESULTS: Over 6.4 +/- 2.9 years, six of the 14 participants with MCI developed additional neurodegenerative signs, five of whom had Lewy body disease features. Four of them progressed to dementia at a mean age 84.8 +/- 4.9 years, three of whom met the criteria for probable dementia with Lewy bodies. One subject with PD developed MCI, but not dementia. DISCUSSION: Our findings from the population-based sample of Olmsted County, Minnesota, residents suggest that a substantial number of RBD patients tend to develop overt synucleinopathy features over time, and RBD patients who develop MCI and subsequent dementia have clinical features most consistent with dementia with Lewy bodies. PMID- 28649598 TI - AN ANALYSIS OF TWO COMMON REFERENCE POINTS FOR EEGS. AB - Clinical electroencephalographic (EEG) data varies significantly depending on a number of operational conditions (e.g., the type and placement of electrodes, the type of electrical grounding used). This investigation explores the statistical differences present in two different referential montages: Linked Ear (LE) and Averaged Reference (AR). Each of these accounts for approximately 45% of the data in the TUH EEG Corpus. In this study, we explore the impact this variability has on machine learning performance. We compare the statistical properties of features generated using these two montages, and explore the impact of performance on our standard Hidden Markov Model (HMM) based classification system. We show that a system trained on LE data significantly outperforms one trained only on AR data (77.2% vs. 61.4%). We also demonstrate that performance of a system trained on both data sets is somewhat compromised (71.4% vs. 77.2%). A statistical analysis of the data suggests that mean, variance and channel normalization should be considered. However, cepstral mean subtraction failed to produce an improvement in performance, suggesting that the impact of these statistical differences is subtler. PMID- 28649597 TI - Early diagnosis of mild cognitive impairment and Alzheimer's disease based on salivary lactoferrin. AB - INTRODUCTION: The Alzheimer's disease (AD) process is likely initiated many years before clinical onset. Biomarkers of preclinical disease are critical for the development of disease-modifying or even preventative therapies. Current biomarkers for early disease, including cerebrospinal fluid tau and amyloid beta (Abeta) levels, structural and functional magnetic resonance imaging, and the use of brain amyloid imaging, are limited because they are very invasive or expensive. Noninvasive biomarkers may be a more accessible alternative, but none can currently detect preclinical AD with the required sensitivity and specificity. METHODS: Here, we show a novel, straight-forward, and noninvasive approach for assessment of early stages of cognitive decline. Salivary samples from cases of amnestic mild cognitive impairment (aMCI) and AD, and neurology controls were analyzed. RESULTS: We have discovered and validated a new single saliva biomarker, lactoferrin, which in our cross-sectional investigation perfectly discriminates clinically diagnosed aMCI and AD patients from a cognitively healthy control group. The accuracy for AD diagnosis shown by salivary lactoferrin was greater than that obtained from core cerebrospinal fluid (CSF) biomarkers, including total tau and CSF Abeta42. Furthermore, salivary lactoferrin can be used for population screening and for identifying those underdiagnosed subjects with very early stages of mild cognitive impairment and AD. CONCLUSION: This biomarker may offer new insights in the early diagnostics for AD. PMID- 28649599 TI - SEMI-AUTOMATED ANNOTATION OF SIGNAL EVENTS IN CLINICAL EEG DATA. AB - To be effective, state of the art machine learning technology needs large amounts of annotated data. There are numerous compelling applications in healthcare that can benefit from high performance automated decision support systems provided by deep learning technology, but they lack the comprehensive data resources required to apply sophisticated machine learning models. Further, for economic reasons, it is very difficult to justify the creation of large annotated corpora for these applications. Hence, automated annotation techniques become increasingly important. In this study, we investigated the effectiveness of using an active learning algorithm to automatically annotate a large EEG corpus. The algorithm is designed to annotate six types of EEG events. Two model training schemes, namely threshold-based and volume-based, are evaluated. In the threshold-based scheme the threshold of confidence scores is optimized in the initial training iteration, whereas for the volume-based scheme only a certain amount of data is preserved after each iteration. Recognition performance is improved 2% absolute and the system is capable of automatically annotating previously unlabeled data. Given that the interpretation of clinical EEG data is an exceedingly difficult task, this study provides some evidence that the proposed method is a viable alternative to expensive manual annotation. PMID- 28649600 TI - Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors. AB - Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA) enhanced rRp450's in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors. PMID- 28649601 TI - Excessive early-life dietary exposure: a potential source of elevated brain iron and a risk factor for Parkinson's disease. AB - Iron accumulates gradually in the ageing brain. In Parkinson's disease, iron deposition within the substantia nigra is further increased, contributing to a heightened pro-oxidant environment in dopaminergic neurons. We hypothesise that individuals in high-income countries, where cereals and infant formulae have historically been fortified with iron, experience increased early-life iron exposure that predisposes them to age-related iron accumulation in the brain. Combined with genetic factors that limit iron regulatory capacity and/or dopamine metabolism, this may increase the risk of Parkinson's diseases. We propose to (a) validate a retrospective biomarker of iron exposure in children; (b) translate this biomarker to adults; (c) integrate it with in vivo brain iron in Parkinson's disease; and (d) longitudinally examine the relationships between early-life iron exposure and metabolism, brain iron deposition and Parkinson's disease risk. This approach will provide empirical evidence to support therapeutically addressing brain iron deposition in Parkinson's diseases and produce a potential biomarker of Parkinson's disease risk in preclinical individuals. PMID- 28649602 TI - Using a smartphone-based self-management platform to support medication adherence and clinical consultation in Parkinson's disease. AB - The progressive nature of Parkinson's disease, its complex treatment regimens and the high rates of comorbid conditions make self-management and treatment adherence a challenge. Clinicians have limited face-to-face consultation time with Parkinson's disease patients, making it difficult to comprehensively address non-adherence. Here we share the results from a multi-centre (seven centres) randomised controlled trial conducted in England and Scotland to assess the impact of using a smartphone-based Parkinson's tracker app to promote patient self-management, enhance treatment adherence and quality of clinical consultation. Eligible Parkinson's disease patients were randomised using a 1:1 ratio according to a computer-generated random sequence, stratified by centre and using blocks of variable size, to intervention Parkinson's Tracker App or control (Treatment as Usual). Primary outcome was the self-reported score of adherence to treatment (Morisky medication adherence scale -8) at 16 weeks. Secondary outcomes were Quality of Life (Parkinson's disease questionnaire -39), quality of consultation for Parkinson's disease patients (Patient-centred questionnaire for Parkinson's disease), impact on non-motor symptoms (Non-motor symptoms questionnaire), depression and anxiety (Hospital anxiety and depression scale) and beliefs about medication (Beliefs about Medication Questionnaire) at 16 weeks. Primary and secondary endpoints were analysed using a generalised linear model with treatment as the fixed effect and baseline measurement as the covariate. 158 patients completed the study (Parkinson's tracker app = 68 and TAU = 90). At 16 weeks Parkinson's tracker app significantly improved adherence, compared to treatment as usual (mean difference: 0.39, 95%CI 0.04-0.74; p = 0.0304) with no confounding effects of gender, number of comorbidities and age. Among secondary outcomes, Parkinson's tracker app significantly improved patients' perception of quality of consultation (0.15, 95% CI 0.03 to 0.27; p = 0.0110). The change in non-motor symptoms was -0.82 (95% CI -1.75 to 0.10; p = 0.0822). 72% of participants in the Parkinson's tracker app group continued to use and engage with the application throughout the 16-week trial period. The Parkinson's tracker app can be an effective and novel way of enhancing self reported medication adherence and quality of clinical consultation by supporting self-management in Parkinson's disease in patients owning smartphones. Further work is recommended to determine whether the benefits of the intervention are maintained beyond the 16 week study period. PMID- 28649603 TI - The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis? AB - The state of the intestinal environment can have profound effects on the activity of the central nervous system through the physiological contributions of the microbiota, regulation of intestinal barrier function, and altered activity of peripheral neurons. The common language employed for much of the gut-brain communication is the modulation of immune activity. Chronic proinflammatory immune activity is increasingly being recognized as a fundamental element of neurodegenerative disorders, and in Parkinson's disease, inflammation in the intestine appears particularly relevant in pathogenesis. We review the evidence that intestinal dysfunction is present in Parkinson's disease and that it may reflect the earliest manifestations of Parkinson's disease pathology, and we link these findings to dysregulated immune activity. Based on this, we present a model for Parkinson's disease pathogenesis in which the disorder originates in the intestine and progresses with inflammation as its underlying mechanism. More in depth investigations into the physiological mechanisms underlying peripheral pre motor symptoms in Parkinson's disease are expected to lead to the development of novel diagnostic and therapeutic measures that can slow or limit progression of the disease to more advanced stages involving debilitating motor and cognitive symptoms. PMID- 28649604 TI - Combined immunotherapy with "anti-insulin resistance" therapy as a novel therapeutic strategy against neurodegenerative diseases. AB - Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid beta and alpha-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid beta immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of alpha-synuclein in Parkinson's disease. Notably, a recent study of solanezumab, an amyloid beta monoclonal antibody, raises hope for the further therapeutic potential of immunotherapy, not only in Alzheimer's disease, but also for other neurodegenerative disorders, including Parkinson's disease. Thus, it is expected that further refinement of immunotherapy against neurodegenerative diseases may lead to increasing efficacy. Meanwhile, type II diabetes mellitus has been associated with an increased risk of neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, and studies have shown that metabolic dysfunction and abnormalities surrounding insulin signaling may underlie disease progression. Naturally, "anti-insulin resistance" therapy has emerged as a novel paradigm in the therapy of neurodegenerative diseases. Indeed, incretin agonists, which stimulate pancreatic insulin secretion, reduce dopaminergic neuronal loss and suppress Parkinson's disease disease progression in clinical trials. Similar studies are ongoing also in Alzheimer's disease. This paper focuses on critical issues in "immunotherapy" and "anti-insulin resistance" therapy in relation to therapeutic strategies against neurodegenerative disease, and more importantly, how they might merge mechanistically at the point of suppression of protein aggregation, raising the possibility that combined immunotherapy and "anti-insulin resistance" therapy may be superior to either monotherapy. PMID- 28649606 TI - Elevated 5hmC levels characterize DNA of the cerebellum in Parkinson's disease. AB - 5-methylcytosine and the oxidation product 5-hydroxymethylcytosine are two prominent epigenetic variants of the cytosine base in nuclear DNA of mammalian brains. We measured levels of 5-methylcytosine and 5-hydroxymethylcytosine by enzyme-linked immunosorbent assay in DNA from post-mortem cerebella of individuals with Parkinson's disease and age-matched controls. 5-methylcytosine levels showed no significant differences between Parkinson's disease and control DNA sample sets. In contrast, median 5-hydroxymethylcytosine levels were almost twice as high (p < 0.001) in both male and female Parkinson's disease individuals compared with controls. The distinct epigenetic profile identified in cerebellar DNA of Parkinson's disease patients raises the question whether elevated 5 hydroxymethylcytosine levels are a driver or a consequence of Parkinson's disease. PMID- 28649607 TI - Synaptic proteins in CSF relate to Parkinson's disease stage markers. AB - Recent findings of morphological and functional changes in Parkinson's disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson's disease patients out of which 30 were drug-naive) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson's disease patients (p = 0.032). Increased neurogranin levels were found in the drug naive patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson's disease group (p = 0.017), as well as in the drug naive (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson's disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson's disease. PMID- 28649608 TI - Distribution and impact on quality of life of the pain modalities assessed by the King's Parkinson's disease pain scale. AB - In Parkinson's disease, pain is a prevalent and complex symptom of diverse origin. King's Parkinson's disease pain scale, assesses different pain syndromes, thus allowing exploration of its differential prevalence and influence on the health-related quality of life of patients. Post hoc study 178 patients and 83 matched controls participating in the King's Parkinson's disease pain scale validation study were used. For determining the respective distribution, King's Parkinson's disease pain scale items and domains scores = 0 meant absence and >=1 presence of the symptom. The regular scores were used for the other analyses. Health-related quality of lifewas evaluated with EQ-5D-3L and PDQ-8 questionnaires. Parkinson's disease patients experienced more pain modalities than controls. In patients, Pain around joints (King's Parkinson's disease pain scale item 1) and Pain while turning in bed (item 8) were the most prevalent types of pain, whereas Burning mouth syndrome (item 11) and Pain due to grinding teeth (item 10) showed the lowest frequency. The total number of experienced pain modalities closely correlated with the PDQ-8 index, but not with other variables. For all pain types except Pain around joints (item 1) and pain related to Periodic leg movements/RLS (item 7), patients with pain had significantly worse health-related quality of life. The influence of pain, as a whole, on the health related quality of life was not remarkable after adjustment by other variables. When the particular types of pain were considered, adjusted by sex, age, and Parkinson's disease duration, pain determinants were different for EQ-5D-3L and PDQ-8. King's Parkinson's disease pain scale allows exploring the distribution of the diverse syndromic pain occurring in Parkinson's disease and its association with health-related quality of life. PMID- 28649605 TI - Presynaptic dopaminergic terminal imaging and non-motor symptoms assessment of Parkinson's disease: evidence for dopaminergic basis? AB - Parkinson's disease (PD) is now considered to be a multisystemic disorder consequent on multineuropeptide dysfunction including dopaminergic, serotonergic, cholinergic, and noradrenergic systems. This multipeptide dysfunction leads to expression of a range of non-motor symptoms now known to be integral to the concept of PD and preceding the diagnosis of motor PD. Some non-motor symptoms in PD may have a dopaminergic basis and in this review, we investigate the evidence for this based on imaging techniques using dopamine-based radioligands. To discuss non-motor symptoms we follow the classification as outlined by the validated PD non-motor symptoms scale. PMID- 28649609 TI - Insomnia and somnolence in idiopathic RBD: a prospective cohort study. AB - Although some sleep disorders are markers of prodromal Parkinson's disease and dementia with Lewy bodies, it is unclear whether insomnia and somnolence can predict disease. We assessed a large cohort of patients with idiopathic rapid eye movement sleep behavior disorder and age/sex matched controls, comparing the Epworth sleepiness scale, the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, and polysomnographic variables. In those with repeated scales, we assessed change over time. Finally, we assessed whether sleep abnormalities predicted defined neurodegenerative disease. The 151 patients (age = 65.9, 75% male) completed sleep scales and were included. Epworth scores were similar between patients and controls (7.0+/-4.6 vs. 7.2+/-4.7, p = 0.77), and did not progress with time (change = +0.46+/-2.1, p = 0.45). Epworth scores were similar between those who developed neurodegenerative disease and those remaining disease free (6.7+/-4.4 vs. 7.1+/-4.7, p = 0.70). Pittsburgh Index scores were higher in patients than controls (7.2+/-3.8 vs. 4.9+/-3.4, p = 0.004), mainly driven by the sleep disturbance/medication components (reflecting rapid eye movement sleep behavior disorder symptoms/treatment). Baseline Pittsburgh scores did not predict conversion to neurodegeneration, although sleep duration increased over time in those converting to neurodegenerative disease (+0.88+/-1.32 h, p = 0.014). Insomnia index scores were higher in patients than controls (10.0+/-5.5 vs. 6.35+/-4.66, p < 0.001), but declined over time (-1.43+/-5.09, p = 0.029) particularly in those converting to neurodegenerative disease. Finally, on polysomnogram, those with increased tonic rapid eye movement had higher risk of developing defined neurodegenerative disease (HR = 1.88, p = 0.039). In summary, we found that somnolence and insomnia do not predict neurodegeneration in idiopathic rapid eye movement sleep behavior disorder. As neurodegeneration progresses through prodromal stages, patients may have increasing sleep drive and duration. PMID- 28649610 TI - Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial. AB - A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non treated controls and 20 Parkinson's disease patients. Both Parkinson's disease patients and controls were monitored for 2 months for baseline profiling. Parkinson's disease patients were then randomized into two equal groups to self administer placebo (saline) or sargramostim subcutaneously at 6 MUg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson's disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson's disease patients and non Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson's disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation. PMID- 28649611 TI - LRRK2 levels in immune cells are increased in Parkinson's disease. AB - Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson's disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (p = 0.0095), T cells (p = 0.029), and CD16+ monocytes (p = 0.01) of Parkinson's disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson's disease patients compared to healthy controls. In addition, Parkinson's disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson's disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T lymphocyte-associated protein 4), was decreased in Parkinson's disease compared to HC in T cells (p = 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson's disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function. PMID- 28649612 TI - Disentangling the neural correlates of corticobasal syndrome and corticobasal degeneration with systematic and quantitative ALE meta-analyses. AB - Corticobasal degeneration is a scarce neurodegenerative disease, which can only be confirmed by histopathological examination. Reported to be associated with various clinical syndromes, its classical clinical phenotype is corticobasal syndrome. Due to the rareness of corticobasal syndrome/corticobasal degeneration and low numbers of patients included in single studies, meta-analyses are particularly suited to disentangle features of the clinical syndrome and histopathology. Using PubMed, we identified 11 magnetic resonance imaging studies measuring atrophy in 22 independent cohorts with 200 patients contrasted to 318 healthy controls. The anatomic likelihood estimation method was applied to reveal affected brain regions across studies. Corticobasal syndrome was related to gray matter loss in the basal ganglia/thalamus, frontal, parietal, and temporal lobes. In corticobasal degeneration patients, atrophy in the thalamus, frontal, temporal, and occipital lobes were found. Finally, in a conjunction analysis, the bilateral thalamus, the bilateral posterior frontomedian cortex, posterior midcingulate cortex and premotor area/supplementary motor area, and the left posterior superior and middle frontal gyrus/precentral gyrus were identified as areas associated with both, corticobasal syndrome and corticobasal degeneration. Remarkably, atrophy in the premotor area/supplementary motor area and posterior midcingulate/frontomedian cortex seems to be specific for corticobasal syndrome/corticobasal degeneration, whereas atrophy in the thalamus and the left posterior superior and middle frontal gyrus/precentral gyrus are also associated with other neurodegenerative diseases according to anatomic likelihood estimation method meta-analyses. Our study creates a new conceptual framework to understand, and distinguish between clinical features (corticobasal syndrome) and histopathological findings (corticobasal degeneration) by powerful data-driven meta-analytic approaches. Furthermore, it proposes regional-specific atrophy as an imaging biomarker for diagnosis of corticobasal syndrome/corticobasal degeneration ante-mortem. PMID- 28649613 TI - Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism? AB - Phosphoglycerate kinase 1 (PGK-1) is a glycolytic enzyme encoded by PGK-1, which maps to the X chromosome. PGK-1 deficiency causes X-linked recessive hereditary chronic hemolytic anemia, myopathy, and neurological disorders due to insufficient ATP regeneration. Early-onset parkinsonism has occasionally been reported as a neurological complication of this condition. However, heterozygous carriers of PGK-1 deficiency were thought to be neurologically asymptomatic. Here, we report a boy with PGK-1 deficiency and his mother, a carrier of a heterozygous mutation in PGK-1, both of whom presented with early-onset parkinsonism. The boy developed parkinsonism at 9 years of age. His parkinsonism partially responded to levodopa treatment. 123l-metaiodobenzylguanidine (MIBG) uptake was normal. His mother, who exhibited normal PGK-1 activity in erythrocytes, developed parkinsonism at 36 years of age. Her symptoms were undistinguishable from those of Parkinson's disease (PD), despite her normal uptake of MIBG. Neither a point mutation in nor multiplication of SNCA was found. Additionally, hotspots of LRRK2 and GBA were not mutated. To our knowledge, this report provides the first description of parkinsonism in a carrier of PGK-1 deficiency. Interestingly, PGK-1 is located within the confirmed susceptibility locus for PD known as PARK12. These observations suggest that PGK-1 mutations confer susceptibility to PD. PMID- 28649614 TI - Integrated molecular landscape of Parkinson's disease. AB - Parkinson's disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson's disease, a common mechanism underlying especially sporadic Parkinson's disease is still largely unknown. In order to gain further insight into the etiology of Parkinson's disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson's disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson's disease, into a molecular interaction landscape. The molecular Parkinson's disease landscape harbors four main biological processes oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation-that interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson's disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron specific signaling cascades. Furthermore, we validate the Parkinson's disease lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson's disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson's disease and highlight a key role for lipids and lipoproteins in Parkinson's disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson's disease. PMID- 28649616 TI - Palliative care for Parkinson's disease: suggestions from a council of patient and carepartners. AB - In 2015, the Parkinson's Disease Foundation sponsored the first international meeting on Palliative Care and Parkinson's disease and the Patient Centered Outcomes Research Institute funded the first comparative effectiveness trial of palliative care for Parkinson's disease. A council of Parkinson's disease patients and carepartners was engaged to assist with both projects. This council wrote the following manuscript as an opinion piece addressed to the clinical and research community on how palliative care could be applied to people living with Parkinson's disease and their families. The council endorses palliative care as an approach to the care of Parkinson's disease patients and their families that seeks to reduce suffering through spiritual, psychosocial, and medical support. This approach should start at the time of diagnosis, as this is a very challenging time for patients and carepartners; includes better emotional support, educational resources, and closer follow-up than is currently standard; and continue through end-of-life care and bereavement. PMID- 28649615 TI - Imaging Parkinson's disease below the neck. AB - Parkinson's disease is a systemic disorder with widespread and early alpha synuclein pathology in the autonomic and enteric nervous systems, which is present throughout the gastrointestinal canal prior to diagnosis. Gastrointestinal and genitourinary autonomic symptoms often predate clinical diagnosis by several years. It has been hypothesized that progressive alpha synuclein aggregation is initiated in hyperbranched, non-myelinated neuron terminals, and may subsequently spread via retrograde axonal transport. This would explain why autonomic nerves are so prone to formation of alpha-synuclein pathology. However, the hypothesis remains unproven and in vivo imaging methods of peripheral organs may be essential to study this important research field. The loss of sympathetic and parasympathetic nerve terminal function in Parkinson's disease has been demonstrated using radiotracers such as 123I-meta iodobenzylguanidin, 18F-dopamine, and 11C-donepezil. Other radiotracer and radiological imaging methods have shown highly prevalent dysfunction of pharyngeal and esophageal motility, gastric emptying, colonic transit time, and anorectal function. Here, we summarize the methodology and main findings of radio isotope and radiological modalities for imaging peripheral pathology in Parkinson's disease. PMID- 28649617 TI - A multifactorial study on nutritional status, binge eating and physical activity as main factors directly influencing body weight in Parkinson's disease. AB - Weight lossisa multifactorial disorder commonly affecting Parkinson's disease patients. The aim of this study was to investigate the relationship between body weight, nutritional status, physical activity, and Parkinson's disease-related factors. A total of 114 consecutive Parkinson's disease patients without dietary restrictions were evaluated prospectively with respect to: nutritional status (Mini Nutritional Assessment), physical activity level (Yale Physical Activity Survey), MDS-UPDRS score, olfactory function, depression, cognitive functionand impulse-control disorders, among other variables. Structural equation modeling was used to build multivariate models and to calculate standardized regression weights (srw) for pairs of variables, which are homologous to correlation coefficients, taking into account the effects of all other variables in the model. Sixty (53%) patients were males. Mean age was 66.1 +/- 9.8 years and mean disease duration was 8.3 +/- 5.6 years. Longer disease duration was negatively related to nutritional status (srw = -0.25; p = 0.01). UPDRS II + III score was associated with reduced cognitive function (srw = -0.39; p = 0.01), which was positivelyrelated to nutritional status (srw = 0.23; p = 0.01). Finally, nutritional status was positively related to body weight (srw = 0.22, p < 0.01). Binge eating and physical activity were also directly and positively related to body weight (srw = 0.32; p = 0.001 and srw = 0.23; p = 0.001). Nutritional status, binge eating and physical activity were directly and independently related to body weight in our sample of Parkinson's disease patients. Therefore, physicians should actively explore nutritional status and binge eating in Parkinson's disease patients to avoid alterations in body weight regulation. Effects of physical activity should be further explored. PMID- 28649618 TI - Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis. AB - Central Nervous System inflammation has been implicated in neurodegenerative disorders including Parkinson's disease (Ransohoff, Science 353: 777-783, 2016; Kannarkat et al. J. Parkinsons Dis. 3: 493-514, 2013). Here, we examined if the H1N1 influenza virus (Studahl et al. Drugs 73: 131-158, 2013) could synergize with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Jackson Lewis et al. in Mark LeDoux (ed) Movement Disorders: Genetics and Models: 287 306, Elsevier, 2015) to induce a greater microglial activation and loss of substantia nigra pars compacta dopaminergic neurons than either insult alone. H1N1-infected animals administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exhibit a 20% greater loss of substantia nigra pars compacta dopaminergic neurons than occurs from the additive effects of H1N1 or 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine alone (p < 0.001). No synergistic effects were found in microglial activation. The synergistic dopaminergic neuron loss is eliminated by influenza vaccination or treatment with oseltamivir carboxylate. This work shows that multiple insults can induce synergistic effects; and even these small changes can be significant as it might allow one to cross a phenotypic disease threshold that would not occur from individual non-interacting exposures. Our observations also have important implications for public health, providing impetus for influenza vaccination or prompt treatment with anti-viral medications upon influenza diagnosis. PMID- 28649620 TI - Use of a self-rating scale of the nature and severity of symptoms in Parkinson's Disease (PRO-PD): Correlation with quality of life and existing scales of disease severity. AB - A self-rating scale was developed to permit patient-reported, remote assessment of Parkinson's disease symptom severity. The goal was to create a continuous outcome measure that does not require a clinical exam, does not fluctuate in response to dopaminergic medications, takes only a few minutes to complete, allows for stratification by symptom(s), and captures both motor and non-motor Parkinson's disease symptoms, major contributors to quality of life. The Patient Reported Outcomes in Parkinson's Disease (PRO-PD) is the cumulative score of 32 slider bars, each evaluating a common Parkinson's disease symptom. The PRO-PD has been used as an outcome measure in three studies. The baseline data from each of these studies were pooled for this analysis. Symptom frequency and severity are described, as well as correlation coefficients with existing measures of Parkinson's disease severity. Data on 1031 participants with Parkinson's disease were available for analysis. Fatigue, impaired handwriting, daytime sleepiness, slowness, tremor, muscle cramps, and forgetfulness were the most frequently reported symptoms. Persons with a relatively long duration of Parkinson's disease tended to report more, and more severe, symptoms. The PRO-PD was most highly correlated with the Parkinson's Disease Questionaire-39 (r = 0.763, P < 0.000) and Patient-Reported Outcome Measurement Information System Global quality of life (r = -0.7293, P < 0.000), other patient-reported quality of life measures. The PRO-PDnon-motor subset was highly correlated with the Non-Motor Symptom Score (r = 0.7533, P < 0.000). There was a moderate correlation seen with Hoehn & Yahr (r = 0.5922, P < 0.000), total Unified Parkinson's disease Rating Scale (r = 0.4724, P < 0.000), and the Timed-Up-&-Go (r = 0.4709, P < 0.000). The PRO-PD may have utility for patients, providers, and researchers as a patient-centered measure of Parkinson's disease symptom severity. Further PRO-PD validation efforts are warranted. PMID- 28649619 TI - Variable frequency of LRRK2 variants in the Latin American research consortium on the genetics of Parkinson's disease (LARGE-PD), a case of ancestry. AB - Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson's disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson's disease, but this finding requires replication. We screened 1734 Parkinson's disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay. Genotypes were determined by TaqMan assay (p.G2019S and p.Q1111H) or by sequencing of exon 31 (p.R1441C/G/H/S). Admixture proportion was determined using a panel of 29 ancestry informative markers. We identified a total of 29 Parkinson's disease patients (1.7%) who carried p.G2019S and the frequency ranged from 0.2% in Peru to 4.2% in Uruguay. Only two Parkinson's disease patients carried p.R1441G and one patient carried p.R1441C. There was no significant difference in the frequency of p.Q1111H in patients (3.8%) compared to controls (3.1%; OR 1.02, p = 0.873). The frequency of LRRK2 p.G2019S varied greatly between different Latin American countries and was directly correlated with the amount of European ancestry observed. p.R1441G is rare in Latin America despite the large genetic contribution made by settlers from Spain, where the mutation is relatively common. PMID- 28649621 TI - Contactless processing of SiGe-melts in EML under reduced gravity. AB - The processing of semiconductors based on electromagnetic levitation is a challenge, because this kind of materials shows a poor electrical conductivity. Here, we report the results of measurements of the thermophysical properties obtained recently from highly doped semiconductors Si1-x Ge x under microgravity conditions in the framework of parabola flight campaigns. Due to the limited time of about 20 s of microgravity especially Ge-rich samples with low melting temperatures were investigated. The measurements were performed contactlessly by video techniques with subsequent digital image processing. Linear and volume thermal expansion coefficients were measured hereby from image data. An anomaly of volume changes near the solidus temperature is visible. Viscosity and surface tension were determined by the oscillating drop technique using optic and electronic data. It was observed that the alloying of Si into Ge increases the surface tension of the melts. The viscosity is following an Arrhenius equation and shows a crossover temperature which separates simple liquid at high temperatures from cooperative liquid at low temperatures. PMID- 28649622 TI - Brain structural plasticity with spaceflight. AB - Humans undergo extensive sensorimotor adaptation during spaceflight due to altered vestibular inputs and body unloading. No studies have yet evaluated the effects of spaceflight on human brain structure despite the fact that recently reported optic nerve structural changes are hypothesized to occur due to increased intracranial pressure occurring with microgravity. This is the first report on human brain structural changes with spaceflight. We evaluated retrospective longitudinal T2-weighted MRI scans and balance data from 27 astronauts (thirteen ~2-week shuttle crew members and fourteen ~6-month International Space Station crew members) to determine spaceflight effects on brain structure, and whether any pre to postflight brain changes are associated with balance changes. Data were obtained from the NASA Lifetime Surveillance of Astronaut Health. Brain scans were segmented into gray matter maps and normalized into MNI space using a stepwise approach through subject specific templates. Non parametric permutation testing was used to analyze pre to postflight volumetric gray matter changes. We found extensive volumetric gray matter decreases, including large areas covering the temporal and frontal poles and around the orbits. This effect was larger in International Space Station versus shuttle crew members in some regions. There were bilateral focal gray matter increases within the medial primary somatosensory and motor cortex; i.e., the cerebral areas where the lower limbs are represented. These intriguing findings are observed in a retrospective data set; future prospective studies should probe the underlying mechanisms and behavioral consequences. PMID- 28649623 TI - Segregation and pattern formation in dilute granular media under microgravity conditions. AB - Space exploration and exploitation face a major challenge: the handling of granular materials in low-gravity environments. Indeed, grains behave quite differently in space than on Earth, and the dissipative nature of the collisions between solid particles leads to clustering. Within poly-disperse materials, the question of segregation is highly relevant but has not been addressed so far in microgravity. From parabolic flight experiments on dilute binary granular media, we show that clustering can trigger a segregation mechanism, and we observe, for the first time, the formation of layered structures in the bulk. PMID- 28649625 TI - The effect of long-term exposure to microgravity on the perception of upright. AB - Going into space is a disorienting experience. Many studies have looked at sensory functioning in space but the multisensory basis of orientation has not been systematically investigated. Here, we assess how prolonged exposure to microgravity affects the relative weighting of visual, gravity, and idiotropic cues to perceived orientation. We separated visual, body, and gravity (when present) cues to perceived orientation before, during, and after long-term exposure to microgravity during the missions of seven astronauts on the International Space Station (mean duration 168 days) and measuring perceived vertical using the subjective visual vertical and the perceptual upright. The relative influence of each cue and the variance of their judgments were measured. Fourteen ground-based control participants performed comparable measurements over a similar period. The variance of astronauts' subjective visual vertical judgments in the absence of visual cues was significantly larger immediately upon return to earth than before flight. Astronauts' perceptual upright demonstrated a reduced reliance on visual cues upon arrival on orbit that re-appeared long after returning to earth. For earth-bound controls, the contributions of body, gravity, and vision remained constant throughout the year-long testing period. This is the first multisensory study of orientation behavior in space and the first demonstration of long-term perceptual changes that persist after returning to earth. Astronauts showed a plasticity in the weighting of perceptual cues to orientation that could form the basis for future countermeasures. PMID- 28649624 TI - Spaceflight-induced neuroplasticity in humans as measured by MRI: what do we know so far? AB - Space travel poses an enormous challenge on the human body; microgravity, ionizing radiation, absence of circadian rhythm, confinement and isolation are just some of the features associated with it. Obviously, all of the latter can have an impact on human physiology and even induce detrimental changes. Some organ systems have been studied thoroughly under space conditions, however, not much is known on the functional and morphological effects of spaceflight on the human central nervous system. Previous studies have already shown that central nervous system changes occur during and after spaceflight in the form of neurovestibular problems, alterations in cognitive function and sensory perception, cephalic fluid shifts and psychological disturbances. However, little is known about the underlying neural substrates. In this review, we discuss the current limited knowledge on neuroplastic changes in the human central nervous system associated with spaceflight (actual or simulated) as measured by magnetic resonance imaging-based techniques. Furthermore, we discuss these findings as well as their future perspectives, since this can encourage future research into this delicate and intriguing aspect of spaceflight. Currently, the literature suffers from heterogeneous experimental set-ups and therefore, the lack of comparability of findings among studies. However, the cerebellum, cortical sensorimotor and somatosensory areas and vestibular-related pathways seem to be involved across different studies, suggesting that these brain regions are most affected by (simulated) spaceflight. Extending this knowledge is crucial, especially with the eye on long-duration interplanetary missions (e.g. Mars) and space tourism. PMID- 28649626 TI - Investigation of simulated microgravity effects on Streptococcus mutans physiology and global gene expression. AB - Astronauts have been previously shown to exhibit decreased salivary lysozyme and increased dental calculus and gingival inflammation in response to space flight, host factors that could contribute to oral diseases such as caries and periodontitis. However, the specific physiological response of caries-causing bacteria such as Streptococcus mutans to space flight and/or ground-based simulated microgravity has not been extensively investigated. In this study, high aspect ratio vessel S. mutans simulated microgravity and normal gravity cultures were assessed for changes in metabolite and transcriptome profiles, H2O2 resistance, and competence in sucrose-containing biofilm media. Stationary phase S. mutans simulated microgravity cultures displayed increased killing by H2O2 compared to normal gravity control cultures, but competence was not affected. RNA seq analysis revealed that expression of 153 genes was up-regulated >=2-fold and 94 genes down-regulated >=2-fold during simulated microgravity high aspect ratio vessel growth. These included a number of genes located on extrachromosomal elements, as well as genes involved in carbohydrate metabolism, translation, and stress responses. Collectively, these results suggest that growth under microgravity analog conditions promotes changes in S. mutans gene expression and physiology that may translate to an altered cariogenic potential of this organism during space flight missions. PMID- 28649628 TI - A hitchhiker's guide to an ISS experiment in under 9 months. AB - The International Space Station National Laboratory gives students a platform to conduct space-flight science experiments. To successfully take advantage of this opportunity, students and their mentors must have an understanding of how to develop and then conduct a science project on international space station within a school year. Many factors influence the speed in which a project progresses. The first step is to develop a science plan, including defining a hypothesis, developing science objectives, and defining a concept of operation for conducting the flight experiment. The next step is to translate the plan into well-defined requirements for payload development. The last step is a rapid development process. Included in this step is identifying problems early and negotiating appropriate trade-offs between science and implementation complexity. Organizing the team and keeping players motivated is an equally important task, as is employing the right mentors. The project team must understand the flight experiment infrastructure, which includes the international space station environment, payload resource requirements and available components, fail-safe operations, system logs, and payload data. Without this understanding, project development can be impacted, resulting in schedule delays, added costs, undiagnosed problems, and data misinterpretation. The information and processes for conducting low-cost, rapidly developed student-based international space station experiments are presented, including insight into the system operations, the development environment, effective team organization, and data analysis. The details are based on the Valley Christian Schools (VCS, San Jose, CA) fluidic density experiment and penicillin experiment, which were developed by 13- and 14 year-old students and flown on ISS. PMID- 28649627 TI - From the bench to exploration medicine: NASA life sciences translational research for human exploration and habitation missions. AB - NASA's Space Biology and Human Research Program entities have recently spearheaded communications both internally and externally to coordinate the agency's translational research efforts. In this paper, we strongly advocate for translational research at NASA, provide recent examples of NASA sponsored early stage translational research, and discuss options for a path forward. Our overall objective is to help in stimulating a collaborative research across multiple disciplines and entities that, working together, will more effectively and more rapidly achieve NASA's goals for human spaceflight. PMID- 28649629 TI - RhoGTPase stimulation is associated with strontium chloride treatment to counter simulated microgravity-induced changes in multipotent cell commitment. AB - Microgravity-related cytoskeletal disorganization is associated with an altered balance between osteoblastogenesis and adipogenesis of multipotent cells. Strontium chloride is known to increase osteoblastogenesis and repress adipogenesis, but its effects in microgravity-related conditions have not been established. Our goal was to investigate early events in this process, focusing on RhoGTPases as controllers of cytoskeletal organization leading to stem cell commitment. We cultivated C3H10T1/2 on microspheres using a rotating wall vessel bioreactor (NASA) in order to simulate microgravity-related conditions in adipogenesis and osteoblastogenesis conditions independently. We observed that rotating wall vessel cultures presented increased adipogenesis, while osteoblastogenesis was reduced. Strontium-treated multipotent cells presented a significant repression in adipogenesis (-90 %, p < 0.001 PPARyD8) and an activation of osteoblastogenesis (+95 %, p < 0.001 bone sialoprotein and osteopontin D8), even in gravity altered conditions. We established that concomitant RhoA/Rac1 activations were associated with osteoblastogenesis enhancement and adipogenesis limitation in uncommitted cells. As vascular endothelial growth factor splicing is mechanosensitive and its signaling is central to stem cell commitment, we investigated vascular endothelial growth factor production, isoforms and receptors expressions in our conditions. We observed that vascular endothelial growth factor and receptors expressions were not significantly affected, but we found that presence of soluble vascular endothelial growth factor was associated with RhoA/Rac1 activations, whereas sequestration of vascular endothelial growth factor by cells was associated with RhoA/Rac1 inhibitions. We propose that strontium triggers secretion of vascular endothelial growth factor and the subsequent Rac1 and RhoA activations leading to repression of adipogenesis and osteogenesis stimulation validating strontium as a counter measure for microgravity-induced alteration of cell commitment. PMID- 28649631 TI - Swing-like pool boiling on nano-textured surfaces for microgravity applications related to cooling of high-power microelectronics. AB - Here, we demonstrate that heat removed in pool boiling from a heater mimicking high-power microelectronics could be used to facilitate a swing-like motion of the heater before being finally dissipated. This swing-like motion could be beneficial for shedding a large vapor bubble that encapsulates high-power heaters in microgravity where buoyancy force is unavailable for vapor bubble removal. The swing-like motion is propelled by vapor bubble recoil, the force which exists irrespective of gravity and buoyancy. We also demonstrate that this force could be significantly enhanced by depositing on the heater surface supersonically blown polymer nanofibers with cross-sectional diameters below 100 nm. These nanofibers provide additional nucleation sites, resulting in much more frequent bubble nucleation and departure, and thus a higher overall vapor recoil force propelling the heater motion. Such nanofibers strongly adhere to the heater surface and withstand prolonged harsh pool boiling. The measured velocity of the model swing-like heater in Novec 7300 fluid is about 1 cm/s. PMID- 28649630 TI - Towards human exploration of space: the THESEUS review series on muscle and bone research priorities. AB - Without effective countermeasures, the musculoskeletal system is altered by the microgravity environment of long-duration spaceflight, resulting in atrophy of bone and muscle tissue, as well as in deficits in the function of cartilage, tendons, and vertebral disks. While inflight countermeasures implemented on the International Space Station have evidenced reduction of bone and muscle loss on low-Earth orbit missions of several months in length, important knowledge gaps must be addressed in order to develop effective strategies for managing human musculoskeletal health on exploration class missions well beyond Earth orbit. Analog environments, such as bed rest and/or isolation environments, may be employed in conjunction with large sample sizes to understand sex differences in countermeasure effectiveness, as well as interaction of exercise with pharmacologic, nutritional, immune system, sleep and psychological countermeasures. Studies of musculoskeletal biomechanics, involving both human subject and computer simulation studies, are essential to developing strategies to avoid bone fractures or other injuries to connective tissue during exercise and extravehicular activities. Animal models may be employed to understand effects of the space environment that cannot be modeled using human analog studies. These include studies of radiation effects on bone and muscle, unraveling the effects of genetics on bone and muscle loss, and characterizing the process of fracture healing in the mechanically unloaded and immuno compromised spaceflight environment. In addition to setting the stage for evidence-based management of musculoskeletal health in long-duration space missions, the body of knowledge acquired in the process of addressing this array of scientific problems will lend insight into the understanding of terrestrial health conditions such as age-related osteoporosis and sarcopenia. PMID- 28649633 TI - Latent virus reactivation in astronauts on the international space station. AB - Reactivation of latent herpes viruses was measured in 23 astronauts (18 male and 5 female) before, during, and after long-duration (up to 180 days) spaceflight onboard the international space station . Twenty age-matched and sex-matched healthy ground-based subjects were included as a control group. Blood, urine, and saliva samples were collected before, during, and after spaceflight. Saliva was analyzed for Epstein-Barr virus, varicella-zoster virus, and herpes simplex virus type 1. Urine was analyzed for cytomegalovirus. One astronaut did not shed any targeted virus in samples collected during the three mission phases. Shedding of Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus was detected in 8 of the 23 astronauts. These viruses reactivated independently of each other. Reactivation of Epstein-Barr virus, varicella-zoster virus, and cytomegalovirus increased in frequency, duration, and amplitude (viral copy numbers) when compared to short duration (10 to 16 days) space shuttle missions. No evidence of reactivation of herpes simplex virus type 1, herpes simplex virus type 2, or human herpes virus 6 was found. The mean diurnal trajectory of salivary cortisol changed significantly during flight as compared to before flight (P = 0.010). There was no statistically significant difference in levels of plasma cortisol or dehydoepiandosterone concentrations among time points before, during, and after flight for these international space station crew members, although observed cortisol levels were lower at the mid and late-flight time points. The data confirm that astronauts undertaking long-duration spaceflight experience both increased latent viral reactivation and changes in diurnal trajectory of salivary cortisol concentrations. PMID- 28649632 TI - Three-dimensional organotypic co-culture model of intestinal epithelial cells and macrophages to study Salmonella enterica colonization patterns. AB - Three-dimensional models of human intestinal epithelium mimic the differentiated form and function of parental tissues often not exhibited by two-dimensional monolayers and respond to Salmonella in key ways that reflect in vivo infections. To further enhance the physiological relevance of three-dimensional models to more closely approximate in vivo intestinal microenvironments encountered by Salmonella, we developed and validated a novel three-dimensional co-culture infection model of colonic epithelial cells and macrophages using the NASA Rotating Wall Vessel bioreactor. First, U937 cells were activated upon collagen coated scaffolds. HT-29 epithelial cells were then added and the three dimensional model was cultured in the bioreactor until optimal differentiation was reached, as assessed by immunohistochemical profiling and bead uptake assays. The new co-culture model exhibited in vivo-like structural and phenotypic characteristics, including three-dimensional architecture, apical-basolateral polarity, well-formed tight/adherens junctions, mucin, multiple epithelial cell types, and functional macrophages. Phagocytic activity of macrophages was confirmed by uptake of inert, bacteria-sized beads. Contribution of macrophages to infection was assessed by colonization studies of Salmonella pathovars with different host adaptations and disease phenotypes (Typhimurium ST19 strain SL1344 and ST313 strain D23580; Typhi Ty2). In addition, Salmonella were cultured aerobically or microaerobically, recapitulating environments encountered prior to and during intestinal infection, respectively . All Salmonella strains exhibited decreased colonization in co-culture (HT-29-U937) relative to epithelial (HT-29) models, indicating antimicrobial function of macrophages. Interestingly, D23580 exhibited enhanced replication/survival in both models following invasion. Pathovar-specific differences in colonization and intracellular co-localization patterns were observed. These findings emphasize the power of incorporating a series of related three-dimensional models within a study to identify microenvironmental factors important for regulating infection. PMID- 28649634 TI - Pyrocystis noctiluca represents an excellent bioassay for shear forces induced in ground-based microgravity simulators (clinostat and random positioning machine). AB - Ground-based facilities, such as clinostats and random positioning machines aiming at simulating microgravity conditions, are tools to prepare space experiments and identify gravity-related signaling pathways. A prerequisite is that the facilities are operated in an appropriate manner and potentially induced non-gravitational effects, such as shearing forces, have to be taken into account. Dinoflagellates, here P. noctiluca, as fast and sensitive reporter system for shear stress and hydrodynamic gradients, were exposed on a clinostat (constant rotation around one axis, 60 rpm) or in a random positioning machine, that means rotating around two axes, whose velocity and direction were chosen at random. Deformation of the cell membrane of P. noctiluca due to shear stress results in a detectable bioluminescence emission. Our results show that the amount of mechanical stress is higher on an random positioning machine than during constant clinorotation, as revealed by the differences in photon counts. We conclude that one axis clinorotation induced negligible non-gravitational effects in the form of shear forces in contrast to random operation modes tested. For the first time, we clearly visualized the device-dependent occurrence of shear forces by means of a bioassay, which have to be considered during the definition of an appropriate simulation approach and to avoid misinterpretation of results. PMID- 28649635 TI - Gravireceptors in eukaryotes-a comparison of case studies on the cellular level. AB - We have selected five evolutionary very different biological systems ranging from unicellular protists via algae and higher plants to human cells showing responses to the gravity vector of the Earth in order to compare their graviperception mechanisms. All these systems use a mass, which may either by a heavy statolith or the whole content of the cell heavier than the surrounding medium to operate on a gravireceptor either by exerting pressure or by pulling on a cytoskeletal element. In many cases the receptor seems to be a mechanosensitive ion channel activated by the gravitational force which allows a gated ion flux across the membrane when activated. This has been identified in many systems to be a calcium current, which in turn activates subsequent elements of the sensory transduction chain, such as calmodulin, which in turn results in the activation of ubiquitous enzymes, gene expression activation or silencing. Naturally, the subsequent responses to the gravity stimulus differ widely between the systems ranging from orientational movement and directed growth to physiological reactions and adaptation to the environmental conditions. PMID- 28649636 TI - Interplay of space radiation and microgravity in DNA damage and DNA damage response. AB - In space, multiple unique environmental factors, particularly microgravity and space radiation, pose constant threat to the DNA integrity of living organisms. Specifically, space radiation can cause damage to DNA directly, through the interaction of charged particles with the DNA molecules themselves, or indirectly through the production of free radicals. Although organisms have evolved strategies on Earth to confront such damage, space environmental conditions, especially microgravity, can impact DNA repair resulting in accumulation of severe DNA lesions. Ultimately these lesions, namely double strand breaks, chromosome aberrations, micronucleus formation, or mutations, can increase the risk for adverse health effects, such as cancer. How spaceflight factors affect DNA damage and the DNA damage response has been investigated since the early days of the human space program. Over the years, these experiments have been conducted either in space or using ground-based analogs. This review summarizes the evidence for DNA damage induction by space radiation and/or microgravity as well as spaceflight-related impacts on the DNA damage response. The review also discusses the conflicting results from studies aimed at addressing the question of potential synergies between microgravity and radiation with regard to DNA damage and cellular repair processes. We conclude that further experiments need to be performed in the true space environment in order to address this critical question. PMID- 28649637 TI - The adaptation of Escherichia coli cells grown in simulated microgravity for an extended period is both phenotypic and genomic. AB - Microorganisms impact spaceflight in a variety of ways. They play a positive role in biological systems, such as waste water treatment but can be problematic through buildups of biofilms that can affect advanced life support. Of special concern is the possibility that during extended missions, the microgravity environment will provide positive selection for undesirable genomic changes. Such changes could affect microbial antibiotic sensitivity and possibly pathogenicity. To evaluate this possibility, Escherichia coli (lac plus) cells were grown for over 1000 generations on Luria Broth medium under low-shear modeled microgravity conditions in a high aspect rotating vessel. This is the first study of its kind to grow bacteria for multiple generations over an extended period under low-shear modeled microgravity. Comparisons were made to a non-adaptive control strain using growth competitions. After 1000 generations, the final low-shear modeled microgravity-adapted strain readily outcompeted the unadapted lac minus strain. A portion of this advantage was maintained when the low-shear modeled microgravity strain was first grown in a shake flask environment for 10, 20, or 30 generations of growth. Genomic sequencing of the 1000 generation strain revealed 16 mutations. Of the five changes affecting codons, none were neutral. It is not clear how significant these mutations are as individual changes or as a group. It is concluded that part of the long-term adaptation to low-shear modeled microgravity is likely genomic. The strain was monitored for acquisition of antibiotic resistance by VITEK analysis throughout the adaptation period. Despite the evidence of genomic adaptation, resistance to a variety of antibiotics was never observed. PMID- 28649638 TI - A cubesat centrifuge for long duration milligravity research. AB - We advocate a low-cost strategy for long-duration research into the 'milligravity' environment of asteroids, comets and small moons, where surface gravity is a vector field typically less than 1/1000 the gravity of Earth. Unlike the microgravity environment of space, there is a directionality that gives rise, over time, to strangely familiar geologic textures and landforms. In addition to advancing planetary science, and furthering technologies for hazardous asteroid mitigation and in situ resource utilization, simplified access to long-duration milligravity offers significant potential for advancing human spaceflight, biomedicine and manufacturing. We show that a commodity 3U (10 * 10 * 34 cm3) cubesat containing a laboratory of loose materials can be spun to 1 r.p.m. = 2pi/60 s-1 on its long axis, creating a centrifugal force equivalent to the surface gravity of a kilometer-sized asteroid. We describe the first flight demonstration, where small meteorite fragments will pile up to create a patch of real regolith under realistic asteroid conditions, paving the way for subsequent missions where landing and mobility technology can be flight-proven in the operational environment, in low-Earth orbit. The 3U design can be adapted for use onboard the International Space Station to allow for variable gravity experiments under ambient temperature and pressure for a broader range of experiments. PMID- 28649639 TI - Initial assessment of the nutritional quality of the space food system over three years of ambient storage. AB - Processed and prepackaged space food is the main source of nutrition for crew aboard the International Space Station, and likely will continue to be the main source of nutrition for future exploration missions. However, very little information is available on the nutritional stability of space foods. To better understand their nutritional stability, 24 micronutrients were measured in 109 space foods stored over 3 years at room temperature. Our analysis indicated that potassium, calcium, vitamin D, and vitamin K concentrations in the food may not be adequate to meet the recommended daily intake requirements even before storage. Decreases in vitamins A, C, B1, and B6 were observed during storage. Notably, vitamins B1 and C may degrade to inadequate levels after 1 year and 3 years, respectively. This assessment suggests that different technological approaches will be required to stabilize processed foods to enable spaceflight missions over 1 year. PMID- 28649640 TI - MRI-derived diffusion parameters in the human optic nerve and its surrounding sheath during head-down tilt. AB - More than half of astronauts present with significant neuro-ophthalmic findings during 6-month missions onboard the International Space Station. Although the underlying cause of this Microgravity Ocular Syndrome is currently unknown, alterations in cerebrospinal fluid dynamics within the optic nerve sheath may play a role. In the presented study, diffusion tensor imaging was used to assess changes in diffusivity of the optic nerve and its surrounding sheath during head down tilt, a ground-based model of microgravity. Nine healthy male subjects (mean age +/- SD: 25 +/- 2.4 years; mean body mass index +/- SD: 24.1 +/- 2.4 kg/m2) underwent 5 head-down tilt conditions: -6 degrees ,-12 degrees , -18 degrees ,-12 degrees and 1% CO2, and -12 degrees and lower body negative pressure. Mean diffusivity, fractional anisotropy, axial diffusivity, radial diffusivity were quantified in the left and right optic nerves and surrounding sheaths at supine baseline and after 4.5 h head-down tilt for each condition. In the optic nerve sheath, mean diffusivity was increased with all head-down tilt conditions by (Best Linear Unbiased Predictors) 0.147 (SE: 0.04) * 10-3 mm2/s (P < 0.001), axial diffusivity by 0.188 (SE: 0.064) * 10-3 mm2/s (P < 0.001), and radial diffusivity by 0.126 (SE: 0.04) * 10-3 mm2/s (P = 0.0019). Within the optic nerve itself, fractional anisotropy was increased by 0.133 (SE: 0.047) (P = 0.0051) and axial diffusivity increased by 0.135 (SE: 0.08) * 10-3 mm2/s (P = 0.014) during head-down tilt, whilst mean diffusivity and radial diffusivity were unaffected (P > 0.3). These findings could be due to increased perioptic cerebral spinal fluid hydrodynamics during head-down tilt, as well as increased cerebral spinal fluid volume and movement within the optic nerve sheath. PMID- 28649641 TI - Multifunctional Poly(amine-co-ester-co-ortho ester) for Efficient and Safe Gene Delivery. AB - Cationic polymers are used for non-viral gene delivery, but current materials lack the functionality to address the multiple barriers involved in gene delivery. Here we describe the rational design and synthesis of a new family of quaterpolymers with unprecedented multifunctionality: acid sensitivity, low cationic charge, high hydrophobicity, and biodegradability, all of which are essential for efficient and safe gene delivery. The polymers were synthesized via lipase-catalyzed polymerization of ortho ester diester, lactone, dialkyl diester, and amino diol monomers. Polymers containing ortho ester groups exhibited acid sensitive degradation at endosomal pH (4~5), facilitated efficient endosomal escape and unpackaging of the genes, and were efficient in delivering genetic materials to HEK293 cells, human glioma cells, primary mouse melanoma cells, and human umbilical vein endothelial cells (HUVECs). We also developed a highly efficient lyophilized formulation of the nanoparticles, which could be stored for a month without loss of efficiency. PMID- 28649642 TI - Disparities in contralateral prophylactic mastectomy use among women with early stage breast cancer. AB - Contralateral prophylactic mastectomy use has increased over the past decades among women with early-stage breast cancer. Racial differences in contralateral prophylactic mastectomy use are well described, but with unclear causes. This study examined contralateral prophylactic mastectomy use among black and white women and the contribution of differences in perceived risk to differences in use. We surveyed women diagnosed with early-stage unilateral breast cancer between ages 41-64 in Pennsylvania and Florida between 2007-2009 to collect data on breast cancer treatment, family history, education, income, insurance, and perceived risk. Clinical factors-age,stage at diagnosis, receptor status-were obtained from cancer registries. The relationships between patient factors and contralateral prophylactic mastectomy were assessed using logistic regression. The interaction between race and contralateral prophylactic mastectomy on the perceived risk of second breast cancers was tested using linear regression. Of 2182 study participants, 18% of whites underwent contralateral prophylactic mastectomy compared with 10% of blacks (p < 0.001). The racial difference remained after adjustment for clinical factors and family history (odds ratio = 2.32, 95% confidence interval 1.76-3.06, p < 0.001). The association between contralateral prophylactic mastectomy and a reduction in the perceived risk of second breast cancers was significantly smaller for blacks than whites. Blacks were less likely than whites to undergo contralateral prophylactic mastectomy even after adjustment for clinical factors. This racial difference in use may relate to the smaller impact of contralateral prophylactic mastectomy on the perceived risk of second breast cancers among blacks than among whites. Future research is needed to understand the overall impact of perceived risk on decisions about contralateral prophylactic mastectomy and how that may explain racial differences in use. PMID- 28649643 TI - Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine. AB - Many women with hormone receptor-positive early breast cancer can be managed effectively with endocrine therapies alone. However, additional systemic chemotherapy treatment is necessary for others. The clinical challenges in managing high-risk women are to identify existing and novel druggable targets, and to identify those who would benefit from these therapies. Therefore, we performed mRNA abundance analysis using the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial pathology cohort to identify a signature of residual risk following endocrine therapy and pathways that are potentially druggable. A panel of genes compiled from academic and commercial multiparametric tests as well as genes of importance to breast cancer pathogenesis was used to profile 3825 patients. A signature of 95 genes, including nodal status, was validated to stratify endocrine-treated patients into high-risk and low-risk groups based on distant relapse-free survival (DRFS; Hazard Ratio = 5.05, 95% CI 3.53-7.22, p = 7.51 * 10-19). This risk signature was also found to perform better than current multiparametric tests. When the 95-gene prognostic signature was applied to all patients in the validation cohort, including patients who received adjuvant chemotherapy, the signature remained prognostic (HR = 4.76, 95% CI 3.61-6.28, p = 2.53* 10-28). Functional gene interaction analyses identified six significant modules representing pathways involved in cell cycle control, mitosis and receptor tyrosine signaling; containing a number of genes with existing targeted therapies for use in breast or other malignancies. Thus the identification of high-risk patients using this prognostic signature has the potential to also prioritize patients for treatment with these targeted therapies. PMID- 28649644 TI - Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort. AB - Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case-case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and k-means were then used to characterize the ancestry of the participants. A random sample of subjects from the main "European" cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2-positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients. PMID- 28649645 TI - A functionally significant SNP in TP53 and breast cancer risk in African-American women. AB - A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal. PMID- 28649646 TI - Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12. AB - The tumor microenvironment is composed of heterogeneous populations of cells, including cancer, immune, and stromal cells. Progression of tumor growth and initiation of metastasis is critically dependent on the reciprocal interactions between cancer cells and stroma. Through RNA-Seq and protein analyses, we found that cancer-associated fibroblasts derived from human breast cancer brain metastasis express significantly higher levels of chemokines CXCL12 and CXCL16 than fibroblasts from primary breast tumors or normal breast. To further understand the interplay between cancer cells and cancer-associated fibroblasts from each site, we developed three-dimensional organoids composed of patient derived primary or brain metastasis cancer cells with matching cancer-associated fibroblasts. Three-dimensional CAF aggregates generated from brain metastasis promote migration of cancer cells more effectively than cancer-associated fibroblast aggregates derived from primary tumor or normal breast stromal cells. Treatment with a CXCR4 antagonist and/or CXCL16 neutralizing antibody, alone or in combination, significantly inhibited migration of cancer cells to brain metastatic cancer-associated fibroblast aggregates. These results demonstrate that human brain metastasis cancer-associated fibroblasts potently attract breast cancer cells via chemokines CXCL12 and CXCL16, and blocking CXCR6-CXCL16/CXCR4 CXCL12 receptor-ligand interactions may be an effective therapy for preventing breast cancer brain metastasis. PMID- 28649647 TI - Moonshots and metastatic disease: the need for a multi-faceted approach when studying atypical responses. AB - Clinical research generally focuses on results involving a statistical mean with little attention in trial design to patients who respond considerably better or worse than average. Exploring the reasons underlying an "atypical response" will increase understanding of the mechanisms involved in cancer progression and treatment resistance, accelerate biomarker identification, and improve precision medicine by allowing clinicians to prospectively select optimal treatments. Based on our review, we suggest two ways to move this field forward. First, we suggest that clear categorization of "atypical responders" is needed. This encompasses three sub-categories of patients: "exceptional responders" (those with an unusually favorable treatment response), "rapid progressors" (patients demonstrating an unusually poor or no therapeutic response), and "exceptional survivors" (patients who have far outlived their initial prognosis). Such categorization may depend upon the clinical context and disease subtype. Second, we suggest that atypical responses may be due not only to somatic mutations in tumors, but also to inherited polymorphisms in non-tumor tissue, host and tumor environments, lifestyle factors, co-morbidities, use of complementary and integrative medicine, and the interaction among these components. Here, we summarize new research initiatives exploring atypical responses, the potential reasons for atypical responses, and a strategic call to action. Rigorous studies of normal and atypical responses to treatment will be needed to strengthen understanding of the role of non-tumor factors. Clinical trial design for targeted and other types of therapies should be enhanced to collect data in a standardized manner beyond tumor genetics, resulting in more thorough study of the whole patient. PMID- 28649648 TI - Dramatic response of metaplastic breast cancer to chemo-immunotherapy. AB - Frequent overexpression of programmed death-ligand 1 has recently been demonstrated in metaplastic breast cancer, which is a rare breast cancer subtype with limited treatment options. This report describes the clinical course of a patient with metastatic metaplastic breast cancer who had a remarkable response to anti-programmed death-1 therapy with pembrolizumab in combination with nab paclitaxel. Tissue correlates are presented including tumor-infiltrating lymphocytes and high-programmed death-ligand 1 expression in the tumor. PMID- 28649650 TI - Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients. AB - Radiation dermatitis occurs frequently during adjuvant radiation therapy for breast cancer. Prevention of radiation dermatitis by applying various creams and ointments has a limited success, and Aqua cream which has urea as one of its active ingredients is used in many institutions as a preventive treatment. The primary goal of this study is to assess the effect of vitamin D (calcipotriol) ointment in prevention of radiodermatitis in breast cancer patients compared to Aqua cream. Twenty-three women with localized breast cancer who underwent breast conserving surgery and opted to receive adjuvant radiotherapy to breast only were enrolled in this study. A cream containing an active vitamin D analog, calcipotriol (Daivonex), was randomly applied either to the medial or to the lateral half of the irradiated breast, while Aqua cream was applied to the complimentary half of the same breast along the whole treatment days, each day, after the delivery of radiation. Skin reaction was recorded and compared between the two halves of the breast. Vitamin D was well tolerated by patients with no local or systemic allergic reactions. Radiation dermatitis was not significantly different between both treatment arms. Topical vitamin D ointment is not superior to Aqua cream for prevention of radiation-induced dermatitis in women treated with adjuvant radiation for breast cancer. PMID- 28649649 TI - Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells. AB - Genomic instability is a hallmark of breast cancer, contributes to tumor heterogeneity, and influences chemotherapy resistance. Although Gap 2 and mitotic checkpoints are thought to prevent genomic instability, the role of these checkpoints in breast cancer is poorly understood. Here, we assess the Gap 2 and mitotic checkpoint functions of 24 breast cancer and immortalized mammary epithelial cell lines representing four of the six intrinsic molecular subtypes of breast cancer. We found that patterns of cell cycle checkpoint deregulation were associated with the intrinsic molecular subtype of breast cancer cell lines. Specifically, the luminal B and basal-like cell lines harbored two molecularly distinct Gap 2/mitosis checkpoint defects (impairment of the decatenation Gap 2 checkpoint and the spindle assembly checkpoint, respectively). All subtypes of breast cancer cell lines examined displayed aberrant DNA synthesis/Gap 2/mitosis progression and the basal-like and claudin-low cell lines exhibited increased percentages of chromatid cohesion defects. Furthermore, a decatenation Gap 2 checkpoint gene expression signature identified in the cell line panel correlated with clinical outcomes in breast cancer patients, suggesting that breast tumors may also harbor defects in decatenation Gap 2 checkpoint function. Taken together, these data imply that pharmacological targeting of signaling pathways driving these phenotypes may lead to the development of novel personalized treatment strategies for the latter two subtypes which currently lack targeted therapeutic options because of their triple negative breast cancer status. PMID- 28649651 TI - Breast cancers are rare diseases-and must be treated as such. PMID- 28649652 TI - The epidemiology, radiology and biological characteristics of interval breast cancers in population mammography screening. AB - An interval breast cancer is a cancer that emerges following a negative mammographic screen. This overview describes the epidemiology, and the radiological and biological characteristics of interval breast cancers in population mammography screening. Notwithstanding possible differences in ascertainment of interval breast cancers, there was broad variability in reported interval breast cancer rates (range 7.0 to 49.3 per 10,000 screens) reflecting heterogeneity in underlying breast cancer rates, screening rounds (initial or repeat screens), and the length and phase of the inter-screening interval. The majority of studies (based on biennial screening) reported interval breast cancer rates in the range of 8.4 to 21.1 per 10,000 screens spanning the two-year interval with the larger proportion occurring in the second year. Despite methodological limitations inherent in radiological surveillance (retrospective mammographic review) of interval breast cancers, this form of surveillance consistently reveals that the majority of interval cancers represent either true interval or occult cancers that were not visible on the index mammographic screen; approximately 20-25% of interval breast cancers are classified as having been missed (false-negatives). The biological characteristics of interval breast cancers show that they have relatively worse tumour prognostic characteristics and biomarker profile, and also survival outcomes, than screen-detected breast cancers; however, they have similar characteristics and prognosis as breast cancers occurring in non-screened women. There was limited evidence on the effect on interval breast cancer frequency and outcomes following transition from film to digital mammography screening. PMID- 28649653 TI - An alternative model for (breast) cancer predisposition. AB - While environmental factors can greatly increase cancer risk, it is clear that an individual's genetic constitution has strong impact on tumor formation. Hereby we present an alternative cancer predisposition model built on the assumption that efficiencies of DNA maintenance mechanisms in normal cells are similar but not identical for each person. Small variations in an individual's genetic constitution may result in slightly increased genomic instability and generate typical mutational signatures in normal cells. With recent and expected advances in the next-generation sequencing field, qualitative and quantitative establishment of such mutational signatures in normal tissue must become feasible, and may meanwhile provide a more accurate estimation of individual cancer risks, even in persons without familial antecedents. An additional advantage of this approach is that cancer risk assessment will not strictly rely on the individual's genetic identity, but will also consider other factors (e.g., environmental and age) that can affect genomic integrity. PMID- 28649655 TI - Gene expression in breast and adipose tissue after 12 months of weight loss and vitamin D supplementation in postmenopausal women. AB - Adipose tissue is involved in the etiology of postmenopausal breast cancer, possibly through increased sex steroid hormone production, inflammation, and altered adipokines. Vitamin D may affect these pathways but its effect on gene expression in different tissues has not been examined. Within a double-blind, 12 month placebo-controlled randomized trial, we compared 2000 IU/day oral vitamin D3 supplementation (N = 39) vs. placebo (N = 40) on the expression of 5 genes in breast and adipose tissue in overweight/obese postmenopausal women (50-75 years). All participants had serum 25-hydroxyvitamin D (25(OH)D) levels >= 10-<32 ng/mL ("insufficient") and concurrently completed a behavioral weight loss program. Random periareolar fine needle aspiration (RPFNA) and abdominal subcutaneous adipose tissue biopsies were performed at baseline and 12 months. Changes in expression of aromatase (CYP19A1), peroxisome proliferator-activated receptor gamma (PPARG), adiponectin (ADIPOQ), monocyte-chemoattractant protein 1 (MCP-1), and vitamin D receptor (VDR) were analyzed by qRT-PCR. Compared to placebo, 2000 IU vitamin D did not show significant effects on gene expression in breast or adipose tissue. Replete women (i.e., 25(OH)D >= 32 ng/mL; N = 17) showed a small decrease in MCP-1 expression compared to an increase among women who remained 'insufficient' despite supplementation (N = 12) (Replete:-1.6% vs. Non-replete: 61.2%, p = 0.015) in breast, but not adipose tissue. No statistically significant differences in gene expression were detected according to degree of weight loss. Vitamin D repletion during weight loss may have different effects on gene expression in breast and adipose tissue. Further research on the localized effects of vitamin D is needed to determine its effect on breast cancer risk. PMID- 28649656 TI - Lgr5 is a marker for fetal mammary stem cells, but is not essential for stem cell activity or tumorigenesis. AB - The search for the bipotent mammary stem cells that drive mammary development requires markers to enable their prospective isolation. There is general agreement that bipotent mouse mammary stem cells are abundant in late fetal development, but their existence in the adult is vigorously debated. Among markers useful for mammary stem cell identification, the Wnt co-receptor Lgr5 has been suggested by some to be both "necessary and sufficient" for bipotency and transplantation of adult mammary stem cell activity, though other studies disagree. Importantly, the relevance of Lgr5 to the bipotency of fetal mammary stem cells has not been studied. We show here that expression of a fluorescent protein driven by the endogenous Lgr5 promoter enables significant fetal mammary stem cell enrichment. We used lineage tracing to demonstrate embryonic cells expressing Lgr5 are bipotent, while their adult counterparts are myoepithelial restricted. Importantly, our data conclusively demonstrate that Lgr5 is dispensable for both fetal and adult mammary stem cell activity and for the development of mammary tumors. PMID- 28649654 TI - Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity. AB - Cellular heterogeneity in cancer represents a significant challenge. In order to develop effective and lasting therapies, it is essential to understand the source of this heterogeneity, and its role in tumor progression and therapy resistance. Here, we consider not only genetic and epigenetic mechanisms, but also inflammation and cell state reprogramming in creating tumor heterogeneity. We discuss similarities between normal mammary epithelial developmental states and various breast cancer molecular sub-types, and the cells that are thought to propagate them. We emphasize that while stem cell phenotypes and mesenchymal character have often been conflated, existing data suggest that the combination of intrinsic genetic and epigenetic changes, and microenvironmental influences generate multiple types of tumor propagating cells distinguishable by their positions along a continuum of epithelial to mesenchymal, stem to differentiated and embryonic to mature cell states. Consequently, in addition to the prospect of stem cell-directed tumor therapies, there is a need to understand interrelationships between stem cell, epithelial-mesenchymal, and tumor associated reprogramming events to develop new therapies that mitigate cell state plasticity and minimize the evolution of tumor heterogeneity. PMID- 28649657 TI - Dual PI3K and Wnt pathway inhibition is a synergistic combination against triple negative breast cancer. AB - Triple negative breast cancer accounts for 15-20% of all breast cancer cases, but despite its lower incidence, contributes to a disproportionately higher rate of mortality. As there are currently no Food and Drug Administration-approved targeted agents for triple negative breast cancer, we embarked on a genomic guided effort to identify novel targeted modalities. Analyses by our group and The Cancer Genome Atlas have identified activation of the PI3K-pathway in the majority of triple negative breast cancers. As single agent therapy is commonly subject to resistance, we investigated the use of combination therapy against compensatory pathways. Herein, we demonstrate that pan-PI3K inhibition in triple negative breast cancers results in marked activation of the Wnt-pathway. Using the combination of two inhibitors currently in clinical trial as single agents, buparlisib(pan-PI3K) and WNT974(WNT-pathway), we demonstrate significant in vitro and in vivo synergy against triple negative breast cancer cell lines and xenografts. Taken together, these observations provide a strong rationale for testing dual targeting of the PI3K and WNT-pathways in clinical trials. PMID- 28649658 TI - Niche-localized tumor cells are protected from HER2-targeted therapy via upregulation of an anti-apoptotic program in vivo. AB - Several lines of evidence suggest that components of the tumor microenvironment, specifically basement membrane and extracellular matrix proteins, influence drug sensitivities. We previously reported differential drug sensitivity of tumor cells localized adjacent to laminin-rich extracellular matrix in three dimensional tumor spheroid cultures. To evaluate whether differential intra-tumor responses to targeted therapy occur in vivo, we examined the sensitivity of human epidermal growth factor receptor 2-positive tumors to lapatinib using a previously described ductal carcinoma in situ-like model characterized by tumor cell confinement within ductal structures surrounded by an organized basement membrane. Here we show that tumor cells localized to a 'niche' in the outer layer of the intraductal tumors adjacent to myoepithelial cells and basement membrane are resistant to lapatinib. We found that the pro-survival protein BCL2 is selectively induced in the niche-protected tumor cells following lapatinib treatment, and combined inhibition of HER2 and BCL-2/XL enhanced targeting of these residual tumor cells. Elimination of the niche-protected tumor cells was achieved with the HER2 antibody-drug conjugate T-DM1, which delivers a chemotherapeutic payload. Thus, these studies provide evidence that subpopulations of tumor cells within specific microenvironmental niches can adapt to inhibition of critical oncogenic pathways, and furthermore reveal effective strategies to eliminate these resistant subpopulations. PMID- 28649659 TI - Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. AB - Growing evidence indicates that adiposity is associated with breast cancer risk and negatively affects breast cancer recurrence and survival, a paracrine role of mammary adipose tissue being very likely in this process. In contrast to other adipose depots, occurrence of a sub-inflammatory state of mammary adipose tissue defined by dying adipocytes surrounded by macrophages forming crown-like structures in overweight and obese subjects, remains only partially described. In a general population of breast cancer patients (107 patients) mostly undergoing breast-conserving surgery, we found a positive association between patient's body composition, breast adipocytes size, and presence of crown-like structures in mammary adipose tissue close to the tumor. Overweight (BMI: 25.0-29.9 kg/m2) and obese (BMI >= 30.0 kg/m2) patients have 3.2 and 6.9 times higher odds ratio of crown-like structures respectively, compared with normal weight patients. The relatively small increase in adipocyte size in crown-like structures positive vs. negative patients suggests that mammary adipose tissue inflammation might occur early during hypertrophy. Our results further highlight that body mass index is an adequate predictor of the presence of crown-like structures in mammary adipose tissue among postmenopausal women, whereas in premenopausal women truncal fat percentage might be more predictive, suggesting that mammary adipose tissue inflammation is more likely to occur in patients exhibiting visceral obesity. Finally, the presence of crown-like structures was positively associated with systemic markers such as the Triglyceride/High-density lipoprotein-cholesterol ratio serum C-reactive protein and glucose/(HbA1c) glycated Haemoglobin. These compelling results demonstrate that excess adiposity, even in overweight patients, is associated with mammary adipose tissue inflammation, an event that could contribute to breast cancer development and progression. PMID- 28649660 TI - How do we increase uptake of tamoxifen and other anti-estrogens for breast cancer prevention? AB - Several randomized controlled trials of anti-estrogens, such as tamoxifen and aromatase inhibitors, have demonstrated up to a 50-65% decrease in breast cancerincidence among high-risk women. Approximately 15% of women, age 35-79 years, in the U.S. meet criteria for breast cancer preventive therapies, but uptake of these medications remain low. Explanations for this low uptake includelack of awareness of breast cancer risk status, insufficient knowledge about breast cancer preventive therapies among patients and physicians, and toxicity concerns. Increasing acceptance of pharmacologic breast cancer prevention will require effective communication of breast cancer risk, accurate representation about the potential benefits and side effects of anti-estrogens, targeting-specific high-risk populations most likely to benefit from preventive therapy, and minimizing the side effects of current anti-estrogens with novel administration and dosing options. One strategy to improve the uptake of chemoprevention strategies is to consider lessons learned from the use of drugs to prevent other chronic conditions, such as cardiovascular disease. Enhancing uptake and adherence to anti-estrogens for primary prevention holds promise for significantly reducing breast cancer incidence, however, this will require a significant change in our current clinical practice and stronger advocacy and awareness at the national level. PMID- 28649661 TI - Inflammatory breast cancer: a model for investigating cluster-based dissemination. AB - Metastases claim more than 90% of cancer-related patient deaths and are usually seeded by a subset of circulating tumor cells shed off from the primary tumor. In circulation, circulating tumor cells are found both as single cells and as clusters of cells. The clusters of circulating tumor cells, although many fewer in number, possess much higher metastatic potential as compared to that of individual circulating tumor cells. In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters-(a) hybrid epithelial/mesenchymal phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells. Building upon these molecular mechanisms, we also offer a possible mechanistic understanding of why clusters are endowed with a higher metastatic potential. Finally, we discuss the highly aggressive Inflammatory Breast Cancer as an example of a carcinoma that can metastasize via clusters and corroborates the proposed molecular mechanisms. PMID- 28649664 TI - Quantitative Analysis of the Spatial Distribution of Metastatic Brain Lesions. AB - Brain metastases (BMs) are the most common intracranial malignancy and afflict ~10%-20% of patients with cancer. BMs tend to present at the boundaries of gray and white matter because of the distribution of small vessels. In addition, metastases may not be randomly distributed across gross anatomical regions of the brain, but this has not previously been quantified. We retrospectively analyzed a series of 28 patients with recurrent BMs with a total of 150 lesions. Each lesion was manually defined based on T1 gadolinium-enhanced imaging. Standard brain atlases were used to identify the anatomical brain region affected by each BM and the frequency of metastases in each region was compared with the expected probability, which was assumed to be a random distribution based on the brain volume. After correction for multiple comparisons, the paracingulate gyrus was found to have a statistically significant increase (P = 4.731 * 10-9) in the rate of BMs relative to the random spatial distribution. A nonstochastic spatial distribution of metastases may be used to guide partial brain radiotherapy with risk-adapted dose delivery and reduce the risk of neurotoxicity due to overtreatment. PMID- 28649662 TI - The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. AB - Understanding the gene-specific risks for development of breast cancer will lead to improved clinical care for those carrying germline mutations in cancer predisposition genes. We sought to detail the spectrum of mutations and refine risk estimates for known and proposed breast cancer susceptibility genes. Targeted massively-parallel sequencing was performed to identify mutations and copy number variants in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA1/2-negative women with familial breast cancer (proband with breast cancer and a family history of breast or ovarian cancer) from a largely European Caucasian multi-institutional cohort. Case-control analysis was performed comparing the frequency of internally classified mutations identified in familial breast cancer women to Exome Aggregation Consortium controls. Mutations were identified in 8.2% of familial breast cancer women, including mutations in high risk (odds ratio > 5) (1.4%) and moderate-risk genes (2 < odds ratio < 5) (2.9%). The remaining familial breast cancer women had mutations in proposed breast cancer genes (1.7%), Lynch syndrome genes (0.5%), and six cases had two mutations (0.3%). Case-control analysis demonstrated associations with familial breast cancer for ATM, PALB2, and TP53 mutations (odds ratio > 3.0, p < 10-4), BARD1 mutations (odds ratio = 3.2, p = 0.012), and CHEK2 truncating mutations (odds ratio = 1.6, p = 0.041). Our results demonstrate that approximately 4.7% of BRCA1/2 negative familial breast cancer women have mutations in genes statistically associated with breast cancer. We classified PALB2 and TP53 as high risk, ATM and BARD1 as moderate risk, and CHEK2 truncating mutations as low risk breast cancer predisposition genes. This study demonstrates that large case control studies are needed to fully evaluate the breast cancer risks associated with mutations in moderate-risk and proposed susceptibility genes. PMID- 28649663 TI - Addictive neurons. AB - Since the reward center is considered to be the area tegmentalis ventralis of the hypothalamus, logically its neurons could mainly be responsible for addiction. However, the literature asserts that almost any neurons of CNS can respond to one or another addictive compound. Obviously not only addictive nicotine, but also alcohol, amphetamine, cannabis, cocaine, heroin and morphine may influence dopaminergic cells alone in VTA. Moreover, paradoxically some of these drugs ameliorate symptoms, counterbalance syndromes, cure diseases and improve health, not only those related to the CNS and in adults, but also almost all other organs and in children, e.g. epilepsy. PMID- 28649666 TI - Social Policy: Targeting programs effectively. AB - By linking data from a 40-year birth cohort study with multiple administrative databases, Caspi and colleagues show that 20% of the population accounts for 60% 80% of several adult social ills. Outcomes for this group can be accurately predicted from as early as age 3, using a small set of indicators of disadvantage. This finding supports policies that target children from disadvantaged families and complements recent literature on the life-cycle benefits of early childhood programmes. PMID- 28649665 TI - TGF-beta-target genes are differentially regulated in corneal epithelial cells and fibroblasts. AB - PURPOSE: Transforming growth factor-beta (TGF-beta) activates the canonical Smad pathway, which includes the Smad family of proteins and SARA (Smad Anchor for Receptor Activation) and other less understood pathways, including one involving p38MAPK. The goal of the current research was to determine if corneal epithelial cells and fibroblasts used the classical or alternative TGF-beta-signaling pathways. To examine this question, we made use of Trx-SARA, which inhibits native SARA, thus blocking the Smad pathway. METHODS: A human corneal epithelial cell line (HCE-TJ), and stromal fibroblasts (HCF) were infected with retroviruses (RTV) containing either Trx-SARA or Trx-GA (a control plasmid). The effect of Trx SARA on thrombospondin-1 (TSP-1) expression in both cell types, p15ink4b expression in HCE-TJ, and cellular fibronectin (cFN) expression in HCF was determined. In addition, the effect of p38MAPK inhibitor on TSP-1 and p15ink4b were examined. RESULTS: In HCE-TJ with TGF-beta1, TSP-1-protein levels increased and peaked at 24 hours. Trx-SARA reduced TSP-1 expression in HCE-TJ, but had no effect on p15ink4b. With HCF, Trx-SARA failed to reduce TSP-1 expression; however, cFN expression decreased and proliferation was inhibited. By blocking the p38MAPK pathway, TSP-1 expression was reduced in HCF and p15ink4b expression was decreased in HCE-TJ. CONCLUSIONS: Surprisingly, TSP-1 was regulated through the Smad pathway in HCE-TJ and the p38MAPK pathway in HCF. The p38MAPK pathway also induced p15ink4b in HCE-TJ. Our results indicate that not all TGF-beta target proteins require the Smad pathway, and it may be possible to block certain TGF-beta-target proteins without blocking the expression of all the TGF-beta target proteins. PMID- 28649667 TI - Impact of protein kinase CK2 inhibitors on proliferation and differentiation of neural stem cells. AB - BACKGROUND: Protein kinases play central roles in cell and tissue development. Protein kinase CK2, an ubiquitously expressed serine/threonine kinase has severe impacts on embryo- and spermatogenesis. Since its role in neurogenesis has so far only been investigated in very few studies, we analysed the role of CK2 in neural stem cells by using two specific inhibitors. METHODS: Neural stem cells were isolated from the subventricular zone of neonatal mice, using a neurosphere approach. Proliferation of the neurospheres, as well as their differentiation was investigated with and without inhibition of CK2. Changes in proliferation were assessed by counting the number and measuring the diameter of the neurospheres. Furthermore, the absolute cell numbers within the neurospheres were estimated. Differentiation was induced by retinoic acid in single cells after dissociation of the neurospheres. CK2 was inhibited at consecutive time points after induction of the differentiation process. RESULTS: CK2 inhibition reduced the amount and size of proliferating neurospheres dose dependently. Adding the CK2 inhibitor CX 4945 at the start of differentiation we observed a dose-dependent effect of CX 4945 on cell viability and glia cell differentiation. Adding quinalizarin, a second CK2 inhibitor, at the start of differentiation led to an elevated level of apoptosis, which was accompanied by a reduced neural differentiation. Adding the CK2 inhibitors at 72 h after the start of differentiation had no effect on stem cell differentiation. Conclusion: Inhibition of CK2 influences early gliogenesis in a time point and concentration dependent manner. GENERAL SIGNIFICANCE: The use of a CK2 inhibitor significantly affects the neural stem cell niche. PMID- 28649668 TI - Metabolic costs of daily activity in older adults (Chores XL) study: design and methods. AB - BACKGROUND: For over 20 years, normative data has guided the prescription of physical activity. This data has since been applied to research and used to plan interventions. While this data seemingly provides accurate estimates of the metabolic cost of daily activities in young adults, the accuracy of use among older adults is less clear. As such, a thorough evaluation of the metabolic cost of daily activities in community dwelling adults across the lifespan is needed. METHODS: The Metabolic Costs of Daily Activity in Older Adults Study is a cross sectional study designed to compare the metabolic cost of daily activities in 250 community dwelling adults across the lifespan. Participants (20+ years) performed 38 common daily activities while expiratory gases were measured using a portable indirect calorimeter (Cosmed K4b2). The metabolic cost was examined as a metabolic equivalent value (O2 uptake relative to 3.5 milliliter* min-1*kg-1), a function of work rate - metabolic economy, and a relative value of resting and peak oxygen uptake. RESULTS: The primary objective is to determine age-related differences in the metabolic cost of common lifestyle and exercise activities. Secondary objectives include (a) investigating the effect of functional impairment on the metabolic cost of daily activities, (b) evaluating the validity of perception-based measurement of exertion across the lifespan, and (c) validating activity sensors for estimating the type and intensity of physical activity. CONCLUSION: Results of this study are expected to improve the effectiveness by which physical activity and nutrition is recommended for adults across the lifespan. PMID- 28649669 TI - Positive and negative polarity contrast sensitivity measuring app. AB - Contrast sensitivity (CS) quantifies an observer's ability to detect the smallest (threshold) luminance difference between a target and its surrounding. In clinical settings, printed letter contrast charts are commonly used, and the contrast of the letter stimuli is specified by the Weber contrast definition. Those paper-printed charts use negative polarity contrast (NP, dark letters on bright background) and are not available with positive polarity contrast (PP, bright letters on dark background), as needed in a number of applications. We implemented a mobile CS measuring app supporting both NP and PP contrast stimuli that mimic the paper charts for NP. A novel modified Weber definition was developed to specify the contrast of PP letters. The validity of the app is established in comparison with the paper chart. We found that our app generates more accurate and a wider range of contrast stimuli than the paper chart (especially at the critical high CS, low contrast range), and found a clear difference between NP and PP CS measures (CSNP>CSPP) despite the symmetry afforded by the modified Weber contrast definition. Our app provides a convenient way to measure CS in both lighted and dark environments. PMID- 28649670 TI - Pretargeted PET Imaging of trans-Cyclooctene-Modified Porous Silicon Nanoparticles. AB - Pretargeted positron emission tomography (PET) imaging based on bioorthogonal chemical reactions has proven its potential in immunoimaging. It may also have great potential in nanotheranostic applications. Here, we report the first successful pretargeted PET imaging of trans-cyclooctene-modified mesoporous silicon nanoparticles, using 18F-labeled tetrazine as a tracer. The inverse electron-demand Diels-Alder cycloaddition (IEDDA) reaction was fast, resulting in high radioactivity accumulation in the expected organs within 10 min after the administration of the tracer. The highest target-to-background ratio was achieved 120 min after the tracer injection. A clear correlation between the efficiency of the in vivo IEDDA labeling reaction and the injected amount of the tracer was observed. The radioactivity accumulation decreased with the increased amount of the co-injected carrier, indicating saturation in the reaction sites. This finding was supported by the in vitro results. Our study suggests that pretargeted imaging has excellent potential in nanotheranostic PET imaging when using high-specific-activity tracers. PMID- 28649671 TI - Early Life Stress, Mood, and Anxiety Disorders. AB - Early life stress has been shown to exert profound short- and long-term effects on human physiology both in the central nervous system and peripherally. Early life stress has demonstrated clear association with many psychiatric disorders including major depression, posttraumatic stress disorder, and bipolar disorder. The Diagnostic and Statistics Manuel of Mental Disorders (DSM) diagnostic categorical system has served as a necessary framework for clinical service, delivery, and research, however has not been completely matching the neurobiological research perspective. Early life stress presents a complex dynamic featuring a wide spectrum of physiologic alterations: from epigenetic alterations, inflammatory changes, to dysregulation of the hypothalamic pituitary axis and has further added to the challenge of identifying biomarkers associated with psychiatric disorders. The National Institute of Mental Health's proposed Research Domain Criteria initiative incorporates a dimensional approach to assess discrete domains and constructs of behavioral function that are subserved by identifiable neural circuits. The current neurobiology of early life stress is reviewed in accordance with dimensional organization of Research Domain Criteria matrix and how the findings as a whole fit within the Research Domain Criteria frameworks. PMID- 28649672 TI - Oxytocin and Stress-related Disorders: Neurobiological Mechanisms and Treatment Opportunities. AB - Novel pharmacotherapies that improve outcomes for individuals with stress-related psychiatric disorders are needed. The neurohormone oxytocin (OT) is a promising candidate given its influence on the social-emotional brain. In this review, we present an overview of evidence supporting OT's utility for treating major depressive disorder and posttraumatic stress disorder. We first discuss endogenous OT, which research suggests is not yet a reliable biomarker of stress related disorders. Second, we review effects of intranasal (IN) OT on processes relevant to stress-related disorders in healthy populations (anhedonia, reward processing, psychosocial stress reactivity, fear/anxiety, and social behavior) and their neurobiological mechanisms (e.g., the salience network and hypothalamic pituitary-adrenal axis). Third, we present the sparse but promising findings from clinical populations, followed by discussion of critical moderating variables to consider in the service of maximizing the therapeutic potential of OT (e.g., patient sex and child maltreatment). We also identify heterogeneous findings and limitations of existing research, including reliance on single-dose studies in psychiatrically healthy samples and unanswered questions regarding the effectiveness of IN drug delivery and dosing schedules. Well-controlled multidose studies including women and measures of potentially moderating variables are sorely needed and would inform our understanding of the utility of OT for preventing and treating stress-related psychiatric disorders. PMID- 28649673 TI - Rapid Acting Antidepressants in Chronic Stress Models: Molecular and Cellular Mechanisms. AB - Stress-associated disorders, including depression and anxiety, impact nearly 20% of individuals in the United States. The social, health, and economic burden imposed by stress-associated disorders requires in depth research efforts to identify suitable treatment strategies. Traditional medications (e.g., selective serotonin reuptake inhibitors, monoamine oxidase inhibitors) have significant limitations, notably a time lag for therapeutic response that is compounded by low rates of efficacy. Excitement over ketamine, a rapid acting antidepressant effective in treatment resistant patients, is tempered by transient dissociative and psychotomimetic effects, as well as abuse potential. Rodent stress models are commonly used to produce behavioral abnormalities that resemble those observed in stress-associated disorders. Stress models also produce molecular and cellular morphological changes in stress sensitive brain regions, including the prefrontal cortex and hippocampus that resemble alterations observed in depression. Rapid acting antidepressants such as ketamine can rescue stress-associated morphological and behavioral changes in rodent models. Here, we review the literature supporting a role for rapid acting antidepressants in opposing the effects of stress, and summarize research efforts seeking to elucidate the molecular, cellular, and circuit level targets of these agents. PMID- 28649674 TI - Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated proteins. Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblasts (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS, and whether these interactions generate pathogenic anti-citrulline adaptive immune responses. NETs containing citrullinated peptides are internalized by FLS through a RAGE-TLR9 pathway promoting FLS inflammatory phenotype and their upregulation of MHC class II. Once internalized, arthritogenic NET-peptides are loaded into FLS MHC class II and presented to Ag-specific T cells. HLADRB1*0401 transgenic mice immunized with mouse FLS loaded with NETs develop antibodies specific to citrullinated forms of relevant RA autoantigens implicated in RA pathogenesis as well as cartilage damage. These results implicate FLS as mediators in RA pathogenesis, through the internalization and presentation of NET citrullinated peptides to the adaptive immune system leading to pathogenic autoimmunity and cartilage damage. PMID- 28649676 TI - Embedding Open-domain Common-sense Knowledge from Text. AB - Our ability to understand language often relies on common-sense knowledge - background information the speaker can assume is known by the reader. Similarly, our comprehension of the language used in complex domains relies on access to domain-specific knowledge. Capturing common-sense and domain-specific knowledge can be achieved by taking advantage of recent advances in open information extraction (IE) techniques and, more importantly, of knowledge embeddings, which are multi-dimensional representations of concepts and relations. Building a knowledge graph for representing common-sense knowledge in which concepts discerned from noun phrases are cast as vertices and lexicalized relations are cast as edges leads to learning the embeddings of common-sense knowledge accounting for semantic compositionality as well as implied knowledge. Common sense knowledge is acquired from a vast collection of blogs and books as well as from WordNet. Similarly, medical knowledge is learned from two large sets of electronic health records. The evaluation results of these two forms of knowledge are promising: the same knowledge acquisition methodology based on learning knowledge embeddings works well both for common-sense knowledge and for medical knowledge Interestingly, the common-sense knowledge that we have acquired was evaluated as being less neutral than than the medical knowledge, as it often reflected the opinion of the knowledge utterer. In addition, the acquired medical knowledge was evaluated as more plausible than the common-sense knowledge, reflecting the complexity of acquiring common-sense knowledge due to the pragmatics and economicity of language. PMID- 28649675 TI - Prenatal Omega-3 Supplementation and Eczema Risk among Offspring at Age 36 Months. AB - BACKGROUND: Long-term follow-up was completed in 84 mother-infant pairs of 118 women who completed a randomized controlled trial of prenatal supplementation with EPA- or DHA-rich fish oil or soy oil placebo. The goal of this study was to determine whether prenatal omega-3 fatty acid supplementation protects offspring against development of early childhood allergies. METHODS AND FINDINGS: Assessment of childhood allergic/atopic disease among offspring at age 36 months was performed by maternal interview using the National Health Interview Survey (NHIS) questions for childhood digestive allergies, wheezing, eczema or skin allergy, and respiratory allergy. Multiple logistic regressions examined the association between prenatal supplementation and childhood outcomes, adjusted for covariates. Eczema was reported in 26/84 (31%) of offspring at age 36 months, and was significantly more prevalent in the omega-3 supplementation groups vs. placebo: EPA 13/31 (41.9%); DHA 10/26 (38.5%); placebo 3/27 (11.1%), p=0.019. Compared to placebo, EPA and DHA were associated with >=5 times risk of offspring eczema [odds ratios (ORs): EPA 5.8 (95% CI 1.4-23.3); DHA 5.0 (95% CI 1.2-21.0)]. After adjusting for other potential risk factors (race, birth weight, vaginal/Cesarean delivery, and maternal eczema) the magnitudes of association for omega-3 supplementation increased: EPA OR 8.1 (95% CI 1.4-45.6); DHA OR 9.6 (95% CI 1.6-58.5). Maternal eczema was also significantly associated with offspring eczema in the adjusted model: OR 10.8 (95% CI 2.1-54.3). CONCLUSION: Contrary to our hypothesis, acids supplementation compared to soy oil was associated with a substantial increase in risk of childhood eczema. This association was not observed on childhood respiratory or digestive outcomes. It is unclear if these findings were driven by unfavorable effects of omega-3s, or whether there may have been unanticipated protective effects of the soy-based placebo with regards to eczema. PMID- 28649677 TI - Outcome Prediction for Patient with High-Grade Gliomas from Brain Functional and Structural Networks. AB - High-grade glioma (HGG) is a lethal cancer, which is characterized by very poor prognosis. To help optimize treatment strategy, accurate preoperative prediction of HGG patient's outcome (i.e., survival time) is of great clinical value. However, there are huge individual variability of HGG, which produces a large variation in survival time, thus making prognostic prediction more challenging. Previous brain imaging-based outcome prediction studies relied only on the imaging intensity inside or slightly around the tumor, while ignoring any information that is located far away from the lesion (i.e., the "normal appearing" brain tissue). Notably, in addition to altering MR image intensity, we hypothesize that the HGG growth and its mass effect also change both structural (can be modeled by diffusion tensor imaging (DTI)) and functional brain connectivities (estimated by functional magnetic resonance imaging (rs-fMRI)). Therefore, integrating connectomics information in outcome prediction could improve prediction accuracy. To this end, we unprecedentedly devise a machine learning-based HGG prediction framework that can effectively extract valuable features from complex human brain connectome using network analysis tools, followed by a novel multi-stage feature selection strategy to single out good features while reducing feature redundancy. Ultimately, we use support vector machine (SVM) to classify HGG outcome as either bad (survival time <= 650 days) or good (survival time >650 days). Our method achieved 75 % prediction accuracy. We also found that functional and structural networks provide complementary information for the outcome prediction, thus leading to increased prediction accuracy compared with the baseline method, which only uses the basic clinical information (63.2 %). PMID- 28649678 TI - ENABLING SMART MANUFACTURING TECHNOLOGIES FOR DECISION-MAKING SUPPORT. AB - Smart manufacturing combines advanced manufacturing capabilities and digital technologies throughout the product lifecycle. These technologies can provide decision-making support to manufacturers through improved monitoring, analysis, modeling, and simulation that generate more and better intelligence about manufacturing systems. However, challenges and barriers have impeded the adoption of smart manufacturing technologies. To begin to address this need, this paper defines requirements for data-driven decision making in manufacturing based on a generalized description of decision making. Using these requirements, we then focus on identifying key barriers that prevent the development and use of data driven decision making in industry as well as examples of technologies and standards that have the potential to overcome these barriers. The goal of this research is to promote a common understanding among the manufacturing community that can enable standardization efforts and innovation needed to continue adoption and use of smart manufacturing technologies. PMID- 28649679 TI - EFFECTIVENESS OF A HEADS-UP ADAPTIVE LANE DEVIATION WARNING SYSTEM FOR MIDDLE AGED & OLDER ADULTS. AB - 46 participants (24 younger and 22 older) completed at least one out of four simulated drives designed to test the effectiveness of an Adaptive Lane Deviation Warning (LDW) system, and they drove through both a warnings-on and warnings-off version of each drive. Findings showed that LDW was effective in reducing reaction time for lane deviation corrections for both older (by 1.2 seconds) and younger drivers (by 1.6 seconds). The older and younger drivers did not differ in correction RTs when the warnings were turned off. But older drivers showed slower correction RTs than younger drivers in the warning-on drives. The data indicate that these benefits were specific to LDW rather than general improvement in driving performance. Cognitive processing speed emerged as a particularly robust predictor of benefits from the LDW compared to other domains of cognitive function. PMID- 28649680 TI - Enzymatic competition and cooperation branch the caerulomycin biosynthetic pathway toward different 2,2'-bipyridine members. AB - In this study, we characterized CaeB6 as a selective hydroxylase and CaeG1 as an O-methyltransferase in the biosynthesis of the 2,2'-bipyridine natural products caerulomycins (CAEs). The C3-hydroxylation activity of CaeB6 competes with the C4 O-methylation activity of CaeG1 and thereby branches the CAE pathway from a common C4-O-demethylated 2,2'-bipyridine intermediate. CaeG1-catalyzed C4-O methylation leads to a main route that produces the major product CAE-A in Actinoalloteichus cyanogriseus NRRL B-2194. In contrast, CaeB6-catalyzed C3 hydroxylation results in a shunt route in which CaeG1 causes C4-O-methylation and subsequent C3-O-methylation to produce a series of minor CAE products. These findings provide new insights into the biosynthetic pathway of CAEs and a synthetic biology strategy for the selective functionalization of the 2,2' bipyridine core. PMID- 28649681 TI - Bio-inspired, colorful, flexible, defrostable light-scattering hybrid films for the effective distribution of LED light. AB - Bioluminescent jellyfish has a unique structure derived from fiber/polymer interfaces that is advantageous for effective light scattering in the dark, deep sea water. Herein, we demonstrate the fabrication of bio-inspired hybrid films by mimicry of the jellyfish's structure, leading to excellent light-scattering performance and defrosting capability. A haze value reaching 59.3% and a heating temperature of up to 292 degrees C were achieved with the films. Accordingly, the developed surface constitutes an attractive optical device for lighting applications, especially for street or vehicle luminaries for freezing Arctic climate countries. The morphological details of the hybrid films were revealed by scanning electron microscopy. The light-scattering properties of these films were examined by ultraviolet-visible-infrared spectrophotometry and anti-glare effect analyses. The defrosting performance of the hybrid films was evaluated via heating tests and infra-red observations. PMID- 28649682 TI - Rhodium-catalyzed redox-neutral coupling of phenidones with alkynes. AB - A switchable synthesis of N-substituted indole derivatives from phenidones via rhodium-catalyzed redox-neutral C-H activation has been achieved. In this protocol, we firstly disclosed that the reactivity of Rh(iii) catalysis could be enhanced through employing palladium acetate as an additive. Some representative features include external oxidant-free, applicable to terminal alkynes, short reaction time and operational simplicity. The utility of this method is further showcased by the economical synthesis of potent anticancer PARP-1 inhibitors. PMID- 28649683 TI - Surface-assisted Ullmann coupling. AB - Surface-assisted Ullmann coupling is the workhorse of on-surfaces synthesis. Among the various couplings that were successfully transferred from solution to solid surfaces, Ullmann coupling is arguably the most reliable, controllable, and widespread coupling reaction. The basic reaction scheme is straightforward: halogenated precursors are deposited onto solid surfaces, normally of coinage metals. In the adsorbed state the halogen substitutents are split off by virtue of the surface's reactivity, thereby generating acitvated species that subsequently recombine by forming C-C bonds. Ullmann coupling is well suited for reticular synthesis of novel organic nanostructures: ideally, the halogen substitution pattern of the precursor - which becomes the monomer upon dehalogenation - predetermines dimensionality and topology of the covalent nanostructures. Also in many relevant systems, side-reactions do not occur. However, in reality topological defects, competing C-H activation on more reactive surfaces, and reaction intermediates render this seemingly simple coupling reaction not only more complex, but also more interesting for fundamental research. This feature article aims to provide an account of the vast amount of already published work and tries to destill important findings and currents trends in surface-assisted Ullmann coupling. PMID- 28649684 TI - Polystyrene-divinylbenzene based nano-CaCO3 composites for the efficient removal of human tumor necrosis factor-alpha. AB - PS-DVB/nano-CaCO3, a novel abundant mesoporous structured polymer nano-composite, was successfully synthesized via suspension polymerization. Characterization of this type of bead nano-composite demonstrated that it exhibits significantly enhanced TNF-alpha adsorption from blood plasma and possesses good mechanical strength. PMID- 28649685 TI - Templated and self-limiting calcite formation directed by coccolith organic macromolecules. AB - The formation of intricately shaped crystalline minerals by organisms is orchestrated by specialized biomacromolecules. The macromolecules associated with coccoliths, nanometer-sized calcite crystal arrays produced by marine microalgae, can form a distinct calcium-rich phase via macromolecular recognition. Here, we show that this calcium-rich phase can be mineralized into a thin film of single crystalline calcite by the balanced addition of carbonate ions. Such a crystallization process provides a strategy to direct crystalline products via local interactions between soluble macromolecules and compatible templates. PMID- 28649686 TI - A visible-light active TiO2 photocatalyst multilayered with WO3. AB - Sputter-deposited TiO2 films with high visible-light photocatalytic activity were successfully realized by a hybrid TiO2/Pt/WO3 film structure with Pt nanoparticles uniformly distributed at the interface of the TiO2 and WO3 films. The TiO2/Pt/WO3 hybrid films enable the complete decomposition of CH3CHO under visible-light irradiation. The water contact angle of the TiO2/Pt/WO3 hybrid films reaches below 5 degrees under visible-light irradiation. Pt nanoparticles are considered to act as a cocatalyst to improve the electron-hole separation efficiency. We demonstrate that the photogenerated holes in WO3 are transferred to the surface of the TiO2 film with less hole-trapping and induce high visible light photocatalytic activity and hydrophilic behavior, and the photogenerated electrons are accumulated in the Pt nanoparticles. The highly hydrophilic thin films with high visible-light photocatalytic activity can be applied to various indoor products possessing self-cleaning and antifogging properties. PMID- 28649687 TI - Vehicle emissions of short-lived and long-lived climate forcers: trends and tradeoffs. AB - Evaluating technology options to mitigate the climate impacts of road transportation can be challenging, particularly when they involve a tradeoff between long-lived emissions (e.g., carbon dioxide) and short-lived emissions (e.g., methane or black carbon). Here we present trends in short- and long-lived emissions for light- and heavy-duty transport globally and in the U.S., EU, and China over the period 2000-2030, and we discuss past and future changes to vehicle technologies to reduce these emissions. We model the tradeoffs between short- and long-lived emission reductions across a range of technology options, life cycle emission intensities, and equivalency metrics. While short-lived vehicle emissions have decreased globally over the past two decades, significant reductions in CO2 will be required by mid-century to meet climate change mitigation targets. This is true regardless of the time horizon used to compare long- and short-lived emissions. The short-lived emission intensities of some low CO2 technologies are higher than others, and thus their suitability for meeting climate targets depends sensitively on the evaluation time horizon. Other technologies offer low intensities of both short-lived emissions and CO2. PMID- 28649688 TI - Versatility and remarkable hypergolicity of exo-6, exo-9 imidazole-substituted nido-decaborane. AB - The combination of an energetic imidazole bonded to a hypergolic trigger, such as certain boron hydride clusters, dramatically improves both the energy density and ignition delay of the resulting compounds while also introducing tunability via alkyl group substitution as demonstrated here with (Rim)2B10H12 (R = H, C1, C2, and C4). PMID- 28649689 TI - The first transition metal phthalocyanines: sensitizing rubrene emission based on triplet-triplet annihilation. AB - Metallophthalocyanines (MPc-o-Cou, M = Fe, Co, Ni, and Cu) with fourth period metal ions have been successfully applied as a sensitizer coupled with rubrene (Rub) in photon upconversion based on triplet-triplet annihilation. An upconversion quantum yield (phiPUC) of up to 4.82% was observed in the CoPc-o-Cou : Rub couple. The absorption and phosphorescence emission spectra showed that the Q bands and phosphorescence emission peaks were dramatically dependent on the number of d-electrons of the metal ions in MPc-o-Cou. These results suggested that the photon upconversion behavior of MPc-o-Cou : Rub systems could be managed by altering the metal ions in MPc-o-Cou. PMID- 28649690 TI - Enzymatic conjugation using branched linkers for constructing homogeneous antibody-drug conjugates with high potency. AB - Antibody-drug conjugates (ADCs) are emerging therapeutic agents in the treatment of cancer, and various conjugation strategies and chemical linkers have been developed to efficiently construct ADCs. Despite previous extensive efforts for improving conjugation efficiency and ADC homogeneity, most ADC linkers developed to date load only single payloads. Branched linkers that can load multiple payload molecules have yet to be fully explored. It is logical to envisage that a multi-loading strategy allows for increase in drug-to-antibody ratio (DAR) with less chemical or enzymatic modification to the antibody structure compared to traditional linear linkers, leading to efficient ADC construction, minimal destabilization of the antibody structure, and enhanced ADC efficacy. Herein, we report that the branched linkers we designed can be quantitatively installed on an anti-HER2 monoclonal antibody by microbial transglutaminase (MTGase)-mediated conjugation without impairing its antigen binding affinity, enabling modular installation of payload molecules and construction of homogeneous ADCs with increased DARs (up to 8). An anti-HER2 antibody-monomethyl auristatin F conjugate constructed using our branched linkers showed greater in vitro cytotoxicity against HER2-expressing breast cancer cell lines than that consisting of linear linkers, demonstrating the effectiveness of the branched linker-based payload delivery. Our finding demonstrates that enzymatic ADC construction using branched linkers is a promising strategy, which may lead to innovative cancer therapeutics. PMID- 28649691 TI - Gluten and Aluminum Content in Synthroid(r) (Levothyroxine Sodium Tablets). AB - INTRODUCTION: Inquiries from healthcare providers and patients about the gluten and aluminum content of Synthroid(r) (levothyroxine sodium tablets) have increased. The objective of this study was to measure and evaluate the gluten content of the raw materials used in the manufacturing of Synthroid. Additionally, this study determined the aluminum content in different strengths of Synthroid tablets by estimating the amount of aluminum in the raw materials used in the manufacturing of Synthroid. METHODS: Gluten levels of three lots of the active pharmaceutical ingredient (API) and one lot of each excipient from different vendors were examined. The ingredients in all current Synthroid formulations (strengths) were evaluated for their quantity of aluminum. RESULTS: Gluten concentrations were below the lowest limit of detection (<3.0 ppm) for all tested lots of the API and excipients of Synthroid tablets. Aluminum content varied across tablet strengths (range 19-137 ug/tablet). Gluten levels of the API and excipients were found to be below the lowest level of detection and are considered gluten-free based on the US Food and Drug Administration (FDA) definition for food products. Across the various tablet strengths of Synthroid, the maximum aluminum levels were well below the FDA-determined minimal risk level for chronic oral aluminum exposure (1 mg/kg/day). CONCLUSION: These data demonstrate that Synthroid tablets are not a source for dietary gluten and are a minimal source of aluminum. FUNDING: AbbVie Inc. PMID- 28649692 TI - Urgent need to strengthen and expand screening and other cancer control programs in the CARICOM Caribbean. AB - PURPOSE: With high mortality in breast, cervical, prostate, and colorectal cancers in Caribbean Community (CARICOM) countries, we examined cancer control initiatives including screening as well as the implementation of relevant international and regional mandates. METHODS: Secondary data were used to examine cancer control initiatives, which included the presence of national policies, programs, and screening services as well as the implementation of international and regional mandates. To identify the data, an on-line search was conducted using Google/Google Scholar. RESULTS: Data were available for 14 of the 15 full members of CARICOM. Although only six countries had distinct cancer control policies, strategies or action plans, all 14 had key elements of cancer control programs. Screening services were available in the 14 countries for cervical, in 12 countries for breast and in 11 for colorectal cancer. However, only four countries had screening policies. In addition, screening guidelines were available for cervical cancer in nine countries, in one country for breast and in none for colorectal cancer. Selected tobacco control policies were present in the 14 countries and immunization policies for human papillomavirus (HPV) in 13. Treatment services included chemotherapy in 10 countries and radiotherapy in six. Nine countries had palliative care services for patients with advanced disease. The countries were at different stages of implementation/compliance with international and regional mandates and frameworks. CONCLUSIONS: There is an urgent need to develop and implement comprehensive and customized cancer control policies addressing screening programs, treatment and palliative care. PMID- 28649693 TI - From febrile pancytopenia to hemophagocytic lymphohistiocytosis-associated organ dysfunction. PMID- 28649694 TI - Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase. AB - In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase. PMID- 28649696 TI - Amaryllidaceae alkaloids: Absolute configuration and biological activity. AB - Plants belonging to the Amaryllidaceae family are well known for their ornamental and medicinal use. Plant members of this group are distributed through both tropical and subtropical regions of the world and are dominant in Andean South America, the Mediterranean basin, and southern Africa. Amaryllidaceae plants have been demonstrated to be a good source of alkaloids with a large spectrum of biological activities, the latter being strictly related to the absolute stereochemistry of the alkaloid scaffold. Among them, great importance for practical applications in medicine has galanthamine, which has already spawned an Alzheimer's prescription drug as a potent and selective inhibitor of the enzyme acetylcholinesterase. Furthermore, lycorine as well as its related isocarbostyryl analogs narciclasine and pancratistatine have shown a strong anticancer activity in vitro against different solid tumors with malignant prognosis. This review addresses the assignment of the absolute configuration of several Amaryllidaceae alkaloids and its relationship with their biological activities. PMID- 28649695 TI - Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn. AB - In both acute and chronic pain conditions, women tend to be more sensitive than men. This sex difference may be regulated by estrogens, such as estradiol, that are synthesized in the spinal cord and brainstem and act locally to influence pain processing. To identify a potential cellular source of local estrogen, here we examined the expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. Our studies focused on primary afferent neurons and on their central targets in the spinal cord and medulla as well as in the nucleus of the solitary tract, the target of nodose ganglion-derived visceral afferents. Immunohistochemical staining in an aromatase reporter mouse revealed that many neurons in laminae I and V of the spinal cord dorsal horn and caudal spinal trigeminal nucleus and in the nucleus of the solitary tract express aromatase. The great majority of these cells also express inhibitory interneuron markers. We did not find sex differences in aromatase expression and neither the pattern nor the number of neurons changed in a sciatic nerve transection model of neuropathic pain or in the Complete Freund's adjuvant model of inflammatory pain. A few aromatase neurons express Fos after cheek injection of capsaicin, formalin, or chloroquine. In total, given their location, these aromatase neurons are poised to engage nociceptive circuits, whether it is through local estrogen synthesis or inhibitory neurotransmitter release. PMID- 28649698 TI - Authors' reply re: Use of a postoperative pad test to identify continence status in women after obstetric vesicovaginal fistula repair: a prospective cohort study. PMID- 28649697 TI - Bioorthogonal Labeling of Human Prostate Cancer Tissue Slice Cultures for Glycoproteomics. AB - Sialylated glycans are found at elevated levels in many types of cancer and have been implicated in disease progression. However, the specific glycoproteins that contribute to the cancer cell-surface sialylation are not well characterized, specifically in bona fide human disease tissue. Metabolic and bioorthogonal labeling methods have previously enabled the enrichment and identification of sialoglycoproteins from cultured cells and model organisms. Herein, we report the first application of this glycoproteomic platform to human tissues cultured ex vivo. Both normal and cancerous prostate tissues were sliced and cultured in the presence of the azide-functionalized sialic acid biosynthetic precursor Ac4 ManNAz. The compound was metabolized to the azidosialic acid and incorporated into cell surface and secreted sialoglycoproteins. Chemical biotinylation followed by enrichment and mass spectrometry led to the identification of glycoproteins that were found at elevated levels or uniquely in cancerous prostate tissue. This work therefore extends the use of bioorthogonal labeling strategies to problems of clinical relevance. PMID- 28649699 TI - A WRKY transcription factor from Withania somnifera regulates triterpenoid withanolide accumulation and biotic stress tolerance through modulation of phytosterol and defense pathways. AB - Withania somnifera produces pharmacologically important triterpenoid withanolides that are derived via phytosterol pathway; however, their biosynthesis and regulation remain to be elucidated. A jasmonate- and salicin-inducible WRKY transcription factor from W. somnifera (WsWRKY1) exhibiting correlation with withaferin A accumulation was functionally characterized employing virus-induced gene silencing and overexpression studies combined with transcript and metabolite analyses, and chromatin immunoprecipitation assay. WsWRKY1 silencing resulted in stunted plant growth, reduced transcripts of phytosterol pathway genes with corresponding reduction in phytosterols and withanolides in W. somnifera. Its overexpression elevated the biosynthesis of triterpenoids in W. somnifera (phytosterols and withanolides), as well as tobacco and tomato (phytosterols). Moreover, WsWRKY1 binds to W-box sequences in promoters of W. somnifera genes encoding squalene synthase and squalene epoxidase, indicating its direct regulation of triterpenoid pathway. Furthermore, while WsWRKY1 silencing in W. somnifera compromised the tolerance to bacterial growth, fungal infection, and insect feeding, its overexpression in tobacco led to improved biotic stress tolerance. Together these findings demonstrate that WsWRKY1 has a positive regulatory role on phytosterol and withanolides biosynthesis, and defense against biotic stress, highlighting its importance as a metabolic engineering tool for simultaneous improvement of triterpenoid biosynthesis and plant defense. PMID- 28649700 TI - Characteristics of acute groin injuries in the adductor muscles: A detailed MRI study in athletes. AB - Acute adductor injuries account for the majority of acute groin injuries; however, little is known about specific injury characteristics, which could be important for the understanding of etiology and management of these injuries. The study aim was to describe acute adductor injuries in athletes using magnetic resonance imaging (MRI). Male athletes with acute groin pain and an MRI confirmed acute adductor muscle injury were prospectively included. MRI was performed within 7 days of injury using a standardized protocol and a reliable assessment approach. 156 athletes presented with acute groin pain of which 71 athletes were included, median age 27 years (range 18-37). There were 46 isolated muscle injuries and 25 athletes with multiple adductor injuries. In total, 111 acute adductor muscle injuries were recorded; 62 adductor longus, 18 adductor brevis, 17 pectineus, 9 obturator externus, 4 gracilis, and 1 adductor magnus injury. Adductor longus injuries occurred at three main injury locations; proximal insertion (26%), intramuscular musculo-tendinous junction (MTJ) of the proximal tendon (26%) and the MTJ of the distal tendon (37%). Intramuscular tendon injury was seen in one case. At the proximal insertion, 12 of 16 injuries were complete avulsions. This study shows that acute adductor injuries generally occur in isolation from other muscle groups. Adductor longus is the most frequently injured muscle in isolation and in combination with other adductor muscle injuries. Three characteristic adductor longus injury locations were observed on MRI, with avulsion injuries accounting for three-quarters of injuries at the proximal insertion, and intramuscular tendon injury was uncommon. PMID- 28649701 TI - A Switchable Open/closed Polyaromatic Macrocycle that Shows Reversible Binding of Long Hydrophilic Molecules. AB - In spite of wide-ranging previous studies on synthetic macrocycles, the installation of open-close functions into the frameworks remains a challenge. We present a new polyaromatic macrocycle capable of switching between open and closed forms in response to external stimuli, namely, base and acid. The macrocycle, which is prepared in three steps, has a well-defined hydrophobic cavity with a length of around 1 nm, surrounded by four pH-responsive acridinium panels. The open and closed structures were confirmed by single-crystal X-ray analysis. The cylindrical cavity can bind long hydrophilic molecules up to 2.7 nm in length in neutral water and then release the bound guests through a reversible open-to-closed structural change upon simple addition of base. PMID- 28649702 TI - Dose considerations for anti-cancer drugs in metastatic prostate cancer. AB - Despite a growing number of treatment options, metastatic castrate resistant prostate cancer remains almost universally fatal. Dose individualization ensures patients receive the maximal benefit from each line of treatment potentially leading to improved outcomes, a reduction in quality of life impairment and minimization of premature cessation for avoidable toxicity. Herein, we review drug-specific issues that may be associated with unexpected or unrecognized variations in drug systemic exposure despite the use of protocol doses. In particular, we discuss the potential for under-exposure of docetaxel and cabazitaxel; over-exposure of enzalutamide; and varied absorption of abiraterone acetate. PMID- 28649703 TI - A retrospective analysis of the relationship between facial injury and mild traumatic brain injury. AB - BACKGROUND/AIMS: The association between facial injury characteristics and mild traumatic brain injury (mTBI) is unclear. The aim of this study was to determine the association between facial injury characteristics and mTBI. METHODS: A retrospective review utilizing patients' medical records at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia, was performed. Records of subjects with a history of facial trauma from 1 April 2012 to 31 December 2012 were selected. Various levels and surgical speciality records were reviewed to ascertain the diagnoses of facial injuries and mTBI. RESULTS: A total of 348 medical records with the diagnosis of facial injuries were included. The prevalence of mTBI among these patients was 41.4% (95% CI 36.2-46.6). The majority of the patients with mTBI were in the age group of 18-25 years old. Patients with or without facial lacerations that were located on the lower face had a significant association with mTBI, P=.001, compared to other types of soft tissue injury. In addition, a statistically significant association was observed between facial fractures occurring to the middle face and mTBI, P=.018. Pearson chi-square test also showed statistically significant association between the severity of facial injuries and mTBI, P=.018. CONCLUSIONS: Mild traumatic brain injury should be suspected in patients with facial injuries and particularly those with lower face lacerations, midface fractures, moderate to severe facial injury and presence of multiple injuries. PMID- 28649704 TI - Latent Fingermark Development on Thermal Paper using 1,2-Indanedione/Zinc and Polyvinylpyrrolidone. AB - Polyvinylpyrrolidone (PVP) has been used in combination with 1,2-indanedione (1,2 IND) and ZnCl2 (Zn) to develop latent fingermarks. The results show that the optimal ratio of 1,2-IND/Zn:PVP is 1.0:0.4 (the concentration of PVP is 8%) for developing fingermark. The developed formulation was tested on the surfaces of 12 kinds of thermal papers. The variation in the fingermark development efficiency was observed within the same and among different kinds of thermal papers. The fingermark development efficiency was mostly better on the thermally sensitive surface compared to the thermally nonsensitive surface. However, similar or even better development was observed from a few thermally nonsensitive surfaces. The present method has shown better efficiency compared to the three other proposed methods on the thermally sensitive surface. In contrast, the present method was proven not the best for the thermally nonsensitive surface. PMID- 28649705 TI - NaOH-HCl neutralized urine preparation for direct testing of uropathogens by Bruker MS. AB - BACKGROUND: We evaluated the analytical performance of a NaOH-HCl neutralization protocol for identifying uropathogens directly from urine samples by a Bruker MS system (Bruker Daltonics, German) and sought to establish a protocol for integrating the method with conventional screening. METHODS: Among all urine samples requested for Gram staining, UF-1000i, and urine cultures by physicians, we selected samples that were positive by both Gram staining and UF-1000i testing. Urine was prepared by neutralization using 0.01M NaOH-HCl, and the samples were processed by Bruker MS. For the low detection limit, one strain each of Escherichia coli and Enterococcus faecium was inoculated in sterile deionized water and sterile urine specimens at sequential dilutions. RESULTS: In a total of 1270 urine samples, 125 samples (9.8%) were positive by both Gram staining and UF 1000i. Of 94 samples showing a single morphotype on agar plates, 82 samples had colony counts >=105 CFU/mL and most uropathogens (95.1%, 78 of 82) had UF-1000i counts >=106 bacteria/mL. Among them, Bruker MS correctly identified 86.6% (71/82) of all isolates, 89.2% (66/74) of Gram-negative bacteria (GNB), and 62.5% (5/8) of Gram-positive cocci (GPC) with higher average scores for GPC (mean score 2.013) and GNB (mean score 2.110). CONCLUSIONS: Bruker MS with urine preparation by NaOH-HCl neutralization provides a simple, cost-effective, and accurate method for identifying uropathogens directly from urine. Using Bruker MS when single morphotype Gram staining and the UF-1000i count as >=106 bacteria/mL may improve the efficiency of bacterial identification in routine practice. PMID- 28649706 TI - Improving efficiency of viability-qPCR for selective detection of infectious HAV in food and water samples. AB - AIM: To improve the efficacy of intercalating dyes to distinguishing between infectious and inactivated hepatitis A virus (HAV) in food. METHODS AND RESULTS: Different intercalating dyes were evaluated for the discrimination between infectious and thermally inactivated HAV suspensions combining with the RT-qPCR proposed in the ISO 15216. Among them, PMAxx was the best dye in removing the RT qPCR signal from inactivated HAV. Applied to lettuce and spinach, PMAxx-Triton pretreatment resulted in complete removal of the RT-qPCR signal from inactivated HAV. Likewise, this study demonstrates that this pretreatment is suitable for the discrimination of inactivated HAV in shellfish without further sample dilution. In mussels and oysters, the developed viability RT-qPCR method reduced the signal of inactivated HAV between 1.7 and 2.2 logs at high inoculation level, and signal was completely removed at low inoculation level. CONCLUSIONS: This study showed that the use of PMAxx is an important improvement to assess HAV infectivity by RT qPCR. It was shown that PMAxx-Triton pretreatment is suitable for the analysis of infectious HAV in complex food samples such as vegetables and shellfish. SIGNIFICANCE AND IMPACT OF THE STUDY: The PMAxx-Triton pretreatment can be easily incorporated to the ISO norm for infectious virus detection. PMID- 28649707 TI - Coordination of the third step of protein splicing in two cyanobacterial inteins. AB - The third step of protein splicing is cyclization of Asn coupled to peptide bond cleavage. In two related cyanobacterial inteins, this step is facilitated by Asn or Gln. For a Synechococcus sp. PCC7002 intein, the isolated third step of protein splicing is more efficient with its native Asn than with substitution to Gln. For a Trichodesmium erythraeum intein, its native Gln facilitates the third step as efficiently as with Asn. Despite these differences, the yield of splicing is not affected, suggesting that the third step is influenced by mechanism-linked conformational changes. A conserved catalytic His and the penultimate residue also play roles in promoting side-chain cyclization. PMID- 28649709 TI - Re: Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data?: Croatian experience supporting inclusion of routine very preterm birth data for valid comparison. PMID- 28649708 TI - Potential benefits of crawl position for prone radiation therapy in breast cancer. AB - PURPOSE: To investigate crawl position with the arm at the treated side alongside the body and at the opposite side above the head for prone treatment in patients requiring breast and regional lymph node irradiation. METHODS: Patient support devices for crawl position were built for CT simulation and treatment. An asymmetric fork design resulted from an iterative process of prototype construction and testing. The fork's large horn supports the hemi-thorax, shoulder, and elevated arm at the nontreated side and the head. The short, narrow horn supports the arm at the treated side. Between both horns, the treated breast and its regional lymph nodes are exposed. Endpoints were pain, comfort, set-up precision, beam access to the breast and lymph nodes, and plan dose metrics. Pain and comfort were tested by volunteers (n = 9); set-up precision, beam access, and plan dose metrics were tested by means of a patient study (n = 10). The AIOTM (Orfit, Wijnegem, Belgium) prone breastboard (AIOTM) was used as a reference regarding comfort and set-up precision. RESULTS: Pain at the sternum, the ipsilateral shoulder, upper arm, and neck was lower in crawl position than with bilateral arm elevation on AIOTM. Comfort and set-up precision were better on the crawl prototype than on AIOTM. In crawl position, beam directions in the coronal and near-sagittal planes have access to the breast or regional lymph nodes without traversing device components. Plan comparison between supine and crawl positions showed better dose homogeneity for the breast and lymph node targets and dose reductions to all organs at risk for crawl position. CONCLUSIONS: Radiation therapy for breast and regional lymph nodes in crawl position is feasible. Good comfort and set-up precision were demonstrated. Planning results support the hypothesis that breast and regional lymph nodes can be treated in crawl position with less dose to organs at risk and equal or better dose distribution in the target volumes than in supine position. The crawl technique is a candidate methodology for further investigation for patients requiring breast and regional lymph node irradiation. PMID- 28649710 TI - Tracking the effect of emotional distraction in working memory brain networks: Evidence from an MEG study. AB - The active maintenance of information in visual working memory (WM) is known to rely on the sustained activity over functional networks including frontal, parietal, occipital, and temporal cortices. Previous studies have described interference-based disturbances in the functional coupling between prefrontal and posterior cortices, and that such disturbances can be restored for a successful WM performance after the presentation of the interfering stimulus. However, very few studies have applied functional connectivity measures to the analysis of the brain dynamics involved in overriding emotional distraction, and all of them have limited their analysis to the particular connections between the amygdala and prefrontal cortex. In this study, we used magnetoencephalography (MEG) to characterize the mutual information-based functional connectivity dynamics among regions of interest located over the prefrontal, the parietal, the temporal, and the occipital cortex. Our results show that the detection of emotional distraction at early latencies (50-150 ms) induces a reduction of functional connectivity involving parietal and temporal cortices that are part of the frontoposterior WM network, while functional coupling among prefrontal areas and between them and posterior cortices is strengthened during the detection of emotional distractors. Later in the processing of the distractor (250-350 and 360 460 ms), the frontoposterior coupling is reestablished for a successful performance, while the orbitofrontal and ventrolateral prefrontal cortex become strongly connected to posterior cortices as a mechanism to cope with emotional distractors. PMID- 28649711 TI - Point-of-Care Ultrasound in General Surgery Residency Training: A Proposal for Milestones in Graduate Medical Education Ultrasound. AB - The use of point-of-care ultrasound (US) in the clinical setting has undergone massive growth, although its incorporation into training and practice is variable. Surgeons are interested in using point-of-care US and can incorporate it effectively into clinical practice. However, the current state of point-of care US training in general surgery is inadequate. The Accreditation Council for Graduate Medical Education introduced the Milestones Project to evaluate resident and fellow performance. Emergency medicine is the only specialty with a point-of care US milestone. We have successfully implemented a US training program into our general surgery residency curriculum and now propose milestones in point-of care US for all general surgery residents. PMID- 28649712 TI - Cross-platform compatibility of de novo-aligned SNPs in a nonmodel butterfly genus. AB - High-throughput sequencing methods for genotyping genome-wide markers are being rapidly adopted for phylogenetics of nonmodel organisms in conservation and biodiversity studies. However, the reproducibility of SNP genotyping and degree of marker overlap or compatibility between datasets from different methodologies have not been tested in nonmodel systems. Using double-digest restriction site associated DNA sequencing, we sequenced a common set of 22 specimens from the butterfly genus Speyeria on two different Illumina platforms, using two variations of library preparation. We then used a de novo approach to bioinformatic locus assembly and SNP discovery for subsequent phylogenetic analyses. We found a high rate of locus recovery despite differences in library preparation and sequencing platforms, as well as overall high levels of data compatibility after data processing and filtering. These results provide the first application of NGS methods for phylogenetic reconstruction in Speyeria and support the use and long-term viability of SNP genotyping applications in nonmodel systems. PMID- 28649713 TI - Mechanistic modeling of the loss of protein sieving due to internal and external fouling of microfilters. AB - Fed-batch and perfusion cell culture processes used to produce therapeutic proteins can use microfilters for product harvest. In this study, new explicit mathematical models of sieving loss due to internal membrane fouling, external membrane fouling, or a combination of the two were generated. The models accounted for membrane and cake structures and hindered solute transport. Internal membrane fouling was assumed to occur due to the accumulation of foulant on either membrane pore walls (pore-retention model) or membrane fibers (fiber retention model). External cake fouling was assumed to occur either by the growth of a single incompressible cake layer (cake-growth) or by the accumulation of a number of independent cake layers (cake-series). The pore-retention model was combined with either the cake-series or cake-growth models to obtain models that describe internal and external fouling occurring either simultaneously or sequentially. The models were tested using well-documented sieving decline data available in the literature. The sequential pore-retention followed by cake growth model provided a good fit of sieving decline data during beer microfiltration. The cake-series and cake-growth models provided good fits of sieving decline data during the microfiltration of a perfusion cell culture. The new models provide insights into the mechanisms of fouling that result in the loss of product sieving. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1323-1333, 2017. PMID- 28649714 TI - Exercise during short-term exposure to hypoxia or hyperoxia - novel treatment strategies for type 2 diabetic patients?! AB - Both hypoxia (decreased oxygen availability) and hyperoxia (increased oxygen availability) have been shown to alter exercise adaptations in healthy subjects. This review aims to clarify the possible benefits of exercise during short-term exposure to hypoxia or hyperoxia for patients with type 2 diabetes mellitus (T2DM). There is evidence that exercise during short-term exposure to hypoxia can acutely increase skeletal muscle glucose uptake more than exercise in normoxia, and that post-exercise insulin sensitivity in T2DM patients is more increased when exercise is performed under hypoxic conditions. Furthermore, interventional studies show that glycemic control can be improved through regular physical exercise in short-term hypoxia at a lower workload than in normoxia, and that exercise training in short-term hypoxia can contribute to increased weight loss in overweight/obese (insulin-resistant) subjects. While numerous studies involving healthy subjects report that regular exercise in hypoxia can increase vascular health (skeletal muscle capillarization and vascular dilator function) to a higher extent than exercise training in normoxia, there is no convincing evidence yet that hypoxia has such additive effects in T2DM patients in the long term. Some studies indicate that the use of hyperoxia during exercise can decrease lactate concentrations and subjective ratings of perceived exertion. Thus, there are interesting starting points for future studies to further evaluate possible beneficial effects of exercise in short-term hypoxia or hyperoxia at different oxygen concentrations and exposure durations. In general, exposure to hypoxia/hyperoxia should be considered with caution. Possible health risks-especially for T2DM patients-are also analyzed in this review. PMID- 28649715 TI - Mild Hydrogenation of Amides to Amines over a Platinum-Vanadium Bimetallic Catalyst. AB - Hydrogenation of amides to amines is an important reaction, but the need for high temperatures and H2 pressures is a problem. Catalysts that are effective under mild reaction conditions, that is, lower than 30 bar H2 and 70 degrees C, have not yet been reported. Here, the mild hydrogenation of amides was achieved for the first time by using a Pt-V bimetallic catalyst. Amide hydrogenation, at either 1 bar H2 at 70 degrees C or 5 bar H2 at room temperature was achieved using the bimetallic catalyst. The mild reaction conditions enable highly selective hydrogenation of various amides to the corresponding amines, while inhibiting arene hydrogenation. Catalyst characterization showed that the origin of the catalytic activity for the bimetallic catalyst is the oxophilic V decorated Pt nanoparticles, which are 2 nm in diameter. PMID- 28649716 TI - Mechanism of Microwave-Assisted Pyrolysis of Glucose to Furfural Revealed by Isotopic Tracer and Quantum Chemical Calculations. AB - Glucose labeled with 13 C or 18 O was used to investigate the mechanism of its conversion into furfural by microwaveassisted pyrolysis. The isotopic content and location in furfural were determined from GC-MS and 13 C NMR spectroscopic measurements and data analysis. The results suggest that the carbon skeleton in furfural is mainly derived from C1 to C5 of glucose, whereas the C of the aldehyde group and the O of the furan ring in furfural primarily originate from C1 and O5 of glucose, respectively. For the first time, the source of O in the furan ring of furfural was elucidated directly by experiment, providing results that are consistent with predictions from recent quantum chemical calculations. Moreover, further theoretical calculations indicate substantially lower energy barriers than previous predictions by considering the potential catalytic effect of formic acid, which is one of the pyrolysis products. The catalytic role of formic acid is further confirmed by experimental evidence. PMID- 28649717 TI - Dissecting the variation in transcriptional circuits between naive and primed pluripotent states. AB - Naive and primed pluripotent states are very similar to each other, but subtle differences exist in their maintenance and differentiation programmes. Transcription factors (TFs) play a key role towards maintaining pluripotency and cellular reprogramming. However, TF expression dynamics and regulatory mechanisms in naive and primed pluripotent states are poorly understood. Here, we performed a comprehensive transcriptional analysis of both states, which revealed a gene expression pattern in mESCs (naive state) that appear to be distinct from mEpiSCs (primed state). We screened 10 TFs essential for maintenance, self-renewal and differentiation, of which the TFs- Notch3, Meis1, Gli3 and Srf can act as novel markers distinguishing the two states. Furthermore, a detailed bioinformatic analysis (involving these TFs) elucidated essential transcriptional circuits between the naive and primed pluripotent states. PMID- 28649718 TI - Anal Sphincters Evaluation by Endoanal Ultrasound in Obstructed Defecation. AB - OBJECTIVES: To evaluate anal sphincter abnormalities detected by endoanal ultrasound in obstructed defecation due to rectocele and rectal intussusception. METHODS: The retrospective analysis includes 45 patients with obstructed defecation syndrome due to rectocele and/or rectal intussusception with or without fecal incontinence, and submitted to endoanal ultrasound. RESULTS: Ninety three percent (n = 42) were women (mean age of 63 +/- 12 years), and 47% (n = 21) of the patients had fecal incontinence. In total, 29% (n = 13) had a previous anorectal surgery, and 93% (n = 39) of the women had a previous vaginal delivery. An isolated rectal intussusception was diagnosed in 20% (n = 9) of the patients, an isolated rectocele in 24% (n = 11), and rectal intussusception and rectocele in 56% (n = 25). Thirty-six percent of patients had anal sphincter lacerations (n = 16): 12% (n = 2) had only internal laceration, 69% (n = 11) had only external laceration, and 19% (n = 3) had both. Two patients had a thinner internal anal sphincter with 0.9 and 1.2 mm, respectively. In total, 25% of the patients without fecal incontinence had an occult anal sphincter laceration, and all were women with an external sphincter laceration in the anterior quadrant and a previous vaginal delivery. In patients with obstructed defecation and fecal incontinence, 48% had sphincter lacerations. Previous anorectal surgery was a predictor of anal sphincter laceration (odds ratio [OR] 4.8; 95% confidence interval [CI] = 1.214-18.971; P = .025), but fecal incontinence (OR 2.7; 95% CI = 0.774-9.613; P = .119) and previous vaginal delivery (OR 1.250; 95% CI = 0.104 15.011; P = .860) were not. CONCLUSIONS: Endoanal ultrasound should be considered in obstructed defecation with or without fecal incontinence, especially if surgical correction is planned. PMID- 28649720 TI - In-season changes in heart rate recovery are inversely related to time to exhaustion but not aerobic capacity in rowers. AB - To determine if in-season changes in heart rate recovery (HRR) are related to aerobic fitness and performance in collegiate rowers. Twenty-two female collegiate rowers completed testing before and after their competitive season. Body fat percentage (BF%) was determined by dual-energy X-ray absorptiometry. Maximal aerobic capacity (VO2max ) and time to exhaustion (Tmax ) were determined during maximal rowing ergometer testing followed by 1 minute of recovery. HRR was expressed absolutely and as a percentage of maximal HR (HRR%1 min ). Variables were compared using paired Wilcoxon tests. Multivariable regression models were used to predict in-season changes in HRR using changes in VO2max and Tmax , while accounting for changes in BF%. From preseason to post-season, VO2max and BF% decreased (3.98+/-0.42 vs 3.78+/-0.35 L/min, P=.002 and 23.8+/-3.4 vs 21.3+/ 3.9%, P<.001, respectively), while Tmax increased (11.7+/-1.3 vs 12.6+/-1.3 min, P=.002), and HRR%1 min increased (11.1+/-2.7 vs 13.8+/-3.8, P=.001). In-season changes in VO2max were not associated with HRR%1 min (P>.05). In-season changes in Tmax were related to changes in HRR%1 min (beta=-1.67, P=.006). In-season changes in BF% were not related to changes in HRR (P>.05 for all). HRR1 min and HRR%1 min were faster preseason to post-season, although the changes were unrelated to VO2max . Faster HRR%1 min post-season was inversely related to changes in Tmax . This suggests that HRR should not be used as a measure of aerobic capacity in collegiate rowers, but is a promising measure of training status in this population. PMID- 28649721 TI - Role of Dynamic Heterogeneities in Ionic Liquids: Insights from All-Atom and Coarse-Grained Molecular Dynamics Simulation Studies. AB - We performed molecular dynamics simulations for the room-temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6 ]). By employing all atom (AA) and coarse-grained (CG) models, we compared the characteristic times of various dynamical modes, from vibration to diffusion, and the importance of dynamical heterogeneities at different levels of chemical resolution and over broad temperature ranges. It was shown that coarse graining leads to a substantial speedup in molecular dynamics, whereas it weakly affects the strength of dynamical heterogeneities. Despite the general speedup, several relationships between dynamical modes on different timescales were preserved. In particular, the heterogeneity timescales of the AA and CG models collapse onto the same curve as a function of the structural (alpha) relaxation time taualpha . Moreover, vibrational amplitudes and relaxation times taualpha are related at both levels of chemical resolution. We argue that the robustness of these relationships assists the development of dynamically consistent coarse-graining strategies and justifies the use of simplified models for a theoretical understanding of viscous liquids. PMID- 28649719 TI - Regulation of growth-defense balance by the JASMONATE ZIM-DOMAIN (JAZ)-MYC transcriptional module. AB - The plant hormone jasmonate (JA) promotes the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins to relieve repression on diverse transcription factors (TFs) that execute JA responses. However, little is known about how combinatorial complexity among JAZ-TF interactions maintains control over myriad aspects of growth, development, reproduction, and immunity. We used loss-of-function mutations to define epistatic interactions within the core JA signaling pathway and to investigate the contribution of MYC TFs to JA responses in Arabidopsis thaliana. Constitutive JA signaling in a jaz quintuple mutant (jazQ) was largely eliminated by mutations that block JA synthesis or perception. Comparison of jazQ and a jazQ myc2 myc3 myc4 octuple mutant validated known functions of MYC2/3/4 in root growth, chlorophyll degradation, and susceptibility to the pathogen Pseudomonas syringae. We found that MYC TFs also control both the enhanced resistance of jazQ leaves to insect herbivory and restricted leaf growth of jazQ. Epistatic transcriptional profiles mirrored these phenotypes and further showed that triterpenoid biosynthetic and glucosinolate catabolic genes are up-regulated in jazQ independently of MYC TFs. Our study highlights the utility of genetic epistasis to unravel the complexities of JAZ-TF interactions and demonstrates that MYC TFs exert master control over a JAZ-repressible transcriptional hierarchy that governs growth-defense balance. PMID- 28649722 TI - Comparison of DVH-based plan verification methods for VMAT: ArcCHECK-3DVH system and dynalog-based dose reconstruction. AB - The purpose of this study was comparing dose-volume histogram (DVH)-based plan verification methods for volumetric modulated arc therapy (VMAT) pretreatment QA. We evaluated two 3D dose reconstruction systems: ArcCHECK-3DVH system (Sun Nuclear corp.) and Varian dynalog-based dose reconstruction (DBDR) system, developed in-house. Fifteen prostate cancer patients (67.6 Gy/26 Fr), four head and neck cancer patient (66 Gy/33 Fr), and four esophagus cancer patients (60 Gy/30 Fr) treated with VMAT were studied. First, ArcCHECK measurement was performed on all plans; simultaneously, the Varian dynalog data sets that contained the actual delivered parameters (leaf positions, gantry angles, and cumulative MUs) were acquired from the Linac control system. Thereafter, the delivered 3D patient dose was reconstructed by 3DVH software (two different calculating modes were used: High Sensitivity (3DVH-HS) and Normal Sensitivity (3DVH-NS)) and in-house DBDR system. We evaluated the differences between the TPS calculated dose and the reconstructed dose using 3D gamma passing rates and DVH dose index analysis. The average 3D gamma passing rates (3%/3 mm) between the TPS calculated dose and the reconstructed dose were 99.1 +/- 0.6%, 99.7 +/- 0.3%, and 100.0 +/- 0.1% for 3DVH-HS, 3DVH-NS, and DBDR, respectively. For the prostate cases, the average differences between the TPS-calculated dose and reconstructed dose in the PTV mean dose were 1.52 +/- 0.50%, -0.14 +/- 0.55%, and -0.03 +/- 0.07% for 3DVH-HS, 3DVH-NS, and DBDR, respectively. For the head and neck and esophagus cases, the dose difference to the TPS-calculated dose caused by an effect of heterogeneity was more apparent under the 3DVH dose reconstruction than the DBDR. Although with some residual dose reconstruction errors, these dose reconstruction methods can be clinically used as effective tools for DVH-based QA for VMAT delivery. PMID- 28649723 TI - Distribution and female reproductive state differences in orexigenic and anorexigenic neurons in the brain of the mouth brooding African cichlid fish, Astatotilapia burtoni. AB - Integration of reproduction and metabolism is necessary for species survival. While the neural circuits controlling energy homeostasis are well-characterized, the signals controlling the relay of nutritional information to the reproductive axis are less understood. The cichlid fish Astatotilapia burtoni is ideal for studying the neural regulation of feeding and reproduction because females cycle between a feeding gravid state and a period of forced starvation while they brood developing young inside their mouths. To test the hypothesis that candidate neuropeptide-containing neurons known to be involved in feeding and energy homeostasis in mammals show conserved distribution patterns, we performed immunohistochemistry and in situ hybridization to localize appetite-stimulating (neuropeptide Y, NPY; agouti-related protein, AGRP) and appetite-inhibiting (cocaine and amphetamine-regulated transcript, CART; pro-opiomelanocortin, pomc1a) neurons in the brain. NPY, AGRP, CART, and pomc1a somata showed distribution patterns similar to other teleosts, which included localization to the lateral tuberal nucleus (NLT), the putative homolog of the mammalian arcuate nucleus. Gravid females also had larger NPY and AGRP neurons in the NLT compared to brooding females, but brooding females had larger pomc1a neurons compared to gravid females. Hypothalamic agrp mRNA levels were also higher in gravid compared to brooding females. Thus, larger appetite-stimulating neurons (NPY, AGRP) likely promote feeding while females are gravid, while larger pomc1a neurons may act as a signal to inhibit food intake during mouth brooding. Collectively, our data suggest a potential role for NPY, AGRP, POMC, and CART in regulating energetic status in A. burtoni females during varying metabolic and reproductive demands. PMID- 28649724 TI - Evaluation of the URiSCAN 2 ACR Strip to estimate the urine albumin/creatinine ratios. AB - BACKGROUND: The urine albumin/creatinine ratio (ACR) test is used to screen patients with chronic diseases, such as diabetes, hypertension and cardiovascular diseases that put them at an increased risk of developing kidney disease. Here, we evaluated the performance of the URiSCAN 2 ACR Strip (URiSCAN; YD diagnostics, Yongin, Korea), a semiquantitative point-of-care testing (POCT) assay, and we compared to an existing POCT assay and a quantitative assay. MATERIALS AND METHODS: A total of 1,020 random urine specimens were analyzed using the semiquantitative URiSCAN 2 ACR Strip and semiquantitative CLINITEK Microalbumin 2 Strip (CLINITEK; Siemens, New York, USA). We evaluated the precision of the URiSCAN 2 ACR Strip and compared the results of the ACR obtained from URiSCAN to those of CLINITEK with the quantitative results of a quantitative assay as a reference. RESULTS: The precision evaluation of the URiSCAN revealed a range between the cutoff (C50 )-20% and C50 +20% bounds, the C5 -C95 interval, with 85.8% confidence. URiSCAN and CLINITEK showed sensitivity and specificity of 87.7% and 72.2%, and 90.2% and 83.0%, respectively. The concordance rates of URiSCAN with CLINITEK and the quantitative assay were 75.6% and 79.1%, respectively. The concordance rate in the abnormal range (>=30 mg/g) between URiSCAN and the quantitative assay were higher than that between CLINITEK and the quantitative assay (78.8% vs 75.4%). CONCLUSIONS: URiSCAN showed good precision and comparable sensitivity with lower specificity than those of CLINITEK. PMID- 28649725 TI - High throughput screening identifies novel, cell cycle-arresting small molecule enhancers of transient protein expression. AB - Transient gene expression in mammalian cells is an efficient process for producing recombinant proteins for various research applications to support large molecule therapeutics development. For the first time, we report a high throughput small molecule (SM) screen to identify novel compounds that increase antibody titers after polyethylenimine (PEI) transient transfection of a HEK293 cell line. After screening 31,413 SMs in a 50 MUL scaled-down process, we validated 164 SMs to improve yields by up to twofold. The titer increase mediated by the SMs varied for different antibodies. SM dose optimizations resulted in almost threefold higher titers. The top 2, structurally distinct SM hits, increased antibody titers more than twofold in a 1 mL production process. Averaged across three antibodies of different expression levels, the compounds enhanced transient productivity by ~80%. Intriguingly, both compounds arrested cells in the G2/M cell cycle phase leading to a decrease in growth and nutrient consumption, while elevating titer, nuclear plasmid DNA (pDNA) copy numbers, and mRNA levels. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 3:1579-1588, 2017. PMID- 28649726 TI - Re: Use of a postoperative pad test to identify continence status in women after obstetric vesicovaginal fistula repair: a prospective cohort study. PMID- 28649727 TI - Grammatical Constructions as Relational Categories. AB - This paper argues that grammatical constructions, specifically argument structure constructions that determine the "who did what to whom" part of sentence meaning and how this meaning is expressed syntactically, can be considered a kind of relational category. That is, grammatical constructions are represented as the abstraction of the syntactic and semantic relations of the exemplar utterances that are expressed in that construction, and it enables the generation of novel exemplars. To support this argument, I review evidence that there are parallel behavioral patterns between how children learn relational categories generally and how they learn grammatical constructions specifically. Then, I discuss computational simulations of how grammatical constructions are abstracted from exemplar sentences using a domain-general relational cognitive architecture. Last, I review evidence from adult language processing that shows parallel behavioral patterns with expert behavior from other cognitive domains. After reviewing the evidence, I consider how to integrate this account with other theories of language development. PMID- 28649728 TI - Death by translation: ribosome-assisted degradation of mRNA by endonuclease toxins. PMID- 28649729 TI - Socializing problems and low self-esteem enhance interpersonal models of eating disorders: Evidence from a clinical sample. AB - OBJECTIVE: The present study evaluated the relative clinical validity of two interpersonal models of the maintenance of eating disorders, IPT-ED (Rieger et al., ) and the interpersonal model of binge eating (Wilfley, MacKenzie, Welch, Ayres, & Weissman, ; Wilfley, Pike, & Striegel-Moore, ). While both models propose an indirect relationship between interpersonal problems and eating disorder symptoms via negative affect, IPT-ED specifies negative social evaluation as the key interpersonal problem, and places greater emphasis on the role of low self-esteem as an intermediate variable between negative social evaluation and eating pathology. METHOD: Treatment-seeking individuals (N = 306) with a diagnosed eating disorder completed measures of socializing problems, generic interpersonal problems, self-esteem, eating disorder symptoms, and negative affect (depression and anxiety). Structural equation models were run for both models. RESULTS: Consistent with IPT-ED, a significant indirect pathway was found from socializing problems to eating disorder symptoms via low self-esteem and anxiety symptoms. There was also a direct pathway from low self-esteem to eating disorder symptoms. Using a socializing problems factor in the model resulted in a significantly better fit than a generic interpersonal problems factor. Inconsistent with both interpersonal models, the direct pathway from socializing problems to eating disorder symptoms was not supported. DISCUSSION: Interpersonal models that included self-esteem and focused on socializing problems (rather than generic interpersonal problems) explained more variance in eating disorder symptoms. Future experimental, prospective, and treatment studies are required to strengthen the case that these pathways are causal. PMID- 28649730 TI - Novel Contrast-Enhanced Ultrasound Evaluation in Neonatal Hypoxic Ischemic Injury: Clinical Application and Future Directions. AB - Sensitive, specific, and safe bedside evaluation of brain perfusion is key to the early diagnosis, treatment, and improved survival of neonates with hypoxic ischemic injury. Contrast-enhanced ultrasound (US) imaging is a novel imaging technique in which intravenously injected gas-filled microbubbles generate enhanced US echoes from an acoustic impedance mismatch. This article describes contrast-enhanced US imaging in 2 neonates with hypoxic ischemic injury and future directions on developing quantitative contrast-enhanced US techniques for improved characterization of perfusion abnormalities. The importance of studying the temporal evolution of brain perfusion in neonatal hypoxic ischemic injury is also highlighted. PMID- 28649731 TI - Protein-Glycan Quinary Interactions in Crowding Environment Unveiled by NMR Spectroscopy. AB - Protein-glycan interactions as modulators for quinary structures in crowding environments were explored. The interaction between human galectin 3 (Gal-3) and distinct macromolecular crowders, such as bovine and human serum albumin (BSA and HSA), Ficoll 70 and PEG3350, was scrutinized. The molecular recognition event of the specific ligand, lactose, by Gal-3 in crowding conditions was evaluated. Gal 3 interactions were monitored by NMR analysing chemical shift perturbation (CSP) and line broadening of 1 H15 N-HSQC signals. The intensity of the Gal-3 1 H15 N HSQC signals decreased in the presence of all crowders, due to the increase in the solution viscosity and to the formation of large protein complexes. When glycosylated containing samples of BSA and HSA were used, signal broadening was more severe than that observed in the presence of the more viscous solutions of PEG3350 and Ficoll 70. However, for the samples containing glycoproteins, the signal intensity of 1 H15 N-HSQC recovered upon addition of lactose. We show that serum proteins interact with Gal-3, through their alpha2,3-linked sialylgalactose moieties exposed at their surfaces, competing with lactose for the same binding site. The quinary interaction between Gal-3 and serum glycoproteins, could help to co-localize Gal-3 at the cell surface, and may play a role in adhesion and signalling functions of this protein. PMID- 28649732 TI - Impact of Medicaid disenrollment in Tennessee on breast cancer stage at diagnosis and treatment. AB - BACKGROUND: States routinely may consider rollbacks of Medicaid expansions to address statewide economic conditions. To the authors' knowledge, little is known regarding the effects of public insurance contractions on health outcomes. The current study examined the effects of the 2005 Medicaid disenrollment in Tennessee on breast cancer stage at the time of diagnosis and delays in treatment among nonelderly women. METHODS: The authors used Tennessee Cancer Registry data from 2002 through 2008 and estimated a difference-in-difference model comparing women diagnosed with breast cancer who lived in low-income zip codes (and therefore were more likely to be subject to disenrollment) with a similar group of women who lived in high-income zip codes before and after the 2005 Medicaid disenrollment. The study outcomes were changes in stage of disease at the time of diagnosis and delays in treatment of >60 days and >90 days. RESULTS: Overall, nonelderly women in Tennessee were diagnosed at later stages of disease and experienced more delays in treatment in the period after disenrollment. Disenrollment was found to be associated with a 3.3-percentage point increase in late stage of disease at the time of diagnosis (P = .024), a 1.9-percentage point decrease in having a delay of >60 days in surgery (P = .024), and a 1.4 percentage point decrease in having a delay of >90 days in treatment (P = .054) for women living in low-income zip codes compared with women residing in high income zip codes. CONCLUSIONS: The results of the current study indicate that Medicaid disenrollment is associated with a later stage of disease at the time of breast cancer diagnosis, thereby providing evidence of the potential negative health impacts of Medicaid contractions. Cancer 2017;123:3312-9. (c) 2017 American Cancer Society. PMID- 28649733 TI - Composition of the root mycorrhizal community associated with Coffea arabica in Fifa Mountains (Jazan region, Saudi Arabia). AB - Arbuscular mycorrhizal fungi (AMF) constitute a key functional group of soil biota that can greatly contribute to crop productivity and ecosystem sustainability. They improve nutrient uptake and enhance the ability of plants to cope with abiotic stresses. The presence of AMF in coffee (Coffea arabica L.) plant roots have been reported in several locations but not in Saudi Arabia despite the fact that coffee has been in cultivation here since ancient times. The objective of the present study was to investigate the diversity of AMF communities colonizing the roots of coffee trees growing in two sites of Fifa Mountains (south-west Saudi Arabia): site 1 at 700 m altitude and site 2 at 1400 m. The AMF large subunit rDNA regions (LSU) were subjected to nested PCR, cloning, sequencing, and phylogenetic analysis. Microscopic observations indicated higher mycorrhizal intensity (24.3%) and spore density (256 spores/100 g of soil) in site 2 (higher altitude). Phylogenetic analysis revealed 10 phylotypes, six belonging to the family Glomeraceae, two to Claroideoglomercea, one to Acaulosporaceae and one to Gigasporaceae family. Glomus was the dominant genus at both sites and the genus Gigaspora was detected only at site 2. This is the first study reporting the presence of AMF in coffee roots and the composition of this particular mycorrhizal community in Saudi Arabia. PMID- 28649734 TI - Hyperfiltration After Donation and Living Kidney Donor Risk. PMID- 28649735 TI - Diagnostic sensitivity of Tc-99m HYNIC PSMA SPECT/CT in prostate carcinoma: A comparative analysis with Ga-68 PSMA PET/CT. AB - BACKGROUND: Emerging data from published studies are demonstrating the superiority of Ga-68 PSMA PET/CT imaging in prostate cancer. However, the low yield of the Ge-68/Ga-68 from which Gallium-68 is obtained and fewer installed PET/CT systems compared to the SPECT imaging systems may limit its availability. We, therefore, evaluated in a head-to-head comparison, the diagnostic sensitivity of Ga-68 PSMA PET/CT and Tc-99m PSMA SPECT/CT in patients with prostate cancer. METHODS: A total of 14 patients with histologically confirmed prostate cancer were prospectively recruited to undergo Ga-68 PSMA PET/CT and Tc-99m HYNIC PSMA SPECT/CT. The mean age of patients was 67.21 +/- 8.15 years and the median PSA level was 45.18 ng/mL (range = 1.51-687 ng/mL). SUVmax of all lesions and the size of lymph nodes with PSMA avidity on Ga-68 PSMA PET/CT were determined. Proportions of these lesions detected on Tc-99m HYNIC PSMA SPECT/CT read independent of PET/CT findings were determined. RESULTS: A total of 46 lesions were seen on Ga-68 PSMA PET/CT localized to the prostate (n = 10), lymph nodes (n = 24), and bones (n = 12). Of these, Tc-99m HYNIC PSMA SPECT/CT detected 36 lesions: Prostate = 10/10 (100%), lymph nodes = 15/24 (62.5%), and bones = 11/12 (91.7%) with an overall sensitivity of 78.3%. Lesions detected on Tc-99m HYNIC PSMA SPECT/CT were bigger in size (P < 0.001) and had higher SUVmax (P < 0.001) as measured on Ga-68 PSMA PET/CT compared to those lesions that were not detected. All lymph nodes greater than 10 mm in size were detected while only 28% of nodes less than 10 mm were detected by Tc-99m HYNIC PSMA SPECT/CT. In a univariate analysis, Lymph node size (P = 0.033) and the SUVmax of all lesions (P = 0.007) were significant predictors of lesion detection on Tc-99m HYNIC PSMA SPECT/CT. CONCLUSION: Tc-99m HYNIC PSMA may be a useful in imaging of prostate cancer although with a lower sensitivity for lesion detection compared to Ga-68 PSMA PET/CT. Its use is recommended when Ga-68 PSMA is not readily available, in planning radio-guided surgery or the patient is being considered for radio-ligand therapy with Lu-177 PSMA. It performs poorly in detecting small-sized lesions hence its use is not recommended in patients with small volume disease. PMID- 28649736 TI - High Aspect Ratio Sub-Micrometer Channels Using Wet Etching: Application to the Dynamics of Red Blood Cell Transiting through Biomimetic Splenic Slits. AB - Nanoparticles delivering drugs, disseminating cancer cells, and red blood cells (RBCs) during splenic filtration must deform and pass through the sub-micrometer and high aspect ratio interstices between the endothelial cells lining blood vessels. The dynamics of passage of particles/cells through these slit-like interstices remain poorly understood because the in vitro reproduction of slits with physiological dimensions in devices compatible with optical microscopy observations requires expensive technologies. Here, novel microfluidic PDMS devices containing high aspect ratio slits with sub-micrometer width are molded on silicon masters using a simple, inexpensive, and highly flexible method combining standard UV lithography and anisotropic wet etching. These devices enabled revealing novel modes of deformations of healthy and diseased RBCs squeezing through splenic-like slits (0.6-2 * 5-10 * 1.6-11 um3 ) under physiological interstitial pressures. At the slit exit, the cytoskeleton of spherocytic RBCs seemed to be detached from the lipid membrane whereas RBCs from healthy donors and patients with sickle cell disease exhibited peculiar tips at their front. These tips disappeared much slower in patients' cells, allowing estimating a threefold increase in RBC cytoplasmic viscosity in sickle cell disease. Measurements of time and rate of RBC sequestration in the slits allowed quantifying the massive trapping of spherocytic RBCs. PMID- 28649737 TI - Quality measures for nurse practitioner practice evaluation. AB - BACKGROUND AND PURPOSE: Evaluating the impact of nurse practitioner (NP) practice has become a priority area of focus for demonstrating outcomes. A number of quality measures are available to enable practice-specific evaluation of NP roles and initiatives. This article reviews sources of quality measures that can be used to facilitate quantifying the outcomes of NP practice as part of an overall evaluation agenda. METHODS: National resources and published literature on NP quality measures were reviewed. CONCLUSIONS: Various resources and toolkits exist to assist NPs in identifying outcomes of practice using quality measures. IMPLICATIONS FOR PRACTICE: The need to demonstrate outcomes of NP practice remains an ongoing priority area regardless of the clinical practice setting. A variety of sources of quality measures exist that can be used to showcase the effect of NP care. The use of quality measures can be effectively integrated into evaluation of NP role and NP-directed initiatives to demonstrate impact, and enhance the conduct of an NP outcomes assessment. The use of organizational, NP specific, and national-related quality measures can help to showcase how NP care improves the quality, safety, and costs of health care. PMID- 28649738 TI - Adjuvant therapy with low-dose interferon-beta for stage II and III melanoma: results of a retrospective analysis. AB - Interferon (IFN)-alfa as an adjuvant therapy has been found to improve relapse free survival in patients with malignant melanoma (MM). However, the efficacy of IFN-beta has not been studied in detail. This study evaluated the contribution of adjuvant IFN-beta therapy to improvements in the prognosis of patients with MM. We reviewed 63 patients with resected stage II/III primary MM at our institution. Of these, 36 had been treated with IFN-beta adjuvant therapy (subcutaneous injection, 3 * 106 IU/day, 10 days), while 27 patients had undergone observation alone. In comparisons of all patients (stage II/III), overall survival and relapse-free survival were significantly better in the IFN-beta group than in the observation group (P < 0.001 for both). The 75-month overall survival rate was 41.2% in the observation group and 68.7% in the IFN-beta group. Adjuvant therapy with IFN-beta may become a new treatment option for patients with stage II/III MM. PMID- 28649739 TI - Professional organization membership: Advancing the nurse practitioner role. AB - With a paucity of literature on professional organization membership by nurse practitioners (NPs), the authors base the discussion of the personal benefits associated with membership on literature focusing on clinicians other than NPs and their personal experiences as members of multiple organizations. Membership is described as related to NP socialization, engagement, networking, mentorship, advocacy, policy, leadership development, research dissemination, professional development, and volunteerism. In addition to encouraging active participation in one or more professional organizations, the need for research into factors influencing the degree to which NPs participate in organizations and the associated benefits is identified. PMID- 28649740 TI - Human versus Robots in the Discovery and Crystallization of Gigantic Polyoxometalates. AB - The discovery of new gigantic molecules formed by self-assembly and crystal growth is challenging as it combines two contingent events; first is the formation of a new molecule, and second its crystallization. Herein, we construct a workflow that can be followed manually or by a robot to probe the envelope of both events and employ it for a new polyoxometalate cluster, Na6 [Mo120 Ce6 O366 H12 (H2 O)78 ]?200 H2 O (1) which has a trigonal-ring type architecture (yield 4.3 % based on Mo). Its synthesis and crystallization was probed using an active machine-learning algorithm developed by us to explore the crystallization space, the algorithm results were compared with those obtained by human experimenters. The algorithm-based search is able to cover ca. 9 times more crystallization space than a random search and ca. 6 times more than humans and increases the crystallization prediction accuracy to 82.4+/-0.7 % over 77.1+/-0.9 % from human experimenters. PMID- 28649741 TI - The emerging science of linked plant-fungal invasions. AB - Contents 1314 I. 1315 II. 1316 III. 1322 IV. 1323 V. 1325 VI. 1326 VII. 1326 VIII. 1327 1328 References 1328 SUMMARY: Invasions of alien plants are typically studied as invasions of individual species, yet interactions between plants and symbiotic fungi (mutualists and potential pathogens) affect plant survival, physiological traits, and reproduction and hence invasion success. Studies show that plant-fungal associations are frequently key drivers of plant invasion success and impact, but clear conceptual frameworks and integration across studies are needed to move beyond a series of case studies towards a more predictive understanding. Here, we consider linked plant-fungal invasions from the perspective of plant and fungal origin, simplified to the least complex representations or 'motifs'. By characterizing these interaction motifs, parallels in invasion processes between pathogen and mutualist fungi become clear, although the outcomes are often opposite in effect. These interaction motifs provide hypotheses for fungal-driven dynamics behind observed plant invasion trajectories. In some situations, the effects of plant-fungal interactions are inconsistent or negligible. Variability in when and where different interaction motifs matter may be driven by specificity in the plant fungal interaction, the size of the effect of the symbiosis (negative to positive) on plants and the dependence (obligate to facultative) of the plant fungal interaction. Linked plant-fungal invasions can transform communities and ecosystem function, with potential for persistent legacies preventing ecosystem restoration. PMID- 28649743 TI - l-arginine modulates inflammation and muscle regulatory genes after a single session of resistance exercise in rats. AB - We investigated the skeletal muscle adaptation to l-arginine supplementation prior to a single session of resistance exercise (RE) during the early phase of muscle repair. Wistar rats were randomly assigned into non-exercised (Control), RE plus vehicle (RE); RE plus l-arginine (RE+L-arg) and RE plus aminoguanidine (RE+AG) groups. Animals received four doses of either vehicle (0.9% NaCl), l-arg (1 g/b.w.), or AG (iNOS inhibitor) (50 mg/b.w.). The animals performed a single RE session until the concentric failure (ladder climbing; 80% overload) and the skeletal muscles were harvested at 0, 8, 24, and 48 hours post-RE. The RE resulted in increased neutrophil infiltrate (24 hours post-RE) (3621 vs 11852; P<.0001) associated with enhanced TNF-alpha (819.49 vs 357.02; P<.005) and IL-6 (3.84 vs 1.08; P<.0001). Prior, l-arginine supplementation attenuates neutrophil infiltration (5622; P<.0001), and also TNF-alpha (506.01; P<.05) and IL-6 (2.51, P<.05) levels. AG pretreatment mediated an inhibition of iNOS levels similar to levels found in RE group. RE animals displayed increased of atrogin-1 (1.9 fold) and MuRF-1 (3.2 fold) mRNA levels, reversed by l-arg supplementation [atrogin-1 (0.6 fold; P<.001); MuRF-1 (0.8-fold; P<.001)] at 24 hours post-RE. MyoD up regulated levels were restricted to l-arg treated animals at 24 hours (2.8 vs 1.5 fold; P<.005) and 48 hours post-RE (2.4 vs 1.1 fold; P<.001). AG pretreatment reversed these processes at 24 hours [atrogin-1 (2.1 fold; P<.0001); MuRF-1 (2.5 fold; P<.0001); MyoD (1.4 fold)]. l-arginine supplementation seems to attenuate the resolution of RE-induced muscle inflammation and up-regulates MyoD expression during the early phase of muscle repair. PMID- 28649742 TI - Genotranscriptomic meta-analysis of the CHD family chromatin remodelers in human cancers - initial evidence of an oncogenic role for CHD7. AB - Chromodomain helicase DNA binding proteins (CHDs) are characterized by N-terminal tandem chromodomains and a central adenosine triphosphate-dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10 000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amplified and mutated, whereas CHD3 was the most deleted across the majority of tumor types, including breast cancer. Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis. CHD7 is required to maintain open, accessible chromatin, thus providing fine-tuning of transcriptional regulation of certain classes of genes. We found that CHD7 expression was positively correlated with a small subset of classical oncogenes, notably NRAS, in breast cancer. Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets, including NRAS, in breast cancer cell lines. Thus, our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer. PMID- 28649744 TI - Mannose-Binding Lectin-Deficient Donors Increase the Risk of Bacterial Infection and Bacterial Infection-Related Mortality After Liver Transplantation. AB - Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT. PMID- 28649745 TI - Robotic TAPP repair of incarcerated femoral hernia with utilization of indocyanine green dye - a video vignette. PMID- 28649746 TI - Unique Spectral Overlap and Resonant Energy Transfer between Europium(II) and Ytterbium(III) Cations: No Quantum Cutting. AB - Samples of the Ca3 Sc2 Si3 O12 (CSS) host singly doped with Eu2+ or Yb3+ , doubly doped with Eu2+ and Yb3+ , and triply doped with Ce3+ , Eu2+ and Yb3+ were synthesized by a sol-gel combustion process under reducing conditions. Unlike previous reports of Eu2+ ->Yb3+ energy transfer in other systems, the energy transfer is resonant in the CSS host and the transfer efficiency reaches 100 % for lightly doped samples. The transfer mechanism is multipolar rather than electron transfer for the sample compositions employed herein. The emission intensity of Yb3+ is further enhanced by co-doping with Ce3+ in addition to Eu2+ . The quantum efficiencies of the doped materials range between 9 % and 93 %. PMID- 28649747 TI - Synthesis, structure, and biological evaluation of a platinum-carbazole conjugate. AB - Cisplatin resistance is caused, in part, by the efficient removal of the helix distorting cisplatin 1,2-intrastrand cross-links by nucleotide excision repair (NER) machinery. To make a platinum-DNA adduct that causes less helical distortion than the cisplatin 1,2-intrastrand adduct, we designed and synthesized a monofunctional platinum-carbazole conjugate (carbazoplatin). The 2.5 A crystal structure of carbazoplatin-DNA adduct revealed both the monoplatination of the N7 of a guanine (G) base and the intercalation into two G:C base pairs, while causing a minor distortion of the DNA helix. A 50-mer dsDNA containing a single carbazoplatin lesion was poorly processed by UvrABC endonuclease, the prokaryotic NER machinery that detects helical distortion and performs dual incision around the lesion. Our cell viability assay indicated that the cytotoxic pathways of carbazoplatin might be different from those of cisplatin; carbazoplatin was 5-8 times more cytotoxic than cisplatin against PANC-1 and MDA-MB-231 cancer cell lines. PMID- 28649748 TI - Sonographic Comparison of Morphologic Characteristics Between Pilonidal Cysts and Hidradenitis Suppurativa. AB - OBJECTIVES: To compare the sonographic characteristics of pilonidal cysts and hidradenitis suppurativa. METHODS: A retrospective study of sonographic examinations was performed on 2 groups: 1 with pilonidal cysts and the other with hidradenitis suppurativa. The sonographic characteristics of the pilonidal cyst and hidradenitis suppurativa groups were analyzed, compared, and correlated, including an analysis of the histologic findings. For the pilonidal cyst group, the distribution, morphologic characteristics, location, shape, diameter, axis, vascularity, and scarring were also described. Statistical analyses included Spearman, Wilcoxon, Kruskall-Wallis, chi2 , and Fisher tests. RESULTS: The sonographic examinations of 84 patients were reviewed: 43 with pilonidal cysts and 41 with hidradenitis suppurativa. The comparison of the morphologic characteristics of the key lesions between the pilonidal cyst and hidradenitis suppurativa groups showed no statistically significant differences (P < .05). Both groups had similar dermal and hypodermal saclike and bandlike structures that communicated with the widened base of the hair follicles. Retained fragments of hair tracts within the lesions were sonographically detected in both pilonidal cysts (100%) and hidradenitis suppurativa (83%) and also found on histologic specimens; however, the density of hair tracts per structure was higher in pilonidal cysts. Sonographic signs of scarring were absent in 63% of pilonidal cysts. Only 2% of pilonidal cysts showed communicating bandlike structures. CONCLUSIONS: Key lesions of pilonidal cysts and hidradenitis suppurativa have similar sonographic morphologic characteristics, which suggests that a pilonidal cyst may be a variant or localized form of hidradenitis suppurativa. The retained fragments of hair tracts frequently detected in both entities may be caused by ectopic production of hair and not by embedding. Common therapeutic strategies and research can be designed for both entities. PMID- 28649749 TI - The more IGRT systems, the merrier? PMID- 28649750 TI - Vasopressin: physiology, assessment and osmosensation. AB - Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP. PMID- 28649751 TI - Long-term management of chronic spontaneous urticaria with omalizumab. AB - BACKGROUND: Clinical trials have shown the efficacy of omalizumabs efficacy in refractory chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), but real-life management strategies are lacking. AIM: To assess the long term efficacy and safety of omalizumab, and to identify predictive factors and optimum dosage regimens. METHODS: This was a prospective study of 13 patients (11 women, 2 men) with severe CSU [weekly urticaria activity score (UAS7) > 28] resistant to anti-H1 antihistamines. Patients were started on omalizumab 150 mg subcutaneously every 4 weeks. Dose and interval between administrations were adjusted according to clinical response (189 administrations; treatment duration range 2-38 months). RESULTS: Mean UAS7 was 36.3 +/- 5.4. Of the 13 patients, all had experienced angio-oedema, while in addition, 7 had delayed pressure urticaria (DPU) and 1 had solar urticaria (SU). After omalizumab treatment, 4 (30.8%) of the 13 patients had complete response (CR), and the remaining 8 (61.5%) had partial response. CR was achieved with a dose of 150 mg every 4 (n = 2 patients) or 5 (n = 2) weeks. One of these patients remained disease-free after stopping treatment. Partial responses were achieved with 150 mg every 4 weeks (n = 4) and with 300 mg (n = 4) at intervals of 5 weeks (n = 1), 4 weeks (n = 2) or 3 weeks (n = 1). Only one patient (7.7%) did not show significant improvement, despite a dose of 300 mg every 4 weeks. There were no significant differences in epidemiological, clinical and laboratory data between the different response groups. Only two adverse events were observed: one was mild headache and the other was severe angio-oedema and aggravation of urticaria within 6 h of omalizumab administration. CONCLUSION: Omalizumab dose and interval between administrations could be individualized for long-term management of CSU. PMID- 28649752 TI - Investigating DNA-, RNA-, and protein-based features as a means to discriminate pathogenic synonymous variants. AB - Synonymous single-nucleotide variants (SNVs), although they do not alter the encoded protein sequences, have been implicated in many genetic diseases. Experimental studies indicate that synonymous SNVs can lead to changes in the secondary and tertiary structures of DNA and RNA, thereby affecting translational efficiency, cotranslational protein folding as well as the binding of DNA-/RNA binding proteins. However, the importance of these various features in disease phenotypes is not clearly understood. Here, we have built a support vector machine (SVM) model (termed DDIG-SN) as a means to discriminate disease-causing synonymous variants. The model was trained and evaluated on nearly 900 disease causing variants. The method achieves robust performance with the area under the receiver operating characteristic curve of 0.84 and 0.85 for protein-stratified 10-fold cross-validation and independent testing, respectively. We were able to show that the disease-causing effects in the immediate proximity to exon-intron junctions (1-3 bp) are driven by the loss of splicing motif strength, whereas the gain of splicing motif strength is the primary cause in regions further away from the splice site (4-69 bp). The method is available as a part of the DDIG server at http://sparks-lab.org/ddig. PMID- 28649753 TI - 'For our garden of remembrance is somewhere else': Narratives of separation through the eyes of Freud's patients. AB - This article presents a unique collection of narratives of separation - unique because the separation here is from psychoanalysis and from Freud as analyst. These narratives were published as part of memoirs written about Freud by three of his patients. Their narratives of separation give us an innovative point of view on the psychoanalytic process, in particular with respect to the importance they place on the termination phase of the analysis at a time when Freud himself had not given it much consideration. The three autobiographical texts are Abram Kardiner's memoir (1977); the memoir of Sergei Pankejeff, known as the Wolf Man (Gardiner, ); and 'Tribute to Freud', by the poet H.D. (). These three distinguished narratives are discussed here as works of translation, as understood by Walter Benjamin (1968 [1955]), Paul Ricoeur (2006 [2004]), and Jean Laplanche (1999 [1992]). They express translation under three aspects: reconstruction of the past (the work of memory), interpreting the conscious residues of the transference (the work of mourning), and, as a deferred action, deciphering the enigmatic messages received from Freud as the parental figure. This representation of the analysand's writing suggests that the separation from analysis is an endless work of translation within the endless process of deciphering the unconscious. PMID- 28649754 TI - Characterization and Differentiation of Geometric Isomers of 3-methylfentanyl Analogs by Gas Chromatography/Mass Spectrometry, Liquid Chromatography/Mass Spectrometry, and Nuclear Magnetic Resonance Spectroscopy. AB - The cis and trans isomers of 3-methylfentanyl and its three analogs were chemically synthesized, and these compounds were characterized and differentiated by gas chromatography/mass spectrometry (GC/MS), liquid chromatography/mass spectrometry (LC/MS), and nuclear magnetic resonance (NMR) spectroscopy. The cis and trans isomers of the 3-methylfentanyl analogs were completely separated by GC/MS. Although the high temperature of the GC injection port caused thermal degradation of beta-hydroxy-3-methylfentanyl, the degradation was completely suppressed by trimethylsilyl derivatization. The isomers were also well separated by LC/MS on an octadecylsilyl column with 10 mM ammonium acetate and methanol as the mobile phase. The proton NMR signals were split when the hydrochloride salts of the 3-methylfentanyl analogs were dissolved in deuterated chloroform because stereoisomers were formed by the coordination of the hydrochloride proton to the nitrogen of the piperidine ring of the 3-methylfentanyl analogs. PMID- 28649755 TI - Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial. AB - AIM: Colorectal cancer (CRC) is prevalent in the older population, and surgery is the mainstay of curative treatment. A preoperative geriatric assessment (GA) can identify frail older patients at risk for developing postoperative complications. In this randomized controlled trial we wanted to investigate whether tailored interventions based on a preoperative GA could reduce the frequency of postoperative complications in frail patients operated on for CRC. METHOD: Patients > 65 years scheduled for elective CRC surgery and fulfilling predefined criteria for frailty were randomized to either a preoperative GA followed by a tailored intervention or care as usual. The primary end-point was Clavien-Dindo Grade II-V postoperative complications. Secondary end-points included complications of any grade, reoperation, length of stay, readmission and survival. RESULTS: One hundred and twenty-two patients with a mean age of 78.6 years were randomized. We found no statistically significant differences between the intervention group and the control group for Grade II-V complications (68% vs 75%, P = 0.43), reoperation (19% vs 11%, P = 0.24), length of stay (8 days in both groups), readmission (16% vs 6%, P = 0.12) or 30-day survival (4% vs 5%, P = 0.79). Grade I-V complications occurred in 76% of patients in the intervention group compared with 87% in the control group (P = 0.10). In secondary analyses adjusting for prespecified prognostic factors, there was a statistically significant difference in favour of the intervention for reducing the total number of Grade I-V complications (P = 0.05). CONCLUSION: A preoperative GA and tailored interventions did not reduce the rate of Grade II-V complications, reoperations, readmission or mortality in frail older patients electively operated on for CRC. PMID- 28649756 TI - Lacto-ghrestatin, a novel bovine milk-derived peptide, suppresses ghrelin secretion. AB - Ghrelin, an endogenous peptide isolated from the stomach, is known to stimulate food intake after peripheral administration. We found that the enzymatic digest of beta-lactoglobulin decreases ghrelin secretion from the ghrelin-producing cell line MGN3-1. The peptides present in the digest were comprehensively analyzed using the nanoLC-OrbitrapMS. Among them, we identified that the nonapeptide LIVTQTMKG, corresponding to beta-lactoglobulin(1-9), suppresses ghrelin secretion from MGN3-1 cells. We named LIVTQTMKG 'lacto-ghrestatin'. We found that lacto ghrestatin decreases intracellular cAMP levels and mRNA expression levels of ghrelin production-related genes in MGN3-1 cells. Orally administered lacto ghrestatin decreases plasma ghrelin levels and food intake in fasted mice. Lacto ghrestatin is the first food-derived peptide to suppress ghrelin secretion in vitro and in vivo. PMID- 28649757 TI - Visual Complexity and Its Effects on Referring Expression Generation. AB - Speakers' perception of a visual scene influences the language they use to describe it-which objects they choose to mention and how they characterize the relationships between them. We show that visual complexity can either delay or facilitate description generation, depending on how much disambiguating information is required and how useful the scene's complexity can be in providing, for example, helpful landmarks. To do so, we measure speech onset times, eye gaze, and utterance content in a reference production experiment in which the target object is either unique or non-unique in a visual scene of varying size and complexity. Speakers delay speech onset if the target object is non-unique and requires disambiguation, and we argue that this reflects the cost of deciding on a high-level strategy for describing it. The eye-tracking data demonstrate that these delays increase when speakers are able to conduct an extensive early visual search, implying that when speakers scan too little of the scene early on, they may decide to begin speaking before becoming aware that their description is underspecified. Speakers' content choices reflect the visual makeup of the scene-the number of distractors present and the availability of useful landmarks. Our results highlight the complex role of visual perception in reference production, showing that speakers can make good use of complexity in ways that reflect their visual processing of the scene. PMID- 28649758 TI - Infective Endocarditis Diagnosed by Pocket Ultrasound at the Bedside. PMID- 28649759 TI - Impact of intravenous thrombolysis on recanalization rates in patients with stroke treated with bridging therapy. AB - BACKGROUND AND PURPOSE: Randomized controlled trials have shown that bridging endovascular therapy (EVT) after intravenous thrombolysis (IVT) therapy improves outcome in patients with stroke with large-artery anterior circulation stroke compared with IVT alone. It remains unknown whether IVT adds any benefit to EVT in these patients. The aim of this study was to assess recanalization rates and thrombus dislocation before initiation of EVT in patients receiving bridging therapy. METHODS: All patients in the Bernese stroke registry (2008-2015) in whom bridging therapy was considered were included in this analysis. Relevant recanalization before EVT, thrombus dislocation and increase in thrombus load between initial and control imaging were assessed retrospectively. RESULTS: A total of 319 patients were included. Relevant recanalization before EVT occurred in 8.8% and thrombus dislocation in 7.2% of patients before EVT. Recanalization rates were significantly higher in distal compared with large and more proximal vessel occlusions of the anterior circulation (occlusion of internal carotid artery, 5.4%; middle cerebral artery segment M1, 8.1%; middle cerebral artery segment M2, 17.6%) and in drip-and-ship patients compared with mother-ship patients. In multivariable regression analysis the occlusion site was the only independent predictor of relevant recanalization before EVT (P = 0.046). CONCLUSIONS: Relevant recanalization after IVT and prior to EVT in patients receiving bridging therapy was highly dependent on the occlusion site. These findings suggest that future randomized controlled trials should consider occlusion site and treatment paradigm to specify patients who benefit most from bridging therapy in comparison to EVT or IVT alone. PMID- 28649760 TI - Immunometabolism of human autoimmune diseases: from metabolites to extracellular vesicles. AB - Immunometabolism focuses on the mechanisms regulating the impact of metabolism on lymphocyte activity and autoimmunity outbreak. The adipose tissue is long known to release adipokines, either pro- or anti-inflammatory factors bridging nutrition and immune function. More recently, adipocytes were discovered to also release extracellular vesicles (EVs) containing a plethora of biological molecules, including metabolites and microRNAs, which can regulate cell function/metabolism in distant tissues, suggesting that immune regulatory function by the adipose tissue may be far more complex than originally thought. Moreover, EVs were also identified as important mediators of immune cell-to-cell communication, adding a further microenvironmental mechanism of plasticity to fine-tune specific lymphocyte responses. This Review will first focus on the known mechanisms by which metabolism impacts immune function, presenting a systemic (nutrition and long-ranged adipokines) and a cellular point of view (metabolic pathway derangement in autoimmunity). It will then discuss the new discoveries concerning how EVs may act as nanometric vehicles integrating immune/metabolic responses at the level of the extracellular environment and affecting pathological processes. PMID- 28649761 TI - Functional assessment of plant and microalgal lipid pathway genes in yeast to enhance microbial industrial oil production. AB - As promising alternatives to fossil-derived oils, microbial lipids are important as industrial feedstocks for biofuels and oleochemicals. Our broad aim is to increase lipid content in oleaginous yeast through expression of lipid accumulation genes and use Saccharomyces cerevisiae to functionally assess genes obtained from oil-producing plants and microalgae. Lipid accumulation genes DGAT (diacylglycerol acyltransferase), PDAT (phospholipid: diacylglycerol acyltransferase), and ROD1 (phosphatidylcholine: diacylglycerol choline phosphotransferase) were separately expressed in yeast and lipid production measured by fluorescence, solvent extraction, thin layer chromatography, and gas chromatography (GC) of fatty acid methyl esters. Expression of DGAT1 from Arabidopsis thaliana effectively increased total fatty acids by 1.81-fold above control, and ROD1 led to increased unsaturated fatty acid content of yeast lipid. The functional assessment approach enabled the fast selection of candidate genes for metabolic engineering of yeast for production of lipid feedstocks. PMID- 28649762 TI - The usefulness of the H-pouch configuration in salvage surgery for failed ileal pouches. AB - AIM: Abdominal salvage surgery for a failed ileal pouch-anal anastomosis (5) is safe and feasible in experienced hands. When salvaging an ileal pouch or creating a new J, S or W pouch may not be feasible, construction of an H-pouch may be the final option. This study reports a single colorectal surgeon's experience on H pouch anal anastomosis in patients referred with a failed ileal pouch. METHOD: Patients undergoing transabdominal salvage surgery with H-pouch formation for a failed pouch from February 2012 to May 2016 were evaluated. RESULTS: Five patients were identified with a mean age of 46 (22-63) years. The pathological diagnosis was mucosal ulcerative colitis in all patients. Three patients had an initial traditional two-stage J-pouch creation and two patients had an initial three-stage approach. The median time to redo pouch surgery after the index IPAA creation was 99 (11-158) months. One patient required excision of the pouch and two patients had a complication within 30 days of surgery. CONCLUSION: The H pouch is a good alternative for a failed IPAA when another type of reservoir is not an option. PMID- 28649763 TI - Transformations of Some Sesquiterpene Lactones by Filamentous Fungi and Cytotoxic Evaluations. AB - Biotransformation is an economically and ecologically viable technology which has been used to modify the structures of many classes of biologically active products. Some fungi may be useful for the biotransformation of sesquiterpene lactones (SLs), leading to unusual structural changes that modify their biological activities, and other transformations mimic their biosynthetic pathways, generating evidences for the proposed biogenesis. Eight filamentous fungi were screened for their ability to transform different SLs (1 - 9), and microbial reactions yielded compounds 10 - 17, which in turn have been isolated as natural products, thus mimicking their biosynthesis. Their structures were identified based on NMR and MS spectroscopic analyses. The cytotoxicities of SLs 1, 4, 6, 7 and 9, and their biotransformed produts (10, 14, 15 and 17) against human cancer cell lines U251 (glia), PC3 (prostate), K562 (leukemia), HCT-15 (colon), MCF7 (breast), and SKLU-1 (lung), were determined, confirming that the presence of Michael acceptor is an important feature for the bioactivity. PMID- 28649764 TI - Re: Intrauterine balloon tamponade for management of severe postpartum haemorrhage in a perinatal network: a prospective cohort study: Exclusion criteria? PMID- 28649765 TI - NExT: creating an interdisciplinary alliance to diminish informational barriers for public health nursing. AB - BACKGROUND: Public health nurses (PHNs) are challenged in obtaining opportunities to learn evidence-based practice (EBP). An interdisciplinary alliance was created between health sciences librarians and nurse educators to create a continuing education (CE) opportunity. OBJECTIVE: To measure the effectiveness of CE training for PHNs on the knowledge gained about the EBP process and information resources. METHODS: Ten in-person CE workshops were offered to 69 attendees in rural and urban areas. A pre-test/post-test survey was administered immediately before and after the training that asked participants to rate their perceived knowledge and comfort levels with EBP concepts and resources. RESULTS: Ninety seven per cent of participants reported the training was a good use of their time. Based on a 5-point Likert scale self-assessment, participants developed new skills (m = 4.06, SD = 0.968) and were able to find evidence-based literature (m = 4.16, SD = 0.980). Participants reported increasing their understanding of EBP concepts and familiarity of information resources. All data were statistically significant at P < 0.001 (95% CI). DISCUSSION: With the interdisciplinary collaboration capitalising on the instructors' disciplinary skill sets, the team was able to create a new effective EBP education intervention for PHNs. CONCLUSION: Public health nurses were able to increase knowledge of EBP concepts and information resources to utilise in practice or grant development. PMID- 28649766 TI - Inferior olivary projection to the zebrin II stripes in lobule IXcd of the pigeon flocculus: A retrograde tracing study. AB - Zebrin II (ZII; a.k.a. aldolase C) is expressed heterogeneously in Purkinje cells (PCs) such that there are sagittal stripes of high expression (ZII+) interdigitated with stripes of little or no expression (ZII-). The pigeon flocculus receives visual-optokinetic information and is important for generating compensatory eye movements. It consists of 4 sagittal zones based on PC complex spike activity (CSA) in response to rotational optokinetic stimuli. There are two zones where CSA responds best to rotation about the vertical axis (VA), interdigitated with two zones where CSA responds best to rotation about an horizontal axis (HA). These optokinetic zones relate to the ZII stripes in folium IXcd of the flocculus, such that an optokinetic zone spans a ZII+/- pair: the HA zones span the P5+/- and P7+/- ZII stripe pairs, whereas the VA zones correspond to ZII stripe pairs P4+/- and P6+/-. In the present study, we used fluorescent retrograde tracing to determine the olivary inputs to the ZII+ and ZII- stripes within the functional pairs. We found that separate but adjacent areas of the medial column of the inferior olive (mcIO) project to the ZII+ and ZII- stripes within each of the functional pairs. Thus, although a ZII+/- stripe pair represents a functional unit in the pigeon flocculus insofar as the CSA of all PCs in the stripe pair encodes similar sensory information, the olivary inputs to the ZII+ and ZII- stripes arise from different, although adjacent, regions of the mcIO. PMID- 28649767 TI - The use of antioxidant agents for chemotherapy-induced peripheral neuropathy treatment in animal models. AB - Antineoplastic drugs such as cisplatin, oxaliplatin, paclitaxel and vincristin are widely used in the treatment of several solid and blood tumours. However, the severity of peripheral neuropathy caused by these agents can affect the patient's quality of life. The major symptoms of chemotherapy-induced peripheral neuropathy (CIPN) involve: sensory loss, paresthesia, dysesthaesia, numbness, tingling, temperature sensitivity, allodynia and hyperalgesia, in a "stocking and glove" distribution. Why many different chemotherapeutic agents result in similar neuropathy profiles is unclear. Many drug classes such as antidepressants, anticonvulsants, antispastic agents and others have been used in clinical practice, but there is no scientific evidence to prove their effectiveness. But drugs as the antioxidant have shown a protective effect against free radical damage. In order to find out a successful treatment for CIPN, animal studies (ie pharmacological and mechanical tests and histopathological immunohistochemical analyses) have been developed to try to determinate the action of the antioxidant agents. This review provides an overview of the major antioxidant agents recently investigated to treat CIPN and the animal models used for this purpose. PMID- 28649768 TI - Measuring canopy loss and climatic thresholds from an extreme drought along a fivefold precipitation gradient across Texas. AB - Globally, trees are increasingly dying from extreme drought, a trend that is expected to increase with climate change. Loss of trees has significant ecological, biophysical, and biogeochemical consequences. In 2011, a record drought caused widespread tree mortality in Texas. Using remotely sensed imagery, we quantified canopy loss during and after the drought across the state at 30-m spatial resolution, from the eastern pine/hardwood forests to the western shrublands, a region that includes the boundaries of many species ranges. Canopy loss observations in ~200 multitemporal fine-scale orthophotos (1-m) were used to train coarser Landsat imagery (30-m) to create 30-m binary statewide canopy loss maps. We found that canopy loss occurred across all major ecoregions of Texas, with an average loss of 9.5%. The drought had the highest impact in post oak woodlands, pinyon-juniper shrublands and Ashe juniper woodlands. Focusing on a 100-km by ~1,000-km transect spanning the State's fivefold east-west precipitation gradient (~1,500 to ~300 mm), we compared spatially explicit 2011 climatic anomalies to our canopy loss maps. Much of the canopy loss occurred in areas that passed specific climatic thresholds: warm season anomalies in mean temperature (+1.6 degrees C) and vapor pressure deficit (VPD, +0.66 kPa), annual percent deviation in precipitation (-38%), and 2011 difference between precipitation and potential evapotranspiration (-1,206 mm). Although similarly low precipitation occurred during the landmark 1950s drought, the VPD and temperature anomalies observed in 2011 were even greater. Furthermore, future climate data under the representative concentration pathway 8.5 trajectory project that average values will surpass the 2011 VPD anomaly during the 2070 2099 period and the temperature anomaly during the 2040-2099 period. Identifying vulnerable ecological systems to drought stress and climate thresholds associated with canopy loss will aid in predicting how forests will respond to a changing climate and how ecological landscapes will change in the near term. PMID- 28649769 TI - Higher rate of central nervous system involvement by flow cytometry than morphology in acute lymphoblastic leukemia. AB - INTRODUCTION: Central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is diagnosed traditionally by cytopathology (CP) of the cerebrospinal fluid (CSF). Role of flow cytometry (FC) to diagnose CNS involvement has not been extensively investigated. METHODS: We aimed to detect CNS involvement in 42 ALL patients (33 B-ALL, nine T-ALL) at diagnosis by FC and comparing it with CP and to correlate it with known risk factors for CNS disease like Lactate dehydrogenase (LDH). A receiver operating characteristic curve was used to determine the cutoff of LDH to predict CSF involvement. For the analysis of categorical/quantitative variables, Fisher's exact test was used. For the analysis of continuous variables, Mann-Whitney test was used. A P value of <.05 was taken as significant. RESULTS: CP and FC were positive in five (11.9%) and 11 patients (26.14%) respectively with FC detecting a significantly higher level of involvement (P=.001). All CP-positive cases were FC positive. A LDH value of >472 U/L had a sensitivity of 61% and specificity of 62.5% for diagnosis of CSF involvement by FC. CONCLUSIONS: CSF FC detects CNS disease in ALL patients at diagnosis at a rate double than CP alone and is statistically associated with an elevated LDH level. It should be incorporated in the evaluation of CSF to detect CNS involvement. PMID- 28649770 TI - Precepting nurse practitioner students: A new view-Results of two national surveys of nurse practitioner preceptors. AB - PURPOSE: The aim of two national studies was to identify characteristics of nurse practitioners (NPs) who precept and the benefits, incentives, and barriers associated with the NP preceptor role. METHODS: Stratified randomized sampling was used to invite a representative number of NPs from each state to participate in a 2015 survey and a follow-up survey in 2016. These descriptive, exploratory studies distributed electronic questionnaires to 5000 randomly selected NPs in the 2015 survey and 40,000 NPs in the 2016 survey. Responses from 10.9% (n = 548) and 9.9% (n = 3970), respectively, were analyzed. CONCLUSIONS: The findings show strong support among our NP colleagues to assist with educating future NPs. Several benefits, barriers, and motivators among stakeholders were identified that need to be considered when working with preceptors. IMPLICATIONS FOR PRACTICE: This study provides a basis for understanding the current climate in education when working with clinical preceptors. Many areas become apparent where NP education could enhance the experience for both the student and the preceptor. Educational settings need to consider preceptor time, issues with online learning, and the rise of specialty practices. Offering incentives linked to the most valued, positive aspects of the role and methods to overcome barriers should be explored. PMID- 28649771 TI - Evaluation of the Sysmex XN-550, a Novel Compact Haematology analyser from the XN L(r) series, compared to the XN-20 system. AB - INTRODUCTION: The XN-550 is a new, automated, compact, haematology analyser designed to generate a full blood count with a standard five-part white blood cell differential and an immature granulocyte count, as well as an optional reticulocyte and optical platelet (PLT) counts. The aim of the study was to evaluate the performance of the XN-550 and compare it to the established XN-20 system. METHODS: We evaluated the basic parameter and special measurement channels of the XN-550, using the XN-20 (which has a similar operating system), as a reference analyser. Precision, carry-over and throughput evaluations were performed. In addition, a total of 202 samples including normal controls and various pathological samples were studied for comparability. RESULTS: Good correlations with the reference analyser were obtained for all parameters except basophils. The XN-550 offers impedance and optical PLT counts and the latter showed a better correlation and less scatter than the impedance count and was comparable to the XN-20 fluorescent count at PLT counts <=40*109 /L. Precision was good, and no significant carry-over was detected. CONCLUSIONS: The XN-550 was simple and easy to use, while maintaining the good diagnostic sensitivity seen with high-range systems such as the XN-20, making this compact device suitable for near-patient services and smaller satellite laboratories. PMID- 28649772 TI - Luminescence Color Tuning from Blue to Near Infrared of Stable Luminescent Solid Materials Based on Bis-o-Carborane-Substituted Oligoacenes. AB - Aryl-substituted o-carboranes have shown highly efficient solid-state emission in previous studies. To demonstrate color tuning of the solid-state emission in an aryl-o-carborane-based system, bis-o-carborane-substituted oligoacenes were synthesized and their properties were systematically investigated. Optical and electrochemical measurements revealed efficient decreases in energy band gaps and lowest unoccupied molecular orbital (LUMO) levels by adding a number of fused benzene rings for the extension of pi-conjugation. As a consequence, bright solid state emission was observed in the region from blue to near infrared (NIR). Furthermore, various useful features were obtained from the modified o-carboranes as an optical material. The naphthalene derivatives exhibited aggregation-induced emission (AIE) and almost 100 % quantum efficiency in the crystalline state. Furthermore, it was shown that the tetracene derivative with NIR-emissive properties had high durability toward photo-bleaching under UV irradiation. PMID- 28649773 TI - Synthesis and pKa determination of new enantiopure dimethyl-substituted acridino crown ethers containing a carboxyl group: Useful candidates for enantiomeric recognition studies. AB - New enantiopure dimethyl-substituted acridino-18-crown-6 and acridino-21-crown-7 ethers containing a carboxyl group at position 9 of the acridine ring [(S,S)-8, (S,S)-9, (R,R)-10] were synthesized. The pKa values of the new crown ethers [(S,S)-8, (S,S)-9, (R,R)-10] and of an earlier reported macrocycle [(R,R)-2] were determined by UV-pH titrations. Crown ether (S,S)-8 was attached to silica gel by covalent bonds and the enantiomeric separation ability of the newly prepared chiral stationary phase [(S,S)-CSP-12] was studied by high-performance liquid chromatography (HPLC). Homochiral preference was observed and the best separation was achieved for the enantiomers of 1-NEA. Ligands (S,S)-9 and (R,R)-10 are precursors of enantioselective sensor and selector molecules for the enantiomers of protonated primary amines, amino acids, and their derivatives. PMID- 28649774 TI - Osteoradionecrosis of the jaws: definition, epidemiology, staging and clinical and radiological findings. A concise review. AB - Osteoradionecrosis (ORN) of the jaws is a pernicious complication of radiation therapy for head and neck tumours. This article aims to provide an update on data related to the definition, epidemiology, staging, and clinical and radiological findings of ORN of the jaws. Using certain keywords, an electronic search was conducted spanning the period from January 1922 to April 2014 to identify the available related investigations. Pooled data were then analysed. ORN is described as exposed irradiated bone that fails to heal over a period of 3 months without evidence of persisting or recurrent tumour. The prevalence of ORN varies in the literature. Several staging or scoring systems of ORN have been proposed. Clinical findings include ulceration or necrosis of the mucosa with exposure of necrotic bone. Radiological findings are not evident in the early stages of ORN. Furthermore ORN may not be apparent in imaging even when the disease is advanced. Taking into account the severity of ORN and the difficulties in diagnosing it early and accurately, the clinician should be aware of this complex entity in order to prevent its appearance or the development of more severe complications. PMID- 28649775 TI - Authors' reply re: Intrauterine balloon tamponade for management of severe postpartum haemorrhage in a perinatal network: a prospective cohort study. PMID- 28649777 TI - Organization of the catecholaminergic systems in the brain of lungfishes, the closest living relatives of terrestrial vertebrates. AB - Lungfishes are a group of sarcopterygian fishes currently considered the closest living relatives of tetrapods, and represent an interesting group for the study of evolutionary traits in the transition from fishes to tetrapods. Catecholaminergic systems in the brain are among the most carefully analyzed neurotransmitter systems in the brain of most vertebrate groups. Their organization shows major shared characteristics, although traits particular to each vertebrate class have also been found, primarily between anamniotes and amniotes. Given the relevance of lungfishes in evolutionary terms, the present study provides the first comprehensive and detailed map of the catecholaminergic structures in the brain of two representative species of lungfishes, an African lungfish (Protopterus dolloi) and the Australian lungfish (Neoceratodus forsteri), as revealed by immunohistochemistry. Distinct groups of catecholaminergic cells were observed in the olfactory bulb, pallium, and preoptic area of the telencephalon, and the subpallium is devoid of these cells. Hypothalamic and diencephalic groups were detected and, in particular, the dopaminergic nucleus of the periventricular organ was evidenced with dopamine antibodies but not with anti-tyrosine hydroxylase. A well developed mesostriatal system was revealed formed by conspicuous groups of dopamine cells in the midbrain tegmentum and profuse innervation of the subpallium. Comparison of these results with those from other classes of vertebrates shows numerous common traits shared by most groups and also highlights particular features in lungfishes different from actinopterygian fishes that resemble those of amphibians and amniotes. PMID- 28649778 TI - Granuloma faciale associated with IgG4-related disease. PMID- 28649776 TI - Improving the baculovirus expression vector system with vankyrin-enhanced technology. AB - The baculovirus expression vector system (BEVS) is a widely used platform for the production of recombinant eukaryotic proteins. However, the BEVS has limitations in comparison to other higher eukaryotic expression systems. First, the insect cell lines used in the BEVS cannot produce glycoproteins with complex-type N glycosylation patterns. Second, protein production is limited as cells die and lyse in response to baculovirus infection. To delay cell death and lysis, we transformed several insect cell lines with an expression plasmid harboring a vankyrin gene (P-vank-1), which encodes an anti-apoptotic protein. Specifically, we transformed Sf9 cells, Trichoplusia ni High FiveTM cells, and SfSWT-4 cells, which can produce glycoproteins with complex-type N-glycosylation patterns. The latter was included with the aim to increase production of glycoproteins with complex N-glycans, thereby overcoming the two aforementioned limitations of the BEVS. To further increase vankyrin expression levels and further delay cell death, we also modified baculovirus vectors with the P-vank-1 gene. We found that cell lysis was delayed and recombinant glycoprotein yield increased when SfSWT-4 cells were infected with a vankyrin-encoding baculovirus. A synergistic effect in elevated levels of recombinant protein production was observed when vankyrin expressing cells were combined with a vankyrin-encoding baculovirus. These effects were observed with various model proteins including medically relevant therapeutic proteins. In summary, we found that cell lysis could be delayed and recombinant protein yields could be increased by using cell lines constitutively expressing vankyrin or vankyrin-encoding baculovirus vectors. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1496-1507, 2017. PMID- 28649779 TI - An integrated framework to identify wildlife populations under threat from climate change. AB - Climate change is a major threat to global biodiversity that will produce a range of new selection pressures. Understanding species responses to climate change requires an interdisciplinary perspective, combining ecological, molecular and environmental approaches. We propose an applied integrated framework to identify populations under threat from climate change based on their extent of exposure, inherent sensitivity due to adaptive and neutral genetic variation and range shift potential. We consider intraspecific vulnerability and population-level responses, an important but often neglected conservation research priority. We demonstrate how this framework can be applied to vertebrates with limited dispersal abilities using empirical data for the bat Plecotus austriacus. We use ecological niche modelling and environmental dissimilarity analysis to locate areas at high risk of exposure to future changes. Combining outlier tests with genotype-environment association analysis, we identify potential climate-adaptive SNPs in our genomic data set and differences in the frequency of adaptive and neutral variation between populations. We assess landscape connectivity and show that changing environmental suitability may limit the future movement of individuals, thus affecting both the ability of populations to shift their distribution to climatically suitable areas and the probability of evolutionary rescue through the spread of adaptive genetic variation among populations. Therefore, a better understanding of movement ecology and landscape connectivity is needed for predicting population persistence under climate change. Our study highlights the importance of incorporating genomic data to determine sensitivity, adaptive potential and range shift potential, instead of relying solely on exposure to guide species vulnerability assessments and conservation planning. PMID- 28649780 TI - Therapeutic efficacy and safety of oral tranexamic acid and that of tranexamic acid local infiltration with microinjections in patients with melasma: a comparative study. AB - BACKGROUND: Tranexamic acid (TXA) has been used orally, intravenously, topically and intradermally (microinjection, microneedling) for treating melasma. However, the comparative efficacy of these different routes of administration remains underevaluated. AIM: To ascertain the comparative efficacy of different routes of administration of TXA. METHODS: In total, 100 consecutive patients with melasma (8 men, 92 women, age range 18-55 years) were randomly assigned to one of two groups comprising 50 patients each. Group A (3 men, 47 women) received oral TXA 250 mg twice daily, while group B (5 men, 45 women) received intradermal microinjections of TXA 4 mg/mL every 4 weeks. The treatment continued for 12 weeks in both groups. Percentage reduction in baseline Melasma Area and Severity Index (MASI) was assessed at 4-week intervals, and response was scored as very good (> 75% reduction), good (50% to < 75% reduction), moderate (25% to < 50% reduction), mild (< 25% reduction) or no response. RESULTS: The study was completed by 39 patients in group A and 41 patients in group B. Very good response was seen in 25 and 32 patients in groups A and B, respectively, while good response was seen in 14 and 9 patients, respectively. Both treatment methods were equally effective, with an average reduction of MASI at 12 weeks of 77.96 +/ 9.39 in group A and 79.00 +/- 9.64 in group B. The main adverse effects were mild epigastric discomfort, hypomenorrhea, headache and injection site pain, which did not warrant discontinuation of treatment. Two patients in group A had relapses at 24 weeks. CONCLUSION: TXA appears to be an effective and safe treatment for melasma, irrespective of its route of administration. PMID- 28649781 TI - Anti-D reagents should be chosen accordingly to the prevalence of D variants in the obstetric population. AB - BACKGROUND: Resolving ambiguous results of D antigen typing is crucial for appropriate and rational administration of anti-D immunoprophylaxis and transfusion practice in obstetric population. The aim of the study was to establish selection criteria of anti-D reagents for our population. METHODS: A total of 12 689 samples from primiparous women in Split-Dalmatia County, Croatia, were typed for RhD antigen during the period of 5 years. Ambiguous results were submitted to additional serologic investigation and genotyping. RHD genotyping was performed by commercial genotyping kits (Ready Gene weak D (r) and Ready gene CDE, Inno-Train, Kronberg, Germany). Relative frequencies and accompanying 95% confidence intervals were used to estimate the prevalence of variants. RESULTS: The prevalence of D variants was 0.42% (95% CI 0.31; 0.53). The most common partial D variant was D Va (RHD*05.05), with the prevalence of 0.08% (95% CI 0.03; 0.13). All weak D variants were weak D types 1, 2 and 3 (RHD*weak D type 1, RHD*weak D type 2, RHD*weak D type 3). Weak D samples were distinguishable from partial D in routine typing due to the difference in reactivity of partial D samples with clones D7B8 and RUM-1. Cell line RUM-1 gives weak or negative reactions with partial DVa category. CONCLUSION: The most common partial D variant in our population is DVa. It is recommended to use cell lines which do not strongly agglutinate DVa variant in routine RhD typing. The appropriate choice of reagents will enable the serology methods to recognize the cases in which RHD genotyping is required. PMID- 28649783 TI - Water and Carbon Dioxide: A Unique Solvent for the Catalytic Polymerization of Ethylene in Miniemulsion. AB - The catalytic polymerization of ethylene is performed in water pressurized with CO2 . The size of the initial monomer droplets and of the resulting polymer particles can be varied by simply changing the CO2 pressure. Furthermore, at identical ethylene partial pressure, the polymerizations performed in the presence of CO2 are significantly faster than in its absence. Thus, the combination of CO2 and water is a promising green solvent for catalytic emulsion polymerizations. PMID- 28649784 TI - Allogeneic hematopoietic stem cell transplantation in congenital disorders: A single-center experience. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for a variety of congenital disorders. We report the experience of children affected by congenital diseases other than bone marrow failure syndromes who received allo-HSCT over a period of 25 years at G. Gaslini Paediatric Research Institute. HSCTs were performed in 57 children with congenital diseases (25 with congenital immunodeficiencies, 10 with severe combined immunodeficiencies, and 22 with metabolic diseases). Overall survival rate at 3 years in the whole group of patients was 76.9%, with a trend in favor of better outcome in children with metabolic diseases and in those who received cord blood cells (85.9%) vs bone marrow cells (72.4%). PMID- 28649785 TI - StaRI Aims to Overcome Knowledge Translation Inertia: The Standards for Reporting Implementation Studies Guidelines. PMID- 28649782 TI - Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. AB - Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder. PMID- 28649786 TI - Polypharmacy and Gait Performance in Community-dwelling Older Adults. AB - OBJECTIVES: To examine the relationship between polypharmacy and gait performance during simple (normal walk (NW)) and complex (walking while talking (WWT)) locomotion. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Community dwelling older adults (N = 482). MEASUREMENTS: Polypharmacy, defined as use of five or more medications and a cohort-specific alternate definition of eight or more medications, was examined. Velocity (cm/s) measured quantitatively during NW and WWT conditions. RESULTS: The 164 participants (34%) with polypharmacy of five or more medications were older (77.0 +/- 6.6 vs 76.0 +/- 6.4) and more likely to have hypertension, congestive heart failure, diabetes mellitus, myocardial infarction, and higher body mass index (BMI) and to have fallen within the last year than the remaining 318 without polypharmacy and walked 6 cm/s slower (P = .004) during NW and 4 cm/s slower during WWT (P = .07), adjusting for age, sex, and education. Group differences were not statistically significant after adjusting for comorbidities. Prevalence of polypharmacy of eight or more medications was 10%. This group walked 11 cm/s slower during NW (P < .001) and 8.6 cm/s slower during WWT (P = .01) than those without polypharmacy, adjusted for age, sex, and education. Participants taking eight or more medications had slower NW (8.5 cm/s; P = .01), and WWT (6.9 cm/s; P = .07), compared to those without polypharmacy, adjusting for comorbidities. Adjustments for BMI, high-risk drugs, falls, and comorbidities yielded slower NW (9.4 cm/s, P = .005) and WWT (7.9 cm/s, P = .04 among those with polypharmacy compared to those without polypharmacy). CONCLUSION: These results suggest an association between polypharmacy and locomotion that medical comorbidities only partly explained. PMID- 28649787 TI - Delays in breast cancer diagnosis after a state policy limiting Medicaid enrollment. PMID- 28649788 TI - Pharmacokinetics and dynamics of mycophenolate mofetil after single-dose oral administration in juvenile dachshunds. AB - Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young-aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose-bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole-blood mitogen-stimulated T-cell proliferation was determined using a flow cytometric assay. Plasma MPA Cmax (mean +/- SD, 9.33 +/- 7.04 MUg/ml) occurred at <1 hr. The AUC0-infinity (mean +/- SD, 12.84+/-6.62 hr*MUg/ml), MRTinf (mean +/- SD, 11.09 +/- 9.63 min), T1/2 (harmonic mean +/- PseudoSD 5.50 +/- 3.80 min), and k/d (mean +/- SD, 0.002 +/- 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets. PMID- 28649790 TI - Safety of a benazepril and pimobendan combination tablet in adult healthy dogs. AB - The objective of the study was to investigate the safety of a combination tablet of benazepril and pimobendan, Fortekor PLUS(r) , in a randomized, blinded, parallel-group design study in healthy adult beagle dogs. The test article, Fortekor PLUS(r) tablets, was administered orally twice daily for 6 months at one, two, and four times the highest recommended dosage of 0.5 mg/kg benazepril hydrochloride/0.25 mg/kg pimobendan (four males and four females per group). An additional control group was sham-dosed. Fortekor PLUS(r) did not induce any treatment-related effects on body weight, food consumption, neurological, ophthalmologic or physical assessments over the 6-month treatment period. The test article was possibly associated with an increased frequency of occasional vomiting. Fortekor PLUS(r) was associated with small, but significant, increases in heart rate and reductions in PR and QT intervals, which were assessed by electrocardiography. These effects were most probably related to reflex tachycardia secondary to reduced systemic blood pressure. Statistically significant changes in some clinical pathology variables were noted after test article administration, but were considered to be of no clinical relevance as values remained within reference ranges and/or were not dose-dependent. No treatment-related macroscopic or microscopic findings were observed. In conclusion, Fortekor PLUS(r) tablets were well tolerated in healthy adult dogs when administered at one, two, and four times the highest recommended dosage for 6 months. PMID- 28649792 TI - Corrigendum: miR-126-3p Promotes Matrix-Dependent Perivascular Cell Attachment, Migration and Intercellular Interaction. PMID- 28649789 TI - Beyond MITF: Multiple transcription factors directly regulate the cellular phenotype in melanocytes and melanoma. AB - MITF governs multiple steps in the development of melanocytes, including specification from neural crest, growth, survival, and terminal differentiation. In addition, the level of MITF activity determines the phenotype adopted by melanoma cells, whether invasive, proliferative, or differentiated. However, MITF does not act alone. Here, we review literature on the transcription factors that co-regulate MITF-dependent genes. ChIP-seq studies have indicated that the transcription factors SOX10, YY1, and TFAP2A co-occupy subsets of regulatory elements bound by MITF in melanocytes. Analyses at single loci also support roles for LEF1, RB1, IRF4, and PAX3 acting in combination with MITF, while sequence motif analyses suggest that additional transcription factors colocalize with MITF at many melanocyte-specific regulatory elements. However, the precise biochemical functions of each of these MITF collaborators and their contributions to gene expression remain to be elucidated. Analogous to the transcriptional networks in morphogen-patterned tissues during embryogenesis, we anticipate that the level of MITF activity is controlled not only by the concentration of activated MITF, but also by additional transcription factors that either quantitatively or qualitatively influence the expression of MITF-target genes. PMID- 28649791 TI - Bioactivity and biomineralization ability of calcium silicate-based pulp-capping materials after subcutaneous implantation. AB - AIM: To evaluate the abilities of three calcium silicate-based pulp-capping materials (ProRoot MTA, TheraCal LC and a prototype tricalcium silicate cement) to produce apatite-like precipitates after being subcutaneously implanted into rats. METHODOLOGY: Polytetrafluoroethylene tubes containing each material were subcutaneously implanted into the backs of Wistar rats. At 7, 14 and 28 days post implantation, the implants were removed together with the surrounding connective tissue, and fixed in 2.5% glutaraldehyde in cacodylate buffer. The chemical compositions of the surface precipitates formed on the implants were analysed with scanning electron microscopy-electron probe microanalysis (SEM-EPMA). The distributions of calcium (Ca) and phosphorus (P) at the material-tissue interface were also analysed with SEM-EPMA. Comparisons of the thicknesses of the Ca- and P rich areas were performed using the Friedman test followed by Scheffe's test at a significant level of 5%. RESULTS: All three materials produced apatite-like surface precipitates containing Ca and P. For each material, elemental mapping detected a region of connective tissue in which the concentrations of Ca and P were higher than those in the surrounding connective tissue. The thickness of this Ca- and P-rich region exhibited the following pattern: ProRoot MTA > prototype tricalcium silicate cement >= TheraCal LC. ProRoot MTA had a significantly thicker layer of Ca and P than the other materials at all time points (P < 0.05), and a significant difference was detected between the prototype cement and TheraCal LC at 28 days (P < 0.05). CONCLUSION: After being subcutaneously implanted, all of the materials produced Ca- and P-containing surface precipitates and a Ca- and P-rich layer within the surrounding tissue. The thickness of the Ca- and P-rich layer of ProRoot MTA was significantly thicker than that of the other materials. PMID- 28649793 TI - Characteristics of acute groin injuries in the hip flexor muscles - a detailed MRI study in athletes. AB - Hip flexor injuries account for one-third of acute groin injuries; however, little is known about specific injury characteristics. The aims of this study were to describe acute hip flexor injuries using magnetic resonance imaging (MRI) in athletes with acute groin pain and to compare specific muscle injuries with reported injury situations. Male athletes with acute groin pain were prospectively and consecutively included during three sports seasons. MRI was performed within 7 days of injury using a standardized protocol and a reliable assessment approach. All athletes with an MRI confirmed acute hip flexor muscle injury were included. A total of 156 athletes presented with acute groin pain of which 33 athletes were included, median age 26 years (range 18-35). There were 16 rectus femoris, 12 iliacus, 7 psoas major, 4 sartorius, and 1 tensor fascia latae injury. Rectus femoris injuries primarily occurred during kicking (10) and sprinting (4), whereas iliacus injuries most frequently occurred during change of direction (5). In 10 (63%) rectus femoris injuries, tendinous injury was observed. The iliacus and psoas major injuries were mainly observed at the musculotendinous junction (MTJ), and two included tendinous injury. We have illustrated specific injury locations within these muscles, which may be relevant for the clinical diagnosis and prognosis of these injuries. Most proximal rectus femoris injuries included tendinous injury. In contrast, distinct acute iliacus and psoas injuries predominantly occurred at the MTJ. Only the iliacus or psoas major were injured during change of direction, whereas rectus femoris injuries occurred primarily during kicking and sprinting. PMID- 28649795 TI - Geometry-Retentive C-Alkenylation of Lithiated alpha-Aminonitriles: Quaternary alpha-Alkenyl Amino Acids and Hydantoins. AB - alpha-Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C-alkenylation on treatment with base by attack of the lithionitrile derivatives on the N'-alkenyl group. A geometry-retentive alkene shift affords stereospecifically the E or Z isomer of the 5-alkenyl-4 iminohydantoin products from the corresponding starting E- or Z-N'-alkenyl urea, each of which may be formed from the same N-allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp2 carbon atom, allows the direct regioselective incorporation of mono-, di-, tri-, and tetrasubstituted olefins at the alpha-carbon of amino acid derivatives. The initially formed 5-alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated alpha-quaternary amino acids. PMID- 28649797 TI - Powder Catalyst Fixation for Post-Electrolysis Structural Characterization of NiFe Layered Double Hydroxide Based Oxygen Evolution Reaction Electrocatalysts. AB - Highly active electrocatalysts for the oxygen evolution (OER) reaction are in most cases powder nanomaterials, which undergo substantial changes upon applying the high potentials required for high-current-density oxygen evolution. Owing to the vigorous gas evolution, the durability under OER conditions is disappointingly low for most powder electrocatalysts as there are no strategies to securely fix powder catalysts onto electrode surfaces. Thus reliable studies of catalysts during or after the OER are often impaired. Herein, we propose the use of composites made from precursors of polybenzoxazines and organophilically modified NiFe layered double hydroxides (LDHs) to form a stable and highly conducting catalyst layer, which allows the study of the catalyst before and after electrocatalysis. Characterization of the material by XRD, SEM, and TEM before and after 100 h electrolysis in 5 m KOH at 60 degrees C and a current density of 200 mA cm-2 revealed previously not observed structural changes. PMID- 28649794 TI - Inverse Opal Scaffolds and Their Biomedical Applications. AB - Three-dimensional porous scaffolds play a pivotal role in tissue engineering and regenerative medicine by functioning as biomimetic substrates to manipulate cellular behaviors. While many techniques have been developed to fabricate porous scaffolds, most of them rely on stochastic processes that typically result in scaffolds with pores uncontrolled in terms of size, structure, and interconnectivity, greatly limiting their use in tissue regeneration. Inverse opal scaffolds, in contrast, possess uniform pores inheriting from the template comprised of a closely packed lattice of monodispersed microspheres. The key parameters of such scaffolds, including architecture, pore structure, porosity, and interconnectivity, can all be made uniform across the same sample and among different samples. In conjunction with a tight control over pore sizes, inverse opal scaffolds have found widespread use in biomedical applications. In this review, we provide a detailed discussion on this new class of advanced materials. After a brief introduction to their history and fabrication, we highlight the unique advantages of inverse opal scaffolds over their non-uniform counterparts. We then showcase their broad applications in tissue engineering and regenerative medicine, followed by a summary and perspective on future directions. PMID- 28649796 TI - Lymph node yield in right colectomy for cancer: a comparison of open, laparoscopic and robotic approaches. AB - AIM: Studies have demonstrated a relationship between lymph node (LN) yield and survival after colectomy for cancer. The impact of surgical technique on LN yield has not been well explored. METHOD: This is a retrospective study of right colectomy (RC) for cancer at a single institution from 2012 to 2014. Exclusion criteria were previous colectomy and emergent and palliative operations. All data were collected by chart review. Primary outcomes were LN yield and the LN to length of surgical specimen (LN-LSS) ratio. Multivariable mixed models were created with surgeon and pathologist as random effects. Sensitivity analyses were performed to exclude Stage IV cancers and to analyse groups on an 'as-treated' basis. RESULTS: We identified 181 open (O-RC), 163 laparoscopic (L-RC) and 119 robotic (R-RC) right colectomies. O-RC was more commonly performed in women with metastatic disease. The mean LN yield was 28, 29 and 34 in O-RC, L-RC and R-RC, respectively; the respective mean LN-LSS ratios were 0.83, 0.91 and 1.0. The R-RC approach produced a higher LN yield than the other approaches (P < 0.01), and a higher LN-LSS ratio than O-RC (P < 0.01). These findings were unchanged in sensitivity analyses. CONCLUSION: Robotic right colectomy improves LN yield and the LN-LSS ratio, which may reflect better mesocolic excision. The effect of these findings on survival requires further investigation. PMID- 28649798 TI - Electrochemical Exfoliation of Layered Black Phosphorus into Phosphorene. AB - Among 2D materials that recently have attracted enormous interest, black phosphorus (BP) is gaining a rising popularity due to its tunable band-gap structure, which is strongly correlated to the thickness and can enable its use in optoelectronic and electronic applications. It is therefore important to provide a facile and scalable methodology to prepare single or few-layer BP nanosheets. We propose herein a simple and fast top-down method to exfoliate a BP crystal into nanosheets of reduced thickness by using electrochemistry. The application of an anodic potential to the crystal in an acidic aqueous solution allows control over the exfoliation efficiency and quality of the nanosheets produced. X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and scanning transmission electron microscopy (STEM) have been applied to fully characterize the exfoliated material, which presented significantly reduced layer thickness compared to the starting bulk material. PMID- 28649799 TI - Synthesis, evaluation of cytotoxic properties of promising curcumin analogues and investigation of possible molecular mechanisms. AB - Curcumin is a popular, plant-derived compound that has been extensively investigated for diverse range of biological activities. Anticancer activity against various types of cancers and high-safety profile associated with curcumin makes it very attractive. In this study, we report the synthesis and evaluation of pyrazole and click chemistry curcumin analogues for Head and Neck cancer. MTT assay against head and neck cancer cell lines CAL27 and UM-SCC-74A revealed the micromolar potency of the synthesized compounds. To determine the possible molecular mechanisms, effect of these analogues in the expression of pSTAT3, pFAK, pERK1/2 and pAKT was studied. Interestingly, compounds 2 and 5 significantly inhibited the pSTAT3 (Tyr 705) phosphorylation. As far as other compounds, they showed potent cytotoxicity against CAL27; however, these compounds did not show any activity on pSTAT3 phosphorylation at IC50 concentration level. Molecular docking studies revealed the possible binding mode of pyrazole compound 2 in the SH2 domain of STAT3. PMID- 28649801 TI - Vaccinia virus detection in dairy products made with milk from experimentally infected cows. AB - Vaccinia virus (VACV) is the agent of bovine vaccinia (BV), an emerging zoonosis that causes exanthematic lesions on the teats of dairy cows and on the hands of milkers. The virus has been detected in the milk of naturally infected cows. The objective of this study was to investigate and quantify VACV DNA as well as the presence of infectious virus particles in samples of cheese curd, cheese whey and pasteurized milk produced using milk from cows experimentally inoculated with VACV-GP2, a Brazilian isolate of VACV (VACV-BR). VACV DNA was detected in samples of cheese and pasteurized milk at different time points, even after the resolution of the typical lesions caused by VACV, which occurred after 22 days post-infection (dpi), on average. Moreover, it was possible to detect infectious viral particles in cheese samples on alternate days until 27 dpi. The presence of both VACV DNA and infectious viral particles in cheese samples throughout the clinical course of BV and even after the disappearance of the typical clinical signs of disease draws attention to the risk associated with consumption of the cheese. Furthermore, VACV-contaminated milk and cheese may represent an occupational risk to cheesemakers who often manipulate milk and cheese curd without wearing gloves. PMID- 28649800 TI - Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness. AB - Epithelial-mesenchymal transition (EMT) is an important process in embryonic development, fibrosis, and cancer metastasis. During cancer progression, the activation of EMT permits cancer cells to acquire migratory, invasive, and stem like properties. A growing body of evidence supports the critical link between EMT and cancer stemness. However, contradictory results have indicated that the inhibition of EMT also promotes cancer stemness, and that mesenchymal-epithelial transition, the reverse process of EMT, is associated with the tumor-initiating ability required for metastatic colonization. The concept of 'intermediate-state EMT' provides a possible explanation for this conflicting evidence. In addition, recent studies have indicated that the appearance of 'hybrid' epithelial mesenchymal cells is favorable for the establishment of metastasis. In summary, dynamic changes or plasticity between the epithelial and the mesenchymal states rather than a fixed phenotype is more likely to occur in tumors in the clinical setting. Further studies aimed at validating and consolidating the concept of intermediate-state EMT and hybrid tumors are needed for the establishment of a comprehensive profile of cancer metastasis. PMID- 28649803 TI - First detection of porcine circovirus type 3 on commercial pig farms in Poland. AB - Porcine circovirus type 3 (PCV3) is a novel circovirus species recently discovered in USA and China in cases of porcine dermatitis and nephropathy syndrome, reproductive failure, respiratory disease and multisystemic inflammation. This study reports on the first identification of PCV3 in Europe, in serum from pigs from Polish farms. A total of 1,050 serum samples were collected between 2014 and 2017 from sows and 3-20 weeks old pigs from 14 commercial farms representing different regions of Poland, different size and health status. The samples were pooled by 4-6 and tested with real-time PCR for PCV3. PCV3 DNA was detected in 12 of 14 farms (85.7%). On the PCV3-positive farms, the virus was detected in 5.9% to 65% serum pools. PCV3 was most common among weaned pigs and finishers (26.1% and 28.0% of serum pools, respectively). Sequence analysis of 359 nucleotide fragment of ORF2 showed highest identity of 99.7% to PCV3-US/SD2016 from USA. Our results indicate that PCV3 is a common virus among Polish pigs but no links to unexplained disease conditions were established. PMID- 28649802 TI - Punctal occlusion for dry eye syndrome. AB - BACKGROUND: Dry eye syndrome is a disorder of the tear film that is associated with symptoms of ocular discomfort. Punctal occlusion is a mechanical treatment that blocks the tear drainage system in order to aid in the preservation of natural tears on the ocular surface. OBJECTIVES: To assess the effects of punctal plugs versus no punctal plugs, different types of punctal plugs, and other interventions for managing dry eye. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 11), MEDLINE Ovid (1946 to 8 December 2016), Embase.com (1947 to 8 December 2016), PubMed (1948 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com; last searched 18 November 2012 - this resource is now archived), ClinicalTrials.gov (www.clinicaltrials.gov; searched 8 December 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en; searched 8 December 2016). We did not use any date or language restrictions in the electronic searches for trials. We also searched the Science Citation Index-Expanded database and reference lists of included studies. The evidence was last updated on 8 December 2016 SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials of collagen or silicone punctal plugs in symptomatic participants diagnosed with aqueous tear deficiency or dry eye syndrome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study investigators for additional information when needed. MAIN RESULTS: We included 18 trials (711 participants, 1249 eyes) from Austria, Canada, China, Greece, Japan, Mexico, Netherlands, Turkey, the UK, and the USA in this review. We also identified one ongoing trial. Overall we judged these trials to be at unclear risk of bias because they were poorly reported. We assessed the evidence for eight comparisons.Five trials compared punctal plugs with no punctal plugs (control). Three of these trials employed a sham treatment and two trials observed the control group. Two trials did not report outcome data relevant to this review. There was very low-certainty evidence on symptomatic improvement. The three trials that reported this outcome used different scales to measure symptoms. In all three trials, there was little or no improvement in symptom scores with punctal plugs compared with no punctal plugs. Low-certainty evidence from one trial suggested less ocular surface staining in the punctal plug group compared with the no punctal plug group however this difference was small and possibly clinically unimportant (mean difference (MD) in fluorescein staining score -1.50 points, 95% CI -1.88 to -1.12; eyes = 61). Similarly there was a small difference in tear film stability with people in the punctal plug group having more stability (MD 1.93 seconds more, 95% CI 0.67 to 3.20; eyes = 28, low certainty evidence). The number of artificial tear applications was lower in the punctal plug group compared with the no punctal plugs group in one trial (MD 2.70 applications, 95% CI -3.11 to -2.29; eyes = 61, low-certainty evidence). One trial with low-certainty evidence reported little or no difference between the groups in Schirmer scores, but did not report any quantitative data on aqueous tear production. Very low-certainty evidence on adverse events suggested that events occurred reasonably frequently in the punctal plug group and included epiphora, itching, tenderness and swelling of lids with mucous discharge, and plug displacement.One trial compared punctal plugs with cyclosporine (20 eyes) and one trial compared punctal plugs with oral pilocarpine (55 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.Five trials compared punctal plugs with artificial tears. In one of the trials punctal plugs was combined with artificial tears and compared with artificial tears alone. There was very low-certainty evidence on symptomatic improvement. Low-certainty evidence of little or no improvement in ocular surface staining comparing punctal plugs with artificial tears (MD right eye 0.10 points higher, 0.56 lower to 0.76 higher, MD left eye 0.60 points higher, 0.10 to 1.10 higher) and low-certainty evidence of little or no difference in aqueous tear production (MD 0.00 mm/5 min, 0.33 lower to 0.33 higher)Three trials compared punctal plugs in the upper versus the lower puncta, and none of them reported the review outcomes at long-term follow-up. One trial with very low-certainty evidence reported no observed complications, but it was unclear which complications were collected.One trial compared acrylic punctal plugs with silicone punctal plugs and the trial reported outcomes at approximately 11 weeks of follow-up (36 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.One trial compared intracanalicular punctal plugs with silicone punctal plugs at three months follow-up (57 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.Finally, two trials with very low-certainty evidence compared collagen punctal plugs versus silicone punctal plugs (98 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision. AUTHORS' CONCLUSIONS: Although the investigators of the individual trials concluded that punctal plugs are an effective means for treating dry eye signs and symptoms, the evidence in this systematic review suggests that improvements in symptoms and commonly tested dry eye signs are inconclusive. Despite the inclusion of 11 additional trials, the findings of this updated review are consistent with the previous review published in 2010. The type of punctal plug investigated, the type and severity of dry eye being treated, and heterogeneity in trial methodology confounds our ability to make decisive statements regarding the effectiveness of punctal plug use. Although punctal plugs are believed to be relatively safe, their use is commonly associated with epiphora and, less commonly, with inflammatory conditions such as dacryocystitis. PMID- 28649804 TI - Fibroblast-derived exosomes promote epithelial cell proliferation through TGF beta2 signalling pathway in severe asthma. AB - BACKGROUND: Bronchial fibroblasts play a key role in airway remodelling in asthma. They regulate epithelial cell functions such as proliferation through growth factors, cytokines, chemokines and exosomes. The role of exosomes in the communication between epithelial cells and fibroblasts by vehiculing these mediators in asthma remains to be determined. OBJECTIVE: To evaluate the role of exosomes released by bronchial fibroblasts on epithelial cell proliferation in severe asthma. METHODS: Exosomes were obtained from culture media of primary bronchial fibroblasts and characterized using Western blot, electron microscopy and flow cytometry. Uptake profile of fluorescent-labelled exosomes in epithelial cells was assessed by flow cytometry. Exosome cytokine content was analysed by Cytokine Arrays. Bronchial epithelial cell proliferation was evaluated by BrdU incorporation test. Exosome biogenesis/release was blocked using sphingomyelinase inhibitor. Plasmid transfection was used to modulate transforming growth factor beta 2 (TGF-beta2) gene expression. RESULTS: We showed that bronchial fibroblasts secreted exosomes, which were internalized by bronchial epithelial cells. Exosomes of severe asthmatic subjects' fibroblasts showed a lower level of TGF beta2 and significantly increased the epithelial cell proliferation of both healthy and severe asthmatic subjects compared to healthy controls' exosomes. Overexpression of TGF-beta2 in severe asthmatics' fibroblasts induced enhanced TGF-beta2 in exosomes leading to a reduced proliferation of epithelial cells, whereas knockdown of TGF-beta2 enhanced epithelial cell proliferation. CONCLUSION: Our study shows that exosomes are involved in fine-tuning intercellular communication in asthma. Exosomes of severe eosinophilic asthmatics' fibroblasts can contribute to airway remodelling, at least in part, by modulating epithelial cell proliferation observed in severe asthma. PMID- 28649805 TI - Cross-country skiing movement factorization to explore relationships between skiing economy and athletes' skills. AB - We investigated the relationships between the biomechanics of the double poling (DP) technique in cross-country skiing, its economy, and athletes' skill. To this aim, skiers' motion has been factorized into components through principal component analysis (PCA). Eight high-level (HL) and eight regional level (RL) male cross-country skiers performed a 5-minute submaximal DP trial while roller skiing on a treadmill at 14 km h-1 and 2 degrees incline. Whole-body kinematics was recorded with a motion capture system. PCA was applied to markers coordinates to extract principal movements (PMk ), which were ranked by their variance. Energy cost (EC) of locomotion was calculated from ergospirometric measurements. Results showed that 96.7%+/-0.6% of total skiing pattern variance can be described with the first three PMk. (Shoulder and trunk flexion-extension are described PM1 and PM2 and elbow flexion-extension are mainly represented in PM2 and PM3. The variance of further components, consisting of residual movements (eg, slow postural changes or high-frequency vibrations), was greater for the RL than the HL skiers (4.0%+/-0.5% vs 2.6%+/-0.3%; P<.001) and was positively correlated with EC (R2 =.646; P<.001). PCA permitted to describe the biomechanics of the DP technique through a limited set of principal movements. Skiing skills and economy appeared to be related to a skier's ability to simplify movement complexity, suggesting that an efficient skier is better able to reduce superfluous movement components during DP. PMID- 28649806 TI - Structure of Amorphous Selenium by 2D 77 Se NMR Spectroscopy: An End to the Dilemma of Chain versus Ring. AB - Amorphous selenium, owing to its tremendous technological importance and perhaps to its chemical simplicity, has been studied for nearly a century and yet an unequivocal structural description of this material remains lacking to date. The primary controversy regarding the structure of amorphous Se relates to the relative fraction of Se atoms residing in infinity1Se chains versus in Se8 rings. Herein we present the results of a two-dimensional solid-state 77 Se nuclear magnetic resonance (NMR) spectroscopic study of the chain and ring crystalline allotropes of Se as well as of amorphous Se to unequivocally demonstrate that 1) the Se8 rings and the infinity1Se chains are characterized by their unique 77 Se NMR signatures and 2) the structure of amorphous Se consists exclusively of infinity1Se chains. PMID- 28649809 TI - Methods used in Pharmaceutical Technology to Increase Bioavailability of Poorly Soluble Drugs after Oral Administration. AB - Bioavailability increasing of poorly soluble drugs has become one of the main topics of modern pharmaceutical technology. Many methods based on the chemical modification, physical modification or new technological processes have been already used to improve bioavailability. Some of these methods (e.g. micronization, preparation of solid dispersions, formulation of an inclusion complex, etc.) have been for many years successfully used by pharmaceutical companies. On the other hand, methods such as liquisolid system and self emulsifying drug delivery systems are still in the early stages of their development. It is expected that this novel methods could play a significant role in the preparation of modern dosage forms. The aim of this paper is to provide the summary of methods improving bioavailability of poorly soluble drugs used in the field of pharmaceutical technology. PMID- 28649807 TI - MicroRNA-196 Regulates HOX Gene Expression in Human Gluteal Adipose Tissue. AB - OBJECTIVE: Lower body fat is associated with diminishing cardiometabolic risk. Physiological differences between gluteofemoral and abdominal subcutaneous adipocyte functions are known, but the molecular basis for depot differences in adipocyte function is poorly understood. The objective of this study was to identify depot differences in microRNA (miRNA) expression in human abdominal and gluteofemoral subcutaneous adipose tissues and their implication in gene regulation. METHODS: Abdominal and gluteofemoral adipose tissue aspirates obtained from 18 participants (9 male and 9 female, age 30 +/- 1.5 y, BMI 27.3 +/ 1.23 kg/m2 ) were analyzed for miRNA expression profiles by next-generation DNA sequencing. The raw reads were mapped to miRBase 17, and differentially expressed miRNAs were confirmed by qRT-PCR. The hsa-mimic-miR196a was transfected into cultured abdominal preadipocytes isolated from five women with obesity. Target gene expression was evaluated by RT-qPCR. RESULTS: Among the 640 miRNAs detected in adipose tissue, miR196a2, miR196a1, miR196b, and miR204 showed a higher expression in the gluteofemoral depot (fold change = 2.7, 2.3, 1.7, and 2.3, respectively) independent of sex. Bioinformatic analyses and human primary preadipocyte transfection with miR196 suggested that the differentially expressed miRNAs could directly or indirectly modulate homeobox (HOX) gene expression. CONCLUSIONS: The miR196 gene family could play an important role in the regulation of HOX gene expression in subcutaneous adipose tissue and in fat distribution variation. PMID- 28649808 TI - Development of a real-time loop-mediated isothermal amplification assay for detection of Burkholderia mallei. AB - Burkholderia mallei is the aetiological agent of glanders, a highly contagious and re-emerging zoonotic disease. Early diagnosis of glanders is critically important to ensure timely treatment with appropriate antibiotics in humans, and to prevent spread of infection in animals. Molecular detection of B. mallei has always been troublesome because of its genetic similarity with Burkholderia pseudomallei, the causative agent of melioidosis. In present investigation, a set of six B. mallei-specific primers were designed and a simple, rapid, specific and sensitive real-time loop-mediated isothermal amplification (LAMP) assay was developed for detection of B. mallei. The LAMP assay could detect as low as 1 pg of B. mallei genomic DNA and 5.5 * 103 CFU/ml of B. mallei in spiked human blood. The assay was highly specific for B. mallei as it did not cross-react with other bacterial strains used in the study. The established LAMP assay is field adaptable and can be a better and viable alternative to PCR-based techniques for detection of B. mallei in glanders endemic areas with resource-limited settings. PMID- 28649810 TI - Drugs and Health Care Expenditure on the Aging Population. AB - The aim of this article is to identify the main factors that affect future trends in healthcare expenditures from the perspective of the anticipated ageing of the population. Attention shall be focused on the elderly demography, the inhabitants' pensions and their expenditures on drugs. The article also shows the results of acase study concerning the use of particular types of drugs by elderly people in the Czech Republic and in European union. For the purpose of this article, Iemployed aliterature search method that uses available sources describing the determinants of public healthcare expenditure and the use of selected types of drugs by the ageing population. The current situation in EU Member Countries is addressed through an analysis of public expenditure using data from public databases, such as Eurostat or OECD. The types of drugs designed for the ageing population are focused on the Czech Republic. It follows from the executed analysis that the basic determinants of public healthcare expenditure are the demographic structure, income, the legislative conditions and productivity. The aim of effective public health care spending should not only be to achieve ahigher age, but also to enable the inhabitants to prolong the period of their work productivity and self-sufficiency. Aging population defines market opportunities open to companies from various sectors. PMID- 28649812 TI - Drug Bioavailability Increasing by Formulation of Liquisolid Systems. PMID- 28649811 TI - Level and Factors Influencing the Patient's Satisfaction with the Pharmaceutical Care in Slovakia. AB - The patients' satisfaction is an integral component of the provided pharmaceutical care and afactor affecting its quality. This study gives an assessment of the patients' satisfaction with the pharmaceutical care provided by the community pharmacists in Slovakia and it identifies the factors influencing it. Atotal of 2,844 respondents from 33 community pharmacies in 23 different Slovak towns took part in the first Slovak nationwide survey during the period from October to December 2013. The survey used amodified and validated questionnaire containing 29 items from three dimensions of pharmaceutical care (Managing Therapy, Interpersonal Relationship, General Satisfaction). The results are presented in percentages and by the level of satisfaction within the following range level: positive evaluation (score 1.00 to 2.50), neutral evaluation (score 2.51 to 3.50) and negative evaluation (score 3.51 to 5.00) based on the calculated average scores from the Likert scale, which is used to express the satisfaction of respondents (1 - very satisfied, 2 - satisfied, 3 - neither satisfied, nor dissatisfied, 4 - dissatisfied, 5 - very dissatisfied). The survey showed high patients' satisfaction with the pharmaceutical care provided by community pharmacists in Slovakia. The evaluation of all three dimensions was positive (scores ranged from 1.85 to 2.24). The proportion of respondents with positive assessments was at the least 65.4% and at the most 86.7%. Interpersonal Relationship was the most positively assessed dimension (score 1.85 +/- 0.598; 86.7% of respondents reached positive evaluation, 12.3% neutral and 1.0% negative evaluation) followed by General Satisfaction (score of 2.02 +/- 0.643; 71.3% of respondents reached positive evaluation, 26.5% neutral and 2.2% negative evaluation). Managing Therapy was the least positively evaluated dimension (score 2.24 +/- 0.704; 65.4% of respondents reached positive evaluation, 31.1% neutral and 3.5% negative evaluation). Age, level of education, number of patronized pharmacies, number of medicines, financial expenses in pharmacies and the region had astatistically significant impact on the evaluation of the patients' satisfaction in all three dimensions (p < 0.001). Gender had no statistically significant effect on satisfaction rating in either of the monitored dimensions (Managing Therapy p = 0,17; Interpersonal Relationship p = 0.002; General Satisfaction p = 0.022). Long-term use of medicines had no significant effect on satisfaction in Managing Therapy (p = 0.170), either. The evaluation of the patients' satisfaction requires further improvement and the analysis of the influence of identified factors which can determine it. PMID- 28649813 TI - Evaluation of Compressibility of Tableting Mixtures Using the Compaction Equation. PMID- 28649814 TI - Branched Polyesters as Mucoadhesive Carriers of Drugs. PMID- 28649815 TI - Evaluation of Water Absorption Rate of Tablets by Using an Enslin-Neff Device. PMID- 28649816 TI - Evaluation of the Influence of Lubricants on the Viscoelastic Properties of Tablets Using the Stress Relaxation Test. PMID- 28649817 TI - Determination of biologically active compounds in the fungi of the genus Cordyceps sinensis by HPLC and NMR. PMID- 28649819 TI - A Comparison of SiO2-, Cu-, and Ni-supported Au nanoparticles for selective glycerol oxidation to acetic acid. PMID- 28649818 TI - Determination of CMC of cationic tenside in aqueous and mixed water-alcohol solutions. PMID- 28649820 TI - Determination of acid-base dissociation constants of newly synthesized arylethanolamine derivatives using capillary zone electrophoresis. PMID- 28649821 TI - HPLC method for stability evaluation of pharmaceutical preparations containing sodium picosulfate. PMID- 28649822 TI - The use of 2,6-dichloroquinone-4chlorimide for quantitative determination of phenylephrine hydrochloride in combined tablets with paracetamol and chlorpheniramine maleate. PMID- 28649823 TI - The utilization of radionuclide X-ray spectrometry in the determination of elements in medicinal plants and medicinal products used as antianemics. AB - The work was based on the identification and determination of selected elements in teas, plants and medicinal products for the treatment of anemia. To evaluate the quality of medicinal plants Urtica dioica L., Papaver somniferum, L., leguminous plant Lens culinaris, M. and also in medicaments Aktiferrin(r) gtt., Ferronat(r) retard pot.tbl and Sorbifer(r) Durulues(r) por. Tbl. Flm. was used nuclear analytical method Radionuclide X-ray Fluorescence Spectrometry. This method is suitable for the analysis of samples in the solid state and a liquid state. Solid samples were homogenized and compressed into tablets of defined shape and weight. Liquid samples were filtered through a chelating membrane 3M EmporeTM, which are used to selectively capture the polyvalent metal cations and are preconcentrating the elements from sample. Samples were analysed using radiation radionuclide 238 Pu and evaluated by means of a semiconductor detector and a multichannel analyser. PMID- 28649824 TI - On-line hyphenated capillary electrophoresis and tandem mass spectrometry used dor the analysis of selected biogenic amines in grape leaves. PMID- 28649825 TI - Validation of spectrophotometric methods of assaying metronidazole in capsules. PMID- 28649826 TI - Increasing Cancer Therapy Efficiency through Targeting and Localized Light Activation. AB - Currently, the potential of cancer therapy is compromised by a variety of problems related to tumor specificity, drug access, and limited efficacy. We report a novel approach to improve the effectiveness of cancer treatment utilizing a light-responsive nanoconstruct. Effectiveness is increased by enhancing drug absorption through heating and the production of free radicals. Treatment specificity is increased through chemical targeting of the nanoconstruct and localization of light delivery to the tumor. When reaching the tumor, magnetic resonance imaging is enhanced and near-infrared fluorescence is activated upon drug release, making it possible to visualize the localized treatment at both the tissue and cellular levels. This dual-modality imaging nanoconstruct enables the synergistic treatment and observable evaluation of solid tumors with dramatically improved efficacy, giving rise to a promising new approach for cancer therapy and evaluation. PMID- 28649827 TI - Self-Poling-Induced Magnetoelectric Effect in Highly Strained Epitaxial BiFeO3/La0.67Sr0.33MnO3-delta Multiferroic Heterostructures. AB - Highly strained epitaxial BiFeO3/La0.67Sr0.33MnO3-delta (BFO/LSMO) heterostructures were fabricated on LaAlO3 substrates by magnetron sputtering. The as-grown downward self-polarization of BFO capping layers was confirmed by piezoelectric force microscopy. Using the electrostatic field-induced charge screening, a hole depletion state was induced in ultrathin (8 nm) LSMO films. As a result of the interfacial charge coupling, appreciable saturated magnetization (MS) increase of about 500 and 100% can be observed in LSMO with BFO capping at 5 and 300 K, respectively. Besides, LSMO phase translations can be revealed by the BFO thickness-related exchange bias field (HE) and MS of the BFO/LSMO heterostructures. The results established a new approach in achieving interfacial magnetoelectric couplings with thin self-polarized multiferroic layers. PMID- 28649828 TI - Dimerization of the Conserved N-Terminal Domain of a Spider Silk Protein Controls the Self-Assembly of the Repetitive Core Domain. AB - Spider silk proteins comprise a repetitive core domain with polyalanine and glycine/proline-rich stretches flanked by highly conserved nonrepetitive N- and C terminal domains. The termini are responsive to assembly triggers, sensing changes in the ionic (H+, phosphate) and mechanical (shear stress) environment along the spinning duct. The N-terminal domain dimerizes in a pH-dependent manner induced by protonation of conserved acidic residues. To date, dimerization of N terminal spider silk domains has been individually investigated in the absence of large core domains. In this work, the impact of an engineered 50 kDa (AQ) core domain was studied on N-terminal dimerization by circular dichroism, fluorescence and absorbance spectroscopy, multiangle light scattering, as well as scanning electron and transmission electron microscopy. Although the core domain showed no apparent influence on the dimerization behavior of the N-terminal domain, the N terminal domain in contrast influenced the behavior of the core domain: the monomeric state enhanced (AQ)'s solubility, and dimer formation triggered self assembly. The monomer-dimer equilibrium was influenced by using several previously established mutants, confirming these results. This work thereby provides molecular insights into how key residues of the N-terminal domain control the dimerization-mediated transformation of soluble spidroins into fibrillary assemblies. PMID- 28649829 TI - Photoelectrochemical Bioanalysis Platform of Gold Nanoparticles Equipped Perovskite Bi4NbO8Cl. AB - We have developed sensitive photoelectrochemical (PEC) detection of cysteine using the gold nanoparticles (Au NPs) equipped perovskite Bi4NbO8Cl heterostructure. The Bi4NbO8Cl was prepared by a solid-state reaction, and the Au NPs/Bi4NbO8Cl electrode was made through the electrostatic layer-by-layer self assembly technique. The Au NPs/Bi4NbO8Cl electrode provided much enhanced photocurrent with a great increase compared to the bare Bi4NbO8Cl electrode and allowed for the plasmon-enhanced PEC detection of cysteine with good performance. It demonstrated rapid response, high stability, wide linear detection range and certain selectivity, implying its great promise in its application. Therefore, the Au NPs/Bi4NbO8Cl heterostructure has provided a promising platform for the development of PEC bioanalysis. More generally, these findings offered an insight into the exploitation of perovskite materials for PEC bioanalytical purposes. PMID- 28649830 TI - Decreasing Li/Ni Disorder and Improving the Electrochemical Performances of Ni Rich LiNi0.8Co0.1Mn0.1O2 by Ca Doping. AB - Decreasing Li/Ni disorder has been a challenging problem for layered oxide materials, where disorder seriously restricts their electrochemical performances for lithium-ion batteries (LIBs). Element doping is a great strategy that has been widely used to stabilize the structure of the cathode material of an LIB and improve its electrochemical performance. On the basis of the results of previous studies, we hypothesized that the element of Ca, which has a lower valence state and larger radius compared to Ni2+, would be an ideal doping element to decrease the Li/Ni disorder of LiMO2 materials and enhance their electrochemical performances. A Ni-rich LiNi0.8Mn0.1Co0.1O2 cathode material was selected as the bare material, which usually shows severe Li/Ni disorder and serious capacity attenuation at a high cutoff voltage. So, a series of Ca-doped LiNi0.8(1 x)Co0.1Mn0.1Ca0.8xO2 (x = 0-8%) samples were synthesized by a traditional solid state method. As hypothesized, neutron diffraction showed that Ca-doped LiNi0.8Co0.1Mn0.1O2 possessed a lower degree of Li/Ni disorder, and potentiostatic intermittent titration results showed a faster diffusion coefficient of Li+ compared with that of LiNi0.8Mn0.1Co0.1O2. The Ca-doped LiNi0.8Mn0.1Co0.1O2 samples exhibited higher discharge capacities and better cycle stabilities and rate capabilities, especially under a high cutoff voltage with 4.5 V. In addition, the problems of polarization and voltage reduction of LiNi0.8Mn0.1Co0.1O2 were also alleviated by doping with Ca. More importantly, we infer that it is crucial to choose an appropriate doping element and our findings will help in the research of other layered oxide materials. PMID- 28649831 TI - Non-Abelian Parton Fractional Quantum Hall Effect in Multilayer Graphene. AB - The current proposals for producing non-Abelian anyons and Majorana particles, which are neither fermions nor bosons, are primarily based on the realization of topological superconductivity in two dimensions. We show theoretically that the unique Landau level structure of bilayer graphene provides a new possible avenue for achieving such exotic particles. Specifically, we demonstrate the feasibility of a "parton" fractional quantum Hall (FQH) state, which supports non-Abelian particles without the usual topological superconductivity. Furthermore, we advance this state as the fundamental explanation of the puzzling 1/2 FQH effect observed in bilayer graphene [ Kim et al. Nano Lett. 2015 , 15 , 7445 ] and predict that it will also occur in trilayer graphene. We indicate experimental signatures that differentiate the parton state from other candidate non-Abelian FQH states and predict that a transverse electric field can induce a topological quantum phase transition between two distinct non-Abelian FQH states. PMID- 28649832 TI - Pyrene-Based Approach to Tune Emission Color from Blue to Yellow. AB - The development of functionalized, luminescent, pyrene-based monomers has been and continues to be an area of great interest in terms of the design and fabrication of optical and electronic devices. Herein, a facile strategy to tune the emission color of pyrene-based chromophores has been established by simple functional group modification at the para position to the diphenylamino on the donor building block. Intriguing photophysical properties were obtained and are described both in different solutions and in the solid state. The results obtained could be explained by the Hammett method and by density functional theory (DFT) calculations. A good correlation was observed between the Hammett sigmapara constants of the functional groups para to the phenyl and the wavenumber (cm-1) of the emission profile. This positive correlation, namely between the sigma constants of the functional groups and the emission properties of the monomers, can be used to develop a predictive method for these types of systems. PMID- 28649833 TI - Functional Prioritization and Hydrogel Regulation Phenomena Created by a Combinatorial Pearl-Associated Two-Protein Biomineralization Model System. AB - In the nacre or aragonitic layer of an oyster pearl, there exists a 12-member proteome that regulates both the early stages of nucleation and nanoscale-to mesoscale assembly of nacre tablets and calcitic crystals from mineral nanoparticle precursors. Several approaches to understanding protein-associated mechanisms of pearl nacre formation have been developed, yet we still lack insight into how protein ensembles or proteomes manage nucleation and crystal growth. To provide additional insights, we have created a proportionally defined combinatorial model consisting of two pearl nacre-associated proteins, PFMG1 and PFMG2 (shell oyster pearl nacre, Pinctada fucata) whose individual in vitro mineralization functionalities are distinct from one another. Using scanning electron microscopy, atomic force microscopy, Ca(II) potentiometric titrations, and quartz crystal microbalance with dissipation monitoring quantitative analyses, we find that at 1:1 molar ratios, rPFMG2 and rPFMG1 co-aggregate in specific molecular ratios to form hybrid hydrogels that affect both the early and later stages of in vitro calcium carbonate nucleation. Within these hybrid hydrogels, rPFMG2 plays a role in defining protein co-aggregation and hydrogel dimension, whereas rPFMG1 defines participation in nonclassical nucleation processes; both proteins exhibit synergy with regard to surface and subsurface modifications to existing crystals. The interactions between both proteins are enhanced by Ca(II) ions and may involve Ca(II)-induced conformational events within the EF-hand rPFMG1 protein, as well as putative interactions between the EF-hand domain of rPFMG1 and the calponin-like domain of rPFMG2. Thus, the pearl associated PFMG1 and PFMG2 proteins interact and exhibit mineralization functionalities in specific ways, which may be relevant for pearl formation. PMID- 28649834 TI - Manipulating the Bulk Band Structure of Artificially Constructed van der Waals Chalcogenide Heterostructures. AB - The bulk band structures of a variety of artificially constructed van der Waals chalcogenide heterostructures IVTe/V2VI3 (IV: C, Si, Ge, Sn, Pb; V: As, Sb, Bi; VI: S, Se, Te) have been systematically examined using ab initio simulations based on density functional theory. The crystal structure and the electronic band structure of the heterostructures were found to strongly depend on the choice of elements as well as the presence of van der Waals corrections. Furthermore, it was found that the use of the modified Becke-Johnson local density approximation functional demonstrated that a Dirac cone is formed when tensile stress is applied to a GeTe/Sb2Te3 heterostructure, and the band gap can be controlled by tuning the stress. Based on these simulation results, a novel electrical switching device using a chalcogenide heterostructure is proposed. PMID- 28649835 TI - Transition-Metal-Free C-H Hydroxylation of Carbonyl Compounds. AB - Transition metal and reductant free alpha-C(sp3)-H hydroxylation of carbonyl compounds are reported. This method is promoted by commercially available inexpensive KO-t-Bu and atmospheric air as an oxidant at room temperature. This unified strategy is also very facile for hydroxylation of various carbonyl compound derivatives to obtain quaternary hydroxyl compounds in excellent yield. A preliminary mechanistic investigation, supported by isotope labeling and computational studies, suggests the formation of a peroxide bond and its cleavage by in situ generated enolate. PMID- 28649836 TI - Anion-Dependent Assembly of Heterometallic 3d-4f Clusters Based on a Lacunary Polyoxometalate. AB - A series of heterometallic 3d-4f clusters, formulated as Na17[Ln3(H2O)5NiII(H2O)3(Sb4O4)(SbW9O33)3(NiIIW6O24)(WO2)3(CH3COO)].(H2O)65 [abbreviated as Ln3Ni2, where Ln = La3+ (1), Pr3+ (2), and Nd3+ (3)], K5Na11[Ln3(H2O)3NiII3(H2O)6(SbW9O33)3(WO4)(CO3)].(H2O)40 [abbreviated as Ln3Ni3, where Ln = La3+ (4), Pr3+ (5), and Nd3+ (6)], and K3Na27[Ln3NiII9(MU3 OH)9(SbW9O33)2(PW9O34)3(CH3COO)3].(H2O)80 [abbreviated as Ln3Ni9, where Ln = Dy3+ (7) and Er3+ (8)], were obtained through the reaction of the lacunary {SbW9O33} precursor with Ln(NO3)3.6H2O and NiCl2.6H2O in a NaAc/HAc buffer in the presence of different anions. Single-crystal X-ray structure analysis revealed that compounds 1-3 possessed tetrameric architectures featuring three Keggin-type {SbW9O33} and one Anderson-type {NiIIW6O24} building blocks encapsulating one {Sb4O4} cluster, three WO2 units, three Ln3+ metal ions, and two Ni2+ metal ions. Compounds 4-6 displayed cyclic trimeric aggregates of three {SbW9O33} units enveloping one CO32--templated trinuclear [Ln3(CO3)]7+ and one WO42--templated [NiII3(WO4)]+ unit. Compounds 7 and 8 exhibited unique pentameric architectures that featured three 3d-4f cubane clusters of {LnNi3(MU3-OH)3} capped by two {SbW9O33} and three {PW9O34} building blocks. Interestingly, the structural regulation of the heterometallic 3d-4f clusters in the polyoxometalate systems with trimers, tetramers, and pentamers was realized by introducing different anions. PMID- 28649837 TI - Methylammonium Lead Bromide Perovskite Light-Emitting Diodes by Chemical Vapor Deposition. AB - Organo-lead-halide perovskites are promising materials for optoelectronic applications. Perovskite solar cells have reached power conversion efficiencies of over 22%, and perovskite light-emitting diodes have recently achieved over 11% external quantum efficiency. To date, most research on perovskite light-emitting diodes has focused on solution-processed films. There are many advantages of a vapor-based growth process to prepare perovskites, including ease of patterning, ability to batch process, and material compatibility. We investigated an all vapor perovskite growth process by chemical vapor deposition and demonstrated luminance up to 560 cd/m2. PMID- 28649838 TI - Formation of Aza-ortho-quinone Methides Under Room Temperature Conditions: Cs2CO3 Effect. AB - Since the first report of a facile, room temperature process to access aza-ortho quinone methides (aoQMs) by Corey in 1999, this chemistry has remained dormant until our report of an enantioselective catalytic example in 2014. We report a theoretical and experimental study of the key to success behind these successful examples to enable broader exploitation of this useful intermediate. We have discovered that transformations involving the aoQM are remarkably facile with barriers <17 kcal/mol. The main difficulty of exploiting aoQM in synthesis is that they are unstable (DeltaG > 30 kcal/mol), precluding their formation under mild conditions. The use of Cs2CO3 as base is critical. It provides a thermodynamically and kinetically favorable means to form aoQMs, independent of the salt solubility and base strength. The exothermic formation of salt byproducts provides a driving force (average DeltaG = -30.8 kcal/mol) compensating for the majority of the inherent unfavorable thermodynamics of aoQM formation. PMID- 28649839 TI - Mechanistic Investigation of RhI-Catalyzed Cycloisomerization of Benzylallene Internal Alkynes via C-H Activation. AB - Treatment of the benzylallene-internal alkynes with [RhCl(CO)2]2 effected a cycloisomerization via a Csp2-H bond activation to produce the tricyclo[9.4.0.03,8]pentadecapentaene skeleton. The reaction mechanism via formation of the rhodabicyclo[4.3.0] intermediates and sigma-bond metathesis between the Csp2-H bond on the benzene ring and the Csp2-RhIII bond was proposed. In addition, a plausible alternative mechanism for the previously reported cycloisomerization of the benzylallene-terminal alkynes could also be proposed. PMID- 28649840 TI - Reaction of a Nitrosyl Complex of Cobalt Porphyrin with Hydrogen Peroxide: Putative Formation of Peroxynitrite Intermediate. AB - The cobalt porphyrin complex [(Cl4TPP)Co], 1, {Cl4TPP = 5,10,15,20-tetrakis(4' chlorophenyl)porphyrinate dianion} in dichloromethane solution was subjected to react with nitric oxide (NO) gas and resulted in the formation of the corresponding nitrosyl complex [(Cl4TPP)Co(NO)], 2, having {CoNO}8 description. It was characterized by spectroscopic studies and single-crystal X-ray structure determination. It did not react with dioxygen. However, in CH2Cl2/CH3CN solution, it reacted with H2O2 to result in the Co-nitrito complex [(Cl4TPP)Co(NO2)], 3, with the simultaneous release of O2. It induced ring nitration to the added phenol in an appreciable yield. The reaction presumably proceeds through the formation of corresponding Co-peroxynitrite intermediate. PMID- 28649841 TI - Elucidating the Mechanisms Driving the Aging of Porous Hollow PtNi/C Nanoparticles by Means of COads Stripping. AB - The oxygen reduction reaction (ORR) activity of Pt-alloy electrocatalysts depends on (i) the strain/ligand effects induced by the non-noble metal (3d-transition metal or a rare-earth element) alloyed to Pt, (ii) the orientation of the catalytic surfaces, and (iii) the density of structural defects (SDs) (e.g., vacancies, voids, interconnections). These SDs influence the "generalized" coordination number of Pt atoms, the Pt-alloy lattice parameter, and thus the adsorption strength of the ORR intermediates (O*, OH*, OOH*). Here, we discuss a set of parameters derived from COads stripping measurements and the Rietveld refinement of X-ray diffraction (XRD) patterns, aiming to show how the leaching of the non-noble metal and the density of SDs influence the ORR activity of porous hollow PtNi/C nanoparticles (PH-PtNi/C NPs). PH-PtNi/C NPs were aged at T = 353 K in an Ar-saturated 0.1 M HClO4 electrolyte during 20 000 potential cycles between E = 0.6 and 1.0 V versus the reversible hydrogen electrode, with an intermediate characterization after 5000 cycles. The losses in the ORR specific activity were attributed to the dissolution of Ni atoms (modifying strain/ligand effects) and to the increase of the crystallite size (dXRD), resulting in a diminution of the density of grain boundaries. In agreement with the Gibbs Thompson equation, the electrocatalysts that presented larger crystallites (dXRD > 3 nm) were far more stable than the ones with the smallest crystallites (dXRD < 2 nm). We also observed that performing intermediate characterizations (in an O2 saturated electrolyte) results in activity losses for the ORR. PMID- 28649842 TI - Lipo-Oligomer Nanoformulations for Targeted Intracellular Protein Delivery. AB - Here, we report novel lipo-oligoaminoamide nanoformulations for targeted intracellular protein delivery. Formulations are generated by first bioreversibly conjugating a sequence-defined amphiphilic lipo-oligomer 728 to the cargo protein via disulfide bonds, followed by formulation of the formed 728-SS-protein conjugate with different helper lipids in various compositions. The triblock oligoaminoamide 728 contains cysteines for reversible covalent protein conjugation and cross-link-stabilization of formed nanoparticles, polyethylene glycol (PEG) for shielding, and providing a hydrophilic domain, eight cationizable succinoyl tetraethylene pentamine (Stp) repeats for endosomal buffering and escape into the cytosol, and a tetra-oleic acid block for hydrophobic stabilization. The added helper lipids are supposed to enhance serum stability of the nanoparticles and provide targeting by lipid-anchored folic acid (FA)-PEG. The optimized protein nanoparticles, including 728, DOPS, cholesterol, DMPE-PEG2000, and the FA-PEG conjugated lipid 1042, presented a high colloidal stability without significant size increase in 72 h. Using cytotoxic ribonuclease A (RNase A) as cargo protein, FA-728-DOPS-DMPE-RNase A nanoformulation could be identified with highest potency of targeted RNase A-mediated folate-receptor positive KB carcinoma cell killing among all tested formulations, resulting in 85% KB cell killing at a low concentration of 2 MUM. These approximately 50 nm sized nanoparticles induced superior 70% KB cell killing even in the presence of 20% serum. Efficient targeted cytosolic delivery by coformulation with helper lipids was also demonstrated by FA-728-DOPS-DMPE-nlsEGFP nanoformulation using enhanced green fluorescent protein (EGFP) as cargo. Furthermore, partial nlsEGFP was imported into the nuclei of KB cells, validating effective endosomal escape, and following nuclear transport mediated by nuclear localization signal on nlsEGFP. As demonstrated, the screening and optimization of nanoformulations with helper lipids and coformulation agents is considered to be an important and rational next step in the development of intracellular biopharmaceuticals, following initial protein conjugate synthesis. PMID- 28649843 TI - Pb@Pb8 Basket-like-Cluster-Based Lead Tellurate-Nitrate Kleinman-Forbidden Nonlinear-Optical Crystal: Pb9Te2O13(OH)(NO3)3. AB - The first lead tellurate-nitrate nonlinear-optical (NLO) crystal, Pb9Te2O13(OH)(NO3)3, featuring a 3D anionic diamondlike toplogical structural motif formulated as [Pb9O13]8- constructed by unique nonanuclear basket-shaped Pb@Pb8O14 clusters has been hydrothermally achieved, in which the Pb@Pb8O14 cluster shows a core-shell structure with one PbO10 polyhedron enclosed by eight PbOx (x = 3 and 4) polyhedera via edge and face sharing. The hexavalent Te in TeO5(OH) octahedra is linked to a [Pb9O13]8- cluster to form a rare [Pb9Te2O13(OH)]3+ cationic framework. The compound demonstrates a powder second harmonic-generation (SHG) response of about 1.2 times that of KH2PO4 (KDP) as well as a wide transparency range. Calculations on the local dipole moment and SHG coefficient reveal that the net polarization is zero because of a Kleinman forbidden point group. Further analysis shows that the SHG response results from structure-induced variations by thermal vibrations of the lattice rather than the intrinsic dipole moment, which offers another insight on the design of new NLO materials. PMID- 28649844 TI - Chemical Constituents with Proprotein Convertase Subtilisin/Kexin Type 9 mRNA Expression Inhibitory Activity from Dried Immature Morus alba Fruits. AB - Phytochemical investigation for a chloroform-soluble extract of dried Morus alba fruits, selected by proprotein convertase subtilisin-kexin type 9 (PCSK9) mRNA expression monitoring assay in HepG2 cells, led to the isolation of a new benzofuran, isomoracin D (1), and a naturally occurring compound, N-(N-benzoyl-l phenylalanyl)-l-phenylalanol (2), along with 13 known compounds (3-15). All of the structures were established by NMR spectroscopic data as well as MS analysis. Of the isolates, moracin C (7) was found to inhibit PCSK9 mRNA expression with an IC50 value of 16.8 MUM in the HepG2 cells. PMID- 28649845 TI - Multifunctional Nanostructured Conductive Polymer Gels: Synthesis, Properties, and Applications. AB - Conductive polymers have attracted significant interest over the past few decades because they synergize the advantageous features of conventional polymeric materials and organic conductors. With rationally designed nanostructures, conductive polymers can further exhibit exceptional mechanical, electrical, and optical properties because of their confined dimensions at the nanoscale level. Among various nanostructured conductive polymers, conductive polymer gels (CPGs) with synthetically tunable hierarchical 3D network structures show great potential for a wide range of applications, such as bioelectronics, and energy storage/conversion devices owing to their structural features. CPGs retain the properties of nanosized conductive polymers during the assembly of the nanobuilding blocks into a monolithic macroscopic structure while generating structure-derived features from the highly cross-linked network. In this Account, we review our recent progress on the synthesis, properties, and novel applications of dopant cross-linked CPGs. We first describe the synthetic strategies, in which molecules with multiple functional groups are adopted as cross-linkers to cross-link conductive polymer chains into a 3D molecular network. These cross-linking molecules also act as dopants to improve the electrical conductivity of the gel network. The microstructure and physical/chemical properties of CPGs can be tuned by controlling the synthetic conditions such as species of monomers and cross-linkers, reaction temperature, and solvents. By incorporating other functional polymers or particles into the CPG matrix, hybrid gels have been synthesized with tailored structures. These hybrid gel materials retain the functionalities from each component, as well as enable synergic effects to improve mechanical and electrical properties of CPGs. We then introduce the unique structure-derived properties of the CPGs. The network facilitates both electronic and ionic transport owing to the continuous pathways for electrons and hierarchical pores for ion diffusion. CPGs also provide high surface area and solvent compatibility, similar to natural gels. With these improved properties, CPGs have been explored to enable novel conceptual devices in diverse applications from smart electronics and ultrasensitive biosensors, to energy storage and conversion devices. CPGs have also been adopted for developing hybrid materials with multifunctionalities, such as stimuli responsiveness, self-healing properties, and super-repellency to liquid. With synthetically tunable physical/chemical properties, CPGs emerge as a unique material platform to develop novel multifunctional materials that have the potential to impact electronics, energy, and environmental technologies. We hope that this Account promotes further efforts toward synthetic control, fundamental investigation, and application exploration of CPGs. PMID- 28649846 TI - Modifying Emission Spectral Bandwidth of Phosphorescent Platinum(II) Complexes Through Synthetic Control. AB - The design, synthesis, and characterization of a series of tetradentate cyclometalated Pt(II) complexes are reported. The platinum complexes have the general structure Pt(ppz-O-CbPy-R), where a tetradentate cyclometalating ligand is consisting of ppz (3,5-dimethyl-1-phenyl-pyrazole), CbPy (carbazolylpyridine) components, and an oxygen bridging group. Variations of the R group on the pyridyl ring with various electron withdrawing and donating substituents are shown to have profound effects on the photophysical properties of Pt complexes. Electrochemical analysis indicates that reduction process occurs mainly on the electron-accepting pyridyl group, and the irreversible oxidation process is primarily localized on the metal-phenyl portions. The studies of their photophysical properties indicate that the lowest excited state of the platinum complexes is a ligand-centered 3pi-pi* state with minor to significant 1MLCT/3MLCT character and are strongly dependent on the nature of the electron accepting pyridyl moiety. A systematic study of the substituent effects on the pyridyl ring demonstrates that the T1 state properties can be tuned by altering the functionality and positions of substituents. Importantly, it is revealed that how the emission spectra of the Pt(II) complexes can be significantly narrowed and why it can be achieved by incorporating an electron-donating group on the 4 position of the pyridyl ring. Most of the Pt(II) complexes reported here are highly emissive at room temperature in dichloromethane solutions (Phi = 1.1-95%) and in doped PMMA films (Phi = 29-88%) with luminescent lifetimes in the microsecond range (tau = 0.6-13.5 MUs in solution and 0.9-11.3 MUs in thin film respectively) and lambdamax = 442-568 nm and 440-544 nm in solution and thin film, respectively. Moreover, these complexes are neutral and thermally stable for sublimation, indicating that they can be useful for display and solid-state lighting applications. PMID- 28649847 TI - Short Communication: The Clinical Value of Cystatin C as a Marker of Renal Function in HIV Patients Receiving Dolutegravir. AB - Dolutegravir (DTG) is an integrase strand transfer inhibitor that is used for the treatment of HIV infection. DTG inhibits organic cation transporter 2 on the basolateral side of proximal tubule cells of the kidney and leads to increased serum creatinine levels without true renal function deterioration. In HIV patients who receive DTG, an alternative test to serum creatinine measurement is needed to determine the correct renal function. We retrospectively evaluated 18 HIV-infected men who had received combination antiretroviral therapy (cART), including DTG, and who had available data on serum creatinine and cystatin C levels. We used paired t-test to assess the changes in estimated glomerular filtration rate (eGFR) calculated by serum creatinine or cystatin C level, after the start of cART. In all 18 patients, only 2 cases were naive, whereas 16 cases switched treatment. Based on serum creatinine level, eGFR significantly changed from 67.9 (61.2-95.7) ml/min per 1.73 m2 [medians and interquartile ranges ] to 63.6 (55.5-83.7) ml/min per 1.73 m2 (p = .0004). Conversely, eGFR was almost unchanged [79.8 (77.7-82.5) to 80.0 (77.1-82.5) ml/min per 1.73 m2; p = .132] when serum cystatin C level was used for estimation. In HIV patients receiving DTG, measurement of serum cystatin C as an alternative renal function test might be clinically valuable because it is not affected by DTG administration. PMID- 28649848 TI - Mogamulizumab for the treatment of T-cell lymphoma. AB - INTRODUCTION: T-cell lymphoma is a relatively rare hematologic malignancy that accounts for 10-20% of non-Hodgkin lymphomas. Treatment strategies for T-cell lymphomas are different from that for B-cell lymphomas and have poor prognoses. Among various subtypes of T-cell lymphomas, adult T-cell leukemia-lymphoma (ATL) has the worst prognosis. To achieve further improvement in the treatment outcome of T-cell lymphomas, several novel agents such as brentuximab vedotin, lenalidomide, romidepsin, and pralatrexate are actively being studied. Mogamulizumab, an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is one of the promising agents for CCR4-positive T-cell lymphomas, especially for ATL. Areas covered: First, basic information about the current treatment strategy of T cell lymphomas including ATL is described. Then, the authors discuss the current clinical development of mogamulizumab and its clinical implications for T-cell lymphomas. Expert opinion: Mogamulizumab has potent clinical efficacy against CCR4-positive T-cell lymphomas, especially against ATL. Among various toxicities associated with mogamulizumab, skin eruptions are the most significant. Although there are several effective competitors, mogamulizumab has a unique mechanism and is expected to be a key agent for treating CCR4-positive T-cell lymphomas, especially ATL. PMID- 28649849 TI - Toward Establishing a Standard Symptom Set for Assessing Sluggish Cognitive Tempo in Children: Evidence From Teacher Ratings in a Community Sample. AB - Despite increasing interest in sluggish cognitive tempo (SCT) in children, the field is stymied by the lack of a standard symptom set that can be used across studies. Without a standard symptom set, it is difficult to determine if differences across studies are due to methodological or sample differences, or simply the way SCT was measured. To move the field toward a standard symptom set, this study evaluates a teacher-report rating scale of SCT revised based on recent meta-analytic findings that identified optimal items for distinguishing SCT from attention-deficit/hyperactivity disorder inattention (ADHD-IN). Participants were 1,349 students (50.7% male) from grades 2 to 5. Teachers provided ratings of SCT, ADHD-IN, academic impairment, and social impairment. Exploratory structural equation modeling found 15 of the 16 SCT items to demonstrate excellent convergent validity and discriminant validity with ADHD-IN. The measurement properties of the SCT construct were also invariant across sex. SCT was uniquely associated with both academic and social impairment above and beyond ADHD-IN and sex. Although replication and extension is needed, the current study provides the strongest evidence to date of a possible standard symptom set that can be used across studies examining SCT in children. PMID- 28649850 TI - Three new noroleanane-type triterpenes from the roots of Pfaffia glomerata. AB - The Amaranthaceae plant, Pfaffia glomerata, which is so-called as Brazil ginseng, is widely distributed in South American countries. Three new noroleanane-type triterpenes and four known oleanane-type triterpenes were isolated from the roots of P. glomerata. Their structures were determined by spectroscopic methods including 1D and 2D NMR experiments. Their effects on melanogenesis were also reported. PMID- 28649851 TI - Avoidance of urinary catheterization to minimize in-hospital complications after transcatheter aortic valve implantation: An observational study. AB - BACKGROUND: Contemporary transcatheter aortic valve implantation (TAVI) devices and approach present opportunities to review historical practices initially informed by early treatment development and cardiac surgery. The avoidance of urinary catheterization in the older TAVI population is a strategy to minimize in hospital complications. The purpose of the study was to explore elimination related complications following the phased implementation of a default strategy of avoiding urinary catheterization in patients undergoing transfemoral (TF) TAVI. METHODS: We conducted an observational study using a retrospective chart review of patients treated between 2011 and 2013 to identify patient characteristics, peri-procedure details, in-hospital outcomes and elimination related complications in patients who did or did not receive a peri-procedure indwelling catheter. Descriptive analyses were used to report differences between the groups; we conducted a regression analysis to explore the relationship between the practice of urinary catheterization and total procedure time. RESULTS: Of the 408 patients who underwent TF TAVR, 188 (46.1%) received a peri procedure indwelling urinary catheter and 220 (53.9%) did not. There was no difference in in-hospital mortality (2.2%), disabling stroke (0.5%), or other major cardiac adverse events. The avoidance of a urinary catheter resulted in significantly lower rates of urinary tract infection requiring a new antibiotic regimen (1.4% versus 6.1%, p = 0.014), haematuria documented by medicine or nursing (3.7% versus 17.6%, p = 0.001), and the need for continuous bladder irrigation (2.7% versus 0%, p = 0.027). CONCLUSION: The avoidance of a urinary catheter may contribute to improved outcomes in patients undergoing TAVI. The intervention should be further evaluated within the broader study of minimalist TAVI. PMID- 28649852 TI - Two new guaiane-type sesquiterpenoids from Valeriana hardwickii and their cytotoxicity. AB - Two new guaiane-type sesquiterpenoids, named 4alpha,5alpha-epoxy-8beta-hydroxy 1alpha-hydro-alpha-guaiene (1) and 4alpha,5alpha-epoxy-1-hydroxy-alpha-guaiene (2), were isolated from the whole plants of Valeriana hardwickii. Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1 and 2 showed weak cytotoxicity against the lung adenocarcinoma (A549) and hepatoma (Bel7402) cell lines with IC50 values of 9.2 and 8.5 MUM, respectively. PMID- 28649853 TI - Cationic liposome co-encapsulation of SMAC mimetic and zVAD using a novel lipid bilayer fusion loaded with MLKL-pDNA for tumour inhibition in vivo. AB - The increase in multidrug resistance among colon cancer cells presents a challenge for the development of effective therapies. Small-molecule analogues of second mitochondria-derived activator of caspase (SMAC) mimetic in association with mixed lineage kinase domain-like protein (MLKL)-pDNA and z-VAD-fmk have shown ideal antitumor effects in colon cancer cells in vitro via induction of RIP3-dependent necroptosis. To achieve synergistic antitumor effects in vivo, liposomes loaded with SMAC mimetic, MLKL-pDNA and z-VAD-fmk have been developed using novel lipid fusion methods to co-localise the molecules of interest within the tumour cells. The co-encapsulation liposome (MLKL-zVAD-BV6-LP) had a high entrapment efficiency of approximately 95% for both zVAD and BV6 and was able to condense MLKL-pDNA very well. The vectors showed good biocompatibility, tumour targeting and small-molecule co-localisation. In a CT26 mouse model, the MLKL zVAD-BV6-LP exhibited a tumour-suppression rate of over 60% in vivo, which was significantly higher than that of both the null-liposome and coadministration groups. Above all, the co-encapsulation system provided a novel approach to combination tumour therapy. PMID- 28649854 TI - Major ginsenoside contents in rhizomes of Panax sokpayensis and Panax bipinnatifidus. AB - This study compared eight major ginsenosides (Rg1, Rg2, Rf, Re, Rd, Rc, Rb1 and Rb2) between Panax sokpayensis and Panax bipinnatifidus collected from Sikkim Himalaya, India. High-performance liquid chromatographic analysis revealed that all major ginsenosides were present in the rhizomes of P. sokpayensis except ginsenoside Rc, whereas ginsenoside Rf, Rc and Rb2 were not detected in P. bipinnatifidus. PMID- 28649855 TI - Quality of Life and Its Factors in Korean Elderly With Mild Cognitive Impairment. AB - Based on the secondary data analysis, this study aimed to identify quality of life and factors that affect quality of life among Korean elderly with mild cognitive impairment. Demographic characteristics, physical factors, and psychosocial factors as well as quality of life of the elderly with mild cognitive impairment were comprehensively measured. The research subjects consisted of 348 home-resident elderly and their quality of life scores were relatively high at 29.86. Their quality of life varied according to education and gender, and instrumental activities of daily living (actual, latent), somatic symptoms, sleep quality, depression, and social support affected their quality of life. Depression and social support were predictors of quality of life. The most powerful predictor was depression (beta = -.583, p < .001). To improve the quality of life among elderly with mild cognitive impairment, nursing interventions to alleviate depression and to enhance social support from family, friends, and relevant neighbors are needed. PMID- 28649856 TI - The efficacy of inactivated Escherichia coli autogenous vaccines against the E. coli peritonitis syndrome in layers. AB - Autogenous Escherichia coli vaccines to prevent the E. coli peritonitis syndrome (EPS) in laying hens are often used in the field, although their effectiveness has not been demonstrated yet. Therefore, in this study, which consisted of two experiments, their efficacy was assessed. In the first experiment, the EPS inducing ability of three E. coli isolates originating from bone marrow of hens that died due to EPS and with different Pulsed-Field Gel Electrophoresis patterns, was examined by intravenous inoculation of the isolates in 17-week-old brown layers. Based on the results one isolate was chosen for the preparation of the vaccines and for homologous challenge and another one for heterologous challenge performed in the second experiment. In the named experiment, groups of laying hens which had been vaccinated intramuscularly at 14 and 18 weeks of age with inactivated vaccine either formulated as aqueous suspension or as water-in oil emulsion were homologously or heterologously challenged per aerosol at 30 weeks of age. The vaccines contained >=108.2 formaldehyde-inactivated colony forming units (cfu) of E. coli per hen dose in 0.5 ml. The estimated E. coli challenge dose uptake ranged from 105.8 to 106.5 cfu per hen. Groups consisted of 18 hens each and were housed in separate isolators from 27 weeks of age. Control groups were included in this experiment, which was ended eight days after challenge. Vaccinations had no effect on body growth and both vaccine types induced (almost) complete protection against homologous challenge, while protection against heterologous challenge was inconclusive. PMID- 28649857 TI - Effect of polysaccharides extracted from Sipunculus nudus (SNP) on the lifespan and immune damage repair of Drosophila melanogaster exposed to Cd (VI). AB - The water-soluble polysaccharides extracted from Sipunculus nudus (SNP) was investigated on the lifespan and immune damage repair of Drosophila melanogaster exposed to Cd (VI). SNP increased superoxyde dismutase (SOD), nitrogen monoxide (NO), glutathione peroxidase (GSH-Px) and total anti-oxidation competence (T AOC), with decreased malondialdehyde (MDA) on D. melanogaster demonstrated that SNP could attenuate oxidative damage of D. melanogaster Exposed to Cd (VI). Real time PCR and western blot analysis showed that SNP enhanced the gene expression of Diptericin, Drosomycin, Defensin, PGRP-LC and the protein level of Toll, p-JNK and Relish, that suggested the promoting effect of SNP on the immune damage repair of D. melanogaster exposed to Cd (VI). The increased level of Indy, Parkin and AMPK indicated the regulated effect of SNP on the longevity-related pathways through ageing-related moleculars of D. melanogaster exposed to Cd (VI). These results suggested that SNP could also improve the lifespan of D. melanogaster exposed to Cd (VI). PMID- 28649858 TI - Two new protostane-type triterpenoids from Alisma orientalis. AB - Two new protostane-type triterpenoids, 17-epi alisolide (1) and 24-epi alismanol D (2), were isolated from Alisma orientalis together with one known compound. Their structural elucidations were conducted by NMR, UV and HRESIMS spectroscopic analyses, and comparison with the literature data. All the isolated compounds were evaluated for inhibitory effects on HCE-2. Compound 2 displayed moderate inhibitory activity against HCE-2 with IC50 value of 23.1 MUM. PMID- 28649859 TI - Medical authority, managerial power and political will: A Bourdieusian analysis of antibiotics in the hospital. AB - Antibiotic resistance poses a significant global threat, yet clinically inappropriate antibiotic use within hospitals continues despite the implementation of abatement strategies. Antibiotic use and the viability of existing antibiotic options now sit precariously at the nexus of political will, institutional governance and clinical priorities 'at the bedside'. Yet no study has hitherto explored the perspectives of managers, instead of focusing on clinicians. In this article, drawing on qualitative interviews with hospital managers, we explore accounts of responding to antimicrobial resistance, managing antibiotic governance and negotiating clinical and managerial priorities. We argue that the managers' accounts articulate the problematic nexus of measurement and accountability, the downflow effects of political will, and core tensions within the hospital between moral, managerial and medical authority. We apply Bourdieu's theory of practice to argue that an understanding of the logics of practice within the 'hospital management classes' will be critical in efforts to protect antibiotics for future generations. PMID- 28649860 TI - Do racial/ethnic disparities exist in recommended migraine treatments in US ambulatory care? AB - Background Racial disparities in migraine have been reported in the US. Migraine in African Americans (AA) is more frequent, more severe, more likely to become chronic and associated with more depression and lower quality of life compared to non-Hispanic Whites (NHW). It is possible that racial differences in prescribing practices contribute to these differences, but little is known about the quality of migraine prescribing patterns in the US or whether racial differences exist. Objective To determine if racial differences in quality of migraine medical prescription care exist. Methods We used data from the National Ambulatory Medical Care Survey to estimate differences in the use of migraine prophylactic and abortive medications by race. Quality of migraine care was defined using the American Academy of Neurology Headache Quality Measure Set (AAN-HQMS). Patients were assigned to one of four categories representing the overall quality of evidence for their abortive and prophylactic medications using the AAN-HQMS. We hypothesized that there would be suboptimal migraine treatment in minority populations. Racial comparisons were made using descriptive statistics after applying NAMCS survey weights. Results Two thousand, eight hundred and sixty visits were included in the study, representing approximately 50 million migraine visits in the US from 2006-2013. In all, 41.3% of AA, 40.8% of NHW, and 41.2% of Hispanic (HI) patients received no prophylactic treatments ( p = 0.99). A total of 18.8% of AA patients, 11.9% of NHW patients, and 6.9% of HI patients received exclusively Level A prophylaxis ( p = 0.30). A total of 47.1% of AA patients, 38.2% of NHW patients, and 36.3% of HI patients received no abortive treatments ( p = 0.23). In total, 15.3% of AA patients, 19.4% of NHW patients, and 17.7% of HI patients received any Level A abortives (i.e. triptans or Dihydroergotamine; DHE, p = 0.64). A total of 15.2% of all patients had a prescription for opiates, but there were no racial differences. Conclusions Migraine may be undertreated with prophylactic medications. Level A acute analgesics may be underused and opiates overused. No major racial/ethnic differences in abortive or prophylactic treatment were identified. PMID- 28649861 TI - Access to Health Care. PMID- 28649862 TI - The role of sociocultural perspectives in eating disorder treatment: A study of health professionals. AB - Eating disorders are now often approached as biopsychosocial problems, because they are widely recognised as multifactorial in origin. However, it has been suggested that there is a substantial and unwarranted imbalance within this biopsychosocial framework, with the 'social' aspects of the equation relegated to secondary or facilitating factors within treatment contexts. Drawing on data from 12 qualitative interviews with health professionals in a UK region, this article examines the extent to which sociocultural perspectives on eating disorders are valued and explored in eating disorder treatment, with a particular focus on the relationship between eating disorders and gender. As girls/women are widely acknowledged to be disproportionately affected by eating problems, the article draws on feminist perspectives on eating disorders to explore whether the relationships between cultural constructions of femininity and experiences of body/eating distress are actively addressed within treatment. The study reveals high levels of inconsistency in this regard, as while some participants see such issues as central to treatment, others have 'never really considered' them before. In addition, the study examines the potential limitations of how such sociocultural issues are conceptualised and addressed, as well as why they might be marginalised in the current climate of evidence-based eating disorder treatment. The article then considers the implications of the findings for thinking about feminist perspectives on eating disorders - and the significance of gender in treatment - at the level of both research and practice. PMID- 28649863 TI - Cytotoxic triterpenoid saponins from the defatted seeds of Camellia oleifera Abel. AB - Five new oleanane-type triterpenoid saponins, oleiferasaponins D1-D5 (1-5), were isolated from the defatted seeds of Camellia oleifera Abel. Their structures were elucidated by spectroscopic and chemical methods. The cytotoxic activities of compounds 1-5 were evaluated against five human tumor cell lines (HCT-116, HepG2, BGC-823, NCI-H1650, and A2780). Compounds 1-2 exhibited cytotoxic activity against five human cancer cell lines, with IC50 values ranging from 3.31 to 10.23 MUM. Compounds 3-5 showed moderate cytotoxic activities toward the tested cell lines. PMID- 28649864 TI - The French addictovigilance network clinical assessment: Z-drugs, true false twins. AB - INTRODUCTION: In France, an addictovigilance network is responsible for evaluating drug dependence, by drawing on pharmacoepidemiological studies, clinical studies and by assessing healthcare professionals' reports on problematic consumption. METHODS: The aim of this study was to determine whether zolpidem and zopiclone have different dependence profiles, based on healthcare professionals' reports, and to identify various consumer dependence profiles among zolpidem users and among zopiclone users. Dependence in reports was assessed using the EGAP scale; a scale developed using the DSM diagnostic dependence criteria. RESULTS: The comparison of dependence profiles for zolpidem and zopiclone showed differences both in total EGAP score and EGAP item positivity. The descriptive analysis showed that EGAP scores were higher for zolpidem than for zopiclone, suggesting more severe problematic consumption with zolpidem. For zolpidem 2 subpopulations of consumers were identified, with one subpopulation's consumption being more severe than the other, with a significantly higher total EGAP score and more harmful consequences. No subpopulation was highlighted for zopiclone. CONCLUSION: These results were in favour of a higher prevalence of physical and compulsive signs of dependence and of harmful consequences of dependence, with zolpidem than with zopiclone. PMID- 28649865 TI - Dental stem cells: recent progresses in tissue engineering and regenerative medicine. AB - Since the disclosure of adult mesenchymal stem cells (MSCs), there have been an intense investigation on the characteristics of these cells and their potentialities. Dental stem cells (DSCs) are MSC-like populations with self renewal capacity and multidifferentiation potential. Currently, there are five main DSCs, dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs) and dental follicle precursor cells (DFPCs). These cells are extremely accessible, prevail during all life and own an amazing multipotency. In the past decade, DPSCs and SHED have been thoroughly studied in regenerative medicine and tissue engineering as autologous stem cells therapies and have shown amazing therapeutic abilities in oro-facial, neurologic, corneal, cardiovascular, hepatic, diabetic, renal, muscular dystrophy and auto-immune conditions, in both animal and human models, and most recently some of them in human clinical trials. In this review, we focus the characteristics, the multiple roles of DSCs and its potential translation to clinical settings. These new insights of the apparently regenerative aptitude of these DSCs seems quite promising to investigate these cells abilities in a wide variety of pathologies. Key messages Dental stem cells (DSCs) have a remarkable self-renewal capacity and multidifferentiation potential; DSCs are extremely accessible and prevail during all life; DSCs, as stem cells therapies, have shown amazing therapeutic abilities in oro-facial, neurologic, corneal, cardiovascular, hepatic, diabetic, renal, muscular dystrophy and autoimmune conditions; DSCs are becoming extremely relevant in tissue engineering and regenerative medicine. PMID- 28649866 TI - Sensory profile of sheep cheeses during a six-month storage period as evaluated by consumers. AB - Over the past decade, the use of check-all-that-apply questions has become an easier and faster alternative to traditional sensory profiles using trained assessors, allowing the characterisation of a product by consumers. In this study, 65 consumers evaluated the acceptability of six artisan Uruguayan sheep cheese samples during a six-month storage period, providing a descriptive profile using a check-all-that-apply questionnaire consisting of 32 sensory and non sensory terms. Although the acceptability of five of the six samples was not modified during storage, the consumers were able to perceive changes in the texture and flavour of products, providing a sensory profile of the cheeses. The categories s trange flavour, animal odour, strange odour, bitter and acidic were associated with negative terms such as bad quality and unpleasant flavour, whereas salty and tasty appeared to be related to positive terms including good quality, pleasant flavour and delicious. Therefore, for the Uruguayan consumer, preference for this type of product appears to be mainly conditioned by the flavour perceived in these cheeses, rather than their texture attributes. PMID- 28649867 TI - Study of isotopes of carbon, thorium, and uranium in travertine and thermal spring samples: implications for effects of changes in geochemical environment and processes. AB - Data on modern radiocarbon activity in the old travertine formations of the Pymvashor hydrothermal system were used, in combination with 230Th/U dating of the travertine, to estimate the 14C contents of the total dissolved inorganic carbon in the ancient thermal water at the time of precipitation of the travertine (14Ccalc). With the known values of 14Ccalc and average age of the thermal water, and under the assumption that the residence time of the water in aquifer was constant over the last 13.9 +/- 1.5 ka, the initial 14C contents (14C0) in the ancient thermal water were estimated. The findings in this study are that (1) both 14C0 and delta13S have decreased in young waters compared to the ancient waters; (2) although atmospheric 14C activity (14Catm) has also decreased in the same time, the decrease in 14C0 is faster than the decrease in 14Catm. Under certain assumptions, one could link changes in 14C0 and delta13C to climate change. Decrease in delta13S of soil CO2 and decrease in 14C0 was caused predominantly by warmer and wetter climate, decomposition of fossil organic matter, and decrease in 14Catm. There could be also increased dissolution of solid carbonate and increased carbon exchange between DIC and soil CO2, caused by thawing permafrost. PMID- 28649868 TI - Early Eye Movement Desensitisation and Reprocessing (EMDR) intervention in a disaster mental health care context. AB - 'Early psychological intervention' is defined as commencing treatment within three months of the traumatic event, with the aim to prevent or treat posttraumatic stress disorder, ongoing distress or acute stress disorder. In natural disaster situations, specific issues may limit the amount of time available for treatment and the possibility of interventions. Eye Movement Desensitisation and Reprocessing (EMDR) can be used without regard to these limits. The aim of the study is to evaluate the effects of EMDR, Recent Traumatic Episode Protocol (R-TEP) provided within three months of the traumatic event to a large sample of individuals exposed to the earthquake that hit Emilia Romagna Region (Northern Italy) in 2012. This study is based on a retrospective review of medical records collected during the activities of psychological and psychosocial unit in the immediate aftermath of earthquake. In total, 529 participants completed the Impact of Event Scale Revised (IES-R) (pre e post treatment). In order to provide a comparison similar to a waitlist-like control group, a method of cohort analysis was applied. In addition, possible time dependent effect was tested. ET (early-treated sample, participants treated within one month after the earthquake) and LT (late-treated sample, participants treated after the first month from the earthquake) reported at post-treatment an improvement to a level below the IES-R cutoff (65.8% of the ET sample and 64.02% of the LT sample). Control group analogue and time-outcome correlation suggest that positive changes in symptoms were likely due to the treatment provided and not merely to the time lapse from the traumatic event. The results of this study suggest that EMDR is a viable treatment option in response to a disaster crisis and in reducing psychological distress of acutely traumatized individuals within the context of a natural disaster. PMID- 28649869 TI - HIVR4P 2016, Partnering for Prevention: Conference Summary and Highlights. AB - HIV Research for Prevention: AIDS Vaccine, Microbicide, and ARV-based Prevention Science (HIVR4P) was built on a growing consensus that effective HIV prevention requires a combination of approaches and that understanding, analyzing, and debating the cross-cutting issues that impact prevention research are all essential to combat the global HIV/AIDS epidemic. To that end, the biennial HIVR4P conference is dedicated to all biomedical HIV prevention research approaches, including HIV vaccines, microbicides, pre-exposure prophylaxis, and treatment as prevention. The HIVR4P 2016 conference was held in Chicago, Illinois (USA), on October 17-21, and included more than 700 scientific presentations and 21 satellite sessions covering the latest and most promising advances across the HIV prevention research field. The theme "Partnering for Prevention" represented the conference's commitment to breaking down silos between research disciplines as well as between researchers, program developers, care providers, advocates, communities, and funders. Delegates spanning 42 countries attended the conference. One-third of those in attendance were early career investigators, which reflects a firm commitment to emerging researchers and ultimately to the goal of developing a sustainable scientific enterprise well into the future. This article presents a concise summary of highlights from the conference. For a more detailed account, one may find full abstracts, daily summaries, and webcasts on the conference website at hivr4p.org. PMID- 28649870 TI - Lubricant Provides Poor Rectal Mucosal HIV Coverage. AB - Given the rising HIV incidence in men who have sex with men (MSM) despite repeatedly proven effectiveness of oral HIV pre-exposure prophylaxis, behaviorally congruent periodic dosing strategies, such as dosing microbicides as lubricants, are now in demand. Rectal microbicide gel studies largely administer gels using vaginal applicators, which have not been well received and do not mimic lubricant use. We compared rectal gel manually dosed as lubricant with applicator dosing in five healthy, HIV-negative MSM who received 10 or 3.5 ml of 99mTc-DTPA-radiolabeled hydroxyethyl cellulose universal placebo gel intrarectally. After washout, participants received 10 ml of radiolabeled Wet(r) Original(r) lubricant to apply to the anus with fingers and/or a phallus in a manner typical of sexual lubricant use with a partner, followed by simulated receptive anal intercourse. Single-photon emission computed tomography with transmission computed tomography was performed 4 h after each gel administration. Manual dosing was associated with more variable rectosigmoid distribution, 4.4 15.3 cm from the anorectal junction, compared with more uniform distribution, 5.9 7.4 and 5.3-7.6 cm after 10 and 3.5 ml applicator dosing, respectively. A significantly smaller fraction of the initial 10 ml dose was retained within the colon after manual dosing, 3.4%, compared with 94.9% and 88.4% after 10 and 3.5 ml applicator dosing, respectively (both p < .001). Manual dosing of a sexual lubricant delivered a small, variable fraction of the dose with variable rectosigmoid distribution compared with applicator dosing. These results raise concern that dosing a rectal microbicide gel as a sexual lubricant may not provide adequate or predictable mucosal coverage for HIV protection. PMID- 28649871 TI - The potential role of nintedanib in treating colorectal cancer. AB - INTRODUCTION: Angiogenesis leads to the growth, progression, and metastases of a variety of solid tumors, including metastatic colorectal cancer (mCRC), involving particularly the family of vascular endothelial growth factors (VEGF) and their receptors (VEGFR). Several anti-angiogenic inhibitors are already registered for mCRC therapy: bevacizumab, aflibercept, ramucirumab, regorafenib. Nintedanib is a new triple angiokinase oral inhibitor that potently blocks the proangiogenic pathways mediated by VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Areas covered: The current state-of-the art of anti-angiogenic inhibitors employed in the treatment mCRC patients, and in particular the role of nintedanib in this setting, is reviewed and discussed here. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert opinion: In first-line therapy, a phase II randomized trial showed that nintedanib plus chemotherapy was not inferior to the bevacizumab-based regimen. In heavily pretreated mCRC patients nintedanib improved some outcomes. During the natural history of mCRC resistances to anti-angiogenic therapies can set in and in this context, nintedanib, due to its triple inhibition, might play a role in compensatory angiogenesis overcoming the resistance developed due to VEGF directed therapy. PMID- 28649872 TI - Indoor swimming pool environments and self-reported irritative and respiratory symptoms among lifeguards. AB - A web survey was conducted among 870 lifeguards (current and former) to assess the relationship between exposure to indoor swimming pool environments and respiratory health. Associations between respiratory symptoms and asthma with varying lengths of occupational exposure were assessed by multiple logistic regression. Lifeguards exposed more than 500 hours in the previous 12 months experienced more cough (adjustedOR = 2.54, IC95 % = 1.51-4.25), throat (aOR = 2.47, IC95 % = 1.44-4.24) and eye irritation (aOR = 4.34, IC95 % = 2.52-7.50) during this period than non-exposed lifeguards. Upper and lower respiratory symptoms while on duty were related to duration of lifetime exposure (> 500 days vs. <= 50 days: Upper aOR = 5.84, IC95 % = 3.60-9.50; Lower aOR = 2.53, IC95 % = 1.58-4.06). Physician-diagnosed asthma was high among lifeguards (23 %). Highly exposed asthmatic lifeguards (> 500 hours) over the previous 12 months had a significantly higher risk (aOR = 3.74, IC95 % = 1.39-10.02) of suffering from asthma attack(s) than non-exposed asthmatic subjects. Exposure to indoor swimming pool environments is related to respiratory symptoms among lifeguards. PMID- 28649873 TI - Can you snooze your way to an 'A'? Exploring the complex relationship between sleep, autonomic activity, wellbeing and performance in medical students. AB - OBJECTIVE: Medical training brings with it multiple stressors, including demanding workloads in highly competitive environments, with well-documented impact on psychiatric morbidity. This study evaluated the impact of sleep-related factors on psychological wellbeing, cognitive task performance and academic standing in medical students. METHODS: A total of 59 undergraduate medical students took part in this cross-sectional study over two consecutive days. Participants responded to questionnaires about their physical and psychological health, sleep, functioning and academic performance at the initial visit. Participants then wore an ambulatory bioharness overnight (to derive heart rate variability measures), before returning to complete a computerised battery of cognitive tasks. A sleep diary was completed for the next 7 days. RESULTS: Poor sleep quality in the month preceding assessment correlated with psychological distress ( p < 0.001) and reduced nocturnal heart rate variability ( p = 0.007). Psychological distress also correlated with reduced nocturnal heart rate variability ( p = 0.031) and less refreshing sleep during the monitoring week ( p < 0.001), but not with sleep timing parameters. A greater increase in heart rate variability during the transition from awake to sleep significantly predicted better spontaneous cognitive performance ( p = 0.021). Better academic standing was predicted by consistently short, less refreshing sleep (all p < 0.001), along with earlier bedtimes ( p = 0.004) and greater psychological wellbeing ( p = 0.009). CONCLUSION: Unrefreshing, short-duration sleep and psychological distress are prevalent in medical students during university training and were associated with reduced nocturnal parasympathetic autonomic activity. Achieving higher academic grades was associated with high psychological wellbeing despite consistently short, unrefreshing sleep. The long-term repercussions of such sleep behaviours on later professional functioning remain unclear, warranting further research. PMID- 28649874 TI - A web application for evaluating Phase I methods using a non-parametric optimal benchmark. AB - BACKGROUND/AIMS: In evaluating the performance of Phase I dose-finding designs, simulation studies are typically conducted to assess how often a method correctly selects the true maximum tolerated dose under a set of assumed dose-toxicity curves. A necessary component of the evaluation process is to have some concept for how well a design can possibly perform. The notion of an upper bound on the accuracy of maximum tolerated dose selection is often omitted from the simulation study, and the aim of this work is to provide researchers with accessible software to quickly evaluate the operating characteristics of Phase I methods using a benchmark. METHODS: The non-parametric optimal benchmark is a useful theoretical tool for simulations that can serve as an upper limit for the accuracy of maximum tolerated dose identification based on a binary toxicity endpoint. It offers researchers a sense of the plausibility of a Phase I method's operating characteristics in simulation. We have developed an R shiny web application for simulating the benchmark. RESULTS: The web application has the ability to quickly provide simulation results for the benchmark and requires no programming knowledge. The application is free to access and use on any device with an Internet browser. CONCLUSION: The application provides the percentage of correct selection of the maximum tolerated dose and an accuracy index, operating characteristics typically used in evaluating the accuracy of dose-finding designs. We hope this software will facilitate the use of the non-parametric optimal benchmark as an evaluation tool in dose-finding simulation. PMID- 28649875 TI - Potential benefits of zolpidem in disorders of consciousness. AB - INTRODUCTION: It has been suggested that zolpidem may arouse patients with decreased level of consciousness. Zolpidem may partially or even completely reverse abnormal cell metabolism following brain damage. In this article, available evidences regarding effects of zolpidem on disorders of consciousness were reviewed. Areas covered: A literature review was conducted using PubMed, Scopus, Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Google Scholar as online databases. Search Keywords were 'vegetative state', 'minimally conscious state', 'semi-comatose', 'arousal', 'zolpidem', 'wakefulness', 'awareness', and 'loss of consciousness'. All English language studies that evaluated the effects of zolpidem on disorders of consciousness as a main surrogate endpoint were included. Finally 21 articles within this subject were included. Expert commentary: Zolpidem showed positive effects in several conditions with decreased level of consciousness. However, benefits of zolpidem were not detected in all patients with disorders of consciousness. Patients with post-anoxic encephalopathy or traumatic brain injury did not experience benefits of zolpidem. Available evidences support positive effects of zolpidem on brain functions in patients with non-brain stem injuries. PMID- 28649876 TI - Myasthenia gravis induced by nivolumab in patients with non-small-cell lung cancer: a case report and literature review. AB - A 76-year-old woman who was diagnosed with non-small-cell lung cancer presented with left eyelid ptosis and grade 4 creatine phosphokinase elevation after the second cycle of nivolumab monotherapy. Nivolumab has demonstrated promising efficacy in patients with non-small-cell lung cancer in several trials. Dyspnea and muscle weakness developed rapidly with an acute exacerbation. She underwent plasmapheresis and intravenous immune globulin followed by treatment with low dose prednisolone. She had gradual symptoms improvement. We diagnosed her with myasthenia gravis (MG) based on her symptoms and the detection of anti acetylcholine receptor antibody. According to postmarketing surveillance in 15,740 Japanese patients, the total incidence rate of MG is 0.1%. We report a rare case of drug-induced MG in a patient receiving nivolumab. PMID- 28649877 TI - Retrospective cohort study and biobanking of patients treated for hemangioma in childhood - telomeres as biomarker of aging and radiation exposure. AB - PURPOSE: Cohorts allowing joint epidemiological and biological analyses are essential for radiation risk assessment. The French Hemangioma Cohort (FHC), studied within the European project EpiRadBio, is one of the rare cohorts suitable for studying the effect of low dose radiation exposure (<100 mGy at organs), with a long-term follow-up. This highly homogeneous cohort consists of healthy individuals belonging to a normal population, except for the presence of skin hemangioma (age at exposure: between 6 months and 3 years of age). Published epidemiological studies have demonstrated that the risk of developing cancer is three times higher in the exposed individuals than in the general population. Here, we present the biobanking of samples (nucleated blood cells, cytogenetic slides of T and B lymphocytes) from the FHC and a primary feasibility study of biomarker analysis focusing on mean telomere length (MTL). Telomeres act as an internal clock, regulating the lifetime of the cell by their shortening during cell division. MTL is thus a biomarker of age. Many in vitro studies have linked MTL and radiosensitivity. The FHC will make it possible to discriminate between the effects of aging and radiation on this biomarker. CONCLUSION: The establishment of a biobank of essentially healthy individuals (369 in total), exposed 40-70 years before, during their early childhood, is a logistical challenge. Even among those who previously participated to a self-questionnaire based study, the response rate was only 30%. The first biomarker to be studied was the MTL to discriminate age effects from those of radiation exposure. MTL showed significant variation within age groups (4-11 kb) in both the exposed and non-exposed groups. MTL within the limited age window (i.e. 40-73 year) examined, showed age-dependent changes of 46 bp/year, consistent with the age-dependent decline of 41 bp/year previously reported. We observed no significant changes in MTL according to the average active bone marrow dose. However, we were able to demonstrate that exposure to radiation causes the loss of cells with, on average, shorter telomeres, by applying a model in which both the heterogeneity of the individual dose received at the bone marrow and the heterogeneity of the intercellular distribution of MTL were taken into account. PMID- 28649878 TI - Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti rheumatic drugs (DMARDs): Post-marketing surveillance in Japan. AB - OBJECTIVES: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti rheumatic drugs (DMARDs). METHODS: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. RESULTS: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. CONCLUSIONS: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting. PMID- 28649879 TI - A protocol for ovulation delay in women who cannot use estrogen, including Jewish women with Niddah issues and a pilot study. AB - Orthodox Jewish women abstain from sexual intercourse from the commencement of menstruation until seven days after the end of menstrual bleeding at which point they can immerse themselves in a ritual bath and recommence relations. For women who ovulate prior to commencing intercourse this results in religious infertility. The traditional treatment for religious infertility is oral estrogens in the early follicular phase to delay ovulation. However, certain groups of women have contraindications to oral estrogens. In this group, no treatment options have existed until now. In this study we proposed a treatment protocol substituting the use of gonadotropin releasing hormone-antagonists in the early follicular phase for the oral estrogens. In a small pilot study, we demonstrate that these two protocols have similar outcomes in terms of ovulation delay (p = 1.0) and likelihood of ongoing pregnancy (p = 1.0). This protocol for ovulation delay also has applications in non-Jewish women who need to delay ovulation due to life constraints. PMID- 28649880 TI - Understanding type 1 diabetes through proteomics. AB - INTRODUCTION: Auto-immunity against pancreatic beta-cells leads to an absolute shortage of the hormone insulin, resulting in hyperglycemia and the onset of type 1 diabetes (T1D). Proteomic approaches have been used to elucidate the mechanisms of beta-cell dysfunction and death. Areas covered: In the present review, we discuss discoveries in the beta-cell proteome that have contributed to better insights in the role of the beta-cell in T1D. Techniques, such as 2D-DIGE and MALDI imaging, together with new approaches for sample preparation, including laser capture microdissection and immunopeptidomics, have resulted in novel mechanistic insights in the pathogenesis of T1D. We describe how proteomic studies in beta-cell lines as well as isolated islets from animal models and humans have discovered intracellular signaling pathways leading to beta-cell destruction, the generation of neo-antigens through post-translational modifications of beta-cell antigens as well as better biomarkers of disease progression. Expert commentary: Proteomics has contributed to the discovery of beta-cell neo-autoantigen generation through post-translational modifications, hybrid insulin peptide formation and the generation of defective ribosomal gene products. These concepts are revolutionizing our insights in the pathogenesis of T1D, acknowledging a central role for the beta-cell in its own destruction. PMID- 28649881 TI - Cost-effectiveness analysis of insulin degludec compared with insulin glargine u100 for the management of type 1 and type 2 diabetes mellitus - from the Spanish National Health System perspective. AB - BACKGROUND: The objective of this study was to assess the cost-effectiveness of insulin degludec versus insulin glargine, from the Spanish NHS in three groups of patients. METHODS: A short-term cost utility model was developed to estimate effectiveness results in terms of the total number of hypoglycaemic events and their disutility impact throughout the year on the initial level of quality of life for patients in each treatment. RESULTS: Degludec was the dominant strategy for T2DM BOT and exhibited an incremental cost-effectiveness ratio of 52.70?/QALY and 11,240.88?/QALY for T1DM B/B and T2DM B/B, respectively. Lower costs are primarily driven by lower nocturnal and severe hypoglycaemic events, which were reduced versus IGlar. Improvements in clinical outcomes in all three patient groups are result of the reduced number of hypoglycaemic events showing 0.0211, 0.0328 and 0.0248 QALYs gained when compared to IGlar for T1DM B/B, T2DM BOT and T2DM B/B, respectively. Different scenario analyses showed that the ICERS were stable to plausible variations in the analysed parameters, except when the same number of SMBG for both treatments is used, with T2DM B/B showing an ICER over the accepted threshold. CONCLUSION: This analysis demonstrates that degludec is a cost-effective option in the Spanish NHS, when used in patients currently treated with long-acting insulin. PMID- 28649882 TI - Neratinib for the treatment of HER2-positive early stage breast cancer. AB - INTRODUCTION: Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required. PMID- 28649884 TI - The long term occupational fitness of UK military personnel following community mental health care. AB - BACKGROUND: Fitness to undertake operational deployment is a key requirement of military service. AIM: To assess individual deployment fitness at a single point from one month to eight years following discharge from mental healthcare. METHOD: Survival analyses assessed levels of deployability; the predictive effects of key covariates upon time to being classified as non-deployable were examined using univariate and multivariate Cox proportional hazards regression procedures. RESULTS: A total of 1405 individuals provided study data. 437 individuals (31.1%) were non-deployable or discharged from service during follow-up. 17.2% were non deployable in the first year following mental healthcare; the proportion did not rise above this level until year seven when it was 19.1% and then 30.6% in year eight. Risk factors for being classified as non-deployable were female sex, receipt of intermediate duration therapy, management by the multidisciplinary team and previous referral to mental health services. Previous deployment was significantly associated with reduced risk. Overall, the levels of non deployability appeared to be no higher than those found among the wider military services. CONCLUSION: Non-deployable status among mental healthcare recipients was broadly similar to that found among the wider UK military; risk factors for non-deployability could be amenable to targeted relapse prevention measures. PMID- 28649883 TI - Middle-down proteomics: a still unexploited resource for chromatin biology. AB - INTRODUCTION: Analysis of histone post-translational modifications (PTMs) by mass spectrometry (MS) has become a fundamental tool for the characterization of chromatin composition and dynamics. Histone PTMs benchmark several biological states of chromatin, including regions of active enhancers, active/repressed gene promoters and damaged DNA. These complex regulatory mechanisms are often defined by combinatorial histone PTMs; for instance, active enhancers are commonly occupied by both marks H3K4me1 and H3K27ac. The traditional bottom-up MS strategy identifies and quantifies short (aa 4-20) tryptic peptides, and it is thus not suitable for the characterization of combinatorial PTMs. Areas covered: Here, we review the advancement of the middle-down MS strategy applied to histones, which consists in the analysis of intact histone N-terminal tails (aa 50-60). Middle down MS has reached sufficient robustness and reliability, and it is far less technically challenging than PTM quantification on intact histones (top-down). However, the very few chromatin biology studies applying middle-down MS resulting from PubMed searches indicate that it is still very scarcely exploited, potentially due to the apparent high complexity of method and analysis. Expert commentary: We will discuss the state-of-the-art workflow and examples of existing studies, aiming to highlight its potential and feasibility for studies of cell biologists interested in chromatin and epigenetics. PMID- 28649885 TI - Can the source of hyperandrogenism in adolescents with polycystic ovary syndrome predict metabolic phenotype? AB - In this study, we demonstrated an association between adrenal hyperandrogenism, as determined by dehydroepiandrostenedione-to-free testosterone (DHEA-S/FT) ratio, and metabolic phenotype in obese and lean adolescents with polycystic ovary syndrome (PCOS). We compared 64 overweight/obese adolescents with PCOS (PCOS-O) with 18 lean (PCOS-L) adolescents. We analyzed the association between DHEA-S/FT ratios and metabolic parameters. Patients in the PCOS-O group were younger (median [interquartile range]) than those in the PCOS-L group (15 [15-17] vs. 16 [16-17] years; p = .04). The median DHEA-S/FT ratio and total testosterone concentrations did not differ. However, androstenedione concentrations were higher in the PCOS-L group (p = .02) and free testosterone levels lower in the PCOS-L group compared with the PCOS-O group (p = .02). Insulin resistance was present in 30 of 64 (46.9%) adolescents with PCOS-O compared with 1 of 18 (5.6%) with PCOS-L (p = .001). A significant negative correlation between DHEA-S/FT ratios and insulin concentrations in PCOS-O (p = .03) and PCOS-L (p = .04) groups was noted. In the PCOS-O group, the DHEA-S/FT ratio was negatively associated with serum triglyceride (p = .03) and total cholesterol concentrations (p = .02). We conclude that in adolescents with PCOS, a higher ratio of adrenal to ovarian androgens, signified by DHEA-S/FT, may be associated with a more favorable metabolic phenotype. PMID- 28649886 TI - Epidermal growth factor inhibitors in first-line for metastatic colorectal cancer with ras wild-type: a perspective based on pharmacological costs. AB - INTRODUCTION: In light of the relevant expenses of pharmacological interventions it might be interesting to make a balance between the cost of the new drugs administered, such as EGFRIs (cetuximab and panitunumab) and the added value represented by the improvement of the clinical parameters of interest such as progression free survival (PFS). Areas covered: The analysis was conducted to assess the effect of front-line chemotherapy on the PFS, separately, on each arm of the evaluated trials. Only phase III randomized controlled trials (RCTs) were considered. We calculated the pharmacological costs necessary to get the benefit in PFS, for each trial. We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to the above phase III RCTs. Our analysis evaluated 9 phase III RCTs, including 7199 patients. ESMO-MCBS reached high scores (grade 4) for the CRYSTAL and PRIME trials. The combination of FOLFOX and panitunumab is associated with low difference per month PFS gained (15 821.9 ?) instead of FOLFIRI plus cetuximab (21 854.6 ?) in KRAS wild-type patients. Expert commentary: Our data demonstrate a huge difference in cost per month of PFS gained in modern front-line treatments in mCRC with RAS wild-type. PMID- 28649887 TI - Has the new Kirkpatrick generation built a better hammer for our evaluation toolbox? AB - Although Kirkpatrick's original outcome-focused model is widely used to evaluate medical education programs, it is subject to criticism. To combat this criticism and address the complexities of learning environments, the New World Kirkpatrick Model has emerged. This brief article describes key aspects of the New World Kirkpatrick Model for program evaluation. Specifically, it highlights three major criticisms of Kirkpatrick's original model and discusses the ways in which this new model attempts to rebut them. By doing so, this article hopes to encourage medical teachers to try the New World Kirkpatrick Model in the evaluation of their complex educational programs and investigate its strengths and weaknesses. PMID- 28649888 TI - Drug-induced large vessel vasculitis with carotid arterial ring sign. PMID- 28649889 TI - Effectiveness of multi-target therapy in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with early-stage interstitial lung disease. PMID- 28649890 TI - Alteration of ghrelin/obestatin ratio in adolescence with polycystic ovarian syndrome. AB - Ghrelin, an endoggenous for the growth hormone secretagogue receptor, has been shown to participate in the regulation of energy homeostasis and pituitary hormone secretion. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. Ghrelin and obestatin are altered in polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and pituitary hormone secretion disorder. The aim of this study was to evaluate ghrelin/obestatin imbalance in relation to insulin resistance and pituitary hormone in adolescence with PCOS. This restrospective case-control study included 33 adolescence with PCOS and 38 control adolescence. Ghrelin and obestatin concentrations in serum were determined by RIA, and the serum fasting glucose and Insulin were determined by the glucose oxidase color method and INS-EASIA. The serum LH and FSH were measured by highly specific hemiluminescence immunoassays. We found that the serum ghrelin levels and ghrelin/obestatin ratio were significant lower in PCOS group than in control group, and the serum obestatin levels were significant higher in PCOS group than in control group. The ghrelin/obestatin ratios were negatively correlation with LH/FSH ratio and insulin resistant index in PCOS group. The findings of this study suggest that ghrelin/obestatin imbalance may play a role in pathogenesis of adolescent PCOS. PMID- 28649892 TI - Are we exaggerating neuropsychological impairment in depression? Reopening a closed chapter. AB - BACKGROUND: Meta-analyses conclude that individuals with depression display neurocognitive deficits. However, the extent to which some of these impairments occur due to secondary influences, and thus in part represent epiphenomena, has rarely been tested. Therefore, the authors examined the impact of performance motivation, attitude towards cognitive assessment, and momentary symptoms during assessment on neuropsychological test results in depression. RESEARCH DESIGN AND METHODS: Forty-five patients with depression and 60 nonclinical individuals underwent a comprehensive neuropsychological test battery. Before and after the assessment, each participant was asked to complete the Momentary Influences, Attitudes and Motivation Impact on Cognitive Performance Scale (MIAMI). RESULTS: As hypothesized, patients with depression performed worse than nonclinical controls on most neuropsychological parameters. Group differences achieved a medium effect size for parameters tapping speed and a large effect for parameters tapping accuracy. Yet, only one fourth of the patient population displayed abnormal scores (>= 1 SD below the population mean). In line with the hypothesis, patients with depression were more fearful of test outcomes, complained more about negative momentary influences, and were less motivated (based on retrospective assessment) than controls, as assessed with the MIAMI. The MIAMI total score mediated the relationship between group status and test scores in three out of four analyses. When MIAMI scores were entered as covariate, group differences were largely reduced. DISCUSSION: Patients with depression show a more negative attitude towards testing, lower performance motivation, and more negative momentary influences, all of which induce malperformance. The results suggest that performance dysfunction does not necessarily mirror brain dysfunction in areas hosting cognitive functions but is confounded with other factors. Greater caution is warranted when interpreting the results of neuropsychological tests in depressed patients. PMID- 28649893 TI - Radium-223 dichloride for the treatment of castration-resistant prostate cancer with symptomatic bone metastases. AB - INTRODUCTION: Castration-resistant prostate cancer (CRPC) is associated with the development of bone metastases, increased mortality, and a reduction in the patient's quality of life (QOL). The management of metastatic CRPC (mCRPC) has rapidly evolved over the past decade, with a number of available therapeutic agents improving overall survival. Radium-223 dichloride (radium-223), the first targeted alpha therapy, improves survival accompanied by QOL benefits with a favorable safety profile. It is approved in over 40 countries for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease. Areas covered: The current management of CRPC in men with bone metastases, and in particular the role of radium-223 in this setting, is reviewed and discussed. A search of bibliographic databases for peer-reviewed literature and major meetings was conducted. Expert commentary: In treating patients with mCRPC, the best sequencing and/or combination of radium-223 with other agents has yet to be fully elucidated. The role of radium-223 in treating patients with hormone-sensitive metastatic prostate cancer who are candidates for chemotherapy should also be investigated in well-designed trials. The ability to tailor radium-223 therapy to both the clinical and genetic profiles of CRPC patients would be a promising development. PMID- 28649891 TI - New targeted therapies for relapsed pediatric acute lymphoblastic leukemia. AB - INTRODUCTION: The improvement in outcomes for children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories of modern oncology however the prognosis for patients who relapse remains dismal. Recent discoveries by high resolution genomic technologies have characterized the biology of relapsed leukemia, most notably pathways leading to the drug resistant phenotype. These observations open the possibility of targeting such pathways to prevent and/or treat relapse. Likewise, early experiences with new immunotherapeutic approaches have shown great promise. Areas covered: We performed a literature search on PubMed and recent meeting abstracts using the keywords below. We focused on the biology and clonal evolution of relapsed disease highlighting potential new targets of therapy. We further summarized the results of early trials of the three most prominent immunotherapy agents currently under investigation. Expert commentary: Discovery of targetable pathways that lead to drug resistance and recent breakthroughs in immunotherapy show great promise towards treating this aggressive disease. The best way to treat relapse, however, is to prevent it which makes incorporation of these new approaches into frontline therapy the best approach. Challenges remain to balance efficacy with toxicity and to prevent the emergence of resistant subclones which is why combining these newer agents with conventional chemotherapy will likely become standard of care. PMID- 28649894 TI - Comparison of all-cause, stroke, and bleed-specific healthcare resource utilization among patients with non-valvular atrial fibrillation (NVAF) and newly treated with dabigatran or warfarin. AB - BACKGROUND: We compared healthcare utilization outcomes and persistence among non valvular atrial fibrillation (NVAF) patients newly treated with dabigatran or warfarin. METHODS: Using a nationwide, US administrative claims database, a retrospective matched-cohort of newly diagnosed NVAF patients (age>=18 years) treated with dabigatran or warfarin (propensity score matched 1:1) in 01/01/2011 12/31/2013 was evaluated. All-cause, stroke-, and bleed-specific per patient per month (PPPM) healthcare resource utilization (HCRU), incidence rate of hospitalization for stroke or bleed, 30-day readmission, and persistence were reported. RESULTS: In total, 18,890 dabigatran patients were matched to corresponding warfarin patients. Compared to warfarin users, dabigatran users PPPM had significantly fewer all-cause hospitalizations (0.04 vs 0.05), total outpatient visits (3.98 vs 5.87), and lower 30-day readmissions (14.5% vs 17.4%, all p < 0.001). Dabigatran users had lower incidence rate for stroke (0.65 vs 1.06) and bleed (1.69 vs 2.20), stroke (0.0006 vs 0.0011, p < 0.001) and bleed specific hospitalizations (0.002 vs 0.003, p = 0.008), and stroke (0.03 vs 0.04, p < 0.001) and bleed-specific outpatient visits (0.07 vs 0.08, p = 0.018), and significantly lower non-persistence (62.1% vs 66.3%, p < 0.001). CONCLUSION: Among newly diagnosed newly treated NVAF patients, dabigatran users had significantly lower all-cause, stroke- and bleed-specific HCRU, lower risk of hospitalization for stroke or bleed events, lower 30-day readmissions, and higher persistence than warfarin users. PMID- 28649895 TI - The safety and efficacy of palbociclib in the treatment of metastatic breast cancer. AB - INTRODUCTION: Palbociclib (Ibrance(r)) is the first-in-class CDK4/6 inhibitor which has been introduced into clinical practice for the treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). It is an orally administered drug, which acts by selectively inhibiting cyclin-dependant kinases CDK4 and CDK6. Given together with anti-estrogens like letrozole and fulvestrant it enhances the antiproliferative effect of these drugs without compromising the favorable toxicity profile of endocrine therapy. Areas covered: This review gives a concise overview of the current available preclinical and clinical data about pabociclib including its chemistry, mechanism of action, pharmacokinetics and evidence of its substantial anti-tumor efficacy and safety profile when combined with endocrine therapy Expert commentary: Palbociclib doubles treatment efficacy of letrozole and fulvestrant with a restricted and well manageable toxicity profile. Efficacy as well as safety results from the three registration trials are remarkably consistent. Patients' quality of life is maintained on palbociclib treatment. The treatment landscape in ER+ HER2- MBC will be highly influenced by this compound and development of two other CDK4/6 inhibitors. PMID- 28649896 TI - Platelet lysate as a serum replacement for skin cell culture on biomimetic PCL nanofibers. AB - Platelets are a popular source of native growth factors for tissue engineering applications. The aim of the study was to verify the use of platelet lysate as a fetal bovine serum (FBS) replacement for skin cell culture. The cytokine content of the platelet lysate was characterized using the Bio-Plex system. The cells (fibroblasts, melanocytes, and keratinocytes) were cultured on PCL nanofibrous scaffolds to mimic their natural microenvironment. The cytokine content of the platelet lysate was determined, and to the cells, a medium containing platelet lysate or platelet lysate in combination with FBS was added. The results showed that 7% (v/v) platelet lysate was sufficient to supplement 10% (v/v) FBS in the culture of fibroblasts and keratinocytes. The combination of platelet lysate and FBS had a rather inhibitory effect on fibroblasts, in contrary to keratinocytes, where the effect was synergic. Platelet lysate did not sufficiently promote proliferation in melanocytes; however, the combination of FBS and platelet lysate yielded a better outcome and resulted in bipolar morphology of the cultured melanocytes. The data indicated that platelet lysate improved cell proliferation and metabolic activity and may be used as an additive to the cell culture media. PMID- 28649897 TI - Platelet concentrates for bone regeneration: Current evidence and future challenges. AB - Activated platelet concentrates are autologous blood preparations containing supraphysiological concentration of platelets. Platelet concentrates are commonly used for bone regeneration purposes based on the fact that growth factors released from activated platelets alpha granules have osteoinductive effects on bone cells. Although most preclinical and clinical studies show that platelet concentrates improve the outcomes of bone regeneration procedures, some studies reported conflicting results and even negative effects on bone healing. Several confounding parameters have been suggested as possible reasons for such inconsistencies (i.e. preparation and activation methods). However, heterogeneity in clinical studies makes drawing evidence-based conclusions difficult. On the other hand, recent findings show that the constituents of platelets dense granules (i.e. serotonin, ATP, Ca2+) have potential inhibitory effects on bone metabolism. Accordingly, we suggest that a partial explanation for the conflicting results could be the potential negative effects that dense granules may have on bone healing. PMID- 28649898 TI - A review of body composition and pharmacokinetics in oncology. AB - INTRODUCTION: Body surface area dosing of chemotherapeutic agents is based on limited scientific data, and often results in unpredictable plasma drug levels. Cross-sectional computed tomography (CT) imaging provides an accurate measurement of lean mass. This review summarizes emerging roles of lean mass in predicting pharmacokinetics and drug toxicities in cancer patients. Areas covered: A concise review of body composition measurement with CT cross-sectional imaging and its relationship to drug pharmacokinetics and toxicities. A comprehensive review of the predictive value of low lean mass (sarcopenia) in dose-limiting toxicities is also included. Expert commentary: Drug dosing in medical oncology faces many challenges, including heterogeneous body composition profiles. The emerging role of sarcopenia in predicting lean mass may provide the tool needed to more accurately dose patients and prevent dose-limiting toxicities. PMID- 28649899 TI - Individual differences in susceptibility to false memories: The effect of memory specificity. AB - Previous research has highlighted the wide individual variability in susceptibility to the false memories produced by the Deese/Roediger-McDermott (DRM) procedure. This study investigated whether susceptibility to false memories is influenced by individual differences in the specificity of autobiographical memory retrieval. Memory specificity was measured using the Sentence Completion for Events from the Past Test (SCEPT). Memory specificity did not correlate with correct recognition, but a specific retrieval style was positively correlated with levels of false recognition. It is proposed that the contextual details that frequently accompany false memories of non-studied lures are more accessible in individuals with specific retrieval styles. PMID- 28649900 TI - Sweet-cheeks vs. pea-brain: embodiment, valence, and task all influence the emotional salience of language. AB - Previous research has found that more embodied insults (e.g. numbskull) are identified faster and more accurately than less embodied insults (e.g. idiot). The linguistic processing of embodied compliments has not been well explored. In the present study, participants completed two tasks where they identified insults and compliments, respectively. Half of the stimuli were more embodied than the other half. We examined the late positive potential (LPP) component of event related potentials in early (400-500 ms), middle (500-600 ms), and late (600-700 ms) time windows. Increased embodiment resulted in improved response accuracy to compliments in both tasks, whereas it only improved accuracy for insults in the compliment detection task. More embodied stimuli elicited a larger LPP than less embodied stimuli in the early time window. Insults generated a larger LPP in the late time window in the insult task; compliments generated a larger LPP in the early window in the compliment task. These results indicate that electrophysiological correlates of emotional language perception are sensitive to both top-down and bottom-up processes. PMID- 28649901 TI - Psychometric properties of the NEPSY-II affect recognition subtest in a preschool sample: a Rasch modeling approach. AB - OBJECTIVE: Understanding a child's ability to decode emotion expressions is important to allow early interventions for potential difficulties in social and emotional functioning. This study applied the Rasch model to investigate the psychometric properties of the NEPSY-II Affect Recognition subtest, a U.S. normed measure for 3-16 year olds which assesses the ability to recognize facial expressions of emotion. METHOD: Data were collected from 1222 children attending preschools in Singapore. We first performed the Rasch analysis with the raw item data, and examined the technical qualities and difficulty pattern of the studied items. We subsequently investigated the relation of the estimated affect recognition ability from the Rasch analysis to a teacher-reported measure of a child's behaviors, emotions, and relationships. Potential gender differences were also examined. RESULTS: The Rasch model fits our data well. Also, the NEPSY-II Affect Recognition subtest was found to have reasonable technical qualities, expected item difficulty pattern, and desired association with the external measure of children's behaviors, emotions, and relationships for both boys and girls. CONCLUSIONS: Overall, findings from this study suggest that the NEPSY-II Affect Recognition subtest is a promising measure of young children's affect recognition ability. Suggestions for future test improvement and research were discussed. PMID- 28649902 TI - Implementation of telehealth is associated with improved timeliness to kidney transplant waitlist evaluation. AB - Introduction The United States Department of Veterans Affairs (VA) National Transplant Program has made efforts to improve access by introducing Web-based referrals and telehealth. The aims of this study were to describe the programmatic implementation and evaluate the effectiveness of new technology on the timeliness to kidney transplant evaluation at a VA medical centre. Methods Between 1 January 2009 and 31 May 2016, 835 patients were approved for evaluation. Monthly data were summarized as: number of applications, median days to evaluation, and median percentage of evaluations that occurred within 30 days. Temporal trends were analysed using non-parametric comparisons of medians between three eras: Pre Web-based submission, Web-based submission, and Web-based submission with videoconference (VC) telehealth. Results The number of applications did not vary between eras ( p = 0.353). The median time to evaluation and the median percentage of patients with appointments within 30 days improved significantly in the Web-based submission with VC era when compared with the Web-based and Pre Web-based eras (37 vs. 260 and 116 days, respectively, p < 0.001; 100% vs. 8% and 0%, respectively, p < 0.001). Discussion We have been able to markedly improve the timeliness to kidney transplant waitlist evaluation with the addition of telehealth. PMID- 28649903 TI - Herbal medicine for psychiatric disorders: Psychopharmacology and neuroscience based nomenclature. AB - OBJECTIVES: Herbs are frequently and concurrently used with prescribed drugs by patients worldwide. While clinical trials have found some herbs to be as useful as standard psychiatric drugs, most clinicians are unaware of their pharmacological mechanisms. METHODS: We searched English language and other language literature with English abstracts listed in PubMed website, supplemented by additional through Google Scholar's free academic paper abstract website for publications on herbs, focussing on their clinical use in mental disorders, their neurobiology and their pharmacology. RESULTS: A major reason for herbs remaining outside of mainstream psychiatry is that the terminology and concepts in herbal medicine are not familiar to psychiatrists in general. Many publications regarding the use of herbal medicine for psychiatric disorders are deficient in details regarding diagnosis, criteria for response and the neurobiology details compared with publications on standard psychotropic drugs. Nomenclature for herbal medicine is usually confusing and is not conducive to an easy understanding of their mode of action in psychiatric disorders. CONCLUSIONS: The recent neuroscience-based nomenclature (NbN) for psychotropics methodology would be a logical application to herbal medicine in facilitating a better understanding of the use of herbal medicine in psychiatry. PMID- 28649904 TI - Debiasing Health-Related Judgments and Decision Making: A Systematic Review. AB - BACKGROUND: Being confronted with uncertainty in the context of health-related judgments and decision making can give rise to the occurrence of systematic biases. These biases may detrimentally affect lay persons and health experts alike. Debiasing aims at mitigating these negative effects by eliminating or reducing the biases. However, little is known about its effectiveness. This study seeks to systematically review the research on health-related debiasing to identify new opportunities and challenges for successful debiasing strategies. METHODS: A systematic search resulted in 2748 abstracts eligible for screening. Sixty-eight articles reporting 87 relevant studies met the predefined inclusion criteria and were categorized and analyzed with regard to content and quality. All steps were undertaken independently by 2 reviewers, and inconsistencies were resolved through discussion. RESULTS: The majority of debiasing interventions ( n = 60) was at least partially successful. Optimistic biases ( n = 25), framing effects ( n = 14), and base rate neglects ( n = 10) were the main targets of debiasing efforts. Cognitive strategies ( n = 36) such as "consider-the-opposite" and technological interventions ( n = 33) such as visual aids were mainly tested. Thirteen studies aimed at debiasing health care professionals' judgments, while 74 interventions addressed the general population. Studies' methodological quality ranged from 26.2% to 92.9%, with an average rating of 68.7%. DISCUSSION: In the past, the usefulness of debiasing was often debated. Yet most of the interventions reviewed here are found to be effective, pointing to the utility of debiasing in the health context. In particular, technological strategies offer a novel opportunity to pursue large-scale debiasing outside the laboratory. The need to strengthen the transfer of debiasing interventions to real-life settings and a lack of conceptual rigor are identified as the main challenges requiring further research. PMID- 28649905 TI - Juvenile idiopathic arthritis in a patient with previous diagnosis of severe congenital lupus. AB - Neonatal lupus (NL) is an acquired autoimmune disease of the newborn, caused by transplacental passage of the maternal autoantibodies anti SS-A/Ro and anti SS B/La. When the clinical picture starts directly at birth, it is known as congenital lupus (CL). The clinical manifestations are variable. Except for cardiac involvement, the other manifestations tend to be benign, and resolve with the child's clearance of maternal antibodies. We report a patient who presented at birth with very severe involvement of the skin, and subsequent contractures of hands and feet, leading to functional impairment. The patient underwent surgical procedures with excellent result. At the age of 18 months, the patient was diagnosed with oligoarticular juvenile idiopathic arthritis (JIA), and bilateral uveitis at the age of 3 years and a half. Our aim is to alert health professionals about the possibility of a severe course of cutaneous manifestations in CL, as well as the role of CL and NL regarding development of other autoimmune diseases. PMID- 28649906 TI - A test for a difference in the associability of blocked and uninformative cues in human predictive learning. AB - In human predictive learning, blocking, A+AB+, and a simple discrimination, UX+ VX-, result in a stronger response to the blocked, B, than the uninformative cue, X (where letters represent cues, and + and - represent different outcomes). In order to assess if these different treatments result in more attention being paid to blocked than uninformative cues, Stage 1 in each of three experiments generated two blocked cues, B and E, and two uninformative cues, X and Y. In Stage 2, participants received two simple discriminations: either BX+ EX- and BY+ EY-, or BX+ BY- and EX+ EY-. If more attention is paid to blocked than uninformative cues, then the first pair of discriminations will be solved more readily than the second pair. In contrast to this prediction, both discriminations were acquired at the same rate. These results are explained by the theory of Mackintosh (1975), by virtue of the assumption that learning is governed by an individual rather than a common error term. PMID- 28649907 TI - Non-menopausal endocrine and non-endocrine causes of flushing and sweating. AB - Hot flushes and generalised sweating are relatively common presenting complaints, with hypogonadism an important differential diagnosis in both sexes and menopause being the most typical cause in females of climacteric age. However, a variety of other conditions do need to be carefully considered in respect of eugonadal individuals and also for those hypogonadal ones where properly dosed sex steroid replacement has failed to control flushing and sweating, or where the presentation is atypical. Alternative aetiologies may be immediately obvious from the history and physical examination, but more unusual conditions may require deeper scrutiny. This clinical review elaborates on the non-menopausal endocrine and non-endocrine causes of flushing and sweating, including both common and rarer conditions. PMID- 28649908 TI - Linear Perspective and Framing in the Vista Paradox. AB - The vista paradox is the illusion in which an object seen through an aperture appears to shrink in apparent size as the observer approaches the aperture. In four studies, we tested the effect of framing and fixating on the target object. The first two studies assessed the vista paradox in a large scale naturalistic setting in which a 162.26 -m long corridor was aligned to a 97.2 -m high tower (1,407 m away). In the first study, the results showed, for each 16 m section, a mean 9.95% tower enlargement in the moving backward condition, and a mean 11.62% shrinking in the moving forward condition. In the second study, participants had to compensate perceived width change adjusting the focal length of a photographic zoom lens. The results showed, for each 16 m section, a mean change in optical size of 26.37% in the experimental condition, and of 53.08% in the control condition. In the third study, we presented an identical vertical rectangle inserted within five frames differing in size. In the fourth study, linear perspective was added to the images. The results showed that both frame size and linear perspective cues were critical factors for the vista paradox illusion. PMID- 28649909 TI - Safety of IV pulse methylprednisolone therapy during breastfeeding in patients with multiple sclerosis. AB - BACKGROUND: Women with multiple sclerosis (MS) experience an increased risk of relapse in the postpartum period. High-dose methylprednisolone is the first-line treatment for acute relapses. OBJECTIVES: To determine the transfer of methylprednisolone into human milk in breastfeeding MS patients. METHODS: Methylprednisolone therapy was given for postpartum relapse to nine patients for three consecutive days, and seven patients received a daily infusion once a month. Breast milk samples were obtained before infusion and 1, 2, 4, 8, and 12 hours after completion of infusion. RESULTS: Methylprednisolone concentrations in milk were below detection limits immediately before infusion. Cmax was measured at 1, 2, 4, 8, and 12 hours after infusion and levels of 2.100, 1.659, 0.680, 0.174, and 0.102 ug/mL were determined, respectively. The absolute infant dose was 98.98 ug/kg/day, and the relative infant dose (RID) was 0.71% of the weight adjusted maternal dose. CONCLUSION: The level of methylprednisolone transfer into breast milk is very low. The RID for methylprednisolone was lower than the generally accepted value. As methylprednisolone therapy is of short duration, infant exposure would be very low should a mother choose to breastfeed 1 hour after infusion. Waiting 2-4 hours after infusion will limit infant exposure still further. PMID- 28649910 TI - * Extracellular Vesicles and Their Versatile Roles in Tissue Engineering. PMID- 28649911 TI - Three-dimensional printed upper-limb prostheses lack randomised controlled trials: A systematic review. AB - BACKGROUND: Three-dimensional printing provides an exciting opportunity to customise upper-limb prostheses. OBJECTIVE: This review summarises the research that assesses the efficacy and effectiveness of three-dimensional printed upper limb prostheses. STUDY DESIGN: Systematic review. METHODS: PubMed, Web of Science and OVID were systematically searched for studies that reported human trials of three-dimensional printed upper-limb prostheses. The studies matching the language, peer-review and relevance criteria were ranked by level of evidence and critically appraised using the Downs and Black Quality Index. RESULTS: After removing duplicates, 321 records were identified. Eight papers met the inclusion criteria. No studies used controls; five were case studies and three were small case-series studies. All studies showed promising results, but none demonstrated external validity, avoidance of bias or statistically significant improvements over conventional prostheses. The studies demonstrated proof-of-concept rather than assessing efficacy, and the devices were designed to prioritise reduction of manufacturing costs, not customisability for comfort and function. CONCLUSION: The potential of three-dimensional printing for individual customisation has yet to be fully realised, and the efficacy and effectiveness to be rigorously assessed. Until randomised controlled trials with follow-up are performed, the comfort, functionality, durability and long-term effects on quality of life remain unknown. Clinical relevance Initial studies suggest that three-dimensional printing shows promise for customising low-cost upper-limb prosthetics. However, the efficacy and effectiveness of these devices have yet to be rigorously assessed. Until randomised controlled trials with follow-up are performed, the comfort, functionality, durability and long-term effects on patient quality of life remain unknown. PMID- 28649912 TI - Comparative effectiveness of rituximab relative to IFN-beta or glatiramer acetate in relapsing-remitting MS from the Swedish MS registry. AB - OBJECTIVE: To compare treatment effectiveness and persistence in relapsing remitting multiple sclerosis patients who initiated rituximab versus glatiramer acetate (GA) or interferon-beta (IFN-beta). METHODS: A total of 461 patients from the Swedish MS registry in the rituximab arm were propensity score matched on a 1:2 basis with 922 patients from the IFN-beta/GA comparator, between April 2005 and November 2015. Annualised relapse rate (ARR) was compared using the Poisson method. A marginal Cox model was used to analyse time to first relapse, 3-month confirmed disability progression and treatment discontinuation in the matched sample. A signed-rank test was used to compare Expanded Disability Status Scale (EDSS) change from baseline. RESULTS: Rituximab was associated with a reduction in ARR (0.003; 95% confidence interval (CI) = 0.001, 0.009) relative to IFN beta/GA (0.026; 95% CI = 0.020, 0.033) ( p < 0.001). Rituximab was associated with an 87% reduction in the relapse rate (hazard ratio (HR) = 0.13; 95% CI = 0.04, 0.41) and an 85% reduction in the discontinuation rate (HR = 0.15; 95% CI = 0.11, 0.20) relative to IFN-beta/GA. EDSS regression from baseline was greater in the rituximab group at 12 and 24 months. CONCLUSION: Rituximab appears to be superior to first-generation disease-modifying treatments (DMTs) with respect to relapse control and tolerability, whereas superiority on disability outcomes is less clear. PMID- 28649913 TI - Faecal calprotectin detects subclinical bowel inflammation and may predict treatment response in spondyloarthritis. AB - OBJECTIVE: Intestinal inflammation is frequent in patients with spondyloarthritis (SpA). Here, we test the validity of faecal calprotectin as a marker of intestinal inflammation in SpA patients and evaluate the response of adalimumab in patients with and without intestinal lesions. METHOD: Patients were included on the basis of active SpA with a Bath Ankylosing Spondylitis Disease Activity Index >= 4. After a 4 week non-steroidal anti-inflammatory drug washout period, patients were divided into two groups based on faecal calprotectin level (> 100 mg/kg, n = 15, and < 50 mg/kg, n = 15). Adalimumab 40 mg every other week was initiated. Patients with calprotectin >100 mg/kg received an additional 40 mg of adalimumab at baseline. Patients were followed with clinical examination at weeks 12, 20, and 52; magnetic resonance imaging (MRI) at weeks 0, 20, and 52; and endoscopy at weeks 0 and 20. RESULTS: The groups were similar with regard to clinical disease activity measures at baseline. Faecal calprotectin above 100 mg/kg accurately identified patients with intestinal inflammation. Twelve of the 15 patients with elevated calprotectin had bowel lesions, compared to only one patient in the control group. On MRI, the group with elevated calprotectin had more inflammation in the sacroiliac joints. Finally, the group with intestinal inflammation had a better clinical response to adalimumab, as evaluated by the Ankylosing Spondylitis Disease Activity Score. CONCLUSION: Elevated faecal calprotectin accurately identified SpA patients with bowel inflammation and more inflammation on MRI. Elevated faecal calprotectin at baseline may predict a better treatment response. PMID- 28649917 TI - Partial reinforcement and conditioned taste aversion: No evidence for resistance to extinction. PMID- 28649914 TI - Characterizing Time to Diagnostic Resolution After an Abnormal Cancer Screening Exam in Older Adult Participants in the Ohio Patient Navigation Research Program. AB - OBJECTIVE: This study aims to test the effectiveness of a patient navigation (PN) intervention to reduce time to diagnostic resolution among older adults age >=65 years versus those <65 years with abnormal breast, cervical, or colorectal cancer screening exams participating in the Ohio Patient Navigation Research Program (OPNRP). METHOD: The OPNRP utilized a nested cohort group-randomized trial design to randomize 862 participants ( n = 67 for >=65 years; n = 795 for <65 years) to PN or usual care conditions. A shared frailty Cox model tested the effect of PN on time to resolution. RESULTS: Older adult participants randomized to PN achieved a 6-month resolution rate that was 127% higher than those randomized to usual care ( p = .001). This effect was not significantly different from participants <65 years. DISCUSSION: PN significantly reduced time to diagnostic resolution among older adults beginning 6 months after an abnormal cancer screening exam. Health care systems should include this population in PN programs to reduce cancer disparities. PMID- 28649918 TI - Molecular analysis of Hsp70 mechanisms in plants and their function in response to stress. AB - Studying the strategies of improving abiotic stress tolerance is quite imperative and research under this field will increase our understanding of response mechanisms to abiotic stress such as heat. The Hsp70 is an essential regulator of protein having the tendency to maintain internal cell stability like proper folding protein and breakdown of unfolded proteins. Hsp70 holds together protein substrates to help in movement, regulation, and prevent aggregation under physical and or chemical pressure. However, this review reports the molecular mechanism of heat shock protein 70 kDa (Hsp70) action and its structural and functional analysis, research progress on the interaction of Hsp70 with other proteins and their interaction mechanisms as well as the involvement of Hsp70 in abiotic stress responses as an adaptive defense mechanism. PMID- 28649919 TI - Decreased colorectal atypia among a cohort of gout patients. PMID- 28649920 TI - Could the WHO's Framework on Engagement with Non-State Actors (FENSA) be a threat to tackling childhood obesity? PMID- 28649921 TI - Leader Trust, Competence, LMX, and Member Performance. AB - Based on social exchange theory, this study examines the influence of leaders' trusting behavior and competence in in-role activities on members' perceived leader-member exchange (LMX) relationships. Our study proposes that a leader's trust in a member contributes to the member's perceived LMX, and that the leader's competence in in-role activities moderates this relationship. Furthermore, our study suggests that perceived LMX mediates the relationship between the leader's trust and members' task performance. Finally, the study proposes that the leader's competence moderates the mediating role of LMX in transmitting the effect of the leader's trust on members' task performance. Analyses of the data collected from soldiers and platoon leaders in the South Korean army support these hypotheses. PMID- 28649922 TI - In vivo imaging of Lyme arthritis in mice by [18F]fluorodeoxyglucose positron emission tomography/computed tomography. AB - OBJECTIVE: Lyme borreliosis (LB) is a tick-borne infectious disease caused by Borrelia burgdorferi spirochaetes, which are able to disseminate from the tick bite site to distant organs. Mouse models are widely used to study LB and especially Lyme arthritis (LA), but only a few whole-animal in vivo imaging studies on the pathogenesis of B. burgdorferi infection in mice have been published so far. The existing imaging techniques have their drawbacks and, therefore, novel tools to complement the array of available LB imaging methodologies are needed. METHOD: The applicability of positron emission tomography combined with computed tomography (PET/CT) imaging was evaluated as a method to monitor LB and especially LA in the C3H/HeN mouse model infected with wild-type B. burgdorferi N40 bacteria. The imaging results were compared with the traditional LA analysis methods, such as tibiotarsal joint swelling and histopathological assessment of joint inflammation. RESULTS: PET/CT imaging provided high-resolution images with quantitative information on the spatial and temporal distribution of the [18F]fluorodeoxyglucose ([18F]FDG) tracer in B. burgdorferi-infected mice. The [18F]FDG accumulated in the affected joints and activated lymph nodes of infected mice, while the tracer signal could not be visualized in these organs in uninfected control animals. Importantly, in vivo PET/CT imaging data were in agreement with the histopathological scoring of inflammation of mouse joints. CONCLUSION: PET/CT imaging with [18F]FDG is a reliable method to longitudinally monitor the development and progression of B. burgdorferi infection-induced inflammation in vivo in mouse joints. PMID- 28649923 TI - Detecting Abnormal Word Utterances in Children With Autism Spectrum Disorders: Machine-Learning-Based Voice Analysis Versus Speech Therapists. AB - Abnormal prosody is often evident in the voice intonations of individuals with autism spectrum disorders. We compared a machine-learning-based voice analysis with human hearing judgments made by 10 speech therapists for classifying children with autism spectrum disorders ( n = 30) and typical development ( n = 51). Using stimuli limited to single-word utterances, machine-learning-based voice analysis was superior to speech therapist judgments. There was a significantly higher true-positive than false-negative rate for machine-learning based voice analysis but not for speech therapists. Results are discussed in terms of some artificiality of clinician judgments based on single-word utterances, and the objectivity machine-learning-based voice analysis adds to judging abnormal prosody. PMID- 28649924 TI - The value of cognitive neuropsychology: The case of vision research. AB - Cognitive neuropsychological evidence is widely viewed as inherently flawed or weak, despite well-reasoned arguments to the contrary by many theorists. Rather than attempting yet another defence of cognitive neuropsychology on logical grounds, we point out through examples that in practice, cognitive neuropsychological evidence is widely accepted as valid and important, and has had a major impact on cognitive theory and research. Objections offered in the abstract rarely arise in the context of actual studies. We develop these points through examples from the domain of vision, discussing cerebral achromatopsia and akinetopsia, selective impairment and sparing of face recognition, perception action dissociations, and blindsight. PMID- 28649925 TI - Preparation and characterization of alginate/chitosan formulations for ciprofloxacin-controlled delivery. AB - In this work, alginate beads loaded with ciprofloxacin (AL_CP) and alginate beads loaded with ciprofloxacin and covered by chitosan (AL_CP_CS) were prepared by emulsification technique in combination with internal gelation method. Physicochemical characterization of the resulting formulations revealed the hydrodynamic diameter and Zeta potential ca. 160 nm and ca. -32 mV in the case of AL_CP and ca. 240 nm and ca. +14 mV in the case of AL_CP_CS (pH = 6.0), respectively. Kinetics of ciprofloxacin release from alginate/chitosan formulations was studied in different media (pH = 1.2, 6.8, and 7.4). Covering alginate core with a polycation such as chitosan moderates the drug release, resulting in a pH-sensitive hybrid controlled-release system. Herein, alginate beads with encapsulated ciprofloxacin covered with chitosan are proposed as an effective oral delivery system since the drug release from alginate core is limited in low pH solution (gastric conditions). PMID- 28649926 TI - Neoliberalization's Propagation of Health Inequity in Urban Rebuilding Processes: The Dependence on Context and Path. AB - This article will discuss how neoliberal processes during urban redevelopment sustain and increase health inequities through uneven wealth accumulation and development. It will use examples of urban development in Baltimore, Maryland, United States, to highlight how key neoliberal strategies of territorial development, economic development, and place promotion- mediated through the process of creative destruction-result in uneven development and wealth accumulation, which in turn result in health inequities. The history of rebuilding processes in Baltimore offers insight into the context and path dependency of current neoliberalization rebuilding processes and current health inequities. PMID- 28649928 TI - Beyond the Medical Model: Future Directions for Suicide Intervention Services. AB - The medical model continues to dominate research and shape policy and service responses to suicide. In this work we challenge the assumption that the medical model always provides the most effective and appropriate care for persons who are suicidal. In particular, we point to service user perspectives of health services which show that interventions are often experienced as discriminatory, culturally inappropriate, and incongruent with the needs and values of persons who are suicidal. We then examine "humanistic" approaches to care that have been proposed as a corrective to an overly medical model. We argue that the focus on improving interpersonal relations set out in humanistic approaches does not mitigate the prevailing risk management culture in contemporary suicide prevention and may impede the provision of more effective care. Finally, we draw attention to the tradition of non-medical approaches to supporting persons who are suicidal. Using Maytree (a U.K. crisis support service) as a case study, we outline some of the key features of alternative service models that we consider central to the design of more culturally appropriate and effective interventions. We conclude by making three key recommendations for improving services to persons who are suicidal. PMID- 28649927 TI - Retrenched Welfare Regimes Still Lessen Social Class Inequalities in Health: A Longitudinal Analysis of the 2003-2010 EU-SILC in 23 European Countries. AB - This article builds on recent work that has explored how welfare regimes moderate social class inequalities in health. It extends research to date by using longitudinal data from the EU-SILC (2003-2010) and examines how the relationship between social class and self-reported health and chronic conditions varies across 23 countries, which are split into five welfare regimes (Nordic, Anglo Saxon, Eastern, Southern, and Continental). Our analysis finds that health across all classes was only worse in Eastern Europe (compared with the Nordic countries). In contrast, we find evidence that the social class gradient in both measures of health was significantly wider in the Anglo-Saxon and Southern regimes. We suggest that this evidence supports the notion that welfare regimes continue to explain differences in health according to social class location. We therefore argue that although downward pressures from globalization and neoliberalism have blurred welfare regime typologies, the Nordic model may continue to have an important mediating effect on class-based inequalities in health. PMID- 28649929 TI - Involvement of core clock genes in lithium response. PMID- 28649931 TI - A novel approach for application of white rot fungi in wastewater treatment under non-sterile conditions: immobilization of fungi on sorghum. AB - In this study, we tested a new approach to facilitate the application of white rot fungi (WRF) under non-sterile conditions, by introducing grain sorghum as carrier and sole carbon and nutrient source for WRF. To this end, Trametes versicolor was immobilized on sorghum, and its ability to remove humic acid (HA) from synthetic and real industrial wastewater was studied. HA removal was measured as colour reduction and also analysed via size exclusion chromatography (SEC). Under sterile conditions, 80% colour removal was achieved for both synthetic and real wastewater using immobilized WRF on sorghum, without adding any additional carbon or nutrient sources. Under non-sterile conditions, immobilized fungi could again remove 80% of the colour and reached a maximum of 40 U/L laccase activity. In contrast, non-immobilized fungi cultivated in non sterile wastewater supplemented with additional nutrients, reached only 10% decolourization and maximum 5 U/L laccase activity. SEC analysis showed that bioremoval of HA by WRF was associated with degradation of HA. Finally, immobilized fungi were used to treat real wastewater, under non-sterile conditions, in a sequential batch order without renewing the immobilized fungi. Four batch feedings were conducted and 80%, 70%, 50% and 40% colour removal was achieved for each batch, respectively, over a total incubation period of 19 days. PMID- 28649930 TI - Expanding the scope beyond mortality: burden and missed opportunities in maternal morbidity in Indonesia. AB - BACKGROUND: Indonesia still faces challenges in maternal health. Specifically, the lack of information on community-level maternal morbidity. The relatively high maternal healthcare non-utilization in Indonesia intensifies this problem. OBJECTIVE: To describe the burden of community-level maternal morbidity in Indonesia. Additionally, to evaluate the extent and determinants of missed opportunities in women with maternal morbidity. METHODS: We used three cross sectional surveys (Indonesian Demographic and Health Survey, IDHS 2002, 2007 and 2012). Crude and adjusted proportions of maternal morbidity burden were estimated from 43,782 women. We analyzed missed opportunities in women who experienced maternal morbidity during their last birth (n = 19,556). Multilevel mixed-effects logistic regressions were used to evaluate the determinants of non-utilization in IDHS 2012 (n = 6762). RESULTS: There were significant increases in the crude and adjusted proportion of maternal morbidity from IDHS 2002 to IDHS 2012 (p < 0.05). In 2012, the crude proportion of maternal morbidity was 53.7%, with adjusted predicted probability of 51.4%. More than 90% of these morbidities happened during labor. There were significant decreases in non-utilization of maternal healthcare among women with morbidity. In 2012, 20.0% of these women did not receive World Health Organization (WHO) standard antenatal care. In addition, 7.1% did not have a skilled provider at birth, and 25.0% delivered outside of health facilities. Higher proportions of non-utilization happened in women who were younger, multiparous, of low socioeconomic status (SES), and living in less developed areas. In multilevel analyses, missed opportunities in healthcare utilization were strongly related to low SES and low-resource areas in Indonesia. CONCLUSION: The prevalence of maternal morbidity in Indonesia is relatively high, especially during labor. This condition is amplified by the concerning missed opportunities in maternal healthcare. Efforts are needed to identify risk factors for maternal morbidity, as well as increasing healthcare coverage for the vulnerable population. PMID- 28649932 TI - A web of gaps: a discussion of research strands concerning Global South families with a disabled child. AB - BACKGROUND: In low- and middle-income countries (LMICs), limited access to a range of supports means that families often carry primary responsibility for the care of a disabled child. The impact of this responsibility is poorly understood. OBJECTIVE: To present a selective review, critique, and comparison of the prominent areas of research aimed at understanding families with disabled children in the Global South. DESIGN: We compare and critically discuss prominent bodies of literature concerning the family-disability-poverty nexus in LMICs. RESULTS: Three prominent bodies of literature concerned with families with a disabled child in LMICs are reviewed. These were selected based on their relative prevalence in a large review of the literature, and comprise (1) work concerning quality of life (FQOL) of families with a disabled child; (2) interventions aimed at supporting families with a disabled child in LMICs; and (3) the ways in which culture mediates the families' experience of disability. FQOL research points to poverty as a primary source of family distress, and directs our focus towards families' own expertise in coping with their circumstances. Intervention literature from LMICs highlights the family as the unit of analysis and praxis concerning disabled children, and reminds us of the contextual factors which must be considered when working with their families. CONCLUSIONS: Culturally oriented research on poverty, disability, and the family nuances our understanding of the locally-determined priorities of families with a disabled child in LMICs. All three research strands carry benefits, limitations and gaps. The complexity of understanding families with a disabled child in LMICs comes to the fore, directing us away from narrow application of any single theoretical or research framework. Future researchers may draw on insights provided here in creating a more integrated approach. PMID- 28649933 TI - Bone mesenchymal stem cell-conditioned medium decreases the generation of astrocytes during the process of neural stem cells differentiation. AB - OBJECTIVES: The aim of this study was to investigate the effect of bone mesenchymal stem cell (BMSC) conditioned medium (CM) and Bone morphogenetic protein-4 (BMP-4) on the generation of astrocytes during the process of NSCs differentiation. DESIGN: Neural stem cells (NSCs) were grown under different culture conditions. SETTING: The First Affiliated Hospital of Anhui Medical University, Hefei, China. OUTCOME MEASURES: The study consisted of four groups: NSCs cultured under control conditions (group 1) or with the addition of BMSC-CM (group 2);(BMP-4) (group 3) or both (group 4).The expression of glial fibrillary acidic protein (GFAP) was detected by immunocytochemical staining and Western blotting. RESULTS: The expression of GFAP was higher in Group3 and lower in Group 2 compared to that in Group 1. The expression of GFAP in Group 4 was intermediate between that of Group 2 and Group 3. CONCLUSIONS: These results suggest that BMSC CM can decrease the generation of astrocytes and that the inhibition of the (BMP 4) /Smad1/5/8 signaling pathway may be the underlying mechanism. This phenomenon may be mediated by increasing the expression of Smad6. PMID- 28649934 TI - The knowledge and attitudes of orthodontic trainees towards orthodontic therapists: a national survey. AB - OBJECTIVE: To assess the knowledge and attitudes of orthodontic trainees towards orthodontic therapists (OTs) in the UK. DESIGN: Cross-sectional survey. SETTING: UK-based orthodontic trainees. MATERIALS AND METHODS: An electronic survey was sent to all members of the Training Grades Group of the British Orthodontic Society assessing exposure to OTs and their knowledge regarding current supervision guidelines and scope of practice. Attitudes towards OTs were also explored. RESULTS: Seventy-six responses (response rate 57%) were returned. Nearly 90% of trainees had no formal training regarding OTs. A total of 15.5% were aware of the correct current supervision guidelines and there was large variation in the knowledge of OTs' scope of practice. The majority of trainees were happy to supervise OTs, but only 22.4% felt prepared for this during training. In total, 63% of trainees felt that OTs could impact their own future job prospects. CONCLUSIONS: Currently, there is minimal formal training provided to trainees regarding the role of OTs. This is reflected in the lack of knowledge regarding supervision guidelines and scope of practice. Overall, trainees felt OTs were positive for the workforce but were concerned regarding the impact of their own future employment. PMID- 28649935 TI - Evidence of sub-optimal sleep in adolescent Middle Eastern academy soccer players which is exacerbated by sleep intermission proximal to dawn. AB - The purpose was to assess sleep patterns, quantity and quality in adolescent (16.2 +/- 1.2 yr) Middle Eastern academy soccer players (n = 20) and the influence of an intermission upon these characteristics. On a 17-day training camp (located one time zone west of home) including three discrete matches, sleep was assessed pre- (PRE) and post-match (POST) via wrist actigraphy. Retrospective actigraphy analysis identified sleep characteristics, including if players experienced a sleep intermission (YES) or not (NO) proximal to dawn, and bedtime (hh:mm), get-up time (hh:mm), time in bed (h), sleep duration (h) and sleep efficiency (%). Within YES two bouts were identified (BOUT1 and BOUT2). No differences were seen between PRE and POST, nor between BOUT1 and BOUT2 (p > .05). Overall players did not meet National Sleep Foundation (NSF) guidelines (7:04 +/- 1:16 h vs. recommended 8-10 h for 14-17 yr). Sleep duration was significantly reduced (~ -13% or -1:06) in YES compared to NO (6:33 +/- 1:05 vs. 7:29 +/- 1:17, p < .01). Despite players in YES waking earlier due to an intermission, they did not compensate for this with a later wake time, rising significantly earlier compared to NO (09:40 +/- 00:38 vs. 10:13 +/- 00:40, p < .05). These players on average do not obtain sufficient sleep durations relative to NSF guidelines, with decrements increased by an intermission proximal to dawn. High inter- and intra-individual variance in the players sleep characteristics indicates the need for individualized sleep education strategies and interventions to promote appropriate sleep. PMID- 28649936 TI - Berlin prehospital or usual delivery of acute stroke care - Study protocol. AB - Rationale Prehospital stroke care in specialized ambulances increases thrombolysis rates, reduces alarm-to-treatment times, and improves the prehospital triage. Preliminary analyses suggest cost-effectiveness. However, scientific proof of better functional outcome compared to usual care is still lacking. Aim To prove better functional outcomes after deployment of the Stroke Emergency Mobile compared to regular ambulances. Sample size estimates A sample size of 686 patients will be required in each arm (Stroke Emergency Mobile group vs. regular care) to detect a difference regarding the primary outcome with 80% power at a two-sided significance level of 0.05. Methods and design This is a pragmatic, prospective study with blinded outcome assessment. Primary outcome will be functional status as defined by modified Rankin Scale score three months after the incident event. We will include cerebral ischemia patients within a predefined catchment area in Berlin, Germany. The study population consists of patients who might be candidates for acute recanalizing treatments, with onset-to alarm time <=4 h, symptoms not resolved at time of ambulance arrival, and able to walk without assistance prior to the qualifying incident. About 45% of Stroke Emergency Mobile dispatches are expected to be handled by regular ambulances, since Stroke Emergency Mobile will be already in operation creating the control group. Primary outcome Functional outcome after three months measured by the modified Rankin Scale over the entire range. Discussion The results will inform decision makers on the effectiveness of Stroke Emergency Mobile. PMID- 28649937 TI - The genetics of platelet count and volume in humans. AB - The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet's role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies-ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)-employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease. PMID- 28649939 TI - Medical Teacher In Ten Minutes. PMID- 28649938 TI - Epidemiology and survival of cervical cancer in the French West-Indies: data from the Martinique Cancer Registry (2002-2011). AB - BACKGROUND: The Caribbean ranks seventh among world regions most affected by cervical cancer. Social health inequalities, such as differences in access to screening services, engender disparities in incidence and mortality between low- and middle-income countries and industrialized countries. The French National Cancer Plan 2014-2019 focuses on reducing inequalities in cervical cancer. OBJECTIVE: The aim of this study was to describe the geographical distribution and overall survival of cervical cancer, based on data from a population-based cancer registry in Martinique (French West-Indies). METHODS: We included all cases of cervical cancer diagnosed between 2002 and 2011. The geographical distribution was described by zone of residence and by aggregated units for statistical information (IRIS). Based on the results of the model, standardized incidence rates (SIRs) were calculated using a Gamma Poisson model. Survival rates were calculated using the Kaplan-Meier method. Cox proportional hazards models were used to investigate the risk factors for cervical cancer mortality. RESULTS: A total of 1253 cases were analyzed (947 in situ tumors and 306 invasive cancers). 1230 cases with geolocalization were used to map the distribution of the incidence of in situ and invasive cervical cancers. Five IRIS were significantly over-incident. The 5-year overall survival rate was 55%, with a median survival of 6.5 years [95% CI: 4.9-10.1]. Multivariate analysis confirmed age at diagnosis (HR = 2.15 [1.50-3.09]; p < 0.0001), FIGO stage (HR = 3.53 [2.50 4.99]; p < 0.0001) and zone of residence (HR = 1.51 [1.06-2.13]; p = 0.02) as risk factors. CONCLUSIONS: Prognostic factors suggest that cervical cancer needs to be diagnosed at an early stage. Our results could allow cervical cancer screening programs to clearly identify geographical areas that would benefit from targeted interventions with a view to reducing incidence and mortality of cervical cancer in the Caribbean. PMID- 28649940 TI - Top-rated AMEE MedEdPublish papers - March 2017. PMID- 28649941 TI - Treatment effects of olanzapine on homotopic connectivity in drug-free schizophrenia at rest. AB - OBJECTIVES: Deficits in homotopic connectivity have been implicated in schizophrenia. However, alterations in homotopic connectivity associated with antipsychotic treatments in schizophrenia remain unclear due to lack of longitudinal studies. METHODS: Seventeen drug-free patients with recurrent schizophrenia and 24 healthy controls underwent resting-state functional magnetic resonance imaging scans. The patients were scanned at three time points (baseline, at 6 weeks of treatment, and at 6 months of treatment). Voxel-mirrored homotopic connectivity (VMHC) was applied to analyse the imaging data to examine alterations in VMHC associated with antipsychotic treatment. RESULTS: The results showed that patients with schizophrenia exhibited decreased VMHC in the default mode network (such as the precuneus and inferior parietal lobule) and the motor and sensory processing regions (such as the lingual gyrus, fusiform gyrus and cerebellum lobule VI), which could be normalised or denormalised by olanzapine treatment. In addition, negative correlations were found between decreased VMHC and symptom severity in the patients at baseline. CONCLUSIONS: The present study shows that olanzapine treatment can normalise or denormalise decreased homotopic connectivity in schizophrenia. The findings also provide a new perspective to understand treatment effects of antipsychotic drugs on homotopic connectivity in schizophrenia that contribute to the disconnection hypothesis of this disease. PMID- 28649942 TI - The impact of an online learning platform about nursing education on enrolled nurse preceptor teaching capabilities: a pre-post-test evaluation. AB - BACKGROUND: Enrolled nurses (ENs) across Australia precept nursing students in the clinical field. Yet learning about the preceptoring role is not widely available to ENs. Educational innovation: EN's in this study participated in a professional development project that utilised the material of an online learning resource, originally designed to inspire clinical registered nurses (RNs), and RN teachers, to develop teaching innovations in their role. AIM: The aim of this paper is to report the results of a pre-post-test questionnaire designed to evaluate the impact of the professional development intervention. RESULTS: The analysis showed high scoring means with many items in the questionnaire statistically significant (p < .05, CI 95%). CONCLUSION: Results indicated positive differences in a number of teaching capabilities between pre- and post test scores. This suggests ENs appreciate education that extends beyond clinical skills and that professional development should include the nursing education role. PMID- 28649943 TI - Cost-effectiveness of insulin detemir versus insulin glargine for Thai type 2 diabetes from a payer's perspective. AB - AIMS: An economic evidence is a vital tool that can inform the decision to use costly insulin analogs. This study aimed to evaluate long-term cost-effectiveness of insulin detemir (IDet) compared with insulin glargine (IGlar) in type 2 diabetes (T2DM) from the Thai payer's perspective. METHODS: Long-term costs and outcomes were projected using a validated IMS CORE Diabetes Model, version 8.5. Cohort characteristics, baseline risk factors, and costs of diabetes complications were derived from Thai data sources. Relative risk was derived from a systematic review and meta-analysis study. Costs and outcomes were discounted at 3% per annum. Incremental cost-effectiveness ratio (ICER) was presented in 2015 US Dollars (USD). A series of one-way and probabilistic sensitivity analyses were performed. RESULTS: IDet yielded slightly greater quality-adjusted life years (QALYs) (8.921 vs 8.908), but incurred higher costs than IGlar (90,417.63 USD vs 66,674.03 USD), resulting in an ICER of ~1.7 million USD per QALY. The findings were very sensitive to the cost of IDet. With a 34% reduction in the IDet cost, treatment with IDet would become cost-effective according to the Thai threshold of 4,434.59 USD per QALY. CONCLUSIONS: Treatment with IDet in patients with T2DM who had uncontrolled blood glucose with oral anti-diabetic agents was not a cost-effective strategy compared with IGlar treatment in the Thai context. These findings could be generalized to other countries with a similar socioeconomics level and healthcare systems. PMID- 28649944 TI - Hearing without listening: Attending to a quiet audiobook. AB - Careful systematic tests of hearing ability may miss the cognitive consequences of sub-optimal hearing when listening in the real world. In Experiment 1, sub optimal hearing is simulated by presenting an audiobook at a quiet but discriminable level over 50 min. Recall of facts, words and inferences are assessed and performance compared to another group at a comfortable listening volume. At the quiet intensity, participants are able to detect, discriminate and identify spoken words but do so at a cost to sequential accuracy and fact recall when attention must be sustained over time. To exclude other interpretations, the effects are studied in Experiment 2 by comparing recall to the same sentences presented in isolation. Here, the differences disappear. The results demonstrate that the cognitive consequences of listening at low volume arise when sustained attention is demanded over time. PMID- 28649945 TI - How noise and coupling influence leading indicators of population extinction in a spatially extended ecological system. AB - Anticipating critical transitions in spatially extended systems is a key topic of interest to ecologists. Gradually declining metapopulations are an important example of a spatially extended biological system that may exhibit a critical transition. Theory for spatially extended systems approaching extinction that accounts for environmental stochasticity and coupling is currently lacking. Here, we develop spatially implicit two-patch models with additive and multiplicative forms of environmental stochasticity that are slowly forced through population collapse, through changing environmental conditions. We derive patch-specific expressions for candidate indicators of extinction and test their performance via a simulation study. Coupling and spatial heterogeneities decrease the magnitude of the proposed indicators in coupled populations relative to isolated populations, and the noise regime and the degree of coupling together determine trends in summary statistics. This theory may be readily applied to other spatially extended ecological systems, such as coupled infectious disease systems on the verge of elimination. PMID- 28649946 TI - Choline Transporter Immunohistochemistry: An Effective Substitute for Acetylcholinesterase Histochemistry to Diagnose Hirschsprung Disease With Formalin-fixed Paraffin-embedded Rectal Biopsies. AB - Acetylcholinesterase enzymatic histochemistry (AChE EHC), which highlights abnormal cholinergic nerves in the mucosa of aganglionic bowel, has been used for decades to evaluate rectal biopsies for Hirschsprung disease (HSCR). While useful diagnostically, AChE EHC is not compatible with conventional formalin-fixed and paraffin-embedded (FFPE) tissues and is not widely available. The choline transporter (ChT) is a putative alternative marker of cholinergic nerves. ChT immunohistochemistry (IHC) was investigated using FFPE biopsies and resections from patients with confirmed HSCR, as well as appropriate non-HSCR controls. ChT immunostaining was effective at identifying cases with HSCR and qualitatively similar to AChE EHC on frozen section. Among 3 pathologists, the diagnostic positive and negative predictive values based on ChT IHC ranged from 0.84-0.94 and 0.85-0.89, respectively, with good inter-observer agreement (Cohen kappa = 0.70-0.90). ChT IHC was useful in unusual scenarios in which calretinin (CR) IHC failed to correctly identify patients with HSCR. In 10 cases of short-segment HSCR, abnormal ChT+ mucosal innervation was present through the entire aganglionic segment and into portions of the TZ with submucosal nerve hypertrophy. In contrast, mucosal CR IHC was retained in the TZ and adjacent aganglionic bowel, which could lead to misinterpretation of a biopsy as ganglionic bowel. Indeed, 6 such patients were identified with paradoxical CR positive mucosal innervation in their diagnostic biopsies. ChT IHC was interpreted as unequivocal HSCR in these cases, and HSCR was confirmed on resection. In summary, ChT IHC in FFPE tissue demonstrates high positive and negative predictive values for HSCR, is superior to CR IHC in a subset of cases, and can be incorporated into routine practice without the need for specialized techniques. PMID- 28649947 TI - Correction: Molecular architecture of the 90S small subunit pre-ribosome. PMID- 28649948 TI - Endovascular thrombectomy in patients with acute ischaemic stroke and atrial fibrillation: a MR CLEAN subgroup analysis. AB - AIMS: Endovascular thrombectomy (EVT) improves outcome after acute ischaemic stroke (AIS) caused by an intracranial occlusion. The aim of the present study was to determine whether atrial fibrillation (AF) modifies the effect of EVT. METHODS AND RESULTS: MR CLEAN was a randomised clinical trial of EVT plus usual care vs. usual care alone for patients with an intracranial occlusion. The primary outcome was the modified Rankin scale (mRS) score at 90 days. The primary effect parameter was the adjusted common odds ratio (acOR), estimated with ordinal logistic regression and adjusted for age and stroke severity at baseline. Treatment effect modification by AF was assessed using a multiplicative interaction variable. We included all 500 patients. In total, 135 (27%) had AF. These patients were older, had a worse pre-stroke mRS score and were less often treated with IV alteplase. In patients without AF, the estimated treatment effect was similar to the overall treatment effect (acOR 1.9, 95% CI: 1.3 to 2.7). In patients with AF, the treatment effect appeared lower (acOR 1.0, 95% CI: 0.6 to 1.9). The interaction of treatment effect and AF was not significant (p=0.09, after adjustment p=0.12). CONCLUSIONS: This study did not show significant difference in the EVT effect between acute stroke patients with and those without AF. PMID- 28649949 TI - Diagnostic performance of a Lattice Boltzmann-based method for CT-based fractional flow reserve. AB - AIMS: Fractional flow reserve (FFR) estimated from coronary computed tomography angiography (CT-FFR) offers non-invasive detection of lesion-specific ischaemia. We aimed to develop and validate a fast CT-FFR algorithm utilising the Lattice Boltzmann method for blood flow simulation (LBM CT-FFR). METHODS AND RESULTS: Sixty-four patients with clinically indicated CTA and invasive FFR measurement from three institutions were retrospectively analysed. CT-FFR was performed using an onsite tool interfacing with a commercial Lattice Boltzmann fluid dynamics cloud-based platform. Diagnostic accuracy of LBM CT-FFR <=0.8 and percent diameter stenosis >50% by CTA to detect invasive FFR <=0.8 were compared using area under the receiver operating characteristic curve (AUC). Sixty patients successfully underwent LBM CT-FFR analysis; 29 of 73 lesions in 69 vessels had invasive FFR <=0.8. Total time to perform LBM CT-FFR was 40+/-10 min. Compared to invasive FFR, LBM CT-FFR had good correlation (r=0.64), small bias (0.009) and good limits of agreement (-0.223 to 0.206). The AUC of LBM CT-FFR (AUC=0.894, 95% confidence interval [CI]: 0.792-0.996) was significantly higher than CTA (AUC=0.685, 95% CI: 0.576-0.794) to detect FFR <=0.8 (p=0.0021). Per-lesion specificity, sensitivity, and accuracy of LBM CT-FFR were 97.7%, 79.3%, and 90.4%, respectively. CONCLUSIONS: LBM CT-FFR has very good diagnostic accuracy to detect lesion-specific ischaemia (FFR <=0.8) and can be performed in less than one hour. PMID- 28649950 TI - Quantification of aortic valve calcification on contrast-enhanced CT of patients prior to transcatheter aortic valve implantation. AB - AIMS: The aim of the study was to develop a formula enabling the quantification of aortic valve calcification (AVC) on contrast-enhanced CT of patients undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Two hundred and seventeen (217) consecutive patients with severe aortic valve stenosis undergoing non-enhanced electrocardiography-gated CT angiography (NECT) and contrast-enhanced electrocardiography-gated CT angiography (CECT) prior to TAVI were subdivided into a training cohort (n=145) and a validation cohort (n=72). Aortic valve calcification (AVC) was semi-automatically segmented on CECT (AVC. PMID- 28649951 TI - Video motion analysis in live coronary angiography differentiates levels of experience and provides a novel method of skill assessment. AB - AIMS: Video motion analysis (VMA) uses fluoroscopic sequences to derive catheter and guidewire movement, and is able to calculate 2D catheter-tip path length (PL) on the basis of frame-by-frame pixel coordinates. The objective of this study was to validate VMA in coronary angiography as a method of skill assessment. METHODS AND RESULTS: Forty-seven coronary interventions performed by 10 low- (<1,000 cases; group A), five medium- (1,000-4,000; group B) and six high- (>4,000; group C) experience-volume cardiologists were prospectively recorded and analysed using VMA software. Total PL was calculated and procedure, fluoroscopy times, and radiation dose were recorded. Comparisons of PL were made between groups of experience. Groups A, B and C performed 24, 14 and 6 paired (right and left coronary) cannulations, respectively. Calculation of PL was possible in all recorded cases and significantly correlated with procedure (p=<0.001, rho=0.827) and fluoroscopy times (p=<0.001, rho=0.888). Median total path length (combined right and left coronaries) was significantly shorter in group C which used 3,836 pixels of movement (IQR: 3,003-4,484) vs. 10,556 (7,242-31,408) in group A (p=<0.001) and 8,725 (5,187-15,150) in group B (p=0.013). CONCLUSIONS: VMA in coronary angiography is feasible and PL is able to differentiate levels of experience. PMID- 28649952 TI - Successful percutaneous aspiration and endovascular stenting of a symptomatic floating thrombus located in the distal aortic arch. PMID- 28649953 TI - Clinical restenosis and its predictors after implantation of everolimus-eluting bioresorbable vascular scaffolds: results from GABI-R. AB - AIMS: The aim of this study was to assess clinical restenosis and its predictors after implantation of bioresorbable vascular scaffolds (BVS) in everyday practice in the large-scale German-Austrian ABSORB Registry (GABI-R). METHODS AND RESULTS: Between November 2013 and January 2016, 3,264 patients underwent BVS implantation in the 93 centres of GABI-R. At six-month follow-up, 24 patients experienced clinically indicated target lesion revascularisation (cTLR) unrelated to BVS thrombosis (cumulative incidence 0.76%; angiographically, 58.3% of in-BVS restenosis of focal pattern). Compared to patients without cTLR, patients with cTLR had more lesions per patient (1.83+/-1.0 vs. 1.36+/-0.7), complex (52.3% vs. 36.2%) and mild-to-moderately calcified lesions (65.9% vs. 60.5%) treated, and more frequently had overlapping BVS (22.2% vs. 10.8%), all p<0.05. Implanted BVS length was 40.0 mm (28.0, 46.9) vs. 23.0 mm (18.0, 30.0), p<0.001, remaining in the multivariable analysis the only independent predictor of cTLR (hazard ratio 1.02, 95% CI: 1.01-1.04, p<0.001). The myocardial infarction rate was also significantly higher among patients with cTLR, 29.2% vs. 1.7%, p<0.0001. CONCLUSIONS: cTLR related to BVS restenosis at six months after BVS implantation is a rare event depending on implanted BVS length. Whether cTLR increases the myocardial infarction risk needs to be evaluated at longer-term follow-up and within the setting of adequately powered randomised trials. PMID- 28649954 TI - In vitro validation of coronary CT angiography for the evaluation of complex lesions. AB - AIMS: The aim of this study was to assess in vitro the diagnostic accuracy of computed tomography angiography (CTA) for the evaluation of complex coronary lesions. METHODS AND RESULTS: Five Plexiglas phantoms with three bifurcation lesions each were designed to mimic the anatomic variations and fractal phenomena of the coronary tree. In addition, luminal stenoses were scaled up with increases of 10% from 40% to 80%, corresponding to luminal areas ranging from 3.0 mm2 to 0.22 mm2. Third-generation dual-source computed tomography was used. Automated quantitative CTA analysis was performed according to the bifurcation segment model. The primary objective was to determine the diagnostic accuracy of quantitative CTA in assessing bifurcation lesions with the phantoms as a reference. The accuracy of CTA for the assessment of minimal luminal diameter was -0.07 mm (limits of agreement -0.75 to 0.61), for reference vessel diameter 0.19 mm (limits of agreement -0.25 to 0.63) and diameter stenosis 8.2% (limits of agreement -13.2 to 29.5) with no difference regarding the location within the bifurcation (i.e., proximal and distal main vessel and side branch). In stenosis with minimal luminal diameter >=1 mm, CTA overestimated the lesion severity (bias 0.19 mm, limits of agreement -0.09 to 0.47), whereas in lesions with severe stenosis and minimal luminal diameter <=1 mm, CTA underestimated the lesion severity (bias -0.48 mm, limits of agreement -0.55 to -0.41). CTA was able to identify the contrast-filled lumen in all degrees of lesion severity. CONCLUSIONS: In vitro, CTA is accurate for the evaluation of bifurcation lesions. CTA was able to distinguish contrast-filled lumen even in severe obstructive lesions. These findings require further validation in the clinical setting. PMID- 28649955 TI - Transcatheter tricuspid valve repair with the MitraClip system using intracardiac echocardiography: proof of concept. PMID- 28649957 TI - The effect of self-depleting in UV photodetector based on simultaneously fabricated TiO2/NiO pn heterojunction and Ni/Au composite electrode. AB - A novel dark self-depleting ultraviolet (UV) photodetector based on a TiO2/NiO pn heterojunction was demonstrated and exhibited lower dark current (I dark) and noise. Both the NiO layer and Ni/Au composite electrode were fabricated by a smart, one-step oxidation method which was first employed in the fabrication of the UV photodetector. In dark, the depleted pn heterojunction structure effectively reduced the majority carrier density in TiO2/NiO films, demonstrating a high resistance state and contributing to a lower I dark of 0.033 nA, two orders of magnitude lower than that of the single-material devices. Under UV illumination, the interface self-depleting effect arising from the dissociation and accumulation of photogenerated carriers was eliminated, ensuring loss-free responsivity (R) and a remarkable specific detectivity (D*) of 1.56 * 1014 cm Hz1/2 W-1 for the optimal device. The device with the structure of ITO/TiO2/NiO/Au was measured to prove the mechanisms of interface self-depleting in dark and elimination of the depletion layer under UV illumination. Meanwhile, shortened decay time was achieved in the pn heterojunction UV photodetector. This suggests that the self-depleting devices possess the potential to further enhance photodetection performance. PMID- 28649956 TI - The ATI score (age-thrombus burden-index of microcirculatory resistance) determined during primary percutaneous coronary intervention predicts final infarct size in patients with ST-elevation myocardial infarction: a cardiac magnetic resonance validation study. AB - AIMS: The age-thrombus burden-index of microcirculatory resistance (ATI) score is a diagnostic tool able to predict suboptimal myocardial reperfusion before stenting, in patients with ST-elevation myocardial infarction (STEMI). We aimed to validate the ATI score against cardiac magnetic resonance imaging (cMRI). METHODS AND RESULTS: The ATI score was calculated prospectively in 80 STEMI patients. cMRI was performed within 48 hours in all patients and in 50 patients at six-month follow-up to assess the extent of infarct size (IS%) and microvascular obstruction (MVO%). The ATI score was calculated using age (>50=1 point), pre-stenting index of microcirculatory resistance (IMR) (>40 and <100=1 point; >=100=2 points) and angiographic thrombus score (4=1 point; 5=3 points). ATI score was closely related to final IS% (ATI. PMID- 28649959 TI - Employment of gold-coated silver nanowires as transparent conductive electrode for organic light emitting diodes. AB - This study proposes a simple method of Au coating on silver nanowires (Ag NWs) transparent conductive films as the anode of organic light emitting diodes (OLED) to increase the work function of the film and thus enhance hole transport. We carefully engineer the process conditions (pretreatment, solution concentrations, and coating number) of the coating using a diluted HAuCl4 solution on the Ag NWs film to minimize etching damage on Ag NWs accompanying the galvanic replacement reaction. Ultraviolet photoelectron spectroscopy and Kelvin probe force microscopy show work function increase of Ag NWs upon Au coating. OLED devices based on Au-coated Ag NWs show a lower turn-on voltage and higher luminance, compared with pristine Ag NWs device. Although the Ag NWs device displays poor efficiencies in the low luminance range due to a high leakage, some of the Au coated Ag NWs devices showed efficiencies higher than those of the ITO device in a high luminance. PMID- 28649958 TI - Modeling mechanical interactions in growing populations of rod-shaped bacteria. AB - Advances in synthetic biology allow us to engineer bacterial collectives with pre specified characteristics. However, the behavior of these collectives is difficult to understand, as cellular growth and division as well as extra cellular fluid flow lead to complex, changing arrangements of cells within the population. To rationally engineer and control the behavior of cell collectives we need theoretical and computational tools to understand their emergent spatiotemporal dynamics. Here, we present an agent-based model that allows growing cells to detect and respond to mechanical interactions. Crucially, our model couples the dynamics of cell growth to the cell's environment: Mechanical constraints can affect cellular growth rate and a cell may alter its behavior in response to these constraints. This coupling links the mechanical forces that influence cell growth and emergent behaviors in cell assemblies. We illustrate our approach by showing how mechanical interactions can impact the dynamics of bacterial collectives growing in microfluidic traps. PMID- 28649960 TI - Gold nanoparticles-decorated electrospun poly(N-vinyl-2-pyrrolidone) nanofibers with tunable size and coverage density for nanomolar detection of single and binary component dyes by surface-enhanced raman spectroscopy. AB - The application of the electrospun nanomaterials to surface-enhanced Raman spectroscopy (SERS) is a rapidly evolving field which holds potential for future developments in the generation of portable plasmonic-based detection platforms. In this study, a simple approach to fabricate electrospun poly(N vinylpyrrolidone) (PVP) mats decorated with gold nanoparticles (AuNPs) by combining electrospinning and calcination was presented. AuNPs were decorated on the fiber mat surface through electrostatic interactions between positively charged aminosilane groups and negatively charged AuNPs. The size and coverage density of AuNPs on the fiber mats could be tuned by varying the calcination temperature. Calcination of AuNPs-decorated PVP fibers at 500 degrees C-700 degrees C resulted in the uniform decoration of high density AuNPs with very narrow gaps on every single fiber, which in turn contribute to strong electromagnetic SERS enhancement. The robust free-standing AuNPs-decorated mat which calcined at 500 degrees C (500/AuNPs-F) exhibited high SERS activity toward cationic (methylene blue, MB) and anionic (methyl orange, MO) dyes in single and binary systems with a detection range from tens of nM to a few hundred MUM. The fabricated SERS substrate demonstrated high reproducibility with the spot-to-spot variation in SERS signal intensities was +/-10% and +/-12% for single and binary dye systems, respectively. The determination of MB and MO in spiked river water and tap water with 500/AuNPs-F substrate gave satisfactory results in terms of the percent spike recoveries (ranging from 92.6%-96.6%) and reproducibility (%RSD values less than 15 for all samples). PMID- 28649961 TI - Optoelectronic device physics and technology of nitride semiconductors from the UV to the terahertz. AB - This paper reviews the device physics and technology of optoelectronic devices based on semiconductors of the GaN family, operating in the spectral regions from deep UV to Terahertz. Such devices include LEDs, lasers, detectors, electroabsorption modulators and devices based on intersubband transitions in AlGaN quantum wells (QWs). After a brief history of the development of the field, we describe how the unique crystal structure, chemical bonding, and resulting spontaneous and piezoelectric polarizations in heterostructures affect the design, fabrication and performance of devices based on these materials. The heteroepitaxial growth and the formation and role of extended defects are addressed. The role of the chemical bonding in the formation of metallic contacts to this class of materials is also addressed. A detailed discussion is then presented on potential origins of the high performance of blue LEDs and poorer performance of green LEDs (green gap), as well as of the efficiency reduction of both blue and green LEDs at high injection current (efficiency droop). The relatively poor performance of deep-UV LEDs based on AlGaN alloys and methods to address the materials issues responsible are similarly addressed. Other devices whose state-of-the-art performance and materials-related issues are reviewed include violet-blue lasers, 'visible blind' and 'solar blind' detectors based on photoconductive and photovoltaic designs, and electroabsorption modulators based on bulk GaN or GaN/AlGaN QWs. Finally, we describe the basic physics of intersubband transitions in AlGaN QWs, and their applications to near-infrared and terahertz devices. PMID- 28649962 TI - Biological sensing using hybridization phase of plasmonic resonances with photonic lattice modes in arrays of gold nanoantennas. AB - We study biological sensing using the hybridization phase of localized surface plasmon resonances (LSPRs) with diffraction modes (photonic lattice modes) in arrays of gold nanoantennas. We map the degree of the hybridization process using an embedding dielectric material (Si), identifying the critical thicknesses wherein the optical responses of the arrays are mainly governed by pure LSPRs (insignificant hybridization), Fano-type coupling of LSPRs with diffraction orders (hybridization state), and their intermediate state (hybridization phase). The results show that hybridization phase can occur with slight change in the refractive index (RI), leading to sudden reduction of the linewidth of the main spectral feature of the arrays by about one order of magnitude while it is shifted nearly 140 nm. These processes, which offer significant improvement in RI sensitivity and figure of merit, are utilized to detect monolayers of biological molecules and streptavidin-conjugated semiconductor quantum dots with sensitivities far higher than pure LSPRs. We further explore how these sensors can be used based on the uncoupled LSPRs by changing the polarization of the incident light. PMID- 28649963 TI - The effect of growth medium on an Escherichia coli pathway mirrored into GC/MS profiles. AB - Escherichia coli (E. coli) is a Gram-negative coliform bacterium that is commonly found in the lower intestine of warm-blooded organisms. Most of the strains are harmless but some serotypes are pathogenic, meaning they can cause illness, either diarrhea or illness outside the intestinal tract. The aim of this work is to assess which components are generated for the purpose of E. coli target analysis. In this study, we intend to emphasize the importance of cultivability and to prove that growth media plays a crucial role in bacteria growth. To do this, E. coli was cultivated in three different growth mediums: (a) trypcase soy broth (TSB), (b) Mueller Hinton (MH), and (c) minimal salts (M9) enriched with glucose, respectively. Solid phase micro extraction was used as a sampling method, followed by gas chromatography-mass spectrometry for subsequent analysis. The relevant microbial volatile organic compounds (MVOCs) released in the headspace over the cultures of the E. coli bacteria and the afferent metabolic processes that occur in order to generate these compounds are presented in this work. The characteristic volatile compounds found in E. coli strain emissions were indole, phenylethyl alcohol and a series of esters when it was grown in TSB. Different pyrazines were found (pyrazine, 2-ethyl-3,5-dimethyl-, pyrazine, 2,5 dimethyl- and pyrazine, trimethyl-) when it was cultivated in MH. Long-chain alcohols such as 2-pentadecanol, 9-tetradecen-1-ol and 11-hexadecenol occurred in M9. Dimethyl disulfide, dimethyl trisulfide and a consistent number of alcohols and ketones were observed for E. coli cultivated in all three growth mediums. The occurrence and biosynthesis of these MVOCs clearly denote that the growth media used plays a crucial role in bacterial cultivation. The biomarker chemicals documented from this work may ultimately be used to identify bacterial infections by analyzing exhaled breath. PMID- 28649964 TI - Characterization of opto-electrical enhancement of tandem photoelectrochemical cells by using photoconductive-AFM. AB - Solar-to-hydrogen conversion by water splitting in photoelectrochemical cells (PECs) is a promising approach to alleviate problems associated with intermittency in solar energy supply and demand. Several interfacial resistances in photoelectrodes limit the performance of such cells, while the properties of interfaces are not easy to analyze in situ. We applied photoconductive-AFM to analyze the performance of WO3/p+n Si photoanodes, containing an ultra-thin metal interface of either Au or Pt. The Au interface consisted of Au nanoparticles with well-ordered interspacing, while Pt was present in the form of a continuous film. Photoconductive-AFM data show that upon illumination significantly larger currents are measured for the WO3/p+n Si anode equipped with the Au interface, as compared to the WO3/p+n Si anode with the Pt interface, in agreement with the better performance of the former electrode in a photoelectrochemical cell. The remarkable performance of the Au-containing electrode is proposed to be the result of favorable electron-hole recombination rates induced by the Au nanoparticles in a plasmon resonance excited state. PMID- 28649965 TI - pawFLIM: reducing bias and uncertainty to enable lower photon count in FLIM experiments. AB - Forster resonant energy transfer measured by fluorescence lifetime imaging microscopy (FRET-FLIM) is the method of choice for monitoring the spatio-temporal dynamics of protein interactions in living cells. To obtain an accurate estimate of the molecular fraction of interacting proteins requires a large number of photons, which usually precludes the observation of a fast process, particularly with time correlated single photon counting (TCSPC) based FLIM. In this work, we propose a novel method named pawFLIM (phasor analysis via wavelets) that allows the denoising of FLIM datasets by adaptively and selectively adjusting the desired compromise between spatial and molecular resolution. The method operates by applying a weighted translational-invariant Haar-wavelet transform denoising algorithm to phasor images. This results in significantly less bias and mean square error than other existing methods. We also present a new lifetime estimator (named normal lifetime) with a smaller mean squared error and overall bias as compared to frequency domain phase and modulation lifetimes. Overall, we present an approach that will enable the observation of the dynamics of biological processes at the molecular level with better temporal and spatial resolution. PMID- 28649966 TI - Self-interaction free local exchange potentials applied to metallic systems. AB - We extend the formalism of local exchange methods to calculate and investigate the electronic structure of metals. It is well-known that the Hartree-Fock method when applied to metals shows unphysical behaviour, however the accurate treatment of exchange via DFT's exact exchange method and using our local Fock exchange method can be used to describe metallic band structures accurately. PMID- 28649967 TI - Structural perturbations on huntingtin N17 domain during its folding on 2D nanomaterials. AB - A globular protein's folded structure in its physiological environment is largely determined by its amino acid sequence. Recently, newly discovered transformer proteins as well as intrinsically disordered proteins may adopt the folding-upon binding mechanism where their secondary structures are highly dependent on their binding partners. Due to the various applications of nanomaterials in biological sensors and potential wearable devices, it is important to discover possible conformational changes of proteins on nanomaterials. Here, through molecular dynamics simulations, we show that the first 17 residues of the huntingtin protein (HTT-N17) exhibit appreciable differences during its folding on 2D nanomaterials, such as graphene and MoS2 nanosheets. Namely, the protein is disordered on the graphene surface but is helical on the MoS2 surface. Despite that the amphiphilic environment at the nanosheet-water interface promotes the folding of the amphipathic proteins (such as HTT-N17), competitions between protein-nanosheet and intra-protein interactions yield very different protein conformations. Therefore, as engineered binding partners, nanomaterials might significantly affect the structures of adsorbed proteins. PMID- 28649968 TI - Real time polymer nanocomposites-based physical nanosensors: theory and modeling. AB - Functionalized carbon nanotubes and graphene nanoribbons nanostructures, serving as the basis for the creation of physical pressure and temperature nanosensors, are considered as tools for ecological monitoring and medical applications. Fragments of nanocarbon inclusions with different morphologies, presenting a disordered system, are regarded as models for nanocomposite materials based on carbon nanosluster suspension in dielectric polymer environments (e.g., epoxy resins). We have formulated the approach of conductivity calculations for carbon based polymer nanocomposites using the effective media cluster approach, disordered systems theory and conductivity mechanisms analysis, and obtained the calibration dependences. Providing a proper description of electric responses in nanosensoring systems, we demonstrate the implementation of advanced simulation models suitable for real time control nanosystems. We also consider the prospects and prototypes of the proposed physical nanosensor models providing the comparisons with experimental calibration dependences. PMID- 28649969 TI - Physics of muscle contraction. AB - In this paper we report, clarify and broaden various recent efforts to complement the chemistry-centered models of force generation in (skeletal) muscles by mechanics-centered models. The physical mechanisms of interest can be grouped into two classes: passive and active. The main passive effect is the fast force recovery which does not require the detachment of myosin cross-bridges from actin filaments and can operate without a specialized supply of metabolic fuel (ATP). In mechanical terms, it can be viewed as a collective folding-unfolding phenomenon in the system of interacting bi-stable units and modeled by near equilibrium Langevin dynamics. The active force generation mechanism operates at slow time scales, requires detachment and is crucially dependent on ATP hydrolysis. The underlying mechanical processes take place far from equilibrium and are represented by stochastic models with broken time reversal symmetry implying non-potentiality, correlated noise or multiple reservoirs. The modeling approaches reviewed in this paper deal with both active and passive processes and support from the mechanical perspective the biological point of view that phenomena involved in slow (active) and fast (passive) force generation are tightly intertwined. They reveal, however, that biochemical studies in solution, macroscopic physiological measurements and structural analysis do not provide by themselves all the necessary insights into the functioning of the organized contractile system. In particular, the reviewed body of work emphasizes the important role of long-range interactions and criticality in securing the targeted mechanical response in the physiological regime of isometric contractions. The importance of the purely mechanical micro-scale modeling is accentuated at the end of the paper where we address the puzzling issue of the stability of muscle response on the so called 'descending limb' of the isometric tetanus. PMID- 28649970 TI - CyberArc: a non-coplanar-arc optimization algorithm for CyberKnife. AB - The goal of this study is to demonstrate the feasibility of a novel non-coplanar arc optimization algorithm (CyberArc). This method aims to reduce the delivery time of conventional CyberKnife treatments by allowing for continuous beam delivery. CyberArc uses a 4 step optimization strategy, in which nodes, beams, and collimator sizes are determined, source trajectories are calculated, intermediate radiation models are generated, and final monitor units are calculated, for the continuous radiation source model. The dosimetric results as well as the time reduction factors for CyberArc are presented for 7 prostate and 2 brain cases. The dosimetric quality of the CyberArc plans are evaluated using conformity index, heterogeneity index, local confined normalized-mutual information, and various clinically relevant dosimetric parameters. The results indicate that the CyberArc algorithm dramatically reduces the treatment time of CyberKnife plans while simultaneously preserving the dosimetric quality of the original plans. PMID- 28649971 TI - Tailoring the nickel nanoparticles anchored on the surface of Fe3O4@SiO2 spheres for nanocatalysis. AB - Herein, we report an efficient and universal strategy for synthesizing a unique triple-shell structured Fe3O4@SiO2@C-Ni hybrid composite. Firstly, the Fe3O4 cores were synthesized by hydrothermal reaction, and sequentially coated with SiO2 and a thin layer of nickel-ion-doped resin-formaldehyde (RF-Ni2+) using an extended Stober method. This was followed by carbonization to produce the Fe3O4@SiO2@C-Ni nanocomposites with metallic nickel nanoparticles embedded in an RF-derived thin graphic carbon layer. Interestingly, the thin SiO2 spacer layer between RF-Ni2+ and Fe3O4 plays a critical role on adjusting the size and density of the nickel nanoparticles on the surface of Fe3O4@SiO2 nanospheres. The detailed tailoring mechanism is explicitly discussed, and it is shown that the iron oxide core can react with the nickel nanoparticles without the SiO2 spacer layer, and the size and density of the nickel nanoparticles can be effectively controlled when the SiO2 layer exits. The multifunctional composites exhibit a significantly enhanced catalytic performance in the reduction of 4-nitrophenol (4 NP). PMID- 28649972 TI - Excitonic gap generation in thin-film topological insulators. AB - In this work, we analyze the excitonic gap generation in the strong-coupling regime of thin films of three-dimensional time-reversal-invariant topological insulators. We start by writing down the effective gauge theory in 2 + 1 dimensions from the projection of the 3 + 1-dimensional quantum electrodynamics. Within this method, we obtain a short-range interaction, which has the form of a Thirring-like term, and a long-range one. The interaction between the two surface states of the material induces an excitonic gap. By using the large-N approximation in the strong-coupling limit, we find that there is a dynamical mass generation for the excitonic states that preserves time-reversal symmetry and is related to the dynamical chiral-symmetry breaking of our model. This symmetry breaking occurs only for values of the fermion-flavor number smaller than [Formula: see text]. Our results show that the inclusion of full dynamical interaction strongly modifies the critical number of flavors for the occurrence of exciton condensation, and therefore cannot be neglected. PMID- 28649973 TI - On the geometric phenomenology of static friction. AB - In this note we introduce a hierarchy of phase spaces for static friction, which give a graphical way to systematically quantify the directional dependence in static friction via subregions of the phase spaces. We experimentally plot these subregions to obtain phenomenological descriptions for static friction in various examples where the macroscopic shape of the object affects the frictional response. The phase spaces have the universal property that for any experiment in which a given object is put on a substrate fashioned from a chosen material with a specified nature of contact, the frictional behaviour can be read off from a uniquely determined classifying map on the control space of the experiment which takes values in the appropriate phase space. PMID- 28649974 TI - The utility of the 13C-methacetin breath test in predicting the long-term survival of patients with decompensated cirrhosis. AB - AIM: The 13C-methacetin breath test (13C-MeBT) is a noninvasive tool that allows evaluation of the functional activity of the liver and the prediction of liver cirrhosis. Nevertheless, there is no information on its potential utility to predict long-term survival in patients with liver disease. METHODS: Patients with cirrhosis were selected. All patients underwent a complete clinical assessment, standard biochemical tests, and 13C-MeBT at the beginning of the study. Death was recorded during the three years of follow-up. Survival curves were calculated by the Kaplan-Meier method, and Cox proportional risk models were used to identify predictive factors. The ability to classify the overall risk was assessed by the C statistic. RESULTS: One hundred and twenty-three patients were included. A significant inverse correlation was found between delta over baseline at the 15 min point (DOB15) after ingestion of 13C-methacetin and the Child-Pugh score (r = -0.411, p < 0.001). In multivariate analysis, DOB15 <= 4.50/00 was associated with mortality, [HR = 2.58 95% CI (1.17-5.69)]. In conclusion, our results confirm the utility of 13C-MeBT as a simple, noninvasive tool to quantitatively assess the liver's functional reserve and as a potential predictor of long-term survival in patients with decompensated cirrhosis. PMID- 28649975 TI - Fabrication of AlGaN nanorods with different Al compositions for emission enhancement in UV range. AB - Highly ordered AlxGa1-xN nanorods with varied aluminum alloy compositions (0.18 <= x <= 0.8) are fabricated with nanoimprint lithography and top-down dry etching techniques. And the structural properties and morphology are obtained by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Compared with as-grown AlGaN samples, nanorod samples reveal outstanding optical performance on account of strain releasing and light extraction enhancement. Through Raman scattering and cathodeluminescence measurements, it has been observed clear red-shifts of E2h modes and near band edge emission (NBE) peaks of AlGaN nanorods compared to the planar ones, indicating the residual strain releasing after nano-fabrication. The integrated intensities of NBE peaks of AlGaN nanorods manifest light emission enhancement up to 2.7 at deep-UV range. Finite-difference time-domain (FDTD) simulations have been adopted to investigate the light extraction and far-field distribution of such structures, it turned out that ordered nanorod array can enhance the TM polarized emission extraction 2-7 folds compared to the planar structure. The optical regulation in nanorod arrays should take the responsibility for the observed optical enhancements, which is proved by the far-field distribution of light, thus it can improve the performance of ultraviolet LEDs. PMID- 28649976 TI - Efficiency of analytical and sampling-based uncertainty propagation in intensity modulated proton therapy. AB - The sensitivity of intensity-modulated proton therapy (IMPT) treatment plans to uncertainties can be quantified and mitigated with robust/min-max and stochastic/probabilistic treatment analysis and optimization techniques. Those methods usually rely on sparse random, importance, or worst-case sampling. Inevitably, this imposes a trade-off between computational speed and accuracy of the uncertainty propagation. Here, we investigate analytical probabilistic modeling (APM) as an alternative for uncertainty propagation and minimization in IMPT that does not rely on scenario sampling. APM propagates probability distributions over range and setup uncertainties via a Gaussian pencil-beam approximation into moments of the probability distributions over the resulting dose in closed form. It supports arbitrary correlation models and allows for efficient incorporation of fractionation effects regarding random and systematic errors. We evaluate the trade-off between run-time and accuracy of APM uncertainty computations on three patient datasets. Results are compared against reference computations facilitating importance and random sampling. Two approximation techniques to accelerate uncertainty propagation and minimization based on probabilistic treatment plan optimization are presented. Runtimes are measured on CPU and GPU platforms, dosimetric accuracy is quantified in comparison to a sampling-based benchmark (5000 random samples). APM accurately propagates range and setup uncertainties into dose uncertainties at competitive run-times (GPU [Formula: see text] min). The resulting standard deviation (expectation value) of dose show average global [Formula: see text] pass rates between 94.2% and 99.9% (98.4% and 100.0%). All investigated importance sampling strategies provided less accuracy at higher run-times considering only a single fraction. Considering fractionation, APM uncertainty propagation and treatment plan optimization was proven to be possible at constant time complexity, while run-times of sampling-based computations are linear in the number of fractions. Using sum sampling within APM, uncertainty propagation can only be accelerated at the cost of reduced accuracy in variance calculations. For probabilistic plan optimization, we were able to approximate the necessary pre-computations within seconds, yielding treatment plans of similar quality as gained from exact uncertainty propagation. APM is suited to enhance the trade-off between speed and accuracy in uncertainty propagation and probabilistic treatment plan optimization, especially in the context of fractionation. This brings fully fledged APM computations within reach of clinical application. PMID- 28649977 TI - Convection shapes the trade-off between antibiotic efficacy and the selection for resistance in spatial gradients. AB - Since penicillin was discovered about 90 years ago, we have become used to using drugs to eradicate unwanted pathogenic cells. However, using drugs to kill bacteria, viruses or cancer cells has the serious side effect of selecting for mutant types that survive the drug attack. A crucial question therefore is how one could eradicate as many cells as possible for a given acceptable risk of drug resistance evolution. We address this general question in a model of drug resistance evolution in spatial drug gradients, which recent experiments and theories have suggested as key drivers of drug resistance. Importantly, our model takes into account the influence of convection, resulting for instance from blood flow. Using stochastic simulations, we study the fates of individual resistance mutations and quantify the trade-off between the killing of wild-type cells and the rise of resistance mutations: shallow gradients and convection into the antibiotic region promote wild-type death, at the cost of increasing the establishment probability of resistance mutations. We can explain these observed trends by modeling the adaptation process as a branching random walk. Our analysis reveals that the trade-off between death and adaptation depends on the relative length scales of the spatial drug gradient and random dispersal, and the strength of convection. Our results show that convection can have a momentous effect on the rate of establishment of new mutations, and may heavily impact the efficiency of antibiotic treatment. PMID- 28649978 TI - Pr-magnetism in the quasi-skutterudite compound PrFe2Al8. AB - The intermetallic compound PrFe2Al8 that possesses a three-dimensional network structure of Al polyhedra centered at the transition metal element Fe and the rare earth Pr is investigated through neutron powder diffraction and inelastic neutron scattering in order to elucidate the magnetic ground state of Pr and Fe and the crystal field effects of Pr. Our neutron diffraction study confirms long range magnetic order of Pr below [Formula: see text] K in this compound. Subsequent magnetic structure estimation reveals a magnetic propagation vector [Formula: see text] with a magnetic moment value of [Formula: see text]/Pr along the orthorhombic c-axis and evidence the lack of ordering in the Fe sublattice. The inelastic neutron scattering study reveals one crystalline electric field excitation near 19 meV at 5 K in PrFe2Al8. The energy-integrated intensity of the 19 meV excitation as a function of [Formula: see text] follows the square of the magnetic form factor of [Formula: see text] thereby confirming that the inelastic excitation belongs to the Pr sublattice. The second sum rule applied to the dynamic structure factor indicates only 1.6(2) [Formula: see text] evolving at the 19 meV peak compared to the 3.58 [Formula: see text] for free [Formula: see text], indicating that the crystal field ground state is magnetic and the missing moment is associated with the resolution limited quasi-elastic line. The magnetic order occurring in Pr in PrFe2Al8 is counter-intuitive to the symmetry-allowed crystal field level scheme, hence, is suggestive of exchange-mediated mechanisms of ordering stemming from the magnetic ground state of the crystal field levels. PMID- 28649979 TI - Hot-pressed polymer nanofiber supported graphene membrane for high-performance nanofiltration. AB - Graphene oxide (GO) sheets can be readily surface-overlaid on hot-pressed electrospun polyacrylonitrile (PAN) nanofiber membrane to form a continuous and crack-free layer; upon thermal reduction at 150 degrees C for 12 h, the resulting reduced GO (rGO) layer can reject ~90% MgSO4 with high water flux (due to the size exclusion mechanism), making the prepared PAN-rGO membranes promising nanofiltration media for water purification. It is important to note that no delamination of GO/rGO sheet layers has been observed throughout this study. We highlight that a simple processing method (i.e., hot pressing) is critical for the successful preparation of 2D materials (e.g., GO/rGO) based membranes/media. It is envisioned that the reported study can benefit many groups working on various membrane applications of 2D materials; in other words, the hot-pressed electrospun nanofiber membranes could be generally utilized as an innovative type of platform to support various 2D sheets for different separation applications such as highly efficient and cost-effective removal of dissolved components (e.g., organic molecules) and even (hydrated) ions from water. PMID- 28649980 TI - Mid-Term Outcomes of Stent Overlap in Long Total Occluded Lesions of Superficial Femoral Artery. AB - BACKGROUND Superficial femoral artery chronic total occlusion (SCTO) is a common type of peripheral arterial disease (PAD). Endovascular therapy is a treatment approach that has a poor long-term success rate in this group. The aim of this study was to compare the mid-term results of two different uses of nitinol stents in long SCTO lesions (>100 mm): the use of one long stent or two shorter stents. MATERIAL AND METHODS Of 154 patients who underwent percutaneous infrainguinal interventions from 2011 to 2014, a total of 170 CTO lesions were selected for this retrospective study analysis. The mean age of the study population was 63.4+/-10.4 years (range 29-89 years); 71.8% of the patients were male. RESULTS Patients were divided into two groups according to the number of stents used. Patients treated with a single stent were placed into group A and patients treated with two stents were placed into group B. The stent fracture rate was significantly higher in group B compared to group A (29.2% vs. 42%). Type 1 and 2 fracture rates were higher in group A, but type 3 and 5 fracture rates were significantly higher in group B. The rate of stent restenosis was significantly higher in group B compared to group A (45.1% vs. 54.5%, p=0.05). CONCLUSIONS Mid term patency rate was low in patients with long totally occluded superficial femoral artery (SFA) lesions. Using a long single stent had an acceptable mid term patency rate compared to using a two stent strategy. Stent fracture seemed to be the main reason for in-stent restenosis in cases of multiple stenting. A long single stent strategy may be more appropriate and reasonable than a two stent strategy in the treatment of long SFA lesions. PMID- 28649981 TI - A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid. AB - Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the introduction of fluorine is of paramount importance in medicinal chemistry. Current synthesis methods for the construction of fluorinated amines rely on air and moisture sensitive reagents that require special handling or harsh reductants that limit functionality. Here we report practical, catalyst-free, reductive trifluoroethylation reactions of free amines exhibiting remarkable functional group tolerance. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or oxygen, and use trifluoroacetic acid as a stable and inexpensive fluorine source. The new methods provide access to a wide range of medicinally relevant functionalized tertiary beta-fluoroalkylamine cores, either through direct trifluoroethylation of secondary amines or via a three component coupling of primary amines, aldehydes and trifluoroacetic acid. A reduction of in situ-generated silyl ester species is proposed to account for the reductive selectivity observed. PMID- 28649982 TI - Structural and regulatory diversity shape HLA-C protein expression levels. AB - Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the alpha1/alpha2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression. PMID- 28649983 TI - High rate of event-free survival at 24 months with everolimus/RCHOP for untreated diffuse large B-cell lymphoma: updated results from NCCTG N1085 (Alliance). PMID- 28649984 TI - CD27 expression and its association with clinical outcome in children and adults with pro-B acute lymphoblastic leukemia. PMID- 28649986 TI - Rewritable ghost floating gates by tunnelling triboelectrification for two dimensional electronics. AB - Gates can electrostatically control charges inside two-dimensional materials. However, integrating independent gates typically requires depositing and patterning suitable insulators and conductors. Moreover, after manufacturing, gates are unchangeable. Here we introduce tunnelling triboelectrification for localizing electric charges in very close proximity of two-dimensional materials. As representative materials, we use chemical vapour deposition graphene deposited on a SiO2/Si substrate. The triboelectric charges, generated by friction with a Pt-coated atomic force microscope tip and injected through defects, are trapped at the air-SiO2 interface underneath graphene and act as ghost floating gates. Tunnelling triboelectrification uniquely permits to create, modify and destroy p and n regions at will with the spatial resolution of atomic force microscopes. As a proof of concept, we draw rewritable p/n+ and p/p+ junctions with resolutions as small as 200 nm. Our results open the way to time-variant two-dimensional electronics where conductors, p and n regions can be defined on demand. PMID- 28649985 TI - Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. AB - Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development. PMID- 28649987 TI - A PPARgamma transcriptional cascade directs adipose progenitor cell-niche interaction and niche expansion. AB - Adipose progenitor cells (APCs) reside in a vascular niche, located within the perivascular compartment of adipose tissue blood vessels. Yet, the signals and mechanisms that govern adipose vascular niche formation and APC niche interaction are unknown. Here we show that the assembly and maintenance of the adipose vascular niche is controlled by PPARgamma acting within APCs. PPARgamma triggers a molecular hierarchy that induces vascular sprouting, APC vessel niche affinity and APC vessel occupancy. Mechanistically, PPARgamma transcriptionally activates PDGFRbeta and VEGF. APC expression and activation of PDGFRbeta promotes the recruitment and retention of APCs to the niche. Pharmacologically, targeting PDGFRbeta disrupts APC niche contact thus blocking adipose tissue expansion. Moreover, enhanced APC expression of VEGF stimulates endothelial cell proliferation and expands the adipose niche. Consequently, APC niche communication and retention are boosted by VEGF thereby impairing adipogenesis. Our data indicate that APCs direct adipose tissue niche expansion via a PPARgamma initiated PDGFRbeta and VEGF transcriptional axis. PMID- 28649988 TI - Iron-mediated soil carbon response to water-table decline in an alpine wetland. AB - The tremendous reservoir of soil organic carbon (SOC) in wetlands is being threatened by water-table decline (WTD) globally. However, the SOC response to WTD remains highly uncertain. Here we examine the under-investigated role of iron (Fe) in mediating soil enzyme activity and lignin stabilization in a mesocosm WTD experiment in an alpine wetland. In contrast to the classic 'enzyme latch' theory, phenol oxidative activity is mainly controlled by ferrous iron [Fe(II)] and declines with WTD, leading to an accumulation of dissolvable aromatics and a reduced activity of hydrolytic enzyme. Furthermore, using dithionite to remove Fe oxides, we observe a significant increase of Fe-protected lignin phenols in the air-exposed soils. Fe oxidation hence acts as an 'iron gate' against the 'enzyme latch' in regulating wetland SOC dynamics under oxygen exposure. This newly recognized mechanism may be key to predicting wetland soil carbon storage with intensified WTD in a changing climate. PMID- 28649989 TI - An L-threonine transaldolase is required for L-threo-beta-hydroxy-alpha-amino acid assembly during obafluorin biosynthesis. AB - beta-Lactone natural products occur infrequently in nature but possess a variety of potent and valuable biological activities. They are commonly derived from beta hydroxy-alpha-amino acids, which are themselves valuable chiral building blocks for chemical synthesis and precursors to numerous important medicines. However, despite a number of excellent synthetic methods for their asymmetric synthesis, few effective enzymatic tools exist for their preparation. Here we report cloning of the biosynthetic gene cluster for the beta-lactone antibiotic obafluorin and delineate its biosynthetic pathway. We identify a nonribosomal peptide synthetase with an unusual domain architecture and an L-threonine:4-nitrophenylacetaldehyde transaldolase responsible for (2S,3R)-2-amino-3-hydroxy-4-(4 nitrophenyl)butanoate biosynthesis. Phylogenetic analysis sheds light on the evolutionary origin of this rare enzyme family and identifies further gene clusters encoding L-threonine transaldolases. We also present preliminary data suggesting that L-threonine transaldolases might be useful for the preparation of L-threo-beta-hydroxy-alpha-amino acids. PMID- 28649990 TI - A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay. AB - Nonsense-mediated decay (NMD) eliminates transcripts with premature termination codons. Although NMD-induced loss-of-function has been shown to contribute to the genesis of particular cancers, its global functional consequence in tumours has not been characterized. Here we develop an algorithm to predict NMD and apply it on somatic mutations reported in The Cancer Genome Atlas. We identify more than 73 K mutations that are predicted to elicit NMD (NMD-elicit). NMD-elicit mutations in tumour suppressor genes (TSGs) are associated with significant reduction in gene expression. We discover cancer-specific NMD-elicit signatures in TSGs and cancer-associated genes. Our analysis reveals a previously unrecognized dependence of hypermutated tumours on hypofunction of genes that are involved in chromatin remodelling and translation. Half of hypermutated stomach adenocarcinomas are associated with NMD-elicit mutations of the translation initiators LARP4B and EIF5B. Our results unravel strong therapeutic opportunities by targeting tumour dependencies on NMD-elicit mutations. PMID- 28649991 TI - The social inefficiency of regulating indirect land use change due to biofuels. AB - Efforts to reduce the indirect land use change (ILUC) -related carbon emissions caused by biofuels has led to inclusion of an ILUC factor as a part of the carbon intensity of biofuels in a Low Carbon Fuel Standard. While previous research has provided varying estimates of this ILUC factor, there has been no research examining the economic effects and additional carbon savings from including this factor in implementing a Low Carbon Fuel Standard. Here we show that inclusion of an ILUC factor in a national Low Carbon Fuel Standard led to additional abatement of cumulative emissions over 2007-2027 by 1.3 to 2.6% (0.6-1.1 billion mega-grams carbon-dioxide-equivalent (Mg CO2e-1) compared to those without an ILUC factor, depending on the ILUC factors utilized. The welfare cost to the US of this additional abatement ranged from $61 to $187 Mg CO2e-1 and was substantially greater than the social cost of carbon of $50 Mg CO2e-1. PMID- 28649992 TI - A Key Role for Neurotensin in Chronic-Stress-Induced Anxiety-Like Behavior in Rats. AB - Chronic stress is a major cause of anxiety disorders that can be reliably modeled preclinically, providing insight into alternative therapeutic targets for this mental health illness. Neuropeptides have been targeted in the past to no avail possibly due to our lack of understanding of their role in pathological models. In this study we use a rat model of chronic stress-induced anxiety-like behaviors and hypothesized that neuropeptidergic modulation of synaptic transmission would be altered in the bed nucleus of the stria terminalis (BNST), a brain region suspected to contribute to anxiety disorders. We use brain slice neurophysiology and behavioral pharmacology to compare the role of locally released endogenous neuropeptides on synaptic transmission in the oval (ov) BNST of non-stressed (NS) or chronic unpredictably stressed (CUS) rats. We found that in NS rats, post synaptic depolarization induced the release of vesicular neurotensin (NT) and corticotropin-releasing factor (CRF) that co-acted to increase ovBNST inhibitory synaptic transmission in 59% of recorded neurons. CUS bolstered this potentiation (100% of recorded neurons) through an enhanced contribution of NT over CRF. In contrast, locally released opioid neuropeptides decreased ovBNST excitatory synaptic transmission in all recorded neurons, regardless of stress. Consistent with CUS-induced enhanced modulatory effects of NT, blockade of ovBNST NT receptors completely abolished stress-induced anxiety-like behaviors in the elevated plus maze paradigm. The role of NT has been largely unexplored in stress and our findings highlight its potential contribution to an important behavioral consequence of chronic stress, that is, exaggerated avoidance of open space in rats. PMID- 28649993 TI - kappa-Opioid Receptor Activation in Dopamine Neurons Disrupts Behavioral Inhibition. AB - The dynorphin/kappa-opioid receptor (KOR) system has been previously implicated in the regulation of cognition, but the neural circuitry and molecular mechanisms underlying KOR-mediated cognitive disruption are unknown. Here, we used an operational test of cognition involving timing and behavioral inhibition and found that systemic KOR activation impairs performance of male and female C57BL/6 mice in the differential reinforcement of low response rate (DRL) task. Systemic KOR antagonism also blocked stress-induced disruptions of DRL performance. KOR activation increased 'bursts' of incorrect responses in the DRL task and increased marble burying, suggesting that the observed disruptions in DRL performance may be attributed to KOR-induced increases in compulsive behavior. Local inactivation of KOR by injection of the long-acting antagonist nor-BNI in the ventral tegmental area (VTA), but not the infralimbic prefrontal cortex (PFC) or dorsal raphe nucleus (DRN), prevented disruption of DRL performance caused by systemic KOR activation. Cre-dependent genetic excision of KOR from dopaminergic, but not serotonergic neurons, also blocked KOR-mediated disruption of DRL performance. At the molecular level, we found that these disruptive effects did not require arrestin-dependent signaling, because neither global deletion of G protein receptor kinase 3 (GRK3) nor cell-specific deletion of GRK3/arrestin dependent p38alpha MAPK from dopamine neurons blocked KOR-mediated DRL disruptions. We then showed that nalfurafine, a clinically available G-biased KOR agonist, could also produce DRL disruptions. Together, these studies demonstrate that KOR activation in VTA dopamine neurons disrupts behavioral inhibition in a GRK3/arrestin-independent manner and suggests that KOR antagonists could be beneficial for decreasing stress-induced compulsive behaviors. PMID- 28649994 TI - Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression. AB - The serine/threonine kinase LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Many downstream pathways controlled by LKB1 have been described but little is known about the upstream regulatory mechanisms. Here we show that targeting of the kinase to the membrane by a direct binding of LKB1 to phosphatidic acid is essential to fully activate its kinase activity. Consequently, LKB1 mutants that are deficient for membrane binding fail to activate the downstream target AMPK to control mTOR signalling. Furthermore, the in vivo function of LKB1 during development of Drosophila depends on its capacity to associate with membranes. Strikingly, we find LKB1 to be downregulated in malignant melanoma, which exhibit aberrant activation of Akt and overexpress phosphatidic acid generating Phospholipase D. These results provide evidence for a fundamental mechanism of LKB1 activation and its implication in vivo and during carcinogenesis. PMID- 28649996 TI - All roads lead to ubiquitin. PMID- 28649995 TI - Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles. AB - The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case control study. Plasma cytokines levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL- 4, IL-6, IL-10, IL-12 and IL 17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN gamma and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFalpha+IL-6+IL-1beta). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNgamma values. 25-OH vitamin D was inversely associated with IFN-gamma levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines. PMID- 28649997 TI - Characterizing sleep spindles in 11,630 individuals from the National Sleep Research Resource. AB - Sleep spindles are characteristic electroencephalogram (EEG) signatures of stage 2 non-rapid eye movement sleep. Implicated in sleep regulation and cognitive functioning, spindles may represent heritable biomarkers of neuropsychiatric disease. Here we characterize spindles in 11,630 individuals aged 4 to 97 years, as a prelude to future genetic studies. Spindle properties are highly reliable but exhibit distinct developmental trajectories. Across the night, we observe complex patterns of age- and frequency-dependent dynamics, including signatures of circadian modulation. We identify previously unappreciated correlates of spindle activity, including confounding by body mass index mediated by cardiac interference in the EEG. After taking account of these confounds, genetic factors significantly contribute to spindle and spectral sleep traits. Finally, we consider topographical differences and critical measurement issues. Taken together, our findings will lead to an increased understanding of the genetic architecture of sleep spindles and their relation to behavioural and health outcomes, including neuropsychiatric disorders. PMID- 28649998 TI - Uniform electroactive fibre-like micelle nanowires for organic electronics. AB - Micelles formed by the self-assembly of block copolymers in selective solvents have attracted widespread attention and have uses in a wide variety of fields, whereas applications based on their electronic properties are virtually unexplored. Herein we describe studies of solution-processable, low-dispersity, electroactive fibre-like micelles of controlled length from pi-conjugated diblock copolymers containing a crystalline regioregular poly(3-hexylthiophene) core and a solubilizing, amorphous regiosymmetric poly(3-hexylthiophene) or polystyrene corona. Tunnelling atomic force microscopy measurements demonstrate that the individual fibres exhibit appreciable conductivity. The fibres were subsequently incorporated as the active layer in field-effect transistors. The resulting charge carrier mobility strongly depends on both the degree of polymerization of the core-forming block and the fibre length, and is independent of corona composition. The use of uniform, colloidally stable electroactive fibre-like micelles based on common pi-conjugated block copolymers highlights their significant potential to provide fundamental insight into charge carrier processes in devices, and to enable future electronic applications. PMID- 28649999 TI - [The relationship between emotional labor and professional burnout: A comparative analysis between work of teachers and employees of commercial service sector]. AB - BACKGROUND: Nowadays more and more employees are required to perform emotional labor (EL) which means that they need to express emotions set by the organizational procedures, simultaneously masking the true feelings. Employees, while performing emotional labor, choose between one of the two strategies (surface acting or deep acting) and this leads to e.g., burnout. As the performance of emotional labor and its consequences depend on the specification of work and chosen strategy, it was assumed that the consequences of EL may be different for workers in various occupations. MATERIAL AND METHODS: The authors performed a comparative analysis between teachers (N = 129) and professionals of commercial service sector (N = 136). In the analysis the Polish adaptation of deep acting and surface acting scale (DASAS) and the Polish version of OLBI (Oldenburg Burnout Inventory) were used. RESULTS: The statistical verification of hypotheses showed that employees of commercial service sector show a greater tendency toward choosing surface acting than teachers. Furthermore, in the group of teachers negative consequences are more related to emotional exhaustion, while both components of burnout are at the same level among employees of the other group. In both groups of respondents surface acting leads to the increase in burnout. CONCLUSIONS: Emotional labor can lead to a variety of negative consequences, e.g., burnout or psychosomatic diseases. Based on this knowledge, organizations can develop standards for the expression of emotions and preventive actions, such as identification with organization, which can counteract the negative EL consequences. Med Pr 2017;68(5):605-615. PMID- 28650000 TI - Andexanet alfa: a recombinant mimetic of human factor Xa for the reversal of anticoagulant therapies. AB - Activated coagulation factor X (FXa) is a common target for classic and newer anticoagulants. Parenteral anticoagulants with an indirect inhibitory action on FXa (low-molecular-weight heparins) have a well-established clinical efficacy in the prophylaxis and therapy of thromboembolic conditions. More recently developed direct oral anticoagulants (DOACs) have emerged as a new class of antithrombotic drugs. Rivaroxaban, apixaban and edoxaban are direct inhibitors of FXa approved for the management of venous thromboembolism and stroke prevention in atrial fibrillation. Although these DOACs are associated with fewer hemorrhagic side effects than classic vitamin K antagonists, bleeding is still a main complication. FXa antagonists had no specific agents that could reverse their antihemostatic effects. Andexanet alfa is a modified, recombinant human FXa molecule with an enhanced ability to bind to both direct and indirect FXa inhibitors, but unable to contribute to blood coagulation mechanisms. Andexanet alfa is designed to reverse the anticoagulant effects of FXa inhibitors. This review will address the preclinical pharmacology and the main aspects of the clinical development of andexanet alfa for the reversal of anticoagulant therapies with an inhibitory action on FXa. It will also summarize additional completed or ongoing studies on andexanet alfa available to the scientific community until present. PMID- 28650001 TI - Brodalumab: the first anti-IL-17 receptor agent for psoriasis. AB - Psoriasis is a chronic immune-mediated inflammatory skin disease in which the alteration of the interleukin-23 (IL-23)/IL-17 cytokine axis appears to be crucial from a pathogenetic perspective. This has been confirmed by the efficacy of monoclonal antibodies blocking IL-17A, such as secukinumab and ixekizumab. Brodalumab is a human anti-IL-17 receptor A (IL-17RA) monoclonal antibody that inhibits the biological activity of IL-17A, IL-17F and other IL-17 isoforms, and has been approved (210 mg s.c. at weeks 0, 1, 2 and every 2 weeks thereafter) for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma in Japan (Lumicef). The U.S. Food and Drug Administration has also recently approved brodalumab (Siliq) for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. Regulatory applications are under review in the E.U. and Canada. The phase III clinical trials in moderate to severe plaque psoriasis met their primary endpoints after 12 weeks' treatment, with PASI 75 (75% improvement in the Psoriasis Area and Severity Index) response rates ranging between 83% and 86% (210 mg) and PASI 100 response rates ranging between 37% and 44%, significantly higher than those achieved with ustekinumab in the head-to-head trials AMAGINE-1 and AMAGINE-2. The most frequently reported adverse events in brodalumab clinical trials consisted of nasopharyngitis, headache, upper respiratory tract infection and arthralgia. In the head-to-head trials, rates of neutropenia were higher with both active drugs than with placebo, and mild or moderate Candida infections were more frequent with brodalumab than with ustekinumab or placebo. Clinical development was terminated by Amgen after adverse events of suicidal ideation and behavior were observed ls involving several indications, but data are inconclusive regarding potential drug causality, and brodalumab has recently been approved in the U.S. with a black box warning and a risk-management program regarding suicidal issues. Blocking IL-17RA provides a highly efficacious therapeutic alternative for moderate to severe psoriasis with a satisfactory safety profile. PMID- 28650002 TI - Cabozantinib use in renal cell carcinoma. AB - In the last several years, many new drugs have been approved to treat metastatic renal cell carcinoma (RCC). Cabozantinib is a novel multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR), proto oncogene tyrosine-protein kinase receptor Ret and other kinases that recently joined this impressive list of approved agents. Cabozantinib is an active agent in the preclinical and clinical setting, having recently demonstrated superiority over everolimus in a blinded, randomized phase III study of patients with progressive RCC after at least one prior line of antiangiogenic therapy. This agent's toxicity profile is similar to those of other multikinase inhibitors approved to treat RCC. This review will explore cabozantinib's pharmacologic and safety profile and its preclinical and clinical activity in RCC. PMID- 28650003 TI - American Academy of Neurology - 69th Annual Meeting (April 22-28, 2017 - Boston, Massachusetts, USA). AB - The Annual Meeting of the American Academy of Neurology (AAN) is the largest conference convening neurology professionals from all over the world to share and discuss the latest breakthroughs in neurology treatment. The conference covers basic scientific research to clinical application through a wide range and interesting programs. This report covers some of the therapeutic highlights presented during the conference. PMID- 28650004 TI - A collagen telopeptide binding peptide shows potential in aiding collagen bundle formation and fibril orientation. AB - Type I collagen, the main component of the extracellular matrix (ECM), assembles into bundles, which are then arranged in an orderly manner in many tissues. Various in vitro methods have been developed to mimic this native characteristic to create aligned, collagen-based materials for constructing tissue-engineered organs. In this study, we examined a new strategy to enhance collagen bundle formation and fibril orientation through administration of a collagen telopeptide binding peptide (CTBP). We found that CTBP, or a double-armed CTBP-PEG-CTBP derivative, could interact with both individual collagen molecules and fibrils. The CTBP interaction with collagen molecules inhibited fibril formation, whereas with reconstituted collagen fibrils, CTBP-PEG-CTBP promoted collagen bundle formation and fibril orientation. Finally, the addition of the CTBP derivative to the collagen matrix showed good cellular compatibility during in vitro cell culture. Taken together, our findings suggest that CTBP may have the potential for creating orderly, aligned, collagen-based matrices for tissue engineering. PMID- 28650006 TI - Positional immobilization of Pd nanoparticles and enzymes in hierarchical yolk shell@shell nanoreactors for tandem catalysis. AB - A hierarchical yolk-shell@shell nanoreactor that spatially positioned Pd nanoparticles and the CALB enzyme in separated domains is constructed, and served as an efficient bifunctional catalyst for the one-pot dynamic kinetic resolution (DKR) reaction of 1-phenylethylamine with excellent activity and selectivity. PMID- 28650005 TI - Sub-picomolar label-free detection of thrombin using electrochemical impedance spectroscopy of aptamer-functionalized MoS2. AB - An ultrasensitive aptasensor for the label free non-faradaic detection of thrombin has been demonstrated on molybdenum disulphide (MoS2) nanosheets. These nanosheets were physiochemically immobilized onto a silicon micro-electrode platform. Thrombin detection was achieved through the charge modulation of the electrical double layer due to the specific and dose dependent binding of thrombin to the surface of thiol terminated ssDNA aptamer functionalized MoS2 nanosheets. Electrical double layer charge modulation associated with thrombin binding was characterized using electrochemical impedance spectroscopy. Dynamic light scattering was also used to confirm the dose dependent behavior. ATR-FTIR spectroscopy and XPS analysis were independently used to validate the functionalization of the ssDNA aptamer onto MoS2 nanosheets. ssDNA aptamer functionalized molybdenum disulfide (MoS2) for selective and specific capture of thrombin was demonstrated both in phosphate buffered saline (PBS) and human serum. The optimized immunoassay enabled the detection of thrombin ranging from 267 fM to 267 pM in phosphate buffer. The limit of detection of 53 pM and the linear dynamic range of detection of thrombin ranged from 53 to 854 pM in human serum. The rapid response time for the electrochemical impedance spectroscopy signal makes it an attractive option for the real-time detection of thrombin based point-of-care diagnostic devices. PMID- 28650007 TI - Dual-channel signals for intracellular mRNA detection via a PRET nanosensor. AB - An intracellular nanosensor was designed and developed to accurately sense mRNA in living cells without false positive results. This nanosensor consists of gold nanoparticles assembled with recognition sequences and dye-labelled nanoflares. By analyzing both the wavelength shifts and intensity recovery of the scattering spectra, this dual-channel nanosensor could efficiently distinguish and avoid the interference induced by other common substances. This novel dual-channel nanosensor would precisely recognize the target mRNA, and it is promising for further cancer diagnoses. PMID- 28650008 TI - CO2 regulates molecular rotor dynamics in porous materials. AB - A crystalline hydrogen-bonded framework with permanent porosity, built by rod like struts and engineered to bear ultra-fast molecular rotors between two triple bonds, offers the possibility of controlling the rotational rates upon CO2 adsorption. CO2 enters the pores from the gas phase and reduces the rotational rates from the extremely fast regime of 107 Hz at 216 K to 105 Hz. The CO2-rotor interaction was evident from the 2H NMR response to the dynamics of the rotors in contact with CO2 in the crystal structure. PMID- 28650009 TI - Charge-transfer and impulsive electronic-to-vibrational energy conversion in ferricyanide: ultrafast photoelectron and transient infrared studies. AB - The photophysics of ferricyanide in H2O, D2O and ethylene glycol was studied upon excitation of ligand-to-metal charge transfer (LMCT) transitions by combining ultrafast photoelectron spectroscopy (PES) of liquids and transient vibrational spectroscopy. Upon 400 nm excitation in water, the PES results show a prompt reduction of the Fe3+ to Fe2+ and a back electron transfer in ~0.5 ps concomitant with the appearance and decay of a strongly broadened infrared absorption at ~2065 cm-1. In ethylene glycol, the same IR absorption band decays in ~1 ps, implying a strong dependence of the back electron transfer on the solvent. Thereafter, the ground state ferric species is left vibrationally hot with significant excitation of up to two quanta of the CN-stretch modes, which completely decay on a 10 ps time scale. Under 265 nm excitation even higher CN stretch levels are populated. Finally, from a tiny residual transient IR signal, we deduce that less than 2% of the excited species undergo photoaquation, in line with early flash photolysis experiments. The latter is more significant at 265 nm compared to 400 nm excitation, which suggests photodissociation in this system is an unlikely statistical process related to the large excess of vibrational energy. PMID- 28650010 TI - [(CH3)3PCH2OH][CdBr3] is a perovskite-type ferroelastic compound above room temperature. AB - A new organic-inorganic perovskite-type compound [(CH3)3PCH2OH][CdBr3] exhibits a ferroelastic phase transition at 339 K. Domain structures were observed and analyzed. The origin of the phase transition can be attributed to the motion or reorientation of the [(CH3)3PCH2OH]+ cations and the displacement of Cd2+ and Br- ions in solid-state crystals. PMID- 28650011 TI - Interconversion of molecular face-rotating polyhedra through turning inside out. AB - We report the post-synthesis interconversion of two enantiomeric organic cages through turning inside out. By scrutinizing the thermodynamics and kinetics, we are able to control the racemization rate by various reaction conditions and reveal that the turning-inside-out interconversion is realized through a partial disassembly pathway. The kinetics investigation also provides insight into the dynamic essence of imine chemistry using different solvents and catalysts. PMID- 28650012 TI - High cross-plane thermoelectric performance of metallo-porphyrin molecular junctions. AB - We investigated the thermoelectric properties of flat-stacked 5,15 diphenylporphyrins containing divalent metal ions Ni, Co, Cu or Zn, which are strongly coordinated with the nitrogens of pyridyl coated gold electrodes. Changing metal atom has little effect on the thermal conductance due to the phonons. The room-temperature Seebeck coefficients of these junctions are rather high, ranging from 90 MUV K-1 for Cu, Ni and Zn-porphyrins to -16 MUV K-1 for Co porphyrin. These values could be further increased by lowering molecular energy levels relative to the DFT-predicted Fermi energy. In contrast, the phonon contribution to the thermal conductance of these junctions is rather insensitive to the choice of metal atom. The thermopower, thermal conductance and electrical conductance combined to yield the room-temperature values for the thermoelectric figure of merit ZT ranging from 1.6 for Cu porphyrin to ~0.02 for Ni-porphyrin. PMID- 28650013 TI - Gram-scale production of nitrogen doped graphene using a 1,3-dipolar organic precursor and its utilisation as a stable, metal free oxygen evolution reaction catalyst. AB - For the first time, a one-step scalable synthesis of a few-layer ~10% nitrogen doped (N-doped) graphene nanosheets (GNSs) from a stable but highly reactive 1,3 dipolar organic precursor is reported. The utilization of these N-doped GNSs as metal-free electrocatalysts for the oxygen evolution reaction (OER) is also demonstrated. This process may open the path for the scalable production of other heteroatom doped GNSs by using the broad library of well-known, stable 1,3 dipolar organic compounds. PMID- 28650014 TI - Pattern transitions in a compressible floating elastic sheet. AB - Thin rigid sheets floating on a liquid substrate appear, for example, in coatings and surfactant monolayers. Upon uniaxial compression the sheet undergoes transitions from a compressed flat state to a periodic wrinkled pattern to a localized folded pattern. The stability of these states is determined by the in plane elasticity of the sheet, its bending rigidity, and the hydrostatics of the underlying liquid. Wrinkles and folds, and the wrinkle-to-fold transition, were previously studied for incompressible sheets. In the present work we extend the theory to include finite compressibility. We analyze the details of the flat-to wrinkle transition, the effects of compressibility on wrinkling and folding, and the compression field associated with pattern formation. The state diagram of the floating sheet including all three states is presented. PMID- 28650015 TI - Enhanced C3H6/C3H8 separation performance on MOF membranes through blocking defects and hindering framework flexibility by silicone rubber coating. AB - The polydimethylsiloxane (PDMS) coating penetrated into the underneath ZIF-8 polycrystalline membrane not only blocking the inter-crystalline defects but also hindering the flexibility of the ZIF-8 framework, resulting in an unusual and highly desired increase in the separation selectivity of the C3H6/C3H8 mixture under high feeding pressures. PMID- 28650016 TI - Prediction of 1H NMR chemical shifts for clusters of imidazolium-based ionic liquids. AB - Nuclear magnetic resonance (NMR) has been widely used to elucidate the bulk structure of ionic liquids. In this work, we calculated 1H NMR chemical shifts of 1-ethyl-3-methylimidazolium (C2mim+) ionic liquids combined with various anions such as chloride (Cl), tetrafluoroborate (BF4), hexafluorophosphate (PF6), acetate (OAc), trifluoroacetate (TFA), and dicyanamide (DCA). The previously established level of theory, HF/6-311G+(3df,2p), was used for the accurate prediction of NMR chemical shifts both in gas phase and in solvents with varying dielectric constant such as CHCl3 and ethanol. The following factors affecting the predicted proton chemical shifts were considered. Firstly, ionic clusters consisting of 2, 8 and 16 ion pairs were optimized to model interionic interactions present in the bulk of ionic liquids. In larger clusters the distribution of the calculated chemical shifts of individual protons in the C2mim+ cation was examined with respect to the position of the cation in the cluster. We further confirmed that electronic properties of ionic liquids such as magnetic shielding had local nature, thus allowing us to accurately predict proton NMR chemical shifts of ionic liquids from relatively small-sized clusters. Secondly, solvent effects in single ion pairs as well as larger ionic clusters were accounted through a Conductor-like Polarisable Continuum Model (CPCM). Solvent effects generated through a dielectric constant of either chloroform or ethanol were found to be important in single ion pairs due to improved description of interionic distances. With increasing cluster size the difference between gas-phase and CPCM optimized structures became minimal, thus resulting in similar values for calculated 1H NMR chemical shifts. We also established that the model size that produced the best results for imidazolium ionic liquids strongly depended on the anion type. Strongly coordinating anions such as chloride and acetate require calculations of clusters consisting of at least 8 ion pairs, whereas weakly coordinating anions produce excellent accuracy for single ion pairs optimized in the presence of solvent. The polarity of the solvent was found to play a minor role. PMID- 28650017 TI - A large pyrene-fused N-heteroacene: fifteen aromatic six-membered rings annulated in one row. AB - Here, we present our recent progress on the synthesis, crystal structure, physical properties and DFT calculations of a novel large pyrene-fused N heteroacene (15RINGS) with 15 aromatic six-membered rings linearly fused in one row. The long conjugated backbone (more than 35 A) of 15RINGS possesses a dual bending feature (the bending angle is about 13.2 degrees ). PMID- 28650018 TI - Hypoglycemic effects of a Fructus Mori polysaccharide in vitro and in vivo. AB - Mulberry fruit polysaccharide (MFP), one of the major active ingredients isolated from the mulberry fruit, possesses numerous bioactivities. In vitro hypoglycemic experiments showed that MFP had significant insulin-sensitizing activity through increasing insulin secretion and promoting pancreatic beta cell proliferation. In vivo, the oral administration of MFP could significantly decrease blood glucose levels and increase body weight loss in streptozotocin (STZ)-induced diabetic mice. MFP also significantly decreased the level of malondialdehyde (MDA) and increased the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) in the liver in STZ-induced diabetic mice. And histopathological examination showed that MFP could markedly alleviate damage to pancreas, liver and kidney tissue in STZ-induced diabetic mice. This study suggested that MFP had antioxidant and hypoglycemic properties and could provide a protective effect on STZ-induced diabetic mice. PMID- 28650020 TI - Difference in chemical bonding between lithium and sodium salts: influence of covalency on their solubility. AB - Recent thermal runaways in lithium-ion batteries have reinforced the focus on the research of safer electrolytes based on ionic liquids. A simple switch from organic solvents to ionic liquids has been proven difficult due to the decreased efficiency of batteries caused by decreased conductivity and increased viscosity of ionic liquids upon addition of lithium salts. The new trend in replacing lithium salts with a cheaper alternative, sodium salts, has resulted in rather poor solubility of sodium salts in commonly used ionic liquids. This phenomenon has been left largely unexplained. Herein, we present a high-level quantum chemical study of the chemical bonding of lithium and sodium salts coupled with ionic liquid anions. Due to their proximity to the anion, the 1s2 electrons on the lithium cation are found to become strongly polarized by the presence of the anion such that they start participating in the bonding, making it more covalent than originally thought. In sodium salts the 2s2 orbitals are rather removed from the anion, making its influence weaker. This polarization results in 90 kJ mol-1 of difference in the interaction magnitude between lithium and sodium salts. Theoretical results have confirmed that increasing covalency in lithium salts results in their excellent solubility since these dissolve as ion-paired complexes. The downside of this ability is decreased conductivity as lithium salts are unlikely to easily dissociate in ionic liquids. Sodium salts are shown to maintain a high degree of ionicity, thus decreasing their chances of being solvated by ionic liquids as a result of their low concentration of ions per unit volume. The theoretical results are further underpinned by solubility studies of MX salts, where M = Li or Na and X = bis(trifluoromethylsulfonyl)imide (NTf2), BF4- or PF6-, conducted in six different ionic liquids. Lithium salts consisting of BF4- or PF6- exhibited significantly better solubility than their sodium analogues by at least an order of magnitude. The findings of this work will have implications on the future direction of the development of safe electrolytes for lithium and sodium-ion secondary batteries. PMID- 28650021 TI - Non-isothermal kinetics of spin crossover. AB - Non-isothermal magnetic studies can be used to estimate the activation energy of cooperative spin transition. Model-free isoconversional integral methods give reliable estimates of the activation barrier height for highly cooperative spin crossover systems with wide thermal hysteresis. PMID- 28650022 TI - Interaction and inhibitory influence of the azo dye carmoisine on lysozyme amyloid fibrillogenesis. AB - The binding of the common food colorant carmoisine and its inhibitory effect on amyloid fibrillation in lysozyme have been investigated. Since humans are increasingly exposed to various food colorants like carmoisine, such studies are highly relevant. In the presence of lysozyme, the carmoisine absorption spectrum exhibited hypochromic changes. The intrinsic fluorescence of lysozyme was also quenched on interaction. Time-resolved fluorescence results suggested that the binding mechanism involved ground state complexation. The binding was predominantly dominated by non-polyelectrolytic forces. The molecular distance between the donor (lysozyme) and the acceptor (carmoisine), calculated from FRET theory, was found to be 3.37 nm, indicating that carmoisine binds close to Trp 62/63 residues in the beta-domain of the protein. Information on alterations in the microenvironment surrounding the Trp-residues was also obtained from synchronous fluorescence data. Carmoisine binding induced significant loss in the alpha helical organization of lysozyme. The binding, nevertheless, did not influence the thermal stability of lysozyme significantly. The binding reaction was exothermic and driven by large negative enthalpy and small but favourable entropic contributions. Thioflavin T assay, far-UV circular dichroism studies and AFM imaging profiles testified that carmoisine had a significant inhibitory effect on amyloid fibrillogenesis in lysozyme. Carmoisine also had a definitive defibrillating effect on existing fibrils. The results may provide new insights for designing new small molecule inhibitors for amyloid related diseases. PMID- 28650023 TI - Ligand-induced conformational preorganization of loops of c-MYC G-quadruplex DNA and its implications in structure-specific drug design. AB - Stabilization of a G-quadruplex (G4) DNA structure in the proto-oncogene c-MYC using small molecule ligands has emerged as an attractive strategy for the development of anticancer therapeutics. To understand the subtle structural changes in the G4 structure upon ligand binding, molecular dynamics (MD) simulations of c-MYC G4 DNA were carried out in a complex with six different potent ligands: 3AQN, 6AQN, 3APN, 360A, Nap-Et, and Nap-Pr. The results show that the ligands 3AQN, 6AQN, 3APN, and 360A stabilize the G4 structure by making stacking interactions with the top quartet. On the other hand, Nap-Et and Nap-Pr bind at the groove of the G4 structure. These groove binding ligands make crucial H-bond contacts with the guanines and electrostatic interactions with the phosphate backbone. Two-dimensional dynamic correlation maps unraveled the ligand induced correlated motions between the guanines in the quartet and a di nucleotide present in the propeller loop-2 of the G4 structure. Cluster analysis and ONIOM calculations revealed the structural dynamics in the loop of the quadruplex upon ligand binding. Overall, the results from the present study suggest that engineering specific contacts with the propeller loop can be an efficient way to design c-MYC G4-specific ligands. PMID- 28650025 TI - Photocatalytic activity of silicon-based nanoflakes for the decomposition of nitrogen monoxide. AB - The photocatalytic decomposition of nitrogen monoxide (NO) was achieved for the first time using Si-based nanomaterials. Nanocomposite powders composed of Si nanoflakes and metallic particles (Ni and Ni3Si) were synthesized using a simple one-pot reaction of layered CaSi2 and NiCl2. The synthesized nanocomposites have a wide optical absorption band from the visible to the ultraviolet. Under the assumption of a direct transition, the photoabsorption behavior is well described and an absorption edge of ca. 1.8 eV is indicated. Conventional Si and SiO powders with indirect absorption edges of 1.1 and 1.4 eV, respectively, exhibit considerably low photocatalytic activities for NO decomposition. In contrast, the synthesized nanocomposites exhibited photocatalytic activities under irradiation with light at wavelengths >290 nm (<4.28 eV). The photocatalytic activities of the nanocomposites were confirmed to be constant and did not degrade with the light irradiation time. PMID- 28650026 TI - The effect of PEGylated hollow gold nanoparticles on stem cell migration: potential application in tissue regeneration. AB - Mesenchymal stem cells (MSCs) not only can be differentiated into different cell types but also have tropism towards injured or inflamed tissues serving as repair cells. Here we have demonstrated that MSCs containing gold nanoparticles (GNPs) whose surface has been functionalized with PEG show accelerated cell migration, successful scaffold colonization and regeneration. We report the impact of GNPs on the migration (by the wound healing assay), and proliferation (by flow cytometry analysis and by the detection of metabolic mitochondrial activity) on the behaviour of different cell lines including MSCs, HeLa cells, and human dermal fibroblasts. We conclude that GNPs are easily internalized by MSCs causing an increase in their migration rate, mediated by actin and tubulin with a 4-fold increased expression level of those proteins. We also demonstrate that MSCs containing GNPs are able to successfully colonize fibrin and PCL-based scaffolds and that an enhanced osteoblastic differentiation is reached when using the nanoparticle-laden cells compared to untreated cells used as a control. These results highlight the potential use of MSCs as therapeutic nanoparticle-carriers in regenerative medicine. PMID- 28650027 TI - Cationic 2,2'-bipyridine complexes of germanium(ii) and tin(ii). AB - We present the first systematic study of 2,2'-bipyridine complexes of E(ii) cationic acceptors (E = Ge, Sn). The complexes were comprehensively characterized by spectroscopic and crystallographic methods to yield complexes of ECl1+ and E2+. Computational DFT methods were also employed to survey the bonding in the cations, along with an examination of their molecular orbitals (MOs). PMID- 28650028 TI - Lanthanide metal organic frameworks based on dicarboxyl-functionalized arylhydrazone of barbituric acid: syntheses, structures, luminescence and catalytic cyanosilylation of aldehydes. AB - Five isostructural lanthanide MOFs, [Ln(1kappaOO',2kappaO'',3kappaO''',4kappaO''''-MU4-L)(NO3)(DMF)2]n.n(DMF) {Ln = La3+ (1), Ce3+ (2), Nd3+ (3), Sm3+ (4) and Dy3+ (5); L = 5-[2-{2,4,6 trioxotetrahydropyrimidin-5(2H)-ylidene}hydrazinyl]isophthalate; DMF = N,N' dimethyl formamide}, based on dicarboxyl-functionalized arylhydrazone of barbituric acid were synthesized under solvothermal conditions. They were characterized by elemental analysis, FT-IR spectroscopy, thermogravimetric and X ray diffraction analyses. Crystal structure analysis revealed that these frameworks possess a similar type of two dimensional (2D) structure with a dinuclear {Ln2(COO-)2} unit acting as a secondary building block. Topological analysis shows that these frameworks display a 3,6-connected kgd; Shubnikov plane (3.6.3.6)/dual net. They exhibit excellent heterogeneous catalytic activities (compound 2 is the most active one) towards the cyanosilylation of aldehydes under solvent-free conditions. These catalysts can be recycled at least up to five cycles without a loss of activity. Compounds 1-5 exhibit luminescence properties in the solid state at room temperature. PMID- 28650029 TI - Nanoparticle-encapsulated baicalein markedly modulates pro-inflammatory response in gingival epithelial cells. AB - Severe gum disease (periodontitis), which is one of the major global oral diseases, results from microbe-host dysbiosis and dysregulated immuno inflammatory responses. It seriously affects oral health and general wellbeing with significant socio-economic implications. It has been well documented that natural flavonoids such as baicalin (BA) and baicalein (BE) possess potent anti inflammatory effects. However, their intrinsic poor solubility and low bioavailability severely limit their biomedical applications. In the present study, BA and BE were encapsulated in our synthesized and amine-modified mesoporous silica nanoparticles (MSNs) (Nano-BA and Nano-BE, respectively), and their loading efficiencies and releasing profiles were investigated. Their cytotoxicity was examined on primary human gingival epithelial cells (hGECs), and the cellular uptake of Nano-BA or Nano-BE was visualized via a transmission electron microscope. Their anti-inflammatory effects were evaluated in IL-1beta treated hGECs using the cytokine array and enzyme-linked immunosorbent assay. The present study shows that the amine-modified MSNs could encapsulate BA and BE, and nano-encapsulation greatly enhances the drug delivery rate and prolongs the release of BA and BE up to 216 h. Moreover, both Nano-BA and Nano-BE could be internalized by hGECs and retained intracellularly in nanoparticle-free media for at least 24 h. Note that Nano-BE pre-treatment effectively down-regulates the IL 1beta-induced expression of IL-6 and IL-8 in hGECs. In conclusion, nanoparticle encapsulated BE exhibits notable anti-inflammatory effects through effective release and cellular internalization approaches. This study may facilitate the development of novel drug delivery systems for improving oral care. PMID- 28650030 TI - Carbon nanoscroll-silk crystallite hybrid structures with controllable hydration and mechanical properties. AB - Hybrid structures of nanomaterials (e.g. tubes, scrolls, threads, cages) and biomaterials (e.g. proteins) hold tremendous potential for applications as drug carriers, biosensors, tissue scaffolds, cancer therapeutic agents, etc. However, in many cases, the interacting forces at the nano-bio interfaces and their roles in controlling the structures and dynamics of nano-bio-hybrid systems are very complicated but poorly understood. In this study, we investigate the structure and mechanical behavior of a protein-based hybrid structure, i.e., a carbon nanoscroll (CNS)-silk crystallite with a hydration level controllable by an interlayer interaction in CNS. Our findings demonstrate that CNS with a reduced core size not only shields the crystallite from a weakening effect of water, but also markedly strengthens the crystallite. Besides water shielding, the enhanced strength arises from an enhanced interaction between the crystallite and CNS due to the enhanced interlayer interaction in CNS. In addition, the interfacial strength for pulling the crystallite out of the CNS-silk structure is found to be dependent on both the interlayer interaction energy in CNS as well as the sequence of protein at the CNS-silk interface. The present study is of significant value in designing drugs or protein delivery vehicles for biomedical applications, and serves as a general guide in designing novel devices based on rolled-up configurations of two-dimensional (2D) materials. PMID- 28650031 TI - Diffusiophoretic manipulation of particles in a drop deposited on a hydrogel. AB - We report an experimental study on the manipulation of colloidal particles in a drop sitting on a hydrogel. The manipulation is achieved by diffusiophoresis, which describes a directed motion of particles induced by solute gradients. By letting the solute concentrations for the drop and the hydrogel be different, we control the motion of particles in a stable suspension, which is otherwise difficult to achieve. We show that diffusiophoresis can cause the particles to move either toward or away from the liquid-air interface depending on the direction of the solute gradient and the surface charge of the particles. We measure the particle adsorption experimentally and rationalize the results with a one-dimensional numerical model. We show that diffusiophoretic motion is significant at the lengthscale of a drop deposited on a hydrogel, which suggests a simple method for the deposition of particles on hydrogels. PMID- 28650032 TI - Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights. AB - Covering: up to 2017The overwhelming majority of antibiotics in clinical use originate from Gram-positive Actinobacteria. In recent years, however, Gram negative bacteria have become increasingly recognised as a rich yet underexplored source of novel antimicrobials, with the potential to combat the looming health threat posed by antibiotic resistance. In this article, we have compiled a comprehensive list of natural products with antimicrobial activity from Gram negative bacteria, including information on their biosynthetic origin(s) and molecular target(s), where known. We also provide a detailed discussion of several unusual pathways for antibiotic biosynthesis in Gram-negative bacteria, serving to highlight the exceptional biocatalytic repertoire of this group of microorganisms. PMID- 28650033 TI - Chloride assisted supramolecular assembly of a luminescent gigantic cluster: [Ag216S56Cl7(C[triple bond, length as m-dash]CPh)98(H2O)12]- with pseudo-Th skeleton and five-shell arrangement. AB - Using a chloride-assisted supramolecular building-block approach, we have employed the molecular Cl@Agm(C[triple bond, length as m-dash]CPh)n entity in the construction of a gigantic cluster namely [Ag216S56Cl7(C[triple bond, length as m dash]CPh)98(H2O)12][Ag3(imidazole)(H2O)4](SbF6)2 (1), which contains the largest discrete organometallic cluster investigated by X-ray crystallography. Based on an icosahedral Cl@Ag12 kernel, this spheroidal cluster features an unprecedented five-shell structure Cl@Ag12@S12@Ag32@S44Cl6@Ag172 with idealized Th symmetry. The MALDI-MS, 1D, 2D 1H NMR, electronic absorption, emission spectra and HR-TEM of 1 were measured. Compound 1 shows intense red luminescence in solution at room temperature (QY = 4.7% in CH2Cl2), in addition to its 3.4 nm diameter, which makes it a unique example that fills the gap between small luminescent silver clusters and large luminescent silver nanoparticles. PMID- 28650034 TI - The sandpile revisited: computer assisted determination of constitutive relations and the breaking of scaling. AB - We revisit the problem of the stress distribution in a frictional sandpile with both normal and tangential (frictional) inter-granular forces, under gravity, equipped with a new numerical method of generating such assemblies. Numerical simulations allow a determination of the spatial dependence of all the components of the stress field, principle stress axis, angle of repose, as a function of systems size, the coefficient of static friction and the frictional interaction with the bottom surface. We compare these results with the predictions of a theory based on continuum equilibrium mechanics. Basic to the theory of sandpiles are assumptions about the form of scaling solutions and constitutive relations for cohesive-less hard grains for which no typical scale is available. We find that these constitutive relations must be modified; moreover for smaller friction coefficients and smaller piles these scaling assumptions break down in the bulk of the sandpile due to the presence of length scales that must be carefully identified. Fortunately, for larger friction coefficient and for larger piles the breaking of scaling is weak in the bulk, allowing an approximate analytic theory which agrees well with the observations. After identifying the crucial scale, triggering the breaking of scaling, we provide a predictive theory to when scaling solutions are expected to break down. At the bottom of the pile the scaling assumption breaks always, due to the different interactions with the bottom surface. The consequences for measurable quantities like the pressure distribution and shear stress at the bottom of the pile are discussed. For example one can have a transition from no dip in the base-pressure to a dip at the center of the pile as friction increases. PMID- 28650035 TI - Sterically encumbered metalla-diphosphines: unlocking alkyne rotation by PtII coordination. AB - We present the synthesis and coordination chemistry of a series of WII alkyne complexes with symmetric and asymmetric acetylene diphosphines. Chelate-like P,P' coordination of PtCl2 cause a drastic potential change of the W centered oxidation proving intermetallic cooperativity. The choice of peripheric P substituents has a measurable influence on the potential itself as well on the respective potential change upon coordination. The enlarged deviation of the diphosphino alkyne from linearity in the dinuclear complexes unlock alkyne rotation making different isomers accessible. PMID- 28650036 TI - Towards the liquid phase exfoliation of bismuth iodide. AB - Liquid phase exfoliation (LPE) of layered compounds towards few- or monolayers has been established as one of the prime methods in the growing field of 2D material research. Here, we present first steps towards an effective LPE of bismuth(iii) iodide, a semiconductor with potential as a photovoltaic absorber material. We highlight guidelines in the choice of exfoliating solvent, which differ significantly from those used with transition metal dichalcogenides or graphene. We also present first evidence of successful few-layer formation from spectroscopic, electron microscopy and electron diffraction investigations. PMID- 28650038 TI - Asymmetric radical alkylation of N-sulfinimines under visible light photocatalytic conditions. AB - In this communication, a new photocatalytic strategy for the addition of alkyl radical derivatives to N-sulfinimines with complete diastereoselectivity and moderate to good yields is presented. This is the first asymmetric photocatalytic addition to N-sulfinimines under visible light irradiation with smooth conditions and functional group tolerance. PMID- 28650039 TI - Stabilization vs. destabilization of G-quadruplex superstructures: the role of the porphyrin derivative having spermine arms. AB - The interaction of the porphyrin derivative H2TCPPSpm4, having spermine pendants in the four meso positions, with the G-quadruplex (GQ) structure formed by the DNA aptamer TGGGAG has been investigated by means of UV, electronic circular dichroism and PAGE studies. The results reported here demonstrate that the porphyrin derivative is capable of stabilizing or destabilizing the higher ordered structures of parallel GQs, depending on the method used to reach their relative stoichiometry (titration vs. single addition). Noteworthily, when two equivalents of H2TCPPSpm4 were mixed directly with one equivalent of the (TGGGAG)4 GQ to reach a 2 : 1 H2TCPPSpm4 : GQ ratio T1/2 higher than 80 degrees C was also observed confirming the presence of higher-ordered GQ structures. PMID- 28650040 TI - Synthesis, functionalisation and post-synthetic modification of bismuth metal organic frameworks. AB - Two new bismuth metal-organic frameworks (Bi-MOFs) were discovered using high throughput experiments employing bismuth(iii) nitrate pentahydrate and triazine 2,4,6-triyl-tribenzoic acid (H3TATB). The reaction was carried out for long reaction times (~5 d) in a water/DMF-mixture and resulted in the formation of [Bi2(O)(OH)(TATB)].H2O (denoted as CAU-35). By switching to short reaction times and a methanol/DMF-mixture as the solvent, an analogue of CAU-7-BTB with the composition [Bi(TATB)].DMF.6H2O (denoted as CAU-7-TATB) was obtained. The use of the amino-functionalised H3TATB linker (H3TATB-NH2) resulted in the formation of a functionalised porous Bi-MOF with the composition [Bi(TATB-NH2)].5H2O.0.5DMF (CAU-7-TATB-NH2). The structures of CAU-35 and CAU-7-TATB were successfully solved and refined from the PXRD data. CAU-7-TATB-NH2 was post-synthetically modified using anhydrides (acetic anhydride and valeric anhydride), cyclic anhydrides (succinic anhydride and phthalic anhydride), and 1,3-propane sultone. The degree of conversion ranged from 33% to 79%. PMID- 28650041 TI - Competition between the H- and D-atom transfer channels in the H2O+ + HD reaction: reduced-dimensional quantum and quasi-classical studies. AB - The ion-molecule reaction between a water cation and a hydrogen molecule has recently attracted considerable interest due to its importance in astrochemistry. In this work, the intramolecular isotope effect of the H2O+ + HD reaction is investigated using a seven-dimensional initial state-selected time-dependent wave packet approach as well as a full-dimensional quasi-classical trajectory method on a full-dimensional ab initio global potential energy surface. The calculated branching ratios for the formation of H3O+ and H2DO+via H- and D-transfer agree reasonably well with the experimental values. The preference to the formation of the H3O+ product observed using the experiment at low collision energies is reproduced by theoretical calculations and explained by a one-dimensional effective potential model. PMID- 28650042 TI - Monitoring aggregation of a pH-responsive polymer via proton exchange. AB - Understanding the changes in the macro-structure of amphiphilic pH-responsive polymers remains a relevant issue due to their potential use as drug delivery carriers. Since some of the amphiphilic polymers are known to exchange hydrogen ions with an aqueous solvent, we monitor the effective change of the surface to volume ratio of such polymer aggregates using solution-state nuclear magnetic resonance (NMR) spectroscopy. The surface to volume ratio with the help of UV visible spectroscopy is shown to yield the average diameter of the polymer aggregates. We show that the proposed method not only satisfactorily corroborates the existing notions of how the aggregation of these polymers takes place as a function of pH, but also provides a quantitative estimate of the size of the aggregates. PMID- 28650043 TI - Heme-containing enzymes and inhibitors for tryptophan metabolism. AB - Iron-containing enzymes such as heme enzymes play crucial roles in biological systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 2,3 dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 2,3 dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of l-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression of these enzymes causes depletion of tryptophan and the accumulation of metabolic products, which contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies. In the past few decades, IDO1 has garnered the most attention as a therapeutic target with great potential in cancer immunotherapy. Many potential inhibitors of IDO1 have been designed, synthesized and evaluated, among which indoximod (d-1-MT), INCB024360, GDC-0919 (formerly NLG 919), and an IDO1 peptide-based vaccine have advanced to the clinical trial stage. However, recently, the roles of TDO and IDO2 have been elucidated in immune suppression. In this review, the current drug discovery landscape for targeting TDO, IDO1 and IDO2 is highlighted, with particular attention to the recent use of drugs in clinical trials. Moreover, the crystal structures of these enzymes, in complex with inhibitors, and the mechanisms of Trp catabolism in the first step, are summarized to provide information for facilitating the discovery of new enzyme inhibitors. PMID- 28650044 TI - One-pot asymmetric synthesis of a spiro[dihydrofurocoumarin/pyrazolone] scaffold by a Michael addition/I2-mediated cyclization sequence. AB - An asymmetric formal one-pot reaction of 4-hydroxycoumarins with unsaturated pyrazolones has been developed by merging a chiral bifunctional organocatalyst with molecular iodine, which furnished a series of optically active spiro[dihydrofurocoumarin/pyrazolone] heterocycles with spiro quaternary stereogenic centers in moderate to excellent yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1 dr) and good to excellent enantioselectivities (up to 99% ee). The application in the gram-scale synthesis of chiral spiro[dihydrofurocoumarin/pyrazolone] compounds was also successfully realized. PMID- 28650045 TI - Targeted delivery of geranylgeranylacetone to mitochondria by triphenylphosphonium modified nanoparticles: a promising strategy to prevent aminoglycoside-induced hearing loss. AB - Prevention of hair cell death is an important target for the prevention of hearing loss. Here, we report the engineering of biodegradable poly(lactic-co glycolic acid) nanoparticles (PLGA NPs) decorated with triphenylphosphonium (TPP) cations as a robust mitochondrial delivery platform, with the aim of preserving mitochondrial integrity and shutting off the initiation of cell death. Geranylgeranylacetone (GGA), a 70 kDa heat shock protein (HSP70) inducer, was used as a therapeutic molecule to attenuate gentamicin (Gen) induced hearing loss. The diameter of the mitochondria-targeting NPs is 145 nm and the encapsulation efficiency is 80.6%. Lysosomal escape and mitochondrial targeting studies indicated the promising therapeutic potential of TPP modified NPs. Finally, the zebrafish lateral line model was applied to verify the efficacy of the GGA loaded targeting NPs for preventing gentamicin-induced death hair cell. The results showed that the prepared targeted NPs provided significant protection: the survival of hair cells increased from 36% to 69% under acute exposure and from 20% to 62% under chronic exposure. In addition, targeted NPs exhibited significantly improved efficiency in alleviating gentamicin-induced hair cell damage compared with free drugs and untargeted NPs, supporting the hypothesis of mitochondrial targeting delivery in the treatment of aminoglycoside induced hearing loss. These TPP modified NPs demonstrated promise for the treatment of mitochondrial dysfunction. PMID- 28650046 TI - Chiroptical inversion for isolated vibronic transitions of supersonic beam-cooled molecules. AB - Circular dichroism-resonance-enhanced multiphoton ionization (CD-REMPI) was used for CD measurements on several single vibronic transitions of supersonic beam cooled (R)-(+)-1-phenylethanol. Due to the low molecular densities within a supersonic beam and the expected small anisotropy factor of 1-phenylethanol in the permille region, the precision of the experimental method had to be significantly improved. Therefore, a single laser pulse evaluation combined with a twin-peak technique enabled within the used supersonic beam setup is presented. For the electronic transition S0 -> S1 of (R)-(+)-1-phenylethanol (pi -> pi* transition of the phenyl ring at 266 nm) ten different vibrational modes as well as the 0-transition were investigated with one-color (1 + 1) CD-REMPI. The results deliver new experimental insights on the influence of molecular vibrations on the anisotropy factor. TD-DFT theoretical predictions show how the angle between the electronic and magnetic transition dipole moments of the electronic transition can be modified by different vibrational modes, making even a flip of the sign of the anisotropy factor possible. PMID- 28650047 TI - Excitation-dependent local symmetry reversal in single host lattice Ba2A(BO3)2:Eu3+ [A = Mg and Ca] phosphors with tunable emission colours. AB - Eu3+ activated phosphors are widely used as red emitters in various display devices and light emitting diodes (LEDs). The emission characteristics of Eu3+ depend on the local site symmetry. The present study demonstrates the role of excitation-dependent local symmetry changes due to the structural reorganization on the emission colour tuning of Eu3+ from orange-red to orange in single host lattices, Ba2Mg(BO3)2 and Ba2Ca(BO3)2. The choice of these lattices was based on the difference in the extent of strain experienced by the oxygen atoms. The samples with Eu3+ at Ba or Mg (Ca) sites were synthesized using the conventional high-temperature solid-state reaction method. The samples were characterized using powder XRD, 11B MAS-NMR, FT-IR, and diffuse reflectance UV-Vis spectroscopic techniques. The room temperature photoluminescence (PL) recorded using different excitation wavelengths revealed a clear difference in the PL emission features due to symmetry reversal from non-inversion to inversion symmetry around Eu3+. The reorganization of highly strained oxygen atoms leads to such symmetry reversal. First-principles calculations were used to deduce the optimized structures of the two borate host lattices, and local geometries and their distortions upon Eu3+ substitution. The outcomes of these calculations support the experimental findings. PMID- 28650048 TI - Cooperative wrapping of nanoparticles of various sizes and shapes by lipid membranes. AB - Understanding the interaction between nanoparticles (NPs) and cell membranes is crucial for the design of NP-based drug delivery systems and for the assessment of the risks exerted by the NPs. Recent experimental and theoretical studies have shown that cell membranes can mediate attraction between NPs and form tubular structures to wrap multiple NPs. However, the cooperative wrapping process is still not well understood, and the shape effect of NPs is not considered. In this article, we use large-scale coarse-grained molecular dynamics (CGMD) simulations to study the cooperative wrapping of NPs when a varying number of NPs adhered to the membrane. Spherical, prolate and oblate NPs of different sizes are considered in this study. We find that, in addition to tubular structures, the membrane can form a pocket-like and a handle-like structure to wrap multiple NPs depending on the size and shape of the NPs. Furthermore, we find that NPs can mediate membrane hemifusion or fusion during this process. Our findings provide new insights into the interaction of NPs with the cell membrane. PMID- 28650049 TI - Lanthanide doped coordination polymers with tunable afterglow based on phosphorescence energy transfer. AB - Lanthanide ion doped coordination polymers (CPs) exhibit an unusual red/green afterglow with long photoemission lifetimes (10.54 ms for Eu3+ and 57.66 ms for Tb3+) due to the phosphorescence energy transfer at room temperature. PMID- 28650051 TI - Low temperature photoluminescence properties of CsPbBr3 quantum dots embedded in glasses. AB - The photoluminescence properties of perovskite CsPbBr3 QDs embedded in glasses were investigated at cryogenic temperature in the range of 40-240 K. CsPbBr3 QDs with radii of 3.3 nm, 4.2 nm and 4.8 nm were precipitated in phosphate glasses using conventional thermal treatment. Photoluminescence (PL) integral intensities, bandgap energies and full with at half maximum of the PL bands of CsPbBr3 QDs showed a strong dependence on temperature. An exciton binding energy of ~40 meV was derived from the temperature-dependent emission intensity. Optical phonon energy involved in the exciton-phonon interaction was found to be ~56 meV, about three times as that of the single phonon energy. Exciton-phonon coupling strength and the lattice thermal expansion coefficient were strongly dependent on the size of CsPbBr3 QDs, and as a result, inflection temperature of the PL peak energies of CsPbBr3 QDs increased as the size increased. PMID- 28650050 TI - Bilayered nanofibrous 3D hierarchy as skin rudiment by emulsion electrospinning for burn wound management. AB - Mimicking skin extracellular matrix hierarchy, the present work aims to develop a bilayer skin graft comprising a porous cotton-wool-like 3D layer with membranous structure of PCL-chitosan nanofibers. Emulsion electrospinning with differential stirring periods of PCL-chitosan emulsion results in development of a bilayer 3D structure with varied morphology. The electrospun membrane has fiber diameter ~274 nm and pore size ~1.16 MUm while fluffy 3D layer has fiber diameter ~1.62 MUm and pore size ~62 MUm. The 3D layer was further coated with collagen I isolated from Cirrhinus cirrhosus fish scales to improve biofunctionality. Surface coating with collagen I resulted in bundling the fibers together, thereby increasing their average diameter to 2.80 MUm and decreasing pore size to ~45 MUm. The architecture and composition of the scaffold promotes efficient cellular activity where interconnected porosity with ECM resembling collagen I coating assists cellular adhesion, infiltration, and proliferation from initial days of fibroblast seeding, while keratinocytes migrate on the surface only without infiltrating in the membranous nanofiber layer. Anatomy of the scaffold arising due to variation in pore size distribution at different layers thereby facilitates compartmentalization and prevents initial cellular transmigration. The scaffold also assists in extracellular matrix protein synthesis and keratinocyte stratification in vitro. Further, the scaffold effectively integrates and attaches with third-degree burn wound margins created in rat models and accelerates healing in comparison to standard Tegaderm dressingTM. The bilayer scaffold is thus a promising, readily available, cost-effective, off-the shelf matrix as a skin substitute. PMID- 28650052 TI - A versatile route to homo- and hetero-bimetallic 5f-5f and 3d-5f complexes supported by a redox active ligand framework. AB - The salt-elimination reaction of the complex [Na2U(bis-salophen)] with metal halides provides an entry to the synthesis of well-defined homobimetallic uranium uranium and rare heterobimetallic uranium-cobalt and uranium-nickel complexes supported by a redox-active dinucleating ligand. PMID- 28650053 TI - In situ crystal growth of gold nanocrystals on upconversion nanoparticles for synergistic chemo-photothermal therapy. AB - A multifunctional cancer therapy nanocomposite was proposed and synthesized by linking the pH-responsive SH-PEG-DOX prodrug onto gold nanocrystals that were grown in situ on the surface of upconversion nanoparticles (UCNPs). In the structure of the SH-PEG-DOX prodrug, a hydrazone bond was utilized for subsequent pH-responsive drug release in the intracellular acidic microenvironment of cancer cells. This innovative assembly method is facile and mild, and can be used to obtain nanocomposites of UCNPs and gold, which show excellent photostability and biocompatibility. The final UCNPs@Au-DOX nanocomposites offer efficient treatment effects in vitro under irradiation with an 808 nm laser due to the synergistic effect of chemotherapy and photothermal therapy. In addition, the UCNPs@Au-DOX nanocomposites show excellent intracellular locating ability via upconversion luminescence (UCL) imaging with Er3+ ions and magnetic resonance imaging (MRI) with Gd3+ ions, indicating that they have potential as a visual tracking agent in cancer treatment. Therefore, the presented bioimaging-guided multifunctional synergistic therapy nanocomposites are promising tools for imaging-guided cancer therapy. PMID- 28650054 TI - Long-pulse laser launch and ionization of tailored large neutral silver nanoparticles with atomic mass assignment. AB - We explore the synthesis, characterization, neutral launch and vacuum ultraviolet ionization of massive perfluorinated-alkyl-capped nanoparticles. The presence of the ligand coating in solution is corroborated by Fourier transform infrared spectroscopy (FT-IR) and the particle size distribution is analyzed by transmission electron microscopy (TEM). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry identifies perfluoralkyl coated silver nanoparticles as the most stable species among the materials studied here. They can be launched in high vacuum using long-pulse low power laser heating - orders of magnitude below typical thresholds for laser desorption. Energy-dispersive X-ray spectroscopy (EDX) of the recaptured silver clusters confirms the expected elemental distribution. Volatilization with subsequent ionization of the neutral nanoparticle beam in high vacuum by 157 nm light allows analyzing their mass with atomic resolution. PMID- 28650055 TI - Non-planar vertical photodetectors based on free standing two-dimensional SnS2 nanosheets. AB - The development trend of modern electronics and optoelectronics is towards continuous high integration and miniaturization. Using vertical configurations with three-dimensional geometry, it is easy to establish a higher integration density than the traditional planar one, and thus, this technology shows great promise for designing the next-generation electronics/optoelectronic devices. Two dimensional (2D) layered metal dichalcogenides (2D-LMDs) are important building blocks for electronic/optoelectronic devices, where they are usually grown in parallel to the substrates during chemical vapor deposition (CVD), and consequently they are solely exploited to fabricate lateral structure devices with planar geometry. In this research, for the first time the vertical growth of free standing 2D layered nanosheets of hexagonal tin disulfide (SnS2) on a flat substrate was realized using a modified CVD method. Furthermore, it was successfully demonstrated, at the first attempt, that a type of non-planar vertical photodetector could be fabricated using free standing SnS2 nanosheets and this detector showed promise for photodetection applications. This work prepares the way for the growth of monodisperse vertical 2D-LMD nanosheets on flat substrates, and expands their use from conventional lateral structure devices to non-planar vertical electronic/optoelectronic devices. PMID- 28650056 TI - Tailoring the local environment around metal ions: a solution chemical and structural study of some multidentate tripodal ligands. AB - Manganese(ii), copper(ii) and zinc(ii) complexes of four polydentate tripodal ligands (tachpyr (N,N',N''-tris(2-pyridylmethyl)-cis,cis-1,3,5 triaminocyclohexane), trenpyr (tris[2-(2-pyridylmethyl)aminoethyl]amine, tach3pyr (N,N',N''-tris(3-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane) and tren3pyr (tris[2-(2-pyridylmethyl)aminoethyl]amine)) were characterized in both solution and solid states. A combined evaluation of potentiometric, UV-VIS, NMR and EPR data allowed the conclusion of both thermodynamic and structural information about the complexes formed in solution. The four tailored polydentate tripodal ligands studied here exhibit a high thermodynamic stability, and a variety of coordination environments/geometries for the studied transition metal ions. Our data indicate that tachpyr is a more efficient zinc(ii) chelator and a similar copper(ii) chelator compared to trenpyr. Considering the higher number of N donors and conformational flexibility of trenpyr, as well as the energy demanding switch to the triaxial conformation required for metal ion binding of tachpyr, the above observation is surprising and is very likely due to the encapsulating effect of the more rigid tachpyr skeleton. This relative binding preference of tachpyr for zinc(ii) may be related to the observation that zinc(ii) is one of the principal metals targeted by tachpyr in cells. In contrast, trenpyr is a considerably more efficient manganese(ii) chelator, since it acts as a heptadentate ligand in the aqueous Mn(trenpyr) complex. The crystal structures of copper(ii) and zinc(ii) complexes of tachpyr indicated important differences in the ligand conformation, induced by the position of counter ions, as compared to earlier reports. The closely related new ligands, tach3pyr and tren3pyr, have been designed to form oligonuclear complexes. Indeed, we obtained a three dimensional polymer with a copper(ii)/tren3pyr ratio of 11/6. Within this metal organic framework, three distinctly different copper geometries can be identified: square pyramidal, trigonal bipyramidal and tetrahedral. Two square pyramidal and four trigonal bipyramidal copper centres create a hexanuclear subunit with a large inside cavity. These moieties are linked by tetrahedral copper(ii) centres, constructing the three-dimensional polymer structure. The formation of such polynuclear complexes was not detected in solution. Both tach3pyr and tren3pyr form only mononuclear complexes with square pyramidal and trigonal bipyramidal geometries, respectively. PMID- 28650057 TI - Enhanced catalytic activity and near room temperature gas sensing properties of SnO2 nanoclusters@mesoporous Sn(iv) organophosphonate composite. AB - A simple, facile and one-pot route for preparing SnO2 nanoclusters embedded on a mesoporous Sn(iv) organophosphonate (MSnP) framework is described. Reaction of SnCl4.5H2O with a flexible tris-phosphonic acid, mesityl-1,3,5 tris(methylenephosphonic acid), in the presence of a surfactant under hydrothermal conditions produced the desired nanocomposite, SnO2@MSnP. Analytical, spectroscopic and microscopic studies establish that SnO2@MSnP composite is comprised of SnO2 nanoparticles of an average size of 5 nm evenly and abundantly dispersed over the MSnP framework. The mesoporous metal organophosphonate support significantly augments the catalytic efficacy and vapor sensitivity of SnO2 nanoparticles. The catalytic efficiency of SnO2@MSnP was tested for two acid-catalyzed reactions: deoximation reaction and esterification of fatty acids. SnO2@MSnP exhibits remarkable sensitivity towards ammonia and acetone vapors at near room temperature and under open atmospheric conditions. The present method represents an important step towards preparation of mesoporous metal organophosphonate supported metal oxide nanoclusters and hence offers easy access to functional metal oxide based nanocomposites. PMID- 28650058 TI - Dynamically tuning near-infrared-induced photothermal performances of TiO2 nanocrystals by Nb doping for imaging-guided photothermal therapy of tumors. AB - Conventional wide bandgap semiconductors can absorb UV/visible light but have no photoabsorption band in the near-infrared (NIR) region, leading to difficulty in their use as NIR-responsive agents. With TiO2 as an example, we report the tuning from UV-responsive TiO2 nanocrystals to blue TiO2 nanocrystals with newly appeared NIR absorption band through the Nb-doping strategy. A strong NIR band should result from the localized surface plasmon resonances due to the considerable free electrons originating from the efficient incorporation of Nb5+ ions (<15.5%). Interestingly, under the irradiation of a 1064 nm laser, Nb-doped TiO2 nanocrystals can convert laser energy into heat, and higher Nb-doping content can lead to higher NIR-induced temperature elevation, highlighting that the photothermal performances of TiO2 nanocrystals can be dynamically modulated by adjusting the Nb-doping levels. After coating with PEGylated phospholipid, the resulting nanocrystals display water dispersibility, high photothermal conversion efficiency and cytocompatibility. Therefore, these Nb-doped TiO2 nanocrystals can be used as efficient and heavy-metal-free nanoagents for the simultaneous NIR/photoacoustic imaging and photothermal therapy of tumors using a 1064 nm laser in the second biological window. PMID- 28650059 TI - Substantial local variation of the Seebeck coefficient in gold nanowires. AB - Nanoscale structuring holds promise to improve the thermoelectric properties of materials for energy conversion and photodetection. We report a study of the spatial distribution of the photothermoelectric voltage in thin-film nanowire devices fabricated from a single metal. A focused laser beam is used to locally heat the metal nanostructure via a combination of direct absorption and excitation of a plasmon resonance in Au devices. As seen previously, in nanowires shorter than the spot size of the laser, we observe a thermoelectric voltage distribution that is consistent with the local Seebeck coefficient being spatially dependent on the width of the nanostructure. In longer structures, we observe extreme variability of the net thermoelectric voltage as the laser spot is scanned along the length of the nanowire. The sign and magnitude of the thermoelectric voltage is sensitive to the structural defects, metal grain structure, and surface passivation of the nanowire. This finding opens the possibility of improved local control of the thermoelectric properties at the nanoscale. PMID- 28650060 TI - An adaptive bias - hybrid MD/kMC algorithm for protein folding and aggregation. AB - In this paper, we present a novel hybrid Molecular Dynamics/kinetic Monte Carlo (MD/kMC) algorithm and apply it to protein folding and aggregation in explicit solvent. The new algorithm uses a dynamical definition of biases throughout the MD component of the simulation, normalized in relation to the unbiased forces. The algorithm guarantees sampling of the underlying ensemble in dependency of one average linear coupling factor tau. We test the validity of the kinetics in simulations of dialanine and compare dihedral transition kinetics with long time MD-simulations. We find that for low tau values, kinetics are in good quantitative agreement. In folding simulations of TrpCage and TrpZip4 in explicit solvent, we also find good quantitative agreement with experimental results and prior MD/kMC simulations. Finally, we apply our algorithm to study growth of the Alzheimer Amyloid Abeta 16-22 fibril by monomer addition. We observe two possible binding modes, one at the extremity of the fibril (elongation) and one on the surface of the fibril (lateral growth), on timescales ranging from ns to 8 MUs. PMID- 28650061 TI - [Effectiveness of education based on neuroscience in the treatment of musculoskeletal chronic pain]. AB - INTRODUCTION: Chronic pain is one of the most frequent health, economic and social problems. Given this, numerous approaches have been described, one of which is pain neuroscience education. AIM: To examine the effectiveness of pain neuroscience education in the treatment of musculoskeletal disorders with chronic pain and to explore the impact of specific aspects of the technique on its effectiveness. MATERIAL AND METHODS: Relevant studies published between 2000 and 2015 were identified by searching PubMed, Scopus and Web of Science. Studies identified by electronic searches were screened against a set of pre-defined inclusion criteria. PEDro and SIGN scales were used to evaluate the methodological quality of the included studies. RESULTS: Ten studies were included in this systematic review. The main outcomes that were measured were pain, disability, neurophysiology pain test, attitudes and beliefs, fear avoidance beliefs, self-care, kinesiophobia, quality of life and algometry. The results suggest that pain neuroscience education is effective in the short term and medium/long term for pain relief, either alone or combined with multimodal treatment. It was also effective in normalizing cognitions about pain, fear avoidance beliefs, and self-care. CONCLUSION: Despite some evidence for a positive effect in the short and medium/long term, the heterogeneity in the technical aspects used does not allow the obtaining of conclusive results. PMID- 28650062 TI - Safety and outcome of rtPA in acute ischemic stroke in patients with active cancer: case-control study. AB - INTRODUCTION: Cancer patients have increased stroke risk from direct and indirect malignancy effects. Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is standard medical treatment for acute ischemic stroke (AIS). AIM: To review rtPA use in AIS patients with active cancer. SUBJECTS AND METHODS: Retrospective observational case-control study evaluating patients with AIS and cancer admitted to our stroke unit between January/2010 and June/2015. RESULTS: Seven cases were identified (86% male; median age: 76), and 20 controls were included matched for age and Oxfordshire Community Stroke Project classification. 29% experienced direct procedure complications vs 30% within the control group, 14% suffered haemorrhagic transformation (vs 20%), one patient experienced serious systemic haemorrhage (case) and one patient experienced serious intracerebral haemorrhage (control). After three months' follow-up, 43% were independent compared with 25% controls, and 29% had died (vs 30%). Undetermined aetiology subtype (TOAST classification) was more frequent in cancer patients when compared to controls (71% vs 20%). CONCLUSION: Severe haemorrhagic complications, potentiated by rtPA, carry increased risk of morbidity and mortality. Nevertheless, selected cancer patients with AIS may benefit from rtPA treatment. Active cancer should not be considered an absolute contraindication to rtPA use. Risk of complications and life expectancy should be assessed when making this decision. PMID- 28650063 TI - [Obstetric brachial plexus palsy: incidence, monitoring of progress and prognostic factors]. AB - INTRODUCTION: Obstetric brachial plexus palsy is related with shoulder dystocia, and its main risk factor is macrosomia. Its incidence is estimated to be between 0.1 and 6.3 cases per 1,000 live newborn infants. Most cases are resolved but can give rise to permanent functional deficiency, which means that there is an interest to identify possible prognostic factors. PATIENTS AND METHODS: We conducted a descriptive study of newborn infants with obstetric brachial plexus palsy born in our hospital between the years 2011 and 2015. Maternal, perinatal and obstetric variables, as well as the type of lesion, were collected and were related with the possibility of recovery at six months. RESULTS: Altogether 32 cases were diagnosed, which represents an incidence of 1.440/00 of live newborn infants. 59% were males and 37.5% of them were macrosomic. The most frequent disorder was injury to the plexus at the proximal level (94%). 44% suffered from shoulder dystocia, and 47% still had sequelae at the sixth month. The antecedent of shoulder dystocia was related with a poor prognosis for recovery. CONCLUSIONS: The incidence of obstetric brachial plexus palsy has remained stable in recent years. The percentage of children who present sequelae at six months is significant. Prospective studies are needed to be able to establish the long-term prognostic factors of this pathology. PMID- 28650064 TI - [A new case of psychotic break as the presenting symptom of anti-NMDA receptor encephalitis. Treatment from a neuropsychiatric approach]. AB - INTRODUCTION: Limbic encephalitis generated by anti-N-methyl D-aspartate (NMDA) receptor antibodies is a severe acute neurological condition that is more prevalent in young females and is associated with an underlying tumour. The appearance of severe initial psychiatric signs and symptoms and the fact that it is accompanied by emotional disorders and severe cognitive impairment make it necessary to reconsider the contributions of neuropsychiatry to the diagnosis, development and treatment of the disease, since these have received little attention from researchers to date. CASE REPORT: We report on what is, to our knowledge, the only case in Navarra, associated with an ovarian teratoma, with special attention paid to its assessment, intervention and neuropsychiatric development. CONCLUSION: Anti-NMDA receptor encephalitis is a disease that is usually accompanied by predominant psychiatric manifestations at the outset of the illness, together with cognitive deterioration that commonly affects memory and the executive functions. Treatment consisting in beginning a process of rehabilitation that includes compensatory strategies for deficits, cognitive stimulation and psychopharmacological treatment in the recovery phase has proved to be effective. PMID- 28650066 TI - [XX Reunion Anual de la Sociedad Neurologica Asturiana. Communications]. PMID- 28650065 TI - Review of the novelties from the 32nd ECTRIMS Congress, 2016, presented at the 9th Post-ECTRIMS Meeting (I). AB - For the ninth year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain) with the aim of presenting and discussing the hottest issues debated at the ECTRIMS Congress by renowned specialists in multiple sclerosis in our country. One outcome of this scientific activity, endorsed by the Spanish Neurology Society, is this review article, which is published in two parts. This first part addresses family planning, pregnancy management and the role of breastfeeding in women with multiple sclerosis. Attention is drawn to the paediatric population, to magnetic resonance imaging features and to the genetic environmental risk factors for developing the disease in children, without neglecting the risk factors for development in adults. The review updates the epidemiology of cognitive deterioration in patients with multiple sclerosis, the advantages and disadvantages of available assessment tools, and current management approaches, while also insisting on the importance of cognitive involvement during the course of the disease. Furthermore, the concept of individualised, precision medicine is introduced, from the diagnosis of the disease until its treatment, with the controversies that inevitably arise in patient management, above all with regard to the change of treatment and the handling of associated risks. PMID- 28650067 TI - [Medical propaedeutics and neurology]. PMID- 28650068 TI - Rational engineering of p-hydroxybenzoate hydroxylase to enable efficient gallic acid synthesis via a novel artificial biosynthetic pathway. AB - Gallic acid (GA) is a naturally occurring phytochemical that has strong antioxidant and antibacterial activities. It is also used as a potential platform chemical for the synthesis of diverse high-value compounds. Hydrolytic degradation of tannins by acids, bases or microorganisms serves as a major way for GA production, which however, might cause environmental pollution and low yield and efficiency. Here, we report a novel approach for efficient microbial production of GA. First, structure-based rational engineering of PobA, a p hydroxybenzoate hydroxylase from Pseudomonas aeruginosa, generated a new mutant, Y385F/T294A PobA, which displayed much higher activity toward 3,4 dihydroxybenzoic acid (3,4-DHBA) than the wild-type and any other reported mutants. Remarkably, expression of this mutant in Escherichia coli enabled generation of 1149.59 mg/L GA from 1000 mg/L 4-hydroxybenzoic acid (4-HBA), representing a 93% molar conversion ratio. Based on that, we designed and reconstituted a novel artificial biosynthetic pathway of GA and achieved 440.53 mg/L GA production from simple carbon sources in E. coli. Further enhancement of precursor supply through reinforcing shikimate pathway was able to improve GA de novo production to 1266.39 mg/L in shake flasks. Overall, this study not only led to the development of a highly active PobA variant for hydroxylating 3,4-DHBA into GA via structure-based protein engineering approach, but also demonstrated a promising pathway for bio-based manufacturing of GA and its derived compounds. Biotechnol. Bioeng. 2017;114: 2571-2580. (c) 2017 Wiley Periodicals, Inc. PMID- 28650069 TI - Transcriptional engineering of the glyceraldehyde-3-phosphate dehydrogenase promoter for improved heterologous protein production in Pichia pastoris. AB - The constitutive glyceraldehyde-3-phosphate dehydrogenase promoter (PGAP ), which is one of the benchmark promoters of Pichia pastoris, was analyzed in terms of putative transcription factor binding sites. We constructed a synthetic library with distinct regulatory properties through deletion and duplication of these putative transcription factor binding sites and selected transcription factor (TF) genes were overexpressed or deleted to understand their roles on heterologous protein production. Using enhanced green fluorescent protein, an expression strength in a range between 0.35- and 3.10-fold of the wild-type PGAP was obtained. Another model protein, recombinant human growth hormone was produced under control of selected promoter variants and 1.6- to 2.4-fold higher product titers were reached compared to wild-type PGAP . In addition, a GAL4-like TF was found to be a crucial factor for the regulation of PGAP , and its overexpression enhanced the heterologous protein production considerably (up to 2.2-fold compared to the parental strain). The synthetic PGAP library generated enabled us to investigate the different putative transcription factors which are responsible for the regulation of PGAP under different growth conditions, ergo recombinant protein production under PGAP . Biotechnol. Bioeng. 2017;114: 2319 2327. (c) 2017 Wiley Periodicals, Inc. PMID- 28650071 TI - In vivo synergistic activity of a CAZyme cassette from Acidothermus cellulolyticus significantly improves the cellulolytic activity of the C. bescii exoproteome. AB - The use of microbial cells to convert plant biomass directly to fuels and chemicals is referred to as consolidated bioprocessing (CBP). Members of the bacterial genus, Caldicellulosiruptor (Gram-positive, anaerobic hyperthermophiles) are capable of deconstructing plant biomass without enzymatic or chemical pretreatment. This is accomplished by the production and secretion of free, multi-domain enzymes that outperform commercial enzyme cocktails on some substrates. Here, we show that the exoproteome of Caldicellulosiruptor bescii may be enhanced by the heterologous expression of enzymes from Acidothermus cellulolyticus that act synergistically to improve sugar release from complex substrates; as well as improve cell growth. In this work, co-expression of the A. cellulolyticus Acel_0615 beta-glucanase (GH6 and GH12) and E1 endoglucanase (GH5) enzymes resulted in an increase in the activity of the exoproteome on Avicel; as well as an increase in growth of C. bescii on Avicel compared to the parental strain or the strain expressing the beta-glucanase alone. Our ability to engineer the composition and effectiveness of the exoproteome of these bacteria provides insight into the natural mechanism of plant cell wall deconstruction, as well as future directions for improving CBP. Biotechnol. Bioeng. 2017;114: 2474-2480. (c) 2017 Wiley Periodicals, Inc. PMID- 28650072 TI - Cognitive interviews in patient-reported outcome measures of function for young people with neurodisabilities. PMID- 28650073 TI - Short-Term-Effectiveness of a Relationship Education Program for Distressed Military Couples, in the Context of Foreign Assignments for the German Armed Forces. Preliminary Findings From a Randomized Controlled Study. AB - This study examines the short-term effectiveness of a relationship education program designed for military couples. Distressed couples were randomly placed in either a wait-list control group or an intervention group. We conducted training sessions before a 3-month foreign assignment, and refresher courses approximately 6-week post-assignment. We analyzed the dyadic data of 32 couples, using hierarchical linear modeling in a two-level model. Reduction in unresolved conflicts was found in the intervention group, with large pre-post effects for both partners. Relationship satisfaction scores were improved, with moderate-to large effects only for soldiers, rather than their partners. Post-follow-up effect sizes suggested further improvement in the intervention group. Future research should examine the long-term effectiveness of this treatment. PMID- 28650074 TI - Ligand- and Solvent-Tuned Chemoselective Carbonylation of Bromoaryl Triflates. AB - The palladium-catalyzed chemoselective carbonylation of bromoaryl triflates is reported. The selective C-Br bond versus C-OTf (OTf=triflate) bond functionalization can be remarkably tuned by the combination of the ligand [4,5 bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) vs. 1,1' bis(diphenylphosphino)ferrocene (DPPF)] and the solvent (toluene vs. DMSO). The respective ligand and solvent effects are rationalized by DFT calculations. In contrast, the monodentate ligands BuPAd2 and tBu3 P prefer the selective C-Br bond activation and are solvent insensitive. PMID- 28650070 TI - The human ventilatory response to stress: rate or depth? AB - Many stressors cause an increase in ventilation in humans. This is predominantly reported as an increase in minute ventilation (VE). But, the same VE can be achieved by a wide variety of changes in the depth (tidal volume, VT ) and number of breaths (respiratory frequency, fR ). This review investigates the impact of stressors including: cold, heat, hypoxia, pain and panic on the contributions of fR and VT to VE to see if they differ with different stressors. Where possible we also consider the potential mechanisms that underpin the responses identified, and propose mechanisms by which differences in fR and VT are mediated. Our aim being to consider if there is an overall differential control of fR and VT that applies in a wide range of conditions. We consider moderating factors, including exercise, sex, intensity and duration of stimuli. For the stressors reviewed, as the stress becomes extreme VE generally becomes increased more by fR than VT . We also present some tentative evidence that the pattern of fR and VT could provide some useful diagnostic information for a variety of clinical conditions. In The Physiological Society's year of 'Making Sense of Stress', this review has wide ranging implications that are not limited to one discipline, but are integrative and relevant for physiology, psychophysiology, neuroscience and pathophysiology. PMID- 28650076 TI - A systematic review of the relationship between glycemic control and necrobiosis lipoidica diabeticorum in patients with diabetes mellitus. AB - The association of specific skin disorders with diabetes mellitus (DM) has been well established. Current literature suggests that approximately 30-91% of patients with diabetes will experience at least one cutaneous manifestation of this systemic disease in their lifetime. To date, there are limited articles summarizing the link between necrobiosis lipoidica diabeticorum (NLD) prognosis and glycemic control in patients with diabetes. The objective of the study is to summarize and appraise the available evidence assessing the relationship between glycemic control and NLD. A literature search was conducted based on MEDLINE (1946-2015), EMBASE (1980-2015), Google Scholar, and PubMed for publications that described the results of diabetes control and NLD. Further studies were identified from bibliographies of all relevant studies, gray literature, and annual scientific assemblies. All studies investigating the relationship between DM (type 1 and type 2) management and NLD were included. Two reviewers independently extracted data including demographics, type of diabetes management measures (glucose, HbA1c, insulin), comorbidities, and outcome. A total of 622 studies were identified, and 10 studies met the inclusion and exclusion criteria: two case series and eight case reports. Of the 24 patients with NLD, 13 patients reported resolution of NLD after implementing various methods of glycemic control (diabetic diet consisting of 1600 kcal/day [1 patient], insulin regimen [3 patients], and pancreatic transplantation [9 patients]). Glycemic control may have a role in influencing the prognosis of necrobiosis lipoidica in patients with diabetes; however, there is currently insufficient evidence to support or refute this claim. PMID- 28650077 TI - Considerations on the assessment of developmental coordination disorder and the elaboration of related contextual pathways. PMID- 28650075 TI - Isl1 Controls Patterning and Mineralization of Enamel in the Continuously Renewing Mouse Incisor. AB - Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, because it is normally generated by the laCL but not the liCL. Here, we show that epithelial-specific deletion of the transcription factor Islet1 (Isl1) is sufficient to drive formation of ectopic enamel by the liCL stem cells, and also that it leads to production of altered enamel on the labial surface. Molecular analyses of developing and adult incisors revealed that epithelial deletion of Isl1 affected multiple, major pathways: Bmp (bone morphogenetic protein), Hh (hedgehog), Fgf (fibroblast growth factor), and Notch signaling were upregulated and associated with liCL-generated ectopic enamel; on the labial side, upregulation of Bmp and Fgf signaling, and downregulation of Shh were associated with premature enamel formation. Transcriptome profiling studies identified a suite of differentially regulated genes in developing Isl1 mutant incisors. Our studies demonstrate that ISL1 plays a central role in proper patterning of stem cell-derived enamel in the incisor and indicate that this factor is an important upstream regulator of signaling pathways during tooth development and renewal. (c) 2017 American Society for Bone and Mineral Research. PMID- 28650078 TI - Genetic diversity of human metapneumovirus in hospitalized children with acute respiratory infections in Croatia. AB - Human metapneumovirus (HMPV) is recognized as a global and frequent cause of acute respiratory tract infections among people of all ages. The objectives of this study were molecular epidemiology and evolutionary analysis of HMPV strains which produced moderate and severe acute respiratory tract infections in children in Croatia during four consecutive seasons (2011-2014). A total of 117 HMPV positive samples collected from hospitalized pediatric patients presenting with acute respiratory tract infections and tested by direct immunofluorescence assay were first analyzed by amplifying a part of the F gene. Sixteen samples were further analyzed based on complete F, G, and SH gene sequences. HMPV genome was identified in 92 of 117 samples (78%) and the circulation of multiple lineages of HMPV was confirmed. In 2011, 2012, and 2014, subgroups A2 and B2 co-circulated, while B1 gained prevalence in 2013 and 2014. The study established the presence of a novel subcluster A2c in Croatia. This subcluster has only recently been detected in East and Southeast Asia. This study provides new insights into epidemiology and genetic diversity of HMPV in this part of Europe. PMID- 28650079 TI - A retrospective analysis of the application of the Elecsys(r) HIV combi PT assay in southern China. AB - BACKGROUND: Fourth-generation HIV assays have been implemented worldwide as a screening test for many years. Understanding the performance of fourth-generation assay in low HIV prevalence region is pivotal to interpret the test result correctly. In this study, retrospective analysis was used to evaluate application of the Elecsys(r) HIV combi PT assay. METHODS: A total of 85 043 specimens from a low prevalence setting were detected between June 2013 and October 2015. We evaluated the false-positive rate (FPR), specificity, and positive predictive value (PPV). RESULTS: The specificity between male and female were 99.85% and 99.82%, respectively. The PPV on male (50.75%) was higher than female (17.05%) significantly, while the FPR was 0.15% and 0.18%. The gap between false-positive (median: 1.83, [IQR]: 1.30, 3.38) and confirmed-positive (median: 407.5, [IQR]: 184.2, 871.7) is enormous. The highest s/co ratio for false-positive cases was 85.45, while the lowest s/co ratio for confirmed-positive cases was 59.68. Various reasons were attributed to false-positive cases. CONCLUSION: Optimal cutoff value is needed to be set to reduce the false-positive cases and predict the final status of HIV infection reliably. Retrospective analysis will help us to understand more about diagnosis of HIV. PMID- 28650080 TI - Effects of central administration of resistin on renal sympathetic nerve activity in rats fed a high-fat diet: a comparison with leptin. AB - Similar to leptin, resistin acts centrally to increase renal sympathetic nerve activity (RSNA). In high-fat fed animals, the sympatho-excitatory effects of leptin are retained, in contrast to the reduced actions of leptin on dietary intake. In the present study, we investigated whether the sympatho-excitatory actions of resistin were influenced by a high-fat diet. Further, because resistin and leptin combined can induce a greater sympatho-excitatory response than each alone in rats fed a normal chow diet, we investigated whether a high-fat diet (22%) could influence this centrally-mediated interaction. Mean arterial pressure (MAP), heart rate (HR) and RSNA were recorded before and for 3 hours after i.c.v. saline (control; n=5), leptin (7 MUg; n=4), resistin (7 MUg; n=5) and leptin and resistin combined (n=6). Leptin alone and resistin alone significantly increased RSNA (71+/-16%, 62+/-4%, respectively). When leptin and resistin were combined, there was a significantly greater increase in RSNA (195+/-41%) compared to either hormone alone. MAP and HR responses were not significantly different between hormones. When the responses in high-fat fed rats were compared to normal chow fed rats, there were no significant differences in the maximum RSNA responses. The findings indicate that sympatho-excitatory effects of resistin on RSNA are not altered by high-fat feeding, including the greater increase in RSNA observed when resistin and leptin are combined. Our results suggest that diets rich in fat do not induce resistance to the increase in RSNA induced by resistin alone or in combination with leptin. PMID- 28650081 TI - Diastereoselective Self-Assembly of a Neutral Dinuclear Double-Stranded Zinc(II) Helicate via Narcissistic Self-Sorting. AB - A new bis(salicylimine) ligand based on the Troger's base scaffold was synthesized in racemic and enantiomerically pure form. Upon coordination to zinc(II) ions this ligand undergoes highly diastereoselective self-assembly into neutral dinuclear double-stranded helicates as proven by XRD analysis and via comparison of experimental ECD spectra with those simulated with quantum-chemical methods. When the racemic ligand was used, self-assembly occurs under narcissistic self-sorting resulting in the formation of a racemic pair of helicates as revealed by NMR spectroscopy and XRD analysis. PMID- 28650082 TI - Circulating high mobility group AT-hook 2 and pleomorphic adenoma gene 1 in blood of patients with oral squamous cell carcinoma. AB - BACKGROUND: High mobility group AT-hook 2 (HMGA2) and pleomorphic adenoma gene 1(PLAG1) have been demonstrated to be elevated in many malignant tumors. However, the aim of this study was to evaluate HMGA2 and PLAG1 levels in blood as a non invasive biomarker for oral squamous cell carcinoma (OSCC) diagnosis. METHODS: qRT-PCR was performed to measure circulating HMGA2 and PLAG1 levels in OSCC patients (n=43) and matched cancer-free blood control group (n=21). Clinical data of all patients were recorded. RESULTS: Circulating HMGA2 and PLAG1 in the 43 OSCC patients was significantly higher than in control group (P<.001, P=.038, respectively). Furthermore, HMGA2 expression in OSCC patients with poor-moderate differentiation was increased compared with well-differentiated group. However, no significant differences in PLAG1 expression were detected when differentiation was considered. In addition, the receiver operating characteristic (ROC) curve analysis for circulating HMGA2 revealed an area under the ROC curve of 0.876 (95% confidence interval, 0.793-0.959; P<.001) with 65.1% sensitivity and 100% specificity in discriminating OSCC from controls at a cutoff value of 14.380, demonstrating significant diagnostic value for OSCC. CONCLUSION: Circulating HMGA2 levels are increased in OSCC patients and may potentially serve as a significant index to evaluate OSCC diagnosis. PMID- 28650083 TI - Additional value of B-flow imaging in arterial wall calcifications. AB - The accuracy of color Doppler ultrasonography (CDU) is hampered by the presence of arterial wall calcifications. B-flow imaging may overcome these limitations. We present a case of a severely calcified stenosis of the right common femoral artery (CFA) diagnosed with the aid of B-flow imaging. Both the CT angiography scan and CDU were limited by the presence of diffuse dense arterial calcifications. B-flow imaging showed a >75% stenosis of the CFA. B-flow imaging appears to improve the accuracy of CDU in the presence of calcified stenosis of the CFA. It is of clinical relevance to improve the duplex sonographic accuracy, ideally reducing the need for other imaging modalities prior to surgery. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:136-139, 2018. PMID- 28650084 TI - Detection of human polyomaviruses JC and BK in liver pretransplant patients. AB - OBJECTIVE: This study aimed to identify and quantify polyomaviruses (BKPyV and JCPyV) in the saliva, mouthwash, blood and urine of liver pretransplant patients. MATERIALS AND METHODS: A case-control study was performed using a convenience sample of 21 end-stage liver disease patients (EG = experimental group) and 20 normoreactive controls (CG = control group). In total, 162 samples were collected. Detection and quantification of polyomaviruses were performed using real-time PCR method. RESULTS: In the EG, 21 samples (25%) were positive for BKPyV and 10 (11.90%) for JCPyV, while in the CG, 27 samples (34.61%) were positive for BKPyV and six (7.69%) for JCPyV. With regard to the number of samples positive for BKPyV and JCPyV, there was no statistically significant difference between EG and CG (p = .52 and p = .25). In the EG, we observed a panorama similar to that of the CG regarding the presence of polyomaviruses in mouthwash, blood and urine. The greatest difference between the samples was that regarding the identification of BKPyV in saliva. CONCLUSION: Cirrhotic patients on the liver transplant waiting list did not show higher prevalence of BKPyV and JCPyV compared to normoreactive controls. PMID- 28650085 TI - Immunogenicity of plant-produced African horse sickness virus-like particles: implications for a novel vaccine. AB - African horse sickness (AHS) is a debilitating and often fatal viral disease affecting horses in much of Africa, caused by the dsRNA orbivirus African horse sickness virus (AHSV). Vaccination remains the single most effective weapon in combatting AHS, as there is no treatment for the disease apart from good animal husbandry. However, the only commercially available vaccine is a live-attenuated version of the virus (LAV). The threat of outbreaks of the disease outside its endemic region and the fact that the LAV is not licensed for use elsewhere in the world, have spurred attempts to develop an alternative safer, yet cost-effective recombinant vaccine. Here, we report the plant-based production of a virus-like particle (VLP) AHSV serotype five candidate vaccine by Agrobacterium tumefaciens mediated transient expression of all four capsid proteins in Nicotiana benthamiana using the cowpea mosaic virus-based HyperTrans (CPMV-HT) and associated pEAQ plant expression vector system. The production process is fast and simple, scalable, economically viable, and most importantly, guinea pig antiserum raised against the vaccine was shown to neutralize live virus in cell based assays. To our knowledge, this is the first report of AHSV VLPs produced in plants, which has important implications for the containment of, and fight against the spread of, this deadly disease. PMID- 28650086 TI - Systemic Thrombolysis, Catheter-Directed Thrombolysis, and Anticoagulation for Intermediate-risk Pulmonary Embolism: A Simulation Modeling Analysis. AB - OBJECTIVES: Decision making around the use of thrombolysis for patients with intermediate-risk (submassive) pulmonary embolism (PE) remains challenging. Studies indicate favorable clinical outcomes with systemic thrombolytics (intravenous tissue plasminogen activator [IV tPA]), but the risk of major bleeding and hemorrhagic stroke is a deterrent. Catheter-directed thrombolysis (CDT) may be a preferable strategy, as it has been shown to have a lower risk of bleeding than systemic thrombolysis. However, a three-arm randomized control study comparing IV tPA, CDT, and anticoagulation alone, with long-term follow up, would be costly and is unlikely to be performed. The aim of this study was to use decision modeling to quantitatively estimate the differences between the three strategies. METHODS: We created an individual-level state-transition model to simulate long-term outcomes of a hypothetical patient cohort treated with IV tPA, CDT, or anticoagulation alone. Our model incorporated clinical randomized controlled trial and longitudinal study data to inform patient characteristics and outcomes specific to each study arm. The base case was a 65-year-old patient. Additionally, we utilized preliminary data published by the Pulmonary Embolism Response Team at the Massachusetts General Hospital. Variance in model inputs was addressed with deterministic and probabilistic sensitivity analyses. Our primary endpoint was quality-adjusted life-years (QALYs). Secondary endpoints included total cost and incremental cost-effectiveness ratios (ICERs). RESULTS: Catheter directed thrombolysis (mean, 95% confidence interval [CI] = 7.388 [7.381-7.396] QALYs) resulted in the most long-term utility for eligible patients compared to anticoagulation alone (7.352 [7.345-7.360] QALYs) or IV tPA (7.343 [7.336-7.351] QALYs). Patients receiving CDT had an elevated risk of hemorrhagic stroke in comparison to anticoagulation alone; however, patients treated with anticoagulation alone were more likely to experience recurrent PE associated adverse outcomes. Results were stable with sensitivity analyses varying age and sex. Our probabilistic sensitivity analysis assessing joint variance predicts CDT to be the most effective strategy, when measured by mean QALYs, in 98.4% of runs, while systemic thrombolysis was favored over anticoagulation alone 34.4% of the time. The ICER of CDT compared to anticoagulation was $317,042 per QALY gained. CONCLUSION: In our model, for those eligible, CDT results in the largest number of QALYs for patients with intermediate-risk PE, although it is relatively expensive and the absolute difference in QALYs between anticoagulation alone and CDT is small. Future studies that provide data on longitudinal quality-of-life outcomes of patients treated for PE and characteristics of CDT would be beneficial to augment model inputs, inform assumptions, and validate results. PMID- 28650087 TI - Educational strategies and atraumatic restorative treatment effect on salivary characteristics: A controlled clinical trial. AB - OBJECTIVE: To evaluate educational strategies and atraumatic restorative treatment (ART)-restoration impact on salivary physicochemical and microbiological characteristics. DESIGN: Two groups of 6- to 7-year-old children were included: GART , with at least one decayed primary molar (n = 36), submitted to four sessions of oral health educational strategy (OHES) and ART restoration; GC , a paired caries-free group (n = 36), submitted to four sessions of OHES. Three evaluations were carried out: baseline, 1 week after OHES, and 1 month after OHES or ART, when biofilm and gingivitis frequencies, salivary flow, pH, buffer capacity, calcium and phosphorus concentrations were assessed. Total bacteria and Streptococcus mutans were quantified in unstimulated saliva (qPCR). RESULTS: Improvement in biofilm and gingivitis scores, salivary pH, and buffering capacity after OHES was observed in GC , with a decrease in total bacteria and S. mutans counts. GART also showed changes in salivary parameters, even before ART restoration was delivered, and total bacteria count remained lower than baseline 1 month after ART restoration, although a trend to increase the proportion of S. mutans was observed. CONCLUSION: Improvements in salivary physicochemical and microbiological characteristics were observed after educational strategies, thus reducing the caries risk of children with decayed teeth, although a trend to increase the S. mutans percentage was observed 1 month after ART restoration. PMID- 28650088 TI - Two Structurally Characterized Conformational Isomers with Different C-P Bonds. AB - The cyclic alkyl(amino) carbene (cAAC) bonded chlorophosphinidene (cAAC)P-Cl (2/2') was isolated from the direct reaction between cAAC and phosphorus trichloride (PCl3 ). Compound 2/2' has been characterized by NMR spectroscopy and mass spectrometry. 31 P NMR investigations [delta~160 ppm (major) and delta~130 ppm (minor)] reveal that there are two different P environments of the P-Cl unit. X-ray single-crystal determination suggests a co-crystallization of two conformational isomers of (cAAC)P-Cl (2/2'); the major compound possessing a cAAC PCl unit with CcAAC -P 1.75 A. This C-P bond length is very close to that of (NHC)2 P2 [NHC=N-heterocyclic carbene]. The residual density can be interpreted as a conformational isomer with a shorter CcAAC -P bond similar to a non conjugated phosphaalkene [R-P=CR2 ]. Our study shows an unprecedented example of two conformational isomers with different Ccarbene -element bonds. Additionally, Br (3c/3c'), I (4c/4c'), and H (5c/5c') analogues [(Me2 -cAAC)P-X; X=Br (3), I (4), H (5)] of 2c/2c'[(Me2 -cAAC)P-Cl] were also synthesized and characterized by NMR spectroscopy suggesting similar equilibrium in solution. The unique property of cAAC and the required electronegativity of the X (X=Cl, Br, I, and H) atom play a crucial role for the existence of the two isomers which were further studied by theoretical calculations. PMID- 28650089 TI - A new formula for estimation of standard liver volume using computed tomography measured body thickness. AB - The objective of this article is to derive a more accurate and easy-to-use formula for finding estimated standard liver volume (ESLV) using novel computed tomography (CT) measurement parameters. New formulas for ESLV have been emerging that aim to improve the accuracy of estimation. However, many of these formulas contain body surface area measurements and logarithms in the equations that lead to a more complicated calculation. In addition, substantial errors in ESLV using these old formulas have been shown. An improved version of the formula for ESLV is needed. This is a retrospective cohort of consecutive living donor liver transplantations from 2005 to 2016. Donors were randomly assigned to either the formula derivation or validation groups. Total liver volume (TLV) measured by CT was used as the reference for a linear regression analysis against various patient factors. The derived formula was compared with the existing formulas. There were 722 patients (197 from the derivation group, 164 from the validation group, and 361 from the recipient group) involved in the study. The donor's body weight (odds ratio [OR], 10.42; 95% confidence interval [CI], 7.25-13.60; P < 0.01) and body thickness (OR, 2.00; 95% CI, 0.36-3.65; P = 0.02) were found to be independent factors for the TLV calculation. A formula for TLV (cm3 ) was derived: 2 * thickness (mm) + 10 * weight (kg) + 190 with R2 0.48, which was the highest when compared with the 4 other most often cited formulas. This formula remained superior to other published formulas in the validation set analysis (R2 , 5.37; interclass correlation coefficient, 0.74). Graft weight/ESLV values calculated by the new formula were shown to have the highest correlation with delayed graft function (C-statistic, 0.79; 95% CI, 0.69-0.90; P < 0.01). The new formula (2 * thickness + 10 * weight + 190) represents the first study proposing the use of CT-measured body thickness which is novel, easy to use, and the most accurate for ESLV. Liver Transplantation 23 1113-1122 2017 AASLD. PMID- 28650090 TI - Liver transplantation in the Kingdom of Saudi Arabia. AB - The first liver transplantation (LT) in Saudi Arabia was performed in 1991; however, it was not until 1994 that the first structured LT program was launched. Until 1997, all LTs in the Kingdom of Saudi Arabia (KSA) were deceased donor liver transplantations. Programs performing LTs needed the authorization of the Saudi Center for Organ Transplantation (SCOT), which provides the essential support for organ procurement and allocation as well as regulatory support for organ transplantation in the country. Currently, there are 4 LT centers in the KSA. Three centers are in Riyadh, the capital city of KSA, and 1 is in the city of Dammam in the Eastern province. Pediatric living donor liver transplantation (LDLT) began in 1997, while the adult LDLT program started 4 years later in 2001. Currently, more than 2000 LTs have been performed by the 4 centers in the KSA. Over 50% of those were performed at King Faisal Specialist Hospital and Research Center in Riyadh. The outcomes of these transplants have been comparable with the international standards. The aim of this review is to provide an overview of LT in KSA. Liver Transplantation 23 1312-1317 2017 AASLD. PMID- 28650091 TI - Localized micronutrient patches induce lateral root foraging and chemotropism in Nicotiana attenuata. AB - Nutrients are distributed unevenly in the soil. Phenotypic plasticity in root growth and proliferation may enable plants to cope with this variation and effectively forage for essential nutrients. However, how micronutrients shape root architecture of plants in their natural environments is poorly understood. We used a combination of field and laboratory-based assays to determine the capacity of Nicotiana attenuata to direct root growth towards localized nutrient patches in its native environment. Plants growing in nature displayed a particular root phenotype consisting of a single primary root and a few long, shallow lateral roots. Analysis of bulk soil surrounding the lateral roots revealed a strong positive correlation between lateral root placement and micronutrient gradients, including copper, iron and zinc. In laboratory assays, the application of localized micronutrient salts close to lateral root tips led to roots bending in the direction of copper and iron. This form of chemotropism was absent in ethylene and jasmonic acid deficient lines, suggesting that it is controlled in part by these two hormones. This work demonstrates that directed root growth underlies foraging behavior, and suggests that chemotropism and micronutrient-guided root placement are important factors that shape root architecture in nature. PMID- 28650092 TI - Photoactivatable Mussel-Based Underwater Adhesive Proteins by an Expanded Genetic Code. AB - Marine mussels exhibit potent underwater adhesion abilities under hostile conditions by employing 3,4-dihydroxyphenylalanine (DOPA)-rich mussel adhesive proteins (MAPs). However, their recombinant production is a major biotechnological challenge. Herein, a novel strategy based on genetic code expansion has been developed by engineering efficient aminoacyl-transfer RNA synthetases (aaRSs) for the photocaged noncanonical amino acid ortho-nitrobenzyl DOPA (ONB-DOPA). The engineered ONB-DOPARS enables in vivo production of MAP type 5 site-specifically equipped with multiple instances of ONB-DOPA to yield photocaged, spatiotemporally controlled underwater adhesives. Upon exposure to UV light, these proteins feature elevated wet adhesion properties. This concept offers new perspectives for the production of recombinant bioadhesives. PMID- 28650093 TI - Stable Covalently Photo-Crosslinked Poly(Ionic Liquid) Membrane with Gradient Pore Size. AB - Porous polyelectrolyte membranes stable in a highly ionic environment are obtained by covalent crosslinking of an imidazolium-based poly(ionic liquid). The crosslinking reaction involves the UV light-induced thiol-ene (click) chemistry, and the phase separation, occurring during the crosslinking step, generates a fully interconnected porous structure in the membrane. The porosity is on the order of the micrometer scale and the membrane shows a gradient of pore size across the membrane cross-section. The membrane can separate polystyrene latex particles of different size and undergoes actuation in contact with acetone due to the asymmetric porous structure. PMID- 28650094 TI - Hydroxyapatite-polymer biocomposites for bone regeneration: A review of current trends. AB - Bone tissue engineering has emerged as one of the most indispensable approaches to address bone trauma in the past few decades. This approach offers an efficient and a risk-free alternative to autografts and allografts by employing a combination of biomaterials and cells to promote bone regeneration. Hydroxyapatite (HA) is a ceramic biomaterial that mimics the mineral composition of bones and teeth in vertebrates. HA, commonly produced via several synthetic routes over the years has been found to exhibit good bioactivity, biocompatibility, and osteoconductivity under both in vitro and in vivo conditions. However, the brittle nature of HA restricts its usage for load bearing applications. To address this problem, HA has been used in combination with several polymers in the form of biocomposite implants to primarily improve its mechanical properties and also enhance the implants' overall performance by simultaneously exploiting the positive effects of both HA and the polymer involved in making the biocomposite. This review article summarizes the past and recent developments in the evolution of HA-polymer biocomposite implants as an "ideal" biomaterial scaffold for bone regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2046-2057, 2018. PMID- 28650095 TI - Sex differences in brain mitochondrial metabolism: influence of endogenous steroids and stroke. AB - Steroids are neuroprotective and a growing body of evidence indicates that mitochondria are a potential target of their effects. The mitochondria are the site of cellular energy synthesis, regulate oxidative stress and play a key role in cell death after brain injury and neurodegenerative diseases. After providing a summary of the literature on the general functions of mitochondria and the effects of sex steroid administrations on mitochondrial metabolism, we summarise and discuss our recent findings concerning sex differences in brain mitochondrial function under physiological and pathological conditions. To analyse the influence of endogenous sex steroids, the oxidative phosphorylation system, mitochondrial oxidative stress and brain steroid levels were compared between male and female mice, either intact or gonadectomised. The results obtained show that females have higher a mitochondrial respiration and lower oxidative stress compared to males and also that these differences were suppressed by ovariectomy but not orchidectomy. We have also shown that the decrease in brain mitochondrial respiration induced by ischaemia/reperfusion is different according to sex. In both sexes, treatment with progesterone reduced the ischaemia/reperfusion-induced mitochondrial alterations. Our findings indicate sex differences in brain mitochondrial function under physiological conditions, as well as after stroke, and identify mitochondria as a target of the neuroprotective properties of progesterone. Thus, it is necessary to investigate sex specificity in brain physiopathological mechanisms, especially when mitochondria impairment is involved. PMID- 28650096 TI - N-Bridged Annulated BODIPYs: Synthesis of Highly Fluorescent Blueshifted Dyes. AB - A series of novel BODIPY dyes has been prepared through the introduction of an N bridged annulated meso-phenyl ring at one of the beta-positions of the BODIPY core. An unusual blueshift of the main spectral bands is observed, since the fusion of a meso-substituent results in a marked relative destabilization of the LUMO. The greater rigidity of the ring-fused structure leads to very high fluorescence quantum yields. The position of the main spectral bands can be fine tuned by introducing electron withdrawing and donating groups onto the meso phenyl ring. PMID- 28650097 TI - Low-Cost Perovskite Solar Cells Employing Dimethoxydiphenylamine-Substituted Bistricyclic Aromatic Enes as Hole Transport Materials. AB - The synthesis, characterization and photovoltaic performance of series of novel molecular hole transport materials (HTMs) based on bistricyclic aromatic enes (BAEs) are presented. The new derivatives were obtained following a simple and straightforward procedure from inexpensive starting reagents mimicking the synthetically challenging 9,9'-spirobifluorene moiety of the well-studied spiro OMeTAD. The novel HTMs were tested in mixed cations and anions perovskite solar cells (PSCs) yielding a power conversion efficiency (PCE) of 19.2 % under standard global 100 mW cm-2 AM1.5G illumination using 9-{2,7-bis[bis(4 methoxyphenyl)amino]-9H-fluoren-9-ylidene}-N2 ,N2 ,N7 ,N7 -tetrakis(4 methoxyphenyl)-9H-thioxanthene-2,7-diamine (coded as KR374). The power conversion efficiency data confirms the easily attainable heteromerous fluorenylidenethioxanthene structure as valuable core for low-cost and highly efficient HTM design and paves the way towards cost-effective PSC technology. PMID- 28650098 TI - Disparities in Eurotransplant liver transplantation wait-list outcome between patients with and without model for end-stage liver disease exceptions. AB - The sickest-first principle in donor-liver allocation can be implemented by allocating organs to patients with cirrhosis with the highest Model for End-Stage Liver Disease (MELD) scores. For patients with other risk factors, standard exceptions (SEs) and nonstandard exceptions (NSEs) have been developed. We investigated whether this system of matched MELD scores achieves similar outcomes on the liver transplant waiting list for various diagnostic groups in Eurotransplant (ET) countries with MELD-based individual allocation (Belgium, the Netherlands, and Germany). A retrospective analysis of the ET wait-list outflow from December 2006 until December 2015 was conducted to investigate the relation of the unified MELD-based allocation to the risk of a negative wait-list outcome (death on the waiting list or delisting as too sick) as opposed to a positive wait-list outcome (transplantation or delisting as recovered). A total of 16,926 patients left the waiting list with a positive (11,580) or negative (5346) outcome; 3548 patients had a SE, and 330 had a NSE. A negative outcome was more common among patients without a SE or NSE (34.3%) than among patients with a SE (22.6%) or NSE (18.6%; P < 0.001). Analysis by model-based recursive partitioning detected 5 risk groups with different relations of matched MELD to a negative outcome. In Germany, we found the following: (1) no SE or NSE, SE for biliary sepsis (BS); (2) SE for hepatocellular carcinoma (HCC), hepatopulmonary syndrome (HPS), or portopulmonary hypertension (PPH); and (3) SE for primary sclerosing cholangitis (PSC) or polycystic liver disease (PcLD). In Belgium and the Netherlands, we found the following: (4) SE or NSE, or SE for HPS or PPH; and (5) SE for BS, HCC, PcLD, or PSC. In conclusion, SEs and NSEs do not even out risks across different diagnostic groups. Patients with SEs or NSEs appear advantaged toward patients with cirrhosis without SEs or NSEs. Liver Transplantation 23 1256 1265 2017 AASLD. PMID- 28650099 TI - Anionic Extraction for Efficient Recovery of Biobased 2,3-Butanediol-A Platform for Bulk and Fine Chemicals. AB - 2,3-Butanediol (BDO) presents a promising platform molecule for the synthesis of basic and fine chemicals. Biotechnological production of BDO from renewable resources with living microbes enables high concentrations in the fermentation broth. The recovery of high-boiling BDO from an aqueous fermentation broth presents a subsequent challenge. A method is proposed for BDO isolation based on reversible complexation with phenylboronate in an anionic complex. BDO can be recovered by back-extraction into an acidic solution. The composition of the extracted species was determined by NMR spectroscopy, MS, and GC-MS methods. The conditions of extraction and back-extraction were optimized by using commercial BDO and finally applied to different fermentation broths. Up to 72-93 % BDO can be extracted and up to 80-90 % can be back-extracted under the optimized conditions. Purified bio-BDO was used in the presence of sulfuric acid for the synthesis of methyl ethyl ketone, an established organic solvent and discussed tailor-made biofuel. PMID- 28650100 TI - Tautomerization and Dissociation of Molecular Peptide Radical Cations. AB - Radical-mediated dissociations of peptide radical cations have intriguing unimolecular gas phase chemistry, with cleavages of almost every bond of the peptide backbone and amino acid side chains in a competitive and apparently "stochastic" manner. Challenges of unraveling mechanistic details are related to complex tautomerizations prior to dissociations. Recent conjunctions of experimental and theoretical investigations have revealed the existence of non interconvertible isobaric tautomers with a variety of radical-site-specific initial structures, generated from dissociative electron transfer of ternary metal-ligand-peptide complexes. Their reactivity is influenced by the tautomerization barriers, perturbing the nature, location, or number of radical and charge site(s), which also determine the energetics and dynamics of the subsequent radical-mediated dissociatons. The competitive radical- and charge induced dissociations are extremely dependent on charge density. Charge sequesting can reduce the charge densities on the peptide backbone and hence enhance the flexibility of structural rearrangement. Analysing the structures of precursors, intermediates and products has led to the discovery of many novel radical migration prior to peptide backbone and/or side chain fragmentations. Upon these successes, scientists will be able to build peptide cationic analogues/tautomers having a variety of well-defined radical sites. PMID- 28650101 TI - Con: Acute-on-chronic liver failure. PMID- 28650102 TI - Endocrine influence on neuroinflammation: the use of reporter systems. AB - Most of the ageing-associated pathologies are coupled with a strong inflammatory component that accelerates the progress of the physiopathological functional decline related to ageing. The currently available pharmacological tools for the control of neuroinflammation present several side effects that restrict their application, particularly in chronic disorders. The discovery of the potential anti-inflammatory action exerted by endogenous oestrogens, as well as the finding that activation of oestrogen receptor alpha results in a significant decrease of inflammation at the cellular level and in models of inflammatory diseases, prompted us to embark in a series of studies aimed at the generation of reporter systems, allowing us to (i) understand the anti-inflammatory action of oestrogens at molecular level; (ii) evaluate the extent to which the action of this steroid hormone was relevant in models of pathologies characterised by a strong inflammatory component; and (iii) investigate the efficacy of novel, synthetic oestrogens endowed with anti-inflammatory activity. Accordingly, we conceived the NFkappaB-luc2 reporter mouse, a model characterised by dual reporter genes for fluorescence and bioluminescence imaging under the control of a synthetic DNA able to bind the transcription factor nuclear factor kappa B, the master regulator of the expression of most of the cytokines responsible for the initial phase of acute inflammation. Here, we summarise the philosophy that has driven our research in the past years, as well as some of the results obtained so far. PMID- 28650103 TI - Giant rhinophyma in low-resource setting: a case report. PMID- 28650104 TI - Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration. AB - Alzheimer's disease (AD) is the most common cause of dementia and one of the most important causes of morbidity and mortality among the aging population. AD diagnosis is made post-mortem, and the two pathologic hallmarks, particularly evident in the end stages of the illness, are amyloid plaques and neurofibrillary tangles. Currently, there is no curative treatment for AD. Additionally, there is a strong relation between oxidative stress, metabolic syndrome, and AD. The high levels of circulating lipids and glucose imbalances amplify lipid peroxidation that gradually diminishes the antioxidant systems, causing high levels of oxidative metabolism that affects cell structure, leading to neuronal damage. Accumulating evidence suggests that AD is closely related to a dysfunction of both insulin signaling and glucose metabolism in the brain, leading to an insulin resistant brain state. Four drugs are currently used for this pathology: Three FDA-approved cholinesterase inhibitors and one NMDA receptor antagonist. However, wide varieties of antioxidants are promissory to delay or prevent the symptoms of AD and may help in treating the disease. Therefore, therapeutic efforts to achieve attenuation of oxidative stress could be beneficial in AD treatment, attenuating Abeta-induced neurotoxicity and improve neurological outcomes in AD. The term inflammaging characterizes a widely accepted paradigm that aging is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses in the absence of overt infection, and is a highly significant risk factor for both morbidity and mortality in the elderly. PMID- 28650105 TI - Psychological Symptoms in Late Adolescence and Long-Term Risk of Suicide and Suicide Attempt. AB - Mental disorders in the general population are associated with increased risk of suicidality, but less is known about the independent predictive ability of self reported psychological symptoms. We followed 49,321 screened and interviewed Swedish conscripts through 36-year follow-up to test whether psychological symptoms predicted suicide and hospitalization for suicide attempts. There were 619 suicides and 1,230 suicide attempts during the follow-up period. After excluding subjects with any psychiatric diagnoses (n = 5,691, 12%) and controlling for other psychological symptoms, severe symptoms of anger, trouble falling asleep, and feeling down predicted suicide. Similarly anger, headaches, feeling down, and nervousness predicted suicide attempt. Self-reported psychological symptoms may have a predictive value beyond psychiatric diagnosis. PMID- 28650106 TI - DOK3 Modulates Bone Remodeling by Negatively Regulating Osteoclastogenesis and Positively Regulating Osteoblastogenesis. AB - Osteoclastogenesis is essential for bone remodeling and normal skeletal maintenance. Receptor activator of NF-kappaB ligand (RANKL) promotes osteoclast differentiation and function but requires costimulation of immunoreceptor tyrosine-based activation motif (ITAM)-coupled immunoreceptors. Triggering receptor expressed on myeloid cells-2 (TREM2) coupled to ITAM-adaptor protein DNAX activation protein 12kDA (DAP12) provides costimulation of intracellular calcium signaling during osteoclastogenesis. Previously, we found that downstream of kinase-3 (DOK3) physically associates with DAP12 to inhibit toll-like receptor (TLR)-induced inflammatory signaling in macrophages. However, whether and how DOK3 modulates DAP12-dependent osteoclastogenesis is unknown and the focus of this study. Bone microarchitecture and histology of sex- and age-matched wild type (WT) and DOK3-deficient (DOK3-/- ) mice were evaluated. Male and female DOK3 /- mice have significantly reduced trabecular bone mass compared with WT mice with increased TRAP+ osteoclasts in vivo. In vitro, DOK3-/- bone marrow-derived macrophages (BMMs) have increased macrophage colony-stimulating factor (M-CSF) induced proliferation and increased sensitivity to RANKL-induced osteoclastogenesis. Compared with WT, DOK3-/- osteoclasts are significantly larger with more nuclei and have increased resorptive capacity. Mechanistically, DOK3 limits osteoclastogenesis by inhibiting activation of Syk and ERK in response to RANKL and M-CSF. DOK3 is phosphorylated in a DAP12-dependent manner and associates with Grb2 and Cbl. Compared with DAP12-/- mice with high bone mass, DOK3- and DAP12- doubly deficient mice (DKO) have normalized bone mass, indicating that DOK3 also limits DAP12-independent osteoclastogenesis in vivo. In vitro osteoclasts derived from DKO mice are mononuclear with poor resorptive capacity similar to DAP12-/- osteoclasts. Histomorphometry reveals that DOK3-/- mice also have reduced osteoblast parameters. DOK3-/- osteoblasts have reduced in vitro osteoblastogenesis and increased osteoprotegerin (OPG) to RANKL expression ratio compared with WT osteoblasts. Co-culture of WT and DOK3-/- osteoblasts with pre-osteoclasts reveals a reduced capacity of DOK3-/- osteoblasts to support osteoclastogenesis. These data indicate that DOK3 regulates bone remodeling by negatively regulating M-CSF- and RANKL-mediated osteoclastogenesis and positively regulating osteoblastogenesis. (c) 2017 American Society for Bone and Mineral Research. PMID- 28650107 TI - When Cultural Norms Discourage Talking to Babies: Effectiveness of a Parenting Program in Rural Senegal. AB - In some areas of rural Africa, long-standing cultural traditions and beliefs may discourage parents from verbally engaging with their young children. This study assessed the effectiveness of a parenting program designed to encourage verbal engagement between caregivers and infants in Wolof-speaking villages in rural Senegal. Caregivers (n = 443) and their 4- to 31-month-old children were observed at baseline in 2013 and 1 year later at follow-up. Results showed that caregivers in program villages nearly doubled the amount of child-directed speech during a play session compared to baseline, whereas caregivers in matched comparison villages showed no change. After 1 year, children in program villages produced more utterances, and showed greater improvement in vocabulary and other language outcomes compared to children in comparison villages. PMID- 28650108 TI - A matched pair analysis of multicenter longterm follow-up after split-liver transplantation with extended right grafts. AB - Split-liver transplantation has been proposed as an alternative to whole liver (WL) transplantation to expand the donor pool, but studies comparing adult longterm outcomes between the 2 methods are conflicting and limited. This is the first Italian multicenter study that retrospectively analyzed 119 matched-pair recipients of whole and extended right grafts (ERGs) for longterm survival outcomes. In the overall population, WL recipients showed higher patient survival at 1 (93% versus 73%), 5 (87% versus 65%), and 10 years (83% versus 60%) after transplantation compared with split-liver recipients (P < 0.001); graft survivals of WL recipients were also superior at 1 (90% versus 76%), 5 (84% versus 57%), and 10 years (81% versus 52%) posttransplant (P < 0.001). However, among the 81 matched pairs that survived the first posttransplant year, 5- and 10-year patient survivals were 90% and 81% for split recipients and 99% and 96% for whole recipients, respectively (P = 0.34). The 5- and 10-year graft survivals were also comparable: 87% and 77% for split recipients, and 86% and 82% for whole recipients (P = 0.86). Cox regression analysis identified donor age >50, donor-to recipient weight ratio < 1, retransplantation status, and United Network for Organ Sharing I-IIA status as risk factors for partial graft use. There were no significant differences in 5-year outcomes based on center volume. In conclusion, we demonstrate that adult liver transplantation with ERGs can achieve longterm success comparable with that of whole grafts in appropriate patients but should be selectively used in patients with risk factors. Liver Transplantation 23 1384 1395 2017 AASLD. PMID- 28650109 TI - Inducible Activation of FGFR2 in Adult Mice Promotes Bone Formation After Bone Marrow Ablation. AB - Apert syndrome is one of the most severe craniosynostoses, resulting from gain-of function mutations in fibroblast growth factor receptor 2 (FGFR2). Previous studies have shown that gain-of-function mutations of FGFR2 (S252W or P253R) cause skull malformation of human Apert syndrome by affecting both chondrogenesis and osteogenesis, underscoring the key role of FGFR2 in bone development. However, the effects of FGFR2 on bone formation at the adult stage have not been fully investigated. To investigate the role of FGFR2 in bone formation, we generated mice with tamoxifen-inducible expression of mutant FGFR2 (P253R) at the adult stage. Mechanical bone marrow ablation (BMX) was performed in both wild type and Fgfr2 mutant (MT) mice. Changes in newly formed trabecular bone were assessed by micro-computed tomography and bone histomorphometry. We found that MT mice exhibited increased trabecular bone formation and decreased bone resorption after BMX accompanied with a remarkable increase in bone marrow stromal cell recruitment and proliferation, osteoblast proliferation and differentiation, and enhanced Wnt/beta-catenin activity. Furthermore, pharmacologically inhibiting Wnt/beta-catenin signaling can partially reverse the increased trabecular bone formation and decreased bone resorption in MT mice after BMX. Our data demonstrate that gain-of-function mutation in FGFR2 exerts a Wnt/beta-catenin dependent anabolic effect on trabecular bone by promoting bone formation and inhibiting bone resorption at the adult stage. (c) 2017 American Society for Bone and Mineral Research. PMID- 28650110 TI - Reproducibility of in vivo magnetic resonance imaging T1 rho and T2 relaxation time measurements of hip cartilage at 3.0T in healthy volunteers. AB - PURPOSE: To assess the T1 rho and T2 values in the hip cartilage of healthy volunteers and to evaluate the reproducibility of these measurements. MATERIALS AND METHODS: The right hip joint of 30 asymptomatic volunteers was explored with 3T magnetic resonance imaging (MRI). Quantitative 3D T1 rho- and T2 -maps sequences were repeated twice with a 30-minute delay (immediate reproducibility). The same protocol was repeated 14 days later (short-term reproducibility). Immediate and short-term reproducibility were estimated using coefficients of variation and correlation concordance coefficients (CCC). The precisions of the measurements were estimated by the ratio of the standard deviations. A mixed linear model was used to analyze the effect of patient's characteristics on T1 rho and T2 values. RESULTS: Immediate reproducibility was significantly better than short-term reproducibility for T1 rho (CCC of 0.75 versus 0.55; P = 0.007) and T2 (CCC 0.65 versus 0.32; P < 0.001). The precisions of the measurements were estimated between 5.5% and 9.1%. Median T1 rho values were 6.0 msec higher in women than in men (P = 0.006), with no significant influence of age, body mass index (BMI), or sports activity. Median T2 values were not significantly different between men and women (0.4 msec lower in women; P = 0.76). There was no significant influence of age, BMI, or sports activity. T1 rho and T2 values were lower in lateral regions than in medial regions (4.9 msec and 2.5 msec lower respectively; P < 0.0001). CONCLUSION: Immediate reproducibility of T1 rho and T2 values is better than short-term, with limited effect of 30 minutes decubitus. T1 rho values are significantly higher in women. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1022-1033. PMID- 28650111 TI - Photochromic Dopamine Receptor Ligands Based on Dithienylethenes and Fulgides. AB - We describe the incorporation of the well-investigated class of photochromic dithienylethenes (DTEs) and fulgides into known dopamine receptor ligands such as 1,4-disubstituted aromatic and hydroxybenzoxazinone piperazines as well as aminoindanes. Subtype and functional selective photochromic ligands were obtained and characterized by NMR and UV/VIS spectroscopic measurements. The photophysical properties of the DTE based dopamine ligands revealed a high fatigue resistance for the diarylmaleimides, but the ringclosure could not be accomplished in polar solvents due to a known twisted intramolecular charge transfer (TICT). Several cyclopentene-DTEs showed high PSS, but a fast degradation by forming an irreversible byproduct. Focusing on the fulgides, high photostationary states and switching in polar solvents were possible. The compounds 43, 45 and 46 containing the isopropyl group showed only isomerization between the open E-form and the closed C-form. At a concentration of 1 nm, the cyclopentene-DTE 29-open showed a more than 11-fold higher activation of D2S , a pharmacologically important G protein-coupled receptor, than its photochromic congener 29-closed. Interestingly, the fulgimide-based pair 52-(E)-open/52-closed could be discovered as an alternative photoswitch with inverse activation properties exhibiting four fold higher activity in the closed state. PMID- 28650112 TI - Liver graft preservation using perfluorocarbon improves the outcomes of simulated donation after cardiac death liver transplantation in rats. AB - The outcomes of liver transplantation (LT) from donation after cardiac death (DCD) donors remain poor due to severe warm ischemia injury. Perfluorocarbon (PFC) is a novel compound with high oxygen carrying capacity. In the present study, a rat model simulating DCD LT was used, and the impact of improved graft oxygenation provided by PFC addition on liver ischemia/reperfusion injury (IRI) and survival after DCD LT was investigated. Orthotopic liver transplants were performed in male Lewis rats, using DCD liver grafts preserved with cold University of Wisconsin (UW) solution in the control group and preserved with cold oxygenated UW solution with addition of 20% PFC in the PFC group. For experiment I, in a 30-minute donor warm ischemia model, postoperative graft injury was analyzed at 3 and 6 hours after transplantation. For experiment II, in a 50-minute donor warm ischemia model, the postoperative survival was assessed. For experiment I, the levels of serum aspartate aminotransferase, alanine aminotransferase, hyaluronic acid, malondialdehyde, and several inflammatory cytokines were significantly lower in the PFC group. The hepatic expression levels of tumor necrosis factor alpha and interleukin 6 were significantly lower, and the expression level of heme oxygenase 1 was significantly higher in the PFC group. Histological analysis showed significantly less necrosis and apoptosis in the PFC group. Sinusoidal endothelial cells and microvilli of the bile canaliculi were well preserved in the PFC group. For experiment II, the postoperative survival rate was significantly improved in the PFC group. In conclusion, graft preservation with PFC attenuated liver IRI and improved postoperative survival. This graft preservation protocol might be a new therapeutic option to improve the outcomes of DCD LT. Liver Transplantation 23 1171-1185 2017 AASLD. PMID- 28650114 TI - The effect of adhesives on inflammatory immune-markers during renal injury healing. AB - Renal injury is common in abdominal trauma. Adhesives and sealants can be used to repair and preserve damaged organs. We describe the effect of three biomaterial treatments (TachoSil, GelitaSpon, and Adhflex) on injured renal tissue. Renal traumatic injuries were experimentally induced in male Wistar rats (n = 90) using a punch. Animals were divided into five groups: (1) sham noninjured (n = 3) and punch injury groups; (2) nontreated (n = 6); (3) TachoSil (n = 27); (4) GelitaSpon (n = 27); and (5) Adhflex (n = 27). Wound healing was evaluated 2, 6, and 18 days postinjury by inflammatory cytokines response, histopathological evolution of lesions, inflammatory reaction markers (CD68), and vascular neoformation (CD31). The TachoSil group showed the least inflammatory reaction among the three treated groups, which showed similarly low inflammatory reaction 18 days postinjury. Ciliary neurotrophic factor, soluble intercellular adhesion molecule-1, L-selectin, thymus chemokine, and TIMP metallopeptidase inhibitor 1 expression peaked between 2 and 6 days postinjury. TachoSil promoted the highest cytokine expression. The Adhflex group had the highest CD31 inflammatory immune marker levels at 2 and 6 days postinjury, but there was a similar decrease in CD31 levels in all three groups at 18 days postinjury. The results show that all three sealant treatments induced a normal healing process with the typical pattern of proinflammatory cytokine and immune-marker expression. Each tested sealant substance could be suitable treatment for renal lacerations. The findings of this study indicate that Adhflex(r) elastic cyanoacrylate does not induce an adverse inflammatory reaction, and therefore, could be considered as one of the first-line treatments for renal injuries. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1444-1455, 2018. PMID- 28650113 TI - Distant metastases in head and neck cancer. AB - BACKGROUND: Most trials in head and neck cancer emphasize locoregional control, as this is the main pattern of therapy failure. However, up to 15% of patients develop distant metastases. The purpose of this study was to present the investigated factors associated with distant metastasis in a single-center patient cohort. METHODS: A retrospective analysis of a single-center patient cohort over an 18-year period has been performed. We report on prevalence and incidence of distant metastasis, timing in relation to locoregional failure, Kaplan-Meier analysis for actuarial distant control rates, and univariate analysis taking into account histological, etiologic, surgical, site-dependent, stage-dependent characteristics, modality of primary therapy, and locoregional control. RESULTS: Of 1022 patients, 141 (13.8%) were diagnosed with distant metastases involving 283 sites. Actuarial rates of distant control were 88%, 84%, 80%, and 79% at 1, 2, 5, and 10 years, respectively. Factors associated with distant metastasis are stage grouping and regional node positivity, extranodal extension, locoregional residual disease, and human papillomavirus (HPV) negative status in oropharyngeal squamous cell carcinoma. CONCLUSION: Distant metastases in head and neck cancer led to dismal prognosis. Factors associated with distant metastasis are related to characteristics of the primary tumor. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1733-1743, 2017. PMID- 28650115 TI - Previous living donor hemihepatectomy as cadaveric donor of remnant liver. PMID- 28650116 TI - Polymeric drug delivery systems for intraoral site-specific chemoprevention of oral cancer. AB - Oral cancer is among the most prevalent cancers in the world. Moreover, it is one of the major health problems and causes of death in many regions of the world. The traditional treatment modalities include surgical removal, radiation therapy, systemic chemotherapy, or a combination of these methods. In recent decades, there has been significant interest in intraoral site-specific chemoprevention via local drug delivery using polymeric systems. Because of its easy accessibility and clear visibility, the oral mucosa is amenable for local drug delivery. A variety of polymeric systems-such as gels, tablets, films, patches, injectable systems (e.g., millicylindrical implants, microparticles, and in situ forming depots), and nanosized carriers (e.g., polymeric nanoparticles, nanofibers, polymer-drug conjugates, polymeric micelles, nanoliposomes, nanoemulsions, and polymersomes)-have been developed and evaluated for the local delivery of natural and synthetic chemopreventive agents. The findings of in vitro, ex vivo, and in vivo studies and the positive outcome of clinical trials demonstrate that intraoral site-specific drug delivery is an attractive, highly effective and patient-friendly strategy for the management of oral cancer. Intraoral site-specific drug delivery provides unique therapeutic advantages when compared to systemic chemotherapy. Moreover, intraoral drug delivery systems are self-administrable and can be removed when needed, increasing patient compliance. This article covers important aspects and advances related to the design, development, and efficacy of polymeric systems for intraoral site-specific drug delivery. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1383-1413, 2018. PMID- 28650126 TI - Editorial. PMID- 28650128 TI - The evolution of photoreception and vision: Or the blind watchmaker gone mad? PMID- 28650129 TI - In vitro efficacy and in silico analysis of cefixime-ofloxacin combination for Salmonella Typhi from bloodstream infection. AB - AIMS: Recently, the cefixime-ofloxacin combination is approved by Drug Controller General of India to treat typhoid fever. We sought to evaluate the antimicrobial activity of cefixime-ofloxacin combination against Salmonella Typhi. METHODS AND RESULTS: A total of 283 nonduplicate S. Typhi isolates collected during 2012-2014 were included in this study. Minimum inhibitory concentration (MIC) of cefixime and ofloxacin was determined by using broth microdilution method. Combinational testing was performed by using checkerboard assay. In checkerboard assay, synergistic activity was seen in 11% of isolates, while the majority of the isolate showed indifference and none of them showed antagonism. An in silico strategy, an alternative to the animal model, was carried out to understand drug interaction and toxicity. Molecular docking results elucidated that cefixime and ofloxacin are capable of inhibiting the cell wall synthesis and DNA replication, respectively. Computational ADMET analysis showed no toxicity and no drug-drug interaction between cefixime and ofloxacin. CONCLUSION: Cefixime-ofloxacin combination could be effective against moderately susceptible fluoroquinolone S. Typhi but not fluoroquinolone-resistant isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: Cefixime-ofloxacin combination with no drug-drug interaction and nontoxic predicted through computational analysis did not show antagonism against S. Typhi in in vitro. Although this study showed no adverse effects with the cefixime ofloxacin combination, further studies on pharmacokinetic and pharmacodynamic (PK PD) parameters of cefixime and ofloxacin combination are warranted. PMID- 28650130 TI - Supplementary IOLs: Monofocal and Multifocal, Their Applications and Limitations. AB - Supplemental intraocular lenses (IOLs) have been developed to replace IOLs designed for in-the-bag placement being used as "piggy-back" IOLs in the sulcus due to unacceptable complications. The new IOLs have unique platform designs to avoid these complications. As a result, a new nomenclature is needed to describe the 4 scenarios when supplemental IOL use is now indicated. PMID- 28650131 TI - Accommodating Intraocular Lenses. AB - With an explosive increase in the worldwide prevalence of presbyopia, development of an accommodating intraocular lens (IOL) with expansive accommodative amplitude remains the holy grail in lens-based refractive surgery. A dynamic change in the dioptric power of the eye can be accomplished by various strategies alone or in combination, including changes in the position, shape, or refractive index of a single- or dual- optic IOL. This article reviews the cumulative advances in these various lens designs, along with clinical outcomes and complications of those that have been implanted. The challenges that remain in each cat-egory are also highlighted. PMID- 28650133 TI - Imaging in primary hyperparathyroidism: focus on the evidence-based diagnostic performance of different methods. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrine disorder usually due to hyperfunctioning parathyroid glands (HP). Surgical removal of HP is the main treatment in PHPT, particularly in symptomatic patients. The correct detection and localization of HP is challenging and crucial as it may guide surgical treatment in patients with PHPT. To date, different imaging methods have been used to detect and localize HP in patients with PHPT including radiology, nuclear medicine and hybrid techniques. This review was focused to describe the diagnostic performance of several imaging methods used in detecting HP in patients with PHPT. METHODS: We have summarized the diagnostic performance of different imaging methods used in detecting HP in patients with PHPT taking into account recent evidence-based articles published in the literature. To this regard, findings of recently published meta-analyses on the diagnostic accuracy of imaging methods in PHPT were reported. Furthermore, a suggested imaging strategy taking into account the diagnostic performance and further consideration has been described. RESULTS: Cervical ultrasound (US) and parathyroid scintigraphy using 99mTc-MIBI are the most commonly employed first-line investigations in patients with PHPT, with many institutions using both methods in combination. The diagnostic performance of US and planar 99mTc-MIBI scintigraphy seems to be similar. The use of tomographic imaging (SPECT and SPECT/CT) increases the detection rate of HP compared to planar 99mTc-MIBI scintigraphy. Whereas traditional computed tomography (CT) has limited usefulness in PHPT, four dimensional CT (4D-CT) has similar diagnostic performance compared to tomographic parathyroid scintigraphy but a higher radiation dose. Although initial encouraging results, to date there is insufficient evidence to recommend the routine use of MRI or positron emission tomography (PET) with several radiopharmaceuticals in patients with PHPT. However, they could be useful alternatives in cases with negative or discordant findings at first-line imaging methods. CONCLUSIONS: Patients with PHPT who are candidates for parathyroidectomy should be referred to an expert clinician to decide which imaging studies to perform based on regional imaging capabilities. The imaging techniques with higher diagnostic performance in detecting and localizing HP seems to be 99mTc MIBI SPECT/CT and 4D-CT. Taking into account several data beyond the diagnostic performance, the combination of cervical US performed by an experienced parathyroid sonographer and 99mTc-MIBI SPECT or SPECT//CT seems to be an optimal first-line strategy in the preoperative planning of patients with PHPT. PMID- 28650134 TI - Risk of hepatocellular carcinoma in HBV cirrhotic patients assessed by the combination of miR-122, AFP and PIVKA-II. AB - BACKGROUND: Reliable biomarkers for early detection of hepatocellular carcinoma (HCC) in patients with cirrhosis are lacking. We evaluated the use of miR-122, alpha-fetoprotein (AFP) and protein induced by vitamin k absence/antagonist II (PIVKA-II) for HCC risk prediction in patients with HBV-related cirrhosis under surveillance. METHODS: We first analyzed a group of 63 patients with HBV-related liver cirrhosis of whom 33 had HCC. Then we performed a retrospective analysis on another group of 13 cirrhotic patients who developed HCC during surveillance, of whom serial serum samples were available (at time of HCC diagnosis [T0], 6-9 months [T-1] and 12-18 months [T-2] before HCC detection). Serum miR-122 levels were assessed by quantitative real time-PCR, whereas AFP and PIVKA-II were measured by fully automated chemiluminescent enzyme immunoassay. RESULTS: Serum levels of miR-122, AFP and PIVKA-II were different between patients with cirrhosis and those with HCC (P=0.024, P<0.001 and P<0.001, respectively). Areas under the curve (AUC) were 0.675 for miR-122, 0.791 for AFP and 0.846 for PIVKA II, while their combination improved the discrimination power between cirrhosis and HCC (AUC=0.918). In the longitudinal study, we found a significant variation overtime for the biomarkers combination (P=0.011) but not for each single biomarker (miR-122, P=0.163; AFP, P=0.170; PIVKA-II, P=0.447). Combined miR 122+AFP+PIVKA-II adjusted Hazard Ratio for HCC development was 10.63, 95% confidence interval 1.87-60.28 (P<0.001). CONCLUSIONS: In HBV-related cirrhosis, the combination of miR-122, AFP and PIVKA-II enables the identification of patients at higher risk of HCC development that could benefit from closer monitoring. PMID- 28650135 TI - Endodontic microleakage studies: correlation among different methods, clinical relevance, and potential laboratory errors. AB - INTRODUCTION: Creation of a tight seal in endodontically treated root canals is of utmost importance. Clinical and laboratory studies have a great role in the assessment of the sealing ability of endodontic materials. The present review was undertaken to evaluate correlation between different techniques used in microleakage studies in endodontics and the potential laboratory errors. EVIDENCE ACQUISITION: A systematic search was run using Medline, Biosis, Cochrane Database, Embase, Google Scholar, and Web of Science databases. Furthermore, the reference lists of the articles published on the subject were thoroughly searched. There was no language restriction in the search. Two reviewers separately evaluated the titles and abstracts. EVIDENCE SYNTHESIS: All the methods used might have proved useful if the study could have been carried out with a larger sample size, with carefully designed control groups. Furthermore, extra evaluations are recommended on the reliability of the method used. Examinations like glucose reactivity test, assessment of antimicrobial activity of the tested materials and in situ FISH examination for the reliability of bacterial leakage model have been recommended. It has been recommended that two or more methods be considered for each material in the same study. On the other hand, long-term animal studies can be useful with histological and radiographic evaluations for meticulous assessment of leakage. Furthermore, long-term clinical trials on humans might be helpful on the condition that confounding factors are controlled. CONCLUSIONS: Studies on microleakage should be focused on animal studies, clinical trials or laboratory tests. On the basis of available evidence, it appears that despite potential errors on microleakage studies they are very valuable. PMID- 28650136 TI - Platform-switching and super-short implants: an effective technique to manage residual jaws bone volume. PMID- 28650137 TI - How to manage the biological risk in a dental clinic: current and future perspectives. AB - Dental personnel (DP) may be exposed to pathogens during dental treatment, either through contact contaminated equipment, or with blood and respiratory secretion. On the other hand, health care professionals are constantly exposed to pathogens and opportunists in their work environment. Consequently, the dental healthcare environment is connected with the risk of exposure to biological agents both for patients and dental workers, and involves a wide number of microorganisms that can be present in biological matrices (gingival fluids, saliva, blood), contaminated and/or non-sanitized surfaces, water used in the dental unit, or emitted by patients suffering or carrier of a transmissible disease. The main determinants of exposure to biological agents in dentistry are related, therefore, to several factors, such as the lack in the application of disinfection/sterilization procedures for surfaces, reusable tools, water, etc.; the lack in the use of protective equipment by workers; an insufficient or inefficient training of personnel; the use of non-targeted, too diluted, or expired biocides. Therefore, each single patient needs to be treated as a potential communicable infectious disease carrier and each case must receive high level of attention in compliance with preventive and hygiene standards, following disinfection and sterilization procedures, and always wearing personal protective equipment. The goal of this article was to discuss on the infection risks related to dental practice both for patients and workers, and to evaluate the state of the art and future perspectives, with particular attention to disinfection procedures, for occupational biological hazards and HAIs prevention in this setting. PMID- 28650138 TI - Photoelectrochemical and Impedance Spectroscopic Analysis of Amorphous Si for Light-Guided Electrodeposition and Hydrogen Evolution Reaction. AB - For more efficient photoelectrochemical water splitting, there is a dilemma that a photoelectrode needs both light absorption and electrocatalytic faradaic reaction. One of the promising strategies is to deposit a pattern of electrocatalysts onto a semiconductor surface, leaving sufficient bare surface for light absorption while minimizing concentration overpotential as well as resistive loss at the ultramicroelectrodes for faradaic reaction. This scheme can be successfully realized by "maskless" direct photoelectrochemical patterning of electrocatalyst onto an SiOx/amorphous Si (a-Si) surface by the light-guided electrodeposition technique. Electrochemical impedance spectroscopy at various pHs tells us much about how it works. The surface states at the SiOx/a-Si interface can mediate the photogenerated electrons for hydrogen evolution, whereas electroactive species in the solution undergo outer-sphere electron transfer, taking electrons tunneling across the SiOx layer from the conduction band. In addition to previously reported long-distance lateral electron transport behavior at a patterned catalyst/SiOx/a-Si interface, the charging process of the surface states plays a crucial role in proton reduction, leading to deeper understanding of the operation mechanisms for photoelectrochemical water splitting. PMID- 28650139 TI - A Strategy To Boost the Efficiency of Rhodanine Electron Acceptor for Organic Dye: From Nonconjugation to Conjugation. AB - Rhodanine-3-acetic acid is a very important and common electron acceptor of organic dye for dye-sensitized solar cells (DSSCs). However, the photovoltaic performances of organic dyes with rhodanine-3-acetic acid are relatively poor in the great majority of cases due to its nonconjugated structure between rhodanine ring and carboxyl anchoring group. Herein, a rhodanine derivative with conjugated structure between rhodanine ring and anchoring group is first employed as electron acceptor for TiO2-based DSSCs. Organic dye with this conjugated electron acceptor can not only maintain wide absorption spectrum but also greatly improve the electronic structure and adsorption geometry on TiO2, which significantly enhances the electron injection and slows the charge recombination. So the power conversion efficiency of DSSC based on organic dye CRD-I with this conjugated electron acceptor is increased by 2 times as compared with DSSC based on organic dye RD-I with nonconjugated rhodanine-3-acetic acid. Moreover, it is also found that CRD-I is superior to RD-I with respect to DSSC stability and binding ability to TiO2. This work unambiguously demonstrates that the conjugated rhodanine derivative is a highly promising electron acceptor and provides a new strategy for high-efficiency rhodanine-based organic dyes in DSSCs. PMID- 28650140 TI - Dual Physically Cross-Linked Nanocomposite Hydrogels Reinforced by Tunicate Cellulose Nanocrystals with High Toughness and Good Self-Recoverability. AB - The weak mechanical properties of hydrogels usually limited their application in biomedical and industrial fields. Herein, we reported a nanocomposite network of poly(acrylic acid-co-acrylamide) (PAAAM) sequentially cross-linked by quaternized tunicate cellulose nanocrystals (Q-TCNCs) and Fe3+. Q-TCNCs acted as both interfacial compatible reinforcements and cross-linkers in the nanocomposite hydrogels to form loose cross-linking, whereas compact cross-linking was built by ionic coordination between Fe3+ and -COO- of PAAAM. The toughness of dual cross linked hydrogel (D-Gel) was 340 times that of mono-cross-linked hydrogel (m-Gel), which was 10 times that of PAAAM hydrogel. Moreover, the nanocomposite hydrogels exhibited excellent self-recoverability after treating the stretched samples in FeCl3 aqueous solution. This work provided a universal strategy for construction of tough nanocomposite hydrogel reinforced with cellulose nanocrystals. PMID- 28650141 TI - Flexible and Foldable Fully-Printed Carbon Black Conductive Nanostructures on Paper for High-Performance Electronic, Electrochemical, and Wearable Devices. AB - In this work, we demonstrate the first example of fully printed carbon nanomaterials on paper with unique features, aiming the fabrication of functional electronic and electrochemical devices. Bare and modified inks were prepared by combining carbon black and cellulose acetate to achieve high-performance conductive tracks with low sheet resistance. The carbon black tracks withstand extremely high folding cycles (>20 000 cycles), a new record-high with a response loss of less than 10%. The conductive tracks can also be used as 3D paper-based electrochemical cells with high heterogeneous rate constants, a feature that opens a myriad of electrochemical applications. As a relevant demonstrator, the conductive ink modified with Prussian-blue was electrochemically characterized proving to be very promising toward the detection of hydrogen peroxide at very low potentials. Moreover, carbon black circuits can be fully crumpled with negligible change in their electrical response. Fully printed motion and wearable sensors are additional examples where bioinspired microcracks are created on the conductive track. The wearable devices are capable of efficiently monitoring extremely low bending angles including human motions, fingers, and forearm. Here, to the best of our knowledge, the mechanical, electronic, and electrochemical performance of the proposed devices surpasses the most recent advances in paper based devices. PMID- 28650142 TI - Conformational Landscapes of Metal(II) Porphyrinato, Chlorinato, and Morpholinochlorinato Complexes. AB - The macrocycle conformation of [meso-tetraarylporphyrinato]metal complexes is metal-dependent. Furthermore, hydroporphyrins and some of their analogues are known to be more conformationally flexible than the parent porphyrins, but the extent to which this is reflected in their metal-dependent conformations was much less studied. meso-Tetraarylmorpholinochlorins are intrinsically nonplanar chlorin analogues in which the five-membered pyrroline moiety was replaced by a six-membered morpholine moiety. The metal complexes (M = Ni2+, Cu2+, Zn2+, Pd2+, Ag2+) of meso-aryl-2,3-dimethoxychlorins and meso-arylmorpholinochlorins were prepared. Their conformations were determined using X-ray crystal structure diffractometry and compared against those of their free bases, as well as against the conformations of the corresponding metalloporphyrins. Out-of-plane displacement plots visualized and quantified the conformational changes upon stepwise conversion of a pyrrole moiety to a dimethoxypyrroline moiety and to a dialkoxymorpholine moiety, respectively. The generally nonplanar macrocycle conformations were found to be central-metal-dependent, with the smaller ions showing more nonplanar conformations and with the metallomorpholinochlorins generally showing a much larger conformational range than the corresponding metallochlorins, which, in turn, were more nonplanar than the corresponding porphyrins. This attests to the larger conformational flexibility of the morpholinochlorin macrocycle compared to that of a chlorin or even a porphyrin macrocycle. The degree of nonplanarity affects the electronic structure of the metal complexes, as can also be seen in a comparison of their UV-vis spectra. We thus further define the conformational and electronic effects governing pyrrole modified porphyrins. PMID- 28650143 TI - Coupled Carbonization Strategy toward Advanced Hard Carbon for High-Energy Sodium Ion Battery. AB - Sodium-ion batteries (SIBs) are expected to be a promising commercial alternative to lithium-ion batteries for grid electricity storage due to their potential low cost in the near future. Up to the present, the anode material still remains a great challenge for the application of SIBs, especially at room temperature. Graphite has an obvious limitation to store larger radius sodium ions (Na+) in comparison with lithium ions (Li+), while the hard carbon with large interlayer distance can demonstrate a relatively high storage capability and durable cycle life. However, the disadvantages of low initial Coulombic efficiency (ICE) mainly caused by large surface area and high cost synthetic approach hinder its practical applications. Herein, a new coupled carbonization strategy is presented to prepare a cost-effective hard carbon material by pyrolyzing and carbonizing the mixture of abundant sucrose and phenolic resin. Benefiting from the specialized pyrolysis reaction process and optimized conditions as studied in detail, the hard carbon has an extremely low surface area of 1.54 m2 g-1 and high initial Coulombic efficiency of 87%, which have been rarely reported before and enhance the utilization efficiency of Na+ consumption within the cathode in the future. More importantly, the hard carbon, with a high interlayer distance 3.95 A, can deliver a higher capacity of 319 mAh g-1 and maintain a finer capacity retention of 90% over 150 cycles. Besides, a full cell with the configuration of as-prepared hard carbon anode versus an air-stable O3-Na0.9[Cu0.22Fe0.30Mn0.48]O2 cathode is further presented, and it has a high ICE of 80% and energy density of 256 Wh kganode-1 (vs hard carbon) with reliable cycle performance. The results demonstrate that our synthetic strategy is feasible and extendable, while the tunable carbon-based materials should have wider applications in addition to the attractive properties in Na-ion batteries. PMID- 28650144 TI - What Are Missing Parts in the Research Story of Trimethylamine-N-oxide (TMAO)? PMID- 28650145 TI - The DEAD-Box Protein CYT-19 Uses Arginine Residues in Its C-Tail To Tether RNA Substrates. AB - DEAD-box proteins are nonprocessive RNA helicases that play diverse roles in cellular processes. The Neurospora crassa DEAD-box protein CYT-19 promotes mitochondrial group I intron splicing and functions as a general RNA chaperone. CYT-19 includes a disordered, arginine-rich "C-tail" that binds RNA, positioning the helicase core to capture and unwind nearby RNA helices. Here we probed the C tail further by varying the number and positions of arginines within it. We found that removing sets of as few as four of the 11 arginines reduced RNA unwinding activity (kcat/KM) to a degree equivalent to that seen upon removal of the C tail, suggesting that a minimum or "threshold" number of arginines is required. In addition, a mutant with 16 arginines displayed RNA unwinding activity greater than that of wild-type CYT-19. The C-tail modifications impacted unwinding only of RNA helices within constructs that included an adjacent helix or structured RNA element that would allow C-tail binding, indicating that the helicase core remained active in the mutants. In addition, changes in RNA unwinding efficiency of the mutants were mirrored by changes in functional RNA affinity, as determined from the RNA concentration dependence of ATPase activity, suggesting that the C tail functions primarily to increase RNA affinity. Interestingly, the salt concentration dependence of RNA unwinding activity is unaffected by C-tail composition, suggesting that the C-tail uses primarily hydrogen bonding, not electrostatic interactions, to bind double-stranded RNA. Our results provide insights into how an unstructured C-tail contributes to DEAD-box protein activity and suggest parallels with other families of RNA- and DNA-binding proteins. PMID- 28650146 TI - Using Predefined M3(MU3-O) Clusters as Building Blocks for an Isostructural Series of Metal-Organic Frameworks. AB - Metal-organic frameworks (MOFs) have attracted much attention in the past decade owing to their unprecedented internal surface areas, tunable topologies, designable surfaces, and various potential applications. One bottleneck in the field regarding MOF synthesis is controlling the metal-containing secondary building unit (SBU) incorporated into the structure. In this work we report the synthesis and characterization of five trimeric [M3(MU3-O)(CH3CO2)6]x clusters (where M = Fe3+, Cr3+, Fe3+/Cr3+, Fe3+/Co2+, or Fe3+/Ni2+ and x = +1 or 0). The monocarboxylate capping ligand, acetate in this case, readily undergoes exchange with several difunctional counterparts, including 1,4-benzenedicarboxylic acid (H2-BDC) and biphenyl-4,4'-dicarboxylic acid (H2-BPDC), for the formation of an isostructural series of MOFs, several of which are newly reported (for M = Fe3+/Cr3+, Fe3+/Co2+, and Fe3+/Ni2+) and show excellent CO2 adsorption properties. In this report, a host of techniques including NMR, ICP, and ESI-MS are used to probe the ligand exchange process and composition of the SBUs, and XAS is used to monitor the Fe3+ and Cr3+ environment throughout the reactions, giving strong evidence that the clusters stay intact throughout the MOF synthesis. This work reveals that predefined SBUs is an effective means to create metal-substituted analogues of known frameworks. Further, CO adsorption and in situ IR are used to probe accessibility of the metals after solvent removal. We show for the first time that the incorporation of the neutral clusters, containing weaker Lewis acids like Ni2+ and Co2+, can promote the formation of open metal sites in the MOF frameworks, structural features known to enhance the binding energy of small guest molecules like CO2. PMID- 28650147 TI - Structural Basis for Aza-Glycine Stabilization of Collagen. AB - Previously, we have demonstrated that replacement of the strictly conserved glycine in collagen with aza-glycine provides a general solution for stabilizing triple helical collagen peptides (Chenoweth, D. M.; et al. J. Am. Chem. Soc. 2016, 138, 9751 ; 2015, 137, 12422 ). The additional hydrogen bond and conformational constraints provided by aza-glycine increases the thermal stability and rate of folding in collagen peptides composed of Pro-Hyp-Gly triplet repeats, allowing for truncation to the smallest self-assembling peptide systems observed to date. Here we show that aza-glycine substitution enhances the stability of an arginine-containing collagen peptide and provide a structural basis for this stabilization with an atomic resolution crystal structure. These results demonstrate that a single nitrogen atom substitution for a glycine alpha carbon increases the peptide's triple helix melting temperature by 8.6 degrees C. Furthermore, we provide the first structural basis for stabilization of triple helical collagen peptides containing aza-glycine and we demonstrate that minimal alteration to the peptide backbone conformation occurs with aza-glycine incorporation. PMID- 28650148 TI - MgZnO/ZnO Two-Dimensional Electron Gas Photodetectors Fabricated by Radio Frequency Sputtering. AB - MgZnO/ZnO two-dimensional electron gas (2DEG) structures with ZnO annealed at various temperatures (600-900 degrees C) and photodetectors (PDs) with and without a 2DEG structure were fabricated using a radio frequency magnetron sputtering system. It was found that the carrier concentration and mobility increase with the annealing temperature owing to the improved crystalline in ZnO; however, high-temperature (800 degrees C or higher) annealing can degrade the crystalline of the ZnO layer. Hall measurements showed that compared with that of bulk ZnO, the sheet carrier concentration of the 2DEG sample increased from 1.3 * 1013 to 1.2 * 1014 cm-2, and the mobility was enhanced from 5.1 to 17.5 cm2/V s. This is because the channel layer is the total thickness (300 nm) in bulk ZnO, whereas the carriers are confined to a 45 nm region beneath the MgZO layer in the 2DEG sample, confirming the 2DEG behavior at the MgZnO/ZnO interface. The PDs with 2DEG structures demonstrate a higher ultraviolet (UV) response and a UV/visible rejection ratio that is six times larger than that of the PDs without a 2DEG structure. The 2DEG structure also induces a photocurrent gain, which results in a 240% quantum efficiency for the 310 nm incident wavelength. The related mechanism is elucidated with a band diagram. PMID- 28650149 TI - RPLC-HILIC and SFC with Mass Spectrometry: Polarity-Extended Organic Molecule Screening in Environmental (Water) Samples. AB - Trace organic compounds are important in environmental analysis because they impact water quality and introduce potential (eco)toxicological effects. Current analytical methods mostly rely on gas chromatography (GC) or reversed-phase liquid chromatography (RPLC) coupled with (tandem) mass spectrometry. However, neither method can easily separate very polar molecules. This study presents two chromatographic separation strategies, a serial RPLC-hydrophilic interaction liquid chromatography (RPLC-HILIC) coupling and an analytical scale supercritical fluid chromatography (SFC) system, and validates their separation effectiveness as polarity-extended chromatographic methods for 274 environmentally relevant compounds. Compounds tested were grouped into three polarity classes, "very polar" {log D (pH 7) below -2.5}, "polar" {log D (pH 7) -2.5 to +2}, and "non polar" {log D (pH 7) higher than +2}). Nearly all compounds could be retained in both systems with relative standard deviations of retention times (RT; n = 6) typically between 2 and 5%. Both techniques have considerable benefits when combined with accurate mass spectrometric detection. Molecules RT and accurate mass were recorded in a database for each set up. This information was used for compound screening measurements like "hidden-target screening" in complex environmental matrices (such as wastewater treatment plant effluents). Results of both techniques are complementary and useful for all types of molecules polarity. In this study, more than 80% of the compounds found in wastewater treatment plant effluent samples possessed a negative log D (pH 7) value. This result highlights the basic necessity to include "very polar" compounds in water monitoring techniques and protocols. PMID- 28650150 TI - Genome-Wide Association Mapping of Seed Coat Color in Brassica napus. AB - Seed coat color is an extremely important breeding characteristic of Brassica napus. To elucidate the factors affecting the genetic architecture of seed coat color, a genome-wide association study (GWAS) of seed coat color was conducted with a diversity panel comprising 520 B. napus cultivars and inbred lines. In total, 22 single-nucleotide polymorphisms (SNPs) distributed on 7 chromosomes were found to be associated with seed coat color. The most significant SNPs were found in 2014 near Bn-scaff_15763_1-p233999, only 43.42 kb away from BnaC06g17050D, which is orthologous to Arabidopsis thaliana TRANSPARENT TESTA 12 (TT12), an important gene involved in the transportation of proanthocyanidin precursors into the vacuole. Two of eight repeatedly detected SNPs can be identified and digested by restriction enzymes. Candidate gene mining revealed that the relevant regions of significant SNP loci on the A09 and C08 chromosomes are highly homologous. Moreover, a comparison of the GWAS results to those of previous quantitative trait locus (QTL) studies showed that 11 SNPs were located in the confidence intervals of the QTLs identified in previous studies based on linkage analyses or association mapping. Our results provide insights into the genetic basis of seed coat color in B. napus, and the beneficial allele, SNP information, and candidate genes should be useful for selecting yellow seeds in B. napus breeding. PMID- 28650151 TI - Orthogonal Comparison of GC-MS and 1H NMR Spectroscopy for Short Chain Fatty Acid Quantitation. AB - Short chain fatty acids (SCFAs) are important regulators of host physiology and metabolism and may contribute to obesity and associated metabolic diseases. Interest in SCFAs has increased in part due to the recognized importance of how production of SCFAs by the microbiota may signal to the host. Therefore, reliable, reproducible, and affordable methods for SCFA profiling are required for accurate identification and quantitation. In the current study, four different methods for SCFA (acetic acid, propionic acid, and butyric acid) extraction and quantitation were compared using two independent platforms including gas chromatography coupled with mass spectrometry (GC-MS) and 1H nuclear magnetic resonance (NMR) spectroscopy. Sensitivity, recovery, repeatability, matrix effect, and validation using mouse fecal samples were determined across all methods. The GC-MS propyl esterification method exhibited superior sensitivity for acetic acid and butyric acid measurement (LOD < 0.01 MUg mL-1, LOQ < 0.1 MUg mL-1) and recovery accuracy (99.4%-108.3% recovery rate for 100 MUg mL-1 SCFA mixed standard spike in and 97.8%-101.8% recovery rate for 250 MUg mL-1 SCFAs mixed standard spike in). NMR methods by either quantitation relative to an internal standard or quantitation using a calibration curve yielded better repeatability and minimal matrix effects compared to GC-MS methods. All methods generated good calibration curve linearity (R2 > 0.99) and comparable measurement of fecal SCFA concentration. Lastly, these methods were used to quantitate fecal SCFAs obtained from conventionally raised (CONV-R) and germ free (GF) mice. Results from global metabolomic analysis of feces generated by 1H NMR and bomb calorimetry were used to further validate these approaches. PMID- 28650152 TI - Accelerated Reduction of Bromate in Frozen Solution. AB - Bromate is a common disinfection byproduct formed during ozonation. Reducing bromate into bromide can remove this toxic pollutant, however, not many studies have been done for its environmental fate. In this work, we demonstrate a new transformation pathway that bromate can be efficiently reduced to bromide in frozen solution in the presence of organic reductants like humic substances (HS). The results showed that bromate in frozen solution could be removed by 30-40% in dark condition and 80-90% in irradiation condition (lambda > 300 nm) in 24 h, while around 1% bromate was reduced in aqueous solution. The bromate reduction by HS induced a partial oxidation of HS, which was confirmed by X-ray photoelectron spectroscopic analysis of the HS sample recovered from the frozen solution. Photoluminescence analysis of HS revealed that the fluorescence quenching by bromate was observed only with very high concentration of bromate (0.1-0.2 M) in aqueous solution whereas the quenching effect in frozen solution was seen with much lower bromate concentration (5-100 MUM). The highly enhanced removal of bromate in ice is ascribed to the freeze concentration effect that bromate and HS are concentrated by orders of magnitude to accelerate the bimolecular transformation in the ice grain boundary region. Freezing process in cold environments would provide a unique chemical mechanism for the removal of persistent bromate. PMID- 28650153 TI - Climate Change Impacts on Harmful Algal Blooms in U.S. Freshwaters: A Screening Level Assessment. AB - Cyanobacterial harmful algal blooms (CyanoHABs) have serious adverse effects on human and environmental health. Herein, we developed a modeling framework that predicts the effect of climate change on cyanobacteria concentrations in large reservoirs in the contiguous U.S. The framework, which uses climate change projections from five global circulation models, two greenhouse gas emission scenarios, and two cyanobacterial growth scenarios, is unique in coupling climate projections with a hydrologic/water quality network model of the contiguous United States. Thus, it generates both regional and nationwide projections useful as a screening-level assessment of climate impacts on CyanoHAB prevalence as well as potential lost recreation days and associated economic value. Our projections indicate that CyanoHAB concentrations are likely to increase primarily due to water temperature increases tempered by increased nutrient levels resulting from changing demographics and climatic impacts on hydrology that drive nutrient transport. The combination of these factors results in the mean number of days of CyanoHAB occurrence ranging from about 7 days per year per waterbody under current conditions, to 16-23 days in 2050 and 18-39 days in 2090. From a regional perspective, we find the largest increases in CyanoHAB occurrence in the Northeast U.S., while the greatest impacts to recreation, in terms of costs, are in the Southeast. PMID- 28650154 TI - Interrogating Detergent Desolvation of Nanopore-Forming Proteins by Fluorescence Polarization Spectroscopy. AB - Understanding how membrane proteins interact with detergents is of fundamental and practical significance in structural and chemical biology as well as in nanobiotechnology. Current methods for inspecting protein-detergent complex (PDC) interfaces require high concentrations of protein and are of low throughput. Here, we describe a scalable, spectroscopic approach that uses nanomolar protein concentrations in native solutions. This approach, which is based on steady-state fluorescence polarization (FP) spectroscopy, kinetically resolves the dissociation of detergents from membrane proteins and protein unfolding. For satisfactorily solubilizing detergents, at concentrations much greater than the critical micelle concentration (CMC), the fluorescence anisotropy was independent of detergent concentration. In contrast, at detergent concentrations comparable with or below the CMC, the anisotropy readout underwent a time-dependent decrease, showing a specific and sensitive protein unfolding signature. Functionally reconstituted membrane proteins into a bilayer membrane confirmed predictions made by these FP-based determinations with respect to varying refolding conditions. From a practical point of view, this 96-well analytical approach will facilitate a massively parallel assessment of the PDC interfacial interactions under a fairly broad range of micellar and environmental conditions. We expect that these studies will potentially accelerate research in membrane proteins pertaining to their extraction, solubilization, stabilization, and crystallization, as well as reconstitution into bilayer membranes. PMID- 28650155 TI - Probing Interface Defects in Top-Gated MoS2 Transistors with Impedance Spectroscopy. AB - The electronic properties of the HfO2/MoS2 interface were investigated using multifrequency capacitance-voltage (C-V) and current-voltage characterization of top-gated MoS2 metal-oxide-semiconductor field effect transistors (MOSFETs). The analysis was performed on few layer (5-10) MoS2 MOSFETs fabricated using photolithographic patterning with 13 and 8 nm HfO2 gate oxide layers formed by atomic layer deposition after in-situ UV-O3 surface functionalization. The impedance response of the HfO2/MoS2 gate stack indicates the existence of specific defects at the interface, which exhibited either a frequency-dependent distortion similar to conventional Si MOSFETs with unpassivated silicon dangling bonds or a frequency dispersion over the entire voltage range corresponding to depletion of the HfO2/MoS2 surface, consistent with interface traps distributed over a range of energy levels. The interface defects density (Dit) was extracted from the C-V responses by the high-low frequency and the multiple-frequency extraction methods, where a Dit peak value of 1.2 * 1013 cm-2 eV-1 was extracted for a device (7-layer MoS2 and 13 nm HfO2) exhibiting a behavior approximating to a single trap response. The MoS2 MOSFET with 4-layer MoS2 and 8 nm HfO2 gave Dit values ranging from 2 * 1011 to 2 * 1013 cm-2 eV-1 across the energy range corresponding to depletion near the HfO2/MoS2 interface. The gate current was below 10-7 A/cm2 across the full bias sweep for both samples indicating continuous HfO2 films resulting from the combined UV ozone and HfO2 deposition process. The results demonstrated that impedance spectroscopy applied to relatively simple top-gated transistor test structures provides an approach to investigate electrically active defects at the HfO2/MoS2 interface and should be applicable to alternative TMD materials, surface treatments, and gate oxides as an interface defect metrology tool in the development of TMD-based MOSFETs. PMID- 28650157 TI - Engineering Mesoporous Single Crystals Co-Doped Fe2O3 for High-Performance Lithium Ion Batteries. AB - To achieve high-efficiency lithium ion batteries (LIBs), an effective active electrode material is vital. For the first time, mesoporous single crystals cobalt-doped Fe2O3 (MSCs Co-Fe2O3) is synthesized using formamide as a pore forming agent, through a solvothermal process followed by calcination. Compared with mesoporous single crystals Fe2O3 (MSCs Fe2O3) and cobalt-doped Fe2O3 (Co Fe2O3), MSCs Co-Fe2O3 exhibits a significantly improved electrochemical performance with high reversible capacity, excellent rate capability, and cycling life as anode materials for LIBs. The superior performance of MSCs Co-Fe2O3 can be ascribed to the combined structure characteristics, including Co-doping and mesoporous single-crystals structure, which endow Fe2O3 with rapid Li+ diffusion rate and tolerance for volume change. PMID- 28650156 TI - Discovery of a Glutamine Kinase Required for the Biosynthesis of the O-Methyl Phosphoramidate Modifications Found in the Capsular Polysaccharides of Campylobacter jejuni. AB - Bacterial capsular polysaccharides (CPS) are complex carbohydrate structures that play a role in the overall fitness of the organism. Campylobacter jejuni, known for being a major cause of bacterial gastroenteritis worldwide, produces a CPS with a unique O-methyl phosphoramidate (MeOPN) modification on specific sugar residues. The formation of P-N bonds in nature is relatively rare, and the pathway for the assembly of the phosphoramidate moiety in the CPS of C. jejuni is unknown. In this investigation we discovered that the initial transformation in the biosynthetic pathway for the MeOPN modification of the CPS involves the direct phosphorylation of the amide nitrogen of l-glutamine with ATP by the catalytic activity of Cj1418. The other two products are AMP and inorganic phosphate. The l-glutamine-phosphate product was characterized using 31P NMR spectroscopy and mass spectrometry. We suggest that this newly discovered enzyme be named l-glutamine kinase. PMID- 28650158 TI - Stable Radical Cations and Their pi-Dimers Prepared from Ethylene- and Propylene 3,4-dioxythiophene Co-oligomers: Combined Experimental and Theoretical Investigations. AB - Co-oligomers composed of two 3,4-ethylenedioxythiophene (EDOT) units and two or three 3,4-propylenedioxythiophene (ProDOT) units, i.e., 2E2PEt and 2E3PEt, were newly synthesized together with the ProDOT trimer 3PMe. On the basis of cyclic voltammetry, the gaps between the first and second oxidation potentials (DeltaE1 2) of 2E2PEt and 2E3PEt were found to be larger than that of the previously synthesized ProDOT tetramer 4PHex. These co-oligomers gave the fairly stable radical cations 2E2PEt*+ and 2E3PEt*+ by chemical oxidation with AgSbF6. The disproportionation of 2E2PEt*+ and 2E3PEt*+ into neutral and dicationic species, which was observed for 4PHex*+, was inhibited in accord with the larger DeltaE1 2. Additionally, the formation of the pi-dimers (3PMe)22+, (2E2PEt)22+, and (2E3PE)22+ was clearly observed in dichloromethane solution at low temperatures with UV-vis-NIR spectroscopy. Furthermore, the pi-dimerization enthalpies of 2E2PEt*+ and 2E3PEt*+ were greater than that of 3PMe*+, suggesting the formation of fully pi-contacted structures. The structures of the pi-dimers were optimized at the B97D3 method, and the calculated absorption spectra of the pi-dimers obtained using TD-DFT methods were in reasonable agreement with the observed ones, supporting the reliability of the calculated structures. PMID- 28650159 TI - Enantioselective Vinylogous Michael-Michael Cascade Reactions of 3-Alkylidene Oxindoles and Nitroolefin Enoates. AB - A novel bifunctional squaramide catalyzed vinylogous Michael-Michael cascade reaction of 3-alkylidene oxindoles with nitroolefin enoates was developed. This convenient, one-pot cascade reaction serves as a powerful tool for the enantioselective construction of potential bioactive chiral chromans, which have three continuous tertiary stereocenters, in moderate to good yields (up to 85%) with excellent stereoselectivities (up to >19:1 dr and >99% ee). PMID- 28650161 TI - Targeted and Systematic Approach to the Study of pKa Values of Imidazolium Salts in Dimethyl Sulfoxide. AB - A range of more than 25 imidazolium salts, chosen for their differing steric and electronic features, were prepared, and their pKa values were determined using the bracketing indicator method. Through the systematic change in the structure of the imidazolium cation, the effect of varying substituents at each position on the heterocyclic ring was determined; particularly, the transmission of electronic effects was quantified using Hammett parameters. These new data give an indication of the strength of base required for deprotonation and the potential to correlate these data with the nucleophilicity of the corresponding carbenes. PMID- 28650160 TI - Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation. AB - Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-alpha-F-2'-beta-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty nine phosphoramidates with N4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e and 4m (EC50 = 0.19-0.25 MUM) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 MUM) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 MUM) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 MUM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation. PMID- 28650162 TI - Lamellar Liquid-Crystalline System with Tunable Iridescent Color by Ionic Surfactants. AB - Liquid crystals formed by the self-assembly of small molecules are very promising smart materials because of their unique properties, such as self-assembled multivalency, biocompatibility, and fast response to external stimuli. Here we report an iridescent liquid-crystal system composed of water layers, which is sandwiched by two bilayer membranes. Such membranes are composed of a self assembled nonionic surfactant, which is called hexadecylglyceryl maleate (HGM), and only a small amount of ionic surfactants. It is found that the iridescent color of the liquid crystal system is very sensitive to the concentration of ionic surfactants, even if a trace of change of the ionic surfactants' concentration will induce the color change of liquid-crystal system. The result shows that with the increase in ionic surfactant concentration, the flat bilayer membrane tends to be curved to form some edge-dislocation defects. The appearance of such defects in the lamellar system leads to the decrease in spacing distance between adjacent bilayer membranes. This is because some vacant spaces emerged inevitably during this process. The ionic surfactant-sensitive HGM system also shows the thermal response. It is because the phase-separation results in the increase in local concentration of SDS in the bilayer membrane, which has the same effect as increasing the SDS concentration in the whole system. PMID- 28650163 TI - Enhanced Hydrogen Production With Chiral Conductive Polymer-Based Electrodes. AB - Efficient photoelectrochemical production of hydrogen from water is the aim of many studies in recent decades. Typically, one observes that the electric potential required to initiate the process significantly exceeds the thermodynamic limit. It was suggested that by controlling the spins of the electrons that are transferred from the solution to the anode, and ensuring that they are co-aligned, the threshold voltage for the process can be decreased to that of the thermodynamic voltage. In the present study, by using anodes coated with chiral conductive polymer, the hydrogen production from water is enhanced and the threshold voltage is reduced, as compared with anodes coated with achiral polymer. When CdSe quantum dots were embedded within the polymer, the current density was doubled. These new results point to a possible new direction for producing inexpensive, environmental friendly, efficient water splitting photoelectrochemical cells. PMID- 28650164 TI - Effect of Ancillary Ligands (A) on Oxidative Addition of CH4 to Rhenium(III) Complexes: A = B, Al, CH, SiH, N, and P Using MP2, CCSD(T), and MCSCF Methods. AB - A computational study of oxidative addition (OA) of methane to Re(OC2H4)3A (A = ancillary ligand, which thus may interact with the metal) was carried out. The choice of ancillary ligands has been made based on their electronic properties: A = B or Al (Lewis acid), CH or SiH (electron precise), N (sigma-donor), and P (sigma-donor/pi-acid). The main objective of this study was to understand how variation in A affects the structural and electronic properties of the reactant d4-Re(III) complex, which can ultimately tune the kinetics and thermodynamics of OA. Results obtained from MP2 calculations revealed that, for OA of CH4 to Re(OC2H4)3A, the order of DeltaG? for a choice of ancillary ligand is B > Al > SiH > CH > N > P. Single point calculations for DeltaG? obtained with CCSD(T) showed excellent agreement with those computed with MP2 methods. MCSCF calculations indicated that oxidative addition transition states are well described by a single electronic configuration, giving further confidence in the MP2 approach used for geometry optimization and DeltaG? determination, and that the transition states are more electronically similar to the d4-Re(III) reactant than the d2-Re(V) product. PMID- 28650165 TI - 1,3-Dipolar Cycloaddition of Nitrile Imine with Carbon Dioxide: Access to 1,3,4 Oxadiazole-2(3H)-ones. AB - Efficient synthesis of 1,3,4-oxadiazole-2(3H)-one was achieved by CsF/18-crown-6 mediated 1,3-dipolar cycloaddition of nitrile imine and 2.0 MPa of CO2. CsF/18 crown-6 played a key role in enhancing the reactivity of CO2 as a 1,3 dipolarophile. The practical utility of this transition-metal-free approach to 1,3,4-oxadiazole-2(3H)-one is highlighted by the convenient synthesis of a commercial herbicide Oxadiazon and a MAO B inhibitor. PMID- 28650166 TI - Geometry Driven Intramolecular Oxidative Cyclization of Enamides: An Umpolung Annulation of Primary Benzamides with Acrylates for the Synthesis of 3 Methyleneisoindolin-1-ones. AB - A palladium-catalyzed tandem oxidative annulation of primary benzamides with acrylates via intermolecular N-alkenylation followed by intramolecular C alkenylation yielded a stereoselective synthesis of (E)-3-methyleneisoindolin-1 ones. The study unveils, for the first time, that only E-enamides could undergo intramolecular oxidative cyclization under the optimized conditions to give isoindolinones. The current strategy represents an umpolung strategy when compared to the literature approaches that use benzamides. PMID- 28650167 TI - Molecular Insight into the Adsorption of Spruce Budworm Antifreeze Protein to an Ice Surface: A Clathrate-Mediated Recognition Mechanism. AB - The principal mechanism of ice recognition by antifreeze protein (AFP) has been a topic of intense discussion in recent times. Despite many experimental and theoretical studies, the detailed understanding of the process remains elusive. The present work aims to explore the molecular mechanism of ice recognition by an insect AFP from the spruce budworm, sbwAFP. As evident from our simulation, the water dynamics becomes very sluggish around the ice binding surface (IBS) as a result of the combined effect of confinement and ordering induced by the perfectly aligned methyl side chains of threonine residues, the THR ladder. The hydroxyl groups of threonine form strong hydrogen bonds with few of those highly ordered water molecules that are close to the THR ladder, which is the origin of anchored clathrate water at the IBS of sbwAFP. We propose anchored clathrate mediated basal plane recognition by sbwAFP. The AFP adsorbed on the basal plane through water clathrate framed around the IBS. The surface of the basal plane and anchored clathrate water completes the caging around the threonine residues, which is the origin of the binding plane specificity of sbwAFP. This adsorbed AFP ice complex undergoes dynamic crossover to a hydrogen-bonded complex within the thermal hysteresis (TH) regime of this particular AFP. The anchored clathrate water becomes part of the newly grown basal front as a result of the geometrical matches between the basal plane and the anchored clathrate water repeat distance. This observation provides a structural rationale for the experimentally observed time-dependent increase in TH activity for insect AFP. Our study proposes clathrate-mediated ice recognition by AFP and elucidates the dynamic events involved during ice binding by the insect AFP. PMID- 28650168 TI - Semisoft Colloidal Crystals in Ionic Liquids. AB - Here, we introduce a technique for the direct formation of semisoft colloidal crystals of hybrid particles in nonvolatile ionic liquid (IL) solvents. The hybrid particles are comprised of a silica core and a densely grafted polymer brush shell, which were synthesized by surface-initiated living radical polymerization. A phase transition of the suspensions from a disordered fluid to a crystallized system was observed within a narrow concentration range. Confocal laser scanning microscopy observation and ultraviolet-visible light (UV-vis) spectrometry confirmed the highly ordered structure of the hybrid particles in ionic liquids. The effect of the hybrid particle structure on the photonic band gap of the colloidal crystals was investigated, and the band gaps varied by changing graft chain lengths. In addition, the colloidal crystal suspensions were successfully immobilized in ILs. PMID- 28650169 TI - Increasing Protein Production Rates Can Decrease the Rate at Which Functional Protein Is Produced and Their Steady-State Levels. AB - The rate at which soluble, functional protein is produced by the ribosome has recently been found to vary in complex and unexplained ways as various translation-associated rates are altered through synonymous codon substitutions. To understand this phenomenon, here, we combine a well-established ribosome traffic model with a master-equation model of cotranslational domain folding to explore the scenarios that are possible for the protein production rate, J, and the functional-nascent protein production rate, F, as the rates of various translation processes are altered for five different E. coli proteins. We find that while J monotonically increases as the rates of translation-initiation, elongation, and -termination increase, F can either increase or decrease. We show that F's nonmonotonic behavior arises within the model from two opposing trends: the tendency for increased translation rates to produce more total protein but less cotranslationally folded protein. We further demonstrate that under certain conditions these nonmonotonic changes in F can result in nonmonotonic variations in post-translational, steady-state levels of functional protein. These results provide a potential explanation for recent experimental observations in which the specific activity of enzymatic proteins decreased with increased synthesis rates. Additionally our model has the potential to be used to rationally design transcripts to maximize the production of functional nascent protein by simultaneously optimizing translation initiation, elongation, and termination rates. PMID- 28650170 TI - Gold(I)-Catalyzed Cycloisomerization-Dimerization Cascade of Benzene-Tethered 1,6 Enynes. AB - An unprecedented stereoselective domino reaction of 1,6-enynes with an aryl ring at C3-C4 in the presence of gold(I) catalysts at low temperature is described. This process involves a novel 5-exo-dig cycloisomerization-dimerization sequence to afford formal Diels-Alder adducts that undergo a smooth gold-catalyzed double bond migration at room temperature. In addition, the first examples of the gold mesoionic carbene mediated [2+2+2] cycloaddition of these enynes with benzaldehyde are reported. PMID- 28650171 TI - Comprehensive Lipoprotein Characterization Using Lipidomics Analysis of Human Plasma. AB - Lipoproteins are responsible for the transport of lipids and other nutrients in the circulation and therefore play an important role in lipid metabolism and dyslipidemia. They have also been linked to multiple metabolic disorders including cardiovascular disease, and thus understanding their lipid composition is of crucial importance. Characterization of lipoproteins is a challenging task due to their heterogeneity. In particular, their fractionation is often laborious and time-consuming, making large sets of clinical samples difficult to analyze. We developed and validated lipidomics analysis of lipoproteins including chylomicrons, very low-density, low-density, and high-density lipoproteins. Lipoproteins were first fractionated by polyacrylamide tube gel electrophoresis, and, after liquid-liquid extraction, lipids were analyzed by direct-infusion mass spectrometry. About 100 unique lipid species were detected with good reproducibility and reliability. In addition to their lipid composition, valuable information on the fatty acid composition of lipoproteins and lipids was obtained. The presented method offers in-depth analysis of the lipid as well as fatty acid composition of lipoproteins while allowing a good sample throughput. It is thus especially suited for studying lipid associated diseases in clinical cohorts. PMID- 28650172 TI - Quantum Molecular Trajectory and Its Statistical Properties. AB - Despite the quantum nature of molecules, classical mechanics is often employed to describe molecular motions that play a fundamental role in a wide range of phenomena including chemical reactions. This is due to the need of assigning well defined positions to the atomic nuclei during the time evolution of the system in order to describe unambiguously the molecular motions, whereas quantum mechanics provides information on probabilistic nature only. One would like to employ a quantum molecular trajectory that defines rigorously the instantaneous nuclear positions and, simultaneously, guarantees the conservation of all quantum mechanics predictions unlike the classical trajectory. We argue that such a quantum molecular trajectory can be formally defined and we prove that it corresponds to a single Bohm trajectory. Our analysis establishes a clear correspondence between the statistical properties of the trajectory and the quantum expectation values. The obvious and undeniable benefit is that of dealing with a quantum methodology fully characterizing the molecular motions without any reference to classical mechanics. PMID- 28650173 TI - Polymer Pen Lithography with Lipids for Large-Area Gradient Patterns. AB - Gradient patterns comprising bioactive compounds over comparably (in regard to a cell size) large areas are key for many applications in the biomedical sector, in particular, for cell screening assays, guidance, and migration experiments. Polymer pen lithography (PPL) as an inherent highly parallel and large area technique has a great potential to serve in the fabrication of such patterns. We present strategies for the printing of functional phospholipid patterns via PPL that provide tunable feature size and feature density gradients over surface areas of several square millimeters. By controlling the printing parameters, two transfer modes can be achieved. Each of these modes leads to different feature morphologies. By increasing the force applied to the elastomeric pens, which increases the tip-surface contact area and boosts the ink delivery rate, a switch between a dip-pen nanolithography (DPN) and a microcontact printing (MUCP) transfer mode can be induced. A careful inking procedure ensuring a homogeneous and not-too-high ink-load on the PPL stamp ensures a membrane-spreading dominated transfer mode, which, used in combination with smooth and hydrophilic substrates, generates features with constant height, independently of the applied force of the pens. Ultimately, this allows us to obtain a gradient of feature sizes over a mm2 substrate, all having the same height on the order of that of a biological cellular membrane. These strategies allow the construction of membrane structures by direct transfer of the lipid mixture to the substrate, without requiring previous substrate functionalization, in contrast to other molecular inks, where structure is directly determined by the printing process itself. The patterns are demonstrated to be viable for subsequent protein binding, therefore adding to a flexible feature library when gradients of protein presentation are desired. PMID- 28650174 TI - Dissolution Processes at Step Edges of Calcite in Water Investigated by High Speed Frequency Modulation Atomic Force Microscopy and Simulation. AB - The microscopic understanding of the crystal growth and dissolution processes have been greatly advanced by the direct imaging of nanoscale step flows by atomic force microscopy (AFM), optical interferometry, and X-ray microscopy. However, one of the most fundamental events that govern their kinetics, namely, atomistic events at the step edges, have not been well understood. In this study, we have developed high-speed frequency modulation AFM (FM-AFM) and enabled true atomic-resolution imaging in liquid at ~1 s/frame, which is ~50 times faster than the conventional FM-AFM. With the developed AFM, we have directly imaged subnanometer-scale surface structures around the moving step edges of calcite during its dissolution in water. The obtained images reveal that the transition region with typical width of a few nanometers is formed along the step edges. Building upon insight in previous studies, our simulations suggest that the transition region is most likely to be a Ca(OH)2 monolayer formed as an intermediate state in the dissolution process. On the basis of this finding, we improve our understanding of the atomistic dissolution model of calcite in water. These results open up a wide range of future applications of the high-speed FM AFM to the studies on various dynamic processes at solid-liquid interfaces with true atomic resolution. PMID- 28650175 TI - Bioactive Peptide Natural Products as Lead Structures for Medicinal Use. AB - The need for new drugs for the treatment of various diseases is enormous. From the previous century until the present, numerous peptide and peptide-derived natural products have been isolated from bacteria and fungi. Hence, microorganisms play a pivotal role as sources for novel drugs with an emphasis on anti-infective agents. Various disciplines from biology, chemistry, and medicine are involved in early stages of the search for peptide natural products including taxonomy, microbiology, bioanalytics, bioinformatics, and medicinal chemistry. Under biochemical aspects, small peptide drugs are basically either ribosomally synthesized and post-translationally modified (RiPPs) or synthesized by multimodular nonribosomal peptide synthetases (NRPSs). Within the context of current developments on bioactive peptide natural products, this Account predominantly highlights recent discoveries, approaches, and research from our laboratory on RiPPs and NRPSs from bacteria and fungi. In our search for peptides showing bioactivities of interest, different approaches were applied: classical screening, in silico prediction, in vitro reconstitution, site-directed mutagenesis, chemoenzymatics, heterologous expression, and total synthesis including structure-activity relationship (SAR) studies in the research on the labyrinthopeptins, albicidin, and the cyclodepsipeptides (CDPs). The ribosomally synthesized labyrinthopeptins, class III lanthipeptides, which have been discovered in a classical screening campaign, display highly attractive antiallodynic (against neuropathic pain caused by dysfunction of the nervous system) and antiviral activities. Therefore, the biosynthetic assembly was investigated by extensive enzymatic studies of the modifying enzymes, and site directed mutagenesis was performed for the generation of analogs. By genome mining, other class III lanthipeptides have been uncovered, while synthetic access proved to be an unmet challenge for the labyrinthopeptins. In contrast, for the gyrase inhibitor albicidin, the establishment of a chemical synthesis followed by medicinal chemistry studies was the only viable option to gain access to derivatives. Albicidin, which has been discovered investigating plant host pathogen interactions, has a strong activity against Gram-negative bacteria, for example, Escherichia coli and Pseudomonas aeruginosa, and a future synthetic derivative may become a lead structure for development of an anti-Gram-negative drug. The compound class of the cyclodepsipeptides contributes already two marketed drugs, enniatin (fusafungine) and emodepside. Cyclodepsipeptides show general antibacterial and antifungal effects, whereas specific insecticidal and anthelmintic activities provide lead structures for drug development. Hence, exploiting the chances of reprogramming NRPSs, the generation of chimeric or otherwise designed synthetases could render a new untapped structural space and thus novel bioactivities. While current developments in the fields of genomics, bioinformatics, and molecular biology facilitate the search for new natural products and the design of new peptide structures, the next decade will show which compounds have been carried on further applications and whether current developments have led to an increase in drug candidates. PMID- 28650176 TI - The Role of Through-Space Interactions in Modulating Constructive and Destructive Interference Effects in Benzene. AB - Quantum interference effects, whether constructive or destructive, are key to predicting and understanding the electrical conductance of single molecules. Here, through theory and experiment, we investigate a family of benzene-like molecules that exhibit both constructive and destructive interference effects arising due to more than one contact between the molecule and each electrode. In particular, we demonstrate that the pi-system of meta-coupled benzene can exhibit constructive interference and its para-coupled analog can exhibit destructive interference, and vice versa, depending on the specific through-space interactions. As a peculiarity, this allows a meta-coupled benzene molecule to exhibit higher conductance than a para-coupled benzene. Our results provide design principles for molecular electronic components with high sensitivity to through-space interactions and demonstrate that increasing the number of contacts between the molecule and electrodes can both increase and decrease the conductance. PMID- 28650177 TI - Learning on hold: Cell phones sidetrack parent-child interactions. AB - Although research suggests that responsive interactions are imperative for language development, the advent of mobile technology means that parent-child exchanges are often fraught with unpredictable interruptions. Less clear is how these momentary breaks in responsiveness affect word learning. In this within subjects design, 38 mothers taught their 2-year-olds (M = 27.15 months) 2 novel words, 1 at a time. One teaching period was interrupted by a cell phone call. Children learned the word when the teaching was not interrupted, but not when it was interrupted. Critically, the number of times each target word was spoken did not differ by condition. This finding supports the literature on responsiveness, offering experimental evidence that interruptions in social interactions can affect learning outcomes. (PsycINFO Database Record PMID- 28650178 TI - The role of morbidity for proxy-reported well-being in the last year of life. AB - Late-life well-being often shows steep deteriorations, but the contributing factors are not well understood, in part because data about people's final year of life are scarce. Here, we draw from and test theoretical perspectives that health-related vulnerabilities undermine the experience and skills older adults typically use to maintain well-being (Charles, 2010). To do so, we examined how various morbidity factors shape final-year well-being trajectories. We applied change score models to retrospective proxy-reports from the Socio-Economic Panel (N = 1,776; age at death = 19-101 years; 47% women) and covary for characteristics of the deceased and the bereaved proxy. Terminal decline in proxy reported well-being amounted to 0.57 SD in less than a year, with larger individual differences at 3 months versus 12 months before death. Declines were reportedly steeper for those in poor health, need of care, not dying from sudden causes of death, dying with cancer, and not dying at home. People who entered their final year with preserved well-being and cognition experienced steeper final-year decrements. Morbidity factors conjointly accounted for less than 20% of variance, indicating that health decrements shape final-year well-being in multifaceted ways, but are not the be-all and the end-all of why well-being declines for some, but not for others. Unique effects of particular morbidity factors were modest, suggesting that prevailing multimorbidity makes the particular conditions in part interchangeable. Extending self-report data typically available until 1 year before death, our findings suggest that proxy based results move our understanding of terminal well-being decline further. (PsycINFO Database Record PMID- 28650179 TI - Political activism and mental health among Black and Latinx college students. AB - OBJECTIVES: The current study investigates the utility of political activism as a protective factor against experiences of racial/ethnic (R/E) discrimination that negatively affect stress, anxiety, and depressive symptoms among Black and Latinx college freshmen at predominately White institutions. METHOD: Data come from the Minority College Cohort Study, a longitudinal investigation of Black and Latinx college students (N = 504; 44% Black). We conducted multiple regression analyses for each mental health indicator and tested for interaction effects. RESULTS: For Black and Latinx students, the relationship between R/E microaggressions and end of freshman year stress varied by political activism. For Black students, the relationship between R/E microaggressions and end of the year anxiety varied by political activism. There was a significant interaction effect for depressive symptoms among Latinx students. CONCLUSIONS: Political activism serves as a protective factor to mitigate the negative effect of R/E discrimination on stress and depressive symptoms for Latinx students. For Black students, higher levels of political activism may exacerbate experiences of R/E microaggressions and relate to more stress and anxiety compared with Black students who are less politically involved. Findings point to the need for a deeper understanding of phenomenological variation in experiences of microaggressions among R/E minorities and how students leverage political activism as an adaptive coping strategy to mitigate race-related stress during college. (PsycINFO Database Record PMID- 28650180 TI - Acculturation, acculturative stressors, and family relationships among Latina/o immigrants. AB - OBJECTIVES: Family relationships, widely recognized as core to Latino cultures, are known to vary for Latina/o immigrants based on time in the United States. Less is known about (a) how acculturation explains differences in family relationships by time in the US, and (b) whether acculturative stressors influence different aspects of immigrants' family relationships. Drawing on an expanded acculturation framework, we explore whether and how attitudinal familism, family contact, and family conflict among immigrant Latina/os vary based on acculturation and acculturative stressors. METHOD: Using nationally representative data on foreign-born Latina/os (National Latino and Asian American Study; N = 1,618), ordered logistic and OLS regression analyses examined whether differences in family relationships by time in the US are explained by acculturation factors, and whether acculturative stressors are associated with family relationships when controlling for other important sociodemographic factors. RESULTS: Accounting for acculturation reduces the effect of time in the US on attitudinal familism and family conflict to nonsignificance. Spanish language proficiency and ethnic identity are associated with higher attitudinal familism, while English proficiency is associated with increased family conflict. Additionally, acculturative stressors (involuntary context of exit, hostile context of reception, limited origin country ties) are associated with lower attitudinal familism and higher conflict. CONCLUSIONS: Results highlight the importance of (a) examining the ways that migration influences multiple aspects of family relationships, (b) adopting a more comprehensive acculturation framework. Particularly novel are our findings on how acculturative stressors are associated with different family outcomes. (PsycINFO Database Record PMID- 28650181 TI - Racial identity invalidation with multiracial individuals: An instrument development study. AB - OBJECTIVES: Racial identity invalidation, others' denial of an individual's racial identity, is a salient racial stressor with harmful effects on the mental health and well-being of Multiracial individuals. The purpose of this study was to create a psychometrically sound measure to assess racial identity invalidation for use with Multiracial individuals (N = 497). METHOD: The present sample was mostly female (75%) with a mean age of 26.52 years (SD = 9.60). The most common racial backgrounds represented were Asian/White (33.4%) and Black/White (23.7%). Participants completed several online measures via Qualtrics. RESULTS: Exploratory factor analyses revealed 3 racial identity invalidation factors: behavior invalidation, phenotype invalidation, and identity incongruent discrimination. A confirmatory factor analysis provided support for the initial factor structure. Alternative model testing indicated that the bifactor model was superior to the 3-factor model. Thus, a total score and/or 3 subscale scores can be used when administering this instrument. Support was found for the reliability and validity of the total scale and subscales. In line with the minority stress theory, challenges with racial identity mediated relationships between racial identity invalidation and mental health and well-being outcomes. CONCLUSIONS: The findings highlight the different dimensions of racial identity invalidation and indicate their negative associations with connectedness and psychological well being. (PsycINFO Database Record PMID- 28650182 TI - Buried layers: On the origins, rise, and fall of stratification theories. AB - This article presents a historical analysis of the origins, rise, and demise of theories of stratification (Schichtentheorien). Following their roots in the ancient metaphysical idea of the "great chain of being," Aristotle's scala naturae, the medieval "Jacob's ladder," and Leibniz's concept of the lex continua, I argue that theories of stratification represent the modern heir to the ancient cosmological idea of a harmonious, hierarchical, and unified universe. Theories of stratification reached their heyday during the interwar period within German academia, proliferating over a vast number of disciplines and rising to special prominence within personality psychology, feeding the hope for a unitary image of the world and of human beings, their biological and mental development, their social organization and cultural creations. This article focuses on the role of visuality as a distinct mode of scientific knowledge within theories of stratification as well as the cultural context that provided the fertile ground for their flowering in the Weimar Republic. Finally, the rapid demise of theories of stratification during the 1950s is discussed, and some reasons for their downfall during the second half of the 20th century are explored. (PsycINFO Database Record PMID- 28650183 TI - Spatial transposition tasks in Indian sloth bears (Melursus ursinus) and Bornean sun bears (Helarctos malayanus euryspilus). AB - Spatial transposition tasks assess individuals' ability to represent nonvisible spatial object displacements. Several nonhuman mammal species have been tested on this task including primates, cats, and dogs, but to date, great apes seem the only taxon that has repeatedly and consistently solved spatial transposition tasks. The authors investigated the ability of captive sloth and sun bears to solve spatial transposition tasks. Both species belong to the same taxonomic group as cats and dogs, but unlike them and similar to apes, they have an omnivorous diet that requires them to keep track of fruit sources in space and time. The bears were first tested on a visible displacement task and those that succeeded were further tested on a spatial transposition task that involved a 180 degrees transposition, followed by 2 tasks with two 360 degrees transpositions. All 7 sloth bears and 7 out of 9 sun bears solved the visible displacement task. The 180 degrees transposition task was solved by 6 out of 7 sloth bears and 1 out of the 5 tested sun bears. Three sloth bears were tested on all 4 experiments and even solved 2-chained 360 degrees transpositions. Control conditions were conducted showing that the bears' performance did not rely on olfactory or auditory cues. The results provide the first indication that bears might be able to track invisible objects. Further studies will be necessary to confirm these results and to control the influence of associative learning. The present study emphasizes the importance of including different animal species in the investigation of what underlies the evolution of different cognitive skills. (PsycINFO Database Record PMID- 28650184 TI - Effects of nicotine versus placebo e-cigarette use on symptom relief during initial tobacco abstinence. AB - Because electronic cigarettes (e-cigs) containing nicotine may relieve smoking abstinence symptoms similar to nicotine replacement therapy medication, we used within-subjects designs to test these effects with a first-generation e-cig in nonquitting and quitting smokers. In Study 1, 28 nontreatment-seeking smokers abstained overnight prior to each of 3 sessions. Minnesota Nicotine Withdrawal Scale (MNWS) withdrawal (and craving item) relief was assessed following 4 exposures (each 10 puffs) over 2 hr to e-cigs that either did (36 mg/ml) or did not (i.e., placebo, 0 mg/ml) contain nicotine or after no e-cig. Relief was greater after nicotine versus placebo e-cig (p < .05) but not after placebo versus no e-cig, showing relief was due to nicotine per se and not simple e-cig use behavior. Using a crossover design in Study 2, smokers preparing to quit soon engaged in 2 experimental 4-day quit periods on separate weeks. In weeks 1 and 3, all received a nicotine or placebo e-cig on Monday to use ad libitum while trying to abstain from smoking on Tuesday through Friday. (Week 2 involved resumption of ad libitum smoking.) MNWS and Questionnaire of Smoking Urges (QSU) craving were assessed at daily visits following 24-hr abstinence. Of 17 enrolled, 12 quit for >=24 hr at least once, allowing test of relief because of e-cig use on quit days. Withdrawal and craving were reduced because of nicotine versus placebo e-cig use (both p < .05). In sum, compared with placebo e-cigs, nicotine e-cigs can relieve smoking abstinence symptoms, perhaps in a manner similar to Food and Drug Administration-approved nicotine replacement therapy products, although much more research with larger samples is needed. (PsycINFO Database Record PMID- 28650186 TI - Incremental prediction of intimate partner violence: An examination of three risk measures. AB - Improvements in the risk prediction of domestic violence against intimate partners have the potential to inform policing practices in the prevention of further victimization. The present study examined the incremental predictive validity of 3 measures of risk for intimate partner violence (IPV)-Spousal Assault Risk Assessment (SARA), Ontario Domestic Assault Risk Assessment (ODARA), and the Family Violence Investigative Report (FVIR)-for IPV, general violence, and general recidivism outcomes. The sample featured 289 men and women who were reported to police for IPV and followed up approximately 3 years post release. Archival ratings of the 3 measures demonstrated that SARA scores showed incremental validity for IPV recidivism, ODARA scores incrementally predicted general violence, and both tools incrementally predicted general recidivism. The FVIR did not incrementally predict any outcomes. Fine grained analyses demonstrated that the Psychosocial Adjustment domain of the SARA contributed most uniquely to the prediction of IPV. Survival analysis supported the use of the SARA and ODARA in tandem for appraising risk for IPV or general criminal recidivism. Calibration analyses using logistic regression modeling also demonstrated 3-year recidivism estimates for SARA and ODARA scores. Implications for the use of multiple tools in clinical practice are discussed, particularly for combining the SARA and ODARA measures to augment IPV risk assessment and management. (PsycINFO Database Record PMID- 28650185 TI - Sexual misconduct in prison: What factors affect whether incarcerated women will report abuses committed by prison staff? AB - More than 80,000 prisoners each year are sexually victimized during incarceration, but only about 8% report victimization to correctional authorities. Complicating reporting is the fact that half of the perpetrators are staff members. Given the restrictive and highly regulated prison environment, studies that examine reporting behaviors are difficult to conduct and to date information available relied on those who have reported or hypothetical victimization studies. This study uses an ecological framework and archival data from a class action lawsuit of sexual misconduct to determine predictors of reporting. Relying on a subsample of 179 women, chosen because they have all experienced at least 1 penetration offense, we use bivariate and multivariable mixed effects logistic regression analyses to examine individual, assault, and context-level predictors of reporting on 397 incidents of staff sexual misconduct. The final model revealed that that 6 predictors (age at time of assault, physical injury, multiple incidents, perpetrator with multiple victims, the year the abuse began, and the number of years women have left on their sentence) account for 58% of the variance in reporting. Disclosure to inmate peers and/or family and friends was significant in the bivariate results. These findings indicate the need for stronger and more systematic implementation of Prison Rape Elimination Act guidelines and remedies that create and enforce sanctions, including termination, for staff violating policy and state law. (PsycINFO Database Record PMID- 28650187 TI - Disentangling the risk assessment and intimate partner violence relation: Estimating mediating and moderating effects. AB - To manage intimate partner violence (IPV), the criminal justice system has turned to risk assessment instruments to predict if a perpetrator will reoffend. Empirically determining whether offenders assessed as high risk are those who recidivate is critical for establishing the predictive validity of IPV risk assessment instruments and for guiding the supervision of perpetrators. But by focusing solely on the relation between calculated risk scores and subsequent IPV recidivism, previous studies of the predictive validity of risk assessment instruments omitted mediating factors intended to mitigate the risk of this behavioral recidivism. The purpose of this study was to examine the mediating effects of such factors and the moderating effects of risk assessment on the relation between assessed risk (using the Domestic Violence Screening Instrument Revised [DVSI-R]) and recidivistic IPV. Using a sample of 2,520 perpetrators of IPV, results revealed that time sentenced to jail and time sentenced to probation each significantly mediated the relation between DVSI-R risk level and frequency of reoffending. The results also revealed that assessed risk moderated the relation between these mediating factors and IPV recidivism, with reduced recidivism (negative estimated effects) for high-risk perpetrators but increased recidivism (positive estimate effects) for low-risk perpetrators. The implication is to assign interventions to the level of risk so that no harm is done. (PsycINFO Database Record PMID- 28650188 TI - Being present: Focusing on the present predicts improvements in life satisfaction but not happiness. AB - Mindfulness theorists suggest that people spend most of their time focusing on the past or future rather than the present. Despite the prevalence of this assumption, no research that we are aware of has evaluated whether it is true or what the implications of focusing on the present are for subjective well-being. We addressed this issue by using experience sampling to examine how frequently people focus on the present throughout the day over the course of a week and whether focusing on the present predicts improvements in the 2 components of subjective well-being over time-how people feel and how satisfied they are with their lives. Results indicated that participants were present-focused the majority of the time (66%). Moreover, focusing on the present predicted improvements in life satisfaction (but not happiness) over time by reducing negative rumination. These findings advance our understanding of how temporal orientation and well-being relate. (PsycINFO Database Record PMID- 28650189 TI - Valuing calm enhances enjoyment of calming (vs. exciting) amusement park rides and exercise. AB - Do people derive more enjoyment from activities that match how they ideally want to feel (their "ideal affect")? Affect valuation theory (AVT) predicts that they do; however, no study has directly examined whether this is the case. Therefore, the authors conducted 4 studies that examined whether valuing calm and other low arousal positive states (LAP) increased enjoyment of calming (vs. exciting) activities. In Study 1, the more participants valued LAP, the more enjoyment they recalled during calming (vs. exciting) episodes from their lives. In Studies 2-3, the more participants valued LAP, the more enjoyment they experienced during calming (vs. exciting) amusement park rides, both in the United States and Hong Kong. To assess causality, in Study 4, participants were randomly assigned to either a "value LAP" or control condition and then engaged in either low or high intensity exercise. Participants in the value LAP condition who engaged in low intensity exercise reported greater enjoyment than those who engaged in high intensity exercise; these differences did not emerge in the control condition. People's trait levels of experienced LAP ("actual LAP") were not related to their enjoyment of calming (vs. exciting) activities. Together, these findings provide evidence that people derive more enjoyment from activities that match their ideal affect. The authors discuss the implications of these findings for AVT as well as interventions aimed at enhancing well-being. (PsycINFO Database Record PMID- 28650190 TI - A method for characterizing semantic and lexical properties of sentence completions in traumatic brain injury. AB - Clinical investigations of individuals with chronic stage traumatic brain injury (TBI) showing mild-to-moderate levels of residual impairment largely use standardized neuropsychological assessments to measure executive functioning. The Hayling Sentence Completion Test (HSCT) relies upon several executive functions but detects cognitive impairments across studies inconsistently. We sought to (a) further characterize sentence completions on the HSCT by quantifying their semantic and lexical properties and (b) investigate cognitive components important for HSCT performance. A sample of 108 mild-to-moderate participants with TBI underwent a comprehensive neuropsychological assessment that evaluated verbal ability, working memory, processing speed, task switching, and inhibitory control. Multiple regression analyses suggest that these 5 cognitive components differentially contribute to describing HSCT performance and measures of semantic and lexical properties of unconnected sentence completions. Across all 3 measures, verbal ability was most predictive of performance, while inhibitory control was the least predictive. Working memory capacity also predicted HSCT performance, while processing speed and task switching ability predicted lexical measures. We present a method for quantitatively measuring the semantic and lexical properties of generated words on the HSCT and how these additional measures relate to executive functions. (PsycINFO Database Record PMID- 28650191 TI - Perceived problem-solving deficits and suicidal ideation: Evidence for the explanatory roles of thwarted belongingness and perceived burdensomeness in five samples. AB - Perceived social problem-solving deficits are associated with suicide risk; however, little research has examined the mechanisms underlying this relationship. The interpersonal theory of suicide proposes 2 mechanisms in the pathogenesis of suicidal desire: intractable feelings of thwarted belongingness (TB) and perceived burdensomeness (PB). This study tested whether TB and PB serve as explanatory links in the relationship between perceived social problem-solving (SPS) deficits and suicidal thoughts and behaviors cross-sectionally and longitudinally. The specificity of TB and PB was evaluated by testing depression as a rival mediator. Self-report measures of perceived SPS deficits, TB, PB, suicidal ideation, and depression were administered in 5 adult samples: 336 and 105 undergraduates from 2 universities, 53 homeless individuals, 222 primary care patients, and 329 military members. Bias-corrected bootstrap mediation and meta analyses were conducted to examine the magnitude of the direct and indirect effects, and the proposed mediation paths were tested using zero-inflated negative binomial regressions. Cross-sectionally, TB and PB were significant parallel mediators of the relationship between perceived SPS deficits and ideation, beyond depression. Longitudinally and beyond depression, in 1 study, both TB and PB emerged as significant explanatory factors, and in the other, only PB was a significant mediator. Findings supported the specificity of TB and PB: Depression and SPS deficits were not significant mediators. The relationship between perceived SPS deficits and ideation was explained by interpersonal theory variables, particularly PB. Findings support a novel application of the interpersonal theory, and bolster a growing compendium of literature implicating perceived SPS deficits in suicide risk. (PsycINFO Database Record PMID- 28650192 TI - Prediction and moderation of improvement in cognitive-behavioral and psychodynamic psychotherapy for panic disorder. AB - OBJECTIVE: To identify variables predicting psychotherapy outcome for panic disorder or indicating which of 2 very different forms of psychotherapy-panic focused psychodynamic psychotherapy (PFPP) or cognitive-behavioral therapy (CBT) would be more effective for particular patients. METHOD: Data were from 161 adults participating in a randomized controlled trial (RCT) including these psychotherapies. Patients included 104 women; 118 patients were White, 33 were Black, and 10 were of other races; 24 were Latino(a). Predictors/moderators measured at baseline or by Session 2 of treatment were used to predict change on the Panic Disorder Severity Scale (PDSS). RESULTS: Higher expectancy for treatment gains (Credibility/Expectancy Questionnaire d = -1.05, CI95% [-1.50, 0.60]), and later age of onset (d = -0.65, CI95% [-0.98, -0.32]) were predictive of greater change. Both variables were also significant moderators: patients with low expectancy of improvement improved significantly less in PFPP than their counterparts in CBT, whereas this was not the case for patients with average or high levels of expectancy. When patients had an onset of panic disorder later in life (>=27.5 years old), they fared as well in PFPP as CBT. In contrast, at low and mean levels of onset age, CBT was the more effective treatment. CONCLUSIONS: Predictive variables suggest possibly fruitful foci for improvement of treatment outcome. In terms of moderation, CBT was the more consistently effective treatment, but moderators identified some patients who would do as well in PFPP as in CBT, thereby widening empirically supported options for treatment of this disorder. (PsycINFO Database Record PMID- 28650193 TI - Evaluation of an open-access CBT-based Internet program for social anxiety: Patterns of use, retention, and outcomes. AB - OBJECTIVE: Internet-delivered cognitive-behavioral therapy (ICBT) has been established as both efficacious and effective in reducing symptoms of social anxiety. However, most research has been conducted in controlled settings, and little is known regarding the utility of such programs in an open-access format. The present study examined the use, adherence, and effectiveness of Joyable, an open-access, Internet-delivered, coach-supported CBT-based intervention for social anxiety. METHOD: Participants were 3,384 registered users (Mage [SD] = 29.82 [7.89]; 54% male) that created an account between 2014 and 2016. Characteristics of use, factors related to attrition and adherence, and within group outcomes were examined. The primary outcome measure was the Social Phobia Inventory. RESULTS: On average, participants remained in the program for 81.02 days (SD = 60.50), during which they completed 12.14 activities (SD = 11.09) and 1.53 exposures (SD = 3.18). About half (57%) had contact with a coach. Full adherence to the program was achieved by 16% of participants, a rate higher than previously published open-access studies of ICBT. Social anxiety symptoms were significantly reduced for participants that engaged in the program, with medium within-group effects from baseline through the cognitive restructuring module (d = 0.63-0.76) and large effects from baseline through the exposure module (d = 1.40-1.83). Response rates were high (72%). Exposures and coach contact were significant predictors of retention and outcome. CONCLUSIONS: This open-access online CBT-based program is effective in reducing social anxiety symptoms and has the potential to extend Internet-based mental health services to socially anxious individuals unwilling or unable to seek face-to-face evidence-based therapy. (PsycINFO Database Record PMID- 28650194 TI - Remotely delivering real-time parent training to the home: An initial randomized trial of Internet-delivered parent-child interaction therapy (I-PCIT). AB - OBJECTIVE: Remote technologies are increasingly being leveraged to expand the reach of supported care, but applications to early child-behavior problems have been limited. This is the first controlled trial examining video-teleconferencing to remotely deliver behavioral parent training to the home setting with a live therapist. METHOD: Racially/ethnically diverse children ages 3-5 years with disruptive behavior disorders, and their caregiver(s), using webcams and parent worn Bluetooth earpieces, participated in a randomized trial comparing Internet delivered parent-child interaction therapy (I-PCIT) versus standard clinic-based PCIT (N = 40). Major assessments were conducted at baseline, midtreatment, posttreatment, and 6-month follow-up. Linear regressions and hierarchical linear modeling using maximum-likelihood estimation were used to analyze treatment satisfaction, diagnoses, symptoms, functioning, and burden to parents across conditions. RESULTS: Intent-to-treat analyses found 70% and 55% of children treated with I-PCIT and clinic-based PCIT, respectively, showed "treatment response" after treatment, and 55% and 40% of children treated with I-PCIT and clinic-based PCIT, respectively, continued to show "treatment response" at 6 month follow-up. Both treatments had significant effects on children's symptoms and burden to parents, and many effects were very large in magnitude. Most outcomes were comparable across conditions, except that the rate of posttreatment "excellent response" was significantly higher in I-PCIT than in clinic-based PCIT, and I-PCIT was associated with significantly fewer parent-perceived barriers to treatment than clinic-based PCIT. Both treatments were associated with positive engagement, treatment retention, and very high treatment satisfaction. CONCLUSION: Findings build on the small but growing literature supporting the promising role of new technologies for expanding the delivery of behavioral parent training. (PsycINFO Database Record PMID- 28650196 TI - Effects of circadian cortisol on the development of a health habit. AB - OBJECTIVE: Given the impact of individuals' habits on health, it is important to study how behaviors can become habitual. Cortisol has been well documented to have a role in habit formation. This study aimed to elucidate the influence of the circadian rhythm of cortisol on habit formation in a real-life setting. METHOD: Forty-eight students were followed for 90 days during which they attempted to adopt a health behavior (psoas iliac stretch). They were randomly assigned to perform the stretch either upon waking in the morning, when cortisol concentrations are high, or before evening bedtime, when cortisol levels approach the nadir. A smartphone application was used to assess the Self-Report Behavioural Automaticity Index every day and to provide reminders for salivary measurements every 30 days. The speed of the health habit formation process was calculated by modeling the learning curves. RESULTS: Extrapolation of the curves indicated that the morning group achieved automaticity at an earlier time point (105.95 days) than did the evening group (154.01 days). In addition, the cortisol level during the performance of the health behavior was identified as a significant mediator of the time point when the health behavior became habitual. CONCLUSION: The present findings suggest that the time course of the development of healthy habits depends on the time of the day and that the effect is mediated through diurnal variation in cortisol levels. Future studies are now needed to determine to what extent cortisol rhythmicity can help individuals to adopt new health behaviors. (PsycINFO Database Record PMID- 28650195 TI - Mechanisms underlying mindfulness-based addiction treatment versus cognitive behavioral therapy and usual care for smoking cessation. AB - OBJECTIVE: To examine cognitive and affective mechanisms underlying mindfulness based addiction treatment (MBAT) versus cognitive-behavioral therapy (CBT) and usual care (UC) for smoking cessation. METHOD: Participants in the parent study from which data were drawn (N = 412; 54.9% female; 48.2% African American, 41.5% non-Latino White, 5.4% Latino, 4.9% other; 57.6% annual income <$30,000) were randomized to MBAT (n = 154), CBT (n = 155), or UC (n = 103). From quit date through 26 weeks postquit, participants completed measures of emotions, craving, dependence, withdrawal, self-efficacy, and attentional bias. Biochemically confirmed 7-day smoking abstinence was assessed at 4 and 26 weeks postquit. Although the parent study did not find a significant treatment effect on abstinence, mixed-effects regression models were conducted to examine treatment effects on hypothesized mechanisms, and indirect effects of treatments on abstinence were tested. RESULTS: Participants receiving MBAT perceived greater volitional control over smoking and evidenced lower volatility of anger than participants in both other treatments. However, there were no other significant differences between MBAT and CBT. Compared with those receiving UC, MBAT participants reported lower anxiety, concentration difficulties, craving, and dependence, as well as higher self-efficacy for managing negative affect without smoking. Indirect effects of MBAT versus UC on abstinence occurred through each of these mechanisms. CONCLUSIONS: Whereas several differences emerged between MBAT and UC, MBAT and CBT had similar effects on several of the psychosocial mechanisms implicated in tobacco dependence. Results help to shed light on similarities and differences between mindfulness-based and other active smoking cessation treatments. (PsycINFO Database Record PMID- 28650198 TI - Buffer or amplifier? Longitudinal effects of social support for functional autonomy/dependence on older adults' chronic pain experiences. AB - OBJECTIVE: This longitudinal study aimed to investigate (a) the moderating role of formal social support for functional autonomy versus dependence on the relationship between pain intensity and pain-related disability among older adults with chronic pain and (b) the mediating role of pain-related self-efficacy and pain-related fear in this moderation. METHOD: One hundred and seventy older adults (Mage = 78.0; SD = 8.7) with chronic musculoskeletal pain participated in a 3-month prospective study, with 3 measurement moments. Participants filled out the Formal Social Support for Autonomy and Dependence in Pain Inventory, the Portuguese versions of the Brief Pain Inventory, the Pain Self-Efficacy Questionnaire, and the Tampa Scale of Kinesiophobia. RESULTS: Using structural equation modeling, it was found that perceived promotion of autonomy, at Time 1, moderated the relationship between pain intensity (T1) and pain-related disability (T2); this moderation was fully mediated by pain-related self-efficacy (T2). Perceived promotion of dependence was not a significant moderator. CONCLUSIONS: These findings highlight the importance of social support for functional autonomy in buffering the impact of pain intensity on older adults' pain-related disability. Also, they clarify the role of pain-related self efficacy in this effect. Implications for the development of intervention programs, with formal caregivers, to reduce the impact of chronic pain on older adults' healthy ageing process, are discussed. (PsycINFO Database Record PMID- 28650197 TI - Anger, hostility, and hospitalizations in patients with heart failure. AB - OBJECTIVE: Heart failure patients have a high hospitalization rate, and anger and hostility are associated with coronary heart disease morbidity and mortality. Using structural equation modeling, this prospective study assessed the predictive validity of anger and hostility traits for cardiovascular and all cause rehospitalizations in patients with heart failure. METHOD: 146 heart failure patients were administered the STAXI and Cook-Medley Hostility Inventory to measure anger, hostility, and their component traits. Hospitalizations were recorded for up to 3 years following baseline. Causes of hospitalizations were categorized as heart failure, total cardiac, noncardiac, and all-cause (sum of cardiac and noncardiac). RESULTS: Measurement models were separately fit for Anger and Hostility, followed by a Confirmatory Factor Analysis to estimate the relationship between the Anger and Hostility constructs. An Anger model consisted of State Anger, Trait Anger, Anger Expression Out, and Anger Expression In, and a Hostility model included Cynicism, Hostile Affect, Aggressive Responding, and Hostile Attribution. The latent construct of Anger did not predict any of the hospitalization outcomes, but Hostility significantly predicted all-cause hospitalizations. Analyses of individual trait components of each of the 2 models indicated that Anger Expression Out predicted all-cause and noncardiac hospitalizations, and Trait Anger predicted noncardiac hospitalizations. None of the individual components of Hostility were related to rehospitalizations or death. CONCLUSION: The construct of Hostility and several components of Anger are predictive of hospitalizations that were not specific to cardiac causes. Mechanisms common to a variety of health problems, such as self-care and risky health behaviors, may be involved in these associations. (PsycINFO Database Record PMID- 28650199 TI - An initial application of a biopsychosocial framework to predict posttraumatic stress following pediatric injury. AB - OBJECTIVE: Each year millions of children suffer from unintentional injuries that result in poor emotional and physical health. This study examined selected biopsychosocial factors (i.e., child heart rate, peritrauma appraisals, early coping, trauma history) to elucidate their roles in promoting emotional recovery following injury. The study evaluated specific hypotheses that threat appraisals (global and trauma-specific) and coping would predict subsequent posttraumatic stress symptoms (PTSS), that coping would mediate the association between early and later PTSS, and that heart rate would predict PTSS and appraisals would mediate this association. METHOD: Participants were 96 children hospitalized for injury and assessed at 3 time points: T1 (within 2 weeks of injury), T2 (6-week follow-up), and T3 (12-week follow-up). Participants completed measures of trauma history and appraisals at T1, coping at T2, and PTSS at T1, T2, and T3. Heart rate was abstracted from medical records. Structural equation modeling was employed to evaluate study hypotheses. RESULTS: Heart rate was not associated with PTSS or appraisals. Models including trauma history, appraisals, coping, and PTSS were constructed to test other study hypotheses and fit the data well. T1 global and trauma-specific threat appraisals were associated with T1 PTSS; T2 avoidant coping was a significant mediator of the relation between T1 and T3 PTSS. CONCLUSION: Findings confirm a role for appraisals and coping in the development of PTSS over the weeks following pediatric injury. Early appraisals and avoidant coping may be appropriate targets for prevention and early intervention. Future researchers should further explicate the utility of a biopsychosocial framework in predicting PTSS. (PsycINFO Database Record PMID- 28650201 TI - Underreporting of End-of-Life Decisions in Critical Care Trials: A Call to Modify the Consolidated Standards of Reporting Trials Statement. PMID- 28650202 TI - The Burden of Specific Symptoms Reported by Survivors After Critical Illness. PMID- 28650200 TI - The cortisol:C-reactive protein ratio and negative affect reactivity in depressed adults. AB - OBJECTIVE: We evaluated the effect of the cortisol (CORT) to high sensitivity C reactive protein (hsCRP) ratio on stress-induced negative affect (NA) reactivity and whether the association was moderated by depressive symptom severity and gender. The CORT/CRP ratio was used to evaluate the integrity of the negative feedback loop between the hypothalamic-pituitary-adrenal axis and inflammatory response system. METHOD: Basal CORT and hsCRP levels were measured in fasting blood samples from 198 medication-free and nonsmoking healthy men and women. Depressive symptom severity was assessed using the Hamilton Rating Scale for Depression (HAMD). NA ratings were collected at baseline and at the completion of the laboratory stressors, the Anger Recall Interview (ARI) and reading. RESULTS: Adjusting for potential confounders and baseline NA, analysis revealed a significant relationship between CORT/CRP ratio and NA reactivity to ARI as a function of depressive symptom severity. Simple effects revealed that for participants with high HAMD, decreasing CORT/CRP ratio, suggestive of an insufficient CORT release relative to higher hsCRP, predicted increasing stress induced NA reactivity. For participants with low HAMD, the CORT/CRP ratio failed to predict NA reactivity. Gender did not moderate the joint effect of depressive symptom severity and the CORT/CRP ratio on stress-induced NA reactivity. CONCLUSIONS: This is the first study to document that a premorbid dysregulation of the neuro-immune relationship, characterized by an insufficient release of CORT in conjunction with higher CRP, plays a role in stress sensitivity, and specifically NA reactivity, in individuals with elevated levels of depression symptoms. (PsycINFO Database Record PMID- 28650203 TI - How Efficacious is Danshen (Salvia miltiorrhiza) Dripping Pill in Treating Angina Pectoris? Evidence Assessment for Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: More than 230 randomized controlled trials (RCTs) of danshen dripping pill (DSP) and isosorbide dinitrate (ISDN) in treating angina pectoris after the first preferred reporting items for systematic reviews and meta-analyses compliant comprehensive meta-analysis were published in 2010. Other meta-analyses had flaws in study selection, statistical meta-analysis, and evidence assessment. This study completed the meta-analysis with an extensive assessment of the evidence. METHODS: RCTs published from 1994 to 2016 on DSP and ISDN in treating angina pectoris for at least 4 weeks were included. The risk of bias (RoB) of included RCTs was assessed with the Cochrane's tool for assessing RoB. Meta analyses based on a random-effects model were performed on two outcome measures: symptomatic (SYM) and electrocardiography (ECG) improvements. Subgroup analysis, sensitivity analysis, metaregression, and publication bias analysis were also conducted. The evidence strength was evaluated with the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) method. RESULTS: Among the included 109 RCTs with 11,973 participants, 49 RCTs and 5042 participants were new (after 2010). The RoB of included RCTs was high in randomization and blinding. Overall effect sizes in odds ratios for DSP over ISDN were 2.94 (95% confidence interval [CI]: 2.53-3.41) on SYM (n = 108) and 2.37 (95% CI: 2.08 2.69) by ECG (n = 81) with significant heterogeneities (I2 = 41%, p < 0.0001 on SYM and I2 = 44%, p < 0.0001 on ECG). Subgroup, sensitivity, and metaregression analyses showed consistent results without publication bias. However, the evidence strength was low in GRADE. CONCLUSION: The efficacy of DSP was still better than ISDN in treating angina pectoris, but the confidence decreased due to high RoB and heterogeneities. PMID- 28650204 TI - XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough. AB - RATIONALE: Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough. OBJECTIVES: XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. METHODS: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes. MEASUREMENTS AND MAIN RESULTS: XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, -19.3 +/- 16.4) coughs; placebo, -1.8 +/- 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7 +/- 16.9 coughs/h; placebo, 0.4 +/- 13.7 coughs/h; P = 0.41). CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registered with www.clinicaltrialsregister.eu (2014-000306-36). PMID- 28650205 TI - Investigation of the Hepatoprotective Effect of Prunus mume Sieb. et Zucc Extract in a Mouse Model of Alcoholic Liver Injury Through High-Resolution Metabolomics. AB - This study aimed to identify the changes in the metabolomics profile of liver damage caused by alcohol consumption and verify the beneficial effect of Prunus mume Sieb. et Zucc extract (PME) in protection of alcohol-induced injury by attenuating the level of identified metabolites. Mice were treated with PME and saline or untreated once daily for 5 days, followed by alcohol injection. The plasma samples were analyzed using liquid chromatography-mass spectrometry-based high-resolution metabolomics followed by a multivariate statistical analysis using MetaboAnalyst 3.0 to obtain significantly expressed metabolites, using a false discovery rate threshold of q = 0.05. Metabolites were annotated using Metlin database and mapped through Kyoto Encyclopedia of Genes and Genomes (KEGG). Among 4999 total features, 101 features were significant among alcohol- and PME-treated mice groups. All the samples cluster showed a clear separation in the heat map, and the scores plot of orthogonal partial least squares discriminant analysis (OPLS-DA) model discriminated the three groups. Phosphatidylcholine, Saikosaponin BK1, Ganoderiol I, and N-2-[4-(3,3 dimethylallyloxy) phenyl] ethylcinnamide were among the significant compounds with a low intensity in alcohol group compared to PME group, suggesting that these compounds have a relation in the development of PME's protective effect. The study confirms the hepatoprotective, antioxidant, and anti-inflammatory effects of PME against alcohol-induced liver steatosis, inflammation, and apoptosis. PMID- 28650206 TI - Socioenvironmental, Personal, and Behavioral Correlates of Severe Obesity among an Ethnically/Racially Diverse Sample of US Adolescents. AB - BACKGROUND: Severe obesity among adolescents, also known as class 2 and 3 obesity, is increasing in prevalence, yet, little is known about adolescents with severe obesity. The objective of this study was to identify the socioenvironmental, personal, and behavioral correlates of severe obesity among an ethnically/racially diverse sample of US adolescents. METHODS: A cross sectional analysis of data from participants in the EAT 2010 study (n = 2706) was conducted. Adolescents completed in-class surveys, and height and weight were measured. Severe obesity was defined as a BMI >=120% of the 95th percentile or >=35 kg/m2; class 1 obesity as a BMI >=95th percentile but below severe obesity cut points, overweight as a BMI <95th percentile but >=85th percentile, and normal weight as a BMI <85th but >5th percentile. General linear models were used to identify differences between adolescents by weight status, adjusted for covariates. RESULTS: Nine percent of adolescents had severe obesity. Compared with peers of other weight statuses, a greater proportion of adolescents with severe obesity reported parental encouragement to diet and peer weight teasing. Adolescents with severe obesity also reported lower self-esteem and body satisfaction. Binge eating was three times as prevalent among adolescents with severe obesity compared with peers of normal weight and twice as prevalent as among peers with class 1 obesity. CONCLUSIONS: Adolescents with severe obesity report several unique socioenvironmental, personal, and behavioral concerns that may diminish quality of life and may predict increased weight gain over time. PMID- 28650207 TI - Epicardial, pericardial and total cardiac fat and cardiovascular disease in type 2 diabetic patients with elevated urinary albumin excretion rate. AB - Background We evaluated the association of cardiac adipose tissue including epicardial adipose tissue and pericardial adipose tissue with incident cardiovascular disease and mortality, coronary artery calcium, carotid intima media thickness and inflammatory markers. Design A prospective study of 200 patients with type 2 diabetes and elevated urinary albumin excretion rate (UAER). Methods Cardiac adipose tissue was measured from baseline echocardiography. The composite endpoint comprised incident cardiovascular disease and all-cause mortality. Coronary artery calcium, carotid intima media thickness and inflammatory markers were measured at baseline. Cardiac adipose tissue was investigated as continuous and binary variable. Analyses were performed unadjusted (model 1), and adjusted for age, sex (model 2), body mass index, low density lipoprotein cholesterol, smoking, glycated haemoglobin, and systolic blood pressure (model 3). Results Patients were followed-up after 6.1 years for non-fatal cardiovascular disease ( n = 29) or mortality ( n = 23). Cardiac adipose tissue ( p = 0.049) and epicardial adipose tissue ( p = 0.029) were associated with cardiovascular disease and mortality in model 1. When split by the median, patients with high cardiac adipose tissue had a higher risk of cardiovascular disease and mortality than patients with low cardiac adipose tissue in unadjusted (hazard ratio 1.9, confidence interval: 1.1; 3.4, p = 0.027) and adjusted (hazard ratio 2.0, confidence interval: 1.1; 3.7, p = 0.017) models. Cardiac adipose tissue ( p = 0.033) was associated with baseline coronary artery calcium (model 1) and interleukin-8 (models 1-3, all p < 0.039). Conclusions In type 2 diabetes patients without coronary artery disease, high cardiac adipose tissue levels were associated with increased risk of incident cardiovascular disease or all-cause mortality even after accounting for traditional cardiovascular disease risk factors. High cardiac adipose tissue amounts were associated with subclinical atherosclerosis (coronary artery calcium) and with the pro-atherogenic inflammatory marker interleukin-8. PMID- 28650208 TI - When Using Facebook to Avoid Isolation Reduces Perceived Social Support. AB - A survey (N = 316) examined how other-directed Facebook use driven by fear of social isolation affects users' perception of social support they possess. As predicted, those higher on fear of isolation were more likely to (a) closely monitor others' activities for self-evaluation (i.e., social comparison) and (b) regulate their self-presentation to garner social approval (i.e., other-directed self-presentation), but less likely to (c) express their true inner feelings and thoughts (i.e., inner-directed self-presentation) on Facebook. Social comparison, in turn, lowered perceived social support among heavy Facebook users, whereas inner-directed self-presentation heightened it. Other-directed self-presentation had no significant effect on perceived social support. Results indicate that the desire to avoid social isolation may paradoxically diminish perceived social support by promoting social comparison, while suppressing the expression of true self on Facebook. PMID- 28650210 TI - Bronchial Provocation Testing Can Be Improved by Using Dry Powder Adenosine Instead of Nebulized Adenosine Monophosphate. PMID- 28650211 TI - Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases; rule of thumb. AB - Response to: Reyes A, Marti J, Marfa S et al. Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases. Future Oncol. 13(10), 875-882 (2017). PMID- 28650209 TI - The intestinal barrier: a fundamental role in health and disease. AB - INTRODUCTION: The gastrointestinal mucosa constitutes a critical barrier where millions of microbes and environmental antigens come in close contact with the host immune system. Intestinal barrier defects have been associated with a broad range of diseases and therefore denote a new therapeutic target. Areas covered: This review is based on an extensive literature search in PubMed of how the intestinal barrier contributes to health and as a trigger for disease. It discusses the anatomy of the intestinal barrier and explains the available methods to evaluate its function. Also reviewed is the importance of diet and lifestyle factors on intestinal barrier function, and three prototypes of chronic diseases (inflammatory bowel disease, celiac disease and nonalcoholic fatty liver disease) that have been linked to barrier defects are discussed. Expert commentary: The intestinal barrier has been investigated by various methods, but correlation of results across studies is difficult, representing a major shortcoming in the field. New upcoming techniques and research on the effect of barrier-restoring therapeutics may improve our current understanding of the gut barrier, and provide a step forward towards personalised medicine. PMID- 28650212 TI - Choosing Medication Alternatives During Breastfeeding, Avoiding Alternative Facts. PMID- 28650213 TI - Visualisation of upper limb activity using spirals: A new approach to the assessment of daily prosthesis usage. AB - BACKGROUND: Current outcome measures used in upper limb myoelectric prosthesis studies include clinical tests of function and self-report questionnaires on real world prosthesis use. Research in other cohorts has questioned both the validity of self-report as an activity assessment tool and the relationship between clinical functionality and real-world upper limb activity. Previously,1 we reported the first results of monitoring upper limb prosthesis use. However, the data visualisation technique used was limited in scope. STUDY DESIGN: Methodology development. OBJECTIVES: To introduce two new methods for the analysis and display of upper limb activity monitoring data and to demonstrate the potential value of the approach with example real-world data. METHODS: Upper limb activity monitors, worn on each wrist, recorded data on two anatomically intact participants and two prosthesis users over 1 week. Participants also filled in a diary to record upper limb activity. Data visualisation was carried out using histograms, and Archimedean spirals to illustrate temporal patterns of upper limb activity. RESULTS: Anatomically intact participants' activity was largely bilateral in nature, interspersed with frequent bursts of unilateral activity of each arm. At times when the prosthesis was worn prosthesis users showed very little unilateral use of the prosthesis (~20-40 min/week compared to ~350 min/week unilateral activity on each arm for anatomically intact participants), with consistent bias towards the intact arm throughout. The Archimedean spiral plots illustrated participant-specific patterns of non-use in prosthesis users. CONCLUSION: The data visualisation techniques allow detailed and objective assessment of temporal patterns in the upper limb activity of prosthesis users. Clinical relevance Activity monitoring offers an objective method for the assessment of upper limb prosthesis users' (PUs) activity outside of the clinic. By plotting data using Archimedean spirals, it is possible to visualise, in detail, the temporal patterns of upper limb activity. Further work is needed to explore the relationship between traditional functional outcome measures and real world prosthesis activity. PMID- 28650214 TI - Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women. AB - DNA methylation affects expression of associated genes and may contribute to the missing genetic effects from genome-wide association studies of osteoporosis. To improve insight into the mechanisms of postmenopausal osteoporosis, we combined transcript profiling with DNA methylation analyses in bone. RNA and DNA were isolated from 84 bone biopsies of postmenopausal donors varying markedly in bone mineral density (BMD). In all, 2529 CpGs in the top 100 genes most significantly associated with BMD were analyzed. The methylation levels at 63 CpGs differed significantly between healthy and osteoporotic women at 10% false discovery rate (FDR). Five of these CpGs at 5% FDR could explain 14% of BMD variation. To test whether blood DNA methylation reflect the situation in bone (as shown for other tissues), an independent cohort was selected and BMD association was demonstrated in blood for 13 of the 63 CpGs. Four transcripts representing inhibitors of bone metabolism-MEPE, SOST, WIF1, and DKK1-showed correlation to a high number of methylated CpGs, at 5% FDR. Our results link DNA methylation to the genetic influence modifying the skeleton, and the data suggest a complex interaction between CpG methylation and gene regulation. This is the first study in the hitherto largest number of postmenopausal women to demonstrate a strong association among bone CpG methylation, transcript levels, and BMD/fracture. This new insight may have implications for evaluation of osteoporosis stage and susceptibility. PMID- 28650216 TI - Brachylaimiasis: Brachylaima spp. (Digenea: Brachylaimidae) Metacercariae Parasitizing the Edible Snail Cornu aspersum (Helicidae) in Spanish Public Marketplaces and Health-Associated Risk Factors. AB - The edible land snail Cornu aspersum (Pulmonata: Stylommatophora) acts as a second intermediate host in the terrestrial life cycle of Brachylaima spp. trematodes, harboring unencysted metacercariae in its kidney. The ingestion of undercooked infected snails by humans may allow metacercariae to potentially develop to adult stage in the intestine, causing brachylaimiasis, as already seen in Australia. The prevalence and dynamics of C. aspersum parasitization by Brachylaima spp. metacercariae in specimens intended for human consumption in Spanish marketplaces were studied. In total, 3,710 C. aspersum specimens were analyzed over 5 yr, which were obtained from public marketplaces in the Spanish cities of Barcelona, Bilbao, Madrid, Tudela, Valencia, and Zaragoza. The overall prevalence was 41.97% (95% CI: 40.38-45.56%). The Tudela marketplace had the highest values for both the seasonal prevalence and abundance in all studies during autumn (93.57% and 3.09, respectively). This market also gave the highest individual metacercarial burden recorded, 212 metacercariae in a single specimen. Overall, the highest prevalence of Brachylaima spp. occurred in autumn (58.65%) and the lowest in winter (22.64%). There was a seasonal effect on prevalence, which increased from summer to autumn and then decreased in winter. In total, 96 experimental Brachylaima adults were obtained from the metacercariae parasitizing the analyzed snails. These were identified through morphometric tools (principal component analysis) as Brachylaima mascomai (56 in Barcelona, 1 in Bilbao, 7 in Tudela, and 3 in Valencia), and Brachylaima llobregatensis (17 in Barcelona, 8 in Bilbao, 1 in Valencia, and 3 in Zaragoza). Logistic regression modeling, conducted to predict the probability of purchasing parasitized snails using city and season as predictors showed a correct prediction overall of 79.0%, with a significant (p = 0.001) risk effect in the Barcelona-autumn interaction (2.551 38.442), a significant (p = 0.049) protection effect in the Tudela-spring interaction (0.076-0.997), a significant (p < 0.001) risk effect in the Tudela autumn interaction (4.330-78.584), and a significant (p = 0.014) protection effect in the Valencia-spring interaction (0.033-0.687). The high overall prevalence of Brachylaima spp. metacercariae should be a matter of concern for public health authorities, mainly in countries where C. aspersum is consumed. PMID- 28650215 TI - Tolerability of Topical Tocilizumab Eyedrops in Dogs: A Pilot Study. AB - PURPOSE: The aim of this study was to examine the tolerability of topical tocilizumab eyedrops in normal dogs and to assess whether this preparation alters tear film cytokine levels or conjunctival cytokine mRNA expression. METHODS: Two percent tocilizumab eyedrops were administered to the right eyes and artificial tears to the left eyes of 10 dogs with no anterior segment pathology 3 times daily for 4 weeks. Portable slit-lamp examinations and Schirmer tear testing were performed at baseline and day 1 week 4, as well as 2 weeks after treatment (week 6). Schirmer strips were also used to collect tears for analyses of cytokine levels using multiplex bead array. Median levels of 8 cytokines in the tear film [interferon gamma (IFN-gamma), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-1beta, IL-2, IL-6, IL-8, and IL-10] were compared among tocilizumab-treated and control eyes. Conjunctival biopsies from both eyes were collected at week 4, and mRNA levels of cytokines were also evaluated. Blood samples were collected at baseline and at the end of treatment to monitor for changes in complete blood count, basic metabolic panel, or liver function tests. RESULTS: At week 4, conjunctival biopsies and tear samples showed no significant differences in either tear cytokine or mRNA levels for IFN-gamma, TNF-alpha, IL 2, IL-6, IL-8, and IL-10. There was no evidence of local irritation or changes in bloodwork results from the topical tocilizumab formulation. CONCLUSIONS: Topical application of tocilizumab eyedrops was well tolerated when used on healthy dog eyes in this pilot study. PMID- 28650217 TI - A new outlook on sporadic flowering of bamboo. AB - Moso bamboo (Phyllostachys edulis) is a temperate grass species with a tree-like habitus and an unusual reproduction strategy. While flowering is irregular and infrequent, new clonal bamboo shoots are established from an underground rhizome network during the spring season. In our previous study, we performed transcriptome analyses using bamboo shoot buds to understand the initiation of bamboo stem elongation. Interestingly, the expression profile in the shoot apical meristem (SAM) region of young bamboo shoots is similar to that of other plants. Specifically, some of the genes that control the timing of flowering and floral development are active in the SAM region. This data raises the question of how bamboo shoots start to elongate, and why they do not proceed to a seasonal cycle of flowering. Our analyses of the activation of shoot buds and subsequent rapid stem elongation provide new hints to unravel the unpredictable flowering pattern of bamboo. In this short communication, we discuss how bamboo might coordinate and integrate the vegetative and reproductive phases in relation to shoot emergence and stem elongation. PMID- 28650218 TI - Bilateral surgical damage of the central tegmental tract resulting in bilateral hypertrophic olivary degeneration: An MRI case report. AB - Hypertrophic olivary degeneration (HOD) is a rare trans-synaptic neuronal degeneration of the inferior olivary nucleus caused by an injury to the dentato rubro-olivary connection, also known as Guillain-Mollaret triangle. It leads to hypertrophy of the affected nucleus rather than atrophy and is characterized by hyperintensity on T2-weighted images. Unilateral and bilateral cases are described. We present a case of a 70-year-old patient affected by a tumor inside the fourth ventricle who suffered from diplopia and right seventh cranial nerve palsy. He underwent surgery and developed left seventh cranial nerve palsy. Three months after resection, magnetic resonance imaging revealed the appearance of bilateral HOD. This is the first report of bilateral HOD occurrence after surgical bilateral damage of the rubro-olivary fibers running in central tegmental tracts. PMID- 28650220 TI - Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants. PMID- 28650219 TI - Interrogating cell division errors using random and chromosome-specific missegregation approaches. AB - Accurate segregation of the duplicated genome in mitosis is essential for maintaining genetic stability. Errors in this process can cause numerical and/or structural chromosome abnormalities - hallmark genomic features commonly associated with both tumorigenesis and developmental disorders. A cell-based approach was recently developed permitting inducible missegregation of the human Y chromosome by selectively disrupting kinetochore assembly onto the Y centromere. Although this strategy initially requires several steps of genetic manipulation, it is easy to use, highly efficient and specific for the Y without affecting the autosomes or the X, and does not require cell cycle synchronization or mitotic perturbation. Here we describe currently available tools for studying chromosome segregation errors, aneuploidy, and micronuclei, as well as discuss how the Y-specific missegregation system has been used to elucidate how chromosomal micronucleation can trigger a class of extensive rearrangements termed chromothripsis. The combinatorial use of these different tools will allow unresolved aspects of cell division defects and chromosomal instability to be experimentally explored. PMID- 28650221 TI - A Cross-Cultural Study of Risky Online Self-Presentation. AB - The use of social media is pervasive among young adults. However, not all posted content is beneficial to their self-presentation, but can have negative and damaging consequences. This study investigated how individual differences in self monitoring and impulsiveness influence risky online self-presentation in British and Italian samples. British participants (n = 88) were more likely to post comments and images related to their alcohol and drug use, whereas Italian (n = 90) participants posted more offensive content and personal information. High self-monitoring and high impulsiveness was positively predictive of risky self presentation online regardless of nationality, highlighting the normative influence of social media culture, and the influence of both spontaneous and deliberative behavior on posting inappropriate content online. These novel insights regarding the way young adults present themselves on social network sites could help explain differences in self-presentation. PMID- 28650222 TI - Understanding Nomophobia: Structural Equation Modeling and Semantic Network Analysis of Smartphone Separation Anxiety. AB - This study explicates nomophobia by developing a research model that identifies several determinants of smartphone separation anxiety and by conducting semantic network analyses on smartphone users' verbal descriptions of the meaning of their smartphones. Structural equation modeling of the proposed model indicates that personal memories evoked by smartphones encourage users to extend their identity onto their devices. When users perceive smartphones as their extended selves, they are more likely to get attached to the devices, which, in turn, leads to nomophobia by heightening the phone proximity-seeking tendency. This finding is also supplemented by the results of the semantic network analyses revealing that the words related to memory, self, and proximity-seeking are indeed more frequently used in the high, compared with low, nomophobia group. PMID- 28650223 TI - Alcohol-Related Posts from Young People on Social Networking Sites: Content and Motivations. AB - Many young people place alcohol-related posts on social networking sites (SNS) which can result in undesirable effects. Although several recent studies have investigated the occurrence of alcohol-related SNS use, it is neither clear (a) what type of alcohol posts are placed on SNS, (b) the motivations to place alcohol posts, nor (c) which young people are most likely to place alcohol posts. This study addressed these three goals. A large cross-sectional study among young participants (12-30 years; N = 561) assessed the posting of different types of alcohol posts, the motivations to (not) post these posts, and potential differences in posting between subgroups (i.e., in terms of age, gender, and religion). Participants reported that they most often placed moderate, instead of more extreme, alcohol posts, in particular, when alcohol was present in the post "by chance". Furthermore, they indicated to post alcohol-related content mostly for entertainment reasons. Finally, we found differences in self-reported posting and motivations to post according to age, gender, and religion. These findings provide relevant implications for future interventions aiming to decrease alcohol posts, for example, by making participants aware of their posting behavior and by targeting specific at risk groups. Future research should explore the effectiveness of such intervention strategies and should investigate whether alcohol posts lead to an underestimation of alcohol-related risks. PMID- 28650224 TI - Efficacy of Structured Organizational Change Intervention on HIV Testing in Correctional Facilities. AB - This article presents findings from a multisite cluster randomized trial of a structured organizational change intervention for improving HIV testing services in jails and prisons. Matched pairs of prison and jail facilities were randomized to experimental and control conditions; all facilities received baseline training about best practices in HIV testing and other HIV services and selected an area of HIV services on which to focus improvement efforts. The experimental facilities formed local change teams and were provided external coaching based on the Network for the Improvement of Addiction Treatment (NIATx) process improvement model. Difference-indifference analyses indicate a significant relative increase in HIV testing in the experimental compared to the control condition. Meta-analyses across the matched pairs indicated a small to medium effect of increased testing overall. The results indicate that the local change team model can achieve significant increases in HIV testing in correctional facilities. Implications for HIV testing policies and challenges for expanding testing are discussed. PMID- 28650225 TI - Men's Perceptions of Treatment as Prevention in South Africa: Implications for Engagement in HIV Care and Treatment. AB - While South Africa provides universal access to treatment, HIV testing and antiretroviral therapy (ART) uptake remains low, particularly among men. Little is known about community awareness of the effects of treatment on preventing transmission, and how this information might impact HIV service utilization. This qualitative study explored understandings of treatment as prevention (TasP) among rural South African men. Narratives emphasized the know value of ART for individual health, but none were aware of its preventive effects. Many expressed that preventing transmission to partners would incentivize testing, earlier treatment, and adherence in the absence of symptoms, and could reduce the weight of a diagnosis. Doubts about TasP impacts on testing and care included enduring risks of stigma and transmission. TasP information should be integrated into clinic-based counseling for those utilizing services, and community-based education for broader reach. Pairing TasP information with alternative testing options may increase engagement among men reluctant to be seen at clinics. PMID- 28650226 TI - Correlates of HIV Risks Among Women on Probation and Parole. AB - This article examines HIV risks among a sample of 406 women on probation and parole with lifetime histories of victimization who were recruited from an urban community in the southern U.S. Guided by the Comprehensive Health Seeking and Coping Paradigm, we analyze the significance of sociodemographic characteristics, substance use, posttraumatic stress disorder, and social support in relationship to three sexual risks and one drug use risk using multivariable regression. Findings indicate that substance use is a significant correlate of nearly all HIV risks examined, including lifetime sexual partners and sexual partners during the past 12 months. Age, race/ethnicity, homelessness, lifetime traumatic event exposure, regular use of alcohol to intoxication and other drugs, functional social support, and substance use treatment in the past 12 months are associated with specific HIV risks. The findings identify potential targets to address in HIV prevention with women on probation and parole who have experienced victimization. PMID- 28650227 TI - Facilitators and Barriers to Participation in PrEP HIV Prevention Trials Involving Transgender Male and Female Adolescents and Emerging Adults. AB - Despite the disproportionate burden of HIV facing transgender youth, they continue to be under-represented in studies to provide an empirical basis for pre exposure prophylaxis (PrEP) programs that can meet the unique needs of this population. This study examined facilitators and barriers to participation in a PrEP adherence study, determined through an online survey administered to 90 transgender male and 60 transgender female 14-21-year-olds attracted to cisgender male sexual partners. Approximately 50% reported likely to participate in the PrEP study. Participation facilitators included prior sexual and health service experiences and study access to PrEP and health services. Participation barriers included lack of concern about HIV, potential medication side effects, the logistics of quarterly meetings, remembering to take PrEP daily, and reluctance to discuss gender identity with study staff. Results suggest that successful recruitment and retention of transgender youth in PrEP prevention studies warrant protocols designed to address these barriers. PMID- 28650228 TI - CDC'S Testing Makes Us Stronger (TMUS) Campaign: Was Campaign Exposure Associated With HIV Testing Behavior Among Black Gay and Bisexual Men? AB - This study assessed exposure among Black gay, bisexual, and other men who have sex with men (BMSM) to a communication campaign, Testing Makes Us Stronger (TMUS), and its association with HIV testing to determine campaign effectiveness. Data from an online survey (N = 3,105) were analyzed using propensity score weight-adjusted logistic regression to examine the effect of exposure on HIV testing. Among BMSM aged 18-44 (n = 702), 43.2% reported TMUS exposure. The majority of those exposed were aged 25-34 (54%), HIV-negative (65%), and had some college education (87%). TMUS exposure was associated with reported increased HIV testing behaviors at 6- and 12-month frequencies. Communication campaigns with clear implementation strategies, focused objectives, and online and event presence can be associated with longer-term outcomes such as HIV testing. PMID- 28650229 TI - HIV Treatment and Re-infection Beliefs Predict Sexual Risk Behavior of Men Who Have Sex With Men. AB - We examined whether beliefs about antiretroviral (ART) efficacy and reinfection prospectively predicted subsequent condomless anal intercourse (CAI). Men who have sex with men in San Francisco (N = 773) were recruited for a longitudinal study using time-location sampling. HIV-negative men were more likely to have sero-discordant receptive CAI and HIV-positive men were more likely to have sero discordant insertive CAI if they previously reported these behaviors at baseline and reported less concern about HIV transmission due to ART. HIV-positive men were more likely to report sero-concordant CAI at follow-up if they reported this behavior at baseline. Previous sexual behavior was consistently the strongest predictor of future sexual behavior. Previous sexual behavior and optimistic beliefs about ART for treatment and prevention predicted subsequent sexual behavior with sero-discordant partners. Since individual-level and population level benefits of ART depend on persons maintaining adequate drug concentrations, prevention messages should continue emphasizing treatment adherence and practicing a combination of risk-reduction strategies. PMID- 28650230 TI - Get Real: Evaluation of a Community-Level HIV Prevention Intervention for Young MSM Who Engage in Episodic Substance Use. AB - Young men who have sex with men (YMSM) have high rates of recreational drug use and binge drinking that are related to increases in unprotected sex and HIV risk. We describe the development of a community-level intervention focused on MSM ages 15 to 29 who identify as Black or White and who reported episodic use of alcohol and/or drugs. Intervention content included culturally-relevant role model stories and peer outreach. Outcome measures, including number of partners and a risk score indicating risk for HIV from protected or unprotected insertive or receptive anal sex, were examined over 36 months in a sample of YMSM in Philadelphia, the intervention site, and Baltimore, the comparison site. Decreases in risk scores over time were significantly larger in the intervention sample than in the comparison sample. Effects were greater for YMSM who engaged in binge drinking and/or marijuana use, compared to those who used other drugs. PMID- 28650231 TI - Pharmacokinetics and safety of ceftiofur crystalline free acid in New Zealand White rabbits (Oryctolagus cuniculus). AB - OBJECTIVE To determine the pharmacokinetics and adverse effects following SC administration of ceftiofur crystalline free acid (CCFA) in New Zealand White rabbits. ANIMALS 6 adult sexually intact female New Zealand White rabbits. PROCEDURES Each rabbit was administered 40 mg of CCFA/kg SC. A blood sample was obtained immediately before (0 minutes), at 5 and 30 minutes after, and at 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 95, 120, 144, and 168 hours after administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured. Pharmacokinetic parameters were calculated. For each rabbit, body weight, food consumption, fecal output, and injection site were monitored. Minimum inhibitory concentrations of ceftiofur for 293 bacterial isolates from rabbit clinical samples were determined. RESULTS Mean +/- SD peak plasma concentration of CFAE and time to maximum plasma concentration were 33.13 +/- 10.15 MUg/mL and 1.75 +/- 0.42 hours, respectively. The mean terminal half life of CFAE was 42.6 +/- 5.2 hours. Plasma CFAE concentration was > 4 MUg/mL for approximately 24 hours and > 1 MUg/mL for at least 72 hours after CCFA administration. An apparently nonpainful subcutaneous nodule developed at the injection site in 3 of 6 rabbits. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that CCFA (40 mg/kg) could be administered SC every 24 to 72 hours to New Zealand White rabbits to treat infections with ceftiofur-susceptible bacteria. Single-dose administration of CCFA resulted in minimal adverse effects. Additional studies are needed to evaluate the effects of repeated CCFA administration in New Zealand White rabbits. PMID- 28650232 TI - Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in cats after oral, intravenous, and intraperitoneal administration of cyclophosphamide. AB - OBJECTIVE To characterize pharmacokinetics of cyclophosphamide and 4 hydoxycyclophosphamide (4-OHCP) in the plasma of healthy cats after oral, IV, and IP administration of cyclophosphamide. ANIMALS 6 healthy adult cats. PROCEDURES Cats were randomly assigned to receive cyclophosphamide (200 mg/m2) via each of 3 routes of administration (oral, IV, and IP); there was a 30-day washout period between successive treatments. Plasma samples were obtained at various time points for up to 8 hours after administration. Samples were treated with semicarbazide hydrochloride to trap the 4-OHCP in stable form, which allowed for cyclophosphamide and trapped 4-OHCP to be simultaneously measured by use of tandem mass spectrometry. Pharmacokinetic parameters were determined from drug concentration-versus-time data for both cyclophosphamide and 4-OHCP. RESULTS Cyclophosphamide was tolerated well regardless of route of administration. Pharmacokinetic parameters for 4-OHCP were similar after oral, IV, and IP administration. Area under the concentration-time curve for cyclophosphamide was lower after oral administration than after IV or IP administration. CONCLUSIONS AND CLINICAL RELEVANCE Cyclophosphamide can be administered interchangeably to cats as oral, IV, and IP formulations, which should provide benefits with regard to cost and ease of administration to certain feline patients. PMID- 28650233 TI - Evaluation of clinical and tenoscopic findings in the carpal flexor sheath of horses. AB - OBJECTIVE To evaluate clinical and tenoscopic findings in a large group of horses undergoing surgery of the carpal flexor sheath (CFS) and determine whether any of the presurgical clinical signs were associated with tenoscopic findings. ANIMALS 242 horses that had undergone diagnostic and therapeutic tenoscopy of the CFS because of aseptic tenosynovitis. PROCEDURES Medical and tenoscopic video records (when available) of 242 horses undergoing tenoscopy of the CFS at a single equine clinic between January 2005 and June 2014 were reviewed. Tenoscopic findings were categorized as present or absent, and tears in the deep digital flexor tendon (DDFT) were subjectively graded according to severity. Logistic regression analysis was used to examine whether presurgical clinical findings were associated with intraoperative tenoscopic findings. RESULTS 242 horses (411 limbs) were evaluated by use of tenoscopy. An exostosis was detected in 228 horses (379 limbs) and was often multipartite. Most exostoses were found medial to, or within, the sagittal plane at the caudal margin of the scar on the distal physis of the radius. Effusion in the CFS was associated with tears in the DDFT. Other presurgical clinical findings were not predictive of intrathecal findings. CONCLUSIONS AND CLINICAL RELEVANCE Synovial effusion was predictive of DDFT lesions within the CFS but was not predictive of the severity of lesions. Further studies will be necessary to determine whether any tenoscopic findings are associated with reduced athletic performance and to assess the effect of surgical intervention in affected horses. PMID- 28650234 TI - Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain MU-opioid receptor mRNA expression in ball pythons. AB - OBJECTIVE To quantify plasma fentanyl concentrations (PFCs) and evaluate antinociceptive and respiratory effects following application of transdermal fentanyl patches (TFPs) and assess cerebrospinal MU-opioid receptor mRNA expression in ball pythons (compared with findings in turtles). ANIMALS 44 ball pythons (Python regius) and 10 turtles (Trachemys scripta elegans). PROCEDURES To administer 3 or 12 MUg of fentanyl/h, a quarter or whole TFP (TFP-3 and TFP-12, respectively) was used. At intervals after TFP-12 application in snakes, PFCs were measured by reverse-phase high-pressure liquid chromatography. Infrared heat stimuli were applied to the rostroventral surface of snakes to determine thermal withdrawal latencies after treatments with no TFP (control [n = 16]) and TFP-3 (8) or TFP-12 (9). Breathing frequency was measured in unrestrained controls and TFP-12-treated snakes. MU-Opioid receptor mRNA expression in brain and spinal cord tissue samples from snakes and turtles (which are responsive to MU-opioid receptor agonist drugs) were quantified with a reverse transcription PCR assay. RESULTS Mean PFCs were 79, 238, and 111 ng/mL at 6, 24, and 48 hours after TFP-12 application, respectively. At 3 to 48 hours after TFP-3 or TFP-12 application, thermal withdrawal latencies did not differ from pretreatment values or control treatment findings. For TFP-12-treated snakes, mean breathing frequency significantly decreased from the pretreatment value by 23% and 41% at the 24- and 48-hour time points, respectively. Brain and spinal cord tissue MU-opioid receptor mRNA expressions in snakes and turtles did not differ. CONCLUSIONS AND CLINICAL RELEVANCE In ball pythons, TFP-12 application resulted in high PFCs, but there was no change in thermal antinociception, indicating resistance to MU opioid-dependent antinociception in this species. PMID- 28650235 TI - Evaluation of infrared thermography as a diagnostic tool to predict heat stress events in feedlot cattle. AB - OBJECTIVE To determine whether infrared thermographic images obtained the morning after overnight heat abatement could be used as the basis for diagnostic algorithms to predict subsequent heat stress events in feedlot cattle exposed to high ambient temperatures. ANIMALS 60 crossbred beef heifers (mean +/- SD body weight, 385.8 +/- 20.3 kg). PROCEDURES Calves were housed in groups of 20 in 3 pens without any shade. During the 6 am and 3 pm hours on each of 10 days during a 14-day period when the daily ambient temperature was forecasted to be > 29.4 degrees C, an investigator walked outside each pen and obtained profile digital thermal images of and assigned panting scores to calves near the periphery of the pen. Relationships between infrared thermographic data and panting scores were evaluated with artificial learning models. RESULTS Afternoon panting score was positively associated with morning but not afternoon thermographic data (body surface temperature). Evaluation of multiple artificial learning models indicated that morning body surface temperature was not an accurate predictor of an afternoon heat stress event, and thermographic data were of little predictive benefit, compared with morning and forecasted weather conditions. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated infrared thermography was an objective method to monitor beef calves for heat stress in research settings. However, thermographic data obtained in the morning did not accurately predict which calves would develop heat stress later in the day. The use of infrared thermography as a diagnostic tool for monitoring heat stress in feedlot cattle requires further investigation. PMID- 28650237 TI - Racing performance of Standardbred trotting horses undergoing surgery of the carpal flexor sheath and age- and sex-matched control horses. AB - OBJECTIVE To determine factors affecting race speed in Swedish Standardbred horses undergoing surgery of the carpal flexor sheath (CFS), to investigate whether preoperative racing speed was associated with specific intraoperative findings and whether horses returned to racing, and to compare the performance of horses undergoing surgery of the CFS with that of age- and sex-matched control horses. ANIMALS 149 Swedish Standardbred trotters undergoing surgery of the CFS and 274 age- and sex-matched control horses. PROCEDURES Medical records of CFS horses were examined. Racing data for CFS and control horses were retrieved from official online records. Generalizing estimating equations were used to examine overall and presurgery racing speeds and the association of preoperative clinical and intraoperative findings with preoperative and postoperative speeds. Multivariable regression analysis was used to examine career earnings and number of career races. Kaplan-Meier survival analysis was used to compare career longevity between CFS and control horses. RESULTS CFS horses were significantly faster than control horses. The CFS horses that raced before surgery were slower as they approached the surgery date, but race speed increased after surgery. There were 124 of 137 (90.5%) CFS horses that raced after surgery. No intrathecal pathological findings were significantly associated with preoperative racing speed. Career longevity did not differ between CFS and control horses. CONCLUSIONS AND CLINICAL RELEVANCE Horses undergoing surgery of the CFS had a good prognosis to return to racing after surgery. Racing careers of horses undergoing surgery of the CFS were not significantly different from racing careers of control horses. PMID- 28650238 TI - Three-dimensional inverse dynamics of the forelimb of Beagles at a walk and trot. AB - OBJECTIVE To perform 3-D inverse dynamics analysis of the entire forelimb of healthy dogs during a walk and trot. ANIMALS 5 healthy adult Beagles. PROCEDURES The left forelimb of each dog was instrumented with 19 anatomic markers. X-ray fluoroscopy was used to optimize marker positions and perform scientific rotoscoping for 1 dog. Inverse dynamics were computed for each dog during a walk and trot on the basis of data obtained from an infrared motion-capture system and instrumented quad-band treadmill. Morphometric data were obtained from a virtual reconstruction of the left forelimb generated from a CT scan of the same dog that underwent scientific rotoscoping. RESULTS Segmental angles, torque, and power patterns were described for the scapula, humerus, ulna, and carpus segments in body frame. For the scapula and humerus, the kinematics and dynamics determined from fluoroscopy-based data varied substantially from those determined from the marker-based data. The dominant action of scapular rotation for forelimb kinematics was confirmed. Directional changes in the torque and power patterns for each segment were fairly consistent between the 2 gaits, but the amplitude of those changes was often greater at a trot than at a walk. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that control of the forelimb joints of dogs is similar for both a walk and trot. Rotation of the forelimb around its longitudinal axis and motion of the scapula should be reconsidered in the evaluation of musculoskeletal diseases, especially before and after treatment or rehabilitation. PMID- 28650239 TI - Use of gadoxetic acid for computed tomographic cholangiography in healthy dogs. AB - OBJECTIVE To evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs. ANIMALS 8 healthy dogs. PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure. Serial CT scans were obtained at predetermined times after contrast injection. In part 2, 4 dogs were sedated and underwent CT angiography 85 minutes after IV administration of the high contrast dose. Contrast enhancement of the biliary tract on all scans was objectively assessed by measurement of CT attenuation and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. All measurements were compared over time and between contrast doses for the dogs of part 1. Subjective measurements were compared between the sedated dogs of part 2 and anesthetized dogs of part 1. RESULTS Enhancement of the biliary tract was positively associated with contrast dose and time after contrast injection. Optimal enhancement was achieved 65 minutes after contrast injection. Subjective visualization of most biliary structures did not differ significantly between sedated and anesthetized dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated CT cholangiography with gadoxetic acid was feasible in sedated dogs. The high contrast dose provided better visualization of biliary structures than the low dose; CT scans should be obtained 65 minutes after contrast injection. PMID- 28650240 TI - Development of a clinical spasticity scale for evaluation of dogs with chronic thoracolumbar spinal cord injury. AB - OBJECTIVE To develop a spasticity scale for dogs with chronic deficits following severe spinal cord injury (SCI) for use in clinical assessment and outcome measurement in clinical trials. ANIMALS 20 chronically paralyzed dogs with a persistent lack of hind limb pain perception caused by an acute SCI at least 3 months previously. PROCEDURES Spasticity was assessed in both hind limbs via tests of muscle tone, clonus, and flexor and extensor spasms adapted from human scales. Measurement of patellar clonus duration and flexor spasm duration and degree was feasible. These components were used to create a canine spasticity scale (CSS; overall score range, 0 to 18). Temporal variation for individual dogs and interrater reliability were evaluated. Gait was quantified with published gait scales, and CSS scores were compared with gait scores and clinical variables. Owners were questioned regarding spasticity observed at home. RESULTS 20 dogs were enrolled: 18 with no apparent hind limb pain perception and 2 with blunted responses; 5 were ambulatory. Testing was well tolerated, and scores were repeatable between raters. Median overall CSS score was 7 (range, 3 to 11), and flexor spasms were the most prominent finding. Overall CSS score was not associated with age, SCI duration, lesion location, or owner-reported spasticity. Overall CSS score and flexor spasm duration were associated with gait scores. CONCLUSIONS AND CLINICAL RELEVANCE The CSS could be used to quantify hind limb spasticity in dogs with chronic thoracolumbar SCI and might be a useful outcome measure. Flexor spasms may represent an integral part of stepping in dogs with severe SCI. PMID- 28650242 TI - Evaluation of a telemetric gastrointestinal pill for continuous monitoring of gastrointestinal temperature in horses at rest and during exercise. AB - OBJECTIVE To evaluate use of a telemetric gastrointestinal (GI) pill to continuously monitor GI temperature in horses at rest and during exercise and to compare time profiles of GI temperature and rectal temperature. ANIMALS 8 Standardbred horses. PROCEDURES Accuracy and precision of the GI pill and a rectal probe were determined in vitro by comparing temperature measurements with values obtained by a certified resistance temperature detector (RTD) in water baths at various temperatures (37 degrees , 39 degrees , and 41 degrees C). Subsequently, both GI and rectal temperature were recorded in vivo in 8 horses over 3 consecutive days. The GI temperature was recorded continuously, and rectal temperature was recorded for 3.5 hours daily. Comparisons were made between GI temperature and rectal temperature for horses at rest, during exercise, and after exercise. RESULTS Water bath evaluation revealed good agreement between the rectal probe and RTD. However, the GI pill systematically underestimated temperature by 0.14 degrees C. In vivo, GI temperature data were captured with minimal difficulties. Most data loss occurred during the first 16 hours, after which the mean +/- SD data loss was 8.6 +/- 3.7%. The GI temperature was consistently and significantly higher than rectal temperature with an overall mean temperature difference across time of 0.27 degrees C (range, 0.22 degrees to 0.32 degrees C). Mean measurement cessation point for the GI pill was 5.1 +/- 1.0 days after administration. CONCLUSIONS AND CLINICAL RELEVANCE This study revealed that the telemetric GI pill was a reliable and practical method for real time monitoring of GI temperature in horses. PMID- 28650243 TI - Antigenicity of mesenchymal stem cells in an inflamed joint environment. AB - OBJECTIVE To determine whether major histocompatability complex (MHC) class II expression in equine mesenchymal stem cells (MSCs) changes with exposure to a proinflammatory environment reflective of an inflamed joint. SAMPLE Cryopreserved bone marrow-derived MSCs from 12 horses and cartilage and synovium samples from 1 horse euthanized for reasons other than lameness. PROCEDURES In part 1 of a 3 part study, the suitability of a quantitative reverse transcriptase PCR (qRT-PCR) assay for measurement of MHC class II expression in MSCs following stimulation with interferon (IFN)-gamma was assessed. In part 2, synoviocyte-cartilage cocultures were or were not stimulated with interleukin (IL)-1beta (10 ng/mL) to generate conditioned media that did and did not (control) mimic an inflamed joint environment. In part 3, a qRT-PCR assay was used to measure MSC MHC class II expression after 96 hours of incubation with 1 of 6 treatments (control conditioned medium, IL-1beta-conditioned medium, and MSC medium alone [untreated control] or with IL-1beta [10 ng/mL], tumor necrosis factor-alpha [10 ng/mL], or IFN-gamma [100 ng/mL]). RESULTS The qRT-PCR assay accurately measured MHC class II expression. Compared with MHC class II expression for MSCs exposed to the untreated control medium, that for MSCs exposed to IL-1beta was decreased, whereas that for MSCs exposed to IFN-gamma was increased. Neither the control conditioned nor tumor necrosis factor-alpha medium altered MHC class II expression. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that MSC exposure to proinflammatory cytokine IL-1beta decreased MHC class II expression and antigenicity. Treatment of inflamed joints with allogeneic MSCs might not be contraindicated, but further investigation is warranted. PMID- 28650244 TI - Cardiac output measured by use of electrocardiogram-gated 64-slice multidector computed tomography, echocardiography, and thermodilution in healthy dogs. AB - OBJECTIVE To evaluate the accuracy of cardiac output (CO) estimated by use of ECG gated multidetector CT (MDCT) and 1-, 2-, and 3-D echocardiography and by use of thermodilution. ANIMALS 6 healthy hound-cross dogs. PROCEDURES Electrocardiogram gated contrast-enhanced 64-slice MDCT and 1-, 2-, and 3-D echocardiography were performed on each dog. The CO for ECG-gated MDCT was calculated as volumetric measurements of stroke volume multiplied by mean heart rate. Echocardiographic left ventricle end-diastolic volumes and end-systolic volumes were measured by use of the Teichholz method (1-D echocardiography) and a single-plane method of disks (2-D echocardiography). Real-time 3-D echocardiographic left ventricle volumes were measured with 3-D functional analysis software on right long-axis and left apical views. The CO of each dog was measured in triplicate by use of thermodilution. Mean CO values, correlations, and limits of agreement for MDCT, echocardiographic modalities, and thermodilution were compared. RESULTS CO measured by use of MDCT, 2-D echocardiography, and 3-D echocardiography had the strongest correlations with CO measured by use of thermodilution. No significant difference in CO was detected between MDCT, any echocardiographic method, and thermodilution. Bland-Altman analysis revealed a systematic underestimation of CO derived by use of MDCT, 2-D echocardiography, and 3-D echocardiography. CONCLUSIONS AND CLINICAL RELEVANCE Use of MDCT, 2-D echocardiography, and 3-D echocardiography to measure CO in healthy dogs was feasible. Measures of CO determined by use of 3-D echocardiography on the right long-axis view were strongly correlated with CO determined by use of thermodilution, with little variance and slight underestimation. PMID- 28650245 TI - Letter in reply: Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases. AB - In response to: S Sabour. Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases; rule of thumb. PMID- 28650246 TI - Economic Outcomes of First-Line Regimen Switching Among Stable Patients with HIV. AB - BACKGROUND: Although switching of antiretroviral therapy (ART) is a valid approach for addressing treatment failure in patients with human immunodeficiency virus (HIV), ART changes among those who are well maintained on their current regimens may lead to the development of new side effects or resistance. OBJECTIVE: To examine the effect of first-line regimen switching on subsequent health care utilization and cost among stable HIV patients. METHODS: This was a retrospective claims data study of adult patients with HIV who initiated ART between 2007 and 2013 and had been treated with their initial regimens for at least 6 continuous months. Those with evidence of pregnancy or HIV-2 were excluded. Patients who underwent an ART change were assigned to a switcher cohort; a nonswitcher cohort was then generated by matching up to 20 nonswitchers for each switcher, with replacement. The index date was the date of the first ART change for switchers and was the claim date closest to the corresponding switcher's switch date for nonswitchers. Patient characteristics at baseline and post-index annualized health care utilization and costs were analyzed descriptively and with multivariable models. Analyses were performed in the full population and among patients designated as virologically stable (had undetectable viral ribonucleic acid [RNA] for 90 days pre-index) and virologically and clinically stable (had undetectable viral RNA and no apparent clinical reason for switching ART). RESULTS: The study population consisted of 6,983 individuals, which included 927 switchers (168 virologically stable; 55 virologically+clinically stable), who were matched with replacement with 18,511 nonswitcher comparators. The switcher cohort was 88.8% male (mean age 43.8 years). Mean preindex and follow-up treatment durations for switchers and nonswitchers were 1.8 years and 1.5 years, respectively; demographic characteristics, pre-index treatment duration, and follow-up duration were similar between cohorts. Significantly more nonswitchers than switchers had a first-line efavirenz-based regimen (67.2% vs. 47.8%, P < 0.001). In the virologically stable subset, follow-up annualized health care utilization for switchers versus nonswitchers, respectively, was 14.8 versus 12.3 ambulatory visits (P < 0.05), 0.8 versus 0.9 emergency department visits (P = 0.652), and 0.05 versus 0.05 inpatient hospitalizations (P = 0.915). Follow-up annualized health care costs were $37,120 for switchers versus $31,771 for nonswitchers (P < 0.05), with the difference driven largely by pharmacy costs. Multivariable adjusted follow-up annualized health care costs were 8.9% higher among switchers versus nonswitchers (P < 0.01), and switchers also had a shorter time to subsequent ART regimen change (P < 0.001). Results were similar for the virologically+clinically stable subset. CONCLUSIONS: In this large, real-world population, stable patients with HIV who switched from their first-line ART regimens had significantly higher health care costs than those who did not change therapies, suggesting that ART regimen changes may be costly and should be undertaken only when clinically warranted. DISCLOSURES: This work was funded by Bristol-Myers Squibb (BMS), which participated in the design of the study, interpretation of the data, revision of the manuscript, and the decision to submit the manuscript for publication. Rosenblatt is an employee and stock owner of BMS; Villasis-Keever was an employee of BMS at the time this study was conducted and is currently an employee of Janssen. Buikema is an employee and stock owner of Optum, and Seare, Bengston, Johnson, and Cao are employees of Optum, which was contracted by BMS to conduct the study. Optum contracts with pharmaceutical companies, such as Janssen, Merck, EMD Serano, GlaxoSmithKline, and Gilead, to conduct research in HIV. Optum is also a subsidiary of a health plan that has interest in managing the health and associated costs of patients with HIV. Study concept and design were contributed by Rosenblatt and Buikema, along with the other authors. Cao and Johnson took the lead in data collection, along with Buikema, Seare, and Bengston. Data interpretation was performed by Buikema, Seare, Bengston, and Villasis-Keever. The manuscript was written by Buikema and Bengston, along with Rosenblatt, Seare, Johnson and Villasis-Keever, and revised by Rosenblatt, Villasis-Keever, and Johnson, along with the other authors. PMID- 28650247 TI - Burden of Alcohol Abuse or Dependence Among Long-Term Opioid Users with Chronic Noncancer Pain. AB - BACKGROUND: Substance abuse disorders among chronic noncancer pain (CNCP) patients add to the clinical challenges and economic burden of caring for such patients. Despite potential risks, some CNCP patients with a history of alcohol abuse or dependence (AAD) and pain that is refractory to nonopioid treatment options may still need opioids for pain management. However, there is a lack of data on adverse outcomes in long-term opioid users with CNCP and a history of substance abuse or AAD disorders. OBJECTIVE: To compare adverse outcomes and all cause health care costs among CNCP patients on long-term opioid treatment with and without a previous diagnosis of AAD. METHODS: Using MarketScan claims databases (2006-2012), CNCP patients with >= 90 days of opioid supply after CNCP diagnosis and continuous enrollment 12 months before CNCP diagnosis (baseline period) and 12 months after opioid start (post-index period) were identified. AAD was defined by diagnosis codes at any time before opioid initiation. Outcomes included opioid overdose, accident, and injury episodes identified by ICD-9-CM diagnoses codes. T-tests and Mann-Whitney tests compared continuous measures, and chi-square and Fisher's exact tests compared categorical measures between those with and without AAD. Multivariable analyses for outcomes were conducted, adjusting for baseline differences between cohorts. RESULTS: Of 21,203 CNCP patients with long-term opioid treatment, 750 (3.5%) had an AAD diagnosis before opioid initiation. AAD patients were significantly younger (48.4 [SD +/- 11.4] years vs. 52.8 [SD +/- 14.8] years), less likely to be enrolled in Medicare (17% commercial vs. 4% Medicare), and more likely to be male (67% vs. 48%; all P < 0.001). There were no differences in type or number of CNCP diagnoses or Charlson Comorbidity Index (CCI) scores. Patients with AAD had significantly higher rates of depression and anxiety diagnoses, antidepressant and benzodiazepine use, and drug abuse/dependence diagnoses in the baseline period. Twelvemonth post-index rates of opioid overdose (1.2% vs. 0.2%), accident (7.3% vs. 2.8%), and injury (46.1% vs. 36.8%) were greater in the AAD cohort (all P < 0.001). The differences were nonsignificant for accidents in multivariable analyses. While mean prescription costs were similar ($3,562 vs. $3,312; P = 0.212), AAD patients had significantly higher mean all-cause medical costs ($28,429 vs. $22,082; P < 0.001) and significantly higher all-cause total health care costs ($31,991 vs. $25,395; P < 0.001). The cost differences remained significant in multivariable analyses. CONCLUSIONS: In the first year after long-term opioid initiation, CNCP patients with a previous AAD diagnosis had 5 times the rate of opioid overdose, 2.3 times the rate of accidents, 1.2 times the rate of injury, and higher all cause health care costs compared with those not diagnosed with AAD. DISCLOSURES: Funding for this research study and resultant publication was provided by Teva Global Health Economics and Outcomes Research, which fully reviewed the manuscript. Gajria and Yeung are employees of Teva Pharmaceuticals. White was an employee of Teva Pharmaceuticals at the time this research was conducted. Blumberg and Coutinho are employees of Xcenda, which received research funding from Teva Pharmaceuticals for the conduct of this study and for the preparation of this manuscript. Katz has received research funding and consulting fees from Teva Pharmaceuticals unrelated to this study. Study concept and design were contributed by Katz, White, and Blumberg, along with Coutinho and Yeung. Coutinho took the lead in data collection, assisted by the other authors. Data interpretation was performed by Blumberg, Katz, and Gajria, along with the other authors. The manuscript was written by Gajria, Yeung, Coutinho, and Blumberg, along with Katz and White, and revised by Gajria, Blumberg, Katz, and Coutinho, along with Yeung and White. PMID- 28650248 TI - Health Services Utilization Among Fee-for-Service Medicare and Medicaid Patients Under Age 65 with Behavioral Health Illness at an Urban Safety Net Hospital. AB - BACKGROUND: In 2011, fee-for-service patients with both Medicare and Medicaid (dual eligible) sustained $319.5 billion in health care costs. OBJECTIVE: To describe the emergency department (ED) use and hospital admissions of adult dual eligible patients aged under 65 years who used an urban safety net hospital. METHODS: This was a retrospective database analysis of patients aged between 18 and 65 years with Medicare and Medicaid, who used an urban safety net academic health center between January 1, 2011, and December 31, 2011. We compared patients with and without behavioral health illness. The main outcome measures were hospital admission and ED use. Chi-square and Wilcoxon rank-sum tests were used for descriptive statistics on categorical and continuous variables, respectively. Greedy propensity score matching was used to control for confounding factors. Rate ratios (RR) and 95% confidence intervals (CI) were determined after matching and after adjusting for those variables that remained significantly different after matching. RESULTS: In 2011, 10% of all fee-for service dual eligible patients aged less than 65 years in Massachusetts were seen at Boston Medical Center. Data before propensity score matching showed significant differences in age, sex, race/ethnicity, marital status, education, employment, physical comorbidities, and Charlson Comorbidity Index score between patients with and without behavioral health illness. Analysis after propensity score matching found significant differences in sex, Hispanic race, and other education and employment status. Compared with patients without behavioral health illness, patients with behavioral health illness had a higher RR for hospital admissions (RR = 2.07; 95% CI = 1.81-2.38; P < 0.001) and ED use (RR = 1.61; 95% CI = 1.46-1.77; P < 0.001). Results were robust after adjusting for characteristics that remained statistically significantly different after propensity score matching. CONCLUSIONS: Adult dual eligible patients aged less than 65 years with behavioral health illness in the Medicaid fee-for-service plan had significantly higher rates of hospital admission and ED use compared with dual eligible patients without behavioral health illness at the largest urban safety net medical center in New England. Safety net hospitals care for a large proportion of dual eligible patients with behavioral health illness. Further research is needed to elucidate the systems-related and patient-centered factors contributing to the utilization behaviors of this patient population. DISCLOSURES: This research was funded in part by a National Research Service Award (T3HP10028-14-01). The authors have no conflicts of interests to disclose. Cancino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design were contributed by Cancino, Jack, and Burgess, with assistance from Cremieux. Cancino and Cremieux took the lead in data collection, along with Jack and Burgess, and data interpretation was performed by Jarvis, Cummings, and Cooper, along with the other authors. The manuscript was written primarily by Cancino, along with Jack and Burgess, and revised primarily by Cancino, along with the other authors. PMID- 28650249 TI - Inpatient Admissions and Costs Associated with Persistent Use of Dalfampridine Extended-Release in Multiple Sclerosis: A Claims Database Analysis. AB - BACKGROUND: While the clinical benefits of dalfampridine extended-release (D-ER) have been established in patients with multiple sclerosis (MS) through multiple clinical trials, there is limited real-world data on D-ER use, in particular the persistent use of D-ER, and associated acute care resource utilization and costs. OBJECTIVE: To examine the real-world association of D-ER use and inpatient admissions and costs among patients with MS. METHODS: This study was a retrospective observational claims analysis of the MarketScan database (April 2009-March 2014). Eligible patients consisted of adult enrollees aged 18-64 years who had (a) 12 months of continuous private plan enrollment preceding (baseline) and following (follow-up) the first D-ER claim; (b) >= 2 MS diagnosis codes with >= 1 during the baseline period; (c) >= 2 consecutive D-ER claims; and (d) no alternate gait-impairing etiologies during the baseline and follow-up periods. Patients were separated into 2 D-ER cohorts in the main analysis: persistent (>= 360 days of D-ER supply) and nonpersistent (< 360 days of supply) users. Sensitivity analyses were conducted, examining additional breakdowns of days of supply within the nonpersistent cohort. Inpatient admissions (all-cause and MS related) and health care expenditures were calculated and compared between the cohorts during follow-up using Wilcoxon rank-sum and chi-square tests. Regression models were conducted, controlling for age, sex, MS relapses, comorbidities, disease-modifying therapy use, and other baseline factors, including inpatient admissions and costs. RESULTS: Of 1,598 eligible patients, 719 (45.0%) were persistent D-ER users, and 879 (55.0%) were nonpersistent D-ER users. The 2 cohorts had similar demographic and clinical characteristics, with mean (SD) ages of 51.0 (8.4) and 50.6 (8.6) years and were 71.3% and 66.6% female, respectively. Compared with nonpersistent D-ER use, persistent D-ER use was associated with lower odds of all-cause inpatient admissions (OR = 0.58, P = 0.010) and MS related inpatient admissions (OR = 0.50, P = 0.004). Persistent use was also associated with lower inpatient expenditures for all-cause admissions ($669 vs. $1,515, P = 0.002) and MS-related admissions ($388 vs. $891, P = 0.008). CONCLUSIONS: Persistent D-ER use was associated with significantly lower rates of all-cause and MS-related inpatient admissions and costs. DISCLOSURES: Funding for this research and medical writing assistance was provided by Acorda Therapeutics. The study sponsor was involved in all stages of the study research and manuscript preparation. Guo and Niyazov were employees of Acorda Therapeutics at the time of this study and may own stock/stock options. Wu, Macaulay, Terasawa, and Schmerold are employees of Analysis Group, which received consultancy fees from Acorda Therapeutics for this project. Krieger was a consultant for Acorda Therapeutics for this project and has the following additional financial interests to report: consulting/advisory board work with Bayer, Biogen, EMD Serono, Novartis, Genentech, Genzyme, and Teva. Study concept and design were contributed by Guo, Niyazov, Macaulay, and Wu. Macaulay, Terasawa, Schmerold, and Wu helped prepare the data, and data interpretation was performed by Krieger, Guo, Niyazov, and Macaulay, along with Terasawa and Wu. The manuscript was written by Terasawa and Schmerold, along with Macaulay, and revised by all the authors. A portion of the current research was presented in poster format at the 2106 American Academy of Neurology Annual Meeting, which took place in Vancouver, BC, Canada, on April 15 21, 2016. PMID- 28650250 TI - A Retrospective, Longitudinal, Claims-Based Comparison of Concomitant Diagnoses Between Individuals with and Without Down Syndrome. AB - BACKGROUND: Individuals with Down syndrome (DS) experience various comorbidities in excess of the prevalence seen among the non-DS population. However, the extent of the excess burden of comorbidities specifically within commercially and publicly insured DS populations aged < 21 years is not currently known. OBJECTIVES: To (a) describe the most common diagnoses among individuals with DS who have either commercial or Medicaid insurance and (b) compare the prevalence of those diagnoses between DS cases and non-DS controls. METHODS: This was a longitudinal, retrospective study using health care claims of commercially insured and Medicaid-insured individuals in the Truven Health MarketScan Databases from 2008 to 2015. Individuals aged < 2, 2-5, 6-11, and 12-20 years with a DS diagnosis (cases; commercial: n = 15,948; Medicaid: n = 11,958) were matched to individuals without DS (controls; commercial: n = 47,844; Medicaid: n = 35,874) using a 1:3 ratio. The annual number of diagnoses was compared between cases and controls within age groups using t-tests, and the prevalence of the most common diagnoses was compared using chi-square tests. RESULTS: Cases in all age groups in both databases had more diagnoses annually than controls (mean =9 17 per year vs. 4-10 per year, P < 0.001), and the number of diagnoses decreased with age for cases and controls. Among the most common case diagnoses were upper respiratory infections (28.9%-59.1% vs. 19.5%-52.9%); suppurative otitis media (25.1%-56.8% vs. 8.7%-51.2%); nutrition/metabolic/developmental symptoms (37.9% 50.4% vs. 7.7%-10.6%); delays in development (22.8%-52.8% vs. 4.1%-10.9%); and general symptoms (35.1%-47.2% vs. 22.1%-37.2%), and the prevalence of each was greater among cases versus controls in all age groups in both databases (P < 0.001). The most common diagnoses among controls included some of the same as among cases, as well as acute pharyngitis (18.7%-31.8% vs. 19.2%-30.5%); allergic rhinitis (19.9%-24.3% vs. 15.3%-20.7%); viral/chlamydial infections (24.2%-26.6% vs. 17.7%-23.5%); and joint disorders (11.6% vs. 16.6%), and most were significantly more prevalent among cases (P < 0.05). CONCLUSIONS: Commercially insured and Medicaid-insured individuals aged < 21 years with DS experience a greater number and prevalence of concomitant diagnoses compared with non-DS individuals. Awareness of these common diagnoses could help facilitate the optimal care of these individuals by the pediatric health care community. DISCLOSURES: This study was sponsored and funded by Genentech. Truven Health Analytics, an IBM Company, receives payment from Genentech to conduct research, including the research for this study. Truven Health Analytics also receives payment from other pharmaceutical companies to conduct research. Kong and Evans are employed by Truven Health Analytics. Csoboth is employed by Genentech. Brixner reports fees paid to the University of Utah by Truven Health Analytics on her behalf for work related to this study. Hurley reports fees from Genentech for work on this study and for work outside of this study. At the time of this study, Visootsak was employed by F. Hoffman-LaRoche Pharmaceuticals, parent company of Genentech. All authors, including those affiliated with the study sponsor, were involved in the design of the study, interpretation of the data, writing of the manuscript, and the decision to submit the manuscript for publication. Study concept and design were contributed by Kong, Hurley, and Brixner, along with Evans. Kong and Evans collected the data, and data interpretation was performed by Csoboth, Visootsak, Brixner, and Hurley, with assistance from Kong. The manuscript was written by Evans, Kong, Hurley, and Brixner and revised by Kong, Hurley, Evans, and Brixner, with assistance from Csoboth and Visootsak. PMID- 28650251 TI - Managed Care Peer-Led Teaching: An Innovative Learning Approach Outside the College of Pharmacy Core Curriculum. AB - BACKGROUND: Managed care pharmacy is a growing field, but there are still limited educational opportunities available in pharmacy school core curricula. Students often seek self-directed learning opportunities to further explore the field. OBJECTIVES: To (a) evaluate practicality and effectiveness of a student-designed managed care pharmacy elective and (b) determine emerging best practices for design and sustainability of peer-led, self-directed courses. METHODS: A managed care elective course was designed as a student, peer-led course during the 2012 2013 school year at the University of Minnesota College of Pharmacy. As the course evolved, coordinators evaluated the effectiveness and sustainability of a student-led elective. The course required students to select a managed care topic of interest and deliver a discussion-based presentation. Teleconferencing was used to maximize participation and flexibility of pharmacist delegates from local managed care organizations who provided industry insight and expert mentorship. Data sources were gathered via course evaluation surveys, peer evaluations of presentations, and postgraduation surveys. Data were used to guide course improvement, gain insight into motivation for student participation, and evaluate the effect on career choices. RESULTS: During the fall and spring semesters of 2014-2015, 45 students participated and completed surveys: 28 in the fall and 17 in the spring. Seventy percent of enrollees took the course because of interest in managed care; 12% took the course because of referrals from past students; and 12% enrolled to explore topics outside of the pharmacy core curriculum. After completion of the course, 50% of students felt "somewhat comfortable" in discussing managed care topics, and 31% felt "very comfortable." None of the 17 students from the spring semester class answered "not comfortable" or "somewhat not comfortable." Suggestions for improvement from the fall semester class led to smaller class size, a roundtable setting, and new meeting times. In a survey of 6 graduates, 1 student pursued a fellowship; 2 students obtained managed care residencies; and 1 student worked as a managed care pharmacist. CONCLUSIONS: Data collected from students enrolled in the managed care elective indicated increased exposure and enhanced knowledge on topics discussed. Data also indicated value and support for the addition of peerled courses to the College of Pharmacy's curriculum. Graduates who took the course have pursued managed care careers and confirmed the benefits of peer-led learning. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by Tang, Smith, Tse, Tan, and Pittenger. Lau took the lead in data collection, along with Tang and Smith. Data interpretation was performed primarily by Lau, along with Tang, Smith, and Pittenger. The manuscript was written by all the authors and revised primarily by Tang, along with Smith, Lau, Pittenger, and Tan. This research was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2015; October 26-29, 2015; Orlando, Florida. PMID- 28650252 TI - The Effect of Endometriosis Symptoms on Absenteeism and Presenteeism in the Workplace and at Home. AB - BACKGROUND: Characterized by pain symptoms, endometriosis affects women's productivity in their prime working years. OBJECTIVE: To evaluate the effect of individual endometriosis symptoms on household chore and employment productivity as measured by presenteeism and absenteeism in a population survey of women with endometriosis. METHODS: An online survey of U.S. women was conducted to evaluate the prevalence of endometriosis, as well as symptoms, demographics, and clinical characteristics of the respondents. Women aged 18-49 years (inclusive) with endometriosis completed the Health-related Productivity Questionnaire to assess presenteeism and absenteeism for employed and household work. Descriptive statistics were used to describe the sample, survey responses, and the effect of endometriosis symptom severity on household chore and employment productivity. Regression analyses were performed to examine the effect of individual endometriosis symptoms on employment and household productivity lost because of presenteeism and absenteeism. RESULTS: Of 59,411 women who completed the prevalence screener, 5,879 women (9.9%) met the inclusion criteria for completing the survey; 1,318 women (2.2%) reported endometriosis and at least 1 hour of scheduled household chores in the past 7 days. Of these, 810 women had least 1 hour of scheduled employment in the past 7 days. Mean age was 34.6 years (standard error [SE] +/- 0.32); 77.2% of the women were white; 59.3% were married or in a civil union; and 59.1% were employed full or part time. Women with endometriosis had a weekly loss of an average of 5.3 hours (SE +/- 0.4) because of employment presenteeism, 1.1 hours (SE +/- 0.2) of employment absenteeism, 2.3 (SE +/- 0.2) hours of household presenteeism, and 2.5 (SE +/- 0.2) hours of household absenteeism. Hourly losses in employment and household chore productivity were significantly greater with increasing symptom severity (mild vs. severe: 1.9 vs. 15.8 total employment hours lost and 2.5 vs. 10.1 total household hours lost; P < 0.0001). Women who experienced 3 endometriosis symptoms concurrently lost a significantly greater number of employment hours because of absenteeism and presenteeism compared with those experiencing 1 or 2 symptoms (P < 0.001). Regression analyses showed that a range of endometriosis symptoms predicted employment and household losses because of presenteeism and absenteeism. CONCLUSIONS: There was a significant relationship between the number and patient-reported severity of endometriosis symptoms experienced and hours of employment and household productivity lost because of presenteeism and absenteeism. Study findings indicate a need for guidance strategies to help women and employers manage endometriosis so as to reduce productivity loss. DISCLOSURES: The design and financial support for this study was provided by AbbVie. AbbVie participated in data analysis, interpretation of data, review, and approval of the manuscript. Coyne and Gries are employees of Evidera- Evidence, Value & Access by PPD and were paid scientific consultants for AbbVie in connection with this study. Soliman, Castelli-Hayley, and Snabes are AbbVie employees and may own AbbVie stock or stock options. Surrey is affiliated with Colorado Center for Reproductive Medicine and was paid by AbbVie as a consultant for this project. Surrey serves as a consultant for AbbVie outside of this project. All authors participated in data analysis and interpretation, and contributed to the development of the manuscript. The authors maintained control over the final contents of the manuscript and the decision to publish. Study concept and design were contributed by Soliman, Coyne, Gries, and Castelli-Haley. Soliman, Castelli-Haley, Coyne, and Gries collected the data, and data interpretation was performed by Snabes, Surrey, Soliman, Coyne, and Gries. The manuscript was written and revised by Soliman, Coyne, and Gries, along with the other authors. PMID- 28650253 TI - Diagnosis and Treatment of Osteoporosis Before and After Fracture: A Side-by-Side Analysis of Commercially Insured and Medicare Advantage Osteoporosis Patients. AB - BACKGROUND: Although treatment for osteoporosis is recommended by U.S. clinical guidelines, a lack of diagnosis and treatment is common among patients with osteoporotic fractures. OBJECTIVE: To determine the rates of osteoporosis diagnosis and treatment before and after various types of fractures. METHODS: This was a retrospective claims analysis using data from the Humana Medicare Advantage claims (Medicare group) and Optum Insight Clinformatics Data Mart commercial claims (Commercial group). Patients included in the study had a claim for a qualifying fracture occurring between January 2008 and December 2013 (the index fracture), were continuously enrolled in the health plan for >= 1 year before and after the index fracture, and were aged >= 65 years in the Medicare group or >= 50 years in the Commercial group at the time of the index fracture. Fragility fractures and osteoporosis diagnoses were identified from ICD-9-CM codes. Treatment for osteoporosis included oral and injectable therapies identified by National Drug Code numbers and Healthcare Common Procedure Coding System codes. Diagnosis and treatment rates were assessed during the 1-year periods before and after the index fracture. All analyses were conducted by fracture type (vertebral, hip, nonhip/nonvertebral [NHNV], and multiple), with stratification by age and sex. No comparisons were made between the Medicare and Commercial groups; rather, McNemar tests were used to compare prefracture versus postfracture diagnosis and treatment rates within each group. RESULTS: For inclusion in the Medicare group, 45,603 patients were identified, and 54,145 patients were identified for the Commercial group. In the prefracture period, the osteoporosis diagnosis rates ranged from 12.0% (NHNV) to 21.5% (vertebral) in the Medicare group and from 5.3% (NHNV) to 12.1% (vertebral) in the Commercial group. In the postfracture period, diagnosis rates significantly increased (P < 0.001) and nearly doubled-for all fracture types but did not exceed 42.1% (vertebral) in the Medicare group and 27.7% (vertebral) in the Commercial group. Pre-index treatment rates were similarly low, ranging from 9.4% (hip) to 16.6% (vertebral) among Medicare patients, and 7.5% (NHNV) to 14.4% (vertebral) in Commercial patients. Osteoporosis treatment rates improved significantly in the postfracture year, ranging from 12.5% (NHNV) to 26.5% (vertebral) among Medicare patients, and 8.3% (NHNV) to 21.4% (vertebral) in Commercial patients. Larger increases in diagnosis rates and smaller increases in treatment rates were observed in stratified analyses of men and women and of different age groups, with women and older patients having higher overall rates of diagnosis and treatment before and after fracture. CONCLUSIONS: In men and women, osteoporosis diagnosis rates were low before the index fracture and improved substantially after the fracture, yet still remained low overall (under 50%). Osteoporosis treatment rates among patients experiencing a fracture were low before the index fracture and improved only minimally afterwards. DISCLOSURES: This study was funded by Merck & Co. Other than through the employer relationship disclosed here, Merck & Co. did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, or in the decision to submit the manuscript for publication. Weaver is an employee of Merck & Co. Sajjan was an employee of Merck & Co. and owned stock in the company at the time of the study. Lewiecki has received consulting and/or speaker honoraria from Merck & Co., AbbVie, AgNovos Healthcare, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Radius Health, Shire, and TheraNova, along with research grant support from Merck & Co., Amgen, and Eli Lilly and Company, and serves as a board member for the National Osteoporosis Foundation, the International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico. Harris has received consulting honoraria from Merck & Co., Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Gilead Sciences, Primus Pharmaceuticals, and Radius Health. Study concept and design were contributed by Weaver and Sajjan. Sajjan collected the data, and data interpretation was performed by all the authors. The manuscript was written and revised by Weaver, Lewiecki, and Harris. PMID- 28650254 TI - Proteomics to predict the response to tumour necrosis factor-alpha inhibitors in rheumatoid arthritis using a supervised cluster-analysis based protein score. AB - OBJECTIVE: In rheumatoid arthritis (RA), it is of major importance to identify non-responders to tumour necrosis factor-alpha inhibitors (TNFi) before starting treatment, to prevent a delay in effective treatment. We developed a protein score for the response to TNFi treatment in RA and investigated its predictive value. METHOD: In RA patients eligible for biological treatment included in the BiOCURA registry, 53 inflammatory proteins were measured using xMAP(r) technology. A supervised cluster analysis method, partial least squares (PLS), was used to select the best combination of proteins. Using logistic regression, a predictive model containing readily available clinical parameters was developed and the potential of this model with and without the protein score to predict European League Against Rheumatism (EULAR) response was assessed using the area under the receiving operating characteristics curve (AUC-ROC) and the net reclassification index (NRI). RESULTS: For the development step (n = 65 patient), PLS revealed 12 important proteins: CCL3 (macrophage inflammatory protein, MIP1a), CCL17 (thymus and activation-regulated chemokine), CCL19 (MIP3b), CCL22 (macrophage-derived chemokine), interleukin-4 (IL-4), IL-6, IL-7, IL-15, soluble cluster of differentiation 14 (sCD14), sCD74 (macrophage migration inhibitory factor), soluble IL-1 receptor I, and soluble tumour necrosis factor receptor II. The protein score scarcely improved the AUC-ROC (0.72 to 0.77) and the ability to improve classification and reclassification (NRI = 0.05). In validation (n = 185), the model including protein score did not improve the AUC-ROC (0.71 to 0.67) or the reclassification (NRI = -0.11). CONCLUSION: No proteomic predictors were identified that were more suitable than clinical parameters in distinguishing TNFi non-responders from responders before the start of treatment. As the results of previous studies and this study are disparate, we currently have no proteomic predictors for the response to TNFi. PMID- 28650255 TI - Patient navigation for traumatic brain injury promotes community re-integration and reduces re-hospitalizations. AB - OBJECTIVE: To determine the effectiveness of a Navigation programme for patients with traumatic brain injury. DESIGN: Prospective programme evaluation. SETTING: Inpatient rehabilitation facility and community settings. PARTICIPANTS: Eighteen individuals who suffered a traumatic brain injury (TBI), were between the ages of 16-70 years, and had a Rancho Score greater than IV. INTERVENTION: Patient navigation programme focused on identifying and addressing barriers to positive outcomes, including coordination of care and facilitating communication among the family and healthcare providers, psychosocial support, caregiver support, adherence to treatment, education, community resources and financial issues. MAIN OUTCOME MEASURES: Functional status, re-hospitalizations, falls, neurobehavioral symptom inventory, neuroendocrine status, activities of daily living, community integration and caregiver burden. RESULTS: There was a significant reduction in re-hospitalization and fall rate when comparing individuals who received navigation services and those who did not. We also observed improved adherence treatment plans and a significant increase in community integration, independence level and functional abilities. CONCLUSIONS: This study begins to highlight the effectiveness of a patient navigation programme for individuals with TBI. Future research with a larger sample will continue to help us refine patient navigation for chronic disabling conditions and determine its sustainability. PMID- 28650256 TI - Extent of impaired axoplasmic transport and neurofilament compaction in traumatically injured axon at various strains and strain rates. AB - PRIMARY OBJECTIVE: Secondary axotomy is more prevalent than the primary axotomy and involves subtle intraaxonal changes in response to the injury leading to cytoskeletal disruptions including neurofilament (NF) misalignment and compaction, which is associated with the genesis of impaired axoplasmic transport (IAT). Recent studies have reported two differential axonal responses to injury, one associated with the cytoskeletal collapse and another with the IAT. The objective of this study was to determine the extent of IAT and early NF changes in axons that were subjected to a stretch of various degrees at different strain rates. RESEARCH DESIGN AND METHODS: Fifty-six L5 dorsal spinal nerve roots were subjected to a predetermined strain at a specified displacement rate (0.01 and 15 mm/second) only once. The histological changes were determined by performing standard immunohistochemical procedures using beta amyloid precursor protein (beta APP) and NF-68 kDa antibodies. RESULTS AND CONCLUSIONS: No significant differences in the occurrence rate of either of the staining in the axons were observed when subjected to similar loading conditions, and the occurrence rate of both beta APP and NF68 staining was strain and rate-dependent. PMID- 28650258 TI - Helper T Cell Responses to Respiratory Viruses in the Lung: Development, Virus Suppression, and Pathogenesis. AB - The lung is an important line of defense that is exposed to respiratory infectious pathogens, including viruses. Lung epithelial cells and/or alveolar macrophages are initially targeted by respiratory viruses. Once respiratory viruses invade the cells of the lung, innate immunity is activated to inhibit viral replication. Innate immune signaling also activates virus-specific adaptive immune responses. The helper T cells play pivotal roles in the humoral and cellular adaptive immune responses. Helper T cells are categorized into several distinct subsets (e.g., TH1, TH2, TFH, TH17, and Treg), differentiated by their corresponding signature cytokine production profiles. Helper T cells migrate into the airways and the lung after respiratory virus infections. The behavior of the helper T cells differs with each respiratory virus-in some cases, the response is beneficial; in other cases, it is harmful. Here, the general mechanisms underlying helper T cell responses to viral infections are summarized, and functions and reactions of the helper T cells against some respiratory viral infections are discussed. In influenza virus infections, TH1 cells, which regulate the cytotoxic T lymphocytes and IgG2 responses, are efficiently activated. TFH cells required for highly specific and memory humoral responses are also activated on influenza infections. In infections with respiratory syncytial virus and rhinovirus, TH2 cells develop in the lung and contribute to pathogenesis. In many cases, Treg cells inhibit excessive virus-specific T cell responses that can contribute to viral pathogenicity. PMID- 28650257 TI - Sequential phosphorylation of CST subunits by different cyclin-Cdk1 complexes orchestrate telomere replication. AB - Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. Telomere homeostasis is central to maintaining genomic integrity. In budding yeast, Cdk1 phosphorylates the telomere-specific binding protein, Cdc13, promoting the recruitment of telomerase to telomere and thereby telomere elongation. Cdc13 is also an integral part of the CST (Cdc13-Stn1-Ten1) complex that is essential for telomere capping and counteracting telomerase-dependent telomere elongation. Therefore, telomere length homeostasis is a balance between telomerase-extendable and CST-unextendable states. In our earlier work, we showed that Cdk1 also phosphorylates Stn1 which occurs sequentially following Cdc13 phosphorylation during cell cycle progression. This stabilizes the CST complex at the telomere and results in telomerase inhibition. Hence Cdk1-dependent phosphorylations of Stn1 acts like a molecular switch that drives Cdc13 to complex with Stn1-Ten1 rather than with telomerase. However, the underlying mechanism of how a single cyclin-dependent kinase phosphorylates Cdc13 and Stn1 in temporally distinct windows is largely unclear. Here, we show that S phase cyclins are necessary for telomere maintenance. The S phase and mitotic cyclins facilitate Cdc13 and Stn1 phosphorylation respectively, to exert opposing outcomes at the telomere. Thus, our results highlight a previously unappreciated role for cyclins in telomere replication. PMID- 28650259 TI - Locomotor effects of a low-frequency fire alarm on C57BL/6 male mice: a preliminary study. AB - Maintaining appropriate acoustic conditions for animal welfare and data collection are crucial in biomedical research facilities. Negative impacts of disruptive sound are known and can include auditory damage, immune function changes, and behavioral alterations. One type of disruptive sound occurring in research facilities is that of fire alarms. To ameliorate this problem, many facilities have incorporated the use of low-frequency fire alarms that emit tones outside the rodent audible range. The impact of these devices has been assumed to be negligible. However, this has yet to be evaluated with controlled behavioral experiments. Thus, our objective was to investigate the impact of low-frequency fire alarm exposure on locomotor behavior in the open field, a test sensitive to acoustic stimuli disruption. Male mice were randomized to three alarm exposure groups (No-Alarm; Alarm-During; and Alarm-After) and placed in individual photobeam-activated locomotor chambers. The Alarm-During group displayed significantly reduced horizontal locomotion, with a trend towards reduced vertical locomotion. These data suggest that a low-frequency brief alarm tone can temporarily disrupt movement, a valuable insight should an alarm be deployed. Further, findings support close collaboration between researchers and institutional facility staff to ensure appropriate acoustic conditions are maintained, whenever possible, for research animals. PMID- 28650265 TI - Autophagy regulates DNA repair through SQSTM1/p62. AB - Macroautophagy/autophagy is primarily a degradative pathway that clears malfunctioning cellular components in response to various types of stress. Recent studies have indicated that autophagy also plays an important role in maintaining genome stability. Loss of autophagy is associated with increased damage to DNA, inappropriate amplification of genomic regions and abnormal chromosome number. In a recent paper by Wang et al. the authors uncover a mechanism through which autophagy regulates the ubiquitination of chromatin. In particular, the autophagy receptor and substrate SQSTM1/p62 inhibits the E3 ligase RNF168-dependent ubiquitination of histone in response to DNA double-strand breaks. Dysregulation of this process leads to a reduced ability to repair DNA and a corresponding increase in the sensitivity of cells to radiation-induced damage. PMID- 28650260 TI - Group 4 late embryogenesis abundant proteins as a model to study intrinsically disordered proteins in plants. AB - Late Embryogenesis Abundant (LEA) proteins comprise a heterogeneous group of proteins that accumulate to high levels in the dry seed and in vegetative plant tissues under water deficit. We recently reported that group 4 LEA proteins from Arabidopsis thaliana, regardless of their structural disorder prevalent in aqueous solution, are able to fold into alpha-helix when subjected to water deficit and/or macromolecular crowding environments. Interestingly, the ability to gain structure under water limiting conditions is circumscribed to the N terminal conserved region. This environment- driven conformational plasticity has a functional impact because the conserved N-terminal region is necessary and sufficient to prevent the inactivation and/or aggregation of reporter enzymes, when they are subjected to partial dehydration or freeze-thaw treatments. In this addendum we present a broader analysis of the data and propose that the mechanism by which group 4 LEA proteins exert their chaperone-like activity occurs via a selection of particular LEA structural conformations favored by water deficit environments. In addition, we include further observations regarding the abundance and conservation of histidine residues in LEA proteins of this group, particularly at the C-terminal variable region, supporting the presence of an additional function in the same polypeptides as metal ion sequesters. The structural characteristics of group 4 LEA proteins together with their conceivable multifunctionality, a widespread feature in Intrinsically Disordered Proteins (IDPs), raises the possibility of using this set of proteins as a model to investigate the structure-function relationship of IDPs in plants. PMID- 28650266 TI - Disease Suppressive Soils: New Insights from the Soil Microbiome. AB - Soils suppressive to soilborne pathogens have been identified worldwide for almost 60 years and attributed mainly to suppressive or antagonistic microorganisms. Rather than identifying, testing and applying potential biocontrol agents in an inundative fashion, research into suppressive soils has attempted to understand how indigenous microbiomes can reduce disease, even in the presence of the pathogen, susceptible host, and favorable environment. Recent advances in next-generation sequencing of microbiomes have provided new tools to reexamine and further characterize the nature of these soils. Two general types of suppression have been described: specific and general suppression, and theories have been developed around these two models. In this review, we will present three examples of currently-studied model systems with features representative of specific and general suppressiveness: suppression to take-all (Gaeumannomyces graminis var. tritici), Rhizoctonia bare patch of wheat (Rhizoctonia solani AG-8), and Streptomyces. To compare and contrast the two models of general versus specific suppression, we propose a number of hypotheses about the nature and ecology of microbial populations and communities of suppressive soils. We outline the potential and limitations of new molecular techniques that can provide novel ways of testing these hypotheses. Finally, we consider how this greater understanding of the phytobiome can facilitate sustainable disease management in agriculture by harnessing the potential of indigenous soil microbes. PMID- 28650267 TI - Robotic-assisted radical cystectomy versus open radical cystectomy for management of bladder cancer: review of literature and randomized trials. AB - Among the many milestones in the last several decades in the management of muscle invasive bladder cancer and high-risk nonmuscle-invasive bladder cancer including the extension of the standard lymph node dissection and the use of neoadjuvant chemotherapy, minimally invasive techniques have gained traction as an attractive option for radical cystectomy. Open radical cystectomy is plagued with high rates of perioperative and postoperative morbidity and mortality, and as robotic assistance has demonstrated benefits in other arenas of surgery and urology, the evolution of the approach to radical cystectomy has likewise incorporated robotic assistance. We thus sought to critically review the literature comparing open radical cystectomy with robotic-assisted radical cystectomy. Perioperative and oncologic outcomes as well as cost analyses and health-related quality of life were compared between the two approaches, and identified manuscripts were categorized according to level of evidence. PMID- 28650273 TI - Long-haul travel and venous thrombosis: What is the evidence? PMID- 28650274 TI - Intranasal Administration of Whole Inactivated Influenza Virus Vaccine as a Promising Influenza Vaccine Candidate. AB - The effect of the current influenza vaccine, an inactivated virus vaccine administered by subcutaneous/intramuscular injection, is limited to reducing the morbidity and mortality associated with seasonal influenza outbreaks. Intranasal vaccination, by contrast, mimics natural infection and induces not only systemic IgG antibodies but also local secretory IgA (S-IgA) antibodies found on the surface of the mucosal epithelium in the upper respiratory tract. S-IgA antibodies are highly effective at preventing virus infection. Although the live attenuated influenza vaccine (LAIV) administered intranasally can induce local antibodies, this vaccine is restricted to healthy populations aged 2-49 years because of safety concerns associated with using live viruses in a vaccine. Instead of LAIV, an intranasal vaccine made with inactivated virus could be applied to high-risk populations, including infants and elderly adults. Normally, a mucosal adjuvant would be required to enhance the effect of intranasal vaccination with an inactivated influenza vaccine. However, we found that intranasal administration of a concentrated, whole inactivated influenza virus vaccine without any mucosal adjuvant was enough to induce local neutralizing S IgA antibodies in the nasal epithelium of healthy individuals with some immunological memory for seasonal influenza viruses. This intranasal vaccine is a novel candidate that could improve on the current injectable vaccine or the LAIV for the prevention of seasonal influenza epidemics. PMID- 28650275 TI - First Description of blaNDM-7 Carried on an IncX4 Plasmid in Escherichia coli ST679 Isolated in Spain. AB - This study describes the molecular characterization of an NDM-7 carbapenemase producing Escherichia coli strain Ec188, recovered from a rectal swab of a male patient who had travelled to Pakistan before his hospitalization at the Hospital del Mar in Barcelona, Spain. The Ec188 isolate, assigned to a new multilocus sequence type ST679, was resistant to all beta-lactams, aminoglycosides (gentamicin, tobramycin, and with reduced susceptibility to amikacin), and ciprofloxacin. The blaNDM-7 gene was located on a 50 kb IncX4 plasmid (pEc188 NDM7), both in the original and transconjugant strains. In addition, blaCTX-M-15 was located on a 150 kb IncFIA plasmid and blaCMY-2 on a 95 kb undetermined plasmid type, only in the wild-type strain. The immediate genetic surroundings of blaNDM-7 included the bleo, trpf, and dsbC genes, and it was flanked by the insertion sequences IS26 and ISAba125, which appeared interrupted by IS5. The res and parA genes were found in the same orientation downstream of the IS26 element. To our knowledge, this is the first report of an NDM-7-carbapenemase carried on an IncX4 plasmid, as well as the first E. coli strain belonging to ST679 harboring an NDM beta-lactamase, possibly associated with previous travel to Pakistan. In addition, this study highlights the dissemination of NDM variants accompanied by IncX-type plasmids. PMID- 28650276 TI - Highlights of the San Antonio Breast Cancer Symposium 2016. AB - The 39th annual San Antonio Breast Cancer Symposium (SABCS) was convened in San Antonio, Texas, on 9-13 December 2016. More than 7000 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, locoregional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with Part 1 focusing onmetastatic breast cancer, extended endocrine therapy and the prognostic significance of BRCA1/2 gene mutations. The second part of this report will discuss a range of topics including anti-HER2 directed treatments, the impact of radiotherapy on implant and autologous flap based reconstruction, biological risk predictors for ductal carcinoma-in situ (DCIS), longer term effects of dietary fat modification and the influence of aromatase inhibitors on endothelial cell function. PMID- 28650277 TI - Attenuated post-exercise heart rate recovery in patients with systemic lupus erythematosus: the role of disease severity and beta-blocker treatment. AB - Objective Sinus tachycardia is frequently reported in systemic lupus erythematosus (SLE), while there are limited data on post-exercise ability to slow heart rate (i.e. heart rate recovery, HRR) in this group of patients. Methods We studied consecutive 70 patients with SLE and 30 healthy controls. All examined individuals underwent detailed clinical examination, echocardiography, Holter monitoring with heart rate variability and treadmill stress test using Bruce's protocol. HRR values were calculated as the difference between maximum HR during exercise and HR at the first (HRR1) and third (HRR3) minute of rest. Individuals with coronary artery disease, diabetes mellitus and suspected pulmonary hypertension were excluded from further analysis ( n = 15). Results Fifty-five SLE patients were eligible for this study: aged 41.5 +/- 12.4 years, 87.3% women, SLICC/ACR-DI score 3.58 +/- 1.85. In the SLE group 36.4% patients received beta-blockers, usually for previously detected sinus tachycardia and/or arterial hypertension. Mean HRR1 (36.9 +/- 12.6 vs 49.5 +/- 18.6, p = 0.0004) and HRR3 (55.5 +/- 14.3 vs 69.2 +/- 16.4, p = 0.0001) were significantly lower in SLE than in healthy individuals. Significantly negative correlations between SLICC/ACR-DI score and HRR1 ( r = -0.299, p = 0.01), HRR3 ( r = -0.361, p = 0.001) and exercise capacity ( r = -0.422, p < 0.0001) were revealed. Additionally, beta-blocker treatment was also revealed to alter significantly HRR1, HRR3 and exercise capacity in SLE. Conclusion Patients with SLE are characterized by attenuated HRR after exercise. In our study impaired HRR was associated with disease severity and beta-blocker treatment and probably with disease duration. The use of HRR assessment in SLE can be used as an additional marker of cardiac autonomic nervous system dysfunction. PMID- 28650278 TI - Late-onset systemic lupus erythematosus: Is it "mild lupus"? AB - Objective The objective of this paper is to investigate the clinical characteristics and prognosis of patients with late-onset systemic lupus erythematosus (SLE) using a prospective observational cohort. Methods Late-onset SLE (>=50 years old) was compared with adult-onset SLE (>=18 and <50 years old) using 1997 ACR classification criteria for SLE, autoantibodies, disease activity measured by Adjusted Mean SLE Disease Activity Index (AMS), and damage measured by Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI). The standardized mortality ratio (SMR) was calculated. Results A total of 917 patients with SLE were enrolled. The mean number of cumulative ACR criteria in late-onset SLE ( n = 32, 3.5%) was lower than that in adult-onset SLE (4.6 +/- 1.2 vs. 5.5 +/- 1.4, p < 0.05). The percentage of patients with low complement was lower in late-onset SLE than adult-onset SLE ( p < 0.05). AMS was also lower in late-onset SLE (2.7 +/- 2.1 vs. 4.3 +/- 2.6, p < 0.01), but SDI was similar between the two groups (50% vs. 43.4%, p = 0.58). The SMR of late-onset SLE was 1.58 (95% CI 0.58-3.43), while the SMR of adult-onset SLE was 3.34 (2.34-4.63). Conclusion Compared with adult-onset SLE, late-onset SLE has a lower number of ACR criteria and lower disease activity. Organ damage is not different, but prognosis and mortality are more favorable. PMID- 28650279 TI - Managing conventional cardiovascular risk factors in the lupus clinic - what can we achieve? PMID- 28650313 TI - Molecular mechanisms and epidemiology of resistance in Streptococcus pneumoniae in the Middle East region. AB - PURPOSE: Streptococcus pneumoniae is a commensal bacterium that normally colonizes the human nasopharyngeal cavity. Once disseminated, it can cause several diseases, ranging from non-invasive infections such as acute otitis media and sinusitis through to invasive infections with higher mortality, including meningitis and septicaemia. Since the identification of the first S. pneumoniae strain with decreased susceptibility to penicillin in the 1960s, antibiotic resistance among S. pneumoniae has increased disturbingly and the mechanisms of resistance have begun to unfold. METHODOLOGY: This work briefly reviewed the available data on the molecular mechanisms underlying antimicrobial resistance and its epidemiology among pneumococcal strains in Middle Eastern countries. KEY FINDINGS: Both intrinsic and acquired mechanisms (mutations, acquisition of novel mobile genetic elements and sometimes gene duplication and overexpression) affect susceptibility to a large variety of antibiotics. In Middle Eastern countries, including Lebanon, Iran, Saudi Arabia and Turkey, surveillance showed a disturbing increase in the strength and prevalence of resistance to antibiotics over the years, especially in the last decade. However, no surveillance reports were found in other Middle Eastern countries, such as Syria and Iraq. CONCLUSION: In order to better survey, control and prevent the emergence of multidrug- and extremely drug-resistant S. pneumoniae strains, antimicrobial stewardship, national surveillance and public awareness programmes should be developed urgently in Middle Eastern countries. PMID- 28650314 TI - Natrinema soli sp. nov., a novel halophilic archaeon isolated from a hypersaline wetland. AB - An extremely halophilic archaeon, designated strain 5-3T, was isolated from a soil sample of Meighan wetland in Iran. Strain 5-3T was strictly aerobic, catalase-positive and oxidase-negative. Cells were Gram-stain-negative, non motile and ovoid. Colonies of strain 5-3T were cream-coloured. The isolate showed optimum growth at 4.0 M NaCl, 40 degrees C and pH 7.0. The major polar lipids of the strain were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, two unknown phospholipids and three glycolipids (including one that was chromatographically identical to S2-DGD). The major respiratory quinone was menaquinone MK-8. The G+C content of the genomic DNA was 61.5 mol%. The closest relative was Natrinema salaciae JCM 17869T with 97.3 % similarity in the orthologous 16S rRNA gene sequence. Analysis of 16S rRNA and rpoB' gene sequences indicated that strain 5-3T is a member of the genus Natrinema in the family Natrialbaceae and forms a distinct cluster. On the basis of phylogenetic analysis, and phenotypic and chemotaxonomic characteristics, a novel species of the family Natrialbaceae, Natrinema soli sp. nov., is proposed. The type strain is 5-3T (=IBRC-M 11063T=LMG 29247T). PMID- 28650315 TI - Transient acidosis while retrieving a fear-related memory enhances its lability. AB - Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories. PMID- 28650316 TI - The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision. AB - Calcium (Ca2+) plays an important role in the function and health of neurons. In vertebrate cone photoreceptors, Ca2+ controls photoresponse sensitivity, kinetics, and light adaptation. Despite the critical role of Ca2+ in supporting the function and survival of cones, the mechanism for its extrusion from cone outer segments is not well understood. Here, we show that the Na+/Ca2+, K+ exchanger NCKX4 is expressed in zebrafish, mouse, and primate cones. Functional analysis of NCKX4-deficient mouse cones revealed that this exchanger is essential for the wide operating range and high temporal resolution of cone-mediated vision. We show that NCKX4 shapes the cone photoresponse together with the cone specific NCKX2: NCKX4 acts early to limit response amplitude, while NCKX2 acts late to further accelerate response recovery. The regulation of Ca2+ by NCKX4 in cones is a novel mechanism that supports their ability to function as daytime photoreceptors and promotes their survival. PMID- 28650317 TI - Serine ADP-ribosylation reversal by the hydrolase ARH3. AB - ADP-ribosylation (ADPr) is a posttranslational modification (PTM) of proteins that controls many cellular processes, including DNA repair, transcription, chromatin regulation and mitosis. A number of proteins catalyse the transfer and hydrolysis of ADPr, and also specify how and when the modification is conjugated to the targets. We recently discovered a new form of ADPr that is attached to serine residues in target proteins (Ser-ADPr) and showed that this PTM is specifically made by PARP1/HPF1 and PARP2/HPF1 complexes. In this work, we found by quantitative proteomics that histone Ser-ADPr is reversible in cells during response to DNA damage. By screening for the hydrolase that is responsible for the reversal of Ser-ADPr, we identified ARH3/ADPRHL2 as capable of efficiently and specifically removing Ser-ADPr of histones and other proteins. We further showed that Ser-ADPr is a major PTM in cells after DNA damage and that this signalling is dependent on ARH3. PMID- 28650320 TI - Combination of exendin-4 and DPP-4 silencing promoted angiogenesis of human coronary artery endothelial cells via activation of PI3K/Akt pathway. AB - This study was aimed to explore the combined effects of Exendin-4 with dipeptidyl peptidase-IV (DPP-4) silencing on vascular endothelial growth factor (VEGF) induced cell proliferation and angiogenesis in Human Coronary Artery Endothelial Cells (HCAECs), as well as the underlying molecular mechanisms which were involved in this process. HCAECs were treated by exendin-4, small interfering RNA (siRNA) targeting DPP-4 (DPP-4-siRNA) or exendin-4 plus DPP-4-siRNA, respectively. Cell migration, proliferation and angiogenesis in vitro were assessed by scratch-wound assay, MTT, tran swell assay, and matrigel tube formation, respectively. Cell apoptosis was investigated by TUNEL assay. Expression of apoptosis and PI3K/Akt related proteins were assessed by Western blotting. Incubation of HCAECs with exendin-4 and silencing of DPP-4 both caused an increase in cell proliferation, migration and tube formation, while a significant decrease in apoptosis (all p<0.05). Furthermore, the combination of the exendin-4 and silencing of DPP-4 had additional effects on HCAECs. Protein levels of p-Akt and p-PI3K were markedly increased by exendin-4 incubation, silencing of DPP-4 in HCAECs. These results suggest that combination of exendin-4 and silencing of DPP-4 had additional promoted effects on angiogenesis of HCAECs via activation of PI3K/Akt pathway. Our study indicated an alternative therapeutic strategy for atherosclerotic neovascularization. PMID- 28650318 TI - Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7. AB - HnRNP A1 regulates many alternative splicing events by the recognition of splicing silencer elements. Here, we provide the solution structures of its two RNA recognition motifs (RRMs) in complex with short RNA. In addition, we show by NMR that both RRMs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing. RRM2 binds to the upstream motif and RRM1 to the downstream motif. Combining the insights from the structure with in cell splicing assays we show that the architecture and organization of the two RRMs is essential to hnRNP A1 function. The disruption of the inter-RRM interaction or the loss of RNA binding capacity of either RRM impairs splicing repression by hnRNP A1. Furthermore, both binding sites within the ISS-N1 are important for splicing repression and their contributions are cumulative rather than synergistic. PMID- 28650321 TI - Effect of camel milk against renal toxicity in experimental rats. AB - Most of the antibiotics are associated with considerable side effects. Gentamicin (GM) is one of the most commonly used antibiotics, but has significant nephrotoxic side effects. Hence, the current study is investigating the beneficial role of camel milk (CM) that ameliorate GM unwanted renal defects and dysfunctions in some experimental animals. Sprague-Dawely rats weighing (200 220g) were divided into groups (four) of six. Group 1 (Control) received normal saline (only). Group 2 was given oral administration of CM at the dose of 5ml/rat/day for fifteen days. Group 3 was injected with GM (80mg/kg b.wt., i.p.) for 10 days. Group 4 was first given oral administration of CM at the dose of 5ml/rat/day alone, for five days, and then followed with the administration GM for next 10 days, accordingly. The results show that administration of GM significantly enhanced the kidney weight and levels of renal toxicity markers like urea and creatinine, in addition to decreased levels of blood glucose. Treatment with CM ameliorated and reversed these drastic changes in levels of creatinine, urea and improved renal weight. Glucose levels were also reversed and increased significantly. Furthermore, GM induced renal histological anomalies like degeneration of glomeruli and tubules were suppressed by CM and showed better progress. The present study confirm that pretreatment with CM attenuates GM unwanted, induced renal dysfunction and cellular damage. PMID- 28650322 TI - In vivo antiviral potential of Glycyrrhiza glabra extract against Newcastle disease virus. AB - Newcastle disease is highly infectious viral disease causing huge economic losses worldwide. These losses can be prevented by control of viral diseases. Medicinal plants have been traditionally used for treatment of different diseases since long. In this study the effect of extracts from Glycyrrhiza glabra leaves are investigated against Newcastle disease virus (NDV) by an in-vivo assay. Seven groups of nine-day-old embryonated chicken eggs were inoculated with various treatments of different plant extracts. All the groups except uninoculated negative control group were inoculated with velogenic NDV strain; five groups received different concentrations of the three extracts. Daily observe the rate of embryo survival. Allantoic fluid from treated eggs was collected for hem agglutination test. Results showed that embryo survival rate was higher 300ug/mL treated group as all the extracts showed antiviral activity. Similarly, the plant extracts effectively control virus as no viruses were identified in the allantoic fluids of all groups treated with low doses of plant. The current results have clearly verified that all the extracts especially that of methanol 300ug/mL from leaves of Glycyrrhiza glabra have strong antiviral activity against NDV in vivo. PMID- 28650319 TI - Somatostatin binds to the human amyloid beta peptide and favors the formation of distinct oligomers. AB - The amyloid beta peptide (Abeta) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Abeta1-42 (oAbeta1-42) and/or monomeric Abeta1-42 (mAbeta1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAbeta1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Abeta1-42. The presence of SST14 inhibited Abeta aggregation and masked the ability of several antibodies to detect Abeta. Notably, Abeta1-42, but not Abeta1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Abeta-directed diagnostics and may signify a role of SST14 in the etiology of AD. PMID- 28650323 TI - The naphthoquinone plumbagin suppresses ADP-induced rat platelet aggregation through P2Y1-PLC signaling pathway. AB - Plumbagin (PLB) isolated from Plumbago zeylanica L (Plumbaginaceae) was evaluated for the suppressive effect and mechanism on ADP induced rat platelet aggregation. Adult male SD rats were randomly divided into control group, clopidogrel group, PLB 25mg/kg group and PLB 50mg/kg group. Clopidogrel (13.5mg/kg per day) and PLB (25 and 50mg/kg per day) were orally given to experimental rats by gavage for seven consecutive days. The antiplatelet properties were assessed by measuring the ADP-induced platelet aggregation rate (Aggmax). The level of cAMP in platelets before aggregation was determined by ELISA. The protein expression of pAkt, Akt, pPLC beta3 and PLC beta3 in platelets was measured by western blot. Our data indicated that PLB (25 and 50mg/kg) significantly inhibited ADP-induced rat platelet aggregation as well as clopidogrel (13.5mg/kg) in a dose dependent manner compared with the control group. PLB (25 and 50mg/kg) remarkably reduced the ADP-induced PLC beta3 phosphorylation but not Akt in platelets as compared with the control group. The present study suggests that PLB exerts a suppressive effect on ADP-induced rat platelet aggregation, at least in part, through P2Y1 PLC signaling pathway. PMID- 28650324 TI - Formulation, Evaluation and release rate characteristics of medicated jelly of vitamin C. AB - Medicated jelly formulations are patient friendly dosage form for pediatric, geriatric and dysphagic patients. These formulations offer rapid dissolution and absorption of drugs through oral mucosa therefore show the early onset of action. The objective of the study was to develop and evaluate oral jelly formulations of vitamin C. Slurry method was adopted using glucose 103gm, sugar 67gm, gelatin 10gm and sorbitol 6.56gm. Preformulation studies were performed including the organoleptic profile, pH, and solubility of both drugs. The medicated jelly of Vitamin C was prepared and evaluated for physical characteristics, weight variation, syneresis, pH, taste and palatability, drug content, release rate characteristics and stability studies. All the jellies were found to have patient welcoming taste and were palatable. All formulations showed more than 50% drug release within 15 minutes, while 93% drug was released in 30 minutes. The results of release kinetics showed that the formulation followed the zero order release kinetics. Thus the drug was released at constant rate independent of the drug concentration involved in the process. All the medicated jellies were found to remain stable stored for 60 days at different temperatures. The present study revealed that medicated jellies of vitamin C could be employed orally in an effective form as an alternative solid oral dosage form for special population such as pediatrics, geriatrics and patients with dysphagia. PMID- 28650325 TI - Evaluation of three plant extracts against biofilm formation and expression of quorum sensing regulated virulence factors in Pseudomonas aeruginosa. AB - Following the increasing antibiotic resistance of pathogenic bacteria, the use of medicinal herbs as antibacterial agents has attracted growing attention. Pseudomonas aeruginosa is a human opportunistic pathogen that uses quorum sensing for regulating virulence gene expression (pyocyanin, protease, and elastase production and biofilm formation). This study examined the anti-quorum sensing activity of Quercus infectoria, Zataria multiflora and Trachyspermum copticum extracts on standard P. aeruginosa strain. The minimum inhibitory concentration (MIC) of Q. infectoria, Z. multiflora and T. copticum extracts for standard P. aeruginosa strain was determined through micro dilution. Microtiter plates were used to evaluate the anti-quorum sensing effects of the three extracts (at a sub MIC concentration) on pyocyanin, protease, and elastase production and biofilm formation. The acetone extract of Q. infectoria showed the highest anti-quorum sensing activity and reduced the pyocyanin, protease, and elastase production and biofilm formation by 89.1%, 78%, 73.3%, and 70.1%, respectively. The corresponding values were 88.2%, 72.1%, 69%, and 61.1% for the methanol extract of Z. multiflora and 70.6%, 63.42%, 60.1%, and 59.1% for the methanol extract of T. copticum. Considering the high anti-quorum sensing activity of the studied extracts, especially the acetone extract of Q. infectoria, these herbs can be used as antipathogenic drugs. PMID- 28650326 TI - To evaluate the efficacy and safety of CofNovex plus (EMA) syrup. AB - The cough and cold are very widespread conditions and a common purpose for advice in general practice. Utmost often the sign and symptoms of cough are produced by acute viral airway infection and the course is frequently benign. But it can be converted into bacterial super-infection and can cause acute bronchitis. Herbal medicines are used to treat symptoms of the cough and cold, and among these medicines Ivy leaf is used to treat mucous discharge and irritation in throat due to the cough and cold. In addition to synthetic substances such as acetylcysteine, carbocisteins, ambroxol and bromhexine, herbal medicines contain saponins, which are used in these indications. Not just Ivy, but also the marshmallow and mustard seeds used for these indications. This clinical trial was conducted in 220 patients, in which 110 receive the CofNovex plus European Medicines Agency (EMA) syrup and 110 receive the placebo. The age range of patients was 3 years to above 15 years. The sample paired t-test was applied to evaluate the significant level. CofNovex plus (EMA) syrup was very effective in treating cough and cold symptoms. The new treatment CofNovex plus (EMA) syrup was safe and well tolerated in patient at given specific age group. PMID- 28650327 TI - Anti-hyperglycemic potential of Lactobacillus spp. in alloxan-induced Wistar rats. AB - This research was aimed to investigate anti-hyperglycemic effects of two Lactobacillus spp. on alloxan induced diabetic rats. Alloxan was administered intraperitoneally to induce the diabetic conditions in experimental rats. Animals were treated with oral administration of Lactobacillus spp., such as L. plantarum and L. acidophilus at the dose of 108 CFU/ml. As a result, administration of Lactobacillus spp. significantly (P<0.05) lowered blood glucose levels in diabetic rats by (201-220mg/dl) as compared to diabetic control (265mg/dl). Also, both the Lactobacillus spp. were able to reduce body weight of experimental animals as compared to control group, suggesting potent anti-hyperglycemic effect of Lactobacillus spp. in terms of their anti-diabetic potential. PMID- 28650328 TI - Studies on self-nanoemulsifying drug delivery system of flurbiprofen employing long, medium and short chain triglycerides. AB - The aim of the study was to successfully design, formulate and evaluate self nanoemulsifying drug delivery system (SNEDDS) of poorly aqueous soluble drug viz. flurbiprofen using long (LCT), medium (MCT) and short chain triglycerides (SCT). The SNEDDS are thermodynamically stable lipid based drug delivery systems which consist of mixture of oil, surfactant and co-surfactant. Upon aqueous dilution, this mixture produces nano-emulsion spontaneously on slight agitation. The excipients intended to be used were screened for their potential to dissolve the drug and to form clear dispersion upon aqueous dilution. Labrafil M 1944 CS, capryol-90 and triacetin were selected as long, medium and short chain triglycerides, respectively, as lipids while tween-80 and polyethylene glycol-400 (PEG-400)/ethanol (3:1 ratio) were selected as surfactant and co-surfactant, respectively. The excipients were studied at every possible combination ratios using pseudo-ternary diagram. The LCT, MCT and SCT-SNEDDS were optimized using thermodynamic studies, percentage transmittance value, viscosity, refractive index (RI), electrical conductivity, globule size analysis and in-vitro drug release studies. The drug release profiles of optimized SNEDDS were then compared with market product at different pH mediums. The LCT-SNEDDS was considered to be superior for enhancement of the drug bioavailability when compared with other SNEDDS formulations and market product. PMID- 28650329 TI - Correlation of thyroid antibodies with TSH, T3 and T4 hormones in patients diagnosed with autoimmune thyroid disorders. AB - The serum concentrations of anti-thyroid peroxidase (anti-TPO) and anti thyroglobulin (anti-TG) antibodies are directly correlate in the induction and diagnosis of autoimmune thyroid disorders (AITDs). Therefore, the evaluation of serum anti-TPO and anti-TG antibodies in relation to thyroid function test parameters including thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4). This evaluation would be helpful in early diagnosis of abnormal thyroid function and associated autoimmune thyroid diseases. In this cross-sectional study, the serum anti-TPO, anti-TG, T3, T4 and TSH levels of 311 suspected patients of autoimmune thyroid disorders and 40 control subjects were evaluated. The data were presented as mean, +/- standard deviations of the mean. Pearson correlation and chi-square tests were used to assess the correlation coefficients and significance in the contingency tables. The thyroid function test parameters in normal and AITDs suspected patients were significantly different in correlation to elevated serum levels of anti-TPO antibody. A significant association was detected between female gender and elevated levels of anti-TPO (P value = 0.047). A higher percentage of women showed elevated levels of anti-TG, but it was not statistically significant (P value= 0.107). The findings of the study reveal a strong correlation between thyroid function test and thyroid antibodies levels, elaborating the clinical importance of thyroid antibodies in clinical examination and follow-up of patients with autoimmune thyroid disorders. PMID- 28650330 TI - Evaluation of hypocholesterolemic activity of extracts of Bidens odorata and Brickellia eupatorioides. AB - We sought to evaluate the hypolipidemic activity of extracts of Bidens odorata and Brickellia eupatorioides using a model of hyperlipidemia induced in rats by Triton WR-1339 (300mg/kg intraperitoneally). The rats were divided into 5 groups of 3 rats each: normal control group, hyperlipidemic control group, hyperlipidemic with 20 mg/kg atorvastatin, hyperlipidemic with 300 mg/kg B. odorata extract, and hyperlipidemic with 300mg/kg B. eupatorioides extract, respectively. After 10 d of treatment by intragastric administration, the extract of B. odorata caused a significant decrease of serum total cholesterol and triglyceride levels without altering the liver enzymes aspartate transaminase and alanine aminotransferase. In addition, the extract had antioxidant potential as shown by the 2,2?-diphenyl-1-picrylhydrazyl technique. These findings indicate that B. odorata has potential as a hypolipidemic agent and might be beneficial in treatment of hyperlipidemia and atherosclerosis. PMID- 28650331 TI - Expression of Th17 and CD4+ CD25+ T regulatory cells in peripheral blood of acute leukemia patients and their prognostic significance. AB - To discuss the expression of T helper cell 17 (Th17) cells and CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in peripheral blood (PB) of patients with acute leukemia (AL), and to explore the relationship between them and disease prognosis. 40 patients diagnosed with acute leukemia in The First Affiliated Hospital of Zhengzhou University from July 2012 to August 2014 were selected as the observation group. Meanwhile, 40 healthy people were taken as the control group. Flow Cytometry Method (FCM) was used to detect the level of Th17 cells and CD4+ CD25+ Foxp3+ cells in peripheral blood of the two groups, and enzyme-linked immuno sorbent assay (ELISA) method was used to test the level of IL17 and TGF beta in peripheral blood of two groups; reverse transcription-polymerase chain reaction (RT-PCR) was adopted to analyze the mRNA levels of RORgammaT and Foxp3 in peripheral blood. In addition, we examined the levels of Th17 and CD4+ CD25+ Foxp3+ cells and associated factor levels in patients with remission after AL chemotherapy. the Th17 cells (CD3+ CD4+ IL-17+) in acute leukemia patients accounted for (1.51+/-0.27)%, which was significantly higher than that of control group (0.36+/-0.23)%, with statistical significance (t=20.51, P<0.001); the percentage of CD4+ CD25+ Foxp3+ cells in AL patients was (3.37+/-0.48)%, which was significantly higher than that of control group of (1.26+/-0.27)%, with statistical significance (t=24.23, P<0.001); the serum levels of IL-17 and TGF beta in AL patients were (28.12+/-6.33) pg/ml and (38.41+/-8.44) pg/ml respectively, which were all significantly higher than that of control group of (14.41+/-6.21) pg/ml and (24.49+/-7.42) pg/ml, with statistical significance (t=7.83, P<0.001; t=7.83, P<0.001); the RORgammaT mRNA and Foxp3 mRNA levels in AL patients were all significantly higher than that of control group, with statistical significance (t=12.27, P<0.001; t=7.89, P<0.001). In addition, compared with before chemotherapy, the levels of Th17 cells and CD4+ CD25+ Foxp3+ cells, and the serum levels of IL-17 and TGF-beta in acute leukemia patients all decreased significantly after 6 months of chemotherapy, and the difference was statistically significant (P<0.001). Th17 cells, CD4+ CD25+ Foxp3+ cells and their secretory proteins IL-17, TGF-beta and transcription factors were significantly increased in AL patients. Therefore, regular detection of peripheral blood Th17 and Treg cells, as well as their secretory proteins are useful for monitoring the immune status and prognosis of patients. PMID- 28650332 TI - Nepeta rtanjensis (Lamiaceae), a plant endemic to the Balkans: Phenolic composition, antioxidant activity, and in vitro antigenotoxic effects in triiodothyronine-induced DNA damage in human lymphocytes. AB - The success of antioxidant therapy in hyperthyroidism implies that disease is mediated by oxidative stress, which is known as one of the causing agents of ageing, degenerative diseases, and cancer. The main objective of our study was to determine possible protective effects of methanolic extract of N. rtanjensis in triiodothyronine (T3)-induced DNA breaks of human lymphocytes under in vitro conditions, based upon plant antioxidant capacity related to its phytochemical profile, mainly its polyphenolic complex. The total phenolic and flavonoid content and the antioxidant activity using in vitro 1,1-dyphenyl-2- picrylhydrazyl reagent (DPPH) was determined in methanolic extracts of plant leaves and flowers. The phenolic compound content of 62.73+/-1.80mg of GaA/g, exhibited solid antioxidant activity (IC50= 112.59+/-0.95MUg/ml). The antigenotoxic activity of 0.2, 0.5 and 1.0mg/ml N. rtanjensis methanol extracts mixture with 100uM of T3 was studied in human lymphocytes in vitro using the Comet assay. It is supposed that the antigenotoxicity of N. rtanjensis methanol extracts was caused by high presence of chlorogenic acid, rosmarinic acid and rutin, all known as efficient antioxidant bioactive compounds, which were determined by ultrahigh-pressure liquid chromatograph with MS/MS Mass Spectroscopy (UHPLC/-HESI-MS / MS). PMID- 28650333 TI - Simultaneous determination of ACE inhibitors and dexibuprofen in active pharmaceutical ingredient, formulations and human serum by RP-HPLC. AB - The contemporary work describes a rapid and cost effective reversed phase High Performance Liquid Chromatography (RP-HPLC) method for the quantification of Captopril, Lisinopril and Dexibuprofen (DXP) simultaneously in dosage formulations, active pharmaceutical ingredients and human serum. The chromatographic system included LC-20A pump, Sil-20A auto sampler and SPD-20A UV/visible detector. The estimation was carried out by using a C18 (5MUm, 250 *4.6 mm) column with mobile phase methanol: water (80:20 v/v, pH 3.0) at 230 nm with a flow rate of 1.0 ml*min-1. The retention time of Dexibuprofen was 5.4 min while that of Captopril and Lisinopril were found to be 3.2 and 1.8 minutes respectively. There was no considerable variation exists in between the tested drug spiked in serum and the extent recovered, without interference of serum in concurrent approximation. The method developed was found to be precise, selective and validated for precision, linearity, specificity, accuracy, limit of detection and limit of quantitation. There is no such method reported earlier for the determination of ACE Inhibitors and DXP simultaneously. The present study helps in assessing the co-administration of both drugs in treatment and can be employed for quality control analysis and drug-drug interaction studies. PMID- 28650334 TI - Expression of Twist protein in colorectal carcinoma and its effect on proliferation and invasion of colorectal cancer cells. AB - This paper aims to study Twist protein expression in colorectal carcinoma and its effect on the proliferation and invasion of colorectal cancer cells, and to explore its specific mechanism of promoting cancer. Tissues of 20 patients and specimens of 20 normal people were examined by colonoscopy biopsy; the Twist mRNA expression level was detected by real-time quantitative PCR; the RNA interference in colorectal carcinoma cell line CT-26 cells was performed by lipid transfection method; the effects of Twist interference on proliferation and invasion of colorectal cancer cells were observed by CCK8 assay and tran swell assay; the mRNA and protein levels of mRNA in CT-26 cells were detected by RT-PCR and Western blot. The Twist mRNA level in colorectal cancer tissues was significantly higher than that in corresponding para-carcinoma tissues and control group (P<0.05); Twist mRNA expression level in the cancer tissues combined with lymph node metastasis was significantly higher than that without lymph node metastasis (P<0.05); the proliferation and migration ability of Twist siRNA transfected CT 26 cells were significantly lower than those of the control group (P<0.05); CT-26 cells with Twist interference could significantly decrease the mRNA and protein levels of Matrix Metalloproteinase-9 (MMP-9). Twist protein can increase the proliferation and migration ability of the colorectal cancer cells, and its mechanism may be related to MMP-9. PMID- 28650335 TI - Development of AD like symptoms following co-administration of AlCl3 and D-gal in rats: A neurochemical, biochemical and behavioural study. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with neurochemical and neurobehavioural alterations. Aluminium (Al) is considered as a contributing factor in the etiology of several neurodegenerative disorders like AD. D-galactose (D-gal) is a physiological nutrient but over supply induces some neurochemical and biochemical changes that exacerbate natural aging process. In this study, we aimed to develop AD animal model by co-administration of Al and D-gal in rats. Male albino Wistar rats were intraperitoneally injected with AlCl3 and D-gal at a dose of 150mg/kg and 300mg/kg respectively for one week. After one week rats were subjected to behavioural analysis. After behavioural analysis rats were decapitated to remove their brain. Biochemical and neurochemical analysis were conducted in whole brain. AlCl3+D-gal significantly induced depressive and anxious behaviour in rats. Rats cognitive abilities were also significantly impaired following AlCl3 and D-gal co-administration. AlCl3+D-gal significantly altered antioxidant enzyme activities and biogenic amine levels in whole brain. A marked increase in brain lipid peroxidation and acetylcholinesterase activity was found in test rats. These findings suggest that co-administration of AlCl3 and D gal for one week could induce AD like symptoms and may be used to develop AD animal model. PMID- 28650336 TI - Design and content determination of Genhuang dispersible tablet herbal formulation. AB - The aim of the present study was to optimize the shaping technology of the traditional herbal formula Genhuang dispersible tablets, and also establish a method for content determination. The optimal formulation of Genhuang dispersible tablets was determined based on the results of single factor test and orthogonal design test. The disintegration was used as the main study indicator. The proportion of each adjuvant in the optimal formulation consisted of 40% MCC as bulking agent, 15% PVPP and 7% L-HPC as disintegrant, ethanol as adhesive, CSD as lubricant, preparing the dispersible tablets with wet granulation. The content of baicalin in Genhuang dispersible tablets was determined by RP-HPLC method, the C18 column (150*4.6 mm, 10um) was used, the mobile phase was methanol-water phosphoric acid (47: 53: 0.2) with the flow rate of 1mL/min, the detection wavelength was at 280 nm and the column temperature was 30oC. The prepared dispersible tablets could be totally disintegrated within three minutes and in accordance with the standard of the Chinese pharmacopoeia. In conclusion, the formulation was suitable for Genhuang dispersible tablets, and the determination method was simple, sensitive and accurate. Therefore, the Genhuang dispersible tablets can be used for industrial production and effectively controlled. PMID- 28650337 TI - Risk factors of neonatal mortality in Faisalabad, Pakistan. AB - The objective of study was to find out major correlates of neonatal mortality. The main focus was in determining the impact of different demographic and health related characteristics of neonates and their mothers. A planned questionnaire was prepared in order to collect the information from mothers of newborns. The data were collected from different public and private hospitals of Faisalabad district. Discharge condition of neonate (dead or alive) was taken as response. Binary logistic regression was applied in order to unveil the impact of different contributory factors on the chances of neonatal mortality. Marriage age of mother, age of mother at baby birth, number of pregnancies, time since last birth, antenatal care, delivery mode, gender of baby, baby weight, baby disease and its nature, domestic violence, baby nutrition and residence were found to be significant factors affecting neonatal mortality. Odds ratio was used as a measure of association. From the results, it can be summed up that marriages at optimal ages, lesser frequency of pregnancies, early initiation of mother feeding, increased care during pregnancy to avoid low birth weight and birth time diseases, and increased facilities of antenatal care in rural areas can effectively reduce the neonatal mortality rates. PMID- 28650338 TI - IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. AB - Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-gamma is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-gamma-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials. PMID- 28650339 TI - ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence. AB - Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guerin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor alpha1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment. PMID- 28650340 TI - Hepatic beta-arrestin 2 is essential for maintaining euglycemia. AB - An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein beta-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific beta-arrestin 2 deficiency did not affect hepatic insulin sensitivity or beta-adrenergic signaling. Adult mice lacking beta-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of beta-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic beta-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes. PMID- 28650341 TI - Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. AB - In rheumatoid arthritis (RA), immunological triggers at mucosal sites, such as the gut microbiota, may promote autoimmunity that affects joints. Here, we used discovery-based proteomics to detect HLA-DR-presented peptides in synovia or peripheral blood mononuclear cells and identified 2 autoantigens, N acetylglucosamine-6-sulfatase (GNS) and filamin A (FLNA), as targets of T and B cell responses in 52% and 56% of RA patients, respectively. Both GNS and FLNA were highly expressed in synovia. GNS appeared to be citrullinated, and GNS antibody values correlated with anti-citrullinated protein antibody (ACPA) levels. FLNA did not show the same results. The HLA-DR-presented GNS peptide has marked sequence homology with epitopes from sulfatase proteins of the Prevotella sp. and Parabacteroides sp., whereas the HLA-DR-presented FLNA peptide has homology with epitopes from proteins of the Prevotella sp. and Butyricimonas sp., another gut commensal. Patients with T cell reactivity with each self-peptide also had responses to the corresponding microbial peptides, and the levels were directly correlated. Furthermore, HLA-DR molecules encoded by shared-epitope (SE) alleles were predicted to bind these self- and microbial peptides strongly, and these responses were more common in RA patients with SE alleles. Thus, sequence homology between T cell epitopes of 2 self-proteins and a related order of gut microbes may provide a link between mucosal and joint immunity in patients with RA. PMID- 28650342 TI - Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. AB - Atherosclerosis is a chronic inflammatory disease, and developing therapies to promote its regression is an important clinical goal. We previously established that atherosclerosis regression is characterized by an overall decrease in plaque macrophages and enrichment in markers of alternatively activated M2 macrophages. We have now investigated the origin and functional requirement for M2 macrophages in regression in normolipidemic mice that received transplants of atherosclerotic aortic segments. We compared plaque regression in WT normolipidemic recipients and those deficient in chemokine receptors necessary to recruit inflammatory Ly6Chi (Ccr2-/- or Cx3cr1-/-) or patrolling Ly6Clo (Ccr5-/-) monocytes. Atherosclerotic plaques transplanted into WT or Ccr5-/- recipients showed reduced macrophage content and increased M2 markers consistent with plaque regression, whereas plaques transplanted into Ccr2-/- or Cx3cr1-/- recipients lacked this regression signature. The requirement of recipient Ly6Chi monocyte recruitment was confirmed in cell trafficking studies. Fate-mapping and single-cell RNA sequencing studies also showed that M2-like macrophages were derived from newly recruited monocytes. Furthermore, we used recipient mice deficient in STAT6 to demonstrate a requirement for this critical component of M2 polarization in atherosclerosis regression. Collectively, these results suggest that continued recruitment of Ly6Chi inflammatory monocytes and their STAT6-dependent polarization to the M2 state are required for resolution of atherosclerotic inflammation and plaque regression. PMID- 28650343 TI - Anthrax toxin receptor 1 is the cellular receptor for Seneca Valley virus. AB - Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. It has shown promise as a cancer therapeutic in preclinical studies and early-phase clinical trials. Here, we have identified anthrax toxin receptor 1 (ANTXR1) as the receptor for SVV using genome-wide loss of-function screens. ANTXR1 is necessary for permissivity in vitro and in vivo. However, robust SVV replication requires an additional innate immune defect. We found that SVV interacts directly and specifically with ANTXR1, that this interaction is required for SVV binding to permissive cells, and that ANTXR1 expression is necessary and sufficient for infection in cell lines with decreased expression of antiviral IFN genes at baseline. Finally, we identified the region of the SVV capsid that is responsible for receptor recognition using cryoelectron microscopy of the SVV-ANTXR1-Fc complex. These studies identify ANTXR1, a class of receptor that is shared by a mammalian virus and a bacterial toxin, as the cellular receptor for SVV. PMID- 28650344 TI - The relationship between cardiac endothelium and fibroblasts: it's complicated. AB - Coronary revascularization is an effective means of treating ischemic heart disease; however, current therapeutic revascularization strategies are limited to large caliber vessels. Because the mammalian heart scars following cardiac injury, recent work showing that cardiac fibroblasts can transdifferentiate into new coronary endothelium raises a new and exciting approach to promoting endogenous revascularization following cardiac injury. In this issue of the JCI, He et al. report on their employment of a battery of lineage-tracing tools to address the developmental origins of fibroblasts that give rise to new endothelial cells. Surprisingly, cardiac fibroblasts did not appear to contribute appreciably to regeneration of cardiac endothelium. Instead, cardiac endothelial cells were likely to proliferate and generate new endothelium following injury. As these conclusions diverge from prior findings, additional work will be required to understand the sources that generate cardiac endothelium in new blood vessels after injury. Clarification of the origins of coronary endothelial cells during cardiac repair is essential for identifying improved approaches to revascularizing damaged myocardium in patients with ischemic heart disease. PMID- 28650346 TI - Real-time monitoring through the use of technology to enhance performances throughout HIV cascades. AB - PURPOSE OF REVIEW: Controlling the HIV epidemic requires strong linkages across a 'cascade' of prevention, testing, and treatment services. Information and communications technology (ICT) offers the potential to monitor and improve the performance of this HIV cascade in real time. We assessed recent (<18 months) peer-reviewed publications regarding uses of ICT to improve performance through expanded and targeted reach, improved clinical service delivery, and reduced loss to follow-up. RECENT FINDINGS: Research on ICT has tended to focus on a specific 'silo' of the HIV cascade rather than on tracking individuals or program performance across the cascade. Numerous innovations have been described, including use of social media to expand reach and improve programmatic targeting; technology in healthcare settings to strengthen coordination, guide clinical decision-making and improve clinical interactions; and telephone-based follow-up to improve treatment retention and adherence. With exceptions, publications have tended to be descriptive rather than evaluative, and the evidence-base for the effectiveness of ICT-driven interventions remains mixed. SUMMARY: There is widespread recognition of the potential for ICT to improve HIV cascade performance, but with significant challenges. Successful implementation of real time cascade monitoring will depend upon stakeholder engagement, compatibility with existing workflows, appropriate resource allocation, and managing expectations. PMID- 28650347 TI - Electronic health, telemedicine, and new paradigms for training and care. AB - PURPOSE OF REVIEW: HIV prevention and care is changing rapidly; guideline revisions and programmatic scale-up require innovative approaches to in-service training and care extension to improve provider practice and care access. We assessed recent (<=12 months) peer-reviewed publications on electronic health (eHealth), telemedicine, and other innovative provider-targeted interventions for HIV-related care. RECENT FINDINGS: Key developments included systems merging electronic medical records (EMR) with provider clinical decision aids to prompt action, demonstration eHealth, and telemedicine projects, reviews or descriptions of technology to improve connectivity in lower resource settings, and a few trials on provider-centered interventions. Most publications were program reports and few data were available regarding efficacy of eHealth interventions for providers on patient HIV-related outcomes, notably identification and management of antiretroviral treatment failure in Kenya. Better evidence is needed for strategies to train providers and care extenders with the goal to improve impact of HIV prevention and care interventions. SUMMARY: Rapid technology introduction and expansion may change the paradigm for improving provider knowledge and practice. Although new, the developments are promising for HIV provider-targeted eHealth and innovations for traditional training. More rigorous testing with randomized trials is needed to demonstrate impact on services for people living with HIV. PMID- 28650348 TI - An update on type 2 diabetes management in primary care. AB - Diabetes mellitus is a chronic disease impacting glucose metabolism. Type 2 diabetes mellitus (T2DM) stems from the inability of the body to utilize endogenous insulin properly. Approximately 90% to 95% of newly diagnosed cases of diabetes are T2DM. This article focuses on the initial treatment of T2DM based on the 2017 American Association of Clinical Endocrinologists and the American College of Endocrinology clinical practice guidelines. The 2017 update includes changes and additions regarding psychosocial management, physical activity, surgery, and hypoglycemia. PMID- 28650345 TI - Preexisting endothelial cells mediate cardiac neovascularization after injury. AB - The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury. PMID- 28650349 TI - New oral antiplatelet medications. AB - New and more potent oral antiplatelet agents have shown better clinical outcomes over the last few years. This article reviews the latest oral antiplatelet therapies available, their indications and contraindications, genetic resistance, and major drug interactions. PMID- 28650350 TI - Performing pediatric eye exams in primary care. AB - Early vision care is critical for all children. If undetected, eye disorders such as amblyopia and strabismus may result in permanent vision loss. Vision exams should include a careful history and physical including fix and follow, red reflex, and cover/uncover testing. Photo screening and visual acuity exams should be administered whenever possible. PMID- 28650351 TI - Changes in Health and Fitness in Firefighter Recruits: An Observational Cohort Study. AB - PURPOSE: To observe longitudinal changes in health and fitness among firefighter recruits. METHODS: Body composition, aerobic capacity, muscular power, muscular strength, and muscular endurance measures were longitudinally collected among 27 male firefighter recruits (mean +/- SD, age = 29.9 +/- 4.1 yr; height, 179.8 +/- 4.6 cm; body mass, 87.2 +/- 9.7 kg) at the beginning (W1) and end (W14) of their firefighter training academy, as well as at the end of their probationary period (W38). RESULTS: Repeated-measures multivariate analyses of variance (RM MANOVA) identified significant changes across time among measures of body composition (F10,17 = 30.390, Lambda = 0.053, P < 0.001), aerobic capacity (F6,21 = 55.111, Lambda = 0.060, P < 0.001), muscular power (F8,17 = 2.785, Lambda = 0.433, P = 0.036), muscular strength (F6,20 = 34.908, Lambda = 0.087, P < 0.001), and muscular endurance (F4,23 = 25.983, Lambda = 0.181, P < 0.001). Follow-up post hoc analyses indicated that all measures, except muscular power, significantly improved from W1 to W14 (P < 0.05). However, significant decrements in many of these measures were also observed from W14 to W38 (P < 0.05). CONCLUSIONS: The results of the current study suggest that measures of health and fitness among firefighter recruits significantly improved throughout the firefighter training academy (W1 to W14). However, many of these positive physiological adaptations are lost before these recruits finish their probationary period as active-duty firefighters (W14 to W38). These results highlight the importance of developing exercise programming that is designed for the active-duty firefighter cohort population to maintain the beneficial adaptations in health and fitness previously created during the firefighter training academy. PMID- 28650352 TI - The Effect of Aging and Priming on Same/Different Judgments Between Text and Partially Masked Speech. AB - OBJECTIVES: It is well known from previous research that when listeners are told what they are about to hear before a degraded or partially masked auditory signal is presented, the speech signal "pops out" of the background and becomes considerably more intelligible. The goal of this research was to explore whether this priming effect is as strong in older adults as in younger adults. DESIGN: Fifty-six adults-28 older and 28 younger-listened to "nonsense" sentences spoken by a female talker in the presence of a 2-talker speech masker (also female) or a fluctuating speech-like noise masker at 5 signal-to-noise ratios. Just before, or just after, the auditory signal was presented, a typed caption was displayed on a computer screen. The caption sentence was either identical to the auditory sentence or differed by one key word. The subjects' task was to decide whether the caption and auditory messages were the same or different. Discrimination performance was reported in d'. The strength of the pop-out perception was inferred from the improvement in performance that was expected from the caption before order of presentation. A subset of 12 subjects from each group made confidence judgments as they gave their responses, and also completed several cognitive tests. RESULTS: Data showed a clear order effect for both subject groups and both maskers, with better same-different discrimination performance for the caption-before condition than the caption-after condition. However, for the two-talker masker, the younger adults obtained a larger and more consistent benefit from the caption-before order than the older adults across signal-to noise ratios. Especially at the poorer signal-to-noise ratios, older subjects showed little evidence that they experienced the pop-out effect that is presumed to make the discrimination task easier. On average, older subjects also appeared to approach the task differently, being more reluctant than younger subjects to report that the captions and auditory sentences were the same. Correlation analyses indicated a significant negative association between age and priming benefit in the two-talker masker and nonsignificant associations between priming benefit in this masker and either high-frequency hearing loss or performance on the cognitive tasks. CONCLUSIONS: Previous studies have shown that older adults are at least as good, if not better, at exploiting context in speech recognition, as compared with younger adults. The current results are not in disagreement with those findings but suggest that, under some conditions, the automatic priming process that may contribute to benefits from context is not as strong in older as in younger adults. PMID- 28650353 TI - The Effect of Hearing Loss on Novel Word Learning in Infant- and Adult-Directed Speech. AB - OBJECTIVES: Relatively little is known about how young children with hearing impairment (HI) learn novel words in infant- and adult-directed speech (ADS). Infant-directed speech (IDS) supports word learning in typically developing infants relative to ADS. This study examined how children with normal hearing (NH) and children with HI learn novel words in IDS and ADS. It was predicted that IDS would support novel word learning in both groups of children. In addition, children with HI were expected to be less proficient word learners as compared with their NH peers. DESIGN: A looking-while-listening paradigm was used to measure novel word learning in 16 children with sensorineural HI (age range 23.2 to 42.1 months) who wore either bilateral hearing aids (n = 10) or bilateral cochlear implants (n = 6) and 16 children with NH (age range 23.1 to 42.1 months) who were matched for gender, chronological age, and maternal education level. Two measures of word learning were assessed (accuracy and reaction time). Each child participated in two experiments approximately 1 week apart, one in IDS and one in ADS. RESULTS: Both groups successfully learned the novel words in both speech type conditions, as evidenced by children looking at the correct picture significantly above chance. As a group, children with NH outperformed children with HI in the novel word learning task; however, there were no significant differences between performance on IDS versus ADS. More fine-grained time course analyses revealed that children with HI, and particularly children who use hearing aids, had more difficulty learning novel words in ADS, compared with children with NH. CONCLUSIONS: The pattern of results observed in the children with HI suggests that they may need extended support from clinicians and caregivers, through the use of IDS, during novel word learning. Future research should continue to focus on understanding the factors (e.g., device type and use, age of intervention, audibility, acoustic characteristics of input, etc.) that may influence word learning in children with HI in both IDS and ADS. PMID- 28650354 TI - Prediction of Hepatocellular Carcinoma Recurrence Beyond Milan Criteria After Resection: Validation of a Clinical Risk Score in an International Cohort. AB - OBJECTIVE: This study aims to validate a previously reported recurrence clinical risk score (CRS). SUMMARY OF BACKGROUND DATA: Salvage transplantation after hepatocellular carcinoma (HCC) resection is limited to patients who recur within Milan criteria (MC). Predicting recurrence patterns may guide treatment recommendations. METHODS: An international, multicenter cohort of R0 resected HCC patients were categorized by MC status at presentation. CRS was calculated by assigning 1 point each for initial disease beyond MC, multinodularity, and microvascular invasion. Recurrence incidences were estimated using competing risks methodology, and conditional recurrence probabilities were estimated using the Bayes theorem. RESULTS: From 1992 to 2015, 1023 patients were identified, of whom 613 (60%) recurred at a median follow-up of 50 months. CRS was well validated in that all 3 factors remained independent predictors of recurrence beyond MC (hazard ratio 1.5-2.1, all P < 0.001) and accurately stratified recurrence risk beyond MC, ranging from 19% (CRS 0) to 67% (CRS 3) at 5 years. Among patients with CRS 0, no other factors were significantly associated with recurrence beyond MC. The majority recurred within 2 years. After 2 years of recurrence-free survival, the cumulative risk of recurrence beyond MC within the next 5 years for all patients was 14%. This risk was 12% for patients with initial disease within MC and 17% for patients with initial disease beyond MC. CONCLUSIONS: CRS accurately predicted HCC recurrence beyond MC in this international validation. Although the risk of recurrence beyond MC decreased over time, it never reached zero. PMID- 28650355 TI - Axillary Dissection and Nodal Irradiation Can Be Avoided for Most Node-positive Z0011-eligible Breast Cancers: A Prospective Validation Study of 793 Patients. AB - OBJECTIVE: To determine rates of axillary dissection (ALND) and nodal recurrence in patients eligible for ACOSOG Z0011. BACKGROUND: Z0011 demonstrated that patients with cT1-2N0 breast cancers and 1 to 2 involved sentinel lymph nodes (SLNs) having breast-conserving therapy had no difference in locoregional recurrence or survival after SLN biopsy alone or ALND. The generalizability of the results and importance of nodal radiotherapy (RT) is unclear. METHODS: Patients eligible for Z0011 had SLN biopsy alone. Prospectively defined indications for ALND were metastases in >=3 SLNs or gross extracapsular extension. Axillary imaging was not routine. SLN and ALND groups and radiation fields were compared with chi-square and t tests. Cumulative incidence of recurrences was estimated with competing risk analysis. RESULTS: From August 2010 to December 2016, 793 patients met Z0011 eligibility criteria and had SLN metastases. Among them, 130 (16%) had ALND; ALND did not vary based on age, estrogen receptor, progesterone receptor, or HER2 status. Five-year event-free survival after SLN alone was 93% with no isolated axillary recurrences. Cumulative 5-year rates of breast + nodal and nodal + distant recurrence were each 0.7%. In 484 SLN-only patients with known RT fields (103 prone, 280 supine tangent, 101 breast + nodes) and follow-up >=12 months, the 5-year cumulative nodal recurrence rate was 1% and did not differ significantly by RT fields. CONCLUSIONS: We confirm that even without preoperative axillary imaging or routine use of nodal RT, ALND can be avoided in a large majority of Z0011 eligible patients with excellent regional control. This approach has the potential to spare substantial numbers of women the morbidity of ALND. PMID- 28650356 TI - Trending Fibrinolytic Dysregulation: Fibrinolysis Shutdown in the Days After Injury Is Associated With Poor Outcome in Severely Injured Children. AB - OBJECTIVE: To trend fibrinolysis after injury and determine the influence of traumatic brain injury (TBI) and massive transfusion on fibrinolysis status. BACKGROUND: Admission fibrinolytic derangement is common in injured children and adults, and is associated with poor outcome. No studies examine fibrinolysis days after injury. METHODS: Prospective study of severely injured children at a level 1 pediatric trauma center. Rapid thromboelastography was obtained on admission and daily for up to 7 days. Standard definitions of hyperfibrinolysis (HF; LY30 >=3), fibrinolysis shutdown (SD; LY30 <=0.8), and normal (LY30 = 0.9-2.9) were applied. Antifibrinolytic use was documented. Outcomes were death, disability, and thromboembolic complications. Wilcoxon rank-sum and Fisher exact tests were performed. Exploratory subgroups included massively transfused and severe TBI patients. RESULTS: In all, 83 patients were analyzed with median (interquartile ranges) age 8 (4-12) and Injury Severity Score 22 (13-34), 73.5% blunt mechanism, 47% severe TBI, 20.5% massively transfused. Outcomes were 14.5% mortality, 43.7% disability, and 9.8% deep vein thrombosis. Remaining in or trending to SD was associated with death (P = 0.007), disability (P = 0.012), and deep vein thrombosis (P = 0.048). Median LY30 was lower on post-trauma day (PTD)1 to PTD4 in patients with poor compared with good outcome; median LY30 was lower on PTD1 to PTD3 in TBI patients compared with non-TBI patients. HF without associated shutdown was not related to poor outcome, but extreme HF (LY30 >30%, n = 3) was lethal. Also, 50% of massively transfused patients in hemorrhagic shock demonstrated SD physiology on admission. All with HF (fc31.2%) corrected after hemostatic resuscitation without tranexamic acid. CONCLUSIONS: Fibrinolysis shutdown is common postinjury and predicts poor outcomes. Severe TBI is associated with sustained shutdown. Empiric antifibrinolytics for children should be questioned; thromboelastography-directed selective use should be considered for documented HF. PMID- 28650357 TI - Defining the Role of Minimally Invasive Proctectomy for Locally Advanced Rectal Adenocarcinoma. AB - OBJECTIVE: National examination of open proctectomy (OP), laparoscopic proctectomy (LP), and robotic proctectomy (RP) in pathological outcomes and overall survival (OS). BACKGROUND: Surgical management for rectal adenocarcinoma is evolving towards utilization of LP and RP. However, the oncological impacts of a minimally invasive approach to rectal cancer have yet to be defined. METHODS: Retrospective review of the National Cancer Database identified patients with nonmetastatic locally advanced rectal adenocarcinoma from 2010 to 2014, who underwent neoadjuvant chemoradiation, surgical resection, and adjuvant therapy. Cases were stratified by surgical approach. Multivariate analysis was used to compare pathological outcomes. Cox proportional-hazard modeling and Kaplan-Meier analyses were used to estimate long-term OS. RESULTS: Of 6313 cases identified, 53.8% underwent OP, 31.8% underwent LP, and 14.3% underwent RP. Higher-volume academic/research and comprehensive community centers combined to perform 80% of laparoscopic cases and 83% of robotic cases. In an intent-to-treat model, multivariate analysis demonstrated superior circumferential margin negativity rates with LP compared with OP (odds ratio 1.34, 95% confidence interval 1.02 1.77, P = 0.036). Cox proportional-hazard modeling demonstrated a lower death hazard ratio for LP compared with OP (hazard ratio 0.81, 95% confidence interval 0.67-0.99, P = 0.037). Kaplan-Meier analysis demonstrated a 5-year OS of 81% in LP compared with 78% in RP and 76% in OP (P = 0.0198). CONCLUSION: In the hands of experienced colorectal specialists treating selected patients, LP may be a valuable operative technique that is associated with oncological benefits. Further exploration of pathological outcomes and long-term survival by means of prospective randomized trials may offer more definitive conclusions regarding comparisons of open and minimally invasive technique. PMID- 28650358 TI - The Volume-outcome Relationship in Deceased Donor Kidney Transplantation and Implications for Regionalization. AB - OBJECTIVE: The aim of this study was to investigate the volume-outcome relationship in kidney transplantation by examining graft and patient outcomes using standardized risk adjustment (observed-to-expected outcomes). A secondary objective was to examine the geographic proximity of low, medium, and high-volume kidney transplant centers in the United States. SUMMARY OF BACKGROUND DATA: The significant survival benefit of kidney transplantation in the context of a severe shortage of donor organs mandates strategies to optimize outcomes. Unlike for other solid organ transplants, the relationship between surgical volume and kidney transplant outcomes has not been clearly established. METHODS: The Scientific Registry of Transplant Recipients was used to examine national outcomes for adults undergoing deceased donor kidney transplantation from January 1, 1999 to December 31, 2013 (15-year study period). Observed-to-expected rates of graft loss and patient death were compared for low, medium, and high-volume centers. The geographic proximity of low-volume centers to higher volume centers was determined to assess the impact of regionalization on patient travel burden. RESULTS: A total of 206,179 procedures were analyzed. Compared with low-volume centers, high-volume centers had significantly lower observed-to-expected rates of 1-month graft loss (0.93 vs 1.18, P<0.001), 1-year graft loss (0.97 vs 1.12, P<0.001), 1-month patient death (0.90 vs 1.29, P=0.005), and 1-year patient death (0.95 vs 1.15, P=0.001). Low-volume centers were frequently in close proximity to higher volume centers, with a median distance of 7 miles (interquartile range: 2 to 75). CONCLUSIONS: A robust volume-outcome relationship was observed for deceased donor kidney transplantation, and low-volume centers are frequently in close proximity to higher volume centers. Increased regionalization could improve outcomes, but should be considered carefully in light of the potential negative impact on transplant volume and access to care. PMID- 28650359 TI - Outcomes of Concurrent Operations: Results From the American College of Surgeons' National Surgical Quality Improvement Program. AB - OBJECTIVE: To determine whether concurrently performed operations are associated with an increased risk for adverse events. BACKGROUND: Concurrent operations occur when a surgeon is simultaneously responsible for critical portions of 2 or more operations. How this practice affects patient outcomes is unknown. METHODS: Using American College of Surgeons' National Surgical Quality Improvement Program data from 2014 to 2015, operations were considered concurrent if they overlapped by >=60 minutes or in their entirety. Propensity-score-matched cohorts were constructed to compare death or serious morbidity (DSM), unplanned reoperation, and unplanned readmission in concurrent versus non-concurrent operations. Multilevel hierarchical regression was used to account for the clustered nature of the data while controlling for procedure and case mix. RESULTS: There were 1430 (32.3%) surgeons from 390 (77.7%) hospitals who performed 12,010 (2.3%) concurrent operations. Plastic surgery (n = 393 [13.7%]), otolaryngology (n = 470 [11.2%]), and neurosurgery (n = 2067 [8.4%]) were specialties with the highest proportion of concurrent operations. Spine procedures were the most frequent concurrent procedures overall (n = 2059/12,010 [17.1%]). Unadjusted rates of DSM (9.0% vs 7.1%; P < 0.001), reoperation (3.6% vs 2.7%; P < 0.001), and readmission (6.9% vs 5.1%; P < 0.001) were greater in the concurrent operation cohort versus the non-concurrent. After propensity score matching and risk-adjustment, there was no significant association of concurrence with DSM (odds ratio [OR] 1.08; 95% confidence interval [CI] 0.96-1.21), reoperation (OR 1.16; 95% CI 0.96-1.40), or readmission (OR 1.14; 95% CI 0.99-1.29). CONCLUSIONS: In these analyses, concurrent operations were not detected to increase the risk for adverse outcomes. These results do not lessen the need for further studies, continuous self-regulation and proactive disclosure to patients. PMID- 28650360 TI - A Statewide Surgical Coaching Program Provides Opportunity for Continuous Professional Development. AB - OBJECTIVE: We sought to develop and evaluate a video-based coaching program for board-eligible/certified surgeons. SUMMARY BACKGROUND DATA: Multiple disciplines utilize coaching for continuous professional development; however, coaching is not routinely employed for practicing surgeons. METHODS: Peer-nominated surgeons were trained as coaches then paired with participant surgeons. After setting goals, each coaching pair reviewed video-recorded operations performed by the participating surgeon. Coaching sessions were audio-recorded, transcribed, and coded to identify topics discussed. The effectiveness with which our coaches were able to utilize the core principles and activities of coaching was evaluated using 3 different approaches: self-evaluation; evaluation by the participants; and assessment by the study team. Surveys of participating surgeons and coach targeted interviews provided general feedback on the program. All measures utilized a 5-point Likert scale format ranging from 1 (low) to 5 (high). RESULTS: Coach-participant surgeon pairs targeted technical, cognitive, and interpersonal aspects of performance. Other topics included managing intraoperative stress. Mean objective ratings of coach effectiveness was 3.1 +/- 0.7, ranging from 2.0 to 5.0 on specific activities of coaching. Subjective ratings by coaches and participants were consistently higher. Coaches reported that the training provided effectively prepared them to facilitate coaching sessions. Participants were similarly positive about interactions with their coaches. Identified barriers were related to audio-video technology and scheduling of sessions. Overall, participants were satisfied with their experience (mean 4.4 +/- 0.7) and found the coaching program valuable (mean 4.7 +/- 0.7). CONCLUSIONS: This is the first report of cross-institutional surgical coaching for the continuous professional development of practicing surgeons, demonstrating perceived value among participants, as well as logistical challenges for implementing this evidence-based program. Future research is necessary to evaluate the impact of coaching on practice change and patient outcomes. PMID- 28650361 TI - Pharmacological Thromboembolic Prophylaxis in Traumatic Brain Injuries: Low Molecular Weight Heparin Is Superior to Unfractionated Heparin. AB - OBJECTIVE: We hypothesized that low molecular weight heparin (LMWH) is superior to unfractionated heparin (UH) for venous thromboembolism (VTE) prophylaxis in patients with severe traumatic brain injuries (TBI). SUMMARY BACKGROUND DATA: Pharmacological VTE prophylaxis with LMWH or UH is the current standard of care in TBI. Clinical work suggests that LMWH may be more effective than UH for VTE prophylaxis in trauma patients. Experimental work shows that heparinoids may have neuroprotective properties. METHODS: ACS TQIP database study including patients with blunt severe TBI (AIS >= 3), those that received LMWH or UH VTE prophylaxis. Patients with severe extracranial injuries (AIS >= 3), death within 72 hours, or hospital stay <48 hours were excluded. Demographic and clinical data on admission was collected, as well as head, thorax, and abdomen AIS, and timing of prophylaxis (within 48 hours, 49-72 hours, and >72 hours). Outcomes included VTE complications, mortality, and unplanned return to the operating room. Multivariate analysis was performed to compare outcomes between patients receiving LMWH and UH. RESULTS: Overall, 20,417 patients met the criteria for inclusion in the study, 10,018 (49.1%) received LMWH and 10,399 (50.9%) UH. Multivariate analysis showed that LMWH was an independent protective factor against mortality and thromboembolic complications, regardless of timing of prophylaxis initiation. The type of prophylaxis had no effect on the need for unplanned return to the operating room. CONCLUSIONS: LMWH prophylaxis in severe TBI is associated with better survival and lower thromboembolic complications than UH. PMID- 28650362 TI - Emergency care in the face of terrorism. PMID- 28650364 TI - Hospice and Palliative Care Services. PMID- 28650363 TI - Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Neonates on Extracorporeal Life Support. AB - OBJECTIVES: To evaluate the population pharmacokinetics and pharmacodynamic target attainment of vancomycin in neonates with a contemporary 1/4-inch extracorporeal life support circuit with a Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC, Wayne, NJ). DESIGN: Retrospective medical record review. SETTING: Two free-standing tertiary/quaternary pediatric children's hospitals. PATIENTS: Neonates receiving either veno-arterial or veno-venous extracorporeal life support and vancomycin for empiric or definitive therapy with resulting serum concentrations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twelve patients with a median gestations age of 39 weeks (range 36-41 wk) and a median postnatal age of 9.5 days (range 0-28 d) accounted for 14 courses of vancomycin therapy while on extracorporeal life support and were included in the analysis. The median weight was 3.1 kg (range 2.2-4.41 kg) with five of 12 patients (41.7%) being female. Vancomycin concentrations were best described by an one-compartment model incorporating allometric scaling of estimated glomerular filtration rate on clearance. The mean total body clearance (mL/min/kg) for the population was 3.48 +/- 1.31 mL/min/kg, and the mean total volume of distribution (L/kg) for the population was 1.2 +/- 0.4 L/kg. The intermittent and continuous infusion dosing regimens that provided for the highest percentage of trough concentrations in the range of 10-20 mg/L were the 10 mg/kg/dose IV q8h, 12.5 mg/kg/dose IV q8-12h, 15 mg/kg/dose IV q12h, and 20 mg/kg/dose IV q12h, and the 20, 25, and 30 mg/kg/d continuous infusion regimens, respectively. All regimens allowed for an area under the concentration:minimum inhibitory concentration ratio of 400:1 for minimum inhibitory concentrations of less than or equal to 0.5 mg/L for a 90% PTA. None of the simulated regimens had a greater than 90% probability of achieving an area under the concentration:minimum inhibitory concentration ratio of 400:1 for vancomycin minimum inhibitory concentrations greater than or equal to 1 mg/L while maintaining trough concentrations in the range of 10-20 mg/L. CONCLUSIONS: To our knowledge, this is the first pharmacokinetic and pharmacodynamic study of neonates receiving vancomycin with a contemporary 1/4-inch extracorporeal life support circuit including the Quadrox-iD Pediatric oxygenator (Maquet Cardiovascular, LLC). The data suggest differences in vancomycin pharmacokinetics compared with previous extracorporeal life support data, notably a more rapid clearance, which could result in lower vancomycin concentrations. Considering this, a more aggressive initial dosing regimen may need to be employed in infants on extracorporeal life support. PMID- 28650366 TI - Community-Based Care of the Fibromyalgia Patient: Strategies to Promote Self Management. AB - Along with a variety of distressing symptoms, a diagnosis of fibromyalgia (FM) brings with it substantial physical, psychosocial, and financial costs. Research shows that self-management is an effective means to manage FM and can lead to fewer healthcare visits. Yet due to the complexity of this disorder, healthcare providers need to be able to tailor treatment to individual patients by understanding effective treatment interventions. Home healthcare nurses (HHNs) are in a unique position to assess and implement effective treatment recommendations in the home setting and as such could consider incorporating self management strategies into the home visit with the FM patient. Therefore, the purpose of this article is to use a case study to describe the assessment of FM patient's functional ability and quality of life and how the HHN may integrate self-management teaching into the established home care visit. A review of the literature and discussion of self-management interventions for the FM patient is presented. A summary of the case study and proposed clinical implications is offered. PMID- 28650367 TI - Palliative Care in Home Health: A Review of the Literature. PMID- 28650368 TI - The Home Healthcare Universal Best Practice Protocol. AB - To address rehospitalization rates and emergency department rates that were above the state and national averages, a quality improvement project was implemented at a midsized home healthcare agency. In order to address these escalating rates, the Home Health Universal Best Practice Protocol was developed and implemented by a home healthcare consultant. The protocol is evidence-based, time-specific, comprehensive, and includes interventions that are linked to reducing avoidable hospital visits. Interventions include risk assessment for rehospitalization, initiation of telehealth, utilization of teach-back method, and timely documentation. The Home Health Universal Best Practice Protocol was effective in not only exceeding objectives regarding decreasing rehospitalization and emergency department rates within a 6-month period but also in improving home healthcare agency referral rates. PMID- 28650369 TI - What's New in Nutrition for Adults With Diabetes? PMID- 28650370 TI - Five Strategies for Encouraging Seafood Consumption: What Health Professionals Need to Know. AB - There is confusion among many Americans, particularly women who are pregnant or breastfeeding and parents and caregivers of young children, regarding seafood consumption. The 2015-2020 Dietary Guidelines for Americans encourages us to eat a greater variety of protein foods. One way to do this is to choose seafood twice a week in place of meats, poultry, or eggs. Seafood, which includes fish and shellfish, is recommended for the total package of nutrients it provides. However, the average American is eating much less seafood than recommended. Whether that's due to taste preferences, lack of confidence with buying or preparing seafood, or concern about potential contaminants like methyl mercury, healthcare professionals have an important role. You can help to clear up confusion and encourage patients and clients-particularly women who are pregnant or breastfeeding and parents and caregivers of young children-to include seafood as part of an overall healthy eating pattern. PMID- 28650371 TI - Pharmacologic Agents Used to Treat Type 2 Diabetes. PMID- 28650372 TI - Understanding Hospice. PMID- 28650373 TI - FentaNYL Patch Not Adhering Properly During Use. PMID- 28650374 TI - Airborne Contaminants: Preventing Infections From Fans Used in the Home. PMID- 28650375 TI - Legislative Advocacy and the Home Healthcare Clinician. PMID- 28650376 TI - Information Governance: An Interview With Ann Meehan, RHIA. PMID- 28650377 TI - Hospice Care. PMID- 28650379 TI - Tenofovir-induced toxicity in renal proximal tubular epithelial cells: involvement of mitochondria. AB - OBJECTIVE: In-vivo studies suggest that mitochondria is involved in tenofovir (TFV)-induced renal toxicity, but the underlying mechanisms are still unclear. The aim of the present study was to assess the effects of TFV and its prodrug, TFV disoproxil fumarate, on mitochondrial function and cell survival/viability in a renal proximal tubular cell line. DESIGN AND METHODS: We evaluated parameters of cellular proliferation/survival (cell count, cell cycle, viability) and mitochondrial function (oxygen consumption, mitochondrial membrane potential, reactive oxygen species production) in NRK-52E cells. Intracellular TFV was measured by HPLC and expression of antioxidant genes was analysed by real-time PCR. RESULTS: Similar intracellular levels of TFV were reached with lower concentrations of the prodrug than of the drug, and correlated directly with a decrease in cell number. Both compounds inhibited proliferation and compromised mitochondrial function by decreasing mitochondrial membrane potential and increasing oxygen consumption and mitochondrial superoxide production. Altered oxidative status was confirmed by the overexpression of antioxidant genes. CONCLUSIONS: Intracellular accumulation of TFV induces mitochondrial toxicity in an in-vitro renal model and alters cell proliferation and viability. Our findings call for caution regarding the use of this nucleotide analogue reverse transcriptase inhibitor in patients with other risk factors that compromise mitochondrial function in the kidney. PMID- 28650381 TI - Potential for immune-driven viral polymorphisms to compromise antiretroviral based preexposure prophylaxis for prevention of HIV-1 infection. AB - OBJECTIVE: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. METHODS: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. RESULTS: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 * 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 * 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. CONCLUSIONS: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase E138X surveillance should be undertaken before use of rilpivirine PrEP. PMID- 28650384 TI - Incident Reporting in Emergency Medicine: A Thematic Analysis of Events. AB - BACKGROUND: Incident reporting is a recognized tool for healthcare quality improvement. These systems, which aim to capture near-misses and harm events, enable organizations to gather critical information about failure modes and design mitigation strategies. Although many hospitals have employed these systems, little is known about safety themes in emergency medicine incident reporting. Our objective was to systematically analyze and thematically code 1 year of incident reports. METHODS: A mixed-methods analysis was performed on 1 year of safety reporting data from a large, urban tertiary-care emergency department using a modified grounded theory approach. RESULTS: Between January 1 and December 31, 2015, there were 108,436 emergency department visits. During this time, 750 incident reports were filed. Twenty-nine themes were used to code the reports, with 744 codes applied. The most common themes were related to delays (138/750, 18.4%), medication safety (136/750, 18.1%), and failures in communication (110/750, 14.7%). A total of 48.8% (366/750) of reports were submitted by nurses. CONCLUSIONS: The most prominent themes during 1 year of incident reports were related to medication safety, delays, and communication. Relative to hospital-wide reporting patterns, a higher proportion of reports were submitted by physicians. Despite this, overall incident reporting remains low, and more is needed to engage physicians in reporting. PMID- 28650385 TI - Identity Crisis. PMID- 28650383 TI - Incomplete viral suppression and mortality in HIV patients after antiretroviral therapy initiation. AB - OBJECTIVE: To determine whether there is a threshold of detectable HIV RNA under 1000 copies/ml after antiretroviral therapy initiation associated with 10-year all-cause mortality. DESIGN: This study included nearly 8000 patients from a US based multicenter clinical cohort who started antiretroviral therapy between 1 January 1998 and 31 December 2013. Viral load was assessed 6 months after initiation of therapy. Patients were followed from 6 months after therapy initiation (between 1 July 1998 and 30 June 2014) until death, and data were administratively censored after 10 years or on 31 December 2014. METHODS: We used nonparametric multiple imputation to account for left-censored viral load measurements, Cox proportional hazards models to estimate all-cause mortality hazard ratios, Nelson-Aalen cumulative hazard estimates to construct risk curves, and inverse probability of exposure weights to standardize estimated hazard ratios and risk curves to the total study population. RESULTS: Plots of standardized hazard ratio estimates and 95% confidence intervals indicated there was no demonstrable viral load threshold between 30 and 500 copies/ml associated with a marked increase in 10-year mortality. The standardized 10-year risk of mortality among patients with viral loads between 400 and 999 copies/ml 6 months after starting treatment was comparable with the risk of mortality among patients with viral loads between 1000 and 4 million copies/ml (20 vs. 23%). CONCLUSION: Incomplete suppression of plasma HIV RNA 6 months after starting therapy is associated with substantial 10-year all-cause mortality risk, highlighting the importance of rapid viral load suppression after therapy initiation. PMID- 28650386 TI - Corneal Nerve Morphology and Tear Film Substance P in Diabetes. AB - PURPOSE: This work aims to characterize the relationship between tear film neuropeptide substance P and the structural integrity of the sub-basal nerve plexus in diabetes. METHODS: Seventeen healthy control participants and nine participants with diabetes were recruited in this cross-sectional study. Total protein content and substance P concentrations were determined in the flush tears of participants. Corneal nerve morphology was assessed by capturing the corneal sub-basal nerve plexus using the Heidelberg Retinal Tomograph II with the Rostock Corneal Module (Heidelberg Engineering GmbH, Heidelberg, Germany) in the central cornea. Corneal nerve fiber density (CNFD) was measured using ACCMetrics (M.A. Dabbah, Imaging Science and Biomedical Engineering, Manchester, UK) on eight captured images. Comparisons between groups were made using independent samples t tests. Correlations between parameters were analyzed using Pearson's correlations. RESULTS: Substance P concentrations were significantly higher in the tears of the control group compared to participants with diabetes (4150 +/- 4752 and 1473 +/- 1671 pg/mL, respectively, P = .047). There was no significant difference in total protein content between the groups (3.4 +/- 1.8 and 2.6 +/- 1.7 mg/mL in the control and diabetes groups, respectively, P = .262). CNFD was significantly lower in the participants with diabetes compared to the control group (16.1 +/- 5.7 and 21.5 +/- 7.0 mm/mm, respectively, P = .041). There was a moderate correlation between substance P and CNFD (r = 0.48, P = .01). CONCLUSIONS: Substance P is expressed at a significantly lower level in the tears of people with diabetes compared with healthy controls. The positive correlation between substance P and corneal nerve density indicates that substance P may be a potential biomarker for corneal nerve health. PMID- 28650397 TI - Action Observation of Motor Skills Followed by Immediate Sleep Enhances the Motor Rehabilitation of Older Adults With Stroke. AB - BACKGROUND AND PURPOSE: Motor rehabilitation following stroke is a demanding challenge in search for new strategies to improve outcome. Rehabilitation through action observation has been reported beneficial for older adults recovering from stroke. Early sleep session following motor learning enhanced the performance of the acquired motor skills. The purpose of this study was to examine whether an early sleep session following action observation has benefit over action observation alone in the rehabilitation of older adults after stroke. METHODS: Twenty patients with paresis of dominant upper limb in first ischemic stroke were assigned to 2 study groups (10 subjects each). The participants were presented a 5-minute video film of phone operation. Participants of the intervention group had a sleep session of 90 to 120 minutes immediately following the film while control participants did not sleep. Identical procedure was repeated for 4 consecutive sessions (4 weeks). A single item of the Chedoke Arm and Hand Activity Inventory was used as rehabilitation's outcome measure. RESULTS: During the 4 weeks of the study, the performances of both groups improved but the intervention group had higher Chedoke Arm and Hand Activity Inventory scores, as indicated by a significant session by group interaction (P < .001). CONCLUSIONS: An early sleep session added to action observation therapy may significantly improve motor performances of patients with stroke. Further studies are required to support this method for inclusion in rehabilitation arsenal. PMID- 28650398 TI - Predictors of Functional Change in a Skilled Nursing Facility Population. AB - BACKGROUND AND PURPOSE: Inability to obtain sufficient gains in function during a skilled nursing facility (SNF) stay impacts patients' functional trajectories and susceptibility to adverse events. The purpose of this study was to identify predictors of functional change in patients temporarily residing in an SNF following hospitalization. METHODS: One hundred forty patients admitted to a single SNF from the hospital who had both evaluation and discharge measures of physical function documented were included. Data from the Minimum Data Set 3.0 and electronic medical record were extracted to record clinical and demographic characteristics. The Short Physical Performance Battery (SPPB) was administered by rehabilitation therapists at evaluation and discharge. The SPPB consists of balance tests, gait speed, and a timed 5-time sit-to-stand test. RESULTS AND DISCUSSION: The Patient Health Questionnaire (PHQ-9) Screening Tool for Depression was the only significant predictor of change in gait speed over an SNF stay. Eighty-seven percent of patients achieved a clinically meaningful change in the SPPB of 1 point or greater from evaluation to discharge, with 78% demonstrating a clinically meaningful change of 0.1 m/s or greater on gait speed. However, 69% of patients demonstrated SPPB scores of 6 points or less and 57% ambulated less than 0.65 m/s at the time of discharge from the SNF, which indicates severe disability. CONCLUSIONS: Poor physical function following an SNF stay places older adult at significant risk for adverse events including rehospitalization, future disability, and institutionalization. Understanding the predictors of functional change from evaluation to discharge may direct efforts toward developing innovative and effective interventions to improve function trajectories for older adults following an acute hospitalization. PMID- 28650399 TI - Social Network Clustering and the Spread of HIV/AIDS Among Persons Who Inject Drugs in 2 Cities in the Philippines. AB - INTRODUCTION: The Philippines has seen rapid increases in HIV prevalence among people who inject drugs. We study 2 neighboring cities where a linked HIV epidemic differed in timing of onset and levels of prevalence. In Cebu, prevalence rose rapidly from below 1% to 54% between 2009 and 2011 and remained high through 2013. In nearby Mandaue, HIV remained below 4% through 2011 then rose rapidly to 38% by 2013. OBJECTIVES: We hypothesize that infection prevalence differences in these cities may owe to aspects of social network structure, specifically levels of network clustering. Building on previous research, we hypothesize that higher levels of network clustering are associated with greater epidemic potential. METHODS: Data were collected with respondent-driven sampling among men who inject drugs in Cebu and Mandaue in 2013. We first examine sample composition using estimators for population means. We then apply new estimators of network clustering in respondent-driven sampling data to examine associations with HIV prevalence. RESULTS: Samples in both cities were comparable in composition by age, education, and injection locations. Dyadic needle-sharing levels were also similar between the 2 cities, but network clustering in the needle-sharing network differed dramatically. We found higher clustering in Cebu than Mandaue, consistent with expectations that higher clustering is associated with faster epidemic spread. CONCLUSIONS: This article is the first to apply estimators of network clustering to empirical respondent-driven samples, and it offers suggestive evidence that researchers should pay greater attention to network structure's role in HIV transmission dynamics. PMID- 28650403 TI - The Classic Pitanguy Technique and Its Modifications in Mammaplasty: Ten Years of Experiences. AB - BACKGROUND: Mammaplasty surgery has been modified in the past few years, as plastic surgeons worked to improve and maintain the breast shape and especially the "bottoming out" of the gland. The classic Pitanguy's technique has been shown to be an anatomically safe technique in the management of the breast. However, as first described, cannot be applied in gigantomastia or in severe breast ptosis cases or in cases of dense breast parenchyma or for a long-lasting breast lift result. Using 2 different modifications, the Pitanguy technique can be applied for breasts of all sizes and for all cases of breast ptosis. METHODS: A retrospective study of 140 patients who underwent the Pitanguy method and its 2 modifications was performed. The first modification consists of dissecting the upper pole of the breast vertically to the fascia of the pectoralis major muscle and laterally to the nac. The medial flap is then advanced superiorly, rotated 90 degrees, and sutured to point A, whereas the lateral flap is placed below the medial one. The second modification describes an inferior chest wall-based flap for achieving a desirable shape that can be maintained over a long period. The inferior flap is based only in the thoracic wall vasculature, completely detached from surrounding structures, maintaining a good volume. The upper flap of the breast covers the inferior flap. RESULTS: The follow-up included 140 patients and the follow-up period ranged from 1 to 10 years. Five patients were operated on less than 4 months ago and were not involved in this study. All patients gained natural-shaped breasts, and they were pleased with the results. Serious complications, including flap necrosis, were avoided because caution was used to preserve the internal mammary perforators while performing the Pitanguy's technique and its 2 modifications. CONCLUSIONS: The classic Pitanguy technique and its 2 modifications provide a versatile, well-vascularized pedicle that allows elevation of the nipple areola complex at the desired height. Using these 2 modifications, the Pitanguy's technique can be applied for breasts of all sizes and for all cases of breast ptosis. PMID- 28650401 TI - Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years. AB - BACKGROUND: Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests that viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared with that of healthy aging participants. METHODS: We examined longitudinal structural brain magnetic resonance imaging atrophy rates using region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants older than 60 years (n = 38) compared with age-matched HIV-uninfected healthy and cognitively normal controls (n = 24). RESULTS: The mean age of participants was 63 years, the mean estimated duration of infection was 21 years, and the median duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, P = 0.016), caudate (0.74% vs. 0.03%, P = 0.012), frontal lobe (0.48% vs. 0.01%, P = 0.034), total cortical gray matter (0.65% vs. 0.16%, P = 0.027), brainstem (0.31% vs. 0.01%, P = 0.026), and pallidum (0.73% vs. 0.39%, P = 0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. CONCLUSIONS: Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared with healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences. PMID- 28650404 TI - Microsurgery Fellowship at St Vincent's Hospital, Sydney, Australia: The Ultimate Hidden Gem. PMID- 28650405 TI - Buccal Mucosa Neourethras Grow Proportionally After Puberty. PMID- 28650406 TI - Discussion: Predictors of Complications After Pectoralis Major Transposition for Sternum Dehiscence. PMID- 28650407 TI - Discussion on "Reduction of the Areolar Diameter After Ultrasound-Assisted Liposuction for Gynecomastia". PMID- 28650408 TI - Objective Effects of Breast Reduction Surgery on Physical Fitness. AB - BACKGROUND: Reduction mammaplasty is known for excellent outcomes and patient satisfaction. Although patients report improvements in pain, weight loss, and exercise levels, objective data on physical fitness benefits are limited. METHODS: Using the Stanford Military Data Repository, we identified 89 US Army active duty women with at least 1 pre- and postoperative Army Physical Fitness Test (APFT) who underwent reduction mammaplasty during 2011 to 2014. We used paired t tests to compare pre- and postoperative APFT score means and raw values for push-ups, sit-ups, and the 2-mile run. RESULTS: There were 56 subjects (62.9%) who improved in total APFT scores. Total score means increased from 235.9 preoperatively to 243.4 postoperatively (P = 0.0065). Of 28 subjects with at least 2 APFT scores before and after surgery, 20 (71.4%) improved in total scores. The subgroup's mean total score increased from 237.8 to 251.3 (P = 0.0009). Comparing individual pre- and postprocedure APFTs, all subjects demonstrated a mean 3.9% (SD, 0.1) improvement in total scores, and the subpopulation of 28 improved by 6.3% (SD, 0.1). In all events, mean performance values trended toward better postoperative scores. Differences were statistically significant for the total population for the number of sit-ups (P = 0.035), and, for the subgroup of 28, differences were statistically significant for the total score (P = 0.0009), sit-ups (P = 0.0002), and push-ups (P = 0.0134). CONCLUSIONS: Reduction mammaplasty was associated with postoperative physical fitness improvements among US Army active duty women. Soldier data are useful for objectively assessing physical fitness effects of breast reduction surgery. PMID- 28650409 TI - Platelet-Rich Fibrin Accelerates Skin Wound Healing in Diabetic Mice. AB - Diabetic foot ulcers (DFUs) are associated with an increased risk of secondary infection and amputation. Platelet-rich fibrin (PRF), a platelet and leukocyte concentrate containing several cytokines and growth factors, is known to promote wound healing. However, the effect of PRF on diabetic wound healing has not been adequately investigated. The aim of the study was to investigate the effect of PRF on skin wound healing in a diabetic mouse model. Platelet-rich fibrin was prepared from whole blood of 8 healthy volunteers. Two symmetrical skin wounds per mouse were created on the back of 16 diabetic nude mice. One of the 2 wounds in each mouse was treated with routine dressings (control), whereas the other wound was treated with PRF in addition to routine dressings (test), each for a period of 14 days. Skin wound healing rate was calculated.Use of PRF was associated with significantly improved skin wound healing in diabetic mice. On hematoxylin and eosin and CD31 staining, a significant increase in the number of capillaries and CD31-positive cells was observed, suggesting that PRF may have promoted blood vessel formation in the skin wound. In this study, PRF seemed to accelerate skin wound healing in diabetic mouse models, probably via increased blood vessel formation. PMID- 28650410 TI - Identification of Risk Factors in Lymphatic Surgeries for Melanoma: A National Surgical Quality Improvement Program Review. AB - INTRODUCTION: Sentinel lymph node biopsy (SLNB) and lymphadenectomy (LAD) are commonly performed in the staging and care of patients with malignant melanoma. These procedures are accompanied by complications that may result in hospital readmission, negatively affecting patient outcomes and potentially affecting surgical procedure reimbursement. The National Surgical Quality Improvement Program (NSQIP) database offers a large data set allowing physicians to evaluate 30-day readmission for surgical complications. We used this database to explore predictors of 30-day hospital readmission for SLNB and LAD in the axillary, cervical, and inguinal regions. METHODS: Data from the years 2005 to 2014 of the American College of Surgeons NSQIP database were used. Cohorts were constructed according to International Classification of Diseases, Ninth Revision, classification and current procedural terminology codes. The outcome of 30-day return to hospital was defined as patients who were readmitted to the hospital or the operating room within 30 days. Multiple logistic regression results are presented for a prespecified set of predictors and predictors that were significant on univariate logistic regression analysis. Odds ratios and confidence intervals were calculated using maximum likelihood estimates, along with Wald test P values. RESULTS: A total of 3006 patients were included. Of those, 151 (5.0%) returned to the hospital. Among 1235 LAD patients, 65 (5.3%) returned; among 1771 SLNB patients, 86 (4.9%) returned. Smoking was a predictor of hospital readmission for overall SLNB and for cervical SLNB on multivariate analysis. Age was a significant predictor for cervical and inguinal LAD. Hypertension was significant for cervical LAD. Diabetes, preoperative hematocrit, and male sex were predictors for inguinal SLNB. There were no significant predictors for axillary SLNB and axillary LAD, as well as overall LAD procedures. CONCLUSIONS: This is the first and largest study using American College of Surgeons NSQIP to examine 30-day readmission after SLNB and LAD for melanoma in 3 commonly operated anatomical regions. We have found several significant risk factors associated with hospital readmission, which are now being used as a quality measure for hospital performance and reimbursement, that may help surgeons optimize patient selection for SLNB and LAD. PMID- 28650411 TI - Recording Fewer Than 20 Potential Pairs With SFEMG May Suffice for the Diagnosis of Myasthenia Gravis. AB - PURPOSE: Our aim in the current study was to determine the minimum number of SFEMG potential pairs required to confirm neuromuscular junction impairment and relate this number to disease severity. METHODS: Ninety-four patients with myasthenia gravis (MG) attending the neuromuscular clinic from February 2013 to November 2015 were included. The SFEMG sensitivity was determined for each number of recorded pairs up to 20. In addition, we compared clinical and electrophysiologic characteristics between patients with abnormality within the first 3, 4 to 7, and >=8 recorded pairs to determine whether this number is associated with disease severity. RESULTS: Ninety-eight percent of patients had abnormal SFEMG, within 17 pairs in ocular MG, and within 15 pairs in generalized MG. All patients with generalized MG had at least one abnormal pair in the first five recorded pairs. Patients with three abnormal pairs apparent earlier during the test had more frequent bulbar, respiratory, and limb muscle weakness, and had higher mean jitter values and decrement values. CONCLUSIONS: In most cases, an abnormal SFEMG examination can be demonstrated in the first 15 recorded potential pairs in patients with generalized MG, and in the first 17 pairs in patients with ocular MG, thus shortening the test time and decreasing patient discomfort while preserving test sensitivity. PMID- 28650412 TI - Pressure Injury Knowledge in Critical Care Nurses. AB - PURPOSE: The purpose of this study was to identify pressure injury knowledge in critical care nurses related to prevention and staging following multimodal education initiatives. DESIGN: Postintervention descriptive study. SETTING AND SAMPLE: The sample comprised 32 RNs employed in medical intensive care/coronary intensive care or surgical intensive care units. The study setting was a 237-bed Veterans Affairs acute care hospital in the Midwestern United States. METHODS: Critical care RNs were asked to participate in this project over a 3-week period following a multimodal 2-year education initiative. Nurses completed the paper version of the 72-item Pieper-Zulkowski Pressure Ulcer Knowledge Test (PZ-PUKT) to determine pressure injury knowledge level. Calculated mean cumulative scores and subscores for items related to prevention and staging, respectively. Pearson correlations were used to examine associations between nursing staff characteristics and the PZ-PUKT prevention and staging scores. RESULTS: The cumulative score on the PZ-PUKT was 51.66 (72%); nurses with 5 to 10 years' experience had a higher mean score than nurses with experiences of 20 years or more (mean +/- SD = 54.25 +/- 4.37 vs 49.5 +/- 7.12), but the difference was not statistically significant. Nurses scored higher on the staging system-related items as compared to the prevention-related items (81% vs 70%). Nurses achieved higher staging subscale scores if they were younger (r =-0.41, P < .05), had less experience (r =-0.43, P < .05), and if they worked in the medical intensive care unit (r = 0.37, P < .05). CONCLUSIONS: Study findings indicate gaps in knowledge related to pressure injury practice; participants had greater knowledge of staging rather than prevention. Cumulative and subscale findings can be used to direct educational efforts needed to improve and maintain an effective pressure injury prevention program. PMID- 28650413 TI - Community Priorities for Hospital-Based Prevention Initiatives: Results From a Deliberating Public. AB - CONTEXT: Internal revenue service provisions require not-for-profit hospitals to provide "community benefit." In addition, the Affordable Care Act requires these hospitals to conduct community health needs assessments that involve appropriate stakeholders. These requirements signal government interest in creating opportunities for developing programs that are well tailored and responsive to the needs of the communities served. Gaining meaningful input from residents is a critical aspect of these processes. OBJECTIVE: To implement public deliberations that explore local resident priorities for use of a hospital's community benefit resources to prevent chronic disease. METHODS: Public deliberation is a method of community engagement that can provide guidance to decision makers on value-laden issues when technical solutions alone are inadequate to provide direction or set priorities. Three deliberations featuring presentations by experts and discussions among participants were convened with a cross section of residents in Brooklyn, New York. Participants were asked whether new hospital initiatives should prioritize: clinical prevention, community-based interventions, or action on broader policies affecting population health. Pre- and postsurveys, as well as qualitative methods, were used to assess knowledge and attitudes. RESULTS: Postdeliberation, participants had significant changes in knowledge, particularly on the impact of education on health. Participants prioritized community-based and policy interventions over expanding clinical prevention capacity. CONCLUSIONS: Public deliberation offers a method to probe informed constituent views of how a hospital can best promote its community's health. Informed local residents felt that hospitals should frame health-promoting activities more broadly than is current practice. Not-for-profit hospitals gain significant tax advantages. Increased insurance rates suggest that some hospitals will experience savings in uncompensated care that can be used to promote health more broadly. Vetting priorities for the use of new resources with informed community members can be accomplished through public deliberation. These results suggest community support for nonclinical approaches to disease prevention. PMID- 28650414 TI - Combined Thoracic Ultrasound Assessment during a Successful Weaning Trial Predicts Postextubation Distress. AB - BACKGROUND: Recent studies suggest that isolated sonographic assessment of the respiratory, cardiac, or neuromuscular functions in mechanically ventilated patients may assist in identifying patients at risk of postextubation distress. The aim of the present study was to prospectively investigate the value of an integrated thoracic ultrasound evaluation, encompassing bedside respiratory, cardiac, and diaphragm sonographic data in predicting postextubation distress. METHODS: Longitudinal ultrasound data from 136 patients who were extubated after passing a trial of pressure support ventilation were measured immediately after the start and at the end of this trial. In case of postextubation distress (31 of 136 patients), an additional combined ultrasound assessment was performed while the patient was still in acute respiratory failure. We applied machine-learning methods to improve the accuracy of the related predictive assessments. RESULTS: Overall, integrated thoracic ultrasound models accurately predict postextubation distress when applied to thoracic ultrasound data immediately recorded before the start and at the end of the trial of pressure support ventilation (learning sample area under the curve: start, 0.921; end, 0.951; test sample area under the curve: start, 0.972; end, 0.920). Among integrated thoracic ultrasound data, the recognition of lung interstitial edema and the increased telediastolic left ventricular pressure were the most relevant predictive factors. In addition, the use of thoracic ultrasound appeared to be highly accurate in identifying the causes of postextubation distress. CONCLUSIONS: The decision to attempt extubation could be significantly assisted by an integrative, dynamic, and fully bedside ultrasonographic assessment of cardiac, lung, and diaphragm functions. PMID- 28650416 TI - Redistribution of Streptococcus pneumoniae Serotypes After Nationwide 13-valent Pneumococcal Conjugate Vaccine Program in Children in Northern Taiwan. AB - BACKGROUND: After the introduction of 13-valent pneumococcal conjugate vaccine (PCV13) against Streptococcus pneumoniae, public health officials in Taiwan monitored a decline in circulating vaccine serotypes and the emergence of nonvaccine serotypes in children with invasive pneumococcal disease. A gradually expanded PCV13 national immunization program was launched in 2013 in Taiwan. Here, we evaluate the changes in the distribution of pneumococcal serotypes and antimicrobial nonsusceptibility in children during the evolution of vaccination policy. METHODS: S. pneumoniae isolates from children with pneumococcal disease were collected and serotyped from 2010 to 2015 in northern Taiwan. PCVs were administered at the recipients' expense between 2010 and 2012, and then PCV13 was partially reimbursed by the government beginning in 2013. The distribution and diversity of serotypes were analyzed along with their antimicrobial susceptibilities. RESULTS: Among a total of 498 isolates, the proportion of invasive pneumococcal disease isolates declined (47.1%-10.6%) during the study period, and serotype diversity increased after 2011. Between 2010 and 2012, the dominant serotypes were 19A, 19F, 3, 6B and 14, and serotype 19A rose from 44.1% to 57.5%. Serotypes 19A, 15A, 19F and 15B were more prevalent from 2013 to 2015, and serotype 19A decreased from 42.1% to 4.5%. Serotypes 19F and 15A became the most commonly detected serotypes in 2015. Overall, PCV13 additional serotypes were reduced by 80% (P < 0.0001) but nonvaccine serotypes increased from 8.8% to 51.5% (P < 0.0001). CONCLUSIONS: The step-by-step PCV13 national immunization program is effective against pneumococcal disease in Taiwanese children, mainly by reducing PCV13 additional serotypes. PMID- 28650417 TI - A 5-year Old Immigrant Child With a Mediastinal Mass. PMID- 28650415 TI - Videolaryngoscopy versus Fiber-optic Intubation through a Supraglottic Airway in Children with a Difficult Airway: An Analysis from the Multicenter Pediatric Difficult Intubation Registry. AB - BACKGROUND: The success rates and related complications of various techniques for intubation in children with difficult airways remain unknown. The primary aim of this study is to compare the success rates of fiber-optic intubation via supraglottic airway to videolaryngoscopy in children with difficult airways. Our secondary aim is to compare the complication rates of these techniques. METHODS: Observational data were collected from 14 sites after management of difficult pediatric airways. Patient age, intubation technique, success per attempt, use of continuous ventilation, and complications were recorded for each case. First attempt success and complications were compared in subjects managed with fiber optic intubation via supraglottic airway and videolaryngoscopy. RESULTS: Fiber optic intubation via supraglottic airway and videolaryngoscopy had similar first attempt success rates (67 of 114, 59% vs. 404 of 786, 51%; odds ratio 1.35; 95% CI, 0.91 to 2.00; P = 0.16). In subjects less than 1 yr old, fiber-optic intubation via supraglottic airway was more successful on the first attempt than videolaryngoscopy (19 of 35, 54% vs. 79 of 220, 36%; odds ratio, 2.12; 95% CI, 1.04 to 4.31; P = 0.042). Complication rates were similar in the two groups (20 vs. 13%; P = 0.096). The incidence of hypoxemia was lower when continuous ventilation through the supraglottic airway was used throughout the fiber-optic intubation attempt. CONCLUSIONS: In this nonrandomized study, first-attempt success rates were similar for fiber-optic intubation via supraglottic airway and videolaryngoscopy. Fiber-optic intubation via supraglottic airway is associated with higher first-attempt success than videolaryngoscopy in infants with difficult airways. Continuous ventilation through the supraglottic airway during fiber-optic intubation attempts may lower the incidence of hypoxemia. PMID- 28650418 TI - Hepatocellular Carcinoma in Perinatally Acquired HIV and HBV Coinfection: A Case Report. AB - This report describes a case of hepatocellular carcinoma in an adolescent with perinatally acquired HIV and hepatitis B virus coinfection, arising despite more than a decade of suppressive antiretroviral therapy for both HIV and hepatitis B virus. This case raises important questions regarding optimal hepatocellular carcinoma screening in this high-risk group and the oncogenic potential of even very well-controlled viral infection. PMID- 28650419 TI - Spondylodiscitis by Kingella Kingae: An Emerging Pathogen in an Older Pediatric Population. AB - In children, greater than 95% of Kingella kingae infections are diagnosed between 6 and 48 months of age. K. kingae has not been systematically investigated, especially in older children. We describe a case of spondylodiscitis by K. kingae in an 8-year-old child. PMID- 28650421 TI - Percutaneous Irreversible Electroporation for Portal Vein Tumor Thrombus: A Case Report. PMID- 28650420 TI - First Detection of Chikungunya Virus in Breast Milk. AB - Chikungunya virus (CHIKV) has never been detected in human breast milk. This is a brief report of CHIKV infection in a breastfeeding woman of a 3-month-old baby. The mother's CHIKV-RT PCR was positive in serum, urine and milk. The baby's CHIKV serology and reverse transcription polimerase chain reaction (RT-PCR) were negative. The detection of CHIKV in milk raises clinical and epidemiologic questions. PMID- 28650422 TI - The Effects of Valsartan on Renal Klotho Expression and Oxidative Stress in Alleviation of Cyclosporine Nephrotoxicity. AB - BACKGROUND: Nephrotoxicity side effect of the immunosuppressive drug, cyclosporine A (CsA), can be a major issue in transplantation medicine. Cyclosporine A-induced nephrotoxicity is multifactorial but oxidative stress has a critical role in this process. It has been demonstrated that Valsartan (Val) as an angiotensin receptor blocker has renoprotective effects, but the molecular mechanisms responsible for the renal protection, independent from its blood pressure lowering effect, have not yet been fully understood. The present study is aim at evaluating the Val effect in alleviation of CsA nephrotoxicity by probable increase in renal Klotho expression and/or reducing oxidative stress. METHODS: Thirty-two Sprague-Dawley rats were divided into 4 groups based on the administration of CsA and/or Val: group A (control, 1 mL/kg per day of olive oil as vehicle), group B (CsA, 30 mg/kg per day), group C (CsA + Val, 30 + 30 mg/kg per day), and group D (Val, 30 mg/kg per day). Real-time polymerase chain reaction and Western blotting were used to evaluate Renal Klotho expression. Serum Klotho level was measured by enzyme-linked immunosorbent assay. 8-Hydroxy deoxy guanosine and malondialdehyde levels as markers of oxidative stress were measured by enzyme-linked immunosorbent assay and spectrophotometrically, respectively. RESULTS: Cyclosporine A treatment reduced renal expression and serum levels of Klotho, improved malondialdehyde and 8-hydroxy-deoxy guanosine levels, and also deteriorated renal function. Valsartan prevented CsA-induced oxidative stress as well as Klotho downregulation and could alleviate CsA-induced renal histological changes and function. CONCLUSIONS: Administration of Val might lead to amelioration of CsA nephrotoxicity by probably diminishing CsA-induced renal Klotho downregulation and oxidative stress. PMID- 28650423 TI - A New Marker for Regulatory Macrophages. PMID- 28650426 TI - Fruit genomics: New apple genome. PMID- 28650428 TI - Breeding barriers: Duplicate S genes form new barrier. PMID- 28650430 TI - Fungal invasion: Eat more fat. PMID- 28650427 TI - Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice. AB - Sepsis is a life-threatening syndrome accompanied by an overwhelming inflammatory response and organ dysfunction. Selective targeting of phosphodiesterase 4 (PDE4) is currently being investigated as an effective therapeutic approach for inflammation-associated diseases. Roflumilast is a selective PDE4 inhibitor, used for the treatment of severe chronic obstructive pulmonary disease in clinic. However, its role in the treatment of sepsis-induced liver damage remains unclear. In the present study, we evaluated the effects of roflumilast in mice with cecal ligation and puncture-induced sepsis, and investigated the underlying mechanism. We found that roflumilast treatment improved survival in septic mice by reducing bacterial load locally and systemically, inhibiting the expression of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor alpha, and alleviating liver injury. These effects were associated with the inhibition of nuclear translocation of nuclear factor-kappa B (NF-kappaB), as well as degradation of NF-kappaB inhibitory protein alpha. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also markedly inhibited by roflumilast. Moreover, roflumilast significantly suppressed the activation of signal transducer and activator of transcription 3 (STAT3) and its upstream Janus kinase 1 and Janus kinase 2. Taken together, these results indicate that roflumilast prevents polymicrobial sepsis likely by suppressing NF-kappaB, p38 MAPK, and STAT3 pathways. PMID- 28650429 TI - Acetate-mediated novel survival strategy against drought in plants. AB - Water deficit caused by global climate changes seriously endangers the survival of organisms and crop productivity, and increases environmental deterioration1,2. Plants' resistance to drought involves global reprogramming of transcription, cellular metabolism, hormone signalling and chromatin modification3-8. However, how these regulatory responses are coordinated via the various pathways, and the underlying mechanisms, are largely unknown. Herein, we report an essential drought-responsive network in which plants trigger a dynamic metabolic flux conversion from glycolysis into acetate synthesis to stimulate the jasmonate (JA) signalling pathway to confer drought tolerance. In Arabidopsis, the ON/OFF switching of this whole network is directly dependent on histone deacetylase HDA6. In addition, exogenous acetic acid promotes de novo JA synthesis and enrichment of histone H4 acetylation, which influences the priming of the JA signalling pathway for plant drought tolerance. This novel acetate function is evolutionarily conserved as a survival strategy against environmental changes in plants. Furthermore, the external application of acetic acid successfully enhanced the drought tolerance in Arabidopsis, rapeseed, maize, rice and wheat plants. Our findings highlight a radically new survival strategy that exploits an epigenetic switch of metabolic flux conversion and hormone signalling by which plants adapt to drought. PMID- 28650432 TI - Corrigendum: A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma. AB - This corrects the article DOI: 10.1038/srep36132. PMID- 28650431 TI - Illuminating vital surface molecules of symbionts in health and disease. AB - The immunomodulatory surface molecules of commensal and pathogenic bacteria are critical to microorganisms' survival and the host's response1,2. Recent studies have highlighted the unique and important responses elicited by commensal-derived surface macromolecules3-5. However, the technology available to track these molecules in host cells and tissues remains primitive. We report, here, an interdisciplinary approach that uses metabolic labelling combined with bioorthogonal click chemistry (that is, reactions performed in living organisms)6 to specifically tag up to three prominent surface immunomodulatory macromolecules peptidoglycan, lipopolysaccharide and capsular polysaccharide-either simultaneously or individually in live anaerobic commensal bacteria. Importantly, the peptidoglycan labelling enables, for the first time, the specific labelling of live endogenous, anaerobic bacteria within the mammalian host. This approach has allowed us to image and track the path of labelled surface molecules from live, luminal bacteria into specific intestinal immune cells in the living murine host during health and disease. The chemical labelling of three specific macromolecules within a live organism offers the potential for in-depth visualization of host-pathogen interactions. PMID- 28650434 TI - Erratum: Direct and accurate measurement of size dependent wetting behaviors for sessile water droplets. AB - This corrects the article DOI: 10.1038/srep18150. PMID- 28650435 TI - Corrigendum: Omega-3 Polyunsaturated Fatty Acids Attenuate Fibroblast Activation and Kidney Fibrosis Involving MTORC2 Signaling Suppression. AB - This corrects the article DOI: 10.1038/srep46146. PMID- 28650433 TI - The evening complex coordinates environmental and endogenous signals in Arabidopsis. AB - Plants maximize their fitness by adjusting their growth and development in response to signals such as light and temperature. The circadian clock provides a mechanism for plants to anticipate events such as sunrise and adjust their transcriptional programmes. However, the underlying mechanisms by which plants coordinate environmental signals with endogenous pathways are not fully understood. Using RNA-sequencing and chromatin immunoprecipitation sequencing experiments, we show that the evening complex (EC) of the circadian clock plays a major role in directly coordinating the expression of hundreds of key regulators of photosynthesis, the circadian clock, phytohormone signalling, growth and response to the environment. We find that the ability of the EC to bind targets genome-wide depends on temperature. In addition, co-occurrence of phytochrome B (phyB) at multiple sites where the EC is bound provides a mechanism for integrating environmental information. Hence, our results show that the EC plays a central role in coordinating endogenous and environmental signals in Arabidopsis. PMID- 28650436 TI - Monitoring the orientation of rare-earth-doped nanorods for flow shear tomography. AB - Rare-earth phosphors exhibit unique luminescence polarization features originating from the anisotropic symmetry of the emitter ion's chemical environment. However, to take advantage of this peculiar property, it is necessary to control and measure the ensemble orientation of the host particles with a high degree of precision. Here, we show a methodology to obtain the photoluminescence polarization of Eu-doped LaPO4 nanorods assembled in an electrically modulated liquid-crystalline phase. We measure Eu3+ emission spectra for the three main optical configurations (sigma, pi and alpha, depending on the direction of observation and the polarization axes) and use them as a reference for the nanorod orientation analysis. Based on the fact that flowing nanorods tend to orient along the shear strain profile, we use this orientation analysis to measure the local shear rate in a flowing liquid. The potential of this approach is then demonstrated through tomographic imaging of the shear rate distribution in a microfluidic system. PMID- 28650438 TI - Cancer therapy: Neutrophils traffic in cancer nanodrugs. PMID- 28650439 TI - 2D materials: Brightening the dark excitons. PMID- 28650437 TI - Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. AB - Immunotherapy holds tremendous promise for improving cancer treatment. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the 'abscopal effect'. Unfortunately, response rates for this strategy remain low. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties. We showed that AC-NPs deliver tumour-specific proteins to antigen-presenting cells (APCs) and significantly improve the efficacy of alphaPD-1 (anti-programmed cell death 1) treatment using the B16F10 melanoma model, generating up to a 20% cure rate compared with 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+T/Treg and CD8+T/Treg ratios (Treg, regulatory T cells). Our work presents a novel strategy to improve cancer immunotherapy with nanotechnology. PMID- 28650440 TI - Probing dark excitons in atomically thin semiconductors via near-field coupling to surface plasmon polaritons. AB - Transition metal dichalcogenide (TMD) monolayers with a direct bandgap feature tightly bound excitons, strong spin-orbit coupling and spin-valley degrees of freedom. Depending on the spin configuration of the electron-hole pairs, intra valley excitons of TMD monolayers can be either optically bright or dark. Dark excitons involve nominally spin-forbidden optical transitions with a zero in plane transition dipole moment, making their detection with conventional far field optical techniques challenging. Here, we introduce a method for probing the optical properties of two-dimensional materials via near-field coupling to surface plasmon polaritons (SPPs). This coupling selectively enhances optical transitions with dipole moments normal to the two-dimensional plane, enabling direct detection of dark excitons in TMD monolayers. When a WSe2 monolayer is placed on top of a single-crystal silver film, its emission into near-field coupled SPPs displays new spectral features whose energies and dipole orientations are consistent with dark neutral and charged excitons. The SPP-based near-field spectroscopy significantly improves experimental capabilities for probing and manipulating exciton dynamics of atomically thin materials, thus opening up new avenues for realizing active metasurfaces and robust optoelectronic systems, with potential applications in information processing and communication. PMID- 28650441 TI - Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. AB - Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours. PMID- 28650442 TI - Magnetic brightening and control of dark excitons in monolayer WSe2. AB - Monolayer transition metal dichalcogenide crystals, as direct-gap materials with strong light-matter interactions, have attracted much recent attention. Because of their spin-polarized valence bands and a predicted spin splitting at the conduction band edges, the lowest-lying excitons in WX2 (X = S, Se) are expected to be spin-forbidden and optically dark. To date, however, there has been no direct experimental probe of these dark excitons. Here, we show how an in-plane magnetic field can brighten the dark excitons in monolayer WSe2 and permit their properties to be observed experimentally. Precise energy levels for both the neutral and charged dark excitons are obtained and compared with ab initio calculations using the GW-BSE approach. As a result of their spin configuration, the brightened dark excitons exhibit much-increased emission and valley lifetimes. These studies directly probe the excitonic spin manifold and reveal the fine spin-splitting at the conduction band edges. PMID- 28650443 TI - Sulfated glycopeptide nanostructures for multipotent protein activation. AB - Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with different polysaccharide-binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal beta-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signalling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than that required in the animal model. These highly bioactive nanostructures may enable many therapies in the future involving proteins. PMID- 28650444 TI - Nutrient recycling facilitates long-term stability of marine microbial phototroph heterotroph interactions. AB - Biological interactions underpin the functioning of marine ecosystems, be it via competition, predation, mutualism or symbiosis processes. Microbial phototroph heterotroph interactions propel the engine that results in the biogeochemical cycling of individual elements, and they are critical for understanding and modelling global ocean processes. Unfortunately, studies thus far have focused on exponentially growing cultures in nutrient-rich media, meaning knowledge of such interactions under in situ conditions is rudimentary at best. Here, we have performed long-term phototroph-heterotroph co-culture experiments under nutrient amended and natural seawater conditions, and show that it is not the concentration of nutrients but rather their circulation that maintains a stable interaction and a dynamic system. Using the Synechococcus-Roseobacter interaction as a model phototroph-heterotroph case study, we show that although Synechococcus is highly specialized for carrying out photosynthesis and carbon fixation, it relies on the heterotroph to remineralize the inevitably leaked organic matter, making nutrients circulate in a mutualistic system. In this sense we challenge the general belief that marine phototrophs and heterotrophs compete for the same scarce nutrients and niche space, and instead suggest that these organisms more probably benefit from each other because of their different levels of specialization and complementarity within long-term stable-state systems. PMID- 28650447 TI - Corrigendum: A Comparative Analysis of Community Detection Algorithms on Artificial Networks. AB - This corrects the article DOI: 10.1038/srep30750. PMID- 28650446 TI - Exosomes from Plasmodium-infected hosts inhibit tumor angiogenesis in a murine Lewis lung cancer model. AB - Previous research to investigate the interaction between malaria infection and tumor progression has revealed that malaria infection can potentiate host immune response against tumor in tumor-bearing mice. Exosomes may play key roles in disseminating pathogenic host-derived molecules during infection because several studies have shown the involvement and roles of extracellular vesicles in cell cell communication. However, the role of exosomes generated during Plasmodium infection in tumor growth, progression and angiogenesis has not been studied either in animals or in the clinics. To test this hypothesis, we designed an animal model to generate and isolate exosomes from mice which were subsequently used to treat the tumor. Intra-tumor injection of exosomes derived from the plasma of Plasmodium-infected mice provided significantly reduced Lewis lung cancer growth in mice. We further co-cultured the isolated exosomes with endothelial cells and observed significantly reduced expression of VEGFR2 and migration in the endothelial cells. Interestingly, high level of micro-RNA (miRNA) 16/322/497/17 was detected in the exosomes derived from the plasma of mice infected with Plasmodium compared with those from control mice. We observed that overexpression of the miRNA 16/322/497/17 in endothelial cell corresponded with decreased expression of VEGFR2, inhibition of angiogenesis and inhibition of the miRNA 16/322/497/17 significantly alleviated these effects. These data provide novel scientific evidence of the interaction between Plasmodium infection and lung cancer growth and angiogenesis. PMID- 28650445 TI - A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling. AB - Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition. PMID- 28650448 TI - Transplant-associated thrombotic microangiopathy is an endothelial complication associated with refractoriness of acute GvHD. AB - There is increasing evidence that endothelial dysfunction is involved in refractoriness of acute GvHD (aGvHD). Here we investigated the hypothesis that another endothelial complication, transplant-associated thrombotic microangiopathy (TMA), contributes to the pathogenesis of aGvHD refractoriness. TMA was retrospectively assessed in 771 patients after allogeneic stem cell transplantation (alloSCT). Incidences of TMA and refractory aGvHD were correlated with biomarkers of endothelial damage obtained before alloSCT for patients receiving or not receiving statin-based endothelial prophylaxis (SEP). Diagnostic criteria for TMA and refractory aGvHD were met by 41 (5.3%) and 76 (10%) patients, respectively. TMA was overrepresented in patients with refractory aGvHD (45.0 vs 2.3% in all other patients, P<0.001). TMA independently increased mortality. Elevated pretransplant suppressor of tumorigenicity-2 and nitrates along with high-risk variants of the thrombomodulin gene were associated with increased risk of TMA. In contrast, SEP abolished the unfavorable outcome predicted by pretransplant biomarkers on TMA risk. Patients on SEP had a significantly lower risk of TMA (P=0.001) and refractory aGvHD (P=0.055) in a multivariate multistate model. Our data provide evidence that TMA contributes to the pathogenesis of aGvHD refractoriness. Patients with an increased TMA risk can be identified pretransplant and may benefit from pharmacological endothelium protection. PMID- 28650449 TI - Parent versus child donor perceptions of the bone marrow donation experience. PMID- 28650450 TI - Endothelial damage is aggravated in acute GvHD and could predict its development. AB - The aim of the present study was to explore whether there is enhanced endothelial dysfunction in patients developing acute GvHD (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT) and to identify biomarkers with predictive and/or diagnostic value. In in vitro experiments, endothelial cells (ECs) were exposed to serum from patients with (aGvHD, n=31) and without (NoGvHD, n=13) aGvHD, to evaluate changes in surface adhesion receptors, the reactivity of the extracellular matrix by measuring the presence of Von Willebrand factor (VWF) and platelet adhesion, and the activation of intracellular signaling proteins. Plasma levels of VWF, ADAMTS-13, TNF receptor 1 (TNFR1), soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1 were also measured. In vitro results showed a more marked proinflammatory and prothrombotic phenotype in ECs in association with aGvHD. Regarding circulating biomarkers, levels of VWF and TNFR1 above an optimal cutoff score, taken independently or combined, at day 7 after allo-HCT, would be able to positively predict that around 90% of patients will develop aGvHD. Our results demonstrate that endothelial damage is aggravated in those allo-HCT recipients developing aGvHD, and that VWF and TNFR1 are promising predictive aGvHD biomarkers. These findings could contribute to improve the understanding of the pathophysiology of aGvHD. PMID- 28650451 TI - Inability to work and need for disability pension among long-term survivors of hematopoietic stem cell transplantation. AB - Return to work is critical goal following HSCT. However, late effects may impede return to normal activity after HSCT. In the case of inability to work, patients may need a work disability pension to ensure a reasonable livelihood. This study evaluated inability to work and need for disability pension among long-term survivors and analyzed possible determinants of need for social support. This retrospective, single-center study included all HSCT patients surviving ?5 years seen at the outpatient clinic between January 2013 and August 2015. There were 203 patients, median age at HSCT 35 years, and 50 years at time of study; median time between HSCT and study control was 12 years; 178 had allo-HSCT, 187 had a malignant disease. At time of study, 156 (77%) were working full or part-time, 47 (23%) were not working. In total, 76 (37%) survivors were receiving a work disability pension compared to 3.17% of the Swiss working population. Patients with a disability pension were significantly older at HSCT, were more often living alone, had more active physical and mental late effects, and higher score of fatigue compared to patients without. These findings underline the importance of screening for employment and the social consequences of non-employment in long term survivors after HSCT. PMID- 28650452 TI - Development of quality of life in patients undergoing allogeneic stem cell transplantation with regard to anxiety, depression and resilience. PMID- 28650453 TI - Regional intra-arterial steroid treatment in 120 patients with steroid-resistant or -dependent GvHD. AB - GvHD results in death in the majority of steroid-resistant patients. This report assesses the safety and efficacy of two regional intra-arterial steroid (IAS) treatment protocols in the largest published cohort of patients with resistant/dependent hepatic and/or gastrointestinal GvHD, as well as identification of predictors of response to IAS and survival. One hundred and twenty patients with hepatic, gastrointestinal GvHD or both were given IAS. Gastrointestinal initial response (IR) and complete response (CR) were documented in 67.9% and 47.6%, respectively, whereas hepatic IR/CR in 54.9% and 33.3%, respectively. The predictors of gastrointestinal CR were lower peak GvHD and steroid-dependent (SD) GvHD. The predictors for hepatic CR were male patient, reduced intensity conditioning and SD GvHD. Twenty-six of the 120 patients (21.6%) are currently alive (median follow-up for the survivors 91.5 months). The 12 months' overall survival is 30% with no treatment-associated deaths. Predictors of 12 months' survival were as follows: first transplant, age<20 years, non-TBI regimen and GvHD CR. Shorter time to gastrointestinal IR but not time to hepatic IR was associated with improved 12 months' survival. IAS appears to be safe and effective. Gastrointestinal treatment is more effective than hepatic treatment. In our study, we conclude our current recommendations for IAS treatment. PMID- 28650454 TI - Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation. AB - Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 * 106 CD34+ cells/kg recipient's weight. One fraction was used for the first transplant after median storage of 60 days (range, 17-165) and another fraction was used after median storage of 1448 days (range, 849-3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11-21) after the first and 13 days (10-20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage. PMID- 28650455 TI - Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Societe Francaise de Greffe de Moelle Osseuse et Therapie Cellulaire and Eurocord. AB - Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery. PMID- 28650457 TI - Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. AB - The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of beta-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting. PMID- 28650458 TI - Duplicated pollen-pistil recognition loci control intraspecific unilateral incompatibility in Brassica rapa. AB - In plants, cell-cell recognition is a crucial step in the selection of optimal pairs of gametes to achieve successful propagation of progeny. Flowering plants have evolved various genetic mechanisms, mediated by cell-cell recognition, to enable their pistils to reject self-pollen, thus preventing inbreeding and the consequent reduced fitness of progeny (self-incompatibility, SI), and to reject foreign pollen from other species, thus maintaining species identity (interspecific incompatibility)1. In the genus Brassica, the SI system is regulated by an S-haplotype-specific interaction between a stigma-expressed female receptor (S receptor kinase, SRK) and a tapetum cell-expressed male ligand (S locus protein 11, SP11), encoded by their respective polymorphic genes at the S locus2-6. However, the molecular mechanism for recognition of foreign pollen, leading to reproductive incompatibility, has not yet been identified. Here, we show that recognition between a novel pair of proteins, a pistil receptor SUI1 (STIGMATIC UNILATERAL INCOMPATIBILITY 1) and a pollen ligand PUI1 (POLLEN UNILATERAL INCOMPATIBILITY 1), triggers unilateral reproductive incompatibility between plants of two geographically distant self-incompatible Brassica rapa lines, even though crosses would be predicted to be compatible based on the S haplotypes of pollen and stigma. Interestingly, SUI1 and PUI1 are similar to the SI genes, SRK and SP11, respectively, and are maintained as cryptic incompatibility genes in these two populations. The duplication of the SRK and SP11 followed by reciprocal loss in different populations would provide a molecular mechanism of the emergence of a reproductive barrier in allopatry. PMID- 28650456 TI - A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease. AB - Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high affinity interactions between suPAR, APOL1 and alphavbeta3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments alphavbeta3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on alphavbeta3 integrin activation is a mechanism for CKD. PMID- 28650459 TI - Corrigendum: The presence of microplastics in commercial salts from different countries. AB - This corrects the article DOI: 10.1038/srep46173. PMID- 28650460 TI - A calcium- and light-gated switch to induce gene expression in activated neurons. AB - Despite recent advances in optogenetics, it remains challenging to manipulate gene expression in specific populations of neurons. We present a dual-protein switch system, Cal-Light, that translates neuronal-activity-mediated calcium signaling into gene expression in a light-dependent manner. In cultured neurons and brain slices, we show that Cal-Light drives expression of the reporter EGFP with high spatiotemporal resolution only in the presence of both blue light and calcium. Delivery of the Cal-Light components to the motor cortex of mice by viral vectors labels a subset of excitatory and inhibitory neurons related to learned lever-pressing behavior. By using Cal-Light to drive expression of the inhibitory receptor halorhodopsin (eNpHR), which responds to yellow light, we temporarily inhibit the lever-pressing behavior, confirming that the labeled neurons mediate the behavior. Thus, Cal-Light enables dissection of neural circuits underlying complex mammalian behaviors with high spatiotemporal precision. PMID- 28650461 TI - A light- and calcium-gated transcription factor for imaging and manipulating activated neurons. AB - Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally applied blue light, which together produce translocation of a membrane anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high- to low-calcium signal ratio of 10 after 10 min of stimulation. Opsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor-activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity dependent processes in neurons and other cells that signal with calcium. PMID- 28650462 TI - Haplotype phasing of whole human genomes using bead-based barcode partitioning in a single tube. AB - Haplotype-resolved genome sequencing promises to unlock a wealth of information in population and medical genetics. However, for the vast majority of genomes sequenced to date, haplotypes have not been determined because of cumbersome haplotyping workflows that require fractions of the genome to be sequenced in a large number of compartments. Here we demonstrate barcode partitioning of long DNA molecules in a single compartment using "on-bead" barcoded tagmentation. The key to the method that we call "contiguity preserving transposition" sequencing on beads (CPTv2-seq) is transposon-mediated transfer of homogenous populations of barcodes from beads to individual long DNA molecules that get fragmented at the same time (tagmentation). These are then processed to sequencing libraries wherein all sequencing reads originating from each long DNA molecule share a common barcode. Single-tube, bulk processing of long DNA molecules with ~150,000 different barcoded bead types provides a barcode-linked read structure that reveals long-range molecular contiguity. This technology provides a simple, rapid, plate-scalable and automatable route to accurate, haplotype-resolved sequencing, and phasing of structural variants of the genome. PMID- 28650463 TI - Type VI secretion TssK baseplate protein exhibits structural similarity with phage receptor-binding proteins and evolved to bind the membrane complex. AB - The type VI secretion system (T6SS) is a multiprotein machine widespread in Gram negative bacteria that delivers toxins into both eukaryotic and prokaryotic cells. The mechanism of action of the T6SS is comparable to that of contractile myophages. The T6SS builds a tail-like structure made of an inner tube wrapped by a sheath, assembled under an extended conformation. Contraction of the sheath propels the inner tube towards the target cell. The T6SS tail is assembled on a platform-the baseplate-which is functionally similar to bacteriophage baseplates. In addition, the baseplate docks the tail to a trans-envelope membrane complex that orients the tail towards the target. Here, we report the crystal structure of TssK, a central component of the T6SS baseplate. We show that TssK is composed of three domains, and establish the contribution of each domain to the interaction with TssK partners. Importantly, this study reveals that the N terminal domain of TssK is structurally homologous to the shoulder domain of phage receptor-binding proteins, and the C-terminal domain binds the membrane complex. We propose that TssK has conserved the domain of attachment to the virion particle but has evolved the reception domain to use the T6SS membrane complex as receptor. PMID- 28650464 TI - beta-catenin downregulates Dicer to promote ovarian cancer metastasis. AB - Ovarian cancer is a nearly uniform lethal disease and its highly aggressive metastatic phenotype portends a poor prognosis. Lack of a well-controlled, relevant experimental model has been a major obstacle to identifying key molecules causing metastasis. Here we describe the creation of a new isogenic model of spontaneous human ovarian cancer metastasis exhibiting opposite phenotypes-highly metastatic (HM) and non-metastatic (NM)-both in vitro and in vivo. HM was unique in its ability to metastasize consistently to the peritoneum, mimicking the major dissemination route of human ovarian cancer. In contrast, NM failed to form detectable metastases, although it was equally tumorigenic. Using comparative label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS), we identified beta-catenin, which we demonstrated for the first time as having a direct role in the pathogenesis of ovarian cancer metastasis. Our studies also revealed a previously unrecognized role of beta catenin in the downregulation of multiple microRNAs (miRNAs) through attenuating miRNA biogenesis by targeting Dicer, a key component of the miRNA-processing machinery. One such downregulated miRNAs was miR-29s involved in epithelial-to mesenchymal transition and subsequent stem cell traits. Silencing beta-catenin or overexpressing Dicer or miR-29 mimics in HM significantly reduced the ability of these cells to migrate. beta-catenin-knockdown cells also failed to metastasize in an orthotopic model of ovarian cancer. Meta-analysis revealed an increase in CTNNB1 and a decrease in DICER1 expression levels in the high-risk group. These results uncover beta-catenin as a critical factor in promoting ovarian cancer aggressiveness and a new mechanism linking between beta-catenin and miRNA downregulation underlying this process. PMID- 28650465 TI - MCU-dependent mitochondrial Ca2+ inhibits NAD+/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells. AB - Mitochondrial Ca2+ signaling, which is strongly dependent on the mitochondrial Ca2+ uniporter (MCU) complex, has a series of key roles in physiopathological processes, including energy metabolism, reactive oxygen species (ROS) production and cell apoptosis. However, a mechanistic understanding of how the mitochondrial Ca2+ signaling is remodeled and its functional roles remains greatly limited in cancers, especially in hepatocellular carcinoma. Here we demonstrated that the MCU complex was dysregulated in hepatocellular carcinoma (HCC) cells and significantly correlated with metastasis and poor prognosis of HCC patients. Upregulation of MCU clearly enhanced the Ca2+ uptake into mitochondria, which significantly promoted ROS production by downregulating nicotinamide adenine dinucleotide+ (NAD+)/reduced form of nicotinamide adenine dinucleotid (NADH) ratio and the NAD+-dependent deacetylase activity of sirtuin 3 to inhibit superoxide dismutase 2 (SOD2) activity. Moreover, our data indicated that the MCU dependent mitochondrial Ca2+ uptake promotes matrix metalloproteinase-2 activity and cell motility by ROS-activated c-Jun N-terminal kinase pathway, and thus contributed to the increased ability of invasion and migration in vitro and intrahepatic and distal lung metastasis in vivo of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly suppressed ROS production and the ability of HCC metastasis. Our study uncovers a mechanism that links the remodeling of mitochondrial Ca2+ homeostasis to ROS production, and provides evidence supporting a metastasis-promoting role for the MCU-dependent mitochondrial Ca2+ uptake in HCC. Our findings suggest that the mitochondrial Ca2+ uptake machinery may potentially be a novel therapeutic target for HCC metastasis. PMID- 28650467 TI - Genome-wide loss-of-function genetic screening identifies opioid receptor MU1 as a key regulator of L-asparaginase resistance in pediatric acute lymphoblastic leukemia. AB - L-asparaginase is a critical chemotherapeutic agent for acute lymphoblastic leukemia (ALL). It hydrolyzes plasma asparagine into aspartate and NH3, causing asparagine deficit and inhibition of protein synthesis and eventually, leukemic cell death. However, patient relapse often occurs due to development of resistance. The molecular mechanism by which ALL cells acquire resistance to L asparaginase is unknown. Therefore, we sought to identify genes that are involved in L-asparaginase resistance in primary leukemic cells. By unbiased genome-wide RNAi screening, we found that among 10 resistant ALL clones, six hits were for opioid receptor mu 1 (oprm1), two hits were for carbonic anhydrase 1 (ca1) and another two hits were for ubiquitin-conjugating enzyme E2C (ube2c). We also found that OPRM1 is expressed in all leukemic cells tested. Specific knockdown of OPRM1 confers L-asparaginase resistance, validating our genome-wide retroviral shRNA library screening data. Methadone, an agonist of OPRM1, enhances the sensitivity of parental leukemic cells, but not OPRM1-depleted cells, to L-asparaginase treatment, indicating that OPRM1 is required for the synergistic action of L asparaginase and methadone, and that OPRM1 loss promotes leukemic cell survival likely through downregulation of the OPRM1-mediated apoptotic pathway. Consistent with this premise, patient leukemic cells with relatively high levels of OPRM1 are more sensitive to L-asparaginase treatment compared to OPRM1-depleted leukemic cells, further indicating that OPRM1 loss has a crucial role in L asparaginase resistance in leukemic patients. Thus, our study demonstrates for the first time, a novel OPRM1-mediated mechanism for L-asparaginase resistance in ALL, and identifies OPRM1 as a functional biomarker for defining high-risk subpopulations and for the detection of evolving resistant clones. Oprm1 may also be utilized for effective treatment of L-asparaginase-resistant ALL. PMID- 28650466 TI - Ror2-mediated alternative Wnt signaling regulates cell fate and adhesion during mammary tumor progression. AB - Cellular heterogeneity is a common feature in breast cancer, yet an understanding of the coexistence and regulation of various tumor cell subpopulations remains a significant challenge in cancer biology. In the current study, we approached tumor cell heterogeneity from the perspective of Wnt pathway biology to address how different modes of Wnt signaling shape the behaviors of diverse cell populations within a heterogeneous tumor landscape. Using a syngeneic TP53-null mouse model of breast cancer, we identified distinctions in the topology of canonical Wnt beta-catenin-dependent signaling activity and non-canonical beta catenin-independent Ror2-mediated Wnt signaling across subtypes and within tumor cell subpopulations in vivo. We further discovered an antagonistic role for Ror2 in regulating canonical Wnt/beta-catenin activity in vivo, where lentiviral shRNA depletion of Ror2 expression augmented canonical Wnt/beta-catenin signaling activity across multiple basal-like models. Depletion of Ror2 expression yielded distinct phenotypic outcomes and divergent alterations in gene expression programs among different tumors, despite all sharing basal-like features. Notably, we uncovered cell state plasticity and adhesion dynamics regulated by Ror2, which influenced Ras Homology Family Member A (RhoA) and Rho-Associated Coiled-Coil Kinase 1 (ROCK1) activity downstream of Dishevelled-2 (Dvl2). Collectively, these studies illustrate the integration and collaboration of Wnt pathways in basal-like breast cancer, where Ror2 provides a spatiotemporal function to regulate the balance of Wnt signaling and cellular heterogeneity during tumor progression. PMID- 28650468 TI - MKP-1 suppresses PARP-1 degradation to mediate cisplatin resistance. AB - Understanding the mechanisms of platinum compound resistance, including cisplatin resistance, has important implications for improving cancer treatments. Previous studies identified a potential role for mitogen-activated protein kinase phosphatase-1 (MKP-1) in cisplatin resistance. This work focuses on the regulation of poly(ADP-ribose) polymerase-1 (PARP-1) expression by MKP-1. We found that MKP-1 overexpression stimulates PARP-1 and poly(ADP-ribose) (PAR) protein expression and cisplatin resistance while its downregulation suppresses PARP-1 and PAR protein expression and cisplatin resistance. Silencing MKP-1 promoted PARP-1 ubiquitination, which decreased PARP-1 protein levels. We also found that silencing c-Jun N-terminal kinase 1/2 (JNK1/2) decreased PARP-1 ubiquitination while increasing total PARP-1 protein levels. Furthermore, we showed that acquired cisplatin-resistant ovarian cancer cells expressed high levels of MKP-1 and PARP-1 proteins, and that silencing MKP-1 or PARP-1 increased cisplatin sensitivity in resistant cells. Notably, the pharmacologic inhibition of PARP activity restored cisplatin sensitivity in MKP-1 overexpressing cells. Thus, this work indicates that suppression of JNK1/2 activity by MKP-1 maintains PARP-1 levels and suggests that MKP-1-mediated cisplatin resistance can be bypassed by PARP-1 inhibition. PMID- 28650471 TI - Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. AB - This corrects the article DOI: 10.1038/onc.2016.243. PMID- 28650469 TI - A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma. AB - Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3. INPP5E promotes SHH signaling during embryonic development via PtdIns(4,5)P2 hydrolysis at cilia, that in turn regulates the cilia recruitment of the SHH suppressor GPR161. However, the role INPP5E plays in cancer is unknown and the contribution of PI3-kinase signaling to cilia function is little characterized. Here, we reveal INPP5E promotes SHH signaling in SHH medulloblastoma by negatively regulating a cilia-compartmentalized PI3-kinase signaling axis that maintains primary cilia on tumor cells. Conditional deletion of Inpp5e in a murine model of constitutively active Smoothened-driven medulloblastoma slowed tumor progression, suppressed cell proliferation, reduced SHH signaling and promoted tumor cell cilia loss. PtdIns(3,4,5)P3, its effector pAKT and the target pGSK3beta, which when non-phosphorylated promotes cilia assembly/stability, localized to tumor cell cilia. The number of PtdIns(3,4,5)P3/pAKT/pGSK3beta-positive cilia was increased in cultured Inpp5e-null tumor cells relative to controls. PI3-kinase inhibition or expression of wild-type, but not catalytically inactive HA-INPP5E partially rescued cilia loss in Inpp5e-null tumor cells in vitro. INPP5E mRNA and copy number were reduced in human SHH medulloblastoma compared to other molecular subtypes and consistent with the murine model, reduced INPP5E was associated with improved overall survival. Therefore our study identifies a compartmentalized PtdIns(3,4,5)P3/AKT/GSK3beta signaling axis at cilia in SHH-dependent medulloblastoma that is regulated by INPP5E to maintain tumor cell cilia, promote SHH signaling and thereby medulloblastoma progression. PMID- 28650472 TI - DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer. AB - This corrects the article DOI: 10.1038/onc.2017.21. PMID- 28650470 TI - Signaling coupled epigenomic regulation of gene expression. AB - Inheritance of genomic information independent of the DNA sequence, the epigenetics, as well as gene transcription are profoundly shaped by serine/threonine and tyrosine signaling kinases and components of the chromatin remodeling complexes. To precisely respond to a changing external milieu, human cells efficiently translate upstream signals into post-translational modifications (PTMs) on histones and coregulators such as corepressors, coactivators, DNA-binding factors and PTM modifying enzymes. Because a protein with multiple residues for putative PTMs is expected to undergo more than one PTM in cells stimulated with growth factors, the outcome of combinational PTM codes on histones and coregulators is profoundly shaped by regulatory interplays between PTMs. The genomic functions of signaling kinases in cancer cells are manifested by the downstream effectors of cytoplasmic signaling cascades as well as translocation of the cytoplasmic signaling kinases to the nucleus. Signaling mediated phosphorylation of histones serves as a regulatory switch for other PTMs, and connects chromatin remodeling complexes into gene transcription and gene activity. Here, we will discuss the recent advances in signaling-dependent epigenomic regulation of gene transcription using a few representative cancer relevant serine/threonine and tyrosine kinases and their interplay with chromatin remodeling factors in cancer cells. PMID- 28650473 TI - Testes-specific protease 50 promotes cell proliferation via inhibiting activin signaling. AB - Testes-specific protease 50 (TSP50), a novelly identified oncogene, has the capacity to induce cell proliferation, cell invasion and tumor growth. Further studies indicated that CAGA-luc (an activin-responsive reporter construct) reporter activity could be significantly suppressed by TSP50 overexpression, implying that the activin signaling may participate in TSP50-mediated cell proliferation. Here, we reported that TSP50 had an inhibitory effect on activin signaling. Mechanistic studies revealed that TSP50 could interact with ActRIIA, inhibit activin typeIreceptor (ActRIB) phosphorylation, repress Smad2/3 nuclear accumulation and finally promote cell proliferation by reducing the expression of activin signal target gene p27. Additionally, we found that ActRIB activation could reverse TSP50-mediated cell proliferation and tumor growth. Furthermore, analysis of human breast cancer specimens by immunohistochemistry indicated that TSP50 expression was negatively related to p-Smad2/3 and p27 protein levels. Most importantly, breast cancer diagnosis-related indicators such as tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) levels, were correlated well with TSP50/p Samd2/3 and TSP50/p27 expression status. Thus, our studies revealed a novel regulatory mechanism underlying TSP50-induced cell proliferation and provided a new favorable intervention target for the treatment of breast cancer. PMID- 28650474 TI - An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia. AB - Leukemias harboring the ETV6-ABL1 fusion represent a rare subset of hematological malignancies with unfavorable outcomes. The constitutively active chimeric Etv6 Abl1 tyrosine kinase can be specifically inhibited by tyrosine kinase inhibitors (TKIs). Although TKIs represent an important therapeutic tool, so far, the mechanism underlying the potential TKI resistance in ETV6-ABL1-positive malignancies has not been studied in detail. To address this issue, we established a TKI-resistant ETV6-ABL1-positive leukemic cell line through long term exposure to imatinib. ETV6-ABL1-dependent mechanisms (including fusion gene/protein mutation, amplification, enhanced expression or phosphorylation) and increased TKI efflux were excluded as potential causes of resistance. We showed that TKI effectively inhibited the Etv6-Abl1 kinase activity in resistant cells, and using short hairpin RNA (shRNA)-mediated silencing, we confirmed that the resistant cells became independent from the ETV6-ABL1 oncogene. Through analysis of the genomic and proteomic profiles of resistant cells, we identified an acquired mutation in the GNB1 gene, K89M, as the most likely cause of the resistance. We showed that cells harboring mutated GNB1 were capable of restoring signaling through the phosphoinositide-3-kinase (PI3K)/Akt/mTOR and mitogen activated protein kinase (MAPK) pathways, whose activation is inhibited by TKI. This alternative GNB1K89M-mediated pro-survival signaling rendered ETV6-ABL1 positive leukemic cells resistant to TKI therapy. The mechanism of TKI resistance is independent of the targeted chimeric kinase and thus is potentially relevant not only to ETV6-ABL1-positive leukemias but also to a wider spectrum of malignancies treated by kinase inhibitors. PMID- 28650475 TI - Division site selection linked to inherited cell surface wave troughs in mycobacteria. AB - Cell division is tightly controlled in space and time to maintain cell size and ploidy within narrow bounds. In bacteria, the canonical Minicell (Min) and nucleoid occlusion (Noc) systems together ensure that division is restricted to midcell after completion of chromosome segregation1. It is unknown how division site selection is controlled in bacteria that lack homologues of the Min and Noc proteins, including mycobacteria responsible for tuberculosis and other chronic infections2. Here, we use correlated optical and atomic-force microscopy3,4 to demonstrate that morphological landmarks (waveform troughs) on the undulating surface of mycobacterial cells correspond to future sites of cell division. Newborn cells inherit wave troughs from the (grand)mother cell and ultimately divide at the centre-most wave trough, making these morphological features the earliest known landmark of future division sites. In cells lacking the chromosome partitioning (Par) system, missegregation of chromosomes is accompanied by asymmetric cell division at off-centre wave troughs, resulting in the formation of anucleate cells. These results demonstrate that inherited morphological landmarks and chromosome positioning together restrict mycobacterial division to the midcell position. PMID- 28650476 TI - CrY2H-seq: a massively multiplexed assay for deep-coverage interactome mapping. AB - Broad-scale protein-protein interaction mapping is a major challenge given the cost, time, and sensitivity constraints of existing technologies. Here, we present a massively multiplexed yeast two-hybrid method, CrY2H-seq, which uses a Cre recombinase interaction reporter to intracellularly fuse the coding sequences of two interacting proteins and next-generation DNA sequencing to identify these interactions en masse. We applied CrY2H-seq to investigate sparsely annotated Arabidopsis thaliana transcription factors interactions. By performing ten independent screens testing a total of 36 million binary interaction combinations, and uncovering a network of 8,577 interactions among 1,453 transcription factors, we demonstrate CrY2H-seq's improved screening capacity, efficiency, and sensitivity over those of existing technologies. The deep coverage network resource we call AtTFIN-1 recapitulates one-third of previously reported interactions derived from diverse methods, expands the number of known plant transcription factor interactions by three-fold, and reveals previously unknown family-specific interaction module associations with plant reproductive development, root architecture, and circadian coordination. PMID- 28650477 TI - Video rate volumetric Ca2+ imaging across cortex using seeded iterative demixing (SID) microscopy. AB - Light-field microscopy (LFM) is a scalable approach for volumetric Ca2+ imaging with high volumetric acquisition rates (up to 100 Hz). Although the technology has enabled whole-brain Ca2+ imaging in semi-transparent specimens, tissue scattering has limited its application in the rodent brain. We introduce seeded iterative demixing (SID), a computational source-extraction technique that extends LFM to the mammalian cortex. SID can capture neuronal dynamics in vivo within a volume of 900 * 900 * 260 MUm located as deep as 380 MUm in the mouse cortex or hippocampus at a 30-Hz volume rate while discriminating signals from neurons as close as 20 MUm apart, at a computational cost three orders of magnitude less than that of frame-by-frame image reconstruction. We expect that the simplicity and scalability of LFM, coupled with the performance of SID, will open up a range of applications including closed-loop experiments. PMID- 28650478 TI - A DNA origami platform for quantifying protein copy number in super-resolution. AB - Single-molecule-based super-resolution microscopy offers researchers a unique opportunity to quantify protein copy number with nanoscale resolution. However, while fluorescent proteins have been characterized for quantitative imaging using calibration standards, similar calibration tools for immunofluorescence with small organic fluorophores are lacking. Here we show that DNA origami, in combination with GFP antibodies, is a versatile platform for calibrating fluorophore and antibody labeling efficiency to quantify protein copy number in cellular contexts using super-resolution microscopy. PMID- 28650479 TI - AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia. AB - Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O methylation resulted in decreased leukaemia self-renewal potential. Genomic deletion of either C/D box snoRNA SNORD14D or SNORD35A suppressed clonogenic potential of leukaemia cells in vitro and delayed leukaemogenesis in vivo. We further showed that AML1-ETO9a, MYC and MLL-AF9 all enhanced snoRNA formation. Expression levels of C/D box snoRNAs in AML patients correlated closely with in vivo frequency of leukaemic stem cells. Collectively, these findings indicate that induction of C/D box snoRNA/RNP function constitutes an important pathway in leukaemogenesis. PMID- 28650480 TI - Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors. AB - The origin and specification of human dendritic cells (DCs) have not been investigated at the clonal level. Through the use of clonal assays, combined with statistical computation, to quantify the yield of granulocytes, monocytes, lymphocytes and three subsets of DCs from single human CD34+ progenitor cells, we found that specification to the DC lineage occurred in parallel with specification of hematopoietic stem cells (HSCs) to the myeloid and lymphoid lineages. This started as a lineage bias defined by specific transcriptional programs that correlated with the combinatorial 'dose' of the transcription factors IRF8 and PU.1, which was transmitted to most progeny cells and was reinforced by upregulation of IRF8 expression driven by the hematopoietic cytokine FLT3L during cell division. We propose a model in which specification to the DC lineage is driven by parallel and inheritable transcriptional programs in HSCs and is reinforced over cell division by recursive interactions between transcriptional programs and extrinsic signals. PMID- 28650481 TI - Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. AB - Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells. GC-MP cells expressed the interleukin 9 (IL-9) receptor and responded to IL-9. Acute treatment with IL-9 or antibody to IL-9 accelerated or retarded the positioning of GC-MP cells toward the GC edge and exit from the GC, and enhanced or inhibited the development of memory B cells, which required B cell-intrinsic responsiveness to IL-9. Follicular helper T cells (TFH cells) produced IL-9, and deletion of IL-9 from T cells or, more specifically, from GC TFH cells led to impaired memory formation of B cells. Therefore, the GC development of memory B cells is promoted by TFH cell-derived IL-9. PMID- 28650482 TI - The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. AB - By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders. PMID- 28650486 TI - Advanced carbon dots via plasma-induced surface functionalization for fluorescent and bio-medical applications. AB - Multifunctional carbon-based nanodots (C-dots) are synthesized using atmospheric plasma treatments involving reactive gases (oxygen and nitrogen). Surface design was achieved through one-step plasma treatment of C-dots (AC-paints) from polyethylene glycol used as a precursor. These AC-paints show high fluorescence, low cytotoxicity and excellent cellular imaging capability. They exhibit bright fluorescence with a quantum yield twice of traditional C-dots. The cytotoxicity of AC-paints was tested on BEAS2B, THLE2, A549 and hep3B cell lines. The in vivo experiments further demonstrated the biocompatibility of AC-paints using zebrafish as a model, and imaging tests demonstrated that the AC-paints can be used as bio-labels (at a concentration of <5 mg mL-1). Particularly, the oxygen plasma-treated AC-paints (AC-paints-O) show antibacterial effects due to increased levels of reactive oxygen species (ROS) in AC-paints (at a concentration of >1 mg mL-1). AC-paints can effectively inhibit the growth of Escherichia coli (E. coli) and Acinetobacter baumannii (A. baumannii). Such remarkable performance of the AC-paints has important applications in the biomedical field and environmental systems. PMID- 28650484 TI - Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma. AB - Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development. PMID- 28650487 TI - Engineering thiophene-based nanoparticles to induce phototransduction in live cells under illumination. AB - We report that nanoparticles prepared from appropriately functionalized polythiophenes once administered to live cells can acquire phototransduction properties under illumination, becoming photoactive sites able to absorb visible light and convert it to an electrical signal through cell membrane polarization. Amine-reactive fluorescent nanoparticles with pendant N-succinimidyl-ester groups (NPs-NHS) are prepared from polythiophenes alternating unsubstituted and 3-(2,5 dioxopyrrolidin-1-yl-8-octanoate)-substituted thiophenes by a nanoprecipitation method. By 1H NMR of nanoparticles prepared using THF-d8/D2O (solvent/non solvent) we demonstrate that the hydrolysis of the N-succinimidyl-ester group to free N-hydroxysuccinimide takes place slowly over several hours. NPs-NHS reactivity towards primary amine groups is tested towards the NH2 of d- and l enantiomers of tryptophan. We show that the formation of a tryptophan nanoparticle amidic bond creates a chiral shell displaying opposite CD signals for the nanoparticles bound to d or l enantiomers. The interaction of NPs-NHS with live HEK-293 cells is monitored via LSCM. We show that the NPs-NHS are not internalized but remain docked on the cell membrane. We assume that this is mainly the result of the reaction of the NHS groups in the external layer with NH2 groups present in cell membrane proteins, although the contribution of alternative mechanisms cannot be excluded. To support this assumption LSCM experiments show that nanoparticles of comparable size obtained from poly(3 hexylthiophene), NPs-P3HT, are rapidly internalized by live HEK-293 cells. Finally, using the whole-cell current clamp technique under light illumination we demonstrate that NPs-NHS can polarize the cell membrane upon light irradiation while NPs-P3HT cannot. PMID- 28650483 TI - Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. AB - Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others. PMID- 28650485 TI - Neuroblastoma is composed of two super-enhancer-associated differentiation states. AB - Neuroblastoma and other pediatric tumors show a paucity of gene mutations, which has sparked an interest in their epigenetic regulation. Several tumor types include phenotypically divergent cells, resembling cells from different lineage development stages. It has been proposed that super-enhancer-associated transcription factor (TF) networks underlie lineage identity, but the role of these enhancers in intratumoral heterogeneity is unknown. Here we show that most neuroblastomas include two types of tumor cells with divergent gene expression profiles. Undifferentiated mesenchymal cells and committed adrenergic cells can interconvert and resemble cells from different lineage differentiation stages. ChIP-seq analysis of isogenic pairs of mesenchymal and adrenergic cells identified a distinct super-enhancer landscape and super-enhancer-associated TF network for each cell type. Expression of the mesenchymal TF PRRX1 could reprogram the super-enhancer and mRNA landscapes of adrenergic cells toward a mesenchymal state. Mesenchymal cells were more chemoresistant in vitro and were enriched in post-therapy and relapse tumors. Two super-enhancer-associated TF networks, which probably mediate lineage control in normal development, thus dominate epigenetic control of neuroblastoma and shape intratumoral heterogeneity. PMID- 28650488 TI - Solvation of a chiral carboxylic acid: effects of hydrogen bonding on the IR and VCD spectra of alpha-methoxyphenylacetic acid. AB - Strong hydrogen bonding to solvent molecules can significantly alter the IR and VCD spectra of a chiral solute. This can be particularly troublesome for the determination of absolute configurations, as all spatial configurations of solute solvent clusters need to be considered explicitly in spectra calculations. With this contribution, we aim to derive general guidelines for the explicit solvation of carboxylic acids, and characterize the solute-solvent interactions of the model compound alpha-methoxyphenylacetic acid (MPAA) in organic solvents of different polarity. We show that, in the typical concentration range employed for VCD studies, MPAA prefers the formation of dimers in chloroform. In the other investigated solvents (acetonitrile, methanol, and dimethyl sulfoxide), hydrogen bonded solute-solvent clusters have to be considered explicitly for the spectral analysis. We discuss the origin of the solvent dependence of the VCD spectra of MPAA in detail, show which vibrational modes are most strongly affected, and that the spectral response correlates with the hydrogen bonding strength. PMID- 28650489 TI - 1,2-Arylalkylation of N-(arylsulfonyl)acrylamides using aliphatic aldehydes as the alkyl source. AB - A metal-free decarbonylative arylalkylation of N-(arylsulfonyl)acrylamides using aliphatic aldehydes as the alkyl radical source was developed, providing a series of alpha-aryl-beta-alkylamides in moderate to good yields. In this reaction, concomitant alkylation, aryl migration and desulfonylation were involved. PMID- 28650490 TI - Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes. AB - Chemotherapeutic drug resistance of tumor cells under hypoxic conditions is caused by the inhibition of apoptosis by autophagy and drug efflux via adenosine triphosphate (ATP)-dependent transporter activation, among other factors. Here, we demonstrate that disrupting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression can reduce the autophagy and ATP levels in tumor cells. To test whether GAPDH knockdown is sufficient to overcome drug resistance, a nanocarrier (asymmetry-membrane liposome) was designed to encapsulate GAPDH-siRNA with a low dose of paclitaxel (PTX). Liposomes were prepared using novel cryogenic inner outer dual reverse phase emulsion liposome manufacturing technology to obtain a high loading of siRNA. The results of dynamic light scattering (DLS) indicated that the liposomes had an average hydrodynamic diameter of 250.5 nm and polydispersity index (PDI) of 0.210, which was confirmed by (Transmission Electron Microscope) TEM images. In in vitro tests, the siRNA liposomes presented a high specificity in the suppression of GAPDH expression and significant synergy in cytotoxicity with co-delivery of PTX against tumor cells (HeLa and MCF-7) under hypoxic conditions. Moreover, in vivo studies (a HeLa tumor xenograft model using female BALB/c nude mice) demonstrate that the liposomes could not only increase the concentration of drugs in tumors over time but also successfully boosted the chemotherapeutic efficacy of PTX (synergistic therapy with GAPDH siRNA). Tumor cells appeared to lose their resistance against PTX therapy, becoming more sensitive to PTX when GAPDH-siRNA was simultaneously administered in long-circulating liposomes. Consequently, the novel delivery of GAPDH-siRNA using nanotargeted liposomes provides a useful and potential tool to overcome multidrug resistant (MDR) tumors and presents a bright prospect compared with the traditional chemotherapeutic strategies in clinic cancer therapy. PMID- 28650491 TI - Tunable and selective hydrogenation of furfural to furfuryl alcohol and cyclopentanone over Pt supported on biomass-derived porous heteroatom doped carbon. AB - The search for and exploitation of efficient catalytic systems for selective conversion of furfural into various high value-added chemicals remains a huge challenge for green synthesis in the chemical industry. Here, novel Pt nanoparticles supported on bamboo shoot-derived porous heteroatom doped carbon materials were designed as highly active catalysts for controlled hydrogenation of furfural in aqueous media. The porous heteroatom doped carbon supported Pt catalysts were endowed with a large surface area with a hierarchical porous structure, a high content of nitrogen and oxygen functionalities, a high dispersion of the Pt nanoparticles, good water dispersibility and reaction stability. Benefiting from these features, the novel Pt catalysts displayed a high activity and controlled tunable selectivity for furfural hydrogenation to produce furfuryl alcohol and cyclopentanone in water. The product selectivity could be easily modulated by controlling the carbonization temperature of the porous heteroatom doped carbon support and the reaction conditions (temperature and H2 pressure). Under mild conditions (100 degrees C, 1 MPa H2), furfuryl alcohol was obtained in water with complete conversion of the furfural and an impressive furfuryl alcohol selectivity of >99% in the presence of Pt/NC-BS-500. A higher reaction temperature, in water, favored rearrangement of the furfural (FFA) with Pt/NC-BS-800 as the catalyst, which resulted in a high cyclopentanone yield of >76% at 150 degrees C and 3 MPa H2. The surface properties and pore structure of the heteroatom doped carbon support, adjusted using the carbonization temperature, might determine the interactions between the Pt nanoparticles, carbon support and catalytic reactants in water, which in turn could have led to a good selectivity control. The effect of different reaction temperatures and reaction times on the product selectivity was also explored. Combined with exploration of the distribution of the reaction products, a reaction mechanism for furfural reduction has been proposed. PMID- 28650492 TI - Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water soluble zirconium(iv) chelator. AB - The water solubility of a natural product-inspired octadentate hydroxamic acid chelator designed to coordinate Zr(iv)-89 has been improved by using a combined microbiological-chemical approach to engineer four ether oxygen atoms into the main-chain region of a methylene-containing analogue. First, an analogue of the trimeric hydroxamic acid desferrioxamine B (DFOB) that contained three main-chain ether oxygen atoms (DFOB-O3) was generated from cultures of the native DFOB producer Streptomyces pilosus supplemented with oxybis(ethanamine) (OBEA), which competed against the native 1,5-diaminopentane (DP) substrate during DFOB assembly. This precursor-directed biosynthesis (PDB) approach generated a suite of DFOB analogues containing one (DFOB-O1), two (DFOB-O2) or three (DFOB-O3) ether oxygen atoms, with the latter produced as the major species. Log P measurements showed DFOB-O3 was about 45 times more water soluble than DFOB. Second, a peptide coupling chain-extension reaction between DFOB-O3 and the synthetic ether-containing endo-hydroxamic acid monomer 4-((2-(2 aminoethoxy)ethyl)(hydroxy)amino)-4-oxobutanoic acid (PBH-O1) gave the water soluble tetrameric hydroxamic acid DFOB-O3-PBH-O1 as an isostere of sparingly water soluble DFOB-PBH. The complex between DFOB-O3-PBH-O1 and natZr(iv), examined as a surrogate measure of the radiolabelling procedure, analysed by LC MS as the protonated adduct ([M + H]+, m/zobs = 855.2; m/zcalc = 855.3), with supporting HRMS data. The use of a microbiological system to generate a water soluble analogue of a natural product for downstream semi-synthetic chemistry is an attractive pathway for developing new drugs and imaging agents. The improved water solubility of DFOB-O3-PBH-O1 could facilitate the synthesis and purification of downstream products, as part of the ongoing development of ligands optimised for Zr(iv)-89 immunological PET imaging. PMID- 28650493 TI - Liquid crystalline epoxy networks with exchangeable disulfide bonds. AB - A liquid crystalline epoxy network (LCEN) with exchangeable disulfide bonds is synthesized by polymerizing a biphenyl-based epoxy monomer with an aliphatic dicarboxylic acid curing agent containing a disulfide bond. The effect of disulfide bonds on curing behavior and liquid crystalline (LC) phase formation of the LCEN is investigated. The presence of the disulfide bonds results in an increase in the reaction rate, leading to a reduction in liquid crystallinity of the LCEN. In order to promote LC phase formation and stabilize the self-assembled LC domains, a similar aliphatic dicarboxylic acid without the disulfide bond is used as a co-curing agent to reduce the amount of exchangeable disulfide bonds in the system. After optimizing the molar ratio of the two curing agents, the resulting LCEN exhibits improved reprocessability and recyclability because of the disulfide exchange reactions, while preserving LC properties, such as the reversible LC phase transition and macroscopic LC orientation, for shape memory applications. PMID- 28650494 TI - Chemical characteristics of an Ilex Kuding tea polysaccharide and its protective effects against high fructose-induced liver injury and vascular endothelial dysfunction in mice. AB - The present study was designed to investigate the protective effects of Ilex Kuding tea polysaccharides (IKTP) on high fructose (HF)-induced liver injury and vascular endothelial dysfunction in mice. IKTP were identified as acidic heteropolysaccharides by FT-IR and HPLC. Healthy male Kunming mice fed 20% fructose in drinking water for 8 consecutive weeks significantly displayed dyslipidemia, hepatic steatosis, oxidative stress and vascular endothelial dysfunction. However, continuous administration of IKTP at 200, 400 and 800 mg per kg bw in HF-fed mice could prevent the damage caused by HF-diets, especially at dosages of 400 and 800 mg per kg bw (p < 0.01). IKTP significantly reduced the HF-induced elevation of the serum TC, TG, LDL-C, TXA2 and ET-1 levels, as well as AST and ALT activities, while markedly increased the HF-induced decline of HDL-C, PGI2 and eNOS levels in the serum compared to HF-fed mice. Meanwhile, the hepatic MDA level was lowered while SOD and GSH-Px activities were increased in IKTP treated mice, compared to HF-fed mice. Histopathology of the liver and cardiovascular aortic by H&E or oil red O staining confirmed the liver steatosis and the vascular injury induced by HF-diets and the protective effects of IKTP. These findings suggest that HF causes oxidative damage, and IKTP alleviates liver injury and vascular endothelial dysfunction. PMID- 28650495 TI - Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus (MRSA) through the replacement of l-allo-enduracididine with its isosteres. AB - The recently discovered cyclic depsipeptide, teixobactin, is a highly potent antibiotic against multi-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobaterium tuberculosis. It comprises of 4 D amino acids and a rare l-allo-enduracididine amino acid. The synthesis of a properly protected l-allo-enduracididine amino acid and its incorporation into teixobactin is time consuming, synthetically challenging and low yielding and is therefore a major bottleneck in the development of potent analogues of teixobactin. In this article, we have synthesised 8 analogues of teixobactin using commercially available building blocks by replacing the l-allo enduracididine amino acid with its isosteres. Furthermore, we have tested all the compounds against a panel of Gram positive bacteria including MRSA and explained the observed trend in biological activity. Although all the analogues were active, three analogues from this work, showed very promising activity against MRSA (MIC 1 MUg mL-1). We can conclude that amino acids which are the closest isosteres of l-allo-enduracididine are the key to synthesising simplified potent analogues of teixobactin using rapid syntheses and improved yields. PMID- 28650496 TI - Orientation and crystallization of regioregular poly(3-dodecylthiophene) in alumina nanopores. AB - The orientation and crystallization of regioregular poly(3-dodecylthiophene) (P3DDT) in different diameter nanopores were investigated. P3DDT nanowires were prepared by a melt-wetting nonporous alumina template with P3DDT melts. The microstructure of the nanowires was analyzed by micro-Fourier transform infrared spectroscopy, grazing incidence wide angle X-ray diffraction, and differential scanning calorimetry. Although Form I modification prevails in all the nanowires, Form I crystals decrease and Form II crystals increase as the pore diameter decreases. The crystallites developed in the nanowires preferentially aligned with pi-pi stacking (b-axis) along the long axis of the wire and this orientation is marked as the wire diameter decreases. These results could provide guidance on designing polymeric nanomaterials for functional nanodevices in high performance organic photovoltaic cells, sensors, and electrodes. PMID- 28650497 TI - Extreme ultraviolet resist materials for sub-7 nm patterning. AB - Continuous ongoing development of dense integrated circuits requires significant advancements in nanoscale patterning technology. As a key process in semiconductor high volume manufacturing (HVM), high resolution lithography is crucial in keeping with Moore's law. Currently, lithography technology for the sub-7 nm node and beyond has been actively investigated approaching atomic level patterning. EUV technology is now considered to be a potential alternative to HVM for replacing in some cases ArF immersion technology combined with multi patterning. Development of innovative resist materials will be required to improve advanced fabrication strategies. In this article, advancements in novel resist materials are reviewed to identify design criteria for establishment of a next generation resist platform. Development strategies and the challenges in next generation resist materials are summarized and discussed. PMID- 28650498 TI - Two-step FRET mediated metal ion induced signalling responses in a probe appended with three fluorophores. AB - A tri-fluorophoric molecular probe (1) with three different derivatized fluorophores, i.e. anthracene (An), 7-nitrobenz-2-oxa-1,3-diazole (NBD) and rhodamine-B (Rh) appended on to a Tren [tris-(2-aminoethyl)amine] receptor was demonstrated to exhibit metal ion induced ratiometric fluorescence signalling through the initiation of a two-step fluorescence resonance energy transfer (FRET) process owing to a compatible and substantial spectral overlap of electronic absorption and fluorescence of initial donor-intermediate donor/acceptor-final acceptor pairs. The steady-state and time-resolved fluorescence spectral investigation of probes (1a-1f) with individual excitation energy donor (D)/acceptor (A) fluorophores as well as different bi-fluorophoric D A pairs appended to the same receptor, and comparison with those of 1 revealed a higher energy transfer efficiency between the initial donor (FAn) and the final acceptor (FRh) in the presence of an intermediate (FNBD) fluorophore. The determination of FRET efficiency involving rhodamine-B derivatized systems is complicated as the dynamics and equilibria of their complexation induced spirolactam to ring-opened transformations are driven by various influential parameters; despite this, the FRET efficiencies in 1 and other intermediates were determined and compared under similar conditions for a better comprehension of individual fluorophoric contribution in two-step FRET-based sensing. The selectivity in chelation induced two-step FRET mediated fluorescence signalling in 1 is controlled by a coordination environment and solvent medium; it exhibited Hg2+ ion selective signalling responses in aqueous-MeCN medium while rendering discriminatory responses towards Fe3+/Fe2+ redox couples in MeCN medium. PMID- 28650499 TI - Silver-catalyzed [3 + 2] domino reaction: an efficient strategy to synthesize imidazole-5-carbaldehydes. AB - An unprecedented regioselective silver-catalyzed [3 + 2] domino reaction of amidines and ynals for the formation of C-N bonds has been developed. The reaction provided a new route to prepare imidazole-5-carbaldehydes which are important intermediates for the construction of fine chemicals. The reaction proceeds smoothly with a broad range of substrates to give imidazoles in good yields. PMID- 28650500 TI - Insight into thiophene hydrodesulfurization on clean and S-modified MoP(010): a periodic density functional theory study. AB - The hydrodesulfurization (HDS) of thiophene on clean and S-modified MoP(010) is investigated to understand the HDS mechanism as well as the surface sulfur (S) atom effect using periodic density functional theory (DFT). The results show that thiophene prefers strongly flat adsorption on both the clean and S-modified surfaces, in either the molecular state or the dissociative state breaking simultaneously one C-S bond, and the adsorption of thiophene can be slightly weakened by the surface S atom. Thermodynamic and kinetic analysis indicates that the HDS of thiophene in both the molecular and dissociative adsorption states prefers to take place along the direct desulfurization (DDS) pathway rather than hydrogenation on both the clean and S-modified MoP(010) surfaces. Surface S shows a promotion effect on the HDS catalytic activity of MoP(010), because the energy barrier/rate constant of the rate-determining step on the DDS pathway is decreased/enlarged under the S modification. Compared with the situation of MoP(001), MoP(010) should have relatively low HDS activity, since a higher energy barrier as well as weaker exothermicity is involved in the reaction on the latter surface. PMID- 28650501 TI - pH-Responsive near-infrared fluorescent cyanine dyes for molecular imaging based on pH sensing. AB - Indocyanine green (ICG) derivatives having nucleophilic substituents were synthesized as pH-responsive near-infrared dyes. pH-responsive dyes 1-C with closed-ring structures smoothly internalized and converted to emissive open-ring structures 1-O in response to relatively low pHs in acidic intracellular compartments of HeLa cells. PMID- 28650502 TI - Zipf's law for pore ranking and pore anisotropy. AB - In this work it is shown that the range of Zipf's law for the ranking of random pores in solids upholds for ~10 orders of magnitude, from nm pore sizes in laboratory-made materials, to cm pore sizes occurring in solidified volcanic magmas. Also it is demonstrated that for MCM-type materials with organized mesopores, the out-of-trend data in the Zipf plots, corresponding to the sudden pore filling during N2 adsorption, can be used for the convenient estimation of local pore anisotropy. PMID- 28650503 TI - Magnetically frustrated synthetic end member Mn2(PO4)OH in the triplite triploidite family. AB - The manganese end member of triplite-triploidite series of compounds, Mn2(PO4)OH, is synthesized by a hydrothermal method. Its crystal structure is refined in the space group P21/c with a = 12.411(1) A, b = 13.323(1) A, c = 10.014(1) A, beta = 108.16(1), V = 1573.3 A3, Z = 8, and R = 0.0375. Evidenced in measurements of magnetization M and specific heat Cp, Mn2(PO4)OH reaches a long range antiferromagnetic order at TN = 4.6 K. As opposed to both triplite Mn2(PO4)F and triploidite-type Co2(PO4)F, the title compound is magnetically frustrated being characterized by the ratio of Curie-Weiss temperature Theta to Neel temperature TN of about 20. The large value of frustration strength |Theta|/TN stems from the twisted saw tooth chain geometry of corner sharing triangles of Mn polyhedra, which may be isolated within tubular fragments of a triploidite crystal structure. PMID- 28650504 TI - Experimental and theoretical studies on fluvastatin primary photoproduct formation. AB - Fluvastatin (FLV) belongs to the group of compounds referred to as statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Statins act as cholesterol-lowering agents and are among the most frequently prescribed drugs. They upregulate low-density lipoprotein receptors in the liver by binding to the active site of HMG-CoA reductase, which is the key enzyme in cholesterol biosynthesis. Statins have been detected as contaminants in natural waters and are susceptible to degradation upon exposure to light. Fluvastatin is extremely sensitive to light; upon irradiation it forms a range of photoproducts. In this study the fluvastatin molar absorption coefficient and the quantum yield of the drug photodegradation were determined. The FLV photodegradation quantum yield value determined in this work (Phi = 0.13 +/- 0.02) was found to be significantly larger than that previously reported in the literature. Our results also showed that the generation of singlet oxygen is not involved in the drug photodecomposition indicating that the excited triplet state of fluvastatin is not populated efficiently. Moreover, experimental methods and DFT calculations were applied to get insight into the possible mechanisms of fluvastatin primary photoproduct formation. Using the transient absorption spectroscopy technique, the transient species formed immediately after the drug excitation were followed, and the scheme for fluvastatin primary photochemistry was suggested. The primary photoproducts were identified on the basis of spectroscopic and spectrometric methods. A new mechanism for photooxygenation leading to the formation of one of the identified photoproducts (FP2) was proposed and a new approach to the formation of the other photoproduct (FP1) was provided. The theoretical mechanistic explanation of the photoproduct formation is in excellent agreement with the experimental data. PMID- 28650505 TI - Photophysics of 7-mercapto-4-methylcoumarin and derivatives: complementary fluorescence behaviour to 7-hydroxycoumarins. AB - The photophysical behaviour of 7-mercapto-4-methylcoumarin (C-SH) and derivatives has been studied in different solvents. In contrast to 7-hydroxy-4 methylcoumarin, C-SH shows poor emission, but high fluorescence when the thiol is alkylated. The origin and character of the lowest singlet states are discussed, specifically proposing that the thione-like C[double bond, length as m-dash]S resonance form plays a key role in excited state deactivation in C-SH. PMID- 28650506 TI - Oxidative dual C-H thiolation of imidazopyridines with ethers or alkanes using elemental sulphur. AB - Dual C-H thiolation reactions using elemental sulphur remain a challenge. This communication discloses an oxidative radical dual sp2/sp3 C-H thiolation strategy for the coupling of imidazopyridines with ethers or alkanes using elemental sulphur. PMID- 28650507 TI - Stabilisation of gold nanoparticles by N-heterocyclic thiones. AB - Gold nanoparticles (Au-NPs) have been prepared using N-heterocyclic thiones (NHTs) as ligand stabilisers. These Au-NPs have been shown to be very stable, even in air, and have been characterized by a combination of several techniques (TEM, HR-TEM, STEM-HAADF, EDX, DLS, elemental analysis and 1H NMR). These nanoparticles are active in the catalytic reduction of nitroarenes to anilines. PMID- 28650508 TI - PbLnB7O13 (Ln = Tb or Eu): a new type of layered polyborate with multi-colour light emission properties. AB - Two new lead rare-earth polyborates, PbTbB7O13 and PbEuB7O13, have been successfully synthesized via a high temperature molten salt method. Single crystal X-ray diffraction analysis reveals that they are isostructural and feature a 2D layer structure that contains alternating layers of [B7O13]infinity and [Tb]infinity. The [B7O13]infinity layer is constructed of BO3 and BO4 groups with the fundamental building block of B7O17 (3Delta4?: Delta). Solid solutions of PbTb1-xEuxB7O13 (x = 0-1) were prepared via a solid state reaction and the photoluminescence properties were studied. The results show that under UV or near-UV excitation, the luminescence colour of samples of PbTb1 xEuxB7O13 (x = 0-1) can be tuned from green through yellow to red by simply adjusting the relative Eu3+ and Tb3+ concentrations, because of the Tb3+ -> Eu3+ energy transfer mechanism. PMID- 28650509 TI - A co-expression strategy to achieve labeling of individual subunits within a dimeric protein for single molecule analysis. AB - A generic co-expression strategy for site-specific incorporation of a single donor-acceptor dye pair into any position in a dimeric protein, allowing single molecule FRET study of proteins previously inaccessible to this technique, such as the intrinsically disordered prion N-domain of Ure2 in the context of its globular dimeric C-domain. PMID- 28650510 TI - Experiment and theory confirm that UV laser photodissociation spectroscopy can distinguish protomers formed via electrospray. AB - The identification of protonation sites in electrosprayed molecules remains a challenge in contemporary physical science. We present the first demonstration that low-resolution, UV laser photodissociation spectroscopy can be applied in situ to identify the protomers of para-aminobenzoic acid (PABA) formed via electrospray from a single solution. Electronic absorption spectra are recorded via photodepletion and photofragmentation for PABA electrosprayed from solutions of water and acetonitrile. Using this approach, two protomers can be straightforwardly identified, with only the carboxylic acid protomer being produced on electrospray from water while the amine-protonated isomer dominates upon electrospray from acetonitrile. High-level SORCI and MRCI calculations are presented to provide insight into the origin of the distinctive electronic spectra displayed by the protomers. Our results are in excellent agreement with previous PABA studies conducted using established techniques, and demonstrate that UV photodissociation spectroscopy of electrosprayed ions has potential as a new diagnostic tool for identifying protomeric species. PMID- 28650511 TI - Effect of mixed anions on the physicochemical properties of a sodium containing alkoxyammonium ionic liquid electrolyte. AB - The physicochemical properties of the ionic liquid N-ethyl-2-(2-methoxyethoxy) N,N-bis(2-(2-methoxyethoxy)ethyl)ethan-1-ammonium bis(trifluoromethylsulfonyl)imide (N2(2O2O1)3TFSI) as well as its solutions with sodium bis(trifluoromethylsulfonyl)imide (NaTFSI) and sodium bis(fluorosulfonyl)imide (NaFSI) are compared in order to study the effects of the anion. The NaFSI solutions show weaker interactions as suggested by lower glass transition temperatures, lower densities, lower viscosities and higher conductivities as compared to their more strongly coordinating NaTFSI analogues. The transport properties follow Vogel-Tamman-Fulcher behaviour suggesting that the mixtures are fragile glass formers. The addition of a higher concentration of Na salts results in decoupling of the translational motion from the viscosity, as observed from Walden plots, and 23Na NMR data suggests that the sodium speciation is independent of the nature of the Na salt or the temperature but is affected by the salt concentration. PMID- 28650512 TI - Elucidating sequence and solvent specific design targets to protect and stabilize enzymes for biocatalysis in ionic liquids. AB - For many different frameworks, the structure, function, and dynamics of an enzyme is largely determined by the nature of its interactions with the surrounding host environment, thus a molecular level understanding of enzyme/host interactions is essential to the design of new processes and applications. Ionic liquid (IL) solvents are a popular class of solvents in which to study enzyme behavior, yet it is still not possible to predict how a given enzyme will behave in a given IL solvent. Furthermore, a dearth of experimental data with which to evaluate simulation force fields has prevented the full integration of experimental and computational techniques to gain a complete picture of enzyme/IL interactions. Utilizing recently published crystallographic data of an enzyme in complex with an IL, this study aims to validate the use of current molecular force fields for studying enzyme/IL interactions, and to provide new mechanistic insight into enzyme stabilization in IL solvents. Classical molecular dynamics (MD) simulations have been performed on both the folded and unfolded state of Bacillus subtilis lipase A and a quadruple-mutant version of lipase A, in solutions of aqueous 1-butyl-3-methylimidazolium chloride. Results show classical MD simulations can predict the preferred surface binding locations of IL cations as well as reductions in IL anion binding to mutated surface residues with high accuracy. The results also point to a mechanistic difference between IL binding to the folded and unfolded state of an enzyme, which we call the "counter-ion effect". These findings could have important implications for future rational design efforts to stabilize enzymes in non-conventional media. PMID- 28650513 TI - Return to work after work-related stress: a randomized controlled trial of a work focused cognitive behavioral intervention. AB - Objectives This study aimed to evaluate the effect of a stress management intervention (SMI) on lasting return to work (RTW) among patients with work related stress complaints. Methods Sickness benefit departments from three local municipalities referred patients on sick leave with work-related adjustment disorders or mild depression to the Department of Occupational Medicine, Regional Hospital West Jutland. A 2* randomization procedure allocated patients into one of three groups: intervention (N=58), control A (which received a clinical assessment; N=56), or control B (no assessment; N=49). Treatment comprised individual work-focused cognitive behavioral therapy (CBT) with an optional workplace intervention. The outcome was time until lasting RTW (16 and 44 weeks follow-up) using register data. Results Median number of weeks until lasting RTW was 15, 19, and 32 for the intervention group, control A, and control B respectively. However, for group B, clinical assessment was not part of the inclusion process, which may have introduced selection bias. In the fully adjusted Cox regression model, the intervention group exhibited significantly faster lasting RTW at 44 weeks; hazard ratio (HR) 1.57 [95% confidence interval (95% CI) 1.01-2.44] relative to control group A, with a non-significant trend evident at 16 weeks; HR 1.70 (95% CI 0.94-3.10), when controlling for age, gender, occupation, sick leave during previous year, full or partial sick leave, and diagnosis. Unadjusted analyses remained directionally consistent but were reduced to marginal significance. Conclusions There was a tendency towards faster lasting RTW in the intervention group compared to control A, which received clinical assessment, in all analyses. The intervention group returned to work about 4 weeks earlier than control A, which could translate into substantial financial gains. PMID- 28650514 TI - Automatic segmentation of the spine by means of a probabilistic atlas with a special focus on ribs suppression. AB - PURPOSE: The development of automatic and reliable algorithms for the detection and segmentation of the vertebrae are of great importance prior to any diagnostic task. However, an important problem found to accurately segment the vertebrae is the presence of the ribs in the thoracic region. To overcome this problem, a probabilistic atlas of the spine has been developed dealing with the proximity of other structures, with a special focus on ribs suppression. METHODS: The data sets used consist of Computed Tomography images corresponding to 21 patients suffering from spinal metastases. Two methods have been combined to obtain the final result: firstly, an initial segmentation is performed using a fully automatic level-set method; secondly, to refine the initial segmentation, a 3D volume indicating the probability of each voxel of belonging to the spine has been developed. In this way, a probability map is generated and deformed to be adapted to each testing case. RESULTS: To validate the improvement obtained after applying the atlas, the Dice coefficient (DSC), the Hausdorff distance (HD), and the mean surface-to-surface distance (MSD) were used. The results showed up an average of 10 mm of improvement accuracy in terms of HD, obtaining an overall final average of 15.51 +/- 2.74 mm. Also, a global value of 91.01 +/- 3.18% in terms of DSC and a MSD of 0.66 +/- 0.25 mm were obtained. The major improvement using the atlas was achieved in the thoracic region, as ribs were almost perfectly suppressed. CONCLUSION: The study demonstrated that the atlas is able to detect and appropriately eliminate the ribs while improving the segmentation accuracy. PMID- 28650515 TI - Reduction mammoplasty: Potential for overtreatment? PMID- 28650516 TI - Asymmetric Synthesis of Pyrrolidine-Containing Chemical Scaffolds via Tsuji-Trost Allylation of N-tert-Butanesulfinyl Imines. AB - A simple and efficient asymmetric synthesis of novel sp3 -rich pyrrolidine chemical scaffolds over five steps starting from simple ketones is described. Key steps involve the use of tert-butanesulfinamide as a chiral auxiliary to perform an asymmetric Tsuji-Trost allylation, with subsequent cross-metathesis with an acrylate ester and reduction of the sulfinimine/cyclisation of the resulting amine giving the pyrrolidine scaffolds in high yields and diastereoselectivites. By removing the chiral auxiliary and functionalising the ester group, the resulting scaffold core can be further derivatised. PMID- 28650517 TI - Adaptive change in chewing-related brain activity while wearing a palatal plate: an functional magnetic resonance imaging study. AB - Prosthodontic treatment success depends on patients' ability to adapt to an altered oral environment containing removable prostheses. We investigated adaptive chewing-related brain activity changes in response to a new oral environment. Twenty-eight fully dentate subjects (mean age: 28.6 years) wore experimental denture-base palatal plates (3 mm thick), for 7 days. We measured food mixing ability and cycle time, and assessed brain activity by functional magnetic resonance imaging during chewing at pre-insertion (Day 0), and immediately (Day 1), 3 days (Day 3) and 7 days (Day 7) after insertion. Food mixing ability significantly decreased and cycle time increased on Day 1 as compared to Day 0 (P < 0.001) and tended to recover to Day 0 level by Day 7. Brain activation in the right face primary sensorimotor cortex and putamen significantly decreased on Day 1 as compared to Day 0 (P < 0.001) and recovered to Day 0 level by Day 7. Brain activation in the left face primary sensorimotor cortex, putamen, anterior cingulate gyrus (ACG) and right posterior medial frontal cortex (pMFC) significantly decreased on Day 1 as compared to Day 0 (P < 0.001) and did not recover by Day 7. Thus, oral environment changes involving palate covering affected chewing and induced adaptive brain activity changes in the face primary sensorimotor cortex and putamen, possibly associated with motor learning. As ACG and pMFC activity remained unrecovered by 7 days after plate insertion, automatisation of chewing while wearing a palatal plate may require longer adaptation periods. PMID- 28650518 TI - A simple in silico strategy identifies candidate biomarkers for the diagnosis of liver fibrosis in morbidly obese subjects. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder, tightly associated with obesity. The histological spectrum of the disease ranges from simple steatosis to steatohepatitis, with different stages of fibrosis, and fibrosis stage is the most significant predictor of mortality in NAFLD. Liver biopsy continues to be the gold standard for its diagnosis and reliable non-invasive diagnostic tools are unavailable. We investigated the accuracy of candidate proteins, identified by an in silico approach, as biomarkers for diagnosis of fibrosis. METHODS: Seventy-one morbidly obese (MO) subjects with biopsy-proven NAFLD were enrolled, and the cohort was subdivided according to minimal (F0/F1) or moderate (F2/F3) fibrosis. The plasmatic level of CD44 antigen (CD44), secreted protein acidic and rich in cysteine (SPARC), epidermal growth factor receptor (EGFR) and insulin-like growth factor 2 (IGF2) were determined by ELISA. Significant associations between plasmatic levels and histological fibrosis were determined by correlation analysis and the diagnostic accuracy by the area under receiver operating characteristic curves (AUROC). RESULTS: Eighty-two percentage of the subjects had F0/F1 and 18% with F2/F3 fibrosis. Plasmatic levels of IGF2, EGFR and their ratio (EGFR/IGF2) were associated with liver fibrosis, correlating inversely for IGF2 (P < .006) and directly (P < .018; P < .0001) for EGFR and EGFR/IGF2 respectively. The IGF2 marker had the best diagnostic accuracy for moderate fibrosis (AUROC 0.83), followed by EGFR/IGF2 ratio (AUROC 0.79) and EGFR (AUROC 0.71). CONCLUSIONS: Our study supports the potential utility of IGF2 and EGFR as non-invasive diagnostic biomarkers for liver fibrosis in morbidly obese subjects. PMID- 28650519 TI - Disassembly-Reassembly Approach to RuO2 /Graphene Composites for Ultrahigh Volumetric Capacitance Supercapacitor. AB - A porous, yet compact, RuO2 /graphene hybrid is successfully prepared by using a disassembly-reassembly strategy, achieving effective and uniform loading of RuO2 nanoparticles inside compact graphene monolith. The disassembly process ensures the uniform loading of RuO2 nanoparticles into graphene monolith, while the reassembly process guarantees a high density yet simultaneously unimpeded ion transport channel in the composite. The resulting RuO2 /graphene hybrid possesses a density of 2.63 g cm-3 , leading to a record high volumetric capacitance of 1485 F cm-3 at the current density of 0.1 A g-1 . When the current density is increased to 20 A g-1 , it remains a high volumetric capacitance of 1188 F cm-3 . More importantly, when the single electrode mass loading is increased to 12 mg cm 2 , it still delivers a high volumetric capacitance of 1415 F cm-3 at the current density of 0.1 A g-1 , demonstrating the promise of this disassembly-reassembly approach to create high volumetric performance materials for energy storage applications. PMID- 28650520 TI - Immature Midbrain Dopaminergic Neurons Derived from Floor-Plate Method Improve Cell Transplantation Therapy Efficacy for Parkinson's Disease. AB - Recent reports have indicated human embryonic stem cells-derived midbrain dopamine (mDA) neurons as proper cell resources for use in Parkinson's disease (PD) therapy. Nevertheless, no detailed and systematic study has been conducted to identify which differentiation stages of mDA cells are most suitable for transplantation in PD therapy. Here, we transplanted three types of mDA cells, DA progenitors (differentiated in vitro for 16 days [D16]), immature DA neurons (D25), and DA neurons (D35), into PD mice and found that all three types of cells showed high viability and strong neuronal differentiation in vivo. Both D25 and D35 cells showed neuronal maturation and differentiation toward TH+ cells and, accordingly, satisfactory behavioral functional recovery. However, transplanted D16 cells were less capable of producing functional recovery. These findings provide a valuable guideline for standardizing the differentiation stage of the transplantable cells used in clinical cell therapy for PD. Stem Cells Translational Medicine 2017;6:1803-1814. PMID- 28650521 TI - JMJ27, an Arabidopsis H3K9 histone demethylase, modulates defense against Pseudomonas syringae and flowering time. AB - Histone methylation is known to dynamically regulate diverse developmental and physiological processes. Histone methyl marks are written by methyltransferases and erased by demethylases, and result in modification of chromatin structure to repress or activate transcription. However, little is known about how histone methylation may regulate defense mechanisms and flowering time in plants. Here we report characterization of JmjC DOMAIN-CONTAINING PROTEIN 27 (JMJ27), an Arabidopsis JHDM2 (JmjC domain-containing histone demethylase 2) family protein, which modulates defense against pathogens and flowering time. JMJ27 is a nuclear protein containing a zinc-finger motif and a catalytic JmjC domain with conserved Fe(II) and alpha-ketoglutarate binding sites, and displays H3K9me1/2 demethylase activity both in vitro and in vivo. JMJ27 is induced in response to virulent Pseudomonas syringae pathogens and is required for resistance against these pathogens. JMJ27 is a negative modulator of WRKY25 (a repressor of defense) and a positive modulator of several pathogenesis-related (PR) proteins. Additionally, loss of JMJ27 function leads to early flowering. JMJ27 negatively modulates the major flowering regulator CONSTANS (CO) and positively modulates FLOWERING LOCUS C (FLC). Taken together, our results indicate that JMJ27 functions as a histone demethylase to modulate both physiological (defense) and developmental (flowering time) processes in Arabidopsis. PMID- 28650522 TI - Full text publication rates of research abstracts presented at the European Society of Endodontology (ESE) Congresses in the last 20 years. AB - AIM: To evaluate the full-text publication rates of scientific research abstracts presented at the European Society of Endodontology (ESE) Congresses held between 1993 and 2013 (a total of 11 occasions) and to determine factors associated with the manuscripts. METHODOLOGY: An electronic database search was conducted from January 2015 to December 2016 to identify full text English written publications of the research abstracts presented at the last 11 ESE Biennial Congresses from 1993 to 2013. For each occasion, research abstract information were retrieved from the International Endodontic Journal (IEJ) through the official website of the ESE and the following parameters for each abstract presentation were recorded: Year of presentation, first author's affiliation, geographic origin, and type of study. Following full-text article identification, additional information was recorded such as: Year and journal of publication, elapsed time until full publication and number of authors per presentation and publication. RESULTS: A total of 1165 research abstracts were presented, of which 401 (34.4%) were finally published as full-length articles. Overall 235 articles (58.6%) were published either in the International Endodontic Journal (IEJ, 35.7%) or Journal of Endodontics (JOE, 22.9%). The mean time between abstract presentation and full text publication was 18.95 months. Munich (2001) had the highest publication rate (44%) whereas Lisbon (2013) had the highest number of published articles (77). Turkey was the country with the highest number of published abstracts (56). However, the Netherlands was the country with the highest number of publications related to the number of presentations (21/26) (80.7%). Differences in authorship between presentation and full publication were found in 179 (44.6%) articles. CONCLUSIONS: A substantial number of research abstracts presented at ESE congresses were not published in peer reviewed journals. Authors prefer to publish their research papers in international journals with high impact factor. This article is protected by copyright. All rights reserved. PMID- 28650523 TI - Characterization of the phosphate-specific transport system in Cronobacter sakazakii BAA-894. AB - AIMS: Characterize the phosphate-specific transport system in Cronobacter sakazakii BAA-894. METHODS AND RESULTS: The genes relevant to phosphate transfer in C. sakazakii BAA-894 were determined by using sequence alignment to the corresponding genes in Escherichia coli. Then, the determined pst operon in C. sakazakii BAA-894 was deleted using the lambda Red recombination system. Using the wild type C. sakazakii BAA-894 as a control, the membrane permeability, auto aggregation, exopolysaccharide biosynthesis, biofilm formation, and adhesion ability of the mutant ?pst grown in media containing high or low concentrations of phosphate were investigated; stronger auto-aggregation, less biofilm formation and higher adhesion ability were observed in ?pst cells grown in low phosphate media. Transcriptome analysis showed that phosphate availability has a global influence to C. sakazakii BAA-894 and ?pst cells. CONCLUSIONS: Phosphorus availability is important for C. sakazakii in many ways including biofilm formation and adhesion ability. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that phosphate availability has a global influence to C. sakazakii, expends our understanding to the phosphate transfer in C. sakazakii, and is helpful for revealing the survival mechanism of C. sakazakii under stress conditions. PMID- 28650524 TI - US-guided core-needle biopsy versus US-guided fine-needle aspiration of suspicious cervical lymph nodes for staging workup of non-head and neck malignancies: A propensity score matching study. AB - BACKGROUND AND OBJECTIVES: To compare US-guided core-needle biopsy (USCNB) and US guided fine-needle aspiration (USFNA) of suspicious cervical lymph nodes for staging workup of malignancies in locations other than the head and neck using propensity score matching (PSM). METHODS: This retrospective cohort study included 108 patients who underwent USFNA and 1058 who underwent USCNB for suspicious cervical lymph nodes detected by imaging modalities during the staging workup for malignancies located in regions other than the head and neck. The primary outcome was defined as the inconclusive results. To evaluate the procedures according to the outcome, we performed univariate and multivariate logistic regression analyses and a 1:1 PSM of USCNB and USFNA. RESULTS: There was no complication for both USFNA and USCNB. The inconclusive results were 6.5% (7/108) for USFNA and 1.6% (17/1058) for USCNB. A significantly lower rate of the inconclusive results in USCNB than in USFNA before matching was maintained after a 1:1 PSM of 103 patients from each group (before PSM, odds ratio (OR) = 4.489, 95% confidence interval (CI) [1.803-11.177], P = 0.001; after PSM, OR = 1.060, 95%CI [1.013-1.109], P = 0.012). CONCLUSIONS: Because USCNB can reduce inconclusive results compared to USFNA, it could be more helpful for staging workup of malignancies in locations other than the head and neck in patients with suspicious cervical lymph nodes. PMID- 28650525 TI - Thermal Synthesis of Perchlorinated Oligosilanes: A Fresh Look at an Old Reaction. AB - A combined experimental and theoretical study of the high-temperature reaction of SiCl4 and elemental silicon is presented. The nature and reactivity of the product formed upon rapid cooling of the gaseous reaction mixture is investigated by comparison with the defined model compounds cyclo-Si5 Cl10 , n-Si5 Cl12 and n Si4 Cl10 . A DFT assessment provides mechanistic insight into the oligosilane formation. Experimental 29 Si NMR investigations, supported by quantum-chemical 29 Si NMR calculations, consistently show that the reaction product is composed of discrete molecular perchlorinated oligosilanes. Low-temperature chlorination is an unexpectedly selective means for the transformation of cyclosilanes to acyclic species by endocyclic Si-Si bond cleavage, and we provide a mechanistic rationalization for this observation. In contrast to the raw material, the product obtained after low-temperature chlorination represents an efficient source of neo-Si5 Cl12 or the amine-stabilized disilene EtMe2 N?SiCl2 Si(SiCl3 )2 through reaction with aliphatic amines. PMID- 28650526 TI - A Dual-Administration Microtracer Technique to Characterize the Absorption, Distribution, Metabolism, and Excretion of [14 C]Seletalisib (UCB5857) in Healthy Subjects. AB - Phosphoinositide 3 kinases are targets for development of small-molecule inhibitors to disrupt progression of immune-inflammatory diseases. This phase 1 open-label study (Eudract 2014-005353-39) evaluated the safety and relative bioavailability of 2 new seletalisib (UCB5857) formulations (A and B) compared with a reference formulation. Absolute bioavailability (period 1a, n = 6) and disposition and metabolism (period 1b, n = 6) of the reference formulation were evaluated: healthy subjects received 30 mg orally plus ~20 MUg of a 14 C-labeled microtracer (intravenously in 1a, orally in 1b). New formulations were evaluated: subjects from periods 1a and 1b were pooled and randomly distributed to receive a single oral dose (30 mg) of formulation A (n = 6) or B (n = 6) in periods 2 and 3, using a crossover design. Absolute oral bioavailability of seletalisib was 97% (90% confidence interval 87, 107). Unchanged [14 C]seletalisib was the predominant radioactive component in plasma (94.8%). After oral dosing, the radioactive dose was primarily recovered in feces (74.6%, geometric coefficient of variation [GeoCV] 18.1%), mostly as metabolites. Seletalisib demonstrated a 24 hour terminal half-life, volume of distribution of 60.9 L (GeoCV 23.8%), and a total plasma clearance of 1.7 L/h (GeoCV 35.4%). Formulations A and B displayed similar or even higher exposure compared with reference seletalisib (areas under the concentration-time curves 19 337 [GeoCV 30.8%], 20 380 [GeoCV 37.7%], and 15 932 [GeoCV 36.4%] h.ng/mL, respectively). New formulations A and B were bioequivalent with each other, and all 3 formulations showed acceptable safety profiles. This radiolabeled microtracer approach successfully informed on the absorption, distribution, metabolism, and excretion of seletalisib and further guided the mechanistic pharmacokinetic modeling. PMID- 28650528 TI - Urinary diversions in low-resource settings. PMID- 28650527 TI - Chemical Structures of Specific Sodium Ion Battery Components Determined by Operando Pair Distribution Function and X-ray Diffraction Computed Tomography. AB - To improve lithium and sodium ion battery technology, it is imperative to understand how the properties of the different components are controlled by their chemical structures. Operando structural studies give us some of the most useful information for understanding how batteries work, but it remains difficult to separate out the contributions of the various components of a battery stack (e.g., electrodes, current collectors, electrolyte, and binders) and examine specific materials. We have used operando X-ray diffraction computed tomography (XRD-CT) to study specific components of an essentially unmodified working cell and extract detailed, space-resolved structural information on both crystalline and amorphous phases that are present during cycling by Rietveld and pair distribution function (PDF) methods. We illustrate this method with the first detailed structural examination of the cycling of sodium in a phosphorus anode, revealing surprisingly different mechanisms for sodiation and desodiation in this promising, high-capacity anode system. PMID- 28650529 TI - Metal-Ion-Activated DNAzymes Used for Regulation of Telomerase Activity in Living Cells. AB - Telomerase is a key regulator in cell metabolism, tissue renewal, and organismal lifespan. Here we develop a simple strategy to modulate cellular telomerase activity, and further control cell fate based on Mg2+ - and Zn2+ -activated DNAzymes in living cells. Through modulation of telomerase activity, we can regulate cell behavior, including cell migration, cell differentiation, cell senescence, and cell cycle. Our work provides a new way to modulate telomerase activity in living cells by using DNAzymes. PMID- 28650530 TI - Microfluidic-based process to sort cells efficiently secreting a protein. PMID- 28650532 TI - Biotechnology and Bioengineering: Volume 114, Number 8, August 2017. PMID- 28650533 TI - A novel, high fidelity site-specific integration system for CHO expression. PMID- 28650535 TI - Insights into exo-exo synergy. PMID- 28650534 TI - Hyperosmolality on protein glycosylation in CHO cells. PMID- 28650536 TI - Surveillance for lung metastasis from giant cell tumor of bone. AB - BACKGROUND AND OBJECTIVES: Literature on surveillance for lung metastasis from giant cell tumor of bone (GCTB) is scarce. We aimed to develop one by determining: (1) the optimal surveillance schedule by analyzing time-to-event data, taking into account the predictive factors, and (2) the effective diagnostic modality. METHODS: A total of 333 patients who underwent surgery for GCTB were followed for at least 2 years. All had chest radiography, and 169 had additional CT for surveillance. Time to lung metastasis and cumulative incidence were calculated, and diagnostic performance between chest radiography and CT was compared. RESULTS: Twenty-five (7.5%) of 333 patients developed lung metastasis, and local recurrence (LR) was the only predictive factor (RR = 6.54). Median interval from LR to metastasis was 15 months, and 17 (85%) of the 20 metastases with LR occurred within 3 years of LR. Cumulative post-LR incidences at 1, 3, and 5 years were 15.4%, 21.5%, and 21.5%, respectively. CT was more sensitive (100% vs 32%), and had higher positive predictive value (81% vs 57%) and accuracy (96% vs 93%). CONCLUSIONS: Intensified lung surveillance is warranted for GCTB patients with LR, especially for 3 years from diagnosis of LR. CT is effective for detecting lung metastasis from GCTB. PMID- 28650537 TI - Predictors of false negative sentinel lymph node biopsy in trunk and extremity melanoma. AB - BACKGROUND: Nodal recurrence following negative sentinel lymph node biopsy (SLNB) for melanoma is known as false-negative (FN) SLNB. Risk factors for FN SLNB among patients with trunk and extremity melanoma have not been well-defined. METHODS: After retrospective review, SLNB procedures were classified FN, true positive (TP; positive SLNB), or true negative (TN; negative SLNB without recurrence). Factors associated with high false negative rate (FNR) and low negative predictive value (NPV) were identified by comparing FNs to TPs and TNs, respectively. Survival was evaluated using Kaplan-Meier methods. RESULTS: Of 1728 patients, 234 were TP and 37 were FN for overall FNR of 14% and NPV of 97.5%. Age >=65 years was independently associated with high FNR (FNR 20% in this group). Breslow thickness >1 mm and ulceration were independently associated with low NPV. Among patients with ulcerated tumors >4 mm, NPV was 88%. Median time to recurrence for FNs was 13 months. Among patients with primary melanomas <=2 mm in depth, overall and distant disease-free survival were significantly shorter with FN SLNB than TP SLNB. CONCLUSIONS: Older age is associated with increased FNR; patients with thick, ulcerated lesions should be considered for increased nodal surveillance after negative SLNB given low NPV in this group. PMID- 28650538 TI - Response to letter to the editor: "Reduction Mammoplasty: Potential for Overtreatment?" PMID- 28650557 TI - Association between metformin prescription and growth rates of abdominal aortic aneurysms. AB - BACKGROUND: It has been suggested that diabetes medications, such as metformin, may have effects that inhibit abdominal aortic aneurysm (AAA) growth. The aim of this study was to examine the association of diabetes treatments with AAA growth in three patient cohorts. METHODS: AAA growth was studied using ultrasound surveillance in cohort 1, repeated CT in cohort 2 and more detailed repeat CT in cohort 3. Growth was estimated by the mean annual increase in maximum AAA diameter. RESULTS: A total of 1697 patients with an AAA were studied, of whom 118, 39 and 16 patients were prescribed metformin for the treatment of diabetes in cohorts 1, 2 and 3 respectively. Prescription of metformin was associated with a reduced likelihood of median or greater AAA growth in all three cohorts (cohort 1: adjusted odds ratio (OR) 0.59, 95 per cent c.i. 0.39 to 0.87, P = 0.008; cohort 2: adjusted OR 0.38, 0.18 to 0.80, P = 0.011; cohort 3: adjusted OR 0.13, 0.03 to 0.61, P = 0.010). No other diabetes treatment was significantly associated with AAA growth in any cohort. CONCLUSION: These findings suggest a potential role for metformin in limiting AAA growth. PMID- 28650558 TI - Kidney transplant recipients with hepatitis C virus experienced 100% sustained virologic response at 12 weeks when treated with sofosbuvir-ledipasvir. PMID- 28650559 TI - The antibacterial activity and modes of LI-F type antimicrobial peptides against Bacillus cereus in vitro. AB - AIMS: LI-Fs are a family of highly potent cyclic lipodepsipeptide antibiotics with a broad antimicrobial spectrum (Gram-positive bacteria and fungi). In this study, LI-F-type antimicrobial peptides (AMP-jsa9) composing of LI-F03a, LI-F03b, LI-F04a, LI-F04b and LI-F05b were isolated from Paenibacillus polymyxa JSA-9. To better understand the antimicrobial mechanism of AMP-jsa9, the potency and action(s) of AMP-jsa9 against Bacillus cereus were examined. METHODS AND RESULTS: Flow cytometry, confocal laser microscopy, scanning electron microscopy, transmission electron microscopy (TEM) and atomic force microscopy observation, as well as determination of peptidoglycan and cell wall-associated protein and other methods were used. The results indicate that AMP-jsa9 exhibits strong, broad-spectrum antimicrobial activity. Moreover, AMP-jsa9 targets the cell wall and membrane of B. cereus to impair membrane integrity, increase membrane permeability and enhance cytoplasm leakage (e.g. K+ , protein, nucleic acid). This leads to bacterial cells with irregular, withered and coarse surfaces. In addition, AMP-jsa9 is also able to bind to DNA and break down B. cereus biofilms. CONCLUSIONS: In this study, the action mechanism of LI-Fs against B. cereus was clarified in details. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study provide a theoretical basis for utilizing AMP-jsa9 or similar analogues as natural and effective preservatives in the food and feed industries. These efforts could also stimulate research activities interested in understanding the specific effects of other antimicrobial agents. PMID- 28650560 TI - Uncovering the role of brain-derived neurotrophic factor/tyrosine kinase receptor B signaling in head and neck malignancies. AB - Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that was first known as responsible for sustain the growth, function, and plasticity of neural cells. BDNF exerts its effects by binding to the tyrosine kinase receptor B (TrkB). The BDNF/TrkB axis has been reported to be overexpressed in several neurogenic and non-neurogenic tumors. Its higher expression was associated with a poor prognosis to patients affected by different human malignancies, tumor growth, invasion, and metastasis; epithelial mesenchymal transition and resistance to chemotherapy. BDNF/TrkB represent promising targets to the development of novel anticancer therapies. Some clinical trials are currently evaluating the efficacy of Trk protein-target drugs in different types of solid tumors. To date, few groups have evaluated the DNF/TrkB pathway in head and neck malignancies. The aims of this study were to review the literature concerning the role of BDNF/TrkB activation in head and neck squamous cell carcinoma and malignant salivary gland tumors and to discuss future perspectives of BDNF/TrkB-target therapy. PMID- 28650561 TI - Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. AB - RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway. PMID- 28650563 TI - Unusual Lipid A from a Cold-Adapted Bacterium: Detailed Structural Characterization. AB - Colwellia psychrerythraea 34H is a Gram-negative cold-adapted microorganism that adopts many strategies to cope with the limitations associated with the low temperatures of its habitat. In this study, we report the complete characterization of the lipid A moiety from the lipopolysaccharide of Colwellia. Lipid A and its partially deacylated derivative were completely characterized by high-resolution mass spectrometry, NMR spectroscopy, and chemical analysis. An unusual structure with a 3-hydroxy unsaturated tetradecenoic acid as a component of the primary acylation pattern was identified. In addition, the presence of a partially acylated phosphoglycerol moiety on the secondary acylation site at the 3-position of the reducing 2-amino-2-deoxyglucopyranose unit caused tremendous natural heterogeneity in the structure of lipid A. Biological-activity assays indicated that C. psychrerythraea 34H lipid A did not show an agonistic or antagonistic effect upon testing in human macrophages. PMID- 28650562 TI - The Economic Value of Hybrid Single-photon Emission Computed Tomography With Computed Tomography Imaging in Pulmonary Embolism Diagnosis. AB - OBJECTIVE: The objective was to quantify the potential economic value of single photon emission computed tomography (SPECT) with computed tomography (CT; SPECT/CT) versus CT pulmonary angiography (CTPA), ventilation-perfusion (V/Q) planar scintigraphy, and V/Q SPECT imaging modalities for diagnosing suspected pulmonary embolism (PE) patients in an emergency setting. METHODS: An Excel-based simulation model was developed to compare SPECT/CT versus the alternate scanning technologies from a payer's perspective. Clinical endpoints (diagnosis, treatment, complications, and mortality) and their corresponding cost data (2016 USD) were obtained by performing a best evidence review of the published literature. Studies were pooled and parameters were weighted by sample size. Outcomes measured included differences in 1) excess costs, 2) total costs, and 3) lives lost per annum between SPECT/CT and the other imaging modalities. One-way (+/-25%) sensitivity and three scenario analyses were performed to gauge the robustness of the results. RESULTS: For every 1,000 suspected PE patients undergoing imaging, expected annual economic burden by modality was found to be 3.2 million (SPECT/CT), 3.8 million (CTPA), 5.8 million (planar), and 3.6 million (SPECT) USD, with a switch to SPECT/CT technology yielding per-patient-per-month cost savings of $51.80 (vs. CTPA), $213.80 (vs. planar), and $36.30 (vs. SPECT), respectively. The model calculated that the incremental number of lives saved with SPECT/CT was six (vs. CTPA) and three (vs. planar). Utilizing SPECT/CT as the initial imaging modality for workup of acute PE was also expected to save $994,777 (vs. CTPA), $2,852,014 (vs. planar), and $435,038 (vs. SPECT) in "potentially avoidable"' excess costs per annum for a payer or health plan. CONCLUSION: Compared to the currently available scanning technologies for diagnosing suspected PE, SPECT/CT appears to confer superior economic value, primarily via improved sensitivity and specificity and low nondiagnostic rates. In turn, the improved diagnostic accuracy accords this modality the lowest ratio of expenses attributable to potentially avoidable complications, misdiagnosis, and underdiagnosis. PMID- 28650564 TI - The impact of extrahepatic disease among patients undergoing liver-directed therapy for neuroendocrine liver metastasis. AB - INTRODUCTION: Management of neuroendocrine liver metastasis (NELM) in the presence of extrahepatic disease (EHD) is controversial. We sought to examine outcomes of patients undergoing liver-directed therapy (resection, ablation, or both) for NELM in the presence of EHD using a large international cohort of patients. METHODS: 612 patients who underwent liver-directed therapy were identified from eight institutions. Postoperative outcomes, as well as and overall (OS) were compared among patients with and without EHD. RESULTS: Most primary tumors were located in the pancreas (N = 254;41.8%) or the small bowel (N = 188;30.9%). Patients underwent surgery alone (N = 471;77.0%), ablation alone (N = 15;2.5%), or a combined approach (N = 126;20.6%). Patients with EHD had more high-grade tumors (EHD: 44.4% vs no EHD: 16.1%; P < 0.001). EHD was often the peritoneum (N = 29;41.4%) or lung (N = 19;27.1%). Among 70 patients with EHD, 20.0% (N = 14) underwent concurrent resection for EHD. After median follow-up of 51 months, 174 (28.4%) patients died with a median OS of 140.4 months. Patients with EHD had a shorter median OS versus patients who did not have EHD (EHD: 87 months vs no EHD: not reached; P = 0.002). EHD was independently associated with an increased risk of death (HR: 2.56, 95%CI 1.16-5.62; P = 0.02). CONCLUSION: Patients with NELM and EHD had more aggressive tumors, conferring a twofold increased risk of death. Surgical treatment of NELM among patients with EHD should be individualized. PMID- 28650566 TI - Immediate versus delayed initiation of the levonorgestrel-releasing intrauterine system following medical termination of pregnancy - 1 year continuation rates: a randomised controlled trial. AB - OBJECTIVE: To assess the 1-year continuation rates and new pregnancies following immediate versus delayed insertion of the levonorgestrel-releasing intrauterine system (LNG-IUS) after medical termination of pregnancy (MTOP) up to 20 weeks of gestation. DESIGN: A randomised controlled trial. SETTING: Helsinki University Hospital, Finland, January 2013 to December 2014. POPULATION: A total of 267 women requesting MTOP and planning LNG-IUS for post-MTOP contraception. METHODS: Insertion of LNG-IUS occurred immediately (0-3 days) or after a delay (2-4 weeks) following MTOP. Follow-up visits were at 3 months and 1 year after MTOP. MAIN OUTCOME MEASURES: LNG-IUS use at 1 year after MTOP. RESULTS: Women were randomised to immediate (n = 134) or delayed (n = 133) insertion of the LNG-IUS, and 133 and 131 were analysed; 127 (95.5%) women received immediate insertion and 111 (84.7%) women had delayed insertion of the LNG-IUS (risk ratio [RR] 1.13, 95% CI 1.04-1.22). The verified numbers of women continuing the LNG-IUS use at 1 year were 83 (62.4%) and 52 (39.7%) (RR 1.57, 95% CI 1.23-2.02). The numbers of new pregnancies were 6 (4.5%) and 16 (12.2%) (RR 0.37, 95% CI 0.15-0.91), and numbers of subsequent TOPs were 4 (3.0%) and 5 (3.8%) (RR 0.79, 95% CI 0.22-2.87). CONCLUSIONS: Immediate insertion of the LNG-IUS following MTOP resulted in higher 1-year continuation rates compared with delayed insertion. In addition, those receiving immediate insertion demonstrated a decreased new pregnancy rate, but no difference in the numbers of another TOP. TWEETABLE ABSTRACT: Immediate LNG-IUS insertion after MTOP results in a higher 1-year continuation compared with delayed insertion. PMID- 28650565 TI - Integrated In Situ Characterization of a Molten Salt Catalyst Surface: Evidence of Sodium Peroxide and Hydroxyl Radical Formation. AB - Sodium-based catalysts (such as Na2 WO4 ) were proposed to selectively catalyze OH radical formation from H2 O and O2 at high temperatures. This reaction may proceed on molten salt state surfaces owing to the lower melting point of the used Na salts compared to the reaction temperature. This study provides direct evidence of the molten salt state of Na2 WO4 , which can form OH radicals, using in situ techniques including X-ray diffraction (XRD), scanning transmission electron microscopy (STEM), laser induced fluorescence (LIF) spectrometry, and ambient-pressure X-ray photoelectron spectroscopy (AP-XPS). As a result, Na2 O2 species, which were hypothesized to be responsible for the formation of OH radicals, have been identified on the outer surfaces at temperatures of >=800 degrees C, and these species are useful for various gas-phase hydrocarbon reactions, including the selective transformation of methane to ethane. PMID- 28650567 TI - Controllable Interlayer Spacing of Sulfur-Doped Graphitic Carbon Nanosheets for Fast Sodium-Ion Batteries. AB - The electrochemical behaviors of current graphitic carbons are seriously restricted by its low surface area and insufficient interlayer spacing for sodium ion batteries. Here, sulfur-doped graphitic carbon nanosheets are reported by utilizing sodium dodecyl sulfate as sulfur resource and graphitization additive, showing a controllable interlayer spacing range from 0.38 to 0.41 nm and a high specific surface area up to 898.8 m2 g-1 . The obtained carbon exhibits an extraordinary electrochemical activity for sodium-ion storage with a large reversible capacity of 321.8 mAh g-1 at 100 mA g-1 , which can be mainly attributed to the expanded interlayer spacing of the carbon materials resulted from the S-doping. Impressively, superior rate capability of 161.8 mAh g-1 is reserved at a high current density of 5 A g-1 within 5000 cycles, which should be ascribed to the fast surface-induced capacitive behavior derived from its high surface area. Furthermore, the storage processes are also quantitatively evaluated, confirming a mixed storage mechanism of diffusion-controlled intercalation behavior and surface-induced capacitive behavior. This study provides a novel route for rationally designing various carbon-based anodes with enhanced rate capability. PMID- 28650568 TI - Enhanced functional properties of human limbal stem cells by inhibition of the miR-31/FIH-1/P21 axis. AB - OBJECTIVE: On the basis of the functional roles of the embryonic stem cell niche (ESCN) in the human limbal stem cells (LSCs), we proposed to explore the potential roles of microRNAs in regulating the self-renewal and differentiation of LSCs cultured in the ESCN. METHODS: The LSCs were cultured in different media, either in CnT-20 media or in CnT-20 + 20% ES culture supernatant (ESC-CM). The LSCs cultured in ESC-CM were then transfected with microRNA-31 (miR-31) mimic or antago-31. The colony-forming efficiency (CFE) was analysed. Cell cycle, apoptosis, mitochondrial potential and reactive oxygen species were analysed by flow cytometry, and quantitative real-time PCR was used to determine the expression levels of FIH-1, P21, P63, ABCG2, CK3, microRNA-31, microRNA-143, microRNA-145 and microRNA-184. Indirect immunostaining was employed to detect the expression of P63, ABCG2, survivin, connexin-43 and CK3. Western blot was employed to detect the expression of FIH-1, P63, P21, CK3, caspase 3, Tcf4, beta catenin, survivin, GSK3beta and pGSK3beta. RESULTS: Compared with cells grown in CnT-20, the level of miR-31 in cells grown in ESC-CM was lower. We investigated the roles that miR-31 and FIH-1 play in regulating the functional properties of LSCs. We used antagomirs (antago) to reduce the level of miR-31 in LSCs. Antago 31 increased FIH-1 levels and significantly reduced P21 expressional level in LSCs compared to irrelevant-antago (Ir-antago) treatment. The downregulation of miR-31 in LSCs promotes the maintenance of stemness. CONCLUSION: ES culture supernatant (ESC-CM) regulates the fate of LSCs in part by inhibiting the miR 31/FIH-1/P21 axis. This study may have a high impact on the expansion of LSCs in regenerative medicine, especially for ocular surface reconstruction. PMID- 28650569 TI - Biomass-Derived Catalysts for Selective Hydrogenation of Nitroarenes. AB - Development of catalytically active materials from biowaste represents an important aspect of sustainable chemical research. Three heterogeneous materials were synthesized from inexpensive biomass-based chitosan and abundant Co(OAc)2 using complexation followed by pyrolysis at various temperatures. These materials were applied in the catalytic hydrogenation of nitroarenes using molecular hydrogen. A variety of diversely functionalized nitroarenes including some pharmaceutically active compounds were converted into aromatic amines in high yields, with high selectivity, and with excellent functional group tolerance. This green protocol has also been implemented for the synthesis of a biologically important TRPC3 inhibitor. PMID- 28650571 TI - Development of Proton-Responsive Catalysts. AB - A changeable ligand, which involves in activation of a catalyst or assists a reaction, draws an increasing attention, in contrast to a classical ligand as spectator. Proton-responsive catalysts, which are capable of undergoing changes of properties on gaining/losing one or more protons, provides interesting features as follows: (i) catalyst activation by electronic effect, (ii) pH-tuning of water-solubility, and (iii) second-coordination-sphere interaction. On the basis of this catalyst design concept, we developed several highly efficient proton-responsive catalysts for CO2 hydrogenation as H2 storage, formic acid (FA) dehydrogenation as H2 production, and transfer hydrogenation. The transformable ligands of proton-responsive catalysts in promoting effective catalysis have aroused our interest. In this account, we summarize our efforts for the development and application of proton-responsive catalysts. Specifically, the important role of pH-dependent proton-responsive complexes will be discussed. PMID- 28650570 TI - Perioperative BRAF inhibitors in locally advanced stage III melanoma. AB - BACKGROUND AND OBJECTIVES: Stage III malignant melanoma is a heterogeneous disease where those cases deemed marginally resectable or irresecatble are frequently incurable by surgery alone. Targeted therapy takes advantage of the high incidence of BRAF mutations in melanomas, most notably the V600E mutation. These agents have rarely been used in a neoadjuvant setting prior to surgery. METHODS: Thirteen consecutive patients with confirmed BRAFV600E regionally advanced melanoma deemed marginally resectable or irrresectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The primary outcome measures were a successful resection and pathological response. Disease-free survival was a secondary outcome measure. RESULTS: Overall, 12/13 patients showed a marked clinical responsiveness to medical treatment, enabling a macroscopically successful resection in all cases. Four patients had a complete pathological response with no viable tumor evident in the resected specimens and eight patients showed evidence of minimally residual tumor with extensive tumoral necrosis and fibrosis. One patient progressed and died before surgery. At a median follow up of 20 months, 10 patients remain free of disease. CONCLUSIONS: Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival. PMID- 28650572 TI - Cloning and characterization of nitrate reductase gene in Ulva prolifera (Ulvophyceae, Chlorophyta). AB - Ulva spp. dominates green tides around the world, which are occurring at an accelerated rate. The competitive nitrogen assimilation efficiency in Ulva is suggested to result in ecological success against other seaweeds. However, molecular characterization of genes involved in nitrogen assimilation has not been conducted. Here, we describe the identification of the nitrate reductase (NR) gene from a green seaweed Ulva prolifera, an alga which is responsible for the world's largest green tide in the Yellow Sea. Using rapid amplification of cDNA ends and genome walking, the NR gene from U. prolifera (UpNR) was cloned, which consisted of six introns and seven exons encoding 863 amino acids. According to sequence alignment, the NR in U. prolifera was shown to possess all five essential domains and 21 key invariant residues in plant NRs. The GC content of third codon position of UpNR (82.75%) was as high as those of green microalgae, and the intron number supported a potential loss issue from green microalga to land plant. Real-time quantitative PCR results showed that UpNR transcript level was induced by nitrate and repressed by ammonium, which could not be removed by addition of extra nitrate, indicating that U. prolifera preferred ammonium to nitrate. Urea would not repress NR transcription by itself, while it weakened the induction effect of nitrate, implying it possibly inhibited nitrate uptake rather than nitrate reduction. These results suggest the use of UpNR as a gene-sensor to probe the N assimilation process in green tides caused by Ulva. PMID- 28650573 TI - Factors associated with thromboembolic events following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND AND OBJECTIVES: We investigated the risk factors, incidence, and role of thromboprophylaxis in the development of thrombosis following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: We reviewed data of patients with CRS/HIPEC in three hospitals. RESULTS: Overall, 192 patients underwent CRS/HIPEC during 2007-2016. Mechanical (thigh-length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h before surgery until discharge) was provided for all patients; and 116 (60.4%) also received an extended course of enoxaparin for 2-4 weeks after discharge. Twenty-six patients experienced thrombotic complications (13.5%) including portal-splenic-mesenteric venous thrombosis (n = 11, 5.7%), pulmonary embolism (n = 10, 5.2%), and deep vein thrombosis (n = 5, 2.6%); most (n = 21, 80.8%) occurred after hospital discharge. Univariate analysis identified Peritoneal Cancer Index, intraoperative transfusion requirement, operative blood loss, operative time, lengths of hospital, and intensive care unit stay, and lack of administration of anticoagulation at discharge as significantly associated with thrombosis. With multivariate analysis, only the lack of anticoagulation therapy at discharge remained significantly associated with thrombosis (P = 0.0001). CONCLUSIONS: Thromboembolic complications are common following CRS/HIPEC. As significantly lower rates of thrombosis were found in patients who received an extended course of anticoagulation, we support its use for at least 2 weeks after discharge. PMID- 28650574 TI - Injection of Microporous Annealing Particle (MAP) Hydrogels in the Stroke Cavity Reduces Gliosis and Inflammation and Promotes NPC Migration to the Lesion. AB - With the number of deaths due to stroke decreasing, more individuals are forced to live with crippling disability resulting from the stroke. To date, no therapeutics exist after the first 4.5 h after the stroke onset, aside from rest and physical therapy. Following stroke, a large influx of astrocytes and microglia releasing proinflammatory cytokines leads to dramatic inflammation and glial scar formation, affecting brain tissue's ability to repair itself. Pathological conditions, such as a stroke, trigger neural progenitor cells (NPCs) proliferation and migration toward the damaged site. However, these progenitors are often found far from the cavity or the peri-infarct tissue. Poststroke tissue remodeling results in a compartmentalized cavity that can directly accept a therapeutic material injection. Here, this paper shows that the injection of a porous hyaluronic acid hydrogel into the stroke cavity significantly reduces the inflammatory response following stroke while increasing peri-infarct vascularization compared to nonporous hydrogel controls and stroke only controls. In addition, it is shown that the injection of this material impacts NPCs proliferation and migration at the subventricular zone niche and results, for the first time, in NPC migration into the stroke site. PMID- 28650575 TI - Creation of Faceted Polyhedral Microgels from Compressed Emulsions. AB - Compressed monodisperse emulsions in confined space exhibit highly ordered structures. The influence of the volume fraction and the confinement geometry on the organized structures is investigated and the mechanism by which structural transition occurs is studied. Based on the understanding of ordering behavior of compressed emulsions, a simple and high-throughput method to fabricate monodisperse polyhedral microgels using the emulsions as the template is developed. By controlling the geometry of the confined spaces, a variety of shapes such as hexagonal prism, Fejes Toth honeycomb prism, truncated octahedron, pyritohedron, and truncated hexagonal trapezohedron are implemented. Moreover, the edge sharpness of each shape is controllable by adjusting the drop volume fraction. This design principle can be readily extended to other shapes and materials, and therefore provides a useful means to create polyhedral microparticles for both fundamental study and practical applications. PMID- 28650576 TI - Prognostic factors for recurrence of locally advanced differentiated thyroid cancer. AB - : Background and Objectives To present treatment outcomes and prognostic factors for surgical management of locally advanced differentiated thyroid cancer (DTC). METHODS: Retrospective review of 70 patients in a single, tertiary referral institution was done. Clinical pathology characteristics were analyzed to investigate prognosticators, based on primary endpoints; locoregional recurrence alone (LRR), total recurrence (LRR or distant metastasis (DM)), and recurrence free survival. RESULTS: Recurrent laryngeal nerve (n = 31) and trachea (n = 30) were most commonly invaded organs by tumor. At the mean follow-up of 81.7 months, LRR occurred in 15 patients and/or DM was detected in 15 patients (10 developed LRR and DM). By multivariate analysis, R1 resection (positive margin) and pN1b stage increased risk of LRR with a fold of 3.16 [95%CI 1.08-9.24, P = 0.03] and 5.92 [1.61-21.7, P = 0.007], respectively. Also, they increased risk of total recurrence with a fold of 3.04 [95%CI 1.26-7.31, P = 0.01] and 3.42 [95%CI 1.16 10.0, P = 0.02], respectively. Patients with pN1b stage showed better LRR-free survival than pN0/N1a stage (P = 0.03). Conclusions Along with careful preoperative evaluation of the extent of primary and neck disease, obtaining negative resection margin and aggressive neck management is critical to improve oncologic outcomes of locally advanced DTC. PMID- 28650577 TI - Time-dependent trends in cardiovascular adverse events during follow-up after carotid or iliofemoral endarterectomy. AB - BACKGROUND: Recent observations have suggested a decline in vulnerable carotid artery and iliofemoral atherosclerotic plaque characteristics over the past decade. The aim of this study was to determine whether, in the presence of clinically manifest carotid or peripheral artery disease, secondary adverse cardiovascular events decreased over this period. METHODS: Patients included in the Athero-Express biobank between 2003 and 2012 were analysed. During 3-year follow-up, composite cardiovascular endpoints were documented yearly, including: myocardial infarction, coronary interventions, stroke, peripheral interventions and cardiovascular death. The major cardiovascular endpoint consisted of myocardial infarction, stroke and cardiovascular death. RESULTS: Some 1684 patients who underwent carotid endarterectomy (CEA) and another 530 who had iliofemoral endarterectomy (IFE) were analysed. In total, 405 (25.2 per cent) and 236 (45.9 per cent) patients had a composite cardiovascular endpoint within 3 years after CEA and IFE respectively. Corrected for possible confounders, the percentage of patients with a secondary cardiovascular event after CEA did not change over time (hazard ratio (HR) 0.91, 95 per cent c.i. 0.65 to 1.28; P = 0.590, for 2011-2012 versus 2003-2004). In patients who had IFE, the incidence of secondary cardiovascular events significantly decreased only in the last 2 years (HR 0.62, 0.41 to 0.94; P = 0.024), owing to a decrease in peripheral (re)interventions in 2011-2012 (HR 0.59, 0.37 to 0.94; P = 0.028). No decrease in major cardiovascular events was observed in either group. CONCLUSION: In patients who had undergone either CEA or IFE there was no evidence of a decrease in all secondary cardiovascular events. There were no differences in major cardiovascular events. PMID- 28650579 TI - Reconstruction using a perforator free flap after malignant melanoma resection of the ankle and foot. AB - BACKGROUND: Surgical excision with adequate margin is the treatment of choice to provide best chance for survival. However, tumors located on distal lower extremity may require reconstruction to salvage the limb which may affect prognosis and quality of life. This retrospective study aimed to evaluate the effect of free flap on overall outcomes of patients with primary malignant melanoma located on the foot and ankle. METHODS: Patients with primary malignant melanoma on the leg and foot who required free flap coverage between August 2005 and January 2014 were evaluated. The reconstruction and oncological outcomes were assessed. RESULTS: The cohort of 59 patients showed 96.7% successful reconstructive outcomes. The mean duration from surgery to partial weight bearing was 9 days. The 5-year overall survival and 5-year progression-free survival rates were 73.2% and 44%, respectively. The overall VAS-FA score was 94.1 implying excellent functional recovery. CONCLUSION: The use of free flaps to close defects after cancer resection can help preserve maximal extremity length and function. This approach does not have negative impact on overall outcome and further provide an increased quality of life with better function. Reconstruction using free flaps should be considered primarily when defects cannot be covered by conventional methods. PMID- 28650578 TI - Intake of Energy and Protein is Associated with Overweight Risk at Age 5.5 Years: Results from the Prospective TEDDY Study. AB - OBJECTIVE: The associations of energy, protein, carbohydrate, and fat intake with weight status up to the age of 5.5 years were prospectively assessed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: Food record data (over 3 days) and BMI measurements between 0.25 and 5.5 years were available from 5,563 children with an increased genetic risk for type 1 diabetes followed from shortly after birth. Odds ratios (ORs) were calculated for overweight and obesity by previous intake of energy, protein, carbohydrate, and fat with adjustment for potential confounders. RESULTS: Having overweight or obesity at the age of 5.5 years was positively associated with mean energy intake in previous age intervals (e.g., adjusted OR [95% CI] for overweight: 1.06 [1.04 1.09] per 100 kcal intake at the age of 4.5-5.0 years) and with protein intake after the age of 3.5 and 4.5 years, respectively (e.g., adjusted OR for overweight: 1.06 [1.03-1.09] per 1% of energy intake at the age of 4.5-5.0 years). The respective associations with carbohydrate and fat intake were less consistent. CONCLUSIONS: These findings indicate that energy and protein intake are positively associated with increased risk for overweight in childhood but yield no evidence for potential programming effects of protein intake in infancy. PMID- 28650580 TI - Single Atomically Sharp Lateral Monolayer p-n Heterojunction Solar Cells with Extraordinarily High Power Conversion Efficiency. AB - The recent development of 2D monolayer lateral semiconductor has created new paradigm to develop p-n heterojunctions. Albeit, the growth methods of these heterostructures typically result in alloy structures at the interface, limiting the development for high-efficiency photovoltaic (PV) devices. Here, the PV properties of sequentially grown alloy-free 2D monolayer WSe2 -MoS2 lateral p-n heterojunction are explores. The PV devices show an extraordinary power conversion efficiency of 2.56% under AM 1.5G illumination. The large surface active area enables the full exposure of the depletion region, leading to excellent omnidirectional light harvesting characteristic with only 5% reduction of efficiency at incident angles up to 75 degrees . Modeling studies demonstrate the PV devices comply with typical principles, increasing the feasibility for further development. Furthermore, the appropriate electrode-spacing design can lead to environment-independent PV properties. These robust PV properties deriving from the atomically sharp lateral p-n interface can help develop the next-generation photovoltaics. PMID- 28650581 TI - Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. AB - Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates. PMID- 28650583 TI - von Hippel-Lindau development in children and adolescents. AB - The autosomal dominant von Hippel-Lindau disease (vHL) is associated with a lifelong risk of tumor development, especially retinal and CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma. Knowledge of paediatric vHL development is limited, and current surveillance guidelines are based on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started surveillance before 18 years: 37 Danish patients from the national vHL research database and 62 international patients reported in 15 articles. Overall, 70% (69 of 99) developed manifestations before 18 years (median age at first manifestation: 12 years (range: 6-17 years)). Thirty per cent (30 of 99) had developed more than one manifestation type; the most frequent were retinal (34%) and CNS (30%) hemangioblastomas. Among the 37 Danish patients, 85% (97 of 116) of their tumors were asymptomatic. Vision outcome is significantly improved in hemangioblastomas that are treated while still asymptomatic. We agree with current guidelines that retinal surveillance be performed from birth. The patients had their first CNS hemangioblastomas at the median ages of 13-14 years (range: 6-17 years). Further, 11% (4 of 37) of the Danish patients had CNS surgery in their teenage years. Although the cohort is too small to make definite conclusions about specific initiation ages, regular CNS surveillance from vHL patients' teenage years seems clinically relevant. PMID- 28650584 TI - Matched Molecular Pair Analysis on Large Melting Point Datasets: A Big Data Perspective. AB - A matched molecular pair (MMP) analysis was used to examine the change in melting point (MP) between pairs of similar molecules in a set of ~275k compounds. We found many cases in which the change in MP (DeltaMP) of compounds correlates with changes in functional groups. In line with the results of a previous study, correlations between DeltaMP and simple molecular descriptors, such as the number of hydrogen bond donors, were identified. In using a larger dataset, covering a wider chemical space and range of melting points, we observed that this method remains stable and scales well with larger datasets. This MMP-based method could find use as a simple privacy-preserving technique to analyze large proprietary databases and share findings between participating research groups. PMID- 28650585 TI - The importance of mitotic rate reporting in primary cutaneous melanoma. PMID- 28650582 TI - Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1. AB - OBJECTIVE: The purpose of the study was to explore the impact of dual targeting of C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) on the metabolic and inflammatory consequences of obesity induced by a high-fat diet (HFD). METHODS: C57BL/6J wild-type, Cx3cr1-/- , Ccr2-/- , and Cx3cr1-/- Ccr2-/- double-knockout male and female mice were fed a 45% HFD for up to 25 weeks starting at 12 weeks of age. RESULTS: All groups gained weight at a similar rate and developed a similar degree of adiposity, hyperglycemia, glucose intolerance, and impairment of insulin sensitivity in response to HFD. As expected, the circulating monocyte count was decreased in Ccr2-/- and Cx3cr1-/- Ccr2-/- mice but not in Cx3cr1-/- mice. Flow cytometric analysis of perigonadal adipose tissue of male, but not female, mice revealed trends to lower CD11c+MGL1- M1-like macrophages and higher CD11c-MGL1+ M2-like macrophages as a percentage of CD45+F4/80+CD11b+ macrophages in Cx3cr1-/- Ccr2-/- mice versus wild-type mice, suggesting reduced adipose tissue macrophage activation. In contrast, single knockout of Ccr2 or Cx3cr1 did not differ in their adipose macrophage phenotypes. CONCLUSIONS: Although CCR2 and CX3CR1 may synergistically impact inflammatory phenotypes, their joint deficiency did not influence the metabolic effects of a 45% HFD-induced obesity in these model conditions. PMID- 28650586 TI - A complete thermodynamic analysis of enzyme turnover links the free energy landscape to enzyme catalysis. AB - Our understanding of how enzymes work is coloured by static structure depictions where the enzyme scaffold is presented as either immobile, or in equilibrium between well-defined static conformations. Proteins, however, exhibit a large degree of motion over a broad range of timescales and magnitudes and this is defined thermodynamically by the enzyme free energy landscape (FEL). The role and importance of enzyme motion is extremely contentious. Much of the challenge is in the experimental detection of so called 'conformational sampling' involved in enzyme turnover. Herein we apply combined pressure and temperature kinetics studies to elucidate the full suite of thermodynamic parameters defining an enzyme FEL as it relates to enzyme turnover. We find that the key thermodynamic parameters governing vibrational modes related to enzyme turnover are the isobaric expansivity term and the change in heat capacity for enzyme catalysis. Variation in the enzyme FEL affects these terms. Our analysis is supported by a range of biophysical and computational approaches that specifically capture information on protein vibrational modes and the FEL (all atom flexibility calculations, red edge excitation shift spectroscopy and viscosity studies) that provide independent evidence for our findings. Our data suggest that restricting the enzyme FEL may be a powerful strategy when attempting to rationally engineer enzymes, particularly to alter thermal activity. Moreover, we demonstrate how rational predictions can be made with a rapid computational approach. PMID- 28650587 TI - The value of N staging with the positive lymph node ratio, and splenectomy, for remnant gastric cancer: A multicenter retrospective study. AB - BACKGROUND: Surgery for remnant gastric cancer (RGC) frequently fails to obtain the >15 lymph nodes necessary for tumor-node-metastasis (TNM) staging. We aimed to evaluate the utility of the recently developed tumor-ratio-metastasis (TRM) staging system. We also examined the pattern of lymph node metastasis and the role of prophylactic splenectomy in RGC. METHODS: Between May 2003 and December 2012, data from 170 patients who underwent surgery for RGC were retrospectively analyzed. RESULTS: RGC arising after previous benign disease (n = 46) was associated with retrieval of more lymph nodes (27.3 vs 10.0; P < 0.001), and a lower rate of retrieving <=15 lymph nodes (15.6% vs 77.4%, P < 0.001), than after previous malignant disease (n = 122). The 5 year survival rate according to TNM staging was 75% in stage I, 77.1% in stage II, and 23.5% in stage III, whereas by TRM staging it was 75%, 81.6%, and 23.2%, respectively. Overall survival was not different between the splenectomy and non-splenectomy groups at each stage (P = 0.751, 0.723, 0.151, and 0.706 for stage I, II, III, and IV, respectively). CONCLUSION: The analyses did not identify a survival benefit from prophylactic splenectomy or show an improvement in staging with the TRM system for RGC. PMID- 28650588 TI - Genetic study of the BRAF gene reveals new variants and high frequency of the V600E mutation among Iranian ameloblastoma patients. AB - BACKGROUND: Ameloblastoma is a benign, slow-growing and locally invasive tumor. It is one of the most prevalent odontogenic tumors, with an incidence rate of 1% of all oral tumors and approximately 18% of odontogenic tumors. A group of genes have been investigated in patients with ameloblastoma. The BRAF V600E mutation has been implicated as the most common mutation in ameloblastoma. The presence or absence of this mutation has been associated with several clinicopathological properties, including location, age at diagnosis, histology, and prognosis. Although some populations have been investigated so far, little data are available on the Iranian population. The current research was launched to study the BRAF V600E mutation among a cohort of Iranian patients with ameloblastoma. METHODS: In this clinicopathological and molecular biology study, a total of 19 formalin-fixed, paraffin-embedded tissues were studied. DNA extraction was performed, followed by PCR-sequencing of exons 10 and 15 of the BRAF gene to identify mutations. In silico analysis was performed for the identified variants. Results were analyzed by T test, Chi-square, and Fisher's exact test. RESULTS: Totally, 12 of 19 samples (63%) harbored the p. V600E hotspot mutation. In addition, we identified several variants, two of which were novel. The c.1769T>G (p. V590G) and c.1751C>T (p.L584F) as the novel variants showed a possible damaging effect by in silico analysis. No variant was found within exon 10. CONCLUSIONS: Our study confirms the role of BRAF mutations in ameloblastoma in the Iranian patients studied. PMID- 28650590 TI - Intra- and interobserver reproducibility of Bruch's membrane opening minimum rim width measurements with spectral domain optical coherence tomography. AB - PURPOSE: To investigate the reproducibility of Bruch's membrane opening minimum rim width (BMO-MRW) and retinal nerve fibre layer thickness (RNFLT) measurements using spectral domain optical coherence tomography (SD-OCT). Additionally, to investigate the reproducibility of BMO area measurements and fovea to BMO centre (FoBMO) angle. METHODS: Participants were healthy subjects (n = 30) and patients with glaucoma (n = 26). One eye of each participant was scanned to obtain optic nerve head (24 radial B-scans) and peripapillary (one circular B-scan) images by three independent examiners. Additionally, one examiner imaged each participant three times on the same day. Intra- and interobserver reproducibilities were estimated by within-subject standard deviation (SW) and coefficient of variation (COV). Spearman's rank correlation coefficient was used to test the correlation between the magnitude of the parameter and its standard deviation. RESULTS: The global BMO-MRW COVs (%) in healthy/glaucoma subjects were 0.87/1.34 and 1.28/3.13 for intra- and interobserver analyses, respectively, and the corresponding global RNFLT figures were 1.50/2.10 and 2.04/2.87. Global mean BMO-MRW and RNFLT showed no correlation with their respective standard deviations. The reproducibilities of BMO area and FoBMO angle were excellent and similar between the groups. CONCLUSION: The reproducibilities of BMO-MRW, BMO area measurements and FoBMO angle were excellent in both healthy subjects and patients with glaucoma. Bruch's membrane opening minimum rim width (BMO-MRW) reproducibility is comparable to that of RNFLT measurements. PMID- 28650589 TI - Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial. AB - : Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/MUL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4 <350 cells/MUL). BMD was measured annually at the lumbar spine and hip by dual-energy X-ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent-to-treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow-up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non-white, 26% women, median CD4 count 642 cells/MUL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow-up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow-up, immediate ART resulted in greater BMD declines than deferred ART at the hip (-2.5% versus -1.0%; difference -1.5%, 95% confidence interval [CI] -2.2 to -0.8, p < 0.001) and spine (-1.9% versus -0.4%; difference -1.6%, 95% CI -2.2 to -1.0, p < 0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer term consequences of the observed reductions in BMD is needed. CLINICAL TRIALS REGISTRATION: NCT00867048. (c) 2017 American Society for Bone and Mineral Research. PMID- 28650591 TI - The silver lining: towards the responsible and limited usage of silver. AB - Silver has attracted a lot of attention as a powerful, broad spectrum and natural antimicrobial agent since the ancient times because of its nontoxic nature to the human body at low concentrations. It has been used in treatment of various infections and ulcers, storage of water and prevention of bacterial growth on the surfaces and within materials. However, there are numerous medical and health benefits of colloidal or nanosilver apart from its microbicidal ability which as yet has not been fully embraced by the medical community. These include antiplatelet activity, antioxidant effect, anticancer activity, wound healing and bone regeneration, enhancement of immunity, and increase in antibiotic efficiency. Additionally silver also provides protection against alcohol toxicity, upper respiratory tract infections and stomach ailments. Although nanosilver has been proposed for various topical applications, its usage by ingestion and inhalation remains controversial due to the lack of detailed and precise toxicity information. These beneficial properties of silver can be utilized by using silver at very low concentrations which are not harmful to the human body and environment. The following review discusses the diverse medical applications of silver and further recommends human clinical studies for its in vivo usage. PMID- 28650592 TI - OM-LV20, a novel peptide from odorous frog skin, accelerates wound healing in vitro and in vivo. AB - The healing of chronic wounds remains a considerable challenge in clinical trials and imposes severe financial and physiological burdens on patients. Many works are being tried to find ideal clinical promoting wound healing biomaterials. Small bioactive peptides with low cost and easy production, store and transfer become excellent candidates. Here, we identified a novel peptide (named OM-LV20) from skin secretions of odorous frog Odorrana margaretae. The peptide had an amino acid sequence of "LVGKLLKGAVGDVCGLLPIC," contained an intramolecular disulfide bridge at the C-terminus, and was produced by post-translational processing of a 71-residue prepropeptide. Our results showed that OM-LV20 had no direct microbe-killing effects, hemolytic activity, or acute toxicity, but did exhibit weak antioxidant activity. OM-LV20 promoted wound healing against human keratinocytes (HaCaT) and human skin fibroblasts (HSF) in both time- and dose dependent manners. In addition, it induced the proliferation of HaCaT but not HSF cells. Of note, OM-LV20 showed strong wound healing-promoting activity in a mice model of full-thickness skin wound. Our research indicates the cellular and animal level wound healing potential of OM-LV20, and thus provides a novel bioactive peptide template for the development of wound healing agents and medicine. PMID- 28650593 TI - HHV-6 in liver transplantation: A literature review. AB - Human herpesvirus 6 (HHV-6A and HHV-6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV-6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate histopathological effects of HHV-6 remains the gold standard for diagnosis of end-organ disease. HHV-6 reactivation may be restricted to the infected organ with no evidence of active infection in the blood. HHV-6 infections in liver transplant patients are mostly asymptomatic, but clinically significant tissue-invasive infections have been treated successfully with ganciclovir, foscarnet or cidofovir. Inherited chromosomally integrated HHV 6 (ciHHV-6), in either the recipient or the donor organ, may create confusion about systemic HHV-6 infection. Recipients with inherited ciHHV-6 may have an increased risk of opportunistic infection and graft rejection. This article reviews the current scientific data on the clinical effects, risk factors, pathogenesis, diagnosis and treatment of HHV-6 infections in liver transplant recipients. PMID- 28650599 TI - Anti-Mullerian hormone - a marker of upcoming menopause or a questionable guesswork? AB - Anti-Mullerian hormone (AMH) is a protein produced by pre-antral and small antral ovarian follicles. It is an acknowledged marker of ovarian reserve and remaining reproductive capacity, commonly used in reproductive medicine. From the third decade of life, AMH serum levels decrease consecutively up to menopause. Since the standardization of commercial assays, novel contributions of that parameter are being observed. Up to date, there is no screening tool for predicting the age of natural menopause (ANM). The following literature review evaluates the utility of AMH measurement in predicting ANM. Eleven studies met the inclusion criteria (original study with at least 9 years follow-up, 150 or more participants and the usage of ELISA assay for measuring AMH). The main finding from all of those studies is that there is an undeniable correlation between lower AMH and time to menopause (TTM). Single measurement of AMH is characterized by up to 0.86 predictive capacity, 86% to 92% accuracy which may be enhanced with additional parameters. AMH level below critical threshold strongly correlates with TTM and may become undetectable few years before menopause. The highest effectiveness was proved in short-term (up to 3 years) prediction. AMH seems to be a better predictor of TTM than FSH or inhibin B. Additionally, patterns in AMH changes are individual and the evaluation of those dynamics may lead to a higher accuracy in predicting ANM. AMH has a significant potential to become a useful tool in clinical practice as a predictor of TTM and ANM, especially with regard to family planning. More studies are required before proposed models may be implemented. PMID- 28650600 TI - Clear cell neuroendocrine tumor of the pancreas in von Hippel-Lindau disease: a case report and literature review. AB - Clear cell neuroendocrine tumor (NET) of the pancreas is found in von Hippel Lindau (VHL) disease, multiple endocrine neoplasia type I (MEN I), and sporadic form. Clear cell NETs are often misdiagnosed as metastatic renal cell carcinoma. A 47-year-old woman with VHL was found to have a mass in the pancreatic tail and two masses in the right kidney with two cysts. A distal pancreatectomy and right radical nephrectomy were performed. The pancreatic lesion was a well circumscribed, golden-yellow solid mass, which was lobulated by septal fibrosis. Microscopically, the tumor consisted of entirely of clear cells with prominent nucleoli. The tumor cell nests were separated by collagen fibrosis. Immunohistochemical studies were positive for the neuroendocrine markers and vimentin. Synchronous kidney tumors were clear cell renal cell carcinoma and cystic renal cell carcinoma. Those with syndrome are younger than those without syndrome. Sporadic tumors have larger size and higher grade than those of VHL and MEN I. Stromal sclerosis is frequently observed in VHL, compared with the other two groups. In the absence of a documented genetic profile and family history, awareness of these features should help us to diagnose clear cell pancreatic NETs resembling metastatic renal cell carcinoma. PMID- 28650601 TI - Multiple sclerosis in an acupuncture practice. AB - Multiple sclerosis (MS) is a severe autoimmune demyelinating disease that affects nervous system, has high morbidity and mortality and no effective targeted therapies are available. We present a case of 66-year-old female patient who has been treated by both conventional and Chinese traditional medicine after diagnosis was confirmed in 2008 as MS and antiphospholipid syndrome associated with CNS vasculitis. After diagnosis with clinical image confirmed with CT and MRI scan, where demyelinating zones were present, she started pharmacological therapy without major improvement. Patient suffered with fatigue, walking difficulties, weakness, was unable to articulate due to vocal cords spasms. We started acupuncture treatment in 2010 with herbal supplement therapy as well and patient had in total of 197 sessions with 10 session's cycle and 2-3 months pause. Patient's mobility was significantly improved after therapy, as well as vocal cord spasms and she gained back her articulation. Subjectively, patient also reported pain relief, mobility and fatigue improvement. Traditional Chinese medicine showed to be effective tool for pain and spasm relieving and can be powerful complementary tool in patients with chronic diseases, such as MS. PMID- 28650602 TI - Intraoperative neurophysiological monitoring to protect the facial nerve during microsurgery for large vestibular schwannomas. AB - OBJECTIVE: Microsurgery is the preferred treatment for large vestibular schwannomas (VSs). However, anatomical and functional preservation of the facial nerve (FN) remains a challenge during this surgery. The aim of this study was to determine whether it is beneficial to the preservation rates of the FN during microsurgical treatment of large VSs using intraoperative neurophysiological monitoring (IONM). METHODS: We retrospectively reviewed 53 patients with large VSs that underwent microsurgical resection via the retrosigmoid approach in our department during April 2009 to March 2016. IONM was used in 29 cases. Postoperative FN function was evaluated using the House-Brankmann (HB) FN grading scale at 2 weeks and 3 and 6 months after surgery. RESULTS: There were two cases (8.3%) of subtotal resection in the monitored group, compared with one case (3.4%) among the controls (p>0.05). The anatomical integrity rate for FNs was 100% in the monitored group, which was significantly different from 83.3% in the controls (p<0.05), which included four cases the FN was injured, mostly around the internal auditory foramen. Functional preservation of the FN in the monitored group differed significantly from that in the controls at 2 weeks and 3 and 6 months postoperatively (p<0.05). CONCLUSIONS: IONM contributes to FN anatomical integrity and functional preservation rates during microsurgery of large VSs. It has no significant effect on differences in the total VS resection rates. PMID- 28650603 TI - Psychometric evaluation of the Czech Beck Depression Inventory-II in a sample of depressed patients and healthy controls. AB - OBJECTIVE: The goal of this study was to explore reliability and validity of the Czech revised Beck Depression Inventory (BDI-II) and to identify the best cut-off for a correct identification of a potentially depressed individual. METHOD: Two groups of adult participants entered the study. The first group consisted of 177 patients with depression (F32x or F33x according to the ICD-10). Furthermore, there were 767 healthy controls. Each participant filled in BDI-II. A part of the patients also completed the Beck Anxiety Inventory (BAI), the Dissociative Experiences Scale (DES), and the subjective Clinical Global Impression scale (CGI). A part of the controls filled in the Adult Dispositional Hope Scale (ADHS) and the Satisfaction with Life Scale (SWLS). RESULT: The average patients' BDI-II score was 30.8+/-10.3, the mean controls' score was 7.2+/-6.8. The internal consistency of the inventory was excellent (the ordinal alpha coefficient was 0.90 for the patients and 0.93 for the controls). The stability in time, measured two weeks apart, was also good (intra-class correlation coefficient r=0.83 for the patients and 0.77 for the controls). The exploratory factor analysis of the patients showed a three-factor solution, while the analysis of the controls' data identified two factors. As expected, BDI-II significantly positively correlated with BAI, DES, and CGI and was negatively connected to ADHS and SWLS. The cut-off score with the best sensitivity and specificity was 17. CONCLUSION: The Czech BDI II shows adequate psychometric characteristics. PMID- 28650604 TI - Serum adiponectin levels in adolescents and young adults with growth hormone deficiency. AB - INTRODUCTION: Adiponectin (APN) is adipose tissue-derived hormone influencing energy metabolism. Growth hormone deficiency (GHD) may contribute to the development of disturbances in the hormonal function of adipose tissue (AT), and many disorders observed in untreated patients with GHD coincides with these contributed to low serum APN levels. OBJECTIVES: The assessment of serum adiponectin levels in adolescents and young adults with severe or partial GHD and analysis of relationships between serum APN and GH/IGF-1 axis function impairment as well as cardiometabolic risk factors. DESIGN AND SETTING: Based on the results of insulin tolerance test (ITT) patients were qualified for one of the following groups: 1) severe GHD - SGHD (26 patients; 8 women and 18 men); 2) partial GHD - PGHD (22 patients, 7 women and 15 men); 3) normal GH status - NGHS (28 patients, 9 women and 19 men). The fourth examined group consisted of healthy individuals - H (46 participants; 15 women, 31 men). Anthropometric measurements (height, weight, BMI), analysis of body composition and serum glucose, lipids, insulin, IGF-1 and APN assays were performed in all participants. RESULTS: There were no significant differences in the concentrations of APN between groups. After calculation of the total APN content in extracellular fluids per unit of fat tissue mass (TAPN/FM), these values were significantly lower in the SGHD (p<0.001) and correlated with the degree of impairment of the GH/IGF-1 axis functioning. In patients with GHD positive correlations between APN and serum HDL cholesterol (r=0.39, p<0.05) have been demonstrated. In the subjects with normal GH secretion serum APN correlated positively with serum HDL cholesterol (r=0.28; p<0.05), and negatively with fasting blood glucose (r=-0.31; p<0.05). CONCLUSIONS: Severe, but not partial growth hormone deficiency impairs adiponectin production in the adipose tissue that is compensated by the increase of fat mass. The degree of GH/IGF-1 axis disruption is related to the TAPN/FM. This parameter may be potentially useful in diagnosing severe growth hormone deficiency in the adults. PMID- 28650605 TI - Angiotensin II enhancement during pregnancy influences the emotionality of rat offspring (Rattus norvegicus) in adulthood. Potential use of the Rat Grimace Scale. AB - OBJECTIVES: One of the systems, which can be prenatally reprogrammed, is the renin-angiotensin-aldosterone system (RAAS). The aim of our experiment was to determine how prenatal activation of RAAS via exposure to elevated levels of angiotensin II (Ang II) influences the rat offspring's emotionality. METHODS: Pregnant female rats were implanted with osmotic minipumps that continually released Ang II and oval object of the same shape and size was implanted into control dams. The adult offspring (AngII and control groups) were tested in rat grimace scale (RGS), open field test (OF) and elevated plus maze (EPM). RESULTS: Psychological stress increased the RGS score in both groups of animals. AngII animals had significantly lower RGS score (i.e. less negative emotions) in the home cage but higher index of emotional reactivity in RGS. AngII animals had also significantly lower frequency of defecation in OF and had no effect on changes in anxiety-like behaviour. CONCLUSION: We concluded that maternal activation of RAAS modified some aspect of emotionality of experimental animals and led to an enhanced emotional response to stress situation. PMID- 28650606 TI - Association of testosterone levels and heroin usage characteristics in male heroin users. AB - BACKGROUND: Previous studies have shown that heroin abuse can alter the gonadal functions. Few studies examined the association between testosterone levels and heroin use in the existing literature. We aimed to determine the association between gonadal hormones and heroin usage characteristics over 12 weeks of abstinence in heroin users. METHODS: We collected data on patient demographics and heroin use patterns for 65 men aged 18 to 45 and for 29 age-matched healthy controls. Serum levels of total testosterone, estradiol, and prolactin were assessed at 5 time points. RESULTS: Testosterone levels gradually increased and prolactin levels decreased in heroin users in this study. In heroin users, a significant positive correlation was observed between the way of using drug and the testosterone levels, the way of using drug and the estradiol levels, between the duration of heroin dependence and the testosterone levels, between the duration of heroin dependence and the estradiol levels on D0, and between relapse time and testosterone levels on D84. CONCLUSIONS: Our data reveal testosterone might promote injection drug use and repeated relapse in male heroin users. PMID- 28650607 TI - Self-Diffusion Driven Ultrafast Detection of ppm-Level Nitroaromatic Pollutants in Aqueous Media Using a Hydrophilic Fluorescent Paper Sensor. AB - Development of fluorescent film probes for toxic nitroaromatic compound pollutants (NACs) such as 2,4,6-trinitrotoluene (TNT) in real water samples implies broad applications in environmental and industrial safety control. Despite many recent advances, there are still some difficult challenges facing this area, for example, the restricted sensitivity and long response time caused by hindered and slow diffusion of aqueous NACs samples inside a dense, solid film. Hence, we report herein a robust fluorescent paper sensor with improved sensing abilities, which is prepared by absorbing hydrophilic pyrene functionalized polymer uniformly into cellulose-based filter papers. Thanks to the numerous oxygen-containing groups grafted on cellulose papers, they allow passive and ultrafast capillary force driving diffusion of aqueous NACs samples into their hydrophilic matrix. Specifically speaking, these paper sensors can offer efficient self-diffusion paths inside the test strips and immediately bring the pyrene fluorophores and NACs quenchers into close proximity. Therefore, the developed paper-based test strips enable both naked-eye detection of low-ppm level TNT and ultrafast fluorescence quenching with a response time of only a few seconds, which are difficult to be achieved by conventional film probes. PMID- 28650608 TI - Internally/Externally Bubble-Propelled Photocatalytic Tubular Nanomotors for Efficient Water Cleaning. AB - We describe a highly effective bubble-propelled nanomotor for the photocatalytic decomposition of organic pollutants in water. Two different tubular TiO2 nanomotor systems are presented: one with Pt nanoparticles decorated on the inner surface and the other with Pt nanoparticles decorated on the outer surface. This is the first time that we have observed the autonomous movement of a tubular nanomotor without the aid of any surfactant, as well as a tubular nanomotor externally decorated with Pt propelled by oxygen bubbles. The synergy between the Pt nanoparticles and the superhydrophilic wetting behavior of the TiO2 nanotubes endows the two nanomotor systems with high speed at very low H2O2 fuel concentrations without the addition of any surfactant. The efficient photodecomposition of rhodamine B demonstrates the intermixing and photocatalytic ability of the two nanomotor systems, which opens new avenues for the development of multifunctional bubble-propelled micro/nanomotors with myriad practical applications. PMID- 28650609 TI - POM Constructed from Super-Sodalite Cage with Extra-Large 24-Membered Channels: Effective Sorbent for Uranium Adsorption. AB - A POMs-based sorbent functionalized by phosphate groups: H33Na14MoV24MoVI2(PO4)11O73 has been successfully isolated under hydrothermal conditions. The cooperative assembly of the ring-shaped polyoxometalate structural building unit {P4Mo6} and MoO4 tetrahedra linkers gives rise to an unprecedented supersodalite cage containing approximately spherical cavities with a 8.76 A diameter. As POMs-based inorganic material, compound 1 was first applied as sorbent to adsorb U(VI) from aqueous solution, exhibiting good stability, high efficiency, and selectivity. The maximum sorption capacity reaches 325.9 mg g-1, which may capture radionuclides through cooperative binding of the phosphate groups. The adsorbed U(VI) could be nearly drastically eluted when using 0.1 M Na2CO3 and the sorption capacity for U(VI) slightly decreased 10.16% through five successive sorption/desorption cycles. This work represents first application of POMs-based inorganic materials as sorbent to adsorb uranium from aqueous solution and provides a feasible approach for the entrapment and recovery of radionuclides. PMID- 28650610 TI - Defect Emission and Optical Gain in SiCxOy:H Films. AB - Luminescent SiCxOy:H films, which are fabricated at different CH4 flow rates using the plasma-enhanced chemical vapor deposition (PECVD) technique, exhibit strong photoluminescence (PL) with tuning from the near-infrared to orange regions. The PL features an excitation-wavelength-independent recombination dynamics. The silicon dangling bond (DB) defects identified by electron paramagnetic resonance spectra are found to play a key role in the PL behavior. The first-principles calculation shows that the Si DB defects introduce a midgap state in the band gap, which is in good agreement with the PL energy. Moreover, the band gap of a-SiCxOy:H is found to be mainly determined by Si and C atoms. Thus, the strong light emission is believed to result from the recombination of excited electrons and holes in Si DB defects, while the tunable light emission of the films is attributed to the substitution of stronger Si-C bonds for weak Si-Si bonds. It is also found that the light emission intensity shows a superlinear dependence on the pump intensity. Interestingly, the film exhibits a net optical gain under ultraviolet excitation. The gain coefficient is 53.5 cm-1 under a pumping power density of 553 mW cm-2. The present results demonstrate that the SiCxOy system can be a very competitive candidate in the applications of photonics and optoelectronics. PMID- 28650611 TI - Integrating Target-Responsive Hydrogel with Pressuremeter Readout Enables Simple, Sensitive, User-Friendly, Quantitative Point-of-Care Testing. AB - Point-of-care testing (POCT) with the advantages of speed, simplicity, and low cost, as well as no need for instrumentation, is critical for the measurement of analytes in a variety of environments lacking access to laboratory infrastructure. In the present study, a hydrogel pressure-based assay for quantitative POCT was developed by integrating a target-responsive hydrogel with pressuremeter readout. The target-responsive hydrogels were constructed with DNA grafted linear polyacrylamide and the cross-linking DNA for selective target recognition. The hydrogel response to the target substance allows release of the preloaded Pt nanoparticles, which have good stability and excellent catalytic ability for decomposing H2O2 to O2. Then, the generated O2 in a sealed environment leads to significant pressure increase, which can be easily read out by a handheld pressuremeter. Using this target-responsive hydrogel pressure-based assay, portable and highly sensitive detection of cocaine, ochratoxin A, and lead ion were achieved with excellent accuracy and selectivity. With the advantages of portability, high sensitivity, and simple sample processing, the hydrogel pressure-based assay shows great potential for quantitative POCT of a broad range of targets in resource-limited settings. PMID- 28650612 TI - Superionic Conductivity of Sm3+, Pr3+, and Nd3+ Triple-Doped Ceria through Bulk and Surface Two-Step Doping Approach. AB - Sufficiently high oxygen ion conductivity of electrolyte is critical for good performance of low-temperature solid oxide fuel cells (LT-SOFCs). Notably, material conductivity, reliability, and manufacturing cost are the major barriers hindering LT-SOFC commercialization. Generally, surface properties control the physical and chemical functionalities of materials. Hereby, we report a Sm3+, Pr3+, and Nd3+ triple-doped ceria, exhibiting the highest ionic conductivity among reported doped-ceria oxides, 0.125 S cm-1 at 600 degrees C. It was designed using a two-step wet-chemical coprecipitation method to realize a desired doping for Sm3+ at the bulk and Pr3+/Nd3+ at surface domains (abbreviated as PNSDC). The redox couple Pr3+/Pr4+ contributes to the extraordinary ionic conductivity. Moreover, the mechanism for ionic conductivity enhancement is demonstrated. The above findings reveal that a joint bulk and surface doping methodology for ceria is a feasible approach to develop new oxide-ion conductors with high impacts on advanced LT-SOFCs. PMID- 28650613 TI - Glucose Oxidase-Polymer Nanogels for Synergistic Cancer-Starving and Oxidation Therapy. AB - Glucose oxidase (GOX) can convert glucose into gluconic acid and hydrogen peroxide (H2O2), which is potentially useful for synergistic cancer-starving and oxidation therapy. Herein we demonstrate a glucose-responsive nanomedicine made of GOX-polymer nanogels to regulate H2O2 production for synergistic melanoma starving and oxidation therapy. GOX-polymer nanogels showed glucose-responsive H2O2-generating activity in vitro, improved stability, and considerably enhanced tumor retention as compared to native GOX. More importantly, they exhibited high antimelanoma efficacy and no obvious systemic toxicity, whereas native GOX was ineffective and systemically toxic at the same dose. This work paves the way for establishing an endogenous and noninvasive cancer treatment paradigm that is based on intratumoral glucose-responsive, H2O2-generating chemical reactions. PMID- 28650614 TI - Electrochemical Stimuli-Driven Facile Metal-Free Hydrogen Evolution from Pyrene Porphyrin-Based Crystalline Covalent Organic Framework. AB - A [2 + 2] Schiff base type condensation between 5,10,15,20-tetrakis(4 aminophenyl)porphyrin (TAP) and 1,3,6,8-tetrakis (4-formylphenyl) pyrene (TFFPy) under solvothermal condition yields a crystalline, quasi-two-dimensional covalent organic framework (SB-PORPy-COF). The porphyrin and pyrene units are alternatively occupied in the vertex of 3D triclinic crystal having permanent microporosity with moderately high surface area (~869 m2 g-1) and promising chemical stability. The AA stacking of the monolayers give a pyrene bridged conducting channel. SB-PORPy-COF has been exploited for metal free hydrogen production to understand the electrochemical behavior using the imine based docking site in acidic media. SB-PORPy-COF has shown the onset potential of 50 mV and the Tafel slope of 116 mV dec-1. We expect that the addendum of the imine based COF would not only enrich the structural variety but also help to understand the electrochemical behavior of these class of materials. PMID- 28650615 TI - Selective Peptide-Mediated Enhanced Deposition of Polymer Fragrance Delivery Systems on Human Hair. AB - The deposition of fragrance delivery systems onto human hair from a shampoo formulation is a challenging task, as the primary function of shampoo is to cleanse the hair by removing primarily hydrophobic moieties. In this work, to tackle this challenge, phage-display-identified peptides that can bind to human hair under shampooing conditions are first identified and subsequently used to enhance the deposition of model fragrance delivery systems. These delivery systems are based on either poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) copolymers as a representative for polymeric profragrances or polyurethane/polyurea-type core-shell microcapsules as a model physical fragrance carrier. The incorporation of a hair-binding peptide enhanced the deposition of PHPMA copolymers by a factor of 3.5-5.0 depending on the extent of peptide incorporation, whereas 10 wt % surface functionalization of microcapsules with the peptide led to a 20-fold increase in their deposition. In a final experiment, treatment of the hair samples under realistic application conditions with the peptide-functionalized microcapsules resulted in an increase in fragrance release from the hair surfaces. PMID- 28650616 TI - Cucurbit[6]uril-Promoted Click Chemistry for Protein Modification. AB - Azide-alkyne cycloaddition is a powerful reaction for the formation of bioconjugates. When catalyzed by Cu(I) or strain promotion, this cycloaddition is considered to be a "click" reaction with many applications in chemical biology and materials science. We report a new type of azide-alkyne click chemistry for the synthesis of protein conjugates using cucurbit[6]uril (CB6) supramolecular chemistry. CB6-promoted azide-alkyne cycloaddition has been previously used for the synthesis of rotaxanes but has not been applied to the development of complex bioconjugates. By developing new substrates for CB6 click that do not contain any cross-reactive functional groups and by optimizing reaction conditions, we converted CB6 click chemistry from a rotaxane synthesis tool into a useful bioconjugation technique. Using these new parameters, we synthesized a series of protein conjugates including protein-peptide, protein-DNA, protein-polymer, and protein-drug conjugates. We further demonstrated that CB6 click can be used in conjunction with strain-promoted azide-alkyne cycloaddition to generate distinct bioconjugates in protein mixtures. CB6 click is a promising new reaction for the development of protein conjugates and can be applied toward the synthesis of complex biomaterials for a wide range of applications. PMID- 28650617 TI - Kinetics and Mechanism of the Autocatalytic Oxidation of Bis(terpyridine)iron(II) by Peroxomonosulfate Ion (Oxone) in Acidic Medium. AB - The autocatalytic oxidation of the bis(terpyridine)iron(II) complex, Fe(tpy)22+ by peroxomonosulfate ion (PMS) proceeds via the formation of the corresponding iron(III) complex (Fe(tpy)23+) as the primary oxidation product. The proton assisted dissociation of Fe(tpy)22+ and subsequent oxidation of Fe2+ are side reactions in this system. In the initial stage of the reaction, a 1:1 adduct is formed between PMS and bis(terpyridine)iron(II), which decomposes in an intramolecular electron transfer reaction step. The autocatalytic role of Fe(tpy)23+ was also confirmed in the overall process. This effect is interpreted by considering the formation of an additional adduct between PMS and Fe(tpy)23+. The decomposition of the adduct yields two strong oxidizing intermediates, an Fe(IV) species and SO4-*, which consume the iron(II) complex in rapid reaction steps. A detailed kinetic model was postulated for the overall oxidation of Fe(tpy)22+ by PMS. The equilibrium constants for the formation of the adducts between PMS and complexes Fe(tpy)22+ and Fe(tpy)23+ were estimated as 129 +/- 18 M-1 and 87 +/- 10 M-1, respectively. In contrast to the closely related Fe(phen)32+-PMS reaction, the N-oxide derivative of the ligand (tpyO) does not have any kinetic role in the overall process because of the very slow formation of the N-oxide in the reaction. PMID- 28650618 TI - Solution and Solid State Correlations of Antimalarial Drug Actions: NMR and Crystallographic Studies of Drug Interactions with a Heme Model. AB - Solution NMR has been used in tandem with a diamagnetic non-iron heme model compound as a simple and effective tool to rapidly probe the structures of the bound complexes formed between the metalloporphyrin and antimalarial drugs from the 4-aminoquinoline, 4-methylenehydroxylquinoline, and 8-aminoquinoline subfamilies. The ability of gallium(III) protoporphyrin IX to mimic heme chemistry is exploited. The 4-aminoquinolines quinacrine and amodiaquine and two novel 3-halo chloroquine analogues are found to bind to the metalloporphyrin through hydrogen-bonding and stacking interactions, while halofantrine and the 4 methylenehydroxylquinolines, quinine and mefloquine bind through the alcohol group of the drug. In each case, detailed structural information is available from the NMR assessment. The mefloquine model is confirmed crystallographically. The 8-aminoquinoline primaquine does not interact strongly. These tools show promise for future applications in assessing antimalarials in preclinical development for heme-binding drug targets. PMID- 28650619 TI - Dual Alkali Solvent System for CO2 Capture from Flue Gas. AB - A novel two-aqueous-phase CO2 capture system, namely the dual alkali solvent (DAS) system, has been developed. Unlike traditional solvent-based CO2 capture systems in which the same solvent is used for both CO2 absorption and stripping, the solvent of the DAS system consists of two aqueous phases. The upper phase, which contains an organic alkali 1-(2-hydroxyethyl) piperazine (HEP), is used for CO2 absorption. The lower phase, which consists of a mixture of K2CO3/KHCO3 aqueous solution and KHCO3 precipitate, is used for CO2 stripping. Only a certain kind of amine (such as HEP) is able to ensure the phase separation, satisfactory absorption efficiency, effective CO2 transfer from the upper phase to the lower phase, and regeneration of the upper phase. In the meantime, due to the presence of K2CO3/KHCO3 in the lower phase, HEP in the upper phase is capable of being regenerated from its sulfite/sulfate heat stable salt, which enables the simultaneous absorption of CO2 and SO2/SO3 from the flue gas. Preliminary experiments and simulations indicate that the implementation of the DAS system can lead to 24.0% stripping energy savings compared to the Econamine process, without significantly lowering the CO2 absorption efficiency (~90%). PMID- 28650620 TI - Influence of the Disposition of the Anisotropy Axes into the Magnetic Properties of MnIII Dinuclear Compounds with Benzoato Derivative Bridges. AB - The two new MnIII dinuclear compounds [{Mn(H2O)(phen)}2(MU-4-CH3C6H4COO)2(MU O)](ClO4)2.3CH3CN.H2O (1.3CH3CN.H2O) and [{Mn(H2O)(phen)}(MU-O)(MU-2 BrC6H4COO)2{Mn(NO3)(phen)}]NO3 (2) have been synthesized. Their structural data reveal significant differences in the shape of the coordination octahedron around the MnIII ions in both compounds. The different distortions from ideal geometry incite a very different magnetic behavior, affecting both the zero-field splitting parameters of the MnIII ions (DMn and EMn) and the magnetic interaction between them. Compound 1, with elongation in the monodentate ligand direction, shows antiferromagnetic coupling (ground state S = 0) and local DMn < 0, while compound 2, with compression in the oxo bridge direction, displays a ferromagnetic interaction (ground state S = 4) and local DMn > 0. Theoretical CASSCF and DFT calculations corroborate the different magnetic anisotropy and exchange coupling found in both compounds. Moreover, with the help of theoretical calculations, some interesting magneto-structural correlations have been found between the degree of distortion of the coordination octahedra and the magnetic coupling; it becomes more antiferromagnetic when the elongation parameter, Delta, in absolute value is increased. PMID- 28650621 TI - Novel CDTA-based, Bifunctional Chelators for Stable and Inert MnII Complexation: Synthesis and Physicochemical Characterization. AB - In the search for MnII MR and PET/MR imaging agents with optimal balance between thermodynamic stability, kinetic inertness, and relaxivity, two novel bifunctional MnII chelators (BFMnCs) based on CDTA (trans-1,2-diaminocyclohexane N,N,N',N'-tetraacetic acid) were synthesized. A six-step synthesis, involving the buildup of a functionalized trans-1,2-diaminocyclohexane core, provided CuAAC reactive 6a and 6b bearing an alkyne or azide substituent on the cyclohexane ring, respectively (CuAAC = CuI-catalyzed azide-alkyne 1,3-dipolar cycloaddition). Thermodynamic, kinetic, and relaxometric studies were performed with 4-HET-CDTA (8a) as a "model chelator," synthesized in two steps from 6a. The protonation constants revealed that 8a is slightly less basic than CDTA and forms a MnII complex of marginally lower thermodynamic stability (log KMnL = 13.80 vs 14.32, respectively), while the conditional stability constant is almost identical for both chelates (pMn = 8.62 vs 8.68, respectively). Kinetic assessment of the CuII-mediated transmetalation of [Mn(4-HET-CDTA)]2- showed that proton-assisted complex dissociation is slightly slower than for [Mn(CDTA)]2- (k1 = 297 vs 400 M-1 s-1, respectively). Importantly, the dissociation half-life near physiological conditions (pH 7.4, 25 degrees C) underlined that [Mn(4-HET CDTA)]2- is ~35% more inert (t1/2 = 16.2 vs 12.1 h, respectively). Those findings may be accounted for by a combination of reduced basicity and increased rigidity of the ligand. Analysis of the 17O NMR and 1H NMRD data attributed the high relaxivity of [Mn(4-HET-CDTA)]2- (r1 = 4.56 mM-1 s-1 vs 3.65 mM-1 s-1 for [Mn(CDTA)]2-; 20 MHz, 25 degrees C) to slower rotational dynamics (tauR298 = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn(CDTA)]2- (kex298 = 17.6 * 107 vs 14.0 * 107 s-1, respectively). Given the exquisite compromise between thermodynamic stability, kinetic inertness, and relaxivity achieved by [Mn(4-HET-CDTA)]2-, appropriately designed CuAAC-conjugates of 6a/6b are promising precursors for the preparation of targeted, bioresponsive, or high relaxivity manganese-based PET/MR tracers (52g/55 MnII) and MR contrast agents (MnII). PMID- 28650622 TI - Lateral Fusion of Chemical Vapor Deposited N = 5 Armchair Graphene Nanoribbons. AB - Bottom-up synthesis of low-bandgap graphene nanoribbons with various widths is of great importance for their applications in electronic and optoelectronic devices. Here we demonstrate a synthesis of N = 5 armchair graphene nanoribbons (5-AGNRs) and their lateral fusion into wider AGNRs, by a chemical vapor deposition method. The efficient formation of 10- and 15-AGNRs is revealed by a combination of different spectroscopic methods, including Raman and UV-vis-near-infrared spectroscopy as well as by scanning tunneling microscopy. The degree of fusion and thus the optical and electronic properties of the resulting GNRs can be controlled by the annealing temperature, providing GNR films with optical absorptions up to ~2250 nm. PMID- 28650623 TI - Spatial Distributions of DDTs in the Water Masses of the Arctic Ocean. AB - There is a scarcity of data on the amount and distribution of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolites in intermediate and deep ocean water masses. Here, the distribution and inventories of DDTs in water of the Arctic shelf seas and the interior basin are presented. The occurrence of ?6DDT (0.10-66 pg L-1) in the surface water was dominated by 4,4'-DDE. In the Central Arctic Ocean increasing concentrations of DDE with depth were observed in the Makarov and Amundsen basins. The increasing concentrations down to 2500 m depth is in accordance with previous findings for PCBs and PBDEs. Similar concentrations of DDT and DDEs were found in the surface water, while the relative contribution of DDEs increased with depth, demonstrating a transformation over time and depth. Higher concentrations of DDTs were found in the European part of the Arctic Ocean; these distributions likely reflect a combination of different usage patterns, transport, and fate of these compounds. For instance, the elevated concentrations of DDTs in the Barents and Atlantic sectors of the Arctic Ocean indicate the northbound Atlantic current as a significant conveyor of DDTs. This study contributes to the very rare data on OCPs in the vast deep-water compartments and combined with surface water distribution across the Arctic Ocean helps to improve our understanding of the large-scale fate of DDTs in the Arctic. PMID- 28650624 TI - Precise Steric Control over 2D versus 3D Self-Assembly of Antimony(III) Alkoxide Cages through Strong Secondary Bonding Interactions. AB - Antimony(III) alkoxide cages were designed as building blocks for predictable supramolecular self-assembly. Supramolecular synthons featuring two Sb...O secondary bonding interactions (SBIs), each SBI stronger than 30 kJ/mol, were used to drive the formation of the supramolecular architectures. Judicious choice of pendant groups provided predictable control over the formation of self assembled 3D columnar helices, which crystallized with hollow morphologies, or a self-assembled 2D bilayer. The Sb-O stretching frequency provides a spectroscopic signature of Sb...O SBI formation. PMID- 28650625 TI - CuI@UiO-67-IM: A MOF-Based Bifunctional Composite Triphase-Transfer Catalyst for Sequential One-Pot Azide-Alkyne Cycloaddition in Water. AB - A CuI-loaded and n-pentadecyl-attached imidazolium salt decorated UiO-67-type metal-organic framework (CuI@UiO-67-IM, 2) based on a new premodified ligand L (n pentadecyl-attached imidazolium (IM) decorated dicarboxylic acid) and ZrCl4 is reported. Compound 2 can be a bifunctional composite heterogeneous phase-transfer catalyst to promote the azide-alkyne cycloaddition (H2O, air, 80 degrees C) from corresponding halogenated compounds and sodium azide as a sequential one-pot procedure with high yields and excellent regioselectivity. PMID- 28650626 TI - Selenium Sequestration in a Cationic Layered Rare Earth Hydroxide: A Combined Batch Experiments and EXAFS Investigation. AB - Selenium is of great concern owing to its acutely toxic characteristic at elevated dosage and the long-term radiotoxicity of 79Se. The contents of selenium in industrial wastewater, agricultural runoff, and drinking water have to be constrained to a value of 50 MUg/L as the maximum concentration limit. We reported here the selenium uptake using a structurally well-defined cationic layered rare earth hydroxide, Y2(OH)5Cl.1.5H2O. The sorption kinetics, isotherms, selectivity, and desorption of selenite and selenate on Y2(OH)5Cl.1.5H2O at pH 7 and 8.5 were systematically investigated using a batch method. The maximum sorption capacities of selenite and selenate are 207 and 124 mg/g, respectively, both representing the new records among those of inorganic sorbents. In the low concentration region, Y2(OH)5Cl.1.5H2O is able to almost completely remove selenium from aqueous solution even in the presence of competitive anions such as NO3-, Cl-, CO32-, SO42-, and HPO42-. The resulting concentration of selenium is below 10 MUg/L, well meeting the strictest criterion for the drinking water. The selenate on loaded samples could be desorbed by rinsing with concentrated noncomplexing NaCl solutions whereas complexing ligands have to be employed to elute selenite for the material regeneration. After desorption, Y2(OH)5Cl.1.5H2O could be reused to remove selenate and selenite. In addition, the sorption mechanism was unraveled by the combination of EDS, FT-IR, Raman, PXRD, and EXAFS techniques. Specifically, the selenate ions were exchanged with chloride ions in the interlayer space, forming outer-sphere complexes. In comparison, besides anion exchange mechanism, the selenite ions were directly bound to the Y3+ center in the positively charged layer of [Y2(OH)5(H2O)]+ through strong bidentate binuclear inner-sphere complexation, consistent with the observation of the higher uptake of selenite over selenate. The results presented in this work confirm that the cationic layered rare earth hydroxide is an emerging and promising material for efficient removal of selenite and selenate as well as other anionic environmental pollutants. PMID- 28650627 TI - Cancer Risk Assessment of Airborne PAHs Based on in Vitro Mixture Potency Factors. AB - Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants associated with adverse human health effects including cancer. However, the risk of exposure to mixtures is difficult to estimate, and risk assessment by whole mixture potency evaluations has been suggested. To facilitate this, reliable in vitro based testing systems are necessary. Here, we investigated if activation of DNA damage signaling in vitro could be an endpoint for developing whole mixture potency factors (MPFs) for airborne PAHs. Activation of DNA damage signaling was assessed by phosphorylation of Chk1 and H2AX using Western blotting. To validate the in vitro approach, potency factors were determined for seven individual PAHs which were in very good agreement with established potency factors based on cancer data in vivo. Applying the method using Stockholm air PAH samples indicated MPFs with orders of magnitude higher carcinogenic potency than predicted by established in vivo-based potency factors. Applying the MPFs in cancer risk assessment suggested that 45.4 (6% of all) cancer cases per year in Stockholm are due to airborne PAHs. Applying established models resulted in <1 cancer case per year, which is far from expected levels. We conclude that our in vitro based approach for establishing MPFs could be a novel method to assess whole mixture samples of airborne PAHs to improve health risk assessment. PMID- 28650628 TI - Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs To Investigate the Function of P-Glycoprotein in the Blood-Brain Barrier. AB - P-glycoprotein is an efflux transporter located in the blood-brain barrier. (R) [11C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer's disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[18F]fluoroethylverapamil ([18F]1) and (R)-O [18F]fluoroethylnorverapamil ([18F]2) has been described. [18F]1 was obtained in reaction of (R)-norverapamil with the volatile [18F]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% +/- 1.2%. [18F]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% +/- 9.9%. Both tracers, [18F]1 and [18F]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [18F]1 and [18F]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6- and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [18F]1 and [18F]2, PET scans in Mdr1a/b(-/-), Bcrp1(-/-), and WT mice were acquired, in which [18F]2 showed a more specific brain uptake in Mdr1a/b(-/-) mice and no increased signal in Bcrp1(-/-) mice. [18F]2 was selected as the best performing tracer and should be evaluated further in clinical studies. PMID- 28650630 TI - Waterborne Electrospinning of Poly(N-isopropylacrylamide) by Control of Environmental Parameters. AB - With increasing toxicity and environmental concerns, electrospinning from water, i.e., waterborne electrospinning, is crucial to further exploit the resulting nanofiber potential. Most water-soluble polymers have the inherent limitation of resulting in water-soluble nanofibers, and a tedious chemical cross-linking step is required to reach stable nanofibers. An interesting alternative route is the use of thermoresponsive polymers, such as poly(N-isopropylacrylamide) (PNIPAM), as they are water-soluble beneath their lower critical solution temperature (LCST) allowing low-temperature electrospinning while the obtained nanofibers are water-stable above the LCST. Moreover, PNIPAM nanofibers show major potential to many application fields, including biomedicine, as they combine the well-known on off switching behavior of PNIPAM, thanks to its LCST, with the unique properties of nanofibers. In the present work, based on dedicated turbidity and rheological measurements, optimal combinations of polymer concentration, environmental temperature, and relative humidity are identified allowing, for the first time, the production of continuous, bead-free PNIPAM nanofibers electrospun from water. More specifically, PNIPAM gelation was found to occur well below its LCST at higher polymer concentrations leading to a temperature regime where the viscosity significantly increases without compromising the polymer solubility. This opens up the ecological, water-based production of uniform PNIPAM nanofibers that are stable in water at temperatures above PNIPAM's LCST, making them suitable for various applications, including drug delivery and switchable cell culture substrates. PMID- 28650629 TI - Biokinetic Analysis and Metabolic Fate of 2,4-D in 2,4-D-Resistant Soybean (Glycine max). AB - The Enlist weed control system allows the use of 2,4-D in soybean but slight necrosis in treated leaves may be observed in the field. The objectives of this research were to measure and compare uptake, translocation, and metabolism of 2,4 D in Enlist (E, resistant) and non-AAD-12 transformed (NT, sensitive) soybeans. The adjuvant from the Enlist Duo herbicide formulation (ADJ) increased 2,4-D uptake (36%) and displayed the fastest rate of uptake (U50= 0.2 h) among treatments. E soybean demonstrated a faster rate of 2,4-D metabolism (M50= 0.2 h) compared to NT soybean, but glyphosate did not affect 2,4-D metabolism. Metabolites of 2,4-D in E soybean were qualitatively different than NT. Applying 2,4-D-ethylhexyl ester instead of 2,4-D choline (a quaternary ammonium salt) eliminated visual injury to E soybean, likely due to the time required for initial de-esterification and bioactivation. Excessive 2,4-D acid concentrations in E soybean resulting from ADJ-increased uptake may significantly contribute to foliar injury. PMID- 28650632 TI - Transition Metal-Free alpha-Csp3-H Methylenation of Ketones to Form C?C Bond Using Dimethyl Sulfoxide as Carbon Source. AB - A direct alpha-Csp3-H methylenation of arylketones to form C?C bond using dimethyl sulfoxide as one-carbon source is achieved under transition metal-free reaction condition. Various aryl ketone derivatives react readily with DMSO, producing the alpha,beta-unsaturated carbonyl compounds in yields of 42 to 90%. This method features a transition metal-free reaction condition, wide substrate scope and using DMSO as novel one-carbon source to form C?C bond, thus providing an efficient and expeditious approach to an important class of alpha,beta unsaturated carbonyl compounds. Based on the preliminary experiments, a plausible mechanism of this transformation is disclosed. PMID- 28650631 TI - Effect of the Biphenyl Neolignan Honokiol on Abeta42-Induced Toxicity in Caenorhabditis elegans, Abeta42 Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation. AB - The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Abeta) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Abeta42 as a convenient in vivo system for examining the effect of honokiol against Abeta induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Abeta42 oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron(II). Honokiol displayed activity similar to that of resveratrol and (-)-epigallocatechin gallate (EGCG) in delaying Abeta42-induced paralysis in C. elegans, and it exhibited moderate-to-weak ability to inhibit Abeta42 on pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered. PMID- 28650633 TI - Two-Photon Spectroscopy of a Series of Platinum Acetylides: Conformation-Induced Ground-State Symmetry Breaking. AB - With the goal of elucidating electronic and conformational effects on structure spectroscopic property relationships in platinum acetylides, we synthesized a series of nominally centrosymmetric chromophores trans-Pt(PBu3)2(C=C-Phenyl-X)2, where X = diphenylamino (DPA), NH2, OCH3, t-Bu, CH3, H, F, benzothiazole (BTH), CF3, CN, and NO2. We collected one- and two-photon absorption spectra and also performed density functional theory (DFT) and time-dependent (TD) DFT calculations on the ground- and excited-state properties of these compounds. The DFT calculations revealed facile rotation between the two ligands, suggesting that the compounds exhibit nonplanar ground-state conformations in solution. TDDFT calculation of the S1 state energy and transition dipole moment for a nonplanar conformation gave good agreement with experiment. Two-photon absorption spectra obtained from these compounds allowed estimation of the change of permanent electric dipole moment upon vertical excitation from ground state to S1 state. The values are small DeltaMU < 1.0 D for neutral substituents such as CH3, H, and F but increase sharply to DeltaMU ~ 11 D for electron-accepting NO2. When in a nonplanar conformation, the corresponding calculated DeltaMU values showed good agreement with the experimental data indicating that the two-photon spectra result from nonplanar ground-state conformations. Previously studied related chromophores having extended conjugation ( Rebane, A.; Drobizhev, M.; Makarov, N. S.; Wicks, G.; Wnuk, P.; Stepanenko, Y.; Haley, J. E.; Krein, D. M.; Fore, J. L.; Burke, A. R.; Slagle, J. E.; McLean, D. G.; Cooper, T. M. J. Phys. Chem. A 2014 , 118 , 3749 - 3759 ) show similar dependence of DeltaMU on the substituents, which allows us to conclude that the excited-state properties of these floppy chromophores are a function of the electronic properties of the substituents, ligand size, and nonplanar molecular conformation. PMID- 28650634 TI - Reversible and Versatile On-Tether Modification of Chiral-Center-Induced Helical Peptides. AB - Modification of the cross-linker of constrained peptides has recently received considerable attention. Here, we present a versatile approach to modifing the cross-linking tether of chiral-center-induced helical (CIH) peptides via the S alkylation reaction. The alkylation process displayed high conversion efficiency, selectivity, and substrate tolerance. Notably, although on-tether S-alkylation could lead to a pair of peptide epimers, the major alkylated product retained the helical structure of its helical precursor peptide. This S-alkylation was readily reversible under reductive conditions, which provides a simple method for traceless modification. In addition to expanding the chemical space of CIH peptides, this strategy is the first on-tether modification platform with known retention of the peptides' original helicity. PMID- 28650635 TI - Ternary Interactions and Energy Transfer between Fluorescein Isothiocyanate, Adenosine Triphosphate, and Graphene Oxide Nanocarriers. AB - The interactions of fluorescent probes and biomolecules with nanocarriers are of key importance to the emerging targeted drug delivery systems. Graphene oxide nanosheets (GONs) as the nanocarriers offer biocompatibility and robust drug binding capacity. The interactions of GONs with fluorophores lead to strong fluorescence quenching, which may interfere with fluorescence bioimaging and biodetection. Herein, we report on the interactions and energy transfers in a model ternary system: GONs-FITC-ATP, where FITC is a model fluorophore (fluorescein isothiocyanate) and ATP is a common biomolecule (adenosine-5' triphosphate). We have found that FITC fluorescence is considerably quenched by ATP (the quenching constant KSV = 113 +/- 22 M-1). The temperature coefficient of KSV is positive (alphaT = 4.15 M-1deg-1). The detailed analysis of a model for internal self-quenching of FITC indicates that the temperature dependence of the net quenching efficiency eta for the FITC-ATP pair is dominated by FITC internal self-quenching modes with their contribution estimated at 79%. The quenching of FITC by GONs is much stronger (KSV = 598 +/- 29 M-1) than that of FITC-ATP and is associated with the formation of supramolecular assemblies bound with hydrogen bonding and pi-pi stacking interactions. For the analysis of the complex behavior of the ternary system GONs-FITC-ATP, a model of chemisorption of ATP on GONs, with partial blocking of FITC quenching, has been developed. Our results indicate that ATP acts as a moderator for FITC quenching by GONs. The interactions between ATP, FITC, and GONs have been corroborated using molecular dynamics and quantum mechanical calculations. PMID- 28650636 TI - Orthogonal Electric Field Measurements near the Green Fluorescent Protein Fluorophore through Stark Effect Spectroscopy and pKa Shifts Provide a Unique Benchmark for Electrostatics Models. AB - Measurement of the magnitude, direction, and functional importance of electric fields in biomolecules has been a long-standing experimental challenge. pKa shifts of titratable residues have been the most widely implemented measurements of the local electrostatic environment around the labile proton, and experimental data sets of pKa shifts in a variety of systems have been used to test and refine computational prediction capabilities of protein electrostatic fields. A more direct and increasingly popular technique to measure electric fields in proteins is Stark effect spectroscopy, where the change in absorption energy of a chromophore relative to a reference state is related to the change in electric field felt by the chromophore. While there are merits to both of these methods and they are both reporters of local electrostatic environment, they are fundamentally different measurements, and to our knowledge there has been no direct comparison of these two approaches in a single protein. We have recently demonstrated that green fluorescent protein (GFP) is an ideal model system for measuring changes in electric fields in a protein interior caused by amino acid mutations using both electronic and vibrational Stark effect chromophores. Here we report the changes in pKa of the GFP fluorophore in response to the same mutations and show that they are in excellent agreement with Stark effect measurements. This agreement in the results of orthogonal experiments reinforces our confidence in the experimental results of both Stark effect and pKa measurements and provides an excellent target data set to benchmark diverse protein electrostatics calculations. We used this experimental data set to test the pKa prediction ability of the adaptive Poisson-Boltzmann solver (APBS) and found that a simple continuum dielectric model of the GFP interior is insufficient to accurately capture the measured pKa and Stark effect shifts. We discuss some of the limitations of this continuum-based model in this system and offer this experimentally self-consistent data set as a target benchmark for electrostatics models, which could allow for a more rigorous test of pKa prediction techniques due to the unique environment of the water-filled GFP barrel compared to traditional globular proteins. PMID- 28650637 TI - DFT/TDDFT Study on the Sensing Mechanism of a Fluorescent Probe for Hydrogen Sulfide: Excited State Intramolecular Proton Transfer Coupled Twisted Intramolecular Charge Transfer. AB - By using density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods, the sensing mechanism of a fluorescent probe 2-(2 hydroxyphenyl) benzothiazole (HBT) derivative HBTPP-S for hydrogen sulfide has been thoroughly studied. The thiolysis reaction has a moderate reaction barrier of 18.40 kcal mol-1, which indicates that the hydrogen sulfide sensing process has a favorable response speed. Because of the nonradiative donor-excited photoinduced electron transfer (d-PET, fluorophore as the electron donor) from the excited HBTPP group to the electron-withdrawing 2,4-dinitrophenyl group, as well as the inhibition of the proton transfer (PT) and the excited state intramolecular proton transfer (ESIPT) process by 2,4-dinitrophenyl group, the probe HBTPP-S is essentially nonfluorescent. On the other hand, the added hydrogen sulfide induces the thiolysis of the 2,4-dinitrophenyl ether bond, and then the thiolysis product HBTPP comes into existence. The theoretically simulated potential energy surface demonstrates that without the electron withdrawing 2,4-dinitrophenyl group, the thiolysis product HBTPP undergoes the excited state intramolecular proton transfer (ESIPT) coupled twisted intramolecular charge transfer (TICT) processes in the first excited state. The absence of the d-PET and the process mentioned above may explain the significant fluorescent turn-on response and large Stokes shift of the thiolysis product HBTPP. PMID- 28650639 TI - On-Site Determination and Monitoring of Real-Time Fluence Delivery for an Operating UV Reactor Based on a True Fluence Rate Detector. AB - At present, on-site fluence (distribution) determination and monitoring of an operating UV system represent a considerable challenge. The recently developed microfluorescent silica detector (MFSD) is able to measure the approximate true fluence rate (FR) at a fixed position in a UV reactor that can be compared with a FR model directly. Hence it has provided a connection between model calculation and real-time fluence determination. In this study, an on-site determination and monitoring method of fluence delivery for an operating UV reactor was developed. True FR detectors, a UV transmittance (UVT) meter, and a flow rate meter were used for fundamental measurements. The fluence distribution, as well as reduction equivalent fluence (REF), 10th percentile dose in the UV fluence distribution (F10), minimum fluence (Fmin), and mean fluence (Fmean) of a test reactor, was calculated in advance by the combined use of computational fluid dynamics and FR field modeling. A field test was carried out on the test reactor for disinfection of a secondary water supply. The estimated real-time REF, F10, Fmin, and Fmean decreased 73.6%, 71.4%, 69.6%, and 72.9%, respectively, during a 6-month period, which was attributable to lamp output attenuation and sleeve fouling. The results were analyzed with synchronous data from a previously developed triparameter UV monitoring system and water temperature sensor. This study allowed demonstration of an accurate method for on-site, real-time fluence determination which could be used to enhance the security and public confidence of UV-based water treatment processes. PMID- 28650638 TI - Identification and Structure-Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli. AB - In Gram-negative bacteria, efflux pumps are able to prevent effective cellular concentrations from being achieved for a number of antibiotics. Small molecule adjuvants that act as efflux pump inhibitors (EPIs) have the potential to reinvigorate existing antibiotics that are currently ineffective due to efflux mechanisms. Through a combination of rigorous experimental screening and in silico virtual screening, we recently identified novel classes of EPIs that interact with the membrane fusion protein AcrA, a critical component of the AcrAB TolC efflux pump in Escherichia coli. Herein, we present initial optimization efforts and structure-activity relationships around one of those previously described hits, NSC 60339 (1). From these efforts we identified two compounds, SLUPP-225 (17h) and SLUPP-417 (17o), which demonstrate favorable properties as potential EPIs in E. coli cells including the ability to penetrate the outer membrane, improved inhibition of efflux relative to 1, and potentiation of the activity of novobiocin and erythromycin. PMID- 28650640 TI - Light-Mediated Reactive Oxygen Species Generation and Iron Redox Transformations in the Presence of Exudate from the Cyanobacterium Microcystis aeruginosa. AB - The photochemical properties of the organic exudate secreted by a toxic strain of Microcystis aeruginosa were studied by measuring reactive oxygen species (ROS) generation and redox transformations of iron in the presence of the organic exudate under acidic (pH 4) and alkaline (pH 8) conditions. Our results show that the organic exudate generates nanomolar concentrations of superoxide and hydrogen peroxide on irradiation with simulated sunlight in a manner consistent with that reported for terrigenous natural organic matter. The photo-generated superoxide plays an important role in Fe(III) reduction under alkaline conditions with nearly 45% of the observed Fe(II) generation on Fe(III) reduction occurring via Fe(III) reduction by superoxide while the rest of the Fe(III) reduction occurs via a ligand-to-metal charge transfer (LMCT) pathway. In contrast, under acidic conditions, 100% of the observed photochemical Fe(II) generation on Fe(III) reduction occurs via a LMCT pathway. These results suggest that steady-state dissolved Fe concentrations and hence Fe availability in natural waters will significantly increase in the presence of these algal exudates. Furthermore, significant diel variation in Fe(II) concentration is to be expected, even in acidic waters, since time scales of light-mediated Fe(III) reduction and thermal Fe(III) reduction differ markedly. A kinetic model is developed that adequately describes both the generation of ROS and the photochemical redox transformations of iron in the presence of M. aeruginosa exudate. PMID- 28650641 TI - A Discovery of Strong Metal-Support Bonding in Nanoengineered Au-Fe3O4 Dumbbell like Nanoparticles by in Situ Transmission Electron Microscopy. AB - The strength of metal-support bonding in heterogeneous catalysts determines their thermal stability, therefore, a tremendous amount of effort has been expended to understand metal-support interactions. Herein, we report the discovery of an anomalous "strong metal-support bonding" between gold nanoparticles and "nano engineered" Fe3O4 substrates by in situ microscopy. During in situ vacuum annealing of Au-Fe3O4 dumbbell-like nanoparticles, synthesized by the epitaxial growth of nano-Fe3O4 on Au nanoparticles, the gold nanoparticles transform into the gold thin films and wet the surface of nano-Fe3O4, as the surface reduction of nano-Fe3O4 proceeds. This phenomenon results from a unique coupling of the size-and shape-dependent high surface reducibility of nano-Fe3O4 and the extremely strong adhesion between Au and the reduced Fe3O4. This strong metal support bonding reveals the significance of controlling the metal oxide support size and morphology for optimizing metal-support bonding and ultimately for the development of improved catalysts and functional nanostructures. PMID- 28650642 TI - Photoswitchable Micro-Supercapacitor Based on a Diarylethene-Graphene Composite Film. AB - Stimuli-responsive micro-supercapacitors (MSCs) controlled by external stimuli can enable a wide range of applications for future on-chip energy storage. Here, we report on a photoswitchable MSC based on a diarylethene-graphene composite film. The microdevice delivers an outstanding and reversible capacitance modulation of up to 20%, demonstrating a prototype photoswitchable MSC. Terahertz spectroscopy indicates that the photoswitching of the capacitance is enabled by the reversible tuning of interfacial charge injection into diarylethene molecular orbitals, as a consequence of charge transfer at the diarylethene-graphene interface upon light modulation. PMID- 28650643 TI - High-Pressure Study of Perovskites and Postperovskites in the (Mg,Fe)GeO3 System. AB - The effect of incorporation of Fe2+ on the perovskite (Pbnm) and postperovskite (Cmcm) structures was investigated in the (Mg,Fe)GeO3 system at high pressures and temperatures using laser-heated diamond anvil cell and synchrotron X-ray diffraction. Samples with compositions of Mg# >= 48 were shown to transform to the perovskite (~30 GPa and ~1500 K) and postperovskite (>55 GPa, ~1600-1800 K) structures. Compositions with Mg# >= 78 formed single-phase perovskite and postperovskite, whereas those with Mg# < 78 showed evidence for partial decomposition. The incorporation of Fe into the perovskite structure causes a decrease in octahedral distortion as well as a modest decrease in bulk modulus (K0) and a modest increase in zero-pressure volume (V0). It also leads to a decrease in the perovskite-to-postperovskite phase transition pressure by ~9.5 GPa over compositions from Mg#78 to Mg#100. PMID- 28650645 TI - Biological Contamination of Nanoparticles and Its Manifestation in Optical Absorbance Measurements. AB - The biological contamination of nanomaterials is a serious problem hampering their widespread use in biomedical products. Existing commercial chromogenic assays for the detection and quantification of biocontaminants such as endotoxin can interfere with nanoparticles thus leading to unreliable data. The results reported in this Letter offer a solution to the aforementioned problems of the nanoparticle interference and correct quantification of biocontaminants by decomposing their optical absorbance into two physically measurable components and analyzing them as a function of the concentration of contaminated nanoparticles. PMID- 28650644 TI - Combination of Plant Virus Nanoparticle-Based in Situ Vaccination with Chemotherapy Potentiates Antitumor Response. AB - Immunotherapeutics are gaining more traction in the armamentarium used to combat cancer. Specifically, in situ vaccination strategies have gained interest because of their ability to alter the tumor microenvironment to an antitumor state. Herein, we investigate whether flexuous plant virus-based nanoparticles formed by the potato virus X (PVX) can be used as an immunotherapeutic for in situ vaccine monotherapy. We further developed dual chemo-immunotherapeutics by incorporating doxorubicin (DOX) into PVX yielding a dual-functional nanoparticle (PVX-DOX) or by coadministration of the two therapeutic regimes, PVX immunotherapy and DOX chemotherapy (PVX+DOX). In the context of B16F10 melanoma, PVX was able to elicit delayed tumor progression when administered as an intratumoral in situ vaccine. Furthermore, the coadministration of DOX via PVX+DOX enhanced the response of the PVX monotherapy through increased survival, which was also represented in the enhanced antitumor cytokine/chemokine profile stimulated by PVX+DOX when compared to PVX or DOX alone. Importantly, coadministered PVX+DOX was better for in situ vaccination than PVX loaded with DOX (PVX-DOX). Whereas the nanomedicine field strives to design multifunctional nanoparticles that integrate several functions and therapeutic regimens into a single nanoparticle, our data suggest a paradigm shift; some therapeutics may need to be administered separately to synergize and achieve the most potent therapeutic outcome. Altogether, our studies show that development of plant viral nanoparticles for in situ vaccines for treatment is a possibility, and dual mechanistic therapeutics can increase efficacy. Nonetheless, combining immunotherapeutics with cytolytic chemotherapy requires detailed investigation to inform optimal integration of cytolytic and immunotherapies and maximize synergy and efficacy. PMID- 28650646 TI - Catalytic Conjugate Addition of Electron-Rich Heteroarenes to beta,beta Disubstituted Enones. AB - Catalytic conjugate additions of heteroarenes to beta,beta-disubstituted enones are reported. Additions of a range of heteroarene nucleophiles, including furans, indoles, a pyrrole, and a thiophene, to a variety of beta,beta-disubstituted enones occur to form the corresponding ketone products containing heteroarylated, all-carbon quaternary centers in up to 90% yield. These reactions occur under mild reaction conditions in the presence of low loadings of bismuth triflate. PMID- 28650647 TI - Highly Efficient and Stable Sn-Rich Perovskite Solar Cells by Introducing Bromine. AB - Compositional engineering of recently arising methylammonium (MA) lead (Pb) halide based perovskites is an essential approach for finding better perovskite compositions to resolve still remaining issues of toxic Pb, long-term instability, etc. In this work, we carried out crystallographic, morphological, optical, and photovoltaic characterization of compositional MASn0.6Pb0.4I3-xBrx by gradually introducing bromine (Br) into parental Pb-Sn binary perovskite (MASn0.6Pb0.4I3) to elucidate its function in Sn-rich (Sn:Pb = 6:4) perovskites. We found significant advances in crystallinity and dense coverage of the perovskite films by inserting the Br into Sn-rich perovskite lattice. Furthermore, light-intensity-dependent open circuit voltage (Voc) measurement revealed much suppressed trap-assisted recombination for a proper Br-added (x = 0.4) device. These contributed to attaining the unprecedented power conversion efficiency of 12.1% and Voc of 0.78 V, which are, to the best of our knowledge, the highest performance in the Sn-rich (>=60%) perovskite solar cells reported so far. In addition, impressive enhancement of photocurrent-output stability and little hysteresis were found, which paves the way for the development of environmentally benign (Pb reduction), stable monolithic tandem cells using the developed low band gap (1.24-1.26 eV) MASn0.6Pb0.4I3-xBrx with suggested composition (x = 0.2-0.4). PMID- 28650648 TI - Indian Ocean Dipole and Cryptosporidiosis in Australia: Short-Term and Nonlinear Associations. AB - The Indian Ocean Dipole (IOD) is a global climate phenomenon that influences the spread of human infectious diseases through climate extremes including droughts and floods. The Dipole Mode Index (DMI), which measures the strength of the IOD, is one of the main indicators of rainfall variability across Australia. Using an ecological, time-series approach we examined the short-term and nonlinear relationship between the DMI and weekly cryptosporidiosis reported from 2001 to 2012 across the temperate, subtropical, and tropical climate zones in Australia, controlling for season, long-term trends, and cryptosporidiosis counts from the past week. The association of DMI with cryptosporidiosis was nonlinear and varied in the short term and by climatic zone. Including cryptosporidiosis counts from the previous week improved model fit in all three zones and modified the DMI disease relationship in the subtropical and temperate regions. In the temperate zone, a 0.1 unit increase in an extreme positive DMI was associated with a higher risk of reported cryptosporidiosis [Relative Risk (RR) 1.23 (95% confidence interval (CI), 1.00-1.52)], compared to the risk associated with mean DMI. This methodology shows the potential for quantifying the short-term and nonlinear response of infections like cryptosporidiosis with climate variability. These findings also suggest that future models that account for lagged disease effects may better represent the time varying environmental exposure-disease relationship. The expected increases in the frequency of positive DMI events will likely result in decreased rainfall across temperate Australia, with potential implications for public health. PMID- 28650651 TI - Tuning Selectivity of CO2 Hydrogenation Reactions at the Metal/Oxide Interface. AB - The chemical transformation of CO2 not only mitigates the anthropogenic CO2 emission into the Earth's atmosphere but also produces carbon compounds that can be used as precursors for the production of chemicals and fuels. The activation and conversion of CO2 can be achieved on multifunctional catalytic sites available at the metal/oxide interface by taking advantage of the synergy between the metal nanoparticles and oxide support. Herein, we look at the recent progress in mechanistic studies of CO2 hydrogenation to C1 (CO, CH3OH, and CH4) compounds on metal/oxide catalysts. On this basis, we are able to provide a better understanding of the complex reaction network, grasp the capability of manipulating structure and combination of metal and oxide at the interface in tuning selectivity, and identify the key descriptors to control the activity and, in particular, the selectivity of catalysts. Finally, we also discuss challenges and future research opportunities for tuning the selective conversion of CO2 on metal/oxide catalysts. PMID- 28650650 TI - Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model. AB - Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a-8a and 9a-e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4-4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy. PMID- 28650649 TI - Decoration of Chondroitin Polysaccharide with Threonine: Synthesis, Conformational Study, and Ice-Recrystallization Inhibition Activity. AB - Several threonine (Thr)- and alanine (Ala)-rich antifreeze glycoproteins (AFGPs) and polysaccharides act in nature as ice recrystallization inhibitors. Among them, the Thr-decorated capsular polysaccharide (CPS) from the cold-adapted Colwellia psychrerythraea 34H bacterium was recently investigated for its cryoprotectant activity. A semisynthetic mimic thereof was here prepared from microbial sourced chondroitin through a four-step strategy, involving a partial protection of the chondroitin polysaccharide as a key step for gaining an unprecedented quantitative amidation of its glucuronic acid units. In-depth NMR and computational analysis suggested a fairly linear conformation for the semisynthetic polysaccharide, for which the antifreeze activity by a quantitative ice recrystallization inhibition assay was measured. We compared the structure activity relationships for the Thr-derivatized chondroitin and the natural Thr decorated CPS from C. psychrerythraea. PMID- 28650652 TI - Droplet Sliding on an Inclined Substrate with a Topographical Defect. AB - Pinning and depinning of droplets on heterogeneous substrates are widely seen in nature and need to be carefully controlled in industrial processes such as substrate cleaning and spray coating. In this work, a two-dimensional droplet sliding on an inclined substrate with a topographical defect is studied with a thin-film evolution equation. Using results from time-dependent finite-difference calculations, we focus our discussion on the dynamic interactions between the sliding droplet and the topographical defect. For a Gaussian defect shape, we find that droplet pinning is primarily determined by the advancing contact line pinning at the defect surface where the topography slope is minimum. We demonstrate that with certain combinations of defect heights and widths, residual droplets can form on the defect as a result of geometric constraints involving the receding droplet meniscus and the defect shape. We show that the delay in sliding caused by the defect is mainly due to the pinning and depinning of the receding contact line, and less affected by the dynamic behavior of the advancing contact line. This topography-induced delay in sliding of an individual droplet may have important implications for controlling the collective sliding behavior of multiple droplets. PMID- 28650654 TI - Evaluation of a Rapid Method for Screening Heat Stress Tolerance Using Three Korean Wheat (Triticum aestivum L.) Cultivars. AB - Thermotolerance in plants is a topic of concern given the current trends in global warming. Here, we aimed to develop a rapid and reproducible screening method for selection of heat stress-tolerant wheat varieties to expedite the breeding process. We tested the robustness of the screen in three Korean wheat cultivars, "BackJung", "KeumKang", and "ChoKyeong". We showed that 4-day-old seedlings of "KeumKang" had the highest survival rates after a 45 degrees C treatment for 20 h. Moreover, the ability to retain chlorophyll and antioxidant activity was also highest in "KeumKang". The increase in malondialdehyde content in "ChoKyeong" indicated that this cultivar showed the greatest damage after heat stress. Collectively, our results showed that "KeumKang" is the most heat tolerant cultivar of the three examined. In conclusion, the most reliable and rapid screening method in our investigation was survival rate examined at lethal temperature. PMID- 28650653 TI - Growth and Metabolic Responses of Rice (Oryza sativa L.) Cultivated in Phosphorus Deficient Soil Amended with TiO2 Nanoparticles. AB - Plants have the natural ability to withstand stress conditions through metabolic adjustments. The present study aimed at investigating the effects of titanium dioxide nanoparticles (TiO2 NPs) application (0, 25, 50, 150, 250, 500, and 750 mg kg-1) in phosphorus-deficient soil in terms of growth responses, P contents, and metabolic alterations in rice. TiO2 NPs application increased shoot length up to 14.5%. Phosphorus contents in rice roots, shoots, and grains were increased by 2.6-, 2.4-, and 1.3-fold, respectively, at 750 mg kg-1 of TiO2 NPs. Gas chromatography-mass spectrometry (GC-MS)-based metabolomics revealed increased levels of amino acids, palmitic acid, and glycerol content in grains resulting from plants grown in 750 mg kg-1 TiO2 NPs-treated soil. Furthermore, no translocation of TiO2 NPs from the treated soil to rice grains was detected by inductively coupled plasma-optical emission spectrometry (ICP-OES), which suggests no risk of TiO2 NPs intake via grain consumption. The observed data indicates the strong relationship among NPs application, P contents, and metabolic alterations. PMID- 28650655 TI - Vibrational Relaxation of the Backbone and Base Modes in LacDNA Complexes by UV Resonance Raman Spectroscopy. AB - Vibrational band shape analysis through time correlation function concept is widely used to obtain experimental information on the molecular dynamics of medium-size molecules in different environments. Interesting details are revealed by extending this technique to biomolecules such as functional groups of the nucleic acids in media approaching the physiological conditions. In this work a study into the UV resonance Raman (UVRR) vibrational half bandwidths of functional groups in LacDNA, upon lowering the pH (pH 6.4, pH 3.45) and in the presence of Mn2+ and Ca2+ ions, respectively, was of interest. The corresponding global relaxation times have been derived. Also, the 793 cm-1 UVRR band, corresponding to nu (backbone O-P-O, dT) oscillator of LacDNA in aqueous solutions, was selected for band shape-analysis. Vibrational relaxation appears as the dominant relaxation process for this mode, with vibrational dephasing being the most efficient for this oscillator. Current theories developed for vibrational dephasing have been applied to this profile, and relevant relaxation parameters have been obtained and discussed. To our knowledge this is the first study on DNA oligomers vibrational band shape analysis through time correlation function concept. PMID- 28650657 TI - Noncovalent PEGylation through Protein-Polyelectrolyte Interaction: Kinetic Experiment and Molecular Dynamics Simulation. AB - Noncovalent binding of polyethylene glycol (PEG) to a protein surface is a unique protein handling technique to control protein function and stability. A diblock copolymer containing PEG and polyelectrolyte chains (PEGylated polyelectrolyte) is a promising candidate for noncovalent attachment of PEG to a protein surface because of the binding through multiple electrostatic interactions without protein denaturation. To obtain a deeper understanding of protein-polyelectrolyte interaction at the molecular level, we investigated the manner in which cationic PEGylated polyelectrolyte binds to anionic alpha-amylase in enzyme kinetic experiments and molecular dynamics (MD) simulations. Cationic PEG-block-poly(N,N dimethylaminoethyl) (PEG-b-PAMA) inhibited the enzyme activity of anionic alpha amylase due to binding of PAMA chains. Enzyme kinetics revealed that the inhibition of alpha-amylase activity by PEG-b-PAMA is noncompetitive inhibition manner. In MD simulations, the PEG-b-PAMA molecule was initially located at six different placements of the x-, y-, and z-axis +/-20 A from the center of alpha amylase, which showed that the PEG-b-PAMA nonspecifically bound to the alpha amylase surface, corresponding to the noncompetitive inhibition manner that stems from the polymer binding to an enzyme surface other than the active site. In addition, the enzyme activity of alpha-amylase in the presence of PEG-b-PAMA was not inhibited by increasing the ionic strength, consistent with the MD simulation; i.e., PEG-b-PAMA did not interact with alpha-amylase in high ionic strength conditions. The results reported in this paper suggest that enzyme inhibition by PEGylated polyelectrolyte can be attributed to the random electrostatic interaction between protein and polyelectrolyte. PMID- 28650656 TI - Cytotoxic and Mutagenic Properties of C3'-Epimeric Lesions of 2' Deoxyribonucleosides in Escherichia coli Cells. AB - Reactive oxygen species (ROS), resulting from endogenous metabolism and/or environmental exposure, can induce damage to the 2-deoxyribose moiety in DNA. Specifically, a hydrogen atom from each of the five carbon atoms in 2-deoxyribose can be abstracted by hydroxyl radical, and improper chemical repair of the ensuing radicals formed at the C1', C3', and C4' positions can lead to the stereochemical inversion at these sites to yield epimeric 2-deoxyribose lesions. Although ROS-induced single-nucleobase lesions have been well studied, the biological consequences of the C3'-epimeric lesions of 2'-deoxynucleosides, i.e., 2'-deoxyxylonucleosides (dxN), have not been comprehensively investigated. Herein, we assessed the impact of dxN lesions on the efficiency and fidelity of DNA replication in Escherichia coli cells by conducting a competitive replication and adduct bypass assay with single-stranded M13 phage containing a site specifically incorporated dxN. Our results revealed that, of the four dxN lesions, only dxG constituted a strong impediment to DNA replication, and intriguingly, dxT and dxC conferred replication bypass efficiencies higher than those of the unmodified counterparts. In addition, the three SOS-induced DNA polymerases (Pol II, Pol IV, and Pol V) did not play any appreciable role in bypassing these lesions. Among the four dxNs, only dxA directed a moderate frequency of dCMP misincorporation. These results provided important insights into the impact of the C3'-epimeric lesions on DNA replication in E. coli cells. PMID- 28650658 TI - Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization. AB - PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 MUM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 MUM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications. PMID- 28650660 TI - pH Triggered Recovery and Reuse of Thiolated Poly(acrylic acid) Functionalized Gold Nanoparticles with Applications in Colloidal Catalysis. AB - Thiolated poly(acrylic acid) (PAA-SH) functionalized gold nanoparticles were explored as a colloidal catalyst with potential application as a recoverable catalyst where the PAA provides pH-responsive dispersibility and phase transfer capability between aqueous and organic media. This system demonstrates complete nanoparticle recovery and redispersion over multiple reaction cycles without changes in nanoparticle morphology or reduction in conversion. The catalytic activity (rate constant) was reduced in subsequent reactions when recovery by aggregation was employed, despite unobservable changes in morphology or dispersibility. When colloidal catalyst recovery employed a pH induced phase transfer between two immiscible solvents, the catalytic activity of the recovered nanoparticles was unchanged over four cycles, maintaining the original rate constant and 100% conversion. The ability to recover and reuse colloidal catalysts by aggregation/redispersion and phase transfer methods that occur at low and high pH, respectively, could be used for different gold nanoparticle catalyzed reactions that occur at different pH conditions. PMID- 28650659 TI - Asymmetric Radical Bicyclization of Allyl Azidoformates via Cobalt(II)-Based Metalloradical Catalysis. AB - Cobalt(II)-based metalloradical catalysis has been successfully applied to radical bicyclization of allyl azidoformates to construct aziridine/oxazolidinone fused bicyclic structures. The Co(II) complex of D2-symmetric chiral amidoporphyrin 3,5-DitBu-QingPhyrin has been identified as an effective metalloradical catalyst for the intramolecular radical aziridination of this type of carbonyl azides, allowing for high-yielding formation of synthetically useful chiral [3.1.0]-bicyclic aziridines with high diastereo- and enantioselectivity. PMID- 28650661 TI - Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms. AB - A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 MUg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 MUg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study. PMID- 28650663 TI - Overexpression and Low Expression of Selenoprotein S Impact Ochratoxin A-Induced Porcine Cytotoxicity and Apoptosis in Vitro. AB - Our previous study demonstrated that selenium could alleviate ochratoxin A (OTA) induced nephrotoxicity in PK15 cells. Selenoprotein S (SelS) has antioxidant activities, but it is unclear whether SelS plays a role in the alleviating effects of selenium on OTA-induced nephrotoxicity. We previously have stably transfected pig pCDNA3.1-SelS to PK15 cells to overexpress SelS. Here, we demonstrated that SelS overexpression alleviated OTA-induced cytotoxicity and apoptosis as demonstrated by cell viabilities, LDH activities, Annexin V-bing, caspase 3 activities, and apoptotic nuclei. SelS overexpression increased glutathione (GSH) levels and decreased reactive oxygen species (ROS) and malondialdehyde levels in PK15 cells, regardless of OTA treatment. SelS overexpression inhibited OTA-induced p38 phosphorylation. Adding buthionine sulfoximine reversed all of the above SelS-induced changes. In addition, the knockdown of SelS by SelS-specific siRNA decreased GSH levels, increased ROS levels, and aggravated OTA-induced p38 phosphorylation. The knockdown of SelS aggravated OTA-induced cytotoxicity and apoptosis in PK15 cells. These data indicate that pig SelS overexpression and lowexpression impact OTA-induced cytotoxicity and apoptosis by modulating the oxidative stress and p38 phosphorylation. Our work provides new insights into the relationship between SelS- and OTA-induced cytotoxicity and apoptosis and describes an antitoxic mechanism of action for Se. PMID- 28650662 TI - Glucose Restriction Combined with Autophagy Inhibition and Chemotherapy in HCT 116 Spheroids Decreases Cell Clonogenicity and Viability Regulated by Tumor Suppressor Genes. AB - Drug resistance is a prevalent phenomenon that decreases the efficacy of cancer treatments and contributes to cancer progression and metastasis. Weakening drug resistant cancer cells prior to chemotherapy is a potential strategy to combat chemoresistance. One approach to damage resistant cancer cells is modulation of nutritional intake. The combination of nutrient restriction with targeted compound treatment results in pronounced molecular changes. This study provides valuable information about augmenting existing chemotherapeutic regimes with simultaneous glucose restriction and autophagy inhibition in colorectal cancer cells. In this study, we explore the chemical pathways that drive the cellular response to nutrient restriction, autophagy inhibition, and the chemotherapy irinotecan using global quantitative proteomics and imaging mass spectrometry. We determined that significant pathways were altered including autophagy and metabolism via glycolysis, gluconeogenesis, and sucrose degradation. We also found that period circadian clock 2 (PER2), a tumor suppressor protein, was significantly up-regulated only when glucose was restricted with autophagy inhibition and chemotherapy. The upstream regulators of these differentially regulated pathways were determined to have implications in cancer, showing an increase in tumor suppressor proteins and a decrease in nuclear protein 1 (NUPR1) an important protein in chemoresistance. We also evaluated the phenotypic response of these cells and discovered autophagy inhibition and chemotherapy treatment increased apoptosis and decreased cell clonogenicity and viability. When glucose restriction was combined with autophagy inhibition and chemotherapy, all of the phenotypic results were intensified. In sum, our results indicate that glucose metabolism is of great importance in the ability of cancer cells to survive chemotherapy. By weakening cancer cells with glucose restriction and autophagy inhibition prior to chemotherapy, cancer cells become more sensitive to therapy. PMID- 28650664 TI - The Dynamical Transition of Lipid Multilamellar Bilayers as a Matter of Cooperativity. AB - The present study is the application of a two-state model formerly developed by Bicout and Zaccai [ Bicout , D. J. and Zaccai , G. Biophys. J. 2001 , 80 ( 3 ), 1115 - 1123 ] to describe the dynamical transition exhibited in the atomic mean square displacements of biological samples in terms of dynamic and thermodynamic parameters. Data were obtained by elastic incoherent neutron scattering on 1,2 dimyristoyl-sn-glycero-3-phosphocholine lipid membranes in various hydration states and on one partially per-deuterated lipid membrane. Fitting the data with the model allowed investigating which parts of lipid molecules were mainly involved in the dynamical transition, heads, tails, or both. Clear differences were found between the fully protonated and partially deuterated membranes. These findings shed light on the question of what is the degree of dynamical cooperativity of the atoms during the transition. Whereas the level of hydration does not significantly affect it, as the dry, the intermediate dry, and fully hydrated membranes all undergo a rather broad transition, the transition of the lipid tails is much sharper and sets in at much lower temperature than that of the heads. Therefore, the dynamical cooperativity appears high among the particles in the tails. Moreover, the transition of the lipid tails has to be completed first before the one of the head groups starts. PMID- 28650665 TI - Understanding the Oxidative Stability of Antifouling Polymer Brushes. AB - Poly(oligoethylene glycol methacrylate) (POEGMA) and zwitterionic polymer brushes have been widely used for constructing biocompatible or antifouling surfaces, and their oxidative stability is very important to the practical application. Herein, POEGMA, poly(sulfobetaine methacrylate) (PSBMA), poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC), and poly(carboxybetaine methacrylate) (PCBMA) were grafted on quartz crystal microbalance (QCM) chips via surface-initiated atom transfer radical polymerization (SI-ATRP). XPS and MS analyses demonstrate that the mass loss of these polymer brushes in oxidative environment is due to the scission of the polymer-anchoring segments. Molecular simulation further illustrates this mass loss mechanism should be always true for those polymer brushes anchored on different substrates. In situ QCM monitoring indicates that, compared with zwitterionic polymethacrylates, POEGMA brushes show the lowest mass loss rate mainly due to their cross-linked structures. This study sheds light on the contradictory reports about the oxidative stability of POEGMA and zwitterionic polymethacrylate brushes up to now, and highlights the important role of the polymer-anchoring segments playing in the oxidative stability of polymer brushes. PMID- 28650666 TI - Labile Incorporation of Cholesterol-Terminated Poly(acrylic acid) for the Facile Surface-Modification of Lipid Vesicles. AB - An amphiphilic cholesterol-terminated poly[acrylic acid] (Chol-PAA) that can be self-aggregated into nanoscale micelles in aqueous media has been prepared via nitroxide-mediated radical polymerization for the facile postformation modification of lipid vesicles. By varying the amount of Chol-PAA addition, the incorporation of Chol-PAA on the liposome templates was verified with zeta potential while the dynamic light scattering measurements revealed the polymer length of Chol-PAA dictated the hydrodynamic diameter of the resulting polymer grafted vesicles (PGVs). The membrane incorporation process of Chol-PAA was monitored through the fluorescence resonance energy transfer (FRET) study, which showed the relatively labile incorporation property of Chol-PAA, compared to the cholesterol-free PAA and the native cholesterol. Additionally, the postmodification of liposomes with such labile Chol-PAA exhibited a negligible leakage of calcein payloads, which can be attributed to the partial modification of the external membrane. These results indicated that our Chol-PAA can be exploited for the facile construction of functional polymer-decorated liposomal delivery systems. PMID- 28650667 TI - Gender-Specific Association Between FGFR4 Gly388Arg Gene Variants and Hypertension. AB - AIMS: Variations in fibroblast growth factor (FGF) levels have been associated with alterations in blood pressure. FGFs mediate their function through binding to their FGF receptor (FGFR). The FGFR4 Gly388Arg polymorphism is associated with cancer and cardiovascular diseases, but its association with hypertension is unclear. Here, we aimed to investigate the association between the FGFR4 Gly388Arg polymorphism and hypertension. MATERIALS AND METHODS: Three hundred Saudi individuals (150 normotensive controls and 150 hypertensive subjects) were genotyped for the FGFR4 Gly388Arg (G/A) polymorphism using polymerase chain reaction-restriction fragment length polymorphism method. Anthropometrics, glucose and lipid profiles were measured for all subjects. The frequency of the FGFR4 Arg388 (A) allele was significantly higher in hypertensive subjects (36%) than controls (24.3%) (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.5 3.83, p < 0.001). In addition, GA (OR 2.51, 95% CI 1.3-4.85, p = 0.006), AA (OR 5.58, 95% CI 1.79-11.8, p = 0.003), and GA + AA (OR 2.91, 95% CI 1.55-5.46, p = 0.001) genotypes were significantly associated with the risk of hypertension, even after adjusting for age, body mass index, and glucose. Gender stratification showed a significant association only in female subjects (p < 0.001). Furthermore, subjects with GA and AA genotypes showed significantly higher diastolic blood pressure than those with GG genotype (p = 0.004). CONCLUSION: The FGFR4 Arg388 allele is associated with an increased risk of hypertension in Saudi female subjects. The lack of association in men needs to be further investigated. PMID- 28650668 TI - Categorization of psychoactive substances into "hard drugs" and "soft drugs": a critical review of terminology used in current scientific literature. AB - BACKGROUND: Precise terminology and definitions are important components of scientific language. Although the terms "hard drugs" and "soft drugs" are used widely by professionals, neither the International Classification of Diseases nor the Diagnostic and Statistical Manual classify psychoactive substances into the categories "hard" and "soft." OBJECTIVES: To analyze the occurrence of the terms "hard drugs" and "soft drugs" in recent scientific literature and to establish the degree of consensus in labeling psychoactive substances as "hard" or "soft." METHODS: A critical review of scientific papers listed in PubMed and Scopus between 2011 and 2015. Three hundred thirty-four articles were initially identified as potentially relevant for review, 132 of which were included in the final analysis. RESULTS: One hundred twenty-four articles used the term "hard drugs" and 84.7% provided examples of substances considered "hard." Forty-four articles used the term "soft drugs" and 90.9% provided examples of substances considered "soft." Citations of relevant articles supporting categorization as "hard" or "soft" were not given in 90% of the articles. The authors often provided no or only very sparse information on their reasons for considering specific drugs as "hard" or "soft." CONCLUSIONS: Although it initially appeared that there is substantial agreement as to which psychoactive substances should be regarded as "hard" and "soft," closer inspection shows that the dividing line is blurred without clear criteria for categorization. At this time, it remains uncertain whether these terms should persist in the scientific literature. We therefore recommend these terms should be avoided or, if used, be clearly and precisely defined. PMID- 28650670 TI - The SDF1 A/G Gene Variant: A Susceptibility Variant for Myocardial Infarction. AB - BACKGROUND: Although environmental factors play an important role in susceptibility to myocardial infarction (MI), genetic determinants also provide a significant contribution. This study aimed to determine whether or not MI susceptibility is influenced by the SDF1-rs1801157A/G and HHEX-rs1111875 A/G polymorphisms in an Iranian population. METHODS: A total of 120 patients with MI and 120 healthy controls were enrolled. Blood samples were collected from all the participants for genomic DNA extraction and testing. Polymorphism genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Multiple logistic regression analysis revealed that the A allele and AA genotype of the SDF1-rs1111875 polymorphism produce a significant risk of MI both before (crude odds ratio [OR] = 8.83, 95% confidence interval [95% CI] = 1.05-73.76, p = 0.025) and after adjustment (adjusted OR = 8.12, 95% CI = 5.02-19.42, p = 0.04). In contrast, the GG genotype of the SDF1 rs1111875 polymorphism provides a protective effect on MI in a recessive model (GG vs. AA+AG) before (crude OR = 0.57, 95% CI = 0.34-0.97, p = 0.037) and after adjustment (adjusted OR = 0.53, 95% CI = 0.3-0.82, p = 0.021). No association was found between the HHEX-rs1111875 A/G polymorphism alleles and the susceptibility to MI. CONCLUSION: Taken together, the current findings suggest that the SDF1 rs1801157A/G gene variant may play an important role in relation to MI in this Iranian population. Nevertheless, more replication studies and meta-analyses should be carried out in this area. PMID- 28650669 TI - Visceral adiposity and expression of clock genes in peripheral blood mononuclear cells: A pilot study. AB - Increasing evidence suggests a close interrelationship between disrupted circadian rhythms and obesity and metabolic disturbances. In particular, abdominal obesity, which contributes to the pathogenesis of metabolic disease, is associated with disrupted clock gene expression. However, little is known about the relationship between clock gene expression and accurate computed tomography (CT)-based measurements of visceral adiposity. Therefore, we examined the relationship between expression of clock genes in peripheral blood mononuclear cells (PBMCs) with visceral and subcutaneous adiposity in 75 healthy overweight or obese individuals. PBMCs were obtained from blood samples collected at 8 AM, and gene expression was analyzed by real-time reverse transcription polymerase chain reaction. Visceral and subcutaneous adiposity were measured by CT. Our results showed that visceral fat area was significantly positively correlated with BMAL1 and CRY1 mRNA levels and significantly negatively correlated with CLOCK, PER2, PER3 and CRY2 mRNA levels. In contrast, subcutaneous fat area was not correlated with the expression of any of the clock genes analyzed. After adjusting for multiple variables, visceral fat area was significantly associated with the expression of BMAL1, PER2 and CRY1. Taken together, our results indicate that visceral adiposity, but not subcutaneous adiposity, correlates with expression of clock genes in PBMCs. PMID- 28650671 TI - Association of CCR2 (+190 G/A) Gene Variants and Ovarian Cancer Severity. AB - AIM: Chemokines and their receptors play an important role in tumor progression. In the current study, we aimed to determine the association between the CCR2 gene (+190 G/A) polymorphism and ovarian cancer severity. METHODS: CCR2 (+190 G/A) genotyping was performed using real-time polymerase chain reaction for DNA isolated from blood samples from a cohort of patients with ovarian cancer (n = 44) and a control group (n = 45). RESULTS: The CCR2 (+190 G/A) GG genotype frequencies for patients were significantly higher in the stage III-IV cancer group (p = 0.036), and A allele carriers were significantly higher in the stage I II ovarian cancer group. CONCLUSION: The CCR2 (+190 G/A) GG genotype may be a potential risk factor for the severe forms of ovarian cancer and the A allele may be a risk-reducing factor for severe ovarian cancer. PMID- 28650673 TI - Evidence of Interleukin 21 Reduction in Osteosarcoma Patients Due to PD-1/PD-L1 Mediated Suppression of Follicular Helper T Cell Functionality. AB - Interleukin 21 (IL-21) is crucial for the development of a robust CD8+ T cell response and has been shown to promote antitumor immunity. Despite the fact that osteosarcoma presents significant genetic instability with a high immunogenic potential, the antitumor immune response in osteosarcoma is ineffective. We investigated whether this was due to impaired IL-21 responses. We found that the circulating CD4+ T cells, a major source of IL-21, had reduced capacity to express IL-21 in osteosarcoma patients compared to healthy controls. The IL-21 expression in healthy controls was equally shared between Th17 and follicular helper T (Tfh) cells, while in osteosarcoma patients, the Tfh cells presented a severe reduction in IL-21 secretion capacity as well as in proliferation capacity. To explain this loss of Tfh functionality, we found that Tfh cells expressed the highest level of PD-1 among all CD4+ T cell subsets examined. While PD-1 might be crucial for normal Tfh function in healthy individuals, in patients with programmed death ligand 1 (PD-L1)+ tumor, the PD-1/PD-L1 pathway on Tfh cells might be sabotaged to mediate immunosuppression. Indeed, the IL-21 production by Tfh cells was significantly reduced in the presence of PD-L1+ tumor cells and was rescued by the anti-PD-L1 antibody. In healthy individuals, CXCR5+ Tfh cells could enhance the interferon (IFN)-gamma secretion, degranulation, and cytotoxicity of CD8+ T cells, but this function of Tfh cells was lost in osteosarcoma patients. Together, this study demonstrated a dysregulated pathway that should be targeted for future immunotherapies in osteosarcoma. PMID- 28650672 TI - Campylobacter Species Isolated from Pigs in Grenada Exhibited Novel Clones: Genotypes and Antimicrobial Resistance Profiles of Sequence Types. AB - Infections caused by Campylobacter species pose a severe threat to public health worldwide. However, in Grenada, the occurrence and characteristics of Campylobacter in food animals, including pigs, remain mostly unknown. In this study, we identified the sequence types (STs) of Campylobacter from young healthy pigs in Grenada and compared the results with previous studies in Grenada and other countries. Antimicrobial resistance patterns and diversity of the Campylobacter clones were evaluated. Ninety-nine Campylobacter isolates (97 Campylobacter coli and 2 Campylobacter jejuni) were analyzed by multilocus sequence typing. Eighteen previously reported STs and 13 novel STs were identified. Of the 18 previously reported STs, eight STs (ST-854, -887, -1068, 1096, -1445, -1446, 1556, and -1579) have been associated with human gastroenteritis in different geographical regions. Among these 18 previously reported STs, ST-1428, -1096, -1450, and -1058 predominated and accounted for 18.2%, 14.1%, 11.1%, and 8.1% of all isolates, respectively. Of the 13 novel STs, ST-7675 predominated and accounted for 20% (4 of 20 isolates), followed by ST 7678, -7682, and -7691, each accounting for 10% (2 of 20 isolates). Antimicrobial resistance testing using Epsilometer test revealed a low resistance rate (1-3%) of all C. coli/jejuni STs to all antimicrobials except for tetracycline (1 10.1%). Some of the C. coli STs (13 STs, 24/99 isolates, 24.2%) were resistant to multiple antimicrobials. This is the first report on antimicrobial resistance and multidrug resistance patterns associated with Campylobacter STs recovered from swine in Grenada. This study showed that pigs in Grenada are not major reservoirs for STs of C. coli and C. jejuni that are associated with human gastroenteritis worldwide. PMID- 28650675 TI - Individual Responsibility vs. System Failure. PMID- 28650676 TI - An off-the-shelf meter for measuring body amperage: A new gold standard for epidemiologic studies? PMID- 28650674 TI - Variation in actigraphy-estimated rest-activity patterns by demographic factors. AB - Rest-activity patterns provide an indication of circadian rhythmicity in the free living setting. We aimed to describe the distributions of rest-activity patterns in a sample of adults and children across demographic variables. A sample of adults (N = 590) and children (N = 58) wore an actigraph on their nondominant wrist for 7 days and nights. We generated rest-activity patterns from cosinor analysis (MESOR, acrophase and magnitude) and nonparametric circadian rhythm analysis (IS: interdaily stability; IV: intradaily variability; L5: least active 5-hour period; M10: most active 10-hour period; and RA: relative amplitude). Demographic variables included age, sex, race, education, marital status, and income. Linear mixed-effects models were used to test for demographic differences in rest-activity patterns. Adolescents, compared to younger children, had (1) later M10 midpoints (beta = 1.12 hours [95% CI: 0.43, 1.18] and lower M10 activity levels; (2) later L5 midpoints (beta = 1.6 hours [95% CI: 0.9, 2.3]) and lower L5 activity levels; (3) less regular rest-activity patterns (lower IS and higher IV); and 4) lower magnitudes (beta = -0.95 [95% CI: -1.28, -0.63]) and relative amplitudes (beta = -0.1 [95% CI: -0.14, -0.06]). Mid-to-older adults, compared to younger adults (aged 18-29 years), had (1) earlier M10 midpoints (beta = -1.0 hours [95% CI: -1.6, -0.4]; (2) earlier L5 midpoints (beta = -0.7 hours [95% CI: -1.2, -0.2]); and (3) more regular rest-activity patterns (higher IS and lower IV). The magnitudes and relative amplitudes were similar across the adult age categories. Sex, race and education level rest-activity differences were also observed. Rest-activity patterns vary across the lifespan, and differ by race, sex and education. Understanding population variation in these patterns provides a foundation for further elucidating the health implications of rest activity patterns across the lifespan. PMID- 28650677 TI - Psychosocial Risk Factors for Perinatal Depression among Female Adolescents: A Systematic Review. AB - Perinatal depression is a health concern among pregnant and postpartum adolescents as it may negatively impact fetal development and result in complications such as preterm delivery, low infant birth weight, and poor maternal-infant attachment. The purpose of this systematic review is to examine psychosocial risk factors for depression among adolescents during pregnancy and postpartum. A literature search was conducted from five databases from 1995 to 2016. A total of 17 studies matched the inclusion criteria. Lack of social support, perceived stress, prior history of depression, and a history of sexual or physical violence were most frequently identified as potential risk factors for perinatal depression. Additional risk factors include the adolescent's perception of her pregnancy, family criticism, self-efficacy, self-esteem, substance use, parental stress, community violence, anxiety, and African-American ethnicity. Research and clinical implications are indicated for adolescents at risk for perinatal depression. PMID- 28650678 TI - An Integrative Approach for Identifying Network Biomarkers of Breast Cancer Subtypes Using Genomic, Interactomic, and Transcriptomic Data. AB - Breast cancer is a complex disease that can be classified into at least 10 different molecular subtypes. Appropriate diagnosis of specific subtypes is critical for ensuring the best possible patient treatment and response to therapy. Current computational methods for determining the subtypes are based on identifying differentially expressed genes (i.e., biomarkers) that can best discriminate the subtypes. Such approaches, however, are known to be unreliable since they yield different biomarker sets when applied to data sets from different studies. Gathering knowledge about the functional relationship among genes will identify "network biomarkers" that will enrich the criteria for biomarker selection. Cancer network biomarkers are subnetworks of functionally related genes that "work in concert" to perform functions associated with a tumorigenic. We propose a machine learning framework that can be used to identify network biomarkers and driver genes for each specific breast cancer subtype. Our results show that the resulting network biomarkers can separate one subtype from the others with very high accuracy. PMID- 28650679 TI - Establishing Maximal Medical Improvement After Arthroscopic Rotator Cuff Repair. AB - BACKGROUND: As health care transitions from a pay-for-service to a pay-for performance infrastructure, the value of orthopaedic care must be defined accurately. Significant efforts have been made in defining quality and cost in arthroplasty; however, there remains a lag in ambulatory orthopaedic care. PURPOSE: Two-year follow-up has been a general requirement for reporting outcomes after rotator cuff repair. However, this time requirement has not been established scientifically and is of increasing importance in the era of value based health care. Given that arthroscopic rotator cuff repair is a common ambulatory orthopaedic procedure, the purpose of this study was to establish a time frame for maximal medical improvement (the state when improvement has stabilized) after arthroscopic rotator cuff repair. STUDY DESIGN: Systematic review. METHODS: A systematic review of the literature was conducted, identifying studies reporting sequential patient-reported outcomes up to a minimum of 2 years after arthroscopic rotator cuff repair. The primary clinical outcome was patient reported outcomes at 3-month, 6-month, 1-year, and 2-year follow-up. Secondary clinical outcomes included range of motion, strength, retears, and complications. Clinically significant improvement was determined between various time intervals by use of the minimal clinically important difference. RESULTS: The review included 19 studies including 1370 patients who underwent rotator cuff repair. Clinically significant improvement in patient-reported outcomes was seen up to 1 year after rotator cuff repair, but no clinical significance was noted from 1 year to 2 years. The majority of improvement in strength and range of motion was seen up to 6 months, but no clinically meaningful improvement was seen thereafter. All reported complications and the majority of retears occurred within 6 months after rotator cuff repair. CONCLUSION: After rotator cuff repair, a clinically significant improvement in patient-reported outcomes, range of motion, and strength was seen up to 1 year after surgery, but not beyond this. This information is important not only to establish appropriate patient expectations but also to determine a time frame for outcome collection after surgery to better define value in orthopaedic care. PMID- 28650680 TI - Transurethral Resection of Prostate and Bleeding: A Prospective, Randomized, Double-Blind Placebo-Controlled Trial to See the Efficacy of Short-Term Use of Finasteride and Dutasteride on Operative Blood Loss and Prostatic Microvessel Density. AB - OBJECTIVE: The aim of this study was to determine the efficacy of short-duration use of finasteride and dutasteride before transurethral resection of the prostate (TURP) on intraoperative blood loss and microvessel density (MVD) of prostate stroma and suburethral tissues in benign prostatic hyperplasia (BPH). METHODS: This study includes 450 patients who were planned for TURP. They were prospectively randomized into three groups (150 patients each). Group 1 received placebo, group 2 received finasteride, 5 mg per day, and group 3 patients received dutasteride, 0.5 mg per day, for 4 weeks before surgery. The total blood loss, requirement of blood, and MVDs in prostate stroma and suburethral tissues were calculated in each patient and then compared among three groups. RESULTS: There was significant reduction in mean blood loss, blood loss/time, and total blood loss per gram of resected tissue in finasteride and dutasteride groups compared with placebo. Prostate stromal and suburethral MVDs were significantly higher compared with placebo. Blood transfusion was required in 9.3%, 2.7%, and 2% of the patients, respectively (p = 0.004). However, no statistically significant differences were observed between finasteride and dutasteride groups for these parameters (p > 0.05). The weight of resected prostate, operating time, and amount of irrigation fluid used did not show any significant difference between the three groups. CONCLUSION: Short-term pretreatment with finasteride and dutasteride has similar efficacy and significantly reduces perioperative bleeding during TURP and has minimal negative impact on sexual function. According to our findings, a 4-week prior administration of 5-alpha-reductase inhibitors may reduce operative blood loss and prostatic MVD in TURP, thus potentially decreasing blood loss-related complications and the requirement of blood transfusion. PMID- 28650681 TI - What Should Be the Cutoff Value of Blood Eosinophilia as a Predictor of Inhaled Corticosteroid Responsiveness in Patients with Chronic Obstructive Pulmonary Disease? PMID- 28650682 TI - De-Escalation Training to Medical-Surgical Nurses in the Acute Care Setting. AB - Violence is increasing on medical-surgical units as a "silent epidemic." This quality improvement project employs a small non-experimental, single-group, pre- and post-test design (N = 11) to determine the effectiveness of de-escalation training on medical-surgical nurses' confidence levels when dealing with agitated patients. Regardless of age, education, or years of experience, scores improved for each question on Thackrey's (1987) Confidence in Coping with Patient Aggression Instrument after implementing Ten Domains of De-escalation by Richmond et al. (2012). A paired-sample two-tailed t-test significantly increased from Time 1 pre-test (M = 49.82, SD = 10.11) to Time 2 post-test (M = 72.82, SD = 14.41), t(10) = 4.46, p <.001. The mean increase was 23.00 [95% CI, 11.51-34.49]; d = 1.84 indicating a large effect size (Pilot, 2010). A sensitivity analysis (Wilcoxon Signed Rank Test) showed a median difference among the matched pairs with a significant increase in confidence levels post-training, z = -2.847, p <.004. The median score increased from the pre-test (Md = 51) to the post-test scores (Md = 71) (Pallant, 2013). PMID- 28650683 TI - Mechanical bowel preparation for laparoscopic hysterectomy, is it really necessary? AB - In this prospective randomised single-blind case-controlled cohort study the aim was to compare the effects of mechanical bowel preparation (MBP) on field of vision and surgical comfort during total laparoscopic hysterectomy procedures. The study group was made of 102 patients that had undergone total laparoscopic hysterectomy (TLH), between July 2012 and June 2014. Statistical comparison was made between the means of durations of operation between the two groups divided by visual indexing (VI). The patients with a VI score of less than 2 and those with VI score of 2 or higher were compared in terms of operation duration in regard to the criteria described above. According to calculations, the p value is .664, therefore, making the result statistically not significant at p <= .05. In conclusion it can safely be reported that mechanical bowel preparation before laparoscopic hysterectomy was not found to be necessary in this study group. Impact statement Considering recent publications on the subject, the benefits of mechanical bowel preparation before gynaecologic laparoscopy is still a debateable subject and in that regard what we wish to share is that our study is based on an objective visual indexing tool not used before thus making our results reliable on deciding whether or not patients should receive mechanical bowel preparation prior to laparoscopic surgery for benign reasons. PMID- 28650684 TI - Intentional ingestion of elemental mercury requiring multi-step decontamination and prophylactic appendectomy: a case report and treatment proposal. AB - BACKGROUND: Ingestion of elemental mercury (Hg0) is considered non-toxic. After massive ingestion, local intestinal complications may develop: retention within appendix is quite frequent but treatment is debated. We describe a case of intentional ingestion of Hg0 requiring multi-step decontamination and prophylactic appendectomy. Case detail: A 19-year-old woman was admitted to ED for abdominal pain. History revealed ingestion of large amount of Hg0 as suicide attempt. To prevent absorption, facilitate elimination, and avoid complications a conservative approach was started. Due to inefficacy of initial maneuvers colonoscopy with irrigation/aspiration was performed, repeated whole bowel irrigation was continued and second colonoscopy was performed to clean residual metal. Abdominal plain films confirmed the presence of retained mercury within the appendix in asymptomatic patient. To reduce risk of appendicitis, potential perforation, and possibly systemic toxicity, a prophylactic laparoscopic appendectomy was performed at day 5 with removal of all retained mercury without peritoneal spillage. Highest mercury concentration was 22.7 mcg/L in serum (1-4.5 mcg/L) and 5.1 mcg/L in urine (0.1-5 mcg/L). CONCLUSIONS: After ingestion, metal retention in appendix is quite frequent. Evidence about optimal treatment are different and based on case reports. A multi-step approach with multidisciplinary evaluation tailored to the patient is suggested. PMID- 28650685 TI - Colored Glasses to Mitigate Photophobia Symptoms Posttraumatic Brain Injury. AB - CONTEXT: After a concussion or mild traumatic brain injury (mTBI), patients often suffer from light sensitivity, or photophobia, which contributes to decreased quality of life post-mTBI. Whereas sunglasses may provide some relief from photophobia, they are not practical indoors or in low light. A light mitigation strategy can be easily used indoors as needed to optimize the relief. We have found that many photophobic patients experience relief using colored sunglasses. OBJECTIVE: To provide the athletic trainer with a means and method to assess whether an athlete is suffering from photophobia after concussion and to determine if colored glasses provide relief. DESIGN: Cross-sectional study. SETTING: Rehabilitation clinic. PATIENTS OR OTHER PARTICIPANTS: Fifty-one patients being treated after concussion. INTERVENTION(S): We assessed postconcussion patients for visual symptoms including photophobia and photosensitivity. Off-the-shelf glasses were used to determine whether specific colors provided relief from photophobia. Screening was done using a penlight and multiple pairs of colored glasses. MAIN OUTCOME MEASURE(S): Self-reported mitigation of photophobia symptoms and the specific color frequency that reduced symptoms in each individual. RESULTS: Of the 39 patients studied who had visual symptoms, 76% complained of photophobia. Using glasses of 1 or more colors, symptoms were relieved in 85% of patients reporting photophobia. The colors that provided the most relief were blue, green, red, and purple. No adverse events were reported. CONCLUSIONS: An empirical assessment of frequency-specific photophobia is easy to perform. A traditional penlight is used to elicit photophobia and then the colored glasses are tested for optimal relief. Frequency specific photophobia can be reduced with a strategy of light-mitigation therapy, including colored glasses, sunglasses, hats, and light avoidance. This, we believe, helps to improve the patient's quality of life and may aid in the recovery process. More work is needed to identify the best colors and methods of mitigating frequency-specific photophobia. PMID- 28650686 TI - The influence of limb alignment and transfemoral amputation technique on muscle capacity during gait. AB - Many factors influence successful outcomes following transfemoral amputation. One factor is surgical technique. In this study, the influence of limb alignment and surgical technique on a muscle's capacity to generate force was examined using musculoskeletal modeling. Non-amputee and transfemoral amputee models were analyzed while hip adduction, femur length, and reattached muscle wrap position, tension and stabilization technique were systematically varied. With muscle tension preserved, wrap position and femur length had little influence on muscle capacity. However, limb alignment, muscle tension and stabilization technique notably influenced muscle capacity. Overall, myodesis stabilization provided greater muscle balance and function than myoplasty stabilization. PMID- 28650687 TI - Mibefradil inhibition of the Cole-Moore shift and K+-conductance of the tumor related Kv10.1 channel. PMID- 28650688 TI - Multidrug-Resistant Enterobacteriaceae in Lebanese Hospital Wastewater: Implication in the One Health Concept. AB - Extended-spectrum beta-lactamases (ESBL) and carbapenemase-producing organisms pose severe problems for hospitalized patients. In the absence of efficient sanitation and sewage disposal, the risks for transmission of hospital organisms into the community are high. Our objectives were to study the occurrence and mechanisms of resistance of multidrug-resistant gram-negative bacilli in two Lebanese hospital sewage treatment plants. Wastewater samples were collected, filtered, and cultivated on MacConckey+cefotaxime agars. ESBL, AmpC, metallo-beta lactamases (MBL), and Klebsiella pneumoniae Carbapenemases (KPC) production were phenotypically detected using plain Mueller Hinton agar plates, and plates impregnated with 5 mM EDTA, 10 mg/mL phenyl boronic acid, and 250 MUg/mL cloxacillin (embedded). Temocillin discs were used for the presumptive detection of OXAs. ESBL, carbapenemase, outer membrane protein F (OMPF), and outer membrane protein C (OMPC) genes were detected using polymerase chain reaction. Pulsed field gel electrophoresis (PFGE) was performed to study the clonality of Enterobacter cloacae isolates. In total, 32 and 38 Enterobacteriaceae were detected from Hospital 1 and Hospital 2, respectively. All Escherichia coli and Klebsiella spp. isolates were ESBL producers. AmpC reached 25% and 28.9% of all isolates. Only one Enterobacter cloacae isolate from one hospital showed full resistance to carbapenems. Molecular tests, however, detected NDM-1 in two strains of Enterobacter cloacae. PFGE results showed 80% similarity between these two strains. The isolation of NDM-1-producing Enterobacter cloacae from hospital wastewater occurred almost a year before the first case of carbapenem-resistant Enterobacter spp. was detected from a patient sample in the laboratory hospital. Understanding the local epidemiology of resistance in hospitals should include areas of potential resistance, such as wastewater and hospital environment. PMID- 28650689 TI - Time- and dose-dependent claudin contribution to biological functions: Lessons from claudin-1 in skin. AB - There are many types of biologic compartments in the body. Tight junctions (TJs) function to create a dynamic paracellular barrier to separate these compartments and maintain homeostasis. The TJ component claudin-1 is the major transmembrane protein responsible for forming the paracellular barrier in the epidermis; other claudins in the epidermis include claudin-3, -4, -12, -23 and -25. Accumulating evidence points to a relationship between claudin-1 and skin diseases; for example, a decrease in claudin-1 is reported in human atopic dermatitis. However, how claudin-1 directly or indirectly contributes to disease in the context of the paracellular barrier is poorly understood. We recently established several mouse lines in which the claudin-1 expression was systematically regulated, and showed that claudin-1 time- and dose-dependently regulates epidermis function and disease in vivo. In this commentary, we will discuss recent progress on this topic, including our latest findings, and remaining or newly arisen issues. PMID- 28650690 TI - Coordinated Expression of acrAB-tolC and Eight Other Functional Efflux Pumps Through Activating ramA and marA in Salmonella enterica serovar Typhimurium. AB - The aim of this study was to determine the expression of eight other functional transporter genes upon acrAB inactivation and also the expression of acrAB when the function of eight other transporters are impaired in Salmonella enterica. We used single- or multigene deletion mutants (i.e., DeltaacrA, DeltaacrB, DeltatolC, DeltaacrAB, DeltaacrEF, DeltaacrD, DeltamdsABC, DeltamdtABC, DeltaemrAB, DeltamacAB, DeltamdfA, DeltamdtK, DeltaacrABramA, DeltaacrABmarA, and DeltaacrABsoxS) and real time (RT)-PCR to quantify the expression of different pump and regulator genes; infection ability was characterized by adhesion and invasion assays. The expression of acrAB operon was increased upon acrB inactivation. Single deletion of acrA or tolC also increased expression of acrB. The deletion of acrAB increased expression of eight other functional efflux pumps genes and vice versa, in which increased expression of ramA and marA was also detected. Mutants containing single deletions of functional pump genes were attenuated in cells. In conclusion, there is a feedback mechanism that coordinates regulation of AcrAB-TolC and eight other functional efflux pumps through the global transcriptional regulators ramA and marA in S. enterica serovar Typhimurium. PMID- 28650691 TI - Changes in Cartilage Biomarker Levels During a Transcontinental Multistage Footrace Over 4486 km. AB - BACKGROUND: Cartilage turnover and load-induced tissue changes are frequently assessed by quantifying concentrations of cartilage biomarkers in serum. To date, information on the effects of ultramarathon running on articular cartilage is scarce. HYPOTHESIS: Serum concentrations of cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, COL2-3/4C long mono (C2C), procollagen type II C-terminal propeptide (CPII), and C2C:CPII will increase throughout a multistage ultramarathon. STUDY DESIGN: Descriptive laboratory study. METHODS: Blood samples were collected from 36 runners (4 female; mean age, 49.0 +/- 10.7 years; mean body mass index, 23.1 +/- 2.3 kg/m2 [start] and 21.4 +/- 1.9 kg/m2 [finish]) before (t0) and during (t1: 1002 km; t2: 2132 km; t3: 3234 km; t4: 4039 km) a 4486-km multistage ultramarathon. Serum COMP, MMP-1, MMP-3, MMP-9, C2C, and CPII levels were assessed using commercial enzyme-linked immunosorbent assays. Linear mixed models were used to detect significant changes in serum biomarker levels over time with the time-varying covariates of body weight, running speed, and daily running time. RESULTS: Serum concentrations of COMP, MMP-9, and MMP-3 changed significantly throughout the multistage ultramarathon. On average, concentrations increased during the first measurement interval (MI1: t1-t0) by 22.5% for COMP (95% CI, 0.29-0.71 ng/mL), 22.3% for MMP-3 (95% CI, 0.24-15.37 ng/mL), and 95.6% for MMP-9 (95% CI, 81.7 414.5 ng/mL) and remained stable throughout MI2, MI3, and MI4. Serum concentrations of MMP-1, C2C, CPII, and C2C:CPII did not change significantly throughout the multistage ultramarathon. Changes in MMP-3 were statistically associated with changes in COMP throughout the ultramarathon race (MMP-3: Wald Z = 3.476, P = .001). CONCLUSION: Elevated COMP levels indicate increased COMP turnover in response to extreme running, and the association between load-induced changes in MMP-3 and changes in COMP suggests the possibility that MMP-3 may be involved in the degradation of COMP. CLINICAL RELEVANCE: These results suggest that articular cartilage is able to adapt even to extreme physical activity, possibly explaining why the risk of degenerative joint disease is not elevated in the running population. PMID- 28650692 TI - The Role of Polyphenols in Rosacea Treatment: A Systematic Review. AB - OBJECTIVES: Various treatment options are available for the management of rosacea symptoms such as facial erythema, telangiectasia, papules and pustules, burning, stinging, and itching. Botanical therapies are commonly used to treat the symptoms. The objective of this review is to evaluate the use of polyphenols in rosacea treatment. DESIGN: PubMed, Embase, Biosis, Web of Knowledge, and Scopus databases were systematically searched for clinical studies evaluating polyphenols in the management of rosacea. RESULTS: Of 814 citations, 6 met the inclusion criteria. The studies evaluated licochalcone (n = 2), silymarin (n = 2), Crysanthellum indicum extract (n = 1), and quassia extract (n = 1). The studies only evaluated topical formations of stated polyphenols. Main results were summarized. CONCLUSIONS: There is evidence that polyphenols may be beneficial for the treatment of rosacea symptoms. Polyphenols appear to be most effective at reducing facial erythema and papule and pustule counts. However, studies included have significant methodological limitations and therefore large scale, randomized, placebo-controlled trials are warranted to further assess the efficacy and safety of polyphenols in the treatment of rosacea. PMID- 28650693 TI - Healthy Bovines as Reservoirs of Major Pathogenic Lineages of Staphylococcus aureus in Portugal. AB - The nosocomial prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Portugal is close to 50% and remains one of the highest in Europe. MRSA reservoirs in the animal setting in Portugal have been very poorly investigated, namely among animal husbandry. A total of 52 samples (nasal, inguinal region, and milk) were obtained from bovine animals and analyzed for the presence of S. aureus. The isolates were characterized by pulsed-field gel electrophoresis (PFGE), spa typing, SCCmec typing, and multilocus sequence typing and tested for antimicrobial susceptibility, presence of mecA and mecC genes, and virulence determinants. Overall, 54% of the screened animals were colonized with S. aureus in at least one body site. Notably, S. aureus nasal carriage followed an increasing trend with animal age (p = 0.0006). None of the isolates harbored the mecA or mecC genes. Resistance to penicillin, rifampicin, and tetracycline was observed in 24%, 18%, and 6% of the isolates, respectively. The isolates were distributed into three clonal lineages: PFGE type A, spa type t1166, ST1247-CC133 (43%), PFGE B-t267-ST352-CC97 (30%), and PFGE C-t091-ST7-CC7 (27%). CC133 was associated to older animals (p = 0.0025), whereas CC97 was isolated from calves (p = 0.0016). Virulence determinants commonly found in mastitis were widely detected in carriage isolates: lukDE and hlgv (100%), hlb (76%), and lukM (35%). Although healthy bovines do not represent a MRSA reservoir in Portugal, they are mainly colonized with S. aureus pathogenic lineages associated to mastitis in cattle (CC97 and CC133). PMID- 28650694 TI - Investigation of the Developmental Potential and Developmental Kinetics of Bovine Parthenogenetic and Somatic Cell Nuclear Transfer Embryos Using a Time-Lapse Monitoring System. AB - A time-lapse monitoring system has predictive value for selecting good-quality embryos with the highest implantation potential. Using this new tool, we investigated the developmental potential and developmental kinetics of bovine parthenogenetic (PA) and two types of somatic cell nuclear transfer (NT) embryos. Bovine non-transgenic ear cells (bECs) or transgenic cells (bTGCs) were used as donor cells. The cleavage and blastocyst development rates did not significantly differ among the PA, NT-bEC, and NT-bTGC groups, and first cleavage occurred an average of 19.3 hours (n = 70), 21.6 hours (n = 60), and 21.3 hours (n = 62) after activation, respectively (20.4 hours [n = 192] for all embryos). When embryos were classified into early cleaving (<=20 hours) and late cleaving (>20 hours) groups, the blastocyst formation rate was much higher in the early cleaving groups (PA, 46%; NT-bEC, 50%; NT-bTGC, 39%) than in the late cleaving groups (PA, 18%; NT-bEC, 23%; NT-bTGC, 28%), while the percentage of embryos whose development was blocked between the two- and eight-cell stages was increased in the late cleaving groups. The percentage of embryos classified as early cleaving with a normal morphology was twofold higher in the PA group (20.0%, n = 14) than in the NT-bTGC group (9.7%, n = 6). The timing of each developmental stage varied widely; the timing of first cleavage varied from 7.6 hours in the PA group to 34.5 hours in the NT-bEC group and the timing of expanded/hatching blastocyst appearance varied from 141.6 hours in the PA group to 196.3 hours in the NT-bTGC group, differences of 26.9 and 54.7 hours, respectively (PA>NT-bEC>NT-bTGC). These results demonstrate that time-lapse monitoring provides novel data regarding individual embryo developmental kinetics and helps to predict developmental potential for improved bovine NT embryo selection based on early cleavage (<=20 hours) and normal morphology. PMID- 28650695 TI - Experiences of Family Stigma among Mothers of Adult Children with Mental Illness in South Korea. AB - : People with mental illness suffer from stigma in addition to the illness itself; their families also suffer from the stigma of having a family member with a mental illness. The aim of the present study was to explore the lived experiences of the family stigma among mothers of mentally ill children in South Korea. The work was qualitative in nature; we used the phenomenological method of Colaizzi. Mothers with an adult child enrolled as mentally ill patients in the Mental Health Centre of K Province in South Korea were eligible for inclusion. FINDINGS: Six themes emerged; these were being ashamed, feeling of being ignored, isolating oneself from social relationships, becoming a mentally sick person, living like a guilty person, and becoming a part of the socially weak. The study contributes to our understanding of stigma experienced by family members in a socio-cultural context and will aid in the development of culturally appropriate strategies for the destigmatization of families of mentally ill persons. PMID- 28650696 TI - Pregnancy in cancer patients and survivors; experience of a university hospital in Turkey. AB - The aim of this study was to assess the obstetrical and neonatal outcomes of pregnancies in cancer patients and survivors. A retrospective analysis of 68 pregnancies with a history of cancer and 31 newly diagnosed pregnant cancer patients were included in the study. The mean birth weight and the mean gestational age at delivery were significantly lower in the pregnant cancer patients (p < .001). The incidences of delivery less than 34 weeks were 8.8% and 29.1% in the cancer survivors and cancer diagnosed during pregnancy groups respectively (p < .01). In 23 (76.4%) pregnant cancer patients, a single or a combination of treatment modalities was initiated. There were four (12.9%) maternal deaths in pregnant cancer patients. There were no early neonatal death and any congenital anomaly detected in the newborns. Pregnancy in cancer patients and cancer survivors has completely different clinical outcome. Pregnancy in cancer patients has increased the risk of pregnancy complication. PMID- 28650697 TI - Erratum. PMID- 28650698 TI - The ROCK isoforms differentially regulate the morphological characteristics of carcinoma cells. AB - Rho-associated kinase (ROCK) activity drives cell migration via actomyosin contractility. During invasion, individual cancer cells can transition between 2 modes of migration, mesenchymal and amoeboid. Changes in ROCK activity can cause a switch between these migration phenotypes which are defined by distinct morphologies. However, recent studies have shown that the ROCK isoforms are not functionally redundant as previously thought. Therefore, it is unclear whether the ROCK isoforms play different roles in regulating migration phenotypes. Here, we found that ROCK1 and ROCK2 differentially regulate carcinoma cell morphology resulting in intermediate phenotypes that share some mesenchymal and amoeboid characteristics. These findings suggest that the ROCK isoforms play unique roles in the phenotypic plasticity of mesenchymal carcinoma cells which may have therapeutic implications. PMID- 28650699 TI - Effect of Euterpe oleracea Mart. Seeds Extract on Chronic Ischemic Renal Injury in Renovascular Hypertensive Rats. AB - Previously, we have demonstrated that the seeds of Euterpe oleracia Mart. (acai) are rich in polyphenols with antihypertensive and antioxidant properties. This study evaluated the renal protective effects of the hydroalcoholic extract obtained from the seeds of acai (ASE) fruits in two-kidney, one-clip (2K1C) renovascular hypertension. Young male Wistar rats were used to obtain 2K1C and sham groups. Animals received ASE (200 mg/(kg.day) in drinking water) or vehicle for 40 days. We evaluated serum and urinary parameters, renal structural changes, and oxidative status. The increase in systolic blood pressure of the 2K1C group was accompanied by a decrease in left kidney volume and number of glomeruli, as well as an increase in glomerular volume and collagen deposition. ASE prevented the alterations of these parameters, except the reduced kidney volume. Serum levels of urea and creatinine and urinary protein excretion were increased in the 2K1C group and treatment with ASE improved all these functional parameters. The increased oxidative damage in the 2K1C group, assessed by lipid and protein oxidation, was prevented by ASE. The nitrite content and both expression and activity of antioxidant enzymes (superoxide dismutase-1, catalase, and glutathione peroxidase) were lower in the 2K1C group and restored by ASE. ASE substantially reduced renal injury and prevented renal dysfunction in 2K1C rats probably through its antihypertensive and antioxidant effects, providing a natural resource for treatment and prevention of renovascular hypertension related abnormalities. PMID- 28650700 TI - The Size and Scope of Collegiate Athletic Training Facilities and Staffing. AB - CONTEXT: Athletic training facilities have been described in terms of general design concepts and from operational perspectives. However, the size and scope of athletic training facilities, along with staffing at different levels of intercollegiate competition, have not been quantified. OBJECTIVE: To define the size and scope of athletic training facilities and staffing levels at various levels of intercollegiate competition. To determine if differences existed in facilities (eg, number of facilities, size of facilities) and staffing (eg, full time, part time) based on the level of intercollegiate competition. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers (ATs) who were knowledgeable about the size and scope of athletic training programs. MAIN OUTCOME MEASURE(S): Athletic training facility size in square footage; the AT's overall facility satisfaction; athletic training facility component spaces, including satellite facilities, game-day facilities, offices, and storage areas; and staffing levels, including full-time ATs, part-time ATs, and undergraduate students. RESULTS: The survey was completed by 478 ATs (response rate = 38.7%) from all levels of competition. Sample means for facilities were 3124.7 +/- 4425 ft2 (290.3 +/- 411 m2) for the central athletic training facility, 1013 +/- 1521 ft2 (94 +/- 141 m2) for satellite athletic training facilities, 1272 +/- 1334 ft2 (118 +/- 124 m2) for game-day athletic training facilities, 388 +/- 575 ft2 (36 +/- 53 m2) for athletic training offices, and 424 +/- 884 ft2 (39 +/- 82 m2) for storage space. Sample staffing means were 3.8 +/- 2.5 full-time ATs, 1.6 +/- 2.5 part-time ATs, 25 +/- 17.6 athletic training students, and 6.8 +/- 7.2 work-study students. Division I schools had greater resources in multiple categories (P < .001). Differences among other levels of competition were not as well defined. Expansion or renovation of facilities in recent years was common, and almost half of ATs reported that upgrades have been approved for the near future. CONCLUSIONS: This study provides benchmark descriptive data on athletic training staffing and facilities. The results (1) suggest that the ATs were satisfied with their facilities and (2) highlight the differences in resources among competition levels. PMID- 28650701 TI - Prevalence of Acinetobacter baumannii strains expressing the Type 6 secretion system in patients with bacteremia. PMID- 28650702 TI - A case report of methadone-associated hypoglycemia in an 11-month-old male. AB - BACKGROUND: Methadone is a synthetic MU-opioid receptor agonist that is used in the management of pain, neonatal abstinence withdrawal syndrome, and opioid dependence. Overdose can cause miosis, respiratory depression, and central nervous system depression. Rarely, hypoglycemia has been reported. We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure. CASE DETAILS: The patient was a previously healthy 11-month-old male who presented in respiratory failure. He was intubated and transferred to a large tertiary care center where his physical exam was notable for miosis. His labs were notable for a blood glucose of 17 mg/dL, an elevated insulin level, and suppressed serum beta hydroxybutyrate. The patient was given a dextrose bolus with improvement in blood glucose. Administration of IV naloxone improved his miosis and mental status. A quantitative methadone level was sent upon arrival and was 123 ng/mL. Testing for ethanol, salicylates, sulfonylureas, and metabolic causes of hypoglycemia was negative. A fasting study showed euglycemia with suppression of insulin and appropriate ketosis. Case discussion: We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure. Alternative explanations for hypoketotic hypoglycemia were rule out. Methadone-induced hypoglycemia has been reported in cancer patients receiving methadone for pain, but a mechanism has not been identified. Based on this case, we believe that the patient's hypoglycemia was the result of methadone-induced insulin secretion. CONCLUSIONS: This case proposes that hyperinsulinism is the mechanism responsible for methadone associated hypoglycemia. Methadone exposure should be included in the differential diagnosis of new onset hypoglycemia. PMID- 28650703 TI - Program Implementation of Option B+ at a President's Emergency Plan for AIDS Relief-Supported HIV Clinic Improves Clinical Indicators But Not Retention in Care in Mbarara, Uganda. AB - 2013 WHO guidelines for prevention of mother to child transmission recommend combination antiretroviral therapy (ART) for all pregnant women, regardless of CD4 count (Option B/B+). We conducted a retrospective analysis of data from a government-operated HIV clinic in Mbarara, Uganda before and after implementation of Option B+ to assess the impact on retention in care. We limited our analysis to women not on ART at the time of their first reported pregnancy with CD4 count >350. We fit regression models to estimate relationships between calendar period (Option A vs. Option B+) and the primary outcome of interest, retention in care. One thousand and sixty-two women were included in the analysis. Women were more likely to start ART within 6 months of pregnancy in the Option B+ period (68% vs. 7%, p < 0.0001) and had significantly greater increases in CD4 count 1 year after pregnancy (+172 vs. -5 cells, p < 0.001). However, there was no difference in the proportion of women retained in care 1 year after pregnancy (73% vs. 70%, p = 0.34). In models adjusted for age, distance to clinic, marital status, and CD4 count, Option B+ was associated with a nonsignificant 30% increased odds of retention in care at 1 year [adjusted odds ratio (AOR) = 1.30, 95% CI 0.98-1.73, p = 0.06]. After transition to an Option B+ program, pregnant women with CD4 count >350 were more likely to initiate combination therapy; however, interventions to mitigate losses from HIV care during pregnancy are needed to improve the health of women, children, and families. PMID- 28650704 TI - Is there a reason for concern or is it just hype? - A systematic literature review of the clinical consequences of switching from originator biologics to biosimilars. AB - INTRODUCTION: While prescribing biosimilars to patients naive to a biologic treatment is a well-accepted practice, switching clinically stable patients from an originator to a biosimilar is an issue for clinicians. Well-designed clinical trials and real-world data which study the consequences of switching from an originator biologic treatment to its biosimilar alternative are limited, especially for monoclonal antibodies. Areas covered: A systematic literature review was conducted on PubMed to identify evidence of the consequences of switching from original biologics to biosimilars. References of included papers were also scrutinized. After a title-, abstract- and full text screening, out of the 153 original hits and 77 additional ones from screening the references, 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) were included. Expert opinion: Preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access. Indeed, it is the opinion of the authors that the concern of switching to biosimilars is overhyped. PMID- 28650706 TI - Commentary on "Comparison of Adjacent Segment Degeneration after Nonrigid Fixation System and Posterior Lumbar Inter-Body Fusion for Single-Level Lumbar Disc Herniation: A New Method of MRI Analysis of Lumbar Nucleuspulposus Volumen". PMID- 28650705 TI - Current and Emerging Treatments for Postsurgical Cleft Lip Scarring: Effectiveness and Mechanisms. AB - Cleft lip with or without cleft palate is the most common congenital malformation of the head and the third-most common birth defect. Surgical repair of the lip is the only treatment and is usually performed during the first year of life. Hypertrophic scar (HTS) formation is a frequent postoperative complication that impairs soft tissue form, function, or movement. Multiple lip revision operations are often required throughout childhood, attempting to optimize aesthetics and function. The mechanisms guiding HTS formation are multifactorial and complex. HTS is the result of dysregulated wound healing, where excessive collagen and extracellular matrix proteins are deposited within the wound area, resulting in persistent inflammation and resultant fibrosis. Many studies support the contribution of dysregulated, exaggerated inflammation in scar formation. Fibrosis and scarring result from chronic inflammation that interrupts tissue remodeling in normal wound healing. Failure of active resolution of inflammation pathways has been implicated. The management of HTS has been challenging for clinicians, since current therapies are minimally effective. Emerging evidence that specialized proresolving mediators of inflammation accelerate wound healing by preventing chronic inflammation and allowing natural uninterrupted tissue remodeling suggests new therapeutic opportunities in the prevention and management of HTS. PMID- 28650707 TI - A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. AB - PURPOSE: The increasing global risk of nuclear and radiological accidents or attacks has driven renewed research interest in developing medical countermeasures to potentially injurious exposures to acute irradiation. Clinical symptoms and signs of a developing acute radiation injury, i.e. the acute radiation syndrome, are grouped into three sub-syndromes named after the dominant organ system affected, namely the hematopoietic, gastrointestinal, and neurovascular systems. The availability of safe and effective countermeasures against the above threats currently represents a significant unmet medical need. This is the first article within a three-part series covering the nature of the radiation sub-syndromes, various animal models for radiation countermeasure development, and the agents currently approved by the United States Food and Drug Administration for countering the medical consequences of several of these prominent radiation exposure-associated syndromes. CONCLUSIONS: From the U.S. and global perspectives, biomedical research concerning medical countermeasure development is quite robust, largely due to increased government funding following the 9/11 incidence and subsequent rise of terrorist-associated threats. A wide spectrum of radiation countermeasures for specific types of radiation injuries is currently under investigation. However, only a few radiation countermeasures have been fully approved by regulatory agencies for human use during radiological/nuclear contingencies. Additional research effort, with additional funding, clearly will be needed in order to fill this significant, unmet medical health problem. PMID- 28650708 TI - Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Susceptibility to Dengue Virus Infection in a Mexican Population. AB - To evaluate the association of the -308 and -238 tumor necrosis factor alpha (TNF alpha) gene polymorphisms with clinical manifestations of dengue and TNF-alpha serum levels in a northwestern Mexican population. The study populations included dengue fever (DF) and dengue hemorrhagic fever (DHF) patients, and a group of healthy controls (HCs) without history of dengue. Polymerase chain reaction restriction fragment length polymorphism and Enzyme-Linked Immunosorbent Assay were performed to determine genotypes and serum concentration of TNF-alpha, respectively. There were no significant differences in alleles, genotypes, and haplotype frequencies between patients and HCs. However, when patients were separated into DF and DHF, there was an increased prevalence of the -308 GA genotype in HCs compared to DHF (odds ratio [OR] = 0.129, 95% confidence interval [CI] = 0.018-0.945, p = 0.025), as well as the GG haplotype (OR = 0.49, 95% CI = 0.273-0.880, p = 0.01757) in DF. The genotypes of both polymorphisms were not associated with hematologic manifestations. Serum TNF-alpha levels were significantly higher in patients than in HCs (p = 0.004). Our results suggest a minimal effect of the -308 and -238 TNF-alpha gene polymorphisms in dengue patients and that their increased serum levels of TNF-alpha are independent of genotypes. PMID- 28650712 TI - Editorial. PMID- 28650711 TI - Editorial. PMID- 28650713 TI - Occupational chemical exposures: a collaboration between the Georgia Poison Center and the Occupational Safety and Health Administration. AB - CONTEXT: In the United States, regional poison centers frequently receive calls about toxic workplace exposures. Most poison centers do not share call details routinely with governmental regulatory agencies. Worker health and safety could be enhanced if regulators such as the Occupational Safety and Health Administration (OSHA) had the ability to investigate these events and prevent similar incidents. With this goal in mind, the Georgia Poison Center (GPC) began referring occupational exposures to OSHA in July 2014. METHODS: GPC began collecting additional employer details when handling occupational exposure calls. When workers granted permission, GPC forwarded call details to the OSHA Regional Office in Atlanta. These referrals enabled OSHA to initiate several investigations. We also analyzed all occupational exposures reported to GPC during the study period to characterize the events, detect violations of OSHA reporting requirements, and identify hazardous scenarios that could form the basis for future OSHA rulemaking or guidance. RESULTS: GPC was informed about 953 occupational exposures between 1 July, 2014 and 7 January, 2016. Workers were exposed to 217 unique substances, and 70.3% of victims received treatment in a healthcare facility. Hydrogen sulfide was responsible for the largest number of severe clinical effects. GPC obtained permission to refer 89 (9.3%) calls to OSHA. As a result of these referrals, OSHA conducted 39 investigations and cited 15 employers for "serious" violations. OSHA forwarded several other referrals to other regulatory agencies when OSHA did not have jurisdiction. At least one employer failed to comply with OSHA's new rule that mandates reporting of all work-related hospitalizations. This collaboration increased OSHA's awareness of dangerous job tasks including hydrofluoric acid exposure among auto detailers and carbon monoxide poisoning with indoor use of gasoline-powered tools. CONCLUSIONS: Collaboration with the GPC generated a useful source of referrals to OSHA. OSHA investigations led to abatement of existing hazards, and OSHA acquired new knowledge of occupational exposure scenarios. PMID- 28650714 TI - Models for nearly every occasion: Part III - One box decreasing emission models. AB - New one box "well-mixed room" decreasing emission (DE) models are introduced that allow for local exhaust or local exhaust with filtered return, as well the recirculation of a filtered (or cleaned) portion of the general room ventilation. For each control device scenario, a steady state and transient model is presented. The transient equations predict the concentration at any time t after the application of a known mass of a volatile substance to a surface, and can be used to predict the task exposure profile, the average task exposure, as well as peak and short-term exposures. The steady state equations can be used to predict the "average concentration per application" that is reached whenever the substance is repeatedly applied. Whenever the beginning and end concentrations are expected to be zero (or near zero) the steady state equations can also be used to predict the average concentration for a single task with multiple applications during the task, or even a series of such tasks. The transient equations should be used whenever these criteria cannot be met. A structured calibration procedure is proposed that utilizes a mass balance approach. Depending upon the DE model selected, one or more calibration measurements are collected. Using rearranged versions of the steady state equations, estimates of the model variables-e.g., the mass of the substance applied during each application, local exhaust capture efficiency, and the various cleaning or filtration efficiencies-can be calculated. A new procedure is proposed for estimating the emission rate constant. PMID- 28650716 TI - Erratum. PMID- 28650715 TI - Transfer of bacteriophage MS2 and fluorescein from N95 filtering facepiece respirators to hands: Measuring fomite potential. AB - Contact transmission of pathogens from personal protective equipment is a concern within the healthcare industry. During public health emergency outbreaks, resources become constrained and the reuse of personal protective equipment, such as N95 filtering facepiece respirators, may be needed. This study was designed to characterize the transfer of bacteriophage MS2 and fluorescein between filtering facepiece respirators and the wearer's hands during three simulated use scenarios. Filtering facepiece respirators were contaminated with MS2 and fluorescein in droplets or droplet nuclei. Thirteen test subjects performed filtering facepiece respirator use scenarios including improper doffing, proper doffing and reuse, and improper doffing and reuse. Fluorescein and MS2 contamination transfer were quantified. The average MS2 transfer from filtering facepiece respirators to the subjects' hands ranged from 7.6-15.4% and 2.2-2.7% for droplet and droplet nuclei derived contamination, respectively. Handling filtering facepiece respirators contaminated with droplets resulted in higher levels of MS2 transfer compared to droplet nuclei for all use scenarios (p = 0.007). MS2 transfer from droplet contaminated filtering facepiece respirators during improper doffing and reuse was greater than transfer during improper doffing (p = 0.008) and proper doffing and reuse (p = 0.042). Droplet contamination resulted in higher levels of fluorescein transfer compared to droplet nuclei contaminated filtering facepiece respirators for all use scenarios (p = 0.009). Fluorescein transfer was greater for improper doffing and reuse (p = 0.007) from droplet contaminated masks compared to droplet nuclei contaminated filtering facepiece respirators and for improper doffing and reuse when compared improper doffing (p = 0.017) and proper doffing and reuse (p = 0.018) for droplet contaminated filtering facepiece respirators. For droplet nuclei contaminated filtering facepiece respirators, the difference in MS2 and fluorescein transfer did not reach statistical significance when comparing any of the use scenarios. The findings suggest that the results of fluorescein and MS2 transfer were consistent and highly correlated across the conditions of study. The data supports CDC recommendations for using proper doffing techniques and discarding filtering facepiece respirators that are directly contaminated with secretions from a cough or sneeze. PMID- 28650718 TI - Subversion of RAB5-regulated autophagy by the intracellular pathogen Ehrlichia chaffeensis. AB - Intracellular pathogens often exploit RAB functions to establish a safe haven in which to survive and proliferate. Ehrlichia chaffeensis, an obligatory intracellular bacterium, resides in specialized membrane-bound inclusions that have early endosome-like characteristics, e.g., resident RAB5 GTPase and RAB5 effectors, including VPS34 (the catalytic subunit of class III phosphatidylinositol 3-kinase), but the inclusions lack late endosomal or lysosomal markers. Within inclusions, Ehrlichia obtains host-derived nutrients by inducing RAB5-regulated autophagy using Ehrlichia translocated factor-1 deployed by its type IV secretion system. This manipulation of RAB5 by a bacterial molecule offers a simple strategy for Ehrlichia to avoid destruction in lysosomes and obtain nutrients, membrane components, and a homeostatic intra-host-cell environment in which to grow. PMID- 28650717 TI - Heart-type fatty acid binding protein is a sensitive biomarker for early AMI detection in troponin negative patients: a pilot study. AB - BACKGROUND: Early detecting AMI in individuals presenting to the ED with chest pain continues to be a challenge. cTn is the gold standard for AMI diagnosis but early presenters (<1 hours from symptom onset) maybe cTn negative on admission. We analysed the diagnostic value of h-FABP and hs-TnI in patients presenting to ED with chest pain and no cTnI elevations. METHODS: 28 AMI and 28 no-AMI individuals both presented to ED within one hour from pain onset were included. Blood donors were analysed for h-FABP cut-off identification. Among AMI patients, 55% were positive for h-FABP and 34.6% were positive for hs-TnI (p = .015), thus 21% were positive only for h-FABP. The diagnostic accuracy was assessed by ROC curve. h-FABP showed a higher sensitivity but lower specificity than hs-TnI. CONCLUSIONS: In our study, the frequency of h-FABP positivity among AMI patients was higher than that of hs-TnI, which would have missed six of them; however, hs TnI AUC was superior to that of h-FABP. These preliminary findings might confirm that h-FABP may be a good candidate for AMI rule-in/rule-out within the ED context. PMID- 28650719 TI - Computational investigation on the effects of H50Q and G51D mutations on the alpha-Synuclein aggregation propensity. AB - The aggregation of alpha-synuclein is linked directly to the histopathology of Parkinson's disease (PD). However, several missense mutations present in the alpha-synuclein gene (SNCA) have been known to be associated with PD. Several studies have highlighted the effect of SNCA mutations on the alpha-synuclein aggregation, but their pathological roles are not completely established. In this study, we have focused on the effects of the recently discovered alpha-synuclein missense mutants (H50Q and G51D) on the aggregation using computational approaches. We performed all atom molecular dynamics (MD) simulation on these mutants and compared their conformational dynamics with Wild-Type (WT) alpha synuclein. We noticed the solvent accessible surface area (SASA), radius of gyration, atomic fluctuations, and beta strand content to be higher in H50Q than G51D and WT. Using PDBSum online server; we analyzed the inter-molecular interactions that drive the association of monomeric units of H50Q, WT, and G51D in forming the respective homo-dimer. We noticed the interface area, number of interacting residues and binding free energy to be higher for H50Q homo-dimer than the WT and G51D homo-dimers. Our findings in this study suggest that in comparison to WT and G51D, H50Q mutation to have a positive effect on increasing the alpha-synuclein aggregation propensity. Hence, we see that H50Q and G51D mutation show conflicting effect on the aggregation propensity of alpha synuclein. PMID- 28650720 TI - Nonclinical Development of ENV905 (Difluprednate) Ophthalmic Implant for the Treatment of Inflammation and Pain Associated with Ocular Surgery. AB - PURPOSE: Topical corticosteroids are widely used in the treatment of inflammation and pain after ocular surgery, but they possess several shortcomings, including frequent dosing and low patient adherence. We evaluated the efficacy and pharmacokinetics of ENV905 (difluprednate or DFBA) Ophthalmic Implant, a single dose drug delivery system, compared with 0.05% Durezol. METHODS: PRINT(r) technology was used to fabricate ENV905 implants for either intracameral (IC) or subconjunctival (SCJ) delivery of extended-release DFBA. A postoperative inflammation model and ocular pharmacokinetics studies of ENV905 or Durezol were conducted in albino rabbits for a maximum of 12 weeks. RESULTS: Suppression of ocular inflammation was marked for both IC and SJC ENV905 compared with placebo, and it was superior or equivalent to that observed with QID Durezol. Concentrations of desacetyl difluprednate (DFB, active metabolite) peaked on day 1 and tapered over time for ENV905, with IC ENV905 delivering DFB to the target tissue at the time of greatest inflammation, whereas SJC produced a longer duration of exposure. Durezol eyes demonstrated consistent exposure over time with maximal exposure in the cornea. Although the pharmacokinetic profile differed for the two routes, efficacy was similar. CONCLUSION: ENV905 was well tolerated and demonstrated a robust reduction in ocular inflammation with targeted drug delivery. The results from these studies show that ENV905 provides a sustained therapeutic effect after a single dose. By resolving low patient compliance and eliminating the peaks and troughs in drug concentration, sustained drug delivery via ENV905 may further improve the overall control of postoperative inflammation and pain. PMID- 28650721 TI - Photographic Memory: The Effects of Volitional Photo Taking on Memory for Visual and Auditory Aspects of an Experience. AB - How does volitional photo taking affect unaided memory for visual and auditory aspects of experiences? Across one field and three lab studies, we found that, even without revisiting any photos, participants who could freely take photographs during an experience recognized more of what they saw and less of what they heard, compared with those who could not take any photographs. Further, merely taking mental photos had similar effects on memory. These results provide support for the idea that photo taking induces a shift in attention toward visual aspects and away from auditory aspects of an experience. Additional findings were in line with this mechanism: Participants with a camera had better recognition of aspects of the scene that they photographed than of aspects they did not photograph. Furthermore, participants who used a camera during their experience recognized even nonphotographed aspects better than participants without a camera did. Meta-analyses including all reported studies support these findings. PMID- 28650722 TI - Optimized DNA Vaccine Enhanced by Adjuvant IL28B Induces Protective Immune Responses Against Herpes Simplex Virus Type 2 in Mice. AB - Antigen-specific immune responses determine the efficacy of herpes simplex virus type 2 (HSV-2) vaccines. To optimize the immunogenicity of the antigen gD2, we developed the gD2DeltaUL25 DNA vaccine encoding HSV-2 glycoprotein D and UL25 gene encoding viral capsid vertex proteins in this study. The gD2 and gD2DeltaUL25 DNA vaccines were compared with formalin-inactivated HSV-2 (FI-HSV 2), and results showed a greater protective immune response induced by gD2DeltaUL25 than by gD2. Therefore, gD2DeltaUL25 was chosen to evaluate further using the IL28B adjuvant. Immunization with gD2DeltaUL25/IL28B elicited stronger humoral and T cell immune responses than with gD2DeltaUL25 alone. Compared with controls, gD2DeltaUL25/IL28B decreased HSV-2 viral loads and induced protective effects against genital tract lesions generated by HSV-2. These findings demonstrated that the prophylactic DNA vaccine gD2DeltaUL25 with IL28B adjuvant could enhance the humoral and T cell immune responses, and improve the protective immune response against HSV-2 in female mice compared with FI-HSV-2. PMID- 28650723 TI - Hospital Chaplains: Through the Eyes of Parents of Hospitalized Children. AB - BACKGROUND: Chaplain services are available in 68% of hospitals, but hospital chaplains are not yet incorporated into routine patient care. OBJECTIVES: To describe how families of hospitalized children view and utilize hospital chaplains. DESIGN: Telephone survey with 40 questions: Likert, yes/no, and short answer responses. SUBJECTS: Parents visited by a hospital chaplain during their child's hospitalization in a tertiary care center. MEASUREMENTS: Descriptive statistics were used to characterize the sample. Nonparametrics were used to compare religious versus nonreligious parents. Regression was used to identify independent predictors of a chaplain visit positively influencing satisfaction with hospital care. RESULTS: Seventy-four parents were interviewed; most were 25 50 years old, and 75% felt their child was very sick. Children ranged from newborn to adolescence. Forty-two percent of parents requested a chaplain visit; of the 58% with an unsolicited visit, 11% would have preferred giving prior approval. Parents felt that chaplains provided religious and secular services, including family support and comfort, help with decision making, medical terminology, and advocacy. Chaplains helped most parents maintain hope and reduce stress. Seventy-five percent of parents viewed chaplains as a member of the healthcare team; 38% reported that chaplains helped medical personnel understand their preferences for care and communication. Most parents (66%) felt that hospital chaplaincy increased their satisfaction with hospital care. CONCLUSION: Families play a fundamental role in the recovery of hospitalized children. Parents view hospital chaplains as members of the healthcare team and report that they play an important role in the well-being of the family during childhood hospitalization. Chaplains positively influence satisfaction with hospital care. PMID- 28650724 TI - Reply: What Should Be the Cutoff Value of Blood Eosinophilia as a Predictor of Inhaled Corticosteroid Responsiveness in Patients with Chronic Obstructive Pulmonary Disease? PMID- 28650725 TI - Exposure to benzene in a pooled analysis of petroleum industry case-control studies. AB - Cases of lymphohematopoietic cancer from three petroleum industry cohorts, matched to controls from the respective cohort, were pooled into single study. Average benzene exposure was quantitatively estimated in ppm for each job based on measured data from the relevant country, adjusted for the specific time period, site and job exposure characteristics and the certainty of the exposure estimate scored. The probability of dermal exposure and of peak exposure was also assessed. Before risk was examined, an exposure estimate comparison and rationalisation exercise was performed across the studies to ensure accuracy and consistency of approach. This article evaluates the final exposure estimates and their use in the risk assessments. Overall benzene exposure estimates were low: 90% of participants accumulated less than 20 ppm-years. Mean cumulative exposure was estimated as 5.15 ppm-years, mean duration was 22 years, and mean exposure intensity was 0.2 ppm. 46% of participants were allocated a peak exposure (>3 ppm at least weekly). 40% of participants had a high probability of dermal exposure (based on the relative probability of at least weekly exposure). There were differences in mean intensity of exposure, probability of peak, and/or dermal exposure associated with job category, job site, and decade of exposure. Terminal Operators handling benzene-containing products were the most highly exposed group, followed by Tanker Drivers carrying gasoline. Exposures were higher around 1940-1950 and lower in more recent decades. Overall confidence in the exposure estimates was highest for recently held jobs and for white-collar jobs. We used sensitivity analyses, which included and excluded case-sets on the basis of exposure certainty scores, to inform the risk assessment. The above analyses demonstrated that the different patterns of exposure across the three studies are largely attributable to differences in jobs, site types, and time frames rather than study. This provides reassurance that the previous rationalisation of exposures achieved inter-study consistency and that the data could be confidently pooled. PMID- 28650726 TI - Maternal health-related behaviours during pregnancy: a critical public health issue. AB - AIM: The aim of the study was to investigate the health-related behaviours of pregnant women. Maternal health-related habits, use of psychoactive medicines, diet, prevention of neural tube defects, oral cavity hygiene, chronic diseases and physical activity were analysed in a group of pregnant women attending antenatal classes. METHODS: Hundred pregnant women recruited from various antenatal classes in Poznan, Poland, were investigated using a questionnaire based on the Pregnancy Risk Assessment Monitoring System. RESULTS: The results showed that 29% of pregnancies were unplanned. In women with higher education, 62% reported that they were taking folic acid supplements during pregnancy, in contrast with 35% women with a lower level of education (p = .012). The study showed that 24% of women were exposed to second-hand smoke during pregnancy, and this was more common among younger study participants (p = .038). Nine percentage of women admitted drinking alcohol during pregnancy. Pre-pregnancy alcohol consumption was more frequent among women with higher education (p = .011). Only 46.7% of women informed their dentist about their pregnancy, and these were more often older participants (p = .023). CONCLUSION: The study found low maternal awareness regarding health-related behaviours, which presents a serious challenge to public health care in Poland. Pregnant women and those who wish to conceive need to be educated effectively about preventive measures in order to maintain optimal maternal and reproductive health, as well as normal fetal development. PMID- 28650727 TI - Models for nearly every occasion: Part IV - Two-box decreasing emission models. AB - New two-box "well-mixed room" decreasing emission (DE) models are introduced for scenarios that involve local controls, such as some form of local exhaust or local exhaust with filtered return. In addition, these models allow for the recirculation of a filtered (or cleaned) portion of the general room ventilation. For each control device scenario, a steady state and transient near and far field model is presented. The transient equations predict the concentration at time t after the application of the substance. The steady state equations can be use to predict the steady, unvarying "average concentration per application" whenever there are continuous applications of a substance and sufficient time has elapsed. The steady state equations can also be used to calculate the TWA for a task (or a series of tasks) whenever the beginning and end concentrations for the task (or task series) are expected to be zero (or near zero). The transient equations should be used to predict TWA exposures whenever these criteria cannot be met, or it is necessary to predict short-term exposures or peak concentrations. A structured calibration procedure, based on a mass balance approach, is proposed for each model. Depending upon the model, one or more calibration measurements are collected. Rearranged versions of the steady state equations are used to calculate estimates of the mass applied during each application, the near field flowrate, and (depending upon the model) the various efficiencies (e.g., local exhaust capture efficiency and the recirculation filtration efficiency). The emission rate constant must be determined using either a published approximation algorithm or experimentally. PMID- 28650729 TI - Aneurysm of the mitral valve. PMID- 28650728 TI - Minor Constituents in Rice Bran Oil and Sesame Oil Play a Significant Role in Modulating Lipid Homeostasis and Inflammatory Markers in Rats. AB - The effects of feeding rats with groundnut oil (GNO), rice bran oil (RBO), and sesame oil (SESO) on serum lipids, liver lipids, and inflammatory markers were evaluated in rats. Male Wistar rats were fed with AIN-93 diet supplemented with 10 wt% of GNO, RBO, and SESO in the form of native (N) and minor constituent removed (MCR) oils. Rats given RBO and SESO showed significant reduction in serum and liver lipids, 8-hydroxy-2-deoxyguanosine, cytokines in liver, and eicosanoids in leukocytes as compared with the rats given GNO and MCR oils. The rats fed with native oils of RBO and SESO showed an upregulation of sterol regulatory element binding protein (SREBP)-2 and peroxisome proliferator-activated receptor gamma (PPARgamma) and downregulation of nuclear factor-kappa B (NF-kappaB) p65. These effects of native oil were significantly compromised when rats were given MCR oils. In conclusion, the minor constituents significantly support the hypolipidemic and anti-inflammatory properties of RBO and SESO. PMID- 28650730 TI - Yield of Staging Laparoscopy for Incurable Factors in Chinese Patients with Advanced Gastric Cancer. AB - BACKGROUND: Although the role of staging laparoscopy (SL) in detecting radiologically occult M1 disease has been widely recognized, it is seldom used in China and its clinical value based on Chinese population has been rarely reported. The aim of this study is to identify the yield of SL for Chinese patients with advanced gastric cancer (AGC) and determine the proportions of patients in whom treatment plan is altered. MATERIALS AND METHODS: The clinical data were retrospectively collected from 879 AGC patients who underwent SL without any definite signs of disseminated disease on imaging examination. The primary outcomes were the proportions of patients whose laparoscopy identified incurable factors (including M1 diseases and unresectable T4b diseases), and who had their treatment plan altered. RESULTS: SL revealed incurable factors in 130 (14.8%) patients, including macroscopic peritoneal metastasis (n = 92), positive peritoneal cytology (n = 10), liver metastasis (n = 12), para-aortic lymph node metastasis (n = 1), and unresectable T4b tumor (n = 18). After SL, treatment plans were altered in 123 (14.0%) patients, among which 82 (63.1%) patients were not offered any further procedure and referred for chemotherapy. Among 749 M0 patients who immediately proceeded to radical gastrectomy after SL, new incurable factors were found at subsequent operations in 21 (2.8%) patients. Multivariate analysis showed that tumor size >=8 cm, Borrmann type III and IV, and tumor invasion of T4a and T4b in preoperative imaging examination were the predictive factors for peritoneal metastasis. CONCLUSIONS: SL detects additional incurable factors in Chinese AGC patients with potentially resectable disease and optimizes their treatments. A systematic and painstaking inspection of the whole abdominal cavity, including routine entry into the bursa omentalis, is necessary for improving the yield of SL. PMID- 28650731 TI - Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. AB - Hyperglycemia leads to diabetes and its diabetic complications. In this study, we investigated the synergistic effects of luteolin and fisetin on proinflammatory cytokine secretion and its underlying epigenetic regulation in human monocytes exposed to hyperglycemic (HG) concentrations. Human monocytic cells (THP-1) were cultured under controlled (14.5 mM mannitol), normoglycemic (5.5 mM glucose), or HG (20 mM glucose) conditions in the absence or presence of the two phytochemicals for 48 h. Whereas HG conditions significantly induced histone acetylation, nuclear factor-kappa B (NF-kappaB) activation, interleukin 6, and tumor necrosis factor-alpha release from THP-1 cells; combination treatments with the two phytochemicals (500 nM fisetin, and l MUM and 500 nM luteolin) suppressed NF-kappaB activity and inflammatory cytokine release. Fisetin, luteolin, and their combination treatments also significantly decreased the activity of histone acetyltransferase, a known NF-kappaB coactivator; inhibited reactive oxygen species production; and activated sirtuin (SIRT)1 and forkhead box O3a (FOXO3a) expressions (P < .05). Thus, combination treatments with the two phytochemicals inhibited HG condition-induced cytokine production in monocytes, through epigenetic changes involving NF-kappaB activation. We, therefore, suggest that combination treatments with luteolin and fisetin may be a potential candidate for the treatment and prevention of diabetes and its complications. PMID- 28650733 TI - When Our Worlds Collide. PMID- 28650732 TI - Air, hand wipe, and surface wipe sampling for Bisphenol A (BPA) among workers in industries that manufacture and use BPA in the United States. AB - For decades, bisphenol A (BPA) has been used in making polycarbonate, epoxy, and phenolic resins and certain investment casting waxes, yet published exposure data are lacking for U.S. manufacturing workers. In 2013-2014, BPA air and hand exposures were quantified for 78 workers at six U.S. companies making BPA or BPA based products. Exposure measures included an inhalable-fraction personal air sample on each of two consecutive work days (n = 146), pre- and end-shift hand wipe samples on the second day (n = 74 each), and surface wipe samples (n = 88). Potential determinants of BPA air and end-shift hand exposures (after natural log transformation) were assessed in univariate and multiple regression mixed models. The geometric mean (GM) BPA air concentration was 4.0 ug/m3 (maximum 920 ug/m3). The end-shift GM BPA hand level (26 ug/sample) was 10-times higher than the pre shift level (2.6 ug/sample). BPA air and hand exposures differed significantly by industry and job. BPA air concentrations and end-shift hand levels were highest in the BPA-filled wax manufacturing/reclaim industry (GMAir = 48 ug/m3, GMHand End = 130 ug/sample) and in the job of working with molten BPA-filled wax (GMAir = 43 ug/m3, GMHand-End = 180 ug/sample), and lowest in the phenolic resins industry (GMAir = 0.85 ug/m3, GMHand-End = 0.43 ug/sample) and in the job of flaking phenolic resins (GMAIR = 0.62 ug/m3, GMHand-End = 0.38 ug/sample). Determinants of increased BPA air concentration were industry, handling BPA containers, spilling BPA, and spending >=50% of the shift in production areas; increasing age was associated with lower air concentrations. BPA hand exposure determinants were influenced by high values for two workers; for all other workers, tasks involving contact with BPA-containing materials and spending >=50% of the shift in production areas were associated with increased BPA hand levels. Surface wipe BPA levels were significantly lower in eating/office areas (GM = 9.3 ug/100 cm2) than in production areas (GM = 140 ug/100 cm2). In conclusion, worker BPA exposure was associated with tasks and conditions affecting both inhalation and dermal exposure. The potential for BPA-related health effects among these workers is unknown. PMID- 28650734 TI - Clostridium difficile-Associated Colitis Post-Transplant Is Not Associated with Elevation of Tacrolimus Concentrations. AB - BACKGROUND: Diarrhea is a common condition after solid organ transplant (SOT); Clostridium difficile-associated colitis (CDAC) is one of the most common infections after SOT. We documented previously that some types of enteritis are associated with an elevation of tacrolimus (TAC) trough concentrations by interfering with the drug's complex metabolism. PATIENTS AND METHODS: Tacrolimus concentrations of 25 SOT recipients including 12 renal and 13 liver recipients before, during, and after CDAC were analyzed retrospectively. RESULTS: Median age of the 25 patients was 54 y (range, 36-71), there were 15 males and 10 females. Clostridium difficile-associated colitis developed at a median of 55 d (range 2 4551) post-SOT. Median TAC concentrations prior to the outbreak of CDAC were 6.9 ng/mL (range, <1.5-17.2), 5.6 ng/mL (range, <1.5-13.2) during diarrhea, and 7.4 ng/mL (range, <1.5-24.3) after resolution of diarrhea (p > 0.05, NS). Treatment of CDAC consisted of metronidazole for 14 d in all cases. All patients recovered from CDAC but seven patients had CDAC relapse. CONCLUSIONS: In contrast to other types of infectious diarrhea such as rotavirus enteritis and cryptosporidiosis, CDAC is not associated with an increase in TAC concentrations. This is because C. difficile causes primarily colitis as opposed to other organisms, which are associated with enteritis. PMID- 28650736 TI - Test-retest reliability of jump execution variables using mechanography: a comparison of jump protocols. AB - Mechanography during the vertical jump may enhance screening and determining mechanistic causes underlying physical performance changes. Utility of jump mechanography for evaluation is limited by scant test-retest reliability data on force-time variables. This study examined the test-retest reliability of eight jump execution variables assessed from mechanography. Thirty-two women (mean+/ SD: age 20.8 +/- 1.3 yr) and 16 men (age 22.1 +/- 1.9 yr) attended a familiarization session and two testing sessions, all one week apart. Participants performed two variations of the squat jump with squat depth self selected and controlled using a goniometer to 80o knee flexion. Test-retest reliability was quantified as the systematic error (using effect size between jumps), random error (using coefficients of variation), and test-retest correlations (using intra-class correlation coefficients). Overall, jump execution variables demonstrated acceptable reliability, evidenced by small systematic errors (mean+/-95%CI: 0.2 +/- 0.07), moderate random errors (mean+/ 95%CI: 17.8 +/- 3.7%), and very strong test-retest correlations (range: 0.73 0.97). Differences in random errors between controlled and self-selected protocols were negligible (mean+/-95%CI: 1.3 +/- 2.3%). Jump execution variables demonstrated acceptable reliability, with no meaningful differences between the controlled and self-selected jump protocols. To simplify testing, a self-selected jump protocol can be used to assess force-time variables with negligible impact on measurement error. PMID- 28650737 TI - Premenstrual Symptom Patterns and Behavioral Risk Factors in Young Women: A Cross Sectional Study. AB - BACKGROUND: Approximately 80% of reproductive age women experience physical or emotional symptoms before onset of menses. Of these women, ~20% experience symptoms severe enough to interfere with social functioning and life activities, and meet clinical criteria for premenstrual syndrome (PMS). More than 100 different symptoms are associated with PMS. Symptom groupings tend to be stable within an individual, but vary distinctly between women. Potential differences in the etiology of symptoms suggest that PMS may have subtypes that represent distinct entities. METHODS: The goal of this study was to identify symptom patterns using factor analysis. We then used linear regression to evaluate relations between PMS risk factors with factor scores for the symptom patterns. Analysis included: (1) 414 healthy women aged 18-30 years; (2) the subgroup of these women meeting established criteria for PMS (n = 80). All participants provided information on the occurrence and severity of 26 premenstrual symptoms by validated questionnaire. RESULTS: Four distinct symptom patterns emerged, labeled Emotional, Psychological/Cognitive, Physical, and Consumption. We observed a linear relationship between body mass index and the Consumption pattern in both the total study population (p = 0.03) and the PMS subset (p = 0.04). Additionally, in the total population, physical activity was inversely associated with the Physical pattern (p = 0.04), but positively associated with the Consumption pattern (p = 0.03). Results from this study are consistent with previously identified patterns and suggest that distinct subtypes of PMS exist. CONCLUSIONS: Future studies of behavioral factors should evaluate associations with symptom patterns in addition to PMS as an aggregate disorder. PMID- 28650738 TI - Recommendations for Measuring Pulmonary Nodules at CT: A Statement from the Fleischner Society. AB - These recommendations for measuring pulmonary nodules at computed tomography (CT) are a statement from the Fleischner Society and, as such, incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. The recommendations address nodule size measurements at CT, which is a topic of importance, given that all available guidelines for nodule management are essentially based on nodule size or changes thereof. The recommendations are organized according to practical questions that commonly arise when nodules are measured in routine clinical practice and are, together with their answers, summarized in a table. The recommendations include technical requirements for accurate nodule measurement, directions on how to accurately measure the size of nodules at the workstation, and directions on how to report nodule size and changes in size. The recommendations are designed to provide practical advice based on the available evidence from the literature; however, areas of uncertainty are also discussed, and topics needing future research are highlighted. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28650739 TI - The effect of high intensity exercise and anticipation on trunk and lower limb biomechanics during a crossover cutting manoeuvre. AB - We investigated the effects of high intensity, intermittent exercise (HIIP) and anticipation on trunk, pelvic and lower limb biomechanics during a crossover cutting manoeuvre. Twenty-eight male, varsity athletes performed crossover cutting manoeuvres in anticipated and unanticipated conditions pre- and post HIIP. Kinematic and kinetic variables were captured using a motion analysis system. Statistical parametric mapping (repeated-measures ANOVA) was used to identify differences in biomechanical patterns. Results demonstrated that both unanticipation and fatigue (HIIP) altered the biomechanics of the crossover cutting manoeuvre, whereas no interactions effects were observed. Unanticipation resulted in less trunk and pelvic side flexion in the direction of cut (d = 0.70 0.79). This led to increased hip abductor and external rotator moments and increased knee extensor and valgus moments with small effects (d = 0.24-0.42), potentially increasing ACL strain. The HIIP resulted in trivial to small effects only with a decrease in internal knee rotator and extensor moment and decreased knee power absorption (d = 0.35), reducing potential ACL strain. The effect of trunk and hip control exercises in unanticipated conditions on the crossover cutting manoeuvre should be investigated with a view to refining ACL injury prevention programmes. PMID- 28650740 TI - In Vivo Investigation of the Safety and Efficacy of Pulsed Dye Laser with Two Spot Sizes in Port-Wine Stain Treatment: A Prospective Side-by-Side Comparison. AB - OBJECTIVE: Pulsed dye laser (PDL) with 7 and 10 mm spot sizes is widely used on a regular basis for the treatment of port-wine stain (PWS). BACKGROUND DATA: No studies have reported on the differences in efficacy outcomes resulting from the use of different laser spot sizes in the treatment of PWS by PDL. Thus, an in vivo investigation into the differences in safety and efficacy of treatment between two spot sizes (7 vs. 10 mm) of PWS by PDL was conducted. MATERIALS AND METHODS: A total of 35 PWS patients underwent three treatment sessions by using a 595 nm wavelength PDL (Vbeam(r), Candela Corp) with two laser settings: (1) 7 mm spot size, radiant exposure of 12 J/cm2 and (2) 10 mm spot size, radiant exposure of 10 J/cm2. Cryogen spray cooling and 1.5 msec pulse duration were applied. Therapeutic outcomes were evaluated by visual and chromametric evaluation 3 months after the final treatment. RESULTS: Average blanching rates were 34.03% and 36.51% at sites treated by PDL with 7 and 10 mm laser spot sizes, respectively (p < 0.05). CONCLUSIONS: On the basis of the laser setting, the therapeutic outcomes of PDL with 7 and 10 mm spot sizes were similar. PDL with a 10 mm laser spot size is more efficacious with lower radiant exposure than PDL with a 7 mm spot size; it can also reduce the treatment time. PMID- 28650741 TI - Microbial Culturomics Application for Global Health: Noncontiguous Finished Genome Sequence and Description of Pseudomonas massiliensis Strain CB-1T sp. nov. in Brazil. AB - Culturomics is a new postgenomics field that explores the microbial diversity of the human gut coupled with taxono-genomic strategy. Culturomics, and the microbiome science more generally, are anticipated to transform global health diagnostics and inform the ways in which gut microbial diversity contributes to human health and disease, and by extension, to personalized medicine. Using culturomics, we report in this study the description of strain CB1T ( = CSUR P1334 = DSM 29075), a new species isolated from a stool specimen from a 37-year old Brazilian woman. This description includes phenotypic characteristics and complete genome sequence and annotation. Strain CB1T is a gram-negative aerobic and motile bacillus, exhibits neither catalase nor oxidase activities, and presents a 98.3% 16S rRNA sequence similarity with Pseudomonas putida. The 4,723,534 bp long genome contains 4239 protein-coding genes and 74 RNA genes, including 15 rRNA genes (5 16S rRNA, 4 23S rRNA, and 6 5S rRNA) and 59 tRNA genes. Strain CB1T was named Pseudomonas massiliensis sp. nov. and classified into the family Pseudomonadaceae. This study demonstrates the usefulness of microbial culturomics in exploration of human microbiota in diverse geographies and offers new promise for incorporating new omics technologies for innovation in diagnostic medicine and global health. PMID- 28650742 TI - Evaluating bioaerosol exposure among bus drivers in the public transport sector. AB - Occupational hazards and consequent health problems suffered by drivers in the public transport sector require preventive measures. The aim of this study was to assess the exposure of drivers to microbiological air contamination (airborne bacteria and fungi) in buses. The air in public transport vehicles was examined in autumn, winter and spring. To evaluate the exposure of drivers to bioaerosols, air samples were collected and examined for the total number of bacteria and fungi in the air, the number of mesophilic aerobic bacteria specified by the number of colony forming units (CFU) per 1 m3 of air. The results of the research show that public transport as a workplace can be considered to be a significant risk to health. PMID- 28650743 TI - Identifying Factors and Root Causes Associated With Near-Miss or Safety Incidents in Patients Treated With Radiotherapy: A Case-Control Analysis. AB - PURPOSE: To identify factors associated with a near-miss or safety incident (NMSI) in patients undergoing radiotherapy and identify common root causes of NMSIs and their relationship with incident severity. METHODS: We retrospectively studied NMSIs filed between October 2014 and April 2016. We extracted patient-, treatment-, and disease-specific data from patients with an NMSI (n = 200; incident group) and a similar group of control patients (n = 200) matched in time, without an NMSI. A root cause and incident severity were determined for each NMSI. Univariable and multivariable analyses were performed to determine which specific factors were contributing to NMSIs. Multivariable logistic regression was used to determine root causes of NMSIs and their relationship with incident severity. RESULTS: NMSIs were associated with the following factors: head and neck sites (odds ratio [OR], 5.2; P = .01), image-guided intensity modulated radiotherapy (OR, 3; P = .009), daily imaging (OR, 7; P < .001), and tumors staged as T2 (OR, 3.3; P = .004). Documentation and scheduling errors were the most common root causes (29%). Communication errors were more likely to affect patients ( P < .001), and technical treatment delivery errors were most associated with a higher severity score ( P = .005). CONCLUSION: Several treatment- and disease-specific factors were found to be associated with an NMSI. Overall, our results suggest that complexity (eg, head and neck, image-guided intensity-modulated radiotherapy, and daily imaging) might be a contributing factor for an NMSI. This promotes an idea of developing a more dedicated and robust quality assurance system for complex cases and highlights the importance of a strong reporting system to support a safety culture. PMID- 28650744 TI - Pursuing Value in Cancer Care: A Model in Progress. PMID- 28650747 TI - Kinetic and kinematic analysis of stamping impacts during simulated rucking in rugby union. AB - Laceration injuries account for up to 23% of injuries in rugby union. They are frequently caused by studded footwear as a result of a player stamping onto another player during the ruck. Little is known about the kinetics and kinematics of rugby stamping impacts; current test methods assessing laceration injury risk of stud designs therefore lack informed test parameters. In this study, twelve participants stamped on an anthropomorphic test device in a one-on-one simulated ruck setting. Velocity and inclination angle of the foot prior to impact was determined from high-speed video footage. Total stamping force and individual stud force were measured using pressure sensors. Mean foot inbound velocity was 4.3 m ? s-1 (range 2.1-6.3 m ? s-1). Mean peak total force was 1246 N and mean peak stud force was 214 N. The total mean effective mass during stamping was 6.6 kg (range: 1.6-13.5 kg) and stud effective mass was 1.2 kg (range: 0.5-2.9 kg). These results provide representative test parameters for mechanical test devices designed to assess laceration injury risk of studded footwear for rugby union. PMID- 28650745 TI - Longer-Duration Antimicrobial Therapy Does Not Prevent Treatment Failure in High Risk Patients with Complicated Intra-Abdominal Infections. AB - BACKGROUND: Recent studies have suggested the length of treatment of intra abdominal infections (IAIs) can be shortened without detrimental effects on patient outcomes. However, data from high-risk patient populations are lacking. We hypothesized that patients at high risk for treatment failure will benefit from a longer course of antimicrobial therapy. METHODS: Patients enrolled in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated retrospectively to identify risk factors associated with treatment failure, which was defined as the composite outcome of recurrent IAI, surgical site infection, or death. Variables were considered risk factors if there was a positive statistical association with treatment failure. Patients were then stratified according to the presence and number of these risk factors. Univariable analyses were performed using the Kruskal-Wallis, chi2, and Fisher exact tests. Logistic regression controlling for risk factors and original randomization group, either a fixed four-day antimicrobial regimen (experimental) or a longer course based on clinical response (control), also was performed. RESULTS: We identified corticosteroid use, Acute Physiology and Chronic Health Evaluation II score >=5, hospital-acquired infection, or a colonic source of IAI as risk factors associated with treatment failure. Of the 517 patients enrolled, 263 (50.9%) had one or two risk factors and 16 (3.1%) had three or four risk factors. The rate of treatment failure rose as the number of risk factors increased. When controlling for randomization group, the presence and number of risk factors were independently associated with treatment failure, but the duration of antimicrobial therapy was not. CONCLUSIONS: We were able to identify patients at high risk for treatment failure in the STOP-IT trial. Such patients did not benefit from a longer course of antibiotic administration. Further study is needed to determine the optimum duration of antimicrobial therapy in high-risk patients. PMID- 28650748 TI - Childhood abuse and adult-onset asthma among Peruvian women. AB - OBJECTIVE: Childhood abuse has been found to be associated with adult-onset asthma; however, this association has not been studied in low- and middle-income countries with a high burden of gender-based violence, including childhood abuse. We examined the odds of asthma diagnosed at age 18 or older in relation to history of physical and sexual abuse among Peruvian pregnant women. METHODS: This cross-sectional study collected demographic characteristics, history of abuse and asthma diagnoses from 3081 pregnant women. Logistic regression procedures estimated adjusted odds ratios and 95% confidence intervals (aOR, [95% CI]) for asthma diagnoses in relation to abuse. RESULTS: Overall, 71% of the women reported a history of abuse (<18 years), and asthma was diagnosed among 2.6% of the cohort participants. The prevalence of physical only, sexual only and both physical and sexual childhood abuse was 38, 8 and 25%, respectively. The history of physical only (1.16, [0.63-2.17]), sexual only (2.11, [0.92-4.84]) or both physical and sexual childhood abuse (1.75, [0.94-3.29]) was positively associated with increased odds of asthma, although the associations were not statistically significant in the multivariate analysis. However, the odds of asthma increased with increasing numbers of abuse events (ptrend = 0.01). Women who reported >=3 abuse events had an increased odds of asthma (1.88, [1.06-3.34]). CONCLUSION: Our results do not provide convincing evidence that childhood abuse is associated with asthma among pregnant Peruvian women; however, we were able to demonstrate that an increased number of abuse events are associated with asthma. Further research is required to better understand the effects of abuse on asthma. PMID- 28650749 TI - Comparative Effectiveness of Radial Extracorporeal Shockwave Therapy and Ultrasound-Guided Local Corticosteroid Injection Treatment for Plantar Fasciitis. AB - BACKGROUND: We compared the long-term clinical and ultrasonographic effects of radial extracorporeal shockwave therapy (rESWT) versus ultrasound-guided corticosteroid injection treatment in patients with plantar fasciitis unresponsive to conservative therapy. METHODS: Seventy-two patients with unilateral plantar fasciitis were randomized to receive either rESWT (three times once per week) (n = 36) or corticosteroid treatment (a single 1-mL dose of betamethasone sodium plus 0.5 mL of prilocaine under ultrasound guidance by injection into the plantar fascia) (n = 36). The primary outcome measures were visual analog scale (VAS) and Foot Function Index (FFI) scores. Secondary outcome measures included the heel tenderness index (HTI) score and plantar fascia thickness (PFT) as obtained by ultrasound examination. All of the assessments were performed at baseline and 1, 3, and 6 months after treatment. RESULTS: Significant improvements were observed in the rESWT group in VAS, HTI, and FFI scores and PFT at the end of treatment and were maintained during follow-up. Posttreatment improvements in VAS, HTI, and FFI scores and PFT were also seen in the corticosteroid group but were not maintained for VAS and FFI scores after the completion of therapy and were lost at 1 and 6 months, respectively. No serious treatment-related complications occurred. CONCLUSIONS: Both rESWT and corticosteroid injection therapy are effective modalities for treatment of chronic plantar fasciitis. However, rESWT seems to be superior to corticosteroid injection therapy due to its longer duration of action. PMID- 28650751 TI - Examining Clinical Outcome Measures. PMID- 28650752 TI - Characteristics Predicting the Outcome in Individuals with Diabetic Foot Ulcerations. AB - BACKGROUND: We sought to determine patient and ulcer characteristics that predict wound healing in patients living with diabetes. METHODS: A prospective observational study was conducted on 99 patients presenting with diabetic foot ulceration. Patient and ulcer characteristics were recorded. Patients were followed up for a maximum of 1 year. RESULTS: After 1 year of follow-up, ulcer characteristics were more predictive of ulcer healing than were patient characteristics. Seventy-seven percent of ulcers had healed and 23% had not healed. Independent predictors of nonhealing were ulcer stage (P = .003), presence of biofilm (P = .020), and ulcer depth (P = .028). Although this study demonstrated that the baseline hemoglobin A1c reading at the start of the study was not a significant predictor of foot ulcer outcome (P = .603, resolved versus amputated), on further statistical analyses, when hemoglobin A1c was compared with the time taken for complete ulcer healing (n = 77), it proved to be significant (P = .009). CONCLUSIONS: The factors influencing healing are ulcer stage, presence of biofilm, and ulcer depth. These findings have important implications for clinical practice, especially in an outpatient setting. Prediction of outcome may be helpful for health-care professionals in individualizing and optimizing clinical assessment and management of patients. Identification of determinants of outcome could result in improved health outcomes, improved quality of life, and fewer diabetes-related foot complications. PMID- 28650753 TI - Lower-Extremity Infections Caused by Serratia marcescens A Report of Three Cases and a Literature Review. AB - Serratia marcescens is a ubiquitous, facultatively anaerobic, gram-negative bacillus that has been cited to cause infection in immunocompromised populations. In the literature, S marcescens infections of the lower extremity have presented as granulomatous ulceration, abscess, bullous cellulitis, and necrotizing fasciitis. Herein we present a series of three cases of lower-extremity infections in which S marcescens was the sole or a contributing pathogen. We discuss the commonalities of these three cases as well as with those previously cited. All three patients presented with some combination of a similar set of clinical characteristics, including bullae formation, liquefactive necrosis, and black necrotic eschar. All three patients were diabetic and had peripheral vascular disease. PMID- 28650754 TI - Structural Changes in the Lower Extremities in Boys Aged 7 to 12 Years Who Engage in Moderate Physical ActivityAn Observational Longitudinal Study. AB - BACKGROUND: Physical activity in children may provide health benefits. We sought to consider the practice of soccer as a possible major factor in the development of the lower limb. The study is based on 3-year data for a group of children who practice this sport. METHODS: For 3 years we monitored 53 children who practiced soccer 3 times a week and had engaged in 2 years of continuous sports activity. Their mean +/- SD age was 8.49 +/- 2.01 years in the first year. Each year, Foot Posture Index, valgus index, subtalar joint axis, and Q angle for the knee were analyzed. RESULTS: The mean +/- SD Foot Posture Index scores ranged from 5.38 +/- 1.79 in the right foot and 4.49 +/- 1.67 in the left foot in the first year to 4.64 +/- 2.51 and 4.34 +/- 2.26, respectively, in the third year. The valgus index for the same period ranged from 14.05 degrees +/- 1.51 degrees (right) and 13.88 degrees +/- 1.46 degrees (left) to 13.09 degrees +/- 1.28 degrees and 13.07 degrees +/- 1.07 degrees , respectively. In the knee, the Q angle ranged from 12.83 degrees +/- 1.98 degrees (right) and 12.74 degrees +/- 1.68 degrees (left) to 13.17 degrees +/- 1.45 degrees and 13.26 degrees +/- 1.46 degrees , respectively. In the subtalar joint, the changes were 37.73% right and 30.19% left between the first and third years toward a neutral subtalar joint axis. CONCLUSIONS: These results show that although playing soccer might cause structural changes in the lower limb, these alterations should not be considered harmful because they may be influenced by age as well. PMID- 28650755 TI - Glomus Tumor of the Toe. AB - A glomus tumor is an uncommon, predominantly benign, neoplastic lesion that primarily involves a thermoregulatory microvascular apparatus, the glomus body. Although these lesions can occur anywhere in the body, the subungual tissue of the hand represents the most common presentation site. Glomus tumors are not often encountered in the foot. Symptoms traditionally include the classic triad of pain, pressure, and cold sensitivity. This case report describes a variant location for a glomus tumor in the subcuticular tissue adjacent to the medial middle phalanx of the second toe. The nonsubungual location for this presentation should prompt the inclusion of glomus tumor in a digital soft-tissue lesion differential diagnosis. The lesion was excised surgically and was subsequently diagnosed histopathologically as a glomus tumor. PMID- 28650756 TI - Accessory Lesser Metatarsal Sesamoids in All of the Metatarsophalangeal JointsA Case Report. AB - Lesser metatarsal sesamoids are one of the most common accessory bones of the foot and are most commonly seen at the fifth metatarsophalangeal joint. They are rarely seen in other metatarsophalangeal joints. In the literature, there are reports of solitary accessory sesamoid bones seen at lesser metatarsophalangeal joints. We report the case of a 68-year-old woman with lesser metatarsal sesamoids accompanying all of the metatarsophalangeal joints. PMID- 28650757 TI - Management Considerations for a Retained Plantar Knife Injury. AB - A 13-year-old girl presented to the emergency department in stable condition with a retained penetrating knife wound injury in her right foot. Routine radiographs taken of the foot revealed deep tissue penetration by the knife without frank bony involvement. It was decided to remove the object in the operating room. Simple removal was performed, followed by wound exploration. The patient was admitted to the hospital for one night of observation and then was discharged without further complications. PMID- 28650759 TI - Evaluation of Plantar Pressure Distribution in Relationship to Body Mass Index in Czech Women During Walking. AB - BACKGROUND: Excessive body weight seems to be a risk factor for foot loading. We sought to investigate the effect of different body mass index (BMI) levels on plantar pressure distribution during walking. METHODS: In total, 163 women aged 45 to 65 years (mean +/- SD: age, 57.4 +/- 5.3 years; BMI, 27.0 +/- 5.3) participated in the study. The women were divided, on the basis of BMI, into a normal-weight, overweight, or obese group. The study used the four following plantar pressure parameters (PPPs): contact percentage, absolute pressure impulse, relative pressure impulse, and absolute peak pressure, which were recorded in ten foot regions using a pressure measurement system. RESULTS: The normal-weight group, compared with the overweight and obese groups, had significantly lower absolute PPP values. In the hallux, second through fifth metatarsals, midfoot, and heel regions, we observed significant between-group differences in the two absolute PPPs (peak pressure and pressure impulse) (P < .001). Between-group differences in the relative PPPs were found in the fourth metatarsal, midfoot, and medial heel (relative impulse) and in the second metatarsal (contact percentage) (P < .001). CONCLUSIONS: Higher BMI values correspond to a higher load on the foot during walking in women. The relative foot load in obese women is characterized by a pressure increase in the lateral forefoot and midfoot and by a pressure decrease in the medial heel. PMID- 28650761 TI - Cryptococcal Osteomyelitis of the First Metatarsal Head in an Immunocompetent Patient. AB - Most fungal infections primarily occur in immunocompromised patients. We describe a case of osteomyelitis involving the first metatarsal head due to Cryptococcus neoformans in a previously healthy immunocompetent patient. She was treated with surgical debridement combined with antifungal drug therapy for 6 months. At 5 year follow-up, she remained symptom free with full range of motion of the first metatarsophalangeal joint. Fungal osteomyelitis should be considered as a possible cause in osteolytic lesions in the metatarsal bone. PMID- 28650762 TI - Angioleiomyoma of the Lower Leg. AB - Angioleiomyomas are benign tumefactions that originate from smooth muscle in vascular structures and are difficult to definitively diagnose preoperatively. Although these lesions are rarely encountered in the foot, the lower extremity is the most common site of occurrence. An angioleiomyoma typically manifests as a small, painful, solitary, mobile lesion. This case report describes a lateral retromalleolar para-Achilles tendon insertional location for a moderately sized immobile solid tumefaction in the subcutaneous tissues. The lesion was nonpainful and progressively enlarged over 5 years. An excisional biopsy was performed, and the nodular lesion was subsequently diagnosed histopathologically as an angioleiomyoma. Owing to the ambiguous nature of the clinical findings, angioleiomyoma should be included in the differential diagnosis of lower extremity soft-tissue manifestations. PMID- 28650763 TI - Posttraumatic Retronychia of the Foot with Clinical and Ultrasound Correlation. AB - Retronychia, the posterior embedding of the nail bed into the proximal nail fold, can be a complex clinical dermatologic diagnosis that may mimic other inflammatory ungual diseases or tumors of the nail. It has been related to a history of severe systemic conditions that secondarily affect the nail matrix and is commonly associated with onychomadesis. We present a case of retronychia of the foot with a purely traumatic origin, nonconcomitant with onychomadesis, that was diagnosed by color Doppler ultrasound in a long-time practitioner of martial arts who was otherwise healthy. Color Doppler ultrasound is an excellent imaging technique for supporting the diagnosis of retronychia. It provides information on the exact location and morphology of the nail plate as well as the presence of inflammatory signs in the ungual and proximal periungual regions. Additionally, this imaging technique can support the differential diagnosis with other nail conditions. Since there are many sports or activities that can potentially injure the toenails, retronychia may be an underestimated entity and the present case can raise the awareness of this condition and show the usefulness of color Doppler ultrasound. PMID- 28650764 TI - Dorsal Fracture-Dislocation of the Tarsal NavicularCase Report and Review of a Rare Injury. AB - Fracture-dislocations of the tarsal navicular are rare and highly complex injuries to the midfoot. The only published data on this type of fracture are clinical case reports. These injuries are normally caused by high-energy trauma, and their pathophysiology and most appropriate treatment remain unclear. We report a clinical case of a dorsal fracture-dislocation of the tarsal navicular bone associated with a medial swivel dislocation of the Chopart joint caused by a bicycle fall in a 20-year-old healthy man. Open reduction and percutaneous pinning in a novel arrangement was performed, with an excellent outcome 18 months after the injury. PMID- 28650765 TI - Oldest Mummified Case of Hallux Valgus from Ancient Egypt. AB - Hallux valgus is the most common orthopedic problem of the adult foot. The etiology can be congenital, associated with the occurrence of metatarsus primus varus, or acquired, which is closely related to wearing ill-fitting shoes. Hallux valgus occurs almost exclusively in shod societies and, therefore, is a very uncommon finding in archaeological remains. We present a partial first ray of the left foot belonging to a dismembered Egyptian mummy recovered in the necropolis of Sharuna (Middle Egypt) and dated to the end of the Old Kingdom (circa 2100 BC). The mummification process led to a metatarsophalangeal joint in connection by means of soft tissues. The alignment of this joint could be diagnosed as a hallux valgus. Further examination showed a metatarsophalangeal angle of 28 degrees . After a comprehensive literature search and noting that all of the previous cases were described by indirect factors, such as mounting the joint in dry bones, we can state with certainty that the piece we present herein is the oldest case of mummified hallux valgus. PMID- 28650767 TI - Resumenes. PMID- 28650769 TI - La evaluacion del impacto en la salud para la promocion, la educacion y el aprendizaje en este campo. PMID- 28650766 TI - Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent. AB - Age-related health decline has been attributed to the accumulation of senescent cells recognized in vivo by p16(Ink4a) expression. The pharmacological elimination of p16(Ink4a)-positive cells from the tissues of mice was shown to extend a healthy lifespan. Here, we describe a population of mesenchymal cells isolated from mice that are highly p16(INK4a)-positive are proficient in proliferation but lack other properties of cellular senescence. These data, along with earlier reports on p16(Ink4a)-positive macrophages, indicate that p16(Ink4a) positive and senescent cell populations only partially intersect, therefore, extending the list of potential cellular targets for anti- aging therapies. PMID- 28650770 TI - Resumes. PMID- 28650771 TI - L'evaluation d'impact sur la sante pour la promotion de la sante, l'education pour la sante et l'apprentissage. PMID- 28650772 TI - L'analyse de contribution pour evaluer l'impact de la demarche EIS sur les processus decisionnels municipaux : un choix methodologique interessant ? AB - La pertinence de l'evaluation d'impact sur la sante (EIS) pour promouvoir le developpement de politiques publiques favorables a la sante au sein des municipalites est de plus en plus reconnue. L'appreciation des effets d'une demarche d'EIS sur les processus decisionnels d'acteurs municipaux peut toutefois etre difficile en raison de la multitude d'influences sociales, economiques, geographiques et personnelles auxquels ils sont soumis. Dans un tel contexte, l'approche evaluative de l'analyse de contribution (AC) s'avere particulierement interessante puisqu'elle permet de documenter les facteurs menant a l'efficacite d'une intervention en tenant compte des elements du contexte. Elle aide l'evaluateur a comprendre comment et pourquoi une intervention fonctionne. Le present article utilise l'etude de cas pour explorer la faisabilite et l'efficacite de l'AC pour apprecier les effets de demarches d'EIS sur le processus decisionnel d'acteurs municipaux. Il decrit les strategies de collecte et d'analyse de donnees utilisees aupres de trois municipalites de la Monteregie, au Quebec. Cette analyse critique montre que l'AC est pertinente dans le contexte decrit. Elle permet d'etablir des associations claires et transparentes entre l'intervention, soit la demarche d'EIS, et l'importance accordee a la sante par les acteurs municipaux. Elle assure la prise en compte des facteurs d'influence contextuels et offre la flexibilite necessaire pour adapter la collecte de donnees a la realite du terrain. Neanmoins, la lourdeur de l'approche peut en contraindre l'application et certaines limites methodologiques ont ete observees au niveau de l'analyse des donnees. Les strategies mises de l'avant pour y remedier sont decrites. PMID- 28650773 TI - A successful live birth with in vitro fertilization and thawed embryo transfer after conservative treatment of recurrent endometrial cancer. AB - Estrogen-dependent early stage endometrial cancer is relatively common in young women of reproductive age. The standard treatment is hysterectomy and bilateral salpingo-oophorectomy (BSO), even in early stage well-differentiated endometrial cancer patients. This surgical option results in permanent loss of fertility. There have been some reports of live births using in vitro fertilization after conservative management of endometrial cancer with high-dose progestin for the purpose of fertility preservation. However, most were not recurrent cases and pregnancy was achieved through conventional in vitro fertilization, which usually raises serum estradiol levels and may lead to the recurrence of endometrial cancer. To date, it is hard to find a case that can be referred for any possible different approach needed for the patients who experience recurrence. Here we report a successful live birth with in vitro fertilization using letrozole to maintain physiological levels of estradiol, and subsequent thawed embryo transfer after elective cryopreservation of embryos in a patient with recurrent endometrial cancer. There has been no evidence of disease recurrence at one year after delivery. PMID- 28650774 TI - Monte Carlo Electron Track Structure Calculations in Liquid Water Using a New Model Dielectric Response Function. AB - Monte Carlo track structure codes provide valuable information for understanding radiation effects down to the DNA level, where experimental measurements are most difficult or unavailable. It is well recognized that the performance of such codes, especially at low energies and/or subcellular level, critically depends on the reliability of the interaction cross sections that are used as input in the simulation. For biological media such as liquid water, one of the most challenging issues is the role of condensed-phase effects. For inelastic scattering, such effects can be conveniently accounted for through the complex dielectric response function of the media. However, for this function to be useful it must fulfill some important sum rules and have a simple analytic form for arbitrary energy- and momentum-transfer. The Emfietzoglou-Cucinotta-Nikjoo (ECN) model offers a practical, self-consistent and fully analytic parameterization of the dielectric function of liquid water based on the best available experimental data. An important feature of the ECN model is that it includes, in a phenomenological manner, exchange and correlation effects among the screening electrons, thus, going beyond the random-phase approximation implicit in earlier models. In this work, inelastic cross sections beyond the plane wave Born approximation are calculated for low-energy electrons (10 eV-10 keV) based on the ECN model, and used for Monte Carlo track structure simulations of physical quantities relevant to the microdosimetry of low-energy electrons in liquid water. Important new developments in the physics of inelastic scattering are discussed and their effect on electron track structure is investigated by a comparison against simulations (under otherwise identical conditions) using the Born approximation and a simpler form of the dielectric function based on the Oak Ridge National Laboratory model. The results reveal that both the dielectric function and the corrections to the Born approximation may have a sizeable effect on track structure calculations at the nanometer scale (DNA level), where the details of inelastic scattering and the role of low-energy electrons are most critical. PMID- 28650775 TI - Urine Interleukin-18 (IL-18) as a Biomarker of Total-Body Irradiation: A Preliminary Study in Nonhuman Primates. AB - We have reported that circulating IL-18 can be used as a radiation biomarker in mice, minipigs and nonhuman primates (NHPs, Macaca mulatta). Here, we report the levels of IL-18 in individual NHP's urine before and at 6 h-7 days after 5.0, 6.5 and 8.5 Gy 60Co total-body irradiation (TBI) using enzyme linked immunosorbent assay (ELISA). Six animals (3.5-5.5 kg, 3-4 years old) per radiation dose were investigated. Correlation values between urine IL-18 and blood cell counts and serum chemistry parameters including lactate dehydrogenase (LDH), lipase, and serum total protein (TP), as well as between urine IL-18 and 60-day survival, were analyzed. Our data, to the best of our knowledge, for the first time, demonstrate that concentrations of urine IL-18 from irradiated NHPs were increased in a radiation dose-dependent manner compared to pre-TBI levels in samples from these animal (N = 18, 11.02 +/- 1.3 pg/ml). A 5.0 Gy low dose of radiation (~LD10/60) did not increase urine IL-18 levels. In contrast, high-dose TBI significantly increased urine IL-18 at day 1 to day 5 in a bell-shaped time course, reaching a peak of 5- to 10-fold of control levels on day 3 after 6.5 Gy (~LD50/60) and 8.5 Gy (~LD90/60), respectively. Statistical analysis using receiver operator characteristic (ROC) and MultiROC analysis indicated that white blood cell and platelet counts, serum LDH, lipase and TP, when combined with urine IL-18, provide discriminatory predictors of total-body radiation injury with a very high ROC area of 0.98. Urine IL-18 measurement, as an early prognostic indicator of survival, may facilitate rapid detection of lethal doses of radiation, based on the currently available data set. PMID- 28650776 TI - Women's preferences for menstrual bleeding frequency in 12 European countries: the Inconvenience Due to Women's Monthly Bleeding (ISY) survey. AB - OBJECTIVES: Our aim was to assess the level of inconvenience associated with menstrual bleeding and determine how many women across 12 European countries would prefer a bleeding frequency of less than once a month and what would motivate their choice. METHODS: A 15-min quantitative online survey was conducted in two waves among 5728 women aged between 18 and 45 years, with an equal distribution of women using a combined hormonal contraceptive (CHC group, n = 2739) and women using a non-hormonal contraceptive or no contraceptive (non-HC group, n = 2989). The first wave was carried out in Austria, Belgium, France, Italy, Poland and Spain, in February 2015, and the results have been published. The second wave was conducted in the Czech Republic, Germany, Hungary, Portugal, Latvia and the Netherlands, between August and September 2015. RESULTS: The menstrual period was significantly longer (5.0 versus 4.6 days) and heavier (15 versus 7%) in non-HC users than in CHC users (p < .0001). Given the choice, ~60% of women would like less frequent menstrual bleeding. There was heterogeneity in the preference across countries. Sexuality, social life, work and sporting activities were key factors affecting women's preference. CONCLUSION: The majority of women in the 12 European countries would prefer to reduce the frequency of menstrual periods. Quality of life was the main factor affecting their preference. PMID- 28650777 TI - A transdiagnostic examination of decreased intolerance of uncertainty and treatment outcome. AB - Intolerance of uncertainty (IU) is characterized by negative beliefs and reactions to uncertainty. IU is present in emotional disorders and may be a mechanism of change in treatment . There are two components of IU, prospective and inhibitory IU, that may be differentially associated with outcome. The current study tested associations between pre- and post-treatment changes in the components of IU, symptoms of anxiety and depression, and treatment outcome in a large diagnostically heterogeneous partial hospital sample. Results suggested that social anxiety disorder was associated with greater pre-treatment prospective and inhibitory IU scores than those without the diagnosis. Results also showed that inhibitory IU predicted change in anxiety and depression symptoms and prospective IU and depression reductions predicted improvements in overall psychological health and psychological inflexibility. Only change in depression predicted improvement in interpersonal relationships throughout treatment. Clinical and theoretical implications of the findings are discussed. PMID- 28650778 TI - Success of Dental Treatments under Behavior Management, Sedation and General Anesthesia. AB - OBJECTIVE: To present comparative study aims to assist the practitioner to choose between behavior modification (BM) techniques, pharmacologic sedation (N2O-O2 alone or combined with midazolam 0.5 mg/ kg) or routine general anesthesia (GA) for the most successful approach in enabling pediatric dental care. STUDY DESIGN: Dental records of 56 children treated in a university dental clinic between 2006 2016 were reviewed, and data on age, gender, required treatment (amalgam restorations, composite restorations, pulpotomy, and stainless steel crowns [SSC]), treatment approaches and therapeutic success at final follow-up were retrieved. RESULTS: Treatment under GA had the best success rates compared to both BM and pharmacologic sedation. N2O-O2 alone had a 6.1-fold greater risk of failure compared to N2O-O2+midazolam (p- <0.008). Amalgam restorations had a 2.61 fold greater risk of failure than SSC (p- <0.008). CONCLUSIONS: The GA mode yielded significantly greater success than the N2O-O2 mode alone. There were no significant differences in success rates between GA and combined midazolam 0.5 mg/kg+N2O-O2. When choosing restoration material, it is important to remember the high success rate of SSC compared to amalgam restoration. PMID- 28650779 TI - Management of Ranula in a Child by Modified Micro-Marsupialization Technique: A Case Report. AB - Ranulas pose a challenging situation, both clinically and surgically, because of their location on the floor of the mouth, an area that exhibits tightly-netted vital structures. Several treatments have been proposed, including excision with or without removal of the sublingual gland, marsupialization with or without cauterization of the roof of the lesion, drainage of the lesion, and micro marsupialization. It has been suggested that a modified micro-marsupialization technique can establish drainage of saliva and formation of new permanent epithelized tracts along the path of sutures, thereby reducing the recurrence. This paper presents a report of a ranula in a 12 year-old child that was successfully managed using a modified micro-marsupialization procedure. PMID- 28650780 TI - I Am a Pediatric Dentist: Why Is Substance Abuse among My Patients My Concern? AB - The rapidly evolving demographic base of our communities intensifies the need for an awareness which in the past seemed beyond the traditional concerns of pediatric dentists; in this case, substance abuse by teenagers. A review was carried out regarding evolving demographics, the proportion of teenagers involved with substance abuse, the rationale for the use of varying elicit substances and the associated symptoms. A series of options for action are considered given the potential for pediatric dentists to be involved in the care of teenagers using elicit substances. PMID- 28650781 TI - Rapid Maxillary Expansion in Obstructive Sleep Apnea in Young Patients: Cardio Respiratory Monitoring. AB - OBJECTIVE(S): Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder which affects from 1 to 3 % of people during development. OSAS treatment may be pharmacological, surgical or based on application of intraoral devices to increase nasal respiratory spaces. The purpose of this study was to determine the efficacy of the Rapid Maxillary Expander in OSAS young patients by measuring cardio-respiratory monitoring parameters (AHI, the average value of complete and incomplete obstructed respiration per hour of sleep, and SAO2, the percentage of oxygen saturation). STUDY DESIGN: The study was conducted on 11 OSAS young subjects (mean age 6.9+/-1.04 years), all treated with rapid maxillary expansion (RME). Cardio-respiratory monitoring (8-channel Polymesam) was performed at the beginning (diagnostic, T0) and after 12 months of treatment. RESULTS: The mean values of cardio-respiratory parameters at TO were: AHI=6.09+/-3.47; SAO2=93.09%+/-1.60. After 12 months of treatment, the mean values of the same polysomnographic parameters were: AHI=2.36 +/- 2.24;SAO2=96.81% +/-1.60. These changes were associated with an improvement in clinical symptoms, such as reduction of snoring and sleep apnea. CONCLUSION(S): This study confirms the therapeutic efficacy of RME in OSAS young patients. This orthopedic-orthodontic treatment may represent a good option in young patients affected by this syndrome. PMID- 28650782 TI - Effect of Probiotic Yogurt and Xylitol-Containing Chewing Gums on Salivary S Mutans Count. AB - BACKGROUND AND AIMS: In addition to improving gastrointestinal health and intestinal microflora, probiotic bacteria have been recently suggested to decrease cariogenic agents in the oral cavity. The aim of this study was to investigate the effects of probiotic yogurt and xylitol-containing chewing gums on reducing salivary Streptococcus mutans levels. STUDY DESIGN: This randomized clinical trial recruited 50 female students with over 105 colony forming units S. mutans per milliliter of their saliva. The participants were randomly allocated to two equal groups to receive either probiotic yogurt containing Lactobacillus acidophilus ATCC 4356 andBifidobacteriumbifidum ATCC 29521 (200 g daily) or xylitol-containing chewing gums (two gums three times daily after each meal; total xylitol content: 5.58 g daily) for three weeks. At baseline and one day, two weeks, and four weeks after the interventions, saliva samples were cultured on mitis-salivarius-bacitracin agar and salivary S. mutans counts were determined. Data were analyzed with independent t-tests, analysis of variance, and Fisher's least significant difference test. RESULTS: In both groups, S. mutans counts on the first day, second week, and fourth weeks after the intervention were significantly lower than baseline values (P < 0.05). The greatest level of reduction in both groups was observed in the second week after the intervention. Moreover, although the reduction was greater in probiotic yogurt consumers, the difference between the two groups was not statistically significant. CONCLUSION: Probiotic yogurt and xylitol-containing chewing gums seem to be as effective in reduction of salivary S. mutans levels. Their constant long-term consumption is thus recommended to prevent caries. PMID- 28650783 TI - Conservative Treatment of Multiple Keratocystic Odontogenic Tumors in a Young Patient with Nevoid Basal Cell Carcinoma Syndrome by Decompression: A 7-year Follow-up Study. AB - Multiple keratocystic odontogenic tumors (KCOT) occurred in a young child is challenging problem in the field of pediatric dentistry, and might have been related to nevoid basal cell carcinoma syndrome (NBCCS). Because of high recurrence rate of KCOTs, complete surgical resection is generally accepted as definitive treatment. However, complete surgical resection could induce negative effect on the development of permanent teeth and growth of jaw. Herein, we reported successful treatment case of young KCOT patient with NBCCS. Although multiple KCOTs occurred continually, the majority of the lesions healed well by decompression and important anatomical structures and permanent teeth were successfully preserved. The purpose of this paper is to report more conservative treatment of multiple keratocystic odontogenic tumors (KCOTs) by repeated decompressions with later peripheral ostectomy during a 7-year follow-up. PMID- 28650784 TI - SEM Analysis of Residual Dentin Surface in Primary Teeth Using Different Chemomechanical Caries Removal Agents. AB - BACKGROUND: The purpose of this in vitro study was to analyze the residual dentinal surfaces following caries removal using two chemomechanical methods (Papacarie Duo and Carie Care), by scanning electron microscopy (SEM). STUDY DESIGN: Twenty extracted primary molars with active occlusal carious lesions were randomly assigned two groups depending on the CMCR agent used for the caries excavation - Group 1 - with Papacarie Duo and Group - 2 with Carie Care. After the caries excavation, the specimens were subjected to SEM analysis. RESULTS: Though both the agents showed the minimal smear layer with the patent dentinal tubules, Carie care showed patent dentinal tubules with a clearly exposed peritubular and intertubular collagen network. CONCLUSION: Carie Care treated surface exhibited better surface morphology of residual dentin. PMID- 28650785 TI - Clinical Performance of Heat-Cured High-Viscosity Glass Ionomer Class II Restorations in Primary Molars: A Preliminary Study. AB - OBJECTIVES: The present preliminary study evaluated the clinical and radiographic performances of heat-cured high viscosity glass ionomer (HCHVGI) in class II restorations of primary molars. STUDY DESIGN: A retrospective study on a cohort of patients who had dental caries restored at a private practice was conducted. Restorations were evaluated radiographically and photographically by two separate examiners. RESULTS: Ninety-three Class II restorations in 44 patients (average age: 108 months +/- 25.3, 24 males, 20 females) were examined. Average recall time was 22.2 months +/- 4.2. All but three restorations (96.8%) were present and intact, with no incidents of secondary caries. Three additional restorations had occlusal defects that required retreatment, resulting in an overall success rate of 93.5%. Ninety-seven percent of the restorations were rated optimal for marginal integrity with no staining of the restoration surfaces. No patients complained of post-operative sensitivity. The most common flaw found was a concavity on the proximal wall of the cavity box (27%, mean age 16 months +/- 3.9). CONCLUSION: The findings in this preliminary study suggest that heat cured high viscosity glass ionomer cement may be an effective restorative material for Class II restorations in primary molars that are a year or two from shedding. PMID- 28650786 TI - Alveolar Fracture Caused by Tooth Extraction at Home. AB - Injuries to the teeth and surrounding structures are relatively common. Although traumatic injuries caused by falls or activities related to sports are widely discussed, the same cannot be said regarding accidents arising from non professional extraction of primary teeth. The present study reports a 6-year-old male child who underwent mandibular alveolar bone fracture during non professional extraction of his central lower left incisor at home, performed by his 30-year-old aunt. The root of the tooth was with an irregular physiological resorption, which acted as a lever component for the mechanical force applied, leading to bone fracture. Although not common, the possibility that dental roots with irregular resorption can act as a possible risk factor for accidents if the parents or guardians of children during the period of transitional dentition try to perform intentional extraction of primary teeth should be highlighted. Parents should always consult a professional, preferably a pediatric dentist, for monitoring this period of transitional dentition. PMID- 28650787 TI - The Effect of Casein Phosphopeptide-Amorf Calcium Phosphate and Acidulated Phosphate Fluoride Gel on Dental Erosion in Primary Teeth: An in Vitro Study. AB - OBJECTIVE: This study aimed to investigate the effect of acidulated phosphate fluoride (APF) gel and casein phosphopeptide/amorphous calciumphosphate (CPP-ACP) on the dental erosion produced by carbonated soft drink in primary teeth. STUDY DESIGN: This study evaluated by an in vitro model the effect of APF gel and CPP ACP on the dental enamel previously subjected to erosive challenge with carbonated soft drink. Sixty sound human primary molars were prepared by embedding the crown sections in acrylic resin blocks leaving the enamel surfaces exposed. The surface roughness of the enamel was measured with prophilometry at baseline. Specimens were randomly divided into three treatment groups (n:20): artificial saliva, CPP-ACP, 1.23% APF gel. All specimens were then exposed to an erosive challenge of carbonated soft drink and artificial saliva for 20 cycles of 20 seconds each. Demineralization-remineralization cycles was repeated twice at eight-hour intervals and roughness values were measured. Enamel samples were treated with artificial saliva, CPP-ACP, 1.23% APF gel applied for 10 min after erosive challenge. The arithmetic average roughness (Ra) readings were recorded after remineralization agents were applied. RESULTS: The mean surface roughness in all groups increased significantly after erosion process and decreased after remineralization treatment. After treatment, the mean surface roughness of the 1.23% APF gel group was significantly less than the other groups and the mean surface roughness of the artificial saliva group was significantly more than the other groups. 1.23% APF gel showed the highest protective effect against erosive enamel loss. CONCLUSIONS: Under the conditions of this study, artificial saliva, CPP-ACP and 1.23% APF treatments were able to reduce erosive enamel loss produced by carbonated soft drink in primary teeth. However, 1.23% APF gel showed the highest protective effect against erosive enamel loss. PMID- 28650788 TI - Comparison of the Antimicrobial Efficacy of the EndoVac System and Conventional Needle Irrigation in Primary Molar Root Canals. AB - PURPOSE: The purpose of this study was to compare the antimicrobial efficacy of the EndoVac system and conventional needle irrigation to eliminate E faecalis in primary molar root canals. STUDY DESIGN: 60 extracted human primary second molar roots were instrumented up to an apical size .04/35 and randomly divided into two groups; Group 1: conventional needle (n=30) and Group 2: EndoVac (n=30), and four subgroups (two experimental subgroups; (a) 2.5% sodium hypochlorite (NaOCl) + ethylenediaminetetraacetic acid (EDTA) (n=20), (b) ozonated water (OW) + EDTA (n=20), and control groups (c) 5.25% NaOCl (n=10) and (d) saline (n=10). All roots were sterilized and then inoculated with E.faecalis. Before and after final irrigation procedures, root canals were sampled and the grown colony forming units (CFUs) were counted. Data were analyzed by Kruskall-Wallis and Mann-Whitney U tests using a 0.05 significance level. RESULTS: The EndoVac reduced more bacteria than the conventional needle did but it was not statistically significant (p>0.05). NaOCl alone or followed by EDTA totally eliminated bacteria. OW + EDTA showed higher reduction of bacteria but could not totally eliminate bacterias. CONCLUSIONS: In the context of bacterial elimination, the EndoVac was not significantly better than the conventional needle. Although, there were fewer CFU/mg when using EndoVac, there was not any statistically significant superiority to conventional needle irrigation. An OW+EDTA regimen showed antibacterial effect in the primary molar root canals but it was significantly less effective than NaOCl+EDTA. PMID- 28650789 TI - Effects of Cola-Flavored Beverages and Caffeine on Streptococcus mutans Biofilm Formation and Metabolic Activity. AB - OBJECTIVE: To examine the effects of cola-flavored beverages and caffeine on growth and metabolism of Streptococcus mutans biofilm. This study was designed to determine if carbonated beverages or caffeine can increase S. mutans growth and biofilm formation and metabolic activity in vitro, potentially leading to increased S. mutans-associated cariogenicity in children that consume them. STUDY DESIGN: Six different cola-flavored products, plus pure caffeine, and pure high fructose corn syrup (HFCS), at different concentrations similar to those in the beverages were tested. A 16-hour culture of S. mutans was treated with different dilutions in bacteriological media. To test for the effect on biofilm formation, the biofilm was stained with crystal violet. The absorbance was determined to evaluate biofilm growth. Biofilm metabolic activity was measured based on biofilm having the ability to reduce XTT to a water-soluble orange compound. RESULTS: The inclusion of HFCS in the beverages, as well as pure HFCS, significantly enhanced bacterial biofilm formation and metabolic activity. Pure caffeine and the presence of caffeine in beverages did not significantly increase biofilm formation, but pure caffeine significantly increased metabolism, and Diet Coke had significantly greater metabolic activity than Caffeine-Free Diet Coke. CONCLUSIONS: HFCS increases both the biofilm formation and metabolism of S. mutans, and caffeine in some cases increases metabolism of S. mutans. PMID- 28650790 TI - Perception of Complete Visually Impaired Children to Three Different Oral Health Education Methods: A Preliminary Study. AB - AIM: To evaluate the perception of visually impaired children to three different methods of oral health education. STUDY DESIGN: Sixty total visually impaired children were divided into three groups of 20 children each. Children in group-I received oral health education through a lecture. Children in group II received Demonstration on a Model by Tell and Touch method (DMTT) and children in group III were self trained on oral hygiene skills. All children received written instructions in Braille. Their knowledge and practice of oral hygiene methods were recorded by a questionnaire and their method of brushing and rinsing was assessed during a personal interview. Data obtained was subjected to statistical analysis. RESULTS: Children in group II were able to brush and rinse significantly better (p <0.05) as compared to the other groups. Demonstration on a Model by Tell and Touch method was found to be the most preferred method of oral health education. CONCLUSION: Oral health education given through DMTT method was perceived well by the visually impaired children. PMID- 28650791 TI - Deproteinizing Agents as an Effective Enamel Bond Enhancer-An in Vitro Study. AB - OBJECTIVE: The aim of this study was to compare the effect of different deproteinizing agents on shear bond strength of composite to primary teeth enamel. STUDY DESIGN: Forty sound primary molars divided in 4 groups of 10 teeth each. In control group 1, enamel was etched for 60 seconds with 37% phosphoric acid and rinsed with water. Group 2: after acid etching deproteinizing agent 5 % sodium hypochlorite was applied for 60 seconds and rinsed. Group 3: after acid etching deproteinizing agent papain gel was applied for 60 seconds and rinsed. Group 4: after acid etching deproteinizing agent bromelain gel applied for 60 seconds and rinsed. Following this, bonding agent was applied to treated enamel surface and composite resin disc were build. Samples were then tested for shear bond strength using Universal Testing Machine. RESULTS: Mean SBS was highest for group 4 and lowest for group 1. No statistically significant difference (p value >0.05) was found between all the four groups. CONCLUSION: Among deproteinizing agents, deproteinization when carried out with bromelain gel and sodium hypochlorite showed effective bond strength as compared to papain. PMID- 28650792 TI - Imipridone family on successful TRAIL. PMID- 28650794 TI - The Great Occlusion Fiasco. PMID- 28650795 TI - Quantitation of Mandibular Symphysis Bone as Source of Bone Grafting: Description in Class I and Class III Skeletal Conditions. AB - The aim of this study was to quantify the cortical and cancellous bone in the mandibular symphysis and relate it to the teeth and to the skeletal class. A descriptive study was conducted using cone beam computerized tomography (CBCT). Class I and class III subjects were included, defined according to dental occlusion and cephalogram results. Linear measurements were taken on the CBCT of the mandibular canines, lateral incisors, and central incisors, where the analysis was related to the axial and apical axes considering the bone in relation to the dental area. With previous definitions, an observer took 2 measurements of the height of the mandibular symphysis, cortical bone of the buccal and lower region, and thickness of cancellous bone at different levels; the correlation coefficient between the first and second measurement was 0.99 and presented P = .001. The results were analyzed with analysis of variance and Tukey's honest significant difference test, with P < .05 being statistically significant. The symphysis height was significantly greater in class III subjects. The cortical bone was an average 1.67 +/- 0.44 mm in vertical distance in the skeletal class I group and 1.74 +/- 0.47 mm in the class III group. The cancellous bone had an average width of 5.03 +/- 1.94 mm in the skeletal class I group and 4.74 +/- 2.05 mm in the class III group. It was observed that cancellous bone was significantly thicker at the incisor level than at the canine level. There were anatomical differences between skeletal class I and class III subjects, although the clinical significance may be questionable. With the values from these analyses, it may be concluded that there are no significant differences in quantitation of the cortical and cancellous bone in the anterior mandibular symphysis. PMID- 28650793 TI - A systematic review of the technology-based assessment of visual perception and exploration behaviour in association football. AB - To visually perceive opportunities for action, athletes rely on the movements of their eyes, head and body to explore their surrounding environment. To date, the specific types of technology and their efficacy for assessing the exploration behaviours of association footballers have not been systematically reviewed. This review aimed to synthesise the visual perception and exploration behaviours of footballers according to the task constraints, action requirements of the experimental task, and level of expertise of the athlete, in the context of the technology used to quantify the visual perception and exploration behaviours of footballers. A systematic search for papers that included keywords related to football, technology, and visual perception was conducted. All 38 included articles utilised eye-movement registration technology to quantify visual perception and exploration behaviour. The experimental domain appears to influence the visual perception behaviour of footballers, however no studies investigated exploration behaviours of footballers in open-play situations. Studies rarely utilised representative stimulus presentation or action requirements. To fully understand the visual perception requirements of athletes, it is recommended that future research seek to validate alternate technologies that are capable of investigating the eye, head and body movements associated with the exploration behaviours of footballers during representative open-play situations. PMID- 28650796 TI - Comparison of Bovine Bone-Autogenic Bone Mixture Versus Platelet-Rich Fibrin for Maxillary Sinus Grafting: Histologic and Histomorphologic Study. AB - Numerous grafting materials have been used to augment the maxillary sinus floor for long-term stability and success for implant-supported prosthesis. To enhance bone formation, adjunctive blood-born growth factor sources have gained popularity during the recent years. The present study compared the use of platelet-rich fibrin (PRF) and bovine-autogenous bone mixture for maxillary sinus floor elevation. A split-face model was used to apply 2 different filling materials for maxillary sinus floor elevation in 22 healthy adult sheep. In group 1, bovine and autogenous bone mixture; and in group 2, PRF was used. The animals were killed at 3, 6, and 9 months. Histologic and histomorphologic examinations revealed new bone formation in group 1 at the third and sixth months. In group 2, new bone formation was observed only at the sixth month, and residual PRF remnants were identified. At the ninth month, host bone and new bone could not be distinguished from each other in group 1, and bone formation was found to be proceeding in group 2. PRF remnants still existed at the ninth month. In conclusion, bovine bone and autogenous bone mixture is superior to PRF as a grafting material in sinus-lifting procedures. PMID- 28650798 TI - Coherent Semantic-Visual Indexing for Large-Scale Image Retrieval in the Cloud. AB - The rapidly increasing number of images on the internet has further increased the need for efficient indexing for digital image searching of large databases. The design of a cloud service that provides high efficiency but compact image indexing remains challenging, partly due to the well-known semantic gap between user queries and the rich semantics of large-scale data sets. In this paper, we construct a novel joint semantic-visual space by leveraging visual descriptors and semantic attributes, which narrows the semantic gap by combining both attributes and indexing into a single framework. Such a joint space embraces the flexibility of coherent semantic-visual indexing, which employs binary codes to boost retrieval speed while maintaining accuracy. To solve the proposed model, we make the following contributions. First, we propose an interactive optimization method to find the joint semantic and visual descriptor space. Second, we prove convergence of our optimization algorithm, which guarantees a good solution after a certain number of iterations. Third, we integrate the semantic-visual joint space system with spectral hashing, which finds an efficient solution to search up to billion-scale data sets. Finally, we design an online cloud service to provide a more efficient online multimedia service. Experiments on two standard retrieval datasets (i.e., Holidays1M, Oxford5K) show that the proposed method is promising compared with the current state-of-the-art and that the cloud system significantly improves performance. PMID- 28650797 TI - LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs. AB - The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5'TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5'TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5' and 3'UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5'UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3'UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis. PMID- 28650799 TI - Learning the Personalized Intransitive Preferences of Images. AB - Most of the previous studies on the user preferences assume that there is a personal transitive preference ranking of the consumable media like images. For example, the transitivity of preferences is one of the most important assumptions in the recommender system research. However, the intransitive relations have also been widely observed, such as the win/loss relations in online video games, in sport matches, and even in rock-paper-scissors games. It is also found that different subjects demonstrate the personalized intransitive preferences in the pairwise comparisons between the applicants for college admission. Since the intransitivity of preferences on images has barely been studied before and has a large impact on the research of personalized image search and recommendation, it is necessary to propose a novel method to predict the personalized intransitive preferences of images. In this paper, we propose the novel Multi-Criterion preference (MuCri) models to predict the intransitive relations in the image preferences. The MuCri models utilize different kinds of image content features as well as the latent features of users and images. Meanwhile, a new data set is constructed in this paper, in order to evaluate the performance of the MuCri models. The experimental evaluation shows that the MuCri models outperform all the baselines. Due to the interdisciplinary nature of this topic, we believe it would widely attract the attention of researchers in the image processing community as well as in other communities, such as machine learning, multimedia, and recommender system. PMID- 28650800 TI - Depth-Aware Salient Object Detection and Segmentation via Multiscale Discriminative Saliency Fusion and Bootstrap Learning. AB - This paper proposes a novel depth-aware salient object detection and segmentation framework via multiscale discriminative saliency fusion (MDSF) and bootstrap learning for RGBD images (RGB color images with corresponding Depth maps) and stereoscopic images. By exploiting low-level feature contrasts, mid-level feature weighted factors and high-level location priors, various saliency measures on four classes of features are calculated based on multiscale region segmentation. A random forest regressor is learned to perform the discriminative saliency fusion (DSF) and generate the DSF saliency map at each scale, and DSF saliency maps across multiple scales are combined to produce the MDSF saliency map. Furthermore, we propose an effective bootstrap learning-based salient object segmentation method, which is bootstrapped with samples based on the MDSF saliency map and learns multiple kernel support vector machines. Experimental results on two large datasets show how various categories of features contribute to the saliency detection performance and demonstrate that the proposed framework achieves the better performance on both saliency detection and salient object segmentation. PMID- 28650801 TI - 300-FPS Salient Object Detection via Minimum Directional Contrast. AB - Global contrast considers the color difference between a target region or pixel and the rest of the image. It is frequently used to measure the saliency of the region or pixel. In previous global contrast-based methods, saliency is usually measured by the sum of contrast from the entire image. We find that the spatial distribution of contrast is one important cue of saliency that is neglected by previous works. Foreground pixel usually has high contrast from all directions, since it is surrounded by the background. Background pixel often shows low contrast in at least one direction, as it has to connect to the background. Motivated by this intuition, we first compute directional contrast from different directions for each pixel, and propose minimum directional contrast (MDC) as raw saliency metric. Then an O(1) computation of MDC using integral image is proposed. It takes only 1.5 ms for an input image of the QVGA resolution. In saliency post-processing, we use marker-based watershed algorithm to estimate each pixel as foreground or background, followed by one linear function to highlight or suppress its saliency. Performance evaluation is carried on four public data sets. The proposed method significantly outperforms other global contrast-based methods, and achieves comparable or better performance than the state-of-the-art methods. The proposed method runs at 300 FPS and shows six times improvement in runtime over the state-of-the-art methods. PMID- 28650802 TI - Translational Motion Tracking of Leg Joints for Enhanced Prediction of Walking Tasks. AB - OBJECTIVE: Walking task prediction in powered leg prostheses is an important problem in the development of biomimetic prosthesis controllers. This paper proposes a novel method to predict upcoming walking tasks by estimating the translational motion of leg joints using an integrated inertial measurement unit. METHODS: We asked six subjects with unilateral transtibial amputations to traverse flat ground, ramps, and stairs using a powered prosthesis while inertial signals were collected. We then performed an offline analysis in which we simulated a real-time motion tracking algorithm on the inertial signals to estimate knee and ankle joint translations, and then used pattern recognition separately on the inertial and translational signal sets to predict the target walking tasks of individual strides. RESULTS: Our analysis showed that using inertial signals to derive translational signals enabled a prediction error reduction of 6.8% compared to that attained using the original inertial signals. This result was similar to that seen by addition of surface electromyography sensors to integrated sensors in previous work, but was effected without adding any extra sensors. Finally, we reduced the size of the translational set to that of the inertial set and showed that the former still enabled a composite error reduction of 5.8%. CONCLUSION AND SIGNIFICANCE: These results indicate that translational motion tracking can be used to substantially enhance walking task prediction in leg prostheses without adding external sensing modalities. Our proposed algorithm can thus be used as a part of a task-adaptive and fully integrated prosthesis controller. PMID- 28650803 TI - Challenges in Improving Cochlear Implant Performance and Accessibility. AB - Here I identify two gaps in cochlear implants that have been limiting their performance and acceptance. First, cochlear implant performance has remained largely unchanged, despite the number of publications tripling per decade in the last 30 years. Little has been done so far to address a fundamental limitation in the electrode-to-neuron interface, with the electrode size being a thousand times larger than the neuron diameter while the number of electrodes being a thousand times less. Both the small number and the large size of electrodes produce broad spatial activation and poor frequency resolution that limit current cochlear implant performance. Second, a similarly rapid growth in cochlear implant volume has not produced an expected decrease in unit price in the same period. The high cost contributes to low market penetration rate, which is about 20% in developed countries and less than 1% in developing countries. I will discuss changes needed in both research strategy and business practice to close the gap between prosthetic and normal hearing as well as that between haves and have-nots. PMID- 28650804 TI - Limb Position Tolerant Pattern Recognition for Myoelectric Prosthesis Control with Adaptive Sparse Representations From Extreme Learning. AB - : Myoelectric signals can be used to predict the intended movements of an amputee for prosthesis control. However, untrained effects like limb position changes influence myoelectric signal characteristics, hindering the ability of pattern recognition algorithms to discriminate among motion classes. Despite frequent and long training sessions, these deleterious conditional influences may result in poor performance and device abandonment. GOAL: We present a robust sparsity-based adaptive classification method that is significantly less sensitive to signal deviations resulting from untrained conditions. METHODS: We compare this approach in the offline and online contexts of untrained upper-limb positions for amputee and able-bodied subjects to demonstrate its robustness compared against other myoelectric classification methods. RESULTS: We report significant performance improvements () in untrained limb positions across all subject groups. SIGNIFICANCE: The robustness of our suggested approach helps to ensure better untrained condition performance from fewer training conditions. CONCLUSIONS: This method of prosthesis control has the potential to deliver real-world clinical benefits to amputees: better condition-tolerant performance, reduced training burden in terms of frequency and duration, and increased adoption of myoelectric prostheses. PMID- 28650805 TI - An In Vitro and Numerical Study of Moxibustion Therapy on Biological Tissue. AB - OBJECTIVE: Moxibustion therapy achieves satisfactory therapeutic effects largely depending on the heat stimulation of burning moxa. Understanding the thermal characteristics of heating process is an effective way to reveal the underlying mechanisms of moxibustion therapy. METHODS: This paper performs experimental study on temperature distributions of burning moxa sticks and fresh in vitro porcine abdominal tissue using an infrared camera and thermocouples. Meanwhile, a moxibustion model incorporating moxa stick burning model and tissue heat transfer model was established with consideration of radiation propagation and water evaporation. RESULTS: The burning features of moxa sticks were acquired and the radiation energy generated by the burning moxa stick was absorbed and scattered in biological tissue, resulting in a large temperature gradient in the skin layer. And the water evaporation led to a mass loss and reduced skin surface temperature. The numerical model was verified by experimental results and the effects of moxibustion treatment distance and duration can be quantified based on model calculation. CONCLUSION: The detailed heat transfer process of moxibustion was obtained experimentally and numerically. During moxibustion, the radiation attenuation and water evaporation have a significant influence on the energy transport in biological tissue which cannot be ignored. The treatment distance of 3 cm is the recommended value to achieve the treatment efficacy without thermal damage and pain. SIGNIFICANCE: This research would reveal the underlying mechanisms of moxibustion therapy. Besides, the developed models are expected to establish a guideline for moxibustion clinical treatment. PMID- 28650806 TI - 3-D Active Contour Segmentation Based on Sparse Linear Combination of Training Shapes (SCoTS). AB - SCoTS captures a sparse representation of shapes in an input image through a linear span of previously delineated shapes in a training repository. The model updates shape prior over level set iterations and captures variabilities in shapes by a sparse combination of the training data. The level set evolution is therefore driven by a data term as well as a term capturing valid prior shapes. During evolution, the shape prior influence is adjusted based on shape reconstruction, with the assigned weight determined from the degree of sparsity of the representation. For the problem of lung nodule segmentation in X-ray CT, SCoTS offers a unified framework, capable of segmenting nodules of all types. Experimental validations are demonstrated on 542 3-D lung nodule images from the LIDC-IDRI database. Despite its generality, SCoTS is competitive with domain specific state of the art methods for lung nodule segmentation. PMID- 28650807 TI - Simultaneous Ultrasound Therapy and Monitoring of Microbubble-Seeded Acoustic Cavitation Using a Single-Element Transducer. AB - Ultrasound-driven microbubble (MB) activity is used in therapeutic applications such as blood clot dissolution and targeted drug delivery. The safety and performance of these technologies are linked to the type and distribution of MB activities produced within the targeted area, but controlling and monitoring these activities in vivo and in real time has proven to be difficult. As therapeutic pulses are often milliseconds long, MB monitoring currently requires a separate transducer used in a passive reception mode. Here, we present a simple, inexpensive, integrated setup, in which a focused single-element transducer can perform ultrasound therapy and monitoring simultaneously. MBs were made to flow through a vessel-mimicking tube, placed within the transducer's focus, and were sonicated with therapeutic pulses (peak rarefactional pressure: 75-827 kPa, pulse lengths: [Formula: see text] and 20 ms). The MB-seeded acoustic emissions were captured using the same transducer. The received signals were separated from the therapeutic signal with a hybrid coupler and a high-pass filter. We discriminated the MB-generated cavitation signal from the primary acoustic field and characterized MB behavior in real time. The simplicity and versatility of our circuit could make existing single-element therapeutic transducers also act as cavitation detectors, allowing the production of compact therapeutic systems with real time monitoring capabilities. PMID- 28650808 TI - Histotripsy Treatment of S. Aureus Biofilms on Surgical Mesh Samples Under Varying Pulse Durations. AB - Prior studies demonstrated that histotripsy generated by high-intensity tone bursts to excite a bubble cloud adjacent to a medical implant can destroy the bacteria biofilm responsible for the infection. The goal of this paper was to treat Staphylococcus aureus (S. aureus) biofilms on surgical mesh samples while varying the number of cycles in the tone burst to minimize collateral tissue damage while maximizing therapy effectiveness. S. aureus biofilms were grown on 1 cm square surgical mesh samples. The biofilms were then treated in vitro using a spherically focused transducer (1.1 MHz, 12.9-cm focal length, 12.7-cm diameter) using either a sham exposure or histotripsy pulses with tone burst durations of 3, 5, or 10 cycles (pulse repetition frequency of 333 Hz, peak compressional pressure of 150 MPa, peak rarefactional pressure of 17 MPa). After treatment, the number of colony forming units (CFUs) on the mesh and the surrounding gel was independently determined. The number of CFUs remaining on the mesh for the sham exposure (4.8 +/- 0.9-log10) (sample mean +/- sample standard deviation-log10 from 15 observations) was statistically significantly different from the 3-cycle (1.9 +/- 1.5-log10), 5-cycle (2.2 +/- 1.1-log10), and 10-cycle exposures (1 +/- 1.5-log10) with an average reduction in the number of CFUs of 3.1-log10. The numbers of CFUs released into the gel for both the sham and exposure groups were the same within a bound of 0.86-log10, but this interval was too large to deduce the fate of the bacteria in the biofilm following the treatment. PMID- 28650809 TI - Beam Diffraction Effects in the Backward Wave Regions of Viscoelastic Leaky Lamb Modes for Plate Transmission at Normal Incidence. AB - Plane-wave theory for fluid-embedded isotropic plates is often used in ultrasonic guided-wave applications, and to estimate wall thickness, corrosion, or sound velocities in plates and pipes. In such structures, measured ultrasonic transmission through the solid material is affected by acoustic beam diffraction effects, and the results may deviate from plane-wave descriptions, which are insufficient to describe the complex effects that occur. When exciting a fluid embedded steel plate with a pulsed ultrasonic beam at normal incidence, resonance frequency downshift, axial sound pressure level increase, and beam narrowing have been observed, for measured resonance peaks in the frequency regions of certain leaky Lamb mode branches of the plate. In the ranges of other leaky Lamb mode branches, the observed effects are different. Measurements, finite element, and angular spectrum modeling are used to indicate a close connection between these beam diffraction phenomena and the backward wave characteristics of certain leaky Lamb mode pairs, in the frequency and Poisson's ratio regions around coincidence of two Lamb mode cutoff frequencies of similar symmetry. In particular, such observations made for the steel plate's fundamental thickness-extensional (TE) mode appear to be caused by acoustic beam excitation of the backward wave regions of the S-2vl and S2vl leaky Lamb modes. PMID- 28650810 TI - Expanding Acquisition and Clutter Filter Dimensions for Improved Perfusion Sensitivity. AB - A method is explored for increasing the sensitivity of power-Doppler imaging without contrast enhancement. We acquire 1-10 s of echo signals and arrange it into a 3-D spatiotemporal data array. An eigenfilter developed to preserve all three dimensions of the array yields power estimates for blood flow and perfusion that are well separated from tissue clutter. This method is applied at high frequency (24-MHz pulses) to a murine model of an ischemic hindlimb. We demonstrate enhancements to tissue perfusion maps in normal and ischemic tissues. The method can be applied to data from any ultrasonic instrument that provides beamformed RF echo data. PMID- 28650811 TI - Regularized Spectral Log Difference Technique for Ultrasonic Attenuation Imaging. AB - The attenuation coefficient slope (ACS) has the potential to be used for tissue characterization and as a diagnostic ultrasound tool, hence complementing B-mode images. The ACS can be valuable for the estimation of other ultrasound parameters such as the backscatter coefficient. There is a well-known tradeoff between the precision of the estimated ACS values and the data block size used in the spectral-based techniques such as the spectral-log difference (SLD). This tradeoff limits the practical usefulness of the spectral-based attenuation imaging techniques. In this paper, the regularized SLD (RSLD) technique is presented in detail, and evaluated with simulations and experiments with physical phantoms, ex vivo and in vivo. The RSLD technique allowed decreasing estimation variance when using small data block sizes, i.e., fivefold reduction in the standard deviation of percentage error when using data block sizes larger than and more than a tenfold reduction when using data blocks. The precision improvement was obtained without sacrificing estimation accuracy (i.e., estimation bias improved in 70% of the cases by 10% of the ground truth-value on average while degraded in 30% of the cases by 3% of the ground truth-value on average). The improvements in precision allowed for better differentiation of inclusions especially when using small data blocks (i.e., smaller than ) where the contrast-to-noise ratio improved by an order of magnitude on average. The results suggest that the RSLD allows for the reconstruction of attenuation coefficient images with an improved tradeoff between spatial resolution and estimation precision. PMID- 28650812 TI - Alpha Matting With KL-Divergence-Based Sparse Sampling. AB - In this paper, we present a new sampling-based alpha matting approach for the accurate estimation of foreground and background layers of an image. Previous sampling-based methods typically rely on certain heuristics in collecting representative samples from known regions, and thus their performance deteriorates if the underlying assumptions are not satisfied. To alleviate this, we take an entirely new approach and formulate sampling as a sparse subset selection problem where we propose to pick a small set of candidate samples that best explains the unknown pixels. Moreover, we describe a new dissimilarity measure for comparing two samples which is based on KL-divergence between the distributions of features extracted in the vicinity of the samples. The proposed framework is general and could be easily extended to video matting by additionally taking temporal information into account in the sampling process. Evaluation on standard benchmark data sets for image and video matting demonstrates that our approach provides more accurate results compared with the state-of-the-art methods. PMID- 28650813 TI - Knowledge-Based Topic Model for Unsupervised Object Discovery and Localization. AB - Unsupervised object discovery and localization is to discover some dominant object classes and localize all of object instances from a given image collection without any supervision. Previous work has attempted to tackle this problem with vanilla topic models, such as latent Dirichlet allocation (LDA). However, in those methods no prior knowledge for the given image collection is exploited to facilitate object discovery. On the other hand, the topic models used in those methods suffer from the topic coherence issue-some inferred topics do not have clear meaning, which limits the final performance of object discovery. In this paper, prior knowledge in terms of the so-called must-links are exploited from Web images on the Internet. Furthermore, a novel knowledge-based topic model, called LDA with mixture of Dirichlet trees, is proposed to incorporate the must links into topic modeling for object discovery. In particular, to better deal with the polysemy phenomenon of visual words, the must-link is re-defined as that one must-link only constrains one or some topic(s) instead of all topics, which leads to significantly improved topic coherence. Moreover, the must-links are built and grouped with respect to specific object classes, thus the must-links in our approach are semantic-specific, which allows to more efficiently exploit discriminative prior knowledge from Web images. Extensive experiments validated the efficiency of our proposed approach on several data sets. It is shown that our method significantly improves topic coherence and outperforms the unsupervised methods for object discovery and localization. In addition, compared with discriminative methods, the naturally existing object classes in the given image collection can be subtly discovered, which makes our approach well suited for realistic applications of unsupervised object discovery.Unsupervised object discovery and localization is to discover some dominant object classes and localize all of object instances from a given image collection without any supervision. Previous work has attempted to tackle this problem with vanilla topic models, such as latent Dirichlet allocation (LDA). However, in those methods no prior knowledge for the given image collection is exploited to facilitate object discovery. On the other hand, the topic models used in those methods suffer from the topic coherence issue-some inferred topics do not have clear meaning, which limits the final performance of object discovery. In this paper, prior knowledge in terms of the so-called must-links are exploited from Web images on the Internet. Furthermore, a novel knowledge-based topic model, called LDA with mixture of Dirichlet trees, is proposed to incorporate the must links into topic modeling for object discovery. In particular, to better deal with the polysemy phenomenon of visual words, the must-link is re-defined as that one must-link only constrains one or some topic(s) instead of all topics, which leads to significantly improved topic coherence. Moreover, the must-links are built and grouped with respect to specific object classes, thus the must-links in our approach are semantic-specific, which allows to more efficiently exploit discriminative prior knowledge from Web images. Extensive experiments validated the efficiency of our proposed approach on several data sets. It is shown that our method significantly improves topic coherence and outperforms the unsupervised methods for object discovery and localization. In addition, compared with discriminative methods, the naturally existing object classes in the given image collection can be subtly discovered, which makes our approach well suited for realistic applications of unsupervised object discovery. PMID- 28650814 TI - Multi-Label Classification by Semi-Supervised Singular Value Decomposition. AB - Multi-label problems arise in various domains, including automatic multimedia data categorization, and have generated significant interest in computer vision and machine learning community. However, existing methods do not adequately address two key challenges: exploiting correlations between labels and making up for the lack of labelled data or even missing labelled data. In this paper, we proposed to use a semi-supervised singular value decomposition (SVD) to handle these two challenges. The proposed model takes advantage of the nuclear norm regularization on the SVD to effectively capture the label correlations. Meanwhile, it introduces manifold regularization on mapping to capture the intrinsic structure among data, which provides a good way to reduce the required labelled data with improving the classification performance. Furthermore, we designed an efficient algorithm to solve the proposed model based on the alternating direction method of multipliers, and thus, it can efficiently deal with large-scale data sets. Experimental results for synthetic and real-world multimedia data sets demonstrate that the proposed method can exploit the label correlations and obtain promising and better label prediction results than the state-of-the-art methods. PMID- 28650815 TI - Joint Chroma Subsampling and Distortion-Minimization-Based Luma Modification for RGB Color Images With Application. AB - In this paper, we propose a novel and effective hybrid method, which joins the conventional chroma subsampling and the distortion-minimization-based luma modification together, to improve the quality of the reconstructed RGB full-color image. Assume the input RGB full-color image has been transformed to a YUV image, prior to compression. For each 2*2 UV block, one 4:2:0 subsampling is applied to determine the one subsampled U and V components, Us and Vs . Based on Us , Vs , and the corresponding 2*2 original RGB block, a main theorem is provided to determine the ideally modified 2*2 luma block in constant time such that the color peak signal-to-noise ratio (CPSNR) quality distortion between the original 2*2 RGB block and the reconstructed 2*2 RGB block can be minimized in a globally optimal sense. Furthermore, the proposed hybrid method and the delivered theorem are adjusted to tackle the digital time delay integration images and the Bayer mosaic images whose Bayer CFA structure has been widely used in modern commercial digital cameras. Based on the IMAX, Kodak, and screen content test image sets, the experimental results demonstrate that in high efficiency video coding, the proposed hybrid method has substantial quality improvement, in terms of the CPSNR quality, visual effect, CPSNR-bitrate trade-off, and Bjontegaard delta PSNR performance, of the reconstructed RGB images when compared with existing chroma subsampling schemes. PMID- 28650816 TI - Collision Avoidance Behavior between Walkers: Global and Local Motion Cues. AB - Daily activities require agents to interact with each other, such as during collision avoidance. The nature of visual information that is used for a collision free interaction requires further understanding. We aim to manipulate the nature of visual information in two forms, global and local information appearances. Sixteen healthy participants navigated towards a target in an immersive computer-assisted virtual environment (CAVE) using a joystick. A moving passive obstacle crossed the participant's trajectory perpendicularly at various pre-defined risks of collision distances. The obstacle was presented with one of five virtual appearances, associated to global motion cues (i.e., a cylinder or a sphere), or local motion cues (i.e., only the legs or the trunk). A full body virtual walker, showing both local and global motion cues, used as a reference condition. The final crossing distance was affected by the global motion appearances, however, appearance had no qualitative effect on motion adaptations. These findings contribute towards further understanding what information people use when interacting with others. PMID- 28650817 TI - MemAxes: Visualization and Analytics for Characterizing Complex Memory Performance Behaviors. AB - Memory performance is often a major bottleneck for high-performance computing (HPC) applications. Deepening memory hierarchies, complex memory management, and non-uniform access times have made memory performance behavior difficult to characterize, and users require novel, sophisticated tools to analyze and optimize this aspect of their codes. Existing tools target only specific factors of memory performance, such as hardware layout, allocations, or access instructions. However, today's tools do not suffice to characterize the complex relationships between these factors. Further, they require advanced expertise to be used effectively. We present MemAxes, a tool based on a novel approach for analytic-driven visualization of memory performance data. MemAxes uniquely allows users to analyze the different aspects related to memory performance by providing multiple visual contexts for a centralized dataset. We define mappings of sampled memory access data to new and existing visual metaphors, each of which enabling a user to perform different analysis tasks. We present methods to guide user interaction by scoring subsets of the data based on known performance problems. This scoring is used to provide visual cues and automatically extract clusters of interest. We designed MemAxes in collaboration with experts in HPC and demonstrate its effectiveness in case studies. PMID- 28650818 TI - Sparse Geometric Representation Through Local Shape Probing. AB - We propose a new shape analysis approach based on the non-local analysis of local shape variations. Our method relies on a novel description of shape variations, called Local Probing Field (LPF), which describes how a local probing operator transforms a pattern onto the shape. By carefully optimizing the position and orientation of each descriptor, we are able to capture shape similarities and gather them into a geometrically relevant dictionary over which the shape decomposes sparsely. This new representation permits to handle shapes with mixed intrinsic dimensionality (e.g., shapes containing both surfaces and curves) and to encode various shape features such as boundaries. Our shape representation has several potential applications; here we demonstrate its efficiency for shape resampling and point set denoising for both synthetic and real data. PMID- 28650819 TI - Towards High-Quality Visualization of Superfluid Vortices. AB - Superfluidity is a special state of matter exhibiting macroscopic quantum phenomena and acting like a fluid with zero viscosity. In such a state, superfluid vortices exist as phase singularities of the model equation with unique distributions. This paper presents novel techniques to aid the visual understanding of superfluid vortices based on the state-of-the-art non-linear Klein-Gordon equation, which evolves a complex scalar field, giving rise to special vortex lattice/ring structures with dynamic vortex formation, reconnection, and Kelvin waves, etc. By formulating a numerical model with theoretical physicists in superfluid research, we obtain high-quality superfluid flow data sets without noise-like waves, suitable for vortex visualization. By further exploring superfluid vortex properties, we develop a new vortex identification and visualization method: a novel mechanism with velocity circulation to overcome phase singularity and an orthogonal-plane strategy to avoid ambiguity. Hence, our visualizations can help reveal various superfluid vortex structures and enable domain experts for related visual analysis, such as the steady vortex lattice/ring structures, dynamic vortex string interactions with reconnections and energy radiations, where the famous Kelvin waves and decaying vortex tangle were clearly observed. These visualizations have assisted physicists to verify the superfluid model, and further explore its dynamic behavior more intuitively. PMID- 28650820 TI - Terahertz Channel Model and Link Budget Analysis for Intrabody Nanoscale Communication. AB - Nanosized devices operating inside the human body open up new prospects in the healthcare domain. Invivo wireless nanosensor networks (iWNSNs) will result in a plethora of applications ranging from intrabody health-monitoring to drug delivery systems. With the development of miniature plasmonic signal sources, antennas, and detectors, wireless communications among intrabody nanodevices will expectedly be enabled at both the terahertz band (0.1-10 THz) as well as optical frequencies (400-750 THz). This result motivates the analysis of the phenomena affecting the propagation of electromagnetic signals inside the human body. In this paper, a rigorous channel model for intrabody communication in iWNSNs is developed. The total path loss is computed by taking into account the combined effect of the spreading of the propagating wave, molecular absorption from human tissues, as well as scattering from both small and large body particles. The analytical results are validated by means of electromagnetic wave propagation simulations. Moreover, this paper provides the first framework necessitated for conducting link budget analysis between nanodevices operating within the human body. This analysis is performed by taking into account the transmitter power, medium path loss, and receiver sensitivity, where both the THz and photonic devices are considered. The overall attenuation model of intrabody THz and optical frequency propagation facilitates the accurate design and practical deployment of iWNSNs. PMID- 28650821 TI - Detecting Essential Proteins Based on Network Topology, Gene Expression Data, and Gene Ontology Information. AB - The identification of essential proteins in protein-protein interaction (PPI) networks is of great significance for understanding cellular processes. With the increasing availability of large-scale PPI data, numerous centrality measures based on network topology have been proposed to detect essential proteins from PPI networks. However, most of the current approaches focus mainly on the topological structure of PPI networks, and largely ignore the gene ontology annotation information. In this paper, we propose a novel centrality measure, called TEO, for identifying essential proteins by combining network topology, gene expression profiles, and GO information. To evaluate the performance of the TEO method, we compare it with five other methods (degree, betweenness, NC, Pec, and CowEWC) in detecting essential proteins from two different yeast PPI datasets. The simulation results show that adding GO information can effectively improve the predicted precision and that our method outperforms the others in predicting essential proteins. PMID- 28650822 TI - Calculating the Expected Time to Eradicate HIV-1 Using a Markov Chain. AB - In this study, the expected time required to eradicate HIV-1 completely was found as the conditional absorbing time in a finite state space continuous-time Markov chain model. The Markov chain has two absorbing states: one corresponds to HIV eradication and another representing the possible disaster. This method allowed us to calculate the expected eradication time by solving systems of linear equations. To overcome the challenge of huge dimension of the problem, we applied a novel stop and resume technique. This technique also helped to stop the numerical computation whenever we wanted and continue later from that point until the final result was obtained. Our numerical study showed the dependence of the expected eradication time of HIV on the half-life of the latently infected cells and there agreed with the previous studies. The study predicted that when the half-life of the latent cells varied from 4.6 to 60 months, it took a mean 4.97 to 31.04 years with a corresponding standard deviation of 0.64 to 3.99 years to eradicate the latent cell reservoir. It also revealed the crucial dependence of eradication time on the initial number of latently infected cells. PMID- 28650823 TI - Bi-level and Bi-objective p-Median Type Problems for Integrative Clustering: Application to Analysis of Cancer Gene-Expression and Drug-Response Data. AB - Recent advances in high-throughput technologies have given rise to collecting large amounts of multidimensional heterogeneous data that provide diverse information on the same biological samples. Integrative analysis of such multisource datasets may reveal new biological insights into complex biological mechanisms and therefore remains an important research field in systems biology. Most of the modern integrative clustering approaches rely on independent analysis of each dataset and consensus clustering, probabilistic or statistical modeling, while flexible distance-based integrative clustering techniques are sparsely covered. We propose two distance-based integrative clustering frameworks based on bi-level and bi-objective extensions of the p-median problem. A hybrid branch-and cut method is developed to find global optimal solutions to the bi-level p-median model. As to the bi-objective problem, an -constraint algorithm is proposed to generate an approximation to the Pareto optimal set. Every solution found by any of the frameworks corresponds to an integrative clustering. We present an application of our approaches to integrative analysis of NCI-60 human tumor cell lines characterized by gene expression and drug activity profiles. We demonstrate that the proposed mathematical optimization-based approaches outperform some state-of-the-art and traditional distance-based integrative and non-integrative clustering techniques. PMID- 28650824 TI - Computing Manhattan Path-Difference MedianTrees: a Practical Local Search Approach. AB - Median tree problems are powerful tools for inferring large-scale phylogenetic trees that hold enormous promise for society at large. Such problems seek a median tree for a given collection of input trees under some problem-specific distance. Here, we introduce a median tree problem under the classic Manhattan path-difference distance. We show that this problem is NP-hard, devise an ILP formulation, and provide an effective local search heuristic that is based on solving a local search problem exactly. Our algorithm for the local search problem improves asymptotically by a factor of n on the best-known (naive) solution, where n is the overall number of taxa in the input trees. Finally, comparative phylogenetic studies using considerably large empirical data and an accuracy analysis for smaller phylogenetic trees reveal the ability of our novel heuristic. PMID- 28650825 TI - DENA: A Configurable Microarchitecture and Design Flow for Biomedical DNA-Based Logic Design. AB - DNA is known as the building block for storing the life codes and transferring the genetic features through the generations. However, it is found that DNA strands can be used for a new type of computation that opens fascinating horizons in computational medicine. Significant contributions are addressed on design of DNA-based logic gates for medical and computational applications but there are serious challenges for designing the medium and large-scale DNA circuits. In this paper, a new microarchitecture and corresponding design flow is proposed to facilitate the design of multistage large-scale DNA logic systems. Feasibility and efficiency of the proposed microarchitecture are evaluated by implementing a full adder and, then, its cascadability is determined by implementing a multistage 8-bit adder. Simulation results show the highlight features of the proposed design style and microarchitecture in terms of the scalability, implementation cost, and signal integrity of the DNA-based logic system compared to the traditional approaches. PMID- 28650826 TI - Delayed Feedback Control for Stabilization of Boolean Control Networks With State Delay. AB - In this brief, we study the delayed feedback stabilization problem for Boolean control networks (BCNs) with state delay. Using the semi-tensor product of matrices, some necessary and sufficient conditions are obtained. For the stabilization of BCNs, detailed procedure to construct the feedback controllers is also presented. We further derive the number of different feedback controllers, which can successfully stabilize the BCN in a finite time. Finally, an illustrative example is presented to show the effectiveness of our method. PMID- 28650827 TI - Neural Decomposition of Time-Series Data for Effective Generalization. AB - We present a neural network technique for the analysis and extrapolation of time series data called neural decomposition (ND). Units with a sinusoidal activation function are used to perform a Fourier-like decomposition of training samples into a sum of sinusoids, augmented by units with nonperiodic activation functions to capture linear trends and other nonperiodic components. We show how careful weight initialization can be combined with regularization to form a simple model that generalizes well. Our method generalizes effectively on the Mackey-Glass series, a data set of unemployment rates as reported by the U.S. Department of Labor Statistics, a time-series of monthly international airline passengers, the monthly ozone concentration in downtown Los Angeles, and an unevenly sampled time series of oxygen isotope measurements from a cave in north India. We find that ND outperforms popular time-series forecasting techniques, including long short-term memory network, echo-state networks, autoregressive integrated moving average (ARIMA), seasonal ARIMA, support vector regression with a radial basis function, and Gashler and Ashmore's model. PMID- 28650828 TI - Convex Formulation for Kernel PCA and Its Use in Semisupervised Learning. AB - In this brief, kernel principal component analysis (KPCA) is reinterpreted as the solution to a convex optimization problem. Actually, there is a constrained convex problem for each principal component, so that the constraints guarantee that the principal component is indeed a solution, and not a mere saddle point. Although these insights do not imply any algorithmic improvement, they can be used to further understand the method, formulate possible extensions, and properly address them. As an example, a new convex optimization problem for semisupervised classification is proposed, which seems particularly well suited whenever the number of known labels is small. Our formulation resembles a least squares support vector machine problem with a regularization parameter multiplied by a negative sign, combined with a variational principle for KPCA. Our primal optimization principle for semisupervised learning is solved in terms of the Lagrange multipliers. Numerical experiments in several classification tasks illustrate the performance of the proposed model in problems with only a few labeled data. PMID- 28650829 TI - Time-Varying System Identification Using an Ultra-Orthogonal Forward Regression and Multiwavelet Basis Functions With Applications to EEG. AB - A new parametric approach is proposed for nonlinear and nonstationary system identification based on a time-varying nonlinear autoregressive with exogenous input (TV-NARX) model. The TV coefficients of the TV-NARX model are expanded using multiwavelet basis functions, and the model is thus transformed into a time invariant regression problem. An ultra-orthogonal forward regression (UOFR) algorithm aided by mutual information (MI) is designed to identify a parsimonious model structure and estimate the associated model parameters. The UOFR-MI algorithm, which uses not only the observed data themselves but also weak derivatives of the signals, is more powerful in model structure detection. The proposed approach combining the advantages of both the basis function expansion method and the UOFR-MI algorithm is proved to be capable of tracking the change of TV parameters effectively in both numerical simulations and the real EEG data. PMID- 28650830 TI - Feature Selection Based on Neighborhood Discrimination Index. AB - Feature selection is viewed as an important preprocessing step for pattern recognition, machine learning, and data mining. Neighborhood is one of the most important concepts in classification learning and can be used to distinguish samples with different decisions. In this paper, a neighborhood discrimination index is proposed to characterize the distinguishing information of a neighborhood relation. It reflects the distinguishing ability of a feature subset. The proposed discrimination index is computed by considering the cardinality of a neighborhood relation rather than neighborhood similarity classes. Variants of the discrimination index, including joint discrimination index, conditional discrimination index, and mutual discrimination index, are introduced to compute the change of distinguishing information caused by the combination of multiple feature subsets. They have the similar properties as Shannon entropy and its variants. A parameter, named neighborhood radius, is introduced in these discrimination measures to address the analysis of real valued data. Based on the proposed discrimination measures, the significance measure of a candidate feature is defined and a greedy forward algorithm for feature selection is designed. Data sets selected from public data sources are used to compare the proposed algorithm with existing algorithms. The experimental results confirm that the discrimination index-based algorithm yields superior performance compared to other classical algorithms. PMID- 28650831 TI - New Precision Metrics for Contrast Sensitivity Testing. AB - Visual sensitivity is comprehensively described by the contrast sensitivity function (CSF), but current routine clinical care does not include its assessment because of the time-consuming need to estimate thresholds for a large number of spatial frequencies. The quick CSF method, however, dramatically reduces testing times by using a Bayesian information maximization rule. We evaluate the test retest variability of a tablet-based quick CSF implementation in a study with 100 subjects who repeatedly assessed their vision with and without optical correction. We first discuss two commonly used measures of repeatability, intraclass correlation and the Bland-Altman Coefficient of Repeatability, and show that they are vulnerable to artifacts. Instead, we propose to formulate precision as an information retrieval task: from all repeat test scores, can we retrieve a certain individual based on their first test score? We then use rank based analyses such as mean average precision as a better measure to compare different test metrics, and show that the highest test-retest precision is achieved using a summary statistic, the area under the log CSF (AULCSF). This demonstrates the benefit of assessment of the whole CSF compared to sensitivity at individual spatial frequencies only. AULCSF also yields best discrimination performance (99.2%) between measurements that were taken with and without glasses, respectively, even better than CSF Acuity. The tablet-based quick CSF thus enables the rapid and reliable home monitoring of visual function, which has the potential to improve early diagnosis and treatment of ophthalmic pathologies such as diabetic retinopathy or age-related macular degeneration. PMID- 28650832 TI - Committee-Based Active Learning for Surrogate-Assisted Particle Swarm Optimization of Expensive Problems. AB - Function evaluations (FEs) of many real-world optimization problems are time or resource consuming, posing a serious challenge to the application of evolutionary algorithms (EAs) to solve these problems. To address this challenge, the research on surrogate-assisted EAs has attracted increasing attention from both academia and industry over the past decades. However, most existing surrogate-assisted EAs (SAEAs) either still require thousands of expensive FEs to obtain acceptable solutions, or are only applied to very low-dimensional problems. In this paper, a novel surrogate-assisted particle swarm optimization (PSO) inspired from committee-based active learning (CAL) is proposed. In the proposed algorithm, a global model management strategy inspired from CAL is developed, which searches for the best and most uncertain solutions according to a surrogate ensemble using a PSO algorithm and evaluates these solutions using the expensive objective function. In addition, a local surrogate model is built around the best solution obtained so far. Then, a PSO algorithm searches on the local surrogate to find its optimum and evaluates it. The evolutionary search using the global model management strategy switches to the local search once no further improvement can be observed, and vice versa. This iterative search process continues until the computational budget is exhausted. Experimental results comparing the proposed algorithm with a few state-of-the-art SAEAs on both benchmark problems up to 30 decision variables as well as an airfoil design problem demonstrate that the proposed algorithm is able to achieve better or competitive solutions with a limited budget of hundreds of exact FEs. PMID- 28650833 TI - Exponential Stabilization of Memristive Neural Networks via Saturating Sampled Data Control. AB - This paper is concerned with the exponential stabilization of memristive neural networks (MNNs) by taking into account the sampled-data control and actuator saturation. On the one hand, the MNNs are converted into a tractable model by defining a class of logical switched functions. Based on this model, the connection weights of MNNs are dealt with by a robust analysis method. On the other hand, a saturating sampled-data controller containing an exponentially decaying term is designed. With the help of generalized sector condition and the Lyapunov stability theory, a novel sufficient condition ensuring the local exponential stability of the closed-loop systems is formulated in terms of linear matrix inequalities. In addition, three optimization problems are given to design the control gain with the aims of enlarging the sampling interval, expanding the estimation of the domain of attraction, and minimizing the size of actuators, while preserving the stability of the closed-loop systems. Two numerical examples are provided to illustrate the effectiveness of the obtained theoretical results. PMID- 28650834 TI - Angle 2DPCA: A New Formulation for 2DPCA. AB - 2-D principal component analysis (2DPCA), which employs squared -norm as the distance metric, has been widely used in dimensionality reduction for data representation and classification. It, however, is commonly known that squared norm is very sensitivity to outliers. To handle this problem, we present a novel formulation for 2DPCA, namely Angle-2DPCA. It employs -norm as the distance metric and takes into consideration the relationship between reconstruction error and variance in the objective function. We present a fast iterative algorithm to solve the solution of Angle-2DPCA. Experimental results on the Extended Yale B, AR, and PIE face image databases illustrate the effectiveness of our proposed approach. PMID- 28650835 TI - A New Representation in PSO for Discretization-Based Feature Selection. AB - In machine learning, discretization and feature selection (FS) are important techniques for preprocessing data to improve the performance of an algorithm on high-dimensional data. Since many FS methods require discrete data, a common practice is to apply discretization before FS. In addition, for the sake of efficiency, features are usually discretized individually (or univariate). This scheme works based on the assumption that each feature independently influences the task, which may not hold in cases where feature interactions exist. Therefore, univariate discretization may degrade the performance of the FS stage since information showing feature interactions may be lost during the discretization process. Initial results of our previous proposed method [evolve particle swarm optimization (EPSO)] showed that combining discretization and FS in a single stage using bare-bones particle swarm optimization (BBPSO) can lead to a better performance than applying them in two separate stages. In this paper, we propose a new method called potential particle swarm optimization (PPSO) which employs a new representation that can reduce the search space of the problem and a new fitness function to better evaluate candidate solutions to guide the search. The results on ten high-dimensional datasets show that PPSO select less than 5% of the number of features for all datasets. Compared with the two-stage approach which uses BBPSO for FS on the discretized data, PPSO achieves significantly higher accuracy on seven datasets. In addition, PPSO obtains better (or similar) classification performance than EPSO on eight datasets with a smaller number of selected features on six datasets. Furthermore, PPSO also outperforms the three compared (traditional) methods and performs similar to one method on most datasets in terms of both generalization ability and learning capacity. PMID- 28650836 TI - Deep ART Neural Model for Biologically Inspired Episodic Memory and Its Application to Task Performance of Robots. AB - Robots are expected to perform smart services and to undertake various troublesome or difficult tasks in the place of humans. Since these human-scale tasks consist of a temporal sequence of events, robots need episodic memory to store and retrieve the sequences to perform the tasks autonomously in similar situations. As episodic memory, in this paper we propose a novel Deep adaptive resonance theory (ART) neural model and apply it to the task performance of the humanoid robot, Mybot, developed in the Robot Intelligence Technology Laboratory at KAIST. Deep ART has a deep structure to learn events, episodes, and even more like daily episodes. Moreover, it can retrieve the correct episode from partial input cues robustly. To demonstrate the effectiveness and applicability of the proposed Deep ART, experiments are conducted with the humanoid robot, Mybot, for performing the three tasks of arranging toys, making cereal, and disposing of garbage. PMID- 28650837 TI - Heterogeneous Face Recognition by Margin-Based Cross-Modality Metric Learning. AB - Heterogeneous face recognition deals with matching face images from different modalities or sources. The main challenge lies in cross-modal differences and variations and the goal is to make cross-modality separation among subjects. A margin-based cross-modality metric learning (MCM2L) method is proposed to address the problem. A cross-modality metric is defined in a common subspace where samples of two different modalities are mapped and measured. The objective is to learn such metrics that satisfy the following two constraints. The first minimizes pairwise, intrapersonal cross-modality distances. The second forces a margin between subject specific intrapersonal and interpersonal cross-modality distances. This is achieved by defining a hinge loss on triplet-based distance constraints for efficient optimization. It allows the proposed method to focus more on optimizing distances of those subjects whose intrapersonal and interpersonal distances are hard to separate. The proposed method is further extended to a kernelized MCM2L (KMCM2L). Both methods have been evaluated on an ID card face dataset and two other cross-modality benchmark datasets. Various feature extraction methods have also been incorporated in the study, including recent deep learned features. In extensive experiments and comparisons with the state-of-the-art methods, the MCM2L and KMCM2L methods achieved marked improvements in most cases. PMID- 28650838 TI - Adaptive Neural Network Finite-Time Output Feedback Control of Quantized Nonlinear Systems. AB - This paper addresses the finite-time tracking issue for nonlinear quantized systems with unmeasurable states. Compared with the existing researches, the finite-time quantized feedback control is considered for the first time. By proposing a new finite-time stability criterion and designing a state observer, a novel adaptive neural output-feedback control strategy is raised by backstepping technique. Under the presented control scheme, the finite-time quantized feedback control problem is coped with without limiting assumption for nonlinear functions. PMID- 28650839 TI - Age at Menopause: Do Chemical Exposures Play a Role? PMID- 28650840 TI - Glycol Ethers and Neurodevelopment: Investigating the Impact of Prenatal Exposures. PMID- 28650841 TI - Another Side of a Low-Salt Diet: Reductions in the Salinity of Drinking Water May Lower Blood Pressure. PMID- 28650842 TI - Ambient Temperature and Stillbirth: A Multi-Center Retrospective Cohort Study. AB - BACKGROUND: Climate change is expected to have adverse health effects, but the association between extreme ambient temperatures and stillbirth is unclear. OBJECTIVES: We investigated acute and chronic associations between extreme ambient temperatures and stillbirth risk, and estimated the attributable risk associated with local temperature extremes in the United States. METHODS: We linked 223,375 singleton births >=23 weeks of gestation (2002-2008) from 12 U.S. sites to local temperature. Chronic exposure to hot (>90th percentile), cold (<10th percentile), or mild (10th-90th percentile) temperatures was defined using window- and site-specific temperature distributions for three-months preconception, first and second trimester, and whole-pregnancy averages. For acute exposure, average temperature for the week preceding delivery was compared to two alternative control weeks in a case-crossover analysis. RESULTS: In comparison with mild, whole-pregnancy exposure to cold [adjusted odds ratio (aOR) = 4.75; 95% confidence interval (CI): 3.95, 5.71] and hot (aOR = 3.71; 95% CI: 3.07, 4.47) were associated with stillbirth risk, and preconception and first and second trimester exposures were not. Approximately 17-19% of stillbirth cases were potentially attributable to chronic whole-pregnancy exposures to local temperature extremes. This is equivalent to ~1,116 cold-related and ~1,019 hot related excess cases in the United States annually. In the case-crossover analysis, a 1 degrees C increase during the week preceding delivery was associated with a 6% (3-9%) increase in stillbirth risk during the warm season (May-September). This incidence translates to ~4 (2-6) additional stillbirths per 10,000 births for each 1 degrees C increase. CONCLUSIONS: Extremes of local ambient temperature may have chronic and acute effects on stillbirth risk, even in temperate zones. Temperature-related effects on pregnancy outcomes merit additional investigation. https://doi.org/10.1289/EHP945. PMID- 28650844 TI - Long-term persistence of HCV NS5A resistance-associated substitutions after treatment with the HCV NS5A inhibitor, ledipasvir, without sofosbuvir. AB - BACKGROUND: Data on persistence of NS5A resistance-associated substitutions (RASs) may have implications for resistance testing approaches and selection of initial and retreatment strategies. METHODS: Long-term persistence of NS5A RASs in HCV genotype (GT) 1 infected subjects (n=76) who did not achieve sustained virological response after receiving ledipasvir (LDV) without sofosbuvir (SOF) and were subsequently enrolled in an ongoing 3-year follow-up registry study was investigated by population or deep sequencing. RESULTS: Of the 76 subjects enrolled, 67 and 9 subjects had GT1a and GT1b infection, respectively. At pretreatment, NS5A RASs were detected in 14% of subjects (11/76) by population sequencing, with three subjects having >1 RAS. All RASs that were detected at pretreatment persisted and were observed at the 96 week visit in the follow-up study (FU96). For the remaining subjects with no detectable RASs at pretreatment, RASs were detected in 98% (63/64) of subjects at virological failure in the parent study and persisted at detectable levels through FU96 in 86% of subjects by deep sequencing (1% cutoff). However, a decline in the quasispecies frequency of most RASs and the number of RASs per subject was observed over time. Phenotypic analysis demonstrated that the majority of NS5A RASs confer similar levels of resistance to LDV and daclatasvir. CONCLUSIONS: The majority of NS5A RASs can persist at detectable levels for >96 weeks post-treatment in subjects who failed treatment with regimens containing an NS5A inhibitor without SOF, suggesting relatively high fitness of NS5A RASs even in the absence of drug pressure. PMID- 28650843 TI - Can CanMEDS competencies be developed in medical school anatomy laboratories? A literature review. AB - Objectives: The purpose of this literature review was to identify potential ways in which undergraduate medical anatomy education may be relevant to the CanMEDS Roles, a competency-based framework used throughout Canadian medical training. Methods: A scoping review of medical education literature was conducted in March 2017 for English language publications that included key words related to anatomy education and to key competencies formally described for each of the Roles in the CanMEDS 2015 framework. Indicated benefits were then collated, characterized, and synthesized for each CanMEDS Role. Results: There were 71 studies identified describing original findings. Perceived benefits of anatomy education were most often identified for competencies related to the Medical Expert Role. Multiple studies also cited benefits related to the Scholar, Professional and Collaborator Roles. There was a lack of literature related to the Health Advocate, Communicator, and Leader Roles. The majority of benefits defined in the literature were limited to student perceptions rather than objectively measured outcomes. Conclusions: There is some evidence to suggest that anatomy education can facilitate the development of core competencies related to several CanMEDS Roles, outside of simply developing medical knowledge in the Medical Expert Role. Future studies need to develop methods to objectively assess outcomes related to these competencies. PMID- 28650845 TI - Sealing-free fast-response paraffin/nanoporous gold hybrid actuator. AB - Paraffin-based actuators can deliver large actuation strokes and high actuation stress, but often suffer from a low response rate and leaking problems. Here, we report a new paraffin/metal hybrid actuator, which was fabricated by infiltrating nanoporous gold with paraffin. It exhibits a fast actuation rate owing to the high thermal conductivity of the inter-connected metal phase, and requires no external sealing because liquid paraffin can be well confined in nanoscale channels, due to the large capillarity. We found that in this hybrid actuator, the stress generated by actuation is negligibly small when the characteristic size of the nanoporous gold (L) is above ~70 nm, and increases dramatically with a decreasing size when L < ~70 nm. The large actuation stress in samples with L < ~70 nm is ascribed to a 'smaller is stronger' effect in paraffin wax-the paraffin in smaller pores can sustain larger tensile stress, and thus the contraction of paraffin during cooling can be translated into larger compression stress and strain energy in a metal framework, leading to a larger actuation stress and energy. We also demonstrate that complex actuation motions can be achieved by incorporating hierarchical-structured nanoporous metal with paraffin. PMID- 28650846 TI - Dosimetric verification in water of a Monte Carlo treatment planning tool for proton, helium, carbon and oxygen ion beams at the Heidelberg Ion Beam Therapy Center. AB - The introduction of 'new' ion species in particle therapy needs to be supported by a thorough assessment of their dosimetric properties and by treatment planning comparisons with clinically used proton and carbon ion beams. In addition to the latter two ions, helium and oxygen ion beams are foreseen at the Heidelberg Ion Beam Therapy Center (HIT) as potential assets for improving clinical outcomes in the near future. We present in this study a dosimetric validation of a FLUKA based Monte Carlo treatment planning tool (MCTP) for protons, helium, carbon and oxygen ions for spread-out Bragg peaks in water. The comparisons between the ions show the dosimetric advantages of helium and heavier ion beams in terms of their distal and lateral fall-offs with respect to protons, reducing the lateral size of the region receiving 50% of the planned dose up to 12 mm. However, carbon and oxygen ions showed significant doses beyond the target due to the higher fragmentation tail compared to lighter ions (p and He), up to 25%. The Monte Carlo predictions were found to be in excellent geometrical agreement with the measurements, with deviations below 1 mm for all parameters investigated such as target and lateral size as well as distal fall-offs. Measured and simulated absolute dose values agreed within about 2.5% on the overall dose distributions. The MCTP tool, which supports the usage of multiple state-of-the-art relative biological effectiveness models, will provide a solid engine for treatment planning comparisons at HIT. PMID- 28650847 TI - Phase transformation in AFM silicon tips. AB - We confirmed the occurrence of phase transformations in an atomic force microscopy silicon tip during loading and unloading experiments performed on a polycrystalline Ti sample. The influence of the phase transformations on the effective mechanical and electrical properties of the tip was observed with the help of load-unload curves measured simultaneously for the tip-sample contact stiffness k * and the effective electrical resistance of the system R eff. We used the atomic force acoustic microscopy (AFAM) method to determine the values of k *. To measure the changes in R eff, we combined a high voltage source/measure unit with the existing AFAM system. The data obtained showed that the phase transformation from Si-I to Si-II is preceded by other structural changes such as formation of distorted diamond structures and formation of Si III. This conclusion was reached after observing a small hysteretic behavior in the load-unload stiffness curve accompanied by only very small changes in the resistance of the tip-sample system occurring on the unloading. The coinciding of a sudden increase in the values of the contact stiffness with a decrease in the resistance of the system indicated that the formation of metallic Si-II occurred in the subsequent measurements. The interpretation of our results found confirmation in the results of molecular dynamics and atomistic simulations performed for silicon under nanoindentation experiments. PMID- 28650848 TI - Ser/Thr protein kinase Bbeta-NADPH oxidase 2 signaling in thromboinflammation. AB - PURPOSE OF REVIEW: Interactions between neutrophils and platelets contribute to the progression of thromboinflammatory disease. However, the regulatory mechanism governing these interactions is poorly understood. The present review focuses on the crucial role of Ser/Thr protein kinase B (AKT)beta-NADPH oxidase 2 (NOX2) signaling in regulating neutrophil and platelet activation and their heterotypic interactions under thromboinflammatory conditions. RECENT FINDINGS: Growing evidence has shown that platelets, leukocytes, and blood coagulation need to be considered to treat thromboinflammatory disease in which inflammation and thrombosis occur concurrently. In addition to plasma proteins and intracellular signaling molecules, extracellular reactive oxygen species (ROS) produced from activated leukocytes could be an important factor in the pathophysiology of thromboinflammatory disease. Recent studies reveal that AKT2-NOX2 signaling has critical roles in Ca mobilization, ROS generation, degranulation, and control of the ligand-binding function of cell surface molecules, thereby promoting heterotypic cell-cell interactions in thromboinflammation. These findings have provided novel insights into attractive therapeutic targets for the prevention and treatment of thromboinflammatory disease. SUMMARY: Recent discoveries concerning molecular mechanisms regulating neutrophil-platelet interactions have bridged some gaps in our knowledge of the complicated signaling pathways exacerbating thromboinflammatory conditions. PMID- 28650850 TI - Systemic Aminoglycosides-Induced Vestibulotoxicity in Humans. AB - OBJECTIVES: This systematic review aimed to investigate the prevalence and characteristics of vestibular adverse effects of aminoglycoside (AG) therapy in humans and to analyze objective vestibular tests for the detection of AG-induced vestibulotoxicity. DESIGN: PubMed, Cochrane Database, Web of Science, and reference lists of all included studies were screened by two independent researchers. The Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) guidelines were followed. Studies were included according to preset inclusion criteria and reported outcomes of studies evaluating vestibular function using one or more objective vestibular function tests in adults and children after systemic AG administration. The methodological quality of each study was assessed using the quality assessment tool for quantitative studies. Interrater reliability was established using Cohen's Kappa. RESULTS: Twenty-seven studies were included, with the vast majority showing AG-induced vestibulotoxic side effects, ranging from 0 to 60%. Most studies reported AG-induced abnormalities by caloric and rotatory testing, whereas only a few studies reported using video Head Impulse test and vestibular evoked myogenic potential testing. CONCLUSIONS: Because type I hair cells (particularly of the semicircular canals) are more susceptible to ototoxicity, video Head Impulse test and vestibular evoked myogenic potential testing seem more promising for the early detection of vestibulotoxicity than caloric and rotatory testing. Prospective studies using an extensive vestibular test battery are needed to further characterize the impact of AGs on the different vestibular end organs and to identify the most sensitive vestibular technique for the early detection of vestibulotoxicity. PMID- 28650849 TI - The ins and outs of endocytic trafficking in platelet functions. AB - PURPOSE OF REVIEW: Although platelet endocytosis has been recognized in granule cargo loading and the trafficking of several platelet surface receptors, its acute physiological relevance is poorly understood as is its mechanism. The present review discusses the current understanding of platelet endocytosis and its implications for platelet function. RECENT FINDINGS: Recent studies are beginning to identify and define the proteins that mediate platelet endocytosis. These studies have shown that platelets contain different endosomal compartments and may use multiple endocytic routes to take in circulating molecules and surface proteins. The studies have also shown that platelet endocytosis is involved in several aspects of platelet function such as signaling, spreading, and granule cargo loading. SUMMARY: Mechanistic studies of platelet endocytosis have shown it to be not only involved in granule cargo loading but also in various other platelet functions important for hemostasis and beyond. PMID- 28650852 TI - Techniques for endoscopic retrograde cholangiopancreatography in altered gastrointestinal anatomy. AB - PURPOSE OF REVIEW: This review highlights the current status of endoscopic retrograde cholangiopancreatography (ERCP) techniques in patients with altered anatomy. Endoscopic treatment of biliopancreatic disorders is particularly challenging in patients with altered anatomy. RECENT FINDINGS: There are two main approaches to perform ERCP in patients with altered anatomy: the transluminal access and the transmural access. The transluminal access uses device-assisted enteroscopy (DAE) to reach and cannulate the biliopancreatic system. The transmural access is created using therapeutic endoscopic ultrasound (EUS) or surgery to reach the biliopancreatic system. Both techniques are under continuous development and optimization. SUMMARY: Based on the currently available data in the literature, the transluminal access is the preferred first-line approach because of an acceptable success rate and an excellent safety profile, whereas the transmural approach may be more efficacious but with a higher complication rate, even in experienced hands. Due to the complexity of both techniques and the relative low number of procedures, patients with altered anatomy are best referred to high-volume centres where both techniques are available for optimal treatment. PMID- 28650851 TI - Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. AB - PURPOSE OF REVIEW: Genetic risk in chronic pancreatitis is partly due to mutations that cause misfolding of digestive enzymes and elicit endoplasmic reticulum stress. This review examines recent developments in this concept. RECENT FINDINGS: The best characterized misfolding variants in the highly expressed digestive proteases cationic trypsinogen (PRSS1) and carboxypeptidase A1 (CPA1) are strong, causative risk factors for chronic pancreatitis and may be associated with autosomal dominant hereditary pancreatitis. SUMMARY: Properties of misfolding digestive enzyme mutants indicate that endoplasmic reticulum stress is a highly relevant pathological mechanism and a potential therapeutic target in chronic pancreatitis. PMID- 28650853 TI - A Case of Functional Dystonia with Associated Functional Neurological Symptoms: Diagnostic and Therapeutic Challenges. PMID- 28650854 TI - Recent developments in deuterium oxide tracer approaches to measure rates of substrate turnover: implications for protein, lipid, and nucleic acid research. AB - PURPOSE OF REVIEW: Methods that inform on dynamic metabolism that can be applied to clinical populations to understand disease progression and responses to therapeutic interventions are of great importance. This review perspective will highlight recent advances, development, and applications of the multivalent stable isotope tracer deuterium oxide (D2O) to the study of substrate metabolism with particular reference to protein, lipids, and nucleic acids, and how these methods can be readily applied within clinical and pharmaceutical research. RECENT FINDINGS: Advances in the application of D2O techniques now permit the simultaneous dynamic measurement of a range of substrates (i.e. protein, lipid, and nucleic acids, along with the potential for OMICs methodologies) with minimal invasiveness further creating opportunities for long-term 'free living' measures that can be used in clinical settings. These techniques have recently been applied to ageing populations and further in cancer patients revealing altered muscle protein metabolism. Additionally, the efficacy of numerous drugs in improving lipoprotein profiles and controlling cellular proliferation in leukaemia have been revealed. SUMMARY: D2O provides opportunities to create a more holistic picture of in-vivo metabolic phenotypes, providing a unique platform for development in clinical applications, and the emerging field of personalized medicine. PMID- 28650855 TI - Intermittent vs. continuous enteral feeding to prevent catabolism in acutely ill adult and pediatric patients. AB - PURPOSE OF REVIEW: In clinical management of acutely ill adults and children, continuous enteral feeding (CEF), being considered the most tolerable approach, in comparison to other temporal patterns of nutrient administration (i.e. intermittent, cyclic and bolus), is the most frequently applied method. However, uncertainties remain about the most efficient approach to counteract protein catabolism. RECENT FINDINGS: In critically ill adults, protein loss is mainly driven by increased protein breakdown whereas, in pediatric patients, acute illness is mainly characterized by blunted regulation of protein synthesis and stunted growth. Kinetic studies in fed adult volunteers indicate that protein synthesis can be stimulated for a limited period only. However, continuous feeding persistently improves protein balance through a sustained suppression of protein breakdown. This leads to the hypothesis that CEF could be more anticatabolic than intermittent enteral feeding (IEF) in these patients. Differently from adults, experimental models of acute disease in growing animals have consistently indicated that IEF can improve protein anabolism more efficiently than CEF, mainly through protein synthesis stimulation. The scarce number of clinical studies in acutely ill adults or pediatric patients, mostly performed with inadequate methodology, could not define the best approach to maintain protein balance. SUMMARY: There is a need for pragmatic studies to directly compare the protein anabolic action of CEF and IEF using accurate methodologies, such as stable isotopes of amino acids, in both adult and pediatric patients with acute illness. PMID- 28650856 TI - A Rare Case of Pupillary Block Glaucoma Following CentraFLOW Implantable Collamer Lens Surgery. AB - A 28-year-old lady with a refractive error of -11.0 D sphere/-1.50 D cylinder at 160 degrees in the right eye underwent an uneventful Implantable Collamer Lens surgery (ICL) with a V4c model, which uses a central Aquaport. This ICL does not require preoperative laser iridotomy or surgical iridectomy, as the centraflow opening is designed to prevent pupillary block. At postoperative day 1, her visual acuity in the right eye was 20/400, with diffuse microcystic corneal edema with fixed, dilated pupil and high intraocular pressure. Following intravenous mannitol, the corneal edema resolved. It was then noted that the ICL was anteriorly displaced, creating acute pupillary block, presumably due to obstruction of the central Aquaport with viscoelastic and inflammatory debris. She underwent AC wash the same day that helped in IOP control; however, the pupil remained permanently dilated and fixed because of extensive sphincter atrophy as a result of acute pupillary block. By 1 month, the visual acuity was 20/30 with an IOP of 14 mm Hg, which was maintained at 1-year follow-up. We report the first case of pupillary block glaucoma with this particular ICL design, suggesting the need for careful attention to complete removal of viscoelastic in the anterior chamber and behind the ICL, to prevent such complications and their cosmetically unacceptable sequelae. PMID- 28650858 TI - Change of an Injured Corticospinal Tract During 3 Weeks' Rehabilitation After Putaminal Hemorrhage. PMID- 28650857 TI - Effects of Transcranial Direct Current Stimulation Plus Physical Therapy on Gait in Patients With Parkinson Disease: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of the study was to study the combined effects of transcranial direct current stimulation (tDCS) and physical therapy on the walking ability of patients with Parkinson disease (PD). STUDY DESIGN: The study used an experimental, double-blinded, randomized controlled trial. RESULTS: After intervention, group 1 (only tDCS) demonstrated a significant increase in gait speed by 0.13 to 0.14 m/sec (17.8%-19.2%) and an increase in step length by 5.9 to 6.1 cm (14.0%-14.5%), whereas group 2 (tDCS and physical therapy) revealed a significant increase in gait speed by 0.10 to 0.13 m/sec (14.9%-19.4%) and step length by 4.5 to 5.4 cm (10.6%-12.8%) and group 3 (sham tDCS and physical therapy) showed a significant increase in gait speed by 0.09 to 0.14 m/sec (13.0% 20.3%) and step length by 3.0 to 5.4 cm (6.8%-12.3%). All these results lasted for at least 8 wks after intervention. Upon comparing the parameters of gait among the three groups at every follow-up visit, no significant difference was observed. CONCLUSIONS: Anodal tDCS or physical therapy could be used alone or together as a combination treatment to improve the walking speed of patients with Parkinson disease. The effects lasted for approximately 8 wks. The combination treatment was not superior to the use of tDCS or physical therapy alone. PMID- 28650859 TI - Regarding: Radial Extracorporeal Shockwave Therapy Is No More Effective Than Placebo in the Management of Lateral Epicondylitis: A Double-Blind, Randomized, Placebo-Controlled Trial. PMID- 28650860 TI - What Is the Effect of Strength Training on Pain and Sleep in Patients With Fibromyalgia? AB - OBJECTIVE: The study aimed to investigate the effect of an 8-wk structured strength training program on pain and sleep quality in patients with fibromyalgia. DESIGN: Fifty-two patients with fibromyalgia were evaluated; 31 submitted to strength training and 21 comprised the control group. The instruments used were the Fibromyalgia Impact Questionnaire and The Pittsburgh Sleep Quality Index. The questionnaires were applied before the first training session, at 12 sessions, and after 24 sessions. Descriptive statistics (mean, SD, and frequency) and inferential tests were used. RESULTS: After 8 wks of intervention, significant differences were found between groups in subjective quality of sleep (P = 0.03), sleep disturbance (P = 0.02), daytime dysfunction (P = 0.04), and total sleep score (P < 0.01). The correlation analysis using Spearman's test indicated a positive relationship between the variables of pain intensity and sleep quality (P < 0.01); when pain intensity increased in patients with fibromyalgia, sleep quality worsened. CONCLUSIONS: Strength training is safe and effective in treating people with fibromyalgia, and a significant decrease in sleep disturbances occurs after 8 wks of intervention. PMID- 28650861 TI - Microbiome in interstitial lung disease: from pathogenesis to treatment target. AB - PURPOSE OF REVIEW: This review summarizes current knowledge of the role of the lung microbiome in interstitial lung disease and poses considerations of the microbiome as a therapeutic target. RECENT FINDINGS: Although historically considered sterile, bacterial communities have now been well documented in lungs in health and disease. Studies in idiopathic pulmonary fibrosis (IPF) suggest that increased bacterial burden and/or abundance of potentially pathogenic bacteria may drive disease progression, acute exacerbations, and mortality. More recent work has highlighted the interaction between the lung microbiome and the innate immune system in IPF, strengthening the argument for the role of both host and environment interaction in disease pathogenesis. In support of this, studies of interstitial lung diseases other than IPF suggest that it may be the host immune response, which shapes the microbiome in these diseases. Some clinical and mouse model data also suggest that the lung microbiome may represent a therapeutic target, via antibiotic administration, immunization against pathogenic organisms, or treatment directed at gastroesophageal reflux. SUMMARY: Evidence suggests that the lung microbiome may serve as a prognostic biomarker, a therapeutic target, or provide an explanation for disease pathogenesis in IPF. PMID- 28650862 TI - The potential combinational effect of miR-34a with celecoxib in osteosarcoma. AB - Advanced osteosarcoma (OS) is usually treated by preoperative and postoperative chemotherapy, but there are a very limited number of active agents. Celecoxib (Cel) is a COX-2-selective nonsteroidal anti-inflammatory drug and its antitumoral effect has been shown widely in a variety of cancers including OS cells in vitro. However, the potential combinational effect of Cel with other biological therapy has not been reported in OS cells. In this study, the effects of Cel, miR-34a mimics, and their combination on cell proliferation (MTT assay), migration (in-vitro scratch assay), invasion (transwell assay), mRNA (real-time PCR), and protein (Western blot) expression of associated signal transductions were investigated in cultured MG63 cells. The results showed that miR-34a mimics transfection and Cel treatment significantly decreased cell viability, migration, and invasion in MG63 cells, with their combination being more effective. In contrast, miR-34a inhibitors transfection exerted an effect opposite to miR-34a mimics on cell viability, migration, and invasion. The antitumoral effects of miR 34a, Cel, and their combination were observed in significant up-regulated expression of PTEN and GSK-3beta, down-regulated expression of ROCK1, Notch1, and MMP9 as well as Akt Ser phosphorylation. Our data suggested that miR-34a exerts a combinational effect with Cel on the cell proliferation, migration, and invasion in OS cells through regulating Notch1/ROCK1-PTEN-Akt-GSK-3beta signaling and MMP9 gene expression. PMID- 28650863 TI - Prediction models for prostate cancer outcomes: what is the state of the art in 2017? AB - PURPOSE OF REVIEW: Prostate cancer (PCa) remains a significant public health burden, with multiple points for decision-making at all stages of the disease. Given the amount and variety of data that may influence disease management, prediction models have been published to assist clinicians and patients in making decisions about the best next course of action at many disease states. We sought to review the most important studies related to PCa prediction models since 2016 and evaluate their impact upon the evolving field of risk modeling in PCa. RECENT FINDINGS: There has been a significant amount of work published in the past year concerning risk modeling in PCa at all stages of disease, ranging from screening to predicting survival with metastatic disease. The majority of recent publications focus upon the addition of a new biomarker to prediction models or upon validating previously published prediction models. In particular, MRI has been the topic of a number of more recent studies. SUMMARY: Prediction modeling in PCa currently compares the area under the receiver operating curve between models with and without the biomarker of interest to predict the outcome of interest in multiple disease states, ranging from diagnosis to prediction of survival with metastatic disease. Future work should provide additional information regarding clinical impact and measures of prediction confidence. PMID- 28650864 TI - Metabolic syndrome and sexual dysfunction. AB - PURPOSE OF REVIEW: To describe the connection between metabolic syndrome and male sexual dysfunction. RECENT FINDINGS: Concurrent with the obesity epidemic, metabolic syndrome in the United States is reaching crisis levels. A myriad of comorbidities are rising as well, affecting cost and quality of life. Sexual dysfunction is one of these comorbidities, with an extremely high prevalence, which will only increase as the population ages.In light of this ubiquity, recent research has explored the mechanisms of decreased libido, hypogonadism and erectile dysfunction through the lens of metabolic syndrome and its individual components. Strong associations are seen between male sexual dysfunction and central obesity, poor glycemic control, hyperlipidemia, as well as hypertension. SUMMARY: The constellation of risk factors that make up metabolic syndrome are linked to male sexual dysfunction and are largely modifiable. Therefore, effective interventions targeting the underlying pathophysiology have the potential to greatly impact and improve patient sexual function and, ultimately, quality of life. PMID- 28650865 TI - Effect of obesity on bladder cancer and renal cell carcinoma incidence and survival. AB - PURPOSE OF REVIEW: The prevalence of obesity has risen dramatically in the general population and among cancer survivors in the last three decades. In this review, we highlight the impact of obesity on carcinogenesis and survival with a focus on bladder cancer and renal cell carcinoma (RCC). RECENT FINDINGS: Obesity presents an established risk factor for an up to 1.8-fold relative risk of RCC. Data with regard to bladder cancer are less abundant but support this association as well. Possible biological mechanisms involved are the insulin/insulin-like growth factor pathway, sex steroids, adipokines and chronic inflammation as well as treatment disparities within normal weight versus obese patients. With regard to survival, no conclusion can be drawn in either tumor entity at this time because of contradictory findings. These can in part be attributed to methodological limitations, while at the same time data exist to support the notion that obese patients exhibit less aggressive tumors. SUMMARY: Obesity drives cancer risk in RCC and potentially bladder cancer. Evidence regarding survival has been contradictory and therefore no clear-cut recommendation can be made regarding weight management in cancer survivors despite to maintain a healthy lifestyle. However, given the future cancer burden that obesity will constitute, physicians should encourage weight loss and help prevent weight gain in the general population. PMID- 28650866 TI - Obesity and metabolic stone disease. AB - PURPOSE OF REVIEW: In this article, we aim to review the data regarding associations between obesity and nephrolithiasis to assist with workup and treatment of these intersecting disorders. As obesity has a multifactorial influence on the risk for urinary stone disease, the complicated mechanisms will be discussed to improve diagnosis and management. RECENT FINDINGS: Obesity and metabolic syndrome interact with nephrolithiasis risk factors to produce a myriad of bodily responses that induce stone formation. For this reason, many societies recommend prompt metabolic workup to evaluate the precise causes of stone formation. Data have shown that dietary and directed medical therapies can produce an excellent therapeutic response in this patient population, although the response may be blunted compared with nonobese patients. SUMMARY: Given the increasing number of obese and overweight patients, the urologist should be familiar with the pathophysiology, workup, and treatment of metabolic stone disease in this population, which are outlined here. PMID- 28650867 TI - Obesity and its implications on oncological urological surgery. AB - PURPOSE OF REVIEW: To review and summarize the contemporary knowledge of the implications of obesity on perioperative outcomes in oncological urologic surgeries. RECENT FINDINGS: In men undergoing radical prostatectomy, obesity seems to confer a higher risk of intraoperative bleeding, biochemical recurrence, urinary incontinence, and postoperative erectile dysfunction. The literature was not consistent regarding the benefits of a minimally invasive approach in overweight and obese patients. Similarly, available data suggest a higher risk of complications in obese patients undergoing radical cystectomy. Obesity does not seem to confer a higher risk of morbidity in patients undergoing radical nephrectomy and nephroureterectomy. However, studies reported conflicting surgical outcomes in obese patients treated with partial nephrectomy. Overweight and obesity status are associated with higher morbidity in patients treated with inguinal lymph node dissection for penile cancer. No data are available regarding the impact of obesity in obese patients treated with retroperitoneal lymph node dissection for testicular cancer. SUMMARY: Although randomized clinical data are lacking and the results of many studies are inconsistent, evidence supports the feasibility and safety of different oncological urological surgeries in obese patients. Nevertheless, obesity is an important comorbidity associated with a higher morbidity rate in most oncological urological surgeries. PMID- 28650868 TI - Obesity and its implications on nononcological urological surgery. AB - PURPOSE OF REVIEW: To review and summarize the current literature of the implications of obesity on nononcological urological surgery. We conducted a comprehensive search of the current literature with emphasis on the published literature in the last 18 months. RECENT FINDINGS: Over time, obese patients have become a more common encounter in clinical practice. Obesity represents a considerable operative challenge and has been linked to a higher rate of postoperative complications. Data regarding surgery for incontinence are inconsistent. Nevertheless, the success rates in obese women are high, and complication rates are relatively low with comparable results to nonobese women. In renal surgery, percutaneous nephrolithotomy and minipercutaneous nephrolithotomy are feasible, well tolerated, and effective even in obese patients. However, certain precautions and availability of proper instruments are necessary. SUMMARY: Although randomized clinical data are lacking and the results of many studies are inconsistent, evidence supports the feasibility and safety of different nononcological urological interventions in obese patients. Moreover, the success rates and the overall complication rates seem to be comparable to nonobese patients with some exceptions. PMID- 28650869 TI - The 2017 hormone therapy position statement of The North American Menopause Society. AB - The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees.Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT.For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociacion Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d'etudes de la menopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Societa Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement. PMID- 28650870 TI - Managing Knowledge in Transitions: Experiences of Health Care Leaders in Succession Planning. AB - Effective and efficient methods of succession planning are integral to the success of organizations across the health care system. We explored current health organizations' senior leadership transition processes. Participants were in senior level leadership and decision-making positions in hospitals within Ontario, Canada. Most of the participants did not have formal transition plans and instead relied on the human resources department to plan for succession. We discuss these processes through three themes: (1) preplanning for a transition, (2) the transition process, and (3) barriers to successful transitions. The results of this study confirm the ideas that leadership style combined with experience and personal preferences dominates a leader's onboarding process. Like any complex organizational process, transitions ought to be iterative, flexible, and in line with the needs of individuals, the organizations, and the context. This research also provides further analysis around the broader contextual and cultural issues inherent to succession planning. PMID- 28650871 TI - Perceptions of College Student-Athletes Regarding the Long-Term Effects of Concussions. AB - A comprehensive review of the literature was completed to investigate college student-athletes' perceptions regarding the long-term effects of concussions. Based on the findings, it was determined that there is a need for more education among student-athletes regarding this topic. This was a quantitative, cross sectional, nonexperimental study with a descriptive design. A survey with 7 demographic and 17 Likert-type statements was collected from 100 student-athletes in a Midwestern college at their specified team practice sites for data collection. PMID- 28650872 TI - Barriers and Facilitators to Implementing a Change Initiative in Long-Term Care Using the INTERACT(r) Quality Improvement Program. AB - Implementation of major organizational change initiatives presents a challenge for long-term care leadership. Implementation of the INTERACT(r) (Interventions to Reduce Acute Care Transfers) quality improvement program, designed to improve the management of acute changes in condition and reduce unnecessary emergency department visits and hospitalizations of nursing home residents, serves as an example to illustrate the facilitators and barriers to major change in long-term care. As part of a larger study of the impact of INTERACT(r) on rates of emergency department visits and hospitalizations, staff of 71 nursing homes were called monthly to follow-up on their progress and discuss successful facilitating strategies and any challenges and barriers they encountered during the yearlong implementation period. Themes related to barriers and facilitators were identified. Six major barriers to implementation were identified: the magnitude and complexity of the change (35%), instability of facility leadership (27%), competing demands (40%), stakeholder resistance (49%), scarce resources (86%), and technical problems (31%). Six facilitating strategies were also reported: organization-wide involvement (68%), leadership support (41%), use of administrative authority (14%), adequate training (66%), persistence and oversight on the part of the champion (73%), and unfolding positive results (14%). Successful introduction of a complex change such as the INTERACT(r) quality improvement program in a long-term care facility requires attention to the facilitators and barriers identified in this report from those at the frontline. PMID- 28650873 TI - Perceptions of Ambulatory Workflow Changes in an Academic Primary Care Setting. AB - As health care moves to a value-based system, the need for team-based models of care becomes increasingly important to adequately address the growing number of clinical quality metrics required of health care providers. Finding ways to better engage certified medical assistants (CMAs) in the process allows providers to focus on more complex tasks while improving the efficiency of each office visit. Although the roles and responsibilities for CMAs across the specialties can vary widely, standardizing the work can be a helpful step in scaling best practices across an institution. This article presents the results of a survey that evaluated various components of a CMA workflow in adult primary care practices within an academic medical center. Although the survey identified improved engagement and satisfaction with standardized changes overall, it also showed time constraints and provider discretion forcing unplanned modifications. Reviewing and reconciling medications seemed to be the most challenging for CMA staff, leading us to reconsider their involvement in this aspect of each visit. It will be important to continue innovating and testing team-based care models to keep up with the demands of a quality-based health care system. PMID- 28650874 TI - Lean Daily Management: Exploring the Effectiveness in Reducing Product Returns and Overnight Shipment Occurrences in a Materials Management Department. AB - Lean Daily Management (LDM) is a performance improvement process used by health care organizations to reduce waste and increase value. Designed to transform health care professionals into organizational problem solvers, LDM tools have been used throughout the health care industry, but full integration of this performance improvement initiative has largely evaded health care organizations. To demonstrate the effectiveness of LDM, research was conducted to evaluate the costs associated with product returns and overnighted products as monitored by a materials management department, which found that these were specific areas where excessive resources were frequently used. PMID- 28650875 TI - Practical approach to syndromic pediatric retinal dystrophies. AB - PURPOSE OF REVIEW: The purpose of this review is to outline those systemic disorders that are associated with pediatric retinal dystrophy, summarize important retinal, and nonretinal clues that aid in syndromic diagnosis, provide an approach for ophthalmic and systematic systemic examination, describe the important systemic findings seen in pediatric syndromic retinal dystrophies and highlight the role of genetic testing. RECENT FINDINGS: With profound advances being made in the field of molecular genetics, a definitive molecular etiology is increasingly being made even in rare and unusual forms of retinal dystrophies. Early recognition and precise diagnosis of a syndromic association has major clinical implications. It not only ensures early and holistic care to the child but also provides an opportunity for the parents in better understanding the nature and course of the disorder. It greatly aids in genetic counseling. SUMMARY: Many syndromic retinal dystrophies may present initially to the ophthalmologist long before they present to the pediatrician with systemic symptoms. The intent of this article is to act as a resource in assisting the ophthalmologist to arrive at an early systemic diagnosis. PMID- 28650876 TI - The role of imaging in strabismus. AB - PURPOSE OF REVIEW: To review the most recent literature regarding the clinical experience of imaging modalities in strabismus. RECENT FINDINGS: MRI of extraocular muscles (EOMs) has elucidated the roles of variation in compartmental contraction of EOMs and further evidence of EOM pulley heterotopy in various strabismus patterns, which may contribute to the clinical and surgical management of patients as this mode of imaging becomes more readily available. Ultrasound biomicroscopy (UBM) and anterior-segment optical coherence tomography (AS-OCT) may play a role in determining the location of EOMs which could also aid in devising a preoperative surgical plan, especially in those who have had prior strabismus surgery. SUMMARY: Although MRI, UBM, and AS-OCT show promise in the formulation of a treatment plan in complex strabismus, more research regarding the role and limitations of these imaging modalities is required before they become the mainstay of strabismus evaluation. PMID- 28650877 TI - The resurgence of botulinum toxin injection for strabismus in children. AB - PURPOSE OF REVIEW: The present review discusses recent advances in the use of botulinum toxin for the management of strabismus in children. RECENT FINDINGS: Botulinum toxin injection produces similar results compared to surgery for certain subtypes of strabismus, especially acute onset esotropia. It may be more effective in many subtypes of esotropia where surgery has been less reliable, including partially accommodative esotropia, esotropia associated with cerebral palsy, and thyroid eye disease. SUMMARY: Small retrospective studies have demonstrated the efficacy of botulinum toxin in the treatment of many types of pediatric strabismus, providing some guidance for clinicians to determine which patients would benefit most from this intervention. Although administration of botulinum toxin is generally accepted as a reasonable option in select cases, many strabismus surgeons have not fully embraced the treatment, in part because of perceived disadvantages compared to surgery and difficulty in identifying subsets with the highest potential for therapeutic success. A recent study compared the administration of botulinum toxin in children with acute-onset esotropia to surgical correction and found botulinum toxin had a statistically equal success rate, but with the advantage of significantly less time under general anesthesia. In addition, botulinum toxin has been recently tried in patients with partially accommodative esotropia, esotropia associated with cerebral palsy, cyclic esotropia, and in patients with thyroid eye disease. The present review will discuss current clinical recommendations based on recent studies on the use of botulinum toxin in children with strabismus. PMID- 28650880 TI - Downward Laminotomy Technique for Hidden Zone Foraminal Disk Herniations: Technical Notes and Preliminary Results. AB - INTRODUCTION: Hidden zone foraminal herniations are among the more rare forms of herniations. As exploration is difficult, and there is a close relationship between the nerve root and pedicle, many surgical approaches have been proposed. The aim of this study was to describe downward laminotomy as a new approach to these herniations. MATERIALS AND METHODS: A downward laminotomy technique was used in 5 cases with hidden zone foraminal disk herniation with no extension to the intervertebral disk space. RESULTS: The herniated disk fragment was located at L4-L5 in 4 cases and at L3-L4 in 1 case. Mean visual analog scale scores reduced from preoperative 8.2 to 2.1 postoperatively. The allodynia was resolved in two months. CONCLUSIONS: It was concluded that downward laminotomy provides a safe, less risky, and minimally invasive approach to hidden zone foraminal disk herniations. PMID- 28650878 TI - Leber hereditary optic neuropathy: bridging the translational gap. AB - PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments. RECENT FINDINGS: LHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY: LHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON. PMID- 28650879 TI - Novel Angular Measures of Cervical Deformity Account for Upper Cervical Compensation and Sagittal Alignment. AB - STUDY DESIGN: This is a retrospective review of a prospective multicenter database. OBJECTIVE: This study introduces 2 new cervical alignment measures accounting for both cervical deformity (CD) and upper cervical compensation. SUMMARY OF BACKGROUND DATA: Current descriptions of CD like the C2-C7 sagittal vertical axis (cSVA) do not account for compensatory mechanisms such as C0-C2 lordosis and pelvic tilt, which makes surgical planning difficult. The craniocervical angle (CCA) combines the slope of McGregor's line and the inclination from C7 to the hard palate. The C2-pelvic tilt (CPT) combines C2 tilt and pelvic tilt. Like the T1 pelvic angle, CPT is less affected by lower extremity and pelvic compensation. METHODS: Novel and existing CD measures were correlated in 781 patients from a thoracolumbar deformity (TLD) database and 61 patients from a prospective CD database. CD patients were subanalyzed by region of deformity driver: cervical or cervico-thoracic junction. TLD patients were substratified according to whether or not they had CD as well, where CD was defined as cSVA>4 cm or T1 slope minus cervical lordosis mismatch (TS-CL) >20. RESULTS: TLD cohort: mean cSVA was 31.7+/-17.8 mm. Subanalysis of TLD patients with CD versus no-CD demonstrated significant differences in CCA (56.2 vs. 60.6, P<0.001) and CPT (32.6 vs. 19.3, P<0.001). CCA and CPT correlated with cSVA (r= 0.488/r=0.418, P<0.001) and C0-C2 lordosis (r=-0.630/r=0.289,P<0.001). CD cohort: mean cSVA was 47.3+/-32.2 mm. CCA and CPT correlated with cSVA (r=-0.811/r=0.657, P<0.001) and C0-C2 lordosis (r=-0.656/r=0.610, P<0.001). CD cohort subanalysis indicated that CT patients were significantly more deformed by cSVA (71.3 vs 24.0 mm, P<0.001), CCA (47.1 vs 59.1 degrees, P<0.001), and CPT (63.3 vs 43.8 degrees, P=0.002). Using linear regression analysis, cSVA of 4 cm corresponded to CCA of 53.2 degrees (r=0.5) and CPT of 48.5 degrees (r=0.4). CONCLUSIONS: CCA and CPT account for both cervical sagittal alignment and upper cervical compensation and can be utilized in assessment of cervical alignment. PMID- 28650881 TI - Intraoperative Radiographic Technique for Visualization of Bicortical or Tricortical Anteromedial Sacral Screw Placement. AB - The bicortical anteromedial sacral screw trajectory is the most widely used for S1 screw fixation. The assessment of anterior cortex purchase is difficult on a lateral view due to the overlapping bony anatomy of the sacrum and pelvis. We describe the intraoperative radiographic technique for a personalized pelvic inlet view that is perpendicular to the superior sacral surface to visualize sacral screw placement. This technique allows for assessment of anterior cortex purchase with anteromedial angulation in the same view. PMID- 28650882 TI - Diagnostic Utility of Intraoperative Neurophysiological Monitoring for Intramedullary Spinal Cord Tumors: Systematic Review and Meta-Analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: The aim of this study was to systematically evaluate the diagnostic utility of intraoperative neurophysiological monitoring (IONM) for detecting postoperative injury in resection of intramedullary spinal cord tumors (IMSCT). SUMMARY OF BACKGROUND DATA: Surgical management of IMSCT can involve key neurological and vascular structures. IONM aims to assess the functional integrity of susceptible elements in real time. The diagnostic value of IONM for ISMCT has not been systematically evaluated. METHODS: We performed a systematic review of the PubMed and MEDLINE databases for studies investigating the use of IONM for IMSCT and conducted a meta-analysis of diagnostic capability. RESULTS: Our search produced 257 citations. After application of exclusion criteria, 21 studies remained, 10 American Academy of Neurology grade III and 11 American Academy of Neurology grade IV. We found that a strong pooled mean sensitivity of 90% [95% confidence interval (CI), 84-94] and a weaker pooled mean specificity of 82% (95% CI, 70-90) for motor-evoked potential (MEP) recording changes. Somatosensory-evoked potential (SSEP) recording changes yielded pooled sensitivity of 85% (95% CI, 75 91) and pooled specificity of 72% (95% CI, 57-83). The pooled diagnostic odds ratio for MEP was 55.7 (95% CI, 26.3-119.1) and 14.3 (95% CI, 5.47-37.3) for SSEP. Bivariate analysis yielded summary receiver operative characteristic curves with area under the curve of 91.8% for MEPs and 86.3% for SSEPs. CONCLUSIONS: MEPs and SSEPs appear to be more sensitive than specific for detection of postoperative injury. Patients with perioperative neurological deficits are 56 times more likely to have had changes in MEPs during the procedure. We observed considerable variability in alarm criteria and interventions in response to IONM changes, indicating the need for prospective studies capable of defining standardized alarm criteria and responses. PMID- 28650883 TI - Iliac Crest Bone Graft: A Minimally Invasive Harvesting Technique. AB - Typical sources for graft material utilized in minimally invasive transforaminal lumbar interbody fusion include both autograft and allograft. Autograft is frequently utilized due to its theorized benefits in promoting fusion. During minimally invasive transforaminal lumbar interbody fusion, autograft is often obtained locally during the laminectomy and facetectomy. However, this locally obtained bone graft has exhibited questionable osteoconductive properties, often necessitating the addition of biologics to improve fusion rates. Iliac crest bone graft (ICBG) has previously been reported to be a safe and efficacious source for bone graft. Although ICBG has been noted to be an excellent material for facilitating fusion, concern for harvest site morbidity has substantially decreased its popularity. The purpose of this surgical technique is to provide a method of minimally invasive ICBG harvesting to potentially reduce the need for extra incisions, shorten operative times, and prevent postoperative graft site morbidity. PMID- 28650884 TI - Can Surgeon Demographic Factors Predict Postoperative Complication Rates After Elective Spinal Fusion? AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: Determine whether surgeon demographic factors influence postoperative complication rates after elective spine fusion procedures. BACKGROUND: Surgeon demographic factors have been shown to impact decision making in the management of degenerative disease of the lumbar spine. Complication rates are frequently reported outcome measurements used to evaluate surgical treatments, quality-of-care, and determine health care reimbursements. However, there are few studies investigating the association between surgeon demographic factors and complication outcomes after elective spine fusions. METHODS: A database of US spine surgeons with corresponding postoperative complications data after elective spine fusions was compiled utilizing public data provided by the Centers for Medicare and Medicaid Services (2011-2013) and ProPublica Surgeon Scorecard (2009-2013). Demographic data for each surgeon was collected and consisted of: surgical specialty (orthopedic vs. neurosurgery), years in practice, practice setting (private vs. academic), type of medical degree (MD vs. DO), medical school location (United States vs. foreign), sex, and geographic region of practice. General linear mixed models using a Beta distribution with a logit link and pairwise comparison with post hoc Tukey-Kramer were used to assess the relationship between surgeon demographics and complication rates. RESULTS: 2110 US-practicing spine surgeons who performed spine fusions on 125,787 Medicare patients from 2011 to 2013 met inclusion criteria for this study. None of the surgeon demographic factors analyzed were found to significantly affect overall complication rates in lumbar (posterior approach) or cervical spine fusion. CONCLUSIONS: Publicly available complication rates for individual spine surgeons are being utilized by hospital systems and patients to assess aptitude and gauge expectations. The increasing demand for transparency will likely lead to emphasis of these statistics to improve outcomes. We conclude that none of the surgeon demographic factors analyzed in this study are associated with differences in overall complications rates in patients undergoing elective spine fusion as published by the ProPublica Surgeon Scorecard. LEVEL OF EVIDENCE: Level 3. PMID- 28650886 TI - Elevated FDG Activity in the Nonpneumatized Sphenoid Bone in an Infant. AB - A 7-month-old boy with malignant rhabdoid tumor of the right lateral neck, status post resection and chemotherapy, underwent FDG PET/CT for restaging. The images showed diffuse increased activity in the spleen and in the bone marrow of the appendicular bones and the spine, which is related to hematopoietin administered after chemotherapy. The images also revealed intense activity in the region of sphenoid bone, which is not a common region to have elevated FDG activity. The subsequent MRI scan showed that this activity was due to not-yet-converted red marrow in the sphenoid bone in this pediatric patient. PMID- 28650885 TI - Aggressive Imaging Features in a Malignant Pheochromocytoma With a Novel Mutation of the SDHB Gene. AB - We describe a 15-year-old boy with a huge bilateral adrenal pheochromocytoma that had a de novo germline mutation in the succinate dehydrogenase subunit B (SDHB) gene. F-FDG PET/CT revealed bilateral metabolically active large masses in the adrenal glands and the activated brown adipose tissues. The I-MIBG scintigraphic findings revealed only a mild accumulation of MIBG in the right adrenal mass, but a high uptake in the left adrenal mass. Thus, F-FDG PET/CT imaging may be more effective than I-MIBG scintigraphy for the evaluation of pheochromocytomas that are associated with highly malignant characteristics resulting from mutations of the SDHB gene. PMID- 28650887 TI - A Pediatric Case of Well-Functioning Supernumerary Kidney: Relative Renal Function Assessment Using Radionuclide Imaging. AB - We present an interesting image of a well-functioning supernumerary kidney evaluated with DMSA (dimercaptosuccinic acid) renal scintigraphy in a 14-year-old girl. At 2 years of age, the patient had a diagnosis of supernumerary kidney. She remained asymptomatic up to childhood age, and then a DMSA study was required to guide the following adequate surveillance strategy. DMSA study provided a clear imaging of supernumerary kidney in the left side of the abdomen showing a regular uptake and a normal function in relation to its own size. PMID- 28650888 TI - False-Positive Uptake of Radioiodine in Renal Hamartoma in a Patient With Differentiated Thyroid Cancer. AB - A 46-year-old woman with a history of papillary thyroid cancer status post total thyroidectomy underwent the second I radioiodine ablation therapy for lung metastases. Posttherapeutic whole-body I planar images showed diffuse uptake in the lungs and intense focal activity in both sides of the upper abdomen. SPECT/CT of the abdomen localized the uptake in the upper pole of the left kidney and the lower pole of the right kidney. The patient received bilateral partial nephrectomy with pathology demonstrating that these 2 renal lesions were renal hamartomas. PMID- 28650889 TI - Occult Renal Granulomatous Inflammatory Lesions in Granulomatosis with Polyangiitis Detected by 18F-FDG PET/CT. AB - A 33-year-old woman with a 7-month history of granulomatosis with polyangiitis F FDG PET/CT scan due to low-grade intermittent fever and elevation of serum inflammatory markers, which revealed multiple hypermetabolic lesions in bilateral kidneys. Biopsy of a lesion showed granulomatosis with polyangiitis, consistent with renal involvement of granulomatosis with polyangiitis. PMID- 28650890 TI - Solitary Choroidal Metastasis From Lung Adenocarcinoma on FDG PET/CT. AB - Solitary choroidal metastasis as an initial presentation of lung cancer is rare. A 67-year-old woman who initially presented with a 3-month history of blurred vision in the right eye was suggestive of choroidal melanoma on MRI. Preoperatively, a pulmonary mass was found on x-ray. She was referred for an FDG PET/CT imaging, which revealed a choroidal lesion with minimal FDG uptake in right eye and increased FDG activity in the known lung mass. A pathological diagnosis of metastatic lung adenocarcinoma was made after enucleation of the right eyeball. PMID- 28650893 TI - Engage... and Go Deep. PMID- 28650891 TI - Pretreatment Primary Tumor SUVmax on 18F-FDG PET/CT Images Predicts Outcomes in Patients With Salivary Gland Carcinoma Treated With Definitive Intensity Modulated Radiation Therapy. AB - PURPOSE: The aim of this study was to investigate the prognostic significance of F-FDG uptake in salivary gland carcinoma (SGC) patients treated with definitive intensity-modulated radiation therapy (IMRT). METHODS: We retrospectively examined 46 SGC patients who received pretreatment F-FDG PET/CT and definitive IMRT between 2007 and 2014. Most tumors were located in the minor salivary glands (n = 35 [76%]). Forty-six percent (n = 21) of the participants had unresectable disease. The median radiation dose was 72 Gy. Treatment outcomes were examined in relation to clinicopathologic parameters and pretreatment primary tumor SUVmax on F-FDG PET/CT. RESULTS: After a median follow-up of 54 months, the 5-year locoregional progression-free survival (LRPFS), distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) rates were 77%, 75%, 63%, and 61%, respectively. The median primary tumor SUVmax was 7.4 (range, 2.3 23.6), and the optimal cutoff value that maximized the prognostic significance for 5-year PFS was 7.4 (P = 0.006). Patients with a high SUVmax (>=7.4) had significantly lower 5-year LRPFS (P = 0.007), distant metastasis-free survival (P = 0.046), and OS (P = 0.013) rates than those with a low SUVmax (<7.4). Multivariate analyses identified SUVmax as the only independent predictor of LRPFS (P = 0.023) and PFS (P = 0.003), whereas both the performance score (P < 0.001) and SUVmax (P = 0.022) were independently associated with OS. CONCLUSIONS: Pretreatment primary tumor SUVmax on F-FDG PET/CT predicts treatment outcomes in SGC patients. Definitive IMRT is an effective treatment strategy when organ function and cosmesis need to be preserved. PMID- 28650894 TI - Pelvic Organ Prolapse. PMID- 28650895 TI - Asymptomatic Microscopic Hematuria in Women. AB - Asymptomatic microscopic hematuria is an important clinical sign of urinary tract malignancy. Asymptomatic microscopic hematuria has been variably defined over the years. In addition, the evidence primarily is based on data from male patients. However, whether the patient is a man or a woman influences the differential diagnosis of asymptomatic microscopic hematuria, and the risk of urinary tract malignancy (bladder, ureter, and kidney) is significantly less in women than in men. Among women, being older than 60 years, having a history of smoking, and having gross hematuria are the strongest predictors of urologic cancer. In low risk, never-smoking women younger than 50 years without gross hematuria and with fewer than 25 red blood cells per high-power field, the risk of urinary tract malignancy is less than or equal to 0.5%. Furthermore, the evaluation may result in more harm than benefit and is unlikely to be cost effective. Thus, data support changing current hematuria recommendations in this low-risk group. The American College of Obstetricians and Gynecologists and the American Urogynecologic Society encourage organizations producing future guidelines on the evaluation of microscopic hematuria to perform sex-specific analysis of the data and produce practical sex-specific recommendations. In the meantime, the American College of Obstetricians and Gynecologists and the American Urogynecologic Society recommend that asymptomatic, low-risk, never-smoking women aged 35-50 years undergo evaluation only if they have more than 25 red blood cells per high power field. PMID- 28650897 TI - Ultrasonographic Evaluation of the Urethral Rhabdosphincter Morphology in Female Patients With Urodynamic Stress Incontinence. AB - OBJECTIVES: During the last 2 decades, ultrasonography has been proposed for the morphologic evaluation of the urethral rhabdosphincter. The aims of this study were to evaluate the feasibility of a simple sonographic technique for the assessment of the urethral rhabdosphincter morphology by using a 2-dimensional (2D) transvaginal transducer and to evaluate any associations between the sonographic parameters of rhabdosphincter morphology with the presence of urodynamic stress incontinence (USI). METHODS: This was a prospective study of women who underwent urodynamic studies and an introital 2D ultrasonography and divided in 2 groups based on the presence or absence of USI. Measurements included rhabdosphincter thickness at the 3-o'clock (right) and 9-o'clock (left) positions and the rhabdosphincter outer (Pi) and inner circumference (pi). Based on these values, the mean thickness of the rhabdosphincter (R + L / 2), the rhabdosphincter differential perimeter (Pi - pi), and area (A - alpha) were also calculated. RESULTS: Statistical analysis showed that women with a rhabdosphincter area of less than 0.65 cm, mean thickness of less than 0.24 cm, and differential perimeter of less than 1.08 cm had 3.98, 5.67, and 5.41 times greater odds for USI, respectively. Receiver operating characteristic curve analysis results showed that the optimal cutoff values for the prediction of USI from rhabdosphincter thickness, differential perimeter. and surface area were 0.24 cm (79.6% sensitivity, 63.4% specificity), 1.08 cm (70.8% sensitivity and 69.1% specificity), and 0.65 cm (71.9% sensitivity, 57.1% specificity), respectively. CONCLUSIONS: Introital ultrasonography with a 2D transvaginal probe allowed the visualization of the urethral rhabdosphincter morphology in greater than 90% of the cases. Sonographic measurements showed that patients with USI had a thinner urethral rhabdosphincter than did women with a normal sphincteric mechanism. PMID- 28650896 TI - Development and Validation of a Quantitative Measure of Adaptive Behaviors in Women With Pelvic Floor Disorders. AB - PURPOSE: To establish validity for the Pelvic Floor Disorders Network (PFDN) self administered Adaptive Behavior Index (ABI) and to assess whether ABI assesses known discordance between severity of pelvic floor symptoms and self-reported bother. METHODS: In addition to the ABI questionnaire, participants in 1 of 6 Pelvic Floor Disorders Network trials completed condition-specific measures of pretreatment symptom severity (including Pelvic Floor Distress Inventory; PFDI) and health-related quality of life (Pelvic Floor Impact Questionnaire; PFIQ). The final survey was developed from an iterative process using subject and expert endorsement, factor analyses, and response distributions. Domains were created using a development cohort (n = 304 women), reliability and validity were established using a validation cohort (n = 596 women), and test-retest reliability was assessed (n = 111 women). RESULTS: Factor analyses supported an 11-item avoidance domain and a 6-item hygiene domain. Cronbach' alphas were 0.88 and 0.68, respectively. Test-retest reliability was 0.84 for both domains. Construct validity was demonstrated in correlations between the ABI domains and baseline PFDI and PFIQ (r values, 0.43-0.79 with all P values <0.0001). Moreover, the ABI accounted for 8% to 26% of unexplained variance between the symptoms severity measure and the impact on health related quality of life. After treatment, avoidance domain scores improved for urinary and fecal incontinence groups and hygiene scores improved for the fecal incontinence group. CONCLUSIONS: The ABI is a reliable and valid measure in women with pelvic floor disorders. Adaptive behaviors account in part for discordance between pelvic floor symptom severity and bother. PMID- 28650898 TI - Retroperitoneal Hemorrhage After Sacral Neurostimulator Placement for Urgency Urinary Incontinence. AB - Sacral neuromodulation (SNM) is an effective therapy for patients who experience urinary incontinence, idiopathic urinary retention, and fecal incontinence. Although typically a low-risk procedure, rarely, it can be associated with significant hemorrhage. A 61-year-old woman on chronic anticoagulation underwent uncomplicated implantation of SNM for refractory urgency urinary incontinence. Anticoagulation was held on the day of surgery and resumed on postoperative day 1. On postoperative day 2, the patient developed an extensive retroperitoneal hemorrhage. This was successfully treated by angioembolization of the left lateral sacral artery with the InterStim device left in situ. At 6-month follow up, the device was functioning properly, and the patient's urinary symptoms were well controlled. Retroperitoneal hemorrhage is a rare complication after SNM placement. Conservative management with angioembolization should be considered as a first-line approach. PMID- 28650899 TI - Evaluation of a Digital Behavioral Counseling Program for Reducing Risk Factors for Chronic Disease in a Workforce. AB - OBJECTIVE: To evaluate a digitally delivered, intensive behavioral counseling program for a workforce at risk for obesity-related chronic disease. METHODS: Employees were offered a digital health program modeled after the diabetes prevention program (DPP). Annual workforce health assessments were used to examine changes in chronic disease risk factors between participants (n = 634) relative to a matched comparison group (n = 1268). RESULTS: Overall, employees were gaining an average of 3.5 pounds annually before program inception. Program engagement was positive; 83% completed the majority of the curriculum and 31% lost at least 5% of their starting weight. Compared with non-participating peers, participants demonstrated reduced weight, improved fasting blood glucose, and improved nutritional intake after a year. CONCLUSIONS: The digital health program was effective for engaging employees in health behavior change. Digital options facilitate widespread implementation. PMID- 28650900 TI - A High-throughput HPLC-MS/MS Assay for the Detection, Quantification and Simultaneous Structural Confirmation of 136 Drugs and Metabolites in Human Urine. AB - BACKGROUND: Because of its superior sensitivity and specificity, multianalyte high-performance liquid chromatography coupled with tandem mass spectrometry has become the gold standard in clinical toxicology. Although several qualitative and quantitative liquid chromatography coupled with tandem mass spectrometry assays on various mass spectrometry platforms have been described in the literature, most methods either analyze only a limited number of compounds and/or require tedious and time-consuming sample preparation. METHODS: A major challenge in urine toxicology screening is the minimization of false-negative and false positive results. This was addressed by screening for a comprehensive panel of 136 compounds of importance for pain and drug addiction clinics, using high-end, high-sensitivity, fast-scanning mass spectrometry in combination with simultaneous structural confirmation based on ion ratios. The assay was validated and successfully participated in proficiency challenges. RESULTS: The assay met all predefined acceptance criteria. The lower limit of quantifications ranged from 10 to 100 ng/mL. Interday trueness and imprecisions ranged from 73.8% to 116.2% and 2.4%-20.0%, respectively. The total assay run time was 10 minutes. CONCLUSIONS: We developed and successfully validated a robust, sensitive, and specific liquid chromatography coupled with tandem mass spectrometry-based urine toxicology screening platform that allows for the addition of drugs to quickly adjust to new clinical needs. To date, more than 3000 clinical samples have successfully been analyzed. Our results also indicated that such a quantitative multianalyte assay is pushing against the limits of current fast-scanning MS/MS instrumentation and that the number of analytes and their internal standards must be balanced with acceptable sensitivity, reproducibility, structural confirmation, and the ability to reliably quantify, all of which was achieved. PMID- 28650901 TI - Application of Quality by Design Approach to Bioanalysis: Development of a Method for Elvitegravir Quantification in Human Plasma. AB - BACKGROUND: The application of Quality by Design (QbD) principles in clinical laboratories can help to develop an analytical method through a systematic approach, providing a significant advance over the traditional heuristic and empirical methodology. In this work, we applied for the first time the QbD concept in the development of a method for drug quantification in human plasma using elvitegravir as the test molecule. METHODS: The goal of the study was to develop a fast and inexpensive quantification method, with precision and accuracy as requested by the European Medicines Agency guidelines on bioanalytical method validation. The method was divided into operative units, and for each unit critical variables affecting the results were identified. A risk analysis was performed to select critical process parameters that should be introduced in the design of experiments (DoEs). Different DoEs were used depending on the phase of advancement of the study. RESULTS: Protein precipitation and high-performance liquid chromatography-tandem mass spectrometry were selected as the techniques to be investigated. For every operative unit (sample preparation, chromatographic conditions, and detector settings), a model based on factors affecting the responses was developed and optimized. The obtained method was validated and clinically applied with success. CONCLUSIONS: To the best of our knowledge, this is the first investigation thoroughly addressing the application of QbD to the analysis of a drug in a biological matrix applied in a clinical laboratory. The extensive optimization process generated a robust method compliant with its intended use. The performance of the method is continuously monitored using control charts. PMID- 28650902 TI - ITPA Activity in Adults and Children Treated With or Without Azathioprine: Relationship Between TPMT Activity, Thiopurine Metabolites, and Co-medications. AB - BACKGROUND: The implication of inosine triphosphate pyrophosphatase (ITPA) on thiopurine drug response variability has been investigated but little data are available on its role on thiopurine metabolites. The ability of ITPA to modify the thiopurine metabolite levels is currently used to optimize azathioprine (AZA) therapy in relation to thiopurine S-methyltransferase (TPMT) activity, the aim of this study is to investigate ITPA phenotype in a large population and to evaluate the relation between ITPA and TPMT activities and thiopurine metabolites. METHODS: ITPA activity was determined in 183 adults and 138 children with or without AZA therapy. 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotides (6-MeMPN) levels, and ITPA as well as TPMT activities were measured in red blood cells. Using the Gaussian mixture model, distribution of ITPA activity was evaluated. Intraindividual variability and influence of age, sex, AZA treatment and associated co-medications on ITPA activity were also assessed. RESULTS: This retrospective study shows a quadrimodal distribution in ITPA activity. No influence of age, sex, AZA therapy, and co-medications was found. In adults, ITPA activity was not significantly associated with 6-TGN or 6-MeMPN concentrations, whereas a weak negative correlation was observed with 6-MeMPN levels in pediatric populations (rs = -0.261; P = 0.024). A weak positive correlation was observed between ITPA and TPMT activities in children (rs = 0.289; P = 0.001). CONCLUSIONS: ITPA activity was poorly influenced by nongenetic parameters and has no influence on 6-TGN and 6-MeMPN concentrations in adults and only a weak correlation with 6-MeMPN and TPMT activity in children. These results demonstrate that ITPA is not a rate-limiting enzyme in the formation of 6-TGN but suggest that a decrease in ITPA activity in children may be a risk factor for accumulation of 6-MeMPN in cells. PMID- 28650903 TI - Thigh Ultrasound Monitoring Identifies Decreases in Quadriceps Femoris Thickness as a Frequent Observation in Critically Ill Children. AB - OBJECTIVES: Significant muscle wasting develops in critically ill adults, with subsequent worse outcomes. In the pediatric setting, occurrence and effects of muscle wasting are undescribed; this is in part due to a lack of validated, objective methods for assessing muscle wasting. A single measurement of quadriceps femoris thickness has failed to show consistent reproducibility. We hypothesized that averaging repeated measurements could afford good reproducibility to allow for quadriceps femoris thickness decline detection and monitoring. DESIGN: A prospective bedside observational study. SETTING: Two PICUs. PATIENTS: Mechanically ventilated critically ill children were 15 years and younger. INTERVENTIONS: Transverse and longitudinal axis measurements of quadriceps femoris anterior thickness were undertaken using bedside ultrasound. The average of four measurement values was recorded. The location of measurement was marked for consistency within subsequent measurements by the same or another trained operator, to assess intra- and interoperator repeatability and reproducibility of the technique. Where feasible, serial measurements were undertaken until the time of extubation in a group of children with prolonged PICU stay (> 5 d). MEASUREMENTS AND MAIN RESULTS: Seventy-three children were enrolled to assess intra- and interoperator ultrasound reliability. Their median (25-75 interquartile range) age and weight were 30 months (4.5-96) and 10 kg (5 23.5). In the intraoperator repeatability study, mean relative difference in quadriceps femoris muscle thickness was 0.36% +/- 2.5% (lower and upper limits of agreement: -4.5/+5.2%). In the interoperator reproducibility study, intraclass correlation coefficient was 0.998. In the 17 children monitored over their PICU stay, quadriceps femoris thickness significantly decreased at day 5 by 9.8% (p = 0.006) and by 13.3% (< 0.001) at the last performed measurement. CONCLUSIONS: Quadriceps femoris thickness decrease, proposed as a surrogate for muscle mass, is an early, frequent, and intense phenomenon in PICU. Quadriceps femoris ultrasonography is a reliable technique to monitor this process and in future could help to guide rehabilitation and nutrition interventions. PMID- 28650905 TI - Beyond the Front Door: A Complex Home Visit Simulation. PMID- 28650904 TI - Pediatric Procedural Sedation Using the Combination of Ketamine and Propofol Outside of the Emergency Department: A Report From the Pediatric Sedation Research Consortium. AB - OBJECTIVES: Outcomes associated with a sedative regimen comprised ketamine + propofol for pediatric procedural sedation outside of both the pediatric emergency department and operating room are underreported. We used the Pediatric Sedation Research Consortium database to describe a multicenter experience with ketamine + propofol by pediatric sedation providers. DESIGN: Prospective observational study of children receiving IV ketamine + propofol for procedural sedation outside of the operating room and emergency department using data abstracted from the Pediatric Sedation Research Consortium during 2007-2015. SETTING: Procedural sedation services from academic, community, free-standing children's hospitals, and pediatric wards within general hospitals. PATIENTS: Children from birth to less than or equal to 21 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 7,313 pediatric procedural sedations were performed using IV ketamine + propofol as the primary sedative regimen. Median age was 84 months (range, < 1 mo to <= 21 yr; interquartile range, 36 144); 80.6% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedation was performed in dedicated sedation or radiology units (76.1%). Procedures were successfully completed in 99.8% of patients. Anticholinergics (glycopyrrolate and atropine) or benzodiazepines (midazolam and lorazepam) were used in 14.2% and 41.3%, respectively. The overall adverse event and serious adverse event rates were 9.79% (95% CI, 9.12-10.49%) and 3.47% (95% CI, 3.07-3.92%), respectively. No deaths occurred. Risk factors associated with an increase in odds of adverse event included ASA status greater than or equal to III, dental suite, cardiac catheterization laboratory or radiology/sedation suite location, a primary diagnosis of having a gastrointestinal illness, and the coadministration of an anticholinergic. CONCLUSIONS: Using Pediatric Sedation Research Consortium data, we describe the diverse use of IV ketamine + propofol for procedural sedation in the largest reported cohort of children to date. Data from this study may be used to design sufficiently powered prospective randomized, double-blind studies comparing outcomes of sedation between commonly administered sedative and analgesic medication regimens. PMID- 28650906 TI - Academic Progression in Nursing Education: Advancing Seamless Educational Mobility. PMID- 28650907 TI - State of Interprofessional Education in Nursing: A Systematic Review. AB - The aim of this systematic review was to synthesize research in the last 5 years to report the current state of the science related to interprofessional education (IPE) in nursing. Findings suggest that more studies with rigorous research designs are needed to compare outcomes for interprofessional interventions and to determine the effectiveness of IPE on patient outcomes. PMID- 28650908 TI - Junior Faculty Teaching Fellowship: A Model to Support Nursing Education Development. PMID- 28650909 TI - Comparison Between 2 Electronic Databases to Evaluate Potential Drug-Drug Interactions in Prescriptions of Surgical Patients. PMID- 28650910 TI - Rare Complication of Coronary Angiography: Contrast-Induced Acute Pancreatitis. PMID- 28650911 TI - Creatinine Clearance Estimations for Vancomycin Maintenance Dose Adjustments. PMID- 28650912 TI - The effect of vasodilator beta-blockers on renal function in hypertensive patients. AB - BACKGROUND: Not only is there a limited number of studies on the effects of vasodilator beta-blocker (VBB) therapy on kidney function - specifically, glomerular filtration rate (GFR), serum creatinine (sCr) and proteinuria - but of those that have been reported, the results are mixed. This meta-analysis seeks to assess the efficacy of VBBs on selected renal parameters in hypertensive patients. METHODS: We conducted a meta-analysis of any prospective trial that provided both baseline and follow-up of at least 4 weeks of VBB therapy - carvedilol, labetalol, dilevalol, nebivolol and celiprolol in patients with hypertension. We used Ovid MEDLINE, EMBASE and PubMed, all without date restrictions. We included 39 studies totaling 3987 patients. RESULTS: Although VBBs did not significantly change GFR or sCr levels after at least 4 weeks of therapy, they did significantly decrease protein excretion by -0.12 SD units [95% confidence interval (CI) -0.19 to -0.04; P < 0.01]. VBBs did not alter renal blood or plasma flow, but renal vascular resistance (RVR) decreased by -20.03 mmHg min/l (95% CI -28.92 to -11.15; P < 0.01). In the analysis which compared VBBs with non-VBBs, the only significant difference was the greater decrease in RVR in the VBB group by -38.44 mmHg min/l (95% CI -60.57 to -16.31; P < 0.01). CONCLUSION: VBBs do not affect GFR or sCr levels, but decrease protein excretion. This class of beta-blockers, however, is not superior to non-VBBs in reducing proteinuria. VBBs decrease RVR significantly more than non-VBBs. PMID- 28650913 TI - Diagnostic and therapeutic approaches to hypertension. PMID- 28650914 TI - Associations of rotational shift work and night shift status with hypertension: a systematic review and meta-analysis. AB - BACKGROUND: The reported risks of hypertension (HTN) in rotating shift and night shift workers are controversial. The objective of this meta-analysis was to assess the association between shift work status and HTN. METHODS: A literature search was performed using MEDLINE, EMBASE and Cochrane Database from inception through October 2016. Studies that reported odds ratios (OR) comparing the risk of HTN in shift workers were included. A prespecified subgroup analysis by rotating shift and night shift statuses were also performed. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. The protocol for this study is registered with International Prospective Register of Systematic Reviews; no. CRD42016051843. RESULTS: Twenty seven observational studies (nine cohort and 18 cross-sectional studies) with a total of 394 793 individuals were enrolled. The pooled ORs of HTN in shift workers in cohort and cross-sectional studies were 1.31 (95% CI, 1.07-1.60) and 1.10 (95% CI, 1.00-1.20), respectively. When meta-analysis was restricted only to cohort studies in rotating shift, the pooled OR of HTN in rotating shift workers was 1.34 (95% CI, 1.08-1.67). The data regarding night shift and HTN in cohort studies was limited. The pooled OR of HTN in night shift workers in cross sectional studies was 1.07 (95% CI, 0.85-1.35). CONCLUSION: Based on the findings of our meta-analysis, shiftwork status may play an important role in HTN, as there is a significant association between rotating shift work and HTN. However, there is no significant association between night shift status and risk of HTN. PMID- 28650915 TI - The brainstem network controlling blood pressure: an important role for pressor sites in the caudal medulla and cervical spinal cord. AB - : Although medullary control of blood pressure (BP) has been extensively studied, the contribution of critical regions, such as pressor sites in the caudal medulla and upper cervical spinal cord and the lateral tegmental field, remains controversial and underappreciated. A series of pressor sites caudal to the caudal ventrolateral medulla (CVLM), including the caudal pressor area (CPA) and medullocervical pressor area, play an important role in control of BP. Activation and inhibition of these sites elicits pressor and depressor responses, respectively. Basal sympathetic tone is provided principally by the medullary lateral tegmental field and rostral ventrolateral medulla (RVLM). RVLM presympathetic neurons, which project to and drive preganglionic sympathetic somata in the intermediolateral cell column, are powerfully regulated by neurons in CVLM via tonic and phasic inhibition. The current state of knowledge is summarized thus: rostrocaudally organized columns of pressor sites caudal to CVLM extend to the upper cervical spinal cord; CPA pressor responses are RVLM dependent; CPA mediates pressor responses by (first) inhibiting RVLM-projecting inhibitory CVLM units and (second) activating RVLM-projecting excitatory CVLM units; the chemoreflex is CPA-dependent; the baroreflex is CPA-independent; pressor responses to raphe obscurus stimulation are CPA-dependent; and medullocervical pressor area pressor responses are RVLM-independent, likely mediated by direct projections to the intermediolateral cell column. In this review, we seek to underscore and characterize the critical role played by the caudal medulla and upper cervical spinal cord in BP regulation and highlight important gaps in knowledge in interactions between the caudal medulla and other regions controlling BP, which may prove critical in revealing central mechanisms underlying pathophysiology of, and pharmacotherapeutic targets for, hypertension. PMID- 28650916 TI - Morning hypertension is more common in elderly hypertensive patients with controlled documented office blood pressure in primary care clinics: the Minhang study. AB - BACKGROUND: Increased morning blood pressure (BP) has been associated with fatal and nonfatal cardiovascular events, especially in Asians. METHOD: To detect the control status of home BP, we performed a home BP monitoring study, including elderly patients with hypertension who had controlled documented office BP in Chinese primary care clinics. In 707 participants from Xinzhuang County Hospital in Shanghai, the home BP was measured by a memory-equipped device three times daily for seven consecutive days. RESULTS: The prevalence of uncontrolled hypertension was 51.3% in the morning and 42% in the evening. Uncontrolled morning hypertension was associated with age [odds ratio (OR): 1.074; 95% confidence interval (CI): 1.041-1.108], office SBP (OR: 1.027; 95% CI: 1.015 1.039), office DBP (OR: 1.042; 95% CI: 1.021-1.064), and the number of antihypertensive drugs taken (OR: 1.387; 95% CI: 1.059-1.817), whereas it was inversely associated with the use of long-acting antihypertensive drugs (OR: 0.588; 95% CI: 0.355-0.973). Compared with office BP, the home morning BP showed a more significant association with age and short-acting antihypertensive drugs. CONCLUSION: The prevalence of uncontrolled home BP is high in elderly Chinese hypertensive patients, especially in the morning, and home BP monitoring might be a feasible method for detecting it. The use of long-acting antihypertensive drugs might help to improve morning hypertension. PMID- 28650917 TI - Long-term changes in left ventricular mass echocardiographic findings from a general population. AB - AIM: We sought to assess the long-term changes in left ventricular (LV) mass in a population-based sample, focusing on new onset, persistence, regression and severity of LV hypertrophy (LVH), as well as on the demographic and clinical variables independently related to this dynamic process. METHODS: A total of 1113 participants with measurable echocardiographic parameters at baseline and after a 10-year follow-up were included in the analysis. Cut points for LVH were derived from current echocardiographic guidelines. RESULTS: LVH prevalence significantly increased from 13 to 33% as a result of LVH new onset in 254 and LVH regression in 31 cases. Severe LVH prevalence increased by 4.3 times from baseline, a trend mainly related to transition from mild-moderate-to-severe LVH in patients with preexisting cardiac hypertrophy. Variables such as age, female sex, baseline SBP, as well as delta follow-up-baseline SBP, BMI, metabolic syndrome and use of antihypertensive drugs were independently related either to new-onset or to persistent LVH. CONCLUSION: Long-term LV mass changes in a general population are associated with a marked increase in the prevalence and severity of LVH, and this unfavourable trend was more frequent in women. As blood pressure, metabolic variables and BMI emerged as key correlates of this adverse process, our findings suggest that interventions aimed to modify such risk factors may have a role in preventing new onset and progression LVH, as well as a marked worsening of cardiovascular risk profile at the community level. PMID- 28650918 TI - The American Heart Association Scientific Statement on salt sensitivity of blood pressure: Prompting consideration of alternative conceptual frameworks for the pathogenesis of salt sensitivity? AB - : Recently, the American Heart Association (AHA) published a scientific statement on salt sensitivity of blood pressure which emphasized a decades old conceptual framework for the pathogenesis of this common disorder. Here we examine the extent to which the conceptual framework for salt sensitivity emphasized in the AHA Statement accommodates contemporary findings and views of the broader scientific community on the pathogenesis of salt sensitivity. In addition, we highlight alternative conceptual frameworks and important contemporary theories of salt sensitivity that are little discussed in the AHA Statement. We suggest that greater consideration of conceptual frameworks and theories for salt sensitivity beyond those emphasized in the AHA Statement may help to advance understanding of the pathogenesis of salt-induced increases in blood pressure and, in consequence, may lead to improved approaches to preventing and treating this common disorder. PMID- 28650919 TI - A sudden death risk score specifically for hypertension: based on 25 648 individual patient data from six randomized controlled trials. AB - OBJECTIVE: To construct a sudden death risk score specifically for hypertension (HYSUD) patients with or without cardiovascular history. METHODS: Data were collected from six randomized controlled trials of antihypertensive treatments with 8044 women and 17 604 men differing in age ranges and blood pressure eligibility criteria. In total, 345 sudden deaths (1.35%) occurred during a mean follow-up of 5.16 years. Risk factors of sudden death were examined using a multivariable Cox proportional hazards model adjusted on trials. The model was transformed to an integer system, with points added for each factor according to its association with sudden death risk. RESULTS: Antihypertensive treatment was not associated with a reduction of the sudden death risk and had no interaction with other factors, allowing model development on both treatment and placebo groups. A risk score of sudden death in 5 years was built with seven significant risk factors: age, sex, SBP, serum total cholesterol, cigarette smoking, diabetes, and history of myocardial infarction. In terms of discrimination performance, HYSUD model was adequate with areas under the receiver operating characteristic curve of 77.74% (confidence interval 95%, 74.13-81.35) for the derivation set, of 77.46% (74.09-80.83) for the validation set, and of 79.17% (75.94-82.40) for the whole population. CONCLUSION: Our work provides a simple risk-scoring system for sudden death prediction in hypertension, using individual data from six randomized controlled trials of antihypertensive treatments. HYSUD score could help assessing a hypertensive individual's risk of sudden death and optimizing preventive therapeutic strategies for these patients. PMID- 28650920 TI - INTRAOPERATIVE IMAGING OF RETAINED PERFLUOROCARBON LIQUID USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To report images of retained perfluorocarbon liquid (PFCL) on the surface of the retina obtained during an intraoperative use of hand-held spectral domain optical coherence tomography. METHODS: A 54-year-old man underwent pars plana vitrectomy with injection of PFCL to repair retinal detachment. Postoperatively, visually significant PFCL droplets were found to be retained in the eye. During the surgical removal of PFCL, a hand-held spectral domain optical coherence tomography was used to image the retina with the patient supine. RESULTS: Spectral domain optical coherence tomography images of the retained PFCL illustrated magnification of the areas of the outer retina underlying PFCL bubbles. The images obtained had some similarities to the patient's own observation of "floaters." CONCLUSION: Droplets of PFCL over the retina result in imaging artifact, most likely due to a lensing effect caused by differences in refractive index between the PFCL and vitreous humor. Although the utility of hand-held spectral domain optical coherence tomography for infants has previously been established, this case presents further application of spectral domain optical coherence tomography in adults when imaging in the supine position is required. PMID- 28650921 TI - Effect of Continuity of Care on Drug-Drug Interactions. AB - BACKGROUND: Drug-drug interaction (DDI) is a critical concern in health care systems because it is directly associated with patient outcomes and is generally preventable. However, few studies have been conducted on whether poor continuity of care (COC) is a determinant of DDIs and whether this effect varies by level of comorbidity. Patients with higher comorbidity normally require more complex treatment regimens than other patients, and hence their COC is more critical for ensuring the accuracy of their medication information. OBJECTIVE: This study investigated the association between COC and DDI, with COC being measured as physician and site COC. The effect of comorbidities on DDI events was also analyzed. METHODS: The Taiwan National Health Insurance claims data of ~1,000,000 randomly selected insurance beneficiaries were used. Each person was longitudinally followed from 2005 to 2013. Negative nominal regressions were estimated to determine the effect of COC on DDI. RESULTS: Higher COC was found to decrease the risk of DDI, and this risk reduction was even greater with physician COC and a higher Charlson comorbidity index. In the 1-year observation interval, patients exhibited a 3% reduction in DDIs for every 0.1 increment in their COC index. The ability of COC to reduce DDIs increased with the level of comorbidity. Similar results were observed when the observation interval was increased. CONCLUSIONS: Improving COC is critical for reducing DDIs. The effect of high quality COC on the reduction of DDI is more significant for patients with higher levels of comorbidity; thus, they should be targeted to improve COC. PMID- 28650923 TI - The Effect of False-positive Mammograms on Antidepressant and Anxiolytic Initiation. AB - BACKGROUND: Despite reported increases in anxiety following a false-positive mammogram, there is little evidence the effect rises to the clinical level of initiating medication. OBJECTIVE: To analyze the effect of a false-positive mammogram on antidepressant or anxiolytic initiation and identify subpopulations most at risk. SUBJECTS: MarketScan commercial and Medicaid claims databases used to identify women ages 40-64 undergoing screening mammography with no prior antidepressant or anxiolytic claims. RESEARCH DESIGN: Using a retrospective cohort design, we estimated the effects of a false-positive relative to a negative mammogram on the likelihood of initiating antidepressants or anxiolytics using multivariate logistic models estimated separately by insurance type. RESULTS: At 3 months after a false-positive mammogram, the relative risk (RR) for antidepressant or anxiolytic initiation was 1.19 [95% confidence interval (CI), 1.06-1.31] for the commercially insured and 1.13 (95% CI, 0.96-1.29) in the Medicaid population. In addition, 4 subgroups were at particularly elevated risk: commercially insured women ages 40-49 (RR=1.33; 95% CI, 1.13-1.54) or whose false positive required multiple tests to resolve (RR=1.37; 95% CI, 1.17-1.57), included a biopsy (RR=1.68; 95% CI, 1.18-2.17), or whose resolution took >1 week (RR=1.21; 95% CI, 1.07-1.34). CONCLUSIONS: False-positive mammograms were associated with significant increases in antidepressant or anxiolytic imitation among the commercially insured. Follow-up resources may be particularly beneficial for cases taking longer to resolve and involving biopsies or multiple tests. The results highlight the need to resolve false-positives quickly and effectively and to monitor depressive symptoms following a positive result. PMID- 28650922 TI - Randomized Trial of Reducing Ambulatory Malpractice and Safety Risk: Results of the Massachusetts PROMISES Project. AB - OBJECTIVE: Evaluate application of quality improvement approaches to key ambulatory malpractice risk and safety areas. STUDY SETTING: In total, 25 small to-medium-sized primary care practices (16 intervention; 9 control) in Massachusetts. STUDY DESIGN: Controlled trial of a 15-month intervention including exposure to a learning network, webinars, face-to-face meetings, and coaching by improvement advisors targeting "3+1" high-risk domains: test result, referral, and medication management plus culture/communication issues evaluated by survey and chart review tools. DATA COLLECTION METHODS: Chart reviews conducted at baseline and postintervention for intervention sites. Staff and patient survey data collected at baseline and postintervention for intervention and control sites. PRINCIPAL FINDINGS: Chart reviews demonstrated significant improvements in documentation of abnormal results, patient notification, documentation of an action or treatment plan, and evidence of a completed plan (all P<0.001). Mean days between laboratory test date and evidence of completed action/treatment plan decreased by 19.4 days (P<0.001). Staff surveys showed modest but nonsignificant improvement for intervention practices relative to controls overall and for the 3 high-risk domains that were the focus of PROMISES. CONCLUSIONS: A consortium of stakeholders, quality improvement tools, coaches, and learning network decreased selected ambulatory safety risks often seen in malpractice claims. PMID- 28650924 TI - Comparison of Approaches for Notification and Authorization in Pragmatic Clinical Research Evaluating Commonly Used Medical Practices. AB - BACKGROUND: For pragmatic clinical research comparing commonly used treatments, questions exist about if and how to notify participants about it and secure their authorization for participation. OBJECTIVE: To determine how patients react when they seek clinical care and encounter one of several different pragmatic clinical research studies. RESEARCH DESIGN: In an online survey using a between-subjects experimental design, respondents read and responded to 1 of 24 hypothetical research scenarios reflecting different types of studies and approaches to notification and authorization (eg, general notification, oral consent, written consent). SUBJECTS: English-speaking US adults 18 years and older. MEASURES: Willingness to participate in the hypothetical study, acceptability of the notification and authorization approach, understanding of the study, perceptions of benefit/harm, trust, and perception of amount of study information received. RESULTS: Willingness to participate did not differ by notification and authorization approach. Some (21%-36%) of the patients randomized to general notification with an explicit opt-out provision were not aware they would be enrolled by default. Acceptability was greatest for and similar among notification and authorization approaches that actively engaged the patient (eg, oral or written consent) and lower for approaches with less engagement (eg, general notification). Problems of understanding were found among 20%-55% of respondents, depending on the particular scenario. Most respondents (77%-94%) felt that participation in the hypothetical study posed no risks of harm to their health or privacy. CONCLUSIONS: Current attitudes about notification and authorization approaches and difficulties understanding pragmatic clinical research pose significant challenges for pragmatic research. Data from this study provide a starting point to developing solutions to these surprisingly complex issues. PMID- 28650926 TI - Hypercapnia-Induced Amelioration of the Intestinal Microvascular Oxygenation in Sepsis is Independent of the Endogenous Sympathetic Nervous System. AB - INTRODUCTION: Insufficient microvascular oxygenation (MUHBO2) of the intestinal mucosa worsens outcome of septic patients. Hypercapnia ameliorates MUHBO2, mediated via endogenous vasopressin release. Under physiological conditions, blockade of the endogenous sympathetic nervous system abolishes this protective effect of hypercapnia. The aim of our study was therefore to evaluate the role of the endogenous sympathetic nervous system during hypercapnia on intestinal MUHBO2 under septic conditions. METHODS: We randomized 80 male Wistar rats into eight groups. Sepsis was induced via colon ascendens stent peritonitis. The animals were subjected to 120 min of normocapnic (pCO2 35 mm Hg-45 mm Hg) or moderate hypercapnic (pCO2 65 mm Hg-75 mm Hg) ventilation 24 h after surgery. Animals received sympathetic blockade (hexamethonium 15 mg . kg (bolus) followed by 15 mg . kg . h (infusion) intravenously) or the same volume as vehicle (NaCl 0.9%). Microcirculatory oxygenation (MUHBO2) and perfusion (MUflow) were recorded using tissue reflectance spectrophotometry and laser Doppler. RESULTS: In septic animals, MUHBO2 decreased during normocapnia (-8.9 +/- 4%) and increased during hypercapnia (+7.8 +/- 7.5%). The additional application of hexamethonium did not influence these effects. MUHBO2 declined in normocapnic septic animals treated with hexamethonium similar to normocapnia alone (-6.1 +/- 5.4%) and increased in hypercapnic animals treated with hexamethonium similar to hypercapnia alone (+7.9 +/- 11.7%). Furthermore, hypercapnic ventilation ameliorated microcirculatory perfusion (MUflow) irrespective of whether animals received hexamethonium (from 113 +/- 54 [AU] to 206 +/- 87 [AU]) or vehicle (from 97 +/- 37 [AU]-169 +/- 52 [AU]). CONCLUSION: The amelioration of the intestinal microcirculation during hypercapnia in sepsis is independent of the endogenous sympathetic nervous system. PMID- 28650925 TI - QUANTITATIVE ANALYSIS OF THE INNER RETINAL LAYER THICKNESSES IN AGE-RELATED MACULAR DEGENERATION USING CORRECTED OPTICAL COHERENCE TOMOGRAPHY SEGMENTATION. AB - PURPOSE: To characterize inner retinal damage in patients with dry age-related macular degeneration (AMD) using high-resolution spectral domain optical coherence tomography images. METHODS: Sixty eyes of 60 patients with AMD were categorized using the Age-Related Eye Disease Study (AREDS) severity scale. Spectral domain optical coherence tomography images of these patients were quantified by manually correcting the segmentation of each retinal layer, including the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer to ensure accurate delineation of layers. The mean ganglion cell complex thickness values (ganglion cell layer + inner plexiform layer + retinal nerve fiber layer) were compared with 30 eyes of 30 healthy subjects. RESULTS: Ninety percent of eyes (81 eyes) required manual correction of segmentation. Compared with healthy subjects, mean ganglion cell complex thicknesses significantly decreased in more advanced dry AMD eyes, and this decrease was predominantly related to a change in inner plexiform layer thickness. There was no significant difference in thickness-related measurements between milder dry AMD (AREDS-2) eyes and healthy eyes (P > 0.05). CONCLUSION: In patients with dry AMD, automatic optical coherence tomography segmentation algorithms may be erroneous. As the severity of dry AMD increases, the inner plexiform layer layer becomes thinned, suggesting that transsynaptic degeneration may be occurring, as the photoreceptor layer is affected by AMD. PMID- 28650927 TI - Dexamethasone Prevents Lipopolysaccharide-Induced Epithelial Barrier Dysfunction in Rat Ileum. AB - Inflammatory mediators have been postulated as elementary inducing factors to the disruption of the intestinal tight junctions (TJ) and consequently, gut permeability and bacterial translocation. Corticosteroids are considered the mainstay in the treatment of septic shock; however, the impact of this therapy on the intestinal epithelial barrier dysfunction during septic shock remains unknown. Our aims were to demonstrate the role of low dexamethasone (DEX) doses in modulation of the inflammatory response, as well as the expression and the arrangement of TJ proteins in endotoxemic rats. One hour before the endotoxemia induction by lipopolysaccharide (LPS) administration, rats were pretreated with DEX at two low-doses (0.1 and 1.0 mg/kg). The parameters assessed included intestinal permeability, bacterial translocation, cytokines production, histology injury, localization, and expression of TJ proteins. Endotoxemic rats displayed intestinal epithelial barrier dysfunction, characterized by increased permeability and bacterial translocation, TJ disruption (opening and changes to its constituent proteins expression) and hyperactivation of the inflammatory response. On the other hand, the pretreatment with DEX attenuated the systemic and mucosal production of inflammatory mediators and also reverted the LPS induced ileal injuries, increasing the expression of occludin and claudin-1, but also reducing claudin-2. Moreover, the histological damages and the morphology of the TJ were preserved by the DEX administration, therefore reducing their LPS induced opening. The present study sheds light on the fact that early DEX treatment breaks the vicious cycle of local gut inflammation and barrier dysfunction in endotoxemia, especially preserving an essential structure of this monolayer epithelium, the TJ. PMID- 28650929 TI - Oxygen-Flow-Pressure Targets for Resuscitation in Critical Hemodynamic Therapy. AB - Far from traditional "vital signs," the field of hemodynamic monitoring (HM) is rapidly developing. However, it is also easy to misunderstand hemodynamic therapy as merely HM and some concrete bundles or guidelines for circulation support. Here, we describe the concept of "critical hemodynamic therapy" and clarify the concepts of the "therapeutic target" and "therapeutic endpoint" in clinical practice. Three main targets (oxygen delivery, blood flow, perfusion pressure) for resuscitation are reviewed in critically ill patients according to the sepsis guidelines and hemodynamic consensus. ScvO2 at least 70% has not been recommended as a directed target for initial resuscitation, and the directed target of mean arterial pressure (MAP) still is 65 mmHg. Moreover, the individual MAP target is underlined, and using flow-dependent monitoring to guide fluid infusion is recommended. The flow-directed target for fluid infusion might be a priority, but it remains controversial in resuscitation. The interpretation of these targets is necessary for adequate resuscitation and the correction of tissue hypoxia. The incoherence phenomenon of resuscitation (macrocirculation and microcirculation, tissue perfusion, and cellular oxygen utilization) is gaining increased attention, and early identification of these incoherences might be helpful to reduce the risk of over-resuscitation. PMID- 28650928 TI - Circulating Exosomes Isolated from Septic Mice Induce Cardiovascular Hyperpermeability Through Promoting Podosome Cluster Formation. AB - Septic shock increases vascular permeability, leading to multiple organ failure including cardiac dysfunction, a major contributor to septic death. Podosome, an actin-based dynamic membrane structure, plays critical roles in extracellular matrix degradation and angiogenesis. However, whether podosome contributes to endothelial barrier dysfunction during septic shock remains unknown. In this study, we found that the endothelial hyperpermeability, stimulated by phorbol 12 myristate 13-acetate and thrombin, was accompanied by increased formation of podosome clusters at the cell periphery, indicating a positive correlation between podosome clusters and endothelial leakage. Interestingly, we observed that circulating exosomes collected from septic mice were able to stimulate podosome cluster formation in cardiac endothelial cells, together with increased permeability in vitro/in vivo and cardiac dysfunction. Mechanistically, we identified that septic exosomes contained higher levels of reactive oxygen species (ROS) than normal ones, which were effectively transported to endothelial cells (ECs). Depletion of ROS in septic exosomes significantly reduced their capacity for promoting podosome cluster formation and thereby dampened vascular leakage. Finally, we elucidated that podosome cluster-induced endothelial hyperpermeability was associated with fragmentation/depletion of zonula occludens 1 (ZO-1) at the cell periphery. Our results demonstrate that septic exosomes were enriched with high amounts of ROS, which can be transported to ECs, leading to the generation of podosome clusters in target ECs and thereby, causing ZO-1 relocation, vascular leakage, and cardiac dysfunction. PMID- 28650930 TI - Clozapine Use in a Cohort of First-Episode Psychosis. AB - PURPOSE/BACKGROUND: For approximately one third of individuals treated for psychosis or schizophrenia, antipsychotic medications will have little or no therapeutic benefit. Clozapine remains the sole medication approved for treatment resistant schizophrenia, and studies have demonstrated its superior efficacy in reducing psychotic symptoms. METHODS/PROCEDURES: Data were collected from the medical records of people who originally presented with a first-episode psychosis between 1995 and 1999 (N = 171). Data were obtained from first presentation up to December 31, 2013 or until the patient was discharged or transferred. Information on service use and physical health was gathered using a data collection template designed specifically for this audit. FINDINGS/RESULTS: Twenty-eight (16.3%) of the cohort were prescribed clozapine. Data were available for 24 individuals. Of this clozapine subsample, the mean age at baseline was 23.11 (SD = 4.58); 82.14% (n = 23) were male; and 82.14% (n = 23) had a baseline diagnosis of schizophrenia. The mean time to first trial of clozapine was 6.7 years. The mean number of antipsychotics prescribed before clozapine trial was 4.85. After the initiation of clozapine, the mean number of hospital admissions reduced from 6.04 per year to 0.88 per year. IMPLICATIONS/CONCLUSIONS: Nearly 1 in 5 of the original cohort was considered to have a suboptimal response to trials of antipsychotic medication. The use of clozapine for treatment-resistant schizophrenia is underutilized, and better understanding of the barriers to prescribing clozapine is necessary given the implications for patient's quality of life and hospital admission rates. Physical health data further emphasizes the importance of physical health monitoring in this vulnerable population. PMID- 28650931 TI - Hypertrophic restrictive cardiomyopathy with apical thinning: a peculiar case of genotype-phenotype correlation. PMID- 28650932 TI - Incremental value of right atrial strain for early diagnosis of hemodynamic deterioration in pulmonary hypertension: a new noninvasive tool for a more comprehensive diagnostic paradigma. AB - AIMS: Increased right atrial size is related to adverse prognosis in pulmonary hypertension. The potential incremental value of right atrial function assessment is still unclear. We tested the relationship between right atrial two-dimensional speckle-tracking echocardiography impairment and hemodynamic, functional and clinical deterioration in patients with pulmonary hypertension. METHODS: We prospectively evaluated 36 patients (27 female, 9 male; mean age 68 +/- 13 years) with suspected pulmonary hypertension undergoing right heart catheterization and 16 matched controls. All patients underwent baseline evaluation by New York Heart Association functional class, 6-min walking test, brain natriuretic peptide (BNP), and standard two-dimensional echocardiography in less than 48 h of right heart catheterization. Right atrial two-dimensional speckle-tracking echocardiography was assessed by averaging all segments in standard four-chamber apical view. RESULTS: Right atrial global integral strain was significantly lower in patients compared with controls (11.40 +/- 5.22% vs. 25.72 +/- 5.95 P < 0.001). Moreover, right atrial global strain, but not right atrial area or volume, was correlated with invasively measured cardiac index (CI) (r = 0.72; P < 0.0001) and pulmonary vascular resistances in all patients, even though stronger in subjects with precapillary pulmonary hypertension (r = -0.42, P = 0.018; r = 0.54, P = 0.007 respectively; P = 0.007). It was also correlated with New York Heart Association (P = 0.027), BNP (P = 0.002), and 6-min walking test (P = 0.006). After multivariate analysis including right atrial volume, tricuspid annular plane systolic excursion, left atrial strain, and BNP, right atrial global strain showed the strongest correlation with CI. Area under the curve optimal cutoff for predicting CI at least 2.4 l/min/m was 17% (area under the curve: 0.83, sensitivity: 90%, specificity: 54%). CONCLUSION: Right atrial global strain can identify right atrial functional impairment before structural changes and may be implemented in a comprehensive, noninvasive right heart assessment for diagnosis and follow-up of pulmonary hypertension patients. PMID- 28650933 TI - CYP2E1 Gene Polymorphisms Related to the Formation of Coronary Artery Lesions in Kawasaki Disease. AB - BACKGROUND: Kawasaki disease (KD) is an acute febrile systemic vasculitis that disturbs coronary arteries. Patients' risks of adverse cardiovascular events and subclinical atherosclerosis have been found to significantly increase with polymorphisms of the human cytochrome P450. This current study aims to research the possible relationship between cytochrome P450, family 2, subfamily E and polypeptide 1 (CYP2E1) polymorphisms with KD. METHODS: We selected 6 tag single nucleotide polymorphisms (SNPs) of the CYP2E1 gene for TaqMan allelic discrimination assay in 340 KD patients and performed analysis on the clinical phenotypes and coronary artery lesions (CALs). CAL associations of tag SNPs were adjusted for age and gender in the logistic regression. RESULTS: The KD patients with a CC genotype of rs915906 demonstrated a greater proportion of CAL formation (P = 0.009). Furthermore, the GG genotype frequencies of rs2070676 showed a significantly greater risk for CAL formation in KD patients (P = 0.007). However, the SNPs of the CYP2E1 gene did not influence CAL formation in the participating KD patients either with or without high-dose acetylsalicylic acid. Using the expression quantitative trait locus analyses, we found that the SNPs associated with CAL formation in KD also affected CYP2E1 expression in certain cell types. CONCLUSION: This study is the first to find that the risk of CAL formation is related to CYP2E1 gene polymorphisms in KD patients. PMID- 28650934 TI - Congenital Cytomegalovirus Infection: Child Development, Quality of Life and Impact on Daily Life. AB - Congenital cytomegalovirus (cCMV) infection is the most common congenital infection worldwide and can lead to long-term impairments such as developmental delay. It is currently unknown how this affects the daily life of children and their parents. Children For this study, children with cCMV were identified by testing stored dried blood spots of 31,484 five-year-old children born in 2008 in the Netherlands. Parents of 133 children with cCMV and 274 children without cCMV participated and filled in questionnaires on the child's development, the child's and parents' quality of life, care provided for the children and consequences of cCMV on daily life. School performance reports at 6 years of age were also investigated. Children with cCMV had delays in general and expressive language development more often, and they attended physical therapists more frequently than children without cCMV. School performance of children with cCMV and symptoms at birth was poorer than that of cCMV-negative children with similar symptoms at birth. The quality of life of children with long-term impairment was lower in children with cCMV than those without cCMV. Parents of children with cCMV and long-term impairments reported more physical and concentration problems than parents of children without cCMV. These findings indicate that cCMV has a considerable impact not only on the child's development and school performance but also on the daily life of children and their parents. The care for children with cCMV should therefore include support for motor and speech-language development as well as family-centered care. PMID- 28650935 TI - Fulminant Sepsis Due to Granulibacter bethesdensis in a 4-Year-Old Boy With X Linked Chronic Granulomatous Disease. AB - Granulibacter bethesdensis is a Gram-negative bacillus described as a pathogen exclusively in patients with chronic granulomatous disease, a phagocytic disorder that impairs the ability to clear catalase-producing organisms. Granulibacter usually causes chronic and recurrent lymphadenopathies. We report the fatal case of a 4-year-old boy with chronic granulomatous disease, who presented with sepsis after a few days of abdominal pain and diarrhea. PMID- 28650936 TI - Colistin Use in Neonates and Children With Infections Due to Carbapenem-resistant Bacteria. AB - Current evidence on the use of colistin in pediatric patients for infections caused by carbapenem-resistant bacteria is based on retrospective case series. The coadministration of colistin with other antimicrobial agents was associated with a relatively low rate of nephrotoxicity and a favorable outcome in >70% of these patients. Further study of colistin pharmacokinetics in children and neonates will likely lead to optimization of dosage recommendations. PMID- 28650937 TI - Weak HIV Antibody Responses in Perinatally Infected Young Adults: Weak HIV Antibody Responses in Perinatally Infected Adults. AB - We compared the antibody response to HIV using 2 serologic cross-sectional incidence assays in adults with perinatally acquired HIV, to elite controllers and individuals exposed to antiretroviral therapy who were all infected as adults. Low antibody responses were seen more frequently in adults with perinatally acquired HIV, both overall and when stratified by viral suppression status. PMID- 28650938 TI - Outbreak Caused by Escherichia coli O18: K1: H7 Sequence Type 95 in a Neonatal Intensive Care Unit in Barcelona, Spain. AB - BACKGROUND: Escherichia coli is one of the most frequent causes of late-onset neonatal sepsis. The aim of this study was to characterize an outbreak of neonatal sepsis occurring in the neonatal intensive care unit of the Hospital Clinic of Barcelona from April to August 2013. METHODS: After presentation of the index case, all E. coli isolates from previously hospitalized neonates, health care workers and neonates admitted to the neonatal intensive care unit from April to October 2013 were tested for K1 antigen positivity and epidemiologically compared by pulse-field gel electrophoresis. Furthermore, the E. coli K1 strains collected from neonates during this period were analyzed by different methods (serotyping, phylotyping, polymerase chain reaction of virulence factors, antimicrobial resistance and "in vitro" assays in Human Brain Microvascular Endothelial Cells (HBMEC)). RESULTS: An E. coli O18:K1:H7 sequence type 95 and phylogenetic group B2 strain was the cause of the outbreak involving 6 preterm neonates: 1 with late septicemia because of a urinary focus and 5 with late-onset septicemia and meningitis, 3 of whom died. All showed the same pulsotype, full resistance to ampicillin and intermediate resistance to gentamicin. The outbreak strain carried the pathogenicity island (PAI) IIJ96-like domain that could explain the high-grade bacteremia necessary to develop meningitis. CONCLUSIONS: All the E. coli isolates responsible for this outbreak belonged to a single clone suggesting a common source of infection, and it was categorized as O18:K1:H7. Despite the bacteria's pathogenicity has an important role in the severity of infection, the host-associated factors were crucial for the fatal outcomes. PMID- 28650939 TI - CD1d-Restricted Natural Killer T Cells Are Preserved in Indian Long-Term Nonprogressors. AB - BACKGROUND: Natural killer T (NKT) cells act as a bridge between innate and adaptive immune responses. Limited information is available regarding the role of NKT cells in the HIV disease progression especially HIV-1 C infection. METHODOLOGY: NKT cells were characterized for their frequency and the activation, aging, exhaustion status, and their proliferation ability in 32 long-term nonprogressors (LTNPs), 40 progressors, 18 patients before and after suppressive combination antiretroviral therapy (cART) along with 35 HIV-1-negative subjects using multicolor flow cytometry. RESULTS: The frequencies of total NKT cells and their subpopulation were significantly higher in LTNPs as compared with those obtained in progressors (P < 0.0001) and were significantly associated with higher CD4 counts and with lower plasma viral loads. The percentage of activated, aged, and exhausted NKT cells were significantly lower in LTNPs as compared with the progressors and inversely correlated with CD4 count and positively with plasma viral loads. The NKT cells from the LTNPs showed higher proliferation ability. The frequency and proliferation ability of the NKT cells were partially restored after 12 months of suppressive cART but still lower than the levels in LTNPs. The degree of restoration after cART was similar in both CD4 and CD4 NKT cells. CONCLUSION: The findings demonstrate significant association of preserved NKT cells with the nonprogressive HIV infection and also showed that exhausted NKT cells are associated with disease progression. Further characterization of their functionality and assessment of sustenance in HIV infection will help to understand the HIV pathogenesis and to develop immune therapies. PMID- 28650940 TI - Surgical Fixation of Periprosthetic Humerus Fractures Using an Extension Plate: Surgical Technique and Report of 5 Cases. AB - Periprosthetic fractures after shoulder arthroplasty occur in up to 2% of patients. In patients with stable components who fail or cannot undergo nonoperative management, stable fixation is required. We present a new technique to obtain proximal fixation around the humeral component using a 4.5-mm large fragment plate and a 3.5-mm attachment plate. PMID- 28650942 TI - Open Supracondylar-Intercondylar Fractures of the Femur Treatment With Taylor Spatial Frame. AB - OBJECTIVES: To evaluate the Taylor spatial frame (TSF) for primary and definitive fixation of open supracondylar-intracondylar femoral (SIF) fractures. DESIGN: Retrospective. SETTING: Level I trauma center. PATIENTS: Subset of 20 SIF open fractures treated with TSF extracted from a consecutive series of 80 SIF fractures treated between 2007 and 2013. INTERVENTION: Eighteen (90%) fractures underwent definitive fixation with the TSF; 2 were treated primarily within 24 hours of injury. Mean time interval between primary treatment and secondary TSF was 5 days. MAIN OUTCOME MEASUREMENTS: Clinical and radiological. RESULTS: Complete union was obtained in 17 (85%) fractures without additional surgery at an average of 33 weeks. Three nonunions and 1 malunion occurred. No deep infection occurred. Results based on Association for the Study and Application of the Method of Ilizarov criteria: 37% excellent, and 63% good for bone outcomes; 5% excellent, 58% good, and 37% fair for functional outcomes. Neer knee scores were 21% excellent, 68% good, and 11% fair. The mechanical lateral distal femoral angle and anatomic posterior distal femoral angle values were within normal range in 80% and 90% of patients, respectively. Abnormal mechanical axis deviation was observed in 4 (20%) cases (2 had associated tibia fractures). CONCLUSIONS: Primary and definitive fixation with the TSF are effective. Advantages include continuity of device until union, reduced risk of infection, early mobilization, restoration of primary defect caused by bone loss, easy and accurate application, convertibility and versatility, and improved union rate and range of motion for SIF open fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28650943 TI - Intramedullary Fixation With Minimally Invasive Clamp-Assisted Reduction for the Treatment of Ipsilateral Femoral Neck and Subtrochanteric Fractures: A Technical Trick. AB - The purpose of this study is to describe a surgical technique for intramedullary fixation and minimally invasive clamp-assisted reduction with selective cerclage wiring for the management of combined ipsilateral femoral neck and subtrochanteric fractures and to present the clinical outcomes in 17 patients after treatment using this technique. PMID- 28650944 TI - Intramedullary Implant Choice and Cost in the Treatment of Pediatric Diaphyseal Forearm Fractures. AB - OBJECTIVES: To compare outcomes and costs between titanium elastic nails (TENs), stainless steel elastic nails (SENs), and Kirschner wires (K-wires) in the treatment of pediatric diaphyseal forearm fractures with intramedullary fixation. DESIGN: Retrospective cohort study. SETTING: Level 1 Pediatric Trauma Center. PATIENTS/PARTICIPANTS: A total of 100 patients (65 male and 35 female) younger than 18 years with diaphyseal forearm fractures treated with intramedullary fixation were included in the study. INTERVENTION: Patients received single or both bone intramedullary fixation with either TENs, SENs, or K-wires. MAIN OUTCOME MEASUREMENTS: Time to radiographic union, complication rate, surgical time, and average cost per implant. RESULTS: One hundred patients were included in the study. Thirty-one patients were treated with TENs, 30 with SENs, and 39 with K-wires. No significant difference in time to radiographic union, complication rate, or surgical time was found between the 3 types of fixation. Average time to union was 9.4 +/- 5.4 weeks, and complication rate was 12.9% for TENs, 10.0% for SENs, and 12.8% for K-wires. There was a significant difference in cost per implant, with an average cost of $639, $172, and $24 for TENs, SENs, and K-wires, respectively (P < 0.001). CONCLUSIONS: This study demonstrates no difference between TENs, SENs, and K-wires in the treatment of pediatric diaphyseal forearm fractures with regards to outcome, time to union, surgical time, or complication rates. Given the significant cost difference between these implants, we recommend that surgeons consider modifying their implant selection to help mitigate cost. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28650945 TI - Treatment Approach for Infection of Healed Fractures After Internal Fixation. AB - OBJECTIVE: To review the efficacy of a treatment approach for patients with infection and colonized implants after open reduction and internal fixation of fractures. DESIGN: Retrospective case series. SETTING: Level one trauma center. PATIENTS: Twenty patients were treated for wound infection with colonized implants after open reduction and internal fixation. INTERVENTION: Surgical debridement, removal of implants, and a short postoperative oral antibiotic course. MAIN OUTCOME MEASUREMENT: The course of patients after surgical debridement and removal of implants, including culture results, antibiotic administration, and presence of recurrent clinical infection and radiographic union. RESULTS: Twenty patients had clinical presentations, including skin breakdown, serous drainage, purulent drainage and/or exposed implants, most commonly of the tibia (15 of 20). Mean time from index procedure to debridement with implant removal was 19.7 months. At the time of debridement and implant removal, 18 of 20 (90%) patients had a positive intraoperative culture (16 routine cultures and 2 broth cultures). The most common bacteria were Enterobacter cloacae (5/17) and methicillin-sensitive Staphylococcus aureus (4/17). All patients had soft tissue healing without signs of recurrent infection after mean follow up of 40 months after implant removal. CONCLUSIONS: Surgical debridement with implant removal plus a short oral antibiotic course is effective to resolve wound infection with a colonized implant in the setting of healed fracture after internal fixation. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28650946 TI - The Hyperextension Tibial Plateau Fracture Pattern: A Predictor of Poor Outcome. AB - OBJECTIVES: To assess the outcome of patients with hyperextension bicondylar tibial plateau fractures (HEBTPs) and those with other complex tibial plateau fractures. DESIGN: Retrospective cohort design. SETTING: Academic Medical Center. PATIENTS: A total of 84 patients were included in the study. There were 69 patients with 69 knees (82%) that had sustained non-HEBTPs and 15 patients with 15 knees (18%) that had HEBTPs. INTERVENTION: Surgical repair of bicondylar tibial plateau fracture. MAIN OUTCOME MEASURES: Clinical and functional outcomes included knee range of motion, postoperative alignment, numerical rating scale pain scores, and Short Musculoskeletal Functional Assessment (SMFA) scores at long-term follow-up. Complications were recorded for both cohorts including infection and posttraumatic osteoarthritis. RESULTS: There was no difference in knee range of motion at 1-year follow-up between hyperextension and nonhypertension patients. Patients with hyperextension mechanisms did however have higher functional (SMFA) scores and a trend of higher pain scores, indicating worsened functional outcomes and were more likely than their nonhyperextension mechanism counterparts to have associated soft-tissue damage and to develop posttraumatic osteoarthritis. CONCLUSIONS: Non-HEBTP and HEBTP fracture patients have similar outcomes in terms of range of motion at approximately 1 year of follow-up, however, differ significantly in terms of functional recovery and the types of complications associated with their injuries. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28650948 TI - Hip Fracture Treatment at Orthopaedic Teaching Hospitals: Better Care at a Lower Cost. AB - OBJECTIVE: To compare the cost and outcomes of patients treated at orthopaedic teaching hospitals (OTHs) with those treated at nonteaching hospitals (NTHs). DESIGN: Retrospective study. SETTING: The Statewide Planning and Research Cooperative Systems (SPARCS) database, which includes all admissions to New York State hospitals from 2000-2011. PATIENTS/PARTICIPANTS: A total of 165,679 patients with isolated closed hip fracture 65 years of age and older met inclusion criteria. Of them, 57,279 were treated at OTH and 108,400 were treated at NTH. INTERVENTION: Admission for the management of a hip fracture. MAIN OUTCOME MEASURE: Cost, length of stay (LOS), and inpatient mortality. RESULTS: Univariate analysis shows that mean total hospital costs were higher at OTH ($16,576 +/- $17,514) versus NTH ($13,358 +/- $11,366) (P < 0.001); LOS was equivalent at OTH (8.0 +/- 9.0 days) versus NTH (8.0 +/- 7.6 days) (P = 0.904); and mortality was lower in OTH (3.4%) versus NTH (4.0%) (P < 0.001). In the multivariate total cost analysis, in addition to demographic differences, we identified total hospital beds and total ICU beds as significant confounding variables. Interestingly, when controlling for these patient and hospital factors, OTH designation was not a significant predictor of cost. In addition, multivariate analysis found that OTH status decreased LOS by 0.743 days (95% confidence interval: 0.632-0.854, P < 0.001) and mortality by 21% (odds ratio 0.794, 95% confidence interval: 0.733-0.859, P < 0.001), confirming the univariate trends. CONCLUSIONS: While OTH may seem to have higher hospital costs for operative hip fractures on cursory analysis, controlling for patient and hospital factors including hospital bed number negates this effect such that OTH has no additional cost compared with NTH. In addition, OTH status is associated with shorter LOS and lower in-hospital mortality. With the results of this study, health care systems and patients should feel confident that the quality of care at teaching hospitals is no less and potentially better than that at NTH with no added cost. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28650950 TI - Neurobiologic Correlates of Attention and Memory Deficits Following Critical Illness in Early Life. AB - OBJECTIVES: Survivors of critical illness in early life are at risk of long-term memory and attention impairments. However, their neurobiologic substrates remain largely unknown. DESIGN: A prospective follow-up study. SETTING: Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands. PATIENTS: Thirty-eight school-age (8-12 yr) survivors of neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia with an intelligence quotient greater than or equal to 80 and a below average score (z score <= -1.5) on one or more memory tests. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intelligence, attention, memory, executive functioning, and visuospatial processing were assessed and compared with reference data. White matter microstructure and hippocampal volume were assessed using diffusion tensor imaging and structural MRI, respectively. Global fractional anisotropy was positively associated with selective attention (beta = 0.53; p = 0.030) and sustained attention (beta = 0.48; p = 0.018). Mean diffusivity in the left parahippocampal region of the cingulum was negatively associated with visuospatial memory, both immediate (beta = -0.48; p = 0.030) and delayed recall (beta = -0.47; p = 0.030). Mean diffusivity in the parahippocampal region of the cingulum was negatively associated with verbal memory delayed recall (left: beta = -0.52, p = 0.021; right: beta = -0.52, p = 0.021). Hippocampal volume was positively associated with verbal memory delayed recall (left: beta = 0.44, p = 0.037; right: beta = 0.67, p = 0.012). Extracorporeal membrane oxygenation treatment or extracorporeal membrane oxygenation type did not influence the structure-function relationships. CONCLUSIONS: Our findings indicate specific neurobiologic correlates of attention and memory deficits in school-age survivors of neonatal extracorporeal membrane oxygenation and congenital diaphragmatic hernia. A better understanding of the neurobiology following critical illness, both in early and in adult life, may lead to earlier identification of patients at risk for impaired neuropsychological outcome with the use of neurobiologic markers. PMID- 28650951 TI - DEVELOPMENT AND PROGRESSION OF A LAMELLAR MACULAR HOLE WITH LAMELLAR HOLE ASSOCIATED EPIRETINAL PROLIFERATION. AB - PURPOSE: To describe evolution and progression of a lamellar macular hole (LMH) with "lamellar hole-associated epiretinal proliferation (LHEP)" using spectral domain optical coherence tomography and fundus autofluorescence. METHODS: Observational case report. RESULTS: We report on a 63-year-old male patient demonstrating a complete history of LMH development with LHEP occurring during a follow-up period of 8 years. Presenting with a normal foveal contour and attached posterior vitreous at first visit, an LMH developed shortly after incomplete posterior vitreous detachment with vitreopapillary adhesion. On spectral-domain optical coherence tomography images, progression of the LMH including enlargement of the intraretinal cavitation and decrease in the retinal thickness were documented. An increase of LHEP was first documented 6 months after LMH evolution. One month after cataract surgery and 6 years after the first visit, a full-thickness macular hole developed that closed spontaneously after 4 weeks. Localization of LHEP had moved into the foveal defect toward the outer retinal layers. Thereafter, the LMH was stable, and the patient presented with a visual acuity of 20/25. CONCLUSION: Proper follow-up time is important for studying eyes with an LMH. Epimacular cell proliferation shows progression over time that appears to be associated with morphologic changes of the LMH including shape of the lamellar defect, amount of LHEP, and contractive properties of epiretinal tissue. The presence of LHEP was documented shortly after posterior vitreous detachment. PMID- 28650952 TI - NOVEL PATIENT POSITIONING APPARATUS FOR RETINAL SURGERY IN A CASE OF SEVERE KYPHOSIS. AB - PURPOSE: To describe a novel patient positioning apparatus for intraocular surgery capable of accommodating patients with thoracic kyphosis. METHODS: Case report. RESULTS: A 60-year-old man presented with a macula-off retinal detachment and severe ankylosing spondylitis. The patient was scheduled for combined pars plana vitrectomy and scleral buckle. Because of the patient's severe kyphosis, a custom-designed positioning apparatus was built. The setup involved a canvas with 10 sewn-on straps and a Skytron operating table with strap inserts. Padding and blankets were also used to secure the patient comfortably in the Trendelenburg position. Surgery was uncomplicated and retinal detachment repair was successfully performed. CONCLUSION: To the authors' knowledge, this is the first report detailing a vest-like support apparatus for patients with thoracic kyphosis used in vitreoretinal surgery. This apparatus can be prepared using any conventional operating table, and it offers an effective approach to intraocular surgery for patients who cannot lie flat. PMID- 28650953 TI - De Novo Paternal FBN1 Mutation Detected in Embryos Before Implantation. AB - BACKGROUND Marfan syndrome (MFS) is an autosomal dominant disease caused by mutations in the Fibrillin (FBN)1 gene and characterized by disorders in the cardiovascular, skeletal, and visual systems. The diversity of mutations and phenotypic heterogeneity of MFS make prenatal molecular diagnoses difficult. In this study, we used pre-implantation genetic diagnosis (PGD) to identify the pathogenic mutation in a male patient with MFS and to determine whether his offspring would be free of the disease. MATERIAL AND METHODS The history and pedigree of the proband were analyzed. Mutation analysis was performed on the couple and immediate family members. The couple chose IVF treatment and 4 blastocysts were biopsied. PGD was carried out by targeted high-throughput sequencing of the FBN1 gene in the embryos, along with single-nucleotide polymorphism haplotyping. Sanger sequencing was used to confirm the causative mutation. RESULTS c.2647T>C (p.Trp883Arg) was identified as the de novo likely pathogenic mutation in the proband. Whole-genome amplification and sequencing of the 3 embryos revealed that they did not carry the mutation, and 1 blastocyst was transferred back to the uterus. The amniocentesis test result analyzed by Sanger sequencing confirmed the PGD. A premature but healthy infant free of heart malformations was born. CONCLUSIONS The de novo mutation c.2647T>C (p.Trp883Arg) in FBN1 was identified in a Chinese patient with MFS. Embryos without the mutation were identified by PGD and resulted in a successful pregnancy. PMID- 28650955 TI - NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis. AB - Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passenger events that hide the contribution of driver events. Here we propose a method, NetNorM, to represent whole-exome somatic mutation data in a form that enhances cancer-relevant information using a gene network as background knowledge. We evaluate its relevance for two tasks: survival prediction and unsupervised patient stratification. Using data from 8 cancer types from The Cancer Genome Atlas (TCGA), we show that it improves over the raw binary mutation data and network diffusion for these two tasks. In doing so, we also provide a thorough assessment of somatic mutations prognostic power which has been overlooked by previous studies because of the sparse and binary nature of mutations. PMID- 28650956 TI - In vitro and in vivo effects of kisspeptin antagonists p234, p271, p354, and p356 on GPR54 activation. AB - Kisspeptins (KPs) and their receptor (GPR54 or KiSS1R) play a key-role in regulation of the hypothalamic-pituitary-gonadal axis and are therefore interesting targets for therapeutic interventions in the field of reproductive endocrinology. As dogs show a rapid and robust LH response after the administration of KP10, they can serve as a good animal model for research concerning KP signaling. The aims of the present study were to test the antagonistic properties of KP analogs p234, p271, p354, and p356 in vitro, by determining the intracellular Ca2+ response of CHEM1 cells that stably express human GPR54, and to study the in vivo effects of these peptides on basal plasma LH concentration and the KP10-induced LH response in female dogs. Exposure of the CHEM1 cells to KP-10 resulted in a clear Ca2+ response. P234, p271, p354, and p356 did not prevent or lower the KP10-induced Ca2+ response. Moreover, the in vivo studies in the dogs showed that none of these supposed antagonists lowered the basal plasma LH concentration and none of the peptides lowered the KP10 induced LH response. In conclusion, p234, p271, p354, and p356 had no antagonistic effects in vitro nor any effect on basal and kisspeptin-stimulated plasma LH concentration in female dogs. PMID- 28650957 TI - Determinants of generic and specific health-related quality of life in patients with Parkinson's disease. AB - OBJECTIVES: Generic and disease-specific health-related quality of life (HRQoL) instruments may reflect different aspects of lives in patients with Parkinson's disease (PD) and thus be associated with different determinants. We used the same cluster of predictors for the generic and disease-specific HRQoL instruments to examine and compare the determinants of HRQoL. METHOD: HRQoL was measured in 92 patients with PD by the 36-item Short-Form Health Survey (SF-36) and the 39-item Parkinson's Disease Questionnaire (PDQ-39). The predictors included demographic and disease characteristics, and motor and non-motor symptoms. Multiple regression analyses were used to identify HRQoL determinants. RESULTS: Depressive symptoms and motor difficulties of daily living were the first two significant determinants for both instruments. The other significant determinant for the SF 36 was fatigue and non-motor difficulties of daily living, and for the PDQ-39 was motor signs of PD. CONCLUSIONS: The results suggest the importance of the evaluation and intervention focused on depressive symptoms and motor difficulties of daily living in patients with PD. In addition, the SF-36 seems more related to non-motor symptoms, while the PDQ-39 appears more associated with motor symptoms. This information is important for understanding results from these two instruments and for choosing which to use. PMID- 28650954 TI - Prevalence of sexual dimorphism in mammalian phenotypic traits. AB - The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans. PMID- 28650958 TI - Dynamics and impact of homologous recombination on the evolution of Legionella pneumophila. AB - Legionella pneumophila is an environmental bacterium and the causative agent of Legionnaires' disease. Previous genomic studies have shown that recombination accounts for a high proportion (>96%) of diversity within several major disease associated sequence types (STs) of L. pneumophila. This suggests that recombination represents a potentially important force shaping adaptation and virulence. Despite this, little is known about the biological effects of recombination in L. pneumophila, particularly with regards to homologous recombination (whereby genes are replaced with alternative allelic variants). Using newly available population genomic data, we have disentangled events arising from homologous and non-homologous recombination in six major disease associated STs of L. pneumophila (subsp. pneumophila), and subsequently performed a detailed characterisation of the dynamics and impact of homologous recombination. We identified genomic "hotspots" of homologous recombination that include regions containing outer membrane proteins, the lipopolysaccharide (LPS) region and Dot/Icm effectors, which provide interesting clues to the selection pressures faced by L. pneumophila. Inference of the origin of the recombined regions showed that isolates have most frequently imported DNA from isolates belonging to their own clade, but also occasionally from other major clades of the same subspecies. This supports the hypothesis that the possibility for horizontal exchange of new adaptations between major clades of the subspecies may have been a critical factor in the recent emergence of several clinically important STs from diverse genomic backgrounds. However, acquisition of recombined regions from another subspecies, L. pneumophila subsp. fraseri, was rarely observed, suggesting the existence of a recombination barrier and/or the possibility of ongoing speciation between the two subspecies. Finally, we suggest that multi-fragment recombination may occur in L. pneumophila, whereby multiple non-contiguous segments that originate from the same molecule of donor DNA are imported into a recipient genome during a single episode of recombination. PMID- 28650959 TI - Peridomestic Aedes malayensis and Aedes albopictus are capable vectors of arboviruses in cities. AB - BACKGROUND: Dengue and chikungunya are global re-emerging mosquito-borne diseases. In Singapore, sustained vector control coupled with household improvements reduced domestic mosquito populations for the past 45 years, particularly the primary vector Aedes aegypti. However, while disease incidence was low for the first 30 years following vector control implementation, outbreaks have re-emerged in the past 15 years. Epidemiological observations point to the importance of peridomestic infection in areas not targeted by control programs. We investigated the role of vectors in peri-domestic areas. METHODS: We carried out entomological surveys to identify the Aedes species present in vegetated sites in highly populated areas and determine whether mosquitoes were present in open-air areas frequented by people. We compared vector competence of Aedes albopictus and Aedes malayensis with Ae. aegypti after oral infection with sympatric dengue serotype 2 and chikungunya viruses. Mosquito saliva was tested for the presence of infectious virus particles as a surrogate for transmission following oral infection. RESULTS: We identified Aedes albopictus and Aedes malayensis throughout Singapore and quantified their presence in forested and opened grassy areas. Both Ae. albopictus and Ae. malayensis can occupy sylvatic niches and were highly susceptible to both arboviruses. A majority of saliva of infected Ae. malayensis contained infectious particles for both viruses. CONCLUSIONS: Our study reveals the prevalence of competent vectors in peri domestic areas, including Ae. malayensis for which we established the vector status. Epidemics can be driven by infection foci, which are epidemiologically enhanced in the context of low herd immunity, selective pressure on arbovirus transmission and the presence of infectious asymptomatic persons, all these conditions being present in Singapore. Learning from Singapore's vector control success that reduced domestic vector populations, but has not sustainably reduced arboviral incidence, we suggest including peri-domestic vectors in the scope of vector management. PMID- 28650960 TI - Phosphatidylserine externalization, "necroptotic bodies" release, and phagocytosis during necroptosis. AB - Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the "find me" and "eat me" signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such "eat me" signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific "find me" and "eat me" signals. PMID- 28650962 TI - Novel inference models for estimation of abundance, survivorship and recruitment in mosquito populations using mark-release-recapture data. AB - BACKGROUND: Experiments involving mosquito mark-release-recapture (MRR) design are helpful to determine abundance, survival and even recruitment of mosquito populations in the field. Obstacles in mosquito MRR protocols include marking limitations due to small individual size, short lifespan, low efficiency in capturing devices such as traps, and individual removal upon capture. These limitations usually make MRR analysis restricted to only abundance estimation or a combination of abundance and survivorship, and often generate a great degree of uncertainty about the estimations. METHODOLOGY/PRINCIPAL FINDINGS: We present a set of Bayesian biodemographic models designed to fit data from most common mosquito recapture experiments. Using both field data and simulations, we consider model features such as capture efficiency, survival rates, removal of individuals due to capturing, and collection of pupae. These models permit estimation of abundance, survivorship of both marked and unmarked mosquitoes, if different, and recruitment rate. We analyze the accuracy of estimates by varying the number of released individuals, abundance, survivorship, and capture efficiency in multiple simulations. These methods can stand capture efficiencies as low as usually reported but their accuracy depends on the number of released mosquitoes, abundance and survivorship. We also show that gathering pupal counts allows estimating differences in survivorship between released mosquitoes and the unmarked population. CONCLUSION/SIGNIFICANCE: These models are important both to reduce uncertainty in evaluating MMR experiments and also to help planning future MRR studies. PMID- 28650961 TI - MFPred: Rapid and accurate prediction of protein-peptide recognition multispecificity using self-consistent mean field theory. AB - Multispecificity-the ability of a single receptor protein molecule to interact with multiple substrates-is a hallmark of molecular recognition at protein protein and protein-peptide interfaces, including enzyme-substrate complexes. The ability to perform structure-based prediction of multispecificity would aid in the identification of novel enzyme substrates, protein interaction partners, and enable design of novel enzymes targeted towards alternative substrates. The relatively slow speed of current biophysical, structure-based methods limits their use for prediction and, especially, design of multispecificity. Here, we develop a rapid, flexible-backbone self-consistent mean field theory-based technique, MFPred, for multispecificity modeling at protein-peptide interfaces. We benchmark our method by predicting experimentally determined peptide specificity profiles for a range of receptors: protease and kinase enzymes, and protein recognition modules including SH2, SH3, MHC Class I and PDZ domains. We observe robust recapitulation of known specificities for all receptor-peptide complexes, and comparison with other methods shows that MFPred results in equivalent or better prediction accuracy with a ~10-1000-fold decrease in computational expense. We find that modeling bound peptide backbone flexibility is key to the observed accuracy of the method. We used MFPred for predicting with high accuracy the impact of receptor-side mutations on experimentally determined multispecificity of a protease enzyme. Our approach should enable the design of a wide range of altered receptor proteins with programmed multispecificities. PMID- 28650963 TI - A new mechanistic approach for the further development of a population with established size bimodality. AB - Usually, the origin of a within-cohort bimodal size distribution is assumed to be caused by initial size differences or by one discrete period of accelerated growth for one part of the population. The aim of this study was to determine if more continuous pathways exist allowing shifts from the small to the large fraction within a bimodal age-cohort. Therefore, a Eurasian perch population, which had already developed a bimodal size-distribution and had differential resource use of the two size-cohorts, was examined. Results revealed that formation of a bimodal size-distribution can be a continuous process. Perch from the small size-cohort were able to grow into the large size-cohort by feeding on macroinvertebrates not used by their conspecifics. The diet shifts were accompanied by morphological shape changes. Intra-specific competition seemed to trigger the development towards an increasing number of large individuals. A stage-structured matrix model confirmed these assumptions. The fact that bimodality can be a continuous process is important to consider for the understanding of ecological processes and links within ecosystems. PMID- 28650964 TI - Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization. AB - Retinal ischemia and pathological angiogenesis cause severe impairment of sight. Oxygen-induced retinopathy (OIR) in young mice is widely used as a model to investigate the underlying pathological mechanisms and develop therapeutic interventions. We compared directly the conventional OIR model (exposure to 75% O2 from postnatal day (P) 7 to P12) with an alternative, accelerated version (85% O2 from P8 to P11). We found that accelerated OIR induces similar pre-retinal neovascularization but greater retinal vascular regression that recovers more rapidly. The extent of retinal gliosis is similar but neuroretinal function, as measured by electroretinography, is better maintained in the accelerated model. We found no systemic or maternal morbidity in either model. Accelerated OIR offers a safe, reliable and more rapid alternative model in which pre-retinal neovascularization is similar but retinal vascular regression is greater. PMID- 28650965 TI - Epigenetic adaptation of the placental serotonin transporter gene (SLC6A4) to gestational diabetes mellitus. AB - We tested the hypothesis that gestational diabetes mellitus (GDM) alters the DNA methylation pattern of the fetal serotonin transporter gene (SLC6A4), and examined the functional relevance of DNA methylation for regulation of the SLC6A4 expression in the human placenta. The study included 50 mother-infant pairs. Eighteen mothers were diagnosed with GDM and 32 had normal glucose tolerance (NGT). All neonates were of normal birth weight and born at term by planned Cesarean section. DNA and RNA were isolated from samples of tissue collected from the fetal side of the placenta immediately after delivery. DNA methylation was quantified at 7 CpG sites within the SLC6A4 distal promoter region using PCR amplification of bisulfite treated DNA and subsequent DNA sequencing. SLC6A4 mRNA levels were measured by reverse transcription-quantitative PCR (RT-qPCR). Functional SLC6A4 polymorphisms (5HTTLPR, STin2, rs25531) were genotyped using standard PCR-based procedures. Average DNA methylation across the 7 analyzed loci was decreased in the GDM as compared to the NGT group (by 27.1%, p = 0.037) and negatively correlated, before and after adjustment for potential confounder/s, with maternal plasma glucose levels at the 24th to 28th week of gestation (p<0.05). Placental SLC6A4 mRNA levels were inversely correlated with average DNA methylation (p = 0.010) while no statistically significant association was found with the SLC6A4 genotypes (p>0.05). The results suggest that DNA methylation of the fetal SLC6A4 gene is sensitive to the maternal metabolic state in pregnancy. They also indicate a predominant role of epigenetic over genetic mechanisms in the regulation of SLC6A4 expression in the human placenta. Longitudinal studies in larger cohorts are needed to verify these results and determine to which degree placental SLC6A4 changes may contribute to long-term outcomes of infants exposed to GDM. PMID- 28650966 TI - Insecticide resistance to permethrin and malathion and associated mechanisms in Aedes aegypti mosquitoes from St. Andrew Jamaica. AB - The emergence of novel diseases spread by the Aedes aegypti mosquito in Jamaica and the Caribbean, has prompted studies on insecticide resistance towards effective management of the vector. Though Jamaica has been using the organophosphate insecticide malathion in its vector control program for more than 30 years, resistance to the pesticide has not been tested in over a decade. We analyzed resistance to malathion and the pyrethroid insecticide, permethrin on mosquitoes collected across St. Andrew, Jamaica, and analyzed the molecular basis of resistance. The Center for Disease Control (CDC) bioassay revealed that Ae. aegypti mosquitoes from St. Andrew, Jamaica were resistant to permethrin (15 MUg/bottle) with mortalities at 0-8% at 30 minute exposure time, while contact with malathion (50 MUg/bottle) revealed <= 50% mortality at 15 minutes, which increased to 100% at 45 minutes. The standard susceptible New Orleans (NO) strain exhibited 100% mortality within15 minutes. The activities of multifunction oxidases and p-nitro phenyl-acetate esterases were significantly greater in most Jamaican populations in comparison to the NO strain, while activities of glutathione-S-transferase, acetylcholinesterase, alpha-esterase and beta-esterase activity were relatively equal, or lower than that of the control strain. The frequency of knockdown resistance mutations in the voltage dependent sodium channel gene were measured. All collections were fixed for Cys1,534 while 56% of mosquitoes were Ile1,016/Val1,016 heterozygotes, and 33% were Ile1,016 homozygotes. Aedes aegypti from St. Andrew Jamaica are resistant to permethrin with variations in the mode of mechanism, and possibly developing resistance to malathion. Continued monitoring of resistance is critically important to manage the spread of the vector in the country. PMID- 28650967 TI - Author contributions to ecological publications: What does it mean to be an author in modern ecological research? AB - Authorship is a central element of scientific research carrying a variety of rewards and responsibilities, and while various guidelines exist, actual author contributions are often ambiguous. Inconsistent or limited contributions threaten to devalue authorship as intellectual currency and diminish authors' responsibility for published content. Researchers have assessed author contributions in the medical literature and other research fields, but similar data for the field of ecological research are lacking. Authorship practices in ecological research are broadly representative of a variety of fields due to the cross-disciplinary nature of collaborations in ecological studies. To better understand author contributions to current research, we distributed a survey regarding co-author contributions to a random selection of 996 lead authors of manuscripts published in ecological journals in 2010. We obtained useable responses from 45% of surveyed authors. Reported lead author contributions in ecological research studies consistently included conception of the project idea, data collection, analysis, and writing. Middle and last author contributions instead showed a high level of individual variability. Lead authorship in ecology is well defined while secondary authorship is more ambiguous. Nearly half (48%) of all studies included in our survey had some level of non-compliance with Ecological Society of America (ESA) authorship guidelines and the majority of studies (78%) contained at least one co-author that did not meet International Committee of Medical Journal Editors (ICMJE) requirements. Incidence of non compliance varied with lead author occupation and author position. The probability of a study including an author that was non-compliant with ESA guidelines was lowest for professor-led studies and highest for graduate student and post doctoral researcher-led studies. Among studies with > two co-authors, all lead authors met ESA guidelines and only 2% failed to meet ICMJE requirements. Middle (24% ESA, 63% ICMJE) and last (37% ESA, 60% ICMJE) authors had higher rates of non-compliance. The probability of a study containing a co author that did not meet ESA or ICMJE requirements increased significantly with the number of co-authors per study although even studies with only two co-authors had a high probability of non-compliance of approximately 60% (ICMJE) and 15 to 40% (ESA). Given the variable and often limited contributions of authors in our survey and past studies of other research disciplines, institutions, journals, and scientific societies need to implement new approaches to instill meaning in authorship status. A byline approach may not alter author contributions but would better define individual contributions and reduce existing ambiguity regarding the meaning of authorship in modern ecological research. PMID- 28650968 TI - Improving hydropower choices via an online and open access tool. AB - This paper describes and validates the HydroCalculator Tool developed by Conservation Strategy Fund. The HydroCalculator Tool allows researchers, policy makers and citizens to easily assess hydropower feasibility, by calculating traditional financial indicators, such as the levelized cost of energy, as well as greenhouse gas emissions and the economic net present value including emissions costs. Currently, people other than project developers have limited or no access to such information, which stifles informed public debate on electric energy options. Within this context, the use of the HydroCalculator Tool may contribute to the debate, by facilitating access to information. To validate the tool's greenhouse gas calculations, we replicate two peer-reviewed articles that estimate greenhouse gas emissions from different hydropower plants in the Amazon basin. The estimates calculated by the HydroCalculator Tool are similar to the ones found in both peer-reviewed articles. The results show that hydropower plants can lead to greenhouse gas emissions and that, in some cases, these emissions can be larger than those of alternative energy sources producing the same amount of electricity. PMID- 28650969 TI - Development and psychometric properties of knee-specific body-perception questionnaire in people with knee osteoarthritis: The Fremantle Knee Awareness Questionnaire. AB - BACKGROUND: Recent systematic reviews have demonstrated that pain associated with knee osteoarthritis (OA) is a complex phenomenon that involves various contributors. People with knee OA exhibit symptoms of impaired body-perception, including reduced tactile acuity, impairments in limb laterality recognition, and degraded proprioceptive acuity. The Fremantle Back Awareness Questionnaire (FreBAQ) was developed to assess body-perception specific to the back in people with chronic low back pain. The aim of this study was to develop and assess the psychometric properties of a knee-specific version of the FreBAQ-J (FreKAQ-J), determine whether people with knee pain experience perceptual impairments and investigate the relationship between disturbed self-perception and clinical status. METHODS: Sixty-five people with knee OA completed the FreKAQ-J. A subset of the participants completed the FreKAQ-J again two-weeks later. Rasch analysis was used to assess item order, targeting, category ordering, unidimensionality, person fit, internal consistency, and differential item functioning. Validity was investigated by examining the relationship between the FreKAQ-J and clinical valuables. RESULTS: The FreKAQ-J had acceptable internal consistency, unidimensionality, good test-retest reliability, and was functional on the category rating scale. The FreKAQ-J was significantly correlated with pain in motion, disability, pain-related catastrophizing, fear of movement, and anxiety symptomatology. CONCLUSIONS: We developed FreKAQ-J by modifying the FreBAQ-J. The FreKAQ-J fits the Rasch measurement model well and is suitable for use in people with knee OA. Altered body perception may be worth evaluating when managing people with knee OA. PMID- 28650971 TI - A lab-on-phone instrument with varifocal microscope via a liquid-actuated aspheric lens (LAL). AB - In this paper, we introduce a novel concept of liquid-actuated aspheric lens (LAL) with a built-in aspheric polydimethylsiloxane lens (APL) to enable the design of compact optical systems with varifocal microscopic imaging. The varifocal lens module consists of a sandwiched structures such as 3d printed syringe pump functionally serves as liquid controller. Other key components include two acrylic cylinders, a rigid separator, a APL/membrane composite (APLMC) embedded PDMS membrane. In functional operation, the fluidic controller was driven to control the pressure difference and ALPMC deformation. The focal length can be changed through the pressure difference. This is achieved by the adjustment of volume change of injected liquid such that a widely tunable focal length. The proposed LAL can transform to 3 modes: microscopic mode (APLMC only), convex-concave mode and biconcave mode. It is noticeable that LAL in the operation of microscopic mode is tunable in focus via the actuation of APLMC (focal length is from 4.3 to 2.3 mm and magnification 50X) and can rival the images quality of commercial microscopes. A new lab-on-phone device is economically feasible and functionally versatile to offer a great potential in the point of care applications. PMID- 28650970 TI - Point-of-care testing for Toxoplasma gondii IgG/IgM using Toxoplasma ICT IgG-IgM test with sera from the United States and implications for developing countries. AB - BACKGROUND: Congenital toxoplasmosis is a serious but preventable and treatable disease. Gestational screening facilitates early detection and treatment of primary acquisition. Thus, fetal infection can be promptly diagnosed and treated and outcomes can be improved. METHODS: We tested 180 sera with the Toxoplasma ICT IgG-IgM point-of-care (POC) test. Sera were from 116 chronically infected persons (48 serotype II; 14 serotype I-III; 25 serotype I-IIIa; 28 serotype Atypical, haplogroup 12; 1 not typed). These represent strains of parasites infecting mothers of congenitally infected children in the U.S. 51 seronegative samples and 13 samples from recently infected persons known to be IgG/IgM positive within the prior 2.7 months also were tested. Interpretation was confirmed by two blinded observers. A comparison of costs for POC vs. commercial laboratory testing methods was performed. RESULTS: We found that this new Toxoplasma ICT IgG-IgM POC test was highly sensitive (100%) and specific (100%) for distinguishing IgG/IgM positive from negative sera. Use of such reliable POC tests can be cost-saving and benefit patients. CONCLUSIONS: Our work demonstrates that the Toxoplasma ICT IgG-IgM test can function reliably as a point-of-care test to diagnose Toxoplasma gondii infection in the U.S. This provides an opportunity to improve maternal fetal care by using approaches, diagnostic tools, and medicines already available. This infection has serious, lifelong consequences for infected persons and their families. From the present study, it appears a simple, low-cost POC test is now available to help prevent morbidity/disability, decrease cost, and make gestational screening feasible. It also offers new options for improved prenatal care in low- and middle-income countries. PMID- 28650972 TI - Contribution of cognitive performance and cognitive decline to associations between socioeconomic factors and dementia: A cohort study. AB - BACKGROUND: Socioeconomic disadvantage is a risk factor for dementia, but longitudinal studies suggest that it does not affect the rate of cognitive decline. Our objective is to understand the manner in which socioeconomic disadvantage shapes dementia risk by examining its associations with midlife cognitive performance and cognitive decline from midlife to old age, including cognitive decline trajectories in those with dementia. METHODS AND FINDINGS: Data are drawn from the Whitehall II study (N = 10,308 at study recruitment in 1985), with cognitive function assessed at 4 waves (1997, 2002, 2007, and 2012). Sociodemographic, behavioural, and cardiometabolic risk factors from 1985 and chronic conditions until the end of follow-up in 2015 (N dementia/total = 320/9,938) allowed the use of inverse probability weighting to take into account data missing because of loss to follow-up between the study recruitment in 1985 and the introduction of cognitive tests to the study in 1997. Generalized estimating equations and Cox regression were used to assess associations of socioeconomic markers (height, education, and midlife occupation categorized as low, intermediate, and high to represent hierarchy in the socioeconomic marker) with cognitive performance, cognitive decline, and dementia (N dementia/total = 195/7,499). In those with dementia, we examined whether retrospective trajectories of cognitive decline (backward timescale) over 18 years prior to diagnosis differed as a function of socioeconomic markers. Socioeconomic disadvantage was associated with poorer cognitive performance (all p < 0.001). Using point estimates for the effect of age, the differences between the high and low socioeconomic groups corresponded to an age effect of 4, 15, and 26 years, for height, education, and midlife occupation, respectively. There was no evidence of faster cognitive decline in socioeconomically disadvantaged groups. Low occupation, but not height or education, was associated with risk of dementia (hazard ratio [HR] = 2.03 [95% confidence interval (CI) 1.23-3.36]) in an analysis adjusted for sociodemographic factors; the excess risk was unchanged after adjustment for cognitive decline but was completely attenuated after adjustment for cognitive performance. In further analyses restricted to those with dementia, retrospective cognitive trajectories over 18 years prior to dementia diagnosis showed faster cognitive decline in the high education (p = 0.006) and occupation (p = 0.001) groups such that large differences in cognitive performance in midlife were attenuated at dementia diagnosis. A major limitation of our study is the use of electronic health records rather than comprehensive dementia ascertainment. CONCLUSIONS: Our results support the passive or threshold cognitive reserve hypothesis, in that high cognitive reserve is associated with lower risk for dementia because of its association with cognitive performance, which provides a buffer against clinical expression of dementia. PMID- 28650973 TI - Interferon signaling in Peromyscus leucopus confers a potent and specific restriction to vector-borne flaviviruses. AB - Tick-borne flaviviruses (TBFVs), including Powassan virus and tick-borne encephalitis virus cause encephalitis or hemorrhagic fevers in humans with case fatality rates ranging from 1-30%. Despite severe disease in humans, TBFV infection of natural rodent hosts has little noticeable effect. Currently, the basis for resistance to disease is not known. We hypothesize that the coevolution of flaviviruses with their respective hosts has shaped the evolution of potent antiviral factors that suppress virus replication and protect the host from lethal infection. In the current study, we compared virus infection between reservoir host cells and related susceptible species. Infection of primary fibroblasts from the white-footed mouse (Peromyscus leucopus, a representative host) with a panel of vector-borne flaviviruses showed up to a 10,000-fold reduction in virus titer compared to control Mus musculus cells. Replication of vesicular stomatitis virus was equivalent in P. leucopus and M. musculus cells suggesting that restriction was flavivirus-specific. Step-wise comparison of the virus infection cycle revealed a significant block to viral RNA replication, but not virus entry, in P. leucopus cells. To understand the role of the type I interferon (IFN) response in virus restriction, we knocked down signal transducer and activator of transcription 1 (STAT1) or the type I IFN receptor (IFNAR1) by RNA interference. Loss of IFNAR1 or STAT1 significantly relieved the block in virus replication in P. leucopus cells. The major IFN antagonist encoded by TBFV, nonstructural protein 5, was functional in P. leucopus cells, thus ruling out ineffective viral antagonism of the host IFN response. Collectively, this work demonstrates that the IFN response of P. leucopus imparts a strong and virus specific barrier to flavivirus replication. Future identification of the IFN stimulated genes responsible for virus restriction specifically in P. leucopus will yield mechanistic insight into efficient control of virus replication and may inform the development of antiviral therapeutics. PMID- 28650974 TI - Resting state electrical brain activity and connectivity in fibromyalgia. AB - The exact mechanism underlying fibromyalgia is unknown, but increased facilitatory modulation and/or dysfunctional descending inhibitory pathway activity are posited as possible mechanisms contributing to sensitization of the central nervous system. The primary goal of this study is to identify a fibromyalgia neural circuit that can account for these abnormalities in central pain. The second goal is to gain a better understanding of the functional connectivity between the default and the executive attention network (salience network plus dorsal lateral prefrontal cortex) in fibromyalgia. We examine neural activity associated with fibromyalgia (N = 44) and compare these with healthy controls (N = 44) using resting state source localized EEG. Our data support an important role of the pregenual anterior cingulate cortex but also suggest that the degree of activation and the degree of integration between different brain areas is important. The inhibition of the connectivity between the dorsal lateral prefrontal cortex and the posterior cingulate cortex on the pain inhibitory pathway seems to be limited by decreased functional connectivity with the pregenual anterior cingulate cortex. Our data highlight the functional dynamics of brain regions integrated in brain networks in fibromyalgia patients. PMID- 28650975 TI - Defective glucocorticoid receptor signaling and keratinocyte-autonomous defects contribute to skin phenotype of mouse embryos lacking the Hsp90 co-chaperone p23. AB - p23 is a small acidic protein with intrinsic molecular chaperone activity. It is best known as a co-chaperone of the major cytosolic molecular chaperone Hsp90. p23 binds the N-terminus of Hsp90 and stabilizes the ATP-bound and N-terminally closed Hsp90 dimer. It is in this configuration that many Hsp90 clients are most stably bound. Considering the important role of p23 in the Hsp90 cycle, it came as a surprise that it is not absolutely essential for viability in the budding yeast or for mouse development. Mice without p23 develop quite normally until birth and then all die perinatally because of immature lungs. The only other apparent phenotype of late stage embryos and newborns is a skin defect, which we have further characterized here. We found that skin differentiation is impaired, and that both apoptosis and cell proliferation are augmented in the absence of p23; the consequences are a severe thinning of the stratum corneum and reduced numbers of hair follicles. The altered differentiation, spontaneous apoptosis and proliferation are all mimicked by isolated primary keratinocytes indicating that they do require p23 functions in a cell-autonomous fashion. Since the phenotype of p23-null embryos is strikingly similar to that of embryos lacking the glucocorticoid receptor, a paradigmatic Hsp90-p23 client protein, we investigated glucocorticoid signaling. We discovered that it is impaired in vivo and for some aspects in isolated keratinocytes. Our results suggest that part of the phenotype of p23-null embryos can be explained by an impact on this particular Hsp90 client, but do not exclude that p23 by itself or in association with Hsp90 affects skin development and homeostasis through yet other pathways. PMID- 28650976 TI - Effect of praziquantel on the differential expression of mouse hepatic genes and parasite ATP binding cassette transporter gene family members during Schistosoma mansoni infection. AB - Schistosomiasis is a chronic parasitic disease caused by sexually dimorphic blood flukes of the genus Schistosoma. Praziquantel (PZQ) is the only drug widely available to treat the disease but does not kill juvenile parasites. Here we report the use of next generation sequencing to study the transcriptional effect of PZQ on murine hepatic inflammatory, immune and fibrotic responses to Schistosoma mansoni worms and eggs. An initial T helper cell 1 (Th1) response is induced against schistosomes in mice treated with drug vehicle (Vh) around the time egg laying begins, followed by a T helper cell 2 (Th2) response and the induction of genes whose action leads to granuloma formation and fibrosis. When PZQ is administered at this time, there is a significant reduction in egg burden yet the hepatic Th1, Th2 and fibrotic responses are still observed in the absence of granuloma formation suggesting some degree of gene regulation may be induced by antigens released from the dying adult worms. Quantitative real-time PCR was used to examine the relative expression of 16 juvenile and adult S. mansoni genes during infection and their response to Vh and PZQ treatment in vivo. While the response of stress genes in adult parasites suggests the worms were alive immediately following exposure to PZQ, they were unable to induce transcription of any of the 9 genes encoding ATP-binding cassette (ABC) transporters tested. In contrast, juvenile schistosomes were able to significantly induce the activities of ABCB, C and G family members, underscoring the possibility that these efflux systems play a major role in drug resistance. PMID- 28650977 TI - Leishmania donovani resides in modified early endosomes by upregulating Rab5a expression via the downregulation of miR-494. AB - Several intracellular pathogens arrest the phagosome maturation in the host cells to avoid transport to lysosomes. In contrast, the Leishmania containing parasitophorous vacuole (PV) is shown to recruit lysosomal markers and thus Leishmania is postulated to be residing in the phagolysosomes in macrophages. Here, we report that Leishmania donovani specifically upregulates the expression of Rab5a by degrading c-Jun via their metalloprotease gp63 to downregulate the expression of miR-494 in THP-1 differentiated human macrophages. Our results also show that miR-494 negatively regulates the expression of Rab5a in cells. Subsequently, L. donovani recruits and retains Rab5a and EEA1 on PV to reside in early endosomes and inhibits transport to lysosomes in human macrophages. Similarly, we have also observed that Leishmania PV also recruits Rab5a by upregulating its expression in human PBMC differentiated macrophages. However, the parasite modulates the endosome by recruiting Lamp1 and inactive pro CathepsinD on PV via the overexpression of Rab5a in infected cells. Furthermore, siRNA knockdown of Rab5a or overexpression of miR-494 in human macrophages significantly inhibits the survival of the parasites. These results provide the first mechanistic insights of parasite-mediated remodeling of endo-lysosomal trafficking to reside in a specialized early endocytic compartment. PMID- 28650978 TI - A study of ticks and tick-borne livestock pathogens in Pakistan. AB - BACKGROUND: As obligate blood-feeding arthropods, ticks transmit pathogens to humans and domestic animals more often than other arthropod vectors. Livestock farming plays a vital role in the rural economy of Pakistan, and tick infestation causes serious problems with it. However, research on tick species diversity and tick-borne pathogens has rarely been conducted in Pakistan. In this study, a systematic investigation of the tick species infesting livestock in different ecological regions of Pakistan was conducted to determine the microbiome and pathobiome diversity in the indigenous ticks. METHODOLOGY/PRINCIPAL FINDINGS: A total of 3,866 tick specimens were morphologically identified as 19 different tick species representing three important hard ticks, Rhipicephalus, Haemaphysalis and Hyalomma, and two soft ticks, Ornithodorus and Argas. The bacterial diversity across these tick species was assessed by bacterial 16S rRNA gene sequencing using a 454-sequencing platform on 10 of the different tick species infesting livestock. The notable genera detected include Ralstonia, Clostridium, Staphylococcus, Rickettsia, Lactococcus, Lactobacillus, Corynebacterium, Enterobacter, and Enterococcus. A survey of Spotted fever group rickettsia from 514 samples from the 13 different tick species generated rickettsial-specific amplicons in 10% (54) of total ticks tested. Only three tick species Rhipicephalus microplus, Hyalomma anatolicum, and H. dromedarii had evidence of infection with "Candidatus Rickettsia amblyommii" a result further verified using a rompB gene-specific quantitative PCR (qPCR) assay. The Hyalomma ticks also tested positive for the piroplasm, Theileria annulata, using a qPCR assay. CONCLUSIONS/SIGNIFICANCE: This study provides information about tick diversity in Pakistan, and pathogenic bacteria in different tick species. Our results showed evidence for Candidatus R. amblyommii infection in Rhipicephalus microplus, H. anatolicum, and H. dromedarii ticks, which also carried T. annulata. PMID- 28650979 TI - Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide. AB - Prenatal exposure to lipopolysaccharide (LPS), which likely occurs due to infection or contact with environmental allergens during pregnancy, is a proposed risk factor that induces anxiety- and autism spectrum disorder-like behaviors in offspring. However, the molecular and behavioral changes in offspring after maternal immune activation have not been completely identified. We hypothesized that a subcutaneous injection of LPS in a pregnant mouse would induce changes in cerebral serotonin (5-HT) in parallel to the appearance of anxiety-like behaviors in the dam's offspring. After LPS injections (total, 100 MUg/Kg), the time spent in the central region during the open field test and the number of times that the mice moved between the light and dark boxes and between the open and closed arms on the elevated plus maze test revealed anxiety-like behaviors in offspring at 5, 6 and 9 weeks of age. The mRNA expression levels of tph2 (5-HT synthesizing enzyme) and slc6a4 (5-HT transporter) were down-regulated in both adolescent (5 weeks of age) and adult (8 weeks of age) brains. Immunohistochemistry revealed that the numbers and sizes of tph2-expressing cells were notably decreased in the raphe nuclei of the midbrain of adults. Moreover, compared with controls (phosphate-buffered saline-treated offspring), the cerebral 5-HT concentration at adolescence and adulthood in LPS-induced offspring was significantly decreased. We concluded that maternal immune activation induced by exposure to a low dose of LPS decreased cerebral 5-HT levels in parallel to the down-regulation of the tph2 and slc6a4 genes and in conjunction with anxiety-like behaviors in offspring. PMID- 28650980 TI - Changes in transcript levels of starch hydrolysis genes and raising citric acid production via carbon ion irradiation mutagenesis of Aspergillus niger. AB - The filamentous ascomycete Aspergillus niger is well known for its ability to accumulate citric acid for the hydrolysis of starchy materials. To improve citric acid productivity, heavy ion beam mutagenesis was utilized to produce mutant A.niger strains with enhanced production of citric acid in this work. It was demonstrated that a mutant HW2 with high concentration of citric acid was isolated after carbon ion irradiation with the energy of 80Mev/MU, which was obvious increase higher than the original strain from liquefied corn starch as a feedstock. More importantly, with the evidence from the expression profiles of key genes and enzyme activity involved in the starch hydrolysis process between original strain and various phenotype mutants, our results confirmed that different transcript levels of key genes involving in starch hydrolysis process between original strain and mutants could be a significant contributor to different citric acid concentration in A.niger, such as, amyR and glaA, which therefore opened a new avenue for constructing genetically engineered A.niger mutants for high-yield citric acid accumulation in the future. As such, this work demonstrated that heavy ion beam mutagenesis presented an efficient alternative strategy to be developed to generate various phenotype microbe species mutants for functional genes research. PMID- 28650981 TI - Health situation of migrant and minority nurses: A systematic review. AB - INTRODUCTION: Globally, life expectancy together with multimorbidity and chronic diseases are increasing. This leads to a growing demand for care and hence for healthcare personnel and nurses. To meet this demand, healthcare workers from abroad are increasingly hired. The nurses' workplace in general is characterized by physically and psychologically demanding tasks, while that of migrant and minority nurses is additionally characterized by discriminatory practices. The present knowledge about the health of migrant and minority nurses and the terminology in this context are diverse. Thus, the purpose of this review is to systematically identify and synthesize international publications that explicitly focus on migrant nurses' health. MATERIALS AND METHODS: A systematic review of relevant studies was undertaken using the databases Medline, PsycINFO, CINAHL and Web of Science. The screening process was conducted in several phases. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines while the methodological quality assessment of the included papers was performed with the Mixed Method Appraisal Tool (MMAT). RESULTS: Out of 11,599 citations initially obtained, 14 empirical studies were included in the final synthesis. The methodological quality of the empirical studies and reviews was diverse. The majority of the studies were conducted in the US and the nurses under study migrated from countries like the Philippines, India, Europe, and Africa. Among migrant nurses of different origins, there are differences in their physiological responses to stress. Migrant nurses and native nurses differ in reporting work-related injuries. DISCUSSION: Migrant and minority nurses are at high risk of work related injuries and discrimination than native or majority nurses. However, mixed results were obtained, namely that the reported health of migrant nurses either improves over time or it decreases. This review revealed that discrimination is the leading cause of impaired health amongst migrant and minority nurses. PMID- 28650982 TI - Seroprevalence and risk factors of Hepatitis E Virus infection among pregnant women in Addis Ababa, Ethiopia. AB - BACKGROUND: Hepatitis E virus (HEV) is highly endemic in several African countries with high mortality rate among pregnant women. The prevalence of antibodies to HEV in Ethiopian pregnant women is not known. The study was conducted to investigate the prevalence of anti-HEV IgG and anti-HEV IgM among pregnant women. MATERIAL AND METHODS: A total of 386 serum samples were collected from pregnant women between April 2014 to January 2015 in Gandhi Memorial Hospital and four selected Health centers in Addis Ababa, Ethiopia. Data were collected for socio demographic characteristics using a structured questionnaire. Serum samples were examined for anti-HEV IgG and anti- HEV IgM using ELISA. The association of anti-HEV status with risk factors was assessed. Factors demonstrating significant association in bivariate analysis were included in multivariate logistic regression models. Analyses were performed using SPSS version 21. RESULTS: Anti- HEV IgG antibody was detected in 122 (31.6%) women and two women (0.5%) were positive for anti-HEV IgM from the total 386 women. Age and educational status had statistically significant association with HEV infection. There was no significant association between anti-HEV antibody seroprevalence rate with trimester, parity, HIV status and other risk factors. CONCLUSION: In this study we found a high seroprevalence rate of anti-HEV IgG among pregnant women in Addis Ababa Ethiopia. Preventive measures like improvement of education and creating awareness may reduce the risk in pregnant women. Moreover nationwide surveillance of HEV especially in rural setting should be conducted to establish a national estimate and validate our findings. PMID- 28650983 TI - Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication. AB - Growing evidence suggests that the pyrrolizidine alkaloids (PAs)-induced hepatotoxicity is mediated by multiple cell death/defence modalities. However, the detailed mechanisms are still lacking. In this study, the hepatotoxic effects of four PAs including three retronecine-type ones (senecionine, seneciphylline and monocrotaline) and one otonecine-type (clivorine) on the proliferation of Huh 7.5 cells and the possible mechanisms were investigated. The results showed that all the PAs could inhibit cell proliferation and induce apoptosis in a concentration-dependent manner. Among them clivorine was the most significant one. In addition to its effect on apoptosis, clivorine treatment could promote autophagy in Huh-7.5 cells, as evidenced by the accumulation of autophagosomes, the enhancement of LC3B expression at the concentrations close to its IC0 value, and the increased conversion of LC3B-I to LC3B-II in the presence of lysosomal inhibitor (chloroquine) and decreased formation of green fluorescent protein (GFP)-LC3 positive puncta in the presence of autophagic sequestration inhibitor (3-methyladenine). Among the other tested PAs, senecionine and seneciphylline also activated autophagy at the same concentrations used for clivorine but monocrotaline did not. Furthermore, our study demonstrated that suppression or enhancement of autophagy resulted in the remarkable enhancement or suppression of senecionine, seneciphylline and clivorine-induced apoptosis at the concentration close to the IC10 for clivorine, respectively, indicating a protective role of autophagy against the PA-induced apoptosis at the low level of exposure. Collectively, our data suggest that PAs in different structures may exert different toxic disturbances on the liver cells. Apoptosis may be one of the most common models of the PA-induced cytotoxicity, while autophagy may be a structure dependent defence model in the early stage of PA intoxication. Differential induction of apoptosis and autophagy probably depending on the concentration is essential for the cytotoxic potency of clivorine. PMID- 28650984 TI - Clinical characteristics of second primary pancreatic cancer. AB - PURPOSE: Several studies reported the increased risk of second primary pancreatic ductal adenocarcinoma (2nd PDAC) in cancer survivors. However, data on the characteristics of 2nd PDAC are insufficient. METHODS: This retrospective cohort study included 1759 patients with PDAC. They were classified as having 2nd PDAC or first primary PDAC (1st PDAC) according to a prior diagnosed cancer of different origin, at least 6 months before PDAC diagnosis. RESULTS: There were 110 patients (6.4%) with 2nd PDAC and 1606 (93.6%) patients with 1st PDAC. Patients with 2nd PDAC presented with older age (66.5 vs. 62.2 years, p < 0.001) and higher rate of resectability (26.4% vs. 15.9%, p = 0.004) at diagnosis than those with 1st PDAC. Multivariate analysis without considering resectable status showed that 2nd PDAC (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56 0.94, p = 0.016) was associated with better overall survival. After adjusting for resectable status, however, 2nd PDAC (HR 0.85, 95% CI 0.66-1.09, p = 0.198) was no longer associated with overall survival. When subgroups were separately analyzed according to initial treatment modality, the effectiveness of surgery and chemotherapy were similar between 2nd and 1st PDAC (33.1 vs. 28.5 months, p = 0.860 and 10.8 vs. 10.7 months, p = 0.952). CONCLUSIONS: The proportion of resectable cases was significantly higher in 2nd PDAC. When surgery with curative aim was possible, the overall survival was increased even in patients with 2nd PDAC. These results suggest the importance of screening for second primary cancer in cancer survivors. PMID- 28650985 TI - Chronic Trichuris muris infection causes neoplastic change in the intestine and exacerbates tumour formation in APC min/+ mice. AB - Incidences of infection-related cancers are on the rise in developing countries where the prevalence of intestinal nematode worm infections are also high. Trichuris muris (T. muris) is a murine gut-dwelling nematode that is the direct model for human T. trichiura, one of the major soil-transmitted helminth infections of humans. In order to assess whether chronic infection with T. muris does indeed influence the development of cancer hallmarks, both wild type mice and colon cancer model (APC min/+) mice were infected with this parasite. Parasite infection in wild type mice led to the development of neoplastic change similar to that seen in mice that had been treated with the carcinogen azoxymethane. Additionally, both chronic and acute infection in the APCmin/+ mice led to an enhanced tumour development that was distinct to the site of infection suggesting systemic control. By blocking the parasite induced T regulatory response in these mice, the increase in the number of tumours following infection was abrogated. Thus T. muris infection alone causes an increase in gut pathologies that are known to be markers of cancer but also increases the incidence of tumour formation in a colon cancer model. The influence of parasitic worm infection on the development of cancer may therefore be significant. PMID- 28650986 TI - Evolutionary history and phylogeographic relationships of shrews from Sorex araneus group. AB - Shrews of the Sorex genus are an evolutionarily successful group that includes more than 77 species widely distributed in Eurasia and North America. The genus is one of the rare cases where karyotypic changes reflect well the evolutionary relationships among its species. The taxa showing the greatest variation in karyotype are usually classified into the Sorex araneus group. Its evolution was associated with chromosomal rearrangements, which could have promoted fast diversification of this group into many chromosomal races and species. These processes were additionally complicated by introgressions of mitochondrial DNA, which made the evolutionary history of this group quite complex and difficult to infer. To tackle the problem, we performed multi-method phylogenetic analyses based on mitochondrial cytochrome b that is considered a good molecular marker available for many representatives of Sorex. The results were compared with phylogenies based on chromosomal rearrangement data and put into temporal and spatial context using molecular dating and historical biogeography methods. We complemented the study with the estimation of diversification rates within the S. araneus group as well as comparing the results with paleontological records and climatic oscillations within the last 4 million years. Based on the gathered data, we proposed a hypothetical scenario for the evolution and geographic dispersion of species belonging to the S. araneus group. The shrews began to diversify about 2.7 million years ago in Eurasia and then migrated at least twice to North America. The evolution of shrews was driven by Pleistocene glacial and interglacial cycles, which increased their speciation rate and the emergence of new lineages. The migrations of populations were accompanied by introgressions of mitochondrial DNA into native shrews and occurred at least twice. PMID- 28650987 TI - Accuracy of Zika virus disease case definition during simultaneous Dengue and Chikungunya epidemics. AB - BACKGROUND: Zika is a new disease in the American continent and its surveillance is of utmost importance, especially because of its ability to cause neurological manifestations as Guillain-Barre syndrome and serious congenital malformations through vertical transmission. The detection of suspected cases by the surveillance system depends on the case definition adopted. As the laboratory diagnosis of Zika infection still relies on the use of expensive and complex molecular techniques with low sensitivity due to a narrow window of detection, most suspected cases are not confirmed by laboratory tests, mainly reserved for pregnant women and newborns. In this context, an accurate definition of a suspected Zika case is crucial in order for the surveillance system to gauge the magnitude of an epidemic. METHODOLOGY: We evaluated the accuracy of various Zika case definitions in a scenario where Dengue and Chikungunya viruses co-circulate. Signs and symptoms that best discriminated PCR confirmed Zika from other laboratory confirmed febrile or exanthematic diseases were identified to propose and test predictive models for Zika infection based on these clinical features. RESULTS AND DISCUSSION: Our derived score prediction model had the best performance because it demonstrated the highest sensitivity and specificity, 86.6% and 78.3%, respectively. This Zika case definition also had the highest values for auROC (0.903) and R2 (0.417), and the lowest Brier score 0.096. CONCLUSIONS: In areas where multiple arboviruses circulate, the presence of rash with pruritus or conjunctival hyperemia, without any other general clinical manifestations such as fever, petechia or anorexia is the best Zika case definition. PMID- 28650988 TI - Transcriptomic analysis to uncover genes affecting cold resistance in the Chinese honey bee (Apis cerana cerana). AB - The biological activity and geographical distribution of honey bees is strongly temperature-dependent, due to their ectothermic physiology. In China, the endemic Apis cerana cerana exhibits stronger cold hardiness than Western honey bees, making the former species important pollinators of winter-flowering plants. Although studies have examined behavioral and physiological mechanisms underlying cold resistance in bees, data are scarce regarding the exact molecular mechanisms. Here, we investigated gene expression in A. c. cerana under two temperature treatments, using transcriptomic analysis to identify differentially expressed genes (DEGs) and relevant biological processes, respectively. Across the temperature treatments, 501 DEGs were identified. A gene ontology analysis showed that DEGs were enriched in pathways related to sugar and amino acid biosynthesis and metabolism, as well as calcium ion channel activity. Additionally, heat shock proteins, zinc finger proteins, and serine/threonine protein kinases were differentially expressed between the two treatments. The results of this study provide a general digital expression profile of thermoregulation genes responding to cold hardiness in A. c. cerana. Our data should prove valuable for future research on cold tolerance mechanisms in insects, and may be beneficial in breeding efforts to improve bee hardiness. PMID- 28650989 TI - Tumor tissue protein signatures reflect histological grade of breast cancer. AB - Histological grade is one of the most commonly used prognostic factors for patients diagnosed with breast cancer. However, conventional grading has proven technically challenging, and up to 60% of the tumors are classified as histological grade 2, which represents a heterogeneous cohort less informative for clinical decision making. In an attempt to study and extend the molecular puzzle of histologically graded breast cancer, we have in this pilot project searched for additional protein biomarkers in a new space of the proteome. To this end, we have for the first time performed protein expression profiling of breast cancer tumor tissue, using recombinant antibody microarrays, targeting mainly immunoregulatory proteins. Thus, we have explored the immune system as a disease-specific sensor (clinical immunoproteomics). Uniquely, the results showed that several biologically relevant proteins reflecting histological grade could be delineated. In more detail, the tentative biomarker panels could be used to i) build a candidate model classifying grade 1 vs. grade 3 tumors, ii) demonstrate the molecular heterogeneity among grade 2 tumors, and iii) potentially re classify several of the grade 2 tumors to more like grade 1 or grade 3 tumors. This could, in the long-term run, lead to improved prognosis, by which the patients could benefit from improved tailored care. PMID- 28650990 TI - Identification of soil P fractions that are associated with P loss from surface runoff under various cropping systems and fertilizer rates on sloped farmland. AB - Soil phosphorus (P) fractions and runoff P concentration were measured to understand the fate of soil P entering surface runoff water during summer cropping season of different double cropping systems under two fertilizer regimes. The dominant form of runoff P was particulate P (PP). Runoff total P (TP) was higher at the vegetative growth stage and lower at the crop reproductive stage. TP and PP were derived mainly from soil Olsen-P, Al-P and Fe-P and amounts increased with sediment content in runoff water. Runoff P discharge was closely related to the changes in soil P forms. Soil Olsen-P, mainly consisting of some Ca2-P and Al-P, was increased by elevating fertilizer rate. Along with crop growth, there were active interconversions among Olsen-P, Org-P, Fe-P and O-Al-P in the soil, and some available P converted into Ca10-P, with O-Fe-P possibly being a transitional form for this conversion. The oilseed rape/corn system had less runoff TP at the early stage, and wheat/sweet potato system had a lower runoff P at the late stage. Intercropping corn with sweet potato in the field with oilseed rape as a previous crop may be helpful for alleviating runoff P load during the summer in this region. PMID- 28650991 TI - Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles. AB - HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic alpha1 and alpha2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism. PMID- 28650992 TI - Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis. AB - Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. beta-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune surveillance circuit. In addition, we show that MS patients generate function blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal 8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS. PMID- 28650993 TI - A novel potential biomarker for metabolic syndrome in Chinese adults: Circulating protein disulfide isomerase family A, member 4. AB - BACKGROUND/OBJECTIVES: Protein disulfide isomerase (PDI) family members are specific endoplasmic reticulum proteins that are involved in the pathogenesis of numerous diseases including neurodegenerative diseases, cancer and obesity. However, the metabolic effects of PDIA4 remain unclear in humans. The aims of this study were to investigate the associations of serum PDIA4 with the metabolic syndrome (MetS) and its components in Chinese adults. SUBJECTS/METHODS: A total of 669 adults (399 men and 270 women) were recruited. Serum PDIA4 concentrations and biochemical variables were recorded. Insulin sensitivity and beta-cell function were examined by homeostasis model assessment. MetS was defined based on the modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asia Pacific. RESULTS: The participants with MetS had significantly higher serum PDIA4 levels than those without MetS (P<0.001). After adjustments, the individuals with the highest PDIA4 tertile were associated with a higher risk of MetS than those with the lowest tertile (OR = 4.83, 95% CI: 2.71-8.60). The concentration of PDIA4 showed a stepwise increase with the components of MetS (P<0.001 for trend). The individuals with the highest PDIA4 tertile were significantly associated with waist circumference (OR = 2.41, 95% CI 1.34-4.32), blood pressure (OR = 2.71, 95% CI 1.57-4.67), fasting glucose concentration (OR = 3.17, 95% CI 1.80-5.57), and serum triglycerides (OR = 4.12, 95% CI 2.30-7.37) than those with the lowest tertile. At cutoff point of 15.24 ng/ml, the diagnostic sensitivity and specificity of PDIA4 for the metabolic syndrome were 67 and 72%, respectively, in male patients and 60 and 78%, respectively, in female patients. Finally, the result showed that PDIA4 had a significantly higher area under the curve compared with blood pressure to detect MetS using receiver operating characteristic analysis. CONCLUSIONS: Serum PDIA4 concentrations are closely associated to MetS and its components in Chinese adults. PMID- 28650994 TI - Abnormal global functional network connectivity and its relationship to medial temporal atrophy in patients with amnestic mild cognitive impairment. AB - BACKGROUND: Amnestic mild cognitive impairment (aMCI), which is recently considered as a high risk status for developing Alzheimer's disease (AD), manifests with gray matter atrophy and increased focal functional activity in the medial temporal lobe (MTL). However, the abnormalities of whole-brain functional network connectivity in aMCI and its relationship to medial temporal atrophy (MTA) remain unknown. METHODS: In this study, thirty-six aMCI patients and thirty five healthy controls (HCs) were recruited. Neuropsychological assessments and MTA visual rating scaling were carried out on all participants. Furthermore, whole brain functional network was constructed at voxel level, and functional connectivity strength (FCS) was computed as the sum of the connections for each node to capture its global integrity. General linear model was used to analyze the FCS values differences between aMCI and HCs. Then, the regions showing significant FCS differences were adopted as the imaging markers for discriminative analysis. Finally, the relationship between FCS values and clinical cognitive scores was correlated in patients with aMCI. RESULTS: Comparing to HCs, aMCI exhibited significant atrophy in the MTL, while higher FCS values within the bilateral MTL regions and orbitofrontal cortices. Notably, the right hippocampus had the highest classification power, with the area under receiver operating characteristics (ROC) curve (AUC) of 0.790 (confidence interval: 0.678, 0.901). Moreover, FCS values of the right hippocampus and the left temporal pole were positively correlated with the cognitive performance in aMCI. CONCLUSION: This study demonstrated significantly structural atrophy and raised global functional integrity in the MTL, suggesting simultaneous disruption and compensation in prodromal AD. Increased intrinsic functional connectivity in the MTL may have the potential to discriminate subjects with tendency to develop AD. PMID- 28650995 TI - Septins restrict inflammation and protect zebrafish larvae from Shigella infection. AB - Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial infection, yet septin function in vivo is poorly understood. Here, we use S. flexneri infection of zebrafish (Danio rerio) larvae to study in vivo the role of septins in inflammation and infection control. We found that depletion of Sept15 or Sept7b, zebrafish orthologs of human SEPT7, significantly increased host susceptibility to bacterial infection. Live-cell imaging of Sept15 depleted larvae revealed increasing bacterial burdens and a failure of neutrophils to control infection. Strikingly, Sept15-depleted larvae present significantly increased activity of Caspase-1 and more cell death upon S. flexneri infection. Dampening of the inflammatory response with anakinra, an antagonist of interleukin-1 receptor (IL-1R), counteracts Sept15 deficiency in vivo by protecting zebrafish from hyper-inflammation and S. flexneri infection. These findings highlight a new role for septins in host defence against bacterial infection, and suggest that septin dysfunction may be an underlying factor in cases of hyper-inflammation. PMID- 28650996 TI - Whole transcriptomic and proteomic analyses of an isogenic M. tuberculosis clinical strain with a naturally occurring 15 Kb genomic deletion. AB - Tuberculosis remains one of the most difficult to control infectious diseases in the world. Many different factors contribute to the complexity of this disease. These include the ability of the host to control the infection which may directly relate to nutritional status, presence of co-morbidities and genetic predisposition. Pathogen factors, in particular the ability of different Mycobacterium tuberculosis strains to respond to the harsh environment of the host granuloma, which includes low oxygen and nutrient availability and the presence of damaging radical oxygen and nitrogen species, also play an important role in the success of different strains to cause disease. In this study we evaluated the impact of a naturally occurring 12 gene 15 Kb genomic deletion on the physiology and virulence of M. tuberculosis. The strains denominated ON-A WT (wild type) and ON-A NM (natural mutant) were isolated from a previously reported TB outbreak in an inner city under-housed population in Toronto, Canada. Here we subjected these isogenic strains to transcriptomic (via RNA-seq) and proteomic analyses and identified several gene clusters with differential expression in the natural mutant, including the DosR regulon and the molybdenum cofactor biosynthesis genes, both of which were found in lower abundance in the natural mutant. We also demonstrated lesser virulence of the natural mutant in the guinea pig animal model. Overall, our findings suggest that the ON-A natural mutant is less fit to cause disease, but nevertheless has the potential to cause extended transmission in at-risk populations. PMID- 28650997 TI - Disambiguating authenticity: Interpretations of value and appeal. AB - While shaping aesthetic judgment and choice, socially constructed authenticity takes on some very different meanings among observers, consumers, producers and critics. Using a theoretical framework positing four distinct meanings of socially constructed authenticity-type, moral, craft, and idiosyncratic-we aim to document empirically the unique appeal of each type. We develop predictions about the relationships between attributed authenticity and corresponding increases in the value ascribed to it through: (1) consumer value ratings, (2) willingness to pay, and (3) behavioral choice. We report empirical analyses from a research program of three multi-method studies using (1) archival data from voluntary consumer evaluations of restaurants in an online review system, (2) a university based behavioral lab experiment, and (3) an online survey-based experiment. Evidence is consistent across the studies and suggests that perceptions of four distinct subtypes of socially constructed authenticity generate increased appeal and value even after controlling for option quality. Findings suggest additional directions for research on authenticity. PMID- 28650998 TI - Functional annotation of Alzheimer's disease associated loci revealed by GWASs. AB - Genome-wide association studies (GWASs) discovered a number of SNPs and genes associated with Alzheimer's disease (AD). However, how these SNPs and genes influence the liability to AD is not fully understood. We deployed computational approaches to explore the function and action mechanisms of AD -related SNPs and genes identified by GWASs, including the effects of 195 GWAS lead SNPs and 338 proxy SNPs on miRNAs binding and protein phosphorylation, their RegulomeDB and 3DSNP scores, and gene ontology, pathway enrichment and protein-protein interaction network of 126 AD-associated genes. Our computational analysis identified 6 lead SNPs (rs10119, rs1048699, rs148763909, rs610932, rs6857 and rs714948) and 2 proxy SNPs (rs12539172 and rs2847655) that potentially impacted the miRNA binding. Lead SNP rs2296160 and proxy SNPs rs679620 and rs2228145 were identified as PhosSNPs potentially influencing protein phosphorylation. AD associated genes showed enrichment of "regulation of beta-amyloid formation", "regulation of neurofibrillary tangle assembly", "leukocyte mediated immunity" and "protein-lipid complex assembly" signaling pathway. Protein-protein interaction network and functional module analyses identified highly interconnected "hub" genes (APOE, PICALM, BIN1, ABCA7, CD2AP, CLU, CR1, MS4A4E and MS4A6A) and bottleneck genes (APOE, TOMM40, NME8, PICALM, CD2AP, ZCWPW1, FAM180B, GAB2 and PTK2B) that created three tight subnetworks. Our results provided the targets for further experimental assessment and further insight on AD pathophysiology. PMID- 28650999 TI - An ancestral haplotype of the human PERIOD2 gene associates with reduced sensitivity to light-induced melatonin suppression. AB - Humans show various responses to the environmental stimulus in individual levels as "physiological variations." However, it has been unclear if these are caused by genetic variations. In this study, we examined the association between the physiological variation of response to light-stimulus and genetic polymorphisms. We collected physiological data from 43 subjects, including light-induced melatonin suppression, and performed haplotype analyses on the clock genes, PER2 and PER3, exhibiting geographical differentiation of allele frequencies. Among the haplotypes of PER3, no significant difference in light sensitivity was found. However, three common haplotypes of PER2 accounted for more than 96% of the chromosomes in subjects, and 1 of those 3 had a significantly low-sensitive response to light-stimulus (P < 0.05). The homozygote of the low-sensitive PER2 haplotype showed significantly lower percentages of melatonin suppression (P < 0.05), and the heterozygotes of the haplotypes varied their ratios, indicating that the physiological variation for light-sensitivity is evidently related to the PER2 polymorphism. Compared with global haplotype frequencies, the haplotype with a low-sensitive response was more frequent in Africans than in non-Africans, and came to the root in the phylogenetic tree, suggesting that the low light sensitive haplotype is the ancestral type, whereas the other haplotypes with high sensitivity to light are the derived types. Hence, we speculate that the high light-sensitive haplotypes have spread throughout the world after the Out-of Africa migration of modern humans. PMID- 28651001 TI - PpTFDB: A pigeonpea transcription factor database for exploring functional genomics in legumes. AB - Pigeonpea (Cajanus cajan L.), a diploid legume crop, is a member of the tribe Phaseoleae. This tribe is descended from the millettioid (tropical) clade of the subfamily Papilionoideae, which includes many important legume crop species such as soybean (Glycine max), mung bean (Vigna radiata), cowpea (Vigna ungiculata), and common bean (Phaseolus vulgaris). It plays major role in food and nutritional security, being rich source of proteins, minerals and vitamins. We have developed a comprehensive Pigeonpea Transcription Factors Database (PpTFDB) that encompasses information about 1829 putative transcription factors (TFs) and their 55 TF families. PpTFDB provides a comprehensive information about each of the identified TFs that includes chromosomal location, protein physicochemical properties, sequence data, protein functional annotation, simple sequence repeats (SSRs) with primers derived from their motifs, orthology with related legume crops, and gene ontology (GO) assignment to respective TFs. (PpTFDB: http://14.139.229.199/PpTFDB/Home.aspx) is a freely available and user friendly web resource that facilitates users to retrieve the information of individual members of a TF family through a set of query interfaces including TF ID or protein functional annotation. In addition, users can also get the information by browsing interfaces, which include browsing by TF Categories and by, GO Categories. This PpTFDB will serve as a promising central resource for researchers as well as breeders who are working towards crop improvement of legume crops. PMID- 28651000 TI - Assessing the impact of Benzo[a]pyrene on Marine Mussels: Application of a novel targeted low density microarray complementing classical biomarker responses. AB - Despite the increasing use of mussels in environmental monitoring and ecotoxicological studies, their genomes and gene functions have not been thoroughly explored. Several cDNA microarrays were recently proposed for Mytilus spp., but putatively identified partial transcripts have rendered the generation of robust transcriptional responses difficult in terms of pathway identification. We developed a new low density oligonucleotide microarray with 465 probes covering the same number of genes. Target genes were selected to cover most of the well-known biological processes in the stress response documented over the last decade in bivalve species at the cellular and tissue levels. Our new 'STressREsponse Microarray' (STREM) platform consists of eight sub-arrays with three replicates for each target in each sub-array. To assess the potential use of the new array, we tested the effect of the ubiquitous environmental pollutant benzo[a]pyrene (B[a]P) at 5, 50, and 100 MUg/L on two target tissues, the gills and digestive gland, of Mytilus galloprovincialis exposed invivo for three days. Bioaccumulation of B[a]P was also determined demonstrating exposure in both tissues. In addition to the well-known effects of B[a]P on DNA metabolism and oxidative stress, the new array data provided clues about the implication of other biological processes, such as cytoskeleton, immune response, adhesion to substrate, and mitochondrial activities. Transcriptional data were confirmed using qRT-PCR. We further investigated cellular functions and possible alterations related to biological processes highlighted by the microarray data using oxidative stress biomarkers (Lipofuscin content) and the assessment of genotoxicity. DNA damage, as measured by the alkaline comet assay, increased as a function of dose.DNA adducts measurements using 32P-postlabeling method also showed the presence of bulky DNA adducts (i.e. dG-N2-BPDE). Lipofiscin content increased significantly in B[a]P exposed mussels. Immunohistochemical analysis of tubulin and actin showed changes in cytoskeleton organisation. Our results adopting an integrated approach confirmed that the combination of newly developed transcriptomic approcah, classical biomarkers along with chemical analysis of water and tissue samples should be considered for environmental bioimonitoring and ecotoxicological studies to obtain holistic information to assess the impact of contaminants on the biota. PMID- 28651002 TI - The N-terminal domain of Mycobacterium tuberculosis PPE17 (Rv1168c) protein plays a dominant role in inducing antibody responses in active TB patients. AB - The PPE (proline-proline-glutamic acid) proteins of Mycobacterium tuberculosis are characterized by a conserved N-terminal domain of approximately 180 amino acids and variable C-terminal domain. Since last decade, these proteins have gained much importance in the serodiagnosis of tuberculosis (TB) as they act as a source of antigenic variation. We have demonstrated earlier that one of the PPE proteins PPE17 (Rv1168c) induces strong B-cell and T-cell responses in active TB disease and also displays a higher antibody titer compared to immunodominant antigens such as ESAT-6, Hsp60 and PPD. However, the immunodominant domain of PPE17 (N-terminal or C-terminal) was not examined in detail. In the present study, we observed that antibody responses elicited in TB patients were directed mostly towards the N-terminal domain of PPE17 (N-PPE17). The antibody generated against N-PPE17 in TB patients did not significantly cross-react with N-terminal domains of other PPE proteins used in this study. Our data suggest that the N terminal domain of PPE17 protein is immunodominant and could be used as a better serodiagnostic marker than the full-length PPE17 protein. PMID- 28651003 TI - Iron elevation and adipose tissue remodeling in the epididymal depot of a mouse model of polygenic obesity. AB - BACKGROUND: Iron dysregulation is a potential contributor to the pathology of obesity-related metabolic complications. KK/HIJ (KK) mice, a polygenic obese mouse model, have elevated serum iron levels. A subset of KK male mice display a bronzing of epididymal adipose tissue (eAT) associated with >100-fold (p<0.001) higher iron concentration. METHODS: To further phenotype and characterize the adipose tissue iron overload, 27 male KK mice were evaluated. 14 had bronzing eAT and 13 had normal appearing eAT. Fasting serum and tissues were collected for iron content, qPCR, histology and western blot. RESULTS: High iron levels were confirmed in bronzing eAT (High Iron group, HI) versus normal iron level (NI) in normal appearing eAT. Surprisingly, iron levels in subcutaneous and brown adipose depots were not different between the groups (p>0.05). The eAT histology revealed iron retention, macrophage clustering, tissue fibrosis, cell death as well as accumulation of HIF-2alpha in the high iron eAT. qPCR showed significantly decreased Lep (leptin) and AdipoQ (adiponectin), whereas Tnfalpha (tumor necrosis factor alpha), and Slc40a1 (ferroportin) were up-regulated in HI (p<0.05). Elevated HIF-2alpha, oxidative stress and local insulin signaling loss was also observed. SIGNIFICANCE: Our data suggest that deposition of iron in adipose tissue is limited to the epididymal depot in male KK mice. A robust adipose tissue remodeling is concomitant with the high iron concentration, which causes local adipose tissue insulin resistance. PMID- 28651004 TI - A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion. AB - Endogenous retroviruses are cellular genes of retroviral origin captured by their host during the course of evolution and represent around 8% of the human genome. Although most are defective and transcriptionally silenced, some are still able to generate retroviral-like particles and proteins. Among these, the HERV-K(HML2) family is remarkable since its members have amplified relatively recently and many of them still have full length coding genes. Furthermore, they are induced in cancers, especially in melanoma, breast cancer and germ cell tumours, where viral particles, as well as the envelope protein (Env), can be detected. Here we show that HERV-K(HML2) Env per se has oncogenic properties. Its expression in a non-tumourigenic human breast epithelial cell line induces epithelial to mesenchymal transition (EMT), often associated with tumour aggressiveness and metastasis. In our model, this is typified by key modifications in a set of molecular markers, changes in cell morphology and enhanced cell motility. Remarkably, microarrays performed in 293T cells reveal that HERV-K(HML2) Env is a strong inducer of several transcription factors, namely ETV4, ETV5 and EGR1, which are downstream effectors of the MAPK ERK1/2 and are associated with cellular transformation. We demonstrate that HERV-K(HML2) Env effectively activates the ERK1/2 pathway in our experimental setting and that this activation depends on the Env cytoplasmic tail. In addition, this phenomenon is very specific, being absent with every other retroviral Env tested, except for Jaagsiekte Sheep Retrovirus (JSRV) Env, which is already known to have transforming properties in vivo. Though HERV-K Env is not directly transforming by itself, the newly discovered properties of this protein may contribute to oncogenesis. PMID- 28651005 TI - Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis. AB - The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High dose BLM also induced dermal fibrosis and increased expression of fibrosis associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model. PMID- 28651006 TI - Application of laboratory and portable attenuated total reflectance infrared spectroscopic approaches for rapid quantification of alpaca serum immunoglobulin G. AB - The objective of this study was to develop and compare the performance of laboratory grade and portable attenuated total reflectance infrared (ATR-IR) spectroscopic approaches in combination with partial least squares regression (PLSR) for the rapid quantification of alpaca serum IgG concentration, and the identification of low IgG (<1000 mg/dL), which is consistent with the diagnosis of failure of transfer of passive immunity (FTPI) in neonates. Serum samples (n = 175) collected from privately owned, healthy alpacas were tested by the reference method of radial immunodiffusion (RID) assay, and laboratory grade and portable ATR-IR spectrometers. Various pre-processing strategies were applied to the ATR IR spectra that were linked to corresponding RID-IgG concentrations, and then randomly split into two sets: calibration (training) and test sets. PLSR was applied to the calibration set and calibration models were developed, and the test set was used to assess the accuracy of the analytical method. For the test set, the Pearson correlation coefficients between the IgG measured by RID and predicted by both laboratory grade and portable ATR-IR spectrometers was 0.91. The average differences between reference serum IgG concentrations and the two IR based methods were 120.5 mg/dL and 71 mg/dL for the laboratory and portable ATR IR-based assays, respectively. Adopting an IgG concentration <1000 mg/dL as the cut-point for FTPI cases, the sensitivity, specificity, and accuracy for identifying serum samples below this cut point by laboratory ATR-IR assay were 86, 100 and 98%, respectively (within the entire data set). Corresponding values for the portable ATR-IR assay were 95, 99 and 99%, respectively. These results suggest that the two different ATR-IR assays performed similarly for rapid qualitative evaluation of alpaca serum IgG and for diagnosis of IgG <1000 mg/dL, the portable ATR-IR spectrometer performed slightly better, and provides more flexibility for potential application in the field. PMID- 28651007 TI - Urban Chikungunya in the Middle East and North Africa: A systematic review. AB - BACKGROUND: The epidemiology of Chikungunya virus (CHIKV) in the Middle East and North Africa (MENA) is not well characterized despite increasing recognition of its expanding infection and disease burden in recent years. METHODOLOGY / PRINCIPAL FINDINGS: Following Cochrane Collaboration guidelines and reporting our findings following PRISMA guidelines, we systematically reviewed records describing the human prevalence and incidence, CHIKV prevalence/infection rates in vectors, outbreaks, and reported cases for CHIKV across the MENA region. We identified 29 human seroprevalence measures, one human incidence study, one study reporting CHIKV infection rates in Aedes, and nine outbreaks and case reports/series reported in the MENA from 1970-2015. Overall, anti-CHIKV antibody or reports of autochthonous transmission were identified from 10 of 23 countries in the MENA region (Djibouti, Egypt, Iraq, Iran, Kuwait, Pakistan, Saudi Arabia, Somalia, Sudan, and Yemen), with seroprevalence measures among general populations (median 1.0%, range 0-43%) and acute febrile illness populations (median 9.8%, range 0-30%). Sudan reported the highest number of studies (n = 11) and the highest seroprevalence among general populations (median 12%, range 0 43%) and undifferentiated acute febrile illness populations (median 18%, range 10 23%). CHIKV outbreaks were reported from Djibouti, Pakistan, Sudan, and Yemen. CONCLUSIONS / SIGNIFICANCE: Seroprevalence studies and outbreak reports suggest endemic transmission of urban cycle CHIKV in at least the Red Sea region and Pakistan. However, indications of seroprevalence despite a low quantity of CHIKV epidemiologic research from the region suggests that CHIKV transmission is currently underrecognized. PMID- 28651008 TI - Production and purification of human Hsp90beta in Escherichia coli. AB - The molecular chaperone Hsp90 is an essential member of the cellular proteostasis system. It plays an important role in the stabilisation and activation of a large number of client proteins and is involved in fatal disease processes, e.g. Alzheimer disease, cancer and cystic fibrosis. This makes Hsp90 a crucial protein to study. Mechanistic studies require large amounts of protein but the production and purification of recombinant human Hsp90 in Escherichia coli is challenging and laborious. Here we identified conditions that influence Hsp90 production, and optimised a fast and efficient purification protocol. We found that the nutrient value of the culturing medium and the length of induction had significant effect on Hsp90 production in Escherichia coli. Our fast, single-day purification protocol resulted in a stable, well-folded and pure sample that was resistant to degradation in a reproducible manner. We anticipate that our results provide a useful tool to produce higher amount of pure, well-folded and stable recombinant human Hsp90beta in Escherichia coli in an efficient way. PMID- 28651009 TI - Interleukin-4 receptor alpha is still required after Th2 polarization for the maintenance and the recall of protective immunity to Nematode infection. AB - There is currently no vaccine against parasitic nematodes and the knowledge on the mechanisms by which protective immunity against this class of parasites is achieved is continuously expanding. Nematode parasites trigger a host protective type 2 immune response via interleukin-4 receptor alpha (IL-4Ralpha). Despite this central role, it is not known whether IL-4Ralpha has a role in maintaining host type 2 immune responses following polarization. To determine the role of IL 4Ralpha after polarization, we used a recently established strain of rosaCreERT2 /+IL-4Ralpha-/Lox mice where il4ralpha gene deletion can be temporally controlled. We show that sustained expression of IL-4Ralpha is required for the maintenance of type 2 immune responses and protective immunity following interruption after polarization with Nippostrongylus brasiliensis primary infection. Moreover, we show by temporal deletion of IL-4Ralpha prior to secondary infection with N. brasiliensis that signaling via this receptor drives more efficient recall of type 2 immune responses and clearance of the parasites. Together, this study demonstrates that sustained IL-4Ralpha mediated signaling is required for the maintenance of anti-nematode type 2 immune responses, describing a novel function for IL-4Ralpha that is distinct from its role in immune polarization. PMID- 28651010 TI - Macrophages, but not neutrophils, are critical for proliferation of Burkholderia cenocepacia and ensuing host-damaging inflammation. AB - Bacteria of the Burkholderia cepacia complex (Bcc) can cause devastating pulmonary infections in cystic fibrosis (CF) patients, yet the precise mechanisms underlying inflammation, recurrent exacerbations and transition from chronic stages to acute infection and septicemia are not known. Bcc bacteria are generally believed to have a predominant extracellular biofilm life style in infected CF lungs, similar to Pseudomonas aeruginosa, but this has been challenged by clinical observations which show Bcc bacteria predominantly in macrophages. More recently, Bcc bacteria have emerged in nosocomial infections of patients hospitalized for reasons unrelated to CF. Research has abundantly shown that Bcc bacteria can survive and replicate in mammalian cells in vitro, yet the importance of an intracellular life style during infection in humans is unknown. Here we studied the contribution of innate immune cell types to fatal pro inflammatory infection caused by B. cenocepacia using zebrafish larvae. In strong contrast to the usual protective role for macrophages against microbes, our results show that these phagocytes significantly worsen disease outcome. We provide new insight that macrophages are critical for multiplication of B. cenocepacia in the host and for development of a fatal, pro-inflammatory response that partially depends on Il1-signalling. In contrast, neutrophils did not significantly contribute to disease outcome. In subcutaneous infections that are dominated by neutrophil-driven phagocytosis, the absence of a functional NADPH oxidase complex resulted in a small but measurably higher increase in bacterial growth suggesting the oxidative burst helps limit bacterial multiplication; however, neutrophils were unable to clear the bacteria. We suggest that paradigm changing approaches are needed for development of novel antimicrobials to efficiently disarm intracellular bacteria of this group of highly persistent, opportunistic pathogens. PMID- 28651011 TI - Indications of airway stenting for severe central airway obstruction due to advanced cancer. AB - BACKGROUND: Management of severe central airway obstruction due to advanced cancer is a medical and technical challenge. The impact of airway stenting on the clinical outcome of such patients is unclear. METHOD: This single-center, retrospective study evaluated 21 patients who underwent airway stenting for advanced cancer. We examined predictors of the post-stenting mortality, including age, serum albumin, tracheal diameter, smoking, opioid use, respiratory failure, and performance status (PS). We also compared survival according to the PS. RESULTS: The mean survival period after stenting was 85.2 days. On univariate analysis, age, albumin, PS before airway stenting, respiratory failure, admission route, and PS grade were the candidates as possible predictors of prognosis after the procedure. On multivariate analysis, PS before airway stenting was identified as possible predictor of prognosis after stenting (HR 1.6180, 95% CI 0.969 to 2.7015, p = 0.066). The mean survival period after stenting was significantly longer in the good PS group, compared to the poor PS group (147.8 days vs. 38.2 days,p = 0.0346). CONCLUSION: Airway stenting for advanced cancer may be more effective for patients in good general condition than in those with poor performance status. PMID- 28651012 TI - The economic burden of human papillomavirus-related precancers and cancers in Sweden. AB - BACKGROUND: High-risk (HR) human papillomavirus (HPV) infection is an established cause of malignant disease. We used a societal perspective to estimate the cost of HR HPV-related cervical, vulvar, vaginal, anal, and penile precancer and cancer, and oropharyngeal cancer in Sweden in 2006, 1 year before HPV vaccination became available in the country. MATERIALS AND METHODS: This prevalence-based cost-of-illness study used diagnosis-specific data from national registries to determine the number of HR HPV-related precancers and cancers. The HR HPV attributable fractions of these diseases were derived from a literature review and applied to the total burden to estimate HR HPV-attributable costs. Direct costs were based on health care utilization and indirect costs on loss of productivity due to morbidity (i.e., sick leave and early retirement) and premature mortality. RESULTS: The total annual cost of all HR HPV-attributable precancers and cancers was ?94 million (?10.3/inhabitant). Direct costs accounted for ?31.3 million (?3.4/inhabitant) of the total annual cost, and inpatient care amounted to ?20.7 million of direct costs. Indirect costs made up ?62.6 million (?6.9/inhabitant) of the total annual cost, and premature mortality amounted to ?36 million of indirect costs. Cervical precancer and cancer was most costly (total annual cost ?58.4 million). Among cancers affecting both genders, anal precancer and cancer, and oropharyngeal cancer were the most costly (?11.2 million and ?11.9 million, respectively). For oropharyngeal cancer, males had the highest health care utilization and represented 71% of the total annual cost. Penile precancer and cancer was least costly (?2.6 million). CONCLUSION: The economic burden of HR HPV-related precancers and cancers is substantial. The disease-related management and treatment costs we report are relevant as a point of reference for future economic evaluations investigating the overall benefits of HPV vaccination in females and males in Sweden. PMID- 28651013 TI - Loss of prion protein induces a primed state of type I interferon-responsive genes. AB - The cellular prion protein (PrPC) has been extensively studied because of its pivotal role in prion diseases; however, its functions remain incompletely understood. A unique line of goats has been identified that carries a nonsense mutation that abolishes synthesis of PrPC. In these animals, the PrP-encoding mRNA is rapidly degraded. Goats without PrPC are valuable in re-addressing loss of-function phenotypes observed in Prnp knockout mice. As PrPC has been ascribed various roles in immune cells, we analyzed transcriptomic responses to loss of PrPC in peripheral blood mononuclear cells (PBMCs) from normal goat kids (n = 8, PRNP+/+) and goat kids without PrPC (n = 8, PRNPTer/Ter) by mRNA sequencing. PBMCs normally express moderate levels of PrPC. The vast majority of genes were similarly expressed in the two groups. However, a curated list of 86 differentially expressed genes delineated the two genotypes. About 70% of these were classified as interferon-responsive genes. In goats without PrPC, the majority of type I interferon-responsive genes were in a primed, modestly upregulated state, with fold changes ranging from 1.4 to 3.7. Among these were ISG15, DDX58 (RIG-1), MX1, MX2, OAS1, OAS2 and DRAM1, all of which have important roles in pathogen defense, cell proliferation, apoptosis, immunomodulation and DNA damage response. Our data suggest that PrPC contributes to the fine-tuning of resting state PBMCs expression level of type I interferon-responsive genes. The molecular mechanism by which this is achieved will be an important topic for further research into PrPC physiology. PMID- 28651014 TI - A decade of HAART in Latin America: Long term outcomes among the first wave of HIV patients to receive combination therapy. AB - BACKGROUND: In Latin America, the first wave of HIV-infected patients initiated highly active antiretroviral therapy (HAART) 10 or more years ago. Characterizing their treatment experience and corresponding outcomes across a decade of HAART may yield insights relevant to the ongoing care of such patients and those initiating HAART more recently in similar clinical settings. METHODS: This retrospective study included adults initiating HAART before 2004 at 8 sites in Argentina, Brazil, Chile, Haiti, Honduras, and Mexico. Patient status (in care, dead, or lost to follow-up [LTFU]) was assessed at 6-month intervals for 10 years, along with CD4 count and HIV-1 viral load (VL) for patients in care. RESULTS: 4,975 patients (66% male) started HAART prior to 2004; 45% were not antiretroviral-naive. At 1, 5, and 10 years, rates of mortality were 4.2%, 9.0%, and 13.6% respectively. LTFU rates for the same periods were 2.4%, 10.9%, and 24.2%. Among patients remaining in care at 10 years, 84.4% were estimated to have VL<=400 copies/mL (Haiti excluded) and median baseline CD4 increased from 158 to 525 cells/mm3. Only 11.4% of all patients remained on their first regimen, 12.6% were on their second, 11.5% were on their third, and 23.0% were on their fourth or subsequent regimen. Outcomes were generally better for patients who were not antiretroviral-naive, except for viral suppression. Heterogeneity among sites was substantial. CONCLUSIONS: Despite advanced disease and predominant use of older antiretrovirals, a large percentage of early HAART initiators in this Latin American cohort were alive and in care with sustained virologic suppression and progressive immune recovery after 10 years. PMID- 28651015 TI - Acute rejection after kidney transplantation promotes graft fibrosis with elevated adenosine level in rat. AB - AIMS: Chronic allograft nephropathy is a worldwide issue with the major feature of progressive allograft fibrosis, eventually ending with graft loss. Adenosine has been demonstrated to play an important role in process of fibrosis. Our study aimed to investigate the relationship between adenosine and fibrosis in renal allograft acute rejection in rat. MATERIALS AND METHODS: Wistar rats and SD rats were selected as experimental animals. Our study designed two groups. In the allograft transplantation group, kidneys of Wistar rats were orthotopically transplanted into SD rat recipients, the same species but not genetically identical, to induce acute rejection. Kidney transplantations of SD rats to SD rats which were genetically identical were served as the control. We established rat models and detected a series of indicators. All data were analyzed statistically. P<0.05 was considered statistically significant. RESULTS: Compared with the control group, levels of adenosine increased significantly in the allograft transplantation group, in which acute rejection was induced (P<0.05). Progressive allograft fibrosis as well as collagen deposition were observed. CONCLUSIONS: These findings suggested that level of adenosine was upregulated in acute rejection after kidney allograft transplantation in rat. Acute rejection may promote renal allograft fibrosis via the adenosine signaling pathways. PMID- 28651016 TI - Enhanced light microscopy visualization of virus particles from Zika virus to filamentous ebolaviruses. AB - Light microscopy is a powerful tool in the detection and analysis of parasites, fungi, and prokaryotes, but has been challenging to use for the detection of individual virus particles. Unlabeled virus particles are too small to be visualized using standard visible light microscopy. Characterization of virus particles is typically performed using higher resolution approaches such as electron microscopy or atomic force microscopy. These approaches require purification of virions away from their normal millieu, requiring significant levels of expertise, and can only enumerate small numbers of particles per field of view. Here, we utilize a visible light imaging approach called Single Particle Interferometric Reflectance Imaging Sensor (SP-IRIS) that allows automated counting and sizing of thousands of individual virions. Virions are captured directly from complex solutions onto a silicon chip and then detected using a reflectance interference imaging modality. We show that the use of different imaging wavelengths allows the visualization of a multitude of virus particles. Using Violet/UV illumination, the SP-IRIS technique is able to detect individual flavivirus particles (~40 nm), while green light illumination is capable of identifying and discriminating between vesicular stomatitis virus and vaccinia virus (~360 nm). Strikingly, the technology allows the clear identification of filamentous infectious ebolavirus particles and virus-like particles. The ability to differentiate and quantify unlabeled virus particles extends the usefulness of traditional light microscopy and can be embodied in a straightforward benchtop approach allowing widespread applications ranging from rapid detection in biological fluids to analysis of virus-like particles for vaccine development and production. PMID- 28651017 TI - Crystal structure of Middle East respiratory syndrome coronavirus helicase. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) remains a threat to public health worldwide; however, effective vaccine or drug against CoVs remains unavailable. CoV helicase is one of the three evolutionary most conserved proteins in nidoviruses, thus making it an important target for drug development. We report here the first structure of full-length coronavirus helicase, MERS-CoV nsp13. MERS-CoV helicase has multiple domains, including an N-terminal Cys/His rich domain (CH) with three zinc atoms, a beta-barrel domain and a C-terminal SF1 helicase core with two RecA-like subdomains. Our structural analyses show that while the domain organization of nsp13 is conserved throughout nidoviruses, the individual domains of nsp13 are closely related to the equivalent eukaryotic domains of Upf1 helicases. The most distinctive feature differentiating CoV helicases from eukaryotic Upf1 helicases is the interaction between CH domain and helicase core. PMID- 28651018 TI - Meta-analysis of miRNA expression profiles for prostate cancer recurrence following radical prostatectomy. AB - BACKGROUND: Prostate cancer (PCa) is a leading reason of death in men and the most diagnosed malignancies in the western countries at the present time. After radical prostatectomy (RP), nearly 30% of men develop clinical recurrence with high serum prostate-specific antigen levels. An important challenge in PCa research is to identify effective predictors of tumor recurrence. The molecular alterations in microRNAs are associated with PCa initiation and progression. Several miRNA microarray studies have been conducted in recurrence PCa, but the results vary among different studies. METHODS: We conducted a meta-analysis of 6 available miRNA expression datasets to identify a panel of co-deregulated miRNA genes and overlapping biological processes. The meta-analysis was performed using the 'MetaDE' package, based on combined P-value approaches (adaptive weight and Fisher's methods), in R version 3.3.1. RESULTS: Meta-analysis of six miRNA datasets revealed miR-125A, miR-199A-3P, miR-28-5P, miR-301B, miR-324-5P, miR-361 5P, miR-363*, miR-449A, miR-484, miR-498, miR-579, miR-637, miR-720, miR-874 and miR-98 are commonly upregulated miRNA genes, while miR-1, miR-133A, miR-133B, miR 137, miR-221, miR-340, miR-370, miR-449B, miR-489, miR-492, miR-496, miR-541, miR 572, miR-583, miR-606, miR-624, miR-636, miR-639, miR-661, miR-760, miR-890, and miR-939 are commonly downregulated miRNA genes in recurrent PCa samples in comparison to non-recurrent PCa samples. The network-based analysis showed that some of these miRNAs have an established prognostic significance in other cancers and can be actively involved in tumor growth. Gene ontology enrichment revealed many target genes of co-deregulated miRNAs are involved in "regulation of epithelial cell proliferation" and "tissue morphogenesis". Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these miRNAs regulate cancer pathways. The PPI hub proteins analysis identified CTNNB1 as the most highly ranked hub protein. Besides, common pathway analysis showed that TCF3, MAX, MYC, CYP26A1, and SREBF1 significantly interact with those DE miRNA genes. The identified genes have been known as tumor suppressors and biomarkers which are closely related to several cancer types, such as colorectal cancer, breast cancer, PCa, gastric, and hepatocellular carcinomas. Additionally, it was shown that the combination of DE miRNAs can assist in the more specific detection of the PCa and prediction of biochemical recurrence (BCR). CONCLUSION: We found that the identified miRNAs through meta-analysis are candidate predictive markers for recurrent PCa after radical prostatectomy. PMID- 28651019 TI - In silico genomic insights into aspects of food safety and defense mechanisms of a potentially probiotic Lactobacillus pentosus MP-10 isolated from brines of naturally fermented Alorena green table olives. AB - Lactobacillus pentosus MP-10, isolated from brines of naturally fermented Alorena green table olives, exhibited high probiotic potential. The genome sequence of L. pentosus MP-10 is currently considered the largest genome among lactobacilli, highlighting the microorganism's ecological flexibility and adaptability. Here, we analyzed the complete genome sequence for the presence of acquired antibiotic resistance and virulence determinants to understand their defense mechanisms and explore its putative safety in food. The annotated genome sequence revealed evidence of diverse mobile genetic elements, such as prophages, transposases and transposons involved in their adaptation to brine-associated niches. In-silico analysis of L. pentosus MP-10 genome sequence identified a CRISPR (clustered regularly interspaced short palindromic repeats)/cas (CRISPR-associated protein genes) as an immune system against foreign genetic elements, which consisted of six arrays (4-12 repeats) and eleven predicted cas genes [CRISPR1 and CRISPR2 consisted of 3 (Type II-C) and 8 (Type I) genes] with high similarity to L. pentosus KCA1. Bioinformatic analyses revealed L. pentosus MP-10 to be absent of acquired antibiotic resistance genes, and most resistance genes were related to efflux mechanisms; no virulence determinants were found in the genome. This suggests that L. pentosus MP-10 could be considered safe and with high-adaptation potential, which could facilitate its application as a starter culture and probiotic in food preparations. PMID- 28651020 TI - The nervous system of the adult ascidian Ciona intestinalis Type A (Ciona robusta): Insights from transgenic animal models. AB - The nervous system of ascidians is an excellent model system to provide insights into the evolutionary process of the chordate nervous system due to their phylogenetic positions as the sister group of vertebrates. However, the entire nervous system of adult ascidians has yet to be functionally and anatomically investigated. In this study, we have revealed the whole dorsal and siphon nervous system of the transgenic adult ascidian of Ciona intestinalis Type A (Ciona robusta) in which a Kaede reporter gene is expressed in a pan-neuronal fashion. The fluorescent signal of Kaede revealed the innervation patterns and distribution of neurons in the nervous system of Ciona. Precise microscopic observation demonstrated the clear innervation of the anterior and posterior main nerves to eight and six lobes of the oral and atrial siphons, respectively. Moreover, visceral nerves, previously identified as unpaired nerves, were found to be paired; one nerve was derived from the posterior end of the cerebral ganglion and the other from the right posterior nerve. This study further revealed the full trajectory of the dorsal strand plexus and paired visceral nerves on either side from the cerebral ganglion to the ovary, and precise innervation between the cerebral ganglion and the peripheral organs including the gonoduct, cupular organ, rectum and ovary. The differential innervation patterns of visceral nerves and the dorsal strand plexus indicate that the peripheral organs including the ovary undergo various neural regulations. Collectively, the present anatomical analysis revealed the major innervation of the dorsal and siphon nervous systems of adult Ciona. PMID- 28651022 TI - Can natural variation in grain P concentrations be exploited in rice breeding to lower fertilizer requirements? AB - Agricultural usage of phosphorus (P) is largely driven by the amount of P removed from fields in harvested plant matter as offtake needs to be balanced by P fertilizer application. Reducing P concentration in grains is a way to decrease P offtake and reduce P fertilizer requirements or soil P mining where insufficient P is applied. Our objective was to assesses the genotypic variation for grain P concentration present within the rice gene pool and resolve to what extent it is affected by environment (P supply) or associated with genetic factors. About 2 fold variation in grain P concentrations were detected in two rice diversity panels, however, environmental effects were stronger than genotype effects. Genome wide association studies identified several putative loci associated with grain P concentrations. In most cases this was caused by minor haplotype associations with high grain P concentrations while associations with reduced P concentrations were identified on chromosomes 1, 6, 8, 11 and 12. Only the latter type of locus is of interest in breeding for reduced P concentrations and the most promising locus was at 20.7 Mb on chromosome 8, where a rare haplotype that was absent from all modern varieties studied reduced grain P concentration by 9.3%. This and all other loci were not consistently detected across environments or association panels, confirming that genetic effects were small compared to effects of environment. We conclude that the genetic effects detected were not sufficiently large or consistent to be of utility in plant breeding. Instead breeding efforts may have to rely on small to medium effect mutants already identified and attempt to achieve a more pronounced reduction in grain P concentration through the introgression of these mutants into a single genetic background. PMID- 28651021 TI - Natural immune response to Plasmodium vivax alpha-helical coiled coil protein motifs and its association with the risk of P. vivax malaria. AB - Protein alpha-helical coiled coil structures are known to induce antibodies able to block critical functions in different pathogens. In a previous study, a total of 50 proteins of Plasmodium vivax erythrocytic asexual stages containing alpha helical coiled coil structural motifs were identified in silico, and the corresponding peptides were chemically synthesized. A total of 43 peptides were recognized by naturally acquired antibodies in plasma samples from both Papua New Guinea (PNG) and Colombian adult donors. In this study, the association between IgG antibodies to these peptides and clinical immunity was further explored by measuring total IgG antibody levels to 24 peptides in baseline samples from a longitudinal study of children aged 1-3 years (n = 164) followed for 16 months. Samples were reactive to all peptides tested. Eight peptides were recognized by >50% of individuals, whereas only one peptide had < 20% reactivity. Children infected at baseline were seropositive to 23/24 peptides. No significant association was observed between antibody titers and age or molecular force of infection, suggesting that antibody levels had already reached an equilibrium. There was a strong association between antibody levels to all peptides and protection against P. vivax clinical episodes during the 16 months follow-up. These results suggest that the selected coiled coil antigens might be good markers of both exposure and acquired immunity to P. vivax malaria, and further preclinical investigation should be performed to determine their potential as P. vivax vaccine antigens. PMID- 28651023 TI - Many-to-one comparisons after safety selection in multi-arm clinical trials. AB - In phase II platform trials, 'many-to-one' comparisons are performed when K experimental treatments are compared with a common control to identify the most promising treatment(s) to be selected for Phase III trials. However, when sample sizes are limited, such as when the disease of interest is rare, only a single Phase II/III trial addressing both treatment selection and confirmatory efficacy testing may be feasible. In this paper, we suggest a two-step safety selection and testing procedure for such seamless trials. At the end of the study, treatments are first screened on the basis of safety, and those deemed to be sufficiently safe are then taken forwards for efficacy testing against a common control. All safety and efficacy evaluations are therefore performed at the end of the study, when for each patient all safety and efficacy data are available. If confirmatory conclusions are to be drawn from the trial, strict control of the family-wise error rate (FWER) is essential. However, to avoid unnecessary losses in power, no type I error rate should be "wasted" on comparisons which are no longer of interest because treatments have been dropped due to safety concerns. We investigate the impact on power and FWER control of multiplicity adjustments which correct efficacy tests only for the number of safe selected treatments instead of adjusting for all K null hypotheses the trial begins testing. We derive conditions under which strict control of the FWER can be achieved. Procedures using the estimated association between safety and efficacy outcomes are developed for the case when the correlation between endpoints is unknown. The operating characteristics of the proposed procedures are assessed via simulation. PMID- 28651024 TI - Short-term proton pump inhibitor treatment may cause hypomagnesaemia in critically ill patients - a pilot study. AB - Many studies have suggested a link between long-term PPI treatment and hypomagnesaemia, though none of them investigated the short-term exposure in high risk patients. We sought to investigate this issue in 90 critically ill patients. We assessed serum Mg concentrations, necessity of Mg supplementation, PPI dose, duration of PPI therapy and route of administration. In multiple analysis we found that Mg supplementation (positive effect/p=0.03) and enteral route of PPI administration (negative effect/p=0.02) had significant impact on Mg concentration. Although the deleterious relationship between short-term PPI treatment and Mg concentration was found, further studies should be provided to confirm this interesting effect. PMID- 28651025 TI - Invasive Cx43high sub-line of human prostate DU145 cells displays increased nanomechanical deformability. AB - Connexin(Cx)43high cells are preferentially recruited to the invasive front of prostate cancer in vitro and in vivo. To address the involvement of Cx43 in the regulation of human prostate cancer DU145 cell invasiveness, we have analysed the nanoelasticity of invasive Cx43high sub-sets of DU145 cells by atomic force microscopy (AFM). The Cx43high DU145 cells displayed considerably higher susceptibility to mechanical distortions than the wild type DU145 cells. Transient Cx43 silencing had no effect on their elastic properties. Our data confirm the relationship between the invasive potential, Cx43 expression and nanoelasticity of the DU145 cells. However, they also show that Cx43 is not directly involved in the maintenance of DU145 invasive phenotype. PMID- 28651027 TI - Dementia Education: Does It Change Nursing Practice? PMID- 28651026 TI - Binding of human plasminogen and high-molecular-mass kininogen by cell surface exposed proteins of Candida parapsilosis. AB - Pathogenic microbes can recruit to their cell surface human proteins that are components of important proteolytic cascades involved in coagulation, fibrinolysis and innate immune response. Once located at the bacterial or fungal surface, such deployed proteins might be utilized by pathogens to facilitate invasion and dissemination within the host organism by interfering with functionality of these systems or by exploiting specific activity of the bound enzymes. Aim of the study presented here was to characterize this phenomenon in Candida parapsilosis (Ashford) Langeron et Talice - an important causative agent of systemic fungal infections (candidiases and candidemias) in humans. We have investigated the interactions of fungal surface-exposed proteins with plasminogen (HPG) and high-molecular-mass kininogen (HK) - the crucial components of human fibrinolytic system and proinflammatory/procoagulant contact-activated kinin forming system, respectively. After confirming ability of the fungal surface exposed proteins to bind HPG and HK, four of them - two agglutinin-like sequence (Als) proteins CPAR2_404780 and CPAR2_404800, a heat shock protein Ssa2 and a moonlighting protein 6-phosphogluconate dehydrogenase 1 - were purified using ion exchange chromatography, gel filtration and chromatofocusing. Then, their affinities to HPG and HK were characterized with surface plasmon resonance measurements. The determined dissociation constants for the investigated protein protein complexes were within a 10-7 M order for the HPG binding and in a range of 10-8-10-9 M for the HK binding. Detailed characterization of adsorption of these two important plasma proteins on the fungal cell surface may help to increase our understanding of molecular mechanisms of C. parapsilosis-dependent candidiasis. PMID- 28651030 TI - Clinical Alerts to Decrease High-Risk Medication Use in Older Adults. AB - High-risk medications (HRMs) account for 14.6% to 54.6% of all medications used in older adults, and have been linked to >50% of adverse drug events (ADEs). HRM related ADEs lead to increased morbidity and mortality, increased hospital length of stay, and financial costs for patients and health care systems. It has been well documented that incorporating information technology in patient care in the form of clinical alert systems can effectively decrease HRM use and improve patient safety. The current article seeks to identify and discuss clinical alert systems focusing on HRMs, their impact on prescribing for older adults, and challenges to the implementation of electronic decision systems. [Journal of Gerontological Nursing, 43(7), 7-12.]. PMID- 28651031 TI - Assessment of Fall Characteristics From Depth Sensor Videos. AB - Falls are a major source of death and disability in older adults; little data, however, are available about the etiology of falls in community-dwelling older adults. Sensor systems installed in independent and assisted living residences of 105 older adults participating in an ongoing technology study were programmed to record live videos of probable fall events. Sixty-four fall video segments from 19 individuals were viewed and rated using the Falls Video Assessment Questionnaire. Raters identified that 56% (n = 36) of falls were due to an incorrect shift of body weight and 27% (n = 17) from losing support of an external object, such as an unlocked wheelchair or rolling walker. In 60% of falls, mobility aids were in the room or in use at the time of the fall. Use of environmentally embedded sensors provides a mechanism for real-time fall detection and, ultimately, may supply information to clinicians for fall prevention interventions. [Journal of Gerontological Nursing, 43(7), 13-19.]. PMID- 28651032 TI - Evidence-Based Practice Guideline: Persistent Pain Management in Older Adults. AB - More individuals develop and endure constant or recurring pain in older adulthood. Although 40% of these individuals receive no treatment, many evidence based treatments are available. Accurate assessment of pain, its impact on functioning, and preventing treatment-related harms lay the foundation of safe, effective pain control. Analgesic agents are often necessary, but require a delicate balance to prevent under-treatment, the unnecessary abandonment of therapy, or exposure to potentially serious adverse effects. Nondrug therapies must be better integrated into the treatment plan to ensure overall safety. Evidence-based approaches help older adults thrive and survive longer despite living with persistent pain. [Journal of Gerontological Nursing, 43(7), 20-31.]. PMID- 28651033 TI - AGS and NHTSA Partner to Plot Course Toward Safe Driving for Older Adults and Caregivers. PMID- 28651034 TI - Reply. PMID- 28651035 TI - Material-Efficient Microfluidic Platform for Exploratory Studies of Visible-Light Photoredox Catalysis. AB - We present an automated microfluidic platform for in-flow studies of visible light photoredox catalysis in liquid or gas-liquid reactions at the 15 MUL scale. An oscillatory flow strategy enables a flexible residence time while preserving the mixing and heat transfer advantages of flow systems. The adjustable photon flux made possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified through droplet screening translate directly to continuous synthesis with minor platform modifications. PMID- 28651036 TI - Copper-Catalyzed Three-Component Carboazidation of Alkenes with Acetonitrile and Sodium Azide. AB - A copper-catalyzed three-component reaction of alkenes, acetonitrile, and sodium azide afforded gamma-azido alkyl nitriles by formation of one C(sp3 )-C(sp3 ) bond and one C(sp3 )-N bond. The transformation allows concomitant introduction of two highly versatile groups (CN and N3 ) across the double bond. A sequence involving the copper-mediated generation of a cyanomethyl radical and its subsequent addition to an alkene, and a C(sp3 )-N bond formation accounted for the reaction outcome. The resulting gamma-azido alkyl nitrile can be easily converted into 1,4-diamines, gamma-amino nitriles, gamma-azido esters, and gamma lactams of significant synthetic value. PMID- 28651037 TI - Fusing Dicarbollide Ions with N-Heterocyclic Carbenes. AB - Discovered by Hawthorne in 1965, dicarbollide ions are an intriguing class of nido-carboranes that mimic the behavior of the cyclopentadienyl anion. Herein, we show that it is possible to directly link the dicarbollide ion to an N heterocyclic carbene (NHC) to form an isolable N-dicarbollide-substituted NHC dianion. This molecule can be accessed by the sequential double deprotonation of a mono-nido-carboranyl imidazolium zwitterion. As revealed by a single-crystal X ray diffraction study, the first deprotonation leads to a monoanionic dicarbollide ion that adopts a bis(dicarbollide) structure in the solid state. Subsequent deprotonation of this monoanion leads to the first N-dicarbollide NHC, which was fully characterized by multinuclear NMR spectroscopy as well as single crystal X-ray diffraction. PMID- 28651039 TI - Remarkable SERS Activity Observed from Amorphous ZnO Nanocages. AB - Enhancement of the semiconductor-molecule interaction, in particular, promoting the interfacial charge transfer process (ICTP), is key to improving the sensitivity of semiconductor-based surface enhanced Raman scattering (SERS). Herein, by developing amorphous ZnO nanocages (a-ZnO NCs), we successfully obtained an ultrahigh enhancement factor of up to 6.62*105 . This remarkable SERS sensitivity can be attributed to high-efficiency ICTP within a-ZnO NC molecule system, which is caused by metastable electronic states of a-ZnO NCs. First principles density functional theory (DFT) simulations further confirmed a stronger ICTP in a-ZnO NCs than in their crystalline counterparts. The efficient ICTP can even generate pi bonding in Zn-S bonds peculiar to the mercapto molecule adsorbed a-ZnO NCs, which has been verified through the X-ray absorption near edge structure (XANES) characterization. To the best of our knowledge, this is the first time such remarkable SERS activity has been observed within amorphous semiconductor nanomaterials, which could open a new frontier for developing highly sensitive and stable SERS technology. PMID- 28651038 TI - Brief Report: Association of Elevated Adipsin Levels With Pulmonary Arterial Hypertension in Systemic Sclerosis. AB - OBJECTIVE: Adipose tissues secrete adipokines, peptides with potent effects modulating fibrosis, inflammation, and vascular homeostasis. Dysregulated adipose tissue biology and adipokine balance have recently been implicated in systemic sclerosis (SSc). This study was undertaken to determine whether altered circulating adipokine levels correlate with SSc disease subsets or clinical manifestations. METHODS: Multiplex assays were used to measure circulating adipokine levels in 198 patients with SSc and 33 healthy controls. Data were evaluated for correlations between serum adipokine levels and demographic and clinical features, including pulmonary arterial hypertension (PAH). To assess the relevance of adipsin, an adipokine involved in complement pathway activation, in SSc, we analyzed publicly available genetic and transcriptomic data. RESULTS: Levels of adiponectin and adipsin differed significantly between controls and patients. Adipsin was significantly elevated in patients with limited cutaneous SSc (odds ratio [OR] 28.3 [95% confidence interval (95% CI) 7.0-113.8]; P < 0.0001), and its levels were associated with serum autoantibody status, pulmonary function and cardiovascular parameters, and PAH (OR 3.3 [95% CI 1.3-8.7]; P = 0.02). Elevated adipsin was more strongly associated with PAH than B-type natriuretic peptide was. Moreover, in SSc patients, adipsin gene single nucleotide polymorphisms were associated with PAH. Transcriptome data set analysis demonstrated elevated adipsin expression in patients with SSc-related PAH. CONCLUSION: We identify adipsin as a novel adipose tissue-derived marker of SSc-related PAH. Circulating adipsin levels might serve as predictive biomarkers in SSc. Mechanistically, adipsin might represent a pathogenic link between adipocyte dysfunction and complement pathway activation and play an important role in the pathogenesis of SSc-related PAH. PMID- 28651040 TI - Is RAPID3 a Good Predictor of Radiographic Outcomes in Rheumatoid Arthritis? Comment on the Article by Khawaja et al. PMID- 28651041 TI - Interaction of [VIV O(acac)2 ] with Human Serum Transferrin and Albumin. AB - [VO(acac)2 ] is a remarkable vanadium compound and has potential as a therapeutic drug. It is important to clarify how it is transported in blood, but the reports addressing its binding to serum proteins have been contradictory. We use several spectroscopic and mass spectrometric techniques (ESI and MALDI-TOF), small-angle X-ray scattering and size exclusion chromatography (SEC) to characterize solutions containing [VO(acac)2 ] and either human serum apotransferrin (apoHTF) or albumin (HSA). DFT and modeling protein calculations are carried out to disclose the type of binding to apoHTF. The measured circular dichroism spectra, SEC and MALDI-TOF data clearly prove that at least two VO-acac moieties may bind to apoHTF, most probably forming [VIV O(acac)(apoHTF)] complexes with residues of the HTF binding sites. No indication of binding of [VO(acac)2 ] to HSA is obtained. We conclude that VIV O-acac species may be transported in blood by transferrin. At very low complex concentrations speciation calculations suggest that [(VO)(apoHTF)] species form. PMID- 28651042 TI - Effect of Dephytinization by Fermentation and Hydrothermal Autoclaving Treatments on the Antioxidant Activity, Dietary Fiber, and Phenolic Content of Oat Bran. AB - Fermentation and hydrothermal methods were tested to reduce the phytic acid (PA) content of oat bran, and the effects of these methods on the dietary fiber (DF) and total phenolic (TP) contents as well as the antioxidant activity (AA) were also investigated. Fermentation with 6% yeast and for 6 h resulted in 88.2% reduction in PA content, while it only resulted in 32.5% reduction in the sample incubated for 6 h without yeast addition. The PA loss in autoclaved oat bran sample (1.5 h, pH 4.0) was 95.2% while it was 41.8% at most in the sample autoclaved without pH adjustment. In both methods, soluble, insoluble, and total DF contents of samples were remarkably higher than the control samples. Also for TP in the oat bran samples, both processes led to 17% and 39% increases, respectively, while AA values were 8% and 15%, respectively. Among all samples, the autoclaving process resulted in the lowest PA and the greatest amount of bioactive compounds. PMID- 28651043 TI - Visualizing the Contributions of Virtual States to Two-Photon Absorption Cross Sections by Natural Transition Orbitals of Response Transition Density Matrices. AB - Observables such as two-photon absorption cross sections cannot be computed from the wave functions of initial and final states alone because of their nonlinear nature. Rather, they depend on the entire manifold of the excited states, which follows from the familiar sum-over-states expressions of second- and higher-order properties. Consequently, the interpretation of the computed nonlinear optical properties in terms of molecular orbitals is not straightforward and usually relies on approximate few-states models. Here, we show that the two-photon absorption (2PA) transitions can be visualized using response one-particle transition density matrices, which are defined as transition density matrices between the zero-order and first-order perturbed states. We also extend the concept of natural transition orbitals to 2PA transitions. We illustrate the utility of this new tool, which provides a rigorous black box alternative to traditional qualitative few-states analysis, by considering 2PA transitions in ethylene, trans-stilbene, and para-nitroaniline. PMID- 28651044 TI - Atmospheric Fate of Monoethanolamine: Enhancing New Particle Formation of Sulfuric Acid as an Important Removal Process. AB - Monoethanolamine (MEA), a potential atmospheric pollutant from the capture unit of a leading CO2 capture technology, could be removed by participating H2SO4 based new particle formation (NPF) as simple amines. Here we evaluated the enhancing potential of MEA on H2SO4-based NPF by examining the formation of molecular clusters of MEA and H2SO4 using combined quantum chemistry calculations and kinetics modeling. The results indicate that MEA at the parts per trillion (ppt) level can enhance H2SO4-based NPF. The enhancing potential of MEA is less than that of dimethylamine (DMA), one of the strongest enhancing agents, and much greater than methylamine (MA), in contrast to the order suggested solely by their basicity (MEA < MA < DMA). The unexpectedly high enhancing potential is attributed to the role of -OH of MEA in increasing cluster binding free energies by acting as both a hydrogen bond donor and acceptor. After the initial formation of one H2SO4 and one MEA cluster, the cluster growth mainly proceeds by first adding one H2SO4, and then one MEA, which differs from growth pathways in H2SO4 DMA and H2SO4-MA systems. Importantly, the effective removal rate of MEA due to participation in NPF is comparable to that of oxidation by hydroxyl radicals at 278.15 K, indicating NPF as an important sink for MEA. PMID- 28651045 TI - Photoinduced Charge Transfer versus Fragmentation Pathways in Lanthanum Cyclopentadienyl Complexes. AB - This study compares two competing pathways of photoexcitations in gas-phase metal organic complexes: first, a sequence of phonon-assisted electronic transitions leading to dissipation of the energy of photoexcitations and, second, a sequence of light-driven electronic transitions leading to photolysis. Phonon-assisted charge carrier dynamics is investigated by combination of the density matrix formalism and on-the-fly nonadiabatic couplings. Light-driven fragmentation is modeled by a time-dependent excited-state molecular-dynamics (TDESMD) algorithm based on Rabi theory and principles similar to the trajectory surface hopping approximation. Numerical results indicate that, under the medium intensity of the laser field, light-driven electronic transitions are more probable than phonon assisted ones. The formation of multiple products is observed in TDESMD trajectories. Simulated mass spectra are extracted from TDESMD simulations and compared to experimental photoionization time-of-flight (PI-TOF) mass spectra. It is found that several features in the experimental mass spectra are reproduced by the simulations. PMID- 28651046 TI - Heparan Sulfate Microarray Reveals That Heparan Sulfate-Protein Binding Exhibits Different Ligand Requirements. AB - Heparan sulfates (HS) are linear sulfated polysaccharides that modulate a wide range of physiological and disease-processes. Variations in HS epimerization and sulfation provide enormous structural diversity, which is believed to underpin protein binding and regulatory properties. The ligand requirements of HS-binding proteins have, however, been defined in only a few cases. We describe here a synthetic methodology that can rapidly provide a library of well-defined HS oligosaccharides. It is based on the use of modular disaccharides to assemble several selectively protected tetrasaccharides that were subjected to selective chemical modifications such as regioselective O- and N-sulfation and selective de sulfation. A number of the resulting compounds were subjected to enzymatic modifications by 3-O-sulfotransferases-1 (3-OST1) to provide 3-O-sulfated derivatives. The various approaches for diversification allowed one tetrasaccharide to be converted into 12 differently sulfated derivatives. By employing tetrasaccharides with different backbone compositions, a library of 47 HS-oligosaccharides was prepared and the resulting compounds were used to construct a HS microarray. The ligand requirements of a number of HS-binding proteins including fibroblast growth factor 2 (FGF-2), and the chemokines CCL2, CCL5, CCL7, CCL13, CXCL8, and CXCL10 were examined using the array. Although all proteins recognized multiple compounds, they exhibited clear differences in structure-binding characteristics. The HS microarray data guided the selection of compounds that could interfere in biological processes such as cell proliferation. Although the library does not cover the entire chemical space of HS-tetrasaccharides, the binding data support a notion that changes in cell surface HS composition can modulate protein function. PMID- 28651048 TI - Nutritional and Metabolic Characteristics of Brassica carinata Co-products from Biofuel Processing in Dairy Cows. AB - The increased utilization of Brassica carinata in the biofuel industry in Canada has resulted in the large-scale production of co-products that can be potentially exploited as alternative protein ingredients in dairy ration. The objectives of this study were to investigate the nutritive value of carinata presscake and meal for dairy cows in terms of (1) nutrient and antinutrient composition, (2) rumen degradation kinetics of organic matter (OM), crude protein (CP), and neutral detergent fiber, (3) hourly effective degradation ratio and potential N to energy synchronization, (4) intestinal digestion of rumen undegraded protein (RUP), and (5) total metabolizable protein (MP) supply to the small intestine. Samples (n = 3) of carinata meal, carinata presscake, and canola meal (as reference feed), collected from three consecutive batches, were evaluated. In comparison to canola meal, carinata presscake and meal had greater (p < 0.05) contents of CP [39.7 versus 48.5 and 53.5% dry matter (DM)], with a high proportion of soluble crude protein (24.0 versus 53.0 and 72.6% CP), resulting in their extensive degradation (59.2 versus 76.3 and 89.3% CP) in the rumen. As a result, carinata presscake and meal supplied smaller (p < 0.05) quantities (92 and 136 g/kg of DM) of MP compared to canola meal (153 g/kg of DM). The contents of glucosinolates were greater (p < 0.05) in carinata presscake (168.5 MUmol/g) and meal (115.2 MUmol/g) compared to canola meal (3.4 MUmol/g), limiting its utilization as a ruminant feed. Carinata co-products can be used as an alternative feed protein source, given their nutrient composition, rumen degradation, and intestinal digestion characteristics, provided that the high glucosinolate content can be reduced. PMID- 28651047 TI - Prioritization of Contaminants of Emerging Concern in Wastewater Treatment Plant Discharges Using Chemical:Gene Interactions in Caged Fish. AB - We examined whether contaminants present in surface waters could be prioritized for further assessment by linking the presence of specific chemicals to gene expression changes in exposed fish. Fathead minnows were deployed in cages for 2, 4, or 8 days at three locations near two different wastewater treatment plant discharge sites in the Saint Louis Bay, Duluth, MN and one upstream reference site. The biological impact of 51 chemicals detected in the surface water of 133 targeted chemicals was determined using biochemical endpoints, exposure activity ratios for biological and estrogenic responses, known chemical:gene interactions from biological pathways and knowledge bases, and analysis of the covariance of ovary gene expression with surface water chemistry. Thirty-two chemicals were significantly linked by covariance with expressed genes. No estrogenic impact on biochemical endpoints was observed in male or female minnows. However, bisphenol A (BPA) was identified by chemical:gene covariation as the most impactful estrogenic chemical across all exposure sites. This was consistent with identification of estrogenic effects on gene expression, high BPA exposure activity ratios across all test sites, and historical analysis of the study area. Gene expression analysis also indicated the presence of nontargeted chemicals including chemotherapeutics consistent with a local hospital waste stream. Overall impacts on gene expression appeared to be related to changes in treatment plant function during rain events. This approach appears useful in examining the impacts of complex mixtures on fish and offers a potential route in linking chemical exposure to adverse outcomes that may reduce population sustainability. PMID- 28651049 TI - Dissolvable and Recyclable Random Lasers. AB - An integrated random laser based on green materials with dissolubility and recyclability is created and demonstrated. The dissolvable and recyclable random laser (DRRL) can be dissolved in water, accompanying the decay of emission intensity and the increment in lasing threshold. Furthermore, the DRRL can be reused after the process of deionized treatment, exhibiting excellent reproducibility with several recycling processes. PMID- 28651050 TI - Brillouin Oscillations from Single Au Nanoplate Opto-Acoustic Transducers. AB - Brillouin oscillations, which are GHz frequency waves that arise from the interaction of light with acoustic waves, are experiencing increasing applications in biology and materials science. They provide information about the speed of sound and refractive index of the material they propagate in, and have recently been used in imaging applications. In the current study, Brillouin oscillations are observed through ultrafast transient reflectivity measurements using chemically synthesized Au nanoplates as opto-acoustic transducers. The Au nanoplates are semitransparent, which allows the Brillouin oscillations to be observed from material on both sides of the plate. The measured frequencies are consistent with the values expected from the speeds of sound in the different materials, however, the attenuation constants are much larger than those reported in previous studies. The increased damping is attributed to diffraction of the acoustic wave as it propagates away from the excitation region. This effect is more significant for experiments with high numerical aperture objectives. These results are important for understanding the relationship between frequency and spatial resolution in Brillouin oscillation microscopy. PMID- 28651051 TI - Molecular Precision at Micrometer Length Scales: Hierarchical Assembly of DNA Protein Nanostructures. AB - Robust self-assembly across length scales is a ubiquitous feature of biological systems but remains challenging for synthetic structures. Taking a cue from biology-where disparate molecules work together to produce large, functional assemblies-we demonstrate how to engineer microscale structures with nanoscale features: Our self-assembly approach begins by using DNA polymerase to controllably create double-stranded DNA (dsDNA) sections on a single-stranded template. The single-stranded DNA (ssDNA) sections are then folded into a mechanically flexible skeleton by the origami method. This process simultaneously shapes the structure at the nanoscale and directs the large-scale geometry. The DNA skeleton guides the assembly of RecA protein filaments, which provides rigidity at the micrometer scale. We use our modular design strategy to assemble tetrahedral, rectangular, and linear shapes of defined dimensions. This method enables the robust construction of complex assemblies, greatly extending the range of DNA-based self-assembly methods. PMID- 28651052 TI - Inhomogeneity in Ethylammonium Nitrate-Acetonitrile Binary Mixtures: The Highest "Low q Excess" Reported to Date. AB - The binary mixtures of the ionic liquid ethylammonium nitrate with acetonitrile have been studied by means of wide- and small-angle X-ray scattering and via two different computational methods, namely, classical molecular dynamics and DFT. The recently debated odd feature in the extreme low q region of some ionic liquid based binary mixtures is linked to density fluctuations within the system. We show how the "low q excess" is due to some nanoscopic objects which are formed at certain compositions. These structures have different density with respect to the surrounding, thus generating the feature observed. Our results also show how the local arrangement is directly linked to the long-range structure. Moreover, we found once again a similarity in the physicochemical behavior of ethylammonium nitrate and water. PMID- 28651053 TI - Hexafluorophosphate-Based Solutions for Mg Batteries and the Importance of Chlorides. AB - The selection of viable conventional magnesium salts in electrolyte solutions for Mg secondary batteries is very limited. Reversible magnesium deposition was demonstrated with only MgTFSI2, in ethereal solutions. A recent report has suggested that Mg can be reversibly deposited from a solution of Mg(PF6)2 in tetrahydrofuran and acetonitrile. In this paper, we dispute that claim and show that PF6- anions passivate Mg anodes and completely inhibit any Mg deposition/dissolution process. We show that addition of chlorides suppresses the passivation phenomena and allows reversible Mg deposition/dissolution processes to commence. The Mg deposits have been examined via elemental analysis, scanning electron microscopy, and X-ray diffraction measurements, depicting a highly oriented, preferential Mg growth. This study evaluates the feasibility of employing PF6-based electrolytes for Mg batteries and exemplifies the aptitude of chlorides for suppressing passivation phenomena. PMID- 28651054 TI - Importance and Nature of Short-Range Excitonic Interactions in Light Harvesting Complexes and Organic Semiconductors. AB - The singlet excitonic coupling between many pairs of chromophores is evaluated in three different light harvesting complexes (LHCs) and two organic semiconductors (amorphous and crystalline). This large database of structures is used to assess the relative importance of short-range (exchange, overlap, orbital) and long range (Coulombic) excitonic coupling. We find that Mulliken atomic transition charges can introduce systematic errors in the Coulombic coupling and that the dipole-dipole interaction fails to capture the true Coulombic coupling even at intermolecular distances of up to 50 A. The non-Coulombic short-range contribution to the excitonic coupling is found to represent up to ~70% of the total value for molecules in close contact, while, as expected, it is found to be negligible for dimers not in close contact. For the face-to-face dimers considered here, the sign of the short-range interaction is found to correlate with the sign of the Coulombic coupling, i.e. reinforcing it when it is already strong. We conclude that for molecules in van der Waals contact the inclusion of short-range effects is essential for a quantitative description of the exciton dynamics. PMID- 28651055 TI - Pharmacokinetic Characterization of [18F]UCB-H PET Radiopharmaceutical in the Rat Brain. AB - The synaptic vesicle glycoprotein 2A (SV2A), a protein essential to the proper nervous system function, is found in presynaptic vesicles. Thus, SV2A targeting, using dedicated radiotracers combined with positron emission tomography (PET), allows the assessment of synaptic density in the living brain. The first-in-class fluorinated SV2A specific radioligand, [18F]UCB-H, is now available at high activity through an efficient radiosynthesis compliant with current good manufacturing practices (cGMP). We report here a noninvasive method to quantify [18F]UCB-H binding in rat brain with microPET. Validation study in rats confirmed the need of high enantiomeric purity to target SV2A in vivo. We demonstrated the reliability of a population-based input function to quantify SV2A in preclinical microPET setting. Finally, we investigated the in vivo metabolism of [18F]UCB-H and confirmed the negligible amount of radiometabolites in the rat brain. Hence, the in vivo quantification of SV2A using [18F]UCB-H microPET seems a promising tool for the assessment of the synaptic density in the rat brain, and opens the way for longitudinal follow-up in neurodegenerative disease rodent models. PMID- 28651056 TI - Significantly Improved Protein Folding Thermodynamics Using a Dispersion Corrected Water Model and a New Residue-Specific Force Field. AB - An accurate potential energy model is crucial for biomolecular simulations. Despite many recent improvements of classical protein force fields, there are remaining key issues: much weaker temperature dependence of folding/unfolding equilibrium and overly collapsed unfolded or disordered states. For the latter problem, a new water model (TIP4P-D) has been proposed to correct the significantly underestimated water dispersion interactions. Here, using TIP4P-D, we reveal problems in current force fields through failures in folding model systems (a polyalanine peptide, Trp-cage, and the GB1 hairpin). By using residue specific parameters to achieve better match between amino acid sequences and native structures and adding a small H-bond correction to partially compensate the missing many-body effects in alpha-helix formation, the new RSFF2+ force field with the TIP4P-D water model can excellently reproduce experimental melting curves of both alpha-helical and beta-hairpin systems. The RSFF2+/TIP4P-D method also gives less collapsed unfolded structures and describes well folded proteins simultaneously. PMID- 28651058 TI - Is Disgust Proneness Associated With Anxiety and Related Disorders? A Qualitative Review and Meta-Analysis of Group Comparison and Correlational Studies. AB - Research suggests that disgust may be linked to the etiology of some anxiety related disorders. The present investigation reviews this literature and employs separate meta-analyses of clinical group comparison and correlational studies to examine the association between disgust proneness and anxiety-related disorder symptoms. Meta-analysis of 43 group comparison studies revealed those high in anxiety disorder symptoms reported significantly more disgust proneness than those low in anxiety symptoms. Although this effect was not moderated by clinical versus analogue studies or type of disorder, larger group differences were observed for those high in anxiety symptoms associated with contagion concerns compared to those high in anxiety symptoms not associated with contagion concerns. Similarly, meta-analysis of correlational data across 83 samples revealed moderate associations between disgust proneness and anxiety-related disorder symptoms. Moderator analysis revealed that the association between disgust proneness and anxiety-related disorder symptoms was especially robust for anxiety symptoms associated with contagion concerns. After controlling for measures of negative affect, disgust proneness continued to be moderately correlated with anxiety-related disorder symptoms. However, negative affect was no longer significantly associated with symptoms of anxiety-related disorders when controlling for disgust proneness. The implications of these findings are discussed in the context of a novel transdiagnostic model. PMID- 28651057 TI - How To Identify Plasmons from the Optical Response of Nanostructures. AB - A promising trend in plasmonics involves shrinking the size of plasmon-supporting structures down to a few nanometers, thus enabling control over light-matter interaction at extreme-subwavelength scales. In this limit, quantum mechanical effects, such as nonlocal screening and size quantization, strongly affect the plasmonic response, rendering it substantially different from classical predictions. For very small clusters and molecules, collective plasmonic modes are hard to distinguish from other excitations such as single-electron transitions. Using rigorous quantum mechanical computational techniques for a wide variety of physical systems, we describe how an optical resonance of a nanostructure can be classified as either plasmonic or nonplasmonic. More precisely, we define a universal metric for such classification, the generalized plasmonicity index (GPI), which can be straightforwardly implemented in any computational electronic-structure method or classical electromagnetic approach to discriminate plasmons from single-particle excitations and photonic modes. Using the GPI, we investigate the plasmonicity of optical resonances in a wide range of systems including: the emergence of plasmonic behavior in small jellium spheres as the size and the number of electrons increase; atomic-scale metallic clusters as a function of the number of atoms; and nanostructured graphene as a function of size and doping down to the molecular plasmons in polycyclic aromatic hydrocarbons. Our study provides a rigorous foundation for the further development of ultrasmall nanostructures based on molecular plasmonics. PMID- 28651060 TI - Mechanism underlying methyl eugenol attenuation of intestinal ischemia/reperfusion injury. AB - Intestinal ischemia/reperfusion (I/R) injury is associated with a high risk of mortality in the clinical situation. Many factors are involved in I/R, including reactive oxygen species, cytokine release, and apoptosis. We aimed to determine whether a pure methyl eugenol (ME) given before intestinal ischemia, protects against intestinal I/R injury and the possible mechanism involved in this protection. Rat received ME (100 mg/kg) for 30 days then underwent intestinal I/R with 30 min ischemia and 60 min reperfusion. Serum lactate dehydrogenase (LDH) level, tissue malondialdehyde (MDA), as well as some antioxidant biomarkers were assessed, while the serum level of tumor necrosis factor alpha (TNF-alpha) was determined by ELISA. The change in TNF-alpha and interleukin 6 (IL-6) gene expressions were evaluated and confirmed by assessing protein level of TNF-alpha in the intestinal tissue by immunohistochemistry. Apoptosis was evaluated using DNA-laddering assay and by detecting caspase-3 immunohistochemically. Administration of ME prior to I/R injury resulted in a modulation of the production of MDA, LDH, and nitric oxide and restoration of the tested oxidative stress biomarkers. Pretreatment with ME downregulated messenger RNA of TNF-alpha and IL-6 inflammatory cytokines and their protein expressions in I/R rats. Marked inhibition of the apoptotic DNA and improvement of the architectures of small intestine were observed after pretreatment with ME. ME exhibits a protective effect against intestinal I/R via amelioration of the oxidative stress and inflammatory cytokines gene expression. Therefore, the supplementation of ME prior to intestinal I/R might be helpful in the attenuation of I/R complications. PMID- 28651061 TI - Modelling of optimal training load patterns during the 11 weeks preceding major competition in elite swimmers. AB - Periodization of swim training in the final training phases prior to competition and its effect on performance have been poorly described. We modeled the relationships between the final 11 weeks of training and competition performance in 138 elite sprint, middle-distance, and long-distance swimmers over 20 competitive seasons. Total training load (TTL), strength training (ST), and low- to medium-intensity and high-intensity training variables were monitored. Training loads were scaled as a percentage of the maximal volume measured at each intensity level. Four training periods (meso-cycles) were defined: the taper (weeks 1 to 2 before competition), short-term (weeks 3 to 5), medium-term (weeks 6 to 8), and long-term (weeks 9 to 11). Mixed-effects models were used to analyze the association between training loads in each training meso-cycle and end-of season major competition performance. For sprinters, a 10% increase between ~20% and 70% of the TTL in medium- and long-term meso-cycles was associated with 0.07 s and 0.20 s faster performance in the 50 m and 100 m events, respectively (p < 0.01). For middle-distance swimmers, a higher TTL in short-, medium-, and long term training yielded faster competition performance (e.g., a 10% increase in TTL was associated with improvements of 0.1-1.0 s in 200 m events and 0.3-1.6 s in 400 m freestyle, p < 0.01). For sprinters, a 60%-70% maximal ST load 6-8 weeks before competition induced the largest positive effects on performance (p < 0.01). An increase in TTL during the medium- and long-term preparation (6-11 weeks to competition) was associated with improved performance. Periodization plans should be adapted to the specialty of swimmers. PMID- 28651062 TI - Reply by Authors. PMID- 28651063 TI - Editorial Comment. PMID- 28651064 TI - Progranulin as a biomarker and potential therapeutic agent. AB - Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases. PMID- 28651065 TI - The removal of particle-reactive radionuclides in shallow water: Bottom scavenging versus particle settling of iodine-131 and beryllium-7. AB - In pelagic waters, the removal of particle-reactive radionuclides is controlled by nuclide sorption to particles and subsequent settling by gravity. However, in shallow nearshore waters, the dominant mechanism of nuclide scavenging is not so clear. Understanding how particle-reactive radionuclides are scavenged from the water column is critical if these tracers are to be used as proxies of particle flux in shallow aquatic systems. In this study, we present evidence that the removal of particle-reactive radionuclides in nearshore and turbulent waters is primarily controlled by bottom scavenging. Specifically, we measured both water column and bottom sediment activities of sewage-sourced iodine-131 (131I, t 1/2 = 8.02 days) and atmospherically-sourced beryllium-7 (7Be, t 1/2 = 53.3 days) in a semi-enclosed harbor. We show that the water column 7Be/131I flux ratio that is required to sustain observed harbor bottom inventories of both nuclides is incongruent with 7Be/131I activity ratios on water column particles, and (2) 131I and 7Be derived mass fluxes of particulate matter to the harbor bottom are in concordance with each other and independently made estimates of river sediment loading to the harbor only when bottom scavenging of both particle-bound and dissolved (<0.7 MUm) nuclide fractions are considered. PMID- 28651066 TI - Thalassemia Major: Transplantation or Transfusion and Chelation. AB - Thalassemia is the most common monogenic hematologic disease that affects millions in the world and kills thousands of patients every year. Without transfusion or transplantation, patients with thalassemia major are expected to die within months of diagnosis. However, long-term transfusion and chelation therapy is highly challenging for many developing countries where the disease is prevalent, representing a major and unsustainable health burden. Stem cell transplantation is the only cure for thalassemia. It has witnessed major developments that have made it less toxic, more successful, and feasible for a larger number of patients with diverse comorbidities and from a wider range of donors. Advances in human leukocyte antigen typing have greatly refined alternate donor selection with results of matched unrelated donors similar to matched sibling donors. Novel strategies such as haploidentical and cord blood transplantation have increased the possibility of patients with no healthy donor to get a better opportunity to survive and avoid chronic transfusion complications. Cost-effectively, transplantation should be considered the primary treatment of choice in the presence of a suitable related or unrelated donor and at centers with a satisfactory experience in the field of transplantation and particularly, in managing those with thalassemia. Despite some complications such as graft-versus-host disease and late conditioning effects, the overall improvement in the quality of life of thalassemia is difficult to deny. Unfortunately, the number of transplants for thalassemia represents only a minority of all transplants conducted globally and the essential requirement for transplants for thalassemia in limited-resources countries should mandate the transplant societies, including Worldwide Network for Blood and Marrow Transplantation, to collaborate to help initiate and support specialized transfusion and transplant programs for managing thalassemia. PMID- 28651067 TI - Necrotizing Lip Infection Causing Septic Thrombophlebitis of the Neck: A Rare Variant of Lemierre Syndrome. AB - Lemierre syndrome is an uncommon condition in which internal jugular vein thrombosis presents after recent oropharyngeal infection. Frequently, this is accompanied by septic emboli. This report outlines a variant of this disease process, with septic thrombophlebitis of the neck associated with a necrotizing skin infection of the lower lip and chin. A 25-year-old man with lower lip and chin swelling, initially managed with intravenous antibiotics, progressed to the development of a left facial vein thrombus, septic emboli to the lungs, and a necrotizing lower lip and chin infection that was managed with debridement, thrombectomy, and prolonged hemodynamic and pulmonary support. A necrotizing skin infection with thrombus of the jugular system and septic emboli is a very rare variant of Lemierre syndrome. Early recognition of an infection with septic emboli and/or necrotizing pathobiological findings allows for prompt antibiotic and surgical therapy, minimizing the mortality of these potentially lethal infections. PMID- 28651068 TI - Effect of Choukroun Platelet-Rich Fibrin Combined With Autologous Micro Morselized Bone on the Repair of Mandibular Defects in Rabbits. AB - PURPOSE: The aim of this study was to explore the effect of Choukroun platelet rich fibrin (PRF) combined with autologous micro-morselized bone on the repair of mandibular defects in rabbits. MATERIALS AND METHODS: Thirty-six healthy New Zealand rabbits were selected for the present study. After models of mandibular defects were established, rabbits were randomly divided into Choukroun PRF, autologous micro-morselized bone (autologous), Choukroun PRF combined with autologous bone (combined) and model groups. After the rabbits were sacrificed at 2, 8, and 12 weeks postoperatively, their bone formation was assessed by x-ray and scanning electron microscopy, and the histologic changes of the mandibular defect area were detected by hematoxylin and eosin staining. Cone-beam computed tomography was used to observe the size of the change of the mandibular defect area. Bone mineral density (BMD) was analyzed by dual-energy x-ray absorptiometry. RESULTS: The bone defect in the combined group showed better repair, increased bone mineral content, and denser callus than the other groups, and the defect area was filled with mature trabecular bone. In the Choukroun PRF and autologous groups, the defect area was smaller and filled with osteoporotic trabecular bone. A clear mandibular defect area was still observed in the model group. Compared with the other groups, the combined group showed more bone regeneration, more fibrous tissue regeneration, and greater bone maturity at all time points. The combined group had the highest BMD, there was no relevant difference in BMD between the Choukroun PRF and autologous groups, and the model group had the lowest BMD. BMD in all 4 groups increased with time. CONCLUSION: These findings indicate that Choukroun PRF combined with autologous micro morselized bone can substantially improve the repair of mandibular defects in rabbits, and the effect is superior to Choukroun PRF or autologous micro morselized bone alone. PMID- 28651069 TI - Automatic MPST-cut for segmentation of carpal bones from MR volumes. AB - In the context of rheumatic diseases, several studies suggest that Magnetic Resonance Imaging (MRI) allows the detection of the three main signs of Rheumatoid Arthritis (RA) at higher sensitivities than available through conventional radiology. The rapid, accurate segmentation of bones is an essential preliminary step for quantitative diagnosis, erosion evaluation, and multi temporal data fusion. In the present paper, a new, semi-automatic, 3D graph-based segmentation method to extract carpal bone data is proposed. The method is unsupervised, does not employ any a priori model or knowledge, and is adaptive to the individual variability of the acquired data. After selecting one source point inside the Region of Interest (ROI), a segmentation process is initiated, which consists of two automatic stages: a cost-labeling phase and a graph-cutting phase. The algorithm finds optimal paths based on a new cost function by creating a Minimum Path Spanning Tree (MPST). To extract the region, a cut of the obtained tree is necessary. A new criterion of the MPST-cut based on compactness shape factor was conceived and developed. The proposed approach is applied to a large database of 96 T1-weighted MR bone volumes. Performance quality is evaluated by comparing the results with gold-standard bone volumes manually defined by rheumatologists through the computation of metrics extracted from the confusion matrix. Furthermore, comparisons with the existing literature are carried out. The results show that this method is efficient and provides satisfactory performance for bone segmentation on low-field MR volumes. PMID- 28651070 TI - Assessment of temporal predictive models for health care using a formal method. AB - Recent developments in the field of sensor devices provide new possibilities to measure a variety of health related aspects in a precise and fine-grained manner. Subsequently, more empirical data will be generated than ever before. While this greatly improves the opportunities for creating accurate predictive models, other types of models besides the more traditional machine learning approaches can provide insights into temporal relationships in the data. Models that express temporal relationships between states in a mathematical manner are examples of such models. However, the evaluation methods traditionally used in the field of predictive modeling are not appropriate for those models, making it difficult to distinguish them in terms of validity. Appropriate assessment methodology is therefore necessary to drive the research of mathematical modeling forward. In this paper we investigate the applicability of such a formalized method. The method takes into account important model aspects, namely descriptive and predictive capability, parameter sensitivity and model complexity. As a case study the method is applied to a mathematical model in the domain of mental health, showing that the method generates useful insights into the behavior of the model. PMID- 28651071 TI - An Independent Active Contours Segmentation framework for bone micro-CT images. AB - Micro-CT is an imaging technique for small tissues and objects that is gaining increased popularity especially as a pre-clinical application. Nevertheless, there is no well-established micro-CT segmentation method, while typical procedures lack sophistication and frequently require a degree of manual intervention, leading to errors and subjective results. To address these issues, a novel segmentation framework, called Independent Active Contours Segmentation (IACS), is proposed in this paper. The proposed IACS is based on two autonomous modules, namely automatic ROI extraction and IAC Evolution, which segments the ROI image using multiple Active Contours that evolve simultaneously and independently of one another. The proposed method is applied on a Phantom dataset and on real datasets. It is tested against several established segmentation methods that include Adaptive Thresholding, Otsu Thresholding, Region Growing, Chan-Vese (CV) AC, Geodesic AC and Automatic Local Ratio-CV AC, both qualitatively and quantitatively. The results prove its superior performance in terms of object identification capability, accuracy and robustness, under normal circumstances and under four types of artificially introduced noise. These enhancements can lead to more reliable analysis, better diagnostic procedures and treatment evaluation of several bone-related pathologies, and to the facilitation and further advancement of bone research. PMID- 28651072 TI - Understanding the quality of typical and atypical dark cutting beef from heifers and steers. AB - Dark cutting beef with pH <6.0 may have glucidic potential approaching that of normal beef but has increased toughness that may also be influenced by cattle sex and carcass characteristics. Beef longissimus thoracis (LT) from normal (Canada AA; n=24), and typical (TB4; pH>5.9, n=20) and atypical (AB4; pH<5.9, n=20) dark cutting carcasses were analyzed to investigate relationships between beef quality, pH, glucidic potential and carcass characteristics. Results indicated that reduced lactate and glucidic potential were accompanied by increased pH and reduced L*, a* and b* values. Mean glucidic potential was lowest (P<0.0001) for TB4 whereas glucidic potentials for heifers and steers AB4 LT were sufficient to attain normal pH, substantiating the existence of atypical dark cutting. Warner Bratzler shear force of AB4 remained higher (P<0.05) than that of Canada AA LT confirming AB4 as the toughest beef irrespective of sex and carcass characteristics. PMID- 28651073 TI - Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy. AB - Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat this antidrug antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and could potentially cause general immunosuppression. Novel approaches to induce tolerance to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize, or kill FVIII-specific lymphocytes. In this review, we discuss the current state of engineered T-cell therapies, and we describe the recent progress in applying these therapies to induce FVIII-specific tolerance. PMID- 28651075 TI - Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients. AB - The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects. PMID- 28651076 TI - Application of water-assisted ultraviolet light in combination of chlorine and hydrogen peroxide to inactivate Salmonella on fresh produce. AB - With the demand for fresh produce increases in recent decades, concerns for microbiological safety of fresh produce are also raised. To identify effective ultraviolet (UV) light treatment for fresh produce decontamination, we first determined the effect of three forms of UV treatment, dry UV (samples were treated by UV directly), wet UV (samples were dipped in water briefly and then exposed to UV), and water-assisted UV (samples were treated by UV while being immersed in agitated water) on inactivation of Salmonella inoculated on tomatoes and fresh-cut lettuce. In general, the water-assisted UV treatment was found to be the most effective for both produce items. Chlorine and hydrogen peroxide were then tested to determine whether they could be used to enhance the decontamination efficacy of water-assisted UV treatment and prevent transfer of Salmonella via wash water by completely eliminating it. Neither of them significantly enhanced water-assisted UV inactivation of Salmonella on tomatoes. Chlorine significantly improved the decontamination effectiveness of the water assisted UV treatment for baby-cut carrots and lettuce, but not for spinach. In general, the single water-assisted UV treatment and the combined treatment of water-assisted UV and chlorine were similar or more effective than the chlorine washing treatment. In most of the cases, no Salmonella was detected in the wash water when the single water-assisted UV treatment was used to decontaminate tomatoes. In a few cases when Salmonella was detected in the wash water, the populations were very low,<=2CFU/mL, and the wash water contained an extremely high level of organic load and soil level. Therefore, the single water-assisted UV treatment could potentially be used as an environmentally friendly and non chemical alternative to chlorine washing for tomatoes after validation in industrial scale. For lettuce, spinach and baby-cut carrots, the combined treatment of water-assisted UV treatment and chlorine was needed to maintain a pathogen free environment in the wash water so that cross contamination could be prevented during fresh produce washing. PMID- 28651074 TI - Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. AB - Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells. PMID- 28651077 TI - Rhizopus oryzae - Ancient microbial resource with importance in modern food industry. AB - Filamentous fungi are microorganisms widely known for their diverse biochemical features. Fungi can efficiently invade a wide variety of substrates under operational conditions producing numerous bioproducts of interest, such as enzymes, organic acids, aromatic compounds and colorants. An additional interesting characteristic of some fungi is their safety classification for different uses, which guarantees that the bioproducts obtained from them do not contain any toxic component deleterious to humans. Rhizopus oryzae is among this group of fungi and is classified as a GRAS filamentous fungus, commonly used for production of some oriental traditional foods. It is mainly recognized as a good producer of lactic acid; however, its potential for other biotechnological processes is under study. This review analyzes and discusses the current scientific and technical contributions which may maximize the potential of R. oryzae as a producer of different compounds of industrial interest. PMID- 28651078 TI - Leuconostoc mesenteroides and Leuconostoc pseudomesenteroides bacteriophages: Genomics and cross-species host ranges. AB - Unveiling virus-host interactions are relevant for understanding the biology and evolution of microbes globally, but in particular, it has also a paramount impact on the manufacture of fermented dairy products. In this study, we aim at characterizing phages infecting the commonly used heterofermentative Leuconostoc spp. on the basis of host range patterns and genome analysis. Host range of six Leuconostoc phages was investigated using three methods (efficiency of plaquing, spot and turbidity tests) against Ln. mesenteroides and Ln. pseudomesenteroides strains. Complete genome sequencing from four out of the six studied Leuconostoc phages were obtained in this work, while the remaining two have been sequenced previously. According to our results, cross-species host specificity was demonstrated, as all phages tested were capable of infecting both Ln. pseudomesenteroides and Ln. mesenteroides strains, although with different efficiency of plaquing (EOP). Phage adsorption rates and ability of low-EOP host strains to propagate phages by crossing the Leuconostoc species' barrier confirm results. At the genome level, phages CHA, CHB, Ln-7, Ln-8 and Ln-9 revealed high similarity with previously characterized phages infecting mostly Ln. mesenteroides strains, while phage LDG was highly similar to phages infecting Ln. pseudomesenteroides. Additionally, correlation between receptor binding protein (RBP) and host range patterns allowed us to unveil a finer clustering of Leuconostoc phages studied into four groups. This is the first report of overlapped phage host ranges between Leuconostoc species. PMID- 28651079 TI - A survey of oenophages during wine making reveals a novel group with unusual genomic characteristics. AB - Oenophages have so far been mostly isolated from red wines under malolactic fermentation (MLF), and correspond to temperate or ex-temperate phages of Oenococcus oeni. Their genomes are clustered into 4 integrase gene sequence groups, which are also related to the chromosomal integration site. Our aims were to survey the occurrence of oenophages in a broader and more diverse collection of samples than those previously explored. Active phages were isolated from 33 out of 166 samples, which mostly originated from must and MLF. Seventy one phage lysates were produced and 30% were assigned to a novel group with unusual genomic characteristics, called unk. All unk members produced similar RAPD and DNA restriction patterns, were negative by PCR for the signature sequences previously identified in the integrase and endolysin genes of oenophages, and lacked any BamHI restriction site in their genome. The data support that development of additional and novel signature genes for assessing oenophage diversity is now required. PMID- 28651080 TI - Robust recursive absolute value inequalities discriminant analysis with sparseness. AB - In this paper, we propose a novel absolute value inequalities discriminant analysis (AVIDA) criterion for supervised dimensionality reduction. Compared with the conventional linear discriminant analysis (LDA), the main characteristics of our AVIDA are robustness and sparseness. By reformulating the generalized eigenvalue problem in LDA to a related SVM-type "concave-convex" problem based on absolute value inequalities loss, our AVIDA is not only more robust to outliers and noises, but also avoids the SSS problem. Moreover, the additional L1-norm regularization term in the objective makes sure sparse discriminant vectors are obtained. A successive linear algorithm is employed to solve the proposed optimization problem, where a series of linear programs are solved. The superiority of our AVIDA is supported by experimental results on artificial examples as well as benchmark image databases. PMID- 28651081 TI - Inactivation of pathogenic microorganisms in freshwater using HSO5-/UV-A LED and HSO5-/Mn+/UV-A LED oxidation processes. AB - Freshwater disinfection using photolytic and catalytic activation of peroxymonosulphate (PMS) through PMS/UV-A LED and PMS/Mn+/UV-A LED [Mn+ = Fe2+ or Co2+] processes was evaluated through the inactivation of three different bacteria: Escherichia coli (Gram-negative), Bacillus mycoides (sporulated Gram positive), Staphylococcus aureus (non-sporulated Gram-positive), and the fungus Candida albicans. Photolytic and catalytic activation of PMS were effective in the total inactivation of the bacteria using 0.1 mM of PMS and Mn+ at neutral pH (6.5), with E. coli reaching the highest and the fastest inactivation yield, followed by S. aureus and B. mycoides. With B. mycoides, the oxidative stress generated through the complexity of PMS/Mn+/UV-A LED combined treatments triggered the formation of endospores. The treatment processes were also effective in the total inactivation of C. albicans, although, due to the ultrastructure, biochemistry and physiology of this yeast, higher dosages of reagents (5 mM of PMS and 2.5 mM of Mn+) were required. The rate of microbial inactivation markedly increased through catalytic activation of PMS particularly during the first 60 s of treatment. Co2+ was more effective than Fe2+ to catalyse PMS decomposition to sulphate radicals for the inactivation of S. aureus and C. albicans. The inactivation of the four microorganisms was well represented by the Hom model. The Biphasic and the Double Weibull models, which are based on the existence of two microbial sub-populations exhibiting different resistance to the treatments, also fitted the experimental results of photolytic activation of PMS. PMID- 28651082 TI - Impact of humic acid on the degradation of levofloxacin by aqueous permanganate: Kinetics and mechanism. AB - Levofloxacin (LF) is a frequently detected fluoroquinolone in surface water, and permanganate (MnO4-) is a commonly used oxidant in drinking water treatment. This study investigated the impact of humic acid (HA) on LF degradation by aqueous MnO4- from both kinetic and mechanistic aspects. In the absence of HA, the second order rate constant (k) of LF degradation by MnO4- was determined to be 3.9 M-1 s 1 at pH 7.5, which increased with decreasing pH. In the presence of HA, the pseudo-first-order rate constant (kobs) of LF degradation at pH 7.5 was significantly increased by 3.8- and 2.8-fold at [HA]o:[KMnO4]o (mass ratio) = 0.5 and 1, respectively. Secondary oxidant scavenging and electron paramagnetic resonance tests indicated that HA could form a complex with Mn(III), a strongly oxidative intermediate produced in the reaction of MnO4- with HA, to induce the successive formation of superoxide radicals (O2-) and hydroxyl radicals (OH). The resulting OH primarily contributed to the accelerated LF degradation, and the complex [HA-Mn(III)] could account for the rest of acceleration. The degradation of LF and its byproducts during MnO4- oxidation was mainly through hydroxylation, dehydrogenation and carboxylation, and the presence of HA led to a stronger destruction of LF. This study helps better understand the degradation of organic micropollutants by MnO4- in drinking water treatment. PMID- 28651083 TI - Characterization of organic precursors in DBP formation and AOC in urban surface water and their fate during managed aquifer recharge. AB - In this study, the organic components were identified that are mainly responsible for the formation of disinfection byproducts (DBPs) and for the biostability of urban surface water. The compositional distribution of dissolved organic matter (DOM) was strongly associated with the potential for both DBP formation and bacterial growth. Further evaluation was carried out (1) to compare the potential for DBP formation upon chlorination of treated water, (2) to determine the biostability that might result from minimizing assimilable organic carbon (AOC), and (3) to use laboratory-scale soil-column experiments to compare the effects of removal of trace organic chemicals (TOrCs) between managed aquifer recharge (MAR) hybrid systems (such as bank filtration followed by artificial recharge and recovery: ARR), and ozonation followed by ARR. Our fractionation and removal methods provided useful insights into the removal of problematic organic components using MAR hybrid systems. Pretreatment with a small amount of ozone (~0.7 mg-O3 mg-C-1) resulted in improved ARR performance, especially from removing organic acids from DOM, which substantially decreased the potential for DBP formation, while the robust removal of AOC was attributed to a significant decrease in non-acidic and more hydrophilic fractions during soil passage. Both pretreatments used in this study were effective in the removal of selected TOrCs, but carbamazepine was persistent during soil passage. The pretreatment, which used ozonation before ARR, significantly enhanced the removal of carbamazepine; therefore, ozonation followed by ARR is considered an effective way to enhance removal of persistent compounds. PMID- 28651084 TI - Treatment of food waste recycling wastewater using anaerobic ceramic membrane bioreactor for biogas production in mainstream treatment process of domestic wastewater. AB - A bench-scale anaerobic membrane bioreactor (AnMBR) equipped with submerged flat sheet ceramic membranes was operated at mesophilic conditions (30-35 degrees C) treating domestic wastewater (DWW) supplemented with food wasterecycling wastewater (FRW) to increase the organic loading rate (OLR) for better biogas production. Coupling ceramic membrane filtration with AnMBR treatment provides an alternative strategy for high organic wastewater treatment at short hydraulic retention times (HRTs) with the potential benefits of membrane fouling because they have a high hydrophilicity and more robust at extreme conditions. The anaerobic ceramic MBR (AnCMBR) treating mixture of actual FRW with DWW (with an influent chemical oxygen demand (COD) of 2,115 mg/L) was studied to evaluate the treatment performance in terms of organic matter removal and methane production. COD removal during actual FRW with DWW operation averaged 98.3 +/- 1.0% corresponding to an average methane production of 0.21 +/- 0.1 L CH4/g CODremoved. Biogas sparging, relaxation and permeate back-flushing were concurrently employed to manage membrane fouling. A flux greater than 9.2 L m-2 h 1 (LMH) was maintained at 13 h HRT for approximately 200 days without chemical cleaning at an OLR of 2.95 kg COD m-3 d-1. On day 100, polyvinyl alcohol (PVA) gel beads were added into the AnCMBR to alleviate the membrane fouling, suggesting that their mechanical scouring effect contributed positively in reducing the fouling index (FI). Although these bio-carriers might accelerate the breaking up of bio-flocs, which released a higher amount of soluble microbial products (SMP), a 95.4% SMP rejection was achieved. Although the retention efficiency of dissolved organic carbons (DOC) was 91.4% across the ceramic membrane, a meaningful interpretation of organic carbon detection (OCD) fingerprints was conducted to better understand the ceramic membrane performance. PMID- 28651085 TI - Evolution of monitoring for Giardia and Cryptosporidium in water. AB - This review describes the evolution of monitoring methodology for Cryptosporidium and Giardia in water since the 1970's. Methods in current use for Giardia and Cryptosporidium in water are highlighted, though attention is given to all available published methods by country and continent. The review is intended to stimulate research leading to future improvements and further developments in monitoring methodology for Giardia, Cryptosporidium and other waterborne protozoan parasites in water. PMID- 28651086 TI - Age at first febrile seizure correlates with perinatal maternal emotional symptoms. AB - OBJECTIVE: Prenatal exposure to stress and fever are factors lowering seizure threshold in animal models. The fever effect on seizure threshold is well documented in human infants, however the associations between maternal perinatal stress and infants' susceptibility to seizures is unknown. This is the first study in humans to investigate longitudinally, whether in humans, the effect of maternal perinatal emotional symptoms such as stress, anxiety and depression that may trigger a biological stress response on age at first seizure occurrence. METHOD: The study sample is a subgroup drawn from a longitudinal follow up cohort (3D cohort study: Design, Develop, Discover, N=2366 mother-infant dyads). Twenty nine otherwise healthy infants who had a febrile seizure (FS) episode before the last follow-up visit (around 24 months of age) were studied. Mothers completed questionnaires regarding their emotional health at each pregnancy trimester and at three months postpartum. The link between maternal emotional symptoms and infant age at first FS was assessed through correlations and multiple regressions. RESULTS: We found that maternal anxiety symptoms during the second trimester of pregnancy are linked to the age at first FS (r(23)=-0.459, p=0.021) and explain 21.1% of its variance. Postnatal maternal depression symptoms at 3 months postpartum were also associated with the age at first FS (r(23)=-0.587, p=0.002) and explained an additional 17.6% of variance. Together, the variables explained 38.7% of the variance in age at first FS. Maternal perceived stress symptoms at 3 months postpartum were also linked to the age at first FS (r(23)= 0.418, p=0.038), however, stress did not significantly contribute to the variance of age at first FS.. SIGNIFICANCE: Our results suggest a link between increased perinatal maternal emotional symptoms and the age at first FS. An earlier age at first FS may be the manifestation of a lower seizure threshold. Early first seizure occurrence is a risk factor for compromised neurological and cognitive development. Further studies should address the mechanisms by which perinatal maternal emotional symptoms may have an impact on seizure threshold in humans. PMID- 28651087 TI - Effects of terrestrial and marine organic matters on deposition of dechlorane plus (DP) in marine sediments from the Southern Yellow Sea, China: Evidence from multiple biomarkers. AB - As an emerging halogenated organic contaminant, Dechlorane Plus (DP) was scarcely reported in marine environments, especially in China. In this work, 35 surface sediments and a sediment core were collected across the Southern Yellow Sea (SYS) to comprehensively explore the spatio-temporal distribution and possible migration pathway of DP. DP concentrations ranged from 14.3 to 245.5 pg/g dry weight in the surface sediments, displaying a seaward increasing trend with the high levels in the central mud zone. This spatial distribution pattern was ascribed to that fine particles with the elevated DP levels were preferentially transported to the central mud zone under hydrodynamic forcing and/or via long range atmospheric transportation and deposition. DP concentrations in sediment core gradually increased from the mid-1950s to present, which corresponded well with the historical production and usage of DP, as well as the economic development in China. Significantly positive correlation between DP and total organic carbon (TOC) in both surface sediments and sediment core indicated TOC dependent natural deposition of DP in the SYS. We used multiple biomarkers, for the first time, to explore the potential effects of terrestrial and marine organic matters (TOM and MOM) on DP deposition. The results showed that competition may occur between TOM and MOM for DP adsorption, and MOM was the predominant contributor in controlling DP deposition in the marine sediments from the SYS. PMID- 28651088 TI - Genetic and epigenetic alterations in normal and sensitive COPD-diseased human bronchial epithelial cells repeatedly exposed to air pollution-derived PM2.5. AB - Even though clinical, epidemiological and toxicological studies have progressively provided a better knowledge of the underlying mechanisms by which air pollution-derived particulate matter (PM) exerts its harmful health effects, further in vitro studies on relevant cell systems are still needed. Hence, aiming of getting closer to the human in vivo conditions, primary human bronchial epithelial cells derived from normal subjects (NHBE) or sensitive chronic obstructive pulmonary disease (COPD)-diseased patients (DHBE) were differentiated at the air-liquid interface. Thereafter, they were repeatedly exposed to air pollution-derived PM2.5 to study the occurrence of some relevant genetic and/or epigenetic endpoints. Concentration-, exposure- and season-dependent increases of OH-B[a]P metabolites in NHBE, and to a lesser extent, COPD-DHBE cells were reported; however, there were more tetra-OH-B[a]P and 8-OHdG DNA adducts in COPD DHBE cells. No increase in primary DNA strand break nor chromosomal aberration was observed in repeatedly exposed cells. Telomere length and telomerase activity were modified in a concentration- and exposure-dependent manner in NHBE and particularly COPD-DHBE cells. There were a global DNA hypomethylation, a P16 gene promoter hypermethylation, and a decreasing DNA methyltransferase activity in NHBE and notably COPD-DHBE cells repeatedly exposed. Changes in site-specific methylation, acetylation, and phosphorylation of histone H3 (i.e., H3K4me3, H3K9ac, H3K27ac, and H3S10ph) and related enzyme activities occurred in a concentration- and exposure-dependent manner in all the repeatedly exposed cells. Collectively, these results highlighted the key role played by genetic and even epigenetic events in NHBE and particularly sensitive COPD-DHBE cells repeatedly exposed to air pollution-derived PM2.5 and their different responsiveness. While these specific epigenetic changes have been already described in COPD and even lung cancer phenotypes, our findings supported that, together with genetic events, these epigenetic events could dramatically contribute to the shift from healthy to diseased phenotypes following repeated exposure to relatively low doses of air pollution-derived PM2.5. PMID- 28651089 TI - Validation of commercial real-time PCR-arrays for environmental risk assessment: Application to the study of p,p'-DDE toxicity in Mus spretus mice liver. AB - Data on gene transcription profiles provide a comprehensive assessment of the toxic and defensive mechanisms that are triggered by pollutants. PCR-arrays have emerged as a reliable tool for analyzing the expression of a panel of relevant, pathway- or disease-focused genes under uniform cycling conditions. By using SYBR Green-optimized primer assays, it is possible to simultaneously amplify a sample with high specificity and amplification efficiencies. However, commercial PCR arrays target a limited group of organisms, excluding most of those with environmental relevance, as is the case with Mus spretus mice. Our previous works with M. spretus showed a high sequence similarity between M. spretus and the model organism M. musculus allowing the use of commercial platforms with M. spretus. This work demonstrates the successful application of a commercial PCR array designed for the model organism M. musculus to assess the biological effects caused by the organochlorine pesticide p,p'-DDE in a focused panel of stress-related genes in M. spretus mice. This cost-effective, easy-to-use platform detected quantitative gene profiling differences between M. spretus hepatic RNA samples and generated data highly concordant with those obtained by absolute qRT-PCR, the most sensitive method to quantify transcripts. This platform is also suitable for use in field studies with free-living M. spretus mice for routine environmental risk assessment. Our results provide a broad impression of the biological consequences of p,p'-DDE on the hepatic health of mice. PMID- 28651090 TI - Spatio-temporal variability of particulate matter in the key part of Gansu Province, Western China. AB - To investigate the spatial and temporal behaviors of particulate matter in Lanzhou, Jinchang and Jiayuguan during 2014, the hourly concentrations of PM2.5 and PM10 were collected from the Ministry of Environmental Protection (MEP) in this study. The analysis indicated that the mean annual PM10 (PM2.5) concentrations during 2014 were 115 +/- 52 MUg/m3 (57 +/- 28 MUg/m3), 104 +/- 75 MUg/m3 (38 +/- 22 MUg/m3) and 114 +/- 72 MUg/m3 (32 +/- 17 MUg/m3) in Lanzhou, Jinchang and Jiayuguan, respectively, all of which exceeded the Chinese national ambient air quality II standards for PM. Higher values for both PM fractions were generally observed in spring and winter, and lower concentrations were found in summer and autumn. Besides, the trend of seasonal variation of particulate matter (PM) in each city monitoring site is consistent with the average of the corresponding cities. Anthropogenic activities along with the boundary layer height and wind scale contributed to diurnal variations in PM that varied bimodally (Lanzhou and Jinchang) or unimodally (Jiayuguan). With the arrival of dust events, the PM10 concentrations changed dramatically, and the PM10 concentrations during dust storm events were, respectively, 19, 43 and 17 times higher than the levels before dust events in Lanzhou, Jinchang and Jiayuguan. The ratios (PM2.5/PM10) were lowest, while the correlations were highest, indicating that dust events contributed more coarse than fine particles, and the sources of PM are similar during dust storms. The relationships between local meteorological parameters and PM concentrations suggest a clear association between the highest PM concentrations, with T <= 7 degrees C, and strong winds (3-4 scale). However, the effect of relative humidity is complicated, with more PM10 and PM2.5 exceedances being registered with a relative humidity of less than 40% and 40-60% in Lanzhou, while higher exceedances in Jinchang appeared at a relative humidity of 80-100%. PMID- 28651091 TI - Loggerhead sea turtles (Caretta caretta): A target species for monitoring litter ingested by marine organisms in the Mediterranean Sea. AB - Marine litter is any persistent, manufactured or processed solid material discarded, disposed of or abandoned in the marine and coastal environment. Ingestion of marine litter can have lethal and sub-lethal effects on wildlife that accidentally ingests it, and sea turtles are particularly susceptible to this threat. The European Commission drafted the 2008/56/EC Marine Strategy Framework Directive with the aim to achieve a Good Environmental Status (GES), and the loggerhead sea turtle (Caretta caretta, Linnaeus 1758) was selected for monitoring the amount and composition of litter ingested by marine animals. An analogous decision has been made under the UNEP/MAP Barcelona Convention for the protection of the Mediterranean Sea, following the Ecosystem Approach. This work provides for the first time, two possible scenarios for the Marine Strategy Framework Directive GES, both related to "Trends in the amount and composition of litter ingested by marine animals" in the Mediterranean Sea. The study validates the use of the loggerhead turtle as target indicator for monitoring the impact of litter on marine biota and calls for immediate use of this protocol throughout the Mediterranean basin and European Region. Both GES scenarios are relevant worldwide, where sea turtles and marine litter are present, for measuring the impact of ingested plastics and developing policy strategies to reduce it. In the period between 2011 and 2014, 150 loggerhead sea turtles, found dead, were collected from the Italian Coast, West Mediterranean Sea Sub-Region. The presence of marine litter was investigated using a standardized protocol for necropsies and lab analysis. The collected items were subdivided into 4 main categories, namely, IND-Industrial plastic, USE-User plastic, RUB-Non plastic rubbish, POL Pollutants and 14 sub-categories, to detect local diversity. Eighty-five percent of the individuals considered (n = 120) were found to have ingested an average of 1.3 +/- 0.2 g of litter (dry mass) or 16 +/- 3 items. PMID- 28651093 TI - The effect of a hydroxyapatite impregnated PCL membrane in rat subcritical calvarial bone defects. AB - OBJECTIVE: The present study evaluated the effect of polymeric-nanofibers membranes impregnated with microparticulate hydroxyapatite (HA) in the subcritical calvarial bone defects (SCBD) healing. DESIGN: PCL membranes with and without HA were obtained by electrospinning. SCBD were perforated (3.3mm) in left and right sides of 36 rat calvarias. The right-side SBCD of 18 animals was filled with HA mixed with blood clot and blood clot at the contralateral side. The remaining animals received PCL+HA membrane at the right-side SCBD and PCL membrane at the contralateral side. Animals were killed after 30, 60 and 90days after surgery. Bone defect volume (in mm3) was measured by tomography (CBCT). Qualitative histological analysis and SBCD area (in mm2) were measured. Quantitative data were submitted to Kruskal-Wallis/Dunn tests. RESULTS: Reduction of SBCD volume was observed in all treatments but PCL. Association with HA significantly improved bone healing induced by PCL and blood clot. PCL+HA induced the lowest SBCD volume at 60 and 90days. Complete bone healing was not observed even at 90days in SCBD treated with blood clot. In every period, more bone formation was observed for SCBD treated with membranes. CONCLUSIONS: We concluded that both PCL membrane and HA were able to improve bone healing. PMID- 28651092 TI - Role of proteoglycans on the biochemical and biomechanical properties of dentin organic matrix. AB - OBJECTIVE: Proteoglycans (PGs) are multifunctional biomacromolecules of the extracellular matrix of collagen-based tissues. In teeth, besides a pivotal regulatory role on dentin biomineralization, PGs provide mechanical support to the mineralized tissue and compressive strength to the biosystem. This study assessed enzymatic protocols for selective PGs removal from demineralized dentin to determine the roles of these biomacromolecules in the bulk mechanical properties and biostability of type I collagen. METHODS: Selective removal of glycosaminoglycans chains (GAGs) and PGs from demineralized dentin was carried out by enzymatic digestion protocols using chondroitinase ABC (c-ABC) and trypsin (Try). A comprehensive study design included assessment of dentin matrix mass loss, biodegradability of the PGs/GAGs-depleted dentin matrix, ultimate tensile strength (UTS) and energy to fracture tests. Quantitative data was statistically analyzed by two-way and one-way ANOVA followed by the appropriate post hoc tests (alpha=0.05). RESULTS: Transmission electron microscopy images show effective GAGs removal by c-ABC and Try and both enzymatic methods released statistically similar amounts of GAGs from the demineralized dentin. Try digestion resulted in about 25% dentin matrix mass loss and increased susceptibility to collagenolytic digestion when compared to c-ABC (p=0.0224) and control (p=0.0901). Moreover, PGs digestion by Try decreased the tensile strengths of dentin. Statistically lower energy to fracture was observed in c-ABC-treated dentin matrix. CONCLUSIONS: GAGs plays a pivotal role on tissue mechanics and anisotropy, while the core protein of PGs have a protective role on matrix biostability. PMID- 28651094 TI - In vitro susceptibility of Brachyspira hyodysenteriae to a commercial citrus fruit extract. AB - Brachyspira hyodysenteriae is the main etiological agent of swine dysentery (SD). Nowadays, treatment and control of SD is increasingly difficult due to the emergence of antimicrobial resistance together with the restrictions on the use of antibiotics in veterinary practice. The aim of this study was to evaluate, as an alternative in the control of this disease, the antimicrobial activity and the main mechanism of action of BIOCITRO, a citrus extract commercialized as raw material and used as feed additive, against B. hyodysenteriae. Ten isolates of B. hyodysenteriae were used to assess the minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) of BIOCITRO by broth microdilution method. Moreover, stationary phase cultures of two B. hyodysenteriae strains were subjected for 90min to four different concentrations of BIOCITRO and compared with the untreated controls by flow cytometry (FC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results showed that BIOCITRO has a relevant bacteriostatic and bactericidal effect against B. hyodysenteriae with MIC and MBC values ranging from 32 to 128partspermillion (ppm). It induces damage in at least 35% and 76% of the bacterial cells when exposed to 128 and 256ppm of BIOCITRO respectively as revealed by the intake of propidium iodide by FC. Relevant changes in the structure of the bacterial cells were observed by SEM and confirmed by FTIR. According to these results, BIOCITRO seems to be a satisfactory alternative to the use of antibiotics in the control of SD. PMID- 28651095 TI - The influence of performance on action-effect integration in sense of agency. AB - Sense of agency refers to the subjective feeling of being able to control an outcome through one's own actions or will. Prior studies have shown that both sensory processing (e.g., comparisons between sensory feedbacks and predictions basing on one's motor intentions) and high-level cognitive/constructive processes (e.g., inferences based on one's performance or the consequences of one's actions) contribute to judgments of sense of agency. However, it remains unclear how these two types of processes interact, which is important for clarifying the mechanisms underlying sense of agency. Thus, we examined whether performance based inferences influence action-effect integration in sense of agency using a delay detection paradigm in two experiments. In both experiments, participants pressed left and right arrow keys to control the direction in which a moving dot was travelling. The dot's response delay was manipulated randomly on 7 levels (0 480ms) between the trials; for each trial, participants were asked to judge whether the dot response was delayed and to rate their level of agency over the dot. In Experiment 1, participants tried to direct the dot to reach a destination on the screen as quickly as possible. Furthermore, the computer assisted participants by ignoring erroneous commands for half of the trials (assisted condition), while in the other half, all of the participants' commands were executed (self-control condition). In Experiment 2, participants directed the dot as they pleased (without a specific goal), but, in half of the trials, the computer randomly ignored 32% of their commands (disturbed condition) rather than assisted them. The results from the two experiments showed that performance enhanced action-effect integration. Specifically, when task performance was improved through the computer's assistance in Experiment 1, delay detection was reduced in the 480-ms delay condition, despite the fact that 32% of participants' commands were ignored. Conversely, when no feedback on task performance was given (as in Experiment 2), the participants reported greater delay when some of their commands were randomly ignored. Furthermore, the results of a logistic regression analysis showed that the threshold of delay detection was greater in the assisted condition than in the self-control condition in Experiment 1, which suggests a wider time window for action-effect integration. A multivariate analysis also revealed that assistance was related to reduced delay detection via task performance, while reduced delay detection was directly correlated with a better sense of agency. These results indicate an association between the implicit and explicit aspects of sense of agency. PMID- 28651096 TI - Predicting actions from subtle preparatory movements. AB - To study how people anticipate others' actions, we designed a competitive reaching task. Subjects faced each other separated by a Plexiglas screen and their finger movements in 3D space were recorded with sensors. The first subject (Attacker) was instructed to touch one of two horizontally arranged targets on the screen. The other subject (Blocker) touched the same target as quickly as possible. Average finger reaction times (fRTs) were fast, much faster than reactions to a dot moving on the screen in the same manner as the Attacker's finger. This suggests the presence of subtle preparatory cues in other parts of the Attacker's body. We also recorded videos of Attackers' movements and had Blockers play against unedited videos as well as videos that had all preparatory cues removed by editing out frames before Attacker finger movements started. Blockers' fRTs in response to the edited videos were significantly slower (~90ms). Also, reversing the preparatory movements in the videos tricked the Blockers into choosing the incorrect target at the beginning of their movement. Next, we occluded various body parts of the Attacker and showed that fRTs slow down only when most of the body of the Attacker is occluded. These results indicate that informative cues are widely distributed over the body and Blockers can use any piece from a set of redundant cues for action prediction. Reaction times in each condition remained constant over the duration of the testing sessions indicating a lack of learning during the experiment. These results suggest that during a dynamic two-person interaction, human subjects possess a remarkable and built-in action reading capacity allowing them to predict others' goals and respond efficiently in this competitive setting. PMID- 28651097 TI - Population and performance analyses of four major populations with Illumina's FGx Forensic Genomics System. AB - The MiSeq FGx Forensic Genomics System (Illumina) enables amplification and massively parallel sequencing of 59 STRs, 94 identity informative SNPs, 54 ancestry informative SNPs, and 24 phenotypic informative SNPs. Allele frequency and population statistics data were generated for the 172 SNP loci included in this panel on four major population groups (Chinese, African Americans, US Caucasians, and Southwest Hispanics). Single-locus and combined random match probability values were generated for the identity informative SNPs. The average combined STR and identity informative SNP random match probabilities (assuming independence) across all four populations were 1.75E-67 and 2.30E-71 with length based and sequence-based STR alleles, respectively. Ancestry and phenotype predictions were obtained using the ForenSeqTM Universal Analysis System (UAS; Illumina) based on the ancestry informative and phenotype informative SNP profiles generated for each sample. Additionally, performance metrics, including profile completeness, read depth, relative locus performance, and allele coverage ratios, were evaluated and detailed for the 725 samples included in this study. While some genetic markers included in this panel performed notably better than others, performance across populations was generally consistent. The performance and population data included in this study support that accurate and reliable profiles were generated and provide valuable background information for laboratories considering internal validation studies and implementation. PMID- 28651099 TI - Brain-shift compensation using intraoperative ultrasound and constraint-based biomechanical simulation. AB - PURPOSE: During brain tumor surgery, planning and guidance are based on preoperative images which do not account for brain-shift. However, this deformation is a major source of error in image-guided neurosurgery and affects the accuracy of the procedure. In this paper, we present a constraint-based biomechanical simulation method to compensate for craniotomy-induced brain-shift that integrates the deformations of the blood vessels and cortical surface, using a single intraoperative ultrasound acquisition. METHODS: Prior to surgery, a patient-specific biomechanical model is built from preoperative images, accounting for the vascular tree in the tumor region and brain soft tissues. Intraoperatively, a navigated ultrasound acquisition is performed directly in contact with the organ. Doppler and B-mode images are recorded simultaneously, enabling the extraction of the blood vessels and probe footprint, respectively. A constraint-based simulation is then executed to register the pre- and intraoperative vascular trees as well as the cortical surface with the probe footprint. Finally, preoperative images are updated to provide the surgeon with images corresponding to the current brain shape for navigation. RESULTS: The robustness of our method is first assessed using sparse and noisy synthetic data. In addition, quantitative results for five clinical cases are provided, first using landmarks set on blood vessels, then based on anatomical structures delineated in medical images. The average distances between paired vessels landmarks ranged from 3.51 to 7.32 (in mm) before compensation. With our method, on average 67% of the brain-shift is corrected (range [1.26; 2.33]) against 57% using one of the closest existing works (range [1.71; 2.84]). Finally, our method is proven to be fully compatible with a surgical workflow in terms of execution times and user interactions. CONCLUSION: In this paper, a new constraint-based biomechanical simulation method is proposed to compensate for craniotomy-induced brain-shift. While being efficient to correct this deformation, the method is fully integrable in a clinical process. PMID- 28651098 TI - An interoceptive model of bulimia nervosa: A neurobiological systematic review. AB - The objective of our study was to examine the neurobiological support for an interoceptive sensory processing model of bulimia nervosa (BN). To do so, we conducted a systematic review of interoceptive sensory processing in BN, using the PRISMA guidelines. We searched PsychInfo, Pubmed, and Web of Knowledge databases to identify biological and behavioral studies that examine interoceptive detection in BN. After screening 390 articles for inclusion and conducting a quality assessment of articles that met inclusion criteria, we reviewed 41 articles. We found that global interoceptive sensory processing deficits may be present in BN. Specifically there is evidence of abnormal brain function, structure and connectivity in the interoceptive neural network, in addition to gastric and pain processing disturbances. These results suggest that there may be a neurobiological basis for global interoceptive sensory processing deficits in BN that remain after recovery. Data from taste and heart beat detection studies were inconclusive; some studies suggest interoceptive disturbances in these sensory domains. Discrepancies in findings appear to be due to methodological differences. In conclusion, interoceptive sensory processing deficits may directly contribute to and explain a variety of symptoms present in those with BN. Further examination of interoceptive sensory processing deficits could inform the development of treatments for those with BN. PMID- 28651100 TI - Methodological challenges in qualitative content analysis: A discussion paper. AB - This discussion paper is aimed to map content analysis in the qualitative paradigm and explore common methodological challenges. We discuss phenomenological descriptions of manifest content and hermeneutical interpretations of latent content. We demonstrate inductive, deductive, and abductive approaches to qualitative content analysis, and elaborate on the level of abstraction and degree of interpretation used in constructing categories, descriptive themes, and themes of meaning. With increased abstraction and interpretation comes an increased challenge to demonstrate the credibility and authenticity of the analysis. A key issue is to show the logic in how categories and themes are abstracted, interpreted, and connected to the aim and to each other. Qualitative content analysis is an autonomous method and can be used at varying levels of abstraction and interpretation. PMID- 28651101 TI - Competitive ligands facilitate dissociation of the complex of bifunctional inhibitor and protein kinase. AB - Dissociation of the complex of a ligand and a protein usually follows the kinetic profile of the first order process and the rate of dissociation is not affected by the presence of competitive ligands. We discovered that dissociation of the complex between a bifunctional ligand and a protein kinase (the catalytic subunit of cAMP-dependent protein kinase), an enzyme possessing 2 different substrate binding sites, was accelerated (facilitated) over 50-fold in the presence of competitive ligands at higher concentrations. Structurally diverse compounds revealed >10-fold different efficiency for acceleration of dissociation of the complex. These results show that the kinetic behavior of flexible biomolecular complexes possessing two spatially separated contact areas is highly dynamic. This property of biomolecular complexes should be carefully considered for effective application of bifunctional ligands for regulation of activity of target proteins in cells. PMID- 28651103 TI - Does cortisol moderate the environmental association between peer victimization and depression symptoms? A genetically informed twin study. AB - Many youths who are victimized by peers suffer from depression symptoms. However, not all bullying victims show depression symptoms and individuals' biological sensitivity may play an important moderating role in this regard. In line with this notion, peer victimization has been associated with increased depressive symptoms in youth with higher basal cortisol secretion. It is unclear, however, whether this moderating effect of cortisol really concerns the environmental effect of peer victimization on depression. Indeed, genetic factors can also influence individuals' environmental experiences, including peer victimization, and part of these genetic factors may be those associated with depression. Using a genetically informed design based on 159 monozygotic and 120 dizygotic twin pairs (52% girls) assessed at age 14 years, this study examined whether cortisol secretion moderates the environmental or the genetic association between peer victimization and depression symptoms. Salivary cortisol at awakening was obtained with buccal swabs during four school week days. Peer victimization and depression were assessed via self-reports. Cholesky modeling revealed that peer victimization was associated with depression symptoms via both genetic and environmental pathways. Moreover, the environmental association between peer victimization and depression symptoms steadily increased with increasing levels of morning cortisol. The genetic association between peer victimization and depression symptoms also varied, albeit less, as a function of individuals' cortisol secretion. These findings support the hypothesis that peer victimization increases internalizing psychopathology mainly in youth with heightened biological reactivity to environmental conditions. PMID- 28651102 TI - Childhood stress and birth timing among African American women: Cortisol as biological mediator. AB - Preterm birth (PTB) occurs among 1:11U.S. white women and 1:7.5 African American women and is a significant driver of racial disparities in infant mortality. Maternal stress is the most common clinical phenotype underlying spontaneous PTB. Specific patterns of stress and biological mediators driving PTB remain unclear. We examined the effect of childhood stress on birth timing among African American women and evaluated maternal cortisol elevation as a biological mediator. A prospective observational design was employed, with a single study visit at 28-32 weeks gestation and medical record review. The Stress and Adversity Inventory was administered, which provides a comprehensive estimate of childhood stress, stress in adulthood, and five core characteristic subscales (interpersonal loss, physical danger, humiliation, entrapment, role disruption). Venipuncture was performed between 11:00am and 4:00pm and plasma cortisol quantified by ELISA. Analyses controlled for stress in adulthood. Among a final sample of 89, cumulative childhood stress predicted birth timing (p=0.01). The association was driven by stress related to interpersonal loss and physical danger, with support for maternal cortisol as a biological mediator (ab=0.02, 95% CI [0.001, 0.045]; ab=0.02, 95% CI [0.001, 0.043], respectively). Results were similar, overall, in sub-group analyses among spontaneously laboring women (n=53); however, role disruption arose as an additional predictor, as mediated by cortisol elevations (ab=0.03, 95% CI [0.005, 0.074]). Of note, cortisol was no longer supported as a mediator linking physical danger to birth timing after adjusting for sleep quality and hours awake prior to venipuncture (ab=0.02, 95% CI [-0.0001, 0.046]). We provide preliminary evidence that, independent of stress in adulthood, childhood stress of specific core characteristics may shape birth timing, with cortisol elevation as a biological mediator. Further investigation is warranted and may bolster the development of biologically-informed screening tools for the prediction and targeted prevention of stress-related PTB. PMID- 28651104 TI - Autophagy is an important event for low-dose cytarabine treatment in acute myeloid leukemia cells. AB - Cytarabine (Ara-c) has been an important agent in acute myeloid leukemia (AML) treatment for more than 40 years. While, the mechanisms underlying low dose cytarabine (LD Ara-c) is poorly understood. In this study, we investigated the therapeutic effect of LD Ara-C in vitro. U937 and HEL cell lines were treated with increasing dose of Ara-C and showed growth inhibition rates in a time and dose-dependent manner. Treatment with LD Ara-C (50nM) induced a time-dependent increase in expression of microtubule-associated protein light chain 3 (LC3) and beclin1, but degradation of sequestosome1 (p62) in both U937 and HEL cells. Characteristic of autophagosomes appeared after 24h treatment. Meanwhile, deregulation of Akt-mTOR pathway was also detected. When cultured in presence of autophagy inhibitors, autophagy and differentiation was reversed, and cell growth inhibition was also attenuated. Similar phenomenon could also be seen when beclin1 expression was down-regulated. Taken together, we concluded that LD Ara-C can induce autophagy in AML cells and appeared to play an important role in differentiation and death. Down-regulation of Akt-mTOR pathway is involved in these processes. We suggest that cytarabine-induced autophagy is not a pro survival mechanism, but accounts for its antineoplastic effects. PMID- 28651105 TI - Heterogeneous epigenetic regulation of HACE1 in Burkitt- Lymphoma-derived cells. AB - We examined the consequences of 3-deazaneplanocin A (DZNep) on HACE1 expression in human Burkitt- Lymphoma-derived cells to investigate fundamental molecular mechanisms that control its expression. We treated the human Burkitt- Lymphoma derived cells lines Ramos and Raji with DZNep and examined HACE1 mRNA expression by RT-PCR. We also studied the effect of DZNep on the methylation of lysine 9 and 27 of histone 3 (H3K27me3 and H3K9me2) associated with the CpG88 and CpG177 islands of the HACE1 promoters by chromatin immunoprecipitation and quantitative PCR. CpG88 (hypomethylated) of the HACE1 promoter was enriched for histone marks H3K27me3 and H3K9me2 whereas CpG177 (hypermethylated) was only enriched for H3K9me2. DZNep treatment increased HACE1 gene expression which was further increased by the addition of trichostatine A (TSA), a promising therapeutic compound for the treatment of human B-Lymphoma. Histone methylation (both H3K9me2 and H3K27me3) of the HACE1 promoter concomitantly decreased. Our experiments suggest that HACE1 can be downregulated by methylation of its promoter region chromatin (H3K27me3 and H3K9me2), making HACE1 a potential target for DZNep combined with TSA. These results highlight the heterogeneity of HACE1 regulation in B-lymphoma and suggest that successful drug-induced restoration of epigenetically silenced tumor suppressor genes will require accurate characterization of cell type- and locus-specific gene silencing mechanisms. PMID- 28651106 TI - Computer-based speech therapy for childhood speech sound disorders. AB - BACKGROUND: With the current worldwide workforce shortage of Speech-Language Pathologists, new and innovative ways of delivering therapy to children with speech sound disorders are needed. Computer-based speech therapy may be an effective and viable means of addressing service access issues for children with speech sound disorders. AIM: To evaluate the efficacy of computer-based speech therapy programs for children with speech sound disorders. METHOD: Studies reporting the efficacy of computer-based speech therapy programs were identified via a systematic, computerised database search. Key study characteristics, results, main findings and details of computer-based speech therapy programs were extracted. The methodological quality was evaluated using a structured critical appraisal tool. MAIN CONTRIBUTION: 14 studies were identified and a total of 11 computer-based speech therapy programs were evaluated. The results showed that computer-based speech therapy is associated with positive clinical changes for some children with speech sound disorders. CONCLUSIONS: There is a need for collaborative research between computer engineers and clinicians, particularly during the design and development of computer-based speech therapy programs. Evaluation using rigorous experimental designs is required to understand the benefits of computer-based speech therapy. LEARNING OUTCOMES: The reader will be able to 1) discuss how computerbased speech therapy has the potential to improve service access for children with speech sound disorders, 2) explain the ways in which computer-based speech therapy programs may enhance traditional tabletop therapy and 3) compare the features of computer-based speech therapy programs designed for different client populations. PMID- 28651107 TI - How seasonality and weather affect perinatal health: Comparing the experiences of indigenous and non-indigenous mothers in Kanungu District, Uganda. AB - Maternal and newborn health disparities and the health impacts of climate change present grand challenges for global health equity, and there remain knowledge gaps in our understanding of how these challenges intersect. This study examines the pathways through which mothers are affected by seasonal and meteorological factors in sub-Saharan Africa in general, and Kanungu District (Uganda), in particular. We conducted a community-based study consisting of focus group discussions with mothers and interviews with health care workers in Kanungu District. Using a priori and a posteriori coding, we found a diversity of perspectives on the impacts of seasonal and weather exposures, with reporting of more food available in the rainy season. The rainy season was also identified as the period in which women performed physical labour for longer time periods, while work conditions in the dry season were reported to be more difficult due to heat. The causal pathways through which weather and seasonality may be affecting size at birth as reported by Kanungu mothers were consistent with those most frequently reported in the literature elsewhere, including maternal energy balance (nutritional intake and physical exertion output) and seasonal illness. While both Indigenous and non-Indigenous mothers described similar pathways, however, the severity of these experiences differed. Non-Indigenous mothers frequently relied on livestock assets or opportunities for less taxing physical work than Indigenous women, who had fewer options when facing food shortages or transport costs. Findings point to specific entry points for intervention including increased nutritional support in dry season periods of food scarcity, increased diversification of wage labour opportunities, and increased access to contraception. Interventions should be particularly targeted towards Indigenous mothers as they face greater food insecurity, may have fewer sources of income, and face greater overall deprivation than non-Indigenous mothers. PMID- 28651108 TI - Synchronous characterization of carbohydrates and ginsenosides yields deeper insights into the processing chemistry of ginseng. AB - Carbohydrates and ginsenosides in ginseng are biologically interrelated. Their synchronous analysis is therefore essential in chemical research on ginseng to characterize its "holistic" quality. Here we investigated the processing chemistry of red ginseng (RG), a ginseng product processed by water-steaming, for which both carbohydrates and ginsenosides were qualitatively and quantitatively determined through multiple analytical techniques. Results revealed that the steam-processing not only qualitatively and quantitatively altered the ginsenosides but also affected the polymeric carbohydrates via changing their physiochemical parameters, i.e. water-solubility, molecular size, types and ratios of constituent monosaccharides. Potential mechanisms involved in the transformation of ginseng chemicals are proposed and discussed, including hydrolysis (deglycosylation, demalonylation, deacetylation), dehydration, polymerization, volatilization, reduction and the Maillard reaction. The study strengthens the research on the processing chemistry of RG, and therefore should be helpful for elucidating the scientific basis of RG preparation and application. PMID- 28651109 TI - Separation of furostanol saponins by supercritical fluid chromatography. AB - Supercritical fluid chromatography (SFC) has good separation efficiency and is suitable for separating weakly polar compounds. Furostanol saponins, as an important kind of steroidal saponins, generally have two sugar chains, which are polar and hydrophilic. The hydroxyl group at the C-22 position of furostanol saponins is active and easily reacts with lower alcohols under appropriate conditions. The separation of hydrophilic furostanol saponins was tested by SFC in this study. The effects of chromatographic conditions on the separation of the mixed furostanol saponins and their hydroxyl derivatives at the C-22 position were studied. The conditions for SFC, which included different column polarity, modifier, additive, and column temperature, were tested. After optimization, the mixed 10 similar structures of furostanol saponins were separated in 22min on the Diol column at a temperature of 40 degrees C. The mobile phase was CO2 (mobile phase A) and methanol (containing 0.2% NH3?H2O and 3% H2O) (mobile phase B). The backpressure was maintained isobarically at 11.03MPa. SFC was found to be effective in separating the furostanol saponins that shared the same aglycone but varied in sugar chains. SFC was sensitive to the number and type of sugars. The resolution of furostanol saponin isomers was not ideal. The extract of Dioscorea zingiberensis C. H. Wright was profiled by SFC-quadrupole time-of-flight mass spectrometry. The main saponins of the extract were well separated. Therefore, SFC could be used for separating hydrophilic furostanol saponins and analyzing traditional Chinese medicines that mainly contained steroidal saponins. PMID- 28651110 TI - Inhibitory assay for degradation of collagen IV by cathepsin B with a surface plasmon resonance sensor. AB - We describe a simple method for evaluating the inhibition of collagen IV degradation by cathepsin B with a surface plasmon resonance (SPR) biosensor. The change in the SPR signal decreased with an increase in the concentration of cathepsin B inhibitors. The order of the inhibitory constant (Ki) obtained by the SPR method was CA074Me~Z-Phe-Phe-FMK < leupeptin. This order was different from that obtained by benzyloxycarbonyl-Phe-Phe-Fluoromethylketone (Z-Phe-Phe-FMK) as a peptide substrate. The comparison of Ki suggested that CA074 and Z-Phe-Phe-FMK inhibited exopeptidase activity, and leupeptin inhibited the endopeptidase activity of cathepsin B more strongly. PMID- 28651111 TI - The rise of Zika infection and microcephaly: what can we learn from a public health emergency? AB - OBJECTIVES: To consider why Zika was declared a Public Health Emergency of International Concern (PHEIC), why it stopped being one and what we can learn from this for the future. STUDY DESIGN: This paper reviews the sequence of events and evidence base for the decision to declare Zika a PHEIC, the global response to this, the challenges in maintaining an evidence-based approach to outbreak response and identifies learning outcomes. METHODS: Evidence review, all published articles in reputable UK and international journals were identified. RESULTS: The association between Zika virus infection and congenital malformations including microcephaly became a PHEIC on 1st February 2016 and was declared to be no longer an emergency in November 2016. This shaped the global response led by WHO in the first global emergency since Ebola in West Africa. CONCLUSION: The response to Zika highlights important issues and lessons for future outbreaks that might pose an international risk. Particular challenges arose in trying to maintain an evidence-based approach to public risk communication when the evidence is unclear or still evolving. The Zika incident also demonstrates the importance of public health practitioners and agencies understanding the political context in which outbreaks must be managed and understanding the competing factors that shape the political response. PMID- 28651112 TI - Secondary harm mitigation: A more humanitarian framework for international drug law enforcement. AB - This article introduces the concept of 'secondary harm mitigation' as a framework for improving the humanitarian credentials of international drug law enforcement agencies. The concept is rooted in a critical analysis of the compatibility of the harm reduction philosophy with Australia's international drug law enforcement practices. On a utilitarian level, the net benefits of international drug law enforcement are determined to be, at best inconclusive, arguably counterproductive and in most cases, incalculable. On a humanitarian level, international drug law enforcement is also determined to be problematic from a criminological standpoint because it generates secondary harms and it is indifferent to the vulnerability of individuals who participate in illicit drug trafficking. Accordingly, the article concludes that a philosophy of harm reduction grounded in the public health perspective is inadequate for mitigating secondary harms arising from Australia's efforts to combat international illicit drug trafficking. A tentative list of secondary harm mitigation principles is presented and the article argues that secondary harm mitigation should replace supply reduction as a core tenet of Australia's National Drug Strategy. The article also concludes that secondary harm mitigation may provide a viable framework for stimulating a productive dialogue between those who advocate prohibition and those who call for decriminalisation at the global level. PMID- 28651113 TI - Trends in PIEDs use among male clients of needle-syringe programs in Queensland, Australia; 2007-2015. PMID- 28651115 TI - Ten-year results of applying an original scoring system for addressing adjuvant therapy use after breast-conserving surgery for ductal carcinoma in situ of the breast. AB - PURPOSE: Although large-scale randomised clinical trials have established that radiotherapy (RT) - alone or combined with hormonal therapy (HT) - is effective in reducing the risk of ipsilateral breast tumour recurrence (IBTR), overall survival does not seem to be improved by adjuvant therapies. We sought to ascertain whether specific criteria can be adopted to avoid RT with an acceptable rate of IBTR after breast-conserving surgery (BCS) achieving tumour-free margins. PATIENTS AND METHODS: This non-randomised prospective study concerned the outcome of patients who underwent BCS for ductal carcinoma in situ (DCIS) and were prospectively assessed by means of an established scoring system based on width of free margins in association with age <40, presence of comedonecrosis, high grade, ER negativity and HER2 positivity, to orient the use of any adjuvant therapies. RESULTS: From March 2000 to April 2006, a total of 224 patients were enrolled and followed up for this study. No adjuvant treatment was considered for 76 patients, while 53, 39 and 56 patients received HT alone, RT alone, and RT plus HT, respectively. After a median follow-up of 129.6 months, 25 patients developed an IBTR, corresponding to a yearly rate of 1.138% (95% CI: 0.769 1.684). CONCLUSION: When the criteria considered in the present study were applied to address the use of adjuvant therapies, no RT was administered to 57.6% of patients, 33.9% received no adjuvant treatments at all, and the rate of IBTR was low. Our findings support the conviction that the risk/benefit of omitting RT may lean on the side of the latter in selected patients. PMID- 28651114 TI - Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. AB - Using primary cultures of normal human prostate epithelial cells, we developed a novel prostasphere-based, label-retention assay that permits identification and isolation of stem cells at a single cell level. Their bona fide stem cell nature was corroborated using in vitro and in vivo regenerative assays and documentation of symmetric/asymmetric division. Robust WNT10B and KRT13 levels without E cadherin or KRT14 staining distinguished individual stem cells from daughter progenitors in spheroids. Following FACS to isolate label-retaining stem cells from label-free progenitors, RNA-seq identified unique gene signatures for the separate populations which may serve as useful biomarkers. Knockdown of KRT13 or PRAC1 reduced sphere formation and symmetric self-renewal highlighting their role in stem cell maintenance. Pathways analysis identified ribosome biogenesis and membrane estrogen-receptor signaling enriched in stem cells with NF-KB signaling enriched in progenitors; activities that were biologically confirmed. Further, bioassays identified heightened autophagy flux and reduced metabolism in stem cells relative to progenitors. These approaches similarly identified stem-like cells from prostate cancer specimens and prostate, breast and colon cancer cell lines suggesting wide applicability. Together, the present studies isolate and identify unique characteristics of normal human prostate stem cells and uncover processes that maintain stem cell homeostasis in the prostate gland. PMID- 28651116 TI - PD-1, PD-L1 and CTLA-4 in pregnancy-related - and in early-onset breast cancer: A comparative study. AB - PURPOSE: We aimed to compare the immunohistochemical expression of PD-1, PD-L1 and CTLA-4 of pregnancy-related breast cancer (PRBC) and early onset non-PRBC (YWBC), and their prognosis prediction potential was correlated to that of conventional clinicopathological factors. METHODS: Twenty-one PRBC cases were paired with 21 YWBC in this matched case-control study. Immune-checkpoint markers (ICM) were evaluated with immunohistochemistry (IHC) on whole slides using the following antibodies: PD-1 (NAT-105), PD-L1 (28-8) and CTLA-4 (F-8). IHC score was defined as the percentage of positive cells, assessed separately among tumor cells, intratumoral lymphocytes and peritumoral lymphocytes. RESULTS: The optimal threshold of PD-L1 expression of tumor cells occurred at 10% for overall survival (OS, AUC = 0.847, p = 0.009), and at 1% for disease-free survival (DFS, AUC = 0.795, p = 0.010). For PD-L1 expression on intratumoral lymphocytes, the optimal cut-off was 1% (AUC = 0.763, p = 0.048). Considering PD-1, PD-L1 and CTLA-4 expression, no significant difference occurred between PRBC and YWBC (p > 0.05 for all comparisons). PD-1, PD-L1 expressed on peritumoral lymphocytes and CTLA-4 failed, but PD-L1 expressed on tumor cells and on intratumoral lymphocytes was suitable to distinguish patient cohorts with different OS and DFS (p <= 0.011 for all comparisons). Higher PD-L1 expression was associated with poor prognosis. PD L1 expressed on tumor cells represented an independent association with OS (p = 0.023) and DFS (p = 0.032). CONCLUSIONS: Our results suggest that PRBC and YWBC do not differ in the expression of PD-1, PD-L1 and CTLA-4. However, our findings emphasize the relevance of PD-L1 expression in early-onset breast cancer, as an independent negative predictor of prognosis. PMID- 28651117 TI - Mantle cell lymphoma - Current standards of care and future directions. AB - Over the past decade we have seen significant changes in the biological characterization and strategies for treatment of mantle cell lymphoma (MCL). MCL is heterogeneous a disease, and so are the people that have it; although guidelines are appropriate, therapeutic approaches must be individualized based on a variety of factors. In this review, we summarize data on the range of therapeutic options, from observation in patients with slowly progressive low tumor-burden MCL, to bendamustine-based regimens in typical MCL, to high-dose cytarabine-based regimens in young, fit patients. The management of previously treated MCL is evolving with the availability of new agents and more changes are expected. Several recent and ongoing clinical trials have the potential to provide new options for patients and are discussed as future directions. Additionally, prognostic tools, measurement of minimal residual disease, and assessment of toxicity are already common research tools and may soon impact therapeutic strategies as a standard of care. Indeed, there has never been a time that management of MCL was as complicated while the promise for real improvements in outcomes is so great. PMID- 28651118 TI - Magnesium in schizophrenia. AB - Many psychopathological symptoms, including schizophrenia, can be associated with magnesium metabolism disturbances. In the literature, contradictory data exist regarding magnesium levels in patients with this disorder. However, this situation might be caused by determination of extracellular concentration of magnesium; although, this is mainly an intracellular ion. There are no data concerning determination of the ionized fraction of magnesium in patients with schizophrenia, while the ionized fraction represents 67% of the total pool of magnesium in healthy people. Also, the mechanism of magnesium action-the effect of magnesium ions on NMDA and GABA receptors-has not yet been fully investigated. There are preliminary studies aimed at increasing the effectiveness of schizophrenia pharmacotherapy via magnesium supplementation. Multidirectional activity of magnesium can significantly increase its therapeutic effect in psychiatry. This observation is confirmed by recent studies conducted by various research teams. However, further studies on the role of magnesium supplementation in patients with schizophrenia are needed. PMID- 28651119 TI - Experimental ultrasonic characterization of polyester-based materials for cultural heritage applications. AB - For several years, the Reunion des musees nationaux - Grand-Palais has produced polyester resin reproductions in order to replace marble sculptures that have weakened by outdoor exposure. These objects are made of a complex multilayered polyester composite material including reinforcements to ensure the mechanical strength of the final structure and mineral fillers that allow to imitate the original aesthetics. However, the final structure also weakens because of constant outdoor exposure and ageing. This observation leads today to conduct research related to the structural health monitoring of reproductions for preventive conservation of cultural heritage. This paper presents a nondestructive technique to study the properties of the composite material used to produce reproductions of marble sculptures. Firstly, classical ultrasonic contact measurements were performed to estimate bulk properties and Rayleigh wave velocity. Secondly, experimental Rayleigh wave was measured using contact and laser vibrometry methods. The results show the potential of using ultrasonic surface wave propagation and laser vibrometry method to develop a minimum contact technique to study these polyester-based materials. The maximum relative uncertainty with respect to the expected theoretical Rayleigh wave velocity was close to 12%. PMID- 28651120 TI - The relationship between emotion regulation strategies and job search behavior among fourth-year university students. AB - The job search process is a stressful experience. This study investigated the effect of emotion regulation strategies on job search behavior in combination with anxiety and job search self-efficacy among Chinese university fourth-year students (N = 816, mean age = 21.98, 31.5% male, 34.9% majored in science, 18.0% from "211 Project" universities). Results showed that cognitive reappraisal was positively related to job search behavior, while expressive suppression was negatively related to job search behavior. Additionally, anxiety was negatively related to job search behavior, while job search self-efficacy was positively associated with job search behavior. Moreover, both anxiety and job search self efficacy mediated the relationship between emotion regulation strategies and job search behavior. In general, emotion regulation strategies played an important role in job search behavior. Implications include the notion that emotion regulation interventions may be helpful to increase job search behavior among university students. PMID- 28651121 TI - Cytomegalovirus UL128 homolog mutants that form a pentameric complex produce virus with impaired epithelial and trophoblast cell tropism and altered pathogenicity in the guinea pig. AB - Guinea pig cytomegalovirus (GPCMV) encodes a homolog pentameric complex (PC) for specific cell tropism and congenital infection. In human cytomegalovirus, the PC is an important antibody neutralizing target and GPCMV studies will aid in the development of intervention strategies. Deletion mutants of the C-terminal domains of unique PC proteins (UL128, UL130 and UL131 homologs) were unable to form a PC in separate transient expression assays. Minor modifications to the UL128 homolog (GP129) C-terminal domain enabled PC formation but viruses encoding these mutants had altered tropism to renal and placental trophoblast cells. Mutation of the presumptive CC chemokine motif encoded by GP129 was investigated by alanine substitution of the CC motif (codons 26-27) and cysteines (codons 47 and 62). GP129 chemokine mutants formed PC but GP129 chemokine mutant viruses had reduced epitropism. A GP129 chemokine mutant virus pathogenicity study demonstrated reduced viral load to target organs but highly extended viremia. PMID- 28651122 TI - Activation of IRF3 contributes to IFN-gamma and ISG54 expression during the immune responses to B16F10 tumor growth. AB - Interferon Regulatory Factor (IRF-3) has been shown to contribute to immune control of B16 melanoma tumor growth. We have shown previously that IRF-3 has a role in IFN-gamma-induced expression of pro-apoptotic interferon stimulated gene 54 (ISG54) in macrophages and IFN-gamma in T cells. To investigate the IRF3-IFN gamma-ISG54 nexus, we injected C57Bl/6 (B6) and IRF3KO mice s.c. with luciferase producing B16-F10 tumor cells. Tumor growth as measured by luciferase levels was similar between B6 and IRF3KO mice at days 2 and 6, but was significantly greater at day 9 in IRF3KO mice compared with B6 mice. Transcription factor assays on splenic protein extracts after tumor inoculation revealed peak activation of IRF3 and IRF7 at day 6 in B6 tumor-bearing mice but not in IRF3KO tumor-bearing mice. Likewise, significant induction of IFN-gamma occurred in spleens and tumors in B6 mice from days 6-9 but failed to occur in tumor-bearing IRF3KO mice. Previous reports from other labs showed that the anti-tumor properties of IFN-gamma are the result of cell cycle arrest. Using B16F1 cells or B16F1 cells deficient in IFN-gamma receptor (B16-IRFGRKO), we found that IFN-gamma alone and in synergy with the TLR3/IRF3 agonists, poly I:C, decreased B16F1 cell growth in significant correlation with increased ISG54 expression. Moreover, IFN-gamma alone increased expression of the cell cycle inhibitor, p27Kip while IFN-gamma plus poly I:C increased cleaved Caspase-3 in B16 cells. Thus, it is likely that an IFN gamma/IRF3/ISG54 nexus can significantly contribute to tumor cell control during anti-tumor immune responses. PMID- 28651123 TI - Seizures, enamel defects and psychomotor developmental delay: The first patient with Kohlschutter-Tonz syndrome caused by a ROGDI-gene deletion. PMID- 28651124 TI - A review of people who did not attend an epilepsy clinic and their clinical outcomes. AB - PURPOSE: To review the clinical outcomes of people who failed to attend or failed subsequent follow up in a Primary Care based specialist epilepsy service. METHOD: The case notes of 200 people who had failed to initially attend the service or subsequent follow up from 2005 to 2013 were reviewed. RESULTS: Clinical outcomes were determined for 152 people, with the remaining 48 having left the area. For those not attending at all, 64% had no further recorded events, a further 22% came under alternative specialist care and were managed appropriately, 6% were already in remission at the time of referral or at follow up and stayed seizure free. For people attending, but were subsequently lost to follow up, 78% were in remission, had improved seizure frequency, and normal pregnancies. In total 6% of those with poor control came under subsequent Neurological care. CONCLUSION: This study suggests that for the majority of people who fail to attend or are lost to follow up in a primary care specialist epilepsy clinic, the primary reasons appear to be that they had no further events, improved seizure control or that seizure remission has been achieved. The majority with persistent poor control came under Neurological care. PMID- 28651125 TI - Online patient information on Vagus Nerve Stimulation: How reliable is it for facilitating shared decision making? AB - PURPOSE: This study evaluates the quality of information available on the internet for carers of children with epilepsy considering treatment with Vagus Nerve Stimulation (VNS). METHODS: Selected key phrases were entered into two popular search engines (GoogleTM, YahooTM). These phrases were: "Vagus nerve stimulator", alone and in combination with "childhood epilepsy", "paediatric epilepsy" and "epilepsy in childhood"; "VNS", and "VNS epilepsy". The first 50 hits per search were then screened. Of 600 identified sites, duplicated (262), irrelevant (230) and inaccessible (15) results were excluded. 93 websites were identified for evaluation using the DISCERN instrument, an online validation tool for patient information websites. RESULTS: The mean DISCERN score of all analysed websites was 39/80 (49%; SD 13.5). This equates to Fair to borderline Poor global quality, (Excellent=80-63; Good=62-51; Fair=50-39; Poor=38-27; Very poor=26-15). None of the analysed sites obtained an Excellent quality rating. 13% (12) obtained a Good score, 40% (37) obtained an Average score, 35% (33) obtained a Poor score, and 12% (11) obtained a Very poor score. The cohort of websites scored particularly poorly on assessment of whether reliable, holistic information was presented, for instance provision of reliable sources, (28%, SD 18) and discussion of alternative treatments, (30%, SD 14). CONCLUSION: To facilitate patient-centred shared decision-making, high quality information needs to be available for patients and families considering VNS. This study identifies that such information is difficult to locate on the internet. There is a need to develop focussed and reliable online patient resources for VNS. PMID- 28651126 TI - TNF-alpha exerts cytotoxic effects on multidrug resistant breast cancer MCF-7/MX cells via a non-apoptotic death pathway. AB - Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in the various physiopathological processes such as autoimmune disorders and inflammation related diseases. Some multidrug resistant (MDR) cancer cell lines including MCF 7/MX are more vulnerable to cytotoxic effects of TNF-alpha than their parental lines. In this study, breast cancer cell line MCF-7 and its MDR derivative MCF 7/MX were exposed to TNF-alpha afterward various downstream signaling mediators of TNF-alpha were analyzed. Although, treatment of MCF-7 cells with TNF-alpha activated NF-kB and caused RIP1 ubiquitination, TNF-alpha exposure led to JNK and RIP1 phosphorylation in MCF-7/MX cells. In both cell lines TNF-alpha did not activate the caspase cascade. Moreover, AnexinV/PI analysis showed that cytotoxic effects of TNF-alpha on MCF-7/MX is mediated via apoptosis independent mechanisms and inhibition of RIP1 kinase activity using necrostatin-1 revealed that kinase activity of RIP1 plays role in the production of ROS, activation of JNK and cellular death following exposure of MCF-7/MX cells to TNF-alpha. Overall, it seems that RIP1 ubiquitination and NF-kB activation are prosurvival signaling mediators protecting MCF-7 cells against cytotoxic effects of TNF-alpha while TNF alpha drives MCF-7/MX cells to non-apoptotic cellular death via kinase activity of RIP1, activation of JNK and ROS production. PMID- 28651127 TI - Vascular endothelial growth factor single nucleotide polymorphisms and haplotypes in pre-eclampsia: A case-control study. AB - An association between vascular endothelial growth factor (VEGFA) gene variants and altered VEGF secretion and preeclampsia (PE) were described, often with inconclusive findings. An ethnic contribution to the association of VEGFA polymorphisms with PE and its associated features was also suggested. To investigate whether common VEGFA single nucleotide polymorphisms (SNP) are linked with PE and associated features in Tunisian women. A case-control study involving 300 women with PE, and 300 age-matched control women. Genotyping of VEGFA rs833052, rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068, rs833070, rs3025020, and rs3025039SNPs was done by real-time PCR. Minor allele frequency (MAF) of rs833052, rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068, rs833070, rs3025020, and rs3025039 VEGFA SNP, were not significantly different between PE cases and control women. In addition, there was lack of association of the genotypes of VEGFA SNPs with PE, irrespective of the genetic model used. Seven-locus (rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068 and rs833070) haplotype analysis demonstrated positive association of ATGCCAA, ACAGCAG and CCAGCGG, and negative association of CCAGCAA and ATGCCGG haplotypes with PE, all of which except for ACAGCAG remained associated with PE after correcting for multiple comparisons. Increased and reduced PE severity was associated with ATGCCAA, and with ATGCCGG and CCAGCAA haplotypes, respectively. Furthermore, carriage of CCGGTAG haplotype was associated with reduced risk of PE. Our study suggests that VEGFA haplotypes, more so than individual SNPs, play a role in PE pathogenesis in Tunisian women. These findings need confirmation in other ethnic populations. PMID- 28651128 TI - Local up-regulation of interferon-gamma (IFN-gamma) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain. AB - Lumbar radicular pain after disc herniation may be associated with release of pro inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-gamma (IFN-gamma) and cluster of differentiation 68 (CD68) in the acute phase of this process. First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-gamma close to the dorsal nerve roots was studied. Next, in patients with lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) are important for the IFN-gamma expression influenced the pain behavior. The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN gamma onto the dorsal nerve roots. A positive correlation between IFN-gamma and CD68 in the NP tissue was also demonstrated. In the patients, a significant increase in Oswestry Disability Index (ODI) score was observed in carriers of the IFN-gamma SNPs; rs2069705 A and rs2069718 G alleles. The present data suggest that IFN-gamma close to the dorsal nerve roots may contribute to the pathogenesis, the nociceptive activity and the pain behavior following lumbar disc herniation. PMID- 28651129 TI - Catalytic upgrading of bio-products derived from pyrolysis of red macroalgae Gracilaria gracilis with a promising novel micro/mesoporous catalyst. AB - Conversion of Gracilaria gracilis (G. gracilis) into bio-products was carried out via pyrolysis at different temperatures to determine its potential for phenol rich bio-oil. Co-Mo supported on zeolites (HZSM-5), mesoporous (HMS) catalysts and their composites (ZH) were investigated and compared to each other on catalytic pyrolysis processes. In non-catalytic tests, the maximum weight percentage of bio-oil was 42wt% at 500 degrees C and had the maximum amount of phenol (6.28wt%). in the catalytic tests by ZH composites; the addition of zeolite content in the structure of composites significantly decreased total concentrations of acetic acid and formic acid from 9.56 to 8.12wt% and slightly decreased phenol and furfural concentrations from 6.65 and 6.98 to 5.88 and 5.49wt%, respectively. Furthermore, the best selectivity for hydrogen yield (6.08mmol/g macroalgae) and lowest amount of acetic acid (5.4wt%) was observed for CoMo/ZH-20 catalyst, that is synthesized by 20wt% of zeolite. PMID- 28651130 TI - Liquefaction of kraft lignin by hydrocracking with simultaneous use of a novel dual acid-base catalyst and a hydrogenation catalyst. AB - In this study, a novel catalyst, S2O82--KNO3/TiO2, which has active acidic and basic sites, was prepared and used in lignin hydrocracking with a co-catalyst, Ru/C. Ru/C is an efficient hydrogenation catalyst and S2O82--KNO3/TiO2 is a dual catalyst, which could efficiently degrade lignin. This catalytic hydrogenation system can reduce solid products to less than 1%, while giving a high liquid product yield of 93%. Catalytic hydrocracking of kraft lignin at 320 degrees C for 6h gave 93% liquid product with 0.5% solid product. Most of this liquid product was soluble in petroleum ether (60% of 93%), which is a clear liquid and comprises mainly of monomeric and dimeric degradation products. These results demonstrated that the combination of the two catalysts is an efficient catalyst for liquefaction of lignin, with little char formation (~1%). This concept has the potential to produce valuable chemicals and fuels from lignin under moderate conditions. PMID- 28651131 TI - Formic acid production using a microbial electrolysis desalination and chemical production cell. AB - The aim of this study was to investigate the feasibility and optimization of formic acid production in the microbial electrolysis desalination and chemical production cell (MEDCC). The maximum current density in the MEDCC with 72cm of the anode fiber length (72-MEDCC) reached 24.0+/-2.0A/m2, which was much higher than previously reported. The maximum average formic acid production rate in the 72-MEDCC was 5.28 times higher than that in the MEDCC with 24cm of the anode fiber length (37.00+/-1.15vs. 7.00+/-0.25mg/h). High performance in the 72-MEDCC was attributed to small membrane spacing (1mm), high flow rate (1500MUL/min) on the membrane surface and high anode biomass. The minimum electricity consumption of 0.34+/-0.04kWh/kg in the 72-MEDCC was only 3.1-18.8% of those in the EDBMs. The MEDCC should be a promising technology for the formic acid production. PMID- 28651132 TI - Enhanced acetone-butanol-ethanol production from lignocellulosic hydrolysates by using starchy slurry as supplement. AB - This study aims to improve acetone-butanol-ethanol production from the hydrolysates of lignocellulosic material by supplementing starchy slurry as nutrients. In the fermentations of glucose, xylose and the hydrolysates of Salix schwerinii, the normal supplements such as buffer, minerals, and vitamins solutions were replaced with the barley starchy slurry. The ABE production was increased from 0.86 to 14.7g/L by supplementation of starchy slurry in the fermentation of xylose and the utilization of xylose increased from 29% to 81%. In the fermentations of hemicellulosic and enzymatic hydrolysates from S. schwerinii, the ABE yields were increased from 0 and 0.26 to 0.35 and 0.33g/g sugars, respectively. The results suggested that the starchy slurry supplied the essential nutrients for ABE fermentation. The starchy slurry as supplement could improve the ABE production from both hemicellulosic and cellulosic hydrolysate of lignocelluloses, and it is particularly helpful for enhancing the utilization of xylose from hemicelluloses. PMID- 28651133 TI - Material flow and sustainability analyses of biorefining of municipal solid waste. AB - This paper presents material flow and sustainability analyses of novel mechanical biological chemical treatment system for complete valorization of municipal solid waste (MSW). It integrates material recovery facility (MRF); pulping, chemical conversion; effluent treatment plant (ETP), anaerobic digestion (AD); and combined heat and power (CHP) systems producing end products: recyclables (24.9% by mass of MSW), metals (2.7%), fibre (1.5%); levulinic acid (7.4%); recyclable water (14.7%), fertiliser (8.3%); and electricity (0.126MWh/t MSW), respectively. Refuse derived fuel (RDF) and non-recyclable other waste, char and biogas from MRF, chemical conversion and AD systems, respectively, are energy recovered in the CHP system. Levulinic acid gives profitability independent of subsidies; MSW priced at 50Euro/t gives a margin of 204Euro/t. Global warming potential savings are 2.4 and 1.3kg CO2 equivalent per kg of levulinic acid and fertiliser, and 0.17kg CO2 equivalent per MJ of grid electricity offset, respectively. PMID- 28651134 TI - Effect of salt type and concentration on the growth and lipid content of Chlorella vulgaris in synthetic saline wastewater for biofuel production. AB - Microalgae can offer several benefits for wastewater treatment with their ability to produce large amounts of lipids for biofuel production and the high economic value of harvested biomass for biogas and fertilizer. This study found that salt concentration (~45gL-1) had more of an effect than salt type on metabolisms of Chlorella vulgaris for wastewater treatment and biofuel production. Salinity stress decreased the algal growth rate in wastewater by 0.003day-1permScm-1 and slightly reduced nutrient removal rates. However, salinity stress was shown to increase total lipid content from 11.5% to 16.1% while also increasing the saturated portions of fatty acids in C. vulgaris. In addition, salinity increased the algal settling rate from 0.06 to 0.11mday-1 which could potentially reduce the cost of harvesting for algal biofuel production. Overall, C. vulgaris makes a suitable candidate for high salinity wastewater cultivation and biofuel production. PMID- 28651135 TI - A model biorefinery for avocado (Persea americana mill.) processing. AB - This research investigated and evaluated a biorefinery for processing avocado Hass variety into microencapsulated phenolic compounds extract, ethanol, oil and xylitol. Avocado was first characterized for its potential valuable compounds; then, the techno-economic and environmental aspects of the biorefinery were developed and finally the total production costs and potential environmental impact of the proposed biorefinery were investigated. Four scenarios of the biorefinery were evaluated with different extent of mass and energy integration as well as the incorporation of a cogeneration system. Results indicated that the main fatty acid in the pulp of the investigated avocado variety was oleic acid (50.96%) and that this fruit contained significant amount of holocellulose (52.88% and 54.36% in the peel and seed, respectively). Techno-economic and environmental assessment suggested an attractive opportunity for a biorefinery for complete utilization of the avocado fruit as well the importance of the level of integration. PMID- 28651136 TI - Production of long chain alkyl esters from carbon dioxide and electricity by a two-stage bacterial process. AB - Microbial electrosynthesis (MES) is a promising technology for the reduction of carbon dioxide into value-added multicarbon molecules. In order to broaden the product profile of MES processes, we developed a two-stage process for microbial conversion of carbon dioxide and electricity into long chain alkyl esters. In the first stage, the carbon dioxide is reduced to organic compounds, mainly acetate, in a MES process by Sporomusa ovata. In the second stage, the liquid end-products of the MES process are converted to the final product by a second microorganism, Acinetobacter baylyi in an aerobic bioprocess. In this proof-of-principle study, we demonstrate for the first time the bacterial production of long alkyl esters (wax esters) from carbon dioxide and electricity as the sole sources of carbon and energy. The process holds potential for the efficient production of carbon neutral chemicals or biofuels. PMID- 28651137 TI - Comparative evaluation of thermal oxidative decomposition for oil-plant residues via thermogravimetric analysis: Thermal conversion characteristics, kinetics, and thermodynamics. AB - Thermal oxidative decomposition characteristics, kinetics, and thermodynamics of rape straw (RS), rapeseed meal (RM), camellia seed shell (CS), and camellia seed meal (CM) were evaluated via thermogravimetric analysis (TGA). TG-DTG-DSC curves demonstrated that the combustion of oil-plant residues proceeded in three stages, including dehydration, release and combustion of organic volatiles, and chars oxidation. As revealed by combustion characteristic parameters, the ignition, burnout, and comprehensive combustion performance of residues were quite distinct from each other, and were improved by increasing heating rate. The kinetic parameters were determined by Coats-Redfern approach. The results showed that the most possible combustion mechanisms were order reaction models. The existence of kinetic compensation effect was clearly observed. The thermodynamic parameters (DeltaH, DeltaG, DeltaS) at peak temperatures were calculated through the activated complex theory. With the combustion proceeding, the variation trends of DeltaH, DeltaG, and DeltaS for RS (RM) similar to those for CS (CM). PMID- 28651138 TI - Effect of the high cross flow velocity on performance of a pilot-scale anaerobic membrane bioreactor for treating antibiotic solvent wastewater. AB - The effect of high cross flow velocity (CFV) on the operational efficiency of a pilot-scale anaerobic membrane bioreactor (AnMBR) treating antibiotic solvent effluents was explored. The average of total Chemical Oxygen Demand (COD) and tetrahydrofuran (THF) removal efficiencies during four Runs were 96.5% and 98.7%. Meanwhile, biological removal contributions were 74.3% and 78%, the rest part was attributed by the physical removal process of the membrane block, VFA (Volatile Fatty Acids) and alpha value (VFA/alkalinity) increased with the increase of CFV, resulted alkalinity decreased. Biomass concentration mixed liquid suspended solids (MLSS) and mixed liquor volatile suspended solids (MLVSS) as well as the polysaccharide increased smoothly in the suspended sludge with the CFV increasing, and the protein content decreased gradually. However, the concentration of biomass, polysaccharide and protein presented opposite trends in the attached sludge of the membrane. The results indicated that AnMBR can effectively treat the antibiotic solvent wastewater under high CFV. PMID- 28651139 TI - Valorization of raw glycerol and crustacean waste into value added products by Yarrowia lipolytica. AB - Crude glycerol has been widely investigated as a renewable carbon source for biodiesel production. In the present study, this feedstock was supplemented by various inducers: surfactants and oils to enhance lipid and lipase production by the newly isolated yeast, Yarrowia lipolytica. Results have shown that a culture medium composed of olive oil could enhance lipase activity at 25U/mL and lipid content up to 35% (w/w). The fortification of the medium with crustacean waste increased the lipase activity up to 38U/mL. The hydrolytic activity of the extracellular lipases produced in mentioned medium was satisfactory and opened avenues for other biotechnological processes. PMID- 28651140 TI - Comparison of kinetic analysis methods in thermal decomposition of cattle manure by themogravimetric analysis. AB - The thermogravimetric (TG) experiments of cattle manure were carried out from room temperature to 900 degrees C at five different heating rates (10, 20, 30, 40 and 50 degrees C/min) and the kinetics of the main decomposition process were analyzed with different methods. TG curves indicate that the major decomposition process of cattle manure could be roughly divided into three stages. The average activation energy of each stage calculated by Coats-Redfern method are 68.95, 2.63 and 55.32kJ/mol respectively. The kinetic parameters given by Distributed Activation Energy Model method, Flynn-Wall-Ozawa method and Vyazovkin method are all show that the activation energies keep stable (at around 122.4, 126 and 123.8kJ/mol respectively) under 60% conversion degree and then changed dramatically (ranging from 129.9 to 454.9kJ/mol). Power law (P3) was determined as an appropriate reaction mechanism using master-plots method. The kinetic parameters calculated by Vyazovkin method can give the best agreement with the experimental results. PMID- 28651141 TI - A comparative study of pilot-scale bio-trickling filters with counter- and cross current flow patterns in the treatment of emissions from chemical fibre wastewater treatment plant. AB - Two pilot-scale bio-trickling filters (BTFs) with counter-current and cross current flow modes were constructed, and their performance tested, for purifying chemical fibre waste gas containing H2S, NH3 and VOCs with a maximum gas flow rate of 1008m3h-1. The counter-current type of BTF presented with superior biodegradation results compared to the cross-current type: it could start up quickly, tolerated high transient shock loadings, and possessed an average contaminant removal efficiency higher than 90% with an empty bed residence time of 59s. The contaminant removal efficiency could be increased by 50% during winter due to the addition of pipeline insulation. The abundance and diversity from microorganism analysis showed that Dyella, Bacillus, Candidimonas, Pandoraea and Thiomonas were the main bacterial strains forming the community treating the pollutants. The counter-current type BTF functioned most effectively and is proposed for practical application. PMID- 28651142 TI - Fast pyrolysis of durian (Durio zibethinus L) shell in a drop-type fixed bed reactor: Pyrolysis behavior and product analyses. AB - Durian shell (DS) was pyrolyzed in a drop-type fixed-bed reactor to study the physicochemical properties of the products. The experiment was carried out with different particle sizes (up to 5mm) and reaction temperatures (250-650 degrees C). The highest bio-oil yield was obtained at 650 degrees C (57.45wt%) with DS size of 1-2mm. The elemental composition and higher heating value of the feedstock, bio-oil (650 degrees C), and bio-char (650 degrees C) were determined and compared. The compositions of product gases were determined via gas chromatography with thermal conductivity detector. The chemical composition of bio-oil was analyzed by gas chromatography-mass spectrometry. The bio-oil produced at lower temperature yields more alcohols, whereas the bio-oil produced at higher temperature contains more aromatics and carbonyls. Bio-oil has potential to be used as liquid fuel or fine chemical precursor after further upgrading. The results further showed the potential of bio-char as a solid fuel. PMID- 28651143 TI - Elemental migration and characterization of products during hydrothermal liquefaction of cornstalk. AB - Biofuel production from lignocellulosic biomass through hydrothermal liquefaction (HTL) is a promising direction. This study characterized the products and investigated the elemental migration during the HTL of cornstalk at seven different operation temperatures (210-375 degrees C). The biocrude oil yield significantly increased from 7.04% (210 degrees C) to 23.32% (290 degrees C) as the temperature increased, and decreased to 21.07% when further increased to 375 degrees C. A carbon recovery of 11.03-38.69%, and a hydrogen recovery of 7.77 25.61% were achieved in the biocrude oil. Hydrogen (27.87-70.94%) and nitrogen (74.56-81.76%) were effectively recovered in the aqueous phase. GC-MS, HPLC, TGA and FT-IR analysis indicated that major organic compounds in the biocrude oil were interestingly similar between 210 degrees C and 270 degrees C. The identified compounds included hydrocarbons, esters and carboxylic acid. The calculative yields of biocrude, hydrogen, methane and biochar reached 7.04-23.32, 0.07-0.29, 7.12-12.08 and 3.01-22.42t/100t cornstalks, respectively. PMID- 28651145 TI - Polymer structure-property requirements for stereolithographic 3D printing of soft tissue engineering scaffolds. AB - This review highlights the synthesis, properties, and advanced applications of synthetic and natural polymers 3D printed using stereolithography for soft tissue engineering applications. Soft tissue scaffolds are of great interest due to the number of musculoskeletal, cardiovascular, and connective tissue injuries and replacements humans face each year. Accurately replacing or repairing these tissues is challenging due to the variation in size, shape, and strength of different types of soft tissue. With advancing processing techniques such as stereolithography, control of scaffold resolution down to the MUm scale is achievable along with the ability to customize each fabricated scaffold to match the targeted replacement tissue. Matching the advanced manufacturing technique to polymer properties as well as maintaining the proper chemical, biological, and mechanical properties for tissue replacement is extremely challenging. This review discusses the design of polymers with tailored structure, architecture, and functionality for stereolithography, while maintaining chemical, biological, and mechanical properties to mimic a broad range of soft tissue types. PMID- 28651144 TI - Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-nitrosated human serum albumin dimer. AB - In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane(r)). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed. PMID- 28651146 TI - The effects of drinking and driving laws on car crashes, injuries, and deaths: Evidence from Chile. AB - This paper analyzes the effects of lowering the legal blood alcohol content limit for drivers from 0.05 to 0.03 grams of alcohol per deciliter of blood (g/dL) and increasing license suspension periods for offenders. We take advantage of a rich data set of administrative records that allow us to identify direct measures of accidents involving alcohol including fatalities and injuries. Results show a significant decrease of 32% in alcohol-related car accidents right after the law was approved but the effects moderate over time (15% after three years). There is also a significant reduction in injuries (31% right after the approval and 11% after three years) but no statistically significant effects on deaths. Complementary analysis of blood samples shows that the law had an effect on blood alcohol content (BAC) of male drivers up to the 90th percentile of the BAC distribution. PMID- 28651147 TI - Desalinated drinking water in the GCC countries - The need to address consumer perceptions. AB - The Gulf Cooperation Council (GCC) countries consist of Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. These countries depend mainly on seawater desalination to meet their water needs. Although great emphasis is given to characterize desalinated water for its physicochemical and microbial properties, e.g. presence of metals, other organic contaminants and for bacteria, sensorial characteristics including smell, taste and color have not received the same attention. This is possibly attributed to the fact that inhabitants of GCC States do not use desalinated tap water for drinking consumption, rather they depend on locally produced or imported bottled water where color, taste and odor are not problematic. To address the consumer needs and perceptions of drinking desalinated water in GCC countries, water quality standards and guidelines, should respond to the public concern about other sensorial characteristics (organoleptic properties) including taste, odor, and trigeminal sensations. Often the root causes of color and smell in water are attributed to the presence of organic and inorganic contaminants and to bacterial growth which is frequently accompanied by the production of metabolites and byproducts that are obnoxious. The unpleasant sensorial problems associated with desalinated drinking tap water may constitute the driving force for most people in GCC countries to depend on bottled water. To encourage people in the GCC countries to consume desalinated tap water, it is essential that water testing include measurements of physicochemical properties, biofilm presence and organoleptic parameters to improve overall water quality. This review highlights the contribution of organoleptics for consumers of desalinated tap water. It extends water quality research to be addressed by standards for organoleptic parameters in desalinated drinking water. Accordingly, consumer awareness and outreach campaigns should be implemented to encourage people to drink tap water in the GCC countries. PMID- 28651148 TI - Aldo-keto reductase activity after diethylhexyl phthalate exposure in eutopic and ectopic endometrial cells. AB - OBJECTIVE: Endometriosis is a multifactorial gynaecological disease in reproductive-age women. Endometriotic tissue is characterized by high prostaglandin levels and progesterone resistance. Human aldo-keto reductases (AKRs) convert progesterone to a less potent metabolite and cause progesterone resistance. Therefore, in this study, we evaluated whether diethylhexyl phthalate (DEHP) alters AKR expression in human ectopic and eutopic endometrium. STUDY DESIGN: We used microarrays and western blotting to study the effects of DEHP, and checked the presence of AKR in endometriosis patients by enzyme-linked immunosorbent assay (ELISA). RESULTS: Cultured human endometrial cells from normal endometrium of women without endometriosis (NE), eutopic endometrium from endometriosis patients (EE), and ectopic endometrium from endometriosis patients (EC) differed in genetic expression changes after DEHP treatment. DEHP upregulated AKR1C1, AKR1C2, AKR1C3, and AKR1B10 expression in EE, while EC showed continuously increased AKR1C3 expression before and after DEHP exposure. In western blot analysis, before and after DEHP exposure, the AKR1B10 protein band was detected in NE, EE, and EC, whereas the AKR1C3 band was detected only in EC. AKR1B10 and AKR1C3 expression levels in the blood of the enrolled patients were evaluated using ELISA. AKR1B10 expression did not differ between groups (without endometriosis [N=13], 0.10 vs. with endometriosis [N=20], 0.11; P=0.27). AKR1C3 expression was significantly higher in the blood of endometriosis patients than in that of patients without endometriosis (without endometriosis, 9.1 vs. with endometriosis, 10.1; P=0.02). Analysis according to menstrual period showed significantly increased AKR1C3 levels in patients with endometriosis only during the secretory phase and not the proliferative phase (P<0.05). CONCLUSION: DEHP induces AKR activity in the endometrium of endometriosis patients, and AKR1C3 might influence the development of endometriosis. PMID- 28651149 TI - Incidence of ovarian endometrioma among women with peritoneal endometriosis with and without a history of hormonal contraceptive use. AB - OBJECTIVE(S): To determine if, among women with peritoneal endometriosis, the incidence of ovarian endometrioma at first laparoscopy differs between those with and without a history of hormonal contraceptive use. STUDY DESIGN: Retrospective case-control study of women who were patients at a fertility center and had first laparoscopy from 2009 through 2015 showing, at minimum, evidence of peritoneal endometriosis (n=136). Chart review was conducted for history of prior birth control use as well as operative and pathology notes of surgeries. Study subjects were grouped as follows: women with peritoneal endometriosis diagnosed by laparoscopy who had a history of hormonal contraceptive use (n=93) and women with peritoneal endometriosis diagnosed by laparoscopy who had never used hormonal contraceptives (n=43). The main outcome measure was the incidence of ovarian endometrioma among women with peritoneal endometriosis who had a history of hormonal contraceptive use as compared to women with peritoneal endometriosis who had a history of no hormonal contraceptive use. RESULTS: Among women with peritoneal endometriosis who had a history of hormonal contraceptive use, 17/93 (18.3%) were found to have endometriomas. Among women with peritoneal endometriosis who had a history of no hormonal contraceptive use, 21/43 (48.8%) were found to have endometriomas. The chi-square statistic was 13.6 (P value<0.001). CONCLUSION(S): Among women with peritoneal endometriosis, those with a history of hormonal contraceptive use had a lower incidence of ovarian endometrioma than those with a history of no hormonal contraceptive use. Possible mechanisms of action include reducing the risk of a corpus luteum formation and subsequent transformation into an ovarian endometrioma or reducing the risk of ectopic endometrium implantation into the ovary via the diminution of retrograde menstruation. Although larger, prospective studies are needed, the findings of this study suggest that the use of hormonal contraception may decrease the likelihood of ovarian endometrioma formation among women with peritoneal endometriosis. PMID- 28651150 TI - Cognitive remediation improves executive functions, self-regulation and quality of life in residents of a substance use disorder therapeutic community. AB - BACKGROUND: Executive dysfunction is common in substance use disorder (SUD) populations and hinders treatment. We previously found that 50% of residents in SUD therapeutic communities had been hospitalized for head injuries; this was a significant determinant of cognitive impairment. The current study aimed to establish whether cognitive remediation improves executive functions (EFs) and self-regulation in an ecologically valid sample of female residents attending SUD therapeutic community treatment, including those with past head injuries and psychiatric comorbidities. METHODS: Controlled sequential groups design with residents (N=33, all female) receiving treatment as usual (TAU). The intervention group (n=16) completed four weeks of cognitive remediation (CR) and the control, TAU only (n=17). Outcome measures assessed pre- and post-intervention included both performance- and inventory-based measures of EFs, and self-reported self regulation and quality of life. RESULTS: CR relative to TAU significantly improved performance-based assessment of inhibition (Color-Word Interference Test; F=4.29, p=0.047), inventory-based assessment of EFs (Behavior Rating Inventory of Executive Function - Adult Version: Global Executive Composite; F=6.38, p=0.017), impulsivity (Barratt Impulsiveness Scale; F=4.61, p=0.040), self-control (Brief Self-Control Scale; F=5.53, p=0.026), and quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form; F=7.68, p=0.010). CONCLUSIONS: Findings suggest that CR improves EFs in a heterogeneous sample of female residents in therapeutic community SUD treatment. Future research may explore the possibility of tailoring CR interventions for various SUD subgroups. PMID- 28651151 TI - Assessment methods and schedules for collecting daily process data on substance use related health behaviors: A randomized control study. AB - BACKGROUND: Interactive voice response (IVR) and short message service (SMS) systems have been used to collect daily process data on substance use. Yet, their relative compliance, use patterns, and user experiences are unknown. Furthermore, recent studies presented the potential of a hybrid weekly protocol requiring recall of behaviors in past week right after the weekend, in order to reduce the concerns about low compliance and measurement reactivity associated with daily data collection and also provide high quality data on the peak of use. METHODS: This study randomized substance users to four (2*2) assessment groups with different combinations of assessment methods (IVR or SMS) and schedules (daily or weekly). The compliance rates and use patterns during the experimental period of 90days and user experiences reported after the period were compared across the groups. RESULTS: When IVR was assigned, the weekly schedule generated a higher compliance rate than the daily schedule. When SMS was used, however, the assessment schedule did not have an effect on compliance. While both the daily and weekly surveys via IVR can be completed within a short time, the weekly survey administered via SMS took much longer than its daily counterpart. Such an increased time consumption may offset the benefit of a less frequent assessment schedule. CONCLUSIONS: IVR is a better choice for delivering the hybrid protocol of weekly collection of daily process data because of its higher compliance rate, shorter duration, and lower likelihood of interruption during data collection. PMID- 28651152 TI - Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users. AB - BACKGROUND AND AIMS: Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. METHODS: A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. RESULTS: Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time consuming than for the other MPH samples. No differences were observed between users and non-users. CONCLUSIONS: To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations. PMID- 28651153 TI - The role of marijuana use disorder in predicting emergency department and inpatient encounters: A retrospective cohort study. AB - BACKGROUND: Marijuana use disorder (MUD) is the most common illegal drug use disorder and its prevalence is increasing. It is associated with psychiatric and medical problems, but little is known about its impact on emergency department (ED) and inpatient utilization rates. DESIGN: In a retrospective cohort design, we used electronic health record (EHR) data to identify patients with MUD (n=2752) and demographically matched patients without MUD (n=2752) in 2010. Logistic regressions determined risk of ED and inpatient visits each year from 2010 to 2014 for MUD patients versus controls; mixed-effect growth models examined differences in utilization rates over 5-years. Patient characteristics predicting increased risk of utilization were examined among the MUD sample only. KEY RESULTS: Rates of ED (OR=0.87, p<0.001) and inpatient (OR=0.76, p<0.001) services use significantly declined over 5 years for all patients. Patients with MUD exhibited a significantly greater decline in ED (OR=0.81, p<0.001) and inpatient (OR=0.64, p<0.001) use relative to controls. However, MUD patients had significantly greater risk of having ED and inpatient visits at each time point (p's<0.001). MUD patients with co-occurring other substance use, medical, and/or psychiatric disorders had a greater risk of having ED or inpatient encounters over 5 years (p's<0.001). CONCLUSIONS: MUD patients remain at high risk for ED and inpatient visits despite decreasing utilization rates over 5 years. Addressing MUD patients' comorbid conditions in outpatient settings may help reduce inappropriate service use. PMID- 28651154 TI - New comprehensive studies of a gold(III) Dithiocarbamate complex with proven anticancer properties: Aqueous dissolution with cyclodextrins, pharmacokinetics and upstream inhibition of the ubiquitin-proteasome pathway. AB - The gold(III)-dithiocarbamate complex AuL12 (dibromo [ethyl-N-(dithiocarboxy kS,kS')-N-methylglycinate] gold(III)), is endowed with promising in vitro/in vivo antitumor activity and toxicological profile. Here, we report our recent strategies to improve its water solubility and stability under physiological conditions along with our efforts for unravelling its tangled mechanism of action. We used three types of alpha-cyclodextrins (CDs), namely beta-CD, Me-beta CD and HP-beta-CD to prepare aqueous solutions of AuL12. The ability of these natural oligosaccharide carriers to enhance water solubility of hydrophobic compounds, allowed drug stability of AuL12 to be investigated. Moreover, pharmacokinetic experiments were first carried out for a gold(III) coordination compound, after i.v. injection of the nanoformulation AuL12/HP-beta-CD to female mice. The gold content in the blood samples was detected at scheduled times by AAS (atomic absorption spectrometry) analysis, highlighting a fast biodistribution with a tbeta1/2 of few minutes and a slow escretion (talpha1/2 of 14.3 h). The in vitro cytotoxic activity of AuL12 was compared with the AuL12/HP beta-CD mixture against a panel of three human tumor cell lines (i.e., HeLa, KB and MCF7). Concerning the mechanism of action, we previously reported the proteasome-inhibitory activity of some our gold(III)-based compounds. In this work, we moved from the proteasome target to upstream of the important ubiquitin proteasome pathway, testing the effects of AuL12 on the polyubiquitination reactions involving the Ub-activating (E1) and -conjugating (E2) enzymes. PMID- 28651155 TI - Covalent inhibitors design and discovery. AB - In the history of therapeutics, covalent drugs occupy a very distinct category. While representing a significant fraction of the drugs on the market, very few have been deliberately designed to interact covalently with their biological target. In this review, the prevalence of covalent drugs will first be briefly covered, followed by an introduction to their mechanisms of action and more detailed discussions of their discovery and the development of safe and efficient covalent enzyme inhibitors. All stages of a drug discovery program will be covered, from target considerations to lead optimization, strategies to tune reactivity and computational methods. The goal of this article is to provide an overview of the field and to outline good practices that are needed for the proper assessment and development of covalent inhibitors as well as a good understanding of the potential and limitations of current computational methods for the design of covalent drugs. PMID- 28651156 TI - Alterations in Aspergillus brasiliensis (niger) ATCC 9642 membranes associated to metabolism modifications during application of low-intensity electric current. AB - The effects of electric current on membranes associated with metabolism modifications in Aspergillus brasiliensis (niger) ATCC 9642 were studied. A 450 mL electrochemical cell with titanium ruthenium-oxide coated electrodes and packed with 15g of perlite, as inert support, was inoculated with A. brasiliensis spores and incubated in a solid inert-substrate culture (12 d; 30 degrees C). Then, 4.5days after starting the culture, a current of 0.42mAcm-2 was applied for 24h. The application of low-intensity electric current increased the molecular oxygen consumption rate in the mitochondrial respiratory chain, resulting in high concentrations of reactive oxygen species, promoting high lipoperoxidation levels, according to measured malondialdehyde, and consequent alterations in membrane permeability explained the high n-hexadecane (HXD) degradation rates observed here (4.7-fold higher than cultures without current). Finally, cell differentiation and spore production were strongly stimulated. The study contributes to the understanding of the effect of current on the cell membrane and its association with HXD metabolism. PMID- 28651157 TI - Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score-matched cohort study. AB - BACKGROUND: Management of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters. METHODS: Among 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography. RESULTS: Among 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m2), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol-lowering effect of TMX. CONCLUSIONS: TMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C. PMID- 28651160 TI - Significance of extranodal tumour deposits in colorectal cancer: A systematic review and meta-analysis. AB - AIMS: The presence and significance of extranodal tumour deposits (ENTDs) in colorectal cancer (CRC) continue to cause controversy in terms of origin, classification and prognostic significance. This review aims to assess current evidence on the origin of ENTDs in CRC and their effect on overall and disease free survival. METHODS: A systematic review and meta-analysis were carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta analyses (PRISMA) guidelines. End-points included prevalence of ENTDs, relationship with extramural venous invasion (EMVI), overall survival (OS) and disease-free survival (DFS). Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using Stata software. RESULTS: Twenty-six studies comprising 19,980 patients were included. The prevalence of ENTDs ranged from 10.2% to 44.2% (median 21.3%). There was a significantly increased odds of having ENTD if EMVI was present with a pooled OR of 2.51 (95% CI 2.27-2.77) p <= 0.001. The pooled HR for adverse OS in patients with ENTD was 1.63 (95% CI 1.44-1.61), p <= 0.001. For adverse DFS the pooled HR was 1.77 (95% CI 1.37-2.11), p <= 0.001. CONCLUSION: This meta-analysis confirms the negative impact of ENTDs on OS and DFS despite variations in classification and prevalence. ENTDs are significantly associated with EMVI. The prognostic implications of ENTDs are not sufficiently recognised in current staging systems. TNM 8 has failed to address this and has not made use of the available evidence to determine the correct position of ENTDs according to their prognostic effect. The prognostic hierarchy should be N0, N1, N2 with N1c being the most severe. Additionally the exclusion of lesions of vascular, lymphatic and perineural origin by TNM 8 has no evidence base. PMID- 28651159 TI - Health-related quality of life results from the phase III CheckMate 067 study. AB - BACKGROUND: Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067. PATIENTS AND METHODS: HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated. RESULTS: Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause. CONCLUSION: These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting. STUDY NUMBER: NCT01844505. PMID- 28651161 TI - Connexin 43 mediates changes in protein phosphorylation in HK-2 cells during chronic cadmium exposure. AB - Connexin 43 (Cx43) is believed to play a role in the mechanisms of toxicity of many chemical species, include cadmium (Cd). In this study, human renal proximal tubule (HK-2) cells were exposed to Cd (1MUM, 10 days). Of the 584 protein residues detected using a Phospho Explorer antibody microarray (PEX100), more than half changed their levels of phosphorylation after chronic Cd exposure. Cx43 siRNA attenuated Cd-induced apoptosis and inhibited proliferation, while also attenuating changes in the levels of phosphorylation of many protein residues. According to DAVID Bioinformatics Resources analysis and KEGG PATHWAY database, AKT signal pathway may be the important one. Focusing on the AKT pathway confirmed that Cx43 mediated increased levels of p-PTENSer380/Ser382/Thr383 and decreased levels of p-AKTThr308, p-AKTTyr326, p-ASK1Ser83, and p-p27Thr187, thereby possibly contributing to the Cd-induced apoptosis and inhibited proliferation. These results suggested that AKT pathway was the dominant pathway involved in Cx43-mediated chronic Cd toxicity. PMID- 28651162 TI - Antibacterial activity, corrosion resistance and wear behavior of spark plasma sintered Ta-5Cu alloy for biomedical applications. AB - Tantalum has been widely used in orthopedic and dental implants. However, the major barrier to the extended use of such medical devices is the possibility of bacterial adhesion to the implant surface which will cause implant-associated infections. To solve this problem, bulk Ta-5Cu alloy has been fabricated by a combination of mechanical alloying and spark plasma sintering. The effect of the addition of Cu on the hardness, antibacterial activity, cytocompatibility, corrosion resistance and wear performance was systematically investigated. The sintered Ta-5Cu alloy shows enhanced antibacterial activity against E. Coli due to the sustained release of Cu ions. However, the addition of Cu would produce slight cytotoxicity and decrease corrosion resistance of Ta. Furthermore, pin-on disk wear tests show that Ta-5Cu alloy has a much lower coefficient of friction but a higher wear rate and shows a distinct wear mode from that of Ta upon sliding against stainless steel 440C. Wear-induced plastic deformation leads to elongation of Ta and Cu grains along the sliding direction and nanolayered structures were observed upon approaching the sliding surface. The presence of hard oxides also shows a profound effect on the plastic flow of the base material and results in localized vortex patterns. The obtained results are expected to provide deep insights into the development of novel Ta-Cu alloy for biomedical applications. PMID- 28651163 TI - Ex vivo assessment of valve thickness/calcification of patients with calcific aortic stenosis in relation to in vivo clinical outcomes. AB - Calcific aortic stenosis (AS) plays a critical role in the risk of cardiovascular disease. This preliminary study examined the relationship between the ex vivo valve thickness/calcification and in vivo clinical outcomes of Chinese patients with calcific AS. Six Chinese patients (3 patients with tricuspid aortic valves (TAV)) and 3 patients with. bicuspid aortic valves (BAV) with calcific AS undergoing heart valve replacement were initially chosen for this study. In vivo medical imaging of these calcific AS patients was evaluated using computed tomography and echocardiography. The ex vivo measurements including the actual thickness, calcified area and components of the calcified aortic values excised were performed by a digimatic caliper, X-ray equipment with a cellSens imaging analysis and portable Raman spectroscopy, respectively. Six patients were diagnosed with symptomatic moderate-to-severe AS. The thickness of noncoronary (N) leaflet in the excised TAV was significantly thicker than left-coronary (L) leaflet (p < 0.01), and right-coronary (R) leaflet was also thicker than L (p < 0.05), but no significant difference occurred between N and R (p > 0.05). The extent of calcification in the excised TAV was a statistically significant difference between N and L (p < 0.01) and between R and L (p < 0.01), respectively. However, there was no significant difference between R and L in both thickness and calcification for the excised BAV (p > 0.05). The patients No. 1-3 were found to be TAV with partial commissural fusion. The patient No. 4 was classified as a type 1 NL-BAV morphotype, but both patients 5 and 6 were found to be true BAV (type 0 lateral-BAV). Each calcified valve leaflet was composed of apatites, proteins (collagen and proteoglycan), and a small amount of beta carotene and cholesterol after Raman spectral determination. The calcified nodules of each valve leaflet were predominately identified to be calcium hydroxyapatite and type-B carbonate apatite. However, octacalcium phosphate was also detected in the protein-rich part of calcified valve leaflets. A positive correlation was observed between thickness and calcification for both excised TAV and BAV after ex vivo examinations. Moreover, a negative relationship was obtained among in vivo AVA index, ex vivo thickness and ex vivo calcification for these calcific AS patients. PMID- 28651164 TI - Serum levels of decabromodiphenyl ether (BDE-209) in women from different European countries and possible relationships with lifestyle and diet. AB - To determine possible effects of lifestyle, diet, housing and professional activities on differences in individual levels of decabromodiphenyl ether (BDE 209) in serum of women, 20 to 40years of age, in The Netherlands, the United Kingdom, Norway and Spain. BDE-209 was measured in serum of 145 female volunteers with no known occupational exposure from Norway, United Kingdom, The Netherlands and Spain. Blood levels of BDE-209 in a subgroup of 40 Dutch women were determined twice at a six months' interval. An extensive questionnaire was used to obtain detailed information about lifestyle factors that might contribute to BDE-209 exposure. Serum levels were used to determine margin of systemic exposure compared with a 28d rat toxicity study. Median BDE-209 serum concentrations were highest in The Netherlands and United Kingdom, respectively 8.8 and 9.3pg/gww. or 2.6 and 2.8ng/g lipid. Median levels in Spain and Norway were lower, respectively 7.4 and 5.2pg/gww. or 3.3 and 0.8ng/g lipid. Maximum levels in individual women were higher by one order of magnitude than the mean or median. The country of residence was the only variable significantly associated with BDE-209 levels; we found that the differences between countries could not be explained by any of the investigated exposure variables, and that these did not explain differences between individuals either. No consistent relationships were determined between diets, household, clothes, number and duration of use of electronics and occupational activities for the whole study group. We could not identify which of the multiple sources of exposure accounted for individual differences in blood levels. Although small differences in mean BDE-209 serum levels were recognized between countries, these differences are unlikely to cause a differential result with respect to risk assessment. PMID- 28651165 TI - Considering common sources of exposure in association studies - Urinary benzophenone-3 and DEHP metabolites are associated with altered thyroid hormone balance in the NHANES 2007-2008. AB - Epidemiological studies have shown that thyroid hormone balances can be disrupted by chemical exposure. However, many association studies have often failed to consider multiple chemicals with possible common sources of exposure, rendering their conclusions less reliable. In the 2007-2008 National Health and Nutrition Examination Survey (NHANES) from the U.S.A., urinary levels of environmental phenols, parabens, and phthalate metabolites as well as serum thyroid hormones were measured in a general U.S. population (>=12years old, n=1829). Employing these data, first, the chemicals or their metabolites associated with thyroid hormone measures were identified. Then, the chemicals/metabolites with possible common exposure sources were included in the analytical model to test the sensitivities of their association with thyroid hormone levels. Benzophenone-3 (BP-3), bisphenol A (BPA), and a metabolite of di(2-ethylhexyl) phthalate (DEHP) were identified as significant determinants of decreased serum thyroid hormones. However, significant positive correlations were detected (p-value<0.05, r=0.23 to 0.45) between these chemicals/metabolites, which suggests that they might share similar exposure sources. In the subsequent sensitivity analysis, which included the chemicals/metabolite with potentially similar exposure sources in the model, we found that urinary BP-3 and DEHP exposure were associated with decreased thyroid hormones among the general population but BPA exposure was not. In association studies, the presence of possible common exposure sources should be considered to circumvent possible false-positive conclusions. PMID- 28651166 TI - Air quality inside subway metro indoor environment worldwide: A review. AB - The air quality in the subway metro indoor microenvironment has been of particular public concern. With specific reference to the growing demand of green transportation and sustainable development, subway metro systems have been rapidly developed worldwide in last decades. The number of metro commuters has continuously increased over recent years in metropolitan cities. In some cities, metro system has become the primary public transportation mode. Although commuters typically spend only 30-40min in metros, the air pollutants emitted from various interior components of metro system as well as air pollutants carried by ventilation supply air are significant sources of harmful air pollutants that could lead to unhealthy human exposure. Commuters' exposure to various air pollutants in metro carriages may cause perceivable health risk as reported by many environmental health studies. This review summarizes significant findings in the literature on air quality inside metro indoor environment, including pollutant concentration levels, chemical species, related sources and health risk assessment. More than 160 relevant studies performed across over 20 countries were carefully reviewed. These comprised more than 2000 individual measurement trips. Particulate matters, aromatic hydrocarbons, carbonyls and airborne bacteria have been identified as the primary air pollutants inside metro system. On this basis, future work could focus on investigating the chronic health risks of exposure to various air pollutants other than PM, and/or further developing advanced air purification unit to improve metro in-station air quality. PMID- 28651167 TI - Error-prone bypass of O6-methylguanine by DNA polymerase of Pseudomonas aeruginosa phage PaP1. AB - O6-Methylguanine (O6-MeG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, generally leads to G:C to A:T mutagenesis. To study DNA replication encountering O6-MeG by the DNA polymerase (gp90) of P. aeruginosa phage PaP1, we analyzed steady-state and pre-steady-state kinetics of nucleotide incorporation opposite O6-MeG by gp90 exo-. O6-MeG partially inhibited full-length extension by gp90 exo-. O6-MeG greatly reduces dNTP incorporation efficiency, resulting in 67-fold preferential error-prone incorporation of dTTP than dCTP. Gp90 exo- extends beyond T:O6-MeG 2-fold more efficiently than C:O6 MeG. Incorporation of dCTP opposite G and incorporation of dCTP or dTTP opposite O6-MeG show fast burst phases. The pre-steady-state incorporation efficiency (kpol/Kd,dNTP) is decreased in the order of dCTP:G>dTTP:O6-MeG>dCTP:O6-MeG. The presence of O6-MeG at template does not affect the binding affinity of polymerase to DNA but it weakened their binding in the presence of dCTP and Mg2+. Misincorporation of dTTP opposite O6-MeG further weakens the binding affinity of polymerase to DNA. The priority of dTTP incorporation opposite O6-MeG is originated from the fact that dTTP can induce a faster conformational change step and a faster chemical step than dCTP. This study reveals that gp90 bypasses O6 MeG in an error-prone manner and provides further understanding in DNA replication encountering mutagenic alkylation DNA damage for P. aeruginosa phage PaP1. PMID- 28651168 TI - The antioxidant and anti-inflammatory properties of lycopene in mice lungs exposed to cigarette smoke. AB - Lycopene is a carotenoid with known antioxidant and anti-inflammatory properties. We aimed to evaluate the in vitro and in vivo effects of lycopene on reducing the redox imbalance and inflammation induced by cigarette smoke (CS). For the in vitro study, J774A.1 (macrophages) cells were incubated in the presence of 0.5, 1.0, 2.0, 4.0, 8.0, 10.0 and 25 MUM of lycopene for 3, 6 and 24 h or in the presence of 0.1%, 0.25%, 0.5%, 0.625%, 1.25%, 2.25%, 5% and 10% cigarette smoke extract (CSE) for 3, 6 and 24 h to assess cell viability and measurement of intracellular reactive oxygen species (ROS). For the in vivo study, 40 mice were divided into 5 groups: a control exposed to ambient air (CG), a vehicle-control group that received 200 MUl of sunflower oil by orogastric gavage, a group exposed to CS and two groups administered lycopene (diluted in sunflower oil) at doses of either 25 or 50 mg/kg/day prior to exposure to CS (LY25+CS and LY50+CS). The total treatment time lasted 5 days. A cell viability decrease was observed at 10- and 25-MUM concentrations of lycopene in 3, 6 and 24 h compared with CG. There was an increase of ROS production in 24 h in CS compared with CG. Lycopene concentrations of 1 MUM and 2 MUM were able to reduce the production of ROS in 24 h compared with CS. In the bronchoalveolar lavage fluid, the total number of leukocytes increased in the CS group compared with the control groups (CG). Administration with lycopene at the highest dose suppressed this CS-induced increase in leukocytes. Lipid peroxidation and DNA damage increased in the CS group compared with that in the controls, and this increase was suppressed by lycopene at the highest dose. In contrast, superoxide dismutase activity decreased in the CS group compared with that in the controls. Catalase activity also increased in the CS group compared with that in both control groups, and this increase was suppressed in LY25+CS and LY50+CS. There was an increase in the levels of tumor necrosis factor-alpha, interferon-gamma and interleukin-10 after exposure to CS, and these effects were suppressed by both doses of lycopene. These data elucidate the role of lycopene as an antioxidant and anti-inflammatory agent in these two models of short-term exposure to CS. PMID- 28651169 TI - Anticancer activity of hydroxy- and sulfonamide-azobenzene platinum(II) complexes in cisplatin-resistant ovarian cancer cells. AB - The syntheses of three platinum(II) complexes bearing sulfonamide- ( (E)-2-(4 methylphenylsulfonamido)-2',6'-difluoroazobenzene, HL1) and hydroxy-azo-2,6 difluorobenzene ((E)-2-((2,6-difluorophenyl)diazenyl)phenol, HL2) bidentate ligands is described. These complexes, [Pt(L1)(DMSO)Cl] (1), [Pt(L2)(DMSO)Cl] (2), and [Pt(L2)2] (3), were characterized by multinuclear NMR spectroscopy, mass spectrometry, and X-ray crystallography. Despite bearing azobenzene functional groups, none of the three complexes undergo photoisomerization. The anticancer activities of these complexes were evaluated in wild-type (A2780) and cisplatin resistant (A2780CP70) ovarian cancer cells. All three complexes exhibited IC50 values below 10MUM and displayed similar activity in both A2780 and A2780CP70 cell lines, indicating that they are not cross-resistant with cisplatin. The DNA binding properties of 1-3 were investigated by circular dichroism spectroscopy and by agarose gel electrophoresis. Both studies suggest that 1 and 2 form monofunctional DNA adducts. PMID- 28651170 TI - An analysis of quality of life (QOL) in patients with epilepsy and comorbid psychogenic nonepileptic seizures (PNES) after vagus nerve stimulation (VNS). AB - PURPOSE: Patients with epilepsy (PWE) may suffer from comorbid psychogenic nonepileptic seizures (PNES). The efficacy of vagus nerve stimulation (VNS) in the treatment of epilepsy and depression is established, however the impact on PNES is unknown. Since many patients with PNES have comorbid depression, we explored the impact on quality of life (QOL) that VNS has on PWE and PNES. METHODS: The video electroencephalogram (vEEG) of all patients who underwent VNS at our institution was reviewed. Patients diagnosed with both psychogenic seizures and epileptic seizures on their vEEG were included in this study. These patients were contacted, and given a QOLIE-31 survey to assess their quality of life after VNS. Patients also completed a separate survey created by our group to categorize the quartile of their improvement. Pre-operative psychiatric disease was retrospectively reviewed. RESULTS: From a period of 2001 to 2016, 518 patients underwent placement of VNS for drug resistant epilepsy (DRE) at our institution. In total, 16 patients were diagnosed with both epilepsy and PNES. 11/16 patients responded to our questionnaire and survey. 9 out of 11 patients felt that their epileptic seizures had improved after VNS, while 7 of the 11 patients felt that their psychogenic episodes had improved. 2(28.6%), 1 (14.3%), and 4 (57.1%) of participants said their PNES improved by 25-50%, 50-75%, and 75 100%, respectively. 3(27.3%), 3 (27.3%), 1 (9.1%), and 4 (36.4%) of the participants said their epileptic seizures improved by 0-25%, 25-50%, 50-75%, and 75-100%, respectively. The average overall score for quality of life for the study participants was found to be 51 (+/-8) out of 100. CONCLUSION: Patients with epilepsy and comorbid PNES may benefit from VNS. It is unclear whether the benefit is conferred strictly from decreased epileptic seizure burden. The possible effect on PNES may be related to the known effect of VNS on depression. Further studies are necessary to elucidate the role of VNS in the treatment of PNES and possibly other psychiatric disease. PMID- 28651158 TI - Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX. AB - BACKGROUND: The prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use. PATIENTS AND METHODS: According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data. RESULTS: Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients. CONCLUSION: Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients. PMID- 28651172 TI - Simultaneous determination of cis-permethrin and trans-permethrin in rat plasma and brain tissue using gas chromatography-negative chemical ionization mass spectrometry. AB - A sensitive method for the simultaneous determination of cis-permethrin (cis PERM) and trans-permethrin (trans-PERM) in small volumes (100MUL) of rat plasma and brain homogenate was developed, using a liquid-liquid extraction for sample preparation and gas chromatography-negative chemical ionization mass spectrometry (GCNCI-MS) for detection. Quantitation of trace levels of the insecticide in small volumes of biological samples is essential to support toxicokinetic studies in small animals. There are currently no validated methods in the literature for determining cis-PERM and trans- PERM in volumes as low as 100MUL of rat plasma or brain homogenate. The method provided a linear range of 0.2-150.0ng/mL for analytes in both matrices. The intra- and inter-batch precision (as% relative standard deviation, RSD) and accuracy (as relative error, RE) of the method were better than 20% at the limit of quantitation and better than 15% across the remaining linear range. The validated method was applied in a toxicokinetic study in adult rats with oral dosing of 10mg/kg (cis-PERM) and 100mg/kg (trans-PERM) in corn oil. cis-PERM and trans- PERM were monitored in rat plasma and brain tissue samples for 6h following dosing, and both analytes were detected in all plasma and brain samples. PMID- 28651173 TI - Development, validation and clinical application of a method for the simultaneous quantification of lamivudine, emtricitabine and tenofovir in dried blood and dried breast milk spots using LC-MS/MS. AB - OBJECTIVES: To present the validation and clinical application of a LC-MS/MS method for the quantification of lamivudine (3TC), emtricitabine (FTC) and tenofovir (TFV) in dried blood spots (DBS) and dried breast milk spots (DBMS). METHODS: DBS and DBMS were prepared from 50 and 30MUL of drug-spiked whole blood and human breast milk, respectively. Following extraction with acetonitrile and water, chromatographic separation utilised a Synergi polar column with a gradient mobile phase program consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Detection and quantification was performed using a TSQ Quantum Ultra triple quadrupole mass spectrometer. The analytical method was used to evaluate NRTI drug levels in HIV-positive nursing mothers-infant pairs. RESULTS: The assay was validated over the concentration range of 16.6-5000ng/mL for 3TC, FTC and TFV in DBS and DBMS except for TFV in DBMS where linearity was established from 4.2-1250ng/mL. Intra and inter-day precision (%CV) ranged from 3.5-8.7 and accuracy was within 15% for all analytes in both matrices. The mean recovery in DBS was >61% and in DBMS >43% for all three analytes. Matrix effect was insignificant. Median AUC0-8 values in maternal DBS and DBMS, respectively, were 4683 (4165-6057) and 6050 (5217-6417)ngh/mL for 3TC, 3312 (2259-4312) and 4853 (4124-6691)ngh/mL for FTC and 1559 (930-1915) and 56 (45-80)ngh/mL for TFV. 3TC and FTC were quantifiable (>16.6ng/mL) in DBS from 2/6 and 1/6 infants respectively whereas TFV was undetectable in all infants. CONCLUSIONS: DBS and DBMS sampling for bioanalysis of 3TC, FTC and TFV is straightforward, robust, accurate and precise, and ideal for use in low-resource settings. PMID- 28651175 TI - Challenges in GC-MS analysis: Case studies on phenibut and ethylphenidate. AB - The challenges associated with drug analysis using GC-MS such as thermal degradation, cyclisation or unwanted side reactions causing potential erroneous identification have become evident in view of the high surge in new drugs available in the market. Two case studies illustrated how alternative methods or modifications to existing techniques can help to circumvent the limitations. In the first case study, phenibut which is a GABA analogue, cyclises to 4-phenyl-2 pyrrolidinone under thermal conditions. The identification of phenibut was achieved through derivatisation and identification of its TMS derivative. The second case study, thermal degradation was minimised on drugs of interest methylphenidate and ethylphenidate by reducing the injector port temperature to 200 degrees C and maintaining the GC oven temperature at below 190 degrees C in order to prevent thermal degradation of the drugs of interest. PMID- 28651174 TI - Label-free chronopotentiometric glycoprofiling of prostate specific antigen using sialic acid recognizing lectins. AB - In recent decades, it has become clear that most of human proteins are glycosylated and that protein glycosylation plays an important role in health and diseases. At present, simple, fast and inexpensive methods are sought for clinical applications and particularly for improved diagnostics of various diseases, including cancer. We propose a label- and reagent-free electrochemical method based on chronopotentiometric stripping (CPS) analysis and a hanging mercury drop electrode for the detection of interaction of sialylated protein biomarker a prostate specific antigen (PSA) with two important lectins: Sambucus nigra agglutinin (SNA) and Maackia amurensis agglutinin (MAA). Incubation of PSA modified electrode with specific SNA lectin resulted in an increase of CPS peak H of the complex as compared to this peak of individual PSA. By adjusting polarization current and temperature, PSA-MAA interaction can be either eliminated or distinguished from the more abundant PSA-SNA complex. CPS data were in a good agreement with the data obtained by complementary methods, namely surface plasmon resonance and fluorescent lectin microarray. It can be anticipated that CPS will find application in glycomics and proteomics. PMID- 28651171 TI - The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy. AB - It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing. PMID- 28651176 TI - Forensic applications of direct analysis in real time (DART) coupled to Q orbitrap tandem mass spectrometry for the in situ analysis of pigments from paint evidence. AB - The accurate examination of paint fragments obtained from an accident, such as those obtained from vehicles involved in a hit-and-run case, is often critical in forensic investigations. However, organic pigments are typically minor components of automotive coatings, which makes discrimination difficult. In this study, direct analysis in real time coupled to Q-orbitrap tandem mass spectrometry (DART MS) was employed to detect a wide range of common organic pigments in vehicle paints. Twelve common organic pigments used in vehicle paints, such as red, yellow, orange, and purple, were tested, and a database was constructed for future examinations of vehicle paint. Two hit-and-run vehicle accident cases, which occurred in New Taipei City, were investigated by Fourier transform infrared (FTIR) spectroscopy and DART-MS. First, FTIR spectroscopy was employed to study the paint samples as a preliminary screening step. Most of the observed IR peaks were attributed to binder and extenders present in paints. The IR peaks corresponding to the organic pigments were found to be weak and overlapped with those corresponding to resins. On the other hand, DART-MS successfully characterized the organic pigments. DART-MS was found to be excellent for rapidly determining the presence of organic pigments in paint samples without the need for a complicated pre-treatment process or lengthy analysis time. PMID- 28651177 TI - Particle-size distribution (PSD) of pulverized hair: A quantitative approach of milling efficiency and its correlation with drug extraction efficiency. AB - Different types of hair were submitted to different milling procedures and their resulting powders were analyzed by scanning electron microscopy (SEM) and laser diffraction (LD). SEM results were qualitative whereas LD results were quantitative and accurately characterized the hair powders through their particle size distribution (PSD). Different types of hair were submitted to an optimized milling conditions and their PSD was quite similar. A good correlation was obtained between PSD results and ketamine concentration in a hair sample analyzed by LC-MS/MS. Hair samples were frozen in liquid nitrogen for 5min and pulverized at 25Hz for 10min, resulting in 61% of particles <104MUm and 39% from 104 to 1000MUm. Doing so, a 359% increment on ketamine concentration was obtained for an authentic sample extracted after pulverization comparing with the same sample cut in 1mm fragments. When milling time was extended to 25min, >90% of particles were <60MUm and an additional increment of 52.4% in ketamine content was obtained. PSD is a key feature on analysis of pulverized hair as it can affect the method recovery and reproducibility. In addition, PSD is an important issue on sample retesting and quality control procedures. PMID- 28651178 TI - The influence of impact direction and axial loading on the bone fracture pattern. AB - : The effect of the direction of the impact and the presence of axial loading on fracture patterns have not yet been established in experimental 3-point bending studies. PURPOSE: To reveal the association between the direction of the force and the fracture pattern, with and without axial loading. MATERIAL AND METHODS: A Dynatup Model POE 2000 (Instron Co.) low energy pendulum impact machine was utilized to apply impact loading on fresh pig femoral bones (n=50). The bone clamp shaft was adjusted to position the bone for three-point bending with and without additional bone compression. Four different directions of the force were applied: anterior, posterior, lateral, and medial. RESULTS: The impacted aspect can be distinguished from the non-impacted aspects based on the fracture pattern alone (the most fractured one); the impact point can be identified on bare bones (the area from which all oblique lines radiate and/or the presence of a chip fragment). None of our experiments (with and without compression) yielded a "true" butterfly fracture, but instead, oblique radiating lines emerged from the point of impact (also known as "false" butterfly). Impacts on the lateral and anterior aspects of the bones produce more and longer fracture lines than impacts on the contralateral side; bones subjected to an impact with axial loading are significantly more comminuted and fragmented. Under axial loading, the number of fracture lines is independent of the impact direction. Our study presents an experimental model for fracture analysis and shows that the impact direction and the presence of axial loading during impact significantly affect the fracture pattern obtained. PMID- 28651179 TI - Sedentary work and the risks of colon and rectal cancer by anatomical sub-site in the Canadian census health and environment cohort (CanCHEC). AB - BACKGROUND: Sedentary behaviour is a potential risk factor for colorectal cancer. We examined the association between sedentary work, based on body position, and colorectal cancer risk in Canadians. METHODS: A working body position category (a. sitting; b. standing and walking; c. sitting, standing, and walking; d. other) was assigned to occupations reported by 1991 Canadian Census respondents based on national occupational counselling guidelines. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated for cancers of the colon (overall, proximal, and distal) and rectum in men and women newly diagnosed from 1992 to 2010. RESULTS: Compared to "sitting" jobs, men in occupations with "other" (non-sitting, -standing, or -walking) body positions had a weakly significant reduced colon cancer risk (HR=0.93, 95% CI: 0.89, 0.98) primarily attributed to protection at the distal site (HR=0.90, 95% CI: 0.84, 0.97). Men in "standing and walking" and "sitting, standing, and walking" jobs did not have significantly reduced colon cancer risks. No effects were observed for rectal cancer in men or colon and rectal cancer in women. CONCLUSION: The two significant findings of this analysis should be followed-up in further investigations with additional information on potential confounders. Null findings for rectal cancer were consistent with other studies. PMID- 28651180 TI - Does a short-term exposure to atrazine provoke cellular senescence in Chlamydomonas reinhardtii? AB - The aim of this study was to investigate the impacts and modes of action of a chemical and nutrient deprivation on the cellular senescence process of Chlamydomonas reinhardtii. Several molecular and cellular parameters related to senescence phenomena were monitored in C. reinhardtii cells exposed for 24h to a sublethal concentration (0.25MUM) of the herbicide atrazine and in unexposed 96h cells in an early stationary phase of growth. All endpoints showed the same pattern of response between treatments, except for the intracellular level of calcium, where a significant increase was observed in 24h-exposed cultures compared to 24h-log controls. Results also indicated that cell viability remained above 98% for all conditions. Reactive oxygen species (ROS) levels and caspase activity increased in all experimental cultures with respect to 24h-log controls and alterations in the nuclear morphology and cells with auto-phagosomes were observed in all treatments. However, a decrease in lipid peroxidation was detected which could be related to the observed increment of autophagic vacuoles that recycle damaged material, such as altered lipids in microalgal membranes. Furthermore, responses at the molecular level were also investigated. Gene transcription analyses, carried out by RT-qPCR technique, indicated an increase in transcripts for genes encoding glutathione S-transferase (GST) and ascorbate peroxidase (APX I) and a decrease for those encoding catalase (CAT), glutathione peroxidase (GPX) and Mn-superoxide dismutase (SOD-1) in both experimental treatments. Overall molecular and cellular results suggest that a short-term exposure to a sublethal concentration of atrazine may induce senescence features in microalgal cells which are the base of aquatic food webs. PMID- 28651181 TI - Antifouling biocides: Impairment of bivalve immune system by chlorothalonil. AB - Marine ecosystems are subjected to a variety of contaminants. Antifouling paints, for example, have been extensively used to protect ship surfaces from marine biofouling, but their toxicity has generated great concern. Thus, we evaluated the effect of the biocide chlorothalonil on the immune system of Perna perna mussels. The mussels were exposed to 0 (control), 0.1MUg/L and 10MUg/L of chlorothalonil for up to 96h. After 24h and 96h of exposure, the following immune related parameters were analyzed in the hemolymph of mussels: total hemocyte count, cell adhesion, phagocytic activity, level of reactive oxygen species, cell viability and comet assay. After 24h and 96h of chlorothalonil exposure, cellular adhesion increased and the hemocyte viability reduced. Moreover, an increase in phagocytic activity was also observed after 96h of exposure to cholorothalonil. The exposure to 10MUg/L of chlorothalonil for 96h reduced the air survival capacity of mussels. Total hemocyte count, ROS generation and DNA damage were not affected by the contaminant exposure. Our results indicate that chlorothalonil affected important immune responses of the bivalves, demonstrating that this biocide has effects on non-target species. This modulation of immune system reduced the health status of mussels, which could compromise their ability to survive in the environment. PMID- 28651182 TI - Chronic effects of atrazine exposure and recovery in freshwater benthic diatoms from two communities with different pollution histories. AB - Diffuse agricultural runoff into rivers can result in contamination with herbicides for prolonged periods of time. Chronic exposure to herbicides has the potential to alter toxic impacts in primary producers such as benthic diatoms. Determining how individual diatom taxa respond to herbicide exposure over varied exposure durations is essential for assessing herbicide impacts. This study investigated the responses of various benthic diatom taxa and effects at the community level over 12days of atrazine exposure. Diatom communities were collected from two sites with differing exposure histories; a relatively unpolluted site (Alligator Creek) and an agricultural stream (Barratta Creek) known to be polluted by atrazine and other herbicides. Diatom community composition and the proportion of healthy cells per taxon were assessed at 0, 2, 3, 6, 9 and 12days of atrazine exposure. Pollution history altered the response of the diatom community to atrazine exposure. In the Alligator Creek diatom community there was a shift in composition towards more tolerant taxa and the loss of sensitive taxa in atrazine exposed treatments. The sensitive taxon (Gomphonema truncatum) was consistently affected by atrazine toxicity. Conversely, the polluted Barratta Creek diatom community was not strongly affected by atrazine exposure. Our study shows that during chronic atrazine exposure some taxa demonstrated the ability to recover despite initial toxicity response. Recovery could be an important trait for understanding the ecological effect of herbicide exposure on diatom species in nature and in applied circumstances such as biomonitoring indices. PMID- 28651183 TI - Investigating the effect of different transducer stiffness values on the contactin complex detachment by steered molecular dynamics. AB - This study investigated the adhesion behavior of Contactin4 (CNTN4), a member of Immunoglobulin Super Family (Ig-SF) of cell adhesion molecules. Contactin4 plays a crucial role in the formation, maintenance, and plasticity of neuronal networks. Contactin in its complex configuration with protein tyrosine phosphatase gamma (PTPRG) was selected for simulation. By utilizing Steered Molecular Dynamics (SMD), the uniaxial force was applied to induce unbinding of the complex, and the force-induced detachment of complex components was probed. Three sets of simulations with three values of transducer stiffness and five pulling speeds were designed. Our results showed the dependence of unbinding force on both accessible parameters of pulling speed and spring stiffness. By increasing the stiffness value and pulling speed the rupture force increased. Accordingly, the dissociation rates due to the Bell's theory based on rupture forces and loading rates were calculated. PMID- 28651184 TI - Computational study of structural, optoelectronic and nonlinear optical properties of dynamic solid-state chalcone derivatives. AB - In the present study, we use the state of art density functional theory (DFT) techniques to calculate the structural, optoelectronic and nonlinear optical (NLO) properties for two novel chalcone derivatives. The geometrical structures of chalcone derivatives compound 1 and 2 are optimized using periodic boundary conditions (PBC) in solid-state phase as well as isolated single molecular geometry in the gas phase. The reasonable agreement is found among experimental, solid-state and gas phase single molecular geometries, which provide us, further confidence to explore the potential of above-entitled derivatives as good functional materials for electro-optical applications. For instance, the frequency dependent real parts of dielectric functions are calculated for compound 1 and 2. The maximum value of real part of the dielectric function for compound 1 and 2 at 0eV are computed as 4.35 and 6.68 for the polarization vectors of (001) directions, respectively, which reveals the fact that the compound 1 and 2 might be good charge transport materials. The reflectivities of the compound 1 and 2 are 0.64 and 0.45 revealing that the compound 2 might be more efficient material for organic photovoltaic (OPV) applications. The results of the refractive index improved by doping the strong electron withdrawing groups (EWGs) shows that the compound 2 might be good refractor of the photon as compared to compound 1. The calculated values for static second-order polarizability are 3498 and 10464 a. u. and for frequency dependent second harmonic generations are 2557 and 6429 a. u. for compound 1 and 2, respectively, which indicates their significant potential for possible nonlinear optical applications. PMID- 28651185 TI - Treatment of neurocognitive symptoms in unipolar depression: A systematic review and future perspectives. AB - BACKGROUND: Cognitive symptoms in Major Depressive Disorder (MDD) are persistent and commonly entail neurocognitive impairment and a decline in quality of life. This systematic review gathers the current scientific evidence on therapeutic strategies for neuropsychological impairment in MDD. METHOD: A systematic search on PubMed, PsycINFO and Clinicaltrials.gov was carried out on December 2016 according to PRISMA using Boolean terms to identify interventions for the treatment of cognitive dysfunction in MDD. Only English-written articles providing original data and focusing in adults with MDD were included with no time restrictions. RESULTS: A total of 95 studies reporting data on 40 pharmacological and non-pharmacological interventions were included. Interventions were grouped into the following categories: 1) Pharmacological Therapies (antidepressants, stimulants, compounds acting on NMDA receptors, compounds acting on the cholinergic system, compounds showing anti-inflammatory or antioxidant properties, other mechanisms of action), 2) Physical Therapies and 3) Psychological Therapies, 4) Exercise. There are some promising compounds showing a positive impact on cognitive symptoms including vortioxetine, lisdexamfetamine or erythropoietin. LIMITATIONS: The studies included showed significant methodological differences in heterogeneous samples. The lack of a standardized neuropsychological battery makes comparisons between studies difficult. CONCLUSION: Current evidence is not sufficient to widely recommend the use of procognitive treatments in MDD although promising results are coming to light. PMID- 28651186 TI - Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) as a novel predictor of clinical outcome after endovascular therapy in patients with peripheral artery disease (PAD). AB - BACKGROUND AND AIMS: Despite advances in the treatment of peripheral artery disease (PAD), cardiovascular events and death rates remain high. This study aimed at identifying markers of outcome in patients with PAD undergoing endovascular therapy (EVT). METHODS: Consecutive patients undergoing EVT were recruited. Markers of oxidative stress (malondialdehyde-modified low-density lipoprotein [MDA-LDL]), inflammation (IL-6; high-sensitivity C-reactive protein [hsCRP]) and fibrinolysis (D-dimer) were measured pre-EVT and at post-EVT time points to 36 h. Clinical follow-up assessed major cardiovascular and/or limb events. RESULTS: In the 35 patients enrolled, mean MDA-LDL levels decreased from a baseline level of 106.2 U/L to 72.6 U/L immediately post-EVT (p<0.0001); levels remained significantly reduced at all time-points. IL-6, hsCRP and D-dimer increased and were significantly higher at the 36 h time-point. A significant, negative association was seen between decreased MDA-LDL and pre-EVT hsCRP levels (r = -0.42, p=0.012). Clinical follow-up data were obtained for a mean period of 16 months. MDA-LDL ratios (obtained by comparison of post- and pre-EVT values) allowed assessment of high (>=0.495) and low (<0.495) ratio groups. A significantly higher rate of major adverse events, including limb-related events or death, was seen in the low ratio group (p<0.001). Cox proportional hazard analysis including traditional risk factors indicated that this ratio is a significant predictor of clinical endpoints (HR = 0.4210, p=0.0154). An association with clinical outcome was not observed with the other candidate biomarkers. CONCLUSIONS: Assessment of pre- and post-EVT MDA-LDL levels is a promising marker of clinical outcome in patients with PAD. PMID- 28651187 TI - Association of ectopic fat with abdominal aorto-illiac and coronary artery calcification in african ancestry men. AB - BACKGROUND AND AIMS: There is strong evidence that fat accumulating in non adipose sites, "ectopic fat", is associated with cardiovascular disease (CVD), including vascular calcification. Most previous studies of this association have assessed only a single ectopic fat depot. Therefore, our aim was to assess the association of total, regional, and ectopic fat with abdominal aorto-illiac calcification (AAC) and coronary artery calcification (CAC) in 798 African ancestry men. METHODS: Participants (mean age 62) were from the Tobago Bone Health Study cohort. Adiposity was assessed via clinical examination, dual x-ray absorptiometry, and computed tomography (CT). Ectopic fat depots included: abdominal visceral adipose tissue (VAT), liver attenuation, and calf intermuscular adipose tissue (IMAT). Vascular calcification was assessed by CT and quantified as present versus absent. Associations were tested using multiple logistic regression adjusted for traditional cardiovascular risk factors. Models of ectopic fat were additionally adjusted for total body fat and standing height. RESULTS: All adiposity measures, except VAT, were associated with AAC. Lower liver attenuation or greater calf IMAT was associated with 1.2-1.3-fold increased odds of AAC (p < 0.03 for both), though calf IMAT was a stronger predictor than liver attenuation (p < 0.001) when entered in a single model. No ectopic fat measure was associated with CAC. CONCLUSIONS: Greater adiposity in the skeletal muscle and liver, but not in the visceral compartment, was associated with increased odds of AAC in African ancestry men. These results highlight the potential importance of both quantity and location of adiposity accumulation throughout the body. PMID- 28651188 TI - Hyperhomocysteinaemia is an independent risk factor for peripheral arterial disease in a Chinese Han population. AB - BACKGROUND AND AIMS: Hyperhomocysteineamia (HHcy) has long been suggested as a risk factor for atherosclerosis. However, the association between HHcy and peripheral arterial disease (PAD) is still controversial. There is a lack of research on this topic in the Chinese population. This study aims to provide further results. METHODS: 240 PAD patients and 240 control subjects were evaluated for both serum total homocysteine levels and ankle brachial indexes (ABIs). Multivariable logistic regression models were used to estimate the association between HHcy and the risk of developing PAD. Interaction and stratified analyses were conducted according to age, sex, smoking status, drinking status, and histories of chronic disease. RESULTS: The multivariate logistic regression analyses revealed that the risk of PAD was significantly associated with serum homocysteine levels. The interaction analysis showed no interactive role in the association between HHcy and PAD, indicating that homocysteine was associated with PAD independently of classical vascular risk factors. CONCLUSIONS: In conclusion, HHcy is an independent risk factor for PAD in the Chinese Han population. A prospective and randomized clinical trial of homocysteine lowering therapy in the Chinese population is needed to assess the causal nature of the relationship. PMID- 28651189 TI - Sex-specific effects of difenoconazole on the growth hormone endocrine axis in adult zebrafish (Danio rerio). AB - Difenoconazole, as one of the most widely used triazole fungicides, is applied to protect crops, fruits, and vegetables. It has been reported that difenoconazole can enter the environment and impair aquatic organisms, but whether difenoconazole can disrupt the growth hormone (GH) balance in adult zebrafish (Danio rerio) is still unclear. In this study, adult female and male zebrafish were exposed to difenoconazole (0, 5, 50, and 500ug/L) for seven days. The results revealed that the bioaccumulation of difenoconazole and its primary metabolite difenoconazole alcohol in females were both larger than that in males. In females, the growth of the liver and ovary were inhibited, which may be due to the decreased transcription of the key genes igf1a, igf2a, and igf2b in both organs. Male fish growth was promoted in response to the increased expression of genes relevant to the GH/insulin-like growth factor axis (GH/IGF) axis in the brain, liver, and testis as well as increased GH levels. It was found that difenoconazole interfered with the growth endocrine system and sex-specifically altered the expression of GH/IGF axis related genes in adult zebrafish after a short-term exposure. PMID- 28651190 TI - Temporal dynamics of the compositions and activities of soil microbial communities post-application of the insecticide chlorantraniliprole in paddy soils. AB - Chlorantraniliprole (CAP) is a newly developed insecticide widely used in rice fields in China. There has been few studies evaluating the toxicological effects of CAP on soil-associated microbes. An 85-day microcosm experiment was performed to reveal the dissipation dynamics of CAP in three types of paddy soils in subtropical China. The effects of CAP on microbial activities (microbial biomass carbon-MBC, basal soil respiration-BSR, microbial metabolic quotient-qCO2, acid phosphatase and sucrose invertase activities) in the soils were periodically evaluated. Microbial phospholipid fatty acid (PLFA) analysis was used to evaluate the change of soil microbial community composition on day 14 and 50 of the experiment. CAP residues were extracted using the quick, easy, cheap, effective, rugged, and safe (QuChERS) method and quantification was measured by high performance liquid chromatography (HPLC). The half-lives (DT50) of CAP were in the range of 41.0-53.0 days in the three soils. The results showed that CAP did not impart negative effects on MBC during the incubation. CAP inhibited BSR, qCO2, acid phosphatase and sucrose invertase activities in the first 14 days of incubation in all the soils. After day 14, the soil microbial parameters of CAP treated soils became statistically at par with their controls. Principal component analysis (PCA) determining abundance of biomarker PLFAs indicated that the application of CAP significantly changed the compositions of microbial communities in all three paddy soils on day 14 but the compositions of soil microbial communities recovered by day 50. This study indicates that CAP does not ultimately impair microbial activities and microbial compositions of these three paddy soil types. PMID- 28651191 TI - Probing safety of nanoparticles by outlining sea urchin sensing and signaling cascades. AB - Among currently identified issues presenting risks and benefits to human and ocean health, engineered nanoparticles (ENP) represent a priority. Predictions of their economic and social impact appear extraordinary, but their release in the environment at an uncontrollable rate is in striking contrast with the extremely limited number of studies on environmental impact, especially on the marine environment. The sea urchin has a remarkable sensing environmental system whose function and diversity came into focus during the recent years, after sea urchin genome sequencing. The complex immune system may be the basis wherefore sea urchins can adapt to a dynamic environment and survive even in hazardous conditions both in the adult and in the embryonic life. This review is aimed at discussing the literature in nanotoxicological/ecotoxicological studies with a focus on stress and innate immune signaling in sea urchins. In addition, here we introduce our current development of in vitro-driven probes that could be used to dissect ENP aftermaths, suggesting their future use in immune-nanotoxicology. PMID- 28651192 TI - Efficient photocatalytic degradation of toxic dyes from aqueous environment using gelatin-Zr(IV) phosphate nanocomposite and its antimicrobial activity. AB - In the present study, gelatin-Zr(IV) phosphate nanocomposite (GT/ZPNC) was synthesized by sol-gel method by mixing the gelatin gel into the inorganic part Zr (IV) phosphate (ZP). The GT/ZPNC was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy (SEM), transmission electron micron scope (TEM), X-ray powder diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The photodegradation activity of GT/ZPNC was explored for the removal of methylene blue (MB) and fast green (FG) dyes from aqueous solution. It was found that 87.81% MB and 89.91% FG were degraded within five hours. Also, the kinetics of photocatalytic degradation for MB and FG was investigated via pseudo first-order kinetic model with higher regression coefficient values (R2). The antimicrobial efficiency of GT/ZPNC was investigated against E. coli. PMID- 28651193 TI - p,p'-Methoxyl-diphenyl diselenideincorporation into polymeric nanocapsules improves its antinociceptive action: Physicochemical and behavioral studies. AB - The p,p'-methoxyl-diphenyl diselenide [(OMePhSe)2] is an, organoselenium compound that elicits antinociceptive action in different, animal models of pain. However, the compound has physicochemical, Limitations that delay its clinical studies. Herein, (OMePhSe)2, nanocapsules were developed and their physicochemical properties were, analyzed using different techniques (Scanning electron microscopy with, field emissionguns, wide-angle X-ray diffractometry, fourier transform, infrared spectroscopy, thermogravimetric analysis and differential, scanning calorimetry). The antinociceptive action of (OMePhSe)2 free or, nanoencapsulated was evaluated in an animal model of thermal nociception., The (OMePhSe)2 nanocapsules or the free compound (25mg/kg, 10ml/kg), were administered to Swiss mice by the intragastric (i.g.), intraperitoneal (i.p.) or subcutaneous (s.c.) route in a single or, repeated administration regimen. The (OMePhSe)2 nanocapsules had, spherical shape, no chemical interaction among the formulation components, and high thermal stability. Treatment with (OMePhSe)2 elicited an, antinociceptive action independent of the administration route and, regimen schedule. The (OMePhSe)2 incorporation into nanocapsules, prolonged and improved the compound antinociceptive action. The, (OMePhSe)2 antinociceptive action was influenced by the route of, administration (intragastric>intraperitoneal>subcutaneous) and by the, vehicle used (NCs>canola oil). Altogether, the current study, demonstrated that the (OMePhSe)2 nanoencapsulation increased the compound, thermal stability and the antinociceptive action in mice, suggesting that, the polymeric nanocapsules provided advantages in comparison to the free, compound form. PMID- 28651194 TI - Reference intervals for hematological and biochemical parameters, acute phase proteins and markers of oxidation in Holstein dairy cows around 3 and 30days after calving. AB - The establishment of specific reference intervals (RIs) is advisable when different metabolic conditions in the patient population are present or when existing RIs are not suitable. Holstein dairy cows, at the start of lactation, experience a negative energy balance and an altered immune function that can lead to different levels of blood parameters compared with cows at peak lactation. The aim of this study was the determination of RIs for Holstein cows at 3+/-1 and 30+/-3days in milk. To this aim, 145 cows, from 4 herds, were sampled. A wide panel of hematological and biochemical analytes was determined, as well as the measurement of markers of inflammation/oxidation. RIs were generated following the American Society of Veterinary Clinical Pathology (ASVCP) guidelines and the effects of lactation period, parity, herd and day of sampling were determined. Data from 39 out of 52 analytes were significantly different according to lactation period. Data of 13 out of 52 analytes were not significantly different between the two groups. Some differences were also recorded between herds and parity groups but the adoption of specific RIs for these subgroups, however, has practical limitations. In conclusion the use of RIs specific for the lactation period is highly justified from both a statistical and a biological point of view. Pre-analytical factors associated with parity or management need to be considered in the evaluation of results of some analytes. PMID- 28651195 TI - Stereological and biophysical characteristics of the ovine surfactant system and its changes caused by ovine pulmonary adenocarcinoma. AB - Surfactant covers the inner surface of lung alveoli and lowers the surface tension to prevent alveoli from collapsing. A lack of surfactant or its dysfunction causes dyspnea. The Jaagsiekte Sheep Retrovirus (JSRV) causes ovine pulmonary adenocarcinoma (OPA), whose typical clinical appearance is fluid running from nostrils. This fluid might contain surfactant as alveolar type II pneumocytes (AEII) are target cells for JSRV. Therefore, the progressive dyspnea during OPA might be caused partially by surfactant alterations. Bronchoalveolar and intracellular surfactant as well as the biophysical function of surfactant were analyzed in OPA sheep and controls. Transmission electron microscopy and stereological methods were used to characterize ultrastructure and distribution of surfactant subtypes in AEII and bronchoalveolar lavage fluid (BALF). Pulsating Bubble Surfactometry enabled studying the surface activity of the surfactant, while lung volumes were detected by computed tomography. The methods used are suitable to determine intraalveolar and intracellular surfactant subtypes in OPA sheep and controls. OPA sheep showed more lamellar body-like forms, multivesicular vesicles and tubular myelin in BALF compared to controls. These higher amounts of active surfactant subtypes might be a consequence of a higher surfactant production and release. Surfactant subtypes in AEII of OPA sheep showed smaller and more immature lamellar bodies compared to controls. The surfactant surface activity of OPA sheep does not show obvious defects. In conclusion, the general quality of surfactant in OPA appears to be equivalent to surfactant produced in controls, however, dyspnea of OPA might be triggered by quantity of fluid production. PMID- 28651196 TI - Dancing to death: A case of heat stroke. AB - Heat stroke is a medical emergency which may lead to mortality unless diagnosed early and treated effectively. Heat stroke may manifest rapidly, hence making it difficult to differentiate it from other clinical causes in a collapsed victim.1 We are presenting a case report of twelve patients who were admitted to our emergency department from a music festival held on 13-15th of March 2014. They developed complications arising from a combination of severe adverse weather condition, prolonged outdoor physical exertion due to long hours of dancing and drug-use, resulting in heat stroke. Three of them died while the remaining patients survived. Their condition was initially misdiagnosed as a classical illicit drug overdose. This was based on the history of drug ingestion by some of the patients who attended the music festival on that day. The information in this case report aims, to create awareness amongst members of the medical team on duty in outdoor events, pre hospital responders and ED physicians when treating and managing similar cases in the future. In addition it is intended to warn the organizers of such events to take adequate precautions to avoid such tragedies in the future. PMID- 28651197 TI - Ascorbic acid protects Coccomyxa subellipsoidea against metal toxicity through modulation of ROS/NO balance and metal uptake. AB - Impact of exogenous ascorbic acid (AsA, 100MUM) on acute metal toxicity (Pb and Hg, 24h of exposure to 100MUM) in unicellular green alga Coccomyxa subellipsoidea was studied. Hg (often extensively) depleted amount of pigments, potassium, soluble proteins, endogenous AsA, non-protein thiols and nitric oxide signal but elevated ROS signal and activities of catalase and superoxide dismutase. Responses to Pb application (if any) were less visible with ROS signal being slightly elevated and amount of non-protein thiols being slightly reduced. Exogenous AsA considerably improved mainly Hg-induced damage at the level of oxidative stress and physiological parameters and evoked an increase in nitric oxide signal. Maximum amount of total Hg was almost 4-fold higher than that of Pb (36.5 vs. 9.73mg/g DW) and AsA depleted both total and intracellular accumulation. At the level of ascorbate-related proteins, exogenous AsA suppressed metal-induced expression and activity of MDHAR and APX but not of DHAR, which may indicate a role of DHAR in algal stress tolerance. Our data suggest that given Coccomyxa species is suitable candidate for remediation of Hg or Pb and that ascorbic acid effectively ameliorates metal-induced toxicity without side effects. PMID- 28651198 TI - The toxicity of cationic surfactant HDTMA-Br, desorbed from surfactant modified zeolite, towards faecal indicator and environmental microorganisms. AB - Surfactant Modified Zeolite (SMZ) represents a versatile, cost-effective permeable reactive material, capable of treating multiple classes of contaminants. The potential for HDTMA-Br, a cationic surfactant commonly used to modify zeolite, to desorb from the zeolite surface has been identified as a potential issue for the ongoing use of SMZ in water remediation contexts. This paper investigates the toxicity of HDTMA-Br towards enteric virus surrogates, F RNA bacteriophage MS2 and E. coli, Bacillus subtilis, and soil microflora. The concentration of surfactant desorbing from SMZ was quantified through a bioassay using E. coli. Results showed HDTMA-Br concentrations of >=10-5M were toxic to MS2, >=10-4M were toxic to E. coli and >=10-6M were toxic to B. subtilis. No toxic relationship was established between HDTMA-Br and soil microflora. Desorption of >=10-4M of HDTMA-Br was shown for the two SMZ samples under the mixing conditions used. Effects of this surfactant on total soil microflora were ambiguous since no toxic relationship could be established, however, HDTMA-Br, at concentrations desorbing from SMZ, were shown to impact the soil bacterium B. subtilis. Further research is required to determine the effect of this surfactant on microbial populations and species diversity in soils. PMID- 28651199 TI - Aberration corrected STEM by means of diffraction gratings. AB - In the past 15 years, the advent of aberration correction technology in electron microscopy has enabled materials analysis on the atomic scale. This is made possible by precise arrangements of multipole electrodes and magnetic solenoids to compensate the aberrations inherent to any focusing element of an electron microscope. Here, we describe an alternative method to correct for the spherical aberration of the objective lens in scanning transmission electron microscopy (STEM) using a passive, nanofabricated diffractive optical element. This holographic device is installed in the probe forming aperture of a conventional electron microscope and can be designed to remove arbitrarily complex aberrations from the electron's wave front. In this work, we show a proof-of-principle experiment that demonstrates successful correction of the spherical aberration in STEM by means of such a grating corrector (GCOR). Our GCOR enables us to record aberration-corrected high-resolution high-angle annular dark field (HAADF-) STEM images, although yet without advancement in probe current and resolution. Improvements in this technology could provide an economical solution for aberration-corrected high-resolution STEM in certain use scenarios. PMID- 28651200 TI - Nanostructured micro-raspberries from superparamagnetic iron oxide nanoparticles: Studying agglomeration degree and redispersibility of nanoparticulate powders via magnetisation measurements. AB - Surface modified superparamagnetic iron oxide nanoparticles are assembled into nanostructured micro-raspberry particles via spray drying. The micro-raspberry powder is readily redispersed to individual nanoparticles or nanostructured sub units, depending on the initially adjusted nanoparticle modification. In this work, it is demonstrated how the technique of magnetic zero-field-cooled/field cooled (ZFC/FC) measurements can be used to judge the degree of agglomeration, i.e. the extent of hard-agglomerates and soft-agglomerates in a system and predict the redispersibility of the powder particles. Furthermore, the uniformity of surface modification of the individual nanoparticles can be judged via this method. In addition, the technique can be applied to characterise complex nanostructured particle systems composed of iron oxide nanoparticles mixed with another type of nanoparticulate building-block. Thus, this work shows that magnetic measurement techniques are a promising approach to characterise agglomeration states of nanoparticles, their degree of surface modification and their distribution in complex particle and composite systems. PMID- 28651201 TI - Ex-situ decoration of ordered mesoporous carbon with palladium nanoparticles via polyoxometalates and for sensitive detection of acetaminophen in pharmaceutical products. AB - In this study, a facile and green method is described for decoration of ordered mesoporous carbon (OMC) with palladium nanoparticles (Pd NPs) through a polyoxometalates (POMs). Serving as both reducing and stabilizing agent, the Keggin-type POMs are used for synthesis of stable colloidal Pd NPs and then link them to the OMC at mild temperature. Current research focuses on the use of Pd POMs-OMC as an effective sensing template for the detection of acetaminophen (AP) has been studied. Linear calibration curves in the range of 0.10-33.15uM (R2=0.998) was obtained for AP with a sensitivity of 985.4uAmM-1; the limit of detection was calculated to be 0.069MUM. Importantly, the successful fabricated Pd-POMs-OMC device accurately measured the amount of AP in pharmaceutical samples. PMID- 28651202 TI - Durable superamphiphobic coatings repelling both cool and hot liquids based on carbon nanotubes. AB - Superamphiphobic coatings have wide potential applications in many fields, however, preparation of superamphiphobic coatings with low sliding angles and high durability is very challenging. Here, we report a facile spray-coating method for the preparation of durable superamphiphobic coatings repelling both cool and hot liquids from polyperfluoroalkylsilane-modified multiwalled carbon nanotubes (MWCNTs@fluoroPOS). The MWCNTs@fluoroPOS suspensions were preparation by hydrolytic condensation of 1H,1H,2H,2H-perfluorodecyltrichlorosilane (PFDTES) and tetraethoxysilane (TEOS) on the surface of MWCNTs. The suspensions and the superamphiphobic coatings were characterized using a variety of analytical techniques such as scanning electron microscopy, transmitting electron microscopy and X-ray photoelectron spectroscopy. The effects of the diameter of MWCNTs, and the concentrations of MWCNTs, TEOS and PFDTES on wettability and microstructure of the coatings were also investigated. The coatings show high contact angles and low sliding angles for water and organic liquids of low surface tension such as n hexadecane, toluene and n-decane. The coatings even exhibit excellent superamphiphobicity for hot water and hot organic liquids up to 80 degrees C, which is seldom achieved according to the previous literatures. Moreover, the coatings feature high mechanical, chemical and environmental durability, and are applicable onto various substrates. The simple method, the high superamphiphobicity to both cool and hot liquids, and the excellent durability of the coatings have paved the way for their practical applications in various fields, e.g., anti-icing, anti-oil climbing and oil transportation, etc. PMID- 28651203 TI - Carbon-coated ZnO mat passivation by atomic-layer-deposited HfO2 as an anode material for lithium-ion batteries. AB - ZnO has had little consideration as an anode material in lithium-ion batteries compared with other transition-metal oxides due to its inherent poor electrical conductivity and large volume expansion upon cycling and pulverization of ZnO based electrodes. A logical design and facile synthesis of ZnO with well controlled particle sizes and a specific morphology is essential to improving the performance of ZnO in lithium-ion batteries. In this paper, a simple approach is reported that uses a cation surfactant and a chelating agent to synthesize three dimensional hierarchical nanostructured carbon-coated ZnO mats, in which the ZnO mats are composed of stacked individual ZnO nanowires and form well-defined nanoporous structures with high surface areas. In order to improve the performance of lithium-ion batteries, HfO2 is deposited on the carbon-coated ZnO mat electrode via atomic layer deposition. Lithium-ion battery devices based on the carbon-coated ZnO mat passivation by atomic layer deposited HfO2 exhibit an excellent initial discharge and charge capacities of 2684.01 and 963.21mAhg-1, respectively, at a current density of 100mAg-1 in the voltage range of 0.01-3V. They also exhibit cycle stability after 125 cycles with a capacity of 740mAhg-1 and a remarkable rate capability. PMID- 28651204 TI - Iron-tannin-framework complex modified PES ultrafiltration membranes with enhanced filtration performance and fouling resistance. AB - In this work, an iron-tannin-framework (ITF) complex was introduced to a poly (ether sulfone) (PES) casting solution as a hydrophilic additive to fabricate ITF/PES ultrafiltration (UF) membranes via non-solvent-induced phase separation (NIPS). The structure and performance of the PES membranes with ITF concentrations ranging from 0 to 0.9wt.% were systematically investigated by scanning electron microscopy, water contact angle, permeability, protein rejection and fouling resistance measurements. The results indicate that the pore structure and surface properties of PES UF membranes can be regulated by incorporating the ITF complex. Compared with classical PES membranes, ITF/PES membranes were found to have an increased hydrophilicity and porosity and reduced surface pore size. Importantly, a simultaneous enhancement of permeability and separation performance was observed for the blend membranes, which indicates that the introduction of the ITF complex can break through the trade-off between permeability and selectivity of UF membranes.When the ITF content was 0.3wt.%, the permeability reached a maximum of 319.4(L/m2h) at 0.1MPa, which is 1.6 times higher than that of the classical PES membrane. Furthermore, the BSA rejection increased from 25.9% for the PES membrane to 95.9% for the enhanced membrane. In addition, the same membrane showed an improved fouling resistance (higher flux recovery and lower adhesion force) and stable hydrophilicity (unchanged after incubation in deionized water for 30days). The simple, green and cost-effective preparation process and the outstanding filtration performance highlight the potential of ITF/PES membranes for practical applications. PMID- 28651205 TI - Understanding size-dependent properties of BiOCl nanosheets and exploring more catalysis. AB - Investigating the dependence of the catalysis on the size and structure of materials is of great significance for exploiting catalysts with characteristics of high activity, low cost, and new property. Non-precious metal catalysts bear high hope to meet the increasing demands of industrial applications in a cost effective and environmentally friendly way. In this work, we take size-controlled BiOCl nanosheets as examples, which are synthesized via a hydrothermal method by changing the reaction conditions. The BiOCl nanosheets were characterized in details to understand their size-property relationships, and were found to exhibit a series of thickness-dependent physicochemical properties, including specific surface area, light absorption, and the separation efficiency of photo generated charge carriers. Moreover, this work demonstrates the first example that BiOCl nanostructures have very high catalytic activity for the reduction of nitrophenols by sodium borohydride, without any light irradiation. The high catalytic activity of BiOCl nanosheets was proved to be due to the metallic Bi0 clusters that were produced by surface Bi (III) reduction. The catalytic activity increased greatly with a decrease in the average thickness from 106.42nm of BiOCl(H2O) to 3.47nm of ultrathin BiOCl, because the increased specific surface area provided more active sites for catalytic reactions. As a result, this work provides evidences for the size-property relationships of nanostructured catalysts as well as some inspirations for exploiting novel heterogeneous catalysis of BiOCl nanomaterials. PMID- 28651206 TI - An investigation of the role of defect levels on the radiation response of synthetic diamond crystals when used as sensors for the detection of mammography X-rays. AB - This study evaluates the role of defects on the performances of synthetic diamond sensors on exposure to mammography X-rays. Through systematic investigations, the main cause of instability of response of examined sensors necessitating pre irradiation was isolated and ascribed to the presence of ambient light which has the effect of emptying shallow trapping levels. The changes in response between measurements in light and dark conditions varied from 2.8 +/- 1.2% to 63.0 +/- 0.3%. Sensitivities between 0.4 and 6.7nCGy-1mm-3 determined for the sensors varied with defect levels. The study indicates that differences in crystal quality due to the presence and influence of defects would cause a discrepancy in the dosimetric performances of various diamond detectors. Once a sensor plate is selected (based on the influence of defect levels) and coupled to the probe housing with the response of the diamond sensor stabilised and appropriately shielded from ambient light, daily priming is not needed. PMID- 28651207 TI - Metacognitive therapy versus disorder-specific CBT for comorbid anxiety disorders: A randomized controlled trial. AB - Few studies have compared the effects of Metacognitive therapy (MCT) and Cognitive behavioral therapy (CBT) for comorbid anxiety disorders. In the current study we compared CBT and MCT for heterogeneous anxiety disorders in a residential setting. Ninety patients with a primary diagnosis of Post Traumatic Stress Disorder, Social Phobia or Panic disorder, with and without Agoraphobia, were randomized to either CBT or MCT. Patients were assessed at pre-treatment, post-treatment and one-year follow-up. Primary outcome measures were Beck Anxiety Inventory and ADIS IV and secondary outcome measures were SCID II, Beck Depression Inventory, Penn State Worry Questionnaire, The Symptom Checklist-90 and the Inventory of Interpersonal Problems-64. Treatment fidelity was satisfactory and therapist credibility was equal in both treatments. There was a significant difference in the level of anxiety favouring MCT at post-treatment (d=0.7), but there were no differences at one-year follow-up, mainly due to a further improvement in the CBT group during the follow-up period. Both treatments were efficacious. No differences in effect on comorbid diagnoses and symptoms were found, but MCT produced larger change in personality problems. MCT seems to have a more rapid effect on anxiety symptoms, but there were no significant differences in the long term for patients with comorbid anxiety disorders. PMID- 28651208 TI - Relationship between THMs/NDMA formation potential and molecular weight of organic compounds for source and treated water in Shanghai, China. AB - Molecular weight (MW) distributions in source and treated water in Shanghai, China were investigated to understand the relationship between trihalomethanes formation potential/N-nitrosodimethylamine formation potential (THMFP/NDMAFP) and dissolved organic carbon (DOC) for different MW ranges (<1K, 1-10K, 10-30K, >30KDa). The result of MW distributions in source water indicated a relationship between THMFP/NDMAFP and DOC such that DOC for <1K and 1-30KDa DOC were linearly related to THMFP and NDMAFP, respectively. In treated water, >30KDa THMFP was totally removed whereas <1KDa THMFP showed linear relationships with R2=0.88 and 0.83 after sand and granular activated carbon (GAC) filtration, respectively. DOC content for 1-10KDa tended to form NDMA according to the results for treated water between DOC and NDMAFP (R2=0.94 and 0.93 for sand and GAC filtration, respectively). The results may provide researchers with targeted treatment strategies to destroy, remove, or reduce the occurrence of THMs and NDMA precursors. The findings presented in this study will be of great value in future work for selecting suitable drinking water treatment processes to minimize the formation of disinfection by-products using chlorine or chloramine disinfection. PMID- 28651209 TI - Removal of pharmaceuticals and personal care products by ammonia oxidizing bacteria acclimated in a membrane bioreactor: Contributions of cometabolism and endogenous respiration. AB - We carried out batch experiments using biomass from a membrane bioreactor (MBR) to study the influence of ammonia oxidizing bacteria (AOB) on the removal of 45 pharmaceuticals and personal care products (PPCPs). Kinetic parameters such as biodegradation constants and adsorption coefficients with and without AOB inhibition were estimated. No significant differences in adsorption tendency were found, but the biodegradability of most compounds was enhanced when ammonia was completely oxidized, indicating that AOB present in MBR played a critical role in eliminating the PPCPs. Moreover, target PPCPs were degraded in 2 stages, first by cometabolic degradation related to AOB growth, and then by endogenous respiration by microorganisms in the absence of other growth substrate. The compounds were classified into 3 groups according to removal performance and cometabolic degradation. Our approach provides new insight into the removal of PPCPs via cometabolism and endogenous respiration under AOB enrichment cultures developed in MBR. PMID- 28651210 TI - Associations between perfluorinated alkyl acids in blood and ovarian follicular fluid and ovarian function in women undergoing assisted reproductive treatment. AB - Endocrine disrupting contaminants, in combination with other environmental variables, are associated with altered reproductive health. Assisted reproductive technology (ART) procedures offer valuable opportunities to explore the connections between environmental contaminants in the ovarian microenvironment and measures of fertility, including impaired responsiveness to gonadotropins. Here, we investigate an emerging class of environmental contaminants, the perfluorinated alkyl acids (PFAAs), to determine whether ovarian contaminant levels are associated with measures of ovarian responsiveness and fertility outcomes in a South Carolina population of women undergoing ART. Levels of PFAAs in plasma and follicular fluid samples collected from women undergoing ovarian stimulation were analyzed by liquid chromatography tandem mass spectrometry (LC MS/MS). Six PFAAs were detected in both plasma and follicular fluid. PFAA concentrations in plasma correlate strongly to those detected in ovary and, with the exception of one compound, remain stable throughout ovarian stimulation. The concentration of PFHxS in follicular fluid inversely relates to baseline follicle counts. While no significant relationships were detected between ovarian response measures and PFAA concentrations, we identified a negative relationship between follicular fluid PFDA and PFuNA and blastocyst conversion rates. Our assessments indicate that plasma levels of PFAAs serve as a sound proxy of those in the ovarian compartment and that follicular fluid levels of specific PFAA compounds are inversely related to important clinical measures of reproductive health including baseline follicle count and post-fertilization success. PMID- 28651211 TI - Effect of insulin degludec versus insulin glargine on glycemic control and daily fasting blood glucose variability in insulin-naive Japanese patients with type 2 diabetes: I'D GOT trial. AB - AIMS: Insulin degludec (IDeg) is an ultra-long-acting insulin that has a smooth time/action profile over more than 42h. The present study compared the effects of IDeg and insulin glargine (IGlar) on HbA1c reduction and on within-subject day-to day variability of fasting blood glucose (FBG) in insulin-naive patients with type 2 diabetes. SUBJECTS AND METHODS: Eligible patients were randomly allocated at a 3:1 ratio to receive once-daily IDeg (n=31) or IGlar (n=12). Both basal insulins were administered before breakfast and titrated to achieve a target FBG <110mg/dl. The primary endpoints were the change in HbA1c from baseline to 24weeks of treatment, as well as the standard deviation (SD) and coefficient of variation (CV) of FBG from 8 to 12weeks and from 20 to 24weeks. Secondary endpoints included the QOL evaluated by the Diabetes Therapy-Related QOL questionnaire. RESULTS: After 24weeks, HbA1c was decreased by 1.6% in the IDeg group and 1.7% in the IGlar at the same insulin dosage. At 24weeks, FBG was significantly lower in the IDeg group than in the IGlar group and the CV of FBG was significantly smaller in the IDeg group. The frequency of total and severe hypoglycemic episodes did not differ between the groups. In the IDeg group, QOL showed significant improvement regarding anxiety and dissatisfaction with treatment. CONCLUSIONS: Treatment with IDeg or IGlar achieved similar improvement in glycemic control in insulin-naive patients with type 2 diabetes. The day-to day variation of FBG was smaller in patients receiving IDeg. PMID- 28651212 TI - AR C-106T gene polymorphism and diabetic nephropathy in the Eastern Asians with T2DM: A meta-analysis including 2120 subjects. AB - BACKGROUND: Aldose reductase (AR) gene C-106T polymorphism may be associated with diabetic nephropathy (DN) susceptibility, but the results of individual studies remain controversial. OBJECTIVE AND METHODS: To explore the relationship between AR gene C-106T gene polymorphism and DN in the Eastern Asians with type 2 diabetes mellitus (T2DM) population, we conducted a meta-analysis of 2120 participants from 5 studies. Pooled odds ratio (ORs) and the corresponding 95% confidence interval (95% CI) were evaluated by either a fixed or random-effects models. RESULTS: AR C-106T gene polymorphism was significantly associated with DN in the Eastern Asians population with T2DM under allelic (OR: 1.81, 95% CI: 1.30 2.52, P=0.0005), recessive (OR: 1.88, 95% CI: 1.20-2.97, P=0.006), dominant (OR: 9.22, 95% CI: 2.73-31.12, P=0.0003), homozygous (OR:2.27, 95% CI: 1.43-3.61, P=0.0005), heterozygous (OR: 5.75, 95% CI: 1.96-16.81, P=0.001), and additive genetic models (OR: 2.27, 95% CI: 1.48-3.48, P=0.0002). CONCLUSIONS: In the Eastern Asians with T2DM, the AR gene C-106T gene polymorphism is correlated with an increased risk of DN. The Eastern Asians with the T allele of AR gene C-106T gene polymorphism might be susceptible to DN. PMID- 28651214 TI - DNA methylation and the preservation of cell identity. AB - DNA methylation is a major epigenetic modification of vertebrate genomes that is mostly associated with transcriptional repression. During embryogenesis, DNA methylation together with other epigenetic factors plays an essential role in selecting and maintaining cell identity. Recent technological advances are now allowing for the exploration of this mark at unprecedented resolution. This has resulted in a wealth of studies describing the developmental roles of DNA methylation in various vertebrate model systems. It is now evident that in certain contexts DNA methylation can act as a key regulator of cell identity establishment, whereas in many other cases the quantity of DNA methylation will merely reflect other upstream regulatory changes. For example, a number of studies have indicated that DNA methylation might be dispensable for pluripotency stages of embryonic development. Nevertheless, targeted deposition and removal of DNA methylation by DNMTs and TET proteins, respectively, appears to be required for vertebrate gastrulation. Here we review the roles of DNA methylation in the establishment and maintenance of cell identity during development, with a special emphasis on insights obtained from in vivo studies. PMID- 28651213 TI - Reward-related frontostriatal activity and smoking behavior among adolescents in treatment for smoking cessation. AB - BACKGROUND: Tobacco use is often initiated during adolescence and continued into adulthood despite desires to quit. A better understanding of the neural correlates of abstinence from smoking in adolescents may inform more effective smoking cessation interventions. Neural reward systems are implicated in tobacco use disorder, and adolescent smokers have shown reduced reward-related ventral striatal activation related to increased smoking. METHODS: The current study evaluated nondrug reward anticipation in adolescent smokers using a monetary incentive delay task in fMRI pre- and post- smoking cessation treatment (n=14). This study tested how changes in neural responses to reward anticipation pre- to post-treatment were related to reduced smoking. An exploratory analysis in a larger sample of adolescents with only pre-treatment fMRI (n=28) evaluated how neural responses to reward anticipation were related to behavioral inhibition and behavioral activation scales. RESULTS: Adolescent smokers showed pre- to post treatment increases in reward anticipation-related activity in the bilateral nucleus accumbens and insula, and medial prefrontal cortex, and greater increases in reward anticipation-related activity were correlated with larger percent days of smoking abstinence during treatment. CONCLUSIONS: These findings suggest that reduced smoking during smoking cessation treatment is associated with a "recovery of function" in frontostriatal responses to nondrug reward anticipation in adolescent smokers, although comparison with a developmental control group of adolescent nonsmokers is warranted. PMID- 28651215 TI - Anticipatory postural adjustment patterns during gait initiation across the adult lifespan. AB - Gait initiation involves a complex sequence of anticipatory postural adjustments (APAs) during the transition from steady state standing to forward locomotion. APAs have four core components that function to accelerate the center of mass forwards and towards the initial single-support stance limb. These components include loading of the initial step leg, unloading of the initial stance leg, and excursion of the center of pressure in the posterior and lateral (towards the stepping leg) directions. This study examined the incidence, magnitude, and timing of these components and how they change across the lifespan (ages 20-79). 157 individuals performed five trials of self-paced, non-cued gait initiation on an instrumented walkway. At least one component of the APA was absent in 24% of all trials. The component most commonly absent was loading of the initial step leg (absent in 10% of all trials in isolation, absent in 10% of trials in conjunction with another missing component). Trials missing all four components were rare (1%) and were observed in both younger and older adults. There was no significant difference across decades in the incidence of trials without an APA, the number or type of APA components absent, or the magnitude or timing of the APA components. These data demonstrate that one or more components of the APA sequence are commonly absent in the general population and the spatiotemporal profile of the APA does not markedly change with ageing. PMID- 28651216 TI - Ultra-sensitive suspended atomically thin-layered black phosphorus mercury sensors. AB - The extraordinary properties of black phosphorus (BP) make it a promising candidate for next-generation transistor chemical sensors. However, BP films reported so far are supported on substrate, and substrate scattering drastically deteriorates its electrical properties. Consequentially, the potential sensing capability of intrinsic BP is highly underestimated and its sensing mechanism is masked. Additionally, the optimum sensing regime of BP remains unexplored. This article is the first demonstration of suspended BP sensor operated in subthreshold regime. BP exhibited significant enhancement of sensitivity for ultra-low-concentration mercury detection in the absence of substrate, and the sensitivity reached maximum in subthreshold regime. Without substrate scattering, the suspended BP device demonstrated 10 times lower 1/f noise which contributed to better signal-to-noise ratio. Therefore, rapid label-free trace detection of Hg2+ was achieved with detection limit of 0.01 ppb, lower than the world health organization (WHO) tolerance level (1 ppb). The time constant for ion detection extracted was 3s. Additionally, experimental results revealed that good stability, repeatability, and selectivity were achieved. BP sensors also demonstrated the ability of detecting mercury ions in environment water samples. The underling sensing mechanism of intrinsic BP was ascribed to the carrier density variation resulted from surface charge gating effect, so suspended BP in subthreshold regime with optimum gating effect demonstrated the best sensitivity. Our results show the prominent advantages of intrinsic BP as a sensing material. PMID- 28651217 TI - Modeling in-sewer transformations at catchment scale - implications on drug consumption estimates in wastewater-based epidemiology. AB - To which extent illicit drugs are transformed during in-sewer transport, depends on a number of factors: i) substance-specific transformation rates, ii) environmental conditions, iii) point of discharge (location of drug user) and iv) sewer network properties, primarily hydraulic residence time (HRT) and the ratio of biofilm contact area to wastewater volume (A/Veq). Assessing associated uncertainties typically requires numerous simulations. Therefore, we propose a new two-step modeling framework: 1) Quantify hydrodynamic conditions. This computationally demanding step was performed once in SWMM to derive HRT and A/Veq for each potential point of discharge (node) in three catchments of different size. 2) Estimate biomarker loss. In this step, Monte Carlo simulations were performed for defined scenarios. Depending on assumptions about drug user distribution and prevalence, a number of nodes was sampled. For each node an empirical first-order transformation model was applied with flow-path corresponding HRT and A/Veq from step 1. Biotic and abiotic transformation rates were sampled from distributions combining variability of different biofilms. In our modeling study, median losses were >30% for amphetamine, 6-monoacetylmorphine and 6-acetylcodeine in all three catchments with high uncertainty (5%-100% loss), which would imply a systematic underestimation of consumption when neglecting in sewer processes. Median losses for 21 other investigated biomarkers were <10% with different uncertainty ranges - "no substantial transformation" was confirmed for nine substances in a real sewer segment with a 2-h residence time. Transferability of these results must be tested for other catchments. To further reduce uncertainty, mainly additional knowledge on transformation rates, particularly in biofilm, and their distribution across a sewer network is needed to update model input objectively. Our approach allows efficient testing and, furthermore, can be expanded for many other human biomarkers. Accounting for biomarker stability during in-sewer transport will avoid biased estimates and further improve wastewater-based epidemiology. PMID- 28651218 TI - Urban water metabolism indicators derived from a water mass balance - Bridging the gap between visions and performance assessment of urban water resource management. AB - Improving resource management in urban areas has been enshrined in visions for achieving sustainable urban areas, but to date it has been difficult to quantify performance indicators to help identify more sustainable outcomes, especially for water resources. In this work, we advance quantitative indicators for what we refer to as the 'metabolic' features of urban water management: those related to resource efficiency (for water and also water-related energy and nutrients), supply internalisation, urban hydrological performance, sustainable extraction, and recognition of the diverse functions of water. We derived indicators in consultation with stakeholders to bridge this gap between visions and performance indicators. This was done by first reviewing and categorising water-related resource management objectives for city-regions, and then deriving indicators that can gauge performance against them. The ability for these indicators to be quantified using data from an urban water mass balance was also examined. Indicators of water efficiency, supply internalisation, and hydrological performance (relative to a reference case) can be generated using existing urban water mass balance methods. In the future, indicators for water-related energy and nutrient efficiencies could be generated by overlaying the urban water balance with energy and nutrient data. Indicators of sustainable extraction and recognising diverse functions of water will require methods for defining sustainable extraction rates and a water functionality index. PMID- 28651219 TI - A 20-Year multi-followup longitudinal study assessing whether antipsychotic medications contribute to work functioning in schizophrenia. AB - To assess the long-term effectiveness of antipsychotic medications in facilitating work functioning in patients with schizophrenia we conducted longitudinal multifollowup research on 139 initially psychotic patients. The 70 patients with schizophrenia and 69 initially psychotic mood disordered control patients were followed up 6 times over 20 years. We compared the influence on work functioning of patients with schizophrenia continuously prescribed antipsychotics with patients with schizophrenia not prescribed antipsychotics, using statistical controls for inter-subject differences. While antipsychotics reduce or eliminate flagrant psychosis for most patients with schizophrenia at acute hospitalizations, four years later and continually until the 20 year followups, patients with schizophrenia not prescribed antipsychotics had significantly better work functioning. The work performance of the patients who were continuously prescribed antipsychotics was at a low rate and did not improve over time. Multiple other factors also interfere with work functioning. The data suggest that some patients with schizophrenia not prescribed antipsychotics for prolonged periods can function relatively well. Multiple other factors are associated with poor post-hospital work performance. The longitudinal data raise questions about prolonged treatment of schizophrenia with antipsychotic medications. PMID- 28651220 TI - Clozapine versus other antipsychotics during the first 18 weeks of treatment: A retrospective study on risk factor increase of blood dyscrasias. AB - Blood dyscrasias excluding agranulocytosis received limited attention in antipsychotic-treated patients during the first 18 weeks of therapy, although severe clinical conditions have been reported in a few cases. We extracted data records of 285 Caucasian patients after 18 weeks of antipsychotic treatments to investigate risk factors of blood dyscrasias. We observed a higher risk to develop both transient and persistent anemia, neutrophilia and eosinophilia in clozapine-treated patients, whereas in those treated with other atypical antipsychotics when compared to a reference group under typical antipsychotics, emerged an increased risk for transient neutrophilia and eosinophilia. Male patients revealed a higher risk of persistent eosinophilia, neutrophilia, and leukocytosis. Concomitant treatments with mood stabilizers or benzodiazepines proved to be risk factors for transient anemia, antidepressants for transient eosinophilia. Severe complications emerged in 3 cases of agranulocytosis. Cross tabulation analysis showed a higher probability of a poor response in clozapine treated patients with persistent anemia and a positive with persistent neutrophilia and eosinophilia. Our data evidenced that emerging blood dyscrasias were not associated with critical adverse effects, and only agranulocytosis required a treatment interruption. Other atypical antipsychotics might represent a viable alternative to potentially harmful clozapine and typical antipsychotics at the onset of life-threatening haematological alterations. PMID- 28651221 TI - Risk element immobilization/stabilization potential of fungal-transformed dry olive residue and arbuscular mycorrhizal fungi application in contaminated soils. AB - The use of biotransformed dry olive residue (DOR) as organic soil amendment has recently been proposed due to its high contents of stabilized organic matter and nutrients. The potential of biotransformed DOR to immobilize risk elements in contaminated soils might qualify DOR as a potential risk element stabilization agent for in situ soil reclamation practices. In this experiment, the mobility of risk elements in response to Penicillium chrysogenum-10-transformed DOR, Funalia floccosa-transformed DOR, Bjerkandera adusta-transformed DOR, and Chondrostereum purpureum-transformed DOR as well as arbuscular mycorrhizal fungi (AMF), Funneliformis mosseae, inoculation was investigated. We evaluated the effect of these treatments on risk element uptake by wheat (Triticum aestivum L.) plants in a pot experiment with Cd, Pb, and Zn contaminated soil. The results showed a significant impact of the combined treatment (biotransformed DOR and AMF inoculation) on wheat plant growth and element mobility. The mobile proportions of elements in the treated soils were related to soil pH; with increasing pH levels, Cd, Cu, Fe, Mn, P, Pb, and Zn mobility decreased significantly (r values between -0.36 and -0.46), while Ca and Mg mobility increased (r = 0.63, and r = 0.51, respectively). The application of biotransformed DOR decreased risk element levels (Cd, Zn), and nutrient concentrations (Ca, Cu, Fe, Mg, Mn) in the aboveground biomass, where the elements were retained in the roots. Thus, biotransformed DOR in combination with AMF resulted in a higher capacity of wheat plants to grow under detrimental conditions, being able to accumulate high amounts of risk elements in the roots. However, risk element reduction was insufficient for safe crop production in the extremely contaminated soil. PMID- 28651222 TI - Assessing habitat quality in relation to the spatial distribution of protected areas in Italy. AB - The conservation of species and habitats is increasingly threatened by anthropogenic impacts, particularly land use change, from local to global scales. Although many efforts have been carried out so far to halt or at least reduce the biodiversity loss (e.g., the establishment of protected areas' networks), there are still both knowledge and policy gaps slowing the conservation of species and habitats in complex environments, such as the Mediterranean region. In particular, the human-driven impacts and threats on biodiversity need more careful analysis. Accordingly, this paper aims to assess the habitat quality and degradation in Italy in relation with the spatial pattern of the current protected areas' network, mainly to identify priority areas of intervention, thus supporting large-scale conservation strategies. A survey of experts was conducted to identify the main threats for biodiversity from different land uses at the national scale. The InVEST software was then applied to assess and map habitat quality and degradation with a high spatial resolution (20 m). The relationship between habitat quality and degradation as well as their hotspots, and alternative PA categories were also explored. Results indicate that: (i) habitat quality and degradation depend on the location and intensity of the anthropogenic impacts and are sensitive to different protection levels; (ii) the combination of the survey of experts and the spatially-explicit assessment of habitat quality and degradation is useful to highlight variations of the current conditions of biodiversity and habitats; and (iii) the identification of hotspots allows one to identify priority areas for conservation. Accordingly, the proposed approach may be used to strengthen the conservation efforts in similar contexts, and thus support the implementation of the biodiversity-related policies over the long term. PMID- 28651223 TI - Impact of wastewater derived dissolved interfering compounds on growth, enzymatic activity and trace organic contaminant removal of white rot fungi - A critical review. AB - White-rot fungi (WRF) and their ligninolytic enzymes have been investigated for the removal of a broad spectrum of trace organic contaminants (TrOCs) mostly from synthetic wastewater in lab-scale experiments. Only a few studies have reported the efficiency of such systems for the removal of TrOCs from real wastewater. Wastewater derived organic and inorganic compounds can inhibit: (i) WRF growth and their enzyme production capacity; (ii) enzymatic activity of ligninolytic enzymes; and (iii) catalytic efficiency of both WRF and enzymes. It is observed that essential metals such as Cu, Mn and Co at trace concertation (up to 1 mM) can improve the growth of WRF species, whereas non-essential metal such as Pb, Cd and Hg at 1 mM concentration can inhibit WRF growth and their enzyme production. In the case of purified enzymes, most of the tested metals at 1-5 mM concentration do not significantly inhibit the activity of laccases. Organic interfering compounds such as oxalic acid and ethylenediaminetetraacetic acid (EDTA) at 1 mM concentration are potent inhibitors of WRF and their extracellular enzymes. However, inhibitory effects induced by interfering compounds are strongly influenced by the type of WRF species as well as experimental conditions (e.g., incubation time and TrOC type). In this review, mechanisms and factors governing the interactions of interfering compounds with WRF and their ligninolytic enzymes are reviewed and elucidated. In addition, the performance of WRF and their ligninolytic enzymes for the removal of TrOCs from synthetic and real wastewater is critically summarized. PMID- 28651224 TI - Patterns of everyday functioning in preschool children born preterm and at term. AB - BACKGROUND/AIM: Children born preterm are at risk of neonatal complications but the long-term consequences for everyday functioning is not well known. The study aimed to identify patterns of everyday functioning in preschool children born preterm and at term in relation to perinatal data, neonatal risk factors, behaviour, and socioeconomic status. Registry data and data from parent rated questionnaires were collected for 331 children. METHOD: A person-oriented approach with a cluster analysis was used. RESULTS: A seven cluster solution explained 65.91% of the variance. Most children (n=232) showed patterns of strong everyday functioning. A minority of the children (n=99), showed diverse patterns of weak everyday functioning. Perinatal characteristics, neonatal risk factors and socio-economics did not predict cluster group membership. Children born preterm were represented in all clusters. CONCLUSION, IMPLICATIONS: Most preschool children are perceived by their parents with strong everyday functioning despite being born preterm. However small groups of children are, for various reasons, perceived with weak functioning, but preterm birth is not the sole contributor to patterns of weak everyday functioning. More critical for all children's everyday functioning is probably the interaction between individual factors, behavioural factors and contextual factors. To gain a broader understanding of children's everyday functioning. Child Health Services need to systematically consider aspects of body function, activity and in addition participation and environmental aspects. PMID- 28651225 TI - Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies. AB - Herein, we described the design and synthesis of a series of pyridazine-3 carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC50 values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC50 = 3.665 +/- 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series. PMID- 28651226 TI - Insight in body dysmorphic disorder (BDD) relative to obsessive-compulsive disorder (OCD) and psychotic disorders: Revisiting this issue in light of DSM-5. AB - INTRODUCTION: In DSM-5, body dysmorphic disorder (BDD) was reclassified under the obsessive-compulsive and related disorders (OCRDs), but little is known about the nature of BDD beliefs. This study aimed to compare level of insight in BDD and consider related implications for DSM-5 classification. METHOD: Participants were 27 BDD, 19 obsessive-compulsive disorder (OCD), and 20 psychosis (SZ) participants as well as 42 non-clinical controls (NC), who completed the Brown Assessment of Beliefs Scale (BABS) and Peters Delusions Inventory (PDI). RESULTS: For total (and most individual) BABS items, BDD and SZ participants scored significantly higher than OCD and NC participants. On the PDI, there were significant group differences in number of questions endorsed, with clinical groups scoring significantly higher than the NC group on dimensions of distress and preoccupation, but not conviction. CONCLUSION: These findings suggest appearance-related concerns in BDD somewhat resemble delusions seen in psychosis (and not OCD), and convey important nosological and therapeutic implications. PMID- 28651227 TI - Double cystic duct preoperatively diagnosed and successfully treated with laparoscopic cholecystectomy: A case report. AB - INTRODUCTION: A single gallbladder with a double cystic duct is a very rare finding. In addition, few cases with this rare condition are preoperatively diagnosed. However, the preoperative confirmation or suspicion of this rare condition could facilitate safe laparoscopic cholecystectomy, which is a minimally invasive therapeutic modality for gallbladder disease. We herein present a case of gallstone disease in a patient with a double cystic duct who was preoperatively diagnosed and successfully treated with laparoscopic cholecystectomy. PRESENTATION OF CASE: A 57-year-old woman was admitted to our hospital with epigastric pain. Gallstone disease in the gallbladder and common bile duct was diagnosed by ultrasonography and computed tomography. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiography (ERC) revealed that the aberrant cystic duct arose from the cystic duct and communicated with the intrahepatic bile duct of the posterior segmental branch. Laparoscopic cholecystectomy was successfully performed in combination with intraoperative cholangiography. DISCUSSION: If an anomaly of the biliary duct system is not identified during surgery, it may turn out to be a bile leak. The preoperative diagnosis of a double cystic duct allows laparoscopic cholecystectomy to be performed safely in combination with intraoperative cholangiography. CONCLUSIONS: A single gallbladder with double cystic duct is a very rare anomaly. However, laparoscopic surgery can be facilitated by the use of preoperative and intraoperative images. PMID- 28651228 TI - Ante situm liver resection with inferior vena cava replacement under hypothermic cardiopolmunary bypass for hepatoblastoma: Report of a case and review of the literature. AB - INTRODUCTION: Hepatoblastoma with tumour thrombi extending into inferior-vena cava and right atrium are often unresectable with an extremely poor prognosis. The surgical approach is technically challenging and might require major liver resection with vascular reconstruction and extracorporeal circulation. However, which is the best surgical technique is yet unclear. PRESENTATION OF CASE: A 11 months-old boy was referred for a right hepatic lobe mass(90*78mm) suspicious of hepatoblastoma with tumoral thrombi extending into the inferior-vena-cava and the right atrium, bilateral lung lesions and serum alpha-fetoprotein level of 50.795IU/mL. After 8 months of chemotherapy (SIOPEL 2004-high-risk-Protocol), the lung lesions were no longer clearly visible and the hepatoblastoma size decreased to 61*64mm. Thus, ante situm liver resection was planned: after hepatic parenchymal transection, hypothermic cardiopulmonary bypass was started and en bloc resection of the extended-right hepatic lobe, the retro/suprahepatic cava and the tumoral trombi was performed with concomitant cold perfusion of the remnant liver. The inferior-vena-cava was replaced with an aortic graft from a blood-group compatible cadaveric donor. The post-operative course was uneventful and after 8 months of follow-up the child has normal liver function and an alpha fetoprotein level and is free of disease recurrence with patent vascular graft. CONCLUSIONS: We report for the first time a case of ante situ liver resection and inferior-vena-cava replacement associated with hypothermic cardiopulmonary bypass in a child with hepatoblastoma. Herein, we extensively review the literature for hepatoblastoma with thumoral thrombi and we describe the technical aspects of ante situm approach, which is a realistic option in otherwise unresectable hepatoblastoma. PMID- 28651229 TI - Coverage of complex defects of the shoulder girdle and posterior neck triangle following tumor resection. AB - INTRODUCTION: Numerous pedicle and free flaps have been used to cover complex defects of the shoulder girdle and posterior neck triangle following tumor resection. We describe our choice of flap selection in these patients with case examples. PRESENTATION OF CASES: Three cases examples demonstrate our choice of flap selection. In the first case, an anterior shoulder girdle defect is covered by an anteriorly transposed latissimus dorsi muscle flap. The second case demonstrates the coverage of a posterior shoulder girdle defect by a posteriorly transposed latissimus dorsi muscle flap. Finally, the third case demonstrates the coverage of a posterior triangle neck defect using a superiorly transposed pectoralis major muscle flap. All reconstructions utilize muscle flaps (covered by split-thickness skin grafts) and not myocutaneous flaps. DISCUSSION: We demonstrate that these two pedicle muscle flaps are adequate for coverage of large complex defects of the shoulder girdle and posterior neck triangle. We also demonstrate the advantages of using muscle rather than myocutaneous flaps. CONCLUSION: Pedicle latissimus dorsi and pectoralis major muscle flaps are simpler and preferred over free flaps for coverage of complex defects of the shoulder girdle and posterior neck triangle. The use of muscle rather than myocutaneous flaps will reduce the size of the original defect, make flap design easier and reduce donor site morbidity. PMID- 28651230 TI - Comparative proteomic and metabolomic studies between Prunus persica genotypes resistant and susceptible to Taphrina deformans suggest a molecular basis of resistance. AB - The worldwide-distributed leaf peach curl disease is caused by the biotroph Taphrina deformans. To characterize the plant-fungus interaction, resistant and susceptible Prunus persica genotypes grown in the orchard were studied. Asymptomatic leaves were tested for fungal presence. In all resistant leaves analyzed the fungus was not detected. Conversely, leaves from the susceptible genotype were categorized according to the presence or absence of the pathogen. Comparative metabolomic analysis disclosed the metabolite composition associated with resistant and susceptible interactions, and of compounds involved in fungal growth inhibition such as chlorogenic acid, whose in vitro antifungal activity was verified in this work. Differential proteome studies revealed that chloroplasts are important site of plant defense responses against T. deformans. Members of the Bet-v1-like family protein differentially responded to the pathogen. Extracellular pathogenesis-related proteins, evaluated by qRT-PCR, and an enone oxidoreductase are constitutively present in leaves of resistant trees and could be related to fungal resistance. This study is a global view of the changes in the metabolome, proteome and transcripts related to plant defense in naturally infected leaves of susceptible plants during the asymptomatic stage. Additionally, it provides clues to the successful molecular mechanisms operating in resistant plants, which neither develop the disease nor harbor the pathogen. PMID- 28651231 TI - Evaluation of in vitro anticancer activity of 1,8-Cineole-containing n-hexane extract of Callistemon citrinus (Curtis) Skeels plant and its apoptotic potential. AB - Plants are the source of a variety of secondary metabolites, which are often used in the anticancer activity. Discovering new anticancer drug from herbal source is more important in both biological and pharmacological activities. Hence, the objective of this study is to identify the anticancer agent in Callistemon citrinus (Curtis) Skeels (CC) for the treatment of cancer. Very recently we have reported an increased antioxidant activity in the ethanolic and methanolic extracts (EE and ME) of CC but significantly reduced activity (rather increased cytotoxicity), in the n-hexane extract (HE). In this study, the cytotoxicity of all the three solvent extracts was tested against A431, MG-63 and HaCaT cell lines by MTT assay. Interestingly HE has showed increased anti-proliferative effect against the cancer cells but was resisted by non-malignant cells. HPLC and GC-MS analysis revealed the presence of 1,8-Cineole as a predominant compound in HE, the semi-purified bioactive extract. Henceforth, this would be called HE-C and be used for further analyses to understand its mode of action on induced apoptosis/necrosis. Alamar blue assay of HE-C showed cytotoxicity and change in morphological characteristics, which was confirmed by AO/EB staining using fluorescence microscopy, ultra-structural features of apoptosis using SEM and TEM. HE-C induced cell death was also detected by FACS using FITC-labelled Annexin-V and Propidium iodide. ROS generation was monitored using DCF-DA by flow cytometry. The overall results suggested that the selective extract (HE-C) containing 1,8-Cineole has shown potential anti-cancer activity in a dose dependent manner, and cell death was induced through ROS-mediated apoptosis. Our findings provide an insight into the potential of 1,8-Cineole as a novel drug for killing cancer cells. PMID- 28651232 TI - Silymarin prevents NLRP3 inflammasome activation and protects against intracerebral hemorrhage. AB - Inflammatory response mediates secondary injury during intracerebral hemorrhage (ICH). In the present study, we determined oxidative stress and involvement of NLRP3 in ICH injury and analyzed whether silymarin might offer protective effect against ICH injury. Post 24h after ICH injury there was increased oxidative stress markers (reactive oxygen species (ROS) and lipid peroxides) compared to sham group. Silymarin (200mg/kg) treatment 30 mins post ICH injury prevented increase in oxidative stress markers and up-regulated antioxidant status. Further, there was significant increase in nuclear levels of NF-kappaB-p65 and pro-inflammatory cytokine expressions post ICH injury. NLRP3 inflammasome activation and downstream targets such as caspase-1 and IL-1beta expressions were significantly up regulated in ICH injury. Silymarin treatment significantly down regulated the inflammatory responses by suppressing NF-kappaB-p65 levels and inflammasome-mediated caspase-1/IL-1beta expressions. Further, treatment with silymarin post ICH injury increased Nrf-2/HO-1 and thereby improved overall cytoprotection. These findings together show that silymarin acts as neuroprotective compound by preventing inflammatory activation and up regulating Nrf-2/HO-1 signaling post ICH injury. PMID- 28651233 TI - Terminalia bellirica (Gaertn.) Roxb. fruit mitigates CCl4 induced oxidative stress and hepatotoxicity in rats. AB - Terminalia bellirica (Gaertn.) Roxb. is a medicinal plant used for the treatment of various ailments in the traditional system of medicine like Ayurveda where it has been prescribed as a rejuvenator and general health tonic. The fruit of the plant is one of the components of the age old ayurvedic formulation-'Triphala'. The present study evaluates curative effect of aqueous acetone extract of Terminalia bellirica fruits (AATB) against CCl4 induced oxidative stress and liver damage in an animal model. Two doses of the fruit extract (200mg/kg body weight and 400mg/kg body weight) were investigated for the beneficial effects. At the end of the treatment, liver function markers (ALT, AST, ALP, GGT, LDH, total bilirubin, total protein, albumin, globulin, albumin-globulin ratio) as well as hepatic oxidative stress markers (SOD, CAT, GSH) were evaluated. Treatment with AATB significantly restored the parameters towards normal level as compared to the elevated biochemical markers in the CCl4 treated animals. Reversal to normal tissue architecture was observed in histological evaluation. The results of AATB (400mg/kg) were found comparable with that of standard drug silymarin in all the parameters. The above findings suggest the therapeutic potential of the plant in alleviating hepatic oxidative stress and tissue damage, hence the traditional use of the plant in this regard stands justified. PMID- 28651234 TI - MicroRNA-493 suppresses hepatocellular carcinoma tumorigenesis through down regulation of anthrax toxin receptor 1 (ANTXR1) and R-Spondin 2 (RSPO2). AB - Hepatocellular carcinoma (HCC) is known as a highly prevalent cancer with a poor prognosis and short survival time, despite intensive research and clinical efforts. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of hepatocellular carcinoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we report that the expression of microRNA-493 (miR-493) is decreased in HCC cell lines and in tumor tissues. Overexpression of miR-493 in HCC cells dramatically inhibited cell proliferation and colony-formation in vitro and inhibited tumor formation of HCC cell xenografts in vivo. miR-493 also suppressed cell migration and invasion in HCC cell lines. Novel targets ANTXR1 and RSPO2 were confirmed to be suppressed by miR-493 directly, and overexpression of ANTXR1 and RSPO2 could restore tumorigenesis in miR-493 treated HCC cell. Moreover, Wnt/beta-catenin signaling pathway, which was reported to be activated by ANTXR1 and RSPO2, was also inhibited by miR-493 overexpression and might be involved in anti-tumor function of miR-493. These findings suggest that miR-493 acts as a negative regulator in hepatocellular carcinoma progression and may be a potential therapeutic target for HCC. PMID- 28651235 TI - Alpinumisoflavone inhibits osteoclast differentiation and exerts anti osteoporotic effect in ovariectomized mice. AB - Alpinumisoflavone (AIF), a naturally occurring flavonoid compound exacted from Derris eriocarpa, has been found to have a number of pharmacological activities. However, its role in bone disorder has not been investigated. The aim of this study is to evaluate the osteoprotective effect of AIF on ovariectomy-induced bone loss in mice model and related underlying mechanisms. Our study provides experimental evidence that AIF could regulate the remodeling process of bone and exert osteoprotective effect against ovariectomy-induced bone loss. Moreover, our results show that AIF suppresses osteoclast differentiation by attenuating RANKL induced activation of p38, ERK and JNK pathways and consequently represses the expression of c-Fos and NFATc1. PMID- 28651236 TI - Tanshinone I alleviates insulin resistance in type 2 diabetes mellitus rats through IRS-1 pathway. AB - Tanshinone I from tanshen has been used in traditional Chinese medicine for treating cardiovascular diseases and inflammatory diseases. Given the link between inflammation and Type 2 diabetes mellitus (T2DM), we suspect that tanshinone I may have a beneficial effect on T2DM. This study was to investigate the potential effects of tanshinone I on T2DM and its underlying mechanism. T2DM was thus induced in Sprague-Dawley (SD) rats using streptozotocin (STZ) and high fat diet. It was observed that T2DM rats had higher levels of total cholesterol (TC), nonesterified fatty acids (NEFAs), total triglyceride (TG) and total low density lipoprotein cholesterol (LDL-C) compared with normal, healthy SD rats. Treatment with tanshinone I decreased these levels and lowered blood glucose level in T2DM rats. In addition, enzyme-linked immunosorbent assay (ELISA) analysis showed that T2DM rats had elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Furthermore, Western blot analysis revealed that T2DM rats had enhanced nuclear translocation of NF-kappaB as well as elevated phosphorylation of Ser307 in IRS-1(insulin receptor substrate 1). Treatment by tanshinone I lowered the levels of IL-6 and TNF-alpha, decreased nuclear translocation of NF-kappaB as well as phosphorylation of Ser307 in IRS-1. These results demonstrated that tanshinone I could alleviate T2DM syndrome in rats. PMID- 28651237 TI - The many postures of noncanonical Wnt signaling in development and diseases. AB - Wnt signaling regulates many aspects of vertebrate development. Its dysregulation causes developmental defects and diseases including cancer. The signaling can be categorized in two pathways: canonical and noncanonical. Canonical pathway plays a key role in regulating proliferation and differentiation of cells whilst noncanonical Wnt signaling mainly controls cellular polarity and motility. During development, noncanonical Wnt signaling is required for tissue formation. Recent studies have shown that noncanonical Wnt signaling is involved in adult tissue development and cancer progression. In this review, we try to describe and discuss the mechanisms behind the biological effects of noncanonical Wnt signaling, diseases caused by its dysregulation, and implications in adult tissue development biology. PMID- 28651238 TI - Inducible nitric oxide synthase: Good or bad? AB - Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Expression of inducible NOS (iNOS) occurs in conditions of inflammation, and produces large amounts of NO. In pathological conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases of the cardiovascular system such as atherosclerosis. In this review, we address the notion that iNOS is a detrimental enzyme in disease and discuss its potentially beneficial roles. Additionally, we describe other molecules associated with iNOS in diseases such as atherosclerosis, and current research on therapeutic inhibitors tested to reduced pathology associated with cardiovascular diseases (CVD). PMID- 28651239 TI - Cardiaprotective effect of crocetin by attenuating apoptosis in isoproterenol induced myocardial infarction rat model. AB - Given study evaluates the cardioprotective effect of crocetin in myocardial infracted (MI) rats. MI was produced by administering isoproterenol (90mg/kg/day, i.p.) in rats for two consecutive days. all the animals were divided in to four groups such as control group receives only saline; MI group which receives only isoproterenol and crocetin treated group which receives crocetin (50, 100 and 200mg/kg/day, p.o.) for the duration of 15 days. At the end of dosing left ventricular functions was assessed to estimate its effect on cardiac functions. Catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), creatine kinase (CK-MB), lactate dehydrogenase (LDH) and inflammatory cytokines were determined in the cardiac tissue homogenate. Histopathology study was also carried out using hematoxylin and eosin staining. Immunohistochemistry was done for the estimation of Caspase-3, Bcl-2, Bax and Nrf-2 level in the myocardial tissues of MI rats. Result of the study suggested that GSH, CAT, CK MB, and LDH were (p<0.01) increased in the tissue homogenate of crocetin treated group than MI group. However crocetin significantly (p<0.01) decreases the level of MDA and activity of SOD in the tissue homogenate than MI group. It was observed that treatment with crocetin attenuates the level of inflammatory cytokines in the myocardial tissues of MI rats. Moreover level of caspase-3, Bax and Nrf-2 significantly reduced and Bcl-2 enhanced in the myocardial tissues of MI rats than MI group. The altered cellular architecture of heart tissue sections in the myocardial infracted rats were reversed by administration of crocetin treatment. Taking all these data together, it may be suggested that the crocetin act as a possible protective agent in myocardial infarction by decreasing oxidative stress and inflammatory cytokines and thereby attenuates the apoptosis of myocardial cells. PMID- 28651240 TI - Indirect spectrophotometric determination of sulfadiazine based on localized surface plasmon resonance peak of silver nanoparticles after cloud point extraction. AB - A novel, efficient, easy to use, environmentally friendly and cost-effective methodology is developed for the indirect spectrophotometric determination of sulfadiazine in different samples. The method is based on the micelle-mediated extraction of silver sulfadiazine and converting the silver content of the resultant surfactant-rich phase to the silver nanoparticles via generation of [Ag(NH3)2]+ followed by its chemical reduction using ascorbic acid. The changes in the amplitude of localized surface plasmon resonance peak of silver nanoparticles as a function of sulfadiazine concentration in the sample solution was monitored using fiber optic linear array spectrophotometry at 457nm. The experimental conditions were thoroughly investigated and optimized. Under the optimized condition, the developed procedure showed dynamic linear calibration within the range of 10.0-800.0MUgL-1 with a detection limit of 2.8MUgL-1 for sulfadiazine. The relative standard deviation of the method for six replicate measurements at 150.0MUgL-1 of sulfadiazine was 4.7%. The developed method was successfully applied to the determination of sulfadiazine in different samples including well water, human urine, milk and pharmaceutical formulation. PMID- 28651241 TI - Al-based metal-organic gels for selective fluorescence recognition of hydroxyl nitro aromatic compounds. AB - The novel class of luminescent Al3+-based metal-organic gels (Al-MOGs) have been developed by mix 4-[2,2':6',2"-terpyridine]-4'-ylbenzoic acid (Hcptpy) with Al3+ under mild condition. The as-prepared Al-MOGs have not only multiple stimuli responsive properties, but selective recognition of hydroxyl nitro aromatic compounds, which can quench the fluorescence of the Al-MOGs, while other nitro aromatic analogues without hydroxyl substitutes cannot. The fluorescence of Al MOGs at 467nm was seriously quenched by picric acid (PA) whose lowest unoccupied molecular orbital (LUMO) energy levels are lower than those of three other hydroxyl nitro aromatic compounds including 4-nitrophenol (4-NP), 3,5 dinitrosalicylic acid (3,5-DNTSA) and 2,4-dinitrophenol (2,4-DNP). Thus, PA was chosen as a model compound under optimal conditions and the relative fluorescence intensity of Al-MOGs was proportional to the concentration of PA in the range of 5.0-320.0MUM with a detection limit of 4.64MUM. Furthermore, the fluorescence quenching mechanism has also been investigated and revealed that the quenching was attributed to inner filter effects (IFEs), as well as electron transfer (ET) between Al-MOGs and PA. PMID- 28651242 TI - Chalcogen substitution: Effect of oxygen-by-sulfur exchange on structural and spectroscopic properties of flavonols. AB - Quantum chemical calculations using density functional theory have revealed that the substitution of the ketone group by a thioketone one doesn't significantly change the structure of 3-hydroxyflavone. Notably, the strong intramolecular hydrogen bond involving the hydroxyl function is preserved if the O atom is substituted by an S atom, but also by Se or Te atoms. However, fundamental modifications are observed in both absorption and emission electronic spectra upon substitution, particularly the non-fluorescent behavior of the flavothione. All these changes were explained by the optimizations of the different excited states carried out by time-dependent DFT method. PMID- 28651243 TI - Structure of the LPS O-chain from Fusobacterium nucleatum strain 12230. AB - Fusobacterium nucleatum is an anaerobic bacterium found in the human mouth where it causes periodontitis. It was also found in colorectal cancer tissues and is linked with pregnancy complications, including pre-term and still births. Cell surface structures of the bacterium could be implicated in pathogenesis. Here we report the following structure of the lipopolysaccharide O-chain of F. nucleatum strain 12230: -6-alpha-d-Glc-4-beta-d-GlcNHBu3NHBuA-3-beta-d-QuiNAc4NABu- where ABu and HBu indicate (R)-3-aminobutanoyl and (R)-3-hydroxybutanoyl, respectively; all monosaccharides are in the pyranose form. PMID- 28651244 TI - The health policy implications of individual adaptive behavior responses to smog pollution in urban China. AB - Smog pollution is a serious public health issue in urban China, where it is associated with public health through a range of respiratory and cardiovascular illnesses. Despite the negative health impacts of smog pollution, individual adaptive behaviors are poorly understood. This knowledge gap hinders the development of effective public policy to support and encourage the adoption of individual adaptive and mitigating behaviors to smog pollution. A questionnaire survey of 1141 randomly sampled individuals in a typical PM2.5-polluted Chinese city was designed to establish smog concerns and behavior changes during smog events. The results demonstrate a variety of behavior responses associated with risk perception, experience of smog, age, and gender of respondents. An understanding of these variations is critical to the development of effective public policy and ultimately to the improvement of public health in cities affected by smog. PMID- 28651246 TI - Development of a Perfusion Platform for Dynamic Cultivation of in vitro Skin Models. AB - Reconstructed skin models are suitable test systems for toxicity testing and for basic investigations on (patho-)physiological aspects of human skin. Reconstructed human skin, however, has clear limitations such as the lack of immune cells and a significantly weaker skin barrier function compared to native human skin. Potential reasons for the latter might be the lack of mechanical forces during skin model cultivation which is performed classically in static well-plate setups. Mechanical forces and shear stress have a major impact on tissue formation and, hence, tissue engineering. In the present work, a perfusion platform was developed allowing dynamic cultivation of in vitro skin models. The platform was designed to cultivate reconstructed skin at the air-liquid interface with a laminar and continuous medium flow below the dermis equivalent. Histological investigations confirmed the formation of a significantly thicker stratum corneum compared to the control cultivated under static conditions. Moreover, the skin differentiation markers involucrin and filaggrin as well as the tight junction proteins claudin 1 and occludin showed increased expression in the dynamically cultured skin models. Unexpectedly, despite improved differentiation, the skin barrier function of the dynamically cultivated skin models was not enhanced compared with the skin models cultivated under static conditions. PMID- 28651245 TI - High-resolution hyperpolarized in vivo metabolic 13C spectroscopy at low magnetic field (48.7mT) following murine tail-vein injection. AB - High-resolution 13C NMR spectroscopy of hyperpolarized succinate-1-13C-2,3-d2 is reported in vitro and in vivo using a clinical-scale, biplanar (80cm-gap) 48.7mT permanent magnet with a high homogeneity magnetic field. Non-localized 13C NMR spectra were recorded at 0.52MHz resonance frequency over the torso of a tumor bearing mouse every 2s. Hyperpolarized 13C NMR signals with linewidths of ~3Hz (corresponding to ~6ppm) were recorded in vitro (2mL in a syringe) and in vivo (over a mouse torso). Comparison of the full width at half maximum (FWHM) for 13C NMR spectra acquired at 48.7mT and at 4.7T in a small-animal MRI scanner demonstrates a factor of ~12 improvement for the 13C resonance linewidth attainable at 48.7mT compared to that at 4.7T in vitro. 13C hyperpolarized succinate-1-13C resonance linewidths in vivo are at least one order of magnitude narrower at 48.7mT compared to those observed in high-field (>=3T) studies employing HP contrast agents. The demonstrated high-resolution 13C in vivo spectroscopy could be useful for high-sensitivity spectroscopic studies involving monitoring HP agent uptake or detecting metabolism using HP contrast agents with sufficiently large 13C chemical shift differences. PMID- 28651247 TI - A Prospective Comparison of Selective Multiparametric Magnetic Resonance Imaging Fusion-Targeted and Systematic Transrectal Ultrasound-Guided Biopsies for Detecting Prostate Cancer in Men Undergoing Repeated Biopsies. AB - INTRODUCTION: The aim of the study was to compare the prostate cancer (PCa) detection rate of systematic transrectal ultrasound-guided biopsies (TRUS-bx) and multiparametric-MRI targeted biopsies (mp-MRI-bx) in a repeat biopsy setting and evaluate the clinical significance following an "MRI-targeted-only" approach. MATERIALS AND METHODS: Patients with prior negative biopsies underwent prostatic multiparametric-MRI that was scored using the Prostate Imaging Reporting and Data System (PI-RADS) classification. All underwent both repeated TRUS-bx and mp-MRI bx using image fusion of any PI-RADS >=3 lesion. Biopsy results from TRUS-bx, mp MRI-bx, and the combination were compared. RESULTS: PCa was detected in 89 out of 206 (43%) patients. Of these, 64 (31%) and 74 (36%) patients were detected using mp-MRI-bx and TRUS-bx, respectively. Overall, mp-MRI-bx detected fewer patients with low-grade (Gleason score [GS] 3 + 3) cancers (14/64 vs. 41/74) and more patients with intermediate/high-grade cancers (GS >=3 + 4) (50/64 vs. 33/74) using fewer biopsy cores compared with TRUS-bx (p < 0.001). Using an "MRI targeted-only" approach in men with PI-RADS >=3 lesions reduced the number of men requiring repeated biopsies by 50%, decreased low-grade cancer diagnoses by 66%, and increased intermediate/high-grade cancer diagnoses by 52%. CONCLUSIONS: MRI targeted biopsies have a high detection rate for significant PCa in patients with prior negative transrectal ultrasound-guided biopsies and preferentially detect intermediate/high-grade compared with low-grade tumors. PMID- 28651248 TI - Evaluation of Plasma Thrombomodulin in Patients with Coronary Slow Flow. AB - BACKGROUND: It has been reported that coronary slow flow (CSF) is associated with acute myocardial infarction, ventricular tachycardia, ventricular fibrillation, and even sudden cardiac death. Although studies concerning the etiopathogenesis of CSF are scarce, diffuse atherosclerosis and endothelial dysfunction are thought to play important roles. It has been suggested that a high plasma thrombomodulin (TM) level seems to play an important role in the pathogenesis of atherosclerosis and endothelial dysfunction. OBJECTIVES: We hypothesized that a high plasma TM level might be associated with CSF and aimed to research the relationship between plasma TM level and CSF. METHODS: Fifty-two CSF patients with angiographically proven CSF and 44 cases with normal coronary flow were included in this study. Coronary flow velocity was determined by the thrombolysis in myocardial infarction (TIMI) frame count method. Plasma TM levels were measured in all the study subjects. RESULTS: Plasma TM levels were significantly higher in the CSF group compared to the control group (3.9 +/- 0.5 vs. 3.6 +/- 0.3 ng/mL, p = 0.01). There was a positive relationship (r = 0.31, p = 0.002) between plasma TM level and mean TIMI frame count (TFC). Factors associated with mean TFC were plasma TM level (beta = 0.206, p = 0.038) and red cell distribution width (beta = 0.088, p = 0.009) in multiple linear regression analysis. CONCLUSIONS: Patients with CSF have a higher plasma TM level, and this may play an important role in the pathogenesis of CSF. An elevated plasma TM level may be a predictor of CSF. Future studies are needed to confirm these results. PMID- 28651249 TI - Administration of the Mitochondrial Permeability Transition Pore Inhibitor, TRO40303, prior to Primary Percutaneous Coronary Intervention, Does Not Affect the Levels of Pro-Inflammatory Cytokines or Acute-Phase Proteins. AB - OBJECTIVES: In the MITOCARE study, reperfusion injury was not prevented after administration of the mitochondrial permeability transition pore (mPTP) opening inhibitor, TRO40303, in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The effects of TRO40303 on pro-inflammatory cytokines and acute-phase proteins were assessed. METHODS: STEMI patients (n = 163, mean age 62 years) with chest pain within 6 h before admission for pPCI were randomized to intravenous bolus of TRO40303 (n = 83) or placebo (n = 80) prior to reperfusion. We tested whether the groups differed in levels of IL-1beta, IL-6, IL-10, TNF, and high-sensitive C reactive protein at various time points (0, 12, and 72 h) after PCI. Further, potential differences between groups in the change of biomarker levels between 0 and 72 h, 0 and 12 h, and 12 and 72 h were tested. RESULTS: There were no statistically significant differences between the two groups, neither in levels of pro-inflammatory cytokines nor in levels of acute-phase proteins, and there were no statistically significant differences in the change of biomarker levels between the groups considering the time intervals from 0 to 72 h, from 0 to 12 h, and from 12 to 72 h. CONCLUSION: The administration of the mPTP, TRO40303, prior to reperfusion does not alter the pharmacokinetics of pro-inflammatory cytokines or acute-phase proteins during the first 72 h after PCI. PMID- 28651250 TI - A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity. AB - BACKGROUND: Alpha-synuclein (alphaS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of alphaS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. alphaS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked alphaS to immune cell activation in the central nervous system. We hypothesized that alphaS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract. METHODS: We immunostained endoscopic biopsies for alphaS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether alphaS exhibited immune-modulatory activity, we examined whether human alphaS induced leukocyte migration and dendritic cell maturation. FINDINGS: We showed that the expression of alphaS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of alphaS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric alphaS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of alphaS stimulate dendritic cell maturation. INTERPRETATION: These findings strongly suggest that alphaS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD. PMID- 28651251 TI - Electrical Potential of Leaping Eels. AB - When approached by a large, partially submerged conductor, electric eels (Electrophorus electricus) will often defend themselves by leaping from the water to directly shock the threat. Presumably, the conductor is interpreted as an approaching terrestrial or semiaquatic animal. In the course of this defensive behavior, eels first make direct contact with their lower jaw and then rapidly emerge from the water, ascending the conductor while discharging high-voltage volleys. In this study, the equivalent circuit that develops during this behavior was proposed and investigated. First, the electromotive force and internal resistance of four electric eels were determined. These values were then used to estimate the resistance of the water volume between the eel and the conductor by making direct measurements of current with the eel and water in the circuit. The resistance of the return path from the eel's lower jaw to the main body of water was then determined, based on voltage recordings, for each electric eel at the height of the defensive leap. Finally, the addition of a hypothetical target for the leaping defense was considered as part of the circuit. The results suggest the defensive behavior efficiently directs electrical current through the threat, producing an aversive and deterring experience by activating afferents in potential predators. PMID- 28651252 TI - Combined Diffusion Tensor and Magnetic Resonance Spectroscopic Imaging Methodology for Automated Regional Brain Analysis: Application in a Normal Pediatric Population. AB - During human brain development, anatomic regions mature at different rates. Quantitative anatomy-specific analysis of longitudinal diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI) data may improve our ability to quantify and categorize these maturational changes. Computational tools designed to quickly fuse and analyze imaging information from multiple, technically different datasets would facilitate research on changes during normal brain maturation and for comparison to disease states. In the current study, we developed a complete battery of computational tools to execute such data analyses that include data preprocessing, tract-based statistical analysis from DTI data, automated brain anatomy parsing from T1-weighted MR images, assignment of metabolite information from MRSI data, and co-alignment of these multimodality data streams for reporting of region-specific indices. We present statistical analyses of regional DTI and MRSI data in a cohort of normal pediatric subjects (n = 72; age range: 5-18 years; mean 12.7 +/- 3.3 years) to establish normative data and evaluate maturational trends. Several regions showed significant maturational changes for several DTI parameters and MRSI ratios, but the percent change over the age range tended to be small. In the subcortical region (combined basal ganglia [BG], thalami [TH], and corpus callosum [CC]), the largest combined percent change was a 10% increase in fractional anisotropy (FA) primarily due to increases in the BG (12.7%) and TH (9%). The largest significant percent increase in N-acetylaspartate (NAA)/creatine (Cr) ratio was seen in the brain stem (BS) (18.8%) followed by the subcortical regions in the BG (11.9%), CC (8.9%), and TH (6.0%). We found consistent, significant (p < 0.01), but weakly positive correlations (r = 0.228-0.329) between NAA/Cr ratios and mean FA in the BS, BG, and CC regions. Age- and region-specific normative MR diffusion and spectroscopic metabolite ranges show brain maturation changes and are requisite for detecting abnormalities in an injured or diseased population. PMID- 28651253 TI - Association of IL-6 Gene (-174 and -572 G/C) Polymorphisms with Proliferative Diabetic Retinopathy of Type 2 Diabetes in a Chinese Population. AB - PURPOSE: To investigate the association of interleukin (IL)-6 with proliferative diabetic retinopathy (PDR) of type 2 diabetes (T2D) in a Chinese population. METHODS: Two subtypes of the IL-6 promoter (-174 and -572 G/C) were genotyped in 215 T2D patients with PDR and 207 T2D patients with a normal retinal function (controls) using the PCR-RFLP method. The mRNA and protein expression of IL-6 was examined by real-time PCR. RESULTS: T2D patients with PDR had a significantly higher frequency of IL-6 -174 GC (OR 0.58; 95% CI 0.34-0.99; p = 0.011) and IL-6 572 GG (OR 0.53; 95% CI 0.24-1.14; p = 0.016) than T2D controls. The mRNA expressions of the rs1800795 GC and rs1800796 GG genotype were significantly increased compared to other cases (Fsig = 0.002, p = 0.001, respectively), followed by a relative increase in IL-6 in protein. CONCLUSIONS: IL-6 genotypes of rs1800795 GC and rs1800796 GG might point to a relatively high risk for T2D patients suffering from PDR in a Chinese population and they were associated with elevation of IL-6 expression in both mRNA and protein. PMID- 28651254 TI - A Preliminary Study of a Spanish Graphic Novella Targeting Hearing Loss Prevention. AB - Purpose: This preliminary study developed a digital graphic novella targeting hearing protection beliefs of Spanish-speaking agricultural workers. Researchers used pretest-posttest interview surveys to establish if the novella had an immediate influence on the participants' beliefs about noise-induced hearing loss and usage of hearing protection devices. Method: Researchers developed a digital graphic novella directed to increase knowledge about noise-induced hearing loss and increase the proper use of hearing protection devices. The novella was tailored to meet the specific linguistic and literacy needs of Spanish-speaking agricultural workers. Thirty-one Spanish-speaking farmworkers of Mexican nationality participated. This study included an interview survey with specific questions on noise-induced hearing loss, myths, and hearing protection device usage. A pretest-posttest design was applied to measure the graphic novella's immediate influence on workers. Results: The posttest scores on Hearing Protection Beliefs statements were significantly better than pretest scores, with a large effect size observed. Conclusion: Digital media may be an effective way to overcome language and literacy barriers with Spanish-speaking workers when providing health education and prevention efforts. PMID- 28651255 TI - Visual Cues Contribute Differentially to Audiovisual Perception of Consonants and Vowels in Improving Recognition and Reducing Cognitive Demands in Listeners With Hearing Impairment Using Hearing Aids. AB - Purpose: We sought to examine the contribution of visual cues in audiovisual identification of consonants and vowels-in terms of isolation points (the shortest time required for correct identification of a speech stimulus), accuracy, and cognitive demands-in listeners with hearing impairment using hearing aids. Method: The study comprised 199 participants with hearing impairment (mean age = 61.1 years) with bilateral, symmetrical, mild-to-severe sensorineural hearing loss. Gated Swedish consonants and vowels were presented aurally and audiovisually to participants. Linear amplification was adjusted for each participant to assure audibility. The reading span test was used to measure participants' working memory capacity. Results: Audiovisual presentation resulted in shortened isolation points and improved accuracy for consonants and vowels relative to auditory-only presentation. This benefit was more evident for consonants than vowels. In addition, correlations and subsequent analyses revealed that listeners with higher scores on the reading span test identified both consonants and vowels earlier in auditory-only presentation, but only vowels (not consonants) in audiovisual presentation. Conclusion: Consonants and vowels differed in terms of the benefits afforded from their associative visual cues, as indicated by the degree of audiovisual benefit and reduction in cognitive demands linked to the identification of consonants and vowels presented audiovisually. PMID- 28651256 TI - The Cardiovascular and Perceptual Response to Very Low Load Blood Flow Restricted Exercise. AB - This study sought to compare cardiovascular and perceptual responses to blood flow restriction (BFR) exercise using various pressure and load combinations. Fourteen participants completed four sets of BFR elbow flexion using 10, 15 and 20% 1RM with 40 and 80% arterial occlusion pressure (AOP). AOP was measured before and after exercise. Perceived exertion (RPE) and discomfort were assessed before exercise and after each set. Data presented as mean (95% CI), except for RPE and discomfort: 25th, 50th, 75th percentiles. AOP increased post-exercise (p<0.001) with larger magnitudes seen when increasing load and pressure (p<0.001) [e. g., 10/40 DeltaAOP: 21 (10, 32) mmHg vs. 20/80 DeltaAOP: 62 (45, 78) mmHg], which also augmented RPE (p<0.001) [e. g., 4th set 10/40: (7, 8.5, 12) vs. 4th set 20/80: (12.75, 15.5, 17.25)] and discomfort (p<0.001) [e. g., 4th set 10/40: (0.75, 2, 4.25) vs. 4th set 20/80: (4.25, 6, 8,)]. Volume increased via greater loads (p<0.001), and participants only reached failure during 20% 1RM conditions [20/40: 74 (74, 75) repetitions; 20/80: 71 (68, 75) repetitions]. When performing BFR exercise with very low loads the magnitudes of the cardiovascular and perceptual responses are augmented by increasing the load and by applying a higher relative pressure. PMID- 28651257 TI - Angles, Traction, and Time after Delivery of Fetal Head: Interobserver Variation of Novel Visual Analogs. PMID- 28651258 TI - A Randomized Trial of Foley Balloon Induction of Labor Trial in Multiparas (FIAT M). PMID- 28651259 TI - New Biguanides as Anti-Diabetic Agents Part I: Synthesis and Evaluation of 1 Substituted Biguanide Derivatives as Anti-Diabetic Agents of Type II Diabetes Insulin Resistant. AB - New 1-substituted-biguanide hydrochloride salts were synthesized via reacting benzo[1,3-d]dioxol-5-amine, phenylhydrazine, N,N-dimethylhydrazinecarboxamide, benzohydrazide and 2-phenyl acetohydrazide with dicyandiamide in acidic medium. Structures of the obtained biguanide salts were characterized by spectroscopic tools. The synthesized compounds were screened for their anti-diabetic activity with standard metformin drug. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives significantly decreased the elevated blood glucose level. Additionally, anti-diabetic properties towards liver function enzyme activities (AST, ALT and ALP), lipids profiles (TC, TG and TL), lipid peroxide and nitrous oxide as well as histopathological studies relative to metformin hydrochloride were investigated and discussed. PMID- 28651260 TI - The CDD System in Computed Tomographic Diagnosis of Diverticular Disease. AB - Purpose This overview sums up the Classification of Diverticular Disease (CDD) with regard to its application in computed tomographic diagnosis and briefly recapitulates its targeted advantages over preliminary systems. Primarily, application of the CDD in computed tomography diagnostics is described. Differences with respect to the categories of the older systems are pointed out on the level of each CDD type using imaging examples. Materials and Methods The presented images are derived from our institute according to the S2k criteria. Literature was researched on PubMed. Results The CDD constitutes an improvement compared to older systems for categorizing the stages of diverticular disease. It provides more discriminatory power on the descriptive-morphological level and defines as well as differentiates more courses of the disease. Furthermore, the categories translate more directly into state-of-the-art decision-making concerning hospitalization and therapy. Conclusion The CDD should be applied routinely in the computed tomographic diagnosis of diverticular disease. Typical imaging patterns are presented. Key points . The CDD is superior to its predecessors. It better stratifies categories of diverticular disease by morphology, course and modern options for treatment of the disease.. . Computed tomography is the dominant imaging modality. Different stages show typical imaging patterns.. . Non-abscessed phlegmonous peridiverticulitis is now interpreted as an uncomplicated course.. . Minimal paracolic air does not constitute a full-fledged perforation in terms of a pneumoperitoneum (CDD type 2c).. Citation Format . Pustelnik D, Elsholtz FH, Bojarski C et al. The CDD System in Computed Tomographic Diagnosis of Diverticular Disease. Fortschr Rontgenstr 2017; 189: 740 - 747. PMID- 28651261 TI - Evaluation of the Value of Contrast-Enhanced Ultrasound (CEUS) within Radiology Departments in Germany. AB - Purpose Contrast-enhanced ultrasound (CEUS) has been established for many years and has become an increasingly important cornerstone of the diagnostic imaging of various organ systems. However, this modality is rarely performed by radiologists and is primarily employed by other medical disciplines. The goal of this questionnaire study is to present the current value of CEUS in radiology and to encourage reevaluation of the method within this medical discipline. Materials and Methods 560 directors of radiology departments throughout Germany were contacted and given a 3-page questionnaire. The questionnaire included 37 questions on 5 different topics (general structures, CEUS and interdisciplinarity, CEUS in pediatric radiology, education/professional development, outlook) to assess the value of ultrasound (US) and in particular CEUS in radiology. Results The response rate was 42.3 %. A statistical analysis of the answers was performed, including subgroup analysis. Overall, it could be shown that CEUS is performed in comparatively few radiology departments (26.6 %), while the current value of the modality is given an average to high range of importance even by radiologists. More than half of all participating radiologists (54.9 %) would like this method to be included in the requirements catalog for the specialist examination. Conclusion The nationwide questionnaire to evaluate CEUS within radiology departments in Germany had a very high response rate, which reflects the assessment of this topic by radiologists. There is a substantial discrepancy between the currently low utilization of CEUS in radiology and the high ranking of CEUS by many radiologists. The analyses of the replies point out important aspects of professional policy regarding this topic within the radiology community. Key points . The high response rate reflects the assessment of this topic by radiologists.. . The questionnaire study depicts the currently low use of CEUS in radiology.. . CEUS is given a high range of importance by radiologists.. Citation Format . Graeter T, Kratzer W, Seufferlein T et al. Evaluation of the Value of Contrast-Enhanced Ultrasound (CEUS) within Radiology Departments in Germany. Fortschr Rontgenstr 2017; 189: 748 - 759. PMID- 28651262 TI - Relationship of Radiographic Osteoarthritis Severity with Treatment Outcomes after Imaging-Guided Knee Injections: A Prospective Outcomes Study. AB - INTRODUCTION: To be able to predict which patients are more likely to have a positive treatment outcome, the purpose of this study is 1: To compare outcomes after intra-articular corticosteroid knee injections with the Kellgren and Lawrence (KL) 5 and 3 grading systems for knee osteoarthritis, the Osteoarthritis Research Society International (OARSI) grading system and actual joint space measurements; and 2: To compare the reliability of these grading systems. MATERIALS AND METHODS: Knee radiographs of 117 patients who received intra articular corticosteroid injections were independently evaluated by two radiologists blinded to the outcome. Evaluation included the KL5, KL3, OARSI systems and actual joint space widths. The numerical rating scale for pain was collected at baseline and along with the Patient's Global Impression of Change on day 1, in week 1 and in month 1. The number of 'improved' patients was compared between the OA grades using the Chi-square test. Logistic regression determined which findings were predictive for improvement. Agreement was assessed using Kappa statistics and the intraclass correlation coefficient (ICC). RESULTS: Patients with OARSI grade 2 reported the highest rates of 'improvement' at all time points, which was significant on day 1 (p = 0.004). No relationship with improvement was found with KL5, KL3 or actual joint space measurements. Patients with OARSI grade 2 were 8 times more likely to report improvement on day 1 (p = 0.024). Reliability was best for joint space measurements (ICC = 0.812 - 0.882), followed by the OARSI. CONCLUSION: The OARSI for joint space narrowing grade 2 (34 - 66 % narrowing) was linked with a better outcome on day 1 with trends in week 1 and month 1. The reliability of the OARSI was better than the KL5 or KL3 systems. KEY POINTS: . OARSI grading of OA had better reliability than KL3 or KL5.. . OARSI grade 2 was related to a better treatment outcome.. . Neither KL grades nor joint space measurements were related to improvement.. CITATION FORMAT: . Miletic I, Agten C, Sutter R et al. Relationship of Radiographic Osteoarthritis Severity with Treatment Outcomes after Imaging-Guided Knee Injections: A Prospective Outcomes Study. Fortschr Rontgenstr 2018; 190: 134 - 143. PMID- 28651264 TI - [Inpatient-Equivalent Treatment According to S 115d SGB V - A First Step Towards Various Treatments in Home Environment]. PMID- 28651263 TI - Quality and Dose Optimized CT Trauma Protocol - Recommendation from a University Level-I Trauma Center. AB - Purpose As a supra-regional level-I trauma center, we evaluated computed tomography (CT) acquisitions of polytraumatized patients for quality and dose optimization purposes. Adapted statistical iterative reconstruction [(AS)IR] levels, tube voltage reduction as well as a split-bolus contrast agent (CA) protocol were applied. Materials and Methods 61 patients were split into 3 different groups that differed with respect to tube voltage (120 - 140 kVp) and level of applied ASIR reconstruction (ASIR 20 - 50 %). The CT protocol included a native acquisition of the head followed by a single contrast-enhanced acquisition of the whole body (64-MSCT). CA (350 mg/ml iodine) was administered as a split bolus injection of 100 ml (2 ml/s), 20 ml NaCl (1 ml/s), 60 ml (4 ml/s), 40 ml NaCl (4 ml/s) with a scan delay of 85 s to detect injuries of both the arterial system and parenchymal organs in a single acquisition. Both the quantitative (SNR/CNR) and qualitative (5-point Likert scale) image quality was evaluated in parenchymal organs that are often injured in trauma patients. Radiation exposure was assessed. Results The use of IR combined with a reduction of tube voltage resulted in good qualitative and quantitative image quality and a significant reduction in radiation exposure of more than 40 % (DLP 1087 vs. 647 mGyxcm). Image quality could be improved due to a dedicated protocol that included different levels of IR adapted to different slice thicknesses, kernels and the examined area for the evaluation of head, lung, body and bone injury patterns. In synopsis of our results, we recommend the implementation of a polytrauma protocol with a tube voltage of 120 kVp and the following IR levels: cCT 5mm: ASIR 20; cCT 0.625 mm: ASIR 40; lung 2.5 mm: ASIR 30, body 5 mm: ASIR 40; body 1.25 mm: ASIR 50; body 0.625 mm: ASIR 0. Conclusion A dedicated adaptation of the CT trauma protocol (level of reduction of tube voltage and of IR) according to the examined body region (head, lung, body, bone) combined with a split bolus CA injection protocol allows for a high-quality CT examination and a relevant reduction of radiation exposure in the examination of polytraumatized patients Key Points . Dedicated adaption of the CT trauma protocol allows for an optimized examination.. . Different levels of iterative reconstruction, tube voltage and the CA injection protocol are crucial.. . A reduction of radiation exposure of more than 40 % with good image quality is possible.. Citation Format . Kahn J, Kaul D, Boning G et al. Quality and Dose Optimized CT Trauma Protocol - Recommendation from a University Level-I Trauma Center. Fortschr Rontgenstr 2017; 189: 844 - 854. PMID- 28651265 TI - [Imaging in Cranial Nerve Neuritis by Lyme-Neuroborreliosis]. PMID- 28651277 TI - ? PMID- 28651279 TI - ? PMID- 28651276 TI - White Paper: Interventional MRI: Current Status and Potential for Development Considering Economic Perspectives, Part 1: General Application. AB - Background MRI is attractive for the guiding and monitoring of interventional procedures due to its high intrinsic soft tissue contrast and the possibility to measure physiologic parameters like flow and cardiac function. Method The current status of interventional MRI for the clinical routine was analyzed. Results The effort needed for the development of MR-safe monitoring systems and instruments initially resulted in the application of interventional MRI only for procedures that could not be performed by other means. Accordingly, biopsy of lesions in the breast, which are not detectable by other modalities, has been performed under MRI guidance for decades. Currently, biopsies of the prostate under MRI guidance are established in a similar fashion. At many sites blind biopsy has already been replaced by MR-guided biopsy or at least by the fusion of MR images with ultrasound. Cardiovascular interventions are performed at several centers for ablation as a treatment for atrial fibrillation. Conclusion Interventional MRI has been established in the clinical routine for a variety of indications. Broader application can be expected in the clinical routine in the future owing to the multiple advantages compared to other techniques. Key points . Due to the significant technical effort, MR-guided interventions are only recommended in the long term for regions in which MRI either facilitates or greatly improves the intervention.. . Breast biopsy of otherwise undetectable target lesions has long been established in the clinical routine. Prostate biopsy is currently being introduced in the clinical routine for similar reasons. Other methods such as MR guided focused ultrasound for the treatment of uterine fibroids or tumor ablation of metastases represent alternative methods and are offered in many places.. . Endovascular MR-guided interventions offer advantages for a number of indications and have already been clinically established for the treatment of children with congenital heart defects and for atrial ablation at individual centers. Greater application can be expected in the future.. Citation format . Barkhausen J, Kahn T, Krombach GA et al. White Paper: Interventional MRI: Current Status and Potential for Development Considering Economic Perspectives, Part 1: General Application. Fortschr Rontgenstr 2017; 189: 611 - 623. PMID- 28651287 TI - ? PMID- 28651286 TI - ? PMID- 28651288 TI - Development of a High-Performance Liquid Chromatographic Method for Asiaticoside Quantification in Different Skin Layers after Topical Application of a Centella asiatica Extract. AB - The topical application of Centella asiatica extract has been commonly used for many different purposes but especially for cosmetic use in the treatment of gynoid lipodystrophy. Asiaticoside, the most active component in this extract, is responsible for its therapeutic activities. However, little is known to date about asiaticoside skin penetration. Thus, an analytical method for asiaticoside quantification in different skin layers after the topical application of C. asiatica extract was developed and skin permeation studies were performed with the plant extract to apply the analytical method developed. An extraction procedure to recover asiaticoside from the biological matrix was also developed. Asiaticoside was assayed by HPLC/UV (high-performance liquid chromatography ultraviolet detection) using a gradient of ACN (acetonitrile) and 0.2% phosphoric acid (flow rate of 1.0 mL/min). The analytical procedure was validated according to U. S. Food and Drug Administration guidelines. Selectivity was shown, as endogenous skin components did not interfere with the asiaticoside peak. Analytical curve was linear (3 to 60 ug/mL) and the lower limit of quantification was determined (3 ug/mL). Asiaticoside recoveries from skin samples were 95.1% and 66.7% for the stratum corneum and remaining skin, respectively. After 48 h of in vitro permeation studies, a substantial amount of asiaticoside was quantified in the skin layers. The presence of asiaticoside was also detected in the receptor solution of Franz diffusion cells after 48 h (5.81 +/- 1.00 ug/mL). The method was reliable and reproducible for asiaticoside quantification in skin samples, thereby making it possible to determine the cutaneous penetration profile of this drug in permeation studies. PMID- 28651289 TI - A Validated Method for the Quality Control of Andrographis paniculata Preparations. AB - Andrographis paniculata is a herbal drug of Asian traditional medicine largely employed for the treatment of several diseases. Recently, it has been introduced in Europe for the prophylactic and symptomatic treatment of common cold and as an ingredient of dietary supplements. The active principles are diterpenes with andrographolide as the main representative. In the present study, an analytical protocol was developed for the determination of the main constituents in the herb and preparations of A. paniculata. Three different extraction protocols (methanol extraction using a modified Soxhlet procedure, maceration under ultrasonication, and decoction) were tested. Ultrasonication achieved the highest content of analytes. HPLC conditions were optimized in terms of solvent mixtures, time course, and temperature. A reversed phase C18 column eluted with a gradient system consisting of acetonitrile and acidified water and including an isocratic step at 30 degrees C was used. The HPLC method was validated for linearity, limits of quantitation and detection, repeatability, precision, and accuracy. The overall method was validated for precision and accuracy over at least three different concentration levels. Relative standard deviation was less than 1.13%, whereas recovery was between 95.50% and 97.19%. The method also proved to be suitable for the determination of a large number of commercial samples and was proposed to the European Pharmacopoeia for the quality control of Andrographidis herba. PMID- 28651290 TI - Anti-Inflammatory Effects of Boldine and Reticuline Isolated from Litsea cubeba through JAK2/STAT3 and NF-kappaB Signaling Pathways. AB - The anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba were evaluated by using xylene-induced ear edema and carrageenan-induced paw edema in mice and rats. Our results demonstrated that intragastric administration with boldine and reticuline significantly mitigated ear weight in mice and decreased paw volume in rats. A combination administration of boldine (0.5 mg/kg) + reticuline (0.25 mg/kg) resulted in a potentiated inhibition in these two models. In parallel, boldine or reticuline reduce the infiltration of neutrophil leukocytes in rat paw tissue, respectively, and the combination of the two groups performed a better anti-inflammatory activity as shown in histopathologies. Boldine, reticuline, and their combination notably inhibited mRNA expressions of TNF-alpha, and IL-6 and reduced the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Beyond that, their combination also can reduce the phosphorylation levels of p65 and IkappaBalpha in the pathological tissues of animals, as observed by real-time PCR and western blot analyses, respectively. These findings indicate for the first time that boldine and reticuline have not only anti inflammatory activity but also potential synergistic effects in vivo. The underlying mechanism may relate to the inhibition on the expression of pro inflammatory cytokines, such as TNF-alpha and IL-6, which may be a consequence of JAK2/STAT3 and NF-kappaB pathway involvements. This study provides useful data for further exploration and application of boldine and reticuline as potential anti-inflammatory medicines. PMID- 28651291 TI - Development of a Reference Standard Library of Chloroplast Genome Sequences, GenomeTrakrCP. AB - Precise, species-level identification of plants in foods and dietary supplements is difficult. While the use of DNA barcoding regions (short regions of DNA with diagnostic utility) has been effective for many inquiries, it is not always a robust approach for closely related species, especially in highly processed products. The use of fully sequenced chloroplast genomes, as an alternative to short diagnostic barcoding regions, has demonstrated utility for closely related species. The U. S. Food and Drug Administration (FDA) has also developed species specific DNA-based assays targeting plant species of interest by utilizing chloroplast genome sequences. Here, we introduce a repository of complete chloroplast genome sequences called GenomeTrakrCP, which will be publicly available at the National Center for Biotechnology Information (NCBI). Target species for inclusion are plants found in foods and dietary supplements, toxin producers, common contaminants and adulterants, and their close relatives. Publicly available data will include annotated assemblies, raw sequencing data, and voucher information with each NCBI accession associated with an authenticated reference herbarium specimen. To date, 40 complete chloroplast genomes have been deposited in GenomeTrakrCP (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA325670/), and this will be expanded in the future. PMID- 28651292 TI - Acute Onset Neurological Disorders during Pregnancy: A Literature Review. AB - Objectives To characterize the most common peripheral and central neurological disorders during pregnancy. Methods Original research and review of the literature on neurological complications during pregnancy. We searched for keywords related to the topic on different databases. Results Pregnancy involves physiological changes that can trigger peripheral neurological and/or central nervous system pathologies, which can sometimes be associated with hypertensive disorders. A definitive diagnosis of neurological disorders can be made according to the trimester of pregnancy and the clinical findings. Carpal tunnel syndrome and peripheral facial palsy are common peripheral neurological disorders, more frequent in the second half of pregnancy. Central nervous disorders are more complex and a precise diagnosis must be made in order to improve perinatal outcomes, provide correct management and treatment and to prevent acute and long term complications. Conclusions It is possible to achieve a precise diagnosis, management and treatment of neurological disorders during pregnancy, but these require a multidisciplinary approach, crucial to improve perinatal outcomes. PMID- 28651293 TI - [Tuberculosis Guideline for Adults - Guideline for Diagnosis and Treatment of Tuberculosis including LTBI Testing and Treatment of the German Central Committee (DZK) and the German Respiratory Society (DGP)]. AB - Since 2015 a significant increase in tuberculosis cases is notified in Germany, mostly due to rising numbers of migrants connected to the recent refugee crisis. Because of the low incidence in previous years, knowledge on tuberculosis is more and more limited to specialized centers. However, lung specialist and healthcare workers of other fields have contact to an increasing number of tuberculosis patients. In this situation, guidance for the management of standard therapy and especially for uncommon situations will be essential. This new guideline on tuberculosis in adults gives recommendations on diagnosis, treatment, prevention and prophylaxis. It provides a comprehensive overview over the current knowledge, adapted to the specific situation in Germany. The German Central Committee against Tuberculosis (DZK e. V.) realized this guideline on behalf of the German Respiratory Society (DGP). A specific guideline for tuberculosis in the pediatrics field will be published separately. Compared to the former recommendations of the year 2012, microbiological diagnostics and therapeutic drug management were given own sections. Chapters about the treatment of drug resistant tuberculosis, tuberculosis in people living with HIV and pharmacological management were extended. This revised guideline aims to be a useful tool for practitioners and other health care providers to deal with the recent challenges of tuberculosis treatment in Germany. PMID- 28651294 TI - [IgE and Anti-IgE in Asthma: A Chequered History]. AB - A long and winding road led to the discovery of immunoglobulin E (IgE) in 1966 and 1967. We are currently on a long and winding road to understand the immunologic basis of the clinical effects of the anti-IgE antibody omalizumab in asthma. It is possible that patients with asthma (as patients with chronic spontaneous urticaria) benefit in different immunologic ways from omalizumab treatment. This article reviews the history of IgE discovery and current concepts of anti-IgE therapy in asthma. PMID- 28651295 TI - ? PMID- 28651296 TI - Early discharge hospital at home. AB - BACKGROUND: Early discharge hospital at home is a service that provides active treatment by healthcare professionals in the patient's home for a condition that otherwise would require acute hospital inpatient care. This is an update of a Cochrane review. OBJECTIVES: To determine the effectiveness and cost of managing patients with early discharge hospital at home compared with inpatient hospital care. SEARCH METHODS: We searched the following databases to 9 January 2017: the Cochrane Effective Practice and Organisation of Care Group (EPOC) register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, and EconLit. We searched clinical trials registries. SELECTION CRITERIA: Randomised trials comparing early discharge hospital at home with acute hospital inpatient care for adults. We excluded obstetric, paediatric and mental health hospital at home schemes. DATA COLLECTION AND ANALYSIS: We followed the standard methodological procedures expected by Cochrane and EPOC. We used the GRADE approach to assess the certainty of the body of evidence for the most important outcomes. MAIN RESULTS: We included 32 trials (N = 4746), six of them new for this update, mainly conducted in high-income countries. We judged most of the studies to have a low or unclear risk of bias. The intervention was delivered by hospital outreach services (17 trials), community-based services (11 trials), and was co-ordinated by a hospital-based stroke team or physician in conjunction with community-based services in four trials.Studies recruiting people recovering from strokeEarly discharge hospital at home probably makes little or no difference to mortality at three to six months (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.57 to 1.48, N = 1114, 11 trials, moderate-certainty evidence) and may make little or no difference to the risk of hospital readmission (RR 1.09, 95% CI 0.71 to 1.66, N = 345, 5 trials, low-certainty evidence). Hospital at home may lower the risk of living in institutional setting at six months (RR 0.63, 96% CI 0.40 to 0.98; N = 574, 4 trials, low-certainty evidence) and might slightly improve patient satisfaction (N = 795, low-certainty evidence). Hospital at home probably reduces hospital length of stay, as moderate certainty evidence found that people assigned to hospital at home are discharged from the intervention about seven days earlier than people receiving inpatient care (95% CI 10.19 to 3.17 days earlier, N = 528, 4 trials). It is uncertain whether hospital at home has an effect on cost (very low-certainty evidence).Studies recruiting people with a mix of medical conditionsEarly discharge hospital at home probably makes little or no difference to mortality (RR 1.07, 95% CI 0.76 to 1.49; N = 1247, 8 trials, moderate-certainty evidence). In people with chronic obstructive pulmonary disease (COPD) there was insufficient information to determine the effect of these two approaches on mortality (RR 0.53, 95% CI 0.25 to 1.12, N = 496, 5 trials, low-certainty evidence). The intervention probably increases the risk of hospital readmission in a mix of medical conditions, although the results are also compatible with no difference and a relatively large increase in the risk of readmission (RR 1.25, 95% CI 0.98 to 1.58, N = 1276, 9 trials, moderate-certainty evidence). Early discharge hospital at home may decrease the risk of readmission for people with COPD (RR 0.86, 95% CI 0.66 to 1.13, N = 496, 5 trials low-certainty evidence). Hospital at home may lower the risk of living in an institutional setting (RR 0.69, 0.48 to 0.99; N = 484, 3 trials, low-certainty evidence). The intervention might slightly improve patient satisfaction (N = 900, low-certainty evidence). The effect of early discharge hospital at home on hospital length of stay for older patients with a mix of conditions ranged from a reduction of 20 days to a reduction of less than half a day (moderate-certainty evidence, N = 767). It is uncertain whether hospital at home has an effect on cost (very low-certainty evidence).Studies recruiting people undergoing elective surgeryThree studies did not report higher rates of mortality with hospital at home compared with inpatient care (data not pooled, N = 856, low-certainty evidence; mainly orthopaedic surgery). Hospital at home may lead to little or no difference in readmission to hospital for people who were mainly recovering from orthopaedic surgery (N = 1229, low-certainty evidence). We could not establish the effects of hospital at home on the risk of living in institutional care, due to a lack of data. The intervention might slightly improve patient satisfaction (N = 1229, low certainty evidence). People recovering from orthopaedic surgery allocated to early discharge hospital at home were discharged from the intervention on average four days earlier than people allocated to usual inpatient care (4.44 days earlier, 95% CI 6.37 to 2.51 days earlier, , N = 411, 4 trials, moderate certainty evidence). It is uncertain whether hospital at home has an effect on cost (very low-certainty evidence). AUTHORS' CONCLUSIONS: Despite increasing interest in the potential of early discharge hospital at home services as a less expensive alternative to inpatient care, this review provides insufficient evidence of economic benefit (through a reduction in hospital length of stay) or improved health outcomes. PMID- 28651297 TI - Anomalous origin of the left main coronary artery arising from the left ventricular outflow tract with a retro-aortic collateral vessel. PMID- 28651298 TI - Coxiella burnetti-associated thoracic endovascular stent graft infection. PMID- 28651299 TI - Survival Estimates after Stopping Sorafenib in Patients with Hepatocellular Carcinoma: NEXT Score Development and Validation. AB - Background/Aims: Limited information is available regarding patient survival after sorafenib discontinuation in patients with hepatocellular carcinoma (HCC). Thus, we developed and validated a novel survival prediction model. Methods: Clinical data from 409 patients with HCC who stopped taking sorafenib between September 2008 and February 2015 were reviewed. Results: In the training cohort, four factors were independent negative predictors of survival (p<0.05). Based on the beta regression coefficient of each factor, we established the NEXT score (Survival after Stopping Nexavar Treatment), allocating 1 point each for an Eastern Cooperative Oncology Group score >=2, Child-Pugh class B or C, serum sodium <=135 mEq/L, and alpha-fetoprotein >400 ng/mL. Area under the receiver operating characteristic curve values to predict 1-, 3-, and 6-month survival rates were 0.805, 0.809, and 0.774, respectively, in the training cohort and 0.783, 0.728, and 0.673, respectively, in the validation cohort (n=137). When the training and validation cohorts were stratified into three risk groups (NEXT score 0 [low-risk] vs 1 to 2 [intermediate-risk] vs 3 to 4 [high-risk]), survival differed significantly between the groups (p<0.05, log-rank test). Conclusions: In patients with HCC, survival after stopping sorafenib is poor. However, risk estimates based on a new "NEXT score" may help predict survival and prognosis even in patients who discontinue sorafenib treatment. PMID- 28651300 TI - Noninvasive Assessment of Advanced Fibrosis Based on Hepatic Volume in Patients with Nonalcoholic Fatty Liver Disease. AB - Background/Aims: Noninvasive liver fibrosis evaluation was performed in patients with nonalcoholic fatty liver disease (NAFLD). We used a quantitative method based on the hepatic volume acquired from gadoxetate disodium-enhanced (Gd-EOB DTPA-enhanced) magnetic resonance imaging (MRI) for diagnosing advanced fibrosis in patients with NAFLD. Methods: A total of 130 patients who were diagnosed with NAFLD and underwent Gd-EOB-DTPA-enhanced MRI were retrospectively included. Histological data were available for 118 patients. Hepatic volumetric parameters, including the left hepatic lobe to right hepatic lobe volume ratio (L/R ratio), were measured. The usefulness of the L/R ratio for diagnosing fibrosis >=F3-4 and F4 was assessed using the area under the receiver operating characteristic (AUROC) curve. Multiple regression analysis was performed to identify variables (age, body mass index, serum fibrosis markers, and histological features) that were associated with the L/R ratio. Results: The L/R ratio demonstrated good performance in differentiating advanced fibrosis (AUROC, 0.80; 95% confidence interval, 0.72 to 0.88) from cirrhosis (AUROC, 0.87; 95% confidence interval, 0.75 to 0.99). Multiple regression analysis showed that only fibrosis was significantly associated with the L/R ratio (coefficient, 0.121; p<0.0001). Conclusions: The L/R ratio, which is not influenced by pathological parameters other than fibrosis, is useful for diagnosing cirrhosis in patients with NAFLD. PMID- 28651301 TI - Real-World Single-Center Experience with Sofosbuvir-Based Regimens for the Treatment of Chronic Hepatitis C Genotype 1 Patients. AB - Background/Aims: The approval of sofosbuvir (SOF), a direct-acting antiviral, has revolutionized the treatment of chronic hepatitis C virus (HCV). Methods: We assessed the sustained virological response (SVR) of SOF-based regimens in a real world single-center setting for the treatment of chronic HCV genotype 1 (G1) patients. This was a retrospective review of chronic HCV G1 adult patients treated with a SOF-based regimen at Virginia Mason Medical Center between December 2013 and August 2015. Results: The cohort comprised 343 patients. Patients received SOF+ledipasvir (LDV) (n=155), SOF+simeprevir (SIM) (n=154), or SOF+peginterferon (PEG)+ribavirin (RBV) (n=34). Of the patients, 50.1% (n=172) had cirrhosis. The SVR rate was 92.2% for SOF/LDV, 87.0% for SOF/SIM, and 82.4% for SOF/PEG/RBV. Compared with the cirrhotic patients, the patients without cirrhosis had a higher SVR (96.8% vs 85.5%, p=0.01, SOF/LDV; 98.2% vs 80.6%, p=0.002, SOF/SIM; 86.4% vs 75.0%, p=0.41, SOF/PEG/RBV). In this study, prior treatment experience adversely affected the response rate in subjects treated with SOF/PEG/RBV. Conclusions: In this single-center, real-world setting, the treatment of chronic HCV G1 resulted in a high rate of SVR, especially in patients without cirrhosis. PMID- 28651302 TI - Useful Endoscopic Ultrasonography Parameters and a Predictive Model for the Recurrence of Esophageal Varices and Bleeding after Variceal Ligation. AB - Background/Aims: To identify the usefulness of endoscopic ultrasonography with a mini-probe (EUM) and to create a predictive model for esophageal variceal (EV) recurrence and bleeding following esophageal variceal ligation (EVL). Methods: A total of 144 patients who received EUM prior to prophylactic EVL and met the inclusion criteria were enrolled. EUM findings, EV diameter, paraesophageal vein diameter, and the number of perforating veins were assessed. Results: EV recurrence was observed in 42 patients (29.2%), 10 of whom experienced EV bleeding. Larger diameter of the paraesophageal vein (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.17 to 1.96; p=0.002) and perforating vein (OR, 3.27; 95% CI, 1.11 to 9.65; p=0.032) were significant predictive factors for EV recurrence. However, the diameter of the paraesophageal vein was the only significant risk factor for EV bleeding (adjusted OR, 1.51; 95% CI, 1.06 to 2.16; p=0.022). The areas under the curves of the predictive model for EV recurrence and bleeding were 0.872 (95% CI, 0.811 to 0.934) and 0.811 (95% CI, 0.630 to 0.992), respectively. Conclusions: The diameter of the paraesophageal vein was a significant predictive factor for EV recurrence and bleeding. The predictive model constructed based on the significant EUM findings exhibited good performance. PMID- 28651303 TI - Nomograms to Predict the Individual Survival of Patients with Solitary Hepatocellular Carcinoma after Hepatectomy. AB - Background/Aims: Solitary hepatocellular carcinoma (HCC) is a subgroup of HCCs. We aimed to establish nomograms for predicting the survival of solitary HCC patients after hepatectomy. Methods: A total of 538 solitary HCC patients were randomly classified into training and validation sets. A Cox model was used to identify predictors of overall survival (OS) in the training set. A nomogram was generated based on these predictors and was validated using the validation set. Results: Tumor size, microvascular invasion, and major vascular invasion were significantly associated with OS in the training set. Nomograms were developed based on these predictors in the multivariate analysis. The C-index was 0.75 for the OS nomogram and 0.72 for the recurrence-free survival nomogram. Compared to the index of conventional staging systems for predicting survival (0.71 for Barcelona Clinic Liver Cancer, 0.66 for the seventh American Joint Committee on Cancer, 0.68 for Cancer of the Liver Italian Program, and 0.70 for Hong Kong Liver Cancer), the index of the OS nomogram was significantly higher. Moreover, the calibration curve fitted well between the predicted and observed survival rate. Similarly, in the validation set, the nomogram discrimination was superior to those of the four staging systems (p<0.001). Conclusions: The nomograms demonstrated good discrimination performance in predicting 3- and 5-year survival rates for solitary HCCs after hepatectomy. PMID- 28651304 TI - Rifaximin and Propranolol Combination Therapy Is More Effective than Propranolol Monotherapy for the Reduction of Portal Pressure: An Open Randomized Controlled Pilot Study. AB - Background/Aims: Non-selective beta blockers (NSBBs) are currently the only accepted regimen for preventing portal hypertension (PHT)-related complications. However, the effect of NSBBs is insufficient in many cases. Bacterial translocation (BT) is one of the aggravating factors of PHT in cirrhosis; therefore, selective intestinal decontamination by rifaximin is a possible therapeutic option for improving PHT. We investigated whether the addition of rifaximin to propranolol therapy can improve hepatic venous pressure gradient (HVPG) response. Methods: Sixty-four cirrhosis patients were randomly assigned to propranolol monotherapy (n=48) versus rifaximin and propranolol combination therapy (n=16). Baseline and post-treatment HVPG values, BT-related markers (lipopolysaccharide [LPS], LPS-binding protein [LBP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNF-alpha]), serological data, and adverse event data were collected. HVPG response rate was the primary endpoint. Results: Combination therapy was associated with better HVPG response rates than monotherapy (56.2% vs 87.5%, p=0.034). In combination therapy, posttreatment BT related markers were significantly decreased (LPS, p=0.005; LBP, p=0.005; IL-6, p=0.005; TNF-alpha, p=0.047). Conclusions: Rifaximin combination therapy showed an additive effect in improving PHT compared to propranolol monotherapy. These pilot data suggest that the addition of rifaximin to NSBBs could be a good therapeutic option for overcoming the limited effectiveness of NSBBs. PMID- 28651305 TI - Effects of Entecavir and Tenofovir on Renal Function in Patients with Hepatitis B Virus-Related Compensated and Decompensated Cirrhosis. AB - Background/Aims: The renal effects of nucleos(t)ide analogs in patients with chronic hepatitis B are controversial. We aimed to compare the impact of entecavir (ETV) and tenofovir (TDF) on renal function in patients with hepatitis B virus (HBV)-related cirrhosis. Methods: We performed a retrospective cohort study of 235 consecutive treatment-naive patients with HBV-related cirrhosis who were treated with ETV or TDF between December 2012 and November 2013 at Severance Hospital, Seoul, Korea. Results: Compensated cirrhosis was noted in 183 patients (ETV 130, TDF 53), and decompensated cirrhosis was noted in 52 patients (ETV 32, TDF 20). There were no significant changes in estimated glomerular filtration rates (eGFR) from baseline in either the ETV- or TDF-treated groups at week 96 (Chronic Kidney Disease Epidemiology Collaboration, ETV -1.68% and TDF -5.03%, p=0.358). Using a multivariate analysis, the significant factors associated with a decrease in eGFR >20% were baseline eGFR, diabetes mellitus (DM), and the use of diuretics. The use of antiviral agents and baseline decompensation were not determined to be significant factors. Conclusions: In patients with HBV-related cirrhosis, TDF has shown similar renal safety to that of ETV over a 2-year period. Renal function should be closely monitored, especially in patients who exhibit decreasing eGFR, DM, and the use of diuretics. PMID- 28651307 TI - Role of Shear Wave Elastography in Evaluating the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B. AB - Background/Aims: To investigate the use of measurements of liver stiffness (LS) by two-dimensional real-time shear wave elastography (SWE) for predicting the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Methods: We retrospectively collected data on 291 enrolled patients with CHB whose LS had been measured using SWE. Results: The mean age of the patients was 46.8 years; males predominated (67%), and 40 of the patients (14%) had clinical cirrhosis. Among the patients, 165 (56.7%) received antiviral treatment. The median LS value was 7.4 kPa, and the median follow-up period was 35.8 months (range, 3.0 to 52.8 months). During follow-up, HCC developed in 13 patients (4.5%), and the cumulative incidence rates of HCC at 1, 2, and 4 years were 1.1%, 3.6%, and 8.4%, respectively. Based on a multivariate analysis, older age (>=50 years) and higher LS value (>=10 kPa) were independently associated with the risk of developing HCC (hazard ratio [HR], 4.53, p=0.023; and HR, 4.08, p=0.022). The cumulative incidence rate of HCC was significantly higher in patients with higher LS values (>=10 kPa) than in those with lower LS values (<10 kPa) (p=0.001). Conclusions: Increased LS measured by SWE at any time point regardless of antiviral treatment is associated with an increased risk of HCC in patients with CHB. PMID- 28651306 TI - Heme Oxygenase-1 Induction and Anti-inflammatory Actions of Atractylodes macrocephala and Taraxacum herba Extracts Prevented Colitis and Was More Effective than Sulfasalazine in Preventing Relapse. AB - Background/Aims: In inflammatory bowel disease (IBD), repeated bouts of remission and relapse occur in patients and can impose a risk of colitis-associated cancer. We hypothesized that plant extracts of Atractylodes macrocephala (AM) or Taraxacum herba (TH) may be better than sulfasalazine for treating this disease because these extracts can promote additional regeneration. Methods: Murine intestinal epithelial IEC-6 cells were pretreated with AM or TH before a lipopolysaccharide (LPS)-induced challenge. Acute colitis was induced with 7 days of dextran sulfate sodium (DSS) in male C57BL/6 mice, and extracts of AM and TH were administered for 2 weeks before DSS administration. Results: In vitro studies demonstrated that AM or TH treatment reduced LPS-induced COX-2 and tumor necrosis factor-alpha mRNA levels but increased heme oxygenase-1 (HO-1). Oral preadministration of AM and TH rescued mice from DSS-induced colitis by inhibiting inflammatory mediators via inactivated extracellular signal regulated kinase and repressed nuclear factor kappaB and signal transducer and activator of transcription 3, but the effect was weaker for sulfasalazine than that for the extracts. Anti-inflammatory activities occurred via the inhibition of macrophage and T lymphocyte infiltrations. Unlike sulfasalazine, which did not induce HO-1, TH extracts afforded significant HO-1 induction. Conclusions: Because the AM or TH extracts were far superior in preventing DSS-induced colitis than sulfasalazine, AM or TH extracts can be considered natural agents that can prevent IBD relapse. PMID- 28651308 TI - Comparison of the Outcomes of Peroral Endoscopic Myotomy for Achalasia According to Manometric Subtype. AB - Background/Aims: We evaluated whether manometric subtype is associated with treatment outcome in patients with achalasia treated by peroral endoscopic myotomy (POEM). Methods: High-resolution manometry data and Eckardt scores were collected from 83 cases at two tertiary referral centers where POEM is performed. Manometric tracings were classified according to the three Chicago subtypes. Results: Among the 83 cases, 48 type I, 24 type II, and 11 type III achalasia cases were identified. No difference was found in pre-POEM Eckardt score, basal lower esophageal sphincter (LES) pressure, or integrated relaxation pressure (IRP) among the type I, type II, and type III groups. All three patient groups showed a significant improvement in post-POEM Eckardt score (6.1+/-2.1 to 1.5+/ 1.5, p=0.001; 6.8+/-2.2 to 1.2+/-0.9, p=0.001; 6.6+/-2.0 to 1.6+/-1.4, p=0.011), LES pressure (26.1+/-13.8 to 15.4+/-6.8, p=0.018; 32.3+/-19.0 to 19.2+/-10.4, p=0.003; 36.8+/-19.2 to 17.5+/-9.7, p=0.041), and 4s IRP (21.5+/-11.7 to 12.0+/ 8.7, p=0.007; 24.5+/-14.8 to 12.0+/-7.6, p=0.002; 24.0+/-15.7 to 11.8+/-7.1, p=0.019) at a median follow-up of 16 months. Conclusions: POEM resulted in a good clinical outcome for all manometric subtypes. PMID- 28651309 TI - The pattern of choosing dialysis modality and related mortality outcomes in Korea: a national population-based study. AB - BACKGROUND/AIMS: Since comorbidities are major determinants of modality choice, and also interact with dialysis modality on mortality outcomes, we examined the pattern of modality choice according to comorbidities and then evaluated how such choices affected mortality in incident dialysis patients. METHODS: We analyzed 32,280 incident dialysis patients in Korea. Patterns in initial dialysis choice were assessed by multivariate logistic regression analyses. Multivariate Poisson regression analyses were performed to evaluate the effects of interactions between comorbidities and dialysis modality on mortality and to quantify these interactions using the synergy factor. RESULTS: Prior histories of myocardial infarction (p = 0.031), diabetes (p = 0.001), and congestive heart failure (p = 0.003) were independent factors favoring the initiation with peritoneal dialysis (PD), but were associated with increased mortality with PD. In contrast, a history of cerebrovascular disease and 1-year increase in age favored initiation with hemodialysis (HD) and were related to a survival benefit with HD (p < 0.001, both). While favoring initiation with HD, having Medical Aid (p = 0.001) and male gender (p = 0.047) were related to increased mortality with HD. Furthermore, although the severity of comorbidities did not inf luence dialysis modality choice, mortality in incident PD patients was significantly higher compared to that in HD patients as the severity of comorbidities increased (p for trend < 0.001). CONCLUSIONS: Some comorbidities exerted independent effects on initial choice of dialysis modality, but this choice did not always lead to the best results. Further analyses of the pattern of choosing dialysis modality according to baseline comorbid conditions and related consequent mortality outcomes are needed. PMID- 28651310 TI - Clinicopathological characteristics of extremely young Korean multiple myeloma patients: therapeutic implications. AB - BACKGROUND/AIMS: Although multiple myeloma (MM) is typically a disease of the elderly, a certain subset of extremely young patients exists. It is necessary to establish clinicopathological characteristics for this population. METHODS: We reviewed the medical records of MM patients whose age was 40 years or younger at diagnosis. RESULTS: A total of 32 patients were analyzed (male to female ratio 19:13, median age 37 years). According to International Staging System, 29%, 48%, and 16% were in stage I, II, and III, respectively. Light chain myeloma accounted for 30%. Clinically significant anemia, hypercalcemia, azotemia, and hypoalbuminemia were present in 29%, 28%, 13%, and 28%, respectively. Three or more lytic bone lesions were detected in 45% of the patients, whereas 13% had no lytic bone lesions. Regarding treatment, 79% of patients received autologous hematopoietic stem cell transplantation. After a median follow-up duration of 64 months, the 1-, 3-, and 5-year overall survival (OS) rates were 84%, 62%, and 54%, respectively. The median OS was 61 months for the entire cohort. CONCLUSIONS: In our study, MM patients aged 40 years or younger at diagnosis showed no superior survival compared to those of the moderately elderly patients based on historical data. PMID- 28651311 TI - Outcomes of very elderly (>= 80 years) critical-ill patients in a medical intensive care unit of a tertiary hospital in Korea. AB - BACKGROUND/AIMS: This study evaluated clinical characteristics and outcomes in very elderly (>= 80 years of age) critical-ill patients admitted to a medical intensive care unit (MICU) in a regional single tertiary hospital. METHODS: We retrospectively evaluated prospectively collected data in the MICU for the period of December 2011 to May 2014. Patients were divided into >= 80 and < 80 years of age and clinical characteristics and outcomes were compared among these patients. RESULTS: A total of 468 patients were evaluated and 102 patients (21.7%) were >= 80 years of age. Overall mortality was 38.5% in the intensive care unit (ICU) and 44.7% in the hospital. There was no significant difference in ICU and in-hospital mortalities between those >= 80 years and those < 80 years (34.9% vs. 39.5% for ICU mortality; 40.6% vs. 45.9% for in-hospital mortality). Lengths of ICU and hospital stays were significantly longer in patients < 80 years compared to patients >= 80 years (10.57 +/- 19.96 days vs. 8.19 +/- 8.78 days for ICU stay; 27.95 +/- 39.62 days vs. 18.17 +/- 15.44 days for hospital stay). The rate of withholding intensive care in hospital stay over 48 hours was significantly higher in patients >= 80 years compared to patients < 80 years (22.9% vs. 11.8%). In multivariate analysis, weaning failure and withdrawal or withholding of intensive care in ICU was significantly related to death in patients with age >= 80. CONCLUSIONS: Clinical outcomes were not significantly different for very elderly critical-ill patients compared to those of their younger counterparts in the MICU in this study. PMID- 28651312 TI - Repeated isolated bilateral coronary ostial stenosis related to the syphilitic aortitis. PMID- 28651313 TI - Defect engineered oxides for enhanced mechanochemical destruction of halogenated organic pollutants. AB - Mechanochemical activation of metal oxides is studied by a novel methodology based on solid state reaction with a stable radical specie. Such approach corroborates that vacancy formation by high energy ball milling, also in nonreducible oxides, is responsible for electron release on particles' surfaces. This finding suggests a new defect engineering strategy to improve effectiveness of metal oxides as co-milling reagent for halogenated organic pollutant destruction. Results prove that high valent metal doping of a commonly employed co-milling reagent such as CaO determines 2.5 times faster pollutant degradation rate. This enhancement is due to electron-rich defects generated by the dopant; electrons are transferred to the organic pollutant thus causing its mineralization. The proposed strategy can be easily applied to other reagents. PMID- 28651314 TI - Stabilization of heavy metals in soil using two organo-bentonites. AB - Stabilization of Cu, Zn, Cd, Hg, Cr and As in soil using tetramethylammonium (TMA) and dodecyltrimethylammonium (DTMA) modified bentonites (T-Bents and D Bents) as amendments was investigated. Toxicity characteristic leaching procedure (TCLP) was used to quantify the metal mobility after soil treatment. The structural parameters of modified bentonites, including the BET surface area, basal spacing and zeta potential were obtained as a function of the TMA and DTMA loading at 40, 80, 120, 160 and 200% of the bentonite's cation exchange capacity, respectively. The results indicated that the characteristics of the organo bentonites fundamentally varied depending on the species and concentration of modifiers loaded on bentonite. T-Bents and D-Bents manifested distinct immobilization effectiveness towards various metals. In association with the organo-bentonite characteristics, the main interactive mechanisms for Cu, Zn and Cd proceeded via cation exchange, Hg proceeded via physical adsorption and partitioning, Cr and As proceeded via specific adsorption and electrostatic attraction, respectively. This study provided operational and mechanistic basis for optimizing the organic clay synthesis and selecting as the appropriate amendment for remediation of heavy metal contaminated soils. PMID- 28651316 TI - A permeation-controlled formaldehyde reference source for application in environmental test chambers. AB - In a wide range of indoor air pollutants, formaldehyde is one of the most-used and best-known substances. In order to protect human health, many countries have established threshold values for the release of formaldehyde from miscellaneous products and revise them constantly. Compliance with these regulations is usually assessed by emission test chamber measurements or derived methods. To control and improve the mechanisms of an emission test chamber, a reliable reference source with sample mimicking emission properties is required but not available so far. This study describes a permeation-controlled reference source based on the application of paraformaldehyde as formaldehyde releasing polymeric compound. Interactions between the formaldehyde release of the source and the governing chamber parameters temperature, relative humidity and air velocity were investigated in 1 m3 emission chambers. Depending on the conditions, constant formaldehyde concentrations between approximately 10 ppb and 150 ppb can be adjusted for up to 600 h. A linear correlation between the logarithm of the chamber concentration and the reciprocal temperature was found. The results support the feasibility of the source for validation of emission test chamber performance. PMID- 28651315 TI - Linking potential nitrification rates, nitrogen cycling genes and soil properties after remediating the agricultural soil contaminated with heavy metal and fungicide. AB - Apart from the contaminant removal, the remediation of agricultural soil should also pay more attention to soil nutrient retention and biogeochemical cycling. This study aimed to evaluate changes of soil properties, potential nitrification rates (PNRs), and functional gene abundances and link their relationships after remediating co-contaminated agricultural soil with Medicago sativa L. (alfalfa) planting, alone or together with biochar application. Compared with the control (CK), alfalfa planting, alone or together with biochar application, could significantly increase soil organic matter (SOM) contents and discrepantly affect soil pH values. The PNRs of the amended treatments were significantly higher than that of the CK. Moreover, alfalfa plantings also enhanced the abundances of functional genes related to soil nitrification and denitrification, with the sole exception of nosZ gene. Stepwise regression analysis revealed that the PNRs were best described by the gene abundance ratios of AOB amoA/nifH and nirS gene abundances. Compared with the CK, alfalfa planting, alone or with biochar application, could restore nitrogen cycling in the co-contaminated agricultural soil and enhance the PNRs via decreasing contaminant bio-availabilities and increasing SOM contents and gene abundance ratios of AOB amoA/nifH. PMID- 28651317 TI - Effects of multi-environmental factors on physiological and biochemical responses of large yellow croaker, Larimichthys crocea. AB - Land-based recirculating aquaculture systems (RAS) and cage culture are important methods of Larimichthys crocea production. The effects of environmental factors on physiological and biochemical aspects of L. crocea require clarification. Temperature and salinity are controlled in RAS and directly affect L. crocea growth and survival. To explore optimal parameters, the oxygen consumption rate (RO), ammonium excretion rate (RN), and O/N ratio at different temperatures (8, 14, 20, 26, and 32 degrees C) and salinities (5, 15, 25, and 350/00) were determined. RO, RN, and O/N first increased and then decreased with elevated temperature and salinity, peaking at 26 degrees C and 250/00, respectively. This suggests that the metabolism of L. crocea was maximal at 26 degrees C and 250/00 salinity, which promote its growth and survival. Additionally, hypoxia affects cage culture, and has significant effects on enzymatic activities and stress inducible gene expression. To accelerate the selective breeding of hypoxia tolerant L. crocea in cage culture, we measured adenosine triphosphatase (ATPase), lactate dehydrogenase (LDH), and succinate dehydrogenase (SDH) activities, and hypoxia-inducing factor 1 (HIF-1) mRNA expression in the myocardium under hypoxia (2.5, 3.5, and 4.5 mg L-1). ATPase and SDH activities first decreased and then increased under hypoxia, whereas LDH activity and HIF 1alpha expression first increased and then decreased. Thus, under hypoxia, the myocardial mitochondria switched from being susceptible to being resistant to injury induced by energy metabolism, and respiration in L. crocea likely converted from aerobic to anaerobic during adaptation. Furthermore, the upregulation of HIF-1alpha mRNA suggests it has an active role in protection against anoxic damage. PMID- 28651318 TI - Fate of polycyclic aromatic hydrocarbons from the North Pacific to the Arctic: Field measurements and fugacity model simulation. AB - Polycyclic aromatic hydrocarbons (PAHs) have accumulated ubiquitously inArctic environments, where re-volatilization of certain organic pollutants as a result of climate change has been observed. To investigate the fate of semivolatile organic compounds in the Arctic, dissolved PAHs in the surface seawaters from the temperate Pacific Ocean to the Arctic Ocean, as well as a water column in the Arctic Ocean, were collected during the 4th Chinese National Arctic Research Expedition in summer 2010. The total concentrations of seven dissolved PAHs in surface water ranged from 1.0 to 5.1 ng L-1, decreasing with increasing latitude. The vertical profile of PAHs in the Arctic Ocean was generally characteristic of surface enrichment and depth depletion, which emphasized the role of vertical water stratification and particle settling processes. A level III fugacity model was developed in the Bering Sea under steady state assumption. Model results quantitatively simulated the transfer processes and fate of PAHs in the air and water compartments, and highlighted a summer air-to-sea flux of PAHs in the Bering Sea, which meant that the ocean served as a sink for PAHs, at least in summer. Acenaphthylene and acenaphthene reached equilibrium in air-water diffusive exchange, and any perturbation, such as a rise in temperature, might lead to disequilibrium and remobilize these compounds from their Arctic reservoirs. PMID- 28651319 TI - Utilization of rice husks functionalized with xanthates as cost-effective biosorbents for optimal Cd(II) removal from aqueous solution via response surface methodology. AB - Pristine rice husk (RH), a kind of agricultural waste based biosorbent, was chemically modified by introducing sulfur-bearing groups with the CS2 treatment under caustic medium. Using response surface methodology (RSM), the interactive effects of three preparation variables on the cadmium uptake and material yield of xanthate-modified rick husk (RH-X) were investigated, and two quadratic regression models were developed to correlate the preparation parameters to the two responses. Through process optimization, the optimal RH-X was finally obtained under the optimum synthesis conditions (i.e., 1.00 CS2-RH ratio, 60.00min xanthation contact time and 18.50 degrees C xanthation temperature), resulting in 138.85mgg-1 of cadmium uptake, and 68.63% of RH-X yield, strictly similar to the values predicted from the models, with extremely small errors of 0.85 and 0.96%, respectively. Overall, cheap and abundant raw materials, low-cost and easily-controlled preparation and excellent cadmium adsorption ability can make RH-X a preferred biosorbent for wastewater decontamination. PMID- 28651320 TI - An efficient production of high-pure xylooligosaccharides from corncob with affinity adsorption-enzymatic reaction integrated approach. AB - Xylooligosaccharides (XOS) are high value-added ingredients for functional foods and they have potential use as prebiotics. In order to reduce the production cost of XOS, we constructed a fusion enzyme consisting of expansin and endo-xylanase from B. subtilis Lucky9 to produce high-pure XOS with affinity adsorption enzymatic reaction integrated approach. By optimization of inserting linker, the specific xylanase activity of fusion enzyme with R2 linker was increased 1.28 fold than that of native xylanase. Electrophoretic pure fusion enzyme was separated from crude enzyme extracts by affinity adsorption on corncob substrate, with 90.3% recovery in optimized conditions. Then, the fusion enzyme-corncob mixture was directly hydrolyzed. The yield of XOS reached 6.91mg/mL. The production of XOS with high purity of 91.7% was obtained by one step of centrifugation. This affinity adsorption-enzymatic reaction integrated XOS production approach provides a green route to alternative XOS traditional enzymatic production. PMID- 28651321 TI - Methane production and characteristics of the microbial community in a two-stage fixed-bed anaerobic reactor using molasses. AB - Molasses is a typical feedstock for fermentation, but the effluent is hard to treat. In this study, molasses containing a high concentration of organic matter was treated by a two-stage Fix-bed reactor system with an increased organic loading rate (OLR). The results indicated at high molasses loading rate, the two stage system was more efficient (i.e. organic matter removal, the COD of effluent and biogas production) than the single-stage system. The relative abundance of Anaerolineaceae and W5_norank was higher in the first stage (R1), where these organisms digest carbohydrates, while the second stage (R2) had higher relative abundance of Synergistaceae and SB-1_norank, which digest VFAs and decomposition resistant compounds to produce compounds used by hydrogen methanogens. The qPCR analysis demonstrated that the Methanosaetaceae dominated the archaeal community in the first stage (R1), while Methanomicrobiales and Methanobacteriales were predominant in the second stage (R2), where they were involved in hydrogen production. PMID- 28651322 TI - Ozonation of tannic acid to model biomass pretreatment for bioethanol production. AB - Lignocellulosic biomass is a promising feedstock for ethanol production, but lignin, a polyphenol, hampers the use of enzymes for its saccharification; pretreatment is thus key to preparing such feedstock. Ozonation was previously demonstrated as an effective pretreatment, but claimed to be uneconomical due to the assumed need for lignin mineralization. We analyzed, for the first time, ozonation of highly concentrated tannic acid (TA) solution (60g/L) as a lignin model. Most of the TA disappeared within 3.5h, following triple-phase kinetics with two transition points: at 7min and 60min of ozonation for 0.4L ozone reactor. Maximal enzymatic activity was found at the first transition point, demonstrating that very short ozonation that results in partial decomposition of TA, is enough to remediate TA's negative effect on cellulase activity. Short ozonation could decrease energy input by up to 97%, making ethanol production more economically competitive. PMID- 28651323 TI - Effect of cellulose as co-substrate on old landfill leachate treatment using white-rot fungi. AB - Conventional wastewater treatment technologies are ineffective for remediation of old LandFill Leachate (LFL), and innovative approaches to achieve satisfactory removal of this recalcitrant fraction are needed. This study focused on old LFL treatment with a selected fungal strain, Bjerkandera adusta MUT 2295, through batch and continuous tests, using packed-bed bioreactors under non-sterile conditions. To optimize the process performance, diverse types of co-substrates were used, including milled cellulose from beverage cups waste material. Extracellular enzyme production was assayed, in batch tests, as a function of a) cellulose concentration, b) leachate initial Chemical Oxygen Demand (COD) and Soluble COD (sCOD), and c) co-substrate type. Bioreactors were dosed with an initial start-up of glucose (Rg) or cellulose (Rc). An additional glucose dosage was provided in both reactors, leading to significant performance increases. The highest COD and sCOD removals were i) 63% and 53% in Rg and ii) 54% and 51% in Rc. PMID- 28651324 TI - Preparation of activated carbon from molasses-to-ethanol process waste vinasse and its performance as adsorbent material. AB - Herein, the preparation of activated carbon from waste vinasse by using hydrothermal H2O2 oxidation combined with a two-step pyrolysis process has been described for the first time as a new utilization approach for the waste vinasse. The characterization studies were performed by TGA, FT-IR, Raman spectroscopy, SEM-EDX and gas adsorption measurements. The approach generated a microporous activated carbon with high specific surface area (989m2/g) from waste vinasse. After simple experiments on various dye solutions, adsorption performance of the activated carbon was specifically studied on the methylene blue solution as functions of solution pH, contact time, adsorbent amount and reusability. The obtained activated carbon had a higher Langmuir adsorption capacity towards methylene blue (909.091+/-31.900mg/g) than many other adsorbents and it is reusable for at least six cycles. The adsorption performance of the obtained activated carbon was also evaluated using both simulated and real dye-house effluents. PMID- 28651325 TI - Design of marine macroalgae photobioreactor integrated into building to support seagriculture for biorefinery and bioeconomy. AB - Seagriculture, which can provide offshore grown macroalgae biomass would play a significant role in bioeconomy. Nevertheless, seagriculture development has been hindered by the lack of laboratory photobioreactors that enable fundamental and pilot scale macroalgae research. In this work, a macroalgae photobioreactor (MPBR) was developed and integrated into the building. The MPBR operation was demonstrated for 6months with cultivation of Cladophora sp., Ulva compressa and Ulva rigida green macroalgae species isolated from 3 sites at the Eastern Mediterranean coast. The growth rate, protein, ash, specific energy density, rhamnose, xylose, arabinose, glucose, galactose and glucuronic acid content of the cultivated species were quantified. The maximum accumulated energy rates were 0.033WhL-1d-1 for Cladophora sp., 0.081WhL-1d-1 for U. compressa and 0.029WhL-1d 1 for U. rigida. This work provides a detailed design of an indoor, urban photobioreactor for cultivation, maintenance and energy balance analysis of macroalgae biomass for biorefinery. PMID- 28651326 TI - Heterogeneity in Cultivation-Based Monitoring of Airborne Bacterial Biodiversity in Animal Farms. AB - Diversity analyses of bioaerosol samples from highly loaded workplaces as found in agricultural production or waste management help to improve the knowledge of exposure levels of workers. However, different used methods resulting in the detection of different bacterial species at the same work places. The present study obviously supports the deviation of received results using cultivation and further isolation approaches. Within the present study, the bacterial community at workplaces was estimated using the powerful tool of 16S rRNA gene sequence analyses after cultivation procedure. To avoid complex isolation procedures, the suitability of cultivation and subsequent cloning procedures was determined in bioaerosols from a duck hatchery. Diversity analysis of one bioaerosol sample, which was prepared independently three times in parallel, resulted in similarity values of 38.5%-57.1%. Further, similarity analysis calculated from three independent bioaerosol samplings on 1 day resulted in 31%-40% similarity. Although similar concentration between 2.22 * 106 and 4.46 * 106 CFU per m3 hatchery air were measured, in a ring-like trail, diversity analyses from six labs differ widely, resulting in 38.9%-78.6% divergence. The present method seems to be very useful for diversity analysis of bioaerosol samples, although heterogeneity in monitoring of airborne bacteria via cultivation was pointed out. PMID- 28651327 TI - Alpha Klotho and Fibroblast Growth Factor-23 Among Alcoholics. AB - Aims: Alcoholism may be a cardiovascular risk factor. Osteocyte derived molecules such as fibroblast growth factor 23 (FGF-23) and soluble alpha Klotho have recently been associated with cardiovascular disease, but their role in alcoholics is unknown. We here analyze the behavior of FGF23 and alpha Klotho in alcoholics. Methods: Ninety-seven alcoholic patients were assessed for liver function, presence of hypertension, diabetes, atrial fibrillation, left ventricular hypertrophy (LVH), vascular calcifications (assessed by chest X-ray) and nutritional status (lean and fat mass measured by densitometry). We measured plasma levels of FGF-23 and serum soluble alpha Klotho, using ELISA in 97 patients and 20 age- and sex-matched controls. Results: FGF-23 levels were higher in patients than in controls (Z = 3.50; P < 0.001). FGF-23 (Z = 5.03; P < 0.001) and soluble alpha Klotho (Z = 5.61; P < 0.001) were higher in cirrhotics, and both were related to liver function, independently of serum creatinine FGF-23 levels were higher among alcoholics with diabetes (Z = 2.55; P = 0.011) or hypertension (Z = 2.56; P = 0.01), and increased body fat (rho = 0.28; P = 0.022 for trunk fat), whereas alpha Klotho levels were higher in patients with LVH (Z = 2.17; P = 0.03) or atrial fibrillation (Z = 2.34; P = 0.019). Conclusions: FGF-23 was higher in alcoholics than in controls, especially among cirrhotics, and soluble alpha Klotho levels were also higher among cirrhotics. Both were related to liver function impairment, independently of serum creatinine levels, and also showed significant associations with vascular risk factors, such as hypertension, diabetes or trunk fat amount in the case of FGF-23, or LVH or atrial fibrillation in the case of alpha Klotho. Short summary: We report increased values of fibroblast growth factor 23 (FGF-23) and soluble alpha Klotho in cirrhotic alcoholics. Both molecules are associated with liver function impairment, and with some cardiovascular risk factors such as diabetes, hypertension, increased body fat, left ventricular hypertrophy and atrial fibrillation independently of serum creatinine. PMID- 28651328 TI - Acute coronary syndrome as a possible immune-related adverse event in a lung cancer patient achieving a complete response to anti-PD-1 immune checkpoint antibody. PMID- 28651329 TI - High-speed and high-ratio referential genome compression. AB - Motivation: The rapidly increasing number of genomes generated by high-throughput sequencing platforms and assembly algorithms is accompanied by problems in data storage, compression and communication. Traditional compression algorithms are unable to meet the demand of high compression ratio due to the intrinsic challenging features of DNA sequences such as small alphabet size, frequent repeats and palindromes. Reference-based lossless compression, by which only the differences between two similar genomes are stored, is a promising approach with high compression ratio. Results: We present a high-performance referential genome compression algorithm named HiRGC. It is based on a 2-bit encoding scheme and an advanced greedy-matching search on a hash table. We compare the performance of HiRGC with four state-of-the-art compression methods on a benchmark dataset of eight human genomes. HiRGC takes <30 min to compress about 21 gigabytes of each set of the seven target genomes into 96-260 megabytes, achieving compression ratios of 217 to 82 times. This performance is at least 1.9 times better than the best competing algorithm on its best case. Our compression speed is also at least 2.9 times faster. HiRGC is stable and robust to deal with different reference genomes. In contrast, the competing methods' performance varies widely on different reference genomes. More experiments on 100 human genomes from the 1000 Genome Project and on genomes of several other species again demonstrate that HiRGC's performance is consistently excellent. Availability and implementation: The C ++ and Java source codes of our algorithm are freely available for academic and non-commercial use. They can be downloaded from https://github.com/yuansliu/HiRGC. Contact: jinyan.li@uts.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28651332 TI - Surfactant protein D is not so friendly outside the lung-aggravation of cardiovascular disease. PMID- 28651331 TI - IL-1beta Upregulates StAR and Progesterone Production Through the ERK1/2- and p38 Mediated CREB Signaling Pathways in Human Granulosa-Lutein Cells. AB - The proinflammatory cytokine interleukin-1beta (IL-1beta) may be involved in several ovulation-associated events, such as protease synthesis, prostaglandin production, and steroidogenesis in granulosa cells. However, the exact effect of IL-1beta on progesterone synthesis in granulosa cells and the underlying mechanism remain unclear. By using cultured granulosa-lutein cells collected from women undergoing in vitro fertilization or intracytoplasmic sperm injection, we found that IL-1beta upregulated steroidogenic acute regulatory protein (StAR) expression and progesterone synthesis in granulosa-lutein cells, which was comparable with luteinizing hormone effect and could be abolished by an IL-1 receptor antagonist. Moreover, IL-1beta activated the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB), and knockdown of CREB attenuated the induction of StAR expression and progesterone synthesis by IL 1beta in granulosa-lutein cells. Furthermore, IL-1beta activated the extracellular signal-regulated kinase (ERK)1/2 and p38 pathways and inhibition of the ERK1/2 and p38 pathways attenuated the IL-1beta-induced phosphorylation of CREB, StAR expression, and progesterone synthesis in granulosa-lutein cells. In conclusion, IL-1beta could upregulate StAR expression and stimulate progesterone biosynthesis through increase in CREB phosphorylation via activating the ERK1/2 and p38 pathways in human granulosa-lutein cells. PMID- 28651330 TI - Rosiglitazone Improves Insulin Resistance Mediated by 10,12 Conjugated Linoleic Acid in a Male Mouse Model of Metabolic Syndrome. AB - Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a dietary fatty acid that promotes weight loss and disproportionate fat loss. Obese mice fed a high fat, high-sucrose (HFHS) diet containing 10,12 CLA are resistant to weight gain and contain markedly reduced subcutaneous fat and adiponectin, with a concurrent lack of improvement in insulin sensitivity despite significant weight loss. Taken together, 10,12 CLA promotes a phenotype resembling peroxisome proliferator activated receptor (PPAR)gamma antagonism. Because thiazolidinediones such as rosiglitazone (Rosi) are used clinically to improve insulin sensitivity by activating PPARgamma, with particular efficacy in subcutaneous white adipose tissue, we hypothesized that Rosi would improve glucose metabolism in mice losing weight with 10,12 CLA. Obese low-density lipoprotein receptor-deficient mice were fed a HFHS control diet, or supplemented with 1% 10,12 CLA with or without Rosi (10 mg/kg) for 8 weeks. Body composition, glucose and insulin tolerance tests, tissue gene expression, and plasma lipid analyses were performed. Mice consuming 10,12 CLA with Rosi lost weight and body fat compared with control groups, but with a healthier redistribution of body fat toward more subcutaneous adipose tissue than with 10,12 CLA alone. Further, Rosi improved 10,12 CLA-mediated insulin resistance parameters and increased plasma and subcutaneous adipose tissue adiponectin levels without adverse effects on plasma or hepatic lipids. We conclude that cotreatment of mice with 10,12 CLA and Rosi promotes fat loss with a healthier fat distribution that leads to improved insulin sensitivity, suggesting that the combination treatment strategy of 10,12 CLA with Rosi could have therapeutic potential for obesity treatment. PMID- 28651333 TI - Responses of lichen communities to 18 years of natural and experimental warming. AB - Background and Aims: Climate change is expected to have major impacts on high alpine and arctic ecosystems in the future, but empirical data on the impact of long-term warming on lichen diversity and richness are sparse. This study report the effects of 18 years of ambient and experimental warming on lichens and vascular plant cover in two alpine plant communities, a dry heath with sparse canopy cover (54 %) and a mesic meadow with a more developed (67 %) canopy cover, in sub-arctic Sweden. Methods: The effects of long-term passive experimental warming using open top chambers (OTCs) on lichens and total vascular plant cover, and the impact of plant cover on lichen community parameters, were analysed. Key Results: Between 1993 and 2013, mean annual temperature increased about 2 degrees C. Both site and experimental warming had a significant effect on cover, species richness, effective number of species evenness of lichens, and total plant canopy cover. Lichen cover increased in the heath under ambient conditions, and remained more stable under experimental warming. The negative effect on species richness and effective number of species was driven by a decrease in lichens under experimental warming in the meadow. Lichen cover, species richness, effective number of species evenness were negatively correlated with plant canopy cover. There was a significant negative impact on one species and a non significant tendency of lower abundance of the most common species in response to experimental warming. Conclusions: The results from the long-term warming study imply that arctic and high alpine lichen communities are likely to be negatively affected by climate change and an increase in plant canopy cover. Both biotic and abiotic factors are thus important for future impacts of climate change on lichens. PMID- 28651334 TI - TSGSIS: a high-dimensional grouped variable selection approach for detection of whole-genome SNP-SNP interactions. AB - Motivation: Identification of single nucleotide polymorphism (SNP) interactions is an important and challenging topic in genome-wide association studies (GWAS). Many approaches have been applied to detecting whole-genome interactions. However, these approaches to interaction analysis tend to miss causal interaction effects when the individual marginal effects are uncorrelated to trait, while their interaction effects are highly associated with the trait. Results: A grouped variable selection technique, called two-stage grouped sure independence screening (TS-GSIS), is developed to study interactions that may not have marginal effects. The proposed TS-GSIS is shown to be very helpful in identifying not only causal SNP effects that are uncorrelated to trait but also their corresponding SNP-SNP interaction effects. The benefit of TS-GSIS are gaining detection of interaction effects by taking the joint information among the SNPs and determining the size of candidate sets in the model. Simulation studies under various scenarios are performed to compare performance of TS-GSIS and current approaches. We also apply our approach to a real rheumatoid arthritis (RA) dataset. Both the simulation and real data studies show that the TS-GSIS performs very well in detecting SNP-SNP interactions. Availability and implementation: R package is delivered through CRAN and is available at: https://cran.r project.org/web/packages/TSGSIS/index.html. Contact: hsiung@nhri.org.tw. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28651335 TI - Critical evaluation of bioinformatics tools for the prediction of protein crystallization propensity. PMID- 28651336 TI - Safety and efficacy of a repositionable and fully retrievable aortic valve used in routine clinical practice: the RESPOND Study. AB - Aims: RESPOND is a prospective, open-label, single-arm study evaluating the outcomes following transcatheter aortic valve implantation (TAVI) with the repositionable and fully retrievable Lotus Valve used in routine clinical practice for the treatment of patients with aortic valve stenosis. Methods and results: RESPOND enrolled 1014 patients at sites across Europe, New Zealand, and Latin America; 996 patients received a Lotus Valve (mean age: 80.8 years; 50.8% female; Society of Thoracic Surgeons score: 6.0 +/- 6.9). Repositioning was attempted in 29.2% of patients, with 99% success. The rate of all-cause mortality in the intent-to-treat population at 30 days (primary endpoint) was 2.6% (P < 0.001 vs. pre-specified performance goal). Thirty-day clinical follow-up was completed for 97.3% of patients. Among patients who received a Lotus Valve, the 30-day overall and disabling stroke rates were 3.0% and 2.2%, respectively. The 30-day permanent pacemaker implantation rate was 30.0% in all patients, and 34.6% in pacemaker-naive patients. Echocardiographic data at baseline and pre-discharge were assessed by an independent core laboratory. Mean aortic valve gradient declined from 37.7 +/- 15.2 mmHg at baseline to 10.8 +/- 4.6 mmHg at hospital discharge (P < 0.001). Aortic valve area increased from 0.7 +/- 0.2 cm2 at baseline to 1.8 +/- 0.4 cm2 at discharge (P < 0.001). At hospital discharge, paravalvular leak (PVL) was absent or trace in 92% of patients; no patients had severe PVL, 0.3% of patients exhibited moderate PVL, and 7.7% of patients had mild PVL. Clinical follow-up in RESPOND will extend to 5 years. Conclusion: The results of RESPOND confirm the safety and efficacy of TAVI with the Lotus Valve in routine clinical practice. Trial registration: ClinicalTrials.gov #NCT 02031302. PMID- 28651337 TI - Preliminary Validation of a Method Combining Cultivation and Cloning-Based Approaches to Monitor Airborne Bacteria. AB - It is already known that occupational exposure to bioaerosols or organic dust could be harmful for occupants, but mostly the correlation to occurring bacteria is missing. Especially, cultivation of bacteria from bioaerosols is important to get an insight on occurring and possibly infectious bacteria. These measures are highly time consuming and cost intensive. Therefore, to monitor bacterial diversity in bioaerosol samples and to avoid isolation procedures, an approach was applied using a combination of cultivation and cloning-based approach. Preliminary validation of the method was determined using 11 different bacterial strains. After DNA extraction and 16S rRNA gene amplification of grown colonies, subsequent cloning and sequencing was conducted. Initially, to figure out a suitable DNA extraction method, applicable for different airborne bacteria, four DNA extraction protocols were compared. Significantly, best results were determined using the FAST DNA(r)Spin Kit for Soil with respect to DNA quantity and quality of bacterial cultures. Cloning approach from a mixture of amplified 16S rRNA genes of 11 isolates and following sequence data analysis shows a recovery of all strains when five clones per bacterial strain were analysed. The results clearly demonstrate that a combination of cultivation-based approaches and cloning processes can simplify bioaerosol monitoring of viable and probably infectious bacteria. The implementation of the present method into practice allows a simple and preventive investigation of bioaerosols at work places. PMID- 28651338 TI - Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study. AB - Background: EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5 fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered. Patients and methods: Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+ and/or p16+ tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level. Results: Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+ and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P = 0.287) or OS (P = 0.118). Conclusions: The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status. PMID- 28651340 TI - Linking quality indicators to clinical trials: an automated approach. AB - Objective: Quality improvement of health care requires robust measurable indicators to track performance. However identifying which indicators are supported by strong clinical evidence, typically from clinical trials, is often laborious. This study tests a novel method for automatically linking indicators to clinical trial registrations. Design: A set of 522 quality of care indicators for 22 common conditions drawn from the CareTrack study were automatically mapped to outcome measures reported in 13 971 trials from ClinicalTrials.gov. Intervention: Text mining methods extracted phrases mentioning indicators and outcome phrases, and these were compared using the Levenshtein edit distance ratio to measure similarity. Main Outcome Measure: Number of care indicators that mapped to outcome measures in clinical trials. Results: While only 13% of the 522 CareTrack indicators were thought to have Level I or II evidence behind them, 353 (68%) could be directly linked to randomized controlled trials. Within these 522, 50 of 70 (71%) Level I and II evidence-based indicators, and 268 of 370 (72%) Level V (consensus-based) indicators could be linked to evidence. Of the indicators known to have evidence behind them, only 5.7% (4 of 70) were mentioned in the trial reports but were missed by our method. Conclusions: We automatically linked indicators to clinical trial registrations with high precision. Whilst the majority of quality indicators studied could be directly linked to research evidence, a small portion could not and these require closer scrutiny. It is feasible to support the process of indicator development using automated methods to identify research evidence. PMID- 28651339 TI - Formation of silica aggregates in sorghum root endodermis is predetermined by cell wall architecture and development. AB - Background and Aims: Deposition of silica in plant cell walls improves their mechanical properties and helps plants to withstand various stress conditions. Its mechanism is still not understood and silica-cell wall interactions are elusive. The objective of this study was to investigate the effect of silica deposition on the development and structure of sorghum root endodermis and to identify the cell wall components involved in silicification. Methods: Sorghum bicolor seedlings were grown hydroponically with (Si+) or without (Si-) silicon supplementation. Primary roots were used to investigate the transcription of silicon transporters by quantitative RT-PCR. Silica aggregation was induced also under in vitro conditions in detached root segments. The development and architecture of endodermal cell walls were analysed by histochemistry, microscopy and Raman spectroscopy. Water retention capability was compared between silicified and non-silicified roots. Raman spectroscopy analyses of isolated silica aggregates were also carried out. Key Results: Active uptake of silicic acid is provided at the root apex, where silicon transporters Lsi1 and Lsi2 are expressed. The locations of silica aggregation are established during the development of tertiary endodermal cell walls, even in the absence of silicon. Silica aggregation takes place in non-lignified spots in the endodermal cell walls, which progressively accumulate silicic acid, and its condensation initiates at arabinoxylan-ferulic acid complexes. Silicification does not support root water retention capability; however, it decreases root growth inhibition imposed by desiccation. Conclusion: A model is proposed in which the formation of silica aggregates in sorghum roots is predetermined by a modified cell wall architecture and takes place as governed by endodermal development. The interaction with silica is provided by arabinoxylan-ferulic acid complexes and interferes with further deposition of lignin. Due to contrasting hydrophobicity, silicification and lignification do not represent functionally equivalent modifications of plant cell walls. PMID- 28651341 TI - Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii. AB - Objectives: Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma concentrations of atovaquone in immunocompromised patients under PCP prophylaxis. Methods: Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax). Results: A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7 haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 MUg/mL (6.2-27.8) and the median Cmax was 13.4 MUg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not different between HIV negative and HIV-positive patients, or between HSCT and non-HSCT patients. Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food. Nineteen of the 33 (58%) patients had Cmin <15 MUg/mL, a threshold associated with a low rate of clinical response in PCP treatment. Conclusions: Atovaquone is poorly absorbed in more than half of immunocompromised patients and its bioavailability varies between individuals. These unpredictable variations raise the question of therapeutic drug monitoring, in order to identify patients with low concentrations and those who could benefit from regimen adaptation or from alternatives. PMID- 28651342 TI - Emissions of volatile odorous metabolites by Clostridium perfringens - in vitro study using two broth cultures. AB - An in vitro study was carried out to investigate the volatile odorous metabolites produced by necrotic enteritis inducing Clostridium perfringens (Cp) type A field strain (EHE-NE18) cultured in two broth media (thioglycollate broth, brain heart infusion broth) at three levels (0, 103 cfu/mL, 106 cfu/mL) using 2 * 3 factorial arrangement of treatments, with each replicated three times. The culture media with and without Cp was freshly prepared on the day of measurement and the culture headspace concentration of odorants was measured using selected ion-flow tube mass spectrometry (SIFT-MS). The results showed that media type and Cp level affected the concentration of a range of volatile odorous metabolites including sulfur compounds, alcohols, ketones, amines, and carboxylic acids. Thus, Cp contributes to the production of a wide range of odorous metabolites that can impart noxious smell during infection. PMID- 28651343 TI - Does a First-Degree Family History of Diabetes Impact Placental Maternal and Fetal Vascular Circulation and Inflammatory Response? AB - Context: Heritability of diabetes is associated with hyperinsulinemia, impaired endothelial function, and inflammatory up-regulation. However, no studies have examined whether a family history of diabetes (FHD) effects placental vascular circulation. Objective: The current study was designed to investigate the impact of a first-degree FHD on placental vascular circulation and inflammatory lesions. Design: Observational cohort study. Setting: Pregnant women who gave birth at Edith Wolfson Medical Center. Patients: Three hundred thirty-nine pregnant women were divided into two groups according to presence of FHD: group 1 included 225 subjects without FHD, and group 2 included 114 subjects with FHD. Intervention: Placental histopathological examination. Main Outcome Measures: Placental vascular supply abnormalities of maternal and fetal origin. Results: Maternal vascular supply (MVS) abnormalities of the placenta were significantly higher in subjects with FHD, compared with subjects without FHD (P < 0.005). Fetal vascular supply abnormalities, as well as maternal and fetal inflammatory response did not differ significantly between groups. In the general linear modeling analysis, FHD was an independent and significant predictor of MVS abnormalities and more than doubled the risk of this outcome. Gestational diabetes mellitus (GDM) incidence was significantly higher in subjects with FHD (P < 0.0001). Significant by-group differences in GDM persisted even after adjustment for age and body mass index. Although incidence of gestational hypertensive disorders was significantly higher in individuals with FHD, after adjustment FHD did not significantly predict this outcome. Conclusions: A first-degree FHD is significantly and independently associated with an increased rate of maternal vascular perfusion abnormalities and risk of GDM. PMID- 28651345 TI - Prioritizing quality measure concepts at the interface of behavioral and physical healthcare. AB - Objective: Integrated healthcare models can increase access to care, improve healthcare quality, and reduce cost for individuals with behavioral and general medical healthcare needs, yet there are few instruments for measuring the quality of integrated care. In this study, we identified and prioritized concepts that can represent the quality of integrated behavioral health and general medical care. Design: We conducted a literature review to identify candidate measure concepts. Experts then participated in a modified Delphi process to prioritize the concepts for development into specific quality measures. Setting: United States. Participants: Expert behavioral health and general medical clinicians, decision-makers (policy, regulatory and administrative professionals) and patient advocates. Main outcome measures: Panelists rated measure concepts on importance, validity and feasibility. Results: The literature review identified 734 measures of behavioral or general medical care, which were then distilled into 43 measure concepts. Thirty-three measure concepts (including a segmentation strategy) reached a predetermined consensus threshold of importance, while 11 concepts did not. Two measure concepts were 'ready for further development' ('General medical screening and follow-up in behavioral health settings' and 'Mental health screening at general medical healthcare settings'). Among the 31 additional measure concepts that were rated as important, 7 were rated as valid (but not feasible), while the remaining 24 concepts were rated as neither valid nor feasible. Conclusions: This study identified quality measure concepts that capture important aspects of integrated care. Researchers can use the prioritization process described in this study to guide healthcare quality measures development work. PMID- 28651346 TI - Effect of APOE epsilon Genotype on Lipoprotein(a) and the Associated Risk of Myocardial Infarction and Aortic Valve Stenosis. AB - Context: APOEepsilon2/3/4 genotypes affect plasma lipoprotein(a); however, the effects of APOE genotypes on the prediction of myocardial infarction and aortic valve stenosis by lipoprotein(a) are unknown. Objective: We tested the hypothesis that APOEepsilon2/3/4 genotype affects plasma lipoprotein(a), the contribution of plasma apoE levels to this association as well as the associated risk of myocardial infarction and aortic valve stenosis. Design and Outcome Measures: In 46,615 individuals from the general population, we examined plasma lipoprotein(a), APOE epsilon2/3/4, and incidence of myocardial infarction (n = 1807) and aortic valve stenosis (n = 345) over 37 years of follow-up (range: 0.3 to 38 years). Results: Compared with epsilon33, age- and sex-adjusted lipoprotein(a) concentrations were lower by 15% in epsilon23, by 24% in epsilon24, and by 36% in epsilon22; adjusted for plasma apolipoprotein E, corresponding values were 22%, 28%, and 62%. These reductions were independent of LPA genotypes. Compared with epsilon2 carriers with lipoprotein(a) <=50 mg/dL, the hazard ratio for myocardial infarction was 1.26 (95% confidence interval: 1.06 to 1.49) for epsilon2 noncarriers with lipoprotein(a) <=50 mg/dL, 1.68 (1.21 to 2.32) for epsilon2 carriers with lipoprotein(a) >50 mg/dL, and 1.92 (1.59 to 2.32) for epsilon2 noncarriers with lipoprotein(a) >50 mg/dL (interaction, P = 0.57); corresponding values for aortic valve stenosis were 1.05 (0.74 to 1.51), 1.49 (0.72 to 3.08), and 2.04 (1.46 to 2.26) (interaction, P = 0.50). Further adjustment for APOE epsilon2/3/4 genotype had minimal influence on these risk estimates. Conclusions: APOE epsilon2 is a strong genetic determinant of low lipoprotein(a) concentrations but does not modify the causal association of lipoprotein(a) with myocardial infarction or aortic valve stenosis. PMID- 28651344 TI - Uterine responses to early pre-attachment embryos in the domestic dog and comparisons with other domestic animal species. AB - In the dog, there is no luteolysis in the absence of pregnancy. Thus, this species lacks any anti-luteolytic endocrine signal as found in other species that modulate uterine function during the critical period of pregnancy establishment. Nevertheless, in the dog an embryo-maternal communication must occur in order to prevent rejection of embryos. Based on this hypothesis, we performed microarray analysis of canine uterine samples collected during pre-attachment phase (days 10 12) and in corresponding non-pregnant controls, in order to elucidate the embryo attachment signal. An additional goal was to identify differences in uterine responses to pre-attachment embryos between dogs and other mammalian species exhibiting different reproductive patterns with regard to luteolysis, implantation, and preparation for placentation. Therefore, the canine microarray data were compared with gene sets from pigs, cattle, horses, and humans. We found 412 genes differentially regulated between the two experimental groups. The functional terms most strongly enriched in response to pre-attachment embryos related to extracellular matrix function and remodeling, and to immune and inflammatory responses. Several candidate genes were validated by semi quantitative PCR. When compared with other species, best matches were found with human and equine counterparts. Especially for the pig, the majority of overlapping genes showed opposite expression patterns. Interestingly, 1926 genes did not pair with any of the other gene sets. Using a microarray approach, we report the uterine changes in the dog driven by the presence of embryos and compare these results with datasets from other mammalian species, finding common , contrary-, and exclusively canine-regulated genes. PMID- 28651347 TI - Minimally invasive CentriMag ventricular assist device support integrated with extracorporeal membrane oxygenation in cardiogenic shock patients: a comparison with conventional CentriMag biventricular support configuration. AB - OBJECTIVES: We recently developed a novel minimally invasive surgical approach that combines extracorporeal membrane oxygenation and CentriMag ventricular assist device (Ec-VAD) for the treatment of cardiogenic shock as a short-term circulatory support. We compared the outcomes of this new approach to conventional CentriMag biventricular assist device (BiVAD) support through a median sternotomy. METHODS: Between July 2015 and August 2016, 22 patients were implanted with CentriMag Ec-VAD and 90 patients were implanted with conventional CentriMag BiVAD. The Ec-VAD circuit was configured with left ventricular apical cannulation via a mini-thoracotomy and femoral venous cannulation as inflows and right axillary artery cannulation as an outflow. RESULTS: Patients with Ec-VAD were older (58 +/- 9.9 vs 53 +/- 13 years, P = 0.06), had more preoperative percutaneous mechanical circulatory support use (82% vs 44%, P < 0.01) and less cardiopulmonary bypass use intraoperatively (0% vs 66%, P < 0.01). Patients who received Ec-VAD required less transfusions. The Ec-VAD group had a significantly lower incidence of major bleeding events during support (32% vs 72%, P < 0.01). Average systemic flow was similar (Ec-VAD: 5.5 +/- 0.94 vs BiVAD: 5.7 +/- 1.1 l/min, P = 0.4). Seventeen patients (77%) with Ec-VAD survived to the next destination compared with 66 patients (73%) with BiVAD (P = 0.45). Thirty-day survival was similar between groups (Ec-VAD 86% vs BiVAD 76%, P = 0.39), and overall 1-year survival was 61% in Ec-VAD and 55% in BiVAD (P = 0.7). CONCLUSIONS: Ec-VAD is a unique approach for the treatment of patients in cardiogenic shock. It eliminates the need for cardiopulmonary bypass and reduces blood product utilization and bleeding events. PMID- 28651348 TI - An E/e' ratio on echocardiography predicts the existence of left atrial low voltage areas and poor outcomes after catheter ablation for atrial fibrillation. AB - Aims: An elevated left atrial pressure has been reported to play an important role in the development of atrial remodelling in atrial fibrillation (AF) patients. The study aimed at elucidating the association between the diastolic early transmitral flow velocity/mitral annular velocity (E/e', a non-invasive surrogate of left atrial pressure) and left atrial low-voltage-area existence, and the prognostic impact of the E/e' on procedural outcomes in patients undergoing AF ablation. Methods and results: Total of 215 consecutive patients were divided into 3 groups based on the estimated left atrial pressure: normal (E/e' < 8.0, n = 58), undetermined (E/e' = 8.0-14.0, n = 114), and elevated (E/e' > 14.0, n = 43). Left atrial endocardial voltage mapping was performed following pulmonary vein isolation. Patients with a high E/e' more frequently had low voltage areas (E/e' < 8.0, 31%, E/e' = 8.0-14.0, 35%; E/e' > 14.0, 67%; P = 0.0001). After adjusting for other correlates, a high E/e' was an independent predictor of low-voltage-area existence (HR = 1.11, 95% CI = 1.02-1.21, P = 0.017). During a mean follow-up period of 12 +/- 6 months, recurrent atrial tachyarrhythmias occurred in 22 (10%) patients after multiple (1.4 +/- 0.5) procedures. Patients with an E/e' > 14 had more frequent recurrent atrial tachyarrhythmias after multiple ablation procedures than those with an E/e' <= 14 (23% vs. 7%, P = 0.001). Conclusion: A high E/e' obtained by pre-ablation echocardiography was associated with a left atrial arrhythmogenic substrate in patients undergoing AF ablation. Furthermore, a high E/e' predicted poor procedural outcomes after pulmonary vein isolation. PMID- 28651349 TI - An autopsy case of sudden cardiac death due to in-scaffold restenosis and late scaffold thrombosis after bioresorbable vascular scaffold implantation; back to past stent era? PMID- 28651350 TI - Targeting an Essential Component of Gram-Positive Type IV Secretion Systems Involved in Gene Transfer Kills 2 Birds With 1 Stone. PMID- 28651351 TI - Applying a Theory-Driven Framework to Guide Quality Improvement Efforts in Nursing Homes: The LOCK Model. AB - Purpose of the Study: Implementing quality improvement (QI) programs in nursing homes continues to encounter significant challenges, despite recognized need. QI approaches provide nursing home staff with opportunities to collaborate on developing and testing strategies for improving care delivery. We present a theory-driven and user-friendly adaptable framework and facilitation package to overcome existing challenges and guide QI efforts in nursing homes. Design and development: The framework is grounded in the foundational concepts of strengths based learning, observation, relationship-based teams, efficiency, and organizational learning. We adapted these concepts to QI in the nursing home setting, creating the "LOCK" framework. The LOCK framework is currently being disseminated across the Veterans Health Administration. Results: The LOCK framework has five tenets: (a) Look for the bright spots, (b) Observe, (c) Collaborate in huddles, (d) Keep it bite-sized, and (e) facilitation. Each tenet is described. We also present a case study documenting how a fictional nursing home can implement the LOCK framework as part of a QI effort to improve engagement between staff and residents. The case study describes sample observations, processes, and outcomes. We also discuss practical applications for nursing home staff, the adaptability of LOCK for different QI projects, the specific role of facilitation, and lessons learned. Implications: The proposed framework complements national efforts to improve quality of care and quality of life for nursing home residents and may be valuable across long-term care settings and QI project types. PMID- 28651352 TI - Circular RNA profiling reveals that circular RNAs from ANXA2 can be used as new biomarkers for multiple sclerosis. AB - Multiple sclerosis is an autoimmune disease, with higher prevalence in women, in whom the immune system is dysregulated. This dysregulation has been shown to correlate with changes in transcriptome expression as well as in gene-expression regulators, such as non-coding RNAs (e.g. microRNAs). Indeed, some of these have been suggested as biomarkers for multiple sclerosis even though few biomarkers have reached the clinical practice. Recently, a novel family of non-coding RNAs, circular RNAs, has emerged as a new player in the complex network of gene expression regulation. MicroRNA regulation function through a 'sponge system' and a RNA splicing regulation function have been proposed for the circular RNAs. This regulating role together with their high stability in biofluids makes them seemingly good candidates as biomarkers. Given the dysregulation of both protein coding and non-coding transcriptome that have been reported in multiple sclerosis patients, we hypothesised that circular RNA expression may also be altered. Therefore, we carried out expression profiling of 13.617 circular RNAs in peripheral blood leucocytes from multiple sclerosis patients and healthy controls finding 406 differentially expressed (P-value < 0.05, Fold change > 1.5) and demonstrate after validation that, circ_0005402 and circ_0035560 are underexpressed in multiple sclerosis patients and could be used as biomarkers of the disease. PMID- 28651353 TI - Protein-Tyrosine Phosphatase-1B Mediates Sleep Fragmentation-Induced Insulin Resistance and Visceral Adipose Tissue Inflammation in Mice. AB - Study Objectives: Sleep fragmentation (SF) is highly prevalent and has emerged as an important contributing factor to obesity and metabolic syndrome. We hypothesized that SF-induced increases in protein tyrosine phosphatase-1B (PTP 1B) expression and activity underlie increased food intake, inflammation, and leptin and insulin resistance. Methods: Wild-type (WT) and ObR-PTP-1b-/- mice (Tg) were exposed to SF and control sleep (SC), and food intake was monitored. WT mice received a PTP-1B inhibitor (RO-7d; Tx) or vehicle (Veh). Upon completion of exposures, systemic insulin and leptin sensitivity tests were performed as well as assessment of visceral white adipose tissue (vWAT) insulin receptor sensitivity and macrophages (ATM) polarity. Results: SF increased food intake in either untreated or Veh-treated WT mice. Leptin-induced hypothalamic STAT3 phosphorylation was decreased, PTP-1B activity was increased, and reduced insulin sensitivity emerged both systemic and in vWAT, with the latter displaying proinflammatory ATM polarity changes. All of the SF-induced effects were abrogated following PTP-1B inhibitor treatment and in Tg mice. Conclusions: SF induces increased food intake, reduced leptin signaling in hypothalamus, systemic insulin resistance, and reduced vWAT insulin sensitivity and inflammation that are mediated by increased PTP-1B activity. Thus, PTP-1B may represent a viable therapeutic target in the context of SF-induced weight gain and metabolic dysfunction. PMID- 28651354 TI - Cambial response of Norway spruce to modified carbon availability by phloem girdling. AB - We tested the hypothesis that increase in carbon (C) availability in Norway spruce saplings (Picea abies (L.) Karst.) intensifies cambial cell division and increases cell lumen diameter (CLD) and cell wall thickness (CWT) when water availability is adequate. To accomplish this, we experimentally subjected 6-year old P. abies saplings (n = 80 trees) to two levels of soil humidity (watered versus drought conditions) and manipulated tree C status by physically blocking phloem transport at three girdling dates (GDs). Stem girdling occurred in mid March (day of the year (doy) 77) and in mid-May (GD doy 138), i.e., ~4 weeks before the onset of bud break and during vigorous stem growth, respectively, and in early July (GD doy 190), i.e., 6 and 4 weeks after cessation of radial growth in drought-stressed trees and shoot growth in both soil humidity (SH) treatments, respectively. In response to phloem blockage a striking increase in the number of xylem cells at all GDs and reactivation of cambial activity in drought-stressed trees was detected above the girdling zone, while below girdling xylem formation stopped in both SH-treatments. Although girdling differently affected wood anatomical parameters (CLD, CWT and CLD:CWT ratio) during earlywood and latewood formation, GD had a minor effect on cambial cell division and xylem cell differentiation. Results also revealed that phloem girdling outweighed drought effects imposed on cambial activity. We explain our findings by accumulation of carbohydrates, osmotically active sugars and/or C based signaling compound(s) in response to girdling. Altogether, we conclude that wood formation in P. abies saplings is limited by C availability, which is most likely caused by high C demand belowground especially under drought. PMID- 28651355 TI - Evaluation of welfare parameters in laying hens on the basis of a Bavarian survey. AB - Health issues like infestation with poultry red mite (Dermanyssus gallinae) and behavioral problems such as feather pecking and cannibalism are reported as current problems on laying hen farms. However, the epidemiological prevalence of these issues in Bavaria, Germany, is not known. The objective of the present survey was to determine the epidemiological prevalence of health and behavioral parameters and the management of hen farms in practice. The survey was sent to all laying hen farmers with more than 1,000 hens in Bavaria, Germany, and contained questions regarding flock management, behavior problems and health issues. The response rate was 40.8% and surveys were answered regarding 293 individual flocks on 147 farms. Three-quarters (77.6%) of the respondents housed their hens under conventional conditions. Farming system had an influence (P <= 0.05) on several management measures and the hens' behavior. An infestation of the flocks with poultry red mite was stated in 65.7%, whereby a relationship existed with the farming system (P = 0.001) and the provision of an additional dust bath (P <= 0.001). The occurrence of feather pecking (18.5%) was related with the farming system (P = 0.001), the presence of roosters (P = 0.034), the locking of laying hens into the aviary (P = 0.006), not allowing access to the entire litter space after housing (P = 0.044) and nervous (P = 0.002) or chasing behavior (P <= 0.001) of laying hens. Similarly, cannibalism (15.0%) was related with locking hens into the aviary system (P <= 0.001) and not allowing access to the entire litter space (P = 0.026). According to these results, farmers should avoid locking the hens into the aviary or not allowing access to the entire litter space, because these measures relate to nervous behavior that may result in feather pecking or cannibalism. The provision of an additional dust bath is one of the management measures that can positively influence hens' health and behavior. PMID- 28651356 TI - Heterologous expression in Pichia pastoris and biochemical characterization of the unmodified sulfatase from Fusarium proliferatum LE1. AB - Sulfatases are a family of enzymes (sulfuric ester hydrolases, EC 3.1.6.-) that catalyze the hydrolysis of a wide array of sulfate esters. To date, despite the discovery of many sulfatase genes and the accumulation of data on numerous sulfated molecules, the number of characterized enzymes that are key players in sulfur metabolism remains extremely limited. While mammalian sulfatases are well studied due to their involvement in a wide range of normal and pathological biological processes, lower eukaryotic sulfatases, especially fungal sulfatases, have not been thoroughly investigated at the biochemical and structural level. In this paper, we describe the molecular cloning of Fusarium proliferatum sulfatase (F.p.Sulf-6His), its recombinant expression in Pichia pastoris as a soluble and active cytosolic enzyme and its detailed characterization. Gel filtration and native electrophoretic experiments showed that this recombinant enzyme exists as a tetramer in solution. The enzyme is thermo-sensitive, with an optimal temperature of 25 degrees C. The optimal pH value for the hydrolysis of sulfate esters and stability of the enzyme was 6.0. Despite the absence of the post translational modification of cysteine into Calpha-formylglycine, the recombinant F.p.Sulf-6His has remarkably stable catalytic activity against p-nitrophenol sulfate, with kcat = 0.28 s-1 and Km = 2.45 mM, which indicates potential use in the desulfating processes. The currently proposed enzymatic mechanisms of sulfate ester hydrolysis do not explain the appearance of catalytic activity for the unmodified enzyme. According to the available models, the unmodified enzyme is not able to perform multiple catalytic acts; therefore, the enzymatic mechanism of sulfate esters hydrolysis remains to be fully elucidated. PMID- 28651357 TI - Using Viral Gene Sequences to Compare and Explain the Heterogeneous Spatial Dynamics of Virus Epidemics. AB - Rabies is an important zoonotic disease distributed worldwide. A key question in rabies epidemiology is the identification of factors that impact virus dispersion. Here we apply new analytical methods, based on phylogeographic reconstructions of viral lineage movement, to undertake a comparative evolutionary-epidemiological study of the spatial dynamics of rabies virus (RABV) epidemics in different hosts and habitats. We compiled RABV data sets from skunk, raccoon, bat and domestic dog populations in order to investigate the viral diffusivity of different RABV epidemics, and to detect and compare the environmental factors that impact the velocity of viral spread in continuous spatial landscapes. We build on a recently developed statistical framework that uses spatially- and temporally-referenced phylogenies. We estimate several spatial statistics of virus spread, which reveal a higher diffusivity of RABV in domestic dogs compared with RABV in other mammals. This finding is explained by subsequent analyses of environmental heterogeneity, which indicate that factors relating to human geography play a significant role in RABV dispersion in domestic dogs. More generally, our results suggest that human-related factors are important worldwide in explaining RABV dispersion in terrestrial host species. Our study shows that phylogenetically informed viral movements can be used to elucidate the factors that impact virus dispersal, opening new opportunities for a better understanding of the impact of host species and environmental conditions on the spatial dynamics of rapidly evolving populations. PMID- 28651359 TI - Altered microRNA and Piwi-interacting RNA profiles in cumulus cells from patients with diminished ovarian reserve. AB - Diminished ovarian reserve (DOR) is defined as decreased number or quality of follicles and oocytes in a woman at childbearing age. It is estimated that up to 10% of women in the general population may suffer from DOR. This study aims to comprehensively characterize microRNA (miRNA) and Piwi-interacting RNA (piRNA) expression profiles in cumulus cells of DOR patients. Cumulus cells were collected from 20 women of similar chronological age who received assisted reproductive technology treatment: 10 with DOR and 10 with normal ovarian reserve (NOR). The small RNAs were extracted from each sample and reverse transcribed. Deep sequencing and bioinformatic analysis were performed to identify the small noncoding RNA profiles. The rRNAs were the most abundant small RNA class in cumulus cells derived from human MII oocytes, following were miRNAs and tRNAs. Twenty-six piRNAs, 79 annotated miRNAs, and 5 novel miRNAs were identified differentially expressed. In DOR group, the chromosomal strand bias patterns of piRNAs on chromosome 1, 3, 5, and X were distinct from its counterpart in NOR group. The involved biological pathways from the putative target genes of differentially expressed miRNAs were enriched by using GO analysis and KEGG pathway annotations, and mTOR pathway and meiosis-associated biological processes were enriched. This study provided additional information on the dysfunctions of cumulus cells in patients with diminished ovarian reserve. Future investigations will involve the characterization of specific functional roles of noncoding small RNA in ovarian reserve regulation. PMID- 28651358 TI - REM Sleep Theta Changes in Frequent Nightmare Recallers. AB - Study Objectives: To replicate and expand upon past research by evaluating sleep and wake electroencephalographic spectral activity in samples of frequent nightmare (NM) recallers and healthy controls. Methods: Computation of spectral activity for sleep (non-REM and REM) and wake electroencephalogram recordings from 18 frequent NM recallers and 15 control participants. Results: There was higher "slow-theta" (2-5 Hz) for NM recallers than for controls during wake, non REM sleep and REM sleep. Differences were clearest for frontal and central derivations and for REM sleep cycles 2-4. There was also higher beta activity during NREM sleep for NM recallers. Findings partially replicate past research by demonstrating higher relative "slow-theta" (3-4Hz) for NM recallers than for controls. Conclusions: Findings are consistent with a neurocognitive model of nightmares that stipulates cross-state anomalies in emotion processing in NM prone individuals. PMID- 28651360 TI - Novel reproductive technologies to prevent mitochondrial disease. AB - BACKGROUND: The use of nuclear transfer (NT) has been proposed as a novel reproductive treatment to overcome the transmission of maternally-inherited mitochondrial DNA (mtDNA) mutations. Pathogenic mutations in mtDNA can cause a wide-spectrum of life-limiting disorders, collectively known as mtDNA disease, for which there are currently few effective treatments and no known cures. The many unique features of mtDNA make genetic counselling challenging for women harbouring pathogenic mtDNA mutations but reproductive options that involve medical intervention are available that will minimize the risk of mtDNA disease in their offspring. This includes PGD, which is currently offered as a clinical treatment but will not be suitable for all. The potential for NT to reduce transmission of mtDNA mutations has been demonstrated in both animal and human models, and has recently been clinically applied not only to prevent mtDNA disease but also for some infertility cases. In this review, we will interrogate the different NT techniques, including a discussion on the available safety and efficacy data of these technologies for mtDNA disease prevention. In addition, we appraise the evidence for the translational use of NT technologies in infertility. OBJECTIVE AND RATIONALE: We propose to review the current scientific evidence regarding the clinical use of NT to prevent mitochondrial disease. SEARCH METHODS: The scientific literature was investigated by searching PubMed database until Jan 2017. Relevant documents from Human Fertilisation and Embryology Authority as well as reports from both the scientific and popular media were also implemented. The above searches were based on the following key words: 'mitochondria', 'mitochondrial DNA'; 'mitochondrial DNA disease', 'fertility'; 'preimplantation genetic diagnosis', 'nuclear transfer', 'mitochondrial replacement' and 'mitochondrial donation'. OUTCOMES: While NT techniques have been shown to effectively reduce the transmission of heteroplasmic mtDNA variants in animal models, and increasing evidence supports their use to prevent the transmission of human mtDNA disease, the need for robust, long-term evaluation is still warranted. Moreover, prenatal screening would still be strongly advocated in combination with the use of these IVF-based technologies. Scientific evidence to support the use of NT and other novel reproductive techniques for infertility is currently lacking. WIDER IMPLICATIONS: It is mandatory that any new ART treatments are first adequately assessed in both animal and human models before the cautious implementation of these new therapeutic approaches is clinically undertaken. There is growing evidence to suggest that the translation of these innovative technologies into clinical practice should be cautiously adopted only in highly selected patients. Indeed, given the limited safety and efficacy data, close monitoring of any offspring remains paramount. PMID- 28651361 TI - Epigallocatechin gallate inhibits the type III secretion system of Gram-negative enteropathogenic bacteria under model conditions. AB - Epigallocatechin gallate (EGCG), a major polyphenol in green tea, inhibits the type III secretion system (T3SS) of enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively), Salmonella enterica serovar Typhimurium, and Yersinia pseudotuberculosis. The inhibitory effect causes the inhibition of hemolysis, cell invasion, cell adhesion and apoptosis, which are functions of the type III secretion device. In the case of EPEC, EspB accumulates in the cells. RT-PCR showed that the translation of EspB was not blocked. The transcription of escN, which supplies energy for the injection of the effector factor into the host cells, was also not inhibited. EGCG does not suppress the transcription and translation of T3SS constitutive protein in bacterial cells, but it seems to suppress the normal construction or secretion of T3SS. When Luria Bertani (LB) medium was used to visualize the EGCG-induced inhibition of T3SS, the inhibitory effect disappeared. The inhibition of T3SS was partially canceled when the T3SS inhibitory potency of EGCG was examined by adding yeast extract, which is a component of LB medium, to DMEM. These results suggest that EGCG probably inhibits secretion by suppressing some metabolic mechanisms of T3SS. PMID- 28651362 TI - Possible macrophage activation in melanoma patients receiving combined kinase inhibitor therapy following anti-PD-1 therapy: a cytokine profiling study of two cases. PMID- 28651363 TI - Multimodal mechanistic signatures for neurodegenerative diseases (NeuroMMSig): a web server for mechanism enrichment. AB - Motivation: The concept of a 'mechanism-based taxonomy of human disease' is currently replacing the outdated paradigm of diseases classified by clinical appearance. We have tackled the paradigm of mechanism-based patient subgroup identification in the challenging area of research on neurodegenerative diseases. Results: We have developed a knowledge base representing essential pathophysiology mechanisms of neurodegenerative diseases. Together with dedicated algorithms, this knowledge base forms the basis for a 'mechanism-enrichment server' that supports the mechanistic interpretation of multiscale, multimodal clinical data. Availability and implementation: NeuroMMSig is available at http://neurommsig.scai.fraunhofer.de/. Contact: martin.hofmann apitius@scai.fraunhofer.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28651364 TI - Temporal effects of prescribed burning on terpene production in Mediterranean pines. AB - Prescribed burning is used to reduce fuel hazard but underburning can damage standing trees. The effect of burning on needle terpene storage, a proxy for secondary metabolism, in fire-damaged pines is poorly understood despite the protection terpenes confer against biotic and abiotic stressors. We investigated variation in needle terpene storage after burning in three Mediterranean pine species featuring different adaptations to fire regimes. In two pure-stands of Pinus halepensis Mill. and two mixed-stands of Pinus sylvestris L. and Pinus nigra ssp. salzmanni (Dunal) Franco, we compared 24 h and 1 year post-burning concentrations with pre-burning concentrations in 20 trees per species, and evaluated the relative contribution of tree fire severity and physiological condition (delta13C and N concentration) on temporal terpene dynamics (for mono- sesqui- and diterpenes). Twenty-four hours post-burning, monoterpene concentrations were slightly higher in P. halepensis than at pre-burning, while values were similar in P. sylvestris. Differently, in the more fire-resistant P. nigra monoterpene concentrations were lower at 24 h, compared with pre-burning. One year post-burning, concentrations were always lower compared with pre- or 24 h post-burning, regardless of the terpene group. Mono- and sesquiterpene variations were negatively related to pre-burning delta13C, while diterpene variations were associated with fire-induced changes in needle delta13C and N concentration. At both post-burning times, mono- and diterpene concentrations increased significantly with crown scorch volume in all species. Differences in post-burning terpene contents as a function of the pine species' sensitivity to fire suggest that terpenic metabolites could have adaptive importance in fire prone ecosystems in terms of flammability or defence against biotic agents post burning. One year post-burning, our results suggest that in a context of fire induced resource availability, pines likely prioritize primary rather than secondary metabolism. Overall, this study contributes to the assessment of the direct and indirect effects of fire on pine terpene storage, providing valuable information about their vulnerability to biotic and abiotic stressors throughout time. PMID- 28651366 TI - Combining fixed effects and instrumental variable approaches for estimating the effect of psychosocial job quality on mental health: evidence from 13 waves of a nationally representative cohort study. AB - Background: Previous studies suggest that poor psychosocial job quality is a risk factor for mental health problems, but they use conventional regression analytic methods that cannot rule out reverse causation, unmeasured time-invariant confounding and reporting bias. Methods: This study combines two quasi experimental approaches to improve causal inference by better accounting for these biases: (i) linear fixed effects regression analysis and (ii) linear instrumental variable analysis. We extract 13 annual waves of national cohort data including 13 260 working-age (18-64 years) employees. The exposure variable is self-reported level of psychosocial job quality. The instruments used are two common workplace entitlements. The outcome variable is the Mental Health Inventory (MHI-5). We adjust for measured time-varying confounders. Results: In the fixed effects regression analysis adjusted for time-varying confounders, a 1 point increase in psychosocial job quality is associated with a 1.28-point improvement in mental health on the MHI-5 scale (95% CI: 1.17, 1.40; P < 0.001). When the fixed effects was combined with the instrumental variable analysis, a 1 point increase psychosocial job quality is related to 1.62-point improvement on the MHI-5 scale (95% CI: -0.24, 3.48; P = 0.088). Conclusions: Our quasi experimental results provide evidence to confirm job stressors as risk factors for mental ill health using methods that improve causal inference. PMID- 28651367 TI - Alternative RNA Splicing Associated With Mammalian Neuronal Differentiation. AB - Alternative pre-mRNA splicing (AS) produces multiple isoforms of mRNAs and proteins from a single gene. It is most prevalent in the mammalian brain and is thought to contribute to the formation and/or maintenance of functional complexity of the brain. Increasing evidence has documented the significant changes of AS between different regions or different developmental stages of the brain, however, the dynamics of AS and the possible function of it during neural progenitor cell (NPC) differentiation is less well known. Here, using purified NPCs and their progeny neurons isolated from the embryonic mouse cerebral cortex, we characterized the global differences of AS events between the 2 cell types by deep sequencing. The sequencing results revealed cell type-specific AS in NPCs and neurons that are important for distinct functions pertinent to the corresponding cell type. Our data may serve as a resource useful for further understanding how AS contributes to molecular regulations in NPCs and neurons during cortical development. PMID- 28651368 TI - Risk of Recurrence in Pituitary Neuroendocrine Tumors: A Prospective Study Using a Five-Tiered Classification. AB - Background: Most pituitary neuroendocrine tumors (PitNETs) show benign behavior, but a substantial number are invasive, recur, or resist medical treatment. Based on a retrospective case-control study, we recently proposed a classification of PitNETs of prognostic relevance. This prospective study aims to test the value of this classification in an independent patient cohort. Methods: All patients who underwent PitNET surgery from 2007 to 2012 in one single center were included. Using a grading system based on invasion on magnetic resonance imaging, immunocytochemical profile, Ki-67, mitotic index, and p53 positivity, tumors were classified. Progression-free survival of the graded tumors was calculated by the Kaplan-Meier method and compared using the log-rank test. A multivariate analysis, using a Cox regression model, was also performed. Results: In total, 365 patients had grade 1a PitNETs (51.2%), followed by grade 2a (32.3%), 2b (8.8%), and 1b tumors (7.7%). Of 213 patients with a follow-up, 42% had recurrent (n = 52) or progressive disease (n = 37) at 3.5 years. Grade was a significant predictor of progression-free survival (P < 0.001). Multivariate analysis indicated grade (P < 0.001), age (P = 0.035), and tumor type (P = 0.028) as independent predictors of recurrence and/progression. This risk was 3.72-fold higher for a grade 2b tumor compared with grade 1a tumor. Conclusions: Our data suggest that classification of PitNETs into five grades is of prognostic value to predict postoperative tumor behavior and identifies patients who have a high risk of early recurrence or progression. It therefore will allow clinicians to adapt their therapeutic strategies and stratify patients in future clinical trials. PMID- 28651365 TI - Cathepsin K Inhibitors for Osteoporosis: Biology, Potential Clinical Utility, and Lessons Learned. AB - Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast-bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for <=5 years of treatment and improves bone strength at the spine and hip. Compared with other antiresorptive agents, cathepsin K inhibition is nearly equally efficacious for reducing biochemical markers of bone resorption but comparatively less active for reducing bone formation markers. Despite multiple efforts to develop cathepsin K inhibitors, potential concerns related to off-target effects of the inhibitors against other cathepsins and cathepsin K inhibition at nonbone sites, including skin and perhaps cardiovascular and cerebrovascular sites, prolonged the regulatory approval process. A large multinational randomized, double-blind phase III study of odanacatib in postmenopausal women with osteoporosis was recently completed. Although that study demonstrated clinically relevant reductions in fractures at multiple sites, odanacatib was ultimately withdrawn from the regulatory approval process after it was found to be associated with an increased risk of cerebrovascular accidents. Nonetheless, the underlying biology and clinical effects of cathepsin K inhibition remain of considerable interest and could guide future therapeutic approaches for osteoporosis. PMID- 28651369 TI - Reduced Thalamus Volume May Reflect Nicotine Severity in Young Male Smokers. AB - Introduction: Nicotine acts as an agonist at presynaptic nicotinic acetylcholine receptors and to facilitate synaptic release of several neurotransmitters including dopamine and glutamate. The thalamus has the highest density of nicotinic acetylcholine receptors in the brain, which may make this area more vulnerable to the addictive effects of nicotine. However, the volume of thalamus abnormalities and the association with smoking behaviors in young smokers remains unknown. Methods: Thirty-six young male smokers and 36 age-, gender- and education-matched nonsmokers participated in the current study. The nicotine dependence severity and cumulative effect were assessed with the Fagerstrom test for nicotine dependence (FTND) and pack-years. We used subcortical volume analyses method in FreeSurfer to investigate the thalamus volume differences between young smokers and nonsmokers. Correlation analysis was used to investigate the relationship between thalamus volume and smoking behaviors (pack years and FTND) in young smokers. Results and Conclusions: Relative to nonsmokers, the young smokers showed reduced volume of bilateral thalamus. In addition, the left thalamus volume was correlated with FTND in young smokers. It is hoped that our findings can shed new insights into the neurobiology of young smokers. Implications: In this article, we investigated the changes of thalamus volume in young male smokers compared with nonsmokers. Reduced left thalamus volume was correlated with FTND in young smokers, which may reflect nicotine severity in young male smokers. PMID- 28651370 TI - Changes in Visceral Adiposity, Subcutaneous Adiposity, and Sex Hormones in the Diabetes Prevention Program. AB - Context: The degree to which changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) relate to corresponding changes in plasma sex steroids is not known. Objective: We examined whether changes in VAT and SAT areas assessed by computed tomography were associated with changes in sex hormones [dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG)] among Diabetes Prevention Program participants. Design: Secondary analysis of a randomized trial. Participants: Overweight and glucose-intolerant men (n = 246) and women (n = 309). Interventions: Intensive lifestyle change with goals of weight reduction and 150 min/wk of moderate intensity exercise or metformin administered 850 mg twice a day or placebo. Main Outcome Measures: Associations between changes in VAT, SAT, and sex hormone changes over 1 year. Results: Among men, reductions in VAT and SAT were both independently associated with significant increases in total testosterone and SHBG in fully adjusted models. Among women, reductions in VAT and SAT were both independently associated with increases in SHBG and associations with estrone differed by menopausal status. Associations were similar by race/ethnicity and by randomization arm. No significant associations were observed between change in fat depot with change in estradiol or DHEAS. Conclusions: Among overweight adults with impaired glucose intolerance, reductions in either VAT and SAT were associated with increased total testosterone in men and higher SHBG in men and women. Weight loss may affect sex hormone profiles via reductions in visceral and subcutaneous fat. PMID- 28651371 TI - Sleep and Physiological Dysregulation: A Closer Look at Sleep Intraindividual Variability. AB - Study Objectives: Variable daily sleep (ie, higher intraindividual variability; IIV) is associated with negative health consequences, but potential physiological mechanisms are poorly understood. This study examined how the IIV of sleep timing, duration, and quality is associated with physiological dysregulation, with diurnal cortisol trajectories as a proximal outcome and allostatic load (AL) as a multisystem distal outcome. Methods: Participants are 436 adults (Mage +/- standard deviation = 54.1 +/- 11.7, 60.3% women) from the Midlife in the United States study. Sleep was objectively assessed using 7-day actigraphy. Diurnal cortisol was measured via saliva samples (four/day for 4 consecutive days). AL was measured using 23 biomarkers from seven systems (inflammatory, hypothalamic pituitary-adrenal axis, metabolic glucose and lipid, cardiovascular, parasympathetic, sympathetic) using a validated bifactor model. Linear and quadratic effects of sleep IIV were estimated using a validated Bayesian model. Results: Controlling for covariates, more variable sleep timing (p = .04 for risetime, p = .097 for bedtime) and total sleep time (TST; p = .02), but not mean sleep variables, were associated with flatter cortisol diurnal slope. More variable sleep onset latency and wake after sleep onset, later average bedtime, and shorter TST were associated with higher AL adjusting for age and sex (p values < .05); after controlling for all covariates, however, only later mean bedtime remained significantly associated with higher AL (p = .04). Conclusions: In a community sample of adults, more variable sleep patterns were associated with blunted diurnal cortisol trajectories but not with higher multisystem physiological dysregulation. The associations between sleep IIV and overall health are likely complex, including multiple biopsychosocial determinants and require further investigation. PMID- 28651372 TI - Living Arrangements, Disability and Gender of Older Adults Among Rural South Africa. AB - Objective: A limited understanding exists of the relationship between disability and older persons' living arrangements in low and middle-income countries (LMICs). We examine the associations between living arrangements, disability, and gender for individuals older than 50 years in rural South Africa. Method: Using the Study on global AGEing and adult health (SAGE) survey and Agincourt Health and socio-Demographic Surveillance System (HDSS) data, we explore older persons' self-reported disability by living arrangements and gender, paying particular attention to various multigenerational arrangements. Results: Controlling for past disability status, a significant relationship between living arrangements and current disability remains, but is moderated by gender. Older persons in households where they may be more "productive" report higher levels of disability; there are fewer differences in women's than men's reported disability levels across living arrangement categories. Discussion: This study underscores the need to examine living arrangements and disability through a gendered lens, with particular attention to heterogeneity among multigenerational living arrangements. Some living arrangements may take a greater toll on older persons than others. Important policy implications for South Africa and other LMICs emerge among vibrant debates about the role of social welfare programs in improving the health of older individuals. PMID- 28651373 TI - Sex-dependent Differences in Liver and Gut Metabolomic Profiles With Acarbose and Calorie Restriction in C57BL/6 Mice. AB - Acarbose, an alpha-glucosidase inhibitor used in treating type 2 diabetes, impairs complex carbohydrate digestion and absorption and extends life span in mice (without a requisite reduction in food intake). To assess sex-differential effects coincident with calorie restriction versus a nonrestricted longevity enhancing intervention, we evaluated the metabolite profiles (by liquid chromatography-mass spectroscopy) from livers and cecal contents of C57BL/6J mice (n = 4/sex/group), which were maintained for 10 months under one of the three diet treatments: ad libitum control diet (CON), ad libitum control diet containing 0.1% acarbose (ACA), or 40% calorie restriction using the control diet (CR). Principal component analysis revealed sex-differential profiles with ACA in livers. Of the identified metabolites (n = 621) in liver, CR significantly altered ~44% (males:187?/131?, females:74?/148?) compared with CON, in contrast with ACA (M:165?/61?, F:52?/60?). Dissimilarity in ACA-F liver metabolites was observed for ~50% of common metabolites from ACA-M and CR-M/F. CR resulted in fewer significant cecal metabolite differences (n = 615 metabolites; M:86?/66?, F:51?/48? vs CON), relative to ACA treatment (M:32?/189?, F:36?/137?). Metabolomic profiling identifies sex-differential and tissue-specific effects with amino acid metabolism sub-pathways including those involving tryptophan, branch-chain and sulfur amino acids, and the urea cycle, as well as bile acid, porphyrin, and cofactor metabolism pathways. PMID- 28651375 TI - Chromatographic and Computational Assessment of Lipophilicity of New Anticancer Acetylenequinoline Derivatives. AB - The lipophilicity of a series of anticancer propargylquinoline derivatives is investigated using both chromatographic and computational methods. The parameters of the tested compounds' relative lipophilicity (logkw) are determined experimentally by the high-performance liquid chromatographic method (RP-HPLC, Accucore C18 column), using mixtures of acetonitrile and water as mobile phases. Mobile phase acetonitrile concentrations range between 50 and 80%. The logk values of the investigated compounds are linearly dependent upon the acetonitrile concentration. The analysis led to the calculation of the logkw parameter values for each of the tested compounds. The parameter logkw is discussed in terms of the relationship between structure and lipophilicity and consequently, transformed into the parameter logPHPLC using the calibration curve. The partition coefficients of the tested compounds (logPcalc) are also calculated by selected computer programs. A regression analysis and the sum of ranking differences are used to compare the lipophilic parameters of 15 acetylenequinoline derivatives, which were experimentally obtained (logPHPLC) and calculated using different mathematical methods (logPcalc). The 13C NMR spectra are used to examine the electronic relationships between properties and lipophilicity for the studied compounds. A regression study conducted on 15 compounds exhibits a linear correlation between lipophilicity and electronic properties, expressed as the 13C NMR chemical shift (R2 = 0.98). PMID- 28651374 TI - CD70, a novel target of CAR T-cell therapy for gliomas. AB - Background: Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. Results: CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. Conclusion: These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas. PMID- 28651376 TI - Comparison of Sampling Strategies for Tobacco Retailer Inspections to Maximize Coverage in Vulnerable Areas and Minimize Cost. AB - Introduction: In the United States, tens of thousands of inspections of tobacco retailers are conducted each year. Various sampling choices can reduce travel costs, emphasize enforcement in areas with greater noncompliance, and allow for comparability between states and over time. We sought to develop a model sampling strategy for state tobacco retailer inspections. Methods: Using a 2014 list of 10,161 North Carolina tobacco retailers, we compared results from simple random sampling; stratified, clustered at the ZIP code sampling; and, stratified, clustered at the census tract sampling. We conducted a simulation of repeated sampling and compared approaches for their comparative level of precision, coverage, and retailer dispersion. Results: While maintaining an adequate design effect and statistical precision appropriate for a public health enforcement program, both stratified, clustered ZIP- and tract-based approaches were feasible. Both ZIP and tract strategies yielded improvements over simple random sampling, with relative improvements, respectively, of average distance between retailers (reduced 5.0% and 1.9%), percent Black residents in sampled neighborhoods (increased 17.2% and 32.6%), percent Hispanic residents in sampled neighborhoods (reduced 2.2% and increased 18.3%), percentage of sampled retailers located near schools (increased 61.3% and 37.5%), and poverty rate in sampled neighborhoods (increased 14.0% and 38.2%). Conclusions: States can make retailer inspections more efficient and targeted with stratified, clustered sampling. Use of statistically appropriate sampling strategies like these should be considered by states, researchers, and the Food and Drug Administration to improve program impact and allow for comparisons over time and across states. Implications: The authors present a model tobacco retailer sampling strategy for promoting compliance and reducing costs that could be used by US states and the Food and Drug Administration (FDA). The design is feasible to implement in North Carolina. Use of the sampling design would help document the impact of FDA's compliance and enforcement program, save money, and emphasize inspections in areas where they are needed most. FDA should consider requiring probability-based sampling in their inspections contracts with states and private contractors. PMID- 28651377 TI - Can epidemiological studies uncover the origin of Behcet's disease? PMID- 28651378 TI - Can beta-blockers be used safely in non-cardiac surgery? Important lessons to be learned. PMID- 28651379 TI - KLF4 is a tumor suppressor in anaplastic meningioma stem-like cells and human meningiomas. AB - Meningiomas are the most common primary tumors in central nervous system. While recent studies have revealed genetic clues to lower grade human meningiomas, the molecular determinants driving the progression and recurrence of anaplastic meningioma, the most malignant subtype with a low prevalence but high morbidity, are still poorly understood. It has been proposed that high recurrence rates of malignant meningiomas are linked to cancer stem cells. Indeed, tumor stem-like cells have been isolated from various meningioma subtypes, but never been obtained from anaplastic meningioma. In this study, we successfully isolated stem like cells from human anaplastic meningioma. These cells are capable of forming spheres and initiating xenograft tumors that recapitulate anaplastic meningioma phenotypes, and thus could serve as an in vitro model for malignant meningiomas. KLF4, a transcription factor known for its role in stemness maintenance, was identified as one of the most frequently mutated genes in the benign secretory meningioma. Interestingly, we found that KLF4 is downregulated in anaplastic meningioma compared with low-grade meningioma subtypes. By manipulating KLF4 expression in anaplastic meningioma stem-like cells, we demonstrated that KLF4 acts as a tumor suppressor during malignant progression in meningioma, affecting apoptosis, proliferation, invasion, and cell cycle. These results suggest a potential therapeutic value of KLF4 for clinical intervention of anaplastic meningioma. PMID- 28651380 TI - Utilization of acid pre-treated coconut dregs as a substrate for production of detergent compatible lipase by Bacillus stratosphericus. AB - In recent years, many efforts have been directed to explore the methods to reduce the production costs of industrial lipase by improving the yield and the use of low-cost agricultural wastes. Coconut dregs, which is a lignocellulosic by product from coconut oil and milk processing plants, is rich in cellulose (36%) and crude fat (9%). A newly isolated Bacillus stratosphericus has been demonstrated to perform cellulose hydrolysis on coconut dregs producing fermentable sugars. The highest extracellular lipase activity of 140 U/mL has been achieved in submerged fermentation with acid pre-treated coconut dregs. The lipase was found to be active over a wide range of temperatures and pHs. The activity of lipase can be generally increased by the presence of detergent ingredients such as Tween-80, cetyltrimethylammonium bromide, hydrogen peroxide and phosphate per sulphate. The great compatibility of lipase in commercial detergents has also underlined its potential as an additive ingredient in biodetergent formulations. PMID- 28651381 TI - Meta-barcoding in combination with palynological inference is a potent diagnostic marker for honey floral composition. AB - Identification of floral samples present in honey is important in order to determine the medicinal value, enhance the production of honey as well as to conserve the honey bees. Traditional approaches for studying pollen samples are based on microscopic observation which is laborious, time intensive and requires specialized palynological knowledge. Present study compares two composite honey metagenome collected from 20 samples in Mizoram, Northeast India using three gene loci- rbcL, matK and ITS2 that was sequenced using a next-generation sequencing (NGS) platform (Illumina Miseq). Furthermore, a classical palynology study for all 20 samples was carried out to evaluate the NGS approach. NGS based approach and pollen microscopic studies were able to detect the most abundant floral components of honey. We investigated the plants that were frequently used by honey bees by examining the results obtained from both the techniques. Microscopic examination of pollens detected plants with a broad taxonomic range covering 26 families. NGS based multigene approach revealed diverse plant species, which was higher than in any other previously reported techniques using a single locus. Frequently found herbaceous species were from the family Poaceae, Myrtaceae, Fabaceae and Asteraceae. The future NGS based approach using multi loci target, with the help of an improved and robust plant database, can be a potential replacement technique for tedious microscopic studies to identify the polleniferous plants. PMID- 28651382 TI - Assignment of sigma factors of RNA polymerase to promoters in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is an important industrial producer of various amino acids and other metabolites. The C. glutamicum genome encodes seven sigma subunits (factors) of RNA polymerase: the primary sigma factor SigA (sigmaA), the primary-like sigmaB and five alternative sigma factors (sigmaC, sigmaD, sigmaE, sigmaH and sigmaM). We have developed in vitro and in vivo methods to assign particular sigma factors to individual promoters of different classes. In vitro transcription assays and measurements of promoter activity using the overexpression of a single sigma factor gene and the transcriptional fusion of the promoter to the gfpuv reporter gene enabled us to reliably define the sigma factor dependency of promoters. To document the strengths of these methods, we tested examples of respective promoters for each C. glutamicum sigma factor. Promoters of the rshA (anti-sigma for sigmaH) and trxB1 (thioredoxin) genes were found to be sigmaH-dependent, whereas the promoter of the sigB gene (sigma factor sigmaB) was sigmaE- and sigmaH-dependent. It was confirmed that the promoter of the cg2556 gene (iron-regulated membrane protein) is sigmaC-dependent as suggested recently by other authors. The promoter of cmt1 (trehalose corynemycolyl transferase) was found to be clearly sigmaD-dependent. No sigmaM dependent promoter was identified. The typical housekeeping promoter P2sigA (sigma factor sigmaA) was proven to be sigmaA-dependent but also recognized by sigmaB. Similarly, the promoter of fba (fructose-1,6-bisphosphate aldolase) was confirmed to be sigmaB-dependent but also functional with sigmaA. The study provided demonstrations of the broad applicability of the developed methods and produced original data on the analyzed promoters. PMID- 28651383 TI - Rising temperature stimulates the biosynthesis of water-soluble fluorescent yellow pigments and gene expression in Monascus ruber CGMCC10910. AB - Monascus species can produce secondary metabolites that have a polyketide structure. In this study, four types of extracellular water-soluble yellow pigments (Y1-Y4) were generated by submerged fermentation with Monascus ruber CGMCC 10910, of which Y3 and Y4 had strong yellow fluorescence. The composition of the pigment mixtures was closely related to the fermentation temperature. The dominating pigments changed from Y1 to Y3 and Y4 when fermentation temperature increased from 30 to 35 degrees C. Increasing the temperature to 35 degrees C changed the metabolic pathways of the pigments, which inhibited the biosynthesis of Y1 and enhanced the biosynthesis of Y3 and Y4. Moreover, the yield of Y1 reduced insignificantly, while the yields of Y3 and Y4 increased by 98.21 and 79.31% respectively under two-stage temperature fermentation condition. The expression levels of the relative pigment biosynthetic genes, such as MpFasA2, MpFasB2, MpPKS5, mppR1, mppB, and mppE, were up-regulated at 35 degrees C. The two-stage temperature strategy is a potential method for producing water-soluble Monascus yellow pigments with strong yellow fluorescence. PMID- 28651384 TI - Agaricus bisporus production on substrates pasteurized by self-heating. AB - The aim of this work was to determine if the self-heating pasteurization procedure is technically applicable to the cultivation of Agaricus bisporus. Firstly the substrates alone (corncob, Pangola grass and a mixture of both ingredients with wood shavings) were tested. Two supplementation trials were then undertaken using soybean, wheat bran, sheep manure, sesame seed, black bean and chia. Highest production values (BE = 176.3% and Y = 26.6 kg/m2) were obtained using a 9% supplement, with a formula consisting of 25% each of soybean, black bean, wheat bran and chia, added at spawning and at casing. These results were comparable to those obtained with the Phase II compost traditionally used for A. bisporus cultivation. PMID- 28651385 TI - Enhancement of Catalytic Activity of Reduced Graphene Oxide Via Transition Metal Doping Strategy. AB - To compare the catalytic oxidation activities of reduced graphene oxide (rGO) and rGO samples doped with five different transition metals (TM-rGO), we determine their effects on the oxidation of L-cysteine (Cys) in aqueous solution by performing electrochemistry (EC) measurements and on the photocatalytic oxidation of Cys by using high-resolution photoemission spectroscopy (HRPES) under UV illumination. Our results show that Cr-, Fe-, and Co-doped rGO with 3+ charge states (stable oxide forms: Cr3+, Fe3+, and Co3+) exhibit enhanced catalytic activities that are due to the charge states of the doped metal ions as we compare them with Cr-, Fe-, and Co-doped rGO with 2+ charge states. The SEM images and the corresponding EC measurements for (a) Cr3+, (b) Fe3+, and PMID- 28651386 TI - Optical and Electrical Characteristics of Silicon Nanowires Prepared by Electroless Etching. AB - Silicon nanowires (SiNWs) were fabricated by the electroless etching of an n-type Si (100) wafer in HF/AgNO3. Vertically aligned and high-density SiNWs are formed on the Si substrates. Various shapes of SiNWs are observed, including round, rectangular, and triangular. The recorded maximum reflectance of the SiNWs is approximately 19.2%, which is much lower than that of the Si substrate (65.1%). The minimum reflectance of the SiNWs is approximately 3.5% in the near UV region and 9.8% in the visible to near IR regions. The calculated band gap energy of the SiNWs is found to be slightly higher than that of the Si substrate. The I-V characteristics of a freestanding SiNW show a linear ohmic behavior for a forward bias up to 2.0 V. The average resistivity of a SiNW is approximately 33.94 Omega cm. PMID- 28651387 TI - [Importance of smoke-free for healthy China]. AB - After WHO Framework Convention on Tobacco Control coming into force for 11 years, the tobacco control has made progress in the world and China. Development and implementation of tobacco control policy are fundamental for tobacco control. This paper introduces the effects of different tobacco control policies in different countries, summarizes the progress and challenges in prohibiting smoking in public place in China. In China, the goal of health for all can be only met by achieving smoke-free. PMID- 28651388 TI - [Tobacco use rate and associated factors in middle school students in China]. AB - Objective: To understand tobacco use rate and explore the factors associated with tobacco use in middle school students in China. Methods: A self-administered questionnaire survey was conducted among 155 117 eligible middle students selected through multi-stage stratified cluster sampling from 31 provinces of China. The questionnaire consists of the following topics: tobacco use and cessation, passive smoking, access to tobacco products, tobacco control and tobacco advertisement, and knowledge about and attitudes to tobacco. Software SAS 9.3 was used for sample weighting and data analysis. Results: Current tobacco use rate was 6.9% in middle school students in China. The rate was higher in boys (11.2%) than in girls (2.2%), and in rural area (7.8%) than in urban area (4.8%). Students in western area had the highest tobacco use rate (10.3%), followed by the students in middle area (6.4%), and the rate in students in eastern area was lowest (4.5%). Parent smoking (especially mother smoking), friend smoking, teacher smoking, pocket money for a week>20 yuan, tobacco advertisement or promotion, passive smoking, misconception of tobacco addiction, active attitude to smoking behavior were the risk factors for tobacco use. Conclusions: Smoking rate in boys in China was higher than the average global level. A comprehensive intervention strategy by Framework Convention on Tobacco Control should be used to reduce tobacco use in adolescents, including health education, increasing cigarette price, banning tobacco advertisement and promotion, and smoke-free legislation. PMID- 28651389 TI - [Survey of degree of passive smoking exposure and related risk awareness in adults in China, 2013]. AB - Objective: To understand the passive smoking exposure level and related risk awareness in adults in China in 2013. Methods: A face-to-face questionnaire survey was conducted in 179 570 adults selected through multistage cluster sampling from Chinese chronic disease and risk factors surveillance sample population (2013) in 302 surveillance sites. The effective sample size was 176 179 adults. After comprehensive weighting of the samples, the passive smoking exposure level and the awareness rate of related risks were analyzed. Results: The passive smoking exposure rate was 52.8% (95%CI: 51.2%-54.4%) and the rate decreased with age (chi(2)=515.8, P<0.000 1). The exposure rate was highest in persons engaged in commercial services (61.6%, 95%CI: 58.6%-64.5%). The awareness rate of related risks was 67.9% (95%CI: 65.8%-69.9%). The awareness rate was higher in urban area (77.0%, 95%CI: 75.0%-79.1%) than in rural area (60.0%, 95%CI: 57.7%-62.4%), in males (69.8%, 95%CI: 67.8%-71.7%) than in females (65.9%, 95%CI: 63.7%-68.1%). The awareness rate of three related diseases in urban residents (49.8%, 95%CI: 47.3%-52.4%) were higher than that in rural residents (37.9%, 95%CI: 35.4%-40.5%); the awareness rate of passive smoking related lung cancer was highest (88.5%, 95%CI: 87.5%-89.5%), followed by lung disease in children (70.0%, 95%CI: 68.1%-71.9%), the awareness rate of passive smoking related heart disease was lowest (46.8%, 95%CI: 44.6%-49.1%). Conclusion: The passive smoking exposure level is relatively high in adults in China, and the awareness rate of passive smoking exposure risks, especially heart disease, is low. PMID- 28651390 TI - [Cross-sectional survey of smoking and smoking cessation behaviors in adults in Jiangxi province, 2013]. AB - Objective: To describe the prevalence of smoking and smoking cessation in adults of Jiangxi province in 2013. Methods: Multi-stage stratified cluster random sampling method was used to select 6 000 individuals aged >=18 years from 10 chronic and non-communicable disease and risk factor surveillance points of Jiangxi province in 2013. A face-to-face questionnaire survey was carried out to collect information about the risk factors for chronic and non-communicable diseases and 5 997 records were used in final analysis of smoking and smoking cessation. Sample was weighted to represent the adult population of Jiangxi province. The prevalence of different groups were analyzed. Results: The prevalence of current smoking of the sample was 21.53% (1 291/5 997). After complex weighting, the prevalence of smoking was 26.07% in adults in Jiangxi (95%CI:23.48%-28.66%), and it was much higher in men (50.62%, 95%CI: 46.31% 54.94%) than in women(1.46%, 95%CI: 0.57%-2.35%), the difference was statistically significant (P<0.05). The differences in smoking prevalence were significant among different age groups (P=0.029), and the smoking prevalence increased with educational level, but decreased with the worse of self-reported health condition. Most current smokers smoked every day (87.16%, 95%CI: 83.29% 91.03%) and averagely 19.27 (95%CI: 17.69-20.85) cigarettes were smoked daily. The proportion of smokers with average daily consumption >=20 cigarettes was 64.74% (95%CI: 55.79%-73.70%). The smokers'average age of starting daily smoking was 20.28 (95%CI: 19.74-20.82) years old, which was lower in men [20.11(95%CI: 19.61-20.61) years old] than in women [26.88(95%CI: 24.73-29.03) years old], the difference was statistically significant (P<0.05). Among the male smokers, 27.04%(95%CI:18.91%-35.16%) of male smokers was less than 18 years old when they started daily smoking, and the proportion was 17.46%(95%CI: 0%-37.71%) in female smokers. The smoking cessation rate was 14.80% (95%CI: 10.88%-18.72%) and increased with age, the increase of income level and the worse of self-reported health condition. The successful smoking cessation rate was 10.89%(95%CI: 8.36% 13.42%). Only 32.10%(95%CI: 21.95%-42.25%) of current smokers attempted to quit smoking. The prevalence of passive smoking was 54.71% (95%CI: 44.20%-65.21%). Conclusion: The prevalence of smoking was high in adults in Jiangxi and the proportion of heavy smokers was large. Less smokers quitted smoking and the proportion of current smokers attempting to quit smoking was small. Males and adolescent smokers are targeted populations for tobacco control and special strategy should be taken according to the characteristics of smoking population in Jiangxi. PMID- 28651391 TI - [Prevalence of myopia and increase trend in children and adolescents aged 7-18 years in Han ethnic group in China, 2005-2014]. AB - Objective: To understand and evaluate the prevalence of myopia and its trend in children and adolescents aged 7-18 years in Han ethnic group in China from 2005 to 2014, and provide evidence for the prevention of myopia. Methods: The data of 2005, 2010 and 2014 Chinese National Students Constitution and Health Surveys were collected. The children and adolescents with complete detection data of binoculus were selected as study subjects. The sample size of three studies were 233 108, 215 319 and 212 743, respectively. The method of curve fitting was used to simulate the myopia detection increase model and analyze the gender and area specific myopia detection increase trends and characteristics from 2005 to 2014. Results: The overall myopia detection rate increased gradually in the children and adolescents aged 7 to 18, which was 47.5% in 2005, 55.5% in 2010 and 57.1% in 2014, respectively. The increase slowed in 2014. A"parabola" shape of myopia detection increase rate was observed. Myopia detection rate increased with age before puberty and decreased with age after puberty gradually. A"cross phenomenon" of myopia detection increase was observed in boys and girls between urban and rural areas. The increase of myopia detection was mainly in urban students before puberty and in rural students after puberty. The age of myopia prevalence peak has become earlier constantly in children and adolescents aged 7 18 years from 2005 to 2014, which was 13 years old in 2005, 12 years old in 2010 and 11 years old in 2014. The increase rate was about 7%. During 2005-2014, the increase rate of myopia detection gradually increased in younger students and tended to zero in older students. Conclusion: The detection rate of myopia was still high in children and adolescents in China. The age of myopia prevalence peak has become earlier gradually. PMID- 28651392 TI - [Analysis of hemoglobin level and anemia prevalence in students aged 7-14 years in China, 2014]. AB - Objective: To analyze the level of hemoglobin level and the prevalence of anemia in students aged 7-14 years in China. Methods: According to the 2010 Chinese National Surveys on Students'Constitution and Health, 71 130 students who were aged 7, 9, 12 and 14 years and had received hemoglobin test were sampled as the subjects, WHO anemia diagnostic criteria was used to explore the hemoglobin level and the prevalence of anemia. Results: The mean concentrations of hemoglobin were (129.25+/-11.37) g/L, (131.04+/-11.08) g/L, (135.02+/-12.12) g/L and (138.47+/ 13.97) g/L and the prevalence of anemia was 9.0%, 6.5%, 8.6% and 7.7% respectively in 7, 9, 12 and 14 years old students. The prevalence of anemia was 9.7% in girls, significant higher than that in boys (6.2%), and 8.8% in rural students, significantly higher than that in urban students (7.1%). The hemoglobin levels were (133.19+/-12.56) g/L, (133.28+/-12.76) g/L, (134.24+/-12.73) g/L and (133.79+/-12.16) g/L and the prevalence of anemia were 8.8%, 8.3%, 6.7% and 5.9% respectively in thin, normal, overweight and fat students, there were significant differences among four groups. Conclusion: The prevalence of anemia in students aged 7-14 years in China was still high, and there was significant differences among different gender, area, age and nutritional status groups. PMID- 28651393 TI - [A cross-section study on physical endurance level in primary and middle school students in China, 2014]. AB - Objective: To understand the physical endurance level of primary and middle school students in China in 2014, and identify the factors influencing students'physical endurance. Methods: Data were collected from"National School Student Physical Fitness and Health Surveillance in 2014" , a total of 142 708 primary and middle school students with complete information were included in the analysis. The age, gender and area specific failure rates of endurance running of students were analyzed, the differences were analyzed with chi(2) test, and the factors influencing students' physical endurance were identified with log binomial regression model. Results: Among the 142 708 students, the failure rate of endurance running was 21.6% (30 867/142 708). The failure rate was 23.7% (16 891/71 388) in boys and 19.6% (13 976/71 320) in girls (chi(2)=347.73, P<0.05). And it was 24.8% in students in urban area (17 713/71 378), higher than that in students in rural area (18.4%, 13 154/71 330) (chi(2)=855.29, P<0.05). The failure rate of endurance running showed an upward trend with age. Insufficient physical education class hour (OR=1.13, 95%CI: 1.11-1.15), not taking breakfast daily (OR=1.22, 95%CI: 1.20-1.25), daily physical exercise time<1 hour (OR=1.44, 95%CI: 1.40-1.48), the screen watching time>2 hours (OR=1.16, 95%CI: 1.14-1.19) and overweight or obesity (OR=1.90, 95%CI: 1.86-1.95) might be the risk factors for the failure of physical endurance. Conclusion: The physical endurance of primary and secondary students in China was not optimistic, and the factors influencing their physical endurance included gender, living area, physical education class time, daily homework time, breakfast, daily exercise time and nutrition status. PMID- 28651394 TI - [Relationship between sleep status and the risk of diabetes in adults]. AB - Objective: To explore the relationship between sleep status and the risk of diabetes in adults. Methods: The baseline data of 53 260 subjects who were aged 30-79 years and had been enrolled into China Kadoorie Biobank (CKB) study from Suzhou, Jiangsu province were analyzed. Multiple logistic regression models were used to investigate the association between sleep status and diabetes after adjusting for potential confounders. Results: Among 53 260 subjects, 5.3% had diabetes. The proportions of difficultly falling asleep, early morning arousal and snoring frequently was 7.2%, 10.0% and 29.5%, respectively. There were 22.6% of subjects reporting sleep duration <=6 hours. After controlling for possible confounders, the subjects with difficulty falling sleep (OR=1.63 for male, 95%CI: 1.30-2.05; OR=1.48 for female, 95%CI: 1.27-1.73), early morning arousal (OR=1.37 for male, 95%CI: 1.12-1.68; OR=1.31 for female, 95%CI: 1.14-1.51) or snoring frequently (OR=1.16 for male, 95%CI: 1.00-1.34; OR=1.39 for female, 95%CI: 1.23 1.57) had a higher risk of diabetes. Using hypnotics regularly was associated with the risk of diabetes in females (OR=1.42, 95%CI: 1.06-1.92). Compared with 8 hours sleep duration daily, shorter sleep duration (<=6 hours) was associated with risk of diabetes in both males (OR=1.37, 95%CI: 1.17-1.60) and females (OR=1.24, 95%CI: 1.08-1.41). No statistical significant association was found between longer sleep duration (>=9 hours) and the risk of diabetes. Conclusion: Sleep problems, including difficulty falling asleep, early morning arousal, snoring frequently and shorter sleep duration, were associated with the risk of diabetes, but no statistical significant association was observed between longer sleep duration and the risk of diabetes. PMID- 28651395 TI - [Analysis of dietary pattern and diabetes mellitus influencing factors identified by classification tree model in adults of Fujian]. AB - Objective: To find out the dietary patterns and explore the relationship between environmental factors (especially dietary patterns) and diabetes mellitus in the adults of Fujian. Methods: Multi-stage sampling method were used to survey residents aged >=18 years by questionnaire, physical examination and laboratory detection in 10 disease surveillance points in Fujian. Factor analysis was used to identify the dietary patterns, while logistic regression model was applied to analyze relationship between dietary patterns and diabetes mellitus, and classification tree model was adopted to identify the influencing factors for diabetes mellitus. Results: There were four dietary patterns in the population, including meat, plant, high-quality protein, and fried food and beverages patterns. The result of logistic analysis showed that plant pattern, which has higher factor loading of fresh fruit-vegetables and cereal-tubers, was a protective factor for non-diabetes mellitus. The risk of diabetes mellitus in the population at T2 and T3 levels of factor score were 0.727 (95%CI:0.561-0.943) times and 0.736 (95%CI: 0.573-0.944) times higher, respectively, than those whose factor score was in lowest quartile. Thirteen influencing factors and eleven group at high-risk for diabetes mellitus were identified by classification tree model. The influencing factors were dyslipidemia, age, family history of diabetes, hypertension, physical activity, career, sex, sedentary time, abdominal adiposity, BMI, marital status, sleep time and high-quality protein pattern. Conclusion: There is a close association between dietary patterns and diabetes mellitus. It is necessary to promote healthy and reasonable diet, strengthen the monitoring and control of blood lipids, blood pressure and body weight, and have good lifestyle for the prevention and control of diabetes mellitus. PMID- 28651396 TI - [Interaction between family history of diabetes and hyperlipidemia on risk of diabetes in population with normotension in Harbin: a cross-sectional study]. AB - Objective: To explore the interaction between family history of diabetes and hyperlipidemia on the risk of diabetes in population with normotension. Methods: A multistage stratified probability random sampling was conducted to select a representative sample of urban residents aged 20-74 years in Harbin. A total of 376 diabetes patients with normotension and 3 692 residents with normal blood pressure, normal fasting glucose, and normal 2 hours glucose from OGTT were surveyed. The interaction was evaluated by using crossover analysis and additive model. Results: Multivariate logistic regression analysis indicated that there was a possible additive interaction between family history of diabetes and hyperlipidemia on the risk of diabetes. The relative excess risk due to the interaction, the attributable proportion due to the interaction, and the synergy index were 1.97 (95%CI:-0.32-4.26), 0.30 (95%CI: 0.03-0.57), and 1.54 (95%CI: 0.96-2.47), respectively. There were significant combination effects between family history of diabetes and high both total cholesterol and triglyceride, isolated high total cholesterol, and isolated high triglyceride levels; the ORs were 10.55 (95%CI: 5.62-19.80), 7.81 (95%CI: 3.65-16.71) and 5.13 (95%CI: 3.22 8.16), respectively. Conclusion: There might be synergistic effect between family history of diabetes and hyperlipidemia on the risk of diabetes in population with normotension. PMID- 28651397 TI - [Study on relationship between mother's animal sourced food intake during pregnancy and neonate birth weight]. AB - Objective: To explore the effect of maternal animal sourced food intake during pregnancy on neonate birth weight and provide scientific basis for guiding the reasonable diet intake in pregnant women and increasing neonate birth weight. Methods: Data were derived from a cross-sectional project of"the prevalence and risk factors of birth defects in Shaanxi province" , which were conducted in 30 counties in Shaanxi province from July to November in 2013. A stratified multistage random sampling method was used to select women who were pregnant between January 2010 and December 2013 for a random semi-quantitative food frequency questionnaire survey to collect the data on the frequency and amount of food consumption on animal protein sources and the data of newborns. Children aged 0-1 years and their mothers were selected as the study subjects. The generalized linear model was used to analyze the relationship between the neonate birth weight and maternal animal sourced food intake during pregnancy, and by using neonate birth weight as dependent variable, food intake frequency as independent variable, three adjustment models were established for stratified analysis. Results: Totally 11 459 participants were involved in this study. The average birth weight of newborn was (3 279.9+/-454.6) g, the average weekly intake of animal sourced foods was4.00 times for egg, 1.50 times for meat, 3.00 times for dairy foods, 0.50 times for fish and 5.00 times for overall animal sourced foods in pregnant women. Without stratification, three models shown that meat and overall animal sourced food intake had effects on neonate birth weight. After adjustment for gestational weeks, maternal age, social and demographic factors and others, meat intake increased by 1 time a week, the increase of neonate birth weight was about 5.26 (95%CI: 1.32-9.20) g, and the overall animal food increased by 1 times a week, the average neonate birth weight increased by 3.24 (95%CI: 1.09-5.39) g. Stratified analysis showed that meat and overall animal sourced food always had more influences on baby girls and those living in rural area. In the region classification, the overall animal sourced food intake had more influences on women living in northern area and Guanzhong area of Shaanxi, and meat intake had greater influence on women living in southern Shaanxi. And the influences were positive, the more animal sourced foods were taken, the greater the birth weight increased. Conclusion: Animal sourced food intake during pregnancy would benefit the increase of neonate birth weight. It suggests that pregnant women should pay more attention to the intake of animal sourced food. PMID- 28651398 TI - [Awareness of health co-benefits of carbon emissions reduction in urban residents in Beijing: a cross-sectional survey]. AB - Objective: To understand the awareness of the health co-benefits of carbon emission reduction in urban residents in Beijing and the influencing factors, and provide information for policy decision on carbon emission reduction and health education campaigns. Methods: Four communities were selected randomly from Fangshan, Haidian, Huairou and Dongcheng districts of Beijing, respectively. The sample size was estimated by using Kish-Leslie formula for descriptive analysis. 90 participants were recruited from each community. chi(2) test was conducted to examine the associations between socio-demographic variables and individuals' awareness of the health co-benefits of carbon emission reduction. Ordinal logistic regression analysis was performed to investigate the factors influencing the awareness about the health co-benefits. Results: In 369 participants surveyed, 12.7% reported they knew the health co-benefits of carbon emission reduction. The final logistic regression analysis revealed that age (OR=0.98), attitude to climate warming (OR=0.72) and air pollution (OR=1.59), family monthly average income (OR=1.27), and low carbon lifestyle (OR=2.36) were important factors influencing their awareness of the health co-benefits of carbon emission reduction. Conclusion: The awareness of the health co-benefits of carbon emissions reduction were influenced by people' socio-demographic characteristics (age and family income), concerns about air pollution and climate warming, and low carbon lifestyle. It is necessary to take these factors into consideration in future development and implementation of carbon emission reduction policies and related health education campaigns. PMID- 28651399 TI - [Immune response to one booster dose of inactivated hepatitis A vaccine in college students]. AB - Objective: To evaluate the safety and immunogenicity of one booster dose of inactivated hepatitis A vaccine in young adults. Methods: The subjects were selected from participants in the clinical trial of immunogenicity of inactivated and attenuated live hepatitis A vaccine in young adults. Eligible subjects were those who had received one dose of inactivated or attenuated hepatitis A vaccine, could be contacted and were sero-negative before primary vaccination. All qualified subjects were immunized with one booster dose of inactivated hepatitis A vaccine. The blood samples were collected before booster dose vaccination and 28 days after the immunization. Anti-HAV antibody titer >=20 mIU/ml was considered to be sero-protected against hepatitis A virus. Results: The GMCs in the inactivated HAV vaccine group and attenuated live vaccine group before booster dose vaccination were 70.80 mIU/ml and 50.12 mIU/ml, respectively, and the sero-protection rates were 94.7% and 65.0%, respectively. After the vaccination of the booster dose, the sero-protection rates in both groups were 100.0%, and the GMCs were 2 816.09 mIU/ml and 2 654.55 mIU/ml, respectively. Conclusion: The GMCs and sero-protection rates of anti-HAV antibody in young adults declined after three years of the primary vaccination. However, the higher GMC and sero-protection rate were observed in the inactivated vaccine group than in the attenuated live vaccine group. Significant increases of GMC levels were observed in both groups after one booster dose vaccination. PMID- 28651400 TI - [Mobile internet based survey of current status of HIV test and related factors in men who have sex with men in college students in China]. AB - Objective: To assess the current status of HIV test during the past year and related factors in men who have sex with men (MSM) in college students in China. Methods: Based on a MSM website, a cross-sectional study was conducted in 500 MSM in college students aged 18-25 years, who were selected based on the estimated HIV detection rate of 50% in this population, by means of mobile phone questionnaire survey. chi(2) test and non-conditional multivariate logistic regression analysis were conducted to identify the factors related with HIV test, respectively. Results: The mean age of MSM in college students was 20.99 (+/ 0.04) years and the HIV test rate during the past year was 47.1%(652/1 384). Multivariate logistic regression analysis indicated that active factors associated with HIV test included awareness of HIV test (OR=6.37, 95%CI: 3.592 11.300), willing to receive regular HIV testing (OR=2.64, 95%CI: 1.191-2.631) well-knowing or not knowing of the HIV infection statues of their regular sex partners (OR=3.58, 95%CI: 2.138-5.996), (OR=2.25, 95%CI: 1.479-3.422), respectively. The negative factors associated with HIV test included believing their regular sex partners not being infected with HIV (OR=0.65, 95%CI: 0.445 0.938), having only one regular sex partner during the past year (OR=0.37, 95%CI: 0.232-0.589). Conclusion: The survey indicated that the HIV test rate in MSM in college students during the past year was low. The MSM in college students are usually sexual active, but less of them received HIV test due to the trust between them and less number of sexual partners. Close attention should be paid to the AIDS intervention in this population. PMID- 28651401 TI - [Investigation of group sex in men who have sex with men in Taizhou, Zhejiang province, 2013-2015]. AB - Objective: To understand the prevalence of group sex in men who have sex with men (MSM) and related factors in Taizhou, Zhejiang province. Methods: From March 2013 to September 2015, a cross-sectional survey was conducted among MSM recruited from gay bars or bath houses in Taizhou by using questionnaire to collect the information about their sexual behavior and HIV test. Results: A total of 1 435 MSM were recruited, 179 of them (12.5%) were HIV infected, 231 (16.1%) reported group sex during the past year. Compared with MSM without group sex, more MSM with group sex had more than ten male sexual partners (53.7% vs. 19.0%, chi(2)=125.527, P<0.01), had both male and female sexual partners (86.6% vs. 68.2%, chi(2)=31.935, P<0.01), used no condom at sex with female partners during the past year (28.1% vs. 19.8%, chi(2)=6.540, P<0.05). After adjusted for educational level and occupation, group sex was associated with age[>=50 years old vs. <=24 years old, adjusted odds ratio (aOR)=2.25, P=0.027], marriage with female (divorced or widowedvs. unmarried, aOR=0.29, P=0.001), census registering (local resident vs. non-local resident, aOR=1.56, P=0.023), number of male seuxal partners (>=21 vs. 2-5, aOR=8.06, P<0.001; 11-20 vs. 2-5, aOR=3.25, P<0.001) and number of female seuxal partners (>=6 vs. 0, aOR=2.63, P=0.005; 2-5 vs. 0, aOR=2.58, P=0.001; 1 vs. 0, aOR=2.01, P=0.010). Conclusion: The prevalence of group sex in MSM was high in Taizhou, and their poor condom use and complex sex behaviors would result in higher HIV infection rate and risk of transmission. PMID- 28651402 TI - [Consecutive cross-sectional survey of prevalence of HIV infection/STD and related factors in Vietnamese female sex workers at a China-Vietnam border area, 2014-2015]. AB - Objective: To investigate the prevalence of HIV infection/STD and related factors in Vietnamese female sex workers (FSWs). Methods: Consecutive cross-sectional surveys were conducted in June 2014, December 2014, May 2015 and November 2015 in Hekou, a county bordering Vietnam in Yunnan province. Convenience sampling were adopted to select 1 058 Vietnamese FSWs aged>16 years. Questionnaire interview were used to collect the information about their demographics, sexual behaviors and drug use. Serum and urine samples were collected for HIV infection/STD detection and drug use test. Trend chi(2) test was applied for HIV infection/STD and drug use trend analysis. Multivariate logistic regression model was used to identify the related factors. Results: The consecutive cross sectional surveys indicated that the prevalence of HIV infection in Vietnamese FSWs were 3.20%(7/219), 2.04%(5/245), 1.89%(5/265) and 1.82%(6/329) respectively; the HSV-2 positive rates were 57.08%(125/219), 58.37%(143/245), 38.11%(101/265) and 51.06% (168/329) respectively. In addition, the prevalence of syphilis were 0.91%, 1.51%, 0.75% and 1.22% respectively. HSV-2 infection prevalence showed a downward trend (chi(2)=4.823, P=0.028). By logistic regression analysis, the related factors for HIV infection in Vietnamese FSWs were being amphetamine type stimulants (ATS) positive (OR=10.18, 95%CI: 4.33-23.92) and being HSV-2 positive (OR=2.89, 95%CI: 1.09-7.88); Age (OR=1.88, 95%CI: 1.32-2.61), no-paid sexual partner (OR=1.59, 95%CI: 1.26-2.01) and being ATS positive (OR=2.48, 95%CI: 1.10 5.57) were related factors for HSV-2 infection. Conclusions: Compared with the results of previous studies, the HIV infection prevalence declined in Vietnamese FSWs, but the HSV-2 infection prevalence was still high. The association between ATS use and HIV infection/STD suggested the necessity of strengthening AIDS intervention in Vietnamese FSWs, including the control of new type drug and sexual transmission. PMID- 28651403 TI - [Compliancy of pre-exposure prophylaxis for HIV infection in men who have sex with men in Chengdu]. AB - Objective: To evaluate the compliancy of HIV pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM) in Chengdu, Sichuan province, and explore the influencing factors. Methods: From 1 July 2013 to 30 September 2015, a random, open, multi-center and parallel control intervention study was conducted in 328 MSM enrolled by non-probability sampling in Chengdu. The MSM were divided into 3 groups randomly, i.e. daily group, intermittent group (before and after exposure) and control group. Clinical follow-up and questionnaire survey were carried out every 3 months. Their PrEP compliances were evaluated respectively and multivariate logistic regression analysis was conducted to identify the related factors. Results: A total of 141 MSM were surveyed, in whom 59(41.8%) had good PrEP compliancy. The PrEP compliancy rate was 69.0% in daily group, higher than that in intermittent group (14.3%), the difference had significance (chi(2)=45.29,P<0.001). Multivariate logistic analysis indicated that type of PrEP was the influencing factors of PrEP compliancy. Compared with daily group, the intermittent group had worse PrEP compliancy (OR=0.07, 95%CI: 0.03-0.16). Conclusion: The PrEP compliance of the MSM in this study was poor, the compliancy would be influenced by the type of PrEP. PMID- 28651404 TI - [Correlation between insufficient methadone dosage and morphine positive urine on drop out of treatment in patients with access to methadone maintenance treatment]. AB - Objective: To estimate the incidence of drop out of treatment in patients with access to methadone maintenance treatment and explore the correlation and interaction between insufficient methadone dosage and morphine positive urine on the drop out in Guangxi Zhuang Autonomous Region. Methods: Face to face interview was conducted in 1 031 patients at 3 methadone maintenance treatment clinics in Guangxi. Results: The study included 1 031 participants, 40.6% of them (419/1 031) had stopped treatment. The drop out rates in urine morphine positive group and methadone dosage<100 mg/d group were 57.6% (99/172) and 37.4% (347/929) respectively, higher than those in urine morphine negative group and methadone dosage >=100 mg/d group (42.3%, 363/859, and 26.5%, 27/102). Orderly logistic regression analysis results showed that after adjusted factors, such as gender, age, marital status, ethnic group, patients who received a dosage less than 100 mg/day (OR=3.05, 95%CI: 1.84-5.06) and had morphine positive urine (OR=2.25, 95%CI: 1.59-3.19) were more likely to drop out of the treatment. Interaction analysis showed that dosage less than 100 mg/d and morphine positive urine during treatment had additive interaction (RERI=256.46, AP=0.87, S= 8.05) and multiplication interaction (OR=2.45, 95%CI: 1.71-3.49). Conclusion: Insufficient dosage and morphine positive urine were significantly correlated with drop out of treatment in patients with access to methadone maintenance treatment. PMID- 28651405 TI - [Clinical stages and outcomes of severe cases on hand, foot and mouth disease]. AB - Objective: To understand the characteristics and relation of clinical stage and outcome of severe cases on hand, foot and mouth disease (HFMD) and to establish the evaluation method for understanding severity of this disease. Methods: According to factors as geographical location, economic and epidemic levels, five provinces (Henan, Shandong, Yunnan, Zhejiang and Sichuan provinces) were selected. Reported severe cases of HFMD from the National Notifiable Diseases Reporting System were selected randomly in the five provinces. Basic epidemiological information, clinical data, and pathogen testing results in the involved hospitals were collected. Clinical stages on all the patients were decided in accordance with"the clinical expert consensus on diagnosis and treatment for severe case of enterovirus type 71 (EV71) infections (2011 edition)" . Data were analyzed using SPSS software 18.0 and other epidemiological methods. Results: A total of657 severe HFMD cases were investigated, with 326 cases positive of EV71, accounting for 91.3% (326/357) among all the laboratory confirmed cases. Of the 657 cases, 542 cases (82.5%, 95%CI: 79.4%-85.3%) were diagnosed as in stage 2 (with nervous system involvement), 99 cases (15.1%, 95%CI: 12.4%-18.0%) in stage 3 (early phase of function failure on heart and lung), and 16 cases (2.4%, 95%CI: 1.4%-3.9%) were in stage 4 (function failure of heart and lung). 11 cases (1.7%, 95%CI: 0.9%-3.0%) were with squeal when discharged from hospital with 8 cases (1.2%, 95%CI: 0.6%-2.3%) died. When comparing the proportions among stage 2, stage 3 and stage 4, significant differences were found between age groups (chi(2)=22.632, P=0.012). The younger the patient was the lower the proportions of stage 2 and the more proportion of stage 3 appeared. When comparing the proportions of clinical stages among the five provinces, significant differences (chi(2)=41.481, P=0.000) were noticed. Proportions of different clinical stages in gender, ethnicity, occupation, place of residence types and the type of pathogen appeared no significant differences, respectively. However, the proportions of squeal and death in stage 2, stage 3 and stage 4 showed significant differences (sequela: chi(2)=12.960, P=0.001; Death: chi(2)=16.850, P=0.001), respectively. Conclusions: The percentage of clinical stages of severe HFMD patients related to the rate of squeal and death. Clinical staging can be used for assessing the clinical severity of complications and the effectiveness of treatment, of HFMD. PMID- 28651406 TI - [Survival time of newly diagnosed HIV/AIDS cases and related factors in China, 2010]. AB - Objective: To analyze the survival time of newly diagnosed HIV/AIDS cases and related factors in China in 2010. Methods: The reporting cards and follow-up cards of HIV/AIDS cases reported as of 31 December 2015 were collected from national AIDS information system. The newly diagnosed HIV/AIDS cases in 2010 were selected. The information of follow-up intervention, CD(4+)T cells (CD(4)) testing, antiretroviral treatment and mortality of the cases from 2010 to 2015 were analyzed. Life table method was applied to calculate the survival probability. Kaplan-Meier was used to draw survival curve and Cox proportion hazard regression model were used to identify the factors related to survival time. Results: Of the 40 335 HIV/AIDS cases, 11 975(29.7%) died of AIDS related diseases. The median survival time was 63.1 months (95%CI: 63.0-63.2), and the survival rates in 1 year and 5 years were 81.2% and 69.9%. Multivariate Cox regression analysis showed that the risk factors for death in the HIV/AIDS cases were age (25-34 years old vs. 15-24 years old: HR=1.41, 95%CI: 1.29-1.54; 35-34 years old vs. 15-24 years old: HR=1.90, 95%CI: 1.74-2.07; 45-54 years old vs. 15 24 years old: HR=2.24, 95%CI: 2.04-2.46; >=55 years old vs. 15-24 years old: HR=2.81, 95%CI: 2.57-3.08). The protective factors for death in the HIV/AIDS cases were level of baseline CD(4) counts (CD(4)>=500 cells/MUl vs. CD(4)<200 cells/MUl: HR=0.12, 95%CI: 0.11-0.13), receiving antiretroviral therapy (ART vs. no ART: HR=0.11,95%CI: 0.10-0.12). Conclusion: Survival time of HIV/AIDS cases might be influenced by age, baseline CD(4) count and access to antiretroviral therapy. The early diagnosed and early antiretroviral therapy could extend the survival time of HIV/AIDS cases. PMID- 28651407 TI - [Homology analysis and historical tracing for inter-continental Burkholderia pseudomallei strains of sequence type 562]. AB - Objective: To understand the homology of sequence type 562 (ST562) strains of Burkholderia pseudomallei which circulated in two separate continents (Asia and Australia) at different times. Methods:SpeIrestriction fragments and 4-locus multiple locus variable number tandem repeat analysis (MLVA-4) profiles were extracted from MSHR5858 (ST562 Australia strain) and 350105 (ST562 historical strain of Hainan) genomes respectively by in silico analysis and then compared with the PFGE and MLVA-4 results of five ST562 clinical isolates from Hainan to test their homology. Synteny and homology between MSHR5858 and 350105 genomes were evaluated with bioinformatics methods. Results: Five ST562 clinical strains from Hainan shared same PFGE pattern (similarity>97%) and this pattern coincided to the map of SpeIrestriction fragments of Australian strain MSHR5858. The amounts of genomic restriction fragments (SpeI) for MSHR5858 and 350105 were 31 and 34 respectively, with 31 of them matched by each other. Five ST562 clinical strains of Hainan were distinct by MLVA-4 profiles, among which HPPH43 (MLVA-4 profile: 10, 8, 10, 8) was close to Australia strain MSHR5858 (10, 8, 8, 6), containing identical repeat numbers at VNTR loci 2341k and 1788k; while HK003 (11, 8, 15, 7) and HK061 (11, 8, 17, 7) similar to Hainan historical strain 350105 (11, 8, 11, 8), with same repeat numbers at loci 2341k and 1788k also. High-degree synteny and consistency on genomic contents were observed between 350105 and MSHR5858, indicating a similar origin for the 2 strains. Conclusion: All inter-continental and historical ST562 strains of B. pseudomallei had similar genomic characteristics, supporting the assumption that they had a common origin. Also, it is possible that Hainan historical strain 350105 is the ancestor of all circulating ST562 strains. PMID- 28651408 TI - [Identification and evaluation of T cell epitopes of Rv0585c from Mycobacterium tuberculosis]. AB - Objective: To investigate the human T cell epitopes of Mycobacterium (M.) tuberculosis Rv0585c protein antigen and their immunogenicity and provide evidence for the development of specific tuberculosis immune diagnostic techniques and tuberculosis vaccine. Methods: We synthesized peptides from M. tuberculosis Rv0585c protein antigen predicted by TE-predict and IEDB human T cell epitope prediction tool. The cellular immunoreactivity of the predicted peptides was evaluated through ELISpot assay with the peripheral blood monouclear cells (PBMC) of clinical tuberculosis patients. In animal experiments, BALB/c mice were respectively immunized with high dose (100 MUg/mice) and low dose (50 MUg/mice) of the peptides of Rv0585c, at the same time, high dose (50 MUg/mice) and low dose (20 MUg/mice) of Ag85B protein were used in positive control group. The levels of IFN-gamma, IL-2, IL-4 and IL-10 were tested with ELISA kit respectively. Results: By means of bioinformatics technique, 66 human T cell epitopes of Rv0585c were predicted, from which9 peptides concentrated epitopes were synthesized for the animal immune experiments. Peptides P10110, P10112 and P10117 were confirmed to be antigenic. The sensitivity and specificity of P10110, P10112 and P10117 were 14.00%, 12.00%, 6.00% and 100.00%, 100.00%, 97.96% respectively when they were used as diagnostic reagents of tuberculosis. The sensitivity and specificity were 22.00% and 97.96% when the epitopes were combined together. The results of animal immunity test showed that high levels of cytokines IFN-gamma, IL-2, IL-4 and IL-10 were induced by high and low dose of P10110, and high levels of IFN-gamma,IL-2 and IL-10 were induced by high and low dose of P10112, which were much higher than that in negative controls, respectively (P<0.001). Conclusion: Rv0585c, including its human T cell epitopes, has good immunogenicity and immunoreactivity, stimulating the body to produce a stronger cellular immune response and has better potential application value in cellular diagnosis of tuberculosis and the development of new type of tuberculosis vaccine. PMID- 28651409 TI - [Drug susceptibility test guided therapy and novel empirical quadruple therapy for Helicobacter pylori infection: a network Meta-analysis]. AB - Objective: To compare the efficacy and the risk of adverse effect of drug susceptibility test guided therapy and novel empirical quadruple therapy for Helicobacter (H.) pylori infection. Methods: Literature retrieval was conducted by using major databases. Related papers published up to June 2015 were considered eligible if they were randomized control trials comparing different pharmacological formulations for H. pylori infection and used in a network Meta analysis and a single rate Meta-analysis to evaluate the relative and absolute rates of H. pylori eradication and the risk of adverse effect. The Jadad score was used to evaluate the methodological quality. Funnel plot was constructed to evaluate the risk of publication bias. Begg's rank correlation test or Egger's regression intercept test was done for the asymmetry of funnel plot. Results: Twenty randomized control trials for the treatment of 6 753 initial treated patients with H. pylori infection were included. Drug susceptibility test guided therapy was significantly superior to concomitant therapy, hybrid therapy, sequential therapy and bismuth quadruple therapy. The culture-based therapy had the highest likelihood of improving clinical efficacy, with lowest risk of adverse effect. Concomitant therapy had the highest probability of causing adverse effect despite its effectiveness. Hybrid therapy and bismuth quadruple therapy were associated with lower risk of adverse effect and higher effectiveness. Conclusion: Drug susceptibility test guided therapy showed superiority to other 4 interventions for H. pylori eradication mentioned above. Hybrid therapy and bismuth quadruple therapy might be applied in the settings where the culture-based strategy is not available. PMID- 28651410 TI - [Application of tipping-point analysis to address missing data in clinical studies]. AB - To use a visualized method, tipping-point analysis to address missing data in clinical study and discuss related problems. All the possible outcomes caused by missing data were listed and the tipping points where P-values of hypothesis test changed at 0.05 significant level were found out, then the ratio of P<0.05 was calculated, reflecting the reliability of the study's result. Tipping-point analysis can be applied to both continuous and binary data to help find points where p-values are changed. The area of P<0.05 of continuous data is 93.6%, indicating that the reliability of success of the study is large; and the area of P<0.05 of binary data is 29.7%, reflecting that the reliability of success of the study is small. Tipping-point analysis, which provides a visualized evidence for decision making, is suitable for analyzing clinical studies with missing data. PMID- 28651411 TI - [Introduction to Bayesian variable selection methods in high-dimensional omics data analysis]. AB - With the rapid development of genome sequencing technology and bioinformatics in recent years, it has become possible to measure thousands of omics data which might be associated with the progress of diseases, i.e."high-dimensional data" . This type of omics data have a common feature that the number of variable p is usually greater than the observation cases n, and often has high correlation between independent variables. Therefore, it is a great statistical challenge to identify really meaningful variables from omics data. This paper summarizes the methods of Bayesian variable selection in the analysis of high-dimensional data. PMID- 28651412 TI - [Comparison of application of Cochran-Armitage trend test and linear regression analysis for rate trend analysis in epidemiology study]. AB - We described the time trend of acute myocardial infarction (AMI) from 1999 to 2013 in Tianjin incidence rate with Cochran-Armitage trend (CAT) test and linear regression analysis, and the results were compared. Based on actual population, CAT test had much stronger statistical power than linear regression analysis for both overall incidence trend and age specific incidence trend (Cochran-Armitage trend P value0.05). The ratios of beds to nurses and beds to full-time burn rehabilitation treating personnel in 4 groups were similar (with F values respectively 0.783 and 0.434, P values above 0.05). (7) Twenty burn treatment units had rehabilitation therapists with rehabilitation treatment related professional background (a total of 73 person, account for 76.0%), 80.8% (59/73) rehabilitation therapists with rehabilitation and therapeutic professions, 60.3% (44/73) with bachelor degree or above, and 87.7% (64/73) with primary and intermediate titles. Besides, 39.7% (29/73) rehabilitation therapists did physical therapy; 12.3% (9/73) rehabilitation therapists did occupational therapy; 38.4% (28/73) rehabilitation therapists did not have specific duties. (8) During the development of burn rehabilitation treatment of 35 burn treatment units, the common problems were reflected in the authorized strength and professional technology level of rehabilitation treatment relating personnel, and the area and equipment for rehabilitation. There were also many problems in cooperation between burn surgeons and rehabilitation therapists and fund. The supports from hospital and department leaders were good. Conclusions: Through the development of several years, the general condition and the development of rehabilitation treatment of burn treatment units in China are improved; the beginning time of burn rehabilitation treatment is advanced; the number of rehabilitation treatment personnel is increased with their speciality improved; the burn rehabilitation work get great support from hospitals and departments. PMID- 28651416 TI - [Clinical effects of Joint Active System on the treatment of joint dysfunction after deep burn]. AB - Objective: To observe the clinical effects of the Joint Active System on the treatment of joint dysfunction after deep burn. Methods: Twenty-two patients with joint dysfunction after deep burn were hospitalized in Institute of Burns of Tongren Hospital of Wuhan University & Wuhan Third Hospital from January 2015 to October 2016, involving 18 elbow joints with flexion disorder, 10 wrist joints with dorsal extension disorder, and 12 ankle joints with dorsal extension disorder. They were treated with the elbow joint activity training device, the wrist joint activity training device, and the ankle joint activity training device of the Joint Active System, respectively. The treatment was carried out 3 times each day with interval of 6 h, 30 minutes each time, and it lasted for four to seven months, with one month as a course of treatment. Before treatment and 1, 2, 3, 4 month (s) after, active motion range of each joint was measured by joint goniometer. Function improvement of each joint was evaluated, and the total effective ratio was calculated 4 months after treatment. Satisfaction degree of patients was assessed by the modified Likert Scale 1, 2, 3, 4 month (s) after treatment. Data were processed with one-way analysis of variance for repeated measurement and LSD test. Results: Before treatment and 1, 2, 3, 4 month (s) after, flexion active motion range of elbow joints were (61+/-23), (78+/-22), (89+/-20), (96+/-20), and (103+/-19) degrees ; dorsal extension active motion range of wrist joints were (23+/-7), (31+/-6), (38+/-9), (44+/-5), and (49+/-8) degrees ; dorsal extension active motion range of ankle joints were (-31+/-12), ( 23+/-10), (-16+/-7), (-12+/-6), and (-8+/-4) degrees , respectively. The active motion range of each joint was obviously higher 1, 2, 3, 4 month (s) after treatment than the previous time point of the same joint (with P values below 0.01). Four months after treatment, the total effective ratios of function improvement of elbow joints, wrist joints, and ankle joints were 5/6, 9/10, and 2/3, respectively. Scores of satisfaction degree of the patients 1, 2, 3, 4 month (s) after treatment were (1.3+/-0.7), (2.2+/-1.0), (2.8+/-0.8), and (3.3+/-0.6) points, respectively. Scores of satisfaction degree of the patients were obviously higher 2, 3, 4 months after treatment than the previous time point (with P values below 0.05). Conclusions: Joint Active System can improve the active range of motion of each joint obviously in treating joint dysfunction after deep burn, with total effective ratio of function improvement of each joint surpassing 0.66, and the majority of patients are quite satisfied with the curative effects. PMID- 28651417 TI - [Influences of different rehabilitative methods on function of hands and psychological anxiety of patients with deeply burned hands retaining denatured dermis and grafting large autologous skin]. AB - Objective: To investigate influences of different rehabilitative methods on function of hands and psychological anxiety of patients with deeply burned hands retaining denatured dermis and grafting large autologous skin. Methods: Forty four patients with deeply burned hands, conforming to the study criteria were admitted to Department of Burns and Reconstructive Surgery of Xiangya Hospital of Central South University from January 2014 to June 2015. Patients were divided into propaganda education rehabilitation group (PER, n=23) and specially-assigned person rehabilitation group (SAPR, n=21) according to the random number table and patients' willingness. On post injury day 3 to 7, 36 burned hands in group PER and 33 burned hands in group SAPR underwent operation of retaining denatured dermis and grafting large autologous skin. Patients in 2 groups received anti scar treatment of hands with silicone gel from postoperative day 10. Besides, patients in group PER underwent active functional exercise under guidance of duty nurse and received psychological guidance from duty nurse with grade two psychological consultant certificate. Patients in group SAPR underwent active and passive functional exercise under guidance of rehabilitation therapist and received psychological guidance from psychotherapist with intermediate title. In postoperative month (POM) 1, 3 and 6, ranges of active motion of burned finger joints of patients in 2 groups were measured with joint goniometer to calculate excellent and good ratio of total active motion (TAM) range. Values of grip strength of burned hands of patients were measured with electronic hand dynamometer, and psychological anxiety was scored with Self-rating Anxiety Scale (SAS). Data were processed with chi-square test, independent sample t test, McNemar test, analysis of variance of repeated measurement, SNK test and Bonferroni correction. Results: (1) Ratio of excellent and good of TAM range of burned finger joints of patients in group SAPR in POM 6 was obviously higher than that in group PER (chi(2)=10.745, P<0.0167 ). Ratio of excellent and good of TAM range of burned finger joints of patients in 2 groups in POM 3 were obviously higher than that in POM 1 of the same group, respectively (with P values below 0.0167). (2) Values of grip strength of burned hands of patients in group SAPR in POM 1, 3, and 6 were respectively (8.2+/-2.6), (21.6+/-2.6) and (30.1+/-2.3) kg, obviously higher than those in group PER [ (5.3+/-1.3), (12.8+/-2.7), (20.0+/ 1.8) kg, respectively, with t values from 5.934 to 20.403, P values below 0.01]. Values of grip strength of burned hands of patients in 2 groups in POM 3 and 6 were obviously higher than those at the previous time point of the same group (with P values below 0.05). (3) SAS scores of patients in group SAPR in POM 1, 3 and 6 were significantly lower than those in group PER (with t values from 2.944 to 4.758, P values below 0.01). SAS scores of patients in 2 groups in POM 3 and 6 were significantly lower than those at the previous time point of the same group (with P values below 0.05). Conclusions: Compared with rehabilitation of propaganda and education, rehabilitation under specially-assigned person can improve TAM range of burned finger joints, value of grip strength, and psychological anxiety of patients with deeply burned hands retaining the denatured dermis and grafting large autologous skin. PMID- 28651418 TI - [Advances in the research of pressure therapy for pediatric burn patients with facial scar]. AB - Facial scar and deformation caused by burn injury severely affect physical and psychological well-being of pediatric burn patients, which needs medical workers and pediatric burn patients' family members to pay much attention to and to perform early rehabilitation treatment. Pressure therapy is an important rehabilitative strategy for pediatric burn patients with facial scar, mainly including wearing headgears and transparent pressure facemasks, which have their own features. To achieve better treatment results, pressure therapy should be chosen according to specific condition of pediatric burn patients and combined with other assistant therapies. Successful rehabilitation for pediatric burn patients relies on cooperation of both family members of pediatric burn patients and society. Rehabilitation knowledge should be provided to parents of pediatric burn patients to acquire their full support and cooperation in order to achieve best therapeutic effects and ultimately to rebuild physical and psychological well-being of pediatric burn patients. PMID- 28651419 TI - [Significance of evaluating the severity of patients with extremely severe burn by platelet count recovery in the early stage post burn]. AB - Objective: To retrospectively analyze the prognostic value of platelet count recovery in the early stage post burn for patients with extremely severe burn, so as to evaluate their severity. Methods: A study involving 244 adult patients with extremely severe burn admitted to our hospital from January 2006 to December 2015, conforming to the inclusion criteria, was conducted. Data of their demography, injury, transmission, disease change in hospital, and platelet count from post injury day (PID) 1 to 10 were collected. (1) Patients were divided into survival group (n=212) and non-survival group (n=32) according to whether death or not. The dynamic change characteristic of platelet count in patients of two groups from PID 1 to 10 was analyzed and compared. (2) Patients were divided into return to normal group (RN, n=163) and non-return to normal group (NRN, n=81) according to whether platelet count returned to normal within one week post burn. The proportion of patients who received mechanical ventilation and mortality in groups RN and NRN, and length of stay in ICU between patients with platelet count that returned to normal and that did not return to normal in the early stage post burn in survival group were compared. Data were processed with independent samples t test , analysis of variance of repeated measurement, chi-square test, and binomial distribution test. Correlation was analyzed between data of sex, age, weight, total burn area, full-thickness burn area, inhalation injury, length of hospital stay, receiving mechanical ventilation, platelet count recovery condition within one week post burn and death of patients using the univariate and multivariate Cox regression analysis. Receiver operating characteristic (ROC) curve of platelet count on PID 8 was drawn to evaluate predicting value for death of 244 patients. Results: (1) The platelet count kept declining from PID 1 to 4, declined to below the normal low limit on PID 2, and reached its lowest level on PID 4 both in survival group and non-survival group. The platelet count both in survival group and non-survival group rose gradually from PID 4 to 10, and returned to normal on PID 8 and 10, respectively. There was no significant difference in platelet count of patients in two groups on PID 1 (t=1.01, P>0.05), while platelet count of patients in non-survival group was obviously lower than that in survival group from PID 2 to 10 (with t values from 2.64 to 7.17, P values below 0.01). The daily increment of platelet count in survival group from PID 4 to 10 was (26+/-13)*10(9)/L, obviously higher than that in non-survival group [(19+/-11)*10(9)/L, t=2.76, P<0.01]. (2) The proportion of patients who received mechanical ventilation was obviously lower than that of patients who did not receive mechanical ventilation in group RN (P<0.01), while the proportion of patients who received mechanical ventilation was obviously higher than that of patients who did not receive mechanical ventilation in group NRN (P<0.05). The proportion of patients who received mechanical ventilation in group NRN was obviously higher than that in group RN (chi(2)=32.93, P<0.01). The mortality of patients in group NRN was obviously higher than that in group RN (chi(2)=20.99, P<0.01). The length of stay in ICU of patients whose platelet count did not return to normal in the early stage was significantly longer than that of patients whose platelet count returned to normal in the early stage in survival group (t=4.20, P<0.01). (3) Total burn area, receiving mechanical ventilation, and platelet count did not return to normal within one week post burn were independent risk factors for death of patients with extremely severe burn (with hazard ratio respectively 1.073, 16.552, and 2.249, 95% confidence interval respectively 1.033-1.115, 2.147-127.580, and 0.993-5.096, P<0.05 or P<0.01). (4) The area under the ROC curve of platelet count on PID 8 to predict death of 244 patients with extremely severe burn was 0.745 (with 95% confidence interval 0.645 0.845, P<0.01), and 150*10(9)/L was chosen as the optimal threshold value, with sensitivity of 71.4% and specificity of 71.0%. Conclusions: Platelet count recovery in the early stage post burn of patients with extremely severe burn was significantly associated with their prognosis and could be used as an important indicator to evaluate the severity of illness. PMID- 28651420 TI - [Effects of hypoxia inducible factor-1alpha on P311 and its influence on the migration of murine epidermal stem cells]. AB - Objective: To explore the effects of hypoxia inducible factor-1alpha (HIF-1alpha) on P311 and its influence on the migration of murine epidermal stem cells (ESCs) under hypoxia in vitro. Methods: Two kinds of murine ESCs were isolated and obtained from 15 neonatal wild-type C57BL/6J mice and 5 congeneric source P311 gene knock-out mice, respectively. The first passage of cells were used in the following experiments after morphologic observation and detection of expression of cell surface markers CD71 and CD49f with flow cytometer. (1) After cell scratch assay, according to the random number table (the same dividing method below), ESCs of P311 gene knock-out mice were divided into normoxia group (cells were cultured with complete medium in normoxic carbon dioxide incubator, and the subsequent normoxic treatments were the same) and hypoxia group (cells were cultured in hypoxic carbon dioxide incubator containing 1% oxygen, and the subsequent hypoxic treatments were the same), with 12 inserts in each group. ESCs of wild-type mice were divided into normoxia group, pure hypoxia group, dimethyl sulfoxide (DMSO) control group (2 MUL DMSO solvent was added for 1 h of normoxia treatment before hypoxia treatment), HIF-1alpha inhibitor group (cells were treated with 11 MUmol/L HIF-1 inhibitor of 2 MUL under normoxia condition for 1 h before hypoxia treatment), HIF-1alpha stabilizer group (the cells were treated with 2 MUmol/L FG-4592 of 2 MUL under normoxia condition for 1 h before hypoxia treatment), with 12 inserts in each group. Three inserts of each time point in each group were adopted respectively to measure the residual width of scratch under inverted phase contrast microscope at post scratch hour (PSH) 0 (immediately), 12, 24, and 48. (2) After hypoxia treatment, the protein level of HIF-1alpha in ESCs of wild-type mice was detected by Western blotting at post hypoxia hour (PHH) 0, 12, 24, and 48. (3) ESCs of wild-type mice were divided into pure hypoxia group, DMSO control group, HIF-1alpha inhibitor group, and HIF 1alpha stabilizer group as that of experiment (1) with the same treatment. The mRNA expression of P311 and expression of P311 in ESCs were determined by real time fluorescent quantitative reverse transcription polymerase chain reaction and immunocytochemical staining, respectively, at PHH 0 (immediately), 12, 24, and 48 (with sample numbers of 12). (4) The second passage of human embryonic kidney 293 (HEK-293) cells were divided into empty vector hypoxia group (cells were cultured under hypoxia condition after being transfected with empty vector plasmid), P311 normoxia group (cells were cultured under normoxia condition after being transfected with P311 reporter gene plasmid), P311 hypoxia group (cells were cultured under hypoxia condition after being transfected with P311 reporter gene plasmid), P311 hypoxia+ HIF-1alpha inhibitor group (cells which were incubated with HIF-1alpha inhibitor were cultured under hypoxia condition after being transfected with P311 reporter gene plasmid). The luciferase activity was detected at post culture hour (PCH) 0 and 12, respectively, and then the P311 transcriptional regulatory binding site of HIF-1alpha and the promoter sequence of P311 were predicted and searched by bioinformatics methods. Data were processed with factorial design variance analysis, one-way analysis of variance, LSD test and Bonferroni correction. Results: (1) The results of ESCs. The cells showed cobblestone-like pattern and different clonal morphology due to the different cell proliferation potential. The proportion of CD71(-)CD49f(+) cells accounted for about 85%. The identification results indicated that the cells showed strong stem cell properties and high purity. Compared with those in cells of normoxia group of P311 gene knock-out mice, the residual widths of scratch of cells in pure hypoxia group were smaller at PSH 12 and 24 (with P values below 0.05), and those in hypoxia group, normoxia group of wild-type mice, DMSO control group, HIF-1alpha inhibitor group, and HIF-1alpha stabilizer group were smaller at PSH 12 (with P values below 0.05). Compared with those in cells of normoxia group of wild-type mice, the residual widths of scratch of cells in hypoxia group, pure hypoxia group, and DMSO control group were smaller at PSH 12 and 24 (with P values below 0.05), and the residual width of scratch of cells in HIF 1alpha stabilizer group was smaller at PSH 12 (P<0.05). Compared with those of cells in pure hypoxia group, the residual widths of scratch of cells in hypoxia group were wider at PSH 12 and 24 (with P values below 0.05), and the residual width of scratch of cells in HIF-1alpha inhibitor group was wider at PSH 12 (P<0.05), and those of cells in HIF-1alpha stabilizer group were smaller at PSH 12 and 24 (with P values below 0.05). There was no obvious difference in the width of scratch in cells among the 7 groups (F=19.02, P>0.05). The protein levels of HIF-1alpha in ESCs of wild-type mice at PHH 0, 12, 24, and 48 were respectively 1.02+/-0.05, 2.56+/-0.09, 1.60+/-0.17, and 1.17+/-0.03. Compared with that at PHH 0, the protein level of HIF-1alpha at PHH 12 was significantly enhanced (P<0.01). It began to decline at PHH 24 but was still higher than that at PHH 0 (P<0.05), and the protein level of HIF-1alpha at PHH 48 was close to the normoxia level (P>0.05). Compared with those of cells in pure hypoxia group, the mRNA expressions of P311 of cells in HIF-1alpha inhibitor group were significantly decreased at each time point (with P values below 0.05), and those in HIF-1alpha stabilizer group were significantly increased at PHH 12 and 24 (with P values below 0.05). Compared with those of cells in HIF-1alpha inhibitor group, the mRNA expressions of P311 of cells in DMSO control group and HIF-1alpha stabilizer group were significantly increased at PHH 0, 12, and 24 (with P values below 0.05). Compared with those of cells in pure hypoxia group, the expressions of P311 of cells in HIF-1alpha inhibitor group were significantly decreased at each time point (with P values below 0.05), while those in HIF-1alpha stabilizer group were significantly increased at PHH 12 and 24 (with P values below 0.05). Compared with those of cells in HIF-1alpha inhibitor group, the expressions of P311 of cells in DMSO control group and HIF-1alpha stabilizer group were significantly increased at PHH 12 and 24 (with P values below 0.05). (2) The results of HEK-293 cells. At PCH 0, there was no significant difference in the luciferase activity among cells of empty vector hypoxia group, P311 normoxia group, P311 hypoxia group, and P311 hypoxia+ HIF-1alpha inhibitor group (F=13.33, P>0.05). At PCH 12, the luciferase activity of cells in P311 hypoxia group was higher than that in empty vector hypoxia group (P<0.01). The luciferase activity of cells in hypoxia group was higher than that in P311 normoxia group (P<0.05), while that of cells in P311 hypoxia+ HIF-1alpha inhibitor group was lower than that in P311 hypoxia group (P<0.01). Conclusions: HIF-1alpha may increase the migration of murine ESCs through inducing the expression of P311 at the early stage of hypoxia. PMID- 28651421 TI - [Effects of change in the activity of vacuolar adenosine triphosphatase of myocardial lysosome on myocardial damage in rats after severe burn and its mechanism]. AB - Objective: To explore the effects of change of activity of vacuolar adenosine triphosphatase (V-ATPase) of myocardial lysosome on myocardial damage in rats after severe burn and its mechanism. Methods: The myocardial lysosomes were extracted from the hearts of 12 SD rats with ultra-high speed gradient density centrifugation, then Western blotting and transmission electron microscope observation were conducted for identification. One hundred and twenty rats were divided into pure burn group, ATP group, normal control group, and bafilomycin group according to the random number table, with 30 rats in each group. Rats in pure burn group and ATP group were inflicted with 40% TBSA full-thickness scald on the back. Immediately after injury, rats in pure burn group were intraperitoneally injected with lactated Ringer's solution in 4 mL.%TBSA(-1).kg( 1,) and rats in ATP group were intraperitoneally injected with ATP in 0.4 mg/kg at 12 h before burn, immediately after burn, and 12 h after burn. Rats in normal control group did not receive any treatment, and rats in bafilomycin group were intraperitoneally injected with bafilomycin A1 in 0.3 mg/kg at the same time points as those of ATP group. At 24 h after burn, 30 rats from each group were collected for determining activity of V-ATPase of myocardial lysosome with coupled-enzyme assay and the expression of myocardium autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3) and P62 by Western blotting. Left ventricular arterial blood was collected to detect the content of 5 items of myocardial enzyme spectrum and cardiac troponin T (cTnT). Data were processed with one-way analysis of variance and t test. Results: (1) After identification, both the expression level of lysosome-related membrane protein 1 and purity of lysosome in the sample were high, and the structure of lysosome was intact. (2) At 24 h after burn, the activity values of V-ATPase of myocardial lysosome in rats of pure burn group, ATP group, normal control group, and bafilomycin group were (2.03+/-0.67), (3.01+/-0.58), (4.29+/-0.26), and (1.83+/-0.52) MUmol.mg( 1).h(-1,) respectively. The activity value of V-ATPase of myocardial lysosome in rats of pure burn group was significantly lower than the values in ATP group and normal control group (with t values respectively 3.14 and 8.87, P values below 0.01). The activity values of V-ATPase of rats in normal control group were significantly higher than those in bafilomycin group (t=11.87, P<0.01). At 24 h after burn, the expressions of myocardial LC3 and P62 in pure burn group were significantly higher than those in ATP group and normal control group (with t values from 3.73 to 5.88, P values below 0.01). The expressions of myocardial LC3 and P62 in normal control group were significantly lower than those in bafilomycin group (with t values respectively 2.64 and 3.07, P<0.05 or P<0.01). At 24 h after burn, the content of 5 items of myocardial enzyme spectrum and cTnT in pure burn group was significantly higher than that in ATP group and normal control group (with t values from 3.24 to 16.72, P values below 0.01). The content of 5 items of myocardial enzyme spectrum and cTnT in normal control group was significantly lower than that in bafilomycin group (with t values from 2.39 to 10. 70, P values below 0.01). Conclusions: The activity of V-ATPase of myocardial lysosome decreased in rats after severe burn, which can result in myocardial damage by inhibiting myocardial autophagy flux. PMID- 28651422 TI - [Meta-analysis on the diagnostic value of laser Doppler imaging for burn depth]. AB - Objective: To evaluate the value of laser Doppler imaging (LDI) in diagnosing deep or superficial partial-thickness burn wound with meta-analysis. Methods: Databases including PubMed, Cochrane Library were searched using key words " burn, burns, burn depth, laser Doppler imaging, laser Doppler perfusion imaging, LDI, LDPI" , and Chinese Journals Full-text Database, Wanfang Database, VIP Database were searched using Chinese key words ",,,," to obtain the published trials of LDI in diagnosing deep or superficial partial-thickness burn wound from the establishment of each database to October 2015. The risk of bias and applicability concerns of the included studies were evaluated by Quality Assessment of Diagnostic Accuracy Studies-2. Data were processed with Meta-DiSc 1.4 statistical software. The heterogeneity among the included studies was evaluated. The pooled estimates of LDI in diagnosing deep or superficial partial thickness burn wound in the included studies, including sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, as well as the area under the curve of summary receiver operating characteristic and index of Q(*) were calculated. The stability of results of the overall pooled estimates of the included studies was validated by sensitivity analysis. The sources of heterogeneity among the included studies were sought through subgroup analysis. The publication bias caused by the results of the included studies was evaluated by drawing the Deek's funnel plot. Results: A total of 5 articles conforming to the inclusion criteria, involving 138 patients and 179 burn wounds, were included. One of the included studies had low risk of bias, while the other 4 studies had high/unclear risk of bias. In applicability concern aspect, one of the included studies had high/unclear concerns regarding applicability, while the other 4 studies had low concerns regarding applicability. There was no heterogeneity caused by threshold effects among the included studies (no " shoulder arm" plot of the scattered-point distribution was observed in the space of the receiver operating characteristic, beta(s)=0.01, P>0.05). There was a high heterogeneity caused by non-threshold effects among the included studies (sensitivity I(2)=54%). The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of the included studies on LDI in diagnosing deep or superficial partial-thickness burn wound were 95% (with 95% confidence interval 88%-99%), 96% (with 95% confidence interval 90%-99%), 9.75 (with 95% confidence interval 4.35-21.81), 0.11 (with 95% confidence interval 0.05-0.22), and 257.93 (with 95% confidence interval 58.96-1 128.41), respectively. The area under the curve of summary receiver operating characteristic was 0.98, with index of Q(*) 94%. The results of the overall pooled estimates of the included studies was stable. The risk of bias of the selection of the patients, equipment type of LDI, and the selection of diagnostic method in control might be sources of the heterogeneity of the included studies. The Deek's funnel plot indicated that there was no publication bias caused by the results of the included studies (P>0.05). Conclusions: LDI has high sensitivity, specificity, positive likelihood ratio, diagnostic odds ratio and index of Q(*,) large area under the curve of summary receiver operating characteristics, and low negative likelihood ratio in diagnosing deep or superficial partial-thickness burn wound, which has relatively high diagnostic value. PMID- 28651423 TI - [Advances in the research of role of integrin-linked kinase in angiogenesis]. AB - Integrin-linked kinase (ILK) has been found for twenty years, and its biological characteristics have been extensively studied by multi-discipline. At present, studies of ILK are mainly focused on its roles in angiogenesis, tumor formation, and tissue fibrosis, etc. In recent years, the regulation effect of ILK in angiogenesis attracts attention of researchers. The studies showed that ILK can stimulate the secretion of angiogenic factor, promote the proliferation and migration of endothelial cells and inhibit their apoptosis, and therefore play an important role in the regulation of angiogenesis. Further research on molecular mechanism about the role of ILK playing in angiogenesis may provide an effective method for the treatment of some diseases. PMID- 28651424 TI - Estimated glomerular filtration rate, renal scan and volumetric assessment of the kidney before and after partial nephrectomy: a review of the current literature. AB - INTRODUCTION: The best method for assessing renal function after partial nephrectomy (PN) continues to be a matter of debate. Early studies evaluated kidney function by measuring serum creatinine (sCr) and/or the estimated glomerular filtration rate (eGFR), potentially underestimating the contribution of the contralateral kidney in masking alterations in renal function. Since then, researchers have studied the operated renal unit with the aid of nuclear renal scans (RS). However, taking into consideration the importance of the amount of renal parenchyma spared or sacrificed during PN, many novel methods have been proposed for determining kidney volume before and after PN. This review presents a critical analysis of the literature concerning renal function assessment using eGFR, renal scan and volumetric methods before and after PN. EVIDENCE ACQUISITION: The literature review was carried out using the Pubmed database and the keywords "eGFR", "renal scan" and "volumetric assessment" in combination with "partial nephrectomy" or "nephron-sparing surgery". The search was limited to English language articles published between June 2006 and June 2016. EVIDENCE SYNTHESIS: Of the available formulas, the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations should be used as they provide the best estimation of GFR. MAG3 RS is the most widely used method in current practice, presenting several distinct advantages. According to studies on volumetric assessment, as a general rule, renal tumors should be removed with resection of a thin rim of healthy parenchyma or by enucleation following the tumor pseudocapsule plane, as a histologic tumor-free resection margin, irrespective of the width of the margin, is sufficient to achieve local control during PN. There are no clear recommendations regarding the best modality to use. CONCLUSIONS: The use of serum creatinine alone should be avoided. The use of glomerular filtration rate, as estimated by means of available formulas, could be a viable option. If available, a nuclear RS should be adopted, whilst taking into account the limitations of this imaging methodology. Volumetric assessment continues to lack certainty. To date, no single proposed method for volumetric assessment appears to be superior above the others. PMID- 28651425 TI - Expression of GFRalpha3 correlates with tumor progression and promotes cell metastasis in urothelial carcinoma. AB - BACKGROUND: Urothelial carcinoma (UC) is a major health problem in the general population. We aimed to evaluate the function of GFRalpha3 and unravel its underlying molecular mechanism to develop novel treatment options equivalent to UC. METHODS: To evaluate the function of GFRalpha3, a group of 60 pairs of UC patients were recruited in for this study. UC tissues and their adjacent normal control tissues (NCTs) were collected between 2012 and 2015. We used immunohistochemistry to analyze the correlation between GFRalpha3 expression and clinicopathologic variables and patient survival. The role of regulation of GFRalpha3 in UC was applied in vitro. In addition, we further investigated the signaling pathway of GFRalpha3 in UC progression. RESULTS: The expression level of GFRalpha3 was remarkably upregulated in 49.3% (19/60) patients and downregulated in 25.0% (15/60) patients. The GFRalpha3 protein expression was upregulated in UC tissues. GFRalpha3 promotes UC cell migration and invasion in vitro. GFRalpha3 also promotes UC cell metastasis in vitro. High level of GFRalpha3 promotes UC cell migration via upregulation of MMP9 expression. CONCLUSIONS: Our results demonstrate that increased GFRalpha3 expression is significantly correlated with poor prognosis of patients with UC. Thus, GFRalpha3 might be an important marker and a therapeutic target for UC. PMID- 28651426 TI - Removing transurethral catheter on postoperative day 2 after robot-assisted laparoscopic radical prostatectomy: towards a new standard? PMID- 28651427 TI - Loeffler endocarditis in chronic eosinophilic leukemia with FIP1L1/PDGFRA rearrangement: full recovery with low dose imatinib. PMID- 28651428 TI - Development of Theoretical Descriptors for Cytotoxicity Evaluation of Metallic Nanoparticles. AB - Motivated by the recent development of quantitative structure-activity relationship (QSAR) methods in the area of nanotoxicology, we proposed an approach to develop additional descriptors based on results of first-principles calculations. For the evaluation of the biochemical activity of metallic nanoparticles, we consider two processes: ion extraction from the surface of a specimen to aqueous media and water dissociation on the surface. We performed calculations for a set of metals (Al, Fe, Cu, Ag, Au, and Pt). Taking into account the diversity of atomic structures of real metallic nanoparticles, we performed calculations for different models such as (001) and (111) surfaces, nanorods, and two different cubic nanoparticles of 0.6 and 0.3 nm size. Significant energy dependence of the processes from the selected model of nanoparticle suggests that for the correct description we should combine the calculations for several representative models. In addition to the descriptors of chemical activity of the metallic nanoparticles for the two studied processes, we propose descriptors for taking into account the dependence of chemical activity from the size and shape of nanoparticles. Routes to minimization of computational costs for these calculations are also discussed. PMID- 28651429 TI - Influence of Hydrogen Bonding on the Surface Diffusion of Molecular Glasses: Comparison of Three Triazines. AB - Surface grating decay measurements have been performed on three closely related molecular glasses to study the effect of intermolecular hydrogen bonds on surface diffusion. The three molecules are derivatives of bis(3,5-dimethyl-phenylamino) 1,3,5-triazine and differ only in the functional group R at the 2-position, with R being C2H5, OCH3, and NHCH3, and referred to as "Et", "OMe", and "NHMe", respectively. Of the three molecules, NHMe forms more extensive intermolecular hydrogen bonds than Et and OMe and was found to have slower surface diffusion. For Et and OMe, surface diffusion is so fast that it replaces viscous flow as the mechanism of surface grating decay as temperature is lowered. In contrast, no such transition was observed for NHMe under the same conditions, indicating significantly slower surface diffusion. This result is consistent with the previous finding that extensive intermolecular hydrogen bonds slow down surface diffusion in molecular glasses and is attributed to the persistence of hydrogen bonds even in the surface environment. This result is also consistent with the lower stability of the vapor-deposited glass of NHMe relative to those of Et and OMe and supports the view that surface mobility controls the stability of vapor deposited glasses. PMID- 28651430 TI - Excited State Dynamics of 6-Thioguanine. AB - Here we present the excited state dynamics of jet-cooled 6-thioguanine (6-TG), using resonance-enhanced multiphoton ionization (REMPI), IR-UV double resonance spectroscopy, and pump-probe spectroscopy in the nanosecond and picosecond time domains. We report data on two thiol tautomers, which appear to have different excited state dynamics. These decay to a dark state, possibly a triplet state, with rates depending on tautomer form and on excitation wavelength, with the fastest rate on the order of 1010 s-1. We also compare 6-TG with 9-enolguanine, for which we observed decay to a dark state with a 2 orders of magnitude smaller rate. At increased excitation energy (~+500 cm-1) an additional pathway appears for the predominant thiol tautomer. Moreover, the excited state dynamics for 6-TG thiols is different from that recently predicted for thiones. PMID- 28651431 TI - A Model To Estimate the Sources of Tobacco-Specific Nitrosamines in Cigarette Smoke. AB - Tobacco-specific nitrosamines (TSNAs) are one of the most extensively and continually studied classes of compounds found in tobacco and cigarette smoke.1-5 The TSNAs N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) have been characterized by the US Food and Drug Administration (FDA) as harmful and potentially harmful constituents in tobacco products,6 and cigarette manufacturers report their levels in cigarette tobacco filler and cigarette smoke to the FDA. NNN and NNK are classified by IARC as carcinogenic to humans.7 TSNAs transfer from tobacco to smoke by evaporation driven by heat and the flow of gases down the cigarette rod. Other TSNA sources in smoke include pyrorelease, where room temperature-unextractable TSNAs are released by smoking, and pyrosynthesis, where TSNAs are formed by reactions during smoking. We propose the first model that quantifies these three sources of TSNA in smoke. In our model, evaporative transfer efficiency of a TSNA is equated to the evaporative transfer efficiency of nicotine. Smoke TSNA measured in excess of what is transferred by evaporation is termed "pyrogeneration," which is the net sum of pyrorelease and pyrosynthesis minus pyrodegredation. This model requires no internal standard, is applicable to commercial cigarettes "as is," and uses existing analytical methods. This model was applied to archived Philip Morris USA data. For commercial blended cigarettes, NNN pyrogeneration appears to be unimportant, but NNK pyrogeneration contributes roughly 30-70% of NNK in smoke with the greater contribution at lower tobacco NNK levels. This means there is an opportunity to significantly reduce smoke NNK by up to 70% if pyrogeneration can be decreased or eliminated, perhaps by finding a way to grow and cure tobacco with reduced matrix-bound NNK. For burley research cigarettes, pyrogeneration may account for 90% or more of both NNN and NNK in smoke. PMID- 28651432 TI - Controlled Intercalation and Chemical Exfoliation of Layered Metal-Organic Frameworks Using a Chemically Labile Intercalating Agent. AB - Creating ordered two-dimensional (2D) metal-organic framework (MOF) nanosheets has attracted extensive interest. However, it still remains a great challenge to synthesize ultrathin 2D MOF nanosheets with controlled thickness in high yields. In this work, we demonstrate a novel intercalation and chemical exfoliation approach to obtain MOF nanosheets from intrinsically layered MOF crystals. This approach involves two steps: first, layered porphyrinic MOF crystals are intercalated with 4,4'-dipyridyl disulfide through coordination bonding with the metal nodes; subsequently, selective cleavage of the disulfide bond induces exfoliation of the intercalated MOF crystals, leading to individual freestanding MOF nanosheets. This chemical exfoliation process can proceed efficiently at room temperature to produce ultrathin (~1 nm) 2D MOF nanosheets in ~57% overall yield. The obtained ultrathin nanosheets exhibit efficient and far superior heterogeneous photocatalysis performance compared with the corresponding bulk MOF. PMID- 28651433 TI - Profile-QSAR 2.0: Kinase Virtual Screening Accuracy Comparable to Four Concentration IC50s for Realistically Novel Compounds. AB - While conventional random forest regression (RFR) virtual screening models appear to have excellent accuracy on random held-out test sets, they prove lacking in actual practice. Analysis of 18 historical virtual screens showed that random test sets are far more similar to their training sets than are the compounds project teams actually order. A new, cluster-based "realistic" training/test set split, which mirrors the chemical novelty of real-life virtual screens, recapitulates the poor predictive power of RFR models in real projects. The original Profile-QSAR (pQSAR) method greatly broadened the domain of applicability over conventional models by using as independent variables a profile of activity predictions from all historical assays in a large protein family. However, the accuracy still fell short of experiment on realistic test sets. The improved "pQSAR 2.0" method replaces probabilities of activity from naive Bayes categorical models at several thresholds with predicted IC50s from RFR models. Unexpectedly, the high accuracy also requires removing the RFR model for the actual assay of interest from the independent variable profile. With these improvements, pQSAR 2.0 activity predictions are now statistically comparable to medium-throughput four-concentration IC50 measurements even on the realistic test set. Beyond the yes/no activity predictions from a typical high throughput screen (HTS) or conventional virtual screen, these semiquantitative IC50 predictions allow for predicted potency, ligand efficiency, lipophilic efficiency, and selectivity against antitargets, greatly facilitating hitlist triaging and enabling virtual screening panels such as toxicity panels and overall promiscuity predictions. PMID- 28651435 TI - Sir FMR Walshe (1885-1973): what a neurologist can teach us about the neurosurgeon. AB - Sir Francis Martin Rouse Walshe (1885-1973) was a decorated neurologist, but he also commented widely on neurosurgery. Many of his comments and his overall approach to medicine remain highly relevant to the practicing neurosurgeon. His focus on the paramount importance of the core principles of clinical medicine, as well as his passion for basic clinical research are values which remain key to neurosurgery to this day. Furthermore his advocacy for those in generalist medical training to find their passion and vocation is highly relevant for a specialty as highly specialised as neurosurgery. PMID- 28651434 TI - Body Mass Index and functional impairment: the explanatory role of anxiety sensitivity among treatment-seeking smokers. AB - Obesity and smoking are highly prevalent public health concerns in the United States. Data indicate that elevated Body Mass Index (BMI) is related to functional impairment. However, there is limited understanding of mechanisms that may explain their comorbidity among smokers. The current study sought to test whether anxiety sensitivity explained the relation between BMI and functional impairment among 420 (46.9% females; Mage = 38 years, SD = 13.42) treatment seeking, adult smokers. Results indicated that BMI yielded a significant indirect effect through anxiety sensitivity for functional impairment, b = 0.01, SE = .01, 95% CI = [.002, .021]. These findings remained significant after controlling for participant sex, negative affectivity, tobacco dependence, psychopathology, and medical conditions (i.e. hypertension, heart problems, respiratory disease, asthma). Such data provide novel empirical evidence that, among smokers, BMI may be a risk factor for functional impairment indirectly through anxiety sensitivity. Overall, such findings could potentially inform the development of personalized interventions among this particularly vulnerable segment of the smoking population. PMID- 28651436 TI - Beyond the beaten path: improving natural products bioprospecting using an eco evolutionary framework - the case of the octocorals. AB - Marine natural products (NPs) represent an impressive source of novel bioactive molecules with major biotechnological applications. Nevertheless, the usual chemical and applied perspective leading most of bioprospecting projects come along with various limitations blurring our understanding of the extensive marine chemical diversity. Here, we propose several guidelines: (i) to optimize bioprospecting and (ii) to refine our knowledge on marine chemical ecology focusing on octocorals, one of the most promising sources of marine NPs. We identified a significant phylogenetic bias in the octocoral bioprospecting, which calls for the development of a concerted discovery strategy. Given the gap existing between the number of isolated NPs and the knowledge regarding their functions, we provide an ecologically centered workflow prioritizing biological function ahead of chemical identification. Furthermore, we illustrate how -omic technologies should rapidly increase our knowledge on solving different aspects of the ecology and evolution of marine NPs. PMID- 28651437 TI - Comparative study on Artemisia halodendron Turcz. and its two related plants by GC-MS analysis and protective effect against carbon tetrachloride-induced hepatotoxicity in mice. AB - A rapid method had been used for comparative study on Artemisia halodendron Turcz. and its two related plants by gas phase-mass spectrometry (GC-MS). The comparison of the volatile oils obtained in three plants by GC-MS were similar in 20 compositions. However, n-Hexadecanoic acid (10.40%), Biphenyl (7.867%) and 9,12-Octadecadienoic acid (7.25%) were the predominant in the volatile oils of A. halodendron Turcz., whereas these constituents did not exist in the other two plants. And the study investigated the effect of three plants against CCl4 induced hepatotoxicity in mice. 70% ethanol extracts of A. halodendron Turcz. showed weaker protective effect than the other two plants. It suggested that they provide a basis for the identification of the A. halodendron Turcz. from the other two plants and the ethanol extract from three plants exerted a protecting effect against hepatotoxicity. PMID- 28651438 TI - Leadership and Physician Burnout: Using the Annual Review to Reduce Burnout and Promote Engagement. PMID- 28651439 TI - Erratum. PMID- 28651440 TI - The timing of surgery may influence causation in medicolegal cases. PMID- 28651441 TI - The Effect of Ex Vivo Factor XIII Supplementation on Clot Formation in Blood Samples From Cardiac and Scoliosis Surgery Patients. AB - Excessive perioperative bleeding remains a substantial problem. Factor XIII (FXIII) contributes to clot stability, and it has therefore been suggested that supplementation with FXIII concentrate may improve perioperative hemostasis. We evaluated the effects of increasing doses of FXIII, alone or in combination with fibrinogen or platelet concentrate, in blood samples from 2 considerably different groups of surgical patients: cardiac and scoliosis surgery patients. Whole-blood samples were collected immediately after operation from cardiac and scoliosis surgery patients. The samples were supplemented with 3 clinically relevant doses of FXIII concentrate (+20%, +40%, and +60%), alone or in combination with a fixed dose of fibrinogen concentrate (+1.0 g/L) or fresh apheresis platelets (+92 * 109/L). Clot formation was assessed with rotational thromboelastometry (ROTEM). When the highest dose of FXIII concentrate was added, EXTEM clotting time was shortened by 10% in both cardiac and scoliosis surgery patients (95% confidence intervals: 2.4%-17% and 3.3%-17%, respectively), and FIBTEM maximum clot firmness was increased by 25% (9.3%-41%) in cardiac patients, relative to baseline. When fibrinogen was added, the dose-dependent effect of FXIII on clot stability was maintained, but the total effect was markedly greater than with FXIII alone, +150% (100%-200%) and +160% (130%-200%) for the highest FXIII dose in cardiac and scoliosis patients, respectively. Ex vivo supplementation with clinically relevant doses of FXIII improved clot formation moderately in blood samples from cardiac and scoliosis surgery patients, both alone and when given in combination with fibrinogen or platelet concentrate. PMID- 28651442 TI - A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects. AB - OBJECTIVES: This Phase I trial (INVICTAN(r)-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin(r), Genentech; EU-approved Avastin, Roche). METHODS: Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early. The primary end point was area under the concentration-time curve (AUC) of the analyte in plasma from time zero extrapolated to infinity (AUC0-infinity). Other pharmacokinetic (PK) parameters, safety, and in vitro binding affinity were also evaluated. RESULTS: The interim analysis demonstrated three-way bioequivalence for all comparisons. The confidence intervals around the geometric mean ratios of the primary and secondary PK parameters were within the predefined acceptance ranges. Study drugs were well tolerated with no clinically relevant differences in safety. CONCLUSION: BI 695502 and US- and EU-approved Avastin showed three-way bioequivalence with similar safety profile. CLINICAL TRIAL REGISTRATION: NCT01608087. PMID- 28651443 TI - Added value of delayed computed tomography angiography in primary intracranial hemorrhage and hematoma size for predicting spot sign. AB - Background The computed tomography angiography (CTA) spot sign represents active contrast extravasation within acute primary intracerebral hemorrhage (ICH) and is an independent predictor of hematoma expansion (HE) and poor clinical outcomes. The spot sign could be detected on first-pass CTA (fpCTA) or delayed CTA (dCTA). Purpose To investigate the additional benefits of dCTA spot sign in primary ICH and hematoma size for predicting spot sign. Material and Methods This is a retrospective study of 100 patients who underwent non-contrast CT (NCCT) and CTA within 24 h of onset of primary ICH. The presence of spot sign on fpCTA or dCTA, and hematoma size on NCCT were recorded. The spot sign on fpCTA or dCTA for predicting significant HE, in-hospital mortality, and poor clinical outcomes (mRS >= 4) are calculated. The hematoma size for prediction of CTA spot sign was also analyzed. Results Only the spot sign on dCTA could predict high risk of significant HE and poor clinical outcomes as on fpCTA ( P < 0.05). With dCTA, there is increased sensitivity and negative predictive value (NPV) for predicting significant HE, in-hospital mortality, and poor clinical outcomes. The XY value (product of the two maximum perpendicular axial dimensions) is the best predictor (area under the curve [AUC] = 0.82) for predicting spot sign on fpCTA or dCTA in the absence of intraventricular and subarachnoid hemorrhage. Conclusion This study clarifies that dCTA imaging could improve predictive performance of CTA in primary ICH. Furthermore, the XY value is the best predictor for CTA spot sign. PMID- 28651444 TI - Novel treatment strategy for advanced hepatocellular carcinoma: combination of conventional transcatheter arterial chemoembolization and modified method with portal vein occlusion for cases with arterioportal shunt: a preliminary study. AB - Background A novel strategy to combine conventional transcatheter arterial chemoembolization (TACE) and TACE during portal vein occlusion (TACE-PVO) in the presence of high-flow arterioportal shunt (APS) has been developed to treat hepatocellular carcinoma (HCC) with portal invasion. Purpose To evaluate the efficacy of this strategy. Material and Methods Twenty-five cases of HCC with portal invasion, treated between April 2006 and December 2015, were evaluated. Balloon occlusion of the portal venous outlet was performed in eight cases of high-flow APS when performing TACE. Conventional TACE was performed in the other 17 cases. The primary endpoint was overall survival. Adverse events and deterioration of liver function were also evaluated. Results The median survival time (MST) was 12 months. One-, two-, and three-year survival rates were 48.0%, 39.3%, and 26.2%, respectively. Subgroup analysis and multivariate analysis revealed the CLIP score as prognostic factor. MST was 2.5 months in the subgroup with CLIP score >=4 and 26.0 months in the subgroup with CLIP score <=3 (hazard ratio = 7.7, 95% confidence interval = 2.3-25.8). Transient elevations of the levels of transaminase and bilirubin were observed; however, deterioration of liver function was infrequent; upgrading of Child-Pugh class in 9.1% of cases. Conclusion A novel strategy, combining conventional TACE and TACE-PVO, is effective for HCC with portal invasion. The CLIP score may be useful for considering treatment indication. PMID- 28651445 TI - Cellular reprogramming technology for dissecting cancer epigenome in vivo. AB - Decades of studies have shown that epigenetic alterations play a significant role on cancer development both in vitro and in vivo. However, considering that many cancers harbor mutations at epigenetic modifier genes and that transcription factor-mediated gene regulations are tightly coupled with epigenetic modifications, the majority of epigenetic alterations in cancers could be the consequence of the dysfunction or dysregulation of epigenetic modifiers caused by genetic abnormalities. Therefore, it remains unclear whether bona fide epigenetic abnormalities have causal roles on cancer development. Reprogramming technologies enable us to actively alter epigenetic regulations while preserving genomic information. Taking advantage, recent studies have provided in vivo evidence for the significant impact of epigenetic abnormalities on the initiation, maintenance and progression of cancer cells. PMID- 28651447 TI - The association between fetal fibronectin and spontaneous preterm birth in twin pregnancies with a shortened cervical length. AB - OBJECTIVE: To estimate the association between a positive fetal fibronectin (fFN) and spontaneous preterm birth (SPTB) in twin pregnancies with a shortened cervical length (CL). STUDY DESIGN: Retrospective cohort study of asymptomatic twin pregnancies managed by a single MFM practice from 2005 to 2016. We included all women with a shortened CL <=25 mm at 22-28 weeks, and compared outcomes between women with a positive and negative fFN result. RESULTS: One hundred fifty five patients were included, 129 (83.2%) of whom had a negative fFN and 26 (16.8%) of whom had a positive fFN. Baseline characteristics were similar between groups, except for the CL at the time of diagnosis of short cervix (15 mm in the positive fFN group versus 20 mm in the negative fFN group, p = .002). The risk of SPTB <32 weeks was significantly higher in the positive fFN group (46.2 versus 12.6%, aOR 3.54, 95% CI 1.26, 9.92) and the mean gestational age at delivery was significantly earlier (31.1 versus 35.2 weeks, p < .001). CONCLUSIONS: In asymptomatic women with twin pregnancies and a shortened CL, a positive fFN is significantly associated with SPTB and can modify the risk substantially. If performing a screening CL assessment in a twin pregnancy, fFN testing should be done concurrently. PMID- 28651446 TI - Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model. AB - OBJECTIVE: To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs. METHODS: C57BL/6 male mice (age 10.5 +/- 2.4 weeks) were exposed for 20 min/day to E-cigarette aerosol generated by a Joyetech 510-T(r) E-cig containing either 0% nicotine (N)/propylene glycol (PG) for 1 week (n = 6), or 3 weeks (n = 9), or 2.4% N/PG for one week (n = 6), or 3 weeks (n = 9), followed by measurement of MCC. Control mice (n = 15) were not exposed to PG alone, or N/PG. MCC was assessed by gamma camera following aspiration of 99mtechnetium aerosol and was expressed as the amount of radioactivity removed from both lungs over 6 hours (MCC6hrs). Venous blood was assayed for cotinine levels in control mice and in mice exposed for 3-weeks to PG alone and N/PG. RESULTS: MCC6hrs in control mice and in mice acutely exposed to PG alone and N/PG was similar, averaging (+/ 1 standard deviation) 8.6 +/- 5.2%, 7.5 +/- 2.8% and 11.2 +/- 5.9%, respectively. In contrast, chronic exposure to PG alone stimulated MCC6hrs (17.2 +/- 8.0)% and this stimulation was significantly blunted following chronic exposure to N/PG (8.7 +/- 4.6)% (p < .05). Serum cotinine levels were <0.5 ng/ml in control mice and in mice exposed to PG alone, whereas, N/PG exposed mice averaged 14.6 +/- 12.0 ng/ml. CONCLUSIONS: In this murine model, a chronic, daily, 20 min-exposure to N/PG, but not an acute exposure, slowed MCC, compared to exposure to PG alone and led to systemic absorption of nicotine. PMID- 28651448 TI - Adverse pregnancy outcomes in deliveries prior to, at and beyond 39 weeks; low- and high-risk women. AB - BACKGROUND: Hypertensive disorders are associated with maternal and neonatal complications. Though they are more common in women with history of prior preeclampsia, they can occur in uncomplicated pregnancies. OBJECTIVE: To determine the proportion of adverse pregnancy outcomes in deliveries prior to or at >=39 weeks, in uncomplicated singleton nulliparous women (low-risk), as well as women with history of preeclampsia in a prior gestation (high-risk). STUDY DESIGN: This was a secondary analysis from the multicenter trials of low dose aspirin for preeclampsia prevention in low and high-risk pregnancies. The proportion of adverse pregnancy outcomes including hypertensive disorders in pregnancy, small for gestational age, placental abruption, neonatal intensive critical unit admission, and respiratory distress syndrome were evaluated in the two groups. Adverse pregnancy outcomes were stratified by gestational age at delivery (<39 weeks and >=39 weeks). Descriptive statistics were performed, and results reported as percentages. RESULTS: Three thousand twenty-one pregnancies were included in the low risk group, and 600 in the high risk one. In the low risk group 362 (12%) had hypertensive disorders, with 58% occurring at >=39 weeks. In the low risk group, the rate of small for gestational age was of 5.9%, placental abruption 0.4%, neonatal intensive care unit admission 9%, and respiratory distress syndrome 3.5%. Sixty percent of all small for gestational age, 31% of all placenta abruptions, 44% of all neonatal intensive care unit admissions and 33% of respiratory distress syndrome cases, occurred at >=39 weeks in the low risk group. In contrast in the high risk group, 197 (33%) patients developed a hypertensive disorder, with 35.5% occurring at >=39 weeks. The overall rate of small for gestational age was 9.2%, abruption 2%, neonatal intensive care unit admission 15.5%, and respiratory distress syndrome 5%. In this group, 24% of all small for gestational age, 8.3% of all placental abruptions, 16% of all neonatal intensive care unit admissions and 3% of respiratory distress syndrome cases, were at >=39 weeks. CONCLUSIONS: We found that in low-risk women, the majority of hypertensive disorders occur at >=39 weeks, whereas in women with prior preeclampsia the majority develops at <39 weeks. Moreover, a third of all placental abruption occurred at or beyond 39 weeks in the low risk group. Our findings suggest that in low-risk women, a policy of delivery at 39 weeks may prevent most of the adverse outcome that occurs beyond that gestational age cutoff. PMID- 28651449 TI - The association between obstetrical history and preterm birth in women with uterine anomalies. AB - OBJECTIVE: To estimate the association between obstetric history and preterm birth in women with uterine anomalies. METHODS: This was a retrospective cohort study of women with uterine anomalies managed by one maternal-fetal medicine practice from 2005 to 2016. Women were separated into three groups based on their most recent pregnancy outcome: preterm birth <37 weeks, nulliparous, and term birth. Delivery outcomes were compared across the three groups, with the primary outcome being preterm birth <37 weeks. A subgroup analysis was performed in women with major uterine anomalies (unicornuate, bicornuate, and didelphys). RESULTS: A total of 283 women with uterine anomalies were included. Preterm birth <37 weeks was 60.4% in women with prior preterm birth versus 18.2% in nulliparous women, versus 15.8% in women with a prior term birth (p < .001). The difference between nulliparous women and women with a prior term birth was not significant (p = .635). Among the 118 women with major uterine anomalies, the likelihood of preterm birth was also highest in the prior preterm birth group (71.4 versus 26.1 versus 25.0%, p < .001), and the difference between nulliparous women and women with a prior term birth was not significant (p = .906). CONCLUSIONS: In women with uterine abnormalities, a prior preterm birth is significantly associated with recurrent preterm birth. However, a prior term birth does not lower the risk of preterm birth as compared to nulliparous women. PMID- 28651450 TI - Determinants of gestational diabetes mellitus: a case-control study. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is glucose intolerance first recognized during pregnancy. The objective of this study was to identify the determinant factors of GDM. METHODS: An unmatched case-control study was conducted. Descriptive statistics were used to describe the profile of study participants and binary logistic regression was used to identify the determinants of GDM. RESULTS: GDM was associated with history of abortion (AOR 5.05 [95% CI: 2.65-9.63]), family history of diabetes mellitus (AOR 8.63 [95% CI: 5.19-14.35]), chronic hypertension (AOR 4.63 [95% CI: 1.27-16.86]), dietary diversification score (AOR 2.96 [95% CI: 2-4.46]), regular physical exercise (AOR 0.03 [95% CI: 0.01-0.04]), history of infertility (AOR 6.19 [95%CI: 1.86-20.16]), history of Caesarean section (AOR 3.24 [95% CI: 1.58-6.63]), previous history of GDM (AOR 8.21 [95% CI: 3.18-21.24]), previous history of intrauterine fetal death (AOR 3.96 [95% CI: 1.56-10.04]), literacy (AOR 0.6 [95% CI: 0.43-0.85]), body mass index (AOR 2.96 [95% CI: 2.08-4.2]), parity (AOR 1.78 [95% CI: 1.3-2.49]). CONCLUSIONS: Regular physical exercise should be used as the main tool in preventing GDM. PMID- 28651451 TI - Incidence of unprovoked venous thromboembolic events in patients with chronic lymphocytic leukemia. PMID- 28651452 TI - Nonvitamin K antagonist oral anticoagulant use in patients with renal impairment. AB - The nonvitamin K antagonist oral anticoagulants (NOACs), also referred to as direct oral anticoagulants (DOACs), dabigatran, apixaban, edoxaban, and rivaroxaban, have emerged as effective alternatives to vitamin K antagonists (VKAs) across several indications, including the prevention of stroke and systemic embolism (SSE) in patients with atrial fibrillation (AF) and the treatment of venous thromboembolism (VTE). Their use in patients with renal impairment is of particular importance, given the prevalence of renal dysfunction in the indicated populations and the impact of renal function on the metabolism of the NOACs. This publication reviews the pharmacokinetic/pharmacodynamic properties of the NOACs and clinical trial results for patients with renal impairment within the AF and VTE indications. Pharmacokinetic/pharmacodynamic data show the NOACs are dependent on renal clearance to varying extents. Relative to VKAs, the efficacy and safety of the NOACs is preserved in patients with moderate renal impairment. The dosing recommendations for patients with renal impairment differ depending on the NOAC, whereby some of the NOACs require dose reductions based solely on renal function, while others require consideration of additional criteria. However, despite these specific dosing recommendations, emerging real-world evidence suggests patients are not being dosed appropriately, indicating a possible knowledge gap. Adherence to recommended dosing algorithms has implications on the optimal efficacy and safety of the NOACs. To this end, renal function should be assessed in patients on a NOAC, as worsening of renal function may warrant change in the dose of a NOAC or change in oral anticoagulant. PMID- 28651453 TI - Pretransplant serum FT3 levels in recipients predict early non-relapse mortality after myeloablative allogeneic haematopoietic cell transplantation from matched sibling donors. AB - OBJECTIVES: Although decreased thyroid function is negatively correlated with clinical outcomes in critically ill patients, its role in allogeneic haematopoietic cell transplantation (allo-HCT) has not been sufficiently described. METHODS: The associations between pre-conditioning thyroid hormone concentrations and transplant-related complications in 474 adult patients with haematologic malignancies who underwent myeloablative allo-HCT were assessed. RESULTS: A receiver-operating characteristic curve showed that the baseline serum free triiodothyronine 3 (FT3) level had an excellent predictive value for non relapse mortality (NRM) within 100 days in sibling HCT with an area under the curve of 0.73 [95% confidence interval (CI), 0.64-0.82]. With a cut-off value of 4.7 pmol/l, the sensitivity and specificity for early NRM were 68% and 73%, respectively. The cumulative incidences of early NRM within 100 days after sibling HCT were 14% (95% CI, 10-18%) in the low FT3 group and 6% (95% CI, 4-8%) in the high-FT3 group (p = 0.033). In multivariate analysis, a lower FT3 level was significantly associated with high early NRM (HR = 3.19, 95% CI, 1.13-9.03, p = 0.029). The difference was also significant at 3 years after HCT (24% vs. 14%, p = 0.046). Recipients with lower FT3 levels also had a trend towards a lower OS at 3 years after HCT (66% vs. 72%, p = 0.235), although the difference did not reach statistical significance. CONCLUSION: A low FT3 level before conditioning may be a useful predictive biomarker for higher early NRM among patients undergoing myeloablative sibling transplantation. PMID- 28651454 TI - Chimney Technique in Supra-Aortic Branch Reconstruction in China: A Systematic and Critical Review of Chinese Published Experience. AB - BACKGROUND: The chimney graft (CG) technique has been proposed as a complete endovascular supra-aortic branch reconstruction for aortic pathologies. Due to the rapid growth of thoracic endovascular aortic repair (TEVAR) in China, we aimed to investigate the current data of the CG technique in this most populous country. METHODS: Studies of supra-aortic branch reconstruction using the CG technique from Chinese centers were collected and analyzed. RESULTS: A total of 294 patients from Chinese centers who underwent TEVAR with CGs were included. There were 301 CGs performed, with a technical successful rate of 97.7%. The rate of early type I endoleaks was 7.1%, and the patency rate of the CGs was desirable. Balloon-expandable bare CGs were significantly associated with good early outcomes and a low rate of endoleaks. CONCLUSION: Current data from China revealed positive outcomes using CGs for supra-aortic branch reconstruction. Balloon-expandable bare CGs may be the first choice according to the data available but should be considered with caution. PMID- 28651455 TI - Envisioning a future for precision health psychology: innovative applied statistical approaches to N-of-1 studies. PMID- 28651456 TI - Phytochemical treatments target kynurenine pathway induced oxidative stress. AB - OBJECTIVE: The objective of this paper was to link the phytochemical and metabolic research treating quinolinic acid induced oxidative stress in neurodegenerative disorders. METHODS: Quinolinic acid, a metabolite of the kynurenine pathway of tryptophan catabolism, plays a role in the oxidative stress associated with many neurological disorders and is used to simulate disorders such as Parkinson's disease. RESULTS: In these models, phytochemicals have been shown to reduce striatal lesion size, reduce inflammation and prevent lipid peroxidation caused by quinolinic acid. CONCLUSION: These results suggest that phenolic compounds, a class of phytochemicals, including flavonoids and diarylheptanoids, should be further studied to develop new treatments for oxidative stress related neurological disorders. PMID- 28651457 TI - Metallosis in a Dog as a Long-Term Complication Following Total Hip Arthroplasty. AB - Metallosis is the accumulation of metallic debris in soft tissues resulting from wear following total joint replacement. A dog was evaluated for lameness 4 years after total hip arthroplasty using a titanium alloy and cobalt chromium total hip system. Radiographs revealed severe acetabular component wear, implant-bone interface deterioration, and peri-acetabular osteolysis. During surgical revision, black periarticular tissue surrounded the implants. Histologically, there was fibrosis and granulomatous inflammation with abundant, intra- and extracellular, black, granular material and smaller amounts of clear punctate to acicular material. Laser capture microdissection followed by x-ray fluorescence microscopy indicated the material contained large amounts of titanium with smaller amounts of vanadium, cobalt, and chromium, confirming the diagnosis of metallosis. The clear material was birefringent under cross-polarized light, stained positive with Oil-Red-O, and thus was consistent with polyethylene. Metallosis exhibits characteristic gross and histologic lesions and is a differential diagnosis for aseptic loosening of hip implants. PMID- 28651458 TI - [Differencial diagnosis of the low alkaline phosphatase activities]. AB - Laboratory diagnostics is especially important in the diagnosis of certain diseases. We compared manual measurements results to laboratory normal values. In some cases, these values depend on the gender and age as well. In the case of alkaline phosphatase, it is rarely considered that reference values change over life periods. Unfortunately, during the daily practice we do not always take into account of the changes with aging. This is especially true if the laboratory does not specify the age related normal values. Another problem that we mostly focus on the results exceeding the normal values, and do not pay enough attention to the low values. Of course, these results should be put in the context of the clinical picture and other diagnostic test results. We would like to draw attention to the measuring of alkaline phosphatase and the differential diagnosis for low serum activity. Orv Hetil. 2017; 158(26): 1003-1007. PMID- 28651459 TI - [Examination of placental three-dimensional power Doppler indices and perinatal outcome in pregnancies complicated by intrauterine growth restriction]. AB - INTRODUCTION: Development of intrauterine growth restriction (IUGR) can be traced back to maternal or fetal factors, but in many cases we find placental factors (reduced placental circulation) in the background. AIM: Our aim was to examine whether the reduced placental bloodperfusion and vascularity show any correlation with cesarean section frequency and the clinical outcome in IUGR pregnancies. The aim of the present study was also to use a properly calibrated and reproducible method for evaluating placental blood flow, that can later be incorporated into the routine examination. METHOD: 254 women were recruited in our prospective case control study. The 3 dimensional power Doppler (3DPD) ultrasound indices; vascularisation index (VI), flow index (FI) and vascularization flow index (VFI) were measured on each participant. RESULTS: Median VI was 3.7% (interquartile range [IQR] 3.2%-4.2%) in the IUGR group and 10.1% (IQR 8.6%-10.9%) in the control group (p = 0.001). Median FI value was 40.0 (IQR 39.7-42.5) in the IUGR group and 45.1 (IQR 44.1-53.1) in the control group (p = 0.012). Median VFI was 2.2 (IQR 2.1-2.4) in the IUGR group and 4.8 (IQR 4.4-5.3) in the control. CONCLUSIONS: The 3DPD indices may be useful for examining changes in circulation in IUGR pregnancies to characterize the underlying pathology. Orv Hetil. 2017; 158(26): 1008-1013. PMID- 28651460 TI - [Gut-liver axis in inflammatory bowel disease. A retrospective study]. AB - INTRODUCTION: Examination of the gut-liver axis came into the spotlight worldwide. Liver enzyme elevations are commonly seen in patients with inflammatory bowel disease (IBD), which is a diagnostic challenge in everyday clinical practice. Liver and biliary diseases are common extra-intestinal manifestations in Crohn's disease and ulcerative colitis. The assessment of routine liver function tests could be an inaccurate reflection of liver damage, so its prevalence could be underestimated. There would be a need for non-invasive biomarkers and/or scoring systems, which would help the diagnosis of liver damage associated with intestinal diseases. AIM: In our work we considered to highlight the importance of the gut-liver axis significance. We used data of patients suffering from ulcerative colitis, as a model for bowel diseases to understand the underlying factors of the pathogenesis of hepatobiliary manifestations. METHOD: In our retrospective study, we investigated the data of 100 ulcerative colitis patients (male = 46, female = 54) (mean age: 42.5 +/- 12.7) and compared to healthy controls (n = 42) (male = 17, female = 25) (mean age: 40.2 +/- 13.5). Liver function tests (ALT, AST, GGT, ALP, bilirubin, albumin, thrombocyte), bile acid levels were determinated, and various free radical markers (global, enzymatic) were used to assess the redox homeostasis of patients. Hydrogen donor activity, reducing power, superoxide dismutase and glutathione peroxidase activity, total antioxidant status and induced chemiluminescence were measured, considering that the patients received 5-aminosalicilate and/or azathioprin and elemental diet treatment. RESULTS: Liver function parameters were increased in ulcerative colitis patients, and total antioxidant status, as well. Reducing power significantly decreased, but there was no significant difference compared to the control group of glutathione peroxidase and H-donor activity, we observed only tendentious decrease. The antioxidant protection of more than 54% of patients had a significantly lower rate, according to all the parameters. With chemiluminescence measurement we measured better free radical scavenging capacity, both in plasma and in erythrocytes as a result of the therapy, however, it showed an increase of superoxide dismutase activity, which warns of inflammatory processes. The cause of the decrease in bile acid levels found in the group of ulcerative colitis patients, can be the accelerated peristaltic. CONCLUSIONS: In the daily routine, liver enzyme values do not give an accurate picture of liver damage associated with ulcerative colitis. With the help of various specific parameters determined by us, we can estimate the background processes of the gut-liver axis alterations. The decrease in bile acid levels can be a predictive factor in ulcerative colitis. Our work highlights the need of non invasive screening for liver diseases in inflammatory bowel disease. Orv Hetil. 2017; 158(26): 1014-1021. PMID- 28651461 TI - [Actor as a simulated patient in medical education at the University of Pecs]. AB - INTRODUCTION: Medical training in the 21st century faces simulation-based education as one of the challenges that efficiently contributes to clinical skills development while moderating the burden on the clinicians and patients alike. AIM: The University of Pecs, Medical School has launched a simulation program in the MediSkillsLab based on history taking with actors to improve patient interviewing communication skills. METHOD: This new program was inspired by experiences gathered in previous medical language teaching and integrates the method of the "Standardized Patient Program". The method has been applied in America since the 1960s. RESULTS: This is the first time the program has been introduced in Hungary and implemented in an interdisciplinary design, where medical specialists, linguists, actor-patients and medical students collaborate to improve professional, language and communicative competence of the students. CONCLUSION: A course like this has its pivotal role in the medical training, and as a result more efficient and patient-oriented communication may take place at the clinical setting. Orv Hetil. 2017; 158(26): 1022-1027. PMID- 28651463 TI - [What do family medicine trainees think about gratitude payment?] AB - INTRODUCTION: The issue of gratuity is one of the most important health policy issues in Hungary. AIM: The authors' aim is to investigate the attitude of Hungarian family medicine trainees towards gratitude payment. METHOD: Quantitative, paper-based survey among trainees from four Departments of Family Medicine in Hungary (n = 152). RESULTS: More than 50 percent of the residents do not approve of accepting gratitude money. Men (p<0.026), and graduating residents accept it significantly more often (p<0.036) while doctors with children tend to accept it more frequently (p<0.051). They think that the reason for this phenomenon is the lack of proper care (65%), vulnerability and the sense of real gratitude patients feel (52%). According to the participants, the least influencing factor was the low salary of physicians (14.4%). They believe that accepting gratuity is a corruption, and it's humiliating for doctors (80-80%). CONCLUSION: Family medicine residents approve of gratitude money even less as compared to the results of previous studies, but related to other gratitude payment issues we have found similar opinions. Orv Hetil. 2017; 158(26): 1028 1035. PMID- 28651464 TI - Are the PCSK9 inhibitors the panacea of atherosclerosis treatment? PMID- 28651465 TI - New 6(17)-epoxylathyrane diterpene: aellinane from Euphorbia aellenii induces apoptosis via mitochondrial pathway in ovarian cancer cell line. AB - Euphorbia species have been used in traditional medicine in many countries for the treatment of cancer. This article aims to evaluate the capability of a new lathyrane diterpene isolated from Euphorbia aellenii to induce apoptosis in the Caov-4 cell line to determine the underlying mechanism of its anticancer effects. A new 6(17)-epoxylathyrane diterpenes: aellinane from Euphorbia aellenii was evaluated for viability of Caov-4 cells by MTT method. Apoptosis induction by lathyrane diterpene was confirmed by annexin V-FITC/PI staining, and caspase-6 activation. The Bcl2 and Bax protein content were detected by Western blot analysis. Finally, we employed the fluorescent ROS detection kit and fluorochrome JC-1 to determine ROS levels and loss of mitochondria membrane potential (DeltaPsim) in Caov-4 cells, respectively. The results show that lathyrane diterpene has significant cytotoxic effect against Caov-4 cells. The IC50 value was 45 MUM. Annexin V/propidium iodide (PI) staining and caspase-6 activity assay confirmed that lathyrane diterpene is able to induce apoptosis in Caov-4 cells. The results also demonstrate that lathyrane diterpene up-regulated Bax and down regulated Bcl-2 proteins. Moreover, apoptotic effect of lathyrane diterpene was also related to ROS production and loss of mitochondrial membrane potential (DeltaPsim). This study demonstrated that lathyrane diterpene has profound activity against Caov-4 cells. Analysis of apoptosis-related proteins revealed that lathyrane diterpene triggered the mitochondrion-mediated apoptosis pathway, which led to the loss of mitochondrial membrane potential (DeltaPsim) and activation of caspase-6. Therefore, we believe that lathyrane diterpene might be a promising natural compound in ovarian cancer therapy. PMID- 28651466 TI - Levels of multiple proteins in gingival crevicular fluid and intra-amniotic complications in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: The primary aim of this study was to identify the association between the local inflammatory response in gingival crevicular fluid measured by the levels of multiple proteins and maternal and intra-amniotic inflammatory responses measured by maternal serum C-reactive protein (CRP) and amniotic fluid interleukin (IL)-6 concentrations, respectively, in women with preterm prelabor rupture of membranes (PPROM). METHODS: A prospective study was performed in which 78 women with singleton pregnancies complicated by PPROM between 24 + 0 and 36 + 6 weeks of gestation were included. Transabdominal amniocenteses were performed at the time of admission. A bedside assessment of amniotic fluid IL-6 was performed. Maternal serum CRP concentration was also measured at the time of admission. Gingival crevicular fluid was collected from the pocket of the selected tooth (the tooth with the deepest pocket) using standard sterile paper strips within 72 h after admission. Twenty-six proteins in the gingival crevicular fluid were assessed by multiplex the Meso-Scale technology. RESULTS: No correlations between the levels of proteins in the gingival crevicular fluid and maternal serum CRP and amniotic fluid IL-6 concentrations were found, except for a weak positive correlation between granulocyte macrophage colony-stimulating factor and CRP. CONCLUSIONS: The local inflammatory response in the gingival crevicular fluid is not related to the maternal and intra-amniotic inflammatory responses in women with PPROM. PMID- 28651467 TI - ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population. AB - Large genome-wide analysis studies (GWAS) and meta-analyses have dramatically increased our knowledge of the genetic risk factors of inflammatory bowel disease (IBD), identifying at least 163 loci. The endoplasmic reticulum aminopeptidase-2 ( ERAP2) gene has been reported as a potential candidate gene for IBD. GWAS have also shown the potential associations between ERAP single nucleotide polymorphisms (SNP) loci and susceptibility to several autoimmune diseases, and ERAP1 and ERAP2 polymorphisms are related to HLA class I-associated diseases, including ankylosing spondylitis and Behcet's disease. Interestingly, these associations were confined to individuals carrying HLA class I-risk alleles. The aim of this study was to investigate the association of ERAP1 and ERAP2 SNPs with IBD in a Spanish population, analysing their possible interaction with specific HLA-C alleles to IBD susceptibility. A total of 367 individuals were divided into 216 IBD cases and 151 controls. SNP genotyping was performed using TaqMan(r) genotyping assays, whereas HLA-C typing was analysed by sequence-specific oligonucleotide probing. Herein, we report an association of the ERAP1 SNP rs30187 with the HLA-C*07 allele. The existence of shared inflammatory pathways in immunologically related diseases together with the understanding of ERAP1 function may offer clues to novel treatment strategies. PMID- 28651468 TI - Human Adolescent Phase Response Curves to Bright White Light. AB - Older adolescents are particularly vulnerable to circadian misalignment and sleep restriction, primarily due to early school start times. Light can shift the circadian system and could help attenuate circadian misalignment; however, a phase response curve (PRC) to determine the optimal time for receiving light and avoiding light is not available for adolescents. We constructed light PRCs for late pubertal to postpubertal adolescents aged 14 to 17 years. Participants completed 2 counterbalanced 5-day laboratory sessions after 8 or 9 days of scheduled sleep at home. Each session included phase assessments to measure the dim light melatonin onset (DLMO) before and after 3 days of free-running through an ultradian light-dark (wake-sleep) cycle (2 h dim [~20 lux] light, 2 h dark). In one session, intermittent bright white light (~5000 lux; four 20-min exposures) was alternated with 10 min of dim room light once per day for 3 consecutive days. The time of light varied among participants to cover the 24-h day. For each individual, the phase shift to bright light was corrected for the free-run derived from the other laboratory session with no bright light. One PRC showed phase shifts in response to light start time relative to the DLMO and another relative to home sleep. Phase delay shifts occurred around the hours corresponding to home bedtime. Phase advances occurred during the hours surrounding wake time and later in the afternoon. The transition from delays to advances occurred at the midpoint of home sleep. The adolescent PRCs presented here provide a valuable tool to time bright light in adolescents. PMID- 28651469 TI - Morbidities associated with patent ductus arteriosus in preterm infants. Nationwide cohort study. AB - PURPOSE: To evaluate the predictive factors for the development of haemodynamically significant patent ductus arteriosus (PDA) in preterm infants and to study the morbidities associated with the treatment of PDA during the first hospitalization. MATERIALS AND METHODS: Data were collected from the Finnish national register of preterm infants (<32 gestational weeks) born in 2005 2013. In total, 3668 infants were included. Morbidities during the first hospitalization were analysed and compared between infants who received treatments for the closure of PDA (n = 1132) and infants who received no treatment for PDA (n = 2536). The results were adjusted for the duration of pregnancy, intrauterine growth pattern, antenatal steroids, delivery hospital and respiratory distress syndrome (RDS). RESULTS: RDS and mechanical ventilation were independently associated with an increased risk of PDA requiring treatment. Medical and surgical treatments were associated with the risk of severe bronchopulmonary dysplasia (BPD). Primary surgical ligation was associated with an increased risk of severe intraventricular haemorrhage (IVH) and necrotizing enterocolitis (NEC). Medical treatment itself and also followed by surgical ligation was associated with lower mortality. CONCLUSION: The severity of lung disease rather than prematurity per se was associated with the development of PDA requiring therapy. Both medical and surgical therapies for PDA were associated with severe BPD, and primary surgical ligation was associated with NEC and severe IVH. PMID- 28651470 TI - Cosmetic talc as a risk factor for pleural mesothelioma: a weight of evidence evaluation of the epidemiology. AB - OBJECTIVE: Due to some historical (and inaccurate) reports that asbestos might be present in some cosmetic talc products, questions are occasionally raised regarding the potential pleural mesothelioma risks associated with cosmetic talc products. Our objective was to determine the incidence of pleural mesothelioma of individuals exposed to cosmetic talc. MATERIALS AND METHODS: We conducted a systematic review of the epidemiological literature for cosmetic talc miners and millers and found three occupational cohort studies that evaluated pleural mesothelioma incidence in workers in Italy, Norway, France, and Austria. We conducted a second literature review to evaluate the incidence and mortality of pleural mesothelioma among patients who received talc pleurodesis treatments before 1965 and found retrospective clinical studies including over 300 patients with follow-up ranging from 14 to 40 years. RESULTS: There were no mesotheliomas reported in any of the cosmetic talc miner and miller cohorts. A pooled analysis of data from the cohort mortality studies indicated that four mesothelioma deaths would have been expected from the 90,022 person-years of observation, and this was associated with 84% and 67% statistical power to observe a 3-fold or 2.5-fold increase in pleural mesothelioma mortality, respectively. None of the patients who received talc pleurodesis treatments developed mesothelioma. CONCLUSION: We conclude that there is no epidemiological evidence to support the hypothesis that exposure to cosmetic talc is associated with the development of pleural mesothelioma. PMID- 28651472 TI - The Impact Factor Is a 20th-Century Relic in an Electronic Journal World of Instant Citation Counts. PMID- 28651471 TI - Grading and Prognostication of Neuroendocrine Tumors of the Pancreas: A Comparison Study of Ki67 and PHH3. AB - Grading of pancreatic neuroendocrine tumors (pNETs) is currently based on mitotic rate and Ki67 proliferation index. Phosphohistone-H3 (PHH3) is an effective marker for mitosis that has been proposed to use in grading various NETs. It remains unclear which method more accurately predicts grade and clinical outcome. Cases of pNET were evaluated using immunohistochemical stains for Ki67 and PHH3. In addition, each case was evaluated for necrosis, lymphovascular invasion, and perineural invasion and compared with stage. R project statistical analysis was used for comparisons. Sixty-three cases were included in the study including 29 males and 34 females (M:F 0.9) with a median age of 59 years (ranging 34-84). There was not a significant discrepancy in the stratification of tumor grades for Ki67 and PHH3. PHH3 significantly predicted lymph node metastasis ( p=0.041). Necrosis correlated with overall survival ( p=0.017). The results suggest that PHH3 is an effective marker for determining mitotic activity and can be used alternative to Ki67. In addition, necrosis may be included in the reporting of pNET as it may play a prognostic role. Larger scale studies are warranted to understand the biology and behavior of these tumors. PMID- 28651473 TI - Corrigendum. AB - Oksvold MP, Skarpen E, Lindeman B, Roos N, Huitfeldt HS. Immunocytochemical localization of Shc and activated EGF receptor in early endosomes after EGF stimulation of HeLa cells. J Histochem Cytochem. 2000;48:21-33. (Original DOI: 10.1177/002215540004800103). PMID- 28651474 TI - Epidemiology and Changes in Mortality of Sepsis After the Implementation of Surviving Sepsis Campaign Guidelines. AB - PURPOSE: To determine the epidemiology and outcome of severe sepsis and septic shock after 9 years of the implementation of the Surviving Sepsis Campaign (SSC) and to build a mortality prediction model. METHODS: This is a prospective, multicenter, observational study performed during a 5-month period in 2011 in a network of 11 intensive care units (ICUs). We compared our findings with those obtained in the same ICUs in a study conducted in 2002. RESULTS: The current cohort included 262 episodes of severe sepsis and/or septic shock, and the 2002 cohort included 324. The prevalence was 14% (95% confidence interval: 12.5-15.7) with no differences to 2002. The population-based incidence was 31 cases/100 000 inhabitants/year. Patients in 2011 had a significantly lower Acute Physiology and Chronic Health Evaluation II (APACHE II; 21.9 +/- 6.6 vs 25.5 +/- 7.07), Logistic Organ Dysfunction Score (5.6 +/- 3.2 vs 6.3 +/- 3.6), and Sequential Organ Failure Assessment (SOFA) scores on day 1 (8 +/- 3.5 vs 9.6 +/- 3.7; P < .01). The main source of infection was intraabdominal (32.5%) although microbiologic isolation was possible in 56.7% of cases. The 2011 cohort had a marked reduction in 48-hour (7% vs 14.8%), ICU (27.2% vs 48.2%), and in-hospital (36.7% vs 54.3%) mortalities. Most relevant factors associated with death were APACHE II score, age, previous immunosuppression and liver insufficiency, alcoholism, nosocomial infection, and Delta SOFA score. CONCLUSION: Although the incidence of sepsis/septic shock remained unchanged during a 10-year period, the implementation of the SSC guidelines resulted in a marked decrease in the overall mortality. The lower severity of patients on ICU admission and the reduced early mortality suggest an improvement in early diagnosis, better initial management, and earlier antibiotic treatment. PMID- 28651475 TI - High-Frequency Ventilation Modalities as Salvage Therapy for Smoke Inhalation Associated Acute Lung Injury: A Systematic Review. AB - BACKGROUND: Smoke inhalation-associated acute lung injury (SI-ALI) is a major cause of morbidity and mortality in victims of fire tragedies. To date, there are no evidence-based guidelines on ventilation strategies in acute respiratory distress syndrome (ARDS) after smoke inhalation. We reviewed the existing literature for clinical studies of salvage mechanical ventilation (MV) strategies in patients with SI-ALI, focusing on mortality and pneumonia as outcomes. METHODS: A systematic search was designed in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Risk of bias assessment was performed using the Newcastle-Ottawa Quality Assessment Scale (NOS; 0 to 9 stars), with a score >=7 being the threshold for inclusion in the meta-analysis. A systematic search strategy was used to search 10 databases. Clinical studies were included in which patients: (1) experienced smoke inhalation, (2) treated with MV, and (3) described a concurrent or historical control group. RESULTS: A total of 226 potentially relevant studies were identified, of which 7 studies on high-frequency percussive ventilation (HFPV) met inclusion criteria. No studies met inclusion for meta-analysis (NOS >= 7). In studies comparing HFPV to conventional mechanical ventilation (CMV), mortality and pneumonia incidence improved in 3 studies and remained unchanged in 3 others. No change in ventilator days or ICU length of stay was observed; however, oxygenation and work of breathing improved with HFPV. CONCLUSIONS: Mechanical ventilation in patients with SI-ALI has not been well studied. High-frequency percussive ventilation may decrease in-hospital mortality and pneumonia incidence when compared to CMV. The absence of "good" quality evidence precluded meta analysis. Based upon low-quality evidence, there was a very weak recommendation that HFPV use may be associated with lower mortality and pneumonia rates in patients with SI-ALI. Given SI-ALI's unique underlying pathophysiology, and its potential implications on therapy, randomized controlled studies are required to ensure that patients receive the safest and most effective care. TRIAL REGISTRATION: The study was registered with PROSPERO International prospective register of systematic reviews (#47015). PMID- 28651476 TI - Molecular mechanisms of intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) is a pregnancy specific disease characterized by decreased growth rate of fetus than the normal growth potential at particular gestational age. In the current scenario it is a leading cause of fetal and neonatal morbidity and mortality. In the last decade exhilarating experimental studies from several laboratories have provided fascinating proof for comprehension of molecular basis of IUGR. Atypical expression of enzymes governed by TGFbeta causes the placental apoptosis and altered expression of TGFbeta due to hyper alimentation causes impairment of lung function. Crosstalk of cAMP with protein kinases plays a prominent role in the regulation of cortisol levels. Increasing levels of NOD1 proteins leads to development of IUGR by increasing the levels of inflammatory mediators. Increase in leptin synthesis in placental trophoblast cells is associated with IUGR. In this review, we emphasize on the regulatory mechanisms of IUGR and its associated diseases. They may help improve the in-utero fetal growth and provide a better therapeutic intervention for prevention and treatment of IUGR. PMID- 28651477 TI - Moderators, mediators and nonspecific predictors of outcome after cognitive rehabilitation of executive functions in a randomised controlled trial. AB - : Moderators, mediators and nonspecific predictors of treatment after cognitive rehabilitation of executive functions in a randomised controlled trial Objective: To explore moderators, mediators and nonspecific predictors of executive functioning after cognitive rehabilitation in a randomised controlled trial, comparing Goal Management Training (GMT) with an active psycho-educative control intervention, in patients with chronic acquired brain injury. METHODS: Seventy patients with executive dysfunction were randomly allocated to GMT (n = 33) or control (n = 37). Outcome measures were established by factor-analysis and included cognitive executive complaints, emotional dysregulation and psychological distress. RESULTS: Higher age and IQ emerged as nonspecific predictors. Verbal memory and planning ability at baseline moderated cognitive executive complaints, while planning ability at six-month follow-up mediated all three outcome measures. Inhibitory cognitive control emerged as a unique GMT specific mediator. A general pattern regardless of intervention was identified; higher levels of self-reported cognitive-and executive-symptoms of emotional dysregulation and psychological distress at six-month follow-up mediated less improvement across outcome factors. CONCLUSIONS: The majority of treatment effects were nonspecific to intervention, probably underscoring the variables' general contribution to outcome of cognitive rehabilitation interventions. Interventions targeting specific cognitive domains, such as attention or working memory, need to take into account the patients' overall cognitive and emotional self-perceived functioning. Future studies should investigate the identified predictors further, and also consider other predictor candidates. PMID- 28651478 TI - Interval Timing Is Preserved Despite Circadian Desynchrony in Rats: Constant Light and Heavy Water Studies. AB - The mechanisms that enable mammals to time events that recur at 24-h intervals (circadian timing) and at arbitrary intervals in the seconds-to-minutes range (interval timing) are thought to be distinct at the computational and neurobiological levels. Recent evidence that disruption of circadian rhythmicity by constant light (LL) abolishes interval timing in mice challenges this assumption and suggests a critical role for circadian clocks in short interval timing. We sought to confirm and extend this finding by examining interval timing in rats in which circadian rhythmicity was disrupted by long-term exposure to LL or by chronic intake of 25% D2O. Adult, male Sprague-Dawley rats were housed in a light-dark (LD) cycle or in LL until free-running circadian rhythmicity was markedly disrupted or abolished. The rats were then trained and tested on 15- and 30-sec peak-interval procedures, with water restriction used to motivate task performance. Interval timing was found to be unimpaired in LL rats, but a weak circadian activity rhythm was apparently rescued by the training procedure, possibly due to binge feeding that occurred during the 15-min water access period that followed training each day. A second group of rats in LL were therefore restricted to 6 daily meals scheduled at 4-h intervals. Despite a complete absence of circadian rhythmicity in this group, interval timing was again unaffected. To eliminate all possible temporal cues, we tested a third group of rats in LL by using a pseudo-randomized schedule. Again, interval timing remained accurate. Finally, rats tested in LD received 25% D2O in place of drinking water. This markedly lengthened the circadian period and caused a failure of LD entrainment but did not disrupt interval timing. These results indicate that interval timing in rats is resistant to disruption by manipulations of circadian timekeeping previously shown to impair interval timing in mice. PMID- 28651479 TI - Evaluating the short-term cost-effectiveness of liraglutide versus lixisenatide in patients with type 2 diabetes in the United States. AB - AIMS: Bringing patients with type 2 diabetes to recommended glycated hemoglobin (HbA1c) treatment targets can reduce the risk of developing diabetes-related complications. The aim of the present analysis was to evaluate the short-term cost-effectiveness of once-daily liraglutide 1.8 mg vs once-daily lixisenatide 20 MUg as an add-on to metformin for treatment of type 2 diabetes in the US by assessing the cost per patient achieving HbA1c-focused and composite treatment targets. MATERIALS AND METHODS: Percentages of patients achieving recommended targets were obtained from the LIRA-LIXI trial, which compared the efficacy and safety of once-daily liraglutide 1.8 mg and once-daily lixisenatide 20 MUg as an add-on to metformin in patients with type 2 diabetes failing to achieve glycemic control with metformin. Annual costs were estimated from a healthcare payer perspective. An economic model was developed to evaluate the annual cost per patient achieving target (cost of control) with liraglutide 1.8 mg vs lixisenatide 20 MUg for five end-points. RESULTS: Annual treatment costs were higher with liraglutide 1.8 mg than lixisenatide 20 MUg, but this was offset by greater clinical efficacy, and the cost of control was lower with liraglutide 1.8 mg than lixisenatide 20 MUg for all five end-points. The annual cost of control was USD 3,850, USD 11,404, USD 3,807, USD 4,299, and USD 6,901 lower for liraglutide 1.8 mg than lixisenatide 20 MUg for targets of HbA1c < 7.0%, HbA1c <= 6.5%, HbA1c < 7.0% and no weight gain, HbA1c < 7.0% with no weight gain and no confirmed hypoglycemia, and HbA1c < 7.0% with no weight gain and systolic blood pressure <140 mmHg, respectively. CONCLUSIONS: Once-daily liraglutide 1.8 mg was associated with greater clinical efficacy than once-daily lixisenatide 20 MUg, which resulted in a lower annual cost of control for HbA1c-focused and composite treatment targets. PMID- 28651480 TI - News on therapeutic management of MDR-tuberculosis: a literature review. AB - In 2015, the World Health Organization registered 10.4 million people who developed tuberculosis worldwide and 480,000 new cases of multidrug-resistant tuberculosis were identified. The care of multi and extensively drug-resistant tuberculosis is based on a combination of pyrazinamide and second-line drugs. These regimens are lengthy, partially effective and poorly tolerated. The challenge is to re-evaluate the use of existing molecules and to develop new agents more effective against resistant strains with shorter treatment duration. This literature review gives an overview of the latest research addressing these therapeutic objectives. Some molecules are in late stage clinical development among which pretomanid is showing promising results. Bedaquiline and delamanid have been recently approved by the Food and Drug Administration. The efficacy of drug regimens combining these molecules is under evaluation. PMID- 28651481 TI - Anti-fibrotic effects of Cuscuta chinensis with in vitro hepatic stellate cells and a thioacetamide-induced experimental rat model. AB - CONTEXT: Cuscuta chinensis Lam. (Convolvulaceae) has been used as a traditional herbal remedy for treating liver and kidney disorders. OBJECTIVE: Anti-fibrotic effects of C. chinensis extract (CCE) in cellular and experimental animal models were investigated. MATERIALS AND METHODS: HSC-T6 cell viability, cell cycle and apoptosis were analysed using MTT assay, flow cytometry and Annexin V-FITC/PI staining techniques. Thioacetamide (TAA)-induced fibrosis model was established using Sprague Dawley rats (n = 10). Control, TAA, CCE 10 (TAA with CCE 10 mg/kg), CCE 100 (TAA with CCE 100 mg/kg) and silymarin (TAA with silymarin 50 mg/kg). Fibrosis was induced by TAA (200 mg/kg, i.p.) twice per week for 13 weeks. CCE and silymarin were administered orally two times per week from the 7th to 13th week. Fibrotic related gene expression (alpha-SMA, Col1alpha1 and TGF-beta1) was measured by RT-PCR. Serum biomarkers, glutathione (GSH) and hydroxyproline were estimated by spectrophotometer using commercial kits. RESULTS: CCE (0.05 and 0.1 mg/mL) and silymarin (0.05 mg/mL) treatment significantly (p < 0.01 and p < 0.001) induced apoptosis (11.56%, 17.52% for CCE; 16.50% for silymarin, respectively) in activated HSC-T6 cells, compared with control group (7.26%). Further, rat primary HSCs showed changes in morphology with CCE 0.1 mg/mL treatment. In in vivo studies, CCE (10 and 100 mg/kg) treatment ameliorated the TAA-induced altered levels of serum biomarkers, fibrotic related gene expression, GSH, hydroxyproline significantly (p < 0.05-0.001) and rescued the histopathological changes. CONCLUSIONS: CCE can be developed as a potential agent in the treatment of hepatofibrosis. PMID- 28651482 TI - Modulation of some markers of erectile dysfunction and malonaldehyde levels in isolated rat penile tissue with unripe and ripe plantain peels: identification of the constituents of the plants using HPLC. AB - CONTEXT: Plantain fruit pulp has been used as a natural remedy to manage erectile dysfunction (ED) in traditional medicine. However, the potency of the peel has not been examined with respect to ED management. OBJECTIVE: This study investigated and compared the inhibitory potential of unripe (UPP) and ripe (RPP) plantain peels on some enzymes associated with ED and Fe2+-induced oxidative stress in albino rat penile homogenate in vitro. MATERIALS AND METHOD: Aqueous extract of the peels was prepared and the effect on phosphodiesterase-5 (PDE-5), arginase, acetylcholinesterase (AChE), angiotensin-I converting enzyme (ACE) and Fe2+-induced malonyladehyde in isolated albino rat penile homogenate were investigated. Phenolic constituents of the peels powder were characterized using high-performance liquid chromatography coupled with diode array detector (HPLC DAD). RESULT: Extract from UPP had higher PDE-5 (IC50 = 3.10 MUg/mL), arginase (IC50 = 0.96 MUg/mL), AChE (IC50 = 6.30 MUg/mL) and ACE (IC50 = 0.41 MUg/mL) inhibitory ability compared with RPP (PDE-5, IC50 = 4.33 MUg/mL; arginase, IC50 = 1.34 MUg/mL; AChE, IC50 = 8.64 MUg/mL; ACE, IC50 = 0.63 MUg/mL). The extract from UPP also had higher inhibition of Fe2+-induced lipid peroxidation. HPLC-DAD analysis revealed that gallic and caffeic acids, rutin, quercitrin and quercetin were abundant in UPP, while catechin, kaempferol, chlorogenic and ellagic acids were the dominant phenolic compounds in RPP. DISCUSSION AND CONCLUSION: Inhibition of enzymes associated with ED and lipid peroxidation could be linked with the phenolic compounds. However, UPP appeared to be more potent. PMID- 28651483 TI - Induced beliefs about a fictive energy drink influences 200-m sprint performance. AB - Placebo and nocebo effects occur in response to subjective expectations and their subsequent neural actions. Research shows that information shapes expectations that, consequently, influence people's behaviour. In this study, we examined the effects of a fictive and inert green colour energy drink provided for three groups (n = 20/group) with different information. The first group was led to expect that the drink augments running performance (positive information), the second group was led to expect that the drink may or may not improve performance (partial-positive information), while the third group was told that earlier research could not demonstrate that the drink improves performance (neutral/control). At baseline, the three groups did not differ in their 200-m sprint performance (p > .05). One week later, 20-min immediately after ingesting the drink, all participants again ran 200 m. The positive information group increased its performance by 2.41 s, which was statistically significant (p < .001) and also perceived its sprint-time shorter (p < .05) than the other two groups. A better performance (0.97 s) that approached but did not reach statistical significance was also noted in the partial-positive information group, and a lesser change (0.72 s) that was statistically not significant was noted in the neutral information control group. These results reveal that drinking an inert liquid, primed with positive information, changes both the actual and the self-perceived time on a 200-m sprint. The current findings also suggest that the level of certainty of the information might be linked to the magnitude of change in performance. PMID- 28651484 TI - Are we making the most of ecological momentary assessment data? A comment on Richardson, Fuller-Tyszkiewicz, O'Donnell, Ling, & Staiger, 2017. PMID- 28651485 TI - Intraoperative left atrium inversion after implantation of HeartMate III ventricular assist device. AB - We report here a case of left atrium inversion after implanting HeartMate III LVAD, which is known to be the first in literature. LVAD can be functional only if there is adequate inflow to the device. Parameters and filling of left ventricle can be assessed by TEE. In our case, initial examination with TEE showed thrombus like images. HeartMate III has a reliable algorithm that automatically reduces pump speed if 'suction effect' is detected. HeartMate III demonstrates clean flow properties and good surface wash. Despite these positive features of the HeartMate III, left atrium inversion can still be seen with it, so users should be alert in this regard. PMID- 28651486 TI - Overexpressed PTOV1 associates with tumorigenesis and progression of esophageal squamous cell carcinoma. AB - PTOV1 has been demonstrated to play an extensive role in many types of cancers. This study takes the first step to clarify the potential relationship between esophageal squamous cell carcinoma and PTOV1 expression and highlight the link between PTOV1 and the tumorigenesis, progression, and prognosis of esophageal squamous cell carcinoma. PTOV1 expression was detected by quantitative reverse transcription polymerase chain reaction and western blotting or immunohistochemical staining in esophageal squamous cell carcinoma cell lines, esophageal squamous cell carcinoma tissues, and its paired adjacent non-cancerous tissues. Moreover, we have analyzed the relationship between PTOV1 expression and clinicopathological features of esophageal squamous cell carcinoma. Survival analysis and Cox regression analysis were used to assess its prognostic significance. We found that PTOV1 expression was significantly higher in the esophageal squamous cell carcinoma cell lines and tissues at messenger RNA level (p < 0.001) and protein level (p < 0.001). Gender, tumor size, or differentiation was tightly associated with the PTOV1 expression. Lymph node involvement (p < 0.001) and TNM stage (p < 0.001) promoted a high PTOV1 expression. A prognostic significance of PTOV1 was also found by Log-rank method, and the overexpression of PTOV1 was related to a shorter OS and DFS. Multiple Cox regression analysis indicated overexpressed PTOV1 as an independent indicator for adverse prognosis. In conclusion, this study takes the lead to demonstrate that the overexpressed PTOV1 plays a vital role in the tumorigenesis and progression of esophageal squamous cell carcinoma, and it is potentially a valuable prognostic predicator and new chemotherapeutic target for esophageal squamous cell carcinoma. PMID- 28651487 TI - Identification of genes and pathways related to lymphovascular invasion in breast cancer patients: A bioinformatics analysis of gene expression profiles. AB - Surgery is the most effective treatment for breast cancer patients. However, some patients developed recurrence and distant metastasis after surgery. Adjuvant therapy is considered for high-risk patients depending on several prognostic markers, and lymphovascular invasion has become one of such prognostic markers that help physicians to identify the risk for distant metastasis and recurrence. However, the mechanism of lymphovascular invasion in breast cancer remains unknown. This study aims to unveil the genes and pathways that may involve in lymphovascular invasion in breast cancer. In total, 108 breast cancer samples were collected during surgery and microarray analysis was performed. Significance analysis of the microarrays and limma package for R were used to examine differentially expressed genes between lymphovascular invasion-positive and lymphovascular invasion-negative cases. Network and pathway analyses were mapped using the Ingenuity Pathway Analysis and the Database for Annotation, Visualization and Integrated Discovery. In total, 86 differentially expressed genes, including 37 downregulated genes and 49 upregulated genes were identified in lymphovascular invasion-positive patients. Among these genes, TNFSF11, IL6ST, and EPAS1 play important roles in cytokine-receptor interaction, which is the most enriched pathway related to lymphovascular invasion. Moreover, the results also suggested that an imbalance between extracellular matrix components and tumor micro-environment could induce lymphovascular invasion. Our study evaluated the underlying mechanisms of lymphovascular invasion, which may further help to assess the risk of breast cancer progression and identify potential targets of adjuvant treatment. PMID- 28651488 TI - Thymidine kinase 1 expression in ovarian serous adenocarcinoma is superior to Ki 67: A new prognostic biomarker. AB - Cancer is a disease with abnormally proliferating cells and therefore proliferation rate is an important index for assessing tumour growth. Ki-67 is a commonly used proliferation marker considered to be an unfavourable prognostic marker in some tumors, while Thymidine kinase 1 (TK1) is an interesting proliferation marker because its levels are highly dependent on the growth stage of cells. To define the immunohistochemistry (IHC) expression of the TK1 in patients with ovarian serous adenocarcinoma and establish its potential role as a new biomarker for progressive disease, we analyzed the expression patterns of TK1 and Ki-67 in 109 patients with ovarian serous adenocarcinoma. TK1 and Ki-67 expression both showed a statistically significant correlation to MD Anderson Cancer Center (MDACC) grade, but not to age, tumour size, lymph node metastasis or pathological TNM (pTNM) stages. TK1 expression, MDACC grades, pathological stages and lymph node metastasis correlate to relapse incident rate and overall survival, but Ki-67 does not. Although TK1 expression, MDACC grade, pTNM stage and lymph node metastasis significantly correlate to relapse in the Cox univariate analysis, in the multivariate Cox analysis only TK1 expression and lymph node metastasis were independent prognostic factors. The overall survival also correlated significantly to TK1 expression, MDACC grade, pTNM stage and lymph node metastasis in the Cox univariate analysis. However, only the pTNM stage was found to be an independent prognostic factor for survival in the Cox multivariate analysis. Therefore, though TK1 expression was an independent prognostic factor for relapse, but not for survival, TK1 is a more informative expression than Ki-67 for LI, relapse and overall survival rates. Thus, when TK1 is combined with MDACC grading, pTNM staging and lymph node metastasis, IHC determination of TK1 expression may improve the overall prediction of prognosis in patients with ovarian cancer. PMID- 28651489 TI - Inorganic polyphosphate enhances radio-sensitivity in a human non-small cell lung cancer cell line, H1299. AB - Inorganic polyphosphate is a linear polymer containing tens to hundreds of orthophosphate residues linked by high-energy phosphoanhydride bonds. Polyphosphate has been recognized as a potent anti-metastasis reagent. However, the molecular mechanism underlying polyphosphate action on cancer cells is poorly understood. In this study, we investigated the involvement of polyphosphate in radio-sensitivity using a human non-small cell lung cancer cell line, H1299. We found that polyphosphate treatment decreases cellular adenosine triphosphate levels, suggesting a disruption of energy metabolism. We also found that the induction of DNA double-strand breaks was enhanced in polyphosphate-treated cells after X-ray irradiation and colony formation assay revealed that cell survival decreased compared with that of the control groups. These findings suggest that polyphosphate is a promising radio-sensitizer for cancer cells. Therefore, we hypothesized that polyphosphate treatment disrupts adenosine triphosphate mediated energy transfer for cellular survival and DNA repair, thereby reducing the cellular capability to resist X-ray irradiation. PMID- 28651490 TI - Antiangiogenic activity of vitexicarpine in experimentally induced hepatocellular carcinoma: Impact on vascular endothelial growth factor pathway. AB - Angiogenesis plays important roles in progression of hepatocellular carcinoma. The antiangiogenic mechanisms of vitexicarpine are not fully defined. Therefore, we conducted the following study to evaluate the antiangiogenic mechanism and antitumor activity of vitexicarpine in vivo model of hepatocellular carcinoma through modulation of vascular endothelial growth factor signaling pathway. Hepatocellular carcinoma was induced in Sprague Dawley rats by thioacetamide. Hepatocellular carcinoma was assessed by measuring serum alpha-fetoprotein and investigating liver sections stained with hematoxylin/eosin. Hepatocellular carcinoma rats were injected with vitexicarpine (150 mg/kg) for 2 weeks. Hepatic vascular endothelial growth factor was measured by enzyme-linked immunosorbent assay. Protein and expression of hepatic phospho-Ser473-AKT (p-AKT) and phospho Tyr419-Src (p-Src) were determined. The apoptotic pathway was evaluated by assessment of protein expression of caspase-3. Vitexicarpine increased rats' survival time and decreased serum alpha-fetoprotein as well as it ameliorated fibrosis and massive hepatic tissue breakdown. It attenuated hepatocellular carcinoma-induced protein and gene expression of vascular endothelial growth factor, p-AKT, p-Src, and caspase-3. In conclusion, this study suggests that vitexicarpine possesses both antiangiogenic and antitumor activities through inhibition of vascular endothelial growth factor, p-AKT/AKT, and p-Src with subsequent inhibition of apoptotic pathway. PMID- 28651491 TI - Manifestation of osteoblastic phenotypes in the sarcomatous component of epithelial carcinoma and sarcomatoid carcinoma. AB - Epithelial carcinomas occasionally have sarcomatous components that consist primarily of spindle and cuboidal cells, which often resemble osteoblasts. Sarcomatoid carcinomas consist of similar cells. Recent studies have characterized these phenomena as a manifestation of epithelial-mesenchymal transition in carcinoma cells, but the mesenchymal phenotypes that manifest in sarcomatous cells of epithelial carcinomas are not well understood. Here, we examined the expression profiles of four osteoblastic differentiation biomarkers in the sarcomatous components of multiple carcinoma types, including five renal clear cell, four breast invasive ductal, two esophageal, one maxillary squamous cell, three larynx, three lung, one liver, and one skin sarcomatoid carcinoma. Expression was analyzed by immunohistochemistry using antibodies against cell adhesion molecule 1, a member of the IgCAM superfamily, osterix transcription factor (Osterix), cluster of differentiation 151, a transmembrane 4 superfamily member, and alkaline phosphatase. Immunostaining intensity was rated in scale 0 (negative), 0.5 (weak), and 1 (strong) for each marker, and the four scale values were summed to calculate osteoblastic scores. In all, 10 cases had a osteoblastic score >=3, and all of these 10 cases were cell adhesion molecule 1- and Osterix positive. Eight and five of the nine samples with a osteoblastic score <3 were negative for cell adhesion molecule 1 ( p < 0.0001) and Osterix ( p = 0.006), respectively. The other markers showed no statistical significance. These results indicate that osteoblastic differentiation can occur in carcinoma cells and that cell adhesion molecule 1 could be a useful marker for identifying this phenomenon in carcinoma tissues. PMID- 28651492 TI - KPNA2 is a potential diagnostic serum biomarker for epithelial ovarian cancer and correlates with poor prognosis. AB - This study aimed to determine whether serum karyopherin alpha 2 levels can be used as a diagnostic biomarker for epithelial ovarian carcinoma. Karyopherin alpha 2 protein was detected by enzyme-linked immunosorbent assay in serum samples from 162 epithelial ovarian carcinoma patients and 48 healthy controls. Serum karyopherin alpha 2 levels in epithelial ovarian carcinoma patients were significantly higher than in healthy controls ( p < 0.001). When a karyopherin alpha 2 serum level of 2.52 ug/mL was used as a cut-off, the sensitivity and specificity of the assay for diagnosing epithelial ovarian carcinoma were 71.4% and 81.2%, respectively. High serum karyopherin alpha 2 levels (>485 ug/mL) correlated with International Federation of Gynecology and Obstetrics stage ( p < 0.0001), lymphatic metastasis ( p = 0.045), overall survival ( p = 0.001), and disease-free progression ( p = 0.006). Serum karyopherin alpha 2 represents a potential diagnostic biomarker for epithelial ovarian carcinoma. PMID- 28651493 TI - Mir-30d suppresses cell proliferation of colon cancer cells by inhibiting cell autophagy and promoting cell apoptosis. AB - MiR-30 family plays an important role in the tumorigenesis of human cancers. The aim of the study is to investigate the role of miR-30d in human colon cancer cell lines and explore the molecular mechanism in the proliferation of colon cancer cells. The expression of miR-30d was determined by real-time polymerase chain reaction assay in colon cancer cell lines (HCT15, HCT116, HT-29, DLD-1, and SW480) and the results demonstrated that miR-30d level was significantly decreased in human colon cancer cell lines, compared with normal colon epithelial cell line. Transfection with miR-30d mimics inhibited cell proliferation, and transfection with miR-30d inhibitors significantly promoted cell viability of colon cancer cells. Furthermore, TargetScan analysis predicted that miR-30d interacted with messenger RNA on its 3' untranslated region of ATG5, phosphoinositide 3-kinase, and Beclin1 to negatively regulate cell autophagy in colon cancer cells. Moreover, transfection with miR-30d induced cell arrest at G2/M phase of HT-29 cells. Overexpression of miR-30d mimics inhibited cell viability probably due to the inhibition of cell autophagy and promotion of cell apoptosis. Thus, MiR-30d inhibited cell autophagy by directly targeting messenger RNA of ATG5, phosphoinositide 3-kinase, and Beclin1 and promoted cell apoptosis of human colon cancer cells. It is helpful to clarify the function of miR-30d in tumorigenesis of human cancers. PMID- 28651494 TI - Decreased expression of TCF12 contributes to progression and predicts biochemical recurrence in patients with prostate cancer. AB - As a member of helix-loop-helix protein family, transcription factor 12 functions as either an oncogene or a tumor suppressor in various human cancers. However, there are no reports on its involvement in prostate cancer. To investigate clinical relevance of transcription factor 12 in prostate cancer and to evaluate its roles in malignant phenotypes of this cancer in vitro and in vivo, we here examined expression patterns of transcription factor 12 protein in 50 prostate cancer tissue specimens by immunohistochemistry. Then, associations of transcription factor 12 expression with various clinicopathological characteristics and patients' prognosis of prostate cancer were evaluated. Its involvements in cancer cell proliferation, migration, invasion, and tumor growth were determined by in vitro and in vivo experiments. As a result, the positive immunostaining of transcription factor 12 protein was localized in cytoplasm and/or nucleus of prostate cancer cells. Its expression levels were decreased with prostate cancer Gleason score increased. Statistically, the decreased expression of transcription factor 12 protein more frequently occurred in prostate cancer patients with high Gleason score, positive metastasis, prostate specific antigen failure, and short biochemical recurrence-free survival (all p < 0.05). Importantly, multivariate analysis showed that the status of transcription factor 12 expression was an independent predictor of biochemical recurrence-free survival in prostate cancer. Functionally, enforced expression of transcription factor 12 suppressed cell proliferation, migration, and invasion in vitro and inhibited tumor growth in vivo. In conclusion, transcription factor 12 protein may be a novel molecule which plays a critical role in prostate cancer progression and patients' prognosis, suggesting it might be a promising therapeutic target for prostate cancer therapy. PMID- 28651495 TI - MiR-205 serves as a prognostic factor and suppresses proliferation and invasion by targeting insulin-like growth factor receptor 1 in human cervical cancer. AB - MicroRNAs are a kind of small and non-coding RNAs, which have been demonstrated to play an important role in the progression of human cervical cancer. Here, we found that the expression of miR-205 was low in cervical cancer cell lines and tissues, compared with matched non-tumor tissues and human endocervical epithelial cells. Also, miR-205 was inversely correlated with histological differentiation, metastasis, International Federation of Gynecology and Obstetrics stage, and the expression of insulin-like growth factor receptor 1 messenger RNA and protein. Besides, miR-205 or insulin-like growth factor receptor 1 expression is an independent prognostic factor. Mechanically, ectopic expression of miR-205 decreased proliferation, colony formation, and some proliferation/apoptosis-related proteins in cervical cancer cells. Ectopic expression of miR-205 caused G1 arrest. Luciferase reporter assays confirmed that binding of miR-205 to the 3' untranslated region of insulin-like growth factor receptor 1 may potentially decrease the expression of insulin-like growth factor receptor 1. Notably, insulin-like growth factor receptor 1 overexpression attenuated the inhibitory effects of miR-205 on cell proliferation and invasion, while small interfering RNA-insulin-like growth factor receptor 1 enhanced the inhibitory effects of miR-205 on cell proliferation and invasion. In conclusion, our findings suggested that miR-205 serves as a prognostic factor and suppresses proliferation and invasion by targeting insulin-like growth factor receptor 1 in human cervical cancer. Thus, miR-205/insulin-like growth factor receptor 1 pathway may be of great benefit to cervical cancer patients. PMID- 28651496 TI - Overexpression of spindle and kinetochore-associated protein 1 contributes to the progression of prostate cancer. AB - Spindle and kinetochore-associated protein 1 is a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. Recently, spindle and kinetochore-associated protein 1 has been highlighted as a biomarker in various cancers; however, the precise role of spindle and kinetochore-associated protein 1 in prostate cancer remains unknown. This study aims to evaluate whether spindle and kinetochore-associated protein 1 affects the biological behaviors of prostate cancer. We investigated the expression of spindle and kinetochore-associated protein 1 in a series of prostate cancer tissues as well as in a panel of prostate cancer cell lines. Cell proliferation, migration, and invasion were evaluated in spindle and kinetochore-associated protein 1 knockdown prostate cancer cell lines by MTT and Transwell assays. Our results showed that the expression of spindle and kinetochore-associated protein 1 was remarkably upregulated in prostate cancer at both messenger RNA and protein levels compared with non-cancerous tissue. Knockdown of spindle and kinetochore associated protein 1 repressed the ability of cell proliferation, migration, and invasion of prostate cancer cells. Moreover, inhibition of spindle and kinetochore-associated protein 1 could inhibit the activity of AKT and ERK pathway. In conclusion, our findings suggest that spindle and kinetochore associated protein 1 could serve as a potential therapeutic target in prostate cancer patients. PMID- 28651497 TI - Angiotensin II type 2 receptor-interacting protein 3a inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated ERK/EMT pathway. AB - Local migration and long-distance metastasis is the main reason for higher mortality of ovarian cancer. Microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein is associated with tumor initiation and progression and exerts anti-tumor effects. High mobility group AT hook 2 is overexpressed in majority of metastatic carcinomas, which contributes to carcinomas metastasis through Snail-induced epithelial-to-mesenchymal transition signal pathway. The purpose of this study was to investigate the signal pathway of microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein-mediated anti-tumor effects. Our data observed that ovarian carcinoma cells exhibited lower expression of angiotensin II type 2 receptor-interacting protein 3a and higher expression of high mobility group AT hook 2 compared to normal ovarian cells. Restoration of angiotensin II type 2 receptor-interacting protein 3a expression in ovarian carcinoma cells inhibited high mobility group AT-hook 2 expression and exhibited anti-proliferative effects. In addition, angiotensin II type 2 receptor-interacting protein 3a treatment suppressed the phosphorylation of epithelial-to-mesenchymal transition and extracellular signal-regulated kinase in ovarian carcinoma cells. We also observed that angiotensin II type 2 receptor-interacting protein 3a restoration downregulated expression of Snail, E-Cadherin, N-Cadherin, and Vimentin in ovarian carcinoma cells, whereas angiotensin II type 2 receptor-interacting protein 3a knockdown enhanced the phosphorylation of extracellular signal regulated kinase and epithelial-to-mesenchymal transition. In vivo assay indicated that angiotensin II type 2 receptor-interacting protein 3a inhibited ovarian tumor growth and elevated survival of tumor-bearing immunodeficient mice. Tumor histological analysis indicated that Snail, E-Cadherin, N-Cadherin, and Vimentin expression levels were downregulated via decreasing high mobility group AT-hook 2 expression. Furthermore, upregulation of angiotensin II type 2 receptor interacting protein 3a impaired the phenotype of extracellular signal-regulated kinase and epithelial-to-mesenchymal transition in ovarian carcinoma cells and tumor tissues. Taken together, angiotensin II type 2 receptor-interacting protein 3a presents potential in suppressing the proliferation and aggressiveness of ovarian carcinoma cells through the high mobility group AT-hook 2-mediated extracellular signal-regulated kinase/epithelial-to-mesenchymal transition signal pathway. PMID- 28651498 TI - The role of microRNAs in colorectal liver metastasis: Important participants and potential clinical significances. AB - Colorectal cancer is one of the most common cancers in the world, and liver metastasis is the leading direct cause of cancer-related deaths in colorectal cancer. MicroRNA is involved in tumor metastasis in many aspects; mounting studies have shown that microRNAs play important roles in colorectal liver metastasis. Although lots of reviews about the association between microRNAs and colorectal cancer metastasis have been published, the reviews specifically focusing on microRNAs and colorectal liver metastasis are still lacking in the literature. To address this issue, here, we summarize the underlying mechanisms of microRNAs in colorectal liver metastasis and explore their potential clinical applications in this aspect. PMID- 28651499 TI - Necroptosis in cancer: An angel or a demon? AB - In the past few decades, apoptosis has been regarded as the only form of programmed cell death. However, the traditional view has been challenged by the identification of several forms of regulated necrosis, including necroptosis. Necroptosis is typified by a necrotic cell death morphology and is controlled by RIP1, RIP3, and mixed lineage kinase domain-like protein. The physiological role of necroptosis is to serve as a "fail-safe" form of cell death for cells that fail to undergo apoptosis during embryonic development and disease defense. Currently, established studies have indicated that necroptosis is involved in cancer initiation and progression. Although elevated necroptosis contributes to cancer cell death, extensive cell death also increases the risk of proliferation and metastasis of the surviving cells by inducing the generation reactive oxygen species, activation of inflammation, and suppression of the immune response. Thus, questions regarding the overall impact of necroptosis on cancer remain open. In this review, we introduce the basic knowledge regarding necroptosis, summarize its dual effects on cancer progression, and analyze its advantages and disadvantages in clinical applications. PMID- 28651500 TI - SPRY4-IT1: A novel oncogenic long non-coding RNA in human cancers. AB - Long non-coding RNAs are classified as a kind of RNA, which are longer than 200 nucleotides in length and cannot be translated into proteins. Multiple studies have demonstrated that long non-coding RNAs are involved in various cellular processes, including proliferation, differentiation, cell death, and metastasis. Among numerous long non-coding RNAs, we focus on Sprouty4-Intron 1 (SPRY4-IT1), a well-known long non-coding RNA that is overexpressed in various kinds of tumor tissues and cell lines. Accumulating evidences show that SPRY4-IT1 was dysregulated in various cancers, including melanoma, breast cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, colon cancer, and hepatocellular carcinoma, and amplification of SPRY4-IT1 was associated with different clinicopathological features of cancer patients. Importantly, SPRY4-IT1 exerts important roles in tumor progression and metastasis. However, detailed molecular mechanisms of SPRY4-IT1 in cancer progression and metastasis were poorly understood. In this review, we have focused on the characteristics of SPRY4-IT1 and illustrated the biological function and mechanism of SPRY4-IT1 in cancer development. PMID- 28651501 TI - The impact on social relationships of moving from congregated settings to personalized accommodation. AB - A natural experiment contrasted the social relationships of people with intellectual disabilities ( n = 110) before and after they moved from congregated settings to either personalized accommodation or group homes. Contrasts could also be drawn with individuals who had enduring mental health problems ( n = 46) and who experienced similar moves. Face-to-face interviews were conducted in each person's residence on two occasions approximately 24 months apart. Multivariate statistical analyses were used to determine significant effects. Greater proportions of people living in personalized settings scored higher on the five chosen indicators of social relationships than did persons living in grouped accommodation. However, multivariate statistical analyses identified that only one in five persons increased their social relationships as a result of changes in their accommodation, particularly persons with an intellectual disability and high support needs. These findings reinforce the extent of social isolation experienced by people with disabilities and mental health problems that changes in their accommodation only partially counter. PMID- 28651502 TI - Co-enrolment for the TAME and TTM-2 trials: the cerebral option. PMID- 28651503 TI - To co-enrol or not to co-enrol: that is the question. PMID- 28651504 TI - Critical care management of aneurysmal subarachnoid haemorrhage in Australia and New Zealand: what are we doing, and where to from here? AB - Patients with an aneurysmal subarachnoid haemorrhage (SAH) frequently require admission to the intensive care unit. There, a variety of therapeutic strategies are initiated, in addition to definitive procedures aimed at securing the aneurysm. Despite a substantial investment in caring for these patients, outcomes for this group remain poor. Although the severity of the initial bleed is crucial in this context, many patients undergo further deterioration in the ICU. Delayed cerebral ischaemia is a significant cause of longterm morbidity and mortality after SAH. There are limited data supporting much of the critical care provided to patients with SAH in the ICU, leading to substantial institutional and practitioner variation in treatment. Whether this influences patient outcomes is unknown, although it represents a major knowledge gap in neurocritical practice in Australia and New Zealand. PMID- 28651505 TI - Considerations for co-enrolment in randomised controlled effectiveness trials in critical care: the SPICE-8 co-enrolment guidelines. AB - The Australian and New Zealand Intensive Care Society Clinical Trials Group and other investigator-led trials groups in critical care publish policies and guidelines outlining the rationale for considering co-enrolment in large, randomised controlled trials in intensive care medicine. However, none present a checklist of criteria by which a request for permission to co-enrol in an existing trial can be assessed. Consequently, such requests tend to be made and assessed on an ad hoc basis. Based on our experience in the SPICE III randomised controlled trial, we propose eight broadly applicable criteria (the SPICE-8 criteria) to be satisfied before co-enrolment should be approved. Reporting co enrolment in trials, for regulatory purposes and in publications, is uncommon, partly because of the complexity involved in explaining a lack of a plausible coenrolment effect. We suggest that noting compliance with these criteria would simplify such reporting and enhance transparency. PMID- 28651506 TI - The College of Intensive Care Medicine of Australia and New Zealand supports global collaboration and respect. PMID- 28651507 TI - Protein delivery and clinical outcomes in the critically ill: a systematic review and meta-analysis. AB - OBJECTIVES: Protein is a fundamental component of critical care nutrition, but there has been uncertainty about the optimal amount. We undertook this systematic review and meta-analysis to examine the relationship between delivered protein and mortality in randomised controlled trials (RCTs) of nutritional interventions involving critically ill adults. Secondary outcomes included the effect of protein dose on lengths of stay, mechanical ventilation and incidence of infections. METHODS: We reviewed the relevant English-language literature published between 1966 and 2015 and identified RCTs comparing different strategies of nutritional support lasting at least 48 hours in critically ill adults. Articles were included if mortality was reported and the difference in delivered protein between interventions was significant (P < 0.05). We calculated summary estimates for mortality as odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects estimator, and we used meta-regression to assess the effect of delivered protein on mortality. RESULTS: From 3016 assessed records, 357 full-text articles were reviewed and 14 studies, investigating various interventions and routes of nutrition and comprising 3238 patients, were included. The mean protein delivered was 42.95 g/day (SD, 20.45 g/day) or 0.67 g//kg/day (SD, 0.38 g/kg/day) in patients receiving less protein, and 67.15 g/day (SD, 28.47 g/day) or 1.02 g/kg/day (SD, 0.42 g/kg/day) in the higher protein group. Provision of less protein did not influence mortality risk (pooled OR, 0.935; 95% CI, 0.716 -1.219; P = 0.618; I2 = 48.2%). Meta-regression analysis did not show a relationship between mean daily protein delivered and mortality (P = 0.433; I2 = 50.18%). There were no differences between groups in any secondary outcomes. CONCLUSIONS: Delivery of varying amounts of nutritional protein was not associated with any effect on mortality. PMID- 28651508 TI - Quality sleep using earplugs in the intensive care unit: the QUIET pilot randomised controlled trial. AB - OBJECTIVE: To assess the feasibility of a definitive, randomised controlled trial of earplugs as a noise-abatement strategy to improve sleep and reduce delirium in patients admitted to the intensive care unit. DESIGN AND SETTING: An open-label trial of 40 patients randomised in a 1:1 ratio to receive earplugs in addition to standard care, or standard care alone, conducted in a 10-bed ICU of a large, private hospital in Perth, Western Australia. PARTICIPANTS AND INTERVENTION: Patients were eligible for participation if they were expected to be undergoing mechanical ventilation (MV) on admission to the ICU. Patients assigned to receive earplugs had earplugs placed on admission to the ICU and were offered earplug placement between 10 pm and 6 am for the first night in the ICU once they were extubated. Earplugs were not provided for patients assigned to standard care. MAIN OUTCOME MEASURE: The primary outcome of study feasibility was assessed using criteria for acceptability of the intervention and protocol compliance. RESULTS: Of the 20 participants randomised to receive earplugs, 19 had earplugs placed within 6 hours of ICU admission, corresponding to 76% of the MV time (mean time with earplugs, 7.5 hours [SD, 5.3 hours]). Earplugs were placed for 18 of 20 participants during their first full night after extubation, corresponding to 78% of the total overnight time (mean time with earplugs, 6.2 hours [SD, 2.5 hours]). CONCLUSION: A definitive study of earplugs as a noiseabatement strategy for patients admitted to the ICU is feasible on the basis of participant acceptability of the intervention and protocol compliance. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615001125516. PMID- 28651509 TI - Drivers of choice of resuscitation fluid in the intensive care unit: a discrete choice experiment. AB - OBJECTIVE: To understand the fundamental drivers, and their relative importance, of doctors' and nurses' choice of resuscitation fluid in critically ill patients in Australia and New Zealand. DESIGN: A discrete choice experiment (DCE) administered via an online survey. Respondents were presented with one of four randomly selected DCE choice sets, each including five patient scenarios. The respondent chose between two types of hypothetical resuscitation fluid. The fluid type was characterised by several attributes and each attribute had pre-specified levels. PARTICIPANTS: Convenience sample of 367 Australian and New Zealand intensive care unit doctors and nurses. MAIN OUTCOME MEASURES: The dependent variable was fluid choice, and a regression equation was used to estimate the effect of each fluid attribute on the probability of observing the sequence of choices made over the five patient scenarios. The relative importance of each of the respective fluid attributes was calculated based on the percentage contribution to overall utility (ie, fluid preference). RESULTS: For doctors, safety concerns, patient type and fluid type were collectively responsible for almost three-quarters of decision-making utility (71%). The volume of intravenous fluid administered was the only clinical parameter not reaching statistical significance as a driver of fluid choice (P = 0.06). For nurses, decision making was influenced to a greater extent by the same three attributes (90%), although other unmeasured attributes may have been driving choice. CONCLUSIONS: Doctors and nurses rely on different information when choosing resuscitation fluids, although both cohorts are heavily influenced by safety concerns, patient type and fluid type. This information can be used to modify prescribing behaviour. PMID- 28651510 TI - Pharmacodynamics of intravenous frusemide bolus in critically ill patients. AB - OBJECTIVE: To assess the physiological, biochemical and haemodynamic response to a single intravenous (IV) dose of frusemide in critically patients. DESIGN, SETTING AND PATIENTS: A prospective observational study of 21 critically ill patients in a tertiary intensive care unit in Australia. INTERVENTIONS: We collected information on urine output (UO), fluid balance, serum and urinary electrolyte levels, serum biochemical levels and haemodynamics. We compared data from the 6-hour period before administration of a single IV bolus of frusemide 40 mg with data from the 6-hour period after administration. RESULTS: We studied 21 patients (12 of whom were women) with a median age of 73 years (interquartile range [IQR], 64-80 years). The IV bolus induced a > 1000 mL increase in UO in six patients (28.6%); a 500-1000 mL increase in six patients (28.6%) and a < 500 mL increase in nine patients (42.8%). The median difference in UO before and after frusemide was 590 mL (IQR, 290-1111 mL). The 6-hour fluid balance became negative in 15 patients (71.4%) and positive in six patients (28.6%), with a median change of -595 mL (IQR, -880 to 98 mL). Frusemide significantly increased urinary sodium, potassium and chloride losses and decreased blood chloride levels. There were no detectable changes in haemodynamics. On linear regression analysis, sodium excretion and UO correlated with higher mean arterial pressure (MAP) and age, and with lower albumin and creatinine levels. CONCLUSIONS: In a cohort of critically ill patients without chronic renal impairment, frusemide increased UO and urinary sodium, potassium and chloride losses, and induced hypochloraemia and metabolic alkalosis. However, its diuretic effects were extremely variable and were modified by age, MAP and creatinine and albumin levels. PMID- 28651511 TI - Outcomes of children admitted to intensive care after out-of-hospital cardiac arrest in Victoria, Australia. AB - OBJECTIVES: Paediatric out-of-hospital cardiac arrest (OHCA) is an uncommon event but is associated with high mortality and severe neurological sequelae among survivors. Most studies of paediatric OHCA are population-based, with very few reports on the cohort admitted to the paediatric intensive care unit (PICU). We sought to determine outcomes and predictors of neurologically intact survival in these children admitted to the PICU. DESIGN AND SETTING: Retrospective analysis of data prospectively collected from the PICU and emergency department (ED) databases and cross-checked with medical records and coronial reports for January 2005 to December 2014. Neurological outcome was assessed using the Paediatric Cerebral Performance Category scale. MAIN OUTCOME MEASURE: Survival with a favourable neurological outcome at hospital discharge. RESULTS: In the 10 years, 283 children presented with OHCA. After 16 study exclusions (because of cardiopulmonary resuscitation [CPR] duration < 1 min or age > 16 years), there were 121 children who died in the ED and 146 admitted to the PICU. Among the PICU cohort, hospital survival with favourable neurological outcome was 42% (60 of 143), and at 1 year after arrest it was 41% (59 of 143). The following factors were associated with the primary outcome: bystander CPR (odds ratio [OR], 4.74 [95% CI, 1.49-15.05]); cardiac aetiology (OR, 6.40 [95% CI, 1.65-24.76]); male sex (OR, 0.32 [95% CI, 0.12- 0.84]); and CPR duration: = 20 min v 0-5 min (OR, 0.05 [95% CI, 0.01-0.16]) and 6-20 min v 0-5 min (OR, 0.45 [95% CI, 0.16-1.28]). CONCLUSIONS: Bystander CPR and primary cardiac aetiology had strong associations with survival with a favourable neurological outcome after paediatric OHCA. Maximising CPR education for the community, and targeting people most likely to witness a paediatric OHCA may further improve outcomes. PMID- 28651512 TI - Survival and functional outcomes of patients with metastatic solid organ cancer admitted to the intensive care unit of a tertiary centre. AB - OBJECTIVE: Metastatic solid organ cancer is associated with a poor prognosis, and admission of patients with these cancers to the intensive care unit remains a dilemma. We aimed to assess outcomesin a cohort of these patients who were admitted to the ICU of a general tertiary centre. DESIGN, SETTING AND PATIENTS: A retrospective observational study of patients with incurable metastatic solid organ malignancies who had unplanned admission to a tertiary hospital ICU between 1 January 2010 and 30 June 2015. MAIN OUTCOME MEASURES: Survival outcomes up to 1 year after ICU admission, and functional outcomes as measured by Eastern Cooperative Oncology Group (ECOG) grade up to 3 months after ICU discharge. We also determined rates of advance care planning documentation. RESULTS: A total of 101 patients were treated in the ICU during the study period. Hospital, 30-day and 1-year mortality rates were 35%, 41% and 77%, respectively, and the median survival was 2.3 months (95% CI, 1.1-3.9 months). On multivariable analysis, lowest albumin level (hazard ratio [HR], 1.10; 95% CI, 1.04-1.15) and highest white cell count (HR, 1.03; 95% CI, 1.00-1.07) were significant, although they were marginal predictors of poorer overall survival. Higher ECOG grade showed a trend towards significance (HR, 1.60; 95% CI, 0.94-2.73; P = 0.08). In patients alive and assessable at 1 month, 17/31 (55%) had functionally declined. At 3 months, 15/22 surviving patients (68%) had returned to their baseline, pre-ICU admission ECOG grade. Ninety per cent had no advance care directive and twothirds did not have a medical enduring power of attorney. CONCLUSIONS: Survival is poor in patients with metastatic cancer after emergent ICU admission, although functional state is often recovered by 3 months in surviving patients. Albumin level, white cell count and ECOG grade are simple prognostic markers of survival. PMID- 28651513 TI - The performance of flash glucose monitoring in critically ill patients with diabetes. AB - OBJECTIVE: Frequent glucose monitoring may improve glycaemic control in critically ill patients with diabetes. We aimed to assess the accuracy of a novel subcutaneous flash glucose monitor (FreeStyle Libre [Abbott Diabetes Care]) in these patients. METHODS: We applied the FreeStyle Libre sensor to the upper arm of eight patients with diabetes in the intensive care unit and obtained hourly flash glucose measurements. Duplicate recordings were obtained to assess test retest reliability. The reference glucose level was measured in arterial or capillary blood. We determined numerical accuracy using Bland- Altman methods, the mean absolute relative difference (MARD) and whether the International Organization for Standardization (ISO) and Clinical and Laboratory Standards Institute Point of Care Testing (CLSI POCT) criteria were met. Clarke error grid (CEG) and surveillance error grid (SEG) analyses were used to determine clinical accuracy. RESULTS: We compared 484 duplicate flash glucose measurements and observed a Pearson correlation coefficient of 0.97 and a coefficient of repeatability of 1.6 mmol/L. We studied 185 flash readings paired with arterial glucose levels, and 89 paired with capillary glucose levels. Using the arterial glucose level as the reference, we found a mean bias of 1.4 mmol/L (limits of agreement, -1.7 to 4.5 mmol/L). The MARD was 14% (95% CI, 12%-16%) and the proportion of measurements meeting ISO and CLSI POCT criteria was 64.3% and 56.8%, respectively. The proportions of values within a low-risk zone on CEG and SEG analyses were 97.8% and 99.5%, respectively. Using capillary glucose levels as the reference, we found that numerical and clinical accuracy were lower. CONCLUSIONS: The subcutaneous FreeStyle Libre blood glucose measurement system showed high test-retest reliability and acceptable accuracy when compared with arterial blood glucose measurement in critically ill patients with diabetes. PMID- 28651514 TI - Study protocol for the Balanced Solution versus Saline in Intensive Care Study (BaSICS): a factorial randomised trial. AB - BACKGROUND: The effectiveness and safety of balanced crystalloid fluids compared with saline (0.9% sodium chloride) as a fluid of choice in critically ill patients remain unclear. The effects of different fluid infusion rates on outcomes are also unknown. OBJECTIVES: To test the hypothesis that a balanced crystalloid solution, compared with saline, decreases 90-day all-cause mortality among critically ill patients; and to test the hypothesis that slow, compared with rapid, infusion rate decreases 90-day mortality in this population of patients. METHODS: The Balanced Solution versus Saline in Intensive Care Study (BaSICS) is a pragmatic, 2 ??2 factorial, randomised controlled trial. A total of 11 000 patients will be recruited from at least 100 Brazilian intensive care units. Patients will be randomised to receive Plasma-Lyte 148 or saline, and to rapid infusion (999 mL/h) or slow infusion (333 mL/h). Study fluids will be used for resuscitation episodes (at rapid or slow infusion rates), dilution of compatible medications and maintenance solutions. Patients, health care providers and investigators will be blinded to the solutions being tested. The rate of bolus infusion will not be blinded. OUTCOMES: The primary outcome is 90-day all cause mortality. Secondary outcomes are: incidence of renal failure requiring renal replacement therapy within 90 days, incidence of acute kidney injury (Kidney Disease: Improving Global Outcomes stages 2 and 3), incidence of non renal organ dysfunction assessed by Sepsis-related Organ Failure Assessment score at Days 3 and 7, and number of mechanical ventilationfree days within the first 28 days after randomisation. RESULTS AND CONCLUSIONS: The BaSICS trial will provide robust evidence on whether a balanced crystalloid, compared with saline, improves important patient outcomes in critically ill patients. BaSICS will also provide relevant information on whether bolus infusion rate affects outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02875873. PMID- 28651515 TI - Statistical analysis plan for the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial. AB - BACKGROUND: The Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial, a 3800-patient, multicentre, randomised controlled trial, will be the largest study to date of corticosteroid therapy in patients with septic shock. OBJECTIVE: To describe a statistical analysis plan (SAP) and make it public before completion of patient recruitment and data collection. The SAP will be adhered to for the final data analysis of this trial, to avoid analysis bias arising from knowledge of study findings. METHODS: The SAP was designed by the chief investigators and statisticians and approved by the ADRENAL management committee. All authors were blind to treatment allocation and to the unblinded data produced during two interim analyses conducted by the Data Safety and Monitoring Committee. The data shells were produced from a previously published protocol. Statistical analyses are described in broad detail. Trial outcomes were selected and categorised into primary, secondary and tertiary outcomes, and appropriate statistical comparisons between groups are planned and described in a way that is transparent, available to the public, verifiable and determined before completion of data collection. RESULTS: We developed a standard SAP for the ADRENAL trial, and have produced a trial profile outline and list of mock tables. We describe analyses of baseline characteristics, processes of care, measures of efficacy and outcomes. Six pre-specified subgroups were defined, and statistical comparisons between groups in these subgroups are described. CONCLUSION: We have developed an SAP for the ADRENAL trial. This plan accords with high-quality standards of internal validity to minimise analysis bias. PMID- 28651516 TI - Correction: Direct cerebral perfusion and cooling in experimental cardiac arrest (Crit Care Resusc 2016; 18: 255-60). PMID- 28651517 TI - Evolving mutation rate advances the invasion speed of a sexual species. AB - BACKGROUND: Many species are shifting their ranges in response to global climate change. Range expansions are known to have profound effects on the genetic composition of populations. The evolution of dispersal during range expansion increases invasion speed, provided that a species can adapt sufficiently fast to novel local conditions. Genetic diversity at the expanding range border is however depleted due to iterated founder effects. The surprising ability of colonizing species to adapt to novel conditions while being subjected to genetic bottlenecks is termed 'the genetic paradox of invasive species'. Mutational processes have been argued to provide an explanation for this paradox. Mutation rates can evolve, under conditions that favor an increased rate of adaptation, by hitchhiking on beneficial mutations through induced linkage disequilibrium. Here we argue that spatial sorting, iterated founder events, and population structure benefit the build-up and maintenance of such linkage disequilibrium. We investigate if the evolution of mutation rates could play a role in explaining the 'genetic paradox of invasive species' for a sexually reproducing species colonizing a landscape of gradually changing conditions. RESULTS: We use an individual-based model to show the evolutionary increase of mutation rates in sexual populations during range expansion, in coevolution with the dispersal probability. The observed evolution of mutation rate is adaptive and clearly advances invasion speed both through its effect on the evolution of dispersal probability, and the evolution of local adaptation. This also occurs under a variable temperature gradient, and under the assumption of 90% lethal mutations. CONCLUSIONS: In this study we show novel consequences of the particular genetic properties of populations under spatial disequilibrium, i.e. the coevolution of dispersal probability and mutation rate, even in a sexual species and under realistic spatial gradients, resulting in faster invasions. The evolution of mutation rates can therefore be added to the list of possible explanations for the 'genetic paradox of invasive species'. We conclude that range expansions and the evolution of mutation rates are in a positive feedback loop, with possibly far-reaching ecological consequences concerning invasiveness and the adaptability of species to novel environmental conditions. PMID- 28651518 TI - Further study of Late Devonian seed plant Cosmosperma polyloba: its reconstruction and evolutionary significance. AB - BACKGROUND: The earliest seed plants in the Late Devonian (Famennian) are abundant and well known. However, most of them lack information regarding the frond system and reconstruction. Cosmosperma polyloba represents the first Devonian ovule in China and East Asia, and its cupules, isolated synangiate pollen organs and pinnules have been studied in the preceding years. RESULTS: New fossils of Cosmosperma were obtained from the type locality, i.e. the Leigutai Member of the Wutong Formation in Fanwan Village, Changxing County, Zhejiang Province, South China. The collection illustrates stems and fronds extensively covered in prickles, as well as fertile portions including uniovulate cupules and anisotomous branches bearing synangiate pollen organs. The stems are unbranched and bear fronds helically. Fronds are dimorphic, displaying bifurcate and trifurcate types, with the latter possibly connected to fertile rachises terminated by pollen organs. Tertiary and quaternary rachises possessing pinnules are arranged alternately (pinnately). The cupule is uniovulate and the ovule has four linear integumentary lobes fused in basal 1/3. The striations on the stems and rachises may indicate a Sparganum-type cortex. CONCLUSIONS: Cosmosperma further demonstrates diversification of frond branching patterns in the earliest seed plants. The less-fused cupule and integument of this plant are considered primitive among Devonian spermatophytes with uniovulate cupules. We tentatively reconstructed Cosmosperma with an upright, semi-self-supporting habit, and the prickles along stems and frond rachises were interpreted as characteristics facilitating supporting rather than defensive structures. PMID- 28651519 TI - Analysis of the genetic variation in mitochondrial DNA, Y-chromosome sequences, and MC1R sheds light on the ancestry of Nigerian indigenous pigs. AB - BACKGROUND: The history of pig populations in Africa remains controversial due to insufficient evidence from archaeological and genetic data. Previously, a Western ancestry for West African pigs was reported based on loci that are involved in the determination of coat color. We investigated the genetic diversity of Nigerian indigenous pigs (NIP) by simultaneously analyzing variation in mitochondrial DNA (mtDNA), Y-chromosome sequence and the melanocortin receptor 1 (MC1R) gene. RESULTS: Median-joining network analysis of mtDNA D-loop sequences from 201 NIP and previously characterized loci clustered NIP with populations from the West (Europe/North Africa) and East/Southeast Asia. Analysis of partial sequences of the Y-chromosome in 57 Nigerian boars clustered NIP into lineage HY1. Finally, analysis of MC1R in 90 NIP resulted in seven haplotypes, among which the European wild boar haplotype was carried by one individual and the European dominant black by most of the other individuals (93%). The five remaining unique haplotypes differed by a single synonymous substitution from European wild type, European dominant black and Asian dominant black haplotypes. CONCLUSIONS: Our results demonstrate a European and East/Southeast Asian ancestry for NIP. Analyses of MC1R provide further evidence. Additional genetic analyses and archaeological studies may provide further insights into the history of African pig breeds. Our findings provide a valuable resource for future studies on whole-genome analyses of African pigs. PMID- 28651520 TI - Surgical anesthesia with a combination of T12 paravertebral block and lumbar plexus, sacral plexus block for hip replacement in ankylosing spondylitis: CARE compliant 4 case reports. AB - BACKGROUND: Anesthesia management for patients with severe ankylosing spondylitis scheduled for total hip arthroplasty is challenging due to a potential difficult airway and difficult neuraxial block. We report 4 cases with ankylosing spondylitis successfully managed with a combination of lumbar plexus, sacral plexus and T12 paravertebral block. CASE PRESENTATION: Four patients were scheduled for total hip arthroplasty. All of them were diagnosed as severe ankylosing spondylitis with rigidity and immobilization of cervical and lumbar spine and hip joints. A combination of T12 paravertebral block, lumbar plexus and sacral plexus block was successfully used for the surgery without any additional intravenous anesthetic or local anesthetics infiltration to the incision, and none of the patients complained of discomfort during the operations. CONCLUSIONS: The combination of T12 paravertebral block, lumbar plexus and sacral plexus block, which may block all nerves innervating the articular capsule, surrounding muscles and the skin involved in total hip arthroplasty, might be a promising alternative for total hip arthroplasty in ankylosing spondylitis. PMID- 28651521 TI - Association study of candidate genes for susceptibility to Kashin-Beck disease in a Tibetan population. AB - BACKGROUND: Many osteoarthritis (OA) susceptibility genes have been identified in recent years. Given the overlap in the phenotype of joint inflammation between OA and Kashin-Beck disease (KBD), the aim of this study is to explore whether the reported OA susceptibility genes and two genes that may link to OA pathophysiology are associated with KBD in the Tibetan population. METHOD: Fifteen single-nucleotide polymorphisms (SNPs) in 12 candidate genes previously reported as OA susceptibility loci were selected for investigation. Genotyping was performed using the SNaPshot method for these SNPs in a Tibetan population composed of 849 KBD patients and 565 normal controls. Meanwhile, the coding regions of two genes, COL10A1 and HABP2, which may involve in the pathological mechanism of OA/KBD, were sequenced by Sanger sequencing to identify susceptibility coding variants for KBD in the Tibetan population. RESULTS: The two arthritis-susceptible candidate SNPs, rs7775 (p.Arg324Gly) in the FRZB gene and rs7033979 in the ASPN gene, showed associations with KBD (OR = 1.568, P = 4 * 10-3 and OR = 0.744, P = 8 * 10-3, respectively). The coding variants rs142463796 (p.Asp128Asn) and rs2228547 (p.Gly545Arg) in the COL10A1 gene (OR = 9.832 and P = 6 * 10-3 and OR = 1.242, P = 0.043, respectively) and rs548354451 (p.Asp272Glu) in the HABP2 gene (OR = 2.813, P = 0.010) were associated with KBD patients. CONCLUSION: These finding suggested that rs7775 in the FRZB gene may increase susceptibility to KBD, while rs7033979 in the ASPN gene may play a protective role in susceptibility to KBD in Tibetans. Moreover, genetic variants in chondrogenesis-related genes COL10A1 and HABP2 may play a role in the risk of developing KBD in the Tibetan population. PMID- 28651522 TI - The role of Enterococcus spp. and multidrug-resistant bacteria causing pyogenic liver abscesses. AB - BACKGROUND: Pyogenic liver abscesses (PLA) remain a significant clinical problem. Unfortunately, little is known about current bacterial susceptibility profiles and the incidence of multidrug resistant organisms (MDROs) causing PLA in Western countries. Yet, this crucial information is pivotal to guide empirical antibiotic therapy. Aim of this study was to provide detailed characteristics of PLA with a special focus on underlying bacterial pathogens and their susceptibility to antibiotics. METHODS: A retrospective study of patients diagnosed with PLA from 2009 to 2015 in a large tertiary reference center in Germany was performed in order to characterize PLA and antimicrobial susceptibility profiles of causative bacterial species. RESULTS: Overall, 86 patients were included. The most common causes of PLA were bile duct stenosis/obstruction (31.4%) and leakage of biliary anastomosis (15.1%). Frequent predisposing diseases were malignancies (34.9%), diabetes (24.4%) and the presence of liver cirrhosis (16.3%). Of note, Enterococcus spp. were the most frequently cultured bacterial isolates (28.9%), and in 1/3 of cases vancomycin resistance was observed. In addition, a relevant frequency of gram-negative MDROs was identified. In particular, an alarming 10% and 20% of gram-negative bacteria were resistant to carbapenems and tigecycline, respectively. Of note, MDRO status did not predict ICU stay or survival in multivariate regression analysis. The mortality rate in our series was 16.3%. CONCLUSION: Our study demonstrates an as yet underreported role of Enterococcus spp., often associated with vancomycin resistance, as well as of gram-negative MDROs causing PLA. PMID- 28651523 TI - Current smoking is associated with extracranial carotid atherosclerotic stenosis but not with intracranial large artery disease. AB - BACKGROUND: Accumulating evidence has shown that cigarette smoking is an important risk factor for ischemic stroke. However, it is not clear about the potential mechanisms through which cigarette smoking affects stroke risk. In the study, we aimed to investigate the relationship between cigarette smoking and the occurrence of extracranial (ECAS) and intracranial atherosclerotic stenosis (ICAS). METHODS: We analyzed patients enrolled in the Chinese intracranial atherosclerosis (CICAS), which was a prospective, multicenter, hospital-based cohort study. Smoking status was classified into never, former and current smoking. For those patients with current smoking, data on time duration (year) and extent (the number of cigarette smoked per day) was recorded and pack year of smoking was calculated. ICAS was evaluated with 3-dimentional time-of-flight MRA and ECAS was evaluated with cervical ultrasonography or contrast-enhanced MRA. Multivariable Logistic regression was performed to identify the association between smoking status and the occurrence of ECAS and ICAS. RESULTS: A total of 2656 patients (92.7%) of acute ischemic stroke and 208 (7.3%) of transient ischemic attack were analyzed. The mean age was 61.9 +/- 11.2 and 67.8% were male. There were 141 (4.9%) patients had only ECAS, 1074 (37.5%) had only ICAS, and 261 (9.1%) had both ECAS and ICAS. Current smoking was significantly associated with the occurrence of ECAS (adjusted OR = 1.47, 95% CI = 1.09-1.99, P < 0.01). In addition, with 1 year of smoking increment, the risk of ECAS increased by 1.1% (adjusted OR = 1.011; 95% CI = 1.003-1.019; P = 0.005); with one cigarette smoked per day increment, the risk of ECAS increased by 1.0% (adjusted OR = 1.010; 95% CI = 1.001-1.020; P = 0.03); and with one pack year of smoking increment, the risk of ECAS increased by 0.7% (adjusted OR = 1.007; 95% CI = 1.002-1.012; P < 0.01). However, no significant association was found between smoking status and the occurrence of ICAS. CONCLUSION: A dose-response relationship was identified between cigarette smoking and the occurrence of ECAS, but not ICAS. Further studies on molecular mechanisms were warranted. PMID- 28651524 TI - Insights into the Geobacillus stearothermophilus species based on phylogenomic principles. AB - BACKGROUND: The genus Geobacillus comprises bacteria that are Gram positive, thermophilic spore-formers, which are found in a variety of environments from hot springs, cool soils, to food manufacturing plants, including dairy manufacturing plants. Despite considerable interest in the use of Geobacillus spp. for biotechnological applications, the taxonomy of this genus is unclear, in part because of differences in DNA-DNA hybridization (DDH) similarity values between studies. In addition, it is also difficult to use phenotypic characteristics to define a bacterial species. For example, G. stearothermophilus was traditionally defined as a species that does not utilise lactose, but the ability of dairy strains of G. stearothermophilus to use lactose has now been well established. RESULTS: This study compared the genome sequences of 63 Geobacillus isolates and showed that based on two different genomic approaches (core genome comparisons and average nucleotide identity) the Geobacillus genus could be divided into sixteen taxa for those Geobacillus strains that have genome sequences available thus far. In addition, using Geobacillus stearothermophilus as an example, we show that inclusion of the accessory genome, as well as phenotypic characteristics, is not suitable for defining this species. For example, this is the first study to provide evidence of dairy adaptation in G. stearothermophilus a phenotypic feature not typically considered standard in this species - by identifying the presence of a putative lac operon in four dairy strains. CONCLUSIONS: The traditional polyphasic approach of combining both genotypic and phenotypic characteristics to define a bacterial species could not be used for G. stearothermophilus where many phenotypic characteristics vary within this taxon. Further evidence of this discordant use of phenotypic traits was provided by analysis of the accessory genome, where the dairy strains contained a putative lac operon. Based on the findings from this study, we recommend that novel bacterial species should be defined using a core genome approach. PMID- 28651525 TI - SOFIA(r)RSV: prospective laboratory evaluation and implementation of a rapid diagnostic test in a pediatric emergency ward. AB - BACKGROUND: Respiratory syncytial virus (RSV) is responsible for severe respiratory infections and higher costs in medical care. The two aims of this work were to assess the performances of SOFIA(r)RSV tests in "real-life laboratory" conditions (study 1) and implemented at point-of-care testing in a pediatric emergency department (ED, study 2), during two consecutive winter seasons. METHODS: In study 1, fresh nasopharyngeal swabs from patients of all ages were sampled in 1.5 ml of Universal virological Transport Medium (UTM) and prospectively tested using SOFIA(r)RSV tests. In study 2, conducted in a pediatric ED, nasopharyngeal swabs were placed in 3 ml of UTM. All SOFIA(r)RSV tests were confirmed by molecular testing, considered as reference method. The epidemiological and clinical features of tested patients, as well as the care of these patients after obtaining quick results were evaluated. RESULTS: The sensitivities of SOFIA(r)RSV in infants (aged under 24 months) performed in the laboratory and in the pediatric ED were respectively 95% (95% CI: 86.8-98.1) and 74.8% (95% CI: 68.0-80.9) compared to PCR. In study 1, the sensitivity among children (from 2 to 15 years old) and adults (above 15 years old) dropped to 45% (95% CI: 23.1-68.5) and 59% (95% CI: 32.9-81.6), respectively. In study 2, there were some differences in bed-management of SOFIA(r)RSV positive compared to SOFIA(r)RSV negative infants. CONCLUSIONS: SOFIA(r)RSV tests performed in the laboratory and in the pediatric ED show high and satisfactory sensitivities among young children under 24 months, which supports its robustness and reliability. However, the impact of these tests on patient care at point-of-care cannot be clearly assessed when considering the limits of the study 2 design. PMID- 28651526 TI - Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study). AB - BACKGROUND: Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to head in longer term studies, or with a superiority design in this patient group. METHODS: The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION: The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION: ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016. PMID- 28651527 TI - Identifying global expression patterns and key regulators in epithelial to mesenchymal transition through multi-study integration. AB - BACKGROUND: Epithelial to mesenchymal transition (EMT) is the process by which stationary epithelial cells transdifferentiate to mesenchymal cells with increased motility. EMT is integral in early stages of development and wound healing. Studies have shown that EMT could be a critical early event in tumor metastasis that is involved in acquisition of migratory and invasive properties in multiple carcinomas. METHODS: In this study, we used 15 published gene expression microarray datasets from Gene Expression Omnibus (GEO) that represent 12 cell lines from 6 cancer types across 95 observations (45 unique samples and 50 replicates) with different modes of induction of EMT or the reverse transition, mesenchymal to epithelial transition (MET). We integrated multiple gene expression datasets while considering study differences, batch effects, and noise in gene expression measurements. A universal differential EMT gene list was obtained by normalizing and correcting the data using four approaches, computing differential expression from each, and identifying a consensus ranking. We confirmed our discovery of novel EMT genes at mRNA and protein levels in an in vitro EMT model of prostate cancer - PC3 epi, EMT and Taxol resistant cell lines. We validate our discovery of C1orf116 as a novel EMT regulator by siRNA knockdown of C1orf116 in PC3 epithelial cells. RESULTS: Among differentially expressed genes, we found known epithelial and mesenchymal marker genes such as CDH1 and ZEB1. Additionally, we discovered genes known in a subset of carcinomas that were unknown in prostate cancer. This included epithelial specific LSR and S100A14 and mesenchymal specific DPYSL3. Furthermore, we also discovered novel EMT genes including a poorly-characterized gene C1orf116. We show that decreased expression of C1orf116 is associated with poor prognosis in lung and prostate cancer patients. We demonstrate that knockdown of C1orf116 expression induced expression of mesenchymal genes in epithelial prostate cancer cell line PC3-epi cells, suggesting it as a candidate driver of the epithelial phenotype. CONCLUSIONS: This comprehensive approach of statistical analysis and functional validation identified global expression patterns in EMT and candidate regulatory genes, thereby both extending current knowledge and identifying novel drivers of EMT. PMID- 28651528 TI - Evaluation of real-time use of electronic patient-reported outcome data by nurses with patients in home dialysis clinics. AB - BACKGROUND: Internationally, the use of patient-reported outcomes (PROs) is increasing. Electronic PROs (ePROs) offer immediate access of such reports to healthcare providers. The objectives of this study were to assess nurses' perspectives on the usefulness and impact of ePRO administration in home dialysis clinics and assess patient perceptions of satisfaction with nursing care following use of ePROs. METHODS: A concurrent, longitudinal, mixed methods study was conducted over 6 months during home dialysis outpatient clinic visits in two cities. Patients (n = 99) provided ePROs using tablet computers when they visited the clinic on two consecutive occasions approximately 3 months apart. Results were scored, printed, and given to nurses before patient appointments. Patients completed satisfaction items from the Comox Valley Nursing Centre Client questionnaire following their appointments. All clinic nurses (n = 11) participated and they were each interviewed twice, three months and six months after the start of the study. RESULTS: The five themes that emerged from the interviews with the nurses include: enhancing focus of the nurses, directing interdisciplinary follow-up, offering support to patients through the process, interpreting results from the visual display, and integrating into workflow. Scores on the Client Questionnaire suggested that patients believed that they received excellent care (97%), and that the nurses perfectly understood their needs (90.9%). However, their satisfaction with care did not change over time when ePRO data was repeatedly provided to their nurses. CONCLUSIONS: Nurses reported that sharing ePRO data in real-time informed their practice. Although there was no statistically significant change in patient satisfaction scores over time, some patients reported changes and benefits from the use of ePROs. Further research is needed to provide guidance about how ePRO data could enhance person centered care. PMID- 28651529 TI - Supporting nurse practitioners' practice in primary healthcare settings: a three level qualitative model. AB - BACKGROUND: While greater reliance on nurse practitioners in primary healthcare settings can improve service efficiency and accessibility, their integration is not straightforward, challenging existing role definitions of both registered nurses and physicians. Developing adequate support practices is therefore essential in primary healthcare nurse practitioners' integration. This study's main objective is to examine different structures and mechanisms put in place to support the development of primary healthcare nurse practitioner's practice in different healthcare settings, and develop a practical model for identifying and planning adequate support practices. METHODS: This study is part of a larger multicentre study on primary healthcare nurse practitioners in the province of Quebec, Canada. It focuses on three healthcare settings into which one or more primary healthcare nurse practitioners have been integrated. Case studies have been selected to cover a maximum of variations in terms of location, organizational setting, and stages of primary healthcare nurse practitioner integration. Findings are based on the analysis of available documentation in each primary healthcare setting and on semi-structured interviews with key actors in each clinical team. Data were analyzed following thematic and cross-sectional analysis approaches. RESULTS: This article identifies three types of support practices: clinical, team, and systemic. This three-level analysis demonstrates that, on the ground, primary healthcare nurse practitioner integration is essentially a team-based, multilevel endeavour. Despite the existence of a provincial implementation plan, the three settings adopted very different implementation structures and practices, and different actors were involved at each of the three levels. The results also indicated that nursing departments played a decisive role at all three levels. CONCLUSIONS: Based on these findings, we suggest that support practices should be adapted to each organization's environment and experience and be modified as needed throughout the integration process. We also stress the importance of combining this approach with a strong coordination mechanism involving managers who have in-depth understanding of nursing professional roles and scopes of practice. Making primary healthcare nurse practitioner integration frameworks more flexible and clarifying and strengthening the role of senior nursing managers could be the key to successful integration. PMID- 28651530 TI - Perspectives of health care professionals on the facilitators and barriers to the implementation of a stroke rehabilitation guidelines cluster randomized controlled trial. AB - BACKGROUND: The Stroke Canada Optimization of Rehabilitation by Evidence Implementation Trial (SCORE-IT) was a cluster randomized controlled trial that evaluated two knowledge translation (KT) interventions for the promotion of the uptake of best practice recommendations for interventions targeting upper and lower extremity function, postural control, and mobility. Twenty rehabilitation centers across Canada were randomly assigned to either the facilitated or passive KT intervention. The objective of the current study was to understand the factors influencing the implementation of the recommended treatments and KT interventions from the perspective of nurses, occupational therapists and physical therapists, and clinical managers following completion of the trial. METHODS: A qualitative descriptive approach involving focus groups was used. Thematic analysis was used to understand the factors influencing the implementation of the recommended treatments and KT interventions. The Clinical Practice Guidelines Framework for Improvement guided the analysis. RESULTS: Thirty-three participants were interviewed from 11 of the 20 study sites (6 sites from the facilitated KT arm and 5 sites from the passive KT arm). The following factors influencing the implementation of the recommended treatments and KT interventions emerged: facilitation, agreement with the intervention - practical, familiarity with the recommended treatments, and environmental factors, including time and resources. Each of these themes includes the sub-themes of facilitator and/or barrier. Improved team communication and interdisciplinary collaboration emerged as an unintended outcome of the trial across both arms in addition to a facilitator to the implementation of the treatment recommendations. Facilitation was identified as a facilitator to implementation of the KT interventions in the passive KT intervention arm despite the lack of formally instituted facilitators in this arm of the trial. CONCLUSIONS: This is one of the first studies to examine the factors influencing the implementation of stroke recommendations and associated KT interventions within the context of a trial. Findings highlight the important role of self-selected facilitators to implementation efforts. Future research should seek to better understand the specific characteristics of facilitators that are associated with successful implementation and clinical outcomes, especially within the context of stroke rehabilitation. PMID- 28651531 TI - Supervision and autonomy of ophthalmology residents in the outpatient Clinic in the United States: a survey of ACGME-accredited programs. AB - BACKGROUND: The development and demonstration of incremental trainee autonomy is required by the ACGME. However, there is scant published research concerning autonomy of ophthalmology residents in the outpatient clinic setting. This study explored the landscape of resident ophthalmology outpatient clinics in the United States. METHODS: A link to an online survey using the QualtricsTM platform was emailed to the program directors of all 115 ACGME-accredited ophthalmology programs in the United States. Survey questions explored whether resident training programs hosted a continuity clinic where residents would see their own patients, and if so, the degree of faculty supervision provided therein. Metrics such as size of the resident program, number of faculty and clinic setting were also recorded. Correlations between the degree of faculty supervision and other metrics were explored. RESULTS: The response rate was 94%; 69% of respondents indicated that their trainees hosted continuity clinics. Of those programs, 30% required a faculty member to see each patient treated by a resident, while 42% expected the faculty member to at least discuss (if not see) each patient. All programs expected some degree of faculty interaction based upon circumstances such as the level of training of the resident or complexity of the clinical situation. 67% of programs that tracked the contribution of the clinic to resident surgical caseloads reported that these clinics provided more than half of the resident surgical volumes. More 3/4 of resident clinics were located in urban settings. The degree of faculty supervision did not correlate to any of the other metrics evaluated. CONCLUSIONS: The majority of ophthalmology resident training programs in the United States host a continuity clinic located in an urban environment where residents follow their own patients. Furthermore, most of these clinics require supervising faculty to review both the patients seen and the medical documentation created by the resident encounters. The different degrees of faculty supervision outlined by this survey might provide a useful guide presuming they can be correlated with validated metrics of educational quality. Finally, this study could provide an adjunctive resource to current international efforts to standardize ophthalmic residency education. PMID- 28651532 TI - Potential accessibility scores for hospital care in a province of Japan: GIS based ecological study of the two-step floating catchment area method and the number of neighborhood hospitals. AB - BACKGROUND: For achieving equity of the accessibility to primary healthcare, measuring potential geographical accessibility is essential. The provider-to population ratio is the most frequently used measure. However, it is difficult to be used in closer region because it does not take into consideration the people and health services beyond its boundary. In order to overcome this problem, we measured the potential access to hospital, using both distance measures and the enhanced two-step floating catchment area (E2SFCA) method. The aim of this study was to compare the number of hospitals in the neighborhood and the E2SFCA score with regard to the amount and equity for access to hospitals. METHODS: This descriptive study used publicly available data from 2010. The E2SFCA score and number of neighborhood hospitals were obtained from Tochigi province in Japan using a geographic information system. Dataset of four measures by each census tract was obtained. The measures were E2SFCA score, number of hospitals within the 5 km range, number of hospitals within the 10 km range, and number of hospitals within the 15 km range. Correlation and disparity analyses with the Lorenz curve and Gini coefficient were performed. RESULTS: The measures were obtained in a smaller area than municipality considering adjacent areas using a geographical approach. The E2SFCA score was 5.3 [3.2-7.3] hospitals/million (median [quantile range]), compared to 5.6 hospitals/million in total for the given district. The median number of hospitals within the 5 km, 10 km, and 15 km ranges were 1, 39, and 47, respectively. There was no hospital within the 5 km range in one third of the blocks. Both the number of hospitals within the 10 km range and those within the 15 km range were well correlated. Regional difference became smaller as the distance to count the number of hospitals increased. The gap between small number of hospitals and the high E2SFCA score indicated the location of community hospital in depopulated areas. CONCLUSIONS: The E2SFCA method is superior for analyzing spatial access to hospital, because it provides information in the closer sub-regions. Regional differences were hardly seen in access to hospital beyond the 10 km range. Further studies in other regions and countries are needed for precise assessment. PMID- 28651533 TI - Profiling of antibiotic resistance of bacterial species recovered from routine clinical isolates in Ethiopia. AB - BACKGROUND: With the alarming rise in antibiotic resistance in African countries, the need for a surveillance system in the region has become pressing. The rapid expansion of data networks makes it possible to set up healthcare applications that can be both cost-efficient and effective. Large data sets are available for assessment of current antibiotic resistance among Ethiopian patients. Based on the data-presentation, a practical approach is proposed on how diagnostic laboratories can participate remedial action against antibiotic resistance in Ethiopia. METHODS: In Addis Ababa (Ethiopia), raw data comprising bacterial species name, specimen type and antibiograms covering the period January 2014 to May 2015 was accessed from the laboratory information management system. Using R code, the data was read and fitted into data-frames and analyzed to assess antibiotic resistance in the Ethiopian patient population. RESULTS: Susceptibility to an antibiotic was tested with 14.983 cultures of 54 different bacterial species or subgroups, isolated from 16 types of specimen. Half of the cultures (n = 6444) showed resistance to an antibiotic. Resistance against penicillin was highest with, on average, 91.1% of 79 bacterial cultures showing resistance. Very high resistance rates were also observed for ampicillin, whereas resistance was lowest with cefoxitin. CONCLUSIONS: Extraction and analysis of raw data from the laboratory database is relatively simple and can provide valuable insight into the relationships between type of sample and drug-resistance in countries where such data is still scarce. With the largest number of antibiotic resistance tests described for Ethiopia, a tool is proposed for consistent data collection with specified core variables. Trends in antibiotic resistance can be revealed and treatment failures avoided when used as an easy accessible reference application for healthcare providers. PMID- 28651534 TI - A survey for potentially zoonotic gastrointestinal parasites in domestic cavies in Cameroon (Central Africa). AB - BACKGROUND: Farm animals are usually suspected to transmit infections to humans. Domestic cavies (Cavia porcellus) are hosts to a variety of pathogens, some of which are zoonotic. Several parasites including the protozoa Giardia spp. and Cryptosporidium spp. may be causative agents of gastrointestinal disorders in domestic cavies and humans. The aim of the study was to investigate the occurrence of potentially zoonotic protozoa as well as any potential zoonotic gastrointestinal parasite in domestic cavies raised under a semi extensive system in the rural areas of Cameroon. RESULTS: Giardia/Cryptosporidium antigens were detected in 12.90% of cavies. Helminthe eggs were found in 1.52% of animals. The prevalence of Paraspidodera uncinata, Heligmosomoides polygyrus (also known as Nematospiroides dubius) and Trichuris sp. was 1% (4/397), 0.3% (1/397), and 0.3% (1/397), respectively. Presence of Giardia/Cryptosporidium was unrelated to the occurrence of diarrhea, as none of the positive samples was from a diarrheic individual. CONCLUSION: Domestic cavies are hosts of Giardia/Cryptosporidium and appear as potential source of human giardiasis, cryptosporidiosis and infection with H. polygyrus in Cameroon. In keeping with the One Health Initiative, veterinarians and medical doctors should collaborate to address the problem of Giardia and Cryptosporidium infection in cavies and cavy breeders both in Cameroon and other countries with a similar cavy breeding system. Follow-up studies are required to further taxonomically characterize these cavy parasites and to determine their routes of transmission to humans. PMID- 28651535 TI - Molecular phylogeny reveals food plasticity in the evolution of true ladybird beetles (Coleoptera: Coccinellidae: Coccinellini). AB - BACKGROUND: The tribe Coccinellini is a group of relatively large ladybird beetles that exhibits remarkable morphological and biological diversity. Many species are aphidophagous, feeding as larvae and adults on aphids, but some species also feed on other hemipterous insects (i.e., heteropterans, psyllids, whiteflies), beetle and moth larvae, pollen, fungal spores, and even plant tissue. Several species are biological control agents or widespread invasive species (e.g., Harmonia axyridis (Pallas)). Despite the ecological importance of this tribe, relatively little is known about the phylogenetic relationships within it. The generic concepts within the tribe Coccinellini are unstable and do not reflect a natural classification, being largely based on regional revisions. This impedes the phylogenetic study of important traits of Coccinellidae at a global scale (e.g. the evolution of food preferences and biogeography). RESULTS: We present the most comprehensive phylogenetic analysis of Coccinellini to date, based on three nuclear and one mitochondrial gene sequences of 38 taxa, which represent all major Coccinellini lineages. The phylogenetic reconstruction supports the monophyly of Coccinellini and its sister group relationship to Chilocorini. Within Coccinellini, three major clades were recovered that do not correspond to any previously recognised divisions, questioning the traditional differentiation between Halyziini, Discotomini, Tytthaspidini, and Singhikaliini. Ancestral state reconstructions of food preferences and morphological characters support the idea of aphidophagy being the ancestral state in Coccinellini. This indicates a transition from putative obligate scale feeders, as seen in the closely related Chilocorini, to more agile general predators. CONCLUSIONS: Our results suggest that the classification of Coccinellini has been misled by convergence in morphological traits. The evolutionary history of Coccinellini has been very dynamic in respect to changes in host preferences, involving multiple independent host switches from different insect orders to fungal spores and plants tissues. General predation on ephemeral aphids might have created an opportunity to easily adapt to mixed or specialised diets (e.g. obligate mycophagy, herbivory, predation on various hemipteroids or larvae of leaf beetles (Chrysomelidae)). The generally long-lived adults of Coccinellini can consume pollen and floral nectars, thereby surviving periods of low prey frequency. This capacity might have played a central role in the diversification history of Coccinellini. PMID- 28651536 TI - Genomic selection for crossbred performance accounting for breed-specific effects. AB - BACKGROUND: Breed-specific effects are observed when the same allele of a given genetic marker has a different effect depending on its breed origin, which results in different allele substitution effects across breeds. In such a case, single-breed breeding values may not be the most accurate predictors of crossbred performance. Our aim was to estimate the contribution of alleles from each parental breed to the genetic variance of traits that are measured in crossbred offspring, and to compare the prediction accuracies of estimated direct genomic values (DGV) from a traditional genomic selection model (GS) that are trained on purebred or crossbred data, with accuracies of DGV from a model that accounts for breed-specific effects (BS), trained on purebred or crossbred data. The final dataset was composed of 924 Large White, 924 Landrace and 924 two-way cross (F1) genotyped and phenotyped animals. The traits evaluated were litter size (LS) and gestation length (GL) in pigs. RESULTS: The genetic correlation between purebred and crossbred performance was higher than 0.88 for both LS and GL. For both traits, the additive genetic variance was larger for alleles inherited from the Large White breed compared to alleles inherited from the Landrace breed (0.74 and 0.56 for LS, and 0.42 and 0.40 for GL, respectively). The highest prediction accuracies of crossbred performance were obtained when training was done on crossbred data. For LS, prediction accuracies were the same for GS and BS DGV (0.23), while for GL, prediction accuracy for BS DGV was similar to the accuracy of GS DGV (0.53 and 0.52, respectively). CONCLUSIONS: In this study, training on crossbred data resulted in higher prediction accuracy than training on purebred data and evidence of breed-specific effects for LS and GL was demonstrated. However, when training was done on crossbred data, both GS and BS models resulted in similar prediction accuracies. In future studies, traits with a lower genetic correlation between purebred and crossbred performance should be included to further assess the value of the BS model in genomic predictions. PMID- 28651537 TI - Improving sperm banking efficiency in endangered species through the use of a sperm selection method in brown bear (Ursus arctos) thawed sperm. AB - BACKGROUND: Sperm selection methods such as Single Layer Centrifugation (SLC) have been demonstrated to be a useful tool to improve the quality of sperm samples and therefore to increase the efficiency of other artificial reproductive techniques in several species. This procedure could help to improve the quality of genetic resource banks, which is essential for endangered species. In contrast, these sperm selection methods are optimized and focused on farm animals, where the recovery task is not as important as in endangered species because of their higher sperm availability. The aim of this study was to evaluate two centrifugation methods (300 x g/20 min and 600 x g/10 min) and three concentrations of SLC media (Androcoll-Bear -80, 65 and 50%) to optimise the procedure in order to recover as many sperm with the highest quality as possible. Sperm morphology could be important in the hydrodynamic relationship between the cell and centrifugation medium and thus the effect of sperm head morphometry on sperm yield and its hydrodynamic relationship were studied. RESULTS: The samples selected with Androcoll-Bear 65% showed a very good yield (53.1 +/- 2.9) although the yield from Androcoll-Bear 80% was lower (19.3 +/- 3.3). The latter showed higher values of motility than the control immediately after post-thawing selection. However, both concentrations of colloid (65 and 80%) showed higher values of viable sperm and viable sperm with intact acrosome than the control. After an incubation of 2 h at 37 degrees C, the samples from Androcoll-Bear 80% had higher kinematics and proportion of viable sperm with intact acrosome. In the morphometric analysis, the sperm selected by the Androcoll-Bear 80% showed a head with a bigger area which was more elongated than the sperm from other treatments. CONCLUSIONS: We conclude that sperm selection with Androcoll-Bear at either 65% or 80% is a suitable technique that allows a sperm population with better quality than the initial sample to be obtained. We recommend the use of Androcoll-Bear 65% since the yield is better than Androcoll-Bear 80%. Our findings pave the way for further research on application of sperm selection techniques to sperm banking in the brown bear. PMID- 28651539 TI - A comparison of physician emigration from Africa to the United States of America between 2005 and 2015. AB - BACKGROUND: Migration of health professionals has been a cause for global concern, in particular migration from African countries with a high disease burden and already fragile health systems. An estimated one fifth of African-born physicians are working in high-income countries. Lack of good data makes it difficult to determine what constitutes "African" physicians, as most studies do not distinguish between their country of citizenship and country of training. Thus, the real extent of migration from African countries to the United States (US) remains unclear. This paper quantifies where African migrant physicians come from, where they were educated, and how these trends have changed over time. METHODS: We combined data from the Educational Commission for Foreign Medical Graduates with the 2005 and 2015 American Medical Association Physician Masterfiles. Using a repeated cross-sectional study design, we reviewed the available data, including medical school attended, country of medical school, and citizenship when entering medical school. RESULTS: The outflow of African educated physicians to the US has increased over the past 10 years, from 10 684 in 2005 to 13 584 in 2015 (27.1% increase). This represents 5.9% of all international medical graduates in the US workforce in 2015. The number of African-educated physicians who graduated from medical schools in sub-Saharan countries was 2014 in 2005 and 8150 in 2015 (304.6% increase). We found four distinct categorizations of African-trained physicians migrating to the US: (1) citizens from an African country who attended medical school in their own country (86.2%, n = 11,697); (2) citizens from an African country who attended medical school in another African country (2.3%, n = 317); (3) US citizens who attended medical school in an African country (4.0%, n = 537); (4) citizens from a country outside Africa, and other than the United States, who attended medical school in an African country (7.5%, n = 1013). Overall, six schools in Africa provided half of all African-educated physicians. CONCLUSIONS: The number of African-educated physicians in the US has increased over the past 10 years. We have distinguished four migration patterns, based on citizenship and country of medical school. The majority of African graduates come to the US from relatively few countries, and from a limited number of medical schools. A proportion are not citizens of the country where they attended medical school, highlighting the internationalization of medical education. PMID- 28651538 TI - Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction. AB - BACKGROUND: The molecular function of a gene is most commonly inferred by sequence similarity. Therefore, genes that lack sufficient sequence similarity to characterized genes (such as certain classes of transcriptional regulators) are difficult to classify using most function prediction algorithms and have remained uncharacterized. RESULTS: To identify novel transcriptional regulators systematically, we used a feature-based pipeline to screen protein families of unknown function. This method predicted 43 transcriptional regulator families in Arabidopsis thaliana, 7 families in Drosophila melanogaster, and 9 families in Homo sapiens. Literature curation validated 12 of the predicted families to be involved in transcriptional regulation. We tested 33 out of the 195 Arabidopsis putative transcriptional regulators for their ability to activate transcription of a reporter gene in planta and found twelve coactivators, five of which had no prior literature support. To investigate mechanisms of action in which the predicted regulators might work, we looked for interactors of an Arabidopsis candidate that did not show transactivation activity in planta and found that it might work with other members of its own family and a subunit of the Polycomb Repressive Complex 2 to regulate transcription. CONCLUSIONS: Our results demonstrate the feasibility of assigning molecular function to proteins of unknown function without depending on sequence similarity. In particular, we identified novel transcriptional regulators using biological features enriched in transcription factors. The predictions reported here should accelerate the characterization of novel regulators. PMID- 28651540 TI - Cattle phenotypes can disguise their maternal ancestry. AB - BACKGROUND: Cattle are bred for, amongst other factors, specific traits, including parasite resistance and adaptation to climate. However, the influence and inheritance of mitochondrial DNA (mtDNA) are not usually considered in breeding programmes. In this study, we analysed the mtDNA profiles of cattle from Victoria (VIC), southern Australia, which is a temperate climate, and the Northern Territory (NT), the northern part of Australia, which has a tropical climate, to determine if the mtDNA profiles of these cattle are indicative of breed and phenotype, and whether these profiles are appropriate for their environments. RESULTS: A phylogenetic tree of the full mtDNA sequences of different breeds of cattle, which were obtained from the NCBI database, showed that the mtDNA profiles of cattle do not always reflect their phenotype as some cattle with Bos taurus phenotypes had Bos indicus mtDNA, whilst some cattle with Bos indicus phenotypes had Bos taurus mtDNA. Using D-loop sequencing, we were able to contrast the phenotypes and mtDNA profiles from different species of cattle from the 2 distinct cattle breeding regions of Australia. We found that 67 of the 121 cattle with Bos indicus phenotypes from NT (55.4%) had Bos taurus mtDNA. In VIC, 92 of the 225 cattle with Bos taurus phenotypes (40.9%) possessed Bos indicus mtDNA. When focusing on oocytes from cattle with the Bos taurus phenotype in VIC, their respective oocytes with Bos indicus mtDNA had significantly lower levels of mtDNA copy number compared with oocytes possessing Bos taurus mtDNA (P < 0.01). However, embryos derived from oocytes with Bos indicus mtDNA had the same ability to develop to the blastocyst stage and the levels of mtDNA copy number in their blastocysts were similar to blastocysts derived from oocytes harbouring Bos taurus mtDNA. Nevertheless, oocytes originating from the Bos indicus phenotype exhibited lower developmental potential due to low mtDNA copy number when compared with oocytes from cattle with a Bos taurus phenotype. CONCLUSIONS: The phenotype of cattle is not always related to their mtDNA profiles. MtDNA profiles should be considered for breeding programmes as they also influence phenotypic traits and reproductive capacity in terms of oocyte quality. PMID- 28651541 TI - The agglomeration state of nanoparticles can influence the mechanism of their cellular internalisation. AB - BACKGROUND: Significant progress of nanotechnology, including in particular biomedical and pharmaceutical applications, has resulted in a high number of studies describing the biological effects of nanomaterials. Moreover, a determination of so-called "critical quality attributes", that is specific physicochemical properties of nanomaterials triggering the observed biological response, has been recognised as crucial for the evaluation and design of novel safe and efficacious therapeutics. In the context of in vitro studies, a thorough physicochemical characterisation of nanoparticles (NPs), also in the biological medium, is necessary to allow a correlation with a cellular response. Following this concept, we examined whether the main and frequently reported characteristics of NPs such as size and the agglomeration state can influence the level and the mechanism of NP cellular internalization. RESULTS: We employed fluorescently-labelled 30 and 80 nm silicon dioxide NPs, both in agglomerated and non-agglomerated form. Using flow cytometry, transmission electron microscopy, the inhibitors of endocytosis and gene silencing we determined the most probable routes of cellular uptake for each form of tested silica NPs. We observed differences in cellular uptake depending on the size and the agglomeration state of NPs. Caveolae-mediated endocytosis was implicated particularly in the internalisation of well dispersed silica NPs but with an increase of the agglomeration state of NPs a combination of endocytic pathways with a predominant role of macropinocytosis was noted. CONCLUSIONS: We demonstrated that the agglomeration state of NPs is an important factor influencing the level of cell uptake and the mechanism of endocytosis of silica NPs. PMID- 28651542 TI - Evidence for an early innate immune response in the motor cortex of ALS. AB - BACKGROUND: Recent evidence indicates the importance of innate immunity and neuroinflammation with microgliosis in amyotrophic lateral sclerosis (ALS) pathology. The MCP1 (monocyte chemoattractant protein-1) and CCR2 (CC chemokine receptor 2) signaling system has been strongly associated with the innate immune responses observed in ALS patients, but the motor cortex has not been studied in detail. METHODS: After revealing the presence of MCP1 and CCR2 in the motor cortex of ALS patients, to elucidate, visualize, and define the timing, location and the extent of immune response in relation to upper motor neuron vulnerability and progressive degeneration in ALS, we developed MCP1-CCR2-hSOD1G93A mice, an ALS reporter line, in which cells expressing MCP1 and CCR2 are genetically labeled by monomeric red fluorescent protein-1 and enhanced green fluorescent protein, respectively. RESULTS: In the motor cortex of MCP1-CCR2-hSOD1G93A mice, unlike in the spinal cord, there was an early increase in the numbers of MCP1+ cells, which displayed microglial morphology and selectively expressed microglia markers. Even though fewer CCR2+ cells were present throughout the motor cortex, they were mainly infiltrating monocytes. Interestingly, MCP1+ cells were found in close proximity to the apical dendrites and cell bodies of corticospinal motor neurons (CSMN), further implicating the importance of their cellular interaction to neuronal pathology. Similar findings were observed in the motor cortex of ALS patients, where MCP1+ microglia were especially in close proximity to the degenerating apical dendrites of Betz cells. CONCLUSIONS: Our findings reveal that the intricate cellular interplay between immune cells and upper motor neurons observed in the motor cortex of ALS mice is indeed recapitulated in ALS patients. We generated and characterized a novel model system, to study the cellular and molecular basis of this close cellular interaction and how that relates to motor neuron vulnerability and progressive degeneration in ALS. PMID- 28651544 TI - SalmoBase: an integrated molecular data resource for Salmonid species. AB - BACKGROUND: Salmonids are ray-finned fishes which constitute 11 genera and at least 70 species including Atlantic salmon, whitefishes, graylings, rainbow trout, and char. The common ancestor of all Salmonidae experienced a whole genome duplication (WGD) ~80 million years ago, resulting in an autotetraploid genome. Genomic rediplodization is still going on in salmonid species, providing an unique system for studying evolutionary consequences of whole genome duplication. In recent years, high quality genome sequences of Atlantic salmon and Rainbow trout has been established, due to their scientific and commercial values. In this paper we introduce SalmoBase ( http://www.salmobase.org/ ), a tool for making molecular resources for salmonids public available in a framework of visualizations and analytic tools. RESULTS: SalmoBase has been developed as a part of the ELIXIR.NO project. Currently, SalmoBase contains molecular resources for Atlantic salmon and Rainbow trout. Data can be accessed through BLAST, Genome Browser (GBrowse), Genetic Variation Browser (GVBrowse) and Gene Expression Browser (GEBrowse). CONCLUSIONS: To the best of our knowledge, SalmoBase is the first database which integrates salmonids data and allow users to study salmonids in an integrated framework. The database and its tools (e.g., comparative genomics tools, synteny browsers) will be expanded as additional public resources describing other Salmonidae genomes become available. PMID- 28651543 TI - Profiling of drought-responsive microRNA and mRNA in tomato using high-throughput sequencing. AB - BACKGROUND: Abiotic stresses cause severe loss of crop production. Among them, drought is one of the most frequent environmental stresses, which limits crop growth, development and productivity. Plant drought tolerance is fine-tuned by a complex gene regulatory network. Understanding the molecular regulation of this polygenic trait is crucial for the eventual success to improve plant yield and quality. Recent studies have demonstrated that microRNAs play critical roles in plant drought tolerance. However, little is known about the microRNA in drought response of the model plant tomato. Here, we described the profiling of drought responsive microRNA and mRNA in tomato using high-throughput next-generation sequencing. RESULTS: Drought stress was applied on the seedlings of M82, a drought-sensitive cultivated tomato genotype, and IL9-1, a drought-tolerant introgression line derived from the stress-resistant wild species Solanum pennellii LA0716 and M82. Under drought, IL9-1 performed superior than M82 regarding survival rate, H2O2 elimination and leaf turgor maintenance. A total of four small RNA and eight mRNA libraries were constructed and sequenced using Illumina sequencing technology. 105 conserved and 179 novel microRNAs were identified, among them, 54 and 98 were differentially expressed upon drought stress, respectively. The majority of the differentially-expressed conserved microRNAs was up-regulated in IL9-1 whereas down-regulated in M82. Under drought stress, 2714 and 1161 genes were found to be differentially expressed in M82 and IL9-1, respectively, and many of their homologues are involved in plant stress, such as genes encoding transcription factor and protein kinase. Various pathways involved in abiotic stress were revealed by Gene Ontology and pathway analysis. The mRNA sequencing results indicated that most of the target genes were regulated by their corresponding microRNAs, which suggested that microRNAs may play essential roles in the drought tolerance of tomato. CONCLUSION: In this study, numerous microRNAs and mRNAs involved in the drought response of tomato were identified using high-throughput sequencing, which will provide new insights into the complex regulatory network of plant adaption to drought stress. This work will also help to exploit new players functioning in plant drought-stress tolerance. PMID- 28651545 TI - Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters. AB - BACKGROUND: Microsatellite instability (MSI) operates as the second major pathway in the colorectal carcinogenesis. Although genetic testing remains the gold standard for the detection of MSI, the College of American Pathologists (CAP) recommends an initial immunohistochemical workup with a four-antibody panel (MLH1, PMS2, MSH2, and MSH6) to screen for a defective mismatch repair system. An increased trend towards young age colorectal carcinoma (CRC) has been noticed in our population over recent years; however, neither screening for MSI by immunohistochemistry (IHC)/genetic testing was done nor were its morphological features studied. We aimed to determine the frequency of mismatch repair deficiency (dMMR) by loss of IHC expression of the aforementioned enzymes in CRC patients and its correlatation with clinicopathologic parameters. METHODS: This was a retrospective study conducted at Liaquat National Hospital, Karachi, between 2012 and 2015. A total of 100 cases of CRC were included in the study that underwent surgical resection. IHC stains using antibodies MLH1, PMS2, MSH2, and MSH6 were performed by DAKO EnVision method on representative tissue blocks. The results were interpreted by senior histopathologists and correlated with clinico-pathological parameters. RESULTS: A total of 100 cases of CRC were studied that included 51 males and 49 females. Thirty-four percent (n = 34) of the patients showed loss of IHC staining for MMR markers. Combined loss of expression for MLH1/PMS2 were observed in 16% (n = 16) of the cases. Loss of MSH2/MSH6 were seen in 6% (n = 6) of the cases. Loss of expression for all markers were noted in 7% (n = 7) of the cases. There were 5% (n = 5) of the cases that showed isolated loss of MLH1 only. The tumors with dMMR status were significantly associated with right-sided location (p = 0.013), exhibited intra tumoral lymphocytosis (p = 0.007), and lymphovascular invasion (p = 0.043). No significant association was seen with gender, age, tumor stage, grade, or other morphological features. CONCLUSION: The frequency of mismatch repair deficiency in CRC patients was found to be 34% in Pakistani population which warrants further genetic testing to exclude Lynch syndrome. Moreover, right-sided location and intra-tumoral lymphocyte count may be used to identify patients who may need further workup. PMID- 28651546 TI - Allocating health care resources: a questionnaire experiment on the predictive success of rules. AB - BACKGROUND: The topic of this paper is related to equity in health within a country. In public health care sectors of many countries decisions on priority setting with respect to treatment of different types of diseases or patient groups are implicitly or explicitly made. Priorities are realized by allocation decisions for medical resources where moral judgments play an important role with respect to goals and measures that should be applied. The aim of this study is to explore the moral intuitions held in the German society related to priorities in medical treatment. METHODS: We use an experimental questionnaire method established in the Empirical Social Choice literature. Participants are asked to make decisions in a sequence of distributive problems where a limited amount of treatment time has to be allocated to hypothetically described patients. The decision problems serve as an intuition pump. Situations are systematically varied with respect to patients' initial health levels, their ability to benefit from treatment time, and the amount of treatment time available. Subjects are also asked to describe their deliberations. We focus on the acceptance of different allocation principles including equity concepts and utilitarian properties. We investigate rule characteristics like order preservation or monotonicity with respect to resources, severity, or effectiveness. We check the consistency of individual choices with stated reasoning. RESULTS: The goals and allocation principles revealed show that the moral intuitions held by our experimental subjects are much more complex than the principles commonly applied in health economic theory. Especially, cost-utility principles are rarely applied, whereas the goal of equality of health gain is observed more often. The principle not to leave any patient untreated is very dominant. We also observe the degrees to which extent certain monotonicity principles, known from welfare economics, are followed. Subjects were able to describe their moral judgments in written statements. We also find evidence that they followed their respective intuitions very consistently in their decisions. CONCLUSIONS: Findings of the kind presented in this paper may serve as an important input for the public and political discussion when decisions on priorities in the public health care sector are formed. PMID- 28651547 TI - Autoantibodies against BAFF, APRIL or IL21 - an alternative pathogenesis for antibody-deficiencies? AB - BACKGROUND: The ability of anti-cytokine antibodies to play a disease-causing role in the pathogenesis of immunodeficiencies is widely accepted. The aim of this study was to investigate whether autoantibodies against BAFF (important B cell survival signal), APRIL (important plasma cell survival signal), or Interleukin-21 (important cytokine for immunoglobulin class switch) present an alternative mechanism for the development of the following primary antibody deficiencies (PADs): common variable immune deficiency (CVID) or selective IgA deficiency (sIgAD). RESULTS: Two hundred thirty-two sera from patients with PADs were screened for autoantibodies against cytokines by ELISA. Statistical data analysis yielded a significant difference (p < 0.01) between the healthy donor sera and both PAD cohorts. The analysis was deepened by subdividing the patient collective into groups with distinct B cell phenotypes but no significant differences were found. For selected sera with notable high ELISA-read outs functional analysis ensued. Anti-BAFF and anti-APRIL antibodies were further examined by a B cell survival assay, whilst the functional relevance of putative anti-IL-21 autoantibodies was investigated by means of a STAT3 phosphorylation assay. However, the results of these experiments revealed no discernible functional effect. CONCLUSION: Whilst statistical analysis of ELISA results showed significant differences between patients and healthy controls, in our set of patients functional tests yielded no evidence for an involvement of autoantibodies against BAFF, APRIL, or IL-21 in the pathogenesis of CVID or sIgAD. PMID- 28651548 TI - Canis mtDNA HV1 database: a web-based tool for collecting and surveying Canis mtDNA HV1 haplotype in public database. AB - BACKGROUND: Canine and wolf mitochondrial DNA haplotypes, which can be used for forensic or phylogenetic analyses, have been defined in various schemes depending on the region analyzed. In recent studies, the 582 bp fragment of the HV1 region is most commonly used. 317 different canine HV1 haplotypes have been reported in the rapidly growing public database GenBank. These reported haplotypes contain several inconsistencies in their haplotype information. To overcome this issue, we have developed a Canis mtDNA HV1 database. This database collects data on the HV1 582 bp region in dog mitochondrial DNA from the GenBank to screen and correct the inconsistencies. It also supports users in detection of new novel mutation profiles and assignment of new haplotypes. DESCRIPTION: The Canis mtDNA HV1 database (CHD) contains 5567 nucleotide entries originating from 15 subspecies in the species Canis lupus. Of these entries, 3646 were haplotypes and grouped into 804 distinct sequences. 319 sequences were recognized as previously assigned haplotypes, while the remaining 485 sequences had new mutation profiles and were marked as new haplotype candidates awaiting further analysis for haplotype assignment. Of the 3646 nucleotide entries, only 414 were annotated with correct haplotype information, while 3232 had insufficient or lacked haplotype information and were corrected or modified before storing in the CHD. The CHD can be accessed at http://chd.vnbiology.com . It provides sequences, haplotype information, and a web-based tool for mtDNA HV1 haplotyping. The CHD is updated monthly and supplies all data for download. CONCLUSIONS: The Canis mtDNA HV1 database contains information about canine mitochondrial DNA HV1 sequences with reconciled annotation. It serves as a tool for detection of inconsistencies in GenBank and helps identifying new HV1 haplotypes. Thus, it supports the scientific community in naming new HV1 haplotypes and to reconcile existing annotation of HV1 582 bp sequences. PMID- 28651549 TI - 6-methylmercaptopurine riboside, a thiopurine nucleoside with antiviral activity against canine distemper virus in vitro. AB - BACKGROUND: Canine distemper (CD) is a widespread infectious disease that can severely impact a variety of species in the order Carnivora, as well as non carnivore species such as non-human primates. Despite large-scale vaccination campaigns, several fatal outbreaks have been reported in wild and domestic carnivore populations. This, in association with expansion of the disease host range and the development of vaccine-escape strains, has contributed to an increased demand for therapeutic strategies synergizing with vaccine programs for effectively controlling canine distemper. 6-methylmercaptopurine riboside (6MMPr) is a modified thiopurine nucleoside with known antiviral properties against certain RNA viruses. METHODS: We tested the inhibitory effects of 6MMPr against a wild-type CDV strain infection in cell culture. We measured infectious particle production and viral RNA levels in treated and untreated CDV-infected cells. Ribavirin (RIB) was used as a positive control. RESULTS: Here, we report for the first time the antiviral effects of 6MMPr against canine distemper virus (CDV) in vitro. 6MMPr was able to reduce viral RNA levels and to inhibit the production of infectious CDV particles. The therapeutic selectivity of 6MMPr was approximately six times higher than that of ribavirin. CONCLUSION: Our results indicate that 6MMPr has high anti-CDV potential and warrants further testing against other paramyxoviruses, as well as clinical testing of the compound against CDV. PMID- 28651550 TI - A novel TRPM8 agonist relieves dry eye discomfort. AB - BACKGROUND: Physical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied. Here, we synthesized a water-soluble TRPM8 receptor agonist called cryosim-3 (C3, 1-diisopropylphosphorylnonane) which selectively activates TRPM8 (linked to cooling) but not TRPV1 or TRPA1 (linked to nociception) and tested C3 in subjects with mild forms of dry eye disease. METHODS: A set of 1-dialkylphosphoryalkanes were tested for activation of TRPM8, TRPV1 and TRPA1 receptors in transfected cells. The bioactivity profiles were compared by perioral, topical, and intravenous delivery to anesthetized rats. The selected lead candidate C3 or vehicle (water) was applied with a cotton gauze pad to upper eyelids of patients with dry eye disease (n = 30). Cooling sensation, tear film break-up time (TBUT), basal tear secretion, and corneal staining were evaluated. C3 was then applied four times daily for 2 weeks to patients using a pre-loaded single unit applicator containing 2 mg/mL of C3 in water (n = 20) or water only. TBUT, basal tear secretion, and corneal staining, and three questionnaires surveys of ocular discomfort (VAS scale, OSDI, and CVS symptoms) were analyzed before and at 1 and 2 weeks thereafter. RESULTS: C3 was a selective and potent TRPM8 agonist without TRPV1 or TRPA1 activity. In test animals, the absence of shaking behavior after C3 perioral administration made it the first choice for further study. C3 increased tear secretion in an animal model of dry eye disease and did not irritate when wiped on eyes of volunteers. C3 singly applied (2 mg/ml) produced significant cooling in <5 min, an effecting lasting 46 min with an increase in tear secretion for 60 min. C3 applied for 2 weeks also significantly increased basal tear secretion with questionnaire surveys of ocular discomfort indices clearly showing improvement of symptoms at 1 and 2 weeks. No complaints of irritation or pain were reported by any subject. CONCLUSIONS: C3 is a promising candidate for study of TRPM8 function on the eye surface and for relief of dry eye discomfort. TRIAL REGISTRATION: ISRCTN24802609 and ISRCTN13359367 . Registered 23 March 2015 and 2 September 2015. PMID- 28651551 TI - Consumer attitudes and misperceptions associated with trends in self-reported cereal foods consumption: cross-sectional study of Western Australian adults, 1995 to 2012. AB - BACKGROUND: The reasons for low adherence to cereal dietary guidelines are not well understood but may be related to knowledge, attitudes, beliefs and perceived barriers. This study aims to assess trends in cereal foods consumption, intention to change and factors associated with intake among Western Australian (WA) adults 18 to 64 years. METHOD: Cross-sectional data from the 1995, 1998, 2001, 2004, 2009, and 2012 Nutrition Monitoring Survey Series involving 7044 adults were pooled. OUTCOME VARIABLES: types and amount of cereals (bread, rice, pasta, and breakfast cereal) eaten the day prior. Attitudes, knowledge, intentions, weight status and sociodemographic characteristics were measured. Descriptive statistics, multiple binary logistic and multinomial logistic regressions assess factors associated with consumption. RESULTS: Bread (78%) was the most commonly consumed cereal food. The proportion eating bread decreased across survey years (Odds Ratio OR = 0.31; 95% Confidence Interval; 0.24-0.40 in 2012 versus 1995), as did the amount (4.1 slices of bread in 1995 to 2.4 in 2012). The odds of consuming whole-grain cereal foods increased since 2009 (OR = 1.27; 1.02-1.58 versus 1995 p < 0.05). The likelihood of trying to eat less cereal food in the past year was greater in 2012 compared to 1995 (Relative Risk Ratio RRR 10.88; 6.81-17.4). Knowledge of cereal recommendations decreased over time (OR = 0.20; 0.15-0.27 in 2012 versus 1995 p < 0.001). Overweight and obese respondents were more likely than healthy weight respondents to have tried to eat less cereals (RRR 1.65; 1.22-2.24 and 1.88; 1.35-2.63 respectively). 'I already eat enough' was the main barrier (75% in 1995 to 84% in 2012 (p < 0.001)). CONCLUSIONS: WA adults are actively reducing the amount of cereal foods they eat and intake is associated with a misperception of adequacy of intake. Nutrition intervention is needed to increase awareness of the health benefits of cereal foods, particularly whole-grains, and to address barriers to incorporating them daily. TRIAL REGISTRATION: Not applicable. PMID- 28651552 TI - Understanding factors affecting collaboration between midwives and other health care professionals in a birth center and its affiliated Quebec hospital: a case study. AB - BACKGROUND: A better understanding of the processes of collaboration between midwives who work in the birthing centers, and hospital-based obstetricians, family physicians and nurses may promote cooperation among professionals providing maternity care in both institutions. The aim of this research was to explore the barriers and facilitators of the interprofessional and interorganizational collaboration between midwives in birthing centers and other health care professionals in hospitals in Quebec. METHODS: A case study design was adopted. Data were collected through semi-structured interviews with midwives, multidisciplinary professionals and administrators, through direct observation of activities in maternity units and field notes, and a variety of organizational and policy documents and archives. A qualitative thematic analysis method was used for analyzing transcribed verbatim. RESULTS: The study suggests the close intertwinement between interactional, organizational and systemic factors in regard to barriers and opportunities for collaboration between midwives in birthing centers, and physicians and nurses in hospitals in Quebec. At interactional level, our findings show a conflict in scope of midwifery practice, myth about midwives, pre-judgment, and lack of communication skills between health care providers in the studied birthing center and hospital. At the organizational level, this investigation shows that although midwives have complete access to the hospital with which a formal agreement was signed, they were not integrated in hospital because of lack of interest of midwives and differences in philosophy and scope of practice among healthcare professionals as well as the culture of organizations. At a systemic level, in spite of excessive demand for midwifery care, there are not enough midwives to cover these demands. CONCLUSION: Maternity care professionals require taking a collaborative approach in working and the boundaries of responsibility need to be redrawn. The inter professional collaborative work between midwives and other maternity care professionals is crucial to improve access and women's choices for maternity care in Canada. Although having collaborative and multidisciplinary teamwork is a goal of maternity care systems, it is hard to achieve. PMID- 28651553 TI - IG and TR single chain fragment variable (scFv) sequence analysis: a new advanced functionality of IMGT/V-QUEST and IMGT/HighV-QUEST. AB - BACKGROUND: IMGT(r), the international ImMunoGeneTics information system(r) ( http://www.imgt.org ), was created in 1989 in Montpellier, France (CNRS and Montpellier University) to manage the huge and complex diversity of the antigen receptors, and is at the origin of immunoinformatics, a science at the interface between immunogenetics and bioinformatics. Immunoglobulins (IG) or antibodies and T cell receptors (TR) are managed and described in the IMGT(r) databases and tools at the level of receptor, chain and domain. The analysis of the IG and TR variable (V) domain rearranged nucleotide sequences is performed by IMGT/V-QUEST (online since 1997, 50 sequences per batch) and, for next generation sequencing (NGS), by IMGT/HighV-QUEST, the high throughput version of IMGT/V-QUEST (portal begun in 2010, 500,000 sequences per batch). In vitro combinatorial libraries of engineered antibody single chain Fragment variable (scFv) which mimic the in vivo natural diversity of the immune adaptive responses are extensively screened for the discovery of novel antigen binding specificities. However the analysis of NGS full length scFv (~850 bp) represents a challenge as they contain two V domains connected by a linker and there is no tool for the analysis of two V domains in a single chain. METHODS: The functionality "Analyis of single chain Fragment variable (scFv)" has been implemented in IMGT/V-QUEST and, for NGS, in IMGT/HighV QUEST for the analysis of the two V domains of IG and TR scFv. It proceeds in five steps: search for a first closest V-REGION, full characterization of the first V-(D)-J-REGION, then search for a second V-REGION and full characterization of the second V-(D)-J-REGION, and finally linker delimitation. RESULTS: For each sequence or NGS read, positions of the 5'V-DOMAIN, linker and 3'V-DOMAIN in the scFv are provided in the 'V-orientated' sense. Each V-DOMAIN is fully characterized (gene identification, sequence description, junction analysis, characterization of mutations and amino changes). The functionality is generic and can analyse any IG or TR single chain nucleotide sequence containing two V domains, provided that the corresponding species IMGT reference directory is available. CONCLUSION: The "Analysis of single chain Fragment variable (scFv)" implemented in IMGT/V-QUEST and, for NGS, in IMGT/HighV-QUEST provides the identification and full characterization of the two V domains of full-length scFv (~850 bp) nucleotide sequences from combinatorial libraries. The analysis can also be performed on concatenated paired chains of expressed antigen receptor IG or TR repertoires. PMID- 28651554 TI - Validation of an International Classification of Disease, Ninth Revision coding algorithm to identify decompressive craniectomy for stroke. AB - BACKGROUND: Although International Classification of Disease, Ninth Revision, Clinical Modification (ICD9-CM) coding is the basis of administrative claims data, no study has validated an ICD9-CM algorithm to identify patients undergoing decompressive craniectomy for space-occupying supratentorial infarction. METHODS: Patients who underwent decompressive craniectomy for stroke at our institution were retrospectively identified and their associated ICD9-CM codes were extracted from billing data. An ICD9-CM algorithm was generated and its accuracy compared against physician review. RESULTS: A total of 10,925 neurosurgical operations were performed from December 2008 to March 2015, of which 46 (0.4%) were decompressive craniectomy for space-occupying stroke. The ICD9-CM procedure code for craniectomy (01.25) was only encoded in 67.4% of patients, while craniotomy (01.24) was used in 19.6% and lobectomy (01.39, 01.53, 01.59) in 13.1%. The ICD-9 CM algorithm included patients with a diagnosis codes for cerebral infarction (433.11, 434.01, 434.11, and 434.91) and a procedure code for craniotomy, craniectomy, or lobectomy. Patients were excluded with an ICD9-CM diagnosis code for brain tumor, intracranial abscess, subarachnoid hemorrhage, vertebrobasilar infarction, intracranial aneurysm, Moyamoya disease, intracranial venous sinus thrombosis, vertebral artery dissection, congenital cerebrovascular anomaly, head trauma or an ICD9-CM procedure code for laminectomy. This algorithm had a sensitivity of 97.8%, specificity of 99.9%, positive predictive value of 88.2%, and negative predictive value of 99.9%. The majority of false-positive results were patients who underwent evacuation of a primary intracerebral hematoma. CONCLUSION: An ICD-9-CM algorithm based on diagnosis and procedure codes can effectively identify patients undergoing decompressive craniectomy for supratentorial stroke. PMID- 28651555 TI - Prevalence of high blood pressure subtypes and its associations with BMI in Chinese children: a national cross-sectional survey. AB - BACKGROUND: Data on prevalence and characteristics of different high blood pressure subtypes are lacking among Chinese children. Regarding the mechanistic differences between isolated systolic high blood pressure and isolated diastolic high blood pressure and their different impact on end organ diseases, it is necessary to examine the prevalence of different high blood pressure subtypes in Chinese children and explore their associations with adiposity. METHODS: Data were derived from the baseline data of a multi-centered cluster randomized controlled trial involving participants from China. High blood pressure was defined according to age-, gender- and height-specific 95th percentile developed by the National High Blood Pressure Education Program Working Group. Body mass index was used to classify underweight, normal weight, overweight and obesity. RESULTS: The prevalence of HBP was 10.2% and 8.9% for boys and girls, respectively. Isolated systolic high blood pressure is the dominant high blood pressure subtype among Chinese boys aged 6-17 years and girls aged 12-17 years, while isolated diastolic high blood pressure was the most common high blood pressure subtype in girls aged 6-11 years. In boys, the status of overweight doubled the risk of isolated systolic high blood pressure (95% CI, 1.73, 2.31; P < 0.001) compared with the normal weight group, and the risk for obese children was 4.32 (95% CI, 3.81, 4.90; P < 0.001). The corresponding odds ratios in girls were 2.04 (95% CI, 1.68, 2.48, P < 0.001) for overweight, and 4.0 (95% CI, 3.36, 4.76, P < 0.001) for obesity. Similar patterns were also observed in the association between combined systolic and diastolic high blood pressure and adiposity. CONCLUSION: The distribution of high blood pressure subtypes in boys differed from those in girls, and boys with adiposity showed a higher risk of high blood pressure than their female counterpart. Difference in strength of association between isolated diastolic high blood pressure and isolated systolic high blood pressure with body mass index was also found. These results may aid current strategies for preventing and controlling pediatric hypertension. PMID- 28651556 TI - Clinical outcomes of transoral videolaryngoscopic surgery for hypopharyngeal and supraglottic cancer. AB - BACKGROUND: Transoral videolaryngoscopic surgery (TOVS) was developed as a new distinct surgical procedure for hypopharyngeal cancer (HPC) and supraglottic cancer (SGC) staged at up to T3. However, long-term treatment outcomes of TOVS remain to be validated. METHODS: Under a straight broad intraluminal view provided by combined use of a distending laryngoscope and a videolaryngoscope, we performed en bloc tumor resection via direct bimanual handling of the ready-made straight-form surgical instruments and devices. We retrospectively analyzed functional and oncologic outcomes of 72 patients with HPC (n = 58) or SGC (n = 14) whose minimum follow-up was 24 months or until death. RESULTS: The cohort comprised nine patients of Tis, 23 of T1, 33 of T2, and 7 of T3. Among 36 patients (50%) who underwent neck dissection simultaneously, all but one were pathologically node-positive. Twelve patients underwent postoperative concurrent chemoradiation (CCRT) as adjuvant treatment, and another four patients underwent radiation or CCRT for second or later primary cancer. The endotracheal tube was removed in an operation room in all but two patients who underwent temporary tracheostomy. Pharyngeal fistula was formed transiently in two patients. The median time until patients resumed oral intake and could take a soft meal was 2 and 5 days, respectively. Eventually, 69 patients (96%) took normal meals. The 5 year cause-specific survival (CSS), overall survival (OS), larynx-preserved CSS, and loco-regional controlled CSS were 87.3%, 77.9%, 86.0%, and 88.0%, respectively. Multivariate analysis revealed N2-3 as an independent prognostic factor in both CSS (hazard ratio [HR] = 25.51, P = 0.008) and OS (HR = 4.90, P = 0.022), which indirectly reflected higher risk of delayed distant metastasis. CONCLUSIONS: Considering its sound functional and oncological outcomes with various practical advantages, TOVS can be a dependable, less invasive, and cost effective surgical option of an organ-function preservation strategy for HPC and SGC. PMID- 28651557 TI - Amphibian and reptile road-kills on tertiary roads in relation to landscape structure: using a citizen science approach with open-access land cover data. AB - BACKGROUND: Amphibians and reptiles are among the most endangered vertebrate species worldwide. However, little is known how they are affected by road-kills on tertiary roads and whether the surrounding landscape structure can explain road-kill patterns. The aim of our study was to examine the applicability of open access remote sensing data for a large-scale citizen science approach to describe spatial patterns of road-killed amphibians and reptiles on tertiary roads. Using a citizen science app we monitored road-kills of amphibians and reptiles along 97.5 km of tertiary roads covering agricultural, municipal and interurban roads as well as cycling paths in eastern Austria over two seasons. Surrounding landscape was assessed using open access land cover classes for the region (Coordination of Information on the Environment, CORINE). Hotspot analysis was performed using kernel density estimation (KDE+). Relations between land cover classes and amphibian and reptile road-kills were analysed with conditional probabilities and general linear models (GLM). We also estimated the potential cost-efficiency of a large scale citizen science monitoring project. RESULTS: We recorded 180 amphibian and 72 reptile road-kills comprising eight species mainly occurring on agricultural roads. KDE+ analyses revealed a significant clustering of road-killed amphibians and reptiles, which is an important information for authorities aiming to mitigate road-kills. Overall, hotspots of amphibian and reptile road-kills were next to the land cover classes arable land, suburban areas and vineyards. Conditional probabilities and GLMs identified road-kills especially next to preferred habitats of green toad, common toad and grass snake, the most often found road-killed species. A citizen science approach appeared to be more cost-efficient than monitoring by professional researchers only when more than 400 km of road are monitored. CONCLUSIONS: Our findings showed that freely available remote sensing data in combination with a citizen science approach would be a cost-efficient method aiming to identify and monitor road-kill hotspots of amphibians and reptiles on a larger scale. PMID- 28651559 TI - Establishing energy requirements for body weight maintenance: validation of an intake-balance method. AB - BACKGROUND: Experimentally establishing a group's body weight maintenance energy requirement is an important component of metabolism research. At present, the reference approach for measuring the metabolizable energy intake (MEI) from foods required for body weight maintenance in non-confined subjects is the doubly labeled water (DLW)-total energy expenditure (TEE) method. In the current study, we evaluated an energy-intake weight balance method as an alternative to DLW that is more flexible and practical to apply in some settings. METHODS: The hypothesis was tested that MEI from foods observed in a group of subjects maintaining a constant energy intake while keeping their weight within +/-1 kg over 10 days is non-significantly different from DLW-measured TEE (TEEDLW). Six non-obese subjects evaluated as part of an earlier study completed the inpatient protocol that included a 3-day initial adjustment period. RESULTS: The group body weight coefficient of variation (X +/- SD) during the 10-day balance period was 0.38 +/- 0.10% and the slope of the regression line for body weight versus protocol day was non-significant at 1.8 g/day (R2, 0.002, p = 0.98). MEI from foods observed during the 10-day balance period (2390 +/- 543 kcal/day) was non-significantly different (p = 0.96) from TEE measured by DLW (2373 +/- 713 kcal/day); the MEI/TEEDLW ratio was 1.03 +/- 0.15 (range 0.87-1.27) and the correlation between MEI from foods and TEEDLW was highly significant (R2, 0.88, p = 0.005). CONCLUSIONS: A carefully managed 10-day protocol that includes a constant MEI level from foods with weight stability (+/-1 kg) will provide a group's body weight maintenance energy requirement similar to that obtained with DLW. This approach opens the possibility of conducting affordable weight balance studies, shorter in duration than those previously reported, that are needed to answer a wide range of questions in clinical nutrition. Trial registration The study is registered at http://www.clinicaltrials.gov (NCT01672632; August 20, 2012). PMID- 28651558 TI - Diapause and quiescence: dormancy mechanisms that contribute to the geographical expansion of mosquitoes and their evolutionary success. AB - Mosquitoes are insects belonging to the order Diptera and family Culicidae. They are distributed worldwide and include approximately 3500 species, of which about 300 have medical and veterinary importance. The evolutionary success of mosquitoes, in both tropical and temperate regions, is due to the various survival strategies these insects have developed throughout their life histories. Of the many adaptive mechanisms, diapause and quiescence, two different types of dormancy, likely contribute to the establishment, maintenance and spread of natural mosquito populations. This review seeks to objectively and coherently describe the terms diapause and quiescence, which can be confused in the literature because the phenotypic effects of these mechanisms are often similar. PMID- 28651560 TI - Intra-abdominal bleeding with hemorrhagic shock: a case of adrenal myelolipoma and review of literature. AB - Background: Adrenal myelolipoma is an uncommon, benign, and hormonally non functioning tumor that is composedof mature adipose tissue and normal hematopoietic tissue. Most cases to date are asymptomatic or have epigastric pain.Acute hemorrhage is the most dramatic manifestation of adrenal myelolipoma; though, it is a rare entity. Hemorrhagicshock due to adrenal myelolipoma, to our knowledge, was much less mentioned so far. Persistent bleeding anduncontrollable hypotension are considered to be absolute indications for immediate surgical operation. Case presentation: Herein we presented a 32-year-old male patient with initial symptoms of nausea, vomiting,and epigastric pain progressing to altered consciousness and hypotension during ER course. Hemorrhagic shockdue to a giant adrenal myelolipoma, R't was diagnosed. Emergent exploratory laparotomy was executed, and enbloc excision of tumor was done. Conclusion: Adrenal myelolipoma might be diagnosed as a adjunction to other main causes of illness; furthermore,adrenal myelolipoma could be asymptomatic in lifetime. In our case, however, manifesting as hemorrhage shock waschallenging to diagnose step by step; instead, maintaining vital organs perfusion and identifying bleeding sourceswere to be done. Management of myelolipoma should be done on a case-to-case basis. PMID- 28651561 TI - The effect of mislabeled phenotypic status on the identification of mutation carriers from SNP genotypes in dairy cattle. AB - BACKGROUND: Statistical and machine learning applications are increasingly popular in animal breeding and genetics, especially to compute genomic predictions for phenotypes of interest. Noise (errors) in the data may have a negative impact on the accuracy of predictions. The effects of noisy data have been investigated in genome-wide association studies for case-control experiments, and in genomic predictions for binary traits in plants. No studies have been published yet on the impact of noisy data in animal genomics. In this work, the susceptibility to noise of five classification models (Lasso-penalised logistic regression-Lasso, K-nearest neighbours-KNN, random forest-RF, support vector machines with linear-SVML-or radial-SVMR-kernel) was tested. As illustration, the identification of carriers of a recessive mutation in cattle (Bos taurus) was used. A population of 3116 Fleckvieh animals with SNP genotypes on the same chromosome as the mutation locus (BTA 19) was available. The carrier status (0/1 phenotype) was randomly sampled to generate noise. Increasing proportions of noise-up to 20%- were introduced in the data. RESULTS: SVMR and Lasso were relatively more robust to noise in the data, with total accuracy still above 0.975 and TPR (true positive rate; accuracy in the minority class) in the range 0.5-0.80 also with 17.5-20% mislabeled observations. The performance of SVML and RF decreased monotonically with increasing noise in the data, while KNN constantly failed to identify mutation carriers (observations in the minority class). The computation time increased with noise in the data, especially for the two support vector machines classifiers. CONCLUSIONS: This work was the first to assess the impact of phenotyping errors on the accuracy of genomic predictions in animal genetics. The choice of the classification method can influence results in terms of higher or lower susceptibility to noise. In the presented problem, SVM with radial kernel performed relatively well even when the proportion of errors in the data reached 12.5%. Lasso was the second best method, while SVML, RF and KNN were very sensitive to noise. Taking into account both accuracy and computation time, Lasso provided the best combination. PMID- 28651562 TI - GRAPE: a pathway template method to characterize tissue-specific functionality from gene expression profiles. AB - BACKGROUND: Personalizing treatment regimes based on gene expression profiles of individual tumors will facilitate management of cancer. Although many methods have been developed to identify pathways perturbed in tumors, the results are often not generalizable across independent datasets due to the presence of platform/batch effects. There is a need to develop methods that are robust to platform/batch effects and able to identify perturbed pathways in individual samples. RESULTS: We present Gene-Ranking Analysis of Pathway Expression (GRAPE) as a novel method to identify abnormal pathways in individual samples that is robust to platform/batch effects in gene expression profiles generated by multiple platforms. GRAPE first defines a template consisting of an ordered set of pathway genes to characterize the normative state of a pathway based on the relative rankings of gene expression levels across a set of reference samples. This template can be used to assess whether a sample conforms to or deviates from the typical behavior of the reference samples for this pathway. We demonstrate that GRAPE performs well versus existing methods in classifying tissue types within a single dataset, and that GRAPE achieves superior robustness and generalizability across different datasets. A powerful feature of GRAPE is the ability to represent individual gene expression profiles as a vector of pathways scores. We present applications to the analyses of breast cancer subtypes and different colonic diseases. We perform survival analysis of several TCGA subtypes and find that GRAPE pathway scores perform well in comparison to other methods. CONCLUSIONS: GRAPE templates offer a novel approach for summarizing the behavior of gene-sets across a collection of gene expression profiles. These templates offer superior robustness across distinct experimental batches compared to existing methods. GRAPE pathway scores enable identification of abnormal gene-set behavior in individual samples using a non-competitive approach that is fundamentally distinct from popular enrichment-based methods. GRAPE may be an appropriate tool for researchers seeking to identify individual samples displaying abnormal gene-set behavior as well as to explore differences in the consensus gene-set behavior of groups of samples. GRAPE is available in R for download at https://CRAN.R-project.org/package=GRAPE . PMID- 28651563 TI - Retraction Note: Human cathelicidin LL-37 enhance the antibiofilm effect of EGCG on Streptococcus mutans. PMID- 28651564 TI - Experiences of Austrian mothers with mobility or sensory impairments during pregnancy, childbirth and the puerperium: a qualitative study. AB - BACKGROUND: Approximately 8% of all women of childbearing age in Austria live with permanent impairments. In everyday life, women with disabilities face various challenges and discrimination, among which the issue of pregnancy and motherhood, in particular, is often considered taboo, and their parenting abilities are doubted. Knowledge in the medical field about the experiences of women with disabilities during pregnancy, childbirth and the puerperium is limited. METHODS: To investigate the personal meanings and experiences of women with disabilities in regard to pregnancy, childbirth and the puerperium, in-depth individual, semi-structured interviews were conducted with ten mothers with various mobility or sensory impairments who reside in Austria. The qualitative interview data were analyzed using the qualitative content analysis proposed by Mayring. RESULTS: Three main themes or categories emerged from the inductive content analysis, namely, (i) the social network, (ii) self-efficacy and self awareness and (iii) communication, transparency and information. Participants reported limited acceptance of their life decisions and experienced an environment of discriminatory attitudes. They experienced a lack of support and lack of confidence in their parenting abilities, which negatively influenced their self-efficacy and self-awareness. Violations of personal borders and a feeling of being watched and controlled were reported. Communication with health care professionals was often characterized by mutual aspects of fear, uncertainty and awkwardness, as perceived by women with disabilities. Adequate information about pregnancy, childbirth and the puerperium, particularly about measures taken and interventions applied, was frequently missing. CONCLUSION: Heath care facilities need to be structured to ensure ease of access for women with disabilities. Education should be offered to health care professionals to improve knowledge about care for women with disabilities and to strengthen communication skills. All necessary information needs to be prepared and provided in an adequate manner. The establishment of a health-promoting environment for mothers, their children and their families requires a sensitive, respectful and non judgmental attitude of society toward women with disabilities during pregnancy, childbirth and the puerperium. PMID- 28651565 TI - Prokinetics for the treatment of functional dyspepsia: Bayesian network meta analysis. AB - BACKGROUND: Controversies persist regarding the effect of prokinetics for the treatment of functional dyspepsia (FD). This study aimed to assess the comparative efficacy of prokinetic agents for the treatment of FD. METHODS: Randomized controlled trials (RCTs) of prokinetics for the treatment of FD were identified from core databases. Symptom response rates were extracted and analyzed using odds ratios (ORs). A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method in WinBUGS and NetMetaXL. RESULTS: In total, 25 RCTs, which included 4473 patients with FD who were treated with 6 different prokinetics or placebo, were identified and analyzed. Metoclopramide showed the best surface under the cumulative ranking curve (SUCRA) probability (92.5%), followed by trimebutine (74.5%) and mosapride (63.3%). However, the therapeutic efficacy of metoclopramide was not significantly different from that of trimebutine (OR:1.32, 95% credible interval: 0.27-6.06), mosapride (OR: 1.99, 95% credible interval: 0.87-4.72), or domperidone (OR: 2.04, 95% credible interval: 0.92-4.60). Metoclopramide showed better efficacy than itopride (OR: 2.79, 95% credible interval: 1.29-6.21) and acotiamide (OR: 3.07, 95% credible interval: 1.43-6.75). Domperidone (SUCRA probability 62.9%) showed better efficacy than itopride (OR: 1.37, 95% credible interval: 1.07-1.77) and acotiamide (OR: 1.51, 95% credible interval: 1.04-2.18). CONCLUSIONS: Metoclopramide, trimebutine, mosapride, and domperidone showed better efficacy for the treatment of FD than itopride or acotiamide. Considering the adverse events related to metoclopramide or domperidone, the short-term use of these agents or the alternative use of trimebutine or mosapride could be recommended for the symptomatic relief of FD. PMID- 28651566 TI - Arginine kinase from Haemonchus contortus decreased the proliferation and increased the apoptosis of goat PBMCs in vitro. AB - BACKGROUND: Arginine kinase (AK), an important member of phosphagen kinase family has been extensively studied in various vertebrates and invertebrates. Immunologically, AKs are important constituents of different body parts, involved in various biological and cellular functions, and considered as immune-modulator and effector for pro-inflammatory cytokines. However, immunoregulatory changes of host cells triggered by AK protein of Haemonchus contortus, a parasitic nematode of ruminants, are still unknown. The current study was focused on cloning and characterisation of Hc-AK, and its regulatory effects on cytokines level, cell migration, cell proliferation, nitric oxide production and apoptosis of goat peripheral blood mononuclear cells (PBMCs) were observed. METHODS: The full length sequence of the Hc-AK gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) and sub-cloned into the prokaryotic expression vector pET-32a. The biochemical characteristics of recombinant protein Hc-AK, which was purified by affinity chromatography, were performed based on the enzymatic assay. Binding of rHc-AK with PBMCs was confirmed by immunofluorescence assay (IFA). Immunohistochemical analysis was used to detect localisation of Hc AK within adult worms sections. The immunoregulatory effects of rHc-AK on cytokine secretions, cell proliferation, cell migration, nitric oxide production and apoptosis were determined by co-incubation of rHc-AK with goat PBMCs. RESULTS: The full-length ORF (1080 bp) of the Hc-AK gene was successfully cloned, and His-tagged AK protein was expressed in the Escherichia coli strain BL21. The recombinant protein of Hc-AK (rHc-AK) was about 58.5 kDa together with the fused vector protein of 18 kDa. The biochemical assay showed that the protein encoded by the Hc-ak exhibited enzymatic activity. Western blot analysis confirmed that the rHc-AK was recognised by the sera from rat (rat-antiHc-AK). The IFA results showed that rHc-AK could bind on the surface of goat PBMCs. Immunohistochemically, Hc-AK was localised at the inner and outer membrane as well as in the gut region of adult worms. The binding of rHc-AK to host cells increased the levels of IL-4, IL-10, IL-17, IFN-gamma, nitric oxide (NO) production and cell apoptosis of goat PBMCs, whereas, TGF-beta1 levels, cell proliferation and PBMCs migration were significantly decreased in a dose dependent manner. CONCLUSIONS: Our findings suggested that rHc-AK is an important excretory and secretory (ES) protein involved in host immune responses and exhibit distinct immunomodulatory properties during interaction with goat PBMCs. PMID- 28651567 TI - Benefits and harms of prostate cancer screening - predictions of the ONCOTYROL prostate cancer outcome and policy model. AB - BACKGROUND: A recent recalibration of the ONCOTYROL Prostate Cancer Outcome and Policy (PCOP) Model, assuming that latent prostate cancer (PCa) detectable at autopsy might be detectable by screening as well, resulted in considerable worsening of the benefit-harm balance of screening. In this study, we used the recalibrated model to assess the effects of familial risk, quality of life (QoL) preferences, age, and active surveillance. METHODS: Men with average and elevated familial PCa risk were simulated in separate models, differing in familial risk parameters. Familial risk was assumed to affect PCa onset and progression simultaneously in the base-case, and separately in scenario analyses. Evaluated screening strategies included one-time screening at different ages, and screening at different intervals and age ranges. Optimal screening strategies were identified depending on age and individual QoL preferences. Strategies were additionally evaluated with active surveillance by biennial re-biopsy delaying treatment of localized cancer until grade progression to Gleason score >= 7. RESULTS: Screening men with average PCa risk reduced quality-adjusted life expectancy (QALE) even under favorable assumptions. Men with elevated familial risk, depending on age and disutilities, gained QALE. While for men with familial risk aged 55 and 60 years annual screening to age 69 was the optimal strategy over most disutility ranges, no screening was the preferred option for 65 year old men with average and above disutilities. Active surveillance greatly reduced overtreatment, but QALE gains by averted adverse events were opposed by losses due to delayed treatment and additional biopsies. The effect of active surveillance on the benefit-harm balance of screening differed between populations, as net losses and gains in QALE predicted for screening without active surveillance in men with average and familial PCa risk, respectively, were both reduced. CONCLUSIONS: Assumptions about PCa risk and screen-detectable prevalence significantly affect the benefit-harm balance of screening. Based on the assumptions of our model, PCa screening should focus on candidates with familial predisposition with consideration of individual QoL preferences and age. Active surveillance may require treatment initiation before Gleason score progression to 7. Alternative active surveillance strategies should be evaluated in further modeling studies. PMID- 28651569 TI - ReTrOS: a MATLAB toolbox for reconstructing transcriptional activity from gene and protein expression data. AB - BACKGROUND: Given the development of high-throughput experimental techniques, an increasing number of whole genome transcription profiling time series data sets, with good temporal resolution, are becoming available to researchers. The ReTrOS toolbox (Reconstructing Transcription Open Software) provides MATLAB-based implementations of two related methods, namely ReTrOS-Smooth and ReTrOS-Switch, for reconstructing the temporal transcriptional activity profile of a gene from given mRNA expression time series or protein reporter time series. The methods are based on fitting a differential equation model incorporating the processes of transcription, translation and degradation. RESULTS: The toolbox provides a framework for model fitting along with statistical analyses of the model with a graphical interface and model visualisation. We highlight several applications of the toolbox, including the reconstruction of the temporal cascade of transcriptional activity inferred from mRNA expression data and protein reporter data in the core circadian clock in Arabidopsis thaliana, and how such reconstructed transcription profiles can be used to study the effects of different cell lines and conditions. CONCLUSIONS: The ReTrOS toolbox allows users to analyse gene and/or protein expression time series where, with appropriate formulation of prior information about a minimum of kinetic parameters, in particular rates of degradation, users are able to infer timings of changes in transcriptional activity. Data from any organism and obtained from a range of technologies can be used as input due to the flexible and generic nature of the model and implementation. The output from this software provides a useful analysis of time series data and can be incorporated into further modelling approaches or in hypothesis generation. PMID- 28651568 TI - Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III. AB - BACKGROUND: Mucopolysaccharidosis type III is a progressive, neurodegenerative lysosomal storage disorder for which there is currently no effective therapy. Though numerous potential therapies are in development, there are several challenges to conducting clinical research in this area. We seek to make recommendations on the approach to clinical research in MPS III, including the selection of outcome measures and trial endpoints, in order to improve the quality and impact of research in this area. RESULTS: An international workshop involving academic researchers, clinical experts and industry groups was held in June 2015, with presentations and discussions on disease pathophysiology, biomarkers, potential therapies and clinical outcome measures. A set of recommendations was subsequently prepared by a working group and reviewed by all delegates. We present a series of 11 recommendations regarding the conduct of clinical research, outcome measures and management of natural history data in Mucopolysaccharidosis type III. CONCLUSIONS: Improving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry. Natural history data should be published as soon as possible and ideally collated in a central repository. There should be agreement on outcome measures and instruments for evaluation of clinical outcomes to maximise the effectiveness of current and future clinical research. PMID- 28651570 TI - Methanol leaves extract Hibiscus micranthus Linn exhibited antibacterial and wound healing activities. AB - BACKGROUND: Infectious diseases are the most common causes of morbidity and mortality in developing countries. Wound and wound infections are also major health problem. Nowadays, medicinal plants play a major role in treatment of infectious diseases and wound healing and they are easily available and more affordable as compared to synthetic compounds. The aim of this study is therefore, to investigate the antibacterial and wound healing activities of 80% methanol extract of Hibiscus micranthus leaves using disc diffusion methods and rat excision model respectively. METHODS: In vitro antibacterial screening was carried out against S. aureus, S.pneumoniae, S. pyogenes, E. coli, P. aeruginosa, K. pneumoniae and P. mirabilis bacterial strains using disc-well diffusion assay. Would healing activity was done in rats divided into four groups each consisting of six animals. Group I was served as a negative control (ointment base), Group II served as a positive control Nitrofurazone (NFZ 0.2% ointment), Groups III and IV was treated 5 and 10% extracts respectively. The acute oral toxicity test and skin sensitivity test were also performed before conducting the actual study. The extract was analyzed for secondary metabolites using standard methods. RESULTS: Preliminary phytochemical screening have revealed the presence of alkaloids, flavonoids, saponins, tannins, steroids, phenols, diterpines, anthraquinones and the absence of glycosides, terpinoides and triterpines. Based on acute oral toxicity test the extract was found to be safe up to a dose of 2 g/kg. In addition, acute dermal toxicity test indicated no sign of skin irritation. The leaves extract exhibited varying degrees of sensitivity with zones of inhibition ranging from 14.00 +/- 0.333 (S.pyogenes) to 22.67 +/- 1.202 mm (S.aureus). It was found that S. aureus and S. pneumonia (p < 0.05) were the most sensitive to the extracts of the leaves at concentrations of 800 MUg/ml and 400 MUg/ml respectively followed by P. aeuruginosa [(18.33 +/- .333 mm) (p < 0.05)] at a concentration of 400 MUg/ml. However, E. coli and P. mirabilis were found to be resistant to the extract at any of the applied doses. In the wound healing study, the 5 and 10% w/w extract exhibited significant wound contraction rate of 99.30% and 99.13% as compared to NFZ ointment and simple ointment base treated groups from 6th to 16th day, respectively (p < 0.05). CONCLUSION: The present study suggests that the methanol extract of the leaves exhibited a potential antibacterial activity against the tested microorganisms and wound healing activity. PMID- 28651571 TI - Expression and phylogenetic analyses reveal paralogous lineages of putatively classical and non-classical MHC-I genes in three sparrow species (Passer). AB - BACKGROUND: The Major Histocompatibility Complex (MHC) plays a central role in immunity and has been given considerable attention by evolutionary ecologists due to its associations with fitness-related traits. Songbirds have unusually high numbers of MHC class I (MHC-I) genes, but it is not known whether all are expressed and equally important for immune function. Classical MHC-I genes are highly expressed, polymorphic and present peptides to T-cells whereas non classical MHC-I genes have lower expression, are more monomorphic and do not present peptides to T-cells. To get a better understanding of the highly duplicated MHC genes in songbirds, we studied gene expression in a phylogenetic framework in three species of sparrows (house sparrow, tree sparrow and Spanish sparrow), using high-throughput sequencing. We hypothesize that sparrows could have classical and non-classical genes, as previously indicated though never tested using gene expression. RESULTS: The phylogenetic analyses reveal two distinct types of MHC-I alleles among the three sparrow species, one with high and one with low level of polymorphism, thus resembling classical and non classical genes, respectively. All individuals had both types of alleles, but there was copy number variation both within and among the sparrow species. However, the number of highly polymorphic alleles that were expressed did not vary between species, suggesting that the structural genomic variation is counterbalanced by conserved gene expression. Overall, 50% of the MHC-I alleles were expressed in sparrows. Expression of the highly polymorphic alleles was very variable, whereas the alleles with low polymorphism had uniformly low expression. Interestingly, within an individual only one or two alleles from the polymorphic genes were highly expressed, indicating that only a single copy of these is highly expressed. CONCLUSIONS: Taken together, the phylogenetic reconstruction and the analyses of expression suggest that sparrows have both classical and non classical MHC-I genes, and that the evolutionary origin of these genes predate the split of the three investigated sparrow species 7 million years ago. Because only the classical MHC-I genes are involved in antigen presentation, the function of different MHC-I genes should be considered in future ecological and evolutionary studies of MHC-I in sparrows and other songbirds. PMID- 28651572 TI - Efficacy of a seal-wing paclitaxel-eluting balloon catheters in the treatment of bare metal stent restenosis. AB - BACKGROUND: Our study aimed to compare the efficacy of seal-wing paclitaxel eluting balloon catheters (PEB) with iopromide-coated PEB and everolimus-eluting stents (EES) for treating bare metal stent restenosis (BMS-ISR). METHODS: We enrolled 64 patients with 69 BMS-ISR. The control group comprised patients from the iopromide-PEB and EES arms of a previous TIS study. The primary end-point was 12-month in-segment late lumen loss (LLL). Secondary end-points included incidence of binary in-stent restenosis and 12-month major adverse cardiac events (MACE). RESULTS: Compared to iopromide-coated PEB, seal-wing PEB was associated with significantly higher 12-month LLL (0.30 vs. 0.02 mm; p < 0.0001), repeated binary restenosis (28.12% vs. 8.7%; p = 0.012), 12-month MACE (26.98% vs. 10.29%; p = 0.003), and target vessel revascularization (TVR; 20.63% vs. 7.35%; p = 0.009). Compared to EES, no significant differences were found in the 12-month LLL (0.30 vs. 0.19 mm; p = 1.000), repeated binary restenosis (28.12% vs. 19.12%; p = 0.666), 12-month MACE (26.98% vs. 19.12%; p = 0.102) or TVR (20.63% vs. 16.18%; p = 0.360). CONCLUSION: BMS-ISR treatment using seal-wing PEB led to significantly higher 12-month LLL, repeated binary restenosis, MACE, and TVR compared to iopromide-coated PEB. However, no significant differences were found in comparison with EES. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01735825. PMID- 28651573 TI - Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to be effective in controlling peri-operative pain in dogs. Robenacoxib is an NSAID with high selectivity for the cyclooxygenase (COX)-2 isoform. The objective of this study was to assess the efficacy and safety of an oral tablet formulation of robenacoxib in client-owned dogs undergoing soft tissue surgery. The study was a prospective, multi-center, randomized, masked, placebo-controlled, parallel-group clinical trial. A total of 239 dogs were included and randomly allocated in a 1:1 ratio to receive either robenacoxib or placebo. Each dog received an oral tablet administration of either robenacoxib, at a target dose of 2 mg/kg, or placebo once prior to surgery and for two additional days post-operatively. All dogs also received a pre-anesthetic dose of 0.2 mg/kg butorphanol (intravenous or intramuscular). Pain assessments were performed using the short form of the Glasgow Composite Measure Pain Scale. Robenacoxib was compared to the placebo group on a success/failure basis. Treatment failure was defined as the need for rescue therapy to control post-operative pain. RESULTS: Significantly (P = 0.019) more dogs administered robenacoxib were considered treatment successes (89 of 116, 76.72%) compared to dogs given placebo (74 of 115, 64.35%). The percentage of treatment failure was therefore 23.28% in the robenacoxib and 35.65% in the placebo group. The least squares mean total pain scores were significantly different between groups and in favor of robenacoxib at 3 and 5 hours (P < 0.05) and 8 hours post-extubation (P < 0.01). Pain at the surgery sites (response to touch) was also significantly improved at 3, 5 and 8 hours post-extubation in dogs receiving robenacoxib versus placebo (P < 0.01). In addition, a significant overall improvement in posture/activity was revealed with robenacoxib having lower scores versus placebo (P < 0.01). No significant differences between the robenacoxib and placebo groups in the frequency of reported adverse events were observed. CONCLUSIONS: Robenacoxib by oral (tablet) administration was effective and well tolerated in the control of peri-operative pain and inflammation associated with soft tissue surgery in dogs. PMID- 28651574 TI - Implementation of a human papillomavirus vaccination demonstration project in Malawi: successes and challenges. AB - BACKGROUND: Cervical cancer is a major public health problem in Malawi. The age standardized incidence and mortality rates are estimated to be 75.9 and 49.8 per 100,000 population, respectively. The availability of the human papillomavirus (HPV) vaccine presents an opportunity to reduce the morbidity and mortality associated with cervical cancer. In 2013, the country introduced a school-class based HPV vaccination pilot project in two districts. The aim of this study was to evaluate HPV vaccine coverage, lessons learnt and challenges identified during the first three years of implementation. METHODS: This was an evaluation of the HPV vaccination project targeting adolescent girls aged 9-13 years conducted in Malawi from 2013 to 2016. We analysed programme data, supportive supervision reports and minutes of National HPV Task Force meetings to determine HPV vaccine coverage, reasons for partial or no vaccination and challenges. Administrative coverage was validated using a community-based coverage survey. RESULTS: A total of 26,766 in-school adolescent girls were fully vaccinated in the two pilot districts during the first three years of the programme. Of these; 2051 (7.7%) were under the age of 9 years, 884 (3.3%) were over the age of 13 years, and 23,831 (89.0%) were aged 9-13 years (the recommended age group). Of the 765 out of-school adolescent girls aged 9-13 who were identified during the period, only 403 (52.7%) were fully vaccinated. In Zomba district, the coverage rates of fully vaccinated were 84.7%, 87.6% and 83.3% in year 1, year 2 and year 3 of the project, respectively. The overall coverage for the first three years was 82.7%, and the dropout rate was 7.7%. In Rumphi district, the rates of fully vaccinated coverage were 90.2% and 96.2% in year 1 and year 2, respectively, while the overall coverage was 91.3%, and the dropout rate was 4.9%. Administrative (facility-based) coverage for the first year was validated using a community based cluster coverage survey. The majority of the coverage results were statistically similar, except for in Rumphi district, where community-based 3 dose coverage was higher than the corresponding administrative-coverage (94.2% vs 90.2%, p < 0.05), and overall (in both districts), facility-based 1-dose coverage was higher than the corresponding community-based (94.6% vs 92.6%, p < 0.05). Transferring out of the district, dropping out of school and refusal were some of the reasons for partial or no uptake of the vaccine. CONCLUSION: In Malawi, the implementation of a school-class-based HPV vaccination strategy was feasible and produced high (>80%) coverage. However, this strategy may be associated with the vaccination of under- and over-aged adolescent girls who are outside of the vaccine manufacturer's stipulated age group (9-13 years). The health facility based coverage for out-of-school adolescent girls produced low coverage, with only half of the target population being fully vaccinated. These findings highlight the need to assess the immunogenicity associated with the administration of a two-dose schedule to adolescent girls younger or older than 9 13 years and effectiveness of health facility-based strategy before rolling out the programme. PMID- 28651575 TI - Ontological interpretation of biomedical database content. AB - BACKGROUND: Biological databases store data about laboratory experiments, together with semantic annotations, in order to support data aggregation and retrieval. The exact meaning of such annotations in the context of a database record is often ambiguous. We address this problem by grounding implicit and explicit database content in a formal-ontological framework. METHODS: By using a typical extract from the databases UniProt and Ensembl, annotated with content from GO, PR, ChEBI and NCBI Taxonomy, we created four ontological models (in OWL), which generate explicit, distinct interpretations under the BioTopLite2 (BTL2) upper-level ontology. The first three models interpret database entries as individuals (IND), defined classes (SUBC), and classes with dispositions (DISP), respectively; the fourth model (HYBR) is a combination of SUBC and DISP. For the evaluation of these four models, we consider (i) database content retrieval, using ontologies as query vocabulary; (ii) information completeness; and, (iii) DL complexity and decidability. The models were tested under these criteria against four competency questions (CQs). RESULTS: IND does not raise any ontological claim, besides asserting the existence of sample individuals and relations among them. Modelling patterns have to be created for each type of annotation referent. SUBC is interpreted regarding maximally fine-grained defined subclasses under the classes referred to by the data. DISP attempts to extract truly ontological statements from the database records, claiming the existence of dispositions. HYBR is a hybrid of SUBC and DISP and is more parsimonious regarding expressiveness and query answering complexity. For each of the four models, the four CQs were submitted as DL queries. This shows the ability to retrieve individuals with IND, and classes in SUBC and HYBR. DISP does not retrieve anything because the axioms with disposition are embedded in General Class Inclusion (GCI) statements. CONCLUSION: Ambiguity of biological database content is addressed by a method that identifies implicit knowledge behind semantic annotations in biological databases and grounds it in an expressive upper-level ontology. The result is a seamless representation of database structure, content and annotations as OWL models. PMID- 28651577 TI - Organelle acidification: an ancient cellular leak detector. AB - Intracellular membrane-bounded organelles of eukaryotic cells transiently contact the extracellular environment during endocytosis and secretion. Such contacts must be precisely timed to prevent leakage of cargo. I argue that early eukaryotes evolved organelle acidification as a way to detect and prevent leakage. PMID- 28651576 TI - Decreased T helper 17 cells in tuberculosis is associated with increased percentages of programmed death ligand 1, T helper 2 and regulatory T cells. AB - BACKGROUND: Tuberculosis (TB) is one of the most common infectious diseases worldwide. During active tuberculosis, T helper (Th) 17 cells are decreased, however the association with inhibitory immune regulation is unclear. METHODS: We enrolled 27 patients with TB and 20 age- and sex-matched controls and studies their lymphocyte status. Peripheral blood lymphocytes were isolated and programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) were measured on Th17 cells by using flow cytometry after the cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 6 h. In addition, Th2 and regulatory T cells were measured and analyzed. RESULTS: The TB group had lower levels of Th17 cells but higher levels of Th2 and Treg cells than the controls. In Th17 cells, the percentage of PD-L1 was higher in the TB group than that in the controls. In Th2 and Treg cells, the percentage of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) was lower in the TB group and PD-1 was higher in Treg cells in the TB group. In the patients with extra-pulmonary TB, levels of Th1, Th2 and T17 cells were lower than those with pulmonary TB. The percentage of PD-1 on Th1 lymphocytes positively correlated with radiographic score. CONCLUSIONS: Lower level of Th17 in TB patients may be associated with increased percentage of PD-L1 and increasing levels of Th2 and Treg cells which influenced by CTLA-4. PMID- 28651578 TI - Characterization of phytoconstituents and evaluation of antimicrobial activity of silver-extract nanoparticles synthesized from Momordica charantia fruit extract. AB - BACKGROUND: Our present study was conducted to characterize the phytoconstituents present in the aqueous extract of Momordica charantia and evaluate the antimicrobial efficacy of silver-extract nanoparticles (Ag-Extract-NPs). METHODS: Silver nanoparticles (AgNPs) were prepared by reducing AgNO3; and NaBH4 served as reducing agent. After screening of phytochemicals; AgNPs and aqueous extract were mixed thoroughly and then coated by polyaniline. These NPs were characterized by using Visual inspection, UV spectroscopy, FTIR, SEM and TEM techniques. Antimicrobial activities were assessed against Staphylococcus aureus, Salmonella typhi, Escherichia coli and Pseudomonas aeruginosa. RESULTS: Aqueous extract of M. charantia fruits contain alkaloid, phenol, saponin etc. UV-Vis spectrum showed strong absorption peak around 408 nm. The presence of -CH, -NH, -COOH etc. stretching in FTIR spectrum of Ag-Extract-NPs endorsed that AgNPs were successfully capped by bio-compounds. SEM and TEM result revealed that synthesized NPs had particle size 78.5-220 nm. Ag-Extract-NPs showed 34.6 +/- 0.8 mm zone of inhibition against E. coli compared to 25.6 +/- 0.5 mm for ciprofloxacin. Maximum zone of inhibition for Ag-Extract-NPs were 24.8 +/- 0.7 mm, 26.4 +/- 0.4 mm, 7.4 +/- 0.4 mm for S. aureus, P. aeruginosa and S. typhi. We found that Ag-Extract-NPs have much better antibacterial efficacy than AgNPs and M. charantia extract has individually. It is also noticed that gram negative bacteria (except S. typhi) are more susceptible to Ag-Extract-NPs than gram positive bacteria. CONCLUSION: Ag-Extract-NPs showed strong antibacterial activity. In order to make a reliable stand for mankind, further study is needed to consider determining the actual biochemical pathway by which AgNPs-extracts exert their antimicrobial effect. PMID- 28651579 TI - Total knee arthroplasty with corrective osteotomy for knee osteoarthritis associated with malunion after tibial plateau fracture: a case report. AB - BACKGROUND: When surgeons perform total knee arthroplasty in patients with knee osteoarthritis due to malunion following fractures around the knee joint, corrective osteotomy is recommended for severe deformities. Most such deformities are coronal plane varus or valgus deformities, and reports of sagittal plane flexion or extension deformities are rare. We describe a case in which a one stage total knee arthroplasty was performed with extension corrective osteotomy in the sagittal plane. CASE PRESENTATION: A 71-year-old Japanese man presented with left knee pain. He had knee osteoarthritis associated with malunion after a tibial plateau fracture. Plain radiography showed a varus deformity in the coronal plane and a marked flexion deformity in the sagittal plane. We performed total knee arthroplasty concurrently with extension corrective osteotomy using a long stem. Full weight bearing was permitted at 6 weeks postoperatively, and the patient was able to walk without assistance. CONCLUSIONS: This surgical method appears to be beneficial for shortening the duration of treatment and improving knee function. PMID- 28651581 TI - Patients' satisfaction towards radiological service and associated factors in Hawassa University Teaching and referral hospital, Southern Ethiopia. AB - BACKGROUND: Patient satisfaction, one of the main components of quality of care, is a crucial phenomenon for the overall health care delivery system. Even though a number of studies have been conducted about patient satisfaction in different health services, studies in radiology services are flimsy in Ethiopia. This study aimed at assessing patient satisfaction towards radiological service and associated factors in Hawassa University Teaching and Referral hospital. METHODS: An institution based cross-sectional study was conducted among 321 adult patients presented for radiological service in the study area using stratified sampling technique. Patient satisfaction was measured using SERVQUAL (Service Quality) tool that consisted of seven items: accessibility, quality of radiological service, courtesy of radiology staff, existence of good communication with service provider and desk worker, physical environment and privacy technique. Exit interviews of patients were conducted using a structured and pretested questionnaire. Data was collected by three grade ten completed trained data collectors from May 12 to May 28, 2016. Multiple logistic regressions were used to identify independent factors associated with patient satisfaction on radiological services using SPSS version 21. RESULTS: The overall patient satisfaction towards radiological service was 71.6%. Satisfaction to accessibility of the service was 84.5% while it was 80.6% to courtesy of the staff. Similarly, 81.6% reported satisfied with quality of the service and 59.4% and 71% of reported satisfied with physical environment and radiological service provider respectively. On the other hand, 99.7% of the respondents were dissatisfied with privacy of the service. The study revealed that patients who attended primary school (AOR = 0.317, 95% CI: 0.11-0.88), unemployed patients (AOR = 0.067, 95% CI: 0.007-0.622) and patients who had short waiting time to enter into examination room less than one hour (AOR = 4.12, 95% CI: 1.4-11.62) were factors associated with patients satisfaction. CONCLUSION: This study found that majority of respondents was satisfied with the radiological services. Respondent's education level, occupation as well as duration of time taken to enter into examination room were important factors influencing the satisfaction condition. Hence, concerted effort is needed to constantly improve on patient satisfaction to better radiology returns arising from improved patient patronage. It is recommended to give great care and attention to clients during radiological examination procedure and also suggested that the department should decrease time taken to enter into examination room. On the other hand, the reasons behind more educated clients were less satisfied with radiologic service than more educated respondents need further investigation. PMID- 28651580 TI - Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero. AB - BACKGROUND: An increasing number of epidemiological and experimental studies have associated exposure to second-hand smoke (SHS) during pregnancy with adverse outcomes in newborns. As we have previously shown in mice, in utero exposure to SHS at critical stages of fetal development, results in altered lung responses and increased disease susceptibility upon re-exposure to irritants (SHS or ovalbumin) in adulthood. In this study, we asked whether the in utero SHS exposure alone is sufficient to alter lung structure and function in adult mice. METHODS: Pregnant BALB/c mice were exposed from days 6 to 19 of pregnancy to 10 mg/m3 of SHS or HEPA-filtered air. Male and female offspring (n = 13-15/group) were sacrificed at 15 weeks of age. We measured lung function with non-invasive and invasive methods, performed lung morphometric analysis on trichrome-stained lung tissue samples, and assessed lung gene expression via RNA sequencing and protein assays. RESULTS: In utero SHS exposure significantly increased mean linear intercept and decreased the surface area per unit volume of the lungs in both males and females, indicating perturbation in alveolar developmental processes. Tidal volume, minute volume and inspiratory capacity were significantly decreased compared with the controls only in male mice exposed in utero to SHS, suggesting that males are more sensitive than females to an SHS insult during lung development. This also suggests that in our model, lung structure changes may be necessary but are not sufficient to impair lung function. SERPINA1A, the mouse ortholog of human alpha1-antitrypsin, deficiency of which is a known genetic risk factor for emphysema, was down-regulated at the protein level in the in utero SHS-exposed mice. Additionally, DNMT3A protein expression was dysregulated, indicating that DNA methylation occurred in the lungs. CONCLUSIONS: Our results indicate that in utero SHS exposure alone alters both lung function and structure well into adulthood (15 weeks) in male mice. Furthermore, lung function alterations in this model are sex-specific, with males being more susceptible to in utero SHS effects. Overall, our data suggest that in utero SHS exposure alone can predispose to adult lung diseases. PMID- 28651582 TI - Intra- and inter-isolate variation of ribosomal and protein-coding genes in Pleurotus: implications for molecular identification and phylogeny on fungal groups. AB - BACKGROUND: The internal transcribed spacer (ITS), RNA polymerase II second largest subunit (RPB2), and elongation factor 1-alpha (EF1alpha) are often used in fungal taxonomy and phylogenetic analysis. As we know, an ideal molecular marker used in molecular identification and phylogenetic studies is homogeneous within species, and interspecific variation exceeds intraspecific variation. However, during our process of performing ITS, RPB2, and EF1alpha sequencing on the Pleurotus spp., we found that intra-isolate sequence polymorphism might be present in these genes because direct sequencing of PCR products failed in some isolates. Therefore, we detected intra- and inter-isolate variation of the three genes in Pleurotus by polymerase chain reaction amplification and cloning in this study. RESULTS: Results showed that intra-isolate variation of ITS was not uncommon but the polymorphic level in each isolate was relatively low in Pleurotus; intra-isolate variations of EF1alpha and RPB2 sequences were present in an unexpectedly high amount. The polymorphism level differed significantly between ITS, RPB2, and EF1alpha in the same individual, and the intra-isolate heterogeneity level of each gene varied between isolates within the same species. Intra-isolate and intraspecific variation of ITS in the tested isolates was less than interspecific variation, and intra-isolate and intraspecific variation of RPB2 was probably equal with interspecific divergence. Meanwhile, intra-isolate and intraspecific variation of EF1alpha could exceed interspecific divergence. These findings suggested that RPB2 and EF1alpha are not desirable barcoding candidates for Pleurotus. We also discussed the reason why rDNA and protein coding genes showed variants within a single isolate in Pleurotus, but must be addressed in further research. CONCLUSIONS: Our study demonstrated that intra isolate variation of ribosomal and protein-coding genes are likely widespread in fungi. This has implications for studies on fungal evolution, taxonomy, phylogenetics, and population genetics. More extensive sampling of these genes and other candidates will be required to ensure reliability as phylogenetic markers and DNA barcodes. PMID- 28651583 TI - Challenges and potential improvements in the admission process of patients with spinal cord injury in a specialized rehabilitation clinic - an interview based qualitative study of an interdisciplinary team. AB - BACKGROUND: The admission process of patients to a hospital is the starting point for inpatient services. In order to optimize the quality of the health services provision, one needs a good understanding of the patient admission workflow in a clinic. The aim of this study was to identify challenges and potential improvements in the admission process of spinal cord injury patients at a specialized rehabilitation clinic from the perspective of an interdisciplinary team of health professionals. METHODS: Semi-structured interviews with eight health professionals (medical doctors, physical therapists, occupational therapists, nurses) at the Swiss Paraplegic Centre (acute and rehabilitation clinic) were conducted based on a maximum variety purposive sampling strategy. The interviews were analyzed using a thematic analysis approach. RESULTS: The interviewees described the challenges and potential improvements in this admission process, focusing on five themes. First, the characteristics of the patient with his/her health condition and personality and his/her family influence different areas in the admission process. Improvements in the exchange of information between the hospital and the patient could speed up and simplify the admission process. In addition, challenges and potential improvements were found concerning the rehabilitation planning, the organization of the admission process and the interdisciplinary work. CONCLUSION: This study identified five themes of challenges and potential improvements in the admission process of spinal cord injury patients at a specialized rehabilitation clinic. When planning adaptations of process steps in one of the areas, awareness of effects in other fields is necessary. Improved pre-admission information would be a first important step to optimize the admission process. A common IT-system providing an interdisciplinary overview and possibilities for interdisciplinary exchange would support the management of the admission process. Managers of other hospitals can supplement the results of this study with their own process analyses, to improve their own patient admission processes. PMID- 28651584 TI - Gender and social mobility modify the effect of birth weight on total and central obesity. AB - BACKGROUND: Little is known about the interaction between gender and low birth weight (LBW) and lifelong social mobility as an explanation of the etiology of obesity. The aim of the present study was to evaluate total and central obesity according to gender, LBW and social mobility, within the context of the epidemiological transition in middle-income countries. We hypothesize that there are more pronounced metabolic consequences of social mobility for women born with LBW. METHODS: We used data from a birth cohort study conducted in Ribeirao Preto, Sao Paulo, Brazil. Data regarding anthropometric measurements, schooling and smoking status were collected at 23-25 years of age. Social mobility was determined based on maternal and adult offspring schooling and categorized as Low Low, Low-High and High-High. Analysis of covariance was performed to assess the association between social mobility and body mass index (BMI) or waist circumference (WC) in adulthood, stratified by LBW and gender. RESULTS: Data on 6827 singleton pregnancies were collected at birth in 1978/79 and a sample was followed up in 2002/04. A total of 2063 subjects were included in the study. Mean age was 23.9 +/- 0.7 years, 51.8% (n = 1068) were female and the LBW was 6.2% (n = 128). There was a triple interaction between social mobility, LBW and gender. Among women born without LBW, BMI and WC were higher in the Low-Low group compared to High-High schooling group. Among LBW women, BMI and WC were higher in the Low-Low group compared to the Low-High group. CONCLUSIONS: Women born with LBW belonging to the low schooling group in early adulthood had high BMI and WC, compared to the Low-High social mobility group. PMID- 28651585 TI - A vessel length-based method to compute coronary fractional flow reserve from optical coherence tomography images. AB - BACKGROUND: Hemodynamic simulation for quantifying fractional flow reserve (FFR) is often performed in a patient-specific geometry of coronary arteries reconstructed from the images from various imaging modalities. Because optical coherence tomography (OCT) images can provide more precise vascular lumen geometry, regardless of stenotic severity, hemodynamic simulation based on OCT images may be effective. The aim of this study is to perform OCT-FFR simulations by coupling a 3D CFD model from geometrically correct OCT images with a LPM based on vessel lengths extracted from CAG data with clinical validations for the present method. METHODS: To simulate coronary hemodynamics, we developed a fast and accurate method that combined a computational fluid dynamics (CFD) model of an OCT-based region of interest (ROI) with a lumped parameter model (LPM) of the coronary microvasculature and veins. Here, the LPM was based on vessel lengths extracted from coronary X-ray angiography (CAG) images. Based on a vessel length based approach, we describe a theoretical formulation for the total resistance of the LPM from a three-dimensional (3D) CFD model of the ROI. RESULTS: To show the utility of this method, we present calculated examples of FFR from OCT images. To validate the OCT-based FFR calculation (OCT-FFR) clinically, we compared the computed OCT-FFR values for 17 vessels of 13 patients with clinically measured FFR (M-FFR) values. CONCLUSION: A novel formulation for the total resistance of LPM is introduced to accurately simulate a 3D CFD model of the ROI. The simulated FFR values compared well with clinically measured ones, showing the accuracy of the method. Moreover, the present method is fast in terms of computational time, enabling clinicians to provide solutions handled within the hospital. PMID- 28651587 TI - ACSC Indicator: testing reliability for hypertension. AB - BACKGROUND: With high-quality community-based primary care, hospitalizations for ambulatory care sensitive conditions (ACSC) are considered avoidable. The purpose of this study was to test the inter-physician reliability of judgments of avoidable hospitalizations for one ACSC, uncomplicated hypertension, derived from medical chart review. METHODS: We applied the Canadian Institute for Health Information's case definition to obtain a random sample of patients who had an ACSC hospitalization for uncomplicated hypertension in Calgary, Alberta. Medical chart review was conducted by three experienced internal medicine specialists. Implicit methods were used to judge avoidability of hospitalization using a validated 5-point scale. RESULTS: There was poor agreement among three physicians raters when judging the avoidability of 82 ACSC hospitalizations for uncomplicated hypertension (kappa = 0.092). The kappa also remained low when assessing agreement between raters 1 and 3 (kappa = 0.092), but the kappa was lower (less than chance agreement) for raters 1 and 2 (kappa = -0.119) and raters 2 and 3 (kappa = -0.008). When the 5-point scale was dichotomized, there was fair agreement among three raters (kappa = 0.217). The proportion of ACSC hospitalizations for uncomplicated hypertension that were rated as avoidable was 32.9%, 6.1% and 26.8% for raters 1, 2, and 3, respectively. CONCLUSIONS: This study found a low proportion of ACSC hospitalization were rated as avoidable, with poor to fair agreement of judgment between physician raters. This suggests that the validity and utility of this health indicator is questionable. It points to a need to abandon the use of ACSC entirely; or alternatively to work on the development of explicit criteria for judging avoidability of hospitalization for ACSC such as hypertension. PMID- 28651586 TI - Development of a computer-tailored physical activity intervention for prostate and colorectal cancer patients and survivors: OncoActive. AB - BACKGROUND: Cancer and cancer treatment coincide with substantial negative physical, psychological and psychosocial problems. Physical activity (PA) can positively affect the negative effects of cancer and cancer treatment and thereby increase quality of life in CPS. Nevertheless, only a minority of CPS meet PA guidelines. We developed the OncoActive (OncoActief in Dutch) intervention: a computer-tailored PA program to stimulate PA in prostate and colorectal CPS, because to our knowledge there are only a few PA interventions for these specific cancer types in the Netherlands METHODS: The OncoActive intervention was developed through systematic adaptation of a proven effective, evidence-based, computer-tailored PA intervention for adults over fifty, called Active Plus. The Intervention Mapping (IM) protocol was used to guide the systematic adaptation. A literature study and interviews with prostate and colorectal CPS and health care professionals revealed that both general and cancer-specific PA determinants are important and should be addressed. Change objectives, theoretical methods and applications and the actual program content were adapted to address the specific needs, beliefs and cancer-related issues of prostate and colorectal CPS. Intervention participants received tailored PA advice three times, on internet and with printed materials, and a pedometer to set goals to improve PA. Pre- and pilot tests showed that the intervention was highly appreciated (target group) and regarded safe and feasible (healthcare professionals). The effectiveness of the intervention is being evaluated in a randomized controlled trial (RCT) (n = 428), consisting of an intervention group and a usual care waiting-list control group, with follow-up measurements at three, six and twelve months. Participants are recruited from seventeen hospitals and with posters, flyers and calls in several media. DISCUSSION: Using the Intervention Mapping protocol resulted in a systematically adapted, theory and evidence-based intervention providing tailored PA advice to prostate and colorectal CPS. If the intervention turns out to be effective in increasing PA, as evaluated in a RCT, possibilities for nationwide implementation and extension to other cancer types will be explored. TRIAL REGISTRATION: The study is registered in the Dutch Trial Register (NTR4296) on November 23rd 2013 and can be accessed at http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4296 . PMID- 28651588 TI - Perceptions on use of home telemonitoring in patients with long term conditions - concordance with the Health Information Technology Acceptance Model: a qualitative collective case study. AB - BACKGROUND: Health information technology (HIT) may be used to improve care for increasing numbers of older people with long term conditions (LTCs) who make high demands on health and social care services. Despite its potential benefits for reducing disease exacerbations and hospitalisations, HIT home monitoring is not always accepted by patients. Using the Health Information Technology Acceptance Model (HITAM) this qualitative study examined the usefulness of the model for understanding acceptance of HIT in older people (>=60 years) participating in a RCT for older people with Chronic Obstructive Pulmonary Disease (COPD) and associated heart diseases (CHROMED). METHODS: An instrumental, collective case study design was used with qualitative interviews of patients in the intervention arm of CHROMED. These were conducted at two time points, one shortly after installation of equipment and again at the end of (or withdrawal from) the study. We used Framework Analysis to examine how well the HITAM accounted for the data. RESULTS: Participants included 21 patients aged between 60-99 years and their partners or relatives where applicable. Additional concepts for the HITAM for older people included: concerns regarding health professional access and attachment; heightened illness anxiety and desire to avoid continuation of the 'sick-role'. In the technology zone, HIT self-efficacy was associated with good organisational processes and informal support; while ease of use was connected to equipment design being suitable for older people. HIT perceived usefulness was related to establishing trends in health status, detecting early signs of infection and potential to self-manage. Due to limited feedback to users opportunities to self-manage were reduced. CONCLUSIONS: HITAM helped understand the likelihood that older people with LTCs would use HIT, but did not explain how this might result in improved self-management. In order to increase HIT acceptance among older people, equipment design and organisational factors need to be considered. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01960907 October 9 2013 (retrospectively registered) Clinical tRials fOr elderly patients with MultiplE Disease (CHROMED). Start date October 2012, end date March 2016. Date of enrolment of the first participant was February 2013. PMID- 28651590 TI - Effect of different incision sites of phacoemulsification on trabeculectomy bleb function: prospective case-control study. AB - BACKGROUND: The aim of this study was to compare superior and temporal clear corneal incisions of uneventful phacoemulsification and in-the-bag intraocular lens implantation on intraocular pressure control and the bleb morphology in eyes that have undergone previous successful trabeculectomy. METHODS: In this Prospective case-control study, a total of 100 eyes of 100 patients previously undergone trabeculectomy without antimetabolites, divided into two groups. Group A (temporal group) including 50 patients underwent phacoemulsification with a temporal corneal incision and group B (superior group) including 50 patients underwent phacoemulsification with a superior corneal incision. Comparisons between the two groups were performed after one year of follow-up regarding Intraocular pressure changes, bleb morphology score using the Wuerzburg bleb classification score and any added glaucoma medications. RESULTS: At the last visit, the mean intraocular pressure for the temporal group was 17.55 +/- 1.47 (p = 0.51) and for the superior group was 16.90 +/- 1.71 (p = 0.85); the difference between the two groups was insignificant (p = 0.21). Regarding the bleb morphology, the mean bleb morphology score in the temporal group was 10.50 +/- 0.95 (p = 0.19) and for the superior group was 10.20 +/- 1.06 (p = 0.01).There was an insignificant difference in the bleb grading morphology regarding both groups (p = 0.35). CONCLUSION: Our study demonstrates that phacoemulsification whether done with a clear temporal or clear superior wound, does not affect intraocular pressure, bleb morphology or function after one year of follow-up in eyes following previous successful trabeculectomy. Furthermore, cataract surgery may be performed safely in eyes with functioning filtering blebs. TRIAL REGISTRATION: ISRCTN91835217 'retrospectively registered' Date Of registration 6/6/2017. PMID- 28651589 TI - Behavioural activation by mental health nurses for late-life depression in primary care: a randomized controlled trial. AB - BACKGROUND: Depressive symptoms are common in older adults. The effectiveness of pharmacological treatments and the availability of psychological treatments in primary care are limited. A behavioural approach to depression treatment might be beneficial to many older adults but such care is still largely unavailable. Behavioural Activation (BA) protocols are less complicated and more easy to train than other psychological therapies, making them very suitable for delivery by less specialised therapists. The recent introduction of the mental health nurse in primary care centres in the Netherlands has created major opportunities for improving the accessibility of psychological treatments for late-life depression in primary care. BA may thus address the needs of older patients while improving treatment outcome and lowering costs.The primary objective of this study is to compare the effectiveness and cost-effectiveness of BA in comparison with treatment as usual (TAU) for late-life depression in Dutch primary care. A secondary goal is to explore several potential mechanisms of change, as well as predictors and moderators of treatment outcome of BA for late-life depression. METHODS/DESIGN: Cluster-randomised controlled multicentre trial with two parallel groups: a) behavioural activation, and b) treatment as usual, conducted in primary care centres with a follow-up of 52 weeks. The main inclusion criterion is a PHQ-9 score > 9. Patients are excluded from the trial in case of severe mental illness that requires specialized treatment, high suicide risk, drug and/or alcohol abuse, prior psychotherapy, change in dosage or type of prescribed antidepressants in the previous 12 weeks, or moderate to severe cognitive impairment. The intervention consists of 8 weekly 30-min BA sessions delivered by a trained mental health nurse. DISCUSSION: We expect BA to be an effective and cost-effective treatment for late-life depression compared to TAU. BA delivered by mental health nurses could increase the availability and accessibility of non pharmacological treatments for late-life depression in primary care. TRIAL REGISTRATION: This study is retrospectively registered in the Dutch Clinical Trial Register NTR6013 on August 25th 2016. PMID- 28651591 TI - The cost of systemic corticosteroid-induced morbidity in severe asthma: a health economic analysis. AB - BACKGROUND: Treatment of severe asthma may include high dose systemic-steroid therapy which is associated with substantial additional morbidity. This study estimates the additional healthcare costs associated with steroid-induced morbidity by comparing three patients groups: those with severe asthma, moderate asthma and no asthma. METHODS: Patients with severe asthma (n = 808, GINA step 5 treatment) were matched by age and gender with patients with mild/moderate asthma (n = 3,975, GINA step 2 and 3 treatment) and a non-asthma control cohort (with a diagnosis of rhinitis; n = 2,412) from the Optimum Patient Care Research Database (OPCRD), a nationally representative primary care database. Prescribed drugs and publicly funded healthcare activity were monetised and annual costs per patient estimated. Regression analyses were used to estimate the additional healthcare cost associated with steroid-induced morbidity. RESULTS: Average healthcare costs per person per year range from L2603 - L4533 for the severe asthma cohort, to L978 - L2072 for the mild/moderate asthma cohort, to L560 - L1324 for the non asthma control cohort, depending on the costing scenario. Differences in induced morbidity costs were evident between patients with asthma differentiated by steroid exposure. In relation to prescription drugs used to treat steroid-induced co-morbidities, females with severe asthma and high steroid exposure cost approximately L789 more per year than a corresponding female with no asthma, while males cost approximately L744 more than their counterparts with no asthma. Estimates were extrapolated to all healthcare costs. CONCLUSIONS: This study provides the first robust estimates of the additional cost of healthcare related to steroid-induced morbidity relative to patients with no steroid exposure. The study will help inform use of steroid-sparing strategies in this patient group. PMID- 28651592 TI - Anatomic comparison of veins of Labbe between autopsy, digital subtraction angiography and computed tomographic venography. AB - OBJECTIVE: The drainage portion of the vein of Labbe varies, and it is difficult to predict whether the operation is likely to damage this vein. The aim of this study was to correlate the microanatomy of the vein of Labbe with digital subtraction angiography (DSA) and computed tomographic venography (CTV), in order to provide a basis for the preservation of the vein of Labbe during a supratentorial surgical approach. METHODS: A total of 30 human cadavers (60 sides) and 61 living patients (110 sides) were examined in this study. Each cadaver head was injected with blue latex via the superior sagittal sinus and the internal jugular veins. The venograms of each patient were obtained from the venous phases of DSA (60 sides for 36 patients) or CTV (50 sides for 25 patients). RESULTS: The patients were divided into four subgroups based on the location where a vein entered the dural sinus: the transverse sinus group, the tentorial group, the petrosal group, and the upper-transverse sinus group. The veins of Labbe in transverse sinus group and petrosal group directly entered dural sinus. The veins of Labbe in tentorial group and upper-transverse sinus group indirectly entered transverse sinus via the tentorium sinus or the upper transverse sinus. These sinuses were meningeal veins running through two layers of the cerebral dura mater. The length of meningeal veins in these groups was 10.0 +/- 7.2 mm. The veins of Labbe were mainly localized around the STP junction, which was the confluence of sigmoid sinus, transverse sinus, and superior petrosal sinus. The distance between the dural entrance of veins and the STP junction was 16.8 +/- 10.2 mm. There was no significant difference in the results of the DSA and CTV examinations when compared to the observations in cadavers. CONCLUSIONS: Preoperative venograms are useful to design an individualized surgical approach for the preservation of the vein of Labbe. In general, the supratentorial median approach has the least chance to damage this vein. However, when preoperative venograms show that the vein of Labbe is too close to the confluence of sinuses or the meningeal veins are too long, an alternative approach should be chosen. PMID- 28651594 TI - The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study. AB - BACKGROUND: Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. RESULTS: We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGFbeta producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGFbeta in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro Th17 environment. CONCLUSIONS: This work provides a first step towards a system level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases. PMID- 28651593 TI - Maternal antibodies protect offspring from severe influenza infection and do not lead to detectable interference with subsequent offspring immunization. AB - BACKGROUND: Various studies have shown that infants under the age of 6 months are especially vulnerable for complications due to influenza. Currently there are no vaccines licensed for use in this age group. Vaccination of pregnant women during the last trimester, recommended by the WHO as protective measure for this vulnerable female population, may provide protection of newborns at this early age. Although it has been observed that maternal vaccination can passively transfer protection, maternal antibodies could possibly also interfere with subsequent active vaccination of the offspring. METHODS: Using a mouse model, we evaluated in depth the ability of maternal influenza vaccination to protect offspring and the effect of maternal immunization on the subsequent influenza vaccination of the offspring. By varying the regimen of maternal immunization we explored the impact of different levels of maternal antibodies on the longevity of these antibodies in their progeny. We subsequently assessed to what extent maternal antibodies can mediate direct protection against influenza in their offspring, and whether these antibodies interfere with protection induced by active vaccination of the offspring. RESULTS: The number of immunizations of pregnant mice correlates to the level and longevity of maternal antibodies in the offspring. When these antibodies are present at time of influenza challenge they protect offspring against lethal influenza challenge, even in the absence of detectable HAI titers. Moreover, no detectable interference of passively transferred maternal antibodies on the subsequent vaccination of the offspring was observed. CONCLUSION: In the absence of a licensed influenza vaccine for young children, vaccination of pregnant women is a promising measure to provide protection of young infants against severe influenza infection. PMID- 28651595 TI - Identification of pathogenic genes and upstream regulators in age-related macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in older individuals. Our study aims to identify the key genes and upstream regulators in AMD. METHODS: To screen pathogenic genes of AMD, an integrated analysis was performed by using the microarray datasets in AMD derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were further discovered by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We constructed the AMD-specific transcriptional regulatory network to find the crucial transcriptional factors (TFs) which target the DEGs in AMD. Quantitative real time polymerase chain reaction (qRT-PCR) was performed to verify the DEGs and TFs obtained by integrated analysis. RESULTS: From two GEO datasets obtained, we identified 1280 DEGs (730 up-regulated and 550 down-regulated genes) between AMD and normal control (NC). After KEGG analysis, steroid biosynthesis is a significantly enriched pathway for DEGs. The expression of 8 genes (TNC, GRP, TRAF6, ADAMTS5, GPX3, FAP, DHCR7 and FDFT1) was detected. Except for TNC and GPX3, the other 6 genes in qRT-PCR played the same pattern with that in our integrated analysis. CONCLUSIONS: The dysregulation of these eight genes may involve with the process of AMD. Two crucial transcription factors (c-rel and myogenin) were concluded to play a role in AMD. Especially, myogenin was associated with AMD by regulating TNC, GRP and FAP. Our finding can contribute to developing new potential biomarkers, revealing the underlying pathogenesis, and further raising new therapeutic targets for AMD. PMID- 28651596 TI - Varying negative work assistance at the ankle with a soft exosuit during loaded walking. AB - BACKGROUND: Only very recently, studies have shown that it is possible to reduce the metabolic rate of unloaded and loaded walking using robotic ankle exoskeletons. Some studies obtained this result by means of high positive work assistance while others combined negative and positive work assistance. There is no consensus about the isolated contribution of negative work assistance. Therefore, the aim of the present study is to examine the effect of varying negative work assistance at the ankle joint while maintaining a fixed level of positive work assistance with a multi-articular soft exosuit. METHODS: We tested eight participants during walking at 1.5 ms-1 with a 23-kg backpack. Participants wore a version of the exosuit that assisted plantarflexion via Bowden cables tethered to an off-board actuation platform. In four active conditions we provided different rates of exosuit bilateral ankle negative work assistance ranging from 0.015 to 0.037 W kg-1 and a fixed rate of positive work assistance of 0.19 W kg-1. RESULTS: All active conditions significantly reduced metabolic rate by 11 to 15% compared to a reference condition, where the participants wore the exosuit but no assistance was provided. We found no significant effect of negative work assistance. However, there was a trend (p = .08) toward greater reduction in metabolic rate with increasing negative work assistance, which could be explained by observed reductions in biological ankle and hip joint power and moment. CONCLUSIONS: The non-significant trend of increasing negative work assistance with increasing reductions in metabolic rate motivates the value in further studies on the relative effects of negative and positive work assistance. There may be benefit in varying negative work over a greater range or in isolation from positive work assistance. PMID- 28651597 TI - Change in body mass index during transition to statutory retirement: an occupational cohort study. AB - BACKGROUND: Retirement is a major life transition affecting health behaviors. The aim of this study was to examine within-individual changes in body mass index (BMI) during transition from full-time work to statutory retirement by sex and physical work characteristics. METHODS: A multiwave cohort study repeated every 4 years and data linkage to records from retirement registers. Participants were 5426 Finnish public-sector employees who retired on a statutory basis in 2000 2011 and who reported their body weight one to three times prior to (w-3, w-2, w 1), and one to three times after (w+1, w+2, w+3) retirement. RESULTS: During the 4-year retirement transition (w+1, vs. w-1) men showed decline in BMI, which was most marked among men with sedentary work (-0.18 kg/m2, 95% CI -.30 to -0.05). In contrast, BMI increased during retirement transition in women and was most marked among women with diverse (0.14 kg/m2, 95% CI 0.08 to 0.20) or physically heavy work (0.31 kg/m2, 95% CI 0.16 to 0.45). Physical activity during leisure time or commuting to work, alcohol consumption or smoking did not explain the observed changes during retirement transition. CONCLUSIONS: In this study statutory retirement was associated with small changes in BMI. Weight loss was most visible in men retiring from sedentary jobs and weight gain in women retiring from diverse and physically heavy jobs. PMID- 28651598 TI - Protective effects of Xinji'erkang on myocardial infarction induced cardiac injury in mice. AB - BACKGROUND: Myocardial infarction (MI) is a major risk factor responsible for morbidity and mortality. Xinji'erkang (XJEK) has been clinically used as an effective medication in the treatment of coronary heart disease and myocarditis. The purpose of this study was to investigate the cardioprotective effect of Xinji'erkang on MI mice. METHODS: Forty male mice were randomly assigned into four groups as follows (n = 10): sham, model, MI with administration of XJEK and fosinopril for four weeks. At the end of studies, hemodynamic parameters and electrocardiography (ECG) were recorded. Heart and body mass were measured and heart weight/body weight (HW/BW) ratio was calculated as index of hypertrophy. The hypertrophy of heart and aorta was examined using the hematoxylin and eosin (HE) staining, and the collagen deposition was evaluated using Van Gieson (VG) staining. Serum nitric oxide level (NO), superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were assayed by colorimetric analysis. The expressions of endothelial NO synthetase (eNOS) expression in serum and cardiac tissues were determined using ELISA assay and immunohistochemistry. Angiotensin II (Ang II) in serum and cardiac tissues was measured using ELISA assay. Besides, tumor necrosis factor-alpha (TNF-alpha), interleukin1beta (IL-1beta) and interleukin10 (IL-10) were observed in cardiac tissues with ELISA assay as well. RESULTS: The administration of XJEK significantly improved cardiac dysfunction and abnormal ECG with reduced HW/BW ratio and ameliorated cardiomyocyte hypertrophy and collagen deposition compared to MI, which was partly due to the decreased SOD and increased MDA in serum. Moreover, XJEK treatment also improved endothelial dysfunction (ED) with not only enhanced eNOS activities in serum and cardiac tissues and elevated NO levels in serum, but also decreased Ang II content in serum and cardiac tissues. Finally, protein expressions of pro inflammation cytokines, TNF-alpha and IL-1beta in the cardiac tissues with XJEK treatment were significantly decreased compared to model. On the contrary, IL-10, an anti-inflammatory cytokine concentrated in cardiac tissues was significantly enhanced compared to model. CONCLUSION: Xinji'erkang exerts cardioprotective effect on myocardial infarction in mice, which may be due to the improvement of endothelial dysfunction and the reduction of oxidative stress and inflammation response. PMID- 28651599 TI - Dosimetric evaluation of synthetic CT for magnetic resonance-only based radiotherapy planning of lung cancer. AB - BACKGROUND: Interest in MR-only treatment planning for radiation therapy is growing rapidly with the emergence of integrated MRI/linear accelerator technology. The purpose of this study was to evaluate the feasibility of using synthetic CT images generated from conventional Dixon-based MRI scans for radiation treatment planning of lung cancer. METHODS: Eleven patients who underwent whole-body PET/MR imaging following a PET/CT exam were randomly selected from an ongoing prospective IRB-approved study. Attenuation maps derived from the Dixon MR Images and atlas-based method was used to create CT data (synCT). Treatment planning for radiation treatment of lung cancer was optimized on the synCT and subsequently copied to the registered CT (planCT) for dose calculation. Planning target volumes (PTVs) with three sizes and four different locations in the lung were planned for irradiation. The dose-volume metrics comparison and 3D gamma analysis were performed to assess agreement between the synCT and CT calculated dose distributions. RESULTS: Mean differences between PTV doses on synCT and CT across all the plans were -0.1% +/- 0.4%, 0.1% +/- 0.5%, and 0.4% +/- 0.5% for D95, D98 and D100, respectively. Difference in dose between the two datasets for organs at risk (OARs) had average differences of -0.14 +/- 0.07 Gy, 0.0% +/- 0.1%, and -0.1% +/- 0.2% for maximum spinal cord, lung V20, and heart V40 respectively. In patient groups based on tumor size and location, no significant differences were observed in the PTV and OARs dose-volume metrics (p > 0.05), except for the maximum spinal-cord dose when the target volumes were located at the lung apex (p = 0.001). Gamma analysis revealed a pass rate of 99.3% +/- 1.1% for 2%/2 mm (dose difference/distance to agreement) acceptance criteria in every plan. CONCLUSIONS: The synCT generated from Dixon-based MRI allows for dose calculation of comparable accuracy to the standard CT for lung cancer treatment planning. The dosimetric agreement between synCT and CT calculated doses warrants further development of a MR-only workflow for radiotherapy of lung cancer. PMID- 28651600 TI - Validation of the graded prognostic assessment for lung cancer with brain metastases using molecular markers (lung-molGPA). AB - BACKGROUND: Many patients with brain metastases from non-small cell lung cancer have limited survival, while others survive for several years, depending on patterns of spread, EGFR and ALK alterations, among others. The purpose of this study was to validate a new prognostic model (Lung-molGPA) originally derived from a North American database. PATIENTS AND METHODS: This retrospective study included 269 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status, histology, EGFR and ALK alterations was collected. The Lung-molGPA score was calculated as described by Sperduto et al. RESULTS: Median survival was 5.4 months. The score predicted survival in patients with adenocarcinoma histology and those with other types. For example, median survival was 3.0, 6.2, 14.7 and 25.0 months in the 4 different prognostic strata for adenocarcinoma. The corresponding figures were 2.4, 5.5 and 12.5 months in the 3 different prognostic strata for non adenocarcinoma. CONCLUSIONS: These results confirm the validity of the Lung molGPA in an independent dataset from a different geographical region. However, median survival was shorter in 6 of 7 prognostic strata. Potential explanations include lead time bias and differences in treatment selection, both brain metastases-directed and systemically. PMID- 28651601 TI - Health and behavioral factors associated with binge drinking among university students in nine ASEAN countries. AB - BACKGROUND: Heavy drinking among university students has been globally recognized as a major public health burden. In the Association of Southeast Asian Nations (ASEAN) region, studies on this issue have been scant, country-specific and in different time frames. The aim of this study was to identify social and behavioral factors associated with binge drinking among university students in nine ASEAN countries. METHODS: This cross-sectional study was conducted in 2015 among 8809 undergraduate university students from 13 universities in Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand and Vietnam using self-administered questionnaire. Multivariate logistic regression analyses were conducted to explore the associated factors. RESULTS: More than half (62.3%) of the study sample were female with a mean age of 20.5 (SD = 2.0) years. Of total, 12.8% were infrequent (= once per month) binge drinkers. After adjustment, among males, higher binge drinking remained significantly associated with being in older age groups, living with parents or guardians, lower level of non-organized religious activity, lack of knowledge on alcohol-heart disease relationship, weak beliefs in the importance of limiting alcohol use, poor subjective health status, lower level of life satisfaction, tobacco and illicit drug use, depressive symptoms and high level physical activity. Among females, higher prevalence of binge drinking remained significantly associated with being in the older age groups, poorer family background, living in an upper-middle- or high-income country, lower level of non-organized religious activity, lack of knowledge on alcohol-heart disease relationship, lack of knowledge on alcohol-high blood pressure relationship, weak beliefs in the importance of limiting alcohol use, lower level of life satisfaction, use of other substances such as tobacco and illicit drug, depressive symptoms and high level of physical activity. CONCLUSIONS: Findings from this study indicate a need for devising or refining university health promotion programs that integrate binge drinking, other substance use, co occurring addictive behaviors and health beliefs in the respective countries. PMID- 28651602 TI - Rapid sociometric mapping of community health workers to identify opinion leaders using an SMS platform: a short report. AB - BACKGROUND: Using opinion leaders to accelerate the dissemination of evidence based public health practices is a promising strategy for closing the gap between evidence and practice. Network interventions (using social network data to accelerate behavior change or improve organizational performance) are a promising but under-explored strategy. We aimed to use mobile phone technology to rapidly and inexpensively map a social network and identify opinion leaders among community health workers in a large HIV program in western Kenya. METHODS: We administered a five-item socio-metric survey to community health workers using a mobile phone short message service (SMS)-based questionnaire. We used the survey results to construct and characterize a social network of opinion leaders among respondents. We calculated the extent to which a particular respondent was a popular point of reference ("degree centrality") and the influence of a respondent within the network ("eigenvector centrality"). RESULTS: Surveys were returned by 38/39 (97%) of peer health workers contacted; 52% were female. The median survey response time was 13.75 min (inter-quartile range, 8.8-38.7). The total cost of relaying survey questions through a secure cloud-based SMS aggregator was $8.46. The most connected individuals (high degree centrality) were also the most influential (high eigenvector centrality). The distribution of influence (eigenvector centrality) was highly skewed in favor of a single influential individual at each site. CONCLUSIONS: Leveraging increasing access to SMS technology, we mapped the network of influence among community health workers associated with a HIV treatment program in Kenya. Survey uptake was high, response rates were rapid, and the survey identified clear opinion leaders. In sum, we offer proof of concept that a "mobile health" (mHealth) approach can be used in resource-limited settings to efficiently map opinion leadership among health care workers and thus open the door to reproducible, feasible, and efficient empirically based network interventions that seek to spread novel practices and behaviors among health care workers. PMID- 28651605 TI - Erratum to: Effect of socioeconomic conditions on health care utilization in marital violence: a cross-sectional investigation from the Japanese Study on stratification, health, income, and neighborhood. PMID- 28651603 TI - A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation. AB - BACKGROUND: Kv1.3 potassium channels regulate microglial functions and are overexpressed in neuroinflammatory diseases. Kv1.3 blockade may selectively inhibit pro-inflammatory microglia in neurological diseases but the molecular and cellular mechanisms regulated by Kv1.3 channels are poorly defined. METHODS: We performed immunoblotting and flow cytometry to confirm Kv1.3 channel upregulation in lipopolysaccharide (LPS)-activated BV2 microglia and in brain mononuclear phagocytes freshly isolated from LPS-treated mice. Quantitative proteomics was performed on BV2 microglia treated with control, LPS, ShK-223 (highly selective Kv1.3 blocker), and LPS+ShK-223. Gene ontology (GO) analyses of Kv1.3-dependent LPS-regulated proteins were performed, and the most representative proteins and GO terms were validated. Effects of Kv1.3-blockade on LPS-activated BV2 microglia were studied in migration, focal adhesion formation, reactive oxygen species production, and phagocytosis assays. In vivo validation of protein changes and predicted molecular pathways were performed in a model of systemic LPS-induced neuroinflammation, employing antigen presentation and T cell proliferation assays. Informed by pathway analyses of proteomic data, additional mechanistic experiments were performed to identify early Kv1.3-dependent signaling and transcriptional events. RESULTS: LPS-upregulated cell surface Kv1.3 channels in BV2 microglia and in microglia and CNS-infiltrating macrophages isolated from LPS treated mice. Of 144 proteins differentially regulated by LPS (of 3141 proteins), 21 proteins showed rectification by ShK-223. Enriched cellular processes included MHCI-mediated antigen presentation (TAP1, EHD1), cell motility, and focal adhesion formation. In vitro, ShK-223 decreased LPS-induced focal adhesion formation, reversed LPS-induced inhibition of migration, and inhibited LPS induced upregulation of EHD1, a protein involved in MHCI trafficking. In vivo, intra-peritoneal ShK-223 inhibited LPS-induced MHCI expression by CD11b+CD45low microglia without affecting MHCI expression or trafficking of CD11b+CD45high macrophages. ShK-223 inhibited LPS-induced MHCI-restricted antigen presentation to ovalbumin-specific CD8+ T cells both in vitro and in vivo. Kv1.3 co-localized with the LPS receptor complex and regulated LPS-induced early serine (S727) STAT1 phosphorylation. CONCLUSIONS: We have unraveled novel molecular and functional roles for Kv1.3 channels in pro-inflammatory microglial activation, including a Kv1.3 channel-regulated pathway that facilitates MHCI expression and MHCI dependent antigen presentation by microglia to CD8+ T cells. We also provide evidence for neuro-immunomodulation by systemically administered ShK peptides. Our results further strengthen the therapeutic candidacy of microglial Kv1.3 channels in neurologic diseases. PMID- 28651604 TI - Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q). AB - BACKGROUND: Particularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed. METHODS: We assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials. RESULTS: A total of 33.9, 34.3, and 31.8% patients were aged <65 years, >=65 to <75 years, and >=75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. >=65 to <75 years; p = 0.047 vs. >=75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray's test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence >=26 weeks. CONCLUSIONS: Baseline disease characteristics and AML progression appear to be more severe in younger lower risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide. TRIAL REGISTRATION: ClinicalTrials.gov NCT00065156 and NCT00179621. PMID- 28651606 TI - About the practice of psychiatric euthanasia: a commentary. AB - Euthanasia motivated by mental disorders is legal in only a few countries and has a short history. In a recent report of all psychiatric euthanasia cases in Belgium between 2002 and 2013, Dierickx and colleagues suggest that the number of these cases is increasing, and provide a profile of the applicants. To date, knowledge of the practice of psychiatric euthanasia is limited, but rising public awareness might increase the number of requests. The authors reveal several shortcomings in cases of psychiatric euthanasia and open avenues for future research.Please see related article: https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-017-1369-0. PMID- 28651607 TI - The long non-coding RNA BC200 (BCYRN1) is critical for cancer cell survival and proliferation. AB - BACKGROUND: BC200 is a long non-coding RNA expressed at high levels in the brain and elevated in a variety of tumour types. BC200 has a hypothesized role in translational regulation; however, to date the functional role of BC200 in both normal and diseased states remains poorly characterized. METHODS: Detailed BC200 expression analyses were performed in tumor cell lines, primary and non tumorigenic cultured breast and lung cells, and a panel of normal human tissues by quantitative real-time PCR and confirmed by northern blot. Subcellular fractionation was performed to assess BC200 distribution and efficient knock-down of BC200 was established using both locked nucleic acid (LNA) GapmeRs and conventional siRNAs. Cell viability following BC200 knockdown and overexpression was assessed by MTT assay and induction of apoptosis was monitored by Annexin V/PI staining and flow cytometry. Cell cycle arrest and synchronization were performed using serum withdrawal as well as the specific inhibitors Lovastatin, Thymidine, RO3306 and Nocodazole. Synchronization was monitored by fluorescent analysis of cellular DNA content by flow cytometry RESULTS: BC200 expression was substantially upregulated in brain and elevated expression was also observed in testes, small intestine and ovary. Expression in cultured tumour cells was dramatically higher than corresponding normal tissue; however, expression in cultured primary cells was similar to that in immortalized and cancer cell lines. BC200 knockdown resulted in a dramatic loss of viability through growth arrest and induction of apoptosis that could be partially rescued by overexpression of wild-type BC200 but not an siRNA-resistant sequence mutant. A substantial decrease in BC200 expression was observed upon cell confluence or serum deprivation, as well as drug induced cell cycle arrest in G1 or G2 but not S- or M-phases. Upon release from cell cycle arrest, BC200 expression was recovered as cells entered S-phase, but did not follow a periodic expression pattern during synchronized progression through the cell cycle. This elevated expression was critical for the survival of proliferating cancerous and non-cancerous cells, but is dispensable upon senescence or cell cycle arrest. CONCLUSIONS: BC200 expression is elevated in proliferating cultured cells regardless of origin. In primary cells, expression is dramatically reduced upon cell cycle arrest by confluence, serum deprivation or chemical inhibition. The lethality of BC200 knockdown is restricted to actively proliferating cells, making it a promising therapeutic target for a broad spectrum of cancers. PMID- 28651608 TI - Linc00152 promotes malignant progression of glioma stem cells by regulating miR 103a-3p/FEZF1/CDC25A pathway. AB - BACKGROUND: Glioma is one of the most frequent intracranial malignant tumors. LncRNAs have been identified as new modulators in the origination and progression of glioma. METHODS: Quantitative real-time PCR were conducted to evaluate the expression of linc00152 and miRNA-103a-3p in glioma tissues and cells. Western blot were used to determine the expression of FEZF1 and CDC25A in glioma tissues and cells. Stable knockdown of linc00152 or over-expression of miR-103a-3p in glioma stem cells (GSCs) were established to explore the function of linc00152 and miR-103a-3p in GSCs. Further, luciferase reports were used to investigate the correlation between linc00152 and miR-103a-3p. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate the function of linc00152 and miR-103a-3p in GSC malignant biological behaviors. ChIP assays were employed to ascertain the correlations between FEZF1 and CDC25A. RESULTS: Linc00152 was up regulated in glioma tissues as well as in GSCs. Knockdown of linc00152 inhibited cell proliferation, migration and invasion, while promoted GSC apoptosis. Linc00152 regulated the malignant behavior of GSCs by binding to miR-103a-3p, which functions as a tumor suppressor. In addition, knockdown of linc00152 down regulated forebrain embryonic zinc finger protein 1 (FEZF1), a direct target of miR-103a-3p which played an oncogenic role in GSCs. FEZF1 elevated promoter activities and up-regulated expression of the oncogenic gene cell division cycle 25A (CDC25A). CDC25A over-expression activated the PI3K/AKT pathways, which regulated the malignant behavior of GSCs. CONCLUSIONS: Linc00152/miR-103a 3p/FEZF1/CDC25A axis plays a novel role in regulating the malignant behavior of GSCs, which may be a new potential therapeutic strategy for glioma therapy. PMID- 28651609 TI - Optimisation of a double-centrifugation method for preparation of canine platelet rich plasma. AB - BACKGROUND: Platelet-rich plasma (PRP) has been expected for regenerative medicine because of its growth factors. However, there is considerable variability in the recovery and yield of platelets and the concentration of growth factors in PRP preparations. The aim of this study was to identify optimal relative centrifugal force and spin time for the preparation of PRP from canine blood using a double-centrifugation tube method. METHODS: Whole blood samples were collected in citrate blood collection tubes from 12 healthy beagles. For the first centrifugation step, 10 different run conditions were compared to determine which condition produced optimal recovery of platelets. Once the optimal condition was identified, platelet-containing plasma prepared using that condition was subjected to a second centrifugation to pellet platelets. For the second centrifugation, 12 different run conditions were compared to identify the centrifugal force and spin time to produce maximal pellet recovery and concentration increase. Growth factor levels were estimated by using ELISA to measure platelet-derived growth factor-BB (PDGF-BB) concentrations in optimised CaCl2-activated platelet fractions. RESULTS: The highest platelet recovery rate and yield were obtained by first centrifuging whole blood at 1000 g for 5 min and then centrifuging the recovered platelet-enriched plasma at 1500 g for 15 min. This protocol recovered 80% of platelets from whole blood and increased platelet concentration six-fold and produced the highest concentration of PDGF-BB in activated fractions. CONCLUSIONS: We have described an optimised double centrifugation tube method for the preparation of PRP from canine blood. This optimised method does not require particularly expensive equipment or high technical ability and can readily be carried out in a veterinary clinical setting. PMID- 28651610 TI - A training manual for event history data management using Health and Demographic Surveillance System data. AB - OBJECTIVE: The objective of this research note is to introduce a training manual for event history data management. The manual provides a first comprehensive guide to longitudinal Health and Demographic Surveillance System (HDSS) data management that allows for a step-by-step description of the process of structuring and preparing a dataset for the calculation of demographic rates and event history analysis. The research note provides some background information on the INDEPTH Network, and the iShare data repository and describes the need for a manual to guide users as to how to correctly handle HDSS datasets. RESULTS: The approach outlined in the manual is flexible and can be applied to other longitudinal data sources. It facilitates the development of standardised longitudinal data management and harmonization of datasets to produce a comparative set of results. PMID- 28651611 TI - Adolescent deliveries in semi-urban Cameroon: prevalence and adverse neonatal outcomes. AB - OBJECTIVES: Adolescent pregnancies are high risk due to the increased probability of adverse outcomes; as adolescents are usually considered to be ill-equipped to deal with the burden of pregnancy. We sought to determine the prevalence of adolescent deliveries in a secondary-level care hospital in semi-urban Cameroon Bamenda, the adverse neonatal outcomes and to assess if previous obstetric history could preclude adolescents from having adverse outcomes in their present pregnancy. RESULTS: The prevalence of adolescent deliveries was 8.7% (95% CI 7.01 10.73%). The neonates of adolescent mothers were more likely to have severe asphyxia (OR 4.0; 95% CI 1.2-12.9; p = 0.03) and low birth weight (OR 2.4; 95% CI 1.3-4.4; p < 0.01). The neonates of primipara adolescents were just as likely to have complications as multipara adolescents. The prevalence of adolescent deliveries (8.7%) in the Regional Hospital Bamenda is high. Their babies are at a high risk of adverse neonatal outcomes irrespective of their previous obstetric history (previous delivery) emphasising that adolescents are generally ill prepared to deal with pregnancy. Strategies to reduce the prevalence of adolescent deliveries should be investigated and implemented in view of attaining the sustainable development goals. PMID- 28651612 TI - Enhancing patient navigation to improve intervention session attendance and viral load suppression of persons with HIV and substance use: a secondary post hoc analysis of the Project HOPE study. AB - BACKGROUND: Interventions are needed to improve viral suppression rates among persons with HIV and substance use. A 3-arm randomized multi-site study (Metsch et al. in JAMA 316:156-70, 2016) was conducted to evaluate the effect on HIV outcomes of usual care referral to HIV and substance use services (N = 253) versus patient navigation delivered alone (PN: N = 266) or together with contingency management (PN + CM; N = 271) that provided financial incentives targeting potential behavioral mediators of viral load suppression. AIMS: This secondary analysis evaluates the effects of financial incentives on attendance at PN sessions and the relationship between session attendance and viral load suppression at end of the intervention. METHODS: Frequency of sessions attended was analyzed over time and by distribution of individual session attendance frequency (PN vs PN + CM). Percent virally suppressed (<=200 copies/mL) at 6 months was compared for low, medium and high rate attenders. In PN + CM a total of $220 could be earned for attendance at 11 PN sessions over the 6-month intervention with payments ranging from $10 to $30 under an escalating schedule. RESULTS: The majority (74%) of PN-only participants attended 6 or more sessions but only 28% attended 10 or more and 16% attended all eleven sessions. In contrast, 90% of PN + CM attended 6 or more visits, 69% attended 10 or more and 57% attended all eleven sessions (attendance distribution chi2[11] = 105.81; p < .0001). Overall (PN and PN + CM participants combined) percent with viral load suppression at 6-months was 15, 38 and 54% among those who attended 0-5, 6-9 and 10-11 visits, respectively (chi2(2) = 39.07, p < .001). CONCLUSION: In this secondary post hoc analysis, contact with patient navigators was increased by attendance incentives. Higher rates of attendance at patient navigation sessions was associated with viral suppression at the 6-month follow-up assessment. Study results support use of attendance incentives to improve rates of contact between service providers and patients, particularly patients who are difficult to engage in care. Trial Registration clinicaltrials.govIdentifier: NCT01612169. PMID- 28651613 TI - An audience research study to disseminate evidence about comprehensive state mental health parity legislation to US State policymakers: protocol. AB - BACKGROUND: A large proportion of the US population has limited access to mental health treatments because insurance providers limit the utilization of mental health services in ways that are more restrictive than for physical health services. Comprehensive state mental health parity legislation (C-SMHPL) is an evidence-based policy intervention that enhances mental health insurance coverage and improves access to care. Implementation of C-SMHPL, however, is limited. State policymakers have the exclusive authority to implement C-SMHPL, but sparse guidance exists to inform the design of strategies to disseminate evidence about C-SMHPL, and more broadly, evidence-based treatments and mental illness, to this audience. The aims of this exploratory audience research study are to (1) characterize US State policymakers' knowledge and attitudes about C-SMHPL and identify individual- and state-level attributes associated with support for C SMHPL; and (2) integrate quantitative and qualitative data to develop a conceptual framework to disseminate evidence about C-SMHPL, evidence-based treatments, and mental illness to US State policymakers. METHODS: The study uses a multi-level (policymaker, state), mixed method (QUAN->qual) approach and is guided by Kingdon's Multiple Streams Framework, adapted to incorporate constructs from Aarons' Model of Evidence-Based Implementation in Public Sectors. A multi modal survey (telephone, post-mail, e-mail) of 600 US State policymakers (500 legislative, 100 administrative) will be conducted and responses will be linked to state-level variables. The survey will span domains such as support for C SMHPL, knowledge and attitudes about C-SMHPL and evidence-based treatments, mental illness stigma, and research dissemination preferences. State-level variables will measure factors associated with C-SMHPL implementation, such as economic climate and political environment. Multi-level regression will determine the relative strength of individual- and state-level variables on policymaker support for C-SMHPL. Informed by survey results, semi-structured interviews will be conducted with approximately 50 US State policymakers to elaborate upon quantitative findings. Then, using a systematic process, quantitative and qualitative data will be integrated and a US State policymaker-focused C-SMHPL dissemination framework will be developed. DISCUSSION: Study results will provide the foundation for hypothesis-driven, experimental studies testing the effects of different dissemination strategies on state policymakers' support for, and implementation of, evidence-based mental health policy interventions. PMID- 28651614 TI - 3D chick embryo chorioallantoic membrane model as an in vivo model to study morphological and histopathological features of feline fibrosarcomas. AB - BACKGROUND: The chick embryo chorioallantoic membrane (CAM) model is well described in human medicine as a cost-effective, easy to perform preclinical oncological model for observing pro- and antiangiogenic response, tumor biology and metastasis. The main objective of this article was to present the modification of the CAM assay in order to evaluate tumor growth from two feline fibrosarcoma cell lines (FFS1, FFS3) and describe their morphological and histopathological features. RESULTS: The authors described morphological and histopathological features of two feline fibrosarcoma cell lines (FFS1 and FFS3) grown on the CAM. Tumors from the FFS1 cell line showed high malignancy (grade III), while tumors from the FFS3 cell line were grade II. Proliferation markers (Ki-67 and PCNA) were determined and the positive correlation between PCNA and tumor grade (r = 0.8247; p < 0.001) was demonstrated, as opposed to Ki-67. CONCLUSIONS: The results obtained indicate that PCNA may be helpful to evaluate the tumor grade, better than Ki-67, for feline fibrosarcomas. However, further investigations of proliferation marker, in bigger number of feline spontaneous fibrosarcomas and feline fibrosarcomas grown on the CAM from different cell lines, are needed to confirm these observations. PMID- 28651615 TI - Effects of dry whey powder and calcium butyrate supplementation of corn/soybean based diets on productive performance, duodenal histological integrity, and Campylobacter colonization in broilers. AB - BACKGROUND: Campylobacter is the main cause of gastroenteritis in humans in industrialized countries, and poultry is its principal reservoir and source of human infections. Dietary supplementation of broiler feed with additives could improve productive performance and elicit health benefits that might reduce Campylobacter contamination during primary production. The aim of this study was to assess the effect of dietary supplementation with whey (a prebiotic) and calcium butyrate (a salt of a short-chain fatty acid) on productive traits, duodenal histological integrity, and Campylobacter colonization and dissemination in broiler chickens during the 42-day rearing period. RESULTS: Six hundred one day-old Ross-308 chickens were placed into 20 ground pens and assigned to one of 4 corn/soybean-based dietary treatments (5 replicates of 30 chicks per treatment) following a randomized complete block design: 1) basal diet with no supplementation as the control, 2) diet supplemented with 6% dry whey powder, 3) diet containing 0.1% coated calcium butyrate, and 4) diet containing 6% whey and 0.1% calcium butyrate. At age 15 days, 6 chickens per pen were experimentally inoculated with Campylobacter jejuni. The results showed that supplementation of the corn/soybean-based diet with 6% whey alone or, preferably, in combination with 0.1% coated calcium butyrate improved growth and feed efficiency, had a beneficial effect on duodenal villus integrity, and decreased mortality. These favourable effects were particularly significant during the starter period. Six days after oral challenge, Campylobacter was widespread in the flock, and the birds remained positive until the end of the rearing period. Although Campylobacter was not isolated from environmental samples, it was detected by real-time polymerase chain reaction (PCR) in dust, air filters, and drinkers while birds shed culturable C. jejuni cells. No differences (p > 0.050) in colonization or shedding levels that could be attributed to the diet were observed during the assay. CONCLUSIONS: Beneficial effects on performance and intestinal health were observed, particularly during the starter period, when chickens were fed a diet supplemented with both whey and coated calcium butyrate. However, none of the tested diets provided the chicks any differential degree of protection against Campylobacter infection. PMID- 28651616 TI - The influence of L4-S1 Dynesys(r) dynamic stabilization versus fusion on lumbar motion and its relationship with lumbar degeneration: a retrospective study. AB - BACKGROUND: The aim of this study is to evaluate the efficacy of Dynesys(r) posterior dynamic stabilization (PDS) in the treatment of L4-S1 degenerative diseases and to assess the influence of postoperative motion on lumbar degeneration. METHODS: Included in this retrospective study were patients with L4 S1 degenerative disease who underwent fusion or PDS from September 2010 to September 2014. Clinical outcomes were assessed by preoperative and postoperative visual analog scale (VAS) and Oswestry Disability Index (ODI). Preoperative and postoperative X-rays assessed range of motion (ROM) of the non-surgical and surgical levels and whole lumbar. MRI assessed degeneration of non-surgical levels. RESULTS: A total of 56 consecutive patients were divided into two groups: group A, PDS, and group B, fusion. Patient demographics and baseline characteristics were similar in the two groups. In both groups, there was a significant difference between preoperative and postoperative VAS and ODI scores (P < 0.05). However, there was a significant difference in a 6-month follow-up ODI between the two groups (P < 0.05). X-rays showed PDS patients partially maintained surgical level ROM and non-surgical level ROM increased less than in the fusion group. MRI showed adjacent segment degeneration (ASD) in both groups, and patients whose preoperative L3-4 Pfirrmann classification was higher than grade 2 had more ASD than lower than grade 2. CONCLUSION: PDS can maintain surgical level ROM and had less influence on whole and non-surgical level ROM. Following PDS, patients recovered faster and had a better lumbar function. It may be a better choice for multi-level lumbar degenerative diseases. PMID- 28651617 TI - Development and validation of a variant detection workflow for BRCA1 and BRCA2 genes and its clinical application based on the Ion Torrent technology. AB - BACKGROUND: Breast cancer is the most common among women worldwide, and ovarian cancer is the most difficult gynecological tumor to diagnose and with the lowest chance of cure. Mutations in BRCA1 and BRCA2 genes increase the risk of ovarian cancer by 60% and breast cancer by up to 80% in women. Molecular tests allow a better orientation for patients carrying these mutations, affecting prophylaxis, treatment, and genetic counseling. RESULTS: Here, we evaluated the performance of a panel for BRCA1 and BRCA2, using the Ion Torrent PGM (Life Technologies) platform in a customized workflow and multiplex ligation-dependent probe amplification for detection of mutations, insertions, and deletions in these genes. We validated the panel with 26 samples previously analyzed by Myriad Genetics Laboratory, and our workflow showed 95.6% sensitivity and 100% agreement with Myriad reports, with 85% sensitivity on the positive control sample from NIST. We also screened 68 clinical samples and found 22 distinct mutations. CONCLUSIONS: The selection of a robust methodology for sample preparation and sequencing, together with bioinformatics tools optimized for the data analysis, enabled the development of a very sensitive test with high reproducibility. We also highlight the need to explore the limitations of the NGS technique and the strategies to overcome them in a clinically confident manner. PMID- 28651618 TI - Relationships between received and perceived social support and health-related quality of life among patients receiving methadone maintenance treatment in Mainland China. AB - BACKGROUND: Social support has been considered one of the most important factors of health-related quality of life (HRQoL) evaluations among different populations; however, few studies have explored the relationships of both received and perceived social support to HRQoL among patients undergoing methadone maintenance treatment (MMT). Thus, the purpose of this cross-sectional study was to clarify these relationships. METHODS: Participants were patients admitted at the two largest privately and publicly funded MMT clinics in Xi'an. The main explanatory variable was social support, both received (i.e., social network support and professional support services) and perceived (Multidimensional Scale of Perceived Social Support). The outcome was HRQoL, which was evaluated using the Short-Form 36 Health Survey version 2 (SF-36v2) and the Quality of Life Scale for Drug Addicts (QOL-DAv2.0). We carried out independent samples t-tests and multiple linear regression analysis to examine the relationships between received and perceived social support and HRQoL. RESULTS: The study findings revealed that patients with good social support had significantly higher scores on the SF-36v2 and QOL-DAv2.0 (p < 0.05). After controlling for individual characteristics, the significant factors predicting HRQoL were good family relationships, usually communicating with others, a convenient service time, appropriate treatment charges, and good perceived social support (p < 0.05). CONCLUSIONS: Our results suggest that received and perceived social support influences HRQoL among individuals receiving MMT. Thus, these variables should be considered during health management efforts and interventions directed at this patient population. PMID- 28651619 TI - Analgesic effects of a hydro-ethanolic whole plant extract of Synedrella nodiflora (L.) Gaertn in paclitaxel-induced neuropathic pain in rats. AB - BACKGROUND: Synedrella nodiflora is used by traditional healers in Ghana for the management of epilepsy and pain. The hydro-ethanolic extract of the whole plant has demonstrated antinociceptive effect in various animal models of pain. This study investigated the potential benefit of the hydro-ethanolic extract in a rat model of paclitaxel-induced neuropathic pain. METHODS: Neuropathy was induced in rats by a continuous intraperitoneal administration of paclitaxel (2 mg/kg) for 5 days. Baseline latencies to thermal pain were recorded before the first injection of paclitaxel and during the 5 day induction period. Following the induction, the rats in designated treatment group were treated with the hydro-ethanolic extract (100, 300 and 1000 mg/kg, p.o) or pregabalin (10, 30 and 100 mg/kg) or vehicle (distilled water) and their responses to thermal hyperalgesia measured every 30 for a total period of 3 h. RESULTS: There was a significant difference between the baseline reaction latency and what was observed on the 5th day of the induction of neuropathy. Two days after the induction of neuropathy, the extract and pregabalin significantly and dose-dependently produced antinociceptive effect during the 3-h test period. CONCLUSION: The hydro-ethanolic extract of the whole plant of Synedrella nodiflora possess analgesic effect in paclitaxel-induced neuropathy in rats. PMID- 28651620 TI - An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol. AB - BACKGROUND: Cellular-based therapies represent a platform technology within the rapidly expanding field of regenerative medicine and are distinct from conventional therapeutics-offering a unique approach to managing what were once considered untreatable diseases. Despite a significant increase in basic science activity within the cell therapy arena, alongside a growing portfolio of cell therapy trials and promising investment, the translation of cellular-based therapeutics from "bench to bedside" remains challenging, and the number of industry products available for widespread clinical use remains comparatively low. This systematic review identifies unique intrinsic and extrinsic barriers in the cell-based therapy domain. METHODS/DESIGN: Eight electronic databases will be searched, specifically Medline, EMBASE (OvidSP), BIOSIS & Web of Science, Cochrane Library & HEED, EconLit (ProQuest), WHOLIS WHO Library Database, PAIS International (ProQuest), and Scopus. Addition to this gray literature was searched by manually reviewing relevant work. All identified articles will be subjected for review by two authors who will decide whether or not each article passes our inclusion/exclusion criteria. Eligible papers will subsequently be reviewed, and key data extracted into a pre-designed data extraction scorecard. An assessment of the perceived impact of broad commercial barriers to the adoption of cell-based therapies will be conducted. These broad categories will include manufacturing, regulation and intellectual property, reimbursement, clinical trials, clinical adoption, ethics, and business models. This will inform further discussion in the review. There is no PROSPERO registration number. DISCUSSION: Through a systematic search and appraisal of available literature, this review will identify key challenges in the commercialization pathway of cellular-based therapeutics and highlights significant barriers impeding successful clinical adoption. This will aid in creating an adaptable, acceptable, and harmonized approach supported by apposite regulatory frameworks and pertinent expertise throughout the respective stages of the adoption cycle to facilitate the adoption of new products and technologies in the industry. PMID- 28651621 TI - Prevalence of malnutrition and associated factors in children aged 6-59 months among rural dwellers of damot gale district, south Ethiopia: community based cross sectional study. AB - BACKGROUND: Malnutrition remains one of the most common causes of morbidity and mortality among children throughout the world. This study aimed to assess prevalence of malnutrition and associated factors among children aged 6-59 months in Damot Gale, South Ethiopia. METHODS: A community based cross sectional study was conducted on 398 children aged 6-59 months in the Damot Gale district. A two stage cluster sample design was used to select kebele and households. Anthropometric measurements and structured questionnaires were used to collect data. Bivariate and multivariate logistic regression was done by using SPSS version 20. RESULTS: The results of this study indicated that 27.6% of children were under-weight and 9% were wasted. Being male (AOR: 1.90; 95% CI: (1.10-3.32), children with shorter birth interval (AOR:2.89;95% CI: (1.23-6.80), children who had sickness some times for past 2 weeks (AOR:0.42; 95% CI:(0.10-0.93) and children whose mothers attended ANC (AOR:0.29; 95% CI: (0.16-0.52) were associated with underweight. Children whose mother's main occupation was non-farm (AOR: 7.06;95% CI: (1.31-38.21), presence of diarrhea (AOR:39.5, 95% CI: (13.68 114.30), and children whose mothers attended ANC (AOR:0.18,95% CI: (0 .18 (0.07 0.45) were associated with wasting. CONCLUSION: The prevalence of malnutrition in the study area was high. Health extension workers and stakeholders should give due concern on promotion of proper nutrition in the community. PMID- 28651623 TI - Association between untreated carious lesions and asthma in adults at Rabat University Hospital, Morocco: a cross sectional study. AB - BACKGROUND: Depending on risk factors, cumulative risk of developing more dental caries by age has been reported. However, the association between dental caries and asthma is less studied among adults. The aims of this study were to evaluate the severity of untreated carious lesions in a population of asthmatic adults and to evaluate the mediation of socio-economic and oral health behaviour variables. METHODS: The study involved participants with diagnosed asthma (N = 100) and control (N = 100) subjects attending a tertiary hospital. Groups were matched by age and gender. Asthma was the exposure of interest. The outcome measure was the rate of carious lesions. Recorded variables included demographics, socio-economic status, tooth brushing habits and oral health status using WHO criteria. Poisson regression analysis examined the association between asthma and untreated dental caries. RESULTS: The adjusted model, after the inclusion of individuals' behaviours regarding oral health, social determinants and asthma, revealed a significant association between the number of untreated carious lesions and asthma (PR = 1.23; 95% CI 1.23-1.58; p < 0.001). CONCLUSION: Patients with asthma showed a greater number of untreated carious lesions. Looking forward, better understanding of the association between asthma and oral health may require exploiting the interactions of behavioural, social determinant and biological factors. PMID- 28651622 TI - Modulation of hepatic perfusion did not improve recovery from hepatic outflow obstruction. AB - BACKGROUND: Focal hepatic venous outflow obstruction frequently occurs after extended liver resection and leads to a portal hypertension, arterial hypoperfusion and parenchymal necrosis. In this study, we investigated the pharmacological modulation of liver perfusion and hepatic damage in a surgical model of hepatic outflow obstruction after extended liver resection by administration of 5 different drugs in comparison to an operative intervention, splenectomy. METHODS: Male inbred Lewis rats (Lew/Crl) were subjected to right median hepatic vein ligation + 70% partial hepatectomy. Treatment consisted of a splenectomy or the application of saline, carvedilol or isosorbide-5-mononitrate (ISMN) (5 mg . kg-1 respectively 7,2 mg . kg-1 per gavage 12 h-1). The splenectomy was performed during operation. The effect of the treatments on hepatic hemodynamics were measured in non-operated animals, immediately after operation (n = 4/group) and 24 h after operation (n = 5/group). Assessment of hepatic damage (liver enzymes, histology) and liver cell proliferation (BrdU immunohistochemistry) was performed 24 h after operation. Furthermore sildenafil (10 MUg . kg-1 i.p. 12h-1), terlipressin (0.05 mg . kg-1 i.v. 12 h-1) and octreotide (10 MUg . kg-1 s.c. 12 h-1) were investigated regarding their effect on hepatic hemodynamics and hepatic damage 24 h after operation (n = 4/group). RESULTS: Carvedilol and ISMN significantly decreased the portal pressure in normal non-operated rats from 11,1 +/- 1,1 mmHg (normal rats) to 8,4 +/- 0,3 mmHg (carvedilol) respectively 7,4 +/- 1,8 mmHg (ISMN). ISMN substantially reduced surgery-induced portal hypertension from 15,4 +/- 4,4 mmHg to 9,6 +/- 2,3 mmHg. Only splenectomy reduced the portal flow immediately after operation by approximately 25%. No treatment had an immediate effect on the hepatic arterial perfusion. In all treatment groups, portal flow increased by approximately 3-fold within 24 h after operation, whereas hepatic arterial flow decreased substantially. Neither treatment reduced hepatic damage as assessed 24 h after operation. The distribution of proliferating cells appeared very similar in all drug treated groups and the splenectomy group. CONCLUSION: Transient relative reduction of portal pressure did not result in a reduction of hepatic damage. This might be explained by the development of portal hyperperfusion which was accompanied by arterial hypoperfusion. PMID- 28651624 TI - Multifaceted interventions for improving spontaneous reporting of adverse drug reactions in a general hospital in China. AB - BACKGROUND: The present study investigates changes in spontaneous reporting (SR) compliance and ADR patterns following adoption of a new hospital SR system, and multiple interventions designed for its improvement use under modified drug administration guidelines. METHODS: In total, 1389 ADR cases were reviewed. Cases were divided into two groups, cases from period 1 (n = 557, from January 2006 to June 2011) under the old SR system and cases in period 2 (n = 832, from July 2011 to December 2016) under the new SR system with multiple interventions to improve physician SR compliance. General information, drug information, and clinical manifestations were investigated and compared between periods. RESULTS: Interventions for improved clinician training, education on knowledge, attitudes, and practices (KAP), and economic incentives substantially improved SR adherence. We also found that changing drug usage patterns (based on the new drug administration guidelines) greatly influenced ADR occurrence and type. CONCLUSIONS: We found the SR compliance can be improved by multifaceted interventions. Drug usage patterns also influence ADR occurrence, so programs tailored for rational use are essential. These results could lead to further improvements in the SR system for ADRs in China, and provide guidance for establishing better methods of pharmacovigilance. PMID- 28651625 TI - Iopromide- and gadopentetic acid-derived preparates used in MR arthrography may be harmful to chondrocytes. AB - BACKGROUND: Magnetic resonance arthrography, a procedure through which contrast agents containing gadolinium and/or iopromide are administered intra-articularly, has become a useful tool in musculoskeletal diagnosis. Nevertheless, despite being considered safe for systemic use, certain tissue toxicities have been identified for both drugs. In this study, the effects of short-term exposure of human primary chondrocyte cell cultures to gadolinium and/or iopromide contrast agents were examined by assaying for stage-specific embryonic antigen-1 (SSEA-1) protein expression (a chondrogenic differentiation marker), cell viability, toxicity, and proliferation. METHODS: Human articular chondrocytes were grown in monolayer culture and were exposed to iopromide and/or gadolinium diethylenetriamine-pentaacetate (Gd-DPT) for 2 and 6 h. Cell cultures with no drug exposure were used as the control group. Cell differentiation status was assessed according to SSEA-1 protein expression. Contrast agent effects on cell viability and proliferation were analyzed using MTT analysis. Further, changes in cell morphology in relation to the control group were evaluated using inverted light microscopy, environmental scanning electron microscopy (ESEM), and 3-tesla magnetic resonance imaging. The obtained data were statistically compared. RESULTS: When compared with the control group, both SSEA-1 protein expression and cell proliferation were lowest in the Gd-DPT group (P = 0.000). There was a statistically significant correlation between SSEA-1 expression and MTT results (rho = 0.351; P = 0.003). CONCLUSIONS: Nevertheless, the data obtained from in vitro experiments may not directly correspond to clinical applications. However, the mere fact that a drug used solely for diagnostic purposes may repress chondrocyte cell proliferation should be carefully considered by clinicians. PMID- 28651626 TI - Selective impairments of alerting and executive control in HIV-infected patients: evidence from attention network test. AB - BACKGROUND: Attention ability can be subdivided into three functionally independent networks, i.e., alerting network, orienting network, and executive network. Previous literature has documented that deficits in attention are a common consequence of HIV infection. However, the precise nature of deficits of attention in HIV-infected patients is poorly understood. Accordingly, the aim of the study was to identify whether the HIV-infected patients showed a specific attention network deficit or a general attentional impairment. METHODS: We investigated 27 HIV-infected patients and 31 normal controls with the Attention Network Test (ANT). RESULTS: The patients exhibited less efficient alerting network and executive network than controls. No significant difference was found in orienting network effect between groups. Our results also indicate a tendency for poorer efficiency on alerting attention and executive attention in patients with CD4 <= 200. CONCLUSIONS: Our findings suggest that HIV-infected patients exhibited selective impairments of attention network of alerting and executive control. The link between lower CD4 T cell count and poorer attention network function imply the importance of starting antiretroviral therapy earlier to avoid irreversible neurocognitive impairment. PMID- 28651627 TI - Induction of endoplasmic reticulum calcium pump expression during early leukemic B cell differentiation. AB - BACKGROUND: Endoplasmic reticulum (ER) calcium storage and release play important roles in B lymphocyte maturation, survival, antigen-dependent cell activation and immunoglobulin synthesis. Calcium is accumulated in the endoplasmic reticulum (ER) by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes). Because lymphocyte function is critically dependent on SERCA activity, it is important to understand qualitative and quantitative changes of SERCA protein expression that occur during B lymphoid differentiation and leukemogenesis. METHODS: In this work we investigated the modulation of SERCA expression during the pharmacologically induced differentiation of leukemic precursor B lymphoblast cell lines that carry the E2A-PBX1 fusion oncoprotein. Changes of SERCA levels during differentiation were determined and compared to those of established early B lymphoid differentiation markers. SERCA expression of the cells was compared to that of mature B cell lines as well, and the effect of the direct inhibition of SERCA dependent calcium transport on the differentiation process was investigated. RESULTS: We show that E2A-PBX1+ leukemia cells simultaneously express SERCA2 and SERCA3-type calcium pumps; however, their SERCA3 expression is markedly inferior to that of mature B cells. Activation of protein kinase C enzymes by phorbol ester leads to phenotypic differentiation of the cells, and this is accompanied by the induction of SERCA3 expression. Direct pharmacological inhibition of SERCA dependent calcium transport during phorbol ester treatment interferes with the differentiation process. CONCLUSION: These data show that the calcium pump composition of the ER is concurrent with increased SERCA3 expression during the differentiation of precursor B acute lymphoblastic leukemia cells, that a cross talk exists between SERCA function and the control of differentiation, and that SERCA3 may constitute an interesting new marker for the study of early B cell phenotype. PMID- 28651628 TI - Separability of motor imagery of the self from interpretation of motor intentions of others at the single trial level: an EEG study. AB - BACKGROUND: We aimed to investigate the separability of the neural correlates of 2 types of motor imagery, self and third person (actions owned by the participant himself vs. another individual). If possible this would allow for the development of BCI interfaces to train disorders of action and intention understanding beyond simple imitation, such as autism. METHODS: We used EEG recordings from 20 healthy participants, as well as electrocorticography (ECoG) in one, based on a virtual reality setup. To test feasibility of discrimination between each type of imagery at the single trial level, time-frequency and source analysis were performed and further assessed by data-driven statistical classification using Support Vector Machines. RESULTS: The main observed differences between self-other imagery conditions in topographic maps were found in Frontal and Parieto-Occipital regions, in agreement with the presence of 2 independent non MU related contributions in the low alpha frequency range. ECOG corroborated such separability. Source analysis also showed differences near the temporo-parietal junction and single-trial average classification accuracy between both types of motor imagery was 67 +/- 1%, and raised above 70% when 3 trials were used. The single-trial classification accuracy was significantly above chance level for all the participants of this study (p < 0.02). CONCLUSIONS: The observed pattern of results show that Self and Third Person MI use distinct electrophysiological mechanisms detectable at the scalp (and ECOG) at the single trial level, with separable levels of involvement of the mirror neuron system in different regions. These observations provide a promising step to develop new BCI training/rehabilitation paradigms for patients with neurodevelopmental disorders of action understanding beyond simple imitation, such as autism, who would benefit from training and anticipation of the perceived intention of others as opposed to own intentions in social contexts. PMID- 28651629 TI - Risk factors, person, place and time characteristics associated with Hepatitis E Virus outbreak in Napak District, Uganda. AB - BACKGROUND: Hepatitis E is self-limiting, but can cause death in most at risk groups like pregnant women and those with preexisting acute liver disease. In developing countries it presents as epidemic, in 2014 Hepatitis E Virus (HEV) outbreak was reported in Napak district Uganda. The role of factors in this setting that might have propagated this HEV epidemic, including host, agent, and environmental characteristics, were still not clear. This study was therefore conducted to investigate the risk factors, person, place and time characteristics, associated with the hepatitis E virus (HEV) epidemic in Napak district. METHODS: Review of line lists data for epidemiological description and matched case control study on neighborhood and age in the ratio of 1:2 were used to assess risk factors for HEV outbreak in Napak. Cluster and random sampling were used to obtain a sample size of 332, (111 cases, 221 controls). Possible interaction and confounding was assessed using conditional logistic regression. RESULTS: Over 1359 cases and 30 deaths were reported during 2013/2014 HEV outbreak. The mean age of patients was 29 +/- years, 57.9% of cases were females. Overall case Fatality Ratio was 2.2% in general population but 65.2% in pregnant women. More than 94% of the cases were reported in the sub counties of Napak, 5.7% of cases were reported in the outside neighboring districts. The epidemic peaked in January 2014 and gradually subsided by December 2014. Risk factors found to be associated with HEV included drinking untreated water (OR 6.69, 95% CI 3.15-14.16), eating roadside food (OR 6.11, 95% CI 2.85-13.09), reported not cleaning utensils (OR 3.24, 95% CI 1.55-1.76), and being a hunter (OR 1.14, 95% CI 1.03-12.66). CONCLUSION: The results of this study suggest that the virus is transmitted by the feco-oral route through contaminated water. They also suggest that active surveillance and appropriate measures targeting community and routine individual health actions are important to prevent transmission and decrease the deaths. PMID- 28651631 TI - In which developing countries are patents on essential medicines being filed? AB - BACKGROUND: This article is based upon data gathered during a study conducted in partnership with the World Intellectual Property Organization on the patent status of products appearing on the World Health Organization's 2013 Model List of Essential Medicines (MLEM). It is a statistical analysis aimed at answering: in which developing countries are patents on essential medicines being filed? METHODS: Patent data were collected by linking those listed in the United States and Canada's medicine patent registers to corresponding patents in developing countries using two international patent databases (INPADOC and Derwent) via a commerical-grade patent search platform (Thomson Innovation). The respective supplier companies were then contacted to correct and verify our data. We next tallied the number of MLEM patents per developing country. Spearman correlations were done to assess bivariate relationships between variables, and a multivariate regression model was developed to explain the number of MLEM patents in each country using SPSS 23.0. RESULTS: A subset of 20 of the 375 (5%) products on the 2013 MLEM fit our inclusion criteria. The patent estate reports (i.e., the global list of patents for a given drug) varied greatly in their number with a median of 48 patents (interquartile range [IQR]: 26-76 ). Their geographic reach had a median of 15% of the developing countries sampled (IQR: 8-28%). The number of developing countries covered appeared to increase with the age of the patent estate (r = .433, p = 0.028). The number of MLEM patents per country was significantly positively associated with human development index (HDI), gross domestic income (GDI) per capita, total healthcare expenditure per capita, population size, the Rule of Law Index, and average education level. Population size, GDI per capita, and healthcare expenditure (in % of national expenditure) were predictors of the number of MLEM patents in countries (p = 0.001, p = 0.001, p = 0.009, respectively). Population size was the most important predictor (beta = 0.59), followed by income (GDI per capita) (beta = 0.32), and healthcare expenditure (beta = 0.15). Holding the other factors constant, (i) 14.3 million more people, (ii) $833.33 more per capita (GDI), or (iii) 0.88% more of national spending on healthcare resulted in 1 additional essential medicine patent. CONCLUSION: Population was a powerful predictor of the number of patent filings in developing countries along with GDI and healthcare expenditure. The age and historical context of the patent estate may make a difference in the number of patents and countries covered. Broad surveillance and benchmarking of the global medicine patent landscape is valuable for detecting significant shifts that may occur over time. With improved international medicine patent transparency by companies and data available through third parties, such studies will be increasingly feasible. PMID- 28651630 TI - Maternal inheritance of bifidobacterial communities and bifidophages in infants through vertical transmission. AB - BACKGROUND: The correct establishment of the human gut microbiota represents a crucial development that commences at birth. Different hypotheses propose that the infant gut microbiota is derived from, among other sources, the mother's fecal/vaginal microbiota and human milk. RESULTS: The composition of bifidobacterial communities of 25 mother-infant pairs was investigated based on an internal transcribed spacer (ITS) approach, combined with cultivation-mediated and genomic analyses. We identified bifidobacterial strains/communities that are shared between mothers and their corresponding newborns. Notably, genomic analyses together with growth profiling assays revealed that bifidobacterial strains that had been isolated from human milk are genetically adapted to utilize human milk glycans. In addition, we identified particular bacteriophages specific of bifidobacterial species that are common in the viromes of mother and corresponding child. CONCLUSIONS: This study highlights the transmission of bifidobacterial communities from the mother to her child and implies human milk as a potential vehicle to facilitate this acquisition. Furthermore, these data represent the first example of maternal inheritance of bifidobacterial phages, also known as bifidophages in infants following a vertical transmission route. PMID- 28651632 TI - Institutionalizing community-focused maternal, newborn, and child health strategies to strengthen health systems: A new framework for the Sustainable Development Goal era. AB - BACKGROUND: Stronger health systems, with an emphasis on community-based primary health care, are required to help accelerate the pace of ending preventable maternal and child deaths as well as contribute to the achievement of the Sustainable Development Goals (SDGs). The success of the SDGs will require unprecedented coordination across sectors, including partnerships between public, private, and non-governmental organizations (NGOs). To date, little attention has been paid to the distinct ways in which NGOs (both international and local) can partner with existing national government health systems to institutionalize community health strategies. DISCUSSION: In this paper, we propose a new conceptual framework that depicts three primary pathways through which NGOs can contribute to the institutionalization of community-focused maternal, newborn, and child health (MNCH) strategies to strengthen health systems at the district, national or global level. To illustrate the practical application of these three pathways, we present six illustrative cases from multiple NGOs and discuss the primary drivers of institutional change. In the first pathway, "learning for leverage," NGOs demonstrate the effectiveness of new innovations that can stimulate changes in the health system through adaptation of research into policy and practice. In the second pathway, "thought leadership," NGOs disseminate lessons learned to public and private partners through training, information sharing and collaborative learning. In the third pathway, "joint venturing," NGOs work in partnership with the government health system to demonstrate the efficacy of a project and use their collective voice to help guide decision-makers. In addition to these pathways, we present six key drivers that are critical for successful institutionalization: strategic responsiveness to national health priorities, partnership with policymakers and other stakeholders, community ownership and involvement, monitoring and use of data, diversification of financial resources, and longevity of efforts. CONCLUSION: With additional research, we propose that this framework can contribute to program planning and policy making of donors, governments, and the NGO community in the institutionalization of community health strategies. PMID- 28651633 TI - Improved methods and resources for paramecium genomics: transcription units, gene annotation and gene expression. AB - BACKGROUND: The 15 sibling species of the Paramecium aurelia cryptic species complex emerged after a whole genome duplication that occurred tens of millions of years ago. Given extensive knowledge of the genetics and epigenetics of Paramecium acquired over the last century, this species complex offers a uniquely powerful system to investigate the consequences of whole genome duplication in a unicellular eukaryote as well as the genetic and epigenetic mechanisms that drive speciation. High quality Paramecium gene models are important for research using this system. The major aim of the work reported here was to build an improved gene annotation pipeline for the Paramecium lineage. RESULTS: We generated oriented RNA-Seq transcriptome data across the sexual process of autogamy for the model species Paramecium tetraurelia. We determined, for the first time in a ciliate, candidate P. tetraurelia transcription start sites using an adapted Cap Seq protocol. We developed TrUC, multi-threaded Perl software that in conjunction with TopHat mapping of RNA-Seq data to a reference genome, predicts transcription units for the annotation pipeline. We used EuGene software to combine annotation evidence. The high quality gene structural annotations obtained for P. tetraurelia were used as evidence to improve published annotations for 3 other Paramecium species. The RNA-Seq data were also used for differential gene expression analysis, providing a gene expression atlas that is more sensitive than the previously established microarray resource. CONCLUSIONS: We have developed a gene annotation pipeline tailored for the compact genomes and tiny introns of Paramecium species. A novel component of this pipeline, TrUC, predicts transcription units using Cap-Seq and oriented RNA-Seq data. TrUC could prove useful beyond Paramecium, especially in the case of high gene density. Accurate predictions of 3' and 5' UTR will be particularly valuable for studies of gene expression (e.g. nucleosome positioning, identification of cis regulatory motifs). The P. tetraurelia improved transcriptome resource, gene annotations for P. tetraurelia, P. biaurelia, P. sexaurelia and P. caudatum, and Paramecium trained EuGene configuration are available through ParameciumDB ( http://paramecium.i2bc.paris-saclay.fr ). TrUC software is freely distributed under a GNU GPL v3 licence ( https://github.com/oarnaiz/TrUC ). PMID- 28651634 TI - Data- and expert-driven rule induction and filtering framework for functional interpretation and description of gene sets. AB - BACKGROUND: High-throughput methods in molecular biology provided researchers with abundance of experimental data that need to be interpreted in order to understand the experimental results. Manual methods of functional gene/protein group interpretation are expensive and time-consuming; therefore, there is a need to develop new efficient data mining methods and bioinformatics tools that could support the expert in the process of functional analysis of experimental results. RESULTS: In this study, we propose a comprehensive framework for the induction of logical rules in the form of combinations of Gene Ontology (GO) terms for functional interpretation of gene sets. Within the framework, we present four approaches: the fully automated method of rule induction without filtering, rule induction method with filtering, expert-driven rule filtering method based on additive utility functions, and expert-driven rule induction method based on the so-called seed or expert terms - the GO terms of special interest which should be included into the description. These GO terms usually describe some processes or pathways of particular interest, which are related to the experiment that is being performed. During the rule induction and filtering processes such seed terms are used as a base on which the description is build. CONCLUSION: We compare the descriptions obtained with different algorithms of rule induction and filtering and show that a filtering step is required to reduce the number of rules in the output set so that they could be analyzed by a human expert. However, filtering may remove information from the output rule set which is potentially interesting for the expert. Therefore, in the study, we present two methods that involve interaction with the expert during the process of rule induction. Both of them are able to reduce the number of rules, but only in the case of the method based on seed terms, each of the created rule includes expert terms in combination with the other terms. Further analysis of such combinations may provide new knowledge about biological processes and their combination with other pathways related to genes described by the rules. A suite of Matlab scripts that provide the functionality of a comprehensive framework for the rule induction and filtering presented in this study is available free of charge at: http://rulego.polsl.pl/framework . PMID- 28651635 TI - An anatomical-like triangular-vector ligament reconstruction for the medial collateral ligament and the posterior oblique ligament injury with single femoral tunnel: a retrospective study. AB - BACKGROUND: The purpose of this study was to evaluate the clinical outcomes of anatomical-like triangular-vector ligament reconstruction (TLR) in treating the combined injury of medial collateral ligament (MCL) and posterior oblique ligament (POL). METHODS: During July 2013 to May 2014, 26 patients who received anatomical-like TLR were included into this study. All patients received clinical physical examination, imaging examination, and knee joint function score both preoperative and follow-up. The stability of the medial structure of the knee joint was examined by physical examination and imaging evaluation, including excessive knee medial opening (EKMO) and tibial external rotation angle (TERA). The function of the knee was evaluated by the subjective questionnaire, including Lysholm, Tegner, and IKDC score. SPSS software was used for statistics analysis. RESULTS: The mean follow-up time exceeds 24 months. Two patients occurred with serious heterotopic ossification, and one patient received revision because of screw breakage. EKMO over the contralateral state at 0 degrees decreased from 9.76 +/- 2.76 mm to 2.79 +/- 1.02 mm with statistical significance (P < .001) and 10.32 +/- 2.75 mm decreased to 3.13 +/- 0.85 mm at 30 degrees (P < .001). Meanwhile, TERA significantly decreased from 53.38 +/- 6.71 degrees to 27.15 +/- 4.92 degrees (P < .001). The postoperative Lysholm, Tegner, and IKDC score were superior to preoperative with statistical significance (P < .001). CONCLUSIONS: Anatomical-like TLR can reconstruct the graft to cover the insertions which can regain anatomic form and function with a cramped space. Not only the valgus stability and rotational stability can be restored obviously at follow-up but also the usage of implantation can be reduced, decreasing the incidence rate of allergy and saving costs. PMID- 28651636 TI - Adult cancer-related hemophagocytic lymphohistiocytosis - a challenging diagnosis: a case report. AB - BACKGROUND: Adult hemophagocytic lymphohistiocytosis is a secondary immunopathologic phenomenon, mainly secondary to malignancy, infection, or autoimmune disorders. The performance of diagnostic criteria, studied in the pediatric population, is yet to be validated in the adult population. Some of the criteria include cytopenias and organomegaly that are inherent features to malignant processes, thus making the diagnosis of hemophagocytic lymphohistiocytosis a challenge in patients with cancer. CASE PRESENTATION: We describe the case of a 54-year-old white man with history of metastatic maxillary sinus adenoid cystic carcinoma who had severe liver injury and cytopenias with progressive clinical deterioration. We performed an evaluation, by flow cytometry, of the expression of surface markers in his natural killer cells that revealed remarkable abnormalities. His syndrome eventually fulfilled criteria for hemophagocytic lymphohistiocytosis and he received therapy with steroids with interval clinical improvement. Unfortunately, he refused further cytotoxic treatment and died 2 weeks later. CONCLUSIONS: The conventional criteria for the diagnosis of hemophagocytic lymphohistiocytosis are suboptimal for adult patients with cancer resulting in delays in diagnosis and timely initiation of treatment. The diagnostic criteria have to be re-evaluated in patients with cancer; novel, easily available, and accurate diagnostic methods are needed. PMID- 28651637 TI - Early postnatal care use by postpartum mothers in Mundri East County, South Sudan. AB - BACKGROUND: Globally, most maternal and newborn deaths are within the first week of delivery. Early postnatal-care (EPNC) visits between 2 and 7 days detects early morbidity and averts deaths. However, there is scarcity of information on use of EPNC in Mundri East County, South Sudan. This study investigated factors associated with EPNC use among postpartum mothers in Mundri East County, South Sudan. METHODS: This was an analytical cross-sectional study of 385 postpartum mothers from 13 health facilities. Data was collected by structured questionnaires, entered in EpiData and analyzed with STATA at 5% significance level. Chi-squared, Fisher's exact and Student's t-tests were used for bivariate analysis and logistic regression for multivariable analysis. RESULTS: The mean age of respondents was 27.9-years (standard deviation: 6.7), 276 (71.7%) were below 30-years, 163 (42.3%) were Muru ethnicity, 340 (88.3%) were single and 331 (86.1%) were unemployed. 44 (11.4%; 95% CI: 8.4-15.0) used EPNC. Poor health services access at government health facilities (Adjusted odds ratio (AOR) = 0.18; 95% CI: 0.05-0.61; P = 0.006), more than 1-h access to health facility (AOR = 0.27; 95% CI: 0.09-0.78; P = 0.015), at least secondary maternal education (AOR = 5.73; 95% CI: 1.14-28.74; P = 0.034) and receipt of PNC health education post delivery (AOR = 3.47; 95% CI: 1.06-11.33; P = 0.004) were associated with EPNC use. CONCLUSIONS: Use of EPNC in Mundri East County, South Sudan was low. It was significantly reduced at government and inaccessible health facilities. However, it increased with receipt of PNC health education after delivery and at least secondary level of education. PMID- 28651638 TI - Comparing regional models of congenital bleeding disorders: preliminary steps in the Italian context. AB - BACKGROUND: Among these diseases, congenital bleeding disorders (CBD) represent a significant societal burden in terms of high morbidity costs and health outcomes. In Italy, the organization and provision of health care is a regional responsibility and regions must assure equity and quality to all their residents. This is also true for CBD care which is provided by 54 multidisciplinary Hemophilia Treatment Centers (HTCs) distributed among the regions. With the present study, we intend to stimulate a debate on the effect that the decentralization process have in the delivery of services to CBD patients across Italy. METHODS: The available comparable measures of caseloads per center and interregional patient mobility, as proxies of quality and responsiveness of the regional network of HTCs, were first analyzed for the using data from the Italian Hemophilia Centers Association for the year 2012. RESULTS: Nine thousand one hundred and thirty four Italian residents with CBD received care in at least one of the Italian HTC in 2012. Preliminary findings suggested room for improvement in health care delivery for CBD patients. In 2012, 16 HTCs out of 51 (31.4%) treated a number of patients under the minimum requirement for treatment center accreditation (10 severe patients). Moreover, data on interregional patient mobility highlighted differences in the ability of each region to retain its own residents or to attract residents from other regions. CONCLUSIONS: Preliminary study results showed significant disparities among regions in terms of volumes and mobility of residents with CBDs that cannot be completely explained by the different geographical characteristics. Therefore, the central government should consider taking concrete measures to bridge the gap between regions to assure access to quality care for all individuals with CBD independently from where they live and therefore to move toward a more integrated and homogeneous national network of care centers. Typology of disease, patients' needs, and cost for outcomes, should have high priority on the political agenda. For CBD patients, even in a federal healthcare system, the national government should have the global responsibility to guaranteeing uniform levels of quality care over the country and overcome local institutions when necessary. PMID- 28651639 TI - Development and testing of a mobile application to support diabetes self management for people with newly diagnosed type 2 diabetes: a design thinking case study. AB - BACKGROUND: Numerous mobile applications have been developed to support diabetes self-management. However, the majority of these applications lack a theoretical foundation and the involvement of people with diabetes during development. The aim of this study was to develop and test a mobile application (app) supporting diabetes self-management among people with newly diagnosed type 2 diabetes using design thinking. METHODS: The app was developed and tested in 2015 using a design based research approach involving target users (individuals newly diagnosed with type 2 diabetes), research scientists, healthcare professionals, designers, and app developers. The research approach comprised three major phases: inspiration, ideation, and implementation. The first phase included observations of diabetes education and 12 in-depth interviews with users regarding challenges and needs related to living with diabetes. The ideation phrase consisted of four interactive workshops with users focusing on app needs, in which ideas were developed and prioritized. Finally, 14 users tested the app over 4 weeks; they were interviewed about usability and perceptions about the app as a support tool. RESULTS: A multifunctional app was useful for people with newly diagnosed type 2 diabetes. The final app comprised five major functions: overview of diabetes activities after diagnosis, recording of health data, reflection games and goal setting, knowledge games and recording of psychological data such as sleep, fatigue, and well-being. Users found the app to be a valuable tool for support, particularly for raising their awareness about their psychological health and for informing and guiding them through the healthcare system after diagnosis. CONCLUSIONS: The design thinking processes used in the development and implementation of the mobile health app were crucial to creating value for users. More attention should be paid to the training of professionals who introduce health apps. TRIAL REGISTRATION: Danish Data Protection Agency: 2012-58-0004. Registered 6 February 2016. PMID- 28651640 TI - Quality in intensive care units: proposal of an assessment instrument. AB - BACKGROUND: There is an increasing need for standardized instruments for quality assessment that are able to reflect the actual conditions of the intensive care practices, especially in low and middle-income countries. The aim of this article is to describe the preparation of an instrument for quality assessment of adult intensive care services adapted to the actual conditions of intensive care in a middle-income country and comprising indicators validated in the literature. METHODS: The study consisted of five steps: (1) a literature survey; (2) a discussion with specialists by consensus method; (3) a pilot field test; (4) a description of indicators; and (5) an elaboration of the final version of the instrument. Each generated indicator was attributed a score ("out of standard" = 0; "below standard" = 1; "standard" = 2) that allowed calculation of the total score for each service assessed. RESULTS: A total of 62 indicators were constructed, distributed as follows: 38 structure indicators (physical structure: 4; human resources: 14; continued education and training: 2; protocols and routines: 12; material resources: 6); 17 process indicators (safety: 7; work: 10); and seven outcome indicators. The maximum possible total score was 124. CONCLUSIONS: Possible future applications of the instrument for the assessment of intensive care units that was constructed in the present study include benchmarking, multicenter studies, self-assessment of intensive care units, and evaluation of changes resulting from interventions. PMID- 28651641 TI - Examining the psychometric properties of a sport-related concussion survey: a Rasch measurement approach. AB - BACKGROUND: Awareness of sport-related concussion (SRC) is an essential step in increasing the number of athletes or parents who report on SRC. This awareness is important, as there is no established data on medical care at youth-level sports and may be limited to individuals with only first aid training. In this circumstance, aside from the coach, it is the players and their parents who need to be aware of possible signs and symptoms. The aim of this study was to examine the psychometric properties of a parent and player concussion survey intended for use before and after an education campaign regarding SRC. METHODS: 1441 questionnaires were received from parents and 284 questionnaires from players. The responses to the sixteen-item section of the questionnaire's 'recognition of signs and symptoms' were submitted to psychometric analysis using the dichotomous and polytomous Rasch model via the Rasch Unidimensional Measurement Model software RUMM2030. The Rasch model of Modern Test Theory can be considered a refinement of, or advance on, traditional analyses of an instrument's psychometric properties. RESULTS: The main finding is that these sixteen items measure two factors: items that are symptoms of concussion and items that are not symptoms of concussion. Parents and athletes were able to identify most or all of the symptoms, but were not as good at distinguishing symptoms that are not symptoms of concussion. Analyzing these responses revealed differential item functioning for parents and athletes on non-symptom items. When the DIF was resolved a significant difference was found between parents and athletes. CONCLUSIONS: The main finding is that the items measure two 'dimensions' in concussion symptom recognition. The first dimension consists of those items that are symptoms of concussion and the second dimension of those items that are not symptoms of concussion. Parents and players were able to identify most or all of the symptoms of concussion, so one would not expect to pick up any positive change on these items after an education campaign. Parents and players were not as good at distinguishing symptoms that are not symptoms of concussion. It is on these items that one may possibly expect improvement to manifest, so to evaluate the effectiveness of an education campaign it would pay to look for improvement in distinguishing symptoms that are not symptoms of concussion. PMID- 28651642 TI - A pilot randomized controlled trial of acupuncture at the Si Guan Xue for cancer pain. AB - BACKGROUND: Pain is a common symptom in cancer patients. Acupuncture is a suggested treatment for a wide range of clinical conditions, usually for its beneficial effects on pain control. Si guan xue (the four points) have been widely used in clinical practice, and has shown that it is highly effective, effective in obtaining qi, shows strong acupuncture stimulation, and is simple to manipulate and safe to use. Therefore, the aim of this study is to test the protocol and safety of acupuncture at the si guan xue in the management of cancer pain. METHODS: This is a single-blind, randomized controlled pilot trial. 42 patients with moderate to severe cancer pain were randomly assigned to three different arms with seven sessions of treatment; that is, treatment arm 1 (the si guan xue arm, n = 14), treatment arm 2 (the si guan xue plus commonly used acupoints arm, n = 14) and the control arm (the commonly used acupoints arm n = 14). Primary outcomes included acupuncture relieving cancer pain, and patients' subjective improvement as measured by the Patient Global Impression of Change (PGIC). Secondary outcomes included the scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) and Karnofsky's Performance Status (KPS). RESULTS: The analysis showed that the cancer pain reduction in treatment arm 2 was most prominent on day 5 when compared with the control arm (P<0.05). There was no difference in the scores of PGIC, EORTC QLQ-C30 or KPS among the three groups (P>0.05). Furthermore, no serious adverse events were observed. CONCLUSIONS: These results indicate that acupuncture at the si guan xue plus commonly used acupoints tends to be effective in reducing cancer pain. However, the sample size was small, and a future multi centre study with a larger sample size is warranted. TRIAL REGISTRATION: ChiCTR IOR-15007471 (Retroactively registered on 28 NOV 2015). PMID- 28651643 TI - Understanding resilience of female adolescents towards teenage pregnancy: a cross sectional survey in Dar es Salaam, Tanzania. AB - BACKGROUND: In Tanzania, teenage pregnancy rates are still high despite the efforts being made to reduce them. Not enough is known about how adolescents experience and cope with sexuality and teenage pregnancy. Over the past few decades, most studies have focused on vulnerability and risk among youth. The concept of 'reproductive resilience' is a new way of looking at teenage pregnancy. It shifts the perspective from a deficit-based to a strength-based approach. The study presented here aimed to identify factors that could contribute to strengthening the reproductive resilience of girls in Dar es Salaam, Tanzania. METHODS: Using a cross-sectional cluster sampling approach, 750 female adolescents aged 15-19 years were interviewed about how they mobilize resources to avoid or deal with teenage pregnancy. The main focus of the study was to examine how social capital (relations with significant others), economic capital (command over economic resources), cultural capital (personal dispositions and habits), and symbolic capital (recognition and prestige) contribute to the development of adolescent competencies for avoiding or dealing with teenage pregnancy and childbirth. RESULTS: A cumulative competence scale was developed to assess reproductive resilience. The cumulative score was computed based on 10 competence indicators that refer to the re- and pro-active mobilization of resources. About half of the women who had never been pregnant fell into the category, 'high competence' (50.9%), meaning they could get the information and support needed to avoid pregnancies. Among pregnant women and young mothers, most were categorized as 'high competence' (70.5%) and stated that they know how to avoid or deal with health problems that might affect them or their babies, and could get the information and support required to do so. Cultural capital, in particular, contributed to the competence of never-pregnant girls [OR = 1.80, 95% CI = 1.06 to 3.07, p = 0.029], pregnant adolescents and young mothers [OR = 3.33, 95% CI = 1.15 to 9.60, p = 0.026]. CONCLUSIONS: The reproductive resilience framework provides new insights into the reproductive health realities of adolescent girls from a strength-based perspective. While acknowledging that teenage pregnancy has serious negative implications for many female adolescents, the findings presented here highlight the importance of considering girls' capacities to prevent or deal with teenage pregnancy. PMID- 28651645 TI - Lead field theory provides a powerful tool for designing microelectrode array impedance measurements for biological cell detection and observation. AB - BACKGROUND: Our aim is to introduce a method to enhance the design process of microelectrode array (MEA) based electric bioimpedance measurement systems for improved detection and viability assessment of living cells and tissues. We propose the application of electromagnetic lead field theory and reciprocity for MEA design and measurement result interpretation. Further, we simulated impedance spectroscopy (IS) with two- and four-electrode setups and a biological cell to illustrate the tool in the assessment of the capabilities of given MEA electrode constellations for detecting cells on or in the vicinity of the microelectrodes. RESULTS: The results show the power of the lead field theory in electromagnetic simulations of cell-microelectrode systems depicting the fundamental differences of two- and four-electrode IS measurement configurations to detect cells. Accordingly, the use in MEA system design is demonstrated by assessing the differences between the two- and four-electrode IS configurations. Further, our results show how cells affect the lead fields in these MEA system, and how we can utilize the differences of the two- and four-electrode setups in cell detection. The COMSOL simulator model is provided freely in public domain as open source. CONCLUSIONS: Lead field theory can be successfully applied in MEA design for the IS based assessment of biological cells providing the necessary visualization and insight for MEA design. The proposed method is expected to enhance the design and usability of automated cell and tissue manipulation systems required for bioreactors, which are intended for the automated production of cell and tissue grafts for medical purposes. MEA systems are also intended for toxicology to assess the effects of chemicals on living cells. Our results demonstrate that lead field concept is expected to enhance also the development of such methods and devices. PMID- 28651644 TI - A new use for an old index: preoperative high-density lipoprotein predicts recurrence in patients with hepatocellular carcinoma after curative resections. AB - BACKGROUND: Hepatocellular carcinoma has high incidence and mortality worldwide. Liver is the site of most metabolic biotransformation, which could reflect the status of cells. Most plasma apolipoproteins, endogenous lipids and lipoproteins are synthesized in the liver. Therefore, the effects of lipid metabolites on prognosis of HCC deserved to be explored. METHODS: We prospectively included 58 healthy donors (HD), 50 chronic hepatitis (CH) patients and a training cohort of 189 patients with HCC who underwent curative resections at Zhongshan Hospital from January 2012 to August 2012. We identified the optimal HDLPO cutoff value at 0.98 mmol/L and used it to stratify patients into low- or high-HDLPO groups for the entire cohort and four low-recurrent-risk subgroups. We also included an independent validation group of 182 HCC patients to validate this cutoff value. Prognostic values of HDLPO and other factors were determined by Kaplan-Meier curves and the Cox proportional hazards model. RESULTS: The low-HDLPO group had a higher median tumor grade (P = 0.020) and a higher recurrence rate (P = 0.032). Results of multivariate analysis showed that preoperative gamma-glutamyl transpeptidase (GGT) and HDLPO were independent predictors of recurrence. Moreover, the predictive value of HDLPO was retained in four low-recurrent-risk subgroups. As expected, clinicopathologic characteristics and predictive values were similar in the validation and training cohorts. CONCLUSIONS: HDLPO is an accessible predictor of HCC recurrence after liver resections that can help identify patients who need more careful monitoring and follow-up care. PMID- 28651646 TI - A large-scale behavior change intervention to prevent Nipah transmission in Bangladesh: components and costs. AB - BACKGROUND: Nipah virus infection (NiV) is a bat-borne zoonosis transmitted to humans through consumption of NiV-contaminated raw date palm sap in Bangladesh. The objective of this analysis was to measure the cost of an NiV prevention intervention and estimate the cost of scaling it up to districts where spillover had been identified. METHODS: We implemented a behavior change communication intervention in two districts, testing different approaches to reduce the risk of NiV transmission using community mobilization, interpersonal communication, posters and TV public service announcements on local television during the 2012 2014 sap harvesting seasons. In one district, we implemented a "no raw sap" approach recommending to stop drinking raw date palm sap. In another district, we implemented an "only safe sap" approach, recommending to stop drinking raw date palm sap but offering the option of drinking safe sap. This is sap covered with a barrier, locally called bana, to interrupt bats' access during collection. We conducted surveys among randomly selected respondents two months after the intervention to measure the proportion of people reached. We used an activity based costing method to calculate the cost of the intervention. RESULTS: The implementation cost of the "no raw sap" intervention was $30,000 and the "only safe sap" intervention was $55,000. The highest cost was conducting meetings and interpersonal communication efforts. The lowest cost was broadcasting the public service announcements on local TV channels. To scale up a similar intervention in 30 districts where NiV spillover has occurred, would cost between $2.6 and $3.5 million for one season. Placing the posters would cost $96,000 and only broadcasting the public service announcement through local channels in 30 districts would cost $26,000. CONCLUSIONS: Broadcasting a TV public service announcement is a potential low cost option to advance NiV prevention. It could be supplemented with posters and targeted interpersonal communication, in districts with a high risk of NiV spillover. PMID- 28651647 TI - Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. AB - BACKGROUND: In the recent decade, iron oxide nanoparticles (IONPs) have been proposed for several applications in the central nervous system (CNS), including targeting amyloid beta (Abeta) in the arteries, inhibiting the microglial cells, delivering drugs, and increasing contrast in magnetic resonance imaging. Conversely, a notable number of studies have reported the role of iron in neurodegenerative diseases. Therefore, this study has reviewed the recent studies to determine whether IONPs iron can threaten the cellular viability same as iron. RESULTS: Iron contributes in Fenton's reaction and produces reactive oxygen species (ROS). ROS cause to damage the macromolecules and organelles of the cell via oxidative stress. Iron accumulation and oxidative stress are able to aggregate some proteins, including Abeta and alpha-synuclein, which play a critical role in Alzheimer's and Parkinson's diseases, respectively. Iron accumulation, oxidative stress, and protein aggregation make a positive feedback loop, which can be toxic for the cell. The release of iron ions from IONPs may result in iron accumulation in the targeted tissue, and thus, activate the positive feedback loop. However, the levels of IONPs induced toxicity depend on the size, concentration, surface charge, and the type of coating and functional groups of IONPs. CONCLUSION: IONPs depending on their properties can lead to iron accumulation, oxidative stress and protein aggregation in the neural cells. Therefore, in order to apply IONPs in the CNS, the consideration of IONPs properties is crucial. PMID- 28651648 TI - The Risk of Oxygen during Cardiac Surgery (ROCS) trial: study protocol for a randomized clinical trial. AB - BACKGROUND: Anesthesiologists administer excess supplemental oxygen (hyper oxygenation) to patients during surgery to avoid hypoxia. Hyper-oxygenation, however, may increase the generation of reactive oxygen species and cause oxidative damage. In cardiac surgery, increased oxidative damage has been associated with postoperative kidney and brain injury. We hypothesize that maintenance of normoxia during cardiac surgery (physiologic oxygenation) decreases kidney injury and oxidative damage compared to hyper-oxygenation. METHODS/DESIGN: The Risk of Oxygen during Cardiac Surgery (ROCS) trial will randomly assign 200 cardiac surgery patients to receive physiologic oxygenation, defined as the lowest fraction of inspired oxygen (FIO2) necessary to maintain an arterial hemoglobin saturation of 95 to 97%, or hyper-oxygenation (FIO2 = 1.0) during surgery. The primary clinical endpoint is serum creatinine change from baseline to postoperative day 2, and the primary mechanism endpoint is change in plasma concentrations of F2-isoprostanes and isofurans. Secondary endpoints include superoxide production, clinical delirium, myocardial injury, and length of stay. An endothelial function substudy will examine the effects of oxygen treatment and oxidative stress on endothelial function, measured using flow mediated dilation, peripheral arterial tonometry, and wire tension myography of epicardial fat arterioles. DISCUSSION: The ROCS trial will test the hypothesis that intraoperative physiologic oxygenation decreases oxidative damage and organ injury compared to hyper-oxygenation in patients undergoing cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02361944 . Registered on the 30th of January 2015. PMID- 28651649 TI - Relationship between knee osteoarthritis and meniscal shape in observation of Japanese patients by using magnetic resonance imaging. AB - BACKGROUND: The aims of this study were to reveal the characteristics of the meniscal shape at each knee osteoarthritis (OA) severity level and to predict trends or patterns of the meniscal shape change as associated with knee OA progression. METHODS: Fifty-one patients diagnosed with knee OA based on X-ray and magnetic resonance (MR) images were evaluated. They were divided into three groups based on the Kellgren-Lawrence (KL) grade: normal group (KL grade of 0 or 1), mild group (KL grade of 2 or 3), and severe group (KL grade of 4). We measured the patients' meniscal size and meniscal extrusion using MR images. In addition, semiquantitative measurement was performed using MR images to determine the arthritic status of the corresponding compartment using a whole-organ magnetic resonance imaging score (WORMS). RESULTS: The longitudinal diameter and posterior wedge angle of the medial meniscus were significantly larger, and the posterior wedge width of the medial meniscus was significantly smaller in the severe group than in the normal group. The WORMS scores for cartilage and osteophytes in the medial region were significantly different among the groups. The WORMS score of each region was strongly correlated with the longitudinal diameter. The WORMS scores of the lateral region were lower than those of the medial region. CONCLUSION: Our observation of the shape change of the medial meniscus in the posterior region was roughly consistent with that in many previous studies of meniscal degeneration. On the other hand, we saw that the most relevant relation between the progression of the knee OA and the deformation of the meniscus was in the longitudinal direction. PMID- 28651651 TI - A rare, giant coronary artery ectasia coexisting with a coronary artery fistula in an older infant. AB - Coronary artery fistula with giant coronary artery ectasia is a rare abnormal CHD. Multidetector CT is useful for the diagnosis. Early diagnosis and surgery are recommended. PMID- 28651650 TI - Ethics review of studies during public health emergencies - the experience of the WHO ethics review committee during the Ebola virus disease epidemic. AB - BACKGROUND: Between 2013 and 2016, West Africa experienced the largest ever outbreak of Ebola Virus Disease. In the absence of registered treatments or vaccines to control this lethal disease, the World Health Organization coordinated and supported research to expedite identification of interventions that could control the outbreak and improve future control efforts. Consequently, the World Health Organization Research Ethics Review Committee (WHO-ERC) was heavily involved in reviews and ethics discussions. It reviewed 24 new and 22 amended protocols for research studies including interventional (drug, vaccine) and observational studies. WHO-ERC REVIEWS: WHO-ERC provided the reviews within on average 6 working days. The WHO-ERC often could not provide immediate approval of protocols for reasons which were not Ebola Virus Disease specific but related to protocol inconsistencies, missing information and complex informed consents. WHO-ERC considerations on Ebola Virus Disease specific issues (benefit-risk assessment, study design, exclusion of pregnant women and children from interventional studies, data and sample sharing, collaborative partnerships including international and local researchers and communities, community engagement and participant information) are presented. CONCLUSIONS: To accelerate study approval in future public health emergencies, we recommend: (1) internally consistent and complete submissions with information documents in language participants are likely to understand, (2) close collaboration between local and international researchers from research inception, (3) generation of template agreements for data and sample sharing and use during the ongoing global consultations on bio-banks, (4) formation of Joint Scientific Advisory and Data Safety Review Committees for all studies linked to a particular intervention or group of interventions, (5) formation of a Joint Ethics Review Committee with representatives of the Ethics Committees of all institutions and countries involved to strengthen reviews through the different perspectives provided without the 'opportunity costs' for time to final approval of multiple, independent reviews, (6) direct information exchange between the chairs of advisory, safety review and ethics committees, (7) more Ethics Committee support for investigators than is standard and (8) a global consultation on criteria for inclusion of pregnant women and children in interventional studies for conditions which put them at particularly high risk of mortality or other irreversible adverse outcomes under standard-of-care. PMID- 28651652 TI - The association between measurements of antimicrobial use and resistance in the faeces microbiota of finisher batches. AB - The objectives were to present three approaches for calculating antimicrobial (AM) use in pigs that take into account the rearing period and rearing site, and to study the association between these measurements and phenotypical resistance and abundance of resistance genes in faeces samples from 10 finisher batches. The AM use was calculated relative to the rearing period of the batches as (i) 'Finisher Unit Exposure' at unit level, (ii) 'Lifetime Exposure' at batch level and (iii) 'Herd Exposure' at herd level. A significant effect on the occurrence of tetracycline resistance measured by cultivation was identified for Lifetime Exposure for the AM class: tetracycline. Furthermore, for Lifetime Exposure for the AM classes: macrolide, broad-spectrum penicillin, sulfonamide and tetracycline use as well as Herd Unit Exposure for the AM classes: aminoglycoside, lincosamide and tetracycline use, a significant effect was observed on the occurrence of genes coding for the AM resistance classes: aminoglycoside, lincosamide, macrolide, beta-lactam, sulfonamide and tetracycline. No effect was observed for Finisher Unit Exposure. Overall, the study shows that Lifetime Exposure is an efficient measurement of AM use in finisher batches, and has a significant effect on the occurrence of resistance, measured either by cultivation or metagenomics. PMID- 28651653 TI - Influence of nitric oxide and phosphodiesterases during in vitro maturation of bovine oocytes on meiotic resumption and embryo production. AB - This study aimed to examine the effects of nitric oxide (NO) and different phosphodiesterase (PDE) families on meiosis resumption, nucleotides levels and embryo production. Experiment I, COCs were matured in vitro with the NO donor S nitroso-N-acetylpenicillamine (SNAP) associated or not with the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), meiotic resumption and nucleotides levels were assessed. SNAP delayed germinal vesicle breakdown (GVBD) (53.4 +/- 1.2 versus 78.4 +/- 2.4% for controls, P 0.05). Cyclic GMP levels were higher in SNAP (3.94 +/- 0.18, P 0.05). Embryo development did not differ from the control for SNAP and cilostamide groups (38.7 +/- 5.8, 37.9 +/- 6.2 and 40.5 +/- 5.8%, P > 0.05), but SNAP + cilostamide decreased embryo production (25.7 +/- 6.9%, P < 0.05). In conclusion, SNAP was confirmed to delay meiosis resumption by the NO/sGC/cGMP pathway, by increasing cGMP, but not cAMP. Inhibiting different PDEs to further increase nucleotides in association with SNAP did not show any additive effects on meiosis resumption, indicating that other pathways are involved. Moreover, SNAP + cilostamide affected the meiosis progression and decreased embryo development. PMID- 28651654 TI - Concomitant imaging and genetic findings in children with unilateral sensorineural hearing loss. AB - OBJECTIVE: To describe the concomitant imaging and genetic findings in children diagnosed with non-syndromic unilateral sensorineural hearing loss. METHODS: A retrospective cohort study was conducted of 60 children diagnosed between January 2005 and December 2015 in a tertiary-level paediatric institution. RESULTS: Average age at diagnosis was 4.3 years. All children were considered non syndromic. Hearing loss was categorised as mild (17 children), moderate (17 children), severe (7 children) or profound (19 children). Imaging was performed in 43 children (71.66 per cent). Nineteen patients (44.2 per cent) had positive computed tomography or magnetic resonance imaging findings. Genetic testing was performed in 51 children (85 per cent). Sixteen children (31 per cent) tested positive to connexin 26 (GJB2); 1 patient (2 per cent) had a homozygous mutation of GJB2 and 15 were heterozygous carriers. Amongst children who tested positive as heterozygous carriers of a GJB2 mutation, there was a high rate of positive imaging findings (47 per cent compared to 37.2 per cent in the total cohort). A genetic abnormality was confirmed in 50 per cent of children with positive imaging findings who underwent genetic testing. CONCLUSION: Rates of concomitant imaging and genetic findings suggest that both investigations are of value in the study of these patients. PMID- 28651655 TI - Addendum. PMID- 28651656 TI - Operable patent ductus arteriosus even with differential cyanosis: a case of patent ductus arteriosus and mitral stenosis. AB - Patients with patent ductus arteriosus and significant left-to-right shunt develop Eisenmenger syndrome at an early age and are not operable after development of irreversible pulmonary artery hypertension. Patients with mitral stenosis, however, are treatable even with suprasystemic pulmonary artery pressures. A combination of these two lesions is rare. We document a patient with differential cyanosis who improved after corrective surgery of both the lesions. The importance of post-capillary pulmonary artery hypertension in shunt lesions needs to be better appreciated. PMID- 28651657 TI - Association between Violent Crime and Psychosis in Men Serving Prison Terms. AB - Psychosis has been associated with committing violent crimes. However, it has been reported that the association is mediated by toxin consumption, personality disorders, and positive symptoms. This study will examine the relationship between different psychological disorders and sociodemographic variables, and violent crime perpetration in a sample of 472 men serving prison terms in Andalusia, Spain. A correlation-based, retrospective study was conducted and data were analyzed through logistic regression. The sample is representative of the Andalusian prison population, with a 95% level of confidence and .02% precision. Inmates were sampled and diagnosed by expert clinicians using the SCID-I and the IPDE-II. We computed bivariate correlations between the aforementioned variables and perpetration of violent crimes (murder, homicide, attempted murder, and injury) to later apply logistic regression and find adjusted odds ratios. We confirmed the association between diagnosis of functional psychoses and violent crime, with a significant adjusted odds ratio in the last model (OR = 3.71; p = .010). Other significant variables that acted like risk factors include suicide attempts (OR = 2.04; p = .046), having received care at a mental health facility in the year before imprisonment (OR = 3.83; p = .008), and more strongly than the psychosis diagnosis, low level of education (OR = 10.32; p = .029). Toxin consumption and personality disorders were not significant in the final model. PMID- 28651658 TI - The impact of diet-based glycaemic response and glucose regulation on cognition: evidence across the lifespan. AB - The brain has a high metabolic rate and its metabolism is almost entirely restricted to oxidative utilisation of glucose. These factors emphasise the extreme dependence of neural tissue on a stable and adequate supply of glucose. Whereas initially it was thought that only glucose deprivation (i.e. under hypoglycaemic conditions) can affect brain function, it has become apparent that low-level fluctuations in central availability can affect neural and consequently, cognitive performance. In the present paper the impact of diet based glycaemic response and glucose regulation on cognitive processes across the lifespan will be reviewed. The data suggest that although an acute rise in blood glucose levels has some short-term improvements of cognitive function, a more stable blood glucose profile, which avoids greater peaks and troughs in circulating glucose is associated with better cognitive function and a lower risk of cognitive impairments in the longer term. Therefore, a habitual diet that secures optimal glucose delivery to the brain in the fed and fasting states should be most advantageous for the maintenance of cognitive function. Although the evidence to date is promising, it is insufficient to allow firm and evidence based nutritional recommendations. The rise in obesity, diabetes and metabolic syndrome in recent years highlights the need for targeted dietary and lifestyle strategies to promote healthy lifestyle and brain function across the lifespan and for future generations. Consequently, there is an urgent need for hypothesis driven, randomised controlled trials that evaluate the role of different glycaemic manipulations on cognition. PMID- 28651659 TI - A facilitated approach to family case conferencing for people with advanced dementia living in nursing homes: perceptions of palliative care planning coordinators and other health professionals in the IDEAL study. AB - BACKGROUND: Palliative care for nursing home residents with advanced dementia is often sub-optimal due to poor communication and limited care planning. In a cluster randomized controlled trial, registered nurses (RNs) from 10 nursing homes were trained and funded to work as Palliative Care Planning Coordinators (PCPCs) to organize family case conferences and mentor staff. This qualitative sub-study aimed to explore PCPC and health professional perceptions of the benefits of facilitated case conferencing and identify factors influencing implementation. METHOD: Semi-structured interviews were conducted with the RNs in the PCPC role, other members of nursing home staff, and physicians who participated in case conferences. Analysis was conducted by two researchers using a thematic framework approach. RESULTS: Interviews were conducted with 11 PCPCs, 18 other nurses, eight allied health workers, and three physicians. Perceived benefits of facilitated case conferencing included better communication between staff and families, greater multi-disciplinary involvement in case conferences and care planning, and improved staff attitudes and capabilities for dementia palliative care. Key factors influencing implementation included: staffing levels and time; support from management, staff and physicians; and positive family feedback. CONCLUSION: The facilitated approach explored in this study addressed known barriers to case conferencing. However, current business models in the sector make it difficult for case conferencing to receive the required levels of nursing qualification, training, and time. A collaborative nursing home culture and ongoing relationships with health professionals are also prerequisites for success. Further studies should document resident and family perceptions to harness consumer advocacy. PMID- 28651660 TI - Sudden improvement in ventricular repolarization abnormality after a short detraining period in an athlete. AB - We describe the case of a 17-year-old male soccer player with T-wave inversion in precordial leads in resting electrocardiography, which also disclosed sinus bradycardia, early repolarization, and increased QRS voltage. These findings strongly suggested cardiomyopathy. The patient's T-wave inversion disappeared during only 2 weeks of detraining, and it re-appeared 2 weeks after resumption of intensive training. This sudden change in electrocardiographic parameters over a short period helped in identifying the adolescent as having athlete's heart. PMID- 28651661 TI - Biological characterization and mating compatibility of Helicoverpa gelotopoeon (D.) (Lepidoptera: Noctuidae) populations from different regions in Argentina. AB - Helicoverpa gelotopoeon, the South American bollworm, is a polyphagous pest of the Heliothinae complex that causes damage to soybean, cotton, and chickpea crops. Some species within this complex have developed resistance to genetically modified crops and insecticides, which has led to increased interest in their genetic diversity and population structure. The objective of this study was to characterize biological and reproductive parameters of two populations of H. gelotopoeon collected in two different provinces of Argentina. Intra- and inter population crosses revealed that H. gelotopoeon populations from both regions of Argentina did not present evidence of pre-zygotic and post-zygotic incompatibility, suggesting that Tucuman and Cordoba populations of H. gelotopoeon belong to a single wide-ranging species. Our data support the occurrence of substantial gene flow between H. gelotopoeon populations, probably due to the widely documented, long-range migratory capacity of Heliothinae species. PMID- 28651662 TI - Epidemiology of electrical and lightning-related injuries among Canadian children and youth, 1997-2010: A Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) study. AB - : IntroductionAlthough death due to electrical injury and lightning are rare in children, these injuries are often preventable. Twenty years ago, most injuries occurred at home, precipitated by oral contact with electrical cords, contact with wall sockets and faulty electrical equipment. We sought to assess the epidemiology of electrical injuries in children presenting to Emergency Departments (EDs) that participate in the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP). METHODS: This study is a retrospective review of electrical and lightning injury data from CHIRPP. The study population included children and youth aged 0-19 presenting to participating CHIRPP EDs from 1997 2010. Age, sex, year, setting, circumstance and disposition were extracted. Variables were tested using Fisher's exact test and simple linear regression. RESULTS: The dataset included 1183 electrical injuries, with 84 (7%) resulting in hospitalization. Most events occurred at home in the 2-5 year age group and affected the hands. Since 1997 there has been a gradual decrease in the number of electrical injuries per year (p<0.01) and there is an annual surge in electrical injuries over the summer (p<0.01). Forty-six percent of injuries involved electrical outlets, 65% of injuries involved some sort of electrical equipment. Injuries due to lightning were rare (n=19). No deaths were recorded in the database. CONCLUSION: Despite the decrease in the number of electrical injuries per year, a large portion of injuries still appear to be preventable. Further research should focus on effective injury prevention strategies. PMID- 28651663 TI - Brief Coping Strategy Enhancement for Distressing Voices: an Evaluation in Routine Clinical Practice. AB - BACKGROUND: Hearing voices can be a common and distressing experience. Psychological treatment in the form of cognitive behavioural therapy for psychosis (CBTp) is effective, but is rarely available to patients. The barriers to increasing access include a lack of time for clinicians to deliver therapy. Emerging evidence suggests that CBTp delivered in brief forms can be effective and offer one solution to increasing access. AIMS: We adapted an existing form of CBTp, coping strategy enhancement (CSE), to focus specifically on distressing voices in a brief format. This intervention was evaluated within an uncontrolled study conducted in routine clinical practice. METHOD: This was a service evaluation comparing pre-post outcomes in patients who had completed CSE over four sessions within a specialist out-patient service within NHS Mental Health Services. The primary outcome was the distress scale of the Psychotic Symptoms Rating Scale - Auditory Hallucinations (PSYRATS-AH). RESULTS: Data were available from 101 patients who had completed therapy. A reduction approaching clinical importance was found on the PSYRATS distress scale post-therapy when compared with the baseline. CONCLUSIONS: The findings from this study suggest that CSE, as a focused and brief form of CBTp, can be effective in the treatment of distressing voices within routine clinical practice. Within the context of the limitations of this study, brief CSE may best be viewed as the beginning of a therapeutic conversation and a low-intensity intervention in a stepped approach to the treatment of distressing voices. PMID- 28651664 TI - The effect of varying proportion and chop length of lucerne silage in a maize silage-based total mixed ration on diet digestibility and milk yield in dairy cattle. AB - The objective was to assess the effects of inclusion rate and chop length of lucerne silage, when fed in a total mixed ration (TMR), on milk yield, dry matter (DM) intake (DMI) and digestion in dairy cows. Diets were formulated to contain a 50 : 50 ratio of forage : concentrate (DM basis) and to be isonitrogenous (170 g/kg CP). The forage portion of the offered diets was comprised of maize and lucerne silage in proportions (DM basis) of either 25 : 75 (high Lucerne (HL)) or 75 : 25 (low lucerne (LL)). Lucerne was harvested and conserved as silage at either a long (L) or short (S) chop length. These variables were combined in a 2*2 factorial arrangement to give four treatments (HLL, HLS, LLL, LLS) which were fed in a Latin square design study to Holstein dairy cows in two separate experiments. In total, 16 and 8 multiparous, mid-lactation cows were used in experiments 1 and 2, respectively. To ensure sufficient silage for both experiments, different cuts of lucerne silage (taken from the same sward) were used for each experiment: first cut for experiment 1 (which was of poorer quality) and second cut for experiment 2. Dry matter intake, milk yield and milk composition where measured in both experiments, and total tract digestibility and nitrogen (N) balance were assessed using four cows in experiment 2. In experiment 1, cows fed LL had increased DMI (+3.2 kg/day), compared with those fed HL. In contrast, there was no difference in DMI due to lucerne silage inclusion rate in experiment 2. A reduction in milk yield was observed with the HL treatment in both experiment 1 and 2 (-3.0 and -2.9 kg/day, respectively). The HL diet had reduced digestibility of DM and organic matter (OM) (-3% and -4%, respectively), and also reduced the efficiency of intake N conversion into milk N (-4%). The S chop length increased total tract digestibility of DM and OM (both +4%), regardless of inclusion rate. Inclusion of lucerne silage at 25% of forage DM increased milk yield relative to 75% inclusion, but a S chop length partially mitigated adverse effects of HL on DMI and milk yield in experiment 1 and on DM digestibility in experiment 2. PMID- 28651665 TI - Using milk leukocyte differentials for diagnosis of subclinical bovine mastitis. AB - This research study aimed to evaluate the use of the milk leukocyte differential (MLD) to: (a) identify quarter milks that are culture-positive; and (b) characterize the milk leukocyte responses to specific groups of pathogens causing subclinical mastitis. The MLD measures the absolute number and relative percentage of inflammatory cells in milk samples. Using the MLD in two dairy herds (170 and 172 lactating cows, respectively), we studied all lactating cows with a most recent monthly Dairy Herd Improvement Association somatic cell count (SCC) >200 * 103 cells/ml. Quarter milk samples from 78 cows meeting study criteria were analysed by MLD and aseptically collected milk samples were subjected to microbiological culture (MC). Based upon automated instrument evaluation of the number and percentage of inflammatory cells in milk, samples were designated as either MLD-positive or - negative for subclinicial mastitis. Positive MC were obtained from 102/156 (65.4%) of MLD-positive milk samples, and 28/135 (20.7%) of MLD-negative milk samples were MC-positive. When MC was considered the gold standard for mastitis diagnosis, the calculated diagnostic Se of the MLD was 65.4% (IC95% = 57.4 to 72.8%) and the Sp was 79.3% (IC95% = 71.4 to 85.7%). Quarter milks positive on MC had higher absolute numbers of neutrophils, lymphocytes and macrophages, with higher neutrophils% and lymphocytes% but lower macrophages%. The Log10 (N/L) ratios were the most useful ratio to differentiate specific subclinical mastitis quarters from healthy quarters. Use of the MLD on cows with monthly composite SCC > 200 * 103 cells/ml for screening at quarter level identified quarters more likely to be culture positive. In conclusion, the MLD can provide an analysis of mammary quarter status more detailed than provided by SCC alone; however, the MLD response to subclinical mastitis was not found useful to specifically identify the causative pathogen. PMID- 28651666 TI - Genetic and phenotypic overlap of specific obsessive-compulsive and attention deficit/hyperactive subtypes with Tourette syndrome. AB - BACKGROUND: The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families. METHOD: OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed. RESULTS: EFA yielded a 2-factor model for ADHD and an 8 factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (?50% for all disorders). CONCLUSIONS: Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders. PMID- 28651667 TI - Results of pulmonary balloon valvuloplasty persist and improve at late follow-up in isolated pulmonary valve stenosis. AB - BACKGROUND: Pulmonary balloon valvuloplasty is a safe and effective treatment for children with pulmonary valve stenosis. A few studies evaluate the long-term outcomes of the procedure, particularly the degree of pulmonary regurgitation. We evaluated the outcomes of children >1 year following valvuloplasty for pulmonary valve stenosis. METHODS: A retrospective analysis of children with pulmonary valve stenosis following pulmonary balloon valvuloplasty at a single institution was performed. Clinic summaries, catheterisation data, and echocardiographic data were reviewed. Inclusion criteria were isolated pulmonary valve stenosis, age <19 years at the time of intervention, and at least one echocardiogram performed at least 1 year after valvuloplasty. RESULTS: A total of 53 patients met inclusion criteria. The median age at valvuloplasty was 0.4 years (0.01-10.6 years). The last follow-up was 4.8+/-2.3 years following valvuloplasty. The pre-valvuloplasty peak instantaneous gradient by echocardiography was 60.6+/-14.6 mmHg. The peak gradient at the first postoperative echocardiography was reduced to 25.5+/-12 mmHg (p<0.001), and further decreased to 14.8+/-15.8 mmHg (p<0.001) at the most recent follow-up. The degree of regurgitation increased from before valvuloplasty to after valvuloplasty (p<0.001) but did not progress at the most recent follow up (p=0.17). Only three patients (5.7%) required re-intervention for increasing pulmonary stenosis (two surgical; one repeat balloon). No significant procedural complications occurred. CONCLUSIONS: Pulmonary balloon valvuloplasty remains a safe and effective treatment for children with isolated pulmonary valve stenosis, with excellent long-term outcomes and no mortality. A few patients require further intervention. Long-term follow-up demonstrates decreased, residual stenosis. Patients have a small, acute increase in pulmonary regurgitation following valvuloplasty, but no long-term progression. PMID- 28651668 TI - Impact of hygiene of housing conditions on performance and health of two pig genetic lines divergent for residual feed intake. AB - Pigs selected for high performance may be more at risk of developing diseases. This study aimed to assess the health and performance of two pig lines divergently selected for residual feed intake (RFI) (low RFI (LRFI) v. high RFI (HRFI)) and housed in two contrasted hygiene conditions (poor v. good) using a 2*2 factorial design (n=40/group). The challenge period (Period 1), started on week zero (W0) when 12-week-old pigs were transferred to good or poor housing conditions. At week 6 (W6), half of the pigs in each group were slaughtered. During a recovery period (Period 2) from W6 to W13 to W14, the remaining pigs (n=20/group) were transferred in good hygiene conditions before being slaughtered. Blood was collected every three (Period 1) or 2 weeks (Period 2) to assess blood indicators of immune and inflammatory responses. Pulmonary lesions at slaughter and performance traits were evaluated. At W6, pneumonia prevalence was greater for pigs housed in poor than in good conditions (51% v. 8%, respectively, P<0.001). Irrespective of hygiene conditions, lung lesion scores were lower for LRFI pigs than for HRFI pigs (P=0.03). At W3, LRFI in poor conditions had the highest number of blood granulocytes (hygiene*line, P=0.03) and at W6, HRFI pigs in poor conditions had the greatest plasma haptoglobin concentrations (hygiene*line, P=0.02). During Period 1, growth rate and growth-to feed ratio were less affected by poor hygiene in LRFI pigs than in HRFI pigs (hygiene*line, P=0.001 and P=0.02, respectively). Low residual feed intake pigs in poor conditions ate more than the other groups (hygiene*line, P=0.002). Irrespective of the line, fasting plasma glucose concentrations were higher in poor conditions, whereas fasting free fatty acids concentrations were lower than in good conditions. At the end of Period 2, pneumonia prevalence was similar for both housing conditions (39% v. 38%, respectively). During Period 2, plasma protein concentrations were greater for pigs previously housed in poor than in good conditions during Period 1. Immune traits, gain-to-feed ratio, BW gain and feed consumption did not differ during Period 2. Nevertheless, at W12, BW of HRFI previously housed in poor conditions was 13.4 kg lower than BW of HRFI pigs (P<0.001) previously housed in good conditions. In conclusion, health of the most feed efficient LRFI pigs was less impaired by poor hygiene conditions. This line was able to preserve its health, growth performance and its feed ingestion to a greater extent than the less efficient HRFI line. PMID- 28651669 TI - Gastrointestinal haemorrhage due to lymphangiectasia caused by protein-losing enteropathy in the Fontan circulation. AB - We report the case of a 14-year-old boy with severe protein-losing enteropathy after Fontan surgery that led to lymphangiectasia, which caused gastrointestinal haemorrhage and required invasive treatment to stop the bleeding. Through this case and a review of the literature on protein-losing enteropathy after Fontan surgery, we highlight a rare and serious presentation of the disease and the difficulties of diagnosis and management. PMID- 28651670 TI - Alterations in vitamin A/retinoic acid homeostasis in diet-induced obesity and insulin resistance. AB - Vitamin A is an essential micronutrient for life and the phytochemical beta carotene, also known as pro-vitamin A, is an important dietary source of this vitamin. Vitamin A (retinol) is the parent compound of all bioactive retinoids but it is retinoic acid (RA) that is the active metabolite of vitamin A. The plasma concentration of retinol is maintained in a narrow range and its normal biological activities strictly regulated since excessive intake can lead to toxicity and thus also be detrimental to life. The present review will give an overview of how vitamin A homeostasis is maintained and move on to focus on the link between circulating vitamin A and metabolic disease states. Finally, we will examine how pharmacological or genetic alterations in vitamin A homeostasis and RA-signalling can influence body fat and blood glucose levels including a novel link to the liver secreted hormone fibroblast growth factor 21, an important metabolic regulator. PMID- 28651671 TI - Purpose-in-Life Test: Comparison of the Main Models in Patients with Mental Disorders. AB - The aim of this study was to compare the main proposed models for the Purpose-In Life Test, a scale for assessing meaning in life, in 229 Spanish patients with mental disorders (195 females and 34 males, aged 13-68, M = 34.43, SD = 12.19). Confirmatory factor-analytic procedures showed that the original model of the Purpose-In-Life Test, a 20-item unidimensional scale, obtained a better fit than the other analyzed models, SBchi2(df) = 326.27(170), SBchi2/df = 1.92, TLI = .93, CFI = .94, IFI = .94, RMSEA = .063 (90% CI [.053, .074]), CAIC = -767.46, as well as a high internal consistency, (alpha = .90). The main conclusion is that the original version of the Purpose-In-Life shows a robust construct validity in a clinical population. However, authors recommend an in-depth psychometric analysis of the Purpose-In-Life Test among clinical population. Likewise, the importance of assessing meaning in life in order to enhance psychotherapeutic treatment is noted. PMID- 28651672 TI - Characterization of the complete nuclear ribosomal DNA sequences of Eurytrema pancreaticum. AB - Eurytrema pancreaticum is one of the most common trematodes of cattle and sheep, and also infects humans occasionally, causing great economic losses and medical costs. In this study, the sequences of the complete nuclear ribosomal DNA (rDNA) repeat units of five E. pancreaticum individuals were determined for the first time. They were 8306-8310 bp in length, including the small subunit (18S) rDNA, internal transcribed spacer 1 (ITS1), 5.8S rDNA, internal transcribed spacer 2 (ITS2), large subunit (28S) rDNA and intergenic spacer (IGS). There were no length variations in any of the investigated 18S (1996 bp), ITS1 (1103 bp), 5.8S (160 bp), ITS2 (231 bp) or 28S (3669 bp) rDNA sequences, whereas the IGS rDNA sequences of E. pancreaticum had a 4-bp length variation, ranging from 1147 to 1151 bp. The intraspecific variations within E. pancreaticum were 0-0.2% for 18S rDNA, 0-0.5% for ITS1, 0% for 5.8S rDNA and ITS2, 0-0.2% for 28S rDNA and 2.9 20.2% for IGS. There were nine types of repeat sequences in ITS1, two types in 28S rDNA, but none in IGS. A phylogenetic analysis based on the 18S rDNA sequences classified E. pancreaticum in the family Dicrocoeliidae of Plagiorchiata, closely related to the suborder Opisthorchiata. These results provide useful information for the further study of Dicrocoeliidae trematodes. PMID- 28651673 TI - The Hidden Sufferers: Parental Reactions to Childhood Cancer during Treatment and at Survival. AB - This study was twofold: 1) to assess parental reactions to childhood cancer throughout the oncological experience and 2) to explore associations between parents' reactions during treatment and cancer-related distress at survival. A cross-sectional descriptive study collecting data (at survival) from retrospective (perceived social support, optimism, distress, coping in the worst situation) and current variables (general stress, distress regarding cancer, benefit finding) was carried out. Forty-one parents of childhood cancer survivors were assessed. High levels of distress (M = 9.5, SD = 1.32, range 4-10) and self reported efforts to overcome difficulties occurring during the hospitalization (M = 7.48, SD = 3.01, range 0-10) were found. However, parents received high social support from very different sources. This could explain the satisfactory levels of optimism found (43.9% of the sample, M >= 16, range 9 - 24). Most parents reported to use engagement (M = 2.57, SD = 0.41, range 1-4) and help-seeking (M = 2.52, SD = 0.53, range 1-4) coping strategies to overcome difficulties. Some parents recognized to use psychological defenses when coping with the distress of cancer. However, this disengagement style was less preferred (M = 1.62, SD = 0.37, range 1-4). Finally, 22% of parents reported positive consequences and 60% reported positive and negative consequences too. When exploring how treatment experiences can influence cancer-related distress in survivorship, we observed that those who received less social support used more disengagement coping and referred higher efforts to overcome difficulties during treatment, displayed persistent distress at survival. These same parents showed higher scores on general stress. Besides, these results were not influenced by child's sequelae at survival. These findings support the hypothesis that "the end of treatment is not the end". Consequently, special attention should be placed in screening parents experiences throughout different milestones of cancer to design tailored interventions aimed at reducing persistent distress at survival. PMID- 28651675 TI - Responses of mothers of children with CHD: quality of life, anxiety and depression, parental attitudes, family functionality. AB - : Introduction The aim of this study was to evaluate the anxiety and depression status, family functions, parenting attitudes, and quality of life in the mothers of children with CHD. METHOD: The study enrolled 120 mothers: 40 of children with cyanotic CHD, 40 of children with non-cyanotic CHD, and 40 of healthy controls. Short Form-36 for quality of life, Hospital Anxiety-Depression Scale for anxiety and depression, Family Assessment Device for the detection of problems affecting family functions, and Parental Attitude Research Instrument for measuring child rearing attitudes were used in the study. RESULTS: Statistically significant decreases were found in the general health standards of mothers of non-cyanotic children (p=0.035) and in the emotional and physical role difficulty of mothers of cyanotic children (p=0.006, p=0.010). When anxiety and depression levels of the parents were examined, the anxiety level of the cyanotic group was found to be significantly higher than that of the other groups (p=0.031). When family behaviours were assessed, there was a statistically significant decrease in role status in the families having a child with cyanotic CHD (p=0.035). In the Parental Attitude Research Instrument test, the husband and wife incompatibility sub-scale was found to be statistically significantly lower in the cyanotic CHD group (p=0.030). CONCLUSION: When there is a diseased person in the family, the focus should not be solely on the problems of the patient but also on preventive methods to be implemented in order to protect the mental health of all family members. PMID- 28651676 TI - Anomalous origin of the left coronary artery from the right pulmonary artery in a univentricular heart. AB - Anomalous origin of the left coronary artery from the right pulmonary artery in single ventricles is a very rare congenital anomaly. Failure to recognise it preoperatively may lead to adverse outcomes, including death. We report the case of a neonate with a univentricular heart in the form of a double-outlet right ventricle, mitral atresia with discrete coarctation of the aorta, and an incidental intraoperative finding of an anomalous origin of the left coronary artery from the right pulmonary artery. The patient underwent a successful repair with an uneventful postoperative course. PMID- 28651674 TI - Associations among prenatal stress, maternal antioxidant intakes in pregnancy, and child temperament at age 30 months. AB - Prenatal stress and prenatal nutrition each have demonstrable impact on fetal development, with implications for child neurodevelopment and behavior. However, few studies have examined their joint influences despite evidence of potential interactive effects. We examined associations among prenatal stress, prenatal antioxidant intakes, and child temperament in a sociodemographically diverse pregnancy cohort (N=137 mother-child dyads). In mid-pregnancy, mothers completed an assessment of recent negative life events as a measure of prenatal stress and an assessment of prenatal diet. When the children were 30 months of age, mothers completed the Early Childhood Behavior Questionnaire-Very Short form, which provides scores on child Negative Affectivity, Effortful Control, and Surgency/Extraversion. Linear regressions tested associations between maternal prenatal negative life events and child temperament, and effect modification by maternal prenatal antioxidant intakes (vitamins A, C, and E, magnesium, zinc, selenium, beta-carotene). Analyses revealed that increased maternal prenatal negative life events were associated with higher child Negative Affectivity (beta=0.08, P=0.009) but not with child Effortful Control (beta=-0.03, P=0.39) or Surgency/Extraversion (beta=0.04, P=0.14). Prenatal intakes of zinc and selenium modified this effect: Maternal exposure to prenatal negative life events was associated with higher child Negative Affectivity in the presence of lower intakes of zinc and selenium. Modification effects approached significance for vitamins A and C. The results suggest that the combination of elevated stress exposures and lower antioxidant intakes in pregnancy increases the likelihood of heightened child temperamental negative affectivity. Increased antioxidant intakes during pregnancy may protect against influences of prenatal stress on child temperament. PMID- 28651677 TI - Influence of weight at the time of first palliation on survival in patients with a single ventricle. AB - BACKGROUND: Numerous advances in surgical techniques and understanding of single ventricle physiology have resulted in improved survival. We sought to determine the influence of various demographic, perioperative, and patient-specific factors on the survival of single-ventricle patients following stage 1 palliation at our institution. METHODS: We conducted a retrospective study of all single-ventricle patients who had undergone staged palliation at our institution over an 8-year period. Data were collected from the Society of Thoracic Surgeons Congenital Heart Surgery database and from patient charts. Information on age, weight at stage 1 palliation, prematurity, genetic abnormalities, non-cardiac anomalies, ventricular dominance, and type of palliation was collected. Information on mortality and unplanned reinterventions was also collected. RESULTS: A total of 72 patients underwent stage 1 palliation over an 8-year period. There were 12 deaths before and one death after stage 2 palliation. There was no hospital mortality following Glenn or Fontan procedures. On univariate analysis, low weight at the time of stage 1 palliation and prematurity were found to be risk factors for mortality following stage 1 palliation. However, multivariable Cox regression analysis revealed weight at stage 1 palliation to be a strong predictor of mortality. The type of stage 1 palliation did not have any influence on the outcome. No difference in survival was noted following the Glenn procedure. CONCLUSION: Low weight has a deleterious impact on survival following stage 1 palliation. This is mitigated by stage 2 palliation. The type of stage 1 palliation itself has no bearing on the outcome. PMID- 28651679 TI - Determinants of quality of life in adults with CHD: an Australian cohort. AB - BACKGROUND: Following improved survival rates in children with CHD, their quality of life and its determinants have become increasingly important. As part of a multicentre study entitled "Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart Disease - International Study", this article reviews the relationships among quality of life, anxiety and depression, sense of coherence, and severity of disease in an Australian cohort of adults with CHD. Methods and results Adults with CHD were recruited from a single, community-based cardiology practice. All patients completed a self-reported questionnaire. A total of 135 patients, 71 males and 64 females, were recruited with a mean age of 26 years. The median quality of life in this cohort was 90; one-fifth of the patients experienced symptoms of anxiety. There was a significant negative correlation between quality of life and symptoms of anxiety and depression and a positive correlation between quality of life and sense of coherence. CONCLUSIONS: The quality of life of this cohort was generally excellent; however, one-fifth of them experienced symptoms of anxiety. Those with less anxiety and depression symptoms appeared to have a better quality of life, as did those who reported a higher sense of coherence. Interestingly, there was no significant relationship between complexity of CHD and quality of life. PMID- 28651678 TI - Latent Cognitive Phenotypes in De Novo Parkinson's Disease: A Person-Centered Approach. AB - OBJECTIVES: Cognitive impairment is an important aspect of Parkinson's disease (PD), but there is considerable heterogeneity in its presentation. This investigation aims to identify and characterize latent cognitive phenotypes in early PD. METHODS: Latent class analysis, a data-driven, person-centered, cluster analysis was performed on cognitive data from the Parkinson's Progressive Markers Initiative baseline visit. This analytic method facilitates identification of naturally occurring endophenotypes. Resulting classes were compared across biomarker, symptom, and demographic data. RESULTS: Six cognitive phenotypes were identified. Three demonstrated consistent performance across indicators, representing poor ("Weak-Overall"), average ("Typical-Overall"), and strong ("Strong-Overall") cognition. The remaining classes demonstrated unique patterns of cognition, characterized by "Strong-Memory," "Weak-Visuospatial," and "Amnestic" profiles. The Amnestic class evidenced greater tremor severity and anosmia, but was unassociated with biomarkers linked with Alzheimer's disease. The Weak-Overall class was older and reported more non-motor features associated with cognitive decline, including anxiety, depression, autonomic dysfunction, anosmia, and REM sleep behaviors. The Strong-Overall class was younger, more female, and reported less dysautonomia and anosmia. Classes were unrelated to disease duration, functional independence, or available biomarkers. CONCLUSIONS: Latent cognitive phenotypes with focal patterns of impairment were observed in recently diagnosed individuals with PD. Cognitive profiles were found to be independent of traditional biomarkers and motoric indices of disease progression. Only globally impaired class was associated with previously reported indicators of cognitive decline, suggesting this group may drive the effects reported in studies using variable-based analysis. Longitudinal and neuroanatomical characterization of classes will yield further insight into the evolution of cognitive change in the disease. (JINS, 2017, 23, 551-563). PMID- 28651680 TI - Full-genome sequence analysis of an uncommon norovirus genotype, GII.21, from South Korea. AB - Noroviruses (NoVs) are major causal agents of acute gastroenteritis in humans. NoV GII.4 is the predominant genotype globally. However, uncommon and minor types of NoVs are consistently detected and some have been shown to dominate over GII.4. Therefore, the prevalence of dominant and uncommon NoVs makes the identification of these viruses important for the prediction and prevention of pandemics. In this study, the full-genome sequence of a NoV (strain JW) detected in Korea was extensively characterized. The full-length genome was 7510 nucleotides long, and phylogenetic analysis based on the whole-genome sequences, including open reading frame (ORF)1, ORF2, and ORF3, indicated that it belonged to the GII.21 genotype. Strain JW showed maximum identity with strain YO284; however, comparison of the amino acid sequence of ORF2, which functions as an antigen, showed substitutions in several amino acids. GII.21 is not a prevalent epidemiological agent of acute gastroenteritis in humans, but it is consistently found in gastroenteritis patients from several countries. The present study provides the first full-genome sequence analysis of NoV GII.21 isolated from a patient in Korea. Our findings provide not only valuable genome information but also data for epidemiology studies, epidemic prevention, and vaccine development strategies. PMID- 28651681 TI - No influence of supplemental dietary calcium intake on the bioavailability of spinach carotenoids in humans. AB - Dietary carotenoid intake, especially from fruits and vegetables, has been associated with a reduced incidence of several chronic diseases. However, its bioavailability can vary, depending on the food matrix and host factors. Recently, it has been suggested that divalent minerals negatively impinge on carotenoid bioavailability by reducing bile-salt and non-esterified fatty-acid levels in the gut, which normally aid in emulsifying carotenoids. The aim of the present study was to investigate whether supplemental Ca would negatively influence carotenoid absorption in humans. A total of twenty-five healthy, non obese men (age: 20-46 years, BMI<30 kg/m2) were recruited for this postprandial, randomised, crossover, double-blinded trial. Following a randomised block design, each participant received (after 2-week washout periods), on three occasions separated by 1 week, 270 g of spinach-based meals (8.61 (sd 1.08) mg carotenoids/100 g fresh weight), supplemented with 0, 500 or 1000 mg of Ca (as calcium carbonate), with each participant acting as his or her own control. Blood samples were collected at regular postprandial intervals for up to 10 h following test meal intake, and standardised lunches were served. TAG-rich lipoprotein fractions were separated and carotenoid concentrations determined. AUC for meals without supplemented Ca were 22.72 (sem 2.78) nmol*h/l (lutein), 0.19 (sem 3.90) nmol*h/l (beta-carotene) and 2.80 (sem 1.75) nmol*h/l (beta-cryptoxanthin). No significant influence of supplementation with either 500 or 1000 mg of supplemental Ca was found. In conclusion, Ca - the most abundant divalent mineral in the diet - given at high but physiological concentrations, does not appear to have repercussions on the bioavailability of carotenoids from a spinach-based meal. PMID- 28651682 TI - The Wuhan Twin Birth Cohort (WTBC). AB - The Wuhan Pre/Post-Natal Twin Birth Registry (WPTBR) is one of the largest twin birth registries with comprehensive medical information in China. It recruits women from the first trimester of pregnancy and their twins from birth. From January 2006 to May 2016, the total number of twins enrolled in WPTBR is 13,869 twin pairs (27,553 individuals). The WPTBR initiated the Wuhan Twin Birth Cohort (WTBC). The WTBC is a prospective cohort study carried out through incorporation of three samples. The first one comprises 6,920 twin pairs, and the second one, 6,949 twin pairs. Both are population-based samples linked to the WPTBR and include pre- and post-natal information from WPTBR. The second sample includes neonatal blood spots as well. Using a hospital-based approach, we recently developed a third sample with a target enrolment of 1,000 twin pairs and their mothers. These twins are invited, via their parents, to participate in a periodic health examination from the first trimester of pregnancy to 18 years. Biological samples are collected initially from the mother, including blood, urine, cord blood, cord, amniotic fluid, placenta, breast milk and meconium, and vaginal secretions, and later from the twins, including meconium, stool, urine, and blood. This article describes the design, recruitment, follow-up, data collection, and measures, as well as ongoing and planned analyses at the WTBC. The WTBC offers a unique opportunity to follow women from prenatal to postnatal, as well as follow-up of their twins. This cohort study will expand the understanding of genetic and environmental influences on pregnancy and twins' development in China. PMID- 28651683 TI - A UK survey of current ENT practice in the assessment of nasal patency. AB - BACKGROUND: Nasal obstruction is a common ENT complaint; however, decisions on its management are challenging, with high rates of dissatisfaction following surgery. This study investigated the practice of UK clinicians in the evaluation of nasal patency. METHOD: Seventy-eight UK-based rhinologists were surveyed at the 2015 British Academic Conference in Otolaryngology. RESULTS: Clinical history and examination are almost universally used to evaluate nasal blockage. The most commonly used test was the nasal misting pattern (73 per cent), followed by peak nasal inspiratory flow (19 per cent). The Sino-Nasal Outcome Test 22 or 23 was utilised by 29 per cent of respondents. Sixty-three per cent of respondents reported that a lack of equipment was the principle reason for not using objective measures, followed by time constraints and a lack of correlation with symptom scores. CONCLUSION: British clinicians rely on clinical skills to evaluate nasal blockage. There is a desire for a simple, non-invasive device that objectively measures airflow for nasal breathing during physiological resting and correlates with subjective symptom scores. PMID- 28651684 TI - Diversity of the auxotrophic requirements in natural isolates of Escherichia coli. AB - Isolates of Escherichia coli, except Shigella, are generally prototrophic; they do not require any growth factors to grow in mineral medium. However, a nicotinic acid requirement is common among B2 phylogroup STc95 O18 E. coli clone strains. Nicotinic acid is a precursor of nicotinamide adenine dinucleotide (NAD), an essential molecule that plays central role in cellular metabolism. The defect in NAD synthesis of these strains is due to alterations in de novo biosynthesis pathway nadB gene. Here, by studying growth on minimal medium with glycolytic (glucose) or gluconeogenic (pyruvate or succinate) substrates as the carbon supply in a large panel of E. coli natural isolates representative of the species diversity, we identify an absolute nicotinic acid requirement in non-STc95 strains due in one case to a nadA inactivation. The growth on glucose medium of some extraintestinal pathogenic E. coli strains belonging to various non-O18 B2 phylogroup STc95 clones is restored either by aspartate or nicotinate, demonstrating that the nicotinic acid requirement can also be due to an intracellular aspartate depletion. The auxotrophic requirements depend on the carbon source available in the environment. Moreover, some strains prototrophic in glucose medium become auxotrophic in succinate medium, and conversely, some strainsauxotrophic in glucose medium become prototrophic in succinate medium. Finally, a partial depletion of intracellular aspartate can be observed in some prototrophic strains belonging to various phylogroups. The observed more or less significant depletion according to isolates may be due to differences in tricarboxylic acid cycle enzyme activities. These metabolic defects could be involved in the adaptation of E. coli to its various niches. PMID- 28651685 TI - Erratum to: Ganglioside GM1 influences the proliferation rate of mouse induced pluripotent stem cells. AB - The BMB Reports would like to correct in the ACKNOWLEDGEMENTS of BMB Rep. 45(12), 713-718 titled "Ganglioside GM1 influences the proliferation rate of mouse induced pluripotent stem cells". PMID- 28651686 TI - Preface. PMID- 28651687 TI - Clinical Pearls in Geriatrics. PMID- 28651689 TI - Clinical Pearls in palliative medicine. PMID- 28651688 TI - Clinical Pearls in Infectious Diseases 2017. PMID- 28651690 TI - Clinical pearls in pulmonary diseases. PMID- 28651691 TI - Clinical Pearls in women's health. PMID- 28651693 TI - Fatty acid and lipid profiles in primary human trophoblast over 90h in culture. AB - Little is known about the mechanisms underlying the preferential transport of long chain polyunsaturated fatty acids (LCPUFA) to the fetus by the syncytiotrophoblast and the role of cytotrophoblasts in placental lipid metabolism and transport. We studied primary human trophoblast (PHT) cells cultured for 90h to determine the fatty acid and lipid composition of cytotrophoblast (18h culture) and syncytiotrophoblast (90h culture) cells. In cultured PHT total lipid fatty acids were significantly (P < 0.05) reduced at 90h compared to 18h in culture including lower levels of palmitic acid (PA, 16:0, 37%), palmitoleic acid (POA, 16:1n-7, -30%), oleic acid (OA, 18:1n-9, -31%), LCPUFA arachidonic acid (AA, 20:4n-6, -28%) and alpha-linolenic acid (ALA, 18:3n 3, -55%). In major lipid classes, OA and most of the n-3 and n-6 LCPUFA were markedly lower at 90h in TG (-57 to -76%; p < 0.05). In the cellular NEFA, n-6 LCPUFA, dihomo-gamma-linolenic acid (DGLA, 20:3n-6) and AA were both reduced by 51% and DHA was -55% lower (p < 0.05) at 90h. In contrast, phospholipid FA content did not change between cytotrophoblasts and syncytiotrophoblast except for OA, which decreased by -62% (p < 0.05). Decreasing PHT TG and NEFA lipid content at 90h in culture is likely due to processes related to differentiation such as alterations in lipase activity that occur as cytotrophoblast cells differentiate. We speculate that syncytiotrophoblast prioritizes PL containing AA and DHA for transfer to the fetus by mobilizing FA from storage lipids. PMID- 28651692 TI - Long chain fatty acids and related pro-inflammatory, specialized pro-resolving lipid mediators and their intermediates in preterm human milk during the first month of lactation. AB - This study aimed to measure longitudinal quantities of the long chain fatty acids, their biologically active terminal metabolites and related intermediates (also called oxylipins) in preterm human milk expressed during the first month of lactation. In a prospective cohort, breast milk was collected throughout the first month of lactation in 30 women who delivered preterm infants. Eighteen bioactive lipids and their intermediates were quantified via solid phase extraction and LC-MS/MS. Analysis by GC-FID quantified the fatty acid precursors. Arachidonic acid (ARA) and docosahexaenoic acid (DHA) milk concentrations significantly declined throughout the first month. Oxylipin concentrations did not change during lactation. Positive associations existed between ARA and thromboxane B2, eicosapentaenoic acid and 18-hydroxyeicosapentaenoic acid, and between DHA and PDX and 14- and 17-hydroxydocosahexaenoic acids. DHA concentrations were 1.5 times higher and 14-HDHA was 1.7 times higher in milk from women taking DHA supplements. This investigation showed conditionally essential fatty acids, ARA and DHA, decreased in preterm milk, suggesting a need to supplement their intake for the breast milk-fed preterm infant. Positive associations between parent fatty acids, bioactive lipids and intermediates, as well as sensitivity of milk to maternal fatty acid intake, support consideration of a comprehensive approach to providing fatty acids for preterm infants through both maternal and infant supplementation. PMID- 28651695 TI - Dietary Salba (Salvia hispanica L) improves the altered metabolic fate of glucose and reduces increased collagen deposition in the heart of insulin-resistant rats. AB - This study reports the effects of dietary Salba (chia) seeds on the mechanisms underlying impaired glucose metabolism in the heart of dyslipemic insulin resistant rats fed a sucrose-rich diet (SRD). Wistar rats were fed a SRD for 3 months. Afterwards, half the animals continued with the SRD; in the other half's diet chia seeds replaced corn oil (CO) for three months (SRD+chia). In the control group, corn starch replaced sucrose. The replacement of CO by chia seeds in the SRD restored the activities of key enzymes involved in heart glucose metabolism decreasing fatty acid oxidation. Chia seeds normalized insulin stimulated GLUT-4 transporter, the abundance of IRS-1 and pAMPK, changed the profile of fatty acid phospholipids, reduced left-ventricle collagen deposition and normalized hypertension and dyslipidemia. New evidence is provided concerning the effects of dietary chia seeds in improving the altered metabolic fate of glucose in the heart of dyslipemic insulin-resistant rats. PMID- 28651694 TI - Maternal plasma phosphatidylcholine polyunsaturated fatty acids during pregnancy and offspring growth and adiposity. AB - BACKGROUND: Polyunsaturated fatty acids (PUFA) are essential for offspring development, but it is less clear whether pregnancy PUFA status affects growth and adiposity. METHODS: In 985 mother-offspring pairs from the ongoing Singaporean GUSTO cohort, we analyzed the associations between offspring growth and adiposity outcomes until age 5 years and five PUFAs of interest, measured in maternal plasma at 26-28 weeks' gestation: linoleic acid (LA), arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). We measured fetal growth by ultrasound (n=924), neonatal body composition (air displacement plethysmography (n=252 at birth, and n=317 at age 10 days), and abdominal magnetic resonance imaging (n=317)), postnatal growth (n=979) and skinfold thicknesses (n=981). Results were presented as regression coefficients for a 5% increase in PUFA levels. RESULTS: LA levels were positively associated with birthweight (beta (95% CI): 0.04 (0.01, 0.08) kg), body mass index (0.13 (0.02, 0.25) kg/m2), head circumference (0.11 (0.03, 0.19) cm), and neonatal abdominal adipose tissue volume (4.6 (1.3, 7.8) mL for superficial subcutanous tissue, and 1.2 (0.1, 2.4) mL for internal tissue), but not with later outcomes. DHA levels, although not associated with birth outcomes, were related to higher postnatal length/height: 0.63 (0.09, 1.16) cm at 12 months and 1.29 (0.34, 2.24) cm at 5 years. CONCLUSIONS: LA was positively associated with neonatal body size, and DHA with child height. Maternal PUFA status during pregnancy may influence fetal and child growth and adiposity. PMID- 28651696 TI - Importance of the regiospecific distribution of long-chain saturated fatty acids on gut comfort, fat and calcium absorption in infants. AB - Gastrointestinal tolerance and fat and calcium (Ca) absorption are different between breast-fed (BF) and formula-fed (FF) infants. Certain components and/or structural particularities in human milk (HM), can contribute to favorable outcomes in BF infants. In HM, the long-chain saturated fatty acid (LCSFA) palmitic acid has a different stereospecific distribution (sn-2 position) compared to most infant formula (IF) (primarily sn-1, 3 positions), which may contribute to unfavorable outcomes. Evidence suggests palmitic acid is important in the formation of stool FA-mineral (or FA-Ca) soaps, associated with harder stools in FF infants. Partial replacement by structured palmitic acid-rich triacylglycerols (TAGs) promotes palmitic acid absorption. However, evidence for stool softening, improved fat absorption and reduced Ca excretion in stools is inconsistent. IFs with less palmitic acid can improve fat and Ca absorption, and stool consistency. The presence of other LCSFAs (myristic and stearic acids) in sn-1, 3 positions may also contribute to reduced absorption of fat and Ca, and stool hardness, in FF infants. Nevertheless, little attention has been given to modifying these other LCSFAs in IF. We review literature comparing the effect of HM and IF with different lipid compositions on stool patterns and/or fat and Ca absorption in healthy, term infants. Based on available data, we estimate a maximum level for sn-1, 3 LCSFAs of 13% of TAGs, under which fat and Ca absorption and stool consistency are improved. IF designed according to this threshold could efficiently improve nutrient absorption and stool patterns in healthy infants who cannot be breast-fed. PMID- 28651697 TI - Docosahexaenoic acid (DHA) and arachidonic acid (ARA) balance in developmental outcomes. AB - The DHA Intake and Measurement of Neural Development (DIAMOND) trial represents one of only a few studies of the long-term dose-response effects of LCPUFA supplemented formula feeding during infancy. The trial contrasted the effects of four formulations: 0.00% docosahexaenoic acid (DHA)/0.00% arachidonic acid (ARA), 0.32% DHA/0.64% ARA, 0.64% DHA/0.64% ARA, and 0.96% DHA/0.64% ARA against a control condition (0.00% DHA/0.00% ARA). The results of this trial have been published elsewhere, and show improved cognitive outcomes for infants fed supplemented formulas, but a common finding among many of the outcomes show a reduction of benefit for the highest DHA dose (i.e., 0.96%DHA/0.64% ARA, that is, a DHA: ARA ratio 1.5:1.0). The current paper gathers and summarizes the evidence for the reduction of benefit at this dose, and in an attempt to account for this reduced benefit, presents for the first time data from infants' red blood cell (RBC) assays taken at 4 and 12 months of age. Those assays indicate that blood DHA levels generally rose with increased DHA supplementation, although those levels tended to plateau as the DHA-supplemented level exceeded 0.64%. Perhaps more importantly, ARA levels showed a strong inverted-U function in response to increased DHA supplementation; indeed, infants assigned to the formula with the highest dose of DHA (and highest DHA/ARA ratio) showed a reduction in blood ARA relative to more intermediate DHA doses. This finding raises the possibility that reduced ARA may be responsible for the reduction in benefit on cognitive outcomes seen at this dose. The findings implicate the DHA/ARA balance as an important variable in the contribution of LCPUFAs to cognitive and behavioral development in infancy. PMID- 28651698 TI - An association between PLA2G6 and PLA2G4C gene polymorphisms and schizophrenia risk and illness severity in a Croatian population. AB - We investigated the allele and genotype frequency of the rs4375 and rs1549637 polymorphisms in phospholipase A2 (PLA2)G6 and PLA2G4C genes in 203 patients with schizophrenia and 191 controls in a Croatian population. We hypothesized that these polymorphic variations might influence the age of schizophrenia onset and Positive and Negative Syndrome Scale psychopathology (PANSS) data. We detected a significant overrepresentation of the PLA2G6-CT and PLA2G4C-AT genotype combination in patients compared with controls (14.7% vs. 7.3%, P < 0.05). The combined PLA2G6/PLA2G4C heterozygosity was associated with about a two-fold higher schizophrenia risk. We found no significant influence of the PLA2G6 and PLA2G4C polymorphisms on mean age at first hospital admission (P > 0.05) and that the investigated polymorphisms significantly influenced the clinical psychopathology only in male patients. The PLA2G4C polymorphism accounted for approximately 12% of negative symptom severity; whereas, the PLA2G6/PLA2G4C interaction contributed to a similar extent to total PANSS symptom variations. PMID- 28651699 TI - Levels of oxylipins, endocannabinoids and related lipids in plasma before and after low-level exposure to acrolein in healthy individuals and individuals with chemical intolerance. AB - Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60min) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24h post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI. PMID- 28651701 TI - Oxidative stress reduction related to the efficacy of n-3 polyunsaturated fatty acids in first episode schizophrenia: Secondary outcome analysis of the OFFER randomized trial. AB - Intervention studies of n-3 polyunsaturated fatty acids (n-3 PUFA) as add-on therapy in patients with schizophrenia have not examined changes in oxidative stress. A randomized placebo-controlled trial of a 26-week intervention composed of 2.2g/day of n-3 PUFA was found to reduce symptom severity in first-episode schizophrenia patients. The present study is an extension of our previous report, whose secondary aim was to assess the association between the clinical effect of n-3 PUFA and changes in oxidative stress indices. Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the study arms. Total plasma antioxidant capacity and 8-epi-isoprostane F2alpha content were assessed at baseline and at weeks 8 and 26 of the study as secondary outcome measures. Significant changes in oxidative stress indices favouring the intervention group were observed: decreases in 8-isoprostane F2alpha (p<0.001) and increases in total plasma antioxidant capacity (p<0.001). Significant correlations between changes in clinical scores relevant to symptom severity and changes in oxidative indices were observed. The results of the present study hence suggest that the efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to improvement in oxidative stress indices. PMID- 28651700 TI - Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: Secondary analyses of longitudinal data from the Women's Health Initiative Memory Study (WHIMS). AB - OBJECTIVE: To assess whether red blood cell (RBC) docosahexaenoic acid and eicosapentaenoic acid (DHA+EPA) levels have a protective association with the risk of dementia in older women. METHODS: RBC DHA+EPA levels were assessed at baseline, and cognitive status was evaluated annually in a cohort of 6706 women aged >=65 years who participated in the Women's Health Initiative Memory Study (WHIMS). Cox regression was used to quantify the association between RBC DHA+EPA and the risk of probable dementia, independent of major dementia risk factors. RESULTS: During a median follow-up period of 9.8 years, 587 incident cases of probable dementia were identified. After adjusting for demographic, clinical, and behavioral risk factors, a one standard deviation increase in DHA+EPA levels was associated with a significantly lower risk of dementia (HR = 0.92, 95% CI: 0.84, 1.00; p < 0.05). This effect estimate did not meaningfully change after further adjustment for baseline cognitive function and APOE genotype. For women with high DHA+EPA exposure (1SD above mean) compared to low exposure (1SD below mean), the adjusted 15-year absolute risk difference for dementia was 2.1% (95% CI: 0.2%, 4.0%). In secondary analyses, we also observed a protective association with longitudinal change in Modified Mini-Mental State (3MS) Exam scores, but no significant association with incident MCI, PD/MCI, or baseline 3MS scores. DISCUSSION: Higher levels of DHA+EPA may help protect against the development of dementia. Results from prospective randomized controlled trials of DHA+EPA supplementation are needed to help clarify whether this association is causal. PMID- 28651702 TI - Effect of DHA supplementation on oxylipin levels in plasma and immune cell stimulated blood. AB - INTRODUCTION: EPA and DHA cause different physiological effects, which are in many cases mediated via their oxidative metabolites (oxylipins). However, metabolism studies investigating the effect of either EPA or DHA on comprehensive oxylipin patterns are lacking. MATERIAL AND METHODS: The short and long term (1, 3, 6, and 12 week) effect of 1076mg/d DHA (free of EPA) on free (unesterified) oxylipin concentrations in plasma and lipopolysacharid (LPS) stimulated blood of 12 healthy men (mean age 25.1 +/- 1.5 years) was investigated. RESULTS: After DHA supplementation, plasma levels of all DHA-oxylipins (HDHAs, EpDPEs, DiHDPEs) significantly increased (up to 600%) in a time-dependent fashion. Oxylipins of EPA and arachidonic acid (AA) were also affected. Whereas a slight increase in several EPA-derived hydroxy-FAs (including the RvE1 precursor 18-HEPE) and dihydroxy-FAs was observed after DHA supplementation, a trend to a slight decline in AA-derived oxylipin levels was found. In LPS stimulated blood, it is shown that DHA supplementation significantly reduces the ability of immune cells to form AA-derived COX (TXB2 and PGB2) and 12-LOX (12-HETE) eicosanoids. While no increase in EPA COX metabolites was found, n-3 PUFA 12-LOX metabolites of EPA (12 HEPE) and DHA (14-HDHA) were highly induced. CONCLUSION: We demonstrated that DHA supplementation causes a time-dependent shift in the entire oxylipin profile suggesting a cross-linked metabolism of PUFAs and subsequent formation of oxygenated lipid mediators. PMID- 28651703 TI - Improving health in the United States: Oral health is key to overall health. PMID- 28651704 TI - Dental operator-anesthetists. PMID- 28651705 TI - Author's response. PMID- 28651706 TI - Selecting continuing education. PMID- 28651707 TI - Behavioral regression in 2 patients with autism spectrum disorder and attention deficit/hyperactivity disorder after oral surgery performed with a general anesthetic. AB - BACKGROUND AND OVERVIEW: Routine dental care for people with autism spectrum disorders can be complex. There is little published on postoperative behavioral changes associated with use of general anesthetics in this population. CASE DESCRIPTION: The authors describe postoperative behavioral changes in 2 patients with autism spectrum disorder and attention deficit hyperactivity disorder that the patients' caretakers described as regression. In both cases, behaviors representative of autism spectrum disorder and attention deficit hyperactivity disorder worsened after uncomplicated oral surgery after receipt of a general anesthetic in the operating room. In both cases, behavioral changes caused great difficulties for the patients and caretakers and were difficult to address. CONCLUSIONS AND PRACTICAL IMPLICATIONS: With little in the scientific literature, these 2 cases have a great importance for the dental care practitioner. Awareness must be raised so that further investigation can occur regarding this phenomenon. PMID- 28651708 TI - Will we see more foreign-trained dentists in the United States? PMID- 28651709 TI - Rules for technology and the dental team member. PMID- 28651710 TI - Single mandibular implant to support complete dentures probably improves patients' satisfaction, regardless of the loading protocol used. PMID- 28651711 TI - Betamethasone does not seem to provide benefits in postoperative pain and swelling when added to ketorolac after placement of multiple implants. PMID- 28651712 TI - Piezoelectric instruments used for odontosection or osteotomy may result in less trismus after surgical mandibular third-molar extraction than rotatory instruments. PMID- 28651713 TI - Immediately placed and restored single-tooth implants in the anterior maxilla shown to have good esthetic outcomes 1 year after treatment. PMID- 28651714 TI - Specific risk factors that may be associated with risk of experiencing mortality owing to dental treatment. PMID- 28651715 TI - Implant stability slightly improved and was no different when placing 2 versus 4 implants to support mandibular overdentures. PMID- 28651716 TI - Patients with a history of chronic periodontitis and high compliance with supportive periodontal therapy do not have different implant survival than patients without periodontitis. PMID- 28651717 TI - Imaging methods add extra variability to risk assessment and treatment decisions when planning for third-molar extraction. PMID- 28651718 TI - Children with mandibular fractures seem to have a low rate of long-term complications. PMID- 28651719 TI - Resin-bonded fixed dental prostheses seem to have high survival rates 5 years after placement. PMID- 28651720 TI - 20-year follow-up shows similar outcomes for periodontal regenerative techniques and flap access in the treatment of intrabony defects. PMID- 28651721 TI - Taking oral bisphosphonates for more than 3 years and undergoing mandibular tooth extraction may be risk factors for osteonecrosis of the jaw. PMID- 28651722 TI - No evidence that education influences willingness to receive dental implants in older adults. PMID- 28651723 TI - Fluoride-based caries prevention program probably results in a small reduction in the incidence of caries compared with advice only. PMID- 28651724 TI - Orthodontic treatment before 18 years of age probably results in a moderate improvement in oral health-related quality of life. PMID- 28651725 TI - High percentage of mesiobuccal roots of maxillary second molars have a complicated configuration and morphology. PMID- 28651726 TI - Tetracaine is not more effective than benzocaine for preventing discomfort in young infants undergoing frenotomy. PMID- 28651727 TI - Ridge preservation reduced the loss of buccal bone height, but no differences were observed in other alveolar bone dimensions or bone width. PMID- 28651728 TI - Fewer appointments, less chair time, and no evidence of differences in patient satisfaction or quality for dentures fabricated using simplified versus conventional techniques. PMID- 28651729 TI - Survival and failure of implant-supported prostheses in partially edentulous patients seems to be highly variable depending on the specific retention system. PMID- 28651730 TI - Low proportion of tooth loss after an average of 18 years of supportive periodontal therapy in patients with chronic periodontitis. PMID- 28651731 TI - Mitochondria in cancer. PMID- 28651732 TI - The Dynamic Landscape of Health Care Insurance-Implications for Our Specialty. PMID- 28651733 TI - Can cannibalizing cancer cells challenge classic cell death classification? AB - In this issue of the Biomedical Journal, we learn about a novel are still largely mysterious mechanism of cell death that is challenging classification systems of cell death pathways and could have important implications for future cancer therapy. We also learn of a promising biomarker to stratify patients into risk groups after stroke. Finally, this issue also includes two studies investigating factors that influence outcome after heart surgery. PMID- 28651734 TI - Entosis: The emerging face of non-cell-autonomous type IV programmed death. AB - The present review summarizes recent experimental evidences about the existence of the non-cell-autonomous death entosis in physiological and pathophysiological contexts, discusses some aspects of this form of cell death, including morphological, biochemical and signaling pathways that distinguish non-cell autonomous demises from other death modalities and propose to define this new modality of death as type IV programmed cell death. PMID- 28651735 TI - Preventing coronary artery lesions in Kawasaki disease. AB - A form of systemic vasculitis that affects mostly small and medium-sized vessels, Kawasaki disease (KD) is most commonly found in children under the age of 5 years old. Though its etiology is unknown, KD has been the most frequent acquired heart disease in developing countries. Its incidence has increased over recent decades in many centuries, including Japan, Korea, and China. The most severe complications of KD are coronary artery lesions (CAL), including dilation, fistula, aneurysm, arterial remodeling, stenosis, and occlusion. Aneurysm formation has been observed in 20-25% of KD patients that do not receive intravenous immunoglobulin (IVIG) treatment, and in 3-5% that do receive it. Coronary artery dilation has been found in about 30% of KD patients in the acute stage, although mostly in the transient form. Diminishing the occurrence and regression of CAL is a vital part of treating KD. In this review article, I demonstrate the clinical method to prevent CAL formation used at the Kawasaki Disease Center in Taiwan. PMID- 28651736 TI - Thyroid functions and serum lipid profile in metabolic syndrome. AB - BACKGROUND: Thyroid hormones are known to affect energy metabolism. Many patients of metabolic syndrome have subclinical or clinical hypothyroidism and vice versa. To study the correlation of thyroid profile and serum lipid profile with metabolic syndrome. METHOD: It is a hospital based cross sectional case-control study carried out in tertiary care health center, we studied thyroid functions test and serum lipid profile in 100 metabolic syndrome patients according to IDF criteria and a similar number of age, gender and ethnicity matched healthy controls. RESULT: We found that serum HDL was significantly lower (p < 0.001) in cases (41.28 +/- 8.81) as compared to controls (54.00 +/- 6.31). It was also found that serum LDL, VLDL, triglyceride levels and total cholesterol were found to be significantly higher (p < 0.001) in cases than controls. Serum TSH levels of subjects in cases group (3.33 +/- 0.78) were significantly higher (p < 0.001) than that of controls (2.30 +/- 0.91) and significantly lower levels of T4 (p < 0.001) in the patients of metabolic syndrome (117.45) than in controls (134.64) while higher levels of T3, although statistically insignificant in the patients of metabolic syndrome. CONCLUSION: Thyroid hormones up-regulate metabolic pathways relevant to resting energy expenditure, hence, obesity and thyroid functions are often correlated. PMID- 28651737 TI - Higher neutrophil counts and neutrophil-to-lymphocyte ratio predict prognostic outcomes in patients after non-atrial fibrillation-caused ischemic stroke. AB - BACKGROUND: We aimed to determine whether higher neutrophil counts (NC) and neutrophil-to-lymphocyte ratio (NLR) were independently predictive of worse in hospital outcome in patients after acute ischemic stroke (IS). METHODS: A retrospective observational study with prospective manner of IS registration. Between April 2012 and August 2014, a total number of 1731 patients with post-IS were consecutively enrolled in the study. Blood samples were drawn upon admission. Primary endpoint was in-hospital mortality. Secondary endpoint was severe stroke (>=16 NIHSS). RESULTS: The NC progressively increased from mild (NIHSS <= 5) to moderate (NIHSS >= 6 < 16) and severe (NIHSS >= 16) stroke (p = 0.006). NLR was independently associated with in-hospital mortality (p = 0.002). Multiple stepwise linear regression analysis showed that NC (p = 0.001) and NLR (p = 0.002) were independently predictive of higher NIHSS. Multiple stepwise logistic regression analysis showed that NC was independently associated with severe stroke (p < 0.0001). The best discriminating factor for in-hospital mortality with respect to NLR was >=3.20 (sensitivity 62.7%, specificity 60.3%, likelihood ratio: 12.2). Patients with NLR >=3.20 had a 2.55-fold increased risk for in-hospital mortality (OR = 1.49-4.37) compared to patients with NLR <3.20. The best discriminating factor for severe stroke (>=16 NIHSS) with respect to NC was >=74% (sensitivity 47.1%, specificity 74.0%, likelihood ratio: 29.0). Patients with NC >74% had a 2.54-fold increased risk of severe stroke (OR = 1.82 3.54) compared to patients with NC <74%. CONCLUSION: NLR was independently associated with in-hospital mortality and higher NC was independently predictive of severe stroke. PMID- 28651738 TI - Gross motor function change after multilevel soft tissue release in children with cerebral palsy. AB - BACKGROUND: Improving motor function is a major goal of therapy for children with cerebral palsy (CP). However, changes in motor function after orthopedic surgery for gait disorders are seldom discussed. This study aimed to evaluate the postoperative changes in gross motor function and to investigate the prognostic factors for such changes. METHODS: We prospectively studied 25 children with CP (4-12 years) who were gross motor function classification system (GMFCS) level II to IV and and underwent bilateral multilevel soft-tissue release for knee flexion gait. Patients were evaluated preoperatively and at 6 weeks and 3 and 6 months postoperatively for Gross Motor Function Measure (GMFM-66), range of motion, spasticity, and selective motor control. The associations between change in GMFM 66 score and possible factors were analyzed. RESULTS: 25 children with gross motor function level II to IV underwent surgery at a mean age of 8.6 years (range, 4-12 years). Mean GMFM-66 score decreased from 55.9 at baseline to 54.3 at 6-weeks postoperatively and increased to 57.5 at 6-months postoperatively (p < 0.05). Regression analysis revealed better gross motor function level and greater surgical reduction of spasticity were predictors for decreased GMFM-66 score at 6 weeks postoperatively. Younger age was a predictor for increased GMFM-66 score at 6-months postoperatively. CONCLUSION: Reduction of contracture and spasticity and improvement of selective motor control were noted after surgery in children with CP. However, a down-and-up course of GMFM-66 score was noted. It is emphasized that deterioration of motor function in children with ambulatory ability and the improvement in young children after orthopedic surgery for gait disorders. LEVEL OF EVIDENCE: case series, therapeutic study, level 4. PMID- 28651739 TI - No correlation between body mass index and 30-day prognostic outcome in Asians with acute ST-elevation myocardial infarction undergoing primary coronary intervention. AB - BACKGROUND: This study investigated whether body mass index (BMI) was a risk factor predictive of 30-day prognostic outcome in Asians with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). MATERIAL AND METHODS: Data regarding the impact of BMI on the prognostic outcome in Asian populations after acute STEMI is scarce. A number of 925 STEMI patients were divided into three groups according to the BMI: normal weight (<25 kg/m2), overweight (>=25.0 to <30.0 kg/m2) and obese (>=30.0 kg/m2). RESULTS: The obese group was significantly younger with significantly higher incidences of smoking and diabetes mellitus. The incidences of multi-vessel disease, final thrombolysis in myocardial infarction (TIMI)-3 flow, advanced Killip score, advance congestive heart failure, 30-day mortality and combined 30 day major adverse clinical outcome (MACO) did not differ among the three groups. Multiple regression analysis showed the age, unsuccessful reperfusion and lower left ventricular ejection fraction were most significant and independent predictor of 30-day mortality. CONCLUSION: BMI is not a predictor of 30-day prognostic outcome in Asians with STEMI undergoing primary PCI. PMID- 28651740 TI - Impact of prior coronary stenting on the outcome of subsequent coronary artery bypass grafting. AB - BACKGROUND: The percentage of patients referred for coronary artery bypass grafting (CABG) who have previously undergone percutaneous coronary interventions (PCIs) is increasing. The purpose of this study was to review the outcomes of patients who had received coronary stenting before CABG, and to examine the validity of a mortality risk stratification system in this patient group. METHODS: From 2010 to 2012, 439 patients who underwent isolated CABG at our medical center were reviewed. The patients were divided into two study groups: those who had previously received coronary artery stenting (97 patients, 24.7%), and those who had not (342 patients, 75.3%). The patients who received balloon angioplasty were excluded. RESULTS: There were no significant differences in baseline characteristics. The prior stenting group had a lower risk of mortality, although the difference was not significant. The prior stenting group had fewer graft anastomoses (p = 0.005), and hence a significantly shorter cardiopulmonary bypass time (p = 0.045) and shorter aortic cross-clamping time. Surgical mortality was similar between the two groups. The durations of intensive care unit stay and hospitalization were also similar. The discriminatory power of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) was lower in both group. CONCLUSIONS: Prior coronary stenting does not affect short term mortality in patients subsequently undergoing CABG surgery. The EuroSCORE does not predict perioperative mortality well for the patients who undergo coronary stenting before CABG. PMID- 28651741 TI - Association between cigarette smoking and impaired clinical symptoms in systemic sclerosis: A review. AB - It has been established that smoking has a profound impact on susceptibility and severity in some rheumatic diseases (e.g., rheumatoid arthritis), a mild impact in others (e.g., systemic lupus erythematosus) through epidemiological studies. And smoking is known to affect many inflammatory and autoimmune diseases through various mechanisms, including immunomodulation and chemical exposure. Although similar studies investigating the role of cigarette exposure in susceptibility to SSc have been rarely reported and specific mechanisms have never been established, the relationship between smoking and some SSc-related symptoms have been demonstrated during the last decade. However, due to the diversity of study designs, control populations, patient populations and the methodology used to determine smoking history, these results are contradictory in some respects. This paper will review current evidence on the association between smoking and SSc and summarize potential mechanisms. PMID- 28651742 TI - STRAP positively regulates TLR3-triggered signaling pathway. AB - Toll-like receptor (TLR) signaling drives the innate immune response by activating nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor (IRF). We have previously shown that STRAP interacts with TAK1 and IKKalpha along with NF-kappaB subunit p65, leading to the activation of pro-inflammatory cytokines. However, the roles of STRAP in TRIF/TBK1-mediated TLR3 activation and the subsequent type I interferon (IFN) production are not fully elucidated. Here, we demonstrate that STRAP acts as a scaffold protein in TLR3-triggered signaling. STRAP strongly interacts with TBK1 and IRF3, which enhances IFN-beta production. As a consequence, STRAP knockdown reduces the level of both pro-inflammatory cytokine and IFN in TLR3 agonist-stimulated macrophages, whereas its overexpression significantly enhances production of these cytokines. Furthermore, the C-terminus of STRAP is essential for its functional activity in TLR3-mediated IL-6 and IFN-beta production. These data suggest that STRAP is a positive regulator of the TLR3-meditated NF-kappaB and IRF signaling pathway. PMID- 28651744 TI - Eying the future: Eye movement in past and future thinking. AB - We investigated eye movement during past and future thinking. Participants were invited to retrieve past events and to imagine future events while their scan path was recorded by an eye-tracker. Past thinking triggered more fixation (p < .05), and saccade counts (p < .05) than future thinking. Past and future thinking triggered a similar duration of fixations and saccades, as well as a similar amplitude of saccades. Interestingly, participants rated past thinking as more vivid than future thinking (p < .01). Therefore, the vividness of past thinking seems to be accompanied by an increased number of fixations and saccades. Fixations and saccades in past thinking can be interpreted as an attempt by the visual system to find (through saccades) and activate (through fixations) stored memory representations. The same interpretation can be applied to future thinking as this ability requires activation of past experiences. However, future thinking triggers fewer fixations and saccades than past thinking: this may be due to its decreased demand on visual imagery, but could also be related to a potentially deleterious effect of eye movements on spatial imagery required for future thinking. PMID- 28651743 TI - The combination of NK and CD8+T cells with CCL20/IL15-armed oncolytic adenoviruses enhances the growth suppression of TERT-positive tumor cells. AB - Adoptive immunotherapy and targeted gene therapy have been extensively used to eliminate tumor cells. The combination treatment is capable of efficiently generating an effective antitumor immune response and disrupting tumor-induced tolerance. Moreover, effective antitumor immune responses are dependent on coordinate interaction among various effector cells. This study focused on whether the combination of cytotoxic effector cell-based adoptive immunotherapy and CCL20/IL15-armed oncolytic adenoviruses could induce enhanced antitumor activity. The CCL20/IL15-armed oncolytic adenovirus was constructed using homologous recombination with shuttle plasmids and full-length Ad backbones. We chose the telomerase reverse transcriptase promoter (TERTp) to replace the E1A promoter to drive the oncolytic adenoviral E1A gene. Thus, this CRAd-CCL20-IL15 could induce apoptosis in TERTp-positive tumor cells due to viral propagation, but these viruses could not replicate efficiently in normal cells. The combination of cytotoxic effector cells and CRAd-CCL20-IL15 showed greater antitumor potential than that of cytotoxic effector cells or CRAd-CCL20-IL15 alone. Moreover, the combined treatment could induce tumor-specific cytotoxicity of CTLs in vitro. Further analysis demonstrated that this combined treatment resulted in significant tumor regression in mouse models. This study has provided preclinical evidence that combined treatment with cytotoxic effector cells and CRAd-CCL20-IL15 may offer alternative treatment options for tumor therapy. PMID- 28651745 TI - The neural monitoring of visceral inputs, rather than attention, accounts for first-person perspective in conscious vision. AB - Why should a scientist whose aim is to unravel the neural mechanisms of perception consider brain-body interactions seriously? Brain-body interactions have traditionally been associated with emotion, effort, or stress, but not with the "cold" processes of perception and attention. Here, we review recent experimental evidence suggesting a different picture: the neural monitoring of bodily state, and in particular the neural monitoring of the heart, affects visual perception. The impact of spontaneous fluctuations of neural responses to heartbeats on visual detection is as large as the impact of explicit manipulations of spatial attention in perceptual tasks. However, we propose that the neural monitoring of visceral inputs plays a specific role in conscious perception, distinct from the role of attention. The neural monitoring of organs such as the heart or the gut would generate a subject-centered reference frame, from which the first-person perspective inherent to conscious perception can develop. In this view, conscious perception results from the integration of visual content with first-person perspective. PMID- 28651747 TI - The rise of artificial intelligence and the uncertain future for physicians. AB - Physicians in everyday clinical practice are under pressure to innovate faster than ever because of the rapid, exponential growth in healthcare data. "Big data" refers to extremely large data sets that cannot be analyzed or interpreted using traditional data processing methods. In fact, big data itself is meaningless, but processing it offers the promise of unlocking novel insights and accelerating breakthroughs in medicine-which in turn has the potential to transform current clinical practice. Physicians can analyze big data, but at present it requires a large amount of time and sophisticated analytic tools such as supercomputers. However, the rise of artificial intelligence (AI) in the era of big data could assist physicians in shortening processing times and improving the quality of patient care in clinical practice. This editorial provides a glimpse at the potential uses of AI technology in clinical practice and considers the possibility of AI replacing physicians, perhaps altogether. Physicians diagnose diseases based on personal medical histories, individual biomarkers, simple scores (e.g., CURB-65, MELD), and their physical examinations of individual patients. In contrast, AI can diagnose diseases based on a complex algorithm using hundreds of biomarkers, imaging results from millions of patients, aggregated published clinical research from PubMed, and thousands of physician's notes from electronic health records (EHRs). While AI could assist physicians in many ways, it is unlikely to replace physicians in the foreseeable future. Let us look at the emerging uses of AI in medicine. PMID- 28651746 TI - The management of colorectal liver metastases. AB - Colorectal cancer remains a leading cause of cancer-related death in Europe. Approximately one-quarter of patients have synchronous hepatic metastases and metachronous liver metastases occur in a further 30%. The scope of surgery in management of colorectal metastases has evolved to include selected patients with extra-hepatic disease for whom R0 resection is considered feasible; however, locoregional treatments are increasingly recognised as viable management options in those patients deemed unsuitable for surgery and there is an expanding body of evidence regarding their ability to achieve local control and increase progression-free survival in the liver. Locoregional therapies increasingly practised in the management of unresectable liver metastatic colorectal cancer (mCRC) include percutaneous ablation, primarily in the form of radiofrequency ablation or microwave ablation, although there remains a lack of data regarding long-term outcome. Radio-embolisation (RE) is the most comprehensively studied embolisation technique in the context of colorectal liver metastases, predominantly using yttrium 90 (90Y). The data published to date suggests that 90Y represents a safe and effective cytoreductive modality. The optimal dose and timing of therapies remains uncertain and further studies are required to determine its relationship with systemic treatment. Irinotecan-loaded drug eluting beads (DEBIRI) transcatheter arterial chemo-embolisation (TACE) represents a further therapy with considerable potential. There is evidence of improved overall survival in the salvage setting. As with the other therapies discussed, further research is required to elucidate the optimal role and timing of these treatments within the increasingly crowded space of therapies for mCRC. PMID- 28651748 TI - Positive predictive value of hospital discharge diagnosis code to identify immunoglobulin A vasculitis in France: A validation study. PMID- 28651749 TI - Editorial Comment. PMID- 28651750 TI - Reduced orexin immunoreactivity in Perry syndrome and multiple system atrophy. AB - INTRODUCTION: Orexin is a neuropeptide that plays a key role in maintaining a state of arousal, and possibly associates with sleep apnea syndrome (SAS). Reduced orexin immunoreactivity has been reported in various neurologic conditions such as narcolepsy, Alzheimer's disease, Lewy body disease and multiple system atrophy (MSA); however, there has been no report investigating orexin in Perry syndrome, a rare hereditary neurodegenerative disease characterized by four clinical cardinal signs (parkinsonism, depression/apathy, weight loss, and central hypoventilation). Perry syndrome patients frequently have sleep disturbances, including SAS and insomnia. METHODS: We evaluated orexin immunoreactivity in Perry syndrome. Using imaging analysis, we quantitatively assessed orexin immunoreactivity in the nucleus basalis of Meynert in three Perry syndrome cases, as well as five cases of frontotemporal lobar degeneration with motor neuron disease, five cases of MSA and five age-matched controls. For these cases, antemortem clinical information on sleep disturbances has been reviewed. RESULTS: In Perry syndrome and MSA, there was reduction of orexin immunoreactivity compared with controls (Perry syndrome: p = 0.020, MSA: p < 0.001). In contrast, FTLD-MND did not have significant reduction of orexin immunoreactivity. Two out of three cases of Perry syndrome had SAS confirmed by polysomnography. CONCLUSIONS: This is the first report assessing orexin immunoreactivity in Perry syndrome, and it showed significant reduction, similar to select neurodegenerative diseases, such as MSA. Further analysis with more cases will be needed to elucidate the specific mechanism of orexin loss in these disorders. PMID- 28651751 TI - No association of PARK10 polymorphism with Parkinson's disease in Han Chinese population. PMID- 28651752 TI - Colonic diverticular disease: A new risk factor for Parkinson's disease? AB - BACKGROUND: Colonic diverticular disease is a chronic gastrointestinal disorder. Previous studies have suggested that chronic gastrointestinal tract is involved in the pathophysiology of Parkinson's disease. OBJECT: This study investigated the potential link between colonic diverticular disease and risk of Parkinson's disease. METHODS: Data in this nationwide population-based cohort study were obtained from the National Health Insurance Research Database. Patients with colonic diverticular disease were identified from among 23.22 million insured Taiwanese residents who had been diagnosed between 2000 and 2005 and were aged >=20 years (n = 23367). The comparison cohort included patients without colonic diverticular disease, matched by sex, age, and all comorbidities with the colonic diverticular disease patients cohort (n = 23367). Using univariable and multivariable Cox proportional hazard regression models, we estimated the adjusted hazard ratio (aHR) for PD with a 95% confidence interval (CI) after adjusting for age, sex, and all of comorbidities. RESULTS: The risk of Parkinson's disease was higher in the CDD cohort than in the comparison cohort (HR = 1.27, 95%CI = 1.10-1.47). Compared with patients aged >=65 years without CDD, the CDD patients in the equal age group had a 1.25-fold increased risk of PD (95% CI = 1.07-1.46). CONCLUSION: Colonic diverticular disease may be associated with an increased risk of Parkinson's disease. Thus, the risk of this neurodegenerative disease should be considered in patients with colonic diverticular disease. PMID- 28651753 TI - Evidence-based practice and the evidence pyramid: A 21st century orthodontic odyssey. AB - Organized evidence-based practice is said to have started in the medical field in the late 20th century. Its principles and usage eventually spread to other health sciences, including orthodontics. Although the conceptual foundations and basic tenets of evidence-based orthodontics are based on the classical approach of testing medical interventions, differences unravel as we encounter the ground realities in orthodontics, which are unique due to the length, complexity, and diversity involved in orthodontic treatment and research. How has this led to the evolution of evidence-based orthodontics and changes in its applications? Is it being translated to better clinical answers, treatment strategies, patient satisfaction, and information for orthodontists? What more needs to be done, considering the rapidly changing orthodontic scenario? This article aims to explore these questions to evaluate how evidence-based orthodontics has played itself out so far, so that it can continue to grow strong and stand up to the challenges of 21st century orthodontics. PMID- 28651754 TI - Authors' response. PMID- 28651755 TI - Miniscrew-assisted customized lingual appliances for predictable treatment of skeletal Class II malocclusion with severe deep overbite and overjet. AB - This report describes the use of miniscrew-assisted customized lingual fixed appliances in a patient with severe skeletal Class II malocclusion. The patient was a 12-year-old Chinese girl with the chief complaint of protrusive lips and anterior teeth. Her diagnosis included a skeletal Class II relationship with maxillary protrusion, a backward-rotated mandible, a full Angle Class II molar relationship, and severe deep overjet and overbite. Four premolars were extracted, and miniscrew anchorage was placed in the maxillary posterior lingual segment to provide maximum anchorage and to achieve vertical control of the intruding molars. The customized lingual fixed appliance and temporary anchorage devices created a smooth and invisible treatment progress, resulting ultimately in a well-aligned dentition with ideal intercuspation and a dramatically improved profile. The 3-year follow-up examination indicated that the excellent treatment outcome was stable. PMID- 28651756 TI - Effects of short-term in-vivo studies on orthodontic root resorption paradigms. PMID- 28651757 TI - Lateral open bite and crossbite correction in a Class III patient with missing maxillary first premolars. AB - Posterior and Class III elastics were used to correct lateral open bite and anterior crossbite in a 29-year-old man. His occlusion, smile esthetics, and soft tissue profile were significantly improved after 25 months of active orthodontic treatment combined with 4 anterior restorations. PMID- 28651758 TI - Authors' response. PMID- 28651759 TI - Orthodontic chart documentation. PMID- 28651760 TI - Harms and adverse events in clinical research. PMID- 28651761 TI - Introduction to incidence rates and time-changing variables for cohort studies. PMID- 28651762 TI - Authors' response. PMID- 28651763 TI - No tricks, please. PMID- 28651764 TI - Compliance with removable orthodontic appliances and adjuncts: A systematic review and meta-analysis. AB - INTRODUCTION: The primary aims of this systematic review were to assess objective levels of wear of removable orthodontic appliances and components vs both stipulated and self-reported levels. We also aimed to consider patient experiences and the effectiveness of interventions geared at enhancing compliance. METHODS: Electronic databases and reference lists of relevant studies were searched with no language restriction (PROSPERO: CRD42016036059). Randomized and nonrandomized controlled trials, prospective cohort studies, case series, qualitative and mixed-methods studies objectively assessing compliance levels were identified. The quality of the studies was assessed using the Cochrane Collaboration's risk of bias tool, risk of bias in non-randomized studies of interventions (ROBINS-I), or mixed-methods appraisal tool based on their design. RESULTS: Of 4269 records, 80 full texts were obtained, with 24 studies meeting the selection criteria. Of these, 11 were included in the quantitative synthesis. A weighted estimate of objectively assessed compliance levels in relation to stipulated wear time was calculated with the discrepancy highest in the headgear group (5.81 hours per day, 95% confidence interval, 4.98, 6.64) based on 6 studies. The mean discrepancy between self-reported and objectively assessed headgear wear was 5.02 hours per day (95% confidence interval, 3.64, 6.40). Compliance level was not directly related to appliance type (P = 0.211). Thematic synthesis was not undertaken because of the limited number of qualitative studies. CONCLUSIONS: Compliance with removable orthodontic appliances and adjuncts is suboptimal, and patients routinely overestimate duration of wear. Techniques for improving compliance have promise but require further evaluation in high-level research. PMID- 28651765 TI - Gingival crevicular fluid bone turnover biomarkers: How postmenopausal women respond to orthodontic activation. AB - INTRODUCTION: Bone turnover associated with orthodontic tooth movement is evidenced by increased bone turnover markers in gingival crevicular fluid (GCF). Postmenopausal women have an increased concentration of serum bone turnover markers. The filtrate of this serum makes up GCF, but little is known of the bone turnover around teeth in this cohort. The objective of this investigation was to compare the GCF bone turnover markers in premenopausal vs postmenopausal women receiving orthodontic treatment at baseline and at orthodontic activation. METHODS: Twenty-eight women were enrolled in the study and separated into 2 groups: premenopausal (16) and postmenopausal (12). Bone turnover was evaluated by GCF at baseline and 24 hours after orthodontic appliance activation. GCF concentrations of RANKL and OPN were measured using ELISA. Baseline and change in concentrations were compared between groups. RESULTS: Baseline RANKL and OPN were significantly different between the premenopausal and postmenopausal groups (P <0.05). Both markers increased significantly from baseline to 24 hours after orthodontic appliance activation in both groups (P <0.05). However, the response to orthodontic activation was not significantly different between groups. CONCLUSIONS: Although postmenopausal women have a different bone turnover profile at baseline than do their premenopausal counterparts, there is no difference in their response to orthodontic activation. This confers a level of security associated with orthodontic activation. Future studies are warranted to construct biomarker curves throughout orthodontic therapy. PMID- 28651766 TI - Prevalence of malocclusion in Canadian children with autism spectrum disorder. AB - INTRODUCTION: The purposes of this study were to determine the prevalence of malocclusion among children with autism spectrum disorder (ASD) and to describe the most common malocclusion traits in this population. METHODS: This cross sectional study included patients diagnosed with ASD aged between 5 and 18 years. Randomly selected healthy children with the same demographic characteristics comprised the control group. Dental charts were reviewed to obtain the children's sociodemographic characteristics and type of occlusion. Information on each child's molar occlusion classification (Angle classification), midline deviation, crossbite, open bite, overbite, overjet, and crowding were recorded. The statistical analysis used descriptive analysis, the Pearson chi-square test, and multivariate logistic regression. RESULTS: Ninety-nine children comprised the ASD group, and 101 children were in the control group. Our results demonstrated a significantly higher prevalence of malocclusion in children with ASD compared with the control group (P <0.001). Patients with ASD were significantly more likely to have posterior crossbite (P = 0.03), increased overjet (P <0.0001), and severe maxillary crowding (P <0.01). Furthermore, children with ASD were more likely to have malocclusion than non-ASD children, independently of their demographic characteristics (odds ratio, 2.6; 95% confidence interval, 1.46, 4.65). CONCLUSIONS: The prevalence of malocclusion was higher among children with ASD. Posterior crossbite, increased overjet, and severe maxillary crowding were the most common malocclusion traits in these children. PMID- 28651767 TI - Midpalatal suture maturation in 11- to 15-year-olds: A cone-beam computed tomographic study. AB - INTRODUCTION: We used cone-beam computed tomography to evaluate the maturation stages of the midpalatal sutures in children aged 11 to 15 years old. Maxillary expansion is successful for most patients in this age group, so we sought to identify the status of suture maturation in these subjects to use as a comparison for the prognosis of rapid maxillary expansion in older patients. METHODS: Tomographic images in axial sections of the midpalatal sutures from 84 children (40 boys, 44 girls; ages, 11-15 years) were classified using a scale denoting the maturation stage of the midpalatal suture (A, B, C, D, and E). The chi-square test was applied to evaluate suture stages by sex and age groups. RESULTS: Stage A was observed in only one 11-year-old girl. Stage B was present at all ages but was more prevalent in those less than 13 years of age. Stage C was the most prevalent in all evaluated ages. Stages D and E showed low prevalence rates. There were higher prevalences of the early stages of maturation in boys. CONCLUSIONS: The results of this study, which showed dominant prevalence of stage C, suggest that conventional, nonsurgical rapid maxillary expansion performed in patients over 15 years old is justified by a satisfactory prognosis when assessment of the sutural status indicates stage C. PMID- 28651768 TI - Elevation of a full-thickness mucoperiosteal flap alone accelerates orthodontic tooth movement. AB - INTRODUCTION: Our objective was to determine whether the elevation of a full thickness mucoperiosteal flap alone, without cortical cuts, decreases the amount of bone around teeth and accelerates mesial tooth movements. METHODS: The mandibular second premolars of 7 beagle dogs were extracted, and on a randomly selected side, a full-thickness mucoperiosteal buccal flap extending from the distal aspect of the third premolar to the mesial aspect of the first premolar was elevated. The other side did not receive flap surgery. The mandibular third premolars were protracted with orthodontic appliances. Tooth movements were analyzed biweekly over an 8-week period with calipers and radiographs. The amount and density of bone were analyzed using microcomputed tomography; bone remodeling was evaluated with histologic sections. RESULTS: Experimental tooth movements measured intraorally between cusp tips were significantly greater (25.3%) than control tooth movements. The approximate center of resistance measured radiographically also moved significantly more (about 31%) on the experimental than on the control side. The experimental premolar tipped more than the control premolar (10.5 degrees vs 8.7 degrees ), but the difference was not statistically significant. The medullary bone volume fraction mesial to the third premolar was significantly less (9.1%) and the bone was significantly less dense (9%) on the experimental side than on the control side. Histology showed no apparent side differences in the numbers of osteoclasts and osteoblasts evident in the medullary bone. CONCLUSIONS: Elevation of a full-thickness mucoperiosteal flap alone (ie, without injury to bone) decreases the amount and density of medullary bone surrounding the tooth and accelerates tooth movement. Due to its limited effects, elevation of a flap alone to increase tooth movements may not be justified. PMID- 28651769 TI - Mesiodistal dental movement toward remodeled edentulous alveolar ridge: Digital model assessment. AB - INTRODUCTION: The aims of this study were to compare the changes in posterior dental inclination and angulation, and the posterior tooth crown sizes and alveolar ridge thicknesses consequent to the orthodontic procedures of closing and opening of mandibular first molar edentulous spaces. METHODS: The sample comprised 16 patients (4 men, 12 women) with an initial mean age of 34.17 years and unilateral or bilateral absence of mandibular permanent first molars. The space closure group (SCG) comprised 12 hemiarches with a mandibular first molar edentulous space varying from 2 to 7 mm, orthodontically treated with space closure. The space opening group (SOG) comprised 14 quadrants with a mandibular first molar edentulous space varying from 7.1 to 12 mm, orthodontically treated with space reopening for prosthetic replacement. Digital dental models were obtained before treatment and after space closure or opening, and posterior tooth angulation and inclination, cervico-occlusal crown height, and alveolar ridge thickness were evaluated. Interphase and intergroup comparisons were performed with dependent t tests and t tests, respectively (P <0.05). RESULTS: Mandibular second molar uprighting and changes in buccolingual inclination of the posterior teeth were similar in the groups. The second molar cervico-occlusal crown height increased in the SCG and decreased in the SOG. The alveolar ridge thickness increased in the SCG and remained stable in the SOG. CONCLUSIONS: The only significant intergroup differences were that the second molar cervico-occlusal crown height and the alveolar ridge thickness increased in the SCG, and decreased and remained stable in the SOG. PMID- 28651770 TI - Correlation between buccolingual tooth inclination and alveolar bone thickness in subjects with Class III dentofacial deformities. AB - INTRODUCTION: The purposes of this study were to identify buccolingual inclinations and alveolar bone thickness in patients with Class III dentofacial deformities and to compare these measurements with those from subjects with normal occlusions to verify, based on the correlation between these 2 variables, whether the natural process of bone remodeling provides uniformity of bone thickness or whether it varies around the roots due to tooth inclination. METHODS: The sample consisted of 35 adults with normal occlusions and 35 adults with Class III dentofacial deformities with no previous orthodontic treatment. Buccolingual inclinations and alveolar bone thickness were measured at 3 heights from the cementoenamel junction from 3-dimensional images generated by cone-beam computed tomography. RESULTS: The region corresponding to the maxillary canines appeared to be thinner, and the palatal area of the maxillary central incisors and the distobuccal region of the mandibular second molars appeared to be thicker. Greater tooth inclinations were observed in the maxillary incisors and mandibular canines, and smaller tooth inclinations were observed on the buccal roots of the mandibular second molars. CONCLUSIONS: In subjects with Class III deformities, more statistically significant correlations were found between inclination and thickness in the mandibular teeth, whereas in subjects with normal occlusion, few statistically significant correlations were found between these 2 variables. PMID- 28651771 TI - Perceived facial changes of Class II Division 1 patients with convex profiles after functional orthopedic treatment followed by fixed orthodontic appliances. AB - INTRODUCTION: The aim of this research was to investigate the perceived facial changes in Class II Division 1 patients with convex profiles after functional orthopedic treatment followed by fixed orthodontic appliances. METHODS: Pretreatment and posttreatment profile photographs of 12 Class II Division 1 patients treated with activators, 12 Class II Division 1 patients treated with Twin-block appliances, and 12 controls with normal profiles treated without functional appliances were presented in pairs to 10 orthodontists, 10 patients, 10 parents, and 10 laypersons. The raters assessed changes in facial appearance on a visual analog scale. Two-way multivariate analysis of variance was used to evaluate differences among group ratings. RESULTS: Intrarater reliability was strong in most cases (intraclass correlation coefficients, >0.7). The internal consistency of the assessments was high (alpha, >0.87), both within and between groups. The raters consistently perceived more positive changes in the Class II Division 1 groups compared with the control group. However, this difference hardly exceeded 1/10th of the total visual analog scale length in its highest value and was mostly evident in the lower face and chin. No significant differences were found between the activator and the Twin-block groups. CONCLUSIONS: Although the raters perceived improvements of the facial profiles after functional orthopedic treatment followed by fixed orthodontic appliances, these were quite limited. Thus, orthodontists should be tentative when predicting significant improvement of a patient's profile with this treatment option. PMID- 28651772 TI - Extraction frequencies. PMID- 28651773 TI - Authors' response. PMID- 28651774 TI - Correlation and reliability of cone-beam computed tomography nasopharyngeal volumetric and area measurements as determined by commercial software against nasopharyngoscopy-supported diagnosis of adenoid hypertrophy. AB - INTRODUCTION: The aim of this study was to evaluate the diagnostic correlation and reliability of Dolphin Imaging fully automated segmentation (Dolphin Imaging and Management Solutions, Chatsworth, Calif) for assessing adenoid hypertrophy. This was investigated through 3 modes: (1) intraobserver and interobserver agreement of repeated airway auto-segmentation procedures, (2) correlation between auto-segmentation measures of volume and minimal cross-sectional airway against nasopharyngoscopy, and (3) optimum diagnostic cutoff thresholds for volume and minimal cross-sectional airway identified and tested with sensitivity and specificity analyses. METHODS: Cone-beam computed tomography scans of 38 patients with suspected upper airway obstruction were analyzed. Two calibrated evaluators applied a previously validated method to quantify nasopharyngeal minimal cross-sectional airway and volume using Dolphin Imaging. Assessments were compared against grades of obstruction provided by otolaryngologists' diagnoses. RESULTS: The reliability between the 2 assessments by the same evaluator on the Dolphin automatic segmentation function for volume (ICC, 0.97; 95% CI, 0.95, 0.98) and minimal cross-sectional airway (ICC, 0.84; 95% CI, 0.69, 0.91) was excellent. The interoperator reliability for volume was also excellent (ICC, 0.97; 95% CI, 0.95, 0.98), but only good (ICC, 0.701; 95% CI, 0.44, 0.85) for minimal cross-sectional airway. In contrast, the Spearman rank correlation test demonstrated weak associations between the values of the automatic measurements for both volume (4.9%; rho = -0.22) and minimal cross-sectional airway (3.7%; rho = 0.19). Assessments of accuracy via Receiver Operating characteristic analysis, sensitivity, specificity, negative predictive values, positive predictive values, and likelihood ratios demonstrated the poor clinical applicability of volume and minimal cross-sectional airway numbers provided by Dolphin Imaging. CONCLUSIONS: The evaluators were reliable at manipulating the selected software, achieving consistent volume and minimal cross-sectional airway measurements, However, Dolphin Imaging volumetric and minimal cross-sectional airway measurements did not correlate well with the nasopharyngoscopy-supported reference standard for adenoid hypertrophy assessment. Under these study conditions, volume and minimal cross-sectional airway used to assess localized adenoid hypertrophy with cone beam computed tomography imaging based on automated measurements may not yield high-quality clinically relevant information about upper airway constriction related to adenoid hypertrophy. PMID- 28651775 TI - Departing from the essential features of a high quality systematic review of psychotherapy: A response to Ost (2014) and recommendations for improvement. AB - Ost's (2014) systematic review and meta-analysis of Acceptance and Commitment Therapy (ACT) has received wide attention. On the basis of his review, Ost argued that ACT research was not increasing in its quality and that, in contradiction to the views of Division 12 of the American Psychological Association (APA), ACT is "not yet well-established for any disorder" (2014, p. 105). We conducted a careful examination of the methods, approach, and data used in the meta-analysis. Based in part on examinations by the authors of the studies involved, which were then independently checked, 91 factual or interpretive errors were documented, touching upon 80% of the studies reviewed. Comparisons of Ost's quality ratings with independent teams rating the same studies with the same scale suggest that Ost's ratings were unreliable. In all of these areas (factual errors; interpretive errors; quality ratings) mistakes and differences were not random: Ost's data were dominantly more negative toward ACT. The seriousness, range, and distribution of errors, and a wider pattern of misinterpreting the purpose of studies and ignoring positive results, suggest that Ost's review should be set aside in future considerations of the evidence base for ACT. We argue that future published reviews and meta-analyses should rely upon diverse groups of scholars rather than a single individual; that resulting raw data should be made available for inspection and independent analysis; that well-crafted committees rather than individuals should design, apply and interpret quality criteria; that the intent of transdiagnostic studies need to be more seriously considered as the field shifts away from a purely syndromal approach; and that data that demonstrate theoretically consistent mediating processes should be given greater weight in evaluating specific interventions. Finally, in order to examine substantive progress since Ost's review, recent outcome and process evidence was briefly examined. PMID- 28651776 TI - Reply to: Unnecessary histologic examination of stapler doughnuts at low anterior resection for rectal cancer: Is it just a blame game? PMID- 28651777 TI - Barriers and benefits to using mobile health technology after operation: A qualitative study. AB - BACKGROUND: Recently, mobile health technology has emerged as a promising avenue for improving physician-patient communication and patient outcomes. The objective of our study was to determine the public's perception of barriers and benefits to using mobile health technology technologies to enhance recovery after operation. METHODS: We used the Empire State Poll to ask 2 open-ended questions to 800 participants assessing their perceptions of benefits and barriers to use mobile health technology after operation. All responses were coded independently, and any discrepancies were resolved by consensus. We used grounded theory to allow themes to arise from the codes. Interrater reliability was calculated using Cohen's Kappa. RESULTS: Participants identified a range of possible barriers to using mobile health technology apps after operation including: protecting personal health information, technology effectiveness and failure, preference for face-to-face interaction with their surgeon, level of effort required, and ability of the older adults to navigate mobile health technology. Participants identified multiple possible benefits including: better monitoring, improved communication with their surgeon, minimizing follow-up visits, improved convenience, and increased patient knowledge. In the study, 15% of all respondents stated there were no barriers whereas 6% stated there were no benefits. CONCLUSION: Participants were receptive to the many potential benefits of this technology to enhance not only their relationships with providers and the convenience of access, but also their health outcomes. We must address participants concerns about data security and their fears of losing a personal relationship with their doctor. PMID- 28651778 TI - Reply to: LODDS or negative to positive lymph nodes ratio? PMID- 28651779 TI - [Randomized prospective study of three different techniques for ultrasound-guided axillary brachial plexus block]. AB - INTRODUCTION: Randomized prospective study comparing two perivascular techniques with the perineural technique for ultrasound-guided axillary brachial plexus block (US-ABPB). The primary objective was to verify if these perivascular techniques are noninferior to the perineural technique. METHOD: 240 patients were randomized to receive the techniques: below the artery (BA), around the artery (AA) or perineural (PN). The anesthetic volume used was 40mL of 0.375% bupivacaine. All patients received a musculocutaneous nerve blockade with 10mL. In BA technique, 30mL were injected below the axillary artery. In AA technique, 7.5mL were injected at 4 points around the artery. In PN technique, the median, ulnar, and radial nerves were anesthetized with 10mL per nerve. RESULTS: Confidence interval analysis showed that the perivascular techniques studied were not inferior to the perineural technique. The time to perform the blockade was shorter for the BA technique (300.4+/-78.4sec, 396.5+/-117.1sec, 487.6+/ 172.6sec, respectively). The PN technique showed a lower latency time (PN - 655.3+/-348.9sec; BA -1044+/-389.5sec; AA-932.9+/-314.5sec), and less total time for the procedure (PN-1132+/-395.8sec; BA -1346.2+/-413.4sec; AA 1329.5+/ 344.4sec). BA technique had a higher incidence of vascular puncture (BA - 22.5%; AA - 16.3%; PN - 5%). CONCLUSION: The perivascular techniques are viable alternatives to perineural technique for US-ABPB. There is a higher incidence of vascular puncture associated with the BA technique. PMID- 28651780 TI - ADM research guidance papers. PMID- 28651781 TI - Should we be taking the p (value) out of statistics? PMID- 28651782 TI - Femoral neck shortening in adult patients under the age of 55 years is associated with worse functional outcomes: Analysis of the prospective multi-center study of hip fracture outcomes in China (SHOC). AB - INTRODUCTION: Young femoral neck fracture patients require surgical fixation to preserve the native hip joint and accommodate increased functional demands. Recent reports have identified a high incidence of fracture shortening and this may have negative functional consequences. We sought to determine if fracture shortening is associated with poor functional outcome in young femoral neck fracture patients. PATIENTS AND METHODS: One hundred and forty-two patients with femoral neck fractures age 18-55 were recruited in this prospective cohort study across three Level 1 trauma hospitals in Mainland China. Patient-reported and objective functional outcomes were measured with the Harris Hip Score (HHS), Timed Up and Go (TUG), and SF-36 Physical Component Summary (SF-36 PCS) at 12 months. Radiographic fracture shortening was measured along the long axis of the femoral neck and corrected for magnification. Severe shortening was defined as >=10mm. The primary analysis measured associations between severe radiographic shortening and HHS at one-year post-fixation. RESULTS: One hundred and two patients had complete radiographic and functional outcomes available for analysis at one year. The mean age of participants was 43.7+/-10.8years and 53% were male. Fifty-five percent of fractures were displaced and 37% were vertically orientated (Pauwels Type 3). The mean functional outcome scores were: HHS 90.0+/-10.8, TUG 12.0+/-5.1s, and PCS 48.5+/-8.6. Severe shortening occurred in 13% of patients and was associated with worse functional outcome scores: HHS mean difference 9.9 (p=0.025), TUG mean difference 3.2s (p=0.082), and PCS mean difference 5.4 (p=0.055). CONCLUSIONS: Severe shortening is associated with clinically important decreases in functional outcome as measured by HHS following fixation of young femoral neck fractures, occurring in 13% of patients in this population. The principle of fracture site compression utilized by modern constructs may promote healing; however, excessive shortening is associated with worse patient-reported outcomes and objective functional measures. PMID- 28651783 TI - Optimal Timing of Heart Transplant After HeartMate II Left Ventricular Assist Device Implantation. AB - BACKGROUND: Optimal timing of heart transplantation in patients supported with second-generation left ventricular assist devices (LVADs) is unknown. Despite this, patients with LVADs continue to receive priority on the heart transplant waiting list. Our objective was to determine the optimal timing of transplantation for patients bridged with continuous-flow LVADs. METHODS: A total of 301 HeartMate II LVADs (Thoratec Corp, Pleasanton, CA) were implanted in 285 patients from October 2004 to June 2013, and 86 patients underwent transplantation through the end of follow-up. Optimal transplantation timing was the product of surviving on LVAD support and surviving transplant. RESULTS: Three year survival after both HeartMate II implantation and heart transplantation was unchanged when transplantation occurred within 9 months of implantation. Survival decreased as the duration of support exceeded this. Preoperative risk factors for death on HeartMate II support were prior valve operation, prior coronary artery bypass grafting, low albumin, low glomerular filtration rate, higher mean arterial pressure, hypertension, and earlier date of implant. Survival for patients without these risk factors was lowest when transplant was performed within 3 months but was relatively constant with increased duration of support. Longer duration of support was associated with poorer survival for patients with many of these risk factors. Device reimplantation, intracranial hemorrhage, and postimplant dialysis during HeartMate II support were associated with decreased survival. CONCLUSIONS: Survival of patients supported by the HeartMate II is affected by preoperative comorbidities and postoperative complications. Transplantation before complications is imperative in optimizing survival. PMID- 28651784 TI - Behavior, brain and astrocytes. PMID- 28651786 TI - Autochthonous Crimean-Congo haemorrhagic fever in Spain: So much to learn. PMID- 28651785 TI - Septic arthritis following arthroscopic reconstruction of cruciate ligaments of the knee: retrospective case review. AB - INTRODUCTION: Rupture of cruciate ligaments of the knee is a common injury that is repaired by arthroscopic reconstruction, which can give rise to septic arthritis. The objective of this article is to describe the clinical and microbiological aspects of this entity. METHODS: Retrospective review of cases of septic arthritis following arthroscopic reconstruction of cruciate ligaments of the knee that occurred at a single institution from 2000-2015. According to time elapsed from surgery, infections were classified as acute (< 14 days), subacute (> 14 days and<30 days), and late (> 30 days). A descriptive and comparative analysis stratified by type of infection and causative microorganism was performed. RESULTS: 3,219 patients underwent arthroscopic reconstruction of cruciate ligaments of the knee and 30 (0.9%) developed septic arthritis. Seventeen (57%) were acute infections and 12 (40%) subacute; there was one late infection. The causative microorganisms were coagulase-negative Staphylococci (n=13; 43%), Staphylococcus aureus (n=12; 40%), other grampositive cocci (n=3; 10%), and gramnegative bacilli (n=2; 7%). All patients underwent arthroscopic debridement; no grafts were removed. All patients received antibiotic therapy for a median of 23.5 days (range: 14 - 78 days); all infections were cured. No significant differences were found in any of the variables analysed among the infection type or the causative microorganism. CONCLUSIONS: Septic arthritis after arthroscopic reconstruction of cruciate ligaments of the knee is uncommon. It generally presents within 4 weeks of surgery and is caused by Staphylococci. Its treatment consists of arthroscopic debridement (without necessarily removing the graft) and antibiotic therapy. PMID- 28651787 TI - A role for proactive control in rapid instructed task learning. AB - Humans are often remarkably fast at learning novel tasks from instructions. Such rapid instructed task learning (RITL) likely depends upon the formation of new associations between long-term memory representations, which must then be actively maintained to enable successful task implementation. Consequently, we hypothesized that RITL relies more heavily on a proactive mode of cognitive control, in which goal-relevant information is actively maintained in preparation for anticipated high control demands. We tested this hypothesis using a recently developed cognitive paradigm consisting of 60 novel tasks involving RITL and 4 practiced tasks, with identical task rules and stimuli used across both task types. A robust behavioral cost was found in novel relative to practiced task performance, which was present even when the two were randomly inter-mixed, such that task-switching effects were equated. Novelty costs were most prominent under time-limited preparation conditions. In self-paced conditions, increased preparation time was found for novel trials, and was selectively associated with enhanced performance, suggesting greater proactive control for novel tasks. These results suggest a key role for proactive cognitive control in the ability to rapidly learn novel tasks from instructions. PMID- 28651788 TI - Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R) Ketamine in a Social Defeat Stress Model. AB - BACKGROUND: The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. METHODS: The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. RESULTS: The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S) ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. CONCLUSIONS: This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine's antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine. PMID- 28651789 TI - Interactions Among Working Memory, Reinforcement Learning, and Effort in Value Based Choice: A New Paradigm and Selective Deficits in Schizophrenia. AB - BACKGROUND: When studying learning, researchers directly observe only the participants' choices, which are often assumed to arise from a unitary learning process. However, a number of separable systems, such as working memory (WM) and reinforcement learning (RL), contribute simultaneously to human learning. Identifying each system's contributions is essential for mapping the neural substrates contributing in parallel to behavior; computational modeling can help to design tasks that allow such a separable identification of processes and infer their contributions in individuals. METHODS: We present a new experimental protocol that separately identifies the contributions of RL and WM to learning, is sensitive to parametric variations in both, and allows us to investigate whether the processes interact. In experiments 1 and 2, we tested this protocol with healthy young adults (n = 29 and n = 52, respectively). In experiment 3, we used it to investigate learning deficits in medicated individuals with schizophrenia (n = 49 patients, n = 32 control subjects). RESULTS: Experiments 1 and 2 established WM and RL contributions to learning, as evidenced by parametric modulations of choice by load and delay and reward history, respectively. They also showed interactions between WM and RL, where RL was enhanced under high WM load. Moreover, we observed a cost of mental effort when controlling for reinforcement history: participants preferred stimuli they encountered under low WM load. Experiment 3 revealed selective deficits in WM contributions and preserved RL value learning in individuals with schizophrenia compared with control subjects. CONCLUSIONS: Computational approaches allow us to disentangle contributions of multiple systems to learning and, consequently, to further our understanding of psychiatric diseases. PMID- 28651790 TI - Re: Multicenter Investigation of the Micro-organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis. PMID- 28651792 TI - Racial and ethnic differences in contraception use and obstetric outcomes: A review. AB - In the United States, racial and ethnic minority women experience higher rates of contraceptive non-use, failure, unintended pregnancy, and lower use of long acting reversible contraception (LARC), compared to whites. Simultaneously researchers have found that unintended pregnancy is associated with poor pregnancy outcomes and pregnancy behaviors, including pre-term birth and late initiation of prenatal care, respectively. Due to the association of pregnancy intention and obstetrical outcomes, public health efforts have focused on the increase in contraception use among these populations as a way to decrease poor pregnancy outcomes. In this review, we present the current literature on unintended pregnancy and contraception use by racial and ethnic minorities in the United States and the association of pregnancy intention and obstetrical outcomes and place these associations within the social and historical context in which these patients live and make their reproductive choices. PMID- 28651791 TI - [Primary lymphedema in childhood]. AB - Lymphedema results from impaired lymphatic transport with increased limb volume and is divided into primary and secondary forms. In children, primary lymphedema is the most frequent, with a sporadic, rarely familial form or associated with complex malformative or genetic disorders. Diagnosis of lymphedema is mainly clinical and lymphoscintigraphy is useful to assess the lymphatic function of both limbs precisely. The main differential diagnosis is overgrowth syndrome. Erysipelas (cellulitis) is the main complication, but psychological or functional discomfort may occur throughout the course of lymphedema. Lymphedema management is based on multilayer low-stretch bandage, skin care, and eventually manual lymph drainage. The objective of treatment is to reduce lymphedema volume and then stabilize it. Multilayer low-stretch bandage and elastic compression are the cornerstone of treatment. Parent's motivation, including self-management, is required to ensure the child's compliance and improve quality of life. PMID- 28651793 TI - Rapid vs Maintenance Vitamin D Supplementation in Deficient Children With Asthma to Prevent Exacerbations. AB - BACKGROUND: Whether vitamin D reduces clinically important exacerbations of childhood asthma remains uncertain. We compared rapid to maintenance vitamin D repletion analyzed by baseline vitamin D level. METHODS: Children presenting to the ED with moderate-to-severe asthma exacerbations and vitamin D levels <= 25 ng/mL underwent masked randomization, and then open dosing to either IM+oral (the latter daily) therapy or daily oral-only therapy, and were followed for 12 months. The primary outcome was patient-initiated unplanned visits for asthma exacerbations, examined two ways: cumulative proportions with an exacerbation, and average exacerbation frequency. As this was a nutrient study, we analyzed treatment groups by quartile of baseline vitamin D level, collecting repeat levels and clinical observations at 3, 6, 9, and 12 months after enrollment. RESULTS: One hundred and sixteen patients in the IM+oral cohort vs 115 in the oral-only cohort had similar mean (SD) baseline levels: 15.1 (5.4) vs 15.8 (5.2) ng/mL (range, 3-25 ng/mL). There was no difference in the primary outcome over the entire 12-month observation period. However, rapid IM+oral supplementation significantly reduced unplanned visits for asthma exacerbations for children with baseline levels of 3 to 11 ng/mL during the initial 3 months: the relative exacerbation rate for the IM+oral cohort compared with the oral-only cohort at 3 months was 0.48 (95% CI, 0.28-0.89; P = .008); average exacerbation frequency per child analysis, relative rate 0.36 (95% CI, 0.13-0.87; P = .017). Otherwise, there were no significant differences between groups. CONCLUSIONS: Rapid compared to maintenance vitamin D supplementation for children with the lowest levels resulted in short- but not long-term reduction in asthma exacerbations. PMID- 28651794 TI - Airflow Shape Is Associated With the Pharyngeal Structure Causing OSA. AB - BACKGROUND: OSA results from the collapse of different pharyngeal structures (soft palate, tongue, lateral walls, and epiglottis). The structure involved in collapse has been shown to impact non-CPAP OSA treatment. Different inspiratory airflow shapes are also observed among patients with OSA. We hypothesized that inspiratory flow shape reflects the underlying pharyngeal structure involved in airway collapse. METHODS: Subjects with OSA were studied with a pediatric endoscope and simultaneous nasal flow and pharyngeal pressure recordings during natural sleep. The mechanism causing collapse was classified as tongue-related, isolated palatal, lateral walls, or epiglottis. Flow shape was classified according to the degree of negative effort dependence (NED), defined as the percent reduction in inspiratory flow from peak to plateau. RESULTS: Thirty-one subjects with OSA (mean apnea-hypopnea index score +/- SD, 54 +/- 27 events/h) who were 50 +/- 9 years of age were studied. NED was associated with the structure causing collapse (P < .001). Tongue-related obstruction (n = 13) was associated with a small amount of NED (median, 19; interquartile range [IQR], 14% 25%). Moderate NED was found among subjects with isolated palatal collapse (median, 45; IQR, 39%-52%; n = 8) and lateral wall collapse (median, 50; IQR, 44% 64%; n = 8). The epiglottis was associated with severe NED (median, 89; IQR, 78% 91%) and abrupt discontinuities in inspiratory flow (n = 9). CONCLUSIONS: Inspiratory flow shape is influenced by the pharyngeal structure causing collapse. Flow shape analysis may be used as a noninvasive tool to help determine the pharyngeal structure causing collapse. PMID- 28651795 TI - Safety, Science, or Both? Deceptive Healthy Volunteers: Psychiatric Conditions Uncovered by Objective Methods of Screening. PMID- 28651796 TI - Neurological manifestations of excessive alcohol consumption. AB - This article reviews the different acute and chronic neurological manifestations of excessive alcohol consumption that affect the central or peripheral nervous system. Several mechanisms can be implicated depending on the disorder, ranging from nutritional factors, alcohol-related toxicity, metabolic changes and immune mediated mechanisms. Recognition and early treatment of these manifestations is essential given their association with high morbidity and significantly increased mortality. PMID- 28651797 TI - Left Ventricular Hypertrophy by the Surface ECG. AB - Left ventricular hypertrophy (LVH) is defined as an increase in left ventricular mass (LVM) associated with structural changes of myocardium. The increase in LVM and associated changes are associated with changes in depolarization and repolarization, manifested as a variety of altered QRS and T patterns. Increased QRS voltage has been considered to be a specific ECG finding in LVH, and ECG criteria based on this increased QRS voltage are generally recommended. These ECG changes are also predictive of adverse cardiovascular outcomes. However, it must also be noted that the majority of patients with increased LVM do not have increased QRS voltage. While this is often considered a limitation of ECG in LVH diagnosis, the authors of this minireview consider it more likely that the electrical effects, represented in the altered ECG, and the increased LVM are independent effects, associated by virtue of their common relationship with an underlying pathologic state. This revised view challenges cardiologists and electrocardiologists to explore the interrelationships between electrical, biochemical, and mechanical alterations of myocardial remodeling seen with heart disease, to advance our understanding of this process and its effects, including the evolution of the ECG changes known as "LVH". PMID- 28651799 TI - Metastatic Dissemination of a Neuroblastoma. PMID- 28651798 TI - Cycling to School and Body Composition, Physical Fitness, and Metabolic Syndrome in Children and Adolescents. AB - OBJECTIVE: To evaluate the association between cycling to/from school and body composition, physical fitness, and metabolic syndrome among a sample of Colombian children and adolescents. STUDY DESIGN: During the 2014-2015 school year, we examined a cross-sectional component of the Association for muscular strength with early manifestation of cardiovascular disease risk factors among Colombian children and adolescents (FUPRECOL) study. Participants included 2877 youths (54.5% girls) from Bogota, Colombia. A self-reported questionnaire was used to measure the frequency and mode of commuting to school. Four components of physical fitness were measured: (1) anthropometric (height, weight, body mass index, and waist circumference); (2) musculoskeletal (handgrip and standing long jump test); (3) motor (speed-agility test; 4 * 10-meter shuttle run); and (4) cardiorespiratory (20-m shuttle run test [20mSRT]). The prevalence of metabolic syndrome was determined by the definitions provided by the International Diabetes Federation. RESULTS: Twenty-three percent of the sample reported commuting by cycle. Active commuting boys had a likelihood of having an unhealthy 4 * 10 m value (OR, 0.72; 95% CI, 0.53-0.98; P = .038) compared with the reference group (passive commuters). Active commuting girls showed a lower likelihood of having unhealthy a 20mSRT value (OR, 0.81; 95% CI, 0.56-0.99; P = .047) and metabolic syndrome (OR, 0.61; 95% CI, 0.35-0.99; P = .048) compared with passive commuters. CONCLUSION: Regular cycling to school may to be associated with better physical fitness and a lower incidence of metabolic syndrome than passive transport, especially in girls. PMID- 28651800 TI - Cellular mechanisms underlying the inhibitory effect of flufenamic acid on chloride secretion in human intestinal epithelial cells. AB - Intestinal Cl- secretion is involved in the pathogenesis of secretory diarrheas including cholera. We recently demonstrated that flufenamic acid (FFA) suppressed Vibrio cholerae El Tor variant-induced intestinal fluid secretion via mechanisms involving AMPK activation and NF-kappaB-suppression. The present study aimed to investigate the effect of FFA on transepithelial Cl- secretion in human intestinal epithelial (T84) cells. FFA inhibited cAMP-dependent Cl- secretion in T84 cell monolayers with IC50 of ~8 MUM. Other fenamate drugs including tolfenamic acid, meclofenamic acid and mefenamic acid exhibited the same effect albeit with lower potency. FFA also inhibited activities of CFTR, a cAMP activated apical Cl- channel, and KCNQ1/KCNE3, a cAMP-activated basolateral K+ channel. Mechanisms of CFTR inhibition by FFA did not involve activation of its negative regulators. Interestingly, FFA inhibited Ca2+-dependent Cl- secretion with IC50 of ~10 MUM. FFA inhibited activities of Ca2+-activated Cl- channels and KCa3.1, a Ca2+-activated basolateral K+ channels, but had no effect on activities of Na+-K+-Cl- cotransporters and Na+-K+ ATPases. These results indicate that FFA inhibits both cAMP and Ca2+-dependent Cl- secretion by suppressing activities of both apical Cl- channels and basolateral K+ channels. FFA and other fenamate drugs may be useful in the treatment of secretory diarrheas. PMID- 28651801 TI - Physician Attitudes toward the First Pediatric Appropriate Use Criteria and Engagement With Educational Intervention to Improve the Appropriateness of Outpatient Echocardiography. AB - BACKGROUND: A survey of pediatric cardiologists who participated in the Pediatric Appropriate Use of Echocardiography study was conducted to assess attitudes toward appropriate use criteria (AUC) and the relationship between perceptions of usefulness of a multifaceted educational intervention (EI) and the appropriateness of transthoracic echocardiography (TTE). METHODS: Self-reported helpfulness and impact of a four-component EI (feedback of personal appropriateness data before EI, lecture, self-assignment of AUC indications, and monthly feedback) was surveyed. Physicians' perceptions were correlated with measured changes in appropriateness after EI by center. RESULTS: Responses were obtained from 54 of 89 physicians (61%; 52% general cardiologists, 24% imaging specialists), and most (72%) felt that AUC were helpful in health care cost reduction. More physicians with <=10 years of experience self-reported ordering TTE less often because of AUC (P = .04). Subspecialty did not influence TTE ordering practice. Centers whose physicians had higher rates of reading the document had higher appropriateness. A change in practice following EI was self reported by 31 of 54 respondents (57%). All components of EI were felt to be helpful. Helpfulness and self-reported impact of each EI component tracked together (r = 0.61; 95% CI, 0.16-0.85; P = .01) but varied among centers. Centers with higher perceived practice impact of EI overall had greater changes in measured appropriateness after EI. CONCLUSIONS: AUC were perceived to be useful by a majority of pediatric cardiologists surveyed. Centers with a positive attitude toward AUC and higher engagement with EI had higher actual appropriateness of TTE orders. Improving physicians' attitudes toward AUC and EI may improve outpatient TTE utilization. PMID- 28651802 TI - Echocardiographic Diagnosis, Surgical Treatment, and Outcomes of Anomalous Left Coronary Artery from the Pulmonary Artery. AB - BACKGROUND: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare condition that can be difficult to diagnose by echocardiography alone. The purpose of this study was to describe the clinical and echocardiographic presentation of ALCAPA, create a set of critical echocardiographic diagnostic criteria, and report outcomes. METHODS: A retrospective review was conducted of all patients diagnosed with isolated ALCAPA at two major cardiac centers between 1990 and 2015. RESULTS: Of the 37 patients identified, only 54% presented in infancy. The anomalous coronary artery (CA) origin was clearly imaged in only 54% of echocardiographic examinations. However, other consistently identified echocardiographic markers were found, including left CA flow reversal (91%), collateral CA flow (85%), right CA dilation (81%), abnormal pulmonary artery flow (79%), mitral regurgitation (74%), left ventricular dysfunction (66%) and endocardial fibroelastosis (57%). Presenting echocardiograms had five of seven markers in 85% of patients. Left ventricular dysfunction was the most common marker in infants (89% vs 38%, P = .005); older children were more likely to have collateral formation visualized by color Doppler (100% vs 75%, P = .04). Following surgery, there were no early surgical deaths. The median follow-up duration was 10.3 years. At last follow-up, 92% had normal left ventricular function, 3% had moderate or worse mitral regurgitation, and 17% had required reintervention. CONCLUSIONS: Echocardiographic markers can reliably identify ALCAPA; these markers vary with the age of presentation. Surgical outcomes are excellent, and most patients will recover left ventricular and mitral valve function. PMID- 28651803 TI - Clinical outcomes research in gynecologic oncology. AB - Clinical outcomes research seeks to understand the real-world manifestations of clinical care. In particular, outcomes research seeks to reveal the effects of pharmaceutical, procedural, and structural aspects of healthcare on patient outcomes, including mortality, disease control, toxicity, cost, and quality of life. Although outcomes research can utilize interventional study designs, insightful use of observational data is a defining feature of this field. Many questions in gynecologic oncology are not amenable to investigation in randomized clinical trials due to cost, feasibility, or ethical concerns. When a randomized trial is not practical or has not yet been conducted, well-designed observational studies have the potential to provide the best available evidence about the effects of clinical care. Such studies may use surveys, medical records, disease registries, and a variety of administrative data sources. Even when a randomized trial has been conducted, observational studies can be used to estimate the real world effect of an intervention, which may differ from the results obtained in the controlled setting of a clinical trial. This article reviews the goals, methodologies, data sources, and limitations of clinical outcomes research, with a focus on gynecologic oncology. PMID- 28651805 TI - Dental implants in patients with osteoporosis: a systematic review with meta analysis. AB - There is currently no consensus regarding the survival rate of osseointegrated implants in patients with osteoporosis. A systematic review with meta-analysis was performed to evaluate the survival rate of implants in such patients. The PubMed/MEDLINE, Web of Science, Cochrane Library, and SciELO databases were used to identify articles published up to September 2016. The systematic review was performed in accordance with PRISMA/PICO requirements and the risk of bias was assessed (Australian National Health and Medical Research Council scale). The relative risk (RR) of implant failure and mean marginal bone loss were analyzed within a 95% confidence interval (CI). Fifteen studies involving 8859 patients and 29,798 implants were included. The main outcome of the meta-analysis indicated that there was no difference in implant survival rate between patients with and without osteoporosis, either at the implant level (RR 1.39, 95% CI 0.93 2.08; P=0.11) or at the patient level (RR 0.98, 95% CI 0.50-1.89; P=0.94). However, the meta-analysis for the secondary outcome revealed a significant difference in marginal bone loss around implants between patients with and without osteoporosis (0.18mm, 95% CI 0.05-0.30, P=0.005). Data heterogeneity was low. An increase in peri-implant bone loss was observed in the osteoporosis group. Randomized and controlled clinical studies should be conducted to analyze possible biases. PMID- 28651804 TI - Efficacy and safety of trabectedin or dacarbazine in patients with advanced uterine leiomyosarcoma after failure of anthracycline-based chemotherapy: Subgroup analysis of a phase 3, randomized clinical trial. AB - OBJECTIVE: Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). METHODS: Of 577 patients randomized 2:1 to receive trabectedin 1.5mg/m2 by 24-hour IV infusion or dacarbazine 1g/m2 by 20-120-minute IV infusion once every three weeks, 232 had uLMS (trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. RESULTS: PFS for trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41-0.81; P=0.0012). OS was similar (trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65-1.24; P=0.51) between groups. ORR was 11% with trabectedin vs. 9% with dacarbazine (P=0.82). CBR for trabectedin was 31% vs. 18% with dacarbazine (P=0.05); median DOR was 6.5months for trabectedin vs. 4.1months for dacarbazine (P=0.32). Grade 3/4 treatment emergent adverse events observed in >=10% of patients in the trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. CONCLUSIONS: In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS. PMID- 28651806 TI - Von Willebrand Factor Deposition and ADAMTS-13 Consumption in Allograft Tissue of Thrombotic Microangiopathy-like Disorder After Living Donor Liver Transplantation: A Case Report. AB - BACKGROUND: Thrombotic microangiopathy (TMA) pathogenesis after living donor liver transplantation (LDLT) is thought to be caused by release of unusually large von Willebrand factor multimers (UL-vWFMs) resulting from sinusoidal endothelial cell damage and induction of platelet adhesion and aggregation. A decrease in a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13 (ADAMTS-13) that cleave UL-vWFMs might cause excessive UL-vWFMs activity and result in platelet thrombus formation. However, this phenomenon has not undergone a full pathologic assessment. PROCEDURES: A 60-year-old man was diagnosed with hepatitis C-related end-stage cirrhosis. His son was the donor, and he underwent LDLT. On postoperative day 44, his laboratory findings met most TMA diagnostic criteria, and he was diagnosed with TMA-like disorder (TMALD). Localization of CD42b as a platelet marker, vWF, and ADAMTS-13 in allograft tissue of this patient were evaluated using immunohistochemistry. RESULTS: CD42b expression was observed as platelet aggregates attached to hepatocytes or within the hepatocyte cytoplasm, a morphology called extravasated platelet aggregation (EPA). vWF expression was observed mainly as deposited compact clusters, and ADAMTS-13 expression resembled distinct dots throughout the liver tissue. CONCLUSION: These findings suggest that EPA indicated sinusoidal endothelial cell damage followed by detachment, and vWF deposition resulted from UL-vWFM oversynthesis. ADAMTS-13 might be consumed in the allograft tissue to cleave UL vWFMs, but ADAMTS-13 levels might be insufficient to cleave all the deposited UL vWFMs. We present the case of an LDLT recipient diagnosed with TMALD using blood tests, which showed the presence of TMA pathogenesis in the allograft. PMID- 28651807 TI - Safety evaluation of transgenic low-gliadin wheat in Sprague Dawley rats: An alternative to the gluten free diet with no subchronic adverse effects. AB - Gluten-associated pathologies have increased in recent years and there is a greater demand for low or gluten-free products. Transgenic low-gliadin wheat lines showed low T-cell response, good bread-making properties, and excellent sensory assets. The aim of this study was to evaluate the safety of the whole wheat flour from one transgenic low-gliadin line (named E82) in a 90-day feeding study. In this study males (n = 50) and females (n = 50) SD rats were used. They were fed with doses of 1.42, 2.83 and 5.67 g/kg/day of the transgenic E82 line, 5.67 g/kg/day of the WT and a blank group. We found that there were no significant differences in the development of animals. Biochemistry for liver and kidney function were similar for males and females of all groups. Other haematological and metabolic blood parameters, as well as organ weight did not show significant differences in the five groups of animals. In the histopathological study performed for the higher dose of transgenic E82 line, WT and blank group no abnormalities were observed. The whole-wheat flour of E82 line administered to rats at tested doses for 90 days did not have any adverse effects and there was no difference with the rats which ate WT wheat. PMID- 28651808 TI - Addendum to Weiner, M.L. (2016) Parameters and Pitfalls to Consider in the Conduct of Food Additive Research, Carrageenan as a Case Study. Food Chemical Toxicology 87, 31-44. AB - This paper is an addendum to a 2016 paper outlining pitfalls and parameters to consider in the conduct of food additive research with carrageenan (Fd. Chem. Tox. 87, 31-44 (2016)). The literature on the food additive, "carrageenan," contains many publications which either erroneously misuse the name, carrageenan, for a sample which is not carrageenan, but "degraded carrageenan" or "poligeenan" and also conduct studies without understanding the physical/chemical properties of carrageenan. Degraded carrageenan and poligeenan are not food additives and have a completely different physical/chemical and toxicological properties from carrageenan. Two recent publication examples, one in vivo and one in vitro, demonstrate the serious misunderstanding promulgated by incorrect sample identity/purity and poor study conduct. These new publication examples reiterate the problems in the literature summarized by the Weiner (2016). It is important to have thorough, rigorous peer review of all studies using carrageenan in vivo or in vitro. PMID- 28651809 TI - Interventional Cardiology: What's New? AB - Interventional cardiology in veterinary medicine continues to expand beyond the standard 3 procedures of patent ductus arteriosus occlusion, balloon pulmonary valvuloplasty, and transvenous pacing. Opportunities for fellowship training; advances in equipment, including high-resolution digital fluoroscopy, real-time 3 dimensional transesophageal echocardiography, fusion imaging, and rotational angiography; ultrasound-guided access and vascular closure devices; and refinement of techniques, including cutting and high-pressure ballooning, intracardiac and intravascular stent implantation, septal defect occlusion, transcatheter valve implantation, and hybrid approaches, are likely to transform the field over the next decade. PMID- 28651810 TI - Comparison of 5468 retreatments after laser in situ keratomileusis by lifting the flap or performing photorefractive keratectomy on the flap. AB - PURPOSE: To assess visual outcomes of retreatment after laser in situ keratomileusis (LASIK) by lifting the flap or performing photorefractive keratectomy (PRK) on the flap, as well as to establish whether there was an increased risk of epithelial ingrowth (EIG) when LASIK and lifting of the flap are separated by a long time interval and to determine the incidence of corneal haze after PRK. METHODS: Retrospective study of 4077 patients (5468 eyes) who underwent LASIK and subsequent retreatment were reviewed in order to study their visual results and identify cases of EIG and corneal haze. RESULTS: Enhancements included 5196 eyes from 3876 patients that were retreated by lifting the flap, and 272 eyes from 201 patients that were retreated by PRK on the flap. No statistically significant differences were found between the retreatments in terms of predictability, efficacy, and safety. A total of 704 cases of EIG were found after lifting the flap, for which surgical cleansing was necessary in 70. Surgical cleansing decreased the efficacy index when compared with patients with EIG who did not need cleansing (P=.01). Differences in terms of safety and predictability were not statistically significant. The incidence of corneal haze after ablation of the surface of the previous flap was 14.34%, although none of these cases were clinically relevant. CONCLUSIONS: Visual outcomes were similar between patients who were retreated by lifting the flap and those who underwent PRK. The incidence of EIG when the flap was lifted was 13.55%. The incidence of EIG increases with the time elapsed between the primary procedure and retreatment. PMID- 28651812 TI - Erratum to "Age-related differences in sleep-based memory consolidation: A meta analysis" [Neuropsychologia 97 (2017) 46-55]. PMID- 28651811 TI - BIlateral juxtapapillary retinal capillary haemangioma: Usefulness of aflibercept in the management of its complications. AB - CASE REPORT: A 45 year-old man with a history of adrenal phaeochromocytoma presented with a subretinal juxtapapillary haemorrhage on his left eye and a small asymptomatic vascular tumour in the contralateral eye. With the mentioned findings, the patient was diagnosed with bilateral retinal capillary haemangioma in the context of a von Hippel Lindau disease. Intravitreal aflibercept was prescribed, with a good outcome of the disease. DISCUSSION: Many treatments have been proposed for the management of juxtapapillary retinal capillary haemangioma with variable results. Intravitreal aflibercept can be a useful treatment with a good safety profile. PMID- 28651814 TI - Falls risk assessments: Too much, too little or just right? PMID- 28651813 TI - Magnetic Oculomotor Prosthetics for Acquired Nystagmus. AB - PURPOSE: Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector-the eye muscles themselves-where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times. Implementing this idea magnetically, herein we describe the successful implantation of a novel magnetic oculomotor prosthesis in a patient. DESIGN: Case report of a pilot, experimental intervention. PARTICIPANT: A 49-year-old man with longstanding, medication resistant, upbeat nystagmus resulting from a paraneoplastic syndrome caused by stage 2A, grade I, nodular sclerosing Hodgkin's lymphoma. METHODS: We designed a 2-part, titanium-encased, rare-earth magnet oculomotor prosthesis, powered to damp nystagmus without interfering with the larger forces involved in saccades. Its damping effects were confirmed when applied externally. We proceeded to implant the device in the patient, comparing visual functions and high-resolution oculography before and after implantation and monitoring the patient for more than 4 years after surgery. MAIN OUTCOME MEASURES: We recorded Snellen visual acuity before and after intervention, as well as the amplitude, drift velocity, frequency, and intensity of the nystagmus in each eye. RESULTS: The patient reported a clinically significant improvement of 1 line of Snellen acuity (from 6/9 bilaterally to 6/6 on the left and 6/5-2 on the right), reflecting an objectively measured reduction in the amplitude, drift velocity, frequency, and intensity of the nystagmus. These improvements were maintained throughout a follow-up of 4 years and enabled him to return to paid employment. CONCLUSIONS: This work opens a new field of implantable therapeutic devices-oculomotor prosthetics-designed to modify eye movements dynamically by physical means in cases where a purely neural approach is ineffective. Applied to acquired nystagmus refractory to all other interventions, it is shown successfully to damp pathologic eye oscillations while allowing normal saccadic shifts of gaze. PMID- 28651815 TI - Crystal clear cerebral ultrasound images mimicking acute asphyxia in an infant with primary hyperoxaluria. AB - Genetic deficiencies in enzymes involved in glyoxylate metabolism lead to primary hyperoxaluria (PH) type I, typically characterized by deposition of oxalate crystals in kidneys. A 2-month-old infant was admitted, and was diagnosed with renal failure. Abdominal ultrasound images revealed enlarged and hyperechoic kidneys. Additionally, on cerebral ultrasound (CUS) hyperechoic changes of thalami and basal ganglia were noted, reminiscent of perinatal hypoxic-ischemic brain damage. However, MRI of the brain did not show any abnormal signal intensities compatible with asphyxia. The hyperechoic appearance of deep grey matter, in particular putamen, was therefore not due to asphyxiated brain damage but seemed related to the deposition of oxalate salts. Moreover, macular crystals were detected at ophthalmoscopy. Our case report shows the potential of US imaging to detect deposition of crystals not only in kidneys but also in brain mimicking, perinatal asphyxia. PMID- 28651816 TI - [Efficacy of anakinra as a treatment for recurrent pericarditis]. PMID- 28651817 TI - Angiogenesis and cancer stem cells: New perspectives on therapy of ovarian cancer. AB - Failure in ovarian cancer therapy, following cytoreduction and chemotherapy, is related to the presence of cancer stem cells - a small subpopulation of cells resistant to chemotherapy and irradiation - in the tumour which may cause cancer relapse and manifestation of metastases. Therapies targeted at Cancer Stem Cells (CSCs), such as those employing metformin (a drug used in the treatment of diabetes type II) and salinomycin, an antibiotic isolated from Streptococcus albus bacteria, seem promising. Anti-angiogenic therapy with bevacizumab was found to be effective in all phases of ovarian cancer treatment. The presence of CSCs has been associated with angiogenesis. Several CSC biomarkers correlate with the markers of angiogenesis and some signalling pathways, e.g. Notch, and are used by both CSCs and by pro-angiogenic factors. PMID- 28651818 TI - Design and validation of a questionnaire on nursing competence in the notification of medication incidents. AB - AIM: To design and perform a face and content validation of a questionnaire to measure the competence of hospital RN to report medication incidents. METHODS: Content and face questionnaire validation descriptive study. A review of the literature was performed for the creation of items. A panel of six experts assessed the relevance of the inclusion of each item in the questionnaire by calculating the position index; items with position index >0.70 were selected. The questionnaire was piloted by 59 RN. Finally, a meeting was convened with experts, in order to reduce the length of the piloted questionnaire through review, discussion and decision by consensus on each item. RESULTS: From the literature review, a battery of 151 items grouped into three elements of competence: attitudes, knowledge and skills was created. 52.9% (n=80) of the items received a position index > 0.70. The response rate in the pilot study was 40.65%. The median time to complete the questionnaire was 23:35minutes. After reduction by the experts, the final questionnaire comprised 45 items grouped into 32 questions. CONCLUSIONS: The NORMA questionnaire, designed to explore the competence of hospital RN to report medication incidents, has adequate face and content validity and is easy to administer, enabling its institutional implementation. PMID- 28651819 TI - Stigma: The relevance of social contact in mental disorder. AB - INTRODUCTION: The stigma associated with mental illness is a health problem, discriminating and limiting the opportunities for sufferers. Social contact with people suffering a mental disorder is a strategy used to produce changes in population stereotypes. The aim of the study was to examine differences in the level of stigma in samples with social contact and the general population. METHOD: The study included two experiments. The first (n=42) included players in an open football league who played in a team with players with schizophrenia. In the second included, a sample without known contact (n=62) and a sample with contact (n=100) were compared. The evaluation tool used was AQ-27, Spanish version (AQ-27-E). The mean difference between the two samples of each of the 9 subscales was analyzed. RESULTS: In the first experiment, all the subscales had lower scores in post-contact than in pre-contact, except for responsibility. The two subscales that showed significant differences were duress (t=6.057, p=.000) and Pity (t=3.661, p=.001). In the second experiment, seven subscales showed a significance level (p=<.05). Segregation and responsibility and did not. CONCLUSIONS: It is observed that the social contact made in daily situations can have a positive impact on the reduction of stigma. This can help to promote equality of opportunity. PMID- 28651820 TI - Site-selective substitution of gold atoms in the Au24(SR)20 nanocluster by silver. AB - The synthesis and structure determination of atomically precise alloy nanoclusters have attracted much attention in recent research. Herein, we report a new alloy nanocluster Au24-xAgx(TBBM)20 (x~1) synthesized via a ligand-exchange induced size/structure transformation method. Its X-ray structure is obtained successfully and the dopant Ag is found to occupy three special positions in the kernel, rather than equivalently over all the kernel sites. This selective occupancy is interesting and DFT calculation results suggest that the relative oxidation state (rationalized as difference in the charge) of the Ag when doped into the cluster is likely determining the most favorable doping positions. This work provides a new strategy for controlled synthesis of new Au-Ag nanoclusters and also reveals a new scenario for the doping position of Ag atoms in Au-Ag bimetal nanoclusters. PMID- 28651821 TI - Sequencing-based network analysis provides a core set of gene resource for understanding kidney immune response against Edwardsiella tarda infection in Japanese flounder. AB - Marine organisms are under a frequent threat from various pathogens. Edwardsiella tarda is one of the major fish pathogens infecting both cultured and wild fish species. It can also infect a variety of other vertebrates, including amphibians, reptiles, and mammals, and bacteremia caused by E. tarda can be fatal in humans. The kidney is the largest lymphoid organ in fish, and generating kidney transcriptomic information under different stresses is crucial for understanding molecular mechanisms underlying the immune responses in the kidneys. In this study, we performed transcriptome-wide gene expression profiling of the Japanese flounder (Paralichthys olivaceus) challenged by 8 and 48 h of E. tarda infection. An average of 40 million clean reads per library was obtained, and approximately 81.6% of these reads were successfully mapped to the reference genome. In addition, 1319 and 4439 differentially expressed genes (DEGs) were found at 8 and 48 h post-injection, respectively. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to search immune-related DEGs. A protein-protein interaction network was constructed to ascertain the relationship between interacting immune genes during pathogen induced stress. Based on the KEGG and protein association networks analysis, 24 hub genes were discovered and validated by qRT-PCR. To our knowledge, this study is the first to represent the kidney transcriptome analysis based on protein protein interaction networks in fish. Our results provide valuable gene resources for further research on kidney immune response in fish, which can significantly improve our understanding of the molecular mechanisms underlying the immune response to E. tarda in humans and other vertebrates. PMID- 28651822 TI - Pharyngeal Dystonia Mimicking Spasmodic Dysphonia. AB - OBJECTIVE: The aim of this study was to describe the presentation of pharyngeal dystonia (PD), which can occur as a focal or segmental dystonia with a primarily pharyngeal involvement for the discussion of treatment methods for controlling consequent symptoms. PD is specific to speech-related tasks. METHODS: A retrospective medical record review of four patients with PD was performed. RESULTS: All patients were initially misdiagnosed with adductor spasmodic dysphonia and failed standard treatment with botulinum toxin type A (BTX). On laryngoscopy, the patients were discovered to have segmental or focal dystonia primarily affecting the pharyngeal musculature contributing to their vocal manifestations. A novel treatment regimen was designed, which involved directing BTX injections into the muscles involved in spasmodic valving at the oropharyngeal level. After titrating to an optimal dose, all patients showed improvement in their voice and speech with only mild dysphagia. These patients have maintained favorable results with repeat injections at 6- to 12-week intervals. CONCLUSIONS: PD, or dystonia with predominant pharyngeal involvement, is a rare entity with vocal manifestations that are not well described. It can be easily mistaken for spasmodic dysphonia. PD is specific to speech-related tasks. A novel method of BTX injections into the involved muscles results in a significant improvement in voice without significant dysphagia. PMID- 28651823 TI - Novel Structural Insights into GPCR-beta-Arrestin Interaction and Signaling. AB - G protein-coupled receptors (GPCRs) are major signal recognition and transmission units in the plasma membrane. The interaction of activated and phosphorylated GPCRs with the multifunctional adaptor proteins beta-arrestins (betaarrs) is crucial for regulation of their signaling and functional outcomes. Over the past few years, a range of structural, biochemical, and cellular studies have revealed novel insights into GPCR-betaarr interaction and signaling. Some of these findings have come as a surprise and therefore have the potential to significantly refine the conceptual framework of the GPCR-betaarr system. Here we discuss these recent advances with particular emphasis on biphasic GPCR-betaarr interaction, the formation of GPCR-G-protein-betaarr supercomplexes, and receptor specific conformational signatures in betaarrs. We also underline the emerging research areas that are likely to be at the center stage of investigations in the coming years. PMID- 28651824 TI - Cryotherapy to treat anogenital warts in nonimmunocompromised adults: Systematic review and meta-analysis. AB - BACKGROUND: Cryotherapy is one of the most commonly used therapeutic modalities to treat anogenital warts (AGWs), but this treatment was not clearly established in the recent international recommendations. OBJECTIVE: To compare the efficacy and safety of cryotherapy versus other AGW treatments. METHODS: Through a systematic search of 12 electronic databases, we identified 11 randomized controlled trials, screened from database inception through October 2016, that met the inclusion criteria (including immunocompetent adults with AGWs receiving cryotherapy in 1 of the comparison groups). Primary endpoint was complete clearance of AGW. Risk-for-bias assessment was based on Cochrane Handbook recommendations. Meta-analyses used Review Manager v5.3 software. RESULTS: Cryotherapy efficacy did not appear to differ from that of trichloroacetic acid, podophyllin, or imiquimod. Electrosurgery was weakly associated with better AGW clearance than cryotherapy (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.65-0.99). Cryotherapy was associated with more immediate low-level adverse events (erythema, stinging, or irritation; RR 3.02, 95% CI 1.38-6.61) and immediate pain requiring oral analgesics (RR 2.11, 95% CI 1.07-4.17) but fewer erosions (RR 0.57, 95% CI 0.36-0.90). LIMITATIONS: All but 1 randomized controlled trial had a high risk for bias. CONCLUSION: With low-level quality of the evidence, cryotherapy is an acceptable first-line therapy to treat AGWs. PMID- 28651825 TI - Prescription patterns and costs of acne/rosacea medications in Medicare patients vary by prescriber specialty. AB - BACKGROUND: Prescription patterns for acne/rosacea medications have not been described in the Medicare population, and comparisons across specialties are lacking. OBJECTIVE: To describe the medications used for treating acne/rosacea in the Medicare population and evaluate differences in costs between specialties. METHODS: A cross-sectional study was performed of the 2008 and 2010 Centers for Medicare and Medicaid Services Prescription Drug Profiles, which contains 100% of Medicare part D claims. RESULTS: Topical antibiotics accounted for 63% of all prescriptions. Patients >=65 years utilized more oral tetracycline-class antibiotics and less topical retinoids. Specialists prescribed brand name drugs for the most common topical retinoids and most common topical antibiotics more frequently than family medicine/internal medicine (FM/IM) physicians by 6%-7%. Topical retinoids prescribed by specialists were, on average, $18-$20 more in total cost and $2-$3 more in patient cost than the same types of prescriptions from FM/IM physicians per 30-day supply. Specialists (60%) and IM physicians (56%) prescribed over twice the rate of branded doxycycline than FM doctors did (27%). The total and patient costs for tetracycline-class antibiotics were higher from specialists ($18 and $4 more, respectively) and IM physicians ($3 and $1 more, respectively) than they were from FM physicians. LIMITATIONS: The data might contain rare prescriptions used for conditions other than acne/rosacea, and suppression algorithms might underestimate the number of specialist brand name prescriptions. CONCLUSION: Costs of prescriptions for acne/rosacea from specialists are higher than those from primary care physicians and could be reduced by choosing generic and less expensive options. PMID- 28651826 TI - Impact of muscle biopsy on diagnosis and management of children with neuromuscular diseases: A 10-year retrospective critical review. AB - BACKGROUND: Muscle biopsy facilitates morphologic, biochemical, and ultrastructural analysis of muscle for the purpose of making definitive neuromuscular diagnosis. However, muscle biopsy is an expensive, invasive, time consuming, and resource-dependent procedure. The need for general anesthesia in children also increases the risks associated with this procedure. The aim of this study was to investigate the benefits of muscle biopsies performed over a 10-year period, with a focus on indications, suspected and histopathologic diagnosis, and impact on diagnosis and management decisions. METHODS: We retrospectively reviewed results of muscle biopsies performed in children at our center during the 2004 to 2014 study period. Clinical presentations, biopsy complications, pathologic results, and changes in management decision were reviewed and analyzed. RESULTS: Biopsies from 92 patients were included. Mean age of patients was 7.1years, and 66.3% were male. There were no perioperative complications, and definitive diagnosis was made in 74 patients. Regardless of whether pathologic changes were found or not, information gained from muscle biopsy significantly impacted prognosis and subsequent genetic counseling. CONCLUSIONS: Muscle biopsy is a safe and useful diagnostic tool in children suspected of having neuromuscular diseases, especially in those with muscle diseases. Definitive pathologic diagnosis helps to optimize treatment, counseling, and surveillance. THE TYPE OF STUDY AND LEVEL OF EVIDENCE: Study of diagnostic test: level 1. PMID- 28651827 TI - Effects of nutrition and physical exercise intervention in palliative cancer patients: A randomized controlled trial. AB - BACKGROUND & AIMS: Cancer cachexia is multifactorial and should be targeted using a multimodal form of intervention. The purpose of the present trial was to test the effects of a combined nutrition and physical exercise program on cancer patients with metastatic or locally advanced tumors of the gastrointestinal and lung tracts. METHODS: Patients were randomized into two groups: One group received a minimum of three standardized individual nutritional counselling sessions and participated in a 60-min exercise program twice a week. The second group received their usual care. The intervention spanned a period of three months. Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0), physical performance (hand grip strength, 6-min walk test, timed sit-to-stand test and 1 repetition maximum leg press), nutritional status (body weight, bioelectrical impedance analysis), dietary intake (three-day dietary record) and clinical data (unexpected hospital days, performance status) were tested at baseline and after three and six months. RESULTS: In total, 18 women and 40 men (mean age 63, range 32-81) with metastatic or locally advanced tumors of the gastrointestinal (n = 38) and lung (n = 20) tracts were included. Median adherence to the supervised exercise program was 75%. The median number of individual nutritional counselling sessions was 3.0 (range 0-7 sessions). Post intervention, no difference in global health status/quality of life (overall QoL) was observed. Intervention was superior to UC for the patient-rated symptom scale regarding nausea and vomiting (p = 0.023) and protein intake (p = 0.01). No statistical differences were observed for energy intake, nutritional status and physical performance. CONCLUSIONS: The results show good adherence to a combined nutrition and exercise program. The multimodal intervention did not improve overall QoL, but contributed to an adequate protein intake and to the general well-being of the patient by reducing nausea and vomiting. PMID- 28651828 TI - Influence of expression of UCP3, PLIN1 and PPARG2 on the oxidation of substrates after hypocaloric dietary intervention. AB - BACKGROUND & AIMS: In addition to environmental and psychosocial factors, it is known that genetic factors can also influence the regulation of energy metabolism, body composition and determination of excess weight. The objective of this study was to evaluate the influence of UCP3, PLIN1 and PPARG2 genes on the substrates oxidation in women with grade III obesity after hypocaloric dietary intervention. SUBJECTS/METHODS: This is a longitudinal study with 21 women, divided into two groups: Intervention Group (G1): 11 obese women (Body Mass Index (BMI) >=40 kg/m2), and Control Group (G2): 10 eutrophic women (BMI between 18.5 kg/m2 and 24.9 kg/m2). Weight (kg), height (m), BMI (kg/m2), substrate oxidation (by Indirect Calorimetry) and abdominal subcutaneous adipose tissue were collected before and after the intervention. For the dietary intervention, the patients were hospitalized for 6 weeks receiving 1200 kcal/day. RESULTS: There was a significant weight loss (8.4 +/- 4.3 kg - 5.2 +/- 1.8%) and reduction of UCP3 expression after hypocaloric dietary intervention. There was a positive correlation between carbohydrate oxidation and UCP3 (r = 0.609; p = 0.04), PLIN1 (r = 0.882; p = 0.00) and PPARG2 (r = 0.791; p = 0.00) expression before dietary intervention and with UCP3 (r = 0.682; p = 0.02) and PLIN1 (r = 0.745; p = 0.00) genes after 6 weeks of intervention. There was a negative correlation between lipid oxidation and PLIN1 (r = -0.755; p = 0.00) and PPARG2 (r = 0.664; p = 0.02) expression before dietary intervention and negative correlation with PLIN1 (r = 0.730; p = 0.02) expression after 6 weeks of hypocaloric diet. CONCLUSION: Hypocaloric diet reduces UCP3 expression in individuals with obesity and the UCP3, PLIN1 and PPARG2 expression correlate positively with carbohydrate oxidation and negatively with lipid oxidation. PMID- 28651829 TI - Evaluation of a 12-week targeted vitamin D supplementation regimen in patients with active inflammatory bowel disease. AB - BACKGROUND & AIMS: Vitamin D at serum 25(OH)D concentrations above 100 nmol/L is associated with disease remission in patients with IBD, suggesting targeted dosing might be anti-inflammatory. This study aimed to assess the effectiveness, safety and predictors of a 12-week regimen of vitamin D supplementation to achieve such a target in patients with active disease. METHODS: In a pilot study, patients with active colitis and a serum 25(OH)D concentration <75 nmol/L were prescribed oral liquid vitamin D supplementation over 12 weeks using a specific protocol with dose adjusted 4-weekly to aim for a target level of 100-125 nmol/L. RESULTS: Five patients each with Crohn's colitis or ulcerative colitis (UC) had mean 25(OH)D concentration 52 (range 27-73 nmol/L). Five reached the targeted level and four 89-95 nmol/L. One withdrew after 4 weeks (88 nmol/L). Target dose was met only in those with BMI <30 kg/m2 and total dose inversely correlated with initial serum 25(OH)D. One patient had developed a high level at 8 weeks (146 nmol/L) and another new hypercalciuria. There were no serious adverse events attributable to the therapy. Clinical disease activity consistently declined, but faecal calprotectin and circulating markers of inflammation did not. CONCLUSIONS: A specified oral vitamin D regimen successfully and safely achieved target or near-target levels, improved symptom-based activity scores, but did not alter objective measures of intestinal or systemic inflammation. A modified version of this dose-escalating regimen would be suitable for a randomised placebo controlled trial, but does require regular safety monitoring. PMID- 28651830 TI - Maternal plasma n-3 and n-6 polyunsaturated fatty acids during pregnancy and features of fetal health: Fetal growth velocity, birth weight and duration of pregnancy. AB - BACKGROUND & AIMS: Maternal fatty acids are essential for fetal growth and development. Here, we examine associations between maternal mid-pregnancy plasma n-3 and n-6 polyunsaturated fatty acids (PUFAs) and fetal health determined by fetal growth velocity, birth weight and duration of pregnancy. METHODS: Participants were 6974 pregnant women and their infants from a population-based birth cohort, the Generation R Study. Maternal plasma n-3:n-6 PUFA ratio and n-3 and n-6 PUFA percentage in glycerophospholipids in mid-pregnancy were related to fetal growth velocity calculated from repeatedly measured weight, length and head circumference, birth weight, and duration of pregnancy. RESULTS: A higher maternal mid-pregnancy n-3:n-6 PUFA ratio was associated with a higher growth velocity of the fetal weight (beta = 0.082 SD-score/week, 95% CI 0.055; 0.108, P < 0.001), length (beta = 0.085 SD-score/week, 95% CI 0.052; 0.119, P < 0.001); and head (beta = 0.055 SD-score/week, 95% CI 0.019; 0.091, P = 0.003). We also observed positive associations between n-3:n-6 PUFA ratio and birth weight (beta = 0.76 SD-score, 95% CI 0.22; 1.29, P = 0.006), and duration of pregnancy (beta = 1.32 weeks, 95% CI 0.24; 2.40, P = 0.02). CONCLUSIONS: These results are consistent with the hypothesis that a higher n-3:n-6 PUFA ratio is important for fetal health. PMID- 28651831 TI - Multicomplex-based pharmacophore modeling coupled with molecular dynamics simulations: An efficient strategy for the identification of novel inhibitors of PfDHODH. AB - Enormous efforts have been made in the past to identify novel scaffolds against the potential therapeutic target, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Fourteen different organic molecules have been crystallized to understand the structural basis of the inhibition. However, the pharmacophoric studies carried out so far, have not exploited all the structural information simultaneously to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore hypotheses from the available PfDHODH structural proteome. Among the generated hypotheses, a representative hypothesis was employed as a primary filter to list the molecules with complimentary features accountable for inhibition. Moreover, the auxiliary evaluations of the filtered molecules were accomplished via docking and drug likeness studies. Subsequently, the stability of the protein-ligand complex was evaluated by using molecular dynamics simulations (MDs). The molecular details of binding interactions of the potential hits were compared with the highly active experimental structure (5FI8) to seek the more potent candidates that can be targeted against PfDHODH. Overall, the combination of screening and stability procedures resulted in the identification of three potent candidates. The drug likeness of these molecules lie within the acceptable range and consequently increased the opportunities for their development to new anti-malarials. PMID- 28651832 TI - HTLV-1 infection in Reunion. AB - OBJECTIVES: Although regularly looked for in blood donors, HTLV infections are very rare in Reunion. We aimed to describe HTLV infections locally. PATIENTS AND METHODS: HTLV infections were identified from the database of the Reunion University Hospital administrative database (PMSI) between 2000 and 2016. Diagnosis was performed with HTLV 1/2 enzyme immunoassay test and confirmed by Western blot. RESULTS: We reported three asymptomatic and four symptomatic HTLV infections, including two tropical spastic paraparesis/HTLV-1 associated myelopathies (TSP/HAM) and two adult T-cell leukemia/lymphoma (ATLL), diagnosed between 2000 and 2016. CONCLUSION: Reunion is a low HTLV prevalence area, which could be explained by its settlement history. The present report underlines the local circulation of HTLV and symptomatic infections. PMID- 28651833 TI - Severe intestinal obstruction due to Strongyloides stercoralis in a pregnant woman. PMID- 28651834 TI - The impact of care management information technology model on quality of care after Coronary Artery Bypass Surgery: "Bridging the Divides". AB - BACKGROUND: Reducing readmissions and improving metrics of care are a national priority. Supplementing traditional care with care management may improve outcomes. The Bridges program was an initial evaluation of a care management platform (CareLinkHub), supported by information technology (IT) developed to improve the quality and transition of care from hospital to home after Coronary Artery Bypass Surgery (CABG) and reduce readmissions. METHODS: CareLink is comprised of care managers, patient navigators, pharmacists and physicians. Information to guide care management is guided by a middleware layer to gather information, PLR (ColdLight Solutions, LLC) and presented to CareLink staff on a care management platform, AerialTM (Medecision). In addition there is an analytic engine to help evaluate and guide care, NeuronTM (Coldlight Solutions, LLC). RESULTS: The "Bridges" program enrolled a total of 716 CABG patients with 850 admissions from April 2013 through March 2015. The data of the program was compared with those of 1111 CABG patients with 1203 admissions in the 3years prior to the program. No impact was seen with respect to readmissions, Blood Pressure or LDL control. There was no significant improvement in patients' reported outcomes using either the CTM-3 or any of the SAQ-7 scores. Patient follow-up with physicians within 1week of discharge improved during the Bridges years. CONCLUSIONS: The CareLink hub platform was successfully implemented. Little or no impact on outcome metrics was seen in the short follow-up time. PMID- 28651835 TI - Andrographolide reduced VEGFA expression in hepatoma cancer cells by inactivating HIF-1alpha: The involvement of JNK and MTA1/HDCA. AB - Andrographolide (Andro) is the main active compound in medicinal herb Andrographis paniculata Nees (Acanthaceae). Vascular endothelial growth factor A (VEGFA), a key pro-angiogenic factor, contributes greatly to tumor growth. The purpose of this study is to observe the inhibition of Andro on VEGFA expression in hepatoma cancer cells and its engaged mechanism. Andro decreased mRNA and protein expression of VEGFA in hepatoma Hep3B and HepG2 cells. Andro also decreased hypoxia-inducible factor 1-alpha (HIF-1alpha) protein expression and its subsequent nuclear translocation. Further results showed that Andro induced the polyubiquitination of HIF-1alpha protein, and proteasome inhibitor MG132 reversed Andro-induced decrease in the expression of HIF-1alpha protein and VEGFA mRNA and protein. Andro reduced the expression of metastasis-associated protein 1 (MTA1) and histone deacetylase 1 (HDAC1) in hepatoma cancer cells. SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), reversed Andro-induced decrease in the expression of HIF-1alpha and VEGFA, but not MTA1 and HDAC1. Andro (10 mg/kg) inhibited tumor growth in mice implanted with hepatoma Hep3B cells in vivo, and reduced the expression of CD31, VEGFA and HIF-1alpha in tumor tissues. In conclusion, Andro inhibited hepatoma tumor growth by reducing HIF-1alpha expression and its-mediated VEGFA expression via inducing ubiquitination-mediated HIF-1alpha protein degradation, and JNK and MTA1/HDAC1 may be involved in this process. Natural product Andro has huge potential in hepatoma cancer treatment. PMID- 28651836 TI - Italy's response to vaccine hesitancy: An innovative and cost effective National Immunization Plan based on scientific evidence. PMID- 28651837 TI - Severe underestimation of pertussis related hospitalizations and deaths in the Netherlands: A capture-recapture analysis. AB - OJECTIVE: Despite vaccination, pertussis has remained endemic, sometimes leading to severe disease. We aimed to quantify the completeness of reporting (CoR) of pertussis hospitalizations and deaths in the Netherlands. STUDY DESIGN: CoR was estimated using capture-recapture analyses. Hospitalizations (2007-2014) from the National Registration Hospital Care (hospital data) were matched to the notifiable Infectious Disease case registry (notifications) providing (month and) year of birth, gender and postal code. Deaths (1996-2014) from Statistics Netherlands (death registry) were matched to notifications using gender, age, year of death and notification date. Cases <2years (y) and >=2y were analysed separately. Chao's estimator estimated the total population, which was used to calculate CoR. RESULTS: Using strict matching criteria, we found 461 matches among 876 (hospital data) and 757 (notifications) hospitalizations <2y. The population estimate of hospitalized infants was 1446, resulting in CoR between 52% and 61%. For hospitalizations >=2y (246; hospital data and 264; notifications) 43 matches were found, with a population estimate of 1512 and CoR between 16.5% and 22%. Among thirteen (death registry) and eight (notifications) deaths <2y, seven cases overlapped. The population estimate was 16. CoR of the two sources was 50-81%. With two (death registry) and eight (notifications) deaths >=2y without overlap, the population estimate was 26 and CoR 8-31%. CONCLUSION: Results showed substantial underestimation of pertussis hospitalizations and deaths. This has to be taken into account in evaluation of current and future immunization programs. PMID- 28651838 TI - Progress and challenges in measles and rubella elimination in the WHO European Region. AB - INTRODUCTION: Despite availability of safe and cost-effective vaccines to prevent it, measles remains one of the significant causes of death among children under five years of age globally. The World Health Organization (WHO) European Region has seen a drastic decline in measles and rubella cases in recent years, and a few of the once common measles genotypes are no longer detected. Buoyed by this success, all Member States of the Region reconfirmed their commitment in 2010 to eliminating measles and rubella, and made this a central objective of the European Vaccine Action Plan 2015-2020 (EVAP). Nevertheless, sporadic outbreaks continue, recently affecting primarily adolescents and young adults with no vaccination or an incomplete vaccination history. The European Regional Verification Commission for Measles and Rubella Elimination was established in 2011 to evaluate the status of measles and rubella elimination based on documentation submitted annually by each country's national verification committee. DISCUSSION: Each country's commitment to eliminate measles and rubella is influenced by competing health priorities, and in some cases lack of capacity and resources. All countries need to improve case-base surveillance for both measles and rubella, ensure documentation of each outbreak and strengthen the link between epidemiology and laboratory data. Achieving high coverage with measles- and rubella-containing vaccines will require a multisectoral approach to address the root causes of lower uptake in identified communities including service delivery challenges or vaccine safety concerns caused by circulating myths about vaccination. CONCLUSIONS: The WHO European Region has made steady progress towards eliminating measles and rubella and over half of the countries interrupted endemic transmission of both diseases by 2015. The programmatic challenges in disease surveillance, vaccination service delivery and communication in the remaining endemic countries should be addressed through periodic evaluation of the strategies by all stakeholders and exploring additional opportunities to accelerate the ongoing elimination activities. PMID- 28651839 TI - Post-vaccination serologic testing of infants born to hepatitis B surface antigen positive mothers in 4 provinces of China. AB - OBJECTIVE: To evaluate prenatal maternal hepatitis B virus (HBV) screening and post-vaccination hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface antigen (anti-HBs) status and titers of babies born to HBsAg positive mothers, and to provide evidence for development of standard postvaccination serologic testing (PVST) strategies for babies born to HBsAg positive mothers in China. METHODS: In 2014, we conducted a baseline survey of HBV mother to child transmission (MTCT) interruption strategy implementation and PVST for babies born to HBsAg positive mothers after received 3 doses of hepatitis B vaccine (HepB) in 8 counties in 4 Provinces. Bivariate analysis and multivariable analyses modeled statistically significant predictor variables associated with infant HBsAg, anti HBs positive, anti-HBs titer. RESULTS: Among the 1563 infants born to HBsAg positive mothers, 1025 (65.6%) maternal-infant pairs were enrolled in PVST after receiving 3 doses of HepB. 38 infants tested HBsAg positive for an HBsAg positive rate of 3.7%. Maternal hepatitis B e antigen (HBeAg) status and age of infant were significantly associated with infant HBsAg positivity. A total of 932 infants were anti-HBs positive when tested at 7-24months of age, yielding an anti HBs positivity rate of 90.9%. Maternal HBeAg status was the factor associated with infant anti-HBs status. Amount of antigen of HepB and infant's age were most associated with anti-HBs titers. PVST performed 1-2months after the 3rd dose of HepB was associated with the highest anti-HBs level and the anti-HBs Geometric Mean Concentration (GMC) decreased as the PVST intervals prolonged. CONCLUSIONS: In China, perinatal HBV transmission is approaching the theoretical minimum possible with the current strategy of HepB coupled with HBIG administration for HBV-exposed newborns. PVST of infants born to an HBsAg positive mother is an essential strategy to ensure full protection for vaccine non-responders and appropriate medical care for those infected. PMID- 28651841 TI - Survey of nulliparous parturients' attitudes regarding timing of epidural analgesia initiation. AB - STUDY OBJECTIVE: At our hospital, although >90% of nulliparous parturients eventually choose epidural analgesia for labor, many delay its initiation, experiencing considerable pain in the interim. This survey probed parturients' views about the timing of initiation of epidural labor analgesia. DESIGN: Single center, nonrandomized quantitative survey. SETTING: Labor and delivery suite in a large tertiary academic medical center. PATIENTS: Two hundred laboring nulliparous women admitted to the labor and delivery suite. INTERVENTIONS: After their pain was relieved, parturients completed a questionnaire regarding their decision to request labor epidural analgesia. MEASUREMENTS: A variety of factors regarding epidural use were assessed including the influence of painful contractions and of childbirth education class attendance on the decision to request epidural analgesia, and parturients' perception of the timing of epidural initiation on the progress and outcome of labor. MAIN RESULTS: Analysis revealed that the desire of parturients to use epidural analgesia was increased from 27.9% before the onset of painful contractions to 48.2% after (p<0.01). Two-thirds of participants attended a non-physician taught childbirth education class. An antepartum plan to definitely forgo an epidural was 1.8 times more likely among women who attended a childbirth class when compared to those who did not attend. (OR=1.8; 95%CI:1.1-3.1; p=0.04). The most common views affecting decision-making were that epidural analgesia should not be administered "too early" (67.5%), and that it would slow labor (68.5%). Both of these views were more likely to be held if the parturient had attended a childbirth class, OR=2.0 (95%CI:1.1-3.8; p=0.03) and OR=2.0 (95% CI: 1.1 to 3.7; p=0.03), respectively. CONCLUSIONS: We found that nulliparous parturients have misconceptions about epidurals, which are not supported by evidence-based medicine. Moreover, we found that attendance at childbirth education classes was associated with believing these misconceptions. PMID- 28651840 TI - The role of anti-NHba antibody in bactericidal activity elicited by the meningococcal serogroup B vaccine, MenB-4C. AB - BACKGROUND: MenB-4C (Bexsero(r)) is a multicomponent serogroup B meningococcal vaccine. For vaccine licensure, efficacy was inferred from serum bactericidal antibody (SBA) against three antigen-specific indicator strains. The bactericidal role of antibody to the fourth vaccine antigen, Neisserial Heparin binding antigen (NHba), is incompletely understood. METHODS: We identified nine adults immunized with two or three doses of MenB-4C who had sufficient volumes of sera and >3-fold increases in SBA titer against a strain with high NHba expression, which was mismatched with the other three MenB-4C antigens that elicit SBA. Using 1month-post-immunization sera we measured the effect of depletion of anti-NHba and/or anti-Factor H binding protein (FHbp) antibodies on SBA. RESULTS: Against three strains matched with the vaccine only for NHba, depletion of anti-NHba decreased SBA titers by an average of 43-79% compared to mock-adsorbed sera (P<0.05). Despite expression of sub-family A FHbp (mismatched with the sub-family B vaccine antigen), depletion of anti-FHbp antibodies also decreased SBA by 45 64% (P<0.05). Depletion of both antibodies decreased SBA by 84-100%. Against a strain with sub-family B FHbp and expression of NHba with 100% identity to the vaccine antigen, depletion of anti-NHba decreased SBA by an average of 26%, compared to mock-adsorbed sera (P<0.0001), and depletion of anti-FHbp antibody decreased SBA by 92% (P<0.0001). CONCLUSIONS: Anti-NHba antibody can contribute to SBA elicited by MenB-4C, particularly in concert with anti-FHbp antibody. However, some high NHba-expressing strains are resistant, even with an exact match between the amino acid sequence of the vaccine and strain antigens. PMID- 28651842 TI - Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE. AB - Diabetic retinopathy is characterized by the breakdown of endothelial blood retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE2 pathway, by blocking the effect of advanced glycation end products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60MUg/ml) or aflibercept (AFL, 40MUg/ml), a VEGF trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA2, an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFkappaB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE2 pathway by reducing AGE-related signaling and downstream NFkappaB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX. PMID- 28651843 TI - [Neisseria meningitidis urethritis: Two case reports]. AB - BACKGROUND: Neisseria meningitidis (NM) is a commensal bacteria present in the oropharyngeal flora that causes invasive infections. There have been rarer reports of presence in the genital region. Herein, we present two cases of acute NM urethritis. PATIENTS AND METHODS: Two men aged 30 and 31years, one of whom is homosexual and seropositive for HIV infection, presented urethral discharge which was diagnosed as acute urethritis. The unit through samples indicated the presence of NM of serogroups B and C. One of the antibiotic sensitivity tests revealed intermediate susceptibility to penicillin G and to amoxicillin. DISCUSSION: The clinical presentation of acute NM urethritis is non-specific, because of which urethral samples should be taken wherever acute urethritis is suspected. NM urethritis is infrequent and primarily affects men who have sex with men (MSM). Its current increase is due to unprotected oral-genital sexual practices. Due to the emergence of resistance to NM, antibiotic susceptibility testing should be carried out routinely to ensure appropriate therapy and prophylaxis. Cases of invasive serogroup C meningococcal infections have been recorded within the MSM population with hypothetical sexual port of entry. Thus, the French High Public Health Authority recommends vaccination against meningitis C in this population. PMID- 28651844 TI - Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor. AB - BACKGROUND: Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects. METHODS: Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients>=12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx. RESULTS: Fewer patients receiving ivacaftor experienced a PEx than patients receiving placebo (33.7% vs. 56.4%; P=0.004) and had a lower adjusted incidence rate of PEx (0.589 vs. 1.382; P<0.001). The proportion of PEx followed by full short-term recovery of percent predicted forced expiratory volume in 1s was similar (ivacaftor vs. placebo, 57.1% vs. 53.7), as was the proportion of patients having long-term recovery (46.4% vs. 47.7%). CONCLUSIONS: Ivacaftor treatment reduces the frequency of PEx but does not improve on the rate of complete lung function recovery after PEx when compared with placebo. PMID- 28651845 TI - A single bout of maximal exercise improves lung function in patients with cystic fibrosis. AB - BACKGROUND: Responses to a single bout of exercise may provide critical information for maximizing improvements in pulmonary function following exercise training in cystic fibrosis (CF). We sought to determine if acute maximal exercise improves pulmonary function in patients with CF. METHODS: Thirty-three patients with CF completed a comprehensive assessment of pulmonary function to determine forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and lung clearance index (LCI) prior to and immediately following maximal aerobic exercise on a cycle ergometer. RESULTS: Following exercise, FVC (?0.08+/ 0.14L) and FEV1 (?0.06+/-0.15L) increased, while LCI decreased (?-0.71+/-0.93) (all p<0.05). Changes in FEV1 (%predicted) were associated with peak work (r=0.40, p=0.02) and peak pulmonary ventilation (r=0.45, p=0.01). CONCLUSIONS: A single bout of maximal exercise acutely improves pulmonary function in patients with CF and improvements may be related to peak work and peak pulmonary ventilation. PMID- 28651848 TI - The first case of multiple pilomatricomas caused by somatic mutations of CTNNB1 without any associated disorder. PMID- 28651846 TI - Molecular basis of beta thalassemia and potential therapeutic targets. AB - The remarkable phenotypic diversity of beta thalassemia that range from severe anemia and transfusion-dependency, to a clinically asymptomatic state exemplifies how a spectrum of disease severity can be generated in single gene disorders. While the genetic basis for beta thalassemia, and how severity of the anemia could be modified at different levels of its pathophysiology have been well documented, therapy remains largely supportive with bone marrow transplant being the only cure. Identification of the genetic variants modifying fetal hemoglobin (HbF) production in combination with alpha globin genotype provide some prediction of disease severity for beta thalassemia but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered. Nonetheless, genetic studies have been successful in characterizing the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation. BCL11A has been established as a quantitative repressor, and progress has been made in manipulating its expression using genomic and gene editing approaches for therapeutic benefits. Recent discoveries and understanding in the mechanisms associated with ineffective and abnormal erythropoiesis have also provided additional therapeutic targets, a couple of which are currently being tested in clinical trials. PMID- 28651847 TI - The Cardiovascular Pharmacology of Nonsteroidal Anti-Inflammatory Drugs. AB - The principal molecular mechanisms underlying the cardiovascular (CV) and renal adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs), such as myocardial infarction and hypertension, are understood in more detail than most side effects of drugs. Less is known, however, about differences in the CV safety profile between chemically distinct NSAIDs and their relative predisposition to complications. In review article, we discuss how heterogeneity in the pharmacokinetics and pharmacodynamics of distinct NSAIDs may be expected to affect their CV risk profile. We consider evidence afforded by studies in model systems, mechanistic clinical trials, a meta-analysis of randomized controlled trials, and two recent large clinical trials, Standard Care vs. Celecoxib Outcome Trial (SCOT) and Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION), designed specifically to compare the CV safety of the cyclooxygenase-2-selective NSAID, celecoxib, with traditional NSAIDs. We conclude that SCOT and PRECISION have apparently not compared equipotent doses and have other limitations that bias them toward underestimation of the relative risk of celecoxib. PMID- 28651849 TI - Meta-Analysis of Head-to-Head Comparison of Intracoronary Versus Intravenous Adenosine for the Assessment of Fractional Flow Reserve. AB - Intravenous (IV) infusion of adenosine represents the gold standard for measuring fractional flow reserve (FFR). However, IV adenosine is more expensive and time consuming compared with intracoronary (IC) boluses of adenosine. We conducted a meta-analysis of studies comparing IC with IV adenosine for FFR assessment in the same coronary lesions. We searched for studies comparing IC with IV adenosine and reporting absolute FFR values or rate of abnormal FFR for both routes. Prespecified subgroup analysis was performed to appraise studies using low-dose (<100 MUg) or high-dose IC adenosine (>=100 MUg). We retrieved 11 studies amounting to 587 patients and 621 lesions. Six studies evaluated low-dose IC boluses (15 to 80 MUg) and 5 studies high-dose boluses (120 to 600 MUg). Absolute FFR values were slightly, yet significantly lower with IV adenosine compared with IC adenosine (mean difference 0.02, 95% confidence interval [CI] 0.00 to 0.03, p = 0.02). This difference, however, did not translate into a significant difference in the rate of abnormal FFR between IC and IV adenosine (hazard ratio 0.93, 95% CI 0.76 to 1.13, p = 0.57); moreover, no statistically significant difference was observed between low-dose and high-dose IC adenosine subgroups. Adverse events were less frequent with IC adenosine compared with IV adenosine (risk ratio 0.17, 95% CI 0.07 to 0.43, p <0.001). In conclusion, IC administration of adenosine, although inducing a slightly lower amount of hyperemia compared with IV infusion of adenosine, yields a similar diagnostic accuracy in identifying hemodynamically significant coronary stenosis and is better tolerated by the patients. PMID- 28651850 TI - Effect of Compliance to Updated AHA/ACC Performance and Quality Measures Among Patients With Atrial Fibrillation on Outcome (from Japanese Multicenter Registry). AB - Performance measures (PMs) are used to accelerate translation of scientific evidence into clinical practice. However, it remains unknown how they are applied in the real world and whether the compliance to these metrics will lead to improved patient's outcome in atrial fibrillation (AF). Within the Japanese multicenter AF registry (n = 1,874), adherence of the AF PMs (based on 2016 American Heart Association/American College of Cardiology criteria) and its association with quality of life scaling and clinical outcomes was evaluated. The patient was deemed "adherent" when all applicable components of the PMs for outpatient settings (CHA2DS2-VASc risk score documentation [PM-4], anticoagulation prescribed [PM-5], and monthly international normalized ratio (INR) for warfarin treatment [PM-6]) were satisfied. The Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire was assessed at baseline and 1 year. About a half of patients (46.1%) were adherent to the AF PMs. PMs were more frequently achieved in patients managed with rhythm control compared with rate control. The achievement rate for each component was 53.9% for PM-4, 85.6% for PM 5, and 90.3% for PM-6, respectively. Although AFEQT global scores at baseline were similar (median 79.2 [interquartile ranges 66.7 to 88.5] vs 77.1 [64.8 to 88.0], p = 0.227), AFEQT global scores at 1-year follow-up were significantly greater in adherence group than those in nonadherence group (89.2 [78.5 to 96.6] vs 86.7 [76.7 to 95.0], p = 0.021). This tendency was consistent regardless of therapeutic strategies. There remains an important opportunity to improve the quality of care in patients with AF. Adherence to the AF PMs might lead to the improvement of patient's quality of life. PMID- 28651851 TI - Meta-Analysis of Cardiovascular Outcomes With Continuous Positive Airway Pressure Therapy in Patients With Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Continuous positive airway pressure (CPAP) is the main treatment of OSA. The present study explores the impact of CPAP on cardiovascular outcomes. A systematic search of electronic databases for randomized controlled trials comparing CPAP with medical therapy alone in patients with OSA who reported cardiovascular outcomes of interest was performed. The main outcome was major adverse cardiac events. Other outcomes included cardiac mortality, myocardial infarction, angina pectoris, stroke, and transient ischemic attack. Fixed effect model was used in all analyses except for subgroup analysis in which the random effect DerSimonian and Laird's model was used. Four randomized controlled trials with a total of 3,780 patients were included. Compared with medical therapy alone, CPAP use was not associated with reduced risk of major adverse cardiac events (relative risk [RR] 0.94, 95% confidence interval [CI] 0.78 to 1.15, p = 0.93, I2 = 0%) except in the subgroup that wore CPAP >4 hours (RR 0.70, 95% CI 0.52 to 0.94, p = 0.02, I2 = 0%). Furthermore, no reduction in the risk of cardiac mortality (RR 1.14, 95% CI 0.66 to 1.97, p <0.36, I2 = 2%), myocardial infarction (RR 0.96, 95% CI 0.64 to 1.44, p <0.15, I2 = 47%), angina pectoris (RR 1.16, 95% CI 0.9 to 1.50, p <0.51, I2 = 0%), stroke (RR 1.01, 95% CI 0.73 to 1.38, p <0.0.86, I2 = 0%), and transient ischemic attack (RR 1.36, 95% CI 00.69 to 2.68, p <0.24, I2 = 30%) was observed. Subgroup analysis of CPAP adherence in regards to cardiac outcomes showed that CPAP use is not associated with decreased risk of heart failure (RR 0.91, 95% CI 0.50 to 1.66, p <0.55, I2 = 0%). In conclusion, compared with medical therapy alone, utilization of CPAP in patients with OSA is not associated with improved cardiac outcomes except in patients who wore it for >4 hours. PMID- 28651852 TI - Differences in Repolarization Heterogeneity Among Heart Failure With Preserved Ejection Fraction Phenotypic Subgroups. AB - Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome associated with multiple medical comorbidities and pathophysiologic pathways or phenotypes. We recently developed a phenomapping method combining deep phenotyping with machine learning analysis to classify HFpEF patients into 3 clinically distinct phenotypic subgroups (phenogroups) with different clinical outcomes. Phenogroup #1 was younger with lower B-type natriuretic peptide levels, phenogroup #2 had the highest prevalence of obesity and diabetes mellitus, and phenogroup #3 was the oldest with the most factors for chronic kidney disease, the most dysfunctional myocardial mechanics, and the highest adverse outcomes. The pathophysiological differences between these phenogroups, however, remain incompletely described. We sought to evaluate whether these 3 groups differ on the basis of repolarization heterogeneity, which has previously been linked to adverse outcomes in HFpEF. The T-peak to T-end (TpTe) interval, a well-validated index of repolarization heterogeneity, was measured by 2 readers blinded to each other and all other clinical data on the electrocardiograms of 201 HFpEF patients enrolled in a systematic observational study. TpTe duration was associated with higher B-type natriuretic peptide level (p = 0.006), increased QRS-T angle (p = 0.008), and lower septal e' velocity (p = 0.007). TpTe duration was greatest in phenogroup #3 (100.4 +/- 24.5 ms) compared with phenogroups #1 (91.2 +/- 17.3 ms) and #2 (90.2 +/- 17.0 ms) (p = 0.0098). On multivariable analyses, increased TpTe was independently associated with the high-risk phenogroup #3 classification. In conclusion, repolarization heterogeneity is a marker of a specific subset of HFpEF patients identified using unsupervised machine learning analysis and therefore may be a key pathophysiologic marker in this subset of HFpEF patients. PMID- 28651853 TI - Common and Distinct Gray Matter Alterations in Social Anxiety Disorder and Major Depressive Disorder. PMID- 28651854 TI - Estimating the effect of differing assumptions on the population health impact of introducing a Reduced Risk Tobacco Product in the USA. AB - We use Population Health Impact Modelling to assess effects on tobacco prevalence and mortality of introducing a Reduced Risk Tobacco Product (RRP). Simulated samples start in 1990 with a US-representative smoking prevalence. Individual tobacco histories are updated annually until 2010 using estimated probabilities of switching between never/current/former smoking where the RRP is not introduced, with current users subdivided into cigarette/RRP/dual users where it is. RRP-related mortality reductions from lung cancer, IHD, stroke and COPD are derived from the histories and the assumed relative risks of the RRP. A basic analysis assumes a hypothetical RRP reduces effective dose 80% in users and 40% in dual users, with an uptake rate generating ~10% RRP and ~6% dual users among current users after 10 years. Sensitivity study changes in tobacco prevalence and mortality from varying effective doses, current smoking risks, quitting half lives and rates of initiation, switching, re-initiation and cessation. They also study extreme situations (e.g. everyone using RRP), and investigate assumptions which might eliminate the RRP-related mortality reduction. The mortality reduction is proportional to the dose reduction, increasing rapidly with time of follow-up. Plausible increases in re-initiation or dual users' consumption, or decreased quitting by smokers would not eliminate the drop. PMID- 28651855 TI - Assessment of pose repeatability and specimen repositioning of a robotic joint testing platform. AB - This paper describes the quantitative assessment of a robotic testing platform, consisting of an industrial robot and a universal force-moment sensor, via the design of fixtures used to hold the tibia and femur of cadaveric knees. This platform was used to study the contributions of different soft tissues and the ability of implants and reconstruction surgeries to restore normal joint functions, in previously published literature. To compare different conditions of human joints, it is essential to reposition specimens with high precision after they have been removed for a surgical procedure. Methods and experiments carried out to determine the pose repeatability and measure errors in repositioning specimens are presented. This was achieved using an optical tracking system (fusion Track 500, Atracsys Switzerland) to measure the position and orientation of bespoke rigid body markers attached to the tibial and femoral pots after removing and reinstalling them inside the rigs. The pose repeatability was then evaluated by controlling the robotic platform to move a knee joint repeatedly to/from a given pose while tracking the position and orientation of a rigid body marker attached to the tibial fixture. The results showed that the proposed design ensured a high repeatability in repositioning the pots with standard deviations for the computed distance and angle between the pots at both ends of the joint equal to 0.1mm, 0.01mm, 0.13 degrees and 0.03 degrees for the tibial and femoral fixtures respectively. Therefore, it is possible to remove and re setup a joint with high precision. The results also showed that the errors in repositioning the robotic platform (that is: specimen path repeatability) were 0.11mm and 0.12 degrees , respectively. PMID- 28651856 TI - Progesterone-Mediated Non-Classical Signaling. AB - Progesterone is essential for pregnancy maintenance and menstrual cycle regulation. Hormone action has been primarily ascribed to the well-characterized classical signaling pathway involving ligand binding, activation of nuclear progesterone receptors (PRs), and subsequent activation of genes containing progesterone response elements (PREs). Recent studies have revealed progesterone actions via non-classical signaling pathways, often mediated by non-genomic signaling. Progesterone signaling, in conjunction with growth factor signaling, impacts on the function of growth factors and regulates important physiological actions such as cell growth and remodeling, as well as apoptosis. This review focuses on non-classical progesterone signaling pathways, both including and excluding PR, and highlights how research in this area will provide a better understanding of progesterone actions and may inform novel therapeutic strategies. PMID- 28651857 TI - A Polygenic Risk Score of glutamatergic SNPs associated with schizophrenia predicts attentional behavior and related brain activity in healthy humans. AB - Multiple genetic variations impact on risk for schizophrenia. Recent analyses by the Psychiatric Genomics Consortium (PGC2) identified 128 SNPs genome-wide associated with the disorder. Furthermore, attention and working memory deficits are core features of schizophrenia, are heritable and have been associated with variation in glutamatergic neurotransmission. Based on this evidence, in a sample of healthy volunteers, we used SNPs associated with schizophrenia in PGC2 to construct a Polygenic-Risk-Score (PRS) reflecting the cumulative risk for schizophrenia, along with a Polygenic-Risk-Score including only SNPs related to genes implicated in glutamatergic signaling (Glu-PRS). We performed Factor Analysis for dimension reduction of indices of cognitive performance. Furthermore, both PRS and Glu-PRS were used as predictors of cognitive functioning in the domains of Attention, Speed of Processing and Working Memory. The association of the Glu-PRS on brain activity during the Variable Attention Control (VAC) task was also explored. Finally, in a second independent sample of healthy volunteers we sought to confirm the association between the Glu-PRS and both performance in the domain of Attention and brain activity during the VAC.We found that performance in Speed of Processing and Working Memory was not associated with any of the Polygenic-Risk-Scores. The Glu-PRS, but not the PRS was associated with Attention and brain activity during the VAC. The specific effects of Glu-PRS on Attention and brain activity during the VAC were also confirmed in the replication sample.Our results suggest a pathway specificity in the relationship between genetic risk for schizophrenia, the associated cognitive dysfunction and related brain processing. PMID- 28651858 TI - The landmark for removal of sialoliths using sialendoscopy alone in parotid gland sialolithiasis. AB - OBJECTIVE: To assess the general guidelines for removal of sialoliths in parotid gland sialolithiasis using sialendoscopy alone. METHODS: We analyzed 34 sialoliths treated using sialendoscopy in 26 patients with parotid gland sialolithiasis. We divided the Stensen's duct and parotid gland into for parts using computed tomography findings: (A) front of the masseter, (B) anterior and lateral to the center (anterolateral) of the masseter, (C) posterior and lateral to the center (posterolateral) of the masseter, (D) behind of the masseter. The location and size of each sialolith was assessed. RESULTS: The removal rates of sialoliths in the different locations by sialendoscopy alone were as follows: front of the masseter, 68.8%; anterolateral of the masseter, 60.0%; posterolateral of the masseter, 0%; and behind of the masseter, 33.3%. The removal rate using sialendoscopy alone was significantly higher in the sections anterior to the center of the masseter than in those posterior to the center of the masseter (66.7% [14/21] vs. 20.0% [2/10]; P=0.019). The size of the sialolith was not correlated to the removal rate by sialendoscopy alone. CONCLUSION: Sialoliths of the parotid gland located in positions anterior to the center of the masseter are significantly easier to remove by sialendoscopy alone. The center of the masseter is a general landmark for removal of sialoliths from the parotid gland using sialendoscopy alone. The size of the sialolith is not correlated with removal, except rare huge sialoliths. PMID- 28651859 TI - Dwell time and risk of central-line-associated bloodstream infection in neonates. AB - BACKGROUND: Umbilical venous catheters (UVCs) or peripherally inserted central catheters (PICCs), widely used in high-risk neonates, may have a threshold dwell time for subsequent increased risk of central-line-associated bloodstream infection (CLABSI). AIM: To evaluate the CLABSI risks in neonates having either UVC, PICC, or those having both sequentially. METHODS: The study included 3985 infants who had UVC or PICC inserted between 2007 and 2009 cared for in 10 regional neonatal intensive care units: 1392 having UVC only (group 1), 1317 PICC only (group 2), and 1276 both UVC and PICC (group 3). FINDINGS: There were 403 CLABSIs among 6000 venous catheters inserted, totalling 43,302 catheter-days. CLABSI rates were higher in group 3 infants who were of lowest gestation (16.9 per 1000 UVC-days and 12.5 per 1000 PICC-days; median: 28 weeks) when compared with group 1 (3.3 per 1000 UVC-days; 37 weeks) and group 2 (4.8 per 1000 PICC days; 30 weeks). Life table and Kaplan-Meier hazard analysis showed that UVC CLABSI rate increased stepwise to 42 per 1000 UVC-days by day 10, with the highest rate in group 3 (85 per 1000 UVC-days). PICC CLABSI rates remained relatively stable at 12-20 per 1000 PICC-days. Compared to PICC, UVC had a higher adjusted CLABSI risk controlled for dwell time. Among group 3, replacing UVC electively before day 4 may have a trend of lower CLABSI risk than late replacement. CONCLUSION: There was no cut-off duration beyond which PICC should be removed electively. Early UVC removal and replacement by PICC before day 4 might be considered. PMID- 28651861 TI - Adaptive internal model guidance law for weaving maneuvering target. AB - For the terminal phase guidance problem of the missile intercepting weaving maneuvering target, an adaptive internal model guidance laws in the three dimensional (3-D) engagement space is proposed in this paper. The guidance law adopts the disturbance rejection theory by treating the target weaving maneuvering accelerations as external disturbance, which comprises of nominal part and adaptive part. The nominal part based on feedback linearization method ensures the whole guidance system stable and the adaptive part based on internal model principle is used to recover the disturbance signals on-line to reject the target maneuver asymptotically. The algorithm guarantees the whole guidance system with satisfying performance both in transient and steady state on the effect of target maneuver on guidance system. The stability analyses and theory proof are provided in this paper. At last, numerical simulations are carried out to illustrate the effectiveness of the proposed guidance law. PMID- 28651860 TI - Fractional fetal thigh volume in the prediction of normal and abnormal fetal growth during the third trimester of pregnancy. AB - BACKGROUND: Currently, 2-dimensional ultrasound estimation of fetal size rather than fetal growth is used to define fetal growth restriction, but single estimates in late pregnancy lack sensitivity and may identify small for gestational age rather than growth restriction. Single or longitudinal measures of 3-dimensional fractional thigh volume may address this problem. OBJECTIVE: We sought to derive normal values for 3-dimensional fractional thigh volume in the third trimester, determine if fractional thigh volume is superior to 2 dimensional ultrasound biometry alone for detecting fetal growth restriction, and determine whether individualized growth assessment parameters have the potential to identify fetal growth restriction remote from term delivery. STUDY DESIGN: This was a longitudinal prospective cohort study of 115 unselected pregnancies in a tertiary referral unit (St Mary's Hospital, Manchester, United Kingdom). Standard 2-dimensional ultrasound biometry measurements were obtained, along with fractional thigh volume measurements (based on 50% of the femoral diaphysis length). Measurements were used to calculate estimated fetal weight (Hadlock). Individualized growth assessment parameters and percentage deviations in longitudinally measured biometrics were determined using a Web-based system (iGAP; http://iGAP. RESEARCH: bcm.edu). Small for gestational age was defined <10th and fetal growth restriction <3rd customized birthweight centile. Logistic regression was used to compare estimated fetal weight (Hadlock), estimated fetal weight (biparietal diameter-abdominal circumference-fractional thigh volume), fractional thigh volume, and abdominal circumference for the prediction of small for gestational age or fetal growth restriction at birth. Screening performance was assessed using area under the receiver operating characteristic curve. RESULTS: There was a better correlation between fractional thigh volume and estimated fetal weight ((biparietal diameter-abdominal circumference-fractional thigh volume) obtained at 34-36 weeks with birthweight than between 2-dimensional biometry measures such as abdominal circumference and estimated fetal weight (Hadlock). There was also a modest improvement in the detection of both small for gestational age and fetal growth restriction using fractional thigh volume derived measures compared to standard 2-dimensional measurements (area under receiver operating characteristic curve, 0.86; 95% confidence interval, 0.79 0.94, and area under receiver operating characteristic curve, 0.92; 95% confidence interval, 0.85-0.99, respectively). CONCLUSION: Fractional thigh volume measurements offer some improvement over 2-dimensional biometry for the detection of late-onset fetal growth restriction at 34-36 weeks. PMID- 28651862 TI - Severe impacts of brown tides caused by Sargassum spp. on near-shore Caribbean seagrass communities. AB - From mid-2014 until the end of 2015, the Mexican Caribbean coast experienced a massive influx of drifting Sargassum spp. that accumulated on the shores, resulting in build-up of decaying beach-cast material and near-shore murky brown waters (Sargassum-brown-tides, Sbt). The effects of Sbt on four near-shore waters included reduction in light, oxygen (hypoxia or anoxia) and pH. The monthly influx of nitrogen, and phosphorus by drifting Sargassum spp. was estimated at 6150 and 61kgkm-1 respectively, resulting in eutrophication. Near-shore seagrass meadows dominated by Thalassia testudinum were replaced by a community dominated by calcareous rhizophytic algae and drifting algae and/or epiphytes, resulting in 61.6-99.5% loss of below-ground biomass. Near-shore corals suffered total or partial mortality. Recovery of affected seagrass meadows may take years or even decades, or changes could be permanent if massive influxes of Sargassum spp. recur. PMID- 28651864 TI - Another possible risk for the Mediterranean Sea? Aspergillus sydowii discovered in the Port of Genoa (Ligurian Sea, Italy). AB - Aspergillus sydowii is a cosmopolitan fungus that has been responsible for the mass destruction of coral in the Caribbean Sea over the last 15years. To our knowledge, this study has found the first case of A. sydowii in the Mediterranean Sea, in marine-bottom sediments, water and calcareous shells of bivalve molluscs sampled during a campaign to characterise the mycobiota in the Port of Genoa (Italy). The area is characterised by adverse environmental conditions (high turbidity, organic pollution and high concentrations of phosphorus and nitrogen compounds). These parameters, in combination with a rising temperature, could contribute to A. sydowii bloom and dispersal. This fungal strain may have been imported into the Port of Genoa in the bilge water of vessels or by torrent input. This work represents the first step in the implementation of a monitoring programme to safeguard calcareous sponges and sea fan corals endemic in the Mediterranean Sea. PMID- 28651863 TI - Monitoring mangrove forests after aquaculture abandonment using time series of very high spatial resolution satellite images: A case study from the Perancak estuary, Bali, Indonesia. AB - Revegetation of abandoned aquaculture regions should be a priority for any integrated coastal zone management (ICZM). This paper examines the potential of a matchless time series of 20 very high spatial resolution (VHSR) optical satellite images acquired for mapping trends in the evolution of mangrove forests from 2001 to 2015 in an estuary fragmented into aquaculture ponds. Evolution of mangrove extent was quantified through robust multitemporal analysis based on supervised image classification. Results indicated that mangroves are expanding inside and outside ponds and over pond dykes. However, the yearly expansion rate of vegetation cover greatly varied between replanted ponds. Ground truthing showed that only Rhizophora species had been planted, whereas natural mangroves consist of Avicennia and Sonneratia species. In addition, the dense Rhizophora plantations present very low regeneration capabilities compared with natural mangroves. Time series of VHSR images provide comprehensive and intuitive level of information for the support of ICZM. PMID- 28651866 TI - Life cycle assessment to compare the environmental impact of seven contemporary food waste management systems. AB - Municipal food waste (FW) represents 35-45% of household residual waste in Australia, with the nation generating 1.6Tg annually. It is estimated that 91% of this FW ends up in landfill. This study used life cycle assessment to determine and compare the environmental impact of seven contemporary FW management systems for two real-life jurisdictions; incorporating the complete waste service and expanding the system to include inert and garden waste. Although, no system exhibited a best ranking across all impact categories, FW digestion based systems were all revealed to have a lower global warming potential than composting and landfilling systems. Mechanical biological treatment, anaerobic co-digestion, and home composting all demonstrated the lowest environmental impacts for two or more of the environmental impact categories assessed. The assessment included market and technological specific variables and uncertainties providing a framework for robust decision making at a municipality level. PMID- 28651865 TI - Pre-operative Carotid Plaque Echolucency Assessment has no Predictive Value for Long-Term Risk of Stroke or Cardiovascular Death in Patients Undergoing Carotid Endarterectomy. AB - INTRODUCTION: In patients with carotid stenosis receiving medical treatment, carotid plaque echolucency has been thought to predict risk of future stroke and of other cardiovascular events. This study evaluated the prognostic value of pre operative plaque echolucency for future stroke and cardiovascular death in patients undergoing carotid endarterectomy in the first Asymptomatic Carotid Surgery Trial (ACST-1). METHODS: In ACST-1, 1832/3120 patients underwent carotid endarterectomy (CEA), of whom 894 had visual echolucency assessment according to the Gray-Weale classification. During follow-up patients were monitored both for peri-procedural (i.e. within 30 days) death, stroke, or MI, and for long-term risk of stroke or cardiovascular death. Unconditional maximum likelihood estimation was used to calculate odds ratios of peri-procedural risk and Kaplan Meier statistics with log-rank test were used to compare cumulative long-term risks. RESULTS: Of 894 operated patients in whom echolucency was assessed, 458 plaques (51%) were rated as echolucent and peri-procedural risk of death/stroke/MI in these patients was non-significantly higher when compared with patients with non-echolucent plaques (OR 1.48 [95% CI 0.76-2.88], p = .241). No differences were found in the 10 year risk of any stroke (30/447 [11.6%] vs. 29/433 [11.0%], p = .900) or cardiovascular (non-stroke) death (85/447 [27.9%] vs. 93/433 [32.1%], p = .301). CONCLUSION: In ACST-1, carotid plaque echolucency assessment in patients undergoing CEA offered no predictive value with regard to peri-operative or long-term stroke risk or of cardiovascular (non-stroke) death. PMID- 28651867 TI - Enhanced growth and hydrocarbon production of Botryococcus braunii KMITL 2 by optimum carbon dioxide concentration and concentration-dependent effects on its biochemical composition and biodiesel properties. AB - The purposes of this study were to find the optimum level of supplementing CO2 for increasing the biomass and hydrocarbon production of B. braunii KMITL 2 (A race) and to determine the effects of CO2 level on CO2 fixation and biodiesel properties. The experimental results showed that the alga supplemented with 10% CO2 produced the highest biomass (1.48+/-0.02gL-1) and CO2 fixation rate (100.43+/-1.42mgL-1d-1) that were 2.7 and 5.3 times higher than the control (0.04% CO2). The gravimetric hydrocarbon content (36.82+/-3.39%) and hydrocarbon titer (0.35+/-0.03gL-1) of the alga supplemented with 5% CO2 were 1.6 and 2.7 times higher than the control. Cultivation of this strain under 5% CO2 gave the highest hydrocarbon yield and good biodiesel properties with the lowest iodine value and a higher CN value than the ASTM D6751 and EN 14214 fuel standards. PMID- 28651868 TI - Production of chemicals and proteins using biomass-derived substrates from a Streptomyces host. AB - Bioproduction using microbes from biomass feedstocks is of interest in regards to environmental problems and cost reduction. Streptomyces as an industrial microorganism plays an important role in the production of useful secondary metabolites for various applications. This strain also secretes a wide range of extracellular enzymes which degrade various biopolymers in nature, and it consumes these degrading substrates as nutrients. Hence, Streptomyces can be employed as a cell factory for the conversion of biomass-derived substrates into various products. This review focuses on the following two points: (1) Streptomyces as a producer of enzymes for degrading biomass-derived polysaccharides and polymers; and, (2) wild-type and engineered strains of Streptomyces as a host for chemical production from biomass-derived substrates. PMID- 28651869 TI - Hydrothermal pretreatment on the anaerobic digestion of washed vinegar residue. AB - The aim of this work was to study the acetate separation from fresh vinegar residue (FVR) to avoid inhibition of methanogenesis and hydrothermal treatment on washed vinegar residue (WVR) to enhance methane production. The optimal liquid solid ratio was 10:1mL/g for the washing of FVR. The methane yields of the FVR, WVR, and washed leachate (WL) were 273L/kgVS, 199L/kgVS, and 306.9L/kgCOD, respectively. The optimal hydrothermal temperature was 160 degrees C for WVR, with maximum methane yield of 258.38L/kgVS. Hydrothermal pretreatment destroyed the structure of lignocellulose and improved the hydrolysis of hemicellulose. Compared with thermophilic digestion of FVR, thermophilic digestion of 160 degrees C treated FVR, and thermophilic digestion of WVR with mesophilic digestion of WL, the thermophilic digestion of 160 degrees C treated WVR with mesophilic digestion of WL obtained the maximum total methane yield of 102.5L/kgFVR. PMID- 28651871 TI - Evaluation of the dynamics of microalgae population structure and process performance during piggery wastewater treatment in algal-bacterial photobioreactors. AB - The dynamics of microalgae population during piggery wastewater (PWW) treatment in four open photobioreactors operated at 27days of hydraulic retention time, and inoculated with Chlorella sp. (R1), Acutodesmus obliquus (R2), Oscillatoria sp. (R3) and in the absence of inoculum (R4), were evaluated for 6months. In addition, the algal-bacterial biomass concentration, removal of organic matter, nutrients and heavy metals were also assessed. The results revealed a high diversity and rapid variations in the structure of microalgae populations, Chlorella sp. being dominant in R4 throughout most of the operational period. Steady state average biomass concentration ranged from 2445-2610mg/L in R1-R3 to 3265mg/L in R4. No significant differences were recorded in the removal efficiencies (REs) of total organic carbon (86-87%), inorganic carbon (62-71%), total nitrogen (82-85%) and total phosphorous (90-92%). Finally, Zn-REs accounted for 26% in R3, 37% in R2, and 49% in R1 and R4. PMID- 28651870 TI - Advanced nutrient removal from surface water by a consortium of attached microalgae and bacteria: A review. AB - Innovative and cost-effective technologies for advanced nutrient removal from surface water are urgently needed for improving water quality. Conventional biotechnologies, such as ecological floating beds, or constructed wetlands, are not effective in removing nutrients present at low-concentration. However, microalgae-bacteria consortium is promising for advanced nutrient removal from wastewater. Suspended algal-bacterial systems can easily wash out unless the hydraulic retention time is long, attached microalgae-bacteria consortium is more realistic. This critical review summarizes the fundamentals and status of attached microalgae-bacteria consortium for advanced nutrient removal from surface water. Key advantages are the various nutrient removal pathways, reduction of nutrients to very low concentration, and diversified photobioreactor configurations. Challenges include poor identification of functional species, poor control of the community composition, and long start-up times. Future research should focus on the selection and engineering of robust microbial species, mathematical modelling of the composition and functionality of the consortium, and novel photobioreactor configurations. PMID- 28651872 TI - Food loss and waste management in Turkey. AB - Food waste can be an environmental and economic problem if not managed properly but it can meet various demands of a country if it is considered as a resource. The purpose of this report is to review the existing state of the field in Turkey and identify the potential of food waste as a resource. Food loss and waste (FLW) was examined throughout the food supply chain (FSC) and quantified using the FAO model. Edible FLW was estimated to be approximately 26milliontons/year. The amount of biodegradable waste was estimated based on waste statistics and research conducted on household food waste in Turkey. The total amount of biodegradable waste was found to be approximately 20milliontons/year, where more than 8.6milliontons/year of this waste is FLW from distribution and consumption in the FSC. Options for the end-of-life management of biodegradable wastes are also discussed in this review article. PMID- 28651873 TI - Improving trehalose synthase activity by adding the C-terminal domain of trehalose synthase from Thermus thermophilus. AB - The aim of this work was to study the activities of four other TreS enzymes from different sources linked with or without TtTreS-C. The results showed that a flexible linker peptide between TreS enzymes and TtTreS-C is essential for their activity enhancement. Moreover, the specific activities of the four enzymes were also improved by linking to the TtTreS-C fragment. Together, our study provides novel insights into the functions of the C-terminal domain of TtTreS, and would facilitate its future application in enzyme engineering. PMID- 28651874 TI - Enhanced production of 2,3-butanediol from xylose by combinatorial engineering of xylose metabolic pathway and cofactor regeneration in pyruvate decarboxylase deficient Saccharomyces cerevisiae. AB - The aim of this study was to produce 2,3-butanediol (2,3-BDO) from xylose efficiently by modulation of the xylose metabolic pathway in engineered Saccharomyces cerevisiae. Expression of the Scheffersomyces stipitis transaldolase and NADH-preferring xylose reductase in S. cerevisiae improved xylose consumption rate by a 2.1-fold and 2,3-BDO productivity by a 1.8-fold. Expression of the Lactococcus lactis noxE gene encoding NADH oxidase also increased 2,3-BDO yield by decreasing glycerol accumulation. Additionally, the disadvantage of C2-dependent growth of pyruvate decarboxylase-deficient (Pdc-) S. cerevisiae was overcome by expression of the Candida tropicalis PDC1 gene. A fed batch fermentation of the BD5X-TXmNP strain resulted in 96.8g/L 2,3-BDO and 0.58g/L-h productivity from xylose, which were 15.6- and 2-fold increases compared with the corresponding values of the BD5X strain. It was concluded that facilitation of the xylose metabolic pathway, oxidation of NADH and relief of C2 dependency synergistically triggered 2,3-BDO production from xylose in Pdc-S. cerevisiae. PMID- 28651875 TI - Biochemicals from food waste and recalcitrant biomass via syngas fermentation: A review. AB - An effective method for the production of value-added chemicals from food waste and lignocellulosic materials is a hybrid thermal-biological process, which involves gasification of the solid materials to syngas (primarily CO and H2) followed by fermentation. This paper reviews the recent advances in this process. The special focus is on the cultivation methods that involve the use of single strains, defined mixed cultures and undefined mixed cultures for production of carboxylic acids and higher alcohols. A rate limiting step in these processes is the low mass transfer between the gas and the liquid phases. Therefore, novel techniques that can enhance the gas-liquid mass transfer including membrane- and trickle-bed bioreactors were discussed. Such bioreactors have shown promising results in increasing the volumetric mass transfer coefficient (kLa). High gas pressure also influences the mass transfer in certain batch processes, although the presence of impurities in the gas would impede the process. PMID- 28651876 TI - Use of magnetic powder to effectively improve the performance of sequencing batch reactors (SBRs) in municipal wastewater treatment. AB - This study aims to investigate the effect of adding magnetic powder in the sequencing batch reactor (SBR) on the reactor performance and microbial community. Results indicated that, the magnetic activated sludge sequencing batch reactor (MAS-SBR) had 7.76% and 4.76% higher ammonia nitrogen (NH4+-N) and chemical oxygen demand (COD) removal efficiencies than that of the conventional SBR (C-SBR). The MAS-SBR also achieved 6.86% sludge reduction compared with the C SBR. High-throughput sequencing demonstrated that the dominant phyla of both SBRs (present as >=1% of the sequence reads) were Protebacteria, Bacteroidetes, Chloroflexi, Saccharibacteria, Chlorobi, Firmicutes, Actinobactoria, Acidobacteria, Planctomycetes and unclassified_Bacteria. The relative abundance of Protebacteria and Bacteroidetes simultaneously declined whereas the other 8 phyla increased following the addition of magnetic powder. Adding magnetic powder in the SBR significantly affected the microbial diversity and richness of activated sludge, consequently affecting the reactor performance. PMID- 28651877 TI - Alternaria alternata keratitis. PMID- 28651878 TI - Spontaneous spinal epidural hematoma as a cause of acute chest pain. PMID- 28651879 TI - Unexpected diagnosis of colon cancer due to obstruction of the large intestine by impaction of the shell of a bivalve. PMID- 28651880 TI - Methotrexate toxicity: More than just reminders. PMID- 28651881 TI - Megestrol acetate. Is its use so harmless as it might seem? PMID- 28651882 TI - Reply. PMID- 28651883 TI - How to harness the private sector for universal health coverage. PMID- 28651884 TI - [Transfusions in myelodysplastic syndromes]. AB - PRBC transfusion remains the mainstay of treatment of anemia in MDS after failure of erythropoiesis stimulating agents. The most common transfusion trigger in transfusion-dependent MDS patients is 80g/L. This level is based only on expert consensus; a randomized controlled trial comparing restrictive against liberal policy is required to evaluate potential impact of transfusion policy on with QoL and survival. Prophylactic antigen matching for RhCE and K must be used in order to reduce the risk of red blood cell (RBC) alloimmunization. Transfusion associated circulatory overload (TACO) is the first fatal complication of transfusion in MDS patients. Prevention, in this high risk group (older people with cardiac comorbidities) requires slow transfusion rates and rigorous monitoring of systolic blood pressure. Long-term transfusion in low risk MDS patients could also induce iron overload complications that could be prevent by iron chelating agents. These latter are usually not very well tolerated, however, a new formulation of Deferasirox(r) seems to be able to improve patient satisfaction. PMID- 28651885 TI - Use of antibiotic beads to salvage infected breast implants. AB - PURPOSE: When an implant becomes infected, implant salvage is often performed where the implant is removed, capsulectomy is performed, and a new implant is inserted. The patient is discharged with a PICC line and 6-8 weeks of intravenous (IV) antibiotics. This method has variable success and subjects the patient to long-term systemic antibiotics. In the 1960s, the use of antibiotic-impregnated beads for the treatment of chronic osteomyelitis was described. These beads deliver antibiotic directly to the site of the infection, thereby eliminating the complications of systemic IV antibiotics. This study aimed to present a case series illustrating the use of STIMULAN calcium sulfate beads loaded with vancomycin and tobramycin to increase the rate of salvage of the infected implant and forgo IV antibiotics. METHODS: A retrospective analysis was performed of patients who were treated at Mount Sinai Hospital for implant infection with salvage and antibiotic beads. RESULTS: Twelve patients were identified, 10 of whom had breast cancer. Comorbidities included hypertension, smoking, and immunocompromised status. Infections were noted anywhere from 5 days to 8 years postoperatively. Salvage was successful in 9 out of the 12 infected implants using antibiotic bead therapy without home IV antibiotics. CONCLUSIONS: The use of antibiotic beads is promising for salvaging infected breast implants without IV antibiotics. Seventy-five percent of the implants were successfully salvaged. Of the three patients who had unsalvageable implants, one was infected with antibiotic-resistant Rhodococcus that was refractory to bead therapy and one was noncompliant with postoperative instructions. PMID- 28651886 TI - Investigation of UCH-L1 levels in ischemic stroke, intracranial hemorrhage and metabolic disorder induced impaired consciousness. AB - OBJECTIVE: We aimed to determine the levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients admitted to the emergency department with impaired consciousness due to metabolic or neurological reasons. MATERIALS - METHODS: The study included 80 patients with ischemic stroke (IS), 40 patients with intracranial hemorrhage (ICH), 80 patients with metabolic disorder induced impaired consciousness (MDIC) and 40 healthy controls. RESULTS: The levels of UCH L1 [median (IQR)] were as follows: 5.59ng/mL (3.90-9.37) in IS, 5.44ng/ml (4.01 13.98) in ICH, 3.34ng/ml (2.29-5.88) in MDIC and 3.94ng/ml (3.31-7.95) in healthy volunteers. Significantly higher levels were detected in IS and ICH than in MDIC and healthy volunteers. In ROC curve analysis, we detected 63.75% sensitivity and 62.5% specificity (AUC=0.626, p<0.0199, 95% CI: 0.533-0.713) with a cutoff value of 4.336ng/ml for IS and 75% sensitivity and 55% specificity (AUC=0.664, p<0.0071, 95% CI: 0.549-0.766) with a cut-off value of 4.036ng/ml for ICH. However, the sensitivity and specificity for MDIC was 36.25% and 77.5%, respectively, with a cut-off value of 3.256ng/ml (AUC=0.525, p=0.6521, 95% CI: 0.432-0.617). UCH-L1 levels were found to increase significantly with increasing time between the onset of symptoms and blood sampling (r=0.345, p<0.001). However, no correlation was found between UCH-L1 levels and age (r=0.014, p=0.833), GCS (r=-0.115, p=0.074), mRS (r=0.063, p=0.475) and NIHSS (r=0.056, p=0.520). CONCLUSION: In this study, we detected significantly higher levels of UCH-L1 in patients with IS and ICH compared to patients with MDIC and healthy volunteers. PMID- 28651887 TI - Alarming increase in electronic nicotine delivery systems-related burn injuries: A serious unregulated public health issue. PMID- 28651888 TI - How can lifeguards recover better? A cross-over study comparing resting, running, and foam rolling. AB - PURPOSE: The aim of this study is to compare the effectiveness of active recovery in form of running or foam rolling on clearing blood lactate compared to remain sitting after a water rescue. METHOD: A quasi experimental cross-over design was used to test the effectiveness of two active recovery methods: foam rolling (FR) and running (RR), compared with passive recovery (PR) on the blood lactate clearance after performing a water rescue. Twelve lifeguards from Marin (Pontevedra) completed the study. The participants performed a 100-meter water rescue and a 25-minute recovery protocol. RESULTS: The post recovery lactate levels were significantly lower for foam rolling (4.4+/-1.5mmol/l, P=0.005, d=0.94) and running (4.9+/-2.3mmol/l, P=0.027, d=1.21) compared with resting (7.2+/-2.5mmol/l); there was no significant difference between foam rolling and running (P=1.000). CONCLUSIONS: We found that surf lifesavers clear out blood lactate more efficient when performing an active recovery protocol. Foam rolling is an effective method of increasing the rate of blood lactate clearance. These two recovery methods are also adequate for surf lifeguards as they do not interfere with the surveillance aspect of their job. PMID- 28651889 TI - A novel expression vector for the secretion of abaecin in Bacillus subtilis. AB - This study aimed to describe a Bacillus subtilis expression system based on genetically modified B. subtilis. Abaecin, an antimicrobial peptide obtained from Apis mellifera, can enhance the effect of pore-forming peptides from other species on the inhibition of bacterial growth. For the exogenous expression, the abaecin gene was fused with a tobacco etch virus protease cleavage site, a promoter Pglv, and a mature beta-glucanase signal peptide. Also, a B. subtilis expression system was constructed. The recombinant abaecin gene was expressed and purified as a recombinant protein in the culture supernatant. The purified abaecin did not inhibit the growth of Escherichia coli strain K88. Cecropin A and hymenoptaecin exhibited potent bactericidal activities at concentrations of 1 and 1.5MUM. Combinatorial assays revealed that cecropin A and hymenoptaecin had sublethal concentrations of 0.3 and 0.5MUM. This potentiating functional interaction represents a promising therapeutic strategy. It provides an opportunity to address the rising threat of multidrug-resistant pathogens that are recalcitrant to conventional antibiotics. PMID- 28651890 TI - Isolation and molecular characterization of Thraustochytrium strain isolated from Antarctic Peninsula and its biotechnological potential in the production of fatty acids. AB - Thraustochytrids are unicellular protists belonging to the Labyrinthulomycetes class, which are characterized by the presence of a high lipid content that could replace conventional fatty acids. They show a wide geographic distribution, however their diversity in the Antarctic Region is rather scarce. The analysis based on the complete sequence of 18S rRNA gene showed that strain 34-2 belongs to the species Thraustochytrium kinnei, with 99% identity. The total lipid profile shows a wide range of saturated fatty acids with abundance of palmitic acid (16:0), showing a range of 16.1-19.7%. On the other hand, long-chain polyunsaturated fatty acids, mainly docosahexaenoic acid and eicosapentaenoic acid are present in a range of 24-48% and 6.1-9.3%, respectively. All factors analyzed in cells (biomass, carbon consumption and lipid content) changed with variations of culture temperature (10 degrees C and 25 degrees C). The growth in glucose at a temperature of 10 degrees C presented the most favorable conditions to produce omega-3fatty acid. This research provides the identification and characterization of a Thraustochytrids strain, with a total lipid content that presents potential applications in the production of nutritional supplements and as well biofuels. PMID- 28651891 TI - Neuroanatomical alterations and synaptic plasticity impairment in the perirhinal cortex of the Ts65Dn mouse model of Down syndrome. AB - Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, is characterized by numerous neurodevelopmental alterations and intellectual disability. Individuals with DS and DS mouse models are impaired in several memory domains, including hippocampus-dependent declarative (spatial, in rodents) memory and visual recognition memory, a form of memory in which the perirhinal cortex (PRC) plays a fundamental role. The anatomo-functional substrates of hippocampus-dependent memory impairment have been largely elucidated in the Ts65Dn mouse model of DS. In contrast, there is a lack of corresponding information regarding visual recognition memory. Therefore, we deemed it of interest to examine at both an anatomical and functional level the PRC of Ts65Dn mice. We found that the PRC of adult (1.5-3.5month-old) Ts65Dn mice exhibited diffused hypocellularity and neurons with a reduced spine density. No difference between Ts65Dn and euploid mice was detected in the abundance of glutamatergic and GABAergic terminals. We examined brain slices for long-term potentiation (LTP), a form of synaptic plasticity involved in long-term memory. Theta burst stimulation of intracortical fibers was used in order to elicit LTP in the superficial layers of the PRC. We found that in trisomic slices LTP had a similar time-course but a reduced magnitude in comparison with euploid slices. While exposure to the GABAA receptor antagonist picrotoxin had no effect on LTP magnitude, exposure to the GABAB receptor antagonist CGP55845 caused an increase in LTP magnitude that became even larger than in euploid slices. Western blot analysis showed increased levels of the G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in the PRC of Ts65Dn mice, consistent with triplication of the gene coding for GIRK2. This suggests that the reduced magnitude of LTP may be caused by GIRK2-dependent exaggerated GABAB receptor-mediated inhibition. Results provide novel evidence for anatomo-functional alterations in the PRC of Ts65Dn mice. These alterations may underlie trisomy-due impairment in visual recognition memory. PMID- 28651892 TI - Construction of a recombinant full-length membrane associated IgG library. AB - HIV/AIDS has become a global pandemic. Development of an effective HIV-1 vaccine eliciting broadly neutralizing monoclonal antibodies (bnmAbs) remains a big challenge. Before an effective vaccine comes out, passive treatment for prevention and protection of HIV-1 infection may alleviate the burden caused by the pandemic. Numerous bnmAbs have been isolated against different epitopes in HIV-1 envelope glycoprotein via phage/yeast display, EBV-immortalization, single cell sorting and micro neutralization. Recombinant antibody library with extended diversity and enlarged size of units are applicable by phage/yeast display and mammalian cell display for monoclonal antibody isolation. Here, we constructed an immune recombinant membrane associated full length IgGs library based on mammalian cell display system. This library can be used for monoclonal antibody screening/isolation by target cell sorting. A full length antibody mz2F11 was screened with potent neutralizing activities against a panel of viruses tested. Our study provides a novel way of antibody library construction and monoclonal antibody screening. Antibodies screened via this method can help broaden the knowledge in passive treatment and prevention against HIV-1 infection. PMID- 28651893 TI - Epidemiology and clinical characteristics of hemangioblastomas in the elderly: An update. AB - Hemangioblastomas are benign tumors, derived from "stromal" cells of unclear origin. While previously thought to be a rare entity in elderly patients, we had previously reported a case series of six elderly patients (aged over 65years at diagnosis) diagnosed with hemangioblastoma in our 12year experience. Here, we report a followup series, describing eight additional cases of hemangioblastomas diagnosed in elderly patients (out of 26 in subjects over age 18). Seven of the eight cases were sporadic, and one case was suspicious for being associated with the von Hippel-Lindau (VHL) syndrome. All eight cases had presented with symptoms related to compression, and surgical resection resulted in good clinical outcomes. Combined with our previous report, 14/103 (13.6%) of the hemangioblastomas diagnosed in a 15-year period in a single hospital were present in elderly patients, suggesting that the prevalence in elderly patients of hemangioblastomas is higher than previously expected. PMID- 28651894 TI - Does chronic kidney disease affect the mortality rate in patients undergoing spine surgery? AB - The number of patients with chronic kidney disease (CKD) and their life expectancy has been increasing. With time number of patients undergoing spine surgery has also been on a rise. This study we did a retrospective review of registry data to investigate the mortality rate of chronic kidney disease patients following spine surgery using a large, multi-center spine registry. 12,276 consecutive spine-fusion patients from January 2009 to December 2012 were included and mortality rates in patients with CKD compared to those with normal kidney function following spine surgery. Logistic regression was usedto evaluate risk of mortality following spine surgery. The average age of the cohort was 59 (SD=13.4). 53% were female. Patients who had stage 3, 4 or 5 CKD were older than non-CKD patients (mean=71,SD=9.2 vs. 59, SD=13.3). After adjusting for confounding variables, patients with stage 3 or 4 CKD had higher mortality rates than patients with normal kidney function (OR 1.78, 95% CI 1.3-2.45) Hemodialysis dependent patients (stage 5 CKD) had even higher rates of mortality compared to patients with normal function (OR 4.18, 95% CI1.87-9.34). our findings suggest that spine surgery is associated with significantly higher mortality rates in patients with CKD compared to patients with normal kidney function. Understanding the additional morbidity and mortality of spine surgery in this medically complicated group of patients is imperative for accurate preoperative risk assessment. PMID- 28651895 TI - Sexual Conflict, Facultative Asexuality, and the True Paradox of Sex. AB - Theory suggests that occasional or conditional sex involving facultative switching between sexual and asexual reproduction is the optimal reproductive strategy. Therefore, the true 'paradox of sex' is the prevalence of obligate sex. This points to the existence of powerful, general impediments to the invasion of obligately sexual populations by facultative mutants, and recent studies raise the intriguing possibility that a key impediment could be sexual conflict. Using Bateman gradients we show that facultative asexuality can amplify sexual conflict over mating, generating strong selection for both female resistance and male coercion. We hypothesize that invasions are most likely to succeed when mutants have negative Bateman gradients, can avoid mating, and achieve high fecundity through asexual reproduction - a combination unlikely to occur in natural populations. PMID- 28651896 TI - Do Social-Ecological Syndromes Predict Outcomes for Ecosystem Services? - a Reply to Bodin et al. PMID- 28651897 TI - Whole Health/Integrative Health in the VHA: Focusing on What Matters to the Veteran Rather Than What is the Matter with Them. PMID- 28651898 TI - Remote ischaemic preconditioning in orthotopic liver transplantation (RIPCOLT trial): a pilot randomized controlled feasibility study. AB - BACKGROUND: Ischaemia Reperfusion (IR) injury is a major cause of morbidity, mortality and graft loss following Orthotopic Liver Transplantation (OLT). Utilising marginal grafts, which are more susceptible to IR injury, makes this a key research goal. Remote Ischaemic Preconditioning (RIPC) has been shown to ameliorate hepatic IR injury in experimental models. Whether RIPC can reduce IR injury in human liver transplant recipients is unknown. METHODS: Forty patients undergoing liver transplantation were randomized to RIPC or a sham. RIPC was induced through three 5 min cycles of alternate ischaemia and reperfusion of the left leg prior to surgery. Data on clinical outcomes was collected prospectively. Per-operative cytokine levels were measured. RESULTS: Fourty five of 51 patients approached (88%) were willing to enroll in the study. Five patients were excluded and 40 randomized, of which 20 underwent RIPC which was successfully completed in all patients. There were no complications following RIPC. Median day 3 AST levels were slightly higher in the RIPC group (221 IU vs 149 IU, p = 1.00). CONCLUSIONS: RIPC is acceptable and safe in liver transplant recipients. This study has not demonstrated evidence of a reduction in short-term measures of IR injury. Longer follow up will be required and consideration of an altered protocol. PMID- 28651899 TI - The cytotrophoblastic shell and complications of pregnancy. AB - Many complications of pregnancy have their pathophysiological roots in the early stages of placentation. Impaired trophoblast invasion and deficient remodelling of the maternal spiral arteries are a common feature. While malperfusion of the placenta may underpin cases of fetal growth restriction and early-onset pre eclampsia, the mechanistic links to spontaneous miscarriage, pre-term labour and premature rupture of the membranes are less obvious. Here, we speculate that formation of a well-developed cytotrophoblastic shell at the maternal-fetal interface is crucial for pregnancy success. Initially, extravillous trophoblast cells differentiate from the outer layer of the shell in contact with the endometrium. Impaired development may thus contribute to reduced invasion and deficient remodelling. In addition, the extent of the shell influences the timing and spatial configuration of onset of the maternal arterial circulation. A thin and fragmentary shell results in premature and disorganised onset, leading to spontaneous miscarriage. In less severe cases it may predispose to haemorrhage at the interface and formation of intrauterine haematomas. If pregnancy continues, these haematomas may act as a source of oxidative stress, promoting senescence and weakening of the membranes, and stimulating inflammation in the uterine wall and premature contractions. Formation of the shell is dependent on proliferation of cytotrophoblast progenitor cells during the first weeks after implantation, when the developing placenta is supported by histotrophic nutrition from endometrial glands. Hence, we propose the fitness of the endometrium prior to conception, and the peri-conceptional dialogue between the endometrium and the trophoblast is critical for avoidance of later complications of pregnancy. PMID- 28651900 TI - Potential clinical applications of placental stem cells for use in fetal therapy of birth defects. AB - Placental stem cells are of growing interest for a variety of clinical applications due to their multipotency and ready availability from otherwise frequently discarded biomaterial. Stem cells derived from the placenta have been investigated in a number of disease processes, including wound healing, ischemic heart disease, autoimmune disorders, and chronic lung or liver injury. Fetal intervention for structural congenital defects, such as spina bifida, has rapidly progressed as a field due to advances in maternal-fetal medicine and improving surgical techniques. In utero treatment of structural, as well as non-structural, congenital disorders with cell-based therapies is of particular interest given the immunologic immaturity and immunotolerant environment of the developing fetus. A comprehensive literature review was performed to assess the potential utilization of placenta-derived stem cells for in utero treatment of congenital disorders. Most studies are still in the preclinical phase, utilizing animal models of common congenital disorders. Future research endeavors may include autologous transplantation, gene transfers, induced pluripotent stem cells, or cell-free therapies derived from the stem cell secretome. Though much work still needs to be done, placental stem cells are a promising therapeutic agent for fetal intervention for congenital disease. PMID- 28651901 TI - Benchmarking numerical codes for tracer transport with the aid of laboratory scale experiments in 2D heterogeneous porous media. AB - We present a combined experimental and numerical modeling study that addresses two principal questions: (i) is any particular Eulerian-based method used to solve the classical advection-dispersion equation (ADE) clearly superior (relative to the others), in terms of yielding solutions that reproduce BTCs of the kind that are typically sampled at the outlet of a laboratory cell? and (ii) in the presence of matches of comparable quality against such BTCs, do any of these methods render different (or similar) numerical BTCs at locations within the domain? To address these questions, we obtained measurements from carefully controlled laboratory experiments, and employ them as a reference against which numerical results are benchmarked and compared. The experiments measure solute transport breakthrough curves (BTCs) through a square domain containing various configurations of coarse, medium, and fine quartz sand. The approaches to solve the ADE involve Eulerian-Lagrangian and Eulerian (finite volume, finite elements, mixed and discontinuous finite elements) numerical methods. Model calibration is not examined; permeability and porosity of each sand were determined previously through separate, standard laboratory tests, while dispersivities are assigned values proportional to mean grain size. We find that the spatial discretization of the flow field is of critical importance, due to the non-uniformity of the domain. Although simulated BTCs at the system outlet are observed to be very similar for these various numerical methods, computed local (point-wise, inside the domain) BTCs can be very different. We find that none of the numerical methods is able to fully reproduce the measured BTCs. The impact of model parameter uncertainty on the calculated BTCs is characterized through a set of numerical Monte Carlo simulations; in cases where the impact is significant, assessment of simulation matches to the experimental data can be ambiguous. PMID- 28651902 TI - ERCP and Laparoscopic cholecystectomy in a patient with situs inversus totalis. PMID- 28651903 TI - The elderly and direct antiviral agents: Constraint or challenge? AB - BACKGROUND: Direct antiviral agents (DAAs) for chronic hepatitis C showed great effectiveness and good safety profile. So far, few data are available about their use in elderly subjects. AIM: To assess management, safety and outcome of DAAs treatments in the elderly. METHODS: This retrospective, single-centre study enrolled all patients aged >=65 years, compared by age (group A: 65-74 years, group B: >=75 years), who completed DAAs between February 2015-November 2016. Variables potentially associated to adverse events (AEs) were analyzed. Sustained virological response (SVR) was evaluated at 12-weeks follow-up. RESULTS: DAAs were administered to 221 patients aged >=65 years (males: 112; group A: 130, group B: 91). Prescribed regimens were: sofosbuvir-based: 44 patients (19.9%), simeprevir-based: 25 (15%), ledipasvir-based: 49 (22.2%), daclatasvir-based: 12 (5.4%), paritaprevir/ritonavir+ombitasvir+/-dasabuvir: 91 (41.2%). Ribavirin was used in 121 patients. In 58 subjects co-medications were adjusted due to drug interactions. At least one AE occurred in 130 patients, including 13 SAEs, mainly in older subjects (p=0.04). Female sex (p=0.04), liver stiffness (p=0.023), use of simeprevir (p=0.03) and ribavirin (p=0.009) were associated with AEs. SVR-12 was achieved in 96,9% of subjects. CONCLUSIONS: A careful baseline evaluation and a strict monitoring allow to optimise management and outcome of DAAs in elderly. PMID- 28651904 TI - Community-based distribution of misoprostol for early abortion: evaluation of a program along the Thailand-Burma border. AB - BACKGROUND: Although abortion is legal in Thailand for a number of indications, women from Burma residing in Thailand are rarely able to access safe services. We evaluated the outcomes of a community-based distribution program that provides migrant, refugee, and cross-border women from Burma with evidence-based information about and access to misoprostol for early pregnancy termination. METHODS: After determination of eligibility based on self-report and counseling, trained Network members instructed women to vaginally administer two 800-mcg doses of misoprostol 24 h apart and a third dose one week later, if needed. We systematically reviewed data from monitoring logbooks recorded over a three-year period to examine pregnancy outcomes. We also conducted in-depth open-ended interviews with the three leaders of the two Networks to understand better their perceptions and experiences as providers and counselors. We analyzed logbook data using descriptive statistics and interviews for content and themes using both deductive and inductive techniques. RESULTS: From January 2012 through December 2014, 918 women received early abortion care using misoprostol through the community-based distribution program. Of these, 885 women (96.4%) were not pregnant at follow-up, 29 were pregnant at follow-up (3.2%), and four women were lost to follow-up (0.4%). Our interviews revealed that providers are motivated to participate due to concerns surrounding unsafe abortion in the community and frame their work as a public health intervention. CONCLUSIONS: The documented outcomes from this initiative may be valuable for those working to reduce harm from unsafe abortion in other legally restricted, low-resource, and/or conflict affected settings. IMPLICATIONS: Our findings demonstrate that community-based distribution of misoprostol can be a safe and effective strategy for increasing access to safe abortion, even in a legally restricted, low-resource setting. Determining if similar strategies can be successfully employed in other contexts appears warranted. PMID- 28651905 TI - Self-etching ceramic primer versus hydrofluoric acid etching: Etching efficacy and bonding performance. AB - AIM: This study assessed the effect of pretreatment of hybrid and glass ceramics using a self-etching primer on the shear bond strength (SBS) and surface topography, in comparison to pretreatment with hydrofluoric acid and silane. METHODS: 40 rectangular discs from each ceramic material (IPS e.max CAD;EM, Vita Mark II;VM, Vita Enamic;VE), were equally divided (n=10) and assigned to one of four surface pretreatment methods; etching with 4.8% hydrofluoric acid followed by Monobond plus (HFMP), Monobond etch & prime (Ivoclar Vivadent) (MEP), No treatment (NT) as negative control and Monobond plus (Ivoclar Vivadent) with no etching (MP) as positive control. SBS of resin cement (Multilink-N, Ivoclar Vivadent) to ceramic surfaces was tested following a standard protocol. Surface roughness was evaluated using an Atomic force microscope (AFM). Surface topography and elemental analysis were analyzed using SEM/EDX. Data were analyzed with two-way analysis of variance (ANOVA) and post-hoc Bonferroni test at a significance level of alpha=0.05. RESULTS: Pretreatment with HFMP resulted in higher SBS and increased surface roughness in comparison to MEP and MP. Regardless the method of surface pretreatment, the mean SBS values of EM ceramic was significantly higher (p<0.05) than those recorded for VM and VE, except when VE was treated with MEP, where the difference was statistically insignificant. Traces of fluoride ion were detected when MEP was used with VE and VM. CONCLUSION: Under limited conditions, using MEP resulted in comparable SBS results to HFMP; meanwhile HFMP remains the gold standard for pretreatment of glass ceramics for resin-luting cementation. PMID- 28651906 TI - Lung clearance index is sensitive to small airway disease in pediatric lung transplant recipients. AB - BACKGROUND: The principal obstacle to long-term survival after lung transplant is chronic lung allograft dysfunction (CLAD), which primarily affects the small airways. After transplant, patients are monitored with spirometry, which is a generally insensitive detector of small airways obstruction. The lung clearance index (LCI) is a measure obtained during multiple breath washout (MBW) maneuvers. We hypothesized that among lung allograft recipients, LCI would detect small airways disease not detected with spirometry. METHODS: This study enrolled 15 patients, 5 of whom already had a diagnosis of CLAD. We added MBW as an additional index of peripheral airway function to the established post-transplant routine care protocol. RESULTS: Of trials, 87.9% yielded valid measurements, and single maneuvers were 2-8 minutes. LCI did not yield any false-negative findings no patients were considered obstructed by forced expiratory volume in 1 second (FEV1) but normal by LCI. At enrollment, 6 patients without CLAD had an elevated LCI, and 4 progressed to CLAD. Only 2 of these 4 patients would have been identified by a decrease in FEV1. CONCLUSIONS: LCI identified lung allograft dysfunction in more patients than the use of standardized spirometric measures, including patients with abnormal FEV1. These data suggest that LCI from MBW may be a more sensitive means to detect allograft peripheral airway disease than standard methods for measurement of small airways function. PMID- 28651907 TI - Tumor necrosis factor-alpha levels and non-surgical bleeding in continuous-flow left ventricular assist devices. AB - BACKGROUND: Non-surgical bleeding (NSB) due to angiodysplasia is common in left ventricular assist device (LVAD) patients. Thrombin-induced angiopoietin-2 (Ang 2) expression in LVAD patients leads to altered angiogenesis and is associated with lower angiopoietin-1 (Ang-1) and increased NSB. However, the mechanism for decreased Ang-1, made by pericytes, is unknown and the origin of thrombin in LVAD patients is unclear. We hypothesized that high tumor necrosis factor-alpha (TNF alpha) levels in LVAD patients induce pericyte apoptosis, tissue factor (TF) expression and vascular instability. METHODS: We incubated cultured pericytes with serum from patients with heart failure (HF), LVAD or orthotopic heart transplantation (OHT), with or without TNF-alpha blockade. We performed several measurements: Ang-1 expression was assessed by reverse transcript-polymerase chain reaction (RT-PCR) and pericyte death fluorescently; TF expression was assessed by RT-PCR in cultured endothelial cells incubated with patient plasma with or without TNF-alpha blockade; and TF expression was assessed in endothelial biopsy samples from these patients by immunofluorescence. We incubated cultured endothelial cells on Matrigel with patient serum with or without TNF-alpha blockade and determined tube formation by microscopy. RESULTS: Serum from LVAD patients had higher levels of TNF-alpha, suppressed Ang-1 expression in pericytes, and induced pericyte death, and there was accelerated endothelial tube formation compared with serum from patients without LVADs. TF was higher in both plasma and endothelial cells from LVAD patients, and plasma from LVAD patients induced more endothelial TF expression. All of these effects were reversed or reduced with TNF-alpha blockade. High levels of TNF-alpha were associated with increased risk of NSB. CONCLUSIONS: Elevated TNF-alpha in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis and expression of TF and Ang-1. PMID- 28651908 TI - Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naive patients with schizophrenia presenting with first episode psychosis. AB - Depressive symptoms are common in first episode schizophrenia. However, the prevalence and its associations of comorbid depressive symptoms with clinical variables are less well characterized in Chinese Han patients with schizophrenia. In this cross-sectional study, we recruited 240 first-episode and drug naive (FEDN) inpatients with schizophrenia. All patients were rated on the 17-item Hamilton Depression Rating Scale (HAMD-17) to measure depressive symptoms, and also on the Positive and Negative Syndrome Scale (PANSS) for psychopathology. Our results showed that 131 patients had a total score of 8 or more points on HAMD 17, making the prevalence of comorbid depressive symptoms 54.6%. Fewer women (48.1%, 62 of 129) than men (62.2%, 69 of 111) had comorbid depressive symptoms. Compared to those patients without depressive symptoms, those with depressive symptoms showed higher PANSS total, general psychopathology, cognitive factor and negative symptom scores (all p<0.05). Further stepwise multiple logistic regression analysis indicated that the PANSS general psychopathology, the PANSS total score and gender (all p<0.05) remained significantly associated with depressive symptoms. In addition, correlation analysis showed significant correlations between HAMD total score and the following parameters: the PANSS general psychopathology, total score, and cognitive factor (Bonferroni corrected p's<0.05). Our results suggest that depressive symptoms occur with high prevalence in FEND schizophrenia in a Chinese Han population, and show association with general psychopathology, as well as with cognitive impairment. PMID- 28651909 TI - Convergence and divergence of neurocognitive patterns in schizophrenia and depression. AB - BACKGROUND: Neurocognitive impairments are frequently observed in schizophrenia and major depressive disorder (MDD). However, it remains unclear whether reported neurocognitive abnormalities could objectively identify an individual as having schizophrenia or MDD. METHODS: The current study included 220 first-episode patients with schizophrenia, 110 patients with MDD and 240 demographically matched healthy controls (HC). All participants performed the short version of the Wechsler Adult Intelligence Scale-Revised in China; the immediate and delayed logical memory of the Wechsler Memory Scale-Revised in China; and seven tests from the computerized Cambridge Neurocognitive Test Automated Battery to evaluate neurocognitive performance. The three-class AdaBoost tree-based ensemble algorithm was employed to identify neurocognitive endophenotypes that may distinguish between subjects in the categories of schizophrenia, depression and HC. Hierarchical cluster analysis was applied to further explore the neurocognitive patterns in each group. RESULTS: The AdaBoost algorithm identified individual's diagnostic class with an average accuracy of 77.73% (80.81% for schizophrenia, 53.49% for depression and 86.21% for HC). The average area under ROC curve was 0.92 (0.96 in schizophrenia, 0.86 in depression and 0.92 in HC). Hierarchical cluster analysis revealed for MDD and schizophrenia, convergent altered neurocognition patterns related to shifting, sustained attention, planning, working memory and visual memory. Divergent neurocognition patterns for MDD and schizophrenia related to motor speed, general intelligence, perceptual sensitivity and reversal learning were identified. CONCLUSIONS: Neurocognitive abnormalities could predict whether the individual has schizophrenia, depression or neither with relatively high accuracy. Additionally, the neurocognitive features showed promise as endophenotypes for discriminating between schizophrenia and depression. PMID- 28651910 TI - Taming the immune system through transfusion in oncology patients. AB - Blood transfusion is a clinical replacement therapy with many successes with some benefit and, also, some harm. Cancer is a multifaceted disease potentially associated with the immune system's weakness where the cancerous tumor cells escape from the immune system. Allogeneic blood transfusion, through five major mechanisms including the lymphocyte-T set, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), natural killer cells (NKCs), and dendritic cells (DCs) can help the recipient's defense mechanisms. On the other hand, the role for each of the listed items includes activation of the antitumor CD8+ cytotoxic T lymphocytes (CD8+/CTL), temporal inactivation of Tregs, inactivation of the STAT3 signaling pathway, the use of bacteria to enhance the antitumor immune response and cellular immunotherapy. The above issues are concisely addressed in this manuscript based on a literature survey on this topic carried out by the first author. PMID- 28651911 TI - Conformational studies of Gram-negative bacterial quorum sensing 3-oxo N-acyl homoserine lactone molecules. AB - In their 1H NMR spectra in CDCl3 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide NH proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the NH to the 3-oxo group. The 1H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1-4.5% in CDCl3 and 6.5-7.2% in CD3CN. In contrast, DFT calculations show that the lowest energy enol tautomer and the keto tautomer are of equal energy in the gas phase, but that the keto tautomer is more stable in chloroform, acetonitrile and water solution. The calculations also show that there is no evidence for any n->pi* or C5H-bonding interactions being present in either the lowest energy keto or enol tautomer of the OHLs in solution or the gas phase, which is in contrast to the reported solid-state structure. PMID- 28651913 TI - Structure-activity relationships of 3-O-beta-chacotriosyl oleanic acid derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus. AB - Highly pathogenic H5N1 virus (H5N1) entry is a key target for the development of novel anti-influenza agents with new mechanisms of action. In our continuing efforts to identify novel potential anti-H5N1 entry inhibitors, a series of 3-O beta-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on two small molecule inhibitors 1 and 2 previously discovered by us. The anti-H5N1 entry activities were determined based on HA/HIV and VSVG/HIV entry assays. Compound 15 displayed the most promising anti-H5N1 entry activities with average IC50 values of 4.05MUM and good selective index (22.9). Detailed structure-activity relationships (SARs) studies suggested that either the introduction of an additional oxo group to position 11 at OA or alteration of the C-3 configuration of OA from 3beta- to 3alpha-forms can significantly enhance the selective index while maintaining their antiviral activities in vitro. Molecular simulation analysis confirmed that the compounds exert their inhibitory activity through binding tightly to hemagglutinin (HA2) protein near the fusion peptide and prevent virus entry. PMID- 28651912 TI - Aligator: A computational tool for optimizing total chemical synthesis of large proteins. AB - The scope of chemical protein synthesis (CPS) continues to expand, driven primarily by advances in chemical ligation tools (e.g., reversible solubilizing groups and novel ligation chemistries). However, the design of an optimal synthesis route can be an arduous and fickle task due to the large number of theoretically possible, and in many cases problematic, synthetic strategies. In this perspective, we highlight recent CPS tool advances and then introduce a new and easy-to-use program, Aligator (Automated Ligator), for analyzing and designing the most efficient strategies for constructing large targets using CPS. As a model set, we selected the E. coli ribosomal proteins and associated factors for computational analysis. Aligator systematically scores and ranks all feasible synthetic strategies for a particular CPS target. The Aligator script methodically evaluates potential peptide segments for a target using a scoring function that includes solubility, ligation site quality, segment lengths, and number of ligations to provide a ranked list of potential synthetic strategies. We demonstrate the utility of Aligator by analyzing three recent CPS projects from our lab: TNFalpha (157 aa), GroES (97 aa), and DapA (312 aa). As the limits of CPS are extended, we expect that computational tools will play an increasingly important role in the efficient execution of ambitious CPS projects such as production of a mirror-image ribosome. PMID- 28651914 TI - Phenylsulfonylfuroxan NO-donor phenols: Synthesis and multifunctional activities evaluation. AB - Phenylsulfonyfuroxan nitric oxide (NO)-donor phenols were designed, synthesized and evaluated. The compounds were designed through a symbiotic approach using selected phenols and phenylsulfonylfuroxan NO-donor. The antioxidant activities of the hybrid compounds T2-T6 showed to be good in vivo. Compounds T4 and T6 revealed excellent yeast alpha-glucosidase inhibitory activity and anti glycosylation activity. All of the compounds exhibited strong NO releasing activity and significant anti-platelet aggregation activity. The inhibition of platelet aggregation was more than 50% at low concentration (1.5MUM) and 95% at higher concentration (15MUM and 150MUM). The vasodilatation experiment demonstrated that the six compounds under test exhibited definite vasodilation activity (pIC50 ranged from 5.698 to 6.383), especially compound T6 (pIC50 was 6.383) which was similar to sodium nitroprusside (pIC50 was 6.786). Both anticoagulant and vasodilatation effects were correlated with their NO releasing activities. These hybrid phenylsulfonyfuroxan-based NO-donor phenols offer a multifunctional prodrug design concept for the development of therapeutic or preventive agents for metabolic syndrome. PMID- 28651915 TI - Novel analogs of N-acylhydroxyethylaminomethyl-4H-chromen-4-one scaffold as IL-5 inhibitors. AB - A number of N-acyl substituted hydroxyethylaminomethyl-4H-chromen-4-ones 6a-u were prepared and evaluated for their IL-5 inhibitory activity. Among them, the compound 6r (95.0% inhibition at 30uM, IC50=10.0uM, ClogP=4.1549) showed most potent inhibitory activity. The structure activity relationship revealed that the bulkier or hydrophobic substituents at urea, carbamate or amide group resulted in good inhibitory activity against IL-5. Moreover, electron donating group at phenyl ring (6g and 6s) is much more active than electron withdrawing group (6f). Finally, replacement of cyclohexylmethoxy group at 5th position of ring A with bulky aliphatic substituents resulted in the loss of activity. PMID- 28651916 TI - Challenges in endometriosis miRNA studies - From tissue heterogeneity to disease specific miRNAs. AB - In order to uncover miRNA changes in endometriosis pathogenesis, both endometriotic lesions and endometrial biopsies, as well as stromal and epithelial cells isolated from these tissues have been investigated and a large number of dysregulated miRNAs have been reported. However, the concordance between the result of different studies has remained small. One potential explanation for limited overlap between the proposed disease-related miRNAs could be the heterogeneity in tissue composition, as some studies have compared highly heterogeneous whole-lesion biopsies with endometrial tissue, some have compared the endometrium from patients and controls, and some have used pure cell fractions isolated from lesions and endometrium. This review focuses on the results of published miRNA studies in endometriosis to reveal the potential impact of tissue heterogeneity on the discovery of disease-specific miRNA alterations in endometriosis. Additionally, functional studies that explore the roles of endometriosis-involved miRNAs are discussed. PMID- 28651917 TI - Response to letter to the editor: Sepsis-associated in-hospital cardiac arrest. PMID- 28651918 TI - Nebulized colistin in ventilator-associated pneumonia: Should we trust it? PMID- 28651920 TI - Ultrasound Image Despeckling Based on Statistical Similarity. AB - Ultrasound images are affected by the speckle phenomenon, a multiplicative noise that degrades image quality. Several methods for denoising have been proposed in recent years, based on different approaches. The so-called non-local mean is considered the state-of-the-art method; the idea is to find similar patches across the image and exploit them to regularize the image. The method proposed here is in the non-local family, although instead of partitioning the target image in patches, it works pixelwise. The similarity between pixels is evaluated by analyzing their statistical behavior, in particular, by measuring the Kolmogorov-Smirnov distance between their distributions. To make this possible, a stack of acquired images is required. The proposed method has been tested on both simulated and real data sets and compared with other widely adopted techniques. Performance is interesting, with quality parameters and visual inspection confirming such findings. PMID- 28651919 TI - ST2 predicts survival in patients undergoing transcatheter aortic valve implantation. AB - OBJECTIVE: To assess soluble suppression of tumorigenicity 2 (sST2) serum concentrations and predict mortality in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: We prospectively enrolled 74 patients with severe aortic stenosis (AS) who underwent TAVI and matched them to patients without aortic valve disease (n=74). AS patients underwent comprehensive echocardiographic and cardiac magnetic resonance imaging and laboratory examinations. sST2 levels were determined by enzyme-linked immunosorbent assay (ELISA), their association with post procedural mortality was investigated using logistic and Cox regression analyses, and the prognostic performance compared to established risk scores. RESULTS: AS patients had substantially higher sST2 levels than controls (39.5 vs. 17.8ng/mL, p<0.001). sST2 significantly correlated with left and right atrial sizes (r=0.25, p=0.033 and r=0.38, p=0.001). At one and two years, 10 (13.9%) and 18 (25%) patients had died, respectively. sST2 significantly predicted survival in uni- and multivariate Cox regression analyses in our cohort (p=0.005 and p=0.025). sST2 also predicted major adverse cardiovascular events (MACE, p=0.046). Adding sST2 to the established STS score improved prediction of two-year mortality in our cohort (DeltaAUC=0.108; 95% CI 0.066-0.281; continuous NRI=0.778; 95% CI: 0.277-1.278 and IDI=0.141; 95% CI: 0.031-0.251), and a model containing both sST2 and the STS score had a negative predictive value of 96.1% and 86.3% regarding one and two-year mortality, respectively. CONCLUSIONS: sST2 is elevated in AS patients and a prognostic marker of survival after TAVI. Implementation of this marker in routine pre-TAVI workup may improve risk prediction and patient selection. PMID- 28651921 TI - Ultrasound Enhances Dentoalveolar Remodeling in an Ex Vivo Orthodontic, Ovariectomy-Induced Osteoporotic Model. AB - The aim of the study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) on dentoalveolar structures during application of force to a cultured mandible slice taken from an ovariectomized rat model of osteoporosis. Rats were divided based on whether they had ovariectomy and/or LIPUS application into four groups: control osteoporosis group, control normal group, ultrasound treated osteoporosis group and ultrasound-treated normal group. The mandibles were dissected, sliced and cultured before application of a 0.5-N force. Tissue specimens from five rats per group received LIPUS; the remaining rats served as untreated controls. Tissue sections were evaluated histologically and histomorphometrically. Osteoporosis significantly affected the alveolar bone without any effect on the dentin-pulp complex. LIPUS enhanced osteoporotic alveolar bone remodeling and increased cementum and predentin thickness. Furthermore, LIPUS application significantly increased odontoblast and periodontal ligament cell counts (p < 0.05) in both groups. Therefore, LIPUS enhances alveolar bone remolding and increases cementum and predentin formation in osteoporotic rat mandible slice organ cultures. PMID- 28651922 TI - Peritoneal Carcinomatosis in Primary Ovarian Cancer: Ultrasound Detection and Comparison with Computed Tomography. AB - We retrospectively compared detection rates and consistency for diagnosis of peritoneal carcinomatosis (PC) of primary ovarian cancer (OC) between ultrasound (US) and computed tomography (CT) scans in 41 patients whose PC of OC (stages IIC IV) had been diagnosed by histopathology findings. Compared with CT detection rates, those for US were significantly higher for metastases to the pelvic area (92.3% vs. 43.6%, p < 0.001) and bowel surface (64.0% vs. 16.0%, p = 0.002); however, they did not significantly differ for other sites: omentum, diaphragm, lateral peritoneum, mesenteric, hepatic and splenic surfaces. Diagnostic consistency between US and CT scans were fair to moderate for splenic (kappa = 0.806), hepatic (kappa = 0.485), lateral peritoneum (kappa = 0.450) and diaphragm (kappa = 0.338) surfaces, but poorly consistent for other parts (kappa = 0.144 0.229). In summary, US can complement CT scans, especially for detecting PC of primary OC metastases in pelvic and bowel surfaces. PMID- 28651923 TI - Randomized controlled trials covering pharmaceutical care and medicines management: A systematic review of literature. AB - OBJECTIVE: To review the effects of pharmaceutical care on hospitalizations, mortality and clinical outcomes in patients. METHODS: Systematic searches were conducted in MEDLINE, EMBASE and International Pharmaceutical Abstracts (IPA) databases to identify studies that were published between 2004 and January 2017. Studies included in this review were randomized controlled trials (RCTs) that spanned across both community and hospital settings. Using strict inclusion/exclusion criteria studies were included if they reported level 1 or 2 outcomes in the hierarchy of outcome measure i.e. clinical and surrogate outcomes (e.g. blood pressure (BP) control, blood glucose level, cholesterol BMI). Each study was assessed for quality using the Jadad scoring system. RESULTS: Fifty four RCTs were included in the present review. Forty-six of these studies ranked high quality according to the Jadad scoring system. Studies were categorized into their general condition groups. Interventions in patients with diabetes, depression, respiratory disorders, cardiovascular disorders, epilepsy, osteoporosis, and interventions in older adults were identified. In the majority of studies pharmaceutical care was found to lead to significant improvements in clinical outcomes and/or hospitalizations when compared to the non-intervention group. Some conditions had a large number of RCTs, for example for cardiovascular conditions and in diabetes. Statistically significant improvements were seen in the majority of the studies included for both of these conditions, with studies indicating positive clinical outcomes and/or hospitalizations rates. Within the cardiovascular condition, a subset of studies, focusing on cardiac heart failure and coronary heart disease, had more mixed results. In other conditions the number of RCTs conducted was small and the evidence did not show improvements after pharmaceutical care, i.e. in depression, osteoporosis, and epilepsy. The majority of interventions were face to face interactions with patients, whilst a smaller number were conducted via the telephone and one via a web-based system. Patient education was a key component of most interventions, either verbal and/or written. Longitudinal data, post intervention cessation, was not collected in the majority of cases. CONCLUSIONS: RCTs conducted to evaluate pharmaceutical care appear to be effective in improving patient short-term outcomes for a number of conditions including diabetes and cardiovascular conditions, however, other conditions such as depression are less well researched. Future research should attempt to evaluate the conditions where there is a lack of data, whether the positive effects of pharmaceutical care persist in patient populations after the interventions cease and what the long-term clinical outcomes would be of continued pharmaceutical care. PMID- 28651925 TI - Engaging small independent practices in value-based payment: Building Aledade's medicare ACOs. PMID- 28651924 TI - Medication understanding among patients living with multiple chronic conditions: Implications for patient-reported measures of adherence. AB - BACKGROUND: Low health literacy is associated with poor medication adherence and poor health outcomes. Limited understanding of prescribed medications may decrease validity of patient-reported adherence measures. OBJECTIVES: To assess knowledge of names and purposes of prescribed medications among patients with multiple chronic conditions. METHODS: Individual interviews were conducted with a convenience sample of patients from six U.S. primary care clinics. Participants (n = 57) were English and/or Spanish-speaking patients prescribed 3+ medications for chronic conditions, for which non-adherence may lead to disability or death. In individual interviews, patients were asked to name their medications, explain the purpose of each, and to explain how they distinguish them from one another. Interviews were audio recorded, transcribed, and coded; coded content was quantified by 1) whether or not the patient could name medications; 2) method of categorizing medications; 3) whether or not the purpose of the medication was understood. Descriptive statistics were compiled using Fisher's exact test to determine the relationship between patient knowledge and medication characteristics. RESULTS: Thirty percent of patients could not name at least one of their medications; 19% did not know their purpose; 30% held misconceptions about the purpose of one or more medications. There was no significant difference in ability to name medications or state their medication's purpose between patients using medi-sets, pre-packaged rolls, or blister packs, and patients who stored pills in their original containers (p = 0.56 and p = 0.73, respectively), or across demographic groups (p = 0.085 to 0.767). CONCLUSIONS: Many patients demonstrated difficulty identifying the name and purpose of prescribed medications; this did not differ by demographic group or medication storage type. Patients may benefit from routine review of medications with their provider in order to improve health literacy, outcomes, and patient-reported adherence measurement. PMID- 28651926 TI - Quality of life after nivolumab treatment for head and neck cancer. PMID- 28651928 TI - Hypoxia-activated prodrug: an appealing preclinical concept yet lost in clinical translation. PMID- 28651927 TI - Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. AB - BACKGROUND: Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. METHODS: We did this international, open-label, randomised, phase 3, multicentre trial (TH CR 406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21 day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. FINDINGS: Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1.06, 95% CI 0.88-1.29; p=0.527), with a median overall survival of 18.4 months (95% CI 15.6-22.1) with doxorubicin plus evofosfamide versus 19.0 months (16.2-22.4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). INTERPRETATION: The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. FUNDING: Threshold Pharmaceuticals. PMID- 28651930 TI - Linking Editorial / Anknupfungseditorial. PMID- 28651931 TI - Upregulated long non-coding RNA LOC90784 promotes cell proliferation and invasion and is associated with poor clinical features in HCC. AB - A growing amount of literature has indicated that long non-coding RNAs (lncRNAs) are important factors in hepatocellular carcinoma (HCC) progression. However, the significance of lncRNAs in the progression and prognosis of liver cancer is largely unknown. In the present study, upregulated lncRNA LOC90784 was identified through integrative analysis of GSE58043 and GSE55191. Furthermore, associations between LOC90784 expression and the clinicopathological characteristics of patients were analyzed with a validated cohort 1 and the Cancer Genome Atlas (TCGA) cohort 2. We investigated the mechanisms by which this highly expressed lncRNA promotes HCC proliferation, invasion and migration via qRT-PCR, fluorescence in situ hybridization (FISH) staining, siRNA transfection, cell proliferation assays, Transwell and colony formation assays, flow cytometry analysis and Western blot. The results showed that LOC90784 expression levels were significantly higher in HCC cell lines and tissues and mainly localized in the cytoplasm. Knockdown of lncRNA LOC90784 expression inhibited proliferation and induced apoptosis and cell cycle arrest by promoting Bax and repressing CDK4 and Cyclin D1 protein expression; it also inhibited invasion and migration by repressing MMP2 and MMP9 expression in HCC cells. LOC90784 overexpression was associated with poor clinical features in the two cohorts and poor overall survival rates in HCC patients with clear resection margins (R0) in cohort 2. These results indicated that LOC90784 upregulation may be a critical oncogene and potential new biomarker in HCC. PMID- 28651929 TI - Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. AB - BACKGROUND: Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). METHODS: CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. FINDINGS: Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2.1 to 5.4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24.5 to 2.4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7.3 vs -7.8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. INTERPRETATION: In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. FUNDING: Bristol-Myers Squibb. PMID- 28651932 TI - TMPRSS4 promotes cancer stem cell traits by regulating CLDN1 in hepatocellular carcinoma. AB - Encouraging advances in the treatment of hepatocellular carcinoma(HCC) have been achieved; however, a considerable part of patients still relapse or metastasize after therapy, and the underlying mechanisms have not been clarified yet. Here, we found that CLDN1 was markedly up-regulated in HCC tissues, and correlated with poor prognosis. Overexpression of CLDN1 dramatically promoted the capability of tumorsphere formation and cancer stem cell (CSC) traits. Furthermore, we found that TMPRSS4 was up-regulated in HCC tissues and there was a positive correlation between TMPRSS4 and CLDN1. In addition, the expression of CLDN1 was regulated by TMPRSS4. Moreover, TMPRSS4 mediated CSC properties and up-regulated CLDN1 by activating ERK1/2 signaling pathway. Taken together, our results revealed that CLDN1 contributed to CSC features of HCC, which was altered by TMPRSS4 expression via ERK1/2 signaling pathway, providing promising targets for novel specific therapies. PMID- 28651933 TI - Nuclear beta-catenin positivity as a predictive marker of long-term survival in advanced epithelial ovarian cancer. AB - BACKGROUND: Classical features as histomorphology, grade, FIGO stage, and residual tumour mass have strong prognostic value in advanced epithelial ovarian carcinomas (AEOC). Most AEOCs are associated with early recurrence and poor overall survival (OS). Despite of early recurrence, general poor outcome, both high grade tumours or tumours with advanced FIGO stage at the time of diagnosis, in some of such cases, long-term survival (LTS) has been recorded . The aim of this study was to compare the utility of "classical" prognostic factors to molecular factors such as beta-catenin- E-cadherin-, mutated TP53-, and MiB-1 (Ki 67) labelling index determination in predicting long-term survival. METHODS: The expression of beta-catenin, E-cadherin, Ki-67, and p53 was determined by immunohistochemistry (IHC) in AEOC. Correlation was sought for between expression of these proteins and the status of classical features vis-a-vis overall survival of patients. Statistical evaluation of the data included Kaplan-Meier analysis, the log-rank test and Cox proportional hazards model. RESULTS: As expected, residual tumour size was an independent adverse prognostic factor for OS (univariate analysis: p=0.003, multivariate analysis: p=0.005). Nuclear expression of beta-catenin in advanced ovarian cancer of LTS patients proved to be not only an independent favourable predictor of OS (univariate analysis: p=0.025, multivariate analysis: p=0.041) but also showed strong correlation with platinum sensitivity and platinum re-induction. CONCLUSIONS: Translocation of stabilized beta-catenin from cytoplasm to the nucleus plays an important role in predicting platinum sensitivity. It also seems to support the chance for platinum re-induction in AEOC and thus enhances long-term survival. PMID- 28651934 TI - Embracing early discharge in patients with lower gastrointestinal bleeding. PMID- 28651935 TI - Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study. AB - BACKGROUND: Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. METHODS: We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. FINDINGS: Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0.84, 95% CI 0.82-0.86) and in the validation cohort (0.79, 0.73-0.84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. INTERPRETATION: We developed and validated a novel clinical prediction model with good discriminative performance to identify patients with lower gastrointestinal bleeding who are suitable for safe outpatient management, which has important economic and resource implications. FUNDING: Bowel Disease Research Foundation and National Health Service Blood and Transplant. PMID- 28651936 TI - Efficacy, safety and tolerability of aripiprazole in bipolar disorder: An updated systematic review and meta-analysis of randomized controlled trials. AB - Numerous studies have investigated aripiprazole as a treatment for bipolar disorder (BD). therefore we conducted this comprehensive meta-analysis to investigate the efficacy and safety profile of aripiprazole in treating BD. Two authors conducted systematic searches of PubMed and ScienceDirect from inception until May 14th, 2017. Randomized controlled trials (RCTs) of people with BD who received aripiprazole were included. A total of 20 RCTs met the eligibility criteria, including two which investigated the efficacy of aripiprazole versus haloperidol (aripiprazole=340; haloperidol=337), three which compared aripiprazole versus lithium (aripiprazole=208; lithium=212), and 15 with multiple comparisons of aripiprazole versus a placebo (aripiprazole=1923; placebo=1499). Compared to a placebo, aripiprazole improved acute mania (Hedges' g: -0.299, p=0.001) and psychosis (Hedges' g: -0.296, p<0.001) in the acute mania state, but did not improve depressive symptoms (Hedges' g: -0.127, p=0.054) in the acute depressive state. Aripiprazole was associated with lower relapse rates in bipolar mania when used in combination versus a placebo in maintenance therapy (odds ratio: 0.522, p<0.029). Aripiprazole was also associated with higher levels of high density lipoprotein, lower dropout rates, but no difference in extrapyramidal symptoms in the maintenance phase versus a placebo or in comparison with other medications (haloperidol or lithium). Our results suggest that aripiprazole is effective and safe in treating bipolar mania. Further trials are necessary to evaluate the efficacy and tolerability versus other medications. PMID- 28651937 TI - Postnatal steroids in extreme preterm infants: Intra-tracheal instillation using surfactant as a vehicle. AB - Chronic Lung Disease (CLD) is a common respiratory morbidity in survivors following extreme preterm birth, and is associated with adverse neurodevelopment in the long term. Besides demographics, multiple risk factors are implicated in the pathogenesis of CLD. However, early lung inflammation appears to be the common pathway that leads to the pathological and clinical changes observed in CLD. Postnatal use of systemic steroids has been successful in reducing the incidence of CLD but resulted in unacceptable adverse neurodevelopmental outcomes. The efficacy of inhaled steroids is not yet established. We review the evidence of tracheal instillation of steroids using surfactant as a lipid vehicle, including published data on drug distribution, in vitro physical studies, and clinical trials in animals and human infants. PMID- 28651939 TI - Competitive flow in coronary bypass surgery: The roles of fractional flow reserve and arterial graft configuration. PMID- 28651938 TI - Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve. AB - OBJECTIVE: Congenital bicuspid aortic valve (BAV) is distinctly associated with the development of ascending aortopathy in adulthood, portending risk of both ascending aortic aneurysm and dissection. Our previous work implicated deficiency in oxidative stress response as a mediator of the BAV-associated aortopathy. We hypothesize that reactive oxygen species generation invokes elevated local oxidative tissue damage in ascending aorta of patients with BAV. METHODS: Ascending aortic specimens were obtained from patients undergoing elective aortic replacement and/or aortic valve replacement and during heart transplant operations. Levels of superoxide anion were measured via high-pressure liquid chromatography-based detection of 2-hydroxyethidium in aortic specimens. Lipid peroxidation and enzymatic activity of superoxide dismutase and peroxidase were quantified in aortic specimens. RESULTS: Superoxide anion production was elevated in aortic specimens from patients with nonaneurysmal BAV (n = 59) compared with specimens from patients with the morphologically normal tricuspid aortic valve (TAV, n = 38). Total superoxide dismutase activity was similar among aortic specimens from patients with TAV versus BAV (n = 27 and 26, respectively), whereas peroxidase activity was increased in aortic specimens from patients with BAV compared with specimens from patients with TAV (n = 14 for both groups). Lipid peroxidation was elevated in aortic specimens from BAV patients compared with TAV patients (n = 14 and 11, respectively). CONCLUSIONS: Superoxide anion accumulation and increased lipid peroxidation demonstrate that, despite increased peroxidase activity, the ascending aortopathy of patients with BAV involves oxidative stress. In addition, the absence of increased superoxide dismutase activity in BAV specimens indicates a deficiency in antioxidant defense. This suggests that the characteristic smooth muscle cell loss observed in BAV aortopathy may be a consequence of superoxide-mediated cell damage. PMID- 28651941 TI - Discussion. PMID- 28651940 TI - Comparison of outcomes between muscle-sparing thoracotomy and video-assisted thoracic surgery in patients with cT1 N0 M0 lung cancer. AB - OBJECTIVE: To compare short-term complications and long-term survival outcomes between muscle-sparing thoracotomy (MST) and video-assisted thoracic surgery (VATS) groups using a propensity-score matching process. METHODS: One thousand eighty-three patients with cT1 N0 M0 lung cancer from January 2009 to December 2014 who underwent lobectomy and a systematic lymph node dissection were retrospectively included, and statistical analyses including a propensity-score matching process were used to compare short-term and long-term outcomes. RESULTS: Before propensity-score matching, for short-term surgical outcomes, the VATS group had fewer chest tube dwelling days (P < .001), less chest tube output (P < .001), shorter hospital stay, and fewer postoperative complications (P = .015). For long-term survival outcomes, the VATS group had a longer recurrence-free survival (P < .001) and overall survival (P < .001). After propensity-score matching, for short-term surgical outcomes, the VATS group had fewer chest tube dwelling days (P < .001), less chest tube output (P < .001), shorter hospital stay (P = .002), and fewer postoperative complications (P = .008). There was no difference in recurrence-free survival and overall survival between the 2 groups (P = .158 and P = .639, respectively). CONCLUSIONS: VATS is less invasive and is associated with shorter length of hospital stay and fewer postoperative complications. The 2 surgical approaches have equivalent long-term survival outcomes. PMID- 28651942 TI - Mitral valve repair for functional regurgitation: Do not miss the last piece of the puzzle! PMID- 28651943 TI - The #NYerORCoverChallenge: What it means for women in cardiothoracic surgery. PMID- 28651944 TI - WITHDRAWN: Advanced thoracoscopy: What is the critical information in case reports and how do we achieve the next level? AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28651945 TI - "Return to sender" or "consider it done"?! The importance of reducing hospital readmission after coronary artery bypass grafting. PMID- 28651946 TI - Layered smooth muscle cell-endothelial progenitor cell sheets derived from the bone marrow augment postinfarction ventricular function. AB - OBJECTIVE: The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of their natural biologic foundation, namely smooth muscle pericytes. We hypothesized that joint delivery of EPCs and smooth muscle cells (SMCs) in a novel, totally bone marrow-derived cell sheet will mimic the native architecture of a mature blood vessel and act as an angiogenic construct to limit post infarction ventricular remodeling. METHODS: Primary EPCs and mesenchymal stem cells were isolated from bone marrow of Wistar rats. Mesenchymal stem cells were transdifferentiated into SMCs by culture on fibronectin-coated culture dishes. Confluent SMCs topped with confluent EPCs were detached from an Upcell dish to create a SMC-EPC bi-level cell sheet. A rodent model of ischemic cardiomyopathy was then created by ligating the left anterior descending artery. Rats were randomized into 3 groups: cell sheet transplantation (n = 9), no treatment (n = 12), or sham surgery control (n = 7). RESULTS: Four weeks postinfarction, mature vessel density tended to increase in cell sheet-treated animals compared with controls. Cell sheet therapy significantly attenuated the extent of cardiac fibrosis compared with that of the untreated group (untreated vs cell sheet, 198 degrees [interquartile range (IQR), 151-246 degrees] vs 103 degrees [IQR, 92-113 degrees], P = .04). Furthermore, EPC-SMC cell sheet transplantation attenuated myocardial dysfunction, as evidenced by an increase in left ventricular ejection fraction (untreated vs cell sheet vs sham, 33.5% [IQR, 27.8%-35.7%] vs 45.9% [IQR, 43.6%-48.4%] vs 59.3% [IQR, 58.8%-63.5%], P = .001) and decreases in left ventricular dimensions. CONCLUSIONS: The bone marrow derived, spatially arranged SMC-EPC bi-level cell sheet is a novel, multilineage cellular therapy obtained from a translationally practical source. Interactions between SMCs and EPCs augment mature neovascularization, limit adverse remodeling, and improve ventricular function after myocardial infarction. PMID- 28651947 TI - Molecular identification and characterization of piroplasm species in Hokkaido sika deer (Cervus nippon yesoensis), Japan. AB - Babesia and Theileria species are tick-borne protozoan parasites that have a veterinary and zoonotic importance. In order to investigate the prevalence and genetic diversity of these parasites, a total of 269 sika deer blood DNA samples collected from Hokkaido, Japan, were examined for Babesia and Theileria species by touch-down PCR targeting the 18S rRNA gene. Reverse line blot (RLB) hybridization was then used to detect 12 piroplasm species. The results revealed that 95.5% (257/269), 94.1% (253/269), 14.1% (38/269), 87.7% (236/269) and 11.5% (31/269) of the examined PCR products hybridized with the probes which were designed to detect all Babesia and Theileria spp., all Theileria spp., all Babesia spp., Theileria sp. Thrivae and Babesia divergens-like, respectively. The 18S rRNA gene partial sequences were divided into Theileria sp. Thrivae, T. capreoli, B. divergens-like and an undescribed Babesia species. This study showed the first detection of the undescribed Babesia sp. from Japan. Therefore, more studies are required to understand the ecology of the newly detected tick-borne pathogens in Hokkaido. PMID- 28651948 TI - Genetic sharing with coronary artery disease identifies potential novel loci for bone mineral density. AB - Bone mineral density (BMD) is a complex trait with high missing heritability. Numerous evidences have shown that BMD variation has a relationship with coronary artery disease (CAD). This relationship may come from a common genetic basis called pleiotropy. By leveraging the pleiotropy with CAD, we may be able to improve the detection power of genetic variants associated with BMD. Using a recently developed conditional false discovery rate (cFDR) method, we jointly analyzed summary statistics from two large independent genome wide association studies (GWAS) of lumbar spine (LS) BMD and CAD. Strong pleiotropic enrichment and 7 pleiotropic SNPs were found for the two traits. We identified 41 SNPs for LS BMD (cFDR<0.05), of which 20 were replications of previous GWASs and 21 were potential novel SNPs that were not reported before. Four genes encompassed by 9 cFDR-significant SNPs were partially validated in the gene expression assay. Further functional enrichment analysis showed that genes corresponding to the cFDR-significant LS BMD SNPs were enriched in GO terms and KEGG pathways that played crucial roles in bone metabolism (adjP<0.05). In protein-protein interaction analysis, strong interactions were found between the proteins produced by the corresponding genes. Our study demonstrated the reliability and high-efficiency of the cFDR method on the detection of trait-associated genetic variants, the present findings shed novel insights into the genetic variability of BMD as well as the shared genetic basis underlying osteoporosis and CAD. PMID- 28651949 TI - gammadelta T-cell function is inhibited in end-stage renal disease and impacted by latent tuberculosis infection. AB - Patients with end-stage renal disease (ESRD) are at elevated risk of acquiring infectious diseases, including tuberculosis (TB). Inflammation and uremia negatively impact immune function in this population, but specific pathways involved in TB immunity have not been identified. Although gammadelta T cells are known to contribute to protection from TB, their phenotype and function in patients with ESRD is relatively unknown. To determine this we recruited 20 patients with and 20 without ESRD (controls), with or without latent TB infection to assess gammadelta T cell frequency, surface phenotype, and cytokine production by flow cytometry in response to stimulation. gammadelta T cells derived from patients with ESRD exhibited significantly lower expression of CCR5, CXCR3, and CD26 compared to controls. Furthermore, patients with ESRD, particularly the group with latent TB infection, exhibited poor IFNgamma, TNFalpha, and GMCSF responses to stimulation with either phosphoantigen HMB-PP, IL-12/IL-18, E. coli, or phorbol myristate acetate and ionomycin. Similar dysfunctional responses were observed in patients with active TB. Surprisingly, neither the gammadelta phenotype nor its function was associated with plasma markers of inflammation or microbial translocation. Thus, there is significant perturbation of the gammadelta T-cell population in patients with ESRD, particularly in those with latent TB infection. PMID- 28651951 TI - Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. AB - Anemia is a common complication of chronic kidney disease and is mainly caused by the inability of injured kidneys to produce adequate amounts of erythropoietin. Studies elucidating the regulation of erythropoietin production led to the identification of hypoxia-inducible factor (HIF), which activates the transcription of genes that mediate adaptive responses to hypoxia. HIF is a heterodimer that consists of an alpha and beta subunit. While HIF-beta is constitutively expressed, HIF-alpha is subjected to ubiquitination and proteasomal degradation under normoxic conditions. This process is mediated by prolyl hydroxylase domain proteins, the inhibition of which results in an increased expression of hypoxia-induced genes, including erythropoietin. These findings led to the development of prolyl hydroxylase domain inhibitors as novel therapeutic agents against anemia in chronic kidney disease. Prolyl hydroxylase domain inhibition improves iron metabolism, which also contributes to erythropoiesis. To date, at least 6 small-molecule inhibitors of the prolyl hydroxylase domain have been tested in humans, and clinical trials have shown that they are effective without causing serious adverse events. However, there is a theoretical concern that the systemic activation of HIF could also induce deleterious effects such as tumorigenesis and severe pulmonary hypertension, which demands careful assessments in future clinical studies. PMID- 28651952 TI - Lung Ultrasound in Pneumothorax: The Continuing Need for Appropriate Use and Correct Interpretation. PMID- 28651950 TI - The loss of Kruppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis. AB - Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to the progression of kidney fibrosis. Although canonical Wnt signaling can trigger the activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Kruppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression are reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis. Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15fl/fl mice and accompanied by the activation of Wnt/beta-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/beta-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho-beta-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/beta-catenin pathway. PMID- 28651953 TI - Ventricular Tachycardia Caused by Ibrutinib. PMID- 28651954 TI - Case Report: Ultrasound-Guided Infraclavicular Brachial Plexus Block for a Case with Posterior Elbow Dislocation. AB - BACKGROUND: The interest in regional anesthesia procedures for the management of upper-extremity emergencies has increased. Toward that end, supraclavicular, interscalene, or infraclavicular approaches, with or without ultrasound guidance, are used for brachial plexus nerve blocks. Although many studies have reported on the use of ultrasound-guided supraclavicular and interscalene brachial plexus blocks for upper-extremity dislocations, very few studies have reported on the use of ultrasound-guided infraclavicular brachial plexus blocks. CASE REPORT: We present an adult patient with posterior elbow dislocation that is treated with reduction after applying an ultrasound-guided infraclavicular brachial plexus block. Additionally, we describe the infraclavicular block in detail and demonstrate the technique using images. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Based on our experience, the ultrasound-guided infraclavicular block is a fast, safe, and efficient anesthesia technique that can be an excellent alternative to sedoanalgesia and other brachial plexus blocks for the management of elbow dislocations in the emergency department. PMID- 28651956 TI - RE: A Practical Approach to the Ethanol-Intoxicated Patient in the Emergency Department. PMID- 28651955 TI - Heaton et al. Reply to Rich. PMID- 28651957 TI - Syringomyelia. PMID- 28651958 TI - Conception by means of in vitro fertilization is not associated with maternal depressive symptoms during pregnancy or postpartum. AB - OBJECTIVE: To study whether conception by means of in vitro fertilization (IVF) is associated with maternal depressive symptoms during pregnancy or postpartum. DESIGN: Longitudinal observational study. SETTING: University hospital. PATIENT(S): A total of 3,283 women with singleton pregnancies receiving antenatal care and delivering in Uppsala from 2010 to 2015. INTERVENTION(S): A web-based self-administered structured questionnaire including sociodemographic, clinical and pregnancy-related items, and the Edinburgh Postnatal Depression Scale (EPDS) was delivered at 17 and 32 gestational weeks and at 6 weeks and 6 months postpartum. MAIN OUTCOME MEASURE(S): Prevalence of significant depressive symptoms (EPDS >=12) and EPDS scores. RESULT(S): A total of 167 women (5%) had conceived via IVF and 3,116 (95%) had a spontaneous pregnancy. IVF mothers were more frequently >=35 years of age (46.1% vs. 22.6%) and primiparous (71.7% vs. 49.9%) and had a higher cesarean delivery rate (22.4% vs. 14.2%). Demographic and clinical characteristics were otherwise similar between the two groups. Significant depressive symptoms were reported by 12.8%, 12.4%, 13.8%, and 11.9% of women at 17 and 32 gestational weeks and 6 weeks and 6 months postpartum, respectively. The prevalence of depressive symptoms and the EPDS scores during pregnancy and postpartum were similar between women conceiving spontaneously or through IVF. The mode of conception was not associated with significant depressive symptoms at any time point, even when adjusting for several possible confounders in multivariable logistic regression analysis. CONCLUSION(S): Despite the psychologic distress characterizing subfertility and its treatment, conception by means of IVF is not associated with maternal depressive symptoms during pregnancy or postpartum. PMID- 28651959 TI - Patients with endometriosis have aneuploidy rates equivalent to their age-matched peers in the in vitro fertilization population. AB - OBJECTIVE: To determine whether endometriosis ultimately results in an increased risk of embryonic aneuploidy. DESIGN: Retrospective cohort. SETTING: Infertility clinic. PATIENT(S): Patients participating in an in vitro fertilization (IVF) cycle from 2009-2015 using preimplantation genetic screening (PGS) who had endometriosis identified by surgical diagnosis or by ultrasound findings consistent with a persistent space-occupying disease whose sonographic appearance was consistent with endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rate of aneuploidy in endometriosis patients undergoing IVF compared to controls without endometriosis undergoing IVF. RESULT(S): There were 305 patients with endometriosis who produced 1,880 blastocysts that met the criteria for inclusion in the endometriosis group. The mean age of the patients with endometriosis was 36.1 +/- 3.9 years. When the aneuploidy rates in patients with endometriosis and aneuploidy rates in patients without endometriosis were stratified by Society for Assisted Reproductive Technology age groups and compared, there were no statistically significant differences in the rate of aneuploidy (odds ratio 0.85; 95% confidence interval, 0.84-0.85). CONCLUSION(S): Patients with endometriosis undergoing IVF have aneuploidy rates equivalent to their age-matched peers in IVF population who do not have endometriosis. PMID- 28651960 TI - Humid versus dry incubator: a prospective, randomized, controlled trial. AB - OBJECTIVE: To evaluate the efficacy of a dry versus humidified incubator on human embryo development ex vivo. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Private fertility centers. PATIENT(S): A total of 297 women undergoing in vitro fertilization randomized into two groups. INTERVENTION(S): From days 0 to day 5 or 6 of culture, intervention group embryos exposed to dry culture and control group embryos exposed to humidified culture. MAIN OUTCOME MEASURE(S): Subsequent ongoing pregnancy rate. RESULT(S): After transfer of embryos, there were statistically significantly lower rates of clinical and ongoing pregnancy in the dry culture arm than in the humidified culture arm (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.36-0.91; versus OR 0.54; 95% CI, 0.34-0.85). On day 3 of culture, embryo quality and compaction were lower in the dry culture group (OR 0.38; 95% CI, 0.32-0.45) than in the group exposed to humidified culture (OR 0.23; 95% CI, 0.19-0.27). On day 5 of culture, embryos in dry culture had a lower rate of blastocyst formation (OR 0.39; 95% CI, 0.33-0.46), quality (OR 0.34; 95% CI, 0.29-0.40), and cryopreservation (OR 0.41; 95% CI, 0.35-0.48). CONCLUSION(S): In this study, human embryos cultivated ex vivo in a dry incubator had statistically significantly decreased implantation and clinical and ongoing pregnancy rates. Our findings indicate the need for larger multicenter, randomized, controlled trials. CLINICAL TRIAL REGISTRATION NUMBER: NCT01695096. PMID- 28651961 TI - Endometriosis and risk of embryonic aneuploidy? PMID- 28651962 TI - Fatty acid composition of free-living and parasitic stages of the bovine lungworm Dictyocaulus viviparus. AB - The development of parasitic nematodes proceeds via multiple stages, often implicating the necessity to adapt to different environments. Especially the transition from free-living to parasitic stages is accompanied by a significant change in the environmental conditions. To shed light on possible adaptations to these transitions, the fatty acid composition of different developmental stages of the bovine lungworm Dictyocaulus viviparus was investigated. Fatty acids of D. viviparus eggs, the free-living first, second and third larval stage (L1-L3) as well as the parasitic preadult stage and adult male and female worms residing in the lungs of infected hosts were quantified by gas chromatography after transesterification to their fatty acid methyl esters. The fatty acid content and diversity were higher in parasitic stages compared to those of free-living larvae. The most prevalent fatty acids in both parasitic and free-living stages were stearic (C18:0), palmitic (C16:0), palmitoleic (C16:1) and caprylic acid (C8:0). A variety of (poly-)unsaturated FAs was found in the parasitic stages and in the eggs, which was similar to the variety of FAs found in bovine surfactant. This finding indicates that parasitic stages of D. viviparus take up FAs from their environment. While eggs contained the highest concentration of fatty acids, a decrease was observed from eggs to L1 and further from L2 to L3. The lowest concentration was found in 38-days-old L3, which suggests that FAs serve as an energy reserve for the free-living, non-feeding larval stages. The free-living larvae contained mainly saturated fatty acids and only traces of unsaturated fatty acids, which is in contrast to the phospholipid saturation hypothesis of cold tolerance. Instead, a trade-off between desiccation stress and temperature adaptation may favour a higher amount of saturated FAs in the free-living larval stages. Further studies explicitly examining the FA composition of the different classes of lipids are necessary to better describe the adaptative responses of the FA metabolism to different environmental conditions. PMID- 28651963 TI - Conversion of procyclic-form Trypanosoma brucei to the bloodstream form by transient expression of RBP10. AB - Bloodstream-form Trypanosoma brucei can lose the ability to differentiate to the procyclic form during prolonged in vitro culture. This can pose a problem during complicated genetic manipulation experiments, especially when the differentiation phenotype is under investigation. Ideally, to preserve differentiation competence, parasites should be cycled after every genetic manipulation step. Conversion of bloodstream-form Trypanosoma brucei to the procyclic form in vitro is routine, but conversion of procyclic forms to bloodstream forms has hitherto only been achieved in transgenic parasites with tetracycline-inducible expression of proteins with RNA-binding domains - either RBP6 or RBP10. This method, however, requires use of a selectable marker which might be needed for other purposes, and restricts options for tetracycline-inducible expression or repression of other genes. A simple method for inter-conversion that does not require permanent genetic manipulation would therefore be useful. Induced expression of RBP10 in procyclic forms gives faster differentiation than expression of RBP6, with a switch towards bloodstream forms within 48h. We here show that bloodstream forms can be obtained by transient transfection of procyclic forms with a circular plasmid designed for expression of RBP10 from an rRNA promoter. This method enables routine cycling of T. brucei without permanent genetic manipulation. PMID- 28651964 TI - Protein network construction using reverse phase protein array data. AB - In this paper, we introduce a novel computational method for constructing protein networks based on reverse phase protein array (RPPA) data to identify complex patterns in protein signaling. The method is applied to phosphoproteomic profiles of basal expression and activation/phosphorylation of 76 key signaling proteins in three breast cancer cell lines (MCF7, LCC1, and LCC9). Temporal RPPA data are acquired at 48h, 96h, and 144h after knocking down four genes in separate experiments. These genes are selected from a previous study as important determinants for breast cancer survival. Interaction networks are constructed by analyzing the expression levels of protein pairs using a multivariate analysis of variance model. A new scoring criterion is introduced to determine relevant protein pairs. Through a network topology based analysis, we search for wiring patterns to identify key proteins that are associated with significant changes in expression levels across various experimental conditions. PMID- 28651966 TI - RNAcompete-S: Combined RNA sequence/structure preferences for RNA binding proteins derived from a single-step in vitro selection. AB - RNA-binding proteins recognize RNA sequences and structures, but there is currently no systematic and accurate method to derive large (>12base) motifs de novo that reflect a combination of intrinsic preference to both sequence and structure. To address this absence, we introduce RNAcompete-S, which couples a single-step competitive binding reaction with an excess of random RNA 40-mers to a custom computational pipeline for interrogation of the bound RNA sequences and derivation of SSMs (Sequence and Structure Models). RNAcompete-S confirms that HuR, QKI, and SRSF1 prefer binding sites that are single stranded, and recapitulates known 8-10bp sequence and structure preferences for Vts1p and RBMY. We also derive an 18-base long SSM for Drosophila SLBP, which to our knowledge has not been previously determined by selections from pure random sequence, and accurately discriminates human replication-dependent histone mRNAs. Thus, RNAcompete-S enables accurate identification of large, intrinsic sequence structure specificities with a uniform assay. PMID- 28651965 TI - Single molecule fluorescence in situ hybridisation for quantitating post transcriptional regulation in Drosophila brains. AB - RNA in situ hybridization is a powerful method to investigate post transcriptional regulation, but analysis of intracellular mRNA distributions in thick, complex tissues like the brain poses significant challenges. Here, we describe the application of single-molecule fluorescent in situ hybridization (smFISH) to quantitate primary nascent transcription and post-transcriptional regulation in whole-mount Drosophila larval and adult brains. Combining immunofluorescence and smFISH probes for different regions of a single gene, i.e., exons, 3'UTR, and introns, we show examples of a gene that is regulated post-transcriptionally and one that is regulated at the level of transcription. Our simple and rapid protocol can be used to co-visualise a variety of different transcripts and proteins in neuronal stem cells as well as deep brain structures such as mushroom body neuropils, using conventional confocal microscopy. Finally, we introduce the use of smFISH as a sensitive alternative to immunofluorescence for labelling specific neural stem cell populations in the brain. PMID- 28651967 TI - Improving the response to toxic inhalation disasters. PMID- 28651968 TI - Sodium P-aminosalicylic acid inhibits sub-chronic manganese-induced neuroinflammation in rats by modulating MAPK and COX-2. AB - Excessive manganese (Mn) accumulation in the brain may induce an extrapyramidal disorder known as manganism. Inflammatory processes play a critical role in neurodegenerative diseases. Therapeutically, non-steroidal anti-inflammatory drugs or analogous anti-inflammatory therapies have neuroprotective effects. As a non-steroidal anti-inflammatory drug, p-aminosalicylic acid (PAS) has anti inflammatory effects, which are mediated by decreased prostaglandins E2 (PGE2) levels. The aim of the current study was to investigate whether PAS-Na treatment prevents Mn-induced behavioral changes and neuroinflammation in vivo. Male Sprague-Dawley rats were intraperitoneally (i.p.) injected with MnCl2.4H2O (15mg/kg) for 12 weeks, followed by 6 weeks PAS-Na treatment. Sub-chronic Mn exposure increased Mn levels in the whole blood, cortex, hippocampus and thalamus, and induced learning and memory deficits, concomitant with astrocytes activation in the cortex, hippocampus and thalamus. Moreover inflammatory cytokine levels in serum and brain of Mn-treated group were increased, including IL-1beta, IL-6, TNF-alphaand PGE2, especially in the hippocampus and thalamus. Furthermore, sub-chronic Mn exposure also increased inflammatory cytokines and COX-2 in transcription levels concomitant with increased MAPK signaling and COX-2 in the same selected brain regions. PAS-Na treatment at the highest doses also decreased Mn levels in the whole blood and selected brain tissues, and reversed the Mn-induced learning and memory deficits. PAS-Na inhibited astrocyte activation as well as the Mn-induced increase in inflammatory cytokine levels, reducing p38, ERK MAPK pathway and COX-2 activity. In contrast PAS-Na had no effects on the JNK MAPK pathway. These data establish the efficacy of PAS-Na not only as a chelating agent to mobilize whole blood Mn, but also as an anti inflammatory agent. PMID- 28651969 TI - Projectivity is the mathematical code of syntax: Comment on "Dependency distance: A new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28651970 TI - Towards a theory of word order: Comment on "Dependency distance: a new perspective on syntactic patterns in natural language" by Haitao Liu et al. PMID- 28651971 TI - Randomised controlled trial of a text messaging intervention for reducing processed meat consumption: The mediating roles of anticipated regret and intention. AB - The present study aimed to extend the literature on text messaging interventions involved in promoting healthy eating behaviours. The theoretical framework was the Theory of Planned Behaviour (TPB). A randomized controlled trial was used to test the impact of daily text messages compared to no message (groups) for reducing processed meat consumption (PMC) over a 2 week period, testing the sequential mediation role of anticipated regret and intention on the relationship between groups and PMC reduction. PMC and TPB variables were assessed both at Time 1 and Time 2. Participants were Italian undergraduates (at Time 1 N = 124) randomly allocated to control and message condition groups. Undergraduates in the message condition group received a daily SMS, which focused on anticipated regret and urged them to self-monitor PMC. Participants in the control group did not receive any message. Those who completed all measures at both time points were included in the analyses (N = 112). Findings showed that a daily messaging intervention, controlling for participants' past behaviour, reduced self-reported consumption of PMC. Mediation analyses indicated partial serial mediation via anticipated regret and intentions. The current study provided support for the efficacy of a daily messaging intervention targeting anticipated regret and encouraging self-monitoring in decreasing PMC. Outcomes showed the important mediating role of anticipated regret and intentions for reducing PMC. PMID- 28651972 TI - Consumption of key food groups during the postpartum period in low-income, non Hispanic black mothers. AB - The postpartum period can impact diet quality and subsequently place women at greater risk for overweight or obesity. This study examined consumption of key food groups during the first 2 years postpartum among low income, non-Hispanic black, first-time mothers. Data were from the Infant Care, Feeding and Risk of Obesity Study, a cohort of 217 mother-infant dyads, followed from 3 to 18 months postpartum, collected from 2003 to 2007. At each study visit (3, 6, 9, 12, and 18 months) 24-h dietary recalls were collected. Consumption levels were compared to those recommended from the 2010 Dietary Guidelines for Americans (DGAs) for each of the following food groups: fruits, vegetables, grains, whole grains, protein foods and dairy, as well as an estimated upper limit for sugar-sweetened beverage (SSB) consumption. At each time point, mothers met recommended intake levels for grains and protein foods only. In random-intercept logistic regression models, no demographic or household characteristics were associated with a likelihood of consuming recommended levels for any of the food groups according to the DGAs. Given the low intake of fruits, vegetables, whole grains and lean protein foods and high intake of SSBs and refined grains, interventions targeting women's diet during the postpartum period are warranted. PMID- 28651973 TI - 1,25(OH)2D3 disrupts glucose metabolism in prostate cancer cells leading to a truncation of the TCA cycle and inhibition of TXNIP expression. AB - Prostate cell metabolism exhibits distinct profiles pre- and post-malignancy. The malignant metabolic shift converts prostate cells from "citrate-producing" to "citrate-oxidizing" cells, thereby enhancing glucose metabolism, a phenotype that contrasts classical tumoral Warburg metabolism. An on-line biosensor chip system (BIONAS 2500) was used to monitor metabolic changes (glycolysis and respiration) in response to the putative anti-cancer nutraceutical 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], in different prostate cancer (PCa) cell lines (LNCaP, VCaP, DU145 and PC3). LNCaP cells exhibited profound metabolic responsiveness to the treatment and thus extensive analysis of metabolism-modulating effects of 1,25(OH)2D3 were performed, including mRNA expression analysis of key metabolic genes (e.g. GLUT1 and PDHK1), analysis of TCA cycle metabolites, glucose uptake/consumption measurements, ATP production, and mitochondrial biogenesis/activity. Altogether, data demonstrate a vivid disruption of glucose metabolism by 1,25(OH)2D3, illustrated by a decreased glucose uptake and an accumulation of citrate/isocitrate due to TCA cycle truncation. Depletion of glycolytic intermediates led to a consistent decrease in TXNIP expression in response to 1,25(OH)2D3, an effect that coincided with the activation of AMPK signaling and a reduction in c-MYC expression. Reduction in TXNIP levels in response to 1,25(OH)2D3 was rescued by an AMPK signaling inhibitor and mimicked by a MYC inhibitor highlighting the possible involvement of both pathways in mediating 1,25(OH)2D3's metabolic effects in PCa cells. Furthermore, pharmacological and genetic modulation of the androgen receptor showed similar and disparate effects on metabolic parameters compared to 1,25(OH)2D3 treatment, highlighting the AR-independent nature of 1,25(OH)2D3's metabolism-modulating effects. PMID- 28651974 TI - Variants of PpuLcc, a multi-dye decolorizing laccase from Pleurotus pulmonarius expressed in Pichia pastoris. AB - A laccase of the basidiomycete Pleurotus pulmonarius (PpuLcc) possessed strong decolorizing abilities towards artificial and natural dyes. The PpuLcc was purified from the culture supernatant via FPLC, and the corresponding gene cloned and expressed in Pichia pastoris GS115. To examine the impact of the C-terminal tail region and the signal peptide on the recombinant expression of PpuLcc, a non modified version or different truncations (-2, -5, -13 AA) of the target protein were combined with different secretion signals. Heterologous expression of codon optimized constructs resulted in extracellular activities of the PpuLcc variants of up to 7000 U L-1 (substrate ABTS) which was six times higher than non-codon optimized constructs. In contrast to previous works, altering the C-terminal end of the protein did not influence kinetic parameters or the rate of expression. The His-Tag purified enzymes showed high temperature optima (50-70 degrees C) and thermo stability. All of the recombinant variants degraded triarylmethane and azo dyes. Rapid bleaching of beta-carotene (E 160a) and the polyene acid norbixin (E 160b) using a laccase was found for the first time. Thus, the enzyme may be useful in decolorizing unwanted polyene pigments, for example from the processing of cheese, bakery, desserts, ice cream or coloured casings. PMID- 28651975 TI - Production of coagulation factor VII in human cell lines Sk-Hep-1 and HKB-11. AB - Recombinant factor VII (rFVII) is the main therapeutic choice for hemophilia patients who have developed inhibitory antibodies against conventional treatments (FVIII and FIX). Because of the post-translational modifications, rFVII needs to be produced in mammalian cell lines. In this study, for the first time, we have shown efficient rFVII production in HepG2, Sk-Hep-1, and HKB-11 cell lines. Experiments in static conditions for a period of 96 h showed that HepG2-FVII produced the highest amounts of rhFVII, with an average of 1843 ng/mL. Sk-hep-1 FVII cells reached a maximum protein production of 1432 ng/mL and HKB-11-FVII cells reached 1468 ng/mL. Sk-Hep-1-rFVII and HKB-11-rFVII were selected for the first step of scale-up. Over 10 days of spinner flask culture, HKB-11 and SK-Hep 1 cells showed a cumulative production of rFVII of 152 MUg and 202.6 MUg in 50 mL, respectively. Thus, these human cell lines can be used for an efficient production of recombinant FVII. With more investment in basic research, human cell lines can be optimized for the commercial production of different bio therapeutic proteins. PMID- 28651976 TI - Observational Learning During Simulation-Based Training in Arthroscopy: Is It Useful to Novices? AB - OBJECTIVE: Observing experts constitutes an important and common learning experience for surgical residents before operating under direct guidance. However, studies suggest that exclusively observing experts may induce suboptimal motor learning, and watching errors from non-experts performing simple motor tasks may generate better performance. We investigated whether observational learning is transferrable to arthroscopy learning using virtual reality (VR) simulation. SETTING/DESIGN: In our surgical simulation laboratory, we compared students learning basic skills on a VR arthroscopy simulator after watching an expert video demonstration of VR arthroscopy tasks or a non-expert video demonstration of the same tasks to a Control group without video demonstration. Ninety students in 3 observing groups (expert, non-expert, and Control) subsequently completed the same procedure on a VR arthroscopy simulator. We hypothesized the non-expert-watching group would outperform the expert-watching group, and both groups to outperform the Control group. We examined performance pretest, posttest, and 1 week later. PARTICIPANTS: Participants were recruited from the final year of medical school and the very early first year of surgical residency training programs (orthopaedic surgery, urology, plastic surgery, and general surgery) at Western University (Ontario, Canada). RESULTS: All participants improved their overall performance from pretest to retention (p < 0.001). At initial retention testing, non-expert-watching group outperformed the other groups in camera path length p < 0.05 and time to completion, p < 0.05, and both the expert/non-expert groups surpassed the Control group in camera path length (p < 0.05). CONCLUSION: We suggest that error-observation may contribute to skills improvement in the non-expert-watching group. Allowing novices to observe techniques/errors of other novices may assist internalization of specific movements/skills required for effective motor performances. This study highlights the potential effect of observational learning on surgical skills acquisition and offers preliminary evidence for peer-based practice (combined non-experts and experts) as a complementary surgical motor skills training strategy. PMID- 28651977 TI - Dexamethasone, Intravenous Immunoglobulin, and Rituximab Combination Immunotherapy for Pediatric Opsoclonus-Myoclonus Syndrome. AB - BACKGROUND: Although pulse-dose dexamethasone is increasingly favored for treating pediatric opsoclonus-myoclonus syndrome (OMS), and multimodal immunotherapy is associated with improved clinical response, there have been no neuroimmunologic studies of dexamethasone-based multimodal disease-modifying therapy. METHODS: In this observational retrospective study, 19 children with OMS (with or without associated neuroblastoma) underwent multibiomarker evaluation for neuroinflammation. Nine children of varying OMS severity, duration, and treatment status were treated empirically with pulse dexamethasone, intravenous immunoglobulin (IVIg), and rituximab combination immunotherapy (DEXIR-CI). Another 10 children on dexamethasone alone or with IVIg at initial evaluation only provided a comparison group. Motor severity (total score) was scored rater blinded via videotapes using the validated OMS Evaluation Scale. RESULTS: DEXIR CI was associated with a 69% reduction in group total score (P = 0.004) and was clinically well tolerated. Patients given the dexamethasone combination exhibited significantly lowered B cell frequencies in cerebrospinal fluid (-94%) and blood (-76%), normalizing the cerebrospinal fluid B cell percentage. The number of patients with positive inflammatory markers dropped 87% (P = 0.002) as did the number of markers. Cerebrospinal fluid oligoclonal bands were positive in four of nine pretreatment patients but zero of six post-treatment patients. In the comparison group, partial response to dexamethasone alone or with IVIg was associated with multiple positive markers for neuroinflammation despite an average of seven months of treatment. CONCLUSIONS: Multimechanistic dexamethasone based combination immunotherapy increases the therapeutic armamentarium for OMS, providing a viable option for less severely affected individuals. Partial response to dexamethasone with or without IVIg is indicative of ongoing neuroinflammation and should be treated promptly and accordingly. PMID- 28651978 TI - Changes in Cerebral Oxygenation in Preterm Infants With Progressive Posthemorrhagic Ventricular Dilatation. AB - BACKGROUND: Optimal timing of intervention in neonatal progressive posthemorrhagic hydrocephalus is often a difficult decision. Unchecked hydrocephalus can lead to irreversible brain injury through impaired perfusion, while placement of a shunt is not without long-term morbidity. The purpose of this study was to assess the use of near-infrared spectroscopy to measure changes in regional cerebral oxygen saturation as an indicator of cerebral perfusion in infants with progressive posthemorrhagic ventricular dilatation. METHODS: Near infrared spectroscopy was used to measure regional cerebral oxygen saturation for more than a one-hour period in infants within 24 hours of cranial ultrasound. Simultaneous pulse oximetry was recorded and oxygen extraction was calculated. Ventricular size was measured by ultrasound using the frontal-occipital horn ratio and compared with average oxygen saturation and oxygen extraction. Statistical analysis was done using the Spearman rank test and analysis of variance. RESULTS: Ventricular measurements were made in 20 very low birth weight premature infants with periventricular-intraventricular hemorrhage and 12 infants with normal ultrasound scans. Ventricular dilatation was associated with lower cerebral oxygen saturation and higher oxygen extraction (P < 0.001). Progressive ventricular dilatation was inversely related to changes in cerebral oxygen saturation (P < 0.001). CONCLUSIONS: Progressive posthemorrhagic ventricular dilatation is associated with a significant decrease in cerebral oxygenation and increase in oxygen extraction suggesting a decrease in cerebral perfusion. Near infrared spectroscopy could potentially provide additional clinical information to assist in determining optimal timing of surgical intervention in preterm infants with progressive ventricular enlargement. PMID- 28651979 TI - Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate. AB - A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50=12nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application. PMID- 28651980 TI - Synthesis of 4- and 5-arylthiazolinethiones as inhibitors of indoleamine 2,3 dioxygenase. AB - Docking studies of 4-phenylthiazolinethione on human IDO1 suggest complexation of the heme iron by the exocyclic sulfur atom further reinforced by hydrophobic interactions of the phenyl ring within pocket A of the enzyme. On this basis, chemical modifications were proposed to increase inhibition activity. Synthetic routes had to be adapted and optimized to yield the desired substituted 4- and 5 arylthiazolinethiones. Their biological evaluation shows that 5-aryl regioisomers are systematically less potent than the corresponding 4-aryl analogs. Substitution on the phenyl ring does not significantly increase inhibition potency, except for 4-Br and 4-Cl derivatives. PMID- 28651981 TI - Synthesis and anthelmintic activity of arctigenin derivatives against Dactylogyrus intermedius in goldfish. AB - To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10mg/L. Compared to traditional drug praziquantel (EC50=2.69mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC50 values of 2.48 and 1.52mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC50 values of 2.13 and 2.07mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs. PMID- 28651982 TI - Design and optimization of highly-selective, broad spectrum fungal CYP51 inhibitors. AB - While the orally-active azoles such as fluconazole and posaconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver, and reproductive toxicities). Recently we described the rationally-designed, antifungal agent VT-1161 that is more selective for fungal CYP51 than related human CYP enzymes such as CYP3A4. Herein, we describe the use of a homology model of Aspergillus fumigatus to design and optimize a novel series of highly selective, broad spectrum fungal CYP51 inhibitors. This series includes the oral antifungal VT-1598 that exhibits excellent potency against yeast, dermatophyte, and mold fungal pathogens. PMID- 28651983 TI - Bioactivity-guided isolation of chemical constituents against H2O2-induced neurotoxicity on PC12 from Cimicifuga dahurica (Turcz.) Maxim. AB - Three new compounds (1, 6, 9), with six known compounds (2-5, 7-8) were obtained from water-soluble extract of Cimicifuga dahurica (Turcz.) Maxim. by bioactivity guided isolation. Their structures were elucidated by chemical and spectral analysis, including 1D, 2D NMR data and HRESIMS. H2O2-induced neurotoxicity on PC12 cells model were conducted to evaluate the neuro-protective capability of these compounds. The piscidic acid derivatives compounds 4-7 showed marked neuro protective effect at certain concentration. PMID- 28651984 TI - Synthesis of 6-hydroxyaurone analogues and evaluation of their alpha-glucosidase inhibitory and glucose consumption-promoting activity: Development of highly active 5,6-disubstituted derivatives. AB - A series of 6-hydroxyaurones and their analogues have been synthesized and evaluated for their in vitro alpha-glucosidase inhibitory and glucose consumption promoting activity. These compounds exhibited varying degrees of alpha glucosidase inhibitory activity, 11 of them showing higher potency than that of the control standard acarbose (IC50=50.30MUM). Surprisingly, analogues devoid of a substituent at C-2 but having an aryl group at C-5 were found to be highly active (e.g., 7f, IC50=9.88MUM). Docking analysis substantiated these findings. The kinetic analysis of compound 7f, the most potent alpha-glucosidase inhibitor of this study, revealed that it inhibited alpha-glucosidase in an irreversible and mixed competitive mode. In addition, compounds 7f and 10c exhibited significant glucose consumption promoting activity at 1MUM. PMID- 28651985 TI - Automatic Release of Radiology Reports via an Online Patient Portal. PMID- 28651986 TI - Educational Jazz. PMID- 28651987 TI - Management of the Incidental Renal Mass on CT: A White Paper of the ACR Incidental Findings Committee. AB - The ACR Incidental Findings Committee (IFC) presents recommendations for renal masses that are incidentally detected on CT. These recommendations represent an update from the renal component of the JACR 2010 white paper on managing incidental findings in the adrenal glands, kidneys, liver, and pancreas. The Renal Subcommittee, consisting of six abdominal radiologists and one urologist, developed this algorithm. The recommendations draw from published evidence and expert opinion and were finalized by informal iterative consensus. Each flowchart within the algorithm describes imaging features that identify when there is a need for additional imaging, surveillance, or referral for management. Our goal is to improve quality of care by providing guidance for managing incidentally detected renal masses. PMID- 28651988 TI - Management of Incidental Adrenal Masses: A White Paper of the ACR Incidental Findings Committee. AB - The ACR Incidental Findings Committee presents recommendations for managing adrenal masses that are incidentally detected on CT or MRI. These recommendations represent an update to the adrenal component of the JACR 2010 white paper on managing incidental findings in the adrenal glands, kidneys, liver, and pancreas. The Adrenal Subcommittee, constituted by abdominal radiologists and an endocrine surgeon, developed this algorithm. The algorithm draws from published evidence coupled with expert subspecialist opinion and was finalized by a process of iterative consensus. Algorithm branches categorize incidental adrenal masses on the basis of patient characteristics and imaging features. For each specified combination, the algorithm concludes with characterization of benignity or indolence (sufficient to discontinue follow-up) and/or a subsequent management recommendation. The algorithm addresses many, but not all, possible pathologies and clinical scenarios. Our goal is to improve the quality of patient care by providing guidance on how to manage incidentally detected adrenal masses. PMID- 28651989 TI - Unraveling the venom components of an encyrtid endoparasitoid wasp Diversinervus elegans. AB - The encyrtid parasitoid, Diversinervus elegans (Hymenoptera: Encyrtidae), is a natural enemy of the notorious scale pests belonging to the family of Coccidae. Venom containing a rich source of bioactive molecules is a key virulent factor used to regulate host physiology by parasitoids. Although knowledge regarding venom constituents accumulated from limited parasitoids has provided insights into their roles in host-parasitoid interaction, toxins involving in manipulating scale physiology remain sparsely documented. Here, a total number of 48 putative venom proteins were identified from D. elegans using an integrative transcriptomic and proteomic approach. The majority of them such as serine protease, esterase, and major royal jelly protein have been found in venom of other several parasitoid species. Several venom proteins including three novel proteins having unknown function were firstly revealed. Quantitative real time PCR analysis demonstrated that 16 venom genes displayed female-biased expression, which might be important for parasitism success. These data enrich our understanding of parasitoid venom evolution and diversity, and will undoubtedly help deciphering functional venom proteins as potential candidates for pest control. PMID- 28651990 TI - A novel function of vitellogenin subdomain, vWF type D, as a toxin-binding protein in the pufferfish Takifugu pardalis ovary. AB - Marine pufferfish of the Tetraodontidae family contain high levels of tetrodotoxin (TTX) in the liver and ovary. TTX is suggested to transfer from the liver to the ovary in female pufferfish during maturation. TTX in pufferfish eggs may act as a repellent against predators and as a sexual pheromone to attract male pufferfish. The toxification mechanism of the pufferfish ovary is poorly understood. Here we evaluated the chemical form of TTX and its related substances in the ovary of the panther pufferfish Takifugu pardalis by LC-ESI/MS. TTX and its analogs 4-epi-TTX, 4, 9-anhydroTTX, deoxyTTX, dideoxyTTX, and trideoxyTTX were detected in a low molecular weight fraction by Sephacryl S-400 column chromatography. The finding of an unknown TTX-related substance in a high molecular weight fraction from the Sephacryl S-400 column suggested the occurrence of toxin-binding protein in the ovary. The toxin-binding protein in the ovary was purified by ion-exchange HPLC, gel filtration HPLC, and SDS-PAGE. Amino acid sequencing and cDNA cloning revealed that the toxin-binding protein, TPOBP-10 (Takifugu pardalis ovary toxin-binding protein with a molecular mass of 10 kDa) was homologous with the predicted vitellogenin-1-like protein [Takifugu rubripes] subdomain, a von Willebrand factor type D domain. TPOBP-10 mRNA was highly expressed in the ovary and liver and less in other organs of female individuals based on RT-PCR. These findings reveal a novel function of the vitellogenin subdomain as binding with TTX-related substances, and its involvement in the toxification of the pufferfish ovary. PMID- 28651991 TI - Ribosome Inactivating Proteins from an evolutionary perspective. AB - Ribosome Inactivating Proteins (RIPs) are rRNA N-glycosidases that inhibit protein synthesis through the elimination of a single adenine residue from 28S rRNA. Many of these toxins have been characterized in depth from a biochemical and molecular point of view. In addition, their potential use in medicine as highly selective toxins is being explored. In contrast, the evolutionary history of RIP encoding genes has remained traditionally underexplored. In recent years, accumulation of large genomic data has fueled research on this issue and revealed unexpected information about the origin and evolution of RIP toxins. In this review we summarize the current evidence available on the occurrence of different evolutionary mechanisms (gene duplication and losses, horizontal gene transfer, synthesis de novo and domain combination) involved in the evolution of the RIP gene family. Finally, we propose a revised nomenclature for RIP genes based on their evolutionary history. PMID- 28651992 TI - [Evaluation of the French practices in brachytherapy using surveys]. AB - INTRODUCTION: Prostate cancer brachytherapy can be used as an alternative to the radical prostatectomy and radiotherapy. In the low-risk group, specific survivals are up to 95% after 10years. The aim of the study is to describe the practices in brachytherapy in France. MATERIALS AND METHODS: A survey made by AFU (French Urologic Association) and SFRO (French Society Of Oncological Radiotherapy) assessing the practices in brachytherapy in France was sent to all the urologists and radiotherapists even if they did not practice it. RESULTS: In total, 1417 surveys were sent, 285 were received coming from 211 urologists (74%) and 74 radiotherapists (26%). Sixty (21%) practiced brachytherapy (31 urologists, 29 radiotherapists). Low dose rate with permanent implants was used in 83,3%. Brachytherapy was advised for low-risk group by 90% who responded the survey, 73% used it in intermediate risk and only 13% in high risk. CONCLUSION: Brachytherapy is hardly used in low risk prostate cancer. It probably needs a reconsideration of recommendations due to the good results in association with a good picking. The urologist-radiotherapist couple is essential in the overall care of the patient. LEVEL OF EVIDENCE: 4. PMID- 28651993 TI - Evaluation of bleeding risk in patients on anticoagulation for mechanical cardiac valve operated for benign prostatic obstruction. AB - OBJECTIVE: To evaluate bleeding risk in patients on anticoagulation for mechanical cardiac valve operated for benign prostatic obstruction (BPO). MATERIAL AND METHOD: Fifty-eight patients operated between 1998 and 2014, in seven French departments of Urology were included. Forty-five patients were operated by conventional surgery (transurethral resection of the prostate 38, open simple prostatectomies 7), and 13 patients were operated by GreenlightTM photovaporization of the prostate (PVP). In order to assess bleeding risk, blood transfusion was considered as the primary outcome. RESULTS: Fifteen (26%) patients received blood transfusion in the postoperative period. Mean duration of hospitalization was 8.5 days. Secondary surgery was required in 12 cases (21%), including endoscopic clot removal under general anaesthesia in 10 patients, and suprapubic haemostasis in 3 patients. One patient died 72hours after transurethral resection of the prostate because of a massive pulmonary embolism. Two independent predictors of blood transfusion were identified: conventional surgery use versus PVP, and high preoperative PSA. Blood transfusion rate was significantly lower in the group of patients operated by PVP compared to conventional surgery (0% versus 33%, P=0.010). In addition, the laser surgery was associated with shorter duration of hospitalization (3.4 days versus 9.9 days, P=0.014). However, it was not found any significant difference between patients operated by PVP compared to conventional surgery in terms of secondary bleeding (3/13 vs 8/45, P=0.7), or second surgery (2/13 vs 10/45, P=0.5). CONCLUSION: Bleeding risk of BPO surgery in patients with mechanical cardiac valve is high. The PVP seems to decrease significantly the early haemorrhagic risk compared to classic surgical procedures for patients with mechanical cardiac valve. LEVEL OF EVIDENCE: 4. PMID- 28651994 TI - Pharmacologic interventions to treat renal colic pain in acute stone episodes: Systematic review and meta-analysis. AB - OBJECTIVE: To assess effectiveness of pharmacologic interventions to relieve pain in patients suffering an acute stone episode. METHODS: Relevant trials that included patients with acute renal colic and radiological findings of urinary stones were identified in four databases. The main outcome was pain relief evaluated by Visual Analogue Scale score (VAS). RESULTS: In overall, diclofenac was superior to other NSAIDs for pain relief (MD of -12.57 [95% CI: -19.26, 5.88]). Paracetamol was superior to morphine for pain reduction at 30minutes (MD of -3.92 [95% CI: -6.41, -1.43]) and also to placebo at 15minutes (MD of -24.77 [95% CI: -33.19, -16.35]) and at 30minutes (MD of -16 [95% CI:-29, -2.96]) after drug administration. Finally, diclofenac was superior to paracetamol for pain reduction at 60 (MD of 6.60 [95% CI: 4.37, 8.83]) and 90minutes (MD of 3.4 [95% CI: 2.01, 4.79]). CONCLUSIONS: Diclofenac was superior to other NSAIDs and paracetamol for diminishing pain in patients suffering an acute stone episode. Paracetamol was superior to morphine and placebo for short pain relief. Future trials should address the role of paracetamol in the management of pain in patients suffering an acute stone episode. PMID- 28651995 TI - [Placement of tension-free vaginal tape in women with stress urinary incontinence: Long-term functional outcomes in a prospective series]. AB - PURPOSE: To evaluate the long-term functional outcomes after retropubic tension free vaginal tape (TVT) placement to treat female stress urinary incontinence (SUI). METHODS: From September 1998 to September 2000, we prospectively enrolled all consecutive women in our center suffering SUI caused by urethral hypermobility. All women had a retropubic TVT inserted by the same surgeon. Patients were evaluated at 1, 3, 6 and 12 months postoperatively, and annually thereafter. Postoperative assessment included a measurement of post-voiding residual volume, urinalysis, a 1-hour pad test, a urinary symptom questionnaire, and an assessment of quality-of-life. Objective continence (defined as no urine leakage at clinical examination) and subjective continence (defined as no urine leakage, whatever the mechanism, reported by the patient) were reported. RESULTS: Overall, 58 consecutive women (median age 59; IQR 49-67; min 21-max 78) were evaluated. Median follow-up was 10.2years (IQR 1.4-16.0; min 1-max 13.2). At the last follow-up, objective and subjective continence rates were 93% and 78%, respectively and remained stable in the long run. Pad tests, urinary symptom questionnaire scores and quality-of-life were significantly improved. Self intermittent catheterisation was required by three women. A section of one TVT and removal of another tape was undertaken in two women with chronic pelvic pain. One patient had a chronic urinary infection. Rate of de novo urgency was 10%. CONCLUSIONS: TVT implantation offered good and stable functional long-term outcomes. This procedure enhanced quality-of-life and had low morbidity. LEVEL OF EVIDENCE: 3. PMID- 28651996 TI - Centenarians as a 21st century healthy aging model: A legacy of humanity and the need for a world-wide consortium (WWC100+). PMID- 28651997 TI - Endovascular Treatment of Asymptomatic Abdominal Aortic Aneurysms in Octogenarians: Factors Influencing Long-term Survival. AB - BACKGROUND: Beyond the age of 80 years, the preventive treatment of an asymptomatic abdominal aortic aneurysm (AAA) has to be decided in light of the life expectancy which it is difficult to evaluate, but it is important to determine who in this population will benefit from it. The objective of our study was to determine the factors influencing short-term mortality and long-term survival in patients aged 80 years and older after the endovascular treatment of AAAs (EVAR). MATERIAL AND METHODS: We present a retrospective analysis of the prospective databases of 4 French academic departments of vascular surgery, bringing together the data of all the patients presenting an AAA who were treated by EVAR between 1998 and 2011. Logistic regression and multivariate analysis with a Cox survival model were used to determine the factors influencing perioperative and long-term mortality. The cumulative rate of events for the measurement of survival was calculated with the technique of Kaplan-Meier. RESULTS: We treated 345 octogenarians and 339 younger patients. The average follow-up was 40 months. Average survival was 75% at 36 months and 49% at 60 months. There was no evidence of any risk factor influencing mortality at 30 days in the octogenarians. However, chronic kidney disease (odds ratio [OR] = 3.95, P <0.001) and chronic respiratory failure (OR = 2.62, P <0.001) proved to be independent factors of a poor long-term prognosis. CONCLUSIONS: The treatment by stent graft in octogenarians is effective in the long term. The presence of an impaired renal function or respiratory failure in this population could put into question the operative indication. PMID- 28651998 TI - Elephant Trunk Technique with a Handmade Skirted Tube Graft: How Do We Prepare It? AB - The surgical treatment of diffuse thoracic aortic pathologies remains a challenge in aortic surgery for surgeons. Traditionally, these aortic diseases are treated with a 2-step approach known as the "elephant trunk procedure." This technique gives us an opportunity for the construction of the distal anastomosis during the initial operation. However, this staged approach is associated with a substantial overall mortality and morbidity. In order to improve the outcomes, few single stage repair methods have been tried. Most of them are performed through a clamshell incision, and for this reason, it is potentially associated with a high incidence of pulmonary complications. Repair techniques of diffuse thoracic aortic pathologies have changed substantially over the last decade; these techniques appear to have a significant lower operative risk for patients. "Frozen elephant trunk" (FET) technique was developed for combined lesions of the thoracic aorta as a single-stage procedure which is a combination of endovascular treatment and conventional surgery. However, experiences are limited in the field of FET and endovascular techniques that is why traditional 2-staged approach still remains as a first choice in our clinic like many centers. In eligible patients, we use a handmade skirted tube graft for conventional technique in 2 staged repair for diffuse thoracic aortic aneurysm. In this report, we aim to explain the possible advantages of this graft and how we do it. PMID- 28651999 TI - A physiologically based model for tramadol pharmacokinetics in horses. AB - This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species. The proposed model is based on physiology but adopts the minimal compartmental architecture necessary to describe the experimental data. The model features a system of ordinary differential equations, where most of the model parameters are either assigned or individualized for a given horse, using literature data and correlations. Conversely, residual parameters, whose value is unknown, are regressed exploiting experimental data. The model proved capable of simulating pharmacokinetic profiles with accuracy. In addition, it provides further insights on un-observable tramadol data, as for instance tramadol concentration in the liver or hepatic metabolism and renal excretion extent. PMID- 28652000 TI - Modeling coexistence of oscillation and Delta/Notch-mediated lateral inhibition in pancreas development and neurogenesis. AB - During pancreas development, Neurog3 positive endocrine progenitors are specified by Delta/Notch (D/N) mediated lateral inhibition in the growing ducts. During neurogenesis, genes that determine the transition from the proneural state to neuronal or glial lineages are oscillating before their expression is sustained. Although the basic gene regulatory network is very similar, cycling gene expression in pancreatic development was not investigated yet, and previous simulations of lateral inhibition in pancreas development excluded by design the possibility of oscillations. To explore this possibility, we developed a dynamic model of a growing duct that results in an oscillatory phase before the determination of endocrine progenitors by lateral inhibition. The basic network (D/N + Hes1 + Neurog3) shows scattered, stable Neurog3 expression after displaying transient expression. Furthermore, we included the Hes1 negative feedback as previously discussed in neurogenesis and show the consequences for Neurog3 expression in pancreatic duct development. Interestingly, a weakened HES1 action on the Hes1 promoter allows the coexistence of stable patterning and oscillations. In conclusion, cycling gene expression and lateral inhibition are not mutually exclusive. In this way, we argue for a unified mode of D/N mediated lateral inhibition in neurogenic and pancreatic progenitor specification. PMID- 28652001 TI - Simple mechanical cues could explain adipose tissue morphology. AB - The mechanisms by which organs acquire their functional structure and realize its maintenance (or homeostasis) over time are still largely unknown. In this paper, we investigate this question on adipose tissue. Adipose tissue can represent 20 to 50% of the body weight. Its investigation is key to overcome a large array of metabolic disorders that heavily strike populations worldwide. Adipose tissue consists of lobular clusters of adipocytes surrounded by an organized collagen fiber network. By supplying substrates needed for adipogenesis, vasculature was believed to induce the regroupment of adipocytes near capillary extremities. This paper shows that the emergence of these structures could be explained by simple mechanical interactions between the adipocytes and the collagen fibers. Our assumption is that the fiber network resists the pressure induced by the growing adipocytes and forces them to regroup into clusters. Reciprocally, cell clusters force the fibers to merge into a well-organized network. We validate this hypothesis by means of a two-dimensional Individual Based Model (IBM) of interacting adipocytes and extra-cellular-matrix fiber elements. The model produces structures that compare quantitatively well to the experimental observations. Our model seems to indicate that cell clusters could spontaneously emerge as a result of simple mechanical interactions between cells and fibers and surprisingly, vasculature is not directly needed for these structures to emerge. PMID- 28652002 TI - Preliminary kinetic evaluation of an immobilized polysaccharide sub-2MUm column using a low dispersion supercritical fluid chromatograph. AB - The performance of a 3*50mm, 1.6MUm dp column with an immobilized polysaccharide stationary phase (ChiralPak IA-U) was evaluated for efficiency, and pressure drop, with respect to flow rate and modifier concentration using supercritical fluid chromatography (SFC). This appears to be the first such report using such a column in SFC. A unique low dispersion (ultra-high performance) SFC was used for the evaluation. The minimum reduced plate height of 2.78, indicates that the maximum efficiency was similar to or better than coated polysaccharide columns. Selectivity was different from ChiralPak AD, with the same chiral selector, as reported by many others. At high flows and high methanol concentrations, pump pressures sometimes approached 600bar. With 5% methanol, pressure vs. flow rate was non-linear suggesting turbulent flow in the connector tubing. The optimum flow rate (Fopt) at 40% methanol was ~0.8mL/min, where the column efficiency was highest. At 5% methanol, Fopt increased to ~1.6mL/min, but efficiency degraded noticeably. The differences in Fopt suggests that the solute diffusion coefficients are a strong function of modifier concentration. Several sub-1min separations, including a 7.5s separation, are presented. PMID- 28652003 TI - Comprehensive two-dimensional gas chromatography-mass spectrometry of complex mixtures of anaerobic bacterial metabolites of petroleum hydrocarbons. AB - Anaerobic biotransformation of petroleum hydrocarbons is an important alteration mechanism, both subsurface in geological reservoirs, in aquifers and in anoxic deep sea environments. Here we report the resolution and identification, by comprehensive two-dimensional gas chromatography-mass spectrometry (GC*GC-MS), of complex mixtures of aromatic acid and diacid metabolites of the anaerobic biodegradation of many crude oil hydrocarbons. An extended range of metabolites, including alkylbenzyl, alkylindanyl, alkyltetralinyl, alkylnaphthyl succinic acids and alkyltetralin, alkylnaphthoic and phenanthrene carboxylic acids, is reported in samples from experiments conducted under sulfate-reducing conditions in a microcosm over two years. The range of metabolites identified shows that the fumarate addition mechanism applies to the alteration of hydrocarbons with up to C8 alkylation in monoaromatics and that functionalisation of up to three ring aromatic hydrocarbons with at least C1 alkylation occurs. The GC*GC-MS method might now be applied to the identification of complex mixtures of metabolites in samples from real environmental oil spills. PMID- 28652004 TI - The effect of high concentration additive on chiral separations in supercritical fluid chromatography. AB - Supercritical Fluid Chromatography is frequently used to efficiently handle separations of enantiomers. The separation of basic analytes usually requires the addition of a basic additive in the mobile phase to improve the peak shape or even to elute the compounds. The effect of increasing the concentration of 2 propylamine as additive on the elution of a series of basic compounds on a Chiralpak-AD stationary phase was studied. In this study, unusual additive concentrations ranging from 0.3% to 10% of 2-propylamine 2-propylaminein the modifier were explored and the effect on retention, peak shape, selectivity and resolution was evaluated. The addition of a large quantity of additive allowed to drastically improve the selectivity and the resolution, and even enantiomers elution order reversal was observed by changing the concentration of basic additive. The role of the ratio additive/modifier appeared a key to tune the enantioselectivity. Finally, the impact of these drastic conditions on the column material was evaluated. PMID- 28652005 TI - Recent trends in determination of thiamine and its derivatives in clinical practice. AB - Over the last five decades, many methods to analyze thiamine (vitamin B1) and its phosphorylated forms in urine, whole blood, serum, plasma and erythrocytes have been proposed. Some of the methods are presently used in routine practice, but analytical problems regarding reproducibility, standardization, lack of automation, time consuming procedures for pretreatment and analysis are often discussed. With modern approaches to bioanalysis in clinical research of vitamins, whole processes can be automated, making analysis less time consuming, with reduced consumption of solvents and samples. This review critically discusses various analytical techniques, their advantages and disadvantages that are used for determination of thiamine and its derivatives in clinical practice, with emphasis on accurate, reliable and fast analytical procedures. PMID- 28652006 TI - 3D-NuS: A Web Server for Automated Modeling and Visualization of Non-Canonical 3 Dimensional Nucleic Acid Structures. AB - The inherent conformational flexibility of nucleic acids facilitates the formation of a range of conformations such as duplex, triplex, quadruplex, etc. that play crucial roles in biological processes. Elucidation of the influence of non-canonical base pair mismatches on DNA/RNA structures at different sequence contexts to understand the mismatch repair, misregulation of alternative splicing mechanisms and the sequence-dependent effect of RNA-DNA hybrid in relevance to antisense strategy demand their three-dimensional structural information. Furthermore, structural insights about nucleic acid triplexes, which are generally not tractable to structure determination by X-ray crystallography or NMR techniques, are essential to establish their biological function(s). A web server, namely 3D-NuS (http://iith.ac.in/3dnus/), has been developed to generate energy-minimized models of 80 different types of triplexes, 64 types of G quadruplexes, left-handed Z-DNA/RNA duplexes, and RNA-DNA hybrid duplex along with inter- and intramolecular DNA or RNA duplexes comprising a variety of mismatches and their chimeric forms for any user-defined sequence and length. It also generates an ensemble of conformations corresponding to the modeled structure. These structures may serve as good starting models for docking proteins and small molecules with nucleic acids, NMR structure determination, cryo-electron microscope modeling, DNA/RNA nanotechnology applications and molecular dynamics simulation studies. PMID- 28652007 TI - Cytokines affecting CD4+T regulatory cells in transplant tolerance. III. Interleukin-5 (IL-5) promotes survival of alloantigen-specific CD4+ T regulatory cells. AB - CD4+T cells mediate antigen-specific allograft tolerance, but die in culture without activated lymphocyte derived cytokines. Supplementation of the media with cytokine rich supernatant, from ConA activated spleen cells, preserves the capacity of tolerant cells to transfer tolerance and suppress rejection. rIL-2 or rIL-4 alone are insufficient to maintain these cells, however. We observed that activation of naive CD4+CD25+FOXP3+Treg with alloantigen and the Th2 cytokine rIL 4 induces them to express interleukin-5 specific receptor alpha (IL-5Ralpha) suggesting that IL-5, a Th2 cytokine that is produced later in the immune response may promote tolerance mediating Treg. This study examined if recombinant IL-5(rIL-5) promoted survival of tolerant CD4+, especially CD4+CD25+T cells. CD4+T cells, from DA rats tolerant to fully allogeneic PVG heart allografts surviving over 100days without on-going immunosuppression, were cultured with PVG alloantigen and rIL-5. The ability of these cells to adoptively transfer tolerance to specific-donor allograft and suppress normal CD4+T cell mediated rejection in adoptive DA hosts was examined. Tolerant CD4+CD25+T cells' response to rIL-5 and expression of IL-5Ralpha was also assessed. rIL-5 was sufficient to promote transplant tolerance mediating CD4+T cells' survival in culture with specific-donor alloantigen. Tolerant CD4+T cells cultured with rIL-5 retained the capacity to transfer alloantigen-specific tolerance and inhibited naive CD4+T cells' capacity to effect specific-donor graft rejection. rIL-5 promoted tolerant CD4+CD25+T cells' proliferation in vitro when stimulated with specific-donor but not third-party stimulator cells. Tolerant CD4+CD25+T cells expressed IL-5Ralpha. This study demonstrated that IL-5 promoted the survival of alloantigen-specific CD4+CD25+T cells that mediate transplant tolerance. PMID- 28652009 TI - Need for molecular characterization in immortalized cell lines. PMID- 28652008 TI - Model-based spike sorting with a mixture of drifting t-distributions. AB - BACKGROUND: Chronic extracellular recordings are a powerful tool for systems neuroscience, but spike sorting remains a challenge. A common approach is to fit a generative model, such as a mixture of Gaussians, to the observed spike data. Even if non-parametric methods are used for spike sorting, such generative models provide a quantitative measure of unit isolation quality, which is crucial for subsequent interpretation of the sorted spike trains. NEW METHOD: We present a spike sorting strategy that models the data as a mixture of drifting t distributions. This model captures two important features of chronic extracellular recordings-cluster drift over time and heavy tails in the distribution of spikes-and offers improved robustness to outliers. RESULTS: We evaluate this model on several thousand hours of chronic tetrode recordings and show that it fits the empirical data substantially better than a mixture of Gaussians. We also provide a software implementation that can re-fit long datasets in a few seconds, enabling interactive clustering of chronic recordings. COMPARISON WITH EXISTING METHODS: We identify three common failure modes of spike sorting methods that assume stationarity and evaluate their impact given the empirically-observed cluster drift in chronic recordings. Using hybrid ground truth datasets, we also demonstrate that our model-based estimate of misclassification error is more accurate than previous unit isolation metrics. CONCLUSIONS: The mixture of drifting t-distributions model enables efficient spike sorting of long datasets and provides an accurate measure of unit isolation quality over a wide range of conditions. PMID- 28652010 TI - Formulating a clinicopathological algorithm for oral lichenoid dysplasia and related lesions. PMID- 28652011 TI - Development and evaluation of polyclonal antisera for detection of the IgM heavy chain of multiple fish species. AB - Antibodies are widely considered to be essential tools for detection of immune responses in various fish species. Here we produced the peptide polyclonal antisera (anti-fish IgH-1 and anti-fish IgH-2) to detect IgM of various fish species. The peptides were designed based on the conserved sequence of the fish immunoglobulin heavy chains of seven fish species (Japanese flounder, seabream, yellowtail, carp, rainbow trout, hybrid sturgeon and banded houndshark). By Western blotting, anti-fish IgH-1 antiserum detected the IgMs of all fish species except banded houndshark. Anti-fish IgH-2 antiserum clearly reacted with the IgMs of only three of the fish species (seabream, yellowtail and rainbow trout). Attempts to use the antisera to measure fish antibody titer by ELISA were unsuccessful. These results demonstrate that anti-fish IgH-1 peptide polyclonal antiserum is a potentially applicable tool for detecting immunoglobulins in various fish species by Western blotting. PMID- 28652012 TI - Secondary metabolites from endophytic fungus Chaetomium sp. induce colon cancer cell apoptotic death. AB - A rare depsipeptide, chaetomiamide A (1), together with two known diketopiperazines (2, 3) were isolated from the cultures of endophytic fungus Chaetomium sp., which was isolated from the root of Cymbidium goeringii. Compound 1 represents a rare skeleton with a 13-membered ring system. It structure was established on the basis of spectroscopic data interpretation. The configuration of 1 was determined by NOESY and Marfey's analysis. These isolates were evaluated for anticancer activity and 3 displayed more potent cytotoxicity than the positive control cisplatin associated with G2/M cell cycle arrest. In addition, 3 induced apoptosis via caspase-3 induction and PARP cleavage, concomitantly with the increase of Bax and decrease of Bcl-2. PMID- 28652013 TI - Willughbeia cochinchinensis prevents scopolamine-induced deficits in memory, spatial learning, and object recognition in rodents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Willughbeia cochinchinensis (WC) has been used in Vietnamese traditional medicine for the treatment of dementia as well as diarrhea, heartburn, and cutaneous abscess and as a diuretic. AIM: Alzheimer's disease (AD) is one of the most prevalent diseases in elderly individuals. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors have been widely used to treat patients with AD. In the present study, we investigated anti AChE and anti-BChE activities of a natural product, WC, for its potential applications in therapies to prevent/treat dementia. MATERIALS AND METHODS: First, compounds extracted from WC were tested for their AChE and BChE inhibitory activities in vitro. Second, in vivo behavioral experiments were performed to investigate the effects of WC at doses of 100, 150, and 200mg/kg on scopolamine (1.5mg/kg)-induced memory and cognitive deficits in mice. The behavior of mice treated with and without WC and/or scopolamine was tested using the Y-maze, Morris water maze, and novel object recognition task. RESULTS: The results of the in vitro assay demonstrated anti-AChE and anti-BChE activities of the compounds extracted from WC. The results of behavioral experiments showed that the administration of WC prevented 1) scopolamine-induced decrease in spontaneous alternation (%) behavior in the Y-maze, 2) scopolamine-induced deficits in spatial learning and memory in the Morris water maze, and 3) scopolamine-induced deficits in novel object recognition. These results indicate that WC prevents cognitive and memory deficits induced by scopolamine injection. CONCLUSIONS: Our findings suggest that WC may represent a novel candidate for the treatment of memory and cognitive deficits in humans with dementia. PMID- 28652014 TI - Anti-inflammatory effect of Man-Pen-Fang, a Chinese herbal compound, on chronic pelvic inflammation in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) has become the focus of research for the treatment of chronic pelvic inflammatory disease (CPID) based on unique medical theory system. Man-Pen-Fang (MPF), a Chinese herbal compound, which is composed of Thlaspi arvense L. (Cruciferae), Gleditsia sinensis Lam. (Leguminosae), Smilax china L. (Liliaceae), Euonymus alatus (Thunb.) Sieb. (Celastraceae) and Vaccaria segetalis (Neck.) (Caryophyllaceae) MPF has been used for the treatment of CPID and exerted significant clinical curative effects. However, the corresponding active principles and anti inflammatory mechanism of MPF are still unknown. AIM OF THE STUDY: The objective of present study is to evaluate the effect of MPF on CPID in the chronic pelvic inflammation (CPI) rat model and elucidate its possible anti-inflammatory mechanism. MATERIALS AND METHODS: The CPI in rats was induced by administration with E. coli, Staphylococcus aureus and Beta-hemolytic streptococcus. MPF (8.112g/(kg d) (20 times of adult dosage), 4.056g/(kg d) (10 times of adult dosage) and 2.028g/(kg d) (5 times of adult dosage)) and Jingangteng Capsule 2g/(kg d) (20 times of adult dosage) were administered orally for 20 days. The serum levels of five inflammation-associated cytokines (IL-2, IL-6, IL-10, TNF alpha and TGF-beta1) were determined by enzyme-linked immunoassay, and the mRNA expression levels of TGF-beta1, P53, Fas, FasL and MMP-2 in the uterus tissue were measured by quantitative RT-PCR. Furthermore, the expression of NF-kappaB p65 in uterus and ovary tissues was detected by immunohistochemistry assay and the pathological changes induced in the uterus and ovary tissues were observed by histology. RESULTS: MPF caused a reduction in serum levels of IL-2, IL-6, IL-10, TNF-alpha and TGF-beta1. The expression of P53 mRNA, Fas/FasL mRNA and MMP-2 mRNA in the uterus tissue was significantly elevated after treating with MPF, in contrast the expression of TGF-beta1 mRNA was decreased. Furthermore, the expression of NF-kappaB p65 in uterus and ovary tissue was inhibited after treating with MPF. CONCLUSIONS: These results taken together suggest that MPF has a significant anti-CPID effect, probably due to inhibition of the inflammation reaction by the promotion, and the induction of the apoptosis of inflammatory cells and downregulation of the serum levels of inflammation cytokines. PMID- 28652015 TI - Landscape of Innovation for Cardiovascular Pharmaceuticals: From Basic Science to New Molecular Entities. AB - PURPOSE: This study examines the complete timelines of translational science for new cardiovascular therapeutics from the initiation of basic research leading to identification of new drug targets through clinical development and US Food and Drug Administration (FDA) approval of new molecular entities (NMEs) based on this research. METHODS: This work extends previous studies by examining the association between the growth of research on drug targets and approval of NMEs associated with these targets. Drawing on research on innovation in other technology sectors, where technological maturity is an important determinant in the success or failure of new product development, an analytical model was used to characterize the growth of research related to the known targets for all 168 approved cardiovascular therapeutics. FINDINGS: Categorizing and mapping the technological maturity of cardiovascular therapeutics reveal that (1) there has been a distinct transition from phenotypic to targeted methods for drug discovery, (2) the durations of clinical and regulatory processes were significantly influenced by changes in FDA practice, and (3) the longest phase of the translational process was the time required for technology to advance from initiation of research to a statistically defined established point of technology maturation (mean, 30.8 years). IMPLICATIONS: This work reveals a normative association between metrics of research maturation and approval of new cardiovascular therapeutics and suggests strategies for advancing translational science by accelerating basic and applied research and improving the synchrony between the maturation of this research and drug development initiatives. PMID- 28652016 TI - Overall Effectiveness of Rivaroxaban in Patients with Pulmonary Embolism. AB - PURPOSE: Due to limited evidence on the impact of rivaroxaban in clinical practice, we compared the effectiveness of rivaroxaban versus standard of care (SOC) among patients in the Veterans Health Administration. METHODS: Adult patients with continuous enrollment in a health plan with medical and pharmacy benefits for >=12 months before and >=3 months after an inpatient diagnosis of pulmonary embolism (PE) between October 1, 2011, and June 30, 2015, and a prescription claim for an anticoagulant during the index hospitalization, were included. SOC drugs were low-molecular-weight heparin, unfractionated heparin, and warfarin. Propensity score matching was used in comparing PE-related outcomes (recurrent venous thromboembolism, major bleeding, and death), hospital-acquired complications (HACs), health care resource utilization, and costs among patients receiving SOC versus rivaroxaban. We defined net clinical benefit as 1 minus the combined rate of PE-related outcomes and HACs. FINDINGS: Among 6746 patients with PE, 208 received rivaroxaban, 4641 received SOC and 1897 received other anticoagulants. Most (95%) were male; 22% were black. After 1:3 propensity score matching, there were 203 rivaroxaban and 609 SOC patients. During the 90-day follow-up, rivaroxaban users had similar rates of PE-related outcomes, but fewer had experienced at least 1 HAC (10.3% vs 15.9%; P = 0.0506), resulting in better net clinical benefit (82.8% vs 71.1%; P = 0.001). Rivaroxaban users had fewer outpatient visits per patient (17.0 vs 19.9; P = 0.0005), a similar rehospitalization rate (0.2 vs 0.3; P = 0.084), lesser inpatient costs (US $3501 vs $6189; P < 0.0001), lesser inpatient costs and lesser total costs ($10,545 vs $14,192; P = 0.0002). When the sample was limited to patients with low-risk PE, we found similar patterns. IMPLICATIONS: Patients with PE prescribed rivaroxaban had similar PE-related outcomes, but fewer HACs and lesser total costs, than did patients on SOC. PMID- 28652017 TI - A time for psycho-spiritual transcendence: The experiences of Iranian women of pain during childbirth. AB - BACKGROUND: The description of women's experiences of childbirth improves our understandings of the nature of childbirth, women's suffering and pain during childbirth. AIM: This study aimed to explore women's experiences of pain during childbirth. METHOD: A qualitative study was conducted using a conventional content analysis method proposed by Graneheim and Lundman (2004). In-depth face to face semi-structured interviews were held with 17 women who met inclusion criteria for participation in this study. FINDINGS: The women's experiences of pain during childbirth was described as 'a time for psycho-spiritual transcendence'. Categories developed during the data analysis were 'conflicting emotions towards pain', 'new insight towards labor pain', 'self-actualization' and 'spiritual development'. CONCLUSION: Most participants had positive experiences and attitudes towards pain during childbirth influenced by cultural, context and religious factors. According to this study, 'transcendental progression' was an eminent feeling that created positive inner feelings along with self-actualization in women. This provides a new insight on labor pain and helps healthcare providers understand the effect of pain during childbirth on women's spiritual, mental and psychological needs. PMID- 28652018 TI - Kinetic properties of the mitochondrial F1FO-ATPase activity elicited by Ca2+ in replacement of Mg2. AB - The mitochondrial F-ATPase can be activated either by the classical cofactor Mg2+ or, with lower efficiency, by Ca2+. The latter may play a role when calcium concentration rises in mitochondria, a condition associated with cascade events leading to cell death. Common and distinctive features of these differently activated mitochondrial ATPases were pointed out in swine heart mitochondria. When Ca2+ replaces the natural cofactor Mg2+, the enzyme responsiveness to the transmembrane electrochemical gradient and to the classical F-ATPase inhibitors DCCD and oligomycin as well as the oligomycin sensitivity loss by thiol oxidation, are maintained. Consistently, the two mitochondrial ATPases apparently share the F1FO complex basic structure and mechanism. Peculiar cation-dependent properties, which may affect the F1 catalytic mechanism and/or the FO proton binding site features, may be linked to a different physiological role of the mitochondrial Ca-activated F-ATPase with respect to the Mg-activated F-ATPase. PMID- 28652019 TI - Sphingolipids from the human fungal pathogen Aspergillus fumigatus. AB - Sphingolipids (SPLs) are key components of the plasma membrane in yeast and filamentous fungi. These molecules are involved in a number of cellular processes, and particularly, SGLs are essential components of the highly polarized fungal growth where they are required for the formation of the polarisome organization at the hyphal apex. Aspergillus fumigatus, a human fungal pathogen, produce SGLs that are discriminated into neutral cerebrosides, glycosylinositolphosphoceramides (GIPCs) and glycosylphosphatidylinositol (GPI) anchors. In addition to complex hydrophilic head groups of GIPCs, A. fumigatus is, to date, the sole fungus that produces a GPI-anchored polysaccharide. These SPLs follow three different biosynthetic pathways. Genetics blockage leading to the inhibition of any SPL biosynthesis or to the alteration of the structure of SPL induces growth and virulence defects. The complete lipid moiety of SPLs is essential for the lipid microdomain organization and their biosynthetic pathways are potential antifungal targets but remains understudied. PMID- 28652020 TI - Development of a realtime RT-PCR assay for the rapid detection of influenza A(H2) viruses. AB - Influenza and other acute respiratory infections are of great concern for public health, causing excessive morbidity and mortality throughout the world. Influenza virus A(H2N2), which caused a pandemic of so called "Asian flu" in 1957 was expelled from the human population by the new pandemic virus subtype H3N2 in 1968, however, influenza A(H2) viruses continue to circulate in wild birds and poultry. The lack of immunity in human population and the continued circulation of influenza A(H2) among animals makes emergence of a new pandemic virus possible. One of the basic techniques of molecular diagnostics of infectious diseases is the realtime polymerase chain reaction (PCR). The aim of this work was to design oligonucleotide primers and probes for the rapid detection of influenza A virus subtype H2 by realtime reverse transcription - polymerase chain reaction (rRT-PCR). Analysis of 539 sequences of influenza A(H2N2) virus hemagglutinin gene from GISAID EpiFlu database revealed conservative regions suitable for use as binding sites for primers and probes. 191 probes were designed and 2 sets of primers and probes (H2-1 and H2-2) were selected for further experimental evaluation. Detection limit of RT-PCR system was 50 copies of DNA per 25 MUl reaction when 10-fold dilutions of pCI-neo-H2 plasmid used as template. Analytical specificity of selected sets of primers and probes were tested on wide range of influenza strains and non-influenza respiratory viruses. H2-2 set found to have insufficient specificity detecting seasonal influenza A(H1N1) viruses and was excluded from further analysis. Analytical sensitivity was further tested on vaccine strain A/17/California/66/395 (H2N2) and A/Japan/305/1957 (H2N2), limit of detection for primers-probe set H2-1 was 3.2 (CI95%: 3.07-3.48) lg EID50/ml. Designed primers and probes for the realtime RT PCR universal detection of influenza A(H2) viruses could be used in clinical trials of vaccines against influenza A(H2) and screening for H2 in cases of unsubtypeable influenza A in humans. PMID- 28652021 TI - Detection of circulating tumor cells from cryopreserved human sarcoma peripheral blood mononuclear cells. AB - Circulating tumor cells (CTCs) enter the vasculature or lymphatic system after shedding from the primary tumor. CTCs may serve as "seed" cells for tumor metastasis. The utility of CTCs in clinical applications for sarcoma is not fully investigated, partly owing to the necessity for fresh blood samples and the lack of a CTC-specific antibody. To overcome these drawbacks, we developed a technique for sarcoma CTCs capture and detection using cryopreserved peripheral blood mononuclear cells (PBMCs) and our proprietary cell-surface vimentin (CSV) antibody 84-1, which is specific to tumor cells. This technique was validated by sarcoma cell spiking assay, matched CTCs comparison between fresh and cryopreserved PBMCs, and independent tumor markers in multiple types of sarcoma patient blood samples. The reproducibility was maximized when cryopreserved PBMCs were prepared from fresh blood samples within 2 h of the blood draw. In summary, as far as we are aware, ours is the first report to capture and detect CTCs from cryopreserved PBMCs. Further validation in other types of tumor may help boost the feasibility and utility of CTC-based diagnosis in a centralized laboratory. PMID- 28652022 TI - CHSY1 promotes aggressive phenotypes of hepatocellular carcinoma cells via activation of the hedgehog signaling pathway. AB - Abnormal expression of chondroitin sulfate has been found in many types of cancer, while its biological functions in hepatocellular carcinoma (HCC) progression remain uninvestigated. Here, we report that chondroitin sulfate synthase 1 (CHSY1), the enzyme that mediates the polymerization step of chondroitin sulfate, is a critical mediator of malignant character in HCC that acts via modulating the activity of the hedgehog signaling. CHSY1 was up regulated frequently in HCC where these events were associated with worse histologic grade and poor survival. Enforced expression of CHSY1 was sufficient to enhance cell growth, migration, invasion, and epithelial-mesenchymal transition, whereas silencing of CHSY1 suppressed these malignant phenotypes. Mechanistic investigations revealed that the increase of cell surface chondroitin sulfate by CHSY1 promoted sonic hedgehog binding and signaling. Inhibiting hedgehog pathway with vismodegib decreased CHSY1-induced migration, invasion, and lung metastasis of HCC cells, establishing the critical role of hedgehog signaling in mediating the effects of CHSY1 expression. Together, our results indicate that CHSY1 overexpression in HCC contributes to the malignant behaviors in cancer cells, we provide novel insights into the significance of chondroitin sulfate in hedgehog signaling and HCC pathogenesis. PMID- 28652023 TI - Ammonia and greenhouse gases losses from mechanically turned cattle manure windrows: A regional composting network. AB - An on-farm composting network operates in the Basque Country (northern Spain), in which solid manure produced in livestock farms (mostly dairy and beef cattle) is composted through windrow turning. This network aims to produce a valuable resource (compost) for the farmers whereas the volume of the solid manure was reduced at farm level The objective of the study was to assess the gaseous losses (NH3 and GHG) from 6 on-farm composting windrows (either deep litter systems or solid fraction after slurry separation) after turning operations. Monitored turning events occurred 1 to 4 months after establishing the heaps on the field. Ammonia and greenhouse gas (GHG) losses were estimated by the open and close chamber techniques, respectively. Results showed overall low emission rates related to the long degradation period of the windrows. Maximum NH3 release was at 2.0 mg m-2 d-1 after the second/third turning events. Baseline N2O losses were below 50 mg m-2 d-1, with maximum rates close to 500 mg m-2 d-1 some days after turning works. Methane emissions were mostly below 100 mg m-2 d-1, while CO2 losses were lower than 25 g m-2 d-1. Carbon dioxide peaks (~250 g m-2 d-1) were reached after the second/third turnings. Overall, gaseous N and C losses accounted for 0.1 and 1% of the initial N and C content of the windrows, respectively. The present study concluded that two/three turning operations in aged solid manure-derived compost windrows do not have significant effects on NH3 and GHG losses. The magnitude of the gaseous losses from on-farm composting systems is dependent on the manure management practices at farm level (e.g. moment of windrow stacking). PMID- 28652024 TI - The lock-in effect and the greening of automotive cooling systems in the European Union. AB - As of 2017, the sale and use of the refrigerants most commonly used in automotive cooling systems - hydrofluorocarbons - are entirely banned in all new vehicles placed on the market in the European Union. These refrigerants have been recognised as potent greenhouse gases and, therefore, direct contributors to climate change. It is within this regulation-driven market that the technologies for a sustainable solution have been developed. However, this paper argues that the market for automotive cooling systems has been 'locked-in', which means that competing technologies, operating under dynamic increasing returns, will allow for one - potentially inferior technology - to dominate the market. Whilst such a situation is not uncommon, this paper discusses the way that regulation has reinforced a patented monopoly in 'picking winners': to the advantage of a synthetic chemical, R-1234yf, as opposed to the natural solution, which is CO2. By developing a generic conceptual framework of path dependence and lock-in, the presented evidence seeks to show how a snowballing effect has led to the intensification of differences in market share. We also argue that the automotive industry is potentially promoting short-term fixes, rather than long-term, sustainable and economically viable solutions. PMID- 28652026 TI - The expression of progesterone receptor coregulators mRNA and protein in corpus luteum and endometrium of cows during the estrous cycle. AB - The aim of this study was to examine whether changes in the mRNA and protein expression of the progesterone receptor (PGR) coactivator P300/CBP-associated factor (PCAF) and the corepressor Nuclear Receptor Corepressor 1 (NCOR1) may participate in the regulation of PGR function during the estrous cycle in corpus luteum (CL) and endometrium and thus modulate the effect of progesterone (P4) within the reproductive system. The experimental material included CL and endometrial tissues from cows on days 2-5, 6-10, 11-16, and 17-20 of the estrous cycle. The mRNA expression of PCAF and NCOR1 was determined by means of real-time PCR, and protein levels were determined using western blotting. The highest mRNA and protein expression for PCAF (P<0.01) and NCOR1 (P<0.01) was found on days 6 16 in CL, whereas mRNA and protein expression for PCAF in endometrium was the highest on days 1-10 (P<0.05), but for NCOR1 it was the highest on days 2-5 (P<0.05) and decreased thereafter. Significant correlations were found between PCAF and NCOR1 mRNA and protein in CL and endometrium, between PCAF mRNA or protein and P4 levels only in CL, and between NCOR1 protein and P4 levels in endometrium only. Correlations between PCAF and NCOR1 mRNA and PCAF and NCOR1 protein were also found. These data suggest that the variable expression of these coregulators in CL and endometrium during the estrous cycle may depend on the influence of P4, and in these tissues both coregulators may compete for binding to the PGR. PMID- 28652025 TI - Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase. AB - Flavin cofactors are widely used by enzymes to catalyze a broad range of chemical reactions. Traditionally, flavins in enzymes are regarded as redox centers, which enable enzymes to catalyze the oxidation or reduction of substrates. However, a new class of flavoenzyme has emerged over the past quarter century in which the flavin functions as a catalytic center in a non-redox reaction. Here we introduce the unifying concept of flavin hot spots to understand and categorize the mechanisms and reactivities of both traditional and noncanonical flavoenzymes. The major hot spots of reactivity include the N5, C4a, and C4O atoms of the isoalloxazine, and the 2' hydroxyl of the ribityl chain. The role of hot spots in traditional flavoenzymes, such as monooxygenases, is briefly reviewed. A more detailed description of flavin hot spots in noncanonical flavoenzymes is provided, with a focus on UDP-galactopyranose mutase, where the N5 functions as a nucleophile that attacks the anomeric carbon atom of the substrate. Recent results from mechanistic enzymology, kinetic crystallography, and computational chemistry provide a complete picture of the chemical mechanism of UDP galactopyranose mutase. PMID- 28652027 TI - Atrial Fibrillation and Sleep Apnoea: Guilt by Association? AB - Atrial fibrillation (AF) and obstructive sleep apnoea (OSA) are both common, often underdiagnosed conditions with serious sequelae. An association between these two conditions has been recognised but the nature of this relationship remains a topic of active debate. Despite that lack of strong, randomised controlled trials, there is a considerable body of data indicating that not only does untreated OSA provide the substrates and triggers for AF but that OSA, itself, is also a therapeutic target for the management of cardiovascular disease in general and of AF in particular. PMID- 28652028 TI - Cryoablation for Atrial Fibrillation in 2017: What Have We Learned? AB - Catheter ablation has become a standard technique for the treatment of atrial fibrillation. Pulmonary vein isolation (PVI) is the most important component of catheter ablation of atrial fibrillation. Radiofrequency (RF) ablation and balloon cryoablation can be used to achieve PVI. This review examines the biophysics and clinical efficacy of balloon cryoablation and discusses the potential advantages and disadvantages compared to RF ablation. PMID- 28652029 TI - Dealing With the Left Atrial Appendage for Stroke Prevention: Devices and Decision-Making. AB - Left atrial appendage (LAA) device occlusion represents a major evolution in stroke prevention for atrial fibrillation (AF). Left atrial appendage device occlusion is now a proven strategy which provides long-term thromboembolic stroke prevention for patients with non-rheumatic AF. Evidence supports its benefit as an alternative to long-term anticoagulation while mitigating long-term bleeding risks and improving cardiovascular mortality. The therapy offers expanded options to physicians and patients negotiating stroke prevention (both primary and secondary prevention), but a good understanding of the risks and benefits is required for decision-making. This review aims to summarise the evolution of LAA device occlusion therapy, current knowledge in the field and a snapshot of current status of the therapy in clinical practice in Australia and around the world. PMID- 28652030 TI - Cardiac Sarcoidosis, Left Ventricular Impairment and Chronic Right Ventricular Pacing: Pacing or Pathology? AB - BACKGROUND: Cardiac sarcoidosis (CS) is an uncommon and under-recognised disease which most frequently presents with atrioventricular (AV) block and may also present with ventricular arrhythmias and left ventricular (LV) systolic dysfunction. Because of its protean clinical manifestations, confirming a diagnosis of CS is often challenging. METHODS: We report two cases where patients presented with atrioventricular (AV) block without evidence of underlying myocardial disease, underwent chronic dual-chamber pacing, and presented several years later with severe LV systolic dysfunction. RESULTS: Both patients were referred for assessment of pacing-induced cardiomyopathy with a view to upgrading their device to cardiac resynchronisation therapy (CRT). Subsequent investigation revealed features consistent with CS and appropriate immunosuppressive therapy resulted in improvement in LV function avoiding the requirement for CRT. CONCLUSION: We present a review of the diagnosis of cardiac sarcoidosis, the importance of imaging modalities and current treatment recommendations. PMID- 28652031 TI - The Utility of Contrast Medium Fractional Flow Reserve in Functional Assessment Of Coronary Disease in Daily Practice. AB - BACKGROUND: Adenosine induced hyperaemic fractional flow reserve (aFFR) is a validated predictor of clinical outcome and part of routine interventional practice. Protocol issues associated with the adenosine infusion limit the use of aFFR in clinical practice. Contrast medium induced hyperaemic FFR (cFFR) is a simpler procedure from a practical standpoint. We compared the two in a real world setting. METHODS: We analysed 76 patients that had both cFFR and aFFR assessment of 100 angiographically indeterminate coronary stenosis. cFFR was performed with intracoronary contrast medium injections (10ml for left coronary lesions and 8ml for right coronary lesions). The diagnostic performance of cFFR was analysed and compared to the gold standard aFFR. RESULTS: Mean cFFR was 0.87 (+/-0.07) and mean aFFR was 0.84 (+/-0.08). Bland-Altman analysis revealed a close agreement between cFFR and aFFR (0.035+/-0.032; 95% CI: -0.028 to 0.098) and good linear correlation (r=0.92, r2=0.86; p<0.0001). Using cFFR cut-off values of <=0.83 in predicting an aFFR value of <=0.80 or a cFFR value >=0.88, predicting an aFFR value of >0.80 yielded a sensitivity of 100%, specificity of 96.1%, positive predictive value of 92.3%, negative predictive value of 100% and diagnostic accuracy of 96%. Only 24% of cFFR values were in the 0.84 to 0.87 range. CONCLUSION: Contrast medium induced hyperaemic FFR as an initial assessment may limit the need for adenosine to when cFFR falls in the 0.84 to 0.87 range. The use of adenosine infusion potentially could have been avoided in the majority of patients in this study. PMID- 28652032 TI - Long-Term Results of Surgical Atrial Fibrillation Radiofrequency Ablation: Comparison of Two Methods. AB - BACKGROUND: This retrospective study aimed to evaluate the long-term results of two kinds of surgical atrial fibrillation radiofrequency ablations in concomitant cardiac operations. METHODS: We enrolled 129 patients from January 2006 to December 2015 and performed cardiac operations concomitantly with surgical atrial fibrillation. The patients were divided into a biatrial MAZE group (94 patients) and a left atrial MAZE group (35 patients). A preoperative baseline was compared with intraoperative and postoperative data. Similarly, complications and follow up results were compared. A matching process based on propensity-score was performed to equalise the potential prognostic factors in both groups and to formulate a balanced 2:1 matched cohort study. RESULTS: There were four deaths (4.3%) in the biatrial MAZE group and one death in left atrial MAZE group due to multiple organ failures followed by low cardiac output. No permanent pacemaker implantations were used in either group. The sinus rhythm maintenance rates at the 6-month, 1-year, 6-year and 8-year follow-ups between the biatrial MAZE group and the left atrial MAZE group were not significantly different (84.7%, 83.3%, 67.3%, and 58.8% vs. 84.9%, 77.4%, 61.1%, and 50%, p>0.05). Similarly, between the propensity-score matched groups, there were no significant differences. CONCLUSION: The left atrial MAZE ablation for the patients with mitral valve diseases who needed open cardiac operation was safe and effective when compared with the biatrial MAZE ablation group. PMID- 28652033 TI - [Heart failure in primary care: Attitudes, knowledge and self-care]. AB - OBJECTIVE: To determine the attitudes, knowledge, and self-care practices in patients with heart failure (HF) in Primary Care, as well as to identify factors associated with better self-care. DESIGN: Cross-sectional and multicentre study. SETTING: Primary Care. PARTICIPANTS: Subjects over 18 years old with HF diagnosis, attended in 10 Primary Health Care Centres in the Metropolitan Area of Barcelona. MAIN MEASUREMENTS: Self-care was measured using the European Heart Failure Self-Care Behaviour Scale. Sociodemographic and clinical characteristics, tests on attitudes (Self-efficacy Managing Chronic Disease Scale), knowledge (Patient Knowledge Questionnaire), level of autonomy (Barthel), and anxiety and depression screening (Goldberg Test), were also gathered in an interview. A multivariate mixed model stratified by centre was used to analyse the adjusted association of covariates with self-care. RESULTS: A total of 295 subjects (77.6%) agreed to participate, with a mean age of 75.6 years (SD: 11), 56.6% women, and 62% with no primary education. The mean self-care score was 28.65 (SD: 8.22), with 25% of patients scoring lower than 21 points. In the final stratified multivariate model (n=282; R2 conditional=0.3382), better self-care was associated with higher knowledge (coefficient, 95% confidence interval: -1.37; 1.85 to -0.90), and coronary heart disease diagnosis (-2.41; -4.36: -0.46). CONCLUSION: Self-care was moderate. The correlation of better self-care with higher knowledge highlights the opportunity to implement strategies to improve self-care, which should consider the characteristics of heart failure patients attended in Primary Care. PMID- 28652034 TI - Adolescent mental health: reasons to be cheerful. PMID- 28652035 TI - Medical marijuana research for chronic pain. PMID- 28652036 TI - Editorial training models for early-career psychiatrists. PMID- 28652037 TI - Corrections. PMID- 28652038 TI - Ethnicity, mortality, and severe mental illness - Authors' reply. PMID- 28652039 TI - Ethnicity, mortality, and severe mental illness. PMID- 28652040 TI - Imipramine for multiple functional somatic syndromes. PMID- 28652041 TI - Imipramine for multiple functional somatic syndromes - Authors' reply. PMID- 28652042 TI - Comorbidity of depression and anxiety in exercise research. PMID- 28652043 TI - On psychiatry unlocked. PMID- 28652044 TI - Sesame Street's recognition of autism. PMID- 28652046 TI - Brenda Penninx: puzzling over depression. PMID- 28652047 TI - Lifestyle interventions to reduce premature mortality in schizophrenia. PMID- 28652049 TI - Evaluation of Texture Analysis Parameter for Response Prediction in Patients with Hepatocellular Carcinoma Undergoing Drug-eluting Bead Transarterial Chemoembolization (DEB-TACE) Using Biphasic Contrast-enhanced CT Image Data: Correlation with Liver Perfusion CT. AB - RATIONALE AND OBJECTIVES: This study aimed to evaluate the potential role of computed tomography texture analysis (CTTA) of arterial and portal-venous enhancement phase image data for prediction and accurate assessment of response of hepatocellular carcinoma undergoing drug-eluting bead transarterial chemoembolization (TACE) by comparison to liver perfusion CT (PCT). MATERIALS AND METHODS: Twenty-eight patients (27 male; mean age 67.2 +/- 10.4) with 56 hepatocellular carcinoma-typical liver lesions were included. Arterial and portal venous phase CT data obtained before and after TACE with a mean time of 39.93 +/- 62.21 days between examinations were analyzed. TACE was performed within 48 hours after first contrast-enhanced CT. CTTA software was a prototype. CTTA analysis was performed blinded (for results) by two observers separately. Combined results of modified Response Evaluation Criteria In Solid Tumors (mRECIST) and PCT of the liver were used as the standard of reference. Time to progression was additionally assessed for all patients. CTTA parameters included heterogeneity, intensity, average, deviation, skewness, and entropy of co-occurrence. Each parameter was compared to those of PCT (blood flow [BF], blood volume, arterial liver perfusion [ALP], portal-venous perfusion, and hepatic perfusion index) measured before and after TACE. RESULTS: mRECIST + PCT yielded 28.6% complete response (CR), 42.8% partial response, and 28.6% stable disease. Significant correlations were registered in the arterial phase in CR between changes in mean heterogeneity and BF (P = .004, r = -0.815), blood volume (P = .002, r = -0.851), and ALP (P = .002, r = -0.851), respectively. In the partial response group, changes in mean heterogeneity correlated with changes in ALP (P = .003) and to a lesser degree with hepatic perfusion index (P = .027) in the arterial phase. In the stable disease group, BF correlated with entropy of nonuniformity (P = .010). In the portal-venous phase, no statistically significant correlations were registered in all groups. Receiver operating characteristic analysis of CTTA parameters yielded predictive cutoff values for CR in the arterial contrast enhanced CT phase for uniformity of skewness (sensitivity: 90.0%; specificity: 45.8%), and in the portal-venous phase for uniformity of heterogeneity (sensitivity: 92.3%; specificity: 81.8%). CONCLUSIONS: Significant correlations exist between CTTA parameters and those derived from PCT both in the pre- and the post-TACE settings, and some of them have predictive value for TACE midterm outcome. PMID- 28652048 TI - The Efficacy of Low-intensity Vibration to Improve Bone Health in Patients with End-stage Renal Disease Is Highly Dependent on Compliance and Muscle Response. AB - RATIONAL AND OBJECTIVES: Low intensity vibration (LIV) may represent a nondrug strategy to mitigate bone deficits in patients with end-stage renal disease. MATERIALS AND METHODS: Thirty end-stage renal patients on maintenance hemodialysis were randomized to stand for 20 minutes each day on either an active or placebo LIV device. Analysis at baseline and completion of 6-month intervention included magnetic resonance imaging (tibia and fibula stiffness; trabecular thickness, number, separation, bone volume fraction, plate-to-rod ratio; and cortical bone porosity), dual-energy X-ray absorptiometry (hip and spine bone mineral density [BMD]), and peripheral quantitative computed tomography (tibia trabecular and cortical BMD; calf muscle cross-sectional area). RESULTS: Intention-to-treat analysis did not show any significant changes in outcomes associated with LIV. Subjects using the active device and with greater than the median adherence (70%) demonstrated an increase in distal tibia stiffness (5.3%), trabecular number (1.7%), BMD (2.3%), and plate-to-rod ratio (6.5%), and a decrease in trabecular separation (-1.8%). Changes in calf muscle cross-sectional area were associated with changes in distal tibia stiffness (R = 0.85), trabecular bone volume/total volume (R = 0.91), number (R = 0.92), and separation (R = -0.94) in the active group but not in the placebo group. Baseline parathyroid hormone levels were positively associated with increased cortical bone porosity over the 6-month study period in the placebo group (R = 0.55) but not in the active group (R = 0.01). No changes were observed in the nondistal tibia locations for either group except a decrease in hip BMD in the placebo group (-1.7%). CONCLUSION: Outcomes and adherence thresholds identified from this pilot study could guide future longitudinal studies involving vibration therapy. PMID- 28652050 TI - Quantitative measurement of retinal vascular diameter changes in the early postoperative period after strabismus surgery. AB - PURPOSE: To investigate quantitatively the retinal vascular diameter changes before and after strabismus surgery, analyzing the potential hemodynamic changes that may occur in the retinal circulation. METHODS: Consecutive patients with horizontal strabismus who underwent strabismus surgery were prospectively enrolled. Color fundus photographs were taken of each eye before and 1 day after surgery. The retinal vessel diameters were measured using computer-assisted quantitative assessment software. Paired-sample t test was used to evaluate the central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and arteriovenous ratio (AVR) before and 1 day after surgery. We also analyzed those changes in different subgroups according to surgical protocols. RESULTS: A total of 217 eyes of 148 patients were included. Compared with the data before surgery, the mean CRAE significantly increased 1 day after surgery (P = 0.01), so did the AVR (P = 0.003). There was no significant difference with respect to CRVE (P = 0.43). The CRAE and AVR were not significantly different in the lateral rectus recession group. CONCLUSIONS: Strabismus surgery on horizontal rectus muscles may change retinal hemodynamics by increasing the central retinal arteriolar diameter during the early postoperative period. PMID- 28652051 TI - The visual system in infants with microcephaly related to presumed congenital Zika syndrome. AB - PURPOSE: To describe and analyze ocular features in infants with microcephaly due to presumed congenital Zika syndrome. METHODS: Ophthalmologic evaluation, including indirect ophthalmoscopy and eye fundus imaging, visual acuity testing with Teller Acuity Cards, and strabismus assessment were performed in infants with microcephaly at a nongovernmental organization clinic for visually disabled children. RESULTS: A total of 70 infants with microcephaly were referred to the clinic. Of these, 25 (mean age, 3 months; 14 males) had ophthalmologic changes: 18 (26%) had intraocular abnormalities, including macular chorioretinal atrophy, mottled retinal pigment epithelium and optic nerve pallor; 7 patients (10%) had strabismus or nystagmus without intraocular abnormalities. Visual acuity was below normal range in all 11 infants tested. CONCLUSIONS: Ophthalmologic abnormalities occurred in 36% of the patients. Macular circumscribed chorioretinal atrophy, focal mottled retinal pigment epithelium, optic nerve pallor, early-onset strabismus, nystagmus and low visual acuity were common ophthalmological features in infants with microcephaly due to presumed congenital Zika syndrome. PMID- 28652052 TI - A double-masked randomized trial of postoperative local anaesthetic for pain control in pediatric strabismus surgery. PMID- 28652053 TI - MR imaging in hyperacute ischemic stroke. AB - Brain and vascular imaging are required components of the emergency assessment of patients with suspected stroke. Either CT or MRI may be used as the initial imaging test. MRI is more sensitive to the presence of acute and chronic ischemic lesions, and chronic microbleeds, but CT remains the most practical and used initial brain imaging test. Although, a non-enhanced CT or T2* MRI sequence showing no haemorrhage is sufficient for deciding intravenous treatment eligibility within the first 4.5h after stroke onset, a non-invasive intracranial vascular study is strongly recommended during the initial imaging evaluation of the acute stroke patient, particularly if mechanical thrombectomy is contemplated. Advanced imaging with multimodal MRI may facilitate accurate ischemic stroke diagnosis and characterization, and should be considered as an alternative to CT, especially for the selection of patients for acute reperfusion therapy in extended time windows, and in patients in which time of stroke onset is unknown. However, MRI should only be considered in the acute stroke workflow if centres are able to achieve speed and triaging efficiency similar to that which is currently available with CT-based imaging. PMID- 28652054 TI - Coracoid bone block transfer procedure: Correlation between subscapularis volume below the bone graft and shoulder stability. AB - INTRODUCTION: Coracoid bone graft transfer has become the gold standard in patients with recurrent anterior shoulder instability associated with bony defect. Several studies have shown that the main stabilizing component of this procedure is the sling effect by the conjoint tendon and the lower portion of subscapularis (SS). The purpose of this study was to determine whether a larger SS volume below the bone block was correlated to greater postoperative shoulder stability. MATERIALS AND METHODS: This prospective study included a cohort of patients who underwent open coracoid bone graft transfer for post-traumatic recurrent anterior shoulder instability. Forty patients were reviewed at 2 years with a clinical and CT scan evaluation. A correlation analysis assessed the relation between the SS volume index (ratio of SS volume below the bone block to volume over the bone block) and Rowe and Walch-Duplay instability scores. RESULTS: There exists a positive and significant correlation between SS volume index and postoperative Rowe score, r=0.37 (P=0.03). The same trend was observed for Walch-Duplay score without statistical significance. A larger inferior SS volume did not result in a limitation of external rotation, greater fatty infiltration, or malposition of the coracoid graft. CONCLUSION: A larger SS volume below the bone block is related to greater postoperative shoulder stability. We recommend performing the split in the middle of the SS or higher instead of the junction of the superior two-thirds and inferior one-third as usually reported. LEVEL OF EVIDENCE: III, prospective study. PMID- 28652055 TI - Access to a Loaded Gun Without Adult Permission and School-Based Bullying. AB - PURPOSE: Gun access and bullying are risk factors for sustaining or perpetrating violence among adolescents. Our knowledge of gun access among bullied students is limited. METHODS: We used data on students, aged 12-18 years, from the 2011 and 2013 School Crime Supplement to the National Crime Victimization Survey to assess the association between self-reported bullying victimization (traditional and cyber) and access to a loaded gun without adult permission. Prevalence ratios (PRs) and confidence intervals (CIs) were obtained from multivariable Poisson regression using the Taylor series after controlling for student age, sex, family income, public/private school, and race. RESULTS: Of 10,704 participants, 4.2% (95% CI: 3.8%-4.6%) reported gun access. Compared with nonbullied students, those who reported traditional bullying (PR = 2.2; 95% CI: 1.7-2.4), cyberbullying (PR = 2.8; 95% CI: 1.6-4.9), and both (PR = 5.9; 95% CI: 4.6-7.7) were more likely to also report gun access. CONCLUSIONS: Adolescents who experience bullying, particularly those who report both traditional bullying and cyberbullying, are more likely to report access to a loaded gun without adult permission. These findings highlight the importance of developing interventions focused on these modifiable risk factors for preventing self-directed or interpersonal violence among youth. PMID- 28652056 TI - Oxidative stress contributes to hepatocyte growth factor-dependent pro-senescence activity of ovarian cancer cells. AB - The cancer-promoting activity of senescent peritoneal mesothelial cells (HPMCs) has already been well evidenced both in vitro and in vivo. Here we sought to determine if ovarian cancer cells may activate senescence in HPMCs. The study showed that conditioned medium (CM) from ovarian cancer cells (OVCAR-3, SKOV-3, A2780) inhibited growth and promoted the development of senescence phenotype (increased SA-beta-Gal, gamma-H2A.X, 53BP1, and decreased Cx43) in HPMCs. An analysis of tumors isolated from the peritoneum of patients with ovarian cancer revealed an abundance of senescent HPMCs in proximity to cancerous tissue. The presence of senescent HPMCs was incidental when fragments of peritoneum free from cancer were evaluated. An analysis of the cells' secretome followed by intervention studies with exogenous proteins and neutralizing antibodies revealed hepatocyte growth factor (HGF) as the mediator of the pro-senescence impact of the cancer cells. The activity of cancerous CM and HGF was associated with an induction of mitochondrial oxidative stress. Signaling pathways involved in the senescence of HPMCs elicited by the cancer-derived CM and HGF included p38 MAPK, AKT and NF-kappaB. HPMCs that senesced prematurely in response to the cancer derived CM promoted adhesion of ovarian cancer cells, however this effect was effectively prevented by the cell protection against oxidative stress. Collectively, our findings indicate that ovarian cancer cells can elicit HGF dependent senescence in HPMCs, which may contribute to the formation of a metastatic niche for these cells within the peritoneal cavity. PMID- 28652057 TI - Carotid Endarterectomy Induces the Release of Inflammatory Markers and the Activation of Coagulation as Measured in the Jugular Bulb. AB - BACKGROUND AND PURPOSE: Transient cerebral hypoxia may induce neuronal injury through an ischemia-reperfusion (I/R) response, with a subsequent activation of inflammation and coagulation-fibrinolysis. During carotid endarterectomy (CEA), the artery is clamped, which might impair the regional cerebral perfusion and initiate a local I/R response. Data suggest that the CD40-CD40 ligand dyad acts as a modulator in the induced activation. The aim of this study was to locally measure soluble CD40 ligand (sCD40L), in conjunction with inflammation and coagulation activation markers, during CEA. SUBJECTS AND METHODS: This is a prospective study of 18 patients undergoing CEA. Blood samples from the venous jugular bulb (JB) and the radial artery (RA) were drawn at baseline and during the procedure. Measurements of sCD40L, interleukin-6 (IL-6), fragment 1 + 2 (F1 + 2), plasminogen activator inhibitor-1 (PAI-1), and d-dimer were analyzed. Comparisons during CEA were made between levels: baselines versus JB, JB versus RA, and sequential JB measurements. Fifty cardiovascular healthy patients were the reference group for the sCD40L baseline comparison. RESULTS: Increased cerebral IL-6 levels were demonstrated throughout the procedure, as well as the temporal influence in F1 + 2, PAI-1, and d-dimer values. sCD40L remained unchanged throughout the procedure . This indicates a local cerebral inflammatory reaction together with an activation of coagulation-fibrinolysis, but it does not appear to primarily involve the CD40-CD40 ligand dyad. CONCLUSIONS: Signs of a local inflammatory reaction and activation of coagulation were observed during CEA, but levels of sCD40L remained stable, unaffected by carotid artery clamping and reperfusion. PMID- 28652058 TI - Repeated Paradoxical Brain Infarctions in a Patient on Self-Managed Home Hemodialysis Using a Long-Term Indwelling Catheter. AB - We describe the case of a 51-year-old Japanese man with an end-stage kidney disease caused by a 30-year history of type 1 diabetes mellitus. The patient had suffered repeated bilateral multiple brain infarctions within a short period of time after the initiation of a self-managed daily home hemodialysis regimen using a long-term indwelling catheter inserted into the right atrium. Despite extensive examinations, we could not find any embolic causes except for the catheter and a patent foramen ovale (PFO). The patient had experienced repeated brain infarctions under antiplatelet and anticoagulation therapies, but suffered no further brain infarctions after the removal of the catheter and the alteration of vascular access from the catheter to an arteriovenous fistula in the forearm. We speculate that the indwelling catheter-associated thrombi or air and the right-to left shunt through the PFO may have caused the repeated paradoxical brain embolisms in this patient. PMID- 28652060 TI - Reliability and Utility of the Alberta Stroke Program Early Computed Tomography Score in Hyperacute Stroke. AB - GOAL: The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on non contrast computed tomography (NCCT) is dependent on the visibility of early ischemic change. The goal of our study was to evaluate whether time from ischemic stroke onset to initial NCCT influences the inter-rater variability and prognostic accuracy of ASPECTS for a 3-month functional outcome. MATERIALS AND METHODS: Ischemic stroke patients treated with intravenous tissue plasminogen activator (IV-tPA) from 2007 to 2014 at the Royal Melbourne Hospital were included. ASPECTS were blindly assessed by 2 independent raters with inter-rater agreement determined by weighted kappa. Onset time to computed tomography time was dichotomized at the median (<=100 and >100 minutes). Outcome was assessed using the modified Rankin Scale. Logistic regression and receiver operating characteristic analysis were used to assess the prognostic utility of ASPECTS in the early and later time periods. RESULTS: There were 379 patients included. Inter-rater agreement was significantly lower in the early time period: kappa = .75 (95% confidence interval (CI), .59-.84) <= 100 minutes versus .92 (95% CI, .91-.93) > 100 minutes, P < .001. The distributions of absolute inter-rater differences in ASPECTS differed significantly between time epochs (P = .03). The prognostic accuracies of ASPECTS across time epochs were area under the receiver operating characteristic curve <= 100 minutes = .57 (95% CI, .50-.64) and >100 minutes = .66 (95% CI, .59-.73), P = .055. CONCLUSIONS: This study demonstrated a significantly lower inter-rater agreement and a trend toward reduced prognostic accuracy of ASPECTS in earlier time periods. The use of ASPECTS to select patients for revascularization in early time windows may be unreliable. PMID- 28652059 TI - Burden and Predictors of Poststroke Cognitive Impairment in a Sample of Ghanaian Stroke Survivors. AB - BACKGROUND AND OBJECTIVE: There are limited data on vascular cognitive impairment (VCI) from low- and middle-income countries where the stroke burden is burgeoning. The aim of this study was to characterize the burden, determinants, and effects of VCI on health-related quality of life in sub-Saharan Africa (SSA). METHODS: From January 2015 to February 2016, we collected information on 147 consecutive stroke survivors (>45 years) seen at a tertiary hospital in Ghana and 49 demographically matched stroke-free controls. Data collected included demographics, clinical factors, health-related quality of life, and presence of depression. Cognitive status was evaluated using a standard Vascular Neuropsychological Battery that assessed memory, executive function and mental speed, language, and visuospatial-visuoconstructive functioning. Expert VCI guideline and Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria were used to classify stroke patients into no VCI, VCI but no dementia, and vascular dementia (VD). RESULTS: The mean age +/- standard deviation of the stroke survivors was 59.9 +/- 13.7 years, of which 47.6% were women. Among the cohort, 77 out of 147 (52.3%) had no VCI, 50 of the 147 (34.0%) had VCI without dementia, and 20 of the 147 (13.6%) had VD. Three factors remained significantly associated with VCI: increasing age for each successive 10 year rise (odds ratio [OR] 1.44, 95% confidence interval [CI]: 1.03-2.02), lack of formal education (OR 5.26, 95% CI: 1.01-27.52), and worse functional disability on the modified Rankin scale (OR 2.46, 95% CI: 1.61-3.75). Patients with VD had the poorest health-related quality of life. CONCLUSIONS: Half of the Ghanaian stroke survivors encountered in this cross-sectional study had evidence of cognitive dysfunction. Future studies in SSA will need to identify strategies to address this immense burden. PMID- 28652061 TI - Resting Heart Rate Predicts Depression and Cognition Early after Ischemic Stroke: A Pilot Study. AB - BACKGROUND: Early detection of poststroke depression (PSD) and cognitive impairment (PSCI) remains challenging. It is well documented that the function of autonomic nervous system is associated with depression and cognition. However, their relationship has never been investigated in the early poststroke phase. This pilot study aimed at determining whether resting heart rate (HR) parameters measured in early poststroke phase (1) are associated with early-phase measures of depression and cognition and (2) could be used as new tools for early objective prediction of PSD or PSCI, which could be applicable to patients unable to answer usual questionnaires. METHODS: Fifty-four patients with first-ever ischemic stroke, without cardiac arrhythmia, were assessed for resting HR and heart rate variability (HRV) within the first week after stroke and for depression and cognition during the first week and at 3 months after stroke. RESULTS: Multiple regression analyses controlled for age, gender, and stroke severity revealed that higher HR, lower HRV, and higher sympathovagal balance (low-frequency/high-frequency ratio of HRV) were associated with higher severity of depressive symptoms within the first week after stroke. Furthermore, higher sympathovagal balance in early phase predicted higher severity of depressive symptoms at the 3-month follow-up, whereas higher HR and lower HRV in early phase predicted lower global cognitive functioning at the 3-month follow-up. CONCLUSIONS: Resting HR measurements obtained in early poststroke phase could serve as an objective tool, applicable to patients unable to complete questionnaires, to help in the early prediction of PSD and PSCI. PMID- 28652062 TI - Measurement Conditions of End-Diastolic Ratio of Common Carotid Arteries Alter Diagnostic Ability for Large Artery Intracranial Occlusive Disease. AB - BACKGROUND: End-diastolic ratio, calculated by the side-to-side ratio of end diastolic flow velocities of the common carotid arteries, is an indicator for large artery intracranial occlusive disease. However, the diagnostic ability of end-diastolic ratios derived from different measurement conditions is unclear. METHODS: End-diastolic ratios were measured twice by single carotid duplex ultrasonography. End-diastolic ratio1st was calculated from separate end diastolic flow velocities measured during routine assessment. End-diastolic ratio2nd was calculated almost simultaneously without head rotation. For each end diastolic ratio, the measurement conditions and prediction ability for occlusions of the internal carotid artery or proximal portion of the middle cerebral artery using an established cutoff of 1.4 or greater were compared. RESULTS: Two hundred thirty-three patients (147 men, median 67 years) were registered, with available intracranial artery information in 158 patients (67.8%) and occlusions detected in 7 patients (4.4%). End-diastolic ratio1st was significantly higher than end diastolic ratio2nd (median 1.21 versus 1.08, P < .001). Compared with end diastolic ratio1st, end-diastolic ratio2nd had a significantly shorter time interval (median 709 versus 28 seconds, P < .001) and smaller pulse rate difference (1.54 +/- 5.10 versus .25 +/- 4.63 beats per minute, P = .004). To predict occlusions, the sensitivity, specificity, and overall accuracy for end diastolic ratio1st of 1.4 or greater were 85.7%, 70.9%, and 71.5%, respectively, and for end-diastolic ratio2nd of 1.4 or greater were 85.7%, 98.0%, and 97.5%, respectively. End-diastolic ratio2nd had better specificity and overall accuracy than end-diastolic ratio1st (P < .001). CONCLUSIONS: End-diastolic ratio varies with measurement conditions. Combined end-diastolic flow velocities measurement may improve diagnostic ability for large artery intracranial occlusive disease. PMID- 28652063 TI - Comparator choice in cariology trials limits conclusions on the comparative effectiveness of caries interventions. AB - OBJECTIVES: Comparator choice has been found as one major factor impacting on the overall evidence supporting clinical interventions. We performed social network analysis (SNA) on trials on the prevention/management of caries/carious lesions, hypothesizing that certain comparators are proportionally overinvestigated, and others underinvestigated, and that comparisons within comparator classes are preferred over comparisons between classes. STUDY DESIGN AND SETTING: A systematic review of randomized controlled trials on the prevention/management of caries/existing carious lesions was carried out. All comparators were classified at each of three levels of granularity, becoming more detailed with each level: (1) degree of invasiveness (noninvasive, microinvasive, or invasive), (2) the specific noninvasive, microinvasive, or invasive approach, and (3) the actual material or technique used. SNA was used to evaluate trial networks. RESULTS: Searching electronic databases found 4,774 articles; of which, 764 were relevant and 605 were included. The networks for all levels were polygonal. There was a high degree of separation of comparisons in prevention vs. management trials. Invasive comparators were tested most frequently (number of comparators: 592), mainly in management trials. Noninvasive comparators were tested next often (464), mainly in caries prevention. Microinvasive strategies were tested next often (234), in both prevention and management trials. On more granular levels, few interventions dominated the networks. Regardless of the level, most trials compared within and not between classes. Prevention trials were mainly conducted in children (number of trials in adults/children/both: 37/240/11), whereas those on managing lesions were conducted in both children and adults (117/176/21). CONCLUSION: Comparator choice in cariology trials is driven by indication and limits conclusions on the true comparative effectiveness of all strategies. There are a variety of comparators that have not been, but should be, compared with one another, which should be addressed by future trials. Factors underlying trialists' comparator choice need to be identified. PMID- 28652064 TI - Randomized Trial on the Effects of Attentional Focus on Motor Training of the Upper Extremity Using Robotics With Individuals After Chronic Stroke. AB - OBJECTIVE: To compare the long-term effects of external focus (EF) and internal focus (IF) of attention after 4 weeks of arm training. DESIGN: Randomized, repeated-measures, mixed analysis of variance. SETTING: Outpatient clinic. PARTICIPANTS: Individuals with stroke and moderate-to-severe arm impairment living in the community (N=33; withdrawals: n=3). INTERVENTIONS: Four-week arm training protocol on a robotic device (12 sessions). MAIN OUTCOME MEASURES: Joint independence, Fugl-Meyer Assessment, and Wolf Motor Function Test measured at baseline, discharge, and 4-week follow-up. RESULTS: There were no between-group effects for attentional focus. Participants in both groups improved significantly on all outcome measures from baseline to discharge and maintained those changes at 4-week follow-up regardless of group assignment (joint independence EF condition: F1.6,45.4=17.74; P<.0005; partial eta2=.39; joint independence IF condition: F2,56=18.66; P<.0005; partial eta2=.40; Fugl-Meyer Assessment: F2,56=27.83; P<.0005; partial eta2=.50; Wolf Motor Function Test: F2,56=14.05; P<.0005; partial eta2=.35). CONCLUSIONS: There were no differences in retention of motor skills between EF and IF participants 4 weeks after arm training, suggesting that individuals with moderate-to-severe arm impairment may not experience the advantages of an EF found in healthy individuals. Attentional focus is most likely not an active ingredient for retention of trained motor skills for individuals with moderate-to-severe arm impairment, whereas dosage and intensity of practice appear to be pivotal. Future studies should investigate the long-term effects of attentional focus for individuals with mild arm impairment. PMID- 28652065 TI - Effects of Transcranial Direct Current Stimulation With Sensory Modulation on Stroke Motor Rehabilitation: A Randomized Controlled Trial. AB - OBJECTIVE: To test whether a multistrategy intervention enhanced recovery immediately and longitudinally in patients with severe to moderate upper extremity (UE) paresis. DESIGN: Double-blind, randomized controlled trial with placebo control. SETTING: Outpatient department of a local medical center. PARTICIPANTS: People (N=25) with chronic stroke were randomly assigned to 1 of 2 groups: a transcranial direct current stimulation with sensory modulation (tDCS SM) group (n=14; mean age +/- SD, 55.3+/-11.4y) or a control group (n=11; mean age +/- SD, 56.9+/-13.5y). INTERVENTIONS: Eight-week intervention. The tDCS-SM group received bilateral tDCS, bilateral cutaneous anesthesia, and high repetitions of passive movements on the paretic hand. The control group received the same passive movements but with sham tDCS and sham anesthesia. During the experiment, all participants continued their regular rehabilitation. MAIN OUTCOME MEASURES: Voluntary UE movement, spasticity, UE function, and basic activities of daily living. Outcomes were assessed at baseline, at postintervention, and at 3- and 6-month follow-ups. RESULTS: No significant differences were found between groups. However, there was a trend that the voluntary UE movement improved more in the tDCS-SM group than in the control group, with a moderate immediate effect (partial eta2 [etap2]=.14, P=.07) and moderate long-term effects (3-mo follow-up: etap2=.17, P=.05; 6-mo follow-up: etap2=.12, P=.10). Compared with the control group, the tDCS-SM group had a trend of a small immediate effect (etap2=.02-.04) on reducing spasticity, but no long-term effect. A trend of small immediate and long-term effects in favor of tDCS-SM was found on UE function and daily function recovery (etap2=.02-.09). CONCLUSIONS: Accompanied with traditional rehabilitation, tDCS-SM had a nonsignificant trend of having immediate and longitudinal effects on voluntary UE movement recovery in patients with severe to moderate UE paresis after stroke, but its effects on spasticity reduction and functional recovery may be limited. PMID- 28652066 TI - Effects of Scapular Stabilization Exercise Training on Scapular Kinematics, Disability, and Pain in Subacromial Impingement: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effects of 2 different exercise programs on 3 dimensional scapular kinematics, disability, and pain in participants with subacromial impingement syndrome (SIS). DESIGN: Randomized controlled trial. SETTING: Outpatient clinic and research laboratory. PARTICIPANTS: Participants who were diagnosed with SIS and who also exhibited scapular dyskinesis (N=30). INTERVENTIONS: The participants were randomized in 2 different exercise groups: (1) shoulder girdle stretching and strengthening with additional scapular stabilization exercises based on a kinetic chain approach (intervention group), and (2) shoulder girdle stretching and strengthening exercises only (control group). MAIN OUTCOME MEASURES: Three-dimensional scapular kinematics, self reported shoulder pain, and disability were evaluated at baseline, after 6 weeks of training, and after 12 weeks of training. RESULTS: Significant differences were observed between the control and intervention groups in external rotation and posterior tilt after 6 weeks of training and in external rotation, posterior tilt, and upward rotation after 12 weeks of training. All groups showed improvement in self-reported pain and disability scores; however, there were no significant differences between the groups. CONCLUSIONS: Progressive exercise training independent from specific scapular stabilization exercises provides decreased disability and pain severity in impingement syndrome. PMID- 28652067 TI - Pain Intensity, Interference, and Medication Use After Spinal Cord Injury: Association With Risk of Mortality After Controlling for Socioeconomic and Other Health Factors. AB - OBJECTIVE: To identify the association of pain intensity, pain interference, and pain medication use with risk of mortality after spinal cord injury, controlling for demographic, injury, socioeconomic, and health factors. DESIGN: Prospective cohort study. SETTING: Academic medical center. PARTICIPANTS: All participants (N=2535) had traumatic spinal cord injury of at least 1-year duration at enrollment, with noncomplete recovery (American Spinal Injury Association Impairment Scale grades A-D). Mortality status was obtained for 2535 individuals, and 335 were deceased as of 2014. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mortality status as of December 31, 2014, identified by the National Death Index. RESULTS: Preliminary bivariate analyses indicated that deceased participants were more likely to be older at injury, have more years postinjury, be men, and have a severe injury, low income, less education, and poorer health indicators. The final Cox model indicated that those who used pain medication daily were 51% more likely to be deceased at follow-up (hazard ratio [HR], 1.51). Pain intensity and pain interference were not statistically significant. Nonchronic pressure ulcer was related to 67% higher mortality risk (HR, 1.67), and chronic pressure ulcer was related to 122% higher risk (HR, 2.22). Other health indicators also increased the risk of mortality from 43% to 73%, including hospitalization (HR, 1.54), depression (HR, 1.43), and amputation (HR, 1.73). CONCLUSIONS: Prescription pain medication use appears to have a direct association with mortality, beyond that associated with other characteristics, and should become a strong focus of prevention efforts. PMID- 28652068 TI - Epigenomic Susceptibility to the Social World: Plausible Paths to a "Newest Morbidity". AB - This article-presented on the celebratory occasion of Dr Robert Haggerty's 91st birthday-describes how a 1962 article by Dr Haggerty and his colleague Dr Roger Meyer launched a previously unexplored, pediatric research enterprise by asserting that: "There are little precise data to explain why one person becomes ill with an infecting agent and another not." Noting a prospective association between family stressors and the acquisition of beta-hemolytic streptococcal infections, the article introduced a generation of young academic pediatricians the author of the present article among them-to the possibility of causal linkages among children's adversity exposures, compromised immunological processes, and the development of immune-mediated, acute or chronic diseases of childhood. That research agenda has led, over the past 40 years, to the advent of psychoneuroimmunology as a field of study, to the recognition of childhood stress and adversity as potential etiologic agents among childhood morbidities, and to the discovery of differential susceptibility to social adversities within populations of children. PMID- 28652069 TI - Facilitating Tough Conversations: Using an Innovative Simulation-Primed Qualitative Inquiry in Pediatric Research. AB - Deep exploration of a complex health care issue in pediatrics might be hindered by the sensitive or infrequent nature of a particular topic in pediatrics. Health care simulation builds on constructivist theories to guide individuals through an experiential cycle of action, self-reflection, and open discussion, but has traditionally been applied to the educational domain in health sciences. Leveraging the emotional activation of a simulated experience, investigators can prime participants to engage in open dialogue for the purposes of qualitative research. The framework of simulation-primed qualitative inquiry consists of 3 main iterative steps. First, researchers determine applicability by consideration of the need for an exploratory approach and potential to enrich data through simulation priming of participants. Next, careful attention is needed to design the simulation, with consideration of medium, technology, theoretical frameworks, and quality to create simulated reality relevant to the research question. Finally, data collection planning consists of a qualitative approach and method selection, with particular attention paid to psychological safety of subjects participating in the simulation. A literature review revealed 37 articles that used this newly described method across a variety of clinical and educational research topics and used a spectrum of simulation modalities and qualitative methods. Although some potential limitations and pitfalls might exist with regard to resources, fidelity, and psychological safety under the auspices of educational research, simulation-primed qualitative inquiry can be a powerful technique to explore difficult topics when subjects might experience vulnerability or hesitation. PMID- 28652070 TI - Peer Victimization and Academic Performance in Primary School Children. AB - OBJECTIVE: Peer victimization is a common antecedent of poor social and emotional adjustment. Its relationship with objectively measured academic performance is unclear. In this study we aimed to quantify the cross-sectional associations between peer victimization and academic performance in a large population sample of children. METHODS: Eight- to 9-year-old children were recruited from a stratified random sample of primary schools in Australia. Academic performance was measured on a national achievement test (1 year of learning equals 40 points). Physical and verbal victimization were measured according to child self report. RESULTS: Multilevel mixed-effects linear regression analyses were conducted. For female children, verbal victimization was associated with poorer academic performance on writing (beta = 17.2; 95% confidence interval [CI], -28.2 to -6.2) and grammar/punctuation (beta = -20.8; 95% CI, -40.1 to -1.6). Physical victimization was associated with poorer performance on numeracy (male children: beta = -29.0; 95% CI, -53.8 to -4.1; female children: beta = -30.1; 95% CI, -56.6 to -3.5), and writing (female children: beta = -21.5; 95% CI, -40.4 to -2.7). Verbal and physical victimization were associated with poorer performance on reading (male children: beta = -31.5; 95% CI, -59.9 to -3.1; female children: beta = -30.2; 95% CI, -58.6 to -1.8), writing (female children: beta = -25.5; 95% CI, -42.8 to -8.2), spelling (female children: beta = -32.3; 95% CI, -59.6 to 4.9), and grammar/punctuation (female children: beta = -32.2; 95% CI, -62.4 to 2.0). CONCLUSIONS: Children who were physically victimized were 6 to 9 months behind their non-victimized peers on measures of academic performance. There are growing reasons for education systems to invest in the prevention of bullying and promotion of positive peer relationships from the earliest years of school. PMID- 28652071 TI - Advances in biomaterials for preventing tissue adhesion. AB - Adhesion is one of the most common postsurgical complications, occurring simultaneously as the damaged tissue heals. Accompanied by symptoms such as inflammation, pain and even dyskinesia in particular circumstances, tissue adhesion has substantially compromised the quality of life of patients. Instead of passive treatment, which involves high cost and prolonged hospital stay, active intervention to prevent the adhesion from happening has been accepted as the optimized strategy against this complication. Herein, this paper will cover not only the mechanism of adhesion forming, but also the biomaterials and medicines used in its prevention. Apart from acting as a direct barrier, biomaterials also show promising anti-adhesive bioactivity though their intrinsic physical and chemical are still not completely unveiled. Considering the diversity of human tissue organization, it is imperative that various biomaterials in combination with specific medicine could be tuned to fit the microenvironment of targeted tissues. With the illustration of different adhesion mechanism and solutions, we hope this review can become a beacon and further inspires the development of anti-adhesion biomedicines. PMID- 28652072 TI - Evaluation of a hepatitis C education intervention with clients enrolled in methadone maintenance and needle/syringe programs in Malaysia. AB - BACKGROUND: Approximately 40%-90% of people who inject drugs (PWID) in Malaysia have hepatitis C (HCV). PWID continue to be disproportionately affected by HCV due to their lack of knowledge, perceived risk and interest in HCV treatment. Education interventions may be an effective strategy for increasing HCV knowledge in PWID, and harm reduction services are uniquely positioned to implement and deploy such interventions. METHODS: We recruited 176 clients from methadone maintenance treatment (MMT: N=110) and needle/syringe programs (NSP: N=66) between November 2015 and August 2016. After baseline knowledge assessments, clients participated in a standardized, 45-min HCV education program and completed post-intervention knowledge assessments to measure change in knowledge and treatment interest. RESULTS: Participants were mostly male (96.3%), Malay (94.9%), and in their early 40s (mean=42.6years). Following the intervention, overall knowledge scores and treatment interest in MMT clients increased by 68% and 16%, respectively (p<0.001). In contrast, NSP clients showed no significant improvement in overall knowledge or treatment interest, and perceived greater treatment barriers. Multivariate linear regression to assess correlates of HCV knowledge post-intervention revealed that optimal dosage of MMT and having had an HIV test in the past year significantly increased HCV knowledge. Having received a hepatitis B vaccine, however, was not associated with increased HCV knowledge after participating in an education session. CONCLUSION: Generally, HCV knowledge and screening is low among clients engaged in MMT and NSP services in Malaysia. Integrating a brief, but comprehensive HCV education session within harm reduction services may be a low-cost and effective strategy in improving overall HCV knowledge and risk behaviors in resource-limited settings. In order to be an effective public health approach, however, education interventions must be paired with strategies that improve social, economic and political outcomes for PWID. Doing so may reduce HCV disparities by increasing screening and treatment interest. PMID- 28652073 TI - Antiviral Strategies against PRRSV Infection. AB - PRRSV (porcine reproductive and respiratory syndrome virus) is a major economically significant pathogen that has adversely impacted the global swine industry for almost 30 years. Currently PRRSV is estimated to cause losses of almost US$600 million per year in the USA. Except for new mutants that continually emerge during PRRSV outbreaks, our understanding of the virology, origin, and evolution of PRRSV and the host's immune response are largely inadequate. Such limited knowledge impedes development of effective methods to eradicate this virus. In this review, we systematically describe recent advances in anti-PRRSV research, especially focusing on those techniques with the potential to transform current anti-PRRSV strategies. Furthermore, a combination of these new techniques may provide creative insights to guide future PRRSV control and prevention. PMID- 28652074 TI - Vitamin D deficiency: Time for a reality check of the epidemiology. Re. "The increasing problem of subclinical and overt hypervitaminosis D in India: An institutional experience and review." PMID- 28652075 TI - Minimizing the discrepancy between implant platform and alveolar bone for tilted implants with a sloped implant platform: A clinical report. AB - In a patient with edentulism, distally tilted implants with a novel sloped implant platform were used to minimize the discrepancy between the implant platform and alveolar bone crest and to restore complete-arch monolithic zirconia implant-supported fixed prostheses. PMID- 28652076 TI - Radical-trapping and preventive antioxidant effects of 2-hydroxymelatonin and 4 hydroxymelatonin: Contributions to the melatonin protection against oxidative stress. AB - BACKGROUND: Melatonin is well known for its antioxidant capacity, which has been attributed to the combined protective effects of the parent molecule and its metabolites. However, the potential role of 2-hydroxymelatonin (2OHM) and 4 hydroxymelatonin (4OHM) in such protection has not been previously investigated. METHODS: The calculations were performed using the Density Functional Theory, with the M05-2X and M05 functionals, the 6-311+G(d,p) basis set and the solvation model based on density (SMD). RESULTS: 4OHM shows excellent antioxidant activity via radical-trapping, reacting with peroxyl radicals faster than Trolox and melatonin. 4OHM can be moderately efficient as a preventing antioxidant by inhibiting Cu(II). This effect would lower the Cu(I) availability, which is the redox state required for the OH to be formed, via Fenton-like reactions. 4OHM turns off the oxidant effects of copper-ascorbate mixtures. The presence of a phenolic group was identified as the key structural feature in the antioxidant activity of 4OHM. On the other hand, 2OHM does not present a phenolic group, despite its formal name. Its keto tautomer was identified as the most abundant one (~100%). This may explain the relative low antioxidant protection of 2OHM. CONCLUSIONS: 4OHM significantly contributes to the overall antioxidant activity exhibited by melatonin, while the effects of 2OHM in this context are predicted to be only minor. This low reactivity might justify the relatively large abundance of 2OHM in biological systems. GENERAL SIGNIFICANCE: Hydroxylated melatonin metabolites, such as 4OHM, may play an important role in the protective effects of melatonin against oxidative stress. PMID- 28652077 TI - Vitamin C deficiency exacerbates diabetic glomerular injury through activation of transforming growth factor-beta signaling. AB - BACKGROUND: The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (VC) in diabetic humans and experimentally diabetic animals. Herein, we access the effects of VC deficiency on the diabetic kidney injury and explore the underlying mechanism. METHODS: l-gulonolactone oxidase conventional knockout (Gulo-/-) mice genetically unable to synthesize VC were subjected to streptozotocin-induced diabetic kidney injury and the role of VC deficiency was evaluated by biochemical and histological approaches. Rat mesangial cells were cultured to investigate the underlying mechanism. RESULTS: Functionally, VC deficiency aggravates the streptozotocin-induced renal insufficiency, exhibiting the increased urine albumin, water intake, and urine volume in Gulo-/- mice. Morphologically, VC deficiency exacerbates the streptozotocin-induced kidney injury, exhibiting the increased glomerular expansion, deposition of Periodic Acid-Schiff- and Masson-positive materials, and expression of alpha-smooth muscle actin, fibronectin and type 4 collagen in glomeruli of Gulo-/- mice. Mechanistically, VC activates protein kinase B (Akt) to destabilize Ski and thereby induce the expression of Smad7, resulting in suppression of TGF-beta/Smad signaling and extracellular matrix deposition in mesangial cells. CONCLUSIONS: VC is essential for the renal function maintenance in diabetes. GENERAL SIGNIFICANCE: Compensation for the loss of VC could be an effective remedy for diabetic kidney injury. PMID- 28652079 TI - Publishing code: an initiative to enhance transparency of data analyses reported in Journal of Physiotherapy. PMID- 28652078 TI - Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions. AB - BACKGROUND: Cytochrome c is well known to be released from mitochondria into the cytosol where it can initiate apoptosis. Recent studies indicate that cytochrome c is also released into the extracellular space by both healthy and damaged cells, where its function is not well understood. We hypothesized that extracellular cytochrome c could function as an intercellular signaling molecule of the brain, which is recognized by brain microglia. These cells belong to the mononuclear phagocyte system and can be activated by endogenous substances associated with diverse pathologies including trauma, ischemic damage and neurodegenerative diseases. METHODS: Three different cell types were used to model microglia. Respiratory burst activity, nitric oxide production and cytotoxic secretions were measured following exposure of microglial cells to cytochrome c. RESULTS: We showed that extracellular cytochrome c primed the respiratory burst response of differentiated HL-60 cells, enhanced nitric oxide secretion by BV-2 cells, and augmented cytotoxicity of differentiated THP-1 cells. We demonstrated that the effects of cytochrome c on microglia-like cells were at least partially mediated by the toll-like receptor 4 (TLR4) and c-Jun N terminal kinases (JNK) signaling pathway. CONCLUSIONS: Extracellular cytochrome c can interact with microglia TLR4 and modulate select functions of these brain immune cells. GENERAL SIGNIFICANCE: Our data identifies extracellular cytochrome c as a potential intercellular signaling molecule, which may be recognized by microglia causing or enhancing their immune activation. The data obtained support targeting TLR4 and JNK signaling as potential treatment strategies for brain diseases characterized by excessive cellular death and activation of microglia. PMID- 28652080 TI - People attending pulmonary rehabilitation demonstrate a substantial engagement with technology and willingness to use telerehabilitation: a survey. AB - QUESTIONS: What is the level of technology engagement by people attending pulmonary rehabilitation? Are participant demographics and level of technology engagement associated with willingness to use telerehabilitation? DESIGN: A cross sectional, multicentre study involving quantitative survey analysis. PARTICIPANTS: Convenience sample of people with chronic respiratory disease attending a pulmonary rehabilitation program, maintenance exercise class or support group. OUTCOME MEASURES: The survey assessed the participants' level of technology engagement (access to and use of devices), self-rated skill competence, access to online health information and willingness to use telerehabilitation. RESULTS: Among the 254 people who were invited, all agreed to complete the survey (100% response rate). Among these 254 respondents, 41% were male, the mean age was 73 years (SD 10), and the mean forced expiratory volume in 1second (FEV1) was 59% predicted (SD 23). Ninety-two percent (n=233) of participants accessed at least one technological device, of whom 85% (n=198) reported regularly using mobile phones and 70% (n=164) regularly used a computer or tablet. Fifty-seven percent (n=144) of participants self-rated their technology skill competence as good and 60% (n=153) of all participants were willing to use telerehabilitation. The multivariate regression model found regular computer use (OR 3.14, 95% CI 1.72 to 5.71) and regular mobile phone use (OR 2.83, 95% CI 1.32 to 6.09) were most associated with a willingness to use telerehabilitation. CONCLUSION: People attending metropolitan pulmonary rehabilitation, maintenance exercise classes and support groups had substantial technology engagement, with high device access and use, and good self-rated technology competence. The majority of participants were willing to use telerehabilitation, especially if they were regular users of technology devices. [Seidman Z, McNamara R, Wootton S, Leung R, Spencer L, Dale M, Dennis S, McKeough Z (2017) People attending pulmonary rehabilitation demonstrate a substantial engagement with technology and willingness to use telerehabilitation: a survey. Journal of Physiotherapy 63: 175-181]. PMID- 28652081 TI - Limited interface between physiotherapy primary care and people with severe mental illness: a qualitative study. AB - QUESTIONS: How do mental health professionals perceive the role of physiotherapists in the care of people with severe and persistent mental illness, and what factors do they perceive as influencing access to physiotherapy services? How do people with severe and persistent mental illness understand the potential role of physiotherapy in their healthcare, and what factors do they perceive as influencing access to physiotherapy services? DESIGN: Qualitative study. PARTICIPANTS: Twenty-four mental health professionals and 35 people with severe and persistent mental illness. METHODS: Interview schedules were developed to explore participants' understanding of physiotherapy, as well as barriers and enablers to service access. Focus groups and interviews were conducted for each group of participants. Transcripts were analysed using an inductive approach to derive key themes. RESULTS: Both the mental health professionals and the people with severe and persistent mental illness expressed a limited understanding of the role and relevance of physiotherapy for physical health in mental healthcare. Common barriers to service access were cost, transport and lack of motivation. Likewise, enablers of reduced cost, provision of transport and education about physiotherapy to improve their understanding were identified. The health system structure and perceived lack of mental health knowledge by physiotherapists influenced referrals from mental health professionals. Consequently, education in mental health for physiotherapists and integration of the service within mental health were identified as potential enablers to physiotherapy access. CONCLUSION: Limited understanding about physiotherapy and its relevance to physical health in mental healthcare among mental health professionals and people with severe and persistent mental illness was found to be a key factor influencing service access. Limited physiotherapy presence and advocacy within mental health were also highlighted. There is a need for greater understanding about physiotherapy among stakeholders, and for physiotherapists to be well equipped with skills and knowledge in mental health to facilitate greater involvement. [Lee S, Waters F, Briffa K, Fary RE (2017) Limited interface between physiotherapy primary care and people with severe mental illness: a qualitative study. Journal of Physiotherapy 63: 168-174]. PMID- 28652083 TI - Visualizing HEV infection in human liver tissue. PMID- 28652082 TI - Medical Care Activities Among Spouses of Older Adults With Functional Disability: Implications for Caregiving Difficulties and Gains. AB - OBJECTIVES: Spouses of older adults with functional disability often provide help with their partner's medical care. Yet little is known about the implications of these activities for spouses' caregiving experiences. We examined how spouses' medical care activities are linked to both positive and negative aspects of caregiving (difficulties and gains), and whether these associations vary by their age, gender, or education. DESIGN: Retrospective analysis of data from the 2011 National Health and Aging Trends Study and National Study of Caregiving cross sectional studies. SETTING: Caregivers and care recipients/proxies were interviewed by telephone at home. PARTICIPANTS: Nationally representative U.S. sample of 345 spousal caregivers and their community-dwelling care recipients aged 65 years and older. MEASUREMENTS: Caregivers' self-reported sociodemographics, care activities, health conditions, well-being, and support resources. Care recipients (or proxies) reported on their health conditions and dementia status. RESULTS: A higher number of health system interaction tasks (e.g., making appointments) were significantly associated with greater emotional caregiving difficulties, whereas a higher number of medical/nursing tasks (e.g., giving shots/injections) were significantly linked to greater caregiving gains. A higher number of medical/nursing tasks were also significantly associated with greater physical difficulties for caregiving wives and spouses with less education. CONCLUSIONS: Medical care activities may have both positive and negative consequences for spousal caregivers, which depend partly on sociodemographics. This study underscores the importance of ensuring that spouses have the resources and support needed to provide complex care to their partners. PMID- 28652084 TI - Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. AB - BACKGROUND AND AIMS: Previous studies suggested spontaneous seroclearance of hepatitis B surface antigen (HBsAg) was still associated with an increased risk of hepatocellular carcinoma (HCC), in patients ?50years of age. This study aimed to evaluate the risk of HCC after HBsAg seroclearance and the impact of gender on HCC. METHODS: All chronic hepatitis B patients under medical care in Hospital Authority, Hong Kong who had cleared HBsAg between January 2000 and August 2016 were identified. The age of the patient at HBsAg seroclearance, gender, and subsequent development of HCC were analyzed. RESULTS: A total of 4,568 patients with HBsAg seroclearance were identified; 793 (17.4%) were treated by nucleos(t)ide analogues and 60 (1.3%) had received interferon treatment. At a median (interquartile range) follow-up of 3.4 (1.5-5.0)years, 54 patients developed HCC; cumulative incidences of HCC at 1, 3 and 5years were 0.9%, 1.3% and 1.5%, respectively. Age above 50years (adjusted hazard ratio 4.31, 95% confidence interval 1.72-10.84; p=0.002) and male gender (2.47, 1.24-4.91; p=0.01) were two independent risk factors of HCC. Female patients aged ?50years (n=545) had zero risk of HCC within 5years of follow-up. Male patients aged ?50years (n=769), female patients aged >50years (n=1,149) and male patients aged >50years (n=2,105) had a 5-year cumulative incidence of HCC 0.7%, 1.0% and 2.5%, respectively. Similar findings were observed in patients with spontaneous and antiviral treatment-induced HBsAg seroclearance. CONCLUSIONS: Female patients aged 50years or below have zero risk of HCC after HBsAg seroclearance, whereas female patients aged above 50years and all male patients are still at risk of HCC. Lay summary: We investigated 4,568 patients with hepatitis B surface antigen (HBsAg) seroclearance. Female patients aged 50years or below have zero risk of hepatocellular carcinoma (HCC) after HBsAg seroclearance, whereas female patients aged above 50years and all male patients are still at risk of HCC. PMID- 28652085 TI - The influence of fathers on children's physical activity: A review of the literature from 2009 to 2015. AB - Parents are influential in promoting children's physical activity. Yet, most research has focused on how mothers influence children's activity, while little empirical attention has been devoted to understanding how fathers may influence children's activity. The purpose of this review was to summarize observational studies from 2009 to 2015 examining the influence of fathers on children's physical activity. A publicly available database, from a prior systematic review, containing information on 667 studies of parenting and childhood obesity from 2009 to 2015 was searched for potential studies. Studies were eligible if: 1) fathers were included as participants, 2) results were presented for fathers separate from mothers, 3) fathers' physical activity or physical activity parenting was assessed, and 4) child physical activity was measured. Ten studies met eligibility criteria. All studies were rated as fair quality. The majority of studies (n=8) assessed the relationship between father and child physical activity. Of 27 associations tested, 14 (52%) were significant, indicating a modest, positive relationship between father and child activity. Of the studies examining fathers' physical activity parenting (n=3), there were three significant associations out of 15 tested (20%) and no consistency among measured constructs. No differences were observed in the influence of mothers vs. fathers on children's physical activity. Limited evidence was available to examine moderating effects of child sex or age. Few studies have examined the effect of fathers on child physical activity and this relationship remains unclear. Future studies should target fathers for research and investigate specific pathways through which fathers can influence child activity. PMID- 28652086 TI - Commentary: Navigating the complexities of marijuana. AB - Science needs to drive our thinking as we navigate a new legislative environment in which many Americans have access to marijuana for therapeutic or recreational use. With the responsibility to fund, conduct, and make use of the research on marijuana, and understand the impacts of new policies, comes the obligation of not thinking in simplistic, black-and-white terms about this substance. The drug's unique harms include neurodevelopmental impacts that may be long lasting or permanent, yet some evidence suggests the drug may benefit people with certain medical conditions (e.g., chronic pain). Marijuana use is also entangled with other substance use and should not be considered in isolation. Finally, policy options are not limited to the extremes of prohibition vs. full commercialization; a spectrum of intermediate options can and should be considered and evaluated as states create new policies around this drug. PMID- 28652087 TI - Determinants of human papillomavirus vaccination uptake among adolescent girls: A theory-based longitudinal study among Hong Kong Chinese parents. AB - Human papillomavirus (HPV) vaccination uptake among Chinese adolescent girls remains extremely low. This two-year longitudinal study examined theoretical predictors of adolescent girls' HPV vaccination uptake using an extended Theory of Planned Behaviour (TPB). Between February and November 2014, a random sample of 1996 (response rate 60%) Hong Kong Chinese parents of 12- to 17-year-old HPV unvaccinated girls completed baseline telephone interviews assessing attitudes and intention towards HPV vaccination. Six and 12months later 1255 and 979 parents reported their daughters' HPV vaccination status, respectively. Structural equation modelling tested data fit to an TPB-derived hypothesized model of baseline factors predicting parental decisionmaking for adolescent girls' subsequent HPV vaccination uptake. Overall, at 1-year follow-up, only 9.8% (97/988) of participants' daughters received at least one dose of HPV vaccines. Descriptive norms (beta=0.28), perceived greater benefits of HPV vaccination (beta=0.17), anticipated affective consequences (beta=0.32), and attitude to general optional vaccines (beta=0.09) were associated with parental vaccination intention. Barriers to HPV vaccination (beta=-0.31), descriptive norms (beta=0.17), perceived self-efficacy (beta=0.73), and vaccination intention (beta=0.11) were associated with vaccination planning. Vaccination intention (beta=0.31) and planning (beta=0.18) modestly predicted vaccination uptake. The lack of government-organized HPV vaccination programme may result in persistent low HPV vaccination uptake and many young women may remain vulnerable to future cervical cancer risk in Hong Kong. PMID- 28652088 TI - Electronic cigarette use as an aid to quit smoking in the representative Italian population PASSI survey. AB - This study explored electronic cigarette (e-cigarette) use as an aid to quit smoking and compared abstinence rates for different quitting methods in a representative sample of the Italian population. In the 2014-2015 PASSI survey, the ongoing Italian behavioural risk factor surveillance system, 6112 adults who smoked and made at least one quit attempt in the previous 12months, were categorized into three groups according to the method used in their most recent quit attempt: e-cigarette only, no aid, other quitting methods (medications; programmes delivered in smoking cessation services; other unspecified methods). The primary outcome was self-reported abstinence for a period >=6months, adjusted for potential confounders. Eleven percent used e-cigarettes only, 86% no aid, 3% other quitting methods. Smoking abstinence was reported among 9% of those using no aid; 8% of e-cigarette users; 15% of those using other methods. No significant differences in abstinence were observed for e-cigarette users compared with those reporting no aid (adjusted Prevalence Ratio [aPR]=0.81; 95%Confidence Interval (CI)=0.58-1.14). Changing the reference group to e-cigarette users, those using other quitting methods were significantly more likely to report abstinence than e cigarette users (aPR=1.76; 95%CI=1.07-2.88). One out of ten smokers who attempted to quit in 2014-2015 in Italy used e-cigarettes. E-cigarettes users were as likely to report abstinence as those using no aid, but were less likely to report abstinence than users of established quitting methods. Further studies are needed to understand the relationship between e-cigarette types used to quit and abstinence rates. PMID- 28652089 TI - In vivo confocal laser endomicroscopy during laparoscopy for gynecological surgery: A promising tool. AB - INTRODUCTION: To investigate the technical feasibility of optical biopsy (probe based confocal laser endomicroscopy [pCLE]) during laparoscopy and by the vaginal route in the exploration of pelvic gynecological cancers. METHODS: Prospective study including 31 patients undergoing laparoscopic hysterectomy (benign or malignant indication). Confocal microlaparoscopy (analysis of tubes, ovaries, and depending on the type de cancer, pelvic adenopathies) and optical biopsy of the endometrium were first carried out by the vaginal route under general anesthesia. The surgical procedure was then carried out. RESULTS: Thirty-one consecutive patients were included (16 for benign hysterectomy, 12 for endometrial cancer and 3 for ovarian carcinoma). pCLE offered dynamic pictures that were correlated with the histopathological images. DISCUSSION AND CONCLUSION: pCLE provides high resolution imaging of cancerous and benign tissues in real-time similar to histopathological results. Both feasibility and safety were confirmed. PMID- 28652090 TI - The Effect of Primary Care Physician Knowledge of Lung Cancer Screening Guidelines on Perceptions and Utilization of Low-Dose Computed Tomography. AB - INTRODUCTION: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) is recommended by the U.S. Preventive Services Task Force (USPSTF) in high risk patients, but a minority of eligible people are screened. It is not clear whether knowledge of USPSTF recommendations among primary care physicians (PCP) affects utilization of LDCT. METHODS: A randomly selected sample of 1384 PCPs in Los Angeles County was surveyed between January and October 2015, using surveys sent by mail, fax, and e-mail. The response rate was 18% (n = 250). Training background, years in practice, practice type, and respondent demographics were collected. We analyzed results based on the response to a question on whether the USPSTF recommends the use of LDCT to screen high-risk individuals for lung cancer. RESULTS: A total of 117 (47%) PCPs responded that the USPSTF recommends LDCT for LCS. Of PCPs who were aware of USPSTF recommendations, 97% responded that CT was effective at reducing lung cancer mortality among individuals meeting eligibility criteria, compared with 90% who were unaware of guidelines (P = .02). A larger proportion of PCPs aware of guidelines ordered LDCT (71% vs. 38%, P < .001) and initiated a discussion on screening (86% vs. 62%, P < .001). Both groups of PCPs reported similar perceptions of barriers to screening, such as insurance coverage, risks of LCS, and cost to society. Practice size, training background, and years in practice did not affect knowledge of guidelines. DISCUSSION: Awareness of USPSTF recommendations for LDCT is associated with increased utilization of LDCT for screening. Educational interventions for PCPs may improve adherence with LCS recommendations. PMID- 28652091 TI - Investigating therapeutic usage of combined Ticagrelor and Aspirin through solid state and analytical studies. AB - The mainstay treatment for patients with acute coronary syndrome is an oral route dual antiplatelet therapy with a P2Y12-receptor antagonist and Aspirin (ASA). To improve patient adherence to such treatments, combination therapies (polypill) are envisioned. Physicochemical solid-state studies have been carried out to develop a preformulation strategy of ASA with the P2Y12-receptor antagonist Ticagrelor (TIC). The investigations were carried out using differential scanning calorimetry, liquid chromatography-high resolution-multistage mass spectrometry (LC-HR-MSn) and as complementary techniques Fourier transform infrared measurements and thermogravimetric analysis. A simple eutectic transition at 98 degrees C with a mole fraction for the eutectic liquid of 0.457 has been observed and the mixing of ASA and TIC molecules in each other's crystal structures appears to be limited. No cocrystals of TIC and ASA have been found. The appearance of the eutectic liquid was linked with a clear onset of chemical instability of the two pharmaceuticals. The decomposition mechanism in the liquid phase involves prior decomposition of ASA, whose residues react with well identified TIC interaction sites. Seven interaction products were observed by LC HR-MSn linked to corresponding degradation products. The most important degradation pathway is N-dealkylation. In conclusion, polypills of ASA and TIC are a viable approach, but the decomposition of ASA should be avoided by eliminating high temperatures and high humidity. PMID- 28652092 TI - Upfront Docetaxel in the Post-STAMPEDE World: Lessons from an Early Evaluation of Non-trial Usage in Hormone-Sensitive Prostate Cancer. PMID- 28652093 TI - Prediction of 90 Day and Overall Survival after Chemoradiotherapy for Lung Cancer: Role of Performance Status and Body Composition. AB - AIMS: If appropriate patients are to be selected for lung cancer treatment, an understanding of who is most at risk of adverse outcomes after treatment is needed. The aim of the present study was to identify predictive factors for 30 and 90 day mortality after chemoradiotherapy (CRT), and factors that were prognostic for overall survival. MATERIALS AND METHODS: A retrospective cohort study of 194 patients with lung cancer who had undergone CRT in South East Scotland from 2008 to 2010 was undertaken. Gender, age, cancer characteristics, weight loss, body mass index (BMI), performance status (Eastern Cooperative Oncology Group; ECOG) and computed tomography-derived body composition variables were examined for prognostic significance using Cox's proportional hazards model and logistic regression. RESULTS: The median overall survival was 19 months (95% confidence interval 16.3, 21.7). Four of 194 patients died within 30 days of treatment completion, for which there were no independent predictive variables; 22/194 (11%) died within 90 days of treatment completion. BMI < 20 and ECOG performance status >=2 were independent predictors of death within 90 days of treatment completion (P = 0.001 and P = 0.004, respectively). Patients with either BMI < 20 or ECOG performance status >= 2 had an odds ratio of death within 90 days of 5.97 (95% confidence interval 2.20, 16.19), rising to an odds ratio of 13.27 (1.70, 103.47) for patients with both BMI < 20 and ECOG performance status >= 2. Patients with low muscle attenuation had significantly reduced overall survival (P = 0.004); individuals with low muscle attenuation had a median survival of 15.2 months (95% confidence interval 12.7, 17.7) compared with 23.0 months (95% confidence interval 18.3, 27.8) for those with high muscle attenuation, equating to a hazard ratio of death of 1.62 (95% confidence interval 1.17, 2.23, P = 0.003). CONCLUSION: Poor performance status, low BMI and low muscle attenuation identify patients at increased risk of premature death after CRT. Risk factors for adverse outcomes should inform personalised discussions with patients about the potential harms as well as the intended benefits of treatment. PMID- 28652094 TI - High-dose-rate brachytherapy boost for prostate cancer treatment: Different combinations of hypofractionated regimens and clinical outcomes. AB - PURPOSE: To report the outcomes of our high-dose-rate brachytherapy (HDR-BT) boost experience in localized prostate cancer treated with different combinations of radiation doses and fractionation. MATERIAL AND METHODS: Between 1999 and 2011, 832 patients were treated with different regimens of external beam radiotherapy (EBRT) and HDR-BT. These regimens were converted into three biologically effective dose (BED) groups. The biochemical failure-free survival (BFFS), reported with the phoenix definition and prostate-specific antigen (PSA) >0.2ng/ml at 5-year, genitourinary (GU) and gastrointestinal (GI) toxicities were compared between the groups. RESULTS: The 5-, 10-year BFFS for the entire cohort were 94.6% and 92.5%, for overall survival (OS) 96.1% and 80.3% and for prostate cancer-specific survival (PCSS) 99.5% and 97.8%. The percentage of patients with a 5-year PSA level <0.2ng/ml was 68.6%, 78.7% and 86.7% in the BED group of <250, 250-260 and >260Gy (p=0.005) while the 5-year BFFS rates according to phoenix definition were 97.3%, 94.3% and 94.9% for BED group <250, 250-260 and >260Gy (p=0.453). On multivariate logistic regression, patients in the BED>260Gy group were significantly more likely to remain free from 5-year PSA values >=0.2ng/mL compared with those in the BED<250Gy group (OR: 0.350, p=0.011). Grade>=3 acute GU toxicity was reported in 2 patients (4.7%) for BED>260Gy while grade>=3 late GU toxicity was reported in 6 (1.7%) and 9 (4.9%) patients for 250-260Gy and >260Gy BED groups. CONCLUSIONS: The increase in BED with the hypofractionated regimens correlates with an improvement in biochemical control with of urinary toxicity. This increase in urinary toxicity is small and clinically acceptable. PMID- 28652095 TI - Fissuration of vertebral artery mycotic aneurysm due to Lemierre syndrome. PMID- 28652096 TI - MR imaging of endometriosis: Spectrum of disease. AB - Endometriosis is a common gynecological disorder defined by the presence of endometrial tissue outside the uterus. It is the most common cause of chronic pelvic pain and typically affects the ovaries, uterine ligaments, peritoneum, tubes, rectovaginal septum and bladder. It may, however, be found at various extrapelvic sites, including the perineum, liver, pancreas, lung or even the central nervous system, and in such cases, diagnosis may be quite challenging. Even though definitive diagnosis requires laparoscopy, preoperative identification of endometriosis is important not only to differentiate it from other diseases with similar clinical presentations but also, for accurate presurgical mapping, since complete removal of all endometriotic foci is critical for the effective treatment of the patient's symptoms. Ultrasound is performed initially, but magnetic resonance imaging (MRI) is increasingly being used, particularly when sonographic findings are unclear, when deep pelvic endometriosis is suspected or when surgery is planned, as it provides better contrast resolution and a larger field of view compared to ultrasound. In this article, we will discuss distinctive MRI appearances of endometriotic foci and we will review common and uncommon locations of endometriosis within the body, in an attempt to familiarize radiologists with its wide spectrum of manifestations. PMID- 28652097 TI - An initial step in examining long-term outcomes for children born after IVF. PMID- 28652098 TI - Mutation analysis of the TUBB8 gene in nine infertile women with oocyte maturation arrest. AB - Mutations in the tubulin beta 8 class VIII (TUBB8) gene have been proven to cause oocyte maturation arrest. The aim of this study was to describe newly discovered mutations in TUBB8 and to investigate the prevalence of TUBB8 mutations in our cohort. Nine women with oocyte maturation arrest and 100 fertile female controls were recruited. Sanger sequencing of the coding regions of TUBB8 revealed a heterozygous variant c.535G > A (p.V179M) in two unrelated affected individuals and a heterozygous variant c.5G > T (p.R2M) in one affected individual. These TUBB8 variants were inherited from the unaffected fathers and were absent in 100 fertile female control individuals. In total, 33.33% (3/9) of the affected individuals in our cohort obtained a clear genetic diagnosis through sequencing of the TUBB8 gene. These two novel variants extend the spectrum of TUBB8 mutations and this study confirmed that TUBB8 mutations occur in a high proportion of infertile women with oocyte maturation arrest. PMID- 28652099 TI - Influence of adjuvant chemotherapy on anti-Mullerian hormone in women below 35 years treated for early breast cancer. AB - The impact of chemotherapy on fertility appears to be of essential importance for the youngest cancer survivors. The aim of this study was to assess plasma anti Mullerian hormone (AMH) evolution, using an automated sensitive AMH immunoassay in women younger than 35 years old before and after treatment with adjuvant chemotherapy for early breast cancer. We selected 54 women aged less than 35 years old, at the time of breast cancer diagnosis, who received chemotherapy between 2008 and 2014, and with plasma samples collected from the diagnosis, to 1 year, 3 years and 5 years post-diagnosis. The median AMH decreased markedly in the year after the diagnosis compared with the pretreatment values (P < 0.0001), and slightly increased 2 years later (P = 0.007, comparing 1-year and 3-years post-diagnosis concentrations), without any additional AMH recovery 5 years after diagnosis. This recovery did not reach age-dependent AMH expected values (P < 0.0001, comparing AMH measured values to AMH expected values). Addition of taxanes to an anthracyclines + alkylating-based regimen was associated with a worse AMH decrease (P = 0.007). Ovarian tissue cryopreservation before treatment did not influence the AMH recovery. These results highlight the necessity of fertility counselling before treatment, especially in women wanting children. PMID- 28652100 TI - Current role for radioisotope synovectomy. AB - Radioisotope synovectomy has been extensively used to treat patients with chronic inflammatory joint disease but has moved to a less prominent position since the introduction of new and highly effective drugs. Remaining indications are refractory synovitis, pigmented villonodular synovitis as an adjunct to surgery, and hemophilic arthropathy. The three main radioisotopes used are yttrium-90, rhenium-186, and erbium-189. Radioisotope synovectomy should be performed only by highly experienced professionals, to minimize the risk of injection-related complications. The available safety data, in particular regarding the risk of malignancy, are reassuring. The efficacy of yttrium-90 in chronic inflammatory joint disease remains controversial. PMID- 28652101 TI - Salt, inflammatory joint disease, and autoimmunity. AB - Salt is a vital nutrient. Excess salt intake, however, has recently been blamed for triggering and/or worsening certain autoimmune diseases. In vitro, the cells involved in innate and adaptive immune responses exhibit an inflammatory profile when placed in hypertonic saline. More specifically, macrophages release increased amounts of proinflammatory cytokines, produce reactive oxygen species, and become capable of activating the inflammasome. T helper cells, via activation of serum and glucocorticoid-regulated kinase 1 (SGK1), overexpress IL-17A and IL 23R and differentiate into Th17 cells; whereas regulatory T cells lose the inhibitory capabilities needed to preserve self-tolerance. The data from animal models of autoimmune diseases and human patients are less consistent. SGK1 has been implicated in polarization toward the Th17 phenotype, which worsens conditions such as multiple sclerosis, systemic lupus erythematosus, autoimmune colitis, and transplant rejection. Observational epidemiological studies of patients with multiple sclerosis have demonstrated an association between excessive salt intake and a higher number of flares. Excessive salt intake is associated with a higher risk of developing rheumatoid arthritis, particularly in smokers. These data suggest that salt may stimulate certain immunological processes. Studies are therefore needed to assess the potential influence of dietary habits on the development and progression of autoimmune diseases. PMID- 28652102 TI - Epilepsy awareness, emergency rescue training and e-test. PMID- 28652103 TI - PC-FACS. AB - PC-FACS(FastArticleCriticalSummaries for Clinicians inPalliativeCare) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at pc facs@aahpm.org. PMID- 28652104 TI - Quantifying Pelvic Periprosthetic Bone Remodeling Using Dual-Energy X-Ray Absorptiometry Region-Free Analysis. AB - The gold standard tool for measuring periprosthetic bone mineral density (BMD) is dual-energy X-ray absorptiometry (DXA). However, resolution of the method is limited due to the aggregation of pixel data into large regions of interest for clinical and statistical analysis. We have previously validated a region-free analysis method (DXA-RFA) for quantitating BMD change at the pixel level around femoral prostheses. Here, we applied the DXA-RFA method to the pelvis, and quantitated its precision in this setting using repeated DXA scans taken on the same day after repositioning in 29 patients after total hip arthroplasty. Scans were semiautomatically segmented using edge detection, intensity thresholding, and morphologic operations, and elastically registered to a common template generated through generalized Procrustes analysis. Pixel-wise BMD precision between repeated scans was expressed as a coefficient of variation %. Longitudinal BMD change was assessed in an independent group of 24 patients followed up for 260 wk. DXA-RFA spatial resolution of 0.31 mm2 provided approximately 12,500 data points per scan. The median data-point precision was 17.8% (interquartile range 14.3%-22.7%). The anatomic distribution of the precision errors showed poorer precision at the bone borders and superior precision to the obturator foramen. Evaluation of longitudinal BMD showed focal BMD change at 260 wk of -26.8% adjacent to the prosthesis-bone interface (1% of bone map area). In contrast, BMD change of +39.0% was observed at the outer aspect of the ischium (3% of bone map area). Pelvic DXA-RFA is less precise than conventional DXA analysis. However, it is sensitive for detecting local BMD change events in groups of patients, and provides a novel tool for quantitating local bone mass after joint replacement. Using this method, we were able to resolve BMD change over small areas adjacent to the implant-bone interface and in the ischial region over 260 wk after total hip arthroplasty. PMID- 28652105 TI - Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan. AB - LCZ-696, sacubitril/valsartan, is a dual-acting molecule consisting of the angiotensin II (Ang II) receptor blocker valsartan and the neprilysin (neutral endopeptidase) inhibitor AHU-377 with significant beneficial effects in patients with hypertension and heart failure (HF). Several recent studies have demonstrated a higher effectiveness of LCZ-696 compared to valsartan in the treatment of hypertension and HF. The rationale for the development and the Food and Drug Administration approval of LCZ-696 was based on the concept of an additive effect of the Ang II receptor blocker valsartan and the neutral endopeptidase (neprilysin) inhibitor AHU-377 for the treatment of hypertension and HF. The synergism from these drugs arises from the vasodilating effects of valsartan through its blockade of Ang II type 1 receptor and the action of natriuretic peptides atrial natriuretic peptide and B-type natriuretic peptide (BNP) by preventing their catabolism with neprilysin resulting in increase of cyclic guanosine monophosphate. This action of neprilysin is associated with increased natriuresis, diuresis, and systemic vasodilation, since these peptides have been shown to have potent diuretic, natriuretic, and vasodilating effects. In addition, it reduces the levels of N terminal pro-BNP. Therefore, administration of LCZ-696 results in significant reduction of wall stress from pressure and volume overload of the left ventricle as demonstrated by the reduction of N terminal pro-BNP, both significant constituents of hypertension and HF, and it is safe, well tolerated and is almost free of cough and angioedema. PMID- 28652106 TI - Show me your tenent setae and I tell you who you are - Telling the story of a neglected character complex with phylogenetic signals using Leiodidae (Coleoptera) as a case study. AB - The tarsal setae in 97 species of Leiodidae and eight outgroups were examined using SEM imaging and dissections. Modified adhesive setae present in males are referred to as "male tenent setae" (MTS). In most cases, dilated tarsomeres were associated with MTS, which were always present on the protarsi and sometimes the mesotarsi. MTS are reported for the first time on the mesotarsi of Leptodirini and on the metatarsi in two genera of Sogdini. Contrary to reports in the literature, the reduction in the number of the MTS bearing mesotarsomeres is considered a derived condition. Both sexes of Leptinus (Platypsyllinae) have modified setae (referred to as tenent setae in the literature), probably related to their specialised association with mammals, and a patch of MTS was recognized for the first time among those modified setae among males. Four main types of MTS are recognised: (1) a plesiomorphic discoidal type that has a shaft with a round cross-section and maintains a similar diameter throughout its length until forming the expanded discoidal terminal plate; (2) a minidiscoidal type, similar to discoidal but with a relatively small terminal plate, found in Cholevinae; (3) a conical type, present in Leiodinae (excluding Estadiini) where the shaft increases in diameter until forming the terminal plate; and (4) a spatulate type, where an even wider terminal plate has a lateral projection, derived from the conical form and synapomorphic for the leiodine tribes Pseudoliodini, Scotocryptini, and possibly Agathidiini. PMID- 28652107 TI - Plasma PPi Deficiency Is the Major, but Not the Exclusive, Cause of Ectopic Mineralization in an Abcc6-/- Mouse Model of PXE. AB - Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders, is caused in most cases by inactivating mutations in the ABCC6 gene. It was recently discovered that absence of ABCC6-mediated adenosine triphosphate release from the liver and consequently reduced plasma inorganic pyrophosphate (PPi) levels underlie PXE. This study examined whether reduced levels of circulating PPi, an antimineralization factor, is the sole mechanism of PXE. The Abcc6-/- and Enpp1asj mice were crossed with transgenic mice expressing human ENPP1, an ectonucleotidase that generates PPi from adenosine triphosphate. We generated Abcc6-/- and Enpp1asj mice, either wild-type or hemizygous for human ENPP1. Plasma levels of PPi and the degree of ectopic mineralization were determined. Overexpression of human ENPP1 in Enpp1asj mice normalized plasma PPi levels to that of wild-type mice and, consequently, completely prevented ectopic mineralization. These changes were accompanied by restoration of their bone microarchitecture. In contrast, although significantly reduced mineralization was noted in Abcc6-/- mice expressing human ENPP1, small mineralization foci were still evident despite increased plasma PPi levels. These results suggest that PPi is the major mediator of ectopic mineralization in PXE, but there might be an alternative, as yet unknown mechanism, independent of PPi, by which ABCC6 prevents ectopic mineralization under physiologic conditions. PMID- 28652108 TI - Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg Cell Axis, Which Is Corrected by Anti-TNF Therapy. AB - Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating disease of hair follicles with 1-4% prevalence and high morbidity. There is a dearth of information on the pathogenesis and immune dysregulation underlying HS; therefore, we carried out a detailed analysis of skin-infiltrating T cells. Cells isolated from skin biopsy samples and blood from HS patients and healthy control subjects were analyzed by 16-parameter flow cytometry to provide detailed profiles of CD4 T-cell subsets. We observed substantial infiltration of inflammatory T cells with a striking T helper (Th) type 17-skewed cytokine profile in HS skin; these cells expressed the Th17 lineage marker CD161 and IL 17, as well as proinflammatory cytokines GM-CSF, IL-22, IFN-gamma, and tumor necrosis factor. Regulatory T cells were also enriched in HS lesional skin; however, the ratio of Th17 to regulatory T cells was nonetheless highly dysregulated in favor of Th17 cells. In contrast, lesional skin from anti-tumor necrosis factor-treated HS patients who showed substantial clinical improvement exhibited a significant reduction in the frequency of Th17 cells and normalization of the Th17 to regulatory T cell ratio. These data suggest that inhibition of pathogenic IL-17 via tumor necrosis factor blockade is associated with improvement in immune dysregulation in HS and may provide a rationale for targeting IL-17 in the disease. PMID- 28652109 TI - Using FDG-PET/CT to Detect Vascular Inflammation in Patients with Psoriasis: Where to Look? And for What?? PMID- 28652110 TI - Response to Hjuler et al. PMID- 28652111 TI - Cannabinoid Reduces Inflammatory Cytokines, Tumor Necrosis Factor-alpha, and Type I Interferons in Dermatomyositis In Vitro. PMID- 28652113 TI - Early versus late diagnosis in community-acquired bacterial meningitis: a retrospective cohort study. AB - OBJECTIVES: To examine clinical characteristics and outcome of patients with late diagnosis of community-acquired bacterial meningitis (CABM). METHODS: We conducted a chart review of all adults with proven CABM in three centres in Denmark from 1998 through to 2014. Patients were categorized as early diagnosis of CABM immediately on admission, or late diagnosis if CABM was not listed in referral or admission records and neither lumbar puncture nor antibiotic therapy for meningitis was considered immediately on admission. We used modified Poisson regression analysis to compute adjusted relative risks with 95% CIs for predictors of late diagnosis and in-hospital mortality. RESULTS: A total of 113/358 (32%) patients were categorized as late diagnosis demonstrating a variety of tentative diagnoses of which 81/113 (72%) were non-infectious. We observed several statistically significant baseline differences (p <0.05) in patients with late versus early diagnosis including age >65 years (56/113, 50% versus 67/245, 27%), neck stiffness (35/97, 36% versus 183/234, 78%), concomitant pneumonia (26/113, 23% versus 26/245, 11%), and meningococcal meningitis (6/113, 5% versus 52/245, 21%). These variables remained statistically significant in multivariate analysis. Moreover, late diagnosis was associated with increased in-hospital mortality (41/113, 36% versus 43/245, 18%; adjusted relative risk 1.7, 95% CI 1.2 2.5). CONCLUSIONS: Late diagnosis of CABM was common and patients were admitted with mostly non-infectious diagnoses. Absence of neck stiffness did not rule out CABM and special attention should be given to patients with pneumonia and the elderly. Late diagnosis was associated with incorrect patient management and increased mortality. PMID- 28652112 TI - Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation. AB - OBJECTIVES: To assess the risk factors for development of late-onset invasive pulmonary aspergillosis (IPA) after kidney transplantation (KT). METHODS: We performed a multinational case-control study that retrospectively recruited 112 KT recipients diagnosed with IPA between 2000 and 2013. Controls were matched (1:1 ratio) by centre and date of transplantation. Immunosuppression-related events (IREs) included the occurrence of non-ventilator-associated pneumonia, tuberculosis, cytomegalovirus disease, and/or de novo malignancy. RESULTS: We identified 61 cases of late (>180 days after transplantation) IPA from 24 participating centres (accounting for 54.5% (61/112) of all cases included in the overall study). Most diagnoses (54.1% (33/61)) were established within the first 36 post-transplant months, although five cases occurred more than 10 years after transplantation. Overall mortality among cases was 47.5% (29/61). Compared with controls, cases were significantly older (p 0.010) and more likely to have pre transplant chronic obstructive pulmonary disease (p 0.001) and a diagnosis of bloodstream infection (p 0.016) and IRE (p <0.001) within the 6 months prior to the onset of late IPA. After multivariate adjustment, previous occurrence of IRE (OR 19.26; 95% CI 2.07-179.46; p 0.009) was identified as an independent risk factor for late IPA. CONCLUSION: More than half of IPA cases after KT occur beyond the sixth month, with some of them presenting very late. Late IPA entails a poor prognosis. We identified some risk factors that could help the clinician to delimit the subgroup of KT recipients at the highest risk for late IPA. PMID- 28652114 TI - Antibiotic innovation for future public health needs. AB - BACKGROUND: The public health threat of antibiotic resistance has gained attention at the highest political levels globally, and recommendations on how to respond are being considered for implementation. Among the recommended responses being explored for their feasibility is the introduction of economic incentives to promote research and development of new antibiotics. There is broad agreement that public investment should stimulate innovation and be linked to policies promoting sustainable and equitable access to antibiotics. Though commonly used, the term 'innovation' is not based on a common understanding. AIMS: This article aims to initiate discussion on the meaning of 'innovation' in this context. SOURCES: Literature and expert opinion. CONTENT: As the definition of a novel class (novel scaffold, novel pharmacophore), a novel target (novel binding site) and a novel mode of action-the three traditional criteria for 'innovation' in this context-may be confounded by the complexities of antibacterial drug discovery, a biological and outcome-oriented definition of innovation is presented to initiate discussion. Such an expanded definition of innovation in this specific context is based on the overarching requirement that a drug not be affected by cross-resistance to existing drugs in the organisms and indications for which it is intended to be used, and that it have low potential for high frequency, high-level single-step resistance if intended as a single drug therapy. IMPLICATIONS: Policy makers, public health authorities and funders could use such a comprehensive definition of innovation to prioritize where publicly funded incentives should be applied. PMID- 28652115 TI - Longitudinal trends of HIV drug resistance in a large Canadian cohort, 1996-2016. AB - OBJECTIVES: We aim to identify long-term trends in HIV drug resistance before and after combined antiretroviral therapy (cART) initiation. METHODS: IAS-USA (2015) mutations were identified in 23 271 HIV protease-reverse transcriptase sequences from 6543 treatment naive adults in British Columbia. Participants who started cART between 1996 and 2014 were followed until April 2016. Equality of proportions test was used to compare the percentage of participants with acquired drug resistance (ADR) or transmitted drug resistance (TDR) in 1996, to those in 2014. Kaplan-Meier was used to estimate time to ADR in four drug resistance categories. Multivariable regression odds ratios (OR) of ADR for select clinical variables were determined by 5-year eras of cART initiation. RESULTS: The proportion of individuals with ADR declined from 39% (51/132) to 3% (8/322) in 1996-2014 (p <0.0001), while the proportion with TDR increased from 12% (16/132) to 18% (59/322) (p 0.14). The estimated proportions of individuals with ADR rose to 29% (NNRTI), 28% (3TC/FTC), 14% (other nRTI), and 7% (PI) after >16 years of therapy. After 5 years on therapy, participants initiating cART in 1996-2000 had 5.5-times more 3TC/FTC ADR, 5.3-times more other nRTI ADR, 4.7-times more NNRTI ADR, and 24-times more PI ADR than those starting in 2011-2014. The individuals with highest odds of developing ADR in 1996-2010 were adherent to regimens at levels between 60% and 80%, which shifted to <40% adherent in 2011-2014. CONCLUSIONS: HIV drug resistance transitioned from being primarily selected de novo to being driven by TDR. Among those who started treatment in the past 5 years, ADR is rare and observed mostly in the lowest adherence strata. PMID- 28652116 TI - First isolation of Conidiobolus sp. in a respiratory sample of a patient in Europe. PMID- 28652117 TI - Simultaneous Resection of Multiple Metastatic Brain Tumors with Multiple Keyhole Craniotomies. AB - BACKGROUND: The proper management of symptomatic patients with 2 or more brain metastases is not entirely clear, and the surgical outcomes of these patients undergoing multiple simultaneous craniotomies have not been well described. In this article, we describe patient outcomes after simultaneously resecting metastatic lesions through multiple keyhole craniotomies. METHODS: We conducted a retrospective review of data obtained for all patients undergoing resection of multiple brain metastases in one operation between 2014 and 2016. We describe a technique for resecting multiple metastatic lesions and share the patient outcomes of this operation. RESULTS: Twenty patients with 46 tumor resections were included in the study. The primary site of metastases for the majority of patients was lung, followed by melanoma, renal, breast, colon, and testes. Nine of 20 (45%) patients had 2 preoperative intracranial lesions, and 11 (55%) had three or more. Karnofsky performance scales were calculated for 14 patients: postoperatively 10 of 14 (71%) scores improved, 2 of 14 (14%) worsened, and 2 of 14 (14%) remained unchanged. After surgery, 9 of 14 (64%) patients were weaned off steroids by 2-month follow-up. The overall median survival time from date of surgery was 10.8 months. CONCLUSIONS: We present patient outcomes after simultaneously resecting metastatic brain tumors through multiple keyhole craniotomies in symptomatic patients. Our results suggest comparable outcomes and similar surgical risk compared with those undergoing resection of a single brain metastasis. Resection of multiple brain metastases may improve Karnofsky Performance Scale scores in the early postoperative period and allow patients to be weaned from steroids. PMID- 28652118 TI - Analysis of Patients with Myelopathy due to Benign Intradural Spinal Tumors with Concomitant Lumbar Degenerative Diseases Misdiagnosed and Erroneously Treated with Lumbar Surgery. AB - OBJECTIVE: When a cervical or thoracic benign intradural spinal tumor (BIST) coexists with lumbar degenerative diseases (LDD), diagnosis can be difficult. Symptoms of BIST-myelopathy can be mistaken as being related to LDD. Worse, an unnecessary lumbar surgery could be performed. This study was conducted to analyze cases in which an erroneous lumbar surgery was undertaken in the wake of failure to identify BIST-associated myelopathy. METHODS: Cases were found in a hospital database. Patients who underwent surgery for LDD first and then another surgery for BIST removal within a short interval were studied. Issues investigated included why the BISTs were missed, how they were found later, and how the patients reacted to the unnecessary lumbar procedures. RESULTS: Over 10 years, 167 patients received both surgeries for LDD and a cervical or thoracic BIST. In 7 patients, lumbar surgery preceded tumor removal by a short interval. Mistakes shared by the physicians included failure to detect myelopathy and a BIST, and a hasty decision for lumbar surgery, which soon turned out to be futile. Although the BISTs were subsequently found and removed, 5 patients believed that the lumbar surgery was unnecessary, with 4 patients expressing regrets and 1 patient threatening to take legal action against the initial surgeon. CONCLUSIONS: Concomitant symptomatic LDD and BIST-associated myelopathy pose a diagnostic challenge. Spine specialists should refrain from reflexively linking leg symptoms and impaired ability to walk to LDD. Comprehensive patient evaluation is fundamental to avoid misdiagnosis and wrong lumbar surgery. PMID- 28652119 TI - A Confirmed Case in the United Kingdom of Hirayama Disease in a Young White Male Presenting with Hand Weakness. AB - BACKGROUND: We present the first reported case of Hirayama disease in the United Kingdom. A literature review of Hirayama disease in the Western literature shows that this case is unique in being the first in the United Kingdom, constituting one of only a few cases in Europe with supporting magnetic resonance imaging and reported treatment outcome. CASE DESCRIPTION: Our patient was a young Caucasian male who presented with progressive bilateral hand weakness, had confirmatory magnetic resonance imaging findings of Hirayama disease, and experienced improvement of symptoms with cervical collar immobilization. CONCLUSIONS: This case lends further evidence to the flexion-induced myelopathy theory of Hirayama disease and supports the findings of other studies in which avoidance of neck flexion and cervical immobilization helped to attenuate disease progression in this patient group. PMID- 28652120 TI - Predictors of Shunt-dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage? A Systematic Review and Meta-Analysis. AB - BACKGROUND: Hydrocephalus is a well-recognized complication after aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to identify predictors for shunt dependent hydrocephalus (SDHC) after aSAH via a systematic review and meta analysis. METHODS: A systematic search was conducted using the Embase, MEDLINE, and Web of Science databases for studies pertaining to aSAH and SDHC. Risk factors were assessed by meta-analysis when they were reported by at least 2 studies. The results were presented as odd ratios or risk ratios according to the study design with the corresponding 95% confidence intervals (CI). RESULTS: Twenty-five studies were included. In primary analysis of 14 potential risk factors, 12 were identified as predictors of SDHC after aSAH including age >=50 years, female gender, high Hunt-Hess grade, Glasgow Coma Scale <=8, Fisher grade >=3, acute hydrocephalus, external ventricular drainage insertion, intraventricular hemorrhage, postcirculation aneurysm, anterior communicating artery aneurysm, meningitis, and rebleeding. The meta-analysis based on cohort studies found a significantly increased risk for SDHC in patients with aSAH treated by coiling (risk ratio, 1.16; 95% CI, 1.05-1.29), while the meta-analysis based on case-controlled studies failed to replicate this finding (odds ratio, 1.27; 95% CI, 0.95-1.71). CONCLUSIONS: Several new predictors of SDHC after aSAH were identified that may assist with the early recognition and prevention of SDHC. The controversial evidence found in this study was insufficient to support the potential of neurosurgical clipping for reducing the risk of shunt dependency. Further well-designed studies are warranted to explore the effect of treatment modality on SDHC risk. PMID- 28652121 TI - High Intensity Focused Ultrasound for Radiorecurrent Prostate Cancer: A North American Clinical Trial. AB - PURPOSE: We determined the safety and efficacy of whole gland high intensity focused ultrasound in men with radiorecurrent prostate cancer. MATERIALS AND METHODS: A total of 100 men with clinically localized recurrent prostate cancer at least 2 years after external beam radiation therapy underwent whole gland high intensity focused ultrasound in an open label trial from 2009 to 2012. Treatments were performed at 16 sites, including 14 in the United States and 2 in Canada. The primary end point was the combination of a prostate specific antigen nadir of 0.5 ng/ml or less and negative biopsy at 12 months. Validated questionnaires were administered to monitor changes in urinary and sexual function. RESULTS: Of the 100 treated men, in whom mean age was 70 years (range 53 to 83), 78 completed the 12-month biopsy, which was negative in 63 (81%). Mean prostate specific antigen was 4.9 ng/ml (range 0.4 to 14) and the median Gleason score was 7. The 1-year end point of a prostate specific antigen nadir of 0.5 ng/ml or less plus negative biopsy was achieved in 50 men. During post-trial followup mean prostate specific antigen at 2 years was 1.1 ng/ml (range 0.1 to 17) in 33 patients. Adverse events developed in 91 men through 12 months, which were CTCAE grade 1 in 67, grade 2 in 80 and grade 3 in 20. Treatment related grade 3 adverse events included rectal fistulas in 5 men, which required surgery in 3, osteitis pubis in 3 and hematuria requiring intervention in 3. Treatment related grade 3 adverse events developed early in the trial and appeared related to operator experience. There were no life threatening adverse events or treatment related deaths. CONCLUSIONS: Whole gland high intensity focused ultrasound appears reasonably safe and effective to treat radiorecurrent prostate cancer. The rate of complications, which are potentially severe, was acceptable, especially considering the advanced, refractory nature of the disease and the limited treatment options. PMID- 28652122 TI - Predictors of Hospital Admission and Urological Intervention in Adult Emergency Department Patients with Computerized Tomography Confirmed Ureteral Stones. AB - PURPOSE: More than 1 million patients annually seek care in an emergency department for kidney stones but a minority require hospital admission or a urological procedure. We describe predictors of hospital admission or urological intervention. MATERIALS AND METHODS: This secondary analysis of prospective data included patients with an obstructing ureteral stone that was confirmed by computerized tomography in an emergency department. All patients also underwent point of care limited renal ultrasound. The need for urological intervention at 90 days was assessed by a followup interview. Logistic regression was used to identify predictors of admission and urological intervention, which were further stratified by disposition. Separate regression models with and without computerized tomography findings (point of care limited renal ultrasound only) were compared using c-statistics. RESULTS: Among a cohort of 475 patients with a symptomatic stone on computerized tomography 95 (20%) were admitted and 68 (72%) received an intervention. Of 380 discharged patients 66 (17%) required urological intervention. Admitted patients were more likely to have undergone a prior procedure, have evidence of kidney injury or infection, need opiate analgesia or have larger stones or hydronephrosis on point of care limited renal ultrasound. Predictors of intervention varied by disposition. However, regression models with and without computerized tomography findings demonstrated similar c-statistics. Discharged patients with larger stones, a longer pain duration at presentation and prior procedures were more likely to undergo intervention. CONCLUSIONS: Intervention was common among admitted patients but it occurred in a minority of those discharged. Predictors of intervention varied by disposition. Models incorporating computerized tomography findings were similar to those that did not incorporate such findings. These data support ultrasound first or delayed computerized tomography diagnostic pathways for patients deemed clinically suitable for discharge home. PMID- 28652123 TI - Delay to Inguinal Lymph Node Dissection Greater than 3 Months Predicts Poorer Recurrence-Free Survival for Patients with Penile Cancer. AB - PURPOSE: To our knowledge it is unknown whether concomitant inguinal lymph node dissection at the time of penectomy improves outcomes in patients with penile cancer. We analyzed predictors of regional recurrence as well as disease specific survival based on time of inguinal lymph node dissection. We also determined an optimal time to perform inguinal lymph node dissection. MATERIALS AND METHODS: We reviewed the records of 84 consecutive patients with available nodal pathology findings. Recurrence-free and disease specific survival was estimated using the Kaplan-Meier method. Optimal time to inguinal lymph node dissection was assessed by ROC curves and used for dichotomization. Cox proportional HRs were used to identify predictors of regional recurrence after inguinal lymph node dissection. RESULTS: A total of 47 (56%) and 37 patients (44%) presented with cN0 and cN+ disease, respectively, during a median followup of 21 months. A cutoff point of 3 months to perform inguinal lymph node dissection was used to dichotomize the cohort into early vs delayed groups. Early dissection in 51 men demonstrated 5 year recurrence-free survival of 77% vs 37.8% in 33 who underwent delayed dissection. Positive node disease (HR 23.2, 95% CI 2.98-181.2) and early inguinal lymph node dissection (HR 0.48, 95% CI 0.21-0.98) were predictors of regional recurrence. Five-year disease specific survival was 64.1% and 39.5% in the early and late dissection groups, respectively. CONCLUSIONS: Three months appears to be an optimal window for performing inguinal lymph node dissection. While prospective trials are needed to define the role of upfront groin dissection, our results may help delineate patterns of referral and timing of inguinal lymph node dissection in patients with penile cancer. PMID- 28652124 TI - Ureterocalicostomy for Reconstruction of Complicated Ureteropelvic Junction Obstruction in Adults: Long-Term Outcome and Factors Predicting Failure in a Contemporary Cohort. AB - PURPOSE: Ureterocalicostomy is a well established treatment option in patients who have recurrent ureteropelvic junction obstruction with postoperative fibrosis and a relatively inaccessible renal pelvis. We evaluated the long-term outcome of ureterocalicostomy and factors predicting its failure. MATERIALS AND METHODS: We retrospectively analyzed data on 72 patients who underwent open or laparoscopic ureterocalicostomy from 2000 to 2014. Variables that may affect the outcomes of ureterocalicostomy were assessed with regard to primary pathology findings, patient age, serum creatinine, preoperative renal size (less than and greater than 15 cm), renal cortical thickness (less than and greater than 5 mm), hydronephrosis grade and preoperative renal function (glomerular filtration rate less than and greater than 20 ml/minute/1.73 m2). The surgery outcome was calculated in terms of success or failure. Factors predicting failure were evaluated by univariate and multivariate analysis. Failure was defined as an additional procedure required postoperatively due to persistent symptoms and/or followup renal scan showing persistent significant obstruction with deterioration of renal function on at least 2 occasions 3 months apart. Patients with less than 2-year followup were excluded from study. RESULTS: We analyzed data on 72 patients who underwent ureterocalicostomy during this period. Mean +/- SD age of the study group was 28.9 +/- 12.3 years and mean baseline serum creatinine was 1.1 +/- 0.3 mg/dl. The mean glomerular filtration rate was 27.8 +/- 11.6 ml/minute/1.73 m2 and mean cortical thickness of the operated kidney was 7 +/- 3.86 mm. Common indications for ureterocalicostomy were failed previous pyeloplasty and/or endopyelotomy in 35 patients (48.6%) and secondary ureteropelvic junction obstruction after pyelolithotomy or percutaneous nephrolithotomy in 24 (33.3%). The most common complication was urinary tract infection, which was seen in 22 patients (30.6%). At a mean followup of 60.3 +/- 13.6 months 50 patients (69.5%) had a successful outcome. Treatment failed in 22 patients (30.5%), including 6 who required nephrectomy, while 13 were treated with frequent changes of Double-J(r) stents or with balloon dilation. In 3 patients ureterocalicostomy was repeated. The rate of failed ureterocalicostomy was higher in patients with a low preoperative glomerular filtration rate (less than 20 ml/minute/1.73 m2), attenuated cortical thickness (less than 5 mm) and higher creatinine (greater than 1.7 mg/dl) on univariate analysis. However, on multivariate analysis poor cortical thickness and a low glomerular filtration rate were independent predictors of failure. CONCLUSIONS: Ureterocalicostomy is an acceptable salvage option with a satisfactory long-term outcome. Patients with a low preoperative glomerular filtration rate (less than 20 ml/minute/1.73 m2) and a thinned out cortex (less than 5 mm) showed a poor outcome after ureterocalicostomy. PMID- 28652125 TI - Probiotic containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophiles (ACTIMEL) for the prevention of Clostridium difficile associated diarrhoea in the elderly with proximal femur fractures. AB - The incidence of Clostridium difficile associated diarrhoea (CDAD) is greater in elderly patients. Probiotics may have a beneficial effect in the prevention of CDAD. However, their effect in elderly orthopaedic patients has not been previously reported. Between April 2013 and April 2014, 105 patients admitted with femoral neck fractures, and who required 3days of antibiotics for infection of any cause, were prescribed the probiotic ACTIMEL until 3days after the last antibiotic dose. The incidence of CDAD was compared with historical controls (April 2011???April 2012). There was no significant reduction in the incidence of CDAD in patients receiving probiotics (OR: 0.9; 95% CI 0.27???2.91; p=0.8) and therefore we cannot recommend the use of ACTIMEL containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophiles for this purpose in this patient group. PMID- 28652126 TI - Patient-specific 3D-printed Cardiac Model for Percutaneous Left Atrial Appendage Occlusion. PMID- 28652127 TI - Efficacy of a Combined Strategy to Improve Low-density Lipoprotein Cholesterol Control Among Patients With Hypercholesterolemia: A Randomized Clinical Trial. AB - INTRODUCTION AND OBJECTIVES: Several interventions can improve low-density lipoprotein cholesterol (LDL-C) control. Our main objective was to evaluate the efficacy of a combined intervention to improve LDL-C control in patients with hypercholesterolemia. The study also assessed the efficacy of the intervention in improving adherence (pharmacological, diet, and exercise). METHODS: A multicenter, parallel group, randomized clinical trial (primary care) was conducted in 358 adults diagnosed with hypercholesterolemia, whether receiving prior drug therapy or not. We compared 178 participants who received the combined intervention (written material, self-completed registration cards, and messages to mobile telephones) with 178 controls. The main outcome variable was the proportion of participants with adequate LDL-C control (target levels of the European guidelines on dyslipidemia and cardiovascular risk) at 24 months. RESULTS: At 24 months, the mean reduction in LDL-C was significantly higher in the intervention group (23.8mg/dL [95%CI, 17.5-30.1]) than in the control group (14.6mg/dL [95%CI, 8.9-20.4]; P=.034). The mean LDL-C decrease was 13.1%+/-28.6%. At 1 year, the proportion of participants with adequate control was significantly higher in the intervention group than in the control group (43.7% vs 30.1%; P=.011; RR, 1.46). Adherence was significantly higher in the intervention group, both to drug therapy (77.2% vs 64.1%; P=.029) and exercise (64.9% vs 35.8; P<.001), but not to diet. CONCLUSIONS: The combined intervention significantly reduced LDL-C (by more than 13% at 2 years) and improved the degree of LDL-C control in patients with hypercholesterolemia at 1 year. PMID- 28652128 TI - The Esophageal Epithelial Barrier in Health and Disease. AB - Dysfunction in the esophageal epithelial barrier function is a major source for morbidity. To better understand the pathophysiologic pathways of the diseases associated with barrier dysfunction, including gastroesophageal reflux disease, eosinophilic esophagitis, Barrett's esophagus, and obesity, it is important to understand the esophageal epithelial embryologic development, microscopic anatomy with a special focus on the barrier structure and function, extraepithelial defense mechanisms, and how these change in the diseased state. In recent years, significant progress has been made in elucidating the esophageal barrier structure and function both in vitro and in vivo. This has enhanced the understanding of mechanisms of disease, and may also allow identification of therapeutic targets that can help in the management of these diseases. This review provides a detailed discussion regarding the esophageal epithelial barrier structure and function, the current and historical techniques used to study the barrier, and how it is affected by common esophageal diseases. PMID- 28652130 TI - TAL1 as a master oncogenic transcription factor in T-cell acute lymphoblastic leukemia. AB - In hematopoietic cell development, the transcriptional program is strictly regulated in a lineage- and stage-specific manner that requires a number of transcription factors to work in a cascade or in a loop, in addition to interactions with nonhematopoietic cells in the microenvironment. Disruption of the transcriptional program alters the cellular state and may predispose cells to the acquisition of genetic abnormalities. Early studies have shown that proteins that promote cell differentiation often serve as tumor suppressors, whereas inhibitors of those proteins act as oncogenes in the context of acute leukemia. A prime example is T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder characterized by clonal proliferation of immature stage thymocytes. Although a relatively small number of genetic abnormalities are observed in T ALL, these abnormalities are crucial for leukemogenesis. Many oncogenes and tumor suppressors in T-ALL are transcription factors that are required for normal hematopoiesis. The transformation process in T-ALL is efficient and orchestrated; the oncogene disrupts the transcriptional program directing T-cell differentiation and also uses its native ability as a master transcription factor in hematopoiesis. This imbalance in the transcriptional program is a primary determinant underlying the molecular pathogenesis of T-ALL. In this review, we focus on the oncogenic transcription factor TAL1 and the tumor-suppressor E proteins and discuss the malignant cell state, the transcriptional circuit, and the consequence of molecular abnormalities in T-ALL. PMID- 28652129 TI - Evolutionary dynamics and significance of multiple subclonal mutations in cancer. AB - For the last 40 years the authors have collaborated on trying to understand the complexities of human cancer by formulating testable mathematical models that are based on mutation accumulation in human malignancies. We summarize the concepts encompassed by multiple mutations in human cancers in the context of source, accumulation during carcinogenesis and tumor progression, and therapeutic consequences. We conclude that the efficacious treatment of human cancer by targeted therapy will involve individualized, uniquely directed specific agents singly and in simultaneous combinations, and take into account the importance of targeting resistant subclonal mutations, particularly those subclones with alterations in DNA repair genes, DNA polymerase, and other genes required to maintain genetic stability. PMID- 28652132 TI - Oral Substitution Treatment of Injecting Opioid Users for Prevention of HIV Infection. PMID- 28652131 TI - HIV Testing and Entry to Care Among Trans Women in Indiana. AB - Trans women in the United States are disproportionately affected by HIV infection. To improve HIV services for this population, more information is needed about their experiences in early stages of the HIV Care Continuum. Trans women in states such as Indiana, which has moderate HIV incidence but little public health investment in HIV prevention and treatment, experience special challenges. Our qualitative descriptive study describes the circumstances influencing HIV testing and entry to care by 18 trans women living with HIV in Central Indiana. In-depth interviews regarding participants' HIV care experiences were analyzed using standard content analysis. Participants discussed three main topics: (a) HIV testing circumstances, (b) facilitators and barriers to entering care, and (c) motivators for entering care after a delay. Findings indicate that social relationships play a significant role in trans women's care experiences and that stigma, discrimination, and adverse life circumstance are powerful deterrents to care. Practice and policy implications are discussed. PMID- 28652133 TI - Acute salinity tolerance and the control of two prolactins and their receptors in the Nile tilapia (Oreochromis niloticus) and Mozambique tilapia (O. mossambicus): A comparative study. AB - Osmoregulation in vertebrates is largely controlled by the neuroendocrine system. Prolactin (PRL) is critical for the survival of euryhaline teleosts in fresh water by promoting ion retention. In the euryhaline Mozambique tilapia (Oreochromis mossambicus), pituitary PRL cells release two PRL isoforms, PRL188 and PRL177, in response to a fall in extracellular osmolality. Both PRLs function via two PRL receptors (PRLRs) denoted PRLR1 and PRLR2. We conducted a comparative study using the Nile tilapia (O. niloticus), a close relative of Mozambique tilapia that is less tolerant to increases in environmental salinity, to investigate the regulation of PRLs and PRLRs upon acute hyperosmotic challenges in vivo and in vitro. We hypothesized that differences in the regulation of PRLs and PRLRs underlie the variation in salinity tolerance of tilapias within the genus Oreochromis. When transferred from fresh water to brackish water (200/00), Nile tilapia increased plasma osmolality and decreased circulating PRLs, especially PRL177, to a greater extent than Mozambique tilapia. In dispersed PRL cell incubations, the release of both PRLs was less sensitive to variations in medium osmolality in Nile tilapia than in Mozambique tilapia. By contrast, increases in pituitary and branchial prlr2 gene expression in response to a rise in extracellular osmolality were more pronounced in Nile tilapia relative to its congener, both in vitro and in vivo. Together, these results support the conclusion that inter-specific differences in salinity tolerance between the two tilapia congeners are tied, at least in part, to the distinct responses of both PRLs and their receptors to osmotic stimuli. PMID- 28652134 TI - Effects of thermal stress on the expression of glucocorticoid receptor complex linked genes in Senegalese sole (Solea senegalensis): Acute and adaptive stress responses. AB - The present study examined the short and mid-term effects of a rise in temperature from 18 degrees C to 24 degrees C on the expression of genes related to the stress response regulation in juveniles of Senegalese sole, Solea senegalensis. The animals were exposed to a temperature increase of 6 degrees C, after 1month of acclimation at 18 degrees C. After this process, samples of different tissues were collected from a total of 96 fish at four sampling points: 1h, 24h, 3days and 1week. The transcript levels of a set of genes involved in the stress response such as glucocorticoid receptors 1 and 2, corticotrophin releasing factor, corticotrophin-releasing factor binding proteins, proopiomelanocortin A and B, and cellular stress defense (heat shock protein 70, 90AA and 90AB) were quantified at these sampling points. Additionally, blood samples were also taken to measure the circulating plasma cortisol concentration. Thermal stress induced by increasing temperature prompted an elevation of plasma cortisol levels in juvenile Senegalese sole after 1h as a short-term response, and a consecutive increase after one week, as a mid-term response. Senegalese sole seemed to respond positively in terms of adaptive mechanisms, with a rapid over-expression of grs and hsps in liver and brain, significantly higher after one hour post stress, denoting the fast and acute response of those tissues to a rapid change on temperature. The ratio hsp90/gr also increased 24h after thermal shock, ratio proposed to be an adaptive mechanism to prevent proteosomal degradation of GR. As a mid-term response, the elevation of brain crfbp gene expression one week after thermal shock could be an adaptive mechanism of negative feedback on HPI axis. Taken together, these data suggested an initial up regulation of the glucocorticoid receptor complex linked genes in response to a temperature increase in Senegalese sole, with heat shock protein 90 potentially being a regulatory factor for the glucocorticoid receptor in the presence of cortisol. PMID- 28652135 TI - Endocrine disruption of phenanthrene in the protogynous dusky grouper Epinephelus marginatus (Serranidae: Perciformes). AB - The dusky grouper Epinephelus marginatus is a protogynous hermaphrodite fish, that maintains high levels of plasma steroids as juveniles, as substrates for sex inversion. These fish are exposed to marine pollution from oil spills during cargo handling. Polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene (Phe), are the main crude oil components and are toxic to fish, acting as endocrine disruptors (ED). This is the first study that investigated impacts of Phe as an ED in E. marginatus juveniles. An in vivo sublethal exposure (96h) to Phe was carried out at two concentrations (0.1mg/L and 1mg/L); exposure to the vehicle (ethanol; ETOH) was also performed. Plasma levels of 17beta-estradiol (E2), testosterone (T) and 11-ketotestosterone (11-KT) were measured by ELISA. Gonads, liver and spleen were processed for histological analysis. In an in vitro bioassay, gonad fragments were incubated with Phe (8.91mg/L) or ETOH. Steroid levels in the culture media were measured by ELISA. The in vivo exposure to Phe triggered an increase of the area of the hepatocytes, increased number of melanomacrophagic centers and hemosiderosis in the spleen; ETOH induced similar effects on spleen. E2 and T levels did not change in plasma or in vitro media. In plasma, ETOH decreased 11-KT levels. Phenanthrene sharply reduced 11-KT levels in vitro. Although in vivo bioassay results were not unequivocal owing to ethanol effects, Phe might disrupt steroidogenesis in juvenile grouper, possibly causing dysfunctions during sex change and gonadal maturity, considering the importance of 11-KT in developing ovaries. PMID- 28652136 TI - Evolution of the receptors for growth hormone, prolactin, erythropoietin and thrombopoietin in relation to the vertebrate tetraploidizations. AB - The receptors for the pituitary hormones growth hormone (GH), prolactin (PRL) and somatolactin (SL), and the hematopoietic hormones erythropoietin (EPO) and thrombopoietin (TPO), comprise a structurally related family in the superfamily of cytokine class-I receptors. GH, PRL and SL receptors have a wide variety of effects in development, osmoregulation, metabolism and stimulation of growth, while EPO and TPO receptors guide the production and differentiation of erythrocytes and thrombocytes, respectively. The evolution of the receptors for GH, PRL and SL has been partially investigated by previous reports suggesting different time points for the hormone and receptor gene duplications. This raises questions about how hormone-receptor partnerships have emerged and evolved. Therefore, we have investigated in detail the expansion of this receptor family, especially in relation to the basal vertebrate (1R, 2R) and teleost (3R) tetraploidizations. Receptor family genes were identified in a broad range of vertebrate genomes and investigated using a combination of sequence-based phylogenetic analyses and comparative genomic analyses of synteny. We found that 1R most likely generated EPOR/TPOR and GHR/PRLR ancestors; following this, 2R resulted in EPOR and TPOR genes. No GHR/PRLR duplicate seems to have survived after 2R. Instead the single GHR/PRLR underwent a local duplication sometime after 2R, generating separate syntenic genes for GHR and PRLR. Subsequently, 3R duplicated the gene pair in teleosts, resulting in two GHR and two PRLR genes, but no EPOR or TPOR duplicates. These analyses help illuminate the evolution of the regulatory mechanisms for somatic growth, metabolism, osmoregulation and hematopoiesis in vertebrates. PMID- 28652137 TI - Subspecies-specific response to ACTH challenge test in the house mouse (Mus musculus). AB - Long term changes in hormonal levels of small and rare animal species can be effectively monitored by non-invasive methods such as immunoenzymatic analysis. These methods generally analyze metabolites instead of the hormone itself and thus do not invade the organism. However, they can be influenced by many factors, so before they are used, they need to be validated. For this purpose we used the "ACTH challenge" test based on stimulating the animal's adrenocortical activity and measuring the consequent increase of the level of its glucocorticoid ("stress") hormones. Specifically, we measured concentrations of fecal glucocorticoid metabolites of two house mouse subspecies, Mus musculus musculus and M. m. domesticus. Using polyclonal antibody we investigated the mice's naturally occurring circadian fluctuation and their reaction to the adrenal stimulation. This study confirmed that the selected method is suitable for analysis of fecal corticosterone metabolites in the wild house mouse. More importantly, we revealed a subspecies-specific stress response at the level of corticosterone production: while the significant effect of ACTH was proved in both subspecies, a notable adrenocortical reaction was also elicited by injecting the saline solution in M. m. domesticus. Our results thus highlight the importance of considering potential cryptic variation within the species under study when designing projects on adrenal stress hormone assessments. PMID- 28652138 TI - Challenging Patients. PMID- 28652139 TI - Characterization of the distal-less homologue gene, PfDlx, involved in regulating the expression of Pif in the pearl oyster, Pinctada fucata. AB - Distal-less (Dlx) homeobox transcription factors play an important role in regulating various aspects of vertebrate biology. In vertebrates and invertebrates, distal-less is a highly conserved and well-studied transcription factor. In pearl oyster, we have identified a homologue of this gene, Dlx, and cloned the full-length cDNA. Genomic structure analysis revealed that PfDlx genomic DNA contained three exons and two introns. Their deduced amino acid sequences all showed the highest identity with homologues in Crassostrea gigas. Analyses of PfDlx mRNA in tissues and developmental stages showed high expressions in gonad, polar body stage, 2-4 cells and 32 cells. After shell notching, the changes in expression of Dlx shows that it reached a maximum at 24h. In co-transfection experiments, PfDlx significantly activates reporter constructs containing a Pif promoter. Through using RNAi techniques, we demonstrated that down-regulation of Dlx in P. fucata did not significantly disrupt the development of the nacreous layer in scanning electron microscopy, but it significantly down-regulated the expression of Pif gene. Thus, our work suggests that PfDlx might participate in regulating the expression of the Pif gene in the pearl oyster. PMID- 28652140 TI - Erythropoietin in diabetic retinopathy. AB - Over the past years, knowledge has expanded with regards to the multiple roles played by erythropoietin (EPO) in the body. Once believed to be a hormone synthesised in the kidney and involved only in the modulation of erythrocyte production, it is recognised now that EPO can be produced in many tissues, including the retina, and by many cells. In these tissues EPO is released in response to "tissue injury" and appears to have protective functions. Despite the extensive research conducted to date, the cues leading to release of EPO and its effects in the normal and diseased retina have not been fully elucidated. In vitro and in vivo experimental studies as well as small interventional clinical studies suggest a potential beneficial effect of externally administered EPO in early diabetic retinopathy and diabetic macular oedema. In contrast, controversy exists with regards to the possible use of EPO in proliferative diabetic retinopathy. Non-erythropoietic EPO-derived peptides, produced with the aim of increasing effectiveness and reducing side effects of EPO, are currently under investigation in early phase clinical trials. PMID- 28652141 TI - Andrographolide-loaded nanoparticles for brain delivery: Formulation, characterisation and in vitro permeability using hCMEC/D3 cell line. AB - Andrographolide (AG) is a major diterpenoid of the Asian medicinal plant Andrographis paniculata which has shown exciting pharmacological potential for the treatment of inflammation-related pathologies including neurodegenerative disorders. Conversely, the low bioavailability of AG still represents a limiting factor for its use. To overcome these limitations, AG was loaded into human serum albumin based nanoparticles (HSA NPs) and poly ethylcyanoacrylate nanoparticles (PECA NPs). HSA NPs were prepared by thermal (HSAT AG NPs) and chemical cross linking (HSAC AG NPs), while PECA AG NPs were produced by emulsion polymerization. NPs were characterized in terms of size, zeta (zeta)-potential, polydispersity, and release studies of AG. In addition, the ability of free AG and AG-loaded in PECA and HSAT NPs to cross the blood-brain barrier (BBB) was assessed using an in vitro BBB model based on human cerebral microvascular endothelial cell line (hCMEC/D3). For BBB drug permeability assays, a quantitative UPLC-MS/MS method for AG in Ringer HEPES buffer was developed and validated according to international regulatory guidelines for industry. Free AG did not permeate the BBB model, as also predicted by in silico studies. HSAT NPs improved by two-fold the permeation of AG while maintaining the integrity of the cell layer, while PECA NPs temporarily disrupted BBB integrity. PMID- 28652142 TI - A randomised exploratory clinical evaluation of dentifrices used as controls in dentinal hypersensitivity studies. AB - OBJECTIVES: To explore relative efficacy of six negative-control dentifrices utilised as controls in clinical studies compared with two dentine hypersensitivity (DH)-relief dentifrices used 2*/day for 8 weeks. METHODS: Six control dentifrices differing in terms of fluoride source (sodium fluoride/sodium monofluorophosphate), abrasive base (silica/dicalcium phosphate), relative dentine abrasivity (RDA) (~17 to ~180) and colour (white/blue/multicoloured stripes) were compared with a depolarising dentifrice (5% KNO3; RDA ~70-97; 'Test 1') and an occlusion-technology dentifrice (0.454% SnF2; RDA ~160-180; 'Test 2'). DH was assessed using tactile and evaporative (air) (measured by Schiff Sensitivity Scale and a visual rating scale [VRS]) stimuli. RESULTS: In total 249 subjects were randomized. All dentifrices yielded statistically significant improvements from baseline on all endpoints. The two DH-relief dentifrices ranked highest in terms of improvement in scores over the control dentifrices. While there was a clear differentiation between Test 1 and control dentifrices on both measures at 4/8 weeks, for Test 2, statistically significant improvements in Schiff scores were observed over all controls at Week 4 but only over three at Week 8. At Week 4 none of the controls separated from Test 2 on tactile threshold; all separated by Week 8. VRS scores did not separate test and control dentifrices. Dentifrices were generally well-tolerated. CONCLUSIONS: The six negative-control dentifrices can be used to assess dentifrices considered to be effective in reducing DH. Although response ranges for commercially available negative controls varied, these results may begin to set acceptable performance ranges for control dentifrices in DH trials. PMID- 28652143 TI - Specific or nonspecific? Evaluation of band, baseline, and cognitive specificity of sensorimotor rhythm- and gamma-based neurofeedback. AB - Neurofeedback (NF) is often criticized because of the lack of empirical evidence of its specificity. Our present study thus focused on the specificity of NF on three levels: band specificity, cognitive specificity, and baseline specificity. Ten healthy middle-aged individuals performed ten sessions of SMR (sensorimotor rhythm, 12-15Hz) NF training. A second group (N=10) received feedback of a narrow gamma band (40-43Hz). Effects of NF on EEG resting measurements (tonic EEG) and cognitive functions (memory, intelligence) were evaluated using a pre-post design. Both training groups were able to linearly increase the target training frequencies (either SMR or gamma), indicating the trainability of these EEG frequencies. Both NF training protocols led to nonspecific changes in other frequency bands during NF training. While SMR NF only led to concomitant changes in slower frequencies, gamma training affected nearly the whole power spectrum. SMR NF specifically improved memory functions. Gamma training showed only marginal effects on cognitive functions. SMR power assessed during resting measurements significantly increased after SMR NF training compared to a pre assessment, indicating specific effects of SMR NF on baseline/tonic EEG. The gamma group did not show any pre-post changes in their EEG resting activity. In conclusion, SMR NF specifically affects cognitive functions (cognitive specificity) and tonic EEG (baseline specificity), while increasing SMR during NF training nonspecifically affects slower EEG frequencies as well (band non specificity). Gamma NF was associated with nonspecific effects on the EEG power spectrum during training, which did not lead to considerable changes in cognitive functions or baseline EEG activity. PMID- 28652144 TI - Extended Segmentectomy II to Left Hepatic Vein: Importance of Preserving Umbilical Fissure Vein to Avoid Congestion of Segment III. PMID- 28652145 TI - Diverse structures, functions and uses of FK506 binding proteins. AB - FK506 (Tacrolimus), isolated from Streptomyces tsukubaenis is a powerful immunosuppressant shown to inhibit T cell activation. FK506 mediated immunosuppression requires the formation of a complex between FK506, a FK506 binding protein (FKBP) and calcineurin. Numerous FKBPs have been identified in a wide range of species, from single celled organisms to humans. FKBPs show peptidylprolyl cis/trans isomerase (PPIase) activity and have been shown to affect a wide range of cellular processes including protein folding, receptor signaling and apoptosis. FKBPs also affect numerous biological functions in addition to immunosuppression including regulation of cardiac function, neuronal function and development and have been implicated in several diseases including cardiac disease, cancer and neurodegenerative diseases such as Alzheimer's disease. More recently, FKBPs have proven useful as molecular tools for studying protein interactions, localization and functions. This review provides an overview of the current state of knowledge of FKBPs and their numerous biological functions and uses. PMID- 28652147 TI - Unusual high-grade features in pediatric diffuse leptomeningeal glioneuronal tumor: comparison with a typical low-grade example. AB - Diffuse leptomeningeal glioneuronal tumor, a recent addition to the World Health Organization classification system, typically presents in the pediatric population with signs and symptoms related to elevated intracranial pressure and imaging characteristics that may mimic infectious etiologies. The tumor is usually low grade and tends to harbor BRAF rearrangement/duplication in up to 75% of cases, BRAF V600E mutation in a smaller subset of cases, and loss of chromosomal arm 1p in approximately 50%-60% of cases, with ~20% of those showing loss of both 1p and 19q (codeletion). We report here 2 contrasting cases of diffuse leptomeningeal glioneuronal tumors, one with typical low-grade features and an indolent, although not benign, course, in which the disease is currently successfully managed by chemotherapy, and a second case with unusually high-grade features on initial presentation, including frank anaplasia and elevated mitotic index, in which the disease showed an initial response to chemoradiation but ultimately was fatal. PMID- 28652148 TI - Value of upper endoscopic biopsies in predicting medical refractoriness in pediatric patients with ulcerative colitis. AB - Refractory ulcerative colitis (UC) occurs in patients who experience a severe disease manifestation that is unresponsive to medical therapy. The assessment of upper endoscopic microscopic findings and its correlation with refractory UC has not been fully studied in pediatric patients and is the focus of this study. Medical records of UC patients treated at a tertiary pediatric center between 2000 and 2014 were reviewed. Endoscopic biopsies of the upper gastrointestinal (GI) tract of patients meeting a priori inclusion criteria were compared between refractory UC patients and nonrefractory UC patients for active inflammation. Statistically significant differences were determined between groups, and tissues shown to have significant differences were further evaluated for their diagnostic performance. A total of 52 patients were included, 26 in each group. Significant differences were observed in intraepithelial neutrophil infiltration and percentage involvement of crypts/glands for the antrum, body, and duodenal bulb (P <= .001, .005, and .01 [intraepithelial neutrophil infiltration] and P = .001, .009, and .015 [% involvement], respectively). Microabscesses of mucosal glands/crypts were also experienced in a greater number of refractory UC patients in the stomach (ie, antrum and/or body of stomach; P = .005) and duodenum (ie, duodenum and/or duodenal bulb; P = .023). The sensitivity and specificity of upper GI tissues to predict refractory UC were moderate, with sensitivities ranging from 38% to 67% and specificities ranging from 81% to 100%. Our results suggest that children with refractory UC are more likely to have active inflammation in the upper GI tract, and thus, this may represent a predictor of responsiveness to current medical therapy. PMID- 28652146 TI - Downregulation of PKCzeta/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion. AB - Atypical protein kinase C zeta (PKCzeta) forms an apico-basal polarity complex with Partitioning Defective (Pard) 3 and Pard6 to regulate normal epithelial cell apico-basolateral polarization. The dissociation of the PKCzeta/Pard3/Pard6 complex is essential for the disassembly of the tight/adherens junction and epithelial-mesenchymal transition (EMT) that is critical for tumor spreading. Loss of cell polarity and epithelial organization is strongly correlated with malignancy and tumor progression in some other cancer types. However, it is unclear whether the PKCzeta/Pard3/Pard6 complex plays a role in the progression of non-small-cell lung cancer (NSCLC). We found that hypoxia downregulated the PKCzeta/Pard3/Pard6 complex, correlating with induction of lung cancer cell migration and invasion. Silencing of the PKCzeta/Pard3/Pard6 polarity complex components induced lung cancer cell EMT, invasion, and colonization in vivo. Suppression of Pard3 was associated with altered expression of genes regulating wound healing, cell apoptosis/death and cell motility, and particularly upregulation of MAP3K1 and fibronectin which are known to contribute to lung cancer progression. Human lung adenocarcinoma tissues expressed less Pard6b and PKCzeta than the adjacent normal tissues and in experimental mouse lung adenocarcinoma, the levels of Pard3 and PKCzeta were also decreased. In addition, we showed that a methylation locus in the gene body of Pard3 is positively associated with the expression of Pard3 and that methylation of the Pard3 gene increased cellular sensitivity to carboplatin, a common chemotherapy drug. Suppression of Pard3 increased chemoresistance in lung cancer cells. Together, these results suggest that reduced expression of PKCzeta/Pard3/Pard6 contributes to NSCLC EMT, invasion, and chemoresistance. PMID- 28652149 TI - Effects of sucrose fatty acid esters on the stability and bonding performance of high amylose starch-based wood adhesive. AB - A facile approach was developed to dramatically boost the performance of high amylose starch-based wood adhesive (HASWA) by addition of sucrose fatty acid esters (SEs). The results showed that the addition of 6% (w/w, dry starch basis) SEs significantly improved the bonding strength in both dry and wet states as well as the mobility and storage stability of the adhesive. The formation of amylose-SEs complexes were proved by blue value or differential scanning calorimetry (DSC) analysis. The results also indicated that the incorporation of SEs into the HASWA hindered the aggregation of latex particles and enhanced the thermal stability of starch molecules. Furthermore, SEs addition in the adhesive system resulted in the inhibition of starch retrogradation as observed by time sweep and pulsed nuclear magnetic resonance (PNMR) analysis. These findings provide important information to prepare bio-based high performance wood adhesive by adding SEs to replace the traditional petro-chemical based stocks adhesives. PMID- 28652150 TI - Biochemical characterization of a novel beta-galactosidase from Paenibacillus barengoltzii suitable for lactose hydrolysis and galactooligosaccharides synthesis. AB - A beta-galactosidase gene (PbBGal2A) was cloned from Paenibacillus barengoltzii and expressed in Escherichia coli. The in silico analysis of the deduced amino acid sequences revealed that PbBGal2A shared the highest identity of 40% with the characterized glycoside hydrolase (GH) family 2 beta-galactosidase from Actinobacillus pleuropneumoniae. The recombinant beta-galactosidase (PbBGal2A) was purified with a molecular mass of 124.2kDa on SDS-PAGE. The optimal pH and temperature of PbBGal2A were determined to be pH 7.5 and 45 degrees C, respectively. PbBGal2A was stable within pH 6.0-8.0 and up to 45 degrees C. It completely hydrolyzed the lactose in milk and whey powder solution. In addition, PbBGal2A exhibited high transglycosylation activity and a maximum yield of 47.9% (w/w) for galactooligosaccharides (GOS) production was obtained in 8h at a lactose concentration of 350g/L. These properties make PbBGal2A an ideal candidate for commercial use in the production of lactose-free milk and GOS. PMID- 28652151 TI - A change in the pathway of dithiothreitol-induced aggregation of bovine serum albumin in the presence of polyamines and arginine. AB - When studying the anti-aggregation activity of chemical chaperones, a kinetic regime of the aggregation process for selected test systems should be established. To elucidate the mechanism of suppression of protein aggregation by polyamines (putrescine, spermidine) and arginine, we used a test system based on dithiothreitol (DTT)-induced aggregation of bovine serum albumin (BSA) at 45 degrees C (0.1M Na-phosphate buffer, pH 7.0; [DTT]=2mM). The rate-limiting stage of DTT-induced aggregation of BSA under the studied conditions is that of unfolding of the protein molecule. The kinetics of BSA aggregation was monitored by dynamic light scattering and asymmetric flow field-flow fractionation. On the basis of the obtained data a mechanism of DTT-induced aggregation of BSA in the presence of polyamines and arginine has been proposed. It is assumed that the chemical chaperones under study stabilize the native form of protein with a subsequent decrease in the aggregation rate. However, they stimulate the sticking of aggregates formed in the aggregation process. To prove this mechanism, plots of the hydrodynamic radius of protein aggregates versus the portion of aggregated protein have been constructed. PMID- 28652152 TI - Improving the integrity of natural biopolymer films used in food packaging by crosslinking approach: A review. AB - Currently used approaches for biopolymer modification are either expensive, poisonous or do not lead into the well-desired characteristics to the final film materials. Development of crosslinking procedure is an innovative strategy to improve mechanical, physical and thermal properties of biopolymer films. This review provides a brief description of film-forming biopolymers (e.g. chitosan, whey protein, alginate and starch) followed by a detailed introduction to definition and classification of various crosslinkers, the effect of crosslinking on emerging attributes of biopolymer films including physical, mechanical and thermal properties, identification of crosslinking occurrence, and cytotoxicity status of commonly used crosslinkers in the field of food and food-related packaging materials. PMID- 28652153 TI - Antimicrobial electrospun ultrafine fibers from zein containing eucalyptus essential oil/cyclodextrin inclusion complex. AB - The aim of this study was to produce ultrafine fibers from zein incorporated with a complex of eucalyptus essential oil (EEO) and beta-cyclodextrin (beta-CD) with antimicrobial properties by electrospinning technique. The EEO was characterized by chemical composition and antimicrobial tests against three Gram positive and four Gram negative bacteria. The inclusion complex (IC) was prepared with beta-CD and EEO by co-precipitation technique and added at different concentrations in zein polymer solution using aqueous ethanol as solvent. The morphology, thermal properties, functional groups, and antimicrobial activity against L. monocytogenes and S. aureus of the ultrafine fibers were evaluated. The composite membranes containing 24% IC exhibited a greater reduction of growth as compared to the fibers without addition of IC. For L. monocytogenes the growth reduction was 28.5% and for S. aureus it was 24.3%. The electrospun IC-beta-CD/EEO composite membranes are promising for use in antimicrobial applications, such as food packaging. PMID- 28652154 TI - New pathways for itching in patients with atopic dermatitis? PMID- 28652155 TI - Advances in atopic dermatitis and urticarial in 2016. AB - This review highlights recent key advances in the pathology and therapies of inflammatory skin diseases, focusing on atopic dermatitis (AD) and chronic spontaneous urticaria (CSU). Regarding AD, transcriptomic analysis with human samples revealed different immune profiles between childhood and adult AD. Phase III clinical trials of dupilumab, an anti-IL-4 receptor alpha antibody, in the treatment of AD have successfully finished, and dupilumab will appear in clinical practice as the first biologic for AD in 2017. In addition, a novel biologic that targets IL-31 shows promising results in a phase II trial. As for the skin microbiome study, novel insights into the mechanisms of microbial dysbiosis, such as colonization of Staphylococcus aureus, a common feature of AD, were proposed. Regarding CSU, autoreactive CD4+ T cells that react to FcepsilonRI were discovered, which might contribute to the development of CSU. These findings provide new insights into the pathogenesis of AD and CSU and will lead to more specific and personalized treatments. PMID- 28652156 TI - Electrospray Synthesis of Poly(lactide-co-glycolide) Nanoparticles Encapsulating Peptides to Enhance Proliferation of Antigen-Specific CD8+ T Cells. AB - Polymer nanoparticles (NP) are of escalating interest for their application as immune stimulatory pharmaceutics. The production of nanosized carrier systems is currently being widely investigated, but commonly used techniques, such as the double emulsion technique, are limited by shortcomings of low encapsulation efficiency and poor control over size distribution. In this study, the electrospray technique was successfully implemented and optimized to produce monodisperse 200-nm poly(lactide-co-glycolide) (PLGA) NP. For cytomegalovirus (CMV) pp65 and IE-1 peptides, a consistent encapsulation efficiency of approximately 85% was achieved. In vitro stimulation of peripheral blood mononuclear cells (PBMCs) from CMV+ donors using electrosprayed pp65489-503 peptide-loaded NP revealed a significantly increased proliferation rate and frequency of antigen-specific CD8+ T cells as compared to the soluble peptide. The results of this study demonstrate the suitability of the electrospray technique for production of monodisperse PLGA NP with high drug encapsulation efficiency as promising peptide-based vaccine carriers. PMID- 28652157 TI - An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kdelta Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs. AB - It is well acknowledged that drugs with poor aqueous solubility are often associated with poor oral absorption. Fortunately, drugs with a basic pKa can take advantage of solubilization in the stomach under the acidic environment to improve exposure. Consequently, high in vivo variability is often observed when stomach pH is altered. When issue encountered, enabling formulations are often used to solve the problem. However, each enabling formulation has its limitations and the situation can be further complicated by other absorption distribution metabolism elimination parameters. Therefore, formulation strategies need to consider various scenarios in order to be effective. Compound 1 is a potent phosphoinositide 3-kinase delta inhibitor with poor intrinsic solubility and 2 basic pKas. It was dosed as a suspension in dogs and found to have mediocre oral bioavailability with high variability. It was hypothesized that this variability was caused by their stomach pH variability. Pharmacokinetic modeling suggested that the issue could be improved with particle size reduction. Meanwhile, it was found that although the Madin-Darby canine kidney permeability was reasonable, Madin-Darby canine kidney transfected with human MDR1 gene (MDCK-MDR1) suggested that Compound 1 is an efflux transporter substrate. Findings were integrated into the design for in vivo studies in dogs. Data obtained from those studies allowed us to quickly narrow down the formulation approaches. PMID- 28652158 TI - In Vitro and In Vivo Skin Distribution of 5alpha-Reductase Inhibitors Loaded Into Liquid Crystalline Nanoparticles. AB - In this study, we developed positively charged liquid crystalline nanoparticles (LCN) coated with chitosan (CHI) to enhance the skin permeation and distribution of 5alpha-reductase inhibitors for the treatment of androgenetic alopecia. LCN and surface-modified LCN (CHI-LCN) were prepared by ultrasonication method, and their physicochemical properties were characterized. In vitro and in vivo skin permeation and retention were studied using porcine abdominal skin and mice skin using the Franz diffusion cell. Skin distribution and cellular uptake of LCN and CHI-LCN were also investigated. The particle size and surface charge were 244.9 +/- 2.1 nm and -19.2 +/- 1.1 mV, respectively, for LCNs and 300.0 +/- 7.6 nm and 24.7 +/- 2.4 mV, respectively, for CHI-LCN. The permeation of 5alpha-reductase inhibitors was significantly greater with CHI-LCN compared with LCN, whereas there was no significant difference observed in the skin distribution. In fluorescence studies, fluorescence intensity was higher for CHI-LCNs throughout the skin, whereas more intense fluorescence was seen only in the epidermis layer for LCN. CHI-LCN showed greater cellular uptake than LCN, resulting in internalization of 98.5 +/- 1.9% of nanoparticles into human keratinocyte cells. In conclusion, surface modification of LCN with CHI is a promising strategy for increasing skin permeation of 5alpha-reductase inhibitors for topical delivery. PMID- 28652159 TI - Skin-to-tumor Distance Predicts Treatment Failure of T1A Renal Cell Carcinoma Following Percutaneous Cryoablation. AB - OBJECTIVE: To determine the impact of skin-to-tumor (STT) distance on the risk for treatment failure following percutaneous cryoablation (PCA). METHODS: We retrospectively reviewed patients who underwent PCA with documented T1a recurrent renal cell carcinoma (RCC) at 2 academic centers between 2005 and 2015. Patient demographics, tumor characteristics, and perioperative and postoperative course variables were collected. Additionally, we measured the STT distance by averaging the distance from the skin to the center of the tumor at 0 degrees , 45 degrees , and 90 degrees on preoperative computed tomography imaging. RESULTS: We identified 86 patients with documented T1a RCC. The mean age at the time of surgery was 69 years (range: 37-91 years), and the mean tumor size was 2.7 cm (range: 1.0-4.0 cm). With a mean follow-up of 24 months (range: 3-63 months), 11 (12.8%) treatment failures occurred. Patients with treatment failure had significantly higher mean STT distance than those without: 11.0 cm (range: 6.3 20.1 cm) compared to 8.4 cm (range: 4.4-15.2 cm), respectively (P = .002). STT distance was an independent predictor of treatment failure (odds ratio: 1.32, 95% confidence interval: 1.04-1.69, P = .029). STT distance greater than 10 cm had a fourfold increased risk of tumor treatment failure (odds ratio: 4.43, 95% confidence interval: 1.19-16.39, P = .018). Tumor size, R.E.N.A.L. Nephrometry score, and number of cryoprobes placed were not associated with treatment failure. CONCLUSION: STT, an easily measured preoperative variable, may inform the risk of RCC treatment failure following PCA. PMID- 28652160 TI - Establishment of a Web-based System for Collection of Patient-reported Outcomes After Radical Prostatectomy in a Statewide Quality Improvement Collaborative. AB - OBJECTIVE: To report on the establishment of a unified, electronic patient reported outcome (PRO) infrastructure and pilot results from the first 5 practices enrolled in the web-based collection system developed by the Michigan Urological Surgery Improvement Collaborative. MATERIALS AND METHODS: Eligible patients were those undergoing radical prostatectomy of 5 academic and community practices. PRO was obtained using a validated 21-item web-based questionnaire, regarding urinary function, erection function, and sexual interest and satisfaction. Data were collected preoperatively, at 3 months, and 6 months postoperatively. Patients were provided a link via email to complete the surveys. Perioperative and PRO data were analyzed as reports for individual patients and summary performance reports for individual surgeons. RESULTS: Among 773 eligible patients, 688 (89%) were enrolled preoperatively. Survey completion rate was 88%, 84%, and 90% preoperatively, at 3 months, and 6 months. Electronic completion rates preoperatively, at 3 months, and 6 months were 70%, 70%, and 68%, respectively. Mean urinary function scores were 18.3, 14.3, and 16.6 (good function >= 17), whereas mean erection scores were 18.7, 7.3, and 9.1 (good erection score >= 22) before surgery, at 3 months, and 6 months. Variation was noted for erectile function among the practices. CONCLUSION: Collection of electronic PRO via this unified, web-based format was successful and provided results that reflect expected recovery and identify opportunities for improvement. This will be extended to more practices statewide to improve outcomes after radical prostatectomy. PMID- 28652161 TI - The Surgical Management of Bladder Polyps in the Setting of Exstrophy Epispadias Complex. AB - OBJECTIVE: To investigate the surgical course for treating bladder polyps in patients with exstrophy epispadias complex (EEC). EEC bladder polyps are unique pathologic entities, with a distinct difference between polyps discovered at birth and polyps developed after failed exstrophy closure. METHODS: A prospectively maintained database of 1300 patients with EEC was reviewed for bladder exstrophy patients with bladder polyps. The following data were obtained: patient demographics, polyp type, past medical and surgical history, and continence outcomes. Polyps were categorized as (1) primary, bladder polyps at birth or during neonatal period; and (2) secondary, bladder polyps following a failed exstrophy closure. RESULTS: Of 1300 EEC patients, 43 patients with polyps met the inclusion criteria. All closures for primary polyp patients were successful, and continence outcomes remained similar in early and delayed closures (P = .689). Secondary polyp patients were more likely to require augmentation to increase bladder capacity (P = .033). Bladder neck reconstruction (n = 8) was successful in 83.0% of patients with primary polyps, and none were successful for those with secondary polyps (P = .035). CONCLUSION: Delaying primary bladder closure for patients with small polypoid bladder templates did not affect closure or continence outcomes. However, primary and secondary polyps may require different surgical interventions. Bladder neck reconstruction was markedly less successful in secondary polyp patients, and secondary polyp patients were more likely to need augmentation to increase bladder capacity. This study emphasizes the importance of a successful primary closure and suggests that secondary polyps are an indicator of decreasing potential for bladder growth. PMID- 28652162 TI - Holding Strength of a Hem-o-lok/Lapra-Ty Clip Combination on Sutures Used During Partial Nephrectomy. AB - OBJECTIVE: To investigate the anti-slip strength of closing systems employing sutures terminated with a Hem-o-lok/Lapra-Ty clip combination to determine which sutures perform best for this application. Partial nephrectomy is the reference standard for treatment of small renal masses. The main disadvantage of partial nephrectomy is the risk of technical complications, including renorrhaphy site bleeding and urine leak. MATERIALS AND METHODS: A materials testing system produced a constant velocity pull on the free end of an anchored suture. A Lapra Ty clip was attached 1 cm from the end of each suture as a backstop for the Hem-o lok. A digital force gauge measured the tension that was applied until the suture slipped in the closing system. Vicryl, Monocryl, Chromic, Stratafix, and V-Loc sutures of diameters 1 to 4-0 were tested (n = 7 for each suture type, 161 total experiments). RESULTS: The holding strength of a Lapra-Ty/Hem-o-lok clip combination is lowest for Vicryl 4-0 (4.3 +/- 1.4N) and highest for Monocryl 0 (16.5 +/- 1.6N) sutures. Larger sutures (1 and 0) hold at higher tensions than sutures with smaller dimensions (4-0 and 3-0). For 2-0 sutures, the holding strength was 5.7N with Vicryl, 13.8N with Stratafix, and 15.9N with V-Loc sutures. CONCLUSION: The mean values of holding tension of this anchoring system for all sutures tested was greater than the amount found to be sufficient for tissue closure in previous studies (3.2N). Barbed sutures (Stratafix, V-Loc) appeared to have superior holding strength when compared with most standard sutures; barb orientation does not influence holding tension. PMID- 28652163 TI - Health-related Quality of Life After Radical Cystectomy: A Cross-sectional Study With Matched-pair Analysis on Ileal Conduit vs Ileal Orthotopic Neobladder Diversion. AB - OBJECTIVE: To examine the different and health-related quality of life (HR-QoL) outcomes between ileal conduit (IC) and ileal orthotopic neobladder (IONB) in patients who underwent radical cystectomy (RC), by using validated self-reported cancer-specific instruments. PATIENTS AND METHODS: This retrospective, cross sectional, multicenter cohort study included 148 and 171 patients with either IC or IONB. HR-QoL was evaluated with Quality of Life Core Questionnaire and bladder module (BLM)-30 European Organisation for Research and Treatment of Cancer questionnaires. Baseline HR-QoL scores were dichotomized at the median to give "good" or "poor" score profiles. A matched-pair analysis compared HR-QoL aspects between 79 IC patients and 79 IONB patients. RESULTS: At univariate analysis IONB resulted favorable for physical functioning, emotional functioning, cognitive functioning (CF), fatigue, dyspnea, appetite loss, constipation (CO), and abdominal bloating flatulence (AB). At multivariate analyses, IONB showed better scores for emotional functioning (85 vs 79, P = .023), CF (93 vs 85, P <.001), CO (16 vs 31, P <.001), and AB (12 vs 25, P <.001). A significant worsening of sexual and urinary function was observed for IONB patients in the long-term. At matched-pair analysis, global health status was similar (65 vs 62, P = .385). Significantly better scores were observed in the IONB group for the following items: CF (P = .007), fatigue (P = .003), pain (P = .019), dyspnea (P = .016), CO (P = .001), and AB (P = .00). CONCLUSION: IONB and IC after RC were similar in terms of global health status. IONB provides better results in some aspects of HR QoL related to bowel function, but a worsening of urinary and sexual functions. Further randomized controlled trials are needed to confirm these data. PMID- 28652164 TI - Schistosoma haematobium: A Delayed Cause of Hematuria. AB - A 22-year-old African American man with recurrent episodes of gross hematuria for 6 months presented to the clinic for evaluation. A thorough history revealed that the patient emigrated from Mozambique to the United States 12 years ago. Urine culture was negative for a urinary tract infection. Cystoscopy revealed 4 lesions in the bladder. Biopsy of the bladder lesion revealed severe cystitis and Schistosoma haematobium. The patient later confirmed that he used to swim in rivers and streams back in Africa. He completed a course of praziquantel and his gross hematuria resolved. PMID- 28652165 TI - Same-Session Bilateral Ureteroscopy: Safety and Outcomes. AB - OBJECTIVE: To assess the complications and outcomes associated with same-session bilateral ureteroscopy in a tertiary referral center, as same-session bilateral ureteroscopy for stone disease has been critiqued for the theoretical risk of injury to both ureters with subsequent risk to renal function. METHODS: We retrospectively reviewed all cases of bilateral ureteroscopy performed for urolithiasis by a single surgeon at out institution between 2009 and 2014. These were compared to a prospective unilateral ureteroscopy database. RESULTS: There were 117 same-session bilateral ureteroscopic procedures performed in 113 patients totaling 234 ureteroscopies. A flexible ureteroscope was used in 228 ureters (97.4%), and 6 (2.6%) were semirigid only. Ureteral dilators were required in 8 (6.8%) cases. Pre-stenting was performed in 23 (19.6%) patients. Short-term complications were observed following 19 (16.2%) procedures, including 11 (9.4%) Clavien I, 4 (3.4%) Clavien II, and 4 (3.4%) Clavien III. Of the 84 (71.8%) patients who completed a 6-week follow-up, there were no long-term complications. Stone-free rates were 91.4% for patients imaged with abdominal x ray and ultrasound, and 84.2% for those imaged with computed tomography scans. Neither complications nor re-admissions were significantly different in the unilateral group. Median length of follow-up for the entire cohort was 2.8 years (range 0-7 years). CONCLUSION: Bilateral ureteroscopy can be performed safely with short-term complications, consistent with published literature. We found no long-term complications and high stone-free rates. Bilateral ureteroscopy in a single procedure represents a viable standard of care for patients with bilateral stone disease. PMID- 28652166 TI - Multilingual Self-Management Resources for Prostate Cancer Survivors and Their Partners: Results of a Long-Term Academic-State Health Department Partnership to Promote Survivorship Care. AB - OBJECTIVE: To provide innovative, evidence-based self management information and supportive care for prostate cancer survivors and their partners. We describe how an academic-public partnership facilitated the broad dissemination of evidence based, multilingual survivorship educational materials via a state-managed prostate cancer website. METHODS: We outline the steps of an academic-public partnership leading to dissemination of online, survivorship materials as a resource for prostate cancer survivors and their partners. We examined the 5-year utilization of the materials from January 2011 to December 2015 according to 14 content areas (e.g., urinary, bowel, and sexual problems, fatigue, communication, cancer stress) and across 3 languages (English, Spanish, Arabic). RESULTS: The total number of prostate cancer survivorship materials downloaded from January 2011 to December 2015 was 89,348. The number of downloaded materials increased over time from 6,421 in 2011 to 17,496 in 2015. The most commonly downloaded content area was urine problems (27.5%), followed by bowel problems (23.4%) and sexual side effects (16.2%). The majority of downloaded materials was in English (86.3%), followed by Spanish (9.8%) and Arabic (3.9%). CONCLUSION: The academic public partnership facilitated broad dissemination of evidence-based informational materials for prostate cancer survivors and their partners through a state-managed website from 2011 to 2015. Given the increasing role of academic public partnerships in funding and development of robust, sustainable prostate cancer survivorship resources, this work serves as an introduction to these evidence-based materials and highlights a successful model of engagement between practitioners, research scientists, and public health administration. PMID- 28652167 TI - Effects of Urinary Incontinence Subtypes on Women's Sexual Function and Quality of Life. AB - OBJECTIVE: To evaluate the effects of different subtypes of urinary incontinence (UI) on sexual function and quality of life (QoL). MATERIALS AND METHODS: Ninety three women with UI were enrolled in the observational study. By the urodynamic findings, 32 women (34.5 %) were diagnosed with stress urinary incontinence (SUI), 35 (37.6%) with urgency urinary incontinence (UUI), and 26 (27.9%) with mixed urinary incontinence (MUI). The Short Form-36 questionnaire was used to investigate the QoL, and the Female Sexual Function Index and Female Sexual Distress Scale questionnaires were used to study sexual function and sexual distress, respectively. RESULTS: Low mean total Female Sexual Function Index scores and high mean Female Sexual Distress Scale total scores were obtained for each group. However, women with MUI showed a significantly higher impairment of female sexual function (P <.05) compared with others. Women with MUI and UUI had more orgasmic disorder than those with SUI, and women with MUI and SUI had mainly lower sexual desire than those with UUI. QoL was worse in women of all groups, particularly in those with UUI and MUI. CONCLUSION: UI, whatever its nature, has a significant impact on sexual function; notwithstanding, the subgroups of UI, namely SUI, UUI, and MUI, may have their sexual function affected in different ways. All subtypes of UI can have severe consequences on perception of QoL, but when compared, a significantly high impairment of QoL was observed in the MUI and the UUI groups. PMID- 28652168 TI - Influence of social interaction on nociceptive-induced changes in locomotor activity in a mouse model of acute inflammatory pain: Use of novel thermal assays. AB - Most acute and chronic animal models of pain rely heavily on reflexive assays for evaluating levels of nociception, which involves removing the animal from its normal social environment. Here, we examine and characterize the influence of social interactions on inflammatory pain-evoked changes in movement in two different mouse strains. To produce inflammatory nociception, we injected CFA bilaterally into the hind paws of Balb/c and C3H mice and then recorded exploratory locomotor activity using an automated detector system to first evaluate the effects of social behavior on nociception. Secondly, we determined if carprofen administration altered the effects of social behavior on nociceptive evoked movement. This methodology was expanded to create a novel thermal activity assay to objectively measure the effect of heat and cold on CFA-evoked animal movement in paired animals. Paired Balb/c and C3H mice exhibited significant hyper-locomotion that lasted for 3h post-injection in Balb/c, but only 1h post injection in C3H. Single Balb/c mice only showed increased activity for 1h post injection, while single C3H mice showed no increase. This CFA-induced increase in activity in paired animals was highly inversely correlated with mechanical allodynia as measured using standard Von Frey filaments. Carprofen administration completely blocked this CFA-induced hyperlocomotor activity. Both heat and cold induced a significant increase in locomotor activity in paired mice injected with CFA, while having no effect on activity in control mice injected with saline. The results presented here indicate that social interactions greatly influence inflammatory pain-induced changes in locomotor activity and indicate that the use of movement-based assays to evaluate nociception in paired mice may provide an alternative and more sensitive method to quantify nociception and characterize novel analgesic effects over time in the context of social interactions in rodent models of pain. PMID- 28652170 TI - Role of the androgen receptor in urothelial cancer. AB - Men have had a substantially higher risk of developing bladder cancer than women. This has prompted research on androgen-mediated androgen receptor (AR) signaling in urothelial cancer. Indeed, increasing preclinical evidence indicates that AR activation correlates with the promotion of urothelial carcinogenesis and tumor outgrowth. In this article, we summarize and discuss available data suggesting the involvement of androgens and the AR pathway in the development and progression of urothelial cancer. Although precise mechanisms for the functions of AR and related signals in urothelial cells remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches for urothelial cancer. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to urothelial cancer patients is thus anticipated. PMID- 28652169 TI - Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia. AB - Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers gammaH2AX and pChk2 T68, and induction of p53 and p19ARF. After 5 months, about half of thyroid lesions escaped OIS and formed tumors that remained dependent on RET/PTC3 expression. This progression was accompanied by activation of AKT-FOXO1/3a pathway and increased serum TSH levels. PMID- 28652172 TI - Enhancement and inhibition effects on the corneal permeability of timolol maleate: Polymers, cyclodextrins and chelating agents. AB - This study investigates how both bioadhesive polymers (chitosan, hyaluronic acid and alginate) and permeability enhancers (ethylene glycol- bis(2-aminoethylether) N, N, N', N'- tetraacetic acid (EGTA) and hydroxypropyl-beta-cyclodextrin) influence the permeability of the anti-glaucoma drug timolol maleate through ex vivo bovine corneas. Our results showed that only the permeability enhancers alone were able to increase drug permeability, whereas the polymers significantly reduced drug permeation, and however, they increased the pre-corneal residence of timolol. Ternary systems (polymer-enhancer-drug) showed a reduced drug permeability compared to the polymers alone. Fluorescence microscopy analysis of the epithelium surface confirmed there was no evidence of epithelial disruption caused by these formulations, suggesting that polymer-enhancer interactions reduce drug solubilization and counteract the disruptive effect of the permeability enhancers on the surface of the cornea. Further mucoadhesive tests, revealed a stable interaction of chitosan and hyaluronic acid with the epithelium, while alginate showed poor mucoadhesive properties. The differences in mucoadhesion correlated with the permeability of timolol maleate observed, i.e. formulations containing mucoadhesive polymers showed lower drug permeabilities. The results of the present study indicate polymers acting as an additional barrier towards drug permeability which is even more evident in the presence of permeability enhancers like EGTA and hydroxypropyl-beta-cyclodextrin. Then, this study highlights the need to adequately select additives intended for ocular applications since interactions between them can have opposite results to what expected in terms of drug permeability. PMID- 28652171 TI - Common and diverse elements of ion channels and receptors underlying electrical activity in endocrine pituitary cells. AB - The pituitary gland contains six types of endocrine cells defined by hormones they secrete: corticotrophs, melanotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. All these cell types are electrically excitable, and voltage-gated calcium influx is the major trigger for their hormone secretion. Along with hormone intracellular content, G-protein-coupled receptor and ion channel expression can also be considered as defining cell type identity. While many aspects of the developmental and activity dependent regulation of hormone and G-protein-coupled receptor expression have been elucidated, much less is known about the regulation of the ion channels needed for excitation-secretion coupling in these cells. We compare the spontaneous and receptor-controlled patterns of electrical signaling among endocrine pituitary cell types, including insights gained from mathematical modeling. We argue that a common set of ionic currents unites these cells, while differential expression of another subset of ionic currents could underlie cell type-specific patterns. We demonstrate these ideas using a generic mathematical model, showing that it reproduces many observed features of pituitary electrical signaling. Mapping these observations to the developmental lineage suggests possible modes of regulation that may give rise to mature pituitary cell types. PMID- 28652173 TI - Development of long-acting ciliary neurotrophic factor by site-specific conjugation with different-sized polyethylene glycols and transferrin. AB - To overcome the deficiency of rapid elimination from blood, the truncated human recombinant ciliary neurotrophic factor was formulated by site-specific attachment of different-sized PEG-maleimide or by cross-linking with human transferrin through a hetero-bi-functional PEG linker (NHS-PEG5k-MAL). The PEGylated CNTF was purified by a two-step chromatography procedure and the transferrin coupling CNTF conjugate was separated through an elegant protocol. The conjugation site on CNTF was identified by peptide mapping analysis and validated that the linkage of the conjugates was specifically happened to Cys17 residue. Although both PEGylated and transferrin coupling CNTF demonstrated decreased cell based residual activity, markedly enhanced pharmacokinetic behaviors in normal male Sprague-Dawley rats were observed, especially for the PEG40k-CNTF with approximately 58-times improvement compared with the unmodified counterpart. The evaluation of the in vivo potency of body weight-losing was performed with normal male C57BL6 mice and the results revealed that both PEGylation and transferrin coupling could achieve improved therapeutic benefits relative to that of CNTF. Besides, PEG20k/40k-CNTF demonstrated more effective than transferrin coupling CNTF (Tf-PEG5k-CNTF) despite that the later showed preferable pharmacokinetic profile and cell based residual activity compared with PEG20k-CNTF. Weekly subcutaneous administration of PEG40k-CNTF with 0.5mg/kg and 1.0mg/kg dose resulted in approximately 35% and 50% decrease in food intake during one interval period of injection, indicating that PEG40k-CNTF is the most potential anti-obese agent for therapeutics. PMID- 28652174 TI - Trigeminal neuralgia (TN): A descriptive literature analysis on the diagnosis and management modalities. AB - OBJECTIVE: The primary objective of this review is to explore the different aspects of the diagnosis and management of Trigeminal neuralgia (TN). We look at the role of radiological imaging in the work-up of this condition, and based on the findings in the literature, we report data on the medical and surgical management of TN. MATERIALS AND METHODS: A literature review was conducted using PubMed and Cochrane search engines in order to explore the data available on the diagnosis and management of TN. Clinical features and various treatment modalities were analyzed by the authors. The identified studies were evaluated and data was reported on the different aspects of the condition in order to provide an evidence-based update on the topic. DISCUSSION: The diagnosis of TN is based on the patient's clinical history and radiological imaging. The commonest cause of TN is a micro-vascular compression by a looping blood vessel. Radiological evaluation is critical in the work-up of the disorder and in order to eliminate other possible causes. Management of the disorder can be medical or surgical, with micro-vascular decompression having the highest remission rate. CONCLUSION: Patients with TN present paroxysmal pain attacks in the territories innervated by the trigeminal nerve. Diagnostic investigations must allow precise anatomical evaluation of the CPA, and MR imaging is the gold-standard radiological investigation for this purpose. Management of TN can be medical or surgical, with micro-vascular decompression having the highest success rate. PMID- 28652175 TI - Is the piezoelectric device the new standard for facial osteotomies? AB - Piezoelectric devices are commonly used in all areas of maxillofacial surgery. Initially applied in preprosthetic surgery, they have steadily become a common practice in major surgery of the facial skeleton, including maxillary and mandibular osteotomies, temporomandibular joint surgery, orbital surgery, craniofacial procedures and rhinoplasty. We will review the current medical literature and establish the "state of the art" of piezosurgery in orthognathic surgery, TMJ surgery and rhinoplasty. PMID- 28652176 TI - Balloon enteroscopy versus spiral enteroscopy for small-bowel disorders: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Two novel enteroscopic procedures, balloon enteroscopy and spiral enteroscopy, have revolutionized the diagnostic and therapeutic approach to small-bowel disorders. These disorders that historically required surgical interventions are now investigated and managed nonsurgically. Only a few weakly powered studies have compared the outcomes of spiral enteroscopy and balloon enteroscopy. We conducted a systematic review and meta-analysis to compare the efficacy and safety of these 2 procedures. METHODS: PubMed, Cochrane Library, Scopus, and clinicaltrials.gov databases were searched for all studies published up to January 12, 2017 comparing the efficacy and safety of balloon enteroscopy (single or double) and spiral enteroscopy. Primary outcomes of interest were diagnostic and therapeutic success rates. Other outcomes included procedure length, depth of maximal insertion (DMI), rate of complete enteroscopy, and adverse events. We calculated Odds ratios (ORs) for categorical variables and mean difference (MD) for continuous variables. The Mantel-Haenszel method was used to analyze the data. Fixed and random effect models were used for <50% heterogeneity and >50% heterogeneity, respectively. RESULTS: Eight studies met the inclusion criteria for this meta-analysis. A total of 615 procedures were analyzed, which included 394 balloon enteroscopy and 221 spiral enteroscopy procedures. There were no significant differences in diagnostic and therapeutic success rates (OR, 1.27; 95% confidence interval [CI], .86-1.88; P = .22; and OR, 1.23; 95% CI, .82-1.84; P = .32, respectively) between the 2 procedures. Similarly, DMI was not significantly different between the 2 groups (MD, 26.29; 95% CI, 20.92-73.49; P = .28). However, the procedure time was significantly shorter for the spiral enteroscopy group compared with the balloon enteroscopy group (MD, 11.26; 95% CI, 2.72-19.79; P = .010). A subgroup analysis comparing double balloon enteroscopy with spiral enteroscopy yielded similar results. CONCLUSIONS: Both procedures achieved similar diagnostic and therapeutic outcomes and with similar depth of insertion. Spiral enteroscopy has the benefit of shorter procedural time. PMID- 28652177 TI - Inhibition of IL-6 and IL-8 production in LPS-stimulated human gingival fibroblasts by glycyrrhizin via activating LXRalpha. AB - The aim of this study was to clarify the anti-inflammatory effects and its molecular mechanism of glycyrrhizin on LPS-stimulated human gingival fibroblasts (HGFs), which will be of benefit for periodontitis treatment. An MTT assay was performed to assess the effects of glycyrrhizin on cellular viability. The levels of IL-6 and IL-8 were measured by ELISA. The expression of iNOS, COX-2, NF kappaB, and LXRalpha were detected by western blot analysis. The results showed that glycyrrhizin significantly inhibited LPS-induced IL-6 and IL-8 production, as well as COX-2 and iNOS expression. LPS-induced NF-kappaB activation in HGFs was also inhibited by treatment of glycyrrhizin. Furthermore, glycyrrhizin increased the expression of LXRalpha in a concentration-dependent manner. In addition, the inhibition of glycyrrhizin on IL-6 and IL-8 production was reversed by LXRalpha inhibitor GGPP. In conclusion, these results indicated that glycyrrhizin exhibited its anti-inflammatory effects in HGFs by activating LXRalpha. PMID- 28652178 TI - In-vitro assessment of antimicrobial properties and lymphocytotoxicity assay of benzoisochromanequinones polyketide from Streptomyces sp JRG-04. AB - The chromanequinone (BIQ) compound produced by the mangrove estuary derived strain, Streptomyces sp. JRG-04 was effective even at low MIC level concentration against Methicillin resistant S. aureus and other clinical pathogens. In this study, we have investigated the antimicrobial potential of chromanequinone compound by using various microscopy and imaging techniques. The flow cytometry (FACS) analysis suggested the BIQ aromatic polyketide compound produced by the Streptomyces sp. JRG-04 has toxic effect on MRSA cell membrane by increased up take of propidium iodide dye. The bacterial imaging analysis by high content screening experiment (HCS) revealed the increased number of dead MRSA cells than the live MRSA populations with chromanequinone treatment. Furthermore, atomic force microscopic study proved the MRSA cell surface ultra-structure changes when the cells exposed to chromanequinone compound at 3 h and 6 h. Further, in-vitro lymphocytotoxicity effect of chromanequinone compound at different concentrations with the combination of complement was performed on human lymphocytes by cell lysis assay. Interestingly, we have found that the higher concentration of BIQ chromanequinone (10 mg/mL) compound without complement induced apoptosis of human lymphocytes. The present investigation reveals that the toxic potential of chromanequinone on human lymphocytes might be associated with the complement dependent. This study strongly suggests that the chromanequinone compound produced by the Streptomyces strain with bioactive property can be developed as a therapeutic leads for various pharmaceutical applications. PMID- 28652179 TI - Non-coding RNA regulation of T cell biology: Implications for age-associated cardiovascular diseases. AB - Prevalence of age-associated cardiovascular diseases (CVD) has dramatically increased as a result of improvements in life expectancy. Chronic inflammation is a shared pathophysiological feature of age-associated CVDs, indicating a role for the immune system in the onset and development of CVDs. Indeed, ageing elicits profound changes in both the cardiovascular and immune system, especially in the T cell compartment. Although such changes have been well described at the cellular level, the molecular mechanisms underlying immune-mediated cardiovascular ageing remain largely unexplored. Non-coding RNAs (ncRNAs) comprise a heterogeneous family of RNA transcripts that regulate gene expression at the epigenetic, transcriptional, post-transcriptional, and post-translational levels. Non-coding RNAs have recently emerged as master modulators of T cell immunity. In this review, the state-of-the-art knowledge on ncRNA regulatory effects over T cell differentiation, function, and ageing in the context of age associated CVDs, such as atherosclerosis, acute coronary syndromes, and heart failure, is discussed. PMID- 28652180 TI - Serum levels of Dickkopf-1 are a potential negative biomarker of survival in geriatric patients. AB - Fragility fractures due to osteoporosis and its most dreaded complication - hip fractures - are the cause of disability, high mortality and place a considerable burden on global health economics. Although much work has been done to accurately predict mortality and find risk factors for poor health outcome, little attention was given to the Wnt-catenin signaling pathway and its role in the posttraumatic course of disease. We studied 238 geriatric patients (175 women (mean age 84yrs) and 63 men (mean age 82yrs)) in total that were admitted to a department of Acute Geriatric Care. 150 out of these patients had suffered a hip fracture and 88 not. After discharge patients were followed up with an average follow-up time of 4.06+/-1.07yrs. The follow-up mortality rate was 15.7%. In an age- and sex adjusted model, low serum levels of Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt signaling pathway, were significantly associated with mortality. The strong association of Dkk-1 levels and mortality has clinical relevance as it suggests Dkk-1 to be a therapeutic target to improve survival after hip fractures. PMID- 28652181 TI - gga-miR-99a targets SMARCA5 to regulate Mycoplasma gallisepticum (HS strain) infection by depressing cell proliferation in chicken. AB - Mycoplasma gallisepticum (MG), one of the primary etiological agents of poultry chronic respiratory disease, has caused significant economic losses worldwide, and increasing evidence has recently indicated that miRNAs are involved in its microbial pathogenesis. gga-miR-99a, a member of the miR-99 family, plays an essential role in a variety of diseases. Through miRNA Solexa sequencing, we previously found that gga-miR-99a is significantly down-regulated in the lungs of MG-infected chicken embryos. In this study, we further verified that the expression of gga-miR-99 was significantly down-regulated in both MG-infected lungs and a chicken embryonic fibroblast cell line (DF-1) by qPCR. Moreover, we predicted and validated SMARCA5 as its target gene through a luciferase reporter assay, qPCR, and western blot analysis. The over-expression of gga-miR-99a significantly depressed SMARCA5 expression, whereas a gga-miR-99a inhibitor enhanced the expression of SMARCA5. Inversely, SMARCA5 was significantly up regulated and gga-miR-99a was obviously down-regulated in MG-HS-infected chicken embryonic lungs and DF-1 cells. At 72h post-transfection, the over-expression of gga-miR-99a significantly repressed the proliferation of DF-1 cells by inhibiting the transition from the G1 phase to the S and G2 phases. This study reveals that gga-miR-99a plays a key role in MG infection through the regulation of SMARCA5 expression and provides new insights regarding the mechanisms of MG pathogenesis. PMID- 28652182 TI - Ulinastatin attenuates neuropathic pain via the ATP/P2Y2 receptor pathway in rat models. AB - Ulinastatin, a serine protease inhibitor, which has anti-inflammatory properties and neuroprotective effects, is used to treat acute inflammatory disorders. Recent evidence indicates that administration of ulinastatin alleviates pain in rat model of neuropathic pain (NPP). However, its effect on NPP and the underlying mechanism requires further study. In this study, we evaluated the role of intrathecal administration of ulinastatin in rats with sciatic nerve ligation and observed the effect of ulinastatin on the ATP/P2Y2 receptor pathway. We performed mechanical and thermal sensitivity measurements, immunohistochemistry and double-label immunofluoresence studies to evaluate P2Y2 receptor and adenosine 5'-monophosphate-activated protein kinase (AMPK) expression in the dorsal horn of the lumbar enlargement region of the spinal cord, and a luciferase assay for the detection of ATP levels in the cerebrospinal fluid. The results showed that ulinastatin prevented the development of mechanical allodynia and thermal hypersensitivity in the rat sciatic nerve ligation model. Ulinastatin reduced the level of extracellular ATP, down-regulated P2Y2 receptor and AMPK expression in the spinal dorsal horn of the chronic constrictive injury model. We found that increased expression of P2Y2 receptor in microglia was likely involved in the activation of microglia after nerve injury, and ulinastatin inhibited the abnormal microglia activation in the dorsal horn after nerve injury. These findings demonstrated that ulinastatin might be a potential and effective drug for the treatment of NPP via the suppression of the ATP/P2Y2 receptor pathway. PMID- 28652183 TI - Genome-wide identification and characterization of the SPL gene family in Ziziphus jujuba. AB - SQUAMOSA Promoter-Binding Protein-Likes (SPLs) are plant specific transcription factors playing important roles in plant growth and development. The SPL gene family has been studied in various plant species; however, there is no report about SPLs in Zizyphus jujuba. In this study, we identified 18 putative ZjSPL genes in Z. jujuba using a genome-wide analysis. Sequence features, gene structures, conserved domains and motifs were analyzed. The phylogenetic relationships of SPLs in Z. jujuba and A. thaliana were revealed. A total of 5 pairs of ZjSPLs were identified, suggesting the importance of gene duplication in SPL gene expansion in Z. jujuba. In addition, 11 of the 18 ZjSPLs, belonging to G1, G2 and G5 subgroups, were found to be targets of miR156, suggesting the conservation of miR156-mediated posttranscriptional regulation in plants. Expression analysis revealed that eight ZjSPL genes were responsive to the infection of witches'-broom phytoplasma. Our results provide a basis for the further elucidation of the biological function of ZjSPLs and their regulation in witches'-broom disease. PMID- 28652184 TI - Mini-DNA barcode in identification of the ornamental fish: A case study from Northeast India. AB - The ornamental fishes were exported under the trade names or generic names, thus creating problems in species identification. In this regard, DNA barcoding could effectively elucidate the actual species status. However, the problem arises if the specimen is having taxonomic disputes, falsified by trade/generic names, etc., On the other hand, barcoding the archival museum specimens would be of greater benefit to address such issues as it would create firm, error-free reference database for rapid identification of any species. This can be achieved only by generating short sequences as DNA from chemically preserved are mostly degraded. Here we aimed to identify a short stretch of informative sites within the full-length barcode segment, capable of delineating diverse group of ornamental fish species, commonly traded from NE India. We analyzed 287 full length barcode sequences from the major fish orders and compared the interspecific K2P distance with nucleotide substitutions patterns and found a strong correlation of interspecies distance with transversions (0.95, p<0.001). We, therefore, proposed a short stretch of 171bp (transversion rich) segment as mini-barcode. The proposed segment was compared with the full-length barcodes and found to delineate the species effectively. Successful PCR amplification and sequencing of the 171bp segment using designed primers for different orders validated it as mini-barcodes for ornamental fishes. Thus, our findings would be helpful in strengthening the global database with the sequence of archived fish species as well as an effective identification tool of the traded ornamental fish species, as a less time consuming, cost effective field-based application. PMID- 28652185 TI - Genetic variation in bitter taste receptor gene TAS2R38, PROP taster status and their association with body mass index and food preferences in Indian population. AB - Polymorphisms in bitter taste receptor gene TAS2R38 alter the ability to sense the intensity of bitterness of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). Genetic variation in sensitivity towards PTC and PROP may affect food preferences and susceptibility to certain diseases. This is the first study aimed at investigating frequency and distribution of TAS2R38 haplotypes in an Indian cohort. Additionally, we studied the association of TAS2R38 and PROP taster status with BMI and food preference. Three hundred and ninety three healthy adults who were 19-55years of age were selected as a convenience sample from 4 geographical regions of India. Single nucleotide polymorphisms (SNPs) of TAS2R38 (rs713598, s1726866 and rs10246939) were analyzed using polymerase chain reaction restriction fragment length polymorphism. The prevalence of PAV/PAV diplotype was 9.9% and that of AVI/AVI diplotype was 43.76% among this Indian population. PROP status was determined on the basis of its threshold concentration of detecting bitterness, as evaluated by one-solution test. The PROP status revealed 25.95% supertasters, 32.06% medium tasters and 41.98% non-tasters (NT). BMI neither significantly (p>0.05) correlated with TAS2R38 genotypes nor with PROP taster status. Food preferences did not significantly (p>0.05) correlate with TAS2R38 diplotypes or PROP phenotypes. PMID- 28652186 TI - IL-6 and IL-18 cytokine gene variants of pulmonary tuberculosis patients with co morbid diabetes mellitus and their household contacts in Hyderabad. AB - PURPOSE: Association of cytokine genes reflects their susceptibility towards infection and disease in household contacts (HHC) of pulmonary tuberculosis (PTB) patients. Hyperglycemia, a common factor in diabetics might influence their risk towards mycobacterium tuberculosis infection and disease development. This study determines the association of IL-6 and IL-18 cytokine gene variants of TB patients with diabetes mellitus (TBDM) and their HHC in Hyderabad. METHODS: Single nucleotide polymorphisms of IL-6 (-174 G>C and -572 G>C) and IL-18 (-137 G>C and -607 C>A) cytokine genes were genotyped by Amplification Refractory Mutation System and Restriction Fragment Length polymerase chain reaction in total of 705 subjects comprising of TBDM, their HHC, PTB, DM and Healthy controls (HC). RESULTS: At IL-6 -174G>C variant, GG genotype, G allele in TBDM and TBDM HHC, at -572G>C variant, C allele in TBDM and GG haplotype in TBDM HHC were showing positive association, however DM have not shown any association at IL-6 polymorphic sites. With respect to the IL-18 gene polymorphisms, at -137 G>C variant, GG genotype was positively associated in PTB while at -607 C>A variant positive association was shown with AC genotype in TBDM, their HHC and DM; GACC diplotype in TBDM and GCGC in PTB. CONCLUSION: Our findings suggest that susceptible combination of IL-6 and IL-18 cytokine genes associated with disease in the HHCs highlight their risk of inclination towards the disease. PMID- 28652187 TI - Hyperglycemia induced the Alzheimer's proteins and promoted loss of synaptic proteins in advanced-age female Goto-Kakizaki (GK) rats. AB - Although both type 2 diabetes mellitus (T2DM) and aging are related with Alzheimer's disease (AD), the effects of aging on the Alzheimer's proteins and the synaptic markers in T2DM have not been investigated. This study, we hypothesized that T2DM rats with advanced-age, aggravates the reduction of synaptic proteins and an increase in the Alzheimer's protein markers. Goto Kakizaki rats (GK) were used as a T2DM group and wild-type rats (WT) were used as a control group. Rats in each group were categorized by age into young-adult (7 months) and advanced-age rats (12.5 months). Blood was collected in all rats to determine plasma glucose and insulin levels. The brains were used for determining the level of Alzheimer's and synaptic proteins. Our data demonstrated that GK rats had a decreased body weight and increased blood glucose levels, compared to their age-matched WT. p-Tau was increased in both advanced-age WT and GK, compared to their young-adult rats. Moreover, amyloid-beta (Abeta) level was higher in advanced-age GK than their age-matched WT. The synaptic proteins were decreased in advanced-age GK, compared to young-adult GK rats. However, no difference in the level of Alzheimer's proteins and synaptic proteins in the brains of young-adult GK compared to age-matched WT was found. Our data suggested that aging contributes to the pathogenesis of AD and the reduction of synaptic proteins to greater extent in a diabetic than in a healthy condition. PMID- 28652188 TI - Streptozocin-induced type-1 diabetes mellitus results in decreased density of CGRP sensory and TH sympathetic nerve fibers that are positively correlated with bone loss at the mouse femoral neck. AB - Type-1 diabetes mellitus (T1DM) results in loss of innervation in some tissues including epidermis and retina; however, the effect on bone innervation is unknown. Likewise, T1DM results in pathological bone loss and increased risk of fracture. Thus, we quantified the density of calcitonin gene-related peptide (CGRP+) sensory and tyrosine hydroxylase (TH+) sympathetic nerve fibers and determined the association between the innervation density and microarchitecture of trabecular bone at the mouse femoral neck. Ten weeks-old female mice received 5 daily administrations of streptozocin (i.p. 50mg/kg) or citrate (control group). Twenty weeks later, femurs were analyzed by microCT and processed for immunohistochemistry. Confocal microscopy analysis revealed that mice with T1DM had a significant loss of both CGRP+ and TH+ nerve fibers in the bone marrow at the femoral neck. Likewise, microCT analysis revealed a significant decrease in the trabecular bone mineral density (tBMD), bone volume/total volume ratio (BV/TB), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) in mice with T1DM as compared to control mice. Analysis of correlation revealed a positive and significant association between density of CGRP+ or TH+ nerve fibers with tBMD, BV/TV, Tb.Th and Tb.Sp, but not with trabecular number (there was a positive association only for CGRP+) and degree of anisotropy (DA). This study suggests an interaction between sensory and sympathetic nervous system and T1DM-induced bone loss. Identification of the factors involved in the loss of CGRP+ sensory and TH+ sympathetic fibers and how they regulate bone loss may result in new avenues to treat T1DM-related osteoporosis. PMID- 28652189 TI - Identifying familial hypercholesterolemia in Colombia. PMID- 28652190 TI - Relationship between simple markers of insulin resistance and coronary artery calcification. AB - BACKGROUND: Insulin resistance in apparently healthy persons is associated with a cluster of metabolic abnormalities that promote coronary atherosclerosis. Identifying these individuals before manifest disease would provide useful clinical information. OBJECTIVE: We hypothesized that combining 2 simple markers of insulin resistance, prediabetes (PreDM) and triglyceride (TG) concentration >=150 mg/dL, would identify apparently healthy persons with adverse cardiometabolic risk profiles and increased coronary artery calcium (CAC) compared with those with neither or only 1 abnormality. METHODS: A cross sectional analysis was performed using data from 25,886 apparently healthy individuals (18,453 men and 7433 women) evaluated at the Cooper Clinic from 1998 to 2015. Participants were divided into those with a normal fasting glucose concentrations (<100 mg/dL = normal fasting glucose) or PreDM (fasting plasma glucose >=100 and <126 mg/dL) and further subdivided into those with a plasma TG concentration <150 or >=150 mg/dL. These 4 groups were compared on the basis of multiple coronary artery disease risk factors and the presence of CAC determined during their evaluation. RESULTS: Participants with PreDM and a TG concentration >=150 mg/dL had a significantly more adverse coronary artery disease risk profile than individuals with either abnormality or only 1 abnormality (PreDM or TG concentration >=150 mg/dL). Furthermore, the odds of detectable CAC were higher in participants with PreDM and a TG >= 150 mg/dL than in participants with neither or only 1 abnormality. CONCLUSION: The presence of 2 markers of insulin resistance, PreDM and TG concentration >=150 mg/dL, is associated with increased cardiometabolic risk and detectable CAC within a population of apparently healthy individuals. PMID- 28652191 TI - Geometric patterns of left ventricular hypertrophy: Is geometry alone to be blamed? PMID- 28652192 TI - Women in cardiology practice in a "man's world". PMID- 28652193 TI - Triglyceride metabolism in exercising muscle. AB - Triglycerides are stored within lipid droplets in skeletal muscle and can be hydrolyzed to produce fatty acids for energy production through beta-oxidation and oxidative phosphorylation. While there was some controversy regarding the quantitative importance of intramyocellular triglyceride (IMTG) as a metabolic substrate, recent advances in proton magnetic resonance spectroscopy and confocal microscopy support earlier tracer and biopsy studies demonstrating a substantial contribution of IMTG to energy production, particularly during moderate-intensity endurance exercise. This review provides an update on the understanding of IMTG utilization during exercise, with a focus on describing the key regulatory proteins that control IMTG breakdown and how these proteins respond to acute exercise and in the adaptation to exercise training. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28652194 TI - Adipose tissue conditioned media support macrophage lipid-droplet biogenesis by interfering with autophagic flux. AB - Obesity promotes the biogenesis of adipose tissue (AT) foam cells (FC), which contribute to AT insulin resistance. Autophagy, an evolutionarily-conserved house keeping process, was implicated in cellular lipid handling by either feeding and/or degrading lipid-droplets (LDs). We hypothesized that beyond phagocytosis of dead adipocytes, AT-FC biogenesis is supported by the AT microenvironment by regulating autophagy. Non-polarized ("M0") RAW264.7 macrophages exposed to AT conditioned media (AT-CM) exhibited a markedly enhanced LDs biogenesis rate compared to control cells (8.3 Vs 0.3 LDs/cells/h, p<0.005). Autophagic flux was decreased by AT-CM, and fluorescently following autophagosomes over time revealed ~20% decline in new autophagic vesicles' formation rate, and 60-70% decrease in autophagosomal growth rate, without marked alternations in the acidic lysosomal compartment. Suppressing autophagy by either targeting autophagosome formation (pharmacologically, with 3-methyladenine or genetically, with Atg12+/-Atg7 siRNA), decreased the rate of LD formation induced by oleic acid. Conversely, interfering with late autophago-lysosomal function, either pharmacologically with bafilomycin-A1, chloroquine or leupeptin, enhanced LD formation in macrophages without affecting LD degradation rate. Similarly enhanced LD biogenesis rate was induced by siRNA targeting Lamp-1 or the V-ATPase. Collectively, we propose that secreted products from AT interrupt late autophagosome maturation in macrophages, supporting enhanced LDs biogenesis and AT-FC formation, thereby contributing to AT dysfunction in obesity. PMID- 28652195 TI - Predicting drug-induced liver injury: The importance of data curation. AB - Drug-induced liver injury (DILI) is a major issue for both patients and pharmaceutical industry due to insufficient means of prevention/prediction. In the current work we present a 2-class classification model for DILI, generated with Random Forest and 2D molecular descriptors on a dataset of 966 compounds. In addition, predicted transporter inhibition profiles were also included into the models. The initially compiled dataset of 1773 compounds was reduced via a 2-step approach to 966 compounds, resulting in a significant increase (p-value<0.05) in model performance. The models have been validated via 10-fold cross-validation and against three external test sets of 921, 341 and 96 compounds, respectively. The final model showed an accuracy of 64% (AUC 68%) for 10-fold cross-validation (average of 50 iterations) and comparable values for two test sets (AUC 59%, 71% and 66%, respectively). In the study we also examined whether the predictions of our in-house transporter inhibition models for BSEP, BCRP, P-glycoprotein, and OATP1B1 and 1B3 contributed in improvement of the DILI mode. Finally, the model was implemented with open-source 2D RDKit descriptors in order to be provided to the community as a Python script. PMID- 28652196 TI - Efficacy of Escherichia coli-derived recombinant human bone morphogenetic protein 2 in posterolateral lumbar fusion: an open, active-controlled, randomized, multicenter trial. AB - BACKGROUND CONTEXT: The efficacy and safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute in spinal fusion has been widely researched. However, no study of the efficacy and safety of Escherichia coli-derived rhBMP-2 (E.BMP-2) with a hydroxyapatite (HA) carrier has been proposed. PURPOSE: This study aimed to compare the efficacy and safety of fusion materials between E.BMP-2 and autogenous iliac bone graft in posterolateral fusion (PLF). STUDY DESIGN/SETTING: An open, active-controlled, randomized, multicenter trial was carried out. PATIENT SAMPLE: This study included 93 patients who underwent single-level lumbar or lumbosacral PLF. OUTCOME MEASURES: The primary outcome measure was computed tomography (CT)-based fusion rate at 12 and 24 weeks. Secondary outcome measures were fusion grade by radiographs and CT at 12 and 24 weeks and changes in Oswestry Disability Index (ODI), Short Form-36 (SF-36) Health Survey, and visual analogue scale (VAS). METHODS: Patients who underwent 1-level PLF (between L1 and S1) for severe spinal stenosis or grade 1 spondylolisthesis were randomized to receive E.BMP-2 with an HA carrier (E.BMP-2 group) or autogenous iliac bone graft (AIBG group). Thin section CT (<2 mm), VAS, ODI, and SF-36 were obtained pre- and postoperatively at 12 and 24 weeks. Outcome measures were compared between the groups. RESULTS: A total of 100 patients were enrolled in this trial. Among them, 93 patients underwent planned surgery. Preoperative demographic and clinical data showed no difference between groups. CT-based fusion rates were 100.0% (41/41) for the E.BMP-2 group and 90.2% (46/51) for the AIBG group (p=.062) at 12 weeks and 100.0% (41/41) and 94.1% (48/51) (p=.251) at 24 weeks, respectively. Fusion grade based on radiographs and CT showed non-inferiority of the E.BMP-2 group compared with the AIBG group. All clinical parameters improved postoperatively. However, there was no difference in changes in VAS, ODI, or SF-36 between the groups. No serious adverse event related to E.BMP-2 was found. CONCLUSIONS: The fusion rate of E.BMP-2 was comparable with that of AIBG following PLF. Good clinical efficacy and safety of E.BMP-2 in spinal fusion were also revealed. It was also suggested that HA shows suitability as a carrier for E.BMP-2. Thus, E.BMP-2 with an HA carrier can be an alternative bone graft material in spinal fusion. PMID- 28652197 TI - Emergence of drug resistant bacteria at the Hajj: A systematic review. AB - BACKGROUND: Hajj is the annual mass gathering of Muslims, and is a reservoir and potential source of bacterial transmission. The emergence of bacterial transmission, including multi-drug resistance (MDR) bacteria, during Hajj has not been systematically assessed. METHODS: Articles in Pubmed, Scopus, and Google scholar were identified using controlled words relating to antibiotic resistance (AR) at the Hajj from January 2002 to January 2017. Eligible studies were identified by two researchers. AR patterns of bacteria were obtained for each study. RESULTS: We included 31 publications involving pilgrims, Hajj workers or local patients attending hospitals in Mecca, Mina, and the Medina area. Most of these publications provided antibiotic susceptibility results. Ten of them used the PCR approach to identify AR genes. MRSA carriage was reported in pilgrims and food handlers at a rate of 20%. Low rates of vancomycin-resistant gram-positive bacteria were reported in pilgrims and patients. The prevalence of third generation cephalosporin-resistant bacteria was common in the Hajj region. Across all studies, carbapenem-resistant bacteria were detected in fewer than 10% of E.coli isolates tested but up to 100% in K. pneumoniae and A. baumannii. Colistin resistant Salmonella enterica, including mcr-1 colistin-resistant E.coli and K.pneumoniae were only detected in the pilgrim cohorts. CONCLUSION: This study provides an overview of the prevalence of MDR bacteria at the Hajj. Pilgrims are at high risk of AR bacterial transmission and may carry and transfer these bacteria when returning to their home countries. Thus, pilgrims should be instructed by health care practitioners about hygiene practices aiming at reducing traveler's diarrhea and limited use of antibiotics during travel in order to reduce the risk of MDR bacterial transmission. PMID- 28652198 TI - Morphological and molecular characterisation of three Indian Neascus-type metacercariae (Digenea: Diplostomidae). AB - Diplostomid digeneans are important parasites whose larval stages infect freshwater snails and fish as first and second intermediate hosts respectively. Diplostomid digeneans as adults are parasitic in many fish-eating birds and mammals. Our understanding of the species diversity of diplostomid digeneans remains incomplete, especially in the Indian sub-continent. Here, we describe three Neascus-type metacercariae (N. hanumanthai, N. gussevi, and N. xenentodoni) from freshwater fish specimens of Channa punctata (Bloch 1793), Trichogaster fasciata (Bloch and Schneider 1801) and Xenentodon cancila (Hamilton, 1822) respectively, collected in India. Next, we characterised these metacecariae using nuclear (28S and ITS1) and mitochondrial DNA (cox1) to determine their systematic and phylogenetic position. Molecular identification using interspecific variation for all three molecular markers revealed a closer relationship between N. hanumanthai and N. gussevi (1.9%-2.4%) than either of N. hanumanthai and N. gussevi to N. xenentodoni (3.1%-3.7% and 4.4%-4.0% respectively). In phylogenetic analyses, estimated by neighbour-joining (NJ) and maximum likelihood (ML) methods, N. gussevi and N. hanumanthai nested as sister groups of Posthodiplostomum Dubois, 1936 for all three markers used; N. xenentodoni, however, nested as a sister taxa of all other diplostomes when using 28S and ITS1 and nested as a sister taxa of Bolbophorus, Alaria and Neodiplostomum using cox1. These findings suggest that N. hanumanthai and N. gussevi are members of Posthodiplostomum, but that N. xenentodoni belongs to a separate and unknown genus. Similarly, by proteomics, we found that the cox1 protein sequences and structures were similar between N. hanumanthai and N. gussevi but distinct for N. xenentodoni. PMID- 28652199 TI - Good night, sleep tight: The effects of sleep deprivation on spatial associative learning in zebrafish. AB - Learning and memory are vital to an animal's survival, and numerous factors can disrupt cognitive performance. Sleep is an evolutionarily conserved physiological process known to be important for the consolidation of learning and memory. The zebrafish has emerged as a powerful model organism sharing organizational and functional characteristics with other vertebrates, providing great translational relevance. In our study, we used a simple spatial associative learning task to quantify the effects of sleep deprivation (partial vs. total) on learning performance in zebrafish, using an animated conspecific shoal image as a reward. Control animals maintained on a regular light:dark cycle were able to acquire the association between the unconditioned and conditioned stimulus, reinforcing zebrafish as a valid and reliable model for appetitive conditioning tasks. Notably, sleep deprivation did not alter the perception of and response to the conspecific image. In contrast, although partial sleep deprivation did not impair cognitive performance, total sleep deprivation significantly impaired performance on the associative learning task. Our results suggest that sleep is important for learning and memory, and that the effects of sleep deprivation on these processes can be investigated in zebrafish. PMID- 28652200 TI - Down-regulation of miRNAs in the brain and development of diet-induced obesity. AB - Novel therapeutic interventions for obesity and comorbid conditions require knowledge of the molecular elements playing a role in the development of obesity. Chronic low-grade inflammation has been consistently reported in obese individuals. In this study, we first determined whether key molecular modulators of inflammation, microRNA-155 (miR-155) and microRNA-146a (miR-146a), are regulated by an obesogenic diet within brain regions associated with reward, metabolism and energy balance. C57BL/6J mice were chronically exposed to a high fat diet (HFD) or a standard chow (CTL). Significant reductions in the levels of miR-155 (82%) and miR-146a (41%) levels were observed within the nucleus accumbens of HFD mice compared to CTL. Further analysis of miR-155 regulation showed no significant changes in levels across peripheral tissue (white adipose, spleen, kidney or liver) between HFD and CTL mice. The effect of lower miR-155 on the development of obesity was determined by exposing wild-type (WT) and miR-155 knockout mice (miR-155 KO) to HFD. Male miR-155 KO gained significantly more weight than WT littermates. Metabolic analyses revealed that miR-155 KO significantly ate more HFD compared to WT, without differing in other metabolic measures including energy expenditure. Together, these data show that miR-155 is physiologically down-regulated after intake of an obesogenic diet, and that loss of miR-155 increases intake of an obesogenic diet. Moreover, these findings shed light on a potential miRNA-based mechanism contributing to the development of diet-induced obesity. PMID- 28652201 TI - Incorporation of in vitro digestive enzymes in an intestinal epithelial cell line model for protein hazard identification. AB - Relatively few proteins in nature produce adverse effects following oral exposure. Of those that do, effects are often observed in the gut, particularly on intestinal epithelial cells (IEC). Previous studies reported that addition of protein toxins to IEC lines disrupted monolayer integrity but innocuous dietary proteins did not. Studies presented here investigated the effects of innocuous (bovine serum albumin, beta-lactoglobulin, RuBisCO, fibronectin) or hazardous (phytohaemagglutinin-E, concanavalin A, wheat germ agglutinin, melittin) proteins that either were untreated or exposed to digestive enzymes prior to addition to Caco-2 human IEC line monolayers. At high concentrations intact fibronectin caused an increase in monolayer permeability but other innocuous proteins did not whether exposed to digestive enzymes or not. In contrast, all untreated hazardous proteins and those that were resistant to digestion (ex. wheat germ agglutinin) disrupted monolayer integrity. However, proteins sensitive to degradation by digestive enzymes (ex. melittin) did not adversely affect monolayers when exposed to these enzymes prior to addition to IEC line monolayers. These results indicate that in vitro exposure of proteins to digestive enzymes can assist in differentiating between innocuous and hazardous proteins as another component to consider in the overall weight of evidence approach in protein hazard assessment. PMID- 28652202 TI - Induction of CYP1A1 increases gefitinib-induced oxidative stress and apoptosis in A549 cells. AB - As the first selective EGFR tyrosine kinase inhibitor, gefitinib has been clinically demonstrated to be effective for certain cancer cell types with EGFR active gene mutations. However, a number of gefitinib-associated adverse pulmonary events have been reported, which could lead to the discontinuation of gefitinib therapy. Although previous reports have implicated that CYP1A1-mediated bioactivation of gefitinib maybe a major reason for the pulmonary toxicity, the roles of CYP1A1 in gefitinib-associated toxicity and the related molecular mechanism have not been well-characterized. This study aimed to reveal whether the induction of CYP1A1 would contribute to the toxic effect of gefitinib in living cells and to investigate the underlying molecular mechanism. The results demonstrated that gefitinib led to the enhancement of the dose-dependent cytotoxicity and the percentage of gefitinib-induced apoptosis was significantly increased on CYP1A1-overexpressed A549 cells, which was accompanied with a substantial increase in the intracellular reactive oxygen species and a remarkable decrease in the mitochondrial membrane potential. These findings strongly suggest that CYP1A1 can enhance the cytotoxicity of gefitinib and gefitinib-induced oxidative stress, which may partially explain the occurrence of pulmonary toxicity in some patients administered with gefitinib. PMID- 28652203 TI - Effects of mild ozonisation on gene expression and nuclear domains organization in vitro. AB - In the last two decades, the use of ozone (O3) as a complementary medical approach has progressively been increasing; however, its application is still limited due to the numerous doubts about its possible toxicity, despite the low concentrations used in therapy. For an appropriate and safe clinical application of a potentially toxic agent such as O3, it is crucial to elucidate the cellular response to its administration. Molecular analyses and transmission electron microscopy were here combined to investigate in vitro the effects of O3 administration on transcriptional activity and nuclear domains organization of cultured SH-SY5Y neuronal cells; low O3 concentrations were used as those currently administered in clinical practice. Mild ozonisation did not affect cell proliferation or death, while molecular analyses showed an O3-induced modulation of some genes involved in the cell response to stress (HMOX1, ERCC4, CDKN1A) and in the transcription machinery (CTDSP1). Ultrastructural cytochemistry after experiments of bromouridine incorporation consistently demonstrated an increased transcriptional rate at both the nucleoplasmic (mRNA) and the nucleolar (rRNA) level. No ultrastructural alteration of nuclear domains was observed. Our molecular, ultrastructural and cytochemical data demonstrate that a mild toxic stimulus such as mild ozonisation stimulate cell protective pathways and nuclear transcription, without altering cell viability. This could possibly account for the positive effects observed in ozone-treated patients. PMID- 28652205 TI - Opioid Analgesics Administered for Pain in the Inpatient Pediatric Setting. AB - : This study aimed to describe utilization of opioid medications among infants, children, and adolescents on the inpatient setting. These data are needed to guide clinical trials and improve research methodologies, as well as to inform more about possible sources of opioid misuse in the United States. A retrospective chart review was conducted covering a span of 1 year, with a special focus on the prescription of opioids for long-term treatment of chronic pain. Opioid medications were prescribed for <5 days in most (75%) patients. Among those who were prescribed opioids for >14 days, the focus was often for reasons other than pain. These data indicate that models of chronic pain that may be utilized in clinical trials of longer-term opioid usage in pediatrics are exceedingly limited. In addition, the patterns of utilization indicate that opioid administration among pediatric inpatients is not a likely contributory factor to concerns about opioid misuse in the United States. PERSPECTIVE: This article presents data on the administration of opioids in a major children's hospital, with a special eye toward usage beyond treatment for short-term acute pain. These data are important to better inform discussions of research strategies for chronic pain, as well as concerns for misuse in the pediatric population. PMID- 28652206 TI - Membrane solid-state NMR in Canada: A historical perspective. AB - This manuscript presents an overview of more than 40years of membrane solid-state nuclear magnetic resonance (NMR) research in Canada. This technique is a method of choice for the study of the structure and dynamics of lipid bilayers; bilayer interactions with a variety of molecules such as membrane peptides, membrane proteins and drugs; and to investigate membrane peptide and protein structure, dynamics, and topology. Canada has a long tradition in this field of research, starting with pioneering work on natural and model membranes in the 1970s in a context of emergence of biophysics in the country. The 1980s and 1990s saw an emphasis on studying lipid structures and dynamics, and peptide-lipid and protein lipid interactions. The study of bicelles began in the 1990s, and in the 2000s there was a rise in the study of membrane protein structures. Novel perspectives include using dynamic nuclear polarization (DNP) for membrane studies and using NMR in live cells. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28652204 TI - Evidence for a Role of Nerve Injury in Painful Intervertebral Disc Degeneration: A Cross-Sectional Proteomic Analysis of Human Cerebrospinal Fluid. AB - : Intervertebral disc degeneration (DD) is a cause of low back pain (LBP) in some individuals. However, although >30% of adults have DD, LBP only develops in a subset of individuals. To gain insight into the mechanisms underlying nonpainful versus painful DD, human cerebrospinal fluid (CSF) was examined using differential expression shotgun proteomic techniques comparing healthy control participants, subjects with nonpainful DD, and patients with painful DD scheduled for spinal fusion surgery. Eighty-eight proteins were detected, 27 of which were differentially expressed. Proteins associated with DD tended to be related to inflammation (eg, cystatin C) regardless of pain status. In contrast, most differentially expressed proteins in DD-associated chronic LBP patients were linked to nerve injury (eg, hemopexin). Cystatin C and hemopexin were selected for further examination using enzyme-linked immunosorbent assay in a larger cohort. While cystatin C correlated with DD severity but not pain or disability, hemopexin correlated with pain intensity, physical disability, and DD severity. This study shows that CSF can be used to study mechanisms underlying painful DD in humans, and suggests that while painful DD is associated with nerve injury, inflammation itself is not sufficient to develop LBP. PERSPECTIVE: CSF was examined for differential protein expression in healthy control participants, pain-free adults with asymptomatic intervertebral DD, and LBP patients with painful intervertebral DD. While DD was related to inflammation regardless of pain status, painful degeneration was associated with markers linked to nerve injury. PMID- 28652207 TI - Characterizing the molecular architectures of chromatin-modifying complexes. AB - Eukaryotic cells package their genome in the form of a DNA-protein complex known as chromatin. This organization not only condenses the genome to fit within the confines of the nucleus, but also provides a platform for a cell to regulate accessibility to different gene sequences. The basic packaging element of chromatin is the nucleosome, which consists of 146 base pairs of DNA wrapped around histone proteins. One major means that a cell regulates chromatin structure is by depositing post-translational modifications on nucleosomal histone proteins, and thereby altering internucleosomal interactions and/or binding to different chromatin associated factors. These chromatin modifications are often catalyzed by multi-subunit enzyme complexes, whose large size, sophisticated composition, and inherent conformational flexibility pose significant technical challenges to their biochemical and structural characterization. Multiple structural approaches including nuclear magnetic resonance spectroscopy, X-ray crystallography, single-particle electron microscopy, and crosslinking coupled to mass spectrometry are often used synergistically to probe the overall architecture, subunit organization, and catalytic mechanisms of these macromolecular assemblies. In this review, we highlight several recent chromatin-modifying complexes studies that embodies this multipronged structural approach, and explore common themes amongst them. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28652208 TI - Recognizing asymmetry in pseudo-symmetry; structural insights into the interaction between amphipathic alpha-helices and X-bundle proteins. AB - An alpha-helix bundle is a small and compact protein fold always composed of more than 2 alpha-helices that typically run nearly parallel or antiparallel to each other. The repertoire of arrangements of alpha-helix bundle is such that these domains bind to a myriad of molecular entities including DNA, RNA, proteins and small molecules. A special instance of alpha-helical bundle is the X-type in which the arrangement of two alpha-helices interact at 45 degrees to form an X. Among those, some X-helix bundle proteins bind to the hydrophobic section of an amphipathic alpha-helix in a seemingly orientation and sequence specific manner. In this review, we will compare the binding mode of amphipathic alpha-helices to X-helix bundle and alpha-helical bundle proteins. From these structures, we will highlight potential regulatory paradigms that may control the specific interactions of X-helix bundle proteins to amphipathic alpha-helices. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28652209 TI - Heightened autoantibody immune response to citrullinated calreticulin in bronchiectasis: Implications for rheumatoid arthritis. AB - Calreticulin (CRT) and citrullinated (citCRT) are implicated in rheumatoid arthritis (RA) pathology. citCRT binds to RA shared epitopes (SE) on HLA-DR molecules with high affinity and triggers pro-inflammatory events in adjacent cells. The aim of the study was to detect the presence of citCRT prior to developing RA and evaluate if citCT is a target for autoantibodies in RA cohorts with and without lung disease. Antibodies were assessed by ELISA against native CRT, citCRT and general protein citrullination, in sera from 50 RA patients without lung disease, 122 bronchiectasis (BR) patients, 52 bronchiectasis patients with RA (BRRA), 87 asthma patients and 77 healthy controls (HC). Serum citCRT was detected by immunoblotting and mass spectrometry. Genomic DNA was genotyped for HLA-DRB1 alleles. Patients were assessed for DAS28, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies. Extracellular citCRT was detected in BR patients sera prior to them developing RA. A citCRT SE binding peptide GEWKPR261citQIDNPDYK was identified. Anti-CRT antibodies were observed in 18% of BR patients with or without RA. Anti-citCRT antibodies were observed in ~35% of BR or RA patients, increasing to 58% in BRRA patients. In the RA alone patients 7/20 (35%) who were negative for RF and anti-CCP were anti-CRT antibody positive and had higher DAS28 scores than triple negative RA alone patients. Three of the four BR patients who developed RA over 18 months were anti-citCRT+ve SE+ve. The detection of citCRT in BR and development of anti-citCRT in BR patients suggests citCRT antigens are early targets of antigenicity in these patients, especially in SE+ve patients prior to the onset of RA. PMID- 28652210 TI - Cyclin F: A component of an E3 ubiquitin ligase complex with roles in neurodegeneration and cancer. AB - Cyclin F, encoded by CCNF, is the substrate recognition component of the Skp1 Cul1-F-box E3 ubiquitin ligase complex, SCFcyclin F. E3 ubiquitin ligases play a key role in ubiquitin-proteasome mediated protein degradation, an essential component of protein homeostatic mechanisms within the cell. By recognising and regulating the availability of several protein substrates, SCFcyclin F plays a role in regulating various cellular processes including replication and repair of DNA and cell cycle checkpoint control. Cyclin F dysfunction has been implicated in various forms of cancer and CCNF mutations were recently linked to familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia, offering a new lead to understanding the pathogenic mechanisms underlying neurodegeneration. In this review, we evaluate the current literature on the function of cyclin F with an emphasis on its roles in cancer and neurodegeneration. PMID- 28652211 TI - CHOP negatively regulates Polo-like kinase 2 expression via recruiting C/EBPalpha to the upstream-promoter in human osteosarcoma cell line during ER stress. AB - Polo-like kinase 2 (Plk2) is a member of the serine/threonine protein kinase family involved in cell-cycle regulation and cellular response to stresses. However, the alteration of Plk2 in response to endoplasmic reticulum (ER) stress has not been well described. In the present study, we focused on the regulation of Plk2 regulation in response to ER stress. Plk2 expression was dramatically decreased under ER stress induced by brefeldin A (BFA), thapsigargin (TG), or tunicamycin (TM), and this down regulation of Plk2 expression was dependent on activating transcription factor 4 (ATF4) and C/EBP homology protein (CHOP). Luciferase activity analysis of the truncated Plk2 promoter indicated that regions from -2506 to -1806 and from -1002 to -830 of the Plk2 promoter were sensitive to BFA. Additionally, ChIP and ChIP Re-IP assays showed that CHOP and C/EBPalpha were assembled on the same region of Plk2 promoter. Notably, we identified two C/EBPalpha responsive elements at positions -2002 and -948, to which C/EBPalpha or CHOP binding was enhanced by BFA under in vitro and in vivo conditions. Finally, overexpression of Plk2 inhibits cell apoptosis and promotes cell proliferation in response to ER stress. In summary, these results demonstrated that ER stress plays a crucial role in Plk2 expression. CHOP may up regulate DNA-binding affinities after BFA treatment, via recruiting C/EBPalpha to the upstream-promoter of Plk2. These findings may contribute to the understanding of the molecular mechanism of Plk2 regulation. PMID- 28652212 TI - The autoinhibitory function of D1 domain of FGFR1 goes beyond the inhibition of ligand binding. AB - Fibroblast growth factors (FGFs) and their plasma membrane-localized receptors (FGFRs) transduce signals that regulate developmental processes and metabolism. In numerous cancer types genetic aberrations of FGFR1 lead to its uncontrolled activation. To circumvent the unrestrained signal transduction, several intramolecular inhibitory mechanisms within FGFR1 have evolved. In vitro experiments with receptor truncation have demonstrated that the N-terminal D1 domain of FGFR1 negatively regulates ligand binding to the receptor. Here, we show that D1-specific monovalent antibody fragments can activate FGFR1 and its downstream signaling cascades in the absence of ligand. These data suggest that the D1 domain of FGFR1 may play autoinhibitory role not only by controlling ligand binding, but also by regulating the overall conformation of FGFR1, keeping it in a state that disfavors autoactivation in the absence of its cognate growth factor. PMID- 28652213 TI - The efficacy of 18F-FDG PET/CT and 67Ga SPECT/CT in diagnosing fever of unknown origin. AB - OBJECTIVE: Fever of unknown origin (FUO) is a diagnostic challenge. This study aimed to assess the efficacy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and gallium-67 single-photon emission computed tomography/computed tomography (67Ga SPECT/CT) in diagnosing FUO. METHODS: A total of 68 patients with FUO underwent 18F-FDG PET/CT and 67Ga SPECT/CT from January 2013 through May 2016. Images were read independently. The imaging results were compared with the final diagnosis and categorized as helpful for diagnosis or non-contributory to diagnosis in the clinical setting. Associations between categorical variables were evaluated with the chi-square test or Fisher's exact test. RESULTS: Ten of the 68 patients were excluded. An infectious underlying disease was found in 23 patients. A malignant disorder was the cause of FUO in 10 patients. Non-infectious inflammatory disease was found in 11 patients. Adrenal insufficiency was the cause of FUO in two patients. The cause of FUO was not found for 12 patients. A high false-positive rate of 44% (7/16) was observed for 18F-FDG PET/CT, while a high false-negative rate of 55% (23/42) was observed for 67Ga SPECT/CT. 18F-FDG PET/CT studies depicted all 67Ga avid lesions. The sensitivity (79% vs. 45%) and clinical contribution (72% vs. 55%) of 18F-FDG PET/CT in diagnosing FUO were significantly higher than those of 67Ga SPECT/CT (p<0.05). CONCLUSIONS: On the basis of this study, the diagnostic performance of 18F-FDG PET/CT is superior to 67Ga SPECT/CT in the work-up of patients with FUO. With its rapid results and superior sensitivity, 18F-FDG PET/CT may replace 67Ga SPECT/CT where this technique is available. PMID- 28652215 TI - Histoplasma capsulatum in the bone marrow of an HIV-infected patient. PMID- 28652214 TI - Elevated levels of von Willebrand factor and high mobility group box 1 (HMGB1) are associated with disease severity and clinical outcome of scrub typhus. AB - OBJECTIVES: This study aimed to investigate whether von Willebrand factor (vWF) and high mobility group box 1 (HMGB1) are associated with the severity and clinical outcome of scrub typhus and to seek novel biomarkers for surveillance and prediction of the prognosis of this infection. METHODS: Serum concentrations of vWF and HMGB1 were measured twice by ELISA for scrub typhus patients (n=103), once prior to doxycycline therapy and then on day 7 of doxycycline therapy; concentrations were measured once for healthy controls (n=32). RESULTS: Among the total 103 patients enrolled, 38 had disease complicated by multiple organ dysfunction syndrome (MODS). Serum concentrations of vWF and HMGB1 were significantly higher in all the patients than in the healthy controls, both prior to doxycycline treatment and on day 7 of doxycycline treatment (p<0.01). Furthermore, serum levels of vWF, HMGB1, and creatinine (SCr) in the patients with MODS increased distinctly, while the platelet (PLT) count diminished markedly compared to the levels in patients without MODS (p<0.01). The concentration of vWF was positively correlated with that of HMGB1 (r=0.764, p<0.001) and SCr (r=0.528, p<0.001), but negatively correlated with the PLT count (r=-0.632, p<0.001). Both HMGB1 and vWF were significantly associated with mortality in scrub typhus (area under the curve (AUC)=0.864, p=0.001, and AUC=0.862, p=0.001, respectively). CONCLUSIONS: Elevated levels of vWF and HMGB1 are associated with the severity and clinical outcome of scrub typhus. These represent possible new biomarkers for use in the assessment and prognostic prediction of this infection. PMID- 28652216 TI - Fungemia and necrotic lymph node infection with Sporopachydermia cereana in a patient with acute myeloid leukemia. AB - Sporopachydermia cereana is a rare yeast found in necrotic cactus tissue, predominantly in the Americas. Infection in humans with clinical data has only been reported in four patients so far, all of whom died, either directly from the pathogen or from other complications of immunosuppression. Treatment of the yeast is complicated by difficulties in identification of the pathogen with conventional diagnostic techniques and by intrinsic resistance to echinocandins. The first patient to survive a disseminated infection with S. cereana is presented herein. The patient had acute myeloid leukemia and was treated successfully with antifungal therapy and subsequently underwent a successful allogeneic hematopoietic stem cell transplantation. PMID- 28652217 TI - Tuberculosis and diabetes in Nigerian patients with and without HIV. AB - BACKGROUND: Type 2 diabetes mellitus (DM) and HIV increase the risk of tuberculosis (TB). The frequency of DM among patients with TB with and without HIV is poorly documented in many low- and middle-income countries. METHODS: This was a cross-sectional hospital-based study performed in Abuja, Nigeria. Adults with presumptive TB were screened consecutively. Sputum culture was used for TB screening and blood was used for HIV screening, as well as fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) assessment for the diagnosis of DM. HbA1c was measured using the D-10 Haemoglobin Testing System and a point-of-care test (A1C Now+ system) for comparison. Patients were classified as having DM or pre diabetes using the D-10 reference test. RESULTS: Four hundred and ten individuals had TB culture, FPG, and HbA1c results. Participants had a mean (+/-standard deviation) age of 37.8+/-12.6 years and 217 (54.8%) were male. One hundred and thirteen (27.6%) patients were culture-positive, 62 (15.1%) had DM, and 46 (11.2%) had pre-diabetes. One hundred and eighty-four (53.3%) participants were HIV-positive and 95 (51.6%) were on antiretroviral therapy (ART). Patients with pre-diabetes and DM were more likely to have TB (odds ratio (OR) 1.94, 95% confidence interval (CI) 0.01-3.74, and OR 2.39, 95% CI 1.35-4.24, respectively). After adjustment for HIV, age, and sex, only DM was statistically associated with TB (adjusted OR (AOR) 3.10, 95% CI 1.62-5.94). HIV-negative patients with DM had a higher risk of TB (AOR 4.32, 95% CI 1.57-11.92) than HIV-positive patients with DM (AOR 3.31, 95% CI 1.29-8.54), but the difference was not statistically significant. A1C Now+ HbA1c measurements correlated poorly with the D-10 HbA1c reference test. CONCLUSION: A high proportion of patients in Abuja have markers of DM and pre-diabetes at the time of TB diagnosis. PMID- 28652218 TI - Quantitative positron emission tomography in brain research. AB - The application of positron emission tomography (PET) in brain research has increased substantially during the past 20years, and is still growing. PET provides a unique insight into physiological and pathological processes in vivo. In this article we introduce the fundamentals of PET, and the methods available for acquiring quantitative estimates of the parameters of interest. A short introduction to different areas of application is also given, including basic research of brain function and in neurology, psychiatry, drug receptor occupancy studies, and its application in diagnostics of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Our aim is to inform the unfamiliar reader of the underlying basics and potential applications of PET, hoping to inspire the reader into considering how the technique could be of benefit for his or her own research. PMID- 28652219 TI - The fate of the brain cholinergic neurons in neurodegenerative diseases. AB - The aims of this review are: 1) to describe which cholinergic neurons are affected in brain neurodegenerative diseases leading to dementia; 2) to discuss the possible causes of the degeneration of the cholinergic neurons, 3) to summarize the functional consequences of the cholinergic deficit. The brain cholinergic system is basically constituted by three populations of phenotypically similar neurons forming a series of basal forebrain nuclei, the midpontine nuclei and a large population of striatal interneurons. In Alzheimer's disease there is an extensive loss of forebrain cholinergic neurons accompanied by a reduction of the cholinergic fiber network of the cortical mantel and hippocampus. The midpontine cholinergic nuclei are spared. The same situation occurs in the corticobasal syndrome and dementia following alcohol abuse and traumatic brain injury. Conversely, in Parkinson's disease, the midpontine nuclei degenerate, together with the dopaminergic nuclei, reducing the cholinergic input to thalamus and forebrain whereas the forebrain cholinergic neurons are spared. In Parkinson's disease with dementia, Lewis Body Dementia and Parkinsonian syndromes both groups of forebrain and midpontine cholinergic nuclei degenerate. In Huntington's disease a dysfunction of the striatal cholinergic interneurons without cell loss takes place. The formation and accumulation of misfolded proteins such as beta-amyloid oligomers and plaques, tau protein tangles and alpha-synuclein clumps, and aggregated mutated huntingtin play a crucial role in the neuronal degeneration by direct cellular toxicity of the misfolded proteins and through the toxic compounds resulting from an extensive inflammatory reaction. Evidences indicate that beta-amyloid disrupts NGF metabolism causing the degeneration of the cholinergic neurons which depend on NGF for their survival, namely the forebrain cholinergic neurons, sparing the midpontine and striatal neurons which express no specific NGF receptors. It is feasible that the latter cholinergic neurons may be damaged by direct toxicity of tau, alpha synuclein and inflammations products through mechanisms not fully understood. Attention and learning and memory impairment are the functional consequences of the forebrain cholinergic neuron dysfunction, whereas the loss of midpontine cholinergic neurons results primarily in motor and sleep disturbances. PMID- 28652220 TI - Inhibition of Alzheimer's amyloid-beta aggregation in-vitro by carbenoxolone: Insight into mechanism of action. AB - BACKGROUND: The major hallmark of Alzheimer's disease (AD) is the formation of amyloid aggregates, which are formed due to improper folding of proteins leading to the aggregation of amyloid beta (Abeta) 42 peptide. Inhibition of Abeta 42 aggregation using a drug such as carbenoxolone (Cbx), which has already been stated as neuroprotective, appears to be an effective approach against AD. OBJECTIVE: The present study was designed to investigate the anti-fibrillation activity of Cbx against the Abeta 42 aggregation. METHODS: The aggregation of Abeta 42 peptide was observed by performing in-vitro studies and the propensity of aggregation of Abeta 42 peptide was evaluated by the prediction of binding sites and amyloidogenic regions. The binding of Cbx in these binding sites was predicted by computational studies. RESULTS: Thioflavin-T (Th-T assay), congo red assay and circular dichroism (CD) analysis suggested significant inhibition of Abeta 42 aggregation by Cbx. The propensity of aggregation of Abeta 42 peptide was evaluated by the prediction of binding sites and amyloidogenic regions. The mechanism of anti-fibrillation activity of Cbx was elucidated by molecular docking and simulation studies and has been predicted to interact with amyloidogenic residues of Abeta 42 peptides as well as fibrils. Cbx also interacts with residues involved in the stabilization of the oligomeric structure. CONCLUSION: These results project Cbx as a suitable candidate for the inhibition of Abeta 42 aggregation and the therapeutic potential of Cbx against AD can further be studied using in-vivo experiments. PMID- 28652221 TI - Statistical vs clinical significance: A matter of debate for orlistat treatment. PMID- 28652222 TI - Hemiconvulsion-hemiplegia-epilepsy syndrome in a child with pre-existing cerebral pathology. PMID- 28652223 TI - ILAE survey of neuropsychology practice in pediatric epilepsy surgery evaluation. AB - To determine the extent to which specific neuropsychological measures are in common use around the world for the assessment of children who are candidates for epilepsy surgery. As part of the work of the International League Against Epilepsy Pediatric Surgical Task Force, a survey was developed and distributed online. The survey consisted of questions related to demographics, training experience, general practice, and specific measures used and at what frequency. Seventy-eight clinicians with an average of 13.5 years of experience from 19 countries responded to the survey; 69% were English-speaking. Pre- and post neuropsychological evaluations were conducted with a majority of children undergoing surgical resection for epilepsy. There was high consistency (>90%) among the domains evaluated, while consistency rate among specific measures was more variable (range: 0-100%). Consistency rates were also lower among respondents in non-English-speaking countries. For English-speaking respondents, at least one measure within each domain was used by a majority (>75%) of clinicians; 19 specific measures met this criterion. There is consensus of measures used in neuropsychological studies of pediatric epilepsy patients which provides a basis for determining which measures to include in establishing a collaborative data repository to study surgical outcomes of pediatric epilepsy. Challenges include selecting measures that promote collaboration with centers in non-English-speaking countries and providing data from children under age 5. PMID- 28652224 TI - Focal epilepsy with paroxysmal pain due to somatic injury. AB - We present two cases with paroxysmal pain that developed after a somatic injury to the trunk. The main characteristic of the episodes was paroxysmal severe pain, mainly located in the original region of somatic injury, with ipsilateral tonic or dystonic behaviour. The clinical characteristics supported a diagnosis of focal epilepsy. Both scalp EEG and MEG findings suggested epileptic activities on the contralateral central cortex. The focal seizures had a good response to antiepileptic drugs. It is hypothesized that peripheral somatic injuries can modify cortical excitability and lead to plastic changes in the sensory/motor cortex, ultimately resulting in focal seizures. We provide additional evidence for the phenomenon that a peripheral somatic injury could induce focal epilepsy. [Published with video sequence on www.epilepticdisorders.com]. PMID- 28652225 TI - Web-Based Interventions for Weight Loss or Weight Loss Maintenance in Overweight and Obese People: A Systematic Review of Systematic Reviews. AB - BACKGROUND: Weight loss is challenging and maintenance of weight loss is problematic. Web-based programs offer good potential for delivery of interventions for weight loss or weight loss maintenance. However, the precise impact of Web-based weight management programs is still unclear. OBJECTIVE: The purpose of this meta-systematic review was to provide a comprehensive summary of the efficacy of Web-based interventions for weight loss and weight loss maintenance. METHODS: Electronic databases were searched for systematic reviews and meta-analyses that included at least one study investigating the effect of a Web-based intervention on weight loss and/or weight loss maintenance among samples of overweight and/or obese individuals. Twenty identified reviews met the inclusion criteria. The Revised Assessment of Multiple SysTemAtic Reviews (R AMSTAR) was used to assess methodological quality of reviews. All included reviews were of sufficient methodological quality (R-AMSTAR score >=22). Key methodological and outcome data were extracted from each review. RESULTS: Web based interventions for both weight loss and weight loss maintenance were more effective than minimal or control conditions. However, when contrasted with comparable non-Web-based interventions, results were less consistent across reviews. CONCLUSIONS: Overall, the efficacy of weight loss maintenance interventions was stronger than the efficacy of weight loss interventions, but further evidence is needed to more clearly understand the efficacy of both types of Web-based interventions. TRIAL REGISTRATION: PROSPERO 2015: CRD42015029377; http://www.crd.york.ac.uk/PROSPERO/display_record.asp? ID=CRD42015029377 (Archived by WebCite at http://www.webcitation.org/6qkSafdCZ). PMID- 28652227 TI - Reducing Parental Uncertainty Around Childhood Cancer: Implementation Decisions and Design Trade-Offs in Developing an Electronic Health Record-Linked Mobile App. AB - BACKGROUND: Parents of children newly diagnosed with cancer are confronted with multiple stressors that place them at risk for significant psychological distress. One strategy that has been shown to help reduce uncertainty is the provision of basic information; however, families of newly diagnosed cancer patients are often bombarded with educational material. Technology has the potential to help families manage their informational needs and move towards normalization. OBJECTIVE: The aim of this study was to create a mobile app that pulls together data from both the electronic health record (EHR) and vetted external information resources to provide tailored information to parents of newly diagnosed children as one method to reduce the uncertainty around their child's illness. This app was developed to be used by families in a National Institutes of Health (NIH)-funded randomized controlled trial (RCT) aimed at decreasing uncertainty and the subsequent psychological distress. METHODS: A 2 phase qualitative study was conducted to elicit the features and content of the mobile app based on the needs and experience of parents of children newly diagnosed with cancer and their providers. Example functions include the ability to view laboratory results, look up appointments, and to access educational material. Educational material was obtained from databases maintained by the National Cancer Institute (NCI) as well as from groups like the Children's Oncology Group (COG) and care teams within Cincinnati Children's Hospital Medical Center (CCHMC). The use of EHR-based Web services was explored to allow data like laboratory results to be retrieved in real-time. RESULTS: The ethnographic design process resulted in a framework that divided the content of the mobile app into the following 4 sections: (1) information about the patient's current treatment and other data from the EHR; (2) educational background material; (3) a calendar to view upcoming appointments at their medical center; and (4) a section where participants in the RCT document the study data. Integration with the NCI databases was straightforward; however, accessing the EHR Web services posed a challenge, though the roadblocks were not technical in nature. The lack of a formal, end-to-end institutional process for requesting Web service access and a mechanism to shepherd the request through all stages of implementation proved to be the biggest barrier. CONCLUSIONS: We successfully deployed a mobile app with a custom user interface that can integrate with the EHR to retrieve laboratory results and appointment information using vendor-provided Web services. Developers should expect to face hurdles when integrating with the EHR, but many of them can be addressed with frequent communication and thorough documentation. Executive sponsorship is also a key factor for success. TRIAL REGISTRATION: ClinicalTrials.gov NCT02505165; https://clinicaltrials.gov/ct2/show/NCT02505165 (Archived by WebCite at http://www.Webcitation.org/6r9ZSUgoT). PMID- 28652226 TI - A Hybrid Web-Based and In-Person Self-Management Intervention to Prevent Acute to Chronic Pain Transition After Major Lower Extremity Trauma (iPACT-E-Trauma): Protocol for a Pilot Single-Blind Randomized Controlled Trial. AB - BACKGROUND: Acute pain frequently transitions to chronic pain after major lower extremity trauma (ET). Several modifiable psychological risk and protective factors have been found to contribute to, or prevent, chronic pain development. Some empirical evidence has shown that interventions, including cognitive and behavioral strategies that promote pain self-management, could prevent chronic pain. However, the efficacy of such interventions has never been demonstrated in ET patients. We have designed a self-management intervention to prevent acute to chronic pain transition after major lower extremity trauma (iPACT-E-Trauma). OBJECTIVE: This pilot randomized controlled trial (RCT) aims to evaluate the feasibility and research methods of the intervention, as well as the potential effects of iPACT-E-Trauma, on pain intensity and pain interference with daily activities. METHODS: A 2-arm single-blind pilot RCT will be conducted. Participants will receive the iPACT-E-Trauma intervention (experimental group) or an educational pamphlet (control group) combined with usual care. Data will be collected at baseline, during iPACT-E-Trauma delivery, as well as at 3 and 6 months post-injury. Primary outcomes are pain intensity and pain interference with daily living activities at 6 months post-injury. Secondary outcomes are pain self-efficacy, pain acceptance, pain catastrophizing, pain-related fear, anxiety and depression symptoms, health care service utilization, and return to work. RESULTS: Fifty-three patients were recruited at the time of manuscript preparation. Comprehensive data analyses will be initiated in July 2017. Study results are expected to be available in 2018. CONCLUSIONS: Chronic pain is an important problem after major lower ET. However, no preventive intervention has yet been successfully proven in these patients. This study will focus on developing a feasible intervention to prevent acute to chronic pain transition in the context of ET. Findings will allow for the refinement of iPACT-E-Trauma and methodological parameters in prevision of a full-scale multi-site RCT. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 91987302; http://www.controlled-trials.com/ISRCTN91987302 (Archived by WebCite at http://www.webcitation.org/6rR8G2vMs). PMID- 28652228 TI - A Community-Based Physical Activity Counselling Program for People With Knee Osteoarthritis: Feasibility and Preliminary Efficacy of the Track-OA Study. AB - BACKGROUND: Physical activity can improve health outcomes in people with knee osteoarthritis (OA); however, participation in physical activity is very low in this population. OBJECTIVE: The objective of our study was to assess the feasibility and preliminary efficacy of the use of wearables (Fitbit Flex) and telephone counselling by a physical therapist (PT) for improving physical activity in people with a physician-confirmed diagnosis of knee OA, or who have passed 2 validated criteria for early OA. METHODS: We conducted a community-based feasibility randomized controlled trial. The immediate group (n=17) received a brief education session by a physical therapist, a Fitbit Flex activity tracker, and a weekly telephone call for activity counselling with the physical therapist. The delayed group (n=17) received the same intervention 1 month later. All participants were assessed at baseline (T0), and the end of 1 month (T1) and 2 months (T2). Outcomes were (1) mean moderate to vigorous physical activity time, (2) mean time spent on sedentary behavior, (3) Knee Injury and Osteoarthritis Outcome Score (KOOS), and (4) Partners in Health Scale. Feasibility data were summarized with descriptive statistics. We used analysis of covariance to evaluate the effect of the group type on the outcome measures at T1 and T2, after adjusting for blocking and T0. We assessed planned contrasts of changes in outcome measures over measurement periods. RESULTS: We identified 46 eligible individuals; of those, 34 (74%) enrolled and no one dropped out. All but 1 participant adhered to the intervention protocol. We found a significant effect, with the immediate intervention group having improved in the moderate to vigorous physical activity time and in the Partners in Health Scale at T0 to T1 compared with the delayed intervention group. The planned contrast of the immediate intervention group at T0 to T1 versus the delayed group at T1 to T2 showed a significant effect in the sedentary time and the KOOS symptoms subscale, favoring the delayed group. CONCLUSIONS: This study demonstrated the feasibility of a behavioral intervention, supported by the use of a wearable device, to promote physical activity among people with knee OA. TRIAL REGISTRATION: ClinicalTrials.gov NCT02313506; https://clinicaltrials.gov/ct2/show/NCT02313506 (Archived by WebCite at http://www.webcitation.org/6r4P3Bub0). PMID- 28652229 TI - Outbreak of CTX-M-15-Producing Enterotoxigenic Escherichia coli O159:H20 in the Republic of Korea in 2016. AB - We investigated an outbreak of enterotoxigenic Escherichia coli (ETEC) O159:H20 associated with the consumption of a tossed-noodle dish in a high school in 2016. Thirty-three ETEC strains isolated from clinical and food samples were genetically indistinguishable. The outbreak strains were resistant to third generation cephalosporins and harbored a blaCTX-M-15 gene on a 97-kb self transferable IncK plasmid. This is the first outbreak caused by CTX-M-15 producing ETEC strains. PMID- 28652230 TI - Multicenter Study of the Relationship between Carbapenem MIC Values and Clinical Outcome of Patients with Acinetobacter Bacteremia. AB - The Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) offer different recommendations for carbapenem MIC susceptibility breakpoints for Acinetobacter species. In addition, the clinical efficacy of the intermediate category remains uncertain. This study was designed to determine the optimal predictive breakpoints based on the survival of patients with Acinetobacter bacteremia treated with a carbapenem. We analyzed the 30-day mortality rates of 224 adults who received initial carbapenem monotherapy for the treatment of Acinetobacter bacteremia at 4 medical centers over a 5-year period, according to the carbapenem MICs of the initial isolates. The 30-day mortality was about 2-fold greater in patients whose isolates had carbapenem MICs of >=8 mg/liter than in those with isolates with MICs of <=4 mg/liter. The differences were significant by bivariate analysis (53.1% [60/113] versus 25.2% [28/111], respectively; P < 0.001) and on survival analysis by the log rank test (P < 0.001). Classification and regression tree analysis revealed a split between MICs of 4 and 8 mg/liter and predicted the same difference in mortality, with a P value of <0.001. Carbapenem treatment for Acinetobacter bacteremia caused by isolates with carbapenem MICs of >=8 mg/liter was an independent predictor of 30-day mortality (odds ratio, 4.218; 95% confidence interval, 2.213 to 8.039; P < 0.001). This study revealed that patients with Acinetobacter bacteremia treated with a carbapenem had a more favorable outcome when the carbapenem MICs of their isolates were <=4 mg/liter than those with MICs of >=8 mg/liter. PMID- 28652231 TI - Complete DNA Sequence of an IncM1 Plasmid Bearing the Novel qnrE1 Plasmid Mediated Quinolone Resistance Variant and blaCTX-M-8 from Klebsiella pneumoniae Sequence Type 147. PMID- 28652232 TI - Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds. AB - Francisella tularensis is a highly infectious Gram-negative intracellular pathogen that causes tularemia. Because of its potential as a bioterrorism agent, there is a need for new therapeutic agents. We therefore developed a whole-animal Caenorhabditis elegans-F. tularensis pathosystem for high-throughput screening to identify and characterize potential therapeutic compounds. We found that the C. elegans p38 mitogen-activate protein (MAP) kinase cascade is involved in the immune response to F. tularensis, and we developed a robust F. tularensis mediated C. elegans killing assay with a Z' factor consistently of >0.5, which was then utilized to screen a library of FDA-approved compounds that included 1,760 small molecules. In addition to clinically used antibiotics, five FDA approved drugs were also identified as potential hits, including the anti inflammatory drug diflunisal that showed anti-F. tularensis activity in vitro Moreover, the nonsteroidal anti-inflammatory drug (NSAID) diflunisal, at 4* MIC, blocked the replication of an F. tularensis live vaccine strain (LVS) in primary human macrophages and nonphagocytic cells. Diflunisal was nontoxic to human erythrocytes and HepG2 human liver cells at concentrations of >=32 MUg/ml. Finally, diflunisal exhibited synergetic activity with the antibiotic ciprofloxacin in both a checkerboard assay and a macrophage infection assay. In conclusion, the liquid C. elegans-F. tularensis LVS assay described here allows screening for anti-F. tularensis compounds and suggests that diflunisal could potentially be repurposed for the management of tularemia. PMID- 28652234 TI - Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. AB - We evaluated the activity of meropenem-vaborbactam against contemporary nonfastidious Gram-negative clinical isolates, including Enterobacteriaceae isolates with resistance phenotypes and carbapenemase genotypes. Meropenem vaborbactam (inhibitor at 8 MUg/ml) and comparators were susceptibility tested by reference broth microdilution methods against 14,304 Gram-negative clinical isolates collected worldwide during 2014. Carbapenemase-encoding genes were screened by PCR and sequencing. Meropenem-vaborbactam (MIC50/90, <=0.015/0.06 MUg/ml) inhibited 99.1 and 99.3% of the 10,426 Enterobacteriaceae isolates tested at <=1 and <=2 MUg/ml, respectively. Meropenem inhibited 97.3 and 97.7% of these isolates at the same concentrations. Against Enterobacteriaceae isolates displaying carbapenem-resistant Enterobacteriaceae (CRE) (n = 265), multidrug resistant (MDR) (n = 1,210), and extensively drug-resistant (XDR) (n = 161) phenotypes, meropenem-vaborbactam displayed MIC50/90 values of 0.5/32, 0.03/1, and 0.5/32 MUg/ml, respectively, whereas meropenem activities were 16/>32, 0.06/32, and 0.5/32 MUg/ml, respectively. Among all geographic regions, the highest meropenem-vaborbactam activities were observed for CRE and MDR isolates from the United States (MIC50/90, 0.03/1 and 0.03/0.12 MUg/ml, respectively). Meropenem-vaborbactam was very active against 135 KPC producers, and all isolates were inhibited by concentrations of <=8 MUg/ml (133 isolates by concentrations of <=2 MUg/ml). This combination had limited activity against isolates producing metallo-beta-lactamases (including 25 NDM-1 and 16 VIM producers) and/or oxacillinases (27 OXA-48/OXA-163 producers) that were detected mainly in Asia Pacific and some European countries. The activity of meropenem-vaborbactam was similar to that of meropenem alone against Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia Meropenem-vaborbactam was active against contemporary Enterobacteriaceae isolates collected worldwide, and this combination demonstrated enhanced activity compared to those of meropenem and most comparator agents against CRE isolates and KPC producers, the latter of which are often MDR. PMID- 28652235 TI - Nifurtimox Is Ineffective against Drug-Resistant Mycobacteria. PMID- 28652233 TI - Potent Inhibition of HIV-1 Replication in Resting CD4 T Cells by Resveratrol and Pterostilbene. AB - HIV-1 infection of resting CD4 T cells plays a crucial and numerically dominant role during virus transmission at mucosal sites and during subsequent acute replication and T cell depletion. Resveratrol and pterostilbene are plant stilbenoids associated with several health-promoting benefits. Resveratrol has been shown to inhibit the replication of several viruses, including herpes simplex viruses 1 and 2, papillomaviruses, severe acute respiratory syndrome virus, and influenza virus. Alone, resveratrol does not inhibit HIV-1 infection of activated T cells, but it does synergize with nucleoside reverse transcriptase inhibitors in these cells to inhibit reverse transcription. Here, we demonstrate that resveratrol and pterostilbene completely block HIV-1 infection at a low micromolar dose in resting CD4 T cells, primarily at the reverse transcription step. The anti-HIV effect was fully reversed by exogenous deoxynucleosides and Vpx, an HIV-1 and simian immunodeficiency virus protein that increases deoxynucleoside triphosphate (dNTP) levels. These findings are consistent with the reported ability of resveratrol to inhibit ribonucleotide reductase and to lower dNTP levels in cells. This study supports the potential use of resveratrol, pterostilbene, or related compounds as adjuvants in anti-HIV preexposure prophylaxis (PrEP) formulations. PMID- 28652236 TI - Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors. AB - Antibiotic-resistant bacteria are an emerging threat to global public health. New classes of antibiotics and tools for antimicrobial discovery are urgently needed. Type III secretion systems (T3SS), which are required by dozens of Gram-negative bacteria for virulence but largely absent from nonpathogenic bacteria, are promising virulence blocker targets. The ability of mammalian cells to recognize the presence of a functional T3SS and trigger NF-kappaB activation provides a rapid and sensitive method for identifying chemical inhibitors of T3SS activity. In this study, we generated a HEK293 stable cell line expressing green fluorescent protein (GFP) driven by a promoter containing NF-kappaB enhancer elements to serve as a readout of T3SS function. We identified a family of synthetic cyclic peptide-peptoid hybrid molecules (peptomers) that exhibited dose dependent inhibition of T3SS effector secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa without affecting bacterial growth or motility. Among these inhibitors, EpD-3'N, EpD-1,2N, EpD-1,3'N, EpD-1,2,3'N, and EpD-1,2,4'N exhibited strong inhibitory effects on translocation of the Yersinia YopM effector protein into mammalian cells (>40% translocation inhibition at 7.5 MUM) and showed no toxicity to mammalian cells at 240 MUM. In addition, EpD-3'N and EpD-1,2,4'N reduced the rounding of HeLa cells caused by the activity of Yersinia effector proteins that target the actin cytoskeleton. In summary, we have discovered a family of novel cyclic peptomers that inhibit the injectisome T3SS but not the flagellar T3SS. PMID- 28652237 TI - The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials. AB - To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the Medicines for Malaria Venture (MMV) Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with a Saccharomyces cerevisiae model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug's action on translation fidelity being mediated through Rli1. The MMV drug also synergized with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine, and primaquine. The data collectively suggest translation fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate. PMID- 28652238 TI - Characterization of the Activities of Dinuclear Thiolato-Bridged Arene Ruthenium Complexes against Toxoplasma gondii. AB - The in vitro effects of 18 dinuclear thiolato-bridged arene ruthenium complexes (1 monohiolato compound, 4 dithiolato compounds, and 13 trithiolato compounds), originally designed as anticancer agents, on the apicomplexan parasite Toxoplasma gondii grown in human foreskin fibroblast (HFF) host cells were studied. Some trithiolato compounds exhibited antiparasitic efficacy at concentrations of 250 nM and below. Among those, complex 1 and complex 2 inhibited T. gondii proliferation with 50% inhibitory concentrations (IC50s) of 34 and 62 nM, respectively, and they did not affect HFFs at dosages of 200 MUM or above, resulting in selectivity indices of >23,000. The IC50s of complex 9 were 1.2 nM for T. gondii and above 5 MUM for HFFs. Transmission electron microscopy detected ultrastructural alterations in the matrix of the parasite mitochondria at the early stages of treatment, followed by a more pronounced destruction of tachyzoites. However, none of the three compounds applied at 250 nM for 15 days was parasiticidal. By affinity chromatography using complex 9 coupled to epoxy activated Sepharose followed by mass spectrometry, T. gondii translation elongation factor 1alpha and two ribosomal proteins, RPS18 and RPL27, were identified to be potential binding proteins. In conclusion, organometallic ruthenium complexes exhibit promising activities against Toxoplasma, and the potential mechanisms of action of these compounds as well as their prospective applications for the treatment of toxoplasmosis are discussed. PMID- 28652239 TI - Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections. AB - This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) of Paracoccidioides brasiliensis, one of the etiological agents of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD, and l-homoserine was modeled by homology. The model with the best output was subjected to gradient minimization, redocking, and molecular dynamics simulation. Virtual screening simulations with 187,841 molecules purchasable from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 MUg . ml-1, respectively, for the Pb18 isolate of P. brasilensis, 64 MUg . ml 1 for two isolates of P. lutzii, and also synergy with itraconazole. The application of these molecules to human-pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover, these compounds may serve as leads in the design of new antifungals. PMID- 28652240 TI - The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone Treated Pseudomonas aeruginosa Airway Infection. AB - Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to beta-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study. PMID- 28652241 TI - Prophylactic Treatment with VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection. AB - We compared prophylactic or continuous therapy with the investigational drug VT 1161 to that with posaconazole in treating murine mucormycosis due to Rhizopus arrhizus var. arrhizus In the prophylaxis studies, only VT-1161 resulted in improved survival and lowered tissue fungal burden of immunosuppressed infected mice. In the continuous therapy, VT-1161 outperformed posaconazole in prolonging mouse survival time despite its comparable effect in lowering tissue fungal burden. These results support the further development of VT-1161 against mucormycosis. PMID- 28652243 TI - Clinical Pathways: Recommendations for Putting Patients at the Center of Value Based Care. AB - Two major trends that have been affecting the provision of oncology care in the United States are a shift from volume-based to value-based care and a push toward patient-centered healthcare. However, these two trends are not always completely aligned with each other. Value-based payment models, including clinical pathways, are one strategy being implemented by oncology stakeholders to help encourage the uptake of value-based oncology care. If structured with the patient in mind, they can improve quality of care for patients with cancer, decrease inappropriate care while enabling appropriate personalization of care, and constrain rising prices by demanding a stronger link between cost and value. If not structured appropriately, they can limit patient choice, impede access to innovative treatments, and encourage one-size-fits-all oncology care. Clin Cancer Res; 23(16); 4545-9. (c)2017 AACR. PMID- 28652242 TI - Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor. AB - Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC50], <0.09 to 0.71 nM) and RSV-B (IC50, 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp 2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC50, 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections. PMID- 28652244 TI - Targeting Adenosine in BRAF-Mutant Melanoma Reduces Tumor Growth and Metastasis. AB - Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAFV600E melanoma. In AJCC stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease. In addition, dabrafenib and trametinib treatment of CD73+ BRAFV600E-mutant melanomas caused profound CD73 downregulation in tumor cells. Inhibition of BRAF and MEK in combination with the A2A adenosine receptor provided significant protection against tumor initiation and metastasis formation in mice. Our results suggest that targeting adenosine may enhance therapeutic responses for melanoma patients receiving targeted or immune-based therapies. Cancer Res; 77(17); 4684-96. (c)2017 AACR. PMID- 28652245 TI - Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function. AB - Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients. Cancer Res; 77(16); 4258-67. (c)2017 AACR. PMID- 28652246 TI - MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy. AB - Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFalpha cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. Cancer Res; 77(17); 4697-709. (c)2017 AACR. PMID- 28652247 TI - Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells. AB - Cancer aggressiveness may result from the selective pressure of a harsh nutrient deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR-IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer. Cancer Res; 77(16); 4460-71. (c)2017 AACR. PMID- 28652248 TI - GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma. AB - Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here, we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K-mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists. Cancer Res; 77(16); 4448-59. (c)2017 AACR. PMID- 28652249 TI - WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non Small Cell Lung Cancer. AB - G1-S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2-M checkpoint for adaptation to stress and DNA repair, making G2-M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2-M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly comutated with oncogenic KRAS mutations. We investigated the preclinical effects of AZD1775 in the context of KRAS/LKB1 in NSCLC. Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in LKB1-deficient NSCLC cells. In vitro, LKB1 deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type LKB1 cells. In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, combined AZD1775 and cisplatin extended overall survival compared with cisplatin alone. Our data suggest that lack of phosphorylation of LKB1 by ATM was involved in AZD1775-mediated cytotoxicity. Collectively, these findings provide a clinical application for AZD1775 with DNA-damaging agents in KRAS/LKB1 NSCLC. Cancer Res; 77(17); 4663-72. (c)2017 AACR. PMID- 28652250 TI - Identification of Interacting Stromal Axes in Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673-83. (c)2017 AACR. PMID- 28652251 TI - Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness. AB - Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. Cancer Res; 77(16); 4305-16. (c)2017 AACR. PMID- 28652252 TI - Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma. AB - Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-alpha (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589-601. (c)2017 AACR. PMID- 28652253 TI - SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression. AB - Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710-22. (c)2017 AACR. PMID- 28652254 TI - Oviductal microvesicles and their effect on in vitro maturation of canine oocytes. AB - The effect of conditioned medium (CM) or microvesicles (MVs), secreted by multicellular spheroids of oviductal cells, and the involvement of some microRNAs (miRNAs) were investigated in canine oocyte maturation. To generate CM, spheroids were cultured for 3 days. MVs were obtained by ultracentrifugation of CM at 100,000 g and measured for size and concentration by NanoSight instrument. Cumulus-oocyte complexes (COCs) were matured at 38.5 degrees C with 5% CO2 and 5% of O2 in synthetic oviductal fluid (SOF) in biphasic systems: for 24 h, with 5.0 MUg/mL of LH and for other 48 h with 10% oestrous bitch serum. SOF was used as control (CTR) or supplemented with 10% CM or 25-50-75-100-150 * 106 MVs/mL labeled with PKH-26. Results show that multicellular aggregates secreted shedding vesicles. By fluorescence microscopy, the incorporation of labeled MVs was visible only at 72 h in oocyte cytoplasm. These MVs had a positive effect (P < 0.05) on maturation rate (MII) at the concentration of 75 and 100 * 106 MVs/mL compared to CM and CTR (20.34% and 21.82% vs 9.09% and 8.66% respectively). The concentration of 150 * 106 MVs/mL provided only 9.26% of MII. The expression of three specific miRNAs (miR-30b, miR-375 and miR-503) was studied. The lower rate of MII with the higher concentration of MVs is possibly due to the high level of miR-375. In conclusion, the oviductal MVs could be involved in cellular trafficking during oocyte maturation and their possible use in vitro could facilitate the exploitment of canine reproductive biotechnologies. PMID- 28652255 TI - Identification of a novel mutation in the APTX gene associated with ataxia oculomotor apraxia. AB - Hereditary ataxias are a clinically and genetically heterogeneous family of disorders defined by the inability to control gait and muscle coordination. Given the nonspecific symptoms of many hereditary ataxias, precise diagnosis relies on molecular genetic testing. To this end, we conducted whole-exome sequencing (WES) on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia. WES in five affected and six unaffected individuals resulted in the identification of a homozygous novel stop-gain mutation in the APTX gene (c.739A>T; p.Lys247*) that segregates with the phenotype. Mutations in the APTX (OMIM 606350) gene are associated with ataxia with oculomotor apraxia type 1 (OMIM 208920). PMID- 28652256 TI - Fundamental Cardiovascular Research: Returns on Societal Investment: A Scientific Statement From the American Heart Association. AB - Recent decades have witnessed robust successes in conquering the acutely lethal manifestations of heart and vascular diseases. Many patients who previously would have died now survive. Lifesaving successes like these provide a tremendous and easily recognized benefit to individuals and society. Although cardiovascular mortality has declined, the devastating impact of chronic heart disease and comorbidities on quality of life and healthcare resources continues unabated. Future strides, extending those made in recent decades, will require continued research into mechanisms underlying disease prevention, pathogenesis, progression, and therapeutic intervention. However, severe financial constraints currently jeopardize these efforts. To chart a path for the future, this report analyzes the challenges and opportunities we face in continuing the battle against cardiovascular disease and highlights the return on societal investment afforded by fundamental cardiovascular research. PMID- 28652257 TI - Courts can decide that vaccine has caused harm despite lack of evidence. PMID- 28652258 TI - Response to: 'Artery tertiary lymphoid organs in giant cell arteritis are not exclusively located in the media of temporal arteries' by Graver et al. PMID- 28652260 TI - Keep calm... and prepare. PMID- 28652259 TI - Is everyone really breathing 20 times a minute? Assessing epidemiology and variation in recorded respiratory rate in hospitalised adults. AB - BACKGROUND: Respiratory rate (RR) is an independent predictor of adverse outcomes and an integral component of many risk prediction scores for hospitalised adults. Yet, it is unclear if RR is recorded accurately. We sought to assess the potential accuracy of RR by analysing the distribution and variation as a proxy, since RR should be normally distributed if recorded accurately. METHODS: We conducted a descriptive observational study of electronic health record data from consecutive hospitalisations from 2009 to 2010 from six diverse hospitals. We assessed the distribution of the maximum RR on admission, using heart rate (HR) as a comparison since this is objectively measured. We assessed RR patterns among selected subgroups expected to have greater physiological variation using the coefficient of variation (CV=SD/mean). RESULTS: Among 36 966 hospitalisations, recorded RR was not normally distributed (p<0.001), but right skewed (skewness=3.99) with values clustered at 18 and 20 (kurtosis=23.9). In contrast, HR was relatively normally distributed. Patients with a cardiopulmonary diagnosis or hypoxia only had modestly greater variation (CV increase of 2%-6%). Among 1318 patients transferred from the ward to the intensive care unit (n=1318), RR variation the day preceding transfer was similar to that observed on admission (CV 0.24 vs 0.26), even for those transferred with respiratory failure (CV 0.25). CONCLUSIONS: The observed patterns suggest that RR is inaccurately recorded, even among those with cardiopulmonary compromise, and represents a 'spot' estimate with values of 18 and 20 breaths per minute representing 'normal.' While spot estimates may potentially be adequate to indicate clinical stability, inaccurate RR may alternatively lead to misclassification of disease severity, potentially jeopardising patient safety. Thus, we recommend greater training for hospital personnel to accurately record RR. PMID- 28652261 TI - BMA annual meeting: Government is trying to keep NHS "running on fumes," departing BMA chair warns. PMID- 28652262 TI - Identification and Metabolite Profiling of Chemical Activators of Lipid Accumulation in Green Algae. AB - Microalgae are proposed as feedstock organisms useful for producing biofuels and coproducts. However, several limitations must be overcome before algae-based production is economically feasible. Among these is the ability to induce lipid accumulation and storage without affecting biomass yield. To overcome this barrier, a chemical genetics approach was employed in which 43,783 compounds were screened against Chlamydomonas reinhardtii, and 243 compounds were identified that increase triacylglyceride (TAG) accumulation without terminating growth. Identified compounds were classified by structural similarity, and 15 were selected for secondary analyses addressing impacts on growth fitness, photosynthetic pigments, and total cellular protein and starch concentrations. TAG accumulation was verified using gas chromatography-mass spectrometry quantification of total fatty acids, and targeted TAG and galactolipid measurements were performed using liquid chromatography-multiple reaction monitoring/mass spectrometry. These results demonstrated that TAG accumulation does not necessarily proceed at the expense of galactolipid. Untargeted metabolite profiling provided important insights into pathway shifts due to five different compound treatments and verified the anabolic state of the cells with regard to the oxidative pentose phosphate pathway, Calvin cycle, tricarboxylic acid cycle, and amino acid biosynthetic pathways. Metabolite patterns were distinct from nitrogen starvation and other abiotic stresses commonly used to induce oil accumulation in algae. The efficacy of these compounds also was demonstrated in three other algal species. These lipid-inducing compounds offer a valuable set of tools for delving into the biochemical mechanisms of lipid accumulation in algae and a direct means to improve algal oil content independent of the severe growth limitations associated with nutrient deprivation. PMID- 28652263 TI - Ripening Transcriptomic Program in Red and White Grapevine Varieties Correlates with Berry Skin Anthocyanin Accumulation. AB - Grapevine (Vitis vinifera) berry development involves a succession of physiological and biochemical changes reflecting the transcriptional modulation of thousands of genes. Although recent studies have investigated the dynamic transcriptome during berry development, most have focused on a single grapevine variety, so there is a lack of comparative data representing different cultivars. Here, we report, to our knowledge, the first genome-wide transcriptional analysis of 120 RNA samples corresponding to 10 Italian grapevine varieties collected at four growth stages. The 10 varieties, representing five red-skinned and five white-skinned berries, were all cultivated in the same experimental vineyard to reduce environmental variability. The comparison of transcriptional changes during berry formation and ripening allowed us to determine the transcriptomic traits common to all varieties, thus defining the core transcriptome of berry development, as well as the transcriptional dynamics underlying differences between red and white berry varieties. A greater variation among the red cultivars than between red and white cultivars at the transcriptome level was revealed, suggesting that anthocyanin accumulation during berry maturation has a direct impact on the transcriptomic regulation of multiple biological processes. The expression of genes related to phenylpropanoid/flavonoid biosynthesis clearly distinguished the behavior of red and white berry genotypes during ripening but also reflected the differential accumulation of anthocyanins in the red berries, indicating some form of cross talk between the activation of stilbene biosynthesis and the accumulation of anthocyanins in ripening berries. PMID- 28652265 TI - A Massively Parallel Fluorescence Assay to Characterize the Effects of Synonymous Mutations on TP53 Expression. AB - Although synonymous mutations can affect gene expression, they have generally not been considered in genomic studies that focus on mutations that increase the risk of cancer. However, mounting evidence implicates some synonymous mutations as driver mutations in cancer. Here, a massively parallel assay, based on cell sorting of a reporter containing a segment of p53 fused to GFP, was used to measure the effects of nearly all synonymous mutations in exon 6 of TP53 In this reporter context, several mutations within the exon caused strong expression changes including mutations that may cause potential gain or loss of function. Further analysis indicates that these effects are largely attributed to errors in splicing, including exon skipping, intron inclusion, and exon truncation, resulting from mutations both at exon-intron junctions and within the body of the exon. These mutations are found at extremely low frequencies in healthy populations and are enriched a few-fold in cancer genomes, suggesting that some of them may be driver mutations in TP53 This assay provides a general framework to identify previously unknown detrimental synonymous mutations in cancer genes.Implications: Using a massively parallel assay, this study demonstrates that synonymous mutations in the TP53 gene affect protein expression, largely through their impact on splicing.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/10/1301/F1.large.jpg Mol Cancer Res; 15(10); 1301-7. (c)2017 AACR. PMID- 28652264 TI - Analysis of the ZAR1 Immune Complex Reveals Determinants for Immunity and Molecular Interactions. AB - Plants depend on innate immunity to prevent disease. Plant pathogenic bacteria, like Pseudomonas syringae and Xanthomonas campestris, use the type III secretion system as a molecular syringe to inject type III secreted effector (T3SE) proteins in plants. The primary function of most T3SEs is to suppress immunity; however, the plant can evolve nucleotide-binding domain-leucine-rich repeat domain-containing proteins to recognize specific T3SEs. The AtZAR1 NLR induces strong defense responses against P. syringae and X. campestris The P. syringae T3SE HopZ1a is an acetyltransferase that acetylates the pseudokinase AtZED1 and triggers recognition by AtZAR1. However, little is known about the molecular mechanisms that lead to AtZAR1-induced immunity in response to HopZ1a. We established a transient expression system in Nicotiana benthamiana to study detailed interactions among HopZ1a, AtZED1, and AtZAR1. We show that the AtZAR1 immune pathway is conserved in N. benthamiana and identify AtZAR1 domains, and residues in AtZAR1 and AtZED1, that are important for immunity and protein protein interactions in planta and in yeast (Saccharomyces cerevisiae). We show that the coiled-coil domain of AtZAR1 oligomerizes, and this domain acts as a signal to induce immunity. This detailed analysis of the AtZAR1-AtZED1 protein complex provides a better understanding of the immune signaling hub controlled by AtZAR1. PMID- 28652266 TI - Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation. AB - Long noncoding RNAs play a pivotal role in tumor progression, but their role in cancer cells in the nutrient-starved tumor microenvironment remains unknown. Here, we show that a nutrient starvation-responsive long noncoding RNA, JHDM1D antisense 1 (JHDM1D-AS1), promotes tumorigenesis by regulating angiogenesis in response to nutrient starvation. Expression of JHDM1D-AS1 was increased in cancer cells. In addition, expression of JHDM1D-AS1 was increased in clinical tumor samples compared to that in normal tissue. Stable expression of JHDM1D-AS1 in human pancreatic cancer (PANC-1 and AsPC-1) cells promoted cell growth in vitro Remarkably, these JHDM1D-AS1-expressing cells showed a significant increase in tumor growth in vivo that was associated with increased formation of CD31+ blood vessels and elevated infiltration of CD11b+ macrophage lineage cells into tumor tissues. Genome-wide analysis of tumor xenografts revealed that expression of genes for tumor-derived angiogenic factors such as hHGF and hFGF1 concomitant with host-derived inflammation-responsive genes such as mMmp3, mMmp9, mS100a8, and mS100a9 was increased in tumor xenografts of JHDM1D-AS1-expressing pancreatic cancer cells, leading to a poor prognosis. Our results provide evidence that increased JHDM1D-AS1 expression under nutrient starvation accelerates tumor growth by upregulating angiogenesis, thus laying the foundation for improved therapeutic strategies. PMID- 28652268 TI - Indian government's advice to pregnant women to shun meat and sex criticised by doctors. PMID- 28652269 TI - South American thieves are targeting European hospitals. PMID- 28652270 TI - Neurogenic pulmonary oedema: a rare cause of maternal collapse. AB - Acute pulmonary oedema is a significant cause of morbidity and mortality in pregnant and postpartum women. We present an unusual case of near-fatal acute pulmonary oedema in a pregnant woman, which was attributed to the acute onset of neurogenic pulmonary oedema secondary to epileptic seizure activity. The patient required supportive management in the intensive care setting for a short period and subsequently made complete recovery with regular neurological follow-up arranged for the management of her epilepsy. PMID- 28652267 TI - Mammalian ECD Protein Is a Novel Negative Regulator of the PERK Arm of the Unfolded Protein Response. AB - Mammalian Ecdysoneless (ECD) is a highly conserved ortholog of the DrosophilaEcd gene product whose mutations impair the synthesis of Ecdysone and produce cell autonomous survival defects, but the mechanisms by which ECD functions are largely unknown. Here we present evidence that ECD regulates the endoplasmic reticulum (ER) stress response. ER stress induction led to a reduced ECD protein level, but this effect was not seen in PKR-like ER kinase knockout (PERK-KO) or phosphodeficient eukaryotic translation initiation factor 2alpha (eIF2alpha) mouse embryonic fibroblasts (MEFs); moreover, ECD mRNA levels were increased, suggesting impaired ECD translation as the mechanism for reduced protein levels. ECD colocalizes and coimmunoprecipitates with PERK and GRP78. ECD depletion increased the levels of both phospho-PERK (p-PERK) and p-eIF2alpha, and these effects were enhanced upon ER stress induction. Reciprocally, overexpression of ECD led to marked decreases in p-PERK, p-eIF2alpha, and ATF4 levels but robust increases in GRP78 protein levels. However, GRP78 mRNA levels were unchanged, suggesting a posttranscriptional event. Knockdown of GRP78 reversed the attenuating effect of ECD overexpression on PERK signaling. Significantly, overexpression of ECD provided a survival advantage to cells upon ER stress induction. Taken together, our data demonstrate that ECD promotes survival upon ER stress by increasing GRP78 protein levels to enhance the adaptive folding protein in the ER to attenuate PERK signaling. PMID- 28652271 TI - NHS and police blamed for killing by psychiatric patient on conditional discharge. PMID- 28652274 TI - Correction to: Lifestyle Factors and Early Clinical Outcome in Patients With Acute Stroke: A Population-Based Study. PMID- 28652275 TI - Correction to: Baseline Blood Pressure Effect on the Benefit and Safety of Intra Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). PMID- 28652276 TI - Questions remain over implementing Scottish scheme to curb harmful drinking. PMID- 28652277 TI - BMA annual meeting: Sending mental health patients out of area for treatment is "endemic," says BMA. PMID- 28652278 TI - Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results. AB - BACKGROUND: The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET). PATIENTS AND METHODS: One hundred eight premenopausal endocrine refractory women >=18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) +/- goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) RESULTS: Median PFS for premenopausal women in the palbociclib (n = 72) versus placebo arm (n = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade <=3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed. CONCLUSION: Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+/HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design. IMPLICATIONS FOR PRACTICE: PALOMA-3, the first registrational study to include premenopausal women in a trial investigating a CDK4/6 inhibitor combined with endocrine therapy, has the largest premenopausal cohort reported in an endocrine-resistant setting. In pretreated premenopausal women with hormone receptor-positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormone-releasing hormone [LHRH] agonist) treatment almost doubled median progression-free survival (PFS) and significantly increased the objective response rate versus endocrine monotherapy, achieving results comparable to those reported for chemotherapy without apparently interfering with LHRH agonist-induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrine-resistant disease who could possibly delay chemotherapy. PMID- 28652280 TI - Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated with Programmed Cell Death 1 Inhibitors. AB - BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead to immune-related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with treatment response in non-melanoma malignancies. MATERIALS AND METHODS: We conducted a retrospective study of patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center. Endpoints included overall response rate (ORR), time to next therapy or death (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression models were used to determine the association between irAE incidence and ORR, and Kaplan-Meier curves with log-rank tests and Cox regression models were used for the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016, 160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%) were treated on a clinical trial. Immune-related adverse events were noted in 64 patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable for clinical response, 28 patients (20%) achieved a partial response at first scan. An association between irAEs and ORR was seen in clinical trial patients (p = .007), but not in non-trial patients (p = .13). When controlling for clinical trial participation and cancer type using multivariate analysis, low-grade irAEs had higher ORR (p = .017) and longer TTNTD (p = .008). No association between irAE incidence and OS was seen (p = .827). Immune-related adverse events that required steroid treatment were marginally associated with increased TTNTD (p = .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We demonstrate several positive associations between the development of irAEs and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated whether the development of immune-related adverse events in non-melanoma patients treated with programmed cell death 1 checkpoint inhibitors correlates with improved clinical outcomes. The results indicate that for a subset of patients, in particular those with low-grade immune-related adverse events, immune-related adverse events predicted for an improved response rate and longer time to next therapy or death. PMID- 28652279 TI - Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial. AB - LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naive CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 +/- 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 +/- 23.1, pregabalin group 79.4 +/- 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN. PMID- 28652281 TI - Implementation of a School-Based Educational Program to Increase Breast Cancer Awareness and Promote Intergenerational Transmission of Knowledge in a Rural Mexican Community. AB - BACKGROUND: Rural women have limited access to breast cancer education, which partially contributes to late diagnosis and treatment. In this pilot study, we tested the feasibility of implementing a school-based breast cancer educational program for adolescents in a rural Mexican community. We hypothesized that the adolescents' knowledge on breast cancer would increase as a result of the program, and that there would be intergenerational transmission of that knowledge to their older female relatives. MATERIALS AND METHODS: Female adolescents from a rural middle school received the educational program. The program would be considered feasible and acceptable if more than 75% reported being satisfied with its contents. Changes in knowledge in the students and their relatives were evaluated using baseline and 4 months follow-up questionnaires. RESULTS: One hundred twenty-six students were enrolled. The program was considered acceptable by 96% of the participants. The students' knowledge regarding breast cancer increased significantly from baseline to 4 months follow-up (63% to 82%). One hundred ninety-four female relatives completed the initial knowledge questionnaires. The relatives' knowledge regarding breast cancer showed a significant increase from baseline to 4 months follow-up (55% to 61%). CONCLUSION: Implementing breast cancer educational programs for adolescents in rural communities is feasible and acceptable. The program increased the adolescents' knowledge on breast cancer, and promoted the intergenerational transmission of that knowledge to their female relatives. Intergenerational transmission of knowledge represents a potential method for providing population based health awareness education globally. IMPLICATIONS FOR PRACTICE: In limited resource settings, education is a valuable tool for achieving early detection and downstaging of breast cancer. Unfortunately, rural women lack access to educational opportunities and information about breast cancer, which is a factor contributing to late diagnosis and treatment. In this study, we demonstrated that implementing a school-based breast cancer educational program for female adolescents in a rural Mexican community was feasible, acceptable, and increased their knowledge about breast cancer. Furthermore, the program encouraged the transmission of information to the students' older relatives. Intergenerational transmission of knowledge represents a novel and potentially effective tool in cancer education and promotion. PMID- 28652285 TI - Abstracts from international Emergency Medicine journals. AB - Editor's note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication. PMID- 28652284 TI - Splashed by a clear liquid. PMID- 28652282 TI - Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits. AB - Tissues use feedback circuits in which cells send signals to each other to control their growth and survival. We show that such feedback circuits are inherently unstable to mutants that misread the signal level: Mutants have a growth advantage to take over the tissue, and cannot be eliminated by known cell intrinsic mechanisms. To resolve this, we propose that tissues have biphasic responses in and the signal is toxic at both high and low levels, such as glucotoxicity of beta cells, excitotoxicity in neurons, and toxicity of growth factors to T cells. This gives most of these mutants a frequency-dependent selective disadvantage, which leads to their elimination. However, the biphasic mechanisms create a new unstable fixed point in the feedback circuit beyond which runaway processes can occur, leading to risk of diseases such as diabetes and neurodegenerative disease. Hence, glucotoxicity, which is a dangerous cause of diabetes, may have a protective anti-mutant effect. Biphasic responses in tissues may provide an evolutionary stable strategy that avoids invasion by commonly occurring mutants, but at the same time cause vulnerability to disease. PMID- 28652286 TI - Point of care ultrasound versus CT pulmonary angiogram in suspected pulmonary embolus. AB - A short cut review was carried out to establish whether non-invasive, multi-organ point of care ultrasound could reduce the need for CTPA in adult patients presenting with clinical suspicion of pulmonary embolus. 3 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that multi-organ POCUS shows promise but that more data is needed to make a definitive statement regarding validity in clinical practice. PMID- 28652288 TI - Inability of a negative faecal occult blood test to rule out intussusception in children. AB - A short cut review was carried out to establish whether a negative faecal occult blood test was sufficiently sensitive to rule out a diagnosis of intussusception in children. 5 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that a negative faecal occult blood test cannot reliably rule out the diagnosis of intussusception . PMID- 28652289 TI - Association of high-sensitivity cardiac troponin T with mortality and cardiovascular events in a community-based prospective study in Beijing. AB - OBJECTIVE: The prognostic value of cardiac troponins in apparently healthy populations is not well established. The aim of this study was to investigate the prognostic properties of high-sensitivity cardiac troponin T (hs-cTnT) for long term adverse outcomes. SETTING: A community-dwelling prospective survey of residents from two communities in Beijing. PARTICIPANTS: From September 2007 to January 2009, 1680 participants were initially enrolled. Of these, 1499 (870 females, mean age: 61.4 years) participants completed the survey and were followed up for a median of 4.8 years (IQR: 4.5-5.2). OUTCOME MEASURES: The primary outcome was the occurrence of all-cause mortality and major cardiovascular events. RESULTS: Overall, 820 individuals (54.7%) had detectable hs-cTnT levels. During the follow-up, 52 participants (3.5%) died, 154 (10.3%) had major cardiovascular events and 99 (6.6%) experienced new-onset coronary events. Compared with those with undetectable hs-cTnT levels, participants with hs-cTnT levels in the highest category (>=14 ng/L) had a significantly increased risk for all-cause mortality (adjusted HR (aHR): 2.07, 95% CI 1.05 to 3.01), major cardiovascular events (aHR: 3.27, 95% CI 1.88 to 5.70) and coronary events (aHR: 4.50, 95% CI 2.26 to 9.02) in covariate-adjusted analyses. No differences in stroke incidence were found (aHR: 1.27, 95% CI 0.69 to 2.62). Also, significant associations were presented when hs-cTnT levels were modelled as a continuous variable and when analysing changes in hs-cTnT levels over time with adverse outcomes. The addition of troponin T levels to clinical variables led to significant increases in risk prediction with a marked improvement in the C statistics (p=0.003 or lower). CONCLUSIONS: In this cohort of individuals from a community-based population, cTnT levels measured with a highly sensitive assay were associated with increases in the subsequent risk for all-cause mortality and major cardiovascular events. These results might support screening for at-risk individuals. PMID- 28652290 TI - Imaging pain relief in osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome. AB - INTRODUCTION: Osteoarthritis (OA) pain is a major cause of long-term disability and chronic pain in the adult population. One in five patients does not receive satisfactory pain relief, which reflects the complexity of chronic pain and the current lack of understanding of mechanisms of chronic pain. Recently, duloxetine has demonstrated clinically relevant pain relief, but only in half of treated patients with OA. Here, the aim is to investigate the neural mechanisms of pain relief and neural signatures that may predict treatment response to duloxetine in chronic knee OA pain. METHODS AND ANALYSIS: This is an ongoing single-centre randomised placebo-controlled mechanistic study (2:1 (placebo) allocation), using a multimodal neuroimaging approach, together with psychophysiological (quantitative sensory testing), genetics and questionnaire assessments. Eighty one subjects with chronic knee OA pain are planned to power for between-group comparisons (placebo, duloxetine responder and duloxetine non-responder). Participants have a baseline assessment and, following 6 weeks of duloxetine (30 mg for 2 weeks, then 60 mg for 4 weeks), a follow-up evaluation. Brain imaging is performed at 3T with blood-oxygen-level dependent functional MRI at rest and during pin-prick nociceptive stimulation for main outcome assessment; arterial spin labelling and structural imaging (T1-weighted) for secondary outcome assessment. Questionnaires evaluate pain, negative affect, quality of sleep and cognition. ETHICS AND DISSEMINATION: The study has been approved by the East Midlands, Nottingham and is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. Results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov (NCT02208778).This work was supported by Arthritis Research UK (Grant 18769). PMID- 28652291 TI - Talking about human papillomavirus and cancer: development of consultation guides through lay and professional stakeholder coproduction using qualitative, quantitative and secondary data. AB - BACKGROUND: High-risk human papillomaviruses (HPVs) cause all cervical cancer and the majority of vulvar, vaginal, anal, penile and oropharyngeal cancers. Although HPV is the most common sexually transmitted infection, public awareness of this is poor. In addition, many clinicians lack adequate knowledge or confidence to discuss sexual transmission and related sensitive issues. Complex science needs to be communicated in a clear, digestible, honest and salient way. Therefore, the aim of this study was to coproduce with patients who have cancer appropriate resources to guide these highly sensitive and difficult consultations. METHODS: A matrix of evidence developed from a variety of sources, including a systematic review and telephone interviews with clinicians, supported the production of a draft list of approximately 100 potential educational messages. These were refined in face-to-face patient interviews using card-sorting techniques, and tested in cognitive debrief interviews to produce a a?~fast and frugala?TM knowledge tool. RESULTS: We developed three versions of a consultation guide, each comprising a clinician guidance sheet and patient information leaflet for gynaecological (cervical, vaginal, vulvar), anal or oropharyngeal cancers. That cancer could be caused by a sexually transmitted virus acquired many years previously was surprising to many and shocking to a few patients. However, they found the information clear, helpful and reassuring. Clinicians acknowledged a lack of confidence in explaining HPV, welcomed the clinician guidance sheets and considered printed information for patients particularly useful. CONCLUSION: Because of the a?~shock factora?TM, clinicians will need to approach the discussion of HPV with sensitivity and take individual needs and preferences into account, but we provide a novel, rigorously developed and tested resource which should have broad applicability in the UK National Health Service and other health systems. PMID- 28652292 TI - Assessing the impact of adjusting for maturity in weight status classification in a cross-sectional sample of UK children. AB - OBJECTIVES: To compare the weight categorisation of a cohort of UK children using standard procedures (ie, comparing body mass index (BMI) centiles to age-matched UK reference data) versus an approach adjusted for maturation status (ie, matching relative to biological age). DESIGN: Analysis of data collected from an observational study of UK primary school children. SETTING: Schools in South West England. PARTICIPANTS: Four hundred and seven 9-11 year-old children (98% white British). MAIN OUTCOME MEASURES: Weight status was classified using BMI centiles using (1) sex and chronological age-matched referents and (2) sex and biological age-matched referents (based on % of predicted adult stature) relative to UK 1990 reference growth charts. For both approaches, children were classified as a normal weight if >2nd centile and <85thcentile, overweight if 85th and <95thcentiles, and obese if >=95thcentile. RESULTS: Fifty-one children (12.5%) were overweight, and a further 51 obese (12.5%) according to standard chronological age-matched classifications. Adjustment for maturity resulted in 32% of overweight girls, and 15% of overweight boys being reclassified as a normal weight, and 11% and 8% of obese girls and boys, respectively, being reclassified as overweight. Early maturing children were 4.9 times more likely to be reclassified from overweight to normal weight than 'on-time' maturers (OR 95% CI 1.3 to 19). CONCLUSIONS: Incorporating assessments of maturational status into weight classification resulted in significant changes to the classification of early-maturing adolescents. Further research exploring the implications for objective health risk and well-being is needed. PMID- 28652293 TI - Improving the primary-secondary care interface in Scotland: a qualitative exploration of impact on clinicians of an educational complex intervention. AB - OBJECTIVES: To determine the impact on clinicians and any consequent influence on patient care of taking part in the bespoke interface-focused educational intervention. DESIGN: Qualitative design. SETTING: Primary and secondary care centres in NHS Highland health board area, Scotland. PARTICIPANTS: 33 urban-based clinicians (18 general practitioners and 15 hospital specialists) in NHS Highland, Scotland. INTERVENTION: An interface-focused educational intervention was carried out in primary and secondary care centres in NHS Highland health board area, Scotland. Eligible clinicians were invited to take part in the intervention which involved facilitated small group work, and use of a bespoke educational module. Subsequent one-to-one interviews explored the impact of the intervention. A standard thematic analysis was used, comprising an iterative process based on grounded theory. RESULTS: Key themes that emerged included fresh insights (in relation to those individuals and processes across the interface), adoption of new behaviours (eg, being more empowered to directly contact a colleague, taking steps to reduce the others workload and changes in professional approach) and changes in terms of communication (including a desire to communicate more effectively, with use of different modes and methods). CONCLUSION: The study highlighted key areas that may serve as useful outcomes for a large-scale randomised trial. Addressing issues identified in the study may help to improve interface relationships and benefit patient care. PMID- 28652295 TI - Correction: Oxfordshire Women and Their Children's Health (OxWATCH): protocol for a prospective cohort feasibility study. PMID- 28652294 TI - Internet- and mobile-based aftercare and follow-up for mental disorders: protocol of a systematic review and meta-analysis. AB - INTRODUCTION: Mental disorders are characterised by a high likelihood of symptom recurrence or chronicity. Thus, in the vulnerable post-discharge phase, aftercare and follow-up aim at stabilising treatment effects, promoting functionality and preventing relapse or readmission. Internet- and mobile-based interventions may represent low threshold and effective extensions to aftercare in tertiary prevention of mental disorders. OBJECTIVES: The planned systematic review and meta-analysis aims to synthesise and analyse existing evidence on the effectiveness of psychological internet- and mobile-based aftercare or follow-up in maintaining treatment effects and/or preventing recurrence in adults with mental disorders. METHODS AND ANALYSIS: Electronic databases (PsycInfo, MEDLINE and Cochrane Central Register of Controlled trials) will be searched systematically, complemented by a hand-search of ongoing trials and reference lists of selected studies. Data extraction and evaluation will be conducted by two independent researchersand quality will be assessed with the Cochrane risk of bias tool. Eligibility criteria for selecting studies will be: randomised controlled trials of internet-based and mobile-based, psychological aftercare and follow-up for the tertiary prevention of mental disorders in an adult population. Primary outcome will be symptom severity. Secondary outcomes will be symptom or disorder recurrence rate, rehospitalisation rate, functionality, quality of life or adherence to primary treatment. Further data items to be extracted will be: study design, intervention and technical characteristics, type of mental disorder or clinical symptom to be treated, target population items, setting, treatment engagement and assessment of additional outcome variables. Meta-analytic pooling will be conducted when data of included studies are comparable in terms of study design, intervention type, endpoints, assessments and target mental disorder. Cumulative evidence will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation framework. ETHICS AND DISSEMINATION: Ethics approval is not required. Results from this review will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: PROSPERO CRD42017055289. PMID- 28652296 TI - Correction: Hyaluronic Acid Binding Sperm Selection for assisted reproduction treatment (HABSelect): study protocol for a multicentre randomised controlled trial. PMID- 28652297 TI - Correction: The impact of demand management strategies on parents' decision making for out-of-hours primary care: Findings from a survey in the Netherlands. PMID- 28652298 TI - A patient-specific intracranial aneurysm model with endothelial lining: a novel in vitro approach to bridge the gap between biology and flow dynamics. AB - OBJECTIVES: To develop an in vitro model for studying the biological effect of complex-flow stress on endothelial cells in three-dimensional (3D) patient specific vascular geometry. MATERIALS AND METHODS: A vessel replica was fabricated with polydimethylsiloxanes using 3D printing technology from vascular image data acquired by rotational angiography. The vascular model was coated with fibronectin and immersed in a tube filled with a cell suspension of endothelium, and then cultured while being slowly rotated in three dimensions. Culture medium with viscosity was perfused in the circulation with the endothelialized vascular model. A computational fluid dynamics (CFD) study was conducted using perfusion conditions used in the flow experiment. The morphology of endothelial cells was observed under a confocal microscope. RESULTS: The CFD study showed low wall shear stress and circulating flow in the apex of the basilar tip aneurysm, with linear flow in the parent artery. Confocal imaging demonstrated that the inner surface of the vascular model was evenly covered with monolayer endothelial cells. After 24 h of flow circulation, endothelial cells in the parent artery exhibited a spindle shape and aligned with the flow direction. In contrast, endothelial cells in the aneurysmal apex were irregular in shape and size. CONCLUSIONS: A geometrically realistic intracranial aneurysm model with live endothelial lining was successfully developed. This in vitro model enables a new research approach combining study of the biological impact of complex flow on endothelial cells with CFD analysis and patient information, including the presence of aneurysmal growth or rupture. PMID- 28652299 TI - Timing of complications during and after elective endovascular intracranial aneurysm coiling. AB - OBJECTIVE: To determine the time to complications during and after elective endovascular intracranial aneurysm coiling. METHODS: A retrospective chart review of patients undergoing elective endovascular aneurysm coiling between March 2006 and October 2013 in one large Eastern Canadian Neurointerventional Service was performed. Data regarding the incidence, time and type of complication related to the endovascular coiling procedure and clinical outcome at last follow-up were collected. Patient, aneurysm and operation factors were analyzed to determine any factors associated with complication occurrence. RESULTS: Of the 150 patient procedures analyzed, 16% experienced a coiling-related complication, although none resulted in death. 6.7% of patients experienced an intraoperative complication, of which thromboembolism was the most common type. The majority of the complications were detected in the first 6 hours after reversal of anesthesia, and a small proportion the next morning prior to discharge. Only 3.3% of patients had persistent neurological deficit after the procedure on last follow-up. Duration of the operation demonstrated a strong association with the occurrence of procedure-related complications. CONCLUSION: This study demonstrates that coiling-related complications of elective endovascular coiling tend to occur either intraoperatively or are detected shortly after reversal of anesthesia. Further investigation with a larger cohort may help to guide important preoperative communication with patients and identify a select group of patients who may not necessarily require prolonged admission to hospital for observation. PMID- 28652300 TI - The proline variant of the W[F/L/M][T/S]R c-di-GMP binding motif suppresses dependence on signal-association for regulator function. AB - Vibrio vulnificus is an estuarine bacteria and potent opportunistic human pathogen. It enters the food-chain by asymptomatically colonizing a variety of marine organisms, most notably oysters. Expression of the brp-encoded extracellular polysaccharide, which enhances cell-surface adherence, is regulated by c-di-GMP and the activator BrpT. The V. cholerae and V. parahaemolyticus homologs, VpsT and CpsQ, directly bind c-di-GMP via a novel W[F/L/M][T/S]R motif and c-di-GMP binding is absolutely required for activity. Notably, BrpT belongs to a distinct subclass of VpsT-like regulators that harbor a proline in the third position of the c-di-GMP binding motif (WLPR) and the impact of this change on activity is unknown. We show that the brp locus is organized as two linked operons with BrpT specifically binding to promoters upstream of brpA and brpH Expression data and structural modelling suggested that BrpT might be less dependent on c-di-GMP binding for activity than VpsT or CpsQ. We show that the affinity of BrpT for c-di-GMP is low and that signal binding is not a requisite for BrpT function. Furthermore, a BrpT mutant engineered to carry a canonical WLTR motif (BrpTP124T) bound c-di-GMP with high affinity and its activity was now c-di-GMP dependent. Conversely, introduction of the WLPR motif into VpsT suppressed its dependence on c-di-GMP for activity. This is the first demonstration of reduced dependence on signal-association for regulator function within this motif family. Thus, BrpT defines a new class of VpsT-like transcriptional regulators and the WLPR motif variant may similarly liberate the activity of other subclass members.Importance A Vibrio genome may encode nearly 100 proteins that make, break and bind c-di-GMP, underscoring its central role in the ecology of these bacteria. The activity of the biofilm regulators VpsT of V. cholerae and CpsQ of V. parahaemolyticus is regulated by the direct binding of c di-GMP via a novel W[F/L/M][T/S]R motif. The V. vulnificus homolog, BrpT, bears an unusual WLPR variant and remains active at low intracellular c-di-GMP levels. This suggests that the WLPR motif may also liberate the activity of other members of this subclass. A single point mutation at the 3rd position of the motif was sufficient to moderate dependence on c-di-GMP binding for activator function, highlighting the simplicity with which complex bacterial signaling networks can be rewired. PMID- 28652301 TI - Stand-Alone EAL Domain Proteins Form a Distinct Subclass of EAL Proteins Involved in Regulation of Cell Motility and Biofilm Formation in Enterobacteria. AB - The second messenger cyclic dimeric GMP (c-di-GMP) is almost ubiquitous among bacteria as are the c-di-GMP turnover proteins, which mediate the transition between motility and sessility. EAL domain proteins have been characterized as c di-GMP-specific phosphodiesterases. While most EAL domain proteins contain additional, usually N-terminal, domains, there is a distinct family of proteins with stand-alone EAL domains, exemplified by Salmonella enterica serovar Typhimurium proteins STM3611 (YhjH/PdeH), a c-di-GMP-specific phosphodiesterase, and the enzymatically inactive STM1344 (YdiV/CdgR) and STM1697, which regulate bacterial motility through interaction with the flagellar master regulator, FlhDC. We have analyzed the phylogenetic distribution of EAL-only proteins and their potential functions. Genes encoding EAL-only proteins were found in various bacterial phyla, although most of them were seen in proteobacteria, particularly enterobacteria. Based on the conservation of the active site residues, nearly all stand-alone EAL domains encoded by genomes from phyla other than proteobacteria appear to represent functional phosphodiesterases. Within enterobacteria, EAL only proteins were found to cluster either with YhjH or with one of the subfamilies of YdiV-related proteins. EAL-only proteins from Shigella flexneri, Klebsiella pneumoniae, and Yersinia enterocolitica were tested for their ability to regulate swimming and swarming motility and formation of the red, dry, and rough (rdar) biofilm morphotype. In these tests, YhjH-related proteins S4210, KPN_01159, KPN_03274, and YE4063 displayed properties typical of enzymatically active phosphodiesterases, whereas S1641 and YE1324 behaved like members of the YdiV/STM1697 subfamily, with Yersinia enterocolitica protein YE1324 shown to downregulate motility in its native host. Of two closely related EAL-only proteins, YE2225 is an active phosphodiesterase, while YE1324 appears to interact with FlhD. These results suggest that in FlhDC-harboring beta- and gammaproteobacteria, some EAL-only proteins evolved to become catalytically inactive and regulate motility and biofilm formation by interacting with FlhDC.IMPORTANCE The EAL domain superfamily consists mainly of proteins with cyclic dimeric GMP-specific phosphodiesterase activity, but individual domains have been classified in three classes according to their functions and conserved amino acid signatures. Proteins that consist solely of stand-alone EAL domains cannot rely on other domains to form catalytically active dimers, and most of them fall into one of two distinct classes: catalytically active phosphodiesterases with well-conserved residues of the active site and the dimerization loop, and catalytically inactive YdiV/CdgR-like proteins that regulate bacterial motility by binding to the flagellar master regulator, FlhDC, and are found primarily in enterobacteria. The presence of apparently inactive EAL-only proteins in the bacteria that do not express FlhD suggests the existence of additional EAL interaction partners. PMID- 28652302 TI - Metabolism Dealing with Thermal Degradation of NAD+ in the Hyperthermophilic Archaeon Thermococcus kodakarensis. AB - NAD+ is an important cofactor for enzymatic oxidation reactions in all living organisms, including (hyper)thermophiles. However, NAD+ is susceptible to thermal degradation at high temperatures. It can thus be expected that (hyper)thermophiles harbor mechanisms that maintain in vivo NAD+ concentrations and possibly remove and/or reuse undesirable degradation products of NAD+ Here we confirmed that at 85 degrees C, thermal degradation of NAD+ results mostly in the generation of nicotinamide and ADP-ribose, the latter known to display toxicity by spontaneously linking to proteins. The hyperthermophilic archaeon Thermococcus kodakarensis possesses a putative ADP-ribose pyrophosphatase (ADPR-PPase) encoded by the TK2284 gene. ADPR-PPase hydrolyzes ADP-ribose to ribose 5-phosphate (R5P) and AMP. The purified recombinant TK2284 protein exhibited activity toward ADP ribose as well as ADP-glucose. Kinetic analyses revealed a much higher catalytic efficiency toward ADP-ribose, suggesting that ADP-ribose was the physiological substrate. To gain insight into the physiological function of TK2284, a TK2284 gene disruption strain was constructed and examined. Incubation of NAD+ in the cell extract of the mutant strain at 85 degrees C resulted in higher ADP-ribose accumulation and lower AMP production compared with those in experiments with the host strain cell extract. The mutant strain also exhibited lower cell yield and specific growth rates in a synthetic amino acid medium compared with those of the host strain. The results obtained here suggest that the ADPR-PPase in T. kodakarensis is responsible for the cleavage of ADP-ribose to R5P and AMP, providing a means to utilize the otherwise dead-end product of NAD+ breakdown.IMPORTANCE Hyperthermophilic microorganisms living under high temperature conditions should have mechanisms that deal with the degradation of thermolabile molecules. NAD+ is an important cofactor for enzymatic oxidation reactions and is susceptible to thermal degradation to ADP-ribose and nicotinamide. Here we show that an ADP-ribose pyrophosphatase homolog from the hyperthermophilic archaeon Thermococcus kodakarensis converts the detrimental ADP ribose to ribose 5-phosphate and AMP, compounds that can be directed to central carbon metabolism. This physiological role for ADP-ribose pyrophosphatases might be universal in hyperthermophiles, as their homologs are widely distributed among both hyperthermophilic bacteria and archaea. PMID- 28652305 TI - Regulation of brain insulin signaling: A new function for tau. AB - In this issue of JEM, Marciniak et al. (https://doi.org/10.1084/jem.20161731) identify a putative novel function of tau protein as a regulator of insulin signaling in the brain. They find that tau deletion impairs hippocampal response to insulin through IRS-1 and PTEN dysregulation and suggest that, in Alzheimer's disease, impairment of brain insulin signaling might occur via tau loss of function. PMID- 28652303 TI - Tau deletion promotes brain insulin resistance. AB - The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients. PMID- 28652304 TI - Thymic progenitors of TCRalphabeta+ CD8alphaalpha intestinal intraepithelial lymphocytes require RasGRP1 for development. AB - Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed agonist selection. The signaling relationships that underlie these three fates are unknown. RasGRP1 is a Ras activator required to transmit weak TCR signals leading to positive selection. Here, we report that, despite being dispensable for thymocyte clonal deletion, RasGRP1 is critical for agonist selection of TCRalphabeta+CD8alphaalpha intraepithelial lymphocyte (IEL) progenitors (IELps), even though both outcomes require strong TCR signaling. Bim deficiency rescued IELp development in RasGRP1-/- mice, suggesting that RasGRP1 functions to promote survival during IELp generation. Additionally, expression of CD122 and the adhesion molecules alpha4beta7 and CD103 define distinct IELp subsets with differing abilities to generate TCRalphabeta+CD8alphaalpha IEL in vivo. These findings demonstrate that RasGRP1-dependent signaling underpins thymic selection processes induced by both weak and strong TCR signals and is differentially required for fate decisions derived from a strong TCR stimulus. PMID- 28652306 TI - Hepcidin-(In)dependent Mechanisms of Iron Metabolism Regulation during Infection by Listeria and Salmonella. AB - During bacterial infection, the pathogenic agent and the host battle for iron, due to its importance for fundamental cellular processes. However, iron redistribution and sequestration during infection can culminate in anemia. Although hepcidin has been recognized as the key regulator of iron metabolism, in some infections its levels remain unaffected, suggesting the involvement of other players in iron metabolism deregulation. In this work, we use a mouse model to elucidate the main cellular and molecular mechanisms that lead to iron redistribution during infection with two different pathogens: Listeria monocytogenes and Salmonella enterica serovar Typhimurium. Both infections clearly impacted iron metabolism, causing iron redistribution, decreasing serum iron levels, decreasing the saturation of transferrin, and increasing iron accumulation in the liver. Both infections were accompanied by the release of proinflammatory cytokines. However, when analyzing iron-related gene expression in the liver, we observed that hepcidin was induced by S Typhimurium but not by L. monocytogenes In the latter model, the downregulation of hepatic ferroportin mRNA and protein levels suggested that ferroportin plays a major role in iron redistribution. On the other hand, S Typhimurium infection induced the expression of hepcidin mRNA, and we show here, for the first time in vivo, that this induction is Toll-like receptor 4 (TLR4) dependent. In this work, we compare several aspects of iron metabolism alterations induced by two different pathogens and suggest that hepcidin-(in)dependent mechanisms contribute to iron redistribution upon infection. PMID- 28652308 TI - B10 Cells Alleviate Periodontal Bone Loss in Experimental Periodontitis. AB - B10 cells can regulate inflammatory responses in innate immunity. Toll-like receptors (TLRs) play an important role in B cell-mediated immune responses in periodontal disease. This study aimed to determine the effects of TLR-activated B10 cells on periodontal bone loss in experimental periodontitis. Spleen B cells isolated from C57BL/6J mice were cultured with Porphyromonas gingivalis lipopolysaccharide (LPS) and cytosine-phospho-guanine (CpG) oligodeoxynucleotides for 48 h. B10-enriched CD1dhi CD5+ B cells were sorted by flow cytometry and were adoptively transferred to recipient mice through tail vein injection. At the same time, P. gingivalis-soaked ligatures were placed subgingivally around the maxillary second molars and remained there for 2 weeks before the mice were euthanized. Interleukin-10 (IL-10) production and the percentage of CD1dhi CD5+ B cells were significantly increased with treatment with P. gingivalis LPS plus CpG compared to those in mice treated with P. gingivalis LPS or CpG alone. Mice with CD1dhi CD5+ B cell transfer demonstrated reduced periodontal bone loss compared to the no-transfer group and the group with CD1dlo CD5- B cell transfer. Gingival IL-10 mRNA expression was significantly increased, whereas expressions of receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG), tumor necrosis factor alpha (TNF-alpha), and IL-1beta were significantly inhibited in the CD1dhi CD5+ B cell transfer group. The percentages of CD19+ IL-10+ cells, CD19+ CD1dhi CD5+ cells, and P. gingivalis-binding CD19+ cells were significantly higher in recovered mononuclear cells from gingival tissues of the CD1dhi CD5+ B cell transfer group than in tissues of the no-transfer group and the CD1dlo CD5- B cell transfer group. This study indicated that the adoptive transfer of B10 cells alleviated periodontal inflammation and bone loss in experimental periodontitis in mice. PMID- 28652307 TI - Both MisR (CpxR) and MisS (CpxA) Are Required for Neisseria gonorrhoeae Infection in a Murine Model of Lower Genital Tract Infection. AB - During infection, Neisseria gonorrhoeae senses and responds to stress; such responses may be modulated by MisRS (NGO0177 and NGO0176), a two-component system that is a homolog of CpxRA. In Escherichia coli, CpxRA senses and responds to envelope stress; CpxA is a sensor kinase/phosphatase for CpxR, a response regulator. When a cpxA mutant is grown in medium containing glucose, CpxR is phosphorylated by acetyl phosphate but cannot be dephosphorylated, resulting in constitutive activation. Kandler and coworkers (J. L. Kandler, C. L. Holley, J. L. Reimche, V. Dhulipala, J. T. Balthazar, A. Muszynski, R. W. Carlson, and W. M. Shafer, Antimicrob Agents Chemother 60:4690-4700, 2016, https://doi.org/10.1128/AAC.00823-16) showed that MisR (CpxR) is required for the maintenance of membrane integrity and resistance to antimicrobial peptides, suggesting a role in gonococcal survival in vivo Here, we evaluated the contributions of MisR and MisS (CpxA) to gonococcal infection in a murine model of cervicovaginal colonization and identified MisR-regulated genes using RNA sequencing (RNA-Seq). The deletion of misR or misS severely reduced the capacity of N. gonorrhoeae to colonize mice or maintain infection over a 7-day period and reduced microbial fitness after exposure to heat shock. Compared to the wild type (WT), the inactivation of misR identified 157 differentially regulated genes, most of which encoded putative envelope proteins. The inactivation of misS identified 17 differentially regulated genes compared to the WT and 139 differentially regulated genes compared to the misR mutant, 111 of which overlapped those differentially expressed in the comparison of the WT versus the misR mutant. These data indicate that an intact MisRS system is required for gonococcal infection of mice. Provided the MisR is constitutively phosphorylated in the misS mutant, the data suggest that controlled but not constitutive activation is required for gonococcal infection in mice. PMID- 28652309 TI - Host and Pathogen Copper-Transporting P-Type ATPases Function Antagonistically during Salmonella Infection. AB - Copper is an essential yet potentially toxic trace element that is required by all aerobic organisms. A key regulator of copper homeostasis in mammalian cells is the copper-transporting P-type ATPase ATP7A, which mediates copper transport from the cytoplasm into the secretory pathway, as well as copper export across the plasma membrane. Previous studies have shown that ATP7A-dependent copper transport is required for killing phagocytosed Escherichia coli in a cultured macrophage cell line. In this investigation, we expanded on these studies by generating Atp7aLysMcre mice, in which the Atp7a gene was specifically deleted in cells of the myeloid lineage, including macrophages. Primary macrophages isolated from Atp7aLysMcre mice exhibit decreased copper transport into phagosomal compartments and a reduced ability to kill Salmonella enterica serovar Typhimurium compared to that of macrophages isolated from wild-type mice. The Atp7aLysMcre mice were also more susceptible to systemic infection by S Typhimurium than wild-type mice. Deletion of the S Typhimurium copper exporters, CopA and GolT, was found to decrease infection in wild-type mice but not in the Atp7aLysMcre mice. These studies suggest that ATP7A-dependent copper transport into the phagosome mediates host defense against S Typhimurium, which is counteracted by copper export from the bacteria via CopA and GolT. These findings reveal unique and opposing functions for copper transporters of the host and pathogen during infection. PMID- 28652310 TI - Bacterial Nucleotidyl Cyclase Inhibits the Host Innate Immune Response by Suppressing TAK1 Activation. AB - Exoenzyme Y (ExoY) is a type III secretion system effector found in 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY is a soluble nucleotidyl cyclase that increases the cytoplasmic levels of nucleoside 3',5' cyclic monophosphates (cNMPs) to mediate endothelial Tau phosphorylation and permeability, its functional role in the innate immune response is still poorly understood. Transforming growth factor beta-activated kinase 1 (TAK1) is critical for mediating Toll-like receptor (TLR) signaling and subsequent activation of NF kappaB and AP-1, which are transcriptional activators of innate immunity. Here, we report that ExoY inhibits proinflammatory cytokine production through suppressing the activation of TAK1 as well as downstream NF-kappaB and mitogen activated protein (MAP) kinases. Mice infected with ExoY-deficient P. aeruginosa had higher levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6), more neutrophil recruitment, and a lower bacterial load in lung tissue than mice infected with wild-type P. aeruginosa Taken together, our findings identify a previously unknown mechanism by which P. aeruginosa ExoY inhibits the host innate immune response. PMID- 28652311 TI - A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. AB - The signaling molecule cyclic diguanylate (c-di-GMP) mediates physiological adaptation to extracellular stimuli in a wide range of bacteria. The complex metabolic pathways governing c-di-GMP synthesis and degradation are highly regulated, but the specific cues that impact c-di-GMP signaling are largely unknown. In the intestinal pathogen Clostridium difficile, c-di-GMP inhibits flagellar motility and toxin production and promotes pilus-dependent biofilm formation, but no specific biological functions have been ascribed to any of the individual c-di-GMP synthases or phosphodiesterases (PDEs). Here, we report the functional and biochemical characterization of a c-di-GMP PDE, PdcA, 1 of 37 confirmed or putative c-di-GMP metabolism proteins in C. difficile 630. Our studies reveal that pdcA transcription is controlled by the nutrient-regulated transcriptional regulator CodY and accordingly increases during stationary phase. In addition, PdcA PDE activity is allosterically regulated by GTP, further linking c-di-GMP levels to nutrient availability. Mutation of pdcA increased biofilm formation and reduced toxin biosynthesis without affecting swimming motility or global intracellular c-di-GMP. Analysis of the transcriptional response to pdcA mutation indicates that PdcA-dependent phenotypes manifest during stationary phase, consistent with regulation by CodY. These results demonstrate that inactivation of this single PDE gene is sufficient to impact multiple c-di-GMP-dependent phenotypes, including the production of major virulence factors, and suggest a link between c-di-GMP signaling and nutrient availability. PMID- 28652312 TI - NanR Regulates nanI Sialidase Expression by Clostridium perfringens F4969, a Human Enteropathogenic Strain. AB - Clostridium perfringens can produce up to three different sialidases, including NanI, its major exosialidase. The current study first showed that human intestinal strains of C. perfringens can grow by utilizing either glucose or sialic acids, such as N-acetylneuraminic acid (Neu5Ac), which are the end products of sialidase activity. For the human enteropathogenic strain F4969, it was then determined that culture supernatant sialidase activity and expression of exosialidase genes, particularly nanI, are influenced by the presence of Neu5Ac or glucose. Low Neu5Ac concentrations increased culture supernatant sialidase activity, largely by stimulating nanI transcription. In contrast, low glucose concentrations did not affect exosialidase activity or nanI transcription. However, either high Neu5Ac or high glucose concentrations repressed F4969 culture supernatant sialidase activity and nanI transcription levels. Furthermore, high glucose levels repressed F4969 culture sialidase activity and nanI expression even in the presence of low Neu5AC concentrations. To begin to evaluate the mechanistic basis for nanI expression, a nanR null mutant was used to demonstrate that NanR, a member of the RpiR family of regulatory proteins, decreases exosialidase activity and nanI transcription in the absence of sialic acid. The ability of C. perfringens to regulate its exosialidase activity, largely by controlling nanI expression, may affect intestinal pathogenesis by affecting the production of NanI, which may affect C. perfringens growth, adhesion, and toxin binding in vivo. PMID- 28652314 TI - Psychological distress and mortality in stable coronary heart disease: persistence of high distress means increased risk. PMID- 28652313 TI - Identification and Characterization of Two Klebsiella pneumoniae lpxL Lipid A Late Acyltransferases and Their Role in Virulence. AB - Klebsiella pneumoniae causes a wide range of infections, from urinary tract infections to pneumonia. The lipopolysaccharide is a virulence factor of this pathogen, although there are gaps in our understanding of its biosynthesis. Here we report on the characterization of K. pneumoniaelpxL, which encodes one of the enzymes responsible for the late secondary acylation of immature lipid A molecules. Analysis of the available K. pneumoniae genomes revealed that this pathogen's genome encodes two orthologues of Escherichia coli LpxL. Using genetic methods and mass spectrometry, we demonstrate that LpxL1 catalyzes the addition of laureate and LpxL2 catalyzes the addition of myristate. Both enzymes acylated E. coli lipid A, whereas only LpxL2 mediated K. pneumoniae lipid A acylation. We show that LpxL1 is negatively regulated by the two-component system PhoPQ. The lipid A produced by the lpxL2 mutant lacked the 2-hydroxymyristate, palmitate, and 4-aminoarabinose decorations found in the lipid A synthesized by the wild type. The lack of 2-hydroxymyristate was expected since LpxO modifies the myristate transferred by LpxL2 to the lipid A. The absence of the other two decorations is most likely caused by the downregulation of phoPQ and pmrAB expression. LpxL2-dependent lipid A acylation protects Klebsiella from polymyxins, mediates resistance to phagocytosis, limits the activation of inflammatory responses by macrophages, and is required for pathogen survival in the wax moth (Galleria mellonella). Our findings indicate that the LpxL2 contribution to virulence is dependent on LpxO-mediated hydroxylation of the LpxL2-transferred myristate. Our studies suggest that LpxL2 might be a candidate target in the development of anti-K. pneumoniae drugs. PMID- 28652315 TI - Persistent psychological distress and mortality in patients with stable coronary artery disease. AB - BACKGROUND: A single assessment of psychological distress, which includes depression and anxiety, has been associated with increased mortality in patients with coronary heart disease, but the prognostic importance of persistence of distress symptoms is less certain. AIM: To determine whether intermittent and/or persistent psychological distress is associated with long-term cardiovascular (CV) and total mortality in patients with stable coronary artery disease. METHODS: 950 participants in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial completed at least four General Health Questionnaires (GHQ-30) at baseline and after 1/2, 1, 2 and 4 years. In a landmark analysis from 4 years, Cox proportional hazards models evaluated the risk of CV and total mortality by increasing levels of psychological distress: never distressed, sometimes any severity (GHQ score >5), persistent mild (GHQ score >5 on three or more occasions) and persistent moderate distress (GHQ score >10) on three or more occasions, over a median of 12.1 (IQR 8.6-12.5) years. The models were both unadjusted and adjusted for known baseline risk factors. RESULTS: Persistent moderate or greater psychological stress was reported on three or more assessments by 35 (3.7%) subjects. These patients had a higher risk of both CV death (adjusted HR 3.94, 95% CI 2.05 to 7.56, p<0.001) and all-cause mortality (adjusted HR 2.85, 95% CI 1.74 to 4.66, p<0.001) compared with patients with no distress. In contrast, patients who reported persistent mild distress (n=73, 7.7%) on three or more visits, and those who met criteria for distress on only one or two assessments (n=255, 26.8%), did not have an increased risk of CV or all-cause mortality during follow-up. CONCLUSION: In patients with stable coronary artery disease, persistent psychological distress of at least moderate severity is associated with a substantial increase in CV and all-cause mortality. PMID- 28652316 TI - The modified 'Jo'burg' technique for securing intercostal chest drains. AB - Insertion of an intercostal chest drain (ICD) is a common intervention in the management of either blunt or penetrating thoracic trauma. It is frequently performed by junior medical personnel as an emergency procedure during the initial resuscitation period and often within a stressful environment. Approximately one-fifth of all ICD insertions are associated with complications. In a retrospective review of over 1000 ICD insertions, 7% of the complications observed were due to inadequate fixation, resulting in dislodgement. The risk of dislodgement is greatest during transit or transfer of a casualty. In a military setting, this may involve movement of a casualty in a non-permissive environment and includes transfer on and off rotary wing, fixed wing, road vehicle and maritime transport platforms as well as between stretchers and hospital beds. While ICD insertion follows a standard technique in accordance with the Advanced Trauma Life Support guidelines, the method of securing ICDs has not been standardised across the Defence Medical Services (DMS). The aim of this paper is to first propose a modified version of a tried and tested technique of securing ICDs with alternative steps described for medical staff unfamiliar with surgical knot tying by hand. Second, we present the results from a pilot validation study of this technique when introduced to candidates on a trauma surgical skills course. We describe and demonstrate a robust, easily teachable and reproducible technique for securing ICDs. We would advocate the use of this technique among both surgically and non-surgically trained medical personnel and suggest that this should become the standardised technique for securing ICDs across the DMS. This could be easily implemented by introducing this technique into the various military trauma courses, for example the Military Operational Surgical Training, Medical Emergency Response Team and Critical Care Air Support Team courses. PMID- 28652317 TI - The protein phosphatase 4 complex promotes the Notch pathway and wingless transcription. AB - The Wnt/Wingless (Wg) pathway controls cell fate specification, tissue differentiation and organ development across organisms. Using an in vivo RNAi screen to identify novel kinase and phosphatase regulators of the Wg pathway, we identified subunits of the serine threonine phosphatase Protein Phosphatase 4 (PP4). Knockdown of the catalytic and regulatory subunits of PP4 cause reductions in the Wg pathway targets Senseless and Distal-less. We find that PP4 regulates the Wg pathway by controlling Notch-driven wg transcription. Genetic interaction experiments identified that PP4 likely promotes Notch signaling within the nucleus of the Notch-receiving cell. Although the PP4 complex is implicated in various cellular processes, its role in the regulation of Wg and Notch pathways was previously uncharacterized. Our study identifies a novel role of PP4 in regulating Notch pathway, resulting in aberrations in Notch-mediated transcriptional regulation of the Wingless ligand. Furthermore, we show that PP4 regulates proliferation independent of its interaction with Notch. PMID- 28652319 TI - Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia. AB - A 70-year-old patient with known hereditary haemorrhagictelangiectasia (HHT) was seen regularly in our outpatient clinic. He underwent multiple therapeutical interventions, including both surgical and medical, for the treatment of recurrent epistaxis without sustained success. Due to a concurrent diagnosis of idiopathic pulmonary fibrosis, treatment with the tyrosine kinase inhibitor nintedanib was initiated, after which point the patient reported a dramatic and unanticipated improvement in his epistaxis and skin telangiectasia. On the basis of this case report, we propose that nintedanib may be a potential treatment option for refractory epistaxis in HHT. PMID- 28652318 TI - A framework for quantification and physical modeling of cell mixing applied to oscillator synchronization in vertebrate somitogenesis. AB - In development and disease, cells move as they exchange signals. One example is found in vertebrate development, during which the timing of segment formation is set by a 'segmentation clock', in which oscillating gene expression is synchronized across a population of cells by Delta-Notch signaling. Delta-Notch signaling requires local cell-cell contact, but in the zebrafish embryonic tailbud, oscillating cells move rapidly, exchanging neighbors. Previous theoretical studies proposed that this relative movement or cell mixing might alter signaling and thereby enhance synchronization. However, it remains unclear whether the mixing timescale in the tissue is in the right range for this effect, because a framework to reliably measure the mixing timescale and compare it with signaling timescale is lacking. Here, we develop such a framework using a quantitative description of cell mixing without the need for an external reference frame and constructing a physical model of cell movement based on the data. Numerical simulations show that mixing with experimentally observed statistics enhances synchronization of coupled phase oscillators, suggesting that mixing in the tailbud is fast enough to affect the coherence of rhythmic gene expression. Our approach will find general application in analyzing the relative movements of communicating cells during development and disease. PMID- 28652320 TI - Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation. AB - PURPOSE: Results of a study to determine trends in oral anticoagulant (OAC) use and OAC switching in patients with atrial fibrillation (AF) or atrial flutter are presented. METHODS: Warfarin has been the most prescribed anticoagulant in patients with AF for decades. Since 2010, several direct OACs (DOACs) have gained U.S. marketing approval for stroke prevention in AF or atrial flutter. A cross sectional longitudinal analysis was conducted using healthcare and prescription claims databases to characterize OAC use and rates of OAC and DOAC switching during the period 2008-14 in cohorts of Medicare beneficiaries 65 years of age or older with AF or atrial flutter. RESULTS: Overall, 66% of patients with AF or atrial flutter were receiving OACs during the study period. The prevalence of warfarin use decreased from 69.8% in 2008 to 42.2% in 2014. This decrease in warfarin use was paralleled by an increase in dabigatran use, which rose from 1.3% in 2010 to 12.1% in 2011 and then declined to 7.6% in 2014. The prevalence of rivaroxaban use increased from 0.13% in 2011 to 13.87% in 2014. Among anticoagulated patients, an average of 6% annually were switched from one OAC to another. CONCLUSION: Overall OAC utilization in patients with AF or atrial flutter remained steady over the study period. Beginning in 2010, a gradual decrease in use of warfarin was paralleled by an increase in use of DOACs. PMID- 28652321 TI - Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice. AB - The evolutionary origins of metabolism, in particular the emergence of the sugar phosphates that constitute glycolysis, the pentose phosphate pathway, and the RNA and DNA backbone, are largely unknown. In cells, a major source of glucose and the large sugar phosphates is gluconeogenesis. This ancient anabolic pathway (re )builds carbon bonds as cleaved in glycolysis in an aldol condensation of the unstable catabolites glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, forming the much more stable fructose 1,6-bisphosphate. We here report the discovery of a nonenzymatic counterpart to this reaction. The in-ice nonenzymatic aldol addition leads to the continuous accumulation of fructose 1,6-bisphosphate in a permanently frozen solution as followed over months. Moreover, the in-ice reaction is accelerated by simple amino acids, in particular glycine and lysine. Revealing that gluconeogenesis may be of nonenzymatic origin, our results shed light on how glucose anabolism could have emerged in early life forms. Furthermore, the amino acid acceleration of a key cellular anabolic reaction may indicate a link between prebiotic chemistry and the nature of the first metabolic enzymes. PMID- 28652322 TI - Cryo-EM structure of the DNA-PK holoenzyme. AB - DNA-dependent protein kinase (DNA-PK) is a large protein complex central to the nonhomologous end joining (NHEJ) DNA-repair pathway. It comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer of DNA-binding proteins Ku70 and Ku80. Here, we report the cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs at 4.4-A resolution and the DNA-PK holoenzyme at 5.8-A resolution. The DNA-PKcs structure contains three distinct segments: the N-terminal region with an arm and a bridge, the circular cradle, and the head that includes the kinase domain. Two perpendicular apertures exist in the structure, which are sufficiently large for the passage of dsDNA. The DNA-PK holoenzyme cryo-EM map reveals density for the C-terminal globular domain of Ku80 that interacts with the arm of DNA-PKcs. The Ku80-binding site is adjacent to the previously identified density for the DNA-binding region of the Ku70/Ku80 complex, suggesting concerted DNA interaction by DNA-PKcs and the Ku complex. PMID- 28652323 TI - Constrained sampling experiments reveal principles of detection in natural scenes. AB - A fundamental everyday visual task is to detect target objects within a background scene. Using relatively simple stimuli, vision science has identified several major factors that affect detection thresholds, including the luminance of the background, the contrast of the background, the spatial similarity of the background to the target, and uncertainty due to random variations in the properties of the background and in the amplitude of the target. Here we use an experimental approach based on constrained sampling from multidimensional histograms of natural stimuli, together with a theoretical analysis based on signal detection theory, to discover how these factors affect detection in natural scenes. We sorted a large collection of natural image backgrounds into multidimensional histograms, where each bin corresponds to a particular luminance, contrast, and similarity. Detection thresholds were measured for a subset of bins spanning the space, where a natural background was randomly sampled from a bin on each trial. In low-uncertainty conditions, both the background bin and the amplitude of the target were fixed, and, in high uncertainty conditions, they varied randomly on each trial. We found that thresholds increase approximately linearly along all three dimensions and that detection accuracy is unaffected by background bin and target amplitude uncertainty. The results are predicted from first principles by a normalized matched-template detector, where the dynamic normalizing gain factor follows directly from the statistical properties of the natural backgrounds. The results provide an explanation for classic laws of psychophysics and their underlying neural mechanisms. PMID- 28652324 TI - Arabidopsis ABCG34 contributes to defense against necrotrophic pathogens by mediating the secretion of camalexin. AB - Plant pathogens cause huge yield losses. Plant defense often depends on toxic secondary metabolites that inhibit pathogen growth. Because most secondary metabolites are also toxic to the plant, specific transporters are needed to deliver them to the pathogens. To identify the transporters that function in plant defense, we screened Arabidopsis thaliana mutants of full-size ABCG transporters for hypersensitivity to sclareol, an antifungal compound. We found that atabcg34 mutants were hypersensitive to sclareol and to the necrotrophic fungi Alternaria brassicicola and Botrytis cinereaAtABCG34 expression was induced by Abrassicicola inoculation as well as by methyl-jasmonate, a defense-related phytohormone, and AtABCG34 was polarly localized at the external face of the plasma membrane of epidermal cells of leaves and roots. atabcg34 mutants secreted less camalexin, a major phytoalexin in Athaliana, whereas plants overexpressing AtABCG34 secreted more camalexin to the leaf surface and were more resistant to the pathogen. When treated with exogenous camalexin, atabcg34 mutants exhibited hypersensitivity, whereas BY2 cells expressing AtABCG34 exhibited improved resistance. Analyses of natural Arabidopsis accessions revealed that AtABCG34 contributes to the disease resistance in naturally occurring genetic variants, albeit to a small extent. Together, our data suggest that AtABCG34 mediates camalexin secretion to the leaf surface and thereby prevents Abrassicicola infection. PMID- 28652325 TI - Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules. AB - Many activating immunoreceptors associate with signaling adaptor molecules like FcepsilonR1gamma or CD247. FcepsilonR1gamma and CD247 share high sequence homology and form disulphide-linked homodimers that contain a pair of acidic aspartic acid residues in their transmembrane (TM) domains that mediate assembly, via interaction with an arginine residue at a similar register to these aspartic acids, with the activating immunoreceptors. However, this model cannot hold true for receptors like CD16A, whose TM domains do not contain basic residues. We have carried out an extensive site-directed mutagenesis analysis of the CD16A receptor complex and now report that the association of receptor with the signaling adaptor depends on a network of polar and aromatic residues along the length of the TM domain. Molecular modeling indicates that CD16A TM residues F202, D205, and T206 form the core of the membrane-embedded trimeric interface by establishing highly favorable contacts to the signaling modules through rearrangement of a hydrogen bond network previously identified in the CD247 TM dimer solution NMR structure. Strikingly, the amino acid D205 also regulates the turnover and surface expression of CD16A in the absence of FcepsilonR1gamma or CD247. Modeling studies indicate that similar features underlie the association of other activating immune receptors, including CD64 and FcepsilonR1alpha, with signaling adaptor molecules, and we confirm experimentally that equivalent F, D, and T residues in the TM domain of FcepsilonR1alpha markedly influence the biology of this receptor and its association with FcepsilonR1gamma. PMID- 28652326 TI - TraR directly regulates transcription initiation by mimicking the combined effects of the global regulators DksA and ppGpp. AB - The Escherichia coli F element-encoded protein TraR is a distant homolog of the chromosome-encoded transcription factor DksA. Here we address the mechanism by which TraR acts as a global regulator, inhibiting some promoters and activating others. We show that TraR regulates transcription directly in vitro by binding to the secondary channel of RNA polymerase (RNAP) using interactions similar, but not identical, to those of DksA. Even though it binds to RNAP with only slightly higher affinity than DksA and is only half the size of DksA, TraR by itself inhibits transcription as strongly as DksA and ppGpp combined and much more than DksA alone. Furthermore, unlike DksA, TraR activates transcription even in the absence of ppGpp. TraR lacks the residues that interact with ppGpp in DksA, and TraR binding to RNAP uses the residues in the beta' rim helices that contribute to the ppGpp binding site in the DksA-ppGpp-RNAP complex. Thus, unlike DksA, TraR does not bind ppGpp. We propose a model in which TraR mimics the effects of DksA and ppGpp together by binding directly to the region of the RNAP secondary channel that otherwise binds ppGpp, and its N-terminal region, like the coiled coil tip of DksA, engages the active-site region of the enzyme and affects transcription allosterically. These data provide insights into the function not only of TraR but also of an evolutionarily widespread and diverse family of TraR like proteins encoded by bacteria, as well as bacteriophages and other extrachromosomal elements. PMID- 28652327 TI - Diffusive dynamics during the high-to-low density transition in amorphous ice. AB - Water exists in high- and low-density amorphous ice forms (HDA and LDA), which could correspond to the glassy states of high- (HDL) and low-density liquid (LDL) in the metastable part of the phase diagram. However, the nature of both the glass transition and the high-to-low-density transition are debated and new experimental evidence is needed. Here we combine wide-angle X-ray scattering (WAXS) with X-ray photon-correlation spectroscopy (XPCS) in the small-angle X-ray scattering (SAXS) geometry to probe both the structural and dynamical properties during the high-to-low-density transition in amorphous ice at 1 bar. By analyzing the structure factor and the radial distribution function, the coexistence of two structurally distinct domains is observed at T = 125 K. XPCS probes the dynamics in momentum space, which in the SAXS geometry reflects structural relaxation on the nanometer length scale. The dynamics of HDA are characterized by a slow component with a large time constant, arising from viscoelastic relaxation and stress release from nanometer-sized heterogeneities. Above 110 K a faster, strongly temperature-dependent component appears, with momentum transfer dependence pointing toward nanoscale diffusion. This dynamical component slows down after transition into the low-density form at 130 K, but remains diffusive. The diffusive character of both the high- and low-density forms is discussed among different interpretations and the results are most consistent with the hypothesis of a liquid-liquid transition in the ultraviscous regime. PMID- 28652329 TI - Photoacoustic trace detection of gases at the parts-per-quadrillion level with a moving optical grating. AB - The amplitude of the photoacoustic effect for an optical source moving at the sound speed in a one-dimensional geometry increases linearly in time without bound in the linear acoustic regime. Here, use of this principle is described for trace detection of gases, using two frequency-shifted beams from a CO2 laser directed at an angle to each other to give optical fringes that move at the sound speed in a cavity with a longitudinal resonance. The photoacoustic signal is detected with a high-[Formula: see text], piezoelectric crystal with a resonance on the order of [Formula: see text] kHz. The photoacoustic cell has a design analogous to a hemispherical laser resonator and can be adjusted to have a longitudinal resonance to match that of the detector crystal. The grating frequency, the length of the resonator, and the crystal must all have matched frequencies; thus, three resonances are used to advantage to produce sensitivity that extends to the parts-per-quadrillion level. PMID- 28652328 TI - Pathogen exploitation of an abscisic acid- and jasmonate-inducible MAPK phosphatase and its interception by Arabidopsis immunity. AB - Phytopathogens promote virulence by, for example, exploiting signaling pathways mediated by phytohormones such as abscisic acid (ABA) and jasmonate (JA). Some plants can counteract pathogen virulence by invoking a potent form of immunity called effector-triggered immunity (ETI). Here, we report that ABA and JA mediate inactivation of the immune-associated MAP kinases (MAPKs), MPK3 and MPK6, in Arabidopsis thaliana ABA induced expression of genes encoding the protein phosphatases 2C (PP2Cs), HAI1, HAI2, and HAI3 through ABF/AREB transcription factors. These three HAI PP2Cs interacted with MPK3 and MPK6 and were required for ABA-mediated MPK3/MPK6 inactivation and immune suppression. The bacterial pathogen Pseudomonas syringae pv. tomato (Pto) DC3000 activates ABA signaling and produces a JA-mimicking phytotoxin, coronatine (COR), that promotes virulence. We found that Pto DC3000 induces HAI1 through COR-mediated activation of MYC2, a master transcription factor in JA signaling. HAI1 dephosphorylated MPK3 and MPK6 in vitro and was necessary for COR-mediated suppression of MPK3/MPK6 activation and immunity. Intriguingly, upon ETI activation, A. thaliana plants overcame the HAI1-dependent virulence of COR by blocking JA signaling. Finally, we showed conservation of induction of HAI PP2Cs by ABA and JA in other Brassicaceae species. Taken together, these results suggest that ABA and JA signaling pathways, which are hijacked by the bacterial pathogen, converge on the HAI PP2Cs that suppress activation of the immune-associated MAPKs. Also, our data unveil interception of JA-signaling activation as a host counterstrategy against the bacterial suppression of MAPKs during ETI. PMID- 28652330 TI - Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. AB - The recent discovery of small molecules targeting the cytochrome bc1 :aa3 in Mycobacterium tuberculosis triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome bc1 :aa3 consists of a menaquinone:cytochrome c reductase (bc1 ) and a cytochrome aa3 -type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome c reductase. Despite the affinity of Q203 for the bc1 :aa3 complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal bd-type oxidase (cytochrome bd oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome bd oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect M. tuberculosis from Q203-induced bacterial death. Upon genetic deletion of the cytochrome bd oxidase-encoding genes cydAB, Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared M. tuberculosis infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome bc1 :aa3 , as well as for the development of a drug combination targeting oxidative phosphorylation in M. tuberculosis. PMID- 28652332 TI - Theory of long binding events in single-molecule-controlled rotation experiments on F1-ATPase. AB - The theory of elastic group transfer for the binding and release rate constants for nucleotides in F1-ATPase as a function of the rotor angle is further extended in several respects. (i) A method is described for predicting the experimentally observed lifetime distribution of long binding events in the controlled rotation experiments by taking into account the hydrolysis and synthesis reactions occurring during these events. (ii) A method is also given for treating the long binding events in the experiments and obtaining the rate constants for the hydrolysis and synthesis reactions occurring during these events. (iii) The theory in the previous paper is given in a symmetric form, an extension that simplifies the application of the theory to experiments. It also includes a theory-based correction of the reported "on" and "off" rates by calculating the missed events. A near symmetry of the data about the angle of -40 degrees and a "turnover" in the binding rate data vs. rotor angle for angles greater than [Formula: see text]40 degrees is also discussed. PMID- 28652331 TI - DNA methylation markers for diagnosis and prognosis of common cancers. AB - The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis. PMID- 28652333 TI - Functional selectivity for face processing in the temporal voice area of early deaf individuals. AB - Brain systems supporting face and voice processing both contribute to the extraction of important information for social interaction (e.g., person identity). How does the brain reorganize when one of these channels is absent? Here, we explore this question by combining behavioral and multimodal neuroimaging measures (magneto-encephalography and functional imaging) in a group of early deaf humans. We show enhanced selective neural response for faces and for individual face coding in a specific region of the auditory cortex that is typically specialized for voice perception in hearing individuals. In this region, selectivity to face signals emerges early in the visual processing hierarchy, shortly after typical face-selective responses in the ventral visual pathway. Functional and effective connectivity analyses suggest reorganization in long-range connections from early visual areas to the face-selective temporal area in individuals with early and profound deafness. Altogether, these observations demonstrate that regions that typically specialize for voice processing in the hearing brain preferentially reorganize for face processing in born-deaf people. Our results support the idea that cross-modal plasticity in the case of early sensory deprivation relates to the original functional specialization of the reorganized brain regions. PMID- 28652335 TI - Economics and computer science of a radio spectrum reallocation. AB - The recent "incentive auction" of the US Federal Communications Commission was the first auction to reallocate radio frequencies between two different kinds of uses: from broadcast television to wireless Internet access. The design challenge was not just to choose market rules to govern a fixed set of potential trades but also, to determine the broadcasters' property rights, the goods to be exchanged, the quantities to be traded, the computational procedures, and even some of the performance objectives. An essential and unusual challenge was to make the auction simple enough for human participants while still ensuring that the computations would be tractable and capable of delivering nearly efficient outcomes. PMID- 28652334 TI - Dissecting and modeling zeaxanthin- and lutein-dependent nonphotochemical quenching in Arabidopsis thaliana. AB - Photosynthetic organisms use various photoprotective mechanisms to dissipate excess photoexcitation as heat in a process called nonphotochemical quenching (NPQ). Regulation of NPQ allows for a rapid response to changes in light intensity and in vascular plants, is primarily triggered by a pH gradient across the thylakoid membrane (?pH). The response is mediated by the PsbS protein and various xanthophylls. Time-correlated single-photon counting (TCSPC) measurements were performed on Arabidopsis thaliana to quantify the dependence of the response of NPQ to changes in light intensity on the presence and accumulation of zeaxanthin and lutein. Measurements were performed on WT and mutant plants deficient in one or both of the xanthophylls as well as a transgenic line that accumulates lutein via an engineered lutein epoxide cycle. Changes in the response of NPQ to light acclimation in WT and mutant plants were observed between two successive light acclimation cycles, suggesting that the character of the rapid and reversible response of NPQ in fully dark-acclimated plants is substantially different from in conditions plants are likely to experience caused by changes in light intensity during daylight. Mathematical models of the response of zeaxanthin- and lutein-dependent reversible NPQ were constructed that accurately describe the observed differences between the light acclimation periods. Finally, the WT response of NPQ was reconstructed from isolated components present in mutant plants with a single common scaling factor, which enabled deconvolution of the relative contributions of zeaxanthin- and lutein dependent NPQ. PMID- 28652336 TI - Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation. AB - Neutral sphingomyelinase 2 (nSMase2, product of the SMPD3 gene) is a key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication. nSMase2 is activated by diverse stimuli, including the anionic phospholipid phosphatidylserine. Phosphatidylserine binds to an integral-membrane N-terminal domain (NTD); however, how the NTD activates the C-terminal catalytic domain is unclear. Here, we identify the complete catalytic domain of nSMase2, which was misannotated because of a large insertion. We find the soluble catalytic domain interacts directly with the membrane-associated NTD, which serves as both a membrane anchor and an allosteric activator. The juxtamembrane region, which links the NTD and the catalytic domain, is necessary and sufficient for activation. Furthermore, we provide a mechanistic basis for this phenomenon using the crystal structure of the human nSMase2 catalytic domain determined at 1.85-A resolution. The structure reveals a DNase-I-type fold with a hydrophobic track leading to the active site that is blocked by an evolutionarily conserved motif which we term the "DK switch." Structural analysis of nSMase2 and the extended N-SMase family shows that the DK switch can adopt different conformations to reposition a universally conserved Asp (D) residue involved in catalysis. Mutation of this Asp residue in nSMase2 disrupts catalysis, allosteric activation, stimulation by phosphatidylserine, and pharmacological inhibition by the lipid-competitive inhibitor GW4869. Taken together, these results demonstrate that the DK switch regulates ceramide generation by nSMase2 and is governed by an allosteric interdomain interaction at the membrane interface. PMID- 28652337 TI - MinE conformational dynamics regulate membrane binding, MinD interaction, and Min oscillation. AB - In Escherichia coli MinE induces MinC/MinD to oscillate between the ends of the cell, contributing to the precise placement of the Z ring at midcell. To do this, MinE undergoes a remarkable conformational change from a latent 6beta-stranded form that diffuses in the cytoplasm to an active 4beta-stranded form bound to the membrane and MinD. How this conformational switch occurs is not known. Here, using hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) we rule out a model in which the two forms are in rapid equilibrium. Furthermore, HDX-MS revealed that a MinE mutant (D45A/V49A), previously shown to produce an aberrant oscillation and unable to assemble a MinE ring, is more rigid than WT MinE. This mutant has a defect in interaction with MinD, suggesting it has difficulty in switching to the active form. Analysis of intragenic suppressors of this mutant suggests it has difficulty in releasing the N-terminal membrane targeting sequences (MTS). These results indicate that the dynamic association of the MTS with the beta-sheet is fine-tuned to balance MinE's need to sense MinD on the membrane with its need to diffuse in the cytoplasm, both of which are necessary for the oscillation. The results lead to models for MinE activation and MinE ring formation. PMID- 28652338 TI - Optimal multivalent targeting of membranes with many distinct receptors. AB - Cells can often be recognized by the concentrations of receptors expressed on their surface. For better (targeted drug treatment) or worse (targeted infection by pathogens), it is clearly important to be able to target cells selectively. A good targeting strategy would result in strong binding to cells with the desired receptor profile and barely binding to other cells. Using a simple model, we formulate optimal design rules for multivalent particles that allow them to distinguish target cells based on their receptor profile. We find the following: (i) It is not a good idea to aim for very strong binding between the individual ligands on the guest (delivery vehicle) and the receptors on the host (cell). Rather, one should exploit multivalency: High sensitivity to the receptor density on the host can be achieved by coating the guest with many ligands that bind only weakly to the receptors on the cell surface. (ii) The concentration profile of the ligands on the guest should closely match the composition of the cognate membrane receptors on the target surface. And (iii) irrespective of all details, the effective strength of the ligand-receptor interaction should be of the order of the thermal energy [Formula: see text], where [Formula: see text] is the absolute temperature and [Formula: see text] is Boltzmann's constant. We present simulations that support the theoretical predictions. We speculate that, using the above design rules, it should be possible to achieve targeted drug delivery with a greatly reduced incidence of side effects. PMID- 28652339 TI - Grc3 programs the essential endoribonuclease Las1 for specific RNA cleavage. AB - Las1 is a recently discovered endoribonuclease that collaborates with Grc3-Rat1 Rai1 to process precursor ribosomal RNA (rRNA), yet its mechanism of action remains unknown. Disruption of the mammalian Las1 gene has been linked to congenital lethal motor neuron disease and X-linked intellectual disability disorders, thus highlighting the necessity to understand Las1 regulation and function. Here, we report that the essential Las1 endoribonuclease requires its binding partner, the polynucleotide kinase Grc3, for specific C2 cleavage. Our results establish that Grc3 drives Las1 endoribonuclease cleavage to its targeted C2 site both in vitro and in Saccharomyces cerevisiae. Moreover, we observed Las1 dependent activation of the Grc3 kinase activity exclusively toward single stranded RNA. Together, Las1 and Grc3 assemble into a tetrameric complex that is required for competent rRNA processing. The tetrameric Grc3/Las1 cross talk draws unexpected parallels to endoribonucleases RNaseL and Ire1, and establishes Grc3/Las1 as a unique member of the RNaseL/Ire1 RNA splicing family. Together, our work provides mechanistic insight for the regulation of the Las1 endoribonuclease and identifies the tetrameric Grc3/Las1 complex as a unique example of a protein-guided programmable endoribonuclease. PMID- 28652340 TI - Correction to Supporting Information for Mao et al., Disruption of quercetin metabolism by fungicide affects energy production in honey bees (Apis mellifera). PMID- 28652341 TI - High-speed acoustic communication by multiplexing orbital angular momentum. AB - Long-range acoustic communication is crucial to underwater applications such as collection of scientific data from benthic stations, ocean geology, and remote control of off-shore industrial activities. However, the transmission rate of acoustic communication is always limited by the narrow-frequency bandwidth of the acoustic waves because of the large attenuation for high-frequency sound in water. Here, we demonstrate a high-throughput communication approach using the orbital angular momentum (OAM) of acoustic vortex beams with one order enhancement of the data transmission rate at a single frequency. The topological charges of OAM provide intrinsically orthogonal channels, offering a unique ability to multiplex data transmission within a single acoustic beam generated by a transducer array, drastically increasing the information channels and capacity of acoustic communication. A high spectral efficiency of 8.0 +/- 0.4 (bit/s)/Hz in acoustic communication has been achieved using topological charges between -4 and +4 without applying other communication modulation techniques. Such OAM is a completely independent degree of freedom which can be readily integrated with other state-of-the-art communication modulation techniques like quadrature amplitude modulation (QAM) and phase-shift keying (PSK). Information multiplexing through OAM opens a dimension for acoustic communication, providing a data transmission rate that is critical for underwater applications. PMID- 28652342 TI - Early phonology revealed by international adoptees' birth language retention. AB - Until at least 6 mo of age, infants show good discrimination for familiar phonetic contrasts (i.e., those heard in the environmental language) and contrasts that are unfamiliar. Adult-like discrimination (significantly worse for nonnative than for native contrasts) appears only later, by 9-10 mo. This has been interpreted as indicating that infants have no knowledge of phonology until vocabulary development begins, after 6 mo of age. Recently, however, word recognition has been observed before age 6 mo, apparently decoupling the vocabulary and phonology acquisition processes. Here we show that phonological acquisition is also in progress before 6 mo of age. The evidence comes from retention of birth-language knowledge in international adoptees. In the largest ever such study, we recruited 29 adult Dutch speakers who had been adopted from Korea when young and had no conscious knowledge of Korean language at all. Half were adopted at age 3-5 mo (before native-specific discrimination develops) and half at 17 mo or older (after word learning has begun). In a short intensive training program, we observe that adoptees (compared with 29 matched controls) more rapidly learn tripartite Korean consonant distinctions without counterparts in their later-acquired Dutch, suggesting that the adoptees retained phonological knowledge about the Korean distinction. The advantage is equivalent for the younger-adopted and the older-adopted groups, and both groups not only acquire the tripartite distinction for the trained consonants but also generalize it to untrained consonants. Although infants younger than 6 mo can still discriminate unfamiliar phonetic distinctions, this finding indicates that native-language phonological knowledge is nonetheless being acquired at that age. PMID- 28652343 TI - Local auxin production underlies a spatially restricted neighbor-detection response in Arabidopsis. AB - Competition for light triggers numerous developmental adaptations known as the "shade-avoidance syndrome" (SAS). Important molecular events underlying specific SAS responses have been identified. However, in natural environments light is often heterogeneous, and it is currently unknown how shading affecting part of a plant leads to local responses. To study this question, we analyzed upwards leaf movement (hyponasty), a rapid adaptation to neighbor proximity, in Arabidopsis We show that manipulation of the light environment at the leaf tip triggers a hyponastic response that is restricted to the treated leaf. This response is mediated by auxin synthesized in the blade and transported to the petiole. Our results suggest that a strong auxin response in the vasculature of the treated leaf and auxin signaling in the epidermis mediate leaf elevation. Moreover, the analysis of an auxin-signaling mutant reveals signaling bifurcation in the control of petiole elongation versus hyponasty. Our work identifies a mechanism for a local shade response that may pertain to other plant adaptations to heterogeneous environments. PMID- 28652346 TI - Correction for Saito et al., Investigation of hindwing folding in ladybird beetles by artificial elytron transplantation and microcomputed tomography. PMID- 28652344 TI - X-ray crystal structure of a reiterative transcription complex reveals an atypical RNA extension pathway. AB - Reiterative transcription is a noncanonical form of RNA synthesis in which a nucleotide specified by a single base in the DNA template is repetitively added to the nascent transcript. Here we determined the crystal structure of an RNA polymerase, the bacterial enzyme from Thermus thermophilus, engaged in reiterative transcription during transcription initiation at a promoter resembling the pyrG promoter of Bacillus subtilis The structure reveals that the reiterative transcript detours from the dedicated RNA exit channel and extends toward the main channel of the enzyme, thereby allowing RNA extension without displacement of the promoter recognition sigma-factor. Nascent transcripts containing reiteratively added G residues are eventually extended by nonreiterative transcription, revealing an atypical pathway for the formation of a transcription elongation complex. PMID- 28652345 TI - DNA cytoskeleton for stabilizing artificial cells. AB - Cell-sized liposomes and droplets coated with lipid layers have been used as platforms for understanding live cells, constructing artificial cells, and implementing functional biomedical tools such as biosensing platforms and drug delivery systems. However, these systems are very fragile, which results from the absence of cytoskeletons in these systems. Here, we construct an artificial cytoskeleton using DNA nanostructures. The designed DNA oligomers form a Y-shaped nanostructure and connect to each other with their complementary sticky ends to form networks. To undercoat lipid membranes with this DNA network, we used cationic lipids that attract negatively charged DNA. By encapsulating the DNA into the droplets, we successfully created a DNA shell underneath the membrane. The DNA shells increased interfacial tension, elastic modulus, and shear modulus of the droplet surface, consequently stabilizing the lipid droplets. Such drastic changes in stability were detected only when the DNA shell was in the gel phase. Furthermore, we demonstrate that liposomes with the DNA gel shell are substantially tolerant against outer osmotic shock. These results clearly show the DNA gel shell is a stabilizer of the lipid membrane akin to the cytoskeleton in live cells. PMID- 28652347 TI - IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts. AB - Here we investigated in primary human erythroid tissues a downstream element of the heterochronic let-7 miRNA pathway, the insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), for its potential to affect the hemoglobin profiles in human erythroblasts. Comparison of adult bone marrow to fetal liver lysates demonstrated developmental silencing in IGF2BP1. Erythroid-specific overexpression of IGF2BP1 caused a nearly complete and pancellular reversal of the adult pattern of hemoglobin expression toward a more fetal-like phenotype. The reprogramming of hemoglobin expression was achieved at the transcriptional level by increased gamma-globin combined with decreased beta-globin transcripts resulting in gamma-globin rising to 90% of total beta-like mRNA. Delta-globin mRNA was reduced to barely detectable levels. Alpha-globin levels were not significantly changed. Fetal hemoglobin achieved levels of 68.6 +/- 3.9% in the IGF2BP1 overexpression samples compared with 5.0 +/- 1.8% in donor matched transduction controls. In part, these changes were mediated by reduced protein expression of the transcription factor BCL11A. mRNA stability and polysome studies suggest IGF2BP1 mediates posttranscriptional loss of BCL11A. These results suggest a mechanism for chronoregulation of fetal and adult hemoglobin expression in humans. PMID- 28652348 TI - Rapid phenotypic antimicrobial susceptibility testing using nanoliter arrays. AB - Antibiotic resistance is a major global health concern that requires action across all sectors of society. In particular, to allow conservative and effective use of antibiotics clinical settings require better diagnostic tools that provide rapid determination of antimicrobial susceptibility. We present a method for rapid and scalable antimicrobial susceptibility testing using stationary nanoliter droplet arrays that is capable of delivering results in approximately half the time of conventional methods, allowing its results to be used the same working day. In addition, we present an algorithm for automated data analysis and a multiplexing system promoting practicality and translatability for clinical settings. We test the efficacy of our approach on numerous clinical isolates and demonstrate a 2-d reduction in diagnostic time when testing bacteria isolated directly from urine samples. PMID- 28652349 TI - Simulation of Deepwater Horizon oil plume reveals substrate specialization within a complex community of hydrocarbon degraders. AB - The Deepwater Horizon (DWH) accident released an estimated 4.1 million barrels of oil and 1010 mol of natural gas into the Gulf of Mexico, forming deep-sea plumes of dispersed oil droplets and dissolved gases that were largely degraded by bacteria. During the course of this 3-mo disaster a series of different bacterial taxa were enriched in succession within deep plumes, but the metabolic capabilities of the different populations that controlled degradation rates of crude oil components are poorly understood. We experimentally reproduced dispersed plumes of fine oil droplets in Gulf of Mexico seawater and successfully replicated the enrichment and succession of the principal oil-degrading bacteria observed during the DWH event. We recovered near-complete genomes, whose phylogeny matched those of the principal biodegrading taxa observed in the field, including the DWH Oceanospirillales (now identified as a Bermanella species), multiple species of Colwellia, Cycloclasticus, and other members of Gammaproteobacteria, Flavobacteria, and Rhodobacteria. Metabolic pathway analysis, combined with hydrocarbon compositional analysis and species abundance data, revealed substrate specialization that explained the successional pattern of oil-degrading bacteria. The fastest-growing bacteria used short-chain alkanes. The analyses also uncovered potential cooperative and competitive relationships, even among close relatives. We conclude that patterns of microbial succession following deep ocean hydrocarbon blowouts are predictable and primarily driven by the availability of liquid petroleum hydrocarbons rather than natural gases. PMID- 28652350 TI - Chimpanzee super strength and human skeletal muscle evolution. AB - Since at least the 1920s, it has been reported that common chimpanzees (Pan troglodytes) differ from humans in being capable of exceptional feats of "super strength," both in the wild and in captive environments. A mix of anecdotal and more controlled studies provides some support for this view; however, a critical review of available data suggests that chimpanzee mass-specific muscular performance is a more modest 1.5 times greater than humans on average. Hypotheses for the muscular basis of this performance differential have included greater isometric force-generating capabilities, faster maximum shortening velocities, and/or a difference in myosin heavy chain (MHC) isoform content in chimpanzee relative to human skeletal muscle. Here, we show that chimpanzee muscle is similar to human muscle in its single-fiber contractile properties, but exhibits a much higher fraction of MHC II isoforms. Unlike humans, chimpanzee muscle is composed of ~67% fast-twitch fibers (MHC IIa+IId). Computer simulations of species-specific whole-muscle models indicate that maximum dynamic force and power output is 1.35 times higher in a chimpanzee muscle than a human muscle of similar size. Thus, the superior mass-specific muscular performance of chimpanzees does not stem from differences in isometric force-generating capabilities or maximum shortening velocities-as has long been suggested-but rather is due in part to differences in MHC isoform content and fiber length. We propose that the hominin lineage experienced a decline in maximum dynamic force and power output during the past 7-8 million years in response to selection for repetitive, low-cost contractile behavior. PMID- 28652351 TI - Varying and unchanging whiteness on the wings of dusk-active and shade-inhabiting Carystoides escalantei butterflies. AB - Whiteness, although frequently apparent on the wings, legs, antennae, or bodies of many species of moths and butterflies, along with other colors and shades, has often escaped our attention. Here, we investigate the nanostructure and microstructure of white spots on the wings of Carystoides escalantei, a dusk active and shade-inhabiting Costa Rican rain forest butterfly (Hesperiidae). On both males and females, two types of whiteness occur: angle dependent (dull or bright) and angle independent, which differ in the microstructure, orientation, and associated properties of their scales. Some spots on the male wings are absent from the female wings. Whether the angle-dependent whiteness is bright or dull depends on the observation directions. The angle-dependent scales also show enhanced retro-reflection. We speculate that the biological functions and evolution of Carystoides spot patterns, scale structures, and their varying whiteness are adaptations to butterfly's low light habitat and to airflow experienced on the wing base vs. wing tip. PMID- 28652352 TI - Insect outbreak shifts the direction of selection from fast to slow growth rates in the long-lived conifer Pinus ponderosa. AB - Long generation times limit species' rapid evolution to changing environments. Trees provide critical global ecosystem services, but are under increasing risk of mortality because of climate change-mediated disturbances, such as insect outbreaks. The extent to which disturbance changes the dynamics and strength of selection is unknown, but has important implications on the evolutionary potential of tree populations. Using a 40-y-old Pinus ponderosa genetic experiment, we provide rare evidence of context-dependent fluctuating selection on growth rates over time in a long-lived species. Fast growth was selected at juvenile stages, whereas slow growth was selected at mature stages under strong herbivory caused by a mountain pine beetle (Dendroctonus ponderosae) outbreak. Such opposing forces led to no net evolutionary response over time, thus providing a mechanism for the maintenance of genetic diversity on growth rates. Greater survival to mountain pine beetle attack in slow-growing families reflected, in part, a host-based life-history trade-off. Contrary to expectations, genetic effects on tree survival were greatest at the peak of the outbreak and pointed to complex defense responses. Our results suggest that selection forces in tree populations may be more relevant than previously thought, and have implications for tree population responses to future environments and for tree breeding programs. PMID- 28652353 TI - Disentangling the effects of selection and loss bias on gene dynamics. AB - We combine mathematical modeling of genome evolution with comparative analysis of prokaryotic genomes to estimate the relative contributions of selection and intrinsic loss bias to the evolution of different functional classes of genes and mobile genetic elements (MGE). An exact solution for the dynamics of gene family size was obtained under a linear duplication-transfer-loss model with selection. With the exception of genes involved in information processing, particularly translation, which are maintained by strong selection, the average selection coefficient for most nonparasitic genes is low albeit positive, compatible with observed positive correlation between genome size and effective population size. Free-living microbes evolve under stronger selection for gene retention than parasites. Different classes of MGE show a broad range of fitness effects, from the nearly neutral transposons to prophages, which are actively eliminated by selection. Genes involved in antiparasite defense, on average, incur a fitness cost to the host that is at least as high as the cost of plasmids. This cost is probably due to the adverse effects of autoimmunity and curtailment of horizontal gene transfer caused by the defense systems and selfish behavior of some of these systems, such as toxin-antitoxin and restriction modification modules. Transposons follow a biphasic dynamics, with bursts of gene proliferation followed by decay in the copy number that is quantitatively captured by the model. The horizontal gene transfer to loss ratio, but not duplication to loss ratio, correlates with genome size, potentially explaining increased abundance of neutral and costly elements in larger genomes. PMID- 28652354 TI - Groundwater declines are linked to changes in Great Plains stream fish assemblages. AB - Groundwater pumping for agriculture is a major driver causing declines of global freshwater ecosystems, yet the ecological consequences for stream fish assemblages are rarely quantified. We combined retrospective (1950-2010) and prospective (2011-2060) modeling approaches within a multiscale framework to predict change in Great Plains stream fish assemblages associated with groundwater pumping from the United States High Plains Aquifer. We modeled the relationship between the length of stream receiving water from the High Plains Aquifer and the occurrence of fishes characteristic of small and large streams in the western Great Plains at a regional scale and for six subwatersheds nested within the region. Water development at the regional scale was associated with construction of 154 barriers that fragment stream habitats, increased depth to groundwater and loss of 558 km of stream, and transformation of fish assemblage structure from dominance by large-stream to small-stream fishes. Scaling down to subwatersheds revealed consistent transformations in fish assemblage structure among western subwatersheds with increasing depths to groundwater. Although transformations occurred in the absence of barriers, barriers along mainstem rivers isolate depauperate western fish assemblages from relatively intact eastern fish assemblages. Projections to 2060 indicate loss of an additional 286 km of stream across the region, as well as continued replacement of large-stream fishes by small-stream fishes where groundwater pumping has increased depth to groundwater. Our work illustrates the shrinking of streams and homogenization of Great Plains stream fish assemblages related to groundwater pumping, and we predict similar transformations worldwide where local and regional aquifer depletions occur. PMID- 28652356 TI - Emotion shapes the diffusion of moralized content in social networks. AB - Political debate concerning moralized issues is increasingly common in online social networks. However, moral psychology has yet to incorporate the study of social networks to investigate processes by which some moral ideas spread more rapidly or broadly than others. Here, we show that the expression of moral emotion is key for the spread of moral and political ideas in online social networks, a process we call "moral contagion." Using a large sample of social media communications about three polarizing moral/political issues (n = 563,312), we observed that the presence of moral-emotional words in messages increased their diffusion by a factor of 20% for each additional word. Furthermore, we found that moral contagion was bounded by group membership; moral-emotional language increased diffusion more strongly within liberal and conservative networks, and less between them. Our results highlight the importance of emotion in the social transmission of moral ideas and also demonstrate the utility of social network methods for studying morality. These findings offer insights into how people are exposed to moral and political ideas through social networks, thus expanding models of social influence and group polarization as people become increasingly immersed in social media networks. PMID- 28652355 TI - Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine. AB - Migraineurs avoid light because it intensifies their headache. However, this is not the only reason for their aversion to light. Studying migraineurs and control subjects, we found that lights triggered more changes in autonomic functions and negative emotions during, rather than in the absence of, migraine or in control subjects, and that the association between light and positive emotions was stronger in control subjects than migraineurs. Seeking to define a neuroanatomical substrate for these findings, we showed that, in rats, axons of retinal ganglion cells converge on hypothalamic neurons that project directly to nuclei in the brainstem and spinal cord that regulate parasympathetic and sympathetic functions and contain dopamine, histamine, orexin, melanin concentrating hormone, oxytocin, and vasopressin. Although the rat studies define frameworks for conceptualizing how light triggers the symptoms described by patients, the human studies suggest that the aversive nature of light is more complex than its association with headache intensification. PMID- 28652357 TI - Neighbor detection at the leaf tip adaptively regulates upward leaf movement through spatial auxin dynamics. AB - Vegetation stands have a heterogeneous distribution of light quality, including the red/far-red light ratio (R/FR) that informs plants about proximity of neighbors. Adequate responses to changes in R/FR are important for competitive success. How the detection and response to R/FR are spatially linked and how this spatial coordination between detection and response affects plant performance remains unresolved. We show in Arabidopsis thaliana and Brassica nigra that localized FR enrichment at the lamina tip induces upward leaf movement (hyponasty) from the petiole base. Using a combination of organ-level transcriptome analysis, molecular reporters, and physiology, we show that PIF dependent spatial auxin dynamics are key to this remote response to localized FR enrichment. Using computational 3D modeling, we show that remote signaling of R/FR for hyponasty has an adaptive advantage over local signaling in the petiole, because it optimizes the timing of leaf movement in response to neighbors and prevents hyponasty caused by self-shading. PMID- 28652358 TI - Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins. AB - Metastasis is responsible for most cancer-related deaths, but the current clinical treatments are not effective. Recently, gold nanoparticles (AuNPs) were discovered to inhibit cancer cell migration and prevent metastasis. Rationally designed AuNPs could greatly benefit their antimigration property, but the molecular mechanisms need to be explored. Cytoskeletons are cell structural proteins that closely relate to migration, and surface receptor integrins play critical roles in controlling the organization of cytoskeletons. Herein, we developed a strategy to inhibit cancer cell migration by targeting integrins, using Arg-Gly-Asp (RGD) peptide-functionalized gold nanorods. To enhance the effect, AuNRs were further activated with 808-nm near-infrared (NIR) light to generate heat for photothermal therapy (PPTT), where the temperature was adjusted not to affect the cell viability/proliferation. Our results demonstrate changes in cell morphology, observed as cytoskeleton protrusions-i.e., lamellipodia and filopodia-were reduced after treatment. The Western blot analysis indicates the downstream effectors of integrin were attracted toward the antimigration direction. Proteomics results indicated broad perturbations in four signaling pathways, Rho GTPases, actin, microtubule, and kinases-related pathways, which are the downstream regulators of integrins. Due to the dominant role of integrins in controlling cytoskeleton, focal adhesion, actomyosin contraction, and actin and microtubule assembly have been disrupted by targeting integrins. PPTT further enhanced the remodeling of cytoskeletal proteins and decreased migration. In summary, the ability of targeting AuNRs to cancer cell integrins and the introduction of PPTT stimulated broad regulation on the cytoskeleton, which provides the evidence for a potential medical application for controlling cancer metastasis. PMID- 28652359 TI - Triplet-triplet energy transfer in artificial and natural photosynthetic antennas. AB - In photosynthetic organisms, protection against photooxidative stress due to singlet oxygen is provided by carotenoid molecules, which quench chlorophyll triplet species before they can sensitize singlet oxygen formation. In anoxygenic photosynthetic organisms, in which exposure to oxygen is low, chlorophyll-to carotenoid triplet-triplet energy transfer (T-TET) is slow, in the tens of nanoseconds range, whereas it is ultrafast in the oxygen-rich chloroplasts of oxygen-evolving photosynthetic organisms. To better understand the structural features and resulting electronic coupling that leads to T-TET dynamics adapted to ambient oxygen activity, we have carried out experimental and theoretical studies of two isomeric carotenoporphyrin molecular dyads having different conformations and therefore different interchromophore electronic interactions. This pair of dyads reproduces the characteristics of fast and slow T-TET, including a resonance Raman-based spectroscopic marker of strong electronic coupling and fast T-TET that has been observed in photosynthesis. As identified by density functional theory (DFT) calculations, the spectroscopic marker associated with fast T-TET is due primarily to a geometrical perturbation of the carotenoid backbone in the triplet state induced by the interchromophore interaction. This is also the case for the natural systems, as demonstrated by the hybrid quantum mechanics/molecular mechanics (QM/MM) simulations of light harvesting proteins from oxygenic (LHCII) and anoxygenic organisms (LH2). Both DFT and electron paramagnetic resonance (EPR) analyses further indicate that, upon T-TET, the triplet wave function is localized on the carotenoid in both dyads. PMID- 28652361 TI - Free will beliefs predict attitudes toward unethical behavior and criminal punishment. AB - Do free will beliefs influence moral judgments? Answers to this question from theoretical and empirical perspectives are controversial. This study attempted to replicate past research and offer theoretical insights by analyzing World Values Survey data from residents of 46 countries (n = 65,111 persons). Corroborating experimental findings, free will beliefs predicted intolerance of unethical behaviors and support for severe criminal punishment. Further, the link between free will beliefs and intolerance of unethical behavior was moderated by variations in countries' institutional integrity, defined as the degree to which countries had accountable, corruption-free public sectors. Free will beliefs predicted intolerance of unethical behaviors for residents of countries with high and moderate institutional integrity, but this correlation was not seen for countries with low institutional integrity. Free will beliefs predicted support for criminal punishment regardless of countries' institutional integrity. Results were robust across different operationalizations of institutional integrity and with or without statistical control variables. PMID- 28652360 TI - Simulating tactile signals from the whole hand with millisecond precision. AB - When we grasp and manipulate an object, populations of tactile nerve fibers become activated and convey information about the shape, size, and texture of the object and its motion across the skin. The response properties of tactile fibers have been extensively characterized in single-unit recordings, yielding important insights into how individual fibers encode tactile information. A recurring finding in this extensive body of work is that stimulus information is distributed over many fibers. However, our understanding of population-level representations remains primitive. To fill this gap, we have developed a model to simulate the responses of all tactile fibers innervating the glabrous skin of the hand to any spatiotemporal stimulus applied to the skin. The model first reconstructs the stresses experienced by mechanoreceptors when the skin is deformed and then simulates the spiking response that would be produced in the nerve fiber innervating that receptor. By simulating skin deformations across the palmar surface of the hand and tiling it with receptors at their known densities, we reconstruct the responses of entire populations of nerve fibers. We show that the simulated responses closely match their measured counterparts, down to the precise timing of the evoked spikes, across a wide variety of experimental conditions sampled from the literature. We then conduct three virtual experiments to illustrate how the simulation can provide powerful insights into population coding in touch. Finally, we discuss how the model provides a means to establish naturalistic artificial touch in bionic hands. PMID- 28652362 TI - Phosphosite charge rather than shootward localization determines OCTOPUS activity in root protophloem. AB - Polar cellular localization of proteins is often associated with their function and activity. In plants, relatively few polar-localized factors have been described. Among them, the plasma membrane-associated Arabidopsis proteins OCTOPUS (OPS) and BREVIS RADIX (BRX) display shootward and rootward polar localization, respectively, in developing root protophloem cells. Both ops and brx null mutants exhibit defects in protophloem differentiation. Here we show that OPS and BRX act genetically in parallel in this process, although OPS dosage increase mends defects caused by brx loss-of-function. OPS protein function is ancient and conserved in the most basal angiosperms; however, many highly conserved structural OPS features are not strictly required for OPS function. They include a BRASSINOSTEROID INSENSITIVE 2 (BIN2) interaction domain, which supposedly mediates gain-of-function effects obtained through ectopic OPS overexpression. However, engineering an increasingly positive charge in a critical phosphorylation site, S318, progressively amplifies OPS activity. Such hyperactive OPS versions can even complement the severe phenotype of brx ops double mutants, and the most active variants eventually trigger gain-of-function phenotypes. Finally, BRX-OPS as well as OPS-BRX fusion proteins localize to the rootward end of developing protophloem cells, but complement ops mutants as efficiently as shootward localized OPS. Thus, our results suggest that S318 phosphorylation status, rather than a predominantly shootward polar localization, is a primary determinant of OPS activity. PMID- 28652363 TI - Vascular disease-causing mutation, smooth muscle alpha-actin R258C, dominantly suppresses functions of alpha-actin in human patient fibroblasts. AB - The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) alpha actin encoded by ACTA2 We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM alpha-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM alpha actin. Telomerase-immortalized lines of control and R258C human dermal fibroblasts were established and SM alpha-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2 Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM alpha-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM alpha-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM alpha-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM alpha-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease. PMID- 28652364 TI - CIDE domains form functionally important higher-order assemblies for DNA fragmentation. AB - Cell death-inducing DFF45-like effector (CIDE) domains, initially identified in apoptotic nucleases, form a family with diverse functions ranging from cell death to lipid homeostasis. Here we show that the CIDE domains of Drosophila and human apoptotic nucleases Drep2, Drep4, and DFF40 all form head-to-tail helical filaments. Opposing positively and negatively charged interfaces mediate the helical structures, and mutations on these surfaces abolish nuclease activation for apoptotic DNA fragmentation. Conserved filamentous structures are observed in CIDE family members involved in lipid homeostasis, and mutations on the charged interfaces compromise lipid droplet fusion, suggesting that CIDE domains represent a scaffold for higher-order assembly in DNA fragmentation and other biological processes such as lipid homeostasis. PMID- 28652365 TI - Reconstruction from limited single-particle diffraction data via simultaneous determination of state, orientation, intensity, and phase. AB - Free-electron lasers now have the ability to collect X-ray diffraction patterns from individual molecules; however, each sample is delivered at unknown orientation and may be in one of several conformational states, each with a different molecular structure. Hit rates are often low, typically around 0.1%, limiting the number of useful images that can be collected. Determining accurate structural information requires classifying and orienting each image, accurately assembling them into a 3D diffraction intensity function, and determining missing phase information. Additionally, single particles typically scatter very few photons, leading to high image noise levels. We develop a multitiered iterative phasing algorithm to reconstruct structural information from single-particle diffraction data by simultaneously determining the states, orientations, intensities, phases, and underlying structure in a single iterative procedure. We leverage real-space constraints on the structure to help guide optimization and reconstruct underlying structure from very few images with excellent global convergence properties. We show that this approach can determine structural resolution beyond what is suggested by standard Shannon sampling arguments for ideal images and is also robust to noise. PMID- 28652366 TI - Aridity and hominin environments. AB - Aridification is often considered a major driver of long-term ecological change and hominin evolution in eastern Africa during the Plio-Pleistocene; however, this hypothesis remains inadequately tested owing to difficulties in reconstructing terrestrial paleoclimate. We present a revised aridity index for quantifying water deficit (WD) in terrestrial environments using tooth enamel delta18O values, and use this approach to address paleoaridity over the past 4.4 million years in eastern Africa. We find no long-term trend in WD, consistent with other terrestrial climate indicators in the Omo-Turkana Basin, and no relationship between paleoaridity and herbivore paleodiet structure among fossil collections meeting the criteria for WD estimation. Thus, we suggest that changes in the abundance of C4 grass and grazing herbivores in eastern Africa during the Pliocene and Pleistocene may have been decoupled from aridity. As in modern African ecosystems, other factors, such as rainfall seasonality or ecological interactions among plants and mammals, may be important for understanding the evolution of C4 grass- and grazer-dominated biomes. PMID- 28652367 TI - Spatially resolved multicolor CsPbX3 nanowire heterojunctions via anion exchange. AB - Halide perovskites are promising semiconductor materials for solution-processed optoelectronic devices. Their strong ionic bonding nature results in highly dynamic crystal lattices, inherently allowing rapid ion exchange at the solid vapor and solid-liquid interface. Here, we show that the anion-exchange chemistry can be precisely controlled in single-crystalline halide perovskite nanomaterials when combined with nanofabrication techniques. We demonstrate spatially resolved multicolor CsPbX3 (X = Cl, Br, I, or alloy of two halides) nanowire heterojunctions with a pixel size down to 500 nm with the photoluminescence tunable over the entire visible spectrum. In addition, the heterojunctions show distinct electronic states across the interface, as revealed by Kelvin probe force microscopy. These perovskite heterojunctions represent key building blocks for high-resolution multicolor displays beyond current state-of-the-art technology as well as high-density diode/transistor arrays. PMID- 28652368 TI - Antagonistic BMP-cWNT signaling in the cnidarian Nematostella vectensis reveals insight into the evolution of mesoderm. AB - Gastrulation was arguably the key evolutionary innovation that enabled metazoan diversification, leading to the formation of distinct germ layers and specialized tissues. Differential gene expression specifying cell fate is governed by the inputs of intracellular and/or extracellular signals. Beta-catenin/Tcf and the TGF-beta bone morphogenetic protein (BMP) provide critical molecular signaling inputs during germ layer specification in bilaterian metazoans, but there has been no direct experimental evidence for a specific role for BMP signaling during endomesoderm specification in the early branching metazoan Nematostella vectensis (an anthozoan cnidarian). Using forward transcriptomics, we show that beta catenin/Tcf signaling and BMP2/4 signaling provide differential inputs into the cnidarian endomesodermal gene regulatory network (GRN) at the onset of gastrulation (24 h postfertilization) in N. vectensis Surprisingly, beta catenin/Tcf signaling and BMP2/4 signaling regulate a subset of common downstream target genes in the GRN in opposite ways, leading to the spatial and temporal differentiation of fields of cells in the developing embryo. Thus, we show that regulatory interactions between beta-catenin/Tcf signaling and BMP2/4 signaling are required for the specification and determination of different embryonic regions and the patterning of the oral-aboral axis in Nematostella We also show functionally that the conserved "kernel" of the bilaterian heart mesoderm GRN is operational in N. vectensis, which reinforces the hypothesis that the endoderm and mesoderm in triploblastic bilaterians evolved from the bifunctional endomesoderm (gastrodermis) of a diploblastic ancestor, and that slow rhythmic contractions might have been one of the earliest functions of mesodermal tissue. PMID- 28652369 TI - Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival. AB - The extracellular microenvironment is an integral component of normal and diseased tissues that is poorly understood owing to its complexity. To investigate the contribution of the microenvironment to lung fibrosis and adenocarcinoma progression, two pathologies characterized by excessive stromal expansion, we used mouse models to characterize the extracellular matrix (ECM) composition of normal lung, fibrotic lung, lung tumors, and metastases. Using quantitative proteomics, we identified and assayed the abundance of 113 ECM proteins, which revealed robust ECM protein signatures unique to fibrosis, primary tumors, or metastases. These analyses indicated significantly increased abundance of several S100 proteins, including Fibronectin and Tenascin-C (Tnc), in primary lung tumors and associated lymph node metastases compared with normal tissue. We further showed that Tnc expression is repressed by the transcription factor Nkx2-1, a well-established suppressor of metastatic progression. We found that increasing the levels of Tnc, via CRISPR-mediated transcriptional activation of the endogenous gene, enhanced the metastatic dissemination of lung adenocarcinoma cells. Interrogation of human cancer gene expression data revealed that high TNC expression correlates with worse prognosis for lung adenocarcinoma, and that a three-gene expression signature comprising TNC, S100A10, and S100A11 is a robust predictor of patient survival independent of age, sex, smoking history, and mutational load. Our findings suggest that the poorly understood ECM composition of the fibrotic and tumor microenvironment is an underexplored source of diagnostic markers and potential therapeutic targets for cancer patients. PMID- 28652370 TI - Small mitochondrial Arf (smArf) protein corrects p53-independent developmental defects of Arf tumor suppressor-deficient mice. AB - The mouse p19Arf (human p14ARF) tumor suppressor protein, encoded in part from an alternative reading frame of the Ink4a (Cdkn2a) gene, inhibits the Mdm2 E3 ubiquitin ligase to activate p53. Arf is not expressed in most normal tissues of young mice but is induced by high thresholds of aberrant hyperproliferative signals, thereby activating p53 in incipient tumor cells that have experienced oncogene activation. The single Arf mRNA encodes two distinct polypeptides, including full-length p19Arf and N-terminally truncated and unstable p15smArf ("small mitochondrial Arf") initiated from an internal in-frame AUG codon specifying methionine-45. Interactions of p19Arf with Mdm2, or separately with nucleophosmin (NPM, B23) that localizes and stabilizes p19Arf within the nucleolus, require p19Arf N-terminal amino acids that are not present within p15smArf We have generated mice that produce either smARF alone or M45A-mutated (smArf-deficient) full-length p19Arf proteins. BCR-ABL-expressing pro/pre-B cells producing smArf alone are as oncogenic as their Arf-null counterparts in generating acute lymphoblastic leukemia when infused into unconditioned syngeneic mice. In contrast, smArf-deficient cells from mice of the ArfM45A strain are as resistant as wild-type Arf+/+ cells to comparable oncogenic challenge and do not produce tumors. Apart from being prone to tumor development, Arf-null mice are blind, and their male germ cells exhibit defects in meiotic maturation and sperm production. Although ArfM45A mice manifest the latter defects, smArf alone remarkably rescues both of these p53-independent developmental phenotypes. PMID- 28652371 TI - Microfluidic guillotine for single-cell wound repair studies. AB - Wound repair is a key feature distinguishing living from nonliving matter. Single cells are increasingly recognized to be capable of healing wounds. The lack of reproducible, high-throughput wounding methods has hindered single-cell wound repair studies. This work describes a microfluidic guillotine for bisecting single Stentor coeruleus cells in a continuous-flow manner. Stentor is used as a model due to its robust repair capacity and the ability to perform gene knockdown in a high-throughput manner. Local cutting dynamics reveals two regimes under which cells are bisected, one at low viscous stress where cells are cut with small membrane ruptures and high viability and one at high viscous stress where cells are cut with extended membrane ruptures and decreased viability. A cutting throughput up to 64 cells per minute-more than 200 times faster than current methods-is achieved. The method allows the generation of more than 100 cells in a synchronized stage of their repair process. This capacity, combined with high throughput gene knockdown in Stentor, enables time-course mechanistic studies impossible with current wounding methods. PMID- 28652372 TI - Muscarinic receptor regulates extracellular signal regulated kinase by two modes of arrestin binding. AB - Binding of agonists to G-protein-coupled receptors (GPCRs) activates heterotrimeric G proteins and downstream signaling. Agonist-bound GPCRs are then phosphorylated by protein kinases and bound by arrestin to trigger desensitization and endocytosis. Arrestin plays another important signaling function. It recruits and regulates activity of an extracellular signal-regulated kinase (ERK) cascade. However, molecular details and timing of ERK activation remain fundamental unanswered questions that limit understanding of how arrestin dependent GPCR signaling controls cell functions. Here we validate and model a system that tracks the dynamics of interactions of arrestin with receptors and of ERK activation using optical reporters. Our intermolecular FRET measurements in living cells are consistent with beta-arrestin binding to M1 muscarinic acetylcholine receptors (M1Rs) in two different binding modes, transient and stable. The stable mode persists for minutes after agonist removal. The choice of mode is governed by phosphorylation on key residues in the third intracellular loop of the receptor. We detect a similar intramolecular conformational change in arrestin in either binding mode. It develops within seconds of arrestin binding to the M1 receptor, and it reverses within seconds of arrestin unbinding from the transient binding mode. Furthermore, we observed that, when stably bound to phosphorylated M1R, beta-arrestin scaffolds and activates MEK-dependent ERK. In contrast, when transiently bound, beta-arrestin reduces ERK activity via recruitment of a protein phosphatase. All this ERK signaling develops at the plasma membrane. In this scaffolding hypothesis, a shifting balance between the two arrestin binding modes determines the degree of ERK activation at the membrane. PMID- 28652373 TI - Materials and processing approaches for foundry-compatible transient electronics. AB - Foundry-based routes to transient silicon electronic devices have the potential to serve as the manufacturing basis for "green" electronic devices, biodegradable implants, hardware secure data storage systems, and unrecoverable remote devices. This article introduces materials and processing approaches that enable state-of the-art silicon complementary metal-oxide-semiconductor (CMOS) foundries to be leveraged for high-performance, water-soluble forms of electronics. The key elements are (i) collections of biodegradable electronic materials (e.g., silicon, tungsten, silicon nitride, silicon dioxide) and device architectures that are compatible with manufacturing procedures currently used in the integrated circuit industry, (ii) release schemes and transfer printing methods for integration of multiple ultrathin components formed in this way onto biodegradable polymer substrates, and (iii) planarization and metallization techniques to yield interconnected and fully functional systems. Various CMOS devices and circuit elements created in this fashion and detailed measurements of their electrical characteristics highlight the capabilities. Accelerated dissolution studies in aqueous environments reveal the chemical kinetics associated with the underlying transient behaviors. The results demonstrate the technical feasibility for using foundry-based routes to sophisticated forms of transient electronic devices, with functional capabilities and cost structures that could support diverse applications in the biomedical, military, industrial, and consumer industries. PMID- 28652374 TI - CRISPR-Cas9 conformational activation as elucidated from enhanced molecular simulations. AB - CRISPR-Cas9 has become a facile genome editing technology, yet the structural and mechanistic features underlying its function are unclear. Here, we perform extensive molecular simulations in an enhanced sampling regime, using a Gaussian accelerated molecular dynamics (GaMD) methodology, which probes displacements over hundreds of microseconds to milliseconds, to reveal the conformational dynamics of the endonuclease Cas9 during its activation toward catalysis. We disclose the conformational transition of Cas9 from its apo form to the RNA-bound form, suggesting a mechanism for RNA recruitment in which the domain relocations cause the formation of a positively charged cavity for nucleic acid binding. GaMD also reveals the conformation of a catalytically competent Cas9, which is prone for catalysis and whose experimental characterization is still limited. We show that, upon DNA binding, the conformational dynamics of the HNH domain triggers the formation of the active state, explaining how the HNH domain exerts a conformational control domain over DNA cleavage [Sternberg SH et al. (2015) Nature, 527, 110-113]. These results provide atomic-level information on the molecular mechanism of CRISPR-Cas9 that will inspire future experimental investigations aimed at fully clarifying the biophysics of this unique genome editing machinery and at developing new tools for nucleic acid manipulation based on CRISPR-Cas9. PMID- 28652375 TI - Evolution of immune chemoreceptors into sensors of the outside world. AB - Changes in gene expression patterns represent an essential source of evolutionary innovation. A striking case of neofunctionalization is the acquisition of neuronal specificity by immune formyl peptide receptors (Fprs). In mammals, Fprs are expressed by immune cells, where they detect pathogenic and inflammatory chemical cues. In rodents, these receptors are also expressed by sensory neurons of the vomeronasal organ, an olfactory structure mediating innate avoidance behaviors. Here we show that two gene shuffling events led to two independent acquisitions of neuronal specificity by Fprs. The first event targeted the promoter of a V1R receptor gene. This was followed some 30 million years later by a second genomic accident targeting the promoter of a V2R gene. Finally, we show that expression of a vomeronasal Fpr can reverse back to the immune system under inflammatory conditions via the production of an intergenic transcript linking neuronal and immune Fpr genes. Thus, three hijackings of regulatory elements are sufficient to explain all aspects of the complex expression patterns acquired by a receptor family that switched from sensing pathogens inside the organism to sensing the outside world through the nose. PMID- 28652377 TI - Causal Genetic Variation Underlying Metabolome Differences. AB - An ongoing challenge in biology is to predict the phenotypes of individuals from their genotypes. Genetic variants that cause disease often change an individual's total metabolite profile, or metabolome. In light of our extensive knowledge of metabolic pathways, genetic variants that alter the metabolome may help predict novel phenotypes. To link genetic variants to changes in the metabolome, we studied natural variation in the yeast Saccharomyces cerevisiae We used an untargeted mass spectrometry method to identify dozens of metabolite Quantitative Trait Loci (mQTL), genomic regions containing genetic variation that control differences in metabolite levels between individuals. We mapped differences in urea cycle metabolites to genetic variation in specific genes known to regulate amino acid biosynthesis. Our functional assays reveal that genetic variation in two genes, AUA1 and ARG81, cause the differences in the abundance of several urea cycle metabolites. Based on knowledge of the urea cycle, we predicted and then validated a new phenotype: sensitivity to a particular class of amino acid isomers. Our results are a proof-of-concept that untargeted mass spectrometry can reveal links between natural genetic variants and metabolome diversity. The interpretability of our results demonstrates the promise of using genetic variants underlying natural differences in the metabolome to predict novel phenotypes from genotype. PMID- 28652376 TI - Protein homeostasis of a metastable subproteome associated with Alzheimer's disease. AB - Alzheimer's disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Abeta peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal-lysosomal and ubiquitin proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer's disease. PMID- 28652378 TI - Caenorhabditis elegans CES-1 Snail Represses pig-1 MELK Expression To Control Asymmetric Cell Division. AB - Snail-like transcription factors affect stem cell function through mechanisms that are incompletely understood. In the Caenorhabditis elegans neurosecretory motor neuron (NSM) neuroblast lineage, CES-1 Snail coordinates cell cycle progression and cell polarity to ensure the asymmetric division of the NSM neuroblast and the generation of two daughter cells of different sizes and fates. We have previously shown that CES-1 Snail controls cell cycle progression by repressing the expression of cdc-25.2 CDC25. However, the mechanism through which CES-1 Snail affects cell polarity has been elusive. Here, we systematically searched for direct targets of CES-1 Snail by genome-wide profiling of CES-1 Snail binding sites and identified >3000 potential CES-1 Snail target genes, including pig-1, the ortholog of the oncogene maternal embryonic leucine zipper kinase (MELK). Furthermore, we show that CES-1 Snail represses pig-1 MELK transcription in the NSM neuroblast lineage and that pig-1 MELK acts downstream of ces-1 Snail to cause the NSM neuroblast to divide asymmetrically by size and along the correct cell division axis. Based on our results we propose that by regulating the expression of the MELK gene, Snail-like transcription factors affect the ability of stem cells to divide asymmetrically and, hence, to self renew. Furthermore, we speculate that the deregulation of MELK contributes to tumorigenesis by causing cells that normally divide asymmetrically to divide symmetrically instead. PMID- 28652379 TI - The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1. AB - The abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with a poorly differentiated and aggressive phenotype of mammary carcinomas. This long non-coding RNA (lncRNA) localizes to nuclear speckles, where it interacts with a subset of splicing factors and modulates their activity. In this study, we demonstrate that oncogenic splicing factor SRSF1 bridges MALAT1 to mutant p53 and ID4 proteins in breast cancer cells. Mutant p53 and ID4 delocalize MALAT1 from nuclear speckles and favor its association with chromatin. This enables aberrant recruitment of MALAT1 on VEGFA pre-mRNA and modulation of VEGFA isoforms expression. Interestingly, VEGFA-dependent expression signatures associate with ID4 expression specifically in basal-like breast cancers carrying TP53 mutations. Our results highlight a key role for MALAT1 in control of VEGFA isoforms expression in breast cancer cells expressing gain-of-function mutant p53 and ID4 proteins. PMID- 28652381 TI - Oxidative DNA damage during night shift work. AB - OBJECTIVES: We previously reported that compared with night sleep, day sleep among shift workers was associated with reduced urinary excretion of 8 hydroxydeoxyguanosine (8-OH-dG), potentially reflecting a reduced ability to repair 8-OH-dG lesions in DNA. We identified the absence of melatonin during day sleep as the likely causative factor. We now investigate whether night work is also associated with reduced urinary excretion of 8-OH-dG. METHODS: For this cross-sectional study, 50 shift workers with the largest negative differences in night work versus night sleep circulating melatonin levels (measured as 6 sulfatoxymelatonin in urine) were selected from among the 223 shift workers included in our previous study. 8-OH-dG concentrations were measured in stored urine samples using high performance liquid chromatography with electrochemical detection. Mixed effects models were used to compare night work versus night sleep 8-OH-dG levels. RESULTS: Circulating melatonin levels during night work (mean=17.1 ng/mg creatinine/mg creatinine) were much lower than during night sleep (mean=51.7 ng/mg creatinine). In adjusted analyses, average urinary 8-OH-dG levels during the night work period were only 20% of those observed during the night sleep period (95% CI 10% to 30%; p<0.001). CONCLUSIONS: This study suggests that night work, relative to night sleep, is associated with reduced repair of 8 OH-dG lesions in DNA and that the effect is likely driven by melatonin suppression occurring during night work relative to night sleep. If confirmed, future studies should evaluate melatonin supplementation as a means to restore oxidative DNA damage repair capacity among shift workers. PMID- 28652382 TI - US medical groups denounce Senate health repeal bill. PMID- 28652380 TI - Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition. AB - To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. (c)2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047. PMID- 28652383 TI - Cosmetic industry regulation is only skin deep. PMID- 28652384 TI - BMA annual meeting: UK government must act to avert future medical workforce crises, says BMA. PMID- 28652385 TI - Margaret McCartney: Are GPs specialists in life? PMID- 28652387 TI - Putting Into Perspective the Hazards of Untreated Familial Hypercholesterolemia. PMID- 28652386 TI - Long-Term Cardiovascular Risk in Heterozygous Familial Hypercholesterolemia Relatives Identified by Cascade Screening. AB - BACKGROUND: Heterozygous familial hypercholesterolemia increases the risk of adverse cardiovascular events. Whether affected relatives of probands are at increased risk remains unknown. We aimed to evaluate the long-term cardiovascular risk in heterozygous familial hypercholesterolemia relatives with a low-density lipoprotein receptor (LDLR) mutation who were all recommended statin therapy. METHODS AND RESULTS: Participants were identified by cascade screening at Aarhus University Hospital during 1992-1994. A comparison cohort from the Danish general population was matched 10:1 to relatives by birth year and sex. Using medical registries, participants were followed until the event of interest, migration, death, or end of follow-up on December 31, 2014. The primary end point was all cause mortality and major adverse cardiovascular events comprising myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, and coronary revascularization. We included 220 relatives. Median age was 37 years (interquartile range: 27-52 years) of which 118 (54%) had an LDLR mutation. By 2004, when prescription data became available, 89% of mutation carrying participants were taking statins during their follow-up period. Despite frequent use of lipid-lowering medication, the adjusted hazard ratio of the primary end point was 1.65 (95% confidence interval, 1.17-2.33) in mutation carrying relatives compared with the general population cohort. The risk in non mutation-carrying relatives was not different from that of the general population cohort (adjusted hazard ratio: 0.85; 95% confidence interval, 0.56-1.29). Comparing mutation-carrying relatives with non-mutation-carrying relatives, the adjusted hazard ratio was 1.94 (95% confidence interval, 1.14-3.31). Results were driven by nonfatal events. CONCLUSION: Heterozygous familial hypercholesterolemia relatives with an LDLR mutation had an increased long-term risk of adverse cardiovascular events. PMID- 28652388 TI - Optimization of Thermolytic Response to A1 Adenosine Receptor Agonists in Rats. AB - Cardiac arrest is a leading cause of death in the United States, and, currently, therapeutic hypothermia, now called targeted temperature management (TTM), is the only recent treatment modality proven to increase survival rates and reduce morbidity for this condition. Shivering and subsequent metabolic stress, however, limit application and benefit of TTM. Stimulating central nervous system A1 adenosine receptors (A1AR) inhibits shivering and nonshivering thermogenesis in rats and induces a hibernation-like response in hibernating species. In this study, we investigated the pharmacodynamics of two A1AR agonists in development as antishivering agents. To optimize body temperature (Tb) control, we evaluated the influence of every-other-day feeding, dose, drug, and ambient temperature (Ta) on the Tb-lowering effects of N6-cyclohexyladenosine (CHA) and the partial A1AR agonist capadenoson in rats. The highest dose of CHA (1.0 mg/kg, i.p.) caused all ad libitum-fed animals tested to reach our target Tb of 32 degrees C, but responses varied and some rats overcooled to a Tb as low as 21 degrees C at 17.0 degrees C Ta Dietary restriction normalized the response to CHA. The partial agonist capadenoson (1.0 or 2.0 mg/kg, i.p.) produced a more consistent response, but the highest dose decreased Tb by only 1.6 degrees C. To prevent overcooling after CHA, we studied continuous i.v. administration in combination with dynamic surface temperature control. Results show that after CHA administration control of surface temperature maintains desired target Tb better than dose or ambient temperature. PMID- 28652390 TI - Thoracic MRI is preferable for neuroblastoma. PMID- 28652391 TI - Author's reply to McHugh. PMID- 28652389 TI - Structural differences between yeast and mammalian microtubules revealed by cryo EM. AB - Microtubules are polymers of alphabeta-tubulin heterodimers essential for all eukaryotes. Despite sequence conservation, there are significant structural differences between microtubules assembled in vitro from mammalian or budding yeast tubulin. Yeast MTs were not observed to undergo compaction at the interdimer interface as seen for mammalian microtubules upon GTP hydrolysis. Lack of compaction might reflect slower GTP hydrolysis or a different degree of allosteric coupling in the lattice. The microtubule plus end-tracking protein Bim1 binds yeast microtubules both between alphabeta-tubulin heterodimers, as seen for other organisms, and within tubulin dimers, but binds mammalian tubulin only at interdimer contacts. At the concentrations used in cryo-electron microscopy, Bim1 causes the compaction of yeast microtubules and induces their rapid disassembly. Our studies demonstrate structural differences between yeast and mammalian microtubules that likely underlie their differing polymerization dynamics. These differences may reflect adaptations to the demands of different cell size or range of physiological growth temperatures. PMID- 28652392 TI - BMA annual meeting: GMC must recognise that a lack of resources puts doctors at risk of mistakes, says the BMA. PMID- 28652394 TI - Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death. AB - Nucleotide-binding oligomerization domain (Nod)-containing proteins Nod1 and Nod2 play important roles in the innate immune response to pathogenic microbes, but mounting data suggest these pattern recognition receptors might also play key roles in adaptive immune responses. Targeting Nod1 and Nod2 signaling pathways in T cells is likely to provide a new strategy to modify inflammation in a variety of disease states, particularly those that depend on Ag-induced T cell activation. To better understand how Nod1 and Nod2 proteins contribute to adaptive immunity, this study investigated their role in alloantigen-induced T cell activation and asked whether their absence might impact in vivo alloresponses using a severe acute graft versus host disease model. The study provided several important observations. We found that the simultaneous absence of Nod1 and Nod2 primed T cells for activation-induced cell death. T cells from Nod1 * 2-/- mice rapidly underwent cell death upon exposure to alloantigen. The Nod1 * 2-/- T cells had sustained p53 expression that was associated with downregulation of its negative regulator MDM2. In vivo, mice transplanted with an inoculum containing Nod1 * 2-/- T cells were protected from severe graft versus host disease. The results show that the simultaneous absence of Nod1 and Nod2 is associated with accelerated T cell death upon alloantigen encounter, suggesting these proteins might provide new targets to ameliorate T cell responses in a variety of inflammatory states, including those associated with bone marrow or solid organ transplantation. PMID- 28652395 TI - Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection. AB - In response to acute viral infection, activated naive T cells give rise to effector T cells that clear the pathogen and memory T cells that persist long term and provide heightened protection. T cell factor 1 (Tcf1) is essential for several of these differentiation processes. Tcf1 is expressed in multiple isoforms, with all isoforms sharing the same HDAC and DNA-binding domains and the long isoforms containing a unique N-terminal beta-catenin-interacting domain. In this study, we specifically ablated Tcf1 long isoforms in mice, while retaining expression of Tcf1 short isoforms. During CD8+ T cell responses, Tcf1 long isoforms were dispensable for generating cytotoxic CD8+ effector T cells and maintaining memory CD8+ T cell pool size, but they contributed to optimal maturation of central memory CD8+ T cells and their optimal secondary expansion in a recall response. In contrast, Tcf1 long isoforms were required for differentiation of T follicular helper (TFH) cells, but not TH1 effectors, elicited by viral infection. Although Tcf1 short isoforms adequately supported Bcl6 and ICOS expression in TFH cells, Tcf1 long isoforms remained important for suppressing the expression of Blimp1 and TH1-associated genes and for positively regulating Id3 to restrain germinal center TFH cell differentiation. Furthermore, formation of memory TH1 and memory TFH cells strongly depended on Tcf1 long isoforms. These data reveal that Tcf1 long and short isoforms have distinct, yet complementary, functions and may represent an evolutionarily conserved means to ensure proper programming of CD8+ and CD4+ T cell responses to viral infection. PMID- 28652396 TI - TLR7 Signaling Regulates Th17 Cells and Autoimmunity: Novel Potential for Autoimmune Therapy. AB - Innate regulation through TLR signaling has been shown to be important for promoting T cell subset development and function. However, limited information is known about whether differential TLR signaling can selectively inhibit Th17 and/or Th1 cells, which are important for controlling excessive inflammation and autoimmune responses. In this article, we demonstrate that activation of TLR7 signaling in T cells can inhibit Th17 cell differentiation from naive T cells and IL-17 production in established Th17 cells. We further report that downregulation of STAT3 signaling is responsible for TLR7-mediated inhibition of Th17 cells due to induction of suppressor of cytokine signaling 3 and 5. TLR7-mediated suppression of Th17 cells does not require dendritic cell involvement. In addition, we show that TLR7 signaling can suppress Th1 cell development and function through a mechanism different from Th17 cell suppression. Importantly, our complementary in vivo studies demonstrate that treatment with the TLR7 ligand imiquimod can inhibit Th1 and Th17 cells, resulting in the prevention of, and an immunotherapeutic reduction in, experimental autoimmune encephalomyelitis. These studies identify a new strategy to manipulate Th17/Th1 cells through TLR7 signaling, with important implications for successful immunotherapy against autoimmune and inflammatory diseases. PMID- 28652398 TI - Cutting Edge: Eosinophils Undergo Caspase-1-Mediated Pyroptosis in Response to Necrotic Liver Cells. AB - Many chronic liver disorders are characterized by dysregulated immune responses and hepatocyte death. We used an in vivo model to study the immune response to necrotic liver injury and found that necrotic liver cells induced eosinophil recruitment. Necrotic liver induced eosinophil IL-1beta and IL-18 secretion, degranulation, and cell death. Caspase-1 inhibitors blocked all of these responses. Caspase-1-mediated cell death with accompanying cytokine release is the hallmark of a novel form of cell death termed pyroptosis. To confirm this response in a disease model, we isolated eosinophils from the livers of Schistosoma mansoni-infected mice. S. mansoni eggs lodge in the hepatic sinusoids of infected mice, resulting in hepatocyte death, inflammation, and progressive liver fibrosis. This response is typified by massive eosinophilia, and we were able to confirm pyroptosis in the infiltrating eosinophils. This demonstrated that pyroptosis is a cellular pathway used by eosinophils in response to large scale hepatic cell death. PMID- 28652397 TI - B Cells Produce Type 1 IFNs in Response to the TLR9 Agonist CpG-A Conjugated to Cationic Lipids. AB - B cells express the innate receptor, TLR9, which signals in response to unmethylated CpG sequences in microbial DNA. Of the two major classes of CpG containing oligonucleotides, CpG-A appears restricted to inducing type 1 IFN in innate immune cells and CpG-B to activating B cells to proliferate and produce Abs and inflammatory cytokines. Although CpGs are candidates for adjuvants to boost innate and adaptive immunity, our understanding of the effect of CpG-A and CpG-B on B cell responses is incomplete. In this study we show that both CpG-B and CpG-A activated B cells in vitro to proliferate, secrete Abs and IL-6, and that neither CpG-B nor CpG-A alone induced type 1 IFN production. However, when incorporated into the cationic lipid, DOTAP, CpG-A, but not CpG-B, induced a type 1 IFN response in B cells in vitro and in vivo. We provide evidence that differences in the function of CpG-A and CpG-B may be related to their intracellular trafficking in B cells. These findings fill an important gap in our understanding of the B cell response to CpGs, with implications for the use of CpG-A and CpG-B as immunomodulators. PMID- 28652399 TI - c-REL and IkappaBNS Govern Common and Independent Steps of Regulatory T Cell Development from Novel CD122-Expressing Pre-Precursors. AB - Foxp3-expressing regulatory T cells (Tregs) are essential regulators of immune homeostasis and, thus, are prime targets for therapeutic interventions of diseases such as cancer and autoimmunity. c-REL and IkappaBNS are important regulators of Foxp3 induction in Treg precursors upon gamma-chain cytokine stimulation. In c-REL/IkappaBNS double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IkappaBNS are pivotal for Treg development. However, despite the highly reduced Treg compartment, double-deficient mice did not develop autoimmunity even when aged to more than 1 y, suggesting that c-REL and IkappaBNS are required for T cell effector function as well. Analyzing Treg development in more detail, we identified a CD122+ subset within the CD25-Foxp3- precursor population, which gave rise to classical CD25+Foxp3- Treg precursors. Importantly, c-REL, but not IkappaBNS, controlled the generation of classical CD25+Foxp3- precursors via direct binding to the Cd25 locus. Thus, we propose that CD4+GITR+CD122+CD25-Foxp3- cells represent a Treg pre-precursor population, whose transition into Treg precursors is mediated via c REL. PMID- 28652400 TI - Activation of Human Basophils by A549 Lung Epithelial Cells Reveals a Novel IgE Dependent Response Independent of Allergen. AB - Evidence for epithelial cell (EC)-derived cytokines (e.g., thymic stromal lymphopoietin [TSLP]) activating human basophils remains controversial. We therefore hypothesize that ECs can directly activate basophils via cell-to-cell interaction. Basophils in medium alone or with IL-3 +/- anti-IgE were coincubated with TSLP, IL-33, or IL-25. Analogous experiments cocultured basophils (1-72 h) directly with EC lines. Supernatants were tested for mediators and cytokines. Abs targeting receptors were tested for neutralizing effects. Lactic acid (pH 3.9) treatment combined with passive sensitization tested the role of IgE. Overall, IL 33 augmented IL-13 secretion from basophils cotreated with IL-3, with minimal effects on histamine and IL-4. Conversely, basophils (but not mast cells) released histamine and marked levels of IL-4/IL-13 (10-fold) when cocultured with A549 EC and IL-3, without exogenous allergen or IgE cross-linking stimuli. The inability to detect IL-33 or TSLP, or to neutralize their activity, suggested a unique mode of basophil activation by A549 EC. Half-maximal rates for histamine (4 h) and IL-4 (5 h) secretion were slower than observed with standard IgE dependent activation. Ig stripping combined with passive sensitization +/- omalizumab showed a dependency for basophil-bound IgE, substantiated by a requirement for cell-to-cell contact, aggregation, and FcepsilonRI-dependent signaling. A yet unidentified IgE-binding lectin associated with A549 EC is implicated after discovering that LacNAc suppressed basophil activation in cocultures. These findings point to a lectin-dependent activation of basophil requiring IgE but independent of allergen or secreted cytokine. Pending further investigation, we predict this unique mode of activation is linked to inflammatory conditions whereby IgE-dependent activation of basophils occurs despite the absence of any known allergen. PMID- 28652401 TI - Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis. AB - von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic ADAMTS13 deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis thrombosis with the AP of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release, and complement activation. PMID- 28652403 TI - Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co internalize, and activate Akt signaling via endosomal recruitment of beta arrestin. AB - Vascular inflammation and thrombosis require the concerted actions of several different agonists, many of which act on G protein-coupled receptors (GPCRs). GPCR dimerization is a well-established phenomenon that can alter protomer function. In platelets and other cell types, protease-activated receptor-4 (PAR4) has been shown to dimerize with the purinergic receptor P2Y12 to coordinate beta arrestin-mediated Akt signaling, an important mediator of integrin activation. However, the mechanism by which the PAR4-P2Y12 dimer controls beta-arrestin dependent Akt signaling is not known. We now report that PAR4 and P2Y12 heterodimer internalization is required for beta-arrestin recruitment to endosomes and Akt signaling. Using bioluminescence resonance energy transfer, immunofluorescence microscopy, and co-immunoprecipitation in cells expressing receptors exogenously and endogenously, we demonstrate that PAR4 and P2Y12 specifically interact and form dimers expressed at the cell surface. We also found that activation of PAR4 but not of P2Y12 drives internalization of the PAR4 P2Y12 heterodimer. Remarkably, activated PAR4 internalization was required for recruitment of beta-arrestin to endocytic vesicles, which was dependent on co expression of P2Y12. Interestingly, stimulation of the PAR4-P2Y12 heterodimer promotes beta-arrestin and Akt co-localization to intracellular vesicles. Moreover, activated PAR4-P2Y12 internalization is required for sustained Akt activation. Thus, internalization of the PAR4-P2Y12 heterodimer is necessary for beta-arrestin recruitment to endosomes and Akt signaling and lays the foundation for examining whether blockade of PAR4 internalization reduces integrin and platelet activation. PMID- 28652404 TI - Current prospects of type II interferon gamma signaling and autoimmunity. AB - Interferon gamma (IFNgamma) is a pleiotropic protein secreted by immune cells. IFNgamma signals through the IFNgamma receptor, a protein complex that mediates downstream signaling events. Studies into IFNgamma signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFNgamma is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFNgamma signaling biology and the functional roles of IFNgamma in the autoimmune response. PMID- 28652405 TI - Mechanism of pathogen recognition by human dectin-2. AB - Dectin-2, a C-type lectin on macrophages and other cells of the innate immune system, functions in response to pathogens, particularly fungi. The carbohydrate recognition domain (CRD) in dectin-2 is linked to a transmembrane sequence that interacts with the common Fc receptor gamma subunit to initiate immune signaling. The molecular mechanism by which dectin-2 selectively binds to pathogens has been investigated by characterizing the CRD expressed in a bacterial system. Competition binding studies indicated that the CRD binds to monosaccharides with modest affinity and that affinity was greatly enhanced for mannose-linked alpha1 2 or alpha1-4 to a second mannose residue. Glycan array analysis confirmed selective binding of the CRD to glycans that contain Manalpha1-2Man epitopes. Crystals of the CRD in complex with a mammalian-type high-mannose Man9GlcNAc2 oligosaccharide exhibited interaction with Manalpha1-2Man on two different termini of the glycan, with the reducing-end mannose residue ligated to Ca2+ in a primary binding site and the nonreducing terminal mannose residue occupying an adjacent secondary site. Comparison of the binding sites in DC-SIGN and langerin, two other pathogen-binding receptors of the innate immune system, revealed why these two binding sites accommodate only terminal Manalpha1-2Man structures, whereas dectin-2 can bind Manalpha1-2Man in internal positions in mannans and other polysaccharides. The specificity and geometry of the dectin-2-binding site provide the molecular mechanism for binding of dectin-2 to fungal mannans and also to bacterial lipopolysaccharides, capsular polysaccharides, and lipoarabinomannans that contain the Manalpha1-2Man disaccharide unit. PMID- 28652406 TI - Deciphering the role of the signal- and Sty1 kinase-dependent phosphorylation of the stress-responsive transcription factor Atf1 on gene activation. AB - Adaptation to stress triggers the most dramatic shift in gene expression in fission yeast (Schizosaccharomyces pombe), and this response is driven by signaling via the MAPK Sty1. Upon activation, Sty1 accumulates in the nucleus and stimulates expression of hundreds of genes via the nuclear transcription factor Atf1, including expression of atf1 itself. However, the role of stress-induced, Sty1-mediated Atf1 phosphorylation in transcriptional activation is unclear. To this end, we expressed Atf1 phosphorylation mutants from a constitutive promoter to uncouple Atf1 activity from endogenous, stress-activated Atf1 expression. We found that cells expressing a nonphosphorylatable Atf1 variant are sensitive to oxidative stress because of impaired transcription of a subset of stress genes whose expression is also controlled by another transcription factor, Pap1. Furthermore, cells expressing a phospho-mimicking Atf1 mutant display enhanced stress resistance, and although expression of the Pap1-dependent genes still relied on stress induction, another subset of stress-responsive genes was constitutively expressed in these cells. We also observed that, in cells expressing the phospho-mimicking Atf1 mutant, the presence of Sty1 was completely dispensable, with all stress defects of Sty1-deficient cells being suppressed by expression of the Atf1 mutant. We further demonstrated that Sty1-mediated Atf1 phosphorylation does not stimulate binding of Atf1 to DNA but, rather, establishes a platform of interactions with the basal transcriptional machinery to facilitate transcription initiation. In summary, our results provide evidence that Atf1 phosphorylation by the MAPK Sty1 is required for oxidative stress responses in fission yeast cells by promoting transcription initiation. PMID- 28652407 TI - Arginine methylation regulates c-Myc-dependent transcription by altering promoter recruitment of the acetyltransferase p300. AB - Protein arginine methyltransferase 1 (PRMT1) is an essential enzyme controlling about 85% of the total cellular arginine methylation in proteins. We have shown previously that PRMT1 is an important regulator of innate immune responses and that it is required for M2 macrophage differentiation. c-Myc is a transcription factor that is critical in regulating cell proliferation and also regulates the M2 transcriptional program in macrophages. Here, we sought to determine whether c Myc in myeloid cells is regulated by PRMT1-dependent arginine methylation. We found that PRMT1 activity was necessary for c-Myc binding to the acetyltransferase p300. PRMT1 inhibition decreased p300 recruitment to c-Myc target promoters and increased histone deacetylase 1 (HDAC1) recruitment, thereby decreasing transcription at these sites. Moreover, PRMT1 inhibition blocked c-Myc mediated induction of several of its target genes, including peroxisome proliferator-activated receptor gamma (PPARG) and mannose receptor C-type 1 (MRC1), suggesting that PRMT1 is necessary for c-Myc function in M2 macrophage differentiation. Of note, in primary human blood monocytes, p300-c-Myc binding was strongly correlated with PRMT1 expression, and in liver sections, PRMT1, c Myc, and M2 macrophage levels were strongly correlated with each other. Both PRMT1 levels and M2 macrophage numbers were significantly lower in livers from individuals with a history of spontaneous bacterial peritonitis, known to have defective cellular immunity. In conclusion, our findings demonstrate that PRMT1 is an important regulator of c-Myc function in myeloid cells. PRMT1 loss in individuals with cirrhosis may contribute to their immune defects. PMID- 28652408 TI - The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation. AB - Kindlin-2 (K2), a 4.1R-ezrin-radixin-moesin (FERM) domain adaptor protein, mediates numerous cellular responses, including integrin activation. The C terminal 15-amino acid sequence of K2 is remarkably conserved across species but is absent in canonical FERM proteins, including talin. In CHO cells expressing integrin alphaIIbbeta3, co-expression of K2 with talin head domain resulted in robust integrin activation, but this co-activation was lost after deletion of as few as seven amino acids from the K2 C terminus. This dependence on the C terminus was also observed in activation of endogenous alphaIIbbeta3 in human erythroleukemia (HEL) cells and beta1 integrin activation in macrophage-like RAW264.1 cells. Kindlin-1 (K1) exhibited a similar dependence on its C terminus for integrin activation. Expression of the K2 C terminus as an extension of membrane-anchored P-selectin glycoprotein ligand-1 (PSGL-1) inhibited integrin dependent cell spreading. Deletion of the K2 C terminus did not affect its binding to the integrin beta3 cytoplasmic tail, but combined biochemical and NMR analyses indicated that it can insert into the F2 subdomain. We suggest that this insertion determines the topology of the K2 FERM domain, and its deletion may affect the positioning of the membrane-binding functions of the F2 subdomain and the integrin-binding properties of its F3 subdomain. Free C-terminal peptide can still bind to K2 and displace the endogenous K2 C terminus but may not restore the conformation needed for integrin co-activation. Our findings indicate that the extreme C terminus of K2 is essential for integrin co-activation and highlight the importance of an atypical architecture of the K2 FERM domain in regulating integrin activation. PMID- 28652410 TI - Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain. AB - Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein-protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain.SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC function. The results suggest that at least some FX-specific neurological defects can be rescued in the adult FX brain after development. PMID- 28652409 TI - Interaction between the PH and START domains of ceramide transfer protein competes with phosphatidylinositol 4-phosphate binding by the PH domain. AB - De novo synthesis of the sphingolipid sphingomyelin requires non-vesicular transport of ceramide from the endoplasmic reticulum to the Golgi by the multidomain protein ceramide transfer protein (CERT). CERT's N-terminal pleckstrin homology (PH) domain targets it to the Golgi by binding to phosphatidylinositol 4-phosphate (PtdIns(4)P) in the Golgi membrane, whereas its C-terminal StAR-related lipid transfer domain (START) carries out ceramide transfer. Hyperphosphorylation of a serine-rich motif immediately after the PH domain decreases both PtdIns(4)P binding and ceramide transfer by CERT. This down regulation requires both the PH and START domains, suggesting a possible inhibitory interaction between the two domains. In this study we show that isolated PH and START domains interact with each other. The crystal structure of a PH-START complex revealed that the START domain binds to the PH domain at the same site for PtdIns(4)P-binding, suggesting that the START domain competes with PtdIns(4)P for association with the PH domain. We further report that mutations disrupting the PH-START interaction increase both PtdIns(4)P-binding affinity and ceramide transfer activity of a CERT-serine-rich phosphorylation mimic. We also found that these mutations increase the Golgi localization of CERT inside the cell, consistent with enhanced PtdIns(4)P binding of the mutant. Collectively, our structural, biochemical, and cellular investigations provide important structural insight into the regulation of CERT function and localization. PMID- 28652411 TI - Saturation in Phosphene Size with Increasing Current Levels Delivered to Human Visual Cortex. AB - Electrically stimulating early visual cortex results in a visual percept known as a phosphene. Although phosphenes can be evoked by a wide range of electrode sizes and current amplitudes, they are invariably described as small. To better understand this observation, we electrically stimulated 93 electrodes implanted in the visual cortex of 13 human subjects who reported phosphene size while stimulation current was varied. Phosphene size increased as the stimulation current was initially raised above threshold, but then rapidly reached saturation. Phosphene size also depended on the location of the stimulated site, with size increasing with distance from the foveal representation. We developed a model relating phosphene size to the amount of activated cortex and its location within the retinotopic map. First, a sigmoidal curve was used to predict the amount of activated cortex at a given current. Second, the amount of active cortex was converted to degrees of visual angle by multiplying by the inverse cortical magnification factor for that retinotopic location. This simple model accurately predicted phosphene size for a broad range of stimulation currents and cortical locations. The unexpected saturation in phosphene sizes suggests that the functional architecture of cerebral cortex may impose fundamental restrictions on the spread of artificially evoked activity and this may be an important consideration in the design of cortical prosthetic devices.SIGNIFICANCE STATEMENT Understanding the neural basis for phosphenes, the visual percepts created by electrical stimulation of visual cortex, is fundamental to the development of a visual cortical prosthetic. Our experiments in human subjects implanted with electrodes over visual cortex show that it is the activity of a large population of cells spread out across several millimeters of tissue that supports the perception of a phosphene. In addition, we describe an important feature of the production of phosphenes by electrical stimulation: phosphene size saturates at a relatively low current level. This finding implies that, with current methods, visual prosthetics will have a limited dynamic range available to control the production of spatial forms and that more advanced stimulation methods may be required. PMID- 28652412 TI - Extracellular Zn2+ Is Essential for Amyloid beta1-42-Induced Cognitive Decline in the Normal Brain and Its Rescue. AB - Brain Abeta1-42 accumulation is considered an upstream event in pathogenesis of Alzheimer's disease. However, accumulating evidence indicates that other neurochemical changes potentiate the toxicity of this constitutively generated peptide. Here we report that the interaction of Abeta1-42 with extracellular Zn2+ is essential for in vivo rapid uptake of Abeta1-42 and Zn2+ into dentate granule cells in the normal rat hippocampus. The uptake of both Abeta1-42 and Zn2+ was blocked by CaEDTA, an extracellular Zn2+ chelator, and by Cd2+, a metal that displaces Zn2+ for Abeta1-42 binding. In vivo perforant pathway LTP was unaffected by perfusion with 1000 nm Abeta1-42 in ACSF without Zn2+ However, LTP was attenuated under preperfusion with 5 nm Abeta1-42 in ACSF containing 10 nm Zn2+, recapitulating the concentration of extracellular Zn2+, but not with 5 nm Abeta1-40 in ACSF containing 10 nm Zn2+ Abeta1-40 and Zn2+ were not taken up into dentate granule cells under these conditions, consistent with lower affinity of Abeta1-40 for Zn2+ than Abeta1-42 Abeta1-42-induced attenuation of LTP was rescued by both CaEDTA and CdCl2, and was observed even with 500 pm Abeta1-42 Abeta1-42 injected into the dentate granule cell layer of rats induced a rapid memory disturbance that was also rescued by coinjection of CdCl2 The present study supports blocking the formation of Zn-Abeta1-42 in the extracellular compartment as an effective preventive strategy for Alzheimer's disease.SIGNIFICANCE STATEMENT Short-term memory loss occurs in normal elderly and increases in the predementia stage of Alzheimer's disease (AD). Amyloid-beta1 42 (Abeta1-42), a possible causing peptide in AD, is bound to Zn2+ in the extracellular compartment in the hippocampus induced short-term memory loss in the normal rat brain, suggesting that extracellular Zn2+ is essential for Abeta1 42-induced short-term memory loss. The evidence is important to find an effective preventive strategy for AD, which is blocking the formation of Zn-Abeta1-42 in the extracellular compartment. PMID- 28652413 TI - Dopaminergic Modulation of Synaptic Integration and Firing Patterns in the Rat Entopeduncular Nucleus. AB - Dopamine is known to differentially modulate the impact of cortical input to the striatum between the direct and indirect pathways of the basal ganglia (BG). However, the role of extrastriatal dopamine receptors (DRs) in BG information processing is less clear. To investigate the role of extrastriatal DRs, we studied their distribution and function in one of the output nuclei of the BG of the rodent, the entopeduncular nucleus (EP). qRT-PCR indicated that all DR subtypes were expressed by EP neurons, suggesting that both D1-like receptors (D1LRs) and D2-like receptors (D2LRs) were likely to affect information processing in the EP. Whole-cell recordings revealed that striatal inputs to the EP were potentiated by D1LRs whereas pallidal inputs to the EP were depressed by D2LRs. Changes to the paired-pulse ratio of inputs to the EP suggested that dopaminergic modulation of striatal inputs is mediated by postsynaptic receptors, and that of globus pallidus-evoked inputs is mediated by presynaptic receptors. We show that these changes in synaptic efficacy changed the information content of EP neuron firing. Overall, the findings suggest that the dopaminergic system affects the passage of feedforward information through the BG by modulating input divergence in the striatum and output convergence in the EP.SIGNIFICANCE STATEMENT The entopeduncular nucleus (EP), one of the basal ganglia (BG) output nuclei, is an important station in information processing in BG. However, it remains unclear how EP neurons encode information and how dopamine affects this process. This contrasts with the well established role of dopamine in the striatum, which is known to redistribute cortical input between the direct and indirect pathways. Here we show that, in symmetry with the striatum, dopamine controls the rebalancing of information flow between the two pathways in the EP. Specifically, we demonstrate that dopamine regulates EP activity by differentially modulating striatal and pallidal GABAergic inputs. These results call for a reassessment of current perspectives on BG information processing by highlighting the functional role of extrastriatal dopamine receptors. PMID- 28652414 TI - Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE epsilon4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance. AB - The present study was designed to investigate the effect of a genetic risk factor for Alzheimer's disease (AD), ApolipoproteinE epsilon4 (APOEepsilon4), on the ability of the brain to modulate activation in response to cognitive challenge in a lifespan sample of healthy human adults. A community-based sample of 181 cognitively intact, healthy adults were recruited from the Dallas-Fort Worth metroplex. Thirty-one APOEepsilon4+ individuals (48% women), derived from the parent sample, were matched based on sex, age, and years of education to 31 individuals who were APOEepsilon4-negative (APOEepsilon4-). Ages ranged from 20 to 86 years of age. Blood oxygen level-dependent functional magnetic resonance imaging was collected during the performance of a visuospatial distance judgment task with three parametric levels of difficulty. Multiple regression was used in a whole-brain analysis with age, APOE group, and their interaction predicting functional brain modulation in response to difficulty. Results revealed an interaction between age and APOE in a large cluster localized primarily to the bilateral precuneus. APOEepsilon4- individuals exhibited age-invariant modulation in response to task difficulty, whereas APOEepsilon4+ individuals showed age related reduction of modulation in response to increasing task difficulty compared with epsilon4- individuals. Decreased modulation in response to cognitive challenge was associated with reduced task accuracy as well as poorer name-face associative memory performance. Findings suggest that APOEepsilon4 is associated with a reduction in the ability of the brain to dynamically modulate in response to cognitive challenge. Coupled with a significant genetic risk factor for AD, changes in modulation may provide additional information toward identifying individuals potentially at risk for cognitive decline associated with preclinical AD.SIGNIFICANCE STATEMENT Understanding how risk factors for Alzheimer's disease (AD) affect brain function and cognition in healthy adult samples may help to identify the biomarkers needed to detect nonsymptomatic, preclinical phases of the disease. Findings from the current study show that ApolipoproteinE epsilon4-positive (APOEepsilon4+) individuals exhibit an altered lifespan trajectory in the ability of the brain to dynamically modulate function to cognitive challenge compared with APOEepsilon4- individuals. This effect manifests in otherwise healthy individuals who are at increased risk for AD in the precuneus, a salient region for early AD changes. Notably, these functional alterations are detrimental to performance, and thus, the combination of a genetic risk factor and altered modulation may provide important information for identifying individuals who are at increased risk for AD. PMID- 28652415 TI - Solid Pseudopapillary Tumor of the Pancreas: A Single-center Experience and Review of the Literature. AB - BACKGROUND: Solid pseudopapillary tumors (SPTs) of the pancreas are a rare occurrence, not exceeding 1-2% of all exocrine pancreatic tumors. SPT was first described in 1959 as "papillary tumor of the pancreas, benign or malignant" and affects mainly young women, in their second or third decade of age. These tumors are of low malignant potential, unclear pathogenesis, grow gradually and become considerably large before causing symptoms. A typical clinical presentation is often described by affected patients and, in some cases, an SPT is an incidental finding during the time the patient undergoes medical imaging studies for other health issues. SPT is frequently located at the head or tail of the pancreas. Metastases are rare but, when present, affect predominantly the liver. PATIENTS AND METHODS: We report a series of five SPT cases in female patients 13-47 years old, presenting with almost identical symptoms of upper abdominal discomfort and non-tender palpable mass. Two out of five patients also reported vomiting, nausea and poor appetite as co-existing non-diagnostic symptoms. Only one patient presented without any symptoms. Tumor location and dimensions varied. One patient underwent a pancreatoduodenectomy (Whipple's procedure), while the remaining patients underwent distal pancreatectomy with concomitant splenectomy. RESULTS: Perioperative morbidity and mortality was zero. All five patients are disease free at a follow-up from 3 months to 13 years. Histopathology reports supported the diagnosis of SPT and no metastatic disease was present in any of the patients. CONCLUSION: The overall prognosis of SPT of the pancreas is excellent due to its favorable biological features, even in the presence of distal metastasis. Although surgical resection is often curative, a close follow-up is advised in order to diagnose a possible local recurrence or distal metastasis and choose the proper therapeutic option for the patients. PMID- 28652418 TI - Enhancement of Wound Healing by the Traditional Chinese Medicine Herbal Mixture Sophora flavescens in a Rat Model of Perianal Ulceration. AB - BACKGROUND/AIM: Hemorrhoidectomy is often associated with significant postoperative complications that may result in slow wound healing. The traditional Chinese medicine (TCM) compound Sophora flavescens (CSF) has shown efficacy on many inflammatory disorders. The aim of the present study was to examine the efficacy of CSF on wound healing in a rat model of perianal ulceration. MATERIALS AND METHODS: A rat model of perianal ulceration was induced by subcutaneous injection of 75% glacial acetic acid. The animals with induced perianal ulcer received topical treatment of low, medium, and high doses of CFS twice daily. Potassium permanganate (PP); 0.02%) was given to the animals for comparison. Macroscopic and histological assessments of the ulcerated area were performed after treatment. The expression of pro-inflammatory cytokines prostaglandin E2 (PGE2) and interleukin-8 (IL-8) was detected by immunohistochemical analysis. RESULTS: Topical administration of medium- and high dose CSF significantly enhanced perianal ulcer healing as compared to the untreated control (p<0.05). The macroscopic ulceration score was significantly reduced only in the high-dose CSF-treated group as compared to the control (p<0.01). All doses of CSF and PP ameliorated histological damages in the rats with induced perianal ulceration. High-dose CSF or PP significantly reduced the expression of PGE2 and IL-8 as compared to the control (p<0.01). No treatment related toxicity was found in either the CSF- or the PP-treated mice. CONCLUSION: CSF enhances wound healing in a rat model of perianal ulceration. The inhibitory effect of CSF on pro-inflammatory cytokines PGE2 and IL-8 may be involved in the mechanism of enhanced wound-healing. PMID- 28652417 TI - K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas. AB - K-ras oncogene is a key factor in colorectal cancer. Based on published and our data we propose that K-ras could be the oncogene responsible for the inactivation of the tumor-suppressor gene APC, currently considered as the initial step in colorectal tumorigenesis. K-ras fulfills the criteria of the oncogene-induced DNA damage model, as it can provoke well-established causes for inactivating tumor suppressors, i.e. DNA double-strand breaks (causing allele deletion) and ROS production (responsible for point mutation). The model we propose is a variation of the currently existing model and hypothesizes that, in a subgroup of colorectal carcinomas, K-ras mutation may precede APC inactivation, representing the earliest driving force and, probably, an early biomarker of colorectal carcinogenesis. This observation is clinically useful, since it may modify the preventive colorectal cancer strategy, restricting numerically patients undergoing colonoscopies to those bearing K-ras mutation in their colorectum, either in benign polyps or the normal accompanying mucosa. PMID- 28652419 TI - Resveratrol Attenuates Nicotine-mediated Oxidative Injury by Inducing Manganese Superoxide Dismutase in Renal Proximal Tubule Cells. AB - BACKGROUND/AIM: Nicotine (NIC) exposure - via smoking and the increasingly popular E-cigarettes- increases oxidative stress and hence, renal risk in smokers. Resveratrol (RES) may help ameliorate this risk by mounting anti-oxidant responses in the kidney. MATERIALS AND METHODS: Renal proximal tubule cells (NRK52E) were treated with vehicle or 20 MUM RES prior to treatment with 200 MUM NIC and generation of reactive oxygen species (ROS) as well as cell viability was determined. RES-induced antioxidant responses were determined in reporter luciferase assays. Gene silencing was used to determine mechanism of RES action. RESULTS: RES protected NRK52E cells from NIC-induced oxidative injury. RES activated the promoter of the anti-oxidant manganese superoxide dismutase (MnSOD) gene via activation of the forkhead box O (FoxO3a) transcription factor. Silencing of MnSOD abolished the protective effects of RES on NIC-associated oxidative injury. CONCLUSION: RES may provide protection to the kidney from the adverse effects of NIC in smokers. PMID- 28652416 TI - Mitochondrial Membrane Dynamics and Inherited Optic Neuropathies. AB - Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and non-syndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical - even in asymptomatic patients - for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities. PMID- 28652420 TI - Cerebral Perfusion After Repair of Congenital Diaphragmatic Hernia with Common Carotid Artery Occlusion After ECMO Therapy. AB - AIM: To prospectively evaluate cerebral perfusion after repair of congenital diaphragmatic hernia (CDH) and right-common-carotid-artery (rCCA) occlusion after extracorporeal membrane oxygenation (ECMO) therapy. PATIENTS AND METHODS: A total of 29 2-year-old-children with a history of CDH repair underwent cerebral magnetic resonance perfusion imaging. In 14 patients, the rCCA was occluded after ECMO therapy. Fifteen patients with CDH without ECMO served as controls. Regional cerebral-blood-flow (rCBF) was measured cortically and subcortically in both hemispheres and compared intra-individually and between both groups. RESULTS: Patients with rCCA-occlusion showed intra-individual side differences between hemispheres, with significantly lower subcortical perfusion of the right hemisphere and reduced cortical perfusion. In one-third of patients with rCCA occlusion, rCBF of the right-hemisphere was reduced by more than 20% when compared to the left hemisphere. Despite intra-individual side differences, mean rCBF in patients with rCCA occlusion was not reduced compared to controls. CONCLUSION: Beside intra-individual side differences, overall right hemisphere perfusion is sufficient after rCCA-occlusion due to collateral blood supply. PMID- 28652421 TI - Clinical Significance of INHBA Gene Expression in Patients with Gastric Cancer who Receive Curative Resection Followed by Adjuvant S-1 Chemotherapy. AB - BACKGROUND: Standard treatment for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. However, the five-year survival remains unsatisfactory. Inhibin betaA (INHBA) has been reported to be associated with cancer cell proliferation and chemoresistance. PATIENTS AND METHODS: We studied the clinical significance of INHBA gene expression in 134 patients with stage II/III gastric cancer who received adjuvant chemotherapy with S-1. INHBA expression of specimens of cancer tissue and adjacent normal mucosa was measured by quantitative real-time, reverse-transcription polymerase chain reaction (RT PCR). RESULTS: INHBA expression levels were significantly higher in cancer tissue than in adjacent normal mucosa. High INHBA expression was associated with significantly poorer 5-year survival than was low expression. On multivariate analysis, INHBA expression was an independent prognostic factor. CONCLUSION: INHBA gene expression in gastric cancer tissue is considered a useful independent predictor of outcomes in patients with stage II/III gastric cancer who receive adjuvant chemotherapy with S-1. PMID- 28652422 TI - Improvement Effect of Dewaxed Brown Rice on Constipation in Antibiotic-treated Mice. AB - BACKGROUND/AIM: A decrease in gastrointestinal motility causing weakened lipopolysaccharide (LPS) - toll-like receptor (TLR)4 signaling along with a decline in the number of enteric bacteria is known to be a cause of constipation due to the administration of antibiotics. A new type of brown rice with its wax layer removed, resulting in quick-cooking and tasty product, contains 100-times more LPS than polished white rice. In this study, the improvement effect on constipation due to intake of dewaxed brown rice was examined. MATERIALS AND METHODS: Dewaxed brown rice was prepared at Toyo Rice from brown rice. Mice were given powdered feed to which powdered rice containing 0-50% of dewaxed brown rice was added. Antibiotics were administered for 10 or 27 days in drinking water containing vancomycin, metronidazole and neomycin. LPS, used as a control, was freely provided in drinking water. The defecation frequency, stool weight per hour and body weight were determined on the last day. RESULTS: Although the 10 day administration of antibiotics reduced the stool weight per hour to half, the dewaxed brown rice and LPS groups showed a trend towards improvement at a level comparable to the group receiving no antibiotics. The body weight significantly decreased after the 27-day administration of antibiotics but was improved in the 50% dewaxed brown rice group at a level comparable to the group receiving no antibiotics. Though the defecation frequency and wet and dry stool weights per hour were reduced by as much as 50% in the group receiving antibiotics, a significant improvement in constipation was observed in the 50% dewaxed brown rice group. CONCLUSION: As the improvement effect of dewaxed brown rice on body weight loss and constipation caused by the long-term administration of antibiotics has been confirmed in animal experimentation, the introduction of dewaxed brown rice as a staple food to patients under long-term antibiotic treatment may improve constipation. PMID- 28652423 TI - Microbicidal Effects of Stored Aqueous Ozone Solution Generated by Nano-bubble Technology. AB - BACKGROUND/AIM: Clinically used disinfectants are often irritating and cause skin problems. Ozone water is unique among disinfectants. It does not damage skin cells and readily decomposes to oxygen without generating harmful residues. On the other hand, it rapidly loses its sanitizing activity. Recently developed nano bubble ozone water (NBOW) can keep its sanitizing activity much longer. This study aimed to examine the microbicidal effects of NBOW after long-term storage. MATERIALS AND METHODS: The concentration of ozone in NBOW was examined by measuring the NBOW redox potential. Microbicidal activity was evaluated by colony formation assays, after incubating bacteria with NBOW for set time periods. RESULTS: NBOW lost its microbicidal activity after 1 year of storage at 4 degrees C. Stocked frozen, NBOW retained appreciable microbicidal activity after 1 year of storage. Mycobacterium smegmatis, one of the most disinfectant-resistant bacteria, was killed within 15 min. NBOW was resistant to freeze-thawing. CONCLUSION: NBOW that had been stored frozen possessed sufficient microbicidal activity to kill bacteria even after 1 year of storage. Moreover, it was shown that NBOW is freeze-thaw resistant. NBOW possesses desirable features rendering it an attractive alternative disinfectant. PMID- 28652424 TI - The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility. AB - BACKGROUND/AIM: Metalloproteinases (MMPs) are a family of multifunctional proteins reported to be overexpressed in several types of cancers. However, the contribution of MMP8 genotype to oral cancer has not been elucidated. In this study, we focused on the contribution of polymorphisms in the promoter region of MMP-8 (C-799T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to Taiwanese oral cancer. MATERIALS AND METHODS: In this case-control study, MMP-8 genotype, was examined among 788 patients with oral cancer and 956 gender- and age-matched healthy controls regarding its potential to determine oral cancer risk. RESULTS: The distributions of MMP-8 C-799T, Val436Ala and Lys460Thr genotypes were not different between the oral cancer and non-cancer control groups. We also analyzed the allelic frequency distributions and no significant difference was found. As for gene-environment interaction analysis, there was an increased risk for smokers, alcohol drinkers or betel quid chewers with variant MMP-8 C-799T or Val436Ala genotypes. CONCLUSION: Our findings suggest that the polymorphisms at MMP-8 C-799T or Val436Ala may not play a major role in mediating personal risk of oral cancer; however, the detailed mechanisms require further investigation. PMID- 28652425 TI - Evaluation of Biological Activity of Mastic Extracts Based on Chemotherapeutic Indices. AB - BACKGROUND: Most previous mastic investigators have not considered its potent cytotoxicity that may significantly affect the interpretation of obtained data. In the present study, we re-evaluated several biological activities of mastic extracts, based on chemotherapeutic indexes. MATERIALS AND METHODS: Pulverized mastic gum was extracted with n-hexane and then with ethyl acetate or independently with methanol or n-butanol. Tumor specificity (TS) of the extracts was determined by their cytotoxicity against human malignant and non-malignant cells. Antibacterial activity was determined by their cytotoxicity against bacteria and normal oral cells. Antiviral activity was determined by their protection of viral infection and cytotoxic activity. Cytochrome P-450 (CYP) 3A4 activity was measured by beta-hydroxylation of testosterone. RESULTS: Ethyl acetate extract showed slightly higher tumor specificity (TS=2.6) and one order higher antibacterial activity (selectivity index (SI)=0.813) than other extracts (TS=1.4-2.5; SI=0.030-0.063). All extracts showed no anti-human immunodeficiency virus (HIV) activity, but some anti-herpes simplex virus (HSV) activity, which was masked by potent cytotoxicity. They showed strong inhibitory activity against CYP3A4. CONCLUSION: Ethyl acetate extraction following the removal of cytotoxic and CYP3A4 inhibitory substances by n-hexane can enhance antitumor and antibacterial activity of mastic. PMID- 28652426 TI - Transcriptome Analysis of Skin from SMP30/GNL Knockout Mice Reveals the Effect of Ascorbic Acid Deficiency on Skin and Hair. AB - BACKGROUND/AIM: Senescence marker protein-30/gluconolactonase knockout mice (SMP 30/GNL-KO) are a very useful model for clarifying the involvement of vitamin C (VC) in aging-related diseases. In this study, the effects of VC deficiency on skin and hair growth were investigated using SMP-30/GNL-KO mice by RNA sequencing. MATERIALS AND METHODS: SMP-30/GNL-KO mice were given water containing 1.5 g/l VC until up to 8 weeks after birth to maintain a VC concentration in their organs and plasma equivalent to that in wild-type mice. The mice were then divided into two groups: a VC(+) group, where VC was administered, and a VC(-) group, where VC was not administered. Skin samples were collected at 4 and 8 weeks after the treatment. RNA was extracted from each skin sample, followed by cDNA synthesis and RNA-seq. In addition, hair growth was compared between the VC( ) and VC(+) groups after shaving. Skin samples were collected from the shaved area for histological examination by hematoxylin & eosin (HE) staining. RESULTS: RNA-seq revealed that there were 1,736 (FDR<0.001) differentially expressed genes in the VC(-) and VC(+) groups. From the functional analysis of the differentially expressed genes in the VC(-) and VC(+) groups, predicted functionalities including cell death and cytotoxicity increased in the VC(+) group. Furthermore, it was predicted that the difference in hair growth between the VC(-) and VC(+) groups was caused by the expression of genes including keratin-related genes and the Sonic hedgehog gene. It was confirmed that hair growth was significantly promoted; hair growth from hair papilla cells was also confirmed by HE staining of the shaved backs of SMP-30/GNL-KO mice in the VC(+) group. CONCLUSION: RNA-seq of the skin from VC-deficient mice showed the effects of VC deficiency on the expression of genes involved in cell growth and the hair cycle. Visual inspection suggested that changes in the expression of the genes are involved in delaying hair growth in the VC(-) group. Further research on the relationship among VC deficiency, the hair cycle, and skin cell growth may contribute to research on hair restoration and skin aging. PMID- 28652427 TI - A Long-term Treatment with Silybin in Patients with Non-alcoholic Steatohepatitis Stimulates Catalase Activity in Human Endothelial Cells. AB - AIM: To compare levels of oxidative stress markers in patients' sera with non alcoholic steatohepatitis (NASH) treated for 12 months (T12) with silybin conjugated with phosphatidylcholine (Realsil(r)) (R) or placebo (P) and investigate oxidative stress responses in human endothelial cells conditioned with patients' sera. PATIENTS AND METHODS: We recruited twenty-seven patients with histological NASH. We measured thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase (CAT) activities in human endothelial cells conditioned with patients' sera exposed or not to H2O2 Results: We found in decreased-TBARS patients' sera, at T12, a decrease of alanine aminotransferase (p=0.038), transforming growth factor-beta (p=0.009) and procollagen I (p=0.001). By dividing patients into two groups, increased (P-I/R I) and decreased TBARS (P-II/R-II) at T12 compared to T0, we found an increased CAT activity in conditioned endothelial cells at T12 in both groups (p=0.05 and p=0.001, respectively). CONCLUSION: Realsil(r) may be effective against endothelial dysfunction by stimulating the cellular antioxidant defense. PMID- 28652428 TI - Grid-climbing Behaviour as a Pain Measure for Cancer-induced Bone Pain and Neuropathic Pain. AB - Despite affecting millions of people, chronic pain is generally treated insufficiently. A major point of focus has been the lack of translation from preclinical data to clinical results, with the predictive value of chronic pain models being a major concern. In contrast to current focus on stimulus-based nociceptive responses in preclinical research, development of behavioural tests designed to quantify suspension of normal behaviour is likely a more equivalent readout for human pain-assessment tests. In this study, we quantified grid climbing behaviour as a non-stimulus-evoked behavioural test for potential use as a measure of neuropathic and cancer-induced bone pain in mice. In both models, the grid-climbing test demonstrated pain-related sparing of the affected leg during climbing. In both models, the behaviour was reversed by administration of morphine, suggesting that the observed behaviour was pain-specific. PMID- 28652429 TI - MicroRNA-1 and MicroRNA-21 Individually Regulate Cellular Growth of Non-malignant and Malignant Renal Cells. AB - BACKGROUND/AIM: Due to its poor prognosis, it is increasingly necessary to understand the biology of renal cell cancer (RCC). Therefore, we investigated the role of microRNAs miR-1 and miR-21 in the growth of RCC cells compared to that of non-malignant renal cells. MATERIALS AND METHODS: Four malignant cell lines (Caki 1, 786-O, RCC4, A498) were examined regarding their cell growth, microRNA and telomerase expression, and were compared to non-malignant RC-124 renal cells. RESULTS: Inconsistencies appeared in the panel of RCC cells regarding antiproliferative and proliferative properties of miR-1 and miR-21, respectively. Notably, and most likely due to immortaliziation, non-malignant RC-124 cells exhibited telomerase expression and activity. CONCLUSION: miR-1 and miR-21 functionality in cancer progression, particularly in tumor growth, may be more dependent on the individual cellular context and may reflect RCC heterogeneity. Thus, both microRNAs, in combination with other stratifying biomarkers, may be useful in terms of RCC diagnosis, prognosis, or treatment response. PMID- 28652430 TI - The Contribution of MMP-7 Promoter Polymorphisms in Renal Cell Carcinoma. AB - BACKGROUND/AIM: Mounting evidence has suggested that polymorphisms in the promoters of matrix metalloproteinase (MMP) genes are associated with the risk of many types of cancer, but no study has ever explored these polymorphisms as biomarkers for renal cell cancer (RCC). Recently, it was suggested that serum MMP 7 levels have both diagnostic and prognostic potential for RCC. In this study, we focused on the contribution of two functional polymorphisms in the promoter region of MMP-7 (A-181G and C-153T) to RCC. MATERIALS AND METHODS: These two polymorphisms were genotyped in 92 patients with RCC and 580 controls by PRC-RFLP analysis. RESULTS: The results showed that there is no significant association of the RCC risk with the MMP-7 A-181G genotype, even after adjusted for the possible confounding factors. The MMP-7 C-153T polymorphism was not identified among the subjects investigated. CONCLUSION: Our findings suggest that the two MMP-7 polymorphisms A-181G and C-153T do not play a major role in determining personal susceptibility to RCC in Taiwan. PMID- 28652431 TI - Cortisol Levels and Gastrointestinal Disorders After Stressful Surgery in Rabbits. AB - Rabbits are widely used in biomedical studies because they are docile and manageable. However, they are prone to gastrointestinal disorders due to their vulnerability to stress. Eighteen adult rabbits were used for allogenic tracheal surgery. The tracheas for allograft, 20-mm length, were transplanted into 20-mm tracheal defects. Immediately after surgery, most rabbits suffered from poor appetite. Food and water intake gradually recovered within 7 days after surgery, but six rabbits had severe anorexia from day 7 post-surgery. Four of these rabbits developed symptoms of diarrhea after surgery; three of them died several days after the onset of diarrhea, while one rabbit recovered. Gastrointestinal disorders need to be prevented in rabbits undergoing stressful surgery. Furthermore, it is important to choose the proper type and dose of analgesics in order to relieve postoperative pain. With this observation in mind, rabbits are not considered to be an appropriate model for stressful surgery. PMID- 28652432 TI - Chromosome 7 Multiplication in EGFR-positive Lung Carcinomas Based on Tissue Microarray Analysis. AB - BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) over-activation is observed in significant proportions of non-small cell lung carcinomas (NSCLC). Our aim was to investigate the role of chromosome 7 multiplication with regard to its influence in EGFR expression, combined or not with gene amplification. MATERIALS AND METHODS: Using tissue microarray technology, fifty (n=50) primary NSCLCs were cored and re-embedded into the final recipient block. Immunohistochemistry (IHC) and also chromogenic in situ hybridization (CISH) were performed. RESULTS: EGFR expression at any level was detected in 40/50 (80%) cores. Over-expression was observed in 23/40 (57.5%) cases. Gene amplification was identified in 11/50 (22%) cases whereas chromosome 7 polysomy in 8/50 (16%) cases. Pure chromosome 7 multiplication alone led to low or moderate levels of expression. Overall EGFR expression was correlated with gene (p=0.001) and interestingly with chromosome 7 centromere numerical imbalances (p=0.004). CONCLUSION: EGFR expression is associated not only with amplification, but also with chromosome 7 centromere multiple copies. Chromosome 7 multiplication -due to centromere region amplification or true polysomy- is critical for applying monoclonal antibody targeted therapeutic strategies excluding the pure non amplified cases. PMID- 28652433 TI - Adipose Tissue Graft Improves Early but not Late Stages of Nerve Regeneration. AB - AIM: The aim of the study was to assess the effect of autologous fat graft on nerve regeneration by means of immunohistochemistry. MATERIALS AND METHODS: The rat sciatic nerve was used; complete transection followed by primary neurorrhaphy was performed on both hind legs, on the left side a processed fat graft was applied, surrounding the nerve. Nerve biopsies were collected and immunohistochemical procedures were performed for glial fibrillary acidic protein (GFAP) and for neurofilament-associated protein(NFAP). RESULTS: At 4 weeks, GFAP positive cells were observed in the connective tissue formed between the two nerve endings on the left side only. At 10 weeks, GFAP-positive structures were present and exhibited a tendency to become linear on both sides, with an increased density on the left. NFAP-positive expression was present in the left treated limb with a disorganized pattern. CONCLUSION: Adipose tissue led to the stimulation of GFAP-positive Schwann cells, which could have a positive impact on nerve regeneration in the clinical setting. PMID- 28652434 TI - Elevated IL-4 and IFN-gamma Levels in Muscle Tissue of Patients with Dermatomyositis. AB - BACKGROUND/AIM: To investigate the contribution of muscle tissue-derived cytokines in dermatomyositis (DM). MATERIALS AND METHODS: Muscle homogenates were prepared from deltoid muscle biopsy specimens of 10 patients with DM and eight controls with no pathological signs of myopathy. Interleukin (IL)-4, interferon (IFN)-gamma and IL-17 levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis. Muscle strength grades were recorded. RESULTS: Patients with DM showed significantly elevated muscle tissue IL-4 and IFN-gamma levels, whereas IL-17 levels were comparable between patients with DM and controls. Immunoblotting studies confirmed ELISA results. In DM muscle specimens, IL-4 and IFN-gamma levels were positively correlated, while no correlation was observed between IL-17 and the other two cytokines. Moreover, IL 4 and IFN-gamma levels were significantly negative correlated with muscle strength grades for the deltoid muscle. CONCLUSION: Our results confirm the involvement of T helper (Th) 1-type and Th2-type immunity in DM pathogenesis. Muscle tissue appears to contribute to muscle weakness in DM by producing inflammatory cytokines. PMID- 28652435 TI - Breast Cancer Prognosis for Young Patients. AB - BACKGROUND/AIMS: Breast cancer (BCa) prognostication is a vital element for providing effective treatment for patients with BCa. Studies suggest that ethnicity plays a greater role in the incidence and poor prognosis of BCa in younger women than in their older counterparts. Therefore, the goal of this study was to assess the association between age and ethnicity on the overall final prognosis. MATERIALS AND METHODS: Nottingham Prognostic Index (NPI) was used to analyze BCa prognosis using Howard University Cancer Center Tumor Registry and the National Cancer Institute's Surveillance, Epidemiology, and End Results BCa datasets. Patients were grouped according to their predicted prognosis based on NPI scheme. RESULTS: There was no correlation between the younger patients compared to their older counterparts for any of the prognostic clusters. The significance of ethnicity in poorer prognosis for younger age is not conclusive either. CONCLUSION: An extended prognostic tool/system needs to be evaluated for its usefulness in a clinical practice environment. PMID- 28652436 TI - Corrupted Colonic Crypts Bordering Regenerating Mucosal Ulcers in Ulcerative Colitis. AB - BACKGROUND/AIM: Histology in protracted ulcerative colitis (UC) discloses high numbers of chronic inflammatory cells and crypts with architectural distortions. In severe cases, ulcerations are frequently found. The histogenesis of colonic crypts with architectural distortions in UC remains elusive. A recent review of colectomy specimens from patients with UC revealed crypts surrounding mucosal ulcerations exhibiting severe architectural distortions. They were called corrupted colonic crypts, CCCs. MATERIAL AND METHODS: Archival hematoxylin and eosin (H&E)-stained sections from three colectomies having several mucosal ulcers were selected for the study. The mucosa bordering mucosal ulcers was particularly scrutinized. RESULTS: The review of 49 sections (mean=16.3, range=14-20) in the three colectomies revealed 60 ulcers (mean=20, range=13-27). The following CCC phenotypes were found bordering mucosal ulcers: with asymmetric lateral fission (n=11), with dual or three-foiled corrupted fission (n=19), with cystic dilatations (n=3), L-shaped crypts (n=7), T-inverted crypts (n=6), shoe-shaped crypts (n=3), horizontal crypts (n=14), multi-lobate crypts (n=2), and/or inter connecting crypts (n=5). CONCLUSION: The regeneration of ulcers in UC seems to proceed with neo-formation of corrupted crypts. In the same colectomies, none to occasional CCCs were found in large areas of the mucosa having severe chronic inflammation. Importantly, none of the occasional CCCs were found in other diseases of the colonic mucosa with chronic inflammation or in unspecific ulcers of the colon. Since neither chronic mucosal inflammation per se, nor unspecific ulcers of the colon are central for the formation of CCCs, it is suggested that crypt distortions of the non-ulcerated colonic mucosa in patients with UC might mirror formerly healed mucosal ulcerations. PMID- 28652437 TI - Increased Resistance of Skin Flora to Antimicrobial Prophylaxis in Patients Undergoing Hip Revision Arthroplasty. AB - BACKGROUND/AIM: Prosthetic joint infection (PJI) remains a major complication after total joint replacement and is the primary indication for revision arthroplasty. Specifically, coagulase-negative Staphylococci (CNS) can cause low grade infections. Despite the use of cephalosporin-based antimicrobial prophylaxis (AMP) and antiseptic treatment at the surgical site, evidence suggests that a significant number of cases of dermal CNS results in low-grade PJI. Thus, this study examined the bacterial colonization and resistance patterns at the surgical site. We hypothesized that the bacteria developed resistance to antibiotics that are frequently used in primary and revision total hip arthroplasty (THA) procedures. PATIENTS AND METHODS: Ninety patients, including 63 primary and 27 revision THA patients, were enrolled in this study. For each patient, a single swab of the skin at the surgical site was subjected to clinical microbiology to assess bacterial colonization. Furthermore, resistance to a sentinel panel of antibiotics (benzylpenicillin, erythromycin, tetracycline, oxacillin, fusidic acid, clindamycin, gentamicin, levofloxacin/moxifloxacin, rifampicin, linezolid and vancomycin) was tested. RESULTS: In 96.7% of the patients, at least one bacterial strain was identified at the surgical site, with CNS strains comprising 93.1% of the total. The sentinel panel showed that 30.7% of the CNS strains exhibited maximal resistance to oxacillin, a commonly used cephalosporin. Additionally, oxacillin resistance increased 1.9-fold (p=0.042) between primary and revision THA. Notably, 8.1% of the CNS stains found on patients undergoing primary THA were resistant to gentamicin, an aminoglycoside, and this rate increased 4.7-fold (p=0.001) for patients undergoing revision THA. CONCLUSION: CNS strains have significant resistance to standard AMP, particularly in individuals undergoing revision THA. PMID- 28652438 TI - A Head to Head Comparison Between SurgiMend(r) - Fetal Bovine Acellular Dermal Matrix and Tutomesh(r) - A Bovine Pericardium Collagen Membrane in Breast Reconstruction in 45 Cases. AB - BACKGROUND/AIM: The use of acellular dermal matrices (ADM) has become a widely used option in breast reconstruction. A great deal of literature is available, totaling over 3,200 ADM reconstructions. Head-to-head comparisons between SurgiMend(r) and Tutomesh(r) are not yet reported. These are the first comparative clinical data reported on the use of Tutomesh(r) in breast reconstruction. Postoperative complication rates and costs for these devices were evaluated. PATIENTS AND METHODS: This is a retrospective analysis of a 2-year experience with both SurgiMend(r) - fetal bovine acellular dermal matrix and Tutomesh(r) - a bovine pericardium collagen membrane in breast reconstruction in 45 cases from 2014-2015. RESULTS: Forty-five patients received a total of 45 implant-based reconstructions using SurgiMend(r) (18 cases; 40%) or Tutomesh(r) (27 cases; 60%). Gross complication rates were 27.8% for SurgiMend(r) and 37.0% for Tutomesh(r) including hematoma, postoperative skin irritation, infection, red breast syndrome and revision surgery. The most common complication was postoperative red breast syndrome. Severe complications requiring revision surgery did not differ significantly in patients treated with SurgiMend(r) (0 cases, 0%) compared to Tutomesh(r) (1 case, 3.7%). CONCLUSION: This retrospective analysis shows similar overall clinical complication rates for Tutomesh(r) and SurgiMend(r). Severe complication rates are comparable to those reported in literature for both products. Although the retrospective nature of this work limits its clinical impact, it is possible to opt for the cheaper alternative (Tutomesh(r)). PMID- 28652439 TI - Which Is the Safer Anastomotic Method for Colon Surgery? - Ten-year Results. AB - BACKGROUND/AIM: In colon surgery, the anastomotic method is generally selected by surgeon's preferences or by local conditions. In this study, we retrospectively analyzed anastomotic complications to assess safe methods of anastomosis in colonic resection. PATIENTS AND METHODS: We retrospectively analyzed a total of 684 cases, performed between July 2003 and June 2013 in our Hospital. Anastomosis complications, such as leakage, stricture and bleeding, were analyzed in relation to the three methods of anastomosis, hand-sewn (HS), functional end-to-end (FEEA) and triangulating anastomosis (TRI). RESULTS: Univariate analysis indicated that the incidence of leakage was significantly lower in laparoscopic surgeries (p=0.034) and TRI (p=0.047). The results of the multivariable analysis indicated that anastomotic leakage was significantly less with TRI (p=0.029). CONCLUSION: In colon surgery, TRI seems to be associated with a low risk of anastomotic leakage compared to HS and FEEA. PMID- 28652440 TI - A Survival Score Based on Symptoms and Performance Status for Patients with High grade Gliomas Receiving Radiochemotherapy. AB - AIM: To create a simple survival score for patients with high-grade gliomas based on clinical symptoms and performance status. PATIENTS AND METHODS: Thirty-six patients received neurosurgical intervention followed by radiochemotherapy for high-grade gliomas. Six pre-treatment symptoms were included in the score depending on their impairment of quality of life, scoring each between 1 and 3. For each patient, the points from the symptoms were added and another 4 points were added for Karnofsky performance status (KPS) <80%. Based on the survival rates of these scores, two groups were formed: 1-4 (group A) and 5-12 points (group B). RESULTS: The 1-, 2- and 3-year survival rates in group A were 100%, 33% and 24% in group A and 47%, 7% and 0% in group B (p<0.001). In addition, complete tumor resection (p<0.001) and tumor grade III (p<0.001) were associated with improved survival. CONCLUSION: A simple survival score was developed helping physicians in decision-making for patients with high-grade gliomas. PMID- 28652441 TI - Diagnostic Accuracy of PIVKA-II, Alpha-Fetoprotein and a Combination of both in Diagnosis of Hepatocellular Carcinoma in Patients Affected by Chronic HCV Infection. AB - BACKGROUND/AIM: Patients affected by liver cirrhosis are at high risk for developing hepatocellular carcinoma (HCC). The aim of this study was to evaluate the feasibility of PIVKA-II (protein induced by vitamin K absence or antagonist II) alone or in combination with alpha-1 fetoprotein (AFP), as a screening marker for development of HCC. MATERIALS AND METHODS: A case-control study was conducted in 2 hospital wards in Naples. All anti-HCV-positive patients affected by HCC were considered as cases, while consecutive anti-HCV-positive patients without HCC were considered as controls. RESULTS: Overall, 160 patients were enrolled, 56 cases and 104 controls. At the set cut-off of 36 mAU/ml, PIVKA-II was more sensitive (78.6% vs. 60%), but less specific than AFP at the set cut-off of 12 ng/ml (66.3% vs. 77.2%). The negative predictive value of PIVKA in combination with AFP was 93.2%. CONCLUSION: PIVKA II, when combined with AFP, may be considered as a screening test for HCC due to its high negative predictive value. PMID- 28652442 TI - Primary Gastric ALK-negative EBV-negative Anaplastic Large Cell Lymphoma Presenting with Iron Deficiency Anemia. AB - Anaplastic large cell lymphoma (ALCL) is a rare subtype of non-Hodgkin lymphoma (NHL). Primary gastric anaplastic lymphoma kinase (ALK) negative ALCL is extremely rare. Diagnosis of primary gastric ALK-negative ALCL is difficult to establish and prognosis is worse than ALK-positive ALCL. Here, we report a case of an 82-year-old man with a history of cerebrovascular disease presented with weakness and iron deficiency anemia. He denied any abdominal discomforts. The esophagogastroduodenoscopy revealed a large ulcerated, friable mass in the gastric body which encompassed about 80% of entire stomach. Biopsy showed a high grade malignant tumor composed of undifferentiated epithelioid atypical cells, making it difficult to determine the cell of origin. Immunostains for lymphoma, carcinoma, and sarcoma were performed. The tumor cells were positive for CD30, CD4, and CD43, negative for CD20, CD3, ALK-1 and Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) in situ hybridization, establishing the diagnosis of primary gastric ALK-negative ALCL. The patient is currently undergoing chemotherapy with clinical improvement. To the best of our knowledge, this is the first reported case of primary gastric ALK-negative and EBV-negative anaplastic large T-cell lymphoma that presented without gastroenterological symptoms. PMID- 28652443 TI - Rare Case of Cecal Signet Ring Cell Carcinoma with Distal Intramural Spread. AB - In this paper, we report a rare case of cecal Signet ring cell carcinoma (SRCC) with Distal intramural spread (DIS) along with a review of the literature. A 71 year-old woman suffering from vomiting, abdominal pain, and abdominal distension was admitted to a hospital and was suspected to have ileus. She was transferred to our hospital and diagnosed with cecal cancer with intestinal obstruction. Laparotomy was performed, after which she was diagnosed with cecal SRCC by histopathological examination. A submucosal lesion was located 55 mm from the distal side of the main tumor. This lesion was also diagnosed as SRCC. It was not exposed to the epithelium or the serous membrane. The submucosal tumor was diagnosed as DIS of cecal SRCC. After the operation, she underwent chemotherapy with FOLFIRI+Cet (5-fluorouracil, leucovorin, and irinotecan plus cetuximab). At a follow-up examination nine months after surgery, she was found to be doing well. PMID- 28652444 TI - Reticulocyte Hemoglobin Content Helps Avoid Iron Overload in Hemodialysis Patients: A Retrospective Observational Study. AB - BACKGROUND/AIM: Anemia in patients suffering from end-stage renal failure is currently treated with Erythropoiesis-Stimulating Agents (ESA). This treatment needs sufficient iron supplementation to avoid an inadequate dosage of ESA. Nowadays modern analytical instruments allow to accurately calculate the content of Hemoglobin (Hb) in reticulocytes (CHr), that can be used as a guide for prescribing patients with the appropriate amount of iron. PATIENTS AND METHODS: Patients, undergoing hemodialysis, were retrospectively selected from the database and were divided in two groups: group A received intravenous (IV) iron and subcutaneously ESA, and their dosages were adjusted on the basis of the following parameters: Hb, Mean corpuscular haemoglobin (MCH), CHr with consequent MCH/CHr ratio and reticulocyte count determined by the ADVIA 120 Hematology System of Siemens; group B patients were administered IV iron and ESA monitoring iron storage, Hb and ferritin. The aforementioned parameters and the administered amount of iron and ESA were monitored at baseline, four and eight months from the begining of the study. RESULTS: For ESA supplementation, no difference was observed between the groups at the various observed times. Despite similar Hb levels, the patients of group A needed significant lower doses of IV iron ( 57.8%) avoiding risks of organ toxicity and obtaining consequent cost saving of nearly 1 ?/patient/month. CONCLUSION: The use of CHr and its related parameters allows the avoidance of overdosage of IV iron, which can potentially damage organs, and the reduction of health care direct and indirect costs. PMID- 28652445 TI - Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer. AB - AIM: Mitochondrial dysfunction plays a central role in carcinogenesis in numerous cancer-related diseases. We examined the copy number variation of mitochondrial DNA (mtDNA) and the expression of energy-producing genes in relation to ulcerative colitis (UC)-associated carcinogenesis. MATERIALS AND METHODS: We studied 17 patients with UC-associated adenocarcinoma (UC-Ca) and 16 without UC associated adenocarcinoma (UC-nonCa). The copy number of mtDNA in non-dysplastic mucosa in both groups was quantified by an array-based digital polymerase chain reaction (PCR) assay. Simultaneously, gene expression related to mitochondrial energy metabolism was determined by a PCR array. RESULTS: We observed a higher copy number of mtDNA in non-dysplastic mucosa in the UC-Ca group compared to the UC-nonCa group (484.2 vs. 747.7 copies/cell, p=0.022). The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of UC-associated adenocarcinoma by mtDNA copy number were 43.8%, 100%, 100%, and 60.9%, respectively. We observed an increased expression of mitochondrial genes related to energy metabolism together with an increased copy number of mtDNA. CONCLUSION: Mitochondrial function and its metabolic process play essential roles in UC carcinogenesis and are possible risk markers for the development of colitic cancer. PMID- 28652446 TI - Debulking Surgery for High-grade Serous Endometrial Cancer with Disseminated Peritoneal Lesions. AB - Endometrial cancer is one of the most common malignancies in postmenopausal women with good results in terms of survival, especially when diagnosed in early stages. However, prognosis significantly worseness when disseminated lesions are found. We present the case of a 60-year-old patient who presented with diffuse abdominal pain and weight loss. The patient was diagnosed with endometrial cancer with disseminated lesions and successfully submitted to debulking surgery. At two year follow-up, the patient presents no recurrent disease. PMID- 28652447 TI - Clinical Predictors for Neutrophil-to-Lymphocyte Ratio Changes in Patients with Chronic Hepatitis B Receiving Peginterferon Treatment. AB - BACKGROUND: A lower neutrophil-to-lymphocyte ratio (NLR) was found to be associated with better clinical outcomes in hepatitis B-related liver cirrhosis and hepatocellular carcinoma. We aimed to identify pre-therapeutic variables capable of predicting NLR changes in patients with hepatitis B receiving peginterferon therapy. PATIENTS AND METHODS: The baseline clinicopathological data were analyzed to correlate with NLR changes before and 1 year after peginterferon treatment in 71 patients with hepatitis B. RESULTS: Univariate analysis revealed that pre-treatment NLR itself negatively predicted NLR changes following peginterferon treatment (odds ratio(OR)=0.320, p=0.013). Further analysis identified pre-treatment NLR, hemoglobin and hepatitis B surface antigen level as independent predictors for NLR changes (adjusted p=0.028, 0.005, and 0.028, respectively). A predictive score composed of these three factors had an area under the curve of 76.5% (p<0.001). CONCLUSION: Pretreatment NLR, hemoglobin and hepatitis B surface antigen level in combination, effectively predicted NLR changes following peginterferon treatment. PMID- 28652448 TI - Locally Advanced or Metastatic Pancreatic Adenocarcinoma: Easily Available Factors of Predictive Prolonged Survival Under Gemcitabine. AB - BACKGROUND: Prognosis of patients with locally advanced or metastatic pancreatic adenocarcinoma is poor. In this study, we assessed the predictive value of easily available baseline factors for prolonged survival. PATIENTS AND METHODS: We conducted a retrospective study on patients who received gemcitabine between 1999 and 2010 for locally advanced or metastatic pancreatic adenocarcinoma. The primary end-point was the 12-month survival rate. RESULTS: We included 195 patients. The median age was 62.9 years; the performance status was 0-1 in 80 and 2-3 in 92 patients. The median number of metastatic sites was one. A total of 73 patients (37.4%) were alive 12 months after beginning chemotherapy. In multivariate analysis, no liver metastasis, CA19-9 level <250 IU/ml and localized or locally advanced cancer at diagnosis were good prognostic factors. According to a clinical score based on these features, overall survival was 7.7, 13.5, 19.7 and 21.0 months, respectively (p<0.001). CONCLUSION: We identified easily available prognostic factors for prolonged survival in patients treated with gemcitabine. PMID- 28652449 TI - Combined Use of Mammography and FNA Eliminates Pitfalls in the Management of Metaplastic Breast Carcinoma. AB - BACKGROUND: Due to its heterogeneity, metaplastic breast carcinoma (MBC) poses diagnostic dilemmas, leading to delayed treatment, thereby aggravating the prognosis. Over the years, there has been controversy regarding the role of fine needle aspiration (FNA) cytology in timely diagnosis. CASE REPORT: A 54-year-old woman presented with a palpable mass in the upper outer quadrant of her right breast with corresponding mammographic findings and FNA was performed. The smears revealed small- and medium-sized cohesive clusters of malignant cells with atypical nuclei. Sporadically, there was a pleomorphic population of notably large mononuclear cells, with disturbance of nuclear/cytoplasmic ratio, and binucleated or multinucleated malignant cells. The presence of chondromyxoid substance with focally embedded cells in a magenta-colored substrate was predominant in the background. These features, along with the corresponding mammographic findings, allowed for high preoperative suspicion of MBC. Surgical resection followed immediately without neoadjuvant chemotherapy; the pathology report led to the definite diagnosis of MBC. DISCUSSION: MBC is a rare clinical entity with unfavorable prognosis, thus early diagnosis is imperative regarding its management. The effectiveness of FNA in the diagnostic algorithm has been questioned, with data from literature being rather contradictory. FNA seems to provide valuable information, which should always be interpreted in correlation with the clinical and mammographic findings. CONCLUSION: High preoperative suspicion of MBC with the combination of mammography and FNA cytology necessitated the surgical excision of the lesion as the principal treatment approach. Although the role of FNA in the diagnosis of MBC is debatable, its combination with clinical presentation and corresponding mammographic findings may prevent the administration of neoadjuvant chemotherapy in patients with ambiguous indications, given the poor response rate of this cancer subtype. PMID- 28652450 TI - Factors Impacting the Overall Survival of Patients Irradiated for Invasive Carcinoma of the Urinary Bladder. AB - BACKGROUND/AIM: To contribute to personalisation of treatment for patients with carcinoma of the urinary bladder, 11 factors were analyzed for survival. PATIENTS AND METHODS: Data from 61 patients receiving definitive irradiation for carcinoma of the urinary bladder were retrospectively evaluated, namely gender, age, T stage, N-stage, grading, pack years, smoking during irradiation, upfront transurethral resection of the bladder tumour (TURBT), equivalent dose in 2-Gy fractions (EQD2), chemotherapy and Karnofsky performance score (KPS). RESULTS: On univariate analysis, female gender (p=0.007), <40 pack years (p=0.029), not smoking during irradiation (p=0.037), TURBT (p=0.007) and KPS >70 (p<0.001) led to improved survival; EQD2 >55 Gy showed a trend (p=0.065) for such association. On Cox regression, gender [risk ratio (RR)=2.81; p=0.039], TURBT (RR=4.44; p=0.033) and KPS (RR=3.45; p=0.018) remained significant. CONCLUSION: This study identified independent predictors of survival in patients irradiated for carcinoma of the urinary bladder and contributes to creation of personalised treatment programs. PMID- 28652451 TI - A New Prognostic Tool for Patients Undergoing Radiotherapy plus Upfront Transurethral Resection for Bladder Cancer. AB - AIM: To create a tool to estimate overall survival (OS) of patients with non metastatic bladder cancer. PATIENTS AND METHODS: Eight parameters were retrospectively evaluated for OS in 42 patients undergoing radiotherapy and upfront transurethral resection for bladder cancer. The prognostic tool included those parameters that were significant on both univariate and multivariate analyses. The tool was based on the 3-year OS rate divided by 10. Patient scores were calculated by adding the points for each significant parameter. RESULTS: On univariate analysis, 3-year OS was associated with gender (p=0.017), pack years (p=0.009) and Karnofsky performance score (KPS) (p<0.001). On Cox regression, pack years (p=0.007) and KPS (p<0.001) remained significant and were incorporated into the tool. Three prognostic groups were designated with 6, 10-11 and 15 points with 3-year OS-rates of 0%, 34% and 83%, respectively (p<0.001). CONCLUSION: A tool was developed to estimate the OS of patients with bladder cancer to improve individualization of treatment. PMID- 28652452 TI - Correlation Between Infection Status of Epstein-Barr Virus and 18F Fluorodeoxyglucose Uptake in Patients with Advanced Gastric Cancer. AB - BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) is one of the four molecular subtypes of gastric cancer, as defined by the classification recently proposed by The Cancer Genome Atlas. We evaluated the correlation between EBV positivity and 18F-fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography/computed tomography (PET/CT) in patients with gastric cancer. MATERIALS AND METHODS: We retrospectively enrolled patients with gastric cancer who underwent pretreatment 18F-FDG PET/CT and subsequent surgical resection, and then were diagnosed with advanced gastric cancer (pathologic stage >=T2 with any N stage). Maximum standardized uptake values (SUVmax) of gastric cancer were measured by pretreatment 18F-FDG PET/CT. EBV sequences were detected by in situ hybridization (ISH) techniques. We analyzed the correlation between EBV positivity, clinicopathologic features and metabolic activity of the primary tumor. RESULTS: A total of 205 patients were included and 15 (7.3%) patients were identified as having EBV-positive gastric cancer. Age, gender, tumor location, and histological type showed no significant differences between EBV-positive and negative groups. EBV-positive cancer is significantly more frequent in the higher metabolic-tumor group than in the lower one (p=0.032). The mean SUVmax of gastric cancers showed significant differences between EBV-positive and negative groups (9.9+/-4.2 vs. 7.0+/-4.8, p=0.026). CONCLUSION: The infection status of EBV was significantly related to the 18F-FDG uptake of primary tumors in patients with advanced gastric cancer. PMID- 28652453 TI - Predictive Factors for Prolonged Urination Disorder After Permanent 125I Brachytherapy for Localized Prostate Cancer. AB - BACKGROUND: We assessed the change in LUTS after prostate brachytherapy to reveal factors for prolonged urination disorder. MATERIALS AND METHODS: Four hundred and four patients received prostate brachytherapy at our institution and were followed-up for at least 2 years. We evaluated the correlation of mean IPSS changes and clinical factors. Using multivariate analysis, we also evaluated clinical factors with potential to delay IPSS resolution. RESULTS: In cases with prostate volume more than 30 cm3, radiation dose to 90% of prostate volume (D90) more than 160 Gy, and radiation dose to 30% of the urethral volume (UD30) more than 240 Gy, mean IPSS levels were significantly higher, even 30 months after treatment. On multivariate analysis, baseline IPSS more than 8 points and D90 more than 160 Gy were significant predictors for delayed IPSS resolution. CONCLUSION: Our data suggest that higher baseline IPSS and higher D90 were predictors for prolonged urination disorder. PMID- 28652454 TI - Hepatic Epithelioid Hemangioendothelioma - a Rare Tumor and Diagnostic Dilemma. AB - BACKGROUND/AIM: Hepatic epithelioid haemangio-endothelioma (HEHE) is a very rare malignant tumor of vascular origin and uncertain biological behaviour that is difficult to diagnose using preoperative radiology diagnostic techniques. PATIENTS AND METHODS: The authors present here two patients with HEHE of different extent. The first patient had a generalised form of disease, with involvement of the liver, lungs and bones and was treated with a combination of bevacizumab and capecitabine. The second patient had a localised form of disease involving the liver and this was resolved using a combination of liver resection and radiofrequency ablation. In both patients, the radiology work-up before surgery was non-specific and metastases of another malignant process were considered. The definitive histological diagnosis was made by the pathologist on the basis of immunohistochemical analysis that demonstrated the presence of CD31, CD34 and calmodulin-binding transcription activator 1 (CAMTA 1). RESULTS: Both patients remain in an overall good condition 27 and 5 months respectively following treatment for HEHE. CONCLUSION: Preoperative radiological diagnosis of HEHE is difficult and immunohistochemical examination of the tumor tissue sample remains the key diagnostic tool. Radical surgical resection or liver transplantation is the method of choice in patients with localised liver involvement. PMID- 28652455 TI - Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma. AB - BACKGROUND/AIM: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma. PATIENTS AND METHODS: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment. RESULTS: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3. CONCLUSION: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting. PMID- 28652457 TI - Heartbeat: Achieving better medication adherence. PMID- 28652456 TI - Lung Cancer in Patients with Severe Idiopathic Pulmonary Fibrosis: Critical Aspects. AB - Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease limited to the lung with an undefined etiopathogenesis and a very short life expectancy (less than 5 years). IPF susceptibility has been associated with several genetic and environmental risk factors and the prognosis is conditioned by comorbidities such as gastro-esophageal reflux, depression, venous thromboembolism, pulmonary hypertension and lung cancer. At 5 years follow-up, 15% of IPF patients develop lung cancer, which can significantly reduce their survival. Because diagnostic or therapeutic procedures such as surgical, radiation or pharmacological treatments may induce acute exacerbations and increase mortality, the management of lung cancer in IPF patients is a very difficult task. This study discusses advantages and disadvantages of lung cancer treatments in patients with severe IPF, highlighting several controversial aspects on this topic, including potential nintedanib treatment. PMID- 28652458 TI - Cardiovascular highlights from non-cardiology journals. PMID- 28652460 TI - Hypertension, Its Treatment, Frailty, Falls, and Mortality. PMID- 28652459 TI - Blood Pressure, Antihypertensive Polypharmacy, Frailty, and Risk for Serious Fall Injuries Among Older Treated Adults With Hypertension. AB - Antihypertensive medication and low systolic blood pressure (BP) and diastolic BP have been associated with an increased falls risk in some studies. Many older adults have indicators of frailty, which may increase their risk for falls. We contrasted the association of systolic BP, diastolic BP, number of antihypertensive medication classes taken, and indicators of frailty with risk for serious fall injuries among 5236 REGARDS study (Reasons for Geographic and Racial Difference in Stroke) participants >=65 years taking antihypertensive medication at baseline with Medicare fee-for-service coverage. Systolic BP and diastolic BP were measured, and antihypertensive medication classes being taken assessed through a pill bottle review during a study visit. Indicators of frailty included low body mass index, cognitive impairment, depressive symptoms, exhaustion, impaired mobility, and history of falls. Serious fall injuries were defined as fall-related fractures, brain injuries, or joint dislocations using Medicare claims through December 31, 2014. Over a median of 6.4 years, 802 (15.3%) participants had a serious fall injury. The multivariable-adjusted hazard ratio for a serious fall injury among participants with 1, 2, or >=3 indicators of frailty versus no frailty indicators was 1.18 (95% confidence interval, 0.99 1.40), 1.49 (95% confidence interval, 1.19-1.87), and 2.04 (95% confidence interval, 1.56-2.67), respectively. Systolic BP, diastolic BP, and number of antihypertensive medication classes being taken at baseline were not associated with risk for serious fall injuries after multivariable adjustment. In conclusion, indicators of frailty, but not BP or number of antihypertensive medication classes, were associated with increased risk for serious fall injuries among older adults taking antihypertensive medication. PMID- 28652461 TI - Cardiovascular Health and Incident Hypertension in Blacks: JHS (The Jackson Heart Study). AB - Several modifiable health behaviors and health factors that comprise the Life's Simple 7-a cardiovascular health metric-have been associated with hypertension risk. We determined the association between cardiovascular health and incident hypertension in JHS (the Jackson Heart Study)-a cohort of blacks. We analyzed participants without hypertension or cardiovascular disease at baseline (2000 2004) who attended >=1 follow-up visit in 2005 to 2008 or 2009 to 2012 (n=1878). Body mass index, physical activity, diet, cigarette smoking, blood pressure (BP), total cholesterol, and fasting glucose were assessed at baseline and categorized as ideal, intermediate, or poor using the American Heart Association's Life's Simple 7 definitions. Incident hypertension was defined at the first visit wherein a participant had systolic BP >=140 mm Hg, diastolic BP >=90 mm Hg, or self-reported taking antihypertensive medication. The percentage of participants with <=1, 2, 3, 4, 5, and 6 ideal Life's Simple 7 components was 6.5%, 22.4%, 34.4%, 25.2%, 10.0%, and 1.4%, respectively. No participants had 7 ideal components. During follow-up (median, 8.0 years), 944 (50.3%) participants developed hypertension, including 81.3% with <=1 and 11.1% with 6 ideal components. The multivariable-adjusted hazard ratios (95% confidence interval) for incident hypertension comparing participants with 2, 3, 4, 5, and 6 versus <=1 ideal component were 0.80 (0.61-1.03), 0.58 (0.45-0.74), 0.30 (0.23-0.40), 0.26 (0.18-0.37), and 0.10 (0.03-0.31), respectively (Ptrend <0.001). This association was present among participants with baseline systolic BP <120 mm Hg and diastolic BP <80 mm Hg and separately systolic BP 120 to 139 mm Hg or diastolic BP 80 to 89 mm Hg. Blacks with better cardiovascular health have lower hypertension risk. PMID- 28652462 TI - Protective Low-Frequency Variants for Preeclampsia in the Fms Related Tyrosine Kinase 1 Gene in the Finnish Population. AB - Preeclampsia is a common pregnancy-specific vascular disorder characterized by new-onset hypertension and proteinuria during the second half of pregnancy. Predisposition to preeclampsia is in part heritable. It is associated with an increased risk of cardiovascular disease later in life. We have sequenced 124 candidate genes implicated in preeclampsia to pinpoint genetic variants contributing to predisposition to or protection from preeclampsia. First, targeted exomic sequencing was performed in 500 preeclamptic women and 190 controls from the FINNPEC cohort (Finnish Genetics of Preeclampsia Consortium). Then 122 women with a history of preeclampsia and 1905 parous women with no such history from the National FINRISK Study (a large Finnish population survey on risk factors of chronic, noncommunicable diseases) were included in the analyses. We tested 146 rare and low-frequency variants and found an excess (observed 13 versus expected 7.3) nominally associated with preeclampsia (P<0.05). The most significantly associated sequence variants were protective variants rs35832528 (E982A; P=2.49E-4; odds ratio=0.387) and rs141440705 (R54S; P=0.003; odds ratio=0.442) in Fms related tyrosine kinase 1. These variants are enriched in the Finnish population with minor allele frequencies 0.026 and 0.017, respectively. They may also be associated with a lower risk of heart failure in 11 257 FINRISK women. This study provides the first evidence of maternal protective genetic variants in preeclampsia. PMID- 28652463 TI - Cardiometabolic Determinants of Carotid and Aortic Distensibility From Childhood to Early Adulthood. AB - : Children who are obese or have familial hypercholesterolemia have stiffer arteries compared with lean, healthy peers. Limited data are, however, available on the association of cardiometabolic risk markers and arterial distensibility in healthy children, particularly in a longitudinal setting. Therefore, we studied in the prospective STRIP (Special Turku Coronary Risk Factor Intervention Project) comprising healthy, predominantly normal weight participants the association of several cardiometabolic and dietary risk markers with arterial distensibility from childhood to early adulthood. Carotid and aortic distensibility (cdist, adist) was assessed repeatedly with ultrasonography at the age of 11, 13, 15, 17, and 19 years in the longitudinal atherosclerosis prevention study (ncdist=420-503, nadist=407-476). Data on cardiometabolic risk markers and diet were available since early childhood. In multivariable analyses, body mass index (beta=-0.0019 [SE 0.0085]; P=0.037), systolic blood pressure (beta=-0.0025 [SE 0.00065]; P=0.0001), low-density lipoprotein cholesterol (beta= 0.026 [SE 0.012]; P=0.034), and homeostasis model of insulin resistance (beta= 0.048 [SE 0.018]; P=0.0071) were independently associated with carotid distensibility. Systolic blood pressure (beta=-0.0069 [SE 0.00097]; P<0.0001) and low-density lipoprotein cholesterol (beta=-0.039 [SE 0.018]; P=0.031) associated independently with aortic distensibility. Dietary variables were not independently associated with arterial distensibility. Participants with low arterial distensibility had higher body mass index (Pcdist=0.0090, Padist=0.098) and higher systolic (Pcdist<0.0001, Padist<0.0001) and diastolic blood pressures (Pcdist<0.0001, Padist=0.0002) already from early childhood. Body mass index, blood pressure, low-density lipoprotein cholesterol, and homeostasis model of insulin resistance identified since childhood associate with arterial distensibility in healthy children and adolescents. These data support the relevance of these factors as part of primordial prevention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00223600. PMID- 28652464 TI - Rapid Diagnosis of Primary Aldosteronism: Oxymoron or One Small Step? PMID- 28652466 TI - Guidelines Under Fire Again! PMID- 28652465 TI - Expertise: No Longer a Sine Qua Non for Guideline Authors? PMID- 28652468 TI - Is Plasma Proteomics Able to Provide Alternative Paths to Better Understand Hypertension? PMID- 28652470 TI - Contribution of Increased Angiotensin II Sensitivity to Microvascular Dysfunction in Women With a History of Preeclampsia. PMID- 28652469 TI - Blood Pressure and Visit-to-Visit Blood Pressure Variability Among Individuals With Primary Proteinuric Glomerulopathies. AB - Hypertension and blood pressure variability (BPV; SD and average real variability) in primary proteinuric glomerulopathies are not well described. Data were from 433 participants in the NEPTUNE (Nephrotic Syndrome Study Network). Hypertensive BP status was defined as previous history of hypertension or BP >=140/90 mm Hg for adults/>=95th percentile for children at baseline. BPV was measured in participants with >=3 visits in the first year. Two-hundred ninety six adults (43 years [interquartile range, 32-57.8 years], 61.5% male) and 147 children (11 years [interquartile range, 5-14 years], 57.8% male) were evaluated. At baseline, 64.8% of adults and 46.9% of children were hypertensive. Histological diagnosis was associated with hypertensive status in adults (P=0.036). In adults, hypertensive status was associated with lower hazard of complete remission (hazard ratio, 0.36; 95% confidence interval, 0.19-0.68) and greater hazard of achieving the composite end point (end-stage renal disease or estimated glomerular filtration rate decline >40%; hazard ratio, 4.1; 95% confidence interval, 1.4-12). Greater systolic and diastolic SD and average real variability were also associated with greater hazard of reaching the composite end point in adults (all P<0.01). In children, greater BPV was an independent predictor of composite end point (determined by systolic SD and average real variability) and complete remission (determined by systolic and diastolic average real variability; all P<0.05). Hypertensive status was common among adults and children enrolled in NEPTUNE. Differences in hypertensive status prevalence, BPV, and treatment were found by age and histological diagnosis. In addition, hypertensive status and greater BPV were associated with poorer clinical outcomes. PMID- 28652467 TI - Systolic Blood Pressure and Biochemical Assessment of Adherence: A Cross Sectional Analysis in the Emergency Department. AB - Elevated blood pressure (BP) is common in the emergency department (ED), but the relationship between antihypertensive medication adherence and BP in the ED is unclear. This cross-sectional study tested the hypothesis that higher antihypertensive adherence is associated with lower systolic BP (SBP) in the ED among adults with hypertension who sought ED care at an academic hospital from July 2012 to April 2013. Biochemical assessment of antihypertensive adherence was performed using a mass spectrometry blood assay, and the primary outcome was average ED SBP. Analyses were stratified by number of prescribed antihypertensives (<3, >=3) and adjusted for age, sex, race, insurance, literacy, numeracy, education, body mass index, and comorbidities. Among 85 patients prescribed >=3 antihypertensives, mean SBP for adherent patients was 134.4 mm Hg (+/-26.1 mm Hg), and in adjusted analysis was -20.8 mm Hg (95% confidence interval, -34.2 to -7.4 mm Hg; P=0.003) different from nonadherent patients. Among 176 patients prescribed <3 antihypertensives, mean SBP was 135.5 mm Hg (+/ 20.6 mm Hg) for adherent patients, with no difference by adherence in adjusted analysis (+2.9 mm Hg; 95% confidence interval, -4.7 to 10.5 mm Hg; P=0.45). Antihypertensive nonadherence identified by biochemical assessment was common and associated with higher SBP in the ED among patients who had a primary care provider and health insurance and who were prescribed >=3 antihypertensives. Biochemical assessment of antihypertensives could help distinguish medication nonadherence from other contributors to elevated BP and identify target populations for intervention. PMID- 28652471 TI - Detecting Nonadherence to Antihypertensive Treatment: Any Time, Anywhere? PMID- 28652472 TI - Proteomic-Biostatistic Integrated Approach for Finding the Underlying Molecular Determinants of Hypertension in Human Plasma. AB - Despite advancements in lowering blood pressure, the best approach to lower it remains controversial because of the lack of information on the molecular basis of hypertension. We, therefore, performed plasma proteomics of plasma from patients with hypertension to identify molecular determinants detectable in these subjects but not in controls and vice versa. Plasma samples from hypertensive subjects (cases; n=118) and controls (n=85) from the InGenious HyperCare cohort were used for this study and performed mass spectrometric analysis. Using biostatistical methods, plasma peptides specific for hypertension were identified, and a model was developed using least absolute shrinkage and selection operator logistic regression. The underlying peptides were identified and sequenced off-line using matrix-assisted laser desorption ionization orbitrap mass spectrometry. By comparison of the molecular composition of the plasma samples, 27 molecular determinants were identified differently expressed in cases from controls. Seventy percent of the molecular determinants selected were found to occur less likely in hypertensive patients. In cross-validation, the overall R2 was 0.434, and the area under the curve was 0.891 with 95% confidence interval 0.8482 to 0.9349, P<0.0001. The mean values of the cross-validated proteomic score of normotensive and hypertensive patients were found to be -2.007+/-0.3568 and 3.383+/-0.2643, respectively, P<0.0001. The molecular determinants were successfully identified, and the proteomic model developed shows an excellent discriminatory ability between hypertensives and normotensives. The identified molecular determinants may be the starting point for further studies to clarify the molecular causes of hypertension. PMID- 28652473 TI - Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia. AB - Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10-7-102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME (NG-nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 umol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10-20-10-4 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3+/-0.5 versus -1.0+/-0.4 logEC50; P<0.001) and NO-dependent dilation (16+/-3% versus 39+/-6%; P=0.006). Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2+/-1.3 versus -8.3+/-0.5; P=0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had preeclampsia have persistent microvascular dysfunction postpartum, mediated, in part, by increased sensitivity to angiotensin II. PMID- 28652475 TI - Correction for Yu et al., "C-Terminal HIV-1 Transframe p6* Tetrapeptide Blocks Enhanced Gag Cleavage Incurred by Leucine Zipper Replacement of a Deleted p6* Domain". PMID- 28652477 TI - Classic Spotlight, 1994 and 1995: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 28652474 TI - Rapid Screening of Primary Aldosteronism by a Novel Chemiluminescent Immunoassay. AB - Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results when measured by radioimmunoassay and development of more rapid assays has been long expected. We have developed chemiluminescent enzyme immunoassays enabling the simultaneous measurement of both aldosterone and renin concentrations in 10 minutes by a fully automated assay using antibody-immobilized magnetic particles with quick aggregation and dispersion. We performed clinical validation of diagnostic ability of this newly developed assay-based screening of 125 patients with primary aldosteronism from 97 patients with essential hypertension. Results of this novel assay significantly correlated with the results of radioimmunoassay (aldosterone, active renin concentration, and renin activity) and liquid chromatography-tandem mass spectrometry (aldosterone). The analytic sensitivity of this particularly novel active renin assay was 0.1 pg/mL, which was better than that of radioimmunoassay (2.0 pg/mL). The ratio of aldosterone-to-renin concentrations of 6.0 (ng/dL per pg/mL) provided 92.0% sensitivity and 76.3% specificity as a cutoff for differentiating primary aldosteronism from essential hypertension. This novel measurement is expected to be a clinically reliable alternative for conventional radioimmunoassay and to provide better throughput and cost effectiveness in diagnosis of hyperaldosteronism from larger numbers of hypertensive patients in clinical settings. PMID- 28652478 TI - Natural health products should be sold separately from drugs. PMID- 28652479 TI - Medical assistance in dying: time for physicians to step up to protect themselves and patients. PMID- 28652481 TI - A 44-year-old man with acute asymmetric polyarthritis and fever. PMID- 28652480 TI - Influences on the start, selection and duration of treatment with antibiotics in long-term care facilities. AB - BACKGROUND: Understanding the extent to which current antibiotic prescribing behaviour is influenced by clinicians' historical patterns of practice will help target interventions to optimize antibiotic use in long-term care. Our objective was to evaluate whether clinicians' historical prescribing behaviours influence the start, prolongation and class selection for treatment with antibiotics in residents of long-term care facilities. METHODS: We conducted a retrospective cohort study of all physicians who prescribed to residents in long-term care facilities in Ontario between Jan. 1 and Dec. 31, 2014. We examined variability in antibiotic prescribing among physicians for 3 measures: start of treatment with antibiotics, use of prolonged durations exceeding 7 days and selection of fluoroquinolones. Funnel plots with control limits were used to determine the extent of variation and characterize physicians as extreme low, low, average, high and extreme high prescribers for each tendency. Multivariable logistic regression was used to assess whether a clinician's prescribing tendency in the previous year predicted current prescribing patterns, after accounting for residents' demographics, comorbidity, functional status and indwelling devices. RESULTS: Among 1695 long-term care physicians, who prescribed for 93 132 residents, there was wide variability in the start of antibiotic treatment (median 45% of patients, interquartile range [IQR] 32%-55%), use of prolonged treatment durations (median 30% of antibiotic prescriptions, IQR 19%-46%) and selection of fluoroquinolones (median 27% of antibiotic prescriptions, IQR 18% 37%). Prescribing tendencies for antibiotics by physicians in 2014 correlated strongly with tendencies in the previous year. After controlling for individual resident characteristics, prior prescribing tendency was a significant predictor of current practice. INTERPRETATION: Physicians prescribing antibiotics exhibited individual, measurable and historical tendencies toward start of antibiotic treatment, use of prolonged treatment duration and class selection. Prescriber audit and feedback may be a promising tool to optimize antibiotic use in long term care facilities. PMID- 28652482 TI - Demodex folliculitis. PMID- 28652483 TI - Serving two masters: the medical and political careers of Sir Charles Tupper. PMID- 28652484 TI - Identifying those infected with hepatitis C virus. PMID- 28652486 TI - Harms of overoxygenation in patients with exacerbation of chronic obstructive pulmonary disease. PMID- 28652485 TI - Hepatitis C testing in Canada: don't leave baby boomers behind. PMID- 28652487 TI - Manitoba's unique health care burdens stall federal deal. PMID- 28652488 TI - The home care conversation we're not having. PMID- 28652489 TI - Nigeria's polio endgame impeded by Boko Haram. PMID- 28652491 TI - Quantum communication with coherent states of light. AB - Quantum communication offers long-term security especially, but not only, relevant to government and industrial users. It is worth noting that, for the first time in the history of cryptographic encoding, we are currently in the situation that secure communication can be based on the fundamental laws of physics (information theoretical security) rather than on algorithmic security relying on the complexity of algorithms, which is periodically endangered as standard computer technology advances. On a fundamental level, the security of quantum key distribution (QKD) relies on the non-orthogonality of the quantum states used. So even coherent states are well suited for this task, the quantum states that largely describe the light generated by laser systems. Depending on whether one uses detectors resolving single or multiple photon states or detectors measuring the field quadratures, one speaks of, respectively, a discrete- or a continuous-variable description. Continuous-variable QKD with coherent states uses a technology that is very similar to the one employed in classical coherent communication systems, the backbone of today's Internet connections. Here, we review recent developments in this field in two connected regimes: (i) improving QKD equipment by implementing front-end telecom devices and (ii) research into satellite QKD for bridging long distances by building upon existing optical satellite links.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652490 TI - An introduction to ghost imaging: quantum and classical. AB - Ghost imaging has been a subject of interest to the quantum optics community for the past 20 years. Initially seen as manifestation of quantum spookiness, it is now recognized as being implementable in both single- and many-photon number regimes. Beyond its scientific curiosity, it is now feeding novel imaging modalities potentially offering performance attributes that traditional approaches cannot match.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652492 TI - Noise management to achieve superiority in quantum information systems. AB - Quantum information systems are expected to exhibit superiority compared with their classical counterparts. This superiority arises from the quantum coherences present in these quantum systems, which are obviously absent in classical ones. To exploit such quantum coherences, it is essential to control the phase information in the quantum state. The phase is analogue in nature, rather than binary. This makes quantum information technology fundamentally different from our classical digital information technology. In this paper, we analyse error sources and illustrate how these errors must be managed for the system to achieve the required fidelity and a quantum superiority.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652493 TI - A portable magneto-optical trap with prospects for atom interferometry in civil engineering. AB - The high precision and scalable technology offered by atom interferometry has the opportunity to profoundly affect gravity surveys, enabling the detection of features of either smaller size or greater depth. While such systems are already starting to enter into the commercial market, significant reductions are required in order to reach the size, weight and power of conventional devices. In this article, the potential for atom interferometry based gravimetry is assessed, suggesting that the key opportunity resides within the development of gravity gradiometry sensors to enable drastic improvements in measurement time. To push forward in realizing more compact systems, techniques have been pursued to realize a highly portable magneto-optical trap system, which represents the core package of an atom interferometry system. This can create clouds of 107 atoms within a system package of 20 l and 10 kg, consuming 80 W of power.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652494 TI - Optical atomic phase reference and timing. AB - Atomic clocks based on laser-cooled atoms have made tremendous advances in both accuracy and stability. However, advanced clocks have not found their way into widespread use because there has been little need for such high performance in real-world/commercial applications. The drive in the commercial world favours smaller, lower-power, more robust compact atomic clocks that function well in real-world non-laboratory environments. Although the high-performance atomic frequency references are useful to test Einstein's special relativity more precisely, there are not compelling scientific arguments to expect a breakdown in special relativity. On the other hand, the dynamics of gravity, evidenced by the recent spectacular results in experimental detection of gravity waves by the LIGO Scientific Collaboration, shows dramatically that there is new physics to be seen and understood in space-time science. Those systems require strain measurements at less than or equal to 10-20 As we discuss here, cold atom optical frequency references are still many orders of magnitude away from the frequency stability that should be achievable with narrow-linewidth quantum transitions and large numbers of very cold atoms, and they may be able to achieve levels of phase stability, DeltaPhi/Phitotal <= 10-20, that could make an important impact in gravity wave science.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652495 TI - Quantum photonic network and physical layer security. AB - Quantum communication and quantum cryptography are expected to enhance the transmission rate and the security (confidentiality of data transmission), respectively. We study a new scheme which can potentially bridge an intermediate region covered by these two schemes, which is referred to as quantum photonic network. The basic framework is information theoretically secure communications in a free space optical (FSO) wiretap channel, in which an eavesdropper has physically limited access to the main channel between the legitimate sender and receiver. We first review a theoretical framework to quantify the optimal balance of the transmission efficiency and the security level under power constraint and at finite code length. We then present experimental results on channel characterization based on 10 MHz on-off keying transmission in a 7.8 km terrestrial FSO wiretap channel.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652496 TI - Harnessing temporal modes for multi-photon quantum information processing based on integrated optics. AB - In the last few decades, there has been much progress on low loss waveguides, very efficient photon-number detectors and nonlinear processes. Engineered sum frequency conversion is now at a stage where it allows operation on arbitrary temporal broadband modes, thus making the spectral degree of freedom accessible for information coding. Hereby the information is often encoded into the temporal modes of a single photon. Here, we analyse the prospect of using multi-photon states or squeezed states in different temporal modes based on integrated optics devices. We describe an analogy between mode-selective sum-frequency conversion and a network of spatial beam splitters. Furthermore, we analyse the limits on the achievable squeezing in waveguides with current technology and the loss limits in the conversion process.This article is part of the themed issue 'Quantum technology for the 21st century'. PMID- 28652497 TI - Global Prevalence of Elder Abuse: A Meta-analysis and Meta-regression. AB - OBJECTIVE: Elder abuse is increasingly recognised as a global public health and social problem. There has been limited inter-study comparison of the prevalence and risk factors for elder abuse. This study aimed to estimate the pooled and subtype prevalence of elder abuse worldwide and identify significant associated risk factors. METHODS: We conducted a meta-analysis and meta-regression of 34 population-based and 17 non-population-based studies. RESULTS: The pooled prevalences of elder abuse were 10.0% (95% confidence interval, 5.2%-18.6%) and 34.3% (95% confidence interval, 22.9%-47.8%) in population-based studies and third party- or caregiver-reported studies, respectively. Being in a marital relationship was found to be a significant moderator using random-effects model. CONCLUSIONS: This meta-analysis revealed that third parties or caregivers were more likely to report abuse than older abused adults. Subgroup analyses showed that females and those resident in non-western countries were more likely to be abused. Emotional abuse was the most prevalent elder abuse subtype and financial abuse was less commonly reported by third parties or caregivers. Heterogeneity in the prevalence was due to the high proportion of married older adults in the sample. Subgroup analysis showed that cultural factors, subtypes of abuse, and gender also contributed to heterogeneity in the pooled prevalence of elder abuse. PMID- 28652498 TI - Prevalence and Correlates of Psychological Distress in Adolescent Students from India. AB - OBJECTIVE: There are limited data on the prevalence and correlates of psychological distress among adolescents in India. This study assessed psychological distress among adolescents who attended school in Kerala, India. METHODS: A total of 7560 students from 73 schools, aged 12 to 19 years completed a self-administered questionnaire that included Kessler Psychological Distress Scale and other standardised instruments to assess various domains. RESULTS: Mild psychological distress was reported by 10.5%, moderate distress by 5.4%, and severe distress by 4.9% of students. Older age, not living with both parents, and urban residence were significantly associated with psychological distress (p < 0.05). Students who experienced psychological distress had a higher risk of reporting academic failure, alcohol and tobacco use, suicidality, and sexual abuse. Increasing severity of psychological distress was associated with higher odds of these correlates. CONCLUSIONS: Psychological distress is common among adolescents and its correlates with negative outcomes suggest the need for early recognition and treatment. PMID- 28652499 TI - A Cross-sectional Cohort Study of Prevalence, Co-Morbidities, and Correlates of Attention-deficit Hyperactivity Disorder among Adult Patients Admitted to the Li Ka Shing Psychiatric Outpatient Clinic, Hong Kong. AB - OBJECTIVE: To examine the prevalence, co-morbidities, and correlates of attention deficit hyperactivity disorder (ADHD) among adult patients who attended the Li Ka Shing psychiatric outpatient clinic (LKSPC), Hong Kong. METHODS: This study was a cross-sectional cohort study of patients consecutively referred to LKSPC over a 3 month period for evaluation of adult ADHD in 2 phases. In the screening phase, the Adult ADHD Self-Report Scale-v1.1 (ASRS-v1.1) Screener and Symptom Checklist and Sheehan Disability Scale (SDS) were used in the evaluation. In the interview phase, ADHD diagnosis was ascertained using the Diagnostic Interview for ADHD in Adults, version 2.0 (DIVA 2.0), with the DSM-5 criteria, in patients who exceeded the cut-off point of either the ASRS-v1.1 Screener or Symptom Checklist. RESULTS: The study included 254 patients of whom 49 were diagnosed with ADHD. Patients with ADHD were aged 18 to 60 (mean, 40.1) years, and 63.3% were women. The estimated prevalence of ADHD in adult psychiatric patients, by sensitivity analysis, was 13% to 19.3% with a higher prevalence in men than women (24.7% vs. 17.1%). Adult ADHD was highly co-morbid with substance / alcohol use disorders and forensic record, and associated with functional impairment. In the ADHD combined presentation group, there was additional co-morbidities of bipolar disorder, active substance use and chronic alcohol use, and a higher associated risk of suicidal attempt. CONCLUSIONS: Efforts are needed to increase the detection and treatment of adult ADHD that affects a relevant proportion of our adult psychiatric outpatient population, and was associated with adverse social outcomes and functional impairment. PMID- 28652500 TI - Positive Aspects of Caregiving Experience among Caregivers of Patients with Dementia. AB - OBJECTIVE: To assess the positive aspects of caregiving and its correlates among caregivers of patients with dementia. METHODS: A total of 55 primary caregivers of patients with dementia were invited to complete the Scale for Positive Aspects of Caregiving Experience (SPACE), Coping Checklist, Social Support Questionnaire, and World Health Organization Quality of Life-BREF version. Caregivers were also assessed by a clinician using the Burden Interview Schedule. Patients were assessed using the Hindi Mental State Examination and Instrumental Activities of Daily Living Scale. RESULTS: The mean SPACE domain score was highest for motivation for caregiving role (2.63) followed by caregiver satisfaction (2.54), caregiving personal gains (2.4), and self-esteem and social aspect of caring (2.23). More educated caregivers scored significantly lower in the self-esteem and social aspect of caring. Married caregivers had a higher mean score in the motivation for caregiving role. There were some correlations between subjective burden and various SPACE domains, but the total objective burden score had no correlation with the SPACE. Higher use of avoidance coping was associated with a positive caregiving experience. Stronger social support was associated with higher score in the motivation for caregiving role. Higher level of caregiver burden in various domains was associated with lower motivation for caregiving. Caregiver satisfaction was associated with better quality of life for caregivers in terms of the environment. CONCLUSIONS: A positive caregiving experience for primary caregivers of patients with dementia is associated with both objective and subjective burdens, avoidance coping, and perceived social support. PMID- 28652501 TI - Serum Levels of Neuroactive Steroids in First-episode Antipsychotic-naive Schizophrenic Patients and Its Correlation with Aggression: A Case-control Study. AB - BACKGROUND: The evidence of hypothalamic-pituitary-adrenal axis dysfunction in schizophrenia has been reviewed in the context of the stress-diathesis model. Overactivation of this axis leads to altered blood levels of cortisol and dehydroepiandrosterone sulfate (DHEA-S). These neurosteroids in turn act on the hippocampus and interact with gamma-aminobutyric acid and N-methyl-D-aspartate receptors leading to neurotoxicity and may be involved in the neurobiology of aggression. This study aimed to explore the blood level of these neurosteroids and ascertain its correlation with state aggression and psychopathology in first episode antipsychotic-naive schizophrenic patients. METHODS: A total of 30 patients with first-episode schizophrenia along with 20 age- and gender-matched healthy controls participated in the study. Both groups were subjected to serum cortisol and DHEA-S measurement after assessment of psychopathology and aggression on a standardised psychometric scale. RESULTS: Serum DHEA-S level was significantly higher in the patient group (p = 0.001). No difference was noted between males and females in the patient group (p = 0.93) but female controls had a significantly lower serum DHEA-S level than male controls (p < 0.01). Serum DHEA-S inversely correlated with scores on Modified Overt Aggression Scale (p = 0.01) but not with Positive and Negative Syndrome Scale (p = 0.39) or Clinical Global Impression Scale (p = 0.28). CONCLUSION: The first-episode antipsychotic naive schizophrenic patients showed a significantly higher blood level of DHEA-S compared with healthy controls. Serum DHEA-S level has an inverse relationship with aggression and may serve as a biological adaptive mechanism to antagonise the neuronal damage caused by cortisol. PMID- 28652502 TI - Acute appendicitis complicating De Garengeot's hernia treated with combined laparoscopic-open technique: a case series and literature review. AB - : An acute appendicitis in the context of a De Garengeot's hernia is a very rare event and represents a hard challenge for surgeons. As only few cases have been reported in literature, there is no consensus about its optimal surgical strategy of treatment. Here we present two consecutive cases of female patients presenting an uncommon acute appendicitis in a femoral hernia treated with a combined laparoscopic/open technique. KEY WORDS: Acute appendicitis, De Garengeot's hernia, Laparoscopy. PMID- 28652503 TI - Camouflage or Surgery? PMID- 28652504 TI - From Planning to Delivery of a Bone-Borne Rapid Maxillary Expander in One Visit. PMID- 28652505 TI - Orthodontic Camouflage vs. Surgical-Orthodontic Treatment of Skeletal Class II Malocclusions. PMID- 28652506 TI - Orthodontic Space Closure for Management of Congenitally Missing Upper Lateral Incisors. PMID- 28652507 TI - A Modified Retainer for Class II or III Functional and Surgical Patients. PMID- 28652508 TI - Aligner Corner. PMID- 28652509 TI - The Readers' Corner. PMID- 28652510 TI - Beta blocker and steroid therapy in the treatment of infantile hepatic hemangioendothelioma. AB - Infantile hepatic hemangioendothelioma (IHHE) is the most common benign vascular liver tumor and typically occurs during the first 6 months of life. A 4-month-old male patient presented with abdominal distention. A physical examination revealed massive hepatomegaly. Liver enzyme levels were normal. The alpha fetoprotein level was 1,323 mg/dL (6-1,000). Abdominal magnetic resonance imaging (MRI) showed multiple, well-defined and hyperintense nodular lesions in the liver. MRI findings suggested IHHE. The thyroid stimulating hormone (TSH) level was high (177.2 uU/mL). He was started on sodium levothyroxine 50 MUg daily. The patient has hypoxemia due to abdominal distention during the follow-up period. Oral methylprednisolone therapy was started at a dose of 2.5 mg/kg/dose, and propranolol at a dose of 1 mg/kg/dose, bid. Fifteen days later his TSH level remained elevated at 212.3 MUU/mL despite repeatedly increasing the dose of levothyroxine up to 200 MUg/daily. One month after the initial presentation, his TSH level was reduced to 11.28 uU/mL. We observed a marked improvement in abdominal distention and respiratory distress within 15 days and an average reduction of 50% in the lesion diameters after a month. Despite its benign nature, IHHE may lead to development of complications. Steroid and propranolol treatment may be useful in in the management of emergency complications. PMID- 28652511 TI - Properties of induced antimicrobial activity in Musca domestica larvae. AB - Insects produce antimicrobial molecules that contribute to their innate immune responses to eliminate invading microorganisms. To explore the potential utility of these antimicrobial molecules, we focused on larvae of the house fly Musca domestica, which is an efficient processor of organic waste and a good resource of protein and oil for animal feeding. The induction of hemagglutinating activity, which is usually accompanied by activation of innate immune responses in fly larvae, was observed in the hemolymph following needle injury. Hemolymph collected from injured larvae demonstrated potent antimicrobial activities against both Gram-positive and Gram-negative bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa. Furthermore, the antimicrobial activity was significantly retained in hemolymph after heat-treatments, suggesting that pasteurization of animal feed prepared from fly larvae would be a useful sterilization method. These observations indicate that injured Musca domestica larvae are a source of antimicrobial agents, and highlight the utility of preparing animal feed from these larvae. PMID- 28652512 TI - Chryseobacterium indolegenes infection in a patient with chronic obstructive pulmonary disease. AB - Chryseobacterium indolegenes is a rare pathogen that causes a variety of infections in inviduals who are mostly hospitalized with severe underlying diseases. Here we present a case of C. indolegenes in a 69-year-old male with chronic obstructive pulonary disease (COPD) who was admitted to the chest disease outpatient clinic with symptoms like cough, fever and sputum production and followed up on a suspicion of pneumonia. Despite the fact that our patient did not have any history of hospitalization for at least one year, pneumonia cause was due to C. indolegenes. Clinicians should pay attention to the rare pathogens such as C. indologenes while managing COPD patients without prior hospitalization history. PMID- 28652513 TI - Study on Students' Impression Data in Practical Training Using Text Mining Method Analysis of Considerable Communication. AB - We analyzed impression data and the scale of communication skills of students using text mining method to clarify which area a student was conscious of in communication in practical training. The results revealed that students tended to be conscious of the difference between practical hospital training and practical pharmacy training. In practical hospital training, specific expressions denoting relationships were "patient-visit", "counseling-conduct", "patient-counseling", and "patient-talk". In practical pharmacy training, specific expressions denoting relationships were "patient counseling-conduct", "story-listen", "patient-many", and "patient-visit". In practical hospital training, the word "patient" was connected to many words suggesting that students were conscious of a patient centered communication. In practical pharmacy training, words such as "patient counseling", "patient", and "explanation" were placed in center and connected with many other words and there was an independent relationship between "communication" and "accept". In conclusion, it was suggested that students attempted active patient-centered communication in practical hospital training, while they were conscious of listening closely in patient counseling in practical pharmacy training. PMID- 28652516 TI - Gastric emptying after artificial ulceration in rats: differences due to the site of the ulcer and the effects of prokinetic drugs. AB - Background This study aimed to evaluate the effects of the position of an acetic acid-induced gastric ulcer and the effects of prokinetic drugs on gastric emptying. Materials and Methods Male Sprague-Dawley rats were used in this study. Acetic acid ulcers were induced either in the region between the fundus and pylorus on the anterior wall of the stomach or in the glandular region on the greater curvature of the stomach to determine whether there were regional differences in the effect of the ulcers. Gastric emptying was evaluated with a breath test using [1-13C] acetic acid. In addition, the effects of the prokinetic drugs, metoclopramide and mosapride, on gastric emptying were also evaluated. Results Acetic acid induced ulcers in the region between the fundus and pylorus on the anterior wall of the stomach significantly delayed gastric emptying as compared with control rats, but not the acetic acid induced ulcers in the glandular region on the greater curvature of the stomach. Metoclopramide and mosapride did not improve the delayed gastric emptying even at doses that enhanced gastric emptying in normal rats. Conclusion These findings show that gastric emptying is influenced by the position of the ulcer and the region between the fundus and pylorus on the anterior wall plays an important role in gastric emptying. Moreover, it was found that metoclopramide and mosapride do not improve the delayed gastric emptying caused by acetic acid ulcers induced on the anterior wall in the region between the fundus and pylorus. PMID- 28652517 TI - Role of prostatic interstitial cells in prostate motility. AB - The prostate is a gland whose secretions contribute to the seminal fluids ejaculated upon activation of autonomic sympathetic nerves. In elder males, the prostate undergoes an increase in stroma mass and myogenic tone, leading to benign prostatic hyperplasia that occludes the proximal urethra and the presentation of various lower urinary tract symptoms that decrease their quality of life. This review summarises the role of prostatic interstitial cells (PICs) in the generation of the spontaneous tone in the prostate. It presents current knowledge of the role of Ca2+ plays in PIC pacemaking, as well as the mechanisms by which this spontaneous activity triggers slow wave generation and stromal contraction. PICs display a small T-type Ca2+ current (ICaT) and a large L-type Ca2+ current (ICaL). In contrast to other interstitial cells in the urinary and gastrointestinal tracts, spontaneous Ca2+ signalling in PICs is uniquely dependent on Ca2+ influx through ICaL channels. A model of prostatic pacemaking is presented describing how ICaL can be triggered by an initial membrane depolarization evoked upon the selective opening of Ca2+-activated Cl- channels by Ca2+ flowing only through ICaT channels. The resulting current flow through ICaL results in release of Ca2+ from internal stores and the summation of Cl- selective spontaneous transient depolarizations (STDs) to form pacemaker potentials that propagate passively into the prostatic stroma to evoke regenerative action potentials and excitation-contraction coupling. PMID- 28652518 TI - The expression of genes involved in myometrial contractility changes during ex situ culture of pregnant human uterine smooth muscle tissue. AB - BACKGROUND: Ex situ analyses of human myometrial tissue has been used to investigate the regulation of uterine quiescence and transition to a contractile phenotype. Following concerns about the validity of cultured primary cells, we examined whether myometrial tissue undergoes culture-induced changes ex situ that may affect the validity of in vitro models. OBJECTIVES: To determine whether human myometrial tissue undergoes culture-induced changes ex situ in Estrogen receptor 1 (ESR1), Prostaglandin-endoperoxide synthase 2 (PTGS2) and Oxytocin receptor (OXTR) expression. Additionally, to determine whether culture conditions approaching the in vivo environment influence the expression of these key genes. METHODS: Term non-laboring human myometrial tissues were cultured in the presence of specific treatments, including; serum supplementation, progesterone and estrogen, cAMP, PMA, stretch or NF-kappaB inhibitors. ESR1, PTGS2 and OXTR mRNA abundance after 48 h culture was determined using quantitative RT-PCR. RESULTS: Myometrial tissue in culture exhibited culture-induced up-regulation of ESR1 and PTGS2 and down-regulation of OXTR mRNA expression. Progesterone prevented culture induced increase in ESR1 expression. Estrogen further up-regulated PTGS2 expression. Stretch had no direct effect, but blocked the effects of progesterone and estrogen on ESR1 and PTGS2 expression. cAMP had no effect whereas PMA further up-regulated PTGS2 expression and prevented decline of OXTR expression. CONCLUSION: Human myometrial tissue in culture undergoes culture-induced gene expression changes consistent with transition toward a laboring phenotype. Changes in ESR1, PTGS2 and OXTR expression could not be controlled simultaneously. Until optimal culture conditions are determined, results of in vitro experiments with myometrial tissues should be interpreted with caution. PMID- 28652519 TI - DNA methylation inhibitor causes cell growth retardation and gene expression changes in feline lymphoma cells. AB - DNA methylation is an epigenetic mechanism controlling gene expression without affecting DNA sequences, and aberrant DNA methylation patterns are features of a number of diseases. Notably, epigenetic errors in cancer cells have been intensively studied over the last two decades in humans; however, little is known concerning dogs and cats. To analyze DNA methylation and gene expression changes in feline lymphoma cells, we added the DNA methylation inhibitor 5-aza-2' deoxycytidine (5-aza) to three cell lines (3281 and FT-1 cells derived from T cell lymphoma and MS4 cells derived from B-cell lymphoma). Adding 5-aza significantly retarded cell growth in a dose-dependent manner in all cell lines, and there were aberrant gene expression patterns. Transcription factor Sox11 expression in 3281 cells was de-repressed by 5-aza treatment, and subsequent promoter DNA demethylation was analyzed by bisulfite sequencing. Cell cycle analysis suggested that inhibition of cell growth was due to DNA replication arrest, and this supported the result of increased expression of p27kip1 gene which disturbed cells of 3281 and FT-1 entering the S phase. In this study, 5-aza suppressed the growth of feline lymphoma cells, but further experiments with normal lymph cells are necessary to confirm specificity of this drug treatment and to expand it for clinical use. PMID- 28652520 TI - Biochemical characterization of variants of canine CYP1A1 using heterologous expression. AB - Cytochrome P450 1A1 (CYP1A1) is a heme-containing mono-oxygenase involved in metabolism of environmental contaminants. Two variants of dog CYP1A1 with a single residue difference were identified and designated Sap1 and Sap2. Compared with Sap1, Sap2 had a Trp50Leu substitution. The biochemical characteristics of the variants were comparatively analyzed using heterologous expression in Escherichia coli. The membrane fraction of E. coli expressing Sap2 exhibited higher CYP holoprotein and heme contents than the Sap1-containing membranes, although the level of total CYP1A1 protein (i.e., apoprotein + holoprotein) was comparable between the groups. As normalized to holo-CYP content, the Sap2 expressing membranes showed lower CYP1A1-specific enzyme activities, such as 7 ethoxyresorufin O-dealkylation (EROD), than the Sap1 group. In single substitution variants of residue 50, proteins with hydrophobic residues having mass similar to Leu exhibited lower EROD activities than those with hydrophobic residues having larger mass than Leu. In addition, variants with polar or charged residues having mass similar to Leu showed activities that were comparable to those of Sap2. Taken together, these findings suggest that the Trp50Leu substitution leads to an enhancement of holo-CYP1A1 formation, but diminishes the enzyme activity because of the small size of Leu compared with Trp. PMID- 28652521 TI - A case of recanalization of innominate artery and right middle cerebral artery embolism due to cardiogenic cerebral infarction with anticoagulation therapy. AB - An 80-year-old woman had an aortic valve replacement 1 month before admission and took warfarin for transient atrial fibrillation. She developed a disturbance of consciousness and left hemiplegia. On admission, the right radial artery was slightly palpable. Head MRI images showed a hyper-intense area in the right middle cerebral artery territory. MRA images showed an occlusion of the right M1 distal site and decreased signal at the right internal carotid artery. Contrast CT images of the ascending aorta showed an embolus in the innominate artery. She was diagnosed with an innominate artery saddle embolus and occlusion of the right cerebral artery due to cardiac embolism. She was treated with a heparin infusion and warfarin. She recovered consciousness and from hemiplegia gradually. Recanalization of the innominate artery and right cerebral artery was confirmed. In cases where the radial artery is slightly palpable, it is necessary to consider an innominate artery saddle embolus in addition to aortic dissection. PMID- 28652522 TI - Botulinum toxin for treatment of the focal dystonia. AB - Dystonia is defined as a movement disorder characterized by sustained or intermittent muscles contraction causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. The precis diagnosis of dystonia is difficult for physicians because neurological brain imaging does not provide enough practical information. The diagnosis is depend on clinical experience of physicians. Botulinum toxin treatment is the accepted standard of care for patients with focal dystonia. Botulinum toxin treatment results in significant improvement of decreasing the symptom of dystonia. The success of treatment is dependent on muscle selection for treating involved muscles. Usually performance of botulinum toxin treatment is injected according to clinical experience of surface anatomy or clinical location method. However, the benefit of guidance of botulinum toxin treatment is improve outcome in dystonia. Injection techniques with ultra sound echogram or EMG guidance to identify dystonic muscles can be more benefit for patients. PMID- 28652523 TI - A case of hereditary neuropathy with liability to pressure palsies due to push-up exercise. AB - A 17-year-old man with no familial history developed motor and sensory disturbance of the left upper limb a few days after starting push-up exercise. Neurological examination revealed broad weakness and radial sensory disturbance of the left upper limb and magnetic resonance neurography showed laterality of brachial plexus intensity signals. Therefore, we suspected left brachial plexopathy. However, a nerve conduction study showed a broad disturbance that could not be explained by only brachial plexopathy. Genetic tests revealed a diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP). HNPP should be included in the differential diagnosis for neuropathy due to slight exercise or nerve compression even when familial history is negative. PMID- 28652524 TI - Single-Breath-Hold Whole-heart Unenhanced Coronary MRA Using Multi-shot Gradient Echo EPI at 3T: Comparison with Free-breathing Turbo-field-echo Coronary MRA on Healthy Volunteers. AB - PURPOSE: We investigated the feasibility of single breath hold unenhanced coronary MRA using multi-shot gradient echo planar imaging (MSG-EPI) on a 3T scanner. METHODS: Fourteen volunteers underwent single breath hold coronary MRA with a MSG-EPI and free-breathing turbo field echo (TFE) coronary MRA at 3T. The acquisition time, signal to noise ratio (SNR), and the contrast of the sequences were compared with the paired t-test. Readers evaluated the image contrast, noise, sharpness, artifacts, and the overall image quality. RESULTS: The acquisition time was 88.1% shorter for MSG-EPI than TFE (24.7 +/- 2.5 vs 206.4 +/ 23.1 sec, P < 0.01). The SNR was significantly higher on MSG-EPI than TFE scans (P < 0.01). There was no significant difference in the contrast on MSG-EPI and TFE scans (1.8 +/- 0.3 vs 1.9 +/- 0.3, P = 0.24). There was no significant difference in image contrast, image sharpness, and overall image quality between two scan techniques. The score of image noise and artifact were significantly higher on MSG-EPI than TFE scans (P < 0.05). CONCLUSION: The single breath hold MSG-EPI sequence is a promising technique for shortening the scan time and for preserving the image quality of unenhanced whole heart coronary MRA on a 3T scanner. PMID- 28652526 TI - Comprehensive Risk Management for the Prevention of Cerebro- Cardiovascular Diseases in Japan. PMID- 28652525 TI - Sugar-Sweetened Beverages Consumption Positively Associated with the Risks of Obesity and Hypertriglyceridemia Among Children Aged 7-18 Years in South China. AB - AIMS: Excessive consumption of sugar-sweetened beverages (SSBs) may increase the prevalence of obesity and other metabolic risk factors. However, data regarding the relationship between SSB consumption and metabolic risk factors are insufficient in Chinese children. Hence, we aimed to explore the association between SSB consumption and cardio-metabolic risk factors in children aged 7-18 years living in South China. METHODS: A cross-sectional study was conducted in a total of 2,032 children aged 7-18 years were enrolled, including 1,013 boys and 1,019 girls. Based on a multistage cluster sampling, five elementary and four secondary schools in Guangzhou, China were included. Fasting blood glucose levels, lipid profiles, and anthropometric characteristics were evaluated. Information on demography, dietary, and physical activities were self-reported. RESULTS: Overall, 34.7% participants were non-drinkers and 21.6% consumed more than 120 mL/day SSB. The body mass index (19.43+/-0.18 kg/m2) and triglyceride concentration (0.96+/-0.03 mmol/L) were higher and high-density lipoprotein concentration (1.32+/-0.31 mmol/L) was lower in consumers than in non-consumers (all P<0.001). Furthermore, in contrast to non-consumers, the adjusted odds ratio of SSB consumption more than 120 mL/day was 2.08 (95% CI: 1.21-3.54) for obesity, 1.83 (95% CI: 1.25-2.69) for abdominal obesity, and 1.70 (95% CI: 1.02-3.06) for hypertriglyceridemia in consumers. CONCLUSION: A positive association between SSB consumption and the risks of obesity and hypertriglyceridemia was observed in children living in South China, which suggests that high SSB consumption enhances the risk of cardio-metabolic risk factors and the consequent cardio-metabolic diseases. PMID- 28652528 TI - Electrophysiological Characteristics and Radiofrequency Catheter Ablation Treatment of Idiopathic Ventricular Arrhythmias Successfully Ablated From the Ostium of the Coronary Sinus. AB - BACKGROUND: Idiopathic ventricular arrhythmias (VAs) rarely arise from the epicardium at the crux of the heart. However, the electrophysiological characteristics of VAs successfully ablated from the ostium of the coronary sinus (CSO) have not yet been documented.Methods and Results:Electrocardiographic and electrophysiological data were analyzed in patients with idiopathic VAs successfully ablated from the CSO.Among 309 patients with idiopathic VAs treated with radiofrequency catheter ablation (RFCA), 6 (1.94%; 3 men; age: 66.3+/-9.7 years) had VAs successfully ablated from the CSO. Only 1 patient had sustained ventricular tachycardia. The morphology of the QRS showed a left superior axis and QS pattern in leads III and aVF. Furthermore, the precordial maximum deflection index was >0.55 in all patients and a right bundle branch block pattern was recorded in 5 of 6 patients. All VAs were successfully eliminated by RFCA within the CSO. Intracardiac ECGs at sites where VAs were eliminated by RFCA showed clear atrial and ventricular potentials (atrial amplitude: 0.21+/-0.11 mV; ventricular amplitude: 0.43+/-0.24 mV), except in 1 case of atrial fibrillation. No patients had recurrence during the 3.4+/-1.8-year follow-up period. CONCLUSIONS: The idiopathic VAs in our study were eliminated by RFCA within the CS, where a clear atrial amplitude was recorded. PMID- 28652527 TI - Hyperglycemia reduces PP2A subunit B expression in a middle cerebral artery occlusion animal model. AB - Diabetes is a metabolic disorder that worsens clinical outcome following cerebral ischemia. Protein phosphatase 2A (PP2A) is a conserved, heterotrimeric, serine/threonine phosphatase with various cellular functions. PP2A subunit B is abundant in brain tissue and modulates PP2A function. The aim of this study was to investigate PP2A subunit B protein expression in the cerebral cortex of non diabetic and diabetic animals with middle cerebral artery occlusion (MCAO) injury. Sprague-Dawley rats were injected with streptozotocin (40 mg/kg, i.p.) to induce diabetic conditions. After 4 weeks of streptozotocin treatment, the rats underwent MCAO to induce focal cerebral ischemia. The cerebral cortex tissue was collected 24 hr after MCAO. Body weight and blood glucose were measured, and Western blot analysis was performed to elucidate the expression of PP2A subunit B. We confirmed decreased body weight and increased blood glucose in diabetic animals. Reverse transcription-PCR and Western blot analyses showed decreased PP2A subunit B expression in the cerebral cortices of MCAO-injured animals. Moreover, diabetic animals with MCAO showed more severe decreases in PP2A subunit B protein levels than non-diabetic animals following MCAO. The decline of PP2A subunit B indicates degradation of neuronal function. These findings suggest that conspicuous decreases in PP2A subunit B may exacerbate cerebral ischemia under diabetic conditions following MCAO. PMID- 28652529 TI - Efficacy and Safety of Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib Administered as Monotherapy in Japanese Patients With Primary Hypercholesterolemia. AB - BACKGROUND: Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia. Primary efficacy measure was the percent change from baseline to week 12 in LDL-C (beta quantification). Treatment with evacetrapib 130 mg once daily for 12 weeks resulted in statistically significant (P<0.001) change in LDL-C (beta quantification) compared with placebo. Least-squares mean percentage changes from baseline were -34.3% in the evacetrapib group vs. 0.0% in the placebo group. Treatment with evacetrapib 130 mg also resulted in a statistically significant (P<0.001) increase in high-density lipoprotein cholesterol compared with placebo in mean percent change from baseline, with a least-squares mean difference of 124.0% (95% confidence interval: 104.6-143.5). No deaths, serious adverse events, or discontinuations because of adverse events were reported; 5 patients (18.5%) in the evacetrapib group and 7 patients (26.9%) in the placebo group experienced treatment-emergent adverse events. CONCLUSIONS: Once-daily evacetrapib 130 mg monotherapy was superior to placebo in lowering LDL-C after 12 weeks. No new safety risks were identified. PMID- 28652530 TI - Achilles Tendon Ultrasonography for Diagnosis of Familial Hypercholesterolemia Among Japanese Subjects. AB - BACKGROUND: Difficulty in detecting and measuring Achilles tendon (AT) xanthomas may be responsible for underdiagnosis of familial hypercholesterolemia (FH). We aimed to determine a cutoff value for AT thickness (AT-T) using ultrasonography to diagnose FH, and to investigate the relationship between AT-T and atherosclerosis.Methods and Results:Ultrasonographic AT-T and carotid intima media thickness (IMT) were evaluated in 130 genetically diagnosed FH patients and 155 non-FH patients. The outline and internal properties of the AT could be clearly determined using ultrasonography, and a good correlation in AT-T was observed between ultrasonography and the conventional method of X-ray radiography (r=0.924, P<0.001). Cutoff values for the diagnosis of FH derived from receiver operating curves were 5.8 mm (sensitivity 71%, specificity 78%) in men, and 5.5 mm (sensitivity 80%, specificity 81%) in women. Importantly, increased AT-T was positively associated with carotid IMT only in the FH group. Additionally, increased AT-T was associated with the presence of coronary artery disease in a logistic regression analysis adjusted for traditional cardiovascular risk factors. CONCLUSIONS: This is the first study to determine a cutoff value for AT T based on ultrasonography for the diagnosis of FH in Japanese subjects. Clearer detection and easier measurement of AT-T using ultrasonography would encourage clinicians to diagnose FH more actively, and could solve the problem of underdiagnosis of FH. PMID- 28652531 TI - Long-Term Outcome of Aortic Root Remodeling for Patients With and Without Acute Aortic Dissection. AB - BACKGROUND: Valve-preserving aortic surgery is increasingly used in acute aortic dissection type A (AADA). The object of this study was to compare the long-term results of aortic root remodeling (remodeling) for patients with and without AADA.Methods and Results:Between October 1995 and December 2013, 776 patients underwent valve-preserving root replacement, of whom 59 patients with AADA (<2 weeks from onset, 56+/-16 years, 48 male) underwent remodeling (the remodeling group); 7 patients had bicuspid anatomy (12%), 3 had Marfan syndrome (5%), and 1 had undergone previous cardiac surgery (2%). For this analysis the control group of patients who underwent remodeling for stable aneurysm (n=59) was generated using a propensity score matching. The long-term outcomes regarding survival and reoperation on the aortic valve were compared between the 2 groups. Pre- and intraoperative patients' characteristics were comparable between groups. Early death was 7% in the AADA group and 3% in the control group (P=0.40). Actuarial survival at 10 years of the AADA group (72+/-6%) was insignificantly lower than that of the control group (83+/-5%) (P=0.16). Freedom from reoperation at 10 years was similar (AADA group: 98+/-2%, control group: 97+/-3%, P=0.99). Multivariable Cox's proportional hazards model could not identify an independent predictor for late reoperation but advanced age for late death. CONCLUSIONS: Long term stability of remodeling was comparable between patients with and without AADA. PMID- 28652532 TI - Eicosapentaenoic Acid-Enriched High-Density Lipoproteins Exhibit Anti-Atherogenic Properties. AB - BACKGROUND: It has previously been reported that oral administration of purified eicosapentaenoic acid (EPA) generates EPA-rich high-density lipoprotein (HDL) particles with a variety of anti-inflammatory properties. In this study, the mechanism underlying the anti-atherogenic effects of EPA-rich HDL using reconstituted HDL (rHDL) was investigated.Methods and Results:rHDL was generated by the sodium cholate dialysis method, using apolipoprotein A-1 protein, cholesterol, and various concentrations of EPA-phosphatidylcholine (PC) or egg PC. Increased EPA-PC contents in rHDL resulted in decreased particle size. Next, the effects of rHDL containing various amounts (0-100% of total PC) of EPA-PC on vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical vein endothelial cells (HUVECs) was examined. Cytokine-stimulated VCAM-1 expression was inhibited in a dose-dependent manner based on the amount of EPA-PC in rHDL. Surprisingly, the incubation of HUVECs with EPA-rich rHDL resulted in the production of resolvin E3 (RvE3), an anti-inflammatory metabolite derived from EPA. Incubation with EPA-PC alone did not adequately induce RvE3 production, suggesting that RvE3 production requires an endothelial cell-HDL interaction. The increased anti-inflammatory effects of EPA-rich HDL may be explained by EPA itself and RvE3 production. Furthermore, the increase in EPA-PC content enhanced cholesterol efflux. CONCLUSIONS: The EPA-enriched HDL particles exhibit cardioprotective properties via the production of anti-inflammatory lipid metabolites and the increase in cholesterol efflux. PMID- 28652533 TI - Angioscopic Findings of Acute Myocardial Infarction After Kawasaki Disease. PMID- 28652534 TI - Poly(U) and CpG ameliorate the unbalanced T cell immunity and pneumonia of mice with RSV vaccine-enhanced disease. AB - Respiratory Syncycial Virus (RSV) is the most important pathogen responsible for children's severe lower respiratory tract infection. So far no RSV vaccine has yet been authorized for clinical use. The main impediment that blocked development of RSV vaccine is that inactivated RSV vaccine could cause RSV vaccine-enhanced disease (RVED). The mechanism of RVED remains unclear. Recently some researchers found that insufficient activation of innate immunity, including Toll-like receptors (TLRs), might be associated with the onset of RVED. Based on the above findings, this research was conducted to further study the mechanism of RVED. We first vaccinated mice with formalin-inactivated RSV vaccine (FIRSV) and then exposed them to RSV to establish a RVED mouse model. Consequently, we found that mice previously inoculated with FIRSV showed obvious weight loss and extensive pneumonia, as well as T helper 2 cells (Th2)-biased immunity and suppressed CD8+T cell immunity after viral exposure, suggesting that we have successfully established a RVED mouse model. Then based on this model, we further added Poly(U) (TLR7/8 agonist) and CpG (TLR9 agonist) in FIRSV to see if RVED could be ameliorated. As a result, mice inoculated with FIRSV supplemented with Poly(U) and CpG had a much relieved weight loss and pneumonia, as well as suppressed Th2-biased immunity and strengthened CD8+T cell function. Thus, the insufficient stimulation of TLR7/8 and (or) TLR9 might play a role in the development of RVED, which could provide evidence for using TLR agonists as vaccine adjuvants to confer a protective immune response against RSV. PMID- 28652535 TI - Clinical application of ghrelin for chronic respiratory failure. AB - Chronic respiratory failure, which is often caused by chronic obstructive pulmonary disease, chronic lower respiratory tract infection, or interstitial pneumonia, often leads to cachexia with disease progression. Patients who have chronic respiratory failure with cachexia exhibit increased morbidity. Although cachectic status is an important clinical problem, there are no effective therapies for cachexia. Ghrelin has various effects, including increasing food intake, attenuating sympathetic nerve activity, inhibiting inflammation, increasing cardiac output, and controlling fat utilization. These effects of ghrelin are ideal targets for the treatment of severely wasting chronic respiratory disease. In a few clinical studies, including a small randomized controlled trial, ghrelin administration to cachectic patients with chronic respiratory failure improved exercise tolerance, dyspnea, and appetite. The patients in these studies gained muscle mass and weight. In another study of chronic lower respiratory tract infection with cachexia, ghrelin suppressed airway inflammation by decreasing neutrophil accumulation in the airway, resulting in improvements in oxygenation and exercise tolerance. Although further clinical investigations are needed to clarify its usefulness, ghrelin is expected to become a novel therapy for cachectic patients with chronic respiratory failure. PMID- 28652536 TI - The important role of ghrelin on gastric contraction in Suncus murinus. AB - Ghrelin, a peptide hormone produced in the stomach, has been known to be involved in the regulation of gastric contraction in humans and rodents. To elucidate the detailed mechanisms of ghrelin on gastric contractions, we used Suncus murinus, a recently established small animal model for gastrointestinal motility. S. murinus produces motilin, a family peptide of ghrelin, and its stomach anatomy and physiological patterns of gastric contractions, in fed and fasted states, are closely similar to humans. Ghrelin administration in phase II, and latter half of phase I, of the migrating motor contractions (MMC) enhanced gastric motility in S. murinus. In addition, we showed that ghrelin and motilin coordinately stimulated strong gastric contractions in vitro and in vivo. We also demonstrated that a pretreatment with a ghrelin antagonist, D-Lys3-GHRP6, inhibited the effects of motilin-induced gastric contractions, and a gamma-aminobutyric acid (GABA) antagonist reversed this inhibition. Our results suggest that ghrelin is essential for motilin-induced gastric contractions and that ghrelin-mediated GABAergic neurons are involved in this neural pathway. PMID- 28652537 TI - Current knowledge of ghrelin in amphibians. AB - We are exploring physiological importance of the ghrelin system in vertebrates. This review summarizes current knowledge of the ghrelin system in amphibians. Our study on ghrelin precursor in various amphibians revealed that the third amino acid with acyl modification has changed to threonine (Thr-3) instead of serine (Ser-3) only in the genus, Rana. Functional analyses of the ghrelin receptor in three species of amphibians, Japanese fire belly newt, American bullfrog and Japanese tree frog revealed that ghrelin and GHS-R1a agonists increase intracellular Ca2+ concentration in HEK293 cells expressing each receptor, and that ligand selectivity of ghrelin with Ser-3 and Thr-3 that expected to see in the bullfrog receptor was not found in the two frog receptors, but in the newt receptor. The brain, gastrointestinal tract, kidney and gonad highly express GHS R1a mRNA. In frogs and newt, fasting did not increase GHS-R1a mRNA expression in the brain, but in the stomach. However, intraperitoneal (IP) injection of ghrelin did not affect food intake. A dehydration treatment increased GHS-R1a mRNA expression in the brain, stomach and ventral skin in the tree frog. However, intracerebroventricular (ICV) injection of ghrelin did not affect water absorption. Ghrelin did not influence gastrointestinal motility in in vitro studies using smooth muscle strips of the bullfrog and newt in vitro. These results suggest that the ghrelin system is present in various amphibians, but little is known about the physiological functions except hypophyseal hormone secretion. PMID- 28652538 TI - The role of acylated-ghrelin in the regulation of sucrose intake. AB - The octanoyl modification of ghrelin by ghrelin O-acyltransferase (GOAT) is essential for exerting its physiologic actions. Since exogenous acylated-ghrelin has shown to stimulate food intake in humans and rodents, GOAT has been regarded as a promising target for modulating appetite, thereby treating obesity and diabetes. However, GOAT-knockout (KO) mice have been reported to show no meaningful body weight reduction, when fed a high-fat diet. In this study, we sought to determine whether GOAT has a role in the regulation of body weight and food intake when fed a dietary sucrose. We found that GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, when fed a high-fat + high-sucrose diet. In addition, GOAT KO mice fed a medium-chain triglyceride (MCT) + high-sucrose diet showed a marked resistance to obesity and reduced feed efficiency. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity caused by overconsumption of palatable food. PMID- 28652539 TI - The effects of inflammatory cytokines on the expression of ghrelin. AB - In the current study, we examined the effects of LPS and inflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 on the expression of ghrelin in MGN3-1 cells. We found that IL-1beta, and TNF-alpha with lesser extent, significantly suppressed ghrelin mRNA expression in the cells. MGN3-1 cells expressed IL-1beta receptor and IL-1beta significantly stimulated NF-kappaB, p38, JNK, and ERK pathways. Knockdown of IKK2 by siRNA significantly attenuated the suppression of ghrelin mRNA by IL-1beta. These results indicate that IL-1beta directly suppressed ghrelin mRNA via NF-kappaB pathway at least partially, which may have a role in the regulation of appetite during inflammation. PMID- 28652540 TI - The study of ghrelin secretion and acyl-modification using mice and ghrelinoma cell lines. AB - Ghrelin is a peptide hormone with a unique structure comprising a medium chain fatty acid modification. Ghrelin cells are known to be abundantly localized in the gastric mucosa and are released into the blood stream to exert their multifunctional physiological effects. To elucidate the regulatory mechanisms of ghrelin secretion and acyl-modification, we developed novel ghrelin-producing cell lines. Using ghrelinoma cell lines, we focused on the mechanisms of ghrelin secretion and found that several GPCRs were highly expressed in ghrelin cells. Then, we showed that noradrenaline treatment stimulated ghrelin secretion via beta1-adrenergic receptor, and fasting-induced ghrelin elevation was completely inhibited by the beta1-adrenergic receptor antagonist in mice. In addition, we demonstrated that long chain fatty acids, glucose, and L-glutamate significantly inhibited ghrelin secretion. Furthermore, we recently revealed that the genes involved in fatty acid synthesis and long chain fatty acid metabolism were expressed in ghrelin cells, and that CPT-1 inhibitor treatment dramatically decreased the levels of acyl-modified ghrelin. Here, we introduce the current knowledge of the mechanisms involving ghrelin secretion and its acyl modification. PMID- 28652541 TI - Development of ghrelin transgenic mice for elucidation of clinical implication of ghrelin. AB - To elucidate the clinical implication of ghrelin, we have been trying to generate variable models of transgenic (Tg) mice overexpressing ghrelin. We generated Tg mice overexpressing des-acyl ghrelin in a wide variety of tissues under the control of beta-actin promoter. While plasma des-acyl ghrelin level in the Tg mice was 44-fold greater than that of control mice, there was no differences in the plasma ghrelin level between des-acyl ghrelin Tg and the control mice. The des-acyl ghrelin Tg mice exhibited the lower body weight and the shorter body length due to modulation of GH-IGF-1 axis. We tried to generate Tg mice expressing a ghrelin analog, which possessed ghrelin-like activity (Trp3-ghrelin Tg mice). The plasma Trp3-ghrelin concentration in Trp3-ghrelin Tg mice was approximately 85-fold higher than plasma ghrelin (acylated ghrelin) concentration seen in the control mice. Because Trp3-ghrelin is approximately 24-fold less potent than ghrelin, the plasma Trp3-ghrelin concentration in Trp3-ghrelin Tg mice was calculated to have approximately 3.5-fold biological activity greater than that of ghrelin (acylated ghrelin) in the control mice. Trp3-ghrelin Tg mice did not show any phenotypes except for reduced insulin sensitivity in 1-year old. After the identification of ghrelin O-acyltransferase (GOAT), we generated doubly Tg mice overexpressing both mouse des-acyl ghrelin and mouse GOAT in the liver by cross-mating the two kinds of Tg mice. The plasma ghrelin concentration of doubly Tg mice was approximately 2-fold higher than that of the control mice. No apparent phenotypic changes in body weight and food intake were observed in doubly Tg mice. Further studies are ongoing in our laboratory to generate Tg mice with the increased plasma ghrelin level to a greater extent. The better understanding of physiological and pathophysiological significance of ghrelin from experiments using an excellent animal model may provide a new therapeutic approach for human diseases. PMID- 28652542 TI - Therapeutic potential of ghrelin and des-acyl ghrelin against chemotherapy induced cardiotoxicity. AB - Cancer was considered an incurable disease for many years; however, with the development of anticancer drugs and state-of-the art technologies, it has become curable. Cardiovascular diseases in patients with cancer or induced by cancer chemotherapy have recently become a great concern. Certain anticancer drugs and molecular targeted therapies cause cardiotoxicity, which limit the widespread implementation of cancer treatment and decrease the quality of life in cancer patients significantly. The anthracycline doxorubicin (DOX) causes cardiotoxicity. The cellular mechanism underlying DOX-induced cardiotoxicity include free-radical damage to cardiac myocytes, leading to mitochondrial injury and subsequent death of myocytes. Recently, circulating orexigenic hormones, ghrelin and des-acyl ghrelin, have been reported to inhibit DOX-induced cardiotoxicity. However, little is known about the molecular mechanisms underlying their preventive effects. In the present study, we show the possible mechanisms underlying the effects of ghrelin and des-acyl ghrelin against DOX induced cardiotoxicity through in vitro and in vivo researches. PMID- 28652543 TI - Ghrelin does not influence cancer progression in a lung adenocarcinoma cell line. AB - Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced in the human stomach. Although ghrelin has therapeutic potential for cancer cachexia, ghrelin treatment may have a concern about accelerating cancer progression. Here, using the human lung adenocarcinoma cell line HLC-1, we investigated the effects of ghrelin on molecular mechanisms linked to cancer progression, including cell viability, proliferation, resistance to apoptosis, and mitochondrial activity. Both types of mouse alveolar epithelial cells (types I and II) expressed the GHSR, as did the human normal airway cell lines BEAS-2B and HLC-1. Treatment with ghrelin (10-2, 10-1, 1, 10 MUM) did not affect cell viability or proliferation. Pretreatment of HLC-1 cells with ghrelin (10 MUM) did not affect resistance to paclitaxel-induced apoptosis. The parameters of mitochondrial respiration, including basal respiration, proton leak, ATP production, maximal respiration, spare respiratory capacity, and non mitochondrial respiration, of the HLC-1 cells pretreated with or without ghrelin were unchanged. Taken together, ghrelin does not influence cancer progression in lung adenocarcinoma cells. PMID- 28652544 TI - Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation. AB - Chronic kidney disease (CKD) impairs physical performance in humans, which leads to a risk of all-cause mortality. In our previous study, we demonstrated that a reduction in muscle mitochondria rather than muscle mass was a major cause of physical decline in 5/6 nephrectomized CKD model mice. Because ghrelin administration has been reported to enhance oxygen utilization in skeletal muscle, we examined the usefulness of ghrelin for a recovery of physical decline in 5/6 nephrectomized C57Bl/6 mice, focusing on the epigenetic modification of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha), a master regulator of mitochondrial biogenesis. The mice were intraperitoneally administered acylated ghrelin (0.1 nmol/gBW; three times per week) for a month. Muscle strength and exercise endurance were measured by using a dynamometer and treadmill, respectively. Mitochondrial DNA copy number was determined by quantitative PCR. The methylation levels of the cytosine residue at 260 base pairs upstream of the translation initiation point (C-260) of PGC-1alpha, which has been demonstrated to decrease the expression, was evaluated by methylation specific PCR and bisulfite genomic sequencing methods after the ghrelin administration. Ghrelin administration improved both muscle strength and exercise endurance in the mice and was associated with an increase in muscle mass and muscle mitochondrial content. Ghrelin administration decreased the methylation ratio of C-260 of PGC-1alpha in the skeletal muscle and increased the expression. Therefore, ghrelin administration effectively reduced the physical decline in 5/6 nephrectomized mice and was accompanied with an increased mitochondrial content through de-methylation of the promoter region of PGC-1alpha in the muscle. PMID- 28652545 TI - The chicken is an interesting animal for study of the functional role of ghrelin in the gastrointestinal tract. AB - Ghrelin has been identified in vertebrates from fish to mammals, and it has multiple biological activities including gastrointestinal (GI) motor-stimulating action. In some non-mammalian vertebrates, we examined the effects of ghrelin on contractility of the isolated GI tract as well as the mRNA expression of growth hormone secretagogue-receptor 1a (GHS-R1a) to determine whether the motor stimulating action of ghrelin is common in vertebrates. The expression level of GHS-R1a mRNA differed depending on the species and on the GI region (stomach, small intestine, and colon). GI region-dependent expression of GHS-R1a mRNA was remarkable in chickens, and the expression levels changed depending on age. In a functional study, ghrelin did not cause contraction of unstimulated GI strips in fish (goldfish and rainbow trout) or amphibians (bullfrog and Japanese fire belly newts) even using their homologous ghrelin. In avian species, ghrelin caused contraction of the unstimulated GI tract of the chicken but not of the Japanese quail, and the responses to ghrelin in the chicken GI tract decreased with aging. Our in vitro studies show that the motor-stimulating action of ghrelin is not conserved across vertebrates and that the chicken is a unique animal species for evaluation of the GI-stimulating action of ghrelin of different age. PMID- 28652546 TI - Clinical application of ghrelin for diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, and its progression significantly worsens the patient's quality of life. Although several drugs are available for DPN, all of these provide only symptomatic relief. We investigated the therapeutic effects of ghrelin for DPN, based on its various physiological functions. Seven patients with type 2 diabetes with typical clinical signs and symptoms of DPN were hospitalized. Synthetic human ghrelin (1.0 MUg/kg) was administered intravenously for 14 days. Motor nerve conduction velocity (MCV) of the posterior tibial nerve improved significantly after the treatment, compared to that at baseline (35.1 +/- 1.8 to 38.6 +/- 1.8 m/s, p < 0.0001), while the MCV in six untreated patients did not change throughout hospitalization. The subjective symptoms assessed based on the total symptom score also significantly improved (15.6 +/- 3.1 to 11.1 +/- 2.2, p = 0.047). Although sensory nerve conduction velocity (SCV) of the sural nerve could not be detected in three patients at baseline, it was detected in two of the three patients after 14 days of ghrelin administration. Overall, SCV did not change significantly. Plasma glucose, but not serum C peptide, levels during a liquid meal tolerance test significantly improved after treatment. These results suggest that ghrelin may be a novel therapeutic option for DPN; however, a double-blind, placebo-controlled trial is needed in the future. PMID- 28652548 TI - Spongian Diterpenes from the Sponge Hyattella aff. intestinalis. AB - Extracts of the sponge Hyattella aff. intestinalis showed moderate inhibition against adenovirus. Chromatographic separation of the extracts followed by analysis of spectroscopic data allowed us to elucidate the structures of three new metabolites as 2alpha-hydroxyspongia-13(16),14-diene-3-one (4), 3beta hydroxyspongia-13(16),14-diene-2-one (7), and 2alpha,3alpha-diacetoxy-17,19 dihydroxyspongia-13(16),14-diene (8) and to identify six known ones 1-3, 5, 6 and 9. Among the molecules, compounds 1 and 3 showed antiviral activity at IC50 17.0 and 52.0 uM. PMID- 28652547 TI - Occupational exposure limits for ethylene glycol monobutyl ether, isoprene, isopropyl acetate and propyleneimine, and classifications on carcinogenicity, occupational sensitizer and reproductive toxicant. PMID- 28652549 TI - An Evaluation Method for Suppression of Pathogenic Fusarium oxysporum by Soil Microorganisms Using the Dilution Plate Technique. AB - Volume 31, No. 3, Page 307-313, 2016Page 310, Legend for Fig. 4 IncorrectFig. 4. Growth degree of Fusarium oxysporum f. sp. spinaciae for organic fertilizers at each dilution based on an estimation of the ellipse area (A) and extension length (B) of the colony. Cont, compound inorganic fertilizer; SBM, steamed bone meal; CDC, cow dung compost; MI, microbial inoculant. Values show mean of medians of degrees with SE (n=3). The ellipse area and extension length for control plates were 4,475 mm2 and 36.5 mm, respectively. CorrectFig. 4. Growth degree of Fusarium oxysporum f. sp. spinaciae for organic fertilizers at each dilution based on an estimation of the ellipse area (A) and extension length (B) of the colony. Cont, compound inorganic fertilizer; SBM, steamed bone meal; CDC, cow dung compost; MI, microbial inoculant. Values show mean of growth degrees with SE (n=3). The ellipse area and extension length for control plates were 4,475 mm2 and 36.5 mm, respectively. Page 311, Legend for Fig. 5 IncorrectFig. 5. Growth degree of Fusarium oxysporum f. sp. spinaciae for soil applied with organic fertilizers at each dilution based on an estimation of the ellipse area (A) and extension length (B) of the colony. Cont, compound inorganic fertilizer; SBM, steamed bone meal; CDC, cow dung compost; MI, microbial inoculant. Values show the mean of medians of degrees with SE (n=3). The ellipse area and extension length for control plates were 5,473 mm2 and 40.5 mm, respectively. CorrectFig. 5. Growth degree of Fusarium oxysporum f. sp. spinaciae for soil applied with organic fertilizers at each dilution based on an estimation of the ellipse area (A) and extension length (B) of the colony. Cont, compound inorganic fertilizer; SBM, steamed bone meal; CDC, cow dung compost; MI, microbial inoculant. Values show the mean of growth degrees with SE (n=3). The ellipse area and extension length for control plates were 5,473 mm2 and 40.5 mm, respectively. Page 312, Legend for Fig. 7 IncorrectFig. 7. Growth degree of Fusarium oxysporum f. sp. spinaciae at each dilution based on an estimation of the ellipse area (A) and extension length (B) of the colony. Cont, compound inorganic fertilizer; SBM, steamed bone meal; CDC, cow dung compost; MI2, microbial inoculant applied with 2,000 kg ha-1; MI10, microbial inoculant applied with 10,000 kg ha-1. Values show the mean of medians of degrees with SE (n=3). The ellipse area and extension length for control plates were 3,404 mm2 and 29.7 mm, respectively. CorrectFig. 7. Growth degree of Fusarium oxysporum f. sp. spinaciae at each dilution based on an estimation of the ellipse area (A) and extension length (B) of the colony. Cont, compound inorganic fertilizer; SBM, steamed bone meal; CDC, cow dung compost; MI2, microbial inoculant applied with 2,000 kg ha-1; MI10, microbial inoculant applied with 10,000 kg ha-1. Values show the mean of growth degrees with SE (n=3). The ellipse area and extension length for control plates were 3,404 mm2 and 29.7 mm, respectively. The authors would like to apologize for these corrections and any inconvenience caused. PMID- 28652550 TI - Quest of Soil Protists in a New Era. PMID- 28652551 TI - Review of titanate coupling agents and their application for dental composite fabrication. AB - Silane is a dominant coupler that is widely used in dentistry to promote adhesion among the components of dental composites. Silica-based fillers can be easily silanized because of their similarly ordered structure. However, silane is hydrolytically degraded in the aqueous oral environment and inefficiently bonds to non-silica fillers. Thus, the development of hydrolytically stable dental composites is an important objective in the research on dental materials. Titanate coupling agents (TCAs) exhibit satisfactory interfacial bonding, enhanced homogeneous filler dispersion, and improved mechanical properties of the composites. Titanates also provide superior hydrolytic stability in wet environments, which should be considered in fabricating dental composites. The addition of a small amount of titanates can improve the resistance of the composites to moisture. This paper reviews the effects of the instability of silanes in moisture on the performance of dental composites and presents TCAs as alternative couplers to silanes for fabricating dental composites. PMID- 28652552 TI - Influence of photoirradiation conditions on dentin bond durability and interfacial characteristics of universal adhesives. AB - The influence of photoirradiation conditions on dentin bond durability and interfacial characteristics of universal adhesives was investigated. Universal adhesives were applied to the dentin surfaces and photoirradiated with 100 mW/cm2 for 40 s, 200 mW/cm2 for 20 s, and 400 mW/cm2 for 10 s. A resin composite was bonded to dentin to determine shear bond strength after 24 h water storage and 30,000 thermal cycles, and water contact angle of cured adhesive were measured by the sessile drop method. Greater dentin bond strengths after 24 h water storage and 30,000 thermal cycles were achieved under these conditions at light intensity exceeding 200 mW/cm2. Universal adhesives photoirradiated above 200 mW/cm2 exhibited significantly higher water contact angles than those at 100 mW/cm2. The results of this study suggested that the photoirradiation conditions affect the dentin bond durability and interfacial characteristics of universal adhesives even at the same total energy. PMID- 28652553 TI - Establishment of experimental models to evaluate the effectiveness of dental trauma splints. AB - The purpose was to describe a novel simple experimental model of injured teeth for developing dental trauma splints (DTS), and to test various splints by combining use of this model and the Periotest(r) device. Rubber O-rings and spring washers were used to simulate and modify injured tooth mobility. Splinting effects were assessed among three kinds of DTS, including a composite splint and two wire-composite splints (1: rectangular orthodontic wire 0.533*0.635 mm, 2: cobalt-chromium alloy wire Phi0.9 mm). The Periotest values were measured three times for each tooth before and after splint insertion. The splinting effect was defined as the change in tooth mobility. Splinting effects significantly increased in the order wire-composite splint 10.1). By incorporating DMAHDM into Transbond XT for the first time, the modified orthodontic cement obtained a strong antibacterial capability without compromising the enamel bond strength. PMID- 28652556 TI - Characteristics of low polymerization shrinkage flowable resin composites in newly-developed cavity base materials for bulk filling technique. AB - The purpose of this study was to evaluate polymerization shrinkage and other physical properties of newly-developed cavity base materials for bulk filling technique, with the brand name BULK BASE (BBS). Polymerization shrinkage was measured according to ISO/FDIS 17304. BBS showed the significantly lowest polymerization shrinkage and significantly higher depth of cure than conventional flowable resin composites (p<0.05). The Knoop hardness, flexural strength and elastic modulus of that were significantly lower than conventional flowable resin composites (p<0.05). BBS had the significantly greatest filler content (p<0.05). SEM images of the surface showed failure of fillers. The lowest polymerization shrinkage was due to the incorporation of a new type of low shrinkage monomer, which has urethane moieties. There were no clear correlations between inorganic filler contents and polymerization shrinkage, flexural strength and elastic modulus. In conclusion, the low polymerization shrinkage of BBS will be useful for cavity treatment in dental clinics. PMID- 28652557 TI - Study of pH Stability of R-Salbutamol Sulfate Aerosol Solution and Its Antiasthmatic Effects in Guinea Pigs. AB - Currently, all commercial available nebulized salbutamol in China is in its racemic form. It is known that only R-salbutamol (eutomer) has therapeutic effects, while S-salbutamol (distomer) may exacerbate asthma after chronic use. Therefore, it is an unmet clinical need to develop R-salbutamol as a nebulized product that is more convenient for young and old patients. In our study, a stable aerosol solution of R-salbutamol sulfate was established, and its antiasthmatic effects were confirmed. The decomposition rate and racemization effect of the R-salbutamol sulfate solution were evaluated over a pH range from 1 to 10 (except pH=7, 8) at 60 degrees C. The aerodynamic particle size of the R salbutamol sulfate solution and commercial RS-salbutamol sulfate solution were both tested in vitro by Next-Generation Impactor (NGI) in 5 degrees C. Laser diffractometer was used to characterize the droplet-size distribution (DSD) of both solutions. We next conducted an in vivo animal study to document the antiasthmatic effect of R-salbutamol aerosol sulfate solution and determine the relationship to RS-salbutamol. The results showed that the R-salbutamol sulfate solution was more stable at pH 6. In vitro comparison studies indicated that there was no distribution difference between R-salbutamol sulfate solution and the commercial RS-salbutamol solution. The animal results showed that R salbutamol was more potent than RS-salbutamol against the same dose of histamine challenge. Unlike commercial RS-salbutamol, which was acidified to a pH of 3.5 to extend bench life but may cause bronchoconstriction in asthmatic patients, the neutralized R-salbutamol solution was more suitable for clinic use. PMID- 28652558 TI - Sex difference of hyperinsulinemia in the C57BL/6J-Daruma (obese) mouse. AB - The C57BL/6J-Daruma mouse is an animal model of obesity derived from the original genetically obese ICR-Daruma mouse by transfer of the phenotype into the C57BL/6J background by backcrossing into the C57BL/6J strain. Although, like the original ICR-Daruma mouse model, both male and female C57BL/6J-Daruma mice develop obesity, the latter strain shows sex differences in several phenotypes. A sex difference in plasma insulin levels was especially notable in C57BL/6J-Daruma mice; only males showed hyperinsulinemia. Orchiectomy suppressed this hyperinsulinemia completely, whereas testosterone supplementation restored it. Glucose administration increased the plasma glucose level in both male and female Daruma mice to a greater extent than in wild-type control mice. Orchiectomy, but not ovariectomy, decreased the plasma glucose level to that seen in wild-type controls. On the other hand, this effect of orchiectomy was abrogated by testosterone supplementation. The expression of mRNAs for several genes related to insulin resistance was significantly changed in white adipose tissue and liver of C57BL/6J-Daruma mice, especially males, as early as 4 weeks of age. The present results suggest that testosterone may be involved in the hyperinsulinemia shown by male C57BL/6J-Daruma mice and that this strain may be an appropriate animal model for examining the relationship between obesity and sex hormones. PMID- 28652559 TI - Expression of thyroid hormone regulator genes in the yolk sac membrane of the developing chicken embryo. AB - Thyroid hormones (THs) are essential for the correct development of nearly every structure in the body from the very early stages of development, yet the embryonic thyroid gland is not functional at these stages. To clarify the roles of the egg yolk as a source of THs, the TH content in the yolk and the expression of TH regulator genes in the yolk sac membrane were evaluated throughout the 21 day incubation period of chicken embryos. The yolk TH content (22.3 ng triiodothyronine and 654.7 ng thyroxine per total yolk on day 4 of incubation) decreased almost linearly along with development. Real-time PCR revealed gene expression of transthyretin, a principal TH distributor in the chicken, and of a TH-inactivating iodothyronine deiodinase (DIO3), until the second week of incubation when the embryonic pituitary-thyroid axis is generally thought to start functioning. The TH-activating deiodinase (DIO2) and transmembrane transporter of thyroxine (SLCO1C1) genes were expressed in the last week of incubation, which coincided with a marked increase of circulating thyroxine and a reduction in the yolk sac weight. DIO1, which can remove iodine from inactive THs, was expressed throughout the incubation period. It is assumed that the chicken yolk sac inactivates THs contained abundantly in the yolk and supplies the hormones to the developing embryo in appropriate concentrations until the second week of incubation, while THs may be activated in the yolk sac membrane in the last week of incubation. Additionally, the yolk sac could serve as a source of iodine for the embryo. PMID- 28652560 TI - Zymosan A enhances humoral immune responses to soluble protein in chickens. AB - Vaccination is the most effective method for controlling the infectious diseases that threaten the poultry industry worldwide. The use of adjuvants or immunostimulants is often necessary to improve vaccine efficacy, particularly for vaccines based on recombinant protein or inactivated pathogens. The adjuvant effects of zymosan A on antigen-specific antibody production were investigated in chickens. First, the optimal adjuvant dose of zymosan A was determined. Chicks were immunized with dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH) at a dosage of 2 mg/kg body weight (BW) with or without zymosan A (at a dosage of 0.5 mg/kg BW) co-administration at 4, 5 and 6 weeks of age. Different routes of immunization (oral, intranasal (i.n.), intraocular (i.o.), subcutaneous (s.c.), intramuscular (i.m.) and intraperitoneal (i.p.) were tested. Anti-DNP IgY and IgA concentrations in serum samples from all chicks were measured by an enzyme-linked immunosorbent assay. The results revealed that co-administration of zymosan A with DNP-KLH significantly increased anti-DNP IgY concentrations in chicks immunized by the oral and s.c. routes of administration when compared with control groups. In addition, co-administration of zymosan A with DNP-KLH significantly increased anti-DNP IgA concentrations in chicks immunized by the oral, i.o. and s.c. routes compared with control groups. In conclusion, zymosan A is a useful immune-potentiator adjuvant in chickens, and its co-administration with vaccine antigens enhances humoral immune responses. PMID- 28652561 TI - Chronic Subdural Hematoma in Elderly Patients: Is This Disease Benign? AB - As the world population becomes progressively older, the overall incidence of chronic subdural hematoma (CSDH) is increasing. Peak age of onset for CSDH has also increased, and recently the 80-year-old level has a peak. Many patients with CSDH have had prior treatment with anticoagulants and antiplatelet drugs, which have an accompanying risk of CSDH. In elderly patients with CSDH, symptoms of cognitive change (memory disturbance, urinary incontinence, and decreased activity) and disturbance of consciousness at admission were more frequent compared to younger patients with CSDH. The literature actually offers conflicting advice regarding CSDH treatment; however, burr hole surgery with drainage under local anesthesia is the most common surgical procedure, even in elderly patients. The recurrence rate of CSDH has not decreased over recent decades, and it has ranged from 0.36-33.3%. Outcomes in patients over 75 years old was significantly worse than for those younger than 75. Moreover, long-term outcomes for elderly patients with CSDH are poor. CSDH in the elderly is no longer a benign disease. In the future, it will be important for us to understand the mechanisms of onset and recurrence of CSDH and to develop more effective medical treatments and noninvasive surgical techniques for elderly patients. PMID- 28652562 TI - Correlation Factors Analysis of Breast Cancer Tumor Volume Doubling Time Measured by 3D-Ultrasound. AB - BACKGROUND Tumor volume doubling time (TVDT) is relatively important for breast cancer diagnosis and prognosis evaluation. This study aimed to analyze the related factors that may affect the TVDT of breast cancer by three-dimensional ultrasound (3D-US). MATERIAL AND METHODS A total of 69 breast cancer patients were selected. 3D-US was applied to measure the volume of breast lumps diagnosed as BI-RADS-US 4A by conventional ultrasound. TVDT was calculated according to the formula TVDT=DT*log2/log(V2/V1). Multiple linear regression analysis was performed to analyze the factors influencing breast cancer TVDT. RESULTS The mean and median TVDT were 185+/-126 (range 66-521) and 164 days, respectively. TVDT showed no statistical significance according to regular shape, coarse margin, spicule sign, peripheral hyperechoic halo, microcalcification, and different posterior echo characteristics (P>0.05). Patients grouped by age, axillary lymphatic metastasis, histological differentiation, and Nottingham prognostic index (NPI) score exhibited significantly different TVDT (P<0.05). On the contrary, patients with different menstrual conditions, breast cancer family history, or pathological types presented similar TVDT (P>0.05). TVDT was obviously different in breast cancer with different ER, PR, Ki-67, and molecular subtyping but not HER2 expression. Multivariate analysis revealed that NPI score, axillary lymphatic metastasis, Ki-67, and molecular subtyping were risk factors of TVDT in breast cancer (P<0.05). CONCLUSIONS Breast cancer TVDT was significantly correlated with NPI score, axillary lymphatic metastasis, Ki-67, and molecular subtyping. Triple-negative breast cancer exhibited the most rapid growth. PMID- 28652563 TI - Vascular Graft Impregnation with Antibiotics: The Influence of High Concentrations of Rifampin, Vancomycin, Daptomycin, and Bacteriophage Endolysin HY-133 on Viability of Vascular Cells. AB - BACKGROUND Rifampin-soaked synthetic prosthetic grafts have been widely used for prevention or treatment of vascular graft infections (VGIs). This in vitro study investigated the effect of the antibiotics daptomycin and vancomycin and the new recombinant bacteriophage endolysin HY-133 on vascular cells, as potential alternatives compared to rifampin. MATERIAL AND METHODS Primary human ECs, vascular smooth muscle cells (vSMC), and fibroblasts were cultivated in 96-well plates and incubated with rifampin, daptomycin, vancomycin, and endolysin HY-133 for 24 h. Subsequently, after washing, cell viability was determined by measuring mitochondrial ATP concentration. Antibiotics were used in their corresponding minimum and maximum serum concentrations, in decimal multiples and in maximum soaking concentration. The experiments were performed in triplicate. RESULTS The 10-fold max serum concentrations of rifampin, daptomycin, and vancomycin did not influence viability of EC and vSMC (100 ug/ml, p>0.170). Higher concentrations of rifampin (>1 mg/ml) significantly (p<0.001) reduced cell viability of all cell types. For the other antibiotics, high concentrations (close to maximum soaking concentration) were most cytotoxic for EC and vSMC and fibroblasts (p<0.001). Endolysin did not display any cytotoxicity towards vascular cells. CONCLUSIONS Results of this in vitro study show the high cytotoxicity of rifampin against vascular cells, and may re-initiate the discussion about the benefit of prophylactic pre-soaking in high concentrations of rifampin. Further studies are necessary to determine the influence of rifampin on the restoration of vessel functionality versus its prophylactic effect against VGIs. Future use of recombinant phage endolysins for alternative prophylactic strategies needs further investigations. PMID- 28652565 TI - Ketoacidosis in Neonatal Diabetes Mellitus, Part of Wolcott-Rallison Syndrome. AB - BACKGROUND Neonatal diabetes mellitus is a rare condition and it is important to differentiate it from other causes, such as hyperglycemia in infancy, for better outcomes. We report a case of an infant who presented to our neonatal intensive care unit in ketoacidosis and a comatose state. CASE REPORT Our case was an infant who presented to the neonatal intensive care unit at 38 days of age in ketoacidosis. The female infant, born to consanguineous parents (first cousins), weighing 2,300 grams at birth, presented with extreme dehydration and pale skin. The infant's head was normocephalic and there were no obvious deformities on the rest of her body. Urine examination was positive for ketones and glucose was 4+. Her blood glucose level was 550 mg/dL (30.5 mmol/L). After taking care of electrolytes, insulin was initiated in the form of a continuous drip. After a few days, insulin glargine was initiated, given twice daily via subcutaneous route. A few days later, blood samples were sent from our hospital in India to the UK and genetic testing was performed free of charge by the Department of Molecular Genetics, University of Exeter Medical School, UK, and confirmed a genetic diagnosis of Wolcott-Rallison syndrome. CONCLUSIONS Regardless of whether permanent neonatal diabetes mellitus is associated with Wolcott-Rallison syndrome or other genetic mutations, it is important to initially stabilize the infant and later do a genetic testing to see whether the infant can be given oral sulfonylureas or has to be given insulin therapy. PMID- 28652564 TI - Risk Factors for Graft-Versus-Host Disease After Transplantation of Hematopoietic Stem Cells from Unrelated Donors in the China Marrow Donor Program. AB - BACKGROUND We identified risk factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) in recipients after hematopoietic stem cell transplantation (HSCT) from unrelated donors in the China Marrow Donor Program (CMDP). MATERIAL AND METHODS We analyzed follow-up clinical information from 1824 patients who underwent HSCT between 2001 and 2010. RESULTS The incidence of aGVHD and cGVHD after transplantation was 49.29% and 27.3%, respectively. aGVHD incidence decreased as HLA matching increased (p<0.001). Incidence of aGVHD and cGVHD was higher in 2 HLA-A locus donor/recipient groups (02: 01/02: 06 and 02: 01/02: 07; p<=0.022). aGVHD incidence was associated with patient age, absence of rabbit anti-thymocyte globulin (ATG) pretreatment, and disease status (p<=0.040). aGVHD appeared to be a risk factor for cGVHD, and total body irradiation (TBI) was also associated with cGVHD. Patients with cGVHD after transplantation had a higher survival rate than patients without cGVHD (p<0.001), which may be due to reduced relapse rates. Survival was also associated with ATG prophylaxis and disease status. CONCLUSIONS The incidence of GVHD after HSCT from unrelated donors in the Chinese population is similar to the results reported from other countries. A high degree of HLA matching, a conditioning regimen without TBI, and the use of ATG may reduce the incidence of aGVHD. PMID- 28652566 TI - A high resolution melting method for the molecular identification of the potentially toxic diatom Pseudo-nitzschia spp. in the Mediterranean Sea. AB - The aim of this study was to develop and validate a high resolution melting (HRM) method for the rapid, accurate identification of the various harmful diatom Pseudo-nitzschia species in marine environments. Pseudo-nitzschia has a worldwide distribution and some species are toxic, producing the potent domoic acid toxin, which poses a threat to both human and animal health. Hence, it is important to identify toxic Pseudo-nitzschia species. A pair of primers targeting the LSU rDNA of the genus Pseudo-nitzschia was designed for the development of the assay and its specificity was validated using 22 control DNAs of the P. calliantha, P. delicatissima/P. arenysensis complex and P. pungens. The post-PCR HRM assay was applied to numerous unidentified Pseudo-nitzschia strains isolated from the northwestern Adriatic Sea (Mediterranean Sea), and it was able to detect and discriminate three distinct Pseudo-nitzschia taxa from unidentified samples. Moreover, the species-specific identification of Pseudo-nitzschia isolates by the HRM assay was consistent with phylogenetic analyses. The HRM assay was specific, robust and rapid when applied to high numbers of cultured samples in order to taxonomically identify Pseudo-nitzschia isolates recovered from environmental samples. PMID- 28652567 TI - Tomographic imaging of the photonic environment of plasmonic nanoparticles. AB - The photonic local density of states (LDOS) governs the enhancement of light matter interaction at the nanoscale, but despite its importance for nanophotonics and plasmonics experimental local density of states imaging remains extremely challenging. Here we introduce a tomography scheme based on electron microscopy that allows retrieval of the three-dimensional local density of states of plasmonic nanoparticles with nanometre spatial and sub-eV energy resolution. From conventional electron tomography experiments we obtain the three-dimensional morphology of the nanostructure, and use this information to compute an expansion basis for the photonic environment. The expansion coefficients are obtained through solution of an inverse problem using as input electron-energy loss spectroscopy images. We demonstrate the applicability of our scheme for silver nanocuboids and coupled nanodisks, and resolve local density of states enhancements with extreme sub-wavelength dimensions in hot spots located at roughness features or in gaps of coupled nanoparticles.Imaging the photonic local density of states of plasmonic nanoparticles remains extremely challenging. Here, the authors introduce a tomography scheme based on electron microscopy that allows retrieval of the three-dimensional local density of states with nanometre spatial and sub-eV energy resolution. PMID- 28652568 TI - Single microtubules and small networks become significantly stiffer on short time scales upon mechanical stimulation. AB - The transfer of mechanical signals through cells is a complex phenomenon. To uncover a new mechanotransduction pathway, we study the frequency-dependent transport of mechanical stimuli by single microtubules and small networks in a bottom-up approach using optically trapped beads as anchor points. We interconnected microtubules to linear and triangular geometries to perform micro rheology by defined oscillations of the beads relative to each other. We found a substantial stiffening of single filaments above a characteristic transition frequency of 1-30 Hz depending on the filament's molecular composition. Below this frequency, filament elasticity only depends on its contour and persistence length. Interestingly, this elastic behavior is transferable to small networks, where we found the surprising effect that linear two filament connections act as transistor-like, angle dependent momentum filters, whereas triangular networks act as stabilizing elements. These observations implicate that cells can tune mechanical signals by temporal and spatial filtering stronger and more flexibly than expected. PMID- 28652569 TI - Characterization of a novel two-component Na+(Li+, K+)/H+ antiporter from Halomonas zhaodongensis. AB - In this study, genomic DNA was screened for novel Na+/H+ antiporter genes from Halomonas zhaodongensis by selection in Escherichia coli KNabc lacking three major Na+/H+ antiporters. Co-expression of two genes designated umpAB, encoding paired homologous unknown membrane proteins belonging to DUF1538 (domain of unknown function with No. 1538) family, were found to confer E. coli KNabc the tolerance to 0.4 M NaCl and 30 mM LiCl, and an alkaline pH resistance at 8.0. Western blot and co-immunoprecipitation establish that UmpAB localize as a hetero dimer in the cytoplasmic membranes. Functional analysis reveals that UmpAB exhibit pH-dependent Na+(Li+, K+)/H+ antiport activity at a wide pH range of 6.5 to 9.5 with an optimal pH at 9.0. Neither UmpA nor UmpB showed homology with known single-gene or multi-gene Na+/H+ antiporters, or such proteins as ChaA, MdfA, TetA(L), Nap and PsmrAB with Na+/H+ antiport activity. Phylogenetic analysis confirms that UmpAB should belong to DUF1538 family, which are significantly distant with the above-mentioned proteins with Na+/H+ antiport activity. Taken together, we propose that UmpAB represent a novel two-component Na+(Li+, K+)/H+ antiporter. To the best of our knowledge, this is the first report on the functional analysis of unknown membrane proteins belonging to DUF1538 family. PMID- 28652570 TI - Effects of Epigallocatechin-3-gallate (EGCG) on the bond strength of fiber posts to Sodium hypochlorite (NaOCl) treated intraradicular dentin. AB - This study was to evaluate the effect of Epigallocatechin-3-gallate (EGCG) on the bond strength of two adhesive systems to the Sodium hypochlorite (NaOCl) treated intraradicular dentin. The roots were accepted regular root canal treatments and post space preparations, and further divided into eight groups according to the four post space pretreatments and two dentin adhesives [Single Bond 2 (SB2) and Clearfil SE Bond (CSB)] used. The push-out strength before and after thermocycling in different root region (coronal and apical), DC of the adhesive and morphologic patterns of treated post space were evaluated. NaOCl + EGCG groups showed the highest push-out strength regardless of the adhesive type, root region and time (P < 0.05). NaOCl pretreatment significantly decreased the push out strengths and DC of CSB (P < 0.05). EGCG could improve the bonding properties of both SB2 and CSB to NaOCl treated intraradicular dentin. The effect of NaOCl on bonding of a fiber post depended on the type of the adhesive. PMID- 28652571 TI - Discovery of long-range inhibitory signaling to ensure single axon formation. AB - A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca2+ waves, which are delivered from the growing axon to the cell body. These Ca2+ waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca2+ wave is responsible for neuronal polarization.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease. PMID- 28652572 TI - Cascaded exciton energy transfer in a monolayer semiconductor lateral heterostructure assisted by surface plasmon polariton. AB - Atomically thin lateral heterostructures based on transition metal dichalcogenides have recently been demonstrated. In monolayer transition metal dichalcogenides, exciton energy transfer is typically limited to a short range (~1 MUm), and additional losses may be incurred at the interfacial regions of a lateral heterostructure. To overcome these challenges, here we experimentally implement a planar metal-oxide-semiconductor structure by placing a WS2/MoS2 monolayer heterostructure on top of an Al2O3-capped Ag single-crystalline plate. We find that the exciton energy transfer range can be extended to tens of microns in the hybrid structure mediated by an exciton-surface plasmon polariton-exciton conversion mechanism, allowing cascaded exciton energy transfer from one transition metal dichalcogenides region supporting high-energy exciton resonance to a different transition metal dichalcogenides region in the lateral heterostructure with low-energy exciton resonance. The realized planar hybrid structure combines two-dimensional light-emitting materials with planar plasmonic waveguides and offers great potential for developing integrated photonic and plasmonic devices.Exciton energy transfer in monolayer transition metal dichalcogenides is limited to short distances. Here, Shi et al. fabricate a planar metal-oxide-semiconductor structure and show that exciton energy transfer can be extended to tens of microns, mediated by an exciton-surface-plasmon polariton-exciton conversion mechanism. PMID- 28652573 TI - Extraordinarily potent proinflammatory properties of lactoferrin-containing immunocomplexes against human monocytes and macrophages. AB - Lactoferrin (LTF), an important first line defense molecule against infection, is a common target for humoral autoimmune reactions in humans. Since LTF is a multifunctional protein capable of activating innate immune cells via various surface receptors, we hypothesized that LTF-containing immune complexes (ICs) (LTF-ICs), likely formed in patients with high titer anti-LTF autoantibodies, could possess unique monocyte/macrophage-activating properties compared with other ICs. ELISA analysis on serum samples from rheumatoid arthritis (RA) patients (n = 80) and healthy controls (n = 35) for anti-LTF autoantibodies confirmed a positive correlation between circulating LTF-specific IgG and RA. ICs between human LTF and LTF-specific IgG purified from patient sera or immunized rabbits and mice, but not control ICs, LTF or Abs alone, elicited strong production of TNF-alpha and IL-1beta by freshly fractionated human peripheral blood monocytes and monocytes-derived macrophages. Furthermore, LTF-ICs utilized both membrane-anchored CD14 and CD32a (FcgammaRIIa) to trigger monocyte activation in an internalization-, Toll-like receptor (TLR)4- and TLR9-dependent manner, and also that LTF-IC-induced cytokine production was blocked by specific inhibitors of caspase-1, NF-kappaB and MAPK. These results uncover a possible pathway for LTF-ICs perpetuating local inflammation and contributing to the pathogenesis of autoimmune diseases by triggering activation of infiltrating monocytes or tissue macrophages in vivo. PMID- 28652574 TI - Clinical Features of Congenital and Developmental Cataract in East China: A Five year Retrospective Review. AB - Congenital/developmental cataract is a significant cause of blindness in children worldwide. Full knowledge of clinical features is essential for early diagnosis and proper treatment to prevent irreversible visual impairment. We conducted a retrospective chart review on 520 congenital/developmental cataract cases based on a five-year clinical data from Eye and ENT Hospital of Fudan University, Shanghai, China. Clinical features including age at the surgery, chief complaints, interval between initial identification of cataract-related manifestations and surgery, etc. were summarized. 56.3% of children were bilateral. The age at surgery ranged from 0.25 to 17.4 years, only 9.2% receiving surgery below 1 year. Interval between initial identification of manifestations and surgery ranged from 2 days to 17 years. Concomitant congenital abnormalities were present in 67 patients, with persistent hyperplastic primary vitreous and congenital heart disease as the most frequent ocular and systemic disorders. Strabismus and nystagmus were seen in 20.6% and 11.9% of patients. In bilateral cataract patients with strabismus, axial lengths of esotropia-affected eyes were statistically shorter than exotropia-affected eyes. These findings provide information on characteristics of congenital/developmental cataract in China and may assist in achievement of comprehensive treating strategies in these cases. PMID- 28652575 TI - Two-step synthesis of chiral fused tricyclic scaffolds from phenols via desymmetrization on nickel. AB - Tricyclic furan derivatives with multiple chiral centers are ubiquitous in natural products. Construction of such tricyclic scaffolds in a stereocontrolled, step-economic, and atom-economic manner is a key challenge. Here we show a nickel catalyzed highly enantioselective synthesis of hydronaphtho[1,8-bc]furans with five contiguous chiral centers via desymmetrization of alkynyl-cyclohexadienone by oxidative cyclization and following formal [4 + 2] cycloaddition processes. Alkynyl-cyclohexadienone was synthesized in one step from easily accessible phenols. This reaction represents excellent chemo-selectivity, regio-selectivity, diastereo-selectivity, and enantio-selectivity (single diastereomer, up to 99% ee). An extraordinary regioselectivity in the formal [4 + 2] cycloaddition step with enones revealed the diverse reactivity of the nickelacycle intermediate. Desymmetrization of alkynyl-cyclohexadienones via oxidative cyclization on nickel was supported by the isolation of a nickelacycle from a stoichiometric reaction. Enantioenriched tricyclic products contain various functional groups such as C=O and C=C. The synthetic utility of these products was demonstrated by derivatization of these functional groups.Tricyclic furanic compounds with multiple chiral centers are found in a variety of natural products. Here, the authors show a highly enantioselective nickel-catalyzed procedure to access tricyclic oxygen-containing scaffolds with five contiguous chiral centers. PMID- 28652576 TI - A Microfluidic Chip for Detecting Cholangiocarcinoma Cells in Human Bile. AB - Cholangiocarcinoma (CCA), a biliary tract malignancy, accounts for 20% of all liver cancers. There are several existing methods for diagnosis of CCA, though they are generally expensive, laborious, and suffer from low detection rates. Herein we first developed a means of partially purifying human bile for consequent injection into a microfluidic chip. Then, the novel microfluidic system, which featured 1) a cell capture module, 2) an immunofluorescence (IF) staining module featuring two CCA-specific biomarkers, and 3) an optical detection module for visualization of antibody probes bound to these CCA marker proteins, was used to detect bile duct cancer cells within partially purified bile samples. As a proof of concept, CCA cells were successfully captured and identified from CCA cell cultures, blood samples inoculated with CCA cells, and clinical bile specimens. In 7.5 ml of bile, this system could detect >2, 0, and 1 positive cells in advanced stage patients, healthy patients, and chemotherapy treated patients, respectively. In conclusion, our microfluidic system could be a promising tool for detection of cancer cells in bile, even at the earliest stages of CCA when cancer cells are at low densities relative to the total population of epithelial cells. PMID- 28652577 TI - Human in vitro-induced regulatory T cells display Dlgh1dependent and PKC-theta restrained suppressive activity. AB - In vitro induced human regulatory T cells (iTregs) have demonstrated in vivo therapeutic utility, but pathways regulating their function have not been elucidated. Here, we report that human iTregs generated in vitro from naive cord blood cells preferentially recruit Disc large homolog 1 (Dlgh1) and exclude protein kinase C (PKC)-theta from immunological synapses formed on supported lipid bilayers with laterally mobile ICAM-1 and anti-CD3 mAb. Also, iTregs display elevated Dlgh1 overall and Dlgh1-dependent p38 phosphorylation, higher levels of phosphatase and tensin homolog (PTEN), and diminished Akt phosphorylation. Pharmacological interruption of PKC-theta increases and Dlgh1 silencing decreases the ability of iTregs to suppress interferon-gamma production by CD4+CD25- effector T cells (Teff). Comparison with expanded cord blood-derived CD4+CD25hi tTreg and expanded Teffs from the same donors indicate that iTreg are intermediate between expanded CD4+CD25hi tTregs and Teffs, whereas modulation of suppressive activities by PKC-theta and Dlgh1 signaling pathways are shared. PMID- 28652578 TI - Rare germline variants in ATM are associated with chronic lymphocytic leukemia. PMID- 28652579 TI - HLA-DPB1 mismatch induces a graft-versus-leukemia effect without severe acute GVHD after single-unit umbilical cord blood transplantation. AB - Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease (GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood. HLA-DPB1 mismatch was associated with a significant reduction in leukemia relapse (hazard ratio 0.61, P<0.001), whereas the other HLA loci allele-level mismatches did not. No significant effect of HLA-DPB1 mismatch was observed in the risk of acute GVHD, engraftment or mortality. This HLA-DPB1 GVL effect without induction of severe acute GVHD or deterioration of survival rate has not been reported in unrelated bone marrow or peripheral blood stem cell transplantations, suggesting apparent advantages of UR-CBT. Accordingly, selection of an HLA-DPB1 mismatch cord blood might be the preferable choice for single-unit UR-CBT. PMID- 28652581 TI - Towards conductive textiles: coating polymeric fibres with graphene. AB - Conducting fibres are essential to the development of e-textiles. We demonstrate a method to make common insulating textile fibres conductive, by coating them with graphene. The resulting fibres display sheet resistance values as low as 600 Omegasq-1, demonstrating that the high conductivity of graphene is not lost when transferred to textile fibres. An extensive microscopic study of the surface of graphene-coated fibres is presented. We show that this method can be employed to textile fibres of different materials, sizes and shapes, and to different types of graphene. These graphene-based conductive fibres can be used as a platform to build integrated electronic devices directly in textiles. PMID- 28652580 TI - Immunological phenotype of the murine Lrba knockout. AB - Biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized by a broad range of clinical manifestations including autoimmunity, organomegaly, hypogammaglobulinemia and recurrent infections. Considering the phenotypic heterogeneity in patients and the severity of the disease, our aim was to assess the role of LRBA in immune cells and to understand the underlying pathomechanisms through the study of a Lrba knockout (Lrba-/-) mouse model. LRBA deficient mice did not show severe clinical or immunological signs of disease, either at steady state under specific-pathogen-free conditions, after vaccination with T-dependent and T-independent antigens, or in the context of acute infections with lymphocytic choriomeningitis virus (LCMV) or Salmonella Typhimurium. Although Lrba-/- mice were able to produce normal serum immunoglobulin M (IgM) and IgG and to mount a specific immune response after immunization, they showed elevated serum and secretory basal IgA levels. LRBA was dispensable for B- and T-cell development, as well as for in vitro B-cell proliferation, survival, isotype switching and plasmablast differentiation. Interestingly, Lrba-/- mice displayed decreased cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression by regulatory T cells and activated conventional CD4+ and CD8+ T lymphocytes, reduced frequency of peritoneal B-1a cells along with diminished interleukin-10 production and increased percentages of T follicular helper cells in Peyer's patches, but without developing overt signs of autoimmunity. Our findings expand the role of LRBA in immune regulatory mechanisms previously reported in patients, and suggest a novel role in IgA production that is crucial for the protection of mucosal surfaces and gut associated immune tolerance. PMID- 28652582 TI - The Timescale of Emergence and Spread of Turnip Mosaic Potyvirus. AB - Plant viruses have important global impacts on crops, and identifying their centre and date of emergence is important for planning control measures. Turnip mosaic virus (TuMV) is a member of the genus Potyvirus in the family Potyviridae and is a major worldwide pathogen of brassica crops. For two decades, we have collected TuMV isolates, mostly from brassicas, in Turkey and neighbouring countries. This region is thought to be the centre of emergence of this virus. We determined the genomic sequences of 179 of these isolates and used these to estimate the timescale of the spread of this virus. Our Bayesian coalescent analyses used synonymous sites from a total of 417 novel and published whole genome sequences. We conclude that TuMV probably originated from a virus of wild orchids in Germany and, while adapting to wild and domestic brassicas, spread via Southern Europe to Asia Minor no more than 700 years ago. The population of basal B group TuMVs in Asia Minor is older than all other populations of this virus, including a newly discovered population in Iran. The timescale of the spread of TuMV correlates well with the establishment of agriculture in these countries. PMID- 28652583 TI - Genome-wide identification and characterization of genes involved in carotenoid metabolic in three stages of grapevine fruit development. AB - Carotenoids not only play indispensable roles in plant growth and development but also enhance nutritional value and health benefits for humans. In this study, total carotenoids progressively decreased during fruit ripening. Fifty-four genes involving in mevalonate (MVA), 2-C-methyl-D-erythritol 4-phosphate (MEP), carotenoid biosynthesis and catabolism pathway were identified. The expression levels of most of the carotenoid metabolism related genes kept changing during fruit ripening generating a metabolic flux toward carotenoid synthesis. Down regulation of VvDXS, VvDXR, VvGGPPS and VvPSY and a dramatic increase in the transcription levels of VvCCD might be responsible for the reduction of carotenoids content. The visible correlation between carotenoid content and gene expression profiles suggested that transcriptional regulation of carotenoid biosynthesis pathway genes is a key mechanism of carotenoid accumulation. In addition, the decline of carotenoids was also accompanied with the reduction of chlorophyll content. The reduction of chlorophyll content might be due to the obstruction in chlorophyll synthesis and acceleration of chlorophyll degradation. These results will be helpful for better understanding of carotenoid biosynthesis in grapevine fruit and contribute to the development of conventional and transgenic grapevine cultivars for further enrichment of carotenoid content. PMID- 28652584 TI - Mapping the Glyco-Gold Nanoparticles of Different Shapes Toxicity, Biodistribution and Sequestration in Adult Zebrafish. AB - Glyconanotechnology offers a broad range of applications across basic and translation research. Despite the tremendous progress in glyco-nanomaterials, there is still a huge gap between the basic research and therapeutic applications of these molecules. It has been reported that complexity and the synthetic challenges in glycans synthesis, the cost of the high order in vivo models and large amount of sample consumptions limited the effort to translate the glyco nanomaterials into clinical applications. In this regards, several promising simple animal models for preliminary, quick analysis of the nanomaterials activities has been proposed. Herein, we have studied a systematic evaluation of the toxicity, biodistribution of fluorescently tagged PEG and mannose-capped gold nanoparticles (AuNPs) of three different shapes (sphere, rod, and star) in the adult zebrafish model, which could accelerate and provide preliminary results for further experiments in the higher order animal system. ICP-MS analysis and confocal images of various zebrafish organs revealed that rod-AuNPs exhibited the fast uptake. While, star-AuNPs displayed prolong sequestration, demonstrating its potential therapeutic efficacy in drug delivery. PMID- 28652585 TI - Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster. AB - FGF21 exerts profound metabolic effects in Siberian hamsters exposed to long day (LD) photoperiods that increase appetite and adiposity, however these effects are attenuated in short day (SD) animals that display hypophagia and reduced adiposity. The aim of this study was to investigate whether the beneficial effects of a novel mimetic of FGF21 in the LD state are a consequence of increased adiposity or of the central photoperiodic state. This was achieved by investigating effects of FGF21 in aged hamsters, which is associated with reduced adiposity. In LD hamsters with increased adiposity, FGF21 lowered body weight as a result of both reduced daily food intake and increased caloric expenditure, driven by an increase in whole-body fat oxidation. However, in LD animals with reduced adiposity, the effect of FGF21 on body weight, caloric intake and fat oxidation were significantly attenuated or absent when compared to those with increased adiposity. These attenuated/absent effects were underpinned by the inability of FGF21 to increase the expression of key thermogenic genes in interscapular and visceral WAT. Our study demonstrates the efficacy of a novel FGF21 mimetic in hamsters, but reveals attenuated effects in the animal model where adiposity is reduced naturally independent of photoperiod. PMID- 28652586 TI - Network model predicts that CatSper is the main Ca2+ channel in the regulation of sea urchin sperm motility. AB - Spermatozoa sea urchin swimming behaviour is regulated by small peptides from the egg outer envelope. Speract, such a peptide, after binding to its receptor in Strongylocentrotus purpuratus sperm flagella, triggers a signaling pathway that culminates with a train of intracellular calcium oscillations, correlated with changes in sperm swimming pattern. This pathway has been widely studied but not fully characterized. Recent work on Arbacia punctulata sea urchin spermatozoa has documented the presence of the Ca2+ CatSper channel in their flagella and its involvement in chemotaxis. However, if other calcium channels participate in chemotaxis remains unclear. Here, based on an experimentally-backed logical network model, we conclude that CatSper is fundamental in the S. purpuratus speract-activated sea urchin sperm signaling cascade, although other Ca2+ channels could still be relevant. We also present for the first time experimental corroboration of its active presence in S. purpuratus sperm flagella. We argue, prompted by in silico knock-out calculations, that CatSper is the main generator of calcium oscillations in the signaling pathway and that other calcium channels, if present, have a complementary role. The approach adopted here allows us to unveil processes, which are hard to detect exclusively by experimental procedures. PMID- 28652587 TI - Novel loop-mediated isothermal amplification (LAMP) assay with a universal QProbe can detect SNPs determining races in plant pathogenic fungi. AB - Tomato wilt pathogen Fusarium oxysporum f. sp. lycopersici (Fol) is grouped into three races based on their pathogenicity to different host cultivars. Rapid detection and discrimination of Fol races in field soils is important to prevent tomato wilt disease. Although five types of point mutations in secreted in xylem 3 (SIX3) gene, which are characteristic of race 3, have been reported as a molecular marker for the race, detection of these point mutations is laborious. The aim of this study is to develop a rapid and accurate method for the detection of point mutations in SIX3 of Fol. Loop-mediated isothermal amplification (LAMP) of SIX3 gene with the universal QProbe as well as two joint DNAs followed by annealing curve analysis allowed us to specifically detect Fol and discriminate race 3 among other races in about one hour. Our developed method is applicable for detection of races of other plant pathogenic fungi as well as their pesticide resistant mutants that arise through point mutations in a particular gene. PMID- 28652588 TI - Identification of Jak-STAT signaling involvement in sarcoidosis severity via a novel microRNA-regulated peripheral blood mononuclear cell gene signature. AB - Sarcoidosis is a granulomatous lung disorder of unknown cause. The majority of individuals with sarcoidosis spontaneously achieve full remission (uncomplicated sarcoidosis), however, ~20% of sarcoidosis-affected individuals experience progressive lung disease or cardiac and nervous system involvement (complicated sarcoidosis). We investigated peripheral blood mononuclear cell (PBMC) microRNA and protein-coding gene expression data from healthy controls and patients with uncomplicated or complicated sarcoidosis. We identified 46 microRNAs and 1,559 genes that were differentially expressed across a continuum of sarcoidosis severity (healthy control -> uncomplicated sarcoidosis -> complicated sarcoidosis). A total of 19 microRNA-mRNA regulatory pairs were identified within these deregulated microRNAs and mRNAs, which consisted of 17 unique protein coding genes yielding a 17-gene signature. Pathway analysis of the 17-gene signature revealed Jak-STAT signaling pathway as the most significantly represented pathway. A severity score was assigned to each patient based on the expression of the 17-gene signature and a significant increasing trend in the severity score was observed from healthy control, to uncomplicated sarcoidosis, and finally to complicated sarcoidosis. In addition, this microRNA-regulated gene signature differentiates sarcoidosis patients from healthy controls in independent validation cohorts. Our study suggests that PBMC gene expression is useful in diagnosis of sarcoidosis. PMID- 28652589 TI - Congenital deafness is associated with specific somatosensory deficits in adolescents. AB - Hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. Here we used a battery of quantitative sensory tests to probe touch, thermal and pain sensitivity in a young control population (14-20 years old) compared to age matched individuals with congenital hearing loss. Sensory testing was performed on the dominant hand of 111 individuals with normal hearing and 36 with congenital hearing loss. Subjects with congenital deafness were characterized by significantly higher vibration detection thresholds at 10 Hz (2-fold increase, P < 0.001) and 125 Hz (P < 0.05) compared to controls. These sensory changes were not accompanied by any major change in measures of pain perception. We also observed a highly significant reduction (30% compared to controls p < 0.001) in the ability of hearing impaired individual's ability to detect cooling which was not accompanied by changes in warm detection. At least 60% of children with non syndromic hearing loss showed very significant loss of vibration detection ability (at 10 Hz) compared to age-matched controls. We thus propose that many pathogenic mutations that cause childhood onset deafness may also play a role in the development or functional maintenance of somatic mechanoreceptors. PMID- 28652590 TI - The Incidence, Risk Factors and Outcomes of Postoperative Acute Kidney Injury in Neurosurgical Critically Ill Patients. AB - We investigated the incidence, perioperative risk factors, and outcomes of postoperative acute kidney injury (AKI) in neurosurgical critically ill patients. A prospective multicenter cohort study was conducted, enrolling adult patients who underwent neurosurgical procedure and admitted to the neurosurgical intensive care units (ICU). Postoperative AKI was diagnosed within 7 days after surgery based on the Kidney Disease Improving Global Outcomes criteria. Of 624 enrolled patients, postoperative AKI occurred in 84 patients. AKI was associated with increased rates of ICU and in-hospital mortality, postoperative renal replacement therapy, postoperative tracheotomy, and postoperative tracheal reintubation. Patients who developed AKI had higher total ICU costs, prolonged length of hospital and ICU stay, and longer duration of postoperative mechanical ventilation. Multivariate analysis identified postoperative reoperation (adjusted odds ratio [OR] 5.70 [95% CI, 1.61-20.14]), postoperative concentration of serum cystatin C (adjusted OR 4.53 [95% CI, 1.98-10.39]), use of mannitol during operation (adjusted OR 1.97 [95% CI, 1.13-3.43]), postoperative APACHE II score (adjusted OR 1.11 [95% CI, 1.06-1.16]), and intraoperative estimated blood loss (adjusted OR 1.04 [95% CI, 1.00-1.08]) as independent risk factors for postoperative AKI. Postoperative AKI in neurosurgical critically ill cohort is prevalent and associated with adverse in-hospital outcomes. PMID- 28652591 TI - Opposite-view digital holographic microscopy with autofocusing capability. AB - Digital holographic microscopy (DHM) has its intrinsic ability to refocusing a sample by numerically propagating an object wave from its hologram plane to its image plane. In this paper opposite-view digital holographic microscopy (OV-DHM) is demonstrated for autofocusing, namely, digitally determining the location of the image plane, and refocusing the object wave without human intervention. In OV DHM, a specimen is illuminated from two sides in a 4pi-alike configuration, and two holograms are generated and recorded by a CCD camera along two orthogonal polarization orientations. The image plane of the sample is determined by finding the minimal variation between the two object waves, and consequently refocusing is performed by propagating the waves to the image plane. Furthermore, the field of view (FOV) of OV-DHM can be extended by combining the two object waves which have an angle in-between. The proposed technique also has the potential to reduce speckle noise and out-of-focus background. PMID- 28652592 TI - Niche comparison among two invasive leafminer species and their parasitoid Opius biroi: implications for competitive displacement. AB - Fundamental to competitive displacement in biological invasion is that exotic species occupy the ecological niches of native species in novel environments. Contrasting outcomes of competitive displacement have occurred between Liriomyza trifolii and L. sativae in different geographical regions following their introduction. Various factors have been advanced in an attempt to explain these different competitive outcomes, although none of these explanations have addressed the effects of niche differences. We conducted field cage experiments to compare the feeding and habitat niches of the two leafminer species and their primary parasitoid, Opius biroi, when occurring together on kidney bean. A wider spatiotemporal niche breadth was found in L. trifolii (0.3670) than in L. sativae (0.3496). With respect to the parasitoid, the proportional niche similarity between L. sativae and the parasitoid was 0.3936 but only 0.0835 for L. trifolii, while similar results were found for niche overlap, indicating that stronger trailing behaviour and parasitic effects of O. biroi occurred in L. sativae. In conclusion, L. trifolii has outperformed L. sativae in occupying the ecological niche and is superior to L. sativae in avoiding parasitization by the pupal parasitoid, O. biroi. PMID- 28652593 TI - Insight into the Electrical Double Layer of an Ionic Liquid on Graphene. AB - Graphene is a promising next-generation conducting material with the potential to replace traditional electrode materials in supercapacitors. Since energy storage in supercapacitors relies on the electrolyte-electrode interface, here we elucidate the interfacial subnanometer structure of a single component liquid composed solely of cations and anions - an ionic liquid- on electrified graphene. We study the effect of applied potential on the interaction between graphene and a silicon tip in an ionic liquid and describe it within the framework of the Derjaguin-Landau-Verwey-Overbeck (DLVO) theory. The energy is stored in an electrical double layer composed of an extended Stern layer, which consists of multiple ion layers over ~2 nanometers, beyond which a diffuse layer forms to compensate the applied potential on graphene. The electrical double layer significantly responds to the applied potential, and it shows the transition from overscreening to crowding of counterions at the interface at the highest applied potentials. It is proposed that surface charging occurs through the adsorption of the imidazolium cation to unbiased graphene (likely due to pi-pi interactions) a nd that the surface potential is better compensated when counterion crowding happens. This study scrutinizes the electrified graphene-ionic liquid interface, with implications not only in the field of energy storage, but also in lubrication. PMID- 28652594 TI - Self-diploidization of human haploid parthenogenetic embryos through the Rho pathway regulates endomitosis and failed cytokinesis. AB - A diploid genome is necessary for normal mammalian development, thus haploid parthenogenetic embryos undergo frequent self-diploidization during preimplantation development; however, the underlying mechanism is unclear. In this study, time-lapse recording revealed that human haploid parthenotes (HPs) undergo self-diploidization via failed cytokinesis (FC) and endomitosis (EM). The frequencies of FC/EM were significantly higher in HPs than in normal fertilized embryos (26.3% vs. 1.6%, P < 0.01; 19.7% vs. 0, P < 0.01), and above 90% of FC/EM occurred at the first cell cycle in HPs. Fluorescent in situ hybridization of chromosome 16,18 and X in HPs identified diploid recovery after the appearance of FC/EM, and FC/EM HPs showed improved blastocyst formation compared with non-FC/EM HPs (18.8% and 40.0% vs. 15.4%, P > 0.05). In 66.7% of the 1-cell stage HPs, furrow ingression was not observed during the time for normal cleavage, and both immunostaining and gene expression analysis of 1-cell stage HPs revealed the absence or down-regulation of several key genes of the Rho pathway, which regulates cytomitosis. Our results suggested that the major mechanism for self diploidization is Rho pathway inhibition leading to FC/EM in the first cell cycle, and fine-tuning of this signalling pathway may help to generate stable haploid embryos for stem cell biology studies. PMID- 28652596 TI - Magnetic particles with perpendicular anisotropy for mechanical cancer cell destruction. AB - We demonstrate the effectiveness of out-of-plane magnetized magnetic microdiscs for cancer treatment through mechanical cell disruption under an applied rotating magnetic field. The magnetic particles are synthetic antiferromagnets formed from a repeated motif of ultrathin CoFeB/Pt layers. In-vitro studies on glioma cells are used to compare the efficiency of the CoFeB/Pt microdiscs with Py vortex microdiscs. It is found that the CoFeB/Pt microdiscs are able to damage 62 +/- 3% of cancer cells compared with 12 +/- 2% after applying a 10 kOe rotating field for one minute. The torques applied by each type of particle are measured and are shown to match values predicted by a simple Stoner-Wohlfarth anisotropy model, giving maximum values of 20 fNm for the CoFeB/Pt and 75 fNm for the Py vortex particles. The symmetry of the anisotropy is argued to be more important than the magnitude of the torque in causing effective cell destruction in these experiments. This work shows how future magnetic particles can be successfully designed for applications requiring control of applied torques. PMID- 28652595 TI - Altered brain metabolic connectivity at multiscale level in early Parkinson's disease. AB - To explore the effects of PD pathology on brain connectivity, we characterized with an emergent computational approach the brain metabolic connectome using [18F]FDG-PET in early idiopathic PD patients. We applied whole-brain and pathology-based connectivity analyses, using sparse-inverse covariance estimation in thirty-four cognitively normal PD cases and thirty-four age-matched healthy subjects for comparisons. Further, we assessed high-order resting state networks by interregional correlation analysis. Whole-brain analysis revealed altered metabolic connectivity in PD, with local decreases in frontolateral cortex and cerebellum and increases in the basal ganglia. Widespread long-distance decreases were present within the frontolateral cortex as opposed to connectivity increases in posterior cortical regions, all suggestive of a global-scale connectivity reconfiguration. The pathology-based analyses revealed significant connectivity impairment in the nigrostriatal dopaminergic pathway and in the regions early affected by alpha-synuclein pathology. Notably, significant connectivity changes were present in several resting state networks especially in frontal regions. These findings expand previous imaging evidence of altered connectivity in cognitively stable PD patients by showing pathology-based connectivity changes and disease-specific metabolic architecture reconfiguration at multiple scale levels, from the earliest PD phases. These alterations go well beyond the known striato-cortical connectivity derangement supporting in vivo an extended neural vulnerability in the PD synucleinopathy. PMID- 28652598 TI - T cells: Staying alive with S1P. PMID- 28652599 TI - Regulatory T cells: Keep your hair on. PMID- 28652597 TI - Defect-induced local variation of crystal phase transition temperature in metal halide perovskites. AB - Solution-processed organometal halide perovskites are hybrid crystalline semiconductors highly interesting for low-cost and efficient optoelectronics. Their properties are dependent on the crystal structure. Literature shows a variety of crystal phase transition temperatures and often a spread of the transition over tens of degrees Kelvin. We explain this inconsistency by demonstrating that the temperature of the tetragonal-to-orthorhombic phase transition in methylammonium lead triiodide depends on the concentration and nature of local defects. Phase transition in individual nanowires was studied by photoluminescence microspectroscopy and super-resolution imaging. We propose that upon cooling from 160 to 140 K, domains of the crystal containing fewer defects stay in the tetragonal phase longer than highly defected domains that readily transform to the high bandgap orthorhombic phase at higher temperatures. The existence of relatively pure tetragonal domains during the phase transition leads to drastic photoluminescence enhancement, which is inhomogeneously distributed across perovskite microcrystals.Understanding crystal phase transition in materials is of fundamental importance. Using luminescence spectroscopy and super resolution imaging, Dobrovolsky et al. study the transition from the tetragonal to orthorhombic crystal phase in methylammonium lead triiodide nanowires at low temperature. PMID- 28652600 TI - Antiviral immunity: IFNlambda offers frontline protection. PMID- 28652601 TI - Germinal centres: An ephrin B1-based guidance system. PMID- 28652602 TI - Standards for reporting implementation studies (StaRI): enhancing reporting to improve care. PMID- 28652603 TI - Skeletal Dysplasia Mutations Effect on Human Filamins' Structure and Mechanosensing. AB - Cells' ability to sense mechanical cues in their environment is crucial for fundamental cellular processes, leading defects in mechanosensing to be linked to many diseases. The actin cross-linking protein Filamin has an important role in the conversion of mechanical forces into biochemical signals. Here, we reveal how mutations in Filamin genes known to cause Larsen syndrome and Frontometaphyseal dysplasia can affect the structure and therefore function of Filamin domains 16 and 17. Employing X-ray crystallography, the structure of these domains was first solved for the human Filamin B. The interaction seen between domains 16 and 17 is broken by shear force as revealed by steered molecular dynamics simulations. The effects of skeletal dysplasia associated mutations of the structure and mechanosensing properties of Filamin were studied by combining various experimental and theoretical techniques. The results showed that Larsen syndrome associated mutations destabilize or even unfold domain 17. Interestingly, those Filamin functions that are mediated via domain 17 interactions with other proteins are not necessarily affected as strongly interacting peptide binding to mutated domain 17 induces at least partial domain folding. Mutation associated to Frontometaphyseal dysplasia, in turn, transforms 16-17 fragment from compact to an elongated form destroying the force-regulated domain pair. PMID- 28652604 TI - Universal framework for edge controllability of complex networks. AB - Dynamical processes occurring on the edges in complex networks are relevant to a variety of real-world situations. Despite recent advances, a framework for edge controllability is still required for complex networks of arbitrary structure and interaction strength. Generalizing a previously introduced class of processes for edge dynamics, the switchboard dynamics, and exploit- ing the exact controllability theory, we develop a universal framework in which the controllability of any node is exclusively determined by its local weighted structure. This framework enables us to identify a unique set of critical nodes for control, to derive analytic formulas and articulate efficient algorithms to determine the exact upper and lower controllability bounds, and to evaluate strongly structural controllability of any given network. Applying our framework to a large number of model and real-world networks, we find that the interaction strength plays a more significant role in edge controllability than the network structure does, due to a vast range between the bounds determined mainly by the interaction strength. Moreover, transcriptional regulatory networks and electronic circuits are much more strongly structurally controllable (SSC) than other types of real-world networks, directed networks are more SSC than undirected networks, and sparse networks are typically more SSC than dense networks. PMID- 28652605 TI - Distinct Levels of Reactive Oxygen Species Coordinate Metabolic Activity with Beta-cell Mass Plasticity. AB - The pancreatic beta-cells control glucose homeostasis by secreting insulin in response to nutrient intake. The number of beta-cells is under tight metabolic control, as this number increases with higher nutrient intake. However, the signaling pathways matching nutrition with beta-cell mass plasticity remain poorly defined. By applying pharmacological and genetic manipulations, we show that reactive oxygen species (ROS) regulate dose-dependently beta-cell proliferation in vivo and in vitro. In particular, reducing ROS levels in beta cells blocks their proliferation in response to nutrients. Using a non-invasive genetic sensor of intracellular hydrogen peroxide (H2O2), we reveal that glucose can directly increase the levels of H2O2. Furthermore, a moderate increase in H2O2 levels can stimulate beta-cell proliferation. Interestingly, while high H2O2 levels are inhibitory to beta-cell proliferation, they expand beta-cell mass in vivo by inducing rapid beta-cell neogenesis. Our study thus reveals a ROS-level dependent mechanism linking nutrients with beta-cell mass plasticity. Hence, given the requirement of ROS for beta-cell mass expansion, antioxidant therapies should be applied with caution in diabetes. PMID- 28652606 TI - Interleukin 33 exacerbates antigen driven airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma. AB - Interleukin 33 (IL-33) represents a potential link between the airway epithelium and induction of Th2-type inflammatory responses associated with the development of asthma. This study investigated the potential of IL-33 to exacerbate antigen driven asthma responses. An ovalbumin (OVA) asthma model was used in which sensitized C57BL/6 mice were exposed to IL-33 before each OVA challenge. IL-33 given to sensitized mice acted synergistically with antigen and aggravated airway inflammation, hyperresponsiveness and remodeling compared with mice that were only OVA sensitized and challenged and mice that were only exposed to IL-33. Elevated levels of local and systemic mast cell protease mMCP-1, as well as antigen-specific IgE production, were observed following IL-33 administration to sensitized mice. Similarly, exposing OVA-sensitized mice to IL-33 increased the Th2 cytokine levels, including IL-4, IL-5 and IL-13. Furthermore, IL-33 and OVA administration to OVA-sensitized mice increased ILC2s in the lung, suggesting a role for ILC2s in IL-33-mediated exacerbation of OVA-induced airway responses. Collectively, these findings show that IL-33 aggravates important features of antigen-driven asthma, which may have implications for asthma exacerbations. PMID- 28652607 TI - Differences in Three-Dimensional Geometric Recognition by Non-Cancerous and Cancerous Epithelial Cells on Microgroove-Based Topography. AB - During metastasis, cancer cells are exposed to various three-dimensional microstructures within the body, but the relationship between cancer migration and three-dimensional geometry remain largely unclear. Here, such geometric effects on cancerous cells were investigated by characterizing the motility of various cancer cell types on microgroove-based topographies made of polydimethylsiloxane (PDMS), with particular emphasis on distinguishing cancerous and non-cancerous epithelial cells, as well as understanding the underlying mechanism behind such differences. The 90-degree walls enhanced motility for all cell lines, but the degrees of enhancements were less pronounced for the cancerous cells. Interestingly, while the non-cancerous epithelial cell types conformed to the three-dimensional geometrical cues and migrated along the walls, the cancerous cell types exhibited a unique behavior of climbing upright walls, and this was associated with the inability to form stable, polarized actin cytoskeleton along the walls of the microgrooves. Furthermore, when non-cancerous epithelial cell lines were altered to different levels of polarization capabilities and cancer malignancy or treated with inhibitory drugs, their three dimensional geometry-dependent motility approached those of cancerous cell lines. Overall, the results suggest that cancerous cells may gradually lose geometrical recognition with increasing cancer malignancy, allowing them to roam freely ignoring three-dimensional geometrical cues during metastasis. PMID- 28652608 TI - High-resolution 3D visualization of ductular proliferation of bile duct ligation induced liver fibrosis in rats using x-ray phase contrast computed tomography. AB - X-ray phase-contrast computed tomography (PCCT) can provide excellent image contrast for soft tissues with small density differences, and it is particularly appropriate for three-dimensional (3D) visualization of accurate microstructures inside biological samples. In this study, the morphological structures of proliferative bile ductules (BDs) were visualized without contrast agents via PCCT with liver fibrosis samples induced by bile duct ligation (BDL) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups: sham operation group, 2-week and 6-week post-BDL groups. All livers were removed after euthanasia for a subsequent imaging. The verification of the ductular structures captured by PCCT was achieved by a careful head-to-head comparison with their corresponding histological images. Our experimental results demonstrated that PCCT images corresponded very well to the proliferative BDs shown by histological staining using cytokeratin 19 (CK19). Furthermore, the 3D density of proliferative BDs increased with the progression of liver fibrosis. In addition, PCCT accurately revealed the architecture of proliferative BDs in a 3D fashion, including the ductular ramification, the elongation and tortuosity of the branches, and the corrugations of the luminal duct surface. Thus, the high resolution PCCT technique can improve our understanding of the characteristics of ductular proliferation from a new 3D perspective. PMID- 28652609 TI - A novel stress response mechanism, triggered by indole, involved in quorum quenching enzyme MomL and iron-sulfur cluster in Muricauda olearia Th120. AB - Indole, as a signal molecule, is involved in multiple physiological behavior including biofilm formation, antibiotic resistance and virulence. In this study, we demonstrated that indole was involved in iron deficient and H2O2 stress response in Muricauda olearia Th120. Transcriptome analysis showed that totally 206 genes were regulated by exogenous indole. Besides, momL-suf gene cluster, consisting of quorum quenching enzyme coding gene momL and iron-sulfur biosynthetic genes suf, were involved in indole-induced stress response pathway. The result indicated that indole not only up-regulated momL-suf gene cluster, but also enhanced the MomL secretion and the growth rates of MomL-bearing strains in H2O2 stress and iron deficient culture conditions. Co-incubation of M. olearia Th120 and Pectobacterium carotovorum subsp. carotovorum under H2O2 condition revealed that M. olearia Th120 bearing MomL possessed an increased competitive advantage, whereas its competitor had a reduced survival. The phenomenon that quorum quenching enzyme is triggered by stress factor has been rarely reported. The study also opens a new clue to explore the indole function towards quorum quenching factor in bacteria. PMID- 28652610 TI - Phylogenetic constrains on Polyporus umbellatus-Armillaria associations. AB - It has been well established that some Armillaria species are symbionts of Polyporus umbellatus, However, little is known about the evolutionary history of P. umbellatus-Armillaria associations. In this research, we used an analysis based on the strength of the phylogenetic signal to investigate P. umbellatus Armillaria associations in 57 sclerotial samples across 11 provinces of China. We isolated Armillaria strains from the invasion cavity inside the sclerotia of P. umbellatus and then phylogenetically analyzed these Armillaria isolates. We also tested the effect of P. umbellatus and Armillaria phylogenies on the P. umbellatus-Armillaria associations. We isolated forty-seven Armillaria strains from 26 P. umbellatus sclerotial samples. All Armillaria isolates were classified into the 5 phylogenetic lineages found in China except for one singleton. Among the 5 phylogenetic lineages, one lineage (lineage 8) was recognized by delimitation of an uncertain phylogenetic lineage in previous study. Results of simple Mantel test implied that phylogenetically related P. umbellatus populations tend to interact with phylogenetically related Armillaria species. Phylogenetic network analyses revealed that the interaction between P. umbellatus and Armillaria is significantly influenced by the phylogenetic relationships between the Armillaria species. PMID- 28652611 TI - Common lipid features of lethal ventricular tarchyarrhythmias (LVTAs) induced by myocardial infarction and myocardial ion channel diseases. AB - Lethal ventricular tachyarrhythmia (LVTA) is the most prevalent electrophysiological underpinning of sudden cardiac death (SCD), a condition that occurs in response to multiple pathophysiological abnormalities. The aim of this study was to identify common lipid features of LVTA that were induced by distinct pathophysiological conditions, thereby facilitating the discovery of novel SCD therapeutic targets. Two rat LVTA-SCD models were established to mimic myocardial infarction (MI) and myocardial ion channel diseases. Myocardial and serum specimens were analyzed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based lipidomics. The lipid profiles of the myocardial and serum specimens were similar between the models. Eleven myocardial lipid classes were altered, including downregulations of: cardiolipin, ceramide, phosphatidylinositol, phosphatidylethanolamine, triacylglycerol, diacylglycerol, phosphatidylglycerol, lysophosphatidylethanolamine and phosphatidylserine, and upregulations of: lysophosphatidylcholine and phosphatidic acid. Serum concentrations of triacylglycerol, lysophosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol were also altered. Alterations of lipids in paired myocardia and sera were closely correlated. Cardiolipin 70:5, cardiolipin 74:9 and ceramide d34:2 were tested as potential biomarkers of LVTA. The results indicate that there are common LVTA lipid profiles induced by MI and myocardial ion channel diseases, potentially offering novel LVTA-SCD therapeutic targets. PMID- 28652612 TI - Karst tiankengs as refugia for indigenous tree flora amidst a degraded landscape in southwestern China. AB - We conducted floristic and community analyses to compare the floristic composition, forest structure, taxonomic richness, and species diversity between two tiankeng (large doline, or sinkhole) habitats and two outside-tiankeng habitats of forest fragments in a degraded karst area in southwestern China. We found remarkably higher taxonomic richness in the tiankeng habitats than in the outside-tiankeng habitats at the species, generic, and familial levels. The inside-tiankeng habitats had higher floristic diversity but lower dominance. The remarkably higher uniqueness at all taxonomic levels and the much larger tree size in the two tiankeng habitats than in the outside-tiankeng habitats demonstrated the old-growth and isolated nature of the tiankeng flora. Plot-scale species richness, Shannon-Wiener index, Pielou's evenness, and Berger-Parker dominance significantly differed across habitats. Heterogeneity in floristic composition at the species, generic, and familial levels was extremely significant across habitats. In pairwise comparisons, except for the Chuandong Tiankeng-Shenmu Tiankeng pair, all the pairs showed significant between-habitat heterogeneity in floristic composition. Our results suggest that as oases amidst the degraded karst landscape, tiankengs serve as modern refugia that preserve old growth forest communities with their rich floristic diversity, and can provide a model for habitat conservation and forest restoration in that area. PMID- 28652614 TI - Wireless MRI Colonoscopy for Sensitive Imaging of Vascular Walls. AB - A Wireless Amplified NMR Detector (WAND) with cylindrical symmetry has been fabricated and non-surgically inserted into a rodent lower digestive track to improve the imaging quality of deep-lying vessels inside the abdominal cavity. This symmetric detector has a compact design using two end-rings and two vertical legs to create two orthogonal resonance modes. Based on the principle of parametric amplification, the detector can harvest wireless pumping power with its end-rings and amplify Magnetic Resonance signals induced on its vertical legs. With good longitudinal and azimuthal homogeneity, the WAND can achieve up to 21-times sensitivity gain over a standard external detector for immediately adjacent regions, and at least 5-times sensitivity gain for regions separated by one diameter away from the detector's cylindrical surface. The WAND can approach the region of interest through the lower digestive track, similar as a colonoscopy detector. But unlike an optical camera, the amplified MR detector can "see" across intestinal boundaries and clearly identify the walls of bifurcated vessels that are susceptible to atherosclerotic lesions. In addition to vascular wall imaging, this detector may also be used as a swallowable capsule to enhance the detection sensitivity of deep-lying organs near the digestive track. PMID- 28652613 TI - Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression. AB - Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of Polycomb repressive complex is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcription. Here, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that Polycomb repressive complex-active genes have greater cell-to-cell variation in expression than active genes, and these results are validated by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development.Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression. PMID- 28652615 TI - Gga-miR-219b targeting BCL11B suppresses proliferation, migration and invasion of Marek's disease tumor cell MSB1. AB - Marek's disease (MD), caused by Marek's disease virus (MDV), is a lymphotropic neoplastic disease. Previous miRNAome analysis showed gga-miR-219b was significantly downregulated in MDV-induced lymphoma, and one of its potential target genes, B-cell chronic lymphocytic /lymphoma 11B (BCL11B) was predicted. In this study, we further investigated the function of gga-miR-219b, and the gain/loss of function assay showed gga-miR-219b inhibited cell migration and reduced cell proliferation by promoting apoptosis not by cell cycle arrest. Gga miR-219b also suppressed expression of two cell invasion-related genes MMP2 and MMP9. The results indicated suppressive effect of gga-miR-219b on MD tumorigenesis. The gene BCL11B was verified as a direct target gene of gga-miR 219b. RNA interference was performed to block BCL11B. As expected, the effects triggered by BCL11B downregulation were in accordance with that triggered by gga miR-219b overexpression, suggesting that BCL11B was a stimulative regulator of MD transformation. Moreover, both gga-miR-219b and BCL11B influenced the expression of Meq gene, the most important oncogene in MDV. Additionally, gene expression level of anti-apoptotic genes BCL2 and BCL2L1 was downregulated and pro-apoptotic gene TNFSF10 was upregulated in MSB1 cells with gga-miR-219b overexpression or BCL11B knockdown, which suggested gga-miR-219b promoted cell apoptosis via regulating gene expression in the apoptosis pathways. PMID- 28652616 TI - Belowground top-down and aboveground bottom-up effects structure multitrophic community relationships in a biodiverse forest. AB - Ecosystem functioning and human well-being critically depend on numerous species interactions above- and belowground. However, unraveling the structure of multitrophic interaction webs at the ecosystem level is challenging for biodiverse ecosystems. Attempts to identify major relationships between trophic levels usually rely on simplified proxies, such as species diversity. Here, we propose to consider the full information on species composition across trophic levels, using Procrustes correlation and structural equation models. We show that species composition data of a highly diverse subtropical forest-with 5,716 taxa across 25 trophic groups- reveal strong interrelationships among plants, arthropods, and microorganisms, indicating complex multitrophic interactions. We found substantial support for top-down effects of microorganisms belowground, indicating important feedbacks of microbial symbionts, pathogens, and decomposers on plant communities. In contrast, aboveground pathways were characterized by bottom-up control of plants on arthropods, including many non-trophic links. Additional analyses based on diversity patterns revealed much weaker interrelationships. Our study suggests that multitrophic communities in our forest system are structured via top-down effects of belowground biota on plants, which in turn affect aboveground arthropod communities across trophic levels. Moreover, the study shows that the consequences of species loss will be more complex than indicated by studies based solely on diversity. PMID- 28652617 TI - Prognostic value of CD146 in solid tumor: A Systematic Review and Meta-analysis. AB - CD146, also known as melanoma cell adhesion molecule, was initially identified as a marker of melanoma progression and metastasis. Recently many clinical studies investigated overexpression of CD146 predict poor prognosis of solid tumor, however, the results was inconclusive, partly due to small numbers of patients included. This present meta-analysis was therefore performed utilizing the results of all clinical studies concerned to determine the prognostic value of CD146 expression in solid tumors. Relevant articles were identified through searching the PubMed, Web of Science and Embase database. In this meta-analysis, 12 studies involving 2,694 participants were included, and we drew the conclusion that strong significant associations between CD146 expression and all endpoints: overall survival (OS) [hazard ratio (HR) = 2.496, 95% confidence interval (95% CI) 2.115-2.946], time to progression (TTP) (HR = 2.445, 95% CI 1.975-3.027). Furthermore, the subgroup analysis revealed that the associations between CD146 overexpression and the outcome endpoints (OS or TTP) were significant in Mongoloid patients and Caucasian patients, as well in patients with lung cancer and digestive system cancer. In conclusion, these results showed that high CD146 was associated with poor survival in human solid tumors. CD146 may be a valuable prognosis predictive biomarker; nevertheless, whether CD146 could be a potential therapeutic target in human solid tumors needs to be further studied. PMID- 28652618 TI - Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting. AB - Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protein kinase B (Akt). Likewise, tumor cells pretreated with LGRFYAASG-pen exhibited an impaired capacity to colonize the lungs in vivo in several mouse models. Together, our findings demonstrate an unrecognized functional link between intracellular annexin A2 and tumor cell adhesion, migration and in vivo grafting. Moreover, this work uncovers a new peptide motif that binds to and inhibits intracellular annexin A2 as a candidate therapeutic lead for potential translation into clinical applications. PMID- 28652619 TI - Testing hypotheses of developmental constraints on mammalian brain partition evolution, using marsupials. AB - There is considerable debate about whether the partition volumes of the mammalian brain (e.g. cerebrum, cerebellum) evolve according to functional selection, or whether developmental constraints of conserved neurogenetic scheduling cause predictable partition scaling with brain size. Here we provide the first investigation of developmental constraints on partition volume growth, derived from contrast-enhanced micro-computed tomography of hydrogel-stabilized brains from three marsupial species. ANCOVAs of partition vs. brain volume scaling, as well as growth curve comparisons, do not support several hypotheses consistent with developmental constraints: brain partition growth significantly differs between species, or between developing vs. adult marsupials. Partition growth appears independent of adult brain volume, with no discernable growth spurts/lags relatable to internal structural change. Rather, adult proportion differences appear to arise through growth rate/duration heterochrony. Substantial phylogenetic signal in adult brain partitions scaling with brain volume also counters expectations of development-mediated partition scaling conservatism. However, the scaling of olfactory bulb growth is markedly irregular, consistent with suggestions that it is less constrained. The very regular partition growth curves suggest intraspecific developmental rigidity. We speculate that a rigid, possibly neuromer-model-like early molecular program might be responsible both for regular growth curves within species and impressions of a link between neurogenesis and partition evolution. PMID- 28652620 TI - Differential cohesin loading marks paired and unpaired regions of platypus sex chromosomes at prophase I. AB - Cohesins are vital for chromosome organisation during meiosis and mitosis. In addition to the important function in sister chromatid cohesion, these complexes play key roles in meiotic recombination, DSB repair, homologous chromosome pairing and segregation. Egg-laying mammals (monotremes) feature an unusually complex sex chromosome system, which raises fundamental questions about organisation and segregation during meiosis. We discovered a dynamic and differential accumulation of cohesins on sex chromosomes during platypus prophase I and specific reorganisation of the sex chromosome complex around a large nucleolar body. Detailed analysis revealed a differential loading of SMC3 on the chromatin and chromosomal axis of XY shared regions compared with the chromatin and chromosomal axes of asynapsed X and Y regions during prophase I. At late prophase I, SMC3 accumulation is lost from both the chromatin and chromosome axes of the asynaptic regions of the chain and resolves into subnuclear compartments. This is the first report detailing unpaired DNA specific SMC3 accumulation during meiosis in any species and allows speculation on roles for cohesin in monotreme sex chromosome organisation and segregation. PMID- 28652622 TI - The prognostic significance of PD-L1 expression in patients with glioma: A meta analysis. AB - A large number of studies have shown that programmed death-ligand 1 (PD-L1) is abnormally expressed in gliomas. However, the prognostic significance of PD-L1 expression in glioma patients remains unresolved. Accordingly, we conducted a meta-analysis to determine the prognostic role of high PD-L1 in patients with glioma. Electronic databases were searched to identify studies evaluating PD-L1 expression and overall survival (OS) in these patients. A total of 6 studies (published in 4 articles) that involved 1052 patients were included. Pooled results showed that high PD-L1 expression was associated with worse OS in glioma patients (HR = 1.30, 95% CI: 1.02-1.65, P = 0.032). Further subgroup analysis indicated that high PD-L1 expression in glioblastoma (GBM) was also associated with worse OS (HR = 1.40, 95% CI: 1.03-1.90, P = 0.030). Conversely, in index subgroup analysis, neither PD-L1 protein (HR = 1.43, 95% CI: 0.97-2.10, P = 0.068) nor gene (HR = 1.20, 95% CI: 0.83-1.74, P = 0.322) expression was significantly associated with OS. PD-L1 may represent a promising biomarker that predicts disease progression in patients with glioma or GBM. However, because of our limited sample size, further prospective or retrospective multi-centre, well designed studies should be performed to verify this result. PMID- 28652621 TI - Silicon amendment is involved in the induction of plant defense responses to a phloem feeder. AB - Plant resistance to herbivores is a key component in integrated pest management. In most cases, silicon (Si) amendment to plants enhances resistance to herbivorous insects. The increase of plant physical barrier and altered insect behaviors are proposed as mechanisms for the enhanced resistance in Si-amended plants, but our understanding of the induced mechanisms involved in Si-enhanced plant resistance to phloem-feeding insects remains unclear. Here, we show that Si amendment to rice (Oryza sativa) plants impacts multiple plant defense responses induced by a phloem-feeder, the brown planthopper (Nilaparvata lugens, BPH). Si amendment improved silicification of leaf sheaths that BPH feed on. Si addition suppressed the increase of malondialdehyde concentration while encouraged increase of H2O2 concentration in plants attacked by BPH. Higher activities of catalase and superoxide dismutase were recorded in Si-amended than in non-amended BPH-infested plants. BPH infestation activated synthases for secondary metabolites, polyphenol oxidase and pheny-lalanine ammonia-lyase, and beta-1,3 glucanase, but the activation was greater in Si-amended than in non-amended plants. Taken together, our findings demonstrate that Si amendment interacts with BPH infestation in the induction of plant defense responses and consequently, to confer enhanced rice plant resistance. PMID- 28652623 TI - Automatic inhibitory function in the human somatosensory and motor cortices: An MEG-MRS study. AB - While the automatic inhibitory function of the human cerebral cortex has been extensively investigated by means of electrophysiological recordings, the corresponding modulating neurochemical mechanisms remain unclear. We aimed to examine whether the primary somatosensory (SI) and primary motor cortical (MI) inhibitory function is associated with endogenous GABA levels. Eighteen young participants received paired-pulse and single-pulse electrical stimulation to the median nerve during magnetoencephalographic recordings. The SI sensory gating (SG), considered as an automatic inhibitory ability, was measured as the amplitude ratio of Stimulus 2 over Stimulus 1, in the paired-pulse paradigm. In addition, stimulus-induced beta activity, considered to originate from MI and also to be related to inhibitory function, was estimated using the single-pulse paradigm. The GABA+ concentration of the sensorimotor cortex was acquired from each subject by using magnetic resonance spectroscopy (MRS). A lower SG ratio in SI was significantly associated with an increased beta power in MI. More importantly, the beta rebound power, but not SI SG ratio, was positively correlated with GABA+ concentration. Our findings show a tight functional relationship between SI and MI during processing of automatic inhibition. GABA+ levels appear to be more closely related to the automatic inhibitory function of MI than SI. PMID- 28652624 TI - Serum hepcidin may be a novel uremic toxin, which might be related to erythropoietin resistance. AB - The clinical importance of serum hepcidin in non-dialysis chronic kidney disease (CKD) patients is unclear. The database of a large-scale multicentre prospective study in Korea of 2238 patients enrolled from 2011-2016 was analysed. After excluding patients with missing serum hepcidin (n = 125) and haemoglobin (n = 23) levels, the study included 2090 non-dialysis CKD patients. Markers of inflammation and iron status were positively associated with serum hepcidin level, regardless of CKD stage. However, estimated glomerular filtration rate was inversely associated with serum hepcidin level, particularly in patients with CKD stages 3b-5 but not in those with CKD stages 1-3a. Use of erythropoiesis stimulating agents was associated with increased serum hepcidin levels, particularly in patients with CKD stages 3b-5 but not in those with CKD stages 1 3a, and serum hepcidin levels positively correlated with the dose of erythropoiesis-stimulating agent. These findings suggest that serum hepcidin may be a uremic toxin and play an important role in erythropoietin resistance. However, future prospective studies are needed to confirm our results. PMID- 28652625 TI - Dendritic mitoflash as a putative signal for stabilizing long-term synaptic plasticity. AB - Mitochondrial flashes (mitoflashes) are recently discovered excitable mitochondrial events in many cell types. Here we investigate their occurrence in the context of structural long-term potentiation (sLTP) at hippocampal synapses. At dendritic spines stimulated by electric pulses, glycine, or targeted glutamate uncaging, induction of sLTP is associated with a phasic occurrence of local, quantized mitochondrial activity in the form of one or a few mitoflashes, over a 30-min window. Low-dose nigericin or photoactivation that elicits mitoflashes stabilizes otherwise short-term spine enlargement into sLTP. Meanwhile, scavengers of reactive oxygen species suppress mitoflashes while blocking sLTP. With targeted photoactivation of mitoflashes, we further show that the stabilization of sLTP is effective within the critical 30-min time-window and a spatial extent of ~2 MUm, similar to that of local diffusive reactive oxygen species. These findings indicate a potential signaling role of dendritic mitochondria in synaptic plasticity, and provide new insights into the cellular function of mitoflashes.Mitoflashes are dynamic events in mitochondria, associated with depolarization and release of reactive oxygen species, and have been associated with several cellular functions. The authors now show that in neurons, dendritic mitoflashes are involved in structural postsynaptic changes during LTP. PMID- 28652626 TI - Deformation pattern in vibrating microtubule: Structural mechanics study based on an atomistic approach. AB - The mechanical properties of microtubules are of great importance for understanding their biological function and for applications in artificial devices. Although microtubule mechanics has been extensively studied both theoretically and experimentally, the relation to its molecular structure is understood only partially. Here, we report on the structural analysis of microtubule vibration modes calculated by an atomistic approach. Molecular dynamics was applied to refine the atomic structure of a microtubule and a C alpha elastic network model was analyzed for its normal modes. We mapped fluctuations and local deformations up to the level of individual aminoacid residues. The deformation is mode-shape dependent and principally different in alpha-tubulins and beta-tubulins. Parts of the tubulin dimer sequence responding specifically to longitudinal and radial stress are identified. We show that substantial strain within a microtubule is located both in the regions of contact between adjacent dimers and in the body of tubulins. Our results provide supportive evidence for the generally accepted assumption that the mechanics of microtubules, including its anisotropy, is determined by the bonds between tubulins. PMID- 28652628 TI - [Recanalization of chronic total occlusions: to all or none? In medio stat virtus!] PMID- 28652627 TI - [Percutaneous treatment of coronary chronic total occlusions: state of the art]. AB - Successful percutaneous coronary intervention of chronic total occlusions (CTO) is associated with favorable clinical outcomes in selected subsets of patients. The success rate of CTO interventions greatly increased over the last decades, thanks to the development of dedicated materials and interventional strategies. Nevertheless, CTO interventions are still challenging with higher complication rates and lower success rates compared to standard percutaneous coronary interventions. Dedicated CTO operators are warranted in order to minimize the rate of complications and to achieve a success rate near to 90%. This state of the art paper is aimed to provide updated evidences on the clinical benefit of CTO recanalization and to describe specific interventional techniques for CTO recanalization. PMID- 28652629 TI - [OBSERVANT II: OBservational Study of Effectiveness of transcatheter aortic valve implantation with new geneRation deVices for severe Aortic steNosis Treatment. Study protocol]. AB - BACKGROUND: The rapid spread of transcatheter aortic valve implantation (TAVI) for the treatment of severe symptomatic aortic stenosis in the last decade in Italy has led to a gradually increasing use of TAVI procedures also in patients potentially eligible for aortic valve replacement (AVR). For this subset of patients, the OBSERVANT study (2011-2012) evaluated the short- and medium term outcome of TAVI vs AVR, at least for the first generations of TAVI devices, but failed to gather information on all the technological innovations occurred in recent years. The launch of a phase II of the study will allow to recruit a new series of TAVI, with different risk profiles compared with the historical OBSERVANT TAVI cohort, in order to assess whether and how much the use of new generation devices mitigate the differences in outcomes recorded in the OBSERVANT study. METHODS: OBSERVANT II is an observational multicenter, prospective, cohort study collecting data on patients with severe symptomatic aortic stenosis undergoing TAVI in Italian hospitals since December 15, 2016, for at least 12 months. For each patient, data on demographic characteristics, health status, type of intervention and presence of comorbidities will be collected. Mortality and incidence of in-hospital major adverse cardiac and cerebrovascular events (MACCE) within 36 months of intervention will be the primary adverse outcome. Secondary outcomes will include 30-day mortality and the incidence of MACCE at 12 and 24 months. The statistical hypotheses were formulated considering the results from the OBSERVANT study. Testing these hypotheses will require the recruitment of at least 823 new TAVI. The risk/propensity-adjustment techniques will be used to comparatively evaluate the effectiveness of TAVI vs AVR. EXPECTED RESULTS: Safety and efficacy profiles of the new-generation TAVI prosthesis; comparative effectiveness of the new TAVI prosthesis as compared to TAVI procedures of the OBSERVANT historical cohort; comparative effectiveness of the new TAVI prosthesis as compared to AVR procedures of the OBSERVANT historical cohort. CONCLUSIONS: The results of OBSERVANT II will provide information on the effectiveness of TAVI employing new-generation devices and will be a valuable support to give professionals and policy makers evidence-based results useful for decision-making processes. PMID- 28652631 TI - [Stenting of multiple peripheral pulmonary stenosis with the coronary technique in an adul patient with Eisenmenger-like syndrome]. AB - Peripheral pulmonary artery stenosis is a quite rare condition that can lead to misdiagnosis, particularly in adults. We describe the case of a 48-year-old woman with multiple stenoses, challenging anatomy and Eisenmenger-like presentation, who was treated percutaneously with a coronary technique. PMID- 28652632 TI - [Notes for difficult times]. PMID- 28652630 TI - [SICI-GISE commuNity CAmpania survey doNna TAVI (INCANTA): perioperative and short-term outcome of transcatheter aortic valve implantation in women]. AB - BACKGROUND: Nowadays the prognostic role of gender as a relevant factor after transcatheter aortic valve implantation (TAVI) is still unfair, since available data in the literature are few and uneven. The aim of this survey was to collect acute and 30-day safety and efficacy clinical data in high- and intermediate-risk women, who underwent TAVI with new-generation devices, in the Campania Region. METHODS: All medium and high-volume TAVI centers in Campania have been invited to fulfill an online, ad-hoc questionnaire, collecting pre-, peri- and post procedural data concerning female patients, treated between January and December 2016. RESULTS: 331 women (representing the 61% of the overall population treated; mean age 83 +/- 7 years) underwent TAVI in the participating Campania centers. Age >80 years (72%), high surgical risk score (63%) and frailty (55%) were found to be the top three reasons for the TAVI choice. Overall, 95% of the procedures were performed by transfemoral approach with local anesthesia; the remaining 5% (16 cases) were conducted via transapical (14, 4%) and transaortic (2, 1%) accesses, under general anesthesia. Edwards Sapien 3 (Edwards Lifesciences, Irvine, CA, USA) and Medtronic Evolut R (Medtronic Inc., Minneapolis, MN, USA) were the most frequently implanted valves (146, 44% and 132, 43%, respectively). The questioned Centers reported a mean length of hospital stay of 5.5 +/- 1.1 days, 1.6 +/- 0.37 of which in a cardiac care unit. The most prevalent in hospital complication was pacemaker implantation (15%), followed by life threatening vascular complications (3%). The 30-day VARC-2 composite endpoint occurred in 7% of cases, all-cause death in 4%, and stroke in 1%. CONCLUSIONS: This survey, the first representative of women undergoing TAVI in Campania, appears to confirm the good safety and efficacy profile of this procedure, also in the high- and intermediate-risk settings, probably favored by a prevalent use of new-generation devices and a low rate prevalence of significant patient comorbidities. PMID- 28652633 TI - [Enteral nutrition during prone positioning in mechanically ventilated patients]. AB - : . Enteral nutrition during prone positioning in mechanically ventilated patients. INTRODUCTION: The Enteral Nutrition (EN) tends to be stopped during prone positioning to prevent the risk of acid reflux and vomiting. AIMS: To compare the gastric residual volume during continuous enteral nutrition in patients in prone and supine position. METHODS: Observational restrospective study on Acute Respiratory Distress Syndrome patients, mechanically ventilated, with continuous enteral nutrition implemented according to the same protocol, in prone and supine position. RESULTS: The 25 patients included had a mean age of 51.13+/-15.93 (range: 16-80) years. Gastic residual volume was checked on 656 occasions (408 in supine and 248 in prone position). Mean infusion rate was 63.3+/-18.5 ml/h: 62.1+/-18.9 ml/h in supine and 66.2+/-16.5 ml/h in prone position. The mean overall gastric residual volume was 24.4+/-54.2 ml: 20.6+/ 18.9 ml in supime and 23.6+/-50.0 ml in prone posizion. In 4 occasions (2 in prone and 2 in supine position9, the gastric residual volume was > 300ml; EN was interrupted on 1 occasion with a gastric residual volume >500ml. CONCLUSIONS: No clinically relevant differences of gastric residual volume were observed in prone and supine position. A protocol for the management of gastric residual volume allows a safe and effective administration of EN also in patients positioned for several hours in prone position. PMID- 28652634 TI - [A pilot study on pain assessment among elderly with severe dementia
in residential aged care facilities of Reggio Emilia district]. AB - : . A pilot study on pain assessment among elderly with severe dementia in residential aged care facilities of Reggio Emilia district. INTRODUCTION: Despite the availability of pain assessment tools and best practice recommendations for the assessment and management of pain in people with severe dementia, pain in residential aged care facilities is still undetected or misinterpreted. OBJECTIVE: To assess pain prevalence and analgesic load medication in people with severe cognitive impairment admitted to residential aged care facilities of Reggio Emilia (Italy) province. METHODS: A pilot cross-sectional study was conducted on 84 elderly patients affected by severe dementia and resident in aged care facilities. Pain was assessed with the PAINAD observational scale, both at rest and during routine procedures: positioning in bed, from bed to standing position, from bed to chair or during the medication of a pressure sore (under challenge). RESULTS: 33.4% of patients had pain at rest, mainly mild, and 86.9 % under challenge. During routine interventions, in 64 patients (76.2%) pain increased compared to at rest condition (for 39, 2/3, moderate-severe); although 46 of them were prescribed as-required analgesic medication, none had received the drug. Also patients with analgesics on regular basis experienced more pain during routine procedures. CONCLUSIONS: Many patients experienced pain during routine procedures. The regular use of pain assessment tools and adequate training of all healthcare professionals are essential requirements for an effective pain control. PMID- 28652635 TI - [Risk factors for delirium in intensive care unit
in liver transplant patients]. AB - : . Risk factors for delirium in intensive care unit in liver transplant patients. INTRODUCTION: Delirium is a disorder of the state of consciousness characterized by acute onset and temporal variability of cognitive abilities. It is frequent in intensive care unit (ICU) and it is associated with worst outcomes. AIM: To identify risk factors for the development of delirium in patients in intensive care unit (ICU) after orthotopic liver transplantation (OLTx). METHODS: Observational retrospective study on all the patients undergoing OLTx between January 2014 and December 2015. The daily assessment for delirium was performed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), by nemed nurses. RESULTS: Of the 123 patients included, 15 (12.2%) developed post-operative delirium. The main risk factor was preoperative hepatic encephalopathy (OR = 8.80, 95% CI 2.70-28.59): the deterioration of the state of consciousness (GCS pre-OLTx score < 15) increased the risk of developing delirium (OR 6.18; IC 95% 1.51 - 25.31). A high Acute Physiologic and Health Evaluation (APACHE II) score (OR=1.29, IC 95%: 1.12-1.47) showed how patients with a more severe clinical situation at ICU admission were more likely to develop delirium. CONCLUSIONS: The risk factors identified predict the development of delirium in ICU. Its prevention with the implementation of pharmacological or other strategies may reduce the onset of delirium and improve the quality of care. PMID- 28652636 TI - [In the eyes of the beholder]. PMID- 28652638 TI - [Blood cultures from peripheral and central venous catheter:
literature review and practical implications]. PMID- 28652637 TI - [Do opioids make chronic users more sensitive to pain?] PMID- 28652639 TI - [Obedience is not (any longer) a virtue]. PMID- 28652640 TI - [Copper surfaces and hospital acquired infections]. PMID- 28652641 TI - High-precision deformation mapping in finFET transistors with two nanometre spatial resolution by precession electron diffraction. AB - Precession electron diffraction has been used to systematically measure the deformation in Si/SiGe blanket films and patterned finFET test structures grown on silicon-on-insulator type wafers. Deformation maps have been obtained with a spatial resolution of 2.0 nm and a precision of +/-0.025%. The measured deformation by precession diffraction for the blanket films has been validated by comparison to energy dispersive x-ray spectrometry, X-Ray diffraction, and finite element simulations. We show that although the blanket films remain biaxially strained, the patterned fin structures are fully relaxed in the crystallographic planes that have been investigated. We demonstrate that precession diffraction is a viable deformation mapping technique that can be used to provide useful studies of state-of-the-art electronic devices. PMID- 28652642 TI - Optical fiber ultrasound transmitter with electrospun carbon nanotube-polymer composite. AB - All-optical ultrasound transducers are promising for imaging applications in minimally invasive surgery. In these devices, ultrasound is transmitted and received through laser modulation, and they can be readily miniaturized using optical fibers for light delivery. Here, we report optical ultrasound transmitters fabricated by electrospinning an absorbing polymer composite directly onto the end-face of optical fibers. The composite coating consisting of an aqueous dispersion of multi-walled carbon nanotubes (MWCNTs) in polyvinyl alcohol was directly electrospun onto the cleaved surface of a multimode optical fiber and subsequently dip-coated with polydimethylsiloxane (PDMS). This formed a uniform nanofibrous absorbing mesh over the optical fiber end-face wherein the constituent MWCNTs were aligned preferentially along individual nanofibers. Infiltration of the PDMS through this nanofibrous mesh onto the underlying substrate was observed and the resulting composites exhibited high optical absorption (>97%). Thickness control from 2.3 MUm to 41.4 MUm was obtained by varying the electrospinning time. Under laser excitation with 11 MUJ pulse energy, ultrasound pressures of 1.59 MPa were achieved at 1.5 mm from the coatings. On comparing the electrospun ultrasound transmitters with a dip-coated reference fabricated using the same constituent materials and possessing identical optical absorption, a five-fold increase in the generated pressure and wider bandwidth was observed. The electrospun transmitters exhibited high optical absorption, good elastomer infiltration, and ultrasound generation capability in the range of pressures used for clinical pulse-echo imaging. All-optical ultrasound probes with such transmitters fabricated by electrospinning could be well-suited for incorporation into catheters and needles for diagnostics and therapeutic applications. PMID- 28652643 TI - Hybrid tandem quantum dot/organic photovoltaic cells with complementary near infrared absorption. AB - Monolithically integrated hybrid tandem solar cells that effectively combine solution-processed colloidal quantum dot (CQD) and organic bulk heterojunction subcells to achieve tandem performance that surpasses the individual subcell efficiencies have not been demonstrated to date. In this work, we demonstrate hybrid tandem cells with a low bandgap PbS CQD subcell harvesting the visible and near-infrared photons and a polymer:fullerene-poly (diketopyrrolopyrrole terthiophene) (PDPP3T):[6,6]-phenyl-C60-butyric acid methyl ester (PC61BM)-top cell absorbing effectively the red and near-infrared photons of the solar spectrum in a complementary fashion. The two subcells are connected in series via an interconnecting layer (ICL) composed of a metal oxide layer, a conjugated polyelectrolyte, and an ultrathin layer of Au. The ultrathin layer of Au forms nano-islands in the ICL, reducing the series resistance, increasing the shunt resistance, and enhancing the device fill-factor. The hybrid tandems reach a power conversion efficiency (PCE) of 7.9%, significantly higher than the PCE of the corresponding individual single cells, representing one of the highest efficiencies reported to date for hybrid tandem solar cells based on CQD and polymer subcells. PMID- 28652644 TI - The Development of Alkoxide-Directed Metallacycle-Mediated Annulative Cross Coupling Chemistry. AB - Alkoxide-directed metallacycle-mediated cross-coupling is a rapidly growing area of reaction methodology in organic chemistry. Over the last decade, developments have resulted in > thirty new and highly selective intermolecular (or "convergent") C-C bond-forming reactions that have established powerful retrosynthetic relationships in stereoselective synthesis. While early studies were focused on developing transformations that forge a single C-C bond by way of a functionalized and unsaturated metallacyclopentane intermediate, recent advances mark the ability to employ this organometallic intermediate in additional stereoselective transformations. Among these more advanced coupling processes, those that embrace the metallacycle in subsequent [4+2] chemistry have resulted in the realization of a number of highly selective annulative cross coupling reactions that deliver densely functionalized and angularly substituted carbocycles. This review discusses the early development of this chemistry, recent advances in reaction methodology, and shares a glimpse of the power of these processes in natural product synthesis. PMID- 28652645 TI - Optical control of capacitance in a metal-insulator-semiconductor diode with embedded metal nanoparticles. AB - This paper describes a metal-insulator-semiconductor (MIS) capacitor with flat capacitance voltage characteristics and a small quadratic voltage capacitance coefficient. The device characteristics resemble a metal-insulator-metal diode except that here the capacitance depends on illumination and exhibits a strong frequency dispersion. The device incorporates Fe nanoparticles (NPs), mixed with SrF2, which are embedded in an insulator stack of SiO2 and HfO2. Positively charged Fe ions induce dipole type traps with an electronic polarization that is enhanced by photogenerated carriers injected from the substrate and/or by inter nanoparticle exchange of carriers. The obtained characteristics are compared with those of five other MIS structures: two based on Fe NPs, one with and the other without SrF2 sublayers. Additionally, devices contain Co NPs embedded in SrF2 sublayers, and finally, two structures have no NPs, with one based on a stack of SiO2 and HfO2 and the other which also includes SrF2. Only structures containing Fe NPs, which are incorporated into SrF2, yield a voltage independent capacitance, the level of which can be changed by illumination. These properties are essential in radio frequency/analog mixed signal applications. PMID- 28652646 TI - Innovation under Regulatory Uncertainty: Evidence from Medical Technology. AB - This paper explores how the regulatory approval process affects innovation incentives in medical technologies. Prior studies have found early mover regulatory advantages for drugs. I find the opposite for medical devices, where pioneer entrants spend 34 percent (7.2 months) longer than follow-on entrants in regulatory approval. Back-of-the- envelope calculations suggest that the cost of a delay of this length is upwards of 7 percent of the total cost of bringing a new high-risk device to market. Considering potential explanations, I find that approval times are largely unrelated to technological novelty, but are meaningfully reduced by the publication of objective regulatory guidelines. Finally, I consider how the regulatory process affects small firms' market entry patterns and find that small firms are less likely to be pioneers in new device markets, a fact consistent with relatively higher costs of doing so for more financially constrained firms. PMID- 28652647 TI - Emotion regulation strategy selection in daily life: The role of social context and goals. AB - Recent studies have begun to document the diversity of ways people regulate their emotions. However, one unanswered question is why people regulate their emotions as they do in everyday life. In the present research, we examined how social context and goals influence strategy selection in daily high points and low points. As expected, suppression was particularly tied to social features of context: it was used more when others were present, especially non-close partners, and when people had instrumental goals, especially more interpersonal ones (e.g., avoid conflict). Distraction and reappraisal were used more when regulating for hedonic reasons (e.g., to feel better), but these strategies were also linked to certain instrumental goals (e.g., getting work done). When contra hedonic regulation occurred, it primarily took the form of dampening positive emotion during high points. Suppression was more likely to be used for contra hedonic regulation, whereas reappraisal and distraction were used more for pro hedonic regulation. Overall, these findings highlight the social nature of emotion regulation and underscore the importance of examining regulation in both positive and negative contexts. PMID- 28652648 TI - Role of pH in the recovery of bovine milk oligosaccharides from colostrum whey permeate by nanofiltration. AB - Milk oligosaccharides are associated with improved health outcomes in infants. Nanofiltration (NF) is used for isolation of bovine milk oligosaccharides (BMO). The study aim was to improve the recovery of BMO from lactose-hydrolyzed colostrum whey permeate. The retention factors of carbohydrates at various pH and transmembrane pressures were determined for a nanofiltration membrane, which was used at pilot scale to purify BMO. Carbohydrates were quantified by liquid chromatography and characterized using nano-LC-Chip-QToF mass spectrometry. BMO purity was improved from an initial 4% in colostrum whey permeate to 98%, with 99.8% permeation of monosaccharides and 96% recovery of oligosaccharides, represented by 23 unique BMO compounds identified in the final retentate. The pH during NF was a determining factor in the selectivity of carbohydrate separation. This NF method can be applied to conventional cheese-whey permeate and other milk types for extraction of bioactive oligosaccharides providing new options for the dairy industry. PMID- 28652649 TI - Bleeding with the artificial heart: Gastrointestinal hemorrhage in CF-LVAD patients. AB - Continuous-flow left ventricular assist devices (CF-LVADs) have significantly improved outcomes for patients with end-stage heart failure when used as a bridge to cardiac transplantation or, more recently, as destination therapy. However, its implantations carries a risk of complications including infection, device malfunction, arrhythmias, right ventricular failure, thromboembolic disease, postoperative and nonsurgical bleeding. A significant number of left ventricular assist devices (LVAD) recipients may experience recurrent gastrointestinal hemorrhage, mainly due to combination of antiplatelet and vitamin K antagonist therapy, activation of fibrinolytic pathway, acquired von Willebrand factor deficiency, and tendency to develop small intestinal angiodysplasias due to increased rotary speed of the pump. Gastrointestinal bleeding in LVAD patients remains a source of increased morbidity including the need for blood transfusions, extended hospital stays, multiple readmissions, and overall mortality. Management of gastrointestinal bleeding in LVAD patients involves multidisciplinary approach in stabilizing the patients, addressing risk factors and performing structured endoluminal evaluation with focus on upper gastrointestinal tract including jejunum to find and eradicate culprit lesion. Medical and procedural intervention is largely successful and universal bleeding cessation occurs in transplanted patients. PMID- 28652650 TI - Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease. AB - The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress. PMID- 28652653 TI - Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis. AB - AIM: To determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis. METHODS: Hepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1alpha) was determined by Western blotting. RESULTS: Treatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1alpha levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1alpha protein levels. CONCLUSION: The combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a potential new treatment strategy. PMID- 28652651 TI - Molecular mimicry in Helicobacter pylori infections. AB - Gram-negative bacteria Helicobacter pylori (H. pylori) colonize gastric mucosa in humans and increase the risk of serious diseases such as gastric and duodenal ulcers, stomach cancers and mucosa associated lymphoid tissue lymphoma. The role of H. pylori infection in the pathogenesis of several extragastric diseases has been suggested including immune thrombocytopenic purpura, iron deficiency anemia, vitamin D deficiency, cardiovascular diseases, diabetes mellitus and dermatological disorders. Also neurological diseases and even lung cancer have attracted researchers concern. The relation between H. pylori infection and a growth retardation in children has also been suggested. Many mechanisms of molecular mimicry between H. pylori and the host have been proposed as a pathogen strategy to manipulate the immune system of the host in order to remain unrecognized and avoid eradication. A lot of effort has been put into the demonstration of homologous sequences between H. pylori and host compounds. However, knowledge about how often autoantibodies or autoreactive T lymphocytes induced during H. pylori infections cause pathological disorders is insufficient. This review provides data on H. pylori antigenic mimicry and possible deleterious effects due to the induction of immune response to the components common to these bacteria and the host. PMID- 28652654 TI - Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells. AB - AIM: To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment. METHODS: As most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators. Here, cells were treated with PLK inhibitor BI6727 (Volasertib), Cisplatin, and in combination of both compounds. Cell viability was assessed by MTT; apoptosis was measured by DAPI staining and caspase-3/-7 assay. Western blot and qRT-PCR were used to measure expression levels of apoptosis-related molecules Bax and Bcl-2. RESULTS: The cell viability in the CCA cell lines KMCH-1 and Mz-Ch 1 was reduced in all treatment conditions compared to vehicle-treated cells. Co treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment. Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1. Moreover, PLK inhibition decreases protein levels of Bcl-2; an effect that can be reversed by the proteasomal degradation inhibitor MG-132. In contrast, protein levels of Bax were not found to be altered by PLK inhibition. These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by cotreatment with BI6727. CONCLUSION: In conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect. PMID- 28652652 TI - Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. AB - Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review. PMID- 28652655 TI - Effect of CXCR3/HO-1 genes modified bone marrow mesenchymal stem cells on small bowel transplant rejection. AB - AIM: To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modified with the HO-1 and CXCR3 genes can augment the inhibitory effect of BMMSCs on small bowel transplant rejection. METHODS: Lewis rat BMMSCs were cultured in vitro. Third-passage BMMSCs were transduced with the CXCR3/HO-1 genes or the HO-1 gene alone. The rats were divided into six groups and rats in the experimental group were pretreated with BMMSCs 7 d prior to small bowel transplant. Six time points (instant, 1 d, 3 d, 7 d, 10 d, and 14 d) (n = 6) were chosen for each group. Hematoxylin-eosin staining was used to observe pathologic rejection, while immunohistochemistry and Western blot were used to detect protein expression. Flow cytometry was used to detect T lymphocytes and enzyme linked immunosorbent assay was used to detect cytokines. RESULTS: The median survival time of BMMSCs from the CXCR3/HO-1 modified group (53 d) was significantly longer than that of the HO-1 modified BMMSCs group (39 d), the BMMSCs group (26 d), and the NS group (control group) (16 d) (P < 0.05). Compared with BMMSCs from the HO-1 modified BMMSCs, BMMSCs, and NS groups, rejection of the small bowel in the CXCR3/HO-1 modified group was significantly reduced, while the weight of transplant recipients was also significantly decreased (P < 0.05). Furthermore, IL-2, IL-6, IL-17, IFN-gamma, and TNF-alpha levels were significantly decreased and the levels of IL-10 and TGF-beta were significantly increased (P < 0.05). CONCLUSION: BMMSCs modified with the CXCR3 and HO-1 genes can abrogate the rejection of transplanted small bowel more effectively and significantly increase the survival time of rats that receive a small bowel transplant. PMID- 28652656 TI - Systemic interleukin-9 in inflammatory bowel disease: Association with mucosal healing in ulcerative colitis. AB - AIM: To evaluate circulating IL9 in inflammatory bowel disease and disease associated anemia/cachexia and assess its potential as a mucosal healing marker. METHODS: Serum IL9 as well as other cytokines (IL1beta, IL6, IL13, IFNgamma, TNFalpha, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP(r) technology. High-sensitive C reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method. RESULTS: Systemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9 19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (rho = 0.32, P = 0.003) and MDAI (rho = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (rho = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (rho = -0.27, P < 0.001). Multiple regression showed IL1beta and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNgamma or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD. CONCLUSION: The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC. PMID- 28652657 TI - Association of keratin 8/18 variants with non-alcoholic fatty liver disease and insulin resistance in Chinese patients: A case-control study. AB - AIM: To test the hypothesis that K8/K18 variants predispose humans to non alcoholic fatty liver disease (NAFLD) progression and its metabolic phenotypes. METHODS: We selected a total of 373 unrelated adult subjects from our Physical Examination Department, including 200 unrelated NAFLD patients and 173 controls of both genders and different ages. Diagnoses of NAFLD were established according to ultrasonic signs of fatty liver. All subjects were tested for population characteristics, lipid profile, liver tests, as well as glucose tests. Genomic DNA was obtained from peripheral blood with a DNeasy Tissue Kit. K8/K18 coding regions were analyzed, including 15 exons and exon-intron boundaries. RESULTS: Among 200 NAFLD patients, 10 (5%) heterozygous carriers of keratin variants were identified. There were 5 amino-acid-altering heterozygous variants and 6 non coding heterozygous variants. One novel amino-acid-altering heterozygous variant (K18 N193S) and three novel non-coding variants were observed (K8 IVS5-9A->G, K8 IVS6+19G->A, K18 T195T). A total of 9 patients had a single variant and 1 patient had compound variants (K18 N193S+K8 IVS3-15C->G). Only one R341H variant was found in the control group (1 of 173, 0.58%). The frequency of keratin variants in NAFLD patients was significantly higher than that in the control group (5% vs 0.58%, P = 0.015). Notably, the keratin variants were significantly associated with insulin resistance (IR) in NAFLD patients (8.86% in NAFLD patients with IR vs 2.5% in NAFLD patients without IR, P = 0.043). CONCLUSION: K8/K18 variants are overrepresented in Chinese NAFLD patients and might accelerate liver fat storage through IR. PMID- 28652658 TI - Barcelona Clinic Liver Cancer outperforms Hong Kong Liver Cancer staging of hepatocellular carcinoma in multiethnic Asians: Real-world perspective. AB - AIM: To compare the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) classification systems when applied to HCC patients from the largest tertiary-level centre in Singapore. METHODS: One thousand two hundred and seventy hepatocellular carcinoma (HCC) patients prospectively enrolled in a tertiary-level centre registry in Singapore since 1988 were studied. Patients were grouped into their respective BCLC and HKLC stages. Data such as demography, aetiology of HCC and type of treatment were collected. Survival data was based on census with the National Registry of Births and Deaths on 31st October 2015. Statistical analyses were done using SPSS version 21 (Chicago, IL, United States). Survival analyses were done by the Kaplan-Meier method. Differences in survival rates were compared using the log-rank test. RESULTS: The median age at presentation was 63 years (range 13-94); male 82.4%; Chinese 89.4%, Malay 7.1%, Indian, 2.8%. Hepatitis B was the predominant aetiology (75.0%; Hepatitis C 7.2%, Hepatitis B and C co-infection 3.8%, non-viral 14.0%). Both BCLC and HKLC staging systems showed good separation with overall log rank test confirming significant survival differences between stages in our cohort (P < 0.001). 206 out of the 240 patients (85.8%) assigned for curative treatment by the BCLC treatment algorithm received curative therapy for HCC [Stage 0 93.2% (68/73); Stage A 82.6% (138/167)]. In contrast, only 341/558 (61.1%) patients received curative treatment despite being assigned for curative treatment by the HKLC treatment algorithm [Stage I 72.7% (264/363); Stage II 40.2% (66/164); Stage Va 35.5% (11/31)]. Patients who were assigned to curative treatment by HKLC but did not receive curative treatment had significantly poorer ECOG (P < 0.001), higher Child-Pugh status (P < 0.001) and were older (median age 66 vs 61, P < 0.001) than those who received curative therapy. Median overall survival in patients assigned to curative treatment groups by BCLC and HKLC were 6.1 and 2.6 years respectively (P < 0.001). When only patients receiving curative treatment were analyzed, BCLC still predicted overall median survival better than HKLC (7.1 years vs 5.5 years, P = 0.037). CONCLUSION: BCLC performs better than HKLC in our multiethnic Asian population in allocating patients to curative treatment in a real-life situation as well as in predicting survival. PMID- 28652659 TI - Single-operator cholangioscopy for biliary complications in liver transplant recipients. AB - AIM: To evaluate cholangioscopy in addition to endoscopic retrograde cholangiopancreatography (ERCP) for management of biliary complications after liver transplantation (LT). METHODS: Twenty-six LT recipients with duct-to-duct biliary reconstruction who underwent ERCP for suspected biliary complications between April and December 2016 at the university hospital of Muenster were consecutively enrolled in this observational study. After evaluating bile ducts using fluoroscopy, cholangioscopy using a modern digital single-operator cholangioscopy system (SpyGlass DSTM) was performed during the same procedure with patients under conscious sedation. All patients received peri-interventional antibiotic prophylaxis and bile was collected during the intervention for microbial analysis and for antibiotic susceptibility testing. RESULTS: Thirty three biliary complications were found in a total of 22 patients, whereas four patients showed normal bile ducts. Anastomotic strictures were evident in 14 (53.8%) patients, non-anastomotic strictures in seven (26.9%), biliary cast in three (11.5%), and stones in six (23.1%). A benefit of cholangioscopy was seen in 12 (46.2%) patients. In four of them, cholangioscopy was crucial for selective guidewire placement prior to planned intervention. In six patients, biliary cast and/or stones failed to be diagnosed by ERCP and were only detectable through cholangioscopy. In one case, a bile duct ulcer due to fungal infection was diagnosed by cholangioscopy. In another case, signs of bile duct inflammation caused by acute cholangitis were evident. One patient developed post interventional cholangitis. No further procedure-related complications occurred. Thirty-seven isolates were found in bile. Sixteen of these were gram-positive (43.2%), 12 (32.4%) were gram-negative bacteria, and Candida species accounted for 24.3% of all isolated microorganisms. Interestingly, only 48.6% of specimens were sensitive to prophylactic antibiotics. CONCLUSION: Single-operator cholangioscopy can provide important diagnostic information, helping endoscopists to plan and perform interventional procedures in LT-related biliary complications. PMID- 28652660 TI - Efficacy and safety of combined directly acting antivirals for treatment of Chinese chronic hepatitis C patients in a real-world setting. AB - AIM: To assess the efficacy and safety of combined directly acting antivirals (DAAs) for the treatment of Chinese chronic hepatitis C (CHC) patients in a real world setting. METHODS: Hospitalized CHC patients who were treated with DAAs at Peking University First Hospital between January 2015 and December 2016 were enrolled. Samples and clinical data were collected at 0 wk, 2 wk, 4 wk, 8 wk, 12 wk, or 24 wk during DAAs treatment and at 4 wk, 12 wk, and 24 wk after the end of treatment. RESULTS: Fifty-four patients who underwent DAAs treatment were included in our study, of whom 83.3% (45/54) achieved rapid virological response at 2 wk after treatment initiation (RVR 2) and 94.4% (51/54) achieved sustained virological response at 24 wk after the end of treatment (SVR 24). Serum creatinine and uric acid levels at the end of treatment were significantly increased compared with baseline levels (83.6 +/- 17.9 vs 88.8 +/- 19.4, P01 < 0.001; 320.8 +/- 76.3 vs 354.5 +/- 87.6, P01 < 0.001), and no significant improvements were observed at 24w after the end of treatment (83.6 +/- 17.9 vs 86.8 +/- 19.1, P02 = 0.039; 320.8 +/- 76.3 vs 345.9 +/- 89.4, P02 = 0.001). The total frequency of adverse events (AEs) during treatment was 33.3% (18/54), with major AEs being fatigue (16.7%), headache (7.4%), anorexia (7.4%), and insomnia (5.6%). CONCLUSION: Though based in a small cohort of patients, the abnormal changes in renal function indices and relative high frequency of AEs during combined DAAs treatment should be taken as a note of caution. PMID- 28652661 TI - Observation of the effect of targeted therapy of 64-slice spiral CT combined with cryoablation for liver cancer. AB - AIM: To observe the effect of targeted therapy with 64-slice spiral computed tomography (CT) combined with cryoablation for liver cancer. METHODS: A total of 124 patients (142 tumors) were enrolled into this study. According to the use of dual-slice spiral CT or 64-slice spiral CT as a guide technology, patients were divided into two groups: dual-slice group (n = 56, 65 tumors) and 64-slice group (n = 8, 77 tumors). All patients were accepted and received targeted therapy by an argon-helium superconducting surgery system. The guided scan times of the two groups was recorded and compared. In the two groups, the lesion ice coverage in diameter of >= 3 cm and < 3 cm were recorded, and freezing effective rate was compared. Hepatic perfusion values [hepatic artery perfusion (HAP), portal vein perfusion (PVP), and the hepatic arterial perfusion index (HAPI)] of tumor tissues, adjacent tissues and normal liver tissues at preoperative and postoperative four weeks in the two groups were compared. Local tumor changes were recorded and efficiency was compared at four weeks post-operation. Adverse events were recorded and compared between the two groups, including fever, pain, frostbite, nausea, vomiting, pleural effusion and abdominal bleeding. RESULTS: Guided scan times in the dual-slice group was longer than that in the 64-slice group (t = 11.445, P = 0.000). The freezing effective rate for tumors < 3 cm in diameter in the dual-slice group (81.58%) was lower than that in the 64-slice group (92.86%) (chi2 = 5.707, P = 0.017). The HAP and HAPI of tumor tissues were lower at four weeks post-treatment than at pre-treatment in both groups (all P < 0.05), and those in the 64-slice group were lower than that in the dual-slice group (all P < 0.05). HAP and PVP were lower and HAPI was higher in tumor adjacent tissues at post-treatment than at pre-treatment (all P < 0.05). Furthermore, the treatment effect and therapeutic efficacy in the dual-slice group were lower than the 64-slice group at four weeks post-treatment (all P < 0.05). Moreover, pleural effusion and intraperitoneal hemorrhage occurred in patients in the dual-slice group, while no complications occurred in the 64-slice group (all P < 0.05). CONCLUSION: 64-slice spiral CT applied with cryoablation in targeted therapy for liver cancer can achieve a safe and effective freezing treatment, so it is worth being used. PMID- 28652662 TI - Inflammatory bowel disease incidence in Czech children: A regional prospective study, 2000-2015. AB - AIM: To examine the incidence and trends in pediatric inflammatory bowel diseases (IBDs) over 2000-2015 and project the incidence to 2018. METHODS: A 16-year prospective study of IBD patients < 19 years of age was conducted in the Czech Republic (the Pilsen region). All incident IBD cases within a well-defined geographical area were retrieved from a prospectively collected computerized clinical database. Historical Czech data were used for comparison (1990-2001). Our catchment population was determined from the census data. We calculated the incidence by relating the number of newly diagnosed cases to the size of the pediatric population-at-risk in each calendar year. Age/sex, disease type, place of residence, and race/ethnicity were identified. RESULTS: In total, 170 new IBD cases [105 Crohn's disease (CD), 48 ulcerative colitis (UC), and 17 IBD unclassified (IBD-U)] were identified. The median age at IBD diagnosis was 14.2 years, 59.4% were males, and 97.1% were Caucasians. A male preponderance of IBD (P = 0.026) and CD (P = 0.016) was observed. With 109209 person-years in the catchment area, the average incidence of IBD per 100000 person-years was 10.0 (6.2 for CD, 2.8 for UC, and 1.0 for IBD-U) for children aged 0 to 19 years; for those aged 0 to 15 years, the incidence rate was 7.3 (4.6 for CD, 2.0 for UC, and 0.7 for IBD-U). An increase in incidence with age was observed (P = 0.0003). Over the 16-year period, the incidence increased for IBD patients (P = 0.01) and CD in particular (P < 0.0001), whereas the incidence for UC (P = 0.09) and IBD-U (P = 0.339) remained unchanged. IBD-projected data from 2016 to 2018 were 12.1, 12.3 and 12.6 per 100000 person-years, respectively. CONCLUSION: Pediatric-onset IBD incidence is around its highest point. The increase, which is particularly pronounced for CD, may be challenging to relate to causes of pediatric disease. PMID- 28652663 TI - Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study. AB - AIM: To analyze 1-year liver injury burden in inflammatory bowel disease (IBD) patients. METHODS: During a 6-mo inclusion period, consecutive IBD cases having a control visit at IBD center were included. Basic demographics, IBD phenotype and IBD treatment were recorded on entry. Aminotransferase (AT) activities of ALT, AST, ALP and gamma-glutamyl transpeptidase (GGT) were measured at baseline, 3 mo prior to study entry and prospectively every 3 mo for 1 year. Liver injury patterns were predefined as: Grade 1 in ALT 1-3 * upper limit of normal (ULN), grade 2 in ALT > 3 * ULN, hepatocellular injury in ALT > 2 * ULN, cholestatic injury in simultaneous GGT and ALP elevation > ULN. Persisting injury was reported when AT elevations were found on > 1 measurement. Risk factors for the patterns of liver injury were identified among demographic parameters, disease phenotype and IBD treatment in univariate and multivariate analysis. Finally, implications for the change in IBD management were evaluated in cases with persisting hepatocellular or cholestatic injury. RESULTS: Two hundred and fifty one patients were included having 917 ALT and 895 ALP and GGT measurements. Over one year, grade 1 injury was found in 66 (26.3%), grade 2 in 5 (2%) and hepatocellular injury in 16 patients (6.4%). Persisting hepatocellular injury was found in 4 cases. Cholestasis appeared in 11 cases (4.4%) and persisted throughout the entire study period in 1 case. In multivariate analysis, hepatocellular injury was associated with BMI (OR = 1.13, 1.02-1.26), liver steatosis (OR = 10.61, 2.22-50.7), IBD duration (1.07, 1.00-1.15) and solo infliximab (OR = 4.57, 1.33-15.7). Cholestatic liver injury was associated with prior intestinal resection (OR = 32.7, 3.18-335), higher CRP (OR = 1.04, 1.00 1.08) and solo azathioprine (OR = 10.27, 1.46-72.3). In one case with transient hepatocellular injury azathioprine dose was decreased. In 4 cases with persisting hepatocellular injury, fatty liver or alcohol were most likely causes and IBD treatment was pursued without change. In the case with persisting cholestatic injury, no signs of portal hypertension were identified and treatment with infliximab continued. CONCLUSION: Liver injury was frequent, mostly transient and rarely changed management. Infliximab or azathioprine were confirmed as its risk factors indicating the need for regular AT monitoring. PMID- 28652664 TI - Can fecal microbiota transplantation cure irritable bowel syndrome? AB - AIM: To verify the utility of treatment with fecal microbiota transplantation (FMT) in patients with irritable bowel syndrome (IBS). METHODS: We searched EMBASE, Cochrane Library and PubMed in March, 2017. The reviewed literature was based on two systematic searches in each of the databases. The MeSH terms used were IBS and fecal microbiota transplantation and the abbreviations IBS and FMT. Reference lists from the articles were reviewed to identify additional pertinent articles. RESULTS: A total of six conference abstracts, one case report, one letter to the editor, and one clinical review were included. In the final analysis, treatment of 48 patients was evaluated. Treatment revealed an improvement in 58% of cases. The varying structure of the nine included studies must be taken into consideration. CONCLUSION: Data on FMT and IBS are too limited to draw sufficient conclusions. Standardized double blinded randomized clinical trials need to be carried out to evaluate the effect of FMT on IBS. PMID- 28652665 TI - Application of novel magnified single balloon enteroscopy for a patient with Cronkhite-Canada syndrome. AB - We present a case of Cronkhite-Canada syndrome (CCS) in which the entire intestine was observed using a prototype of magnifying single-balloon enteroscope (SIF Y-0007, Olympus). CCS is a rare, non-familial gastrointestinal polyposis with ectodermal abnormalities. To our knowledge, this is the first report showing magnified intestinal lesions of CCS. A 73-year-old female visited our hospital with complaints of diarrhea and dysgeusia. The blood test showed mild anemia and hypoalbuminemia. The esophagogastroduodenoscopy and colonoscopy revealed diffuse and reddened sessile to semi-pedunculated polyps, resulting in the diagnosis of CCS. In addition to the findings of conventional balloon-assisted enteroscopy or capsule endoscopy, magnifying observation revealed tiny granular structures, non uniformity of the villus, irregular caliber of the loop-like capillaries, scattered white spots in the villous tip, and patchy redness of the villus. Histologically, the scattered white spots and patchy redness of the villus reflect lymphangiectasia and bleeding to interstitium, respectively. PMID- 28652666 TI - Synchronous triple occurrence of MALT lymphoma, schwannoma, and adenocarcinoma of the stomach. AB - We present a case of a 56-year-old man with 3 synchronous gastric tumors. The patient presented with melena, and 3 gastric abnormalities were detected on gastroduodenoscopic examination, including a small ulcerative lesion in the gastric antrum, a submucosal mass in the gastric body, and severe erosion in the fundus. Histological examination of biopsy samples yielded respective diagnoses of gastric adenocarcinoma, gastritis, and mucosa-associated lymphoid tissue (MALT) lymphoma. The patient first received medication to eradicate any underlying Helicobacter pylori infection, which might have been a cause of the MALT lymphoma. Four weeks later, after examination of repeat biopsy samples revealed that the MALT lymphoma had resolved, the patient underwent subtotal gastrectomy. Further histological examination of resected tissue confirmed the antrum lesion as adenocarcinoma and the body lesion as schwannoma. To our knowledge, this is the first reported case of synchronous triple primary gastric adenocarcinoma, MALT lymphoma, and schwannoma. PMID- 28652667 TI - Is tremor related to celiac disease? AB - Neurological features in celiac disease (CD) are not rare (5%-36%), but tremor is scarcely described. Subjects with CD and healthy controls completed an online survey using WHIGET tremor rating scale. One thousand five hundred and twelve subjects completed the survey, finally 674 CD patients and 290 healthy subjects were included. A higher prevalence of tremor in CD patients was observed in comparison to controls (28% vs 14%, P < 0.001). Frequency of family history of tremor in CD patients with and without tremor was 25% and 20% (P = 0.2), while in the control group it was 41% and 10% (P < 0.001). Controls with tremor showed a higher frequency of family history of tremor when compared to CD patients with tremor (41.5% vs 24.6%, P = 0.03). The results suggested that tremor in CD might be more frequent and possibly related to the disease itself and not due to associated essential tremor. PMID- 28652668 TI - Prevalence and prognostic significance of anemia in patients presenting for ST elevation myocardial infarction in a Tunisian center. AB - BACKGROUND: Anemia on admission is a powerful predictor of major cardiovascular events in patients presenting for acute coronary syndromes. We sought to determine the prevalence and prognostic impact of anemia in patients presenting for ST-elevation myocardial infarction (STEMI). METHODS: We analyzed data from a Tunisian retrospective single center STEMI registry. Patients were enrolled between January 1998 and October 2014. Anemic and nonanemic patients were compared for clinical and prognostic features and according to four prespecified hemoglobin level subgroups. In patients with severe anemia, factors associated with in-hospital death were studied. RESULTS: A total of 1498 patients were enrolled. Mean age was 60.47 +/- 12.7 years and prevalence of anemia was 36.6%. Anemic patients were more likely to be elderly, hypertensive, and diabetic in comparison to nonanemic patients. In-hospital mortality was significantly higher in anemic patients (14.9% vs. 5%, p < 0.001). Lower hemoglobin levels were significantly associated with a higher prevalence of heart failure on admission, cardiogenic shock, and in-hospital mortality (p < 0.001 for all). In univariate analysis, factors associated with in-hospital death in patients with severe anemia were hypertension (p = 0.044), heart failure on admission (p < 0.001), renal failure on admission (p < 0.001), and primary percutaneous coronary intervention (pPCI) use (p = 0.016). The absence of pPCI use was independently associated with in-hospital death in multivariate analysis (odds ratio = 2.22, 95% confidence interval: 1.07-4.76, p = 0.033). CONCLUSION: According to this study, anemic patients presenting for STEMI have a higher in-hospital mortality rate. The absence of pPCI use was independently associated with in-hospital death. PMID- 28652669 TI - Early postoperative paravalvular leak among Egyptian population: An observational study. AB - OBJECTIVES: Several reports described the incidence of postoperative paravalvular leakage (PVL) early after valve replacement surgery, however, there is a paucity of data regarding the outcomes and complications correlated to the severity of PVL. The aim of the current study was to evaluate the incidence, causes, and short term outcome of early postoperative PVL. METHODS: Data were collected from patients presenting to the cardiovascular department at Cairo University Hospital for aortic and/or mitral valve replacement surgery from May 2014 to May 2015. Transthoracic echocardiography (TTE) was done for all patients early postoperative. Transesophageal echocardiography (TEE) was done if diagnosis was not confirmed by TTE. All patients with detected PVL were subjected to TTE and TEE after a 3 month follow-up period. RESULTS: Two hundred patients were enrolled in the study. Seventy five percent of patients were known to have rheumatic heart disease, while 16.5% had infective endocarditis. The mitral valve was replaced in 40% of patients, the aortic valve was replaced in 36%, and other patients had both valves replaced. Early postoperative period PVL was detected in 25 patients. The most common underlying etiologies were rheumatic heart disease and infective endocarditis. PVL was common in patients with both valves replaced compared with either mitral or aortic valve replacement. Infective endocarditis as underlying valve disease was significantly high in patients with PVL compared with those without (p < 0.001). CONCLUSION: The incidence of PVL was high in patients with both valves replaced compared with either mitral or aortic valve replacement. Moreover, every patient with PVL should be properly investigated for infective endocarditis. Surgical intervention, although associated with high morbidity and mortality, reduces PVL recurrence. PMID- 28652670 TI - Satisfaction with and adherence to warfarin treatment: A cross-sectional study among Sudanese patients. AB - BACKGROUND: Satisfaction with and adherence to oral anticoagulant treatment are important measures that decrease morbidity and mortality. Higher satisfaction and adherence to warfarin therapy was found to be associated among other factors with good International Normalized Ratio (INR) control. OBJECTIVES: To assess patient satisfaction with and adherence to oral anticoagulant therapy and to identify predictors of the two studied domains. METHODS: A cross-sectional study was conducted at the Cardiothoracic Clinic in Alshaab Teaching Hospital; Khartoum; Sudan during March-April 2015. A representative sample of patients on oral anticoagulant treatment was recruited. Data was collected through face-to-face interview method using oral Anti-Clot Treatment Scale (ATCS) to measure satisfaction and the 4-items Morisky Scale to measure adherence to therapy. Data was processed using SPSS. Logistic regression analysis was performed. P value <0.05 was considered statistically significant. RESULTS: A total of 93 patients was included, of them 46 were males. Overall, 47 (50.5%) were classified as satisfied with anti-clot treatment. Patients attained secondary and above educational level were approximately 8 times more satisfied with their anti-clot treatment, compared to those educated below this level, [OR 7.9 (2.9-21.7), P < 0.001]. Similarly, patients currently working were found to be approximately 3 times more satisfied with warfarin therapy, compared those who had no jobs, [OR 2.9 (1.1-7.6), P = 0.035]. Overall, 5.4% of the patients were found to be adherent to warfarin therapy. No definite background characteristic variable was found to be associated with adherence to treatment. No association was found between patient satisfaction and adherence to treatment, (P = 0.490). CONCLUSIONS: Ensuring health education on warfarin together with continuous patients motivation are needed, specifically among patients with low educational level. Efficient multidisciplinary effort from all healthcare providers is needed to make warfarin treatment more successful. PMID- 28652671 TI - Aortic velocity propagation: A novel echocardiographic method in predicting atherosclerotic coronary artery disease burden. AB - BACKGROUND: The major burden of cardiovascular disease mortality around the globe is due to atherosclerosis and its complications. Hence its early detection and management with easily accessible and noninvasive methods are valuable. Aortic velocity propagation (AVP) through color M-mode of the proximal descending aorta determines aortic stiffness, reflecting atherosclerosis. The aim of this study was to find the utility of AVP in predicting coronary artery disease (CAD) burden assessed through SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) score and compared with carotid intima-media thickness (CIMT), which is an established surrogate marker of atherosclerosis. METHODS: In this cross-sectional comparative study, we measured AVP by color M-mode and CIMT by using Philips QLAB-IMT software in 100 patients, who underwent conventional coronary angiogram (CAG) between May 2013 and November 2014. Coronary artery disease is considered significant if >50% diameter stenosis is present in any epicardial coronary artery and insignificant if otherwise. RESULTS: Initially, to know the normal range we measured AVP and CIMT in 50 patients without any major risk factors for CAD but CAG was not done. Aortic velocity propagation ranged from 46 cm/s to 76 cm/s (mean = 58.62 +/- 6.46 cm/s), CIMT ranged from 0.50 mm to 0.64 mm (mean = 0.55 +/- 0.03 mm). Among 100 patients who underwent CAG we found 69% had significant CAD, 13% had insignificant CAD, and 18% had normal coronaries. Those with significant CAD had significantly lower AVP (41.65 +/- 4.94 cm/s) [F (2,97) = 44.05, p < 0.0001] and significantly higher CIMT (0.86 +/- 0.11 mm) [F (2,97) =35.78, p < 0.0001]. AVP had significant strong negative correlation with CIMT (r = -0.836, p < 0.0001, n = 100) and SYNTAX score (r = 0.803, p < 0.0001, n = 69), while CIMT was positively correlated with SYNTAX score significantly (r = 0.828, p < 0.0001, n = 69). CONCLUSIONS: AVP and CIMT can predict CAD burden in a robust way. AVP may emerge as an exquisite bedside tool to predict atherosclerotic burden and guide in implementing preventive therapy for cardiovascular disease. PMID- 28652672 TI - Independent predictors of developing pulmonary hypertension in heart failure with reduced versus preserved ejection fraction. AB - OBJECTIVES: To investigate the different clinical and echocardiographic predictors of evolving PH in patients with heart failure with and without reduced ejection fraction. METHODS AND RESULTS: The study included 153 heart failure patients with reduced ejection fraction (HFrEF) (n = 89) and preserved ejection fraction (HFpEF) (n = 64) both of which were subdivided into 2 subgroups according to the presence of PH. All patients were subjected to detailed clinical assessment and full transthoracic echocardiogram. There were significant differences between the 2 HFrEF subgroups regarding systolic BP, presence of diabetes, dyslipidemia, diuretics usage, all LV parameters, LAD, LAV and LAV indexed to BSA, E/A ratio, DT and severity of TR. Using multivariate analysis, the presence of diabetes (P = 0.04), diuretics usage (P = 0.04), LAV (P = 0.007) and TR grade (P < 0.001) were significant independent predictors for the development of PH among HFrEF patients. There were significant differences between the 2 HFpEF subgroups regarding presence of hypertension, diuretics usage, LAD, LAA, TR severity. Using multivariate analysis, only diuretics usage (P = 0.02) and TR grade (P < 0.0001) were significant independent predictors for the development of PH among HFpEF patients. CONCLUSION: Neither the decrease in EF among HFrEF patients nor the DD grade in HFpEF patients act as independent predictor for evolving PH. Common independent predictors for evolving PH in both HFrEF and HFpEF patients are TR grade and use of diuretics. Other independent predictors in HFrEF and not HFpEF patients are the presence of diabetes and increased LAV. PMID- 28652673 TI - Cardiovascular risk factors in Middle Eastern patients undergoing percutaneous coronary intervention: Results from the first Jordanian percutaneous coronary intervention study. AB - : Background and aims: Cardiovascular disease (CVD) is the leading cause of death in the Middle East. We sought to study the prevalence and coexistence of 6 cardiovascular risk factors (RFs) among patients who underwent percutaneous coronary intervention (PCI), and to evaluate the impact of age and gender on the presence of multiple RFs. METHODS AND RESULTS: In this prospective, multicenter study, 2426 consecutive patients were enrolled. Mean age was 59.0 +/- 10.1 years and 500 (20.6%) were women. Acute coronary syndrome and stable coronary disease were the indications for PCI in 77.1% and 22.9%, respectively. Hypertension was present in 62.3%, diabetes in 53.8%, hypercholesterolemia in 48.8%, smoking in 43.5%, family history of premature CVD 39.4% and obesity in 28.8%. Only 3.8% did not have any of these RFs. Presence of ?3 and ?4 RFS was observed in 57.4% and 29.5% of patients, respectively. Presence of ?3 RFs was more common in women than men (69.0% vs. 54.5%, p < 0.0001), and among patients 41-65 years of age than older or younger patients (60.1% vs. 52.0% vs. 48.3%, respectively, p = 0.017). Conclusions: Cardiovascular RFs are highly prevalent in this PCI Middle Eastern population undergoing PCI. More than half and more than one-fourth of the patients had at least 3 or 4 RFs; respectively. More women than men and more middle aged patients than older or younger patients had significantly higher rates of presence of multiple RFs. PMID- 28652675 TI - Eosinophilic myocarditis and hypereosinophilic syndrome. AB - Hypereosinophilic syndrome (HES) is a heterogeneous group of hematological disorders characterized by a chronic, unexplained hypereosinophilia with tissue damage. Cardiac involvement occurs in ~20% of patients with HES and represents a major turning point. Cardiac injuries related to eosinophilia are divided into three chronological phases: eosinophilic infiltration, thrombosis, and fibrosis. We report a case of a 33-year-old woman diagnosed with HES, with pulmonary and gastrointestinal involvement and eosinophilic myocarditis in cardiogenic shock. The evolution was favorable with dobutamine, anticoagulation, corticosteroids, and later, beta-blockers and angiotensin-converting enzyme inhibitors. Cardiac involvement in HES is rare but carries a poor prognosis. Corticosteroids are considered by many to be the mainstay of treatment. Although new treatments have been suggested, only a few seem promising. PMID- 28652674 TI - Evolution of ventricular outpouching through the fetal and postnatal periods: Unabating dilemma of serial observation or surgical correction. AB - Ventricular outpouching is a rare finding in prenatal sonography and the main differential diagnoses are diverticulum, aneurysm, and pseudoaneurysm in addition to congenital cysts and clefts. The various modes of fetal presentation of congenital ventricular outpouching include an abnormal four-chamber view on fetal two-dimensional echocardiogram, fetal arrhythmia, fetal hydrops, and pericardial effusion. Left ventricular aneurysm (LVA)/nonapical diverticula are usually isolated defects. Apical diverticula are always associated with midline thoracoabdominal defects (epigastric pulsating diverticulum or large omphalocele) and other structural malformations of the heart. Most patients with LVA/congenital ventricular diverticulum remain clinically asymptomatic but they can potentially give rise to complications such as ventricular tachyarrhythmias, systemic embolism, sudden death, spontaneous rupture, and severe valvular regurgitation. The treatment of asymptomatic LVA and isolated congenital ventricular diverticulum is still undefined. In this review, our aim is to outline a systematic approach to a fetus detected with ventricular outpouching. Starting with prevalence and its types, issues in fetal management, natural course and evolution postbirth, and finally the perpetual dilemma of serial observation or surgical correction is discussed. PMID- 28652676 TI - Utility of cardiac magnetic resonance in recurrent myocarditis. AB - We report a 26-year-old man who presented to the emergency department four times within a 4-year period with recurrent myocarditis. His presentations were characterized by chest pain, elevated troponin I, and normal coronary angiography. Endomyocardial biopsy showed nonspecific inflammatory process. Laboratory workup including viral screening and autoimmune markers were negative. Cardiac magnetic resonance imaging showed evidence of recurrent myocarditis with progressive appearance of new areas of myocardial delayed enhancement seen in each admission. PMID- 28652677 TI - Anomalous origin of circumflex coronary artery from right pulmonary artery associated with atrial septal defect. AB - We describe a 4-year-old girl with anomalous origin of the left circumflex coronary artery from the right pulmonary artery and large atrial septal defect. This is the first reported case of such association. Surgical reimplantation of the anomalous left circumflex coronary artery to the aorta and atrial septal defect surgical closure was performed, with no postoperative complications. PMID- 28652678 TI - Pectus excavatum: Right ventricular compromise with orthostatic syndrome and Brugada phenocopy. AB - Pectus excavatum (PEXT) consists of an overgrowth of the chondral region with posterior displacement of the inferior part of the sternum, resulting in a concave chest deformity. Characteristic clinical and imaging findings may occur, depending on the compression that right cardiac chambers suffer, when squeezed between the sternum and the column vertebrae. PMID- 28652679 TI - Contrast-induced thrombocytopenia following percutaneous coronary intervention. AB - Contrast-induced thrombocytopenia is a rare complication distinguished by acute and severe platelet consumption, with spontaneous recovery within days. We describe a case of acute thrombocytopenia 6 hours after coronary angioplasty in a patient with a negative antiplatelet factor 4 test. The count reached 1 * 103/uL, but improved spontaneously to 210 * 103/uL after 8 days. In conclusion, physicians should be aware of this complication, particularly when dual antiplatelet therapy is being considered. PMID- 28652680 TI - Giant aortic pseudoaneurysm following prosthetic aortic root substitution. PMID- 28652681 TI - Recurrent takotsubo syndrome with long QTc and torsade de pointes : Can cellular phone-based acquisition/transmission of electrocardiogram be of value? PMID- 28652682 TI - Assessing Model Selection Uncertainty Using a Bootstrap Approach: An update. AB - Model comparisons in the behavioral sciences often aim at selecting the model that best describes the structure in the population. Model selection is usually based on fit indices such as AIC or BIC, and inference is done based on the selected best-fitting model. This practice does not account for the possibility that due to sampling variability, a different model might be selected as the preferred model in a new sample from the same population. A previous study illustrated a bootstrap approach to gauge this model selection uncertainty using two empirical examples. The current study consists of a series of simulations to assess the utility of the proposed bootstrap approach in multi-group and mixture model comparisons. These simulations show that bootstrap selection rates can provide additional information over and above simply relying on the size of AIC and BIC differences in a given sample. PMID- 28652683 TI - The linear stability of Hunt-Rayleigh-Benard flow. AB - The stability of a pressure driven flow in a duct heated from below and subjected to a vertical magnetic field (Hunt-Rayleigh-Benard flow) is studied. We use the Chebyshev collocation approach to solve the eigenvalue problem for the small amplitude perturbations. It is demonstrated that the magnetic field can stabilize the flow, while the temperature field can disturb the flow. There exists a threshold for the Hartmann number below which the growth rate changes with the Prandtl number non-monotonously (first increases and then decreases) with a critical Prandtl number for the maximum growth rate. By comparing the [Formula: see text] neutral curves at different Rayleigh numbers, we find that the critical Reynolds number decreases with the increase in the Rayleigh number, which has an obvious influence on the long-wave instability and a little influence on the short-wave instability. The dominant mode of the long-wave instability changes from the boundary layer instability to the inflectional instability with the increase in the growth rate, which forms a new flow map. We also compare the [Formula: see text] curves and find that the critical Rayleigh number decreases with the increase in the Reynolds number. The obtained results gain an insight into the flow stability affected by the temperature field and the magnetic field. PMID- 28652685 TI - Numerical analysis of ion temperature effects to the plasma wall transition using a one-dimensional two-fluid model. I. Finite Debye to ionization length ratio. AB - A one-dimensional, two-fluid, steady state model is used for the analysis of ion temperature effects to the plasma-wall transition. In this paper, the model is solved for a finite ratio epsilon between the Debye and the ionization length, while in Part II [T. Gyergyek and J. Kovacic, Phys Plasmas 24, 063506 (2017)], the solutions for [Formula: see text] are presented. Ion temperature is treated as a given, independent parameter and it is included in the model as a boundary condition. It is shown that when the ion temperature larger than zero is selected, the ion flow velocity and the electric field at the boundary must be consistent with the selected ion temperature. A numerical procedure, how to determine such "consistent boundary conditions," is proposed, and a simple relation between the ion temperature and ion velocity at the boundary of the system is found. The effects of the ion temperature to the pre-sheath length, potential, ion temperature, and ion density drops in the pre-sheath and in the sheath are investigated. It is concluded that larger ion temperature results in a better shielding of the plasma from the wall. An attempt is made to include the ion heat flux qi into the model in its simplest form [Formula: see text], where [Formula: see text] is a constant heat conduction coefficient. It is shown that inclusion of such a term into the energy transfer equation introduces an additional ion heating mechanism into the system and the ion flow then becomes isothermal instead of adiabatic even in the sheath. PMID- 28652686 TI - Pragmatic Failure and Referential Ambiguity when Attorneys Ask Child Witnesses "Do You Know/Remember" Questions. AB - "Do you know" and "Do you remember" (DYK/R) questions explicitly ask whether one knows or remembers some information while implicitly asking for that information. This study examined how 104 4- to 9-year-old children testifying in child sexual abuse cases responded to DYK/R wh- and yes/no questions. When asked DYK/R questions containing an implicit wh- question requesting information, children often provided unelaborated "Yes" responses. Attorneys' follow-up questions suggested that children usually misunderstood the pragmatics of the questions. When DYK/R questions contained an implicit yes/no question, unelaborated "Yes" or "No" responses could be responding to the explicit or the implicit questions resulting in referentially ambiguous responses. Children often provided referentially ambiguous responses and attorneys usually failed to disambiguate children's answers. Although pragmatic failure following DYK/R wh- questions decreased with age, the likelihood of referential ambiguity following DYK/R yes/no questions did not. The results highlight the risks of serious miscommunications caused by pragmatic misunderstanding and referential ambiguity when children testify. PMID- 28652687 TI - Towards a generalized energy prediction model for machine tools. AB - Energy prediction of machine tools can deliver many advantages to a manufacturing enterprise, ranging from energy-efficient process planning to machine tool monitoring. Physics-based, energy prediction models have been proposed in the past to understand the energy usage pattern of a machine tool. However, uncertainties in both the machine and the operating environment make it difficult to predict the energy consumption of the target machine reliably. Taking advantage of the opportunity to collect extensive, contextual, energy-consumption data, we discuss a data-driven approach to develop an energy prediction model of a machine tool in this paper. First, we present a methodology that can efficiently and effectively collect and process data extracted from a machine tool and its sensors. We then present a data-driven model that can be used to predict the energy consumption of the machine tool for machining a generic part. Specifically, we use Gaussian Process (GP) Regression, a non-parametric machine learning technique, to develop the prediction model. The energy prediction model is then generalized over multiple process parameters and operations. Finally, we apply this generalized model with a method to assess uncertainty intervals to predict the energy consumed to machine any part using a Mori Seiki NVD1500 machine tool. Furthermore, the same model can be used during process planning to optimize the energy-efficiency of a machining process. PMID- 28652684 TI - Laser-plasmas in the relativistic-transparency regime: Science and applications. AB - Laser-plasma interactions in the novel regime of relativistically induced transparency (RIT) have been harnessed to generate intense ion beams efficiently with average energies exceeding 10 MeV/nucleon (>100 MeV for protons) at "table top" scales in experiments at the LANL Trident Laser. By further optimization of the laser and target, the RIT regime has been extended into a self-organized plasma mode. This mode yields an ion beam with much narrower energy spread while maintaining high ion energy and conversion efficiency. This mode involves self generation of persistent high magnetic fields (~104 T, according to particle-in cell simulations of the experiments) at the rear-side of the plasma. These magnetic fields trap the laser-heated multi-MeV electrons, which generate a high localized electrostatic field (~0.1 T V/m). After the laser exits the plasma, this electric field acts on a highly structured ion-beam distribution in phase space to reduce the energy spread, thus separating acceleration and energy-spread reduction. Thus, ion beams with narrow energy peaks at up to 18 MeV/nucleon are generated reproducibly with high efficiency (~5%). The experimental demonstration has been done with 0.12 PW, high-contrast, 0.6 ps Gaussian 1.053 MUm laser pulses irradiating planar foils up to 250 nm thick at 2-8 * 1020 W/cm2. These ion beams with co-propagating electrons have been used on Trident for uniform volumetric isochoric heating to generate and study warm-dense matter at high densities. These beam plasmas have been directed also at a thick Ta disk to generate a directed, intense point-like Bremsstrahlung source of photons peaked at ~2 MeV and used it for point projection radiography of thick high density objects. In addition, prior work on the intense neutron beam driven by an intense deuterium beam generated in the RIT regime has been extended. Neutron spectral control by means of a flexible converter-disk design has been demonstrated, and the neutron beam has been used for point-projection imaging of thick objects. The plans and prospects for further improvements and applications are also discussed. PMID- 28652688 TI - Influence of Graphene Oxide Supports on Solution-Phase Catalysis of Thiolate Protected Palladium Nanoparticles in Water. AB - The influence of graphene oxide supports and thiolate surface ligands on the catalytic activity of colloidal Pd nanoparticles for alkyne hydrogenation in water is investigated. The studies show that unsupported, water-soluble thiolate capped Pd nanoparticle catalysts favor the semi-hydrogenation over full hydrogenation of dimethyl acetylene dicarboxylate (DMAD) under the atmospheric pressure and at room temperature. Pd nanoparticles supported on graphene oxide exhibit a similar activity for the hydrogenation of DMAD, but they show an improved long-term colloidal stability in aqueous solution after multiple catalytic cycles. After the heat treatment of Pd nanoparticles supported on graphene oxide at 300 degrees C, these heated hybrids exhibit an enhanced catalytic activity towards the full-hydrogenation. Overall, the studies suggest some influences of graphene oxide supports on the stability and thiolate surface ligands on the activity and selectivity of Pd nanoparticle catalysts. PMID- 28652689 TI - Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: results of an open label observational study. AB - BACKGROUND: Efficacy, tolerability and safety of the novel preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% (Taptiqom(r)) were investigated in an observational study in Germany. OBJECTIVE: To assess efficacy, tolerability and safety of the preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% in a real-life setting. METHODS: Intraocular pressure (IOP) was recorded for each eye at baseline (any previous therapy or untreated) and 4 16 weeks after changing medical treatment to or initiating treatment with the preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5%. Change in IOP was evaluated over the study period for all patients and for specific pretreatment subgroups. Clinical signs such as conjunctival hyperemia and lid parallel conjunctival folds (LIPCOF) were recorded using standardized comparative photographs. Corneal staining, subjective symptoms and local comfort were measured using a four-step scale. All adverse events were recorded. RESULTS: Among 1,157 patients enrolled, 1,075 patients were treated with the preservative free fixed combination as the only medication at the final visit. Medical treatment was initiated in 741 patients because of an insufficient IOP-lowering effect of the prior medication. In 343 patients, medication was changed because of tolerability issues. The preservative-free fixed combination lowered IOP significantly in the subgroup of naive patients, all subgroups with prior monotherapy and patients with prior fixed combinations: naive patients: -8.9 mmHg, alpha- 2-agonists: -6.4 mmHg, beta-blockers: -5.7 mmHg, carbonic anhydrase inhibitors: -5.2 mmHg, prostaglandins: -4.7 mmHg, fixed-combination prostaglandins/timolol: -2.4 mmHg. At the final visit, clinical signs and subjective symptoms were improved in patients with prior medical therapy. Local comfort was rated as "very good" or "good" by 89.1% of patients at the final visit. Only few adverse events occurred during the treatment period. CONCLUSION: The preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% was effective, well tolerated and showed a good safety profile. PMID- 28652690 TI - Combined resection-recession versus combined recession-retroequatorial myopexy of medial rectus muscles for treatment of near-distance disparity Esotropia. AB - PURPOSE: To compare and evaluate the efficacy of two different surgical techniques for the treatment of near-distance disparity esotropia; combined resection-recession and recession-retroequatorial myopexy of medial rectus muscles. PATIENTS AND METHODS: This prospective study included 28 patients diagnosed with convergence excess esotropia who had worn their full cycloplegic refraction and/or bifocal glasses for at least 6 months and still had near distance disparity esotropia. The patients were divided into 2 groups; Group I underwent combined bimedial rectus muscles resection 2.5 mm from the insertion end with recession based on near-angle esotropia according to current surgical tables with 1 mm add of recession for each muscle, while Group II underwent bimedial recession based on far angle combined with retroequatorial myopexy at 13 14 mm from insertion. A satisfactory result was defined as orthophoria or esotropia <10 prism diopters (Delta) at near and distance with reduction of the near-distance disparity to <10 Delta. The patients were followed up for at least 2 years for stability of correction and late onset consecutive exotropia. RESULTS: In Group I, all the patients had satisfactory alignments at near and far with residual near-far disparity #10 Delta, no cases of overcorrection at far was reported; while in Group II, all cases had orthophoria at far, but 4 cases (28.6%) showed near-far disparity >10 Delta. CONCLUSION: The technique of combined resection-recession is safe, easy and more effective in the treatment of near-distance disparity esotropia regardless of the level of accommodative convergence/accommodation ratio, with stability of results though longer follow up period is still needed. PMID- 28652691 TI - A quality of life study comparing scleral buckle and pneumatic retinopexy for the treatment of rhegmatogenous retinal detachment. PMID- 28652692 TI - Combined 30-degree bevel up and down technique against 0-degree phaco tip for phacoemulsification surgery of hard cataracts. AB - PURPOSE: To evaluate the effective phaco time (EPT), cumulative dissipated energy (CDE) and nucleus emulsification time (NET) as phaco parameters with 0- and 30 degree phaco tip. PATIENTS AND METHODS: This prospective, interventional and observational case series included 294 patients scheduled for cataract removal by phacoemulsification technique. Patients with nuclear cataracts of grade 4 and 5 nuclear opalescence of Lens Opacities Classification System III were included in the study. Patients were consecutively allocated to phaco chop technique with 0 degree (0-degree group, n=147) and combined bevel up and down position using 30 degree phaco tip (combined bevel up/down group, n=147). The 0-degree group had phacoemulsification with 0-degree phaco tip, while the 30-degree group had chopping of the nucleus with bevel down phaco tip and emulsification of nuclear fragments was accomplished with bevel up tip. EPT, CDE, NET and intraoperative complications were noted and compared between the groups using analysis of variance. RESULTS: Average EPT, CDE and NET were lower in the 30-degree group than in the 0-degree group. However, no statistically significant difference was found in EPT (P=0.0733), CDE (P=0.0663) and NET (P=0.0633) between the two groups. No serious intraoperative complications were noted. The anterior chamber was maintained throughout the procedure in both groups. No patients had wound burn and miosis during the procedure. None of the patients developed bullous keratopathy, uveitis and cystoid macular edema during the follow-up period. CONCLUSION: Combined bevel up and down 30-degree tip can yield effective hard nucleus phacoemulsification. Bevel down tip of 30-degree helps in effective chopping and bevel up tip assists in emulsification of the nuclear fragments. Although combined bevel up and down 30-degree tip can yield effective hard nucleus phacoemulsification, no statistically significant difference was found in EPT, CDE and NET between the two groups. PMID- 28652693 TI - Trifocal intraocular lenses: a comparison of the visual performance and quality of vision provided by two different lens designs. AB - PURPOSE: To compare two different diffractive trifocal intraocular lens (IOL) designs, evaluating longer-term refractive outcomes, visual acuity (VA) at various distances, low contrast VA and quality of vision. PATIENTS AND METHODS: Patients with binocularly implanted trifocal IOLs of two different designs (FineVision [FV] and Panoptix [PX]) were evaluated 6 months to 2 years after surgery. Best distance-corrected and uncorrected VA were tested at distance (4 m), intermediate (80 and 60 cm) and near (40 cm). A binocular defocus curve was collected with the subject's best distance correction in place. The preferred reading distance was determined along with the VA at that distance. Low contrast VA at distance was also measured. Quality of vision was measured with the National Eye Institute Visual Function Questionnaire near subset and the Quality of Vision questionnaire. RESULTS: Thirty subjects in each group were successfully recruited. The binocular defocus curves differed only at vergences of -1.0 D (FV better, P=0.02), -1.5 and -2.00 D (PX better, P<0.01 for both). Best distance corrected and uncorrected binocular vision were significantly better for the PX lens at 60 cm (P<0.01) with no significant differences at other distances. The preferred reading distance was between 42 and 43 cm for both lenses, with the VA at the preferred reading distance slightly better with the PX lens (P=0.04). There were no statistically significant differences by lens for low contrast VA (P=0.1) or for quality of vision measures (P>0.3). CONCLUSION: Both trifocal lenses provided excellent distance, intermediate and near vision, but several measures indicated that the PX lens provided better intermediate vision at 60 cm. This may be important to users of tablets and other handheld devices. Quality of vision appeared similar between the two lens designs. PMID- 28652694 TI - Pooled analysis of two studies evaluating efficacy and safety of olopatadine hydrochloride 0.77% in patients with allergic conjunctivitis. AB - PURPOSE: Two individual phase 3 conjunctival allergen challenge (CAC) studies of similar design have assessed the efficacy and safety of olopatadine hydrochloride (HCl) 0.77% for the treatment of allergic conjunctivitis. The purpose of this study is to evaluate the integrated efficacy and safety of olopatadine HCl 0.77% from a larger dataset by pooling data from the two individual CAC studies. METHODS: Data were pooled from two phase 3, randomized, multicenter, double masked, active- and vehicle-controlled CAC studies. The primary comparison was on ocular itching scores between olopatadine HCl 0.77% versus vehicle (at onset and 24 hours) and olopatadine HCl 0.77% versus olopatadine 0.2% (at 24 hours). Additional end points included conjunctival redness, total redness, and proportion of itching responders at onset and 24-hour duration of CAC. For both primary and secondary analysis, mixed model repeated measures analysis was used, except for proportion of ocular itching responders. Sensitivity analyses were carried out using a two-sample t-test. RESULTS: This analysis included 448 patients. Olopatadine HCl 0.77% was superior to vehicle (P<0.0001) at onset and 24-hour duration of action (difference in means: -1.14 to -1.52) and to olopatadine 0.2% (P=0.0009) at 24-hour duration of action in relieving ocular itch. Additionally, olopatadine HCl 0.77% substantially reduced conjunctival redness and total redness over vehicle and olopatadine 0.2% at onset and 24-hour duration of action. At 24 hours CAC, there were a higher proportion of itching responders with olopatadine HCl 0.77% compared to vehicle or olopatadine 0.2% (difference in proportion of responders: 43.17%, P<0.0001, and 17.25%, P=0.0012, respectively). No safety concerns were identified. CONCLUSION: This analysis confirms the findings from the individual studies. The rapid onset and prolonged duration of action (for 24 hours) of olopatadine HCl 0.77% supports once-daily dosing in the treatment of allergic conjunctivitis. PMID- 28652695 TI - Patient adherence to the face-down positioning after macular hole surgery. AB - PURPOSE: To determine adherence to face-down positioning (FDP) among patients who underwent vitrectomy and gas tamponade for macular hole (MH) repair. METHOD: A total of 69 patients (37 females and 32 males) who underwent primary vitrectomy for MH repair were studied. Nurses recorded whether the patient complied with FDP each time they examined the patient. FDP score was obtained from the nursing records; patients were given a score of 1 if they complied with the FDP and 0 if they did not. The score was recorded four times per day for the first 3 postoperative days. A perfect FDP score was 12. RESULTS: The mean +/- standard deviation of the FDP scores was 10.6+/-1.8 (range: 4-12). Overall, 32 (46.4%) patients scored a perfect 12, and 7 (10.1%) patients scored <8. Failure of the MH closure was observed in only one patient (1.4%), who showed the poorest adherence to FDP (score =4). Consequently, the closure rate in patients with FDP score <7 (2/3, 66.7%) was significantly lower than in patients with an FDP score >=7 (66/66, 100%) (P<0.05, Fisher's exact probability test). CONCLUSION: While adherence to FDP after MH surgery was better than that observed after vitrectomy for rhegmatogenous retinal detachments in our previous study, the percentage of patients with FDP scores <8 did not differ. Statistically, the poor adherence to FDP can negatively impact the effectiveness of the surgery for MH repair. PMID- 28652696 TI - No improvement in injection frequency or in visual outcome over time in two cohorts of patients from the same Swedish county treated for wet age-related macular degeneration. AB - BACKGROUND: Although ranibizumab has been used for the treatment of wet age related macular degeneration (AMD) since 2007, real-world studies still report undertreatment resulting in a less favorable visual outcome. In this study, two different time cohorts of patients treated with ranibizumab for wet AMD in routine care were analyzed to observe whether there was a change over time regarding visual outcome, injection frequency, and quality of life (QoL). METHODS: We compared patients with treatment-naive wet AMD in two observational follow-up cohorts 2007-2010 (n=50 patients) and 2009-2013 (n=26). After a loading dose of three intravitreal ranibizumab injections, the patients were treated under the pro re nata regimen. Visual acuity (VA) was examined by Early Treatment Diabetic Retinopathy Study (ETDRS) charts. The National Eye Institute Visual Functioning Questionnaire 25 was answered by patients at baseline and at 37+/-7 months (cohort 1) and at 45+/-4 months (cohort 2). RESULTS: At baseline, the cohorts were homogeneous considering mean age (76+/-7 vs 75+/-8 years), mean VA (53+/-14 vs 52+/-15 ETDRS letters), and mean self-reported symptom duration (14+/ 11 vs 13+/-11 weeks). Mean VA decreased in both cohorts over time, from 53+/-14 to 45+/-24 letters (P=0.011) and from 52+/-15 to 46+/-22 letters (P=0.175), respectively. The patients received a mean of 8+/-5 and 9+/-7 injections, respectively. The mean composite score change from baseline to follow-up decreased in cohort 1 from 64+/-21 to 59+/-25 scores (P=0.04) but increased in cohort 2 from 64+/-28 to 67+/-23 scores (P=0.38). CONCLUSION: We could not demonstrate any improvement in the number of injections in two different time cohorts of patients treated with ranibizumab for wet AMD in a Swedish county. Visual outcomes decreased after 3 years of follow-up, but QoL scores were divergent. PMID- 28652697 TI - Efficacy and safety of a 3-month loteprednol etabonate 0.5% gel taper for routine prophylaxis after photorefractive keratectomy compared to a 3-month prednisolone acetate 1% and fluorometholone 0.1% taper. AB - PURPOSE: To compare the outcome of photorefractive keratectomy (PRK) and complications in patients treated with either loteprednol etabonate 0.5% gel or prednisolone acetate 1% suspension and fluorometholone (fml) 0.1% suspension. SETTING: John A Moran Eye Center, University of Utah, Salt Lake City, UT, USA. DESIGN: Prospective, randomized, partially masked trial. METHODS: PRK was performed on 261 eyes of 132 participants. Patients were randomized to a postoperative corticosteroid regimen of either loteprednol etabonate 0.5% gel (loteprednol) or prednisolone 1% acetate suspension followed by fluorometholone 0.1% suspension (prednisolone/fml). Primary outcome measures included incidence and grade of postoperative corneal haze and incidence of increased intraocular pressure of 10 mmHg above baseline, or any intraocular pressure over 21 mmHg. Secondary outcome measures included uncorrected distance visual acuity, best corrected distance visual acuity, and manifest refraction spherical equivalent. RESULTS: The incidence of haze in the first 3 months was 2.6% (3/114 eyes) in the loteprednol group and 4.8% (7/147 eyes) in the prednisolone/fml group and was not statistically significant between groups (P=0.37). The incidence of elevated intraocular pressure was 1.8% (2/114 eyes) in the loteprednol group and 4.1% (6/147 eyes) in the prednisolone/fml group, and was not statistically significant between the groups (P=0.12). The mean 3-month postoperative logMAR uncorrected visual acuity was -0.078+/-0.10 and -0.075+/-0.09 in the loteprednol and prednisolone/fml groups, respectively (P=0.83). CONCLUSION: Postoperative corneal haze and elevated intraocular pressure were uncommon in both treatment arms. There was no statistically significant difference between each postoperative regimen. Refractive results were similar and excellent in both treatment arms. A tapered prophylactic regimen of loteprednol 0.5% gel is equally effective to prednisolone 1%/fml 0.1% after PRK. PMID- 28652698 TI - Comment on "Clinical effectiveness of currently available low-vision devices in glaucoma patients with moderate-to-severe vision loss". PMID- 28652699 TI - Ophthalmological findings in Cameroonian boxers. AB - BACKGROUND: The purpose of this prospective, noncomparative consecutive study was to examine active and retired amateur boxers in order to evaluate the nature and incidence of ocular pathologic conditions related to the boxing practice. RESULTS: A total of 35 boxers were included in this study. The mean age of the boxers was 28.09+/-7.57 years (range 18-52 years). Sixteen (45.7%) boxers had >5 years of boxing experience. Fifteen (42.85%) of the boxers reported wearing protective equipment in the bouts and sparring rounds. The number of bouts ranged from 3 to 103, with a median of 20 (interquartile range [IQR] =7-44). The percentages of wins varied from 25% to 100%, with a median of 68.29% (IQR =50.00 79.54). Most of the eye injuries recorded were minor injuries (66.66%), with subconjunctival hemorrhage being the most common (24.24%). Lid scars were the second most common lesion, accounting for 18.18% of all lesions. Sight threatening eye lesions accounted for 33.34% of injuries and included cataracts (12.12%), lens dislocation (3.03%), pseudoexfoliation syndrome (3.03%), unilateral glaucoma (3.03%), retinal detachment (3.03%), vitreous opacity (6.06%), and lattice degeneration (3.03%). CONCLUSION: Boxing-related ocular traumas are common in Cameroon, and ocular surface lesions are the most common injury reported. Severe lesions are indications for premature retirement from boxing practice. PMID- 28652700 TI - Macular hole surgery: an analysis of risk factors for the anatomical and functional outcomes with a special emphasis on the experience of the surgeon. AB - PURPOSE: The aim of this study was to evaluate risk factors for the anatomical and functional outcomes of macular hole (MH) surgery with special emphasis on the experience of the surgeon. METHODS: A total of 225 surgeries on idiopathic MHs (IMHs) performed by 6 surgeons with a mean follow-up period of 20.5 months were reviewed in this retrospective study. Outcome parameters focused on IMH closure, complications and visual acuity improvement. The results of MH surgeries performed by experienced surgeons were compared to those of surgeons in training. RESULTS: The average MH size was 381 um (standard deviation [SD]=168). Brilliant blue G (BBG) for internal limiting membrane (ILM) staining was used in 109 (48%) eyes and indocyanine green (ICG) in 116 (52%) eyes. As endotamponade, 20% SF6 was used in 38 (17%) cases, 16% C2F6 in 33 (15%) cases and 16% C3F8 in 154 (68%) cases. IMH closure was achieved in 194 eyes (86%). Mean preoperative visual acuity was 0.84 logarithm of the minimum angle of resolution (log MAR; SD=0.29, range: 0.3-1.5); surgery led to a mean improvement of 0.40 (SD=0.37) log MAR. Although the MH closure rate was the same using BBG or ICG for ILM peeling, visual acuity improvement was better in eyes peeled with BBG compared to eyes peeled with ICG (log MAR: BBG: 0.38 [95% CI: 0.32, 0.44] vs ICG: 0.48 [95% CI: 0.42, 0.54], P=0.029). Surgeons with previous experience in vitreoretinal surgery of >=6 years achieved better visual outcomes compared to surgeons with 0-3 years of experience, regardless of the MH size, preoperative visual acuity, time to follow-up or dye used for ILM peeling (0-3 years [0.27, Deltalog MAR] vs >=6 years [0.43, Deltalog MAR], P=0.009). CONCLUSION: Our results indicate that vitrectomy with ILM peeling performed by non-experienced surgeons is a safe procedure leading to good anatomical and functional results. Very experienced surgeons may achieve even better functional outcomes. PMID- 28652701 TI - Follow-up of the retinal nerve fiber layer thickness of diabetic patients type 2, as a predisposing factor for glaucoma compared to normal subjects. AB - PURPOSE: To evaluate and follow-up the retinal nerve fiber layer (RNFL) thickness in patients with diabetes mellitus type 2 compared to a group of healthy individuals with similar demographic characteristics. PATIENTS AND METHODS: This is a prospective, noninvasive, observational case series study. For the purposes of the study, 27 eyes of diabetic patients without diabetic retinopathy, 24 eyes of patients with mild retinopathy, and 25 normal age-matched subjects (control group [CG]) were examined. All participants underwent complete ophthalmological examination and imaging with GDx variable corneal compensation scanning laser polarimetry. Follow-up was 2 years for all three groups. RESULTS: The mean inferior average was statistically significantly lower in both diabetic groups compared to CG at baseline examination and during follow-up. The nerve fiber indicator (NFI) was higher in both diabetic groups compared to CG, both at baseline examination and during follow-up. The NFI was 21.7+/-11.9 and 22.0+/ 11.8 for the diabetic group without retinopathy, 20.8+/-9.6 and 21.9+/-9.8 for the group with mild retinopathy, and 15.3+/-5.4 and 15.9+/-5.5 for the normal subjects, at baseline and 24 months, respectively. There was no statistically significant reduction of the RNFL thickness in all three groups compared to baseline examination. CONCLUSION: This is the first long-term study documenting the RNFL thickness in diabetic patients in comparison with normal controls. Although the lower RNFL was found thinner in diabetics, the 2-year follow-up showed no significant reduction of RNFL thickness in all groups, indicating that RNFL damage may occur early in diabetic patients. PMID- 28652702 TI - Spotlight on ixekizumab for the treatment of moderate-to-severe plaque psoriasis: design, development, and use in therapy. AB - Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population, associated with discomfort and impaired quality of life. In recent years, the pathogenic cytokine network of psoriasis has been extensively studied leading to the development of new treatments that provide greater efficacy. Interleukin 17A (IL-17A) has been recognized as a crucial cytokine that mediates immunopathogenesis of psoriasis. Ixekizumab - indicated for the treatment of adults with moderate-to-severe plaque psoriasis - is a subcutaneously administered humanized monoclonal antibody that targets IL-17A. A large percentage of patients affected by psoriasis achieved consistent benefits in terms of disease control and rapid onset of action during clinical trials. Overall, ixekizumab brought clinical improvement and a favorable safety profile in phase III trials. Ixekizumab is characterized by consistent efficacy and rapid onset of response; it is not influenced by previous exposure to biologics and has shown good results in areas that are difficult to treat and in severe clinical variants of psoriasis. Ixekizumab has shown significant improvements in the activity of the disease and in those physical functions that inhibit radiographic progression in patients with concomitant involvement of joints. Our data support ixekizumab as a successful therapeutic option for patients affected by moderate to-severe plaque-type psoriasis. PMID- 28652703 TI - CT-P13: design, development, and place in therapy. AB - The introduction of biological agents has revolutionized the management of many life-threatening and debilitating immune-mediated diseases. Because of the high cost of biological drugs and their patent expiration, the market has opened to biosimilar agents, copy versions of the originators, which can lead to reduced health care expenditure and increase treatment access worldwide. CT-P13 is the first biosimilar of infliximab (IFX) and has been approved for the same indications as its originator drug. It obtained regulatory approval by the European Medicines Agency in September 2013 and by the US Food and Drug Administration in April 2016. The Phase I and Phase III clinical trials conducted in ankylosing spondylitis and rheumatoid arthritis have demonstrated pharmacokinetic and efficacy equivalence with comparable safety and immunogenicity to IFX. For these reasons, the use of CT-P13 has been extrapolated also to inflammatory bowel disease. There have been some initial concerns regarding the use of CT-P13 in inflammatory bowel disease patients, because of the lack of randomized controlled trials. However, emerging real-world data have further confirmed the comparability between CT-P13 and its reference product in terms of efficacy, safety, and immunogenicity, in patients naive to the anti tumor necrosis factor alpha agents and after switching from IFX, and will be summarized in this review. PMID- 28652704 TI - Rhein attenuates inflammation through inhibition of NF-kappaB and NALP3 inflammasome in vivo and in vitro. AB - Rhein is an important component in traditional Chinese herbal medicine formulations for gastrointestinal disorders, including inflammatory bowel diseases such as ulcerative colitis. In this study, we investigated the beneficial effects of rhein in inflammation models in the transgenic zebrafish line TG (corolla eGFP), in which both macrophages and neutrophils express eGFP and RAW264.7 macrophages. We found that the tail-cutting-induced migration of immune cells was significantly reduced in transgenic zebrafish treated with rhein. In addition, the production of proinflammatory cytokines, including IL-6, IL-1beta, and tumor necrosis factor-alpha, were significantly reduced in lipopolysaccharide (LPS)-induced RAW264.7 macrophages treated with rhein. Parallel to the inhibition of proinflammatory cytokines, rhein significantly reduced phosphorylation levels of NF-kappaB p65 and inducible nitric oxide synthase, as well as COX-2 protein expression levels. Furthermore, rhein significantly reduced NALP3 and cleaved IL-1beta expression in LPS + ATP-induced RAW264.7 macrophages. Thus, the present study demonstrates that rhein may exhibit its anti-inflammatory action via inhibition of NF-kappaB and NALP3 inflammasome pathways. PMID- 28652706 TI - Experimental, molecular docking investigations and bioavailability study on the inclusion complexes of finasteride and cyclodextrins. AB - Finasteride (FIN) is a Class II candidate of the Biopharmaceutics Classification System (BCS). The lipophilic cavity of cyclodextrins (CyDs) enables it to construct a non-covalent inclusion complex with different insoluble drugs. Only beta-cyclodextrin (beta-CyD) and hydroxypropyl-beta-CyD (HP-beta-CyD) have been previously examined with FIN. This study aimed to investigate the consistence of FIN with different kinds of beta-CyDs, including dimethyl-beta-cyclodextrin (DM beta-CyD), carboxymethyl-beta-cyclodextrin (CM-beta-CyD), HP-beta-CyD, sulfobutyl ether-beta-cyclodextrin (SBE-beta-CyD), and beta-CyD, by the coprecipitation method. The resultant inclusion systems were characterized by differential scanning calorimetry, infrared spectroscopy, X-ray diffractometry, and dissolution studies. Moreover, molecular docking for the selected inclusion systems was carried out to explore the suitable arrangements of FIN in the cavity of beta-CyD or its derivatives. The results suggested that the DM-beta-CyD inclusion system gave the higher complexation efficiency for improvement in solubility of FIN and hence enhancement of its bioavailability. Pharmacokinetic parameters displayed a higher absorption rate and higher area under the curve of the FIN/DM-beta-CyD inclusion complex when compared with the drug alone, which indicates an improvement in the absorption and bioavailability of FIN in the DM beta-CyD inclusion system. PMID- 28652705 TI - Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy. AB - BACKGROUND: A calcineurin inhibitor (CNI)-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs) seems to be attractive in patients after heart transplantation (HTX) in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC)-based vs cyclosporine-A (CSA)-based immunosuppression (in combination with mycophenolate mofetil). However, data regarding renal function after HTX in mTOR/CNI patients remain limited. AIM: Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression. METHODS: Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR) calculated from Modification of Diet in Renal Disease equation. RESULTS: Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P=not statistically significant). Analysis of variances with repeated measurements detected a similar change of renal function in both study groups. CONCLUSION: The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen. PMID- 28652707 TI - Development of new promising antimetabolite, DFP-11207 with self-controlled toxicity in rodents. AB - To reduce 5-fluorouracil (5-FU)-induced serious toxicities without loss of antitumor activity, we have developed DFP-11207, a novel fluoropyrimidine, which consists of 1-ethoxymethyl-5-fluorouracil (EM-FU; a precursor form of 5-FU), 5 chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-FU degradation), and citrazinic acid (CTA; an inhibitor of 5-FU phosphorylation). In vitro studies of DFP-11207 indicated that it strongly inhibited the degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD) in homogenates of the rat liver, and also inhibited the phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT) in tumor tissues in a similar magnitude of potency by CDHP and CTA, respectively. Especially, DFP-11207 inhibited the intracellular phosphorylation of 5-FU in tumor cells in a dose-dependent manner whereas CTA alone did not protect intracellular 5-FU phosphorylation. These results postulate that DFP-11207 rapidly entered into the cell and the free CTA produced from DFP-11207 inhibited the phosphorylation of 5-FU in the cell. Furthermore, following oral administration of DFP-11207, CTA was found to be highly retained in the gastrointestinal (GI) tract compared to other tissues in rats. Interestingly, EM FU, the prodrug of 5-FU was found to specifically produce 5-FU by various species of liver microsomes. When DFP-11207 was administered to rats, the plasma level of 5-FU was persisted for a long-time with lower Cmax and longer half-life than that from other 5-FU prodrugs. The antitumor activity of DFP-11207 was evaluated in human tumor xenografts in nude rats and found that DFP-11207 showed an antitumor activity in a dose-dependent fashion and its efficacy is equivalent to reference 5-FU drugs. In striking contrast, DFP-11207 manifested no or less 5-FU-related toxicities, such as a decrease in body weights, GI injury, and myelosuppression, especially thrombocytopenia. Taken together, the preclinical evaluation of DFP 11207 strongly indicates that DFP-11207 be a potential new version of the oral fluoropyrimidine prodrug for further clinical development. PMID- 28652708 TI - Controlled-release nanoencapsulating microcapsules to combat inflammatory diseases. AB - The World Health Organization (WHO) has reported that globally 235 million people suffer from chronic and other inflammatory diseases. The short half-lives of nonsteroidal anti-inflammatory drugs (NSAIDs) and their notoriety in causing gastrointestinal discomforts, warrants these drugs to be released in a controlled and sustained manner. Although polymeric particles have been widely used for drug delivery, there are few reports that showcase their ability in encapsulating and sustaining the release of NSAIDs. In this paper, polymeric nanoencapsulating microcapsules loaded with NSAIDs were fabricated using solid/water/oil/water emulsion solvent evaporation method. Two NSAIDs, ibuprofen and naproxen, were first pre-loaded into nanoparticles and then encapsulated into a larger hollow microcapsule that contained the third NSAID, celecoxib. A high encapsulation efficiency (%) of these NSAIDs was achieved and a sustained release (up to 30 days) of these drugs in phosphate-buffered saline was observed. Then, a gastrointestinal drug - cimetidine (CIM) - was co-loaded with the NSAIDs. This floating delivery system exhibited excellent buoyancy (~88% up to 24 h) in simulated gastric fluid. It also allowed a sequential release of the drugs, whereby an immediate release of CIM followed by NSAIDs was observed. Drug release of the NSAIDs observed Fickian diffusion mechanism, whereas CIM observed non Fickian diffusion. Therefore, this delivery system is a promising platform to control the delivery of NSAIDs to combat inflammatory diseases, thereby protecting against possible gastrointestinal side effects that may arise from the overuse of NSAIDs. PMID- 28652709 TI - Efficacy of antibiotic treatment of implant-associated Staphylococcus aureus infections with moxifloxacin, flucloxacillin, rifampin, and combination therapy: an animal study. AB - The efficacy of antibiotic monotherapy and combination therapy in the treatment of implant-associated infection by Staphylococcus aureus was evaluated in an animal study. The femoral medullary cavity of 66 male Wistar rats was contaminated with S. aureus (ATCC 29213) and a metal device was implanted, of which 61 could be evaluated. Six treatment groups were studied: flucloxacillin, flucloxacillin in combination with rifampin, moxifloxacin, moxifloxacin in combination with rifampin, rifampin, and a control group with aqua. The treatment was applied for 14 days. After euthanasia, the bacterial counts in the periprosthetic bone, the soft tissue, and the implant-associated biofilm were measured. Both antibiotic combination treatments (moxifloxacin plus rifampin and flucloxacillin plus rifampin) achieved a highly significant decrease in microbial counts in the bone and soft tissue and in the biofilm. Mono-antibiotic treatments with either moxifloxacin or flucloxacillin were unable to achieve a significant decrease in microbial counts in bone and soft tissue or the biofilm, whilst rifampin was able to reduce the counts significantly only in the biofilm. Antibiotic resistance was measured in 1/3 of the cases in the rifampin group, whereas no resistance was measured in all other groups. The results show that combinations of both moxifloxacin and flucloxacillin plus rifampin are adequate for the treatment of periprosthetic infections due to infections with S. aureus, whereas monotherapies are not effective or not applicable due to the rapid development of antibiotic resistance. Therefore, moxifloxacin is an effective alternative in combination with rifampin for the treatment of implant-associated infections. PMID- 28652710 TI - Coming full circle in the measurement of medication adherence: opportunities and implications for health care. AB - There is little debate that medication nonadherence is a major public health issue and that measuring nonadherence is a crucial step toward improving it. Moreover, while measuring adherence is becoming both more feasible and more common in the era of electronic information, the reliability and usefulness of various measurements of adherence have not been well established. This paper outlines the most commonly used measures of adherence and discusses the advantages and disadvantages of each that depend on the purpose for which the measure will be used. International consensus statements on definitions and guidelines for selection and use of medication adherence measures were reviewed. The quality of recommended measures was evaluated in selected publications from 2009 to 2014. The most robust medication adherence measures are often ill suited for large-scale use. Less robust measures were found to be commonly misapplied and subsequently misinterpreted in population-level analyses. Adherence assessment and measurement were rarely integrated into standard patient care practice patterns. Successful scalable and impactful strategies to improve medication adherence will depend on understanding how to efficiently and effectively measure adherence. PMID- 28652711 TI - Comparison of clinical outcomes with orodispersible versus standard oral olanzapine tablets in nonadherent patients with schizophrenia or bipolar disorder. AB - PURPOSE: Medication nonadherence is common in the treatment of patients with severe mental illness and is a frequent cause of relapse. Different formulations have been developed in an effort to improve medication adherence. The aim of this study was to explore whether there are differential clinical outcomes between two different formulations of olanzapine (orodispersible tablets [ODTs] vs standard oral tablets [SOT]) for the treatment of nonadherent patients with schizophrenia or bipolar disorder. METHODS: Data for this analysis were from an observational study conducted in Europe (N=903). Adult schizophrenia and bipolar disorder patients in outpatient settings who initiated or changed to either olanzapine ODT or SOT according to physician decision within the last 45 days were eligible for enrollment. The follow-up period was 1 year. Of the 903 participants, 266 nonadherent patients (Medication Adherence Rating Scale score 0-4 at baseline) were included in the analysis. Clinical outcomes of interest were: 1) hospitalization and 2) relapse identified by the participating psychiatrist or hospitalization. An adjusted logistic regression model was fitted. RESULTS: Patients taking ODT had more severe illness at baseline (P<0.001) as assessed with the Clinical Global Impression with mean (standard deviation [SD]) scores of ODT 4.63 (1.03) and SOT 4 (1.16). In the regression models adjusted for potential confounders, patients taking ODT had significantly lower odds for hospitalization (odds ratio =0.355; 95% confidence interval =0.13-0.974) and relapse or hospitalization (odds ratio =0.368; 95% confidence interval =0.183-0.739), respectively. CONCLUSION: Nonadherent patients with schizophrenia or bipolar disorder treated with the orodispersible formulation were less likely to be hospitalized or suffer relapse compared to those patients taking the standard oral coated tablets. PMID- 28652712 TI - Medication-related issues associated with adherence to long-term tyrosine kinase inhibitors for controlling chronic myeloid leukemia: a qualitative study. AB - PURPOSE: Poor adherence to tyrosine kinase inhibitors (TKIs) could compromise the control of chronic myeloid leukemia (CML) and contributes to poorer survival. Little is known about how medication-related issues affect CML patients' adherence to TKI therapy in Malaysia. This qualitative study aimed to explore these issues. PATIENTS AND METHODS: Individual face-to-face, semistructured interviews were conducted at the hematology outpatient clinics of two medical centers in Malaysia from August 2015 to January 2016. CML patients aged >=18 years who were prescribed a TKI were invited to participate in the study. Interviews were audio-recorded, transcribed verbatim, and thematically analyzed. RESULTS: Four themes were identified from 18 interviews: 1) concerns about adverse reactions to TKIs, 2) personal beliefs regarding the use of TKIs, 3) mismanagement of TKIs in daily lives, and 4) financial burden in accessing treatment. Participants skipped their TKIs due to ineffective emesis control measures and perceived wastage of medication from vomiting. Participants also modified their TKI therapy due to fear of potential harm from long-term use, and stopped taking their TKIs based on belief in curative claims of traditional medicines and misconception about therapeutic effects of TKIs. Difficulty in integrating the dosing requirements of TKIs into daily lives led to unintentional skipping of doses, as well as the risk of toxicities from inappropriate dosing intervals or food interactions. Furthermore, financial constraints also resulted in delayed initiation of TKIs, missed clinic appointments, and treatment interruptions. CONCLUSION: Malaysian CML patients encountered a range of medication-related issues leading to a complex pattern of nonadherence to TKI therapy. Further studies should investigate whether regular contact with patients to improve understanding of treatment rationale, to elicit and address patients' concerns about adverse reactions, and to empower patients with skills to self manage their medications might promote better adherence to TKIs and improve CML patients' outcome. PMID- 28652713 TI - Effect of barium-coated halloysite nanotube addition on the cytocompatibility, mechanical and contrast properties of poly(methyl methacrylate) cement. AB - Halloysite nanotubes (HNTs) were investigated as a platform for tunable nanoparticle composition and enhanced opacity in poly(methyl methacrylate) (PMMA) bone cement. Halloysite has been widely used to increase the mechanical properties of various polymer matrices, in stark contrast to other fillers such as barium sulfate that provide opacity but also decrease mechanical strength. The present work describes a dry deposition method for successively fabricating barium sulfate nanoparticles onto the exterior surface of HNTs. A sintering process was used to coat the HNTs in barium sulfate. Barium sulfate-coated HNTs were then added to PMMA bone cement and the samples were tested for mechanical strength and tailored opacity correlated with the fabrication ratio and the amount of barium sulfate-coated HNTs added. The potential cytotoxic effect of barium-coated HNTs in PMMA cement was also tested on osteosarcoma cells. Barium coated HNTs were found to be completely cytocompatible, and cell proliferation was not inhibited after exposure to the barium-coated HNTs embedded in PMMA cement. We demonstrate a simple method for the creation of barium-coated nanoparticles that imparted improved contrast and material properties to native PMMA. An easy and efficient method for coating clay nanotubes offers the potential for enhanced imaging by radiologists or orthopedic surgeons. PMID- 28652714 TI - The safety issues and hardware-related complications of deep brain stimulation therapy: a single-center retrospective analysis of 478 patients with Parkinson's disease. AB - INTRODUCTION: Deep brain stimulation (DBS) is a well-established therapy for the treatment of advanced Parkinson's disease (PD) in patients experiencing motor fluctuations and medication-refractory tremor. Despite the relative tolerability and safety of this procedure, associated complications and unnatural deaths are still unavoidable. METHODS: In this study, hardware-related complications and the causes of unnatural death were retrospectively analyzed in 478 patients with PD who were treated with DBS. RESULTS: The results showed a 3-year survival rate of 98.6% and a 5-year survival rate of 96.4% for patients with PD who underwent DBS treatment at the study center. Pneumonia was the cause of death with the highest frequency. Prophylactic antibiotics and steroids or antihistamine drugs were adopted to reduce the risk of infection. Twenty-two patients (4.6%) experienced hardware-related complications. CONCLUSION: Deaths of PD patients who receive DBS are typically unrelated to the disease itself or complications associated with the surgery. Pneumonia, malignant tumors, asphyxia, and multiple-organ failure are the common causes of death. Swallowing-related problems may be the most important clinical symptom in late-stage PD, as they cannot be stabilized or improved by DBS alone, and are potentially lethal. Although prophylactic antibiotics and steroids or antihistamine drugs may reduce the risk of infection, it is imperative to identify high-risk patients for whom a therapeutic approach not requiring an implantable device is more suitable, for example, pallidotomy and potentially transcranial ultrasound. PMID- 28652715 TI - Association of arteriosclerosis and/or atherosclerosis with hypertensive target organ damage in the community-dwelling elderly Chinese: the Northern Shanghai Study. AB - OBJECTIVE: Vascular abnormality includes two forms, arteriosclerosis (ARS) and atherosclerosis (ATS), which coexist in patients with cardiovascular (CV) diseases. However, whether their combination may lead to a worsening status in those patients remains unclear. We therefore aimed to investigate the association of ARS and/or ATS with hypertensive target organ damage (TOD). METHODS: From June 2014 to August 2015, a total of 1,599 community-dwelling elderly subjects (aged >65 years) from northern Shanghai were recruited. Vascular measurements, such as carotid-femoral pulse wave velocity (cf-PWV), ankle-brachial index (ABI) and carotid plaque, were conducted on each participant, and ARS was defined as cf-PWV >12 m/s, while ATS was defined as participants who have carotid plaque or ABI <0.9. Within the framework of comprehensive CV examinations, CV risk factors were assessed, and asymptomatic TOD was evaluated by measuring participants' left ventricular mass index (LVMI), peak transmitral pulsed Doppler velocity/early diastolic tissue Doppler velocity (E/Ea), urinary albumin-creatinine rate (UACR) and estimated glomerular filtration rate (eGFR). RESULTS: Although LVMI, E/Ea and eGFR were significantly different among subjects with or without ARS and/or ATS (P<0.02), in full adjustment model, only E/Ea showed the independent and significant difference (P=0.023). Moreover, E/Ea was significantly different between participants with ARS or ATS and those without ARS or ATS (P=0.045), while there was no significant difference between participants with ARS and ATS and those without ARS or ATS (P=0.28). Similar results were obtained in the multivariate logistic regression of left ventricular diastolic dysfunction (LVDD). With similar adjustment, LVDD was significantly associated with ATS (P=0.01) but not with ARS (P=0.99). CONCLUSION: In the community-dwelling elderly Chinese, among hypertensive TOD, LVDD was significantly associated with ATS but not with ARS. The proportion of patients with LVDD was not significantly different despite the presence of both ATS and ARS, when compared to patients with ATS alone. PMID- 28652717 TI - Elder self-neglect: research and practice. AB - Elder self-neglect is a global public health and human rights issue that threatens older people's health and safety. It commonly refers to refusal or failure to provide oneself with care and protection in areas of food, water, clothing, hygiene, medication, living environments, and safety precautions. While prevalent, the status of self-neglecting individuals remains largely unclear, in particular within community-dwelling populations. By reviewing the epidemiology of elder self-neglect (definition, prevalence, risk factors, and consequences) to date, the present paper identifies key research gaps such as methodological inconsistency in case identification and measurement, and study designs that are inadequate to determine risk factors of self-neglect. More importantly, in light of the rapidly growing older population, relevant stakeholders (researchers, healthcare providers, social service providers, legal professionals, community organizations, and policymakers) must be prepared for an expected increasing number of self-neglect cases and enlarging scope of the problem. Hence, in this article, I present an overview regarding the management issues of elderly self neglect related to the detection, assessment, reporting and referral, and decision-making capacity. Based on the current literature, the paper is aimed to explore the present knowledge and challenges, and how they can pave the way for solutions to self-neglect research, practice, and policy. PMID- 28652716 TI - Can we improve pain and sleep in elderly individuals with transcranial direct current stimulation? - Results from a randomized controlled pilot study. AB - BACKGROUND: The prevalence of chronic pain and sleep disturbances substantially increases with age. Pharmacotherapy remains the primary treatment option for these health issues. However, side effects and drug interactions are difficult to control in elderly individuals. AIMS: The objective of this study was to assess the feasibility of conducting a randomized sham-controlled trial and to collect preliminary data on the efficacy of transcranial direct current stimulation (tDCS) to reduce pain and improve sleep in older adults suffering from chronic pain. METHODS: Fourteen elderly individuals (mean age 71+/-7 years) suffering from chronic pain and sleep complaints were randomized to receive either anodal tDCS, applied over the primary motor cortex (2 mA, 20 minutes), or sham tDCS, for 5 consecutive days. Pain was measured with visual analog scales, pain logbooks and questionnaires, while sleep was assessed with actigraphy, sleep diaries and questionnaires. RESULTS: There were no missing data for pain and sleep measures, except for actigraphy, that generated several missing data. Blinding was maintained throughout the study, for both the evaluator and participants. Active but not sham tDCS significantly reduced pain (P<0.05). No change was observed in sleep parameters, in both the active and sham tDCS groups (all P>=0.18). CONCLUSION: The present study provides guidelines for the implementation of future tDCS studies in larger populations of elderly individuals. M1 anodal tDCS in this population appears to be effective to reduce pain, but not to improve sleep. PMID- 28652718 TI - An analysis of the economic and patient outcome impact of an integrated COPD service in east London. AB - Exacerbations of COPD carry a huge burden of morbidity and a significant economic impact. It has been shown that home care may be useful for exacerbations of COPD. This article presents a review of an integrated COPD service in east London. Hospital Episode Statistics, Public Health Mortality Files and clinical data were used to analyze differences in health care usage and COPD patient outcomes, including COPD assessment test (CAT) scores for a subsample, before and after the introduction of the integrated service. There was a significant (30%) reduction in the number of hospital bed days for COPD patients (P<0.05), alongside a significant increase in patients with only a short stay (0-1 days) in hospital (P<0.0001). There was a significant increase in the number of patients dying outside of hospital (a proxy for quality of end-of-life care) following introduction of the service (P=0.00015). Patients also reported a clinically significant improvement in CAT scores. A locally developed economic model shows that the economic benefits of the service (via impact on place of death and reduction in length of hospital stay) were almost equal to the cost of the service. The increase in proportion of short-stay admissions and the reduction in bed days suggest an impact of the service on early supported discharge and that this along with an improvement in patient clinical outcomes and in quality of end of-life care shows that an exemplar integrated COPD service can provide benefits that equate to a nearly cost-neutral service. PMID- 28652719 TI - Validity and interpretation of spirometric recordings to diagnose COPD in UK primary care. AB - BACKGROUND: The diagnosis of COPD is dependent upon clinical judgment and confirmation of the presence of airflow obstruction using spirometry. Spirometry is now routinely available; however, spirometry incorrectly performed or interpreted can lead to misdiagnosis. We aimed to determine whether spirometry undertaken in primary care for patients suspected to have COPD was of sufficient quality and whether their spirometry was correctly interpreted. METHODS: Two chest physicians re-read all spirometric readings for both quality of the procedure and interpretation, received as a part of COPD validation studies using data from the Clinical Practice Research Datalink (CPRD). We then used logistic regression to investigate predictors of correct interpretation. RESULTS: Spirometry traces were obtained for 306 patients, of which 221 (72.2%) were conducted in primary care. Of those conducted in primary care, 98.6% (n=218) of spirometry traces were of adequate quality. Of those traces that were of adequate quality and conducted in primary care, and in whom a general practitioner (GP) diagnosis of COPD had been made, 72.5% (n=218) were consistent with obstruction. Historical records for asthma diagnosis significantly decreased odds of correct interpretation. CONCLUSION: The quality of the spirometry procedure undertaken in primary care is high. However, this was not reflected in the quality of interpretation, suggesting an unmet training in primary care. The quality of the spirometry procedure as demonstrated by spirometric tracings provides a re assurance for the use of spirometric values available in the electronic health care record databases for research purposes. PMID- 28652720 TI - Development of a training program to support health care professionals to deliver the SPACE for COPD self-management program. AB - BACKGROUND: With the growing burden of COPD and associated morbidity and mortality, a need for self-management has been identified. The Self-management Programme of Activity, Coping and Education for Chronic Obstructive Pulmonary Disease (SPACE for COPD) manual was developed to support self-management in COPD patients. Currently, there is no literature available regarding health care professionals' training needs when supporting patients with COPD on self management. AIM: This study sought to identify these needs to inform, design and develop a training program for health care professionals being trained to deliver a self-management program in COPD. METHODS: Fourteen health care professionals from both primary and secondary care COPD services participated in face-to-face semistructured interviews. Thematic analysis was used to produce a framework and identify training needs and views on delivery of the SPACE for COPD self management program. Components of training were web-based knowledge training, with pre-and posttraining knowledge questionnaires, and a 1-day program to introduce the self-management manual. Feedback was given after training to guide the development of the training program. RESULTS: Health care professionals were able to identify areas where they required increased knowledge to support patients. This was overwhelming in aspects of COPD seen to be outside of their current clinical role. Skills in goal setting and behavioral change were not elicited as a training need, suggesting a lack of understanding of components of supporting self-management. An increase in knowledge of COPD was demonstrated following the training program. CONCLUSION: Both knowledge and skill gaps existed in those who would deliver self-management. Analysis of this has enabled a training program to be designed to address these gaps and enable health care professionals to support patients in self-management. PMID- 28652721 TI - Alpha-1 antitrypsin Pi*SZ genotype: estimated prevalence and number of SZ subjects worldwide. AB - The alpha-1 antitrypsin (AAT) haplotype Pi*S, when inherited along with the Pi*Z haplotype to form a Pi*SZ genotype, can be associated with pulmonary emphysema in regular smokers, and less frequently with liver disease, panniculitis, and systemic vasculitis in a small percentage of people, but this connection is less well established. Since the detection of cases can allow the application of preventive measures in patients and relatives with this congenital disorder, the objective of this study was to update the prevalence of the SZ genotype to achieve accurate estimates of the number of Pi*SZ subjects worldwide, based on studies performed according to the following criteria: 1) samples representative of the general population, 2) AAT phenotyping characterized by adequate methods, and 3) selection of studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop tables and maps with an inverse distance-weighted (IDW) interpolation method, to provide numerical and geographical information of the Pi*SZ distribution worldwide. A total of 262 cohorts from 71 countries were included in the analysis. With the data provided by these cohorts, a total of 1,490,816 Pi*SZ were estimated: 708,792 in Europe; 582,984 in America and Caribbean; 85,925 in Africa; 77,940 in Asia; and 35,176 in Australia and New Zealand. Remarkably, the IDW interpolation maps predicted the Pi*SZ prevalence throughout the entire world even in areas lacking real data. These results may be useful to plan strategies for future research, diagnosis, and management of affected individuals. PMID- 28652722 TI - Pulmonary rehabilitation in COPD - available resources and utilization in Swedish primary and secondary care. AB - INTRODUCTION: Pulmonary rehabilitation is effective in all stages of COPD. The availability and utilization of pulmonary rehabilitation resources, and the characteristics of COPD patients receiving rehabilitation, were investigated in primary and secondary care in central Sweden. MATERIALS AND METHODS: Data on available pulmonary rehabilitation resources were collected using questionnaires, to 14 hospitals and 54 primary health care centers, and information on utilization of different rehabilitation professionals was obtained from questionnaires completed by 1,329 COPD patients from the same centers. Multivariable logistic regression examined associations with having received rehabilitation in the previous year. RESULTS: In primary care, nurse-based asthma/COPD clinics were common (87%), with additional separate access to other rehabilitation professionals. In secondary care, rehabilitation was more often offered as part of a multidisciplinary teamwork (71%). In total, 36% of the patients met an asthma/COPD nurse in the previous year. Utilization was lower in primary than in secondary care for physiotherapists (7% vs 16%), occupational therapists (3% vs 10%), nutritionists (5% vs 13%), and counselors (1% vs 4%). A higher COPD Assessment Test score and frequent exacerbations were associated with higher utilization of all rehabilitation professionals. CONCLUSION: Pulmonary rehabilitation resources are available but underutilized, and receiving rehabilitation is more common in severe COPD. Treatment recommendations need to be better implemented, especially in mild and moderate COPD. PMID- 28652723 TI - Features of self-management interventions for people with COPD associated with improved health-related quality of life and reduced emergency department visits: a systematic review and meta-analysis. AB - BACKGROUND: Self-management interventions (SMIs) are recommended for individuals with COPD to help monitor symptoms and optimize health-related quality of life (HRQOL). However, SMIs vary widely in content, delivery, and intensity, making it unclear which methods and techniques are associated with improved outcomes. This systematic review aimed to summarize the current evidence base surrounding the effectiveness of SMIs for improving HRQOL in people with COPD. METHODS: Systematic reviews that focused upon SMIs were eligible for inclusion. Intervention descriptions were coded for behavior change techniques (BCTs) that targeted self-management behaviors to address 1) symptoms, 2) physical activity, and 3) mental health. Meta-analyses and meta-regression were used to explore the association between health behaviors targeted by SMIs, the BCTs used, patient illness severity, and modes of delivery, with the impact on HRQOL and emergency department (ED) visits. RESULTS: Data related to SMI content were extracted from 26 randomized controlled trials identified from 11 systematic reviews. Patients receiving SMIs reported improved HRQOL (standardized mean difference =-0.16; 95% confidence interval [CI] =-0.25, -0.07; P=0.001) and made fewer ED visits (standardized mean difference =-0.13; 95% CI =-0.23, -0.03; P=0.02) compared to patients who received usual care. Patients receiving SMIs targeting mental health alongside symptom management had greater improvement of HRQOL (Q=4.37; P=0.04) and fewer ED visits (Q=5.95; P=0.02) than patients receiving SMIs focused on symptom management alone. Within-group analyses showed that HRQOL was significantly improved in 1) studies with COPD patients with severe symptoms, 2) single-practitioner based SMIs but not SMIs delivered by a multidisciplinary team, 3) SMIs with multiple sessions but not single session SMIs, and 4) both individual- and group-based SMIs. CONCLUSION: SMIs can be effective at improving HRQOL and reducing ED visits, with those targeting mental health being significantly more effective than those targeting symptom management alone. PMID- 28652724 TI - Palliative care and prognosis in COPD: a systematic review with a validation cohort. AB - Current recommendations to consider initiation of palliative care (PC) in COPD patients are often based on an expected poor prognosis. However, this approach is not evidence-based, and which and when COPD patients should start PC is controversial. We aimed to assess whether current suggested recommendations for initiating PC were sufficiently reliable. We identified prognostic variables proposed in the literature for initiating PC; then, we ascertained their relationship with 1-year mortality, and finally, we validated their utility in our cohort of 697 patients hospitalized for COPD exacerbation. From 24 articles of 499 screened, we selected 20 variables and retrieved 48 original articles in which we were able to calculate the relationship between each of them and 1-year mortality. The number of studies where 1-year mortality was detailed for these variables ranged from 9 for previous hospitalizations or FEV1 <=30% to none for albumin <=25 mg/dL. The percentage of 1-year mortality in the literature for these variables ranged from 5% to 60%. In the validation cohort study, the prevalence of these proposed variables ranged from 8% to 64%; only 10 of the 18 variables analyzed in our cohort reached statistical significance with Cox regression analysis, and none overcame an area under the curve >=0.7. We conclude that none of the suggested criteria for initiating PC based on an expected poor vital prognosis in COPD patients in the short or medium term offers sufficient reliability, and consequently, they should be avoided as exclusive criteria for considering PC or at least critically appraised. PMID- 28652725 TI - Improvement in 24-hour bronchodilation and symptom control with aclidinium bromide versus tiotropium and placebo in symptomatic patients with COPD: post hoc analysis of a Phase IIIb study. AB - BACKGROUND: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study. METHODS: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RSTM] in COPD baseline score >=10 units) received aclidinium bromide 400 MUg twice daily (BID), tiotropium 18 MUg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed. RESULTS: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P<0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P<0.05). Aclidinium improved trough FEV1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P<0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P<0.05). Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks. Tolerability showed similar incidence of AEs in each arm. CONCLUSION: In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 MUg BID provided additional improvements compared with tiotropium 18 MUg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity. PMID- 28652726 TI - A novel scoring index by Doppler echocardiography for predicting severe pulmonary hypertension due to chronic lung diseases: a cross-sectional diagnostic accuracy study. AB - BACKGROUND: Severe pulmonary hypertension (PH) resulting from a chronic lung disease (CLD) (severe CLD-PH) requires more aggressive treatment due to its increased mortality compared with mild PH. Therefore, we developed a Doppler echocardiography scoring index (ESI) to predict severe CLD-PH. METHODS: A derivation cohort of 107 patients with CLD who underwent echocardiography was classified into two groups, the normal/mild PH group and the severe PH group, based on the right heart catheterization. Meanwhile, we designed the ESI by multivariate logistic regression to validate the predicted outcomes. The ESI was calculated using the following formula: ESI = ESIRVEDTD + ESIPASP + ESIPAd - ESITAPSE. Additionally, the ESI was weighted by +2 points for right ventricular end-diastolic transverse dimension >=3.8 cm or pulmonary artery diameter >=2.7 cm, +3 points for systolic pulmonary artery pressure (PASP) >=61 mmHg, and -3 points for tricuspid annular plane systolic excursion >=1.65 cm. RESULTS: In the derivation cohort, PASP >=61 mmHg estimated by echocardiography exhibited 80.4% sensitivity and 84.3% specificity with area under receiver-operating characteristic curve of 0.823 (95% CI: 0.797-0.942, P<0.0001). Compared with PASP, ESI >=1.0 exhibited 91.1% sensitivity and 80.4% specificity, resulting in a net improvement in model performance with a change in the c-statistic from 0.823 to 0.937 and an integrated discrimination improvement of 11.3% (95% CI: 4.5% 18.2%, P=0.001). The ESI was applied to the validation cohort, resulting in 84.2% sensitivity and 81.3% specificity with 82.9% accuracy. CONCLUSION: The ESI showed high capacity for predicting severe CLD-PH, further implying the value of noninvasive examinations in clinic. PMID- 28652727 TI - Biodegradable and biocompatible cationic polymer delivering microRNA-221/222 promotes nerve regeneration after sciatic nerve crush. AB - MicroRNA (miRNA) has great potential to treat a wide range of illnesses by regulating the expression of eukaryotic genes. Biomaterials with high transfection efficiency and low toxicity are needed to deliver miRNA to target cells. In this study, a biodegradable and biocompatible cationic polymer (PDAPEI) was synthetized from low molecular weight polyethyleneimine (PEI1.8kDa) cross linked with 2,6-pyridinedicarboxaldehyde. PDAPEI showed a lower cytotoxicity and higher transfection efficiency than PEI25kDa in transfecting miR-221/222 into rat Schwann cells (SCs). The upregulation of miR-221/222 in SCs promoted the expression of nerve growth factor and myelin basic protein in vitro. The mouse sciatic nerve crush injury model was used to evaluate the effectiveness of PDAPEI/miR-221/222 complexes for nerve regeneration in vivo. The results of electrophysiological tests, functional assessments, and histological and immunohistochemistry analyses demonstrated that PDAPEI/miR-221/222 complexes significantly promoted nerve regeneration after sciatic nerve crush, specifically enhancing remyelination. All these results show that the use of PDAPEI to deliver miR-221/222 may provide a safe therapeutic means of treating nerve crush injury and may help to overcome the barrier of biomaterial toxicity and low efficiency often encountered during medical intervention. PMID- 28652728 TI - Ti-GO-Ag nanocomposite: the effect of content level on the antimicrobial activity and cytotoxicity. AB - Surface modification of titanium (Ti) implants are extensively studied in order to obtain prominent biocompatibility and antimicrobial activity, especially preventing implant-associated infection. In this study, Ti substrates surface were modified by graphene oxide (GO) thin film and silver (Ag) nanoparticles via electroplating and ultraviolet reduction methods so as to achieve this purpose. Microstructures, distribution, quantities and spectral peaks of GO and Ag loading on the Ti sheets surface were characterized. GO-Ag-Ti multiphase nanocomposite exhibited excellent antimicrobial ability and anti-adherence performance. Subsequently, morphology, membrane integrity, apoptosis and relative genes expression of bacteria incubated on the Ti samples surface were monitored to reveal the bactericidal mechanism. Additionally, the cytotoxicity of Ti substrates incorporating GO thin film and Ag nanoparticles were investigated. GO Ag-Ti composite configuration that have outstanding antibacterial properties will provide the foundation to study bone integration in vitro and in vivo in the future. PMID- 28652729 TI - NIR responsive liposomal system for rapid release of drugs in cancer therapy. AB - To design a rapid release liposomal system for cancer therapy, a NIR responsive bubble-generating thermosensitive liposome (BTSL) system combined with photothermal agent (Cypate), doxorubicin (DOX), and NH4HCO3 was developed. Cypate/DOX-BTSL exhibited a good aqueous stability, photostability, and photothermal effect. In vitro release suggested that the amounts of DOX released from BTSL were obviously higher than that of (NH4)2SO4 liposomes at 42 degrees C. After NIR irradiation, the hyperthermic temperature induced by Cypate led to the decomposition of NH4HCO3 and the generation of a large number of CO2 bubbles, triggering a rapid release of drugs. Confocal laser scanning microscope and acridine orange staining indicated that Cypate/DOX-BTSL upon irradiation could facilitate to disrupt the lysosomal membranes and realize endolysosomal escape into cytosol, improving the intracellular uptake of DOX clearly. MTT and trypan blue staining implied that the cell damage of Cypate/DOX-BTSL with NIR irradiation was more severe than that in the groups without irradiation. In vivo results indicated that Cypate/DOX-BTSL with irradiation could dramatically increase the accumulation of DOX in tumor, inhibit tumor growth, and reduce systemic side effects of DOX. These data demonstrated that Cypate/DOX-BTSL has the potential to be used as a NIR responsive liposomal system for a rapid release of drugs in thermochemotherapy. PMID- 28652730 TI - Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin. AB - Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents. PMID- 28652731 TI - Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an alpha-tocopherol derivative in a rat model of mammary gland carcinosarcoma. AB - Maghemite (gamma-Fe2O3) nanoparticles were obtained by coprecipitation of ferrous and ferric salts in an alkaline medium followed by oxidation; the nanoparticles were coated with poly(N,N-dimethylacrylamide) (PDMA) and characterized by transmission electron microscopy, attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering, thermogravimetric and elemental analyses, and magnetic measurements in terms of particle morphology, size, polydispersity, amount of coating, and magnetization, respectively. The effects of alpha-tocopherol (Toc) and its phenolic (Toc-6-OH) and acetate (Toc-6-Ac) derivatives on Fe2+ release from gamma-Fe2O3@PDMA, as well as from gamma-Fe2O3 and CuFe2O4 nanoparticles (controls), were examined in vitro using 1,10-phenanthroline. The presence of tocopherols enhanced spontaneous Fe2+ release from nanoparticles, with Toc-6-OH exhibiting more activity than neat Toc. All of the nanoparticles tested were found to initiate blood lipid oxidation in a concentration-dependent manner, as determined by analysis of 2-thiobarbituric acid reactive species. Wistar rats with Walker-256 carcinosarcoma (a model of mammary gland carcinosarcoma) received Toc-6-Ac, magnetic nanoparticles, or their combination per os, and the antitumor activity of each treatment was determined in vivo. gamma-Fe2O3@PDMA nanoparticles exhibited increased antitumor activity compared to both commercial CuFe2O4 particles and the antitumor drug doxorubicin. Moreover, increased antitumor activity was observed after combined administration of gamma-Fe2O3@PDMA nanoparticles and Toc-6-Ac; however, levels of bilirubin, aspartate aminotransferase, and white bloods normalized and did not differ from those of the intact controls. The antitumor activity of the gamma-Fe2O3 nanoparticles strongly correlated with Fe2+ release from the nanoparticles but not with nanoparticle-initiated lipid peroxidation in vitro. PMID- 28652732 TI - Preparation, characterization, and evaluation of amphotericin B-loaded MPEG-PCL-g PEI micelles for local treatment of oral Candida albicans. AB - Fatal Candida albicans infections in the mucosal system can occur in association with immune-compromised diseases and dysbacteriosis. Currently, amphotericin B (AmB) is considered to be the most effective antibiotic in the treatment of C. albicans infections, but its clinical application is limited by side effects and poor bioavailability. In order to use AmB in the local treatment of oral C. albicans infections, AmB/MPEG-PCL-g-PEI (monomethoxy poly(ethylene glycol) poly(epsilon-caprolactone)-graft-polyethylenimine, MPP) micelles were prepared. A series of characterizations were performed. The micelles allowed a sustained in vitro release in both normal oral conditions (pH 6.8) and C. albicans infection conditions (pH 5.8). Then, buccal tablets containing freeze-dried powder of AmB/MPP micelles were produced by direct compression process and evaluated as regards to weight variation, hardness, and friability. In vitro drug release of the buccal tablets was measured in both the United States Pharmacopeia dissolution apparatus and the dissolution rate test apparatus, which was previously designed for simulating in vivo conditions of the oral cavity. The buccal tablets could sustainably release within 8 h and meet the antifungal requirements. Regarding safety assessment of AmB/MPP micelles, in vivo histopathological data showed no irritation toward buccal mucosa of the rats in both optical microscopy and ultrastructure observation of the tissues. MTT experiment proved that AmB/MPP micelles reduced the cytotoxicity of AmB. The micelles delivered through the gastrointestinal route were also found to be non systemic toxicity by liquid chromatography-mass spectrometry analysis. Furthermore, the antifungal action of AmB/MPP micelles was evaluated. Although AmB/MPP had no obvious improvement as compared to AmB alone in the antifungal effect on planktonic C. albicans, the micelles significantly enhanced the antifungal activity against the biofilm state of C. albicans. Thus, it was concluded that AmB/MPP micelles represent a promising novel drug delivery system for the local treatment of oral C. albicans infections. PMID- 28652733 TI - In vitro studies of nanosilver-doped titanium implants for oral and maxillofacial surgery. AB - The addition of an antibacterial agent to dental implants may provide the opportunity to decrease the percentage of implant failures due to peri implantitis. For this purpose, in this study, the potential efficacy of nanosilver-doped titanium biomaterials was determined. Titanium disks were incorporated with silver nanoparticles over different time periods by Tollens reaction, which is considered to be an eco-friendly, cheap, and easy-to-perform method. The surface roughness, wettability, and silver release profile of each disc were measured. In addition, the antibacterial activity was also evaluated by using disk diffusion tests for bacteria frequently isolated from the peri-implant biofilm: Streptococcus mutans, Streptococcus mitis, Streptococcus oralis, Streptococcus sanguis, Porphyromonas gingivalis, Staphylococcus aureus, and Escherichia coli. Cytotoxicity was evaluated in vitro in a natural human osteoblasts cell culture. The addition of nanosilver significantly increased the surface roughness and decreased the wettability in a dose-dependent manner. These surfaces were significantly toxic to all the tested bacteria following a 48-hour exposure, regardless of silver doping duration. A concentration of 0.05 ppm was sufficient to inhibit Gram-positive and Gram-negative species, with the latter being significantly more susceptible to silver ions. However, after the exposure of human osteoblasts to 0.1 ppm of silver ions, a significant decrease in cell viability was observed by using ToxiLightTM BioAssay Kit after 72 hours. Data from the present study indicated that the incorporation of nanosilver may influence the surface properties that are important in the implant healing process. The presence of nanosilver on the titanium provides an antibacterial activity related to the bacteria involved in peri-implantitis. Finally, the potential toxicological considerations of nanosilver should further be investigated, as both the antibacterial and cytotoxic properties may be observed at similar concentration ranges. PMID- 28652734 TI - Luminescent/magnetic PLGA-based hybrid nanocomposites: a smart nanocarrier system for targeted codelivery and dual-modality imaging in cancer theranostics. AB - Cancer diagnosis and treatment represent an urgent medical need given the rising cancer incidence over the past few decades. Cancer theranostics, namely, the combination of diagnostics and therapeutics within a single agent, are being developed using various anticancer drug-, siRNA-, or inorganic materials-loaded nanocarriers. Herein, we demonstrate a strategy of encapsulating quantum dots, superparamagnetic Fe3O4 nanocrystals, and doxorubicin (DOX) into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymeric nanocomposites using the double emulsion solvent evaporation method, followed by coupling to the amine group of polyethyleneimine premodified with polyethylene glycol-folic acid (PEI PEG-FA [PPF]) segments and adsorption of vascular endothelial growth factor (VEGF)-targeted small hairpin RNA (shRNA). VEGF is important for tumor growth, progression, and metastasis. These drug-loaded luminescent/magnetic PLGA-based hybrid nanocomposites (LDM-PLGA/PPF/VEGF shRNA) were fabricated for tumor specific targeting, drug/gene delivery, and cancer imaging. The data showed that LDM-PLGA/PPF/VEGF shRNA nanocomposites can codeliver DOX and VEGF shRNA into tumor cells and effectively suppress VEGF expression, exhibiting remarkable synergistic antitumor effects both in vitro and in vivo. The cell viability was14% when treated with LDM-PLGA/PPF/VEGF shRNA nanocomposites ([DOX] =25 MUg/mL), and in vivo tumor growth data showed that the tumor volume decreased by 81% compared with the saline group at 21 days postinjection. Magnetic resonance and fluorescence imaging data revealed that the luminescent/magnetic hybrid nanocomposites may also be used as an efficient nanoprobe for enhanced T2 weighted magnetic resonance and fluorescence imaging in vitro and in vivo. The present work validates the great potential of the developed multifunctional LDM PLGA/PPF/VEGF shRNA nanocomposites as effective theranostic agents through the codelivery of drugs/genes and dual-modality imaging in cancer treatment. PMID- 28652735 TI - Involvement of autophagy in tantalum nanoparticle-induced osteoblast proliferation. AB - Porous tantalum (Ta) implants are highly corrosion resistant and biocompatible, and they possess significantly better initial stability than that of conventional titanium (Ti) implants. During loading wear, Ta nanoparticles (Ta-NPs) that were deposited on the surface of a porous Ta implant are inevitably released and come into direct contact with peri-implant osteoblasts. The wear debris may influence cell behavior and implant stabilization. However, the interaction of Ta-NPs with osteoblasts has not been clearly investigated. This study aimed to investigate the effect of Ta-NPs on cell proliferation and their underlying mechanism. The Cell Counting Kit-8 (CCK-8) assay was used to measure the cell viability of MC3T3 E1 mouse osteoblasts and showed that Ta-NP treatment could increase cell viability. Then, confocal microscopy, Western blotting, and transmission electron microscopy were used to confirm the autophagy induced by Ta-NPs, and evidence of autophagy induction was observed as positive LC3 puncta, high-LC3-II expression, and autophagic vesicle ultrastructures. The CCK-8 assay revealed that the cell viability was further increased and decreased by the application of an autophagy inducer and inhibitor, respectively. In addition, pre-treatment with autophagy inhibitor 3-methyladenine (3-MA) inhibited the Ta-NP-induced autophagy. These results indicate that the Ta-NPs can promote cell proliferation, that an autophagy inducer can further strengthen this effect and that an autophagy inhibitor can weaken this effect. In conclusion, autophagy was involved in Ta-NP induced cell proliferation and had a promoting effect. PMID- 28652736 TI - Magnetic alginate microspheres detected by MRI fabricated using microfluidic technique and release behavior of encapsulated dual drugs. AB - Alginate microspheres loaded with superparamagnetic iron oxide nanoparticles (SPIO NPs) have been fabricated by a T-junction microfluidic device combined with an external ionic crosslinking. The obtained microspheres possess excellent visuality under magnetic resonance due to the presence of only 0.6 mg/mL SPIO NPs. The microspheres also show uniform size with narrow distribution and regular spherical shape characterized by optic microscope and environmental scanning electron microscope. Furthermore, dual drugs (5-fluorouracil and doxorubicin hydrochloride) have been loaded within the microspheres. The release behavior of dual drugs from the microspheres show typical sustained release profiles. As a novel embolic agent, such microspheres in blood vessels can be tracked by magnetic resonance scanner. Thus, the integration of embolotherapy, chemotherapy, and postoperative diagnosis can be realized. PMID- 28652737 TI - Development of graphene oxide-wrapped gold nanorods as robust nanoplatform for ultrafast near-infrared SERS bioimaging. AB - The rapid development of near-infrared surface-enhanced Raman scattering (NIR SERS) imaging technology has attracted strong interest from scientists and clinicians due to its narrow spectral bandwidth, low background interference, and deep imaging depth. In this report, the graphene oxide (GO)-wrapped gold nanorods (GO@GNRs) were developed as a smart and robust nanoplatform for ultrafast NIR SERS bioimaging. The fabricated GO@ GNRs could efficiently load various NIR probes, and the in vitro evaluation indicated that the nanoplatform could exhibit a higher NIR SERS activity in comparison with traditional gold nanostructures. The GOs were prepared by directly pyrolyzing citric acid for greater convenience, and GO@GNRs were fabricated via a facile synthesis strategy. Higher NIR SERS activity, facile synthesis method, excellent biocompatibility, and superb stability make the GO@GNRs/probe complex promising nanoprobes for NIR SERS-based bioimaging applications. PMID- 28652738 TI - Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier. AB - In this study, a glycyrrhetinic acid-functionalized mesoporous silica nanoparticle (MSN-GA) was prepared for active tumor targeting. MSN-GA exhibited satisfactory loading capacity for insoluble drugs, uniform size distribution, and specific tumor cell targeting. Glycyrrhetinic acid, a hepatocellular carcinoma targeting group, was covalently decorated on the surface of MSN via an amido bond. The successful synthesis of MSN-GA was validated by the results of Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), and zeta potential measurement. TEM images revealed the spherical morphology and uniform size distribution of the naked MSN and MSN-GA. Curcumin (CUR), an insoluble model drug, was loaded into MSN-GA (denoted as MSN-GA-CUR) with a high-loading capacity (8.78%+/-1.24%). The results of the in vitro cellular experiment demonstrated that MSN-GA-CUR significantly enhanced cytotoxicity and cellular uptake toward hepatocellular carcinoma (HepG2) cells via a specific GA receptor-mediated endocytosis mechanism. The results of this study provide a promising nanoplatform for the targeting of hepatocellular carcinoma. PMID- 28652740 TI - Optical coding of fusion genes using multicolor quantum dots for prostate cancer diagnosis. AB - Recent studies have found that prostate cancer expresses abnormal genetic markers including multiple types of TMPRSS2-ERG fusion genes. The expression level of different TMPRSS2-ERG fusion genes is correlated to pathologic variables of aggressive prostate cancer and disease progression. State-of-the-art methods for detection of TMPRSS2-ERG fusion genes include reverse transcription polymerase chain reaction (RT-PCR) with a detection limit of 1 fmol at urinary condition. RT PCR is time consuming, costly, and inapplicable for multiplexing. Ability to identify multiple fusion genes in a single sample has become important for diagnostic and clinical purposes. There is a need for a sensitive diagnostic test to detect multiple TMPRSS2-ERG fusion genes for an early diagnosis and prognosis of prostate cancer. Here, we propose to develop an assay for prostate cancer diagnosis using oligonucleotide-functionalized quantum dot and magnetic microparticle for optical detection of rearranged TMPRSS2-ERG fusion genes at a low concentration in urine. We found that our assay was able to identify three different types of fusion gene with a wide detection range and detection limit of 1 fmol (almost the same level of the RT-PCR result reported). Here, we show detection of multiple TMPRSS2-ERG fusion genes using color-coded oligonucleotides in cell lysate and urine. PMID- 28652741 TI - Determination of the spatiotemporal dependence of Pseudomonas aeruginosa biofilm viability after treatment with NLC-colistin. AB - The emergence of colistin-resistant Pseudomonas aeruginosa in cystic fibrosis (CF) patients, particularly after long-term inhalation treatments, has been recently reported. Nanoen-capsulation may enable preparations to overcome the limitations of conventional pharmaceutical forms. We have determined the time dependent viability of P. aeruginosa biofilms treated with both free and nanoencapsulated colistin. We also examined the relationship between the optimal anti-biofilm activity of nanostructured lipid carrier (NLC)-colistin and the structural organization of the biofilm itself. The results showed the more rapid killing of P. aeruginosa bacterial biofilms by NLC-colistin than by free colistin. However, the two formulations did not differ in terms of the final percentages of living and dead cells, which were higher in the inner than in the outer layers of the treated biofilms. The effective anti-biofilm activity of NLC colistin and its faster killing effect recommend further studies of its use over free colistin in the treatment of P. aeruginosa infections in CF patients. PMID- 28652739 TI - Physiological origin of biogenic magnetic nanoparticles in health and disease: from bacteria to humans. AB - The discovery of biogenic magnetic nanoparticles (BMNPs) in the human brain gives a strong impulse to study and understand their origin. Although knowledge of the subject is increasing continuously, much remains to be done for further development to help our society fight a number of pathologies related to BMNPs. This review provides an insight into the puzzle of the physiological origin of BMNPs in organisms of all three domains of life: prokaryotes, archaea, and eukaryotes, including humans. Predictions based on comparative genomic studies are presented along with experimental data obtained by physical methods. State-of the-art understanding of the genetic control of biomineralization of BMNPs and their properties are discussed in detail. We present data on the differences in BMNP levels in health and disease (cancer, neurodegenerative disorders, and atherosclerosis), and discuss the existing hypotheses on the biological functions of BMNPs, with special attention paid to the role of the ferritin core and apoferritin. PMID- 28652742 TI - ATIQCTPC: a nanomedicine capable of targeting tumor and blocking thrombosis in vivo. AB - To overcome the harmful side effects, low tolerance, and undesirable outcomes of the anticancer drugs, we used ethane-1,2-diamine to bridge antitumoral (S)-3 acetyl-4-oxo-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid (ATIQC) and tumor-targeting d-glucuronic acid, thereby providing (6S)-3-acetyl-4-oxo-N-(2 (3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxamido)ethyl)-4,6,7,12 tetrahydroindolo[2,3-a]quinolizine-6-carboxamide (ATIQCTPC). Atomic force microscopy images visualized, that in serum, ATIQCTPC formed particles of height <81 nm. These particles effectively avoided phagocytosis of macrophages and were stable in blood circulation. Distribution analysis indicated that ATIQCTPC accumulated and released ATIQC in the tumor tissue through a targeting manner. Thus, the antitumor and the anti-thrombotic activities of ATIQCTPC were 100-fold higher than those of ATIQC, and ATIQCTPC was able to prevent cancer patients from suffering from thrombosis. Based on the observation that ATIQCTPC decreased serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) in S180 mice, we hypothesized that this is the mechanism that ATIQCTPC utilized to slow tumor growth. Additionally, we observed that ATIQCTPC inhibited thrombosis by decreasing serum P-selectin of thrombotic rats. The intermolecular association and the hexamerization manner of ATIQCTPC were experimentally evidenced and correlated with the formation of the nanoparticles. PMID- 28652744 TI - Assessment of safety and efficacy of lamotrigine over the course of 1-year observation in Japanese patients with bipolar disorder: post-marketing surveillance study report. AB - BACKGROUND: A post-marketing surveillance (PMS) study was conducted with a 1-year observation period to assess the safety and efficacy of lamotrigine in routine clinical practice in patients with bipolar disorder (BD). PATIENTS AND METHODS: Central enrollment method was used to recruit patients diagnosed with BD who were being treated for the first time with lamotrigine to prevent the recurrence/relapse of BD mood episodes. Adverse drug reactions (ADRs) and recurrence/relapse were assessed. Improvement of mania and depression was also assessed using the Hamilton's Rating Scale for Depression (HAM-D) and the Young Mania Rating Scale (YMRS) at treatment initiation, 4-6 months post treatment initiation, and 10-12 months post treatment initiation. RESULTS: A total of 237/989 patients (24.0%) reported ADRs, most commonly rash (9.1%), and the incidence of serious ADRs was 3.3% (33/989 patients). Skin disorders occurred in 130 patients (13.1%), mostly within 8 weeks post treatment. A total of 237/703 patients (33.7%) experienced recurrence/relapse of mood episodes. The 25th percentile of the time to recurrence/relapse of mood episodes was 105 days. Remission of depression symptoms (HAM-D <=7) occurred in 147/697 patients (21.1%) at treatment initiation, rising to 361 patients (67.4%) at 10-12 months post treatment. Remission of manic symptoms (YMRS <=13) occurred in 615/676 patients (91.0%) at treatment initiation, rising to 500 patients (97.3%) at 10-12 months post treatment. CONCLUSION: The results of this PMS study suggest that lamotrigine is a well-tolerated and effective drug for preventing recurrence/relapse of BD in clinical practice. PMID- 28652743 TI - Zinc oxide nanoparticle-induced atherosclerotic alterations in vitro and in vivo. AB - Engineered zinc oxide nanoparticles (ZnO-NPs) are currently being produced in high tonnage. Exposure to ZnO-NPs presents potential risks to cardiovascular system. Thus far, the toxicological effects of ZnO-NPs on cardiovascular system have not been well characterized. In this study, human coronary artery endothelial cells (HCAECs) were exposed to ZnO-NPs directly or indirectly using a transwell coculture system with human alveolar epithelial cell line A549 to mimic the lung/circulation interaction. It was shown that levels of proinflammatory mediators (interleukin-8 [IL-8] and tumor necrosis factor-alpha [TNF-alpha]) and biomarkers of atherosclerogenesis (heme oxygenase-1 [HO-1] and platelet endothelial cell adhesion molecules-1 [PECAM-1]) in the supernatants of culture media were significantly increased. Pretreatment of A549 cells on the apical side of the coculture system with the phagocytosis inhibitor cytochalasin B (CB) blocked ZnO-NP-induced HO-1 and PECAM-1 expression in HCAEC, indicating that endocytosis of ZnO-NPs by alveolar epithelial cells was involved in ZnO-NP induced HO-1 or PECAM-1 expression in endothelial cells. Moreover, Wistar rats were intratracheally instilled with ZnO-NP suspension and high fat diet (positive control). ZnO-NP treatment induced lung and systemic inflammation, dyslipidemia, increased levels of serum HO-1 and PECAM-1, and aortic pathological damage. Taken together, exposure to ZnO-NPs could induce atherosclerotic alterations, which might involve phagocytosis of nanoparticles and inflammation in the lung. PMID- 28652745 TI - Regional impairment of intrinsic functional connectivity strength in patients with chronic primary insomnia. AB - Several neuroimaging studies have suggested that brain impairment and plasticity occur in patients with chronic primary insomnia (CPI); however, the effects of insomnia on the intrinsic organization of the brain remain largely unknown. In this study, a voxel-based functional connectivity strength (FCS) assessment, a data-driven method based on a theoretical approach, was applied to investigate the effects of insomnia on the intrinsic organization of the whole brain in 27 treatment-naive CPI patients and 26 well-matched healthy controls (HCs). Compared with HCs, CPI patients exhibited decreased FCS primarily in the right dorsolateral prefrontal cortex, the right medial prefrontal cortex (MPFC), the left basal ganglia/insula, and the right cerebellum anterior lobe (CAL) due to decreased functional connectivity patterns. These results suggest that poor sleep quality could impair FCS within the brain, including the MPFC and the CAL, which are important for cognitive control and modulating motor and limbic functions. Additionally, a receiver operator characteristic analysis revealed that altered FCS has moderate sensitivity (76.9%-88.5%) and specificity (59.3%-70.4%) as a reference indicator to discriminate CPI patients from HCs. Taken together, these findings provide evidence for abnormal intrinsic brain activity in CPI patients and might improve our understanding of the pathophysiological processes that occur in insomnia patients. PMID- 28652746 TI - Association between serotonin transporter polymorphisms (5-HTTLPR) and the MADRS Dysphoria, Retardation, and Vegetative Subscale scores in the treatment of depression. AB - OBJECTIVE: We investigated the association between serotonin- or 5 hydroxytryptamine (5-HT)-related gene polymorphisms and response to antidepressant treatment in a specific symptom cluster of major depression by using the three-factor model of the Montgomery-Asberg Depression Rating Scale (MADRS), ie, dysphoria (items of sadness, pessimistic thoughts, and suicidal thoughts), retardation (items of lassitude, inability to feel, apparent sadness, and concentration difficulties), and vegetative symptoms (items of reduced sleep, reduced appetite, and inner tension). METHODS: This study was an open-label and nonrandomized trial. A total of 160 patients with baseline MADRS scores of >=21, who were treated with fluvoxamine or milnacipran for 6 weeks, were included in the statistical analysis. Polymorphisms within a 5-HT transporter (5-HTT) gene linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the second intron of the 5-HTT gene (5-HTTVNTR), and 5HT2A receptor (1438G/A) were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The 5-HTTLPR polymorphisms affected the MADRS score change in dysphoria, but not in retardation, vegetative, or total symptoms. Dysphoria scores significantly decreased in patients with the S/S genotype compared to those in patients with the short (S)/long (L) + L/L genotype. However, 5-HTTVNTR and 1438G/A polymorphisms were not significantly associated with the treatment response to any cluster of depressive symptoms. When a Bonferroni correction was made, however, our results did not reach the criteria for statistical significance. CONCLUSION: The use of a single total depression rating scale may not be sufficient to accurately estimate the clinical response to antidepressants. Analyzing a subset of symptoms in psychological scales could be important when performing pharmacogenetic studies. PMID- 28652747 TI - Disrupted small-world brain functional network topology in male patients with severe obstructive sleep apnea revealed by resting-state fMRI. AB - PURPOSE: Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder that can damage cognitive function. However, the functional network organization remains poorly understood. The aim of this study was to investigate the topological properties of OSA patients using a graph theoretical analysis. PATIENTS AND METHODS: A total of 30 male patients with untreated severe OSA and 25 male education- and age-matched good sleepers (GSs) underwent functional magnetic resonance imaging (MRI) examinations. Clinical and cognitive evaluations were conducted by an experienced psychologist. GRETNA (a toolbox for topological analysis of imaging connectomics) was used to construct the brain functional network and calculate the small-world properties (gamma, lambda, sigma, Eglob, and Eloc). Relationships between these small-world properties and clinical and neuropsychological assessments were investigated in OSA patients. RESULTS: The networks of both OSA patients and GSs exhibited efficient small-world topology over the sparsity range of 0.05-0.40. Compared with GSs, the OSA group had significantly decreased gamma, but significantly increased lambda and sigma. The OSA group's brain network showed significantly decreased Eglob (P<0.05) over the sparsity range of 0.09-0.15, but significantly increased Eloc over the sparsity range of 0.23-0.40. In OSA patients, gamma was significantly negatively correlated with apnea-hypopnea index (AHI; r=-0.326, P=0.015) and Epworth Sleepiness Scale (ESS; r=-0.274, P=0.043), lambda was significantly positively correlated with AHI (r=0.373, P=0.005) and ESS (r=0.269, P=0.047), and sigma was significantly negatively correlated with AHI (r=-0.363, P=0.007) and ESS (r= 0.295, P=0.029). CONCLUSION: Our results suggest that the high degree of local integration and integrity of the brain connections in OSA patients may be disrupted. The topological alterations of small-world properties may be the mechanism of cognitive impairment in OSA patients. In addition, sigma, gamma, and lambda could be used as a quantitative physiological index for auxiliary clinical diagnoses. PMID- 28652748 TI - PAC1 receptor (ADCYAP1R1) genotype and problematic alcohol use in a sample of young women. AB - BACKGROUND: Recent studies revealed the role of the PAC1 (ADCYAP1R1) gene variability in vulnerability to posttraumatic stress disorder in women. Due to the relatively high comorbidity of posttraumatic stress disorder and substance use disorder, we hypothesized about possible associations between PAC1 gene and problematic alcohol use. METHOD: The sample studied consisted of 491 women aged 18-28 years (mean age =21.76 years; SD =1.83) and the Alcohol Use Disorders Identification Test was used to assess drinking problems. We successfully genotyped 17 single-nucleotide polymorphisms in the PAC1 gene. RESULTS: Single locus analysis revealed a significant (after correction for multiple testing) association between intronic polymorphism rs2302475 and problematic alcohol use (P=0.00048; recessive model). This result was strengthened by the haplotype analysis (P=0.00379). CONCLUSION: Our results suggest that the PACAP/PAC1 signaling system is implicated in the development of problematic alcohol use in women. PMID- 28652749 TI - Sleep apnea leading to Parkinson's disease - an important association. PMID- 28652750 TI - The prevalence and risk factors of young male schizophrenics with non-alcoholic fatty liver disease. AB - OBJECTIVE: In this study, we compared the prevalence rate of non-alcoholic fatty liver disease (NAFLD) between young males with schizophrenia and the general young males as the control group, and we also investigated the risk factors of NAFLD in young males with schizophrenia. MATERIALS AND METHODS: This is a large cross-sectional study consisting of the study group and parallel control group. The study group comprises 202 cases of young males with schizophrenia recruited from Liaoning province Demobilized Soldiers Kangning Hospital, and 149 healthy young males were recruited as the control group. The clinical evaluation included Positive and Negative Syndrome Scale (PANSS), basic information, disease-related information, and physical examination information. The laboratory tests included fasting blood glucose, total cholesterol, triglyceride, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The physical examination included liver ultrasonography. RESULTS: No statistical difference was observed between the study and control groups regarding age (30.5+/-3.9 vs 30.7+/-3.6), body mass index (BMI), blood pressure, fasting glucose level, and total cholesterol. NAFLD was observed in both the study and control groups. The prevalence of NAFLD was 49.5% (100/202) in the study group, and 20.1% (30/149) in the control group. The study group was further divided into NAFLD group and non-NAFLD group. There were significant differences in medication combination, drug dosage, negative factor score in PANSS (14.1+/-4.0 vs 12.7+/-4.5), BMI, fasting glucose level, total cholesterol, triglyceride, ALT, and AST between NAFLD group and non-NAFLD group. According to the results of the multiple-factor analysis, the onset of NAFLD among young males with schizophrenia was significantly correlated with the following factors: triglyceride, BMI, medication combination, drug dosage, and negative factor score in PANSS. CONCLUSION: The prevalence of NAFLD in the study group was significantly higher than that in the control group. Multivariate analysis indicated that, triglyceride, BMI, medication combination, drug dosage, and negative factor score in PANSS were significantly related to NAFLD in patients with schizophrenia. PMID- 28652751 TI - Effects of Canon chord progression on brain activity and motivation are dependent on subjective feelings, not the chord progression per se. AB - A number of studies have indicated that relaxing and pleasant melodies are useful for the treatment of patients with psychiatric disorders, including schizophrenia, depression, and dementia. However, few studies have investigated what constitutive elements of the music had an effect on brain activity. As Canon chord progression is one of critical elements for pleasant melodies, we sought to examine the effects of Canon chord progression and pitch-shifted Canon chord progression on brain activity using performance on the auditory oddball task during event-related potentials (ERPs) in 30 healthy subjects. Unexpectedly, we found no differences in ERP components between subjects listening to Canon chord progression (n=15) or pitch-shifted Canon chord progression (n=15). Next, we divided participants into two groups: those who found the melody pleasant (n=17) and those who did not (n=13), for both Canon chord progression and pitch-shifted Canon chord progression. The average of P300 amplitude was higher at Fz in subjects found the music pleasant versus those finding it unpleasant. Moreover, subjects who found it pleasant exhibited higher motivation scores than those who felt it was unpleasant, whereas listening to Canon chord progression did not matter. These findings suggest that the effects of Canon chord progression on brain activity and motivation depend on subjective feelings, not the chord progression per se. PMID- 28652753 TI - Pituitary abscess: report of two cases and review of the literature. AB - Pituitary abscess is a rare but critical disorder caused by an infectious process where purulent material accumulates inside the sella turcica. Since symptoms, signs and radiographic characteristics of pituitary abscess are similar to several other pituitary lesions, correct diagnosis before surgery is challenging. In this article, two cases of pituitary abscess treated in our department are reported, followed by a literature review. In these two cases, both patients presented with intermittent fever. Magnetic resonance imaging revealed a suprasellar lesion with rim enhancement after contrast injection. After transsphenoidal surgery, the diagnosis of pituitary abscess was confirmed. The patients were then given antibiotic treatment and recovered fully in less than 2 months. Findings of this article support timely diagnosis and proper treatment including transsphenoidal surgery and antibiotic therapy for pituitary abscess, leading to lower mortality rates and higher probability of pituitary hormone function recovery. PMID- 28652754 TI - Unusual delayed presentation of diaphragmatic hernia complicated by transverse colon and total small-bowel obstruction after postoperative chemotherapy of esophageal cancer. AB - Diaphragmatic hernia (DH) is defined as the passage of abdominal contents into the chest cavity through a defect in the diaphragm. DH occurs after chest or abdominal surgery, and is very rare and sporadically reported in the literature. However, the complications are significant and put the patient at great risk. The aim of the present report was to describe a special case with postesophagectomy diaphragmatic hernia (PDH) because of its appearance during chemotherapy and confusion of the symptoms with the side effects of chemotherapy. A high index of suspicion needs to be maintained in clinical practice. PMID- 28652752 TI - Cognitive dysfunction in major depression and Alzheimer's disease is associated with hippocampal-prefrontal cortex dysconnectivity. AB - Cognitive dysfunction is prevalent in psychiatric disorders. Deficits are observed in multiple domains, including working memory, executive function, attention, and information processing. Disability caused by cognitive dysfunction is frequently as debilitating as the prominent emotional disturbances. Interactions between the hippocampus and the prefrontal cortex are increasingly appreciated as an important link between cognition and emotion. Recent developments in optogenetics, imaging, and connectomics can enable the investigation of this circuit in a manner that is relevant to disease pathophysiology. The goal of this review is to shed light on the contributions of this circuit to cognitive dysfunction in neuropsychiatric disorders, focusing on Alzheimer's disease and depression. PMID- 28652755 TI - Comparison of the efficacy and safety of retroperitoneal laparoscopic and open surgery for the correction of retrocaval ureter. AB - OBJECTIVE: The aim of this study was to compare the clinical efficacy and safety of retroperitoneal laparoscopic and open surgery for the correction of retrocaval ureter. PATIENTS AND METHODS: Clinical data of 14 patients with retrocaval ureter were analyzed retrospectively. Among them, nine were treated by open surgical therapy and five by retroperitoneal laparoscopic surgery. The ureter was transpositioned to a normal anatomic position followed by laparoscopic intracorporeal uretero and ureteric anastomosis. RESULTS: Open surgery was successfully performed in nine cases. The mean surgery time was 95.6+/-22.0 min, and blood loss was 108.6+/-34.5 mL. The mean hospitalization time was 14.8+/-1.1 days, and the recovery time was 52.8+/-1.3 days. Retroperitoneal laparoscopic surgery was successfully performed in five cases without conversion to open surgery and without severe perioperative complications. The mean surgery time was 112.0+/-42.1 min, and blood loss was 45.3+/-15.1 mL. The mean hospitalization time was 7.3+/-1.9 days, and the recovery time was 23.6+/-2.4 days. Postoperative urine leakage occurred in one patient. No postoperative ureter stenosis occurred in patients who were treated by retroperitoneal laparoscopic surgery. CONCLUSION: Retroperitoneal laparoscopic ureteroplasty in patients with retrocaval ureter is safe and effective with less trauma and faster recovery and could be used as first choice for the treatment of retrocaval ureter. PMID- 28652756 TI - Noncontact plating technique in an open fracture. AB - AIM: In comparison with closed fractures, open fractures have an increased risk of infection, there are soft tissue-related problems, and difficulties are experienced in union. The aim of this study was to evaluate and discuss the results of osteosynthesis applied with a noncontact plate in Gustilo-Anderson Type 2, 3a, and 3b fractures. METHOD: The study included 23 patients applied with debridement + noncontact plate osteosynthesis + soft tissue procedures in a single session for the treatment of an open fracture. A follow-up card was created to evaluate the patients in respect of age, gender, fracture level, fracture etiology, open fracture type, preoperative and postoperative sedimentation and C-reactive protein values, antibiotics used and duration of use, time to union, and complications. RESULTS: In all 23 patients, full bone union was obtained at mean 22.5 weeks (range: 16-36 weeks). Complications developed in 9 patients. Implant failure occurred in 3 patients. In 5 patients, infection developed which required repeated debridements. CONCLUSION: In open fractures, noncontact plating following debridement seems to be a good alternative treatment method to intramedullar nailing, especially in metaphyseal and metaphyseo-diaphyseal fractures and in spiral oblique diafiz fractures. Noncontact plating may also be a good alternative to intramedullar nailing for open fracture treatment if the patients have additional pathologies such as contusion and thoracic injury. PMID- 28652757 TI - Transnasal endoscopic and combined intra-extranasal approach for the surgical treatment of frontal sinus cerebrospinal fluid rhinorrhea. AB - The aim of this study was to summarize and analyze the outcomes of frontal sinus cerebrospinal fluid rhinorrhea (FS-CSFR) treated by transnasal endoscopic and combined intra-extranasal approach. Clinical data on 20 cases of FS-CSFR patients from 2005 to 2013, with emphasis on the postoperative complications, clinical outcomes, and key technology involved in the combined intra-extranasal procedure, were retrospectively reviewed. Among the 20 cases, 12 were treated by combined intra-extranasal procedure; the other eight cases were initially treated by trans nasal endoscopic approach alone, and five of them (5/8, 62.5%) were successfully treated and three failed. The three failed cases subsequently underwent combined intra-extranasal approach. A total of 15 cases, who received combined procedure, experienced fast recovery, had mild complications, and had no significant facial scars, and no CSFR recurrence was observed. Combined intra-extranasal approach offers advantages in not only overcoming the difficulty of insufficient exposure of defects during transnasal endoscopic procedure but also improving the success rate of repair. PMID- 28652758 TI - Blood lead level is a positive predictor of uremic pruritus in patients undergoing hemodialysis. AB - Although uremic pruritus (UP) is a common and annoying symptom for end-stage renal disease patients on hemodialysis (HD) and peritoneal dialysis, its pathogenesis is poorly understood. However, systemic inflammation is one of the possible pathogenesis of UP, and blood lead level (BLL) has been noted to be associated with inflammation and nutritional status in long-term HD patients. There might be an interaction or association, therefore, between BLL and UP through systemic inflammation. We analyzed cross-sectional data among 866 participants. All of the 866 patients in this study were stratified into groups with low-normal (<10 MUg/dL), high-normal (10-20 MUg/dL), and abnormal BLLs (>20 MUg/dL). The associations between UP and BLL and the clinical data were analyzed. Multivariate logistic regression demonstrated that HD duration, non-anuria, log ferritin, serum low-density lipoprotein, log BLL, high-normal BLL, and high BLL were associated with UP. In conclusion, BLL was positively associated with UP. PMID- 28652760 TI - Worksite-based cardiovascular risk screening and management: a feasibility study. AB - BACKGROUND: Established cardiovascular risk factors are highly prevalent and contribute substantially to cardiovascular morbidity and mortality because they remain uncontrolled in many Canadians. Worksite-based cardiovascular risk factor screening and management represent a largely untapped strategy for optimizing risk factor control. METHODS: In a 2-phase collaborative demonstration project between Alberta Health Services (AHS) and the Alberta Newsprint Company (ANC), ANC employees were offered cardiovascular risk factor screening and management. Screening was performed at the worksite by AHS nurses, who collected baseline history, performed automated blood pressure measurement and point-of-care testing for lipids and A1c, and calculated 10-year Framingham risk. Employees with a Framingham risk score of >=10% and uncontrolled blood pressure, dyslipidemia, or smoking were offered 6 months of pharmacist case management to optimize their risk factor control. RESULTS: In total, 87 of 190 (46%) employees volunteered to undergo cardiovascular risk factor screening. Mean age was 44.5+/-11.9 years, 73 (83.9%) were male, 14 (16.1%) had hypertension, 4 (4.6%) had diabetes, 12 (13.8%) were current smokers, and 9 (10%) had dyslipidemia. Of 36 employees with an estimated Framingham risk score of >=10%, 21 (58%) agreed to receive case management and 15 (42%) attended baseline and 6-month follow-up case management visits. Statistically significant reductions in left arm systolic blood pressure (-8.0+/-12.4 mmHg; p=0.03) and triglyceride levels (-0.8+/-1.4 mmol/L; p=0.04) occurred following case management. CONCLUSION: These findings demonstrate the feasibility and usefulness of collaborative, worksite-based cardiovascular risk factor screening and management. Expansion of this type of partnership in a cost effective manner is warranted. PMID- 28652761 TI - Understanding the impact of interprofessional collaboration on the quality of care: a case report from a small-scale resource limited health care environment. AB - BACKGROUND: A critical assessment of current health care practices, as well as the training needs of various health care providers, is crucial for improving patient care. Several approaches have been proposed for defining these needs with attention on communication as a key competency for effective collaboration. Taking our cultural context, resource limitations, and small-scale setting into account, we researched the applicability of a mixed focus group approach for analysis of the communication between doctors and nurses, as well as the measures for improvement. STUDY OBJECTIVE: Assessment of nurse-physician communication perception in patient care in a Caribbean setting. METHODS: Focus group sessions consisting of nurses, interns, and medical specialists were conducted using an ethnographic approach, paying attention to existing communication, risk evaluation, and recommendations for improvement. Data derived from the focus group sessions were analyzed by thematic synthesis method with descriptive themes and development of analytic themes. RESULTS: The initial focus group sessions produced an extensive list of key recommendations which could be clustered into three domains (standardization, sustainment, and collaboration). Further discussion of these domains in focus groups showed nurses' and physicians' domain perspectives and effects on patient care to be broadly similar. Risks related to lack of information, knowledge sharing, and professional respect were clearly described by the participants. CONCLUSION: The described mixed focus group session approach for effectively determining current interprofessional communication and key improvement areas seems suitable for our small-scale, limited resource setting. The impact of the cultural context should be further evaluated by a similar study in a different cultural context. PMID- 28652759 TI - Reference values assessment in a Mediterranean population for small dense low density lipoprotein concentration isolated by an optimized precipitation method. AB - BACKGROUND: High serum concentrations of small dense low-density lipoprotein cholesterol (sd-LDL-c) particles are associated with risk of cardiovascular disease (CVD). Their clinical application has been hindered as a consequence of the laborious current method used for their quantification. OBJECTIVE: Optimize a simple and fast precipitation method to isolate sd-LDL particles and establish a reference interval in a Mediterranean population. MATERIALS AND METHODS: Forty five serum samples were collected, and sd-LDL particles were isolated using a modified heparin-Mg2+ precipitation method. sd-LDL-c concentration was calculated by subtracting high-density lipoprotein cholesterol (HDL-c) from the total cholesterol measured in the supernatant. This method was compared with the reference method (ultracentrifugation). Reference values were estimated according to the Clinical and Laboratory Standards Institute and The International Federation of Clinical Chemistry and Laboratory Medicine recommendations. sd-LDL c concentration was measured in serums from 79 subjects with no lipid metabolism abnormalities. RESULTS: The Passing-Bablok regression equation is y = 1.52 (0.72 to 1.73) + 0.07x (-0.1 to 0.13), demonstrating no significant statistical differences between the modified precipitation method and the ultracentrifugation reference method. Similarly, no differences were detected when considering only sd-LDL-c from dyslipidemic patients, since the modifications added to the precipitation method facilitated the proper sedimentation of triglycerides and other lipoproteins. The reference interval for sd-LDL-c concentration estimated in a Mediterranean population was 0.04-0.47 mmol/L. CONCLUSION: An optimization of the heparin-Mg2+ precipitation method for sd-LDL particle isolation was performed, and reference intervals were established in a Spanish Mediterranean population. Measured values were equivalent to those obtained with the reference method, assuring its clinical application when tested in both normolipidemic and dyslipidemic subjects. PMID- 28652762 TI - MicroRNA-148b suppresses proliferation, migration, and invasion of nasopharyngeal carcinoma cells by targeting metastasis-associated gene 2. AB - PURPOSE: MicroRNAs (miRNAs) play important roles in tumorigenesis and metastasis by regulating genes expression. MiRNA-148b (miR-148b) had been reported to inhibit tumor progression in some kinds of cancers, but the functions of miR-148b in nasopharyngeal carcinoma (NPC) remain largely unknown. The aim of this study was to investigate the functional role of miR-148b in NPC. METHODS: Expression of miR-148b in NPC tissues and cell lines was detected by quantitative reverse transcription polymerase chain reaction. MiR-148b was overexpressed in CNE2 and C666-1 cells by miR-148b mimic transfection. The effects of miR-148b on cell proliferation, migration, and invasion were determined by colony formation assays, cell viability assays, and transwell assays. The target gene of miR-148b was investigated by luciferase assays, and the rescue experiment was performed. RESULTS: MiR-148b was downregulated in NPC tissues and cell lines. Ectopic miR 148b expression significantly inhibited proliferation, migration, and invasion of CNE2 and C666-1 cells. We identified that metastasis-associated gene 2 (MTA2) is a direct target of miR-148b. Rescue experiment demonstrated that the tumor suppressive effects of miR-148b on C666-1 cell were partly reversed by restoration of MTA2 expression. Moreover, miR-148b expression was negatively related to mRNA level of MTA2 in NPC tissues. CONCLUSION: Our findings elucidate that miR-148b negatively regulates the growth, migration, and invasion of NPC cells, at least in part, by targeting MTA2. The present study indicates that miR 148b is a potential therapeutic agent for NPC. PMID- 28652763 TI - Letter to the editor regarding the article "Prognostic role of long noncoding RNA NEAT1 in various carcinomas: a meta-analysis". PMID- 28652764 TI - SUN1 silencing inhibits cell growth through G0/G1 phase arrest in lung adenocarcinoma. AB - PURPOSE: Cytoskeleton is critical for carcinoma cell proliferation, migration, and invasion. Sad-1 and UNC-84 domain containing 1 (SUN1) is one of the core linkers of nucleoskeleton and cytoskeleton. However, the functions of SUN1 in lung adenocarcinoma are largely unknown. METHODS: In this study, we first transduced the lentivirus delivering the short hairpin RNA (shRNA) against SUN1 to lung adenocarcinoma cells (A549 and 95D cells) with high efficiency. After lentivirus infection, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expressions of SUN1 mRNA and protein. The cell proliferation and colony formation were detected by MTT assay and colony formation assay, respectively. The cell distribution in the cell cycle was analyzed by flow cytometry. RESULTS: Both mRNA and protein levels of SUN1 were significantly decreased in A549 and 95D cells after lentivirus infection, as indicated by quantitative real-time polymerase chain reaction and Western blot. Next, we found that cell proliferation and colony formation were markedly reduced in SUN1 silenced cells. Moreover, suppression of SUN1 led to cell cycle arrest at G0/G1 phase. Furthermore, Cyclin D1, CDK6, and CDK2 expressions were obviously reduced in A549 cells after SUN1 silencing. CONCLUSION: These results suggest that SUN1 plays an essential role in proliferation of lung adenocarcinoma cells in vitro and may be used as a potential therapeutic target for the treatment of lung adenocarcinoma in the future. PMID- 28652765 TI - Disruption of human papillomavirus 16 E6 gene by clustered regularly interspaced short palindromic repeat/Cas system in human cervical cancer cells [Retraction]. AB - [This retracts the article on p. 37 in vol. 8, PMID: 25565864.]. PMID- 28652766 TI - Role of matrix metalloproteinase-9 in transforming growth factor-beta1-induced epithelial-mesenchymal transition in esophageal squamous cell carcinoma. AB - Epithelial-mesenchymal transition (EMT) is thought to be a crucial event during the early metastasis of tumor cells. Transforming growth factor (TGF)-beta1 is involved in the process of EMT in a variety of human malignancies. Matrix metalloproteinase (MMP)-9 plays an important role in tumor invasion and metastasis, and its expression is regulated by various growth factors, including TGF-beta1, in different cell types. To date, the role of MMP-9 in TGF-beta1 induced EMT in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we aimed to elucidate the mechanism underlying MMP-9-mediated TGF-beta1 induction of EMT in ESCC. We analyzed the expression of MMP-9, E-cadherin, and vimentin, in ESCC cells (EC-1), before and after the treatment with exogenous TGF beta1 or a broad spectrum MMP inhibitor, GM6001. Additionally, we analyzed the activity of MMP-9 in these cells and performed MMP-9 knockdown experiments. The results obtained in this study demonstrated that the treatment of EC-1 cells with TGF-beta1 can induce EMT, together with the upregulation of vimentin and downregulation of E-cadherin expression in a time-dependent manner. The treatment with GM6001 was shown to attenuate TGF-beta1-induced EMT. Furthermore, the exposure of EC-1 cells to TGF-beta1 increased the expression and activity of MMP 9, while MMP-9 knockdown blocked TGF-beta1-induced EMT and inhibited cell invasiveness and migration. Additionally, treatment with the recombinant human MMP-9 was shown to induce EMT and enhance ESCC cell invasion and metastasis. The obtained data suggest that the regulation of MMP-9 by TGF-beta1 may represent a novel mechanism underlying TGF-beta1-induced EMT in ESCC. PMID- 28652767 TI - Prognostic value of high IMP3 expression in solid tumors: a meta-analysis. AB - BACKGROUND: Accumulated studies have investigated the prognostic role of insulin like growth factor II mRNA-binding protein 3 (IMP3) in various cancers, but inconsistent and controversial results were obtained. Therefore, we performed a systematic review and meta-analysis to investigate the potential value of IMP3 in the prognostic prediction of human solid tumors. MATERIALS AND METHODS: A systematic literature search in the electronic databases PubMed, Embase, Web of Science, and Cochrane library (updated to April 2016) was conducted to identify eligible studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for survival outcomes were calculated and gathered using STATA 12.0 software. RESULTS: A total of 53 studies containing 8,937 patients with solid tumors were included in this meta-analysis. High IMP3 expression was significantly associated with worse overall survival (OS) of solid tumors (HR =2.08, 95% CI: 1.80-2.42, P<0.001). Similar results were observed in cancer-specific survival (CSS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), and metastasis-free survival (MFS). Further subgroup analysis stratified by tumor type showed that elevated IMP3 expression was associated with poor OS in renal cell carcinoma (RCC), lung cancer, oral cancer, urothelial carcinoma, hepatocellular carcinoma (HCC), colorectal cancer, pancreatic cancer, gastric cancer, and intrahepatic cholangiocarcinoma (ICC). CONCLUSION: The current evidence suggests that high IMP3 expression is associated with poor prognosis in most solid tumors. IMP3 is a potential valuable prognostic factor and might serve as a promising biomarker to guide clinical decisions in human solid tumors. PMID- 28652768 TI - PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy. AB - Endometrial cancer (EC) is now one of the most common malignant tumors in young women. In all, 90% of young patients with EC have a high expression of progesterone recep tor, can be treated with progestin, and have very good prognosis. However, some of the young EC patients are resistant to progestin, the mechanism of which is unclear. To illuminate the mechanism by which endometrial cells acquire progestin resistance, we treated Ishikawa cells by slowly increasing dosage of progestin and established a progestin-resistant cell subline. We show here that progesterone resistant cells acquire increased proliferation rate and interestingly decreased autophagy. To uncover the mechanism by which cells increase proliferation and bypass autophagy, we found higher activation of phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway was necessary to this malignant acquirement by RNAi technique. Further, we elucidated that activation of mTOR was sufficient and necessary for progestin resistance. RAD001, an inhibitor of mTOR, decreased phosphorylation of mTOR and inhibited proliferation of progestin-resistant cancer cells by promoting autophagy. Thus, our results indicated that mTOR can be a target to treat the progestin-resistant EC. PMID- 28652769 TI - Upregulated long noncoding RNA PANDAR predicts an unfavorable prognosis and promotes tumorigenesis in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is one of the most malignant human cancers with increasing incidence worldwide. LncRNAs have emerged as gene regulators and prognostic biomarkers in a variety of neoplasms. PANDAR, a novel cancer-related lncRNA, has been reported to be upregulated in diverse human carcinomas. In this study, we aimed to investigate the clinical significance of lncRNA PANDAR in CCA and explore its functional roles in CCA cells including cell proliferation, apoptosis, migration, invasion and epithelial-to-mesenchymal transition (EMT). The results showed that PANDAR was significantly upregulated in CCA tissue specimens and cell lines, and its high expression was closely associated with lymph node invasion (P=0.004), TNM stage (P=0.034) and postoperative relapse (P=0.006) in patients with CCA. Thus, overexpression of PANDAR could serve as an independent prognostic biomarker of CCA. Furthermore, silencing of PANDAR followed by siRNA significantly inhibited cell proliferation and increased apoptosis in CCA cells. In addition, suppression of PANDAR impaired migration and invasion capacity in vitro partly by affecting EMT. Overall, our findings showed that lncRNA PANDAR serves as a novel prognostic biomarker and therapeutic target for CCA. PMID- 28652770 TI - Stereotactic body radiotherapy or stereotactic ablative radiotherapy versus surgery for patients with T1-3N0M0 non-small cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has been reported to be a comparable alternative therapy to surgery for patients with T1-3N0M0 non-small cell lung cancer (NSCLC). However, it has not been clarified whether SBRT/SABR is as effective as surgery. We conducted this study to compare the efficacy of SBRT/SABR and surgery in the treatment of T1-3N0M0 NSCLC. MATERIALS AND METHODS: An electronic and a manual search of the literature was conducted in PubMed, Embase, and the Wiley Online Library in all published data before January 1, 2017. The pooled data included overall survival (OS), recurrence-free survival (RFS), and locoregional/distant recurrence rate. Hazard ratio (HR) of OS (SBRT/SABR vs surgery) was used as the measure of differential effects. RESULTS: Fifteen studies, including 7,810 patients with T1-3N0M0 NSCLC, 2,986 patients in the SBRT/SABR group, and 4,824 patients in the surgery group, were pooled for the meta-analysis. Results showed that patients with SBRT/SABR had a significantly worse 5-year survival rate (HR =1.40; 95% confidence interval [CI]: 1.21, 1.61; P<0.01), and RFS rate (HR =1.84; 95% CI: 1.26, 2.68; P=0.002). Meanwhile, the locoregional recurrence rate (HR =1.17; 95% CI: 0.68, 1.98; P=0.57), and distant recurrence rate (HR =1.36; 95% CI: 0.77, 2.39; P=0.29) were also lower in the surgery group although results were not statistically significant. In subgroup analyses, SBRT/SABR had a significantly lower rate of 5-year survival (HR =1.46; 95% CI: 1.03, 2.06; P=0.03) compared with lobectomy. Similarly, significant differences of OS exist in comparisons of SBRT/SABR versus sublobectomy (HR =1.40; 95% CI: 1.09, 1.80; P=0.008), and wedge resection (HR =1.48; 95% CI: 1.01, 2.16; P=0.04). CONCLUSION: Surgery, both lobectomy and sublobectomy, might be superior to SBRT/SABR with regard to survival of patients with T1-3N0M0 NSCLC. Patients with T1-3N0M0 NSCLC should preferably be treated surgically prior to SBRT/SABR. PMID- 28652771 TI - The prognostic value of cyclooxygenase-2 expression in patients with esophageal cancer: evidence from a meta-analysis. AB - Published studies have investigated the prognostic role of cyclooxygenase-2 (COX 2) expression in patients with esophageal cancer (EC), but the result remains controversial. Thus, this meta-analysis was conducted to comprehensively evaluate the impact of COX-2 expression on the prognostic value in patients with EC. Relevant studies were identified from PubMed, EMBASE, and Web of Science databases. Studies that detected the COX-2 expression by immunohistochemistry and evaluated the relationship between COX-2 expression and overall survival (OS) or clinicopathological parameters were used in our analysis. The summary hazard ratios (HRs) or odds ratios were calculated to assess the risk or hazard association. A total of 25 studies, which included 2,465 patients, were included in our meta-analysis. Our analysis suggested that overexpression of COX-2 was associated with poor OS (HR =1.60, 95% CI =1.32-1.94, P<0.001). Subgroup analyses by race, percentage of high/positive COX-2 expression, histology type, treatment, and sample size all suggested significant association. Moreover, overexpression of COX-2 was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and TNM stage. This meta-analysis suggested that overexpression of COX-2 might serve as a prognostic biomarker for EC. Large well designed prospective studies are needed to confirm our conclusion. PMID- 28652772 TI - Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment. AB - BACKGROUND: There are limited data available on the treatment and outcome of epidermal growth factor receptor (EGFR) exon 20-mutated lung cancer patients. Hence, we planned an analysis of the demographic details, clinical profile and survival of lung cancer patients with exon 20 mutations. We compared our results to patients with EGFR tyrosine kinase inhibitor (TKI)-sensitizing activating and EGFR/anaplastic lymphoma kinase (ALK)-negative mutations. METHODS: This was a retrospective analysis of lung cancer patients who were treated at our center between January 2010 and August 2014. We reviewed the results of EGFR mutation testing by real-time polymerase chain reaction and Sanger sequencing. We also reviewed the data relating to baseline demographics, clinical profile, patient treatment and outcome measures in terms of response and overall survival (OS). RESULTS: A total of 580 patients fulfilled the selection criteria. In all, 227 (39.1%) patients had EGFR TKI-sensitizing activating mutations, 20 (3.4%) patients had exon 20 insertion mutations and 333 patients were EGFR/ALK mutation negative (57.5%). The median OS was 5 months (95% confidence interval [CI] 0.17 9.8 months) in exon 20 insertion mutations, 16.1 months (95% CI 12.8-19.5 months) in EGFR TKI-sensitizing activating mutations and 10 months (95% CI 7.9-12.1 months) in EGFR/ALK mutation-negative patients. The median OS was significantly better for the EGFR TKI-sensitizing activating mutation group (P=0.000, log-rank test) and for the EGFR/ALK-negative group (P=0.037, log-rank test) compared to the exon 20-mutated group. CONCLUSION: Exon 20 mutation results in a poorer OS prognosis compared to EGFR- and ALK-negative patients and patients harboring EGFR TKI-sensitizing activating mutations. The incidence of de novo exon 20 insertions was 3.4%. Different types of exon mutations seem to have different outcomes. PMID- 28652773 TI - Long-term outcomes of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (CCRT) vs CCRT alone for nasopharyngeal carcinoma in the era of intensity-modulated radiation therapy using propensity score matching method. AB - PURPOSE: Whether neoadjuvant chemotherapy (NCT) followed by concurrent chemoradiotherapy (CCRT) could improve survival in nasopharyngeal carcinoma (NPC) remains controversial especially in the era of intensity-modulated radiation therapy (IMRT), and we explored the role of NCT for NPC patients. PATIENTS AND METHODS: A retrospective review was conducted of 255 NPC patients treated with NCT+CCRT (n=67) or CCRT alone (n=188) based on IMRT between December 2006 and December 2012. To control the imbalance, a 1:2 match was performed using propensity score matching (PSM) method based on patient's heterogeneity and regimens of concurrent chemotherapy (CCT). The long-term treatment outcomes and toxicity between NCT group (n=67) and concurrent chemoradiotherapy (CRT) group (n=134) after PSM were compared. RESULTS: The 5-year overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), local recurrence free survival (LRFS), regional recurrence-free survival (RRFS) and distant failure-free survival (DFFS) were 78.8%, 69.1%, 90.0%, 90.0%, 100% and 78.3% for NCT group, while 79.5%, 75.7%, 92.7%, 94.2%, 96.1% and 82.7% for CRT group (P=0.305, 0.448, 0.790, 0.512, 0.104 and 0.671). It indicated that the treatment method (NCT+CCRT vs CCRT) was not the independent prognostic factor for the survival in NPC patients, and only patients who had completed at least two cycles of CCT got better OS, RFS and DFFS (P=0.009, 0.016 and 0.043), whether to receive NCT or not. No difference in the incidences of any acute and most late toxicity between the two groups was shown. CONCLUSION: Our study did not show the exact advantage of NCT followed by CCRT compared with CCRT alone or higher incidences of toxicity in NCT group. It suggests that NCT might not be necessary if two or more cycles of CCT are finished well in the era of IMRT, and when NCT is finished well, less than two cycles of CCT with IMRT could be enough. However, in the era of IMRT, the role of NCT still needs to be further explored. PMID- 28652774 TI - Vasculogenic mimicry is associated with increased tumor-infiltrating neutrophil and poor outcome in esophageal squamous cell carcinoma. AB - PURPOSE: Vasculogenic mimicry (VM) is known to be a mechanism to nourish the tumor, but little is known about its prognostic significance in esophageal squamous cell carcinoma (ESCC). We characterized the predictive relevance of VM expression and tumor-infiltrating neutrophil (TIN) density in patients with resectable ESCC. METHODS: We retrospectively collected clinicopathologic characteristics of 117 esophageal cancer (EC) patients undergoing complete resection and without preoperative therapy. Immunohistochemistry was used to detect the expression of E-cadherin and CD66b. CD34/periodic acid-schiff (PAS) double staining was used to detect the expression of VM. RESULTS: VM expression was observed in 56 (47.9%) patients. VM was negatively correlated with E-cadherin (correlation coefficient =-0.364, P<0.001) and was positively correlated with infiltration of CD66b neutrophil (correlation coefficient =0.421, P<0.001). VM and CD66b+ neutrophil infiltration are important markers for poor overall survival and disease-free survival. Multivariate analysis showed that VM, CD66b+ neutrophil infiltration, pathologic tumor node metastasis (TNM) (pTNM) stage, and tumor differentiation are significant independent prognostic predictors in ECs (P=0.001, 0.025, 0.001, 0.011, respectively). VM expression is identified in ~47.9% of ESCC, and it is associated with poor outcome and increased TIN. CONCLUSION: TIN is an important factor for VM formation. Therefore, studies of invasive ability of EC in patients with VM could supply significant information for therapeutic strategy. PMID- 28652775 TI - WWC3 downregulation correlates with poor prognosis and inhibition of Hippo signaling in human gastric cancer. AB - The aim of this study was to investigate the clinicopathological significance and biological roles of WWC3 in human gastric cancer (GC). Clinical significance of WWC3 in human GCs was examined by using immunohistochemistry (IHC). WWC3 was downregulated in 48 of 111 human GCs, and its downregulation was associated with advanced stage, positive nodal status, and higher relapse rate. Importantly, WWC3 downregulation correlated with poor survival. It was also found that WWC3 protein expression was downregulated in GC cell lines compared with normal cell line GES 1. On one hand, WWC3 overexpression inhibited the cell growth rate and invading ability in HGC-27 cell line. On the other hand, depleting WWC3 by small interfering RNA (siRNA) promoted proliferation rate and invading ability in the SGC-7901 cell line. In addition, cell cycle analysis showed that WWC3 overexpression inhibited while its depletion accelerated cell cycle progression at the G1/S transition. Western blot (WB) analysis demonstrated that WWC3 repressed cyclin D1 and cyclin E while upregulated p27 expression. Luciferase reporter assay showed that WWC3 activated Hippo signaling pathway by suppressing TEAD transcription activity, with downregulation of total and nuclear YAP and its target CTGF. WWC3 siRNA depletion exhibited the opposite effects. In conclusion, this study indicates that WWC3 serves as a tumor suppressor in GC by activating Hippo signaling. PMID- 28652776 TI - Prognosis of prostate cancer with initial prostate-specific antigen >1,000 ng/mL at diagnosis. AB - PURPOSE: Prostate cancer patients with surprisingly high prostate-specific antigen (PSA) are encountered clinically. However, descriptions of this group of patients are extremely rare in the published literature. This study reports treatment outcome and long-term prognosis for this group of patients. PATIENTS AND METHODS: Between January 2007 and December 2012, 2,064 patients with PCa diagnosed at a tertiary medical center were retrospectively reviewed. A total of 90 PCa cases were identified with initial PSA (iPSA) >1,000 ng/mL at diagnosis. A retrospective study was conducted in this cohort, with comparison among stratified patient age groups, PSA, treatment options, and overall survival. RESULTS: The mean PSA at PCa diagnosis in this cohort was 3,323 ng/mL (1,003 23,126, median: 2,050 ng/mL). Most patients were in the age group 65-79 years (55/90, 61%). Males older than 80 years had a poor prognosis (P<0.001). Forty-six patients (51%) underwent orchiectomy with a median follow-up period of 16.2 (1.3 72.7) months, compared to 44 patients treated with medical castration and a median follow-up of 9.1 (0.3-70.5) months. Kaplan-Meier analysis revealed survival benefit from treatment with orchiectomy (P<0.001). PSA reduction >90% of iPSA following primary androgen deprivation therapy (reaching true nadir) could be a predictor of longer survival (P<0.001). Cox regression revealed the hazard ratio (HR) of variables were age (HR: 4.57, 95% confidence interval [CI]: 1.45 14.37, P=0.009), reaching true nadir (HR: 0.12, 95% CI: 0.03-0.58, P=0.008), and the treatment option with orchiectomy (HR: 0.22, 95% CI: 0.65-0.76, P=0.016). CONCLUSION: Age >=80 years indicated poor overall survival in PCa patients with iPSA >1,000 ng/mL. Reaching a true nadir of PSA following primary androgen deprivation therapy could be a predictor of longer survival. Bilateral orchiectomy is recommended for this group of patients. PMID- 28652777 TI - Overexpression of the cancer stem cell marker CD117 predicts poor prognosis in epithelial ovarian cancer patients: evidence from meta-analysis. AB - PURPOSE: Cancer stem cells have recently been identified as a key driving factor for tumor metastasis and chemoresistance. CD117 is a well-established cancer stem cell marker, but its clinical significance in epithelial ovarian cancer (EOC) remains controversial. Therefore, we aimed to identify correlations between CD117 expression and clinical features and outcomes in EOC patients in this meta analysis. MATERIALS AND METHODS: A literature search was performed in the PubMed, Cochrane Library, Web of Science, EMBASE, and OVID databases to identify eligible studies. Correlations between CD117 expression and clinicopathological parameters and overall survival or disease-free survival were analyzed. A subgroup analysis was then performed, which was classified by patient ethnicity and age at diagnosis, study sample size, and tumor histological type. RESULTS: A total of seven studies enrolling 1,247 EOC patients were included in this meta-analysis. Our results demonstrated that CD117 expression was significantly correlated with age (pooled odds ratio [OR] =1.67, 95% confidence interval [CI] =1.05-2.66), International Federation of Gynecology and Obstetrics stage (pooled OR =1.99, 95% CI =1.31-3.02), tumor differentiation grade (pooled OR =2.46, 95% CI =1.48-4.10), and histological type (pooled OR =1.85, 95% CI =1.05-3.26). EOC patients with high CD117 expression had significantly worse OS (hazard ratio [HR] =1.39, 95% CI =1.03-1.90) than patients with low CD117 expression. However, no significant correlation was found between CD117 expression and disease-free survival (HR =1.31, 95% CI =0.79-2.17). In subgroup analysis, CD117 was identified as a significant prognostic factor for overall survival in European patients (HR =1.59, 95% CI =1.13-2.23), younger patients (<60 years) (HR =1.59, 95% CI =1.10 2.30), studies with sample sizes >200 (HR =1.84, 95% CI =1.32-2.56), and the mixed histological types (HR =1.47; 95% CI =1.08-2.00). CONCLUSION: Our meta analysis suggests that CD117 is associated with EOC progression and can serve as a promising prognostic predictor for EOC patients. However, larger scale multicenter clinical trials are still needed to further validate our results. PMID- 28652778 TI - Serum levels of IGF-1 and IGF-BP3 are associated with event-free survival in adult Ewing sarcoma patients treated with chemotherapy. AB - BACKGROUND: Activation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy. PATIENTS AND METHODS: Serum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O'Quigley procedure. Survival analyses were performed using Cox regression analysis. RESULTS: High baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009-0.602 and HR 0.090, 95% CI 0.011-0.712, respectively) in univariate and multivariate analyses (HR 0.063, 95% CI 0.007-0.590 and HR 0.057, 95% CI 0.005-0.585, respectively). OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively). CONCLUSION: High circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated with improved EFS and a trend for improved OS in Ewing sarcoma patients treated with VIDE chemotherapy. These findings suggest the need for further investigation of the IGF-1 pathway as a biomarker of disease progression in patients with Ewing sarcoma. PMID- 28652779 TI - Accelerated or hyperfractionated radiotherapy for esophageal carcinoma: a meta analysis of randomized controlled trials. AB - OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of modified (accelerated and/or hyperfractionated) radiotherapy in the treatment of esophageal carcinoma, compared with conventional radiotherapy. METHODS: Studies published in the PubMed, Cochrane Library, EMBASE, CBM, VIP, CNKI and Wanfang databases in the most recent two decades were searched for use in this meta analysis. Only randomized controlled trials were included. The heterogeneity analysis and calculation of the pooled odds ratio (OR) were performed using RevMan 5.3 software. The assessment of publication bias and sensitivity analyses was conducted using Stata 13.0 software. RESULTS: Twenty trials with a total of 1,742 Chinese patients who met the inclusion criteria were included. The pooled results showed that modified radiotherapy improved the response rate compared with conventional schedules (OR =3.90, 95% confidence interval [CI]: 2.47-6.16, P<0.001). Favorable results were observed for the 1-year (OR =2.58, 95% CI: 2.05 3.26, P<0.001), 3-year (OR =2.30, 95% CI: 1.83-2.89, P<0.001) and 5-year (OR =2.36, 95% CI: 1.74-3.21, P<0.001) overall survival and for the 1-year (OR =2.46, 95% CI: 1.72-3.51, P<0.001), 3-year (OR =2.08, 95% CI: 1.49-2.90, P<0.001) and 5 year (OR =2.15, 95% CI: 1.38-3.34, P<0.001) overall local control rate in the modified fractionation radiotherapy group. However, the altered radiotherapy increased the risk of acute radiation esophagitis (OR =1.70, 95% CI: 1.27-2.28, P<0.001) and acute radiation tracheitis (OR =1.47, 95% CI: 1.09-1.99, P=0.01). No significant differences in the risk of esophageal perforation (OR =1.30, 95% CI: 0.51-3.32, P=0.58) or esophagorrhagia (OR =0.88, 95% CI: 0.41-1.88, P=0.74) were found between the two groups. CONCLUSION: Chinese patients with squamous cell esophagus carcinomas gained a significant benefit in terms of the response rate, survival and local control rates from the modified fractionation radiotherapy, but also had an increased risk of acute radiation reactions. Otherwise, there was no observed statistically significant difference in terms of early adverse reactions. PMID- 28652780 TI - Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors. AB - OBJECTIVES: PD-1/PD-L1 and CTLA-4 have been investigated and are thought to play an important role in tumor evasion. This study aimed to investigate expression patterns of immune-related molecules, and their clinical impacts in malignant salivary gland tumors. PATIENTS AND METHODS: We performed immunohistochemical staining for PD-L1, PD-L2, CTLA-4, PD-1, and CD8+ tumor-infiltrating lymphocytes in 70 malignant salivary gland tumors. Protein expression was assessed by H-score by multiplying the staining intensity by the percentage of cells with positive staining. RESULTS: The tumors comprised mucoepidermoid carcinomas (38.6%), adenoid cystic carcinomas (21.4%), salivary duct carcinomas (15.7%), and others. In malignant salivary gland tumors, PD-L2 expression was high, while expression of PD-L1 was relatively low in terms of the percentage of positively stained cells and the staining intensity. In univariate analysis, PD-L2 expression (H score <1 vs >=1), PD-1 (H-score <1 vs >=1), and CD8+ tumor-infiltrating lymphocytes (H-score <1 vs >=1) were significant prognostic factors. In multivariate analysis, low PD-L2 expression (H-score <1) was independently associated with shorter relapse-free survival (hazard ratio =6.514; 95% confidence interval, 1.2-36.2; P=0.032). CONCLUSION: In summary, PD-L2 is potentially an important biomarker in malignant salivary gland tumors, especially in regard to relapse. PMID- 28652781 TI - Combination of azacitidine and trichostatin A decreased the tumorigenic potential of lung cancer cells. AB - PURPOSE: This study aims to investigate the possibility of using epigenetic inhibitors against lung cancer. METHODS: The changes in the proliferation of human lung cancer cells, NCI-H1975 and NCI-H1299 cells, treated with various doses of inhibitors of DNA methyltransferase (azacitidine [5-AZA]) or histone deacetylase inhibitors (trichostatin A [TSA]) were determined by cell counting. The cell viability of NCI-H1975 and NCI-H1299 cells treated with 5-AZA and/or TSA was measured by the MTT assay. The changes in expression of the AKT signaling pathway molecules caused by the application of 5-AZA and TSA were analyzed through their protein and mRNA levels. A xenograft model was used to observe the effects of 5-AZA and TSA on tumor growth in vivo. RESULTS: 5-AZA and TSA inhibited the proliferation and viability of NCI-H1975 and NCI-H1299 cells. Their joint application significantly influenced the expression of key molecules in AKT signaling pathway in vitro, and inhibited the growth of xenograft tumors in vivo. Furthermore, TSA and 5-AZA decreased the tumorigenic ability of NCI-H1975 cells in vivo. CONCLUSION: The decreased cell viability and tumorigenic ability, as well as increased anti-oncogene expression following the joint application of 5 AZA and TSA, make these epigenetic inhibitors prospective therapeutic agents for lung cancer. PMID- 28652782 TI - Hepatic artery-infusion chemotherapy improved survival of hepatocellular carcinoma after radical hepatectomy. AB - OBJECTIVE: To evaluate the effect of postoperative hepatic artery-infusion chemotherapy (HAIC) on survival probability in patients with hepatocellular carcinoma (HCC) after radical hepatectomy. PATIENTS AND METHODS: This retrospective study included 85 patients with HCC who received radical hepatectomy from May 2005 to May 2010. Among these patients, 42 underwent two sessions of HAIC (5-fluoruracil [1,000 mg/m2], oxaliplatin [85 mg/m2], and mitomycin-C [6 mg/m2]) after radical hepatectomy (HAIC group), and 43 underwent radical hepatectomy only (the control group). HAIC-related side effects and long term survival were retrospectively analyzed. RESULTS: The HAIC group showed a significantly higher 5-year intrahepatic recurrence-free survival probability and lower risk of intrahepatic recurrence (HR 0.5615, 95% CI 0.3234-0.9749 [log-rank test]; P=0.0332). The HAIC group also had significantly higher 5-year disease free survival probability (HR 0.591, 95% CI 0.3613-0.9666 [log-rank test]; P=0.0298) and overall survival probability than the control group (HR 0.5768, 95% CI 0.3469-0.9589 [log-rank test]; P=0.0278). No HAIC-related deaths in the HAIC group were reported. All toxicities and complications were controlled, and no patients quit the treatment. CONCLUSION: HAIC can effectively and safely reduce intrahepatic recurrence and improve the long-term survival of patients with HCC after radical hepatectomy. PMID- 28652783 TI - Prioritizing single-nucleotide polymorphisms and variants associated with clinical mastitis. AB - Next-generation sequencing technology has provided resources to easily explore and identify candidate single-nucleotide polymorphisms (SNPs) and variants. However, there remains a challenge in identifying and inferring the causal SNPs from sequence data. A problem with different methods that predict the effect of mutations is that they produce false positives. In this hypothesis, we provide an overview of methods known for identifying causal variants and discuss the challenges, fallacies, and prospects in discerning candidate SNPs. We then propose a three-point classification strategy, which could be an additional annotation method in identifying causalities. PMID- 28652784 TI - Current perspective on emergence, diagnosis and drug resistance in Candida auris. AB - Candida auris is an emerging fungus that presents a serious threat to global health. The organism is difficult to identify using conventional biochemical methods. C. auris has also attracted attention because of its reduced susceptibility to azoles, polyenes, and echinocandins, with a few strains even resistant to all three classes of antifungals. In this review paper we discuss the trends in emergence of C. auris in different parts of the world, associated risk factors, drug resistance, and diagnostic challenges. Strategies for prevention and therapeutic options for such infections is also addressed. PMID- 28652785 TI - Prevalence and antibiotic resistance of coagulase-negative Staphylococci isolated from poultry farms in three regions of Ghana. AB - The use of antibiotics in animal production has been associated with the development and spread of antibiotic-resistant organisms including commensals. Coagulase-negative Staphylococcus (CoNS) species, which were until recently considered non-pathogenic, have been associated with opportunistic infections and high resistance to several antibiotics. This study sought to determine the prevalence, identity, and phenotypic resistance of coagulase-negative Staphylococcus spp. isolated from some selected poultry farms and farm workers in the Ashanti, Brong Ahafo, and Greater Accra regions of Ghana. Poultry litter samples and oral swabs of poultry farm workers were collected, from which bacterial species were isolated, identified, and analyzed. Various selective media were used for the presumptive identification of the different species. Confirmation of bacterial identity was done using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry. Antibiotic susceptibility testing of the isolates was performed using the Kirby-Bauer disk diffusion method. Zones of growth inhibition were interpreted based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Two hundred and fifty-six coagulase-negative Staphylococcus spp., comprising S. sciuri (42.97%), S. lentus (35.94%), S. gallinarum (6.64%), S. xylosus (4.30%), S. haemolyticus (3.91%), S. saprophyticus (1.95%), and S. cohnii (0.39%) were confirmed by MALDI-TOF. CoNS were isolated from samples from the Brong Ahafo (48.83%), Ashanti (33.59%), and Greater Accra (17.78%) regions. Isolates from poultry litter constituted 55.47%, and farm workers 44.53%. All the isolates were susceptible to amoxicillin/clavulanic acid and amikacin. The isolates exhibited high resistance toward tetracycline (57.03%), doxycycline (43.75%), and oxacillin (43.36%). Multi-drug resistance (MDR) was observed in 19.14% of the isolates. MDR was higher in isolates obtained from poultry farm workers (61.22%) than isolates from poultry litter (38.78%). The above findings call for stricter monitoring of antibiotic usage in both animal production and in humans. PMID- 28652786 TI - Rifampicin-resistant Mycobacterium tuberculosis among tuberculosis-presumptive cases at University of Gondar Hospital, northwest Ethiopia. AB - BACKGROUND: Various studies have reported that the emergence of drug-resistant tuberculosis poses a significant threat to tuberculosis-control programs worldwide. Rifampicin resistance is a surrogate marker of multidrug-resistant tuberculosis, since it reveals the presence of greater than 90% isoniazid resistance. Evidence on rifampicin-resistant Mycobacterium tuberculosis is scarce in the literature. OBJECTIVE: To determine the prevalence of rifampicin-resistant M. tuberculosis among tuberculosis-presumptive cases at the University of Gondar Hospital. MATERIALS AND METHODS: A retrospective study was conducted at the University of Gondar Hospital from January 2013 to August 2015. Data were collected from registration books using a data-extraction format after securing ethical approval and checking the completeness of necessary information. Data were double-entered and rechecked to ensure accuracy and analyzed using SPSS version 20. Results were summarized using descriptive statistics. Associations were assessed using Fisher's exact test, and P<0.05 was considered statistically significant. RESULTS: A total of 1,820 M. tuberculosis-presumptive patients were included in the study. The majority of the study participants were males (59.2%). The mean age of the participants was 36.6+/-15.8 years. The preponderant age group was 24-30 years, with 477 (23.5%) patients. The overall prevalence of M. tuberculosis-confirmed cases was 448 (24.6%, 95% CI 0.23-0.27). Of the 448 M. tuberculosis-confirmed cases, 71 (15.8%, 95% CI 1.12-1.19) were resistant to rifampicin. Rifampicin-resistant M. tuberculosis was observed among HIV seropositives (14 [18.7%]), males (45[17.3%]), and previously treated tuberculosis patients (61 [16.5%]), although no significant association was found in this study. CONCLUSION: The overall prevalence of M. tuberculosis and rifampicin resistance was found to be high in tuberculosis patients in this study. Therefore, early detection of drug-resistant M. tuberculosis should be strengthened for management of tuberculosis patients. PMID- 28652787 TI - Oncology drugs for orphan indications: how are HTA processes evolving for this specific drug category? AB - Orphan drugs (ODs) are intended for the diagnosis, prevention, or treatment of rare diseases. Many cancer subtypes, including all childhood cancers, are defined as rare diseases, and over one-third of ODs are now intended to treat oncology indications. However, market access for oncology ODs is becoming increasingly challenging; ODs are prone to significant uncertainty around their cost effectiveness, while payers must balance the need for these vital innovations with growing sensitivity to rising costs. The objective of this review was to evaluate different mechanisms that have been introduced to facilitate patient access to oncology ODs in five different countries (Australia, Canada, England, France, and Sweden), using eight oncology ODs and non-orphan oncology drugs as examples of their application. A targeted literature review of health technology assessment (HTA) agency websites was undertaken to identify country-specific guidance and HTA documentation for recently evaluated oncology ODs and non-orphan oncology drugs. None of these countries were found to have explicit HTA criteria for the assessment of ODs, and therefore, oncology ODs are assessed through the usual HTA process. However, distinct and additional processes are adopted to facilitate access to oncology ODs. Review of eight case-study drugs showed that these additional assessment processes were rarely used, and decisions were largely driven by proving cost-effectiveness using standard incremental cost effectiveness ratio (ICER) thresholds. The predominant implication arising from this study is that application of standard HTA criteria to oncology ODs in many countries fails to take into account any uncertainties around their clinical- and cost-effectiveness, resulting in disparities in HTA reimbursement decisions based on differences in addressing or accepting uncertainty. In order to address this issue, HTA agencies should adopt a more flexible approach to cost-effectiveness, as typified by the Tandvards-och Lakemedelsformansverket in Sweden, which takes into account the small patient numbers involved, limited budget impact, and high unmet medical needs. PMID- 28652788 TI - Economic and organizational sustainability of a negative-pressure portable device for the prevention of surgical-site complications. AB - PURPOSE: Surgical-site complications (SSCs) affect patients' clinical pathway, prolonging their hospitalization and incrementing their management costs. The present study aimed to assess the economic and organizational implications of a portable device for negative-pressure wound therapy (NPWT) implementation, compared with the administration of pharmacological therapies alone for preventing surgical complications in patients undergoing general, cardiac, obstetrical-gynecological, or orthopedic surgical procedures. PATIENTS AND METHODS: A total of 8,566 hospital procedures, related to the year 2015 from one hospital, were evaluated considering infection risk index, occurrence rates of SSCs, drug therapies, and surgical, diagnostic, and specialist procedures and hematological exams. Activity-based costing and budget impact analyses were implemented for the economic assessment. RESULTS: Patients developing an SSC absorbed i) 64.27% more economic resources considering the length of stay (? 8,269+/-2,096 versus ? 5,034+/-2,901, p<0.05) and ii) 42.43% more economic resources related to hematological and diagnostic procedures (? 639+/-117 versus ? 449+/-72, p<0.05). If the innovative device had been used over the 12-month time period, it would have decreased the risk of developing SSCs; the hospital would have realized an average reduction in health care expenditure equal to 0.69% (-? 483,787.92) and an organizational saving in terms of length of stay equal to -1.10% (-898 days), thus allowing 95 additional procedures. CONCLUSION: The implementation of a portable device for NPWT would represent an effective and sustainable strategy for reducing the management costs of patients. Economic and organizational savings could be reinvested, thus i) treating a wider population and ii) reducing waiting lists, with a higher effectiveness in terms of a decrease in complications. PMID- 28652789 TI - Community-based health insurance and communities' scheme requirement compliance in Thehuldere district, northeast Ethiopia: cross-sectional community-based study. AB - BACKGROUND: Community-based health insurance (CBHI) is becoming a prominent and promising concept in tackling financial health care issues confronting the poor rural communities in developing countries. Ethiopia endorsed and constituted CBHI schemes in 13 pilot "woredas" in 2010/11. This study aimed to assess the compliance of the community to CBHI scheme requirements in Thehuledere district, northeast Ethiopia. METHODS: A community-based cross-sectional study was conducted among 530 respondents between April and June 2015 in Thehuledere District, South Wollo Zone, northeast Ethiopia. A systematic random sampling technique was deployed to select the study participants. A self-administered, structured, pre-tested questionnaire was used to collect the data. Bivariate and multivariate logistic regression analyses were used to identify factors associated with CBHI compliance. RESULTS: A total of 511 study participants were included in the study. Approximately 77.9% of the study population complied with CBHI requirements: members' age (AOR = 0.74, 95% CI: 0.62-0.8), premium fee affordability (AOR: 2.66, 95% CI: [1.13-4.42]), members' occupation (AOR = 0.14, 95% CI: 0.04-0.45), members' attitude toward CBHI management (AOR = 2.11 [1.14 3.90]), and CBHI members' knowledge (AOR = 0.24, 95% CI: [0.13-0.42]) were found to be major predictors of community compliance to CBHI requirements. CONCLUSION: CBHI requirement compliance at the early stage was relatively high. We observed that members' age, premium fee affordability, occupation, attitude, and knowledge were significant predictors. CBHI management's involvement in awareness creation and training on requirements of the CBHI scheme would contribute to better outcomes and success. PMID- 28652790 TI - Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway. AB - BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor used in type 2 diabetes therapy, has demonstrated protective effects in diabetic chronic kidney disease, in part due to its pleiotropic actions. However, its potential direct effects on the kidney are still not completely defined. Here, by means of proteomics and miRNA profiling, we have further unveiled the role of sitagliptin in oxidative stress, as well as the underlying mechanisms. METHODS: Renal cortex samples from 9-month-old wild-type (Wistar), type II diabetic Goto-Kakizaki (GK) and sitagliptin-treated GK rats (GK+Sita) (10 mg kg-1 per day) were subjected to quantitative miRNA transcriptomic array, immunohistochemistry and Western blot studies. Renal GK and GK+Sita samples were also analyzed by differential in-gel electrophoresis. Bioinformatic tools were used to find out the relationships between altered proteins and related miRNA expression. Studies were also carried out in cultured tubular cells to confirm in vivo data. RESULTS: Diabetic GK rats exhibited proteinuria, renal interstitial inflammatory infiltrates and fibrosis, which improved by 20 weeks of sitagliptin treatment. Proteomic analysis of diabetic GK and Wistar rats showed a differential expression of 39 proteins mostly related to oxidative stress and catabolism. In addition, 15 miRNAs were also significantly altered in GK rats. CONCLUSION: Treatment with sitagliptin was associated with modulation of antioxidant response in the diabetic kidney, involving a downregulation of miR-200a, a novel Keap-1 inhibitor and miR-21, coincidentally with the clinical and the morphological improvement. These data further support the concept that DPP-4 inhibitors could exert a direct reno protective effect in patients with diabetic nephropathy. PMID- 28652792 TI - Severe atypical herpes zoster as an initial symptom of fatal myelodysplastic syndrome with refractory anemia and blast excess (RAEB II). AB - Herpes zoster is a common disease caused due to varicella zoster virus (VZV) infection with increasing incidence by age. If the patient has a severe, extended, or treatment-recalcitrant course of herpes zoster, this must be a red flag to search for underlying pathologies. Here, we report about a 64-year-old male patient with diabetes, who came to our emergency department because of general malaise, fever, chills, and a pronounced nuchal and facial swelling on the left side. Based on herpetiform-grouped vesicles and yellowish crusts, an impetiginized facial herpes zoster was diagnosed, and combined antiviral and antibiotic treatment was initiated. He was HIV negative. Despite intensified treatment, his situation worsened. We observed blasts in peripheral blood, but bone marrow biopsy was initially denied. Some days later after deterioration of his disease, he accepted further diagnostics. A myelodysplastic syndrome with blast excess (refractory anemia and blast excess II, RAEB II) could be confirmed. The following translocations were detected: t(2;12)(p13; q13) and t(6;9)(p22;q34). REAB II has an unfortunate prognosis. Cytoreductive treatment was initiated by the hematooncologist. Unfortunately, the patient deceased due to septic shock. PMID- 28652791 TI - Off-label drugs for weight management. AB - The global pandemic of obesity and overweight now affects between 2.8 and 3.5 billion of the world population and shows no signs of abatement. Treatment for what is now recognized as a chronic disease includes pharmacotherapy, considered an essential component of comprehensive therapy. New drug discovery is robust, but the pace of the US Food and Drug Administration approval for obesity drugs has been glacial, and only a handful of approved drugs are available for treating obesity. In the last 20 years, the US Food and Drug Administration has approved 208 drugs for cancer, 118 for cardiovascular diseases, 168 for neurological diseases, and 223 endocrinologic drugs, but only 6 for obesity, 2 of which have been taken off market. Currently, there are only 9 drugs approved by the FDA for obesity treatment. US physicians have turned to off-label drug use in their effort to care for increasing numbers of patients with excess adiposity. Phentermine is the most commonly used drug for treating obesity. Although approved only for short-term use, US physicians have used it successfully for long-term since its initial approval in 1959. This drug, used off-label for long term, has proven to be safe and effective, far safer than the disease it is used to treat. Phentermine and diethylpropion, an equally safe but somewhat less effective drug, are both generic and therefore inexpensive. These drugs have been maligned inappropriately because their two-dimensional structure diagrams resemble amphetamine and also because of unproven presumptions about their potential adverse effects. In the face of an increasing epidemic, worldwide obese and overweight patients deserve effective treatment that prescribing these drugs could provide, if rehabilitated and used more frequently. US physicians will likely continue to use any drug proven useful off-label for this illness until such time as more effective drugs are approved. PMID- 28652793 TI - Evaluation of a novel very high sun-protection-factor moisturizer in adults with rosacea-prone sensitive skin. AB - BACKGROUND/OBJECTIVE: Rosacea-prone sensitive skin requires high sun-protection factor (SPF) moisturizers. This study evaluated Daylong Extreme SPF 50+ lotion, a novel cream containing five ultraviolet filters, two emollients, and three skin conditioners. SUBJECTS AND METHODS: This was an open-label, single-center study. On day 1, before treatment, subjects answered a questionnaire on their skin conditions and sunscreen habits, and both subjects and dermatologist evaluated skin status. Subjects applied the product once daily in the morning to the face for 21 days, and after approximately 3-5 minutes they assessed tolerability and short-term cosmetic acceptability in a questionnaire and daily diary. On day 22, the dermatologist and subjects evaluated skin status for long-term tolerance and cosmetic acceptability. RESULTS: The study enrolled 44 individuals (mean age 58.8 years, 91% female). At baseline, most subjects (39 of 44) showed erythema, and ~30% showed dryness and scaling. Dermatologists noted four cases of pustules and one case of papules. After 21 days' treatment with the product, the dermatologist reported significantly less erythema, dryness and scaling, three cases of pustules and two cases of papules. At baseline, ~75% of subjects noted a feeling of dryness, >50% reported tension, and nearly 25% reported tickling. After using the product for 21 days, subjects reported significantly less tension, dryness, and tickling. Some subjects noted itching and burning before and after using the product. One subject noted papules during treatment. Most subjects said that the product was pleasant, did not irritate the skin or cause stinging/burning, was easy to apply, quickly absorbed, and nongreasy, improved skin moisturization, helped prevent sun-provoked facial redness, did not worsen rosacea, and was easily incorporated into their skincare regimen. Half would switch to the product, and 80% of subjects would buy and recommend the product. CONCLUSION: The product was well tolerated in rosacea-prone subjects, producing objective and subjective improvements in skin status and symptoms. PMID- 28652794 TI - Epidemiology of fragile skin: Internet-based surveys in Mexico and Russia. AB - BACKGROUND: Fragile skin is a poorly understood skin condition, particularly in the general adult population. There are currently limited epidemiological data on the prevalence of fragile skin in adults. The objectives of this study were to assess the prevalence of perceived fragile skin across different skin types in representative samples of the general adult populations in Mexico and Russia, and to identify skin characteristics associated with perceived fragile skin. METHODS: Two identical cross-sectional surveys, using a short online self-administered questionnaire, were conducted on samples of recruited individuals that were representative of the general Mexican and Russian populations. Participants responded to questions about fragile skin, with the main question being "In your opinion, do you have fragile skin (ie, skin less resistant and reacting quickly to external aggressions)?". The survey also covered questions relating to skin appearance, skin symptoms, skin disease, dermatological procedures, and living environment and climate. RESULTS: Overall, 1,210 individuals in Mexico (N=606) and Russia (N=604) completed the online survey. Fragile skin was perceived in 50.0% and 45.9% of participants in Mexico and Russia, respectively. The principal skin appearance characteristics reported by individuals with perceived fragile skin were thin, easily wrinkled, and transparent; the main skin symptoms were dryness, redness, and/or itching (>=50% of individuals in Mexico), and dryness, tightness, and/or redness (>60% of individuals in Russia). Individuals with perceived fragile skin had experienced skin disease and/or undergone a dermatological procedure in the past 12 months, and they reported being exposed to stress (>80% of individuals in both surveys). CONCLUSION: A substantial proportion of the general adult population of Mexico and Russia perceived that they had fragile skin, regardless of their skin type; fragile skin was perceived more frequently in women. These findings should assist dermatologists to extend their understanding and management of individuals with perceived fragile skin. PMID- 28652795 TI - Minimal recovery time needed to return to social engagement following nasolabial fold correction with hyaluronic acid fillers produced with XpresHAn technology. AB - INTRODUCTION: The appeal of hyaluronic acid fillers for facial soft tissue augmentation is attributable to both an immediate aesthetic effect and relatively short recovery time. Although recovery time is an important posttreatment variable, as it impacts comfort with appearance and perceived treatment benefit, it is not routinely evaluated. Natural-looking aesthetic outcomes are also a primary concern for many patients. MATERIALS AND METHODS: A single-center, noncomparative study evaluated the time (in hours) until subjects return to social engagement (RtSE) following correction of moderate and severe nasolabial folds (NLFs) with RR (Restylane(r) Refyne)(r) and RD (Restylane Defyne), respectively. Twenty subjects (aged 35-57 years) who received bilateral NLF correction documented their RtSE and injection-related events posttreatment. Treatment efficacy was evaluated by improvements in Wrinkle Severity Rating Scale (WSRS) and subject satisfaction questionnaire at days 14 and 30, and by Global Aesthetic Improvement Scale (GAIS) at day 30. Safety was evaluated by injection related events and treatment-emergent adverse events. RESULTS: Fifty percent of subjects reported RtSE within 2 hours posttreatment. WSRS for the RR group improved significantly from baseline at day 14 (-1.45+/-0.42) and day 30 (-1.68+/ 0.46) (P<0.001), respectively. WSRS for the RD group improved significantly from baseline at day 14 (-2.22+/-0.44) and day 30 (-2.50+/-0.50) (P<0.004), respectively. All GAIS improvements were clinically significant at day 30. The majority of injection-related events were mild or moderate. Two subjects experienced 3 related treatment-emergent adverse events; 1 RR subject experienced severe bruising, and 1 RD subject experienced severe erythema and mild telangiectasia. Subject satisfaction was high regarding aesthetic outcomes and natural-looking results. CONCLUSION: Optimal correction of moderate NLFs with RR and severe NLFs with RD involved minimal time to RtSE for most subjects. Treatments that significantly improved WSRS and GAIS, were generally well tolerated, and provided natural-looking aesthetic outcomes. PMID- 28652797 TI - FLLL32, a curcumin analog, ameliorates intestinal injury in necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that primarily affects premature infants. It is characterized by inflammation and leukocyte infiltration that can progress to intestinal necrosis, perforation, systemic inflammatory response, and death. In this study, we examined the effect of FLLL32, a curcumin analog, on an NEC-like neonatal intestinal injury model. METHODS: NEC was induced in CD-1 mice pups using the Paneth cell ablation and Klebsiella infection model. Pups were divided into sham, NEC, and NEC + FLLL32 groups. At the end of the experiment, pups were euthanized; whole blood and small intestines were harvested. Intestinal inflammatory cytokine profile, in vivo intestinal permeability using serum fluorescein isothiocyanate dextran, and histological injury scores were compared between the groups. RESULTS AND CONCLUSION: FLLL32-treated pups had lower intestinal injury, improved intestinal permeability, and lower proinflammatory cytokine profiles compared to those in untreated pups with NEC. These results suggest that FLLL32 plays a protective role in NEC. PMID- 28652796 TI - The microbiota in inflammatory bowel disease: current and therapeutic insights. AB - Inflammatory bowel disease is a heterogeneous group of chronic disorders that result from the interaction of the intestinal immune system with the gut microbiome. Until recently, most investigative efforts and therapeutic breakthroughs were centered on understanding and manipulating the altered mucosal immune response that characterizes these diseases. However, more recent studies have highlighted the important role of environmental factors, and in particular the microbiota, in disease onset and disease exacerbation. Advances in genomic sequencing technology and bioinformatics have facilitated an explosion of investigative inquiries into the composition and function of the intestinal microbiome in health and disease and have advanced our understanding of the interplay between the gut microbiota and the host immune system. The gut microbiome is dynamic and changes with age and in response to diet, antibiotics and other environmental factors, and these alterations in the microbiome contribute to disease onset and exacerbation. Strategies to manipulate the microbiome through diet, probiotics, antibiotics or fecal microbiota transplantation may potentially be used therapeutically to influence modulate disease activity. This review will characterize the factors involved in the development of the intestinal microbiome and will describe the typical alterations in the microbiota that are characteristic of inflammatory bowel disease. Additionally, this manuscript will summarize the early but promising literature on the role of the gut microbiota in the pathogenesis of inflammatory bowel disease with implications for utilizing this data for diagnostic or therapeutic application in the clinical management of patients with these diseases. PMID- 28652798 TI - Combined aquaretic and diuretic therapy in acute heart failure. AB - INTRODUCTION: Acute heart failure (AHF) is a leading cause of hospitalization and readmission in the US. The present study evaluated maximum diuresis while minimizing electrolyte imbalances, hemodynamic instability, and kidney dysfunction, to achieve a euvolemic state safely in a shorter period of time. METHODS AND RESULTS: A protocol of combined therapy with furosemide, metolazone, and spironolactone, with or without tolvaptan and acetazolamide, was used in 17 hospitalized patients with AHF. The mean number of days on combination diuretic protocol was 3.8 days. The mean daily fluid balance was 3.0+/-2.1 L negative. The mean daily urine output (UOP) was 4.1+/-2.0 L (range 1.8-10.5 L). There were minimal fluctuations in serum electrolyte levels and serum creatinine over the duration of diuretic therapy. There was no statistically significant change in patients' creatinine from immediately prior to therapy to the last day of therapy, with a mean increase in creatinine of 0.14 mg/dL (95% CI -0.03, +0.30, p=0.10). CONCLUSION: Our strategy of treating AHF by achieving high UOP, while maintaining stable electrolytes and creatinine in a short period to euvolemic state, is safe. PMID- 28652799 TI - Direct oral anticoagulants in patients with chronic kidney disease: patient selection and special considerations. AB - Many patients with chronic kidney disease (CKD) receive anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOAC) inhibiting factor Xa or thrombin represent an alternative for VKAs. In patients with acute and chronic kidney disease, caution is warranted, as DOACs can accumulate as they are partly eliminated by the kidneys. Thus, they can potentially increase the bleeding risk in patients with CKD. In patients with an estimated glomerular filtration rate (eGFR) above 60 mL/min, DOACs can be used safely with greater efficacy and safety as compared to VKAs. In patients with CKD 3, DOACs are as effective as VKAs with a lower bleeding rate. The more the renal function declines, the lower is the advantage of DOACs over VKAs. Thus, use of DOACs should be avoided in patients with an eGFR below 30 mL/min, particularly, the compounds with a high renal elimination. Available data suggest that DOACs can also be used safely in older patients. In this review, use of DOACs in comparison with VKAs, heparins, and heparinoids, together with special considerations in patients with impaired renal function will be discussed. PMID- 28652800 TI - Nutritional status among peritoneal dialysis patients after oral supplement with ONCE dialyze formula. AB - BACKGROUND: Malnutrition is an important problem in patients treated with long term dialysis, and most dialysis patients have lower dietary energy and protein intake. This study was undertaken to examine whether orally administered Otsuka Nutrition Pharmaceutical (ONCE) dialyze formula (ODF) supplement would improve energy intake without mineral and electrolyte disturbances in patients with continuous ambulatory peritoneal dialysis (CAPD). METHODS: The effects of ODF supplementation on nutrition markers including serum albumin and prealbumin concentrations and inflammatory stress in patients with chronic CAPD were evaluated. All patients received daily oral ODF supplements for 15 days. During follow-up, all patients were evaluated clinically and biochemically, and nutritional status was assessed. RESULTS: Thirty patients with mean age 61.9+/ 12.3 years and weekly Kt/V 2.2+/-0.4 were studied. The mean values for nutritional parameters included a body weight of 53.7+/-9.5 kg, a serum albumin level of 3.3+/-0.4 g/dL, a serum prealbumin level of 33.8+/-11.1 mg/dL, a dietary energy intake of 21.9+/-7.1 kcal/kg/day, and a dietary protein intake of 0.9+/ 0.3 g/kg/day. After 15-day ODF treatment, these patients had significant dietary energy and protein, carbohydrate, fat, fiber, potassium, calcium, and magnesium intake from baseline (P<0.05). Furthermore, significant improvements were found in nutritional markers including body weight, blood urea nitrogen, and prealbumin levels, but no changes were observed in serum albumin and high-sensitivity C reactive protein levels. At the end of follow-up, the frequency of patients with moderate malnutrition decreased from 24.2% to 18.2%, and no increased incidence was observed of hyperkalemia, hyperphosphatemia, and metabolic acidosis. CONCLUSION: ODF supplementation ameliorates low dietary energy and nutrient intake as well as improves serum prealbumin and body weight in patients with long term CAPD. PMID- 28652801 TI - Outcome of tuberculosis treatment and its predictors among HIV infected patients in southwest Ethiopia. AB - BACKGROUND: Co-infection with HIV challenges treatment of tuberculosis (TB) and worsens the outcome. This study aimed to assess the outcome of TB treatment and its predictors among HIV infected patients at Mizan-Tepi University Teaching Hospital (MTUTH), Ethiopia. METHODS: Medical records of 188 TB/HIV co-infected patients who attended the TB clinic of MTUTH from September 2012 to December 2015 were reviewed from March 14 to April 1, 2016. The primary endpoints of the study were treatment outcome of TB and its predictors. Data were analyzed by Statistical Package for Social Sciences version 21. Multivariable binary logistic regression analysis was carried out to identify predictors of treatment outcome. Statistical significance was considered at p-value <0.05. RESULT: The treatment outcomes of TB patients included in this study were 18 (9.57%) cured, 20 (10.64%) defaulted, 24 (12.77%) died, 39 (20.74%) completed the treatment, and 87 (46.28%) transferred out. A successful treatment outcome was achieved in 57 (30.32%) patients. Initial World Health Organization (WHO) clinical stage III (COR: 2.60; 95%CI: 1.17-5.76) and stage IV (COR: 4.00; 95%CI: 1.29-12.40) were associated with unfavorable outcome. Both WHO stages (III, IV) at the time of HIV diagnosis were independent predictors of poor treatment outcome (AOR: 3.08; 95%CI: 1.14 8.38; AOR: 5.80; 95%CI: 1.36-24.71 respectively). However, smear positive TB was an independent predictor of a favorable treatment outcome (AOR: 2.50; 95%CI: 1.13 5.51). CONCLUSION: This study revealed that treatment outcome of TB patients was unsatisfactory, which signals a need for improved care. Advanced WHO clinical stages were predictors of poor outcome, while smear positive TB favors good outcome. PMID- 28652802 TI - Comparison of QuadrapolarTM radiofrequency lesions produced by standard versus modified technique: an experimental model. AB - Lower back pain (LBP) is a global public health issue and is associated with substantial financial costs and loss of quality of life. Over the years, different literature has provided different statistics regarding the causes of the back pain. The following statistic is the closest estimation regarding our patient population. The sacroiliac (SI) joint pain is responsible for LBP in 18% 30% of individuals with LBP. QuadrapolarTM radiofrequency ablation, which involves ablation of the nerves of the SI joint using heat, is a commonly used treatment for SI joint pain. However, the standard Quadrapolar radiofrequency procedure is not always effective at ablating all the sensory nerves that cause the pain in the SI joint. One of the major limitations of the standard Quadrapolar radiofrequency procedure is that it produces small lesions of ~4 mm in diameter. Smaller lesions increase the likelihood of failure to ablate all nociceptive input. In this study, we compare the standard Quadrapolar radiofrequency ablation technique to a modified Quadrapolar ablation technique that has produced improved patient outcomes in our clinic. The methodology of the two techniques are compared. In addition, we compare results from an experimental model comparing the lesion sizes produced by the two techniques. Taken together, the findings from this study suggest that the modified Quadrapolar technique provides longer lasting relief for the back pain that is caused by SI joint dysfunction. A randomized controlled clinical trial is the next step required to quantify the difference in symptom relief and quality of life produced by the two techniques. PMID- 28652803 TI - Effects of acculturation, coping strategies, locus of control, and self-efficacy on chronic pain: study of Chinese immigrant women in Italy - insights from a thematic field analysis. AB - Chronic pain represents a common public health concern worldwide. It is a complex phenomenon, owing to the interaction of different factors, including biological, physiological, psychological, environmental, and social variables. Some groups, such as women and immigrants, are particularly vulnerable. However, little is known about how Chinese women in Italy live with and face chronic pain. The present study aimed at filling this knowledge gap by examining the burden of chronic pain in Chinese immigrants in Italy in terms of acculturation processes, perceived control over disease, social networks, and coping strategies. A qualitative approach was used, performing a thematic field analysis. We interviewed 82 Chinese women from different Italian towns (Genoa, Milan, Turin, Bologna, Florence, and Prato) in depth. The sense of belonging to the host culture was strong in our sample. However, this did not simply reflect or translate into a linear engagement with medical systems, as health care pathways were more complex and dual (both Chinese and Western). Chinese women who felt deeply rooted in the Italian environment did not discontinue the use of traditional Chinese medicine. Chronic pain extensively and adversely affected daily life, particularly interfering with work. Coping strategies were mainly adaptive behaviors, being problem focused or maladaptive, relying upon "cope and avoid" mechanisms. Chinese women preferred to use traditional Chinese remedies rather than conventional medicine, while using the Italian system in emergencies. Perceived control over chronic pain was usually external. Finally, Chinese women with chronic pain benefit from social networks and support, which were mainly composed of Chinese peers. In conclusion, our findings underline the tremendous burden of chronic pain affecting all aspects of Chinese women's lives. Health care workers and providers should be aware of the complexity of chronic pain Therefore, a holistic approach, involving different stakeholders, should be adopted when managing chronic pain and approaching immigrant patients. PMID- 28652804 TI - Success with neurotropin in treating pediatric lower extremity pain induced by spinal cord injury after epidural anesthesia. AB - Spinal cord injury (SCI) complicated by epidural anesthesia, though rare, can result in neuropathic pain. However, the treatment for this kind of life-altering injury remains a challenge. A 7-year-old girl was referred with dyskinesia and severe pain in her right lower extremity due to an accidental SCI following lumbar puncture. After treatment with analgesics such as gabapentin, mecobalamin, and dexamethasone/methylprednisolone for 1 week, the myodynamia had improved, but progressive pain persisted. After treatment with neurotropin, a gradual decrease in visual analog scale score from 7 to 0 was observed. We herein first describe that neurotropin produced sustained relief of pain induced by SCI. This case suggests that neurotropin might be a promising drug in treating pediatric neuropathic pain caused by SCI. PMID- 28652805 TI - Provider confidence in opioid prescribing and chronic pain management: results of the Opioid Therapy Provider Survey. AB - INTRODUCTION: Many providers report lack of confidence in managing patients with chronic pain. Thus, the primary aim of this study was to investigate the associations of provider confidence in managing chronic pain with their practice behaviors and demographics. MATERIALS AND METHODS: The primary outcome measure was the results of the Opioid Therapy Provider Survey, which was administered to clinicians attending a pain-focused continuing medical education conference. Nonparametric correlations were assessed using Spearman's rho. RESULTS: Of the respondents, 55.0% were women, 92.8% were white, and 56.5% were physicians. Primary care providers accounted for 56.5% of the total respondents. The majority of respondents (60.8%) did not feel confident managing patients with chronic pain. Provider confidence in managing chronic pain was positively correlated with 1) following an opioid therapy protocol (P=0.001), 2) the perceived ability to identify patients at risk for opioid misuse (P=0.006), and 3) using a consistent practice-based approach to improve their comfort level with prescribing opioids (P<0.001). Provider confidence was negatively correlated with the perception that treating pain patients was a "problem in my practice" (P=0.005). CONCLUSION: In this study, the majority of providers did not feel confident managing chronic pain. However, provider confidence was associated with a protocolized and consistent practice-based approach toward managing opioids and the perceived ability to identify patients at risk for opioid misuse. Future studies should investigate whether provider confidence is associated with measurable competence in managing chronic pain and explore approaches to enhance appropriate levels of confidence in caring for patients with chronic pain. PMID- 28652806 TI - Characterization of cortical source generators based on electroencephalography during tonic pain. AB - OBJECTIVE: The aim of the present study was to characterize the cortical source generators evoked by experimental tonic pain. METHODS: Electroencephalography (EEG) was recorded on two separate days during rest and with immersion of the hand in ice water for 2 minutes (cold pressor test). Exact low-resolution brain electromagnetic tomography source localization was performed in 31 healthy volunteers to characterize the cortical source generators. RESULTS: Reliability was high in all eight frequency bands during rest and cold pressor conditions (intraclass coefficients =0.47-0.83 in the cingulate and insula). Tonic pain increased cortical activities in the delta (1-4 Hz), theta (4-8 Hz), beta1 (12-18 Hz), beta2 (18-24 Hz), beta3 (24-32 Hz), and gamma (32-60 Hz) bands (all P<0.011) in widespread areas mainly in the limbic system, whereas decreased cortical activities were found in cingulate and pre- and postcentral gyri in the alpha2 (10-12 Hz) band (P=0.007). The pain intensity was correlated with cingulate activity in the beta2, beta3, and gamma bands (all P<0.04). CONCLUSION: Source localization of EEG is a reliable method to estimate cortical source generators. Activities in different brain regions, mainly in the limbic system, showed fluctuations in various frequency bands. Cingulate changes were correlated with pain intensity. SIGNIFICANCE: This method might add information to the objective assessment of the cortical pain response in future experimental pain studies. PMID- 28652807 TI - A-MUPS score to differentiate patients with somatic symptom disorder from those with medical disease for complaints of non-acute pain. AB - PURPOSE: To develop a clinical score to discriminate patients with somatic symptom disorder (SSD) from those with medical disease (MD) for complaints of non acute pain. METHODS: We retrospectively examined the clinical records of consecutive patients with pain for a duration of >=1 month in our department from April 2003 to March 2015. We divided the subjects according to the diagnoses of definite SSD (as diagnosed and tracked by psychiatrists in our hospital), probable SSD (without evaluation by psychiatrists in our hospital), matched MD (randomly matched two patients by age, sex, and pain location for each definite SSD patient), unmatched MD, other mental disease, or functional somatic syndrome (FSS). We investigated eight clinical factors for definite SSD and matched MD, and developed a diagnostic score to identify SSD. We subsequently validated the model with cases of probable SSD and unmatched MD. RESULTS: The number of patients with definite SSD, probable SSD, matched MD, unmatched MD, other mental disease, and FSS was 104 (3.5%), 214 (7.3%), 197 (6.7%), 742 (25%), 708 (24%), and 978 (33%), respectively. In a conditional logistic regression analysis, the following five factors were included as independent predictors of SSD: Analgesics ineffective, Mental disorder history, Unclear provocative/palliative factors, Persistence without cessation, and Stress feelings/episodes (A-MUPS). The area under the receiver operating characteristic curve (AUC) of the model was 0.900 (95% CI: 0.864-0.937, p<0.001), and the McFadden's pseudo-R-squared was 0.709. For internal validation, the AUC between probable SSD and unmatched MD was 0.930 (95% CI: 0.910-0.950, p<0.001). The prevalence and the likelihood ratio of SSD increased as the score increased. CONCLUSION: The A-MUPS score was useful for discriminating patients with SSD from those with MD for complaints of non-acute pain, although external validation and refinement should be needed. PMID- 28652808 TI - Persistent cauda equina syndrome after caudal epidural injection under severe spinal stenosis: a case report. AB - Caudal epidural injection (CEI) is one of the most common treatments for low-back pain with sciatica. CEI rarely leads to neurologic complications. We report a case of persistent cauda equina syndrome after CEI. A 44-year-old male patient with severe L4 and L5 spinal ste-nosis underwent CEI for low-back pain and sciatica. The CEI solution consisted of bupivacaine, hyaluronidase, triamcinolone acetonide, and normal saline. He experienced motor weakness and sensory loss in both lower extremities and neurogenic bladder for more than 1 year after the procedure. His ankle dorsiflexors, big-toe extensors, and ankle plantar flexors on both sides were checked and categorized as motor-power Medical Research Council grade 0. His bilateral ankle-jerk reflection was absent. An electrophysiological study showed lumbosacral polyradiculopathy affecting both sides of the L5 and S1 nerve roots. A urodynamic study revealed hypoactive neurogenic bladder affecting both sacral roots. PMID- 28652809 TI - Anatomical study of middle cluneal nerve entrapment. AB - OBJECT: Entrapment of the middle cluneal nerve (MCN) under the long posterior sacroiliac ligament (LPSL) is a possible, and underdiagnosed, cause of low-back and/or leg symptoms. To date, detailed anatomical studies of MCN entrapment are few. The purpose of this study was to ascertain, using cadavers, the relationship between the MCN and LPSL and to investigate MCN entrapment. METHODS: A total of 30 hemipelves from 20 cadaveric donors (15 female, 5 male) designated for education or research, were studied by gross anatomical dissection. The age range of the donors at death was 71-101 years with a mean of 88 years. Branches of the MCN were identified under or over the gluteus maximus fascia caudal to the posterior superior iliac spine (PSIS) and traced laterally as far as their finest ramification. Special attention was paid to the relationship between the MCN and LPSL. The distance from the branch of the MCN to the PSIS and to the midline and the diameter of the MCN were measured. RESULTS: A total of 64 MCN branches were identified in the 30 hemipelves. Of 64 branches, 10 (16%) penetrated the LPSL. The average cephalocaudal distance from the PSIS to where the MCN penetrated the LPSL was 28.5+/-11.2 mm (9.1-53.7 mm). The distance from the midline was 36.0+/ 6.4 mm (23.5-45.2 mm). The diameter of the MCN branch traversing the LPSL averaged 1.6+/-0.5 mm (0.5-3.1 mm). Four of the 10 branches penetrating the LPSL had obvious constriction under the ligament. CONCLUSION: This is the first anatomical study illustrating MCN entrapment. It is likely that MCN entrapment is not a rare clinical entity. PMID- 28652810 TI - An effective deep-inspiration breath-hold radiotherapy technique for left-breast cancer: impact of post-mastectomy treatment, nodal coverage, and dose schedule on organs at risk. AB - BACKGROUND: We developed, applied, and prospectively evaluated a novel deep inspiration breath-hold (DIBH) screening and delivery technique to optimize cardiac sparing in left-breast radiotherapy (RT) at our clinic. The impact of set up and dose variables upon organs at risk (OAR) dose in DIBH RT was investigated. METHODS AND MATERIALS: All patients with left-breast cancer referred between 2011 and 2014 - of all disease stages, set-up variations, and dose prescriptions - were included. Radiographers used simple screening criteria at CT simulation, to systematically assess patients for obvious DIBH benefit and capability. Selected patients received forward-planned intensity-modulated RT (IMRT) based on a DIBH CT scan. A 3D-surface monitoring system with visual feedback assured reproducible DIBH positioning during gated radiation delivery. Patient, target set-up, and OAR dose information were collected at treatment. RESULTS: Of 272 patients who were screened, 4 withdrew, 56 showed no obvious advantage, and 56 showed benefit but had suitability issues; 156 patients were selected and successfully completed DIBH treatment. The technique was compatible with complex set-up and optimal target coverage was maintained. Comparison of free-breathing (FB) and DIBH treatment plans in the first five patients enrolled confirmed DIBH reduced heart radiation by ~80% (p = 0.032). Low OAR doses were achieved overall: the mean (95% confidence interval [CI]) heart dose was 1.17 (1.12-1.22) Gy, and the mean ipsilateral lung dose was 5.26 (5.01-5.52) Gy. Patients who underwent a standard radiation schedule (40 Gy/15#) after breast-conserving surgery had the lowest OAR doses: post-mastectomy treatment, simultaneous supraclavicular (SCV) node coverage, and alternative dose schedule (50 Gy/25#) were interrelated variables associated with increased OAR risk and compromised ipsilateral lung dose constraints. CONCLUSION: The DIBH technique was successfully implemented and resulted in optimally low heart radiation. All patients who demonstrate sufficient DIBH technique at planning CT are now offered DIBH RT at our clinic. Patients with more advanced disease, particularly those with additional pulmonary risk factors, warrant additional focus to improve lung sparing. PMID- 28652811 TI - Structure-based virtual screening and molecular docking for the identification of potential multi-targeted inhibitors against breast cancer. AB - Breast cancer is characterized by an uncontrolled growth of cells in breast tissue. Genes that foster cell growth in breast cells are overexpressed, giving rise to breast tumors. The identification of effective inhibitors represents a rational chemopreventive strategy. The current in silico study provides a pharmacoinformatic approach for the identification of active compounds against a co-chaperone HSP90 and the human epidermal growth factor receptors EGFR and HER2/neu receptor. The elevated levels of expression of these target proteins have been documented in breast cancer. The utilization of drug-likeness filters helped to evaluate the pharmacological activity of potential lead compounds. Those fulfilling this criterion were subjected to energy minimization for 1000 steepest descent steps at a root means square gradient of 0.02 with an Amber ff12SB force field. Based on molecular docking results and binding interaction analysis, this study represents five chemical compounds (S-258282355, S 258012947, S-259417539, S-258002927, and S-259411474) that indicate high binding energies that range between -8.7 to -10.3 kcal/mol. With high cytochrome P inhibitory promiscuity activity, these multi-targeted potential hits portray not only good physiochemical interactions but also an excellent profile of absorption, distribution, metabolism, excretion, and toxicity, which hypothesizes that these compounds can be developed as anticancer drugs in the near future. PMID- 28652812 TI - Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. AB - Immune checkpoint inhibitors, including cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) inhibitors, represent an effective treatment modality for multiple malignancies. Despite the exciting clinical benefits, checkpoint inhibition is associated with a series of immune-related adverse events (irAEs), many of which can be life-threatening and result in significant treatment delays. Pneumonitis is an adverse event of special interest as it led to treatment-related deaths in early clinical trials. This review summarizes the incidence of pneumonitis during treatment with the different checkpoint inhibitors and discusses the prognostic significance of tumor type. The wide range of clinical, radiographic, and histologic characteristics of checkpoint inhibitor-related pneumonitis is reviewed and followed by guidance on the different management strategies. PMID- 28652813 TI - Charlson comorbidity index derived from chart review or administrative data: agreement and prediction of mortality in intensive care patients. AB - PURPOSE: This study compared the Charlson comorbidity index (CCI) information derived from chart review and administrative systems to assess the completeness and agreement between scores, evaluate the capacity to predict 30-day and 1-year mortality in intensive care unit (ICU) patients, and compare the predictive capacity with that of the Simplified Acute Physiology Score (SAPS) II model. PATIENTS AND METHODS: Using data from 959 patients admitted to a general ICU in a Norwegian university hospital from 2007 to 2009, we compared the CCI score derived from chart review and administrative systems. Agreement was assessed using % agreement, kappa, and weighted kappa. The capacity to predict 30-day and 1-year mortality was assessed using logistic regression, model discrimination with the c-statistic, and calibration with a goodness-of-fit statistic. RESULTS: The CCI was complete (n=959) when calculated from chart review, but less complete from administrative data (n=839). Agreement was good, with a weighted kappa of 0.667 (95% confidence interval: 0.596-0.714). The c-statistics for categorized CCI scores from charts and administrative data were similar in the model that included age, sex, and type of admission: 0.755 and 0.743 for 30-day mortality, respectively, and 0.783 and 0.775, respectively, for 1-year mortality. Goodness of-fit statistics supported the model fit. CONCLUSION: The CCI scores from chart review and administrative data showed good agreement and predicted 30-day and 1 year mortality in ICU patients. CCI combined with age, sex, and type of admission predicted mortality almost as well as the physiology-based SAPS II. PMID- 28652814 TI - Return to work for patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation. AB - BACKGROUND: Autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL) or transformed indolent lymphoma (TIL). The treatment is mainly considered for younger patients still available for the work market. In this study, social outcomes after ASCT in terms of return to work (RTW) are described. PATIENTS AND METHODS: Information from national administrative registers was combined with clinical information on patients, who received ASCT for relapse of DLBCL or TIL between 2000 and 2012. A total of 164 patients were followed until RTW, disability or old-age pension, death, or December 31, 2015, whichever came first. A total of 205 patients were followed with disability pension as the event of interest. Cox models were used to determine cause-specific hazards. RESULTS: During follow-up, 82 (50%) patients returned to work. The rate of returning to work in the first year following ASCT was decreased for patients being on sick leave at the time of relapse (hazard ratio [HR] 0.3 [0.2;0.5]) and increased for patients aged >=55 years (HR 1.9 [1.1;3.3]). In all, 56 (27%) patients were granted disability pension. Being on sick leave at the time of relapse was positively associated with receiving a disability pension in the first 2 years after ASCT (HR 3.7 [1.8;7.7]). CONCLUSION: Patients on sick leave at the time of relapse have a poorer prognosis regarding RTW and have a higher rate of disability pension. Furthermore, patients >55 are more likely to RTW compared to younger patients. These results indicate an unmet need for focused social rehabilitation. PMID- 28652815 TI - Effect modification, interaction and mediation: an overview of theoretical insights for clinical investigators. AB - We revisited the three interrelated epidemiological concepts of effect modification, interaction and mediation for clinical investigators and examined their applicability when using research databases. The standard methods that are available to assess interaction, effect modification and mediation are explained and exemplified. For each concept, we first give a simple "best-case" example from a randomized controlled trial, followed by a structurally similar example from an observational study using research databases. Our explanation of the examples is based on recent theoretical developments and insights in the context of large health care databases. Terminology is sometimes ambiguous for what constitutes effect modification and interaction. The strong assumptions underlying the assessment of interaction, and particularly mediation, require clinicians and epidemiologists to take extra care when conducting observational studies in the context of health care databases. These strong assumptions may limit the applicability of interaction and mediation assessments, at least until the biases and limitations of these assessments when using large research databases are clarified. PMID- 28652816 TI - Esthetic smile rehabilitation of anterior teeth by treatment with biomimetic restorative materials: a case report. AB - BACKGROUND: In daily clinical practice, esthetics of anterior teeth is a common presenting complaint of patients. OBJECTIVE: This case report discusses the management of asymmetric smile associated with unsatisfactory extensive composite restorations and describes a clinical protocol using the direct composite resin for smile enhancement to restore the dental harmony of anterior teeth. METHODS: The treatment planning was based on a diagnostic wax-up and cosmetic mock-up. After clinical and patient approvals were obtained, the patient was subjected to direct and indirect restorative treatment. CONCLUSION: Nanocomposites are an effective alternative for anterior teeth restorations. Additionally, good planning enables satisfactory esthetic results, leading to the correction of an inappropriate axial inclination of incisors. PMID- 28652817 TI - Effect of preheating and light-curing unit on physicochemical properties of a bulk fill composite. AB - OBJECTIVE: The aim of this study is to evaluate the effect of composite preheating and polymerization mode on degree of conversion (DC), microhardness (KHN), plasticization (P), and depth of polymerization (DP) of a bulk fill composite. METHODS: Forty disc-shaped samples (n = 5) of a bulk fill composite were prepared (5 * 4 mm thick) and randomly divided into 4 groups according to light-curing unit (quartz-tungsten-halogen [QTH] or light-emitting diode [LED]) and preheating temperature (23 or 54 degrees C). A control group was prepared with a flowable composite at room temperature. DC was determined using a Fourier transform infrared spectrometer, KHN was measured with a Knoop indenter, P was evaluated by percentage reduction of hardness after 24 h of ethanol storage, and DP was obtained by bottom/top ratio. Data were statistically analyzed by analysis of variance and Tukey's test (alpha = 0.05). RESULTS: Regardless of light-curing, the highest preheating temperature increased DC compared to room temperature on bottom surface. LED showed a higher DC compared to QTH. Overall, DC was higher on top surface than bottom. KHN, P, and DP were not affected by curing mode and temperature, and flowable composite showed similar KHN, and lower DC and P, compared to bulk fill. CONCLUSION: Composite preheating increased the polymerization degree of 4-mm-increment bulk fill, but it led to a higher plasticization compared to the conventional flowable composite evaluated. PMID- 28652818 TI - Adaptation of the European Commission-recommended user testing method to patient medication information leaflets in Japan. AB - BACKGROUND: The safe use of drugs relies on providing accurate drug information to patients. In Japan, patient leaflets called Drug Guide for Patients are officially available; however, their utility has never been verified. This is the first attempt to improve Drug Guide for Patients via user testing in Japan. PURPOSE: To test and improve communication of drug information to minimize risk for patients via user testing of the current and revised versions of Drug Guide for Patients, and to demonstrate that this method is effective for improving Drug Guide for Patients in Japan. METHOD: We prepared current and revised versions of the Drug Guide for Patients and performed user testing via semi-structured interviews with consumers to compare these versions for two guides for Mercazole and Strattera. We evenly divided 54 participants into two groups with similar distributions of sex, age, and literacy level to test the differing versions of the Mercazole guide. Another group of 30 participants were divided evenly to test the versions of the Strattera guide. After completing user testing, the participants evaluated both guides in terms of amount of information, readability, usefulness of information, and layout and appearance. Participants were also asked for their opinions on the leaflets. RESULTS: Response rates were 100% for both Mercazole and Strattera. The revised versions of both Guides were superior or equal to the current versions in terms of accessibility and understandability. The revised version of the Mercazole guide showed better ratings for readability, usefulness of information, and layout (p<0.01) than did the current version, while that for Strattera showed superior readability and layout (p<0.01). CONCLUSION: User testing was effective for evaluating the utility of Drug Guide for Patients. Additionally, the revised version had superior accessibility and understandability. PMID- 28652819 TI - Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: findings from a cross-sectional survey analysis. AB - PURPOSE: To estimate the prevalence of women diagnosed with uterine fibroids and the associated symptom burden in the US. PATIENTS AND METHODS: Responses of women aged 18-54 years, who completed an online survey, were analyzed. Data were weighted based on age, education, race, geographic region, income, and propensity score to derive national estimates of the prevalence of women diagnosed with uterine fibroids and associated symptom burden. Weighted means and percentages were reported. Prevalence across age and ethnic groups was examined. Symptom burden among women with and without uterine fibroids was compared using weighted logistic regressions. RESULTS: Of 59,411 respondents who met study inclusion criteria, 7.7% reported receiving a diagnosis of uterine fibroids. Of these, 5,670 women (1,402 in the uterine fibroid group and 4,268 in the control group) were excluded from analysis because they had a hysterectomy. Among the non hysterectomized study participants, 3,031 self-reported a diagnosis of uterine fibroids (prevalence: 5.8%, 95% confidence interval [CI]: 5.5%-6.1%); prevalence increased as women aged and was greatest in the 50-54 age group (11.4%; 95% CI: 10.4%-12.4%). In addition, prevalence was greater in black vs white women (9.8%; 95% CI: 8.7%-11.0% vs 5.4%; 95% CI: 5.1%-5.7%). A greater percentage of women with uterine fibroids (vs those without) experienced severe heavy menstrual bleeding (16.7% vs 7.7%), severe constipation/bloating/diarrhea (7.7% vs 4.7%), severe passage of clots (6.7% vs 2.4%), severe spotting/bleeding between periods (1.7% vs 1.0%), and severe pelvic pressure (1.6% vs 0.6%). Among uterine fibroid patients with these typical uterine fibroid-related symptoms, 56.4%, 32.3%, 26.4%, 25.8%, and 20.4% reported heavy menstrual bleeding, passage of clots, spotting/bleeding between periods, constipation/bloating/diarrhea, and pelvic pressure, respectively, as extremely bothersome. CONCLUSION: Uterine fibroids impose a heavy burden on women aged 18-54 years in the US. PMID- 28652820 TI - A higher degree of expression of DNA methyl transferase 1 in cervical cancer is associated with poor survival outcome. AB - BACKGROUND: Even though novel therapies based on aberrant DNA methylation could be of particular importance for the treatment of cervical cancer (CC) because the oncoproteins E6/E7 of high-risk human papillomaviruses, the causative agents for developing CC, have the capacity to bind and upregulate DNA methyltransferases (DNMTs), to our knowledge, no previous studies have evaluated the expression of this enzyme in CC in relation to survival outcomes. The purpose of the study was to evaluate the expression of DNMT1 in CC and its association with survival outcomes. METHODS: The study population consisted of 76 women treated for primary CC and followed up by the University of Alabama at Birmingham (UAB) cancer registry. The expression of DNMT1 was examined using immunohistochemistry, and the degree of expression of DNMT1 was expressed as a percentage of cells positive for DNMT1 and its intensity. Cox proportional hazards model was used to assess the relationship between the degree of expression of DNMT1 and overall survival after adjusting for relevant covariates. RESULTS: The expression of DNMT1 was significantly higher in CC cells compared to that in the normal cervical epithelium. A higher percentage of cells positive for DNMT1 and a higher intensity score for DNMT1 were significantly associated with poor survival outcome (hazard ratio [HR] =4.3, P=0.03 and HR =4.9, P=0.02, respectively). CONCLUSION: Our findings suggested that the degree of expression of DNMT1 could be considered as a target in the epigenetic treatment of CC. Replication of our results in other study populations with CC could create the opportunity of using DNMT inhibitors to treat CC. PMID- 28652821 TI - HIV risk and barriers to care for African-born immigrant women: a sociocultural outlook. AB - BACKGROUND: Data from the Minnesota Department of Health (MDH) HIV/AIDS Surveillance Report 2015 show that African-born (AB) women continue to be disproportionately affected by HIV. In 2015, these women accounted for more than half (54%) of all new cases of HIV reported among females in Minnesota and 34% of all known female cases in the state. This study was a needs assessment for HIV pre-exposure prophylaxis (PrEP) in vulnerable subgroups within the AB population and adequacy of HIV care for AB persons. The primary objective of this study was to gain an insight into the strategies that will limit the spread of HIV infection and enhance HIV care among AB immigrants. METHODS: Community advocates, community-based organizations (CBOs), clinicians, and other HIV-related service providers were invited to participate in a focus group, structured interview or complete an assessment tool using the same questionnaire about HIV and PrEP among AB persons. A thematic analysis was then conducted on the open-ended questions addressing perceived barriers. RESULTS: Findings suggest the following gender specific sociocultural factors that drive HIV transmission and constitute barriers to HIV treatment for AB women: domestic/intimate partner violence, gender-biased stigma, discriminatory cultural beliefs and normative values/expectations, unprotected sex with husbands who have sex with other men, gender discordance in health care (preference for female provider), and sexual/reproductive health illiteracy. RECOMMENDATION: Based on recommendations, a community-based sexual and reproductive health education is being initiated with a curriculum that will be 1) broad (inclusive but not limited to HIV), 2) culturally sensitive/responsive, and 3) at appropriate literacy level for all women, including those who have little or no formal education. PMID- 28652822 TI - Anemia in pregnancy in Western Jamaica. AB - BACKGROUND: Anemia is one of the most prevalent problems in pregnancy. In 2011, 29.9% of all pregnant women in Jamaica were diagnosed with anemia. OBJECTIVE: The objective of this study was to determine the prevalence and predictors of anemia in pregnancy in Western Jamaica. METHODS: A cross-sectional study was conducted among 293 mothers attending post-natal clinics in Western Jamaica. A questionnaire was administered to the mothers, and an abstraction form was used to collect clinical data from the mothers' records. RESULTS: The prevalence of anemia among the women was 37.6%. Younger mothers (aged 18-24 years) were more likely to be anemic compared to those >=35 years (odds ratio [OR]: 3.44, 95% CI: 1.07-11.06). Mothers who reported not always washing their hands after using the toilet were almost 10 times more likely to be anemic (OR: 9.7, 95% CI: 1.72 54.78) compared to those who reported always washing their hands. Mothers who attended a public facility for antenatal care were 2.3 times more likely to be anemic (OR: 2.31, 95% CI: 1.03-5.18) compared to those who obtained care at a private facility, and mothers who reported being told that they were anemic by a health care provider (HCP) were almost six times more likely to be anemic compared with those who were not told (OR: 5.58, 95% CI: 1.73-17.93). CONCLUSION: The results of the study indicate that early identification and treatment of anemia, especially among younger pregnant women, should be a priority. HCP should ensure that women understand the need to be cured of their anemia and to adhere to preventive hygienic practices. PMID- 28652823 TI - Optic perineuritis: a retrospective case series. AB - Optic perineuritis (OPN) is a rare inflammatory disorder involving the optic nerve sheath characterized by visual loss. OPN may be isolated and idiopathic or part of an underlying disorder. This case series aimed to help clinicians investigate and manage this disorder. Presentation, clinical findings, and treatment of OPN are discussed. After review of medical records at the ophthalmology clinic at Sahlgrenska University hospital in Gothenburg, Sweden, seven OPN patients (three men and four women) were identified and included in the present case series. These included idiopathic cases and patients with underlying disorders. Age at OPN diagnosis ranged from 26 to 64 years (mean age 55 years, median age 58 years). Five of the patients were treated with corticosteroids. This study suggests that a high-dose course of corticosteroids is important in the treatment of OPN in severely affected patients. PMID- 28652824 TI - Fungal endophthalmitis in an elderly woman: differing responses in each eye. AB - Candida endophthalmitis is caused by hematogenous metastasis of the yeast. To ensure early diagnosis, serodiagnosis, or surveillance culturing is usually performed. If fungemia is apparent upon successive serological testing (in at least two tests: blood culture and/or measurement of beta-d-glucan level), ophthalmic consultation is necessary, even if no ophthalmic complaint is evident. This is because early detection with prompt prescription of systemic antifungal agents inhibits progression of the distinctive cholioretinitis. If the initial fungemia is not promptly diagnosed, or if it is missed, fungal endophthalmitis may develop, associated with a poor prognosis in terms of visual acuity. Here, we report on a case of Candida endophthalmitis in a 92-year-old woman with severe visual disturbance in one eye that was first diagnosed on ophthalmic examination. It was already difficult to recover. Fungemic systemic/ophthalmic symptoms must be checked in the early stage; in addition, prompt ophthalmological consultation is essential. PMID- 28652825 TI - A familial study of Hallermann-Streiff-Francois syndrome. AB - Hallermann-Streiff-Francois syndrome is a rare sporadic genetic pathology characterized by a phenotype consisting of growth retardation, ocular abnormalities, and a "bird-like head". We hereby report a case of this syndrome found in three generations of the same family - father, daughter, and grand daughter - who presented with a short stature and facial dysmorphic features, nystagmus, cataract, and bilateral microphthalmia. The discussion is based on the clinical and genetic aspects, and the challenges in management of this oculo mandibulo-facial syndrome. The association of congenital cataract, facial dysmorphic features, and microphthalmia, should guide the diagnosis of dysmorphic syndromes such as Hallermann-Streiff-Francois syndrome. PMID- 28652826 TI - Interatrial shunt devices for heart failure with normal ejection fraction: a technology update. AB - Heart failure with normal ejection fraction (HeFNEF) accounts for ~50% of heart failure admissions. Its pathophysiology and diagnostic criteria are yet to be defined clearly which may hinder the search for effective treatments. The clinical hallmark of HeFNEF is exertional breathlessness, often due to an abnormal increase in left atrial pressure during exercise. Creation of an interatrial communication to offload the left atrium is a possible therapeutic approach. There are two percutaneously delivered devices currently under investigation which are discussed in this review. PMID- 28652827 TI - Role of intrafamilial transmission in high prevalence of hepatitis C virus in Egypt. AB - BACKGROUND: Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. Although an effective HCV treatment program has been adopted, it is estimated that the number of newly reported cases in Egypt is still high. Intrafamilial transmission may play a role in the high prevalence of HCV in Egypt. Identification of risk factors for the transmission of HCV may help in decreasing its prevalence and eliminating its infection. AIM: The aim of this study was to estimate the prevalence of HCV infection among the household contacts of HCV patients and identify the possible risk factors associated with intrafamilial transmission. METHODS: This study was designed as a cohort study of 90 families of patients with confirmed chronic HCV and 38 families of non-HCV infected persons. Diagnosis of HCV infection was performed by detection of HCV antibodies by fourth-generation enzyme-linked immunosorbent assay and confirmed by HCV RNA polymerase chain reaction. A pre-prepared questionnaire on risk factors was filled out by the participants. The prevalence of HCV was calculated, and univariate and multivariate analyses were carried out to identify the independent risk factors. RESULTS: Among 90 positive-index families, 32 (35.6%) had contact persons with HCV infection compared to two of 38 (5.3%) negative index families (P < 0.001, odds ratio [OR] = 9.9). Out of 257 index-positive contacts, 38 (14.8%) were infected compared to three of 75 (4%) of index-negative contacts (P = 0.01, OR = 4.3). Infection was associated with older age (6.9% of those aged <20 years, 10.4% of those aged 20-39 years, and 22% of those aged >=40 years were infected) (P = 0.007). Husbands of infected wives were at a higher risk (33% infected) than wives (13.5%) and sons (16.9%) (P < 0.001). A history of hepatic encephalopathy was the independent predictor of intrafamilial transmission (P < 0.001, OR = 5.4). CONCLUSION: Intrafamilial transmission was found to possibly play a major role in the high prevalence of HCV in Egypt. Transmission was associated with older age and contact with patients with hepatic encephalopathy and was high among husbands of infected wives. PMID- 28652828 TI - Prevention, treatment, and rehabilitation of anterior cruciate ligament injuries in children. AB - As more children and adolescents participate in competitive organized sports, there has been an increase in the reported incidence of anterior cruciate ligament (ACL) injuries in these age groups. ACL injuries in skeletally immature athletes present a challenge, as reconstruction must preserve the physis of the distal femur and of the proximal tibia to avoid growth disturbances. Historically, a skeletally immature athlete with an ACL injury was treated with a brace and activity modification until skeletal maturity, with ACL reconstruction being performed at that time in the "non-copers" who experienced instability. More recently, evidence has shown that delayed reconstruction may lead to increased damage to the meniscus and articular cartilage. As a result, early reconstruction is favored to protect the meniscus and allow continued physical activity. While adolescents at or those near skeletal maturity may be treated with standard reconstruction techniques, they may result in growth disturbances in younger athletes with significant growth remaining. In response to the growing need for ACL reconstruction techniques in skeletally immature individuals, physeal-sparing and physeal-respecting reconstruction techniques have been developed. In addition to the advancements in surgical technique, ACL injury prevention has also gained attention. This growing interest in ACL prevention is in part related to the high risk of ACL re-tear, either of the ACL graft or of the contralateral ACL, in children and adolescents. Recent reports indicate that well-designed neuromuscular training programs may reduce the risk of primary and subsequent ACL injuries. PMID- 28652829 TI - Patellofemoral pain in athletes. AB - Patellofemoral pain (PFP) is a frequent cause of anterior knee pain in athletes, which affects patients with and without structural patellofemoral joint (PFJ) damage. Most younger patients do not have any structural changes to the PFJ, such as an increased Q angle and a cartilage damage. This clinical entity is known as patellofemoral pain syndrome (PFPS). Older patients usually present with signs of patellofemoral osteoarthritis (PFOA). A key factor in PFPS development is dynamic valgus of the lower extremity, which leads to lateral patellar maltracking. Causes of dynamic valgus include weak hip muscles and rearfoot eversion with pes pronatus valgus. These factors can also be observed in patients with PFOA. The available evidence suggests that patients with PFP are best managed with a tailored, multimodal, nonoperative treatment program that includes short-term pain relief with nonsteroidal anti-inflammatory drugs (NSAIDs), passive correction of patellar maltracking with medially directed tape or braces, correction of the dynamic valgus with exercise programs that target the muscles of the lower extremity, hip, and trunk, and the use of foot orthoses in patients with additional foot abnormalities. PMID- 28652830 TI - Clinical and serological characteristics of Ecuadorian patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, wherein late diagnosis and treatment leads to deformities and disability. OBJECTIVE: The aim of the study was to assess and describe the clinical and immunological characteristics, activity status of the disease, and functional capacity in a cohort of Ecuadorian patients with RA. METHODS: This is a cross-sectional, descriptive study conducted on a population of patients with prediagnosed RA from public and private Ecuadorian rheumatology clinics. This study investigated 400 patients with a mean age of 50 years, 353 (82.25%) of which were female. RESULTS: The study showed that 44.3%, 83.5%, 60.3%, 41.8%, 37.5%, and 11.5% had an acute onset of the disease, symmetrical polyarthritis, morning stiffness exceeding 1 h, dry eyes, dry mouth, and rheumatoid nodules, respectively. A total of 89.7% presented with positive rheumatoid factor, and 96.5% were anti-citrullinated protein antibody positive. CONCLUSION: This is the largest Ecuadorian cohort of patients with RA; clinical features are similar to those of other Latin American populations. PMID- 28652831 TI - A study in a hospital setting in Trinidad and Tobago, West Indies, on the psychological factors that cause road traffic collisions. AB - The following research paper aims to examine the psychological factors that have led to road traffic collisions (RTCs) by conducting research on drivers who had been admitted to the Accident and Emergency department at four major hospitals in Trinidad as RTC cases. A cross-sectional survey was conducted in four major hospitals in Trinidad. Sample size was 900 participants admitted to the hospital as RTC cases, and the sample was selected using Daniel's formula. All 900 participants were drivers involved in an RTC and were mostly male, and majority of drivers involved in an RTC were within the age group of 30-39 years. The survey was conducted in a 3-month window between March and June 2013. The results of the survey indicated that there was a significant relationship between most of the factors and RTCs, that is, p<0.05. This indicated that the null hypotheses did not hold. Thus, there was an positive correlation. The study revealed that attitude of drivers, real driving practice and the driving knowledge possessed by the driver were associated factors for RTCs. The survey also established that factors such as stress, the lack of sleep and fatigue were also likely to be associated with RTC. PMID- 28652834 TI - Fractures in Kuwait: incidence and distribution. AB - The absence of descriptive epidemiological data on the frequency and distribution of fractures in a population is serious and may underestimate the actual importance of this public health problem. In this study, we report the crude and standardized incidence rates of fractures in the population of Kuwait during the period 2009-2012. Using the Ministry of Public Health's national registry, demographic data of all fracture cases between 2009 and 2012 were retrieved. These were further categorized into fractures at the hip or any other sites. Average annual incidence rates were calculated and standardized using the world's population in 2010 as a reference. Thus, 18,119 fractures among males and 6,362 among females were recorded. The overall estimated annual incidence rates of fractures per 100,000 person-years were 207 for males and 111.8 for females. Moreover, 13.3% of all fractures were in the hip, with incidence rates of 24.8 for males and 18.9 for females; while 86.7% were in other sites, with corresponding incidence rates of 182.2 and 92.8, respectively. The age-specific fracture incidence rates in females remained below the corresponding rates of males until >=50 years of age, after which the female age groups showed successively higher rates. The age-standardized incidence rates for all fractures (hip and other sites) were 247.4 for males, 175.4 for females, and 216.2 for both sexes. The burden of this major public health challenge is set to rise, and such population-based incidence data call for an urgent need for action to reduce the projected human impact and socioeconomic costs of fracture. PMID- 28652832 TI - Cognitive behavioral therapy to aid weight loss in obese patients: current perspectives. AB - Obesity is a chronic condition associated with risk factors for many medical complications and comorbidities such as cardiovascular diseases, some types of cancer, osteoarthritis, hypertension, dyslipidemia, hypercholesterolemia, type-2 diabetes, obstructive sleep apnea syndrome, and different psychosocial issues and psychopathological disorders. Obesity is a highly complex, multifactorial disease: genetic, biological, psychological, behavioral, familial, social, cultural, and environmental factors can influence in different ways. Evidence based strategies to improve weight loss, maintain a healthy weight, and reduce related comorbidities typically integrate different interventions: dietetic, nutritional, physical, behavioral, psychological, and if necessary, pharmacological and surgical ones. Such treatments are implemented in a multidisciplinary context with a clinical team composed of endocrinologists, nutritionists, dietitians, physiotherapists, psychiatrists, psychologists, and sometimes surgeons. Cognitive behavioral therapy (CBT) is traditionally recognized as the best established treatment for binge eating disorder and the most preferred intervention for obesity, and could be considered as the first line treatment among psychological approaches, especially in a long-term perspective; however, it does not necessarily produce a successful weight loss. Traditional CBT for weight loss and other protocols, such as enhanced CBT, enhanced focused CBT, behavioral weight loss treatment, therapeutic education, acceptance and commitment therapy, and sequential binge, are discussed in this review. The issue of long-term weight management of obesity, the real challenge in outpatient settings and in lifestyle modification, is discussed taking into account the possible contribution of mHealth and the stepped-care approach in health care. PMID- 28652835 TI - A randomized controlled trial to validate the Alice PDX ambulatory device. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent condition; however, the majority of patients remain undiagnosed. There is a potential to expand the diagnostic capacity of sleep laboratories. The study objective was to validate a portable respiratory monitoring device (Alice PDX) against polysomnography (PSG) in the laboratory and to assess its reliability at home. METHODS: A total of 85 patients with suspected OSA (80% male, mean age 49.1+/ 13.5 years, body mass index 29.7+/-6.9 kg/m2, Epworth Sleepiness Scale 10.0+/ 5.1) were randomized to 3 diagnostic nights: 1 night simultaneous in-laboratory PSG and PDX recording; 1 night self-applied PDX at home, and 1 night in laboratory PSG. Study data were manually scored according to American Academy of Sleep Medicine criteria. RESULTS: The Alice PDX was in diagnostic agreement with simultaneously recorded reference PSG in 96.4% of studies. In 2.4% of studies the in-laboratory PDX underestimated and in 1.2% of studies it overestimated the apnea hypopnea index (AHI). The difference between the AHI from the reference PSG and the home study was similar to the difference between the PSGs (2.79 vs 0.79, p=0.08). CONCLUSION: In a population with a high suspicion of OSA, the Alice PDX showed a high level of diagnostic agreement with a simultaneous PSG and performed valid home diagnostic studies for OSA. If manually scored, the portable device can be used by sleep specialists for diagnosing moderate-to-severe obstructive sleep apnea in cases with a high pretest probability for the disease over a wide range of disease severity. The technology can be deployed reliably outside of the sleep laboratory setting. PMID- 28652833 TI - A narrative literature review of depression following traumatic brain injury: prevalence, impact, and management challenges. AB - Depression is one of the most common conditions to emerge after traumatic brain injury (TBI), and despite its potentially serious consequences it remains undertreated. Treatment for post-traumatic depression (PTD) is complicated due to the multifactorial etiology of PTD, ranging from biological pathways to psychosocial adjustment. Identifying the unique, personalized factors contributing to the development of PTD could improve long-term treatment and management for individuals with TBI. The purpose of this narrative literature review was to summarize the prevalence and impact of PTD among those with moderate to severe TBI and to discuss current challenges in its management. Overall, PTD has an estimated point prevalence of 30%, with 50% of individuals with moderate to severe TBI experiencing an episode of PTD in the first year after injury alone. PTD has significant implications for health, leading to more hospitalizations and greater caregiver burden, for participation, reducing rates of return to work and affecting social relationships, and for quality of life. PTD may develop directly or indirectly as a result of biological changes after injury, most notably post-injury inflammation, or through psychological and psychosocial factors, including pre injury personal characteristics and post injury adjustment to disability. Current evidence for effective treatments is limited, although the strongest evidence supports antidepressants and cognitive behavioral interventions. More personalized approaches to treatment and further research into unique therapy combinations may improve the management of PTD and improve the health, functioning, and quality of life for individuals with TBI. PMID- 28652836 TI - Initial development of a patient-reported outcome measure of experience with cognitive impairment associated with schizophrenia. AB - Cognitive impairment is a serious, often distressing aspect of schizophrenia that affects patients' day-to-day lives. Although several interview-based instruments exist to assess cognitive functioning, a reliable measure developed based on the experiences of patients facing cognitive difficulties is needed to complement the objective performance-based assessments. The present article describes the initial development of a patient-reported outcome (PRO) measure to assess the subjective experience of cognitive impairment among patients with schizophrenia, the Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS). The phases of development included the construction of a conceptual model based on the existing knowledge and two sets of qualitative interviews with patients: 1) concept elicitation interviews to ensure face and content validity from the perspective of people with schizophrenia and 2) cognitive debriefing of the initial item pool. Input from experts was elicited throughout the process. The initial conceptual model included seven domains. The results from concept elicitation interviews (n=80) supported these domains but yielded substantive changes to concepts within domains and to terminology. Based on these results, an initial pool of 53 items was developed to reflect the most common descriptions and languages used by the study participants. Cognitive debriefing interviews (n=22) resulted in the removal of 18 items and modification of 22 other items. The remaining 35 items represented 23 concepts within six domains plus two items assessing bother. The draft PRO measure is currently undergoing psychometric testing as a precursor to broad-based clinical and research use. PMID- 28652837 TI - A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma. AB - PURPOSE: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid) inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells. PATIENTS AND METHODS: We investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) positron emission tomography criteria. Secondary end points were progression-free survival (PFS) and overall survival (OS). Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels. RESULTS: Eight male patients (median age of 62 years) with the following clinical characteristics were treated; ECOG PS was 0-2, 75% with epithelioid type, and 62% had prior chemotherapy Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease) was 37.5%. Median PFS was 2 months (0.5-21 months) and median OS was 7 months (0.8-28 months). No treatment-related toxicities were observed. Lower VEGF levels were predictive of favorable response and mesothelin levels correlated with disease course. CONCLUSION: Zoledronic acid shows modest clinical activity without significant toxicity in patients with advanced MPM. PMID- 28652838 TI - Pregnancy outcomes in younger and older adolescent mothers with severe preeclampsia. AB - BACKGROUND: Adolescent mothers are at higher risk for preeclampsia, but the effect of their age on the outcome of the pregnancy complication is not clear. OBJECTIVE: To describe maternal and neonatal outcomes among singleton adolescent pregnancies complicated with severe preeclampsia in a low-income-setting hospital and compare results according to age. MATERIALS AND METHODS: Maternal and neonatal outcomes of 213 adolescent mothers complicated with severe preeclampsia delivering at the Enrique C. Sotomayor Obstetrics and Gynecology Hospital (Guayaquil, Ecuador) were analyzed and compared according to their age (16 or less years, n=82 vs 17-19 years, n=131). RESULTS: Cesarean section rate was high in both studied groups; otherwise, obstetrical outcome did not differ and there were no maternal deaths or severe complications. Neonatal outcome was adverse in the two groups evidenced by high rates of preterm birth, small-for-gestational age and low-birth-weight infants, low first-minute Apgar scores and admissions to neonatal intensive care; however, it was not significantly different between the analyzed groups. There were no neonatal deaths among mothers aged 16 or less and 4 in the group aged 17-19 years. This was, however, not significant (p=0.30). CONCLUSION: Pregnancy outcome in this adolescent population with severe preeclampsia was similarly adverse, independent of maternal age. PMID- 28652839 TI - Increasing patient safety with neonates via handoff communication during delivery: a call for interprofessional health care team training across GME and CME. AB - Hospitals have struggled for years regarding the handoff process of communicating patient information from one health care professional to another. Ineffective handoff communication is recognized as a serious patient safety risk within the health care community. It is essential to take communication into consideration when examining the safety of neonates who require immediate medical attention after birth; effective communication is vital for positive patient outcomes, especially with neonates in a delivery room setting. Teamwork and effective communication across the health care continuum are essential for providing efficient, quality care that leads to favorable patient outcomes. Interprofessional simulation and team training can benefit health care professionals by improving interprofessional competence, defined as one's knowledge of other professionals including an understanding of their training and skillsets, and role clarity. Interprofessional teams that include members with specialization in obstetrics, gynecology, and neonatology have the potential to considerably benefit from training effective handoff and communication practices that would ensure the safety of the neonate upon birth. We must strive to provide the most comprehensive systematic, standardized, interprofessional handoff communication training sessions for such teams, through Graduate Medical Education and Continuing Medical Education that will meet the needs across the educational continuum. PMID- 28652840 TI - Social media as an open-learning resource in medical education: current perspectives. AB - PURPOSE: Numerous studies evaluate the use of social media as an open-learning resource in education, but there is a little published knowledge of empirical evidence that such open-learning resources produce educative outcomes, particularly with regard to student performance. This study undertook a systematic review of the published literature in medical education to determine the state of the evidence as to empirical studies that conduct an evaluation or research regarding social media and open-learning resources. METHODS: The authors searched MEDLINE, ERIC, Embase, PubMed, Scopus, and Google Scholar from 2012 to 2017. This search included using keywords related to social media, medical education, research, and evaluation, while restricting the search to peer reviewed, English language articles only. To meet inclusion criteria, manuscripts had to employ evaluative methods and undertake empirical research. RESULTS: Empirical work designed to evaluate the impact of social media as an open learning resource in medical education is limited as only 13 studies met inclusion criteria. The majority of these studies used undergraduate medical education as the backdrop to investigate open-learning resources, such as Facebook, Twitter, and YouTube. YouTube appears to have little educational value due to the unsupervised nature of content added on a daily basis. Overall, extant reviews have demonstrated that we know a considerable amount about social media use, although to date, its impacts remain unclear. CONCLUSION: There is a paucity of outcome-based, empirical studies assessing the impact of social media in medical education. The few empirical studies identified tend to focus on evaluating the affective outcomes of social media and medical education as opposed to understanding any linkages between social media and performance outcomes. Given the potential for social media use in medical education, more empirical evaluative studies are required to determine educational value. PMID- 28652841 TI - Nephritic cell damage and antioxidant status in rats exposed to leachate from battery recycling industry. AB - Limited studies have assessed the toxic effect of sub-acute and sub-chronic exposure of leachate (mixture of metals) in mammalian kidney. The sub-acute and sub-chronic exposure of mature male Wistar-strain albino rats (200-220 g) were given by oral administration with leachate from Elewi Odo municipal battery recycling industry (EOMABRIL) for period of 7 and 60 days respectively, at different concentrations (20%, 40%, 60%, 80% and 100%). This was to evaluate its toxic effects on male renal functions using biomarkers of oxidative stress and nephro-cellular damage. Control groups were treated equally, but given distilled water instead of the leachate. All the groups were fed with the same standard food and had free access to drinking water. Following the exposure, results showed that the treatment induced systemic toxicity at the doses tested by causing a significant (p<0.05) alteration in enzymatic antioxidants-catalase (CAT) and superoxide dismutase (SOD) in the kidneys which resulted into elevated levels of malonaldehyde (MDA). Reduced glutathione (GSH) levels were found to be significantly (p<0.05) depleted relative to the control group. Considerable renal cortical congestion and numerous tubules with protein casts were observed in the lumen of EOMABRIL-treated rats. These findings conclude that possible mechanism by which EOMABRIL at the investigated concentrations elicits nephrotoxicity could be linked to the individual, additive, synergistic or antagonistic interactions of this mixture of metals with the renal bio-molecules, alteration of kidney detoxifying enzymes and necrosis of nephritic tubular epithelial cells. PMID- 28652842 TI - Toxic effect of sodium fluoride on hydroxyproline level and expression of collagen-1 gene in rat bone and its amelioration by Tamrindus indica L. fruit pulp extract. AB - Excessive fluoride intoxication plays an important role in the development of dental, skeletal and non-skeletal fluorosis. The aim of this study was to ascertain the toxic effect of excessive fluoride ingestion on the level of hydroxyproline and expression of type 1 collagen gene in rat bone and its amelioration by supplementation with Tamarindus indica fruit pulp extract. Forty albino rats were randomly assigned to four groups. The first group served as control and received only tap water. The second group received sodium fluoride (200 ppm) through drinking water. The third group received T. indica fruit pulp extract (200 mg/kg body weight) alone and the fourth group received the T. indica fruit pulp extract (200 mg/kg body weight) along with fluorinated drinking water (200 ppm) daily by gavage for a period of 90 days. The level of hydroxyproline and expression of type 1 collagen gene using quantitative real time PCR in the tibia bone decreased significantly with continuous exposure to sodium fluoride. Co-administration of T. indica fruit pulp extract during exposure to fluoride through drinking water restored the level of calcium, phosphorus and alkaline phosphatase in serum and the concentration of hydroxyproline in urine. It increased the level of hydroxyproline and expression of type 1 collagen gene in the tibia as compared to untreated fluoride-exposed rats. It is concluded that T. indica fruit pulp extract has an ameliorative potential to protect the bone from fluoride induced collagen damage. PMID- 28652843 TI - Inflammatory effect of 2-aminoanthracene (2AA) on adipose tissue gene expression in pregnant Sprague Dawley rats. AB - Adipocyte dysfunction may be a critical link between obesity and insulin resistance as a result of abnormal fat storage and mobilization. Adipocytes uniquely secrete adipokines and cytokines, such as leptin and TNFalpha, wich promote insulin sensitivity. Previously we reported insulin-signaling related altered gene expression in animals exposed to 2-Aminoanthracene (2AA). 2AA is an amino-substituted polycyclic aromatic hydrocarbon used in manufacturing dyes, chemicals, inks, resins, and polyurethanes. The objective of this study was to examine the inflammation related effects of 2AA exposure from gestation to postnatal period on dams that ingested 2AA. To examine 2AA effects, pregnant dams were assigned into dose regimens of 2AA. Dams were fed 2AA contaminated diet during the period of gestation and postpartum. The expression of key gene transcripts reported to be important in mediating inflammatory processes was examined via quantitative RT-PCR. Histologic examination of adipose tissue (AT) was also carried out to understand the anatomy of AT due to 2AA exposure during gestation and two weeks postpartum. Examination of the adipose tissue for microscopic changes revealed no alterations between control and low-dose animals. However, AT of the high-dose animals was infiltrated by increased numbers of CD68+mononuclear cells (macrophages) and small numbers of eosinophils and mast cells, consistent with inflammation. In addition, analysis of the mRNA expression of cytokines and adipokines demonstrated the importance of inflammation in AT dysfunction. For instance, TNFalpha, LEPTIN and IL-6 transcripts were relatively more expressed in the low dose animals than in the high dose and control rats. At the protein level, however, high amounts of cytokines were noted. The effects of 2AA on pregnant dams appear to be more pronounced in the high dose group than in the low dose group, possibly indicating increased susceptibility of rat offspring within this group to elicit a diabetic-type response. PMID- 28652844 TI - Toxicity of Glandularia selloi (Spreng.) Tronc. leave extract by MTT and neutral red assays: influence of the test medium procedure. AB - Cytotoxicity assays using cell cultures may be an alternative to assess biological toxicity of plant extracts with potential phytotherapeutic properties. This study compared three methods to prepare culture media for the exposure of Vero cells to plant extracts. Leaves of Glandularia selloi (Spreng.) Tronc. were used to prepare culture medium with aqueous extract, extract in culture medium and methanol extract. Toxicity was assessed using the MTT and neutral red (NR) assays. In general, alterations in the cellular functions were found in all extracts and assays. Cytotoxic effect occurred at lower doses in aqueous extract and the range of effect of the methanol extract was small. The procedure of preparing the test medium has an effect on the outcome of the assay. Cytotoxicity of plant extract can be assessed by MTT and NR assays. Aqueous extract added to the culture medium presented the best profile to assess cytotoxicity. PMID- 28652845 TI - The first report of pyrrolizidine alkaloid poisoning in a gazelle (Gazella Subgutturosa) - histopathologic diagnosis. AB - Pyrrolizidine alkaloids (PAs) are natural phytotoxins found in thousands of plant species around the world. They are probably the most common poisonous plants affecting livestock, wildlife and humans. The disease occurs almost entirely as a consequence of chronic poisoning and in general ends fatally. In the present study, PAs poisoning was investigated in a gazelle with hepatic encephalopathy associated with severe neurologic signs. The main clinical signs included head pressing, progressive depression and weakness, ataxia and reluctance to move, turn the head to the left and to paddle, hyperesthesia and decreased food intake. Histopathological examination revealed major lesions in the liver consisting of severe hepatocyte megalocytosis and hypertrophy with nuclei enlargement, mild bile duct hyperplasia, centriacinar fatty change and hepatocellular necrosis. Moreover, pulmonary congestion and edema with endothelium necrosis and alveolar septa thickening, severe congestion in vessels of the brain and meninges, and myocardial necrosis were observed. PMID- 28652847 TI - Adverse hematological effects of hexavalent chromium: an overview. AB - Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increases the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders. PMID- 28652848 TI - Mitigation of diazinon-induced cardiovascular and renal dysfunction by gallic acid. AB - Studies of the link between environmental pollutants and cardiovascular dysfunction, neglected for decades, have recently provided new insights into the pathology and consequences of these killers. In this study, rats were divided into four groups, each containing 10 rats. The rats in group one served as controls and were administered normal saline, whereas the rats in group two were orally gavaged with 3 mg/kg of diazinon (DZN) alone for twenty one consecutive days. The rats in groups 3 and 4 were administered respective 60 mg/kg and 120 mg/kg gallic acid (GA) in addition to DZN for twenty one consecutive days. Exposure of rats to diazinon significantly (p<0.05) reduced the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and reduced glutathione (GSH) content. Malondialdehyde, hydrogen peroxide (H2O2) and nitric oxide (NO) contents were also significantly (p<0.05) elevated following DZN exposure. DZN further caused a significant (p<0.05) decrease of heart rate and QT interval prolongation. Hematologic analysis revealed significant reduction (p<0.05) in packed cell volume (PCV), hemoglobin concentration (Hb), red blood cell (RBC) count, and total white blood cell count of rats administered only DZN. Observations in this study suggest a modulatory role of gallic acid in diazinon-induced anemia and associated cardiovascular dysfunction in rats. Treatment with gallic acid reversed the oxidative stress markers studied, increased the antioxidant defence system and reduced deleterious effects on hematological parameters in rats. Pathologic findings of the heart and kidney were also found to be lessened. PMID- 28652849 TI - Protective effect of resveratrol against neuronal damage through oxidative stress in cerebral hemisphere of aluminum and fluoride treated rats. AB - Aluminum has no defined biological function and it is potentially involved in the pathogenesis of neurodegenerative disorders. Furthermore, the presence of fluoride causes more aluminum to accumulate in the brain, resulting in increased neuronal damage. In recent years, resveratrol through its ameliorative effects was found to be a neuroprotectant. This study reports the protective effects of resveratrol on combined aluminum and fluoride induced neuronal damage through oxidative stress in rats. Protective effects of resveratrol (30 mg/kg b.w) on markers of oxidative stress were determined in rats exposed to aluminum chloride (100 mg/kg b.w) along with sodium fluoride (10 mg/kg b.w) for 8 weeks. The results showed a statistically significant (p<0.05) increase in lipid peroxidation (LPx) as well as a significant (p<0.05) decrease in superoxide dismutase and catalase activity. Enlarged cells, neurofibrillary tangles, and vacuolar spaces showing oxidative stress in the cerebral cortex were also observed in hematoxylin and eosin stained sections in aluminum and fluoride treated rats. Administration of resveratrol along with aluminum + fluoride showed significant reversal of oxidative stress and neuronal damage in rats. Thus resveratrol potentially acts as a neuroprotectant against aluminum chloride + sodium fluoride induced neuronal damage through its anti-oxidant efficacy. PMID- 28652850 TI - Questionable information on poisonings by alcohol surrogates. PMID- 28652846 TI - Predicting disease onset in clinically healthy people. AB - Virtually all human disease is induced by oxidative stress. Oxidative stress, which is caused by toxic environmental exposure, the presence of disease, lifestyle choices, stress, chronic inflammation or combinations of these, is responsible for most disease. Oxidative stress from all sources is additive and it is the total oxidative stress from all sources that induces the onset of most disease. Oxidative stress leads to lipid peroxidation, which in turn produces Malondialdehyde. Serum malondialdehyde level is an additive parameter resulting from all sources of oxidative stress and, therefore, is a reliable indicator of total oxidative stress which can be used to predict the onset of disease in clinically asymptomatic individuals and to suggest the need for treatment that can prevent much human disease. PMID- 28652851 TI - Technical aspects of oxygen level regulation in primary cell cultures: A review. AB - Oxygen (O2) is an essential element for aerobic respiration. Atmospheric concentration of O2 is approximately 21%. Mammalian cells, however, are generally adapted to O2 levels much lower than atmospheric conditions. The pericellular levels of O2 must also be maintained within a fairly narrow range to meet the demands of cells. This applies equally to cells in vivo and cells in primary cultures. There has been growing interest in the performance of cell culture experiments under various O2 levels to study molecular and cellular responses. To this end, a range of technologies (e.g. gas-permeable technology) and instruments (e.g. gas-tight boxes and gas-controlled incubators) have been developed. It should be noted, however, that some of these have limitations and they are still undergoing refinement. Nevertheless, better results should be possible when technical concerns are taken into account. This paper aims to review various aspects of O2 level adjustment in primary cell cultures, regulation of pericellular O2 gradients and possible effects of the cell culture medium. PMID- 28652852 TI - Organochlorine pesticides, their toxic effects on living organisms and their fate in the environment. AB - Organochlorine (OC) pesticides are synthetic pesticides widely used all over the world. They belong to the group of chlorinated hydrocarbon derivatives, which have vast application in the chemical industry and in agriculture. These compounds are known for their high toxicity, slow degradation and bioaccumulation. Even though many of the compounds which belong to OC were banned in developed countries, the use of these agents has been rising. This concerns particularly abuse of these chemicals which is in practice across the continents. Though pesticides have been developed with the concept of target organism toxicity, often non-target species are affected badly by their application. The purpose of this review is to list the major classes of pesticides, to understand organochlorine pesticides based on their activity and persistence, and also to understand their biochemical toxicity. PMID- 28652853 TI - Protection studies of new bis quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives (HNK-series) oximes against acute poisoning by dichlorvos (DDVP) in Swiss albino mice. AB - The available antidotal therapy against acute poisoning by organophosphates involves the use of atropine alone or in combination with one of the oximes, e.g. 2-PAM, Obidoxime, TMB-4 or HI-6. Each of these oximes has some limitation, raising the question of the universal antidotal efficacy against poisoning by all OPs/nerve agents. In the present study, newly synthesized bis quaternary 2 (hydroxyimino)-N-(pyridin-3yl) acetamide derivatives (HNK-series) oximes were evaluated for their antidotal efficacy against DDVP intoxicated Swiss mice, in terms of the Protection Index (PI) and AChE reactivation in brain and serum. The inhibition concentration (IC50) was determined in brain and serum after optimizing the time point for maximum inhibition (60 min post DDVP exposure). AChE reactivation efficacy of the HNK series was evaluated at IC50 and compared with 2-PAM. HNK-102 showed a ~2 times better Protection Index (PI) as compared to 2-PAM against DDVP toxicity. IC50 at 60 min DDVP post exposure was found to be approximately one fifth and one half of the LD50 dose for brain and serum AChE, respectively. Out of three HNK oximes, HNK-102 & 106 at 0.20 LD50 dose significantly reactivated DDVP intoxicated brain AChE (p<0.05) as compared to 2 PAM at double IC50 dose of DDVP. In light of double PI and higher AChE reactivation, HNK 102 was found to be a better oxime than 2-PAM in the treatment of acute poisoning by DDVP. PMID- 28652854 TI - Study of the cytotoxic/toxic potential of the novel anticancer selenodiazoloquinolone on fibroblast cells and 3D skin model. AB - The new synthetically prepared quinolone derivative 7-ethyl 9-ethyl-6-oxo-6,9 dihydro[1,2,5]selenadiazolo [3,4-h]quinoline-7-carboxylate (E2h) showed in our previous study cytotoxic effects towards tumor cells and immunomodulatory activities on RAW 264.7 cell line murine macrophages. E2h may have a potential use as a novel chemotherapeutic agent with immunomodulatory properties and the ability to induce apoptotic death of cancer cells. The aim of the present study was to examine the antiproliferative/cytotoxic activities of E2h on human non cancer fibroblast BHNF-1 cells and reconstructed human epidermis EpiDermTM. Further the effects of E2h on tissue structure and morphology were examined. Cytotoxic/toxic studies showed that selenadiazoloquinolone is not toxic on normal human fibroblast cells BHNF-1 and dimensional skin constructs EpiDermTM. Evaluation of morphological changes in EpiDermTM showed no change in the construction and morphology of skin tissue treated by E2h compared to control. PMID- 28652855 TI - Thermal proteome profiling: unbiased assessment of protein state through heat induced stability changes. AB - In recent years, phenotypic-based screens have become increasingly popular in drug discovery. A major challenge of this approach is that it does not provide information about the mechanism of action of the hits. This has led to the development of multiple strategies for target deconvolution. Thermal proteome profiling (TPP) allows for an unbiased search of drug targets and can be applied in living cells without requiring compound labeling. TPP is based on the principle that proteins become more resistant to heat-induced unfolding when complexed with a ligand, e.g., the hit compound from a phenotypic screen. The melting proteome is also sensitive to other intracellular events, such as levels of metabolites, post-translational modifications and protein-protein interactions. In this review, we describe the principles of this approach, review the method and its developments, and discuss its current and future applications. While proteomics has generally focused on measuring relative protein concentrations, TPP provides a novel approach to gather complementary information on protein stability not present in expression datasets. Therefore, this strategy has great potential not only for drug discovery, but also for answering fundamental biological questions. PMID- 28652857 TI - Fiber Optic Force Sensors for MRI-Guided Interventions and Rehabilitation: A Review. AB - Magnetic Resonance Imaging (MRI) provides both anatomical imaging with excellent soft tissue contrast and functional MRI imaging (fMRI) of physiological parameters. The last two decades have witnessed the manifestation of increased interest in MRI-guided minimally invasive intervention procedures and fMRI for rehabilitation and neuroscience research. Accompanying the aspiration to utilize MRI to provide imaging feedback during interventions and brain activity for neuroscience study, there is an accumulated effort to utilize force sensors compatible with the MRI environment to meet the growing demand of these procedures, with the goal of enhanced interventional safety and accuracy, improved efficacy and rehabilitation outcome. This paper summarizes the fundamental principles, the state of the art development and challenges of fiber optic force sensors for MRI-guided interventions and rehabilitation. It provides an overview of MRI-compatible fiber optic force sensors based on different sensing principles, including light intensity modulation, wavelength modulation, and phase modulation. Extensive design prototypes are reviewed to illustrate the detailed implementation of these principles. Advantages and disadvantages of the sensor designs are compared and analyzed. A perspective on the future development of fiber optic sensors is also presented which may have additional broad clinical applications. Future surgical interventions or rehabilitation will rely on intelligent force sensors to provide situational awareness to augment or complement human perception in these procedures. PMID- 28652856 TI - Photo-affinity labeling (PAL) in chemical proteomics: a handy tool to investigate protein-protein interactions (PPIs). AB - Protein-protein interactions (PPIs) trigger a wide range of biological signaling pathways that are crucial for biomedical research and drug discovery. Various techniques have been used to study specific proteins, including affinity chromatography, activity-based probes, affinity-based probes and photo-affinity labeling (PAL). PAL has become one of the most powerful strategies to study PPIs. Traditional photocrosslinkers are used in PAL, including benzophenone, aryl azide, and diazirine. Upon photoirradiation, these photocrosslinkers (Pls) generate highly reactive species that react with adjacent molecules, resulting in a direct covalent modification. This review introduces recent examples of chemical proteomics study using PAL for PPIs. PMID- 28652858 TI - Tandem C(sp3)-H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones. AB - Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of the isoindolinones with aryl bromides (22 examples) using a Pd(OAc)2/NIXANTPHOS-based catalyst system. Additionally 3-aryl 3-hydroxy isoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxyl group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials. PMID- 28652859 TI - LncRNA H19 promotes the differentiation of bovine skeletal muscle satellite cells by suppressing Sirt1/FoxO1. AB - BACKGROUND: H19 is a well-characterized Long noncoding RNA (lncRNA) that has been proven to promote myoblast differentiation in humans and mice. However, its mechanism of action is still not fully interpreted. METHODS: Using RT-qPCR, we examined H19 RNA levels in various tissues from 1-week, 1-month, 6-month and 36 month old male cattle (i.e., newborn, infant, young and adult). The protein and mRNA levels of MyoG, MyHC, Sirt1 and FoxO1 in the satellite and C2C12 cells with an H19 silencing or overexpression vector were respectively detected using western blot and real-time qPCR. RESULTS: H19 was highly expressed in skeletal muscle at all the studied ages. High expression of H19 was required for the differentiation of bovine satellite cells. Knockdown of H19 caused a remarkable increase in the myoblast-inhibitory genes Sirt1/FoxO1, suggesting that H19 suppresses Sirt1/FoxO1 expression during myogenesis. Western blotting analysis of co-transfection of Sirt1 or FoxO1 expression vectors with pcDNA-H19 indicated that Sirt1/FoxO1 overexpression neutralized the promotion of myoblast differentiation through transfection of pcDNA-H19. CONCLUSION: H19 promoted the differentiation of bovine skeletal muscle satellite cells by suppressing Sirt1/FoxO1. PMID- 28652860 TI - Qualitative exploration of psychological reactions and coping strategies of breastfeeding mothers living with HIV in the Greater Accra Region of Ghana. AB - BACKGROUND: Exploring the psychological reactions of breastfeeding mothers living with Human Immunodeficiency Virus (HIV) is an important step which may improve guidelines for counselling. The purpose of this study was to explore the psychological reactions and coping strategies of breastfeeding mothers living with HIV in the Greater Accra Region of Ghana. METHODS: Qualitative descriptive exploratory design was used to explore the psychological experiences and coping strategies of 13 breastfeeding mothers living with HIV in a main referral public hospital, at the greater Accra Region of Ghana. An interview guide was designed and piloted before it was used to collect data between November, 2014 and February, 2015. Data was content analyzed for themes and subthemes to emerge. RESULTS: The two major themes that emerged included psychological reactions and coping strategies. Some of the subthemes were fear, anxiety, blame, hope, denial, prayer and trust in positive situations of life. CONCLUSION: The women used denial, prayer and hope in ART, among others to cope with their emotions. This highlights the need for HIV counsellors to detect signs of denial since it can lead to non-adherence to ART as well as relapse. Health workers should therefore put the coping strategies in context during counselling of mothers in this category. PMID- 28652861 TI - Erratum to: Outcome of HIV-associated lymphoma in a resource-limited setting of Jos, Nigeria. AB - [This corrects the article DOI: 10.1186/s13027-017-0144-7.]. PMID- 28652862 TI - Dysfunctional maltreatment-related cognitions in children and adolescents. AB - BACKGROUND: Dysfunctional trauma-related cognitions correlate highly with chronic stress. Studies on maltreatment-related cognitions and their predictors in children and adolescents are rare. METHODS: The study sample consisted of 231 children aged 8-17 years who had experienced maltreatment including domestic violence, emotional abuse, neglect, physical, and sexual abuse. Using multiple linear regression analysis, gender, age, index-event, multi-type maltreatment, out-of-home-care, and migration background were investigated as possible predictors of dysfunctional maltreatment-related cognitions. Additionally, the associations between dysfunctional cognitions and posttraumatic stress symptoms (PTSS) as well as further internalizing and externalizing symptoms were calculated. RESULTS: Gender emerged as a significant predictor of dysfunctional maltreatment-related cognitions. Moreover, there was an interaction effect of gender and age, with female adolescents showing most dysfunctional cognitions. Furthermore, experiencing five different maltreatment types had an impact, leading to more dysfunctional cognitions compared to single-type maltreatment. Dysfunctional maltreatment-related cognitions correlated highly with PTSS and internalizing symptoms, and moderately with externalizing symptoms. CONCLUSIONS: Dysfunctional maltreatment-related cognitions are associated with psychological symptoms after maltreatment and, therefore, need to be addressed in assessment and treatment. Trial registration DRKS00003979. Registered 03 July 2012. PMID- 28652863 TI - Stimulation and inhibition of enzymatic hydrolysis by organosolv lignins as determined by zeta potential and hydrophobicity. AB - BACKGROUND: Lignin typically inhibits enzymatic hydrolysis of cellulosic biomass, but certain organosolv lignins or lignosulfonates enhance enzymatic hydrolysis. The hydrophobic and electrostatic interactions between lignin and cellulases play critical roles in the enzymatic hydrolysis process. However, how to incorporate these two interactions into the consideration of lignin effects has not been investigated. RESULTS: We examined the physicochemical properties and the structures of ethanol organosolv lignins (EOL) from hardwood and softwood and ascertained the association between lignin properties and their inhibitory and stimulatory effects on enzymatic hydrolysis. The zeta potential and hydrophobicity of EOL lignin samples, isolated from organosolv pretreatment of cottonwood (CW), black willow (BW), aspen (AS), eucalyptus (EH), and loblolly pine (LP), were determined and correlated with their effects on enzymatic hydrolysis of Avicel. EOLs from CW, BW, and AS improved the 72 h hydrolysis yield by 8-12%, while EOLs from EH and LP decreased the 72 h hydrolysis yield by 6 and 16%, respectively. The results showed a strong correlation between the 72 h hydrolysis yield with hydrophobicity and zeta potential. The correlation indicated that the hydrophobicity of EOL had a negative effect and the negative zeta potential of EOL had a positive effect. HSQC NMR spectra showed that beta-O 4 linkages in lignin react with ethanol to form an alpha-ethoxylated beta-O-4' substructure (A') during organosolv pretreatment. Considerable amounts of C2,6 H2,6 correlation in p-hydroxybenzoate (PB) units were observed for EOL-CW, EOL BW, and EOL-AS, but not for EOL-EH and EOL-LP. CONCLUSIONS: This study revealed that the effect of lignin on enzymatic hydrolysis is a function of both hydrophobic interactions and electrostatic repulsions. The lignin inhibition is controlled by lignin hydrophobicity and the lignin stimulation is governed by the negative zeta potential. The net effect of lignin depends on the combined influence of hydrophobicity and zeta potential. This study has potential implications in biomass pretreatment for the reduction of lignin inhibition by increasing lignin negative zeta potential and decreasing hydrophobicity. PMID- 28652864 TI - The LacI family protein GlyR3 co-regulates the celC operon and manB in Clostridium thermocellum. AB - BACKGROUND: Clostridium thermocellum utilizes a wide variety of free and cellulosomal cellulases and accessory enzymes to hydrolyze polysaccharides present in complex substrates. To date only a few studies have unveiled the details by which the expression of these cellulases are regulated. Recent studies have described the auto regulation of the celC operon and determined that the celC-glyR3-licA gene cluster and nearby manB-celT gene cluster are co-transcribed as polycistronic mRNA. RESULTS: In this paper, we demonstrate that the GlyR3 protein mediates the regulation of manB. We first identify putative GlyR3 binding sites within or just upstream of the coding regions of manB and celT. Using an electrophoretic mobility shift assay (EMSA), we determined that a higher concentration of GlyR3 is required to effectively bind to the putative manB site in comparison to the celC site. Neither the putative celT site nor random DNA significantly binds GlyR3. While laminaribiose interfered with GlyR3 binding to the celC binding site, binding to the manB site was unaffected. In the presence of laminaribiose, in vivo transcription of the celC-glyR3-licA gene cluster increases, while manB expression is repressed, compared to in the absence of laminaribiose, consistent with the results from the EMSA. An in vitro transcription assay demonstrated that GlyR3 and laminaribiose interactions were responsible for the observed patters of in vivo transcription. CONCLUSIONS: Together these results reveal a mechanism by which manB is expressed at low concentrations of GlyR3 but repressed at high concentrations. In this way, C. thermocellum is able to co-regulate both the celC and manB gene clusters in response to the availability of beta-1,3-polysaccharides in its environment. PMID- 28652866 TI - An isolated cellulolytic Escherichia coli from bovine rumen produces ethanol and hydrogen from corn straw. AB - BACKGROUND: Lignocellulosic biomass is the most abundant resource on earth. Lignocellulose is mainly composed of cellulose, hemicelluloses, and lignin. The special construction of three kinds of constituents led to the prevention of effective degradation. The goal of this work was to investigate the great potentials of bovine rumen for novel cellulolytic bacterial isolation, which may be used for chemicals and biofuel production from lignocellulose. RESULTS: A cellulolytic strain, ZH-4, was isolated from Inner Mongolia bovine rumen. This strain was identified as Escherichia coli by morphological, physiological, and biochemical characteristics and 16S rDNA gene sequencing. The extracellular enzyme activity analysis showed that this strain produces extracellular cellulases with an exoglucanase activity of 9.13 IU, an endoglucanase activity of 5.31 IU, and a beta-glucosidase activity of 7.27 IU at the pH 6.8. This strain was found to produce 0.36 g/L ethanol and 4.71 mL/g hydrogen from corn straw with cellulose degradation ratio of 14.30% and hemicellulose degradation ratio of 11.39%. CONCLUSIONS: It is the first time that a cellulolytic E. coli was isolated and characterized form the bovine rumen. This provided a great opportunity for researchers to investigate the evolution mechanisms of the microorganisms in the rumen and provided great chance to produce biofuels and chemicals directly from engineered E. coli using consolidated bioprocess. PMID- 28652865 TI - CRISPR-Cas9-enabled genetic disruptions for understanding ethanol and ethyl acetate biosynthesis in Kluyveromyces marxianus. AB - BACKGROUND: The thermotolerant yeast Kluyveromyces marxianus shows promise as an industrial host for the biochemical production of fuels and chemicals. Wild-type strains are known to ferment high titers of ethanol and can effectively convert a wide range of C5, C6, and C12 sugars into the volatile short-chain ester ethyl acetate. Strain engineering, however, has been limited due to a lack of advanced genome-editing tools and an incomplete understanding of ester and ethanol biosynthesis. RESULTS: Enabled by the design of hybrid RNA polymerase III promoters, this work adapts the CRISPR-Cas9 system from Streptococcus pyogenes for use in K. marxianus. The system was used to rapidly create functional disruptions to alcohol dehydrogenase (ADH) and alcohol-O-acetyltransferase (ATF) genes with putative function in ethyl acetate and ethanol biosynthesis. Screening of the KmATF disrupted strain revealed that Atf activity contributes to ethyl acetate biosynthesis, but the knockout reduced ethyl acetate titers by only ~15%. Overexpression experiments revealed that KmAdh7 can catalyze the oxidation of hemiacetal to ethyl acetate. Finally, analysis of the KmADH2 disrupted strain showed that the knockout almost completely eliminated ethanol production and resulted in the accumulation of acetaldehyde. CONCLUSIONS: Newly designed RNA polymerase III promoters for sgRNA expression in K. marxianus enable a CRISPR Cas9 genome-editing system for the thermotolerant yeast. This system was used to disrupt genes involved in ethyl acetate biosynthesis, specifically KmADH1-7 and KmATF. KmAdh2 was found to be critical for aerobic and anaerobic ethanol production. Aerobically produced ethanol supplies the biosynthesis of ethyl acetate catalyzed by KmAtf. KmAdh7 was found to exhibit activity toward the oxidation of hemiacetal, a possible alternative route for the synthesis of ethyl acetate. PMID- 28652868 TI - Costs, Innovation, And Change Management. PMID- 28652867 TI - Scattered genomic amplification in dedifferentiated liposarcoma. AB - BACKGROUND: Atypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes. RESULTS: The present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q. CONCLUSIONS: The observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis. PMID- 28652869 TI - Knowing our "best before date": Developing an exit plan. PMID- 28652870 TI - Global implementation of advanced urological care: Policy implementation research. AB - INTRODUCTION: In high-resource countries, modern treatments for urological diseases have led to significant reductions in mortality and morbidity; however, the benefits of modern treatment have yet to reach the majority of people worldwide. As attention is focused on improving urological care in the global community, policy and implementation research (PIR) offers a platform for effective organization and engagement. METHODS: We have compiled a photo essay to illustrate the fundamental components of PIR. RESULTS: There are four central components to the conduct of PIR. These are: 1) understanding the unique characteristics of the environment; 2) studying the implementation processes that fit within the environment; 3) testing innovative and novel ways to implement; and 4) programmatic implementation and scale-up. CONCLUSIONS: PIR is a process that will help to identify, quantify, prioritize, and implement translation of modern methods of care to meet specific global needs. PMID- 28652871 TI - Pursuing fellowship training: There are no traffic jams along the extra mile. PMID- 28652872 TI - Exploring the business of urology: Change management. PMID- 28652873 TI - The value of complementing administrative data with abstracted information on smoking and obesity: A study in kidney cancer. AB - INTRODUCTION: Variables, such as smoking and obesity, are rarely available in administrative databases. We explored the added value of including these data in an administrative database study evaluating the association of statin use with survival in kidney cancer. METHODS: We linked administrative data with chart abstracted data on smoking and obesity for 808 patients undergoing nephrectomy for kidney cancer. Base models consisted of variables from administrative databases (age, sex, year of surgery, and different measures of comorbidity [to compare their sensitivity to smoking and obesity data]); extended models added chart-abstracted data. We compared coefficients for statin use with overall (OS) and cancer-specific survival (CSS), and used the c-statistic and net reclassification improvement (NRI) to compare predications of five-year survival obtained from Cox proportional hazard models. RESULTS: The coefficient for statin use changed minimally following addition of abstracted data (<6% for OS, <2% for CSS). Base models performed similarly for OS, with c-statistics of 0.75 (95% confidence interval [CI] 0.72-0.79) for Charlson score and 0.73 (95% CI 0.69 0.78) for John Hopkins Aggregated Diagnosis Groups score. After including abstracted data, c-statistics modestly improved (change <0.02); CSS demonstrated similar findings. NRIs were 0.210 (95% CI 0.062-0.297) and 0.186 (-0.031-0.387) when using the Charlson score, and 0.207 (0.068-0.287) and 0.197 (0.007-0.399) when using the Aggregated Diagnosis Groups score, for OS and CSS, respectively. CONCLUSIONS: The inclusion of data on smoking and obesity marginally influences survival models in kidney cancer studies using administrative data. PMID- 28652874 TI - In search of the perfect model. PMID- 28652875 TI - Contemporary cost-consequence analysis of blue light cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer. AB - INTRODUCTION: Previous studies have suggested cost-savings using blue light cystoscopy (BLC) with hexaminolevulinate (HAL) compared to white light cystoscopy (WLC) during transurethral resection of bladder tumour (TURBT) for non-muscle invasive bladder cancer (NMIBC), secondary to improvements in recurrence and progression rates; however, these studies have used 'best case scenario' recurrence rate probabilities, thus decreasing generalizability of the findings. The objective of this study was to perform a contemporary cost-effectiveness assessment of BLC compared to WLC at the time of TURBT. METHODS: A decision and cost-effectiveness model with a five-year time horizon following initial TURBT was used. The model was created from the healthcare payer perspective. Comprehensive literature review was performed to obtain contemporary recurrence and progression rates. These values were meta-analyzed for inclusion into the model. Cost variables included in the model were from three large Canadian bladder cancer centres. Model outputs were number of recurrences prevented, bed days saved, and overall costs. One-way sensitivity and scenario analyses were performed to assess model robustness. RESULTS: The five-year amortized cost of using BLC with HAL on all incident NMIBC compared to WLC assistance was $4 832,908 for Ontario (n=4696; $1372/patient); $1 168 968 for British Columbia (n=1204; $1295/patient); and $2 484, 872 (n=2680; $1236/patient) for Quebec. Use of BLC with HAL would result in 87 338 fewer recurrences annually. On sensitivity/scenario analyses for Ontario data, if BLC with HAL equipment were provided to the province at no cost, five-year costs would be $4 158 814 and $1181 cost per patient. If BLC with HAL were only used for cystoscopically appearing aggressive tumours, the five-year amortized cost would be $3 874 098, with a cost per patient of $1222. If there was a 20% or 50% improvement in progression rates with BLC plus HAL, the five-year amortized cost would be $2 660 529 and -$598 039 (cost-saving), respectively. CONCLUSIONS: TURBT using BLC with HAL for patients with NMIBC is associated with a five-year cost of approximately $1-5 million for jurisdictions of 4-13 million people. Although this translates to a cost of $1200-1400 per patient for their initial TURBT, BLC with HAL improves patients care, reduces recurrences, and decreases the need for hospital beds after TURBT. If this diagnostic procedure eventually improves progression rates, there would be considerably improved cost-effectiveness. PMID- 28652877 TI - Pathology review impacts clinical management of patients with T1-T2 bladder cancer. AB - INTRODUCTION: We sought to evaluate the contemporary role of a pathology review on management implications of patients with bladder cancer. METHODS: A total of 98 consecutive specimens from transurethral resections in patients with suspected bladder tumours were reviewed at our institution by genitourinary pathologist. Patients were classified into risk groups according to pathology reports obtained before and after review. A management course was proposed according to local institutional practice patterns and main urological guidelines. RESULTS: Overall, 34.7% of pathological reviews had significant changes associated with management implications, the majority of which were due to changes in risk category (and/or stage). On review pathology, 12 patients were recommended radical cystectomy instead of conservative management and two patients avoided radical cystectomy. Six patients initially staged as T1 and whose staging did not change after review had a proposed change in management in the form of early cystectomy as a treatment option, as they were deemed very high-risk secondary to high-risk features (such as carcinoma in situ or lymphovascular invasion found on review). Ten patients initially staged as T2 demonstrated high-risk features on review. CONCLUSIONS: Review by genitourinary pathologist remains important, as it defines more clearly the tumour risk category and influences the management of T1-T2 bladder cancer patients. A complete initial pathological report has the potential to further decrease the discrepancy between initial and review reports. PMID- 28652876 TI - Positive surgical margins during partial nephrectomy for renal cell carcinoma: Results from Canadian Kidney Cancer information system (CKCis) collaborative. AB - INTRODUCTION: We sought to determine the incidence, risk factors, and prognosis for patients with positive surgical margin (PSM) during partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: From the Canadian Kidney Cancer information system (CKCis) database, a historical cohort of PN patients with PSM were identified and compared to negative surgical margin (NSM). Risk factors for PSM were examined through multivariable logistic regression. Kaplan-Meier curves were used to compare progression-free survival. RESULTS: Of 1103 patients, 972 (88.1%), 71 (6.4%), and 60 (5.4%) had NSM, PSM, and unknown status, respectively. Median patient age and tumour size were 61 years and 3.0 cm for both groups. From multivariable analysis, pathological stage >=T3 (odds ratio [OR] 2.51; 95% confidence interval [CI] 1.13-5.60) and Fuhrman grade 4 (OR 5.35; 95% CI 1.11 25.72) were associated with PSM, whereas age, operative technique, and tumour size were not. Forty-nine (5.0%) patients from the NSM cohort and seven (9.9%) from the PSM cohort had a local/systemic progression of disease (adjusted hazard ratio [HR] 1.4; 95% CI 0.6-3.6). There were three (0.3%) cancer-related deaths in the NSM group and none in the PSM group. After median followup of 19 (interquartile range [IQR] 5-42) and 15 (IQR 7-30) months, 855 (91.4%) and 61 (89.7%) patients were alive in the NSM and PSM groups, respectively. CONCLUSIONS: PSM occurred in 6.4% of PNs performed for RCC in this pan-Canadian cohort. Higher stage and grade are associated with a higher risk of positive margin. The small association between a PSM and progression suggests that complete nephrectomy is not necessary in patients with a PSM. The main study limitations are lack of nephrometry score and possible reporting bias. PMID- 28652878 TI - Randomized, controlled trial of laser vs. bipolar plasma vaporization treatment of benign prostatic hyperplasia. AB - INTRODUCTION: Prostate vaporization technology is becoming a standard of care for treatment of moderate, symptomatic benign prostatic hyperplasia (BPH). We compared two transurethral prostate vaporization technologies with respect to cost, efficiency, efficacy, safety, and surgical team satisfaction. METHODS: Fifty-five patients meeting standardized symptom criteria for BPH were randomized to either Olympus Plasma ButtonTM or Biolitec EVOLVE(r) diode laser vaporization. Primary outcome of cost with secondary outcomes of clinical efficacy, resection time, surgical team satisfaction, and safety were analyzed. Followup was carried out at six and 12 weeks. Patient factors included baseline, as well as six- and 12-week International Prostate Symptom Score (IPSS) with quality of life (QoL) scores. We recorded surgical team satisfaction with a Likert-style survey investigating ease of set-up, reliability, efficiency, and ability to reach desired endpoint. All complications or side effects detected within three months and the resulting management were included in the cost analysis. RESULTS: Mean cost per patient was $3418 for the Olympus group and $4564 for Biolitec (p<0.05). Surgical vaporization time was significantly less for the Olympus group, 24.3 vs. 33.5 minutes (p<0.05). Surgical and nursing staff preferred the Olympus device (p<0.05). IPPS symptom improvement and complication rates were similar between groups. Patients in the Biolitec arm had more intraoperative bleeding episodes requiring conversion to monopolar transurethral resection of the prostate (TURP) (three vs. none). CONCLUSIONS: In a head-to-head randomized trial, Olympus Plasma Button transurethral vaporization was more cost-effective, faster, and preferred by surgical staff when compared to Biolitetec Diode Laser vaporization. Both devices showed similar safety and efficacy. PMID- 28652879 TI - Are renal tumour scoring systems better than clinical judgement at predicting partial nephrectomy complexity? AB - INTRODUCTION: We aimed to determine how renal tumour scoring systems, such as RENAL, PADUA, and Centrality (C)-index, compare to clinical judgement at predicting time required for tumour removal and kidney reconstruction during partial nephrectomy. METHODS: A consecutive cohort of partial nephrectomy patients treated at The Ottawa Hospital, a tertiary care uro-oncological centre, was retrospectively reviewed. Preoperative axial images were reviewed by four experienced urological oncologists who independently rated the complexity of a partial nephrectomy from 1-10 to generate a clinical judgement score. Two independent reviewers determined the RENAL, PADUA, and C-index scores. The time to complete tumour resection and renal reconstruction during partial nephrectomy was prospectively recorded. RESULTS: During the study period, 104 partial nephrectomies were performed. The mean partial nephrectomy complexity score based on clinical judgement was 3.4 (standard deviation [SD] 2.1) out of 10. There was good agreement between surgeons in assessing tumour complexity (intraclass correlation coefficient 0.72; 95% confidence interval [CI] 0.65, 0.78). The mean RENAL score was 6.7 (SD 1.6) out of a maximum of 12, the mean PADUA score was 8.5 (SD 1.5) out of a maximum of 14, and the mean C-index score was 3.8 (SD 2). Mean resection and reconstruction time was 24 minutes (SD 10 minutes). The correlation between clinical judgement score and time was 0.27 (p=0.005). The correlation between renal tumour scoring systems and time was 0.20 (p=0.04) for RENAL, 0.21 (p=0.03) for C-index, and 0.26 (p=0.007) for PADUA. RENAL and PADUA scores were significantly associated with surgical and total complications. CONCLUSIONS: The majority of variance in ischemia time is not explained by clinical judgement or renal tumour scoring systems. Renal tumour scoring systems were not better than the clinical judgement of urological oncologists at predicting ischemia time during partial nephrectomy. PMID- 28652880 TI - Testosterone monitoring for men with advanced prostate cancer: Review of current practices and a survey of Canadian physicians. AB - Androgen-deprivation therapy (ADT) is a standard of care in the treatment of advanced prostate cancer; however, testosterone monitoring practices for men undergoing ADT vary across Canada. Although a testosterone level of 1.7 nmol/L or lower has historically been defined as the accepted castrate level, newer assays with improved sensitivity have shown that both medical and surgical castration can suppress testosterone levels to below 0.7 nmol/L. This review explores the evidence supporting a redefinition of the castrate testosterone level as 0.7 nmol/L or lower, and presents results of a survey of testosterone monitoring practices among 153 Canadian urologists, uro-oncologists, and radiation oncologists who manage the treatment of men with hormone-sensitive prostate cancer. PMID- 28652882 TI - Legendary urologist Yosh Taguchi retires. PMID- 28652881 TI - Taking the first steps in establishing recommendations for testosterone monitoring in men with prostate cancer on androgen-deprivation therapy. AB - The paper by Shayegan et al in this issue of CUAJ represents an important initial step in establishing recommendations for hormonal monitoring in men with prostate cancer on androgen-deprivation therapy (ADT). As with most subjects related to the actions of testosterone, the survey adds to the controversies, but also opens the opportunity to explore several of the concerns relevant to the hormonal management of prostate cancer. PMID- 28652883 TI - ? PMID- 28652884 TI - Drug absorption related nephrotoxicity assessment on an intestine-kidney chip. AB - Drug absorption in the intestine is tightly related to drug-induced nephrotoxicity, which is a relatively common side effect in clinical practice. It highlights a great need to develop predictive models with high accuracy in the early stage during new drug discovery and development. Herein, we presented a novel intestine-kidney chip, which recapitulated drug absorption in the intestine and its resultant drug toxicity on the kidney. This work aims to provide an integrated tool for accurate assessment of drug absorption-related nephrotoxicity in vitro. A microfluidic device with multi-interfaces was designed, which facilitated the co-culture of the intestinal and glomerular endothelial cells in compartmentalized micro-chambers. Thus, drug absorption and following nephrotoxicity could be explored in a single assay based on the formation of the intact intestine function on the chip. Specifically, we adopt digoxin (DIG) as a model drug combined with colestyramine (COL) or Verapamil (VER), which significantly influence DIG absorption in the intestine. Different degrees of nephrotoxicity under drug combinations were further observed on the chip, including cell apoptosis, cell viability, and lactate dehydrogenase leakage. These features were consistent with the variance of DIG absorption by the intestinal cells. In agreement with clinical observations, our data demonstrated that DIG-induced nephrotoxicity was enhanced combined with VER but weakened with COL. All of these findings suggest that the established microdevice might provide a useful and cost-effective platform in vitro for testing drug absorption and nephrotoxicity in preclinical trials during new drug development. PMID- 28652885 TI - Rapid concentration and elution of malarial antigen histidine-rich protein II using solid phase Zn(II) resin in a simple flow-through pipette tip format. AB - Rapid diagnostic tests (RDTs) designed to function at the point of care are becoming more prevalent in malaria diagnostics because of their low cost and simplicity. While many of these tests function effectively with high parasite density samples, their poor sensitivity can often lead to misdiagnosis when parasitemia falls below 100 parasites/MUl. In this study, a flow-through pipette based column was explored as a cost-effective means to capture and elute more Plasmodium falciparum histidine-rich protein II (HRPII) antigen, concentrating the biomarker available in large-volume lysed whole blood samples into volumes compatible with Plasmodium falciparum-specific RDTs. A systematic investigation of immobilized metal affinity chromatography divalent metal species and solid phase supports established the optimal design parameters necessary to create a flow-through column incorporated into a standard pipette tip. The bidirectional flow inherent to this format maximizes mixing efficiency so that in less than 5 min of sample processing, the test band signal intensity was increased up to a factor of twelve from HRPII concentrations as low as 25 pM. In addition, the limit of detection per sample was decreased by a factor of five when compared to the RDT manufacturer's suggested protocol. Both the development process and commercial viability of this application are explored, serving as a potential model for future applications. PMID- 28652886 TI - A magneto-fluidic nanoparticle trapping platform for surface-enhanced Raman spectroscopy. AB - A microfluidic device utilizing magnetically activated nickel (Ni) micropads has been developed for controlled localization of plasmonic core-shell magnetic nanoparticles, specifically for surface enhanced Raman spectroscopy (SERS) applications. Magnetic microfluidics allows for automated washing steps, provides a means for easy reagent packaging, allows for chip reusability, and can even be used to facilitate on-chip mixing and filtration towards full automation of biological sample processing and analysis. Milliliter volumes of gold-coated 175 nm silica encapsulated iron oxide nanoparticles were pumped into a microchannel and allowed to magnetically concentrate down into 7.5 nl volumes over nano-thick lithographically defined Ni micropads. This controlled aggregation of core-shell magnetic nanoparticles by an externally applied magnetic field not only enhances the SERS detection limit within the newly defined nanowells but also generates a more uniform (~92%) distribution of the SERS signal when compared to random mechanical aggregation. The microfluidic flow rate and the direction and strength of the magnetic field determined the overall capture efficiency of the magneto fluidic nanoparticle trapping platform. It was found that a 5 MUl/min flow rate using an attractive magnetic field provided by 1 * 2 cm neodymium permanent magnets could capture over 90% of the magnetic core-shell nanoparticles across five Ni micropads. It was also observed that the intensity of the SERS signal for this setup was 10-fold higher than any other flow rate and magnetic field configurations tested. The magnetic concentration of the ferric core-shell nanoparticles causes the SERS signal to reach the steady state within 30 min can be reversed by simply removing the chip from the magnet housing and sonicating the retained particles from the outlet channel. Additionally, each magneto fluidic can be reused without noticeable damage to the micropads up to three times. PMID- 28652887 TI - Amphiphilic nanoparticles suppress droplet break-up in a concentrated emulsion flowing through a narrow constriction. AB - This paper describes the break-up behavior of a concentrated emulsion comprising drops stabilized by amphiphilic silica nanoparticles flowing in a tapered microchannel. Such geometry is often used in serial droplet interrogation and sorting processes in droplet microfluidics applications. When exposed to high viscous stresses, drops can undergo break-up and compromise their physical integrity. As these drops are used as micro-reactors, such compromise leads to a loss in the accuracy of droplet-based assays. Here, we show droplet break-up is suppressed by replacing the fluoro-surfactant similar to the one commonly used in current droplet microfluidics applications with amphiphilic nanoparticles as droplet stabilizer. We identify parameters that influence the break-up of these drops and demonstrate that break-up probability increases with increasing capillary number and confinement, decreasing nanoparticle size, and is insensitive to viscosity ratio within the range tested. Practically, our results reveal two key advantages of nanoparticles with direct applications to droplet microfluidics. First, replacing surfactants with nanoparticles suppresses break up and increases the throughput of the serial interrogation process to 3 times higher than that in surfactant system under similar flow conditions. Second, the insensitivity of break-up to droplet viscosity makes it possible to process samples having different composition and viscosities without having to change the channel and droplet geometry in order to maintain the same degree of break-up and corresponding assay accuracy. PMID- 28652888 TI - Fabrication of concave micromirrors for single cell imaging via controlled over exposure of organically modified ceramics in single step lithography. AB - This work describes the fabrication of concave micromirrors to improve the sensitivity of fluorescence imaging, for instance, in single cell analysis. A new approach to fabrication of tunable round (concave) cross-sectional shaped microchannels out of the inorganic-organic hybrid polymer, Ormocomp(r), via single step optical lithography was developed and validated. The concave micromirrors were implemented by depositing and patterning thin films of aluminum on top of the concave microchannels. The round cross-sectional shape was due to residual layer formation, which is inherent to Ormocomp(r) upon UV exposure in the proximity mode. We show that it is possible to control the residual layer thickness and thus the curved shape of the microchannel cross-sectional profile and eventually the focal length of the micromirror, by simply adjusting the UV exposure dose and the distance of the proximity gap (to the photomask). In general, an increase in the exposure dose or in the distance of the proximity gap results in a thicker residual layer and thus an increase in the radius of the microchannel curvature. Under constant exposure conditions, the radius of curvature is almost linearly dependent on the microchannel aspect ratio, i.e., the width (here, 20-200 MUm) and the depth (here, 15-45 MUm). Depending on the focal length, up to 8-fold signal enhancement over uncoated, round Ormocomp(r) microchannels was achieved in single cell imaging with the help of the converging micromirrors in an epifluorescence microscopy configuration. PMID- 28652889 TI - Chemical and Lattice Stability of the Tin Sulfides. AB - The tin sulfides represent a materials platform for earth-abundant semiconductor technologies. We present a first-principles study of the five known and proposed phases of SnS together with SnS2 and Sn2S3. Lattice-dynamics techniques are used to evaluate the dynamical stability and temperature-dependent thermodynamic free energy, and we also consider the effect of dispersion forces on the energetics. The recently identified pi-cubic phase of SnS is found to be metastable with respect to the well-known orthorhombic Pnma/Cmcm equilibrium. The Cmcm phase is a low-lying saddle point between Pnma local minima on the potential-energy surface and is observed as an average structure at high temperatures. Bulk rocksalt and zincblende phases are found to be dynamically unstable, and we show that whereas rocksalt SnS can potentially be stabilized under a reduction of the lattice constant the hypothetical zincblende phase proposed in several previous studies is extremely unlikely to form. We also investigate the stability of Sn2S3 with respect to SnS and SnS2 and find that both dispersion forces and vibrational contributions to the free energy are required to explain its experimentally observed resistance to decomposition. PMID- 28652890 TI - Silver Deposition onto Modified Silicon Substrates. AB - Trimethylphosphine(hexafluoroacetylacetonato)silver(I) was used as a precursor to deposit silver onto silicon surfaces. The deposition was performed on silicon based substrates including silica, H-terminated Si(100), and OH-terminated (oxidized) Si(100). The deposition processes at room temperature and elevated temperature (350 degrees C) were compared. The successful deposition resulted in nanostructures or nanostructured films as confirmed by atomic force microscopy (AFM) and scanning electron microscopy (SEM) with metallic silver being the majority deposited species as confirmed by X-ray photoelectron spectroscopy (XPS). The reactivity of the precursor depends drastically not only on the temperature of the process but also on the type of substrate. Density functional theory (DFT) was used to explain these differences and to propose the mechanisms for the initial deposition steps. PMID- 28652892 TI - Abdominal cross-sectional imaging of the associating liver partition and portal vein ligation for staged hepatectomy procedure. AB - Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a recently introduced technique aimed to perform two-stage hepatectomy in patients with a variety of primary or secondary neoplastic lesions. ALPSS is based on a preliminary liver resection associated with ligation of the portal branch directed to the diseased hemiliver (DH), followed by hepatectomy after an interval of time in which the future liver remnant (FLR) hypertrophied adequately (partly because of preserved arterialization of the DH). Multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) play a pivotal role in patients' selection and FLR assessment before and after the procedure, as well as in monitoring early and late complications, as we aim to review in this paper. Moreover, we illustrate main abdominal MDCT and MRI findings related to ALPPS. PMID- 28652893 TI - Low bone mineral density and the severity of cholestasis in biliary atresia. AB - AIM: To investigate the prevalence of osteopenia and osteoporosis in postoperative biliary atresia (BA) children and the association of bone mineral density (BMD) and biochemical parameters in postKasai BA subjects. METHODS: A total of 70 patients with postKasai BA were enrolled in this prospective study. The patients were classified into two groups according to their jaundice status. BMD of the lumbar spine was analyzed using dual energy X-ray absorptiometry. RESULTS: The prevalence of low bone mass (osteopenia and osteoporosis) in BA patients were 51.4% (36 out of 70). Ten patients (35.7%) in the jaundice group and 8 patients (19.0%) in the non-jaundice group had osteopenia. Sixteen patients (57.1%) in the jaundice group and 2 patients (4.8%) in the no jaundice group had osteoporosis. In addition, lumbar spine BMD Z-score was substantially lower in the jaundice BA patients compared with non-jaundice patients. BA subjects with persistent jaundice had significantly lower serum 25-hydroxyvitamin D than those without jaundice. Further analysis revealed that lumbar spine BMD was correlated with age (r = 0.774, P < 0.001), serum albumin (r = 0.333, P = 0.005), total bilirubin (r = -0.476, P < 0.001), aspartate aminotransferase (r = -0.583, P < 0.001), alanine aminotransferase (r = -0.428, P < 0.001), and alkaline phosphatase(r = -0.456, P < 0.001). CONCLUSION: Low BMD was associated with biochemical parameters reflecting the severity of cholestasis in postKasai BA patients. PMID- 28652894 TI - Successful surgical resection of ruptured cholangiolocellular carcinoma: A rare case of a primary hepatic tumor. AB - Spontaneous rupture is one of the most fatal complications of hepatic tumors such as hepatocellular carcinoma. In fact, many studies have shown that the in hospital and 30-d mortality rates are as high as 25%-100%. Cholangiolocellular carcinoma (CoCC) is a rare primary hepatic tumor, usually small in size, that is thought to originate from the ductules and/or canals of Hering. Here, we present a case of spontaneous rupture of a CoCC that was successfully resected by radical surgery. Although CoCC is a rare primary hepatic tumor, it demonstrates certain specific clinical features, including a better prognosis than for other primary liver cancers, and thus should be distinguished from those other cancers. Moreover, CoCC can appear as a ruptured huge tumor, and when it does, radical hepatectomy can be an effective measure to achieve both absolute hemostasis and curability of tumor. PMID- 28652891 TI - Non-alcoholic fatty liver disease: An expanded review. AB - Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients. PMID- 28652895 TI - Exploring Components of the CO2-Concentrating Mechanism in Alkaliphilic Cyanobacteria Through Genome-Based Analysis. AB - In cyanobacteria, the CO2-concentrating mechanism (CCM) is a vital biological process that provides effective photosynthetic CO2 fixation by elevating the CO2 level near the active site of Rubisco. This process enables the adaptation of cyanobacteria to various habitats, particularly in CO2-limited environments. Although CCM of freshwater and marine cyanobacteria are well studied, there is limited information on the CCM of cyanobacteria living under alkaline environments. Here, we aimed to explore the molecular components of CCM in 12 alkaliphilic cyanobacteria through genome-based analysis. These cyanobacteria included 6 moderate alkaliphiles; Pleurocapsa sp. PCC 7327, Synechococcus spp., Cyanobacterium spp., Spirulina subsalsa PCC 9445, and 6 strong alkaliphiles (i.e. Arthrospira spp.). The results showed that both groups belong to beta cyanobacteria based on beta-carboxysome shell proteins with form 1B of Rubisco. They also contained standard genes, ccmKLMNO cluster, which is essential for beta carboxysome formation. Most strains did not have the high-affinity Na+/HCO3- symporter SbtA and the medium-affinity ATP-dependent HCO3- transporter BCT1. Specifically, all strong alkaliphiles appeared to lack BCT1. Beside the transport systems, carboxysomal beta-CA, CcaA, was absent in all alkaliphiles, except for three moderate alkaliphiles: Pleurocapsa sp. PCC 7327, Cyanobacteriumstranieri PCC 7202, and Spirulina subsalsa PCC 9445. Furthermore, comparative analysis of the CCM components among freshwater, marine, and alkaliphilic beta-cyanobacteria revealed that the basic molecular components of the CCM in the alkaliphilic cyanobacteria seemed to share more degrees of similarity with freshwater than marine cyanobacteria. These findings provide a relationship between the CCM components of cyanobacteria and their habitats. PMID- 28652897 TI - Low-Level Laser Therapy in Russia: History, Science and Practice. AB - In Russia (formerly USSR) study of biomodulation action (BMA) mechanisms of low intensity laser irradiation (LILI) began in 1964, immediately after the development of lasers. During the period from 1965 to 1972 several dozens of scientific conferences were held, hundreds of studies were published. Generally, secondary mechanisms and results of LILI effect on patients with various diseases were studied. This data was immediately implemented into practical medicine in the fields of oncology, surgery, dermatology and dentistry, and since 1974 low level laser therapy (LLLT) is included in the standard of state medical care. For 50 years no less than 1000 books were published (monographs, collections, methodical and clinical materials), thousands of researches were carried out. Primary mechanism and patterns of interaction of LILI with acceptors within cells can be represented in the following order: absorption of photon's energy - emergence of a local temperature gradient - release of Ca2+ from intracellular stores - stimulating Ca2+-dependent processes. Understanding of this process allowed the explanation of all known secondary effects, optimized methods and extremely increased effectiveness of LLLT. Owing to the knowledge of BMA mechanisms of LILI, numerous associated and combined LLLT techniques were developed and are widely used nowadays: locally, on the projection of internal organs, laser acupuncture, reflexology, intracavitary, transdermal and intravenous laser blood illumination, magnetic-laser therapy, laser phoresis, laser-vacuum massage, biomodulation, etc. About 400 000 laser therapeutic devices are used in Russian practical healthcare. Unique, having no analogues in the world devices, are produced - red pulsed laser diodes (wavelength 635 nm, power 5 40 W, pulse duration 100 ns, frequency 10 000 Hz) are designed specially for effective laser therapy. PMID- 28652896 TI - Resurrecting the Dead (Molecules). AB - Biological molecules, like organisms themselves, are subject to genetic drift and may even become "extinct". Molecules that are no longer extant in living systems are of high interest for several reasons including insight into how existing life forms evolved and the possibility that they may have new and useful properties no longer available in currently functioning molecules. Predicting the sequence/structure of such molecules and synthesizing them so that their properties can be tested is the basis of "molecular resurrection" and may lead not only to a deeper understanding of evolution, but also to the production of artificial proteins with novel properties and even to insight into how life itself began. PMID- 28652898 TI - Effects of Root Debridement With Hand Curettes and Er:YAG Laser on Chemical Properties and Ultrastructure of Periodontally-Diseased Root Surfaces Using Spectroscopy and Scanning Electron Microscopy. AB - Introduction: The efficacy of erbium-doped yttrium aluminum garnet (Er:YAG) laser for root debridement in comparison with curettes has been the subject of many recent investigations. Considering the possibility of chemical and ultra structural changes in root surfaces following laser irradiation, this study sought to assess the effects of scaling and root planing (SRP) with curettes and Er:YAG laser on chemical properties and ultrastructure of root surfaces using spectroscopy and scanning electron microscopy (SEM). Methods: In this in vitro experimental study, extracted sound human single-rooted teeth (n = 50) were randomly scaled using manual curettes alone or in conjunction with Er:YAG laser at 100 and 150 mJ/pulse output energies. The weight percentages of carbon, oxygen, phosphorous and calcium remaining on the root surfaces were calculated using spectroscopy and the surface morphology of specimens was assessed under SEM. Data were analyzed using one-way analysis of variance (ANOVA). Results: No significant differences (P > 0.05) were noted in the mean carbon, oxygen, phosphorous and calcium weight percentages on root surfaces following SRP using manual curettes with and without laser irradiation at both output energies. Laser irradiation after SRP with curettes yielded rougher surfaces compared to the use of curettes alone. Conclusion: Although laser irradiation yielded rougher surfaces, root surfaces were not significantly different in terms of chemical composition following SRP using manual curettes with and without Er:YAG laser irradiation. Er:YAG laser can be safely used as an adjunct to curettes for SRP. PMID- 28652900 TI - Proteomic Analysis of the Effect of Extremely Low-Frequency Electromagnetic Fields (ELF-EMF) With Different Intensities in SH-SY5Y Neuroblastoma Cell Line. AB - Introduction: During the last 3 decades, human is exposed to extremely low frequency electromagnetic fields (ELF-EMF) emitted by power lines and electronic devices. It is now well accepted that ELF-EMF are able to produce a variety of biological effects, although the molecular mechanism is unclear and controversial. Investigation of different intensities effects of 50 Hz ELF-EMF on cell morphology and protein expression is the aim of this study. Methods: SH-SY5Y human neuroblastoma cell line was exposed to 0.5 and 1 mT 50 Hz (ELF-EMF) for 3 hours. Proteomics techniques were used to determine the effects of these fields on protein expression. Bioinformatic and statistical analysis of proteomes were performed using Progensis SameSpots software. Results: Our results showed that exposure to ELF-EMF changes cell morphology and induces a dose-dependent decrease in the proliferation rate of the cells. The proteomic studies and bioinformatic analysis indicate that exposure to 50 Hz ELF-EMF leads to alteration of cell protein expression in both dose-dependent and intensity dependent manner, but the later is more pronounced. Conclusion: Our data suggests that increased intensity of ELF-EMF may be associated with more alteration in cell protein expression, as well as effect on cell morphology and proliferation. PMID- 28652899 TI - Comparison of the Antimicrobial Efficacy of Calcium Hydroxide and Photodynamic Therapy Against Enterococcus faecalis and Candida albicans in Teeth With Periapical Lesions; An In Vivo Study. AB - Introduction: Elimination of pathological microflora of root canal systems is a major goal in endodontic treatment. This study aimed to compare the antimicrobial efficacy of calcium hydroxide as an intracanal medication and antibacterial photodynamic therapy (aPDT) against Enterococcus faecalis and Candida albicans in teeth with periapical (PA) lesions. Methods: This in vivo study was conducted on 20 patients with single-rooted mandibular premolar with previously failed endodontic treatment. This study was performed as a clinical trial (IRCTID: IRCT2016090429686N1). After conventional chemo-mechanical root canal preparation (hand and rotary instruments and 2.5% NaOCl), microbiological samples were obtained using sterile paper points, then stored in thioglycolate solution and transferred to a microbiology laboratory. Group 1 (n = 10) specimens underwent aPDT (diode laser 808 nm + 50 mg/mL methylene blue), while creamy calcium hydroxide paste was used in group 2 for a duration of 1 week. A control sample was taken with sterile paper points and F3 Protaper rotary file. The samples were dispersed in transport medium, serially diluted, and cultured on selective mediums to determine the number of colony forming units (CFUs). Data were analyzed by Mann-Whitney U test at 5% significance level. The significance level for all analyses was set at P < 0.05. Results: Number of CFU significantly decreased in both groups after the interventions (P < 0.001); however, there was no significant difference in the colony count between the 2 groups. Conclusion: aPDT and calcium hydroxide therapy showed the same antimicrobial efficacy on E. faecalis and C. albicans. PMID- 28652901 TI - The Efficacy and Safety of Laser Lithotripsy in Pregnancy. AB - Introduction: The aim of our study was to assess the efficacy and safety of laser lithotripsy in pregnant patients. Methods: In this retrospective study, we reviewed the 15 pregnant women who have been treated for ureteral stones with semi-rigid ureteroscope and holmium laser at our center between Januarys 2007and April 2015. Results: The mean age of patients and mean gestational age was 29.3 years old 27.3 weeks respectively. Mean size of stones was 7.84 mm. Twelve patients had renal colic, and hematuria was found in 3 cases. Irritative urinary symptoms such as frequency and urgency detected in 6 ones and 2 patients had fever. The stone of all patients were fragmented by using holmium laser lithotripter. In 5 patients stone residual fragments were removed by grasper while other 10 patients were left to pass fragments spontaneously. No intraoperative and postoperative urological or obstetric complication was seen. Conclusion: Laser lithotripsy is safe and efficacious in pregnant patients who have ureteral stone that does not respond to conservative management. PMID- 28652902 TI - Efficacy of Conventional Laser Irradiation Versus a New Method for Gingival Depigmentation (Sieve Method): A Clinical Trial. AB - Introduction: Diode laser irradiation has recently shown promising results for treatment of gingival pigmentation. This study sought to compare the efficacy of 2 diode laser irradiation protocols for treatment of gingival pigmentations, namely the conventional method and the sieve method. Methods: In this split-mouth clinical trial, 15 patients with gingival pigmentation were selected and their pigmentation intensity was determined using Dummett's oral pigmentation index (DOPI) in different dental regions. Diode laser (980 nm wavelength and 2 W power) was irradiated through a stipple pattern (sieve method) and conventionally in the other side of the mouth. Level of pain and satisfaction with the outcome (both patient and periodontist) were measured using a 0-10 visual analog scale (VAS) for both methods. Patients were followed up at 2 weeks, one month and 3 months. Pigmentation levels were compared using repeated measures of analysis of variance (ANOVA). The difference in level of pain and satisfaction between the 2 groups was analyzed by sample t test and general estimate equation model. Results: No significant differences were found regarding the reduction of pigmentation scores and pain and scores between the 2 groups. The difference in satisfaction with the results at the three time points was significant in both conventional and sieve methods in patients (P = 0.001) and periodontists (P = 0.015). Conclusion: Diode laser irradiation in both methods successfully eliminated gingival pigmentations. The sieve method was comparable to conventional technique, offering no additional advantage. PMID- 28652903 TI - Complete Clearance of Resistant Granuloma Faciale With Pulsed Dye Laser After Pre treatment With Mometasone and Tacrolimus. AB - Introduction: Granuloma faciale is an uncommon inflammatory dermatosis which usually affects the face and is often resistant to treatment. Case Report: A 39 year-old English lady with Fitzpatrick skin phototype II presented with typical lesions of granuloma faciale, confirmed on biopsy, on her cheeks and nose. Treatment with ScleroPlus pulsed dye laser (Candela Corporation, Wayland, Mass) produced no visible improvement. The patient re-presented 5 years later with the same lesions, now more prominent. No improvement was noted with topical mometasone, however addition of topical tacrolimus caused significant flattening. Since the erythema and telangiectases persisted, treatment with ScleroPlus pulsed dye laser was re-attempted. Treatments were performed with a wavelength of 595 nm, pulse duration of 1.5 ms and 7 mm spot at a fluence of 8.5 J/cm2 in the first session and 9.5 J/cm2 in the subsequent 2 sessions. This resulted in complete resolution without scarring or pigmentary change. There was no recurrence at follow-up one year later. Conclusion: Our observation supports the use of combination therapy in resistant cases of granuloma faciale. One such combination would be the application of a topical corticosteroid and tacrolimus followed by pulsed dye laser. PMID- 28652904 TI - Successful Treatment of Unilateral Klippel-Trenaunay Syndrome With Pulsed-Dye Laser in a 2-Week Old Infant. AB - Introduction: Klippel-Trenaunay syndrome (KTS) is a rare congenital mesodermal abnormality characterized by varicose veins, cutaneous capillary malformation, as well as bone and soft tissue hypertrophy. Case Report: A 2-week-old female infant presented to our clinic because of vascular nevus and progressive enlargement of her right extremities and trunk since birth. The patient was treated with 595-nm pulsed-dye laser (PDL). Her port-wine stain (PWS) disappeared completely after third PDL session and the soft tissue hypertrophy stopped. The patient experienced neither recurrence nor any change in size after 7 years of follow up. Conclusion: PDL can treat KTS completely with no reccurence if it is used in "early stage" of disease. PMID- 28652905 TI - Retrospective Analysis of Endemic Melasma Patients. AB - Melasma is an acquired diffuse hypermelanosis characterized by localized, symmetrical, irregular, light-to-dark brown maculae occurring in sun-exposed areas of skin. The aim of this retrospective study was to determine demographics of patients, analysis of etiologic factors, clinical features, efficacy and side effects of available topical treatments due to high incidence of melasma patients. In this study melasma patients in Birecik State Hospital were investigated retrospectively. Between January 2014 and October 2015, 1008 patients had diagnosis of melasma in 49,809 applications of 24,603 different patients who admitted to Dermatology Outpatient Clinics. Of the 1008 patients, 263 had completed 3-month treatment period. These patients did not receive treatment in June, July, August and September. All melasma patients were rural and dealing with agriculture. There was no significant difference between female and male patients in terms of age. Of the 253 female melasma patients, only 2 of them had not child and none of them were using hormone drug. Of the 263 patients with melasma, Fitzpatrick skin type was 3 in 79 (30%) patients, 4 in 184 (70%) patients. Sanliurfa city showed higher fertility rate, sun exposure, and skin type than Turkey as a whole. These predisposing factors may explain higher melasma occurrence in Sanliurfa. Patient information about preventive measures and treatment play important role in treatment of cosmetic condition. The most important measure seems to advise patients about sun-protection especially during pregnancy. PMID- 28652906 TI - Photoepilation and Skin Photorejuvenation: An Update. AB - The effectiveness of intense pulsed light (IPL) and laser devices is widely accepted in aesthetic dermatology for unwanted hair removal and treatment of a variety of cutaneous conditions. Overall, most comparative trials have demonstrated similar effectiveness for IPL and laser devices. Literature studies alternatively favor the IPL and laser concepts, but the incidence of severe local pain and side effects were generally lower with IPL. IPL phototherapy, already established as a sound option in photoepilation and treatment of photoaging, hyperpigmentation and other skin conditions, is also considered first choice in the phototherapy of skin vascular malformations. When treating large areas, as often required in photoepilation and many aesthetic dermatology indications, IPL technologies show advantages over laser-based devices because of their high skin coverage rate. Compared to lasers, the wide range of selectable treatment settings, though a strong advantage of IPL, may also imply some more risk of local thermal side effects, but almost only in the hands of poorly trained operators. Overall, the strongest advantages of the IPL technologies are robust technology, versatility, lower purchase price, and the negligible risk of serious adverse effects in the hands of skilled and experienced operators. PMID- 28652907 TI - A Study Case in Photoepilation, the HPPLTM and IFLTM Technologies. AB - The High Power Pulsed LightTM [HPPLTM] and Incoherent Fast LightTM technologies [IFLTM, Novavision Group S.p.A., 20826 Misinto (MB), Italy] are recent innovations in the field of unwanted hair removal with intense pulsed light devices. IFLTM is a further improvement over the already advanced characteristics of the HPPLTM technology. A selection of photoepilation case histories with the HPPLTM and IFLTM technologies is presented; a short introduction highlights the main features of the two technologies. All study materials were appropriately peer-reviewed for ethical problems. PMID- 28652908 TI - Case Histories of Intense Pulsed Light Phototherapy in Dermatology - the HPPLTM and IFLTM Technologies. AB - The intense pulsed light (IPL) and laser technologies are widely used for skin rejuvenation and for treating several dermatological disorders such as skin dyschromia and acne, and for non-ablative dermal remodeling of rhytides and hypertrophic scars. Technological evolution is rapid. The High Power Pulsed LightTM [HPPLTM] and Incoherent Fast LightTM technologies [IFLTM, Novavision Group S.p.A., 20826 Misinto (MB), Italy] are recent innovations in the field of IPL technologies; IFLTM is a further evolution of the already advanced HPPLTM system. The paper presents a selection of case histories of dermatological lesions treated with the HPPLTM and IFLTM technologies. All study materials were appropriately peer-reviewed for ethical problems. PMID- 28652909 TI - A Case of Hypoglycemiainduced QT Prolongation Leading to Torsade de Pointes and a Review of Pathophysiological Mechanisms. AB - Torsades de pointes is a life-threatening cardiac arrhythmia. Occurrence of this arrhythmia as a result of hypoglycemia has not been reported in the literature. We describe an interesting case of an insulin-dependent diabetic patient presenting with torsades de pointes resulting from hypoglycemia. A 62-year-old male was admitted to the hospital following an episode of severe insulin-induced hypoglycemia and a cardiac arrest. He was found to unresponsive at home after taking insulin. His serum glucose was found to be 18. He was given juice initially to normalize his glucose and was then transferred by EMS to ER where he was given 5% dextrose infusion. Analysis of the LifeVest rhythm recording showed torsades de pointes that was terminated by defibrillation of the LifeVest. Several mechanisms are responsible for torsade, including QT interval prolongation, adrenalin secretion and calcium overload leading to intracellular calcium oscillations. These mechanisms are a trigger to torsade de pointes. Predisposing factors were present leading torsade to occur. PMID- 28652910 TI - Profiling changes to natively-bound metals during Caenorhabditis elegans development. AB - Relatively little is known about the changing metalloproteome during early development. In this proof-of-concept study, we used size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) to examine the changing soluble metal-binding protein profiles for iron, copper and zinc during the development of the nematode, Caenorhabditis elegans. Samples of eggs, larval stages and young adults were compared using an approach selected to ensure weak metal-ligand bonds were maintained. All three metals showed marked changes in associated proteins and total metal levels per protein mass, and the pattern of this change was unique to each metal. Additionally, to characterise the shifting metabolic needs throughout each life stage we examined changing levels of phosphorus in each developmental stage. The utility of this method can be further exploited through integration with existing proteomics workflows to identify and track the changes in metal-containing proteins during key stages of development. PMID- 28652911 TI - Rare mycotic aneurysms of internal jugular vein and innominate vein secondary to untreated parapharyngeal abscess: A case report. AB - We report a 31 year old woman presented with three months history of large untreated parapharyngeal abscess and bleeding from the mouth. On evaluation chest CT scan identified the abscess extending down to the superior mediastinum and multiple small lung abscesses. Echocardiography showed tricuspid valve insufficiency. Patient was brought to the operating room (OR) and intra operatively it was found that she had multiple large mycotic pseudoaneurysms of the internal jugular vein and right brachiocephalic veins. All these pseudoaneurysms were repaired with pericardial patches under cardiopulmonary bypass. Patient did well in the short postoperative follow up and was then referred to plastic surgery and ENT for further surgical interventions. PMID- 28652912 TI - Efficacy of submucosal epinephrine injection for the prevention of postpolypectomy bleeding: A meta-analysis of randomized controlled studies. AB - BACKGROUND: Bleeding is the most common major complication following colonoscopic polypectomy. The purpose of this study is to evaluate whether submucosal epinephrine injections could prevent the occurrence of postpolypectomy bleeding. METHOD: The dataset was defined by searching PubMed, EMBASE, Google Scholar, and the Cochrane database for appropriate randomized controlled studies published before April 2015. A meta-analysis was conducted to investigate the preventative effect of submucosal epinephrine injection for overall, early, and delayed postpolypectomy bleeding. RESULTS: The final analysis examined the findings of six studies, with data from 1388 patients. The results demonstrated that prophylactic treatment with epinephrine injection significantly reduced the occurrence of overall (OR = 0.38, 95% CI: 0.21, 0.66; p = 0.0006) and early bleeding (OR = 0.38, 95% CI: 0.20, 0.69; p = 0.002). However, for delayed bleeding complications, epinephrine injections were not found to be any more effective than treatment with saline injection or no injection (OR = 0.45, 95% CI: 0.11, 1.81; p = 0.26). Moreover, for patients with polyps larger than 20 mm, mechanical hemostasis devices (endoloops or clips) were found to be more effective than epinephrine injection in preventing overall bleeding (OR = 0.33, 95% CI: 0.13, 0.87; p = 0.03) and early bleeding (OR = 0.29, 95% CI: 0.08, 1.02; p = 0.05). This was not established for delayed bleeding. CONCLUSION: The routine use of prophylaxis submucosal epinephrine injection is safe and beneficial preventing postpolypectomy bleeding. PMID- 28652913 TI - Evaluation of immunization coverage and its associated factors among children 12 23 months of age in Techiman Municipality, Ghana, 2016. AB - BACKGROUND: In Ghana, Expanded Programme on Immunization administrative coverages are usually high while childhood immunization status remains low. Majority of children do not receive all the recommended 7 vaccines in 15 doses before 1 year of age. Surveys to validate administrative coverages and identify predictors of immunization status are not given the desired attention. Thus, the objective of this study was to evaluate the immunization coverage and its associated factors among children aged 12-23 months in Techiman Municipality, Ghana. METHODS: A cross-sectional cluster survey was conducted among 600 children. Data was collected using semi-structured questionnaire through face-to-face interviews. The tools were pre-tested in three communities with similar characteristics. The mothers/caregivers were interviewed and additional information extracted from child immunization cards. We observed the presence of Bacillus Calmette-Guerin scar on each child. Data was entered, cleaned and analyzed using Statistical Package for Social Sciences (SPSS) version 17.0. Descriptive statistics such as percentages, frequencies and cross tabulations performed using SPSS while bivariate and multivariate logistic regression analysis conducted using Stata 12.1 version to estimate the Odds Ratio of not being fully immunized. RESULTS: In total, 89.5% (537/600) of the children were fully immunized, 9.5% partially immunized and 1.0% received no vaccine. In the multivariate analysis, the following determinants were significantly associated with the likelihood of being not fully vaccinated (Odds Ratio (AOR) larger than 1) : age of the mother/caregiver 40-49 years (AOR = 0.15, 95%CI = 0.05-0.87) compared to less than 20 years; marital status (compared to never married/single: being married AOR = 0.29, 95%CI = 0.13-0.68), ethnicity (compared to the main ethnic group Akan: Frafra (AOR = 4.71, 95%CI = 146-15.18) and Kusaasi (AOR = 0.09, 95%CI = 0.02-0.51), religion (compared to Islam: Christianity AOR = 0.17, 95%CI = 0.06 0.50), sex of child (compared to male: female AOR = 0.39, 95%CI = 0.19-0.80) and possession of immunization card (compared to those having the card: those without the card AOR = 84.43, 95%CI = 17.04-418.33). Mothers/caregivers aged 40-49 years, being married, Kusaasi ethnic groups, Christian and female child have a higher likelihood of being fully immunized, while Frafra ethnic group and no immunization card have a higher likelihood of not being fully immunized. We found no association between immunization status and child's relationship to respondent; parity; education; occupation and child's age. CONCLUSION: Immunization status (89.5%) and coverages ranged 92 to 99% of the vaccine doses is high compared to national and regional. Problems of not fully immunized persists and needs urgent attention. Education on immunization should be intensified by health providers. Moreover, disadvantaged populations should be reached with immunization services using out-reach activities. PMID- 28652914 TI - Erratum to: Recent advances in capsule-based dry powder inhaler technology. AB - [This corrects the article DOI: 10.1186/s40248-017-0092-5.]. PMID- 28652915 TI - Ablation of the sacroiliac joint using MR-guided high intensity focused ultrasound: a preliminary experiment in a swine model. AB - BACKGROUND: Dysfunction of the Sacroiliac Joint (SIJ) is one of the key sources of low back pain. For prolonged pain relief, some patients undergo fluoroscopic guided radio-frequency (RF) ablation of SIJ, during which a number of RF probes are inserted to create thermal lesions that disrupt the posterior sacral nerve supply. This procedure is minimally invasive, laborious, time-consuming and costly. To study if High Intensity Focused Ultrasound (HIFU) ablation is a feasible alternative approach to SIJ pain treatment, we performed experiments using HIFU to ablate SIJ in the swine model. METHODS: Three female Yorkshire swine (36, 35.2 and 34 kg) underwent bilateral Magnetic Resonance guided HIFU (MRgHIFU) ablation of the SIJs. Treatment assessment was performed using contrast enhanced imaging, histopathology and evaluation of pain and changes in ambulation and gait. RESULTS: Contiguous lesions along the right and left SIJs were achieved in all animals. In one out of three animals, excessive heating of the muscle and skin tissue in the near-field resulted in unwanted muscle necrosis. No changes in animal behavior, ambulation or gait were detected. CONCLUSIONS: The initial experiments with MRgHIFU ablation of SIJs in sub-acute swine model show promise for this ablation modality as a non invasive and more precise alternative to the currently used fluoroscopically - guided RF ablations and injections. PMID- 28652916 TI - Tunable delayed controlled release profile from layered polymeric microparticles. AB - Composite microparticles (MPs) with layered architecture, engineered from poly(L lactic acid) (PLLA) and poly(D,L-lactic-co-glycolic acid) (PLGA), are promising devices for achieving the delayed release of proteins. Here, we build on a water in-oil-in-oil-in-water emulsion method of fabricating layered MPs with an emphasis on modulating the delay period of the protein release profile. Particle hardening parameters (i.e. polymer precipitation rate and total hardening time) following water-in-oil-in-oil-in-water emulsions are known to affect MP structure such as the core/shell material and cargo localization. We demonstrate that layered MPs fabricated with two different solvent evaporation parameters not only alter polymer and protein distribution within the hardened MPs, but also affect their protein release profiles. Secondly, we hypothesize that ethanol (EtOH), a semi-polar solvent miscible in both the solvent (dichloromethane; DCM) and non solvent aqueous phases, likely alters DCM and water flux from the dispersed oil phase. The results reveal that EtOH affects protein distribution within MPs, and may also influence MP structural properties such as porosity and polymer distribution. To our knowledge, we are the first to demonstrate EtOH as a means for modulating critical release parameters from protein-loaded, layered PLGA/PLLA MPs. Throughout all the groups in the study, we achieved differential delay periods (between 0 - 30 days after an initial burst release) and total protein release periods (~30 - >58 days) as a function of solvent evaporation parameters and EtOH content. The layered MPs proposed in the study potentially have wide reaching applications in tissue engineering for delayed and sequential protein release. PMID- 28652917 TI - Photocrosslinkable, biodegradable hydrogels with controlled cell adhesivity for prolonged siRNA delivery to hMSCs to enhance their osteogenic differentiation. AB - Photocrosslinked, biodegradable hydrogels have been extensively investigated for biomedical applications, including drug delivery and tissue engineering. Here, dextran (DEX) was chemically modified with mono(2-acryloyloxyethyl) succinate (MAES) via an esterification reaction, resulting in macromers that could be photocrosslinked to form hydrolytically degradable hydrogels. Hydrogel swelling ratio and degradation rate were controlled by varying the degree of MAES modification. Thiolated cell adhesion peptides (GRGDSPC) were conjugated to acrylated dextran via thiol-acrylate reaction to regulate the interactions of human mesenchymal stem cells (hMSCs) with the photocrosslinkable hydrogels. The hydrogels permitted sustained release of short interfering RNA (siRNA) over 7 weeks and were cytocompatible with hMSCs. Sustained presentation of siRNA from these photocrosslinked DEX hydrogels enhanced the osteogenic differentiation of encapsulated hMSCs. These DEX hydrogels with tunable siRNA delivery and cell adhesive properties may provide an excellent platform for bioactive molecule delivery and tissue regeneration applications. PMID- 28652918 TI - Engineering CAR-T cells. AB - Chimeric antigen receptor redirected T cells (CAR-T cells) have achieved inspiring outcomes in patients with B cell malignancies, and are now being investigated in other hematologic malignancies and solid tumors. CAR-T cells are generated by the T cells from patients' or donors' blood. After the T cells are expanded and genetically modified, they are reinfused into the patients. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. In this review, we first discuss the structure and evolution of chimeric antigen receptors. We then report on the tools used for production of CAR-T cells. Finally, we address the challenges posed by CAR-T cells. PMID- 28652919 TI - 'Khelaifiella massiliensis', 'Niameybacter massiliensis', 'Brachybacterium massiliense', 'Enterobacter timonensis', 'Massilibacillus massiliensis', new bacterial species and genera isolated from the gut microbiota of healthy infants. AB - The main characteristics of 'Khelaifiella massiliensis' strain Mt13T (= CSUR P1935, = DSM100591), 'Niameybacter massiliensis' strain Mt14T (= CSUR P1909, = DSM100592), 'Brachybacterium massiliense' strain MT5T (= CSUR P2240, = DSM101766), 'Enterobacter timonensis' strain mt20T (= CSUR P2201, = DSM 101775) and 'Massilibacillus massiliensis' strain Marseille-P2411T (= CSUR P2411, = DSM102838), new species isolated from the gut of healthy African infants, are presented. PMID- 28652920 TI - Perception of and attitude toward ethical issues among Korean occupational physicians. AB - BACKGROUND: Occupational physicians (OPs) have complex relationships with employees, employers, and the general public. OPs may have simultaneous obligations towards third parties, which can lead to variable conflicts of interests. Among the various studies of ethical issues related to OPs, few have focused on the Korean OPs. The aim of the present survey was to investigate the ethical contexts, the practical resolutions, and the ethical principles for the Korean OPs. METHODS: An email with a self-administered questionnaire was sent to members of the Korean Society of Occupational and Environmental Medicine, comprising 150 specialists and 130 residents. The questionnaire was also distributed to 52 specialists and 46 residents who attended the annual meeting of the Korean Association of Occupational and Environmental Clinics in October 2015, and to 240 specialists by uploading the questionnaire to the online community 'oem-doctors' in February 2016. The responses to each question (perception of general ethical conflicts, recognition of various ethical codes for OPs, core professional values in ethics of occupational medicine, and a mock case study) were compared between specialists and residents by the chi-squared test and Fisher's exact test. RESULTS: Responses were received from 80 specialists and 71 residents. Most participants had experienced ethical conflicts at work and felt the need for systematic education and training. OPs suffered the most ethical conflicts in decisions regarding occupational health examination and evaluation for work relatedness. Over 60% of total participants were unaware of the ethical codes of other countries. Participants thought 'consideration of worker's health and safety' (26.0%) and 'neutrality' (24.7%) as the prominent ethical values in professionality ofoccupational medicine. In mock cases, participants chose beneficence and justice for fitness for work and confidential information acquired while on duty, and beneficence and respect for autonomy in pre-placement examinations. CONCLUSIONS: This study evaluated the current perception of and attitude toward ethical issues among the Korean OPs. These findings will facilitate the development of a code of ethics and the ethical decision-making program forthe Korean OPs. PMID- 28652921 TI - Comparison of facet joint degeneration in firefighters and hospital office workers. AB - BACKGROUND: There are few published studies on the relationship between occupational lumbar load and facet joint degeneration (FJD). This cross-sectional study was conducted to evaluate the effect of physical lumbar load on FJD by comparing magnetic resonance imaging (MRI) findings of firefighters (FFs) and hospital office workers (HOWs). METHODS: We randomly sampled 341 male FFs and 80 male HOWs by age stratification. A questionnaire and clinical examination, including MRI of the lumbar spine (T12-S1), were conducted. FJD was diagnosed and graded by using the classification of Pathria et al., and reclassified into two groups as follows: no FJD (grade 0) and FJD (grades 1, 2, and 3). The prevalence of FJD was analyzed according to occupational group. RESULTS: The prevalence of FJD ranged from 31% (L1-L2) to 75% (L4-L5) in the FFs, and from 18% (L1-L2) to 69% (L4-L5) in the HOWs. After adjustment for age, body mass index, and frequency of physical exercise, the adjusted odds ratios (OR) for FJD in the FFs were significantly higher than those in the HOWs at all lumbar spinal levels, except for L3-L4 (L1-L2: OR, 2.644; 95% confidence interval [CI], 1.317-5.310; L2-L3: OR, 2.285; 95% CI, 1.304-4.006; L4-L5: OR, 1.918; 95% CI, 1.037-3.544; L5-S1: OR, 1.811; 95% CI, 1.031-3.181). CONCLUSION: This study shows that FFs exhibit a greater likelihood of having FJD than HOWs after controlling for other risk factors of FJD. This suggests that the physical occupational demands of FFs affect their risk of developing FJD. PMID- 28652923 TI - JC virus granule cell neuronopathy onset two months after chemotherapy for low grade lymphoma. AB - BACKGROUND: Granule cell neuronopathy (GCN) is a rare disease caused by the JC virus, leading to degeneration of cerebellar granule cell neurons. Primarily described in patients with AIDS, it has also been diagnosed in patients with lymphoproliferative diseases and after long-term treatment with immune suppressing medications such as natalizumab. CASE PRESENTATION: A 69 year old woman presented with progressive ataxia which began 2 months after initiation of treatment for follicular low-grade B cell lymphoma with rituximab/bendamustine, and progressed for 2 years prior to admission. Extensive prior evaluation included MRI that showed atrophy of the cerebellum but normal CSF analysis and serum studies. Neurologic exam on admission was notable for severe appendicular ataxia and fatigable end-gaze direction-changing horizontal nystagmus. FDG-PET/CT scan was unremarkable and repeat lumbar puncture revealed 2 WBCs/mm3, 148 RBCs/mm3, glucose 70 mg/dL, protein 37.7 mg/dL and negative flow cytometry/cytopathology. Standard CSF JC virus PCR testing was negative, but ultrasensitive TaqMan real-time JC virus PCR testing was positive, consistent with JC virus-related GCN. CONCLUSIONS: Because of the diagnostic challenges in identifying GCN, a high threshold of suspicion should be maintained in patients with an immune-suppressing condition such as lymphoma or on immune-suppressing agents such as rituximab, even shortly after initiation of therapy. PMID- 28652922 TI - The relationship between serum vitamin D levels and sleep quality in fixed day indoor field workers in the electronics manufacturing industry in Korea. AB - BACKGROUND: Although recent studies have investigated the influence of vitamin D on sleep patterns, there is a lack of research on the relationship between vitamin D and sleep patterns in Korean workers. This study focused on the relationship between serum vitamin D levels and sleep in fixed day indoor field workers in the electronics manufacturing industry in Korea. METHODS: The 1472 subjects who were included in this study were selected from fixed day workers in the electronics manufacturing industry who had received a worker's special health examination at a hospital in Changwon, South Gyeongsang Province between January 2015 and December 2015. Nighttime workers and those who showed symptoms of depression were excluded from this study. The sociodemographic and lifestyle variables of the participants were investigated, including age, sex, marital status, level of education, body mass index, smoking habits, alcohol consumption habits, and regular exercise. Work-related factors were evaluated, such as employee tenure and occupational stress. Serum 25-hydroxyvitamin D was measured as an indicator of vitamin D levels, and quality of sleep was evaluated using the Pittsburgh Sleep Quality Index (PSQI) translated into Korean. RESULTS: The subjects had a mean serum vitamin D level of 13.70 +/- 5.93 ng/mL. Vitamin D deficiency, defined as a serum vitamin D level of <10 ng/mL, was found in 24.8% of males and significantly more frequently in females (47.6%). Poor sleep quality was reported by 19.8% of participants with serum vitamin D levels >=10 ng/mL and by 21.7% of those with serum vitamin D levels <10 ng/mL, which was a significant difference (P = .007). Multiple logistic regression analysis adjusting for significant variables found that poor sleep quality was more likely in those with vitamin D deficiency than those with higher serum vitamin D levels (odds ratio = 1.36; 95% CI, 1.01-1.82). A comparison of serum vitamin D levels and PSQI components showed that the mean scores for subjective sleep quality, sleep latency, and sleep duration were significantly higher in the vitamin D-deficient participants, indicating that the vitamin D-deficient participants had poorer sleep quality. CONCLUSIONS: This study investigated serum vitamin D levels in fixed day indoor field workers in the manufacturing industry in Korea and analyzed the relationship of vitamin D deficiency with sleep quality. A significant correlation was found between serum vitamin D deficiency and poor sleep quality. Based on the results of this study, sleep disorder management for workers can be improved by providing regular examinations checking their serum vitamin D levels and supplying vitamin D to workers with serum vitamin D deficiency to enhance their quality of sleep. PMID- 28652924 TI - Usefulness of limited sampling strategy for mycophenolic acid area under the curve considering postoperative days in living-donor renal transplant recipients with concomitant prolonged-release tacrolimus. AB - BACKGROUND: The optimal dose of mycophenolate mofetil (MMF) in renal transplant patients has been recommended to be decided on the basis of area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). Although meta analysis has revealed that postoperative day (POD) is an influencing factor in MPA pharmacokinetics, there are no reports regarding a limited sampling strategy (LSS) for MPA AUC in consideration of POD. The aim of this study was to construct of an LSS considering POD that appropriately expresses the MPA AUC following renal transplantation and evaluation of the usefulness. METHODS: Serum concentration-time profiles (measured AUC0-12) comprising nine sampling points over 12 h were analyzed in 36 living-donor renal transplant recipients after MMF administration with concomitant once-daily prolonged-release tacrolimus. Two LSSs were developed by stepwise multiple regression analysis (Method A: not classified by PODs; Method B: classified by PODs into POD < 31 and POD >= 31). Each LSS comprised four blood-sampling points within 6 h after MMF administration. Precision and reliability were verified by using root-mean-square error (RMSE), correlation coefficient (R2), and coefficient of determination (q2) by using leave-one-out cross-validation. The absolute values of the difference between measured and estimated AUCs (delta AUC) were compared for both estimating equations. RESULTS: One-hundred samples obtained from 36 recipients for AUC0-12 comprised POD < 31 (n = 39) and POD >= 31 (n = 61). Estimation of AUC0-12 by Method B resulted in better accuracy and reliability (Method A: RMSE = 5.5, R2 = 0.85, q2 = 0.83; Method B: POD < 31: RMSE = 5.5, R2 = 0.86, q2 = 0.83; POD >= 31: RMSE = 3.9, R2 = 0.92, q2 = 0.89) and significantly lower median delta AUC compared with that by Method A (delta AUC: 2.6 (0.0-11.6) v.s. 3.9 (0.1-18.1), p = 0.032). CONCLUSION: These results suggest that LSS, classified as POD < 31 or POD > 31, would provide more accurate and reliable estimation of MPA AUC0-12 in Japanese living-donor renal transplant patients. PMID- 28652925 TI - Effect of feeding garlic leaves on rumen fermentation, methane emission, plasma glucose kinetics, and nitrogen utilization in sheep. AB - BACKGROUND: Garlic and its constituents are reported to have been effective in reducing methane emission and also influence glucose metabolism in body; however, studies in ruminants using garlic leaves are scarce. Garlic leaves contain similar compounds as garlic bulbs, but are discarded in field after garlic bulb harvest. We speculate that feeding garlic leaves might show similar effect as garlic constituents in sheep and could be potential animal feed supplement. Thus, we examined the effect of freeze dried garlic leaves (FDGL) on rumen fermentation, methane emission, plasma glucose kinetics and nitrogen utilization in sheep. METHODS: Six sheep were fed Control diet (mixed hay and concentrate (60:40)) or FDGL diet (Control diet supplemented with FDGL at 2.5 g/kg BW0.75 of sheep) using a crossover design. Methane gas emission was measured using open circuit respiratory chamber. Plasma glucose turnover rate was measured using isotope dilution technique of [U-13C]glucose. Rumen fluid, feces and urine were collected to measure rumen fermentation characteristics and nitrogen utilization. RESULT: No significant difference in rumen fermentation parameters was noticed except for rumen ammonia tended to be higher (0.05 < P < 0.1) in FDGL diet. Methane emission per kg dry matter ingested and methane emission per kg dry matter digested were lower (P < 0.05) in FDGL diet. Plasma glucose concentration was similar between diets and plasma glucose turnover rate tended to be higher in FDGL diet (0.05 < P < 0.1). Nitrogen retention was higher (P < 0.05) and microbial nitrogen supply tended to be higher (0.05 < P < 0.1) in FDGL diet. CONCLUSION: FDGL diet did not impair rumen fermentation, improved nitrogen retention; while absence of significant results in reduction of methane emission, glucose turnover rate and microbial nitrogen supply, further studies at higher dose would be necessary to conclude the merit of FDGL as supplement in ruminant feedstuff. PMID- 28652926 TI - Silk fibroin/hydroxyapatite composite hydrogel induced by gamma-ray irradiation for bone tissue engineering. AB - BACKGROUND: In this study, silk fibroin (SF) composite hydrogels containing hydroxyapatite (HAP) nanoparticles (NPs) for bone tissue engineering were fabricated using gamma-ray (gamma-ray) irradiation treatment. During the irradiation, the HAP dispersed SF solution was changed to the chemically crosslinked SF hydrogel. METHODS: Distribution of HAP NPs in the SF hydrogel was examined by SEM imagery and energy dispersive X-ray spectrophotometry, and the crystalline structure of SF composite hydrogels was also confirmed by X-ray diffractometry. An optimum preparation condition of the SF/HAP composite hydrogels was determined with various HAP contents. For evaluation of the osteogenic differentiation of human mesenchymal stem cells (hMSCs), alkaline phosphatase activity (ALP), HAP nucleation in SBF and in vitro calcium accumulation were measured. RESULTS: The results revealed that compared with the pure SF hydrogels, the SF/HAP composite hydrogels improved osteogenic differentiation. CONCLUSION: This paper demonstrates the great potential of the SF/HAP composite hydrogels in terms of the production of the bone tissue engineering scaffolds for which osteogenesis is required. PMID- 28652927 TI - Anticancer activity of drug-loaded calcium phosphate nanocomposites against human osteosarcoma. AB - BACKGROUND: Calcium phosphate (CaP) based nanoparticles are considered to be ideal drug carriers for delivery of anticancer drugs because of their excellent biocompatibility and pH responsiveness. However, CaP nanoparticles have the problems of limited drug load capacity, initial burst release, and short-term release. Thus, we prepared the CaP nanocomposites containing anticancer drug such as caffeic acid (CA-NP), chlorogenic acid (CG-NP), or cisplatin (CP-NP) in the presence of alginate as a polymer template to control the release rate of drugs. RESULTS: The drug-loaded CaP nanocomposites exhibited spherical shape with a size of under 100 nm and the size of nanocomposites was hardly affected by the addition of drug. UV-visible spectroscopic analysis confirmed the insertion of drug into the CaP nanocomposites. These nanocomposites showed an initial burst release of drug, followed by a prolonged release, in which the release profile of drugs was depended on the solution pH. In addition, the drug-loaded CaP nanocomposites revealed anticancer activity on human osteosarcoma in a manner dependent on concentration of drugs and time. CONCLUSIONS: The drug-loaded CaP nanocomposites can contribute to the development of a new generation of controlled drug release carriers for chemotherapy of cancers. PMID- 28652928 TI - pH of anti-VEGF agents in the human vitreous: low impact of very different formulations. AB - BACKGROUND: The aim of the study was to measure pH changes of the human vitreous caused by the intravitreal drugs bevacizumab, ranibizumab, aflibercept, and ziv aflibercept. METHODS: Fresh human vitreous samples were obtained during core vitrectomy (23-gauge) from patients with epiretinal gliosis. Aliquots of bevacizumab, ranibizumab, aflibercept or ziv-aflibercept (2 ul) were added consecutively to 200 ul of vitreous samples or 0.9% NaCl saline. The pH was measured using a pH-sensitive microelectrode. Rituximab, in off-label use against intraocular lymphoma, was tested as an IgG1 antibody. RESULTS: The pH of the administered drugs was 5.91 for bevacizumab (95% CI 5.63-6.19), 5.32 for ranibizumab (95% CI 5.0-5.63), 6.05 for aflibercept (95% CI 5.78-6.31), ziv aflibercept 6.1 (95% CI 6.05-6.15), and 6.29 for rituximab (95% CI 5.97-6.61). While the fresh and undiluted vitreous fluid showed pH values of 7.0-7.4, pH values increased if saline or rituximab were added. In contrast, the pH decreased slightly if aflibercept, bevacizumab, ranibizumab or ziv-aflibercept were supplemented. The observed pH decreases were not significant after ranibizumab was added. Significant changes were only notable with higher-than-normal amounts of bevacizumab (26-40 ul). The vitreous showed the most robust buffering capacity towards ranibizumab and rituximab. CONCLUSIONS: The pH changes in vitreous samples elicited by the usual intravitreal anti-VEGF drugs differed clearly, but only by much higher concentrations than used in the clinical routine. Although the ingredient solution of ranibizumab showed the lowest pH, it caused only moderate changes of vitreal pH compared to bevacizumab, aflibercept or ziv aflibercept. PMID- 28652929 TI - TNF-alpha and Beyond: Rapid Mitochondrial Dysfunction Mediates TNF-alpha-Induced Neurotoxicity. AB - This short communication describes our research which demonstrates that TNF-alpha causes a rapid decline in mitochondrial function, leading to neuronal cell death. As such, this neurotoxic proinflammatory cytokine may play a role in brain damage from stroke and neurodegeneration in chronic conditions such as Alzheimer's disease (AD) and Parkinson's disease. We have extended this initial observation by demonstrating that TNF-alpha stimulates a microRNA (miR-34a) which we have shown reduces five key proteins in the mitochondrial electron transport chain through base-pair complementarity. miR-34a is increased in affected brain regions of Alzheimer's patients and transgenic AD mouse models. We have further shown that oligomeric amyloid beta 42 (oAbeta42) stimulates miR-34a. Collectively, these data suggest that TNF-alpha, oAbeta42, and miR-34a participate in a vicious cycle, resulting in mitochondrial dysfunction, which is critical to the neuropathology of AD. PMID- 28652930 TI - A simple electroelution method for rapid protein purification: isolation and antibody production of alpha toxin from Clostridium septicum. AB - Clostridium septicum produces a number of diseases in human and farm animals which, in most of the cases, are fatal without clinical intervention. Alpha toxin is an important agent and the unique lethal virulent factor produced by Clostridium septicum. This toxin is haemolytic, highly lethal and necrotizing activities but is being used as an antigen to develop animal vaccines. The aim of this study was to isolate the alpha toxin of Clostridium septicum and produce highly specific antibodies against it. In this work, we have developed a simple and efficient method for alpha toxin purification, based on electroelution that can be used as a time-saving method for purifying proteins. This technique avoids contamination by other proteins that could appear during other protein purification techniques such chromatography. The highly purified toxin was used to produce polyclonal antibodies. The specificity of the antibodies was tested by western blot and these antibodies can be applied to the quantitative determination of alpha toxin by slot blot. PMID- 28652931 TI - Piwi1 is essential for gametogenesis in mollusk Chlamys farreri. AB - Piwi (P-element induced wimpy testis) is an important gene involved in stem cell maintenance and gametogenesis in vertebrates. However, in most invertebrates, especially mollusks, the function of Piwi during gametogenesis remains largely unclear. To further understand the function of Piwi during gametogenesis, full length cDNA of Piwi1 from scallop Chlamys farreri (Cf-Piwi1) was characterized, which consisted of a 2,637 bp open reading frame encoding an 878-amino acid protein. Cf-Piwi1 mRNA was mainly localized in the spermatogonia, spermatocytes, oogonia, oocytes of early development and intra-gonadal somatic cells. Additionally, the knockdown of Cf-Piwi1 by injection of Cf-Piwi1-dsRNA (double stranded RNA) into scallop adductor led to a loss of germ cells in C. farreri gonads. Apoptosis was observed mainly in spermatocytes and oocytes of early development, as well as in a small number of spermatogonia and oogonia. Our findings indicate that Cf-Piwi1 is essential for gametogenesis in the scallop C. farreri. PMID- 28652932 TI - A study of the progression of damage in an axially loaded Branta leucopsis femur using X-ray computed tomography and digital image correlation. AB - This paper uses X-ray computed tomography to track the mechanical response of a vertebrate (Barnacle goose) long bone subjected to an axial compressive load, which is increased gradually until failure. A loading rig was mounted in an X-ray computed tomography system so that a time-lapse sequence of three-dimensional (3D) images of the bone's internal (cancellous or trabecular) structure could be recorded during loading. Five distinct types of deformation mechanism were observed in the cancellous part of the bone. These were (i) cracking, (ii) thinning (iii) tearing of cell walls and struts, (iv) notch formation, (v) necking and (vi) buckling. The results highlight that bone experiences brittle (notch formation and cracking), ductile (thinning, tearing and necking) and elastic (buckling) modes of deformation. Progressive deformation, leading to cracking was studied in detail using digital image correlation. The resulting strain maps were consistent with mechanisms occurring at a finer-length scale. This paper is the first to capture time-lapse 3D images of a whole long bone subject to loading until failure. The results serve as a unique reference for researchers interested in how bone responds to loading. For those using computer modelling, the study not only provides qualitative information for verification and validation of their simulations but also highlights that constitutive models for bone need to take into account a number of different deformation mechanisms. PMID- 28652933 TI - Climate, soil or both? Which variables are better predictors of the distributions of Australian shrub species? AB - BACKGROUND: Shrubs play a key role in biogeochemical cycles, prevent soil and water erosion, provide forage for livestock, and are a source of food, wood and non-wood products. However, despite their ecological and societal importance, the influence of different environmental variables on shrub distributions remains unclear. We evaluated the influence of climate and soil characteristics, and whether including soil variables improved the performance of a species distribution model (SDM), Maxent. METHODS: This study assessed variation in predictions of environmental suitability for 29 Australian shrub species (representing dominant members of six shrubland classes) due to the use of alternative sets of predictor variables. Models were calibrated with (1) climate variables only, (2) climate and soil variables, and (3) soil variables only. RESULTS: The predictive power of SDMs differed substantially across species, but generally models calibrated with both climate and soil data performed better than those calibrated only with climate variables. Models calibrated solely with soil variables were the least accurate. We found regional differences in potential shrub species richness across Australia due to the use of different sets of variables. CONCLUSIONS: Our study provides evidence that predicted patterns of species richness may be sensitive to the choice of predictor set when multiple, plausible alternatives exist, and demonstrates the importance of considering soil properties when modeling availability of habitat for plants. PMID- 28652934 TI - Phytochemical-rich medicinal plant extracts suppress bacterial antigens-induced inflammation in human tonsil epithelial cells. AB - BACKGROUND: Pharyngitis is an inflammatory condition of the pharynx and associated structures commonly caused by the Group A streptococci (GAS). There is a growing interest in discovering plant-based anti-inflammatory compounds as potential alternatives to conventional drugs. This study evaluated anti inflammatory activity of phytochemical-rich extracts prepared from 12 herbal plants using human tonsil epithelial cells (HTonEpiC) in vitro. METHODS: The HTonEpiC were induced by a mixture of lipoteichoic acid (LTA) and peptidoglycan (PGN) (10 ug/mL; bacterial antigens) for 4 h and then exposed to ethanol extracts (EE) or aqueous extracts (AE) for 20 h. The secretion of four pro-inflammatory cytokines was measured using enzyme-linked immunosorbent assays (ELISA). Total phenolic and total flavonoid contents of the extracts were determined using spectrophotometric methods. RESULTS: The herbal plant extracts (<=5 ug/mL) were not cytotoxic to HTonEpiC. The extracts exhibited a broad range of reduction (1.2%-92.6%) of secretion of interleukin-8 (IL-8), human beta defensin-2 (hBD-2), epithelial-derived neutrophil activating protein-78 (ENA-78), and granulocyte chemotactic protein-2 (GCP-2). Both EE and AE of clove, ginger, and echinacea flower and EE from danshen root significantly inhibited the pro-inflammatory cytokine production as induced by LTA and PGN in HTonEpiCs at the concentrations of 1 and 5 ug/mL. DISCUSSION: Our observations indicate that danshen root, clove, ginger, and echinacea flower extracts exhibit an anti-inflammatory effect in HTonEpiCs. The most efficacious extracts from danshen root, clove, ginger and echinacea flowers have potential to be used as natural sources for developing phytotherapeutic products in the management of painful inflammation due to streptococcal pharyngitis. PMID- 28652935 TI - Segal's Law, 16S rRNA gene sequencing, and the perils of foodborne pathogen detection within the American Gut Project. AB - Obtaining human population level estimates of the prevalence of foodborne pathogens is critical for understanding outbreaks and ameliorating such threats to public health. Estimates are difficult to obtain due to logistic and financial constraints, but citizen science initiatives like that of the American Gut Project (AGP) represent a potential source of information concerning enteric pathogens. With an emphasis on genera Listeria and Salmonella, we sought to document the prevalence of those two taxa within the AGP samples. The results provided by AGP suggest a surprising 14% and 2% of samples contained Salmonella and Listeria, respectively. However, a reanalysis of those AGP sequences described here indicated that results depend greatly on the algorithm for assigning taxonomy and differences persisted across both a range of parameter settings and different reference databases (i.e., Greengenes and HITdb). These results are perhaps to be expected given that AGP sequenced the V4 region of 16S rRNA gene, which may not provide good resolution at the lower taxonomic levels (e.g., species), but it was surprising how often methods differ in classifying reads-even at higher taxonomic ranks (e.g., family). This highlights the misleading conclusions that can be reached when relying on a single method that is not a gold standard; this is the essence of Segal's Law: an individual with one watch knows what time it is but an individual with two is never sure. Our results point to the need for an appropriate molecular marker for the taxonomic resolution of interest, and calls for the development of more conservative classification methods that are fit for purpose. Thus, with 16S rRNA gene datasets, one must be cautious regarding the detection of taxonomic groups of public health interest (e.g., culture independent identification of foodborne pathogens or taxa associated with a given phenotype). PMID- 28652936 TI - Divide and Conquer (DC) BLAST: fast and easy BLAST execution within HPC environments. AB - Bioinformatics is currently faced with very large-scale data sets that lead to computational jobs, especially sequence similarity searches, that can take absurdly long times to run. For example, the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST and BLAST+) suite, which is by far the most widely used tool for rapid similarity searching among nucleic acid or amino acid sequences, is highly central processing unit (CPU) intensive. While the BLAST suite of programs perform searches very rapidly, they have the potential to be accelerated. In recent years, distributed computing environments have become more widely accessible and used due to the increasing availability of high-performance computing (HPC) systems. Therefore, simple solutions for data parallelization are needed to expedite BLAST and other sequence analysis tools. However, existing software for parallel sequence similarity searches often requires extensive computational experience and skill on the part of the user. In order to accelerate BLAST and other sequence analysis tools, Divide and Conquer BLAST (DCBLAST) was developed to perform NCBI BLAST searches within a cluster, grid, or HPC environment by using a query sequence distribution approach. Scaling from one (1) to 256 CPU cores resulted in significant improvements in processing speed. Thus, DCBLAST dramatically accelerates the execution of BLAST searches using a simple, accessible, robust, and parallel approach. DCBLAST works across multiple nodes automatically and it overcomes the speed limitation of single-node BLAST programs. DCBLAST can be used on any HPC system, can take advantage of hundreds of nodes, and has no output limitations. This freely available tool simplifies distributed computation pipelines to facilitate the rapid discovery of sequence similarities between very large data sets. PMID- 28652937 TI - Primary health clinic toilet/bathroom surface swab sampling can indicate community profile of sexually transmitted infections. AB - BACKGROUND: The microbiome of built environment surfaces is impacted by the presence of humans. In this study, we tested the hypothesis that analysis of surface swabs from clinic toilet/bathroom yields results correlated with sexually transmitted infection (STI) notifications from corresponding human populations. We extended a previously reported study in which surfaces in toilet/bathroom facilities in primary health clinics in the Australian Northern Territory (NT) were swabbed then tested for nucleic acid from the STI agents Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis. This was in the context of assessing the potential for such nucleic acid to contaminate specimens collected in such facilities. STIs are notifiable in the NT, thus allowing comparison of swab and notification data. METHODS: An assumption in the design was that while absolute built environment loads of STI nucleic acids will be a function of patient traffic density and facility cleaning protocols, the relative loads of STI nucleic acids from different species will be largely unaffected by these processes. Another assumption was that the proportion of swabs testing positive for STIs provides a measure of surface contamination. Accordingly, "STI profiles" were calculated. These were the proportions that each of the three STIs of interest contributed to the summed STI positive swabs or notifications. Three comparisons were performed, using swab data from clinics in remote Indigenous communities, clinics in small-medium towns, and a single urban sexual health clinic. These data were compared with time and place-matched STI notifications. RESULTS: There were significant correlations between swab and notifications data for the both the remote Indigenous and regional data. For the remote Indigenous clinics the p values ranged from 0.041 to 0.0089, depending on data transformation and p value inference method. Further, the swab data appeared to strongly indicate known higher relative prevalence of gonorrhoeae in central Australia than in northern Australia. Similarly, the regional clinics yielded p values from 0.0088-0.0022. In contrast, swab and notifications data from the sexual health clinic were not correlated. DISCUSSION: Strong correlations between swab and notifications were observed. However, there was evidence for limitations of this approach. Despite the correlation observed with the regional clinics data, one clinic yielded zero positive swabs for C. trachomatis, although this STI constituted 25.1% of the corresponding notifications. This could be ascribed to stochastic effects. The lack of correlation observed for sexual health clinic data was also likely due to stochastic effects. It was concluded that toilet/bathroom surface swab sampling has considerable potential for public health surveillance. The approach may be applicable in situations other than primary health clinics, and for targets other than STIs. PMID- 28652938 TI - Euphilomedes biacutidens (Ostracoda, Myodocopida, Philomedidae), a new species from China Sea. AB - Ostracods are one of the major groups of marine benthos, inhabiting virtually all oceanic environments worldwide, and a total of 31 species have been recorded in genus Euphilomedes Kornicker, 1967. In the present study, we describe a new species Euphilomedes biacutidens collected from the Taiwan Strait and South China Sea. E. biacutidens sp. nov. differs from the related species of the genus Euphilomedes in having a unique combination of the characteristics of spines on carapace, the filaments on sensory seta, the arrangement of setae on tip of the first antenna, the numbers of setae on appendages, the claws on fifth limb, the teeth on the comb of the seventh limb and furcal claws. It is particularly obvious that it has a bifurcated and pointed ventral corner of the rostrum, two spines on the posterior margin of right valve, a row of teeth along the inner margin of article 3 of the endopod of the second antenna, and some long claws instead of setae on the fifth limb. PMID- 28652939 TI - Sea star Henricia spiculifera (Clark, 1901) in the northwestern Pacific: one species or three? AB - Three species of the sea stars are reported from the waters of the northwestern Pacific. These species were referred by earlier authors as Henricia spiculifera or H. leviuscula spiculifera. Two of them, H. lineata and H. uluudax, were recently described from the Aleutian Islands. These species are reported for the first time from the western Pacific (southeastern Kamchatka shore, Commander Islands, and the northern Kurile Islands). The third species, H. olga sp. n. is herein described from the northern Sea of Japan. It is very likely that similar sea stars recorded in Yellow Sea and the southern Kurile Islands belong to H. olga sp. n. These three species are a part of a phylogenetic clade within the subgenus Setihenricia, which also includes H. sanguinolenta, H. multispina, and several undescribed species occurring in the northeastern Pacific. PMID- 28652940 TI - Utility of a time frame in assessing psychological pain and suicide ideation. AB - BACKGROUND: Assessing psychological pain has been recommended as an integral part of a comprehensive suicide risk assessment. The Psychache Scale, an established measure of psychological pain, does not specify a time frame for when pain is experienced, which may inadvertently increase the likelihood of identifying individuals as being at elevated suicide risk when they complete the Psychache Scale based on psychological pain experienced at some undefined time in the past. METHODS: We conducted a national general population survey among United States adults to determine whether addition of a time frame to the instructions of the Psychache Scale would more accurately reflect current psychological pain and more effectively identify people with current suicide ideation. A between-subjects design was used where respondents were randomized to complete the original Psychache scale or a modified scale with time frame. Data were collected online from September 2015 to June 2016. A total of 242 respondents had complete psychological pain data: 133 completed the original Psychache Scale and 109 completed the Psychache Scale with time frame. RESULTS: Addition of a time frame did not result in differences in psychological pain scores. However, when screening for participants with current suicide ideation, 13% fewer false positives were observed with the modified scale at higher cut-off values than previously reported (38 vs. 24). The substantial increase in positive predictive value suggests that a time frame is a worthwhile addition to the Psychache Scale. DISCUSSION: We recommend using the Psychache Scale with a time frame and testing the cut-off score for suicide ideation in population samples that reflect the general population more accurately. Psychological pain cut-off scores in clinical samples have yet to be established. PMID- 28652941 TI - Two-headed butterfly vs. mantis: do false antennae matter? AB - The colour patterns and morphological peculiarities of the hindwings of several butterfly species result in the appearance of a head at the rear end of the insect's body. Although some experimental evidence supports the hypothesis that the "false head" deflects predator attacks towards the rear end of the butterfly, more research is needed to determine the role of the different components of the "false head". We explored the role of hindwing tails (presumably mimicking antennae) in predator deception in the "false head" butterfly Callophrys xami. We exposed butterflies with intact wings and with hindwing tails experimentally ablated to female mantises (Stagmomantis limbata). We found no differences in the number of butterflies being attacked and the number of butterflies escaping predation between both groups. However, our behavioural observations indicate that other aspects of the "false head" help C. xami survive some mantis attacks, supporting the notion that they are adaptations against predators. PMID- 28652942 TI - Time to cash in on positive interactions for coral restoration. AB - Coral reefs are among the most biodiverse and productive ecosystems on Earth, and provide critical ecosystem services such as protein provisioning, coastal protection, and tourism revenue. Despite these benefits, coral reefs have been declining precipitously across the globe due to human impacts and climate change. Recent efforts to combat these declines are increasingly turning to restoration to help reseed corals and speed-up recovery processes. Coastal restoration theory and practice has historically favored transplanting designs that reduce potentially harmful negative species interactions, such as competition between transplants. However, recent research in salt marsh ecosystems has shown that shifting this theory to strategically incorporate positive interactions significantly enhances restoration yield with little additional cost or investment. Although some coral restoration efforts plant corals in protected areas in order to benefit from the facilitative effects of herbivores that reduce competitive macroalgae, little systematic effort has been made in coral restoration to identify the entire suite of positive interactions that could promote population enhancement efforts. Here, we highlight key positive species interactions that managers and restoration practitioners should utilize to facilitate the restoration of corals, including (i) trophic facilitation, (ii) mutualisms, (iii) long-distance facilitation, (iv) positive density-dependence, (v) positive legacy effects, and (vi) synergisms between biodiversity and ecosystem function. As live coral cover continues to decline and resources are limited to restore coral populations, innovative solutions that increase efficiency of restoration efforts will be critical to conserving and maintaining healthy coral reef ecosystems and the human communities that rely on them. PMID- 28652943 TI - Diverse habitat use during two life stages of the critically endangered Bahama Oriole (Icterus northropi): community structure, foraging, and social interactions. AB - Our ability to prevent extinction in declining populations often depends on effective management of habitats that are disturbed through wildfire, logging, agriculture, or development. In these disturbed landscapes, the juxtaposition of multiple habitat types can be especially important to fledglings and young birds, which may leave breeding grounds in human-altered habitat for different habitats nearby that provide increased foraging opportunities, reduced competition, and higher protection from predators. In this study, we evaluated the importance of three habitat types to two life stages of the critically endangered Bahama Oriole (Icterus northropi), a synanthropic songbird endemic to Andros, The Bahamas. First, we determined the avian species composition and relative abundance of I. northropi among three major vegetation types on Andros: Caribbean pine (Pinus caribaea) forest, coppice (broadleaf dry forest), and anthropogenic areas, dominated by nonnative vegetation (farmland and developed land). We then compared the foraging strategies and social interactions of two age classes of adult Bahama Orioles in relation to differential habitat use. Bird surveys late in the Bahama Oriole's breeding season indicated the number of avian species and Bahama Oriole density were highest in coppice. Some bird species occurring in the coppice and pine forest were never observed in agricultural or residential areas, and may be at risk if human disturbance of pine forest and coppice increases, as is occurring at a rapid pace on Andros. During the breeding season, second-year (SY) adult Bahama Orioles foraged in all vegetation types, whereas after-second year (ASY) adults were observed foraging only in anthropogenic areas, where the species nested largely in introduced coconut palms (Cocos nucifera). Additionally, SY adults foraging in anthropogenic areas were often observed with an ASY adult, suggesting divergent habitat use for younger, unpaired birds. Other aspects of foraging (vegetation features, food-gleaning behavior, and food items) were similar for the two age classes. Older Bahama Orioles exhibited relatively higher rates of social interactions (intraspecific and interspecific pooled) in anthropogenic areas, and won more interaction outcomes compared to younger adults. Our findings concur with those of other studies indicating dry broadleaf forest is vitally important to migrating, wintering, and resident birds, including the critically endangered Bahama Oriole, which appears to depend heavily on this vegetation type during certain life stages. PMID- 28652944 TI - Extranodal Natural Killer/T-Cell Lymphoma: An Incidental Finding. AB - Extranodal natural killer/T-cell lymphoma (ENKTCL) is a rare form of non-Hodgkin lymphoma. This neoplasm is more prevalent in regions of Asia and Latin America and most commonly involves the sinonasal tract, presenting with signs of nasal obstruction, epistaxis, or sinus infection. It is a locally destructive and angioinvasive neoplasm. The treatment of ENKTCL is dependent on the extent of the tumor. For localized disease, the treatment is chemoradiation. For disseminated disease, treatment is mainly chemotherapy-based. This report describes a case of a 41-year-old Hispanic woman who initially presented with signs of nasal congestion for four weeks and was subsequently diagnosed and treated for chronic sinusitis. The patient underwent endoscopic surgery for persistent chronic sinusitis, with a presumptive diagnosis of allergic fungal rhinosinusitis based on clinical and radiographic presentation. The pathologic exam revealed a diagnosis of ENKTCL. The patient underwent three cycles of chemotherapy comprised of steroid (hydrocortisone), methotrexate, ifosfamide, pre-asparaginase, and etoposide (SMILE) followed by radiation, resulting in clinical and radiographic remission. On review of the literature, ENKTCL is very rare in the United States and diagnosis is commonly delayed due to non-specific signs. We report this case to increase awareness of this disease entity and remind clinicians to include this in the differential diagnosis of nasal obstruction. PMID- 28652945 TI - Spontaneous Intracranial Hypotension after Vestibular Schwannoma Resection Due to an Unexpected Pathology: Tarlov Cysts. AB - While infrequent, cerebrospinal fluid (CSF) leaks are known to occur after surgical resection of vestibular schwannomas. Early signs of CSF leak often include headache and altered mental status. If untreated, life-threatening complications can occur, including brainstem herniation and meningitis. The appropriate surgical treatment for a CSF leak requires accurate localization of the source. While the most likely location of a CSF leak after lateral skull base surgery is through the aerated portions of the temporal bone, we present a unique case of a man with a prolonged CSF leak after an acoustic tumor removal who was ultimately found to have an occult spinal perineural (Tarlov) cyst as the source. Accurate localization was ultimately achieved with CT myelogram after empirically obliterating his mastoid failed to restore intracranial CSF volume. Tarlov cysts are the most common cause of idiopathic intracranial hypotension, and this case highlights the importance of considering this entity in the differential diagnosis of postoperative CSF leaks. PMID- 28652946 TI - Treatment-Related Cardiovascular Outcomes in Patients with Symptomatic Subclavian Artery Stenosis. AB - BACKGROUND: Subclavian artery stenosis (SAS) is narrowing of the subclavian artery most commonly caused by atherosclerosis. It serves as a marker for cerebrovascular and myocardial ischemic events. METHODS: A retrospective cohort study was conducted to determine the association of treatment via combination therapy (antiplatelet drug plus either by-pass surgery or percutaneous transluminal angioplasty (PTA) with or without stent implantation) versus antiplatelet drug therapy alone on cardiovascular events and all-cause mortality in Marshfield Clinic patients diagnosed with symptomatic SAS from January 1, 1995 to December 31, 2009. RESULTS: Of the total 2153 cases, 100 patients were identified as eligible to be included in the study. Of these 100 patients that met inclusion criteria, 30 underwent combination therapy while 70 were managed only with drug treatment. A median length of follow-up was 8.45 years. Adverse cardiovascular events occurred in 5/30 (17%) of combination therapy patients compared to 28/70 (40%) of antiplatelet drug therapy only patients (p = 0.0355). Accordingly, all-cause mortality was higher (47%) in the antiplatelet drug therapy only group than the combination therapy group (13%) [hazard ratio = 3.45, p = 0.0218]. CONCLUSIONS: Preliminary findings in this pilot data set suggest that combination therapy (medications plus either surgical or interventional repair) of subclavian artery stenosis is associated with less cardiovascular adverse events and higher survival rates. However, prospective randomized studies with larger number of patients are needed to validate these findings. PMID- 28652947 TI - Ertapenem-Induced Thrombocytosis. AB - Ertapenem is a beta-lactam antibiotic that has a broad spectrum of anti-microbial coverage. Hematological adverse events like thrombocytosis, neutropenia, and neutropenia are infrequent. Here we report a rare case of drug-induced thrombocytosis in a 68-year-old female, who was treated with ertapenem for the diagnosis of complicated abdominal infection. This case emphasizes that any patient with thrombocytosis should be assessed with a careful and detailed history with consideration for possible drug side effects. PMID- 28652948 TI - Streptococcus Mutans: A Potential Risk Factor in Recurrent Hemorrhagic Stroke. AB - Stroke is the fifth leading cause of death and is responsible for approximately nine percent of all deaths worldwide. Cases of Streptococcus mutans (S. mutans) induced intracerebral hemorrhage as a result of bloodstream infections have seldom been reported. New reports show that bacteria with specific collagen binding proteins (CBPs), such as the Cnm type produced by S. mutans, may inhibit platelet aggregation and cause bleeding. In this article, we report on a 62-year old man with a recent history of left frontal intracerebral hemorrhage (ICH) who presented to the emergency department after a fall due to suspected seizure while in rehabilitation. Computed tomography (CT) scan of the brain showed a right cerebellar hemorrhage with surrounding edema and mass effect on the fourth ventricle. A suboccipital craniotomy to evacuate the cerebellar ICH was completed without complication. Radiologic and angiographic assessments regarding the etiology of this patient's stroke did not reveal any evidence of vascular pathology or mycotic aneurysms to explain his recurrent intracranial hemorrhages. Through persistent patient and family interviews, it came to light that a few weeks prior to the patient's first ICH, he was diagnosed with a bloodstream infection by S. mutans. Bacteremia is known to be associated with embolic stroke, but only recently has it been shown that bacteremia can also be implicated in hemorrhagic stroke. S. mutans of the k serotype have specific CBPs that are attracted to exposed collagen in previously damaged small vessel walls. These bacterial proteins can interrupt the blood clotting cascade through the prevention of platelet aggregation, increasing the risk of intracerebral hemorrhage. PMID- 28652949 TI - Cerebrospinal Fluid Total Tau is Increased in Normal Pressure Hydrocephalus Patients who Undergo Successful Lumbar Drain Trials. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is a neurologic disease that affects <1% of those aged >65 years, but is difficult to distinguish from other diseases that present in this age group, such as Alzheimer's disease. Large volume lumbar puncture and an external lumbar drain trial (ELD) are used to make a clinical diagnosis of INPH, but the accuracy of ELD is suspected. OBJECTIVE: To investigate proteomic cerebrospinal fluid (CSF) biomarker patterns in patients with INPH undergoing ELD to develop a quantitative diagnostic. METHODS: Twenty patients with suspected INPH underwent an ELD trial and the CSF biomarkers AB1-42, total tau, and tau phosphorylated at amino acid 181 (p-tau) were quantified with immunoassays in specimens taken prior to ELD placement, after the ELD trial, and from ventricular samples collected at the time of permanent ventriculoperitoneal shunt placement. RESULTS: CSF total tau was elevated, on average, in pre- and post-ELD samples from patients who failed to improve clinically during the ELD trial, but the findings were marginally significant after correction for multiple comparisons. AB1-42 and p-tau concentrations were not significantly different in patients who either did or did not clinically improve after the ELD. CONCLUSIONS: CSF total tau is a potential novel biomarker for suspected INPH patients who will clinically improve, or have clinically improved, after an ELD trial. The small sample size of this study, which was due to the relative rarity of this condition, indicates that larger studies are needed to confirm the utility of this approach. PMID- 28652950 TI - Highlights on Cerebral Arteriovenous Malformation Treatment Using Combined Embolization and Stereotactic Radiosurgery: Why Outcomes are Controversial? AB - Cerebral arteriovenous malformations (AVMs) are abnormal tangling between brain arteries and veins causing an arteriovenous shunt called nidus with an intervening network of vessels from the region of formation and spans through the brain. AVM effect is debilitating to the affected individual due to associated persistent intracerebral hemorrhage, resulting in significant occurrences of seizures and neurological damage. Recent innovative treatments involve a combination of embolization (Embo) procedures followed by stereotactic radiosurgery (SRS), designed to optimize less-invasive practice for the obliteration of the AVMs. Three groups of investigators reported different outcomes based on obliteration rates and adverse events, making the effectiveness of options for therapy, controversial. We have taken the case-oriented-approach to highlight on varying outcomes from various studies and provide insights as to why findings from different operation settings could be so conflicting. We chose 18 articles for systematic analysis based on initial electronic database selection of 40 key papers already identified for inclusion, followed by independent blinding assessment by two co-authors. Our evaluation was based first on our specific inclusion criteria, examining method quality, obliteration rates, serious adverse events (SAEs) and mortality rates. Second, we made a comparison between SRS or embo alone treatments versus combined embo/SRS procedures, relative to AVM sizes, following Spetzler-Martin (SM) method. Third, we considered publications which had concrete statistics with well-defined P-values and clarified outcomes for accurate evaluation. We found that patients with small to medium-sized AVM were susceptible to either embo alone or SRS alone treatments, yielding obliteration rates from 71%-100%. Except for one report, giant sizes AVMs were not amenable to these single treatments, subjecting patients to embo/SRS procedures, which yielded mixed results: One group reported 52%-65% obliteration rates, compared to 23%-28% embo alone treatment. A second group contradicted this apparent beneficial outcome, obtaining obliteration rates of 53% with combined treatment compared to 71% with SRS alone, four-year postoperative. A third group reported there was no difference between single and combined treatments and obtained complete obliteration of 70%-82%, ranging from three-five-years postoperative follow-up. In all the cases analyzed, obliteration rates improved with time. SAEs, such as persistent hemorrhage and permanent neurologic deficits (P-NDs), as well as mortality, were minimal during intraoperative and postoperative follow-ups. The problem of conflicting outcomes in combined treatments of AVM by EMBO/SRS exists. Previous investigators, however, have overlooked to address this issue satisfactorily. Our analysis found that the reported inconsistencies in AVM treatment outcomes are attributable to key factors making therapy unpredictable, which includes: the size of the AVM, nidus localization and accessibility of either Embo or radiation dose applied, certain Embo materials lowering obliteration rates by masking radioactive effect on the nidus during SRS and follow-up timing for obtaining obliteration rates determine the extent of obliteration. We have indicated critical factors which require consideration when planning strategies for treatment of AVM patients and have made suggestions of how to overcome such hurdles. PMID- 28652952 TI - Fibromuscular Dysplasia with Spontaneous Coronary Artery Disease Presenting as Acute Myocardial Infarction. AB - A 40-year-old female presented to a rural hospital with crushing substernal chest pain. An initial electrocardiogram showed ST elevation in lead II and aVF with elevated troponin I. She was immediately transferred to a tertiary care hospital. An emergent coronary angiogram did not show any significant coronary artery disease. On the second day, the patient experienced recurrence of severe chest pain with ST elevations in leads I, aVL, V5-V6, ST depressions in V1-V3, T-wave inversion over V2-V5. The troponin I level increased to > 40 ng/ml (normal 0.0 to 0.04 ng/ml). An emergent angiogram was performed revealing local dissection of the mid to distal left main coronary artery and a totally occluded diagonal artery. It was deemed unsafe to perform percutaneous coronary intervention because it was a non-flow limiting left main coronary artery dissection and was difficult to cannulate with the guide catheter. Subsequently, an elective angiogram was performed after a 48-hour interval to evaluate the progression of dissection and to make a definitive decision for revascularization versus medical management. On the third angiogram, stenosis seen in the diagonal branch on the previous angiogram progressed to dissection, and local dissection of the left main coronary artery seen on the previous angiogram spontaneously resolved. The patient was symptom-free and hemodynamically stable. It was decided to manage the patient conservatively due to the spontaneous resolution of occlusion in the diagonal artery and dissection of the left main coronary artery. The patient was started on conservative medical treatment. A magnetic resonance angiography of the right internal carotid artery revealed a "string of beads" appearance, which confirmed the diagnosis of fibromuscular dysplasia. She was followed closely in the clinic and has remained asymptomatic for the past one year. PMID- 28652951 TI - Current Practices in Assessing Professionalism in United States and Canadian Allopathic Medical Students and Residents. AB - Professionalism is a critically important competency that must be evaluated in medical trainees but is a complex construct that is hard to assess. A systematic review was undertaken to give insight into the current best practices for assessment of professionalism in medical trainees and to identify new research priorities in the field. A search was conducted on PubMed for behavioral assessments of medical students and residents among the United States and Canadian allopathic schools in the last 15 years. An initial search yielded 594 results, 28 of which met our inclusion criteria. Our analysis indicated that there are robust generic definitions of the major attributes of medical professionalism. The most commonly used assessment tools are survey instruments that use Likert scales tied to attributes of professionalism. While significant progress has been made in this field in recent years, several opportunities for system-wide improvement were identified that require further research. These include a paucity of information about assessment reliability, the need for rater training, a need to better define competency in professionalism according to learner level (preclinical, clerkship, resident etc.) and ways to remediate lapses in professionalism. Student acceptance of assessment of professionalism may be increased if assessment tools are shifted to better incorporate feedback. Tackling the impact of the hidden curriculum in which students may observe lapses in professionalism by faculty and other health care providers is another priority for further study. PMID- 28652953 TI - A Robust and Affordable Table Indexing Approach for Multi-isocenter Dosimetrically Matched Fields. AB - Purpose Radiotherapy treatment planning of extended volume typically necessitates the utilization of multiple field isocenters and abutting dosimetrically matched fields in order to enable coverage beyond the field size limits. A common example includes total lymphoid irradiation (TLI) treatments, which are conventionally planned using dosimetric matching of the mantle, para aortic/spleen, and pelvic fields. Due to the large irradiated volume and system limitations, such as field size and couch extension, a combination of couch shifts and sliding of patients are necessary to be correctly executed for accurate delivery of the plan. However, shifting of patients presents a substantial safety issue and has been shown to be prone to errors ranging from minor deviations to geometrical misses warranting a medical event. To address this complex setup and mitigate the safety issues relating to delivery, a practical technique for couch indexing of TLI treatments has been developed and evaluated through a retrospective analysis of couch position. Methods The indexing technique is based on the modification of the commonly available slide board to enable indexing of the patient position. Modifications include notching to enable coupling with indexing bars, and the addition of a headrest used to fixate the head of the patient relative to the slide board. For the clinical setup, a Varian Exact CouchTM (Varian Medical Systems, Inc, Palo Alto, CA) was utilized. Two groups of patients were treated: 20 patients with table indexing and 10 patients without. The standard deviations (SDs) of the couch positions in longitudinal, lateral, and vertical directions through the entire treatment cycle for each patient were calculated and differences in both groups were analyzed with Student's t-test. Results The longitudinal direction showed the largest improvement. In the non-indexed group, the positioning SD ranged from 2.0 to 7.9 cm. With the indexing device, the positioning SD was reduced to a range of 0.4 to 1.3 cm (p < 0.05 with 95% confidence level). The lateral positioning was slightly improved (p < 0.05 with 95% confidence level), while no improvement was observed in the vertical direction. Conclusions The conventional matched field TLI treatment is error-prone to geometrical setup error. The feasibility of full indexing TLI treatments was validated and shown to result in a significant reduction of positioning and shifting errors. PMID- 28652954 TI - Fighting the Dengue Virus. AB - The incidence of dengue has been on the upsurge in the last decade. It has affected around one-third of the world's population living in endemic areas. It can be asymptomatic or may present with some specific symptoms. No control measures have proven beneficial to decrease the prevalence of this disease. The emergence of dengue vaccine has been a revolutionary hope in the future of patients affected with this disease. No doubt, this vaccine has its limitations and may do more harm than good, but with correct use, it can prove to be the most beneficial step taken in managing dengue so far. PMID- 28652955 TI - Perioperative Fasting and the Patient Experience. AB - Standard preparation for a surgical procedure requires patients to fast (nulla per os [NPO]) after midnight before their operation. Unfortunately, given the unpredictable nature of operating room scheduling and unavoidable delays, patients may find themselves anxiously waiting and fasting much longer than expected. In recent years, the usefulness of prolonged fasting to prevent pulmonary aspiration has been questioned. According to the American Society of Anesthesiologists (ASA) guidelines, unnecessarily prolonged fasting can be avoided by allowing patients to have clear liquids with the minimal fasting time of only two hours. This study examines a random sampling of elective scheduled surgeries at a 439-bed safety-net teaching hospital in Southern California in October 2016. The study revealed significantly prolonged NPO times caused by delays in the scheduling of operation times. An analysis of delays revealed that prior surgical procedures running longer than scheduled were the most common reason for a delay in starting an operation and, subsequently, prolonging patient fasting time. Significantly prolonged fasting times warrant the need for institutional management strategy changes and a revamping of clinical education curriculums. PMID- 28652956 TI - A Case of Transient ST Elevation and Polymorphic Tachycardia without Angina Diagnosed by Holter Monitoring. AB - We report the case of 52-year-old female with recurrent episodes of palpitations and dizziness. Holter monitoring revealed transient ST elevations followed by episodes of polymorphic ventricular tachycardia associated with episodes of palpitations and dizziness. Coronary angiography revealed mildly irregular right coronary artery with 90% stenosis. The patient underwent percutaneous coronary intervention with successful placement of a stent to the mid-right coronary artery. The patient has been followed closely over a period of 12 months. There haven't been any recorded episodes of tachycardia, and the patient has remained symptom-free. PMID- 28652957 TI - A Retrospective Study of Acute Renal Failure in Children: Its Incidence, Etiology, Complications and Prognosis. AB - BACKGROUND: Acute renal failure (ARF) developed due to various causes and may lead to significant morbidity and mortality among pediatric patients. OBJECTIVES: The study was conducted to determine the incidence, etiology, outcome of treatment and clinical presentation of ARF in pediatric patients in Somalia. METHODS: Comprehensive case history of 39 pediatric patients below 12 years of age, admitted with renal diseases in four tertiary care hospitals in Hargeisa and Borama cities in Somalia during December 2015 to November 2016. They were subjected to clinical investigation and laboratory test analysis based on the inclusion criteria of renal insufficiency characterized by serum creatinine level more than 1.5 mg/dl. RESULTS: ARF was most commonly found in five to 12 years age group (53.8%) compared to infant (zero to one year) and pre-school (one to five years) children (23.08%). Mean age of presentation was 6.14 years. Male female ratio in this study was 1.2: 1. Most common presenting clinical feature in our study was oliguria (97.43%), swelling (69.2%), fever (84.1%), abdomen pain and nausea-vomiting (41.02%). Common clinical signs were edema (66.66%), altered sensorium (51.28%), hematuria (48.71%) and hypertension (38.46%). Snake bite and acute post streptococcal glomerulonephritis were the two most common causes of ARF in children in our study. Common complications were hypertension (38.46%), anemia (35.89%), hyperkalemia (25.64%) and infection (20.51%), all of which were within the previously reported range. The factors which correlated positively with increased mortality and morbidity were females with age below one year , etiology like septicemia and systemic lupus erythematosus (SLE), high peak serum creatinine concentration and complicated by disseminated intravascular coagulation (DIC). CONCLUSION: Many causes of ARF are preventable and it should be possible to reduce mortality and morbidity due to ARF through purposive preventive measure and availability of the better medical facility. PMID- 28652958 TI - Lidocaine-Induced Systemic Toxicity: A Case Report and Review of Literature. AB - For the past 50 years, local anesthetics such as lidocaine have been commonly used in various clinical settings. Its use is not just limited to anesthesia and surgery but is also frequently utilized in internal medicine and in primary care setting for bedside procedures. Despite its widespread use, most physicians are not familiar with the life-threatening manifestations of lidocaine toxicity and its treatment. Our case demonstrates a successful resuscitation after cardiac arrest in a healthy 33-year-old female with systemic lidocaine toxicity after she received lidocaine as a local anesthetic. Our goal is to educate general internists and primary care physicians of the possible hazards of lidocaine use. We also aim to create mindfulness of the symptoms of lidocaine toxicity and the use of intravenous lipid emulsion as an antidote. PMID- 28652959 TI - Surgical Supervisor Feedback Affects Performance: A Blinded Randomized Study. AB - While performing a simple task of following: a suture while closing a surgical wound in a simulated environment, we hypothesized that negative reinforcement results in increased procedural errors, longer operating time and poorer trainee satisfaction. We aimed to measure the effect on participant performance and the perception of the instructor, following positive or negative supervisor feedback during the task. A blinded randomized study was conducted assessing positive and negative supervisor feedback styles on participant performance in a simulated operation room. Students performed the task twice, with a reflection in between the repeated task. We found that the change in procedure time between the two tasks was adversely affected by feedback style. Participants receiving negative feedback sought cues to improve. From this study, it was found that negative supervisor feedback has the potential to adversely affect elements of performance. Despite this, participants receiving negative feedback express a willingness to improve their performance by seeking cues from the supervisor. PMID- 28652961 TI - Successful long-term terbinafine therapy in an asthmatic patient with Aspergillus sensitization and bronchiectasis. AB - Severe asthma with fungal sensitization (SAFS) is estimated to affect ~25% of patients with poorly controlled asthma. Tri-azole therapy is effective in only 60 80% and side effects are common. We report a 25 years-old woman with severe asthma, Aspergillus sensitization and marked bronchiectasis that developed a rare Achilles-tendinopathy with both itraconazole and voriconazole. She started a trial with terbinafine as salvage therapy that led to a striking improvement and long-term control of her respiratory disease. PMID- 28652962 TI - Cryptogenic organising pneumonia presenting with spontaneous pneumothorax and the value of procalcitonin: A case report. AB - Cryptogenic Organising Pneumonia (COP) is a relatively rare condition and can be difficult to differentiate from Community acquired pneumonia (CAP). We report two cases which demonstrate the importance of considering this differential diagnosis in patients with spontaneous pneumothorax who have raised inflammatory markers or lung infiltrates. Our report highlights the value of serum procalcitonin as a biomarker in differentiating between community acquired pneumonia and cryptogenic organising pneumonia especially in the context of a high serum C-reactive protein. Furthermore, the cases show early diagnosis and prompt treatment with corticosteroids may impact the clinical outcome. PMID- 28652960 TI - The baseline characteristics of parents and African American girls in an online obesity prevention program: A feasibility study. AB - The objective of this paper was to identify the relationships and associations between child and parent characteristics with child fruit and vegetable (FV) consumption in an online obesity prevention program for 8-10 year old African American girls. Girls and a parent (n = 342 child-parent pairs) in the southwestern US completed baseline data collection from 2012 to 2014. Girls and a parent completed self-report questionnaires online. Girls also completed two unannounced 24 hour telephone-based dietary recalls. The relationships of parent demographic characteristics, child FV intake, and psychosocial variables (child and parent) were examined by analysis of variance. Pearson correlation coefficients were calculated to determine the relationships between psychosocial variables and child FV intake. Child FV intake was significantly greater in the highest household education (p = 0.001) and income groups (p = 0.004). FV home availability was higher with older parents (p = 0.007) and two-parent households (p = 0.033). Child FV intake was positively related to child FV preferences (p < 0.001), FV home availability (p = 0.022), and FV home accessibility (p = 0.002) but was negatively related to family barriers to FV consumption (p = 0.000). The study highlighted significant findings between child FV consumption and parent psychosocial variables and demographic characteristics that may offer insights for the design of effective obesity prevention interventions for 8-10 year old African American girls. ClinicaTrials.gov (NCT01481948). PMID- 28652963 TI - Switching from sildenafil to riociguat for the treatment of PAH and inoperable CTEPH: Real-life experiences. AB - Riociguat is a novel soluble guanylate cyclase stimulator that is approved for the treatment of patients with pulmonary arterial hypertension (PAH) and patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA). As riociguat is a relatively new drug, experience of its use in clinical practice is limited, especially in patients who would not have met the inclusion criteria for the pivotal Phase III clinical trials, PATENT-1 and CHEST-1. This article shares our initial practical and clinical experience in switching patients with PAH and CTEPH from the phosphodiesterase type-5 inhibitor sildenafil to riociguat, based on three selected case reports of patients who discontinued sildenafil therapy owing to side effects or disease progression (one patient with idiopathic PAH and two patients with persistent/recurrent CTEPH after PEA). Two cases illustrate our experience with direct switch from sildenafil to riociguat (6-8 h between the last sildenafil dose and the first riociguat dose), and one case illustrates switch to riociguat in a patient who underwent treatment with other PAH-specific therapies between stopping sildenafil and starting riociguat. Symptoms improved with riociguat therapy in two cases; in the third case the patient experienced worsening symptoms 1 month after initiating riociguat and was switched back to sildenafil. These case experiences contribute practical information to assist clinicians in the switch from sildenafil to riociguat therapy in patients with PAH or CTEPH. PMID- 28652964 TI - A necrotic tonsillar lesion: An unusual presentation of disseminated histoplasmosis. AB - We report a case of tonsillar histoplasmosis with hematogenous dissemination in a woman receiving infliximab for Crohn's disease. She also had a history of sarcoidosis. Due to the unusual location and confounding medical history, our case provided a diagnostic dilemma. Histoplasma infection was confirmed histologically, and the patient responded well to appropriate treatment. PMID- 28652965 TI - A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI. AB - Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19-32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 * 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases. PMID- 28652966 TI - Disruption to control network function correlates with altered dynamic connectivity in the wider autism spectrum. AB - Autism is a common developmental condition with a wide, variable range of co occurring neuropsychiatric symptoms. Contrasting with most extant studies, we explored whole-brain functional organization at multiple levels simultaneously in a large subject group reflecting autism's clinical diversity, and present the first network-based analysis of transient brain states, or dynamic connectivity, in autism. Disruption to inter-network and inter-system connectivity, rather than within individual networks, predominated. We identified coupling disruption in the anterior-posterior default mode axis, and among specific control networks specialized for task start cues and the maintenance of domain-independent task positive status, specifically between the right fronto-parietal and cingulo opercular networks and default mode network subsystems. These appear to propagate downstream in autism, with significantly dampened subject oscillations between brain states, and dynamic connectivity configuration differences. Our account proposes specific motifs that may provide candidates for neuroimaging biomarkers within heterogeneous clinical populations in this diverse condition. PMID- 28652967 TI - Neural circuit of verbal humor comprehension in schizophrenia - an fMRI study. AB - Individuals with schizophrenia exhibit problems with understanding the figurative meaning of language. This study evaluates neural correlates of diminished humor comprehension observed in schizophrenia. The study included chronic schizophrenia (SCH) outpatients (n = 20), and sex, age and education level matched healthy controls (n = 20). The fMRI punchline based humor comprehension task consisted of 60 stories of which 20 had funny, 20 nonsensical and 20 neutral (not funny) punchlines. After the punchlines were presented, the participants were asked to indicate whether the story was comprehensible and how funny it was. Three contrasts were analyzed in both groups reflecting stages of humor processing: abstract vs neutral stories - incongruity detection; funny vs abstract - incongruity resolution and elaboration; and funny vs neutral - complete humor processing. Additionally, parametric modulation analysis was performed using both subjective ratings separately. Between-group comparisons revealed that the SCH subjects had attenuated activation in the right posterior superior temporal gyrus (BA 41) in case of irresolvable incongruity processing of nonsensical puns; in the left dorsomedial middle and superior frontal gyri (BA 8/9) in case of incongruity resolution and elaboration processing of funny puns; and in the interhemispheric dorsal anterior cingulate cortex (BA 24) in case of complete processing of funny puns. Additionally, during comprehensibility ratings the SCH group showed a suppressed activity in the left dorsomedial middle and superior frontal gyri (BA 8/9) and revealed weaker activation during funniness ratings in the left dorsal anterior cingulate cortex (BA 24). Interestingly, these differences in the SCH group were accompanied behaviorally by a protraction of time in both types of rating responses and by indicating funny punchlines less comprehensible. Summarizing, our results indicate neural substrates of humor comprehension processing impairments in schizophrenia, which is accompanied by fronto-temporal hypoactivation. PMID- 28652968 TI - Acute effects and after-effects of acoustic coordinated reset neuromodulation in patients with chronic subjective tinnitus. AB - Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As shown computationally, acoustic coordinated reset (CR) neuromodulation causes a long lasting desynchronization of pathological synchrony by downregulating abnormal synaptic connectivity. In a previous proof of concept study acoustic CR neuromodulation, employing stimulation tone patterns tailored to the dominant tinnitus frequency, was compared to noisy CR-like stimulation, a CR version significantly detuned by sparing the tinnitus-related pitch range and including substantial random variability of the tone spacing on the frequency axis. Both stimulation protocols caused an acute relief as measured with visual analogue scale scores for tinnitus loudness (VAS-L) and annoyance (VAS-A) in the stimulation-ON condition (i.e. 15 min after stimulation onset), but only acoustic CR neuromodulation had sustained long-lasting therapeutic effects after 12 weeks of treatment as assessed with VAS-L, VAS-A scores and a tinnitus questionnaire (TQ) in the stimulation-OFF condition (i.e. with patients being off stimulation for at least 2.5 h). To understand the source of the long-lasting therapeutic effects, we here study whether acoustic CR neuromodulation has different electrophysiological effects on oscillatory brain activity as compared to noisy CR-like stimulation under stimulation-ON conditions and immediately after cessation of stimulation. To this end, we used a single-blind, single application, cross over design in 18 patients with chronic tonal subjective tinnitus and administered three different 16-minute stimulation protocols: acoustic CR neuromodulation, noisy CR-like stimulation and low frequency range (LFR) stimulation, a CR type stimulation with deliberately detuned pitch and repetition rate of stimulation tones, as control stimulation. We measured VAS-L and VAS-A scores together with spontaneous EEG activity pre-, during- and post stimulation. Under stimulation-ON conditions acoustic CR neuromodulation and noisy CR-like stimulation had similar effects: a reduction of VAS-L and VAS-A scores together with a decrease of auditory delta power and an increase of auditory alpha and gamma power, without significant differences. In contrast, LFR stimulation had significantly weaker EEG effects and no significant clinical effects under stimulation-ON conditions. The distinguishing feature between acoustic CR neuromodulation and noisy CR-like stimulation were the electrophysiological after-effects. Acoustic CR neuromodulation caused the longest significant reduction of delta and gamma and increase of alpha power in the auditory cortex region. Noisy CR-like stimulation had weaker and LFR stimulation hardly any electrophysiological after-effects. This qualitative difference further supports the assertion that long-term effects of acoustic CR neuromodulation on tinnitus are mediated by a specific disruption of synchronous neural activity. Furthermore, our results indicate that acute electrophysiological after-effects might serve as a marker to further improve desynchronizing sound stimulation. PMID- 28652969 TI - Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients. AB - Cerebral plasticity-inducing approaches like repetitive transcranial magnetic stimulation (rTMS) are of high interest in situations where reorganization of neural networks can be observed, e.g., after stroke. However, an increasing number of studies suggest that improvements in motor performance of the stroke affected hand following modulation of primary motor cortex (M1) excitability by rTMS shows a high interindividual variability. We here tested the hypothesis that in stroke patients the interindividual variability of behavioral response to excitatory rTMS is related to interindividual differences in network connectivity of the stimulated region. Chronic stroke patients (n = 14) and healthy controls (n = 12) were scanned with functional magnetic resonance imaging (fMRI) while performing a simple hand motor task. Dynamic causal modeling (DCM) was used to investigate effective connectivity of key motor regions. On two different days after the fMRI experiment, patients received either intermittent theta-burst stimulation (iTBS) over ipsilesional M1 or control stimulation over the parieto occipital cortex. Motor performance and TMS parameters of cortical excitability were measured before and after iTBS. Our results revealed that patients with better motor performance of the affected hand showed stronger endogenous coupling between supplemental motor area (SMA) and M1 before starting the iTBS intervention. Applying iTBS to ipsilesional M1 significantly increased ipsilesional M1 excitability and decreased contralesional M1 excitability as compared to control stimulation. Individual behavioral improvements following iTBS specifically correlated with neural coupling strengths in the stimulated hemisphere prior to stimulation, especially for connections targeting the stimulated M1. Combining endogenous connectivity and behavioral parameters explained 82% of the variance in hand motor performance observed after iTBS. In conclusion, the data suggest that the individual susceptibility to iTBS after stroke is influenced by interindividual differences in motor network connectivity of the lesioned hemisphere. PMID- 28652970 TI - APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study. AB - Transgenic animal models of Abeta pathology provide mechanistic insight into some aspects of Alzheimer disease (AD) pathology related to Abeta accumulation. Quantitative neuroimaging is a possible aid to improve translation of mechanistic findings in transgenic models to human end phenotypes of brain morphology or function. Therefore, we combined MRI-based morphometry, MRS-based NAA-assessment and quantitative histology of neurons and amyloid plaque load in the APPswe/PS1dE9 mouse model to determine the interrelationship between morphological changes, changes in neuron numbers and amyloid plaque load with reductions of NAA levels as marker of neuronal functional viability. The APPswe/PS1dE9 mouse showed an increase of Abeta plaques, loss of neurons and an impairment of NAA/Cr ratio, which however was not accompanied with brain atrophy. As brain atrophy is one main characteristic in human AD, conclusions from murine to human AD pathology should be drawn with caution. PMID- 28652971 TI - Loss of integrity and atrophy in cingulate structural covariance networks in Parkinson's disease. AB - BACKGROUND: In Parkinson's disease (PD), the relation between cortical brain atrophy on MRI and clinical progression is not straightforward. Determination of changes in structural covariance networks - patterns of covariance in grey matter density - has shown to be a valuable technique to detect subtle grey matter variations. We evaluated how structural network integrity in PD is related to clinical data. METHODS: 3 Tesla MRI was performed in 159 PD patients. We used nine standardized structural covariance networks identified in 370 healthy subjects as a template in the analysis of the PD data. Clinical assessment comprised motor features (Movement Disorder Society-Unified Parkinson's Disease Rating Scale; MDS-UPDRS motor scale) and predominantly non-dopaminergic features (SEverity of Non-dopaminergic Symptoms in Parkinson's Disease; SENS-PD scale: postural instability and gait difficulty, psychotic symptoms, excessive daytime sleepiness, autonomic dysfunction, cognitive impairment and depressive symptoms). Voxel-based analyses were performed within networks significantly associated with PD. RESULTS: The anterior and posterior cingulate network showed decreased integrity, associated with the SENS-PD score, p = 0.001 (beta = - 0.265, etap2 = 0.070) and p = 0.001 (beta = - 0.264, etap2 = 0.074), respectively. Of the components of the SENS-PD score, cognitive impairment and excessive daytime sleepiness were associated with atrophy within both networks. CONCLUSIONS: We identified loss of integrity and atrophy in the anterior and posterior cingulate networks in PD patients. Abnormalities of both networks were associated with predominantly non-dopaminergic features, specifically cognition and excessive daytime sleepiness. Our findings suggest that (components of) the cingulate networks display a specific vulnerability to the pathobiology of PD and may operate as interfaces between networks involved in cognition and alertness. PMID- 28652973 TI - Influenza-associated seizures in healthy adults: Report of 3 cases. AB - To describe seizures occurring in 3 healthy adults with influenza infection. Seizures associated to influenza infection are rare in adults without encephalitis. Clinical observations of 3 healthy adult patients with influenza A and B infection and seizures. We present here 3 healthy adult patients with seizures related to influenza A or B infection without evidence encephalitis, encephalopathy or any other cause for seizures. Prognosis was excellent. Seizures can occur in healthy adults with influenza infection without evidence of encephalitis, a possibility to be borne in mind to avoid potentially harmful therapeutic and diagnostic procedures. PMID- 28652972 TI - In utero diffusion tensor imaging of the fetal brain: A reproducibility study. AB - Our purpose was to evaluate the within-subject reproducibility of in utero diffusion tensor imaging (DTI) metrics and the visibility of major white matter structures. Images for 30 fetuses (20-33. postmenstrual weeks, normal neurodevelopment: 6 cases, cerebral pathology: 24 cases) were acquired on 1.5 T or 3.0 T MRI. DTI with 15 diffusion-weighting directions was repeated three times for each case, TR/TE: 2200/63 ms, voxel size: 1 * 1 mm, slice thickness: 3-5 mm, b-factor: 700 s/mm2. Reproducibility was evaluated from structure detectability, variability of DTI measures using the coefficient of variation (CV), image correlation and structural similarity across repeated scans for six selected structures. The effect of age, scanner type, presence of pathology was determined using Wilcoxon rank sum test. White matter structures were detectable in the following percentage of fetuses in at least two of the three repeated scans: corpus callosum genu 76%, splenium 64%, internal capsule, posterior limb 60%, brainstem fibers 40% and temporooccipital association pathways 60%. The mean CV of DTI metrics ranged between 3% and 14.6% and we measured higher reproducibility in fetuses with normal brain development. Head motion was negatively correlated with reproducibility, this effect was partially ameliorated by motion-correction algorithm using image registration. Structures on 3.0 T had higher variability both with- and without motion correction. Fetal DTI is reproducible for projection and commissural bundles during mid-gestation, however, in 16-30% of the cases, data were corrupted by artifacts, resulting in impaired detection of white matter structures. To achieve robust results for the quantitative analysis of diffusivity and anisotropy values, fetal-specific image processing is recommended and repeated DTI is needed to ensure the detectability of fiber pathways. PMID- 28652974 TI - The draft genome sequence of Hymenobacter sp. CRA2 isolated from Nama Karoo shrub land soils from South Africa. AB - Here we report the draft genome sequence of Hymenobacter sp. CRA2 isolated from the Nama Karoo shrub land soils of the Northern Cape, South Africa. This genome is approximately 5.88 Mb long and the assembly comprised 45 contigs. The draft genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number NZ_MVBC00000000 and is available for download at: https://www.ncbi.nlm.nih.gov/nuccore/NZ_MVBC00000000.1. PMID- 28652975 TI - Draft genome sequence of Massilia sp. KIM isolated from South African grassland biome soils. AB - Massilia sp. are aerobic, Gram-negative, rod-shaped bacteria that are found in air, water, and soils. Here we describe the draft genome sequence of Massilia sp. KIM, isolated from the South African grassland soils. The total length of the genome was estimated at 5.73 Mb, comprised of 17 contigs. The draft genome has been deposited in the DDBJ/EMBL/GenBank under the accession MVAD10000000 and is available for download at: https://www.ncbi.nlm.nih.gov/nuccore/MVAD00000000. Additionally, the raw short reads are available in the NCBI SRA database under the accession number: SRR5469241. PMID- 28652977 TI - Variables influencing fluorimetric N-sulfoglucosamine sulfohydrolase (SGSH) activity measurement in brain homogenates. AB - Deficient N-sulfoglucosamine sulfohydrolase (SGSH) enzyme activity causes mucopolysaccharidosis (MPS) type IIIA. A fluorimetric SGSH activity assay is commonly used to examine patient cells. Here, we modified this method for brain homogenates and define the parameters for assay linearity. SGSH activity was suppressed outside of these parameters. This method will enable the accurate measurement of SGSH activity in MPS IIIA tissues to examine disease pathogenesis and evaluate therapies. PMID- 28652976 TI - Noninvasive real-time characterization of non-melanoma skin cancers with handheld optoacoustic probes. AB - Currently, imaging technologies that enable dermsurgeons to visualize non melanoma skin cancers (NMSC) in vivo preoperatively are lacking, resulting in excessive or incomplete removal. Multispectral optoacoustic tomography (MSOT) is a volumetric imaging tool to differentiate tissue chromophores and exogenous contrast agents, based on differences in their spectral signatures and used for high-resolution imaging of functional and molecular contrast at centimeter scale depth. We performed MSOT imaging with two- and three-dimensional handheld scanners on 21 Asian patients with NMSC. The tumors and their oxygenation parameters could be distinguished from normal skin endogenously. The lesion dimensions and depths were extracted from the spectral melanin component with three-dimensional spatial resolution up to 80 MUm. The intraclass correlation coefficient correlating tumor dimension measurements between MSOT and ex vivo histology of excised tumors, showed good correlation. Real-time 3D imaging was found to provide information on lesion morphology and its underlying neovasculature, indicators of the tumor's aggressiveness. PMID- 28652978 TI - Occipital condylar dysplasia in a Jacob lamb (Ovis aries). AB - Jacob sheep (Ovis aries) are a pedigree breed known for their "polycerate" (multihorned) phenotype. We describe a four-horned Jacob lamb that exhibited progressive congenital hindlimb ataxia and paresis, and was euthanased four weeks post-partum. Necropsy and CT-scan revealed deformity and asymmetry of the occipital condyles, causing narrowing of the foramen magnum and spinal cord compression. Histopathology demonstrated Wallerian degeneration of the cervical spinal cord at the level of the foramen magnum. These findings are consistent with occipital condylar dysplasia. This condition has been infrequently reported in the literature as a suspected heritable disease of polycerate Jacob sheep in the USA, and is assumed to arise during selection for the polycerate trait. This is the first reported case in European-bred Jacob sheep. Occipital condylar dysplasia should be considered as a differential diagnosis in polycerate Jacob lambs showing ataxia. It is important to raise awareness of this disease due to its suspected heritability and link to the popular polycerate trait. PMID- 28652979 TI - Metastatic intraocular hemangiopericytoma in a dog. AB - A 10-year-old Labrador Retriever who had been undergoing therapy for a recurrent hemangiopericytoma of the right flank presented to the Kansas State University Ophthalmology service for evaluation of a painful left eye. Examination revealed secondary glaucoma and irreversible blindness of the affected eye and multifocal chorioretinal lesions in the fellow eye. Therapeutic and diagnostic enucleation of the left eye was performed and histopathologic examination demonstrated the presence of a presumed metastatic spindle cell sarcoma. Further immunohistochemical staining confirmed the intraocular neoplasia to be metastatic spread from the previously removed flank mass. Rapid progression in size and number of chorioretinal lesions in the right eye was noted in the post-operative period until the patient was euthanized one month after surgery. This case report is the first to document intraocular metastasis of hemangiopericytoma in a veterinary patient. PMID- 28652980 TI - Treatment of hemorrhagic hepatic cysts with omentalization in a serval. AB - A 2 year old, spayed female African serval was evaluated for a history of abdominal distention. Physical examination findings were consistent with cranial abdominal masses and anemia. Abdominal imaging revealed soft tissue opacity masses in the cranial abdomen and hypoechoic cysts arising from the liver parenchyma. Conservative management failed to improve clinical signs, and a midline exploratory laparotomy was performed. Three large hemorrhagic cysts were visualized occupying a significant amount of the liver parenchyma. The cysts were drained, omentalized and partially closed with a surgical stapler and suture. Histopatological evaluation of the resected tissue was consistent with a chronic hepatic hematoma. The patient recovered well and was discharged 3 days postoperatively. Two years later, the patient was readmitted with the same clinical signs and large multiple hepatic cysts involving most of the liver lobes. These were surgically omentalized similarly to the previous surgery and the patient recovered well postoperatively. Two years later, return to normal life and no recurrence of the cysts was reported. PMID- 28652981 TI - Baseline values of immunologic parameters in the lizard Salvator merianae (Teiidae, Squamata). AB - The genus Salvator is widely distributed throughout South America. In Argentina, the species most abundant widely distributed is Salvator merianae. Particularly in Santa Fe province, the area occupied by populations of these lizards overlaps with areas where agriculture was extended. With the aim of established baseline values for four immunologic biomarkers widely used, 36 tegu lizards were evaluated tacking into account different age classes and both sexes. Total leukocyte counts were not different between age classes. Of the leucocytes count, eosinophils levels were higher in neonates compared with juvenile and adults; nevertheless, the heterophils group was the most prevalent leukocyte in the peripheral blood in all age classes. Lymphocytes, monocytes, heterophils, azurophils and basophils levels did not differ with age. Natural antibodies titres were higher in the adults compared with neonates and juveniles lizards. Lastly, complement system activity was low in neonates compared with juveniles and adults. Statistical analysis within each age group showed that gender was not a factor in the outcomes. Based on the results, we concluded that S. merianae demonstrated age (but not gender) related differences in the immune parameters analyzed. Having established baseline values for these four widely-used immunologic biomarkers, ongoing studies will seek to optimize the use of the S. merianae model in future research. PMID- 28652982 TI - Reactivity of commercially available monoclonal antibodies to human CD antigens with peripheral blood leucocytes of dromedary camels (Camelus dromedarius). AB - Monoclonal antibodies (mAbs) to cell surface molecules have been proven as a key tool for phenotypic and functional characterization of the cellular immune response. One of the major difficulties in studying camel cellular immunity consists in the lack of mAbs that dtect their leukocyte differentiation antigens. In the present study two-parameter flow cytometry was used to screen existing commercially available mAbs to human leukocyte antigens and major histocompatibility molecules (MHC) for their reactivity with camel leukocytes. The comparison of patterns of reactivity obtained after labelling human and camel leukocytes have shown that mAbs specific to human cluster of differentiation (CD) 18, CD11a, CD11b and CD14 are predicted to be cross-reactive with homologous camel antigens. PMID- 28652983 TI - Modulation of the innate immune responses in the striped snakehead murrel, Channa striata upon experimental infection with live and heat killed Aeromonas hydrophila. AB - It is well-known that the innate immune mechanisms in fish serve as the first line of defence against wide variety of pathogens. In most of the situations, innate responses get induced and enhanced after the pathogen invasion. It would be interesting to look into the inducibility of various innate immune mechanisms and the level of enhancement after infection with the pathogen. Hence, in the present investigation, modulation of the innate immune responses in the striped snakehead murrel, Channa striata on experimental challenge with either live virulent or heat killed Aeromonas hydrophila at a dose of 1x107 CFU (suspended in 0.2 mL PBS) were measured. Most of the non-specific (both humoral and cellular) immune responses tested were substantially induced or enhanced in both the experimental groups in comparison with the unchallenged control group. Significant increase in the lysozyme, total peroxidase, antiprotease and respiratory burst activities were observed after the pathogen challenge. Thus, most of the innate non-specific immune responses are inducible though they are constitutive of fish immune system exhibiting a basal level of activity even in the absence of pathogen challenge. PMID- 28652984 TI - Direct evidence of Rickettsia typhi infection in Rhipicephalus sanguineus ticks and their canine hosts. AB - Murine typhus is a rickettsiosis caused by Rickettsia typhi, whose transmission is carried out by rat fleas in urban settlements as classically known, but it also has been related to cat fleas in a sub-urban alternative cycle that has been suggested by recent reports. These studies remarks that in addition to rats, other animals like cats, opossums and dogs could be implied in the transmission of Rickettsia typhi as infected fleas obtained from serologically positive animals have been detected in samples from endemic areas. In Mexico, the higher number of murine typhus cases have been detected in the Yucatan peninsula, which includes a great southeastern region of Mexico that shows ecologic characteristics similar to the sub-urban alternative cycle recently described in Texas and California at the United States. To find out which are the particular ecologic characteristics of murine typhus transmission in this region, we analyzed blood and Rhipicephalus sanguineus ticks obtained from domestic dogs by molecular approaches, demonstrating that both samples were infected by Rickettsia typhi. Following this, we obtained isolates that were analyzed by genetic sequencing to corroborate this infection in 100% of the analyzed samples. This evidence suggests for the first time that ticks and dogs could be actively participating in the transmission of murine typhus, in a role that requires further studies for its precise description. PMID- 28652985 TI - Longevity of Cane Corso Italiano dog breed and its relationship with hair colour. AB - The Cane Corso Italiano belongs among the new dog breeds that were fully recognised by Federation Cynologique Internationale (FCI) in 2007. For the first time, this study describes a median lifespan using the data of 232 dogs of the Cane Corso Italiano breed collected from kennels and individual owners from 25 countries. The median lifespan of the whole examined group is 9.29 years (IQR 6.98-11.12, IQR = Interquartile Range). This paper is the first to describe the possible relationship between median lifespan and hair colour within one breed. The longest living group is formed by black brindle coloured dogs, with a median of 10.30 years (IQR 8.33-13.00), and brindle coloured dogs, with a median of 10.13 years (IQR 7.12-11.25). The median lifespan of black brindle dogs exceeded the overall median lifespan of all dogs by 1.01 year and the median lifespan of other colour dogs by 2.21 years. Our results suggest a possible way for a prolongation of age at death of the Cane Corso Italiano breed using appropriate breeding. The median lifespan of male Cane Corso Italiano dogs is 9.25 years (IQR 6.97-11.00) and female Cane Corso Italiano dogs 9.33 years (IQR 7.00-11.31). The statistical analysis using the Independent Samples Student's t test confirmed that the lifespan of female dogs did not exceed the median lifespan of male dogs (P>0.01). PMID- 28652986 TI - The first three years of Autopsy and Case Reports: an interesting journey. PMID- 28652987 TI - Aortic stenosis concomitant with microscopic polyangiitis: a challenge in medical reasoning and thinking. AB - Microscopic polyangiitis (MPA) is part of the anti-neutrophil cytoplasmic antibodies (ANCA)-related vasculitis, which usually presents as renal pulmonary syndrome. It is defined as a pauci-immune necrotizing small vessel vasculitis, which usually affects the kidneys, followed by the lungs. It also presents systemic symptoms. The etiology of MPA is still unclear, but evidence reinforces the autoimmune mechanisms as the main etiopathogenic factor. Aortic valve stenosis (AS) is not an uncommon disease whose etiology varies according to geographical differences and the patient's age. The natural history of AS begins with a prolonged asymptomatic period, but when symptomatic, respiratory failure is one of its main clinical presentations. The authors present the case of a 55 year-old woman who was admitted with the diagnosis of renal failure, anemia, and a cardiac murmur. The patient had been recently diagnosed with pneumonia. During hospitalization, diagnostic workup disclosed a normal kidney size as well as parenchymal thickness. A renal biopsy was undertaken but the specimen was exiguous, showing 4 sclerotic glomeruli and 1 glomerulus with crescentic glomerulonephritis. The search for ANCA was positive. The investigation of the cardiac murmur disclosed AS. The patient, on hemodialysis, presented episodes of respiratory failure, which was interpreted as acute pulmonary edema, but a suspicion of ANCA-related pulmonary renal syndrome was raised. However, the aortic valve replacement was prioritized. While awaiting cardiac surgery, the patient died because of respiratory insufficiency. Autopsy findings concluded that MPA with pulmonary hemorrhage due to vasculitis was the immediate cause of death. Although AS was present at autopsy and classified as moderate/severe, this lesion was a bystander in the process of this patient's end of life, demonstrating the value of autopsy for medical learning and reasoning purposes. PMID- 28652988 TI - Small-cell neuroendocrine carcinoma of the esophagus: an autopsy case report. AB - Small-cell neuroendocrine carcinoma is a well-known aggressive neoplasia, which is usually associated with a poor prognosis. The lung is the most common primary site, but other organs may be involved, especially those of the digestive tract. The authors report the case of a 71-year-old Caucasian, male patient who was admitted because of congestive heart failure and loss of vision accompanied by right proptosis. Skull and sinuses computed tomography showed a tumoral mass involving the posterior region of the right eye, local bones, and paranasal sinuses. Because of severe hemodynamic instability, the patient died and no diagnostic investigation could be performed. Autopsy findings revealed small-cell neuroendocrine carcinoma of the esophagus and metastases to the posterior region of the right ocular globe, which affected the sinuses, the muscles of the ocular region, the orbit bones, the skull, the meninges and the brain, plus the liver, adrenal glands, and the pericardium. This case called the author's attention to the extent of the metastatic disease in a patient who was firstly interpreted as presenting solely with congestive heart failure. The autopsy findings substantially aid the understanding of the immediate cause of death. PMID- 28652989 TI - Unusual clinical presentation of anaplastic large cell lymphoma. AB - Anaplastic large cell lymphoma (ALCL), a well-recognized entity, presents a varied clinical picture and epidemiological characteristics associated with the expression of the anaplastic lymphoma kinase (ALK) protein. When classic symptoms are present (weight loss, fever, and night sweats) and combine with enlarged and easily accessible peripheral lymph nodes, diagnosis is not that difficult. But when the clinical presentation is nonspecific, a tough diagnostic task is required. HIV infection is highly associated with neoplastic disorders-mainly with those of hematological origin. However, ALCL is exceptionally associated with HIV infection, and the few reported cases are ALK- ALCL. The authors report two cases of ALK+ ALCL with the unusual clinical presentation: one is associated with the HIV infection and the other presents as a fever of unknown origin (FUO) without peripheral lymphadenopathy. The latter was autopsied and was characterized by nodal and extra nodal involvement. The authors call attention to the plurality of clinical presentation of this group of lymphomas, and the early indication of bone marrow examination in cases of an FUO with elevated hepatic enzymes and lactic dehydrogenase. PMID- 28652990 TI - Adult-onset opsoclonus-myoclonus-ataxia syndrome as a manifestation of brazilian lyme disease-like syndrome: a case report and review of literature. AB - Described in 1962, the opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare, neurologically debilitating disorder with distinct characteristics that may begin in childhood or adult life. Although many cases remain without etiological diagnosis, others are related to neoplasms and infectious diseases. We report a 41-year-old previously healthy male with an 8-day history of headache, vertigo, nausea, vomiting, and nystagmus. After a normal brain computed tomography and lymphocytic pleocytosis in cerebral spinal fluid (CSF), intravenous acyclovir therapy was initiated in the emergency room. On the third day of hospitalization, the diagnosis of OMAS was made based on the presence of chaotic and irregular eye movements, dysarthric speech, gait instability, generalized tremor, and myoclonic jerks. In the face of his neurological worsening, ampicillin followed by nonspecific immunotherapy (methylprednisolone and intravenous immunoglobulin) was prescribed, with mild clinical improvement. After a thorough laboratory workup, the definite diagnosis of neuroborreliosis was established and ceftriaxone (4 g/daily/3 wks) and doxycycline (200 mg/day/2 mo) was administered. Toward the end of the ceftriaxone regimen, the neurologic signs substantially improved. We believe this to be the first case description of OMAS as clinical presentation of Brazilian Lyme disease-like syndrome (Baggio-Yoshinari syndrome). PMID- 28652991 TI - Granulosa cell tumor of the testis in a newborn. AB - Testicular neoplasms are uncommon tumors of childhood. These tumors comprise the germ cell tumors, and other tumors that may originate from histological testicular components, which are unrelated to the germinal lineage. Among the latter are the sex cord-stromal tumors (SCST), an important entity in newborns. SCSTs comprise, among others, granulosa cell tumors, which are more common in the ovary, but in rare cases may develop in the testis. The prognosis is excellent since it is universally benign. Diagnosis, which is sometimes challenging, is usually made after orchiectomy and pathological examination, which is characterized by morphological features and positive expression of inhibin, calretinin, and vimentin, and negative for alpha-fetoprotein. The authors present the case of a newborn with a right enlarged testis detected during the first examination after birth. Ultrasonography showed a heterogeneous solid/cystic mass in the right testis, without retroperitoneal lymphadenopathy. A right inguinal orchiectomy was performed 21 hours after birth. Pathologic examination revealed a juvenile granulosa cell tumor of the right testicle. After 4 years of follow-up, as expected, the child presented an uneventful outcome. PMID- 28652992 TI - Malignant paratesticular mesothelioma. AB - Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumor that usually affects patients after the sixth decade of life. Exposure to asbestos is a known risk factor. Enlargement of the scrotal volume is the most common initial clinical manifestation, and about 15% of cases present metastasis at diagnosis. The treatment relies on surgical resection while the role of adjuvant chemotherapy and radiotherapy remains unclear. The prognosis for patients is generally poor, with a lethal outcome in 30% over a 24-month period. The authors report a case of a 62-year-old patient with the diagnosis of MTVT without a history of asbestos exposure. After surgical treatment, metastatic disease ensued. Chemotherapy was initiated, but could not be continued due to marked and fast clinical deterioration. The authors call attention to the difficulty of early diagnosis of MTVT due to a nonspecific clinical picture, the lack of action by the patient when the scrotal enlargement was first noticed, and the lack of tumor markers. Delayed diagnosis is definitely related to unfavorable prognosis. PMID- 28652993 TI - Medullary carcinoma of the thyroid metastatic to the breast: a case report and literature review. AB - Breast malignancies, apart from skin cancer, are the leading cause of cancer from cancer among the female population. Unlike the high prevalence of primary mammary malignancies, metastases to the breast are uncommon, and account for only 0.2 2.7% of all malignancies affecting this organ. We report the case of a 35-year old woman who sought medical care because of a breast lump. A mammogram suggested a breast tumor, which was biopsied. The histopathological workup resulted in the diagnosis of a metastasis from a medullary thyroid cancer. The authors review the most useful clinical, radiological, histological, and immunohistochemical features concerning extramammary malignancy to the breast. PMID- 28652994 TI - Nasotracheal tube wire support: a safety device in maxillofacial surgery technical note after five years of experience. AB - A well fixed endotracheal tube is essential for safety during general anesthesia. In maxillofacial surgeries, securely fixing a nasotracheal tube in place has always been problematic. The aim of this article is to describe a simple but effective technique to fasten the nasotracheal tube using a wire support that allows a full range of head movement without interference in the surgical field. During the last 5 years, this device was successfully used in almost two hundred patients with very few complications. PMID- 28652995 TI - Ureteric carcinoma. PMID- 28652996 TI - Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia. AB - PURPOSE: Detrusor overactivity contributes to bothersome constellation of lower urinary tract symptoms (LUTS) in men and women as they age. However, the underlying mechanisms of non-obstructive detrusor overactivity and LUTS remain largely unknown. Growing evidence suggests that ischemia may be an independent factor in the development of non-obstructive bladder dysfunction. Our goal was to determine the effects of ischemia on detrusor function and voiding behavior and define redox-mediated cellular stress and cell survival signaling in the ischemic bladder. MATERIALS AND METHODS: Male Sprague Dawley rats were randomly divided into treatment (n=8) and control (n=8) groups. In the treatment group, iliac artery atherosclerosis and chronic bladder ischemia were induced. At 8 weeks after bladder ischemia, voiding patterns were examined in metabolic cages, cystometrograms were recorded in conscious animals, and then bladder blood flow was measured under general anesthesia. Bladder tissues were processed for assessment of transcription factors, markers of cellular and mitochondrial stress, mitochondrial respiration, and cell survival signaling pathway. RESULTS: Atherosclerotic occlusive disease spread from the common iliac arteries to the internal iliac and vesical arteries and produced sustained bladder ischemia. Studies in metabolic cages showed increased micturition frequency and decreased voided volume in bladder ischemia. Conscious cystometrograms produced consistent data showing significant increase in micturition frequency and decreased voided volume and bladder capacity. Voiding behavior and cystometric changes in bladder ischemia were associated with significant decrease in DNA binding activity of Nrf2, significant increase in cellular levels of stress protein Hsp70 and mitochondrial stress protein GRP75, and significant decrease in mitochondrial oxygen consumption and upregulation of PI3K and Akt expression. CONCLUSION: Chronic bladder ischemia may be a mediating variable in the development of detrusor overactivity in the non-obstructive bladder. The mechanism may involve ischemia-induced cellular stress, Nrf2 functional deficit, depression of mitochondrial respiration, and upregulation of PI3K/Akt cell survival signaling pathway. PMID- 28652997 TI - Neoadjuvant therapy prior to surgical resection for previously explored pancreatic cancer patients is associated with improved survival. AB - BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently referred to tertiary centers after unsuccessful attempted resections at other institutions. The outcome of these patients who are ultimately resected is not well understood. METHODS: We performed a retrospective review of patients with PDAC who underwent re-exploration between 1995 and 2013 at a single high volume tertiary care institution. We aimed to evaluate the association of neoadjuvant therapy prior to re-exploration on pathologic findings and clinical outcome in previously explored patients with PDAC. RESULTS: Between 1995 and 2013, 50 of the 2,062 patients who were surgically explored underwent pancreatic resection following a previous exploration where they were deemed unresectable. The most common reason for unresectability at initial operation was vascular invasion (80%) and a presumed R2 resection. Thirty-seven (74%) patients received neoadjuvant therapy. Neoadjuvant therapy was associated with improved TNM stage (P=0.002), fewer positive lymph nodes (0 vs. 2, P=0.025), and improved median survival (24 vs. 13 months, P=0.044). Compared to R2 resected patients with PDAC who had not previously been explored, re-explored patients had significantly lower pathologic T and N stages (P<0.001) and a longer median survival (19 vs. 10 months, P<0.001). CONCLUSIONS: Patients with PDAC deemed unresectable may warrant re-exploration. Treatment with neoadjuvant therapy between operations is associated with improved pathological stage and survival. In this highly selected group of patients, successful resection is associated with improved survival compared to R2 resections. PMID- 28652998 TI - Association of primary tumor lymph node ratio with burden of liver metastases and survival in stage IV colorectal cancer. AB - BACKGROUND: The primary objective of our study was to assess the association of primary tumor lymph node ratio (LNR) in stage IV colorectal adenocarcinomas (CRC) with overall survival (OS) and the extent of metastatic disease in the liver. METHODS: We analyzed data on 53 stage IV CRC patients who underwent surgical resection of the primary tumor. The median LNR of 0.25 was used to stratify patients into high LNR (H-LNR) and low LNR (L-LNR) groups. Statistical comparison was performed using chi square test and multiple regression models. OS was calculated using the Kaplan-Meier (KM) method while cox regression was used for multivariate analysis. RESULTS: H-LNR status was associated with the presence of >3 liver metastases (LM) [odds ratio (OR): 2.43, P=0.047] and bilobar LM (OR: 3.94, P=0.039). The OS in H-LNR patients was significantly worse in the entire cohort compared to L-LNR (9% vs. 34% at 3 years, P=0.027). The 5-year OS in patients undergoing liver resection for LM was also significantly worse in the H LNR group (0% vs. 37%, P=0.013). LNR was independently associated with survival on multivariate analysis [HR: 2.63; 95% confidence intervals (CI), 1.13-6.14; P=0.025]. CONCLUSIONS: In stage IV CRC, LNR is associated with the extent of hepatic tumor burden and was an independent predictor of survival in patients undergoing liver resection. PMID- 28652999 TI - Management of colorectal cancer with synchronous liver metastases: impact of multidisciplinary case conference review. AB - BACKGROUND: While no evidence exists to support mandatory multidisciplinary case conference (MCC) review for patients with synchronous colorectal cancer and liver metastases, this unique population may benefit greatly from multidisciplinary discussion. METHODS: We retrospectively identified patients who underwent liver resection with curative intent for colorectal liver metastases (CRLM) at a tertiary center between January 2008 and June 2015. The characteristics of patients discussed at a weekly regional MCC were examined, and the effect of MCC review on treatment approach was assessed. RESULTS: Sixty-six patients underwent elective surgery for synchronous colorectal cancer and liver metastases during the study period. Twenty-nine patients (44%) were presented at a MCC. Presentation was associated with greater likelihood of undergoing simultaneous or liver-first resection (P<=0.0001), with no difference in the extent of liver resection or location of primary tumor between the groups. A greater proportion of patients received chemotherapy and/or radiation following MCC discussion, without statistical significance. CONCLUSIONS: The treatment approach for patients with synchronous colorectal cancer and liver metastases may be significantly altered based on MCC review. Multidisciplinary discussion is advocated in order to facilitate equal access to individualized care. PMID- 28653000 TI - Updates in Mirizzi syndrome. AB - Mirizzi syndrome, known as extrinsic bile compression syndrome, is a rare complication of cholecystitis and chronic cholelithiasis, secondary to the obliteration of the infundibulum of the gallbladder or cystic duct caused by the impact of one or more calculations in these anatomical structures, which leads to compression of the adjacent bile duct, resulting in partial or complete obstruction of the common hepatic duct, triggering liver dysfunction. Our aim is to identify and describe the current epidemiology, diagnostic methods, and treatment of Mirizzi syndrome. A literature search was performed using different databases, including Medline, Cochrane, Embase, Medscape, PubMed, using keywords: Mirizzi syndrome, epidemiology, markers, pathophysiology, clinical presentation, diagnosis, and treatment. Selected original articles, review articles or case reports from 1997 to 2015 were collected, written in English or Spanish. The endoscopic retrograde cholangiopancreatography (ERCP) is the most accurate diagnostic method. The traditional treatment has been surgery and involves an incision at the bottom of the gallbladder and calculus removal. If fistulas are observed, it is performed a partial cholecystectomy; otherwise, a cholecystocholedochoduodenostomy is an alternative. Endoscopic treatment includes biliary drainage and stone extraction. Many surgeons claim that laparoscopic cholecystectomy is contraindicated in Mirizzi syndrome because of the presence of inflammatory tissue and adhesions in the Calot's triangle. If dissection is attempt, it can cause unnecessary injury to the bile duct. However, other surgeons consider the laparoscopic approach is feasible, although technically challenging. Currently, laparoscopic cholecystectomy for this condition is considered controversial and technically challenging; however, it has shown that with the right skills and equipment, it is a safe and feasible way to treat some cases of Mirizzi syndrome type I and II. PMID- 28653001 TI - Follicular dendritic cell sarcoma of the liver with metachronous small bowel and splenic metastases: a case report and literature review. AB - Follicular dendritic cell sarcoma (FDCS) of the liver is an extremely rare disease, accounting for a mere 0.4% of all soft tissue sarcomas. FDCS most commonly involves lymph nodes but also affects extranodal sites such as the gastrointestinal system, oral cavity, liver, spleen and pancreas, albeit less commonly. It is widely considered a low-to-intermediate grade malignancy. We report a case of FDCS with metachronous involvement of the liver, small intestines and spleen, its imaging, histological findings and its management. PMID- 28653002 TI - Window-of-opportunity: neonatal gut microbiota and atopy. PMID- 28653003 TI - Importance of sarcopenia parameter changes after living donor liver transplantation. PMID- 28653004 TI - Sarcopenia in liver transplant recipients: its relevance to peritransplant morbidity and mortality. PMID- 28653005 TI - Laparoscopic hepatectomy for hepatocellular carcinoma: are oncologic outcomes truly superior to an open approach? PMID- 28653006 TI - Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients: a potential game changer toward global standardization of care. PMID- 28653007 TI - A call for scientific integrity. PMID- 28653008 TI - Comments on "Liver resection using total vascular exclusion of the liver preserving the caval flow, in situ hypothermic portal perfusion and temporary porta-caval shunt: a new technique for central tumors". PMID- 28653009 TI - Multinodular liver involvement in Abernethy syndrome. PMID- 28653010 TI - Functional Near Infrared Spectroscopy, Part 1. PMID- 28653011 TI - Influence of study design on digital pathology image quality evaluation: the need to define a clinical task. AB - Despite the current rapid advance in technologies for whole slide imaging, there is still no scientific consensus on the recommended methodology for image quality assessment of digital pathology slides. For medical images in general, it has been recommended to assess image quality in terms of doctors' success rates in performing a specific clinical task while using the images (clinical image quality, cIQ). However, digital pathology is a new modality, and already identifying the appropriate task is difficult. In an alternative common approach, humans are asked to do a simpler task such as rating overall image quality (perceived image quality, pIQ), but that involves the risk of nonclinically relevant findings due to an unknown relationship between the pIQ and cIQ. In this study, we explored three different experimental protocols: (1) conducting a clinical task (detecting inclusion bodies), (2) rating image similarity and preference, and (3) rating the overall image quality. Additionally, within protocol 1, overall quality ratings were also collected (task-aware pIQ). The experiments were done by diagnostic veterinary pathologists in the context of evaluating the quality of hematoxylin and eosin-stained digital pathology slides of animal tissue samples under several common image alterations: additive noise, blurring, change in gamma, change in color saturation, and JPG compression. While the size of our experiments was small and prevents drawing strong conclusions, the results suggest the need to define a clinical task. Importantly, the pIQ data collected under protocols 2 and 3 did not always rank the image alterations the same as their cIQ from protocol 1, warning against using conventional pIQ to predict cIQ. At the same time, there was a correlation between the cIQ and task aware pIQ ratings from protocol 1, suggesting that the clinical experiment context (set by specifying the clinical task) may affect human visual attention and bring focus to their criteria of image quality. Further research is needed to assess whether and for which purposes (e.g., preclinical testing) task-aware pIQ ratings could substitute cIQ for a given clinical task. PMID- 28653012 TI - Optically tracked, single-coil, scanning magnetic induction tomography. AB - Recent work has shown that single-coil, magnetic induction tomography (MIT) is useful for visualizing three-dimensional electrical conductivity distributions within biological targets. Coil-induced eddy currents and the associated secondary field are detected as an inductive loss while the coil is relocated to several unique positions and orientations near a target. Image reconstruction is then accomplished by inversion of a convolution integral that quantitatively maps inductive loss with conductivity. Previously, coil position and orientation had to be established by a template, which required assignment of fixed locations for the coil to visit. Here, our existing device is modified so that coil position and orientation are optically tracked while measuring inductive loss. Optical tracking is accomplished via a set of infrared reflective spheres mounted on the same enclosure that supports the coil. The coil center can be tracked with submillimeter accuracy while orientation angle is known to within a fraction of a degree. This work illustrates the use of single-coil MIT in full, position orientation-tracked scan mode while imaging laboratory phantoms consisting of features having biologically relevant conductivity. PMID- 28653013 TI - Estimation of signal and noise for a whole-body research photon-counting CT system. AB - Photon-counting detector CT has a large number of acquisition parameters that require optimization, particularly the energy threshold configurations. Fast and accurate estimation of both signal and noise in photon-counting CT (PCCT) images can facilitate such optimization. Using the detector response function of a research PCCT system, we derived mathematical models for both signal and noise estimation, taking into account beam spectrum and filtration, object attenuation, water beam hardening, detector response, radiation dose, energy thresholds, and the propagation of noise. To determine the absolute noise value, a noise lookup table (LUT) for all available energy thresholds was acquired using a number of calibration scans. The noise estimation algorithm then used the noise LUT to estimate noise for scans with a variety of combination of energy thresholds, dose levels, and object attenuations. Validation of the estimation algorithms was performed on a whole-body research PCCT system using semianthropomorphic water phantoms and solutions of calcium and iodine. Clinical feasibility of noise estimation was assessed with scans of a cadaver head and a living swine. The algorithms achieved accurate estimation of both signal and noise for a variety of scanning parameter combinations. Maximum discrepancies were below 15%, while most errors were below 5%. PMID- 28653014 TI - Retrospective four-dimensional magnetic resonance imaging with image-based respiratory surrogate: a sagittal-coronal-diaphragm point of intersection motion tracking method. AB - A four-dimensional magnetic resonance imaging (4-D-MRI) technique with Sagittal Coronal-Diaphragm Point-of-Intersection (SCD-PoI) as a respiratory surrogate is proposed. To develop an image-based respiratory surrogate, the SCD-PoI motion tracking method is used for retrospective 4-D-MRI reconstruction. Single-slice sagittal MR cine was acquired at a location near the center of the diaphragmatic dome. Multiple-slice coronal MR cines were acquired for 4-D-MRI reconstruction. As a motion surrogate, the diaphragm motion was measured from the PoI among the sagittal MRI cine plane, coronal MRI cine planes, and the diaphragm surface. These points were defined as the SCD-PoI. This point is used as a one-dimensional diaphragmatic navigator in our study. The 4-D-MRI technique was evaluated on a 4 D digital extended cardiac-torso (XCAT) human phantom, a motion phantom, and seven human subjects (five healthy volunteers and two cancer patients). Motion trajectories of a selected region of interest were measured on 4-D-MRI and compared with the known XCAT motion that served as references. The mean absolute amplitude difference ([Formula: see text]) and the cross-correlation coefficient (CC) of the comparisons were determined. 4-D-MRI of the XCAT phantom demonstrated highly accurate motion information ([Formula: see text], [Formula: see text]). Motion trajectories of the motion phantom measured on 4-D-MRI matched well with the references ([Formula: see text], [Formula: see text]). 4-D-MRI of human subjects showed minimal artifacts and clearly revealed the respiratory motion of organs and tumor (mean [Formula: see text]; mean [Formula: see text]). A 4-D-MRI technique with image-based respiratory surrogate has been developed and tested on phantoms and human subjects. PMID- 28653015 TI - Classification of breast masses in ultrasound images using self-adaptive differential evolution extreme learning machine and rough set feature selection. AB - A method using rough set feature selection and extreme learning machine (ELM) whose learning strategy and hidden node parameters are optimized by self-adaptive differential evolution (SaDE) algorithm for classification of breast masses is investigated. A pathologically proven database of 140 breast ultrasound images, including 80 benign and 60 malignant, is used for this study. A fast nonlocal means algorithm is applied for speckle noise removal, and multiresolution analysis of undecimated discrete wavelet transform is used for accurate segmentation of breast lesions. A total of 34 features, including 29 textural and five morphological, are applied to a [Formula: see text]-fold cross-validation scheme, in which more relevant features are selected by quick-reduct algorithm, and the breast masses are discriminated into benign or malignant using SaDE-ELM classifier. The diagnosis accuracy of the system is assessed using parameters, such as accuracy (Ac), sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), Matthew's correlation coefficient (MCC), and area ([Formula: see text]) under receiver operating characteristics curve. The performance of the proposed system is also compared with other classifiers, such as support vector machine and ELM. The results indicated that the proposed SaDE algorithm has superior performance with [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] compared to other classifiers. PMID- 28653016 TI - Gland segmentation in prostate histopathological images. AB - Glandular structural features are important for the tumor pathologist in the assessment of cancer malignancy of prostate tissue slides. The varying shapes and sizes of glands combined with the tedious manual observation task can result in inaccurate assessment. There are also discrepancies and low-level agreement among pathologists, especially in cases of Gleason pattern 3 and pattern 4 prostate adenocarcinoma. An automated gland segmentation system can highlight various glandular shapes and structures for further analysis by the pathologist. These objective highlighted patterns can help reduce the assessment variability. We propose an automated gland segmentation system. Forty-three hematoxylin and eosin stained images were acquired from prostate cancer tissue slides and were manually annotated for gland, lumen, periacinar retraction clefting, and stroma regions. Our automated gland segmentation system was trained using these manual annotations. It identifies these regions using a combination of pixel and object level classifiers by incorporating local and spatial information for consolidating pixel-level classification results into object-level segmentation. Experimental results show that our method outperforms various texture and gland structure-based gland segmentation algorithms in the literature. Our method has good performance and can be a promising tool to help decrease interobserver variability among pathologists. PMID- 28653018 TI - Outrunning damage: Electrons vs X-rays-timescales and mechanisms. AB - Toward the end of his career, Zewail developed strong interest in fast electron spectroscopy and imaging, a field to which he made important contributions toward his aim of making molecular movies free of radiation damage. We therefore compare here the atomistic mechanisms leading to destruction of protein samples in diffract-and-destroy experiments for the cases of high-energy electron beam irradiation and X-ray laser pulses. The damage processes and their time-scales are compared and relevant elastic, inelastic, and photoelectron cross sections are given. Inelastic mean-free paths for ejected electrons at very low energies in insulators are compared with the bioparticle size. The dose rate and structural damage rate for electrons are found to be much lower, allowing longer pulses, reduced beam current, and Coulomb interactions for the formation of smaller probes. High-angle electron scattering from the nucleus, which has no parallel in the X-ray case, tracks the slowly moving nuclei during the explosion, just as the gain of the XFEL (X-ray free-electron laser) has no parallel in the electron case. Despite reduced damage and much larger elastic scattering cross sections in the electron case, leading to not dissimilar elastic scattering rates (when account is taken of the greatly increased incident XFEL fluence), progress for single-particle electron diffraction is seen to depend on the effort to reduce emittance growth due to Coulomb interactions, and so allow formation of intense sub-micron beams no larger than a virus. PMID- 28653017 TI - Automatic extraction of cell nuclei from H&E-stained histopathological images. AB - Extraction of cell nuclei from hematoxylin and eosin (H&E)-stained histopathological images is an essential preprocessing step in computerized image analysis for disease detection, diagnosis, and prognosis. We present an automated cell nuclei segmentation approach that works with H&E-stained images. A color deconvolution algorithm was first applied to the image to get the hematoxylin channel. Using a morphological operation and thresholding technique on the hematoxylin channel image, candidate target nuclei and background regions were detected, which were then used as markers for a marker-controlled watershed transform segmentation algorithm. Moreover, postprocessing was conducted to split the touching nuclei. For each segmented region from the previous steps, the regional maximum value positions were identified as potential nuclei centers. These maximum values were further grouped into [Formula: see text]-clusters, and the locations within each cluster were connected with the minimum spanning tree technique. Then, these connected positions were utilized as new markers for a watershed segmentation approach. The final number of nuclei at each region was determined by minimizing an objective function that iterated all of the possible [Formula: see text]-values. The proposed method was applied to the pathological images of the tumor tissues from The Cancer Genome Atlas study. Experimental results show that the proposed method can lead to promising results in terms of segmentation accuracy and separation of touching nuclei. PMID- 28653019 TI - Modeling nonequilibrium dynamics of phase transitions at the nanoscale: Application to spin-crossover. AB - In this article, we present a continuum mechanics based approach for modeling thermally induced single-nanoparticle phase transitions studied in ultrafast electron microscopy. By using coupled differential equations describing heat transfer and the kinetics of the phase transition, we determine the major factors governing the time scales and efficiencies of thermal switching in individual spin-crossover nanoparticles, such as the thermal properties of the (graphite) substrate, the particle thickness, and the interfacial thermal contact conductance between the substrate and the nanoparticle. By comparing the simulated dynamics with the experimental single-particle diffraction time profiles, we demonstrate that the proposed non-equilibrium phase transition model can fully account for the observed switching dynamics. PMID- 28653020 TI - Ultrafast carrier thermalization and trapping in silicon-germanium alloy probed by extreme ultraviolet transient absorption spectroscopy. AB - Semiconductor alloys containing silicon and germanium are of growing importance for compact and highly efficient photonic devices due to their favorable properties for direct integration into silicon platforms and wide tunability of optical parameters. Here, we report the simultaneous direct and energy-resolved probing of ultrafast electron and hole dynamics in a silicon-germanium alloy with the stoichiometry Si0.25Ge0.75 by extreme ultraviolet transient absorption spectroscopy. Probing the photoinduced dynamics of charge carriers at the germanium M4,5-edge (~30 eV) allows the germanium atoms to be used as reporter atoms for carrier dynamics in the alloy. The photoexcitation of electrons across the direct and indirect band gap into conduction band (CB) valleys and their subsequent hot carrier relaxation are observed and compared to pure germanium, where the Ge direct [Formula: see text] and Si0.25Ge0.75 indirect gaps ([Formula: see text]) are comparable in energy. In the alloy, comparable carrier lifetimes are observed for the X, L, and Gamma valleys in the conduction band. A midgap feature associated with electrons accumulating in trap states near the CB edge following intraband thermalization is observed in the Si0.25Ge0.75 alloy. The successful implementation of the reporter atom concept for capturing the dynamics of the electronic bands by site-specific probing in solids opens a route to study carrier dynamics in more complex materials with femtosecond and sub-femtosecond temporal resolution. PMID- 28653022 TI - Robust reconstruction of time-resolved diffraction from ultrafast streak cameras. AB - In conjunction with ultrafast diffraction, streak cameras offer an unprecedented opportunity for recording an entire molecular movie with a single probe pulse. This is an attractive alternative to conventional pump-probe experiments and opens the door to studying irreversible dynamics. However, due to the "smearing" of the diffraction pattern across the detector, the streaking technique has thus far been limited to simple mono-crystalline samples and extreme care has been taken to avoid overlapping diffraction spots. In this article, this limitation is addressed by developing a general theory of streaking of time-dependent diffraction patterns. Understanding the underlying physics of this process leads to the development of an algorithm based on Bayesian analysis to reconstruct the time evolution of the two-dimensional diffraction pattern from a single streaked image. It is demonstrated that this approach works on diffraction peaks that overlap when streaked, which not only removes the necessity of carefully choosing the streaking direction but also extends the streaking technique to be able to study polycrystalline samples and materials with complex crystalline structures. Furthermore, it is shown that the conventional analysis of streaked diffraction can lead to erroneous interpretations of the data. PMID- 28653021 TI - Ligand manipulation of charge transfer excited state relaxation and spin crossover in [Fe(2,2'-bipyridine)2(CN)2]. AB - We have used femtosecond resolution UV-visible and Kbeta x-ray emission spectroscopy to characterize the electronic excited state dynamics of [Fe(bpy)2(CN)2], where bpy=2,2'-bipyridine, initiated by metal-to-ligand charge transfer (MLCT) excitation. The excited-state absorption in the transient UV visible spectra, associated with the 2,2'-bipyridine radical anion, provides a robust marker for the MLCT excited state, while the transient Kbeta x-ray emission spectra provide a clear measure of intermediate and high spin metal centered excited states. From these measurements, we conclude that the MLCT state of [Fe(bpy)2(CN)2] undergoes ultrafast spin crossover to a metal-centered quintet excited state through a short lived metal-centered triplet transient species. These measurements of [Fe(bpy)2(CN)2] complement prior measurement performed on [Fe(bpy)3]2+ and [Fe(bpy)(CN)4]2- in dimethylsulfoxide solution and help complete the chemical series [Fe(bpy)N(CN)6-2N]2N-4, where N = 1-3. The measurements confirm that simple ligand modifications can significantly change the relaxation pathways and excited state lifetimes and support the further investigation of light harvesting and photocatalytic applications of 3d transition metal complexes. PMID- 28653023 TI - Electronic Cigarette Expectancies in Smokers with Psychological Distress. AB - OBJECTIVES: Very few studies have evaluated perceptions of electronic nicotine delivery systems (ENDS) among smokers with mental illness. This study assessed expectancies about the effects of smoking combustible cigarettes or using ENDS among current smokers with and without severe psychological distress (SPD). METHODS: We used a crowdsourcing system to survey 268 smokers on their expectancies for the effects of combustible cigarettes and ENDS. Positive expectancies assessed included negative affect reduction, stimulation, positive social effects and weight control, and negative expectancies included negative physical effects, negative psychosocial effects and future health concerns. RESULTS: Smokers with SPD had higher positive expectancies for weight control and social effects of both products compared to those without such distress, and higher expectancies for stimulation from combustible cigarettes compared to ENDS. All participants had significantly lower negative expectancies for ENDS compared to combustible cigarettes, with no significant differences between the groups. CONCLUSIONS: Smokers with SPD may be more vulnerable toward ENDS use, as they are for combustible cigarette use, due to greater positive expectancies of the products. Challenging positive expectancies may increase the efficacy of tobacco control efforts in this vulnerable population. PMID- 28653024 TI - Data for Korean college students' anxious and avoidant attachment, self compassion, anxiety and depression. AB - The data presented in this article are from 473 Korean college students' responses to an online survey consisting of measures of anxious and avoidant attachment (the Experiences in Close Relationships-Revised Scale: ECR-R), self compassion (Neff's Self-Compassion Scale: SCS), depression (the Center for Epidemiological Studies-Depression Scale: CES-D) and anxiety (the State-Trait Anxiety Inventory-the Trait Anxiety Scale: STAT-T). Each variable was measured by a Korean version of the instrument. Participants were recruited from three universities in South Korea: 288 were men and 185 were women; 199 were undergraduate and 273 were graduate students. The online program used to collect the data prompted for but did not require responses to items; 26 surveys were not completed, and data from these surveys were not included in the dataset. Major findings based on the data presented here are reported in the article "Insecure attachment and emotional distress: Fear of self-compassion and self-compassion as mediators" (Joeng et al., 2017) [1]. The data, an SPSS file, are included as supplementary material. PMID- 28653025 TI - Proteomics data on MAP Kinase Kinase 3 knock out bone marrow derived macrophages exposed to cigarette smoke extract. AB - This data article reports changes in the phosphoproteome and total proteome of cigarette smoke extract (CSE) exposed WT and MAP Kinase Kinase 3 knock out (MKK3 /-) bone marrow derived macrophages (BMDM). The dataset generated is helpful for understanding the mechanism of CSE induced inflammation and the role of MAP kinase signaling pathway. The cellular proteins were labeled with isobaric tags for relative and absolute quantitation (iTRAQ(r)) reagents and analyzed by LC MS/MS. The standard workflow module for iTRAQ(r) quantification within the Proteome Discoverer was utilized for the data analysis. Ingenuity Pathway Analysis (IPA) software and Reactome was used to identify enriched canonical pathways and molecular networks (Mannam et al., 2016) [1]. All the associated mass spectrometry data has been deposited in the Yale Protein Expression Database (YPED) with the web-link to the data: http://yped.med.yale.edu/repository/ViewSeriesMenu.do;jsessionid=6A5CB07543D8B529 AE8C3FCFE29471D?series_id=5044&series_name=MMK3+Deletion+in+MEFs. PMID- 28653026 TI - MONO, DI and TRI SSRs data extraction & storage from 1403 virus genomes with next generation retrieval mechanism. AB - Now a day's SSRs occupy the dominant role in different areas of bio-informatics like new virus identification, DNA finger printing, paternity & maternity identification, disease identification, future disease expectations and possibilities etc., Due to their wide applications in various fields and their significance, SSRs have been the area of interest for many researchers. In the SSRs extraction, retrieval algorithms are used; if retrieval algorithms quality is improved then automatically SSRs extraction system will achieve the most relevant results. For this retrieval purpose in this paper a new retrieval mechanism is proposed which will extracted the MONO, DI and TRI patterns. To extract the MONO, DI and TRI patterns using proposed retrieval mechanism in this paper, DNA sequence of 1403 virus genome data sets are considered and different MONO, DI and TRI patterns are searched in the data genome sequence file. The proposed Next Generation Sequencing (NGS) retrieval mechanism extracted the MONO, DI and TRI patterns without missing anything. It is observed that the retrieval mechanism reduces the unnecessary comparisons. Finally the extracted SSRs provide the useful, single view and useful resource to researchers. PMID- 28653027 TI - Primary cutaneous marginal zone lymphoma with leptomeningeal involvement and a durable response to rituximab. PMID- 28653028 TI - Green palmoplantar vesicular eruption in a patient with hyperbilirubinemia. PMID- 28653029 TI - An adolescent with granulomatous mycosis fungoides infiltrating skeletal muscle successfully treated with oral prednisone. PMID- 28653030 TI - Inflammatory melanoma in transit metastases with complete response to talimogene laherparepvec. PMID- 28653031 TI - The "hook effect" causing a negative pregnancy test in a patient with an advanced molar pregnancy. AB - *At high hCG levels in molar pregnancies, a "hook effect" can cause an artificially negative value.*Delay in diagnosis of a molar pregnancy due to the "hook effect" can lead to severe complications.*Suspicion of a molar pregnancy should be communicated so a diluted sample is used to quantify hCG. PMID- 28653032 TI - Paraneoplastic antigens as biomarkers for early diagnosis of ovarian cancer. AB - Paraneoplastic syndromes are a group of rare disorders that can be triggered by an abnormal immune response to proteins from tumors of the lung, ovary, lymphatics, or breast. Paraneoplastic clinical syndromes affect < 1% of patients with cancer; however, the frequency of subclinical levels of paraneoplastic autoantibodies in asymptomatic patients with cancer is unknown. Numerous studies have reported that ovarian cancer patients show signs of paraneoplastic neurological syndromes (PNSs) before or after their cancers are diagnosed. PNSs arise from a tumor-elicited immune response against onconeural antigens that are shared by tissues of nervous system, muscle, and tumor cells. Studies on the serum IgGs obtained from ovarian cancer patients have indicated the presence of onconeural antibodies in the absence of any PNS symptoms. The occurrence of PNSs is low in ovarian cancer patients and it can be accompanied by onconeural antibodies. The diagnosis of PNSs is accompanied by a suspicion of a malignant tumor such that neurologists typically refer such patients for a tumor diagnostic workup. There will be tremendous utility if subclinical levels (without paraneoplastic neurological symptoms or myositis) of these autoantibodies to paraneoplastic antigens can be exploited to screen asymptomatic high-risk patients for ovarian cancer, and used as biomarkers in immunoassays for the early detection or recurrence of ovarian cancer. Ovarian cancer overall survival is likely to be improved with early detection. Therefore, a panel of onconeural antigens that can detect paraneoplastic autoantibodies in patient sera should provide diagnostic utility for an earlier therapeutic intervention. Here we review the usefulness of PNS and other paraneoplastic syndromes and their association with paraneoplastic antigens to exploit these autoantibody biomarkers to form diagnostic multi-analyte panels for early detection of ovarian cancer. PMID- 28653033 TI - Neuroticism, depression, and anxiety traits exacerbate the state of cognitive impairment and hippocampal vulnerability to Alzheimer's disease. AB - INTRODUCTION: Certain personality traits are associated with higher risk of Alzheimer's disease, similar to cognitive impairment. The identification of biological markers associated with personality in mild cognitive impairment could advance the early detection of Alzheimer's disease. METHODS: We used hierarchical multivariate linear models to quantify the interaction between personality traits, state of cognitive impairment, and MRI biomarkers (gray matter brain volume, gray matter mean water diffusion) in the medial temporal lobe (MTL). RESULTS: Over and above a main effect of cognitive state, the multivariate linear model showed significant interaction between cognitive state and personality traits predicting MTL abnormality. The interaction effect was mainly driven by neuroticism and its facets (anxiety, depression, and stress) and was associated with right-left asymmetry and an anterior to posterior gradient in the MTL. DISCUSSION: Our results support the hypothesis that personality traits can alter the vulnerability and pathoplasticity of disease and therefore modulate related biomarker expression. PMID- 28653034 TI - Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer's disease dementia. AB - INTRODUCTION: Synaptic membrane formation depends on nutrients that fuel metabolic pathways for the synthesis of constituent phospholipids. Consequently, insufficient availability of such nutrients may restrict membrane formation and contribute to synaptic dysfunction in Alzheimer's disease (AD). We assessed whether blood and cerebrospinal fluid (CSF) concentrations of nutrients related to phospholipid synthesis differ among patients with AD, mild cognitive impairment (MCI), and control subjects. METHODS: Concentrations of uridine, choline, folate, homocysteine, and other related metabolites were analyzed in paired blood and CSF samples from subjects selected from the Amsterdam Dementia Cohort with AD (n = 150; age, 66 +/- 7 years; 37% female), MCI (n = 148; age, 66 +/- 8 years; 37% female), and control subjects (n = 148; age, 59 +/- 8 years; 38% female). RESULTS: Age- and gender-adjusted analysis of variance revealed different concentrations of circulating uridine, choline, and folate and CSF uridine, folate, and homocysteine (all P < .05) among the three diagnostic groups. Post hoc pairwise comparison showed that subjects with AD had lower CSF uridine, plasma choline and higher CSF homocysteine concentrations, whereas subjects with MCI had lower plasma and CSF uridine, serum and CSF folate, and higher CSF homocysteine concentrations compared with control subjects (all P < .05), with differences ranging from -11 to +22%. DISCUSSION: AD and MCI patients have lower levels of nutrients involved in phospholipid synthesis. The current observations warrant exploration of the application of nutritional strategies in the early stages of AD. PMID- 28653035 TI - A classification algorithm for predicting progression from normal cognition to mild cognitive impairment across five cohorts: The preclinical AD consortium. AB - INTRODUCTION: We established a method for diagnostic harmonization across multiple studies of preclinical Alzheimer's disease and validated the method by examining its relationship with clinical status and cognition. METHODS: Cognitive and clinical data were used from five studies (N = 1746). Consensus diagnoses established in each study used criteria to identify progressors from normal cognition to mild cognitive impairment. Correspondence was evaluated between these consensus diagnoses and three algorithmic classifications based on (1) objective cognitive impairment in 2+ tests only; (2) a Clinical Dementia Rating (CDR) of >=0.5 only; and (3) both. Associations between baseline cognitive performance and cognitive change were each tested in relation to progression to algorithm-based classifications. RESULTS: In each study, an algorithmic classification based on both cognitive testing cutoff scores and a CDR >=0.5 provided optimal balance of sensitivity and specificity (areas under the curve: 0.85-0.95). Over an average 6.6 years of follow-up (up to 28 years), N = 186 initially cognitively normal participants aged on average 64 years at baseline progressed (incidence rate: 15.3 people/1000 person-years). Baseline cognitive scores and cognitive change were associated with future diagnostic status using this algorithmic classification. DISCUSSION: Both cognitive tests and CDR ratings can be combined across multiple studies to obtain a reliable algorithmic classification with high specificity and sensitivity. This approach may be applicable to large cohort studies and to clinical trials focused on preclinical Alzheimer's disease because it provides an alternative to implementation of a time-consuming adjudication panel. PMID- 28653036 TI - Assessment of amyloid beta in pathologically confirmed frontotemporal dementia syndromes. AB - INTRODUCTION: The diagnostic utility of in vivo amyloid beta (Abeta) imaging to aid in the clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease remains unclear without data on the prevalence and severity of Abeta in pathologically confirmed FTD syndromes. METHODS: Abeta was assessed in 98 autopsy-confirmed FTD and 36 control cases, and the pathological accuracy of 11C-Pittsburgh compound B (PiB)-positron emission tomography imaging was assessed in a subset of FTD cases (n = 15). RESULTS: Abeta was identified in a similar proportion of FTD syndromes and age-matched controls and increases with age. Alzheimer's disease pathology was identified in all cases with high PiB retention and in one case with low PiB retention. We further demonstrate a strong regional correlation between volume fraction of histological Abeta with PiB standard uptake value ratio scaled to the white matter. DISCUSSION: The present study provides a pathologic reference to assist in the interpretation of in vivo assessments in FTD syndromes. PMID- 28653037 TI - A Case Study Examining Fixed Versus Randomized Criteria for Treating a Child With Conduct Problems and Callous-Unemotional Traits. AB - Children with conduct problems and callous unemotional traits (CPCU) seem to show a decreased response to behavioral treatment (Hawes, Price, & Dadds, 2014). It was hypothesized that children with CPCU may respond differently to behavior therapy when the target behavior criteria are fixed a priori versus when the target behavior criteria are randomly determined post hoc. A single-case study experiment was conducted as an initial step toward investigating this hypothesis. The study was conducted using a daily report card implemented in the context of an intensive behavioral summer treatment program. Results indicated that rates of negative behaviors were higher when rewards were delivered using randomly determined levels of target behaviors as compared to using fixed levels of target behaviors. Results suggest the importance of providing children with CPCU specific and predictable treatment goals when using contingency management procedures. Additional research that examines how children with CPCU react to components of behavioral treatment may help improve their response to behavior therapy. PMID- 28653038 TI - Interleukins and large domestic animals, a bibliometric analysis. AB - Interleukins have been well described in mice and humans. In large domestic animals the situation is drastically different and there is still a need for further researches aiming at identifying all the homologous interleukins and comparing their functions among species. We performed here a bibliometric analysis of all interleukins described in the literature in various large animal species to identify what is known so far and to underline where there is a need for new studies. Using indicators such as H index but also M quotient, A index, G index, GH ratio, and HG index we ranked 39 interleukins identified so far in bovine, caprine, equine, ovine, and porcine, the main large domestic animals. Indexes and ratio under investigations were higher for IL1, IL2, IL4, IL5, IL6, IL8, IL10, IL12, and IL18 than for other interleukins, particularly in bovine and porcine species and to a certain extent in equine species. Recently discovered interleukins presented low values for the different indexes, quotient, and ratio. Even some "old" interleukins showed low values highlighting the need for further developments in comparative immunology. For instance an interleukin such as IL4 demonstrated variation in its functions between species. In conclusion, this study provides the first bibliometric analysis dedicated to large domestic animal interleukins and underlines the need for more studies to fully determine the structure and the functions of interleukins in other mammal species. PMID- 28653039 TI - Statistical modeling of an integrated boiler for coal fired thermal power plant. AB - The coal fired thermal power plants plays major role in the power production in the world as they are available in abundance. Many of the existing power plants are based on the subcritical technology which can produce power with the efficiency of around 33%. But the newer plants are built on either supercritical or ultra-supercritical technology whose efficiency can be up to 50%. Main objective of the work is to enhance the efficiency of the existing subcritical power plants to compensate for the increasing demand. For achieving the objective, the statistical modeling of the boiler units such as economizer, drum and the superheater are initially carried out. The effectiveness of the developed models is tested using analysis methods like R2 analysis and ANOVA (Analysis of Variance). The dependability of the process variable (temperature) on different manipulated variables is analyzed in the paper. Validations of the model are provided with their error analysis. Response surface methodology (RSM) supported by DOE (design of experiments) are implemented to optimize the operating parameters. Individual models along with the integrated model are used to study and design the predictive control of the coal-fired thermal power plant. PMID- 28653040 TI - Prospective thinking and decision making in primary school age children. AB - In this study, we seek to widen our understanding of the developmental processes underlying bargaining behaviour in children addressing the concept of prospective thinking. We argue that the emergence of the capacity to think prospectively about future outcomes or behaviours in response to current actions is a required precedent to strategic decision making. To test this idea, we compared 6, 8 and 10 years old children's performance on three tasks: the ultimatum game assessing fairness/inequality aversion, the marshmallow task, an intertemporal choice task evaluating the ability to delay gratification, and the dictator game assessing altruism. The children's socio-demographic and cognitive variables were also evaluated. We hypothesized that development of strategic thinking in the ultimatum game is related to an increased ability to delay gratification - given that both tasks require looking at prospective benefits - and, crucially, not to altruism, which benefits from immediate selfless reward. Our results confirmed our hypothesis suggesting that increased strategic planning with age would also stem from the development of competencies like prospective thinking. PMID- 28653041 TI - Plasmodium falciparum genotypes in matched peripheral, placental and umbilical cord blood in an area characterised by unstable malaria transmission in eastern Sudan. AB - BACKGROUND: There are few published studies on Plasmodium falciparum genotypes in peripheral, placental and umbilical cord blood in areas characterised by unstable malaria transmission. METHOD: A cross-sectional study was conducted to investigate P. falciparum genotypes in matched peripheral, placental and umbilical cord blood in eastern Sudan. Thick blood smears and P. falciparum merozoite surface protein 1 (MSP1) and 2 (MSP2) genes as polymorphic markers in polymerase chain reactions were investigated in 3 kinds of samples of 153 pregnant women at delivery. RESULTS: There was no significant difference in the prevalence of blood film-detected P. falciparum in which 5 (3.3%), 7 (4.6%) and 3 (2.0%) (P = 0.437) of the 153 samples were determined to be P. falciparum positive by microscopy for maternal peripheral, placental and cord blood samples, respectively. Out of these 145 samples, 24 (16.6%), 39 (26.9%) and 24 (16.6%) (P = 0.039) of the peripheral, placental and cord samples, respectively, had submicroscopic parasitaemia (blood films were negative). There was no association between submicroscopic parasitaemia and age or parity. RO33 and K1 (MSP1 alleles) were detected in 21/29 (72.4%), 42/46 (85.7%), 26/27 (92.2%) and 6/29 (20.6), 16/46 (32.6) and 0(0) (P < 0.001) of the maternal, placental and cord samples, respectively. MAD20 was not detected in any of the samples. While the 3D7/IC1 allele was detected in 12 (41.3%), 30 (65.2%) and 4 (14.8%) (P < 0.001) of the peripheral, placental and cord samples, respectively, the FC (MSP2) allele was detected in only the 6 (20.6) placental samples. Multi-clonal infection was detected in 10 (34.4), 27 (58.6) and 3 (11.1) (P < 0.001) of the maternal placental and cord samples, respectively. CONCLUSION: Compared with the peripheral and cord samples, placental samples had a higher prevalence of submicroscopic parasitaemia. MSP1 alleles were predominant in the cord, while MSP2 alleles were predominant in the placental samples, which had a significant higher multiplicity of the infection. PMID- 28653042 TI - Mechanical properties in crumple-formed paper derived materials subjected to compression. AB - The crumpling of precursor materials to form dense three dimensional geometries offers an attractive route towards the utilisation of minor-value waste materials. Crumple-forming results in a mesostructured system in which mechanical properties of the material are governed by complex cross-scale deformation mechanisms. Here we investigate the physical and mechanical properties of dense compacted structures fabricated by the confined uniaxial compression of a cellulose tissue to yield crumpled mesostructuring. A total of 25 specimens of various densities were tested under compression. Crumple formed specimens exhibited densities in the range 0.8-1.3 g cm-3, and showed high strength to weight characteristics, achieving ultimate compressive strength values of up to 200 MPa under both quasi-static and high strain rate loading conditions and deformation energy that compares well to engineering materials of similar density. The materials fabricated in this work and their mechanical attributes demonstrate the potential of crumple-forming approaches in the fabrication of novel energy-absorbing materials from low-cost precursors such as recycled paper. Stiffness and toughness of the materials exhibit density dependence suggesting this forming technique further allows controllable impact energy dissipation rates in dynamic applications. PMID- 28653045 TI - Ultrasound Needle Visibility in Contrast Mode Imaging: An In Vitro and Ex Vivo Study. AB - PURPOSE: To evaluate needle visibility in ultrasound under contrast mode conditions. MATERIALS AND METHODS: Needle visibility was evaluated for bevel, EchoTip (r) and shaft of 18G Chiba biopsy needle with a 9 MHz linear probe (GE Logiq E9). Insertion angles varied between 30 degrees (steep) and 90 degrees (parallel to the probe surface). The acoustic output varied from 5-28%. 2 different contrast mode presets with either 'Amplitude Modulation' (Penetration) or 'Phase Inversion Harmonics' (High Resolution) were assessed. All other imaging parameters were kept constant. The visibility of bevel, EchoTip (r) and shaft was assessed for grayscale and color-coded images with a 3-point Likert-like scale (not, poorly, well visible) by 2 independent readers. The echogenicity of the needle bevel, EchoTip (r) and shaft was assessed in deciBel (dB) on the color coded images. RESULTS: With the parallel insertion angle, all needle areas were well visible. With steep insertion the EchoTip (r) was the only visible area. High Resolution was superior to Penetration (p<0.001). The visibility and echogenicity of the needle bevel ( rgrayscale =0.109, p grayscale =0.178; rcolor coded =0.236, p color-coded =0.266; rdB =0.956, p dB =0.001), EchoTip (r) ( rgrayscale += 0.477, p grayscale += 0.018; rcolor-coded =0.540, p color-coded += 0.006; rdB =0.911, p dB =0.001) and shaft ( rgrayscale =0.124, p grayscale =0.563; rcolor-coded =0.061, p color-coded += 0.775; rdB += 0.926, p dB =0.001) increased with increasing acoustic output. Grayscale images were superior to color-coded images for needle visibility (p=0.004). CONCLUSION: Parallel needle insertion, use of an echogenic tip, adequate choice of presets, increased acoustic output, and dual view of grayscale and color-coded images improve needle visibility in ultrasound under contrast mode conditions. PMID- 28653046 TI - Editorial: Dentistry inspired by nature. PMID- 28653044 TI - Neuroclinical Framework for the Role of Stress in Addiction. AB - Addiction has been conceptualized as a three-stage cycle-binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation-that worsens over time and involves allostatic changes in hedonic function via changes in the brain reward and stress systems. Using the withdrawal/negative affect stage and negative reinforcement as an important source of motivation for compulsive drug seeking, we outline the neurobiology of the stress component of the withdrawal/negative affect stage and relate it to a derivative of the Research Domain Criteria research construct for the study of psychiatric disease, known as the Addictions Neuroclinical Assessment. Using the Addictions Neuroclinical Assessment, we outline five subdomains of negative emotional states that can be operationally measured in human laboratory settings and paralleled by animal models. We hypothesize that a focus on negative emotionality and stress is closely related to the acute neurobiological alterations that are experienced in addiction and may serve as a bridge to a reformulation of the addiction nosology to better capture individual differences in patients for whom the withdrawal/negative affect stage drives compulsive drug taking. PMID- 28653047 TI - Noninvasive bilaminar CAD/CAM composite resin veneers: ?a semi-(in)direct approach. AB - Direct composite resin restorations have been recognized for their valuable clinical service and respect of intact hard tissue. The cost-effectiveness and inherent minimally invasive approach of resin-based materials means that they are also gaining popularity for use in computer-aided design/computer-aided manufacture (CAD/CAM) procedures. Several cases from the student clinics at the Herman Ostrow School of Dentistry of USC are presented that could have been resolved either with direct composite resin restorations or with indirect porcelain veneers. A novel semi-indirect CAD/CAM approach, characterized by its absolute noninvasiveness and simplicity, was chosen instead. The bilaminar restoration consists of a customized histoanatomical CAD/CAM dentin base (incisoproximal cutback), and a generic enamel skin. The patients can be treated either in one clinical session (semi-directly) or in two clinical sessions (semi indirectly). The purpose of this article is to present another tool from the anterior restorative armamentarium to bridge the gap between direct and indirect techniques. PMID- 28653043 TI - Bioactive polymeric scaffolds for tissue engineering. AB - A variety of engineered scaffolds have been created for tissue engineering using polymers, ceramics and their composites. Biomimicry has been adopted for majority of the three-dimensional (3D) scaffold design both in terms of physicochemical properties, as well as bioactivity for superior tissue regeneration. Scaffolds fabricated via salt leaching, particle sintering, hydrogels and lithography have been successful in promoting cell growth in vitro and tissue regeneration in vivo. Scaffold systems derived from decellularization of whole organs or tissues has been popular due to their assured biocompatibility and bioactivity. Traditional scaffold fabrication techniques often failed to create intricate structures with greater resolution, not reproducible and involved multiple steps. The 3D printing technology overcome several limitations of the traditional techniques and made it easier to adopt several thermoplastics and hydrogels to create micro-nanostructured scaffolds and devices for tissue engineering and drug delivery. This review highlights scaffold fabrication methodologies with a focus on optimizing scaffold performance through the matrix pores, bioactivity and degradation rate to enable tissue regeneration. Review highlights few examples of bioactive scaffold mediated nerve, muscle, tendon/ligament and bone regeneration. Regardless of the efforts required for optimization, a shift in 3D scaffold uses from the laboratory into everyday life is expected in the near future as some of the methods discussed in this review become more streamlined. PMID- 28653048 TI - Porcelain veneer post-bonding crack repair by resin infiltration. AB - Ceramic laminate veneer restorations are indicated in several clinical situations. Indirect restorations are usually chosen if the less-invasive options - bleaching, resin infiltration, or composite resin restorations - are not possible, or when it is too difficult to achieve an esthetically pleasing result in the long term. Bonded indirect partial restorations are highly dependent on their adhesive interface, as these thin restorations have a relatively low cohesive strength. Therefore, preservation of sound enamel, conditioning of the restorations and of the substrate, and luting procedures are of paramount importance for a successful outcome. Even when utmost care is taken during every step of the procedure, failures such as fractures, chipping, or marginal discoloration and defects sometimes occur. Only very few of these cases of failure are presented or are a subject of interest. In this case presentation, a fracture repair is performed using an infiltration technique with a resin composite material. PMID- 28653049 TI - Precision and security in restorative dentistry: the synergy of isolation and magnification. AB - It is often presumed that, since its introduction in 1864, the use of rubber dam in multiple dental procedures has increased. However, its use is not as widespread as one might expect. There still seem to be many obstacles that prevent clinicians from adopting it as a standard of care. Furthermore, it appears very difficult to scientifically prove the impact of its use on the final outcome of a given procedure. The fundamental idea of isolating the operatory field and preventing contamination is simple; the practical execution of it is more demanding. In this article, the authors not only focus on the essential criteria for predictable isolation, they also present an isolation strategy that can be translated into a step-by-step procedure. It is suggested that by adopting this strategy, clinicians can eliminate the most commonly experienced obstacles and optimize the full potential of isolation, even in extremely difficult clinical situations. PMID- 28653050 TI - eLABor_aid: a new approach ?to digital shade management. AB - Contemporary dental patients present with high expectations and demand seamless optical integration of restorative interventions. As a result, clinicians and technicians are required to develop methodologies that remain practical yet increase the accuracy and objectivity of shade analysis and estimation. There have been significant advances in digital technologies over the past 20 years, with digital photography being at the forefront. Digital photography has made an immediate and profound impact on applied clinical dentistry, primarily due to instantaneous image visualization and distribution. However, standardization protocols in terms of image acquisition and objective analysis remain equivocal. By utilizing reflective cross-polarized light digital photography with a standardized white balance gray reference card serving as the known reference, in conjunction with a specific digital single-lens reflex (DSLR) camera profile and digital photographic processing software working in the CIE L*a*b* (1976) color space, one can achieve standardized image acquisition and subsequent objective image analysis. The goal of this systematic approach is to identify the most efficient and effective means to generate consistent and optimum visual integration and restorative outcomes through numerical quantification, in order to enable clinicians and technicians to work predictably even when they are in different geographic locations. PMID- 28653051 TI - Posterior indirect adhesive ?restorations: updated indications ?and the Morphology Driven ?Preparation Technique. AB - The aim of this article is to identify the indications for adhesively cemented restorations and to provide a correct step-by-step protocol for clinicians. New cavity preparation principles are based on morphological considerations in terms of geometry (maximum profile line and inclination of cusp lines), and structure (dentin concavity and enamel convexity). In this article, we discuss previous preparation concepts that were not designed purely for adhesive restorations and were therefore not conservative enough or suitable for adhesive procedures. The novel cavity shape consists of continuous inclined plane cavity margins (hollow chamfer or concave bevel) on axial walls, whenever they are coronal to the equatorial tooth line. A 1.2 mm-thick butt-joint preparation is performed in the interproximal box and on the axial walls when the margins are apical to the equatorial line. The occlusal surface is anatomically prepared, free of slots and angles. The author's suggestion is to avoid shoulder finish line preparation around cusps, occlusal slots, and pins, as they are less conservative, incompatible with adhesive procedures, and involve unnecessary dentin exposure. The clinical advantages of this new "anatomic" preparation design are 1) improving adhesion quality (optimizing the cutting of enamel prisms, and increasing the available enamel surface); 2) minimizing dentin exposure; 3) maximizing hard tissue preservation (the cavity being designed for cementation with reinforced composite resins, improvement of flow, and removal of excess material); 4) optimization of esthetic integration due to the inclined plane design, which permits a better blending at the transition area between tooth and restoration. These preparation principles may be effectively used for all adhesively cemented restorations, both according to traditional concepts (inlay, onlay, overlay) and new ones (additional overlay, occlusal-veneer, overlay veneer, long-wrap overlay, adhesive crown). Thus, a balance between restoration and prosthodontics is created, which is characterized by a more conservative approach. PMID- 28653053 TI - Proceedings of the 12th Closed Meeting of the European Academy of Esthetic Dentistry (EAED), Cracow, September 23-24, 2016. PMID- 28653052 TI - Assessment of gingival symmetry with digital measuring tools and its reproducibility. AB - OBJECTIVE: The aim of this study was to investigate the accuracy of digital measuring tools to measure the position of gingival zeniths and to assess its reproducibility between different examiners. MATERIALS AND METHODS: A total of 108 subjects were photographed at the Louisiana State University School of Dentistry. The settings, positioning of the digital camera, and subjects' Frankfurt levels were standardized. A photograph was taken of the six anterior maxillary teeth of each subject, and their corresponding free gingival margins. Digital caliper measurements were taken intraorally from the zenith to the incisal edge of the right maxillary central incisor. A reference line was drawn across the screen on each image at the level of the zenith of tooth 8. Three calibrated examiners then measured the distance from the reference line to the zeniths of the other five anterior maxillary teeth. RESULTS/CONCLUSIONS: There was no statistically significant difference between the examiners regarding any of the measurements. Central incisors were at the same level in 84.24% of the subjects, and lateral incisors were within 0.5 mm of central incisors in only 58% of the subjects. Canine zeniths were within 0.5 mm of each other in 43% of the subjects. Only 28% of the subjects presented with zeniths of tooth 6 to tooth 11 within 0.5 mm of each other. Lateral incisors were at or beneath the line drawn from central incisors to cuspids in 90.8% of the subjects. Standardized digital photography taken with the aid of a stadiometer and used to evaluate esthetic parameters allowed for reproducible measurements. PMID- 28653054 TI - The Tissue Master Concept (TMC): innovations for alveolar ridge preservation. PMID- 28653055 TI - The application of rapid prototyping to improve bone reconstruction in immediate dentoalveolar restoration: a case report. AB - PURPOSE: This article describes the use of rapid prototyping (RP) for diagnosis, planning, and execution of the reconstruction of hard and soft tissue in socket defects using immediate dentoalveolar restoration (IDR). SUMMARY: In cases of tissue loss in anterior dental areas, esthetic rehabilitation poses a major challenge with respect to treatment planning with the goal of long-term tissue maintenance. The IDR technique consists of immediate reconstruction in a single procedure of bone and soft tissue around implants placed immediately after extraction, and prosthetic rehabilitation. As this procedure is immediate and flapless, the correct diagnosis of tissue loss and correct graft adaptation are mandatory. RP can increase the precision of the procedure, as demonstrated using a clinical case characterized by total loss of the buccal bone wall and gingival recession. The results were evaluated by clinical assessment, photography, radiography, cone beam computed tomography (CBCT), and prototyping. CONCLUSION: The application of RP facilitated the execution of IDR as it enabled more accurate diagnosis of the socket defect and more precise adaptation of the tissue graft. A clinical study should be conducted to evaluate the effects of RP on the clinical results of the IDR technique. PMID- 28653056 TI - Innovative treatment concepts in the rehabilitation of the worn dentition - clinical strategies outside the box. PMID- 28653057 TI - Potential of innovative digital technologies and CAD/CAM composites in complex cases with change in the VDO. PMID- 28653058 TI - Controlling selectivity in the Ullmann reaction on Cu(111). AB - Using a surface science approach, the selectivity in the Ullmann cross-coupling of aryl halides on Cu(111) has been understood and controlled. The binding strength of the reactants and repulsion between them dictates which organometallic intermediates form, and hence the product distribution. Cross coupling can be maximized at low reactant concentrations. PMID- 28653059 TI - A fast, highly sensitive and selective assay of iodide ions with single-stranded DNA-templated copper nanoparticles as a fluorescent probe for its application in Kunming mice samples. AB - The development of fast, sensitive, selective and flexible methods for the detection of iodide is highly demanded and is of great significance. In this work, single-stranded DNA-templated copper nanoparticles (ssDNA-CuNPs) generated by sodium ascorbate reduction of Cu2+ along the single-stranded DNA of poly-T were utilized as a fluorescent probe for the determination of iodide ions (I-). The detection scheme is based on the instant quenching of the fluorescence of ssDNA-CuNPs by iodide ions. I- can be quantified in the concentration range from 0.050 to 40 MUM and from 40 to 80 MUM, and the limit of detection is as low as 15 nM. This method provides a simple and convenient strategy for the biochemical assay of I-, which is also helpful for early diagnosis of related diseases. The establishment of a low cost and fast detection method would be particularly important in developing countries where medical supplies are lacking. PMID- 28653060 TI - Pd-catalyzed regioselective intramolecular direct arylation of 3 indolecarboxamides: access to spiro-indoline-3,3'-oxindoles and 5,11-dihydro-6H indolo[3,2-c]quinolin-6-ones. AB - We report regioselective intramolecular direct C-3 and C-2 arylations of the indole rings of N-(o-bromophenyl)-3-indolecarboxamides for diastereospecific production of spiro-indoline-3,3'-oxindoles and 5,11-dihydro-6H-indolo[3,2 c]quinolin-6-ones, respectively, under different reaction conditions and possibly involving two different pathways. PMID- 28653061 TI - A NiCo2O4@Ni-Co-Ci core-shell nanowire array as an efficient electrocatalyst for water oxidation at near-neutral pH. AB - It is attractive but still remains challenging to develop efficient water oxidation electrocatalysts working in a carbonate (Ci) electrolyte. In this communication, we report that a Ni-Co-Ci layer can be developed on a NiCo2O4 nanowire array supported on carbon cloth (NiCo2O4/CC) via electrochemical surface derivation of NiCo2O4. The resulting NiCo2O4@Ni-Co-Ci core-shell nanowire array on carbon cloth (NiCo2O4@Ni-Co-Ci/CC) exhibits high activity toward water oxidation in 1.0 M KHCO3 (K-Ci, pH = 8.3) with the overpotential requirement of 309 mV to drive 10 mA cm-2. NiCo2O4@Ni-Co-Ci/CC also shows long-term electrochemical stability for 20 h and a high turnover frequency of 0.464 mol O2 s-1 at an overpotential of 600 mV. PMID- 28653062 TI - Expeditious synthesis of pyrano[2,3,4-de]quinolines via Rh(iii)-catalyzed cascade C-H activation/annulation/lactonization of quinolin-4-ol with alkynes. AB - Rh(iii)-catalyzed cascade C-H activation/annulation/lactonization of quinoline-4 ols and alkynes has been reported. A broad range of tetracyclic pyrano[2,3,4 de]quinolines have been prepared in one-step with good functional group tolerance, excellent site selectivity, and high efficiency. PMID- 28653063 TI - Layered perovskite LiEuTiO4 as a 0.8 V lithium intercalation electrode. AB - ~1 V lithium intercalation materials are promising anodes for lithium-ion batteries, because such materials give consideration to both the tolerance of lithium plating (e.g., graphite with ~0.1 V versus Li+/Li easily results in lithium plating due to a too low potential) and the energy density of the batteries (e.g., Li4Ti5O12 with ~1.55 V decreases the battery voltage, and thus reduces the energy density). Herein, the layered perovskite compound LiEuTiO4 with a 0.8 V lithium intercalation/deintercalation potential plateau was successfully synthesized by the ion-exchange reaction with NaEuTiO4 prepared via a sol-gel method. LiEuTiO4 can deliver a high capacity of 219.2 mA h g-1 (2nd discharge) at a rate of 100 mA g-1. Even after 500 cycles, the discharge capacity remains at ~217 mA h g-1 and the Coulombic efficiency is 99.2%. To our knowledge, the cycle stability of LiEuTiO4 exceeds all previous ~1 V electrodes. Different from the common lithium intercalation Ti-based electrodes (such as Li4Ti5O12) based on the reduction of the Ti4+ to Ti3+, electrochemical lithium intercalation into LiEuTiO4 leads to the reduction of the Eu3+ to Eu2+. PMID- 28653064 TI - Efficient simulation of ultrafast magnetic resonance experiments. AB - Magnetic resonance spectroscopy and imaging experiments in which spatial dynamics (diffusion and flow) closely coexists with chemical and quantum dynamics (spin spin couplings, exchange, cross-relaxation, etc.) have historically been very hard to simulate - Bloch-Torrey equations do not support complicated spin Hamiltonians, and the Liouville-von Neumann formalism does not support explicit spatial dynamics. In this paper, we formulate and implement a more advanced simulation framework based on the Fokker-Planck equation. The proposed methods can simulate, without significant approximations, any spatio-temporal magnetic resonance experiment, even in situations when spatial motion co-exists intimately with quantum spin dynamics, relaxation and chemical kinetics. PMID- 28653065 TI - CrIII as an alternative to RuII in metallo-supramolecular chemistry. AB - Compared to divalent ruthenium coordination complexes, which are widely exploited as parts of multi-component photonic devices, optically active trivalent chromium complexes are under-represented in multi-metallic supramolecular architectures performing energy conversion mainly because of the tricky preparation of stable heteroleptic CrIII building blocks. We herein propose some improvements with the synthesis of a novel family of kinetically inert heteroleptic bis-terdentate mononuclear complexes, which can be incorporated into dinuclear rod-like dyads as a proof-of-concept. The mechanism and magnitude of intermetallic CrCr communication have been unraveled by a combination of magnetic, photophysical and thermodynamic investigations. Alternated aromatic/alkyne connectors provided by Sonogashira coupling reactions emerge as the most efficient wires for long distance communication between two chromium centres bridged by Janus-type back-to back bis-terdentate receptors. PMID- 28653066 TI - On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging. AB - Organometallic compounds currently occupy an important place in the field of medicinal inorganic chemistry due to the unique chemical properties of metal coordination compounds. Particularly, metal compounds ligated by N-heterocyclic carbenes (NHC) have shown high potential for biomedical applications as antimicrobial and anticancer agents during the recent 15 years. Although further studies are necessary to validate the modes of action of this family of compounds, a number of biological targets have been identified, including DNA secondary structures. This perspective review aims at providing an overview of the most representative examples of metal NHC complexes reacting with nucleic acids via different binding modes. It is organized according to the type of DNA secondary structure targeted by metal NHCs, highlighting the possible advantages of biomedical applications, including therapy and imaging. PMID- 28653067 TI - Thermal decomposition pathways of nitro-functionalized metal-organic frameworks. AB - The decomposition behavior of high energy metal-organic frameworks (MOFs) with extensive nitration is disclosed. In contrast to the detonation behavior observed in molecular energetic compounds, deflagration transforms cubic MOFs into anisotropic carbon structures with highly dispersed metal. Both the structural metal and intimate mixing are found to be critical. PMID- 28653069 TI - Understanding the polymorphism-dependent emission properties of molecular crystals using a refined QM/MM approach. AB - A refined QM/MM approach demonstrated that a monomer model is suitable for describing the emission spectra of crystals without the pipi stacking interaction. Whereas for the crystals with notable intermolecular pipi stacking interaction, the most stable trimer model (or at least a dimer model) should be used for accurately describing the corresponding emission spectra. This approach is applied to understand the emission properties of two kinds of organic polymorphs. PMID- 28653070 TI - Colloidal diffusion over a quenched two-dimensional random potential. AB - A two-layer colloidal system is developed for the study of diffusion over a quenched two-dimensional random potential. A mixture of bidisperse silica spheres is used to form a randomly packed colloidal monolayer on the bottom substrate. The corrugated surface of the bottom colloidal monolayer provides a gravitational potential field for the dilute diffusing particles in the top layer. The population probability histogram P(x,y) of the diffusing particles is obtained to fully characterize the random potential landscape U(x,y) via the Boltzmann distribution. The dynamical properties of the top diffusing particles, such as their mean square displacement (MSD), histogram of the escape time, and long-time self-diffusion coefficient, are simultaneously measured from the particle trajectories. A quantitative relationship between the long-time diffusion coefficient and the random potential is obtained, which is in good agreement with the theoretical prediction. The measured MSD reveals a wide region of subdiffusion resulting from the structural disorders. The crossover from subdiffusion to normal diffusion is explained by the Lorentz model for tracer diffusion through a heterogeneous space filled with a set of randomly distributed obstacles. PMID- 28653071 TI - Correction: Systematic investigation of the SERS efficiency and SERS hotspots in gas-phase deposited Ag nanoparticle assemblies. AB - Correction for 'Systematic investigation of the SERS efficiency and SERS hotspots in gas-phase deposited Ag nanoparticle assemblies' by L. B. He et al., Phys. Chem. Chem. Phys., 2017, 19, 5091-5101. PMID- 28653072 TI - From graphite to interconnected reduced graphene oxide: one-pot synthesis and supercapacitor application. AB - An innovative one-pot approach for the scalable production of novel interconnected reduced graphene oxide (IC-RGO) is demonstrated, and we name it the streamlined Hummers method (SHM). The formed IC-RGO represents a new type of three-dimensional platform, promising for many graphene related energy, environmental and medical applications. PMID- 28653068 TI - Targeting heparin and heparan sulfate protein interactions. AB - Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged glycans play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. These biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection. PMID- 28653073 TI - Electro-mechano responsive properties of gelatin methacrylate (GelMA) hydrogel on conducting polymer electrodes quantified using atomic force microscopy. AB - Electrical stimulation of hydrogels has been performed to enable micro-actuation or controlled movement of ions and biomolecules such as in drug release applications. Hydrogels are also increasingly used as low modulus, biocompatible coatings on electrode devices and thus are exposed to the effects of electrical stimulation. As such, there is growing interest in the latter, especially on the dynamic and nanoscale physical properties of hydrogels. Here, we report on the electro-mechano properties of photocrosslinkable gelatin methacrylate (GelMA) hydrogel applied as coatings on conducting polymer polypyrrole-dodecylbenze sulfonate (PPy-DBSA) electrodes. In particular, Electrochemical-Atomic Force Microscopy (EC-AFM) was used to quantify the nanoscale actuation and dynamic changes in Young's modulus as the GelMA coating was electrically stimulated via the underlying PPy-DBSA electrode. Pulsed electrical stimulation was shown to induce dynamic expansion and contraction, or nanoscale actuation, of the GelMA hydrogel due to the reversible ingress of electrolyte ions and associated changes in osmotic pressure during oxidation and reduction of the PPy-DBSA film. In addition, dynamic changes in the Young's modulus of up to 50% were observed in the hydrogel and correlated with the actuation process and ion diffusion during oxidation and reduction of the underlying PPy-DBSA film. These dynamic properties were investigated for hydrogels with varying degrees of cross-linking, porosity and modulus, the latter ranging from ~0.2-1 kPa. The study demonstrates an AFM based approach to quantify the dynamic physical properties of hydrogels, which are shown to be modulated via electrical stimulation. This can enable a better understanding of the electro-mechano mechanisms that are important for the controlled release of drugs or controlling cell interactions at the hydrogel-cell interface. PMID- 28653074 TI - Parameterization of a coarse-grained model with short-ranged interactions for modeling fuel cell membranes with controlled water uptake. AB - The design of polymer electrolyte membranes with controlled water uptake is of high importance for high-performance fuel cells, because the water content of the membranes modulates their conductivity, chemical stability and mechanical strength. The water activity aw controls the equilibrium water uptake of a system. Predicting aw of materials is currently a daunting challenge for molecular simulations, because calculations of water activity require grand canonical simulations that are extremely expensive even with classical non polarizable force fields. Moreover, force fields do not generally reproduce aw of solutions. Here, we first present a general strategy to parameterize force fields that reproduce the experimental aw of solutions, and then implement that strategy to re-parameterize the interactions in FFcomp, a coarse-grained model for hydrated polyphenylene oxide/trimethylamine chloride (PPO/TMACl) membranes in which the TMA cation is attached to the PPO backbone and the Cl anion is in the mobile water nanophase. Coarse-grained models based on short-ranged potentials successfully model fuel cell membranes and other concentrated aqueous electrolyte solutions because electrostatic interactions are highly screened in these systems. The new force field, FFpvap, differs from the original FFcomp only in the parameters of the ion-ion interactions, yet it reproduces aw in TMACl solutions with accuracy within 0.5 and 3% of the experimental value in all the concentration range relevant to the operation of fuel cell membranes. We find that the heat needed to vaporize water in solutions with as little as five water molecules per ion pair is essentially the same as in pure water, despite the strong water-ion interactions and their impact on the water activity. We review the literature to demonstrate that this is independent of the model and a general feature of water solutions. FFpvap reproduces the radial distribution functions and captures well the relative diffusivities of water and ions in the ionic solution as predicted by the reference atomistic GAFF-TIP4P/2005 model, while providing a hundred-fold gain in computing efficiency with respect to the atomistic model. With the backbone fragments inherited from FFcomp, the new FFpvap force field can be used to model hydrated polymer electrolyte membranes and advance the design of fuel cell membranes with controlled water uptake and conductivity. PMID- 28653075 TI - Controllable porosity conversion of metal-organic frameworks composed of natural ingredients for drug delivery. AB - Two extremely rare beta-cyclodextrin (beta-CD) supported metal-organic frameworks (MOFs), CD-MOF-1 and CD-MOF-2, were induced to crystallize for the first time through a template-induced approach. The targeted CD-MOFs were employed to perform controlled drug delivery and cytotoxicity assays that confirmed their favourable biological potential of being used as drug carriers. PMID- 28653076 TI - Reversible crystal-to-crystal transformation from a trinuclear cluster to a 1D chain and the corresponding spin crossover (SCO) behaviour change. AB - Reversible crystal-to-crystal transformation between a linear trinuclear Fe(ii) complex [Fe3(NH2-trz)6(SCN)5(H2O)] (SCN).4H2O (1, NH2-trz = 4-amino-1,2,4 triazole) and a 1D chain [Fe3(NH2-trz)6(SCN)5]n(SCN)n (1a) and the SCO behaviour change have been studied by X-ray single-crystal diffraction, magnetic measurements and DSC. Complex 1a exhibits one more SCO step at a low temperature. PMID- 28653077 TI - Work-related biomechanical exposure and job strain in midlife separately and jointly predict disability after 28 years: a Finnish longitudinal study. AB - Objectives We investigated whether the extent of biomechanical exposures and job strain in midlife separately and jointly predict disability in old age. Methods Participants of the Finnish Longitudinal Study on Aging Municipal Employees (FLAME) in 1981 (aged 44-58 years) responded to disability questionnaires in 2009 (1850 women and 1082 men). Difficulties in performing five activities of daily living (ADL) and seven instrumental ADL (IADL) were used to assess severity of disability (score range: 0-12, 0=no disability). Information on biomechanical exposures and job strain was collected by questionnaire at baseline. Adjusted prevalence proportion ratios (PR) and 95% confidence intervals (95% CI) were modelled using mixed negative binomial regression with robust variance. The joint effect of two exposures was quantified using the concept of relative excessive risk due to interaction (RERI). Results The overall prevalence of disability (score: 1-12) was 46.7% (women: 41%; men: 57%). Compared to low-level exposures in an adjusted model, the PR of high baseline biomechanical exposures for each one unit increase in the disability score was 1.31 (95% CI 1.10-1.55) and PR of high job strain was 1.71 (95% CI 1.26-2.32). Associations were rather similar in gender-stratified analyses. Furthermore, the joint effect (high strain/high biomechanical) was multiplicative (women: PR 1.32, 95% CI 1.21-1.45; men: PR 1.27, 95% CI 1.13-1.44), but no additive effect was observed when fully adjusted. Conclusion High biomechanical exposure and job strain in midlife were strongly associated with the severity of disability in later life. The workplace could serve as arena for preventive interventions regarding disability in old age. PMID- 28653078 TI - MRI characteristics of torn and untorn post-operative menisci. AB - OBJECTIVE: To compare magnetic resonance imaging (MRI) characteristics of torn and untorn post-operative menisci. METHODS: The study group consisted of 140 patients with 148 partially resected menisci who were evaluated with a repeat knee MRI examination and subsequent repeat arthroscopic knee surgery. Two musculoskeletal radiologists retrospectively assessed the following MRI characteristics of the post-operative meniscus: contour (smooth or irregular), T2 line through the meniscus (no line, intermediate signal line, intermediate-to high signal line, and high fluid-like signal line), displaced meniscus fragment, and change in signal pattern through the meniscus compared with baseline MRI. Positive predictive values (PPV) and negative predictive values (NPV) were calculated using arthroscopy as the reference standard. RESULTS: All 36 post operative menisci with no T2 line were untorn at surgery (100% NPV), whereas 46 of the 79 post-operative menisci with intermediate T2 line, 16 of the 18 post operative menisci with intermediate-to-high T2 line, and 14 of the 15 post operative menisci with high T2 line were torn at surgery (58.2%, 88.9%, and 93.3% PPV respectively). Additional MRI characteristics associated with torn post operative meniscus at surgery were irregular meniscus contour (PPV 85.7%), displaced meniscus fragment (PPV 100%), and change in signal pattern through the meniscus (PPV 99.4%). CONCLUSIONS: Post-operative menisci with no T2 signal line were untorn at surgery. The most useful MRI characteristics for predicting torn post-operative menisci at surgery were change in signal pattern through the meniscus compared with baseline MRI, and displaced meniscus fragment followed by high T2 line through the meniscus, intermediate-to-high T2 line through the meniscus, and irregular meniscus contour. PMID- 28653079 TI - Naloxone effects on extinction of ethanol- and cocaine-induced conditioned place preference in mice. AB - RATIONALE: Previous studies found that naloxone (NLX) facilitated choice extinction of ethanol conditioned place preference (CPP) using long (60 min) test sessions, but there is little information on the variables determining this effect. OBJECTIVES: These studies examined repeated exposure to NLX during extinction of ethanol- or cocaine-induced CPP using both short and long tests. METHODS: DBA/2J mice were injected with NLX (0 or 10 mg/kg) before three 10- or 60-min choice extinction tests (experiment 1). All mice received a final 60-min test without NLX. Post-test NLX was given in experiment 2. Experiment 3 tested whether NLX would affect a forced extinction procedure. Experiment 4 tested its effect on extinction of cocaine-induced CPP. RESULTS: Pre-test (but not post test) injections of NLX-facilitated choice extinction of ethanol CPP at both test durations. Pre-test NLX also facilitated forced extinction. However, pre-test NLX had no effect on choice extinction of cocaine CPP. CONCLUSIONS: Extinction test duration is not critical for engaging the opioid system during ethanol CPP extinction (experiment 1). Moreover, NLX's effect does not depend on CPP expression during extinction, just exposure to previously conditioned cues (experiment 3). The null effect of post-test NLX eliminates a memory consolidation interpretation (experiment 2) and the failure to alter cocaine CPP extinction argues against alteration of general learning or memory processes (experiment 4). Overall, these data suggest that the endogenous opioid system mediates a conditioned motivational effect that normally maintains alcohol induced seeking behavior, which may underlie the efficacy of opiate antagonists in the treatment of alcoholism. PMID- 28653081 TI - Erratum to: Reward functions of the basal ganglia. PMID- 28653080 TI - Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self administration: a RNA sequencing study. AB - INTRODUCTION: Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain. OBJECTIVES: The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice. METHOD: Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration procedure (4 h/day, 0.25 mg/kg/infusion, FR1) and were euthanized 1 h after the last session. The dorsal and ventral striata were dissected, and total RNAs were extracted. Gene expressions were examined using RNA sequencing. RESULT: We found that oxycodone self-administration exposure led to alterations of expression in numerous genes related to inflammation/immune functions in the dorsal striatum (54 upregulated genes and 1 downregulated gene) and ventral striatum (126 upregulated genes and 15 downregulated genes), with 38 upregulated genes identified in both brain regions. CONCLUSION: This study reveals novel neurobiological mechanisms underlying some of the effects of a commonly abused prescription opioid. We propose that inflammation/immune gene systems may undergo a major change during chronic self-administration of oxycodone. PMID- 28653082 TI - Clinical practice guideline for post-ERCP pancreatitis. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERPC) is used for the diagnosis and treatment of pancreatic and biliary diseases. Post-ERCP pancreatitis (PEP) is a complication which needs special care and clinical practice guideline for this morbidity is also needed. METHODS: The key clinical issues of diagnosis and treatment of PEP were listed and checked, and then the clinical questions were formulated. PubMed (MEDLINE) and Ichushi-web (Japanese medical literature) were used as databases. For the study of diagnostic test accuracy, items similar to QUADAS-2, i.e., random selection from a population to which the diagnostic test is applied, blinding of index tests and reference tests, completeness of reference standard, completeness of test implementations, the same timing of tests, and missing data were assessed as well as the indirectness of the study subjects, index tests, reference standard, and outcomes. Grading of recommendations was determined as strong or weak. In clinical practice, the judgment of attending doctors should be more important than recommendations described in clinical practice guidelines. Gastroenterologists are the target users of this clinical practice guideline. General practitioners or general citizens are not supposed to use this guideline. The guideline committee has decided to include wide clinical issues such as etiological information, techniques of ERCP, the diagnosis, treatments, and monitoring of PEP in this guideline. RESULTS: In this concise report, we described ten clinical questions, recommendations, and explanations pertaining to risk factors, diagnosis, prognostic factors, treatments, and preventive interventions in the medical practice for PEP. CONCLUSIONS: We reported here the essence of the clinical practice guideline for PEP. PMID- 28653083 TI - Determining soil quality in urban agricultural regions by soil enzyme-based index. AB - Urban agricultural soils are highly variable, and careful selection of sensitive indicators is needed for the assessment of soil quality. This study is proposed to develop an index based on soil enzyme activities for assessing the quality of urban agricultural soils. Top soils were collected from urban agricultural areas of Korea, and soil chemical properties, texture, microbial fatty acids, and enzyme activities were determined. The soils belonged to five textural classes with the highest frequency of sandy loam. There was no clear correlation between the soil chemical properties and soil microbial properties. Principal component analysis (PCA) and factor analysis were applied to microbial groups for identification of microbial community variation in soils. Two soil groups, namely group 1 (G1) and group 2 (G2), based on microbial community abundance were examined by PCA, and those were more prominent in factor analysis. The G1 soils showed higher microbial community abundance than G2 soils. The canonical discriminant analysis was applied to the enzyme activities of sandy loam soil to develop an index, and the index validation was confirmed using the unused soils and published data. The high-quality soils in published literature assigned the high valued index. Microbial fatty acids and soil enzyme activities can be suitable indicators for soil quality evaluation of urban agricultural soils. PMID- 28653084 TI - Bacillus alcaliphilum sp. nov., a bacterium isolated from a soda lake. AB - Two novel (14BT and 7B) Gram-stain-positive, rod-shaped, motile and endospore forming bacterial strains were isolated from Lonar soda lake, India. Based on 16S rRNA gene sequence analysis, the strains 14BT and 7B were identified as belonging to the class Firmibacteria and were most closely related to Bacillus halodurans LMG 7121T (99.7 and 99.8%, respectively), Bacillus okuhidensis LMG 22468T (99.1 and 99.2%, respectively) and other members in the genus Bacillus (<97.0%). However, the DNA-DNA relatedness studies indicated that the strains 14BT and 7B were distantly related to B. halodurans LMG 7121T (49.1 +/- 0.6 and 45.7 +/- 0.6, respectively) and B. okuhidensis LMG 22468T (40.9 +/- 0.9 and 42.1 +/- 0.5, respectively). The high 16S rRNA gene sequence similarity (99.9%) and DNA-DNA relatedness (88 +/- 9) indicated that strains 14BT and 7B were members of a single species. The strains grew optimally at a pH of 9.0-9.5 with 2-5% (w/v) NaCl and temperature of 37 degrees C. Strains 14BT and 7B were catalase positive and oxydase negative. The cell wall of strain 14BT contained meso-diaminopimelic acid as the diagnostic diamino acid. Polar lipids include diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), an unknown aminophospholipid (APL1) and three unknown lipids (L1-3). The predominant isoprenoid quinone is MK-7. anteiso-C15:0 (30.8%) was the predominant fatty acid, and significant proportions of iso-C15:0 (24.9%), iso-C16:0 (17.9%) and anteiso C17:0 (12.3%) were also detected in strains 14BT and 7B. The DNA G+C content of strains 14BT and 7B was 41.6 and 41.3 mol%, respectively. The results of molecular, physiological and biochemical tests allowed a clear differentiation of strains 14BT and 7B from all other members of the genus Bacillus, for which the name Bacillus alcaliphilum sp. nov. is proposed. The type strain is 14BT (=KCTC 33777T = CGMCC 1.15474T). PMID- 28653093 TI - [Intravesical Bacillus Calmette-Guerin with interferon-alpha versus intravesical Bacillus Calmette-Guerin for treating non-muscle-invasive bladder cancer : Comment on a recently published Cochrane Review]. PMID- 28653085 TI - Assessment of the Validity and Reproducibility of a Novel Standardized Test Meal for the Study of Postprandial Triacylglycerol Concentrations. AB - Lipotest(r) is a standardized fat-rich meal designed for use as a test meal during a fat tolerance test (FTT) for the study of postprandial triacylglycerol (TAG) concentrations. Herein we examined the precision and reproducibility of examination using Lipotest(r) on postprandial TAG levels. A total of 26 healthy consenting subjects were examined twice after 8-10 h fasting with an interval of approximately 1 week apart. Blood samples were collected at baseline and 1, 2, 3, and 4 h after consumption of the test meal for measurement of plasma total TAG levels. We examined agreement, precision, and accuracy between the two visits using the Altman plots and correlation coefficient. Reproducibility was tested using the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Moreover, the area under the curve (AUC) as a summary measure of the overall postprandial TAG levels was calculated. The agreement, precision (r >= 0.74, p < 0.001), and accuracy (>=0.99) between the measurements in plasma TAG during Lipotest(r) testing in the two visits were high. In terms of reproducibility, the values of CV were 15.59-23.83% while those of ICC were >=0.75. The values of the AUCs in the visits were not different (p = 0.87). A single measurement of plasma TAG levels at 4 h after Lipotest(r) consumption depicted peak postprandial TAG concentration. A FTT using Lipotest(r) as a standardized meal has good precision and reproducibility for the study of postprandial TAG levels in healthy individuals. A single determination of plasma TAG concentration at 4 h after Lipotest(r) consumption captures peak postprandial TAG response. PMID- 28653094 TI - Post-partum chronic relapsing idiopathic optic neuropathy. PMID- 28653096 TI - Correction of dropped head deformity through combined anterior and posterior osteotomies to restore horizontal gaze and improve sagittal alignment. AB - OBJECTIVE: The aim of this study is to present our technique for a large focal correction of a partially flexible dropped head deformity through combined anterior and posterior osteotomies, as well as anterior soft tissue releases. METHODS: One patient with dropped head deformity underwent an anterior and posterior osteotomy with anterior soft tissue release. RESULTS: The patient recovered well, with postoperative radiographs demonstrating significant improvement in coronal and sagittal alignment. His C2-C7 sagittal vertical axis improved from 7.5 cm preoperatively to less than 4 cm postoperatively and his C2 C7 sagittal Cobb improved from 35 degrees of kyphosis to 10 degrees of lordosis. CONCLUSION: In this report, we present our technique for a large focal correction of a partially flexible dropped head deformity through combined anterior and posterior osteotomies and anterior soft tissue releases. These more conservative osteotomies permitted gradual deformity correction and alleviated the need for pedicle subtraction osteotomy. We were able to restore horizontal gaze and improve sagittal malalignment. Although the technique we present here is one of many possible options for managing the deformity, we believe this combined approach is safe and effective and well tolerated by patients. PMID- 28653095 TI - QPY/RAH haplotypes of the GZMB gene are associated with natural killer cell cytotoxicity. AB - Granzyme B (GzmB) is a component of cytolytic granules within NK cells and is involved in several pathologies. It has previously been reported that there are three non-synonymous coding SNPs (rs8192917; Q48R, rs11539752; P88A, and rs2236338; Y245H) in the GZMB gene and that the QPY/RAH allele was clustered together close to the C-terminal alpha-helix. However, it is unknown whether the function of GzmB produced from NK cells is influenced by QPY/RAH polymorphism. The authors investigated the distribution of QPY/RAH polymorphism of the GZMB gene in a Japanese population (n = 106), and the involvement of Q48R polymorphism in NK cell cytotoxicity, degranulation, and production of GzmB. A strong linkage disequilibrium was observed among these SNPs, and NK cell cytotoxicity was influenced by rs8192917 (Q48R). Moreover, it found that R48-GzmB is a stable protein that accumulates to similar levels in activated NK cells as Q48-GzmB. rs8192917 polymorphism may influence antitumor activity and the effect of antitumor cellular immunotherapy. The authors expect that these new informations about QPY/RAH polymorphism of the GZMB gene could help to assess the impact of NK cell cytotoxicity in several pathologies and aid their treatment. PMID- 28653097 TI - Treatment and outcome of metastatic paraganglioma of the spine. AB - BACKGROUND: Spinal metastatic paraganglioma (MPG) is rare and only reported in individual case reports. The low incidence makes it difficult to define appropriate therapy and prognosis. Our study illustrated the largest series to discuss the possible treatment and outcomes of patients with spinal MPG. METHODS: A retrospective study of 15 patients with spinal MPG who were surgically treated between 2005 and 2014 was performed. Three surgical modalities were applied, and radiotherapy and chemotherapy were utilized as adjuvant therapy. RESULTS: The mean patients age was 40.9 (range 23-58) years. The period between primary surgery and spinal metastasis averaged 8.2 (0.5-15) years. Lesions were mainly located in cervical spine (2), thoracic spine (8), lumbar spine (3), and sacrum (2). The mean follow-up period was 35.0 months. Lesion progression was detected in nine patients, whereas five patients (33.3%) passed away. For solitary spine, multiple bone and both bone and nonosseous metastasis cases, the mean progression free survival was 41 (range 9-56), 22.5 (range 12-38) and 8.3 (range 3-18) months, respectively. CONCLUSIONS: The cases presented in the current study highlight the crucial role of surgery. Total en bloc for solitary spinal MPG could result in a satisfying prognosis and piecemeal total resection with postoperative radiotherapy could be an alternative therapy. Radiotherapy and chemotherapy were advocated, especially for the multiple metastasis. PMID- 28653099 TI - Meeting report of the 6th Heidelberg Myeloma Workshop: current status and developments in diagnosis and therapy of multiple myeloma. AB - PURPOSE: The 6th Heidelberg Myeloma Workshop was held on May 5th and 6th, 2017 in the lecture hall of the University Hospital Heidelberg. METHODS AND RESULTS: Main topics of the meeting were (1) biology and genomics of multiple myeloma, (2) diagnostics and prognostic factors, (3) role of immunotherapy in multiple myeloma, as well as (4) therapy of multiple myeloma-drugs and treatment strategies. CONCLUSION: The landscape for the treatment of newly diagnosed and relapsed disease has significantly changed since the last Heidelberg Myeloma Workshop in 2015. Updates on the current developments were presented at the meeting. PMID- 28653098 TI - Overexpression of glutathione peroxidase 1 predicts poor prognosis in oral squamous cell carcinoma. AB - PURPOSE: Intracellular antioxidant enzymes are commonly upregulated in various cancer types and are associated with treatment outcomes. Because the relationship has rarely been examined in oral squamous cell carcinoma (OSCC), we aimed to evaluate the association between the levels of glutathione peroxidase (GPX)1, GPX4, and thioredoxin reductase (TrxR)1 expression and prognosis in patients with OSCC who underwent curative surgical resection. METHODS: This study included 233 patients who underwent curative surgery for previously untreated OSCC between 2000 and 2012. Tumour GPX1, GPX4, and TrxR1 expression was evaluated by immunohistochemistry and was dichotomised to low and high values according to defined expression levels. The association between GPX1, GPX4, and TrxR1 expression and clinicopathological results was analysed. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to assess the significance of differences in recurrence or survival outcomes between variables. RESULTS: High GPX1, GPX4, and TrxR1 expression was observed in 99 (42.5%), 133 (57.1%), and 46 (19.7%) patients, respectively. GPX1 overexpression was significantly correlated with nodal metastasis, advanced overall stage, depth of invasion of >10 mm, high grade and perineural invasion (P < 0.05). High GPX4 expression was also related to nodal metastasis, overall advanced stage and high grade (P < 0.05). Univariate and multivariate analyses showed that increased GPX1 expression was significantly associated with poor disease-free, cancer-specific and overall survival (all P < 0.05), while increased GPX4 or TrxR1 expression was not (all P > 0.1). CONCLUSIONS: Tumour GPX1 expression is a useful biomarker predictive of recurrence and survival in OSCC patients. PMID- 28653100 TI - Ethics and the Law. AB - Health care providers' interpretation of law can have intended and unintended effects on health care delivery in Canada. At times, health care providers encounter situations where they perceive the law to conflict with their sense of what is most ethically justified. In many cases, these health care providers feel especially torn because they assume that the legal requirements must dictate the decision, and cannot be explored or questioned. We challenge this assumption: the law is not as cut-and-dried as some assume; therefore, its significance to health care decisions should be carefully considered. Within a systematic ethics process, legal considerations can be a source of values and information and can create opportunities for further dialogue. This approach is justified because it appropriately reflects the relationship of the law to ethics. This way of thinking about the law and ethics also avoids potentially harmful consequences of legalistic approaches to decision-making, such as breakdowns in communication, adversarial relationships, and a reduction of ethically complex decisions to simple rule following. PMID- 28653101 TI - CT-guided cement sacroplasty (CSP) as pain therapy in non-dislocated insufficiency fractures. AB - INTRODUCTION: In elderly patients with reduced bone quality, insufficiency fractures of the sacrum are relatively common and are typically associated with severe disabling pain. The objective of the present study was to examine the feasibility of cement augmentation by CSP, to determine post-interventional leakages and other complications, and to present the outcome of pain over the course of 18 months. MATERIALS AND METHODS: In 23 patients (20 women and 3 men) with an average age of 81.3 (71-92) years, a total of 41 sacral fractures were detected by MRI, 5 of them unilateral and 18 bilateral. Conservative treatment initially performed over a period of 3 weeks did not bring any satisfactory reduction in the severe disabling pain. The indication for intervention was established after an interdisciplinary case conference. The intervention was performed under intubation anaesthesia. Single-shot antibiotic prophylaxis was given routinely immediately prior to the intervention. Under sterile conditions, a Jamshidi needle was then advanced into the respective fracture zone in the sacrum from dorsal to ventral (short axis) or from lateral to medial transiliac (transiliac axis). After removing the inner needle, a flexible osteotome was inserted through the positioned hollow needle and used to extend the spongious space in the fracture zone and thus prepare a cavity for the cement filling. High viscosity PMMA cement was then inserted discontinuously with the aid of a pressure gauge under low-dose CT control. Cement leakages were determined in the CT image on the day after the intervention, all cement outside of the cortical boundary being rated as a leakage. Pain was documented on a visual analogue scale (VAS) on the day before the intervention, on the second day, and 6, 12, and 18 months after the intervention. Additionally occurring complications were recorded, and the patients were asked to rate their satisfaction after 6 and 18 months. RESULTS: CSP was technically feasible in all patients. In the control CT scan, sufficient cement distribution and interlocking with vital bone were found along the course of the fracture in the sacrum. An average of 6.0 +/- 0.83 ml of cement was inserted per fracture. Leakage was found in 5 of 41 (12.2%) of the fractures treated, although none were symptomatic. The mean pain score on the VAS was 8.8 +/- 0.59 before the intervention, a significant pain reduction (p < 0.0005) was seen on the second post-operative day, with an average value of 2.1 +/- 0.36, and this was stable at 2.2 +/- 0.28 after 6, 2.3 +/- 0.31 after 12, and 2.2 +/- 0.41 after 18 months. Now that they no longer experienced disabling pain, all of the patients were fully remobilised and discharged back home. A high level of patient satisfaction was found after 6 and 18 months. CONCLUSION: As a minimally invasive procedure, CSP is an effective treatment method for rapid, significant, and sustained pain reduction. PMID- 28653102 TI - Identification of Set11 from Staphylococcus aureus Mu50 strain as a ortholog of SSL7 via bioinformatic analysis and determination of its possible targets from human serum using CNBr-pull down assays. AB - OBJECTIVES: To identify and characterize staphylococcus exotoxin-like (SET) protein Set11 from Staphylococcus aureus Mu50 strain and its possible targets proteins from human blood/serum. RESULTS: Set11 is a member of the staphylococcal superantigen-like (SSL) proteins (also called Staphylococcus exotoxin-like (SET) proteins) family that is found in staphylococcal strain Mu50. Its structure and function, however, remain unknown. We performed bioinformatics analysis of Set11: it had 90% sequence identity to SSL7 in NCTC 8325 strain, indicating Set11 is a SSL7 ortholog. SSL7 in ATCC 12598 strain binds complement C5 to inhibit complement system. To investigate if Set11 binds C5, we made the homology model of Set11 and the Set11-C5 complex model based on SSL7 and SSL7-C5 structures, respectively. Structural analysis and sequence alignment reveal that the residues in SSL7 involved in C5 binding are conserved in Set11, indicating C5 as the potential target for Set11. To identify new targets of Set11, we cloned, expressed and purified Set11 and performed CNBr-pull down combined mass spectrum assays using human blood and serum. CONCLUSIONS: We identified Set11 as the ortholog of SSL7 and determined C5, fibronectin 1 isoform 3 preproprotein, albumin, alpha-1-microglobulin precursor and complement C3 processor as the potential target proteins for Set11, indicating new functions of Set11/SSL7. PMID- 28653103 TI - Re: Intraprocedural Distal Embolization After Femoropopliteal Angioplasty: Is There a Role for Below-the-knee Stents? A Statistical Analysis Point of View. PMID- 28653104 TI - Reply to: Intraprocedural Distal Embolization After Femoropopliteal Angioplasty: Is There a Role for Below-the-Knee Stents? A Statistical Analysis Point of View. PMID- 28653106 TI - From will to live to will to die: oncologists, nurses, and social workers identification of suicidality in cancer patients. AB - PURPOSE: The purpose of this research was to examine how oncologists, nurses, and social workers identify suicidality in cancer patients. METHODS: Sixty-one healthcare professionals (23 oncologists, 18 social workers, and 20 nurses) at two academic cancer centers were interviewed using an in-depth interview guide. This was a qualitative study based on grounded theory methodology. Analysis involved line-by-line coding, with categories and themes emerging from participants' narratives. RESULTS: Suicidality in cancer patients exists on a wide spectrum that ranges from an active will to live to an active will to die. Four phases were identified that included: (A) a strong will to live expressed in themes of active treatments, seeking second opinions, overtreatment, and alternative treatments; (B) a decreasing will to live indicated in themes of mental health distress and physical pain and suffering; (C) a readiness to die expressed in themes of mental health distress, previous mental health diagnoses, physical pain, avoiding more suffering, preserving quality of life in old age, nearing end of life, lack of social support, and maintaining a sense of control; and (D) a will to die indicated in themes of euthanasia and active suicidality. CONCLUSIONS: Suicidality in cancer patients exists on a continuum. Cancer patients fluctuate on this spectrum depending on circumstances such as degree of suffering, their personalities and life circumstances, and whether they are nearing the end of life. Results of the study emphasize the need to collect more context specific data on suicidality among cancer patients and the importance of early integration of psychosocial and palliative care in the cancer treatment trajectory. PMID- 28653107 TI - A multicenter study of attitudinal barriers to cancer pain management. AB - PURPOSE: The purpose of this study was to examine attitudinal barriers to cancer pain management and their relationship to pain, analgesic use, clinical, and demographic variables, as well as QOL, in a large sample of patients receiving strong opioids for pain in three European countries. METHODS: Participants in the present study were 555 patients with cancer, 18 years and older recruited from six centers in Germany, Iceland, and Norway. All had received strong opioids for at least 72 h. Data was collected with the Barriers Questionnaire-II, the Brief Pain Inventory, and the European Organization for Research and Treatment of Cancer QLQ-C30. RESULTS: The mean (SD) age of patients was 61.68 (12.35) years and 53% were men. Most common diagnoses were gastrointestinal, lung, prostate, and breast cancer. The mean (SD) time from diagnosis was 32.24 (44.55) and 4.97 (9.64) months from start of opioid therapy. Mean (SD) pain severity was 3.19 (1.93) on a 0 to 10 scale, and 46.5% reported worst pain of 7 or higher. Attitudinal barriers had a mean (SD) of 1.95 (0.82) on a 0-5 scale, with fear of addiction as the strongest barrier across countries 2.85 (1.49). Barrier scores increased with age, and were higher among men than women. Higher barrier scores were associated with higher pain severity and interference, and lower performance status, but not with global health-QOL. Patients who had been on opioids for a shorter time reported higher barriers. CONCLUSIONS: Attitudinal barriers are frequent in cancer pain patients on opioids and are associated with less effective pain control. PMID- 28653108 TI - Prevention of palmoplantar erythrodysesthesia in patients treated with pegylated liposomal doxorubicin (Caelyx(r)). AB - PURPOSE: Palmoplantar erythrodysesthesia (PPE) is one of the most frequent side effects during systemic treatment with pegylated liposomal doxorubicin (PLD, Caelyx(r)). PPE lesions show a range of symptoms, from numbness to painful erosions, and can have a major impact on the quality of life in affected patients. Previously, a possible pathomechanism of PPE was found in doxorubicin treated patients based on radical formation in the skin. Here, a preventive strategy using a topically applied ointment with a high radical protection factor was investigated. METHODS: In this randomized placebo-controlled double-blind study the antioxidant-containing ointment was compared with a placebo ointment regarding PPE grade III occurrence, overall PPE grade I-III occurrence and PPE severity in PLD patients. The verum or placebo cream was topically applied for a period of 16 weeks, starting 3 days prior to the first cycle of chemotherapy. Clinical evaluations were carried out by a dermatologist prior to the first cycle of chemotherapy and every 4 weeks for the duration of 16 weeks. RESULTS: Thirty two patients were enrolled in total, of which 17 (66%) completed the study. No PPE grade III was found in the verum group, while five out of seven patients (71%) had to be unblinded in the placebo arm due to PPE grade III (p = 0.003). General PPE occurrence of all grades was 60% under verum and 86% under placebo treatment. CONCLUSIONS: The preventive application of an antioxidant-containing ointment was shown to be significantly more effective in the prevention of PPE grade III compared to placebo treatment. PMID- 28653109 TI - The life of [PSI]. AB - The AAA+ disaggregase Hsp104 is essential for the maintenance and inheritance of nearly all known prions of the yeast Saccharomyces cerevisiae. Uniquely for [PSI +], the prion form of the Sup35 protein, there seem to be two activities, involving differing co-chaperones, by which Hsp104 affects the inheritance of [PSI +], the prion form of the Sup35 protein. Each pathway is also involved in protection against ageing, one through disaggregation of damaged proteins and the other through their retention in the mother cell during budding. Mutations in both Hsp104 and Sup35 affect prion inheritance by one or other of these pathways, as does manipulation of either Hsp104 enzyme activity or expression, in both vegetative (budding) divisions and in sporulation. Based on our recent finding (Ness et al. in Molec Microbiol 104:125-143, 2017) we suggest that the management of the heritable prion forms of Sup35 in [PSI +] cells in sporulation may be a marker for a role for Hsp104 in rejuvenation during sporulation. PMID- 28653110 TI - Development of a Semi-nested PCR-Based Method for Specific and Rapid Detection of Alternaria solani Causing Potato Early Blight in Soil. AB - Early blight, caused by Alternaria solani, is one of the most devastating diseases of potato that causes severe yield loss worldwide. The infected potato debris existed in the soil serve as the initial infection sources for the next growing potato. Current identification of A. solani in soil relies primarily on cultural and morphological characteristics, which are time-consuming and inaccurate. In this study, a semi-nested PCR method was developed using primers based on internal transcribed spacer region that is specific to A. solani. 20 isolates including 6 Alternaria species and 10 other species of common potato pathogens were used to examine the specificity of the primers. The primer set ptAsQ-F/ptAs-R was highly specific to A. solani, as a product of 251 bp was amplified only from A. solani isolates and no amplification signal was observed from other tested species. The sensitivity of this method determined using A. solani genomic DNA was 10 fg. This PCR assay was also successfully employed to detect A. solani in soil with the detection sensitivity of one conidia spore in 0.5 g of soil. To the best of our knowledge, this is the first report of molecular detection of A. solani in soil, which provides a useful tool for early and rapid detection of early blight in soil before next growing season. PMID- 28653111 TI - Seed weight differences between wild and domesticated soybeans are associated with specific changes in gene expression. AB - KEY MESSAGE: Our study systematically explored potential genes and molecular pathways as candidates for differences in seed weight resulting from soybean domestication. In addition, potential contributions of lncRNAs to seed weight were also investigated. Soybeans have a long history of domestication in China, and there are several significant phenotypic differences between cultivated and wild soybeans, for example, seeds of cultivars are generally larger and heavier than those from wild accessions. We analyzed seed transcriptomes from thirteen soybean samples, including six landraces and seven wild accessions using strand specific RNA sequencing. Differentially expressed genes related to seed weight were identified, and some of their homologs were associated with seed development in Arabidopsis. We also identified 1251 long intergenic noncoding RNAs (lincRNAs), 243 intronic RNAs and 81 antisense lncRNAs de novo from these soybean transcriptomes. We then profiled the expression patterns of lncRNAs in cultivated and wild soybean seeds, and found that transcript levels of a number of lncRNAs were sample-specific. Moreover, gene transcript and lincRNA co-expression network analysis showed that some soybean lincRNAs might have functional roles as they were hubs of co-expression modules. In conclusion, this study systematically explored potential genes and molecular pathways as candidates for differences in seed weight resulting from soybean domestication, and will provide a useful future resource for molecular breeding of soybeans. PMID- 28653112 TI - The role of intraoperative nerve monitoring in tracheal surgery: 20-year experience with 110 cases. AB - PURPOSE: To determine the utility of intraoperative nerve monitoring (IONM) during tracheal resection or slide tracheoplasty to prevent recurrent laryngeal nerve injury. METHODS: 110 patients underwent tracheal resection or tracheoplasty between 1997 and 2016. During the first 10-year period, IONM was not used while during the second 10-year period, IONM was used. 49 patients had surgery without IONM while 61 had surgery with IONM. During the post-operative period, patients with nerve injury were compared to determine if significant difference existed between the two modalities. RESULTS: In patients who had surgery without IONM, 7 (14.2%) patients were found to have compromised nerve function whereas 8 (13.1%) patients in the group with IONM had nerve injury. 3 patients regained function in the first group while four regained function in the second. A Fisher's exact test was run on the entire cohort and the difference in vocal fold injury was not found to be statistically significant (p > 0.05). CONCLUSION: Based on this single surgeon experience, there may be no protective benefit with the use of IONM during tracheal surgery. PMID- 28653113 TI - Association of soluble ST2 with functional capacity in outpatients with heart failure. AB - BACKGROUND: Biomarkers play an important role in the risk stratification of patients with heart failure (HF). Recent studies have shown that soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin 1 receptor family, is associated with disease prognosis in acute and chronic HF. In this study we aimed to investigate the relation between sST2 level and functional capacity in outpatients with systolic HF. PATIENTS AND METHODS: This study included 120 HF patients with reduced ejection fraction (HFrEF; EF <= 40%). The mean age of patients was 66 +/- 11 years. Advanced HF (New York Heart Association [NYHA] functional class III-IV) was observed in 35 patients (29%). RESULTS: sST2 levels were on average higher in patients with NYHA functional classes III and IV than in patients with NYHA functional classes I and II (51 [9-198] vs. 25 ng/ml [9-118], p < 0.001). In a multiple logistic regression model, sST2 level (OR: 1.044, p = 0.004, 95% CI: 1.014-1.075), hemoglobin level (OR: 0.590, p = 0.001, 95% CI: 0.433-0.805), total cholesterol level (OR: 0.977, p = 0.004, 95% CI: 0.962-0.993), and age (OR: 1.066, p = 0.047, 95% CI: 1.001-1.136) were associated with poor functional capacity. In receiver operating characteristic (ROC) curve analysis, the optimal cut-off value of sST2 for predicting poor functional capacity was >42 ng/ml, with 63% sensitivity and 88% specificity (AUC: 0.810, 95% CI: 0.728- 0.875). CONCLUSION: Higher sST2 levels were strongly associated with poor NYHA functional class, independent of cardiac risk factors, in outpatients with HFrEF. PMID- 28653115 TI - Recognition of human faces by dogs (Canis familiaris) requires visibility of head contour. AB - Researchers have suggested that dogs are able to recognise human faces, but conclusive evidence has yet to be found. Experiment 1 of this study investigated whether dogs can recognise humans using visual information from the face/head region, and whether this also occurs in conditions of suboptimal visibility of the face. Dogs were presented with their owner's and a stranger's heads, protruding through openings of an apparatus in opposite parts of the experimental setting. Presentations occurred in conditions of either optimal or suboptimal visibility; the latter featured non-frontal orientation, uneven illumination and invisibility of outer contours of the heads. Instances where dogs approached their owners with a higher frequency than predicted by chance were considered evidence of recognition. This occurred only in the optimal condition. With a similar paradigm, Experiment 2 investigated which of the alterations in visibility that characterised the suboptimal condition accounted for dogs' inability to recognise owners. Dogs approached their owners more frequently than predicted by chance if outer head contours were visible, but not if heads were either frontally oriented or evenly illuminated. Moreover, male dogs were slightly better at recognition than females. These findings represent the first clear demonstration that dogs can recognise human faces and that outer face elements are crucial for such a task, complementing previous research on human face processing in dogs. Parallels with face recognition abilities observed in other animal species, as well as with human infants, point to the relevance of these results from a comparative standpoint. PMID- 28653114 TI - Precision medicine approach to genetic cardiomyopathy. AB - Precision medicine aims to achieve improved survival by strategies that recognize the genetic and phenotypic individuality of patients and stratify treatment accordingly. Genetic cardiomyopathies represent an ideal disease group to fully embark on this concept: they are in total frequent diseases with a marked morbidity and mortality and there is ample knowledge about their predisposing genetic factors and associated functional mechanisms. The current review highlights the genetic etiology and gives examples of the diverse treatment strategies that are envisaged in the future. PMID- 28653116 TI - Sleep and Psychiatric Disorders in Persons With Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) frequently challenges the integrity of sleep function by affecting multiple brain areas implicated in controlling the switch between wakefulness and sleep and those involved in circadian and homeostatic processes; the malfunction of each causes a variety of disorders. In this review, we discuss recent data on the dynamics between disorders of sleep and mental/psychiatric disorders in persons with mTBI. This analysis sets the stage for understanding how a variety of physiological, emotional and environmental influences affect sleep and mental activities after injury to the brain. Consideration of the intricate links between sleep and mental functions in future research can increase understanding on the underlying mechanisms of sleep-related and psychiatric comorbidity in mTBI. PMID- 28653117 TI - Treating Eating Disorders at Higher Levels of Care: Overview and Challenges. AB - Higher levels of care (HLC)-including inpatient hospitalization, residential treatment, partial hospitalization, and intensive outpatient treatment-are frequently utilized within routine care for eating disorders. Despite widespread use, there is limited research evaluating the efficacy of HLC, as well as clinical issues related to care in these settings. This review describes the different levels of care for eating disorders and briefly reviews the most up-to date guidelines and research regarding how to choose a level of care. In addition, as HLC approaches for ED continue to be developed and refined, pragmatic and conceptual challenges have emerged that provide barriers to clinical efficacy and the execution of high-quality treatment research. This review includes a discussion of various issues specific to HLC, as well as a summary of recent literature addressing them. PMID- 28653118 TI - Quantitative Pneumatic Otoscopy Using a Light-Based Ranging Technique. AB - Otitis media is the leading cause of hearing loss in children. It is commonly associated with fluid in the ear, which can result in up to 45 dB of hearing loss for extended periods of time during a child's most important developmental years. Accurate assessment of middle ear effusions is an important part of understanding otitis media. Current technologies used to diagnose otitis media with effusion are pneumatic otoscopy, tympanometry, and acoustic reflectometry. While all of these techniques can reasonably diagnose the presence of an effusion, they provide limited information about the infection present behind the tympanic membrane.We have developed a technique based on low-coherence interferometry-a non-invasive optical ranging technique capable of sensing depth-resolved microscopic scattering features through the eardrum-to quantify eardrum thickness and integrity, as well as detect any effusion, purulence, or biofilm behind the tympanic membrane. In this manuscript, the technique is coupled with a pneumatic otoscope to measure minute deflections of the tympanic membrane from insufflation pressure stimuli. This results in quantitative measurements of tympanic membrane mobility, which may be used to gain a better understanding of the impact of infection on the membrane dynamics. A small pilot study of 15 subjects demonstrates the ability of pneumatic low-coherence interferometry to quantitatively differentiate normal ears from ears with effusions present. Analysis of the strengths and weaknesses of the technique, as well as focus areas of future research, is also discussed. PMID- 28653119 TI - Surveillance of anal carcinoma after radiochemotherapy : A retrospective analysis of 80 patients. AB - BACKGROUND: Surveillance after radiochemotherapy of anal carcinoma (ACa) with curative intent is recommended in guidelines, but data regarding the effectiveness of follow-up are lacking. We aimed to assess the performance of an ACa surveillance program in a real-life setting. METHODS: We retrospectively summarized clinical history, physical findings, and follow-up investigations (endoanal ultrasound, endoscopy, CT scan) obtained during 42 months (+/-27 months) from 80 patients after radiochemotherapy of ACa. RESULTS: In 7/80 cases (8.8%) an incomplete response to therapy was identified at or before the 6-month time point after the end of treatment; 4 of the 7 cases were identified during scheduled follow-up. In 6 cases (7.5%), recurrent disease was found after the 6 month time point. Recurrence was systemic in 5 cases and local/inguinal in 1 case. In 3 of the 6 cases (50%), recurrence was identified during scheduled follow-up. In one asymptomatic patient, a single liver metastasis was detected during scheduled follow-up and the patient remains free of disease 19 months after surgery. Surveillance resulted in a high rate of false-positive findings (70 findings in 604 investigations), of which only 14 could be confirmed. CONCLUSION: Scheduled follow-up after treatment of ACa detected recurrent disease at systemic sites, enabling potentially curative treatment in a single case. Effectiveness of abdominal imaging during follow-up after ACa treatment should be tested in a prospective trial. PMID- 28653120 TI - Automation of radiation treatment planning : Evaluation of head and neck cancer patient plans created by the Pinnacle3 scripting and Auto-Planning functions. AB - BACKGROUND: Intensity-modulated radiotherapy (IMRT) techniques are now standard practice. IMRT or volumetric-modulated arc therapy (VMAT) allow treatment of the tumor while simultaneously sparing organs at risk. Nevertheless, treatment plan quality still depends on the physicist's individual skills, experiences, and personal preferences. It would therefore be advantageous to automate the planning process. This possibility is offered by the Pinnacle3 treatment planning system (Philips Healthcare, Hamburg, Germany) via its scripting language or Auto Planning (AP) module. MATERIALS AND METHODS: AP module results were compared to in-house scripts and manually optimized treatment plans for standard head and neck cancer plans. Multiple treatment parameters were scored to judge plan quality (100 points = optimum plan). Patients were initially planned manually by different physicists and re-planned using scripts or AP. RESULTS AND DISCUSSION: Script-based head and neck plans achieved a mean of 67.0 points and were, on average, superior to manually created (59.1 points) and AP plans (62.3 points). Moreover, they are characterized by reproducibility and lower standard deviation of treatment parameters. Even less experienced staff are able to create at least a good starting point for further optimization in a short time. However, for particular plans, experienced planners perform even better than scripts or AP. Experienced-user input is needed when setting up scripts or AP templates for the first time. Moreover, some minor drawbacks exist, such as the increase of monitor units (+35.5% for scripted plans). CONCLUSION: On average, automatically created plans are superior to manually created treatment plans. For particular plans, experienced physicists were able to perform better than scripts or AP; thus, the benefit is greatest when time is short or staff inexperienced. PMID- 28653121 TI - [Radiation with additional antiandrogen therapy in recurrent prostate cancer]. PMID- 28653122 TI - Machine Learning: Discovering the Future of Medical Imaging. PMID- 28653123 TI - Pixel-Level Deep Segmentation: Artificial Intelligence Quantifies Muscle on Computed Tomography for Body Morphometric Analysis. AB - Pretreatment risk stratification is key for personalized medicine. While many physicians rely on an "eyeball test" to assess whether patients will tolerate major surgery or chemotherapy, "eyeballing" is inherently subjective and difficult to quantify. The concept of morphometric age derived from cross sectional imaging has been found to correlate well with outcomes such as length of stay, morbidity, and mortality. However, the determination of the morphometric age is time intensive and requires highly trained experts. In this study, we propose a fully automated deep learning system for the segmentation of skeletal muscle cross-sectional area (CSA) on an axial computed tomography image taken at the third lumbar vertebra. We utilized a fully automated deep segmentation model derived from an extended implementation of a fully convolutional network with weight initialization of an ImageNet pre-trained model, followed by post processing to eliminate intramuscular fat for a more accurate analysis. This experiment was conducted by varying window level (WL), window width (WW), and bit resolutions in order to better understand the effects of the parameters on the model performance. Our best model, fine-tuned on 250 training images and ground truth labels, achieves 0.93 +/- 0.02 Dice similarity coefficient (DSC) and 3.68 +/- 2.29% difference between predicted and ground truth muscle CSA on 150 held out test cases. Ultimately, the fully automated segmentation system can be embedded into the clinical environment to accelerate the quantification of muscle and expanded to volume analysis of 3D datasets. PMID- 28653124 TI - EPR spectral investigation of radiation-induced radicals of gallic acid. AB - In the present work, spectroscopic features of the radiation-induced radicals of gallic acid compounds were investigated using electron paramagnetic resonance (EPR) spectroscopy. While un-irradiated samples presented no EPR signal, irradiated samples exhibited an EPR spectrum consisting of an intense resonance line at the center and weak lines on both sides. Detailed microwave saturation investigations were carried out to determine the origin of the experimental EPR lines. It is concluded that the two side lines of the triplet satellite originate from forbidden "spin-flip" transitions. The spectroscopic and structural features of the radiation-induced radicals were determined using EPR spectrum fittings. The experimental EPR spectra of the two gallic acid compounds were consistent with the calculated EPR spectroscopic features of the proposed radicals. It is concluded that the most probable radicals are the cyclohexadienyl-type, [Formula: see text] radicals for both compounds. PMID- 28653125 TI - Eosinophilic Esophagitis in Children. AB - PURPOSE OF REVIEW: EoE is a significant cause of gastrointestinal morbidity affecting 1:2000. Patients with EoE typically have multiple atopic comorbidities, and additionally, many patients with EoE can be controlled well with elimination diets. The purpose of this review is to summarize the care of pediatric eosinophilic esophagitis patients. RECENT FINDINGS: EoE represents a distinct clinical syndrome which is characterized by esophageal dysfunction and eosinophil predominant inflammation of the esophageal mucosa. Patients with EoE can present with varying symptoms depending on their age; in this review, we review the presenting features of eosinophilic esophagitis in children as well as a diagnostic algorithm for EoE. The mucosal inflammation in EoE is driven by exposure to food antigens in many patients with EoE. Therefore, for the majority of patients, the mainstays of treatment remain food elimination diets or swallowed steroids. This review summarizes the diagnostic approach to eosinophilic esophagitis (EoE) in pediatric patients, focusing on the importance of accurate diagnosis and selection of appropriate therapy. PMID- 28653127 TI - A synthesis of oxo-thioxo[3.3.3]propellanes from dithiocarbamates and ninhydrin malononitrile adduct. AB - An efficient method for the synthesis of oxo-thioxo[3.3.3]propellanes via reaction of dithiocarbamates, generated from primary amines and carbon disulfide, with the Knoevenagel adduct resulting from ninhydrin and malononitrile in [Formula: see text] at room temperature is described. These transformations are highlighted by their chemo- and regioselectivity, lack of activator or metal promoters, inert atmosphere, and formation of four new bonds in one operation. PMID- 28653126 TI - Impact of Metabolic Hormones Secreted in Human Breast Milk on Nutritional Programming in Childhood Obesity. AB - Obesity is the most common metabolic disease whose prevalence is increasing worldwide. This condition is considered a serious public health problem due to associated comorbidities such as diabetes mellitus and hypertension. Perinatal morbidity related to obesity does not end with birth; this continues affecting the mother/infant binomial and could negatively impact on metabolism during early infant nutrition. Nutrition in early stages of growth may be essential in the development of obesity in adulthood, supporting the concept of "nutritional programming". For this reason, breastfeeding may play an important role in this programming. Breast milk is the most recommended feeding for the newborn due to the provided benefits such as protection against obesity and diabetes. Health benefits are based on milk components such as bioactive molecules, specifically hormones involved in the regulation of food intake. Identification of these molecules has increased in recent years but its action has not been fully clarified. Hormones such as leptin, insulin, ghrelin, adiponectin, resistin, obestatin and insulin-like growth factor-1 copeptin, apelin, and nesfatin, among others, have been identified in the milk of normal-weight women and may influence the energy balance because they can activate orexigenic or anorexigenic pathways depending on energy requirements and body stores. It is important to emphasize that, although the number of biomolecules identified in milk involved in regulating food intake has increased considerably, there is a lack of studies aimed at elucidating the effect these hormones may have on metabolism and development of the newborn. Therefore, we present a state-of-the-art review regarding bioactive compounds such as hormones secreted in breast milk and their possible impact on nutritional programming in the infant, analyzing their functions in appetite regulation. PMID- 28653128 TI - Structure-based design of new poly (ADP-ribose) polymerase (PARP-1) inhibitors. AB - Poly (ADP-ribose) polymerase (PARP-1) is a well-established nuclear protein with prominent role in signaling and DNA repair. Various clinical candidates have been identified with the role in PARP-1 inhibition. Based on the pharmacophoric features identified from previous studies and molecular docking interactions, thiazolidine-2,4-dione derivatives have been evaluated for their PARP inhibitory activity. From an in vitro assay, 5-((1-(4-isopropylbenzyl)-1H-indol-3 yl)methylene)thiazolidine-2,4-dione (16) was identified as a potent inhibitor having low micromolar inhibitory activity [Formula: see text]. Thus, a structure based design approach utilized in the present study helped to identify thiazolidine-2,4-dione as a novel scaffold against PARP-1 for potential development of potent anticancer therapeutics. PMID- 28653129 TI - Cu(II) complex of pyridine-based polydentate as a novel, efficient, and highly reusable catalyst in C-N bond-forming reaction. AB - In this paper, a highly reusable copper(II) complex of pyridine-based polydentate is able to efficiently catalyze a C-N bond-forming reaction under mild conditions. A variety of N-heterocyclic and amine compounds arylated with different aryl iodides, bromides, and chlorides produced N-substituted compounds in good to excellent yields. This methodology can be also used for the arylation of N-unsubstituted compounds using arylboronic acids under solvent-free conditions. All reactions are performed in short times under air, and the catalyst can be reused up to seven times. PMID- 28653130 TI - Reduction and ring fixation of instable C1 fractures with monoaxial pedicle screws. AB - INTRODUCTION: Ring fixation of C1 can be performed using pedicle screws and a rod in case of unstable Jefferson or lateral mass fractures of C1. MATERIALS AND METHODS: In a case series of three patients, we stabilized C1 fractures surgically using a modified technique of C1 ring fixation by using monoaxial instead of polyaxial screws. Functional outcome and pain was recorded postoperatively. RESULTS: In this very small case series, we observed good results concerning pain and functional outcome. All fractures were bony healed within 13 weeks. In one case, a screw penetrated the spinal canal and had to be repositioned. A mild irritation of C2 nerve root occurred in two cases postoperatively. CONCLUSION: C1 Ring fusion with monoaxial screws provides a good ability to reduce the fracture indirectly by the screws and the rod itself. PMID- 28653132 TI - Food Insecurity and Aging Outcomes in Older Adults Living with HIV. AB - Little is known about food insecurity and its association with geriatric outcomes in older people living with HIV (PLWH). This was a cross-sectional study of 230 HIV-infected patients aged 50 and older recruited in December 2012 through June 2016. Poisson logistic regression models estimated the prevalence ratio (PR) and 95% confidence intervals (CI) for the association between food insecurity and the following geriatric outcomes: frailty, physical health and function, social support, mental health and cognition, and behavioral health. 157 (68%) participants were food secure, 35 (15%) had low food security, and 38 (17%) had very low food security. After adjusting the analyses for other significant covariates, at risk alcohol or drug use (PR = 3.14; 95% CI 1.75-5.64), being sedentary (PR = 3.30; 95% CI 1.09-10.00) depressive symptoms (PR = 1.77; 95% CI 1.13-2.76), and dependent instrumental activities of daily living (PR = 2.46; 95% CI 1.13-5.36) were significantly associated with very low food security. These results highlight a need for structural HIV interventions that incorporate targeted food assistance strategies for older PLWH. PMID- 28653131 TI - Novel Risk Stratification Assays for Acute Coronary Syndrome. AB - PURPOSE OF REVIEW: Since identification of aspartate aminotransferase as the first cardiac biomarker in the 1950s, there have been a number of new markers used for myocardial damage detection over the decades. There have also been several generations of troponin assays, each with progressively increasing sensitivity for troponin detection. Accordingly, the "standard of care" for myocardial damage detection continues to change. The purpose of this paper is to review the clinical utility, biological mechanisms, and predictive value of these various biomarkers in contemporary clinical studies. RECENT FINDINGS: As of this writing, a fifth "next" generation troponin assay has now been cleared by the US Food and Drug Administration for clinical use in the USA for subjects presenting with suspected acute coronary syndromes. Use of these high-sensitivity assays has allowed for earlier detection of myocardial damage as well as greater negative predictive value for infarction after only one or two serial measurements. Recent algorithms utilizing these assays have allowed for more rapid rule-out of myocardial infarction in emergency department settings. In this review, we discuss novel assays available for the risk assessment of subjects presenting with chest pain, including both the "next generation" cardiac troponin assays as well as other novel biomarkers. We review the biological mechanisms for these markers, and explore the positive and negative predictive value of the assays in clinical studies, where reported. We also discuss the potential use of these new markers within the context of future clinical care in the modern era of higher sensitivity troponin testing. Finally, we discuss advances in new platforms (e.g., mass spectrometry) that historically have not been considered for rapid in vitro diagnostic capabilities, but that are taking a larger role in clinical diagnostics, and whose prognostic value and power promise to usher in new markers with potential for future clinical utility in acute coronary syndrome. PMID- 28653134 TI - Goal-directed therapy: hit early and personalize! PMID- 28653133 TI - Dysregulation of Cerebellar Adrenomedullin Signaling During Hypertension. AB - Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM activates three different receptors, the AM type 1 (AM1), type 2 (AM2), and calcitonin gene-related peptide 1 (CGRP1) receptors. AM triggers several signaling pathways such as adenylyl cyclase (AC), guanylyl cyclase (GC), and extracellular signal-regulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. Cerebellar AM, AM-binding sites, and its receptor components are altered during hypertension, although it is unknown if these alterations are associated with changes in AM signaling. Thus, we assessed AM signaling pathways in cerebellar vermis of 16-week-old Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Animals were sacrificed by decapitation, and cerebellar vermis was microdissected under stereomicroscopic control. Tissue was stimulated in vitro with AM. Then the production of cyclic guanosine monophosphate (cGMP), nitric oxide (NO) and cyclic adenosine monophosphate (cAMP) were assessed along with ERK1/2 activation and three antioxidant enzymes' activity: glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Our findings demonstrate that in the cerebellar vermis of normotensive rats, AM increases cGMP, NO, cAMP production, and ERK1/2 phosphorylation, while decreases basal antioxidant enzyme activity. In addition, AM antagonizes angiotensin II (ANG II)-induced increment of antioxidant enzyme activity. Hypertension blunts AM-induced cGMP and NO production and AM-induced decrease of antioxidant enzyme activity. Meanwhile, AM-induced effects on cAMP production, ERK1/2 activation, and AM-ANG II antagonism were not altered in SHR rats. Our results support a dysregulation of several AM signaling pathways during hypertension in cerebellar vermis. PMID- 28653135 TI - Closed-loop mechanical ventilation for lung injury: a novel physiological feedback mode following the principles of the open lung concept. AB - Adherence to low tidal volume (VT) ventilation and selected positive end expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low VT-ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions. PMID- 28653136 TI - Efficacy and Safety of 2% Topical Propranolol Cream for the Treatment of Proliferating Infantile Strawberry Hemangiomas: Correspondence. PMID- 28653137 TI - Duchenne Muscular Dystrophy: A Practice Update. AB - Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder caused by a deficient or defective synthesis of dystrophin protein. DMD is the most common form of muscular dystrophy with an incidence of about 1 in 5000 live boys. Though primarily resulting in progressive muscle weakness, it affects various other organs as well. Heart, brain and smooth muscles are commonly involved, because of expression of dystrophin in these organs. The management of DMD requires a multidisciplinary liaison, anticipatory management and prevention of the complications. Consensus based international recommendation for management of DMD have been published in the year 2010, recognizing DMD as a multi-systemic and progressive disease. The proper management of a boy with DMD can improve ambulation, independence, quality of life and delay disease - related complications. A lot can be done to comfort affected children and their care givers even in a resource limited setting. This review discusses these options and also the current understanding of the disease. PMID- 28653138 TI - Erratum to: A Network Epidemic Model with Preventive Rewiring: Comparative Analysis of the Initial Phase. PMID- 28653139 TI - Spreading, proliferation and differentiation of human dental pulp stem cells on chitosan scaffolds immobilized with RGD or fibronectin. AB - Nowadays, human dental pulp stem cells (hDPSCs) became more attractive for therapeutic purposes because of their high proliferation and differentiation potential. Thus, coupling the desired cellular characteristics of hDPSCs with good biomaterial properties of the chitosan scaffolds provide an interesting approach for tissue engineering applications. On the other hand, scaffold surface modification is also needed to promote stem cell adhesion since chitosan lacks adhesion motifs to support direct cell anchorage. In this study, hDPSCs were isolated from third molars of healthy female individuals (aged 16-25) with enzymatic digestion. For cell culture studies, the chitosan scaffolds which have approximately 9 mm diameter and 2 mm thickness with interconnected structure were prepared by freeze-drying. To support cellular attachment the scaffolds were covalently immobilized with either RGD (arginine-glycine-aspartic acid) or fibronectin (Fn) molecules. Cells were seeded on chitosan scaffolds with or without immobilized RGD and fibronectin. Cell attachment, spreading, adhesion behaviors and proliferation capacity were examined by scanning electron microscopy, immunofluorescence staining and PrestoBlue(r) assays, respectively. In addition, differentiation potential of hDPSCs on Fn immobilized chitosan scaffolds was determined with real time reverse transcriptase polymerase chain reaction analysis. The results showed that chitosan scaffolds were not able to support stem cell attachment. hDPSCs on chitosan scaffolds formed spheroids more quickly and the size of spheroids were smaller than on chitosan-RGD while Fn immobilized chitosan scaffolds strongly supported cellular attachment but not odontogenic differentiation. The results suggest that the Fn-immobilized chitosan scaffolds may serve as good three-dimensional substrates for dental pulp stem cell attachment and proliferation. In the case of dental regeneration, they must be supported by appropriate biosignals to induce odontogenic differentiation. PMID- 28653140 TI - Comment on: "A Unique Clinicopathological Manifestation of Fungal Infection: A Case Series of Deep Dermatophytosis in Immunosuppressed Patients". PMID- 28653142 TI - Prognostic Significance of Preoperative Controlling Nutritional Status (CONUT) Score in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma. AB - BACKGROUND: The Controlling Nutritional Status (CONUT) score is an objective tool widely used to assess nutritional status in patients with inflammatory disease, chronic heart failure, and chronic liver disease. The relationship between CONUT score and prognosis in patients who have undergone hepatic resection, however, has not been evaluated. METHODS: Data were retrospectively collected for 357 consecutive patients with hepatocellular carcinoma (HCC) who had undergone hepatic resection with curative intent between January 2004 and December 2015. The patients were assigned to two groups, those with preoperative CONUT scores <=3 (low CONUT score) and >3 (high CONUT score), and their clinicopathological characteristics, surgical outcomes, and long-term survival were compared. RESULTS: Of the 357 patients, 69 (19.3%) had high (>3) and 288 (80.7%) had low (<=3) preoperative CONUT scores. High CONUT score was significantly associated with HCV infection, low serum albumin and cholesterol concentrations, low lymphocyte count, shorter prothrombin time, Child-Pugh B and liver damage B scores, and blood transfusion. Multivariate analysis identified six factors prognostic of poor overall survival (older age, liver damage B score, high CONUT score, poor tumor differentiation, the presence of intrahepatic metastases, and blood transfusion) and five factors prognostic of reduced recurrence-free survival (older age, higher ICGR15, larger tumor size, presence of intrahepatic metastasis, and blood transfusion). CONCLUSIONS: In patients with HCC, preoperative CONUT scores are predictive of poorer overall survival, even after adjustments for other known predictors. PMID- 28653143 TI - Impact of Time Since Last Childbirth on Survival of Women with Premenopausal and Postmenopausal Breast Cancers. AB - BACKGROUND: Reproductive factors are associated with risk of breast cancer, but the association with breast cancer survival is less well known. Previous studies have reported conflicting results on the association between time since last childbirth and breast cancer survival. We determined the association between time since last childbirth (LCB) and survival of women with premenopausal and postmenopausal breast cancers in Malaysia. METHOD: A historical cohort of 986 premenopausal, and 1123 postmenopausal, parous breast cancer patients diagnosed from 2001 to 2012 in University Malaya Medical Centre were included in the analyses. Time since LCB was categorized into quintiles. Multivariable Cox regression was used to determine whether time since LCB was associated with survival following breast cancer, adjusting for demographic, tumor, and treatment characteristics. RESULTS: Premenopausal breast cancer patients with the most recent childbirth (LCB quintile 1) were younger, more likely to present with unfavorable prognostic profiles and had the lowest 5-year overall survival (OS) (66.9; 95% CI 60.2-73.6%), compared to women with longer duration since LCB (quintile 2 thru 5). In univariable analysis, time since LCB was inversely associated with risk of mortality and the hazard ratio for LCB quintile 2, 3, 4, and 5 versus quintile 1 were 0.53 (95% CI 0.36-0.77), 0.49 (95% CI 0.33-0.75), 0.61 (95% CI 0.43-0.85), and 0.64 (95% CI 0.44-0.93), respectively; P trend = 0.016. However, this association was attenuated substantially following adjustment for age at diagnosis and other prognostic factors. Similarly, postmenopausal breast cancer patients with the most recent childbirth were also more likely to present with unfavorable disease profiles. Compared to postmenopausal breast cancer patients in LCB quintile 1, patients in quintile 5 had a higher risk of mortality. This association was not significant following multivariable adjustment. CONCLUSION: Time since LCB is not independently associated with survival in premenopausal or postmenopausal breast cancers. The apparent increase in risks of mortality in premenopausal breast cancer patients with a recent childbirth, and postmenopausal patients with longer duration since LCB, appear to be largely explained by their age at diagnosis. PMID- 28653141 TI - Physiology and pathophysiology of excitation-contraction coupling: the functional role of ryanodine receptor. AB - Calcium (Ca2+) release from intracellular stores plays a key role in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation-contraction (E-C) coupling. This article explores the role of RyR1 in skeletal muscle physiology and pathophysiology. PMID- 28653144 TI - Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis. AB - BACKGROUND: Ethnic variability in the pharmacokinetics of organic anion transporting polypeptide (OATP) 1B1 substrates has been observed, but its basis is unclear. A previous study hypothesizes that, without applying an intrinsic ethnic variability in transporter activity, allele frequencies of transporters cannot explain observed ethnic variability in pharmacokinetics. However, this hypothesis contradicts the data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates. OBJECTIVE: The objective of this study is to evaluate a hypothesis that is physiologically reasonable and more consistent with clinical observations. METHODS: We evaluated if allele frequencies of two transporters (OATP1B1 and BCRP) are key contributors to ethnic variability. In this hypothesis, the same genotype leads to the same activity independent of ethnicity, in contrast to the previous hypothesis of intrinsic ethnic variability in OATP1B1 activity. As a validation, we perform mechanistic pharmacokinetic modeling for SLCO1B1 (encoding OATP1B1) and ABCG2 (encoding BCRP) genotyped pharmacokinetic data from 18 clinical studies with healthy Caucasian and/or Asian subjects. RESULTS: Simulations based on the current hypothesis reasonably describe SLCO1B1 and ABCG2 genotyped pharmacokinetic time course data for five transporter substrates (atorvastatin, pitavastatin, pravastatin, repaglinide, and rosuvastatin) in Caucasian and Asian populations. CONCLUSION: This hypothesis covers the observations that can (e.g., ethnic differences in rosuvastatin pharmacokinetics) or cannot (e.g., lack of differences for pitavastatin pharmacokinetics) be explained by the previous hypothesis. It helps to characterize sources of ethnic variability and provides a foundation for predicting ethnic variability in transporter substrate pharmacokinetics. PMID- 28653145 TI - A very cool electrocardiogram: Osborn waves of hypothermia. PMID- 28653146 TI - Investigation of the optimum heel pad stiffness: a modeling study. AB - Due to the controversy regarding the criterion for diagnosing heel pad (HP) pathology based on evaluating the state of the heel pad stiffness (HPS), this paper intended to apply modeling to understand the influence of the HPS on the mechanical responses of the HP at heelstrike during locomotion, in an attempt to investigate the optimum HPS in terms of the health-related mechanical responses. Two different models, a finite element model and a classical mechanical model, were used to simulate the mechanical responses (force loading and deformation) experienced by the HP at heelstrike. Both excessive force loading and deformation are believed to be detrimental to the heel pad. In the simulation, the corresponding force loading, deformation and net effect (the adding of the normalized force loading and deformation) were calculated for each HPS value. Two models found consistent trends that the stiffer the HP, the greater the force loading and the lower the deformation. In contrast, a softer HP experienced a lower force loading and a greater deformation. Both the force loading and deformation were at medium levels and the net effect was minimal at a HPS value between the highest and lowest values used in the simulation. The modeling result suggested that the optimum HPS should be in a state at which both the force loading and deformation were at medium levels and the net effect was minimal, in terms of the health-related mechanical responses. The abnormal level of HPS, either too high or too low, may correlate to respective pathologies. PMID- 28653147 TI - [Altered orientation and aggressiveness in an 89-year-old woman]. AB - An 89-year-old woman with Alzheimer's dementia was admitted because of altered orientation, aggressiveness and inability to take care of herself at home. Her patient history indicated that 14 days ago the battery of the pacemaker had be renewed. During that time the patient suffered from psychomotor alterations. Therefore, melperone had been initiated. Inspection of the urine and laboratory findings pointed towards an acute exacerbation of acute intermittent porphyria as a possible cause of the delirium. After discontinuation of melperone with additional parenteral therapy with physiological fluids, the signs of delirium significantly improved. PMID- 28653149 TI - Development and comparative genomic mapping of Dasypyrum villosum 6V#4S-specific PCR markers using transcriptome data. AB - KEY MESSAGE: Twenty-five Dasypyrum villosum 6V#4S-specific PCR markers were developed using transcriptome data and further assigned to comparative genomic maps of wheat chromosome 6A, 6B, and 6D and barley chromosome 6H contrasting their homologous genes in these genomes. Two Dasypyrum villosum accessions, D.v#2 and No. 1026 from England and Russia, respectively, contain Pm21 on chromosome 6V#2S and PmV on chromosome 6V#4S. Both genes confer high resistance to powdery mildew (PM) in wheat. Even though several molecular markers have been developed to detect Pm21 and PmV, only the MBH1 marker can simultaneously detect both Pm21 and PmV. In this study, we first used a high-throughput sequencing technique to obtain the transcriptome sequences of a wheat-D. villosum translocation line, Pm97033-which contains chromosome 6V#4S carrying the PmV locus, under wheat PM pathogen induction. Twenty-five 6V#4S chromosome-specific markers were developed. Three of them were able to clearly distinguish chromosomes 6V#4S and 6V#2S by product size, four amplified the product specific for chromosome 6V#4S only, and the remaining 18 markers identified chromosome 6VS in wheat backgrounds. Two different D. villosum accessions, their derived translocation lines and wheat varieties carrying different chromosome 6VS were identified using these specific markers. The 25 newly developed markers together with the known PM resistance gene Stpk-V were used to construct comparative genomic maps with the homoeologous chromosome arms of wheat and barley. The colinearity of the identified gene sequences amplified by the 25 markers among wheat chromosomes 6A, 6B, and 6D and barley chromosome 6H was not very conserved and interrupted frequently by inversion and insertion. Our markers have potential in marker assisted selection for PM resistance breeding, and for locating other potential important genes and cloning the PmV gene on chromosome 6V#4S. PMID- 28653148 TI - [New pharmacologic therapies for chronic heart failure]. AB - Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor. Whether digitalis affects the prognosis in heart failure remains unclear; however, serum concentration should be targeted at the lower therapeutic range. Iron supplementation in heart failure with reduced systolic function and iron deficiency improves symptoms and quality of life. PMID- 28653150 TI - Linkage map construction and QTL analysis for internal heat necrosis in autotetraploid potato. AB - KEY MESSAGE: A tetraploid potato population was mapped for internal heat necrosis (IHN) using the Infinium (r) 8303 potato SNP array, and QTL for IHN were identified on chromosomes 1, 5, 9 and 12 that explained 28.21% of the variation for incidence and 25.3% of the variation for severity. This research represents a significant step forward in our understanding of IHN, and sets the stage for future research focused on testing the utility of these markers in additional breeding populations. Internal heat necrosis (IHN) is a significant non pathogenic disorder of potato tubers and previous studies have identified AFLP markers linked to IHN susceptibility in the tetraploid, B2721 potato mapping population. B2721 consists of an IHN susceptible*resistant cross: Atlantic*B1829 5. We developed a next-generation SNP-based linkage map of this cross using the Infinium(r) 8303 SNP array and conducted additional QTL analyses of IHN susceptibility in the B2721 population. Using SNP dosage sensitive markers, linkage maps for both parents were simultaneously analyzed. The linkage map contained 3427 SNPs and totaled 1397.68 cM. QTL were detected for IHN on chromosomes 1, 5, 9, and 12 using LOD permutation thresholds and colocation of high LOD scores across multiple years. Genetic effects were modeled for each putative QTL. Markers associated with a QTL were regressed in models of effects for IHN incidence and severity for all years. In the full model, the SNP markers were shown to have significant effects for IHN (p < 0.0001), and explained 28.21% of the variation for incidence and 25.3% of the variation for severity. We were able to utilize SNP dosage information to identify and model the effects of putative QTL, and identify SNP loci associated with IHN resistance that need to be confirmed. This research represents a significant step forward in our understanding of IHN, and sets the stage for future research focused on testing the utility of these markers in additional breeding populations. PMID- 28653151 TI - Identification of quantitative trait loci associated with resistance to net form net blotch in a collection of Nordic barley germplasm. AB - KEY MESSAGE: Association mapping of resistance to Pyrenophora teres f. teres in a collection of Nordic barley germplasm at different developmental stages revealed 13 quantitative loci with mostly small effects. Net blotch, caused by the necrotrophic fungus Pyrenophora teres, is one of the major diseases in barley in Norway causing quantitative and qualitative yield losses. Resistance in Norwegian cultivars and germplasm is generally insufficient and resistance sources have not been extensively explored yet. In this study, we mapped quantitative trait loci (QTL) associated with resistance to net blotch in Nordic germplasm. We evaluated a collection of 209 mostly Nordic spring barley lines for reactions to net form net blotch (NFNB; Pyrenophora teres f. teres) in inoculations with three single conidia isolates at the seedling stage and in inoculated field trials at the adult stage in 4 years. Using 5669 SNP markers genotyped with the Illumina iSelect 9k Barley SNP Chip and a mixed linear model accounting for population structure and kinship, we found a total of 35 significant marker-trait associations for net blotch resistance, corresponding to 13 QTL, on all chromosomes. Out of these QTL, seven conferred resistance only in adult plants and four were only detectable in seedlings. Two QTL on chromosomes 3H and 6H were significant during both seedling inoculations and adult stage field trials. These are promising candidates for breeding programs using marker-assisted selection strategies. The results elucidate the genetic background of NFNB resistance in Nordic germplasm and suggest that NB resistance is conferred by a number of genes each with small-to-moderate effects, making it necessary to pyramid these genes to achieve sufficient levels of resistance. PMID- 28653152 TI - [R1 resection for pancreatic carcinoma]. AB - BACKGROUND: Surgery is the only potentially curative therapeutic approach in patients with pancreatic ductal adenocarcinoma (PDAC); however, achieving a negative (R0) resection margin is not always possible. OBJECTIVE: The impact of R1 resection margins on survival rates and treatment options (surgical and multimodal) for intraoperatively and postoperatively identified R1 resection margins. RESULTS: For intraoperatively diagnosed R1 resection margins, a re resection (e.g. pancreas, main bile duct, stomach, superior mesenteric and portal vein) can be performed to achieve R0 resection margins. Arterial resections and the resection of additional organs are occasionally technically feasible and can be performed in an individual approach. New neoadjuvant and adjuvant treatment strategies have increased the rate of resectable PDAC and have improved the outcome of patients with R0/R1 resected PDACs. CONCLUSION: An R0 resection is the primary goal of surgery in patients with PDAC as R1 resections are correlated with a poor outcome. PMID- 28653153 TI - Application of Benford's law: a valuable tool for detecting scientific papers with fabricated data? : A case study using proven falsified articles against a comparison group. AB - BACKGROUND: In naturally occurring numbers the frequencies of digits 1-9 in the leading position are counterintuitively distributed because the frequencies of occurrence are unequal. Benford-Newcomb's law describes the expected distribution of these frequencies. It was previously shown that known fraudulent articles consistently violated this law. OBJECTIVE: To compare the features of 12 known fraudulent articles from a single Japanese author to the features of 13 articles in the same research field from other Japanese authors, published during the same time period and identified with a Medline database search. RESULTS: All 25 articles were assessed to determine whether the data violated the law. Formulas provided by the law were used to determine the frequencies of occurrence for the first two leading digits in manually extracted numbers. It was found that all the known fraudulent papers violated the law and 6 of the 13 articles used for comparison followed the law. Assuming that the articles in the comparison group were not falsified or fabricated, the sensitivity of assessing articles with Benford-Newcomb's law was 100% (95% confidence interval CI: 73.54-100%) but the specificity was only 46.15% (95% CI: 19.22-74.87%) and the positive predictive value was 63.16% (95% CI: 38.36-83.71%). CONCLUSION: All 12 of the known falsified articles violated Benford-Newcomb's law, which indicated that this analysis had a high sensitivity. The low specificity of the assessment may be explained by the assumptions made about the articles identified for comparison. Violations of Benford-Newcomb's law about the frequencies of the leading digits cannot serve as proof of falsification but they may provide a basis for deeper discussions between the editor and author about a submitted work. PMID- 28653155 TI - Poly(aryleneethynylene)s: Properties, Applications and Synthesis Through Alkyne Metathesis. AB - Functional polymeric materials have seen their way into every facet of materials chemistry and engineering. In this review article, we focus on a promising class of polymers, poly(aryleneethynylene)s, by covering several of the numerous applications found thus far for these materials. Additionally, we survey the current synthetic strategies used to create these polymers, with a focus on the emerging technique of alkyne metathesis. An overview is presented of the most recent catalytic systems that support alkyne metathesis as well as the more useful alkyne metathesis reaction capable of synthesizing poly(aryleneethynylene)s. PMID- 28653154 TI - DNA persistence of bite marks on food and its relevance for STR typing. AB - In forensic DNA analysis, salivary traces at crime scenes are a promising way to identify a person. However, crime scenes are oftentimes investigated a while after the crime and recovered samples might have been degraded leading to poor PCR amplification. Probably due to decomposition and negative visual impression of spoiled food, bite mark samples make up only a small part of our casework routine. In this study, bite marks on apples and chocolate bars as well as on an inert surface (microscope slide) were stored up to 3 weeks indoors and outdoors during different seasons and analyzed for amylase activity and DNA quantity and quality. The results underlined the stability of human nuclear DNA not only on inert but also on biological surfaces and their forensic usefulness even when bite marks are stored 21 days under adverse but realistic conditions at a crime scene. Overall, amylase activity as well as DNA quantity decreased over time depending on storage environment with a certain inter- and intrapersonal variation. But amylase activity testing was not found to be an appropriate screening tool for further analysis. Apple bite marks resulted in generally higher DNA amounts than chocolate bars and microscope slides. Although mold reduced the DNA quantity, complete STR profiles could be analyzed. High air humidity and cold temperatures were found to act preservative on raw food with high water content but caused loss of information over time for smooth inert surfaces and hygroscopic foods like sweets. Many factors are involved in the stability of DNA in bite marks and its resulting quality and quantity available for an STR analysis. However, since there was a substantial proportion of informative STR profiles even from bite marks stored for 21 days, the results encourage the analysis of those even if their visual appearance seems unfavorable. PMID- 28653156 TI - Revealing the potency of Annona muricata leaves extract as FOXO1 inhibitor for diabetes mellitus treatment through computational study. AB - FOXO1 protein inactivation in the nucleus is one of targets for the treatment of diabetes mellitus. Annona muricata leaves contain flavonoid and phenolic compound alkaloids that were known to be able to increase pancreatic beta cell proliferation in animal experiment. This research aimed to predict the active compound ability of the Annona muricata leaves to bind and inhibit FOXO1 protein through in silico study. Analysis of molecular docking was performed by using Autodock Vina PyRx. this research proved that anonaine, rutin, muricatocin a, isolaureline, xylopine, and kaempferol 3-O-rutinoside had an equal or smaller free binding energy compared to the control compound. Rutin and Muricatocin A had the same binding ability toward 66% amino acid residues, compared to control compound with hydrogen bond type, while xylopine, anonaine, isolaureline, kaempferol 3-O-rutinoside had a similar binding ability towards 33% amino acid residues compared to control compound with hydrogen bond type. PMID- 28653158 TI - Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget's Disease. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy; however, the standard treatment of EMPD has not been established. In this study, we applied mapping biopsy to penoscrotal EMPD and evaluated its effects. METHODS: A retrospective chart review was performed to determine the outcomes of patients with primary penoscrotal EMPD who underwent surgery at our institution between 2007 and 2014. Patients were divided into two groups (one group underwent mapping biopsy, while the other group did not), and the difference between the two groups was analyzed. The 5-year tumor-free rate was estimated using the Kaplan-Meier method, and the risk factors for local recurrence were also estimated. RESULTS: A total of 44 patients were analyzed, and the mean follow-up of patients was 50.27 months. Patients who underwent mapping biopsy showed significantly lower tumor involvement at permanent and frozen biopsies and a lower local recurrence rate than those who did not undergo mapping biopsy. The 5-year tumor-free rate was significantly higher in the mapping biopsy group than in the non-mapping biopsy group. Multivariable analysis demonstrated that age at operation, mapping biopsy, and false-negative results at frozen biopsy were associated with local recurrence. CONCLUSIONS: Mapping biopsy is beneficial to reduce local recurrence in penoscrotal EMPD. PMID- 28653157 TI - Computational Analysis on Down-Regulated Images of Macrophage Scavenger Receptor. AB - BACKGROUND: Thiolated-graphene quantum dots (SH-GQDs) were developed and assessed for an efficient preventive means against atherosclerosis and potential toxicity through computational image analysis and animal model studies. EXPERIMENTS: Zebrafish (wild-type, wt) were used for evaluation of toxicity through the assessment of embryonic mortality, malformation and ROS generation. The amounts of SH-GQDs uptaken by mouse macrophage cells (Raw264.7) were analyzed using a flow cytometer. For the time-dependent cellular uptake study, Raw264.7 cells were treated with SH-GQDs (200 MUg/ml) at specific time intervals (0.5, 1, 2, 5, 10 and 24 h). The efficacy of SH-GQDs on DiO-oxLDL efflux by Raw264.7 cells was evaluated (DiO, 3,3'-dioctadecyl-oxacarbocyanine) based on the percentage of positive cells containing DiO-oxLDL. TEER of human primary umbilical vein endothelial cells (hUVECs) were examined to assess the barrier function of the cell layers upon being treated with oxLDL. RESULTS: SH-GQDs significantly enhanced the efflux of oxLDL and down-regulated macrophage scavenger receptor (MSR) in Raw264.7. The ROS levels stimulated by oxidative stress were alleviated by SH-GQDs. oxLDL (10 MUg/ml) significantly impaired the barrier function (TEER) of adherence junctions, which was recovered by SH-GQDs (10 MUg/ml) (oxLDL: 67.2 +/- 2.2 Omega-cm2 for 24 h; SH-GQDs: 114.6 +/- 8.5 Omega-cm2 for 24 h). The mortality rate (46% for 1 mg/ml) of the zebra fish increased, as the concentrations and exposure duration of SH-GQDs increased. SH-GQDs exerted negligible side effects. CONCLUSION: SH-GQDs have target specificity to macrophage scavenger receptor (MSR) and efficiently recovered the ROS levels and TEER. SH-GQDs did not induce endothelial cell layer disruption nor affected zebrafish larvae survival. PMID- 28653159 TI - Could a Feeding Jejunostomy be Integrated into a Standardized Preoperative Management of Oeso-gastric Junction Adenocarcinoma? AB - PURPOSE: To evaluate the impact of a feeding jejunostomy (FJ) on the preoperative management of patients with an oesogastric adenocarcinoma (OGA). METHODS: From January 2007 to December 2014, patients with potentially resectable OGA were enrolled in a perioperative chemotherapy protocol. FJ was performed before starting perioperative treatments in patients presenting with dysphagia or with a nutritional risk index (NRI) <97.5. The patients who did not require a FJ served as a control group. RESULTS: Among the 114 patients with OGA consecutively admitted in our surgical department, 88 (77.2%) were enrolled for neoadjuvant treatment. A FJ was placed in 50 patients (56.8%) before the neoadjuvant treatment (FJ group), whereas 38 patients (43.2%) started neoadjuvant treatments without FJ (control group). Ninety-six percent of patients (n = 48) in the FJ group successfully completed the neoadjuvant treatment but only 81.6% of patients without FJ (n = 31; p = 0.004). The FJ group was divided between responders: 37 patients with a weight response (74%), and nonresponders: 13 patients without weight response (26%). In the FJ group, the nutritional response during preoperative chemotherapy was a significant predictive factor for the achievement of second stage oesogastric resection (p = 0.002). CONCLUSIONS: FJ with enteral nutritional support during the preoperative management of OGA is a safe and effective support for the completion of the preoperative chemotherapy. The weight response to the enteral support is a predictor factor for a completion of the preoperative chemotherapy and could identify a group of patients who would have a better chance of reaching radical surgery. PMID- 28653160 TI - Relevance of Dissection of the Posterior Superior Pancreaticoduodenal Lymph Nodes in Gallbladder Carcinoma. AB - BACKGROUND: This study was designed to evaluate the prognostic value of positive posterior superior pancreaticoduodenal lymph nodes to clarify the need for dissection of these nodes. METHODS: A total of 148 patients with gallbladder carcinoma who underwent radical resection including dissection of the posterior superior pancreaticoduodenal nodes were enrolled. The incidence of metastasis and the survival rates among patients with metastasis to each lymph node group were calculated. RESULTS: Of the 148 patients, 70 (47%) had nodal disease. The incidences of metastasis in the cystic duct, pericholedochal, retroportal, and hepatic artery node groups, defined as regional nodes in the UICC TNM staging system, ranged from 8.3 to 24.3% with 5-year survival rates of 12.5-46.4% in patients with positive nodes. The incidence of metastasis to the posterior superior pancreaticoduodenal nodes was 12.8% with a 5-year survival rate of 31.6% in patients with positive nodes. Survival after resection was significantly better in patients with distant nodal disease affecting only the posterior superior pancreaticoduodenal nodes (5-year survival, 55.6%) than in patients with distant nodal disease beyond these nodes (5-year survival, 15.0%; p = 0.046), whereas survival after resection was comparable between the former group and patients with regional nodal disease alone (5-year survival, 40.7%; p = 0.426). CONCLUSIONS: In gallbladder carcinoma, involvement of the posterior superior pancreaticoduodenal nodes is similar to that of regional nodes in terms of both the incidence of metastasis and the impact on survival. Inclusion of the posterior superior pancreaticoduodenal nodes among the regional nodes should be considered. PMID- 28653161 TI - The Post-SIR-Spheres Surgery Study (P4S): Retrospective Analysis of Safety Following Hepatic Resection or Transplantation in Patients Previously Treated with Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres. AB - BACKGROUND: Reports show that selective internal radiation therapy (SIRT) may downsize inoperable liver tumors to resection or transplantation, or enable a bridge-to-transplant. A small-cohort study found that long-term survival in patients undergoing resection following SIRT appears possible but no robust studies on postsurgical safety outcomes exist. The Post-SIR-Spheres Surgery Study was an international, multicenter, retrospective study to assess safety outcomes of liver resection or transplantation following SIRT with yttrium-90 (Y-90) resin microspheres (SIR-Spheres(r); Sirtex). METHODS: Data were captured retrospectively at participating SIRT centers, with Y-90 resin microspheres, surgery (resection or transplantation), and follow-up for all eligible patients. Primary endpoints were perioperative and 90-day postoperative morbidity and mortality. Standard statistical methods were used. RESULTS: The study included 100 patients [hepatocellular carcinoma: 49; metastatic colorectal cancer (mCRC): 30; cholangiocarcinoma, metastatic neuroendocrine tumor, other: 7 each]; 36% of patients had one or more lines of chemotherapy pre-SIRT. Sixty-three percent of patients had comorbidities, including hypertension (44%), diabetes (26%), and cardiopathy (16%). Post-SIRT, 71 patients were resected and 29 received a liver transplant. Grade 3+ peri/postoperative complications and any grade of liver failure were experienced by 24 and 7% of patients, respectively. Four patients died <90 days postsurgery; all were trisectionectomies (mCRC: 3; cholangiocarcinoma: 1) and typically had one or more previous chemotherapy lines and presurgical comorbidities. CONCLUSIONS: In 100 patients undergoing liver surgery after receiving SIRT, mortality and complication rates appeared acceptable given the risk profile of the recruited patients. PMID- 28653162 TI - Completely Intracorporeal Handsewn Laparoscopic Anastomoses During Whipple Procedure. AB - BACKGROUND: Whipple procedure has been described since 1935,1 using classic open surgery. With the advent of minimally invasive surgery (MIS), it has been described to be feasible using the latest technology.2 , 3 In this video the authors report a full laparoscopic Whipple procedure, realizing the three anastomoses by intracorporeal handsewn method. VIDEO: A 70-year-old man who presented with adenocarcinoma of the ampulla of Vater, infiltrating the pancreatic parenchyma underwent to a laparoscopic Whipple. Preoperative work-up shows a T3N1M0 tumor. RESULTS: No perioperative complications were registered. The pancreatico-jejunostomy was created in end-to-side fashion using two PDS 3/0 running sutures (Fig. 1), the hepatico-jejunostomy in end-to-side method using two PDS 4/0 running sutures (Fig. 2), and the gastro-jejunostomy in end-to-side method using two PDS 1 running sutures (Fig. 3). Total operative time was 8 h 20 min. Time for the dissection was 6 h 20 min, time for the specimen's extraction was 20 min, and time for the three laparoscopic intracorporeal handsewn anastomoses was 1 h 40 min. Operative bleeding was 350 cc. Patient was discharged on postoperative day 9. Pathologic report confirmed the moderately differentiated adenocarcinoma of the ampulla of Vater, with perinervous infiltration and lymphovascular emboli, free margins, 2 metastatic lymphnodes on 23 isolated; 8 edition UICC stade: pT3bN1. CONCLUSIONS: Laparoscopic Whipple remains an advanced procedure to be performed by laparoscopy as well as by open surgery. All the advantages of MIS, such as reduced abdominal trauma, less postoperative pain, shorter hospital stay, improved patient's comfort, and enhanced cosmesis are offered using using laparoscopy. PMID- 28653163 TI - [Nutritional medicine in elderly patients : Advances and challenges]. PMID- 28653165 TI - Living-Donor Kidney Transplantation in Developing Countries: Walking Sometimes the Tightrope Without a Net.... PMID- 28653164 TI - Should DBS for Psychiatric Disorders be Considered a Form of Psychosurgery? Ethical and Legal Considerations. AB - Deep brain stimulation (DBS), a surgical procedure involving the implantation of electrodes in the brain, has rekindled the medical community's interest in psychosurgery. Whereas many researchers argue DBS is substantially different from psychosurgery, we argue psychiatric DBS-though a much more precise and refined treatment than its predecessors-is nevertheless a form of psychosurgery, which raises both old and new ethical and legal concerns that have not been given proper attention. Learning from the ethical and regulatory failures of older forms of psychosurgery can help shed light on how to address the regulatory gaps that exist currently in DBS research. To show why it is important to address the current regulatory gaps within psychiatric DBS, we draw on the motivations underlying the regulation of earlier forms of psychosurgery in the US. We begin by providing a brief history of psychosurgery and electrical brain stimulation in the US. Against this backdrop, we introduce psychiatric DBS, exploring current research and ongoing clinical trials. We then draw out the ethical and regulatory similarities between earlier forms of psychosurgery and psychiatric DBS. As we will show, the factors that motivated strict regulation of earlier psychosurgical procedures mirror concerns with psychiatric DBS today. We offer three recommendations for psychiatric DBS regulation, which echo earlier motivations for regulating psychosurgery, along with new considerations that reflect the novel technologies used in DBS. PMID- 28653166 TI - World Map of Scientific Misconduct. AB - A comparative world map of scientific misconduct reveals that countries with the most rapid growth in scientific publications also have the highest retraction rate. To avoid polluting the scientific record further, these nations must urgently commit to enforcing research integrity among their academic communities. PMID- 28653167 TI - Why Frankenstein is a Stigma Among Scientists. AB - As one of the best known science narratives about the consequences of creating life, Mary Shelley's Frankenstein; or, The Modern Prometheus (1818) is an enduring tale that people know and understand with an almost instinctive familiarity. It has become a myth reflecting people's ambivalent feelings about emerging science: they are curious about science, but they are also afraid of what science can do to them. In this essay, we argue that the Frankenstein myth has evolved into a stigma attached to scientists that focalizes the public's as well as the scientific community's negative reactions towards certain sciences and scientific practices. This stigma produces ambivalent reactions towards scientific artifacts and it leads to negative connotations because it implies that some sciences are dangerous and harmful. We argue that understanding the Frankenstein stigma can empower scientists by helping them revisit their own biases as well as responding effectively to people's expectations for, and attitudes towards, scientists and scientific artifacts. Debunking the Frankenstein stigma could also allow scientists to reshape their professional identities so they can better show the public what ethical and moral values guide their research enterprises. PMID- 28653168 TI - Science as a Matter of Honour: How Accused Scientists Deal with Scientific Fraud in Japan. AB - Practices related to research misconduct seem to have been multiplied in recent years. Many cases of scientific fraud have been exposed publicly, and journals and academic institutions have deployed different measures worldwide in this regard. However, the influence of specific social and cultural environments on scientific fraud may vary from society to society. This article analyzes how scientists in Japan deal with accusations of scientific fraud. For such a purpose, a series of scientific fraud cases that took place in Japan has been reconstructed through diverse sources. Thus, by analyzing those cases, the social basis of scientific fraud and the most relevant aspects of Japanese cultural values and traditions, as well as the concept of honour which is deeply involved in the way Japanese scientists react when they are accused of and publicly exposed in scientific fraud situations is examined. PMID- 28653169 TI - Trust in Science: CRISPR-Cas9 and the Ban on Human Germline Editing. AB - In 2015 scientists called for a partial ban on genome editing in human germline cells. This call was a response to the rapid development of the CRISPR-Cas9 system, a molecular tool that allows researchers to modify genomic DNA in living organisms with high precision and ease of use. Importantly, the ban was meant to be a trust-building exercise that promises a 'prudent' way forward. The goal of this paper is to analyse whether the ban can deliver on this promise. To do so the focus will be put on the precedent on which the current ban is modelled, namely the Asilomar ban on recombinant DNA technology. The analysis of this case will show (a) that the Asilomar ban was successful because of a specific two-step containment strategy it employed and (b) that this two-step approach is also key to making the current ban work. It will be argued, however, that the Asilomar strategy cannot be transferred to human genome editing and that the current ban therefore fails to deliver on its promise. The paper will close with a reflection on the reasons for this failure and on what can be learned from it about the regulation of novel molecular tools. PMID- 28653170 TI - Should Internet Researchers Use Ill-Gotten Information? AB - This paper describes how the ethical problems raised by scientific data obtained through harmful and immoral conduct (which, following Stan Godlovitch, is called ill-gotten information) may also emerge in cases where data is collected from the Internet. It describes the major arguments for and against using ill-gotten information in research, and shows how they may be applied to research that either collects information about the Internet itself or which uses data from questionable or unknown sources on the Internet. Three examples (the Internet Census 2012, the PharmaLeaks study, and research into keylogger dropzones) demonstrate how researchers address the ethical issues raised by the sources of data that they use and how the existing arguments concerning the use of ill gotten information apply to Internet research. The problems faced by researchers who collect or use data from the Internet are shown to be the same problems faced by researchers in other fields who may obtain or use ill-gotten information. PMID- 28653171 TI - Editing mammalian genomes: ethical considerations. AB - Genome editing is facilitating the manipulation of genomes on an unprecedented scale. It promises to revolutionize our ability to study gene function and generate models of human genetic disease in a range of organisms, most notably in mammals such as the mouse. Is this new technology likely to be disruptive to our research practices in any way? Will it alter the ways in which we implement the ethical imperatives of the 3Rs? In short, what ethical questions are raised by genome editing of mammals in a biomedical research context? PMID- 28653174 TI - Erratum to: What is new in CDG? PMID- 28653172 TI - A cis-eQTL genetic variant of the cancer-testis gene CCDC116 is associated with risk of multiple cancers. AB - Recent studies have found that cancer-testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls. We found a significant association between rs3747093 located in the CCDC116 promoter and lung cancer risk (OR = 0.91, P meta = 7.81 * 10-6). Although CCDC116 was expressed at lower levels in somatic tissues compared to the testis, the protective allele A of rs3747093 was associated with decreased CCDC116 expression in many normal tissues, including the lung (P = 8.1 * 10-13). We subsequently genotyped this variant in another four commonly diagnosed cancers (gastric, esophageal, colorectal, and breast cancers), as we found expression quantitative trait locus (eQTL) signals for rs3747093 and CCDC116 in their corresponding normal tissues. Interestingly, we observed consistent associations between rs3747093 and multiple cancers (gastric cancer: OR = 0.85, P = 2.21 * 10-4; esophageal cancer: OR = 0.91, P = 2.57 * 10-2; colorectal cancer: OR = 0.80, P = 1.85 * 10-6; and breast cancer: OR = 0.87, P = 1.55 * 10-3). Taken together, the A allele of rs3747093 showed significant protective effects on cancer risk (OR = 0.88, P pool = 6.52 * 10-13) in an Asian population. Moreover, our findings suggest that low abundance expression of CT genes in normal tissues may also contribute to tumorigenesis, providing a new mechanism of CT genes in the development of cancer. PMID- 28653173 TI - Human Metaplastic Breast Carcinoma and Decorin. AB - Metaplastic breast carcinoma (MBC) is a rare subtype of invasive breast cancer and has poor prognosis. In general, cancers are heterogeneous cellular masses comprised of different cell types and their extracellular matrix (ECM). However, little is known about the composition of the ECM and its constituents in MBC. Decorin is a ubiquitous ECM macromolecule known of its oncosuppressive activity. As such, it provides an intriguing molecule in the development of novel therapeutics for different malignancies such as MBC. In this study, decorin immunoreactivity and the effect of adenoviral decorin cDNA (Ad-DCN) transduction were examined in MBC. Multiple immunohistochemical stainings were used to characterize a massive breast tumour derived from an old woman. Furthermore, three-dimensional (3D) explant cultures derived from the tumour were transduced with Ad-DCN to study the effect of the transduction on the explants. The MBC tumour was shown to be completely negative for decorin immunoreactivity demonstrating that the malignant cells were not able to synthesize decorin. Ad DCN transduction resulted in a markedly altered cytological phenotype of MBC explants by decreasing the amount of atypical cells and by inhibiting cell proliferation. The results of this study support approaches to develop new, decorin-based adjuvant therapies for MBC. PMID- 28653177 TI - Reply to Letter to the Editor to J-shaped relationship between habitual coffee consumption and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA study. PMID- 28653176 TI - Amino acid synthesis deficiencies. AB - In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the "classical" inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. This makes the biochemical diagnosis of this relatively new group of metabolic diseases challenging. Defects in the synthesis pathways of serine metabolism, glutamine, proline and, recently, asparagine have all been reported. Although these amino acid synthesis defects are in unrelated metabolic pathways, they do share many clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early onset seizures and varying degrees of mental disability. The brain abnormalities are accompanied by skin disorders such as cutis laxa in defects of proline synthesis, collodion-like skin and ichthyosis in serine deficiency, and necrolytic erythema in glutamine deficiency. Hypomyelination with accompanying loss of brain volume and gyration defects can be observed on brain MRI in all synthesis disorders. In adults with defects in serine or proline synthesis, spastic paraplegia and several forms of polyneuropathy with or without intellectual disability appear to be the major symptoms in these late-presenting forms of amino acid disorders. This review provides a comprehensive overview of the disorders in amino acid synthesis. PMID- 28653178 TI - J-shaped relationship between habitual coffee consumption and 10-year (2002-2012) cardiovascular disease incidence: methodological issues. PMID- 28653179 TI - Tree of Vater-Pacinian corpuscles in the human finger and thumb: a comparison between the late fetal stage and old age. AB - Using histological sections of 12 hands from 12 human fetuses at 20-34 weeks of gestation (150-290 mm) and 14 fingers (index and small) from seven donated cadavers of elderly individuals (aged 78-95 years), we compared the features of Vater-Pacinian corpuscles between these two stages of life. Corpuscles with thin, tightly packed lamellae appeared to undergo a change to thick, loosely packed lamellae at 23-32 weeks. The typical fetal corpuscle had two parts: (1) a rod like proximal part (0.2-0.6 mm in length) extending along the proximodistal axis of the finger, and (2) a distal end (0.1 mm) after acute bending of the proximal part. Corpuscles were associated with palmar digital nerves in the fingers, but were also present along the dorsal nerves in the thumb. A flower bouquet- or tree like arrangement including 5-10 corpuscles extended to the dermis of the skin along a perforating artery. Serial sections of the thumb and fifth finger revealed approximately 80-180 corpuscles in the distal phalangeal segment. In elderly individuals, the corpuscles were distributed along the palmar digital nerve, but (1) their density was much lower than in fetuses and (2) a bouquet- or tree-like arrangement was rarely seen. In the distal segment, there were fewer than 40 adult corpuscles, being 0.2-0.5 mm thick and 1.0-2.5 mm long. Wavy or coiled corpuscles were evident. Because of the considerable differences in the distribution and number of corpuscles between the fetus and adult, they appear to undergo considerable depletion with age, especially along thin, superficial nerve branches. PMID- 28653180 TI - Regional interaction between myocardial sympathetic denervation, contractile dysfunction, and fibrosis in heart failure with preserved ejection fraction: 11C hydroxyephedrine PET study. AB - PURPOSE: This investigation aimed to identify significant predictors of regional sympathetic denervation quantified by 11C-hydroxyephedrine (HED) positron emission tomography (PET) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). METHODS: Included in the study were 34 patients (age 63 +/- 15 years, 23 men) with HFpEF (left ventricular ejection fraction >=40%) and 11 age-matched volunteers without heart failure. Cardiac magnetic resonance imaging was performed to measure left ventricular size and function, and the extent of myocardial late gadolinium enhancement (LGE). 11C-HED PET was performed to quantify myocardial sympathetic innervation that was expressed as a 11C-HED retention index (RI, %/min). To identify predictors of regional 11C-HED RI in HFpEF patients, we propose a multivariate mixed-effects model for repeated measures over segments with an unstructured covariance matrix. RESULTS: Global 11C-HED RI was significantly lower and more heterogeneous in HFpEF patients than in volunteers (P < 0.01 for all). Regional 11C-HED RI was correlated positively with systolic wall thickening (r = 0.42, P < 0.001) and negatively with the extent of LGE (r = -0.43, P < 0.001). Segments in HFpEF patients with a large extent of LGE had the lowest regional 11C-HED RI among all segments (P < 0.001 in post hoc tests). Multivariate analysis demonstrated that systolic wall thickening and the extent of LGE were significant predictors of regional 11C-HED RI in HFpEF patients (both P <= 0.001). CONCLUSION: Regional sympathetic denervation was associated with contractile dysfunction and fibrotic burden in HFpEF patients, suggesting that regional sympathetic denervation may provide an integrated measure of myocardial damage in HFpEF. PMID- 28653181 TI - Laparoscopic Sleeve Gastrectomy for the Management of Type 1 Diabetes Mellitus. AB - BACKGROUND: The prevalence of obesity is on a continuous rise worldwide, with major studies clearly correlating obesity with the development of chronic metabolic disorders including type 2 diabetes. Bariatric surgery has proven to be beneficial in the management of this condition; however, a limited number of studies exist on its effect on type 1 diabetes. OBJECTIVE: The objective of this study is to evaluate the outcome of laparoscopic sleeve gastrectomy for the management of patients with type 1 diabetes (DM1). SETTING: This is a retrospective cohort study conducted in a university hospital and private practice in Kuwait. RESEARCH DESIGN AND METHODS: Analysis was conducted on 10 patients diagnosed with type 1 diabetes that underwent bariatric surgery from October 2008 until December 2016 at Amiri Hospital and Royale Hayat Hospital, Kuwait. Primary parameters included body mass index (BMI), % excess weight (%EWL) loss at follow-up, glycosylated hemoglobin (A1C), and basal insulin requirements. Total cholesterol readings and fasting blood glucose (FBS) levels were considered secondary outcomes. Statistical analysis of the data was carried out using Statistical Package for the Social Sciences (SPSS) software. RESULTS: Mean BMI showed a reduction from 41.9 +/- 5.4 to 31.4 +/- 8.4 kg/m2. Mean %EWL after the follow-up period was 74.4 +/- 25.3%. A1C levels failed to show a significant difference 12 months post-op (p = 0.189). Cholesterol levels did not display a significant decrease either (p = 0.447). When it came to insulin requirements, a significant difference was perceived, with the mean number of units of insulin required dropping from 76.6 to 18.2 (p = 0.026). FBS readings also showed a drop from 15.1 +/- 3.8 to 7.8 +/- 2.9 mmol/L (p = 0.001). CONCLUSIONS: Laparoscopic sleeve gastrectomy resulted in significant weight loss, comorbidity resolution as well as reduction in their insulin doses post-op. However, glycemic control does not seem to show significant improvement in these patients. Larger, more long term studies are needed to reach a definite conclusion on this topic. PMID- 28653182 TI - Coronal femoral TKA position significantly influences in vivo patellar loading in unresurfaced patellae after primary total knee arthroplasty. AB - PURPOSE: As patellar tracking and loading is influenced by tibial tuberosity and trochlear groove (TT-TG) distance, patellar height, thickness and tilt as well as TKA component position, it was our hypothesis that these parameters significantly correlate with patellar BTU intensity and localization in SPECT/CT. The purpose of the study was to investigate whether TKA component position as well as the height, thickness and tilt of the unresurfaced patella influences the intensity and the distribution pattern of BTU in SPECT/CT. METHODS: A total of 62 consecutive patients who underwent primary TKA without patellar resurfacing were prospectively included. Demographic data such as age, gender, side and type of primary TKA were noted. All patients underwent clinical and radiological examination in a specialized knee clinic, including standardized radiographs (anterior-posterior and lateral weight bearing, patellar skyline view) and Tc-99m HDP-SPECT/CT before, 12 and 24 months after TKA. SPECT/CT images were analysed on 3D reconstructed images. Rotational, sagittal and coronal position of the tibial and femoral TKA components was assessed using a previously validated analysis software. Measurements of BTU including intensity and anatomical distribution pattern were also performed from 3D data. The patellar height, thickness and tilt were measured, and the distance between TT and TG was measured using axial CT images. Univariate analysis was performed to identify any correlations between BTU and TKA component position and patellar measurements (p < 0.05). RESULTS: The highest median BTU was measured in the superior posterior parts of the patella. A statistically significant correlation was found between valgus alignment of the femoral TKA and increased BTU at the lateral patellar regions (p < 0.05). External rotation of the tibial TKA correlated with increased BTU at the lateral superior joint adjacent part (p < 0.05). No correlation was found between the tibial TKA position (varus-valgus, anterior and posterior slope), TT-TG distance, patellar height and patellar BTU values. CONCLUSIONS: A significant correlation of increased patellar BTU was found with femoral valgus TKA alignment. These findings highlight the importance of femoral TKA position in coronal plane with regard to post-operative patellar tracking. Moreover, these facts might explain anterior knee pain in unhappy TKA with femoral valgus alignment. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 28653183 TI - Patient satisfaction with health is substantially improved following ACL reconstruction. AB - PURPOSE: To prospectively monitor health-related quality of life and return to work after arthroscopic anterior cruciate ligament (ACL) reconstruction in patients with isolated ACL tears. METHODS: Sixty consecutive patients with isolated ACL tears who underwent arthroscopic ACL reconstruction were prospectively monitored using the "Questions on Life Satisfaction Modules" (FLZM) and "Short-Form 12 (SF-12)" quality-of-life outcome measures. The Lysholm score and Tegner activity index were used as functional outcome measures. Additionally, return to work (months) together with level of physical workload was analysed. Outcome measures were assessed the day before surgery and at 6, 12 weeks and 6, 12, and 24 months post-operatively. Quality-of-life outcomes were correlated with functional outcome scores. RESULTS: Satisfaction with health (FLZM) significantly improved within the first 2 years (p < 0.05), and the physical component scale (SF12) showed a significantly higher score after 3, 6, 12 and 24 months as compared with preoperative values (p < 0.05). "General life satisfaction (FLZM)" was initially decreased at 6 weeks (p < 0.05) but increased during the further follow-up period, reaching a score not significantly different from preoperative values. Mean Lysholm score improved from 66 preoperatively to 89 post-operatively (p < 0.05) and the median Tegner activity index improved from four to six points (p < 0.05) at final follow-up. Mean time to return to work was 7 weeks (range 1 34 weeks), and it strongly depended on physical workload. A positive correlation between quality of life and functional outcome (Lysholm score) was observed. CONCLUSION: General life satisfaction is impaired during the early post-operative course, but returns to preoperative values after 2 years. Satisfaction with health reaches higher values after 6, 12 and 24 months post-operatively, and the SF-12 physical component scale was seen to improve during the follow-up period. Improved functional outcomes were observed to correlate with quality-of-life measurements. Thus, patients can preoperatively be informed that they will benefit from ACL reconstruction in terms of an improved knee function and satisfaction with health. Heavy physical workload must be considered as a risk factor for prolonged time lost to return to work. These patients have to be identified and informed about realistic expectations. LEVEL OF EVIDENCE: II. PMID- 28653184 TI - Reversal of the platelet inhibitory effect of the P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor in vitro: a new approach to an old issue. AB - AIM: Platelet transfusion is an effective option to reverse platelet inhibition in thienopyridine-treated patients suffering from bleedings or requiring urgent surgery. However, in ticagrelor-treated patients, the previous studies revealed significant clinical effects to platelet rich plasma (PRP) but poor response to pooled platelets (PP) as used in clinical routine. The aim of this study was to elucidate a potential pathomechanism to explain the poor response of ticagrelor to PP. METHODS AND RESULTS: From 79 whole blood samples of patients treated with ticagrelor, prasugrel, or clopidogrel, the PRI-VASP was determined before and after in vitro platelet supplementation of PP or PRP at increasing concentrations. Compared to prasugrel- and clopidogrel-treated patients, the PRI VASP of ticagrelor-treated patients showed no significant increase after in vitro administration of PP. PRI-VASP was performed in ticagrelor-treated samples after in vitro addition of 1: centrifuged PRP platelets resuspended in PP buffer, 2: PP with human serum, 3: human serum alone. Surprisingly, PP with human serum or human serum alone were able to significantly increase PRI-VASP in samples of ticagrelor-treated patients (11.7 +/- 10.9 -> 61.3 +/- 10.9%, p = 0.006; 11.7 +/- 10.9 -> 54.1 +/- 2.7%, p < 0.001). This effect could also be shown using human albumin (18.9 +/- 5.1% -> 80 g/l human albumin: 48.1 +/- 8.3%, p < 0.001). CONCLUSION: The present study demonstrates that addition of human serum and human albumin alone is able to reverse the ticagrelor effects in vitro and supports our novel hypothesis of the importance of proteins in reversing the effects of ticagrelor by binding active ticagrelor. PMID- 28653186 TI - Ebola Virus Disease in Humans: Pathophysiology and Immunity. AB - Viruses of the Ebolavirus genus cause sporadic epidemics of severe and systemic febrile disease that are fueled by human-to-human transmission. Despite the notoriety of ebolaviruses, particularly Ebola virus (EBOV), as prominent viral hemorrhagic fever agents, and the international concern regarding Ebola virus disease (EVD) outbreaks, very little is known about the pathophysiology of EVD in humans and, in particular, about the human immune correlates of survival and immune memory. This lack of basic knowledge about physiological characteristics of EVD is probably attributable to the dearth of clinical and laboratory data gathered from past outbreaks. The unprecedented magnitude of the EVD epidemic that occurred in West Africa from 2013 to 2016 has allowed, for the first time, evaluation of clinical, epidemiological, and immunological parameters in a significant number of patients using state-of-the-art laboratory equipment. This review will summarize the data from the literature regarding human pathophysiologic and immunologic responses to filoviral infection. PMID- 28653187 TI - Virus-Host Gene Interactions Define HIV-1 Disease Progression. AB - In this chapter, we will review recent research on the virology of HIV-1 transmission and the impact of the transmitted virus genotype on subsequent disease progression. In most instances of HIV-1 sexual transmission, a single genetic variant, or a very limited number of variants from the diverse viral quasi-species present in the transmitting partner establishes systemic infection. Transmission involves both stochastic and selective processes, such that in general a minority variant in the donor is transmitted. While there is clear evidence for selection, the biological properties that mediate transmission remain incompletely defined. Nevertheless, the genotype of the transmitted founder virus, which reflects prior exposure to and escape from host immune responses, clearly influences disease progression. Some escape mutations impact replicative capacity, while others effectively cloak the virus from the newly infected host's immune response by preventing recognition. It is the balance between the impact of escape mutations on viral fitness and susceptibility to the host immunogenetics that defines HIV-1 disease progression. PMID- 28653188 TI - Guide to the Correct Use of Filoviral Nomenclature. AB - The International Committee on Taxonomy of Viruses (ICTV) currently recognizes three genera and seven species as part of the mononegaviral family Filoviridae. Eight distinct filoviruses (Bundibugyo virus, Ebola virus, Lloviu virus, Marburg virus, Ravn virus, Reston virus, Sudan virus, and Tai Forest virus) have been assigned to these seven species. This chapter briefly summarizes the status quo of filovirus classification and focuses on the importance of differentiating between filoviral species and filoviruses and the correct use of taxonomic and vernacular filovirus names and abbreviations in written and oral discourse. PMID- 28653185 TI - Nitrate transporters: an overview in legumes. AB - MAIN CONCLUSION: The nitrate transporters, belonging to NPF and NRT2 families, play critical roles in nitrate signaling, root growth and nodule development in legumes. Nitrate plays an essential role during plant development as nutrient and also as signal molecule, in both cases working via the activity of nitrate transporters. To date, few studies on NRT2 or NPF nitrate transporters in legumes have been reported, and most of those concern Lotus japonicus and Medicago truncatula. A molecular characterization led to the identification of 4 putative LjNRT2 and 37 putative LjNPF gene sequences in L. japonicus. In M. truncatula, the NRT2 family is composed of 3 putative members. Using the new genome annotation of M. truncatula (Mt4.0), we identified, for this review, 97 putative MtNPF sequences, including 32 new sequences relative to previous studies. Functional characterization has been published for only two MtNPF genes, encoding nitrate transporters of M. truncatula. Both transporters have a role in root system development via abscisic acid signaling: MtNPF6.8 acts as a nitrate sensor during the cell elongation of the primary root, while MtNPF1.7 contributes to the cellular organization of the root tip and nodule formation. An in silico expression study of MtNPF genes confirmed that NPF genes are expressed in nodules, as previously shown for L. japonicus, suggesting a role for the corresponding proteins in nitrate transport, or signal perception in nodules. This review summarizes our knowledge of legume nitrate transporters and discusses new roles for these proteins based on recent discoveries. PMID- 28653189 TI - Small Animal Models for Studying Filovirus Pathogenesis. AB - Filovirus small animal disease models have so far been developed in laboratory mice, guinea pigs, and hamsters. Since immunocompetent rodents do not exhibit overt signs of disease following infection with wild-type filoviruses isolated from humans, rodent models have been established using adapted viruses produced through sequential passage in rodents. Rodent-adapted viruses target the same cells/tissues as the wild-type viruses, making rodents invaluable basic research tools for studying filovirus pathogenesis. Moreover, comparative analyses using wild-type and rodent-adapted viruses have provided beneficial insights into the molecular mechanisms of pathogenicity and acquisition of species-specific virulence. Additionally, wild-type filovirus infections in immunodeficient rodents have provided a better understanding of the host factors required for resistance to filovirus infection and of the immune response against the infection. This chapter provides comprehensive information on the filovirus rodent models and rodent-adapted filoviruses. Specifically, we summarize the clinical and pathological features of filovirus infections in all rodent models described to date, including the recently developed humanized and collaborative cross (CC) resource recombinant inbred (RI) intercrossed (CC-RIX) mouse models. We also cover the molecular determinants responsible for adaptation and virulence acquisition in a number of rodent-adapted filoviruses. This chapter clearly defines the characteristic and advantages/disadvantages of rodent models, helping to evaluate the practical use of rodent models in future filovirus studies. PMID- 28653190 TI - Therapeutics Against Filovirus Infection. AB - Therapies for filovirus infections are urgently needed. The paradoxical issue facing therapies is the need for rigorous safety and efficacy testing, adhering to the principle tenant of medicine to do no harm, while responding to the extreme for a treatment option during an outbreak. Supportive care remains a primary goal for infected patients. Years of research into filoviruses has provided possible medical interventions ranging from direct antivirals, host factor supportive approaches, and passive immunity. As more basic research is directed toward understanding these pathogens and their impact on the host, effective approaches to treat patients during infection will be identified. The ability to manage outbreaks with medical interventions beyond supportive care will require clinical trial design that will balance the benefits of the patient and scientific community. PMID- 28653191 TI - MicroRNA Dysregulation to Identify Novel Therapeutic Targets. AB - This paper describes how we discovered the juxtaposition of the MYC gene to the human immunoglobulin loci and how that finding was extended to characterize molecularly the t(14;18) chromosome translocation of follicular lymphoma and to clone the BCL2 gene. BCL2 is also overexpressed in CLL, the most common human leukemia. We discovered that most of human CLLs have a deletion of two microRNAs residing in the same polycistronic RNA, miR-15a and miR-16-1, and that these two microRNAs are negative regulators of BCL2. Thus, loss of miR-15/16 leads to overexpression of BCL2 that can be targeted by the new drug, venetoclax, that was recently approved by the FDA for the treatment of aggressive CLLs. PMID- 28653192 TI - Risky economic choices and frontal EEG asymmetry in the context of Reinforcer Sensitivity-Theory-5. AB - This study investigated individual risky choice behavior in a gambling task and its relation with traits proposed by the Reinforcer-Sensitivity-Theory-5 (RST-5; Corr & McNaughton in Neuroscience and Biobehavioral Reviews, 36(10), 2339-2354, 2012) as well as with frontal EEG asymmetry. As assumed by the RST-5, the results showed independent influences of approach/avoidance and gain/loss sensitivities on participants' behavior in risky choices. Individual approach/avoidance sensitivity was predicted by trait measures of the behavioral approach system (BAS) and the behavioral inhibition system (BIS), while no such correlation was present for gain/loss sensitivity. EEG recordings revealed relatively stronger left-frontal cortical activity for trials with approach motivation compared to conflict and avoidance motivation. On the individual level, relatively stronger left-frontal cortical activity was associated with trait BAS. In addition, activity changes in frontal EEG asymmetry were associated relatively higher behavioral approach sensitivity. We conclude that frontal EEG asymmetry is an especially useful neuronal marker of BAS sensitivity and that the traits proposed by the RST-5 (measured by frontal EEG asymmetry and self-report) can be used to explain individual differences in risky choice behavior. PMID- 28653193 TI - Effects of ripasudil hydrochloride hydrate (K-115), a Rho-kinase inhibitor, on ocular blood flow and ciliary artery smooth muscle contraction in rabbits. AB - PURPOSE: Ripasudil, a Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, is a novel drug for glaucoma in Japan. ROCK inhibition not only reduces intraocular pressure (IOP) but also increases ocular blood flow. We investigated the effects of ripasudil on optic disc blood flow (ODBF) in rabbit eyes and in isolated rabbit ciliary arteries. METHODS: We measured IOP by tonometry and ODBF by laser speckle flowgraphy (LSFG) in male Dutch rabbits. A single drop (20 MUL) of 0.8% ripasudil was delivered to the ocular surface after topical application of phenylephrine hydrochloride to reduce the ODBF. The effects of ripasudil on isolated rabbit ciliary artery smooth muscle contractions were measured in vitro with a myograph. RESULTS: Ripasudil inhibited the reduction of ODBF induced by phenylephrine at 30 and 120 min after instillation (P < .05). The blood flow change was not significantly correlated with the IOP change. Ripasudil induced a concentration-dependent relaxation in isolated rabbit ciliary arteries precontracted with a high-potassium solution. This relaxation was not mediated through the endothelium-dependent activities of nitric oxide synthase, prostacyclin, or the large-conductance calcium-activated K+ channel as shown by the inability of specific inhibitors of these pathways to block the ripasudil-induced relaxation. CONCLUSIONS: Taken together, our results showed that ripasudil not only decreased IOP but also increased ODBF in rabbits. However, the changes in IOP were not correlated with the changes in ODBF. Ripasudil also induced a concentration-dependent relaxation of isolated rabbit ciliary arteries through a NO-independent mechanism. Further investigation of the effect of ripasudil on ODBF is needed. PMID- 28653194 TI - Giardia duodenalis and Cryptosporidium spp. as contaminant protozoa of the main rivers of western Romania: genetic characterization and public health potential of the isolates. AB - The objective of this study was to establish the prevalence, contamination level, and public health significance of Giardia duodenalis and Cryptosporidium spp. in the primary rivers of western Romania. A total of 53 sampling points in the 24 most important western Romanian rivers in four counties (Arad, Bihor, Caras Severin, and Timis) were investigated from March to September 2016. Surface water samples were collected by microfiber filtration. Cryptosporidium and Giardia (oo)cysts were isolated using immunomagnetic separation (IMS) according to the USEPA 1623 method and, after staining with fluorescently labeled (FITC) monoclonal antibodies, were identified and counted under a microscope. The Cryptosporidium and Giardia (oo)cysts were identified to species and assemblage/sub-assemblage level through the nested PCR-RFLP procedure targeting the 18S ribosomal RNA and gdh genes, respectively. PCR-based techniques were utilized for all water samples. Overall, 22 samples (41.5%) were determined to be positive for Giardia cysts (ranging from 0.05 to 300 cysts per liter), and four samples (7.5%) tested positive for Cryptosporidium oocysts (0.17-48 oocysts/l). G. duodenalis was molecularly identified in 13 water samples (24.5%), indicating the presence of the sub-assemblage A-II (n = 12) and assemblage E (n = 1). PCR RFLP showed that two samples (3.8%) contained Cryptosporidium DNA, and the identified species were Cryptosporidium parvum and Cryptosporidium canis. All positive results were successfully confirmed by DNA sequencing. Subtyping of the zoonotic C. parvum isolate based on sequence analysis of the GP60 gene revealed the occurrence of the IIaA16G1R1 subtype. The results of this study highlight considerable contamination of river waters with pathogenic Giardia spp. and Cryptosporidium spp., suggesting a potential risk for the public and animal health. This report presents the first extended published description of the presence of Giardia spp. and Cryptosporidium spp. in the aquatic environment in Romania. PMID- 28653195 TI - Effects of residue incorporation and plant growth on soil labile organic carbon and microbial function and community composition under two soil moisture levels. AB - This study investigates the effects of residue incorporation coupled with plant growth and soil moisture level on wheat biomasses, soil nutrients, labile organic carbon (LOC), microbial metabolic profiles, and community composition. Four management practices were used in a 180-day pot experiment: (1) control (CON), (2) maize (Zea mays L.) residue incorporation without plants (MR), (3) wheat (Triticum aestivum L.) plants without maize residue (WP), and (4) maize residue incorporation with wheat plants (MRWPs). Each management practice included soil moisture at both 40 and 80% of field capacity. At wheat harvest, soil nutrient contents in the WP and MRWP treatments were significantly lower than in the CON and MR treatments. In comparison with the CON treatment, MR, WP, and MRWP treatments resulted in 35, 23, and 67% increases in dissolved organic carbon content; 17, 12, and 34% increases in hot-water extractable organic carbon content; and 78, 50, and 150% increases in microbial biomass carbon content. Furthermore, microbial utilizations of carboxylic acids and polymer carbon sources in the MR, WP, and MRWP treatments were 261 and 88%, 239 and 105%, and 300 and 126% higher than in the CON treatment. The MR and CON treatments had similar phospholipid fatty acid (PLFA) content but the WP and MRWP treatments had significantly increased gram-negative content and changes to community composition compared with the CON and MR treatments. The wheat biomass, LOC, and PLFA contents significantly increased with greater soil moisture. Overall, these results suggest an additive effect of residue incorporation and plant growth on LOC contents, primarily due to the changes in microbial utilization of carbon sources and community composition. PMID- 28653196 TI - Air pollution and hospital visits for acute upper and lower respiratory infections among children in Ningbo, China: A time-series analysis. AB - Acute upper and lower respiratory infections are main causes of mortality and morbidity in children. Air pollution has been recognized as an important contributor to development and exacerbation of respiratory infections. However, few studies are available in China. In this study, we investigated the short-term effect of air pollution on hospital visits for acute upper and lower respiratory infections among children under 15 years in Ningbo, China. Poisson generalized models were used to estimate the associations between air pollution and hospital visits for acute upper and lower respiratory infections adjusted for temporal, seasonal, and meteorological effects. We found that four pollutants (PM2.5, PM10, NO2, and SO2) were significantly associated with hospital visits for acute upper and lower respiratory infections. The effect estimates for acute upper respiratory infections tended to be higher (PM2.5 ER = 3.46, 95% CI 2.18, 4.76; PM10 ER = 2.81, 95% CI 1.93, 3.69; NO2 ER = 11.27, 95% CI 8.70, 13.89; SO2 ER = 15.17, 95% CI 11.29, 19.19). Significant associations for gaseous pollutants (NO2 and SO2) were observed after adjustment for particular matter. Stronger associations were observed among older children and in the cold period. Our study suggested that short-term exposure to outdoor air pollution was associated with hospital visits for acute upper and lower respiratory infections in Ningbo. PMID- 28653197 TI - Municipal solid waste leachate impact on metabolic activity of wheat (Triticum aestivum L.) seedlings. AB - Municipal solid waste (MSW) contains contaminants that could possibly leach out and pollute the soil, water sources. In this investigation, the MSW leachate toxicity was evaluated using wheat seedling plant bioassay. The eco-toxicity activities of leachate at several time intervals were explored, and the toxicity of these leachates on wheat (Triticum aestivum L.) seed germination and chlorophyll a and chlorophyll b (Chl a and Chl b) levels were determined. The findings showed that leachate can affect the metabolic activity of the wheat plant. Therefore, in order to protect the environment, the polluted leachate should be treated. PMID- 28653198 TI - A combined NMR- and HPLC-MS/MS-based metabolomics to evaluate the metabolic perturbations and subacute toxic effects of endosulfan on mice. AB - Endosulfan is the newly persistent organic pollutants (POPs) added to the Stockholm Convention as its widespread use, persistence, bioaccumulation, long range transport, endocrine disruption, and toxicity related to various adverse effects. In the present study, male mice were administrated endosulfan at 0, 0.5, and 3.5 mg/kg by gavage for 2 weeks. 1H-NMR-based urinary metabolomics, HPLC MS/MS-based targeted serum metabolomics, clinical analysis, and histopathology techniques were employed to evaluate the metabolic perturbations of subacute endosulfan exposure. Endosulfan exposures resulted in weight loss, liver inflammation and necrosis, and alterations in serum amino acids and urine metabolomics. Based on altered metabolites, several significantly perturbed pathways were identified including glycine, serine, and threonine metabolism; TCA cycle; pyruvate metabolism; glycolysis or gluconeogenesis; glycerophospholipid metabolism; and glyoxylate and dicarboxylate metabolism. Such pathways were highly related to amino acid metabolism, energy metabolism, and lipid metabolism. In addition, metabolomic results also demonstrated that gut microbiota was remarkably altered after endosulfan exposure. These observations may provide novel insight into revealing the potential toxic mechanism and evaluating the health risk of endosulfan exposure at metabolomic level. PMID- 28653199 TI - Evaluation of air pollution tolerance index and anticipated performance index of plants and their application in development of green space along the urban areas. AB - Air pollution due to vehicular emissions has become one of the most serious problems in the whole world and has resulted in huge threat to both the environment and the health of living organisms (plants, humans, animals, microorganisms). Plants growing along the roadsides get affected at the maximum as they are the primary recipients to different air pollutants and show varied levels of tolerance and sensitivity. Taking this into account, the present work was based on assessment of seasonal variation in air pollution tolerance index (APTI) and anticipated performance index (API) of four roadside plants, namely, Alstonia scholaris, Nerium oleander, Tabernaemontana coronaria, and Thevetia peruviana belonging to family Apocynaceae. APTI was calculated by the determination of four important biochemical parameters, viz., pH, relative water content (RWC), total chlorophyll (TChl), and ascorbic acid (AsA) content of leaves. The leaf samples were collected from plants growing at seven different sites of Amritsar (Punjab), India, for pre-monsoon and post-monsoon seasons. Highest APTI (82.14) was reported in N. oleander during the pre-monsoon season while the lowest was recorded in T. coronaria (18.59) in the post-monsoon season. On the basis of API score, A. scholaris was anticipated to be an excellent performer during the pre-monsoon and post-monsoon seasons followed by N. oleander, T. coronaria, and T. peruviana. Linear regression analysis and Pearson's correlation coefficient depicted significant positive correlation between APTI and ascorbic acid content during the pre-monsoon and post-monsoon seasons. PMID- 28653200 TI - Effect of different nitrogen forms on the toxicity of Zn in wheat seedling root: a modeling analysis. AB - Heavy metal stress in culture media is always rhizotoxic. Our study aims to investigate the role of negative potential (psi 0) at root cell membrane surface (CMs) on modeling Zn2+ toxicity to wheat seedling roots and to examine the effects of different nitrogen forms (NH4+ and NO3-) on psi 0 and Zn rhizotoxicity. Solution culture experiments were conducted to measure the root elongation and Zn accumulation under Zn2+ exposure. The role of two nitrogen forms in affecting Zn2+ toxicity was compared, giving particular consideration to psi 0 and Zn2+ activities at CMs ({Zn2+}0). Results showed that NH4+ alleviates Zn2+ rhizotoxicity and NO3- increases Zn2+ rhizotoxicity. In modeling the rhizotoxicity, root length correlated better with {Zn2+}0 than {Zn2+}b, and the predictive accuracy (r 2) of NH4+ treatment increased from 0.748 to 0.917 when incorporation of {Zn2+}0 and {Ca2+}0 into analysis. Oppositely, psi 0 played a limited role in modeling Zn2+ rhizotoxicity and bioavailability in NO3- treated medium (r 2 = 0.609). Moreover, higher concentration of Zn in roots was found in NO3- treatment, compared with the NH4+ treatment. psi 0 rather than the rhizotoxicity data correlated better with Zn accumulation especially in the NO3- treatment (r 2 > 0.7), which meant the electrical driving force at CMs playing a dominant role in modeling the metal accumulation. In conclusion, the alleviatory role of NH4+ on Zn toxicity and uptake was well explained and modeled by electrostatic effects at CMs. Though our data do not explore mechanisms for the NO3--Zn2+ interactions, we propose that psi 0 worked better in affecting the driving force for root Zn uptake, than influencing metal bioavailability at CMs. PMID- 28653201 TI - Chondrolipoma of the breast as a rare variant of myofibroblastoma: an immunohistochemical study of two cases. AB - Chondrolipoma of the breast is a very rare tumor whose histogenesis remains obscure. We report two cases (56-year-old and 43-year-old women) and present the results of an immunohistochemical study which strongly suggests that this tumor is a variant of myofibroblastoma. The tumors predominantly consisted of lipoma like, mature adipose tissue, and many islands of hyaline cartilage. A proliferation of spindle cells associated with the deposition of collagen fibers was also seen. On immunohistochemical examination, spindle cells showed cytoplasmic reactivity for vimentin, desmin, bcl-2, and alpha-smooth muscle actin, as well as nuclear reactivity for estrogen receptor (ER) and progesterone receptor (PgR). Chondrocytes were immunoreactive for ER, PgR, S-100 protein, and Sox9. The nuclei of adipocytes, chondrocytes, and spindle cells were not immunoreactive for Rb (retinoblastoma) protein. The immunoreactivity of spindle cells for muscle markers indicates myofibroblastic differentiation, and the lack of the nuclear expression of Rb protein suggests the close relationship of this tumor with myofibroblastoma and spindle cell lipoma. The immunoreactivity of chondrocytes for ER and PgR suggests that they are derived from metaplasia of hormone-sensitive spindle cells. These findings support the concept that chondrolipoma of the breast could be a lipomatous variant of myofibroblastoma associated with cartilaginous metaplasia and that it should be added to members of the "13q/Rb family of tumors." PMID- 28653202 TI - A gastric MANEC with an adenocarcinoma of fundic-gland type as exocrine component. PMID- 28653203 TI - RAS screening in colorectal cancer: a comprehensive analysis of the results from the UK NEQAS colorectal cancer external quality assurance schemes (2009-2016). AB - Evidence strongly indicates that extended RAS testing should be undertaken in mCRC patients, prior to prescribing anti-EGFR therapies. With more laboratories implementing testing, the requirement for External Quality Assurance schemes increases, thus ensuring high standards of molecular analysis. Data was analysed from 15 United Kingdom National External Quality Assessment Service (UK NEQAS) for Molecular Genetics Colorectal cancer external quality assurance (EQA) schemes, delivered between 2009 and 2016. Laboratories were provided annually with nine colorectal tumour samples for genotyping. Information on methodology and extent of testing coverage was requested, and scores given for genotyping, interpretation and clerical accuracy. There has been a sixfold increase in laboratory participation (18 in 2009 to 108 in 2016). For RAS genotyping, fewer laboratories now use Roche cobas(r), pyrosequencing and Sanger sequencing, with more moving to next generation sequencing (NGS). NGS is the most commonly employed technology for BRAF and PIK3CA mutation screening. KRAS genotyping errors were seen in <=10% laboratories, until the 2014-2015 scheme, when there was an increase to 16.7%, corresponding to a large increase in scheme participants. NRAS genotyping errors peaked at 25.6% in the first 2015-2016 scheme but subsequently dropped to below 5%. Interpretation and clerical accuracy scores have been consistently good throughout. Within this EQA scheme, we have observed that the quality of molecular analysis for colorectal cancer has continued to improve, despite changes in the required targets, the volume of testing and the technologies employed. It is reassuring to know that laboratories clearly recognise the importance of participating in EQA schemes. PMID- 28653204 TI - Developments in the International Society of Biometeorology over the decade, 2007 2016. AB - Over the decade 2007-2016, the International Society of Biometeorology (ISB) has pursued its purpose of advancing the science of biometeorology through its Congresses and sponsoring conferences, meetings and workshops. In conjunction with Springer, ISB has introduced a new book series: Biometeorology, and published three volumes. ISB's journal, the International Journal of Biometeorology, has increased the number of issues to 12 per year and added the Fields of 'Aerobiology', 'Climate Change and Ecology' and 'Climate Change and Public Health'. Within ISB, there are currently six Commissions, reflecting the interests of the members and the needs of society. The newest, Biophysics of Adaptation and Response Commission, formed in 2015. Another group which formed over the decade was the Students and New Professionals Group. The Universal Thermal Climate Index Commission was formally dissolved in 2014 having met its aim of developing an easily understood human thermal index. At the Executive Board level, geographical representation has increased, with Councillors now being elected to represent six regions: Africa, Asia, Europe, Latin America and the Caribbean, Oceania and Northern America. The ISB has worked to better coordinate and communicate biometeorological research, collaborating strategically with international partners to achieve this objective. PMID- 28653205 TI - Author's reply to Paravidino et al.: Comment on: "Effect of exercise training on non-exercise physical activity: a systematic review and meta-analysis of randomized controlled trials". PMID- 28653206 TI - Comment on: "Effect of Exercise Training on Non-exercise Physical Activity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". PMID- 28653207 TI - [Familial exsudative vitreoretinopathy (FEVR) in childhood]. AB - A case of secondary neovascularization of the optic disc in familial exsudative vitreoretinopathy (FEVR) is reported. A 12-year-old girl presented with decreased visual acuity of the right eye to 0.05. Funduscopy showed a prominent fibrovascular neovascularization of the optic disc covering the macula. Fluorescein angiography demonstrated circular peripheral ischemia as well as vascular anomalies in both eyes. Peripheral laser coagulation of the ischemic retina of the right eye was conducted with the patient under general anesthesia. The central neovascularization regressed and visual acuity increased up to 0.4. Molecular genetic examination detected the LRP5 gene for FEVR. PMID- 28653208 TI - [Employed and self-employed specialists in outpatient ophthalmological care : Comparison with other specialist fields]. AB - AIM: The aim of the study was to evaluate the contribution to outpatient care and the perspectives of employed and self-employed ophthalmologists in isolation and in comparison to other professional groups. METHOD: Based on statistical data (source: statistical information provided by the National Association of Statutory Health Insurance Physicians) from 31 December 2015, newly admitted physicians in 2015 and their contribution differentiated by employment relationships were evaluated according to head count and working time equivalents (using "planning of demand equivalents"). The results were subdivided into type of outpatient facility, e.g. single practice, group practice and medical care centers (MVZ). RESULTS: The proportion of employed ophthalmologists (head count) in outpatient care (23%) and newly admitted physicians (81%) is above the interdisciplinary average (16% and 65%, respectively). In all medical professional groups the contribution according to time equivalents of employed physicians compared to self-employed physicians is lower (utilization rate: 65% in total and 70% in ophthalmology). In ophthalmology employment is seen in all types of outpatient practices: the number of ophthalmologists working in group practices is above average, compared to other groups they are underrepresented in MVZ and are working in single practices as frequently as all other specialties. DISCUSSION AND CONCLUSION: Employment of physicians is more common in all types of outpatient ophthalmological facilities than in other specialized professional groups. Possible reasons are the working conditions in ophthalmology attracting physicians preferring employment and the competitive situation for practice takeover. Since employed physicians contribute less time to medical care than self-employed physicians, ophthalmology has a higher risk of a shortage in medical care despite an increasing number of physicians. An increasing number of employed physicians has an impact on the structures of outpatient care; however, the intensity of concentration in healthcare structures can only be partially evaluated due to insufficient data. Based on the available data there is no end in sight for the trend towards employment in outpatient ophthalmological care. PMID- 28653209 TI - [Early onset of fingolimod-associated macular edema]. AB - BACKGROUND: Fingolimod, a disease-modifying sphingosine 1-phosphate receptor modulator, which was approved in Germany in 2011, decreases the relapse rate and reduces neuroinflammation in patients with relapsing-remitting multiple sclerosis. Macular edema is a well-known ocular side effect of fingolimod therapy. Specific intervals for ophthalmologic check-ups after starting fingolimod and definite treatment schedules for fingolimod-associated macular edema are, however, still lacking. CASE REPORT: We present a case of early fingolimod-associated macular edema in a 45-year-old female patient with relapsing-remitting multiple sclerosis. The patient complained about visual impairment 1 month after the start of fingolimod and visited an eye specialist. Funduscopic examination and imaging diagnostics revealed macular edema in both eyes. The treatment with fingolimod was immediately stopped. For therapy of macular edema topical application of nepafenac and oral acetazolamide were given. During the 6 months of treatment the macular edema completely disappeared and visual function recovered completely. DISCUSSION: At the time of diagnosis, it is fundamentally important to discuss the continuation of fingolimod administration with the attending neurologist and if necessary to discontinue the drug. Regular ophthalmologic check-ups at 4-week intervals over a period of 3 months are meaningful after beginning fingolimod treatment. As before, it is still a key aspect to determine predictive opthalmologic and neurological factors before beginning treatment to evaluate which patients are at risk of fingolimod associated macular edema. PMID- 28653211 TI - Functional (psychogenic) stereotypies. AB - Functional (psychogenic) movement disorders (FMDs) may present with a broad spectrum of phenomenology including stereotypic movements. We aimed to characterize the phenomenology of functional stereotypies and compare these features with those observed in 65 patients with tardive dyskinesia (TD). From a cohort of 184 patients with FMDs, we identified 19 (10.3%) with functional stereotypies (FS). There were 15 women and 4 men, with a mean age at onset of 38.6 +/- 17.4 years. Among the patients with FS, there were 9 (47%) with orolingual dyskinesia/stereotypy, 9 (47%) with limb stereotypies, 6 (32%) with trunk stereotypies, and 2 (11%) with respiratory dyskinesia as part of orofacial laryngeal-trunk stereotypy. These patients showed signs commonly seen in FMDs such as sudden onset (84%), prominent distractibility (58%), and periods of unexplained improvement (84%) that were not reported in patients with TD. Besides a much lower frequency of exposure to potential offending drugs, patients with FS differed from those with classic TD by a younger age at onset, lack of self biting, uncommon chewing movements, more frequent lingual movements without mouth dyskinesia, and associated functional tremor and abnormal speech. Lack of self biting showed the highest sensitivity (1.0) and abnormal speech showed the highest specificity (0.9) for the diagnosis of functional orolingual dyskinesia. FS represent part of the clinical spectrum of FMDs. Clinical and demographic features are helpful in distinguishing patients with FS from those with TD. PMID- 28653210 TI - Lateralized microstructural changes in early-stage Parkinson's disease in anterior olfactory structures, but not in substantia nigra. AB - Parkinson's disease (PD) is a progressive neurological disorder characterized by motor symptoms as well as severe deficits in olfactory function and microstructural changes in olfactory brain regions. Because of the evidence of asymmetric neuropathological features in early-stage PD, we examined whether lateralized microstructural changes occur in olfactory brain regions and the substantia nigra in a group of early-stage PD patients. Using diffusion tensor imaging (DTI) and the University of Pennsylvania Smell Identification Test (UPSIT), we assessed 24 early-stage PD patients (Hoehn and Yahr stage 1 or 2) and 26 healthy controls (HC). We used DTI and a region of interest (ROI) approach to study the microstructure of the left and right anterior olfactory structures (AOS; comprising the olfactory bulbs and anterior end of the olfactory tracts) and the substantia nigra (SN). PD patients had reduced UPSIT scores relative to HC and showed increased mean diffusivity (MD) in the SN, with no lateralized differences. Significant group differences in fractional anisotropy (FA) and MD were seen in the AOS, but these differences were restricted to the right side and were not associated with the primary side of motor symptoms amongst PD patients. No associations were observed between lateralized motor impairment and lateralized microstructural changes in AOS. Impaired olfaction and microstructural changes in AOS are useful for early identification of PD but asymmetries in AOS microstructure seem unrelated to the laterality of PD motor symptoms. PMID- 28653212 TI - Higher blood-brain barrier permeability is associated with higher white matter hyperintensities burden. AB - The pathogenesis of white matter hyperintensities (WMH) is incompletely understood but blood-brain barrier (BBB) dysfunction may play a key role. This study aimed to investigate the relationship between BBB permeability and the severity of WMH burden. Consecutive participants without symptomatic stroke history presented for physical examination were recruited in this cross-sectional study and divided into three WMH burden groups according to total Fazekas scores. They received dynamic contrast-enhanced-magnetic resonance imaging to measure BBB permeability, and received Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A total of 102 participants aged 49-90 years (mean age of 69.82 years) were enrolled (36 with low WMH burden, 35 with medium WMH burden, and 31 with high WMH burden). Multivariable linear regression analyses revealed that participants with higher WMH burden had significantly higher BBB leakage rate and area under the leakage curve in normal-appearing white matter, WMH, cortical gray matter, and deep gray matter (DGM) after adjustment for age, sex, and vascular risk factors. Scores on MMSE and MoCA decreased with increasing leakage rate in WMH and DGM after adjustment for age, sex, WMH burden, and education years. We found that higher BBB permeability is associated with higher WMH burden and cognitive decline. The compromised BBB integrity may be a critical contributor to the pathogenesis of WMH and part of a series of pathological processes that finally lead to cognitive impairment. PMID- 28653213 TI - External input for gait in people with Parkinson's disease with and without freezing of gait: One size does not fit all. AB - Cueing or feedback provided when gait deviates from a predefined goal (intelligent input) can now be provided with wearable technology for Parkinson's disease (PD). As people with and without freezing of gait (FOG) have distinct cognitive profiles, they may respond differently to various types of input. This study compared the effects of four input modalities during prolonged walking and explored the relationship with cognition, subjective preference, and FOG. Participants (15 with and 13 without FOG) walked 30 min while exposed to continuous cueing; intelligent cueing; intelligent feedback; or no input. Cueing consisted of metronome beats matched to comfortable cadence. Intelligent input represented bouts of ten beats indicating comfortable cadence (intelligent cueing) or an instruction to adapt gait speed (intelligent feedback) when cadence deviated from the comfortable target. Preference for one condition over the other was gathered. Freezers produced most stable gait under continuous cueing, but the majority favored intelligent feedback. Non-freezers showed no differences between conditions, but gait was more stable under intelligent input than in freezers. Interestingly, lower cognitive scores were related to worse gait during intelligent input, most prominently seen in freezers. These results suggest that cognitive ability is an aspect to take into account when deciding on the most appropriate cueing modality in different PD subgroups. PMID- 28653214 TI - Three-dimensional black-blood multi-contrast carotid imaging using compressed sensing: a repeatability study. AB - OBJECTIVE: The purpose of this work is to evaluate the repeatability of a compressed sensing (CS) accelerated multi-contrast carotid protocol at 3 T. MATERIALS AND METHODS: Twelve volunteers and eight patients with carotid disease were scanned on a 3 T MRI scanner using a CS accelerated 3-D black-blood multi contrast protocol which comprises T 1w, T 2w and PDw without CS, and with a CS factor of 1.5 and 2.0. The volunteers were scanned twice, the lumen/wall area and wall thickness were measured for each scan. Eight patients were scanned once, the inter/intra-observer reproducibility of the measurements was calculated. RESULTS: In the repeated volunteer scans, the interclass correlation coefficient (ICC) for the wall area measurement using a CS factor of 1.5 in PDw, T 1w and T 2w were 0.95, 0.81, and 0.97, respectively. The ICC for lumen area measurement using a CS factor of 1.5 in PDw, T 1w and T 2w were 0.96, 0.92, and 0.96, respectively. In patients, the ICC for inter/intra-observer measurements of lumen/wall area, and wall thickness were all above 0.81 in all sequences. CONCLUSION: The results show a CS accelerated 3-D black-blood multi-contrast protocol is a robust and reproducible method for carotid imaging. Future protocol design could use CS to reduce the scanning time. PMID- 28653215 TI - NLRP1, PTPN22 and PADI4 gene polymorphisms and rheumatoid arthritis in ACPA positive Singaporean Chinese. AB - Studies have shown that the genetic risk factors for rheumatoid arthritis (RA) differ substantially between Asian and Caucasian populations. Even among Asian populations, the genetic contributions of NLRP1, PTPN22 and PADI4 have been controversial. Consequently, we sought to address these separate findings and determine whether any of these proposed risk variants are associated with RA susceptibility, onset, DAS activity and erosion in a Singaporean Chinese cohort. We genotyped five SNPs within NLRP1 (rs878329 and rs6502867), PTPN22 (rs2488457 and rs6665194), and PADI4 (rs2240340) in 500 anti-cyclic citrullinated peptide antibody-positive (ACPA) patients with RA and 500 healthy controls using TaqMan assays. The CC genotype of NLRP1 rs878329 and TT genotype of PADI4 rs2240340 were associated with RA susceptibility. The risk association of the T allele of PADI4 rs2240340 with RA was confirmed through a meta-analysis based on previous reports in Asian populations. The GG genotype of PTPN22 rs6665194 (-3508A>G) was associated with significantly reduced risk of RA. No significant association was found for NLRP1 rs6502867 T/C and PTPN22 rs2488457 G/C polymorphisms. None of the five SNPs was associated with RA's clinical features. This work supports the association of the T allele of PADI4 rs2240340 with RA in Asians. The roles of NLRP1 rs878329 G/C and PTPN22 rs6665194 A/G polymorphisms were demonstrated for the first time. We also propose rs6665194 to be a promising candidate for RA risk evaluation between ethnicities. PMID- 28653217 TI - Health-related quality of life as measured by the EQ-5D in the prevention, screening and management of cervical disease: A systematic review. AB - PURPOSE: Cost-effectiveness analyses (CEAs) of screening can be highly sensitive to the health-related quality of life (HRQoL) effects of screen tests and subsequent treatment. Accordingly, accurate assessment of HRQoL is essential. We reviewed the literature regarding HRQoL in cervical prevention and management in order to appraise the current evidence regarding this important input to CEA. METHODS: We searched the MEDLINE, Scopus and EconLit databases for studies that estimated HRQoL in cervical cancer prevention and management published January 1995-December 2015. The primary inclusion criterion was for studies that assess HRQoL using the EQ-5D. Data were abstracted from eligible studies on setting, elicitation group, sample size, elicitation instruments, health state valuations, study design and follow-up. We assessed the quality and comparability of the studies with a particular focus on the HRQoL reported across states and groups. RESULTS: Fifteen papers met the inclusion criteria. Most used patient elicitation groups (n = 11), 2 used the general public and 2 used a mix of both. Eight studies were cross-sectional and seven were longitudinal. Six studies used both the EQ-5D-3L and the EQ-VAS together with other measures of overall HRQoL or condition-specific instruments. Extensive heterogeneity was observed across study characteristics. CONCLUSIONS: Our results reveal the challenges of sourcing reliable estimates of HRQoL for use in CEAs of cervical cancer prevention and treatment. The EQ-5D appears insufficiently sensitive for some health states. A more general problem is the paucity of HRQoL estimates for many health states and their change over time. PMID- 28653216 TI - NMR characterization of HtpG, the E. coli Hsp90, using sparse labeling with 13C methyl alanine. AB - A strategy for acquiring structural information from sparsely isotopically labeled large proteins is illustrated with an application to the E. coli heat shock protein, HtpG (high temperature protein G), a 145 kDa dimer. It uses 13C alanine methyl labeling in a perdeuterated background to take advantage of the sensitivity and resolution of Methyl-TROSY spectra, as well as the backbone centered structural information from 1H-13C residual dipolar couplings (RDCs) of alanine methyl groups. In all, 40 of the 47 expected crosspeaks were resolved and 36 gave RDC data. Assignments of crosspeaks were partially achieved by transferring assignments from those made on individual domains using triple resonance methods. However, these were incomplete and in many cases the transfer was ambiguous. A genetic algorithm search for consistency between predictions based on domain structures and measurements for chemical shifts and RDCs allowed 60% of the 40 resolved crosspeaks to be assigned with confidence. Chemical shift changes of these crosspeaks on adding an ATP analog to the apo-protein are shown to be consistent with structural changes expected on comparing previous crystal structures for apo- and complex- structures. RDCs collected on the assigned alanine methyl peaks are used to generate a new solution model for the apo protein structure. PMID- 28653219 TI - Participation Bias and Social Desirability Effects in Research on Extramarital Affairs: Considerations of Meaning and Implications for Sexual Behavior Research. PMID- 28653218 TI - 2K1C-activated Angiotensin II (Ang II) exacerbates vascular damage in a rat model of arthritis through the ATR/ERK1/2 signaling pathway. AB - OBJECTIVE: To explore the role and mechanism of the two-kidney one-clip (2K1C) activated Angiotensin II (Ang II) in the development of vascular damage in adjuvant-induced arthritis (AA) rats. METHODS: 2K1C rats were established in normal and AA rats for 35 days. Hypertension, endothelial dysfunction, and vascular hypertrophy induced by 2K1C-activated Ang II in systemic inflammation rats were evaluated. The levels of Ang II and TNF-alpha in serum were observed by ELISA kits. Expressions of Ang II/ATR/ERK1/2 signaling pathway molecules in the aorta were tested by immunohistochemistry or western blot. The migration and capillary tube formation abilities of human umbilical vein endothelial cells (HUVECs) were tested by migration chamber and capillary tube formation assays. RESULTS: The level of Ang II in serum was significantly increased in 2K1C rats. Compared with AA rats, the high level of Ang II activated by 2K1C reduced the endothelium-dependent vasodilator responses to acetylcholine (ACh) in the thoracic aorta and exacerbated endothelial dysfunction and vascular hypertrophy. Expressions of ATR, GRK2, p-ERK1/2, and p-NF-kappaB were significantly increased in the aorta of AA combined with 2K1C rats. The migration and capillary tube formation abilities of HUVECs were significantly enhanced by Ang II and TNF-alpha co-stimulations in vitro through the ATR/ERK1/2 signaling pathway compared to those stimulated with TNF-alpha. CONCLUSIONS: 2K1C-activated Ang II is involved in aggravated vascular injury and endothelial dysfunction through the ATR/ERK1/2 signaling pathway in AA rats. PMID- 28653220 TI - Response to Commentaries. PMID- 28653221 TI - Effect of an obesity best practice alert on physician documentation and referral practices. AB - The Centers for Medicare & Medicaid Services Electronic Health Record Meaningful Use Incentive Program requires physicians to document body mass index (BMI) and a follow-up treatment plan for adult patients with BMI >= 25. To examine the effect of a best practice alert on physician documentation of obesity-related care and referrals to weight management treatment, in a cluster-randomized design, 14 primary care clinics at an academic medical center were randomized to best practice alert intervention (n = 7) or comparator (n = 7). The alert was triggered when both height and weight were entered and BMI was >=30. Both intervention and comparator clinics could document meaningful use by selecting a nutrition education handout within the alert. Intervention clinics could also select a referral option from the list of clinic and community-based weight management programs embedded in the alert. Main outcomes were proportion of eligible patients with (1) obesity-related documentation and (2) referral. There were 26,471 total primary care encounters with 12,981 unique adult patients with BMI >= 30 during the 6-month study period. Documentation doubled (17 to 33%) with implementation of the alert. However, intervention clinics were not significantly more likely to refer patients to weight management than comparator clinics (2.8 vs. 1.3%, p = 0.07). Although the alert was associated with increased physician meaningful use compliance, it was not an effective strategy for improving patient access to weight management services. Further research is needed to understand system-level characteristics that influence obesity management in primary care. PMID- 28653222 TI - Anatomical responses of leaf and stem of Arabidopsis thaliana to nitrogen and phosphorus addition. AB - Nitrogen (N) and phosphorus (P) availabilities play crucial roles in plant morphogenesis and physiological processes, but how plant anatomical traits respond to the N and P supply is not well elucidated. We evaluated the effects of N and P supply on multiple leaf and stem anatomical traits of Arabidopsis thaliana. The addition of N increased the stem diameter, cortex thickness, rosette radius, midrib thickness, and size of leaf and stem vasculature significantly. Abaxial stomatal length (LSL) increased while adaxial epidermal cell density decreased significantly with increasing N supply. P addition did not affect stem size and leaf epidermal traits, but enhanced the thickness of stem xylem. The nutrient limiting status did not affect most traits except for LSL. The anatomical traits measured varied a lot in the extent of response to N and P addition, despite relatively stronger response to N addition overall. Cortex thickness, rosette radius, stomatal density and epidermal cell density exhibited relatively high plasticity to both nutrients, while stomatal length and stomatal index were relatively stable. Thus, these results suggested that the anatomical traits of shoot vasculature of A. thaliana were enhanced by both nutrients but more affected by N addition, satisfying the plant growth and nutrient requirements. Our findings may help shed light on plant adaptation to nutrient availability changes under the ongoing anthropogenic impacts, but the generality across numerous plant species still warrants further researches. PMID- 28653223 TI - Multi-targeted therapy of everolimus in Kaposi's sarcoma associated herpes virus infected primary effusion lymphoma. AB - Kaposi's sarcoma associated herpes virus (KSHV) infected primary effusion lymphoma (PEL) is a rare aggressive form of non-Hodgkin's lymphoma of B cells. KSHV latent and lytic antigens modulate several host cellular signalling pathways especially mammalian target of rapamycin (mTOR), STAT-3 and nuclear factor-kappa B (NF-kappaB) for rapid tumor progression and immune evasion. Current chemotherapeutic strategies are becoming ineffective as they kill only dividing cells and inefficient to target molecular pathways crucial for active virus replication and its survival. In this study, we evaluated the efficacy of everolimus, an mTOR inhibitor in inducing apoptosis of PEL cells. Dose-dependent treatment of everolimus triggered mitochondria-mediated caspase-dependent apoptosis in PEL cells. Everolimus downregulated KSHV latent antigen expression with concurrent blocking of lytic reactivation for active virus replication. Everolimus also inhibited latent antigen mediated constitutively active STAT-3 and NF-kappaB signalling. We co-cultured everolimus treated PEL cells with immature dendritic cells and found activation of dendritic cells with increase in surface expression of CD86 and HLA-DR. As everolimus targets and disrupts KSHV antigens as well as antigen facilitated multiple signalling pathways necessary for KSHV survival and maintenance of infection with synchronised boosting of immune system against viral infection, it can be a better therapeutic approach towards treatment of PEL. PMID- 28653224 TI - Acquisition of anoikis resistance promotes alterations in the Ras/ERK and PI3K/Akt signaling pathways and matrix remodeling in endothelial cells. AB - Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix. Anoikis resistance is a critical mechanism in tumor metastasis. Cancer cells deregulate and adapt their metabolism to survive in the absence of adhesion, spreading metastases to distant organs. These adaptations include abnormal regulation of growth factor receptors activating prosurvival signaling pathways, such as the Ras/ERK and PI3K/Akt pathways, and extracellular matrix remodeling, leading to metastasis by an increase of invasiveness and inhibiting anoikis. This study investigates the possible involvement of ECM components and signaling pathways in the regulation of resistance to anoikis in endothelial cells (EC). Endothelial cells submitted to stressful conditions by blocking adhesion to substrate (anoikis resistance) display an up-regulation of Ras/ERK and PI3k/Akt pathways by high expression of Ras, ERK, PI3K (p110alpha) and Akt (Thr 308). After ERK and PI3K inhibiting, all EC-derived cell lines studied showed lower growth, a decrease in invasive potential and a higher rate of apoptosis. Furthermore, anoikis-resistant cell lines display a decrease in the expression of fibronectin, collagen IV and hyaluronic acid and an increase in the expression of laminin, perlecan, alphav, beta3, alpha5 and beta1 integrins subunits, hyaluronidades 1, 2 and 3 and metalloproteinases 2 and 9. These results indicate that the acquisition of anoikis resistance induced remodeling of the extracellular matrix and overexpression of the PI3K/Akt and Ras/ERK pathway components. Acquisition of resistance to anoikis is a potentially crucial step in endothelial cell transformation. PMID- 28653225 TI - Erratum to: Impact of hemoglobin levels on renal and non-renal clinical outcomes differs by chronic kidney disease stages: the Gonryo study. PMID- 28653226 TI - Urinary biomarkers in the early detection and follow-up of tubular injury in childhood urolithiasis. AB - BACKGROUND: To investigate relationships among urinary biomarkers [kidney injury molecule-1 (KIM-1), N-acetyl-beta-glucosaminidase (NAG)], neutrophil gelatinase associated lipocalin (NGAL) levels and renal tubular injury in childhood urolithiasis. METHODS: Seventy children [36 girls, mean age: 7.3 +/- 5.0 years (0.5-18.2)] with urolithiasis/microlithiasis and 42 controls [18 girls, mean age: 8.5 +/- 3.8 years (0.9-16.2)] were included in this multicenter, controlled, prospective cohort study. Patients were evaluated three times in 6-month intervals (0, 6 and 12th months). Anthropometric data, urinary symptoms, family history and diagnostic studies were recorded. Urine samples were analyzed for metabolic risk factors (urinary calcium, uric acid, oxalate, citrate, cystine, magnesium, and creatinine excretion), and the urinary KIM-1, NAG, and NGAL levels were measured. RESULTS: Stones were mostly located in the upper urinary system (82.9%), and six patients (8.6%) had hydronephrosis. Thirty patients (42.9%) had several metabolic risk factors, and the most common metabolic risk factor was hypocitraturia (22.9%). Urinary KIM-1/Cr, NAG/Cr and NGAL/Cr ratios were not significantly different between patients and controls. Furthermore, no significant changes in their excretion were shown during follow-up. Notably, the urinary KIM-1/Cr, NAG/Cr, and NGAL/Cr levels were significantly higher in children under 2 years of age (p = 0.011, p = 0.006, and 0.015, respectively). NAG/Cr and NGAL/Cr ratios were significantly increased in patients with hydronephrosis (n = 6, p = 0.031 and 0.023, respectively). CONCLUSIONS: The results of this study suggest that none of the aforementioned urinary biomarkers (KIM-1, NAG and NGAL levels) may be useful for the early detection and/or follow up of renal tubular injury and/or dysfunction in childhood urolithiasis. PMID- 28653227 TI - Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention? AB - OPINION STATEMENT: Migraine is a very disabling disorder with severe impact on patients' lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder. PMID- 28653229 TI - The latest technology of musculoskeletal ultrasonography: iterative revolution. PMID- 28653228 TI - Enlargement of the infraorbital canal following Caldwell-Luc surgery. AB - OBJECTIVES: The infraorbital canal (IOC), which runs in the roof of the maxillary sinus, is a useful anatomical landmark for the infraorbital nerve (ION) on computed tomography (CT) images. Enlargement of the IOC on CT images is thought to be a pathological state that usually affects the ION. However, we have frequently observed enlargement of the IOC in patients with a history of radical surgery of the maxillary sinus: so-called Caldwell-Luc (CL) surgery. In this study, the size of the IOC of the maxillary sinus was compared between patients with a history of CL surgery (post-CL IOCs) and those with no history of CL surgery (control IOCs). METHODS: A total of 347 consecutive patients who underwent facial CT from January 2014 to October 2014 for various indications were evaluated. After excluding groove-type IOCs and IOCs with pathological lesions that could affect their diameters, 47 post-CL IOCs in 26 patients were finally compared with 504 control IOCs in 252 patients. To evaluate IOC size, the short-axis diameter of the IOC was measured on a reconstructed coronal image at the level of the posterior pole of the eyeball. RESULTS: The short-axis diameters of the post-CL IOCs and control IOCs were 3.0 +/- 0.6 and 1.4 +/- 0.3 mm, respectively (p < 0.005). CONCLUSIONS: The short-axis diameters of post-CL IOCs are significantly enlarged (approximately double the diameter) compared to those of control IOCs. PMID- 28653230 TI - Five High-Cost Patient Groups. PMID- 28653231 TI - Measuring Multimorbidity: A Risky Business. PMID- 28653232 TI - Capsule Commentary on McCoy Et al. Hospital Readmissions Among Commercially Insured and Medicare Advantage Beneficiaries with Diabetes and the Impact of Severe Hypoglycemic and Hyperglycemic Events. PMID- 28653233 TI - Ethical practice in Telehealth and Telemedicine. AB - This article summarizes the report of the American Medical Association's (AMA) Council on Ethical and Judicial Affairs (CEJA) on ethical practice in telehealth and telemedicine. Through its reports and recommendations, CEJA is responsible for maintaining and updating the AMA Code of Medical Ethics (Code). CEJA reports are developed through an iterative process of deliberation with input from multiple stakeholders; report recommendations, once adopted by the AMA House of Delegates, become ethics policy of the AMA and are issued as Opinions in the Code. To provide enduring guidance for the medical profession as a whole, CEJA strives to articulate expectations for conduct that are as independent of specific technologies or models of practice as possible. The present report, developed at the request of the House of Delegates, provides broad guidance for ethical conduct relating to key issues in telehealth/telemedicine. The report and recommendations were debated at meetings of the House in June and November 2015; recommendations were adopted in June 2016 and published as Opinion E-1.2.12, Ethical Practice in Telemedicine, in November 2016. A summary of the key points of the recommendations can be found in Appendix A (online), and the full text of the opinion can be found in Appendix B (online). PMID- 28653234 TI - Reducing Health Disparities by Tackling Tobacco Use. PMID- 28653235 TI - The clinical features and surgical outcomes of intracranial tanycytic ependymomas: a single-institutional experience. AB - Tanycytic ependymoma is a rare subtybe of ependymoma with a predilection for the spinal cord and intracranial tanycytic ependymoma is thus extremely rare. Most studies on intracranial tanycytic ependymomas included only one or two cases. Here we report nine patients with pathologically confirmed intracranial tanycytic ependymomas. The clinical characteristics, including radiological and histological examination, operative records, and prognoses were reviewed. The case series included six male and three female patients with an average age of 19.3 years. Tumors were located in the lateral ventricle (3/9), the fourth ventricle (2/9), and the supratentorial extraventricle (4/9). Gross total resection (GTR) of the tumor was achieves in seven cases, and subtotal resection (STR) was achieved in the other two cases. One patient died 21 months after discharge. The left eight patients showed improved symptoms after surgery, and no tumor recurrence was found in these cases during the follow-up. It seems that intracranial tanycytic ependymoma has the best long-term prognosis compared to the other two subtypes of ependymoma. According to our experience, we recommend surgery including GTR and STR followed by radiotherapy for patients with intracranial tanycytic ependymomas. PMID- 28653236 TI - Erratum to: Using Parameter Constraints to Choose State Structures in Cost Effectiveness Modelling. PMID- 28653237 TI - The Economic Burden of Insulin-Related Hypoglycemia in Spain. AB - INTRODUCTION: An analysis was conducted to estimate the economic burden of insulin-related hypoglycemia in adults in Spain, derived from a novel concept developed for the UK known as the Local Impact of Hypoglycemia Tool. METHODS: Costs per severe and non-severe hypoglycemic episode were calculated for patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The costs per episode were applied to the population of adults with T1DM and T2DM using insulin in Spain according to the number of severe and non-severe episodes experienced per year. Costs were calculated using Spanish-specific resource costs and published values for resource utilization, including ambulance, accident and emergency (A&E) department, hospitalization, healthcare professional visits, and extra self monitoring of blood glucose (SMBG) tests used in the week following the episode. A one-way sensitivity analysis on all model inputs was then performed. RESULTS: The cost of insulin-related hypoglycemia in Spain is estimated as ?662.0 m per year, ?292.6 m of which is due to severe episodes and ?369.4 m to non-severe episodes. The cost per episode varies from ?1.25 for patients with T1DM and ?1.48 for patients with T2DM for a non-severe episode where extra SMBG testing after the episode is the only action taken, to ?4378.22 for T1DM and ?3005.74 for T2DM for a severe episode that was treated in hospital and requires an ambulance, A&E visit, hospitalization, and a diabetes specialist visit. A reduction in severe and non-severe hypoglycemia rates of just 20% could lead to considerable cost savings of ?284,925 per 100,000 general population. CONCLUSION: This analysis highlights the substantial economic burden of hypoglycemia in Spain, and gives budget holders the ability to assess the costs of new treatments or patient education programs in relation to the potential cost savings due to lower hypoglycemia rates. PMID- 28653239 TI - Adapted ERAS Pathway vs. Standard Care in Patients with Perforated Duodenal Ulcer a Randomized Controlled Trial. AB - OBJECTIVES: The objective of this study was to evaluate the feasibility and efficacy of ERAS pathways in patients undergoing emergency simple closure of perforated duodenal ulcer (PDU). METHODS: This single-center, prospective, open labeled, superiority, RCT was carried out from August 2014 to July 2016. Patients of PDU undergoing open simple closure were randomized preoperatively in 1:1 ratio into standard care and adapted ERAS group. Patients with refractory shock, ASA class >=3, and perforation size >=1 cm were excluded. Primary outcome was the length of hospitalization (LOH). Secondary outcomes were functional recovery parameters and morbidity. RESULTS: Forty-nine and 50 patients were included in standard care and ERAS group, respectively. Patients in ERAS group had a significantly early functional recovery (days) for the time to first flatus (1.47 +/- 0.18; p < 0.001), first stool (2.25 +/- 0.20; p < 0.001), first fluid diet (2.72 +/- 0.38; p < 0.001), and solid diet (3.70 +/- 0.44; p < 0.001). LOH in ERAS group was significantly shorter (mean difference of 4.41 +/- 0.64 days; p < 0.001). There was a significant reduction in postoperative morbidity such as superficial SSI (RR 0.35, p = 0.02), postoperative nausea and vomiting (RR 0.28, p < 0.0001), and pulmonary complications (RR 0.24, p = 0.04) in the ERAS vs. standard care group with similar leak rates (1/50 vs.2/49). CONCLUSION: ERAS pathways are safe and feasible in select patients undergoing emergency simple closure of PDU. PMID- 28653238 TI - AMPK/NF-kappaB signaling pathway regulated by ghrelin participates in the regulation of HUVEC and THP1 Inflammation. AB - Endothelial inflammation and monocyte plays an essential role in the initiation and progression of atherosclerosis. Ghrelin is beneficial for atherosclerosis progression. However, the detailed and precise molecular mechanisms of how ghrelin regulates endothelial inflammation are not clear. In this study, we investigated the regulation mechanism of ghrelin on TNF-alpha-activated endothelial inflammation and monocyte adhesion. It was found that TNF-alpha induced monocyte adhesion on HUVEC was significantly attenuated by ghrelin. Furthermore, we found that ghrelin effectively suppressed TNF-alpha-induced inflammatory factors' (including ICAM-1, VCAM-1, MCP-1, and IL-1beta) expression through inhibiting AMPK phosphorylation and p65 expression both in HUVEC and THP 1. This phenomenon was further demonstrated by using AMPK agonist AICAR and inhibitor compound C, respectively. Our findings suggest that ghrelin may mediate TNF-alpha-induced endothelial inflammation and monocyte adhesion, in part via AMPK/NF-kappaB signaling pathway. These novel anti-inflammatory and immunoregulatory actions of ghrelin may play a certain role in understanding the formation and development of atherosclerosis. PMID- 28653240 TI - ImmunoPET Imaging of alphavbeta6 Expression Using an Engineered Anti-alphavbeta6 Cys-diabody Site-Specifically Radiolabeled with Cu-64: Considerations for Optimal Imaging with Antibody Fragments. AB - PURPOSE: Increased expression of the alphavbeta6 integrin correlates with advanced tumor grade and poor clinical outcome, identifying alphavbeta6 as a prognostic indicator and an attractive target for molecular imaging. This work investigated the ability of a disulfide-stabilized [64Cu]NOTA-alphavbeta6 cys diabody to image alphavbeta6 expression in vivo using a nu/nu mouse model bearing human melanoma xenografts and positron-emission tomography. PROCEDURES: Small animal positron emission tomography (PET) imaging, quantitative ROI analysis, and ex vivo biodistribution were conducted to ascertain tumor uptake and organ distribution of the [64Cu]NOTA-alphavbeta6 cys-diabody. Immunohistochemical staining of tumors and mouse organs and immunoreactivity assays were utilized to correlate in vivo and ex vivo observations. RESULTS: PET imaging of the [64Cu]NOTA-alphavbeta6 cys-diabody revealed low tumor uptake at 24 h p.i. in DX3Purobeta6 tumors (2.69 +/- 0.45 %ID/g) with comparable results found in the DX3Puro tumors (2.24 +/- 0.15 %ID/g). Quantitative biodistribution confirmed that DX3Purobeta6 tumor uptake was highest at 24 h p.i. (4.63 +/- 0.18 %ID/g); however, uptake was also observed in the stomach (4.84 +/- 2.99 %ID/g), small intestines (4.50 +/- 1.69 %ID/g), large intestines (4.73 +/- 0.97 %ID/g), gallbladder (6.04 +/- 1.88 %ID/g), and lungs (3.89 +/- 0.69 %ID/g). CONCLUSIONS: Small-animal PET imaging was successful in visualizing alphavbeta6-positive tumor uptake of the [64Cu]NOTA-alphavbeta6 cys-diabody. Cys-diabody cross-reactivity was observed between human and murine alphavbeta6 and immunohistochemical staining confirmed the presence of an endogenous alphavbeta6 antigen sink, which led to suboptimal tumor contrast in this mouse model. Future investigations will focus on dose escalation studies to overcome the endogenous antigen sink while increasing DX3Purobeta6 tumor uptake. PMID- 28653241 TI - Anti-Prostate Cancer Activity of 8-Hydroxyquinoline-2-Carboxaldehyde Thiosemicarbazide Copper Complexes by Fluorescent Microscopic Imaging. AB - Copper 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazide (CuHQTS) and copper 8-hydroxyquinoline-2-carboxaldehyde-4,4-dimethyl-3-thiosemicarbazide (CuHQDMTS) are two copper thiosemicarbazone complexes with potent anticancer activity on cisplatin-resistant neuroblastoma cells. This study aimed to evaluate anti prostate cancer activity of these two copper complexes in vitro. Both CuHQTS and CuHQDMTS inhibited proliferation of prostate cancer cells and showed cytotoxicity on prostate cancer cells carrying green fluorescent protein (GFP) by fluorescent microscopic imaging. The findings of this study demonstrated anti-prostate cancer activity of CuHQTS and CuHQDMTS and suggested that GFP-carrying prostate cancer cells might be used for testing anticancer activity of copper complexes by fluorescent microscopic imaging. PMID- 28653242 TI - Variables Affecting the Internal Energy of Peptide Ions During Separation by Differential Ion Mobility Spectrometry. AB - Differential ion mobility spectrometry (DIMS) devices separate ions on the basis of differences in ion mobility in low and high electric fields, and can be used as a stand-alone analytical method or as a separation step before further analysis. As with other ion mobility separation techniques, the ability of DIMS separations to retain the structural characteristics of analytes has been of concern. For DIMS separations, this potential loss of ion structure originates from the fact that the separations occur at atmospheric pressure and the ions, during their transit through the device, undergo repeated collisions with the DIMS carrier gas while being accelerated by the electric field. These collisions have the ability to increase the internal energy distribution of the ions, which can cause isomerization or fragmentation. The increase in internal energy of the ions is based on a number of variables, including the dispersion field and characteristics of the carrier gas such as temperature and composition. The effects of these parameters on the intra-DIMS fragmentation of multiply charged ions of the peptides bradykinin (RPPGFSPFR) and GLISH are discussed herein. Furthermore, similarities and differences in the internal energy deposition that occur during collisional activation in tandem mass spectrometry experiments are discussed, as the fragmentation pathways accessed by both are similar. Graphical Abstract ?. PMID- 28653243 TI - Novel Concepts of MS-Cleavable Cross-linkers for Improved Peptide Structure Analysis. AB - The chemical cross-linking/mass spectrometry (MS) approach is gaining increasing importance as an alternative method for studying protein conformation and for deciphering protein interaction networks. This study is part of our ongoing efforts to develop innovative cross-linking principles for a facile and efficient assignment of cross-linked products. We evaluate two homobifunctional, amine reactive, and MS-cleavable cross-linkers regarding their potential for automated analysis of cross-linked products. We introduce the bromine phenylurea (BrPU) linker that possesses a unique structure yielding a distinctive fragmentation pattern on collisional activation. Moreover, BrPU delivers the characteristic bromine isotope pattern and mass defect for all cross-linker-decorated fragments. We compare the fragmentation behavior of the BrPU linker with that of our previously described MS-cleavable TEMPO-Bz linker (which consists of a 2,2,6,6 tetramethylpiperidine-1-oxy moiety connected to a benzyl group) that was developed to perform free-radical-initiated peptide sequencing. Comparative collisional activation experiments (collision-induced dissociation and higher energy collision-induced dissociation) with both cross-linkers were conducted in negative electrospray ionization mode with an Orbitrap Fusion mass spectrometer using five model peptides. As hypothesized in a previous study, the presence of a cross-linked N-terminal aspartic acid residue seems to be the prerequisite for the loss of an intact peptide from the cross-linked products. As the BrPU linker combines a characteristic mass shift with an isotope signature, it presents a more favorable combination for automated assignment of cross-linked products compared with the TEMPO-Bz linker. ?. PMID- 28653244 TI - gamma-Hydroxybutyric Acid (GHB) Pharmacokinetics and Pharmacodynamics: Semi Mechanistic and Physiologically Relevant PK/PD Model. AB - An overdose of gamma-hydroxybutyric acid (GHB), a drug of abuse, results in fatality caused by severe respiratory depression. In this study, a semi mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize monocarboxylate transporter 1 (MCT1)-mediated transport of GHB, as well as effects of GHB on respiration frequency, for IV doses of 200, 600, and 1500 mg/kg in rats. The proposed PK/PD model for GHB consists of nonlinear metabolism of GHB in the liver, MCT1-mediated renal reabsorption with physiologically relevant concurrent fluid reabsorption, MCT1-mediated uptake into the brain, and direct effects of binding of GHB to GABAB receptors on the PD parameter, respiration frequency. Michaelis-Menten affinity constants for metabolism, renal reabsorption, and uptake into and efflux from the brain were fixed to the observed in vitro values. The IC 50 value for the effect of GHB on respiration frequency was fixed to a reported value for binding of GHB to GABAB receptors. All physiological parameters were fixed to the reported values for a 300-g rat. The model successfully captured the GHB PK/PD data and was further validated using the data for a 600-mg/kg dose of GHB after IV bolus administration. Unbound GHB brain ECF/blood partition coefficient (Kp u,u ) values obtained from the model agreed well with values calculated using experimental ECF concentrations obtained with brain microdialysis, demonstrating the physiological relevance of this model. Sensitivity analysis indicated that the PK/PD model was stable. In conclusion, we developed a semi-mechanistic and physiologically relevant PK/PD model of GHB using in vitro drug-transporter kinetics and in vivo PK/PD data in rats. PMID- 28653246 TI - Allergy and Sexual Behaviours: an Update. AB - The exact prevalence of hypersensitivity reactions related to sexual behaviours is not known; however, they heavily impact on the quality of life and of sex life of affected patients. In fact, not only common respiratory and skin allergies, such as asthma, rhinitis, urticaria and atopic dermatitis, but also food and drug allergy have been found to negatively affect the quality of sex life. Allergic diseases impact on the sexual function in both physical and psychological ways, representing one of the main complaints of a considerable proportion of patients. Sexual behaviours may act as the triggers of allergic reactions or as the carriers of allergens. Food and drug allergens can be carried through human organic fluids, like saliva and semen. Latex in condoms and numerous substances in lubricants, spermicides, topical medications and cosmetics can cause allergic reactions or contact dermatitis. Sexual activity itself is also a potential trigger of symptoms in patients affected by respiratory allergies, like honeymoon asthma and rhinitis. In seminal plasma hypersensitivity, seminal fluid proteins are the culprit allergens. The present review aims at summarizing the state of the art about allergy and sexual behaviours. In clinical practice, the influence of common allergic diseases on the sexual quality of life should be taken carefully into account. Sexual behaviours need to be accounted in the differential diagnosis of hypersensitivity reactions, and awareness on those exposure routes should be raised between different specialists and general practitioners. PMID- 28653245 TI - Muscadinia rotundifolia 'Noble' defense response to Plasmopara viticola inoculation by inducing phytohormone-mediated stilbene accumulation. AB - Downy mildew (DM), one of the most devastating grape diseases worldwide, is caused by the biotrophic oomycete Plasmopara viticola (Pv). In general, grapevine responds to Pv infection with the accumulation of phytoalexins as part of the innate immune system, and diverse phytoalexins are induced on grapevines with different DM-resistance levels in response to Pv invasion. However, the regulation of phytoalexin biosynthesis during grapevine against Pv is still unclear. Herein, we detected stilbenes by UPLC-ESI-MS/MS and found that resveratrol was accumulated to higher level and earlier in the DM-immune Muscadinia rotundifolia 'Noble' than that in the DM-susceptible Vitis vinifera 'Thompson Seedless' after Pv inoculation. Additionally, a considerable amount of pterostilbene and epsilon-viniferin was found in 'Noble', while a little was detected in 'Thompson Seedless'. Resveratrol was glycosylated into piceid both in 'Noble' and 'Thompson Seedless' after Pv inoculation. The qPCR analysis of gene expression indicated that the resveratrol-synthesis gene (STS) was induced by Pv inoculation earlier in 'Noble' than that in 'Thompson Seedless', while the pterostilbene-synthesis gene (ROMT) was induced in 'Noble' but not in 'Thompson Seedless' at all. The piceid-synthesis gene (GT) was generally up-regulated in both cultivars. Sequence analysis of STS, ROMT, and GT promoters revealed that they contained cis-regulatory elements responsive to phytohormones and pathogens. Following Pv inoculation, the level of SA, MeJA, and ABA was found to be consistently higher in 'Noble' than those in 'Thompson Seedless'. The results of exogenous hormone elicitation further demonstrated that the accumulation of stilbenes was regulated by phytohormones. The earlier and higher accumulation of phytohormones and consequent induction of stilbene synthesis may play an important role in grapevine defense against downy mildew disease. PMID- 28653247 TI - Post-traumatic headache in patients with minimal traumatic intracranial hemorrhage after traumatic brain injury: a retrospective matched case-control study. AB - BACKGROUND: No evidence is available on the risks of neurologically asymptomatic minimal traumatic intracranial hemorrhage (mTIH) in patients with traumatic brain injury (TBI) for post-traumatic headache (PTH). The purpose of this study was to investigate whether mTIH in patients with TBI was associated with PTH and to evaluate its risk factors. METHODS: Between September 2009 and December 2014, 1484 patients with TBI were treated at our institution, 57 of whom had mTIH after TBI and were include in this study. We performed propensity score matching to establish a control group among the 823 patients with TBI treated during the same period. Patients with TBI rated their headaches prospectively using a numeric rating scale (NRS). We compared NRS scores between mTIH group (n = 57) and non mTIH group (n = 57) and evaluated risk factors of moderate-to-severe PTH (NRS >= 4) at the 12-month follow-up. RESULTS: Moderate-to-severe PTH was reported by 21.9% of patients (29.8% in mTIH group and 14.0% in non-mTIH group B, p = 0.012) at the 12-month follow-up. The mean NRS was higher in mTIH group than in non-mTIH group throughout the follow-up period (95% confidence interval [CI], 0.11 to 1.14; p < 0.05, ANCOVA). Logistic regression analysis showed that post-traumatic seizure (odds ratio, 1.520; 95% CI, 1.128-6.785; p = 0.047) and mTIH (odds ratio, 2.194; 95% CI, 1.285-8.475; p = 0.039) were independently associated with moderate-to-severe PTH at the 12-month follow-up. CONCLUSIONS: Moderate-to-severe PTH can be expected after TBI in patients with mTIH and post-traumatic seizure. PTH occurs more frequently in patients with mTIH than in those without mTIH. PMID- 28653248 TI - [Cleft lip and palate]. AB - BACKGROUND: Cleft lip and palate (CLP) represents a group of malformations of unknown etiology but similar phenotypes. This implies consequences for the diagnostics, therapy, prevention, prognosis and risk estimation. OBJECTIVE: Definition of CLP subtypes and the embryonic development, clarification of correlations and differences between entities using epidemiological data, overview of the present state of genetic analyses, correlation to syndromes, sequences and associations and resulting consequences for clinical practice. MATERIAL AND METHODS: Update on embryological development of the face, summary of epidemiological and genetic studies and considerations on pedopathological and forensic aspects. RESULTS: Syndromic and non-syndromic CLP exhibit different and highly variable etiologies, therapeutic needs and prognosis. A thorough understanding is mandatory to distinguish between the different subgroups. In addition to specific aspects of CLP for the pediatric (forensic) pathologist this article provides an overall view of the topic which aims to help understand these malformations. PMID- 28653249 TI - Erratum to: Comparative clinical utility of tumor genomic testing and cell-free DNA in metastatic breast cancer. PMID- 28653250 TI - Cognitive function and discontinuation of adjuvant hormonal therapy in older breast cancer survivors: CALGB 369901 (Alliance). AB - PURPOSE: To investigate the effects of cognitive function on discontinuation of hormonal therapy in breast cancer survivors ages 65+ ("older"). METHODS: Older breast cancer survivors with invasive, non-metastatic disease, and no reported cognitive difficulties were recruited from 78 Alliance sites between 2004 and 2011. Eligible survivors (n = 1280) completed baseline interviews; follow-up was conducted annually for up to 7 years. Survivors with estrogen-receptor-positive (ER+) cancers who initiated hormonal therapy (n = 990) were included. Self reported cognitive function was measured using the EORTC-QLQ30 scale; a difference of eight points on the 0-100 scale was considered clinically significant. Based on varying rates of discontinuation over time, discontinuation was evaluated separately for three time periods: early (<1 year); midpoint (1-3 years); and late discontinuation (>3-5 years). Cox models for each time period were used to evaluate the effects of cognition immediately preceding discontinuation, controlling for age, chemotherapy, and other covariates. RESULTS: Survivors were 65-91 years old (mean 72.6 years), and 79% had stages 1 or 2A disease. Overall, 43% discontinued hormonal therapy before 5 years. Survivors who reported lower cognitive function in the period before discontinuation had greater hazards of discontinuing therapy at the treatment midpoint (HR 1.22 per 8-point difference, CI 1.09-1.40, p < 0.001), considering covariates, but cognition was not related to discontinuation in the other periods. CONCLUSIONS: Self-reported cognitive problems were a significant risk factor for discontinuation of hormonal therapy 1-3 years post-initiation. Additional research is needed on the temporality of cognitive effects and hormonal therapy to support survivorship care needs of older survivors. PMID- 28653252 TI - sIL-24 peptide, a human interleukin-24 isoform, induces mitochondrial-mediated apoptosis in human cancer cells. AB - PURPOSE: Interleukin-24 (IL-24) is a unique cytokine in the IL-10 family that reveals tumor-suppressive activity against a broad range of cancers. Alternative splicing of human IL-24 generates several isoforms with different pro-apoptotic activities. In the current study, we aimed to investigate the cytotoxic properties of a recombinant smallest isoform of IL-24 (sIL-24) and the underlying molecular mechanisms in PC-3, A549, U937, and Raji cancer cells as well as normal cell line MRC-5. METHODS: Following treatment of the cells with recombinant sIL 24 peptide and full-length IL-24 protein, cytotoxicity was determined by MTT assay. Apoptosis induction was evaluated using annexin-V/PI double staining flow cytometry and Hoechst 33342 staining. The expression of Bax, Bcl-2, cytochrome c, and caspase-3 was analyzed by Western blotting. RESULTS: MTT assay exhibited that sIL-24 dose and time dependently inhibited the proliferation of IL-24 receptor positive PC-3, U937, and Raji cells more effectively than full-length IL-24. In contrast, sIL-24 had little cytotoxic effect on A549 cells lacking the IL-24 receptor, or on MRC-5 normal cells. Flow cytometric analysis and morphological observation revealed an efficient apoptosis induction in the receptor-positive cells. Furthermore, Western blot assay demonstrated that cell death induced by sIL-24 was associated with upregulation of the Bax/Bcl-2 ratio, cytochrome c release, and the expression of cleaved caspase-3, suggesting that sIL-24 induced apoptosis mainly through the mitochondrial pathway. Notably, among the tested cells, induction of apoptosis was more significant in PC-3 cells. CONCLUSION: Our results suggest that the sIL-24 peptide is a promising candidate for potential treatment of human cancers. PMID- 28653251 TI - Suggestion of added value by bevacizumab to chemotherapy in patients with unresectable or recurrent small bowel cancer. AB - PURPOSE: Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA. METHODS: The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome. RESULTS: Median patient age was 65 years (range 39-83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab containing CT patients was 21.9 months. No unexpected serious adverse events were observed. CONCLUSIONS: The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients. PMID- 28653253 TI - Two-track virtual screening approach to identify both competitive and allosteric inhibitors of human small C-terminal domain phosphatase 1. AB - Despite a wealth of persuasive evidence for the involvement of human small C terminal domain phosphatase 1 (Scp1) in the impairment of neuronal differentiation and in Huntington's disease, small-molecule inhibitors of Scp1 have been rarely reported so far. This study aims to the discovery of both competitive and allosteric Scp1 inhibitors through the two-track virtual screening procedure. By virtue of the improvement of the scoring function by implementing a new molecular solvation energy term and by reoptimizing the atomic charges for the active-site Mg2+ ion cluster, we have been able to identify three allosteric and five competitive Scp1 inhibitors with low-micromolar inhibitory activity. Consistent with the results of kinetic studies on the inhibitory mechanisms, the allosteric inhibitors appear to be accommodated in the peripheral binding pocket through the hydrophobic interactions with the nonpolar residues whereas the competitive ones bind tightly in the active site with a direct coordination to the central Mg2+ ion. Some structural modifications to improve the biochemical potency of the newly identified inhibitors are proposed based on the binding modes estimated with docking simulations. PMID- 28653254 TI - Prognostic value of short-term decline of forced expiratory volume in 1 s over height cubed (FEV1/Ht3) in a cohort of adults aged 80 and over. AB - BACKGROUND: Forced expiratory volume in 1 s over height cubed (FEV1/Ht3) is an FEV1 expression that uses no reference values and is independently associated with adverse outcomes in older adults. No studies have reported on the prognostic value of its decline over time in adults aged 80 and over. AIM: To investigate the prognostic value of FEV1/Ht3 decline for adverse outcomes in a cohort of adults aged 80 and over. METHODS: 328 community-dwelling adults aged 80 and over of the BELFRAIL prospective cohort had two valid FEV1 measurements as part of their comprehensive geriatric assessment at baseline and follow-up (after 1.7 +/- 0.21 years). Kaplan-Meier survival curves, Cox and logistic multivariable regression, assessed association of excessive decline of FEV1/Ht3 (lowest quintile of percentage change) with all-cause mortality (3 years after follow-up assessment), time to first hospitalization (1 year), and new/ worsened disability in activities of daily living (ADL) at the follow-up assessment. RESULTS: Participants with excessive FEV1/Ht3 decline had increased adjusted hazard ratio for all-cause death 1.61 (95% CI 1.01-2.55) and first hospitalization 1.71 (1.08 2.71) and increased odds ratio for new/worsened ADL disability at follow-up 2.02 (1.10-3.68) compared to the rest of the study population. CONCLUSIONS: Excessive, short-term decline in FEV1/Ht3 was independently associated with all-cause mortality, time to first, unplanned hospitalization, and ADL disability in a cohort of adults aged 80 and over. This FEV1 expression should be further investigated in studies of longitudinal FEV1 change in older adults. PMID- 28653256 TI - BMLA Abstracts 2017. PMID- 28653255 TI - Clinical evaluation of near-infrared light transillumination in approximal dentin caries detection. AB - The objective of this clinical study was to compare conventional caries detection techniques, pen-type laser fluorescence device, and near-infrared light transillumination method in approximal dentin caries lesions. The study included 157 patients, aged 12-18, without any cavity in the posterior teeth. Two calibrated examiners carried out the assessments of selected approximal caries sites independently. After the assessments, the unopened sites were excluded and a total of 161 approximal sites were included in the study. When both the examiners arrived at a consensus regarding the presence of dentin caries, the detected lesions were opened with a conical diamond burr, the cavity extent was examined and validated (gold standard). Sensitivity, specificity, negative predictive value, positive predictive value, accuracy, and area under the ROC curve (Az) values among the caries detection methods were calculated. Bitewing radiography and near-infrared (NIR) light transillumination methods showed the highest sensitivity (0.83-0.82) and accuracy (0.82-0.80) among the methods. Visual inspection showed the lowest sensitivity (0.54). Laser fluorescence device and visual inspection showed nearly equal performance. Near-infrared light transillumination can be used as an alternative method to approximal dentin caries detection. Visual inspection and laser fluorescence device alone should not be used for approximal dentin caries. PMID- 28653257 TI - Human adipose-derived stem cell spheroid treated with photobiomodulation irradiation accelerates tissue regeneration in mouse model of skin flap ischemia. AB - Skin flap grafting is a form of transplantation widely used in plastic surgery. However, ischemia/reperfusion injury is the main factor which reduces the survival rate of flaps following grafting. We investigated whether photobiomodulation (PBM) precondition prior to human adipose-derived stromal cell (hASC) spheroid (PBM-spheroid) transplantation improved skin tissue functional recovery by the stimulation of angiogenesis and tissue regeneration in skin flap of mice. The LED had an emission wavelength peaked at 660 +/- 20 nm (6 J/cm2, 10 mW/cm2). The expression of angiogenic growth factors in PBM-spheroid hASCs was much greater than that of not-PBM-treated spheroid or monolayer-cultured hASCs. From immunochemical staining analysis, the hASCs of PBM-spheroid were CD31+, KDR+, and CD34+, whereas monolayer-cultured hASCs were negative for these markers. To evaluate the therapeutic effect of hASC PBM-spheroid in vivo, PBS, monolayer-cultured hASCs, and not-PBM-spheroid were transplanted into a skin flap model. The animals were observed for 14 days. The PBM-spheroid hASCs transplanted into the skin flap ischemia differentiated into endothelial cells and remained differentiated. Transplantation of PBM-spheroid hASCs into the skin flap ischemia significantly elevated the density of vascular formations through angiogenic factors released by the skin flap ischemia and enhanced tissue regeneration at the lesion site. Consistent with these results, the transplantation of PBM spheroid hASCs significantly improved functional recovery compared with PBS, monolayer-cultured hASCs, and not-PBM-spheroid treatment. These findings suggest that transplantation of PBM-spheroid hASCs may be an effective stem cell therapy for the treatment of skin flap ischemia. PMID- 28653259 TI - A medication assessment tool to evaluate prescribers' adherence to evidence-based guidelines in bipolar disorder. AB - Background The goal of evidence-based clinical practice has led to an increased interest in the development of tools to measure adherence to national guidelines in different diseases. This aids in detecting and measuring inappropriate prescribing to specific patient groups by using quality standards extracted from evidence-based guidelines, and ultimately provide the basis of consistent standardized prescribing. Objective To design and validate a medication assessment tool to assess prescribers' adherence to international guideline recommendations in the management of bipolar disorder (MATBD). Setting Outpatient psychiatry clinic at a secondary healthcare setting in Kuwait. Method International guidelines concerned with the management of bipolar disorder were reviewed in order to develop MATBD. Face and content validity of the developed tool (MATBD) was performed with a research and expert group. A 4-point Likert scale was used to assess the expert group's level of agreement to individual criterion. Content validity ratio (CVR) was calculated for each criterion (n = 54) and the content validity index (CVI) was calculated for each section (n = 5) of the MATBD. Finally, feasibility testing was performed on 19 patient records to confirm the tool's fitness for purpose. Main Outcomes Measure Perceived relevance, utility, and clarity of individual criteria, and reliability of their application to clinical settings. Results Face validity and content validity were achieved with a research and expert group (n = 14). Content validity ratio (CVR) was demonstrated for 54 criteria; criteria with a negative CVR were removed. This resulted in a draft MATBD comprising of 52 criteria (CVI: 0.814). Feasibility testing on 19 patients' records resulted in a final MATBD comprising of 49 criteria divided into 3 sections: initial assessment, acute management and monitoring. Conclusion A medication assessment tool was developed and validated to be used as a means of profiling potential opportunities for medication therapy management optimization, and improving therapeutic interventions regarding the management of bipolar disorder. PMID- 28653258 TI - Azole Resistance in Aspergillus fumigatus in Patients with Cystic Fibrosis: A Matter of Concern? AB - Aspergillus fumigatus is the most frequent filamentous fungus isolated from respiratory specimens from patients with cystic fibrosis (CF). Triazoles are the most widely used antifungals in the treatment of allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA) in CF patients. Treatment success could be severely compromised by the occurrence of azole-resistant A. fumigatus (ARAf), which is increasingly reported worldwide from both clinical samples and the environment. In previous studies, ARAf has been detected in up to 8% of CF patients. Isolates from CF patients requiring antifungal treatment should therefore be routinely subjected to antifungal susceptibility testing. The optimal treatment of ABPA or IA in CF patients with azole-resistant isolates has not been established; treatment options include liposomal amphotericin B i.v. and/or echinocandins i.v. PMID- 28653260 TI - Contributions of community pharmacists to patients on antidepressants-a qualitative study among key informants. AB - Background Patients with an antidepressant drug treatment (ADT) report unmet needs and a significant proportion stop their ADT prematurely. Community pharmacists can play a key role in supporting these patients. Objective To explore the perspectives of various leaders in health care about the current and potential contributions of community pharmacists to patients on ADT. Setting The province of Quebec (Canada). Method We conducted a qualitative descriptive exploratory study using interviews among leaders who were involved in health care services, pharmaceutical services, physician and pharmacist education, as well as patient and healthcare professional associations. Verbatim transcripts of interviews were analyzed using computer-assisted thematic analysis. Main outcome measure Perspectives about the contributions of community pharmacists to patients on ADT. Results Interviews revealed that pharmacists are perceived to be accessible drug experts whose particular strengths are their thorough knowledge of drugs, their commitment to ensure ADT safety and tolerability, as well as their commitment to inform and support patients. Leaders trained in pharmacy or representatives of pharmacy organizations had concrete expectations for pharmacists' increased involvement in monitoring ADT adherence and efficacy. They extensively discussed the regulatory and organizational changes required to enhance this role. Leaders also stated that, in addition to patients, health care teams could benefit from pharmacists' expertise and support. Conclusion Participating key informants perceived the need for enhanced pharmacist monitoring of ADT adherence and efficacy. They also expressed their openness to an increased collaboration between health care teams and pharmacists. PMID- 28653261 TI - Future enhanced clinical role of pharmacists in Emergency Departments in England: multi-site observational evaluation. AB - Background There are concerns about maintaining appropriate clinical staffing levels in Emergency Departments. Pharmacists may be one possible solution. Objective To determine if Emergency Department attendees could be clinically managed by pharmacists with or without advanced clinical practice training. Setting Prospective 49 site cross-sectional observational study of patients attending Emergency Departments in England. Method Pharmacist data collectors identified patient attendance at their Emergency Department, recorded anonymized details of 400 cases and categorized each into one of four possible options: cases which could be managed by a community pharmacist; could be managed by a hospital pharmacist independent prescriber; could be managed by a hospital pharmacist independent prescriber with additional clinical training; or medical team only (unsuitable for pharmacists to manage). Impact indices sensitive to both workload and proportion of pharmacist manageable cases were calculated for each clinical group. Main outcome measure Proportion of cases which could be managed by a pharmacist. Results 18,613 cases were observed from 49 sites. 726 (3.9%) of cases were judged suitable for clinical management by community pharmacists, 719 (3.9%) by pharmacist prescribers, 5202 (27.9%) by pharmacist prescribers with further training, and 11,966 (64.3%) for medical team only. Impact Indices of the most frequent clinical groupings were general medicine (13.18) and orthopaedics (9.69). Conclusion The proportion of Emergency Department cases that could potentially be managed by a pharmacist was 36%. Greatest potential for pharmacist management was in general medicine and orthopaedics (usually minor trauma). Findings support the case for extending the clinical role of pharmacists. PMID- 28653262 TI - Stereotactic accuracy must be as high as possible in stereoelectroencephalography procedures. PMID- 28653263 TI - Standardizing and personalizing the treat to target (T2T) approach for rheumatoid arthritis using the Patient-Reported Outcomes Measurement Information System (PROMIS): baseline findings on patient-centered treatment priorities. AB - A treat to target (T2T) approach to management has become the standard of care for patients with rheumatoid arthritis (RA). While consensus T2T recommendations call for patient involvement in the treatment process, the targets commonly used to drive therapeutic decisions involve limited patient input. A pilot study was developed to explore whether the Patient-Reported Outcomes Measurement Information System (PROMIS) could add value to the T2T approach by providing a way to bring patient goals into the process. We report here the baseline data from this study. RA patients from an academic rheumatology practice were recruited to participate in this 1-year study. Patients were asked to complete PROMIS computer-assisted testing at quarterly visits during the year. At baseline, they were asked to identify the PROMIS domain (Pain Interference, Fatigue, Depression, Physical Function, and Social Function) that felt most important to their quality of life. They were then asked to select five representative items from this domain, to be followed through the year. Complete baseline data was available for 119 patients. Most selected Physical Function (39%) or Pain Interference (37%) as their highest priority PROMIS domain. Sixty percent ranked Depression as their lowest priority domain. Younger patients more frequently prioritized Social Function, while older patients more frequently prioritized Fatigue. The incorporation of PROMIS questionnaires into routine clinic visits is a feasible mechanism for incorporating patient preferences into a T2T approach to managing RA. PMID- 28653265 TI - What's Religion Got to Do with It? Exploring College Students' Sexual and Reproductive Health Knowledge and Awareness of Sexual and Reproductive Health Services in Relation to Their Gender and Religiosity. AB - The purpose of this study was to examine the relationship between religiosity and sexual and reproductive health (SRH) knowledge and awareness of campus SRH services among college students on a racially and ethnically diverse college campus. The sample included 996 undergraduate students at a large public university in California. For women, there was a consistent pattern across religious affiliations of more frequent attenders reporting lower SRH knowledge than less frequent attenders. These findings suggest that higher rates of religious attendance among Catholic, Protestant, and Evangelical women pose a risk for lower SRH knowledge. The results suggest the need for SRH outreach and educational materials targeting men in general, who had lower levels of SRH knowledge and awareness of SRH services overall, and taking religiosity into account, particularly with regard to women. PMID- 28653264 TI - Survival analysis of patients with systemic lupus erythematosus in a tertiary hospital in southern Brazil. AB - Systemic lupus erythematosus (SLE) treatments progress over the years. However, the mortality remains higher than in the general population. Few studies have examined SLE patients' survival in Brazil. This study aims to identify the main characteristics and risk factors to predict mortality and recognize the main causes of death in Brazilian patients with SLE. We retrospectively assessed clinical, demographic, and serological characteristics from 600 patients followed since 2001 in SLE outpatient clinic from Hospital de Clinicas de Porto Alegre. Risk factors for mortality were examined by univariate and multivariate Cox proportional hazards regression analyses. A p < 0.05 was considered significant. There were 527 survivors (87.83%). The main causes of death were cardiovascular disease (17%), infection (17%), and infection and SLE activity (17%). Risk factors for death were age at diagnosis (HR 1.065, CI 95% 1.039-10.092), SLICC damage index (HR 1.299, CI 95% 1.076-1569), antiphospholip syndrome (HR 3.021, CI 95% 1.307-6.985), and metilprednisolone pulse (HR 2.628, CI 95% 1.283-5.383). Antimalarials was a protective factor for death (HR 0.191, CI 95% 0.064-0.570). Cardiovascular disease, infection, and SLE activity associated with infection were the main known causes of deaths in our SLE patients. Secondary antiphospolipid syndrome, highest score in SLICC damage index, advanced age at diagnosis, and high dose of corticosteroids were risk factors for mortality. Antimalarials was an important protective factor. PMID- 28653266 TI - Generalization from Single Cases and the Concept of Double Dialogicality. AB - The present paper addresses how the concept of double-dialogicality may contribute to our understanding of how to generalize from single cases. Various attempts have been made within qualitative social research to define how generalization is possible from single cases. One problem with generalization in psychology is that any human activity and sense making is situated/occasioned and all psychological phenomenon are hence unique. However, they are not arbitrary but dialogically intertwined with socio-cultural traditions of sense making and acting. Discursive practices play a pivotal role in this. In social interactions, persons draw on culturally available resources without which communicative meaning would be impossible. Double dialogicality as introduced by Per Linell helps to understand this relation and allows for identifying the general in the unique. PMID- 28653267 TI - Association of Helicobacter pylori infection with olfactory function using smell identification screening test. AB - The aim of the present study is to investigate the role of Helicobacter pylori in olfactory function. Thirty-six patients (mean age 38.5) aged between 18 and 55 years who were diagnosed with H. pylori by gastric biopsies and age- and sex matched 30 healthy adults (mean age 33.6) were included in the study. All participants underwent a detailed ear-nose-throat examination including endoscopic examination of the nasal cavity and laryngeal area, and olfactory tests were performed using the Sniffin' Sticks, a 12-item screening test (Sniffin'Sticks; Burghart, Wedel, Germany) and odor scores were recorded. The mean odor score was 7.9 +/- 1.7 (range 2-10) in the patient group and 10.3 +/- 1.4 (range 6-12) in the control group. There were significant lower scores in the patient group compared to the control group (p < 0.05). In conclusion, it is apparent that there is an association of H. pylori infection with olfactory dysfunction. H. pylori infection should be considered as possible etiological factors in patients with olfactory dysfunction. PMID- 28653268 TI - In response to Letter to the Editor entitled "It is prudent to consider use of endoscopic tympanoplasty to treat complicated middle ear disease". PMID- 28653269 TI - eHealth in otorhinolaryngology: a disruptive innovation. PMID- 28653270 TI - Revision adenoidectomy in children: a population-based cohort study in Taiwan. AB - There is a lack of population-level analysis of revision adenoidectomy in children. This study reveals the revision rates and factors associated with paediatric revision adenoidectomy in Taiwan. From the Taiwan National Health Insurance Research Database, we identified all in-hospital children (age <18 years) who underwent adenoidectomy between 2000 and 2007. All children had received at least 5 years of follow-up from the index date, and the clinical records until 2012 were examined. Factors affecting the paediatric revision adenoidectomy were analysed using the multivariable Cox proportional hazards model. A total of 10,396 children were enrolled (mean age 7.3 years; 66% boys; mean follow-up period 8.7 years). Two hundred and seventy-five children underwent revision adenoidectomy, and the mean interval between primary adenoidectomy and revision surgery was 2.97 years. Only 58.5% of children underwent revision surgery at the initial hospital. The incidence of revision surgery was highest in the second year (0.69%), followed by the third year (0.53%) after primary adenoidectomy. The multivariable Cox proportional hazards model revealed that young age [hazard ratio (HR) = 0.8], male gender (HR = 1.57), surgery at an eastern hospital (HR = 2.08), surgical indication of adenoid hypertrophy (HR = 1.51), and concurrent ventilation tube insertion (HR = 2.61) or nasal surgeries (HR = 4.84) were associated with revision adenoidectomy. The incidence of revision adenoidectomy in Taiwan was 2.6%. Male gender, young age, concurrent nasal or ventilation tube insertion, and surgery at an eastern hospital increased the risk of revision. PMID- 28653272 TI - Progress through accreditation, still room for quality improvement. PMID- 28653271 TI - Regadenoson use in chronic kidney disease and end-stage renal disease: A focused review. AB - Regadenoson is a selective A2A adenosine receptor agonist that has been approved as a vasodilator stress agent with single-photon emission-computed tomography (SPECT) myocardial perfusion imaging (MPI). Since its approval by the Food and Drug Administration (FDA) in 2008, it has become the most commonly used pharmacologic stress agent with SPECT-MPI. Given that it is predominantly renally excreted, its use in patients with chronic kidney disease has been the subject of active post-marketing clinical research. Until recently, prescribing information regarding the use of regadenoson in patients with end-stage renal disease (ESRD) was not defined in the package insert. Based on accumulating data since its initial approval, the FDA has recently outlined the use of regadenoson in patients with ESRD in a label update on January 17, 2017. In this review, we discuss the evidence leading to the recent label update, focusing on the pharmacokinetics of regadenoson in patients with impaired kidney function, the safety and tolerability of regadenoson in patients with chronic kidney disease and ESRD, and the prognostic value of regadenoson stress MPI in this patient population. PMID- 28653273 TI - Attentional focus affects how events are segmented and updated in narrative reading. AB - Readers generate situation models representing described events, but the nature of these representations may differ depending on the reading goals. We assessed whether instructions to pay attention to different situational dimensions affect how individuals structure their situation models (Exp. 1) and how they update these models when situations change (Exp. 2). In Experiment 1, participants read and segmented narrative texts into events. Some readers were oriented to pay specific attention to characters or space. Sentences containing character or spatial-location changes were perceived as event boundaries-particularly if the reader was oriented to characters or space, respectively. In Experiment 2, participants read narratives and responded to recognition probes throughout the texts. Readers who were oriented to the spatial dimension were more likely to update their situation models at spatial changes; all readers tracked the character dimension. The results from both experiments indicated that attention to individual situational dimensions influences how readers segment and update their situation models. More broadly, the results provide evidence for a global situation model updating mechanism that serves to set up new models at important narrative changes. PMID- 28653274 TI - Spatial updating of multiple targets: Comparison of younger and older adults. AB - When walking without vision, people mentally keep track of the directions and distances of previously viewed objects, a process called spatial updating. The current experiment indicates that while people across a large age range are able to update multiple targets in memory without perceptual support, aging negatively affects accuracy, precision, and decision time. Participants (20 to 80 years of age) viewed one, three, or six targets (colored lights) on the floor of a dimly lit room. Then, without vision, they walked to a target designated by color, either directly or indirectly (via a forward turning point). The younger adults' final stopping points were both accurate (near target) and precise (narrowly dispersed), but updating performance did degrade slightly with the number of targets. Older adults' performance was consistently worse than the younger group, but the lack of interaction between age and memory load indicates that the effect of age on performance was not further exacerbated by a greater number of targets. The number of targets also significantly increased the latency required to turn toward the designated target for both age groups. Taken together, results extend previous work showing impressive updating performance by younger adults, with novel findings showing that older adults manifest small but consistent degradation of updating performance of multitarget arrays. PMID- 28653275 TI - A Conceptual Model for Home Based Primary Care of Older Refugees. AB - The needs of refugees in the United States can often optimally be met through home based primary care (HBPC). Until recently, however, there has been little research into the methods of best practice and challenges of providing home based care to refugee groups. The model for the HBPC of refugees proposed here is the result of a comprehensive review of the literature combined with professional practice. Emphasis is placed on the elements of care identified as most affecting health and quality of life outcomes for refugees receiving HBPC. The key inputs for positive health and quality of life outcomes identified are: (1) Linguistic communication; (2) Cultural safety; and (3) Interprofessional team. PMID- 28653276 TI - Histopathological factors predicting response to neoadjuvant therapy in gastric carcinoma. AB - BACKGROUND: Neoadjuvant therapy (NAT) is a useful therapeutic option. However, some patients respond poorly to it and can even show tumor progression. It is important to define factors that can predict response to NAT. MATERIALS AND METHODS: This is a retrospective cohort study to define histopathological factors predicting response to NAT in gastric tubular carcinoma. This study has enrolled 80 patients receiving chemotherapy for locally advanced gastric carcinoma. RESULTS: 44.5% of the patients were men; mean age was 64.49 years. Only 5.7% of the patients showed a complete response to therapy, 10% had grade 1, 21.4% grade 2, and 62.9% grade 3 regression. On follow-up, 43.8% of the patients showed recurrence of disease (57.1% distant metastasis) and 33.8% eventually died of it. We found a statistically significant association between response and prognosis. We found a statistically significant association between regression and perineural, vascular, and lymph vessel invasion. Logistic regression model showed that only lymph vessel invasion had independent influence. Lymph vessel invasion not only indicated lack of response to therapy, but also higher incidence of lymph node involvement in the gastrectomy specimen. DISCUSSION: Our study indicates that the presence of vascular or perineural invasion in the endoscopic biopsies and high histopathological grade predict poor response to therapy. This seems peculiar, for undifferentiated tumors are supposed to have better response to therapy. CONCLUSION: Our study indicates that undifferentiated tumors respond worse to therapy. Furthermore, studies are necessary to define lack of response, to help avoid neoadjuvant therapy in unfavorable cases. PMID- 28653277 TI - Moving Beyond Serendipity to Mechanism-Driven Psychiatric Therapeutics. PMID- 28653278 TI - Evidence-Based Psychotherapy: Advantages and Challenges. AB - Evidence-based psychotherapies have been shown to be efficacious and cost effective for a wide range of psychiatric conditions. Psychiatric disorders are prevalent worldwide and associated with high rates of disease burden, as well as elevated rates of co-occurrence with medical disorders, which has led to an increased focus on the need for evidence-based psychotherapies. This chapter focuses on the current state of evidence-based psychotherapy. The strengths and challenges of evidence-based psychotherapy are discussed, as well as misperceptions regarding the approach that may discourage and limit its use. In addition, we review various factors associated with the optimal implementation and application of evidence-based psychotherapies. Lastly, suggestions are provided on ways to advance the evidence-based psychotherapy movement to become truly integrated into practice. PMID- 28653279 TI - Chronic Paroxetine Treatment Prevents the Emergence of Abnormal Electroencephalogram Oscillations in Huntington's Disease Mice. AB - Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington's disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalogram/electromyogram from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25-45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice. PMID- 28653280 TI - Clozapine as a Model for Antipsychotic Development. AB - Schizophrenia is a devastating illness that affects up to 1% of the population; it is characterized by a combination of positive symptoms, negative symptoms, and cognitive impairment. Currently, treatment consists of one class of medications known as antipsychotics, which include typical (first-generation) and atypical (second-generation) agents. Unfortunately, antipsychotic medications have limited efficacy, with up to a third of patients lacking a full response. Clozapine, the first atypical antipsychotic developed, is the only medication shown to be superior to all other antipsychotics. However, owing to several life-threatening side effects and required enrollment in a registry with routine blood monitoring, clozapine is greatly underutilized in the US. Developing a medication as efficacious as clozapine with limited side effects would likely become the first line therapy for schizophrenia and related disorders. In this review, we discuss the history of clozapine, landmark studies, and its clinical advantages and disadvantages. We further discuss the hypotheses for clozapine's superior efficacy based on neuroreceptor binding, and the limitations of a receptor-based approach to antipsychotic development. We highlight some of the advances from pharmacogenetic studies on clozapine and then focus on studies of clozapine using unbiased approaches such as pharmacogenomics and gene expression profiling. Finally, we examine how these approaches could provide insights into clozapine's mechanism of action and side-effect profile, and lead to novel and improved therapeutics. PMID- 28653281 TI - Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model. AB - One of the major challenges in the epilepsy field is identifying disease modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in 2 different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early long term treatment with fingolimod (1 mg/kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in WAG/Rij rats. However, these effects were transitory, as 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control levels. Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced phosphorylated mammalian target of rapamycin and phosphorylated p70S6k levels, and by increased phosphorylated Akt in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic effects of fingolimod. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of lysine 8 of histone H4 (at both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects of fingolimod. However, the antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline. PMID- 28653282 TI - Therapeutic Targets for Multiple Sclerosis: Current Treatment Goals and Future Directions. AB - Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, and the most common cause of nontraumatic disability in young adults. Most patients have a relapsing-remitting course, and roughly half of them will eventually enter a degenerative progressive phase, marked by gradual accrual of disability over time in the absence of relapses. Early initiation of treatment has delayed the onset of disability progression. Thus, there is increased interest in treating to target in MS, particularly targeting no evidence of disease activity. This review will describe the most common treatment goals in MS: the Rio scores, disease-free survival, and no evidence of disease activity. We will also cover how well current disease-modifying therapies achieve no evidence of disease activity, and discuss future options for improving MS treatment targets. PMID- 28653283 TI - Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation. AB - Ketogenic diets (KDs) have gained popularity among patients and researchers alike due to their putative anti-tumor mechanisms. However, the question remains which conclusions can be drawn from the available human data thus far concerning the safety and efficacy of KDs for cancer patients. A realist review utilizing a matrix analytical approach was conducted according to the RAMESES publication standards. All available human studies were systematically analyzed and supplemented with results from animal studies. Evidence and confirmation were treated as separate concepts. In total, 29 animal and 24 human studies were included in the analysis. The majority of animal studies (72%) yielded evidence for an anti-tumor effect of KDs. Evidential support for such effects in humans was weak and limited to individual cases, but a probabilistic argument shows that the available data strengthen the belief in the anti-tumor effect hypothesis at least for some individuals. Evidence for pro-tumor effects was lacking completely. Feasibility of KDs for cancer patients has been shown in various contexts. The probability of achieving an anti-tumor effect seems greater than that of causing serious side effects when offering KDs to cancer patients. Future controlled trials would provide stronger evidence for or against the anti-tumor effect hypothesis. PMID- 28653284 TI - Salvage treatment for testicular cancer with standard- or high-dose chemotherapy: a systematic review of 59 studies. AB - Relapsed germ cell tumor (GCT) is a highly curable cancer with standard-dose platinum-based chemotherapy (CT); however, high-dose CT (HDCT) is seldom used as salvage therapy instead or after conventional CT. We conducted a systematic review of published trials to compare outcomes between standard-dose CT and HDCT in patients with relapsed GCT after first-line therapy for advanced disease. A literature search was carried out in multiple electronic databases (PubMed, Embase, Scopus, Web of Science, and The Cochrane Library), and studies reporting salvage treatment of relapsed GCT with standard-dose or carboplatin-etoposide based HDCT were selected. Overall response rate, median overall survival (OS), and the 1-, 2-, 3-, and 5-year OS rates were pooled, and the significance of difference between arms was assessed with a Chi-square test. Twenty-nine standard dose and 31 HD studies were included in the meta-analysis. For standard-dose CT versus HDCT, there was no significant difference in median OS (14.8 months and 24.09 months, respectively; P = 0.09) or in 1-, 2-, 3-, or 5-year survival rate (standard-dose CT, 64.2, 63.6, 45.1, and 43%, respectively; HDCT, 63.7, 51.2, 46.7, and 45%, respectively; P = 0.9, P = 0.4, P = 0.75, and P = 0.06). Conventional dose regimens and HDCT were associated with comparable efficacy when used as salvage therapies in relapsed GCTs as second-line therapy or beyond. However, the selection of ideal candidates for more or less intensive treatments deserves further research in the near future. PMID- 28653285 TI - Innate defense regulator IDR-1018 activates human mast cells through G protein-, phospholipase C-, MAPK- and NF-KB-sensitive pathways. AB - : Host defense (antimicrobial) peptides not only display antimicrobial activities against numerous pathogens but also exert a broader spectrum of immune-modulating functions. Innate defense regulators (IDRs) are a class of host defense peptides synthetically developed from natural or endogenous cationic host defense peptides. Of the IDRs developed to date, IDR-1018 is more efficient not only in killing bacteria but also in regulating the various functions of macrophages and neutrophils and accelerating the wound healing process. Because mast cells intimately participate in wound healing and a number of host defense peptides involved in wound healing are also known to activate mast cells, this study aimed to investigate the effects of IDR-1018 on mast cell activation. Here, we showed that IDR-1018 induced the degranulation of LAD2 human mast cells and caused their production of leukotrienes, prostaglandins and various cytokines and chemokines, including granulocyte-macrophage colony-stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and -3, macrophage-inflammatory protein-1alpha and -1beta, and tumor necrosis factor-alpha. Furthermore, IDR-1018 increased intracellular calcium mobilization and induced mast cell chemotaxis. The mast cell activation was markedly suppressed by pertussis toxin, U-73122, U0126, SB203580, JNK inhibitor II, and NF-kappaB activation inhibitor II, suggesting the involvement of G-protein, phospholipase C, ERK, p38, JNK and NF-kappaB pathways, respectively, in IDR-1018-induced mast cell activation. Notably, we confirmed that IDR-1018 caused the phosphorylation of MAPKs and IkappaB. Altogether, the current study suggests a novel immunomodulatory role of IDR-1018 through its ability to recruit and activate human mast cells at the sites of inflammation and wounds. HIGHLIGHTS: We report that IDR-1018 stimulates various functions of human mast cells. IDR-1018-induced mast cell activation is mediated through G protein, PLC, MAPK and NF-kappaB pathways. IDR-1018 will be a useful therapeutic agent for wound healing. PMID- 28653286 TI - User input in iterative design for prevention product development: leveraging interdisciplinary methods to optimize effectiveness. AB - The development of HIV-preventive topical vaginal microbicides has been challenged by a lack of sufficient adherence in later stage clinical trials to confidently evaluate effectiveness. This dilemma has highlighted the need to integrate translational research earlier in the drug development process, essentially applying behavioral science to facilitate the advances of basic science with respect to the uptake and use of biomedical prevention technologies. In the last several years, there has been an increasing recognition that the user experience, specifically the sensory experience, as well as the role of meaning making elicited by those sensations, may play a more substantive role than previously thought. Importantly, the role of the user-their sensory perceptions, their judgements of those experiences, and their willingness to use a product-is critical in product uptake and consistent use post-marketing, ultimately realizing gains in global public health. Specifically, a successful prevention product requires an efficacious drug, an efficient drug delivery system, and an effective user. We present an integrated iterative drug development and user experience evaluation method to illustrate how user-centered formulation design can be iterated from the early stages of preclinical development to leverage the user experience. Integrating the user and their product experiences into the formulation design process may help optimize both the efficiency of drug delivery and the effectiveness of the user. PMID- 28653287 TI - Role of Jagged1-Notch pathway in thyroid development. AB - The zebrafish thyroid gland shows a unique pattern of growth. Despite the lack of a compact gland, the zebrafish thyroid tissue originates from the pharyngeal endoderm and the main genes involved in its patterning and early development are conserved between zebrafish and mammals. In recent years, the research has been focused to the search of novel candidate genes and environmental factors underlying congenital hypothyroidism. Among these, it has been demonstrated that the Notch signalling plays a central role during zebrafish thyroid development. In this review, we will provide an overview of the current knowledge of the distinct roles of the Notch signalling and of the jag1a and jag1b ligands during the different phases of thyroid organogenesis. Furthermore, we will discuss the role of JAG1 variants in congenital thyroid defects. PMID- 28653288 TI - Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status - a short report. AB - PURPOSE: Pre-operative progesterone treatment of breast cancer has been shown to confer survival benefits to patients independent of their progesterone receptor (PR) status. The underlying mechanism and the question whether such an effect can also be observed in PR negative breast cancer cells remain to be resolved. METHODS: We performed proteome profiling of PR-positive and PR-negative breast cancer cells in response to progesterone using a phospho-kinase array platform. Western blotting was used to validate the results. Cell-based phenotypic assays were conducted using PR-positive and PR-negative breast cancer cells to assess the effect of progesterone. RESULTS: We found that progesterone induces de phosphorylation of 12 out of 43 kinases tested, which are mostly involved in cellular invasion and migration regulation. Consistent with this observation, we found through cell-based phenotypic assays that progesterone inhibits the invasion and migration of breast cancer cells independent of their PR status. CONCLUSION: Our results indicate that progesterone can inhibit breast cancer cell invasion and migration mediated by the de-phosphorylation of kinases. This inhibition appears to be independent of the PR status of the breast cancer cells. In a broader context, our study may provide a basis for an association between progesterone treatment and recurrence reduction in breast cancer patients, thereby providing a lead for modelling a randomized in vitro study. PMID- 28653289 TI - Histamine H4 receptor signalling in tongue cancer and its potential role in oral carcinogenesis - a short report. AB - PURPOSE: Recent reports indicate that histamine and its novel, high-affinity histamine H4 receptor (H4R) play a role in carcinogenesis, and thus H4R signalling has become a focus of increasing interest in the pathogenesis of many cancers. The roles of H4R in oral epithelial dysplasia (OED) and oral tongue squamous cell carcinoma (OTSCC) are unknown. The purpose of this study was to assess H4R expression in OTSCC patients and in OTSCC-derived cell lines. METHODS: Biopsies taken from OED, OTSCC and healthy oral mucosa were studied by immunostaining. Primary human oral keratinocytes (HOKs) and two OTSCC-derived cell lines (HSC-3 and SCC-25) were used for the in vitro studies. Quantitative real-time PCR was used to measure oncogene expression in the stimulated HOKs. RESULTS: We found that H4R-immunoreactivity was significantly reduced in the OED and OTSCC samples, especially in the samples with higher histopathological grades and noticeably increased mast cell counts. The presence of H4R in HSC-3 cells had clearly waned, in contrast to the HOKs. Gene expression data indicated that histamine-relevant inflammatory and environmental elements may participate in the regulation of oncogenes. CONCLUSIONS: Our results suggest an association between H4R and oral carcinogenesis. Furthermore, our findings raise a potential implication of histamine-mediated factors in the regulation of oncogenes, possibly via mast cells, as crucial components of the tumor microenvironment. The identification of new elements that govern oral cancer development is highly relevant for the development of novel therapeutic approaches in OTSCC. PMID- 28653291 TI - Patients' Perspectives on Adverse Drug Reaction Reporting in a Developing Country: A Case Study from Ghana. AB - INTRODUCTION: Recent efforts to introduce direct patient reporting into pharmacovigilance systems have proved that patient reports contribute significantly to medicine safety, but there is a paucity of information relating to patients' perspectives regarding adverse drug reaction reporting in developing countries. OBJECTIVE: The objective of this study was to explore patients' knowledge, attitudes, behaviours and opinions on spontaneous adverse drug reaction reporting in Ghana. METHODS: A cross-sectional study using questionnaires administered through face-to-face interviews was carried out from 25 August, 2016 to 20 September, 2016 with 442 patients aged 18 years and above selected by convenience sampling from two community pharmacies in urban and rural Ghana. Reasons and opinions on patients' reporting on adverse drug reactions were surveyed using a 5-point Likert scale. The Pearson chi-square test was used to determine associations between background variables and responses on knowledge of adverse drug reaction reporting. RESULTS: Responses from 434 patients (86.7%) were included in the analysis. Among those interviewed, there was a high level of awareness regarding the existence of the National Pharmacovigilance Centre (81.6%). Approximately half of the respondents (49.5%) were aware that patients were able to report adverse drug reactions associated with medicinal products directly to the National Pharmacovigilance Centre. Of the respondents, 46.3% stated that they had an adverse drug reaction to their medicines in the past; of these, 53.2% reported to healthcare professionals and 36.9% failed to report because they stopped their medication. The three main reasons for patients' reporting were desire for extra information (92.4%), desire to share experiences with other people (91.7%) and expectation for the National Pharmacovigilance Centre to inform others about the possible adverse drug reactions (88.0%). Patients' opinions were to contribute to research/knowledge (96.5%) and improvements in drug safety (96.5%). Patients' behaviour towards adverse drug reaction reporting was affected by the likely consequences of reporting, influence of others and the ease of reporting. CONCLUSION: Patients have a positive attitude and good knowledge on adverse drug reaction reporting to the National Pharmacovigilance Centre and report because they expect extra information and to contribute to drug safety. Patients' positive attitude towards adverse drug reaction reporting could be sustained by hosting periodic public awareness campaigns addressing the importance of adverse drug reaction reporting and by providing timely feedback to patients on regulatory decisions taken as a result of the reports that they submitted. PMID- 28653290 TI - Cardiovascular Complications of Androgen Deprivation Therapy for Prostate Cancer. AB - OPINION STATEMENT: Prostate cancer is a common hormone-sensitive malignancy, and androgen deprivation therapy (ADT) is a cornerstone of therapy in advanced disease. The most important and controversial of ADT side effects is cardiovascular (CV) toxicity. Prospective trials have demonstrated that ADT increases CV risk by lowering insulin sensitivity, causing dyslipidemia, and causing weight gain thus mimicking metabolic syndrome. Retrospective data suggests that ADT increases CV risk; however, data on cardiovascular mortality is equivocal. This discrepancy can be explained by study design limitations and selection bias inherent to post hoc analysis of trials not designed to study CV outcomes. Despite the adverse CV and metabolic sequelae of ADT, little data is available for optimal cardiac screening or management in these patients. The short-term CV risk is higher in patients who have had CV events in the year prior to starting ADT. A careful discussion of risk and benefit of ADT must take place with patients with pre-existing CV disease prior to initiating hormonal therapy. The duration of ADT must be considered. We recommend diligent pretherapy screening and optimization of cardiac risk factors and close surveillance especially within the first year of ADT. PMID- 28653292 TI - Development of an Electromechanical Grade to Assess Human Knee Articular Cartilage Quality. AB - Quantitative assessments of articular cartilage function are needed to aid clinical decision making. Our objectives were to develop a new electromechanical grade to assess quantitatively cartilage quality and test its reliability. Electromechanical properties were measured using a hand-held electromechanical probe on 200 human articular surfaces from cadaveric donors and osteoarthritic patients. These data were used to create a reference electromechanical property database and to compare with visual arthroscopic International Cartilage Repair Society (ICRS) grading of cartilage degradation. The effect of patient-specific and location-specific characteristics on electromechanical properties was investigated to construct a continuous and quantitative electromechanical grade analogous to ICRS grade. The reliability of this novel grade was assessed by comparing it with ICRS grades on 37 human articular surfaces. Electromechanical properties were not affected by patient-specific characteristics for each ICRS grade, but were significantly different across the articular surface. Electromechanical properties varied linearly with ICRS grade, leading to a simple linear transformation from one scale to the other. The electromechanical grade correlated strongly with ICRS grade (r = 0.92, p < 0.0001). Additionally, the electromechanical grade detected lesions that were not found visually. This novel grade can assist the surgeon in assessing human knee cartilage by providing a quantitative and reliable grading system. PMID- 28653293 TI - Erratum to: Numerical Modelling of Femur Fracture and Experimental Validation Using Bone Simulant. PMID- 28653294 TI - Electrospun PLGA Nanofiber Scaffolds Release Ibuprofen Faster and Degrade Slower After In Vivo Implantation. AB - While delayed delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with improved tendon healing, early delivery has been associated with impaired healing. Therefore, NSAID use is appropriate only if the dose, timing, and mode of delivery relieves pain but does not impede tissue repair. Because delivery parameters can be controlled using drug-eluting nanofibrous scaffolds, our objective was to develop a scaffold for local controlled release of ibuprofen (IBP), and characterize the release profile and degradation both in vitro and in vivo. We found that when incubated in vitro in saline, scaffolds containing IBP had a linear release profile. However, when implanted subcutaneously in vivo or when incubated in vitro in serum, scaffolds showed a rapid burst release. These data demonstrate that scaffold properties are dependent on the environment in which they are placed and the importance of using serum, rather than saline, for initial in vitro evaluation of biofactor release from biodegradable scaffolds. PMID- 28653297 TI - Adherence of psychopharmacological prescriptions to clinical practice guidelines in patients with eating behavior disorders. AB - PURPOSE: The purpose of this study was to analyze the adherence of psychopharmacological prescriptions to clinical practice guidelines (CPGs) for patients with eating behavior disorders (EDs) and to compare the effectiveness, safety, and cost of treatment according to adherence. METHODS: This retrospective observational study included ED patients admitted to the eating disorders unit (EDU) of Ciudad Real Hospital (Spain) between January 2006 and December 2009 and followed until December 2014. Psychopharmaceuticals prescribed during EDU stay(s) were compared with guidelines published by American Psychiatric Association (APA), National Institute for Clinical Excellence (NICE), and Spanish Ministry of Health and Consumption (SMHC). Adherence was considered as the percentage of patients whose prescription followed all recommendations. RESULTS: The study included 113 ED patients. Adherence to APA and NICE/SMHC was 30.1% and 45.1%, respectively. Weekly weight gain during hospital stay was higher (p = 0.037) in the APA "adherence" (807.6 g) versus "non-adherence" (544.4 g) group. An association was found between CPG adherence and higher 5-year full recovery rate (p < 0.040). Adherence to NICE/SMHC was associated with lower incidence (p = 0.001) of adverse effects (33.3% in adherence vs. 66.1% in non-adherence group). CPG adherence was associated with lower medication costs (p < 0.020). The age was higher and there was a greater frequency of self-harm behavior and psychiatric comorbidities in the non-adherence than adherence group (p <= 0.040). CONCLUSIONS: CPG adherence was low in EDU-admitted patients. Long-term follow-up showed that clinical outcomes were better and medication costs lower in patients with versus without CPG-adherent prescriptions, likely influenced by the apparently greater severity of illness in those with non-CPG-adherent prescriptions. PMID- 28653298 TI - Two new miniature inverted-repeat transposable elements in the genome of the clam Donax trunculus. AB - Repetitive sequences are important components of eukaryotic genomes that drive their evolution. Among them are different types of mobile elements that share the ability to spread throughout the genome and form interspersed repeats. To broaden the generally scarce knowledge on bivalves at the genome level, in the clam Donax trunculus we described two new non-autonomous DNA transposons, miniature inverted repeat transposable elements (MITEs), named DTC M1 and DTC M2. Like other MITEs, they are characterized by their small size, their A + T richness, and the presence of terminal inverted repeats (TIRs). DTC M1 and DTC M2 are 261 and 286 bp long, respectively, and in addition to TIRs, both of them contain a long imperfect palindrome sequence in their central parts. These elements are present in complete and truncated versions within the genome of the clam D. trunculus. The two new MITEs share only structural similarity, but lack any nucleotide sequence similarity to each other. In a search for related elements in databases, blast search revealed within the Crassostrea gigas genome a larger element sharing sequence similarity only to DTC M1 in its TIR sequences. The lack of sequence similarity with any previously published mobile elements indicates that DTC M1 and DTC M2 elements may be unique to D. trunculus. PMID- 28653295 TI - Targeting the Wnt Pathway in Cancer: A Review of Novel Therapeutics. AB - Wnt signaling is an evolutionarily conserved pathway that controls cell-to-cell interactions during embryogenesis. In adults, Wnt signaling plays a role in tissue homeostasis in almost every organ system. Aberrations within this pathway are implicated in a spectrum of human diseases. A variety of perturbations have been described in both solid and hematologic malignancies, lending way to Wnt signaling as a target for anti-cancer therapy. Of particular interest is the role of Wnt signaling in the development and maintenance of cancer stem cells, a rare population of cells that are able to maintain a tumor via self-renewal and thought to be more resistant to chemotherapy than bulk tumor cells. The ability to eradicate cancer stem cells may decrease the risk of cancer relapse and metastasis. A number of therapeutic agents specifically targeting the Wnt pathway have entered clinical trials, either as monotherapy or in combination with chemotherapy. We will provide an overview of agents that have been developed to target the Wnt pathways and a summary of pre-clinical and clinical trials. PMID- 28653299 TI - First case report of a curative wedge resection in epithelial-myoepithelial carcinoma of the lung. AB - Epithelial-myoepithelial carcinoma is a well differentiated malignant neoplasm, which originates from the salivary glands. The primary pulmonary manifestation is rare-about 30 cases have been reported worldwide. In the literature, anatomical resection has been described as the standard surgical approach. In the presented case, a wedge resection was performed, with no evidence for tumor relapse in the follow-up reevaluation after 24 months. This is the first case report of a primary pulmonary epithelial-myoepithelial carcinoma that has been treated with a non-anatomical wedge resection and lymph node dissection as a curative approach. PMID- 28653301 TI - Morphological assessment of the stylohyoid complex variations with cone beam computed tomography in a Turkish population. AB - BACKGROUND: The aim of this investigation was to evaluate the length, thickness, sagittal and transverse angulations and the morphological variations of the stylohyoid complex (SHC), to assess their probable associations with age and gender, and to investigate the prevalence of it in a wide range of a Turkish sub population by using cone beam computed tomography (CBCT). MATERIALS AND METHODS: The CBCT images of the 1000 patients were evaluated retrospectively. The length, thickness, sagittal and transverse angulations, morphological variations and ossification degrees of SHC were evaluated on multiplanar reconstructions (MPR) adnd three-dimensional (3D) volume rendering (3DVR) images. The data were analysed statistically by using nonparametric tests, Pearson's correlation coefficient, Student's t test, c2 test and one-way ANOVA. Statistical significance was considered at p < 0.05. RESULTS: It was determined that 684 (34.2%) of all 2000 SHCs were elongated (> 35 mm). The mean sagittal angle value was measured to be 72.24 degrees and the mean transverse angle value was 70.81 degrees . Scalariform shape, elongated type and nodular calcification pattern have the highest mean age values between the morphological groups, respectively. Calcified outline was the most prevalent calcification pattern in males. There was no correlation between length and the calcification pattern groups while scalariform shape and pseudoarticular type were the longest variations. CONCLUSIONS: We observed that as the anterior sagittal angle gets wider, SHC tends to get longer. The most observed morphological variations were linear shape, elongated type and calcified outline pattern. Detailed studies on the classification will contribute to the literature. (Folia Morphol 2018; 77, 1: 79 89). PMID- 28653300 TI - Defining the Incidence and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Children with Chronic Diseases. AB - INTRODUCTION: REGAL (RSV Evidence-a Geographical Archive of the Literature) has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This review covers the risk and burden of RSV infection in children with underlying medical conditions or chronic diseases (excluding prematurity and congenital heart disease). METHODS: A systematic review of publications between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov was supplemented by papers identified by the authors through March 2017. Studies reporting data for hospital visits/admissions for RSV infection as well as studies reporting RSV-associated morbidity and mortality were included. Study quality and strength of evidence (SOE) were graded. RESULTS: A total of 2703 studies were identified and 58 were included. Down syndrome, irrespective of prematurity and congenital heart disease (moderate SOE), immunocompromised children (low SOE), cystic fibrosis (low SOE), and neurologic conditions (low SOE) were associated with a significantly increased risk of RSV hospitalization. A number of other congenital malformations and chronic conditions were also associated with severe RSV disease (low SOE). In general, pre-existing disease was also a predisposing factor for RSV-related mortality (low SOE). CONCLUSION: Severe RSV infection in infants and young children with underlying medical conditions or chronic diseases poses a significant health burden. Further studies are needed to fully quantify the epidemiology, burden and outcomes in these populations, in particular RSV attributable mortality. PMID- 28653302 TI - Foetal development of the human gluteus maximus muscle with special reference to its fascial insertion. AB - The human gluteus maximus muscle (GMX) is characterised by its insertion to the iliotibial tract (a lateral thick fascia of the thigh beneath the fascia lata), which plays a critical role in lateral stabilisation of the hip joint during walking. In contrast, in non-human primates, the GMX and biceps femoris muscle provide a flexor complex. According to our observations of 15 human embryos and 11 foetuses at 7-10 weeks of gestation (21-55 mm), the GMX anlage was divided into 1) a superior part that developed earlier and 2) a small inferior part that developed later. The latter was adjacent to, or even continuous with, the biceps femoris. At 8 weeks, both parts inserted into the femur, possibly the future gluteal tuberosity. However, depending on traction by the developing inferior part as well as pressure from the developing major trochanter of the femur, most of the original femoral insertion of the GMX appeared to be detached from the femur. Therefore, at 9-10 weeks, the GMX had a digastric muscle-like appearance with an intermediate band connecting the major superior part to the small inferior mass. This band, most likely corresponding to the initial iliotibial tract, extended laterally and distally far from the muscle fibres. The fascia lata was still thin and the tensor fasciae latae seemed to develop much later. It seems likely that the evolutionary transition from quadripedality to bipedality and a permanently upright posture would require the development of a new GMX complex with the iliotibial tract that differs from that in non-human primates. (Folia Morphol 2018; 77, 1: 144-150). PMID- 28653303 TI - The importance of body mass normalisation for ultrasound measurements of the morphology of oblique abdominis muscles: the effect of age, gender, and sport practice. AB - Some studies have not considered body mass as a confounder in analysis of oblique abdominis muscles (OAM) (including the oblique externus [OE] and oblique internus [OI]), which may have led to improper interpretation of results. To assess the differences in the effect of age, gender, and physical activity between normalised for body mass and actual values of the OAM as well as to establish the effect of age, gender, and physical activity on normalised for body mass OAM thicknesses in adolescents. A real-time ultrasound was used to obtain images of the OAM. Body mass normalisation for OAM thicknesses was performed with allometric scaling and the following equations: Allometric-scaled OE = OE thickness/body mass0.88; Allometric-scaled OI = OI thickness/body mass0.72. Analysis showed that boys have significantly thicker OAM than girls, and those who practise sports have thicker OAM than non-active individuals. For allometric scaled OAM, there was only a significant gender effect, where boys have thicker allometric-scaled OAM than girls. There was a significant correlation between participants' age and the actual value of the OAM. The correlations between age and allometric-scaled OAM were insignificant. An analysis of OAM without body mass normalisation can lead to improper interpretation of study results. Thus, future studies should analyse OE and OI thickness measurements after normalisation rather than actual values. In the adolescent population, there is no effect of age and physical activity on allometric-scaled OAM; males have thicker allometric-scaled OAM than females. (Folia Morphol 2018; 77, 1: 123-130). PMID- 28653304 TI - The impact of pelvicalyceal anatomy on the stone formation in patients with lower pole renal stones. AB - BACKGROUND: The aim of our study was to determine whether various anatomic factors constitute a predisposition to a lower pole renal stones. MATERIALS AND METHODS: We analysed the computed tomography (CT) urography of 75 patients with a single lower pole stone. Measurements were taken of the infundibulopelvic angle (IPA), infundibular width (IW), infundibular length (IL) and calyceopelvic height (CPH). RESULTS: The mean patient age was 50 years (range 17-79 years). The mean stone size was 11.9 mm. The mean IPA using Sampaio method in affected kidney was 113.4 +/- 15.3o (range 80-139o), 59.5 +/- 17.3o using Elbahnasy method. The values of IPA on the contralateral kidney were 119.86 +/- 15.37o (range 79-141o; p = = 0.001) using Sampaio method of measurement and 59.78 +/- 12o (range 34-90 o; p = 0.465) using the method described by Elbahnasy. We reported statistically significant differences between stone-bearing kidney and contralateral kidney in measurement IPA using only Sampaio method. The mean infundibular width was 4.22 +/- 1.81 mm on the affected kidney and 3.72 +/- 2.5 mm on the contralateral side (p = 0.164). The mean infundibular length was 15.37 +/- 4.57 mm on the affected kidney and 14.66 +/- 4.35 mm on the unaffected side (p = 0.329). The CPH was 10.19 +/- 4.05 mm on the affected kidney and 10.44 +/- 3.83 mm on the normal side (p = 0.688). CONCLUSIONS: Pelvicalyceal morphology of the kidney is one of the factors that determine the risk of developing kidney stones. Out of the analysed morphological parameters of kidney IPA is a statistically significant risk factor to form lower pole kidney stones. Other anatomic parameters did not seem to have a significant role in predisposing to form lower pole kidney stone. (Folia Morphol 2018; 77, 1: 16-21). PMID- 28653305 TI - Volumetric evaluation of temporal bone structures in the cases with bilateral tinnitus: clinical and morphometrical study. AB - BACKGROUND: Tinnitus is the recognition of sound in the absence of any external auditory stimulus to the noise of ringing in the ears. Middle ear aeration carries important role for ossicular coupling and normal hearing. There is restricted morphometric data on the cases with bilateral tinnitus. MATERIALS AND METHODS: In this study we evaluated hearing findings of 18 cases with subjective nonpulsatile bilateral tinnitus and also morphometry and volumetry of temporal bone substructures on the computed tomography images using stereological method compared with the gender and age matched 12 healthy subjects. Duration of tinnitus, exposing acoustic trauma or/and high level noise levels, evaluation of middle ear volume, jugular bulb levels, distances between jugular bulb and both oval window and middle ear were evaluated. RESULTS: Both males and females with tinnitus showed worse hearing thresholds through bone and air conductions than healthy subjects but it was not statistically significant. Pure tone thresholds through bone and air conductions were not statistically different in both sexes with bilateral tinnitus. Right middle ear volume of the cases with bilateral tinnitus was mean 5.57 cm3 for males and 5.64 cm3 for females; and also the left middle ear volume of the cases with bilateral tinnitus was mean 5.87 cm3 for males and 5.65 cm3 for females. There were no significant differences between the cases with bilateral tinnitus and the control subjects according to the side of the body. CONCLUSIONS: The data on the hearing findings and morphometrical evaluation of the cases with bilateral tinnitus may be important for anatomists and clinicians. (Folia Morphol 2018; 77, 1: 57-64). PMID- 28653306 TI - The gross anatomy of the male reproductive system of the European hedgehog (Erinaceus Europaeus). AB - Hedgehogs are small spiny-coated insectivores. Due to their low body weight, calm character, and easy maintenance, they are kept as pets. It is therefore worthwhile to care about hedgehogs' health problems and to provide pet owners with information about their reproduction. Moreover, it is necessary to be familiar with their anatomy so as to satisfy the need to improve nutrition and medical care, even surgery. This study was carried out on five adult male European hedgehogs euthanased in a chloroform chamber. The European hedgehog's oval testes are invisible in inguinal region because they have no true scrotal sac. The testes are located in the craniocaudal direction with dorsolateral epididymal attachments. The vesicular glands, the European hedgehog's largest accessory sex glands, are lobulated structures containing dorsomedial and ventrolateral parts on each side. The prostate is an oval gland with right and left lobes. The paired bulbourethral glands are laid on the ischiocavernosus muscle. Histologically the vesicular, prostate gland ducts and ductus deferens as well as urethra separately were discharged in a diverticlum at the level of the pelvic urethra end. A sigmoid flexure exists in the proximal part of shaft body of the penis. There are two retractor penile muscles. In dorsal end of the penile glans, there is a small urethral process with two nail- -like, needle-shaped structures. They are on both sides of the urethral process. Furthermore, there are two intromittent sacs (Sacculus urethralis) in the ventral part of the end of the penis. (Folia Morphol 2018; 77, 1: 36-43). PMID- 28653307 TI - Complete right- and left-sided thoracic ducts associated with aberrant left vertebral artery: unreported case with surgical implications. AB - Anatomy is the keystone to an appropriate understanding of surgical and radiological sciences. Here the authors report on a rare case of complete right- and left-sided thoracic ducts (TDs) associated with aberrant left-vertebral artery (LVA) arising from the aortic arch. The TDs originated from right and left cisterna chyli and terminated separately close to the left venous angle. Superior to the aortic arch, the TDs showed different relationships to the LVA; the right TD was ventral, while the left was dorsal in position. This report is associated with other variations detailed below, and may have important implications in cervicothoracic surgery. (Folia Morphol 2018; 77, 1: 156-160). PMID- 28653308 TI - Arteria trigemina primitiva - radiological report of three cases and review of literature. AB - The main aim of this paper is to present three cases of persistent (patent) primitive trigeminal artery, presence was incidentally revealed during various radiological examinations. The presence and function of these vessels in extrauterine life is sometimes associated with other vascular abnormalities e.g. aneurysms, hemangiomas, moyamoya disease but frequently found incidentally without any negative signs or symptoms. The presented cases of patients with primitive trigeminal artery clearly show that the reported ailments, which had made the diagnostic imagining necessary, were not associated with the patency of this artery. PMID- 28653309 TI - Refined heart failure detection algorithm for improved clinical reliability of OptiVol alerts in CRT-D recipients. AB - BACKGROUND: The reliability of intrathoracic impedance monitoring for prediction of heart failure (HF) by implantable cardiac devices is controversial. Despite using additional device-based parameters described in the PARTNERS HF study, such as new onset of arrhythmias, abnormal autonomics, low biventricular pacing rate or patient activity level, the predictive power of device diagnostic algorithm is still in doubt. The objective of this study was to compare the device diagnostic algorithm described in the PARTNERS HF study to a newly developed algorithm applying refined diagnostic criteria. METHODS: Fourty two patients were prospectively enrolled who had been implanted with an intrathoracic impedance and remote monitoring capable implantable cardiac defibrillator with a cardiac resychroniza-tion therapy (CRT-D) device in this observational study. If a remote OptiVolTM alert occurred, patients were checked for presence of HF symptoms. A new algorithm was derived from the original PARTNERS HF criteria, considering more sensitive cut-offs and changes of patterns of the device-based parameters. RESULTS: During an average follow-up of 38 months, 722 remote transmissions were received. From the total of 128 transmissions with OptiVol alerts, 32 (25%) corresponded to true HF events. Upon multivariate discriminant analysis, low patient activity, high nocturnal heart rate, and low CRT pacing (< 90%) proved to be independent predictors of true HF events (all p < 0.01). Incorporating these three refined criteria in a new algorithm, the diagnostic yield of OptiVol was improved by increasing specific-ity from 37.5% to 86.5%, positive predictive value from 34.1% to 69.8% and area under the curve from 0.787 to 0.922 (p < 0.01), without a relevant loss in sensitivity (96.9% vs. 93.8%). CONCLUSIONS: A refined device diagnostic algorithm based on the parameters of low activity level, high nocturnal heart rate, and suboptimal biventricular pacing might improve the clinical reliability of OptiVol alerts. PMID- 28653310 TI - The impact of proximal cell rewiring compared with distal cell rewiring with single-stent deployment and subsequent kissing balloon inflation in the inadequate jailing of a Kaname stent on the side branch ostium. AB - BACKGROUND: The aim of the study was to identify differences between proximal and distal cell rewir-ing with subsequent kissing balloon inflation (KBI) in the presence of a link connected to a carina on the jailed side branch ostium (SBO). METHODS: Kaname stents were deployed in bifurcation models (n = 12) with subsequent KBI and were confirmed by optical coherence tomography. The jailing configuration and cell rewiring were completely controlled and classified as follows: FC-Dist, free carina (no links connected to a carina) and distal cell re wiring; CC-Prox, connected to a carina (the presence of a link connected to a central carina) and proximal cell rewiring; CC-Dist, connected to a carina and distal cell rewiring; and FarDist, far-distal cell rewiring. RESULTS: The number of frames with malapposed struts (MS) in the SBO was significantly smaller in the CC-Prox group than in the CC-Dist group (26.7 +/- 1.5 and 39.7 +/- 0.6, respectively, p < 0.05). The number of frames with MS continuously present from the distal end to the proximal side of the SBO was significantly smaller in the CC-Prox group than in the CC-Dist group (17.0 +/- 2.0 and 36.7 +/- +/- 5.8, respectively, p < 0.05). The ratio of the maximal opened stent cell area to the SBO area was significantly larger in the CC-Prox group than in the CC-Dist group (64.2 +/- 1.2% and 38.8 +/- 5.6%, respectively, p < 0.05). CONCLUSIONS: This study showed that in cases with a link connected to a carina, fewer malapposed struts may be present in proximal cell rewiring with subsequent KBI than in distal cell rewiring. PMID- 28653311 TI - Blood urea nitrogen in the prediction of in-hospital mortality of patients with acute aortic dissection. AB - BACKGROUND: Blood urea nitrogen (BUN) has been shown to be associated with adverse cardiovascular disease outcomes. The aim of the present study was to evaluate the prognostic role of BUN in patients with acute aortic dissection (AAD). HYPOTHESIS: BUN has correlation with in-hospital mortality of patients with AAD. METHODS: Patients admitted to the emergency room within the first 24 h of onset of AAD were included in the study. BUN levels were measured on admission and the endpoints were mortality during hospi-talization after receiving surgical or endovascular repair. RESULTS: A total of 192 patients with AAD were enrolled. During hospitalization, 19 patients died and 173 patients survived. Increased levels of BUN (8.9 [7.0-9.7] vs. 6.0 [5.1-7.2] mmol/L, p < 0.001) were found in non-survivors compared with those survived. Using multivariable logistic analysis, BUN was an independent predictor of in-hospital mortality in patients with AAD (OR 1.415, 95% CI 1.016-1.971, p = 0.040). Furthermore, using receiver operating characteristic analysis, the optimal cutoff value for BUN was 6.95 mmol/L. Under this value, the area under the curve was 0.785 (95% CI 0.662-0.909, p < 0.001) and the sensitivity and specificity to predict in-hospital mortality was 78.9%, and 72.2%, respectively. CONCLUSIONS: Admission BUN levels were an independent predictor for in hospital mortality in pa-tients with AAD. PMID- 28653312 TI - Link of renal microcirculatory dysfunction to increased coronary microcirculatory resistance in hypertensive patients. AB - BACKGROUND: This study investigated the correlation between renal microcirculation and coronary microcirculation in hypertensive patients. METHODS: Participants consisted of 231 consecutive candidates who were referred to the Second Affiliated Hospital of Wenzhou Medical University from March 2014 to May 2016 for elective coronary angiography due to suspected myocardial ischemia. All participants were evaluated for the index of microvascular resistance (IMR), coronary flow reserve (CFR), and fractional flow reserve (FFR) us!ing a pressure wire. Blood and urine samples were collected for determination of the levels of urinary microalbuminuria (mALB), b2-microglobulin (b2-MG), serum cystatin C (CysC), and uric acid (UA). All participants were categorized into two groups according to the renal microcirculatory function. RESULTS: Participants in the observation group had a higher IMR (31 +/- 5 vs. 22 +/- 6; p < 0.01) and a lower FFR (0.84 +/- 0.10 vs. 0.87 +/- 0.09 U; p < 0.05) during hyperemia than those in the control group. Linear regression tests revealed that mALB, b2-MG, CysC, and UA levels were positively cor!related with IMR (r = 0.610, 0.553, 0.701, and 0.647, respectively, p < 0.01). The hs-CRP levels were positively correlated with IMR (r = 0.419, p < 0.01). Multiple regression analysis indicated that renal microcirculation was an independent predictor of IMR. CONCLUSIONS: Renal microcirculatory dysfunction in hypertensive patients is characterized by higher IMR and lower FFR; in addition, it is closely correlated with an increased coronary microcirculatory resistance. PMID- 28653313 TI - Newly developed post-operative atrial fibrillation is associated with an increased risk of late recurrence of atrial fibrillation in patients who underwent open heart surgery: Long-term follow up. AB - BACKGROUND: Herein is sought to determine whether the occurrence of post operative atrial fibrillation (POAF) increases the risk of late recurrence of atrial fibrillation (AF) in patients undergoing open heart surgery (OHS). METHODS: This study included 938 patients (56.7 +/- 13.1 years old, 550 males) with no history of AF who underwent OHS. All patients were monitored continuously for development of POAF after surgery until the time of hospital discharge and received clinical follow up with serial evaluation of rhythm status. RESULTS: Among the total population, POAF occurred in 207 (22.1%) patients and late AF in 88 (9.4%) patients during the mean follow up period of 78.1 +/- 39.1 months. Development of late AF oc!curred more frequently in patients with POAF than in those without [29.0% (60/207) vs. 3.8% (28/731), p < 0.01]. Higher septal E/e' ratio (HR 1.04, 95% CI 1.00-1.08, p = 0.04) was an independent predic!tor of late occurrence of AF and an episode of POAF (HR 27.12, 95% CI 8.46-86.96, p < 0.01) was the most powerful predictor. CONCLUSIONS: POAF is significantly associated with an increased risk of late AF recurrence during long-term follow up. Careful concern regarding late recurrence of AF with serial evaluation of rhythm status is required in patients with POAF. PMID- 28653314 TI - Fractional flow reserve (FFR)-based therapy in patients presenting with acute coronary syndrome: Current data and everyday practice. AB - Fractional flow reserve (FFR) is an evidence-based diagnostic tool of physiological significance of coronary artery stenosis in patients with stable coronary artery disease (CAD). Due to microvascular dysfunction in acute coronary syndrome (ACS), information obtained from FFR assessment could be less reliable and, thus, its clinical role remains controversial. Indeed, results of currently published studies are essentially discrepant. Only a few randomized clinical trials have been performed showing the efficacy of FFR-guided percutaneous coronary intervention in ACS. Consequently, its role in acute scenarios remains substantially understudied. Herein, is presented the current state of knowledge re-garding FFR use in ACS setting. (Cardiol J 2017; 24, 4: 426-435). PMID- 28653315 TI - Effectiveness of Medtronic CareLink Express System in identifying patients with high-energy electrotherapy devices requiring clinically significant intervention. AB - BACKGROUND: The number of patients with implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy and defibrillator (CRT-D) is growing. This results in high workloads for centers performing standard controls (SC) of these systems. Medtronic CareLink Express(r) (MCLE) is a solution enabling remote controls (RC) of implantable devices. In cases of detecting arrhythmias or device malfunctioning, it automatically generates alarms transmitted to the controlling physician. The objective of the study was to evaluate the effectiveness of alarms generated by MCLE in identification of patients that require clinically significant intervention during SC. METHODS: A total of 119 patients (age 64 +/- 14, 17 women) implanted with ICD/CRT-D were included in the trial. Device reprogramming or pharmacological treatment modifications during SC were as-sessed as significant if they were required for optimal clinical management of the patient (effectiveness of antiarrhythmic and resynchronization therapy, also patient safety). Analysis of generated alarms was then performed to assess the effectiveness (sensitivity and specificity) of MCLE in identifying patients that require changes in therapy. RESULTS: Data from 129 transmissions and 129 subsequent SCs were analyzed. 179 alarms were recorded during 96 (74%) transmissions. A total of 333 program changes of implanted devices took place during 107 (83%) SCs. Device reprogramming was considered clinically significant in 27 cases Additionaly, 13 pharmacological treatment modifications were performed. Sensitivity and specificity of alarms generated by MCLE with regards to identification of patients requiring clinically significant intervention was 87% and 31%, respectively. Finally, a statistically significant difference was observed in the number of clinically significant interventions among patients with and without MCLE alarms (33 [86.8%] vs. 5 [13.2%], p = 0.037). CONCLUSIONS: Medtronic CareLink Express(r) is an RC system enabling high-sensitivity supervision of patients with cardiac. PMID- 28653316 TI - Structural basis for alpha fetoprotein-mediated inhibition of caspase-3 activity in hepatocellular carcinoma cells. AB - Alpha-fetoprotein (AFP) is an early serum growth factor in the foetal liver development and hepatic carcinogenesis; However, the precise biological role of cytoplasmic AFP remains elusive. Although we recently demonstrated that cytoplasmic AFP might interact with caspase-3 and inhibit the signal transduction of apoptosis in human hepatocellular carcinoma (HCC) cells, the details of this interaction are not clear. To reveal the molecular relationship between AFP and caspase-3, we performed molecular docking, co-immunoprecipitation (Co-IP), laser confocal microscopy, site-directed mutagenesis and functional experiments to analyse the key amino acid residues in the binding site of caspase-3. The results of Co-IP, laser confocal microscopy and functional analyses were consistent with the computational model. We also used the model to explain why AFP cannot bind to caspase-8. These results provide the molecular basis for the AFP-mediated inhibition of caspase-3 activity in HCC cells. Altogether, we found that AFP interacts with caspase-3 through precise amino acids, namely loop-4 residues Glu 248, Asp-253 and His-257. The results further demonstrated that AFP plays a critical role in the inhibition of the apoptotic signal transduction that mediated by caspase-3. Thus, AFP might represent a novel biotarget for the therapy of HCC patients. PMID- 28653317 TI - [OsF6 ]x- : Molecular Models for Spin-Orbit Entangled Phenomena. AB - Heavy 5d elements, like osmium, feature strong spin-orbit interactions which are at the origin of exotic physical behaviors. Revealing the full potential of, for example, novel osmium oxide materials ("osmates") is however contingent upon a detailed understanding of the local single-ion properties. Herein, two molecular osmate analogues, [OsF6 ]2- and [OsF6 ]- , are reported as model systems for Os4+ and Os5+ centers found in oxides. Using X-ray absorption spectroscopy (XAS) and X ray magnetic circular dichroism (XMCD) techniques, combined with state-of-the-art ab initio calculations, their ground state was elucidated; mirroring the osmium electronic structure in osmates. The realization of such molecular model systems provides a unique chemical playground to engineer materials exhibiting spin-orbit entangled phenomena. PMID- 28653318 TI - In-session behaviours and adolescents' self-concept and loneliness: A psychodrama process-outcome study. AB - As adolescents spend many hours a day in school, it is crucial to examine the ways in which therapeutic practices in schools promote their well-being. This longitudinal pilot study examined the contribution of school-based psychodrama group therapy to the self-concept dimensions and perceived loneliness of 40 Israeli adolescents (aged 13-16, 60% boys) in public middle schools. From a process-outcome perspective, we also examined the understudied trajectory of adolescents' in-session behaviours (process variables) and its associations with changes in their self-concepts and loneliness (outcome variables). Psychodrama participants reported increases in global, social, and behavioural self-concepts and a decrease in loneliness compared to the control group. In-session productive behaviours increased and resistance decreased throughout the therapy, but varied process-outcome relationships were found. The study suggests that conducting further research into the process-outcome relationships in psychodrama group therapy is warranted to pinpoint specific mechanisms of change. Suggestions for future studies are provided. PMID- 28653319 TI - Body height and the spread of spinal anaesthesia for caesarean section: a prospective controlled trial. AB - BACKGROUND: No conclusive evidence exists on the effect of patient height on the spread of spinal anaesthesia. Our aim was to measure the ED50 and ED95 values of intrathecal ropivacaine in taller and shorter patients, and thus investigate the hypothesis that the spinal dose requirement in shorter patients is lower than that in taller patients undergoing caesarean section. METHODS: In this study, 270 pregnant women were assigned to the taller (Group T) or shorter group (Group S) based on their heights. Subjects in both groups were further randomly assigned to one of nine subgroups based on the dosage of intrathecal isobaric ropivacaine to be administered (7, 8, 9, 10, 11, 12, 13, 14 or 15 mg respectively). RESULTS: The ED50 and ED95 values of ropivacaine were 9.24 mg and 13.36 mg in Group S, and 10.11 mg and 14.63 mg in Group T, with no inter-group difference (P = 0.886). There was a significant inter-group difference in the incidence of hypotension and the changes in mean arterial pressure after spinal anaesthesia using 15 mg ropivacaine. The dose of ephedrine administered in Group S was higher than that in Group T when 15 mg ropivacaine was administered (P = 0.031). CONCLUSION: The taller and shorter patients did not respond differently to modest intrathecal doses of ropivacaine. However, a larger dose of ropivacaine was associated with an increased incidence of hypotension in shorter patients compared to that in taller patients. PMID- 28653320 TI - pi???H+ ???pi Hydrogen Bonds and Their Lithium and Gold Analogues: MP2 and CASPT2 Calculations. AB - Molecular systems in which two simple pi-electron species, acetylene and ethylene, are linked by a cation located between them are analyzed in this study. In particular, the C2 H2 ???M+ ???C2 H2 , C2 H4 ???M+ ???C2 H2 , and C2 H4 ???M+ ???C2 H4 complexes (M+ =H+ , Li+ , Au+ ) are calculated with the use of MP2 and CASPT2 methods. The Quantum Theory of Atoms in Molecules (QTAIM), energy decomposition analysis (EDA), and Natural Bond Orbital (NBO) approaches are applied to deepen the understanding of the nature of M+ ???pi interactions in these complexes. It is found that the interactions in gold and proton complexes are characterized by at least partial covalency, whereas interactions in lithium complexes are rather electrostatic in nature. PMID- 28653321 TI - Clinical and treatment-related features determining the risk of late relapse in patients with diffuse large B-cell lymphoma. AB - It is still unclear whether there are clinically exploitable differences in the biology and behaviour of early versus late relapses in diffuse large B-cell lymphoma (DLBCL). The present study aimed to analyse a large population-based DLBCL cohort in order to identify (i) the frequency of late relapses (LR), (ii) parameters influencing the risk of LR, and (iii) the impact of introducing rituximab on the occurrence of LR. The data of 7247 DLBCL patients was obtained from the Danish Lymphoma Group Registry. Patients with LR had a lower International Prognostic Index and better performance score than early relapse (ER) patients. The use of radiotherapy lowered only the rate of ER while the use of rituximab yielded a lower occurrence of both ER and LR (P < 0.0001 and P < 0.0001, respectively), possibly suggesting a longer-lasting biological effect. Additionally, we found a female overrepresentation among LR patients that had received a rituximab-containing first line treatment. It was found that patients with LR had a significantly better 5-year overall survival compared to ER patients. In conclusion, LR was more frequently associated with low-risk features than ER. Furthermore, we found that the use of modern immunochemotherapy regimens in DLBCL lowers the risk of both ER and LR. PMID- 28653322 TI - Differentiating the Cochran-Armitage Trend Test and Pearson's chi2 Test: Location and Dispersion. AB - In genetic case-control association studies, a standard practice is to perform the Cochran-Armitage (CA) trend test with 1 degree-of-freedom (d.f.) under the assumption of an additive model. However, when the true genetic model is recessive or near recessive, it is outperformed by Pearson's chi2 test with 2 d.f. In this article, we analytically reveal the statistical basis that leads to the phenomenon. First, we show that the CA trend test examines the location shift between the case and control groups, whereas Pearson's chi2 test examines both the location and dispersion shifts between the two groups. Second, we show that under the additive model, the effect of location deviation outweighs that of the dispersion deviation and vice versa under a near recessive model. Therefore, Pearson's chi2 test is a more robust test than the CA trend test, and it outperforms the latter when the mode of inheritance evolves to the recessive end. PMID- 28653323 TI - Increased fracture risk in plasma cell dyscrasias is associated with poorer overall survival. AB - Pathological fractures are a common complication of plasma cell dyscrasias (PCD) and are associated with significant morbidity. Routine use of bisphosphonates over the past decade has aimed to reduce the risk of fractures in patients with multiple myeloma, but despite this, fractures continue to represent a significant burden of disease. In this study we report the fracture rate of hospital in patients with PCD in England. Data from the national registry Hospital Episode Statistics between 2001 and 2015 were used to determine fracture rate and its effect on overall survival. Fracture rates were 17.8 times higher than the general population in the first year after admission with PCD, and remained elevated for up to 10 years after first admission. The increased fracture risk preceded the first admission with PCD and, conversely, the incidence of PCD increased after admission with one or more fractures. Overall survival is improving with PCD, however poorer survival is found in patients with a preceding fracture (Hazard ratio 1.20). Despite widespread bisphosphonate use, fractures remain common in PCD, and are associated with poorer outcomes. PMID- 28653324 TI - The EVerT2 (Effective Verruca Treatments 2) trial: a randomized controlled trial of needling vs. nonsurgical debridement for the treatment of plantar verrucae. AB - BACKGROUND: Verrucae are a common foot skin pathology, which can in some cases persist for many years. Plantar verrucae can be unsightly and painful. There are a range of treatment options including needling. OBJECTIVES: The EVerT2 (Effective Verruca Treatments 2) trial aimed to evaluate the clinical and cost effectiveness of the needling procedure for the treatment of plantar verrucae, relative to callus debridement. METHODS: This single-centre randomized controlled trial recruited 60 participants (aged >= 18 years with a plantar verruca). Participants were randomized 1 : 1 to the intervention group (needling) or the control group (debridement of the overlying callus). The primary outcome was clearance of the index verruca at 12 weeks after randomization. Secondary outcomes included recurrence of the verruca, clearance of all verrucae, number of verrucae, size of the index verruca, pain and participant satisfaction at 12 and 24 weeks. A cost-effectiveness analysis was carried out from the National Health Service perspective over 12 weeks. RESULTS: Sixty eligible patients were randomized (needling group n = 29, 48%; debridement group n = 31, 52%) and 53 were included in the primary analysis (needling n = 28, 97%; debridement n = 25, 81%). Clearance of the index verruca occurred in eight (15%) participants (needling n = 4, 14%; debridement n = 4, 16%; P = 0.86). The needling intervention costs were on average L14.33 (95% confidence interval 5.32-23.35) more per patient than for debridement. CONCLUSIONS: There is no evidence that the needling technique is more clinically or cost-effective than callus debridement. The results show a significant improvement in pain outcomes after needling compared with the debridement treatment alone. PMID- 28653326 TI - No support for Heincke's law in hagfish (Myxinidae): lack of an association between body size and the depth of species occurrence. AB - This study tests for interspecific evidence of Heincke's law among hagfishes and advances the field of research on body size and depth of occurrence in fishes by including a phylogenetic correction and by examining depth in four ways: maximum depth, minimum depth, mean depth of recorded specimens and the average of maximum and minimum depths of occurrence. Results yield no evidence for Heincke's law in hagfishes, no phylogenetic signal for the depth at which species occur, but moderate to weak phylogenetic signal for body size, suggesting that phylogeny may play a role in determining body size in this group. PMID- 28653325 TI - Medical and economic implications of strategies to prevent alloimmunization in sickle cell disease. AB - BACKGROUND: The pathogenesis of alloimmunization is not well understood, and initiatives that aim to reduce the incidence of alloimmunization are generally expensive and either ineffective or unproven. In this review, we summarize the current medical literature regarding alloimmunization in the sickle cell disease (SCD) population, with a special focus on the financial implications of different approaches to prevent alloimmunization. STUDY DESIGN AND METHODS: A review of EMBASE and MEDLINE data from January 2006 through January 2016 was conducted to identify articles relating to complications of SCD. The search was specifically designed to capture articles that evaluated the costs of various strategies to prevent alloimmunization and its sequelae. RESULTS: Currently, there is no proven, inexpensive way to prevent alloimmunization among individuals with SCD. Serologic matching programs are not uniformly successful in preventing alloimmunization, particularly to Rh antigens, because of the high frequency of variant Rh alleles in the SCD population. A genotypic matching program could offer some cost savings compared to a serologic matching program, but the efficacy of gene matching for the prevention of alloimmunization is largely unproven, and large-scale implementation could be expensive. CONCLUSIONS: Future reductions in the costs associated with genotype matching could make a large scale program economically feasible. Novel techniques to identify patients at highest risk for alloimmunization could improve the cost effectiveness of antigen matching programs. A clinical trial comparing the efficacy of serologic matching to genotype matching would be informative. PMID- 28653327 TI - Are severely injured trauma victims in Norway offered advanced pre-hospital care? National, retrospective, observational cohort. AB - BACKGROUND: Studies of severely injured patients suggest that advanced pre hospital care and/or rapid transportation provides a survival benefit. This benefit depends on the disposition of resources to patients with the greatest need. Norway has 19 Emergency Helicopters (HEMS) staffed by anaesthesiologists on duty 24/7/365. National regulations describe indications for their use, and the use of the national emergency medical dispatch guideline is recommended. We assessed whether severely injured patients had been treated or transported by advanced resources on a national scale. METHODS: A national survey was conducted collecting data for 2013 from local trauma registries at all hospitals caring for severely injured patients. Patients were analysed according to hospital level; trauma centres or acute care hospitals with trauma functions. Patients with an Injury Severity Score (ISS) > 15 were considered severely injured. RESULTS: Three trauma centres (75%) and 17 acute care hospitals (53%) had data for trauma patients from 2013, a total of 3535 trauma registry entries (primary admissions only), including 604 victims with an ISS > 15. Of these 604 victims, advanced resources were treating and/or transporting 51%. Sixty percent of the severely injured admitted directly to trauma centres received advanced services, while only 37% of the severely injured admitted primarily to acute care hospitals received these services. CONCLUSION: A highly developed and widely distributed HEMS system reached only half of severely injured trauma victims in Norway in 2013. PMID- 28653328 TI - A randomized double-blind controlled trial of different filling pressures in operative outpatient hysteroscopy. AB - OBJECTIVE: To identify the optimal filling pressure during operative outpatient hysteroscopy that allows completion of the procedure while minimizing pain. METHODS: A double-blind randomized controlled trial of women aged 20-60 years undergoing operative hysteroscopy (including biopsy sampling, polypectomy, septum excision, adhesiolysis, or intrauterine device removal) was undertaken at a university hospital in Egypt between May 2014 and July 2016. Using a computer generated randomization sequence, patients were randomly assigned into three equal groups: filling pressures of 40 mm Hg (group 1), 60 mm Hg (group 2), and 80 mm Hg (group 3; control). The primary outcome was the proportion of successfully completed procedures. Analyses were by intention to treat. RESULTS: Each group contained 80 women. The procedure was completed for 63 (79%) women in group 1, 73 (91%) in group 2, and 76 (95%) in group 3 (P=0.004). The proportion of completed procedures in group 3 was significantly different from that in group 1 (P=0.002), but did not differ significantly from that in group 2 (P=0.349). CONCLUSION: A uterine filling pressure of 60 mm Hg does not reduce the frequency of completion when compared with 80 mm Hg in operative outpatient hysteroscopy. CLINICALTRIALS. GOV REGISTRATION: NCT02142673. PMID- 28653330 TI - Quality assurance and tests of platelet function. PMID- 28653329 TI - Acquired RhD mosaicism identifies fibrotic transformation of thrombopoietin receptor-mutated essential thrombocythemia. AB - BACKGROUND: Acquired copy-neutral loss of heterozygosity has been described in myeloid malignant progression with an otherwise normal karyotype. CASE REPORT: A 65-year-old woman with MPL-mutated essential thrombocythemia and progression to myelofibrosis was noted upon routine pretransplant testing to have mixed field reactivity with anti-D and an historic discrepancy in RhD type. The patient had never received transfusions or transplantation. RESULTS: Gel immunoagglutination revealed group A red blood cells and a mixed-field reaction for the D phenotype, with a predominant D-negative population and a small subset of circulating red blood cells carrying the D antigen. Subsequent genomic microarray single nucleotide polymorphism profiling revealed copy-neutral loss of heterozygosity of chromosome 1 p36.33-p34.2, a known molecular mechanism underlying fibrotic progression of MPL-mutated essential thrombocythemia. The chromosomal region affected by this copy-neutral loss of heterozygosity encompassed the RHD, RHCE, and MPL genes. We propose a model of chronological molecular events that is supported by RHD zygosity assays in peripheral lymphoid and myeloid-derived cells. CONCLUSION: Copy-neutral loss of heterozygosity events that lead to clonal selection and myeloid malignant progression may also affect the expression of adjacent unrelated genes, including those encoding for blood group antigens. Detection of mixed-field reactions and investigation of discrepant blood typing results are important for proper transfusion support of these patients and can provide useful surrogate markers of myeloproliferative disease progression. PMID- 28653331 TI - Phytosterol-based oleogels self-assembled with monoglyceride for controlled volatile release. AB - BACKGROUND: Oleogels have recently emerged as a subject of growing interest among industrial and academic researchers as an alternative to saturated/trans-fat and delivery of functional ingredients. Phytosterols, comprising plant-derived natural steroid compounds, are preferred for oleogel production because they are both natural and healthy. In the present study, phytosterol-based oleogels self assembled with monoglyceride were studied with respect to tuning volatile release. RESULTS: Microscopy images of the bicomponent oleogels of beta sitosterol and monoglyceride showed the formation of a new three-dimensional network of entangled crystals and a controllable microstructure. Our analysis from differential scanning calorimetry and small angle X-ray scattering results suggests the self-assembly of beta-sitosterol and monoglyceride via intermolecular hydrogen bonds into spherulitic microstructures. The results showed that the release rate (v0 ), maximum headspace concentrations (Cmax ) and partition coefficients (ka/o ) for oleogels showed a significantly controlled release and were tunable via the microstructure of phytosterol-based oleogels under both dynamic and static conditions. In addition, the solid-like oleogels had interesting thixotropic and thermoresponsive behaviors, probably as a result of intermolecular hydrogen bonding. CONCLUSION: The self-assembly of phytosterol based oleogels with monoglyceride was attributed to intermolecular hydrogen and is demonstrated to be a promising tunable and functional strategy for delivering flavor compounds. (c) 2017 Society of Chemical Industry. PMID- 28653332 TI - Transvaginal mesh removal with native-tissue repair for mesh shrinkage and recurrent uterovaginal prolapse following vaginal mesh-augmented surgery. PMID- 28653333 TI - Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records. AB - Clopidogrel efficacy is influenced by genetic variation of cytochrome P450 (CYP)2C19, however, few studies have considered patients who have a stroke. We used electronic medical records (EMRs) linked to a bioresource to examine real world implications of clopidogrel pharmacogenetics in stroke. Patients hospitalized for any arterial thrombo-occlusive (ATO) event who subsequently redeemed clopidogrel prescriptions in the community were entered into the study (n = 651). During 24-month follow-up, the primary endpoint of recurrent ATO or death occurred in 299 patients (46%). CYP2C19*2 loss-of-function allele carriers had an increased risk (hazard ratio (HR) = 1.29; 95% confidence interval (CI) = 1.04-1.59; P = 0.019). In the ischemic stroke subgroup (n = 94), the estimate of risk was greater (HR = 2.23; 95% CI = 1.17-4.24; P = 0.015), which was further supported by a meta-analysis of available studies. In conclusion, we have demonstrated the clinical impact of CYP2C19*2 on clopidogrel efficacy using a purely EMR approach. This suggests that the risk in the ischemic stroke population may be particularly high. PMID- 28653334 TI - Vector competence of Malaysian Aedes albopictus with and without Wolbachia to four dengue virus serotypes. AB - OBJECTIVE: To determine the susceptibility status of Aedes albopictus with and without Wolbachia to the four dengue virus serotypes. METHODS: Two newly colonised colonies of Ae. albopictus from the wild were used for the study. One colony was naturally infected with Wolbachia while in the other Wolbachia was removed by tetracycline treatment. Both colonies were orally infected with dengue virus-infected fresh blood meal. Dengue virus load was measured using quantitative RT-PCR at four-time intervals in the salivary glands, midguts and ovaries. RESULTS: Wolbachia did not significantly affect Malaysian Ae. albopictus dengue infection or the dissemination rate for all four dengue virus serotypes. Malaysian Ae. albopictus had the highest replication kinetics for DENV-1 and the highest salivary gland and midgut infection rate for DENV-4. CONCLUSION: Wolbachia, which naturally exists in Malaysian Ae. albopictus, does not significantly affect dengue virus replication. Malaysian Ae. albopictus is susceptible to dengue virus infections and capable of transmitting dengue virus, especially DENV-1 and DENV-4. Removal of Wolbachia from Malaysian Ae. albopictus would not reduce their susceptibility status. PMID- 28653335 TI - Catlas: An magnetic resonance imaging-based three-dimensional cortical atlas and tissue probability maps for the domestic cat (Felis catus). AB - Brain atlases play an important role in effectively communicating results from neuroimaging studies in a standardized coordinate system. Furthermore, brain atlases extend analysis of functional magnetic resonance imaging (MRI) data by delineating regions of interest over which to evaluate the extent of functional activation as well as measures of inter-regional connectivity. Here, we introduce a three-dimensional atlas of the cat cerebral cortex based on established cytoarchitectonic and electrophysiological findings. In total, 71 cerebral areas were mapped onto the gray matter (GM) of an averaged T1-weighted structural MRI acquired at 7 T from eight adult domestic cats. In addition, a nonlinear registration procedure was used to generate a common template brain as well as GM, white matter, and cerebral spinal fluid tissue probability maps to facilitate tissue segmentation as part of the standard preprocessing pipeline for MRI data analysis. The atlas and associated files can also be used for planning stereotaxic surgery and for didactic purposes. PMID- 28653337 TI - Hardystonite-Coated Poly(l-lactide) Nanofibrous Scaffold and Efficient Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells. AB - In this study, a ceramic-coated nanofibrous scaffold has been fabricated to biomimic the microstructure of natural extracellular matrix and the stiffening inorganic compartment of bone. Poly-l-lactic acid (PLLA) nanofibers were electrospun and exposed to oxygen plasma to induce hydrophilicity and promote ceramic adsorption. Hardystonite (HS), which possesses superior osteoinduction potential over hydroxyapatite, was coated on plasma-treated PLLA nanofibers by drenching the nanofibers in HS suspension. Pure and composite PLLA-based scaffolds were characterized in terms of physical and biological properties. In vitro cultivation of adipose-derived mesenchymal stem cells (AMSCs) on the scaffolds displayed that the composite scaffold is able to further support cell attachment and proliferation. In case of osteogenic differentiation of AMSCs, HS coating significantly increased the synthesis and activity of alkaline phosphate over 21 days period. In addition, the composite scaffold showed improved mineralization. The expression level of osteonectin and osteocalcin genes was significantly enhanced by HS coating of nanofibers. The biological improvement of PLLA nanofibrous matrix in the presence of HS nanoparticles could either be attributed to the release and stimulatory effect of constituent ions of HS or to the modification of chemico-physical properties of the resultant ceramic by silicon and zinc present in HS. PMID- 28653336 TI - Targeting carbon for crop yield and drought resilience. AB - Current methods of crop improvement are not keeping pace with projected increases in population growth. Breeding, focused around key traits of stem height and disease resistance, delivered the step-change yield improvements of the green revolution of the 1960s. However, subsequently, yield increases through conventional breeding have been below the projected requirement of 2.4% per year required by 2050. Genetic modification (GM) mainly for herbicide tolerance and insect resistance has been transformational, akin to a second green revolution, although GM has yet to make major inroads into intrinsic yield processes themselves. Drought imposes the major restriction on crop yields globally but, as yet, has not benefited substantially from genetic improvement and still presents a major challenge to agriculture. Much still has to be learnt about the complex process of how drought limits yield and what should be targeted. Mechanisms of drought adaptation from the natural environment cannot be taken into crops without significant modification for the agricultural environment because mechanisms of drought tolerance are often in contrast with mechanisms of high productivity required in agriculture. However, through convergence of fundamental and translational science, it would appear that a mechanism of sucrose allocation in crops can be modified for both productivity and resilience to drought and other stresses. Recent publications show how this mechanism can be targeted by GM, natural variation and a new chemical approach. Here, with an emphasis on drought, we highlight how understanding fundamental science about how crops grow, develop and what limits their growth and yield can be combined with targeted genetic selection and pioneering chemical intervention technology for transformational yield improvements. (c) 2017 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28653338 TI - A method for detailed movement pattern analysis of tadpole startle response. AB - Prolonged space flight, specifically microgravity, presents a problem for space exploration. Animal models with altered connections of the vestibular ear, and thus altered gravity sensation, would allow the examination of the effects of microgravity and how various countermeasures can establish normal function. We describe an experimental apparatus to monitor the effects of ear manipulations to generate asymmetric gravity input on the tadpole escape response. To perform the movement pattern analysis, an imaging apparatus was developed that uses a high speed camera to obtain time-resolved, high-resolution images of tadpole movements. Movements were recorded in a temperature-controlled test chamber following mechanical stimulation with a solenoid actuator, to elicit a C-start response. Temperature within the test cell was controlled with a recirculating water bath. Xenopus laevis embryos were obtained using a standard fertilization technique. Tadpole response to a controlled perturbation was recorded in unprecedented detail and the approach was validated by describing the distinct differences in response between normal and one-eared tadpoles. The experimental apparatus and methods form an important element of a rigorous investigation into the response of the tadpole vestibular system to mechanical and biochemical manipulations, and can ultimately contribute to improved understanding of the effects of altered gravity perception on humans. PMID- 28653339 TI - Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study. AB - We aimed to compare hypofibrinogenaemia prevalence in major bleeding patients across all clinical contexts, fibrinogen supplementation practice, and explore the relationship between fibrinogen concentrations and mortality. This cohort study included all adult patients from 20 hospitals across Australia and New Zealand who received massive transfusion between April 2011 and October 2015. Of 3566 patients, 2829 (79%) had fibrinogen concentration recorded, with a median first and lowest concentration of 2.0 g/l (interquartile range [IQR] 1.5-2.7) and 1.8 g/l (IQR 1.3-2.4), respectively. Liver transplant (1.7 g/l, IQR 1.2-2.1), trauma (1.8, IQR 1.3-2.5) and vascular surgery (1.9 g/l, IQR 1.4-2.5) had lower concentrations. Total median fibrinogen dose administered from all products was 7.3 g (IQR 3.3-13.0). Overall, 1732 (61%) received cryoprecipitate and 9 (<1%) fibrinogen concentrate. Time to cryoprecipitate issue in those with initial fibrinogen concentration <1 g/l was 2.5 h (IQR 1.2-4.3 h). After adjustment, initial fibrinogen concentration had a U-shaped association with in-hospital mortality [adjusted odds ratios: fibrinogen <1 g/l, 2.31 (95% confidence interval (CI) 1.48-3.60); 1-1.9 g/l, 1.29 (95% CI 0.99-1.67) and >4 g/l, 2.03 (95% CI 1.35 3.04), 2-4 g/l reference category]. The findings indicate areas for practice improvement including timely administration of cryoprecipitate, which is the most common source of concentrated fibrinogen in Australia and New Zealand. PMID- 28653340 TI - Aortic perfusion score for pulmonary atresia with intact ventricular septum: An antegrade coronary perfusion scoring system that is predictive of need for transplant and mortality. AB - BACKGROUND: Pulmonary atresia with intact ventricular septum is a unique congenital malformation of the heart in which patients may undergo single-, two- or 11/2- ventricle repair. Size of the tricuspid valve annulus, morphology of the right ventricle and presence of ventriculocoronary connections can all impact the selection of appropriate palliative strategy. We developed the aortic perfusion score, a novel scoring system based on anterograde coronary perfusion with the aim of being able to identify patients at risk for death or transplant. METHODS: A retrospective study was conducted. Patients were included if an initial catheterization was done prior to any intervention. Each patient was assigned an aortic perfusion score based on the amount of antegrade perfusion to the four main coronary arteries. Various characteristics, including aortic perfusion score, were compared between those who required transplant or died during follow up vs those who did not. Receiver operator curve analysis was done to determine a cutoff point predictive of a composite endpoint of death or transplant. RESULTS: A total of 64 patients were included in the analysis with 10 reaching the composite outcome. An aortic perfusion score of 227.5 predicted the endpoint with a sensitivity of 90% and a specificity of 83%. For each 1-point increase in the APS, the odds of death or transplant decreased by 1.7%. CONCLUSION: The aortic perfusion score can be used to predict a composite endpoint of death or transplant and may be helpful in selecting patients that should be listed for transplant. PMID- 28653341 TI - OpenSimRoot: widening the scope and application of root architectural models. AB - OpenSimRoot is an open-source, functional-structural plant model and mathematical description of root growth and function. We describe OpenSimRoot and its functionality to broaden the benefits of root modeling to the plant science community. OpenSimRoot is an extended version of SimRoot, established to simulate root system architecture, nutrient acquisition and plant growth. OpenSimRoot has a plugin, modular infrastructure, coupling single plant and crop stands to soil nutrient and water transport models. It estimates the value of root traits for water and nutrient acquisition in environments and plant species. The flexible OpenSimRoot design allows upscaling from root anatomy to plant community to estimate the following: resource costs of developmental and anatomical traits; trait synergisms; and (interspecies) root competition. OpenSimRoot can model three-dimensional images from magnetic resonance imaging (MRI) and X-ray computed tomography (CT) of roots in soil. New modules include: soil water-dependent water uptake and xylem flow; tiller formation; evapotranspiration; simultaneous simulation of mobile solutes; mesh refinement; and root growth plasticity. OpenSimRoot integrates plant phenotypic data with environmental metadata to support experimental designs and to gain a mechanistic understanding at system scales. PMID- 28653342 TI - Thrombocytosis-related glomerulopathy in a patient with hyposplenia. PMID- 28653343 TI - Guided bone regeneration at zirconia and titanium dental implants: a pilot histological investigation. AB - AIM: To test whether guided bone regeneration (GBR) of peri-implant defects at zirconia (ZrO2 ) implants differs from GBR at titanium (Ti) implants regarding the bone integration of the implant and of the grafting material. MATERIALS AND METHODS: Maxillary premolars and molars were extracted in seven dogs. After 5 months, four semi-saddle bone defects were created in each maxilla. Implant placement and simultaneous GBR were performed using the following randomly assigned modalities: (1) ZrO2 implant + deproteinized bovine bone mineral (DBBM) granules + a collagen membrane (CM), (2) ZrO2 implant + DBBM with 10% collagen matrix + CM, (3) ZrO2 implant + DBBM block + CM, and (4) Ti implant + DBBM granules + CM. After 3 months, one central histological section of each site was prepared. Histomorphometrical assessments were performed evaluating the augmented area (AA) within the former bone defect (primary outcome), the area of new bone (NB), bone substitute (BS), and non-mineralized tissue (NMT) within AA in mm2 . In addition, the distance between the most coronal bone-to-implant contact and the margin of the former bone defect (fBIC-DEF), and the bone-to-implant contact fraction (BIC) were measured in mm. RESULTS: AA measured 8.6 +/- 4.0 mm2 for ZrO2 implant + DBBM granules, 4.7 +/- 1.6 mm2 for ZrO2 implant + DBBM-collagen, 5.1 +/ 1.9 mm2 for ZrO2 implant + DBBM block, and 7.6 +/- 2.8 mm2 for Ti implant + DBBM granules. There were no statistically significant differences between the treatment modalities (P > 0.05). NB reached 2.0 +/- 1.7 mm2 for ZrO2 implant + DBBM granules, 0.9 +/- 0.9 mm2 for ZrO2 implant + DBBM-collagen, 2.1 +/- 0.9 mm2 for ZrO2 implant + DBBM block, and 0.8 +/- 0.6 mm2 for Ti implant + DBBM granules. fBIC-DEF amounted to 2.1 +/- 1.7 mm2 for ZrO2 implant + DBBM granules, to 2.7 +/- 1.1 mm2 for ZrO2 implant + DBBM-collagen, to 2.9 +/- 1.2 mm2 for ZrO2 implant + DBBM block, and to 3.4 +/- 0.4 mm2 for Ti implant + DBBM granules. BIC measured 70 +/- 19% for ZrO2 implant + DBBM granules, 69 +/- 22% for ZrO2 implant + DBBM-collagen, 77 +/- 30% for ZrO2 implant + DBBM block, and 66 +/- 27% for Ti implant + DBBM granules. CONCLUSIONS: The findings of the present pilot study suggest that zirconia and titanium implants grafted with DBBM granules and covered with a collagen membrane do not perform differently regarding the augmented ridge contour, the NB formation, and the implant osseointegration. PMID- 28653344 TI - Establishing the overlap of IONP quantification with echo and echoless MR relaxation mapping. AB - PURPOSE: Iron-oxide nanoparticles (IONPs) have shown tremendous utility for enhancing image contrast and delivering targeted therapies. Quantification of IONPs has been demonstrated at low concentrations with gradient echo (GRE) and spin echo (SE), and at high concentrations with echoless sequences such as swept imaging with Fourier transform (SWIFT). This work examines the overlap of IONP quantification with GRE, SE, and SWIFT. METHODS: The limit of quantification of GRE, SE, inversion-recovery GRE, and SWIFT sequences was assessed using IONPs at a concentration range of 0.02 to 89.29 mM suspended in 1% agarose. Empirically derived limits of quantification were compared with International Union of Pure and Applied Chemistry definitions. Both commercial and experimental IONPs were used. RESULTS: All three IONPs assessed demonstrated an overlap of concentration quantification with GRE, SE, and SWIFT sequences. The largest dynamic range observed was 0.004 to 35.7 mM with Feraheme. CONCLUSIONS: The metrics established allow upper and lower quantitative limitations to be estimated given the relaxivity characteristics of the IONP and the concentration range of the material to be assessed. The methods outlined in this paper are applicable to any pulse sequence, IONP formulation, and field strength. Magn Reson Med 79:1420 1428, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28653345 TI - Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof-of-Concept Study. AB - OBJECTIVES: To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations. DESIGN: A 24 week, randomized, double-blind, placebo-controlled, parallel-arm, proof-of concept study. SETTING: Five centers in the United States. PARTICIPANTS: Community-dwelling adults (N = 40) aged 65 and older with gait speed between 0.4 and 1.0 m/s over 4 m and an appendicular skeletal muscle index of 7.25 kg/m2 or less for men and 5.67 kg/m2 or less for women. INTERVENTION: Intravenous bimagrumab 30 mg/kg (n = 19) or placebo (n = 21). MEASUREMENTS: Change from baseline in thigh muscle volume (TMV), subcutaneous and intermuscular fat, appendicular and total lean body mass, grip strength, gait speed, and 6-minute walk distance (6MWD). RESULTS: Thirty-two (80%) participants completed the study. TMV increased by Week 2, was sustained throughout the treatment period, and remained above baseline at the end of study in bimagrumab-treated participants, whereas there was no change with placebo treatment (Week 2: 5.15 +/- 2.19% vs 0.34 +/- 2.59%, P < .001; Week 4: 6.12 +/- 2.56% vs 0.16 +/- 3.42%, P < .001; Week 8: 8.01 +/- 3.70% vs 0.35 +/- 3.32%, P < .001; Week 16: 7.72 +/- 5.31% vs 0.42 +/- 5.14%, P < .001; Week 24: 4.80 +/- 5.81% vs -1.01 +/- 4.43%, P = .002). Participants with slower walking speed at baseline receiving bimagrumab had clinically meaningful and statistically significantly greater improvements in gait speed (mean 0.15 m/s, P = .009) and 6MWD (mean 82 m, P = .022) than those receiving placebo at Week 16. Adverse events in the bimagrumab group included muscle-related symptoms, acne, and diarrhea, most of which were mild in severity and resolved by the end of study. CONCLUSION: Treatment with bimagrumab over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed. PMID- 28653346 TI - Identification of young-of-the-year great hammerhead shark Sphyrna mokarran in northern Florida and South Carolina. AB - Two sharks, visually identified in the field as young-of-the-year (YOY) scalloped hammerhead Sphyrna lewini, were identified as great hammerhead Sphyrna mokarran based on nuclear-encoded single nucleotide polymorphisms (SNP) and sequences of mtDNA. Individuals were captured and released in Bulls Bay, SC, and Saint Joseph Bay, FL, in 2013 and 2014, respectively. These findings indicate S. mokarran may be pupping in or around these areas and highlight new regions that may be a productive focus for future research on early life history of S. mokarran. PMID- 28653347 TI - Preliminary evaluation of Pleurotus ostreatus for the removal of selected pharmaceuticals from hospital wastewater. AB - The fungus Pleurotus ostreatus was investigated to assess its ability to remove diclofenac, ketoprofen, and atenolol spiked at 10 mg/L each one in hospital wastewater. The degradation test was carried out in a fluidized bed bioreactor testing both the batch and the continuous mode (hydraulic retention time in the range 1.63-3 days). In batch mode, diclofenac disappeared in less than 24 h, ketoprofen was degraded up to almost 50% in 5 days while atenolol was not removed. In continuous mode, diclofenac and ketoprofen removals were about 100% and 70% respectively; atenolol degradation was negligible during the first 20 days but it increased up to 60% after a peak of laccase production and notable biomass growth. In order to identify the enzymatic system involved, further experiments were carried out in flasks. Purified laccase completely transformed atenolol and diclofenac in less than 5 h, but not ketoprofen. In vivo experiments suggested that cytochrome P450 could be involved in diclofenac and ketoprofen degradation, while partial correlation studies confirmed the role of laccase in atenolol and diclofenac degradation. Two intermediates of diclofenac and ketoprofen were detected by nuclear magnetic resonance. Moreover P. ostreatus was able to reduce chemical oxygen demand of the hospital wastewater which is an important advantage comparing to other fungi in order to develop a wastewater treatment process. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1529-1537, 2017. PMID- 28653348 TI - Asystole caused by Hydroxycut Hardcore: A case report and literature review. AB - Obesity is a rising epidemic worldwide driving people to search for remedy through nonconventional therapies. Hydroxycut products are popular supplements used as weight loss aids. Many reports revealed serious adverse effects related to their ingestion. We report the case of a 37-year-old healthy male patient who presented following an episode of syncope. On telemetry, he manifested recurrent sinus node arrests, including a symptomatic 24 s sinus pause. The patient admitted to taking Hydroxycut Hardcore for 10 days previously. After discontinuation of the drug, his symptoms completely resolved. This is the first case of Hydroxycut-associated syncope secondary to bradyarrhythmia. PMID- 28653351 TI - Cutaneous Leishmania tropica in children: report of three imported cases successfully treated with liposomal amphotericin B. PMID- 28653350 TI - Zoledronic acid and alendronate sodium and the implications in orthodontic movement. AB - OBJECTIVE: To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z). DESIGN: In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5 mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02 mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25 days before OTM started and during 10 days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/104 m2 ) in periodontal ligament (PDL) of the distobuccal root. RESULTS: A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z. CONCLUSION: Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement. PMID- 28653349 TI - Assignment of the molecular origins of CEST signals at 2 ppm in rat brain. AB - PURPOSE: Chemical exchange saturation transfer effects at 2 ppm (CEST@2ppm) in brain have previously been interpreted as originating from creatine. However, protein guanidino amine protons may also contribute to CEST@2ppm. This study aims to investigate the molecular origins and specificity of CEST@2ppm in brain. METHODS: Two experiments were performed: (i) samples containing egg white albumin and creatine were dialyzed using a semipermeable membrane to demonstrate that proteins and creatine can be separated by this method; and (ii) tissue homogenates of rat brain with and without dialysis to remove creatine were studied to measure the relative contributions of proteins and creatine to CEST@2ppm. RESULTS: The experiments indicate that dialysis can successfully remove creatine from proteins. Measurements on tissue homogenates show that, with the removal of creatine via dialysis, CEST@2ppm decreases to approximately 34% of its value before dialysis, which indicates that proteins and creatine have comparable contribution to the CEST@2ppm in brain. However, considering the contribution from peptides and amino acids to CEST@2ppm, creatine may have much less contribution to CEST@2ppm. CONCLUSIONS: The contribution of proteins, peptides, and amino acids to CEST@2ppm cannot be neglected. The CEST@2ppm measurements of creatine in rat brain should be interpreted with caution. Magn Reson Med 78:881-887, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28653352 TI - Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs. AB - Pharmacokinetic (PK) models exist for most antiepileptic drugs (AEDs). Yet their use in clinical practice to assess interindividual differences and derive individualized doses has been limited. Here we show how model-based dosing algorithms can be used to ensure attainment of target exposure and improve treatment response in patients. Using simulations, different treatment scenarios were explored for 11 commonly used AEDs. For each drug, five scenarios were considered: 1) all patients receive the same dose. 2) Individual clearance (CL), as predicted by population PK models, is used to personalize treatment. 3-5) Individual CL, obtained by therapeutic drug monitoring (TDM) according to different sampling schemes, is used to personalize treatment. Attainment of steady-state target exposure was used as the performance criterion to rank each scenario. In contrast to current clinical guidelines, our results show that patient demographic and clinical characteristics should be used in conjunction with TDM to personalize the treatment of seizures. PMID- 28653354 TI - A new strategy for umbilical cord blood collection developed at the first Colombian public cord blood bank increases total nucleated cell content. AB - BACKGROUND: The total nucleated cell dosage of umbilical cord blood (UCB) is an important factor in determining successful allogeneic hematopoietic stem cell transplantation after a minimum human leukocyte antigen donor-recipient match. The northern South American population is in need of a new-generation cord blood bank that cryopreserves only units with high total nucleated cell content, thereby increasing the likelihood of use. Colombia set up a public cord blood bank in 2014; and, as a result of its research for improving high total nucleated cell content, a new strategy for UCB collection was developed. STUDY DESIGN AND METHODS: Data from 2933 collected and 759 cryopreserved cord blood units between 2014 and 2015 were analyzed. The correlation of donor and collection variables with cellularity was evaluated. Moreover, blood volume, cell content, CD34+ count, clonogenic capacity, and microbial contamination were assessed comparing the new method, which combines in utero and ex utero techniques, with the conventional strategies. RESULTS: Multivariate analysis confirmed a correlation between neonatal birth weight and cell content. The new collection method increased total nucleated cell content in approximately 26% and did not alter pre cryopreservation and post-thaw cell recovery, viability, or clonogenic ability. Furthermore, it showed a remarkably low microbial contamination rate (1.2%). CONCLUSION: The strategy for UCB collection developed at the first Colombian public cord blood bank increases total nucleated cell content and does not affect unit quality. The existence of this bank is a remarkable breakthrough for Latin American patients in need of this kind of transplantation. PMID- 28653353 TI - Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. AB - The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti-lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains. PMID- 28653355 TI - Strip meniscometry in dogs, cats, and rabbits. AB - OBJECTIVE: The purpose of this study was to establish the normal values of strip meniscometry (SM) as a lacrimal function test and to compare the results with Schirmer tear test I (STT I) in dogs, cats, and rabbits. ANIMALS STUDIED: Sixty healthy adult dogs from twelve different breeds (120 eyes), twenty adult healthy domestic shorthair cats (40 eyes) and eighteen adult healthy New Zealand white rabbits (36 eyes) were used in this study. PROCEDURES: Lacrimal function was tested by SM tube in all animals. After 24 h at the same time of day, tear production was measured using STT I. RESULTS: Mean SM and STT I values for all of the dogs, cats, and rabbits were 9.66 +/- 2.15 mm/5 s and 15.10 +/- 3.06 mm/min; 10.50 +/- 0.7 mm/5 s and 11.00 +/- 1.41 mm/min; 4.72 +/- 1.20 mm/5 s and 4.22 +/- 2.47 mm/min, respectively. There was a correlation (r = 0.281; P = 0.018) between SM and STT I values in dogs, but no correlation was observed in cats and rabbits (P = 0.61, P = 0.06). No correlation was found between age of animals and obtained SM values in each species (P > 0.29). Sex had no effect on SM values in each species (P > 0.08). CONCLUSIONS: The result of this study provided the normal clinical values of strip meniscometry as lacrimal function test in three species. PMID- 28653356 TI - Arcuate nucleus homeostatic systems reflect blood leptin concentration but not feeding behaviour during scheduled feeding on a high-fat diet in mice. AB - Hypothalamic homeostatic and forebrain reward-related genes were examined in the context of scheduled meal feeding without caloric restriction in C57BL/6 mice. Mice fed ad libitum but allowed access to a palatable high-fat (HF) diet for 2 hours a day rapidly adapted their feeding behaviour and consumed approximately 80% of their daily caloric intake during this 2-hour scheduled feed. Gene expression levels were examined during either the first or second hour of scheduled feeding vs 24 hours ad libitum feeding on the same HF diet. Gene expression of neuropeptide Y, agouti-related peptide, cocaine- and amphetamine regulated transcript, pro-opiomelanocortin, long-form leptin receptor and suppressor of cytokine signalling-3 in the hypothalamic arcuate nucleus (ARC), as well as enkephalin, dynorphin, dopamine-2-receptor and dopamine-3-receptor in the nucleus accumbens (NAcc) in the forebrain, were measured by in situ hybridisation. Mice fed ad libitum on a HF diet had the highest total caloric intake, body weight gain, fat mass and serum leptin, whereas schedule-fed mice had a mild obese phenotype with intermediate total caloric intake, body weight gain, fat mass and serum leptin. The effects of feeding regime on ARC gene expression were emphasised by significant positive or negative correlations with body weight gain, fat mass and blood leptin, although they did not appear to be related to feeding behaviour in the schedule-fed groups (ie, the large, binge type meals) and did not reveal any potential candidates for the regulation of these meals. Mechanisms underlying large meal/binge-type eating may be regulated by nonhomeostatic hedonic processes. However, assessment of opioid and dopamine receptor gene expression in the NAcc did not reveal evidence of involvement of these genes in regulating large meals. This complements our previous characterisation of ARC and NAcc genes in schedule-fed mice and rats, although it still leaves open the fundamental question about the underlying mechanisms of meal feeding. PMID- 28653358 TI - Peripartum cardiomyopathy for the clinician: the known and the unknown. PMID- 28653359 TI - Ultrasound assessment of gastric content in the immediate postpartum period: a prospective observational descriptive study. AB - INTRODUCTION: Pulmonary aspiration of gastric contents in pregnant women undergoing general anesthesia or sedation/analgesia in the peripartum period is a feared complication in obstetric anesthesia. We assessed the changes in antral cross-sectional area (CSA) with ultrasonography in laboring women and in the immediate postpartum period. PATIENTS AND METHODS: In an observational study in a university-affiliated maternity, gastric ultrasonography examinations were performed in non-consecutive laboring women, after epidural analgesia insertion and after childbirth. Assessment of antral CSA, difficulty of performance on a numerical scale, and factors that could influence gastric content were noted. A cut-off value of 381 mm2 was taken for the diagnosis of empty stomach. RESULTS: One hundred women were enrolled in the study. Median antral CSA was 469 mm2 [25th 75th] [324-591] after epidural insertion and 427 mm2 [316-574] after delivery. Antral CSA was >= 381 mm2 in 59 of 90 women (65%) after epidural insertion vs. 48 of 100 women (48%) after delivery (P = 0.59). Median variation of antral CSA between two measurements was 36 mm2 [-42 to 114]. Gastric ultrasonography was significantly more difficult to perform during labor than immediately post delivery (median difficulty score 5 [2-7] vs. 2 [1-4], P < 0.0001). No risk factors (pain, anxiety, diabetes, smoking) were significantly associated with the occurrence of full stomach post-delivery. CONCLUSION: This study demonstrated that 48% of parturients in the immediate postpartum period presented an antral CSA >= 381 mm2 , cut-off being accepted for diagnosis of empty stomach and emphasizes the need for re-assessing before any general anesthetic procedure. PMID- 28653357 TI - Pharmacokinetics of Monoclonal Antibodies. AB - Monoclonal antibodies (mAbs) have developed in the last two decades into the backbone of pharmacotherapeutic interventions in a variety of indications, with currently more than 40 mAbs approved by the US Food and Drug Administration, and several dozens more in clinical development. This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product-specific and patient-specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy. PMID- 28653360 TI - Identification of genes dysregulated by elevation of microRNA-210 levels in human trophoblasts cell line, Swan 71. AB - PROBLEM: Preeclampsia is a serious pregnancy disorder characterized by gestational hypertension and proteinuria. miR-210 is significantly overexpressed in the placentas of preeclampsia patients. METHOD OF STUDY: Swan 71 cells, first trimester human trophoblastic cell line, were transfected with hsa-miR-210-3p oligonucleotides by electroporation. Altered transcriptome was analyzed using microarray technique. Differentially expressed genes (DEGs) were clustered into Gene Ontology annotation biological processes. The extent of physical interaction between miR-210 and IGFBP3 mRNA was assessed via ribonucleoprotein immunoprecipitation. RESULTS: Microarray analysis showed 408 DEGs by elevated levels of miR-210 in Swan 71 cells. These genes were enriched in several biological processes involved in the pathogenesis of preeclampsia. IGFBP3, a gene associated with preeclampsia pathophysiology, was validated as a target gene of miR-210. CONCLUSION: We have demonstrated that elevated miR-210 levels in human trophoblast alter the expression profile of known preeclampsia-associated genes, and of gene targets involved in various biological processes essential to preeclampsia progression. PMID- 28653362 TI - Teeth penetration force of the tiger shark Galeocerdo cuvier and sandbar shark Carcharhinus plumbeus. AB - This study examined the minimum force required of functional teeth and replacement teeth in the tiger shark Galeocerdo cuvier and the sandbar shark Carcharhinus plumbeus to penetrate the scales and muscle of sheepshead Archosargus probatocephalus and pigfish Orthopristis chrysoptera. Penetration force ranged from 7.7-41.9 and 3.2-26.3 N to penetrate A. probatocephalus and O. chrysoptera, respectively. Replacement teeth required significantly less force to penetrate O. chrysoptera for both shark species, most probably due to microscopic wear of the tooth surfaces supporting the theory shark teeth are replaced regularly to ensure sharp teeth that are efficient for prey capture. PMID- 28653361 TI - Spike threshold dynamics in spinal motoneurons during scratching and swimming. AB - KEY POINTS: Action potential threshold can vary depending on firing history and synaptic inputs. We used an ex vivo carapace-spinal cord preparation from adult turtles to study spike threshold dynamics in motoneurons during two distinct types of functional motor behaviour - fictive scratching and fictive swimming. The threshold potential depolarizes by about 10 mV within each burst of spikes generated during scratch and swim network activity and recovers between bursts to a slightly depolarized level. Slow synaptic integration resulting in a wave of membrane potential depolarization is the factor influencing the threshold potential within firing bursts during motor behaviours. Depolarization of the threshold potential decreases the excitability of motoneurons and may provide a mechanism for stabilization of the response of a motoneuron to intense synaptic inputs to maintain the motor commands within an optimal range for muscle activation. ABSTRACT: During functional spinal neural network activity motoneurons receive intense synaptic input, and this could modulate the threshold for action potential generation, providing the ability to dynamically adjust the excitability and recruitment order for functional needs. In the present study we investigated the dynamics of action potential threshold during motor network activity. Intracellular recordings from spinal motoneurons in an ex vivo carapace spinal cord preparation from adult turtles were performed during two distinct types of motor behaviour - fictive scratching and fictive swimming. We found that the threshold of the first spike in episodes of scratching and swimming was the lowest. The threshold potential depolarizes by about 10 mV within each burst of spikes generated during scratch and swim network activity and recovers between bursts to a slightly depolarized level. Depolarization of the threshold potential results in decreased excitability of motoneurons. Synaptic inputs do not modulate the threshold of the first action potential during episodes of scratching or of swimming. There is no correlation between changes in spike threshold and interspike intervals within bursts. Slow synaptic integration that results in a wave of membrane potential depolarization rather than fast synaptic events preceding each spike is the factor influencing the threshold potential within firing bursts during motor behaviours. PMID- 28653363 TI - Quiet echo planar imaging for functional and diffusion MRI. AB - PURPOSE: To develop a purpose-built quiet echo planar imaging capability for fetal functional and diffusion scans, for which acoustic considerations often compromise efficiency and resolution as well as angular/temporal coverage. METHODS: The gradient waveforms in multiband-accelerated single-shot echo planar imaging sequences have been redesigned to minimize spectral content. This includes a sinusoidal read-out with a single fundamental frequency, a constant phase encoding gradient, overlapping smoothed CAIPIRINHA blips, and a novel strategy to merge the crushers in diffusion MRI. These changes are then tuned in conjunction with the gradient system frequency response function. RESULTS: Maintained image quality, SNR, and quantitative diffusion values while reducing acoustic noise up to 12 dB (A) is illustrated in two adult experiments. Fetal experiments in 10 subjects covering a range of parameters depict the adaptability and increased efficiency of quiet echo planar imaging. CONCLUSION: Purpose-built for highly efficient multiband fetal echo planar imaging studies, the presented framework reduces acoustic noise for all echo planar imaging-based sequences. Full optimization by tuning to the gradient frequency response functions allows for a maximally time-efficient scan within safe limits. This allows ambitious in utero studies such as functional brain imaging with high spatial/temporal resolution and diffusion scans with high angular/spatial resolution to be run in a highly efficient manner at acceptable sound levels. Magn Reson Med 79:1447 1459, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 28653364 TI - Bigeminal sandwiches galore. AB - A long run of PVCs "sandwiched" in between the sinus beats resulting in an almost doubling of the heart rate-interpolated PVCs in bigeminy-is described. This case illustrates three interesting aspects of interpolated PVCs. Although they are not uncommon, long runs of interpolated PVCs in bigeminy are rare findings. In this case, the arrhythmia had a duration of 3 minutes. Second, it illustrates the "age old wisdom" of partial retrograde conduction. Also, even though the arrhythmia resulted in an almost doubling of the heart rate, the patient remained asymptomatic. PMID- 28653365 TI - Heart transplantation for anthracycline cardiomyopathy: Pump up the volume. PMID- 28653366 TI - Method and Excel VBA Algorithm for Modeling Master Recession Curve Using Trigonometry Approach. AB - A new method was developed and implemented into an Excel Visual Basic for Applications (VBAs) algorithm utilizing trigonometry laws in an innovative way to overlap recession segments of time series and create master recession curves (MRCs). Based on a trigonometry approach, the algorithm horizontally translates succeeding recession segments of time series, placing their vertex, that is, the highest recorded value of each recession segment, directly onto the appropriate connection line defined by measurement points of a preceding recession segment. The new method and algorithm continues the development of methods and algorithms for the generation of MRC, where the first published method was based on a multiple linear/nonlinear regression model approach (Posavec et al. 2006). The newly developed trigonometry-based method was tested on real case study examples and compared with the previously published multiple linear/nonlinear regression model-based method. The results show that in some cases, that is, for some time series, the trigonometry-based method creates narrower overlaps of the recession segments, resulting in higher coefficients of determination R2 , while in other cases the multiple linear/nonlinear regression model-based method remains superior. The Excel VBA algorithm for modeling MRC using the trigonometry approach is implemented into a spreadsheet tool (MRCTools v3.0 written by and available from Kristijan Posavec, Zagreb, Croatia) containing the previously published VBA algorithms for MRC generation and separation. All algorithms within the MRCTools v3.0 are open access and available free of charge, supporting the idea of running science on available, open, and free of charge software. PMID- 28653367 TI - Significance of l-carnitine for human health. AB - Carnitine acyltransferases catalyze the reversible transfer of acyl groups from acyl-coenzyme A esters to l-carnitine, forming acyl-carnitine esters that may be transported across cell membranes. l-Carnitine is a water-soluble compound that humans may obtain both by food ingestion and endogenous synthesis from trimethyl lysine. Most l-carnitine is intracellular, being present predominantly in liver, skeletal muscle, heart and kidney. The organic cation transporter-2 facilitates l carnitine uptake inside cells. Congenital dysfunction of this transporter causes primary l-carnitine deficiency. Carnitine acetyltransferase is involved in the export of excess acetyl groups from the mitochondria and in acetylation reactions that regulate gene transcription and enzyme activity. Carnitine octanoyltransferase is a peroxysomal enzyme required for the complete oxidation of very long-chain fatty acids and phytanic acid, a branched-chain fatty acid. Carnitine palmitoyltransferase-1 is a transmembrane protein located on the outer mitochondrial membrane where it catalyzes the conversion of acyl-coenzyme A esters to acyl-carnitine esters. Carnitine acyl-carnitine translocase transports acyl-carnitine esters across the inner mitochondrial membrane in exchange for free l-carnitine that exits the mitochondrial matrix. Carnitine palmitoyltransferase-2 is anchored on the matrix side of the inner mitochondrial membrane, where it converts acyl-carnitine esters back to acyl-coenzyme A esters, which may be used in metabolic pathways, such as mitochondrial beta-oxidation. l Carnitine enhances nonoxidative glucose disposal under euglycemic hyperinsulinemic conditions in both healthy individuals and patients with type 2 diabetes, suggesting that l-carnitine strengthens insulin effect on glycogen storage. The plasma level of acyl-carnitine esters, primarily acetyl-carnitine, increases during diabetic ketoacidosis, fasting, and physical activity, particularly high-intensity exercise. Plasma concentration of free l-carnitine decreases simultaneously under these conditions. (c) 2017 IUBMB Life, 69(8):578 594, 2017. PMID- 28653368 TI - Decrease of externalized phosphatidylserine density on red blood cell-derived microparticles in SCA patients treated with hydroxycarbamide. PMID- 28653369 TI - Recognition of Chronic Migraine by Medicine Trainees: A Cross-Sectional Survey. AB - OBJECTIVE: Chronic migraine is a diagnosis that can be abstracted through the clinical history, although some providers may struggle in properly applying diagnostic criteria. We aimed to learn how well medicine trainees would be able to recognize the diagnostic criteria for chronic migraine and apply that medical knowledge to case vignettes illustrating different symptom interpretation strategies of the identical information. METHODS: An electronic, anonymous and multiple-choice response questionairre assessing selected trainee characteristics, headache case vignettes, and chronic migraine diagnostic criteria was distributed to all regional medicine program directors and coordinators in Kentucky and surrounding states. Program directors and coordinators could then individually decide whether or not they would forward to their trainees. The primary outcome measure was the frequency of chronic migraine recognition as a function of history style (ie, lumping versus splitting). Secondary outcome measures included recognition of chronic migraine diagnosis as a function of program affiliation (academic versus community), training year, gender, and recognition of ICHD-3 beta chronic migraine diagnostic criteria. Nominal variables were described as counts and percentages, and compared using chi-square tests. Statistical tests were considered to be two-sided and P <= .05 was considered to be statistically significant. Statistical analyses were performed using the JMP 11.0.0 (SAS Institute Inc., Cary, NC, USA). RESULTS: Fifty-six medicine trainees completed the survey. Episodic migraine and chronic tension-type headache were correctly recognized by 85.7% and 96.4%, respectively. Chronic migraine was recognized by a greater proportion of trainees when the identical information was presented using a lumped versus split symptom interpretation strategy (24.1% vs 3.6%, chi-square = 6.5, df =1, P = .01). Accurate recognition of chronic migraine was more likely among trainees in community versus academic/university program (40% vs 14.7%, chi-square = 4.4, df = 1, P = .03) and among male versus female trainees (33.3% vs 9.5%, chi-square = 3.9, df = 1, P = .04). Interestingly, accurate recognition of chronic migraine diagnosis was neither related to training year nor correct recognition of the ICHD-3 beta diagnostic criteria for chronic migraine. CONCLUSIONS: Despite accurate individual recognition of episodic migraine and chronic tension-type headache, participants were poor at recognizing that features of these primary headache disorders can co-exist to comprise a uniform diagnosis of chronic migraine. Accurate diagnosis of chronic migraine was improved with use of a lumping strategy to the headache history. PMID- 28653370 TI - Multicenter study to evaluate a new enumeration method for hematopoietic stem cell collection management. AB - BACKGROUND: CD34 flow cytometry is the gold standard for stem cell enumeration in peripheral blood at the mobilization stage and in the final apheresis product. The new stem cell mode of the Sysmex XN Series analyzer enumerates an immature cell population in the white progenitor and pathological cell (WPC) channel, based on the cell size, internal cellular complexity, and fluorescence intensity. STUDY DESIGN AND METHODS: In this multicenter study we analyzed 147 peripheral blood samples, 22 samples during collection of stem cells, and 45 samples from the apheresis product of 18 healthy allogeneic donors and 84 autologous patients. RESULTS: In this multicenter study we demonstrate that the XN stem cell enumeration method correlates well with viable CD34+ cells determined by flow cytometry during the stem cell mobilization phase to determine apheresis start time, during apheresis for real-time monitoring and adjustment, and for quality control of the final stem cell harvest. CONCLUSION: Our data show that there is an improvement in the correlation of XN stem cells and CD34+ cells in the peripheral blood during stem cell mobilization as well as in stem cell harvests compared to SE or XE Series analyzers. The XN stem cell enumeration method has a number of advantages compared to CD34 flow cytometry: it is fast, simple, reproducible, and less expensive. CE marking for the European market has been obtained, making the stem cell count on the XN analyzer a reportable clinical variable. PMID- 28653371 TI - Sculpting Computational-Level Models. AB - In this commentary, I advocate for strict relations between Marr's levels of analysis. Under a strict relationship, each level is exactly implemented by the subordinate level. This yields two benefits. First, it brings consistency for multilevel explanations. Second, similar to how a sculptor chisels away superfluous marble, a modeler can chisel a computational-level model by applying constraints. By sculpting the model, one restricts the (potentially infinitely large) set of possible algorithmic- and implementational-level theories. PMID- 28653372 TI - The effects of environmental salinity on the growth and physiology of totoaba Totoaba macdonaldi and shortfin corvina Cynoscion parvipinnis. AB - Totoaba Totoaba macdonaldi and shortfin corvina Cynoscion parvipinnis, were acclimated and reared together at salinities of 0, 2, 5, 10, 20 and 35 for 56 days. Initial overall mean +/- s.d. body masses of 67.6 +/- 7.1 g T. macdonaldi and 37.3 +/- 3.1 g C. parvipinnis increased to final overall masses of 217.4 +/- 30.3 and 96.5 +/- 16.5 g, respectively, at the end of the study. Totoaba macdonaldi was not able to tolerate salinities of 0 and 2 and C. parvipinnis of 0. In contrast, both species had 100% survival at salinities >= 10. Somatic growth was highest not at natural seawater salinity of 35, but at 10. Plasma osmolality ranged from 172.5 to 417.0 mOsmol kg-1 for T. macdonaldi and from 207.0 to 439.5 mOsmol kg-1 for C. parvipinnis and varied in direct proportion to salinity. The estimated isosmotic salinities of T. macdonaldi and C. parvipinnis were 12.3 and 13.4, respectively. Cynoscion parvipinnis reared at two had significantly lower plasma lysozyme activity (95.0 Units ml-1 ) than fish held at salinities from 5 to 35 (ranging from 215.0 to 355.0 Units ml-1 ), but without clear trends over this range. Blood neutrophil oxidative radical production (NBT) (ranging from 3.9 to 6.7 mg ml-1 ) had some significant differences among salinities, but these did not follow a clear pattern. For T. macdonaldi, neither lysozyme activity nor NBT was affected by salinity. Ash content of whole fishes varied directly and moisture content inversely, with salinity for both species. PMID- 28653373 TI - Association between Parkinson's disease and diabetes: Data from NEDICES study. AB - BACKGROUND: Despite growing evidence showing an association between Parkinson's disease (PD) and diabetes, epidemiological studies have shown conflicting results. AIMS OF THE STUDY: To evaluate the association between PD and diabetes and the impact of diabetes duration in this association in an elderly (>=65 years) Spanish population. METHODS: Data for this cross-sectional population based analysis were obtained from NEDICES study. Subjects were identified from census list. Diagnosis of PD was confirmed by neurological examination. Diabetes was defined by self-report, being on antidiabetic medication or diagnosis on medical records. Logistic regression analysis adjusted by potential confounders was performed to estimate the association between both conditions and also after dividing patients into short-duration (<10 years) and long-duration (>=10 years) diabetes. RESULTS: A total of 4998 subjects were included (79 PD and 4919 controls). Univariate analysis did not show any association between prevalence of PD and diabetes (OR 1.89, 95% CI 0.90-3.98, P=.09), although subgroup analysis showed a positive association in those with long-duration diabetes (3.27, 95% CI 1.21-8.85, P=.02). CONCLUSIONS: Diabetes duration might be an important factor in the association between PD and diabetes, and the risk might be limited to those with longer disease duration. PMID- 28653374 TI - A familial mediterranean fever flare induced by a drug reaction with eosinophilia and systemic symptoms. PMID- 28653376 TI - Has the income of the residential area impact on the use of intensive care? AB - BACKGROUND: The socioeconomic factors have an impact on case mix and outcome in critical illness, but how these factors affect the use of intensive care is not studied. The aim of this study was to evaluate the incidence of intensive care unit (ICU) admissions in patients from residential areas with different annual incomes. METHODS: Single-center, retrospective study in Northern Finland. All the non-trauma-related emergency admissions from the hospital district area were included. The postal codes were used to categorize the residential areas according to each area's annual median income: the low-income area, ?18,979 to ?28,841 per year; the middle-income area, ?28,879 to ?33,856 per year; and the high-income area, ?34,221 to ?53,864 per year. RESULTS: A total of 735 non-trauma related admissions were included. The unemployment or retirement, psychiatric comorbidities and chronic alcohol abuse were common in this population. The highest incidence, 5.5 (4.6-6.7)/1000/year, was in population aged more than 65 years living in high-income areas. In working-aged population, the incidence was lowest in high-income areas (1.5 (1.3-1.8/1000/year) compared to middle-income areas (2.2 (1.9-2.6)/1000/year, P = 0.001) and low-income areas (2.0 (1.7 2.4)/1000/, P = 0.009). Poisonings were more common in low-income areas. There were no differences in outcome. CONCLUSION: The incidence of ICU admission in working-aged population was 25% higher in those areas where the annual median income was below the median annual income of ?38,775 per inhabitant per year in Finland. PMID- 28653375 TI - Cardiac quantitative susceptibility mapping (QSM) for heart chamber oxygenation. AB - PURPOSE: To demonstrate the feasibility of in vivo quantitative susceptibility mapping (QSM) in cardiac MRI and to show that mixed-venous oxygen saturation (SvO2 ) can be measured non-invasively using QSM. METHODS: Electrocardiographic gated multi-echo 2D gradient echo data were collected at 1.5 T from 14 healthy volunteers during successive breath-holds. Phase wraps and fat chemical shift were removed using a graph-cut-based phase analysis and IDEAL in an iterative approach. The large susceptibility range from air in the lungs to blood in the heart was addressed by using the preconditioning approach in the dipole field inversion. SvO2 was calculated based on the difference in blood susceptibility between the right ventricle (RV) and left ventricle (LV). Cardiac QSM quality was assessed by two independent readers. RESULTS: Nine out of fourteen volunteers (64%) yielded interpretable cardiac QSM. QSM maps showed strong differential contrast between RV and LV blood with RV blood having higher susceptibility values (291.5 +/- 32.4 ppb), which correspond to 78.3 +/- 2.3% SvO2 . CONCLUSION: In vivo cardiac QSM is feasible and can be used to measure SvO2 , but improvements in data acquisition are needed. Magn Reson Med 79:1545-1552, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28653377 TI - Effects of hydroxyethyl starch 130/0.42 vs. Ringer's acetate on cytokine levels in severe sepsis. AB - BACKGROUND: The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial showed increased 90-day mortality with hydroxyethyl starch (HES) 130/0.42 vs. Ringer's acetate. To explore the underlying pathophysiology, we compared early changes in plasma cytokine concentrations between patients resuscitated with HES vs. Ringer's acetate. METHODS: In a subgroup of 226 patients from the 6S trial, we calculated delta plasma concentrations of tumour necrosis factor alpha (TNF alpha), interleukin (IL)-6 and IL-10 from randomization to day 2. We used multiple linear and logistic regression analyses to assess differences between the groups and associations between delta cytokine concentrations and 90-day mortality, respectively. RESULTS: Baseline characteristics and day 2 mortality were comparable between the groups. We observed similar delta cytokine concentrations in the HES vs. Ringer's group (mean difference in delta TNF-alpha: -1.5 pg/ml (95% CI, -4.9 to 1.9), P = 0.39; IL-6: 36.0 pg/ml (-24.1 to 96.1), P = 0.24; IL-10: -3.9 pg/ml (-21.1 to 28.9), P = 0.76). In all included patients, we observed a linear relationship between increases in TNF-alpha and 90-day mortality (P = 0.005). CONCLUSION: Resuscitation with HES 130/0.42 vs. Ringer's acetate did not appear to affect plasma concentrations of TNF-alpha, IL-6 or IL 10 differently during the first days after randomization into the 6S trial. In the overall cohort, increases in TNF-alpha were associated with increased 90-day mortality. Although interpretation should be done with caution, it seems unlikely that the increased mortality observed with the use HES in the 6S trial is signalled by early changes in three biomarkers of systemic inflammation. PMID- 28653378 TI - Beneficial role of increased FOXP3+ regulatory T-cells in acute myeloid leukaemia therapy response. PMID- 28653379 TI - Only one small sin: How self-construal affects self-control. AB - Past research has shown that self-construal can influence self-control by reducing interdependent people's impulsivity in the presence of peers. We broaden these findings by examining the hypothesis that an interdependent (vs. independent) self-construal fosters self-control even in the absence of peers and for non-impulsive decisions. We further explore whether this effect could be mediated by the more interrelated (vs. isolated) processing style of interdependent (vs. independent) people. Such an interrelated (vs. isolated) processing style of temptations makes the impact of a single temptation more salient and can thereby increase self-control. Study 1 demonstrated that more interdependent participants show more self-control behaviour by refraining from chocolate consumption to secure a monetary benefit. Studies 2a and 2b highlighted a link between self-construal and trait self-control via the processing of temptations. Study 3 suggested that an interrelated (vs. isolated) perspective on temptations could mediate the effect of (primed) self-construal on self-control. Taken together, self-construal shapes self-control across various decision contexts. PMID- 28653380 TI - Trypanosomiasis in an Australian little red flying fox (Pteropus scapulatus). AB - CASE REPORT: An adult female Australian little red flying fox (Pteropus scapulatus) presented with icterus and anaemia. Examination of a blood smear revealed numerous trypanosomes 20.4-30.8 um long with tapered ends. Necropsy and histological findings were consistent with trypanosome infection of lymphoid tissue and intravascular haemolysis. Sequence and phylogenetic analysis demonstrated this trypanosome species to be genetically distinct and most similar to Trypanosoma minasense and Trypanosoma rangeli (with a genetic distance of 1% at the 18S rRNA locus for both). CONCLUSION: To the authors' knowledge this is the first report of a trypanosome infection associated with clinical disease in bats. PMID- 28653381 TI - Efficacy of a commercial vaccine against different strains of rabbit haemorrhagic disease virus. AB - BACKGROUND: This study investigated the ability of a commercial rabbit haemorrhagic disease virus (RHDV) vaccine (Cylap(r)) to protect rabbits from disease caused by two different strains of the virus (v351 and K5) that are used or proposed to be used for wild rabbit control in Australia. These strains of the RHDV1 genotype belong to the 'classical RHDV' and 'antigenic variant RHDVa' subtypes, respectively. METHODS: Vaccinated rabbits were exposed to very high doses of the virus either by direct oral dosing or by exposure to infected rabbit livers. RESULTS & CONCLUSION: All vaccinated rabbits were protected against rabbit haemorrhagic disease, indicating that the Cylap(r) vaccine is effective against both strains of the virus under experimental conditions. PMID- 28653383 TI - Hyperoxaluria, hyperglycoluria and renal oxalosis in Gilbert's potoroos (Potorous gilbertii). AB - CASE REPORT: Six Gilbert's potoroos (Potorous gilbertii) in a captive colony, five of which were closely related, died or were euthanased with severe renal disease. Clinical signs were mostly non-specific. Renal calculi were seen on ultrasound of two affected potoroos and oxalate crystalluria was seen in two of three affected potoroos that had urine samples examined. Necropsies revealed extensive severe renal oxalosis in all affected potoroos. These findings and markedly increased concentrations of glycolate in the urine of the four affected potoroos for which it was measured, confirmed a disorder of oxalate metabolism and suggested a condition similar to primary hyperoxaluria type 1 in humans. Liver alanine : glyoxylate aminotransferase activity and intracellular location were assessed as normal in one affected potoroo, which is inconsistent with human primary hyperoxaluria type 1. Although a condition similar to human primary hyperoxaluria type 2 or 3 was not ruled out, other clinicopathological findings were not consistent with those seen in humans with these conditions. A lack of faecal oxalate-degrading activity was observed in two affected potoroos in which it was measured, whereas oxalate-degrading activity was variably present in healthy captive and wild potoroos. CONCLUSION: Although the pathogenesis of renal oxalosis in these cases was not clear, the biochemical findings of elevated urinary oxalate and glycolate excretion indicate an abnormality of oxalate metabolism. The familial pattern of disease suggests it could be an inherited condition. PMID- 28653385 TI - Cricopharyngeal dysphagia and phenobarbitone-responsive sialoadenosis in a Miniature Poodle. AB - CASE REPORT: An 11-year-old male neutered Miniature Poodle was investigated for ptyalism, weight loss and anorexia. Cricopharyngeal dysphagia was diagnosed using fluoroscopy, and non-inflammatory salivary disease was diagnosed using a combination of cytology and computed tomography. The dog was successfully managed with phenobarbitone. CONCLUSION: To the authors' knowledge this is the first time acquired cricopharyngeal dysphagia and phenobarbitone-responsive sialoadenosis have been described together. PMID- 28653386 TI - Long-term control of olfactory neuroblastoma in a dog treated with surgery and radiation therapy. AB - BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the nasal cavity in dogs that is thought to arise from specialised sensory neuroendocrine olfactory cells derived from the neural crest. CASE REPORT: An 8-year-old dog was presented for reclusiveness and pacing. On CT and MRI, a contract-enhancing mass was disclosed within the rostral fossa, extending caudally from the cribriform plate into the left nasal sinus. Surgical excision was performed and the diagnosis was histological grade III (Hyams grading scheme) olfactory neuroblastoma. Based on human CT criteria this was high stage (modified Kadish stage C). Surgical excision was incomplete and was followed by curative-intent radiation therapy using a linear accelerator to a total dose of 48 Gy. CONCLUSION: The dog survived 20 months after diagnosis. Although olfactory neuroblastoma is a rare tumour in dogs, aggressive local therapy may allow for prolonged survival, even when the tumour is advanced. PMID- 28653387 TI - Outbreaks of sarcoptic mange in free-ranging koala populations in Victoria and South Australia: a case series. AB - OBJECTIVE: To describe outbreaks of sarcoptic mange caused by Sarcoptes scabiei in free-ranging koalas in Victoria (December 2008 to November 2015) and South Australia (October 2011 to September 2014). METHODS: Koalas affected by mange like lesions were reported by wildlife carers, veterinary practitioners or State Government personnel to the Faculty of Veterinary and Agricultural Sciences at The University of Melbourne and the School of Animal and Veterinary Sciences at The University of Adelaide. Skin scrapings were taken from live and dead koalas and S. scabiei mites were identified. Tissues from necropsied koalas were examined histologically. RESULTS: Outbreaks of sarcoptic mange were found to occur in koalas from both Victoria (n = 29) and South Australia (n = 29) for the first time. The gross pathological and histopathological changes are described. CONCLUSION: We present the first reported cases of sarcoptic mange outbreaks in free-ranging koalas. PMID- 28653388 TI - Factors associated with colostrum immunoglobulin G concentration in northern Victorian dairy cows. AB - OBJECTIVES: To determine the proportion of first-milking colostrum samples produced on four northern-Victorian dairy farms that meet industry standards in terms of immunoglobulin G (IgG) concentration and to identify risk factors that affect colostrum quality. METHODS: Colostrum IgG concentrations from 442 dairy cows on four farms were estimated using a Brix refractometer and risk factors for colostrum IgG concentration were determined using multivariable logistic regression. RESULTS: Only 39% of samples met the definition of high quality. The strongest predictor for colostrum quality was the interval from calving to colostrum harvesting. Colostrum harvested from cows within 12 h of calving was 6 fold more likely to be high quality compared with colostrum harvested later. Colostrum from cows in >= 4th lactation was nearly twice as likely to be high quality compared with cows entering their 1st lactation. If the calf was not allowed to suckle from the dam prior to colostrum harvesting, the odds of producing high-quality colostrum were nearly 4-fold greater. If the cow had not leaked colostrum prior to harvesting, it was more than 3-fold more likely to produce high-quality colostrum. CONCLUSIONS: The majority of samples assessed were below industry standard. Herd, lactation number, calf suckling or cow leaking colostrum prior to harvesting and time between calving and colostrum harvesting were factors that influenced colostrum IgG concentration. The results support current industry recommendations of harvesting colostrum shortly after parturition (ideally within 12 h of calving) and testing the quality of all colostrum prior to feeding to dairy calves. PMID- 28653389 TI - John McCormack Howell 1932-2017. PMID- 28653390 TI - Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs. AB - BACKGROUND: High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (8202 feet). Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of commonly-used pharmacological interventions for preventing acute HAI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text terms to search. SELECTION CRITERIA: We included randomized-controlled and cross-over trials conducted in any setting where commonly-used classes of drugs were used to prevent acute HAI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants)The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants)Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants)For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality. AUTHORS' CONCLUSIONS: Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety. PMID- 28653391 TI - Multiple phenotype association tests using summary statistics in genome-wide association studies. AB - We study in this article jointly testing the associations of a genetic variant with correlated multiple phenotypes using the summary statistics of individual phenotype analysis from Genome-Wide Association Studies (GWASs). We estimated the between-phenotype correlation matrix using the summary statistics of individual phenotype GWAS analyses, and developed genetic association tests for multiple phenotypes by accounting for between-phenotype correlation without the need to access individual-level data. Since genetic variants often affect multiple phenotypes differently across the genome and the between-phenotype correlation can be arbitrary, we proposed robust and powerful multiple phenotype testing procedures by jointly testing a common mean and a variance component in linear mixed models for summary statistics. We computed the p-values of the proposed tests analytically. This computational advantage makes our methods practically appealing in large-scale GWASs. We performed simulation studies to show that the proposed tests maintained correct type I error rates, and to compare their powers in various settings with the existing methods. We applied the proposed tests to a GWAS Global Lipids Genetics Consortium summary statistics data set and identified additional genetic variants that were missed by the original single-trait analysis. PMID- 28653392 TI - Impact of starting material (fresh versus cryopreserved marrow) on mesenchymal stem cell culture. AB - BACKGROUND: Mesenchymal stem cells (MSCs) continue to be investigated in multiple clinical trials as potential therapy for different disorders. There is ongoing controversy surrounding the clinical use of cryopreserved versus fresh MSCs. However, little is known about how cryopreservation affects marrow as starting material. The growth kinetics of MSC cultures derived from fresh versus cryopreserved marrow were compared. STUDY DESIGN AND METHODS: Data were reviewed on the growth kinetics of MSCs derived from fresh versus cryopreserved marrow of nine donors. Marrow harvested from each donor was separated into four aliquots (one fresh and three cryopreserved for culture). Data on the date of mononuclear cell cryopreservation/thaw, MSC counts at Passages 1 and 2, MSC doubling, MSC fold expansion, viability (of mononuclear cells and final MSCs), and on flow cytometry markers of mononuclear cells and final MSCs were analyzed for the fresh and cryopreserved marrow groups. RESULTS: In total, 21 MSC lots (seven fresh and 14 cryopreserved) were obtained. The average age of cryopreserved mononuclear cell product was 295 days (range, 18-1241 days). There were no significant differences between MSC numbers at Passage 1 (p = 0.1), final MSC numbers (p = 0.5), MSC doubling (p = 0.7), or MSC fold expansion (p = 0.7). A significant difference was observed in viability by flow cytometry for both mononuclear cells (p = 0.002) and final MSCs (p = 0.009), with higher viability in the fresh marrow group. CONCLUSION: This study demonstrates that MSCs derived from cryopreserved marrow have the same growth characteristics as fresh marrow-derived MSCs. Further studies are needed to explore potential differences in clinical efficacy. PMID- 28653393 TI - Positive Youth Development and Resilience: Growth Patterns of Social Skills Among Youth Investigated for Maltreatment. AB - Maltreated children are a vulnerable population, yet many of these youth follow positive developmental pathways. The primary aim was to identify social skills growth trajectories among at-risk youth to understand processes underlying resilience. Nationally representative, longitudinal data from 1,179 families investigated for child maltreatment (Mage = 12.75) were obtained from the National Survey of Child and Adolescent Well-Being. Four trajectories were identified-stress-resistant, emergent resilience, breakdown, and unresponsive maladaptive. Protective resources from multiple levels of the youth ecology (individual, family, school, and social service) predicted positive growth social skills trajectories. Resilience process and attendant positive outcomes in multiple domains of functioning were evident among the stress-resistant and emergent resilience trajectories. Results underscore the saliency of social skills development for resilient outcomes in youth. PMID- 28653394 TI - Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non-flow-limiting coronary artery stenosis. AB - BACKGROUND: Experimental evidence suggests that ranolazine decreases susceptibility to ischemia-induced arrhythmias independent of effects on coronary artery blood flow. OBJECTIVE: In symptomatic diabetic patients with non-flow limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, we explored whether ranolazine reduces T-wave heterogeneity (TWH), an electrocardiographic (ECG) marker of arrhythmogenic repolarization abnormalities shown to predict sudden cardiac death. METHODS: We studied all 16 patients with analyzable ECG recordings during rest and exercise tolerance testing before and after 4 weeks of ranolazine in the double-blind, crossover, placebo-controlled RAND-CFR trial (NCT01754259). TWH was quantified without knowledge of treatment assignment by second central moment analysis, which assesses the interlead splay of T waves in precordial leads about a mean waveform. Myocardial blood flow (MBF) was measured by positron emission tomography. RESULTS: At baseline, prior to randomization, TWH during rest was 54 +/- 7 MUV and was not altered following placebo (47 +/- 6 MUV, p = .47) but was reduced by 28% (to 39 +/- 5 MUV, p = .002) after ranolazine. Ranolazine did not increase MBF at rest. Exercise increased TWH after placebo by 49% (to 70 +/- 8 MUV, p = .03). Ranolazine did not reduce TWH during exercise (to 75 +/- 16 MUV), and there were no differences among the groups (p = .95, ANOVA). TWH was not correlated with MBF at rest before (r2 = .07, p = .36) or after ranolazine (r2 = .23, p = .06). CONCLUSIONS: In symptomatic diabetic patients with non-flow limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, ranolazine reduced TWH at rest but not during exercise. Reduction in repolarization abnormalities appears to be independent of alterations in MBF. PMID- 28653396 TI - Parinaud syndrome: Any clinicoradiological correlation? AB - INTRODUCTION: The significance of MRI findings of patients with Parinaud syndrome (PS) with respect to clinical characteristics is poorly defined. Over the past decades, all patients with PS undergo magnetic resonance imaging which allows a better identification of the lesion localization. We compared the neuro ophthalmological findings of patients with PS caused by intrinsic (intra-axial) vs extrinsic (pineal gland tumor) brainstem lesions. METHODS: Medical records of patients with PS evaluated between 2000 and 2016 were retrospectively reviewed. RESULTS: Twenty-six patients with PS were included. Eight patients had pineal gland tumors and hydrocephalus. Two patients had hydrocephalus due to aqueduct stenosis and fourth ventricle tumor. Sixteen patients suffered from an intrinsic brainstem lesion and seven associated with hydrocephalus. The neuro ophthalmological findings did not differ between patients with extrinsic and intrinsic brainstem lesions. No correlation was found between the grade of hydrocephalus and number of clinical findings except for more findings in low grade hydrocephalus in intrinsic (40%) vs extrinsic (0%) lesions (P=.003). Patients with moderate brainstem lesions and hydrocephalus had more clinical findings (65%) than patients with the same grade of brainstem involvement without hydrocephalus (29%) (P=.03). The resolution rate of ophthalmological findings was comparable in all groups of patients. CONCLUSIONS: Our results did not show differences in neuro-ophthalmological findings between intra- and extra-axial lesions causing PS. However, the presence of hydrocephalus was an important factor influencing clinical findings. The prognosis of PS was less favorable than generally reported. PMID- 28653395 TI - Poly-ADP ribose polymerase-14 limits severity of allergic skin disease. AB - Poly-ADP ribose polymerase-14 (PARP14 or ARTD8) was initially identified as a transcriptional co-activator for signal transducer and activator of transcription 6 (Stat6), where the presence of interleukin-4 (IL-4) and activated Stat6 induces the enzymatic activity of PARP14 that promotes T helper type 2 differentiation and allergic airway disease. To further our understanding of PARP14 in allergic disease, we studied the function of PARP14 in allergic inflammation of skin using mice that express constitutively active Stat6 in T cells (Stat6VT) and develop spontaneous inflammation of the skin. We mated Stat6VT mice to Parp14-/- mice and observed that approximately 75% of the Stat6VT * Parp14-/- mice develop severe atopic dermatitis (AD)-like lesions, compared with about 50% of Stat6VT mice, and have increased morbidity compared with Stat6VT mice. Despite this, gene expression in the skin and the cellular infiltrates was only modestly altered by the absence of PARP14. In contrast, we saw significant changes in systemic T-cell cytokine production. Moreover, adoptive transfer experiments demonstrated that decreases in IL-4 production reflected a cell intrinsic role for PARP14 in Th2 cytokine control. Hence, our data suggest that although PARP14 has similar effects on T-cell cytokine production in several allergic disease models, the outcome of those effects is distinct, depending on the target organ of disease. PMID- 28653397 TI - Acute myeloid leukaemia genomics. AB - Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies. PMID- 28653398 TI - Lung transplant recipients on long-term extracorporeal photopheresis. AB - Extracorporeal photophoresis (ECP) is an increasingly used therapy to address chronic lung allograft dysfunction (CLAD) following lung transplantation. In 2008, we reported the first single-center experience showing that ECP not only reduces lung function decline in patients with bronchiolitis obliterans syndrome (BOS) but results in stabilization of patients with recurrent acute cellular rejection (ACR). In this study, the original cohort was followed up further 5 years. In addition, patients with CLAD were retrospectively classified according to recently published phenotypes. The current cohort included 21 of the original 24 patients, of which nine were initially treated for CLAD, 12 were initially treated for recurrent ACR. Our results show that survival of patients treated with ECP for CLAD was inferior to patients treated for recurrent ACR (66% vs. 82% survival rate). Long-term survivors in the CLAD subgroup were mostly classified as BOS 1 at time of ECP initiation. These long-term data show that patients started on ECP at early BOS stages have better long-term outcome. The subgroup of ECP patients with recurrent ACR has an overall superior survival. To assist prediction of therapy response, we agree with other authors that patients with CLAD should be aimed to be phenotyped and evaluated for an early treatment with ECP. PMID- 28653399 TI - Timing of stressors alters interactive effects on a coastal foundation species. AB - The effects of climate-driven stressors on organismal performance and ecosystem functioning have been investigated across many systems; however, manipulative experiments generally apply stressors as constant and simultaneous treatments, rather than accurately reflecting temporal patterns in the natural environment. Here, we assessed the effects of temporal patterns of high aerial temperature and low salinity on survival of Olympia oysters (Ostrea lurida), a foundation species of conservation and restoration concern. As single stressors, low salinity (5 and 10 psu) and the highest air temperature (40 degrees C) resulted in oyster mortality of 55.8, 11.3, and 23.5%, respectively. When applied on the same day, low salinity and high air temperature had synergistic negative effects that increased oyster mortality. This was true even for stressor levels that were relatively mild when applied alone (10 psu and 35 degrees C). However, recovery times of two or four weeks between stressors eliminated the synergistic effects. Given that most natural systems threatened by climate change are subject to multiple stressors that vary in the timing of their occurrence, our results suggest that it is important to examine temporal variation of stressors in order to more accurately understand the possible biological responses to global change. PMID- 28653401 TI - Authors' reply re: Guilt, blame and litigation: can an overenthusiastic 'safety culture' cause harm? PMID- 28653400 TI - Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial. AB - Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56.7%; TP2, 6.0%), diarrhoea (grade 3/4: TP1, 24.1%; TP2, 7.1%), and fatigue (grade 3/4: TP1, 16.3%; TP2, 1.8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes. PMID- 28653402 TI - A future research agenda for selection into healthcare. PMID- 28653403 TI - Dermatitis caused by arthropods in domestic environment: an Italian multicentre study. AB - BACKGROUND: Skin diseases caused by mites and insects living in domestic environments have been rarely systematically studied. OBJECTIVES: To study patients with dermatitis induced by arthropods in domestic environment describing their clinical features, isolating culprit arthropods and relating the clinical features to the parasitological data. METHODS: The study was performed in 105 subjects with clinical and anamnestic data compatible with the differential diagnosis of ectoparasitoses in domestic environments. Clinical data and arthropods findings obtained by indoor dust direct examination were studied. RESULTS: Indoor dust direct examination demonstrated possible arthropods infestation in 98 subjects (93.3%), more frequently mites (56.1%) (mainly Pyemotes ventricosus and Glycyphagus domesticus) than insects (43.9%) (mainly Formicidae and Bethylidae). Strophulus (46.9%) and urticaria-like eruption (36.7%) in upper limbs and trunk with severe extent were prevalent. Itch was mostly severe (66.3%) and continuous (55.1%). Ectoparasitoses occurred frequently with acute course in summer (44.9%) and spring (30.6%). CONCLUSIONS: Possible correlation between clinical and aetiological diagnosis of arthropods ectoparasitoses in domestic environments needs the close cooperation between dermatologist and parasitologist. This is crucial to successfully and definitely resolve skin lesions by eradicating the factors favouring infestation. PMID- 28653404 TI - Neuroanatomical Characteristics Associated With Response to Deep Brain Stimulation of the Nucleus Basalis of Meynert for Alzheimer's Disease. AB - OBJECTIVES: First reports on the application of deep brain stimulation (DBS) of the Nucleus basalis of Meynert (NBM) showed feasibility and safety of the intervention in patients with Alzheimer's disease. However, clinical effects vary and the mechanisms of actions are still not well understood. The aim of this study was to characterize neuroimaging changes that are associated with the responsiveness to the treatment. MATERIALS AND METHODS: We examined preoperative T1-weighted MR images of ten patients with Alzheimer's disease (AD) treated with DBS of the NBM and correlated the clinical outcome with volumetric differences of cortical thickness. Subsequently, we sought to identify brain regions that carry out the clinical effects by correlating the outcome with streamlines connected to the volume of activated tissue. Clinical assessments at baseline, 6 and 12 months after the intervention included the AD Assessment Scale as well as the mini mental status examination. RESULTS: A fronto-parieto-temporal pattern of cortical thickness was found to be associated with beneficial outcome. Modulation of streamlines connected to left parietal and opercular cortices was associated with better response to the intervention. CONCLUSION: Our results indicate that patients with less advanced atrophy may profit from DBS of the NBM. We conclude that beneficial effects of the intervention are related to preserved fronto parieto-temporal interplay. PMID- 28653405 TI - Positive Youth Development Among Diverse Racial-Ethnic Children: Quality Afterschool Contexts as Developmental Assets. AB - Positive youth development (PYD) deserves more empirical attention, particularly among children of diverse racial-ethnic backgrounds. Given the need among families for monitoring and supervision during out-of-school time, community based afterschool is a potentially promotive ecological setting. This study explores the quality of afterschool experiences upon PYD. This multimethod study includes over 500 elementary school children in Grades 2-5 (Mage = 8.80, SD = 1.12). The sample comprises of 49% White, 27% African American, 7% Latino, and 17% mixed race/others with 45% free/reduced lunch eligible children. In multilevel models, independently observed quality across time positively impacted competence, connection, caring for all youth, and cultural values for racial ethnic minority youth. Afterschool fosters PYD, including sociocultural dimensions, when comprised of appropriately structured, supportive, and engaging interactions. PMID- 28653406 TI - An exonic missense mutation c.28G>A is associated with weak B blood group by affecting RNA splicing of the ABO gene. AB - BACKGROUND: The amino acid substitutions caused by ABO gene mutations are usually predicted to impact glycosyltransferase's function or its biosynthesis. Here we report an ABO exonic missense mutation that affects B-antigen expression by decreasing the mRNA level of the ABO gene rather than the amino acid change. STUDY DESIGN AND METHODS: Serologic studies including plasma total GTB transfer capacity were performed. The exon sequences of the ABO gene were analyzed by Sanger sequencing. B310 cDNA with c.28G>A (p.G10R) mutation was expressed in HeLa cells and total GTB transfer capacity in cell supernatant was measured. Flow cytometry was performed on these HeLa cells after transfection, and agglutination of Hela-Bweak cells was also examined. The mRNA of the ABO gene was analyzed by direct sequencing and real-time reverse transcriptase-polymerase chain reaction. A minigene construct was prepared to evaluate the potential of splicing. RESULTS: While plasma total GTB transfer capacity was undetectable in this B3 -like individual, the relative percentage of antigen-expressing cells and mean fluorescence index of the Bweak red blood cells (RBCs) were 19 and 14% of normal B RBCs, respectively. There was no significant difference of total GTB transfer capacity in cell supernatant and B-antigen expression on cell surfaces between HeLa cells transfected with B310 cDNA and B cDNA. The mRNA expression level of B310 in peripheral whole blood was significantly reduced. The amount of splicing is significantly lower in c.28G>A construct compared to that in wild-type construct after transfection in K562 cells. CONCLUSION: ABO c.28G>A mutation may cause B3 -like subgroup by affecting RNA splicing of the ABO gene. PMID- 28653408 TI - Evaluating principal surrogate markers in vaccine trials in the presence of multiphase sampling. AB - This article focuses on the evaluation of vaccine-induced immune responses as principal surrogate markers for predicting a given vaccine's effect on the clinical endpoint of interest. To address the problem of missing potential outcomes under the principal surrogate framework, we can utilize baseline predictors of the immune biomarker(s) or vaccinate uninfected placebo recipients at the end of the trial and measure their immune biomarkers. Examples of good baseline predictors are baseline immune responses when subjects enrolled in the trial have been previously exposed to the same antigen, as in our motivating application of the Zostavax Efficacy and Safety Trial (ZEST). However, laboratory assays of these baseline predictors are expensive and therefore their subsampling among participants is commonly performed. In this article, we develop a methodology for estimating principal surrogate values in the presence of baseline predictor subsampling. Under a multiphase sampling framework, we propose a semiparametric pseudo-score estimator based on conditional likelihood and also develop several alternative semiparametric pseudo-score or estimated likelihood estimators. We derive corresponding asymptotic theories and analytic variance formulas for these estimators. Through extensive numeric studies, we demonstrate good finite sample performance of these estimators and the efficiency advantage of the proposed pseudo-score estimator in various sampling schemes. We illustrate the application of our proposed estimators using data from an immune biomarker study nested within the ZEST trial. PMID- 28653407 TI - Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy. AB - This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma (DLBCL) after failure of front line anthracycline-based immunochemotherapy (IC). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B-cell lymphoma (PMBL) patients treated with front line anthracycline-based IC were followed for relapse. Patients with relapse on follow-up and subsequently retreated were included in this analysis. 1039 patients received anthracycline-based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years (OS4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (autoHCT) with OS4 from autoHCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS4 of 47% but those with a transient or no response to initial therapy had OS4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo autoHCT. The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL. PMID- 28653409 TI - A time-adjusted cortisol cut-off can reduce referral rate for Synacthen stimulation test whilst maintaining diagnostic performance. AB - OBJECTIVE: Cortisol cut-offs can predict requirement for Synacthen stimulation tests (SST). We assessed the performance of a standard cortisol cut-off (375 nmol/L) across the morning and compared this with a time-adjusted cut-off. DESIGN: Retrospective audit PATIENTS: Community reference set (n=12 550) and SST patients (n=757). MEASUREMENTS: In the reference population, time-specific cortisol medians were calculated and used to convert cortisol to time-adjusted Multiples of the Median (MoM). In 757 SST patients, the predictive performance of a standard cortisol cut-off (375 nmol/L) and its time-adjusted MoM equivalent were compared. RESULTS: Median cortisol decreased by ~30 nmol/L per hour between 0700 and 1200h. In the reference population, proportions below the 375 nmol/L cut off increased throughout the morning (range 35%-64%), whereas using the time adjusted MoM cut-off proportions were consistent (range 46%-50%), with a 17% maximal difference in referral rates between the two cut-offs after 1100h. A similar pattern was noted in the SST cohort. When a cortisol MoM cut-off was used to predict SST success, the excess proportion of patients tested and misclassification rates were lower and more consistent than when the standard cut off was used. A median cortisol of 375 nmol/L equated to 444 and 313 nmol/L before 0800 and after 1100 h, respectively. CONCLUSION: The use of a standard cortisol cut-off results in 17% more patients being referred for SST later in the morning. A time-adjusted cortisol cut-off provides consistent and lower referral rates, whilst maintaining similar or better performance than a standard single cut-off in predicting outcome of SST. PMID- 28653410 TI - Breeding density, fine-scale tracking, and large-scale modeling reveal the regional distribution of four seabird species. AB - Population-level estimates of species' distributions can reveal fundamental ecological processes and facilitate conservation. However, these may be difficult to obtain for mobile species, especially colonial central-place foragers (CCPFs; e.g., bats, corvids, social insects), because it is often impractical to determine the provenance of individuals observed beyond breeding sites. Moreover, some CCPFs, especially in the marine realm (e.g., pinnipeds, turtles, and seabirds) are difficult to observe because they range tens to ten thousands of kilometers from their colonies. It is hypothesized that the distribution of CCPFs depends largely on habitat availability and intraspecific competition. Modeling these effects may therefore allow distributions to be estimated from samples of individual spatial usage. Such data can be obtained for an increasing number of species using tracking technology. However, techniques for estimating population level distributions using the telemetry data are poorly developed. This is of concern because many marine CCPFs, such as seabirds, are threatened by anthropogenic activities. Here, we aim to estimate the distribution at sea of four seabird species, foraging from approximately 5,500 breeding sites in Britain and Ireland. To do so, we GPS-tracked a sample of 230 European Shags Phalacrocorax aristotelis, 464 Black-legged Kittiwakes Rissa tridactyla, 178 Common Murres Uria aalge, and 281 Razorbills Alca torda from 13, 20, 12, and 14 colonies, respectively. Using Poisson point process habitat use models, we show that distribution at sea is dependent on (1) density-dependent competition among sympatric conspecifics (all species) and parapatric conspecifics (Kittiwakes and Murres); (2) habitat accessibility and coastal geometry, such that birds travel further from colonies with limited access to the sea; and (3) regional habitat availability. Using these models, we predict space use by birds from unobserved colonies and thereby map the distribution at sea of each species at both the colony and regional level. Space use by all four species' British breeding populations is concentrated in the coastal waters of Scotland, highlighting the need for robust conservation measures in this area. The techniques we present are applicable to any CCPF. PMID- 28653411 TI - Impact of dispersant on early life stages of the water flea Daphnia magna and the eastern oyster Crassostrea virginica. AB - In response to the 2010 Deepwater Horizon oil spill, over 1 million gallons of dispersant were applied in Gulf of Mexico offshore waters; Corexit 9500 was the most applied dispersant. The impact on organisms in nearshore and freshwaters has received little scrutiny. Acute 48 h toxicity of Corexit 9500 and a new hyperbranched polyethylenimine (HPEI) dispersant-like compound were evaluated for the freshwater indicator organism, Daphnia magna and for larval and early spat stages of the Eastern oyster, Crassostrea virginica. For D. magna, Corexit 9500 demonstrated toxicity (EC50 of 0.14 [0.13, 0.15] ppm) similar to the 10-kDa HPEI (EC50 of 0.16 [0.12, 0.19] ppm). HPEI toxicity increased as a function of molecular weight (1.2 to 750 kDa). The 10 kDa size HPEI was further investigated because it dispersed crude oil with equal effectiveness as Corexit. For Corexit, 100% oyster mortality was detected for the <=0.2-mm size classes and mortality >50% for the 0.3- and 0.7-mm size classes at the two greatest concentrations (25 and 50 ppm). HPEI (10 kDa) exhibited low mortality rates (<30%) for all concentrations for all oyster size classes except the 0.1-mm class. Although mortality rates for this size class were up to 60%, mortality was still less than the mortality caused by Corexit 9500. The low toxicity of HPEI polymers for C. virginica in comparison with Corexit 9500 suggests that HPEI polymers warrant further study. PMID- 28653412 TI - A selective colorimetric chemosensor for Fe3. AB - Two simple colorimetric receptors PS and PP (thiophene and pyridine appended derivative) were prepared and their cation sensing properties were investigated. Receptors PS and PP displayed a selective colorimetric change (from colorless to orange) upon binding to Fe3+ in MeOH solution. The association constants for receptors PS-Fe3+ and PP-Fe3+ in MeOH were determined to be 1.15 * 106 and 4.31 * 106 M-1 , respectively, using Hill plots. The detection limits of PS and PP were 490.7 ppm and 393.7 ppm, respectively. PMID- 28653413 TI - Normalizing trust: Participants' immediately post-hoc explanations of behaviour in Milgram's 'obedience' experiments. AB - We bring an ethnomethodological perspective on language and discourse to a data source crucial for explaining behaviour in social psychologist Stanley Milgram's classic 'obedience' experiments - yet one largely overlooked by the Milgram literature. In hundreds of interviews conducted immediately after each experiment, participants sought to justify their actions, often doing so by normalizing the situation as benign, albeit uncomfortable. Examining 91 archived recordings of these interviews from several experimental conditions, we find four recurrent accounts for continuation, each used more frequently by 'obedient' than 'defiant' participants. We also discuss three accounts for discontinuation used by 'defiant' participants. Contrary to what a leading contemporary theory of Milgramesque behaviour - engaged followership - would predict, 'obedient' participants, in the minutes immediately following the experiment, did not tend to explain themselves by identifying with science. Rather, they justified compliance in several distinct and not entirely consistent ways, suggesting that multiple social psychological processes were at work in producing Milgram's 'obedient' outcome category. PMID- 28653414 TI - Three new species of Curimatopsis (Characiformes: Curimatidae) from the Amazon basin. AB - Three new species of Curimatopsis are described from major tributaries of the Amazon basin. Curimatopsis guaporensis n. sp., from the Rio Madeira, belongs to the Curimatopsis evelynae clade and can be distinguished by the distinctive shape of the dark blotch on the caudal peduncle and by the position and shape of the nostrils. Curimatopsis pallida n. sp., from the Rio Negro, also related to C. evelynae, is distinguished from all congeners by the complete absence of pigmentation on the lateral surface of the caudal peduncle. Curimatopsis jaci n. sp., apparently endemic to the upper Rio Tapajos, belongs to the Curimatopsis macrolepis clade and differs from all congeners in details of body pigmentation. Meristic and morphometric features supplement diagnoses for the three new species. These species are hypothesized to belong to the two main clades of Curimatopsis on the basis of previous studies of osteology and external morphology and supplement a recent genetic study that revealed several cryptic and yet undescribed species within the genus. An updated identification key to the species of Curimatopsis is also provided. PMID- 28653415 TI - Computed Tomography of the Abdomen in Eight Clinically Normal Common Marmosets (Callithrix jacchus). AB - The aim of this study was to provide a detailed anatomical description of the abdomen in the clinically normal common marmoset by means of computed tomography (CT). Eight clinically healthy mature common marmosets ranging from 12 to 48 months and 235 to 365 g bodyweight were anesthetized and pre- and post-contrast CT examinations were performed using different CT settings in dorsal recumbency. Abdominal organs were identified and visibility noted. Diagnostic quality abdominal images could be obtained of the common marmoset despite its small size using a dual-slice CT scanner. Representative cross-sectional images were chosen from different animals illustrating the abdominal CT anatomy of clinically normal common marmosets. Identification or delineation of abdominal organs greatly improved with i.v. contrast. A modified high-frequency algorithm with edge enhancement added valuable information for identification of small structures such as the ureters. The Hounsfield unit (HU) of major abdominal organs differed from that of small animals (domestic dogs and cats). Due to their size and different anatomy, standard small animal CT protocols need to be critically assessed and adapted for exotics, such as the common marmoset. The established normal reference range of HU of major abdominal organs and adapted settings for a CT protocol will aid clinical assessment of the common marmoset. PMID- 28653416 TI - Design of anti-thyroid drugs: Binding studies and structure determination of the complex of lactoperoxidase with 2-mercaptoimidazole at 2.30 A resolution. AB - Lactoperoxidase (LPO) belongs to mammalian heme peroxidase superfamily, which also includes myeloperoxidase (MPO), eosinophil peroxidase (EPO), and thyroid peroxidase (TPO). LPO catalyzes the oxidation of a number of substrates including thiocyanate while TPO catalyzes the biosynthesis of thyroid hormones. LPO is also been shown to catalyze the biosynthesis of thyroid hormones indicating similar functional and structural properties. The binding studies showed that 2 mercaptoimidazole (MZY) bound to LPO with a dissociation constant of 0.63 uM. The inhibition studies showed that the value of IC50 was 17 uM. The crystal structure of the complex of LPO with MZY showed that MZY bound to LPO in the substrate binding site on the distal heme side. MZY was oriented in the substrate-binding site in such a way that the sulfur atom is at a distance of 2.58 A from the heme iron. Previously, a similar compound, 3-amino-1,2,4-triazole (amitrole) was also shown to bind to LPO in the substrate-binding site on the distal heme side. The amino nitrogen atom of amitrole occupied the same position as that of sulfur atom in the present structure indicating a similar mode of binding. Recently, the structure of the complex of LPO with a potent antithyroid drug, 1-methylimidazole 2-thiol (methimazole, MMZ) was also determined. It showed that MMZ bound to LPO in the substrate-binding site on the distal heme side with 2 orientations. The position of methyl group was same in the 2 orientations while the positions of sulfur atom differed indicating a higher preference for a methyl group. PMID- 28653417 TI - Oral problems and quality of life of preschool children: self-reports of children and perception of parents/caregivers. AB - The purpose of this study was to evaluate the association between oral health problems and oral health-related quality of life (OHRQoL) of preschool children according to both self-reports and the reports of parents/caregivers. A school based, cross-sectional study was conducted with 769 preschool children and their parents/caregivers. The OHRQoL was evaluated using the Scale of Oral Health Outcomes for Five-Year-Old Children (SOHO-5). Based on logistic regression for complex samples, the following variables were found to be associated with poorer OHRQoL in the parent/caregiver version: toothache (OR = 6.77; 95% CI: 3.95 11.59); consequences of untreated dental caries (OR = 2.69; 95% CI: 1.27-5.70); and anterior open bite (OR = 2.01; 95% CI: 1.13-3.56). The following variables were associated with poorer OHRQoL in the child self-report version: toothache (OR = 3.34; 95% CI: 2.11-5.29); cavitated lesions (anterior teeth) (OR = 2.20; 95% CI: 1.26-3.84); occurrence of traumatic dental injury (OR = 1.77; 95% CI: 1.19-2.61); and anterior open bite (OR = 1.95; 95% CI: 1.16-3.29). We conclude that children with dental caries (or its sequelae) had poorer OHRQoL. Having experienced a traumatic dental injury and having a malocclusion were also associated with a poorer OHRQoL. PMID- 28653418 TI - Syphilis testing practices in the Americas. AB - OBJECTIVE: To present the findings of the Pan American Health Organization's 2014 survey on syphilis testing policies and practices in the Americas. METHODS: Representatives of national/regional reference and large, lower-level laboratories from 35 member states were invited to participate. A semi structured, electronically administered questionnaire collected data on syphilis tests, algorithms, equipment/commodities, challenges faced and basic quality assurance (QA) strategies employed (i.e. daily controls, standard operating procedures, technician training, participating in external QA programmes, on-site evaluations). RESULTS: The 69 participating laboratories from 30 (86%) member states included 41 (59%) national/regional reference and 28 (41%) lower-level laboratories. Common syphilis tests conducted were the rapid plasma reagin (RPR) (62% of surveyed laboratories), venereal disease research laboratory (VDRL) (54%), fluorescent treponemal antibody absorption (FTA-ABS) (41%) and Treponema pallidum haemagglutination assay (TPHA) (32%). Only three facilities reported using direct detection methods, and 28 (41% overall, 32% of lower-level facilities) used rapid tests. Most laboratories (62%) used only traditional testing algorithms (non-treponemal screening and treponemal confirmatory testing); however, 12% used only a reverse sequence algorithm (treponemal test first), and 14% employed both algorithms. Another nine (12%) laboratories conducted only one type of serologic test. Although most reference (97%) and lower-level (89%) laboratories used at least one QA strategy, only 16% reported using all five basic strategies. Commonly reported challenges were stock-outs of essential reagents or commodities (46%), limited staff training (73%) and insufficient equipment (39%). CONCLUSIONS: Many reference and clinical laboratories in the Americas face challenges in conducting appropriate syphilis testing and in ensuring quality of testing. PMID- 28653419 TI - Conformational switch of harmonin, a submembrane scaffold protein of the hair cell mechanoelectrical transduction machinery. AB - Mutations in the gene encoding harmonin, a multi-PDZ domain-containing submembrane protein, cause Usher syndrome type 1 (congenital deafness and balance disorder, and early-onset sight loss). The structure of the protein and biological activities of its three different classes of splice isoforms (a, b, and c) remain poorly understood. Combining biochemical and biophysical analyses, we show that harmonin-a1 can switch between open and closed conformations through intramolecular binding of its C-terminal PDZ-binding motif to its N-terminal supramodule NTD-PDZ1 and through a flexible PDZ2-PDZ3 linker. This conformational switch presumably extends to most harmonin isoforms, and it is expected to have an impact on the interaction with some binding partners, as shown here for cadherin-related 23, another component of the hair cell mechanoelectrical transduction machinery. PMID- 28653420 TI - Impact of endotracheal tube shortening on work of breathing in neonatal and pediatric in vitro lung models. AB - BACKGROUND: Work of breathing accounts for a significant proportion of total oxygen consumption in neonates and infants. Endotracheal tube inner diameter and length significantly affect airflow resistance and thus work of breathing. While endotracheal tube shortening reduces endotracheal tube resistance, the impact on work of breathing in mechanically ventilated neonates and infants remains unknown. AIM: The objective of this in vitro study was to quantify the effect of endotracheal tube shortening on work of breathing in simulated pediatric lung settings. We hypothesized that endotracheal tube shortening significantly reduces work of breathing. METHODS: We used the Active-Servo-Lung 5000 to simulate different clinical scenarios in mechanically ventilated infants and neonates under spontaneous breathing with and without pressure support. Endotracheal tube size, lung resistance, and compliance, as well as respiratory settings such as respiratory rate and tidal volume were weight and age adapted for each lung model. Work of breathing was measured before and after maximal endotracheal tube shortening and the reduction of the daily energy demand calculated. RESULTS: Tube shortening with and without pressure support decreased work of breathing to a maximum of 10.1% and 8.1%, respectively. As a result, the calculated reduction of total daily energy demand by endotracheal tube shortening was between 0.002% and 0.02%. CONCLUSION: In this in vitro lung model, endotracheal tube shortening had minimal effects on work of breathing. Moreover, the calculated percentage reduction of the total daily energy demand after endotracheal tube shortening was minimal. PMID- 28653421 TI - Comparison of biosimilar filgrastim, originator filgrastim, and lenograstim for autologous stem cell mobilization in patients with multiple myeloma. AB - BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) originators such as filgrastim (Neupogen) and lenograstim (Granocyte) are widely used for peripheral blood stem cell (PBSC) mobilization. In recent years, biosimilar agents have been approved for the same indications. The aim of this retrospective study was to compare the mobilization efficiency of the three G-CSF variants originator filgrastim, lenograstim, and the biosimilar Filgrastim Hexal in a homogeneous group of multiple myeloma (MM) patients in first-line therapy. STUDY DESIGN AND METHODS: Overall mobilization data of 250 patients with MM were included. Of these patients, 74 (30%), 131 (52%), and 45 (18%) were mobilized with originator filgrastim, biosimilar Filgrastim Hexal, or lenograstim, respectively, at a dose of 5 to 10 ug/kg body weight subcutaneously starting from Day 5 after chemomobilization with CAD (cyclophosphamide, doxorubicin, dexamethasone) until completion of PBSC collection. RESULTS: All but one patient reached the collection goal of a minimum of at least 2 * 106 CD34+ cells/kg body weight during a median of one (range, one to three) leukapheresis session. No significant differences in CD34+ mobilization and collection yields between the filgrastim-mobilized (median, 10.5; range, 2.7-40.4), Filgrastim Hexal-mobilized (median, 9.9; range, 0.2-26.0), and lenograstim-mobilized (median, 10.7; range, 3.1-27.9 CD34+ cells * 106 /kg body weight) patients were observed. CONCLUSION: Concerning the clinically relevant efficiencies of PBSC mobilization and in terms of reaching the individual collection target, this retrospective study did not detect any significant differences between the three G-CSF variants in the analyzed patient cohort. PMID- 28653422 TI - Transcutaneous Recharge: A Comparison of Numerical Simulation to In Vivo Experiments. AB - OBJECTIVE: Numerical simulation and animal experiments quantified tissue temperatures during the transcutaneous recharge of neuromodulation implants. The temperature results were used to determine the likelihood of tissue injury in humans. MATERIALS AND METHODS: Experiments were completed using sheep with implants at different depths ranging from 0.7 to 2.15 cm. The calculations were replicates of the experiments. Additional calculations were completed for laterally offset implants (up to 2 cm). Benchtop tests were performed to determine the power dissipation in the components. These power dissipation rates were inputs to the simulation. The now-verified model was next applied to a human situation with a core temperature of 37 degrees C. RESULTS: There was excellent agreement between the simulations and the animal-model for all depths; the experimental and simulated temperatures near the implant were almost identical. The results were negligibly affected by a misalignment of the implant. The maximum experimental temperatures in the sheep were 41.8, 43.2, and 41.8 degrees C while the calculated maxima were 41.9, 43.3, and 41.2 degrees C for the shallow, medium, and deep cases, respectively. The experimental values are 3.1, 4.5, and 3.1 degrees C above the body core temperature. The simulation results are 3.2, 4.6, and 2.5 degrees C above the core temperature. The model was then applied to a human situation with a body core temperature of 37 degrees C. The maximum values of the simulated temperatures are 39.9, 41.2, and 39.1 degrees C. The cumulative equivalent exposure at 43 degrees C (CEM43) for these three implant depths are 0.30, 0.88, and 0.12 min. These thermal exposures are below those known to cause thermal injury in human skin tissue. CONCLUSIONS: The numerical simulation predicts tissue temperatures during transcutaneous recharge of implants. Results show that the implant depth does not have a large impact on the tissue temperatures and thermal exposures are sufficiently low so that they are unlikely to have any physiologic consequence. PMID- 28653423 TI - Angiotensin 1-7 inhibits angiotensin II-stimulated head and neck cancer progression. AB - Angiotensin II (Ang II) is the product of the proteolytic action of angiotensin converting enzyme (ACE) on the precursor peptide, angiotensin I (Ang I). In addition to its vasoactive properties, Ang II is able to stimulate angiogenesis and act as a mitogen, promoting cellular proliferation. Recently, evidence has emerged that Ang II is also able to promote tumour invasion, a key step in the metastatic cascade, although the mechanisms by which it does so remain largely obscure. Here we show that Ang II is able to promote the invasion and migration of head and neck squamous cell carcinoma (HNSCC) cells both in an autocrine manner and by triggering stromal tumour-paracrine interactions. The effects of Ang II on autocrine and paracrine signalling pathways are mediated by angiotensin receptor 1 (AT1 R) and inhibited by angiotensin 1-7 (Ang 1-7), a peptide produced from Ang II by the action of angiotensin-converting enzyme 2 (ACE2). These data are the first to demonstrate a role for the renin-angiotensin system in oral carcinogenesis and raise the possibility of utilizing AT1 R receptor antagonists and/or Ang 1-7 as novel therapeutic agents for HNSCC. PMID- 28653425 TI - Storage time of platelet concentrates and all-cause bacteremia in hematologic patients. AB - BACKGROUND: Extension of storage time of platelet (PLT) concentrates may result in an increased risk of bacteremia, directly via transfusion of contaminated products or indirectly via transfusion-related immunomodulation. We aimed to quantify the association of storage time of PLT concentrates and all-cause bacteremia in hematologic patients. STUDY DESIGN AND METHODS: We established a cohort of hematologic patients who received a PLT transfusion between 2005 and 2015. Cases were defined as patients with a bacteremia the day after transfusion and matched to as many controls as possible. A conditional logistic regression was performed, stratified by storage medium. RESULTS: Among 3514 patients receiving 36,032 PLT concentrates stored in plasma, 613 cases of bacteremia were found. The relative risk of all-cause bacteremia the day after transfusion was 0.80 (95% confidence interval [CI], 0.58-1.12) for PLT concentrates stored 3 to 4 days and 0.67 (95% CI, 0.49-0.92) for at least 5 days, compared to no more than 2 days. Among 1527 patients receiving 11,822 PLT concentrates stored in PLT additive solution, 182 cases of bacteremia were found. The relative risk of all cause bacteremia was 1.14 (95% CI, 0.70-1.84) for PLT concentrates stored for 3 to 4 days and 1.19 (95% CI, 0.70-2.01) for at least 5 days, compared to not more than 2 days. CONCLUSION: Storage time of PLT concentrates was not associated with increased occurrence of all-cause bacteremia the day after transfusion. If anything, fewer cases of bacteremia occurred with increasing storage time of PLT concentrates in plasma. These bacteremias are not directly caused by transfusion of a contaminated product and the underlying mechanism warrants further research. PMID- 28653424 TI - Anesthetic ointment only (lidocaine/prilocaine) instead of injectable local lidocaine in trans-radial catheterization: A viable no-needle alternative. AB - OBJECTIVE: The aim of the present study was to assess the level of access site pain in patients undergoing transradial coronary catheterization by using topical application of an anesthetic ointment (lidocaine/prilocaine-AO) compared to standard local anesthesia (LA) by means of injectable lidocaine. METHODS: We prospectively studied 444 patients undergoing elective trans-radial coronary angiography. The quality of analgesia was assessed using a visual analogue scale (VAS) immediately after the puncture and 30 min after the removal of the sheath. The number and duration of attempts before successful sheath insertion, as well as artery spasm, were compared between the two groups. RESULTS: Pain levels measured by VAS were found to be similar between the two groups during sheath insertion (VAS: AO: 4.84 +/- 1.0 vs 4.82 +/- 1.2, P = NS), as well as 30 min after sheath removal (VAS: AO: 0.07 +/- 0.5 vs LA: 0.15 +/- 0.6, P = NS). The time to obtain radial access was also not affected by the use of anesthetic ointment (AO: 62.24 +/- 25.7 s vs LA: 64.04 +/- 18.78 sec, P = NS). The rate of clinical or angiographic radial artery spasm was similar (8-10%) between the groups (P = NS) CONCLUSION: Use of a local anesthetic ointment, versus injectable lidocaine, in trans-radial cardiac catheterization as means of local anesthesia, was found to be equally effective in terms of pain, artery spasm, or artery cannulation speed. PMID- 28653426 TI - Achieving success in clinically based research: the importance of mentoring. AB - Within the professions of radiation therapy and medical imaging, clinician led research activity is becoming more prevalent. However, more is needed. A key component of continuing to develop professional groups who are both research active and producing high quality clinical research, is research mentoring. The authors of this paper share a common interest in enhancing research capacity through research mentoring within the health workforce, and came together to run a workshop on this issue at the 11th Annual Scientific Meeting of Medical Imaging and Radiation Therapy (ASMMIRT 2016) conference in Brisbane. Theory, clinical insights and issues regarding research mentoring were raised in the workshop as were the benefits of having dedicated research positions embedded within the health workforce to help provide support and build capacity. Key elements from this workshop are shared within this article, with the objective to encourage clinicians and clinical researchers to invest the time and effort into seeking and providing good quality research mentoring. A single service example is used to demonstrate how this can lead to enhanced research engagement and productivity. PMID- 28653427 TI - Circumcision does not have effect on premature ejaculation: A systematic review and meta-analysis. AB - We attempted to evaluate whether circumcision has an effect on premature ejaculation. We searched three databases: PubMed, EMBASE and Google scholar on 1 May 2016 for eligible studies that referred to male sexual function after circumcision. No language restrictions were imposed. The Cochrane Collaboration's RevMan 5.2 software was employed for data analysis, and the fixed or the random effect model was selected depending on the heterogeneity. Twelve studies were included in the meta-analysis, containing a total of 10019 circumcised and 11570 uncircumcised men. All studies were divided into five subgroups by types of study design to evaluate the effect of circumcision on premature ejaculation (PE). Intravaginal ejaculation latency time (IELT), difficulty of orgasm, erectile dysfunction (ED) and pain during intercourse were also assessed because PE was usually discussed along with these subjects. There were no significant differences in PE (odds ratio [OR], 0.90; 95% confidence interval (CI), 0.72 1.13; p = .37) and orgasm (OR, 1.04; 95% CI, 0.89-1.21; p = .65) between circumcised and uncircumcised group. However, IELT (OR, 0.72; 95% CI, 0.60-0.83; p < .00001), ED (OR, 0.42;95% CI, 0.22-0.78; p = .40) and pain during intercourse (OR, 0.36; 95% CI, 0.17-0.76; p = .007) favoured circumcised group. Based on these findings, circumcision does not have effect on PE. PMID- 28653428 TI - Effects of dextroamphetamine in subacute traumatic brain injury: A randomized, placebo-controlled pilot study. AB - Psychostimulants that affect neurotransmitters implicated in cognitive function and neural plasticity have potential to enhance the rate and extent of recovery after traumatic brain injury (TBI). Ten milligrams dextroamphetamine (DEX) or an identical placebo was administered daily for 3 weeks to 32 participants with moderate to severe TBI, engaged in inpatient rehabilitation, at a mean of 2 months post injury. A variety of outcome measures assessing cognitive function and overall functional status was administered at weekly intervals, to examine effect sizes that may inform a larger trial, and to evaluate safety. Results indicated trivial-to-small effect sizes for DEX-placebo differences, with the largest effects seen on speed of information processing (more improvement with DEX) and agitation (exacerbation with DEX). Examination of adverse events and vital signs suggested safety of DEX, but the pattern of results did not suggest accelerated recovery due to the drug. Future trials of DEX in this population need to consider the impact of floor effects of commonly used measures of cognitive and physical function, and the heterogeneity of TBI. Although the small sample precludes definitive conclusions, these findings are not encouraging with regard to clinical trials of DEX in subacute TBI. PMID- 28653429 TI - Paederus dermatitis outbreak in Luanda City, Angola. PMID- 28653430 TI - Misdiagnosis of Spontaneous Intracranial Hypotension as a Risk Factor for Subdural Hematoma. AB - OBJECTIVE: This study aimed to evaluate the association between misdiagnosis of spontaneous intracranial hypotension (SIH) and subdural hematoma development. BACKGROUND: Although SIH is more prevalent than expected and causes potentially life-threatening complications including subdural hematoma (SDH), the association between misdiagnosis of SIH and SDH development is not yet evaluated. METHODS: Retrospective observational study was conducted between January 1, 2005, and December 31, 2014. Adult patients with spontaneous intracranial hypotension (age >= 18 years) were enrolled. RESULTS: Of the 128 patients with SIH, 111 (86.7%) were in no SDH group and 17 (13.3%) were in SDH group. Their clinical presentation did not show significant different between the two groups, except age, the days from symptom onset to correct diagnosis, and the number of misdiagnoses. Age (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.07 1.23) and the number of times SIH was misdiagnosed (OR, 1.82; 95% CI, 1.03-3.21) were independent risk factors for the development of SDH in SIH patients by multivariate logistic analysis. The clinical outcomes, including length of hospital stay and revisit rate, were similar in the two groups. CONCLUSIONS: The number of times SIH was misdiagnosed was associated with the later development of SDH perhaps because of delay in correct diagnosis of SIH. Clinicians would prevent the later complication of SDH in SIH patients by increasing the awareness and a high index of suspicion of SIH. PMID- 28653431 TI - Synthesis of Copper Oxide/Graphite Composite for High-Performance Rechargeable Battery Anode. AB - A novel copper oxide/graphite composite (GCuO) anode with high capacity and long cycle stability is proposed. A simple, one-step synthesis method is used to prepare the GCuO, through heat treatment of the Cu ion complex and pristine graphite. The gases generated during thermal decomposition of the Cu ion complex (H2 and CO2 ) induce interlayer expansion of the graphite planes, which assists effective ion intercalation. Copper oxide is formed simultaneously as a high capacity anode material through thermal reduction of the Cu ion complex. Material analyses reveal the formation of Cu oxide nanoparticles and the expansion of the gaps between the graphite layers from 0.34 to 0.40 nm, which is enough to alleviate layer stress for reversible ion intercalation for Li or Na batteries. The GCuO cell exhibits excellent Li-ion battery half-cell performance, with a capacity of 532 mAh g-1 at 0.2 C (C-rate) and capacity retention of 83 % after 250 cycles. Moreover, the LiFePO4 /GCuO full cell is fabricated to verify the high performance of GCuO in practical applications. This cell has a capacity of 70 mAh g-1 and a coulombic efficiency of 99 %. The GCuO composite is therefore a promising candidate for use as an anode material in advanced Li- or Na-ion batteries. PMID- 28653432 TI - Low-Cost Carbazole-Based Hole-Transport Material for Highly Efficient Perovskite Solar Cells. AB - A low-cost carbazole-based small-molecule material, 1,3,6,8-tetra(N,N-p dimethoxyphenylamino)-9-ethylcarbazole, was designed and synthesized through a facile three-step synthetic route. The material was characterized and applied as a hole-transport material (HTM) for low-temperature-processed planar perovskite solar cells (PSCs). Devices based on this new HTM exhibit a high power-conversion efficiency of 17.8 % that is comparable to that of PSCs based on the costly 2,2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'-spirobifluorene (Spiro OMeTAD) (18.6 %) . PMID- 28653433 TI - Immediate loading of four interforaminal implants supporting a locator-retained mandibular overdenture in the elderly. Results of a 3-year randomized, controlled, prospective clinical study. AB - BACKGROUND: Implant-retained overdentures have become a standard option for the prosthetic treatment of the edentulous mandible in the elderly. PURPOSE: This prospective study aimed to compare immediate and conventional loading of four interforaminal implants supporting a Locator-retained mandibular overdenture in elderly patients regarding implant survival, implant stability, and implant related complications. MATERIAL AND METHODS: The study population comprised 20 completely edentulous patients (11 males) aged 60 years and older with severe mandible resorption. Each patient received four interforaminal implants (Neoss Ltd., Harrogate, UK). Following randomization, implants were loaded either immediately after dental implant surgery or 3 months after implant placement with the Locator-abutment system. At follow-up visits 3, 6 12, 24, and 36 months after loading, implant stability was evaluated with Periotest and Ostell. RESULTS: Twenty patients received 80 implants. In eight patients, 32 implants were loaded immediately. Two patients had to be switched from the immediate to the conventional loading group due to insufficient primary stability (<=30 Ncm). Implant survival was similar in both groups after 36 months. No implant was lost. Decreasing Periotest, and accordingly, increasing Ostell measurements indicated adequate osseointegration in both groups. The course of treatment was not significantly different in the two groups. There were comparable incidences of postoperative complaints like swelling, hematoma, or wound dehiscence, as well as need for prosthetic treatment due to abutment loosening or occlusal discrepancies. Incidence of pressure marks and number of patient visits were significantly higher in the conventional loading group. CONCLUSION: With sufficient primary stability, immediate loading of four interforaminal implants in the edentulous mandible might be the preferential choice in the elderly, reducing total treatment time, and number of patient visits. PMID- 28653434 TI - Injury from falls in infants under one year. AB - AIM: Falls in infants are a common cause of injury. Compared to older children, infants under age one are likely to have distinctive causation and injury patterns, as they are pre-mobile or have limited independent mobility and falls are more directly the responsibility of the care giver. There is little known about the mechanistic factors, predictors of injury and injury patterns in this age group. METHODS: We conducted a retrospective review of infants under age one who presented after a fall to a paediatric trauma centre in Sydney, Australia. Circumstances and mechanisms of the fall, injury patterns, burden of investigations and outcomes were analysed. RESULTS: Over a 3-year period (2011 2013), 916 infants presented following a fall. One hundred and six (11.6%) were admitted and there was one death. Head injury was the most common reason for admission (85%). While there were severe and critical head injuries (Abbreviated Injury Scale 4-5) these were infrequent (2% of presentations). All admitted cases involved a short distance fall. Patients dropped by others were three times more likely to be admitted than infants presenting following other fall types (95% CI 1.9-4.8). Compared to other mechanisms, patients who fell from furniture had significantly longer hospital stays. CONCLUSIONS: Fall mechanisms involving infants being dropped by adults, and falls from beds or couches carry the highest clinical burden. These mechanisms should be targets for injury prevention and inform the design of safe equipment and environments for babies. PMID- 28653436 TI - Compositional analysis gives insight into leukaemia cell lines expression profiles compared to those within patient sub-groups. PMID- 28653435 TI - RICE CRISPR: Rapidly increased cut ends by an exonuclease Cas9 fusion in zebrafish. AB - Application of CRISPR-Cas9 technology in diverse organisms has resulted in an explosion of genome modification efforts. To expand the toolbox of applications, we have created an E. coli Exonuclease I (sbcB)-Cas9 fusion that has altered enzymatic activity in zebrafish embryos. This Cas9 variant has increased mutation efficiency and favors longer deletions relative to wild-type Cas9. We anticipate that this variant will allow for more efficient screening for F0 phenotypes and mutation of a larger spectrum of genomic targets including deletion of regulatory regions and creating loss of function mutations in transcription units with poor sequence conservation such as lncRNAs where larger deletions may be required for loss of function. PMID- 28653437 TI - Erratum. PMID- 28653438 TI - Antibiotic-prescribing habits among Norwegian dentists: a survey over 25 years (1990-2015). AB - Bacterial antibiotic resistance is a steadily growing global problem, which today is compared with issues such as global warming, ozone depletion, and extinction of species. Consequently, calls come from global, Pan-European, and national authorities to gain insight into, limit, and stringently qualify the use of antibiotics in human and veterinary medicine, as well as in food production. Dentists are not considered to be frequent prescribers of antibiotics. However, few studies have identified how much, and in which situations, dentists prescribe such drugs. The aims of the present study were to survey Norwegian dentists' antibiotic-prescribing habits in 2015 and to compare the findings with previous studies (1990 and 2004) and with the actual numbers of dispensed prescriptions obtained from the 'Norwegian National Prescription Register'. The results from 1990 to 2004 show that there was a general increase in antibiotic prescriptions by Norwegian dentists, followed by a reduction or flattening of the prescription volume curve from 2004 to 2015. Despite this, possibilities for further improvements have been identified and recommendations given for targeted campaigns to reduce the prescription volume in dentistry by a further 30%, which has been ordered by the Norwegian National Assembly. PMID- 28653439 TI - Intraepidermal neutrophilic dermatosis type of IgA pemphigus with circulating linear IgA disease antibodies associated with ulcerative colitis. PMID- 28653440 TI - Treatment of Breast Cancer-Related Lymphedema with Adipose-Derived Regenerative Cells and Fat Grafts: A Feasibility and Safety Study. AB - Breast cancer-related lymphedema (BCRL) is a debilitating late complication with a lack of treatment opportunities. Recent studies have suggested that mesenchymal stromal cells can alleviate lymphedema. Herein, we report the results from the first human pilot study with freshly isolated adipose-derived regenerative cells (ADRC) for treating lymphedema with 6 months follow-up. Ten BCRL patients were included. ADRC was injected directly into the axillary region, which was combined with a scar-releasing fat graft procedure. Primary endpoints were change in arm volume. Secondary endpoints were change in patient reported outcome and safety. The study is registered with ClinicalTrials.gov (NCT02592213). During follow-up, a small volume reduction was noted but was not significant. Five patients reduced their use of conservative management. Patient-reported outcomes improved significantly over time. ADRCs were well tolerated and only minor transient adverse events related to liposuction were noted. In this pilot study, a single injection of ADRC improved lymphedema based on patient-reported outcome measures, and there were no serious adverse events in the 6 months follow-up period. In addition, half of the patients reduced their use of conservative management. ADRC therapy is a promising interventional therapy for alleviating lymphedema, but results need to be confirmed in randomized clinical trials. Stem Cells Translational Medicine 2017;6:1666-1672. PMID- 28653441 TI - Prior pregnancy and antenatal rubella sero-negativity-evidence of persistent maternal immunologic alteration? AB - PROBLEM: It is unclear if the immunologic alterations induced by pregnancy could persist. METHOD OF STUDY: Antenatal rubella sero-negativity was correlated with gravidity, abortions and parity in 112 083 gravidae managed during 1997-2015, with further analysis stratified for factors known to influence rubella serology. RESULTS: The 10.2% sero-negative gravidae had different characteristics, and the incidence showed significant difference and positive trend (P<.001 for both) with gravidity, abortions and parity. The pattern remained consistent when analysis was stratified for advanced age, high body mass index and medical history, but was negated by hepatitis B virus infection except for abortions, and by high body mass index for parity. For gravidity 2-4, no difference in rubella sero negativity was found between gravidae with all previous pregnancies ended in abortion vs delivery. CONCLUSION: Prior pregnancies diminished rubella immunity in a dose-dependent manner, which may be a reflection of the cumulative effect of pregnancy-associated maternal immunologic alteration. PMID- 28653442 TI - Attachment and dissociation as mediators of the link between childhood trauma and psychotic experiences. AB - Exposure to childhood trauma has been implicated in the development of paranoia and hearing voices, but the mechanisms responsible for these associations remain unclear. Understanding these mechanisms is essential for ensuring that targeted interventions can be developed to better support people experiencing distress associated with paranoia and voices. Recent models have proposed that dissociation may be a mechanism specifically involved in the development of voices and insecure attachment in the development of paranoia. Recent theoretical proposals have added to this and argued that fearful attachment could also lead to increased vulnerability for voices. This study was the first to examine whether dissociation and insecure attachment styles mediated the relationship between childhood trauma and these psychotic experiences. One hundred and twelve participants experiencing clinical levels of psychosis completed measures of dissociation, childhood trauma, attachment, voices, and paranoia. Results revealed positive associations between fearful (but not dismissive and anxious) attachment, dissociation, trauma, and psychotic experiences. Mediation analyses indicated that dissociation, but not fearful attachment, significantly mediated the relationship between trauma and voices. Conversely, both dissociation and fearful attachment significantly mediated the relationship between trauma and paranoia. The findings suggest that insecure attachment might be more strongly related to paranoia than hallucinations and suggest that fearful attachment may be a more promising mechanism to explain this relationship. Furthermore, the findings suggest that the impact of dissociation on psychotic experiences may extend to paranoia. Future research is required to replicate these findings using interview-based attachment measures. PMID- 28653443 TI - Stem Cell-Derived Extracellular Vesicles as a Novel Potential Therapeutic Tool for Tissue Repair. AB - Stem cells, with their therapeutic potential in tissue repair and regeneration, have been widely used in translational medicine. Recent evidence suggests that the beneficial effects are mediated largely by their paracrine actions rather than the engraftment and differentiation at the injured sites. Extracellular vesicles (EVs), actively released from cells, play important roles in cell-to cell communication and display multiple functions in tissue regeneration. In the present report, we will briefly review the current knowledge related to the therapeutic potential of EVs, particularly stem cell or progenitor cell-derived ones for promoting tissue repair and regeneration, and focus on the restorative properties of exosomes/microvesicles in cutaneous wound healing, bone regeneration, hindlimb ischemia, and vascular injury repair. Stem Cells Translational Medicine 2017;6:1753-1758. PMID- 28653444 TI - Ambient temperature-mediated changes in hepatic gene expression of a mammalian herbivore (Neotoma lepida). AB - Herbivores regularly ingest natural toxins produced by plants as a defence against herbivory. Recent work suggests that compound toxicity is exacerbated at higher ambient temperatures. This phenomenon, known as temperature-dependent toxicity (TDT), is the likely result of decreased liver function at warmer temperatures; however, the underlying cause of TDT remains speculative. In the present study, we compared the effects of temperature and dietary plant toxins on differential gene expression in the liver of an herbivorous rodent (Neotoma lepida), using species-specific microarrays. Expression profiles revealed a greater number of differentially expressed genes at an ambient temperature below the thermal neutral zone for N. lepida (22 degrees C) compared to one within (27 degrees C). Genes and pathways upregulated at 22 degrees C were related to growth and biosynthesis, whereas those upregulated at 27 degrees C were associated with gluconeogenesis, apoptosis and protein misfolding, suggestive of a stressed state for the liver. Additionally, few genes associated with xenobiotic metabolism were induced when woodrats ingested plant toxins compared to nontoxic diets, regardless of temperature. Taken together, the results highlight the important role of ambient temperature on gene expression profiles in the desert woodrat. Temperatures just below the thermal neutral zone might be a favourable state for liver metabolism. Furthermore, the reduction in the number of genes expressed at a temperature within the thermal neutral zone indicates that liver function may be reduced at temperatures that are not typically considered as thermally stressful. Understanding how herbivorous mammals will respond to ambient temperature is imperative to accurately predict the impacts of climate change. PMID- 28653445 TI - Systemic treatment for psoriasis and malignancies: A real risk? PMID- 28653446 TI - The evolution and functions of nuclei of the visual pulvinar in primates. AB - In this review, we outline the history of our current understanding of the organization of the pulvinar complex of mammals. We include more recent evidence from our own studies of both New and Old World monkeys, prosimian galagos, and close relatives of primates, including tree shrews and rodents. Based on cumulative evidence, we provide insights into the possible evolution of the visual pulvinar complex, as well as the possible co-evolution of the inferior pulvinar nuclei and temporal cortical visual areas within the MT complex. PMID- 28653447 TI - Dividing Attention Between Tasks: Testing Whether Explicit Payoff Functions Elicit Optimal Dual-Task Performance. AB - We test people's ability to optimize performance across two concurrent tasks. Participants performed a number entry task while controlling a randomly moving cursor with a joystick. Participants received explicit feedback on their performance on these tasks in the form of a single combined score. This payoff function was varied between conditions to change the value of one task relative to the other. We found that participants adapted their strategy for interleaving the two tasks, by varying how long they spent on one task before switching to the other, in order to achieve the near maximum payoff available in each condition. In a second experiment, we show that this behavior is learned quickly (within 2-3 min over several discrete trials) and remained stable for as long as the payoff function did not change. The results of this work show that people are adaptive and flexible in how they prioritize and allocate attention in a dual-task setting. However, it also demonstrates some of the limits regarding people's ability to optimize payoff functions. PMID- 28653448 TI - Adult disseminated Langerhans cell histiocytosis: incidence, racial disparities and long-term outcomes. PMID- 28653449 TI - The value of biomarkers in bone metastasis. AB - The worst complication of cancer is represented by its spread to distant sites. In particular, bone provides a fertile soil for several cancer types, especially those derived from breast, prostate and lung tumours. Despite the progress in diagnostic and therapeutic strategies, bone metastases (BM) still impact on quality of life and overall survival, making it necessary to identify the "high risk" patients at an earlier stage. Since BM affect physiological bone turnover, measurement of bone turnover markers (BTM) has been widely investigated for diagnostic and prognostic purposes, as well as to support the development of anti cancer drugs. Furthermore, biomarkers are still under intensive investigation for their potential BM predictive role. The review summarises the current knowledge on BM development and the most recent advances in biomarker research, focusing on breast, prostate and lung malignancies. PMID- 28653450 TI - Environmental risk modelling and potential sand fly vectors of cutaneous leishmaniasis in Chitral district: a leishmanial focal point of mount Tirich Mir, Pakistan. AB - OBJECTIVE: To provide baseline information about suspected vectors and the incidence, distribution and an active zone of transmission for cutaneous leishmaniasis (CL) in Chitral, Pakistan, using GIS tools; and to investigate the role of environmental factors in the disease dynamics. METHOD: Two surveys in 2014 and 2016 as a basis for choropleth and environmental risk mapping. RESULTS: A total of 769 captured specimens yielded 14 Phlebotomus and six Sergentomyia species including two potential vectors of CL, i.e. Phlebotomus papatasi and Phlebotomus sergenti. P. papatasi (71%) was dominant, followed by P. sergenti (18%). A choropleth map generated in Arcmap 10.1 based on 1560 CL case reports displayed maximum prevalence (0.92-2.5%) in Ayun, Broz, Charun, Chitral 1 and 2 and Darosh 1 and 2 union councils. An environmental risk map constructed by MaxEnt 3.3.3 defined an active zone of transmission based on leishmaniasis occurrence records (n = 315). The analysis of variable contribution in MaxEnt indicates significance of elevation (54.4%), population density (23.3%) and land use/land cover (6.6%) in CL disease dynamics. CONCLUSION: The probability of CL increases (0.6-1 on logistic scale) in severely deforested areas, in lowland valleys and in regions with high-population density. PMID- 28653451 TI - Identifying and Distinguishing Value Profiles in American and Israeli Adolescents. AB - Although research has examined how values are correlated with behavior, little has examined how the system of values predicts behavior. In a cross-cultural sample of American (109 European American; 216 African American) and Israeli (318 Arab Israeli; 216 Jewish Israeli) adolescents, the present study used latent profile analysis to identify groups which reflected the theoretical structure of values across both cultures. Four profiles were found: self-focused, anxiety free, other-focused, and undifferentiated. Results indicated that Self-Focused adolescents were the most aggressive and viewed as leaders by their peers compared to the other groups. Self-Focused and anxiety-free youth reported more delinquency than their peers. Few differences between cultural groups emerged, suggesting that this approach is a promising avenue for understanding heterogeneity in behavior. PMID- 28653452 TI - Cutaneous implantation of papillary thyroid carcinoma secondary to percutaneous ethanol injection into nodal metastasis. PMID- 28653453 TI - AHNS Series - Do you know your guidelines? Principles of treatment for glottic cancer: A review of the National Comprehensive Cancer Network guidelines. AB - This article is a continuation of the "Do You Know Your Guidelines" series, an initiative of the American Head and Neck Society's Education Committee to increase awareness of current best practices pertaining to head and neck cancer. The National Comprehensive Cancer Network (NCCN) guidelines for primary and adjuvant treatment of cancer of the glottic larynx are reviewed here in a systematic fashion according to stage. PMID- 28653454 TI - Effect of cotrimoxazole prophylaxis on malaria occurrence among HIV-infected adults in West Africa: the MALHIV Study. AB - INTRODUCTION: Cotrimoxazole (CTX) should be given to all HIV-infected adults with mild or severe HIV-disease or those with CD4 counts below 350/mm3 according to 2006 WHO guidelines. We assessed the impact of CTX prophylaxis on the risk of malaria episodes in HIV-1-infected adults from four West African countries with different patterns of malaria transmission. METHOD: Multicentric cohort study, conducted between September 2007 and March 2010 in four West African cities. Antiretroviral therapy (ART) naive HIV-infected adults started CTX at enrolment (CTX group) if they had CD4 < 350 cells/mm3 or were at WHO clinical stage >=2. For patients who did not start CTX at enrolment (non-CTX group) and started CTX afterwards, follow-up was censored at CTX initiation. We used Cox's proportional hazard model to compare the risk of malaria between CTX groups. RESULTS: A total of 514 participants (median CD4 count 238 cells/mm3 ) were followed for a median of 15 months. At enrolment, 347 started CTX, and 261 started ART. During the follow-up, 28 started CTX. The incidence of malaria was 8.7/100 PY (95%CI 6.3 11.5) overall, 5.2/100 PY (95%CI 3.1-8.3) in the CTX group and 15.5/100 PY (95%CI 10.3-22.1) in the non-CTX group. In multivariate analysis, CTX led to a 69% reduction in the risk of malaria (aHR 0.31, 95%CI 0.10-0.90). CONCLUSION: Patients in the CTX group had an adjusted risk of malaria three times lower than those in the non-CTX group. The prolonged large-scale use of CTX did not blunt the efficacy of CTX to prevent malaria in this region. PMID- 28653455 TI - Nocturnal behavior of orphaned Asian elephant (Elephas maximus) calves in Sri Lanka. AB - Many animals exhibit circadian variation in behavior; thus, studying nocturnal behavior is important to fully understand species activity patterns. The nocturnal behavior of Asian elephants, and specifically calves, has received little previous study. We carried out observational study of the nocturnal behavior of orphaned Asian elephant calves at three age groups: "infant" (0-24 months), "young juvenile" (25-36 months) and "old juveniles" (over 36 months). Project aims were to build a nocturnal activity budget, to investigate key age differences, and whether calves exhibited synchronous behavior patterns. We carried out focal animal sampling and instantaneous group scan sampling on 34 calves for 18 nights using an infra-red camera. Focal results indicated that calves spent the highest percentage of scans in lying rest (46.2%) and feeding (28.4%). There was no significant difference between lying rest in the three age groups. Calves spent the majority of time within 5 m of their nearest neighbor, with infants remaining in closest proximity to conspecifics compared to older calves. Synchronous behavior could not be proved statistically but two distinct lying rest periods between 2300 and 0100, and 0330 and 0530, were noted. We found that calves spent more time in lying rest than previously observed in adult elephants. Activity patterns observed suggest that the orphaned group behavior is similar to that reported in the wild and captive zoological collections, and appears to be in concordance with "natural" behavior patterns, a defining feature of animal welfare. This research provides valuable data as a preliminary study. PMID- 28653456 TI - Detecting Ebola with limited laboratory access in the Democratic Republic of Congo: evaluation of a clinical passive surveillance reporting system. AB - BACKGROUND: Ebola virus disease (EVD) can be clinically severe and highly fatal, making surveillance efforts for early disease detection of paramount importance. In areas with limited access to laboratory testing, the Integrated Disease Surveillance and Response (IDSR) strategy in the Democratic Republic of Congo (DRC) may be a vital tool in improving outbreak response. METHODS: Using DRC IDSR data from the nation's four EVD outbreak periods from 2007-2014, we assessed trends of Viral Hemorrhagic Fever (VHF) and EVD differential diagnoses reportable through IDSR. With official case counts from active surveillance of EVD outbreaks, we assessed accuracy of reporting through the IDSR passive surveillance system. RESULTS: Although the active and passive surveillance represent distinct sets of data, the two were correlated, suggesting that passive surveillance based only on clinical evaluation may be a useful predictor of true cases prior to laboratory confirmation. There were 438 suspect VHF cases reported through the IDSR system and 416 EVD cases officially recorded across the outbreaks examined. CONCLUSION: Although collected prior to official active surveillance cases, case reporting through the IDSR during the 2007, 2008 and 2012 outbreaks coincided with official EVD epidemic curves. Additionally, all outbreak areas experienced increases in suspected cases for both malaria and typhoid fever during EVD outbreaks, underscoring the importance of training health care workers in recognising EVD differential diagnoses and the potential for co-morbidities. PMID- 28653457 TI - Intravoxel incoherent motion analysis of renal allograft diffusion with clinical and histopathological correlation in pediatric kidney transplant patients: A preliminary cross-sectional observational study. AB - The purpose of this study was to compare IVIM values in pediatric renal transplants with histopathology and clinical management change. Fifteen pediatric renal transplant recipients (mean 15.7+/-2.9 years) were prospectively scanned on a 3T MR scanner with multi-b DTI, prior to same-day transplant biopsy. IVIM maps from 14 subjects were analyzed (one excluded due to motion). Mean values were computed from cortical ROIs and medullary ROIs corresponding to the biopsy site. Subjects were also grouped according to whether or not the biopsy resulted in a change in clinical management. Cortico-medullary IVIM estimates and histopathologic Banff scores were correlated with KT. Cortico-medullary IVIM differences between the "change" and "no change" groups was compared with Mann Whitney U test. Cortical Dp showed significant moderate negative correlation with Banff t and ci scores (KT=-0.497, P=.035 and KT=-0.46, P=.046) and moderate positive correlation with Banff i score (KT=0.527, P=.028). Cortical Pf showed significant moderate correlation with ci and ct scores (KT=0.489, P=.035 and KT=0.457, P=.043). Tissue diffusivity, Dt , estimated with IVIM was significantly different between the "change" and "no change" groups in medullary ROIs (U=6, P=.021). IVIM analysis has potential as a noninvasive biomarker in assessment of pediatric renal allograft pathology. PMID- 28653458 TI - Left ventricular-only pacing in heart failure patients with normal atrioventricular conduction improves global function and left ventricular regional mechanics compared with biventricular pacing: an adaptive cardiac resynchronization therapy sub-study. AB - AIMS: Right ventricular (RV) pacing can impair left ventricular (LV) function. When timed with native RV activation, LV-only pacing may cause greater improvements in LV function than biventricular pacing. This study compared the chronic effects of cardiac resynchronization therapy (CRT) on LV mechanics between biventricular pacing and LV-only pacing in patients with normal atrioventricular (AV) conduction. METHODS AND RESULTS: The Adaptive CRT (aCRT) algorithm provides LV-only pacing timed with native RV activation when the AV interval is normal (<=200 ms during sinus rhythm). We studied patients from the aCRT trial with normal AV conduction at their baseline visit and compared changes in cardiac function after 12 months of treatment with conventional biventricular or mostly (>=80%) LV-only pacing. Speckle tracking echocardiography was used to assess LV myocardial strain before and after treatment. Despite similar improvements in Packer's clinical composite scores and LV volumes, LV-only paced patients (n = 70) had a greater improvement in LV ejection fraction (8.5 +/- 11.3% vs. 5.5 +/- 10.3%, P = 0.038) and global LV radial strain (6.3 +/- 8.6% vs. 4.0 +/- 10.1%, P = 0.046) than those randomized to biventricular pacing (n = 91). Strain was improved to a greater extent near the RV pacing lead, in septal and apical regions (P < 0.05 for both regions), in patients receiving LV-only pacing. CONCLUSION: In heart failure patients with normal AV conduction, LV-only pacing timed with native RV activation may result in greater improvements in LV ejection fraction and myocardial strain compared with biventricular pacing due to better apical and septal function. PMID- 28653459 TI - Collaborative study to establish World Health Organization international reference reagents for dengue virus Types 1 to 4 RNA for use in nucleic acid testing. AB - BACKGROUND: Dengue is the most important reemerging mosquito-borne viral disease worldwide. Caused by dengue virus (DENV), a member of the genus Flavivirus in the Flaviviridae family, dengue can be asymptomatic (approx. 80% of cases) or symptomatic, ranging from a flu-like illness known as dengue fever, to a life threatening form called severe dengue. DENV is primarily transmitted from human to human through the bite of mosquitoes of the genus Aedes; however, it is also transmissible by transfusion of blood and blood components and by solid organ transplant. Nucleic acid test (NAT) assays are considered the most appropriate approach for blood donor screening for recent DENV infections, but there is no Food and Drug Administration-approved assay for the screening of blood for DENV. STUDY DESIGN AND METHODS: An international collaborative study was conducted to assess the suitability of reference reagent (RR) candidates for DENV Types 1 to 4 RNA for use in NAT-based assays. RESULTS: Two sets of RR candidates were prepared for each DENV type, one liquid frozen (Set 1) and one lyophilized (Set 2). A total of 28 laboratories from 20 countries agreed to participate in the study, of which 21 submitted the results for qualitative and/or quantitative assessments. CONCLUSION: The World Health Organization has established the lyophilized materials as international RRs for DENV RNA with a unitage of 13,500, 69,200, 23,400, and 33,900 units/mL for DENV-1 to -4, respectively. PMID- 28653460 TI - Dual anti-inflammatory and anti-parasitic action of topical ivermectin 1% in papulopustular rosacea. AB - BACKGROUND: Recently, therapy of rosacea with inflammatory lesions (papulopustular) has improved substantially with the approval of topical ivermectin 1% cream. It is assumed to have a dual mode of action with anti inflammatory capacities and anti-parasitic effects against Demodex, which however has not yet been demonstrated in vivo. AIM: To find scientific rationale for the dual anti-inflammatory and anti-parasitic mode of action of topical ivermectin 1% cream in patients with rosacea. METHODS: A monocentric pilot study was performed including 20 caucasion patients with moderate to severe rosacea, as assessed by investigator global assessment (IGA score >=3) and a Demodex density >=15/cm2 . Patients were treated with topical ivermectin 1% cream once daily (Soolantra(r) ) for >=12 weeks. The density of Demodex mites was assessed with skin surface biopsies. Expression of inflammatory and immune markers was evaluated with RT-PCR and by immunofluorescence staining. RESULTS: The mean density of mites was significantly decreased at week 6 and week 12 (P < 0.001). The gene expression levels of IL-8, LL-37, HBD3, TLR4 and TNF-alpha were downregulated at both time points. Reductions in gene expression were significant for LL-37, HBD3 and TNF alpha at both follow-up time points and at week 12 for TLR4 (all P < 0.05). Reduced LL-37 expression (P < 0.05) and IL-8 expression were confirmed on the protein level by immunofluorescence staining. All patients improved clinically, and 16 of 20 patients reached therapeutic success defined as IGA score <=1. CONCLUSION: Topical ivermectin 1% cream acts by a dual, anti-inflammatory and anti-parasitic mode of action against rosacea by killing Demodex spp. in vivo, in addition to significantly improving clinical signs and symptoms in the skin. PMID- 28653461 TI - Choosing an optimal input for an intravenous glucose tolerance test to aid parameter identification. AB - OBJECTIVE: The minimal model is used to estimate insulin sensitivity in patients with diabetes, following an intravenous glucose tolerance test (IVGTT). Issues have been reported regarding parameter estimation, including correlation between insulin sensitivity and action parameters. The objective was to reduce these issues, by modifying the input of glucose in the test. METHODS: Data were available for 24 volunteers following an IVGTT and glucose clamp test. Correlation between parameters was explored using likelihood heatmaps. An integrated glucose-insulin model was used to simulate glucose and insulin concentrations following new glucose inputs. The improved input for the test was selected by finding the minimum inverse of the determinant of the Fisher information matrix. KEY FINDINGS: When the minimal model was fitted to the IVGTT data, there was clear correlation between the insulin parameters. With the glucose clamp, all parameters were correlated and badly estimated. The modified input, a bolus dose followed by constant infusion, resulted in improvement in parameter estimation and reduction in parameter correlation. CONCLUSIONS: It is possible to reduce the issues with parameter estimation in the minimal model by modifying the glucose input, leading to a simplified test deign and a reduction in the total amount of glucose infused. PMID- 28653462 TI - No effect of treatment with intravenous ganciclovir on Epstein-Barr virus viremia demonstrated after pediatric liver transplantation. AB - EBV after pediatric LT is a risk factor for PTLD. We wanted to evaluate the effect of intravenous ganciclovir on EBV viremia and to identify risk factors for chronic EBV viremia. All pediatric patients who underwent LT in Norway from 2002 until 2015 were reviewed. Twenty-two of 38 patients with viremia were treated with intravenous ganciclovir for a median of 22 (21-38) days. Treated and untreated patients were not different with respect to EBV seroconversion prior to transplantation or age at transplantation, but treated patients had significantly earlier viremia after transplantation (P=.005). There was no difference in the proportion of patients with reduction in virus load in patients treated with ganciclovir compared to untreated patients at 8 weeks. After 1 year, five of 19 patients treated with ganciclovir and six of 14 untreated patients had reduced virus load compared to start of viremia (P=.27). In conclusion, treatment with intravenous ganciclovir did not change the proportion of patients with reduction in EBV load at 8 weeks and 1 year after viremia. Younger age at transplantation, short time from transplantation to viremia, and lack of EBV seroconversion prior to transplantation were significant predictors of chronic EBV viremia. PMID- 28653463 TI - Does hypothermia impair cerebrovascular autoregulation in neonates during cardiopulmonary bypass? AB - BACKGROUND: Autoregulation monitoring has been proposed as a means to identify optimal arterial blood pressure goals during cardiopulmonary bypass, but it has been observed that cerebral blood flow is pressure passive during hypothermic bypass. When neonates cooled during cardiopulmonary bypass are managed with vasodilators and controlled hypotension, it is not clear whether hypothermia or hypotension were the cause of impaired autoregulation. AIM: We sought to measure the effect of both arterial blood pressure and hypothermia on autoregulation in a cohort of infants cooled for bypass, hypothesizing a collinear relationship between hypothermia, hypotension, and dysautoregulation. METHODS: Cardiopulmonary bypass was performed on 72 infants at Texas Children's Hospital during 2015 and 2016 with automated physiologic data capture, including arterial blood pressure, nasopharyngeal temperature, cerebral oximetry, and a cerebral blood volume index derived from near infrared spectroscopy. Cooling to 18 degrees C, 24 degrees C, and 30 degrees C was performed on 33, 12, and 22 subjects, respectively. The hemoglobin volume index was calculated as a moving correlation coefficient between mean arterial blood pressure and the cerebral blood volume index. Positive values of the hemoglobin volume index indicate impaired autoregulation. Relationships between variables were assessed utilizing a generalized estimating equation approach. RESULTS: Hypothermia was associated with hypotension, dysautoregulation, and increased cerebral oximetry. Comparing the baseline temperature of 36 degrees C with 18 degrees C, arterial blood pressure was 44 mm Hg (39-52) vs 25 mm Hg (21-31); the hemoglobin volume index was 0.0 (-0.02 to 0.004) vs 0.5 (0.4-0.7) and cerebral oximetry was 59% (57-61) vs 88% (80-92) (Median, 95% CI of median; P<.0001 for all three associations by linear regression with generalized estimation of equations with data from all temperatures measured). CONCLUSIONS: Arterial blood pressure, temperature, and cerebral autoregulation were collinear in this cohort. The conclusion that hypothermia causes impaired autoregulation is thus confounded. The effect of temperature on autoregulation should be delineated before clinical deployment of autoregulation monitors to prevent erroneous determination of optimal arterial blood pressure. Showing the effect of temperature on autoregulation will require a normotensive hypothermic model. PMID- 28653464 TI - Implementing a new curriculum for computer-assisted restorations in prosthetic dentistry. AB - INTRODUCTION: Computer-aided design/computer-aided manufacturing (CAD/CAM) of fixed prosthetic restorations has gained popularity in the last decade. However, this field of dentistry has not been integrated in the dental curriculum at most universities. MATERIAL AND METHODS: According to the method of Kern, a curriculum was designed and established on a voluntary basis in the prosthetic education of a German dental school. The success of the implementation was measured by evaluation carried out by the participants on a visual analogue scale. Furthermore, the clinical performance of the fabricated restorations was evaluated. RESULTS: Ninety-four percent of all students participated in the CAD/CAM curriculum indicating considerable interest. Nearly half of all students used the acquired knowledge to design crowns for their patients. All restorations fabricated by participants of the new CAD/CAM programme showed good clinical performance. DISCUSSION: By phasing-in the CAD/CAM training programme, independent CAD/CAM-based fabrication of all-ceramic crowns increased student's self-confidence in tooth preparation. A tendency was found that students using CAD/CAM technology prepared more teeth than their fellow students who did not use CAD/CAM technology. Further studies are required to investigate the influence of independent CAD/CAM-based single-crown fabrication on the quality of the preparation. PMID- 28653465 TI - Introduction to anomalous aortic origin of a coronary artery. AB - Anomalous aortic origin of a coronary artery (AAOCA) occurs when both coronary arteries arise from the same aortic sinus from a single ostium or two separate ostia. While most coronary anomalies are benign, the two most common subtypes that predispose to sudden cardiac death in the young are interarterial anomalous right coronary artery and interarterial anomalous left coronary artery. Practitioners face many challenges with AAOCA. Diagnosing patients may be difficult because children and adolescents are often asymptomatic and first presentation may be sudden death or sudden cardiac arrest. Risk stratification is also challenging as determining which unique characteristics place the child at highest risk of sudden death has not been adequately delineated and ischemic testing may give false negative results. Last, there is significant variability in decision making regarding management of youth with AAOCA. Future research is needed to help determine the best way to identify at-risk children and which treatment is the safest and most efficacious. PMID- 28653466 TI - Hailey-Hailey disease due to ATP2C1 splice site mutation, successfully treated with minocycline hydrochloride. PMID- 28653467 TI - Improving Management of Urinary Tract Infections in Older Adults: A Paradigm Shift or Therapeutic Nihilism? PMID- 28653468 TI - Chiral Gold Nanoclusters: Atomic Level Origins of Chirality. AB - Chiral nanomaterials have received wide interest in many areas, but the exact origin of chirality at the atomic level remains elusive in many cases. With recent significant progress in atomically precise gold nanoclusters (e.g., thiolate-protected Aun (SR)m ), several origins of chirality have been unveiled based upon atomic structures determined by using single-crystal X-ray crystallography. The reported chiral Aun (SR)m structures explicitly reveal a predominant origin of chirality that arises from the Au-S chiral patterns at the metal-ligand interface, as opposed to the chiral arrangement of metal atoms in the inner core (i.e. kernel). In addition, chirality can also be introduced by a chiral ligand, manifested in the circular dichroism response from metal-based electronic transitions other than the ligand's own transition(s). Lastly, the chiral arrangement of carbon tails of the ligands has also been discovered in a very recent work on chiral Au133 (SR)52 and Au246 (SR)80 nanoclusters. Overall, the origins of chirality discovered in Aun (SR)m nanoclusters may provide models for the understanding of chirality origins in other types of nanomaterials and also constitute the basis for the development of various applications of chiral nanoparticles. PMID- 28653469 TI - Development of quality metrics for ambulatory pediatric cardiology: Chest pain. AB - OBJECTIVE: As part of the American College of Cardiology Adult Congenital and Pediatric Cardiology Section effort to develop quality metrics (QMs) for ambulatory pediatric practice, the chest pain subcommittee aimed to develop QMs for evaluation of chest pain. DESIGN: A group of 8 pediatric cardiologists formulated candidate QMs in the areas of history, physical examination, and testing. Consensus candidate QMs were submitted to an expert panel for scoring by the RAND-UCLA modified Delphi process. Recommended QMs were then available for open comments from all members. PATIENTS: These QMs are intended for use in patients 5-18 years old, referred for initial evaluation of chest pain in an ambulatory pediatric cardiology clinic, with no known history of pediatric or congenital heart disease. RESULTS: A total of 10 candidate QMs were submitted; 2 were rejected by the expert panel, and 5 were removed after the open comment period. The 3 approved QMs included: (1) documentation of family history of cardiomyopathy, early coronary artery disease or sudden death, (2) performance of electrocardiogram in all patients, and (3) performance of an echocardiogram to evaluate coronary arteries in patients with exertional chest pain. CONCLUSIONS: Despite practice variation and limited prospective data, 3 QMs were approved, with measurable data points which may be extracted from the medical record. However, further prospective studies are necessary to define practice guidelines and to develop appropriate use criteria in this population. PMID- 28653470 TI - Characterization of pseudo-continuous arterial spin labeling: Simulations and experimental validation. AB - PURPOSE: To characterize pseudo-continuous arterial spin labeling (pCASL) through simulations of spin inversion and to discuss suitable parameter settings for measuring cerebral perfusion. METHODS: Simulations of arterial spin inversion in pCASL were performed based on the Bloch equation. Both the labeling and the control condition of pCASL were analyzed separately, and the labeling efficiency, alpha, was calculated depending on the averages of both, the radiofrequency (RF) field amplitude and labeling gradient strength. The influence of additional parameters characterizing the pCASL pulse sequence, such as the interpulse interval, the RF duty cycle, and the labeling gradient, also were studied. An echo-planar imaging protocol utilizing a short repetition time was developed for experimental validation by estimating alpha in the internal carotid artery. RESULTS: The effectiveness of the control condition of balanced pCASL crucially depends on both the labeling gradient amplitude and the RF duty cycle. The use of large values for both quantities improves the insensitivity to off-resonance gradients caused by magnetic field inhomogeneities. In addition, balanced and unbalanced pCASL become comparably effective. CONCLUSION: By use of appropriate parameter settings, labeling efficiencies of around 90% are feasible, independent of expected off-resonance gradients at 3T. Magn Reson Med 79:1638-1649, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28653471 TI - Experimental warming alters migratory caribou forage quality. AB - Global declines in caribou and reindeer (Rangifer) populations have drawn attention to the myriad of stressors that these Arctic and boreal forest herbivores currently face. Arctic warming has resulted in increased tundra shrub growth and therefore Rangifer forage quantity. However, its effects on forage quality have not yet been addressed although they may be critical to Rangifer body condition and fecundity. We investigated the impact of 8 yrs of summer warming on the quality of forage available to the Bathurst caribou herd using experimental greenhouses (n = 5) located in mesic birch hummock tundra in the central Canadian Low Arctic. Leaf forage quality and digestibility characteristics associated with nutrients (nitrogen and phosphorus), phenolics, and fiber were measured on the deciduous shrub Betula glandulosa (an important Rangifer diet component) at six time points through the growing season, and on five other very common vascular plant and lichen species in late summer. Experimental warming reduced B. glandulosa leaf nitrogen concentrations by ~10% in both late June and mid-July, but not afterwards. It also reduced late summer forage quality of the graminoid Eriophorum vaginatum by increasing phenolic concentrations 38%. Warming had mixed effects on forage quality of the lichen Cetraria cucullata in that it increased nutrient concentrations and tended to decrease fiber contents, but it also increased phenolics. Altogether, these warming-induced changes in forage quality over the growing season, and response differences among species, highlight the importance of Rangifer adaptability in diet selection. Furthermore, the early season reduction in B. glandulosa nitrogen content is a particular concern given the importance of this time for calf growth. Overall, our demonstration of the potential for significant warming impacts on forage quality at critical times for these animals underscores the importance of effective Rangifer range conservation to ensure sufficient appropriate habitat to support adaptability in forage selection in a rapidly changing environment. PMID- 28653472 TI - Residual risk of bacterial contamination of platelets: six years of experience with sterility testing. AB - BACKGROUND: Canadian Blood Services screens 100% of platelet concentrates (PCs) for bacterial contamination with the BacT/ALERT system. Quality-control sterility testing of 1% (>=10 units) of outdated PCs is performed monthly. Data from routine screening, quality-control testing, and septic reactions obtained from 2010 to 2016 are presented herein. STUDY DESIGN AND METHODS: In total, 601,988 buffy coat PC pools and 186,737 apheresis PCs were routinely screened with aerobic cultures over 6 years. Outdate quality-control testing of 8535 buffy coat and 8498 apheresis PCs was performed using aerobic and anaerobic cultures during the same period. Results were classified as "true-positives" when the same bacterium was isolated in initial and confirmatory cultures or "false-negatives" when bacteria were missed in early screening and were captured during quality control sterility testing or through investigation of sepsis cases. RESULTS: During routine screening, the true-positive rates between buffy coat (0.94 per 10,000) and apheresis (0.96 per 10,000) PCs were similar (p = 0.9473). Seventy five bacteria isolated during PC screening included Gram-positive and Gram negative organisms. Six false-negative septic reactions were reported that implicated coagulase-negative staphylococci (n = 3) and Staphylococcus aureus (n = 3) for approximate rates of 1 per 100,000 transfusion reactions and 1 per 500,000 fatalities. During quality-control testing, the false-negative rates between buffy coat (8 per 10,000) and apheresis (9 per 10,000) PCs were similar (p = 0.7897). All 15 quality-control isolates were Gram-positive bacteria. CONCLUSION: The current bacterial screening protocol is efficacious for identifying Gram-negative bacteria. However, the high proportion of Gram-positive organisms detected on outdate quality-control testing and septic transfusion events demonstrates a residual safety risk that merits further intervention. PMID- 28653473 TI - Rab11 is required for tubulogenesis of Malpighian tubules in Drosophila melanogaster. AB - Intracellular vesicular trafficking is one of the important tools in maintaining polarity, adhesion, and shape of epithelial cells. Rab11, a subfamily of the Ypt/Rab gene family of ubiquitously expressed GTPases and a molecular marker of recycling endosomes, transports different components of plasma membrane. Here, we report that Rab11 affects tubulogenesis of Malpighian tubules (MTs). MTs are simple polarized epithelial tubular structures, considered as functional analogue of human kidney. Rab11 has pleiotropic effects on MTs development as down regulation of Rab11 in principal cells (PCs) of MTs from embryonic stages of development results in reduced endoreplication, clustering of cells, disorganized cytoskeleton, and disruption of polarity leading to shortening of MTs in third instar larvae. Rab11 is also required for proper localization of different transporters in PCs, essential for physiological activity of MTs. Collectively, our data suggest that Rab11 plays a key role in the process of tubulogenesis of MTs in Drosophila. PMID- 28653474 TI - Single triangular suture: A modified technique for hyoid suspension as a treatment for obstructive sleep apnea: Our experience with 24 patients. PMID- 28653475 TI - Amylosucrase-mediated beta-carotene encapsulation in amylose microparticles. AB - The beta-carotene embedded amylose microparticles (BC-AmMPs) were prepared in one step by utilizing the unique catalytic activity of amylosucrase from Deinococcus geothermalis (DgAS), which synthesizes linear amylose chains using sucrose as the sole substrate. Synthesized amylose chains self-assembled with beta-carotene to form well-defined spherical microparticles with an encapsulation yield of 65%. The BC-AmMPs produced (average diameter ~8 um) were bright orange due to the embedded beta-carotene, and this was confirmed by Raman analysis. XRD showed BC AmMPs had a B-type amylose crystal structure with a degree of crystallinity lower than that of AmMPs. This lower crystallinity of AmMP after BC encapsulation was confirmed by DSC analysis. Decreased enthalpy of gelatinization (DeltaHgel ) of BC-AmMP implied that molecular order within the amylose microstructure was influenced by the presence of BC. The stability of BC against environmental stresses, such as UV light and oxidative stress, was significantly enhanced by its encapsulation. The authors propose a new approach to the preparation of an amylose based carrier system for active compounds or expensive food ingredients with poor stabilities during storage or processing. Given that amylose is a safe food material, the devised encapsulation system will find wide range of practical applications in the food industry. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1640-1646, 2017. PMID- 28653476 TI - Heterotrophic production of Chlorella sp. TISTR 8990-biomass growth and composition under various production conditions. AB - The green microalga Chlorella sp. TISTR 8990 was grown heterotrophically in the dark using various concentrations of a basal glucose medium with a carbon-to nitrogen mass ratio of 29:1. The final biomass concentration and the rate of growth were highest in the fivefold concentrated basal glucose medium (25 g L-1 glucose, 2.5 g L-1 KNO3 ) in batch operations. Improving oxygen transfer in the culture by increasing the agitation rate and decreasing the culture volume in 500 mL shake flasks improved growth and glucose utilization. A maximum biomass concentration of nearly 12 g L-1 was obtained within 4 days at 300 rpm, 30 degrees C, with a glucose utilization of nearly 76% in batch culture. The total fatty acid (TFA) content of the biomass and the TFA productivity were 102 mg g-1 and 305 mg L-1 day-1 , respectively. A repeated fed-batch culture with four cycles of feeding with the fivefold concentrated medium in a 3-L bioreactor was evaluated for biomass production. The total culture period was 11 days. A maximum biomass concentration of nearly 26 g L-1 was obtained with a TFA productivity of 223 mg L-1 day-1 . The final biomass contained (w/w) 13.5% lipids, 20.8% protein and 17.2% starch. Of the fatty acids produced, 52% (w/w) were saturated, 41% were monounsaturated and 7% were polyunsaturated (PUFA). A low content of PUFA in TFA feedstock is required for producing high quality biodiesel. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1589-1600, 2017. PMID- 28653477 TI - Radiomic analysis of soft tissues sarcomas can distinguish intermediate from high grade lesions. AB - PURPOSE: To assess the feasibility of grading soft tissue sarcomas (STSs) using MRI features (radiomics). MATERIALS AND METHODS: MRI (echo planar SE, 1.5T) from 19 patients with STSs and a known histological grading, were retrospectively analyzed. The apparent diffusion coefficient (ADC) maps, obtained by diffusion weighted imaging acquisitions, were analyzed through 65 radiomic features, intensity-based (first order statistics, FOS) and texture (gray level co occurrence matrix, GLCM; and gray level run length matrix, GLRLM) features. Feature selection (sequential forward floating search) and classification (k nearest neighbor classifier) were performed to distinguish intermediate- from high-grade STSs. Classification was performed using the three different sub groups of features separately as well as all the features together. The entire dataset was divided in three subsets: the training, validation and test set, containing, respectively, 60, 30, and 10% of the data. RESULTS: Intermediate grade lesions had a higher and less disperse ADC values compared with high-grade ones: most of FOS related to intensity are higher for the intermediate-grade STSs, while FOS related to signal variability were higher in the high grade (e.g., the feature variance is 2.6*105 +/- 0.9*105 versus 3.3*105 +/- 1.6*105 , P = 0.3). The GLCM features related to entropy and dissimilarity were higher in the high-grade. When performing classification, the best accuracy is obtained with a maximum of three features for each subgroup, FOS features being those leading to the best classification (validation set: FOS accuracy 0.90 +/- 0.11, area under the curve [AUC] 0.85 +/- 0.16; test set: FOS accuracy 0.88 +/- 0.25, AUC 0.87 +/- 0.34). CONCLUSION: Good accuracy and AUC could be obtained using only few Radiomic features, belonging to the FOS class. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:829-840. PMID- 28653478 TI - Different RNA and protein expression of surface markers in rabbit amniotic fluid derived mesenchymal stem cells. AB - Over the years, there has been much confusion in defining molecular markers of mesenchymal stem cells (MSCs) for other than human species due to a lack of species-specific antibodies. Therefore, the aim of our study was to define rabbit amniotic fluid-derived mesenchymal stem cells (rAF-MSCs) and to reflect upon the current identification of AF-MSCs by providing a summary of detected surface markers in different species. The expression of rAF-MSC surface markers was analyzed at the protein and mRNA level. Flow cytometry analyses showed that rAF MSCs were positive for CD29 and CD44, low positive for CD90, but negative for CD73, CD105, and CD166. Interestingly, RT-PCR (reverse transcription-polymerase chain reaction) exposed a discprepancy between transcribed mRNA and protein expression, as the cells expressed mRNA of all MSC markers: CD29, CD44, CD73, CD90, CD105, and CD166. Our results also confirmed the mesenchymal nature of isolated cells by morphology, ultrastructure, and intracellular marker expression profile. In addition, the expression of few pluripotency markers was also detected. We also found that passaging did not affect apoptosis and viability. Similarly, changes in karyotype were not observed during passaging. In conclusion, the provided characteristics may be used as a comprehensive set of criteria to define and characterize rAF-MSCs, required for the identification of these cells in preclinical investigations. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1601-1613, 2017. PMID- 28653479 TI - A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses. AB - Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis-Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure-response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin. PMID- 28653480 TI - Eltrombopag for secondary failure of platelet recovery post-allogeneic hematopoietic stem cell transplant in children. AB - Secondary failure of platelet engraftment occurs in 20% of patients undergoing allogeneic HSCT and is associated with poor outcome. Currently, there are no guidelines for treatment of late thrombocytopenia and platelet transfusion is the mainstay of treatment. Here, we describe the use of Eltrombopag to treat secondary failure of platelet recovery following HSCT in a child with severe aplastic anemia. Eltrombopag resulted in recovery of platelet count with no need for platelet transfusion support with no reported side effects. Eltrombopag may be used successfully in children with secondary failure of platelet recovery post HSCT for SAA. PMID- 28653481 TI - Commentary on the MID3 Good Practices Paper. AB - During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective. PMID- 28653482 TI - StimVision Software: Examples and Applications in Subcallosal Cingulate Deep Brain Stimulation for Depression. AB - OBJECTIVE: Create a software tool to facilitate tractography-based deep brain stimulation (DBS) electrode targeting within the patient-specific stereotactic coordinate system used in the operating room. APPROACH: StimVision was developed with Visualization Toolkit libraries and integrates four major components: 1) medical image visualization, 2) tractography visualization, 3) DBS electrode positioning, and 4) DBS activation volume calculation with tractography intersection. RESULTS: Initial applications of StimVision are focused on the study of subcallosal cingulate (SCC) DBS for the treatment of depression. Retrospective modeling results on SCC DBS have suggested that direct stimulation of a specific collection of tractographic pathways are necessary for therapeutic benefit; thereby creating a tractography-based DBS surgical targeting hypotheses. StimVision is the tool we created to facilitate prospective clinical evaluation of that hypothesis. SIGNIFICANCE: Retrospective tractography-based analyses are common in DBS research; however, intraoperative software tools for interactive selection of a tractography-based DBS target are not readily available. StimVision provides an academic research tool to assist clinical implementation of new DBS targeting strategies and postoperative evaluation of targeting outcome. PMID- 28653483 TI - Morphology of laryngeal cartilage of the nine-banded armadillo (Dasypus novemcinctus) Linnaeus, 1758. AB - Armadillos, Xenarthras representatives, known for adaptability to different ecosystems, own specific morphophysiological characteristics that are not known and deserve to be studied. The aim of this study was to describe the morphology of cartilage of the larynx of the nine-banded armadillo (Dasypus novemcinctus). Five dead armadillos were donated by the Chico Mendes Institute of Biodiversity (ICMBio-PI) to the Federal University of Piaui. The animals were fixed and dissected for removal of the larynx. The cartilages were identified and described, photodocumented, and schematized. Fragments with about 0.5 cm of each cartilage were collected and submitted to classical histology for Hematoxylin Eosin coloring. The slides were assembled in enterlan and analyzed under a light microscope. The larynx of the armadillo (D. novemcinctus) is located in the mentonian region, ventral to the esophagus, and due to the total positioning of the tongue in the oral cavity, there is also a cranial cervical position in this species. The larynx has five cartilages, they are: a cricoid, a thyroid, an epiglottis, and two arytenoids. The corniculate process is present; however, the cuneiform process is absent. The epiglottis has a discrete bifurcation at its apex. In all cartilages epithelial variations are observed. The tissues are varied from squamoso stratified to cylindrical pseudostratified, with propria lamina rich in mucoserosas glands. With the exception of epiglottic cartilage, predominantly elastic, the rest are hyaline. The larynx of D. novemcinctus, although the same number of cartilages, differs morphologically and microscopically from the larynx of other species. PMID- 28653485 TI - A highly sensitive sensor for ethyl acetate by changing fluorescent colour of lanthanide complex. AB - A lanthanide complex, namely, [La2 (L-DBTA)3 (CH3 OH)2 (H2 O)2 ]?2H2O has been synthesized using a simple reaction of L-O,O'-dibenzoyl tartaric acid with LaCl3 ?6H2 O under ambient temperature. The luminescence spectrum in the solid state at room temperature revealed that the complex exhibited blue-light emission that originated from ligand. In addition, the lanthanide complex is developed as a fluorescent probe for sensing small molecules. Luminescence studies reveal that the lanthanide complex could detect ethyl acetate sensitively through fluorescence colour change from blue to yellow. Furthermore, the complex exhibited appealing features including high sensitivity and an ultrafast response. PMID- 28653484 TI - Theoretical implications of quantitative properties of interval timing and probability estimation in mouse and rat. AB - In three experiments with mice ( Mus musculus ) and rats (Rattus norvigicus), we used a switch paradigm to measure quantitative properties of the interval-timing mechanism. We found that: 1) Rodents adjusted the precision of their timed switches in response to changes in the interval between the short and long feed latencies (the temporal goalposts). 2) The variability in the timing of the switch response was reduced or unchanged in the face of large trial-to-trial random variability in the short and long feed latencies. 3) The adjustment in the distribution of switch latencies in response to changes in the relative frequency of short and long trials was sensitive to the asymmetry in the Kullback-Leibler divergence. The three results suggest that durations are represented with adjustable precision, that they are timed by multiple timers, and that there is a trial-by-trial (episodic) record of feed latencies in memory. PMID- 28653486 TI - The occurrence of porcine circovirus 3 without clinical infection signs in Shandong Province. AB - Porcine circovirus type 3 (PCV3) was detected in Shandong, China. One hundred and thirty-two of 222 (59.46%) samples were PCV3 positive, while 52 of 132 (39.39%) samples were co-infected with PCV2. There were no clinical signs of infection in either multiparous sows or live-born infants. Two strains of PCV3 were indentified from natural stillborn foetuses. Phylogenetic analysis showed the two strains of PCV3 are 96% identical to the known PCV3/Pig/USA (KX778720.1, KX966193.1 and KX898030.1) and closely related to Barbel Circovirus. Further studies of the epidemiology of PCV3 and the co-infection with PCV2 are needed. PMID- 28653487 TI - Catalytic Stereoselective 1,4-Addition Reactions Using CsF on Alumina as a Solid Base: Continuous-Flow Synthesis of Glutamic Acid Derivatives. AB - A novel methodology using CsF?Al2 O3 as a highly efficient, environmentally benign, and reusable solid-base catalyst was developed to synthesize glutamic acid derivatives by stereoselective 1,4-addition of glycine derivatives to alpha,beta-unsaturated esters. CsF?Al2 O3 showed not only great selectivity toward 1,4-addtion reactions by suppressing the undesired formation of pyrrolidine derivations by [3+2] cycloadditions, but also offered high yields for the 1,4-adduct with excellent anti diastereoselectivities. The catalyst was well characterized by using XRD, 19 F MAS-NMR and 19 F NMR spectroscopy, FT-IR, CO2 TPD, and XPS. And highly basic F from Cs3 AlF6 was identified as the most probable active basic site for the 1,4-addition reactions. Continuous-flow synthesis of 3-methyl glutamic acid derivative was successfully demonstrated by using this solid-base catalysis. PMID- 28653488 TI - Drugs for rare disorders. AB - Estimates of the frequencies of rare disorders vary from country to country; the global average defined prevalence is 40 per 100 000 (0.04%). Some occur in only one or a few patients. However, collectively rare disorders are fairly common, affecting 6-8% of the US population, or about 30 million people, and a similar number in the European Union. Most of them affect children and most are genetically determined. Diagnosis can be difficult, partly because of variable presentations and partly because few clinicians have experience of individual rare disorders, although they may be assisted by searching databases. Relatively few rare disorders have specific pharmacological treatments (so-called orphan drugs), partly because of difficulties in designing trials large enough to determine benefits and harms alike. Incentives have been introduced to encourage the development of orphan drugs, including tax credits and research aids, simplification of marketing authorization procedures and exemption from fees, and extended market exclusivity. Consequently, the number of applications for orphan drugs has grown, as have the costs of using them, so much so that treatments may not be cost-effective. It has therefore been suggested that not-for-profit organizations that are socially motivated to reduce those costs should be tasked with producing them. A growing role for patient organizations, improved clinical and translational infrastructures, and developments in genetics have also contributed to successful drug development. The translational discipline of clinical pharmacology is an essential component in drug development, including orphan drugs. Clinical pharmacologists, skilled in basic pharmacology and its links to clinical medicine, can be involved at all stages. They can contribute to the delineation of genetic factors that determine clinical outcomes of pharmacological interventions, develop biomarkers, design and perform clinical trials, assist regulatory decision making, and conduct postmarketing surveillance and pharmacoepidemiological and pharmacoeconomic assessments. PMID- 28653489 TI - Household sanitation is associated with lower risk of bacterial and protozoal enteric infections, but not viral infections and diarrhoea, in a cohort study in a low-income urban neighbourhood in Vellore, India. AB - OBJECTIVE: This study examined associations between household sanitation and enteric infection - including diarrhoeal-specific outcomes - in children 0-2 years of age in a low-income, dense urban neighbourhood. METHODS: As part of the MAL-ED study, 230 children in a low-income, urban, Indian neighbourhood provided stool specimens at 14-17 scheduled time points and during diarrhoeal episodes in the first 2 years of life that were analysed for bacterial, parasitic (protozoa and helminths) and viral pathogens. From interviews with caregivers in 100 households, the relationship between the presence (and discharge) of household sanitation facilities and any, pathogen-specific, and diarrhoea-specific enteric infection was tested through mixed-effects Poisson regression models. RESULTS: Few study households (33%) reported having toilets, most of which (82%) discharged into open drains. Controlling for season and household socio-economic status, the presence of a household toilet was associated with lower risks of enteric infection (RR: 0.91, 95% CI: 0.79-1.06), bacterial infection (RR: 0.87, 95% CI: 0.75-1.02) and protozoal infection (RR: 0.64, 95% CI: 0.39-1.04), although not statistically significant, but had no association with diarrhoea (RR: 1.00, 95% CI: 0.68-1.45) or viral infections (RR: 1.12, 95% CI: 0.79-1.60). Models also suggested that the relationship between household toilets discharging to drains and enteric infection risk may vary by season. CONCLUSIONS: The presence of a household toilet was associated with lower risk of bacterial and protozoal enteric infections, but not diarrhoea or viral infections, suggesting the health effects of sanitation may be more accurately estimated using outcome measures that account for aetiologic agents. PMID- 28653491 TI - The role of gammadelta-T cells during human pregnancy. AB - Pregnancy is an evolutionarily important and mysterious process. The placenta, as the nutrient and gas exchange organ, plays an essential role during this process. In addition, the interaction between trophoblast and maternal immune cells at the maternal-fetal interface is also associated with successful pregnancy. Human leukocyte antigen (HLA) molecules on trophoblast cells are involved in protecting the fetus from maternal rejection. Trophoblast cells comprise three subpopulations, including syncytiotrophoblast cells, cytotrophoblast cells, and extravillous trophoblast cells, and these cells express different HLA molecules. Syncytiotrophoblast and extravillous trophoblast cells encounter maternal immune cells from different sources, such as blood or decidua. The increased gammadelta T cells during human normal pregnancy indicate that these cells may play a role in this process. In peripheral blood, Vgamma9Vdelta2-T cells display cytotoxicity through the recognition of phosphoantigens derived from pathogens. However, HLA-E molecules protect the trophoblast cells from the cytotoxicity of Vgamma9Vdelta2-T cells through binding to the inhibitory receptor, CD94/NKG2A. In decidua, the main Vdelta1-T cells maintain the pregnancy through the secretion of cytokines. In addition, the imbalance between Vgamma9Vdelta2-T and Vdelta1-T cells, and the abnormal expression of the receptors on gammadelta-T cells were observed in adverse pregnancy. PMID- 28653493 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 28/2017. PMID- 28653492 TI - Corrigendum: Aryl(triethyl)silanes for Biaryl and Teraryl Synthesis by Copper(II) Catalyzed Cross-Coupling Reaction. PMID- 28653490 TI - The role of IL-23 and the IL-23/TH 17 immune axis in the pathogenesis and treatment of psoriasis. AB - Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL-23)/T-helper 17 (TH 17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL-23, a heterodimer composed of a p40 subunit also found in IL-12 and a p19 subunit exclusive to IL-23. IL-23 is important for maintaining TH 17 responses, and levels of IL-23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit IL 23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL-23/TH 17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways. PMID- 28653494 TI - An amazing cause of false PET positivity: Diagnosed after a lung cancer surgery. AB - Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has an effective role in both diagnosis and management of patients with lung cancer. There are many reasons could cause false positivity on PET/CT.A 60-year old man was admitted a mass on thorax CT and diagnosed as squamous cell carcinoma. Lobectomy with lymph node dissection was performed after evaluation of distant metastases. There were pathological lymph nodes detected on PET/CT at six month following period. Endobronchial ultrasonography guided transbronchial needle aspiration was performed for differantial diagnosis. The pathologic diagnosis was granuloma which developed in response to suture material. We interpreted this granulomatous reaction as gossypiboma which developed against long-left or forgotten suture material. In conclusion, based on this case, gossypiboma (or granulomatous inflammation in response to foreign bodies) should be also considered in differential diagnosis of intrathoracic lymph nodes with PET positivity in a previously operated patient. PMID- 28653495 TI - Tobacco education in UK dental schools: A survey of current practice. AB - OBJECTIVE: To investigate the current provision of tobacco education (tobacco use and cessation), assessment and e-cigarette education in UK dental and dental hygiene and therapy (DHT) undergraduate programmes. MATERIALS AND METHODS: The study was conducted using a self-administered questionnaire sent to all UK institutions training dental and DHT students during the academic year 2015/2016. RESULTS: Twenty-five programmes returned completed questionnaires (response rate 68%). All programmes (100%) reported delivering tobacco education, delivered by multiple individuals in 78% of the programmes. Assessment of the theoretical and practical aspects of tobacco education was reported in 80% and 72% of the programmes, respectively. More formal teaching time was devoted to the theoretical aspects (100% >2 hours) rather than the practical aspects (76% > 2 hours) of tobacco education. All programmes expected their graduates to be clinically competent at discussing the health consequences of smoking, deliver a brief smoking cessation intervention, and referring patients to stop smoking services. The use of the National Centre for Smoking Cessation and Training "Very Brief Advice" (NCSCT VBA) training package was reported to be mandatory in 36%, and recommended, in 44% of programmes. Specialised stop smoking services delivered teaching in 40% of both dental and DHT training programmes whilst another 40% reported previous input from specialist smoking cessation services but not in 2015/2016. Most programmes reported delivery of teaching on electronic cigarettes, with 12% delivering a standalone lecture on this topic. CONCLUSIONS: Tobacco education is an important component of dental training. Dental education programmes should remain responsive to a rapidly changing field and fully utilise the available resources. PMID- 28653496 TI - Middle East respiratory syndrome coronavirus experimental transmission using a pig model. AB - Dromedary camels are the main reservoir of Middle East respiratory syndrome coronavirus (MERS-CoV), but other livestock species (i.e., alpacas, llamas, and pigs) are also susceptible to infection with MERS-CoV. Animal-to-animal transmission in alpacas was reported, but evidence for transmission in other species has not been proved. This study explored pig-to-pig MERS-CoV transmission experimentally. Virus was present in nasal swabs of infected animals, and limited amounts of viral RNA, but no infectious virus were detected in the direct contact pigs. No virus was detected in the indirect contact group. Furthermore, direct and indirect contact pigs did not develop specific antibodies against MERS-CoV. Therefore, the role of pigs as reservoir is probably negligible, although it deserves further confirmation. PMID- 28653497 TI - Corrigendum: Eating behavior and obesity at Chinese buffets. PMID- 28653498 TI - Childhood obesity prevention in the women, infants, and children program: Outcomes of the MA-CORD study. AB - OBJECTIVE: To examine the extent to which a Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) intervention improved BMI z scores and obesity-related behaviors among children age 2 to 4 years. METHODS: In two Massachusetts communities, practice changes in WIC were implemented as part of the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) initiative to prevent obesity among low-income children. One WIC program was the comparison. Changes in BMI z scores pre and post intervention and prevalence of obesity related behaviors of WIC participants were assessed. Linear mixed models were used to examine BMI z score change, and logistic regression models were used to examine changes in obesity-related behaviors in each intervention site versus comparison over 2 years. RESULTS: WIC-enrolled children in both intervention sites (vs. comparison) had improved sugar-sweetened beverage consumption and sleep duration. Compared to the comparison WIC program (n = 626), no differences were observed in BMI z score among children in Intervention Site #1 (n = 198) or #2 (n = 637). In sensitivity analyses excluding Asian children, a small decline was observed in BMI z score (-0.08 units/y [95% confidence interval: -0.14 to 0.02], P = 0.01) in Intervention Site #2 versus comparison. CONCLUSIONS: Among children enrolled in WIC, the MA-CORD intervention was associated with reduced prevalence of obesity risk factors in both intervention communities and a small improvement in BMI z scores in one of two intervention communities in non-Asian children. PMID- 28653500 TI - Designing effective and sustainable multifaceted interventions for obesity prevention and healthy communities. PMID- 28653499 TI - Exercise's effect on mobility disability in older adults with and without obesity: The LIFE study randomized clinical trial. AB - OBJECTIVE: Some data suggest that obesity blunts the benefits of exercise on mobility in older adults. This study tested the homogeneity of the effect of a physical activity intervention on major mobility disability (MMD) across baseline obesity classifications in the Lifestyle Interventions and Independence for Elders (LIFE) Study. LIFE randomized 1,635 sedentary men and women aged 70 to 89 years to a moderate-intensity physical activity (PA) or health education program. METHODS: MMD, defined as the inability to walk 400 m, was determined over an average follow-up of 2.6 years. Participants were divided into four subgroups: (1) nonobese (BMI < 30 kg/m2 ; n = 437); (2) nonobese with high waist circumference (WC > 102 cm [men], > 88 cm [women]; n = 434); (3) class 1 obesity (30 kg/m2 <= BMI < 35 kg/m2 ; n = 430); and (4) class 2 + obesity (BMI >= 35 kg/m2 ; n = 312). Cox proportional hazard modeling was used to test an obesity by intervention interaction. RESULTS: The PA intervention had the largest benefit in participants with class 2 + obesity (hazard ratio 0.69, 95% confidence interval 0.48, 0.98). However, there was no statistically significant difference in benefit across obesity categories. CONCLUSIONS: A structured PA program reduced the risk of MMD even in older adults with extreme obesity. PMID- 28653501 TI - Perceived weight discrimination and high-risk health-related behaviors. AB - OBJECTIVE: Perceived weight discrimination has been associated with several health-risk behaviors related to eating and physical activity. The purpose of this research is to test whether weight discrimination is associated with nonweight-related high-risk behaviors that put the individual's health at risk. METHODS: As part of a larger survey on health and well-being, participants (N = 5,163) reported on their experiences with weight discrimination and their engagement in four high-risk behaviors: current cigarette smoking, driving while intoxicated, risky sexual/drug use behaviors, and seat belt use. Logistic regression was used to test the association between weight discrimination and each behavior, controlling for relevant demographics and BMI. RESULTS: Perceived weight discrimination was associated with increased risk of cigarette smoking (odds ratio [OR] = 1.64, 95% confidence interval [CI] = 1.36-1.99), driving while intoxicated (OR = 2.01, 95% CI = 1.60-2.54), risky sexual/drug use behaviors (OR = 2.17, 95% CI = 1.69-2.80), and not using a seat belt (OR = 1.53, 95% CI = 1.15 2.03). With the exception of seat belt use, all associations remained significant controlling for depressive symptoms. CONCLUSIONS: The results of this research indicate that the harmful associations between weight discrimination and health risk behaviors are not limited to behaviors related to eating and physical activity but extend to high-risk behaviors that may contribute to the association between weight discrimination and poor health. PMID- 28653503 TI - Estimation of WIC effects in multilevel, cross-sector obesity prevention interventions. PMID- 28653502 TI - Student obesity prevalence and behavioral outcomes for the massachusetts childhood obesity research demonstration project. AB - OBJECTIVE: To examine changes in prevalence of obesity and target health behaviors (fruit, vegetable, and beverage consumption; physical activity; screen time; sleep duration) among students from communities that participated in the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project compared to controls. METHODS: MA-CORD was implemented in two low-income communities. School-level prevalence of obesity among students in first, fourth, and seventh grades was calculated for the intervention communities and nine matched control communities pre and post intervention. Fourth- and seventh-grade students' self reported health behaviors were measured in intervention communities at baseline and post intervention. RESULTS: Among seventh-graders (the student group with greatest intervention exposure), a statistically significant decrease in prevalence of obesity from baseline to post intervention in Community 2 (-2.68%, P = 0.049) and a similar but nonsignificant decrease in Community 1 (-2.24%, P = 0.099) was observed. Fourth- and seventh-grade students in both communities were more likely to meet behavioral targets post intervention for sugar-sweetened beverages (both communities: P < 0.0001) and water (Community 1: P < 0.01; Community 2: P = 0.04) and in Community 2 for screen time (P < 0.01). CONCLUSIONS: This multisector intervention was associated with a modest reduction in obesity prevalence among seventh-graders in one community compared to controls, along with improvements in behavioral targets. PMID- 28653504 TI - Clinical effectiveness of the massachusetts childhood obesity research demonstration initiative among low-income children. AB - OBJECTIVE: To examine the extent to which a clinical intervention resulted in reduced BMI z scores among 2- to 12-year-old children compared to routine practice (treatment as usual [TAU]). METHODS: The Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project is a multifaceted initiative to prevent childhood obesity among low-income children. At the federally qualified community health centers (FQHCs) of two communities (Intervention Site #1 and #2), the following were implemented: (1) pediatric weight management training, (2) electronic decision supports for clinicians, (3) on-site Healthy Weight Clinics, (4) community health worker integration, and (5) healthful clinical environment changes. One FQHC in a demographically matched community served as the TAU site. Using electronic health records, we assessed BMI z scores and used linear mixed models to examine BMI z score change over 2 years in each intervention site compared to a TAU site. RESULTS: Compared to children in the TAU site (n = 2,286), children in Intervention Site #2 (n = 1,368) had a significant decline in BMI z scores following the start of the intervention (-0.16 units/y; 95% confidence interval: -0.21 to -0.12). No evidence of an effect was found in Intervention Site #1 (n = 111). CONCLUSIONS: The MA-CORD clinical interventions were associated with modest improvement in BMI z scores in one of two intervention communities compared to a TAU community. PMID- 28653506 TI - Effect of different home-cooking methods on textural and nutritional properties of sweet potato genotypes grown in temperate climate conditions. AB - BACKGROUND: The European Union (EU) market for sweet potato is small but is growing considerably and and has increased by 100% over the last 5 years. The cultivation of sweet potato in temperate climate conditions has not considered extensively and could be a new opportunity for the EU market. Healthy and qualitative traits of different sweet potato cultivars grown in temperate climate conditions were evaluated in accordance with four cooking methods. RESULTS: Traditional cultivars showed high hardness and adhesiveness values. The highest concentrations of sugars (especially maltose) and phenolic acids (caffeic and chlorogenic) were found in samples treated by boiling and steaming. High antioxidant activity was found in fried potatoes. Qualitative traits of sweet potatoes treated by microwaves did not report any significant variation compared to the control. CONCLUSION: Traditional and new sweet potato cultivars can be cultivated in temperate climate conditions and show interesting qualitative properties, especially as a result of the presence of antioxidant compounds. Concerning global quality, colored varieties expressed a better profile than traditional Italian ones and they are suitable for the European market, giving new opportunities for consumers and producers. (c) 2017 Society of Chemical Industry. PMID- 28653505 TI - Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage-specific gene Gprc5a. AB - Despite the urgency for prevention and treatment of lung adenocarcinoma (LUAD), we still do not know drivers in pathogenesis of the disease. Earlier work revealed that mice with knockout of the G-protein coupled receptor Gprc5a develop late onset lung tumors including LUADs. Here, we sought to further probe the impact of Gprc5a expression on LUAD pathogenesis. We first surveyed GPRC5A expression in human tissues and found that GPRC5A was markedly elevated in human normal lung relative to other normal tissues and was consistently downregulated in LUADs. In sharp contrast to wild-type littermates, Gprc5a-/- mice treated chronically with the nicotine-specific carcinogen NNK developed LUADs by 6 months following NNK exposure. Immunofluorescence analysis revealed that the LUADs exhibited abundant expression of surfactant protein C and lacked the clara cell marker Ccsp, suggesting that these LUADs originated from alveolar type II cells. Next, we sought to survey genome-wide alterations in the pathogenesis of Gprc5a-/ LUADs. Using whole exome sequencing, we found that carcinogen-induced LUADs exhibited markedly higher somatic mutation burdens relative to spontaneous tumors. All LUADs were found to harbor somatic mutations in the Kras oncogene (p. G12D or p. Q61R). In contrast to spontaneous lesions, carcinogen-induced Gprc5a-/ LUADs exhibited mutations (variants and copy number gains) in additional drivers (Atm, Kmt2d, Nf1, Trp53, Met, Ezh2). Our study underscores genomic alterations that represent early events in the development of Kras mutant LUAD following Gprc5a loss and tobacco carcinogen exposure and that may constitute targets for prevention and early treatment of this disease. PMID- 28653507 TI - T1 nuclear magnetic relaxation dispersion of hyperpolarized sodium and cesium hydrogencarbonate-13 C. AB - In vivo pH mapping in tissue using hyperpolarized hydrogencarbonate-13 C has been proposed as a method to study tumor growth and treatment and other pathological conditions related to pH changes. The finite spin-lattice relaxation times (T1 ) of hyperpolarized media are a significant limiting factor for in vivo imaging. Relaxation times can be measured at standard magnetic fields (1.5 T, 3.0 T etc.), but no such data are available at low fields, where T1 values can be significantly shorter. This information is required to determine the potential loss of polarization as the agent is dispensed and transported from the polarizer to the MRI scanner. The purpose of this study is to measure T1 dispersion from low to clinical magnetic fields (0.4 mT to 3.0 T) of different hyperpolarized hydrogencarbonate formulations previously proposed in the literature for in vivo pH measurements. 13 C-enriched cesium and sodium hydrogencarbonate preparations were hyperpolarized using dynamic nuclear polarization, and the T1 values of different samples were measured at different magnetic field strengths using a fast field-cycling relaxometer and a 3.0 T clinical MRI system. The effects of deuterium oxide as a dissolution medium for sodium hydrogencarbonate were also analyzed. This study finds that the cesium formulation has slightly shorter T1 values compared with the sodium preparation. However, the higher solubility of cesium hydrogencarbonate-13 C means it can be polarized at greater concentration, using less trityl radical than sodium hydrogencarbonate-13 C. This study also establishes that the preparation and handling of sodium hydrogencarbonate formulations in relation to cesium hydrogencarbonate is more difficult, due to the higher viscosity and lower achievable concentrations, and that deuterium oxide significantly increases the T1 of sodium hydrogencarbonate solutions. Finally, this work also investigates the influence of pH on the spin-lattice relaxation of cesium hydrogencarbonate-13 C measured over a pH range of 7 to 9 at 0.47 T. PMID- 28653508 TI - Evaluation of the use of a sensory room on an adolescent inpatient unit and its impact on restraint and seclusion prevention. AB - TOPIC: Restraint and seclusion (R/S) reduction initiatives require multimodal efforts, particularly proactive approaches to facilitate patients' regulation. Sensory approaches are an increasingly popular method for helping patients self regulate. A plan-do-check-act quality improvement model was used to measure practical aspects of a newly implemented sensory room on an adolescent psychiatric inpatient unit. PURPOSE: This article describes an adolescent unit's implementation processes and methods used to evaluate a sensory room and its impact on R/S use, staff-patient relationships, and patients' aggressive behaviors. SOURCES USED: Selected multidisciplinary literature on sensory rooms and R/S reduction, adolescent unit staff/patient surveys, and institutional quality metrics. CONCLUSIONS: The use of a sensory room intervention substantially decreased patients' distress and reduced R/S use and aggressive behaviors. Improvements were also found in patient and staff members' sense of safety. No differences in the quality of staff-patient relationships were found based on sensory room use. An increase in the durations of R/S did occur and was attributed to a few patients who were "high users" of R/S. Considerations for continuous program improvement and research are discussed. PMID- 28653509 TI - Management of pancreaticojejunal strictures after pancreaticoduodenectomy: clinical experience and review of literature. AB - BACKGROUND: Symptomatic pancreaticojejunal anastomotic stricture (PJS) is a rare complication following pancreaticoduodenectomy. The incidence, presentation and management of this condition are infrequently reported in the literature. Revision surgery is thought to be an effective treatment. Recent literature shows some success from endoscopic management. METHODS: The patients treated for symptomatic PJS from January 2005 to June 2014 were identified. Their clinical presentation and management was retrospectively reviewed. Patients were followed up in clinic or by telephonic interviews to assess their symptoms. RESULTS: Three patients (two females and one male) had symptomatic PJS out of 314 who underwent pancreaticoduodenectomy (0.9%). Main presentating symptom was intermittent abdominal pain. The diagnosis was confirmed by computed tomography scan and/or magnetic resonance cholangiopancreatography. One patient underwent a failed endoscopic retrograde cholangiopancreatography attempt to dilate the stricture. A redo-pancreaticojejunostomy was performed in all patients. At a mean follow-up of 8 months, two patients had complete resolution of symptoms and one patient had partial benefit. Five out of seven case series in literature support surgical management. CONCLUSION: Symptomatic PJS can be successfully treated with redo pancreaticojejunostomy, with good medium-term outcomes. Although endoscopic intervention has been described, review of the literature shows that success rates are low and the long-term results are unknown. PMID- 28653510 TI - ? PMID- 28653511 TI - ? PMID- 28653512 TI - ? PMID- 28653514 TI - [At the intersection of neurology and psychiatry : the impact of the differential diagnosis]. AB - Psychotic symptoms in the context of a neurological pathology, like a multiple sclerosis have been described for the first time by Cottrell and Wilson in 1926. The differential diagnosis between organic disease and psychiatric illness, when confronted to the onset of psychotic symptoms is essential. The somatic examination is essential to guide the best clinical care. The implications of a delay in diagnosis are both medical, psychological but also prognostic. This article will discuss the situation of a young 16 years old patient, cannabis user, with atypical psychotic symptoms for several months, for which the diagnosis ofmultiple sclerosis was finally established, after an hospitalization in a child and juvenile psychiatry unit. PMID- 28653513 TI - [Barriers related to the use of self-catheterization : preliminary survey of perception and implications]. AB - INTRODUCTION: the use of clean intermittent catheterization (CIC) has been widely advocated after spinal cord injury. Nevertheless, implementing this technique remains problematic in practice; reasons for this reluctance range from lack of experience to availability of material. MATERIAL AND METHODS: 1. To identify a list of barriers related to the use of intermittent catheterization ; 2. To identify specific assessment tools in relation with these barriers ; 3. To conduct a survey on four groups of people: patients - nurses in neurology, neurosurgery and intensive care - nurses in rehabilitation, - nurses in home care. Each group has to select from this list and rank the ten most important barriers ; 4. To compare the barriers those that have been highlighted by each of these groups. RESULTS: overall, the main preoccupation of the patient is mostly related to the material, while a large proportion of care-givers consider that the most prevalent barrier for the implementation of the CIC lies in the patient himself. An analysis was also carried out to highlight trends within groups (i) (iv) of care-givers. CONCLUSION: the perception of burden is different for patients and care-givers, depending on the service within which they operate. A careful analysis will enable us to adapt the therapeutic education of the patients and to tailor the information transmitted to care-givers. Such continuous process of care will emphasise the concept of 'pelvic perineal health- care pathway'. PMID- 28653515 TI - [Post-traumatic diaphragmatic herniation : case report and literature review]. AB - Post-traumatic diaphragmatic herniation is not common, but its diagnosis can be easily missed in the early management. Late diagnosis is shown to increase morbidity and mortality of those patients. It is thus extremely important to keep that possibility in mind while examining post- traumatic patients, and interpreting CT scan images. This article will first describe a case report of a young man presenting an intrathoracic herniation of the stomach, before proceeding to a literature review to describe and recognize this particular entity. PMID- 28653516 TI - [Refractory Sweet syndrome complicated by monoclonal gammopathy of undetermined significance]. AB - The association between Sweet syndrome and monoclonal gammopathy of undetermined significance (MGUS) is exceptional. We report the case of a 44 years-old woman in whom recurrent Sweet syndrome was complicated by monoclonal gammopathy of undetermined significance (MGUS) after 3 years of evolution. PMID- 28653517 TI - [Cervical pain radiating to the upper limb]. AB - A 31 years old male, HIV negative, with past history of sarcoidosis with articular and pulmonary involvement, without immuno-suppressive therapy, presents two years later with cervical pain radiating to the upper limb. Cervical imaging shows several para vertebral collections and lytic bone lesions. A diagnosis of tuberculous osteo-arthritis is established based on imaging and mycobacterial data. PMID- 28653518 TI - [Infants poisoned with cannabis]. AB - We reported three cases of infants poisoned with cannabis. These patients presented with acute neurological disorders such as drowsiness accompanied by hypotonia, mydriasis and seizure. Cannabis was found in all children either in the urine or in the blood. These cases illustrated that young age should not exclude toxicologic analysis in acute neurological disorders. Cannabis poisoning in infants is a rare reason for consultation. Clinical signs and symptoms are unspecific and severe manifesta- tions in pediatric age are not well known by emergency physicians and paediatricians. PMID- 28653519 TI - [Dyspnea and cardia cancer, an unusual etiology]. AB - CASE REPORT: a 63-year old man, followed for a metastatic cardia cancer, develop a pericardial effusion with sign of pre-tamponade. A CT scanner suggests the presence of a gastro- esophageal-pericardial fistula. A surgical drainage brings a purulent fluid, infected by a polymicrobial flora. Despite early antibiotics with vancomycin and piperacillin-tazobactam, the patient dies five days after the drainage. DISCUSSION: purulent pericarditis associated with gastrointestinal neoplasia may be due to sepsis or a proximity invasion . The diagnosis is based on ultrasound and pericardiocentesis. The most commonly involved organism is Streptococcus pneumoniae. The treatment involves intravenous antibiotics, pericardial drainage and intrapericardial instillation of antibiotics. The mortality rate remains high, especially in cases associated with gastrointestinal neoplasia. PMID- 28653520 TI - [Pseudotumor cerebri due to taking minocycline]. AB - The cerebral pseudotumor (PTC) is defined by the increase in cerebrospinal fluid (CSF) pressure, a normal composition of the latter in the absence of identified intracranial structural abnormalities, in particular by neuroimaging. The pathophysiology of PTC is poorly understood although its diagnostic criteria are well established. Drugs such as minocycline, tetracycline and doxycycline have been repeatedly implicated as a causative factor in PTC. The prognosis of PTC related to minocycline, reported in the literature is quite variable. Some authors suggest a benign condition with spontaneous healing by stopping the antibiotic, while others report permanent loss of vision. A 12-year-old girl is admitted to the emergency room for progressively progressive pulsatile temporal headaches associated with diplopia. The patient reported the use of minocycline 50 mg / d for five months, prescribed by her attending physician as part of an acne treatment. PTC will be demonstrated by severe papillary edema and cerebral NMR will demonstrate an enlargement of the subarachnoid space around the optic nerves. After three lumbar punctures, the condition of the patient stabilized and there was a marked improvement in headache despite the persistence of bilateral papillary edema. This work describes a clinical case of PTC induced by the use of minocycline and reviews the physiopathology, the diagnosis and the management of this one. PMID- 28653521 TI - [Egg-shaped macro-lithiasis]. AB - We report a 76 years-old female patient who consults for left flank pain and inflammatory biology, due to the presence of an egg-shaped 5 cm diameter macro lithiasis. Because of the presence of a Proteus bacteriuria, the patient receives a 7 days levofloxacin treatment, before a laparoscopic resection of the kidney stone is performed. The analysis reveals a struvite lithiasis with a disorganized radial-section nuclear structure (type IVc). PMID- 28653522 TI - [Immunotherapy and non-small cell lung cancer : a (r)evolution]. AB - Immunotherapy renews in non-small cell lung cancer. Antibodies directed against PD1 and PD-L1, blocking the relationship between the cancer cells and the immune system, allowed in randomised trials to significantly improve cancer control with an interesting survival impact of treated patients. However, it remains to determine the most benefiting populations from this expensive and potentially toxic therapy. PMID- 28653523 TI - ? PMID- 28653525 TI - ? PMID- 28653524 TI - [Total hip arthroplasty : history and perspective of an iconic surgerical intervention]. AB - With nearly 2 million implants placed annually, total hip arthroplasty is one of the most frequently performed surgerical procedure. A historical review of this intervention reminds us of the times when surgery was done by barber, before the first attempts of interposition arthroplasty. It is only in 1970 that Sir John Charnley lay the foundations of modern arthroplasty. The pharmaceutical industry, by sharing this lucrative market of $ 5 billion annual revenue, is now playing a major role in the development of the next generation of implants. PMID- 28653526 TI - Elucidating the Origin of Hydrogen Evolution Reaction Activity in Mono- and Bimetallic Metal- and Nitrogen-Doped Carbon Catalysts (Me-N-C). AB - In this work, we present a comprehensive study on the role of metal species in MOF-based Me-N-C (mono- and bimetallic) catalysts for the hydrogen evolution reaction (HER). The catalysts are investigated with respect to HER activity and stability in alkaline electrolyte. On the basis of the structural analysis by X ray diffraction, X-ray-induced photoelectron spectroscopy, and transmission electron microscopy, it is concluded that MeN4 sites seem to dominate the HER activity of these catalysts. There is a strong relation between the amount of MeN4 sites that are formed and the energy of formation related to these sites integrated at the edge of a graphene layer, as obtained from density functional theory (DFT) calculations. Our results show, for the first time, that the combination of two metals (Co and Mo) in a bimetallic (Co,Mo)-N-C catalyst allows hydrogen production with a significantly improved overpotential in comparison to its monometallic counterparts and other Me-N-C catalysts. By the combination of experimental results with DFT calculations, we show that the origin of the enhanced performance of our (Co,Mo)-N-C catalyst seems to be provided by an improved hydrogen binding energy on one MeN4 site because of the presence of a second MeN4 site in its close vicinity, as investigated in detail for our most active (Co,Mo)-N-C catalyst. The outstanding stability and good activity make especially the bimetallic Me-N-C catalysts interesting candidates for solar fuel applications. PMID- 28653527 TI - Insights into the Silver Reflection Layer of a Vertical LED for Light Emission Optimization. AB - In this work, Ag as a highly reflective mirror layer of gallium nitride (GaN) based blue vertical light-emitting diodes (VLEDs) has been systematically investigated by correlating scanning electron microscopy/energy dispersive X-ray spectroscopy/transmission Kikuchi diffraction/electron backscatter diffraction, aberration-corrected scanning transmission electron microscopy, and atomic force microscopy techniques. In the context of high-efficiency lighting, three critical aspects have been scrutinized on the nanoscale: (1) chemical diffusion, (2) grain morphology, and (3) surface topography of the Ag layer. We found that nanoscale inhomogeneous distribution of In in InGaN/GaN quantum wells (QWs), interfacial diffusion (In/Ga out-diffusion into the Ag layer and diffusion of Ag into p-GaN and QWs), and Ag agglomeration deteriorate the light reflectivity, which account for the decreased luminous efficiency in VLEDs. Meanwhile, the surface morphology and topographical analyses revealed the nanomorphology of the Ag layer, where a nanograin size of ~300 nm with special nanotwinned boundaries and an extremely smooth surface of ~3-4 nm are strongly desired for better reflectivity. Further, on the basis of these microscopy results, suggestions on light extraction optimization are given to improve the performance of GaN-based blue VLEDs. Our findings enable fresh and deep understanding of performance-microstructure correlation of LEDs on the nanoscale, providing guidance to the design and manufacture of high-performance LED devices. PMID- 28653528 TI - Vanadium-Catalyzed Oxidative C(CO)-C(CO) Bond Cleavage for C-N Bond Formation: One-Pot Domino Transformation of 1,2-Diketones and Amidines into Imides and Amides. AB - A novel vanadium-catalyzed one-pot domino reaction of 1,2-diketones with amidines has been identified that enables their transformation into imides and amides. The reaction proceeds by dual acylation of amidines via oxidative C(CO)-C(CO) bond cleavage of 1,2-diketones to afford N,N'-diaroyl-N-arylbenzamidine intermediates. In the reaction, these intermediates are easily hydrolyzed into imides and amides through vanadium catalysis. This method provides a practical, simple, and mild synthetic approach to access a variety of imides as well as amides in high yields. Moreover, one-step construction of imide and amide bonds with a long chain alkyl group is an attractive feature of this protocol. PMID- 28653529 TI - Difluorination of Furonaphthoquinones. AB - An unprecedented difluorination reaction was developed based on the furonaphthoquinone skeleton of natural products tanshinones and their analogues. By using Selectfluor as the fluorinating source and H2O as the hydroxyl source, a wide range of unique polycyclic alpha,alpha-difluoro beta,beta-dihydroxyl para quinone products were achieved with yields up to 90%. The mechanistic studies revealed that the reaction might undergo tandem multiple electrophilic and nucleophilic substitutions, as well as cleavages of C-O and C-C bonds. This approach not only provides a new method to synthesis of alpha,alpha-difluoro ketones, but also affords a series of unique chemotypes for biological activity screening. PMID- 28653531 TI - Wireless Bipolar Nanopore Electrode for Single Small Molecule Detection. AB - Solid-state nanopore-based techniques have become a promising strategy for diverse single molecule detections. Owing to the challenge in well and rapid fabrication of solid-state nanopores with the diameter less than 2 nm, small molecule detection is hard to be addressed by existing label-free nanopore methods. In this work, we for the first time propose a metal-coated wireless nanopore electrode (WNE) which offers a novel and generally accessible detection method for analyzing small molecules and ions at the single molecule/ion level. Here, a silver-coated WNE is developed as a proof-of-principle model which achieves the detection the self-generated H2, the smallest known molecule, and Ag+ at single molecule/ion level by monitoring the enhanced ionic signatures. Under a bias potential of -800 mV, the WNE could accomplish the distinction of as low as 14 H2 molecules and 28 Ag+ from one spike signal. The finite element simulation is introduced to suggest that the generation of H2 at the orifice of the WNE results in the enhanced spike of ionic current. As a proof-of-concept experiment, the WNE is further utilized to directly detect Hg2+ from 100 pM to 100 nM by monitoring the frequency of the spike signals. This novel nanoelectrode provides a brand new label-free, ultrasensitive, and simple detection mechanism for various small molecules/ions detection, especially for redox analytes. PMID- 28653532 TI - Enhanced Electrocatalytic Activity of Pt/3D Hierarchical Bimodal Macroporous Carbon Nanospheres. AB - Proton exchange membrane fuel cells require electrocatalysts with a high platinum (Pt) loading, large active surface area, and favorable hydrodynamic profile for practical applications. Here, we report the design of three-dimensional hierarchical bimodal macroporous carbon nanospheres with an interconnected pore system, which are applied as an electrocatalyst support. Carbon-supported Pt (Pt/C) catalysts were prepared by aerosol spray pyrolysis followed by microwave chemical deposition. The hierarchical porous structures not only increased the dispersion of Pt nanoparticles but also improved catalytic performance. A hierarchical bimodal macroporous Pt/C catalyst with a mixture of 30 and 120 nm size pores showed the best performance. The electrochemical surface area and mass activity values of this support were 96 m2 g-1-Pt and 378 mA mg-1-Pt, respectively at a Pt loading of 15 wt %. PMID- 28653533 TI - Novel Perovskite Solar Cell Architecture Featuring Efficient Light Capture and Ultrafast Carrier Extraction. AB - A new perovskite solar cell (PSC) structure with a functionalized interface between perovskite and a hole transport material has been proposed in this report. The short circuit current density of PSC was notably enhanced with the novel architecture (with an increase of 8.7%), and a power conversion efficiency (PCE) of 16.93% was achieved. With the increased perovskite/hole conductor interface, hysteresis suppression was observed. The advantages of this structure in light-harvesting efficiency, trap density, and carrier separation rate were proved by various characterization and analysis studies. It is noteworthy that a PCE of 14.67% was achieved with poly(3-hexyl-thiophene), which to our knowledge is the highest performing PSC based on this material. PMID- 28653534 TI - Oxygen-Induced Bi5+-Self-Doped Bi4V2O11 with a p-n Homojunction Toward Promoting the Photocatalytic Performance. AB - Bi5+-self-doped Bi4V2O11 (Bi5+-BVO) nanotubes with p-n homojunctions are fabricated via an oxygen-induced strategy. Calcinating the as-spun fibers with abundant oxygen plays a pivotal role in achieving Bi5+ self-doping. Density functional theory calculations and experimental results indicate that Bi5+ self doping can narrow the band gap of Bi4V2O11, which contributes to enhancing light harvesting. Moreover, Bi5+ self-doping endows Bi4V2O11 with n- and p-type semiconductor characteristics simultaneously, resulting in the construction of p n homojunctions for retarding rapid electron-hole recombination. Benefiting from these favorable properties, Bi5+-BVO exhibits a superior photocatalytic performance in contrast to that of pristine Bi4V2O11. Furthermore, this is the first report describing the achievement of p-n homojunctions through self-doping, which gives full play to the advantages of self-doping. PMID- 28653535 TI - Digestibility of Glyoxal-Glycated beta-Casein and beta-Lactoglobulin and Distribution of Peptide-Bound Advanced Glycation End Products in Gastrointestinal Digests. AB - This work reports the influence of glyoxal (GO)-derived glycation on the gastrointestinal enzymatic hydrolysis of beta-lactoglobulin and beta-casein. Reduced digestibility of glycated proteins was found in both gastric and intestinal stage. Distribution of Maillard reaction products in digests with different molecular weight ranges was investigated subsequently. The colorless and brown MRPs largely presented in the digests smaller than 20 kDa. However, the resistance of fluorescent advanced glycation end products (AGEs) to enzymatic hydrolysis gradually increased during glycation, rendering fluorescent AGEs largely present in the digests larger than 20 kDa. No free N (epsilon) carboxymethyllysine (CML) was detected in digests. The relative amount of CML in digests larger than 1 kDa was higher than that of Lys, demonstrating the hindrance of CML to enzymatic hydrolysis. This study highlights the resistance of GO-derived AGEs to digestive proteases via blockage of tryptic cleavage sites or steric hindrance, which is a barrier to the absorption of dietary AGEs. PMID- 28653536 TI - Correction to Spin-Free CC2 Implementation of Induced Transitions between Singlet Ground and Triplet Excited States. PMID- 28653537 TI - Selectivity of C-H Activation and Competition between C-H and C-F Bond Activation at Fluorocarbons. AB - Partially fluorinated alkanes, arenes, and alkenes can be transformed by a variety of transition metal and lanthanide systems. Although the C-H bond is weaker than the C-F bond regardless of the hybridization of the carbon, the reaction of the C-F bond at the metal is usually more exothermic than the corresponding reaction of the C-H bonds. Both bonds are activated by the metal systems, but the preference for activating these bonds depends on the nature of the hydrocarbon and of the metal system, so that the reaction can be directed exclusively toward C-H or C-F bonds or yield a mixture of products. Additionally, the presence of fluorine differentiates between C-H bonds at different positions resulting in regioselective C-H bond activation; paradoxically, the strongest C-H bond reacts preferentially. The purpose of this review is to describe the field of reactions of partially fluorinated substrates with transition metal atoms, ions, and molecular complexes. The controlling physical properties (thermodynamics and kinetics) are described first, followed by a description of stoichiometric reactions, with the competition between the C-H and C-F activations as focus. A few representative catalytic systems are discussed. The review also highlights the benefit of combining experimental and theoretical studies. PMID- 28653538 TI - Cationic Polypeptoids with Optimized Molecular Characteristics toward Efficient Nonviral Gene Delivery. AB - The rational design of gene vectors relies on the understanding of their structure-property relationship. Polypeptoids, which are structural isomers of natural polypeptides, hold great potential as gene delivery vectors due to their facile preparation, structural tunability, and most importantly, their desirable proteolytic stability. We herein designed a library of polypeptoids with different cationic side-chain terminal groups, degree of polymerizations (DPs), side-chain lengths, and incorporated aliphatic side chains, to unravel the structure-property relationships so that gene delivery efficiency can be maximized and cytotoxicity can be minimized. In HeLa cells, a polypeptoid bearing a primary amine side-chain terminal group exhibited remarkably higher transfection efficiency than that of its analogues containing secondary, tertiary, or quaternary amine groups. Elongation of the polypeptoid backbone length (from 28 to 251 mer) led to enhanced DNA condensation as well as cellular uptake levels, however it also caused higher cytotoxicity. Upon a proper balance between DNA uptake and cytotoxicity, the polypeptoid with a DP of 46 afforded the highest transfection efficiency. Elongating the aliphatic spacer between the backbone and side amine groups enhanced the hydrophobicity of the side chains, which resulted in notably increased membrane activities and transfection efficiency. Further incorporation of hydrophobic decyl side chains led to an improvement in transfection efficiency of ~6 fold. The top-performing material identified, P11, mediated successful gene transfection under serum-containing conditions, outperforming the commercial transfection reagent poly(ethylenimine) by nearly 4 orders of magnitude. Reflecting its excellent serum-resistant properties, P11 further enabled effective transfection in vivo following intratumoral injection to melanoma-bearing mice. This study will help the rational design of polypeptoid-based gene delivery materials, and the best performing material identified may provide a potential supplement to existing gene vectors. PMID- 28653539 TI - Copper-Catalyzed Borylative Cyclization of in Situ Generated o-Allenylaryl Nitriles with Bis(pinacolato)diboron. AB - A Cu-catalyzed cascade borylcupration/cyclization of in situ generated allene nitriles with B2pin2 has been developed, which provides highly substituted 3 boryl-1-naphthylamines with excellent regioselectivity and wide functional group compatibility. It has been shown that, for the first time, the catalytically generated allylcopper species can be captured by a cyano group from a normal nitrile to furnish a carbocycle. PMID- 28653540 TI - Iron-Catalyzed ortho-Selective C-H Borylation of 2-Phenylpyridines and Their Analogs. AB - Treatment of 2-phenylpyridines (or their analogs) with a 9-bicycloboranonane dimer (9-BBN dimer) in the presence of a catalytic amount of a commercially available iron salt, FeBr3, gave ortho-borylated products in moderate to excellent yields with good functional group tolerance. The reaction proceeded in good yield, even in gram-scale, and also occurred at the C-H bond of heteroaromatic compounds. The cost of the C-H borylation is dramatically lower than that of a previously reported similar palladium-catalyzed reaction. The products exhibit an intramolecular B-N Lewis acid-base interaction and fluoresce in both solution and solid states due to their electron push-pull structures. PMID- 28653541 TI - Eliminative Deoxofluorination Using XtalFluor-E: A One-Step Synthesis of Monofluoroalkenes from Cyclohexanone Derivatives. AB - The eliminative deoxofluorination of cyclohexanone derivatives using XtalFluor-E is described. The corresponding monofluoroalkenes are obtained in up to 79% yield. Notably, this one-step procedure occurs at room temperature using readily accessible and cost-effective reagents. PMID- 28653542 TI - A General Strategy for the Construction of Functionalized Azaindolines via Domino Palladium-Catalyzed Heck Cyclization/Suzuki Coupling. AB - The preparation of substituted azaindolines utilizing a domino palladium catalyzed Heck cyclization/Suzuki coupling is described. The approach is amenable for the construction of all four azaindoline isomers. A range of functional groups such as esters, amides, ketones, sulfones, amines, and nitriles are all tolerated under the reaction conditions. PMID- 28653543 TI - Current-Induced Magnetic Polarons in a Colloidal Quantum-Dot Device. AB - Electrical spin manipulation remains a central challenge for the realization of diverse spin-based information processing technologies. Motivated by the demonstration of confinement-enhanced sp-d exchange interactions in colloidal diluted magnetic semiconductor (DMS) quantum dots (QDs), such materials are considered promising candidates for future spintronic or spin-photonic applications. Despite intense research into DMS QDs, electrical control of their magnetic and magneto-optical properties remains a daunting goal. Here, we report the first demonstration of electrically induced magnetic polaron formation in any DMS, achieved by embedding Mn2+-doped CdSe/CdS core/shell QDs as the active layer in an electrical light-emitting device. Tracing the electroluminescence from cryogenic to room temperatures reveals an anomalous energy shift that reflects current-induced magnetization of the Mn2+ spin sublattice, that is, excitonic magnetic polaron formation. These electrically induced magnetic polarons exhibit an energy gain comparable to their optically excited counterparts, demonstrating that magnetic polaron formation is achievable by current injection in a solid state device. PMID- 28653544 TI - Operative Management of Unstable Radial Head Fractures in a Young Active Population. AB - BACKGROUND: Radial head and neck fractures are the most common elbow fracture in the general adult population; however, the optimal treatment for radial head fractures remains a topic of ongoing clinical controversy. The purpose of this study was to determine the rate of return to function, complications, and reoperation following operative management of unstable radial head fractures in a young, active patient population with intense upper extremity demands. METHODS: A military health care database was queried for all US military servicemembers undergoing open reduction with internal fixation (ORIF; Current Procedural Terminology [CPT] code: 24665) and radial head arthroplasty (RHA; CPT code: 24666) between 2010 and 2015. All patients with minimum 2-year follow-up were included. Univariate and chi-square analyses were performed to evaluate the association between potential risk factors and the primary outcome measures. RESULTS: A total of 67 ORIF (n = 69 elbows) and 10 RHA patients were included. The average age was 31 +/- 8.0 years. At mean follow-up of 3.5 +/- 1.1 years, 90% of patients overall were able to return to active military service, 96% of which with unrestricted upper extremity function. Nearly one-third (31.2%) of patients developed at least 1 postoperative complication. RHA has higher overall complication rates (70% vs 48%) when compared with ORIF, but this finding did not reach statistical significance ( P = .073). However, RHA had significantly higher rates of implant failure (20% vs 2.9%, P = .0498). Seventeen (21%) individuals required reoperation, 5 of which (6.3%) were revision procedures. Dislocation, coronoid fracture, and concomitant ligamentous repair portended a significantly increased risk of sustaining 1 or more complications ( P < .05), while dislocation and requirement for ligamentous repair independently predicted revision surgery ( P < .05). CONCLUSIONS: Arthroplasty and ORIF are both viable options for treating unstable radial head fractures in a young, athletic population, offering comparable return to function despite increased complications with RHA. PMID- 28653545 TI - Family inclusion in mental health services: Reality or rhetoric? AB - BACKGROUND: Contemporary mental health policies require family inclusion in the design, implementation and evaluation of services. MATERIALS: This scoping review considers the factors in mental health practice which either mediate or promote family inclusion. A wide range of factors are reported to obstruct family inclusion, while a smaller number of studies report that meaningful family inclusion rests on a partnership approach which values the input of families and services users. DISCUSSION: When it comes to family inclusion, there is a gap between policy and service delivery practice. Changes in service delivery attitudes, values and culture are necessary to meaningfully and systematically include families and service users. PMID- 28653546 TI - Cruciate Retaining compared with Posterior Stabilised Nexgen total knee arthroplasty: results at 10 years in a matched cohort. AB - INTRODUCTION Debate has persisted for many years about whether to sacrifice or replace the posterior cruciate ligament when performing total knee arthroplasty. A paucity of long-term follow-up studies comparing outcomes between cruciate retaining and posterior-stabilised knees exist. We aimed to compare results at ten-year follow-up. METHODS A matched paired study comparing a cohort of 107 Zimmer Nexgen(r) Cruciate Retaining (CR) patients with a cohort of 107 Nexgen Posterior-Stabilised (PS) knees matched for age, sex, body mass index and preoperative American Knee Society score was undertaken. All patients underwent independent clinical assessment and knee society scoring preoperatively and at 1, 3, 5, 7 and 10 years postoperatively. RESULTS Fifty-three patients (49.5%) in the CR group and 44 patients (41.1%) in the PS group were alive at 10-year follow-up. There were no significant differences between the CR and PS groups with regards to functional assessment (P = 0.95), overall range of movement (P = 0.46) or patient satisfaction (P = 1.0) at 10 years. However, there was a significantly better score improvement in range of movement in PS knees compared with CR knees (P = 0.027). There were six revisions (5.6%) in the PS group and 1 (0.93%) in the CR group (P = 0.12). Both CR and PS knees showed excellent survivorship with no significant difference at 10 years (P = 0.068). CONCLUSIONS There were no significant differences in functional score, overall range of motion or patient satisfaction between the Nexgen cruciate retaining and posterior stabilised total knee arthroplasty at 10-year follow-up. However, PS knees had a greater score improvement in range of motion compared with CR knees. PMID- 28653547 TI - Assessment of mood in aphasia following stroke: validation of the Dynamic Visual Analogue Mood Scales (D-VAMS). AB - OBJECTIVES: To validate a non-verbal self-report measure of mood - the Dynamic Visual Analogue Mood Scales (D-VAMS) - against the Hospital Anxiety and Depression Scale (HADS) and assess its suitability as an outcome measure or screening measure for depressed mood following stroke. DESIGN: Cross-sectional observational cohort study. PARTICIPANTS: Forty-six stroke survivors (24% with aphasia) recruited from online, from stroke clubs and via an NHS rehabilitation service. METHODS: A set of seven bipolar scales was developed enabling users to report mood by modifying facial expression images using a slider. Participants completed a tablet/computer task, reporting their mood on these scales mixed randomly with versions which used only words. The HADS was then completed, followed by a repeat run of the two versions in a different, random sequence. RESULTS: Exploratory factor analysis identified one factor consistent with pleasantness of mood accounting for 80% of the variance. Internal consistency of D-VAMS was high ( alpha = 0.95), and there was a high correlation between face only D-VAMS scores and HADS total scores ( r = -0.80, P < 0.001), as well as HADS D/HADS-A subscale scores ( r = -0.73, P < 0.001; r = -0.71, P < 0.001). D-VAMS showed good sensitivity and specificity against HADS, with means of 85%/77% (sensitivity/specificity) against the HADS-D and 80%/77% against the HADS-A across nine cut-offs. CONCLUSION: D-VAMS is a valid and reliable measure likely suitable for assessment of depressed mood in aphasia following stroke. Though D VAMS performed well as a screening measure in this study sample, further study is needed in the acute stage post-stroke. PMID- 28653548 TI - Co-constructing engagement in stroke rehabilitation: a qualitative study exploring how practitioner engagement can influence patient engagement. AB - OBJECTIVE: To explore how practitioner engagement and disengagement occurred, and how these may influence patient care and engagement. DESIGN: A qualitative study using the Voice Centred Relational Methodology. Data included interviews, focus groups and observations. SETTING: Inpatient and community stroke rehabilitation services. SUBJECTS: Eleven people experiencing communication disability after stroke and 42 rehabilitation practitioners. INTERVENTIONS: Not applicable. RESULTS: The practitioner's engagement was important in patient engagement and service delivery. When patients considered practitioners were engaged, this helped engagement. When they considered practitioners were not engaged, their engagement was negatively affected. Practitioners considered their engagement was important but complex. It influenced how they worked and how they perceived the patient. Disengagement was taboo. It arose when not feeling confident, when not positively impacting outcomes, or when having an emotional response to a patient or interaction. Each party's engagement influenced the other, suggesting it was co-constructed. CONCLUSIONS: Practitioner engagement influenced patient engagement in stroke rehabilitation. Practitioner disengagement was reported by most practitioners but was often a source of shame. PMID- 28653549 TI - Sociodemographic and clinical profiles of homeless mentally ill admitted in mental health institute of South India: 'Know the Unknown' project. AB - OBJECTIVES: A significant number of homeless mentally ill (HMI) patients without any personal, family or other identification details represent a unique problem in the psychiatric services of developing countries like India in the context of legal, humanitarian and treatment issues. These patients pose challenge to the mental health professional in diagnosis and management. AIMS: To study the sociodemographic and clinical profiles of HMI patients admitted under psychiatry. METHODS: We performed a retrospective chart review of 'HMI' patients from 1 January 2002 to 31 December 2015, who were admitted to the Department of Psychiatry at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Sociodemographic and clinical profiles of the patients were analyzed by descriptive statistics. RESULTS: Mean age of the sample was 34.6 years (+/-12.21 years), 42 (53.8%) were females, 74 (94.9%) were registered as Medico Legal Case and 53 (80.8%) were admitted under reception order issued by a magistrate. HMI patients brought by police were 32 (41.0%), by the public were 32 (41.0%) and 14 (18.0%) by nongovernmental organization /ambulance/social worker. In total, 51 (65.4%) of them had schizophrenia and other psychotic disorders, 24 (30.8%) had mental retardation and 23 (29.5%) had a comorbid substance use disorder. The mean Clinical Global Impression severity at admission was 5.07 (+/ 1.7), and the mean duration of inpatient care was 15 weeks. Anemia and malnutrition were found in 34 (43.6%) and 25 (32.1%) patients, respectively. CONCLUSION: This study shows that schizophrenia, comorbid mental retardation and substance use disorder are common causes of admission of HMI patients in psychiatry. It is an emerging problem, which needs urgent interventions, and there is a need for an efficient system, guidelines and collaboration with government and nongovernmental agencies. PMID- 28653550 TI - Group sequential designs for stepped-wedge cluster randomised trials. AB - BACKGROUND/AIMS: The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs. METHODS: Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored. RESULTS: We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial's type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate. CONCLUSION: The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped wedge cluster randomised trials according to the needs of the particular trial. PMID- 28653551 TI - Perception of the Lexical Accent Contrast in One Variety of East Norwegian. AB - The perception of the lexical pitch accents was examined in the Trondersk dialect of Norwegian. Based on a production study, a categorization of stimuli with manipulated pitch contours was conducted. The experiment tested which acoustic cues (height and alignment of fundamental frequency (F0) minimum, and alignment of F0 maximum and turning point from maximum to minimum) are necessary for the perception of the tonal contrast. The results are consistent with the production findings in that changes in all of the examined acoustic cues contributed to the shift in accent categorization. The later alignment of the main F0 landmarks (F0 maximum, F0 minimum and turning point from maximum to minimum) induced accent 2 identification. Raising F0 minimum height also led to more accent 2 responses. The analysis of the perception patterns furthermore revealed that the effect of a later alignment of F0 minimum was weak unless combined with a later alignment of the other F0 landmarks, or a higher F0 minimum level, all of which contributed to more accent 2 responses. These results indicate that accent 1 is characterized by an early fall, and accent 2 by a salient initial high tone. Implications of these findings for the phonological analysis of the tonal contrasts in the Trondersk dialect are also discussed. PMID- 28653552 TI - The agency of patients and carers in medical care and self-care technologies for interacting with doctors. AB - People living with Parkinson's disease engage in self-care for most of the time but, two or three times a year, they meet with doctors to re-evaluate the condition and adjust treatment. Patients and (informal) carers participate actively in these encounters, but their engagement might change as new patient centred technologies are integrated into healthcare infrastructures. Drawing on a qualitative study that used observations and interviews to investigate consultations, and digital ethnography to understand interactions in an online community, we describe how patients and carers living with Parkinson's participate in the diagnosis and treatment decisions, engage in discussions to learn about certain topics, and address inappropriate medication. We contrast their engagement with a review of self-care technologies that support interactions with doctors, to investigate how these artefacts may influence the agency of patients and carers. Finally, we discuss design ideas for improving the participation of patients and carers in technology-mediated scenarios. PMID- 28653553 TI - Surgical Complications from Superior Canal Dehiscence Syndrome Repair: Two Decades of Experience. AB - Objective To determine the incidence of surgical complications associated with superior canal dehiscence syndrome (SCDS) repair and identify the demographic, medical, and intraoperative risk factors that are associated with SCDS complications. Study Design Cases series with chart review, including patients who underwent SCDS repair between 1996 and 2015. Setting A tertiary care academic medical center. Subjects and Methods Data were collected from 220 patients, including demographic information, medical comorbidities, prior otologic surgical history, surgical approach, intraoperative findings, and postoperative complications. Relative risk analysis and multivariable logistic regression evaluated the associations between perioperative risk factors and SCDS complications. Results A total of 242 consecutive cases were performed: 95.5% middle fossa and 4.5% transmastoid approach (mean age: 47.8 +/- 10.6 years; 54.5% female). Surgical complications were reported in 27 (11.2%) cases; 20 (8.3%) had Clavien-Dindo grade I complications, most commonly benign paroxysmal positional vertigo (n = 11, 4.5%) and profound sensorineural hearing loss (n = 6, 2.5%). Two cases (0.8%) had grade II; 4 cases (1.7%), grade III; and 1 case (0.4%), grade IV complications. In the analysis of comorbidities, only preoperative coagulopathy was significantly associated with increased risk of complications (relative risk = 6.4, P < .01). Following multivariate logistic regression adjusting for demographic covariates, coagulopathy was still associated with increased odds of complications (odds ratio = 15.7, P = .03). There were no significant associations between other risk factors and complications. Conclusion SCDS repair has low rates of adverse events. We observed an incidence of 11.2% complications, most commonly postoperative benign paroxysmal positional vertigo. The risk of nonotologic intracranial complications (1.7%) is low. PMID- 28653554 TI - The role of simulation to support donation after circulatory death with extracorporeal membrane oxygenation (DCD-ECMO). AB - Maintaining the viability of organs from donors after circulatory death (DCD) for transplantation is a complicated procedure, from a time perspective in the absence of appropriate organizational capabilities, that makes such transplantation cases difficult and not yet widespread in Poland. We present the procedural preparation for Poland's first case of organ (kidney) transplantation from a DCD donor in which perfusion was supported by extracorporeal membrane oxygenation (ECMO). Because this organizational model is complex and expensive, we used advanced high-fidelity medical simulation to prepare for the real-life implementation. The real time scenario included all crucial steps: prehospital identification, cardiopulmonary resuscitation (CPR), advanced life support (ALS); perfusion therapy (CPR-ECMO or DCD-ECMO); inclusion and exclusion criteria matching, suitability for automated chest compression; DCD confirmation and donor authorization, ECMO organs recovery; kidney harvesting. The success of our first simulated DCD-ECMO procedure in Poland is reassuring. Soon after this simulation, Maastricht category II DCD procedures were performed, involving real patients and resulting in two successful double kidney transplantations. During debriefing, it was found that the previous simulation-based training provided the experience to build a successful procedural chain, to eliminate errors at the stage of identification, notification, transportation, donor qualifications and ECMO organ perfusion to create DCD-ECMO algorithm architecture. PMID- 28653555 TI - Usher's Syndrome Type II: A Comparative Study of Genetic Mutations and Vestibular System Evaluation. AB - Objective Usher's syndrome type II (USH2) is characterized by moderate to profound congenital hearing loss, later onset of retinitis pigmentosa, and normal vestibular function. Recently, a study investigating the vestibular function of USH2 patients demonstrated a pathologic response to vestibular tests. In this cross-sectional study we performed vestibular tests of a group patients with genetic diagnosis of USH2 syndrome to demonstrate if vestibular damage is present in USH2 patients. Study Design Cross-sectional study. Setting Tertiary referral center. Subjects and Methods Mutated genes of 7 patients with a clinical diagnosis of USH2 were evaluated. Vestibular function was investigated by audiometry, Fitzgerald-Hallpike caloric vestibular testing, cervical vestibular evoked myogenic potentials (C-VEMPs), ocular vestibular evoked myogenic potentials (O-VEMPs), and video head impulse test (v-HIT). Results Genetic tests confirmed the USH2 diagnosis in 5 of 7 patients examined, with 1 patient reporting a unique mutation on genetic tests. Four (80%) of the 5 patients with a genetic diagnosis of USH2 showed pathological O-VEMPs. Two patients (40%) reported bilateral absent or abnormal values of C-VEMPs. The superior semicircular canal presented a significant deficit in 2 (40%) patients. The same 2 cases showed a pathologic response of the v-HIT of the horizontal semicircular canal. Finally, the posterior semicircular canal presented a significant deficit in 4 (40.0%) patients. Conclusion A vestibular evaluation with vestibular evoked myogenic potentials and v-HIT seems to identify latent damage to the vestibular receptors of USH2 patients. PMID- 28653556 TI - Supra-Segmental Changes in Speech Production as a Result of Spectral Feedback Degradation: Comparison with Lombard Speech. AB - Perturbations to acoustic speech feedback have been typically localized to specific phonetic characteristics, for example, fundamental frequency (F0) or the first two formants (F1/F2), or affect all aspects of the speech signal equally, for example, via the addition of background noise. This paper examines the consequences of a more selective global perturbation: real-time cochlear implant (CI) simulation of acoustic speech feedback. Specifically, we examine the potential similarity between speakers' response to noise vocoding and the characteristics of Lombard speech. An acoustic analysis of supra-segmental characteristics in speaking rate, F0 production, and voice amplitude revealed changes that paralleled the Lombard effect in some domains but not others. Two studies of speech intelligibility complemented the acoustic analysis, finding that intelligibility significantly decreased as a result of CI simulation of speaker feedback. Together, the results point to differences in speakers' responses to these two superficially similar feedback manipulations. In both cases we see a complex, multi-faceted behavior on the part of talkers. We argue that more instances of global perturbation and broader response assessment are needed to determine whether such complexity is present in other feedback manipulations or if it represents a relatively rare exception to the typical compensatory feedback response. PMID- 28653557 TI - Trends in Cigarette Smoking Among Older Male Adults in China: An Urban-Rural Comparison. AB - This study compared urban/rural trends in cigarette smoking rates among older male adults in China. Data were derived from the China Health and Nutrition Survey ( N = 5,147). Logistic models were computed to assess the occurrence of cigarette smoking between 1991 and 2011 across urban/rural administrative districts. Cigarette smoking rates remained consistent (about 50%) in rural villages over the last two decades but decreased by about 1.1 percentage points annually in urban neighborhoods. After adjusting for individual and community characteristics, divergent urban/rural trends in cigarette smoking rates did not vary statistically. Trends in cigarette smoking may be associated with unbalanced social and economic development in urban and rural China, and are an indicator of social determinants of health inequalities. Results suggest tobacco control policies and interventions should specifically focus on older adults vulnerable to economic inequality. Findings have implications for health and economic inequality among older adults in general. PMID- 28653558 TI - Analysis of adverse events as a contribution to safety culture in the context of practice development AB - Background: Analysing adverse events is an effective patient safety measure. Aim: We show, how clinical nurse specialists have been enabled to analyse adverse events with the "Learning from Defects-Tool" (LFD-Tool). Method: Our multi component implementation strategy addressed both, the safety knowledge of clinical nurse specialists and their attitude towards patient safety. The culture of practice development was taken into account. Results: Clinical nurse specialists relate competency building on patient safety due to the application of the LFD-tool. Applying the tool, fosters the reflection of adverse events in care teams. Conclusion: Applying the "Learning from Defects-Tool" promotes work based learning. Analysing adverse events with the "Learning from Defects-Tool" contributes to the safety culture in a hospital. PMID- 28653559 TI - Are written information or counseling (WOMAN-PRO II program) able to improve patient satisfaction and the delivery of health care of women with vulvar neoplasms? Secondary outcomes of a multicenter randomized controlled trial AB - Background: Patients with vulvar neoplasms report a lack of information, missing support in self-management and a gap in delivery of health care. Aim: The aim of the study was to investigate if written information or counseling based on the WOMAN-PRO II program are able to improve patient satisfaction and the delivery of health care from the health professional's perspective of women with vulvar neoplasms. Method: Patient satisfaction and the delivery of health care have been investigated as two secondary outcomes in a multicenter randomized controlled parallel-group phase II study (Clinical Trial ID: NCT01986725). In total, 49 women, from four hospitals (CH, AUT), completed the questionnaire PACIC-S11 after written information (n = 13) and counseling (n = 36). The delivery of health care was evaluated by ten Advanced Practice Nurses (APNs) by using the G-ACIC before and after implementing counseling based on the WOMAN-PRO II program. Results: There were no significant differences between the two groups identified (p = 0.25). Only few aspects were rated highly by all women, such as the overall satisfaction (M = 80.3 %) and satisfaction with organization of care (M = 83.0 %). The evaluation of delivery of health care by APNs in women who received counseling improved significantly (p = 0.031). Conclusions: There are indications, that the practice of both interventions might have improved patient satisfaction and counseling the delivery of health care. The aspects that have been rated low in the PACIC-S11 and G-ACIC indicate possibilities to optimize the delivery of health care. PMID- 28653560 TI - Difficulties in Comprehending Affirmative and Negative Sentences: Evidence From Chinese Children With Reading Difficulties. AB - Recent experimental results suggest that negation is particularly challenging for children with reading difficulties. This study looks at how young poor readers, speakers of Mandarin Chinese, comprehend affirmative and negative sentences as compared with a group of age-matched typical readers. Forty-four Chinese children were tested with a truth value judgment task. The results reveal that negative sentences were harder to process than affirmative ones, irrespective of the distinction between poor and typical readers. Moreover, poor readers performed worse than typical readers in comprehending sentences, regardless of whether they were affirmative or negative sentences. We interpret the results as (a) confirming the two-step simulation hypothesis, based on the result that the difficulty in processing negation has a general validity (persisting in pragmatically felicitous contexts), and (b) disconfirming that negation, as far as behavioral data are concerned, can be used as a reliable linguistic predictor of reading difficulties. PMID- 28653561 TI - Incidence of Secondary Surgery after Modified Furlow Palatoplasty: A 20-Year Single-Surgeon Case Series. AB - Objective To determine the occurrence of velopharyngeal insufficiency (VPI) requiring surgery and fistula repair after primary palatoplasty using a "modified" Furlow technique. Study Design Case series with chart review. Setting Academic multidisciplinary cleft and craniofacial center. Subjects and Methods Children younger than 18 years at presentation, with unrepaired cleft palate, with or without cleft lip, including submucous clefts, who underwent palatoplasty were included. No cleft patients having primary repair were excluded. All operations were conducted by a single surgeon from March 1994 through December 2013. Charts were reviewed for demographics, cleft type, genetic syndrome, operations performed, and complications, including VPI and oronasal fistula. Results In total, 312 consecutive patients underwent primary palatoplasty (160 [51.3%] male) with a median age of repair of 0.95 (range, 0.47-17.6) years and followed for 6.49 (range, 4.0-20.2) years. Robin sequence was diagnosed in 109 (34.9%), 104 (33.4%) had alveolar clefts, and 27 (8.7%) had concomitant gingivoperiosteoplasty. A modified Furlow was performed in 289 (92.6%). Overall, 16 (5.1%) required subsequent pharyngeal flap for VPI, and 48 (15.4%) required oronasal fistula repair. Veau class II had higher pharyngeal flap rates ( P = .033). Fistula repair was lower in Veau I ( P < .001) but higher in Veau II ( P < .001) and IV ( P = .002). Older age ( P = .034) and Robin sequence ( P = .017) were associated with higher rates of oronasal fistula repair. Conclusions The modified Furlow palatoplasty yields acceptable rates of secondary surgery for VPI without selection based on cleft width. While our oronasal fistula repair rate is high, it is concordant with previous reports and is likely related to our rare use of lateral relaxing incisions. PMID- 28653562 TI - McGill Thyroid Nodule Score in Differentiating Benign and Malignant Pediatric Thyroid Nodules: A Pilot Study. AB - Objective The McGill Thyroid Nodule Score (MTNS) is a preoperative tool used to predict the risk for well-differentiated thyroid cancer given a specific nodule in adults. We evaluated the clinical utility of a modified pediatric MTNS with children and adolescents. Study Design Case series with chart review. Setting Tertiary care children's hospital. Subjects and Methods This is a retrospective chart review of 46 patients <=18 years of age presenting with a solitary or dominant thyroid nodule treated with surgical resection between September 2008 and December 2015. The cumulative MTNS for each nodule was calculated and compared with the final pathology. Results Of 46 patients, 10 (21.7%) were diagnosed with well-differentiated thyroid cancer (80% papillary thyroid carcinoma, 10% follicular variant of papillary thyroid carcinoma, 10% follicular thyroid carcinoma). Malignant nodules were associated with a greater mean MTNS (benign, 5.72 +/- 3.03; malignant, 16 +/- 3.13; P < .05). The sensitivity, specificity, and positive predictive value of malignancy were 100%, 94.4%, and 83.3% for scores >=10 and 80%, 100%, and 100% for scores >=11, respectively. In nodules with indeterminate cytology (Bethesda III and IV), the pediatric MTNS showed good differentiation between benign and malignant disease, with mean scores of 7.95 and 12.5, respectively ( P = .006). Conclusion This pilot study suggests that a comprehensive scoring system may help assess the risk of malignancy in pediatric thyroid nodules and differentiate nodules with indeterminate cytology into higher- and lower-risk categories. Given these findings, larger, multi-institutional studies are warranted. PMID- 28653564 TI - Blake's pouch cyst in children: Atypical clinical presentation. AB - Blake's pouch cyst is a posterior fossa cystic malformation characterized by a infracerebellar cyst, absence of communication between the fourth ventricle and the subarachnoid space, and tetraventricular hydrocephalus. Children with Blake's pouch cyst typically present with macrocephaly due to hydrocephalus during the neonatal period or infancy. Atypical presentation is, however, possible. Here we present clinical and neuroimaging findings, as well as management and outcome, of an 18-month-old girl with atypical presentation of Blake's pouch cyst characterized by cerebellar ataxia. Familiarity with the neuroimaging findings of Blake's pouch cyst and differentiation between Blake's pouch cyst and other posterior fossa cystic malformations is important in terms of diagnosis, management, prognosis, and counseling of the affected families. PMID- 28653563 TI - Long-Term Otologic and Audiometric Outcomes in Patients with Cleft Palate. AB - Objective Describe longitudinal audiometric and otologic outcomes in patients with cleft palates. Study Design Case series with chart review. Setting Single academic medical center. Methods Charts of 564 patients with a diagnosis of cleft palate (59% syndromic etiology, 41% nonsyndromic) from 1998 to 2014 were reviewed. Patients without at least 1 audiometric follow-up were excluded from analysis. Patient demographics, surgeries, audiometric tests, and otologic data were recorded for 352 patients. Results Forty-five percent had isolated cleft palates, 34% had unilateral cleft lip and palate, and 21% had bilateral cleft lip and palate. Patients were followed for a mean of 50.3 months with a mean of 3.2 separate audiograms performed. Patients received a mean of 2.93 pressure equalization tubes. Increased number of pressure equalization tubes was not associated with incidence of cholesteatoma, which was identified in only 4 patients. Nine patients underwent eventual tympanoplasty with an 89% closure rate. Analysis of mean air-bone gap by cleft type did not reveal significant differences ( P = .08), but conductive losses and abnormal tympanometry persisted into teenage years. Conclusions Patients with cleft palates have eustachian tube dysfunction, which, in our cohort, resulted in persistent conductive hearing loss, highlighting the importance of long-term follow-up. Cholesteatoma incidence was low and not associated with number of tubes, which at our institution were placed prophylactically. Tympanoplasty was successful in those with persistent perforations. PMID- 28653565 TI - Prevalence and factors associated with non-utilization of healthcare facility for childbirth in rural and urban Nigeria: Analysis of a national population-based survey. AB - AIM: The aim of this study was to assess the rural-urban differences in the prevalence and factors associated with non-utilization of healthcare facility for childbirth (home delivery) in Nigeria. METHODS: Dataset from the Nigeria demographic and health survey, 2013, disaggregated by rural-urban residence were analyzed with appropriate adjustment for the cluster sampling design of the survey. Factors associated with home delivery were identified using multivariable logistic regression analysis. RESULTS: In rural and urban residence, the prevalence of home delivery were 78.3% and 38.1%, respectively ( p < 0.001). The lowest prevalence of home delivery occurred in the South-East region for rural residence (18.6%) and the South-West region for urban residence (17.9%). The North-West region had the highest prevalence of home delivery, 93.6% and 70.5% in rural and urban residence, respectively. Low maternal as well as paternal education, low antenatal attendance, being less wealthy, the practice of Islam, and living in the North-East, North-West and the South-South regions increased the likelihood of home delivery in both rural and urban residences. Whether in rural or urban residence, birth order of one decreased the likelihood of home delivery. In rural residence only, living in the North-Central region increased the chances of home delivery. In urban residence only, maternal age ? 36 years decreased the likelihood of home delivery, while 'Traditionalist/other' religion and maternal age < 20 years increased it. CONCLUSION: The prevalence of home delivery was much higher in rural than urban Nigeria and the associated factors differ to varying degrees in the two residences. Future intervention efforts would need to prioritize findings in this study. PMID- 28653566 TI - Educational inequalities in hospital care for mortally ill patients in Norway. AB - AIMS: Health care should be allocated fairly, irrespective of patients' social standing. Previous research suggests that highly educated patients are prioritized in Norwegian hospitals. This study examines this contentious issue by a design which addresses two methodological challenges. Control for differences in medical needs is approximated by analysing patients who died from same causes of death. Area fixed effects are used for avoiding that observed educational inequalities are contaminated by geographical differences. METHODS: Men and women who died 2009-2011 at age 55-94 were examined ( N=103,000) with register data from Statistics Norway and the Norwegian Patient Registry. Educational differences in quantity of hospital-based medical care during the 12-24 months before death were analysed, separate for main causes of death. Multivariate negative binomial regression models were estimated, with fixed effects for residential areas. RESULTS: High-educated patients who died from cancers had significantly more outpatient consultations at somatic hospitals than low educated patients during an average observation period of 18 months prior to death. Similar, but weaker, educational inequalities appeared for outpatient visits for patients whose deaths were due to other causes. Also, educational inequalities in number of hospital admissions were marked for those who died from cancers, but insignificant for patients who died from other causes. CONCLUSIONS: Even when medical needs are similar for mortally ill patients, those with high education tend to receive more medical services in Norwegian somatic hospitals than patients with low education. The roles played by physicians and patients in generating these patterns should be explored further. PMID- 28653567 TI - Parental health and psychosomatic symptoms in preschool children: A cross sectional study in Scania, Sweden. AB - AIM: The aim of the study was to assess the association between parental self rated health and recurrent abdominal pain (RAP) in preschool children. METHODS: A questionnaire, including questions about sociodemographic and psychosocial factors, lifestyle, parental and child health, was sent to parents of all 4-year old children in Scania, Sweden. The response rate was 43.6%. The outcome was RAP and the main exposure was parental self-rated health (SRH). Covariates included sociodemographic, lifestyle and psychosocial factors. Logistic regression analyses were used in a five-step model to estimate the odds ratio (OR) and 95% confidence interval (CI) of parental SRH in relation to child RAP. RESULTS: Logistic regression analysis showed higher odds of RAP among children whose parents reported domestic violence, economic worries and poor SRH (mothers OR = 2.1 (95% CI: 1.6, 2.7) and fathers OR = 1.5 (95% CI: 1.1, 2.0)). Adjustment for sociodemographic, lifestyle and psychosocial factors reduced the OR for RAP in the children of mothers with poor SRH (OR = 1.6 (95% CI: 1.2, 2.2)) and fathers with poor SRH (OR = 1.2 (CI 95%: 0.8, 1.7)). Poor SRH was associated with less reading to the child as well as parental perceptions of insufficiency in the interaction with the child. CONCLUSIONS: Health professionals have a key position to prevent psychosomatic symptoms in childhood by identifying the living conditions of children with RAP and particularly, to pay attention to parental poor health to identify if support to the family and/or child protection interventions are needed. Health professionals meeting adult patients with poor health should identify whether they are parents and have children who might need information, support and/or protection. PMID- 28653568 TI - Time to leave rigid traditions in Type 1 diabetes research. PMID- 28653569 TI - The mutable vaccine for mutable viruses. AB - Mutable viruses, such as HIV, pose difficult obstacles to prevention and/or control by vaccination. Mutable viruses rapidly diversify in populations and in individuals, impeding development of effective vaccines. We devised the 'mutable vaccine' to appropriate the properties of mutable viruses that undermine conventional strategies. The vaccine consists of a DNA construct encoding viral antigen and regulatory sequences that upon delivery to B cells target the enzymatic apparatus of 'somatic hypermutation' causing the construct to mutate one million-times baseline rates and allowing production and presentation of antigen variants. We postulate the mutable vaccine might thus anticipate diversification of mutable viruses, allowing direct control or slowing of evolution. Initial work presented here should encourage consideration of this novel approach. PMID- 28653570 TI - The second wave of immune checkpoint inhibitor tsunami: advance, challenges and perspectives. AB - After the first wave of the tsunami of immune checkpoint inhibitors, 2016 was marked by the second wave, revealed by numerous US FDA approvals, publications and abstracts in relation with these drugs in different cancers and settings. First, we reported all new indications of anti-CTLA4, anti-programmed cell death protein 1 and anti-PDL1 approved by the FDA, the positive clinical trials published and the abstracts reported at important scientific meetings during 2016. Then, we highlighted the updates on debatable issues related to checkpoint inhibitors, since the first wave published in a previous issue. We focused on the predictive biomarkers, combination therapies, tumor response patterns and efficacy in particular settings and the side effect management. Finally, the impact of checkpoint inhibitors development on the care management of cancer centers will be discussed. PMID- 28653571 TI - Chimeric antigen receptor T cells for the treatment of cancer and the future of preclinical models for predicting their toxicities. AB - Chimeric antigen receptor T-cell therapy has achieved highly promising results in clinical trials, particularly in B-cell malignancies. However, reports of serious adverse events including a number of patient deaths have raised concerns about safety of this treatment. Presently available preclinical models are not designed for predicting toxicities seen in human patients. Besides choosing the right animal model, careful considerations must be taken in chimeric antigen receptor T cell design and the amount of T cells infused. The development of more sophisticated in vitro models and humanized mouse models for preclinical modeling and toxicity tests will help us to improve the design of clinical trials in cancer immunotherapy. PMID- 28653572 TI - Regulatory T cells, as a target in anticancer immunotherapy. PMID- 28653573 TI - The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. AB - The adaptive immune system plays an important role in eradicating malignant cells. Co-stimulatory and co-inhibitory signals to T cells though immune checkpoint receptors are involved in tumorigenesis and metastasis. Exploitation of immune checkpoint inhibitors, PD-1 and CTLA-4, with monoclonal antibodies has created impressive clinical responses. Many other immune checkpoint co-inhibitors and co-stimulators exist, including the B7 superfamily and tumor necrosis factor receptors superfamily. Here, we will examine co-inhibitors and co-stimulators beyond PD-1 and CTLA-4 that are being investigated in active clinical trials. We will review the immunology and preclinical studies that support investigation of these targets. Finally, we will briefly discuss the potential for immunotherapy to be combined with other treatment modalities. PMID- 28653574 TI - Combination of sorafenib and cytokine-induced killer cells in metastatic renal cell carcinoma: a potential regimen. AB - Metastatic renal cell carcinoma (MRCC) exhibits primary resistance to both chemotherapy and radiotherapy. As an immunogenic cancer, MRCC is relatively sensitive to immunotherapy such as that with cytokines, immune checkpoint inhibitors and adoptive T-cell therapy. In addition, many targeted agents developed over the past decade exhibit greater efficacy than cytokines and have become the standard first-line therapy for MRCC. Several preclinical studies have shown that the targeted agent sorafenib possesses an immunomodulation function and may be suitable for combination with immunotherapy. Here, combinatorial therapy consisting of sorafenib and cytokine-induced killer cell immunotherapy was administered to an MRCC patient resulting in a synergistic effect without serious adverse effects. These results suggest a potential combinatorial regimen for MRCC patients. PMID- 28653575 TI - Evaluation of a new protocol for wheat desensitization in patients with wheat induced anaphylaxis. AB - AIM: New approaches such as oral immunotherapy (OIT) may be useful in IgE mediated anaphylaxis to wheat. PATIENTS & METHODS: 12 patients underwent OIT protocol that comprised of two phases: the first with semolina flour and the second with spaghetti. Total and specific wheat IgE were assayed by ELISA before and after OIT and 18 months later. Skin prick tests were also performed. RESULTS: Patients successfully tolerated 50 g of wheat. The median baseline total IgE was decreased after up-dosing phase and decreased after follow-up (p < 0.01). The median baseline wheat-specific IgE was increased after up-dosing and decreased after follow-up (p < 0.001). CONCLUSION: The efficiency and safety of our OIT protocol were shown on wheat allergic patients but further investigation is needed. PMID- 28653576 TI - Clinical roles in clinical biochemistry: a national survey of practice in the UK Comment. PMID- 28653577 TI - The Emerging British Verticillium longisporum Population Consists of Aggressive Brassica Pathogens. AB - Verticillium longisporum is an economically important fungal pathogen of brassicaceous crops that originated from at least three hybridization events between different Verticillium spp., leading to the hybrid lineages A1/D1, A1/D2, and A1/D3. Isolates of lineage A1/D1 generally cause stem striping on oilseed rape (Brassica napus), which has recently been reported for the first time to occur in the United Kingdom. Intriguingly, the emerging U.K. population is distinct from the north-central European stem striping population. Little is known about the pathogenicity of the newly emerged U.K. population; hence, pathogenicity tests were executed to compare British isolates to previously characterized reference strains. In addition to the model plant Arabidopsis thaliana, the pathogenicity of four British isolates was assessed on four cultivars of three Brassica crop species: oilseed rape (Quartz and Incentive), cauliflower (Clapton), and Chinese cabbage (Hilton). To this end, vascular discoloration of the roots, plant biomass accumulations, and fungal stem colonization upon isolate infection were evaluated. The British isolates appeared to be remarkably aggressive, because plant biomass was significantly affected and severe vascular discoloration was observed. The British isolates were successful stem colonizers and the extent of fungal colonization negatively correlated with plant biomass of cauliflower and Quartz oilseed rape. However, in Quartz, the fungal colonization of A1/D1 isolates was significantly lower than that of the virulent reference isolate from lineage A1/D3, PD589. Moreover, despite levels of stem colonization similar to those of A1/D1 strains, PD589 did not cause significant disease on Incentive. Thus, A1/D1 isolates, including British isolates, are aggressive oilseed rape pathogens despite limited colonization levels in comparison with a virulent A1/D3 isolate. PMID- 28653578 TI - Potato virus Y (PVY) Isolates from Physalis peruviana are Unable to Systemically Infect Potato or Pepper and Form a Distinct New Lineage Within the PVYC Strain Group. AB - Poha, or cape gooseberry (Physalis peruviana L.), is a plant species cultivated in Hawaii for fresh fruit production. In 2015, an outbreak of virus symptoms occurred on poha farms in the South Kohala District of the island of Hawaii. The plants displayed mosaic, stunting, and leaf deformation, and produced poor fruit. Initial testing found the problem associated with Potato virus Y (PVY) infection. Six individual PVY isolates, named Poha1 to Poha6, were collected from field grown poha plants and subjected to biological and molecular characterization. All six isolates induced mosaic and vein clearing in tobacco, and three of them exhibited O-serotype while the other three reacted only with polyclonal antibodies and had no identifiable serotype. Until now, PVY isolates have been broadly divided into pepper or potato adapted; however, these six PVY isolates from poha were unable to establish systemic infection in pepper and in four tested potato cultivars. Whole-genome sequences for the six isolates were determined, and no evidence of recombination was found in any of them. Phylogenetic analysis placed poha PVY isolates in a distinct, monophyletic "Poha" clade within the PVYC lineage, suggesting that they represented a novel, biologically and evolutionarily unique group. The genetic diversity within this poha PVYC clade was unusually high, suggesting a long association of PVYC with this solanaceous host or a prolonged geographical separation of PVYC in poha in Hawaii. PMID- 28653579 TI - Automated Identification of Northern Leaf Blight-Infected Maize Plants from Field Imagery Using Deep Learning. AB - Northern leaf blight (NLB) can cause severe yield loss in maize; however, scouting large areas to accurately diagnose the disease is time consuming and difficult. We demonstrate a system capable of automatically identifying NLB lesions in field-acquired images of maize plants with high reliability. This approach uses a computational pipeline of convolutional neural networks (CNNs) that addresses the challenges of limited data and the myriad irregularities that appear in images of field-grown plants. Several CNNs were trained to classify small regions of images as containing NLB lesions or not; their predictions were combined into separate heat maps, then fed into a final CNN trained to classify the entire image as containing diseased plants or not. The system achieved 96.7% accuracy on test set images not used in training. We suggest that such systems mounted on aerial- or ground-based vehicles can help in automated high-throughput plant phenotyping, precision breeding for disease resistance, and reduced pesticide use through targeted application across a variety of plant and disease categories. PMID- 28653580 TI - Short-Term Host Selection Pressure Has Little Effect on the Evolution of a Monoclonal Population of Verticillium dahliae Race 1. AB - Understanding pathogen evolution over time is vital for plant breeding and deployment of host resistance. In the context of a soilborne pathogen, the potential of host-directed evolution of a Verticillium dahliae race 1 isolate and genotypic variation of V. dahliae associated with two major hosts (lettuce and tomato) were determined. In total, 427 isolates were recovered over 6 years from a resistance screening nursery infested with a single V. dahliae race 1 isolate. In a separate study, an additional 206 isolates representing 163 and 43 isolates from commercial lettuce and tomato fields, respectively, were collected. Analyses of isolates recovered from the screening nursery over 6 years revealed no changes in the race and mating type composition but did uncover seven simple sequence repeat (SSR) variant genotypes. No significant genotypic variation in V. dahliae was observed between or within fields of either lettuce or tomato but pathogen populations were significantly differentiated between these two hosts. Replicated virulence assays of variant SSR genotypes on lettuce differential cultivars suggested no significant difference in virulence from the wild-type race 1 isolate introduced into the field. This suggests that deployed race 1 host resistance will be robust against the widespread race 1 populations in lettuce growing regions at least for 6 years unless novel pathogen genotypes or races are introduced into the system. PMID- 28653581 TI - Global stability of the coexistence equilibrium for a general class of models of facultative mutualism. AB - Many models of mutualism have been proposed and studied individually. In this paper, we develop a general class of models of facultative mutualism that covers many of such published models. Using mild assumptions on the growth and self limiting functions, we establish necessary and sufficient conditions on the boundedness of model solutions and prove the global stability of a unique coexistence equilibrium whenever it exists. These results allow for a greater flexibility in the way each mutualist species can be modelled and avoid the need to analyse any single model of mutualism in isolation. Our generalization also allows each of the mutualists to be subject to a weak Allee effect. Moreover, we find that if one of the interacting species is subject to a strong Allee effect, then the mutualism can overcome it and cause a unique coexistence equilibrium to be globally stable. PMID- 28653582 TI - Waste management outlook for mountain regions: Sources and solutions. AB - Following the release of the global waste management outlook in 2015, the United Nations Environment Programme (UN Environment), through its International Environmental Technology Centre, is elaborating a series of region-specific and thematic waste management outlooks that provide policy recommendations and solutions based on current practices in developing and developed countries. The Waste Management Outlook for Mountain Regions is the first report in this series. Mountain regions present unique challenges to waste management; while remoteness is often associated with costly and difficult transport of waste, the potential impact of waste pollutants is higher owing to the steep terrain and rivers transporting waste downstream. The Outlook shows that waste management in mountain regions is a cross-sectoral issue of global concern that deserves immediate attention. Noting that there is no 'one solution fits all', there is a need for a more landscape-type specific and regional research on waste management, the enhancement of policy and regulatory frameworks, and increased stakeholder engagement and awareness to achieve sustainable waste management in mountain areas. This short communication provides an overview of the key findings of the Outlook and highlights aspects that need further research. These are grouped per source of waste: Mountain communities, tourism, and mining. Issues such as waste crime, plastic pollution, and the linkages between exposure to natural disasters and waste are also presented. PMID- 28653583 TI - Warm and Humidified Versus Cold and Dry CO2 Pneumoperitoneum in Minimally Invasive Colon Resection: A Randomized Controlled Trial. AB - INTRODUCTION: Peritoneal insufflation with warm-humidified (WH) CO2 gas during minimally invasive surgical procedures is purported to prevent hypothermia and peritoneal desiccation and is associated with decreased postoperative IL-6 levels. This randomized study's purpose was to determine the clinical impact of WH versus cold-dry (CD) CO2 in minimally invasive colon resection (MICR), and to assess perioperative plasma levels of IL-6, TIMP-1, sVEGF-R1, and HSP-70 after MICR. METHODS: Operative and short-term clinical data plus perioperative blood samples were collected on MICR patients randomized to receive either WH (36.7 degrees C, 95% humidity) or CD (room temperature, 0% humidity) CO2 perioperatively. Peritoneal biopsies were taken at the start and end of surgery. Outcomes tracked included core temperature, postoperative in-hospital pain levels, analgesia requirements, and standard recovery parameters. Preoperative and postoperative days (PODs) 1 and 3 plasma protein levels were determined via ELISA. RESULTS: A total of 101 patients were randomized to WH CO2 (50) or CD CO2 (51). The WH group contained more diabetics ( P = .03). There were no differences in indication, minimally invasive surgical method used, or core temperature. Pain scores were similar; however, the WH patients required less narcotics on PODs 1 to 3 ( P < .05), and less ketorolac on PODs 1 and 2 ( P < .03). No differences in length of stay, complication rates, or time to flatus/diet tolerance were noted. Plasma levels of the 4 proteins were similar postoperatively. Though insignificant, the WH group had less marked histologic changes on "end-of-case" peritoneal biopsies. CONCLUSION: This study found significantly lower pain medication requirements for PODs 1 to 3 for the WH group; however, because there were no differences in the pains scores between the groups, firm conclusions regarding WH CO2 cannot be made. PMID- 28653585 TI - International workshop on "professionalism in the practice of medicine- where are we now?" AB - Medical professionalism refers to attributes, values, behaviors, responsibilities and commitments of physicians that are congruent with the public's expectations. An international workshop on medical professionalism took place at the Dead Sea, Israel, on December 11-12, 2016. The meeting brought together local medical professionals, physicians and others, as well as international experts, to discuss definitions of professionalism and wrestle with current challenges facing the profession including its perceived status and physician satisfaction, unprofessional behavior and its relation to health care quality and patient safety, and professionalism as a learned competence. Individual medical schools reported on educational efforts to promote professionalism in their curricula. Patient complaints as an improvement mechanism were explored on a national and health plan level. I was found that complaints regarding physician behavior are rare in the Israeli context and need to be dealt with expeditiously at a local level in order to be effective tools for change. The meeting provided a venue to understand local and international strategies and mechanism for regulation and self-regulation, highlighting the role of the Israel Medical Association. A major focus of the meeting was on intergenerational differences in attitude and practice and the necessary adaptation of medicine to the digital age. We provide an overview of the topics addressed, synopsis, evaluation and lessons learned in this first-ever national meeting on medical professionalism in Israel. PMID- 28653584 TI - Immunotherapy biomarkers 2016: overcoming the barriers. AB - This report summarizes the symposium, 'Immunotherapy Biomarkers 2016: Overcoming the Barriers', which was held on April 1, 2016 at the National Institutes of Health in Bethesda, Maryland. The symposium, cosponsored by the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI), focused on emerging immunotherapy biomarkers, new technologies, current hurdles to further progress, and recommendations for advancing the field of biomarker development. PMID- 28653586 TI - Effect of high-protein meal replacement on weight and cardiometabolic profile in overweight/obese Asian Indians in North India. AB - The aim of the present study was to evaluate the impact of a high-protein meal replacement (HPMR) on weight and metabolic, lipid and inflammatory parameters in overweight/obese Asian Indians. In this 12-week open-label, parallel-arm randomised controlled trial, 122 overweight/obese men and women were administered either a HPMR or a control diet after 2 weeks of diet and exercise run-in. Body weight, waist circumference (WC), percentage body fat (%BF), fasting blood glucose, post-oral glucose tolerance test (post-OGTT) blood glucose, fasting and post-OGTT serum insulin, lipid profile, high-sensitivity C-reactive protein (hs CRP), kidney function and hepatic aminotransferases were assessed before and after the intervention. Additional improvement in mean values for the following parameters in the HPMR group compared with the control group was observed: body weight, 4.9 % (95 % CI 3.8, 6.1; P<0.001); WC, 3.8 % (95 % CI 2.5, 5.1; P<0.001); %BF, 6.3 % (95 % CI 4.3, 8.2; P<0.001); systolic blood pressure, 2.8 % (95 % CI 0.4, 5.1; P=0.002); diastolic blood pressure, 3.5 % (95 % CI 0.7, 6.3; P= 0.01); post-OGTT blood glucose, 7.3 % (95 % CI 1.4, 13.1; P=0.02); total cholesterol, 2.5 % (95 % CI 1.6, 3.5; P<0.001); LDL-cholesterol, 7.3 % (95 % CI 1.7, 12.9; P<0.01); alanine aminotransferase, 22.0 % (95 % CI 2.1, 42; P=0.03) and aspartate aminotransferase, 15.2 % (95 % CI 0.9, 29.5; P=0.04). The absolute reduction in BMI was 0.9 units in the intervention arm compared with the control arm (-0.9 %, 95 % CI -1.4, -0.5; P<0.001) and in serum TAG was 11.9 mg/dl (-11.9 mg/dl, 95 % CI -21.1, -2.7; P<0.01). The reduction in fasting serum insulin in the intervention v. the control arm was 3.8 v. 0 % (P=0.002); post-OGTT serum insulin was 50.3 v. 77.3 mU/l (P=0.005); and hs-CRP, 16.7 % v. 0 % (P=0.002). These findings show that intervention with HPMR may lead to significant weight loss and improvement in obesity measures, metabolic, lipid and inflammatory parameters and hepatic transaminases in overweight/obese Asian Indians. PMID- 28653587 TI - East-West Divide: temperature and land cover drive spatial variation of Toxoplasma gondii infection in Eurasian otters (Lutra lutra) from England and Wales. AB - Toxoplasma gondii, a zoonotic parasite of global importance, infects all endothermic vertebrates, with extensive health implications. The prevalence of this parasite is seldom monitored in wildlife. Here, a semi-aquatic species, the Eurasian otter (Lutra lutra) was used as a model to assess the potential effect of climate, land cover and biotic factors on T. gondii seroprevalence in British wildlife. The Sabin-Feldman cytoplasm-modifying dye test identified T. gondii antibodies in 25.5% of blood samples from otters found dead, mainly as road kill, in England and Wales, between 2004 and 2010. Otters in the east of England were more likely to be infected with T. gondii than those in western regions. Land cover and temperature are key determinants of T. gondii infection risk, with more infection in arable areas and lower infection where temperatures are higher. The probability of T. gondii infection increased with host age, reflecting cumulative exposure with time, but there was no association between T. gondii seroprevalence and cause of host death. PMID- 28653588 TI - Positive density-dependent growth supports costs sharing hypothesis and population density sensing in a manipulative parasite. AB - Parasites manipulate their hosts' phenotype to increase their own fitness. Like any evolutionary adaptation, parasitic manipulations should be costly. Though it is difficult to measure costs of the manipulation directly, they can be evaluated using an indirect approach. For instance, theory suggests that as the parasite infrapopulation grows, the investment of individual parasites in host manipulation decreases, because of cost sharing. Another assumption is that in environments where manipulation does not pay off for the parasite, it can decrease its investment in the manipulation to save resources. We experimentally infected rainbow trout Oncorhynchus mykiss with the immature larvae of the trematode Diplostomum pseudospathaceum, to test these assumptions. Immature D. pseudospathaceum metacercariae are known for their ability to manipulate the behaviour of their host enhancing its anti-predator defenses to avoid concomitant predation. We found that the growth rate of individual parasites in rainbow trout increased with the infrapopulation size (positive density-dependence) suggesting cost sharing. Moreover, parasites adjusted their growth to the intensity of infection within the eye lens where they were localized suggesting population density sensing. Results of this study support the hypothesis that macroparasites can adjust their growth rate and manipulation investment according to cost sharing level and infrapopulation size. PMID- 28653589 TI - Parasite dynamics in an invaded ecosystem: helminth communities of native wood mice are impacted by the invasive bank vole. AB - It is becoming increasingly evident that biological invasions result in altered disease dynamics in invaded ecosystems, with knock-on effects for native host communities. We investigated disease dynamics in an invaded ecosystem, using the helminth communities of the native wood mouse (Apodemus sylvaticus) in the presence and absence of the invasive bank vole (Myodes glareolus) in Ireland. Native wood mice were collected over 2 years from four sites to assess the impact of the presence of the bank vole on wood mouse helminth community dynamics both at the component and infracommunity level. We found evidence for dilution (Syphacia stroma), spill-back (Aonchotheca murissylvatici) and spill-over (Taenia martis) in native wood mice due to the presence of the bank vole. Site of capture was the most important factor affecting helminth community structure of wood mice, along with year of capture and host-age and the interactions between them. PMID- 28653590 TI - Guinea worm: from Robert Leiper to eradication. AB - Guinea worm disease, dracunculiasis or dracontiasis, is an ancient disease with records going back over 4500 years, but until the beginning of the 20th century, little was known about its life cycle, particularly how humans became infected. In 1905, Robert Thomas Leiper was sent by the British colonial authorities to West Africa to investigate the spread of Guinea worm disease and to recommend measures to prevent it. While carrying out his investigations, he made important contributions to the aetiology, epidemiology and public health aspects of Guinea worm disease and provided definitive answers to many outstanding questions. First, he tested the validity of previous theories; second, he confirmed the role of water fleas, which he identified as Cyclops, as the intermediate hosts in the life cycle; third, he investigated the development of the parasite in its intermediate host; and fourth, he recommended measures to prevent the disease. [The crustacean Order Cyclopoida in the Family Cyclopidae contains 25 genera, including Cyclops which itself contains over 400 species and may not even be a valid taxon. It is not known how many of these species (or indeed species belonging to related genera) can act as intermediate hosts of Dracunculus medinensis nor do we know which species Fedchenko, Leiper and other workers used in their experiments. It is, therefore, best to use the terms copepod, or copopoid crustacean rather than Cyclops in scientific texts. In this paper, these crustaceans are referred to as copepods except when referring to an original text.] Leiper described the remarkable changes that took place when an infected copepod was placed in a dilute solution of hydrochloric acid; the copepod was immediately killed, but the Dracunculus larvae survived and were released into the surrounding water. From this, he concluded that if a person swallowed an infected copepod, their gastric juice would produce similar results. He next infected monkeys by feeding them copepods infected with Guinea worm larvae, and thus conclusively demonstrated that humans became infected by accidentally ingesting infected crustaceans. Based on these conclusions, he advocated a number of control policies, including avoidance of contaminated drinking water or filtering it, and these preventive measures paved the way for further research. The challenge to eradicate Guinea worm disease was not taken up until about seven decades later since when, with the support of a number of governmental and non governmental organizations, the number of cases has been reduced from an estimated 3.5 million in 1986 to 25 in 2016 with the expectation that this will eventually lead to the eradication of the disease. PMID- 28653591 TI - Mechanism of dexamethasone in the context of Toxoplasma gondii infection. AB - Toxoplasmosis is a serious zoonoses disease and opportunistic, and can be life threatening. Dexamethasone (DEX) is widely used in the clinic for treatment of inflammatory and autoimmune diseases. However, long-term use of DEX is often easy to lead to acute toxoplasmosis in patients, and the potential molecular mechanism is still not very clear. The aims of this study were to investigate the effect of DEX on proliferation of Toxoplasma and its molecular mechanisms, and to establish the corresponding control measures. All the results showed that dexamethasone could enhance the proliferation of Toxoplasma gondii tachyzoites. After 72 h of DEX treatment, 566 (+/-7) tachyzoites were found in 100 host cells, while only 86 (+/-8) tachyzoites were counted from the non-treated control cells (P < 0.01). Gas chromatography (GC) analysis showed changes in level and composition of fatty acids in DEX-treated host cells, and T. gondii. Fish oil was added as a modulator of lipid metabolism in experimental mice. It was found that mice fed with fish oil did not develop the disease after infection with T. gondii, and the structure of fatty acids in plasma changed significantly. The metabolism of fatty acid in the parasites was limited, and the desaturase gene expression was downregulated. These results indicate that the molecular mechanism of dexamethasone to promote the proliferation of T. gondii may be that dexamethasone induces the change of fatty acids composition of tachyzoites and host cells. Therefore, we recommend supplementation of fatty acid in immunosuppressive and immunocompromised patients in order to inhibit toxoplasmosis. PMID- 28653592 TI - Catalase expression impairs oxidative stress-mediated signalling in Trypanosoma cruzi. AB - Trypanosoma cruzi is exposed to oxidative stresses during its life cycle, and amongst the strategies employed by this parasite to deal with these situations sits a peculiar trypanothione-dependent antioxidant system. Remarkably, T. cruzi's antioxidant repertoire does not include catalase. In an attempt to shed light on what are the reasons by which this parasite lacks this enzyme, a T. cruzi cell line stably expressing catalase showed an increased resistance to hydrogen peroxide (H2O2) when compared with wild-type cells. Interestingly, preconditioning carried out with low concentrations of H2O2 led untransfected parasites to be as much resistant to this oxidant as cells expressing catalase, but did not induce the same level of increased resistance in the latter ones. Also, presence of catalase decreased trypanothione reductase and increased superoxide dismutase levels in T. cruzi, resulting in higher levels of residual H2O2 after challenge with this oxidant. Although expression of catalase contributed to elevated proliferation rates of T. cruzi in Rhodnius prolixus, it failed to induce a significant increase of parasite virulence in mice. Altogether, these results indicate that the absence of a gene encoding catalase in T. cruzi has played an important role in allowing this parasite to develop a shrill capacity to sense and overcome oxidative stress. PMID- 28653593 TI - A morphological and molecular study of Clinostomid metacercariae from African fish with a redescription of Clinostomum tilapiae. AB - The genus Clinostomum Leidy, 1856 (Digenea: Clinostomidae) has been reported in all ecozones of the world and a clear separation between the species of the 'Old World' and 'New World' has been recognized based on molecular studies. Recent works on Afrotropical species include redescriptions of C. cutaneum and C. phalacrocoracis, while C. tilapiae has yet to be studied using modern taxonomic approaches. In the present research, morphological redescription of C. tilapiae metacercariae from a new host, Synodontis batensoda sampled at Anambra River Basin, Nigeria, together with molecular analysis of nuclear internal transcribed spacer rDNA and cytochrome c oxidase 1 mtDNA are reported. We also provide morphological and molecular data from four further putative species of Clinostomum (morphotypes 1-4) from different areas of Africa, as well as the first report of C. phalacrocoracis in South Africa. PMID- 28653594 TI - The fruit and vegetable intake of young Australian adults: a population perspective. AB - OBJECTIVE: To examine intakes and variety of fruit and vegetables consumed by Australian young adults, also assessing differences by meal occasion and sociodemographic characteristics. DESIGN: Secondary analysis of cross-sectional 24 h recall data collected through the 2011-12 National Nutrition and Physical Activity Survey. Crude means and proportions consuming fruits and vegetables were calculated. Pearson chi 2 tests, Kruskal-Wallis analyses and linear regression models were used to assess differences in mean intakes by age, BMI and sociodemographic variables. The variety eaten was determined based on the number of fruit and vegetable subgroups consumed. SETTING: Representative sample of metropolitan and rural areas across Australia. SUBJECTS: Respondents aged 18-34 years were included (n 2397). RESULTS: Mean daily intake of fruit (128 g/0.9 servings) and vegetables (205 g/2.7 servings) was lower than the minimum recommended intake set at 2 and 5 servings, respectively. Age was positively associated with fruit and vegetable intake (P=0.002, P<0.001), with 18-24-year olds reporting the poorest vegetable variety compared with 25-29- and 30-34-year olds (P=0.002). When controlling for total energy, males consumed less vegetables than females (P=0.002). A large proportion of the 15 % of respondents who consumed adequate amounts of fruits and vegetables on the day prior to the survey reported intake across all meal occasions (P<0.001). CONCLUSIONS: Fruit and vegetable intake is suboptimal among Australian young adults. An age-appropriate campaign is recommended to target increased consumption, particularly for those aged 18-24 years, with opportunity to promote increased variety and consumption across the day. PMID- 28653595 TI - Cohort differences in exercise adherence among primary care patients referred for mental health versus physical health conditions. AB - : Aim To compare the characteristics of mental health and physical health participants attending an exercise referral scheme (ERS) and investigate associations with their adherence to exercise. BACKGROUND: While people referred to an ERS with a mental health diagnosis have similar initial rates of uptake as physical health participants, they are more likely to drop out. Comparisons of the groups to understand their differences and how these might impact on their adherence have been limited by the typically low numbers of mental health referrals in many schemes. METHODS: Retrospective analysis of a participant cohort. Data were extracted on all participants enrolled over a 12- month period (n = 701) and included measurements at baseline, mid-point (13 weeks) and end of programme (20-26 weeks). Differences were explored between the mental health (n=141) and physical health (n=560) subcohorts, and between adherers and non adherers in each group. Binomial logistic regression estimated the effect of group-level factors associated with adherence. Findings Mental health referrals were more likely to be younger, White and unemployed, and had a lower mean body mass index and lower proportion of participants with high blood pressure. They were also more likely to drop out. While occupation was associated with exercise adherence among the physical health group, no predictive factors were identified in the mental health group. CONCLUSION: Participants referred for mental health disorders are more likely to drop out of exercise referral schemes than those with physical health problems. While no factors were found to be predictive of their exercise adherence, an understanding of their distinguishing characteristics and attendance behaviour can guide in making better referral decisions concerning them and planning more appropriately tailored support. PMID- 28653596 TI - Worms at war: interspecific parasite competition and host resources alter trematode colony structure and fitness. AB - Parasites competing over limited host resources are faced with a tradeoff between reproductive success and host overexploitation jeopardizing survival. Surprisingly little is known about the outcome of such competitive scenarios, and we therefore aimed at elucidating interactions between the trematodes Himasthla elongata and Renicola roscovita coinfecting the periwinkle first intermediate host. The results show that the success of Himasthla colonies (rediae) in terms of cercarial emission is unaffected by Renicola competition (sporocysts), whereas deteriating host condition decreases fitness. Furthermore, double infection has no bearing on Himasthla's colony size but elevated the proportion of non reproductive rediae that play a decisive role in colony defence. Opposite, the development of the Renicola colony (size/maturity), and in turn fitness, is markedly reduced in presence of Himasthla, whereas the nutritional state of the host appears less important. Hence, the intramolluscan competition between Himasthla and Renicola is asymmetrical, Himasthla being the superior competitor. Himasthla not only adjusts its virulence according to the hosts immediate nutritional state, it also nullifies the negative impact of a heterospecific competitor on own fitness. The latter is argued to follow in part from direct predation on the competitor, for which purpose more defensive non-reproductive rediae are strategically produced. PMID- 28653597 TI - Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis. AB - New oral treatments are needed for all forms of leishmaniasis. Here, the improved oral efficacy of quercetin (Qc) and its penta-acetylated derivative (PQc) was evaluated in cutaneous leishmaniasis after encapsulation in lipid-core nanocapsules (LNCs) of poly(epsilon-caprolactone). Leishmania amazonensis infected BALB/c mice were given 51 daily oral doses of free drugs (16 mg kg-1) or LNC-loaded drugs (0.4 mg kg-1). While treatment with free Qc reduced the lesion sizes and parasite loads by 38 and 71%, respectively, LNC-Qc produced 64 and 91% reduction, respectively. The antileishmanial efficacy of PQc was similar but not as potently improved by encapsulation as Qc. None of the treatments increased aspartate aminotransferase, alanine aminotransferase or creatinine serum levels. These findings indicate that when encapsulated in LNC, Qc and, to a lesser extent, PQc can safely produce an enhanced antileishmanial effect even at a 40 fold lower dose, with implications for the development of a new oral drug for cutaneous leishmaniasis. PMID- 28653598 TI - Identifying attributes of food literacy: a scoping review. AB - OBJECTIVE: An absence of food literacy measurement tools makes it challenging for nutrition practitioners to assess the impact of food literacy on healthy diets and to evaluate the outcomes of food literacy interventions. The objective of the present scoping review was to identify the attributes of food literacy. DESIGN: A scoping review of peer-reviewed and grey literature was conducted and attributes of food literacy identified. Subjects included in the search were high-risk groups. Eligible articles were limited to research from Canada, USA, the UK, Australia and New Zealand. RESULTS: The search identified nineteen peer-reviewed and thirty grey literature sources. Fifteen identified food literacy attributes were organized into five categories. Food and Nutrition Knowledge informs decisions about intake and distinguishing between 'healthy' and 'unhealthy' foods. Food Skills focuses on techniques of food purchasing, preparation, handling and storage. Self-Efficacy and Confidence represent one's capacity to perform successfully in specific situations. Ecologic refers to beyond self and the interaction of macro- and microsystems with food decisions and behaviours. Food Decisions reflects the application of knowledge, information and skills to make food choices. These interdependent attributes are depicted in a proposed conceptual model. CONCLUSIONS: The lack of evaluated tools inhibits the ability to assess and monitor food literacy; tailor, target and evaluate programmes; identify gaps in programming; engage in advocacy; and allocate resources. The present scoping review provides the foundation for the development of a food literacy measurement tool to address these gaps. PMID- 28653599 TI - MicroRNA-539 Inhibits the Epithelial-Mesenchymal Transition of Esophageal Cancer Cells by Twist-Related Protein 1-Mediated Modulation of Melanoma-Associated Antigen A4. AB - MicroRNAs (miRs) play key roles in cancers, yet the potential molecular mechanisms of miR-539 on esophageal squamous cell carcinoma (ESCC) are not well understood. Utilizing informatics screening, Twist-related protein 1 (TWIST1) was hypothesized to be a possible target gene of miR-539. Since the melanoma associated antigen (MAGE) A4 is reported to be upregulated by TWIST1, this study aimed to examine the biological functions and mechanism involving TWIST1 and MAGE4 of miR-539 in ESCC. miR-539 mimics or scrambled miRs were transfected into human ESCC TE3 cells to interfere with the expression of miR-539. Then qRT-PCR and Western blot analyses were performed to determine the expression levels of epithelial-mesenchymal transition (EMT)-related factors at mRNA and protein levels. The association between miR-539 and TWIST1 as well as TWIST1 and MAGEA4 was evaluated. The connection of miR-539 and TWIST1-MAGEA4 during the EMT progress of ESCC was also explored. Our data demonstrated that miR-539 inhibited the EMT of TE3 cells by downregulating TWIST1, and TWIST1 was a target of miR 539. Moreover, MAGEA4 was positively correlated with TWIST1, and its knockdown inhibited EMT in TE3 cells. Collectively, miR-539 could inhibit EMT in TE3 cells through TWIST1-mediated regulation of MAGEA4. All these findings suggested that miR-539 may be involved in the progression of ESCC and could be a new therapeutic target for this disease. PMID- 28653600 TI - miR-205 Inhibits Neuroblastoma Growth by Targeting cAMP-Responsive Element Binding Protein 1. AB - Accumulating evidence indicates that microRNA-205 (miR-205) is involved in tumor initiation, development, and metastasis in various cancers. However, its functions in neuroblastoma (NB) remain largely unclear. Here we found that miR 205 was significantly downregulated in human NB tissue samples and cell lines. miR-205 expression was lower in poorly differentiated NB tissues and those of advanced International Neuroblastoma Staging System stage. In addition, restoration of miR-205 in NB cells suppressed proliferation, migration, and invasion and induced cell apoptosis in vitro, as well as impaired tumor growth in vivo. cAMP-responsive element-binding protein 1 (CREB1) was identified as a direct target gene of miR-205. Expression of an miR-205 mimic in NB cells significantly diminished expression of CREB1 and the CREB1 targets BCL-2 and MMP9. CREB1 was also found to be upregulated in human NB tissues, its expression being inversely correlated with miR-205 expression (r = -0.554, p = 0.003). Importantly, CREB1 upregulation partially rescued the inhibitory effects of miR 205 on NB cells. These findings suggest that miR-205 may function as a tumor suppressor in NB by targeting CREB1. PMID- 28653601 TI - Dexmedetomidine Inhibits Osteosarcoma Cell Proliferation and Migration, and Promotes Apoptosis by Regulating miR-520a-3p. AB - This study aimed to investigate the effect of dexmedetomidine (DEX) on osteosarcoma (OS) cell line MG63 and to explore the possible relationship between DEX and miR-520-3p in OS. The results showed that DEX could upregulate miR-520 3p, which directly targeted AKT1. Additionally, miR-520-3p also inhibited MG63 cell proliferation and migration, promoted apoptosis, and suppressed protein expressions of AKT, p-AKT, p-mTOR, and p-ERK1/2. DEX can inhibit OS cell proliferation and migration and promote apoptosis by upregulating the expression level of miR-520a-3p. DEX may serve as a potential therapeutic agent in OS treatment, and miR-520a-3p may be a potential target in the therapy of OS. PMID- 28653602 TI - miR-144-3p Targets FosB Proto-oncogene, AP-1 Transcription Factor Subunit (FOSB) to Suppress Proliferation, Migration, and Invasion of PANC-1 Pancreatic Cancer Cells. AB - This study aimed to investigate the role of miR-144-3p in pancreatic cancer (PC) carcinogenesis and to explore the mechanism of its function in PC. miR-144-3p was downregulated in PC tissues and cells. miR-144-3p overexpression significantly inhibited PC cell proliferation, migration, and invasion. FosB proto-oncogene, AP 1 transcription factor subunit (FOSB) was a target gene of miR-144-3p. miR-144-3p could repress PC cell proliferation, migration, and invasion by inhibiting the expression of FOSB. In conclusion, miR-144-3p plays an important role in PC cell proliferation, migration, and invasion by targeting FOSB. miR-144-3p may provide a new target for the development of therapeutic agents against PC. PMID- 28653604 TI - MicroRNA-139-5p Inhibits Cell Proliferation and Invasion by Targeting RHO Associated Coiled-Coil-Containing Protein Kinase 2 in Ovarian Cancer. AB - Increasing evidence indicates that the dysregulation of microRNAs is associated with the development and progression of various cancers. MicroRNA-139-5p (miR-139 5p) has been reported to have a tumor suppressive role in many types of cancers. The role of miR-139-5p in ovarian cancer (OC) is poorly understood. The purpose of the present study was to explore the expression of miR-139-5p and its function in OC. The results showed that miR-139-5p expression was markedly downregulated in OC tissues and cell lines. In addition, underexpression of miR-139-5p was significantly associated with FIGO stage, lymph mode metastasis, and poor overall survival of OC patients. Functional analyses indicated that overexpression of miR 139-5p significantly inhibited proliferation, colony formation, migration, and invasion of OC cells. Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) was identified as a direct target of miR-139-5p using luciferase reporter assays, qualitative real-time reverse transcriptase PCR (qRT-PCR), and Western blot. In addition, ROCK2 expression was upregulated and was inversely correlated with miR-139-5p levels in OC tissues. Rescue experiments showed that overexpression of ROCK2 effectively reversed the inhibitory effect of OC cells induced by miR-139-5p. Most interestingly, in vivo studies indicated that miR-139 5p markedly suppressed the growth of tumors by repressing ROCK2 expression in nude mice. Taken together, these findings demonstrated that miR-139-5p plays an important tumor suppressor role in OC by directly binding to ROCK2, providing a novel target for the molecular treatment of OC. PMID- 28653605 TI - WITHDRAWN: Knockdown of LncRNA HOXA11 Antisense Promotes Glioma Cell Apoptosis Via Sponging MiR-140-5p. AB - Long non-coding RNAs (lncRNAs) are proved as important regulators in many diseases, including multiple cancers. HOXA11antisense RNA (HOXA11-AS) is a novel identified lncRNA associated with cancer progression. However, the role of HOXA11 AS in glioma remains poorly understood and needs to be elucidated. The purpose of this study is to investigate the role and regulating mechanism of HOXA11-AS on gliomagenesis. Expression of HOXA11-AS was significantly up-regulated in glioma tissue and cell lines compared to the adjacent normal tissue and cells. Moreover, patients with high HOXA11-AS expression had a shorter survival time and poorer prognosis than that of lower expression. Loss-of-function experiments revealed that HOXA11-AS knockdown inhibited the proliferation, induced cell cycle arrest at G0/G1 phase and enhanced the apoptosis. Bioinformatics prediction forecast that miR-140-5p directly targeted HOXA11-AS at 3'-UTR, which was confirmed by luciferase reporter assay. In vitro rescue experiment assays, miR-140-5p inhibitor transfection could reverse the function of HOXA11-AS knockdown on the proliferation, cell cycle arrest and apoptosis. Together, present study illustrates that the pathway of HOXA11-AS sponging miR-140-5p might play a vital regulating role in the development and progression of glioma. PMID- 28653606 TI - miR-181a-5p Promotes Proliferation and Invasion and Inhibits Apoptosis of Cervical Cancer Cells via Regulating Inositol Polyphosphate-5-Phosphatase A (INPP5A). AB - Expression of miR-181a-5p associates with the proliferation and progression of cancer cells via its targets. This study was designed to investigate the effect of miR-181a-5p and its target inositol polyphosphate-5-phosphatase A (INPP5A) on the progression of cervical cancers. Upregulation of miR-181a-5p was revealed in the cervical cancer cell lines HeLa and SiHa in comparison with a normal cervical epithelium cell line End1/E6E7 (p < 0.001). The inhibition and upregulation of miR-181a-5p in cervical cancer cell lines significantly reduced or increased cell proliferation and invasion capacity, accompanied with enhanced or reduced apoptosis (p < 0.05). Moreover, INPP5A overexpression significantly inhibited cell proliferation and invasion capacity and enhanced cell apoptosis. The target relationship of miR-181a-5p to INPP5A was demonstrated by both the results of the Dual-Luciferase Reporter Assay and the fact that the miR-181a-5p mimic attenuated INPP5A's effect on cell proliferation, invasion, and apoptosis. To sum up, the overexpression of miR-181a-5p enhanced cell proliferation and invasion and inhibited apoptosis of cervical cancer cells by negatively targeting INPP5A. Therefore, inhibition of miR-181a-5p might benefit the inhibition of cervical cancer cell invasion. PMID- 28653607 TI - Overexpression of Glutathione S-transferase P1 Inhibits the Viability and Motility of Prostate Cancer via Targeting MYC and Inactivating the MEK/ERK1/2 Pathways. AB - Prostate cancer (PC) is one of the most common malignancies of men. Glutathione S transferase P1 (GSTP1) has been suggested to play a protective role in the prostate. The proto-oncogene MYC has been extensively proved to be a key regulator of tumor transformation from early stage to malignant. Our study aims to investigate the mechanism of GSTP1 in the biological behavior of PC. Compared with normal prostate tissues, the expression of GSTP1 was decreased in PC tissues. Conversely, the level of MYC was increased in PC tissues compared with normal tissues. MYC was convinced a direct target of GSTP1. Besides, the overexpression of GSTP1 or MYC siRNA strongly reduced cell viability via decreasing the volume of cell spheres and cell proliferation rate. GSTP1 overexpression or MYC siRNA also decreased cell motility of PC via reducing the closing rate of scratch wounds and the number of invasive cells. We further explored the underlying mechanism, and found that the level of p-MEK and p-ERK1/2 was strongly decreased in PC3 cells with pcDNA-GSTP1 or MYC siRNA transfection compared with control group. The inhibitory effect on cell viability, p-MEK and p ERK1/2 was stronger when pcDNA-GSTP1 and MYC siRNA function together. Finally, the in vivo experiment displayed that pcDNA-GSTP1 transfection reduced tumor growth and tumor volume in PC xenografts. The decreased level of metastasis related proteins VEGF (vascular endothelial growth factor) and MMP (metal matrix proteinase)-9 in GSTP1 overexpression model mice was detected by immunohistochemistry. Besides, the expression of MYC, p-MEK and p-ERK1/2 was strongly inhibited in mice with pcDNA-GSTP1 transfection. Taken together, our research indicates that GSTP1 overexpression inhibits the viability and motility of PC in vitro and in vivo, and may through targeting MYC and inactivating MEK/ERK1/2 pathway. PMID- 28653608 TI - MicroRNA-138 Inhibits Cell Growth, Invasion, and EMT of Non-Small Cell Lung Cancer via SOX4/p53 Feedback Loop. AB - Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop. PMID- 28653609 TI - Long Noncoding RNA MEG3 Inhibits Cell Proliferation and Metastasis in Chronic Myeloid Leukemia via Targeting miR-184. AB - Maternally expressed gene 3 (MEG3), a long noncoding RNA, has been reported to be associated with the pathogenesis of multiple malignancies. However, little is known regarding the role of MEG3 in leukemia. In this study, we found that the expression of MEG3 was decreased in leukemia patients and cell lines and has potential to be considered as a biomarker for leukemia. In addition, overexpression of MEG3 inhibited cell proliferation and invasion in vitro and in vivo. Moreover, a potential bonding site between miR-184 and MEG3 was predicted, and low expression of miR-184 was found in leukemia patients and cell lines. In vitro loss and gain of function showed that overexpression of MEG3 significantly decreased the expression of miR-184, and MEG3 knockdown markedly increased it. Furthermore, our results showed that MEG3 interacted with miR-184 and subsequently mitigated the proliferation and invasion of leukemia cells by downregulating related proteins. In conclusion, our study has identified a novel pathway through which MEG3 acts as a tumor suppressor in leukemia at the level of miRNAs and provided a molecular basis for potential applications of MEG3 in the prognosis and treatment of leukemia. PMID- 28653610 TI - WITHDRAWN: Downregulation of MicroRNA-152 and Inhibition of Cell Proliferation, Migration, and Invasion in Breast Cancer. AB - Ahead of Print article withdrawn by publisher. PMID- 28653611 TI - Interval versus external fixation for the treatment of pelvic fractures: a comparative study. AB - PURPOSE: This retrospective study evaluated the efficacy and safety of internal fixation (IF) in the treatment of pelvic fractures (PF). METHODS: A total of 263 unstable PF patients were treated from February 2009 to April 2015. Patients were divided into two groups according to type of fixation used to treat their PF: 136 cases received IF surgery (IF group); and, 127 cases received external fixation (EF) surgery (EF group). Postoperative follow-ups were conducted to record the clinical data, perioperative clinical indicators, Matta scores for fracture displacements, Majeed scores for hip functions and postoperative complications. RESULTS: Operation time, blood loss, the total length of the wound, postoperative fever rate, hospitalization time and complication rate for the IF group were significantly decreased in comparison with the EF group, while the ratings of pain, working and sitting ability and Matta and Majeed scores of the IF group were significantly higher than those of the EF group. CONCLUSION: IF was found to be associated with shorter operation times, less blood loss and better postoperative rehabilitation in comparison with EF, suggesting that it is an effective therapy for the treatment of unstable PF and will lead to restoration of normal pelvis functions. PMID- 28653612 TI - Addition of dexmedetomidine to bupivacaine in supraclavicular brachial plexus block. AB - PURPOSE: Research is ongoing to determine the lowest dose of local anesthetics in brachial plexus block that provides adequate anesthesia and postoperative analgesia and reduces complications related to local anesthetics. METHODS: Patients 18-65 years of age who underwent upper limb surgery and who received ultrasound-guided supraclavicular brachial plexus block at the Erciyes University Faculty of Medicine Hospital between February 2014 and January 2015 were included in the study (n=50). Supraclavicular brachial plexus blocks were performed on Group B cases by adding 30 ml 0.33% bupivacaine and on Group BD cases by adding 15 ml 0.33% bupivacaine and 1 ug / kg dexmedetomidine. Block success was evaluated by the onset and block duration of motor and sensory block and the duration of analgesia. RESULTS: The block success of Group B and Group BD was 92.6% and 89.3%, respectively (P = 1.000). Onset time of sensory block, degree of sensory block, duration of sensory block, onset time of motor block, degree of motor block and duration of motor block were similar in both groups in the intergroup comparison (P > 0.05). Duration of analgesia and the operative conditions of groups were similar (P > 0.05). CONCLUSIONS: In the implementation of ultrasound-guided supraclavicular brachial plexus block, block success, sensory and motor block and analgesia duration were similar for patients anaesthetized with 30 ml of bupivacaine in comparison with dexmedetomidine+bupivacaine (when the bupivacaine dose was reduced by 50% by the addition of the adjuvant). PMID- 28653613 TI - Myopia correction in children: a meta-analysis. AB - PURPOSE: The purpose of this study was to conduct a meta-analysis comparing rigid gas permeable lenses (RGP) with soft contact lenses (SCL), spectacles and orthokeratology (OK) lenses for myopia control with respect to axial length elongation, spherical equivalent and measures of corneal curvature. METHODS: Medline, Cochrane, EMBASE, and Google Scholar databases were searched to September 29, 2015 using the following keywords: rigid gas permeable contact lens; refractive error; and refractive abnormalities. Randomized controlled trials, two-arm prospective studies and retrospective studies of children with myopia treated with RGP lenses compared with spectacles, SCL, and OK lenses were included. Outcome measures were changes of axial length, spherical equivalent, flatter meridian, steeper meridian and corneal apical radius. RESULTS: Five studies were included. Three studies reported axial length change after 2-3 years of treatment with RGP lenses and SCL/spectacles and no difference between the groups was noted (pooled mean difference = -0.077, 95% confidence interval [CI]: 0.120 to 0.097, p = 0.840). Two studies reported a change of spherical equivalent after 2-3 years of treatment with RGP lenses and SCL/spectacles, and no difference between the groups was noted (pooled mean difference = 0.275, 95% CI: 0.390 to 0.941, p = 0.417). Two studies compared corneal curvature measures between RGP and OK lenses after 3-6 months of treatment and no differences in any measures of corneal curvature were seen. CONCLUSIONS: The effect of RGP lenses and SCL/spectacles on axial length elongation and spherical equivalent and of RGP and OK lenses on corneal curvature in children with myopia was similar. PMID- 28653614 TI - Conservative management and health-related quality of life in end-stage renal disease: a systematic review. AB - PURPOSE: Few studies have addressed health-related quality of life (QoL) in patients who chose conservative management over dialysis. This systematic review aims to better define the role of conservative management in improving health related QoL in patients with end-stage renal disease (ESRD). METHODS: Medline, Cochrane and EMBASE were searched for prospective or retrospective studies published until June 30, 2016, that examined QoL of ESRD patients. The primary outcome was health-related QoL. RESULTS: Four studies were included (405 patients received dialysis and 332 received conservative management). Two studies that used the Short Form-36 Survey (SF-36) showed that the dialysis group had higher physical component scores, but the conservative management group had similar, or better, mental component scores at the end of intervention. Another study using the SF-36 showed that the physical and mental component scores of the dialysis group did not significantly change after intervention. In the conservative management group, the physical component scores did not change, but the mental component scores increased significantly over time (0.12 +/- 0.32, p < 0.05). One study, which used the Kidney Disease Quality of Life-Short Form (KD QoL-SF), found no change after intervention in either physical or mental component scores in the dialysis group; however, the physical component score declined (p = 0.047) and the mental component score increased (p = 0.033) in the conservative management group. CONCLUSION: Although there are only a limited number of published articles, ESRD patients who receive conservative management may have improved mental health-related QoL when compared with those who receive dialysis. PMID- 28653615 TI - Maternal and neonatal morbidity: repeat Cesarean versus a trial of labour after previous Cesarean delivery. AB - PURPOSE: The purpose of this study was to perform a meta-analysis comparing the rates of uterine rupture, and other maternal and neonatal complications, between women who undergo a trial of labour (TOL) after a prior Cesarean delivery and those to undergo elective repeat Cesarean delivery (ERCD). SOURCE: Medline, Cochrane, EMBASE and Google Scholar were searched until May 6, 2015 using the keywords/phrases: trial of labour, Cesarean section, elective, repeat, pregnancy and vaginal birth. Randomized controlled trials (RCTs), two-arm prospective studies, one-arm studies and retrospective studies were included. The primary outcome was uterine rupture. PRINCIPAL FINDINGS: Sixteen studies were included in the meta-analysis. TOL after prior Cesarean delivery was associated with higher odds of uterine rupture as compared with ERCD (Peto odds ratio [OR] = 4.685, 95% confidence interval [CI]: 3.077 to 7.133, p < 0.001). TOL was associated with a higher rate of endometritis, a lower rate of hysterectomy, and a lower rate of respiratory problems in newborns. There were no differences between the groups with respect to neonatal intensive care unit admissions, postpartum hemorrhage, thromboembolic disease, sepsis and neonatal mortality. CONCLUSIONS: TOL may be associated with a higher risk of uterine rupture and endometritis, but lower risk of hysterectomy and neonatal respiratory problems than ERCD. PMID- 28653616 TI - Head-to-head comparisons of bisphosphonates and teriparatide in osteoporosis: a meta-analysis. AB - PURPOSE: This meta-analysis aimed to compare the efficacy and safety of teriparatide vs. bisphosphonates in the management of osteoporosis. METHODS: A total of 1,967 patients from eight randomized controlled trials were analyzed; outcomes included bone mineral density (BMD) of the femoral neck, total hip and lumbar spine, vertebral and nonvertebral fractures and any adverse event. A subgroup analysis of treatment effectiveness was performed according to the etiology of osteoporosis; i.e., glucocorticoid-induced osteoporosis (GIO) vs. post-menopausal osteoporosis (PO). RESULTS: Teriparatide increased the BMD of the lumbar spine, femoral neck and total hip to a greater extent than bisphosphonates. Patients treated with teriparatide also had a lower risk of vertebral fractures compared with bisphosphonates; however, no difference in risk of nonvertebral fractures (or adverse events) was found. GIO subgroups showed larger increases in BMD of the lumbar spine, total hip and femoral neck in patients treated with teriparatide compared with bisphosphonates. The PO subgroup showed larger increases in BMD of the lumbar spine in patients treated with teriparatide compared with bisphosphonates. Patients in the GIO subgroup (but not the PO subgroup) were less likely to suffer a vertebral fracture on teriparatide as compared with bisphosphonates. In contrast, no significant difference in the percentage of nonvertebral fractures was noted between the two types of treatment for either subgroup. CONCLUSION: Teriparatide significantly increased the BMD of lumbar spine, total hip and femoral neck, particularly in GIO-induced osteoporosis. Teriparatide did not lower the risk of nonvertebral fractures when compared with bisphosphonates. PMID- 28653617 TI - Replication Study: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. AB - In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al., 2011). Further, I-BET151 resulted in a statistically significant decrease in BCL2 expression in MV4;11 cells, but not in K-562 cells; again this is similar to the findings reported in the original study (Figure 3D; Dawson et al., 2011). We did not find a statistically significant difference in survival when testing I-BET151 efficacy in a disseminated xenograft MLL mouse model, whereas the original study reported increased survival in I-BET151 treated mice compared to vehicle control (Figure 4B,D; Dawson et al., 2011). Differences between the original study and this replication attempt, such as different conditioning regimens and I-BET151 doses, are factors that might have influenced the outcome. We also found I-BET151 treatment resulted in a lower median disease burden compared to vehicle control in all tissues analyzed, similar to the example reported in the original study (Supplementary Figure 16A; Dawson et al., 2011). Finally, we report meta-analyses for each result. PMID- 28653618 TI - Poly(A) tail length regulates PABPC1 expression to tune translation in the heart. AB - The rate of protein synthesis in the adult heart is one of the lowest in mammalian tissues, but it increases substantially in response to stress and hypertrophic stimuli through largely obscure mechanisms. Here, we demonstrate that regulated expression of cytosolic poly(A)-binding protein 1 (PABPC1) modulates protein synthetic capacity of the mammalian heart. We uncover a poly(A) tail-based regulatory mechanism that dynamically controls PABPC1 protein synthesis in cardiomyocytes and thereby titrates cellular translation in response to developmental and hypertrophic cues. Our findings identify PABPC1 as a direct regulator of cardiac hypertrophy and define a new paradigm of gene regulation in the heart, where controlled changes in poly(A) tail length influence mRNA translation. PMID- 28653619 TI - Semen amyloids participate in spermatozoa selection and clearance. AB - Unlike other human biological fluids, semen contains multiple types of amyloid fibrils in the absence of disease. These fibrils enhance HIV infection by promoting viral fusion to cellular targets, but their natural function remained unknown. The similarities shared between HIV fusion to host cell and sperm fusion to oocyte led us to examine whether these fibrils promote fertilization. Surprisingly, the fibrils inhibited fertilization by immobilizing sperm. Interestingly, however, this immobilization facilitated uptake and clearance of sperm by macrophages, which are known to infiltrate the female reproductive tract (FRT) following semen exposure. In the presence of semen fibrils, damaged and apoptotic sperm were more rapidly phagocytosed than healthy ones, suggesting that deposition of semen fibrils in the lower FRT facilitates clearance of poor quality sperm. Our findings suggest that amyloid fibrils in semen may play a role in reproduction by participating in sperm selection and facilitating the rapid removal of sperm antigens. PMID- 28653621 TI - A tail of translational regulation. AB - An RNA-binding protein called PABPC1 has an important role in determining protein synthesis rates and hypertrophy in the heart. PMID- 28653620 TI - Cryo-electron tomography reveals novel features of a viral RNA replication compartment. AB - Positive-strand RNA viruses, the largest genetic class of viruses, include numerous important pathogens such as Zika virus. These viruses replicate their RNA genomes in novel, membrane-bounded mini-organelles, but the organization of viral proteins and RNAs in these compartments has been largely unknown. We used cryo-electron tomography to reveal many previously unrecognized features of Flock house nodavirus (FHV) RNA replication compartments. These spherular invaginations of outer mitochondrial membranes are packed with electron-dense RNA fibrils and their volumes are closely correlated with RNA replication template length. Each spherule's necked aperture is crowned by a striking cupped ring structure containing multifunctional FHV RNA replication protein A. Subtomogram averaging of these crowns revealed twelve-fold symmetry, concentric flanking protrusions, and a central electron density. Many crowns were associated with long cytoplasmic fibrils, likely to be exported progeny RNA. These results provide new mechanistic insights into positive-strand RNA virus replication compartment structure, assembly, function and control. PMID- 28653622 TI - Simultaneous measurement of chromatin accessibility, DNA methylation, and nucleosome phasing in single cells. AB - Gaining insights into the regulatory mechanisms that underlie the transcriptional variation observed between individual cells necessitates the development of methods that measure chromatin organization in single cells. Here I adapted Nucleosome Occupancy and Methylome-sequencing (NOMe-seq) to measure chromatin accessibility and endogenous DNA methylation in single cells (scNOMe-seq). scNOMe seq recovered characteristic accessibility and DNA methylation patterns at DNase hypersensitive sites (DHSs). An advantage of scNOMe-seq is that sequencing reads are sampled independently of the accessibility measurement. scNOMe-seq therefore controlled for fragment loss, which enabled direct estimation of the fraction of accessible DHSs within individual cells. In addition, scNOMe-seq provided high resolution of chromatin accessibility within individual loci which was exploited to detect footprints of CTCF binding events and to estimate the average nucleosome phasing distances in single cells. scNOMe-seq is therefore well-suited to characterize the chromatin organization of single cells in heterogeneous cellular mixtures. PMID- 28653623 TI - Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2 hydroxyglutarate. AB - In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fiehn et al., 2016), that described how we intended to replicate selected experiments from the paper "The common feature of leukemia associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate" (Ward et al., 2010). Here, we report the results of those experiments. We found that cells expressing R172K mutant IDH2 did not display isocitrate-dependent NADPH production above vector control levels, in contrast to the increased production observed with wild-type IDH2. Conversely, expression of R172K mutant IDH2 resulted in increased alpha ketoglutarate-dependent consumption of NADPH compared to wild-type IDH2 or vector control. These results are similar to those reported in the original study (Figure 2; Ward et al., 2010). Further, expression of R172K mutant IDH2 resulted in increased 2HG levels within cells compared to the background levels observed in wild-type IDH2 and vector control, similar to the original study (Figure 3D; Ward et al., 2010). In primary human AML samples, the 2HG levels observed in samples with mutant IDH1 or IDH2 status were higher than those observed in samples without an IDH mutation, similar to what was observed in the original study (Figure 5C; Ward et al., 2010). Finally, we report meta-analyses for each result. PMID- 28653625 TI - Between the devil and the deep blue sea. PMID- 28653624 TI - Parallel evolution of influenza across multiple spatiotemporal scales. AB - Viral variants that arise in the global influenza population begin as de novo mutations in single infected hosts, but the evolutionary dynamics that transform within-host variation to global genetic diversity are poorly understood. Here, we demonstrate that influenza evolution within infected humans recapitulates many evolutionary dynamics observed at the global scale. We deep-sequence longitudinal samples from four immunocompromised patients with long-term H3N2 influenza infections. We find parallel evolution across three scales: within individual patients, in different patients in our study, and in the global influenza population. In hemagglutinin, a small set of mutations arises independently in multiple patients. These same mutations emerge repeatedly within single patients and compete with one another, providing a vivid clinical example of clonal interference. Many of these recurrent within-host mutations also reach a high global frequency in the decade following the patient infections. Our results demonstrate surprising concordance in evolutionary dynamics across multiple spatiotemporal scales. PMID- 28653626 TI - Zika enhancement: a reality check. PMID- 28653628 TI - Corrections. PMID- 28653627 TI - Improving communication about viral hepatitis in Africa. PMID- 28653630 TI - Consequence of prioritising pathogens for global antibiotic research. PMID- 28653629 TI - How artificial is the antibiotic resistance definition? PMID- 28653631 TI - Fighting drug-resistant tuberculosis in eastern Europe. PMID- 28653632 TI - Post-migration follow-up of migrants at risk of tuberculosis. PMID- 28653633 TI - 23-valent pneumococcal polysaccharide vaccine against pneumococcal pneumonia. PMID- 28653634 TI - Guillain-Barre syndrome and arboviral infection in Brazil. PMID- 28653635 TI - HPV control and resistance in the Middle East and north Africa. PMID- 28653636 TI - Laminar flow: the better choice in orthopaedic implants. PMID- 28653637 TI - Laminar flow: the better choice in orthopaedic implants - Authors' reply. PMID- 28653638 TI - Neisseria meningitidis subdural empyema causing acute cauda equina syndrome. PMID- 28653639 TI - Integrating palliative care into neurological practice. PMID- 28653640 TI - Identification of patients at risk for poor outcome after mTBI. PMID- 28653641 TI - Gadolinium deposition: practical guidelines in the face of uncertainty. PMID- 28653642 TI - Corrections. PMID- 28653643 TI - Atrial fibrillation in high-risk patients with ischaemic stroke. PMID- 28653644 TI - Atrial fibrillation in high-risk patients with ischaemic stroke - Authors' reply. PMID- 28653645 TI - The cerebrovascular health of Thomas Aquinas. PMID- 28653646 TI - Early predictors of outcome after mild traumatic brain injury (UPFRONT): an observational cohort study. AB - BACKGROUND: Mild traumatic brain injury (mTBI) accounts for most cases of TBI, and many patients show incomplete long-term functional recovery. We aimed to create a prognostic model for functional outcome by combining demographics, injury severity, and psychological factors to identify patients at risk for incomplete recovery at 6 months. In particular, we investigated additional indicators of emotional distress and coping style at 2 weeks above early predictors measured at the emergency department. METHODS: The UPFRONT study was an observational cohort study done at the emergency departments of three level-1 trauma centres in the Netherlands, which included patients with mTBI, defined by a Glasgow Coma Scale score of 13-15 and either post-traumatic amnesia lasting less than 24 h or loss of consciousness for less than 30 min. Emergency department predictors were measured either on admission with mTBI-comprising injury severity (GCS score, post-traumatic amnesia, and CT abnormalities), demographics (age, gender, educational level, pre-injury mental health, and previous brain injury), and physical conditions (alcohol use on the day of injury, neck pain, headache, nausea, dizziness)-or at 2 weeks, when we obtained data on mood (Hospital Anxiety and Depression Scale), emotional distress (Impact of Event Scale), coping (Utrecht Coping List), and post-traumatic complaints. The functional outcome was recovery, assessed at 6 months after injury with the Glasgow Outcome Scale Extended (GOSE). We dichotomised recovery into complete (GOSE=8) and incomplete (GOSE<=7) recovery. We used logistic regression analyses to assess the predictive value of patient information collected at the time of admission to an emergency department (eg, demographics, injury severity) alone, and combined with predictors of outcome collected at 2 weeks after injury (eg, emotional distress and coping). FINDINGS: Between Jan 25, 2013, and Jan 6, 2015, data from 910 patients with mTBI were collected 2 weeks after injury; the final date for 6-month follow-up was July 6, 2015. Of these patients, 764 (84%) had post-traumatic complaints and 414 (45%) showed emotional distress. At 6 months after injury, outcome data were available for 671 patients; complete recovery (GOSE=8) was observed in 373 (56%) patients and incomplete recovery (GOSE <=7) in 298 (44%) patients. Logistic regression analyses identified several predictors for 6-month outcome, including education and age, with a clear surplus value of indicators of emotional distress and coping obtained at 2 weeks (area under the curve [AUC]=0.79, optimism 0.02; Nagelkerke R2=0.32, optimism 0.05) than only emergency department predictors at the time of admission (AUC=0.72, optimism 0.03; Nagelkerke R2=0.19, optimism 0.05). INTERPRETATION: Psychological factors (ie, emotional distress and maladaptive coping experienced early after injury) in combination with pre-injury mental health problems, education, and age are important predictors for recovery at 6 months following mTBI. These findings provide targets for early interventions to improve outcome in a subgroup of patients at risk of incomplete recovery from mTBI, and warrant validation. FUNDING: Dutch Brain Foundation. PMID- 28653648 TI - Gadolinium deposition in the brain: summary of evidence and recommendations. AB - Emerging evidence has linked MRI signal changes in deep nuclei of the brain with repeated administration of gadolinium-based contrast agents. Gadolinium deposits have been confirmed in brain tissue, most notably in the dentate nuclei and globus pallidus. Although some linear contrast agents appear to cause greater MRI signal changes than some macrocyclic agents, deposition of gadolinium has also been observed with macrocyclic agents. However, the extent of gadolinium deposition varies between agents. Furthermore, the clinical significance of the retained gadolinium in the brain, if any, remains unknown. No data are available in human beings or animals to show adverse clinical effects due to the gadolinium deposition in the brain. On behalf of the International Society for Magnetic Resonance in Medicine, we present recommendations for the clinical and research use of gadolinium-based contrast agents. These recommendations might evolve as new evidence becomes available. PMID- 28653647 TI - Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. AB - Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated with a characteristic 4-repeat tau neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic criteria include syndromes with few or mild symptoms that are suggestive of underlying PSP pathology and could provide an opportunity for earlier therapeutic interventions in the future. These criteria also include definitions for variant PSP syndromes with different patterns of movement, language, or behavioural features than have been conclusively associated with PSP pathology. Data from new diagnostic biomarkers can be combined with the clinical features of disease to increase the specificity of the new criteria for underlying PSP pathology. Because PSP is associated with tau protein abnormalities, there is growing interest in clinical trials of new tau-directed therapies. These therapies are hypothesised to have disease-modifying effects by reducing the concentration of toxic forms of tau in the brain or by compensating for loss of tau function. Since tau pathology is also central to Alzheimer's disease and chronic traumatic encephalopathy, a successful tau therapeutic for PSP might inform treatment of other neurodegenerative diseases. PMID- 28653649 TI - Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase. AB - Phenylketonuria (PKU) and hyperphenylalaninemia (HPA) are a group of genetic disorders predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. To date, more than 950 variants have been identified, however the pathogenic mechanism of many variants remains unknown. In this study, in silico prediction and in vitro prokaryotic and eukaryotic expression systems were used to functionally characterize five PAH missense variants (p.F233I, p.R270I, p.F331S, p.S350Y, and p.L358F) previously identified in Slovak and Czech patients. p.F233I, p.R270I, and p.S350Y were classified as deleterious mutations since they showed no specific activity in functional assay and no response to chaperone co-expression. Protein levels of these PAH variants were very low when expressed in HepG2 cells, and only p.S350Y responded to BH4 precursor overload by significant increase in PAH monomer, probably due to reduced rate of protein degradation as the result of proper protein folding. Variants p.F331S and p.L358F exerted residual enzymatic activity in vitro. While the first can be classified as probably pathogenic due to its very low protein levels in HepG2 cells, the latter is considered to be mild mutation with protein levels of approximately 17.85% compared to wt PAH. Our findings contribute to better understanding of structure and function of PAH mutated enzymes and optimal treatment of PKU patients carrying these mutations using BH4 supplementation. PMID- 28653650 TI - Cross-reacting material 197 (CRM197) affects actin cytoskeleton of endothelial cells. AB - CRM197, cross-reacting material 197, is a mutant of diphtheria toxin (DTx). CRM197 is used in pharmacology as a carrier protein. It has been recently shown that CRM197 causes breakdown in actin filaments. In order to show intracellular localization of CRM197 and visualize cell structure via actin cytoskeleton, endothelial cells were cultured and subjected to CRM197 in vitro. To address the interaction between CRM197 and actin both experimental and theoretical studies were carried out. Colocalization of CRM197 with actin filaments was determined by immunofluorescence microscopy. Following 24-hour incubation, the loss of cell cell contact between cells was prominent. CRM197 was shown to bind to G-actin by gel filtration chromatography, and this binding was confirmed by Western blot analysis of eluted samples obtained following chromatography. Based on crystal structure, docked model of CRM197-actin complex was generated. Molecular dynamics simulation revealed that Lys42, Cys218, Cys233 of CRM197 interacts with Gly197, Arg62 and Ser60 of G-actin, respectively. CRM197 binding to G-actin, colocalization of CRM197 with actin filament, and actin cytoskeleton rearrangement resulting in the loss of cell-cell contact show that actin comes into sight as target molecule for CRM197. PMID- 28653651 TI - Biodegradable nanoparticles loaded with tetrameric melittin: preparation and membrane disruption evaluation. AB - Melittin is the main component of bee venom consisting of 26 amino acids that has multiple effects, including antibacterial, antiviral and anti-inflammatory in various cell types. This peptide forms pores in biological membranes and triggers cell death. Therefore it has potential as an anti-cancer therapy. However, the therapeutic application of melittin is limited due to its main side effect, hemolysis, which is especially pronounced following intravenous administration. In the present study, we formulated tetrameric melittin-carrying poly-D,L-lactic co-glycolic acid nanoparticles (PLGA-NPs) and analyzed the lytic activity of this system on liposomes that resembles breast cancer cells. Tetrameric melittin binds avidly to PLGA-NPs with an encapsulation efficiency of 97% and retains its lytic activity demonstrating the effectiveness of PLGA-NPs as nanocarriers for this cytolytic peptide. PMID- 28653652 TI - Obesity- and age-related alterations in FAT/CD36 translocation and lipin-1 subcellular localization in skeletal muscle of the Zucker rats. AB - Fatty acid (FA) uptake and/or intramuscular triglyceride (TG) accumulation in skeletal muscle are increased in obesity, type 2 diabetes and aging. FA translocase (FAT/CD36) translocation, lipin-1 subcellular localization and nuclear factor kappa B (NF-kappaB) p65 protein content in quadriceps muscle of young and old obese Zucker fa/fa rats and their lean controls were analyzed by immunoblot to define obesity- and aging-related alterations in FA uptake, their subsequent metabolic fate and potential to activate pro-inflammatory signaling. As expected, obesity increased FAT/CD36 content in plasma membrane in quadriceps muscle of fa/fa rats. Aging increased cytosolic lipin-1 content in both, obese rats and their lean controls. Also, old obese rats had decreased level of nuclear extract lipin-1compared to that in old lean rats. Neither obesity nor age altered NF-kappaB p65 protein content in cytosol and nuclear extract of quadriceps muscle suggesting that obesity/aging-induced changes in FA handling are not accompanied by NF-kappaB-mediated inflammation. Increase in plasma membrane FAT/CD36 content in obese rats and failure in lipin-1 export to nucleus with progression of obesity, implying an increase in FA uptake and their different channeling into lipid intermediates synthesis pathway in old fa/fa rats versus FA usage in lean rats of the same age. PMID- 28653653 TI - Effect of lipoic acid on paraoxonase-1 and paraoxonase-3 protein levels, mRNA expression and arylesterase activity in liver hepatoma cells. AB - Paraoxonase-1 (PON1) and PON3 (PON3) are anti-atherosclerotic enzymes, synthesized primarily in liver and bound to HDL in circulation. The aim of the present study was to investigate the effects of therapeutic doses of lipoic acid on PON1 and PON3 protein levels, mRNA expression and arylesterase activity in liver. We treated HepG2 cells with 10, 40 and 200 MUM lipoic acid for 72 h. Cell viability was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assay. PON1 and PON3 protein levels were measured by Western blotting, their mRNA expression was measured by quantitative PCR and arylesterase activity was measured spectrophotometrically. 200 uM lipoic acid caused a significant increase on PON1 and PON3 protein levels and arylesterase activity as compared with control, 10 uM and 40 uM lipoic acid-treated cells. 200 uM lipoic acid also caused a significant decrease on PON1 mRNA expression whereas on a significant increase PON3 mRNA expression as compared with control, 10 uM and 40 uM lipoic acid-treated cells. Our study showed that although lipoic acid up regulates PON3 but down-regulates PON1 mRNA expression, it increases both PON1 and PON3 protein levels and arylesterase activity in HepG2 cells. We can report that lipoic acid may be useful for preventing atherosclerosis at therapeutic doses. PMID- 28653654 TI - MPP1 interacts with DOPC/SM/Cholesterol in an artificial membrane system using Langmuir-Blodgett monolayer. AB - The interaction between membrane palmitoylated protein -1 (MPP1) with lipid bi- and mono-layers composed of a DOPC/SM/Chol mixture was investigated. MPP1 co migrates with liposomes to the top of the liposome flotation gradient, indicating binding of MPP1 with liposomes. The injection of MPP1 into the subphase of an LB monolayer of the above lipid composition induced an increase in surface pressure, indicating that MPP1 molecules were incorporated into the lipid monolayer. The compressibility modulus isotherms of MPP1, lipids and lipid-MPP1 films have essentially different shapes from one another. Pure MPP1 isotherms were characterized by a peak in surface pressure of 25-35 mNm-1. This transition disappears in isotherms obtained with lipid monolayers in the presence of MPP1, which suggests an interaction between the protein and the lipid monolayers. In addition, this interaction is sensitive to the presence of cholesterol in the lipid monolayer, as adding of MPP1 into the subphase of lipid monolayers containing cholesterol resulted in a much larger increase in surface area than when MPP1 is injected into the subphase of a lipid monolayer devoid of cholesterol. In conclusion, the data demonstrates that MPP1 interacts with lipid mixtures in two different model membrane systems. PMID- 28653655 TI - The role of microsomal oxidation in the regulation of monoamine oxidase activity in the brain and liver of rats. AB - It has been shown in our previous study that monoamine oxidase (MAO) activity in different brain regions are correlated with a microsomal oxidation phenotype. The data obtained in this study, using the microsomal oxidation inhibitor SKF525, and using animals with different duration of hexobarbital sleep, has shown that increased intensity of microsomal oxidation might be associated with increased MAO activity. Since the rats with short hexobarbital sleep time had higher content of hepatic microsomal cytochrome P450 than did rats with long hexobarbital sleep time. In addition, the rats with higher hepatic content of CYP450 had higher activities of MAO-A and MAO-B. Moreover, the microsomal oxidation inhibitor SKF-525 reduced brain and liver activities of MAOA and MAO-B. Consequently, MAO activities in a brain and a liver depend on the microsomal oxidation process. PMID- 28653656 TI - Effect of maternal renin-angiotensin-aldosterone system activation on social coping strategies and gene expression of oxytocin and vasopressin in the brain of rat offspring in adulthood. AB - The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 MUg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy. PMID- 28653657 TI - From two-dimensional nano-sheets to roll-up structures: expanding the family of nanoscroll. AB - The carbon nanoscroll (CNS), a spiral structure rolled up from a flat graphene sheet, has attracted significant attention due to its large surface area and broad electrochemical window. Despite the rapid emergence of many new two dimensional (2D) materials, studies on nanoscrolls beyond CNS, however, remain limited. In this work, we combine first-principles calculations and theoretical analyses to determine the stable configuration of nanoscrolls constructed from several 2D materials, including graphene, h-BN, MoS2, graphyne, phosphorene, and graphene oxide. Our study shows that the inner radius of these nanoscrolls ranges from 0.36-2.3 nm, significantly expanding that of CNS (about 1.2 nm). In addition, it is shown that the difference between the inner and outer pressures of nanoscrolls can be used to tune their core sizes. Furthermore, the effect of interlayer friction is found to be significant and may play a dominant role in determining the core sizes. The present study not only expands the nanoscroll family, but also enriches the understanding of nanoscrolls in terms of the effects of pressure and friction, thus widening the application range of nanoscrolls as nano-actuators, ion/water channels, nano-sensors, and hydrogen/energy storage devices, etc. PMID- 28653658 TI - Charge ordering and magnetic frustration in CsFe2F6. AB - The structural, electronic and magnetic properties of a charge-ordered iron fluoride material CsFe2+Fe3+F6 have been explored by density functional theory calculations based on the generalized gradient approximation + U approach, which was implemented in the VASP code. The material exhibits a 3D pyrochlore related structure which consists of corner-shared Fe2+F6 and Fe3+F6 octahedra. Our results confirm that CsFe2F6 is a Mott-Hubbard insulator, and bears a magnetically frustrated ground state in which the localized 3d electrons are antiferromagnetically coupled between the homogeneous Fe ions (Fe3+-Fe3+ along the b axis, and Fe2+-Fe2+ along the a axis), while interactions between the heterogeneous Fe ions (Fe3+-Fe2+ along the c axis) are frustrated, consistent with Goodenough-Kanamori superexchange interactions. Although the disproportionation of the total 3d charge is extremely low, explicit evidence is provided on the charge ordering by an order parameter, which is defined as the difference in minority d yz orbital (in the local coordinates) occupations between the Fe3+ and Fe2+ cations. In addition, spin ordering and the spin-orbit coupling effect play an insignificant role in the charge ordering and the preferential occupation of the d yz orbital scenario in CsFe2F6. PMID- 28653659 TI - Continuous assessment of schizophrenia using heart rate and accelerometer data. AB - OBJECTIVE: Schizophrenia has been associated with changes in heart rate (HR) and physical activity measures. However, the relationship between analysis window length and classifier accuracy using these features has yet to be quantified. APPROACH: Here we used objective HR and activity data to classify contiguous days of data as belonging to a schizophrenia patient or a healthy control. HR and physical activity recordings were made on 12 medicated subjects with schizophrenia and 12 healthy controls. Features derived from these data included classical statistical characteristics, rest-activity metrics, transfer entropy, and multiscale fuzzy entropy. We varied the analysis window length from two to eight days, and selected features via minimal-redundancy-maximal-relevance. A support vector machine was trained to classify schizophrenia from control windows on a daily basis. Model performance was assessed via subject-wise leave-one-out crossfold-validation. MAIN RESULTS: An analysis window length of eight days resulted in an area under a receiver operating characteristic curve (AUC) of 0.96. Reducing the analysis window length to two days only lowered the AUC to 0.91. The type of most predictive features varied with analysis window length. SIGNIFICANCE: Our results suggest continuous tracking of subjects with schizophrenia over short time scales may be sufficient to estimate illness severity on a daily basis. PMID- 28653660 TI - Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability. AB - DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability. PMID- 28653661 TI - The structural and functional characterization of human RecQ4 reveals insights into its helicase mechanism. AB - RecQ4 is a member of the RecQ helicase family, an evolutionarily conserved class of enzymes, dedicated to preserving genomic integrity by operating in telomere maintenance, DNA repair and replication. While reduced RecQ4 activity is associated with cancer predisposition and premature aging, RecQ4 upregulation is related to carcinogenesis and metastasis. Within the RecQ family, RecQ4 assumes an exceptional position, lacking several characteristic RecQ domains. Here we present the crystal structure of human RecQ4, encompassing the conserved ATPase core and a novel C-terminal domain that lacks resemblance to the RQC domain observed in other RecQ helicases. The new domain features a zinc-binding site and two distinct types of winged-helix domains, which are not involved in canonical DNA binding or helicase activity. Based on our structural and functional analysis, we propose that RecQ4 exerts a helicase mechanism, which may be more closely related to bacterial RecQ helicases than to its human family members. PMID- 28653663 TI - Engineering the thermal conductivity along an individual silicon nanowire by selective helium ion irradiation. AB - The ability to engineer the thermal conductivity of materials allows us to control the flow of heat and derive novel functionalities such as thermal rectification, thermal switching and thermal cloaking. While this could be achieved by making use of composites and metamaterials at bulk length-scales, engineering the thermal conductivity at micro- and nano-scale dimensions is considerably more challenging. In this work, we show that the local thermal conductivity along a single Si nanowire can be tuned to a desired value (between crystalline and amorphous limits) with high spatial resolution through selective helium ion irradiation with a well-controlled dose. The underlying mechanism is understood through molecular dynamics simulations and quantitative phonon-defect scattering rate analysis, where the behaviour of thermal conductivity with dose is attributed to the accumulation and agglomeration of scattering centres at lower doses. Beyond a threshold dose, a crystalline-amorphous transition was observed. PMID- 28653662 TI - CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. AB - Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours. PMID- 28653664 TI - Compulsive Seekers: Our take. Two Clinicians' Perspective on a New Animal Model of Addiction. PMID- 28653667 TI - Appendectomy and the Risk of Colectomy in Ulcerative Colitis: A National Cohort Study. AB - OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory disease usually responding well to anti-inflammatory drugs but many patients will still need colectomy. Appendectomy is associated with a lower risk of later developing UC. We aimed to assess the longitudinal relationship between appendectomy, appendicitis, and disease course in UC patients. METHODS: A national cohort of UC patients with a diagnosis in 1964-2010 was identified from the Swedish National Patient Register that also provided information regarding appendicitis and/or appendectomy before or after the UC diagnosis. The risk for colectomy and UC related hospital admissions was evaluated. RESULTS: Among 63,711 UC patients, 2,143 had appendectomy and 7,690 underwent colectomy. Appendectomy for appendicitis before 20 years of age and for non-appendicitis at all ages before UC diagnosis was associated with a lower risk of colectomy (hazard ratio (HR) 0.44, 0.27-0.72 and HR 0.62, 0.43-0.90, respectively), and fewer hospital admissions (incidence rate ratio (IRR) 0.68, 95% confidence interval (CI) 0.64 0.73 and IRR 0.54, 0.47-0.63, respectively). Appendectomy for appendicitis after the UC diagnosis was associated with a higher risk of colectomy (HR 1.56, 1.20 2.03), whereas no such association was found for other pathology (HR 1.40, 0.79 2.47). CONCLUSIONS: Appendectomy early in life and before developing UC is associated with a lower risk of colectomy as well as UC-related hospital admissions. Appendectomy for appendicitis after established UC appears associated with a worse disease course, with an increased rate of subsequent colectomy. PMID- 28653665 TI - Circulating Endocannabinoids: From Whence Do They Come and Where are They Going? AB - The goal of this review is to summarize studies in which concentrations of circulating endocannabinoids in humans have been examined in relationship to physiological measurements and pathological status. The roles of endocannabinoids in the regulation of energy intake and storage have been well studied and the data obtained consistently support the hypothesis that endocannabinoid signaling is associated with increased consumption and storage of energy. Physical exercise mobilizes endocannabinoids, which could contribute to refilling of energy stores and also to the analgesic and mood-elevating effects of exercise. Circulating concentrations of 2-arachidonoylglycerol are very significantly circadian and dysregulated when sleep is disrupted. Other conditions under which circulating endocannabinoids are altered include inflammation and pain. A second important role for endocannabinoid signaling is to restore homeostasis following stress. Circulating endocannabinoids are stress-responsive and there is evidence that their concentrations are altered in disorders associated with excessive stress, including post-traumatic stress disorder. Although determination of circulating endocannabinoids can provide important information about the state of endocannabinoid signaling and thus allow for hypotheses to be defined and tested, the large number of physiological factors that contribute to their circulating concentrations makes it difficult to use them in isolation as a biomarker for a specific disorder. PMID- 28653668 TI - Reminders of past choices bias decisions for reward in humans. AB - We provide evidence that decisions are made by consulting memories for individual past experiences, and that this process can be biased in favour of past choices using incidental reminders. First, in a standard rewarded choice task, we show that a model that estimates value at decision-time using individual samples of past outcomes fits choices and decision-related neural activity better than a canonical incremental learning model. In a second experiment, we bias this sampling process by incidentally reminding participants of individual past decisions. The next decision after a reminder shows a strong influence of the action taken and value received on the reminded trial. These results provide new empirical support for a decision architecture that relies on samples of individual past choice episodes rather than incrementally averaged rewards in evaluating options and has suggestive implications for the underlying cognitive and neural mechanisms. PMID- 28653666 TI - Endocannabinoid Regulation of Reward and Reinforcement through Interaction with Dopamine and Endogenous Opioid Signaling. AB - The endocannabinoid system (eCB) is implicated in the mediation of both reward and reinforcement. This is evidenced by the ability of exogenous cannabinoid drugs to produce hedonia and maintain self-administration in both human and animal subjects. eCBs similarly facilitate behaviors motivated by reward through interaction with the mesolimbic dopamine (DA) and endogenous opioid systems. Indeed, eCB signaling in the ventral tegmental area stimulates activation of midbrain DA cells and promotes DA release in terminal regions such as the nucleus accumbens (NAc). DA transmission mediates several aspects of reinforced behavior, such as motivation, incentive salience, and cost-benefit calculations. However, much research suggests that endogenous opioid signaling underlies the hedonic aspects of reward. eCBs and their receptors functionally interact with opioid systems within the NAc to support reward, most likely through augmenting DA release. This review explores the interaction of these systems as it relates to reward and reinforcement and examines current literature regarding their role in food reward. PMID- 28653670 TI - Beam electrons as a source of Halpha flare ribbons. AB - The observations of solar flare onsets show rapid increase of hard and soft X rays, ultra-violet emission with large Doppler blue shifts associated with plasma upflows, and Halpha hydrogen emission with red shifts up to 1-4 A. Modern radiative hydrodynamic models account well for blue-shifted emission, but struggle to reproduce closely the red-shifted Halpha lines. Here we present a joint hydrodynamic and radiative model showing that during the first seconds of beam injection the effects caused by beam electrons can reproduce Halpha line profiles with large red-shifts closely matching those observed in a C1.5 flare by the Swedish Solar Telescope. The model also accounts closely for timing and magnitude of upward motion to the corona observed 29 s after the event onset in 171 A by the Atmospheric Imaging Assembly/Solar Dynamics Observatory. PMID- 28653669 TI - dNK cells facilitate the interaction between trophoblastic and endothelial cells via VEGF-C and HGF. AB - Decidual NK (dNK) cells, identified as CD56brightCD16-CD3-, account for ~70% of lymphocytes within the uterine wall during early pregnancy. Accumulating evidence suggests that tight interactions between placental trophoblasts and dNK cells are critical for trophoblast cell differentiation. However, the underlying mechanism remains to be explored in detail. In the present study, conditioned medium (CM) was collected from cultured primary human dNK cells. Primary cytotrophoblasts (CTBs) or the human trophoblast cell line HTR8/SVneo was treated with dNK-CM and co-cultured with human umbilical vein endothelial cells (HUVECs) in a three dimensional Matrigel scaffold, and the formation of tube structures was dynamically monitored with live cell imaging. Trophoblast invasion was analyzed with a transwell invasion assay. The data demonstrated that the treatment of HTR8/SVneo cells or CTBs with dNK-CM remarkably promoted trophoblast invasion and tube formation in the presence of HUVECs. The epithelial marker E-cadherin was reduced, while the expression of endothelial markers NCAM, VE-cadherin and integrin beta1 was significantly promoted in the HTR8/SVneo cells upon treatment with dNK-CM. Antibody blocking experiments revealed that the dNK cells promoted trophoblast invasion through the production of IL-8 and HGF, and they induced trophoblast differentiation toward endothelial phenotype by producing VEGF-C and HGF. These results provide new evidence to clarify the finely tuned interactions between trophoblasts and dNK cells at the maternal-fetal interface. PMID- 28653673 TI - The use of the neurologic exam to predict awareness and control of lower urinary tract function post SCI. AB - This corrects the article DOI: 10.1038/sc.2017.55. PMID- 28653671 TI - A dynamic and adaptive network of cytosolic interactions governs protein export by the T3SS injectisome. AB - Many bacteria use a type III secretion system (T3SS) to inject effector proteins into host cells. Selection and export of the effectors is controlled by a set of soluble proteins at the cytosolic interface of the membrane spanning type III secretion 'injectisome'. Combining fluorescence microscopy, biochemical interaction studies and fluorescence correlation spectroscopy, we show that in live Yersinia enterocolitica bacteria these soluble proteins form complexes both at the injectisome and in the cytosol. Binding to the injectisome stabilizes these cytosolic complexes, whereas the free cytosolic complexes, which include the type III secretion ATPase, constitute a highly dynamic and adaptive network. The extracellular calcium concentration, which triggers activation of the T3SS, directly influences the cytosolic complexes, possibly through the essential component SctK/YscK, revealing a potential mechanism involved in the regulation of type III secretion. PMID- 28653672 TI - The impact of spinal cord injury on the quality of life of primary family caregivers: a literature review. AB - STUDY DESIGN: Literature review. OBJECTIVES: To provide a detailed review of the literature regarding the impact of spinal cord injury (SCI) on the quality of life (QOL) of family members who have become the primary caregiver and to highlight potential interventions available. METHODS: Appropriate databases were searched for relevant peer-reviewed studies. Twenty-five studies (four qualitative and 21 quantitative) were identified which investigated the role that family members play in caring for people with SCI and the impact it has on their QOL. RESULTS: Depression, anxiety, physical symptoms and reduced satisfaction with life in primary family caregivers of patients with SCI were commonly reported across the literature. Isolation, loss of identity and role changes were also regularly reported as negative outcomes of caregiving for someone with an SCI. A range of interventions (including family training, problem-solving training and support groups) have been shown to have benefits for family caregivers' QOL. CONCLUSION: SCI impacts significantly on the QOL of family caregivers, with major implications for physical, mental and social aspects of caregiver health. This review highlights that these important issues are problematic internationally and may persist over several decades. The need for focused interventions to support family caregivers of spinal cord injured persons, with particular emphasis on increasing patient/family education and access to support groups, is recommended. PMID- 28653674 TI - Effects of orthotic therapeutic electrical stimulation in the treatment of patients with paresis associated with acute cervical spinal cord injury: a randomized control trial. AB - STUDY DESIGN: A randomized controlled trial. OBJECTIVES: To determine the effects of orthotic therapeutic electrical stimulation (TES) on the hand in patients with paresis associated with acute cervical spinal cord injury. SETTING: Spinal Injuries Center, Fukuoka, Japan. METHODS: The study included patients treated for spinal cord injuries (Frankel classification, grades B and C) at our institution within 1 week post injury between May 2011 and December 2014. The patients were allocated randomly to TES and control groups at the time of admission and underwent TES+conventional training or conventional training alone, respectively. Both hands of each patient were treated in the same way. The primary outcome was total passive motion (TPM) of the fingers (degrees). The secondary outcomes were edema (cm) and the upper-extremity motor scores of the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI). After randomization, outcomes were assessed at 1 week, 1 month and 3 months post injury in both groups. RESULTS: Twenty-nine individuals were assessed at 3 months (15, TES; 14, control). There were no significant between-group differences for TPM of the fingers, edema and upper-extremity motor scores at 1 week, 1 month and 3 months after injury, although TPM of the fingers tended to be lower in the control group. CONCLUSIONS: It is unclear from the results of this study whether TES has a therapeutic effect on TPM, edema or the upper-extremity motor score of the ISNCSCI. The results of this study provide useful data for future meta analyses. PMID- 28653676 TI - Erratum: Organocatalytic atroposelective synthesis of axially chiral styrenes. AB - This corrects the article DOI: 10.1038/ncomms15238. PMID- 28653675 TI - Periprostatic adipose inflammation is associated with high-grade prostate cancer. AB - BACKGROUND: Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown. METHODS: In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi square, or Fisher's exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics. RESULTS: Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P's <0.05). CONCLUSION: Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC. PMID- 28653678 TI - Immunotherapy: PD-1 blockade exploiting MMR deficiency. PMID- 28653679 TI - Targeted therapies: Defining the best-in-class in NSCLC. PMID- 28653677 TI - Monitoring immune-checkpoint blockade: response evaluation and biomarker development. AB - Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy. In addition, biomarkers that can predict responsiveness to ICB are being extensively investigated to further advance precision immunotherapy. Herein, we review the biological mechanisms underlying the unconventional response patterns associated with ICB, describe strategies for the objective assessments of such responses, and also highlight the ongoing efforts to identify biomarkers, in order to guide treatment with ICB. We provide state-of-the-art knowledge of immune-related response evaluations, identify unmet needs requiring further investigations, and propose future directions to maximize the benefits of ICB therapy. PMID- 28653680 TI - Fungal pathogenesis: Combatting the oxidative burst. PMID- 28653681 TI - Metabolism: Built on stable catalysts. PMID- 28653682 TI - Advocating for vaccination in a climate of science denial. PMID- 28653683 TI - Vector control gets new impetus and direction. PMID- 28653684 TI - Host response: Inflammation promotes TB growth. PMID- 28653685 TI - The thalamic paradox. PMID- 28653686 TI - Erratum: Infantile amnesia reflects a developmental critical period for hippocampal learning. PMID- 28653687 TI - Sampling memory to make profitable choices. PMID- 28653688 TI - Direction selectivity starts early. PMID- 28653689 TI - Addendum: A viral strategy for targeting and manipulating interneurons across vertebrate species. PMID- 28653690 TI - A checkpoint to pain. PMID- 28653691 TI - Corrigendum: A viral strategy for targeting and manipulating interneurons across vertebrate species. PMID- 28653692 TI - Corrigendum: Opportunities and challenges in modeling human brain disorders in transgenic primates. PMID- 28653693 TI - Topological Kondo insulators: Negative pressure tuning. PMID- 28653694 TI - Playing with defects in metals. PMID- 28653695 TI - A sustainable material world. PMID- 28653696 TI - Environmental life-cycle assessment. PMID- 28653697 TI - Towards sustainable concrete. PMID- 28653698 TI - Material Witness: Making anyon soup. PMID- 28653699 TI - Produce and use with care. PMID- 28653700 TI - Corrigendum to "First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children" [Mol. Genet. Metab. Rep. 2 (2016) 81-84]. AB - [This corrects the article DOI: 10.1016/j.ymgmr.2015.01.005.]. PMID- 28653701 TI - Identification of actin as a direct proteomic target of berberine using an affinity-based chemical probe and elucidation of its modulatory role in actin assembly. AB - Despite the diverse pharmacological activities of berberine, including anti cancer and anti-inflammatory effects, the direct proteomic targets of berberine have remained largely unknown. Here, we have identified actin as a direct proteomic target of berberine using an affinity-based chemical probe. In addition, we found that actin assembly was significantly modulated by berberine in vitro at the biochemical level and cellular level. PMID- 28653702 TI - Two-dimensional graphene-like N, Co-codoped carbon nanosheets derived from ZIF-67 polyhedrons for efficient oxygen reduction reactions. AB - Two-dimensional graphene-like N, Co-codoped carbon nanosheets (N, Co-CNSs), which exhibit excellent stability, competitive catalytic activity and superior methanol tolerance compared to the commercial Pt/C catalyst, have been successfully fabricated using Co-based zeolitic imidazolate framework (ZIF-67) polyhedrons as precursors in a molten salt medium. PMID- 28653703 TI - Pitfalls in metal-organic framework crystallography: towards more accurate crystal structures. AB - Single crystal X-ray diffraction (SC-XRD) is the principal method for determining the crystal structures of metal-organic frameworks (MOFs). This tutorial deals with the handling of MOF crystals and analysis of crystallographic data obtained from single-crystal X-ray diffraction, focusing on two features that are particularly important in MOF crystallography and have a large impact on the quality and reliability of the final crystal structures: (1) the treatment of pore-occupying entities (both in the physical crystals and in the crystallographic model) and (2) crystallographic twinning. Proper handling of samples and data will reduce the need for using solvent masking software (e.g. SQUEEZE) to obtain acceptable crystal structures. If SC-XRD is to retain its position as the definitive method of MOF structure determination, these issues must be addressed when a new MOF structure is determined and reported. The issues addressed in this review is also valid for other porous, crystalline solids such as porous organic cages, metal-organic polyhedra, covalent organic frameworks and zeotype materials. PMID- 28653704 TI - Chrysanthemum flower-like NiCo2O4-nitrogen doped graphene oxide composite: an efficient electrocatalyst for lithium-oxygen and zinc-air batteries. AB - Chrysanthemum flower-like NiCo2O4-nitrogen doped graphene oxide composite material has been explored as a bifunctional cathode electrocatalyst for aqueous zinc-air and non-aqueous lithium-oxygen batteries. This cathode exhibits maximum discharge capacities of 712 and 15 046 mA h g-1 for zinc-air and lithium-oxygen batteries, respectively, with stable cycling over 50 cycles. PMID- 28653705 TI - ESIPT-active organic compounds with white luminescence based on crystallization induced keto emission (CIKE). AB - Structurally simple pyrazole derivatives that exhibit excited-state intramolecular proton transfer (ESIPT) were synthesized. While these compounds displayed deep violet fluorescence in solution, in the crystalline state they showed white emission from the enol and keto forms. PMID- 28653711 TI - Controlling the kinetic and thermodynamic stability of cationic clusters by the addition of molecules or counterions. AB - Whereas ion pairing is one of the most fundamental atomic interactions in chemistry and biology, pairing between like-charged ions remains an elusive concept. This phenomenon was only reported for large-scaled structures, assemblies or stabilizing frameworks. Recently, we could report the formation of cationic clusters in pure ionic liquids. In such structures like-charge repulsion is attenuated by cooperative hydrogen bonds. In the present work, we investigate the possible formation of cationic clusters in the gas phase beyond those found in the neutral ionic liquids wherein the positive charges are fully balanced by anions. Based on the ionic liquid (2-hydroxyethyl)trimethylammonium bis(trifluoromethylsulfonyl)imide we calculated differently charged cationic clusters including varying numbers of cation-like molecules (3-3-dimethyl-1 butanol) or ionic liquid anions (NTf2). We give the number of molecules or anions which are needed to transfer the cationic clusters from the meta-stable into the thermodynamically stable regime. We analyze the charge, the size and the structural motif of these clusters. A particular focus we put on the cooperativity of hydrogen bonding and the role of dispersion forces for the cluster stability. We also show that interaction energies and charge transfer within the cationic clusters can be related to spectroscopic parameters such as NMR chemical shifts and IR vibrational frequencies. Finally, we suggest clusters which should be observable in demanding gas phase experiments. PMID- 28653712 TI - Rhodium-catalyzed asymmetric hydrogenation of tetrasubstituted beta-acetoxy-alpha enamido esters and efficient synthesis of droxidopa. AB - A rhodium-catalyzed asymmetric hydrogenation of challenging tetrasubstituted beta acetoxy-alpha-enamido esters was developed, giving chiral beta-acetoxy-alpha amido esters in high yields with excellent enantioselectivities (up to >99% ee). The products could be easily transformed to beta-hydroxy-alpha-amino acid derivatives which are valuable chiral building blocks and a novel route for the synthesis of droxidopa was also developed. PMID- 28653713 TI - Cu supported on mesoporous ceria: water gas shift activity at low Cu loadings through metal-support interactions. AB - We have synthesized and tested a highly active Cu doped mesoporous CeO2 catalyst system for the low temperature water-gas shift (WGS) reaction. While typical oxide-supported copper WGS catalysts are characterized by high copper loadings (30-40%), the morphological properties of the mesoporous CeO2 material enable high catalytic activity at copper loadings as low as 1%. Operando X-ray diffraction, in situ X-ray absorption near-edge structure spectroscopy (XANES), and operando diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) methods were used to probe the interactions between the metal and mesoporous oxide components under reaction conditions. Copper was observed to undergo reduction from oxide to metal under WGS conditions at 150 degrees C, while the CeO2 lattice was observed to expand upon heating, indicating Ce3+ formation correlated with CO2 production. The active state of the catalysts was confirmed by in situ XANES to contain Cu0 and partially reduced CeO2. DRIFTS analysis revealed carboxyl species bound to copper during reduction, as well as formate and carbonate surface species on ceria. Lower concentrations of copper were observed to foster enhanced metal-support interactions. PMID- 28653714 TI - Quasi-classical trajectory studies on the full-dimensional accurate potential energy surface for the OH + H2O = H2O + OH reaction. AB - For the symmetric reaction OH + H2O -> H2O + OH, ~48 000 data points are sampled and calculated at the level of the explicitly correlated unrestricted coupled cluster method with single, double, and perturbative triple excitations with the augmented correlation-consistent polarized triple zeta basis set (CCSD(T) F12a/AVTZ). The data set is then employed to fit the full dimensional accurate potential energy surface (PES) by using the permutation invariant polynomial neural network (PIP-NN) method, resulting in a total root mean square error (RMSE) of 0.12 kcal mol-1. The quasi-classical trajectory (QCT) method is used to study its reaction dynamics. It has been found that the integral cross section (ICS) is increased gradually as a function of the collision energy ranging from 8 to 30 kcal mol-1 with a threshold around 8 kcal mol-1. At a collision energy of 20 kcal mol-1, detailed dynamics show that the OH product is a spectator and the differential cross section (DCS) is dominated by backward scattering with considerable contributions from sideway scattering, consistent with the direct rebound and stripping mechanisms. PMID- 28653715 TI - Plasmon-enhanced spectroscopy of absorption and spontaneous emissions explained using cavity quantum optics. AB - The purpose of this tutorial review is to provide a comprehensive explanation of plasmon-enhanced spectroscopies, such as plasmon-enhanced Raman scattering, fluorescence, absorption, Rayleigh scattering, and hyper Raman scattering. Plasmon-enhanced spectroscopy implies the spectroscopy of enhanced optical responses of molecules in close proximity to plasmonic nanostructures, resulting in a strong enhancement in sensitivity. In this review, we explain the enhancement in plasmon-enhanced spectroscopy as an optical response of a molecule interacting with an optical resonator, which represents a plasmonic nanostructure, in analogy to cavity quantum optics to easily understand all types of plasmon-enhanced spectroscopy in the same manner. The keys to understanding the enhancement factor of each plasmon-enhanced spectroscopy are a quality factor and a mode volume of plasmonic resonators, which are well-known parameters in the Purcell effect of standard optical cavity resonators. PMID- 28653716 TI - Correction: Synthesis and characterization of novel Li-stuffed garnet-like Li5+2xLa3Ta2-xGdxO12 (0 <= x <= 0.55): structure-property relationships. AB - Correction for 'Synthesis and characterization of novel Li-stuffed garnet-like Li5+2xLa3Ta2-xGdxO12 (0 <= x <= 0.55): structure-property relationships' by Dalia M. Abdel Basset, et al., Dalton Trans., 2017, 46, 933-946. PMID- 28653722 TI - Porous PDMS structures for the storage and release of aqueous solutions into fluidic environments. AB - Typical microfluidic systems take advantage of multiple storage reservoirs, pumps and valves for the storage, driving and release of buffers and other reagents. However, the fabrication, integration, and operation of such components can be difficult. In particular, the reliance of such components on external off-chip equipment limits their utility for creating self-sufficient, stand-alone microfluidic systems. Here, we demonstrate a porous sponge made of polydimethylsiloxane (PDMS), which is fabricated by templating microscale water droplets using a T-junction microfluidic structure. High-resolution microscopy reveals that this sponge contains a network of pores, interconnected by small holes. This unique structure enables the sponge to passively release stored solutions very slowly. Proof-of-concept experiments demonstrate that the sponge can be used for the passive release of stored solutions into narrow channels and circular well plates, with the latter used for inducing intracellular calcium signalling of immobilised endothelial cells. The release rate of stored solutions can be controlled by varying the size of interconnecting holes, which can be easily achieved by changing the flow rate of the water injected into the T junction. We also demonstrate the active release of stored liquids into a fluidic channel upon the manual compression of the sponge. The developed PDMS sponge can be easily integrated into complex micro/macro fluidic systems and prepared with a wide array of reagents, representing a new building block for self-sufficient microfluidic systems. PMID- 28653724 TI - Probing functional roles of Wilson disease protein (ATP7B) copper-binding domains in yeast. AB - After Ctr1-mediated uptake into human cells, copper (Cu) ions are transported by the cytoplasmic Cu chaperone Atox1 to the Wilson disease protein (ATP7B) in the Golgi network. Cu transfer occurs via direct protein-protein interactions and leads to incorporation of Cu into Cu-dependent enzymes. ATP7B is a large multi domain membrane-spanning protein which, in contrast to homologs, has six cytoplasmic metal-binding domains (MBDs). The reason for multiple MBDs is proposed to be indirect modulation of activity but mechanistic studies of full length ATP7B are limited. We here developed a system that probes Cu flow through human Atox1 and ATP7B proteins when expressed in yeast. Using this assay, we assessed the roles of the different MBDs in ATP7B and found that the presence of the most N-terminal MBD increased, whereas the third MBD decreased, overall ATP7B mediated Cu transport activity. Upon removal of all MBDs in ATP7B, the ability to transport Cu disappeared. The designed system can be expanded to include other yeast viability parameters and will be a useful tool for further mechanistic insights on human Cu transport as well as diseases involving Cu imbalance. PMID- 28653725 TI - Hybrid polymer microfluidic platform to mimic varying vascular compliance and topology. AB - Several cardiovascular pathologies and aging have been associated with alterations in the mechanical and structural properties of the vascular wall, leading to a reduction in arterial compliance and the development of constriction. In the past, rare efforts have been directed to understand the endothelial cell response to combined mechanical stimuli from fluid flow and substrate rigidity. Recent approaches using microfluidic platforms have limitations in precisely mimicking healthy and diseased vasculature conditions from altered topological and substrate compliance perspectives. To address this, we demonstrated an effective fabrication process to realize a hybrid polymer platform to test these mechanistic features of blood vessels. The salient features of the platform include circular microchannels of varying diameters, variation in substrate rigidity along the channel length, and the coexistence of microchannels with different cross sections on a single platform. The platform demonstrates the combined effects of flow-induced shear forces and substrate rigidity on the endothelial cell layer inside the circular microchannels. The experimental results indicate a pronounced cell response to flow induced shear stress via its interplay with the underlying substrate mechanics. PMID- 28653727 TI - A novel wireless paper-based potentiometric platform for monitoring glucose in blood. AB - A novel low-cost, compact and sensitive paper-based platform for the accurate monitoring of glucose in biological fluids is presented. Paper-based working and reference electrodes are combined to build a whole potentiometric cell, which also fits a sampling module for simple and fast determination of glucose in a single drop of blood. The working electrode is built using a platinized filter paper coated with a Nafion membrane that entraps the enzyme glucose oxidase; the reference electrode is made by casting a polyvinylbutyral-based membrane onto a conductive paper. The system works by detecting the hydrogen peroxide generated as a result of the enzymatic reaction. Selectivity is achieved due to the permselective behaviour of Nafion, while a significant enhancement of the sensitivity is reached by exploiting the Donnan-coupled formal potential. Under optimum conditions, a sensitivity of -95.9 +/- 4.8 mV per decade in the 0.3-3 mM range is obtained. Validation of the measurements has been performed against standard methods in human serum and blood. Final integration with a wireless reader allows for truly in situ measurements with a less than 2 minute procedure including a two-point calibration, washing and measurement. This low-cost analytical device opens up new prospects for rapid diagnostic results in non laboratory settings. PMID- 28653734 TI - Selective oxidation of lignocellulosic biomass to formic acid and high-grade cellulose using tailor-made polyoxometalate catalysts. AB - The main goal of this project was to identify and optimize tailor-made polyoxometalate catalysts for a fractionated oxidation of lignocellulosic biomass (i.e. wood and residues from sugar or paper industries) to produce formic acid (FA) and high-grade cellulose for further processing e.g. in white biotechnology to provide bio-ethanol. Homogeneous vanadium precursors like sodium metavanadate and vanadyl sulfate as well as Keggin-type polyoxometalates (POMs) and more exotic structures like Anderson-, Wells-Dawson- and Lindqvist-type POMs were screened for the desired catalytic performance. The most promising behaviour was found using the Lindqvist-type POM K5V3W3O19, showing for the first time in the literature a selective oxidation of only hemicellulose and lignin to formic acid, while the cellulose fraction was untrapped. However, this can only be a first step towards the project goal as low product yields were obtained. PMID- 28653733 TI - Effects of heat treatment on the antioxidative and anti-inflammatory properties of orange by-products. AB - This study investigated the changes in the functional components, antioxidative activities, antibacterial activities, anti-inflammatory activities of orange (Citrus sinensis (L.) Osbeck) by-products (OBP) on heat treatment at 50 and 100 degrees C (hereafter denoted 50D and 100D extracts, respectively). Optimal heating conditions were also investigated. The total phenolic content, flavonoid content and antioxidative activities of OBP extracts significantly increased on heat treatment. The lag time of Cu2+-induced oxidation of human LDL was increased by 2.61, 8.61 and 8.76-fold with the addition of 0.6, 0.8 and 1.0 mg ml-1 100D extracts, respectively. The 100D extracts may significantly inhibit the growth of E. coli O157, Salmonella typhimurium and Listeria monocytogenes. 1 MUg mL-1 of 100D extract may suppress the TNF-alpha-induced ICAM-1 protein expression. The optimal heating time for OBP was 26 h at 100 degrees C, which resulted in the highest antioxidant activities. PMID- 28653735 TI - Unavoidable food supply chain waste: acid-free pectin extraction from mango peel via subcritical water. AB - Mango peel is the major by-product of mango processing, and compromises 7-24% of the total mango weight. In this study, pectin was extracted from mango peel waste by using subcritical water extraction (SWE) in the absence of mineral acid. A highest yield of 18.34% was achieved from the Kesar variety and the pectin was characterised using ATR-IR spectroscopy, TGA and 13C solid-state NMR spectroscopy to confirm the structure. The degree of esterification (DE) of the pectin was analysed with both titrimetry and 13C solid-state NMR spectroscopy, and a high DE (>70%) was observed for all three varieties (Keitt, Sindhri and Kesar). This is the first report on acid-free subcritical water extraction of pectin from mango peel, which provides a green route for the valorisation of mango peel waste and contributes to a source of biobased materials and chemicals for a sustainable 21st century. PMID- 28653737 TI - A validated algorithm for selecting non-toxic chemical concentrations. AB - The maximal chemical concentration that causes an acceptably small or no effect in an organism or isolated cells is an often-sought-after value in toxicology. Existing approaches to derive this value have raised several concerns; thus, it is often chosen case-by-case based on personal experience. To overcome this ambiguity, we propose an approach for choosing the non-toxic concentration (NtC) of a chemical in a rational, tractable way. We developed an algorithm that identifies the highest chemical concentration that causes no more than 10% effect (= EC10) including the modeled 95% confidence intervals and considering each of the measured biological replicates; and whose toxicity is not significantly different from no effect. The developed algorithm was validated in two steps: by comparing its results with measured and modeled data for 91 dose-response experiments with fish cell lines and/or zebrafish embryos; and by measuring actual effects caused by NtCs in a separate set of experiments using a fish cell line and zebrafish embryos. The algorithm provided an NtC that is more protective than NOEC (no-observed-effect-concentration), NEC (modeled no-effect concentration), EC10 and BMD (benchmark dose). Despite focusing on small-scale bioassays here, this study indicates that the NtC algorithm could be used in various systems. Its application to the survival of zebrafish embryos and to metabolic activity in cell lines showed that NtCs can be applied to different effect measurements, time points, and levels of biological organization. The algorithm is available as Matlab and R source code, and as a free, user-friendly online application. PMID- 28653738 TI - Differential gene expression in the peripheral blood of Chinese Sanhe cattle exposed to severe cold stress. AB - Livestock is an important food resource for the inhabitants of cold regions, such as northern Asia and alpine regions, where agriculture is limited. In these regions, cold stress largely affects livestock production, thereby reducing the productivity and survival of animals. Despite the importance of breeding cold tolerant animals, few studies have investigated the effects of cold stress on cattle. Furthermore, whether severe cold stress alters gene expression or affects molecular genetic mechanisms remains unknown. Thus, we investigated gene expression changes in the peripheral blood samples of the Chinese Sanhe cattle exposed to severe cold. A total of 193 genes were found to exhibit significant alteration in expression (P < 0.05; fold change > 1.3), with 107 genes showing upregulation and 86 showing downregulation after cold exposure. The differences in the expression of 10 selected genes were further validated by real-time qRT PCR. Further analyses showed that these differentially expressed genes (DEGs) were predominantly associated with important biological pathways and gene networks, such as lipid metabolism and cell death and survival, which are potentially associated with severe cold-stress resistance. Identification and description of these cold stress-induced DEGs might lead to the discovery of novel blood biomarkers that could be used to assess cold-stress resistance in cattle. To our knowledge, this is the first genomic evidence of differences in the transcript expression pattern in cattle exposed to severe cold stress. Our findings provide insights on the potential molecular mechanisms underlying cold stress response in cattle. PMID- 28653739 TI - Clinical significance of fascin-1 and laminin-5 in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer death in men and the second leading cause of cancer death in women worldwide. Fascin-1 and laminin-5 were associated with the invasiveness and prognoses of several cancers. The expression and the serum levels of fascin-1 and laminin-5 in patients with non-small cell lung cancer (NSCLC) were analyzed in this study. The expression of fascin-1 and laminin-5 were examined in 378 patients and their serum level was measured in 154 patients. The health of all patients was followed post-surgery. The expression of fascin-1 (P = 0.000) and lanminin-5 (P = 0.001) and the serum levels of fascin-1 (P = 0.015) and laminin-5 (P = 0.046) were related to the relapse of patients with NSCLC. Both serum levels and expression of fascin-1 and laminin-5 can be used to effectively evaluate the prognoses of patients with NSCLC. PMID- 28653740 TI - Isolation, diversity, and biotechnological potential of rhizo- and endophytic bacteria associated with mangrove plants from Saudi Arabia. AB - Marine bacteria have been exceptional sources of halotolerant enzymes since decades. The aim of the present study was to isolate bacteria producing hydrolytic enzymes from seven different mangroves collected from the coastal area of Thuwal, Jeddah, Saudi Arabia, and to further screen them for other enzymatic and antifungal activities. We have isolated 46 different rhizo- and endophytic bacteria from the soil, roots, and leaves of the mangroves using different enzymatic media. These bacterial strains were capable of producing industrially important enzymes (cellulase, protease, lipase, and amylase). The bacteria were screened further for antagonistic activity against fungal pathogens. Finally, these bacterial strains were identified on the basis of the16S rDNA sequence. Taxonomic and phylogenetic analysis revealed 95.9-100% sequence identity to type strains of related species. The dominant phylum was Gammaproteobacteria (gamma Proteobacteria), which comprised 10 different genera - Erwinia, Vibrio, Psychrobacter, Aidingimonas, Marinobacter, Chromohalobacter, Halomonas, Microbulbifer, and Alteromonas. Firmicutes was the second dominant phylum, which contained only the genus Bacillus. Similarly, only Isoptericola belonged to Actinobacteria. Further these enzyme-producing bacteria were tested for the production of other enzymes. Most of the active strains showed cellulytic and lipolytic activities. Several were also active against fungal pathogens. Our results demonstrated that the mangroves represent an important source of potentially active bacteria producing enzymes and antifungal metabolites (bioactive products). These bacteria are a source of novel halophilic enzymes and antibiotics that can find industrial and medicinal use. PMID- 28653741 TI - Gas exchanges and water use efficiency in the selection of tomato genotypes tolerant to water stress. AB - Water stress can affect the yield in tomato crops and, despite this, there are few types of research aiming to select tomato genotypes resistant to the water stress using physiological parameters. This experiment aimed to study the variables that are related to the gas exchanges and the efficiency in water use, in the selection of tomato genotypes tolerant to water stress. It was done in a greenhouse, measuring 7 x 21 m, in a randomized complete block design, with four replications (blocks), being five genotypes in the F2BC1 generation, which were previously obtained from an interspecific cross between Solanum pennellii versus S. lycopersicum and three check treatments, two susceptible [UFU-22 (pre commercial line) and cultivar Santa Clara] and one resistant (S. pennellii). At the beginning of flowering, the plants were submitted to a water stress condition, through irrigation suspension. After that CO2 assimilation, internal CO2, stomatal conductance, transpiration, leaf temperature, instantaneous water use efficiency, intrinsic efficiency of water use, instantaneous carboxylation efficiency, chlorophyll a and b, and the potential leaf water (Psif) were observed. Almost all variables that were analyzed, except CO2 assimilation and instantaneous carboxylation efficiency, demonstrated the superiority of the wild accession, S. pennellii, concerning the susceptible check treatments. The high photosynthetic rate and the low stomatal conductance and transpiration, presented by the UFU22/F2BC1#2 population, allowed a better water use efficiency. Because of that, these physiological characteristics are promising in the selection of tomato genotypes tolerant to water stress. PMID- 28653742 TI - Phenotypic and genotypic correlations between soybean agronomic traits and path analysis. AB - The goals of this research were to evaluate the phenotypic and genotypic correlations between agronomic traits, to perform path analysis, having as main character grain yield, and to identify indirect selection criteria for grain yield. The experiment was carried out in an experimental area located at Capim Branco farm, which belongs to Federal University of Uberlandia, during the growing season of 2015/2016.Twenty-four soybean genotypes were evaluated under randomized complete block design with three repetitions, of which agronomic traits and grain yield were measured. There was genetic variability for all traits at 5% probability level through the F-test. Thirty significant phenotypic correlations were also observed with values oscillating from 0.42 to 0.87, which indicated a high level of association between some evaluated traits. Additionally, we verified that phenotypic and genotypic correlations were essential of the same direction, being the genotypic ones of superior magnitudes. Plants with superior vegetative cycle had longer life cycles; this fact could be explained by the significant phenotypic correlations between the number of days to the blooming and number of days to maturity (0.76). Significantly positive phenotypic and genotypic correlations for the total number of pods per plant and grain yield per plant (0.84) were observed. Through the path analysis, the trait that contributed the most over grain yield was the number of pods with three seeds as it showed the highest direct effect on grain yield per plant, as well as a strong indirect effect on the total number of pods. Therefore, the phenotypic and genotypic correlations suggested high correlations between grain yield and number of branched nodes, the number of pods with two and three seeds, and the total number of pods. Also, the path analysis determined the number of pods with three seeds as having the highest favorable effect on grain yield, and thus, being useful for indirect selection toward productive soybean genotypes. PMID- 28653743 TI - Genetic diversity and pectinolytic activity of epiphytic yeasts from grape carposphere. AB - The genetic diversity of epiphytic yeasts from grape carposphere is susceptible to environmental variations that determine the predominant carposphere microbiota. Understanding the diversity of yeasts that inhabit grape carposphere in different environments and their pectinolytic activity is a way to understand the biotechnological potential that surrounds us and help improve winemaking. Therefore, this study aimed to evaluate the pectinolytic activity and characterize the genetic diversity of isolated epiphytic yeasts from grape carposphere. Grapes of the Bordeaux cultivar were collected from different regions of Parana and Rio Grande do Sul States, in Brazil, and the yeasts were isolated from these grape carpospheres. Monosporic isolates were morphologically and genetically characterized on potato dextrose agar medium and by PCR-RFLP and rep-PCR (BOX-PCR) in the ITS1-5.8S-ITS2 region of rDNA. The index of pectinolytic activity of isolates was also evaluated estimating the ratio between the halo diameter of enzymatic degradation and the diameter of the colony when the isolates were grown in cultivation medium containing 10 g/L pectin, 5 g/L yeast extract, 15 g/L agar, 0.12% (w/v) Congo red, and pH 6.2. We observed that the grape carposphere is an environment with a great genetic diversity of epiphytic yeasts of the following genera: Cryptococcus (31.25%), Pichia (25.0%), Candida (25.0%), Dekkera (12.5%), and Saccharomyces (6.25%). The PCR-RFLP technique allowed analyzing existing polymorphism among individuals of a population based on a more restrict and evolutionarily preserved region, mostly utilized to differentiate isolates at the genus level. Approximately 33% of yeast isolates presented pectinolytic activity with potential biotechnological for wine and fruit juice production. This great genetic variability found indicated that it is a potential reservoir of genes to be applied in viniculture improvement programs. PMID- 28653744 TI - Estimates of genetic parameters and genotypic values prediction in maize landrace populations by REML/BLUP procedure. AB - The REML/BLUP statistics are analyses that can be used as selective criteria in the routine of maize breeding programs. The present study aims to determine the genetic potential in crosses of landrace populations applying the REML/BLUP methodology, and to identify populations for the synthesis of new populations and intrapopulation selection for family farming systems, as well as genetic constitutions for use in maize breeding programs. Nine top cross hybrids obtained in the 2012/2013 harvest were evaluated along with their testator, the landraces used as parents, and four commercial hybrids, in a randomized block design, with information taken from the average of each plot. The evaluated traits were: leaf angle, number of ramifications of the tassel, spike insertion height, plant height, spike diameter, number of grains per spike, mass of grains per spike, spike mass, spike length, prolificity, mass of one hundred grains, and grain yield per plot. The data were analyzed using the Selegen-REML/BLUP software. The top cross hybrids Cateto Branco x Planalto, Amarelao x Planalto and the population Cateto Branco are ranked among the ten best crosses, simultaneously, for the traits: leaf angle, number of ramifications of the tassel, spike insertion height, and plant height (Cateto Branco x Planalto), and leaf angle, spike insertion height, and plant height (Amarelao x Planalto and Cateto Branco). The top cross hybrids Criolao x Planalto, Branco 8 Carreiras x Planalto, Caiano Rajado x Planalto, Amarelao x Planalto, Branco Roxo Indio x Planalto stand out for their high genotypic value of the individual BLUP mean components among the ten best genotypes for grain yield, and by combining three or more traits of interest together, being, for effects of selection, the most indicated. PMID- 28653745 TI - St John's wort for depression: scoping review about perceptions and use by general practitioners in clinical practice. AB - BACKGROUND: Extracts of Hypericum perforatum, more commonly known as St John's wort (SJW), have good evidence for treating depression. The herb is easily accessible and widely used by consumers, although it has potential for interaction with other medicines. Consumers' use of SJW is often not discussed with their general practitioners (GPs). It is unclear how GPs perceive use of SJW in practice and the implications for consumers and pharmacists. OBJECTIVE: Explore GPs' perception of SJW use in practice. METHODS: Scoping review. KEY FINDINGS: Few studies explore GPs' perceptions of SJW for depression, but they appear to recommend it infrequently, except in Germany. Reasons for limited use in practice include lack of knowledge, particularly regarding which preparations and dosages have trial evidence, and lack of standardisation of active ingredients. Guidelines either do not mention SJW or advise against its use. CONCLUSIONS: Consumers drive SJW use but often do not disclose to their GPs, which is concerning due to issues about safety. Pharmacists could play an important role here. Improved education about SJW is required for both GPs and consumers, including the need for communication between them and their pharmacists. Lack of adoption of evidence-based therapy for depression should be explored further. PMID- 28653746 TI - Discovery of the oldest record of Nitellopsis obtusa (Charophyceae, Charophyta) in North America. AB - Studies of the colonization and spread of invasive species improves our understanding of key concepts in population biology as well as informs control and prevention efforts. The characean green alga Nitellopsis obtusa (starry stonewort) is rare in its native Eurasian range but listed by the United States Geological Survey (USGS) as an aggressive invasive in North America. First documented in North America in 1978 from New York, United States, it has since been reported from numerous inland lakes from Minnesota to Vermont, and from Lake Ontario and inland lakes in southern Ontario, Canada. While the ecological impacts of N. obtusa are not clearly understood in its invasive range, initial results show negative environmental effects. We have discovered a liquid preserved herbarium specimen that predates the 1978 records by at least 4 years, and is the first confirmed record of N. obtusa in Quebec. PMID- 28653748 TI - Adaptive dynamics of the 5-HT systems following chronic administration of selective serotonin reuptake inhibitors: a meta-analysis. AB - Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants. However, a major concern is their delayed onset of action, which is hypothesized to be associated with the time required for serotonin (5-HT) autoreceptors to desensitize, which should be reflected by actual neurochemical changes. Numerous in vivo microdialysis studies have been published that report on 5-HT levels in different brain sites following SSRI administration. Here, we performed a meta-analysis on dynamic changes of 5-HT neurotransmission during the course of chronic SSRI treatment. We conducted a meta-analysis on research articles of 5-HT neurotransmission measured by in vivo microdialysis in rat brain after subchronic and chronic SSRI administrations. In total, data from 42 microdialysis studies (798 rats) were analyzed. Within the first week of SSRI treatment, extracellular 5-HT concentrations drop in frontal cortex. Over the next 2 weeks of treatment, a linear increase in extracellular 5 HT levels up to 350% of prior treatment baseline is evident (n = 269). However, in hippocampus, prefrontal cortex, nucleus accumbens, and ventral tegmental area we found increased 5-HT levels within the first 3 days of SSRI administration. The time course of 5-HT dynamics in frontal cortex is in line with the hypothesis that 5-HT autoreceptors desensitize over 2-3 weeks of SSRI treatment and thereby enhanced extracellular 5-HT levels ensue. Yet, in other regions we did not find evidence supporting the traditional autoreceptor-mediated feedback loops hypothesis and thus other neurobiological adaptation mechanisms may also play a role in the delayed onset of SSRI action. PMID- 28653749 TI - Transintestinal cholesterol excretion: A secondary, nonbiliary pathway contributing to reverse cholesterol transport. PMID- 28653750 TI - Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer. AB - : The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate between "high-" and "low-benefit" patients. To do so, the concept of intention-to-treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987-2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non-LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End-Stage Liver Disease, alpha-fetoprotein, Milan-Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors ("no-benefit group"; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor ("large-benefit group"; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months. CONCLUSION: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de-listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910-1919). PMID- 28653751 TI - Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease. AB - BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBD). Evidence implicates disturbances of the gastrointestinal microbiota in their pathogenesis. AIM: To perform a systematic review and meta analysis to examine the efficacy of probiotics in IBD. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (until November 2016). Eligible randomised controlled trials (RCTs) recruited adults with UC or CD, and compared probiotics with 5-aminosalicylates (5-ASAs) or placebo. Dichotomous symptom data were pooled to obtain a relative risk (RR) of failure to achieve remission in active IBD, or RR of relapse of disease activity in quiescent IBD, with 95% confidence intervals (CIs). RESULTS: The search identified 12 253 citations. Twenty-two RCTs were eligible. There was no benefit of probiotics over placebo in inducing remission in active UC (RR of failure to achieve remission=0.86; 95% CI=0.68-1.08). However, when only trials of VSL#3 were considered there appeared to be a benefit (RR=0.74; 95% CI=0.63-0.87). Probiotics appeared equivalent to 5-ASAs in preventing UC relapse (RR=1.02; 95% CI=0.85 1.23). There was no benefit of probiotics in inducing remission of active CD, in preventing relapse of quiescent CD, or in preventing relapse of CD after surgically induced remission. CONCLUSIONS: VSL#3 may be effective in inducing remission in active UC. Probiotics may be as effective as 5-ASAs in preventing relapse of quiescent UC. The efficacy of probiotics in CD remains uncertain, and more evidence from RCTs is required before their utility is known. PMID- 28653752 TI - The potential of Epimedium koreanum Nakai for herb-drug interaction. AB - OBJECTIVES: This study aims to investigate potential herb-drug interactions (HDI) of Epimedium koreanum Nakai. METHODS: Human liver microsomes (HLMs) were used to determine the enzyme kinetics of the major human cytochrome P450s (CYPs). Inducible potential of E. koreanum on CYP1A2, 2B6, 2C19 and 3A4 activities of human primary hepatocytes was also examined. KEY FINDINGS: Ethanol extract of E. koreanum showed direct inhibitory potency for CYP1A2 (IC50 = 121.8 MUg/ml, Ki = 110.7 +/- 36.8 MUg/ml) and CYP2B6 (IC50 = 59.5 MUg/ml, Ki = 18.1 +/- 2.9 MUg/ml). For CYP2C9, 2C19, 2D6, 2E1 and 3A4, only negligible effect was observed. Time-dependent (irreversible) inhibition by E. koreanum was observed for CYP1A2 (KI = 32.9 +/- 18.4 MUg/ml, kinact = 0.031 +/- 0.006 min-1 ). However, ethanol extract of E. koreanum (1.5-150 MUg/ml) did not change the activity or mRNA expressions for CYP3A4, 1A2, 2C19 and 2B6. CONCLUSIONS: The ethanol extract of E. koreanum is not likely to cause HDI via inducing the major human CYPs. But the potential for interactions between E. koreanum extract and substrates of CYP1A2 or 2B6 cannot be overlooked. PMID- 28653754 TI - Adipose-derived exosomal MicroRNAs orchestrate gene regulation in the liver: Is this the missing link in nonalcoholic fatty liver disease? PMID- 28653753 TI - The development of a magnetic resonance imaging index for fistulising Crohn's disease. AB - BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81 0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument. PMID- 28653755 TI - Bulk hydrogen stable isotope composition of seaweeds: Clear separation between Ulvophyceae and other classes. AB - Little is known about the bulk hydrogen stable isotope composition (delta2 H) of seaweeds. This study investigated the bulk delta2 H in several different seaweed species collected from three different beaches in Brazil, Australia, and Argentina. Here, we show that Ulvophyceae (a group of green algae) had lower delta2 H values (between -940/00 and -1300/00) than red algae (Florideophyceae), brown algae (Phaeophyceae), and species from the class Bryopsidophyceae (another group of green algae). Overall the latter three groups of seaweeds had delta2 H values between -500/00 and -900/00. These findings were similar at the three different geographic locations. Observed differences in delta2 H values were probably related to differences in hydrogen (H) metabolism among algal groups, also observed in the delta2 H values of their lipids. The marked difference between the delta2 H values of Ulvophyecae and those of the other groups could be useful to trace the food source of food webs in coastal rocky shores, to assess the impacts of green tides on coastal ecosystems, and to help clarify aspects of their phylogeny. However, reference materials for seaweed delta2 H are required before the full potential of using the delta2 H of seaweeds for ecological studies can be exploited. PMID- 28653756 TI - A zinc oxide-modified hydroxyapatite-based cement facilitated new crystalline stoichiometric and amorphous apatite precipitation on dentine. AB - AIM: To evaluate the remineralization ability of two endodontic sealer cements. METHODOLOGY: Mid-coronal dentine surfaces were subjected to: (i) 37% phosphoric acid (PA) or (ii) 0.5 mol L-1 ethylenediaminetetraacetic acid (EDTA) conditioning prior to the application of two experimental hydroxyapatite-based cements, containing sodium hydroxide (calcypatite) or zinc oxide oxiapatite respectively. Samples were stored in simulated body fluid for 24 h or 21 days. Remineralization of the dentine surfaces were studied by Raman spectroscopy (mapping with K-means cluster and hierarchical cluster analysis) was undertaken. Nanoroughness and collagen fibril width measurements were performed with an atomic force microscopy. ANOVA and Student-Newman-Keuls test were performed (alpha=0.05). RESULTS: Phosphoric acid+oxiapatite promoted both the highest dentine mineralization (P < 0.05) and crystallographic maturity at the dentine surface. Noncrystalline amorphous-like apatites were also formed. Dentine treated with PA+calcypatite attained the roughest surface (P < 0.05) with minimal fibril width (P < 0.05). Cross-linking of collagen only became greater in the group PA+oxiapatite after 21 days. The maximum relative mineral concentration and structure of collagen linked to the amide I and ratio amide III/AGEs was obtained after using PA+calcypatite at 21-days time-point (P < 0.05). EDTA produced a lower stoichiometric hydroxyapatite (P < 0.05) with decreased maturity, at the expense of carbonate band widening, although it favoured the nucleation of carbonated calcium phosphate. CONCLUSIONS: Dentine surfaces treated with PA+oxiapatite attained the highest dentine remineralization with both crystalline stoichiometric and amorphous apatites, at 21 days. EDTA conditioning facilitated amorphous-bulk mineral precipitation. The amorphization was more intense after using oxiapatite and provided an ion-rich environment favouring in situ dentine remineralization. PMID- 28653757 TI - Does Bernard-Soulier syndrome protect against thrombotic thrombocytopenic purpura? PMID- 28653758 TI - Periodontitis and breast cancer: A case-control study. AB - OBJECTIVES: The aim of this case-control study was to evaluate the association between periodontitis and breast cancer in a sample of adult Brazilian women. METHODS: This was a hospital-based study, which included 67 cases and 134 controls (1:2). Women were selected consecutively between April, 2013 and June, 2015 among those attending the Department of Gynecology at the University Hospital of Santa Maria. Cases were selected among women diagnosed with breast cancer (ICD-10 C50), and controls were matched for age (+/-2 years), and smoking status (never, former and current smoker). Conditional logistic regression was used to model the association between periodontitis and breast cancer with and without adjustment for potential confounders. Four case definitions for periodontitis were used. RESULTS: Cases had significantly greater clinical attachment loss than controls (P=.04). After adjusting for important covariates, women diagnosed with periodontitis had two to three times higher odds of breast cancer than women without periodontitis depending on the case definition of periodontitis (P<.05). CONCLUSIONS: A significant association was observed between periodontitis and breast cancer. PMID- 28653759 TI - Trends in socioeconomic inequalities in oral health among 15-year-old Danish adolescents during 1995-2013: A nationwide, register-based, repeated cross sectional study. AB - BACKGROUND: Scandinavian welfare states, despite having better population oral health than less egalitarian societies, are characterized by ubiquitous social gradients and large relative socioeconomic inequalities in oral health. However, trends in these inequalities among Scandinavian children and adolescents have not been studied in detail. OBJECTIVES: To describe the associations between socioeconomic position (SEP) and oral health in adolescents and to investigate the trends in these associations between 1995 and 2013. METHODS: Nationwide repeated cross-sectional studies (using individual-level data) were conducted on 15-year-olds in Denmark from 1995, 2003, and 2013 (N=154,750). Dental data were obtained from the national dental register of the Danish Health Authority (Sundhedsstyrelsens Centrale Odontologiske Register [SCOR]) and data on social variables from administrative registers at Statistics Denmark. SEP measures included previous year's parental education (highest attained educational level by either of the parents), income (equivalized household disposable income), and occupational social class (highest recorded occupational class between the parents). Covariates were immigration status, country of origin, number of children and persons in the family, and household type. The outcome was dental caries experience, represented by the decayed, missing, and filled surfaces (DMFS) index. Negative binomial regression models were used to examine the association between DMFS count and each of the explanatory variables separately while accounting for cluster-correlated family data. Furthermore, hierarchical multiple regressions of DMFS on SEP indicators-using the zero-inflated negative binomial (ZINB) distribution as the outcome distribution-were estimated while successively adjusting for the potential effects of the included covariates. RESULTS: Caries prevalence declined from 71% in 1995 to 63% in 2003 and 45% in 2013. Separate assessment of each covariate showed statistically significant graded associations between each covariate and DMFS count at all time points. Similarly, in the ZINB models, in all 3 years, clear gradients were observed in terms of caries differentials in all three SEP categories, with statistically significant associations (Type 3 P values, <.0001) even after adjustment for all other covariates. For instance, in 2013, even among adolescents with positive caries experience, being of lower occupational social class was associated with up to 2.4-fold (95% confidence interval [CI]: 2.2-2.6) higher caries experience. Between 1995 and 2013, relative inequalities increased in all SEP categories, while absolute inequalities decreased in the education and occupation categories. CONCLUSION: Considerable progress has been made in reducing dental caries rates among Danish adolescents; however, this progress has benefited the disadvantaged social groups less than the better-off groups. PMID- 28653761 TI - A prospective clinical study of regenerative endodontic treatment of traumatized immature teeth with necrotic pulps using bi-antibiotic paste. AB - AIM: To evaluate the treatment outcomes of a revitalization endodontic technique (RET) for the management of traumatized immature teeth with necrotic pulps in children. METHODOLOGY: Fifteen healthy children (age range = 7-10 years) with traumatized immature maxillary incisors with necrotic pulps treated with bi antibiotic revitalization endodontic technique were prospectively assessed over approximately two years (mean = 22 months). One operator undertook all treatments, clinical reviews and standardized radiographic exposures with radiographic analysis being carried out by two calibrated experienced clinicians. Crown colour change was assessed using an objective published methodology. Wilcoxon signed-rank test was used to compare root lengths, root dentinal widths and apical foramen widths over time. RESULTS: Interoperator measurement reliability was consistently strong for all measurements. There was no significant difference in root lengths or root dentinal wall widths following RET. A significant difference in apical foramen widths was observed after 2 years (P = 0.013) with resolution of clinical signs of infection in all cases. Despite omitting minocycline and using Portland cement (nonbismuth containing cement), a noticeable crown colour change (yellower, redder and lighter), as measured by an objective colour measurement system with DeltaE = 7.39, was recorded. Most patients, however, were satisfied with the aesthetic outcome. CONCLUSION: Traumatized immature teeth with necrotic pulps treated with revitalization endodontic technique did not demonstrate continuation of root development or dentine formation when assessed by periapical radiographs. However, apical closure and periodontal healing were observed. A measurable change in crown colour (yellower, redder and lighter), with mostly no aesthetic concern to the patients/parents, was also observed. PMID- 28653762 TI - Critical updates in the 7th edition of the American Society for Apheresis guidelines. AB - The 7th edition of the American Society for Apheresis (ASFA) guidelines was composed by an international physicians committee, and includes 14 new diseases, and 2 new indications for diseases described in the former guidelines. Several indications have either changed names or were excluded from this edition. The guidelines are developed after taking into account documented evidence, either supporting or negating use of apheresis technology in the treatment of diseases. Based on this evidence, the committee revises, updates and includes or excludes disease entities/indications in the guidelines. This article describes the revisions to the 7th edition of the ASFA guidelines, in a comprehensive manner. PMID- 28653760 TI - Hepatitis C virus reactivation in patients receiving cancer treatment: A prospective observational study. AB - : Hepatitis C virus (HCV) reactivation in patients receiving cancer treatment has been reported in retrospective studies. We sought to determine prospectively the incidence, predictors, and clinical significance of HCV reactivation during cancer treatment. HCV-infected patients receiving cancer treatment at our institution between November 2012 and July 2016 were studied. Reactivation was defined as an increase in HCV-RNA >=1 log10 IU/mL over baseline and hepatitis flare as an increase in alanine aminotransferase to >=3 times the upper limit of normal. One hundred patients were studied, 50 with hematologic malignancies and 50 with solid tumors. Reactivation occurred in 23 (23%) patients, including 18 (36%) patients with hematologic malignancies and 5 (10%) patients with solid tumors. In univariate analysis, patients with reactivation were more likely than those without reactivation to have prolonged lymphopenia (median, 95 versus 22 days; P = 0.01) and to have received rituximab (44% versus 9%; P < 0.0001), bendamustine (22% versus 0%; P < 0.001), high-dose steroids (57% versus 21%; P = 0.001), or purine analogs (22% versus 5%; P = 0.02). Rituximab (odds ratio = 9.52; P = 0.001), and high-dose steroids (odds ratio = 5.05; P = 0.01) retained significance in multivariable analysis. Of the 23 patients with reactivation, 10 (43%) had hepatitis flare. No patient with reactivation experienced liver failure or liver-related death within 36 weeks after initiation of cancer treatment. Fourteen patients with hepatitis flare, six of whom had reactivation, required discontinuation or dose reduction of cancer treatment. CONCLUSION: HCV reactivation occurred in 23% of HCV-infected patients receiving cancer treatment, and most had an unremarkable clinical course. However, reactivation can affect the cancer treatment plan. Our findings suggest that HCV infection should not contraindicate cancer therapy and infected patients should have access to multiple cancer treatments with close monitoring while receiving regimens associated with HCV reactivation. (Hepatology 2018;67:36-47). PMID- 28653764 TI - Pregnancy outcome in women undergoing liver biopsy during pregnancy: A nationwide population-based cohort study. AB - : Liver biopsy is an important procedure in the investigation of liver disease. We examined pregnancy outcomes in women who underwent liver biopsy during pregnancy. In a nationwide population-based cohort study we linked data from the Swedish Medical Birth Registry (for births between 1992 and 2011) with those from the Swedish Patient Registry. We identified 23 pregnancies exposed to liver biopsy. We calculated relative risks (RRs) for adverse pregnancy outcomes according to liver biopsy status using 1,953,887 unexposed pregnancies with and without a record of liver disease as reference. Our main outcome measures were stillbirth and preterm birth. There were no stillbirths in pregnancies exposed to liver biopsies compared with 0.3% stillbirths in unexposed pregnancies, and 3/23 (13%) exposed pregnancies were preterm (RR, 2.6; 95% confidence interval, 0.9 7.5). Compared to women with a record of liver disease, preterm birth was not increased in those exposed to liver biopsy (RR, 0.9; 95% confidence interval, 0.1 6.0). Except for an increased risk of small for gestational age birth in pregnancies exposed to liver biopsy (RR, 5.2; 95% confidence interval, 1.8-14.8), other adverse pregnancy outcomes were independent of liver biopsy status when the analysis was restricted to women with a diagnosis of liver disease. Compared with unexposed sibling pregnancies, pregnancies with a liver biopsy were 7 days shorter, but birth weights did not differ between the siblings (-67 g; P > 0.05). CONCLUSION: Apart from a moderately increased risk of preterm birth and small for gestational age, there was no association between liver biopsy during pregnancy and adverse pregnancy outcome; potential excess risks should be weighed against the advantages of having a liver biopsy that may influence clinical management of the patient and indirectly fetal health. (Hepatology 2017). PMID- 28653763 TI - Pericentral hepatocytes produce insulin-like growth factor-2 to promote liver regeneration during selected injuries in mice. AB - : Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long term treatments of CCl4 . However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl4 . Remarkably, most IGF-2-expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase-deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF-2 overexpression, which could be inhibited by adeno-associated virus-delivered IGF 2 short hairpin RNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 through both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. CONCLUSION: IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post-PHx. (Hepatology 2017;66:2002-2015). PMID- 28653767 TI - If You're Happy and You Know It: Positive Moods Reduce Age-Related Differences in False Memory. AB - When tested in the Deese-Roediger-McDermott paradigm, children typically exhibit fewer false memories than do adolescents or adults. Here, participants' moods and the valence of word lists were manipulated to explore the mechanism responsible for this developmental reversal in memory performance. Children (7- to 8-year olds), adolescents (11- to 12-year-olds), and young adults (18- to 22-year-olds; N = 270) were assigned to one of three induced mood conditions and were presented with emotional word lists. In negative moods, adolescents and adults falsely recalled more negative information than did children, showing the typical developmental reversal effect. This effect, however, was eliminated when participants were in positive moods. The findings provide support for associative activation theory and have important implications for our understanding of the development of emotional false memories. PMID- 28653766 TI - Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I. AB - Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme. PMID- 28653765 TI - A liquid calcium+vitamin D3 supplement is effective prophylaxis against hypocalcemic toxicity during apheresis platelet donation. AB - Hypocalcemic toxicity, because of return of citrate anion to the donor, is the major toxicity of apheresis platelet donation. Oral calcium carbonate, given prophylactically at the start of donation, has shown limited ability to alleviate this toxicity. We examined whether repeated prophylactic doses of calcium carbonate, or of a liquid preparation containing calcium citrate, calcium phosphate, and vitamin D3 , would be more effective at preventing symptoms of hypocalcemic toxicity. Symptoms were reported by 48% of donors who received no prophylaxis and 60% of donors who received 1000 mg of oral calcium carbonate at the start of, and every 20 minutes during, donation (P = 0.711). Only 19.2% of donors who received the liquid preparation (1000 mg calcium, 1000 IU vitamin D3 ) reported symptoms (P = 0.040 versus no prophylaxis, P = 0.039 versus calcium carbonate). This difference was not because of gender, weight, age, or blood volume of the donor. Neither calcium preparation prevented a measurable fall in plasma ionized calcium during donation. We conclude that liquid calcium citrate/calcium phosphate/vitamin D3 provides effective prophylaxis against hypocalcemic toxicity during platelet donation, however it does not prevent a fall in plasma ionized calcium. PMID- 28653768 TI - Improving care for patients with pancreatitis. PMID- 28653769 TI - Examining the importance of laboratory and diagnostic testing when treating and diagnosing onychomycosis. AB - Onychomycosis is a fungal nail infection caused primarily by dermatophytes. Several other nail disorders, including psoriasis, can simulate onychomycosis. Accurate diagnosis is therefore vital for the ongoing treatment and management of onychomycosis and to avoid misdiagnosis and treatment delay, which can be both lengthy and costly. Often, a combination of histologic and laboratory techniques is used to obtain an accurate diagnosis. The potential diagnostic challenges associated with the differential diagnosis of onychomycosis caused by dermatophytes and the most common techniques used to confirm the diagnosis are discussed. PMID- 28653770 TI - Studies on N-Acetyltransferase (NAT2) Genotype Relationships in Emiratis: Confirmation of the Existence of Phenotype Variation among Slow Acetylators. AB - BACKGROUND AND PURPOSE: Individuals with slow N-acetylation phenotype often experience toxicity from drugs such as isoniazid, sulfonamides, procainamide, and hydralazine, whereas rapid acetylators may not respond to these medications. The highly polymorphic N-acetyltransferase 2 enzyme encoded by the NAT2 gene is one of the N-acetylators in humans with a clear impact on the metabolism of a significant number of important drugs. However, there are limited studies on N acetylation phenotypes and NAT2 genotypes among Emiratis, and thus this study was carried out to fill this gap. METHODS: Five hundred seventy-six Emirati subjects were asked to consume a soft drink containing caffeine (a nontoxic and reliable probe for predicting the acetylation phenotype) and then provide a buccal swab along with a spot urine sample. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotype of each individual. Phenotyping was carried out by analyzing the caffeine metabolites using high-performance liquid chromatography (HPLC) analysis. RESULTS: We found that 78.5%, 19.1%, and 2.4% of the Emirati subjects were slow, intermediate, and rapid acetylators, respectively. In addition, we found that 77.4% of the subjects were homozygous or heterozygous for two nonreference alleles, whereas 18.4% and 4.2% were heterozygous or homozygous for the reference allele (NAT2*4), respectively. The most common genotypes found were NAT2*5B/*7B, NAT2*5B/*6A, NAT2*7B/*14B, and NAT2*4/*5B, with frequencies of 0.255, 0.135, 0.105, and 0.09, respectively. The degree of phenotype/genotype concordance was 96.2%. The NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, and NAT2*5A/*5B genotypes were found to be associated with the lowest 5-acetylamino-6-formylamino-3-methyluracil/1 methylxanthine (AFMU/1X) ratios. CONCLUSIONS: There is a high percentage of slow acetylators among Emiratis, which correlates with the presence of nonreference alleles for the NAT2 gene. Individuals who carried NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, or NAT2*5A/*5B genotypes might be at higher risk of toxicity with some drugs and some diseases compared to others, as these genotypes are associated with the slowest acetylation status. PMID- 28653771 TI - Resource intensification and osteoarthritis patterns: changes in activity in the prehistoric Sacramento-San Joaquin Delta region. AB - OBJECTIVES: Ethnohistoric accounts and archaeological research from Central California document a shift from the use of lower-cost, high-ranked resources (e.g., large game) toward the greater use of higher-cost, low-ranked resources (e.g., acorns and small seeds) during the Late Holocene (4500-200 BP). The subsistence transition from higher consumption of large game toward an increased reliance on acorns was likely associated with increases in levels of logistical mobility and physical activity. This study predicts that mobility and overall workload patterns changed during this transition to accommodate new food procurement strategies and incorporate new dietary resources during the Late Holocene in Central California. MATERIALS AND METHODS: Osteoarthritis prevalence was scored in the shoulder, elbow, hip, and knee of adult individuals (n = 256) from seven archaeological sites in the Sacramento-San Joaquin Delta region. Comparisons were made between osteoarthritis prevalence, sex, age-at-death, and time period using ANCOVAs. RESULTS: The results of this study indicate significant increases in osteoarthritis prevalence in the hip of adult males and females during the Late Period (1200-200 BP), even after correcting for the cumulative effects of age. No differences were observed between the sexes or between time periods for the shoulder, elbow, and knee joints. DISCUSSION: The temporal increase in hip osteoarthritis supports the hypothesis that there was an increasing need for greater logistical mobility over time to procure key resources away from the village sites. Additionally, the lack of sex differences in osteoarthritis prevalence may suggest that females and males likely performed similar levels of activity during these periods. PMID- 28653772 TI - Serum carcinoembryonic antigen is positively associated with leukocyte count in Korean adults. AB - BACKGROUND: Emerging evidence shows that serum carcinoembryonic antigen (CEA) levels may modestly be increased in non-neoplastic conditions such as cardiometabolic diseases, which are increasingly being seen as inflammatory diseases. Leukocyte count is widely evaluated marker of inflammation in clinical practice and a useful predictor of cardiometabolic disease. In this study, we aimed to determine the relationship between serum CEA levels and leukocyte counts in Korean adults. METHODS: This cross-sectional study included a total of 19 834 individuals enrolled from a health promotion center between November 2006 and July 2010. Multiple linear regression analysis was performed to investigate the association between serum CEA levels and leukocyte counts after adjusting for confounding variables. RESULTS: According to both stepwise-method and enter method multiple linear regression analyses, serum CEA levels were positively and independently associated with leukocyte counts (P<.001) after adjusting for age, sex, body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, HDL-cholesterol, cigarette smoking, alcohol ingestion, physical activity, diabetes mellitus, and anti-inflammatory drugs. CONCLUSIONS: We demonstrate a positive relationship between serum CEA levels and leukocyte counts in Korean adults. Our results suggested that an elevated serum CEA level may reflect chronic inflammation state. PMID- 28653773 TI - A Target-Directed Chemo-Photothermal System Based on Transferrin and Copolymer Modified MoS2 Nanoplates with pH-Activated Drug Release. AB - Molybdenum disulfide (MoS2 ) nanosheets have attracted significant attention due to their photothermal properties, but the poor solubility and colloidal stability limited their further application in biomedical field. Here, we report a targeted photothermal controllable nanocarrier consisting of MoS2 nanosheets modified with block copolymer P(OEG-A)-b-P(VBA-co-KH570) and targeting ligand transferrin. P(OEG-A)-b-P(VBA-co-KH570) is synthesized by RAFT polymerization and utilized not only to improve the solubility of MoS2 nanosheets but also efficiently load the anti-cancer drug doxorubicin (DOX) through an acid-cleavable Schiff base linker. Thiol-functionalized transferrin (Tf-SH) is anchored onto the surface of MoS2 nanosheets by the formation of disulfide bonds, which could further enhance the cellular uptake of DOX and MoS2 to HepG2 cells for high-efficiency synergetic therapy. The drug release experiments exhibited the minimal release of DOX at room temperature and neutral pH, and the maximal drug release of 53 % at acidic tumor pH and hyperthermia condition after 48 h. In addition, the DOX-loaded, Tf SH and P(OEG-A)-b-P(VBA-co-KH570) modified MoS2 (DOX-POVK-MoS2 -Tf) showed better a therapeutic effect than DOX-POVK-MoS2 and POVK-MoS2 , probably owing to the combined effects of target-directed uptake, acid-triggered drug release, and NIR induced localized heating, which suggest the designed MoS2 nanocarriers are promising for applications in multi-modal cancer therapy. PMID- 28653774 TI - Design and Synthesis of Cyclic Mismatch-Binding Ligands (CMBLs) with Variable Linkers by Ring-Closing Metathesis and their Photophysical and DNA Repeat Binding Properties. AB - Cyclophane-containing bis(2-amino-1,8-naphthyridine) moieties attached to variable linkers at the C2-position (linker B) were synthesized as cyclic mismatch-binding ligands (CMBLs). Ring-closing metathesis (RCM) is used as a key step for the introduction of double bonds at the linker B. Decreasing the size of the linker of the substrate, formation of the RCM products with an increasing trans/cis (E/Z) ratio was observed with moderate to high overall yields. Concentration-dependent fluorescence spectra were observed for CMBLs with longer linkers (n=3), whereas concentration-independent spectra were observed for CMBLs with shorter linkers (n=2 and/or 1) with a marked exception of the E-alkene 6 a. Concomitant changes in the absorption as well as in the fluorescence spectra were also observed for the CMBLs with an increasing hydrophobicity of the solvent. Absorption and fluorescence spectra of the CMBLs in solutions containing 99-100 % methanol resembled to that of the monomer. The binding behavior of these CMBLs with repeat DNA structures was investigated by using a surface plasmon resonance (SPR) assay and circular dichroism (CD) spectra. The cyclic E-alkenes 1 a (n=3) and 3 a (n=2) show an orthogonal binding relationship with d(CCTG)9 and d(CAG)9 . However, the selectivity for the cyclic Z-alkenes increased with decreasing the length of the linker from compound 2 b (n=3) to compound 7 b (n=1). These compounds display a large molecular diversity, which allowed the tuning of the binding affinity and selectivity of the CMBLs by varying the linkers towards various biologically significant repeat DNA structures. PMID- 28653775 TI - Evaluation of change in dietitians' perceived comprehensibility and difficulty of the Patient-Generated Subjective Global Assessment (PG-SGA) after a single training in the use of the instrument. AB - BACKGROUND: The Patient-Generated Subjective Global Assessment (PG-SGA) is an instrument used to assess malnutrition and its risk factors. Some items of the PG SGA may be perceived as hard to comprehend or as difficult by healthcare professionals. The present study aimed to determine whether and how dietitians' perceptions of comprehensibility and difficulty of the PG-SGA change after a single training in PG-SGA use. METHODS: In this prospective evaluation study, Dutch PG-SGA-naive dietitians completed a questionnaire regarding perceived comprehensibility and difficulty of the PG-SGA before (T0) and after (T1) receiving a single training in the use of the instrument. Perceived comprehensibility and difficulty were operationalised by calculating item and scale indices for comprehensibility (I-CI, S-CI) and difficulty (I-DI, S-DI) at T0 and T1. An item index of 0.78 was considered acceptable, a scale index of 0.80 was considered acceptable and a scale index of 0.90 was considered excellent. RESULTS: A total of 35 participants completed the questionnaire both at T0 and T1. All item indices related to comprehensibility and difficulty improved, although I-DI for the items regarding food intake and physical examination remained below 0.78. Scale indices for difficulty and comprehensibility of the PG SGA changed significantly (P < 0.001) from not acceptable at T0 (S-CI = 0.69; S DI = 0.57) to excellent for comprehensibility (S-CI = 0.95) and acceptable for difficulty (S-DI = 0.86) at T1. CONCLUSIONS: The findings of the present study suggest that significant improvement in PG-SGA-naive dietitians' perception of comprehensibility and difficulty of the PG-SGA can be achieved quickly by providing a 1 day of training in the use of the PG-SGA. PMID- 28653776 TI - Can inactive blood donors be re-recruited? A stratified randomised pilot study. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of recruitment of inactive donors by telephone call and cell phone short message service (SMS), to assess the causes of donor self-deferral and to determine the appropriate sample size for a formal study BACKGROUND: Blood donor retention is essential for sustaining blood safety and sufficiency. METHODS: We conducted a single-centre open-label parallel randomised controlled trial in Guangzhou, China. A total of 1188 inactive donors with the last donation between 2009 and 2013 were enrolled and randomly assigned to two intervention groups (telephone call and SMS groups) and one control group without any intervention. Donors were followed up for 7 months; their responses including donation activities were analysed. RESULTS: The re-donation rates among the three groups were statistically significantly different (P = 0.044), particularly between the phone call group and the control group (P = 0.017). Within the phone call group, the re-donation rate was positively associated with the frequency of prior donation (P = 0.026), and the age of the donors (P = 0.043). Medical issues, time constraints and group donation were the main causes of self-deferral. The appropriate sample size for each group for a formal study to detect difference between the phone call and SMS groups was estimated to be 1429 participants. CONCLUSIONS: Our findings suggest that active interventions, especially phone call reminders, can increase blood donation. Further studies are required to compare the efficacy and effectiveness between phone call and SMS reminders using a larger sample size. PMID- 28653777 TI - Vertical-Aligned Li2 S-Graphene Encapsulated within a Carbon Shell as a Free Standing Cathode for Lithium-Sulfur Batteries. AB - Construction of a novel matrix with both high conductivity and an excellent confinement effect for polysulfides is of great importance for developing high performance lithium-sulfur (Li-S) batteries. In this work, we have developed a double-modification strategy to integrate lithium sulfide (Li2 S) into a conductive composite network consisting of vertical graphene (VG) arrays and an amorphous carbon shell, forming an integrated cathode (VG/Li2 S-C). Facile liquid solution/evaporation methods in combination with chemical vapor deposition were successfully adopted for preparation of the above cathode. Due to the enhanced electrical conductivity and noticeable blocking effect for the shuttle of polysulfides, the binder-free flexible VG/Li2 S-C cathode exhibits high rate performance and reinforced cycles (656.2 mAh g-1 after 100 cycles). The pronounced electrochemical performance is ascribed to the unique architecture with a coherent conductive network of VG and the carbon shell, which not only provides a conductive network for fast reaction kinetics, but also forms a durable protective shield to suppress the shuttle of polysulfides. Our research further demonstrates the synergistic effectiveness by means of inner and outer carbon matrixes for electrochemical enhancement of Li-S batteries. PMID- 28653778 TI - Activatable Near-Infrared Probe for Fluorescence Imaging of gamma-Glutamyl Transpeptidase in Tumor Cells and In Vivo. AB - gamma-Glutamyl transpeptidase (GGT) is a cell-membrane-bound enzyme that is involved in various physiological and pathological processes and is regarded as a potential biomarker for many malignant tumors, precise detection of which is useful for early cancer diagnosis. Herein, a new GGT-activatable near-infrared (NIR) fluorescence imaging probe (GANP) by linking of a GGT-recognitive substrate gamma-glutamate (gamma-Glu) and a NIR merocyanine fluorophore (mCy-Cl) with a self-immolative linker p-aminobenzyl alcohol (PABA) is reported. GANP was stable under physiological conditions, but could be efficiently activated by GGT to generate ~100-fold enhanced fluorescence, enabling high sensitivity (detection limit of ~3.6 mU L-1 ) and specificity for the real-time imaging of GGT activity as well as rapid evaluation of the inhibition efficacy of GGT inhibitors in living tumor cells. Notably, the deep tissue penetration ability of NIR fluorescence could further allow GANP to image GGT in frozen tumor tissue slices with large penetration depth (>100 MUm) and in xenograft tumors in living mice. This GGT activatable NIR fluorescence imaging probe could facilitate the study and diagnosis of other GGT-correlated diseases in vivo. PMID- 28653779 TI - Adrenal maturation, nutritional status, and mucosal immunity in Bolivian youth. AB - OBJECTIVES: Humans-and several other apes-exhibit a unique pattern of post-natal adrenal maturation; however, the causes and consequences of variation in adrenal development are not well understood. In this study, we examine developmental and age-related maturation of the adrenal gland (measured via dehydroepiandrosterone sulfate [DHEA-S]) for potential life-history associations with growth and mucosal immunity in a rural population of immune-challenged Bolivian juveniles and adolescents. METHODS: Salivary DHEA-S, anthropometrics, and salivary mucosal immunity (secretory IgA [sIgA]) were measured in 171 males and females, aged 8 23. RESULTS: Males with greater energy (i.e. fat) stores showed higher DHEA-S levels. Controlling for age and energetic condition (to control for phenotypic correlation), higher DHEA-S was associated with higher mucosal immunity (sIgA) among both males and females. Higher DHEA-S levels were positively associated with growth (i.e. height and strength) in males. CONCLUSIONS: In accordance with predictions derived from life-history theory, males with higher energy stores secrete more adrenal androgens. This suggests that adrenal maturation is costly and subject to constraints; that is, only males with sufficient reserves will invest in accelerated adrenal maturation. Further, DHEA-S appears to have a measureable influence on immunocompetence in adolescent males and females; therefore, deficits in DHEA-S may have important consequences for health and maturation during this period. Adrenal maturation is an important, but understudied component of human growth and development. PMID- 28653780 TI - Gait training for chronic ankle instability improves neuromechanics during walking. AB - A novel gait-training device has been shown to improve gait patterns while patients with chronic ankle instability (CAI) are using the device and our current objective was to analyze the effect of structured gait training with the device on plantar pressure and surface electromyography (sEMG) following repeated gait training sessions. Sixteen CAI patients participated. Plantar pressure and sEMG were collected simultaneously during walking pre- and post-gait training. Plantar pressure (pressure time integral, peak pressure, time to peak pressure, contact area, contact time, and center of pressure trajectory) of the entire foot and nine specific regions of the foot were recorded concurrently with sEMG root mean square amplitudes from the anterior tibialis, peroneus longus, medial gastrocnemius, and gluteus medius. Five gait training sessions were performed with each session lasting approximately 15 min. Pre- and post-gait training self reported function, plantar pressure, and sEMG were compared using paired t-tests with a priori level of significance of p <= 0.05. Gait training improved self reported function (FAAM-Sport scale: Pre = 75.1 +/- 7.1%, Post = 85.7 +/- 12.2%, p < 0.001) and caused a medial shift in the COP from 10% of stance through toe off (p < 0.05 for all analyses). The medial shift in COP was driven by concurrent increases in peroneus longus muscle activity from 21% to 60% and 81% to 90% of stance (p < 0.05 for all analyses). There was a corresponding reduction in gluteus medius muscle activity during 71-100% of stance (p < 0.05 for all analyses). Overall, gait training with a device that targets the peroneus longus and gluteus medius throughout the gait cycle improved gait patterns in CAI patients. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:515-524, 2018. PMID- 28653781 TI - Differential expression profile of long non-coding RNA in cardiomyocytes autophagy induced by angiotensin II. AB - Autophagy is a ubiquitous intracellular process for cellular homeostasis maintenance by recycling damaged protein and organelles. Dysregulation of cardiomyocytes autophagic activity is implicated in various heart diseases. Recent studies had demonstrated that long non-coding RNAs (lncRNAs) played crucial roles on modulation of autophagic activity. In this study, we first established an angiotensin II-induced autophagy model on neonatal rat cardiomyocytes. Western blot assay confirmed that the expression of Beclin 1 and the conversion of soluble LC3-I to lipid bound LC3-II were significantly increased at 12 h after angiotensin II stimulation, but the cardiomyocytes surface area and hypertrophic markers expression had no significant change. Then microarray analysis and real-time PCR were applied to detect differentially expressed lncRNAs during cardiomyocytes autophagy. A total of 1,249 lncRNAs were determined as differentially expressed, including 700 upregulated lncRNAs and 549 downregulated lncRNAs. LncRNAs subgroup analysis showed there were 43 transcribed ultra-conserved noncoding RNAs (T-UCRs) differentially expressed in cardiomyocytes autophagy, of which 26 T-UCRs were upregulated and 17 T-UCRs were downregulated. Bioinformatics analysis further showed that 94 differentially expressed lncRNAs contained potential binding sites of miR-22, a pro-hypertrophic and pro-autophagic microRNA. Therefore, these differentially expressed lncRNAs might play critical roles in cardiomyocytes autophagy. This finding would provide an experimental basis for future investigation on ischemic heart disease. PMID- 28653782 TI - Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program. AB - : This qualitative study summarizes information that individuals shared online about use of OxyContin following the August 2010 introduction of the abuse deterrent formulation (ADF). PURPOSE: The primary objective was to study online posts that endorsed continued use of OxyContin or a switch from OxyContin to another formulation of oxycodone or another substance altogether following the introduction of the ADF. A secondary objective was to determine whether posts revealed that the ADF led to cessation of OxyContin use. METHODS: Data were collected with the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program, an online surveillance system that collects and organizes posts about prescription drugs from social media websites, blogs, and forums from 3Q2009 to 4Q2014 using a commercially available web platform. RESULTS: Posts were categorized by whether they conveyed a switch to drugs other than reformulated OxyContin or a continuation of reformulated OxyContin abuse. "Switch posts" primarily discussed switching to immediate release opioids. "Continue abusing" posts identified tampering strategies for alternate routes of administration, oral use, and continued use although post authors were generally unhappy with the experience. No reference to OxyContin cessation as a function of the introduction of the ADF was found; however, discontinued use was discussed. CONCLUSIONS: Web Monitoring data are useful for capturing cross sections of Internet conversation reflecting reactions to new drug formulations. These data support the notion that users will gravitate to non ADFs generally, and to immediate-release non-ADF opioid formulations, specifically, as long as these options remain on the market. PMID- 28653783 TI - Protein phosphatases potentially associated with regulation of microtubules, their spatial structure reconstruction and analysis. AB - According to the sequence and profile comparison with known catalytic domains, where identified protein phosphatases potentially involved in regulation of microtubule dynamics and structure from Arabidopsis thaliana, Nicotiana tabacum, Medicago sativa, Oryza sativa subsp. japonica, Zea mays, and Triticum aestivum. Selected proteins were related to classical non-receptor, serine/threonine specific and dual protein phosphatases. By application of template structures of human protein phosphatases, it was performed homology modelling of the catalytic domains of 17 plant protein phosphatases. Based on the results of the structural alignment, molecular dynamics, and conservatism in positions of functionally importance, it was confirmed homology of selected plant proteins and known protein phosphatases regulating structure and dynamics of microtubules. PMID- 28653784 TI - Massive tumor embolism in the abdominal aorta from pulmonary squamous cell carcinoma: Case report and review of the literature. AB - Acute arterial tumor embolism is a rare complication in cancer patients. Most of the previously reported cases of arterial tumor embolism have been associated with pulmonary malignancies and occurred during the intraoperative and postoperative periods. Very few cases occurred spontaneously. To our knowledge, there is no previous report of spontaneous and massive tumor embolism occluding the abdominal aorta in patients suffering from primary pulmonary carcinoma. We describe the case of 64-year-old man who presented with left homonymous hemianopsia and backache. Further evaluation revealed a mass in the right lung, severe coagulopathy, and cerebral hemorrhagic infarction in the right occipital lobe. He suddenly developed lower limb ischemia 4 weeks after his first clinical visit, and finally, died of multiple organ failure. Autopsy showed non keratinizing squamous cell carcinoma in the right lung and massive tumor emboli in the abdominal aorta containing nests of squamous cell carcinoma. Infarct regions were found in the bilateral kidneys, spleen, liver, and brain; fibrin thrombi, but not tumor emboli, were found in these regions. This case suggested that tumor embolism should be considered when patients suffering from primary pulmonary malignancies develop arterial embolism and arterial tumor emboli could be massive enough to occlude the abdominal aorta. PMID- 28653785 TI - Lung function in relation to farm dwelling and farming activities in rural dwelling children. AB - BACKGROUND AND OBJECTIVE: The relationship between farming exposures and pulmonary function in a rural paediatric population was evaluated. METHODS: Baseline data collection records of the Saskatchewan Rural Health Study (SRHS), a population-based study, were used. A subset of children (6-14 years old) participated in clinical testing, including anthropometric measures and pulmonary function testing (PFT), using spirometry (n = 584). PFTs followed ATS criteria and all statistical analyses were controlled for age, sex and height. RESULTS: Among clinical testing participants, 47.5% were females and 54.5% were farm dwelling. Of those living on farms, 77.5% were livestock farms. Mean percent predicted value (PPV) for forced expiratory volume in 1 s (FEV1 ) and forced vital capacity (FVC) among children living on a farm were 104.8% and 105.4%, respectively. Mean PPV for FEV1 and FVC among children not living on a farm were 102.7% and 101.4%, respectively. After adjustment, higher FEV1 (=0.079, SE = 0.033, P = 0.03) and FVC (=0.110, SE = 0.039, P = 0.006) were seen among children living on a farm. A trend towards lower FEV1 /FVC ratio (-0.013, SE = 0.008, P = 0.09) among children living on a farm was seen compared with children not living on a farm. Higher FVC and lower FEV1 /FVC ratio were seen in children who regularly emptied grain bins (P < 0.05). Trends towards higher FEV1 (P = 0.14) and FVC (P = 0.08) were also seen with children living on a farm in the first year of life. Since the majority of the population was Caucasian (91%), the results were not race-corrected. CONCLUSION: We addressed the lack of knowledge regarding the association between lung function and rural exposures, and found that differences in lung function were seen between children living on a farm and not living on a farm in rural areas and certain farming activities, specifically emptying grain bins, where lung function was generally better in those living on a farm. PMID- 28653786 TI - Surveillance of BIRADS 3 lesions. PMID- 28653788 TI - miR-497 accelerates oxidized low-density lipoprotein-induced lipid accumulation in macrophages by repressing the expression of apelin. AB - microRNAs (miRNAs) play important roles in the pathogenesis of atherosclerosis. A previous study has reported that miR-497 is elevated in advanced atherosclerotic lesions in an apoE-deficient (apoE-/-) mouse model. The purpose of this study is to test whether miR-497 can modulate macrophage foam cell formation, an initiating event in atherosclerosis. We found that miR-497 was upregulated in THP 1 macrophages after treatment with oxidized low-density lipoprotein (oxLDL). Enforced expression of miR-497 promoted lipid accumulation and decreased cholesterol efflux in oxLDL-exposed THP-1 macrophages. In contrast, downregulation of miR-497 suppressed oxLDL-induced lipid accumulation in THP-1 macrophages. Apelin was identified to be a downstream target of miR-497. Overexpression of miR-497 significantly reduced the expression of apelin in THP-1 macrophages. Interestingly, delivery of a miR-497-resistant variant of apelin significantly inhibited lipid accumulation and enhanced cholesterol efflux in miR 497-overexpressing THP-1 macrophages in response to oxLDL. In addition, miR-497 expression was increased and negatively correlated with apelin protein expression in human atherosclerotic lesions. In conclusion, miR-497 contributes to oxLDL induced lipid deposition in macrophages largely via targeting of apelin and thus represents a potential therapeutic target for atherosclerosis. PMID- 28653787 TI - Antibacterial resistance and the success of tailored triple therapy in Helicobacter pylori strains isolated from Slovenian children. AB - BACKGROUND: Primary Helicobacter pylori (H. pylori) infection occurs predominantly in childhood. Antimicrobial resistance is the leading cause for H. pylori eradication failure. The aims of this study were (i) to establish for the first time the antimicrobial resistance of H. pylori strains in infected Slovenian children not previously treated for H. pylori infection and (ii) to evaluate the effectiveness of tailored triple therapy, assuming that eradication rate with tailored triple therapy will be >90%. METHODS: Data on all treatment naive children 1-18 years old and treated for H. pylori infection according to susceptibility testing were retrospectively analyzed. All relevant clinical information and demographical information were retrospectively collected from the hospital information systems and/or patients' medical documentation. RESULTS: The inclusion criteria were met by 107 children (64.5% girls) with a median age of 12.0 years (range 2.0-17.6 years). Primary antimicrobial resistance rates of H. pylori were 1.0% to amoxicillin (AMO), 23.4% to clarithromycin (CLA), 20.2% to metronidazole (MET), 2.8% to levofloxacin (LEV), and 0.0% to tetracycline (TET). Dual resistances were detected to CLA and MET in 11.5% (n=12) of strains, to CLA and LEV in 2.8% (n=3), and to MET and LEV in 2.9% (n=3). Results of treatment success were available for 71 patients (66.2% girls). Eradication of H. pylori was evaluated using the 13C-urea breath test, monoclonal stool antigen test or in some cases with repeated upper GI endoscopy with histology and cultivation/molecular tests. Eradication was achieved in 61 of 71 (85.9%) patients. CONCLUSIONS: The primary resistance rates of H. pylori to CLA and MET in Slovenia are high. Our data strongly support the fact that in countries with high prevalence of resistant H. pylori strains susceptibility testing and tailored therapy is essential. PMID- 28653789 TI - Congenital epiglottic cyst: Neck position-dependent respiratory distress in newborns. PMID- 28653790 TI - vigiRank for statistical signal detection in pharmacovigilance: First results from prospective real-world use. AB - PURPOSE: vigiRank is a data-driven predictive model for emerging safety signals. In addition to disproportionate reporting patterns, it also accounts for the completeness, recency, and geographic spread of individual case reporting, as well as the availability of case narratives. Previous retrospective analysis suggested that vigiRank performed better than disproportionality analysis alone. The purpose of the present analysis was to evaluate its prospective performance. METHODS: The evaluation of vigiRank was based on real-world signal detection in VigiBase. In May 2014, vigiRank scores were computed for pairs of new drugs and WHO Adverse Reaction Terminology critical terms with at most 30 reports from at least 2 countries. Initial manual assessments were performed in order of descending score, selecting a subset of drug-adverse drug reaction pairs for in depth expert assessment. The primary performance metric was the proportion of initial assessments that were decided signals during in-depth assessment. As comparator, the historical performance for disproportionality- guided signal detection in VigiBase was computed from a corresponding cohort of drug-adverse drug reaction pairs assessed between 2009 and 2013. During this period, the requirement for initial manual assessment was a positive lower endpoint of the 95% credibility interval of the Information Component measure of disproportionality, observed for the first time. RESULTS: 194 initial assessments suggested by vigiRank's ordering eventually resulted in 6 (3.1%) signals. Disproportionality analysis yielded 19 signals from 1592 initial assessments (1.2%; P < .05). CONCLUSIONS: Combining multiple strength-of-evidence aspects as in vigiRank significantly outperformed disproportionality analysis alone in real world pharmacovigilance signal detection, for VigiBase. PMID- 28653791 TI - The left dorsolateral prefrontal cortex and caudate pathway: New evidence for cue induced craving of smokers. AB - Although the activation of the prefrontal cortex (PFC) and the striatum had been found in smoking cue induced craving task, whether and how the functional interactions and white matter integrity between these brain regions contribute to craving processing during smoking cue exposure remains unknown. Twenty-five young male smokers and 26 age- and gender-matched nonsmokers participated in the smoking cue-reactivity task. Craving related brain activation was extracted and psychophysiological interactions (PPI) analysis was used to specify the PFC efferent pathways contributed to smoking cue-induced craving. Diffusion tensor imaging (DTI) and probabilistic tractography was used to explore whether the fiber connectivity strength facilitated functional coupling of the circuit with the smoking cue-induced craving. The PPI analysis revealed the negative functional coupling of the left dorsolateral prefrontal cortex (DLPFC) and the caudate during smoking cue induced craving task, which positively correlated with the craving score. Neither significant activation nor functional connectivity in smoking cue exposure task was detected in nonsmokers. DTI analyses revealed that fiber tract integrity negatively correlated with functional coupling in the DLPFC caudate pathway and activation of the caudate induced by smoking cue in smokers. Moreover, the relationship between the fiber connectivity integrity of the left DLPFC-caudate and smoking cue induced caudate activation can be fully mediated by functional coupling strength of this circuit in smokers. The present study highlighted the left DLPFC-caudate pathway in smoking cue-induced craving in smokers, which may reflect top-down prefrontal modulation of striatal reward processing in smoking cue induced craving processing. Hum Brain Mapp 38:4644 4656, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28653792 TI - Neural correlates underlying the attentional spotlight in human parietal cortex independent of task difficulty. AB - Changes in the size of the attentional focus and task difficulty often co-vary. Nevertheless, the neural processes underlying the attentional spotlight process and task difficulty are likely to differ from each other. To differentiate between the two, we parametrically varied the size of the attentional focus in a novel behavioral paradigm while keeping visual processing difficulty either constant or not. A behavioral control experiment proved that the present behavioral paradigm could indeed effectively manipulate the size of the attentional focus per se, rather than affecting purely perceptual processes or surface processing. Imaging results showed that neural activity in a dorsal frontoparietal network, including right superior parietal cortex (SPL), was positively correlated with the size of the attentional spotlight, irrespective of whether task difficulty was constant or varied across different sizes of attentional focus. In contrast, neural activity in the ventral frontoparietal network, including the right inferior parietal cortex (IPL), was positively correlated with increasing task difficulty. Data suggest that sub-regions in parietal cortex are differentially involved in the attentional spotlight process and task difficulty: while SPL was involved in the attentional spotlight process independent of task difficulty, IPL was involved in the effect of task difficulty independent of the attentional spotlight process. Hum Brain Mapp 38:4996-5018, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28653793 TI - Intrinsic connectivity of hippocampal subfields in normal elderly and mild cognitive impairment patients. AB - Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty-six HE and 27 aMCI patients underwent resting-state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high-resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922-4932, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28653794 TI - Predicting the brain activation pattern associated with the propositional content of a sentence: Modeling neural representations of events and states. AB - Even though much has recently been learned about the neural representation of individual concepts and categories, neuroimaging research is only beginning to reveal how more complex thoughts, such as event and state descriptions, are neurally represented. We present a predictive computational theory of the neural representations of individual events and states as they are described in 240 sentences. Regression models were trained to determine the mapping between 42 neurally plausible semantic features (NPSFs) and thematic roles of the concepts of a proposition and the fMRI activation patterns of various cortical regions that process different types of information. Given a semantic characterization of the content of a sentence that is new to the model, the model can reliably predict the resulting neural signature, or, given an observed neural signature of a new sentence, the model can predict its semantic content. The models were also reliably generalizable across participants. This computational model provides an account of the brain representation of a complex yet fundamental unit of thought, namely, the conceptual content of a proposition. In addition to characterizing a sentence representation at the level of the semantic and thematic features of its component concepts, factor analysis was used to develop a higher level characterization of a sentence, specifying the general type of event representation that the sentence evokes (e.g., a social interaction versus a change of physical state) and the voxel locations most strongly associated with each of the factors. Hum Brain Mapp 38:4865-4881, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28653795 TI - Reduced energy density of close-up diets decrease ruminal pH and increase concentration of volatile fatty acids postpartum in Holstein cows. AB - The objective of this study was to determine the effect of reduced energy density of close-up diets on ruminal fermentation parameters in transition cows. Fourteen Holstein dry cows were blocked and assigned randomly to three groups fed a high energy density diet (HD, 1.62 Mcal of net energy for lactation (NEL )/kg dry matter (DM)), or a middle energy density diet (MD, 1.47 Mcal NEL /kg DM), or a low energy density diet (LD, 1.30 Mcal NEL /kg DM) prepartum, and were fed the same diet postpartum. The reduced energy density diets decreased the average dry matter intake (DMI) prepartum and tended to increase the DMI postpartum. The ruminal pH of the LD group was significantly higher prepartum and lower during the first week of lactation compared with the other two groups. The reduced energy density diet depressed the average ruminal concentration of propionate and butyrate prepartum, and increased the average concentration of total volatile fatty acids (VFA) postpartum. The LD group had higher populations of Butyrivibrio fibrisolvens and Ruminococcus flavefaciens relative to HD and MD groups on 7 days in milk. In conclusion, the cows fed reduced energy density diet prepartum had higher VFA concentration, but were more susceptible to subacute ruminal acidosis postpartum. PMID- 28653796 TI - Cycloaddition Reactions: Why Is It So Challenging To Move from Six to Ten Electrons? AB - High on cycloaddi(c)tions: The impact of the Woodward-Hoffmann [4n+2] rule for thermally allowed cycloaddition reactions and the challenges associated with moving from six to ten electrons are discussed in this Essay. PMID- 28653798 TI - Spinal Cord Injury Pain Instrument and painDETECT questionnaire: Convergent construct validity in individuals with Spinal Cord Injury. AB - BACKGROUND: Neuropathic pain (NeuP) is a frequent sequel of spinal cord injury (SCI). The SCI Pain Instrument (SCIPI) was developed as a SCI-specific NeuP screening tool. A preliminary validation reported encouraging results requiring further evaluation in terms of psychometric properties. The painDETECT questionnaire (PDQ), a commonly applied NeuP assessment tool, was primarily validated in German, but not specifically developed for SCI and not yet validated according to current diagnostic guidelines. We aimed to provide convergent construct validity and to identify the optimal item combination for the SCIPI. The PDQ was re-evaluated according to current guidelines with respect to SCI related NeuP. METHODS: Prospective monocentric study. Subjects received a neurological examination according to the International Standards for Neurological Classification of SCI. After linguistic validation of the SCIPI, the IASP-grading system served as reference to diagnose NeuP, accompanied by the PDQ after its re-evaluation as binary classifier. Statistics were evaluated through ROC-analysis, with the area under the ROC curve (AUROC) as optimality criterion. The SCIPI was refined by systematic item permutation. RESULTS: Eighty-eight individuals were assessed with the German SCIPI. Of 127 possible combinations, a 4-item-SCIPI (cut-off-score = 1.5/sensitivity = 0.864/specificity = 0.839) was identified as most reasonable. The SCIPI showed a strong correlation (rsp = 0.76) with PDQ. ROC-analysis of SCIPI/PDQ (AUROC = 0.877) revealed comparable results to SCIPI/IASP (AUROC = 0.916). ROC-analysis of PDQ/IASP delivered a score threshold of 10.5 (sensitivity = 0.727/specificity = 0.903). CONCLUSION: The SCIPI is a valid easy-to-apply NeuP screening tool in SCI. The PDQ is recommended as complementary NeuP assessment tool in SCI, e.g. to monitor pain severity and/or its time-dependent course. SIGNIFICANCE: In SCI-related pain, both SCIPI and PainDETECT show strong convergent construct validity versus the current IASP grading system. SCIPI is now optimized from a 7-item to an easy-to-apply 4-item screening tool in German and English. We provided evidence that the scope for PainDETECT can be expanded to individuals with SCI. PMID- 28653797 TI - Neural correlates of formal thought disorder: An activation likelihood estimation meta-analysis. AB - Formal thought disorder (FTD) refers to a psychopathological dimension characterized by disorganized and incoherent speech. Whether symptoms of FTD arise from aberrant processing in language-related regions or more general cognitive networks, however, remains debated. Here, we addressed this question by a quantitative meta-analysis of published functional neuroimaging studies on FTD. The revised Activation Likelihood Estimation (ALE) algorithm was used to test for convergent aberrant activation changes in 18 studies (30 experiments) investigating FTD, of which 17 studies comprised schizophrenia patients and one study healthy subjects administered to S-ketamine. Additionally, we analyzed task dependent and task-independent (resting-state) functional connectivity (FC) of brain regions showing convergence in activation changes. Subsequent functional characterization was performed for the initial clusters and the delineated connectivity networks by reference to the BrainMap database. Consistent activation changes were found in the left superior temporal gyrus (STG) and two regions within the left posterior middle temporal gyrus (p-MTG), ventrally (vp MTG) and dorsally (dp-MTG). Functional characterization revealed a prominent functional association of ensuing clusters from our ALE meta-analysis with language and speech processing, as well as auditory perception in STG and with social cognition in dp-MTG. FC analysis identified task-dependent and task independent networks for all three seed regions, which were mainly related to language and speech processing, but showed additional involvement in higher order cognitive functions. Our findings suggest that FTD is mainly characterized by abnormal activation in brain regions of the left hemisphere that are associated with language and speech processing, but also extend to higher order cognitive functions. Hum Brain Mapp 38:4946-4965, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28653800 TI - French validation of the Maslach Burnout Inventory-Student Survey (MBI-SS). AB - INTRODUCTION: Several international studies have been conducted on student burnout. To contribute to the clinical examination as well as research on the mental health of students, the MBI-SS (Maslach Burnout Inventory-Student Survey) has been validated and used in different countries but not in French. OBJECTIVE: The aim of this study is to examine the validity of the 3-dimensional model of the French version of the MBI-SS, which is characterized by emotional "Emotional Exhaustion" (EE); "Cynicism" (CY); and low scores in "Academic Efficacy" (AE). METHOD: A total of 667 university students were questioned to study the 3 dimensional structure of the French translation of the MBI-SS. RESULTS AND CONCLUSION: The results validate the 3-dimensional structure of the MBI-SS and indicate satisfactory psychometric values. It is concluded that the MBI-SS can be used to assess burnout in French students. PMID- 28653799 TI - Longitudinal cognitive trajectories and associated clinical variables in youth with bipolar disorder. AB - OBJECTIVE: There is substantial interest in delineating the course of cognitive functioning in bipolar (BP) youth. However, there are no longitudinal studies aimed at defining subgroups of BP youth based on their distinctive cognitive trajectories and their associated clinical variables. METHOD: Cognitive functioning was measured in 135 participants from the Course and Outcome of BP Youth (COBY) study using several subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Youth were prospectively evaluated three times on average every 13.75 months over 2.5 years. Clinical and functional outcomes were assessed using the Longitudinal Interval Follow-Up Evaluation (LIFE). RESULTS: Latent class growth analysis identified three longitudinal patterns of cognitive functioning based on a general cognitive index: class 1, "persistently high" (N=21; 15.6%); class 2, "persistently moderate" (N=82; 60.74%); and class 3, "persistently low" (N=32; 23.7%). All classes showed normal cognitive functioning when compared with the CANTAB normative data. After adjustment for confounders, youth from class 3 had a significantly greater percentage of time with overall, manic, and depressive syndromal symptoms than youth in the other two classes. Also, after adjustment for confounders, youth from class 3 had significantly poorer global, academic, and social functioning than youth from class 1. CONCLUSIONS: BP youth showed normal overall cognitive functioning that remained stable during the follow-up within each class. However, 24% of BP youth showed poorer cognitive functioning than the other BP youth. This subgroup had poorer mood course and functioning, and may benefit from cognitive remediation and early management with evidence-based pharmacological treatments. PMID- 28653803 TI - Mitochondrial DNA haplogroup variation of contemporary mixed South Americans reveals prehistoric displacements linked to archaeologically-derived culture history. AB - OBJECTIVE: The purpose of this study was to examine South American population structure and prehistoric population displacements prior to the Spanish conquest, utilizing mitochondrial DNA haplogroups of extant mixed populations from Mexico, Costa Rica, Venezuela, Colombia, Ecuador, Peru, Bolivia, Brazil, Argentina, and Chile. METHOD: Relative frequencies of four pan-American haplogroups, obtained from published databases, were analyzed to evaluate patterns of variations, population structure and possible prehistoric migration pathways. RESULTS: Patterns of mtDNA variation verify biogeographic drift processes and possible migratory pathways. CONCLUSIONS: We propose an updated model of South American colonization that is fully compatible with previous studies based on autosomal, mtDNA, and Y chromosome variation and with archaeologically-derived culture history. PMID- 28653802 TI - Safety profile of H1-antihistamines in pediatrics: an analysis based on data from VigiBase. AB - PURPOSE: H1-antihistamines are commonly used in infants and children for the relief of histamine-mediated symptoms in a variety of conditions. Little is known about their safety profile in these patients. We performed a comparative analysis of the safety profiles of H1-antihistamines using data from the WHO database (VigiBase). METHODS: We selected adverse drug reaction (ADR) reports on H1 antihistamines in children (0-16 years) up to June 2014 from VigiBase. ADRs were codified according to MedDRA terminology. The reporting odds ratios (RORs) with 95% confidence for drug-reaction pairs were calculated. RESULTS: The analysis was performed on 8918 reports related to antihistamines, corresponding to 19503 drug reaction pairs for 68 different drugs. Most of reports involved children aged 2 to 6 years (32%) and 6 to 12 years (34%). Most reported drugs were cetirizine (1608 reports, corresponding to 18%), loratadine (16%), and diphenhydramine (10%). ADRs were classified as serious in 23% of cases, and 400 cases had a fatal outcome. We found a significant associations for several drug-reaction pairs such as levocetirizine and epilepsy (ROR, 6.57; 95% confidence interval [CI], 1.51 28.53) and chlorphenamine and toxic epidermal necrolysis (ROR, 7.29; 95% CI, 2.39 22.2). CONCLUSIONS: H1-antihistamines are among the most used drugs in pediatrics, also in an off-label manner. Our data highlights associations with serious and unexpected ADRs. Educative intervention to clinicians and parents are needed to help doctors to make proper choices on the drug treatment and for the early detection of ADRs to maximize the benefits and reduce the risk of ADRs in these patients. PMID- 28653801 TI - A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity. AB - GPR55, an orphan G-protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs' functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long-term potentiation, a common form of synaptic plasticity. Using quantitative RT-PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT-PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55+/+ mice significantly enhanced CA1 LTP. This effect was absent in GPR55-/- mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired-pulse ratios of GPR55-/- and GPR55+/+ mice with or without LPI and noted significant enhancement in paired-pulse ratios by LPI in GPR55+/+ mice. Behaviorally, GPR55-/- and GPR55+/+ mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55-/- mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity. PMID- 28653804 TI - Opening a Can of Worm(-like Micelle)s: The Effect of Temperature of Solutions of Functionalized Dipeptides. AB - A simple heat/cool cycle can be used to significantly affect the properties of a solution of a low-molecular-weight gelator at high pH. The viscosity and extensional viscosity are increased markedly, leading to materials with very different properties than when the native solution is used. PMID- 28653805 TI - MicroRNA-30e-5p promotes cell growth by targeting PTPN13 and indicates poor survival and recurrence in lung adenocarcinoma. AB - Aberrant microRNA expression is involved in the regulation of various cellular processes, such as proliferation and metastasis in multiple diseases including cancers. MicroRNA-30e-5p (miR-30e) was previously reported as an oncogenic or tumour suppressing miRNA in some malignancies, but its function in lung adenocarcinoma (LAC) remains largely undefined. In this study, we found that the expression of miR-30e was increased in LAC tissues and cell lines, associated with tumour size and represented an independent prognostic factor for overall survival and recurrence of LAC patients. Further functional experiments showed that knockdown of miR-30e suppressed cell growth while its overexpression promoted growth of LAC cells and xenografts in vitro and in vivo. Mechanistically, PTPN13 was identified as the direct target of miR-30e in LAC, in which PTPN13 expression was down-regulated in LAC tissues and showed the inverse correlation with miR-30e expression. Overexpression of PTPN13 inhibited cell growth and rescued the proliferation-promoting effect of miR-30e through inhibition of the EGFR signalling. Altogether, our findings suggest that miR-30e could function as an oncogene in LAC via targeting PTPN13 and act as a potential therapeutic target for treating LAC. PMID- 28653807 TI - Authors' reply re: Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data? PMID- 28653808 TI - A novel technique for reference point generation to aid in intraoral scan alignment. AB - OBJECTIVE: When using a completely digital workflow on larger prosthetic cases it is often difficult to communicate to the laboratory or chairside Computer Aided Design and Computer Aided Manufacturing system the provisional prosthetic information. The problem arises when common hard tissue data points are limited or non-existent such as in complete arch cases in which the 3D model of the complete arch provisional restorations must be aligned perfectly with the 3D model of the complete arch preparations. In these instances, soft tissue is not enough to ensure an accurate automatic or manual alignment due to a lack of well defined reference points. A new technique is proposed for the proper digital alignment of the 3D virtual model of the provisional prosthetic to the 3D virtual model of the prepared teeth in cases where common and coincident hard tissue data points are limited. Clinical considerations: A technique is described in which fiducial composite resin dots are temporarily placed on the intraoral keratinized tissue in strategic locations prior to final impressions. These fiducial dots provide coincident and clear 3D data points that when scanned into a digital impression allow superimposition of the 3D models. CONCLUSIONS: Composite resin dots on keratinized tissue were successful at allowing accurate merging of provisional restoration and post-preparation 3D models for the purpose of using the provisional restorations as a guide for final CLINICAL SIGNIFICANCE: Composite resin dots placed temporarily on attached tissue were successful at allowing accurate merging of the provisional restoration 3D models to the preparation 3D models for the purposes of using the provisional restorations as a guide for final restoration design and manufacturing. In this case, they allowed precise superimposition of the 3D models made in the absence of any other hard tissue reference points, resulting in the fabrication of ideal final restorations. PMID- 28653806 TI - Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events. AB - Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (~3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals. PMID- 28653809 TI - A prenatal diagnosis of mosaic trisomy 5 reveals a postnatal complete uniparental disomy of chromosome 5 with multiple congenital anomalies. AB - Mosaic trisomy 5 is a very rare condition in liveborns, with few cases reported in the last four decades. There are some reports of prenatally diagnosed mosaic trisomy 5 resulting in phenotypically normal offspring, suggesting a low level of mosaicism, but there are also reports associated with multiple congenital anomalies, cardiovascular malformations, and intrauterine growth restriction. We report an infant male diagnosed with mosaic trisomy 5 (5/15 cells) via amniocentesis. The patient was subsequently found to have uniparental disomy 5 (UPD5) by postnatal chromosome microarray, but high-resolution chromosome analysis on peripheral blood did not identify trisomy 5. Dysmorphic features included a tall forehead with low anterior hairline, hypertelorism, low-set ears, and a prominent nose and midface. Other anomalies included bilateral bifid thumbs, hypospadias, a perineal fistula, unilateral multicystic kidney, and decreased subcutaneous fat with loose skin. He had complex congenital heart disease consisting of ventricular and atrial septal defects and polyvalvular defects. The patient died at age one after a prolonged admission. We add this case to the literature with the added benefit of data from a postnatal microarray, which was not available in other cases, to broaden the phenotype of mosaic trisomy 5 and UPD5.With the current available technology, we stress the importance of postnatal genetic testing to confirm prenatal cytogenetic findings in order to further define such phenotypes. This will provide the most accurate information and counseling to affected families. PMID- 28653810 TI - The Piwi-piRNA pathway: road to immortality. AB - Despite its medical, social, and economic significance, understanding what primarily causes aging, that is, the mechanisms of the aging process, remains a fundamental and fascinating problem in biology. Accumulating evidence indicates that a small RNA-based gene regulatory machinery, the Piwi-piRNA pathway, represents a shared feature of nonaging (potentially immortal) biological systems, including the germline, somatic cancer stem cells, and certain 'lower' eukaryotic organisms like the planarian flatworm and freshwater hydra. The pathway primarily functions to repress the activity of mobile genetic elements, also called transposable elements (TEs) or 'jumping genes', which are capable of moving from one genomic locus to another, thereby causing insertional mutations. TEs become increasingly active and multiply in the genomes of somatic cells as the organism ages. These characteristics of TEs highlight their decisive mutagenic role in the progressive disintegration of genetic information, a molecular hallmark associated with aging. Hence, TE-mediated genomic instability may substantially contribute to the aging process. PMID- 28653811 TI - Biochemical characterization of a medaka (Oryzias latipes) orthologue for mammalian Factor XIII and establishment of a gene-edited mutant. AB - In the final process of blood coagulation, fibrin molecules are stabilized via a catalytic reaction by Factor XIIIA (FXIIIA), a member of the transglutaminase (TGase) family that catalyzes protein cross-linking reactions. In this study, we characterized the orthologue of this enzyme in medaka (Oryzias latipes), an established model fish in which a coagulation system is also preserved. The recombinant protein of this orthologue enzyme was produced in baculovirus infected insect cells and used for analysis of its biochemical properties including activation by thrombin proteolysis and calcium dependence of the TGase enzymatic activity. Immunostaining and immunoblotting revealed that medaka FXIIIA is expressed in the kidney, bone, and esophagus in addition to blood cells. Furthermore, a gene-mutant fish was established using the CRISPR/Cas9 system. The loss of FXIIIA expression was validated in the mutants, and phenotypes, such as absence of fibrin cross-linking, were investigated in the established mutant fish. PMID- 28653812 TI - Synthesis and luminescence of novel near-infrared emitting BaZrSi3 O9 :Cr3+ phosphors. AB - The BaZrSi3 O9 :Cr3+ phosphors were prepared by a high temperature solid state method. Their structures were confirmed with XRD and their luminescence properties were investigated. Under excitation at 455 nm, BaZrSi3 O9 :Cr3+ phosphors exhibited a broad near infrared emission band peaked at 800 nm, which was assigned to the 4 T2 ->4 A2 transition of Cr3+ . The near infrared emission intensity reached a maximum at Cr3+ concentration of 0.7%. There was a concentration quenching phenomenon of Cr3+ in BaZrSi3 O9 matrix and the corresponding concentration quenching mechanism was investigated. With efficient near infrared emission in the range of 700-1000 nm, BaZrSi3 O9 :Cr3+ phosphors may find applications in solar energy conversion. PMID- 28653814 TI - Normative data for quantitative calcaneal ultrasound in young males and females. AB - OBJECTIVE: The quantitative ultrasound (QUS) method has been recognized as an optimal screening tool for assessing bone mass status. The aim of this study was to provide standardized values for bone health status measured by the QUS technique based on age, sex, and body mass index (BMI). METHODS: The study population consisted of 1322 healthy individuals (822 females and 500 males) aged 14-25 years. Bone mass in both calcaneus was estimated with QUS to obtain Broadband ultrasound attenuation (BUA) (dB/MHz). RESULTS: The linear models revealed statistically significant differences between bone mass status of the calcaneus and age, sex, and BMI (P < .001). Bone mass increased at a rate of approximately 0.015 units per year after the age of 14 and these values increased in approximately 0.1 units in males in comparison to females. There was an increase of approximately 0.17 units for each increase in categories of BMI. CONCLUSION: It is crucial to provide standardized values for the QUS parameter in young males and females to allow reliable comparisons and evaluate trends in preventive programs that may enable the identification of individuals at risk for osteoporosis. PMID- 28653813 TI - Eplerenone for chronic central serous chorioretinopathy-a randomized controlled prospective study. AB - PURPOSE: To evaluate the efficacy and safety of eplerenone for chronic nonresolving central serous chorioretinopathy (CSC). METHODS: Prospective, double blind, randomized placebo-controlled study. Nineteen eyes of 17 patients with persistent subretinal fluid (SRF) due to CSC were enrolled and randomized to receive eplerenone 50 mg/day or placebo for 3 months, followed by a 3-month follow-up. The main outcome measure was change in SRF from baseline to 3 months of treatment. Secondary outcomes included change in SRF at any time-point, complete resolution of SRF, improvement in choroidal thickness and change in best corrected visual acuity (BCVA). RESULTS: Thirteen eyes were treated with eplerenone and six with placebo. Both groups showed reduction in SRF throughout the treatment period, with a significant reduction at months 1, 3 and 5 only in the treatment group. Twenty-three per cent in the treatment group and 30.8% per cent in the placebo group experienced complete resolution of SRF. A significant improvement in BCVA was noted in the placebo group at 4 months, as well as a significant difference in BCVA between groups at 3 months in favour of the placebo group (p = 0.005). There was no significant difference in choroidal thickness in either group throughout the study period. No adverse events related to eplerenone were noted in the treatment group. CONCLUSION: In this study, eplerenone was not found to be superior to placebo in eyes with chronic CSC. PMID- 28653815 TI - Factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy: a systematic review. AB - Oxaliplatin is a platinum-derivative chemotherapeutic agent used for colorectal cancer in the adjuvant and metastatic setting in combination with folinic acid and 5-fluorouracil. Oxaliplatin causes an acute cold-induced neurotoxicity and a chronic cumulative neuropathy, which can require dose modification and impact quality of life. To date, no prevention and treatment strategies have proved effective thus reinforcing the importance of identifying at-risk patients in order to maximize therapeutic benefit while minimizing neurotoxicity. Here we reviewed studies on risk and prognostic factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy. A systematic search was conducted in MEDLINE and Embase, and studies investigating clinical and patient-related factors associated with oxaliplatin-induced peripheral neuropathy as their primary focus were identified, and quantitative data were extracted when available. We identified 15 studies, of which only three were prospective. Notable factors were acute neurotoxicity symptoms predicting chronic neuropathy, baseline laboratory findings, patient demographics such as age and gender, comorbidities, and environmental factors. No factor was consistently identified across multiple studies other than the association with oxaliplatin dose. Further investigation into these factors may yield insight into potential neuropathy prevention and treatment strategies. PMID- 28653816 TI - Validation of the CHOP model for detecting severe retinopathy of prematurity in a cohort of Colorado infants. PMID- 28653817 TI - Cataract Surgery: From Today's Standards to Future Progress. PMID- 28653818 TI - The Continuing Evolution of Cataract Surgery. PMID- 28653819 TI - The Impact of Prenatal Exposure to Power Plant Emissions on Birth Weight: Evidence from a Pennsylvania Power Plant Located Upwind of New Jersey. AB - To examine the infant health impact of prenatal exposure to power plant emissions, we draw scientific evidence on the impacted region downwind of a large polluter, a coal-fired power plant located on the border of two states and proven to be the sole contributor to the violation of air quality standards of the impacted region. Our results show that among all live singleton births that occurred during 1990 through 2006, those born to mothers living as far as 20 to 30 miles away downwind from the power plant (which is also an affluent region) during pregnancy are at greater risks of low birth weight (LBW) and very low birth weight (VLBW): the likelihoods of LBW and VLBW could increase approximately by 6.50 and 17.12 percent, respectively. In light of the continual efforts of The U.S. Environmental Protection Agency in reducing cross-state air pollution caused by transboundary power plant emissions, our study is aimed at broadening the scope of cross-border pollution impact analysis by taking into account adverse infant health effects of upwind polluters, which can impose disproportionate burdens of health risks on downwind states due to air pollutants transported by wind. PMID- 28653820 TI - U.S. Child Safety Seat Laws: Are they Effective, and Who Complies? AB - This paper assesses the effectiveness of child safety seat laws in the United States. Over the past 35 years, these laws have steadily increased mandatory child safety seat restraint ages. We exploit state-year level variation in the age until which children are required to ride in child safety seats to estimate triple difference models using Fatality Analysis Reporting System (FARS) data from 1975 to 2011. Our findings show that increasing the age thresholds is effective in increasing the actual age of children in safety seats. Across the child-age distribution, restraint rates increase by between 10 and 30 percentage points or by between 50 and 170 percent, in the long run. We also estimate the impact of the child safety seat laws on the likelihood that a child dies in a fatal accident. We find that the laws saved up to 39 children per year. Finally, we find that the laws primarily induce compliant parents to switch from traditional seatbelt use to child safety seat use, with only small effects among parents who do not restrain their children. PMID- 28653821 TI - Effects of ACA Medicaid Expansions on Health Insurance Coverage and Labor Supply. AB - We examined the effect of the expansion of Medicaid eligibility under the Affordable Care Act on health insurance coverage and labor supply of low-educated and low-income adults. We found that the Medicaid expansions were associated with large increases in Medicaid coverage, for example, 50 percent among childless adults, and corresponding decreases in the proportion uninsured. There was relatively little change in private insurance coverage, although the expansions tended to decrease such coverage slightly. In terms of labor supply, estimates indicated that the Medicaid expansions had little effecton work effort despite the substantial changes in health insurance coverage. Most estimates suggested that the expansions increased work effort, although not significantly. PMID- 28653822 TI - Uniform Growth of Sub-5-Nanometer High-kappa Dielectrics on MoS2 Using Plasma Enhanced Atomic Layer Deposition. AB - Regardless of the application, MoS2 requires encapsulation or passivation with a high-quality dielectric, whether as an integral aspect of the device (as with top gated field-effect transistors (FETs)) or for protection from ambient conditions. However, the chemically inert surface of MoS2 prevents uniform growth of a dielectric film using atomic layer deposition (ALD)-the most controlled synthesis technique. In this work, we show that a plasma-enhanced ALD (PEALD) process, compared to traditional thermal ALD, substantially improves nucleation on MoS2 without hampering its electrical performance, and enables uniform growth of high kappa dielectrics to sub-5 nm thicknesses. Substrate-gated MoS2 FETs were studied before/after ALD and PEALD of Al2O3 and HfO2, indicating the impact of various growth conditions on MoS2 properties, with PEALD of HfO2 proving to be most favorable. Top-gated FETs with high-kappa films as thin as ~3.5 nm yielded robust performance with low leakage current and strong gate control. Mechanisms for the dramatic nucleation improvement and impact of PEALD on the MoS2 crystal structure were explored by X-ray photoelectron spectroscopy (XPS). In addition to providing a detailed analysis of the benefits of PEALD versus ALD on MoS2, this work reveals a straightforward approach for realizing ultrathin films of device quality high-kappa dielectrics on 2D crystals without the use of additional nucleation layers or damage to the electrical performance. PMID- 28653823 TI - Commendable Eu2+-Doped Oxide-Matrix-Based LiBa12(BO3)7F4 Red Broad Emission Phosphor Excited by NUV Light: Electronic and Crystal Structures, Luminescence Properties. AB - In this work, we synthesized a new Eu2+-doped oxide-matrix-based LiBa12(BO3)7F4 broad red emission phosphor. It can emit red light peaking at ~644 nm under NUV excitation with the coordinate at (0.6350, 0.3586) and a sensitive color gamut for eyes. This phosphor with a special kind of tunnel crystal structure and layered distribution of Ba2+ is contributed to longer wavelength emission. By theoretical calculation and analysis using local state density energy band structure simulation of Eu2+ doped in different site, the origin of the observed emission center was distinguished. Furthermore, decay curves analysis also indicated there are three possible Ba2+ sites for Eu2+ to occupy. Temperature dependent PL spectra appeared anomalous phenomena that the intensity increases first and then decreases, which is due to the traps energy level's contribution of electron's transition. The phosphor also has cathodoluminescence (CL) property which the spectra take on typical current saturation phenomenon. The CL curves indicated that this phosphor has a very good stability under much electron beam bombardment time. After fabricated combining with BAM, (Sr, Ba)2SiO4 and our red phosphor excited under 405-nm NUV chips, warm light LED was obtained. Its CIE coordinate is (0.3475, 0.3416) and the CCT, Ra, and luminous efficiency are 4856 K, 84.1, and 72.6 lm/W, respectively. PMID- 28653824 TI - Rational Design and Functionalization of a Zinc Metal-Organic Framework for Highly Selective Detection of 2,4,6-Trinitrophenol. AB - To develop potential metal-organic frameworks (MOFs) for 2,4,6-trinitrophenol (TNP) detection, an amino-functionalized Zn-MOF, [NH2(CH3)2][Zn4O(bpt)2(bdc NH2)0.5].5DMF (where H3bpt = biphenyl-3,4',5-tricarboxylate, H2bdc-NH2 = 2 aminoterephthalic acid, and DMF = N,N-dimethylformamide), has been designed theoretically and synthesized experimentally. Its structure is composed of Zn4O(CO2)7 secondary building units linked by mixed ligands, exhibiting a three dimensional framework. Fluorescence exploration revealed that the amino functionalized Zn-MOF shows high selectivity and sensitivity for TNP, which agrees well with the predictions of theoretical simulations. This work provides a suitable means to develop new potential MOFs for TNP detection performance with a combination of experimental and theoretical perspectives. PMID- 28653825 TI - Effects of Deposition Temperature on the Device Characteristics of Oxide Thin Film Transistors Using In-Ga-Zn-O Active Channels Prepared by Atomic-Layer Deposition. AB - We demonstrated the physical and electrical properties of the In-Ga-Zn-O (IGZO) thin films prepared by atomic-layer deposition (ALD) method and investigated the effects of the ALD temperature. The film composition (atomic ratio of In:Ga:Zn) and film density were examined to be 1:1:3 and 5.9 g/cm3, respectively, for all the temperature conditions. The optical band gaps decreased from 3.81 to 3.21 eV when the ALD temperature increased from 130 to 170 degrees C. The amounts of oxygen-related defects such as oxygen vacancies increased with increasing the ALD temperature. It was found from the in situ temperature-dependent electrical conductivity measurements that the electronic natures including the defect structures and conduction mechanism of the IGZO thin films prepared at different temperatures showed marked variations. The carrier mobilities in the saturation regions (MUsat's) for the fabricated thin film transistors (TFTs) using the IGZO channel layers were estimated to be 6.1 to 14.8 cm2 V-1 s-1 with increasing the ALD temperature from 130 to 170 degrees C. Among the devices, when the ALD temperature was controlled to be 150 degrees C, the IGZO TFTs showed the best performance, which resulted from the fact that the amounts of oxygen vacancies and interstitial defects could be appropriately modulated at this condition. Consequently, the MUsat, subthreshold swing, and on/off ratio for the TFT using the IGZO channel prepared at 150 degrees C showed 10.4 cm2 V-1 s-1, 90 mV/dec, and 2 * 109, respectively. The threshold voltage shifts of this device could also be effectively reduced to be 0.6 and -3.2 V under the positive-bias and negative bias-illumination stress conditions. These obtained characteristics can be comparable to those for the sputter-deposited IGZO TFTs. PMID- 28653826 TI - Dynamic Defrosting on Scalable Superhydrophobic Surfaces. AB - Recent studies have shown that frost can grow in a suspended Cassie state on nanostructured superhydrophobic surfaces. During defrosting, the melting sheet of Cassie frost spontaneously dewets into quasi-spherical slush droplets that are highly mobile. Promoting Cassie frost would therefore seem advantageous from a defrosting standpoint; however, nobody has systematically compared the efficiency of defrosting Cassie ice versus defrosting conventional surfaces. Here, we characterize the defrosting of an aluminum plate, one-half of which exhibits a superhydrophobic nanostructure while the other half is smooth and hydrophobic. For thick frost sheets (>1 mm), the superhydrophobic surface was able to dynamically shed the meltwater, even at very low tilt angles. In contrast, the hydrophobic surface was unable to shed any appreciable meltwater even at a 90 degrees tilt angle. For thin frost layers (?1 mm), not even the superhydrophobic surface could mobilize the meltwater. We attribute this to the large apparent contact angle of the meltwater, which for small amounts of frost serves to minimize coalescence events and prevent droplets from approaching the capillary length. Finally, we demonstrate a new mode of dynamic defrosting using an upside down surface orientation, where the melting frost was able to uniformly detach from the superhydrophobic side and subsequently pull the frost from the hydrophobic side in a chain reaction. Treating surfaces to enable Cassie frost is therefore very desirable for enabling rapid and low-energy thermal defrosting, but only for frost sheets that are sufficiently thick. PMID- 28653827 TI - Black Phosphorus Field-Effect Transistors with Work Function Tunable Contacts. AB - Black phosphorus (BP) has been recently rediscovered as an elemental two dimensional (2D) material that shows promising results for next generation electronics and optoelectronics because of its intrinsically superior carrier mobility and small direct band gap. In various 2D field-effect transistors (FETs), the choice of metal contacts is vital to the device performance, and it is a major challenge to reach ultralow contact resistances for highly scaled 2D FETs. Here, we experimentally show the effect of a work function tunable metal contact on the device performance of BP FETs. Using palladium (Pd) as the contact material, we employed the reaction between Pd and H2 to form a Pd-H alloy that effectively increased the work function of Pd and reduced the Schottky barrier height (PhiB) in a BP FET. When the Pd-contacted BP FET was exposed to 5% hydrogen concentrated Ar, the contact resistance (Rc) improved between the Pd electrodes and BP from ~7.10 to ~1.05 Omega.mm, surpassing all previously reported contact resistances in the literature for BP FETs. Additionally, with exposure to 5% hydrogen, the transconductance of the Pd-contacted BP FET was doubled. The results shown in this study illustrate the significance of choosing the right contact material for high-performance BP FETs in order to realize the real prospect of BP in electronic applications. PMID- 28653828 TI - Generating Color from Polydisperse, Near Micron-Sized TiO2 Particles. AB - Single particle Mie calculations of near micron-sized TiO2 particles predict strong light scattering dominating the visible range that would give rise to a white appearance. We demonstrate that a polydisperse collection of these "white" particles can result in the generation of visible colors through ensemble scattering. The weighted averaging of the scattering over the particle size distribution modifies the sharp, multiple, high order scattering modes from individual particles into broad variations in the collective extinction. These extinction variations are apparent as visible colors for particles suspended in organic solvent at low concentration, or for a monolayer of particles supported on a transparent substrate viewed in front of a white light source. We further exploit the color variations on optical sensitivity to the surrounding environment to promote micron-sized TiO2 particles as stable and robust agents for detecting the optical index of homogeneous media with high contrast sensitivities. Such distribution-modulated scattering properties provide TiO2 particles an intriguing opportunity to impart color and optical sensitivity to their widespread electronic and chemical platforms such as antibacterial windows, catalysis, photocatalysis, optical sensors, and photovoltaics. PMID- 28653830 TI - Photocontrollable Probe Spatiotemporally Induces Neurotoxic Fibrillar Aggregates and Impairs Nucleocytoplasmic Trafficking. AB - The abnormal assembly of misfolded proteins into neurotoxic aggregates is the hallmark associated with neurodegenerative diseases. Herein, we establish a photocontrollable platform to trigger amyloidogenesis to recapitulate the pathogenesis of amyotrophic lateral sclerosis (ALS) by applying a chemically engineered probe as a "switch" in live cells. This probe is composed of an amyloidogenic peptide from TDP-43, a photolabile linker, a polycationic sequence both to mask amyloidogenicity and for cell penetration, and a fluorophore for visualization. The photocontrollable probe can self-assemble into a spherical vesicle but rapidly develops massive nanofibrils with amyloid properties upon photoactivation. The photoinduced in vitro fibrillization process is characterized by biophysical techniques. In cellular experiments, this cell penetrable vesicle was retained in the cytoplasm, seeded the mislocalized endogenous TDP-43 into aggregates upon irradiation, and consequently initiated apoptosis. In addition, this photocontrollable vesicle interfered with nucleocytoplasmic protein transport and triggered cortical neuron degeneration. Our developed strategy provides in vitro and in vivo spatiotemporal control of neurotoxic fibrillar aggregate formation, which can be readily applied in the studies of protein misfolding, aggregation-induced protein mislocalization, and amyloid-induced pathogenesis in different diseases. PMID- 28653829 TI - Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N [2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis. AB - In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin 1beta (IL-1beta) release from J774A.1 macrophages with an IC50 of 8.45 +/- 1.56 MUM. Selective inhibition of the NLRP3 inflammasome induced IL-1beta release by this compound was also confirmed using mouse bone-marrow-derived macrophages and LPS-challenged mice in vivo. Furthermore, immunoprecipitation study revealed that JC-171 interfered with NLRP3/ASC interaction induced by LPS/ATP stimulation. More importantly, JC-171 treatment delayed the progression and reduced the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, in both prophylactic and therapeutic settings. This coincided with blocking of IL-1beta production and a pathogenic Th17 response. Collectively, these results suggest that JC-171 is a selective NLRP3 inflammasome inhibitor with biological activity in vivo, thus strongly encouraging further development of this lead compound as a potential therapeutic agent for human MS. PMID- 28653831 TI - Detoxification of a Sulfur Mustard Simulant Using a BODIPY-Functionalized Zirconium-Based Metal-Organic Framework. AB - Effective detoxification of chemical warfare agents is a global necessity. As a powerful photosensitizer, a halogenated BODIPY ligand is postsynthetically appended to the Zr6 nodes of the metal-organic framework (MOF), NU-1000, to enhance singlet oxygen generation from the MOF. The BODIPY/MOF material is then used as a heterogeneous photocatalyst to produce singlet oxygen under green LED irradiation. The singlet oxygen selectively detoxifies the sulfur mustard simulant, 2-chloroethyl ethyl sulfide (CEES), to the less toxic sulfoxide derivative (2-chloroethyl ethyl sulfoxide, CEESO) with a half-life of approximately 2 min. PMID- 28653832 TI - Rigidity-Induced Delayed Fluorescence by Ortho Donor-Appended Triarylboron Compounds: Record-High Efficiency in Pure Blue Fluorescent Organic Light-Emitting Diodes. AB - A synthetic approach to highly efficient thermally activated delayed fluorescence (TADF) is proposed that uses ortho donor (D)-acceptor (A) compounds (PXZoB, DPAoB, and CzoB), wherein the acceptor is based on triarylboron and the donor is phenoxazine (PXZ), diphenylamine (DPA), or carbazole (Cz). Combined with the ortho D-A connectivity, the bulky nature of the triarylboron endows the D-A dyads with inherent steric "locking" for a highly twisted arrangement, leading to a small energy difference between singlet and triplet excited states (DeltaEST) and thus exhibiting very efficient TADF with microsecond-range lifetimes. In sharp contrast, the corresponding para D-A derivatives, DPApB and CzpB, only display short-lived, normal fluorescence. Organic light-emitting diodes (OLEDs) incorporating the proposed ortho D-A compounds as emitters display orange, greenish-blue, and pure blue emission and exhibit high external quantum efficiency (etaEQE). In particular, the pure blue OLEDs based on the proposed ortho D-A emitters with a carbazole donor (CzoB) show a record-high etaEQE of 22.6% with CIE color coordinates of (0.139, 0.150), well illustrating the validity of the proposed approach. Upon optical optimization, the etaEQE is further improved to 24.1%. PMID- 28653833 TI - Porphyrinic Metal-Organic Framework-Templated Fe-Ni-P/Reduced Graphene Oxide for Efficient Electrocatalytic Oxygen Evolution. AB - The sluggish kinetics of oxygen evolution reaction (OER) hampers the H2 production by H2O electrolysis, and it is very important for the development of highly efficient and low-priced OER catalysts. Herein, a representative metalloporphyrinic MOF, PCN-600-Ni, integrated with graphene oxide (GO), serves as an ideal precursor and template to afford bimetallic iron-nickel phosphide/reduced graphene oxide composite (denoted as Fe-Ni-P/rGO-T; T represents pyrolysis temperature) via pyrolysis and subsequent phosphidation process. Thanks to the highly porous structure, the synergetic effect of Fe and Ni elements in bimetallic phosphide, and the good conductivity endowed by rGO, the optimized Fe-Ni-P/rGO-400 exhibits remarkable OER activity in 1 M KOH solution, affording an extremely low overpotential of 240 mV at 10 mA/cm2, which is far superior to the commercial IrO2 and among the best in all non-noble metal based electrocatalysts. PMID- 28653835 TI - Di(1H-tetrazol-5-yl)methane as Neutral Ligand in Energetic Transition Metal Complexes. AB - The synthesis of di(1H-tetrazol-5-yl)methane (1, 5-DTM), starting from commercially available sodium azide and malononitrile, is described. This tetrazole was characterized and investigated for use as a neutral nitrogen-rich ligand in various energetic transition metal complexes: ([CuCl2(5-DTM)2].2H2O (2), [Co(H2O)2(5-DTM)2]Cl2 (3), [Ni(H2O)2(5-DTM)2]Cl2 (4), [Co(H2O)2(5 DTM)2](NO3)2 (6), [Ni(H2O)2(5-DTM)2](NO3)2 (7), [Zn(H2O)2(5-DTM)2](NO3)2 (8), {[Cu3(SO4)2(5-DTM-H)2(H2O)4(5-DTM)2].2H2O}infinity (9), [Cu(H2O)2(5-DTM)2](NO3)2 (11), [Cu(NO3)2(5-DTM)2].2H2O (12), [Cu(NO3)2(5-DTM)2] (13), [Cu(H2O)2(5 DTM)2](ClO4)2 (14), and [Cu(ClO4)2(5-DTM)2] (15). Obtained coordination compounds were characterized using single crystal X-ray diffraction (except for 7 and 13), IR spectroscopy, elemental analysis, and differential thermal analysis. The sensitivities to external stimuli (impact, friction, electrostatic discharge) were determined. Complexes 12 and 13 were tested for their ignitability by laser irradiation. PMID- 28653836 TI - Significance of Anthropogenic Factors to Freely Dissolved Polycyclic Aromatic Hydrocarbons in Freshwater of China. AB - Assessment of surface water pollution by organic pollutants is a top priority in many parts of the world, as it provides critical information for implementing effective measures to ensure drinking water safety. This is particularly important in China, where insufficient data of national scale have been acquired on the occurrence of any organic pollutants in the country's water bodies. To fill the knowledge gap, we employed passive samplers to survey polycyclic aromatic hydrocarbons (PAHs) in 42 freshwaters throughout the country. The dissolved Sigma24PAH concentrations ranged from 0.28 to 538 ng L-1, with the highest and lowest values obtained in Southern Lake in Wuhan and in the Nam Co Lake in Tibet, respectively. Average Sigma24PAH concentrations in West, Central, and East China correlated well with the population densities in these regions. The composition profiles of PAHs showed a mixed PAH source of coal combustion, fossil fuel combustion, and oil spills. In addition, all dissolved PAH concentrations were below the water guidelines developed by the U.S. Environmental Protection Agency, the European Union, and the Canadian government, except for anthracene in Southern Lake. Our results also demonstrated the feasibility of establishing a global network of monitoring organic pollutants in the aquatic environment with passive sampling techniques. PMID- 28653834 TI - Residue-Specific Peptide Modification: A Chemist's Guide. AB - Advances in bioconjugation and native protein modification are appearing at a blistering pace, making it increasingly time consuming for practitioners to identify the best chemical method for modifying a specific amino acid residue in a complex setting. The purpose of this perspective is to provide an informative, graphically rich manual highlighting significant advances in the field over the past decade. This guide will help triage candidate methods for peptide alteration and will serve as a starting point for those seeking to solve long-standing challenges. PMID- 28653837 TI - Quantifying Reactive Transport Processes Governing Arsenic Mobility after Injection of Reactive Organic Carbon into a Bengal Delta Aquifer. AB - Over the last few decades, significant progress has been made to characterize the extent, severity, and underlying geochemical processes of groundwater arsenic (As) pollution in S/SE Asia. However, comparably little effort has been made to merge the findings into frameworks that allow for a process-based quantitative analysis of observed As behavior and for predictions of its long-term fate. This study developed field-scale numerical modeling approaches to represent the hydrochemical processes associated with an in situ field injection of reactive organic carbon, including the reductive dissolution and transformation of ferric iron (Fe) oxides and the concomitant release of sorbed As. We employed data from a sucrose injection experiment in the Bengal Delta Plain to guide our model development and to constrain the model parametrization. Our modeling results illustrate that the temporary pH decrease associated with the sucrose transformation and mineralization caused pronounced, temporary shifts in the As partitioning between aqueous and sorbed phases. The results also suggest that while the reductive dissolution of Fe(III) oxides reduced the number of sorption sites, a significant fraction of the released As was rapidly scavenged through coprecipitation with neo-formed magnetite. These secondary reactions can explain the disparity between the observed Fe and As behavior. PMID- 28653838 TI - On-Top Pair Density as a Measure of Left-Right Correlation in Bond Breaking. AB - To better understand left-right electron correlation and the effect of bond breaking on the on-top pair density, analytic expressions for the total density, the on-top pair density, and the ratio of the on-top pair density to the square of the total density were derived for H2 for both a restricted Hartree-Fock wave function and a complete active space self-consistent-field wave function with two electrons in two active orbitals. These quantities are compared for the two wave functions for various points in space around the molecule as functions of internuclear distance. At some points in space, in the CASSCF(2,2) wave function, electron correlation, perhaps counterintuitively, increases the probability that two electrons are at the same point in space. At the Coulson-Fischer point, the on-top pair density for the complete active space wave function starts to rapidly approach zero, and this can be taken as an indicator of bond breaking. PMID- 28653839 TI - One-Pot Cascade Synthesis of Quinazolin-4(3H)-ones via Nickel-Catalyzed Dehydrogenative Coupling of o-Aminobenzamides with Alcohols. AB - In this paper, we report a general, efficient, and environmentally benign method for the one-pot cascade synthesis of quinazolin-4(3H)-ones via acceptorless dehydrogenative coupling of o-aminobenzamide with alcohols catalyzed by a simple Ni(II) catalyst, [Ni(MeTAA)], featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)). A wide variety of substituted quinazolin-4(3H)-ones were synthesized in high yields starting from readily available benzyl alcohols and o-aminobenzamides. Several controlled reactions along with deuterium labeling studies were carried out to establish the acceptorless dehydrogenative nature of the reactions. PMID- 28653840 TI - Photochemically Promoted Aza-Diels-Alder-Type Reaction: High Catalytic Activity of the Cr(III)/Bipyridine Complex Enhanced by Visible Light Irradiation. AB - Aza-Diels-Alder-type cycloaddition reactions between a range of N-arylimines and functionalized alkenes were effectively catalyzed by the Cr(III)/bipyridine complex under irradiation of blue light, to give the corresponding 1,2,3,4 tetrahydroquinoline derivatives in high yields with excellent diastereoselectivity. Typically, the reaction of benzylideneaniline with 1-vinyl 2-pyrrolidinone proceeded smoothly with a substrate-to-catalyst molar ratio (S/C) of 1000 and completed within 4 h at room temperature (20-25 degrees C), affording the cycloaddition product in 97% yield. PMID- 28653841 TI - Correction to When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode? PMID- 28653842 TI - Controlling the Surface Hydroxyl Concentration by Thermal Treatment of Layered Double Hydroxides. AB - Layered double hydroxides (LDHs) are important materials in the field of catalyst supports, and their surface hydroxyl functionality makes them interesting candidates for supporting well-defined single-site catalysts. Here, we report that the surface hydroxyl concentration can be controlled by thermal treatment of these materials under vacuum, leading to hydroxyl numbers (alphaOH) similar to those of dehydroxylated silica, alumina, and magnesium hydroxide. Thermal treatment of [Mg0.74Al0.26(OH)2](SO4)0.1(CO3)0.03.0.62(H2O).0.04(acetone) prepared by the aqueous miscible organic solvent treatment method (Mg2.84Al-SO4-A AMO-LDH) is shown to yield a mixed metal oxide above 300 degrees C by a combination of thermogravimetric analysis, powder X-ray diffraction (PXRD), BET surface area analysis, and FTIR spectroscopy. PXRD shows the disappearance of the characteristic LDH 00l peaks at 300 degrees C indicative of decomposition to the layered structure, coupled with a large increase in the BET surface area (95 vs 158 m2 g-1 from treatment at 275 and 300 degrees C, respectively). Titration of the surface hydroxyls with Mg(CH2Ph)2(THF)2 indicates that the hydroxyl number is independent of surface area for a given treatment temperature. Treatment at 450 degrees C under vacuum produces a mixed metal oxide material with a surface hydroxyl concentration (alphaOH) of 2.14 OH nm-2 similar to the hydroxyl number (alphaOH) of 1.80 OH nm-2 for a sample of SiO2 dehydroxylated at 500 degrees C. These materials appear to be suitable candidates for use as single-site organometallic catalyst supports. PMID- 28653843 TI - Scalable and Low Cost Synthesis of Highly Conducting Polypyrrole Nanofibers Using Oil-Water Interfacial Polymerization under Constant Stirring. AB - In the present work, we report a low cost and scalable oil-water interfacial polymerization method to synthesize one-dimensional (1-D) highly conducting polypyrrole (PPy) nanofibers doped with p-toluenesulfonic (p-TSA) and hydrochloric (HCl) acids. Polymerization of pyrrole (monomer) has been carried out at the interface formed between the immiscible oil and aqueous water droplets under constant magnetic stirring at room temperature. Formation of smaller diameter (16-20 nm) PPy nanofibers has been confirmed from the high resolution transmission electron microscopy (HRTEM) studies, and the average diameter of p TSA doped PPy nanofibers is found to be smaller than that of HCl doped nanofibers. The polymer chain ordering or crystallinity of both p-TSA and HCl doped PPy nanofibers have been studied with X-ray diffraction (XRD). Studies of Fourier transform infrared (FTIR) spectra suggest the presence of all the characteristic vibration bands in doped PPy nanofibers. The doping of PPy nanofibers has been confirmed from the formation of polaron and bipolaron bands in their UV-vis spectra. The optical band gap energy (Eg) and Urbach energy (EU) for PPy nanofibers doped with p-TSA and HCl doped PPy nanofibers were determined from their UV-vis absorption spectra. The red shift of the polaron absorption band in p-TSA doped PPy nanofibers confirms a higher conjugation length of the polymer nanofiber chains than that in the HCl doped PPy nanofibers. Thermogravimetric (TGA) and derivative plots of TGA studies predict that PPy nanofibers doped with p-TSA are thermally and structurally more stable as compared to HCl doped PPy nanofibers. Current-voltage (I-V) characteristics exhibit nonlinear behavior with voltage in both p-TSA and HCl doped PPy nanofibers. PMID- 28653844 TI - A Strong Donor-Acceptor System Based on a Metal Chalcogenide Cluster and Porphyrin. AB - Although great progress has been made for charge transfer (CT) compounds of various organic donor-acceptor systems, no CT compounds containing both inorganic chalcogenide cluster anions and organic porphyrin cations have been reported. Herein, a germanium chalcogenide cluster (Ge4S104-) is chosen as an electron donor and a methylated tetrakis(4-pyridyl)porphyrin (5,10,15,20-tetrakis(N-methyl 4-pyridyl)porphyrin, TMPyP) is selected as an electron acceptor to create chalcogenide cluster-porphyrin CT compounds (TMPyP-Ge4S10).5H2O (1) and (MnTMPyP Ge4S10).13H2O (2). Their crystal structures have been characterized by single crystal X-ray diffraction. Compound 1 is an ionic CT salt assembled through interion interactions, and compound 2 is a neutral CT dyad formed by metal-ligand axial coordination of the chalcogenide cluster with manganese porphyrin. The strong charge transfer properties are revealed by electronic spectra, theoretical calculations, 1H NMR, and ESR. The CT intensity of the chalcogenide cluster porphyrin system can be modulated by metalation. The fluorescence and photocurrent response properties of 1 and 2 are related to the CT intensity. PMID- 28653845 TI - 3-Hydroxy-N'-arylidenepropanehydrazonamides with Halo-Substituted Phenanthrene Scaffolds Cure P. berghei Infected Mice When Administered Perorally. AB - Structural optimization of 3-hydroxy-N'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the Plasmodium berghei mouse model when administered perorally. PMID- 28653847 TI - Glucuronides as Potential Anionic Substrates of Human Cytochrome P450 2C8 (CYP2C8). AB - Glucuronidation is in general considered as a terminal metabolic step that leads to direct elimination of drugs and generally abolishes their biological activity. However, there is growing evidence to suggest that glucuronides can be ligands of human CYP2C8, making CYP2C8 distinct from the other CYP isoforms. Several classes of glucuronide conjugates, which include acyl glucuronides, ether glucuronides, N glucuronides, and carbamoyl glucuronides, have been shown to be substrates or time-dependent inhibitors of CYP2C8. Although the structures of CYP2C8 glucuronide complexes have not been determined, the structural features of CYP2C8 active site support its binding to anionic and bulky ligands like glucuronides. As interaction perpetrators with CYP2C8, glucuronides of gemfibrozil and clopidogrel showed marked clinical drug-drug interactions (e.g., with cerivastatin and repaglinide), which are more than expected from the parent drug. This review summarizes glucuronides as CYP2C8 ligands and the active-site structural features of CYP2C8 that allow potential binding to glucuronides. PMID- 28653846 TI - In Vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin 4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents. AB - 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2), a promising anticancer lead previously identified by us, inhibited tumor growth by 62% in mice at 1.0 mg/kg without obvious signs of toxicity. Moreover, compound 2 exhibited extremely high antiproliferative activity in the NIH-NCI 60 human tumor cell line panel, with low to sub-nanomolar GI50 values (10-10 M level). It also showed a suitable balance between aqueous solubility and lipophilicity, as well as moderate metabolic stability in vivo. Mechanistic studies using Mayer's hematoxylin and eosin and immunohistochemistry protocols on xenograft tumor tissues showed that 2 inhibited tumor cell proliferation, induced apoptosis, and disrupted tumor vasculature. Moreover, evaluation of new synthetic analogues (6a 6t) of 2 indicated that appropriate 2-substitution on the quinazoline ring could enhance antitumor activity and improve druglike properties. Compound 2 and its analogues with a 4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one scaffold thus represent a novel class of tubulin-binding tumor-vascular disrupting agents (tumor-VDAs) that target established blood vessels in tumors. PMID- 28653848 TI - Ultrafast Nuclear Dynamics of Photoexcited Guanosine-5'-Monophosphate in Three Singlet States. AB - We report measurement of resonance Raman (RR) spectra of guanosine-5' monophosphate (GMP), a DNA nucleotide at excitation wavelengths throughout its pipi* absorption band (Bb) in the 210-230 nm range. From these data, we constructed wavelength-dependent Raman intensity excitation profiles (REPs) for all observed modes. These profiles and the absorption spectrum were then modeled using self-consistent simulations based on the time-dependent wave packet propagation formalism. We inferred the initial structural dynamics of GMP immediately after photoexcitation in terms of dimensionless displacements. The simulations also provide linewidth-broadening parameters that in turn report on the time scale of dynamics. We compared deduced structural changes in the purine ring upon photoabsorption into the Bb state with those deduced for the two lowest lying pipi* (La and Lb at 280 and 248 nm, respectively) excited states of GMP. We find that excitation to the Lb state lengthens C6-N1 and C2?N3 bonds, which lie along the formation coordinate of various oxidative adducts but Bb excitation does not. We also find that photoabsorption by the Bb state weakens the C8-N9 bond and thus might assist imidazole ring opening via cleavage of the same bond. Electronic excitation to different pipi* states of the guanine chromophore results in contrasting structural changes; although absorption by the La and Lb states induces expansion of pyrimidine and contraction of imidazole rings, excitation results in overall shrinkage of both the rings. Computed absolute changes in internal coordinates imply that photoexcitation to any of the three singlet states of GMP does not lead directly to the formation of a cation radical of guanine. PMID- 28653849 TI - Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors. AB - We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13.inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs. PMID- 28653850 TI - Discovery and Evaluation of Anti-Fibrinolytic Plasmin Inhibitors Derived from 5 (4-Piperidyl)isoxazol-3-ol (4-PIOL). AB - Inhibition of plasmin has been found to effectively reduce fibrinolysis and to avoid hemorrhage. This can be achieved by addressing its kringle 1 domain with the known drug and lysine analogue tranexamic acid. Guided by shape similarities toward a previously discovered lead compound, 5-(4-piperidyl)isoxazol-3-ol, a set of 16 structurally similar compounds was assembled and investigated. Successfully, in vitro measurements revealed one compound, 5-(4 piperidyl)isothiazol-3-ol, superior in potency compared to the initial lead. Furthermore, a strikingly high correlation (R2 = 0.93) between anti-fibrinolytic activity and kringle 1 binding affinity provided strong support for the hypothesized inhibition mechanism, as well as revealing opportunities to fine tune biological effects through minor structural modifications. Several different ligand-based (Freeform, shape, and electrostatic-based similarities) and structure-based methods (e.g., Posit, MM/GBSA, FEP+) were used to retrospectively predict the binding affinities. A combined method, molecular alignment using Posit and scoring with Tcombo, lead to the highest coefficient of determination (R2 = 0.6). PMID- 28653851 TI - Controlled Levitation of Colloids through Direct Current Electric Fields. AB - We report the controlled levitation of surface-modified colloids in direct current (dc) electric fields at distances as far as 75 MUm from an electrode surface. Instead of experiencing electrophoretic deposition, colloids modified through metallic deposition or the covalent bonding of poly(ethylene glycol) (PEG) undergo migration and focusing that results in levitation at these large distances. The levitation is a sensitive function of the surface chemistry and magnitude of the field, thus providing the means to achieve control over the levitation height. Experiments with particles of different surface charge show that levitation occurs only when the absolute zeta potential is below a threshold value. An electrodiffusiophoretic mechanism is proposed to explain the observed large-scale levitation. PMID- 28653852 TI - Chemical Warfare Agents Detoxification Properties of Zirconium Metal-Organic Frameworks by Synergistic Incorporation of Nucleophilic and Basic Sites. AB - The development of protective self-detoxifying materials is an important societal challenge to counteract risk of attacks employing highly toxic chemical warfare agents (CWAs). In this work, we have developed bifunctional zirconium metal organic frameworks (MOFs) incorporating variable amounts of nucleophilic amino residues by means of formation of the mixed ligand [Zr6O4(OH)4(bdc)6(1-x)(bdc NH2)6x] (UiO-66-xNH2) and [Zr6O4(OH)4(bpdc)6(1-x)(bpdc-(NH2)2)6x] (UiO-67 x(NH2)2) systems where bdc = benzene-1,4-dicarboxylate; bdc-NH2= benzene-2-amino 1,4-dicarboxylate; bpdc = 4,4'-biphenyldicarboxylate; bpdc-(NH2)2 = 2,2'-diamino 4,4'-biphenyldicarboxylate and x = 0, 0.25, 0.5, 0.75, 1. In a second step, the UiO-66-xNH2 and UiO-67-x(NH2)2 systems have been postsynthetically modified by introduction of highly basic lithium tert-butoxide (LiOtBu) on the oxohydroxometallic clusters of the mixed ligand MOFs to yield UiO-66-xNH2@LiOtBu and UiO-67-x(NH2)2@LiOtBu materials. The results show that the combination of pre and postsynthetic modifications on these MOF series gives rise to fine-tuning of the catalytic activity toward the hydrolytic degradation of both simulants and real CWAs in unbuffered aqueous solutions. Indeed, UiO-66-0.25NH2@LiOtBu is able to hydrolyze both CWAs simulants (diisopropylfluorophosphate (DIFP), 2 chloroethylethylsulfide (CEES), and real CWAs (soman (GD), sulfur mustard (HD)) quickly in aqueous solution. These results are related to a suitable combination of robustness, nucleophilicity, basicity, and accessibility to the porous framework. PMID- 28653854 TI - A Thermogelling Supramolecular Hydrogel with Sponge-Like Morphology as a Cytocompatible Bioink. AB - Biocompatible polymers that form thermoreversible supramolecular hydrogels have gained great interest in biomaterials research and tissue engineering. When favorable rheological properties are achieved at the same time, they are particularly promising candidates as material that allow for the printing of cells, so-called bioinks. We synthesized a novel thermogelling block copolymer and investigated the rheological properties of its aqueous solution by viscosimetry and rheology. The polymers undergo thermogelation between room temperature and body temperature, form transparent hydrogels of surprisingly high strength (G' > 1000 Pa) and show rapid and complete shear recovery after stress. Small angle neutron scattering suggests an unusual bicontinuous sponge-like gel network. Excellent cytocompatibility was demonstrated with NIH 3T3 fibroblasts, which were incorporated and bioplotted into predefined 3D hydrogel structures without significant loss of viability. The developed materials fulfill all criteria for future use as bioink for biofabrication. PMID- 28653853 TI - Post-Translational Modifications (PTMs), Identified on Endogenous Huntingtin, Cluster within Proteolytic Domains between HEAT Repeats. AB - Post-translational modifications (PTMs) of proteins regulate various cellular processes. PTMs of polyglutamine-expanded huntingtin (Htt) protein, which causes Huntington's disease (HD), are likely modulators of HD pathogenesis. Previous studies have identified and characterized several PTMs on exogenously expressed Htt fragments, but none of them were designed to systematically characterize PTMs on the endogenous full-length Htt protein. We found that full-length endogenous Htt, which was immunoprecipitated from HD knock-in mouse and human post-mortem brain, is suitable for detection of PTMs by mass spectrometry. Using label-free and mass tag labeling-based approaches, we identified near 40 PTMs, of which half are novel (data are available via ProteomeXchange with identifier PXD005753). Most PTMs were located in clusters within predicted unstructured domains rather than within the predicted alpha-helical structured HEAT repeats. Using quantitative mass spectrometry, we detected significant differences in the stoichiometry of several PTMs between HD and WT mouse brain. The mass spectrometry identification and quantitation were verified using phospho-specific antibodies for selected PTMs. To further validate our findings, we introduced individual PTM alterations within full-length Htt and identified several PTMs that can modulate its subcellular localization in striatal cells. These findings will be instrumental in further assembling the Htt PTM framework and highlight several PTMs as potential therapeutic targets for HD. PMID- 28653856 TI - Measurement of the Ligand Field Spectra of Ferrous and Ferric Iron Chlorides Using 2p3d RIXS. AB - Ligand field spectra provide direct information about the electronic structure of transition metal complexes. However, these spectra are difficult to measure by conventional optical techniques due to small cross sections for d-to-d transitions and instrumental limitations below 4000 cm-1. 2p3d resonant inelastic X-ray scattering (RIXS) is a second order process that utilizes dipole allowed 2p to 3d transitions to access d-d excited states. The measurement of ligand field excitation spectra by RIXS is demonstrated for a series of tetrahedral and octahedral Fe(II) and Fe(III) chlorides, which are denoted Fe(III)-Td, Fe(II)-Td, Fe(III)-Oh, and Fe(II)-Oh. The strong 2p spin-orbit coupling allows the measurement of spin forbidden transitions in RIXS spectroscopy. The Fe(III) spectra are dominated by transitions from the sextet ground state to quartet excited states, and the Fe(II) spectra contain transitions to triplet states in addition to the spin allowed 5Gamma -> 5Gamma transition. Each experimental spectrum is simulated using a ligand field multiplet model to extract the ligand field splitting parameter 10Dq and the Racah parameters B and C. The 10Dq values for Fe(III)-Td, Fe(II)-Td, and Fe(III)-Oh are found to be -0.7, -0.32, and 1.47 eV, respectively. In the case of Fe(II)-Oh, a single 10Dq parameter cannot be assigned because Fe(II)-Oh is a coordination polymer exhibiting axially compressed Fe(II)Cl 6 units. The 5T -> 5E transition is split by the axial compression resulting in features at 0.51 and 0.88 eV. The present study forms the foundation for future applications of 2p3d RIXS to molecular iron sites in more complex systems, including iron-based catalysts and enzymes. PMID- 28653855 TI - Iron L2,3-Edge X-ray Absorption and X-ray Magnetic Circular Dichroism Studies of Molecular Iron Complexes with Relevance to the FeMoco and FeVco Active Sites of Nitrogenase. AB - Herein, a systematic study of a series of molecular iron model complexes has been carried out using Fe L2,3-edge X-ray absorption (XAS) and X-ray magnetic circular dichroism (XMCD) spectroscopies. This series spans iron complexes of increasing complexity, starting from ferric and ferrous tetrachlorides ([FeCl4]-/2-), to ferric and ferrous tetrathiolates ([Fe(SR)4]-/2-), to diferric and mixed-valent iron-sulfur complexes [Fe2S2R4]2-/3-. This test set of compounds is used to evaluate the sensitivity of both Fe L2,3-edge XAS and XMCD spectroscopy to oxidation state and ligation changes. It is demonstrated that the energy shift and intensity of the L2,3-edge XAS spectra depends on both the oxidation state and covalency of the system; however, the quantitative information that can be extracted from these data is limited. On the other hand, analysis of the Fe XMCD shows distinct changes in the intensity at both L3 and L2 edges, depending on the oxidation state of the system. It is also demonstrated that the XMCD intensity is modulated by the covalency of the system. For mononuclear systems, the experimental data are correlated with atomic multiplet calculations in order to provide insights into the experimental observations. Finally, XMCD is applied to the tetranuclear heterometal-iron-sulfur clusters [MFe3S4]3+/2+ (M = Mo, V), which serve as structural analogues of the FeMoco and FeVco active sites of nitrogenase. It is demonstrated that the XMCD data can be utilized to obtain information on the oxidation state distribution in complex clusters that is not readily accessible for the Fe L2,3-edge XAS data alone. The advantages of XMCD relative to standard K-edge and L2,3-edge XAS are highlighted. This study provides an important foundation for future XMCD studies on complex (bio)inorganic systems. PMID- 28653858 TI - Transplantation of a Human Tissue-Engineered Bowel in an Athymic Rat Model. AB - Intestinal failure is a serious clinical condition characterized by loss of motility, absorptive function, and malnutrition. Current treatments do not provide the optimal solution for patients due to the numerous resulting complications. A bioengineered bowel that contains the necessary cellular components provides a viable option for patients. In this study, human tissue engineered bowel (hTEB) was developed using a technique, whereby human-sourced smooth muscle cells were aligned and neoinnervated using human-sourced neural progenitor cells, resulting in the formation of intrinsically innervated smooth muscle sheets. The sheets were then rolled around hollow tubular chitosan scaffolds and implanted in the omentum of athymic rats for neovascularization. Four weeks later, biopsies of hTEB showed vascularization, normal cell alignment, phenotype, and function. During the biopsy procedure, hTEB was transplanted into the same rat's native intestine. The rats gained weight and 6 weeks later, hTEB was harvested for studies. hTEB was healthy in color with normal diameter and with digested food in the lumen, indicating propulsion of luminal content through the hTEB. Histological studies indicated neomucosa with evidence of crypts and villi structures. This study provides proof of concept that hTEB could provide a viable treatment to lengthen the gut for patients with gastrointestinal disorders. PMID- 28653859 TI - Unnecessary emergency medical services transport associated with alcohol intoxication. AB - Objective This study investigated medically unnecessary emergency medical services (EMS) transportation by comparing non-intoxicated versus intoxicated patients who did not receive emergency department (ED) treatment but utilized EMS transport. Methods Patients who used EMS but did not receive ED treatment were classified into non-intoxicated and intoxicated groups. Reasons for not receiving ED treatment were categorized according to whether the decision was made by the patient against medical advice or if the decision was based on a physician's evaluation and their recommendations. Results There were 212 patients reviewed; 120 in the non-intoxicated group and 92 in the intoxicated group. The intoxicated group had a higher proportion of males than the non-intoxicated group. The most common cause of non-disease symptoms in the intoxicated group was assault. In the non-intoxicated group, the most common reason for the lack of ED treatment was that treatment could take place on an outpatient basis, while in the intoxicated group, the reason was lack of patient cooperation. Conclusions The intoxicated group was older, male and more likely to present with symptoms not related to a disease process than those in the non-intoxicated group when using unnecessary EMS transport. PMID- 28653857 TI - Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. AB - Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease with rates of non-responsiveness to antidepressants ranging from 30-50%. Historically, the monoamine depletion hypothesis has dominated the view on the pathophysiology of depression. However, the lack of responsiveness to antidepressants and treatment resistance suggests that additional mechanisms might play a role. Evidence has shown that a subgroup of depressive patients may have an underlying immune deregulation that could explain the lack of therapeutic benefit from antidepressants. Stimuli like inflammation and infection can trigger the activation of microglia to release pro-inflammatory cytokines, acting on two main pathways: (1) activation of the hypothalamic-pituitary adrenal axis, generating an imbalance in the serotonergic and noradrenergic circuits; (2) increased activity of the enzyme indoleamine-2,3-dioxygenase, resulting in depletion of serotonin levels and the production of quinolinic acid. If this hypothesis is proven true, the subgroup of MDD patients with increased levels of pro-inflammatory cytokines, mainly IL-6, TNF-alpha and IL-1beta, might benefit from an anti-inflammatory intervention. Here, we discuss the pre-clinical and clinical studies that have provided support for treatment with non-steroidal anti inflammatory drugs in depressed patients with inflammatory comorbidities or an elevated immune profile, as well as evidences for anti-inflammatory properties of standard antidepressants. PMID- 28653860 TI - Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial Abnormalities. AB - Purpose To determine whether gadolinium deposits in neural tissues of patients with intracranial abnormalities following intravenous gadolinium-based contrast agent (GBCA) exposure might be related to blood-brain barrier integrity by studying adult patients with normal brain pathologic characteristics. Materials and Methods After obtaining antemortem consent and institutional review board approval, the authors compared postmortem neuronal tissue samples from five patients who had undergone four to 18 gadolinium-enhanced magnetic resonance (MR) examinations between 2005 and 2014 (contrast group) with samples from 10 gadolinium-naive patients who had undergone at least one MR examination during their lifetime (control group). All patients in the contrast group had received gadodiamide. Neuronal tissues from the dentate nuclei, pons, globus pallidus, and thalamus were harvested and analyzed with inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy with energy-dispersive x ray spectroscopy, and light microscopy to quantify, localize, and assess the effects of gadolinium deposition. Results Tissues from the four neuroanatomic regions of gadodiamide-exposed patients contained 0.1-19.4 MUg of gadolinium per gram of tissue in a statistically significant dose-dependent relationship (globus pallidus: rho = 0.90, P = .04). In contradistinction, patients in the control group had undetectable levels of gadolinium with ICP-MS. All patients had normal brain pathologic characteristics at autopsy. Three patients in the contrast group had borderline renal function (estimated glomerular filtration rate <45 mL/min/1.73 m2) and hepatobiliary dysfunction at MR examination. Gadolinium deposition in the contrast group was localized to the capillary endothelium and neuronal interstitium and, in two cases, within the nucleus of the cell. Conclusion Gadolinium deposition in neural tissues after GBCA administration occurs in the absence of intracranial abnormalities that might affect the permeability of the blood-brain barrier. These findings challenge current understanding of the biodistribution of these contrast agents and their safety. (c) RSNA, 2017. PMID- 28653861 TI - Transforming Growth Factor beta1- and Bone Morphogenetic Protein 2/PPARgamma regulated MicroRNAs in Pulmonary Arterial Hypertension. PMID- 28653862 TI - Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile. AB - BACKGROUND: The precise mechanism of action of dimethyl fumarate (DMF) treatment in MS remains unknown. OBJECTIVE: To identify the changes in the blood lymphocyte profile of MS patients predicting no evidence of disease activity (NEDA) status after DMF treatment. METHODS: We studied blood lymphocyte subsets of 64 MS patients treated with DMF at baseline and after 6 months of treatment by flow cytometry. NEDA (41 patients) or ongoing disease activity (ODA, 23 patients) were monitored after a year of follow-up. RESULTS: During treatment, all patients experienced an increase in the naive T cells and a decrease in effector memory ones. However, only NEDA patients showed a significant reduction in central memory CD4+ and CD8+ T cells, memory B cells, CD4+ T cells producing interferon (IFN)-gamma, CD8+ T cells producing tumor necrosis factor-alpha (TNF-alpha), and IFN-gamma and B cells producing TNF-alpha. Additionally, they had an increase in regulatory CD56bright cells not observed in ODA group. After treatment, there was a negative correlation between CD56bright cells and CD8+ T cells producing IFN gamma and TNF-alpha. CONCLUSION: A pro-tolerogenic shift in the blood leukocyte profile associates with an optimal response to DMF in MS. PMID- 28653865 TI - Sagittal-Plane Knee Moment During Gait and Knee Cartilage Thickness. AB - CONTEXT: Understanding the factors associated with thicker cartilage in a healthy population is important when developing strategies aimed at minimizing the cartilage thinning associated with knee osteoarthritis progression. Thicker articular cartilage is commonly thought to be healthier cartilage, but whether the sagittal-plane biomechanics important to gait are related to cartilage thickness is unknown. OBJECTIVE: To determine the relationship of a weight bearing region of the medial femoral condyle's cartilage thickness to sagittal gait biomechanics in healthy individuals. DESIGN: Descriptive laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-eight healthy participants (15 women: age = 21.1 +/- 2.1 years, height = 1.63 +/- 0.07 m, weight = 64.6 +/- 9.9 kg; 13 men: age = 22.1 +/- 2.9 years, height = 1.79 +/- 0.05 m, weight = 75.2 +/- 9.6 kg). MAIN OUTCOME MEASURE(S): Tibiofemoral angle ( degrees ) was obtained via goniometric assessment, thickness of the medial femoral condyle cartilage (mm) was obtained via ultrasound imaging, and peak internal knee-extensor moment (% body weight . height) was measured during 10 trials of over-ground walking at a self-selected pace. We used linear regression to examine the extent to which peak internal knee-extensor moment predicted cartilage thickness after accounting for tibiofemoral angle and sex. RESULTS: Sex and tibiofemoral angle (12.3 degrees +/- 3.2 degrees ) were entered in the initial step as control factors (R2 = 0.01, P = .872). In the final step, internal knee-extensor moment (1.5% +/- 1.3% body weight . height) was entered, which resulted in greater knee-extensor moment being related to greater cartilage thickness (2.0 +/- 0.3 mm; R2Delta = 0.31, PDelta = .003). CONCLUSION: Individuals who walked with a greater peak internal knee-extensor moment during gait had a cartilage structure that is generally considered beneficial in a healthy population. Our study offers promising findings that a potentially modifiable biomechanical factor is associated with cartilage status in a healthy population. Establishing these baseline relationships in uninjured populations may help us to better understand potential factors related to maladaptive gait patterns that predispose a person to adverse changes in the cartilage environment. PMID- 28653867 TI - Association Between the Single Assessment Numeric Evaluation and the Western Ontario and McMaster Universities Osteoarthritis Index. AB - CONTEXT: Patient-reported outcomes (PROs) evaluate how patients describe symptoms as well as level of physical function or quality of life. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index is one of the most common PROs used to assess disability in patients with knee osteoarthritis (OA), yet the Single Assessment Numeric Evaluation (SANE) is a single-question instrument that may improve the efficiency associated with the measurement of patient function. OBJECTIVE: To determine the associations between (1) SANEFunction and the physical dysfunction subsection of the WOMAC index (WOMACDysfunction) before rehabilitation and after a 4-week therapeutic exercise intervention as well as (2) the percentage change in SANEFunction and WOMACDysfunction in people with knee OA after 4 weeks of therapeutic exercise. DESIGN: Cross-sectional study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-six participants (15 men, 21 women) with radiographic knee OA. INTERVENTION(S): Participants completed 12 sessions (over a 4-week period) of therapeutic exercise to strengthen the lower extremity. MAIN OUTCOME MEASURE(S): The SANEFunction and WOMACDysfunction (WOMACDysfunction normalized to 100%) scores were collected before and after the 4-week intervention. Percentage change scores over the 4-week intervention were calculated for both measures. RESULTS: Participants with a higher SANEFunction score demonstrated a lower WOMACDysfunction score at baseline (rs = -0.44, P = .007) and at the 4-week time point (rs = -0.69, P < .001). There was a nonsignificant and weak association between the changes in the SANEFunction and WOMACDysfunction scores over the 4 weeks of therapeutic exercise (rs = -0.17, P < .43). CONCLUSIONS: The SANEFunction and WOMACDysfunction scores demonstrated moderate to weak associations before and after a 4-week exercise program, respectively, whereas the changes in SANEFunction and WOMACDysfunction scores were not associated. These PROs may be measuring different aspects of self reported function and therefore should not be used interchangeably to determine a therapeutic response. PMID- 28653866 TI - The Role of Athletic Trainers in Preventing and Managing Posttraumatic Osteoarthritis in Physically Active Populations: a Consensus Statement of the Athletic Trainers' Osteoarthritis Consortium. AB - OBJECTIVE: To provide athletic trainers with a fundamental understanding of the pathogenesis and risk factors associated with the development of posttraumatic osteoarthritis (PTOA) as well as the best current recommendations for preventing and managing this condition. BACKGROUND: Posttraumatic osteoarthritis, or osteoarthritis that develops secondary to joint injury, accounts for approximately 5.5 million US cases annually. A young athlete with a joint injury is at high risk for PTOA before the age of 40, which could lead to the patient living more than half of his or her life with a painful and disabling disorder. Given our frequent contact with physically active people who often sustain traumatic joint injuries, athletic trainers are in a unique position to help prevent and manage PTOA. We can, therefore, regularly monitor joint health in at risk patients and implement early therapies as necessary. RECOMMENDATIONS: The recommendations for preventing and managing PTOA are based on the best available evidence. Primary injury prevention, self-management strategies, maintenance of a healthy body weight, and an appropriate level of physical activity should be encouraged among those at risk for PTOA after acute traumatic joint injury. Education of athletic trainers and patients regarding PTOA is also critical for effective prevention and management of this disease. PMID- 28653869 TI - An 8-Week Neuromuscular Exercise Program for Patients With Mild to Moderate Knee Osteoarthritis: A Case Series Drawn From a Registered Clinical Trial. AB - OBJECTIVE: To describe the feasibility of a neuromuscular exercise (NEMEX) program in patients with mild to moderate knee osteoarthritis (KOA). BACKGROUND: Neuromuscular exercise has been increasingly used in patients with osteoarthritis to achieve sensorimotor control and improved daily function. TREATMENT: A study of the first 23 physically active patients (11 men, 12 women; age range = 48-70 years) who had mild to moderate KOA and were undergoing an 8-week, twice-weekly program, consisting of 11 exercises with 3 to 4 levels of difficulty, as part of an ongoing randomized controlled trial. The level of difficulty was noted for each exercise and session. We recorded exertion, pain, adverse events, and adherence. For the 18 patients who participated in 6 or more sessions, a progression of at least 1 level of difficulty (out of 3-4) was observed in half or more of the exercises. However, few patients progressed to jumping activities. Exertion ranged from light to very heavy. Four patients reported a clinically relevant increase in short-term pain after 1 to 2 of the 16 scheduled sessions. No adverse musculoskeletal events were reported. Notably, 3 patients dropped out due to increased (n = 2) or persisting (n = 1) knee pain. However, their pain ratings did not show worsening symptoms. UNIQUENESS: This NEMEX-KOA program was designed for physically active middle-aged patients with mild to moderate KOA; therefore, it involved exercises and difficulty levels that were more challenging than a previously described NEMEX program for patients eligible for total joint replacement. CONCLUSIONS: In patients with baseline mild to severe pain with activity, the NEMEX-KOA program was feasible. Progression was achieved with few incidents of clinically relevant increases in pain and no adverse events. However, jumping activities were not feasible. These findings hold promise for investigating the efficacy of the NEMEX-KOA program in individuals with mild to moderate KOA. PMID- 28653868 TI - Knee Frontal-Plane Biomechanics in Adults With or Without Bone Marrow Edema-Like Lesions After Anterior Cruciate Ligament Injury. AB - CONTEXT: Lateral subchondral bone bruises (BBs) occur frequently with anterior cruciate ligament (ACL) injuries. These BBs are associated with pain during weight bearing, leading individuals to increase medial tibiofemoral loading to alleviate pain laterally. Increased medial tibiofemoral loading may precipitate the development or progression of posttraumatic osteoarthritis; however, no in vivo biomechanical data exist to confirm that lateral BBs increase medial tibiofemoral loading as measured by the external knee-adduction moment (KAM). OBJECTIVE: To determine whether lateral BBs after ACL injury increase the external KAM during walking. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Eleven volunteers with an ACL injury (age = 20.36 +/- 4.03 years, height = 177.60 +/- 8.59 cm, mass = 79.70 +/- 16.33 kg), 12 with an ACL injury and a lateral BB (ACL + BB; age = 19.25 +/- 5.58 years, height = 170.71 +/- 9.40 cm, mass = 66.79 +/- 11.91 kg), and 12 healthy controls (age = 19.67 +/- 5.19 years, height = 173.29 +/- 11.58 cm, mass = 67.07 +/- 11.25 kg) participated. INTERVENTION(S): We recorded peak KAM during 3 walking trials (1.1 +/- 0.6 m/s) in which participants walked over a force platform located in the field of view of a motion-capture system. MAIN OUTCOME MEASURE(S): Peak KAM was calculated during the first half of stance using standard inverse-dynamics analysis, averaged across trials, and examined via 1-way analysis of variance. Knee pain and function were determined from the International Knee Documentation Committee Subjective Knee Evaluation Form and compared among groups via the Kruskal-Wallis test. RESULTS: Peak KAM did not differ among groups (ACL injury = 0.14 +/- 0.07 Nm.kg-1.m-1, ACL + BB = 0.21 +/- 0.08 Nm.kg-1.m-1, control = 0.20 +/- 0.08 Nm.kg-1.m-1; F2,35 = 3.243, P = .052). Knee-pain frequency and severity were greater in the ACL-injury (frequency = 2.55 +/- 1.81, severity = 3.36 +/- 1.75; both P < .001) and ACL + BB (frequency = 3.58 +/- 2.81, severity = 4.08 +/- 3.20; both P < .001) groups than in the control group (frequency = 0.00 +/- 0.00, severity = 0.00 +/- 0.00). Knee function was greater in the control group (100.00 +/- 0.00) than in the ACL injury (59.35 +/- 17.31; P < .001) and ACL + BB (46.46 +/- 25.85; P < .001) groups. CONCLUSIONS: The ACL + BB groups did not walk with a greater external KAM than the ACL-injury or control groups. Thus, lateral tibiofemoral BB did not influence knee frontal-plane loading after ACL injury. PMID- 28653871 TI - Athletic Trainers Have an Important Role in Preventing and Treating Osteoarthritis. PMID- 28653870 TI - Osteoarthritis Prevalence in Retired National Football League Players With a History of Concussion and Lower Extremity Injury. AB - CONTEXT: Dynamic balance deficits have been described postconcussion, even after athletes return to play. Lower extremity (LE) musculoskeletal injury rates increase for up to 1 year after concussion, but the long-term musculoskeletal implications of concussion are unclear. OBJECTIVE: To (1) examine the association of concussion and LE injury histories with osteoarthritis (OA) prevalence in retired National Football League players and (2) examine the association of concussion and LE injury histories with OA prevalence in those <=55 years of age. DESIGN: Case-control study. SETTING: Survey. PATIENTS OR OTHER PARTICIPANTS: We administered the Health Survey of Retired National Football League Players, which collects information about demographics, OA, LE injury, and concussion history. MAIN OUTCOME MEASURE(S): Twelve discrete categories were created based on concussion and LE injury history, ranging from 0 concussions and 0 LE injuries (referent group) to 3+ concussions and 2+ LE injuries. Binomial regression analysis modeled lifetime OA prevalence. Covariates were body mass index, age at the time of the survey, and total years playing professional football. RESULTS: Complete data were available for 2696 participants. Lifetime OA prevalence was smallest in the referent group (21.1%) and largest in the 3+ concussion and 2+ LE group (50.6%; 2.5 times the referent; 95% confidence interval [CI] = 2.1, 3.1). Participants in all concussion groups (1, 2, 3+) who reported a history of 0 LE injuries had a greater OA prevalence than the referent group. When participants were stratified by age, the <=55 years of age, 3+ concussions, and 2+ LE injuries group prevalence ratio (3.6; 95% CI = 2.7, 5.2) was larger than that of the >55 years of age, 3+ concussions, and 2+ LE injuries group (1.8; 95% CI = 1.3, 2.4) compared with the respective referent groups. CONCLUSIONS: Concussion with or without a history of LE injury may be an important moderator of OA. Future researchers should seek to better understand the mechanisms that influence the association among concussion, LE injury, and OA. PMID- 28653873 TI - The prognostic value of pretreatment neutrophil-to-lymphocyte ratio in breast cancer: Deleterious or advantageous? AB - Breast cancer is one of the leading malignant tumors that endanger women's health worldwide. Despite the rapid progress on the therapies, including chemotherapy, surgical resection, and other auxiliary methods, there were still numerous people died of breast cancer, which promoted the researchers to concentrate on the prognostic factor of breast cancer. In recent years, an increasing number of studies have been focused on the prognostic value of pretreatment neutrophil-to lymphocyte ratio in breast cancer. This article is a brief review of the associations between neutrophil-to-lymphocyte ratio and the prognosis of breast cancer patients, which may give a greater insight into the development of breast cancer and enable clinicians to cure it completely. PMID- 28653872 TI - Posttraumatic Bone Marrow Lesion Volume and Knee Pain Within 4 Weeks After Anterior Cruciate Ligament Injury. AB - CONTEXT: After an anterior cruciate ligament (ACL) injury, a majority of patients have a traumatic bone marrow lesion (BML, or bone bruise). The clinical relevance of posttraumatic lesions remains unclear. OBJECTIVE: To explore the cross-sectional associations between traumatic BML volume and self-reported knee pain and symptoms among individuals within 4 weeks of ACL injury. DESIGN: Cross sectional exploratory analysis of a randomized clinical trial. SETTING: Orthopaedic departments at 2 hospitals in Sweden. PATIENTS OR OTHER PARTICIPANTS: As part of a randomized trial (knee anterior cruciate ligament nonoperative versus operative treatment [KANON] study), 121 young active adults (74% men, age = 26 +/- 5 years, height = 1.8 +/- 0.1 m, weight = 76 +/- 13 kg) with an ACL tear were studied. MAIN OUTCOME MEASURE(S): The BML volume in the proximal tibia and distal femur was segmented using magnetic resonance images obtained within 4 weeks of injury. A radiologist evaluated the presence of depression fractures on the images. Pain and symptoms of the injured knee (Knee Injury and Osteoarthritis Outcome Score [KOOS] pain and symptoms subscales) were obtained the same day as imaging. We used linear regression models to assess the associations. RESULTS: Most knees had at least 1 BML (96%), and the majority (57%) had a depression fracture. Whole-knee BML volume was not related to knee pain for the entire cohort (beta = -0.09, P = .25). Among those without a depression fracture, larger whole-knee BML volume was associated with increased knee pain (beta = -0.46, P = .02), whereas no association was found for those with a depression fracture (beta = 0.0, P = .96). Larger medial (beta = -0.48, P = .02) but not lateral (beta = 0.03, P = .77) tibiofemoral BML volume was associated with greater pain. We found no association between BML volume and knee symptoms. CONCLUSIONS: We confirmed the absence of relationships between whole-knee BML volume and pain and symptoms within 4 weeks of ACL injury. Our findings extend previous reports in identifying weak associations between larger BML volume in the medial compartment and greater pain and between BML volume and greater pain among those without a depression fracture. PMID- 28653874 TI - Invalidation of mitophagy by FBP1-mediated repression promotes apoptosis in breast cancer. AB - Fructose-1,6-bisphosphatase 1, a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor. However, the functions of fructose-1,6 bisphosphatase 1 in the regulation of mitophagy and apoptosis remain unknown. Here, we investigated the effects of fructose-1,6-bisphosphatase 1 on mitophagy and apoptosis as well as their underlying mechanisms in breast cancer cells. In this work, the messenger RNA and protein expression of various molecules were determined by quantitative realtime polymerase chain reaction and western blot, respectively. Gene-expression correlations were obtained from The Cancer Genome Atlas Breast Cancer database and analyzed using cBioPortal. The levels of cellular reactive oxygen species and apoptotic index were detected by flow cytometry. The mitochondrial membrane potentials were assessed with a JC-1 fluorescent sensor. Subcellular structures were observed under a transmission electron microscope. The intracellular distribution of translocase of outer membrane 20 was detected by immunofluorescence staining. Protein-protein interactions were analyzed by immunoprecipitation. Our results indicated that fructose-1,6-bisphosphatase 1 expression was negatively correlated with autophagy level in breast cancer. Fructose-1,6-bisphosphatase 1 restrained autophagy activity by increasing the level of p62 and decreasing the levels of LC3 and Beclin 1. Additionally, fructose-1,6-bisphosphatase 1 promoted cell apoptosis by upregulating the levels of intracellular ROS and expression of pro-apoptotic proteins such as cleaved PARP, cleaved Caspase 3, and Bax and downregulating the levels of anti-apoptotic proteins such as PARP, Caspase 3, and Bcl-2. Finally, fructose-1,6-bisphosphatase 1 limited the efficient removal of diseased mitochondria and reduced the messenger RNA and protein expressions of HIF-1alpha, BNIP3L/NIX, and BNIP3. More importantly, fructose-1,6-bisphosphatase 1 facilitated co-action between Bcl-2 and Beclin 1, which may be important in the mechanism of fructose-1,6-bisphosphatase 1-mediated mitophagy inhibition. In summary, loss of mitophagy by fructose-1,6-bisphosphatase 1-mediated repression promotes apoptosis in breast cancer. PMID- 28653875 TI - MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling. AB - Several studies have revealed that MFG-E8 (milk fat globule-epidermal growth factor 8) is related to tumour development and progression. However, the relationship between MFG-E8 expression and metastasis in colorectal cancer patients and the role of MFG-E8 in colorectal cancer invasion and progression remain unknown. In this study, we performed immunohistochemistry and quantitative real-time polymerase chain reaction to assess MFG-E8 expression in colorectal cancer and adjacent non-cancerous tissues. Colorectal cancer RNAseq data from The Cancer Genome Atlas project were downloaded and MFG-E8 expression was analysed. Gene set enrichment analysis was performed for gene ontology and pathway analysis associated with MFG-E8 expression. For in vitro studies, we used lentivirus mediated MFG-E8 RNA interference and commercialized recombinant human MFG-E8 to investigate its role in colorectal cancer cell growth, migration and invasion. It seems that MFG-E8 was overexpressed in advanced colorectal cancer tissues compared with early-stage colorectal cancer tissues and adjacent non-cancerous tissues. Correlation analysis revealed that MFG-E8 expression was significantly related to plasma membrane invasion, lymph node metastasis, distant metastasis and tumour-node-metastasis stage. Survival analysis revealed that high MFG-E8 expression predicted a poorer prognosis than low MFG-E8 expression group both in our colorectal cancer cohort and The Cancer Genome Atlas colorectal cancer cohort. In vitro study suggested that MFG-E8 knockdown can suppress the growth of colorectal cancer cells without affecting the expression of the proliferation related gene Ki67. MFG-E8 knockdown also suppressed colorectal cancer cell migration and invasion, a change accompanied by MMP-2 and MMP-9 downregulation. Moreover, MFG-E8 knockdown induced a shift from mesenchymal makers to epithelial makers, while pretreatment with rhMFG-E8 had the opposite effect. The effect of MFG-E8 on colorectal cancer cell migration, invasion and epithelial-to mesenchymal was partially dependent on the PI3K/AKT signalling pathway. These findings provide a better understanding of the molecular mechanism underlying colorectal cancer progression and suggest a predictive role for MFG-E8 in colorectal cancer metastasis and prognosis. PMID- 28653876 TI - Nuclear ubiquitin C-terminal hydrolase L5 expression associates with increased patient survival in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma is a lethal disease with an overall 5-year survival of less than 5%. Prognosis among surgically treated patients is difficult and identification of new biomarkers is essential for accurate prediction of patient outcome. As part of one of the major cellular protein degradation systems, the proteasome plays a fundamental role in both physiological and pathophysiological conditions including cancer. The proteasome associated deubiquitinating enzyme ubiquitin C-terminal hydrolase L5 (UCHL5)/Uch37 is a modulator of proteasome activity with cancer prognostic marker potential. Cytoplasmic and nuclear immunoexpression of UCHL5 was evaluated in 154 surgical specimens from pancreatic ductal adenocarcinoma patients treated at Helsinki University Hospital, Finland, in 2000-2011. UCHL5 expression in relation to clinicopathological parameters and the association between UCHL5 In this study, positive expression and patient survival were assessed. Positive nuclear UCHL5 expression was associated with increased patient survival ( p = 0.005). A survival benefit was also detectable in these subgroups of patients: over 65 years ( p < 0.001), at tumor stages IIB to III ( p = 0.007), or with lymph-node positivity ( p = 0.006). In stages IIB to III disease, patients with positive nuclear UCHL5 expression showed a twofold increase in 5-year cancer-specific survival compared to those with negative expression. Multivariate analysis identified positive nuclear UCHL5 expression as an independent prognostic factor ( p = 0.012). In conclusion, UCHL5 expression could function as a prognostic marker in pancreatic ductal adenocarcinoma, particularly at disease stages IIB to III. As UCHL5 is one of the few markers predicting increased survival, our results may be of clinical relevance. PMID- 28653877 TI - Long non-coding RNA tumor suppressor candidate 7 advances chemotherapy sensitivity of endometrial carcinoma through targeted silencing of miR-23b. AB - Endometrial carcinoma is the most common malignant tumor of the female genital tract worldwide. TUSC7 (tumor suppressor candidate 7) is an antisense long non coding RNA and is downregulated and acts as a potential tumor suppressor in several malignant tumors. In this study, the low expression of TUSC7 was confirmed in endometrial carcinoma tissues and was associated with high pathological stages of endometrial carcinoma, which revealed that TUSC7 might be involved in tumorigenesis and progression of endometrial carcinoma. Moreover, the expression of TUSC7 in endometrial carcinoma tissues and cell lines resistant to CDDP and Taxol was lower than that in sensitive endometrial carcinoma tissues and cell lines, which indicated that the TUSC7 expression level was positively correlated with the response of endometrial carcinoma patients to chemotherapy with CDDP and Taxol. TUSC7 upregulation inhibited proliferation, blocked cells at G1 phase, and advanced apoptosis and chemotherapy sensitivity to CDDP and Taxol in HEC1A/CR cell line. Furthermore, miR-23b was upregulated in endometrial carcinoma and negatively correlated with the expression of TUSC7. RNA pull-down assay indicated that TUSC7 could specifically silence the expression of miR-23b in HEC1A/CR cell line; miR-23b was a target gene of TUSC7. MiR-23b upregulation mostly reversed the TUSC7-induced regulatory effects on HEC1A/CR cell line. In summary, long non-coding RNA TUSC7 was underexpressed in endometrial carcinoma, especially in endometrial carcinoma chemotherapy-resistant tissues and cell lines and acted as a potential tumor suppressor gene to inhibit cell growth as well as advance the chemotherapy sensitivity through targeted silencing of miR-23b, which might provide a new therapeutic target to endometrial carcinoma. PMID- 28653878 TI - Sirtuin 6 plays an oncogenic role and induces cell autophagy in esophageal cancer cells. AB - Sirtuin 6, a member of sirtuin family, is generally regarded as a tumor suppressor as it participates in suppressing hypoxia-inducible factor 1alpha and MYC transcription activity by deacetylating H3K9 (histone H3 lysine 9) and H3K56 (histone H3 lysine) at promoters of target genes, leading to the aerobic glycolysis inhibition and cell growth suppression. However, its expression has recently been reported to be highly elevated in a series of tumors, including prostate cancer, breast cancer, and non-small cell lung cancer, indicating that sirtuin 6 plays dual roles in tumorigenicity in a cell/tumor type-specific manner. To our knowledge, the biological roles of sirtuin 6 in esophageal cancer cells have still been underestimated. In the study, data from quantitative reverse transcriptase polymerase chain reaction-based assays and immunohistochemical assays revealed that sirtuin 6 was remarkably overexpressed in esophageal squamous tumor tissues. Moreover, its upregulation was closely related with clinical features, such as gender, pathology, tumor-node-metastasis, and cell differentiation. Subsequently, the biological tests showed that it promoted cell proliferation and induced the expression of Bcl2, a key anti apoptotic factor, in esophageal carcinoma cells. Moreover, using the ratio of LC3II/I, a widely recognized autophagy biomarker, we showed that it apparently induced cell autophagy, which was further confirmed by the autophagy flux assays. In addition, results from western blotting assays and immunoprecipitation assays displayed that sirtuin 6 specifically interacted with ULK1 and positively regulated its activity by inhibiting its upstream factor mammalian target of rapamycin activity. In summary, our studies shed insights into the crucial functions of sirtuin 6 in esophageal carcinoma cells and provide evidence supporting sirtuin 6-based personalized therapies in esophageal carcinoma cell patients. PMID- 28653879 TI - TP53 alteration determines the combinational cytotoxic effect of doxorubicin and an antioxidant NAC. AB - The anticancer effect of doxorubicin is closely related to the generation of reactive oxygen species. On the contrary, doxorubicin-induced reactive oxygen species induces heart failure, a critical side effect of doxorubicin. Antioxidant supplementation has been proposed to reduce the side effects. However, the use of antioxidants may hamper the anticancer effect of doxorubicin. In this study, doxorubicin-induced reactive oxygen species was shown to differentially affect cancer cells based on their TP53 genetic status; doxorubicin-induced apoptosis was attenuated by an antioxidant, N-acetylcysteine, in TP53 wild cells; however, N-acetylcysteine caused a synergistic increase in the apoptosis rate in TP53 altered cells. N-acetylcysteine prevented phosphorylation of P53 protein that had been induced by doxorubicin. However, N-acetylcysteine increased the cleavage of poly (ADP-ribose) polymerase in the presence of doxorubicin. Synergy score of 26 patient-derived cells were evaluated after the combination treatment of doxorubicin and N-acetylcysteine. The synergy score was significantly higher in TP53-altered group compared with those in TP53 wild group. In conclusion, TP53 genetic alteration is a critical factor that determines the use of antioxidant supplements during doxorubicin treatment. PMID- 28653880 TI - MiR-129-5p influences the progression of gastric cancer cells through interacting with SPOCK1. AB - The purpose of our study is to clarify the effect of microRNA-129-5p in the progression of human gastric cancer cells by regulating SPOCK1. The expression of microRNA-129-5p and SPOCK1 was tested by quantitative real-time polymerase chain reaction in tissues and cell lines. We validated the targeted relationship between microRNA-129-5p and SPOCK1 by dual luciferase reporter gene assay. 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, flow cytometry, transwell, and wound scratch assays were used to analyze the effects of microRNA-129-5p on SGC-7901 cell viability, proliferation, cell cycle and apoptosis, invasiveness, and migration. MicroRNA-129-5p was downregulated while SPOCK1 was upregulated in gastric cancer tissues and cell lines. The result of luciferase reporter gene assay demonstrated that microRNA-129-5p can target SPOCK1 by binding to the 3'untranslated region. The overexpression of microRNA 129-5p or the inhibition of SPOCK1 inhibited SGC-7901 viability, proliferation, migration, and invasion while promoted cell cycle arrest in G0/G1 stage and cell apoptosis. Our results suggested that microRNA-129-5p could directly specifically suppress SPOCK1, which might be one of the potential mechanisms in inhibiting cell processes including viability, proliferation, cell mitosis, migration, and invasiveness of gastric cancer cells. PMID- 28653881 TI - Effects of DTX3L on the cell proliferation, adhesion, and drug resistance of multiple myeloma cells. AB - Cell adhesion-mediated drug resistance is an important factor that influences the effects of chemotherapy in multiple myeloma. DTX3L, a ubiquitin ligase, plays a key role in cell-cycle-related process. Here, we found that the expression of DTX3L gradually increased during the proliferation of myeloma cells, which resulted in arrest of the cell cycle in the G1 phase and promoted the adherence of myeloma cells to fibronectin or bone marrow stromal cells. In addition, silencing of DTX3L improved sensitivity to chemotherapy drugs in multiple myeloma cell lines adherent to bone marrow stromal cells and increased the expression of caspase-3 and poly-adenosine diphosphate-ribose polymerase, two markers of apoptosis. Finally, we also found that DTX3L expression was regulated by focal adhesion kinase. Taken together, the results of this study show that DTX3L plays an important role in the proliferation and cell adhesion-mediated drug resistance of multiple myeloma cells and as such may play a key role in the development of multiple myeloma. PMID- 28653882 TI - Overexpression of LAMC2 predicts poor prognosis in colorectal cancer patients and promotes cancer cell proliferation, migration, and invasion. AB - Laminin gamma2 (LAMC2) has been reported to be involved in the development and progression of a variety of tumors. However, its function in human colorectal cancer is unclear. Our study aimed to investigate the role of laminin gamma2 in colorectal cancer. We first performed the multiple Kaplan-Meier survival analysis of laminin gamma2 in a cohort of Gene Expression Omnibus datasets and evaluated its relationship with clinical outcomes of colorectal cancer patients. Then, we established stable colorectal cancer cell lines with laminin gamma2 overexpression and examined the functional assays in vitro. Finally the expression pattern of laminin gamma2 in colorectal cancer clinical samples was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. We found that laminin gamma2 was significantly correlated with poor clinical outcomes such as disease-specific, recurrence-free, disease-free, and overall survival in colorectal cancer. Moreover, stably overexpressing laminin gamma2 promoted proliferation, migration, and invasion of colorectal cancer cells. In addition, overexpressed laminin gamma2 was identified in tumor tissues compared with paired adjacent normal tissues and was related to tumor-node metastasis stage (p = 0.001) and lymph node metastasis (p < 0.001). In summary, our results strongly suggest that laminin gamma2 may be a potential prognostic biomarker and therapeutic target in colorectal cancer. PMID- 28653883 TI - The nitric oxide donor JS-K sensitizes U87 glioma cells to repetitive irradiation. AB - As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4 ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death. In vivo efficacy of JS-K and repetitive irradiation were investigated in an orthotopic U87 xenograft model in mice. For the first time, we could show that JS-K acts as a potent cytotoxic and radiosensitizing agent in U87 cells in vitro. This dose- and time-dependent effect is due to an enhanced induction of DNA double-strand breaks leading to mitotic catastrophe as the dominant form of cell death. However, this potent cytotoxic and radiosensitizing effect could not be confirmed in an intracranial U87 xenograft model, possibly due to insufficient delivery into the brain. Although NO donor treatment was well tolerated, neither a retardation of tumor growth nor an extended survival could be observed after JS-K and/or radiotherapy. PMID- 28653884 TI - Photobiomodulation of breast and cervical cancer stem cells using low-intensity laser irradiation. AB - Breast and cervical cancers are dangerous threats with regard to the health of women. The two malignancies have reached the highest record in terms of cancer related deaths among women worldwide. Despite the use of novel strategies with the aim to treat and cure advanced stages of cancer, post-therapeutic relapse believed to be caused by cancer stem cells is one of the challenges encountered during tumor therapy. Therefore, further attention should be paid to cancer stem cells when developing novel anti-tumor therapeutic approaches. Low-intensity laser irradiation is a form of phototherapy making use of visible light in the wavelength range of 630-905 nm. Low-intensity laser irradiation has shown remarkable results in a wide range of medical applications due to its biphasic dose and wavelength effect at a cellular level. Overall, this article focuses on the cellular responses of healthy and cancer cells after treatment with low intensity laser irradiation alone or in combination with a photosensitizer as photodynamic therapy and the influence that various wavelengths and fluencies could have on the therapeutic outcome. Attention will be paid to the biomodulative effect of low-intensity laser irradiation on cancer stem cells. PMID- 28653885 TI - Eukaryotic translation initiation factors and cancer. AB - Recent technological advancements have shown tremendous mechanistic accomplishments in our understanding of the mechanism of messenger RNA translation in eukaryotic cells. Eukaryotic messenger RNA translation is very complex process that includes four phases (initiation, elongation, termination, and ribosome recycling) and diverse mechanisms involving protein and non-protein molecules. Translation regulation is principally achieved during initiation step of translation, which is organized by multiple eukaryotic translation initiation factors. Eukaryotic translation initiation factor proteins help in stabilizing the formation of the functional ribosome around the start codon and provide regulatory mechanisms in translation initiation. Dysregulated messenger RNA translation is a common feature of tumorigenesis. Various oncogenic and tumor suppressive genes affect/are affected by the translation machinery, making the components of the translation apparatus promising therapeutic targets for the novel anticancer drug. This review provides details on the role of eukaryotic translation initiation factors in messenger RNA translation initiation, their contribution to onset and progression of tumor, and how dysregulated eukaryotic translation initiation factors can be used as a target to treat carcinogenesis. PMID- 28653886 TI - The miR-608 rs4919510 polymorphism may modify cancer susceptibility based on type. AB - Previous meta-analysis has not shown different effects of miR-608 rs4919510 polymorphism in specific cancer types and reported no significant association between rs4919510 and cancer risk among Chinese. However, more recent findings have been inconsistent. Therefore, we performed an updated meta-analysis to examine whether this polymorphism is associated with cancer risk based on ethnicity and type. A total of 18 case-control studies, comprising 12,517 cases and 15,624 controls, were included in our study. Surprisingly, in contrast with previous meta-analysis, a significant association between the rs4919510 polymorphism and cancer risk was observed in Chinese (CG vs CC: odds ratio = 1.11; 95% confidence interval = 1.04-1.19). In further stratified analyses based on cancer type, rs4919510 was significantly associated with an increased risk of papillary thyroid cancer (CG vs CC: odds ratio = 1.25; 95% confidence interval = 1.01-1.54) and exhibited borderline significant associations with increased risk of gastric cancer (GG vs CC: odds ratio = 1.27; 95% confidence interval = 1.00 1.62) and lung cancer (CG vs CC: odds ratio = 1.14; 95% confidence interval = 0.99-1.32), but a decreased risk of colorectal cancer (GG vs CC: odds ratio = 0.74; 95% confidence interval = 0.60-0.91). Moreover, the RegulomeDB database indicated that rs4919510 may affect the expression of two nearby genes ( SEMA4G and MRPL43), and the Cancer Genome Atlas database revealed that the expression level of SEMA4G was significantly lower in colorectal cancer and lung cancer tissues than that in adjacent non-tumour tissues, while the expression level of SEMA4G was significantly higher in gastric cancer tissues than that in adjacent non-tumour tissues. These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate tumour development in a type-specific manner. Further studies with experimental evaluations are warranted. PMID- 28653888 TI - DJ-1 as a potential biomarker for the early diagnosis in lung cancer patients. AB - DJ-1 is a novel oncogene that can transform NIH3T3 cells in cooperation with the activated ras gene. DJ-1 appears to have its greatest effect on tumourigenesis, and it may have a greater impact on early-stage lung cancers. In this study, we proposed to investigate the clinical value of DJ-1 protein in the early diagnosis of lung cancer and compared its diagnostic value with other biomarkers. Preoperative serum DJ-1 levels were measured in 300 lung cancer patients and compared with benign pulmonary disease (n = 44) and healthy volunteers (n = 64). Using tissue microarrays and immunohistochemical analyses, we compared the DJ-1 expression between the primary squamous cell carcinoma tumours and matched metastatic tissues from a lymph node. The baseline preoperative serum DJ-1 of lung cancer patients was significantly higher than that of benign diseases and healthy controls (p < 0.001). In the early-stage subgroup, the median DJ-1 concentration (ng/mL) was significantly higher than that of the advanced stage (12.90 vs 7.75, p < 0.05). Using immunohistochemistry, we observed that the DJ-1 staining intensity was generally weaker and less common in the metastatic tissues compared with that in the primary tumour (McNemar-Bowker Test, p = 0.008). DJ-1 was highly expressed in the early stage of lung cancer, and its expression was significantly decreased after metastasis. Therefore, DJ-1 may be a potential biomarker for the early diagnosis and monitoring of lung cancer metastasis. PMID- 28653887 TI - The effect of distant metastases sites on survival in de novo stage-IV breast cancer: A SEER database analysis. AB - To investigate the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer. From 2010 to 2013, patients with a diagnosis of de novo stage-IV breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on breast cancer-specific survival and overall survival. A total of 7575 patients were identified. The most common metastatic sites were bone, followed by lung, liver, and brain. Patients with hormone receptor+/human epidermal growth factor receptor 2- and hormone receptor+/human epidermal growth factor receptor 2+ status were more prone to bone metastases. Lung and brain metastases were common in hormone receptor-/human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2- subtypes, and patients with hormone receptor+/ human epidermal growth factor receptor 2+ and hormone receptor /human epidermal growth factor receptor 2+ subtypes were more prone to liver metastases. Patients with liver and brain metastases had unfavorable prognosis for breast cancer-specific survival and overall survival, whereas bone and lung metastases had no effect on patient survival in multivariate analyses. The hormone receptor-/human epidermal growth factor receptor 2- subtype conferred a significantly poorer outcome in terms of breast cancer-specific survival and overall survival. hormone receptor+/human epidermal growth factor receptor 2+ disease was associated with the best prognosis in terms of breast cancer-specific survival and overall survival. Patients with liver and brain metastases were more likely to experience poor prognosis for breast cancer-specific survival and overall survival by various breast cancer subtypes. Distant metastases sites have differential impact on clinical outcomes in stage-IV breast cancer. Follow-up screening for brain and liver metastases might be effective in improving breast cancer-specific survival and overall survival. PMID- 28653889 TI - Bioinformatics methods for identifying differentially expressed genes and signaling pathways in nano-silica stimulated macrophages. AB - The incidence of disease relating to nanoparticle exposure has been rising rapidly in recent years, for which there is no effective treatment. Macrophage is suggested to play a crucial role in the development of pulmonary disease. To investigate the changes in macrophage after being stimulated by nanometer silica dust and to explore potential biomarkers and signaling pathways, the gene chip GSE13005 was downloaded from Gene Expression Omnibus database, which contained 21 samples: 3 samples per group and 7 groups in total. Macrophages in the control group were cultured in serum-free medium, while the experimental groups were treated with nanometer silica dust in different sizes and concentrations, respectively. To identify the differentially expressed genes and explore their potential functions, we adopted the gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and also constructed protein protein interaction network. As a result, 1972 differentially expressed genes were identified from 22,690 microarray data in the gene chip, 1069 genes were upregulated and 903 genes were downregulated. Results of the gene ontology analysis indicated that the differentially expressed genes were widely distributed in intracellular and extracellular regions, regulating macrophage apoptosis, inflammatory response, and cell differentiation. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the majority of differentially expressed genes were enriched in cytokine-cytokine receptor interaction, cancer or phagosome transcriptional misregulation. The top 10 hub genes, S100a9, Nos3, Psmd14, Psmd4, Lck, Atp6v1h, Jun, Foxh1, Pex14, and Fadd were identified from protein-protein interaction network. In addition, Nos3, Psmd14, Atp6v1h, and Jun were clustered into module M2 (rc = 0.74, p < 0.01), which mainly regulates cell carcinogenesis and antivirus process. In conclusion, differentially expressed genes screened from this study may provide new insights into the exploration of mechanisms, biomarkers, and therapeutic targets for diseases relating to nanoparticle exposure. PMID- 28653890 TI - Expression of Fra-1 in human hepatocellular carcinoma and its prognostic significance. AB - This study aimed to explore the clinical significance and prognostic value of Fra 1 in hepatocellular carcinoma patients after curative resection. Fra-1 expression was investigated using a combination of techniques: immunohistochemistry for 66 samples of hepatocellular carcinoma and quantitative real-time polymerase chain reaction and western blotting assays for 19 matched hepatocellular carcinoma specimens. Fra-1 was present in 38 of 66 (57.6%) tumor tissues, with intense staining in the nuclei. There was also positive staining in 14 of 66 (21.2%) adjacent peritumoral tissues, with weak staining in the cytoplasm. Quantitative real-time polymerase chain reaction and western blotting assays confirmed higher expression of Fra-1 messenger RNA and Fra-1 protein in tumor tissues than adjacent non-tumor tissues for 19 hepatocellular carcinoma samples (p < 0.001). Positive expression of Fra-1 was significantly related to vascular invasion and serum alpha-fetoprotein. Kaplan-Meier survival analysis found that overexpressed Fra-1 was correlated with poor overall survival and disease-free survival. Multivariate analysis identified Fra-1 as an independent prognostic factor. Fra-1 may be involved in the progress of hepatocellular carcinoma and could be a promising molecular candidate in the diagnosis and treatment of hepatocellular carcinoma. PMID- 28653891 TI - Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1alpha under hypoxia condition. AB - Hypoxia plays a critical role in the progression and metastasis of hepatocellular carcinoma by activating the key transcription factor, hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of hypoxia-inducible factor-1alpha in hepatocellular carcinoma. We found that histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular carcinoma, strengthened the migration and invasion of hepatocellular carcinoma cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 5 induced the transcription of hypoxia-inducible factor-1alpha by silencing homeodomain-interacting protein kinase-2 expression, which was also dependent on hypoxia. And then knockdown of hypoxia-inducible factor-1alpha decreased the expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin, increased. Phenotype experiments showed that the migration and invasion of hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 5 or hypoxia-inducible factor-1alpha but rescued when eliminating homeodomain interacting protein kinase-2 in hepatocellular carcinoma cells, which suggested the critical role of histone deacetylase 5-homeodomain-interacting protein kinase 2-hypoxia-inducible factor-1alpha pathway in hypoxia-induced metastasis. Finally, clinical analysis confirmed the positive correlation between histone deacetylase 5 and hypoxia-inducible factor-1alpha in hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of histone deacetylase 5 and hypoxia-inducible factor-1alpha. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular carcinoma. PMID- 28653892 TI - Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4). AB - The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2, <2.5 ug/L; human epidermal growth factor receptor 3, <2.8 ug/L; and human epidermal growth factor receptor 4, <1.8 ug/L. There were significant differences in human epidermal growth factor receptor 2 and human epidermal growth factor receptor 3 serum levels between the patients with tissue human epidermal growth factor receptor 2-positive and tissue human epidermal growth factor receptor 2 negative ( p = 0.0026, p = 0.000011) tumors, but not in the serum levels of human epidermal growth factor receptor 4 ( p = 0.054). There was good agreement between the in-house human epidermal growth factor receptor 2 assay and the chemiluminescent immunoassay. Our new specific antibodies for all the three human epidermal growth factor receptors may prove valuable in the development of novel anti-human epidermal growth factor receptor targeted therapies with sensitive immunoassays for measuring serum levels of the respective targets and in monitoring established treatment. PMID- 28653893 TI - HIF-2alpha not HIF-1alpha overexpression confers poor prognosis in non-small cell lung cancer. AB - HIF-alpha may play an important role in the process of tumorigenesis as well as tumor progression. Although a number of investigations have established the significance of HIF-1alpha in several human tumors, there is still little information available on the clinical significance of HIF-2alpha expression in non-small cell lung cancer (NSCLC). In present study, immunohistologic expression of HIF-1alpha/ HIF-2alpha was studied in a tissue microarray of 140 Stage I-III NSCLCs and correlated with clinicopathologic parameters and clinical outcome. We found that HIF-1alpha/ HIF-2alpha showed a cytoplasmic pattern of expression in tumor cells while normal lung components showed negative or weak cytoplasmic staining. High HIF-1alpha and HIF-2alpha expression was noted in 49/140 (35.0%) and in 64/140 (45.7%) of the cases respectively. There was no direct correlation between HIF-1alpha and HIF-2alpha expression ( p = 0.200). The high HIF-2alpha expression was associated with histology (squamous cell carcinoma vs. adenocarcinomas) in these patients ( p = 0.001). Patients in advanced tumor stage had frequent high expression of HIF-2alpha ( p = 0.007), and the similar high expression was also observed in advanced T or N stage ( p = 0.030 and 0.043, respectively). HIF-1alpha showed a marginal association with T stage ( p = 0.084), which showed a higher expression in early tumor stage. Univariate analysis of the overall survival demonstrates that HIF-2alpha expression but not HIF-1alpha was related to poor outcome ( p = 0.005) and it retained significance in multivariate analysis ( p = 0.046). In conclusion, HIF-2alpha expression was related to tumor size, lymph node metastasis, tumor stage and histology. We also found a positive prognostic value of HIF-2alpha protein expression. HIF-2alpha might serve as a potential prognosis biomarker in evaluating progression and prognosis of NSCLC. We believe that our study will be of great benefit to the clinical treatment and prognostic evaluation of NSCLC. PMID- 28653894 TI - Molecular and clinical attributes of uterine leiomyomas. AB - Uterine leiomyomas, also called uterine fibroids or myomas, represent one of the most common benign tumour types in women of a fertile age. Leiomyomas arise due to transformation of the layer of smooth muscle cells of corpus uteri - the myometrium. Despite frequent occurrence of this disease, the molecular mechanisms behind the origin and development of leiomyomas are still relatively unknown. Most predisposed are obese women and women of African origin. In more than half of cases, leiomyomas remain asymptomatic. Genetic factors also have an important impact on the development of these hormone-dependent tumours. However, the clinical and molecular characteristics of familiar and sporadic leiomyomas can widely differ. The main reason is the heterogeneity of this disease and the abundance of factors which can underlie their tumourigenesis. Clinical diagnosis of uterine leiomyomas without surgical interference can be hindered in the case of small, mostly submucosal leiomyomas or if it is necessary to avoid potential malignancy of tumour. Also, medical treatment of uterine leiomyomas cannot be nowadays considered sufficient with many medical agents still being tested only within clinical research. The main goal of this article is to summarise known facts about the aetiology of leiomyomas, risk factors that contribute to their development, known molecular-genetic aberrations connected with the presence of leiomyomas as well as the possibilities of their diagnosis and treatment. PMID- 28653895 TI - Cancer risk in patients with Peutz-Jeghers syndrome: A retrospective cohort study of 336 cases. AB - Peutz-Jeghers syndrome is a rare autosomal dominant inherited disorder characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyposis. A growing body of evidence has shown that Peutz-Jeghers syndrome could cause an increased risk of various cancers, yet the range of cancer risk estimates was wide among different studies. In this retrospective cohort study, 336 patients with Peutz-Jeghers syndrome in China were enrolled. The clinical characteristics, cancer spectrum, relative cancer risks, and cumulative cancer risks were analyzed. In total, 52 patients were diagnosed of cancer in the follow up period, at a median age of 41 years (range: 21-67). The relative risk for cancer in Peutz-Jeghers syndrome patients was 63.858 (confidence interval: 47.514 85.823), and the cumulative cancer risk at the age of 60 years was 55%. Colorectal cancer was the most common cancer for Peutz-Jeghers syndrome patients (relative risk: 237.918, confidence interval: 154.417-366.572) and the cumulative cancer risk at the age of 60 years was 28%. There was a statistically significant difference in the cumulative cancer risk between patients with family history and those without family history, as well as between patients living in rural area and those living in urban areas ( p < 0.05), while no significant effects of gender and intussusception history on the cumulative cancer risk was found ( p > 0.05). Hopefully, our study may contribute to the management of this rare disorder and establishment of related surveillance projects, especially in China. PMID- 28653896 TI - Ganoderma lucidum targeting lung cancer signaling: A review. AB - Lung cancer causes huge mortality to population, and pharmaceutical companies require new drugs as an alternative either synthetic or natural targeting lung cancer. The conventional therapies cause side effects, and therefore, natural products are used as a therapeutic candidate in lung cancer. Chemical diversity among natural products highlights the impact of evolution and survival of fittest. One such neglected natural product is Ganoderma lucidum used for promoting health and longevity for a longer time. The major bioconstituents of G. lucidum are mainly terpenes, polysaccharides, and proteins, which were explored for various activities ranging from apoptosis to autophagy. The bioconstituents of G. lucidum activate plasma membrane receptors and initiate various downstream signaling leading to nuclear factor-kappaB, phosphoinositide 3-kinase, Akt, and mammalian target of rapamycin in cancer. The bioconstituents regulate the expression of various genes involved in cell cycle, immune response, apoptosis, and autophagy in lung cancer. This review highlights the inextricable role of G. lucidum and its bioconstituents in lung cancer signaling for the first time. PMID- 28653897 TI - Progress in the treatment of esophageal neuroendocrine carcinoma. AB - Esophageal neuroendocrine neoplasms are rare. With the improvement and popularization of diagnostic methods, the morbidity statistics have increased annually in recent years. There are currently no treatment guidelines for esophageal neuroendocrine neoplasms, and surgery is the only cure. This usually involves radical surgery when the tumor is limited to the primary site or when only regional lymph node metastasis occurs. Surgical treatment is key to treating esophageal neuroendocrine neoplasms, but combined treatment with chemotherapy and radiotherapy can significantly improve patient survival. The effect of radiotherapy alone on this disease is poor. However, targeted endocrine therapy can improve endocrine hormone symptoms. The prognosis of patients with esophageal neuroendocrine neoplasms is mainly determined by the pathological stage. With the development of molecular biology techniques, the combination of targeted drugs and traditional chemotherapy is expected to provide novel ideas and directions for the treatment of esophageal neuroendocrine neoplasms in the coming years. In this article, the status of esophageal neuroendocrine tumor treatments was reviewed in detail. PMID- 28653898 TI - Toll-like receptor 4 promotes proliferation and apoptosis resistance in human papillomavirus-related cervical cancer cells through the Toll-like receptor 4/nuclear factor-kappaB pathway. AB - Toll-like receptor 4 is overexpressed in various tumors, including cervical carcinoma. However, the role of Toll-like receptor 4 in cervical cancer remains controversial, and the underlying mechanisms are largely elusive. Therefore, Toll like receptor 4 in cervical cancer and related mechanisms were investigated in this study. Quantitative reverse transcription polymerase chain reaction and western blot analyses were used to detect messenger RNA and protein levels in HeLa, Caski, and C33A cells with different treatments. Proliferation was quantified using Cell Counting Kit-8. Cell cycle distribution and apoptosis were assessed by flow cytometry. Higher levels of Toll-like receptor 4 expression were found in human papillomavirus-positive cells compared to human papillomavirus negative cells. Proliferation of HeLa and Caski cells was promoted in lipopolysaccharide-stimulated groups but suppressed in short hairpin RNA transfected groups. Apoptosis rates were lower in lipopolysaccharide-stimulated groups relative to short hairpin RNA-transfected groups. In addition, G2-phase distribution was enhanced when Toll-like receptor 4 was downregulated. Moreover, the pNF-kappaBp65 level was positively correlated with the Toll-like receptor 4 level in HeLa and Caski cells, though when an nuclear factor-kappaB inhibitor was applied to lipopolysaccharide-stimulated groups, the patterns of proliferation and apoptosis were opposite to those of the lipopolysaccharide-stimulated groups without inhibitor treatment. In conclusion, these data suggest that Toll-like receptor 4 promotes proliferation and apoptosis resistance in human papillomavirus-related cervical cancer cells at least in part through the Toll like receptor 4/nuclear factor-kappaB pathway, which may be correlated with the occurrence and development of cervical carcinoma. PMID- 28653899 TI - Mutation-promoting molecular networks of uncontrolled inflammation. AB - More and more studies show that chronic inflammation can lead to tumor formation. The complex interactions of inflammatory cells, stroma and tumor parenchymal cell are closely related to tumor formation. Under the state of chronic inflammatory microenvironment, long-term interaction of inflammatory cells and stromal cells as well as the parenchymal cells makes signaling pathway in parenchyma cells disordered. A series of gene level editor modification, epigenetic changes, and the regulation of transcription and translation changes will happen based on signaling pathway disorder. The changes ultimately lead to cell mutations and phenotypic transformation occurred. Recent findings provide an objective basis for cancer treatment and prevention. However, further discusses at the core of the possible molecular in tumor formation provide a theoretical foundation for future study of the pathogenesis and molecular targeted therapy of cancer. This review summarizes the research in the field of chronic inflammation and cancer in recent years, and analyze the molecules network in the process of the carcinogenic inflammation comprehensively. Beyond that, this review intends to describe possible carcinogenic inflammation core molecular and provides a theoretical basis for future study of the pathogenesis, chemoprevention and molecular targeted therapy of cancer. PMID- 28653900 TI - Overexpression of WDFY2 inhibits prostate cancer cell growth and migration via inactivation of Akt pathway. AB - Prostate cancer is the most commonly diagnosed malignancy and is the second leading deadly reason among male cancer. WDFY2, which is found to be a cancer specific fusion gene with CDKN2D in ovarian cancer, is a new gene with unknown function in carcinogenesis. In this study, we investigated the role of WDFY2 in prostate cancer development. We examined WDFY2 expression in human prostate tissue specimens and prostate cancer cell lines BPH-1, LNCaP, PC3, and DU-145. Overexpression of WDFY2 was performed to evaluate the role of WDFY2 in cell proliferation, migration, and colony formation of prostate cancer cells. We analyzed the clinical impact and prognosis of WDFY2 expression on the progress of prostate cancer through data from online datasets. Our results showed that WDFY2 had lower expression level in prostate tumors than in normal tissues. Overexpression of WDFY2 in prostate cancer cells DU145 and PC-3 led to the suppression of cancer cell migration and colony formation. Furthermore, we found that WDFY2 exerted its role by suppressing the activity of Akt pathway other than the epithelial-mesenchymal transition progression. In conclusion, we have uncovered WDFY2 as a tumor suppressor gene and a new potential biomarker for cancer progression. Our results showed that WDFY2 inhibited cancer cell colony formation and migration via suppressing Akt pathway, making it a potential new therapeutic target in prostate cancer. PMID- 28653901 TI - Gankyrin promotes the proliferation of gastric cancer and is associated with chemosensitivity. AB - Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in gastric cancer is not clear. In this study, we evaluated the function and mechanism of gankyrin in gastric cancer. The effects of gankyrin on gastric cancer growth, proliferation, and chemosensitivity were determined. Gankyrin expression was significantly increased in gastric cancer compared to non-cancerous tissues. This expression significantly enhanced cancer cell proliferation and growth in vitro and in vivo. Suppression of gankyrin downregulated cyclin D1, cyclin E, proliferating cell nuclear antigen, phosphoinositide 3-kinase, AKT, p-PI3K, and p-AKT but upregulated Rb, p53, and p27. However, gankyrin overexpression led to opposite results. Downregulation of gankyrin expression enhanced chemosensitivity to 5-fluorouracil and cisplatin by inducing cell apoptosis. However, upregulation of gankyrin expression led to the opposite outcomes. Gankyrin enhanced gastric cancer cell proliferation by regulating cell cycle-related proteins and by activating PI3K/AKT signaling pathway. Gankyrin played an important role in gastric carcinogenesis and could be a potential effective therapeutic target for enhancing chemosensitivity to 5 fluorouracil and cisplatin. PMID- 28653902 TI - NF-kappaB as the main node of resistance to receptor tyrosine kinase inhibitors in triple-negative breast cancer. AB - Graphical abstract Although accounting for merely a minute portion of diagnosed breast cancers, disproportionate number of deaths and associated low survival rate of patients have made triple-negative breast cancer to be considered as the most lethal breast cancer subtype. More importantly, intrinsic or developed resistance to chemotherapeutic regimens and disappointing outcomes of trials associated with many newly developed agents are other obstacles in establishment of a durable response in these patients. Interestingly, these happen despite the outstanding preclinical outcomes observed by these agents, most importantly among them, targeted receptor tyrosine kinase inhibitors. Pursuing these disappointing outcomes, especially in the case of targeted receptor tyrosine kinase inhibitors, many researches have focused on identification of the hidden factors involved. Highly inflammatory, rich in reactive oxygen species, and hypoxic microenvironment of triple-negative breast cancer tumors and the involving mediators were the first suggestions for observed resistance and poor clinical outcomes of targeted receptor tyrosine kinase inhibitors. Interestingly, for all aberrantly expressed mediators observed in microenvironment, downstream pathways converge in a common node, nothing but the nuclear factor-kappaB, the insidious factor proposed to be the cause of many events opposing achievement of a desired outcome. In first section of current review, we describe the signaling pathways underlying activation of receptor tyrosine kinases and their convergence at the nuclear factor-kappaB node, and in next section, we demonstrate how unique hypoxic, inflammatory, rich in free-radical microenvironment of triple-negative breast cancer exacerbate pathways in which otherwise could become mostly suppressed by receptor tyrosine kinase inhibitors. PMID- 28653903 TI - Biological function of long noncoding RNA snaR in HER2-positive breast cancer cells. AB - PURPOSE: Long noncoding RNA, snaR (small NF90-associated RNA), has been reported to be upregulated in various cancer cell lines. We evaluated the additional role of snaR in HER2-positive breast cancer cell lines. METHODS: We explored changes of expression of snaR among the selected long noncoding RNAs which have a potential in cancer proliferation or progression. The proliferation, migration, and invasion of HER2-positive breast cancer cells (SK-BR3) were evaluated by snaR with RNA interruption in 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, wound-healing assay, and Transwell assay. RESULTS: The expression of snaR was remarkably upregulated in SK-BR3 cell lines together with ANRIL, while the SFMBT2 was downregulated in SK-BR3 cell lines. Although Nespas, 7SK, PSF inhibiting RNA, mascRNA, Hoxa11as, NRON, AK023948, MER11C, p53 mRNA, CAR Intergenic 10, HUC 1 and 2, ZFAS1, SCA8, and SNHG5 were also upregulated and UCA1 was downregulated, the differences were not dominent. Based on the expression result, we explored the functional role of snaR in HER2-positive breast cancer. Downregulation of snaR with small interfering RNA was identified to significanlty inhibit migration as well as proliferation of SK-BR3 cells. CONCLUSION: In this study, snaR was identified as upregulated and to play a role in cancer progression of HER2-positive breast cancer cells. These results suggest snaR as a potential biomarker for HER2-positive breast cancer. PMID- 28653904 TI - Reply: Transforming Growth Factor beta1- and Bone Morphogenetic Protein 2/PPARgamma-regulated MicroRNAs in Pulmonary Arterial Hypertension. PMID- 28653905 TI - Structure and in situ organisation of the Pyrococcus furiosus archaellum machinery. AB - The archaellum is the macromolecular machinery that Archaea use for propulsion or surface adhesion, enabling them to proliferate and invade new territories. The molecular composition of the archaellum and of the motor that drives it appears to be entirely distinct from that of the functionally equivalent bacterial flagellum and flagellar motor. Yet, the structure of the archaellum machinery is scarcely known. Using combined modes of electron cryo-microscopy (cryoEM), we have solved the structure of the Pyrococcus furiosus archaellum filament at 4.2 A resolution and visualise the architecture and organisation of its motor complex in situ. This allows us to build a structural model combining the archaellum and its motor complex, paving the way to a molecular understanding of archaeal swimming motion. PMID- 28653906 TI - Organ sculpting by patterned extracellular matrix stiffness. AB - How organ-shaping mechanical imbalances are generated is a central question of morphogenesis, with existing paradigms focusing on asymmetric force generation within cells. We show here that organs can be sculpted instead by patterning anisotropic resistance within their extracellular matrix (ECM). Using direct biophysical measurements of elongating Drosophila egg chambers, we document robust mechanical anisotropy in the ECM-based basement membrane (BM) but not in the underlying epithelium. Atomic force microscopy (AFM) on wild-type BM in vivo reveals an anterior-posterior (A-P) symmetric stiffness gradient, which fails to develop in elongation-defective mutants. Genetic manipulation shows that the BM is instructive for tissue elongation and the determinant is relative rather than absolute stiffness, creating differential resistance to isotropic tissue expansion. The stiffness gradient requires morphogen-like signaling to regulate BM incorporation, as well as planar-polarized organization to homogenize it circumferentially. Our results demonstrate how fine mechanical patterning in the ECM can guide cells to shape an organ. PMID- 28653908 TI - Antibacterial, anti-inflammatory and anti-oxidatant activities of various isolated compounds from Cratoxylum species. AB - The objective of this study was to investigate the bioactivity of twenty-nine known isolated compounds from Cratoxylum species including three anthraquinones, four triterpenes, and twenty-two xanthones. All isolated compounds were subjected to antibacterial, anti-inflammatory and anti-oxidant activities. Cytotoxicity evaluations were performed by MTT assay. The anti-oxidatant activity was performed using DPPH assay. The anti-inflammatory activity was evaluated from the production of cytokines TNF-alpha and IL1-beta using ELISA assay. Human gingival fibroblasts and monocytes could tolerate both anthraquinones and triterpenes. All isolated anthraquinones showed moderate-to-high antibacterial efficacy while compound A3 also demonstrated moderate anti-inflammatory effect. None of the isolated triterpenes, except for T1, inhibited the expression of TNF-alpha. A number of isolated xanthones was toxic to HGFs and monocytes. Compound X5, X14 and a 1:1 mixture of X5 and X6 showed comparative anti-inflammatory activity to dexamethasone. Several triterpene and xanthone compounds also expressed antibacterial effect against P. gingivalis. Some isolated xanthones exerted anti oxidant activity comparable to ascorbic acid. Accordingly, selected pure compounds from plants of Cratoxylum genus might be of benefit in developing medications that are important in treating periodontal diseases. PMID- 28653909 TI - Synthetic N-[(substitutedsulfamoyl)phenyl]acetamides as moderate chymotrypsin inhibitors. AB - A facile method has been implemented for the synthesis of different N-substituted sulfamoylacetamides by reacting 4-acetamidobenzenesulfonyl chloride (1) with different alkyl/aralkyl/aryl amines (2a-q) in basic aqueous media under controlled pH to afford -[(Substitutedsulfamoyl) phenyl]acetamides (3a-q) which were confirmed through spectral analysis like FT-IR, EIMS and 1H-NMR. Moreover, the synthesized derivatives were screened against alpha-Chymotrypsin. The enzyme inhibitory results revealed that most of the synthesized compounds were found to be moderate enzyme inhibitors. PMID- 28653907 TI - Olfactory receptor neurons use gain control and complementary kinetics to encode intermittent odorant stimuli. AB - Insects find food and mates by navigating odorant plumes that can be highly intermittent, with intensities and durations that vary rapidly over orders of magnitude. Much is known about olfactory responses to pulses and steps, but it remains unclear how olfactory receptor neurons (ORNs) detect the intensity and timing of natural stimuli, where the absence of scale in the signal makes detection a formidable olfactory task. By stimulating Drosophila ORNs in vivo with naturalistic and Gaussian stimuli, we show that ORNs adapt to stimulus mean and variance, and that adaptation and saturation contribute to naturalistic sensing. Mean-dependent gain control followed the Weber-Fechner relation and occurred primarily at odor transduction, while variance-dependent gain control occurred at both transduction and spiking. Transduction and spike generation possessed complementary kinetic properties, that together preserved the timing of odorant encounters in ORN spiking, regardless of intensity. Such scale-invariance could be critical during odor plume navigation. PMID- 28653910 TI - Oral supplementation of Thuja oreintalis leaf extract moderately affects the behavior in albino mice in a gender specific manner. AB - Present study was designed to demonstrate the effect ethanolic leaf extract of Thuja orientalis on the learning and memory formation in albino mice. Four week old albino mice were either orally supplemented with 50mg/ml solvent/Kg body weight of Thuja orientalis or with equal volume of saline solution (0.9% NaCl) for seven days. A battery of neurological tests (Elevated plus maze, Rota Rod, light and dark box, open field and novel object recognition test) were applied at the end of dose supplementation. Thuja orientalis leaf extract treated female mice spent significantly les time on rotating rod (P = 0.02) than male treated with saline solution [indicating poor neuromuscular coordination]. While all other neurological test performances varied non significantly (P > 0.05) when compared between Thuja orientalis treated albino mice (of both genders) with their respective control groups indicating a moderate effect of 50mg/ml solvent/Kg body weight of Thuja orientalis on the behavior of young albino mice. PMID- 28653911 TI - Bacterial communities in soil samples from the Mingyong Glacier of southwestern China. AB - The present study was an effort to determine the bacterial diversity of soils in Mingyong Glacier located at the Meili Snow Mountains of southwestern China. Mingyong Glacier has different climatic zones within a very narrow area, and bacterial community diversity in this low temperature area remains largely unknown. In this study, soil samples were collected from four different climatic zones: M11A (dry warm valley), M14 (forest), M15 (grass land), and M16 (glacier zones). Phylogenetic analysis based on 16S rRNA gene V6 hypervariable region showed high bacterial abundance in the glacier. The number of Operational Taxonomic Units ranged from 2.24*103 to 5.56*103 in soil samples. Statistical analysis of 16S rRNA gene clone libraries results showed that bacterial diversity in zones M11A,M14 and M16 are higher than in zone M15. The bacterial community structures are clearly distinguishable, and phylogenetic analysis showed that the predominant phyla were Proteobacteria, Deinococcus-Thermus, Firmicutes, Actinobacteria, and Nitrospirae in Mingyong Glacier. Seventy-nine different orders from four zones have been isolated. Bacterial diversity and distribution of bacterial communities related to the anthropogenic perturbations in zone (M15) were confirmed by diversity index analysis, and the diversity index of other three zones was satisfactory through this analysis software. The results suggest that bacterial diversity and distribution analyses using bacterial 16S rRNA gene V6 hypervariable region were successful, and bacterial communities in this area not only had the same bacterial phyla compared to other glaciers but also had their own rare species. PMID- 28653912 TI - Antimicrobial, antioxidant potential and phytochemical screening of Fagonia olivieri. AB - The present paper investigates antioxidant, antimicrobial and photochemical screening different extracts of Fagonia olivieri. Analysis of the data indicated that the subject plant contained a good amount of flavonoids, tannins, saponins, terpenoids and steroids. Maximum concentrations of phenolic compounds was found in methanol fraction (29.0+/-6.12 mg GAE/g) while minimum (22.10+/-6.31mg GAE/g) in methylated spirit fraction. Similarly, ethanol fraction contained higher concentration of flavonoid content (135.4+/-7.63mg Quercetin/g) followed by methanol fraction (138.4+/-2.96 mg Quercetin/g). Analysis of the data revealed that maximum antioxidant activity was recorded in mthylated spirit fraction (IC50= 10.69+/-1.66) followed by methanol fraction (IC50= 9.10+/-0.76) while no activity was noted in hexane fraction. The data indicated good antibacterial and antifungal activity against S. typhi, S. aureus, P. aeruginosa and A. flavus. PMID- 28653913 TI - Evaluation of anti-oxidative, antimicrobial and anti-diabetic potential of Adiantum venustum and identification of its phytochemicals through GC-MS. AB - The present study aimed to explore antioxidant, antimicrobial and anti-diabetic properties of the fern Adiantum venustum. The TPC (total phenolic content) of methanolic extract of the plant was 247.95+/-0.0007MUg of Gallic acid equivalents per gram of dried extract (mg GAE/g). The highest TPC was in n-butanolic fraction, which was 981.45+/-0.1562mg GAE/g. Hexane fraction showed lowest TPC (256.95+/-0.0420mg GAE/g). Ethyl acetate fraction exhibited highest total flavonoid content (TFC), i.e., 62.0+/-0.050mg of Rutin equivalents per gram of sample. DPPH (1,1-diphenyl-2- picryl hydrazyl) radical scavenging activity of the plant was significant. n-Butanolic fraction was most potent with IC50 being 1.06mg/mL. The IC50 of methanolic extract was 1.50mg/mL, that of aqueous fraction was 2.51 mg/mL, and that of chloroform fraction was 2.65mg/mL. Antibacterial potential of the fern was tested against two Gram-positive bacterial strains, Pseudomonas aeruginosa and Escherichia coli and two Gram-negative bacterial strains, Bacillus subtilis and Staphylococcus aureus. n-Butanolic fraction showed highest zone of inhibition (ZOI, 25.13+/-1.237 mm) against P. aeruginosa. Ethyl acetate fraction was most active (ZOI, 15.75+/-1.060 mm) against S. aureus. Against E. coli, aqueous and n-butanolic fractions were most active (ZOI, 14.75+/ 0.353 and 14.50+/-0.707mm, respectively). Minimum inhibitory concentration (MIC) of methanolic extract against B. subtilis was as low as 1.98mg/mL. The hexane fraction was least toxic against all the fractions. The plant displayed significant alpha-amylase inhibitory activity. Chloroform fraction was most effective with lowest IC50 (1.10mg/mL) followed by ethyl acetate fraction (1.92mg/mL). A. venustum is rich in phenolics and has substantial antioxidant, antimicrobial and alpha-amylase inhibitory potential. PMID- 28653914 TI - Chemotherapy-related risk management toward safe administration of medications: Apply failure mode and effects analysis to reduce the incidence of chemotherapy errors. AB - Chemotherapy is considered a high-risk procedure where system failures are more likely to occur. Failure mode and effects analysis (FMEA) is a systematic, multidisciplinary team-based approach to error prevention. We described our experience of using FMEA as a prospective risk-management technique throughout the chemotherapy process. The occurrence, detectability and severity were assessed. Fifteen potential risk factors associated with 10 failure modes were identified. Improvement measures were proposed according to risk priority number. A computerized physician order entry (CPOE) and complete prescription audit system (CPAS) were introduced to reduce potential risks during chemotherapy. Introduction of this system was associated with a decrease from 2.60% to 0.60%. As a result, FMEA is a useful tool to evaluate potential risk in healthcare processes. PMID- 28653915 TI - Protective role of Sargassum species in liver and kidney dysfunctions and associated disorders in rats intoxicated with carbon tetrachloride and acetaminophen. AB - Hepatoprotective and reno-potective effect of Sargassum species was investigated in rats against carbon tetrachloride (CCl4) and acetaminophen (AAP) intoxication. The rats were given ethanol extracts of Sargassum ilicifolium, S. lanceolatum and S.swartzii orally at dose of 200mg/kg b.w. (body weight) daily for 14 days. These seaweed treated rats were then intoxicated with single intra-peritoneal dose of CCl4 or AAP on14th day. The administration of CCl4 and AAP caused significant (p<0.05) elevation in liver enzymes; alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and other biochemical parameters, bilirubin, glucose, triglyceride and kidney function markers: urea and creatinine. The pre-treatment with ethanol extracts of S. ilicifolium and S. swartzii protected the liver and kidney significantly (p<0.05) by lowering the elevated level of hepatic enzymes, liver and kidney function markers towards normal range. Sargassum species have also showed positive effect on serum glucose, total cholesterol and triglyceride. PMID- 28653916 TI - Biological activities of Allium sativum and Zingiber officinale extracts on clinically important bacterial pathogens, their phytochemical and FT-IR spectroscopic analysis. AB - The spread of bacterial infectious diseases is a major public threat. Herbs and spices have offered an excellent, important and useful source of antimicrobial agents against many pathological infections. In the current study, the antimicrobial potency of fresh, naturally and commercial dried Allium sativum and Zingiber officinale extracts had been investigated against seven local clinical bacterial isolates such as Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus epidermidis, and Serratia marcesnces by the agar disc diffusion method. All tested pathogens except P. aeruginosa and E. coli were most susceptible to ethanolic and methanolic extracts of A. sativum. Similarly, chloroform and diethyl ether extracts of Z. officinale showed a greater zone of inhibition of tested pathogens except for P. aeruginosa and E. coli. We found that all extracts of A. sativum and Z. officinale have a strong antibacterial effect compared to recommended standard antibiotics through activity index. All results were evaluated statistically and a significant difference was recorded at P< 0.05. Antioxidant activity of extracts showed that 10 out of 13 extracts have high scavenging potential. Thin layer chromatography profiling of all extracts of A. sativum and Z. officinale proposed the presence of various phytochemicals such as tannins, phenols, alkaloids, steroids and saponins. Retention factor of diverse phytochemicals provides a valuable clue regarding their polarity and the selection of solvents for separation of phytochemicals. Significant inhibition of S. aureus was also observed through TLC-Bioautography. FT-IR Spectrometry was also performed to characterize both natural and commercial extracts of A. sativum and Z. officinale to evaluate bioactive compounds. These findings provide new insights to use A. sativum and Z. officinale as potential plant sources for controlling pathogenic bacteria and potentially considered as cost-effective in the management of diseases and to the threat of drug resistance phenomenon. PMID- 28653917 TI - In vitro and in vivo antioxidant and antimicrobial activities of extracts from Platycarya strobilacea infructescence. AB - We determined the in vitro antioxidant and antimicrobial activities of Platycarya strobilacea infructescence (PSI) from various solvent extracts (methanol, ethyl acetate, water and tannin polymers) and quantified the content of total phenolic of each extract. The ethyl acetate extract was found to have the best radical scavenging activity and ferric reducing power, as well as antimicrobial activity. In order to investigate the protective effect on oxidative stress in vivo, each extract was administered to rats, and the serum, liver and heart were analyzed. The water extract and tannin polymers significantly decreased malonyldialdehyde (MDA) concentrations in serum, liver and heart compared to the control group (P<0.01). Furthermore, super oxide dismutase (SOD) and glutathione per oxidase (GSH-Px) activities were increased by administration of all extracts. We concluded that the ethyl acetate extract of PSI has strong antioxidant activity in vitro and possesses antimicrobial activity. These results indicated PSI the potential of medicinal uses and food preservation. PMID- 28653918 TI - Evaluation of anti-inflammatory and anti-oxidant potential of seed extracts of Vernonia anthelmintica. AB - Seeds of Vernonia anthelmintica in the form of Ethanol seed extract of Vernonia anthelmintica (EEVA), Hexane extract of Vernonia anthelmintica (HEVA) and water decoction of Vernonia anthelmintica (WDVA) were evaluated for their in-vivo anti Inflammatory potential in carrageenan induced rat paw model. The results were compared to anti-inflammatory activity of standard drug (ibuprofen) and untreated groups. In-vitro evaluation of antioxidant potential of EEVA and HEVA were also conducted by "DPPH scavenging assay". The results of present study depicts that HEVA and EEVA in higher dose possess a strong anti-inflammatory potential as compared to standard anti-inflammatory drugs, whereas WDVA showed milder anti inflammatory potential. DPPH assay has revealed strong anti-oxidant potential of EEVC with the percentage Radical Scavenging activity (%RSA) of 89.709 at concentrations of 500 ul as compared to standard drugs gallic acid (23.436+/ 0.43) and acetyl salicylic acid (111.44+/-0.7) at concentrations of 95.95 MUM. The other extract HEVC has shown to have insignificant %RSA at the concentration of 500MUl. Hence the present study revealed that selected extracts of Vernonia anthelmintica exhibited significant in-vitro antioxidant and in-vivo anti inflammatory potential. PMID- 28653919 TI - DPPH, ABTS free radical scavenging, antibacterial and phytochemical evaluation of crude methanolic extract and subsequent fractions of Chenopodium botrys aerial parts. AB - We investigated antioxidant, antibacterial potentials and secondary metabolites of Chenopodium botrys aerial parts to rationalize its effectiveness in free radicals induced disorders and infectious diseases. Antioxidant activity of plant extracts were investigated using DPPH and ABTS free radicals scavenging assays. Antibacterial potential was studied using well diffusion method. Phytochemical analysis was performed for the presence of secondary metabolites. In DPPH assay chloroform fraction (CHF), ethyl acetate fraction (EAF) and n-hexane fraction (NHF) were most active causing average inhibition of 65.9, 59.2 and 55.9% at concentration of 1mg/ml with IC50 values of 140, 30 and 590 MUgml respectively. EAF, CHF and aqueous fraction (AQF) revealed highest scavenging effect against ABTS free radicals causing 85.46, 82.73 and 68.80% inhibition with of IC50 of 75, 94 and 530 MUg/ml respectively. In antibacterial assay, CHF was found most effective against S. aureus presenting an inhibitory zone of 19 mm whereas; EAF, CHF and NHF were most active against K. pneumoneae with inhibitory zones of 27.1 mm, 25.4 and 18.7 mm respectively. C. botrys was tested positive for flavonoids, anthraquinones, saponins and tannins. Current findings revealed that that C. botrys is rich source of natural antioxidant and antibacterial bioactive compounds and may be further investigated. PMID- 28653920 TI - Antibacterial and antioxidant properties of various solvents extracts of Abutilon theophrasti Medic. leaves. AB - This paper described the extraction procedure of six extracts from Abutilon theophrasti Medic. leaves and evaluated antioxidant and antibacterial activity of different extracts by hydroxyl radical, DPPH radical scavenging, broth micro dilution and agar-well diffusion methods. The six extracts were prepared by the two extraction procedures: (I) water was the extraction solvent; (II) 90% alcohol extract was extracted by petroleum ether, chloroform, ethyl acetate and n-butanol in turn. Extract yields were 7.34%, 7.31%, 0.45%, 0.12%, 2.70% and 5.68% for extract I to VI. It was revealed that the various extracts had effective antibacterial activity against four test strains from Staphylococcus aureus (ATCC 25923), Streptococcus (ATCC 49619), Escherichia coli (ATCC 25922) and Salmonella (ATCC 01303); meanwhile, the six extracts demonstrated potent antioxidant activity, achieved by hydroxyl radical and DPPH radical scavenging assay. Minimum inhibitory concentrations (MICs) for the bacterial species ranged from 2.21 to 539.46 mg/ml, diameter of inhibition zone ranged from 2.08 to 15.05mm. The scavenging *OH and DPPH* rates were 62.37% to 81.86% with the concentration 0.06 to 1.89mg/ml and 37.80% to 81.23% with the concentration 1.07 to 35.52mg/ml. According to the results, these extracts have antioxidant and antibacterial activity. In view of all the facts collectively, the six extracts will become natural and nontoxic antioxidant and antibacterial agent, and be applied in food and pharmaceutical industries for the prevention or treatment caused by microorganisms and free radicals. PMID- 28653921 TI - Conservation of indigenous knowledge of medicinal plants of Western Himalayan region Rawalakot, Azad Kashmir, Pakistan. AB - The aim of present was to document indigenous knowledge of medicinal plants traditionally used by inhabitants of Rawalakot Azad Kashmir and to screen selected medicinal plants for their antibacterial potential. Several field surveys were conducted to document indigenous knowledge of medicinal plants through interviews from local inhabitants during 2010-2013. During the study, 58 plant species, belonging to 37 families, were identified and their medicinal uses were recorded. Ethnobotanical data indicates that inhabitants of Rawalakot use medicinal plant mainly for the treatment of stomach, liver and sexual disorders. Usually fresh plant materials were used for medicinal preparations and administrated orally. Among all the species studied, three most frequently used medicinal plants Achillea millefolium, Berberis lycium and Zanthoxylum armatum were screened for their antibacterial potential by using disc diffusion method. The crude aqueous, petroleum ether and ethanolic extracts were found to be very active against selected bacterial strains. The present study contributes significantly to the medicinal plant knowledge and shows that medicinal plant knowledge is deteriorating among younger generations. Therefore, further research is needed to document indigenous knowledge, to find conservation status of medicinal plant species and to find antimicrobial compounds for more sophisticated usage of medicinal plants in future. PMID- 28653922 TI - Complexation of ibuprofen with water soluble p-sulfonatocalix [4]arene: A potential candidate for drug delivery applicatio. AB - Complexation of ibuprofen with water soluble p-sulfonatocalix[4]arene (3) was evaluated. Both molecules exhibit a host and guest type complexation. pH, complex stoichiometry and binding constant were determined by UV-Vis and FT-IR spectroscopy. The maximum complexation of 3 with ibuprofen occurs at pH 2. Stability constant values (9.897) show that there is favorable complex formed due to vital role of p-sulfonatocalix[4]arene, while the thermodynamic parameters, i.e. deltaG, DeltaH and deltaS have been found as -24.09 KJ/mol, 0.012 KJ/mol and 0.12 KJ/mol. K, respectively. The results show that 3 has efficiency to carry the drug at particular conditions and can be used for drug delivery as a carrier. PMID- 28653923 TI - Kitchen phytochemicals from Allium cepa - their role in multidrug resistance. AB - Bacterial resistance to antibiotics is increasingly becoming a concern to public health. Current antibiotics have failed to bring desirable results to many bacterial infections due to multi-resistant strains. So, concerted efforts are being made to curve this with the help of dietary phytohemicals. A number of dietary phytochemical are being put to trials for antimicrobial activity; however it is worthwhile to search such a part of diet that is very frequently used by major population. Keeping this view in mind an effort has been made to evaluate the antimicrobial activity of most common vegetable component Allium cepa. Methanolic and aqueous extracts were prepared from Allium cepa and antibacterial activity was tested on four pathogenic bacteria (Gram-positive and Gram negative) Staphylococcus aureus, Bacillus Subtilis, Escherichia coli and Pseudomonas aeruginosa using Disc diffusion method and Minimum inhibitory concentration by the Microtitre well plate method. Conventional antibiotic discs of Tetracycline and Gentamycin were used as positive control. Among the two extracts, methanolic extract exhibited a significant antimicrobial activity on the test organisms Ps. aeruginosa (17.5mm) and B. subtilis (11.3mm). The minimum inhibitory concentration value for Ps. aeruginosa was 500MUl and for B. subtilis was 250MUl for methanolic extract. The growth of other two bacteria i.e. E. coli and S. aureus were not inhibited by methanolic as well as aqueous extract that indicates non susceptibility to aqueous and methanol extract of Allium cepa. From the study, it was concluded that the commonly used Allium cepa possess potent antibacterial property against Bacillus Subtilis and Pseudomonas aeruginosa. PMID- 28653924 TI - Screening of leaves extracts from Calamus aromaticus for their antimicrobial activity by disc diffusion assay. AB - The current research investigates the anti-microbial activities of different solvent extracted samples from the leaves of Calamus aromaticus against Gram positive, Gram negative bacteria and fungi using 500, 1000 and 2000 MUg disc-1 concentrations. Escherichia coli, Citorbacter freundii and Candida albicans showed resistivity to crude methanolic extract and the same microbes were more susceptible to water extracted fractions. Maximum activity was measured by hexane extracted fractions against Pseudomonas aeruginosa, Bacillus subtilis and Xanthomonas campestris and minimum growth inhibition by water extracted fractions. Maximum growth of Klebsiella pneumoniae and Staphylococcus aureus was measured by ethyl acetate fraction. Majority of the tested microbes were resistant to water and butanol extracted fractions. Staphylococcus aureus revealed maximum susceptibility among gram positive bacteria and Bacillus subtilis showed minimum. Among Gram negative bacteria, Citorbacter freundii was more susceptibile while Xanthomonas campestris revealed resistively. PMID- 28653925 TI - NSAIDs ameliorate cognitive and motor impairment in a model of parkinsonism induced by chlorpromazine. AB - Parkinson's disease (PD) is a long-lasting neurodegenerative brain disease. It is characterized by a gradual decline in motor and non motor symptoms especially postural instability, tremors and memory impairment with localized loss of neurons mainly in the Substantia nigra. In the current research we evaluated the effects of Non-steroidal anti inflammatory drugs (NSAIDs) on motor coordination and memory in chlorpromazine (CPZ) induced Parkinson's experimental model. Intraperitoneal (i.p.) injection of CPZ (3 mg/kg) was given to all rats for 21 days to induce Parkinson like symptoms; ibuprofen (40mg/kg/day) and celecoxib (20mg/kg) were administered 30 minutes after CPZ injection. Behavioral parameters like Catalepsy, muscle strength (wire hanging test), locomotor activity (open field test) were observed. Moreover, its effect on memory was explored by the use of water maze and passive avoidance test. Our results showed CPZ significantly induced motor fluctuation and cognitive impairment in a period of 21 days. Celecoxib and ibuprofen significantly improved cataleptic scores (P<0.01), locomotion and muscular coordination in open field (P<0.01) and in wire hanging test (P<0.01). Significant improvement in memory was observed with celecoxib (P<0.01) and ibuprofen (P<0.05) in water maze test as well as in passive avoidance test. Therefore, the present study showed neuroprotective and memory enhancing effect of ibuprofen and celecoxib against CPZ induced Parkinson's model. PMID- 28653926 TI - Comparison of the curdione in brain of blood stasis pregnant rats and its offsprings with the normal group rats by UPLC-Q-TOF-MS. AB - Curdione is a main active component of curcuma rhizomes (Ezhu), which shows an excellent antithrombotic activity. In this study, the concentration of Curdione in pregnant rats and their offspring brain was determined using ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry (UPLC-Q-TOF-MS) method. The water extraction then alcohol precipitation extract from Ezhu was administered through tail intravenous injection. The pharmacokinetic parameters were analyzed to compare the differences between the blood stasis group rats and normal group rats. Using Schisandrol A as an internal standard, samples were extracted using dichloromethane and isopropanol (90:10, v/v). Calibration plot was linear over the range of 0.5-200MUg*mL.-1. for Curdione in brain with the lower quantification limit being 0.5MUg*mL-1. The recoveries of Curdione and IS from brain were more than 93.31% and 90.90% separately. The RSD for both intra- and inter-day precision were <6.49%, RE were -14.84%~-2.8%. The pharmacokinetic parameters Cmax and AUC among the four kinds of rats had significant difference. The Curdione distributed in rat brain in model group is less than normal group. Ezhu medicine may show the therapeutic effect but not the reproductive toxicity on mother or unborn baby to cure the pregnant women under the adaptive symptoms. PMID- 28653927 TI - Detection of interleukins-6 and 8 in saliva as potential biomarkers of oral pre malignant lesion and oral carcinoma: A breakthrough in salivary diagnostics in Pakistan. AB - Oral cancer is at rise in our population due to increasing use of areca nut (Betel nut) with or without tobacco. It is the second frequent malignant tumour for both the gender in Pakistan. This non-interventional case control study was carried out with the aim to explore saliva as diagnostic medium for detecting interleukins (IL) 6 and 8 as biomarkers of pre-malignant lesions (PML) and oral carcinoma. Total 105 subjects were recruited and were divided into three groups "A", "B" and "C" each comprising of 35 subjects. Group "A" comprised of cases with strong clinical evidence of oral PML. Group "B" constitute clinical and histologically proven OSCC and group "C" include disease free subjects as controls. Saliva from all the recruited subjects was procured by drooling method and stored at-200C before further process. All the collected samples were centrifuged at 4500 rpm for 15 minutes at 4oC. Supernatant fluid was used in ELISA for detection and quantification of IL-6 & IL-8. Data was analysed by using Chi-square test and multivariate analysis was done by non-parametric test. P value of 0.05 was taken as standard reference. Significant co-relation was found for qualitative salivary detection of IL-6 and IL-8 among the groups (P<0.001 and <0.0001 respectively). Regarding quantitative salivary concentration of leukotrienes, no significant co-relation was found in levels of IL-6 among the groups while there was significant association of IL-8 levels between the groups (P<0.0001).On post Hoc multiple comparison, significant co-relation was found among oral PML group and controls (P=0.001) and OSCC group and control (P=<0.0001). In conclusion salivary detection of IL-6 & IL-8 could be used as probable biomarker for early detection of oral PML & OSCC in etiologically distinct population of Pakistan. PMID- 28653928 TI - Synthesis, characterization and enzyme inhibitory activity of new pyrazinamide iron complexes. AB - The present paper deals with synthesis, characterization and amylase inhibitory activity of pyrazinamide (PYZ) with iron in its both (II) and (III) oxidation states. The synthesized complexes were characterized on the basis of IR, UV, 1H NMR, 13C-NMR, elemental analysis and SEM. Changes in IR data shows that PYZ form complex with octahedral geometry and binding sites are ring nitrogen and carbonyl group, wherein two sides are satisfied with two chloride ions. SEM images indicate the crystalline state and surface morphology of PYZ and its complexes. Elemental analysis proves the composition of complexes. Pyrazinamide and the complexes showed no significant effect on amylase activity but the activity was inhibited in the presence of ferrous chloride. PMID- 28653929 TI - Evaluation of ED50 and 5alpha-reductase inhibitor activities of some thiopyrimidine, pyrane, pyrazoline, and thiazolopyrimidine derivatives. AB - In this work, twenty-one thiopyrimidine (1-21) candidates containing a pyrane, pyrazoline and thiazolopyrimidine ring screened for their ED50 and 5alpha reductase inhibitors comparable to that of Anastrozole as positive drug. Some of the tested product showed moderate 5alpha-reductase inhibitors with lower toxicity. The detailed ED50 and 5alpha-reductase inhibitor activities of the synthesized compounds were studied. PMID- 28653930 TI - Identification and growth optimization of a Marine Bacillus DK1-SA11 having potential of producing broad spectrum antimicrobial compounds. AB - Control of harmful bacteria in food, aquaculture, pharmaceuticals, agriculture, hospitals and recreation water pools are of great global concern. Marine bacteria are an enormous source of bio-controlling agents. The aim of this study was to identify and optimize the growth conditions including effect of different biotic and abiotic factors on antimicrobial activity of strain DK1-SA11 isolated from Qingdao Bay of China Yellow Sea. Microscopic characterization, API(r) 20E and 50 CHB kit base carbohydrates utilization, 16S rDNA and DNA gyrB gene sequencing studies identified the bacterium as Bacillus subtilis subsp. spizizenii DK1-SA11. Antimicrobial spectrum of cell free supernatant (CFS) has shown antimicrobial activities against all test strains including methicillin-resistant Staphylococcus aureus, E. coli O157:H7, Candida albicans, Klebsiella pneumoniae, Listeria monocytogenes, Vibrio parahaemolyticus, E. coli, Pseudomonas fluorescens, Salmonella typhimurium and Vibrio cholerae. Among all the media tested, Marine Broth 2216 was found to be the best medium for bacterial growth and production of antibacterial compounds. The other optimum conditions for growth were pH:7 and incubation temperature: 25 degrees C with < 180 rpm for 60 72 h. Out of 49 different carbohydrates tested, D-mannose increases the antibacterial activity by 33.3% while D-arabitol decreases it by 44.4%. Crude CFS showed activity even after three months of storage below -20 degrees C and boiling for 10 min, whereas it loses 100% of its antimicrobial activity after enzymatic treatments of lipase, trypsin and papain. The production of antimicrobial compounds and broad spectrum of antimicrobial activity against all tested pathogens suggested that the strain DK1-SA11 can be used as a source for probiotics, synbiotics and antibiotics. PMID- 28653931 TI - Impact of different organic acids on solubility enhancement of cefpodxime proxetil immediate release tablet and its stability studies. AB - Cefpodoxime proxetil is a third generation cephalosporin antibiotic demonstrates pH dependent solubility and is highly soluble only in acidic pH. The purpose of this investigation was to design and develop immediate release tablets of cefpodoxime proxetil by direct compression method and determine the effect of different solid buffers (organic acids) such as fumaric acid (formulations F1 F4), maleic acid (formulations M1-M4) and citric acid (formulations C1-C4) by using cefpodoxime and acid in the ratios of 4:1, 2:1, 1:1 and 1:2 to achieve pH independent release of the drug. Physical parameters and assay were found to be within the acceptable range as prescribed in USP 36 / NF 31. In vitro dissolution studies of each formulation were performed in distilled water, USP dissolution medium, HCl buffer solution of pH 1.2, phosphate buffer solutions of pH 4.5 and 6.8 to observe the drug release. The formulations F3, F4, M4 were selected for film coating on the basis of better drug release profile, to protect the drug from chemical degradation through hydrolysis. Film coated formulation F3, F4 and M4 showed a remarkable in vitro release of the drug (72.88+/-0.43 to 92.67+/ 0.71%) within 30min of observation in all dissolution media and further evaluated by model independent and model dependent approaches. The drug release was found to be best fit to Weibull model as highest r2adjusted (0.924-0.998) and lowest AIC (18.416-54.710) values were obtained in all dissolution media. R Gui(r) applied for stability studies of F3 and F4 formulations, showing shelf lives of 28 & 27months at ambient and 33 months at accelerated temperatures. Formulation F4 was chosen as best formulation on the basis of physical properties, highest dissolution rate and stability studies. PMID- 28653932 TI - Influence of water-soluble channeling agents on the release of diclofenac sodium from Irvingia malayana wax matrix tablets. AB - Irvingia malayana wax (IW) is majorly composed of esters of medium chain fatty acids. Its melting point is low and closed to the body temperature. This study aimed at investigating the potential of IW as a matrix-forming agent and evaluate the effect of soluble channeling agents on the release of diclofenac sodium (DS) from IW matrix tablets. The preformulation study by infrared spectroscopy and differential scanning calorimetry showed no incompatibility between IW and DS or soluble channeling agents, namely PEG 4000, PEG 6000 and lactose. IW retarded the release of DS from the matrix tablets more efficiently than carnauba wax due to its greater hydrophobicity and its ability to become partial molten wax at 37 degrees C. Factors affecting the release of DS from IW matrix were drug concentrations, and types and concentrations of channeling agents. The release of DS significantly improved when DS concentration reached approximately 33%. The fast dissolving channeling agent, lactose, could enhance the drug release rate more effectively than PEG 4000 and PEG 6000, respectively. The linear relationship between the DS release rate and the concentration of the chosen channeling agent, PEG 6000, was found (r2=0.9866). PMID- 28653933 TI - Comparative studies on rabbit plasma lipid profile fed with Silybum marianum oil, sunflower oil and vegetable ghee. AB - Present work is aimed to compare the physicochemical characterization and biochemical effects of oil extracted from Silybum Marianum and Sunflower oil, collected from Peshawar (Pakistan). To investigate the comparative effects on the body weight, organ weight and lipid profile, the crude oil of Silybum marianum, edible sunflower oil and vegetable ghee were given to three groups of rabbits under study. Percent proximate composition and food consumption of all rabbits were determined which showed no significant statistical variation. There is no data available about Silybum marianum oil on animal model in literature. This study clearly revealed that oil from Silybum marianum significantly reduces plasma cholesterol level in rabbits. A threefold higher Triglyceride levels was observed in vegetable ghee feeding groups compared with the sunflower and Silybum marianum oil feeding groups. The crude oil of Silybum marianum was found to be safe in rabbits compared with sunflower oil and vegetable ghee. The results of these studies revealed most valuable information and also support the refining and purification to convert this non-edible oil to edible oil. PMID- 28653934 TI - Evaluation of nephroprotective activity of Musa paradisiaca L. in gentamicin induced nephrotoxicity. AB - The objective of the study was to investigate the nephroprotective activity of methanolic extract of different morphological parts (bract, flower, trachea and tracheal fluid) of Musa paradisiaca L. (Family: Musaceae) against gentamicin induced nephrotoxicity in mice. Gentamicin produced significant changes in biochemical (increased levels of blood urea nitrogen level, blood urea, and serum creatinine), and histological parameters in mice. Treatment with methanolic extract of bract (100 and 250mg/kg, b.w) and flowering stalk (trachea) (250 and 500mg/kg, b.w) significantly prevented biochemical and histological changes produced by gentamicin toxicity. The extracts of M. paradisiaca (bract and flowering stalk) could contribute a lead to discovery of a new drug for the treatment of drug-induced nephrotoxicity. PMID- 28653935 TI - Impact of bovine and human serum albumin on Curcumin in vitro activity against Staphylococcus aureus. AB - This study evaluated the impact of pH (7.4 and 6.5), bovine serum albumin (BSA), and human serum albumin (HSA) on Curcumin activity against 2 reference, 1 clinical, and 10 environmental strains of Staphylococcus aureus (S. aureus). Minimal inhibitory concentrations (MICs) of Curcumin against S. aureus were statistically indifferent (p>0.05) at pH7.4 and pH6.5. Activity of Curcumin against S. aureus was reduced by two folds in the presence of 1.25-5% BSA/HSA. PMID- 28653936 TI - Repeated treatment with reserpine as a progressive animal model of depression. AB - Treatment-resistant depression is a major health problem worldwide. Restricted validity of the existing animal models of depression along with the need for the study of progressive development of resistance to antidepressants, demands the modeling of a progressive animal model of depression. Present study was designed to test the hypothesis that the repeated administration of reserpine could serve as a progressive animal model of depression. Animals were injected with reserpine (1.0mg/kg; once a day) for three weeks. Results from the present study showed impaired locomotive effects of reserpine in Skinner's box following second as well as third week. These hypolocomotive effects were more pronounced after third week than the second week. Reserpine-induced behavioral depression was evident in the animals after 2 weeks, as assessed by using forced swim test. Depletion of 5 HT, dopamine and metabolites was also observed in the brain samples. Results from the present study suggest that repeated administration of reserpine could be serve as a progressive model of depression and could be used as a convenient and economic animal model for the face validity of anxiolytic compounds. Findings have potential implications with reference to the understanding and the management of treatment-resistant depression. PMID- 28653937 TI - Report - Analysis of designer drugs in human blood using gas chromatography-mass spectrometry. AB - A robust gas chromatography-mass spectrometry method was utilized in the qualitative and quantitative analysis of designer drugs in human blood. Designer drugs, including methcathinone, 3, 4-methylenedioxymethcathinone, 4'-methyl-alpha pyrrolidinopropiophenone and methylenedioxy-pyrovalerone were simultaneously analyzed by gas chromatography-mass spectrometry. Liquid-liquid small volume extraction was employed in the pretreatment of human blood sample, and the experimental results showed that the method was validated with high extraction efficiency, low limits of detection and good linearity throughout the studied concentration ranges. Furthermore, the method not only exhibited good accuracy and precision in the determination of designer drugs in human blood, but also showed the potential of the approach in the determination of trace evidence in forensic science. PMID- 28653938 TI - Report - Screening of the Anti-hyperglycemic activity of some medicinal plants of Jordan. AB - Diabetes represents a group of common diseases that are characterized by dysregulation of blood glucose levels. Plants are traditionally used for management of diseases including diabetes. In this study, we screened the anti diabetic effect of extracts of 21 plants grown in Jordan. Extracts of plants were screened for their antihyperglycemic activity. Diabetes was induced in Sprague Dawley rats using Alloxan. Plant extracts were dosed at 1gm/kg. Blood glucose was measured at baseline and at every hour for 3 hours. Results showed that five plants out of the 21 screened showed antihyperglycemic activity. These plants are Phoenix dactylifera L., Tecoma stans (L.) Kunth, Cichorium pumilum Jacq., Phaseolus vulgaris L., and Teucrium polium L. On the other hand, Sarcopoterium spinosum (L.) Spach. and Brassica oleracea L. var. capitata significantly increased blood glucose levels in diabetic rats. The following plant extracts showed neutral effect on blood glucose levels: Plantago major L., Taraxacum cyprium H. Lindb, Artemisia inculta Delile, Marrubium vulgare L., Inula viscosa (L.) Ai, Rubus sanguineus Friv, Coriandrum sativum L., Cucurbita pepo var ovefera, Cucumis sativus L., Hordeum vulgare L., Apium graveolens L., Avena sativa L., Helianthus annus L., and Anethum graveolens L. In conclusion, Jordanian medicinal plants might be useful for managements of blood glucose levels in patients with diabetes. PMID- 28653939 TI - Report - Cerebral electrical impedance value reflects brain edema caused by cardiopulmonary bypass in infants. AB - The study aimed to investigate if the dynamic changes in cerebral electrical impedance (CEI) values could be used to monitor brain edema during cardiopulmonary bypass (CPB) in infants. Forty infants (mean age: 1.4+/-0.38y) with acyanotic congenital heart disease who underwent CPB open-heart surgery between September 2009 and March 2010 were prospectively enrolled, and divided into 2 groups based on aortic cross-clamping (ACC) time: CPB-A (ACC<50 min) and CPB-B (ACC<50 min). During the same period, twenty infants (aged 1-3y) who underwent surgery for indirect inguinal hernias were selected as controls. Serum astrocyte S100 protein (S100) and neuron-specific enolase (NSE) levels were determined before and after CPB. Changes in CEI were detected using the BORN-BE system. No intraoperative death occurred. Compared with controls, left and right side CEI values, serum S100 and NSE levels in the CPB groups significantly increased from surgery beginning to end (P<0.05). After surgery, these levels decreased (P<0.05). Detection rates of cerebral edema in the CPB-B group 24h post operative were significantly higher than in the CPB-A group (P<0.05). CEI value can be used to dynamically monitor brain edema in infants undergoing CPB, and is an index reflecting brain damage during CPB in infants. PMID- 28653940 TI - Review - Medication errors and strategies for their prevention. AB - Medication errors occur every day causing injury to the patients and even deaths. The health care professionals are not fully aware of the damages done by medication errors in terms of patients' discomfort and economic burden. There is a need to provide information about medication errors to health care providers. This article reviews research done on the various aspects of medication errors. The research work done on prescribing errors, transcribing errors, dispensing errors, administration errors and discharged summaries errors have been examined. Eight strategies to reduce the occurrence of medication errors have been reviewed: (1) Electronic prescribing and computerized physician order entry (CPOE) with clinical decision support systems (CDSSs), (2) Bar Code, (3) Interventions to reduce medication errors, (4) Medication Error Reporting Systems (MERSs), (5) Alerts about medication errors, (6) Prevention of harm from high alert drugs, (7) Smart Infusion Pumps and (8) Telemedicine or Telehealth or Telepharmacy. Statistical tests used in medication error studies have also been stated. PMID- 28653941 TI - Transient thyrotoxicosis during nivolumab treatment. AB - Two patients presented with transient thyrotoxicosis within 2-4 weeks after starting treatment with nivolumab. This thyrotoxicosis turned into hypothyroidism within 6-8 weeks. Temporary treatment with a beta blocker may be sufficient. PMID- 28653942 TI - Torsade de pointes in a patient with severe hypercalcaemia and multiple myeloma. AB - We report a case of a 48-year-old female patient with newly diagnosed multiple myeloma. She developed recurrent torsade de pointes and required cardiopulmonary resuscitation and defibrillation. Atrial arrhythmias in patients with multiple myeloma and hypercalcaemia have been described, but, to the best of our knowledge, this is the first report of torsade de pointes in this setting. PMID- 28653943 TI - A patient with a 'typical presentation' of Wernicke encephalopathy was found to have sporadic Creutzfeldt-Jakob disease. AB - Creutzfeldt-Jakob disease (CJD) has a significant degree of clinical heterogeneity that is especially found in the features at onset. Here we present a patient with the sporadic form of CJD mimicking Wernicke encephalopathy. We first treated him with a high dose of thiamine; however, the vitamin B1 levels proved to be normal, which ruled out Wernicke encephalopathy. Meanwhile, his clinical condition progressively worsened and he developed a rapidly progressive cognitive disorder, mutism and myoclonus of the muscles. At this point, the diagnosis of CJD was most likely. The patient died two months after the first symptoms. Autopsy showed prion-protein depositions in several regions. Genetic analysis was negative for familial CJD. Those findings confirmed the diagnosis of 'sporadic Creutzfeldt-Jakob disease'. CJD presents in a wide range of sequences and clinical symptoms. Therefore, recognition in the early stage can be difficult. PMID- 28653944 TI - Association between serum 25(OH) vitamin D and metabolic disturbances in polycystic ovary syndrome. AB - BACKGROUND: To assess the relationship between serum 25(OH) vitamin D levels and metabolic parameters together with androgenic hormone levels in women with polycystic ovary syndrome (PCOS). METHODS: This is a single-centre study from the Endocrinology Institute at Firouzgar Hospital in Iran. Seventy-three women aged 15-45 years were recruited from May 2013 to December 2013. Serum 25(OH) vitamin D level, other laboratory biomarkers and anthropometric indexes were measured. Data were analysed with statistical software SPSS version 16.0 for windows and we used specific analytical tests to assess data. RESULTS: Serum 25(OH) vitamin D levels were < 20 ng/ml in 64 patients (79%). Nine patients (12.3%) were diagnosed with metabolic syndrome. A significant difference was found between the women with and without severe vitamin D deficiency with regard to waist circumference, fasting insulin level and HOMA-IR, and abnormal systolic and diastolic blood pressures. The serum 25(OH) vitamin D levels had a reverse but weak correlation with systolic and diastolic blood pressures. CONCLUSION: This study showed an association between serum 25(OH) vitamin D levels and some metabolic parameters; however, there was no significant linear correlation between serum 25(OH) vitamin D levels and metabolic variables, except for systolic and diastolic blood pressure. PMID- 28653947 TI - Vitamin D, many associations but few that seem to matter. PMID- 28653945 TI - Microbiological outcomes and antibiotic overuse in Emergency Department patients with suspected sepsis. AB - OBJECTIVE: To study the presence of bacterial disease and antibiotic use in patients in the emergency department (ED) included in the local sepsis protocol. METHODS: An observational retrospective cohort study. Adults aged > 18 years, presenting to the ED of a large teaching hospital, from 1 January to 1 June 2011, with more than two SIRS criteria and a clinical suspicion of sepsis were included. RESULTS: Bacterial disease was suspected or confirmed in only 71% of all the patients with suspected sepsis (2008 definition) and consequently treated with antibiotics. Most of these patients (58%) suffered from systemic inflammatory response syndrome (SIRS) without signs of organ dysfunction, hypotension or hypoperfusion. Despite absence of bacterial disease in 29% of the patients after rigorous diagnostics, median antibiotic treatment in this group was still seven days (IQR 4-10). CONCLUSIONS: Standard sepsis detection using SIRS criteria and clinical suspicion identified patients with suspected or confirmed bacterial disease in 71% of the cases. A significant proportion of patients were exposed to prolonged antibiotic use without proof of bacterial disease. This study illustrates the difficulties in correctly identifying bacterial disease and sepsis, and shows that overuse of antibiotics may be the consequence. PMID- 28653946 TI - The truth on current peritoneal dialysis: state of the art. AB - The share of peritoneal dialysis (PD) in the spectrum of chronic dialysis has decreased markedly in the Netherlands in the last 15 years. Consequently, the knowledge of nephrologists and nursing staff on PD has declined leading to a negative spiral in which loss of experience resulted in loss of enthusiasm to offer PD to patients and also in less interest in the new PD developments. All these changes took place while the results of PD improved and patient survival was at least similar to that on haemodialysis. The aim of this review is first to give a summary of the principles and practice of patient and staff education and to describe the role of the medical contribution in decision-making. On this basis, the second aim is to update internist-nephrologists on a number of issues that have been underexposed in the past. Recent patient and technique survival data of PD patients is reviewed, and also the new insights into dialysis adequacy. The presence of residual renal function is the main determinant of patient survival together with prevention of overhydration. Urea and creatinine removal are not important at all when patients are still passing urine. Many early problems with PD are due to the peritoneal catheter and suggestions are made for improvement of its function. The prevention and management of infections is reviewed, and also the regular assessment of peritoneal function. Free water transport is a predictor of encapsulating peritoneal sclerosis (EPS), which should be assessed regularly. The pathogenesis of EPS, treatment and the decreasing incidence are discussed. PMID- 28653948 TI - An unexpected cause of nausea and vomiting in a patient with metastasised lung cancer. PMID- 28653949 TI - Answer to Photo Quiz: An unexpected cause of nausea and vomiting in a patient with metastasised lung cancer. PMID- 28653950 TI - A gap in memory tape. PMID- 28653951 TI - Answer to Photo Quiz: A gap in memory tape. PMID- 28653952 TI - What can smudge the 'tough body' corpus callosum? PMID- 28653953 TI - Answer to Photo Quiz: What can smudge the 'tough body' corpus callosum? PMID- 28653955 TI - Answer to Photo Quiz: A pulmonary masquerade.... PMID- 28653954 TI - A pulmonary masquerade.... PMID- 28653958 TI - Excitation spectra of liquid iron up to superhigh temperatures. AB - Investigation of excitation spectra of liquids is one of the hot test topics nowadays. In particular, recent experimental works showed that liquid metals can demonstrate transverse excitations and positive sound dispersion. However, the theoretical description of these experimental observations is still missing. Here we report a molecular dynamics study of excitation spectra of liquid iron. We compare the results with available experimental data to justify the method. After that we perform calculations for high temperatures to find the location of the Frenkel line introduced in our previous works. PMID- 28653959 TI - Mechanical-optical-electro modulation by stretching a polymer-metal nanocomposite. AB - We report the simultaneous investigation of both the plasmonic resonance and electrical conductance evolution in stretchable metal-polymer nanocomposite films. The films are produced by the implantation of neutral gold nanoparticles in a polydimethylsiloxane substrate by aerodynamic acceleration in a supersonic expansion. A redshift of the gold nanoparticle plasmon peak is found upon stretching as well as a strong correlation between the plasmonic peak wavelength and the nanocomposite electrical resistance. Optical simulations attribute the optical response to the compression of the polymer perpendicular to the stretching direction, which brings the gold particles closer to each other, increasing the plasmonic coupling. Mechanical stretching can induce a simultaneous modulation of the optical and electrical properties of the nanocomposite. PMID- 28653960 TI - Effect of doping on lattice dynamics and electron-phonon coupling of the actinides Ac-Th alloy. AB - We have studied the electronic, lattice dynamical, and electron-phonon properties of the actinides [Formula: see text]Th x alloy within the framework of density functional perturbation theory. The self-consistent virtual crystal approximation is used for the alloy modeling, and spin-orbit coupling is included in the calculation of all relevant quantities. An overall decrease of the electron phonon coupling (lambda) by [Formula: see text] from Ac to Th was observed. However, its dependence on x shows a non-linear behavior. lambda reduces just 6% from Ac to a Th content of [Formula: see text], then drops drastically (~[Formula: see text]) from there until [Formula: see text]. The large decrease of lambda for [Formula: see text] is due to the reduction of the density of states at the Fermi level ([Formula: see text]), combined with a general phonon hardening. On contrast, the behavior for [Formula: see text] is the result of a subtle balance between an enhancement of phase space and the above mentioned effects on [Formula: see text] and the phonons. The phase-space enhancement is related to the appearance of Kohn anomalies, which fade away as the Th concentration increases. PMID- 28653961 TI - Subtleties of catanionic surfactant reverse micelle assemblies revealed by a fluorescent molecular probe. AB - In this work, the absorption and emission behavior of the cationic hemicyanine trans-4-[4-(dimethylamino)styryl]-N-methylpyridinium iodide (HC) in reverse micelles (RMs) formed by the catanionic surfactants benzyl-n hexadecyldimethylammonium-1,4-bis-2-ethylhexylsulfosuccinate (AOT-BHD) and cetyltrimethylammonium-1,4-bis-2-ethylhexylsulfosuccinate (AOT-CTA) have been investigated. Our results show that the spectroscopic behavior of HC changes when the dye is dissolved in AOT-BHD or in AOT-CTA RMs. While HC undergoes an intramolecular charge-transfer process upon excitation in AOT-CTA RMs, in AOT-BHD RMs this process is inhibited due to a specific interaction between HC and the polar head group of the BHD+ cation. This implies that the chemical structure of CTA+ and BHD+ cations has a large impact on the excited stated from which HC emission occurs. Additionally, the structural difference between the two cations impacts on the water-RM interface interaction, which provides a way of controlling the solvation process in these RMs. Furthermore, differences in the interfacial fluidity between the two catanionic RMs is observed, a result that is particularly interesting with regard to these systems being used as nanoreactors. PMID- 28653962 TI - A proposed simulation method for directed self-assembly of nanographene. AB - A methodology for predictive kinetic self-assembly modeling of bottom-up chemical synthesis of nanographene is proposed. The method maintains physical transparency in using a novel array format to efficiently store molecule information and by using array operations to determine reaction possibilities. Within a minimal model approach, the parameter space for the bond activation energies (i.e. molecule functionalization) at fixed reaction temperature and initial molecule concentrations is explored. Directed self-assembly of nanographene from functionalized tetrabenzanthracene and benzene is studied with regions in the activation energy phase-space showing length-to-width ratio tunability. The degree of defects and reaction reproducibility in the simulations is also determined, with the rate of functionalized benzene addition providing additional control of the dimension and quality of the nanographene. Comparison of the reaction energetics to available density functional theory data suggests the synthesis may be experimentally tenable using aryl-halide cross-coupling and noble metal surface-assisted catalysis. With full access to the intermediate reaction network and with dynamic coupling to density functional theory-informed tight-binding simulation, the method is proposed as a computationally efficient means towards detailed simulation-driven design of new nanographene systems. PMID- 28653963 TI - Does Acupressure Hit the Mark? A Three-Arm Randomized Placebo-Controlled Trial of Acupressure for Pain and Anxiety Relief in Athletes With Acute Musculoskeletal Sports Injuries. AB - OBJECTIVES: Injuries are a common consequence of sports and recreational activity. The optimal management of symptoms is a crucial element of sports injury management. Acupressure has previously been shown to effectively decrease symptoms of musculoskeletal injury, thus may be considered a potentially useful intervention in the management of sport-related injuries. Therefore, this study was conducted to examine the effectiveness of acupressure in decreasing pain and anxiety in acutely injured athletes. DESIGN: A prospective 3-arm randomized placebo-controlled trial. SETTING: A sports injury clinic, Dunedin, New Zealand. PATIENTS: Seventy-nine athletes who sustained a sport-related musculoskeletal injury on the day. INTERVENTION: Three minutes of either acupressure, sham acupressure, or no acupressure. MAIN OUTCOME MEASURES: The primary outcomes of pain and anxiety intensity were measured before and immediately after the intervention on a 100-mm visual analog scale (VAS). Pain and anxiety relief, satisfaction with treatment, willingness to repeat a similar treatment, and belief in the effect of acupressure were secondary outcomes measured on Likert scales after the intervention. RESULTS: The acupressure group reported 11 mm less pain (95% CI: 5-17) on average than the sham acupressure group, and 9 mm less (95% CI: 3-16) than the control group as a result of the intervention (P < 0.05). There was no difference between groups in: anxiety levels, or in any of the secondary outcome measures. CONCLUSIONS: Three minutes of acupressure was effective in decreasing pain intensity in athletes who sustained an acute musculoskeletal sports injury when measured on the VAS, but did not change anxiety levels. PMID- 28653964 TI - A Comparison of Clinical Outcome Between Athletes and Nonathletes Undergoing Hip Arthroscopy for Femoroacetabular Impingement. AB - OBJECTIVE: To compare the clinical outcome of arthroscopic surgery for femoroacetabular impingement (FAI) between athlete and nonathlete patients. DESIGN: Retrospective case-control study. Level of Evidence III. PATIENTS AND METHODS: Seventy-four patients who underwent arthroscopic FAI correction from March 2009 to April 2012 were enrolled in this study. The patients were divided into 2 groups, according to their sports participation (47 in the athlete group and 27 in the nonathlete group). MAIN OUTCOME MEASURES: We reviewed clinical and radiographic data for all patients, up to a minimum of 2 years after surgery. We used analysis of covariance to compare the mean patient reported outcome scores including modified Harris hip score (MHHS) and the nonarthritis hip score (NAHS) preoperatively, at 6, 12, and 24 months after surgery. RESULTS: The mean age at the time of surgery in the athlete group was significantly lower than that in the nonathlete group. Although there was no significant difference in preoperative MHHS and NAHS, the mean NAHS at 6, 12, and 24 months postoperatively and the mean MHHS at 24 months postoperatively in athletes were significantly higher than that in nonathletes (P < 0.05). CONCLUSIONS: Although arthroscopic FAI correction and labral preservation surgery is generally beneficial, it appears to provide a better clinical outcome in athletes than in nonathletes. PMID- 28653965 TI - Factors Influencing the Underreporting of Concussion in Sports: A Qualitative Study of Minor Hockey Participants. AB - OBJECTIVE: The present study is to identify factors contributing to underreporting of concussion in adolescent athletes. DESIGN: Qualitative interviews. SETTING: Participants were interviewed in an office environment. PARTICIPANTS: Interviews were conducted with 31 minor hockey players, 10 parents, 6 coaches, 4 trainers, 2 managers, and one game official. Players were 13 to 15 year old. With selective sampling, an inductive approach of analyzing the interviews was undertaken and themes were identified and analyzed. ASSESSMENT OF RISK FACTORS: Underreporting is a complex phenomenon. A number of risk factors related to hockey culture, players, reference others, and rules of play were assessed. MAIN OUTCOME MEASURES: Reasons not reporting concussion is accepted in minor hockey. RESULTS: Aspects of hockey culture such as an overemphasis on winning games and upheld misperceptions about the risks associated with concussion were identified as relevant to the underreporting of concussions. Various factors relevant to the underreporting of concussions include player's motivation to win, group membership dynamics such as a player's role as the team's "enforcer," coaches' own motivation to win to further their own opportunities in the sport, and parents' personal financial interest or alternative agenda in terms of time commitments and their child's future career prospects. CONCLUSIONS: Our findings indicate that underreporting of concussion among those players interviewed appears to be prevalent and associated with misconceptions about injury risk, and a culture that both reinforces and encourages underreporting with tacit or overt complicity of parents and coaches. Our findings support the need to alter the culture of violence and tough play in hockey by education, rule changes, economic measures, and changes in governance of the sport. Interviewing more stakeholders and policy makers would shed light on such potential interventions. PMID- 28653966 TI - Reliability and Practicality of the Core Score: Four Dynamic Core Stability Tests Performed in a Physician Office Setting. AB - OBJECTIVE: Pilot study to determine the practicality and inter-rater reliability of the "Core Score," a composite measure of 4 clinical core stability tests. DESIGN: Repeated measures. SETTING: Academic hospital physician clinic. PARTICIPANTS: 23 healthy volunteers with mean age of 32 years (12 females, 11 males). ASSESSMENT OF VARIABLES: All subjects performed 4 core stability maneuvers under direct observation from 3 independent physicians in sequence. MAIN OUTCOME MEASURES: Inter-rater reliability and time necessary to perform examination. RESULTS: The Core Score scale is 0 to 12, with 12 reflecting the best core stability. The mean composite score of all 4 tests for all subjects was 9.54 (SD, 1.897; range, 4-12). The intraclass correlation coefficients (ICC 1,1) for inter-rater reliability for the composite Core Score and 4 individual tests were 0.68 (Core Score), 0.14 (single-leg squat), 0.40 (supine bridge), 0.69 (side bridge), and 0.46 (prone bridge). The time required for a single examiner to assess a given subject's core stability in all 4 maneuvers averaged 4 minutes (range, 2-6 minutes). CONCLUSIONS: Even without specialized equipment, a clinically practical and moderately reliable measure of core stability may be possible. Further research is necessary to optimize this measure for clinical application. CLINICAL RELEVANCE: Despite the known value of core stability to athletes and patients with low back pain, there is currently no reliable and practical means for rating core stability in a typical office-based practice. This pilot study provides a starting point for future reliability research on clinical core stability assessments. PMID- 28653967 TI - Exercise-Associated Hyponatremia in a Lactating Female. AB - A 37-year-old woman presented to the emergency department with severe headache, which quickly progressed to altered mental status and seizure activity in hospital. Her initial serum sodium concentration ([Na]) was 126 mmol/L. In the 24 hours before admission, she exercised vigorously for 120 minutes (interval training plus yoga) and also consumed more than 4 liters of fluid during that time to both stay hydrated and facilitate milk production because she was actively nursing 2 children. Her serum [Na] and altered mental status corrected slowly over the next 48 hours with furosemide, hypertonic saline, and fluid restriction. This case is unique because it discusses the possible pathogenic role that lactation-induced oxytocin release may have on sustained antidiuresis and dilutional exercise-associated hyponatremia (EAH). This would be the first report documenting EAH in a lactating woman, which may highlight an underrecognized risk factor for physically active women who are concurrently breast-feeding. PMID- 28653968 TI - An Unusual Cause of Headache and Fatigue in a Division 1 Collegiate Athlete. AB - Variegate porphyria (VP) is an autosomal dominant disorder of porphyrin metabolism. We report a case of a 21-year-old male collegiate athlete who complained of recurrent headache and fatigue. Extensive testing after initial presentation failed to identify a cause. Months later, his grandmother was diagnosed with VP after being hospitalized; hence, he was tested. He was positive for a heterozygous missense mutation, R168H, in one protoporphyrinogen oxidase allele. This case highlights a rare disorder of heme synthesis that should be considered in the differential diagnosis of exertional fatigue and headaches in athletes. When other more common causes of fatigue and/or headache are unable to be identified, a more focused history and examination may lead to a more unusual but crucial diagnosis. To our knowledge, there are no reported cases of this condition in Division I collegiate athletes. PMID- 28653969 TI - Changes in Fertility at the Population Level in the Era of ART in Rural Malawi. AB - INTRODUCTION: HIV reduces fertility through biological and social pathways, and antiretroviral treatment (ART) can ameliorate these effects. In northern Malawi, ART has been available since 2007 and lifelong ART is offered to all pregnant or breastfeeding HIV-positive women. METHODS: Using data from the Karonga Health and Demographic Surveillance Site in Malawi from 2005 to 2014, we used total and age specific fertility rates and Cox regression to assess associations between HIV and ART use and fertility. We also assessed temporal trends in in utero and breastfeeding HIV and ART exposure among live births. RESULTS: From 2005 to 2014, there were 13,583 live births during approximately 78,000 person years of follow up of women aged 15-49 years. The total fertility rate in HIV-negative women decreased from 6.1 [95% confidence interval (CI): 5.5 to 6.8] in 2005-2006 to 5.1 (4.8-5.5) in 2011-2014. In HIV-positive women, the total fertility rate was more stable, although lower, at 4.4 (3.2-6.1) in 2011-2014. In 2011-2014, compared with HIV-negative women, the adjusted (age, marital status, and education) hazard ratio was 0.7 (95% CI: 0.6 to 0.9) and 0.8 (95% CI: 0.6 to 1.0) for women on ART for at least 9 months and not (yet) on ART, respectively. The crude fertility rate increased with duration on ART up to 3 years before declining. The proportion of HIV-exposed infants decreased, but the proportion of ART-exposed infants increased from 2.4% in 2007-2010 to 3.5% in 2011-2014. CONCLUSIONS: Fertility rates in HIV-positive women are stable in the context of generally decreasing fertility. Despite a decrease in HIV-exposed infants, there has been an increase in ART-exposed infants. PMID- 28653970 TI - Impact of Sexual Violence Across the Lifespan on HIV Risk Behaviors Among Transgender Women and Cisgender People Living With HIV. AB - BACKGROUND: To examine sexual violence across the lifespan among transgender and cisgender people living with HIV and its associations with recent risk behaviors. SETTING: Seven community-based sites serving priority populations disproportionately affected by HIV in the United States, including major metropolitan areas in the West and East Coast, as well as the suburban Mid Atlantic and rural Southeastern regions. METHODS: From 2013 to 2016, baseline survey data were collected from participants (N = 583) of a multisite community based HIV linkage to/retention in care study conducted at 7 sites across the United States. Adjusted mixed-effects logistic regression models with random effect for site-assessed associations of sexual violence and gender identity with risk outcomes including condomless sex, sex trade involvement, and substance use related harms. RESULTS: One-third of participants reported a history of sexual violence; transgender [adjusted odds ratio (AOR) = 5.1, 95% confidence interval (CI): 2.6 to 10.1] and cisgender women (AOR = 3.8, 95% CI: 2.3 to 6.4) were more likely than cisgender men to experience sexual violence. Sexual violence was associated with experiencing drug-related harms (AOR = 2.6, 95% CI: 1.2 to 5.5). Transgender women were more likely than cisgender men to have sold sex (AOR = 9.3, 95% CI: 1.7 to 50.0). CONCLUSIONS: A history of sexual violence is common among transgender and cisgender women PLWH, and it increases risk for drug related harms. Transgender women are also more likely to report selling sex. PMID- 28653971 TI - Addition of Etravirine Does Not Enhance the Initial Decline of HIV-1 RNA in Treatment-Experienced Patients Receiving Raltegravir. AB - OBJECTIVE: The importance of an early reduction of HIV-1 RNA as a marker for positive longer term outcome is still under debate. We investigate whether antiretroviral-experienced patients receiving raltegravir plus etravirine have a higher early reduction of HIV-1 RNA compared with patients receiving raltegravir. DESIGN: An observational study of treatment-experienced patients. METHODS: The objective is to investigate 349 patients included in a raltegravir resistance study. The early outcome is defined as a reduction of HIV-1 RNA at week 8. The crude method defines all measurements below the limit of quantification to be equal to the limit of quantification provides biased estimates. Such a reduction is censored by the limit of quantification and is subject to selection bias in observational studies. RESULTS: The crude method showed a significant higher reduction in HIV-1 RNA reduction in patients receiving raltegravir plus etravirine compared with patients receiving raltegravir (mean reduction of 2.1 versus 1.8 log10 copies/mL). However, survival methods adjusted for both censoring, due to the limit of quantification, and confounding factors lead to a nonsignificant difference between the 2 treatment groups (mean reduction of 2.8 versus 2.7 log10 copies/mL). CONCLUSION: Taking into account censoring and confounding factors, our study did not demonstrate a higher early reduction of HIV-1 RNA in patients receiving raltegravir with versus without etravirine. PMID- 28653972 TI - Active HCV Replication but Not HCV or CMV Seropositive Status Is Associated With Incident and Prevalent Type 2 Diabetes in Persons Living With HIV. AB - OBJECTIVE: To analyze the association between chronic hepatitis C virus (HCV) and cytomegalovirus (CMV) infections with type 2 diabetes in HIV-infected patients. METHODS: HIV-1-infected patients enrolled in ICONA, a prospective cohort study involving 42 tertiary care centers in Italy, were selected with the following characteristics: for the diabetes incidence analysis, all patients with available CMV IgG results (first available test = baseline) and without type 2 diabetes were followed until onset of type 2 diabetes, last available clinical follow-up, death or September 30, 2014, whichever occurred first; for the prevalence analysis, all ICONA patients were analyzed at their last follow-up visit. Main outcome measures were the new onset of type 2 diabetes (incidence analysis) and the prevalence of type 2 diabetes at last follow-up. RESULTS: During 38,062 person-years of follow-up (PYFU) in 6505 individuals, we observed 140 cases of incident type 2 diabetes (Incidence rate 3.7, 95% CI: 3.1 to 4.3, per 1000 PYFU). In a multivariable Poisson regression model, HCV-antibody (Ab)+/HCV RNA+ patients [adjusted relative rate versus HCV-Ab negative 1.73 (95% CI: 1.08 to 2.78)] but not HCV Ab+RNA- or CMV IgG+ patients, had a higher risk of diabetes. Among 12,001 patients, 306 (2.5%) prevalent cases of type 2 diabetes were detected. HCV Ab+RNA+ status was independently associated with prevalent diabetes (adjusted Odds Ratio vs HCV Ab- 2.49; 95% CI: 1.08 to 5.74), whereas HCV-Ab+/HCV RNA- and CMV IgG+ status were not. CONCLUSION: In HIV-infected individuals, active HCV replication but not prior HCV exposure or latent CMV infection is associated with incident and prevalent type 2 diabetes. PMID- 28653973 TI - Research on a Novel Exciting Method for a Sandwich Transducer Operating in Longitudinal-Bending Hybrid Modes. AB - A novel exciting method for a sandwich type piezoelectric transducer operating in longitudinal-bending hybrid vibration modes is proposed and discussed, in which the piezoelectric elements for the excitations of the longitudinal and bending vibrations share the same axial location, but correspond to different partitions. Whole-piece type piezoelectric plates with three separated partitions are used, in which the center partitions generate the first longitudinal vibration, while the upper and lower partitions produce the second bending vibration. Detailed comparisons between the proposed exciting method and the traditional one were accomplished by finite element method (FEM) calculations, which were further verified by experiments. Compared with the traditional exciting method using independent longitudinal ceramics and bending ceramics, the proposed method achieves higher electromechanical coupling factors and larger vibration amplitudes, especially for the bending vibration mode. This novel exciting method for longitudinal-bending hybrid vibrations has not changed the structural dimensions of the sandwich transducer, but markedly improves the mechanical output ability, which makes it very helpful and meaningful in designing new piezoelectric actuators operated in longitudinal-bending hybrid vibration modes. PMID- 28653975 TI - Development of RP-HPLC, Stability Indicating Method for Degradation Products of Linagliptin in Presence of Metformin HCl by Applying 2 Level Factorial Design; and Identification of Impurity-VII, VIII and IX and Synthesis of Impurity-VII. AB - The novel reverse phase-high performance liquid chromatography (RP-HPLC), stability indicating method was developed for determination of linagliptin (LGP) and its related substances in linagliptin and metformin HCl (MET HCl) tablets by implementing design of experiment to understand the critical method parameters and their relation with critical method attributes; to ensure robustness of the method. The separation of nine specified impurities was achieved with a Zorbax SB Aq 250 * 4.6 mm, 5 um column, using gradient elution and a detector wavelength of 225 nm, and validated in accordance with International Conference on Harmonization (ICH) guidelines and found to be accurate, precise, reproducible, robust, and specific. The drug was found to be degrading extensively in heat, humidity, basic, and oxidation conditions and was forming degradation products during stability studies. After slight modification in the buffer and the column, the same method was used for liquid chromatography-mass spectrometry (LC-MS) and ultra-performance liquid chromatography -time-of-flight/mass spectrometry UPLC TOF/MS analysis, to identify m/z and fragmentation of maximum unspecified degradation products i.e., Impurity-VII (7), Impurity-VIII (8), and Impurity-IX (9) formed during stability studies. Based on the results, a degradation pathway for the drug has been proposed and synthesis of Impurity-VII (7) is also discussed to ensure an in-depth understanding of LGP and its related degradation products and optimum performance during the lifetime of the product. PMID- 28653974 TI - HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer. AB - Polymorphisms in drug-metabolizing enzymes might not completely explain inter individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3' untranslated region (3'UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3'UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3'UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC. PMID- 28653976 TI - Experimental Demonstration of Long-Range Underwater Acoustic Communication Using a Vertical Sensor Array. AB - This paper proposes a composite channel virtual time reversal mirror (CCVTRM) for vertical sensor array (VSA) processing and applies it to long-range underwater acoustic (UWA) communication in shallow water. Because of weak signal-to-noise ratio (SNR), it is unable to accurately estimate the channel impulse response of each sensor of the VSA, thus the traditional passive time reversal mirror (PTRM) cannot perform well in long-range UWA communication in shallow water. However, CCVTRM only needs to estimate the composite channel of the VSA to accomplish time reversal mirror (TRM), which can effectively mitigate the inter-symbol interference (ISI) and reduce the bit error rate (BER). In addition, the calculation of CCVTRM is simpler than traditional PTRM. An UWA communication experiment using a VSA of 12 sensors was conducted in the South China Sea. The experiment achieves a very low BER communication at communication rate of 66.7 bit/s over an 80 km range. The results of the sea trial demonstrate that CCVTRM is feasible and can be applied to long-range UWA communication in shallow water. PMID- 28653977 TI - Exploitation of SPR to Investigate the Importance of Glycan Chains in the Interaction between Lactoferrin and Bacteria. AB - Bovine lactoferrin (LF) has been shown to prevent adhesion to and invasion of mammalian cell lines by pathogenic bacteria, with evidence for direct bacterial binding by the milk glycoprotein. However, the glycosylation pattern of LF changes over the lactation cycle. In this study, we aim to investigate the effect that this variation has on the milk glycoprotein's ability to interact with pathogens. Surface plasmon resonance technology was employed to compare the binding of LF from colostrum (early lactation) and mature milk (late lactation) to a panel of pathogenic bacteria (Staphylococcus aureus, Escherichia coli, Cronobacter sakazakii, Streptococcus pneumoniae, Pseudomonas aeruginosa, Listeria monocytogenes and Salmonella typhimurium). Novel interactions with LF were identified for C. sakazakii, S. pneumoniae and P. aeruginosa with the highest binding ability observed for mature milk LF in all cases, with the exception of S. typhimurium. The difference in bacterial binding observed may be as a result of the varying glycosylation profiles. This work demonstrates the potential of LF as a functional food ingredient to prevent bacterial infection. PMID- 28653978 TI - Transdiagnostic Clinical Global Impression Scoring for Routine Clinical Settings. AB - Although there is great interest in the improving the ability to track patients' change over time in routine clinical care settings, no standardized transdiagnostic measure is currently available for busy clinicians to apply. The Clinical Global Impression (CGI) scales are simple measures widely used as outcomes in psychiatric clinical trials. However, the CGI suffers from poorly defined scoring anchors. Efforts to improve the anchors by enhancing the anchor descriptions have proven useful but are limited by being disease-specific, thereby acting as a barrier to the routine clinical adoption of the CGI. To inform the development of more broadly applicable CGI scoring anchors, we surveyed 24 clinical trial investigators, asking them to rank-order seven elements that inform their CGI-Severity (CGI-S) scoring. Symptom severity emerged as the most important element in determining CGI-S scores; the functional status of the patient emerged as a second element. Less importance was given to self report symptom scores, staff observations, or side effects. Relative rankings of the elements' importance did not differ by investigators' experience nor time usually spent with patients. We integrated these results with published illness specific CGI anchors to develop the Transdiagnostic CGI (T-CGI), which employs standardized scoring anchors applicable across psychiatric illnesses. Pending validity and reliability evaluations, the T-CGI may prove well-suited for inclusion in routine clinical settings and for incorporation into electronic medical records as a simple and useful measure of treatment efficacy. PMID- 28653979 TI - Hypermethylation of Synphilin-1, Alpha-Synuclein-Interacting Protein (SNCAIP) Gene in the Cerebral Cortex of Patients with Sporadic Parkinson's Disease. AB - OBJECTIVE: To determine and compare DNA methylation patterns between patients with Parkinson's disease (PD) and age- and sex-similar matched non-PD controls. BACKGROUND: Epigenetic regulation is one of the major mechanisms for an organism to respond to the environment through changes in gene expression and has been implicated in numerous disease processes. We would like to examine epigenetic modification patterns that may predispose or protect against PD. METHODS: Frozen tissue samples of the human cerebral cortex from 12 PD patients and 12 subjects without PD pathology were obtained. Genome-wide DNA methylation profiling was performed using the Illumina HumanMethylation450 BeadChip array. Differential methylation was defined as a mean methylation level difference (delta beta) of at least 0.20 (Deltabeta >= 0.20). Methylation regions with an absolute delta beta value >= 0.20 were selected for further gene function studies. RESULTS: We identified 2795 differentially methylated CpG sites in the frontal cortex of PD cases with a detection p-value of <= 0.01 and 328 differentially methylated CpG sites with a detection p-value of <= 0.001. A pattern of robust hypermethylation of synphilin-1, alpha-synuclein-interacting protein (SNCAIP) gene was found in the brain of PD cases (p = 4.93 * 10-7 and delta beta = 0.60). CONCLUSION: Our findings support a link between SNCAIP methylation and PD risk. Hypomethylation of SNCAIP may function to protect against PD. The current results may suggest that the methylation status of SNCAIP could be useful as a marker in PD diagnosis and treatment and warrants further investigation. PMID- 28653980 TI - Ligand Shaping in Induced Fit Docking of MraY Inhibitors. Polynomial Discriminant and Laplacian Operator as Biological Activity Descriptors. AB - Docking-i.e., interaction of a small molecule (ligand) with a proteic structure (receptor)-represents the ground of drug action mechanism of the vast majority of bioactive chemicals. Ligand and receptor accommodate their geometry and energy, within this interaction, in the benefit of receptor-ligand complex. In an induced fit docking, the structure of ligand is most susceptible to changes in topology and energy, comparative to the receptor. These changes can be described by manifold hypersurfaces, in terms of polynomial discriminant and Laplacian operator. Such topological surfaces were represented for each MraY (phospho MurNAc-pentapeptide translocase) inhibitor, studied before and after docking with MraY. Binding affinities of all ligands were calculated by this procedure. For each ligand, Laplacian and polynomial discriminant were correlated with the ligand minimum inhibitory concentration (MIC) retrieved from literature. It was observed that MIC is correlated with Laplacian and polynomial discriminant. PMID- 28653981 TI - The Role of Replication-Associated Repair Factors on R-Loops. AB - The nascent RNA can reinvade the DNA double helix to form a structure termed the R-loop, where a single-stranded DNA (ssDNA) is accompanied by a DNA-RNA hybrid. Unresolved R-loops can impede transcription and replication processes and lead to genomic instability by a mechanism still not fully understood. In this sense, a connection between R-loops and certain chromatin markers has been reported that might play a key role in R-loop homeostasis and genome instability. To counteract the potential harmful effect of R-loops, different conserved messenger ribonucleoprotein (mRNP) biogenesis and nuclear export factors prevent R-loop formation, while ubiquitously-expressed specific ribonucleases and DNA-RNA helicases resolve DNA-RNA hybrids. However, the molecular events associated with R-loop sensing and processing are not yet known. Given that R-loops hinder replication progression, it is plausible that some DNA replication-associated factors contribute to dissolve R-loops or prevent R-loop mediated genome instability. In support of this, R-loops accumulate in cells depleted of the BRCA1, BRCA2 or the Fanconi anemia (FA) DNA repair factors, indicating that they play an active role in R-loop dissolution. In light of these results, we review our current view of the role of replication-associated DNA repair pathways in preventing the harmful consequences of R-loops. PMID- 28653982 TI - The Deep-Sea Polyextremophile Halobacteroides lacunaris TB21 Rough-Type LPS: Structure and Inhibitory Activity towards Toxic LPS. AB - The structural characterization of the lipopolysaccharide (LPS) from extremophiles has important implications in several biomedical and therapeutic applications. The polyextremophile Gram-negative bacterium Halobacteroideslacunaris TB21, isolated from one of the most extreme habitats on our planet, the deep-sea hypersaline anoxic basin Thetis, represents a fascinating microorganism to investigate in terms of its LPS component. Here we report the elucidation of the full structure of the R-type LPS isolated from H. lacunaris TB21 that was attained through a multi-technique approach comprising chemical analyses, NMR spectroscopy, and Matrix-Assisted Laser Desorption Ionization (MALDI) mass spectrometry. Furthermore, cellular immunology studies were executed on the pure R-LPS revealing a very interesting effect on human innate immunity as an inhibitor of the toxic Escherichia coli LPS. PMID- 28653983 TI - Isoprenoids from the Soft Coral Sarcophyton glaucum. AB - Five new isoprenoids, 3,4,8,16-tetra-epi-lobocrasol (1), 1,15beta-epoxy deoxysarcophine (2), 3,4-dihydro-4alpha,7beta,8alpha-trihydroxy-Delta2-sarcophine (3), ent-sarcophyolide E (4), and 16-deacetyl- halicrasterol B (5) and ten known compounds 6-15, were characterized from the marine soft coral Sarcophyton glaucum, collected off Taitung coastline. Their structures were defined by analyzing spectra data, especially 2D NMR and electronic circular dichroism (ECD). The structure of the known compound lobocrasol (7) was revised. Cytotoxicity potential of the isolated compounds was reported, too. PMID- 28653984 TI - Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing. AB - The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL, expression of certain transcripts has been found to be tissue-specific and the characterisation of ANRIL transcripts remains incomplete. Several functions have been associated with ANRIL. In our judgement, studies on ANRIL functionality are premature pending a more complete appreciation of the profusion of isoforms. We found differential expression of ANRIL exons, which indicates that multiple isoforms exist in melanoma cells. In addition to linear isoforms, we identified circular forms of ANRIL (circANRIL). Further characterisation of circANRIL in two patient-derived metastatic melanoma cell lines (NZM7 and NZM37) revealed the existence of a rich assortment of circular isoforms. Moreover, in the two melanoma cell lines investigated, the complements of circANRIL isoforms were almost completely different. Novel exons were also discovered. We also found the family of linear ANRIL was enriched in the nucleus, whilst the circular isoforms were enriched in the cytoplasm and they differed markedly in stability. With respect to the variable processing of circANRIL species, bioinformatic analysis indicated that intronic Arthrobacter luteus (Alu) restriction endonuclease inverted repeats and exon skipping were not involved in selection of back-spliced exon junctions. Based on our findings, we hypothesise that "ANRIL" has wholly distinct dual sets of functions in melanoma. This reveals the dynamic nature of the locus and constitutes a basis for investigating the functions of ANRIL in melanoma. PMID- 28653985 TI - Human MAP Tau Based Targeted Cytolytic Fusion Proteins. AB - Some of the most promising small molecule toxins used to generate antibody drug conjugates (ADCs) include anti-mitotic agents (e.g., auristatin and its derivatives) which are designed to attack cancerous cells at their most vulnerable state during mitosis. We were interested in identifying a human cystostatic protein eventually showing comparable activities and allowing the generation of corresponding targeted fully human cytolytic fusion proteins. Recently, we identified the human microtubule associated protein tau (MAP tau), which binds specifically to tubulin and modulates the stability of microtubules, thereby blocking mitosis and presumably vesicular transport. By binding and stabilizing polymerized microtubule filaments, MAP tau-based fusion proteins skew microtubule dynamics towards cell cycle arrest and apoptosis. This biological activity makes rapidly proliferating cells (e.g., cancer and inflammatory cells) an excellent target for MAP tau-based targeted treatments. Their superior selectivity for proliferating cells confers additional selectivity towards upregulated tumor-associated antigens at their surface, thereby preventing off target related toxicity against normal cells bearing tumor-associated antigens at physiologically normal to low levels. In this review, we highlight recent findings on MAP tau-based targeted cytolytic fusion proteins reported in preclinical immunotherapeutic studies. PMID- 28653988 TI - Unequivocal Identification of 1-Phenylethyl Acetate in Clove Buds (syzygium aromaticum (L.) Merr. & L.M.Perry) and Clove Essential Oil. AB - The natural occurrence of 1-phenylethyl acetate (styrallyl acetate) was confirmed in commercially available dried clove buds and also in the hydrodistilled oil from clove buds. This confirms previous reports and other anecdotal evidence for its occurrence in nature. PMID- 28653986 TI - 3D-QSAR and Molecular Docking Studies on the TcPMCA1-Mediated Detoxification of Scopoletin and Coumarin Derivatives. AB - The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is an economically important agricultural pest that is difficult to prevent and control. Scopoletin is a botanical coumarin derivative that targets Ca2+-ATPase to exert a strong acaricidal effect on carmine spider mites. In this study, the full-length cDNA sequence of a plasma membrane Ca2+-ATPase 1 gene (TcPMCA1) was cloned. The sequence contains an open reading frame of 3750 bp and encodes a putative protein of 1249 amino acids. The effects of scopoletin on TcPMCA1 expression were investigated. TcPMCA1 was significantly upregulated after it was exposed to 10%, 30%, and 50% of the lethal concentration of scopoletin. Homology modeling, molecular docking, and three-dimensional quantitative structure-activity relationships were then studied to explore the relationship between scopoletin structure and TcPMCA1-inhibiting activity of scopoletin and other 30 coumarin derivatives. Results showed that scopoletin inserts into the binding cavity and interacts with amino acid residues at the binding site of the TcPMCA1 protein through the driving forces of hydrogen bonds. Furthermore, CoMFA (comparative molecular field analysis)- and CoMSIA (comparative molecular similarity index analysis)-derived models showed that the steric and H-bond fields of these compounds exert important influences on the activities of the coumarin compounds.Notably, the C3, C6, and C7 positions in the skeletal structure of the coumarins are the most suitable active sites. This work provides insights into the mechanism underlying the interaction of scopoletin with TcPMCA1. The present results can improve the understanding on plasma membrane Ca2+-ATPase-mediated (PMCA-mediated) detoxification of scopoletin and coumarin derivatives in T. cinnabarinus, as well as provide valuable information for the design of novel PMCA-inhibiting acaricides. PMID- 28653987 TI - The Emerging Role of Zfp217 in Adipogenesis. AB - Zinc finger protein 217 (Zfp217), a member of the kruppel-type zinc finger protein family, plays diverse roles in cell differentiation and development of mammals. Despite extensive research on the functions of Zfp217 in cancer, pluripotency and reprogramming, its physiological roles in adipogenesis remain unknown. Our previous RNA sequencing data suggest the involvement of Zfp217 in adipogenesis. In this study, the potential function of Zfp217 in adipogenesis was investigated through bioinformatics analysis and a series of experiments. The expression of Zfp217 was found to be gradually upregulated during the adipogenic differentiation in C3H10T1/2 cells, which was consistent with that of the adipogenic marker gene Pparg2. Furthermore, there was a positive, significant relationship between Zfp217 expression and adipocyte differentiation. It was also observed that Zfp217 could not only trigger proliferative defect in C3H10T1/2 cells, but also interact with Ezh2 and suppress the downstream target genes of Ezh2. Besides, three microRNAs (miR-503-5p, miR-135a-5p and miR-19a-3p) which target Zfp217 were found to suppress the process of adipogenesis. This is the first report showing that Zfp217 has the capacity to regulate adipogenesis. PMID- 28653989 TI - Allergens with Protease Activity from House Dust Mites. AB - Globally, house dust mites (HDM) are one of the main sources of allergens causing Type I allergy, which has a high risk of progressing into a severe disabling disease manifestation such as allergic asthma. The strong protease activities of a number of these allergens are thought to be involved in several steps of the pathophysiology of this allergic disease. It has been a common notion that protease activity may be one of the properties that confers allergenicity to proteins. In this review we summarize and discuss the roles of the different HDM proteases in the development of Type I allergy. PMID- 28653991 TI - Analysis of Public Datasets for Wearable Fall Detection Systems. AB - Due to the boom of wireless handheld devices such as smartwatches and smartphones, wearable Fall Detection Systems (FDSs) have become a major focus of attention among the research community during the last years. The effectiveness of a wearable FDS must be contrasted against a wide variety of measurements obtained from inertial sensors during the occurrence of falls and Activities of Daily Living (ADLs). In this regard, the access to public databases constitutes the basis for an open and systematic assessment of fall detection techniques. This paper reviews and appraises twelve existing available data repositories containing measurements of ADLs and emulated falls envisaged for the evaluation of fall detection algorithms in wearable FDSs. The analysis of the found datasets is performed in a comprehensive way, taking into account the multiple factors involved in the definition of the testbeds deployed for the generation of the mobility samples. The study of the traces brings to light the lack of a common experimental benchmarking procedure and, consequently, the large heterogeneity of the datasets from a number of perspectives (length and number of samples, typology of the emulated falls and ADLs, characteristics of the test subjects, features and positions of the sensors, etc.). Concerning this, the statistical analysis of the samples reveals the impact of the sensor range on the reliability of the traces. In addition, the study evidences the importance of the selection of the ADLs and the need of categorizing the ADLs depending on the intensity of the movements in order to evaluate the capability of a certain detection algorithm to discriminate falls from ADLs. PMID- 28653990 TI - The between Now and Then of Lung Cancer Chemotherapy and Immunotherapy. AB - Lung cancer is the most common cancer worldwide. Disappointingly, despite great effort in encouraging screening or, at least, a close surveillance of high-risk individuals, most of lung cancers are diagnosed when already surgically unresectable because of local advancement or metastasis. In these cases, the treatment of choice is chemotherapy, alone or in combination with radiotherapy. Here, we will briefly review the most successful and recent advances in the identification of novel lung cancer genetic lesions and in the development of new drugs specifically targeting them. However, lung cancer is still the leading cause of cancer-related mortality also because, despite impressive initial responses, the patients often develop resistance to novel target therapies after a few months of treatment. Thus, it is literally vital to continue the search for new therapeutic options. So, here, on the basis of our recent findings on the role of the tumor suppressor CCDC6 protein in lung tumorigenesis, we will also discuss novel therapeutic approaches we envision for lung cancer. PMID- 28653992 TI - Flexible Packaging by Film Assisted Molding for Microintegration of Inertia Sensors. AB - Packaging represents an important part in the microintegration of sensors based on microelectromechanical system (MEMS). Besides miniaturization and integration density, functionality and reliability in combination with flexibility in packaging design at moderate costs and consequently high-mix, low-volume production are the main requirements for future solutions in packaging. This study investigates possibilities employing printed circuit board (PCB-)based assemblies to provide high flexibility for circuit designs together with film assisted transfer molding (FAM) to package sensors. The feasibility of FAM in combination with PCB and MEMS as a packaging technology for highly sensitive inertia sensors is being demonstrated. The results prove the technology to be a viable method for damage-free packaging of stress- and pressure-sensitive MEMS. PMID- 28653994 TI - Special Issue: Chitin, Chitosan and Related Enzymes. AB - n/a. PMID- 28653995 TI - NutriNet: A Deep Learning Food and Drink Image Recognition System for Dietary Assessment. AB - Automatic food image recognition systems are alleviating the process of food intake estimation and dietary assessment. However, due to the nature of food images, their recognition is a particularly challenging task, which is why traditional approaches in the field have achieved a low classification accuracy. Deep neural networks have outperformed such solutions, and we present a novel approach to the problem of food and drink image detection and recognition that uses a newly-defined deep convolutional neural network architecture, called NutriNet. This architecture was tuned on a recognition dataset containing 225,953 512 * 512 pixel images of 520 different food and drink items from a broad spectrum of food groups, on which we achieved a classification accuracy of 86 . 72 % , along with an accuracy of 94 . 47 % on a detection dataset containing 130 , 517 images. We also performed a real-world test on a dataset of self-acquired images, combined with images from Parkinson's disease patients, all taken using a smartphone camera, achieving a top-five accuracy of 55 % , which is an encouraging result for real-world images. Additionally, we tested NutriNet on the University of Milano-Bicocca 2016 (UNIMIB2016) food image dataset, on which we improved upon the provided baseline recognition result. An online training component was implemented to continually fine-tune the food and drink recognition model on new images. The model is being used in practice as part of a mobile app for the dietary assessment of Parkinson's disease patients. PMID- 28653993 TI - Mechanistic Insight into Long Noncoding RNAs and the Placenta. AB - Long non-coding RNAs (lncRNAs) are classified as RNAs greater than 200 nucleotides in length that do not produce a protein product. lncRNAs are expressed with cellular and temporal specificity and have been shown to play a role in many cellular events, including the regulation of gene expression, post transcriptional modifications and epigenetic modifications. Since lncRNAs were first discovered, there has been increasing evidence that they play important roles in the development and function of most organs, including the placenta. The placenta is an essential transient organ that facilitates communication and nutrient exchange between the mother and foetus. The placenta is of foetal origin and begins to form shortly after the embryo implants into the uterine wall. The placenta relies heavily on the successful differentiation and function of trophoblast cells, including invasion as well as the formation of the maternal/foetal interface. Here, we review the current literature surrounding the involvement of lncRNAs in the development and function of trophoblasts and the human placenta. PMID- 28653996 TI - Clinical Identification of Geriatric Patients with Hypovitaminosis D: The 'Vitamin D Status Predictor for Geriatrics' Study. AB - The 16-item Vitamin D Status Predictor (VDSP) tool identifies healthy older community-dwellers at risk of hypovitaminosis D and may guide the use of blood tests in this population. The objective of the present hospital-based study was to test the efficacy of the VDSP to identify geriatric patients with hypovitaminosis D. The study included 199 nonsupplemented geriatric in- and outpatients consecutively admitted to Angers University Hospital, France (mean +/ SD, 82.0 +/- 7.8 years; 53.3% female). Serum 25-hydroxyvitaminD (25(OH)D) was measured at the time of the physician-administered VDSP. Hypovitaminosis D was defined as serum 25(OH)D concentration <= 75 nmol/L for vitamin D insufficiency, 25(OH)D <= 50 nmol/L for vitamin D deficiency, and 25(OH)D <= 25 nmol/L for severe vitamin D deficiency. We found that 184 participants (92.4%) had vitamin D insufficiency, 136 (68.3%) had vitamin D deficiency, and 67 (33.7%) had severe vitamin D deficiency. The VDSP identified severe vitamin D deficiency with an area under curve (AUC) = 0.83 and OR = 24.0. The VDSP was able to identify vitamin D deficiency and vitamin D insufficiency with less accuracy (AUC = 0.71 and AUC = 0.73, respectively). In conclusion, the 16-item VDSP is a short questionnaire that accurately identifies geriatric patients with severe vitamin D deficiency. This tool may guide the use of blood collection for determining geriatric patients' vitamin D status. PMID- 28653998 TI - Cell-Free Production of Pentacyclic Triterpenoid Compound Betulinic Acid from Betulin by the Engineered Saccharomyces cerevisiae. AB - Betulinic acid is a product of plant secondary metabolism which has shown various bioactivities. Several CYP716A subfamily genes were recently characterized encoding multifunctional oxidases capable of C-28 oxidation. CYP716A12 was identified as betulin C-28 oxidase, capable of modifying betulin. This study aimed to induce the transformation of betulin to betulinic acid by co-expressing enzymes CYP716A12 from Medicago truncatula and ATR1 from Arabidopsis thaliana in Saccharomyces cerevisiae. The microsome protein extracted from the transgenic yeast successfully catalyzed the transformation of betulin to betulinic acid. We also characterized the optimization of cell fragmentation, protein extraction method, and the conversion conditions. Response surface methodology was implemented, and the optimal yield of betulinic acid reached 18.70%. After optimization, the yield and the conversion rate of betulin were increased by 83.97% and 136.39%, respectively. These results may present insights and strategies for the sustainable production of betulinic acid in multifarious transgenic microbes. PMID- 28653999 TI - FGF-2 Gene Polymorphism in Osteoporosis among Guangxi's Zhuang Chinese. AB - Osteoporosis is a complex multifactorial disorder of gradual bone loss and increased fracture risk. While previous studies have shown the importance of many genetic factors in determining peak bone mass and fragility fractures and in suggesting involvement of fibroblast growth factor-2 (FGF-2) in bone metabolism and bone mass, the relationship of FGF-2 genetic diversity with bone mass/osteoporosis has not yet been revealed. The current study investigated the potential relevance of FGF-2 gene polymorphism in osteoporosis among a Zhuang ethnic Chinese cohort of 623, including 237 normal bone mass controls, 227 osteopenia, and 159 osteoporosis of different ages. Bone density was examined by calcaneus ultrasound attenuation measurement, and single nucleotide polymorphisms (SNPs) and linkage disequilibrium analyses were performed on five SNP loci of FGF 2 gene. Significant differences were found in bone mass in males between the 45 year-old and >=70-year-old groups (p < 0.01), and in females among 55, 60, 65 and 70-year-old groups (p < 0.05). Males had higher bone mass values than females in the same age (over 55-year-old) (p < 0.05). The proportions of individuals with normal bone mass decreased with age (65.2% to 40% in males, and 50% to 0% in females), whereas prevalence of osteoporosis increased with age (15.4% to 30% in men, and 7.7% to 82% in women). Out of five FGF-2 SNP loci, the TA genotype of rs308442 in the osteoporosis group (40.2%) was higher than in the control group (29.5%) (p < 0.05). The TA genotype was significantly correlated with the risk of osteoporosis (odds ratio OR = 1.653), 95% confidence interval (CI): 1.968-1.441). Strong linkage disequilibrium in FGF-2 gene was also detected between rs12644427 and rs3747676, between rs12644427 and rs3789138, and between rs3747676 and rs3789138 (D' > 0.8, and r2 > 0.33). Thus, the rs308442 locus of FGF-2 gene is closely correlated to osteoporosis in this Zhuang ethnic Chinese cohort, and the TA may be the risk genotype of osteoporosis. PMID- 28653997 TI - Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology. AB - Human Endogenous Retroviruses (HERVs) are ancient infection relics constituting ~8% of our DNA. While HERVs' genomic characterization is still ongoing, impressive amounts of data have been obtained regarding their general expression across tissues. Among HERVs, one of the most studied is the W group, which is the sole HERV group specifically mobilized by the long interspersed element-1 (LINE 1) machinery, providing a source of novel insertions by retrotransposition of HERV-W processed pseudogenes, and comprising a member encoding a functional envelope protein coopted for human placentation. The HERV-W group has been intensively investigated for its putative role in several diseases, such as cancer, inflammation, and autoimmunity. Despite major interest in the link between HERV-W expression and human pathogenesis, no conclusive correlation has been demonstrated so far. In general, (i) the absence of a proper identification of the specific HERV-W sequences expressed in a given condition, and (ii) the lack of studies attempting to connect the various observations in the same experimental conditions are the major problems preventing the definitive assessment of the HERV-W impact on human physiopathology. In this review, we summarize the current knowledge on the HERV-W group presence within the human genome and its expression in physiological tissues as well as in the main pathological contexts. PMID- 28654000 TI - Long-Lived Epidermal Cancer-Initiating Cells. AB - Non-melanomatous skin cancers (NMSCs), which include basal and squamous cell carcinoma (BCC and SCC respectively), represent a significant burden on the population, as well as an economic load to the health care system; yet treatments of these preventable cancers remain ineffective. Studies estimate that there has been a 2-fold increase in the incidence of NMSCs between the 1960s and 1980s. The increase in cases of NMSCs, as well as the lack of effective treatments, makes the need for novel therapeutic approaches all the more necessary. To rationally develop more targeted treatments for NMSCs, a better understanding of the cell of origin, in addition to the underlying pathophysiological mechanisms that govern the development of these cancers, is urgently required. Research over the past few years has provided data supporting both a "bottom up" and "top down" mechanism of tumourigenesis. The "bottom up" concept involves a cancer stem cell originating in the basal compartment of the skin, which ordinarily houses the progenitor cells that contribute towards wound healing and normal cell turnover of overlying epidermal skin layers. The "top down" concept involves a more differentiated cell undergoing genetic modifications leading to dedifferentiation, giving rise to cancer initiating cells (CICs). This review explores both concepts, to paint a picture of the skin SCC cell of origin, the underlying biology, and also how this knowledge might be exploited to develop novel therapies. PMID- 28654002 TI - Integration of Sensors, Controllers and Instruments Using a Novel OPC Architecture. AB - The interconnection between sensors, controllers and instruments through a communication network plays a vital role in the performance and effectiveness of a control system. Since its inception in the 90s, the Object Linking and Embedding for Process Control (OPC) protocol has provided open connectivity for monitoring and automation systems. It has been widely used in several environments such as industrial facilities, building and energy automation, engineering education and many others. This paper presents a novel OPC-based architecture to implement automation systems devoted to R&D and educational activities. The proposal is a novel conceptual framework, structured into four functional layers where the diverse components are categorized aiming to foster the systematic design and implementation of automation systems involving OPC communication. Due to the benefits of OPC, the proposed architecture provides features like open connectivity, reliability, scalability, and flexibility. Furthermore, four successful experimental applications of such an architecture, developed at the University of Extremadura (UEX), are reported. These cases are a proof of concept of the ability of this architecture to support interoperability for different domains. Namely, the automation of energy systems like a smart microgrid and photobioreactor facilities, the implementation of a network accessible industrial laboratory and the development of an educational hardware in-the-loop platform are described. All cases include a Programmable Logic Controller (PLC) to automate and control the plant behavior, which exchanges operative data (measurements and signals) with a multiplicity of sensors, instruments and supervisory systems under the structure of the novel OPC architecture. Finally, the main conclusions and open research directions are highlighted. PMID- 28654001 TI - Profiling the Extended Cleavage Specificity of the House Dust Mite Protease Allergens Der p 1, Der p 3 and Der p 6 for the Prediction of New Cell Surface Protein Substrates. AB - House dust mite (HDM) protease allergens, through cleavages of critical surface proteins, drastically influence the initiation of the Th2 type immune responses. However, few human protein substrates for HDM proteases have been identified so far, mainly by applying time-consuming target-specific individual studies. Therefore, the identification of substrate repertoires for HDM proteases would represent an unprecedented key step toward a better understanding of the mechanism of HDM allergic response. In this study, phage display screenings using totally or partially randomized nonameric peptide substrate libraries were performed to characterize the extended substrate specificities (P5-P4') of the HDM proteases Der p 1, Der p 3 and Der p 6. The bioinformatics interface PoPS (Prediction of Protease Specificity) was then applied to define the proteolytic specificity profile of each protease and to predict new protein substrates within the human cell surface proteome, with a special focus on immune receptors. Specificity profiling showed that the nature of residues in P1 but also downstream the cleavage sites (P' positions) are important for effective cleavages by all three HDM proteases. Strikingly, Der p 1 and Der p 3 display partially overlapping specificities. Analysis with PoPS interface predicted 50 new targets for the HDM proteases, including 21 cell surface receptors whose extracellular domains are potentially cleaved by Der p 1, Der p 3 and/or Der p 6. Twelve protein substrate candidates were confirmed by phage ELISA (enzyme linked immunosorbent assay). This extensive study of the natural protein substrate specificities of the HDM protease allergens unveils new cell surface target receptors for a better understanding on the role of these proteases in the HDM allergic response and paves the way for the design of specific protease inhibitors for future anti-allergic treatments. PMID- 28654003 TI - A Force-Sensing System on Legs for Biomimetic Hexapod Robots Interacting with Unstructured Terrain. AB - The tiger beetle can maintain its stability by controlling the interaction force between its legs and an unstructured terrain while it runs. The biomimetic hexapod robot mimics a tiger beetle, and a comprehensive force sensing system combined with certain algorithms can provide force information that can help the robot understand the unstructured terrain that it interacts with. This study introduces a complicated leg force sensing system for a hexapod robot that is the same for all six legs. First, the layout and configuration of sensing system are designed according to the structure and sizes of legs. Second, the joint toque sensors, 3-DOF foot-end force sensor and force information processing module are designed, and the force sensor performance parameters are tested by simulations and experiments. Moreover, a force sensing system is implemented within the robot control architecture. Finally, the experimental evaluation of the leg force sensor system on the hexapod robot is discussed and the performance of the leg force sensor system is verified. PMID- 28654004 TI - Self-Reported Oil Spill Exposure and Pregnancy Complications: The GROWH Study. AB - Adverse infant outcomes often rise in the aftermath of disaster, but few studies have assessed the effects of disaster on maternal health. 1091 southern Louisiana women were interviewed about their pregnancy history, including pregnancy complications. Associations between oil spill exposures and gestational diabetes, hypertensive disorders, and nausea/vomiting were assessed for all reported pregnancies. 631 women had a pregnancy both before and after the oil spill. Generalized estimating equations (logistic regression) with adjustment for confounders were used. To assess possible unmeasured confounding, instead of considering oil spill exposure as a time-varying exposure, women were defined as oil spill-exposed or not. If oil spill-exposed women were equally prone to complications in pregnancies that occurred prior to the oil spill as after it, it was considered that any associations were likely due to selection or reporting issues. Women who reported oil spill exposure, particularly loss of use of the coast, were more likely to report gestational diabetes; however, the level of association was similar for pregnancies before and after the spill (p for interaction >0.10 and odds ratios (ORs) for pregnancies prior to the spill > than those after the spill). No associations were found between oil spill exposure and hypertensive disorders. This analysis does not suggest an increased risk of pregnancy complications associated with exposure to the oil spill; however, future studies should assess exposure and outcomes prospectively and clinically instead of relying on self-report. PMID- 28654006 TI - Algorithms for Lightweight Key Exchange. AB - Public-key cryptography is too slow for general purpose encryption, with most applications limiting its use as much as possible. Some secure protocols, especially those that enable forward secrecy, make a much heavier use of public key cryptography, increasing the demand for lightweight cryptosystems that can be implemented in low powered or mobile devices. This performance requirements are even more significant in critical infrastructure and emergency scenarios where peer-to-peer networks are deployed for increased availability and resiliency. We benchmark several public-key key-exchange algorithms, determining those that are better for the requirements of critical infrastructure and emergency applications and propose a security framework based on these algorithms and study its application to decentralized node or sensor networks. PMID- 28654005 TI - An Integrated Approach for the Environmental Characterization of a Wide Potentially Contaminated Area in Southern Italy. AB - This paper deals with the environmental characterization of a large and densely populated area, with a poor reputation for contamination, considering the contribution of environmental features (air, soil, soil hydraulic and groundwater) and the potential effects on human health. The use of Geographic Information System (GIS) has made possible a georeferenced inventory and, by overlaying environmental information, an operational synthesis of comprehensive environmental conditions. The cumulative effects on environmental features were evaluated, taking into account superposition effects, by means of the Spatial MultiCriteria Decision Analysis (S-MCDA). The application of the S-MCDA for converging the combination of heterogeneous factors, related to soil, land and water, deeply studied by heterogeneous groups of experts, constitutes the novelty of the paper. The results confirmed an overall higher potential of exposure to contaminants in the environment and higher mortality rates in the study area for some tumours, but hospital admissions for tumours were generally similar to the regional trend. Besides, mortality data may be strictly dependent on the poor socioeconomic conditions, quality of therapy and a lack of welfare in the area relative to the rest of Italy. Finally, as regards the possible relationship between presence of contaminants in the environment and health conditions of the population no definite conclusions can be drawn, although the present study encourages the use of the new proposed methods, that increase the possibilities for studying the combined effect of more environmental factors. PMID- 28654007 TI - Susceptibility and Lethality of Western Equine Encephalitis Virus in Balb/c Mice When Infected by the Aerosol Route. AB - Western equine encephalitis virus (WEEV) naturally cycles between mosquitos and birds or rodents, with a case fatality rate of up to 15% in humans during epizootic outbreaks. There are no medical countermeasures to treat WEEV infection, and accidental aerosol exposure increases the case fatality rate up to 40%. Understanding the pathogenesis of infection is required to develop and assess medical countermeasures. This study describes the clinical and pathological findings of mice infected with WEEV by the aerosol route, and use as a model for WEEV infection in humans. Balb/c mice were infected by the aerosol route with a dose range of high-virulence WEEV strain Fleming to establish the median lethal dose (MLD). The disease course was acute, culminating in severe clinical signs, neuroinvasion, and dose-dependent mortality. Further groups of mice were exposed by the aerosol route, periodically sacrificed, and tissues excised for histopathological examination and virology. Viral titres peaked four days post-challenge in the brain and lungs, corresponding with severe bilateral lesions in rostroventral regions of the encephalon, especially in the olfactory bulb and piriform cortex. Recapitulation of the most serious clinical presentations of human WEEV disease in mice may prove a useful tool in the evaluation of medical countermeasures. PMID- 28654009 TI - Labradorins with Antibacterial Activity Produced by Pseudomonas sp. AB - The urgent need for new antibacterial drugs has led to renewed interest in microorganisms, which historically have been the main source of previously discovered antibiotics. The present study describes the discovery of two new antibacterial oxazolylindole type alkaloids, labradorins 5 (1) and 6 (2), which were isolated and characterized from two isolates of Pseudomonas sp., along with four previously known tryptophane derived alkaloids. The structures of 1 and 2 were determined by NMR spectroscopy and MS, and confirmed by synthesis. During bioassay-guided isolation using several human bacterial pathogens, 1 and 2 displayed activity towards Staphylococcus aureus and Acinetobacter baumannii. The minimal inhibitory concentrations (MIC) of compounds 1 and 2 against S. aureus were 12 MUg.mL-1 and 50 MUg.mL-1, respectively, whereas the MICs against A. baumannii were >50 MUg.mL-1. The CC50 values of compound 1 towards a liver cell line (HEP-G2) and a T-cell line (MT4) were 30 MUg.mL-1 and 20 MUg.mL-1, respectively, and for compound 2 were >100 MUg.mL-1 and 20 MUg.mL-1, respectively. Due to the limited potency of compounds 1 and 2, along with their toxicity, the compounds do not warrant further development towards new antibiotics. PMID- 28654008 TI - Exposure to Perfluorinated Alkyl Substances and Health Outcomes in Children: A Systematic Review of the Epidemiologic Literature. AB - Perfluoroalkyl substances (PFAS), chemicals used to make products stain and stick resistant, have been linked to health effects in adults and adverse birth outcomes. A growing body of literature also addresses health effects in children exposed to PFAS. This review summarizes the epidemiologic evidence for relationships between prenatal and/or childhood exposure to PFAS and health outcomes in children as well as to provide a risk of bias analysis of the literature. A systematic review was performed by searching PubMed for studies on PFAS and child health outcomes. We identified 64 studies for inclusion and performed risk of bias analysis on those studies. We determined that risk of bias across studies was low to moderate. Six categories of health outcomes emerged. These were: immunity/infection/asthma, cardio-metabolic, neurodevelopmental/attention, thyroid, renal, and puberty onset. While there are a limited number of studies for any one particular health outcome, there is evidence for positive associations between PFAS and dyslipidemia, immunity (including vaccine response and asthma), renal function, and age at menarche. One finding of note is that while PFASs are mixtures of multiple compounds few studies examine them as such, therefore the role of these compounds as complex mixtures remains largely unknown. PMID- 28654010 TI - Effects of Pup Separation on Stress Response in Postpartum Female Rats. AB - There is a complex collection of neuroendocrine function during the postpartum period. Prolactin (PRL) released by suckling stimulus and its PRL receptors (PRL R) in the central nervous system (CNS) are involved in hyporesponsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in lactating mammals including rodents and humans. It is not clear how long it takes to reestablish the attenuated HPA axis activity of lactating rats to a pre-pregnancy state after pup separation. We first tested the hypothesis that HPA axis activity in response to an acute stress in postpartum rats would return to a pre-pregnancy state after pup separation. Restraint stress for 30 min was performed at the end of pup separation as an acute stressor. Plasma levels of corticosterone (CORT) were measured following restraint stress or no-stress (control) in virgin rats and postpartum rats housed with their pups or with pup removal for different periods of time of one hour, 24 h, or eight days. We then tested the hypothesis that circulating PRL level and CNS PRL-R gene expression were involved in mediating the acute stress response in postpartum rats. Plasma levels of PRL and PRL-R mRNA levels in the choroid plexus of the CNS were determined in both no-stress and stress, virgin rats, and postpartum rats housed with their pups or with pup removal for various periods, and their correlation with plasma CORT levels was assessed. The results demonstrated that PRL levels declined to virgin state in all postpartum rats separated from their pups, including the dams with one-hour pup separation. Stress-induced HPA activity dampened in lactating rats housed with pups, and returned to the pre-pregnancy state after 24 h of pup separation when both circulating PRL level and CNS PRL-R expression were restored to a pre-pregnancy state. Additionally, basal plasma CORT and CNS PRL-R expression were significantly correlated in rats with various pup status. This study suggested that stress-induced HPA activation occurred when PRL-R expression was similar to the level of virgin females, indicating that PRL-R upregulation contributes to an attenuated HPA response to acute stress. Understanding neuroendocrine responses to stress during the postpartum period is critical to understand postpartum related neuropsychiatric illnesses and to maintain mental health in postpartum women. PMID- 28654011 TI - Thermoelectric and Transport Properties of Delafossite CuCrO2:Mg Thin Films Prepared by RF Magnetron Sputtering. AB - P-type Mg doped CuCrO2 thin films have been deposited on fused silica substrates by Radio-Frequency (RF) magnetron sputtering. The as-deposited CuCrO2:Mg thin films have been annealed at different temperatures (from 450 to 650 degrees C) under primary vacuum to obtain the delafossite phase. The annealed samples exhibit 3R delafossite structure. Electrical conductivity sigma and Seebeck coefficient S of all annealed films have been measured from 40 to 220 degrees C. The optimized properties have been obtained for CuCrO2:Mg thin film annealed at 550 degrees C. At a measurement temperature of 40 degrees C, this sample exhibited the highest electrical conductivity of 0.60 S.cm-1 with a Seebeck coefficient of +329 uV.K-1. The calculated power factor (PF = sigmaS2) was 6 uW.m 1.K-2 at 40 degrees C and due to the constant Seebeck coefficient and the increasing electrical conductivity with measurement temperature, it reached 38 uW.m-1.K-2 at 220 degrees C. Moreover, according to measurement of the Seebeck coefficient and electrical conductivity in temperature, we confirmed that CuCrO2:Mg exhibits hopping conduction and degenerates semiconductor behavior. Carrier concentration, Fermi level, and hole effective mass have been discussed. PMID- 28654012 TI - I-V and C-V Characterization of a High-Responsivity Graphene/Silicon Photodiode with Embedded MOS Capacitor. AB - We study the effect of temperature and light on the I-V and C-V characteristics of a graphene/silicon Schottky diode. The device exhibits a reverse-bias photocurrent exceeding the forward current and achieves a photoresponsivity as high as 2.5 A / W . We show that the enhanced photocurrent is due to photo generated carriers injected in the graphene/Si junction from the parasitic graphene/SiO2/Si capacitor connected in parallel to the diode. The same mechanism can occur with thermally generated carriers, which contribute to the high leakage current often observed in graphene/Si junctions. PMID- 28654013 TI - In Vitro Anti-Leishmanial Activity of Essential Oils Extracted from Vietnamese Plants. AB - Leishmania mexicana is one of the pathogens causing cutaneous leishmaniasis which is associated with patient morbidity. In our researches for new safe and effective treatments, thirty-seven essential oils (EOs) extracted from Vietnamese plants were screened in vitro for the first time on Leishmania mexicana mexicana(Lmm) promastigotes at the maximum concentration of 50 nL/mL. Active EOs were also analyzed for cytotoxicity on mammalian cell lines (WI38, J774) and their selectivity indices (SI) were calculated. Their composition was determined by GC-MS and GC-FID. Our results indicated that EOs extracted from Cinnamomum cassia, Zingiber zerumbet, Elsholtzia ciliata and Amomum aromaticum, possessed a moderate anti-leishmanial activity, with IC50 values of 2.92 +/- 0.08, 3.34 +/- 0.34, 8.49 +/- 0.32 and 9.25 +/- 0.64 nL/mL respectively. However, they also showed cytotoxicity with SI < 10. The most promising EO was extracted from Ocimum gratissimum, displaying an IC50 of 4.85 +/- 1.65 nL/mL and SI > 10. It contained 86.5% eugenol, which was demonstrated to be effective on Lmm with IC50 of 2.57 +/ 0.57 nL/mL and not toxic on mammalian cells, explaining the observed activity. PMID- 28654014 TI - Ultrasonic Assisted-Reflux Synergistic Extraction of Camptothecin and Betulinic Acid from Camptotheca acuminata Decne. Fruits. AB - A novel and efficient ultrasonic assisted-reflux synergistic extraction (UARSE) method for extracting camptothecin (CPT) and betulinic acid (BA) from Camptotheca acuminata Decne. fruits has been developed in this study. The advantages of the ultrasonic and reflux extraction methods have been combined in the UARSE method and used to extract CPT and BA for the first time. The parameters influencing the efficiency of UARSE were optimized using the Box-Behnken design (BBD) to obtain the maximum extraction yield of CPT and BA. The optimal extraction conditions were as follows: 225 W for the ultrasonic power; 24 min for the extraction time; and 32 mL/g for the liquid-solid ratio. The extraction yields obtained by UARSE were 2.386 +/- 0.112 mg/g for CPT and 17.192 +/- 0.808 mg/g for BA, which were 1.43-fold and 1.33-fold, respectively, higher than by using heating reflux extraction (HRE) and ultrasonic-assisted extraction (UAE). In addition, the 24 min extraction time using UARSE was 80% and 60% less than those provided by HRE and UAE, respectively. Therefore, UARSE can be considered a rapid and efficient method for extracting CPT and BA from the fruits of C. acuminata Decne. PMID- 28654015 TI - LMP1 and Dynamic Progressive Telomere Dysfunction: A Major Culprit in EBV Associated Hodgkin's Lymphoma. AB - Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells in classical EBV-positive Hodgkin's lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In a conditional, germinal-center-derived B-cell in vitro system, LMP1 reversibly down-regulates the shelterin proteins, telomeric repeat binding factor (TRF)1, TRF2, and protection of telomeres (POT)1. This down regulation is associated with progressive 3D shelterin disruption, resulting in telomere dysfunction, progression of complex chromosomal rearrangements, and multinuclearity. TRF2 appears to be the key player. Thus, we hypothesize that the 3D interaction of telomeres and TRF2 is disrupted in H cells, and directly associated with the formation of H and RS cells. Using quantitative 3D co-immuno TRF2-telomere fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) applied to monolayers of primary H and RS cells, we demonstrate TRF2-telomere dysfunction in EBV-positive cHL. However, in EBV-negative cHL a second molecular mechanism characterized by massive up-regulation of TRF2, but attrition of telomere signals, is also identified. These facts point towards a shelterin-related pathogenesis of cHL, where two molecularly disparate mechanisms converge at the level of 3D Telomere-TRF2 interactions, leading to the formation of RS cells. PMID- 28654016 TI - Salivary Immune and Metabolic Marker Analysis (SIMMA): A Diagnostic Test to Predict Caries Risk. AB - By using ELISA and colorimetric tests, we have measured 25 compounds in individuals with and without dental caries at different time points of dental biofilm formation and time of the day. We find that some compounds appear to be affected by circadian rhythms, others by dental plaque maturity, and others show constant values during a 24 h period. Using univariate analysis and cross validation techniques, we have selected six components measured at specific time points that maximize the diagnostic separation of health and disease conditions. Two out of the six selected compounds are related to immune competence, another two to the adhesion capacity of micro-organisms, and another two to acid production or pH buffering. We conclude that, in order to design a robust caries risk test, the time of saliva sampling must be standardized and biomarkers from different categories must be included. The preliminary data shown in this paper provide a proof of principle of a caries risk test based on risk-associated categories. Thus, the test will provide not only a general caries risk assessment, but also the likely biological origin of that risk, namely: immune imbalance, and/or a tendency to adhesion of cariogenic organisms, and/or a lack of acid buffering. When tested longitudinally and validated in larger cohorts, this could open the possibility to develop preventive and personalized treatments. PMID- 28654018 TI - A Quantitative Acetylomic Analysis of Early Seed Development in Rice (Oryza sativa L.). AB - PKA (protein lysine acetylation) is a critical post-translational modification that regulates various developmental processes, including seed development. However, the acetylation events and dynamics on a proteomic scale in this process remain largely unknown, especially in rice early seed development. We report the first quantitative acetylproteomic study focused on rice early seed development by employing a mass spectral-based (MS-based), label-free approach. A total of 1817 acetylsites on 1688 acetylpeptides from 972 acetylproteins were identified in pistils and seeds at three and seven days after pollination, including 268 acetyproteins differentially acetylated among the three stages. Motif-X analysis revealed that six significantly enriched motifs, such as (DxkK), (kH) and (kY) around the acetylsites of the identified rice seed acetylproteins. Differentially acetylated proteins among the three stages, including adenosine diphosphate (ADP) -glucose pyrophosphorylases (AGPs), PDIL1-1 (protein disulfide isomerase like 1 1), hexokinases, pyruvate dehydrogenase complex (PDC) and numerous other regulators that are extensively involved in the starch and sucrose metabolism, glycolysis/gluconeogenesis, tricarboxylic acid (TCA) cycle and photosynthesis pathways during early seed development. This study greatly expanded the rice acetylome dataset, and shed novel insight into the regulatory roles of PKA in rice early seed development. PMID- 28654017 TI - Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders? AB - Vitamin C (Vit C) is considered to be a vital antioxidant molecule in the brain. Intracellular Vit C helps maintain integrity and function of several processes in the central nervous system (CNS), including neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection. The importance of Vit C for CNS function has been proven by the fact that targeted deletion of the sodium-vitamin C co-transporter in mice results in widespread cerebral hemorrhage and death on post-natal day one. Since neurological diseases are characterized by increased free radical generation and the highest concentrations of Vit C in the body are found in the brain and neuroendocrine tissues, it is suggested that Vit C may change the course of neurological diseases and display potential therapeutic roles. The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders. PMID- 28654019 TI - Preventive Effect of Cow's Milk Fermented with Lactobacillus paracasei CBA L74 on Common Infectious Diseases in Children: A Multicenter Randomized Controlled Trial. AB - : Background: Fermented foods have been proposed to prevent common infectious diseases (CIDs) in children attending day care or preschool. OBJECTIVES: To investigate the efficacy of dietary supplementation with cow's skim milk fermented with the probiotic Lactobacillus paracasei CBA L74 in reducing CIDs in children attending day care or preschool. Methods: Multicenter, randomized, double-blind, placebo-controlled trial on healthy children (aged 12-48 months) consuming daily 7 grams of cow's skim milk fermented with L. paracasei CBA L74 (group A), or placebo (maltodextrins group B) attending day care or preschool during the winter season. The main outcome was the proportion of children who experienced >=1 episode of CID during a 3-month follow-up. Fecal biomarkers of innate (alpha- and beta-defensins, cathelicidin) and acquired immunity (secretory IgA) were also monitored. Results: A total of 126 children (71 males, 56%) with a mean (SD) age of 33 (9) months completed the study, 66 in group A and 60 in group B. At intention to treat analysis, the proportion of children presenting >=1 CID was 60% in group A vs. 83% in group B, corresponding to an absolute risk difference (ARD) of -23% (95% CI: -37% to -9%, p < 0.01). At per-protocol analysis (PPA), the proportion of children presenting >=1 CID was 18% in group A vs. 40% in group B, corresponding to an absolute risk difference (ARD) of -22% (95% CI: -37% to -6%, p < 0.01). PPA showed that the proportion of children presenting >=1 acute gastroenteritis (AGE) was significantly lower in group A (18% vs. 40%, p < 0.05). The ARD for the occurrence of >=1 AGE was -22% (95% CI: 37% to -6%, p < 0.01) in group A. Similar findings were obtained at PPA regarding the proportion of children presenting >=1 upper respiratory tract infection (URTI), which was significantly lower in group A (51% vs. 74%, p < 0.05), corresponding to an ARD of -23% (95% CI: -40% to -7%, p < 0.01). Significant changes in innate and acquired immunity biomarkers were observed only in subjects in group A. Conclusions: Dietary supplementation with cow's skim milk fermented with L. paracasei CBA L74 is an efficient strategy in preventing CIDs in children. PMID- 28654022 TI - Recent advances in the management of gastroenteropancreatic neuroendocrine tumors: insights from the 2017 ASCO Gastrointestinal Cancers Symposium. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies that originate in the gastrointestinal system. GEP-NETs are typically indolent, but tumors known as "functional" secrete hormones that can lead to a complex of symptoms, including flushing, diarrhea, bronchospasm, and valvular heart disease. Management of patients with GEP-NETs requires a multidisciplinary approach, as treatment modalities include surgery, radiology, and pharmacotherapy. The available pharmacologic agents have increased in recently, and now include cytotoxic chemotherapies, somatostatin analogues, multitargeted tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and radioisotopic radiotherapies. The optimal sequencing of treatments is unknown. Advances in the management of GEP-NETs have been based on the results of recently completed clinical trials that have shown improvement in disease outcome and symptom management. The amount of positive data that has emerged from these studies is unprecedented in the GEP-NETs field. At the 2017 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, several abstracts provided subanalyses of previous trials and new data for emerging treatments. Management will likely evolve as these therapies are incorporated into clinical care. PMID- 28654023 TI - Refining the management of patients with gastroenteropancreatic neuroendocrine tumors. PMID- 28654024 TI - Emerging treatment options for patients with gastroenteropancreatic neuroendocrine tumors. PMID- 28654020 TI - Effects of Non-Starch Polysaccharides on Inflammatory Bowel Disease. AB - The incidence of inflammatory bowel disease (IBD) has increased considerably over the past few decades. In the present review, we discuss several disadvantages existing in the treatment of IBD and current understandings of the structures, sources, and natures of various kinds of non-starch polysaccharides (NSPs). Available evidences for the use of different sources of NSPs in IBD treatment both in vitro and in vivo are analyzed, including glucan from oat bran, mushroom, seaweed, pectin, gum, prebiotics, etc. Their potential mechanisms, especially their related molecular mechanism of protective action in the treatment and prevention of IBD, are also summarized, covering the anti-inflammation, immune stimulating, and gut microbiota-modulating activities, as well as short-chain fatty acids (SCFAs) production, anti-oxidative stress accompanied with inflammation, the promotion of gastric epithelial cell proliferation and tissue healing, and the reduction of the absorption of toxins of NSPs, thus ameliorating the symptoms and reducing the reoccurrence rate of IBD. In summary, NSPs exhibit the potential to be promising agents for an adjuvant therapy and for the prevention of IBD. Further investigating of the crosstalk between immune cells, epithelial cells, and gut microorganisms in addition to evaluating the effects of different kinds and different molecular weights of NSPs will lead to well designed clinical intervention trials and eventually improve the treatment and prevention of IBD. PMID- 28654025 TI - Surgical approaches for patients with gastroenteropancreatic nuroendocrine tumors. PMID- 28654021 TI - Vitamin C, Aging and Alzheimer's Disease. AB - Accumulating evidence in mice models of accelerated senescence indicates a rescuing role of ascorbic acid in premature aging. Supplementation of ascorbic acid appeared to halt cell growth, oxidative stress, telomere attrition, disorganization of chromatin, and excessive secretion of inflammatory factors, and extend lifespan. Interestingly, ascorbic acid (AA) was also found to positively modulate inflamm-aging and immunosenescence, two hallmarks of biological aging. Moreover, ascorbic acid has been shown to epigenetically regulate genome integrity and stability, indicating a key role of targeted nutrition in healthy aging. Growing in vivo evidence supports the role of ascorbic acid in ameliorating factors linked to Alzheimer's disease (AD) pathogenesis, although evidence in humans yielded equivocal results. The neuroprotective role of ascorbic acid not only relies on the general free radical trapping, but also on the suppression of pro-inflammatory genes, mitigating neuroinflammation, on the chelation of iron, copper, and zinc, and on the suppression of amyloid-beta peptide (Abeta) fibrillogenesis. Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease is rapidly increasing. Thus, dietary interventions, as a way to epigenetically modulate the human genome, may play a role in the prevention of AD. The present review is aimed at providing an up to date overview of the main biological mechanisms that are associated with ascorbic acid supplementation/bioavailability in the process of aging and Alzheimer's disease. In addition, we will address new fields of research and future directions. PMID- 28654026 TI - Recent advances in the management of gastroenteropancreatic neuroendocrine tumors: Discussion. PMID- 28654028 TI - Highlights in ovarian cancer from the 2017 Society of Gynecologic Oncology annual meeting on women's cancer: Commentary. PMID- 28654027 TI - Highlights in ovarian cancer from the 2017 Society of Gynecologic Oncology annual meeting on women's cancer. PMID- 28654029 TI - Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding. AB - G-Protein-Coupled Receptors (GPCRs) are a large family of transmembrane receptors that play critical roles in normal cellular physiology and constitute a major pharmacological target for multiple indications, including analgesia, blood pressure regulation, and the treatment of psychiatric disease. Upon ligand binding, GPCRs catalyze the activation of intracellular G-proteins by stimulating the incorporation of guanosine triphosphate (GTP). Activated G-proteins then stimulate signaling pathways that elicit cellular responses. GPCR signaling can be monitored by measuring the incorporation of a radiolabeled and non hydrolyzable form of GTP, [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS), into G-proteins. Unlike other methods that assess more downstream signaling processes, [35S]GTPgammaS binding measures a proximal event in GPCR signaling and, importantly, can distinguish agonists, antagonists, and inverse agonists. The present protocol outlines a sensitive and specific method for studying GPCR signaling using crude membrane preparations of an archetypal GPCR, the u-opioid receptor (MOR1). Although alternative approaches to fractionate cells and tissues exist, many are cost-prohibitive, tedious, and/or require non-standard laboratory equipment. The present method provides a simple procedure that enriches functional crude membranes. After isolating MOR1, various pharmacological properties of its agonist, [D-Ala, N-MePhe, Gly-ol]-enkephalin (DAMGO), and antagonist, naloxone, were determined. PMID- 28654030 TI - In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging. AB - Cerebral malaria is a sign of severe malarial disease and is often a harbinger of death. While aggressive management can be life-saving, the detection of cerebral malaria can be difficult. We present an experimental mouse model of cerebral malaria that shares multiple features of the human disease, including edema and microvascular pathology. Using magnetic resonance imaging (MRI), we can detect and track the blood-brain barrier disruption, edema development, and subsequent brain swelling. We describe multiple MRI techniques that can visualize these pertinent pathological changes. Thus, we show that MRI represents a valuable tool to visualize and track pathological changes, such as edema, brain swelling, and microvascular pathology, in vivo. PMID- 28654031 TI - Treatment of Ligament Constructs with Exercise-conditioned Serum: A Translational Tissue Engineering Model. AB - In vitro experiments are essential to understand biological mechanisms; however, the gap between monolayer tissue culture and human physiology is large, and translation of findings is often poor. Thus, there is ample opportunity for alternative experimental approaches. Here we present an approach in which human cells are isolated from human anterior cruciate ligament tissue remnants, expanded in culture, and used to form engineered ligaments. Exercise alters the biochemical milieu in the blood such that the function of many tissues, organs and bodily processes are improved. In this experiment, ligament construct culture media was supplemented with experimental human serum that has been 'conditioned' by exercise. Thus the intervention is more biologically relevant since an experimental tissue is exposed to the full endogenous biochemical milieu, including binding proteins and adjunct compounds that may be altered in tandem with the activity of an unknown agent of interest. After treatment, engineered ligaments can be analyzed for mechanical function, collagen content, morphology, and cellular biochemistry. Overall, there are four major advantages versus traditional monolayer culture and animal models, of the physiological model of ligament tissue that is presented here. First, ligament constructs are three dimensional, allowing for mechanical properties (i.e., function) such as ultimate tensile stress, maximal tensile load, and modulus, to be quantified. Second, the enthesis, the interface between boney and sinew elements, can be examined in detail and within functional context. Third, preparing media with post-exercise serum allows for the effects of the exercise-induced biochemical milieu, which is responsible for the wide range of health benefits of exercise, to be investigated in an unbiased manner. Finally, this experimental model advances scientific research in a humane and ethical manner by replacing the use of animals, a core mandate of the National Institutes of Health, the Center for Disease Control, and the Food and Drug Administration. PMID- 28654032 TI - Assessing Working Memory in Children: The Comprehensive Assessment Battery for Children - Working Memory (CABC-WM). AB - The Comprehensive Assessment Battery for Children - Working Memory (CABC-WM) is a computer-based battery designed to assess different components of working memory in young school-age children. Working memory deficits have been identified in children with language-based learning disabilities, including dyslexia1,2 and language impairment3,4, but it is not clear whether these children exhibit deficits in subcomponents of working memory, such as visuospatial or phonological working memory. The CABC-WM is administered on a desktop computer with a touchscreen interface and was specifically developed to be engaging and motivating for children. Although the long-term goal of the CABC-WM is to provide individualized working memory profiles in children, the present study focuses on the initial success and utility of the CABC-WM for measuring central executive, visuospatial, phonological loop, and binding constructs in children with typical development. Immediate next steps are to administer the CABC-WM to children with specific language impairment, dyslexia, and comorbid specific language impairment and dyslexia. PMID- 28654033 TI - Scanning Light Scattering Profiler (SLPS) Based Methodology to Quantitatively Evaluate Forward and Backward Light Scattering from Intraocular Lenses. AB - The scanning light scattering profiler (SLSP) methodology has been developed for the full-angle quantitative evaluation of forward and backward light scattering from intraocular lenses (IOLs) using goniophotometer principles. This protocol describes the SLSP platform and how it employs a 360 degrees rotational photodetector sensor that is scanned around an IOL sample while recording the intensity and location of scattered light as it passes through the IOL medium. The SLSP platform can be used to predict, non-clinically, the propensity for current and novel IOL designs and materials to induce light scatter. Non-clinical evaluation of light scattering properties of IOLs can significantly reduce the number of patient complaints related to unwanted glare, glistening, optical defects, poor image quality, and other phenomena associated with the unintended light scattering. Future studies should be conducted to correlate SLSP data with clinical results to help identify which measured light scatter is most problematic for patients that have undergone cataract surgery subsequent to IOL implantation. PMID- 28654034 TI - Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity (AIDN): A Translational Neuroscience Approach. AB - Anesthesia cannot be avoided in many cases when surgery is required, particularly in children. Recent investigations in animals have raised concerns that anesthesia exposure may lead to neuronal apoptosis, known as anesthesia-induced developmental neurotoxicity (AIDN). Furthermore, some clinical studies in children have suggested that anesthesia exposure may lead to neurodevelopmental deficits later in life. Nonetheless, an ideal animal model for preclinical study has yet to be developed. The neonatal piglet represents a valuable model for preclinical study, as they share a striking number of developmental similarities with humans. The anatomy and physiology of piglets allow for implementation of rigorous human perioperative conditions in both survival and non-survival procedures. Femoral artery catheterization allows for close monitoring, thus enabling prompt correction of any deviation of the piglet's vital signs and chemistries. In addition, there are multiple developmental similarities between piglets and human neonates. The techniques required to use piglets for experimentation will require experience to master. A pediatric anesthesiologist is a critical member of the investigative team. We describe, in a general sense, the appropriate use of a piglet model for neurodevelopmental study. PMID- 28654035 TI - Measurement of the Rheology of Crude Oil in Equilibrium with CO2 at Reservoir Conditions. AB - A rheometer system to measure the rheology of crude oil in equilibrium with carbon dioxide (CO2) at high temperatures and pressures is described. The system comprises a high-pressure rheometer which is connected to a circulation loop. The rheometer has a rotational flow-through measurement cell with two alternative geometries: coaxial cylinder and double gap. The circulation loop contains a mixer, to bring the crude oil sample into equilibrium with CO2, and a gear pump that transports the mixture from the mixer to the rheometer and recycles it back to the mixer. The CO2 and crude oil are brought to equilibrium by stirring and circulation and the rheology of the saturated mixture is measured by the rheometer. The system is used to measure the rheological properties of Zuata crude oil (and its toluene dilution) in equilibrium with CO2 at elevated pressures up to 220 bar and a temperature of 50 degrees C. The results show that CO2 addition changes the oil rheology significantly, initially reducing the viscosity as the CO2 pressure is increased and then increasing the viscosity above a threshold pressure. The non-Newtonian response of the crude is also seen to change with the addition of CO2. PMID- 28654036 TI - In Ovo Electroporation in the Chicken Auditory Brainstem. AB - Electroporation is a method that introduces genes of interest into biologically relevant organisms like the chicken embryo. It is long established that the chicken embryo is an effective research model for studying basic biological functions of auditory system development. More recently, the chicken embryo has become particularly valuable in studying gene expression, regulation and function associated with hearing. In ovo electroporation can be used to target auditory brainstem regions responsible for highly specialized auditory functions. These regions include the chicken nucleus magnocellularis (NM) and nucleus laminaris (NL). NM and NL neurons arise from distinct precursors of rhombomeres 5 and 6 (R5/R6). Here, we present in ovo electroporation of plasmid-encoded genes to study gene-related properties in these regions. We show a method for spatial and temporal control of gene expression that promote either gain or loss of functional phenotypes. By targeting auditory neural progenitor regions associated with R5/R6, we show plasmid transfection in NM and NL. Temporal regulation of gene expression can be achieved by adopting a tet-on vector system. This is a drug inducible procedure that expresses the genes of interest in the presence of doxycycline (Dox). The in ovo electroporation technique - together with either biochemical, pharmacological, and or in vivo functional assays - provides an innovative approach to study auditory neuron development and associated pathophysiological phenomena. PMID- 28654037 TI - Non-invasive Assessments of Subjective and Objective Recovery Characteristics Following an Exhaustive Jump Protocol. AB - Fast recovery after strenuous exercise is important in sports and is often studied via cryotherapy applications. Cryotherapy has a significant vasoconstrictive effect, which seems to be the leading factor in its effectiveness. The resulting enhanced recovery can be measured by using both objective and subjective parameters. Two commonly measured subjective characteristics of recovery are delayed-onset muscle soreness (DOMS) and ratings of perceived exertion (RPE). Two important objective recovery characteristics are countermovement jump (CMJ) performance and peak power output (PPO). Here, we provide a detailed protocol to induce muscular exhaustion of the frontal thighs with a self-paced, 3 x 30 countermovement jump protocol (30-s rest between each set). This randomized controlled trial protocol explains how to perform local cryotherapy cuff application (+ 8 degrees C for 20 min) and thermoneutral cuff application (+ 32 degrees C for 20 min) on both thighs as two possible post exercise recovery modalities. Finally, we provide a non-invasive protocol to measure the effects of these two recovery modalities on subjective (i.e., DOMS of both frontal thighs and RPE) and objective recovery (i.e., CMJ and PPO) characteristics 24, 48, and 72 h post-application. The advantage of this method is that it provides a tool for researchers or coaches to induce muscular exhaustion, without using any expensive devices; to implement local cooling strategies; and to measure both subjective and objective recovery, without using invasive methods. Limitations of this protocol are that the 30 s rest period between sets is very short, and the cardiovascular demand is very high. Future studies may find the assessment of maximum voluntary contractions to be a more sensitive assessment of muscular exhaustion compared to CMJs. PMID- 28654038 TI - Rewiring Neuronal Circuits: A New Method for Fast Neurite Extension and Functional Neuronal Connection. AB - Brain and spinal cord injury may lead to permanent disability and death because it is still not possible to regenerate neurons over long distances and accurately reconnect them with an appropriate target. Here a procedure is described to rapidly initiate, elongate, and precisely connect new functional neuronal circuits over long distances. The extension rates achieved reach over 1.2 mm/h, 30-60 times faster than the in vivo rates of the fastest growing axons from the peripheral nervous system (0.02 to 0.04 mm/h)28 and 10 times faster than previously reported for the same neuronal type at an earlier stage of development4. First, isolated populations of rat hippocampal neurons are grown for 2-3 weeks in microfluidic devices to precisely position the cells, enabling easy micromanipulation and experimental reproducibility. Next, beads coated with poly-D-lysine (PDL) are placed on neurites to form adhesive contacts and pipette micromanipulation is used to move the resulting bead-neurite complex. As the bead is moved, it pulls out a new neurite that can be extended over hundreds of micrometers and functionally connected to a target cell in less than 1 h. This process enables experimental reproducibility and ease of manipulation while bypassing slower chemical strategies to induce neurite growth. Preliminary measurements presented here demonstrate a neuronal growth rate far exceeding physiological ones. Combining these innovations allows for the precise establishment of neuronal networks in culture with an unprecedented degree of control. It is a novel method that opens the door to a plethora of information and insights into signal transmission and communication within the neuronal network as well as being a playground in which to explore the limits of neuronal growth. The potential applications and experiments are widespread with direct implications for therapies that aim to reconnect neuronal circuits after trauma or in neurodegenerative diseases. PMID- 28654040 TI - Video Tracking Protocol to Screen Deterrent Chemistries for Honey Bees. AB - The European honey bee, Apis mellifera L., is an economically and agriculturally important pollinator that generates billions of dollars annually. Honey bee colony numbers have been declining in the United States and many European countries since 1947. A number of factors play a role in this decline, including the unintentional exposure of honey bees to pesticides. The development of new methods and regulations are warranted to reduce pesticide exposures to these pollinators. One approach is the use of repellent chemistries that deter honey bees from a recently pesticide-treated crop. Here, we describe a protocol to discern the deterrence of honey bees exposed to select repellent chemistries. Honey bee foragers are collected and starved overnight in an incubator 15 h prior to testing. Individual honey bees are placed into Petri dishes that have either a sugar-agarose cube (control treatment) or sugar-agarose-compound cube (repellent treatment) placed into the middle of the dish. The Petri dish serves as the arena that is placed under a camera in a light box to record the honey bee locomotor activities using video tracking software. A total of 8 control and 8 repellent treatments were analyzed for a 10 min period with each treatment was duplicated with new honey bees. Here, we demonstrate that honey bees are deterred from the sugar-agarose cubes with a compound treatment whereas honey bees are attracted to the sugar-agarose cubes without an added compound. PMID- 28654039 TI - Electrophysiological Method for Whole-cell Voltage Clamp Recordings from Drosophila Photoreceptors. AB - Whole-cell voltage clamp recordings from Drosophila melanogaster photoreceptors have revolutionized the field of invertebrate visual transduction, enabling the use of D. melanogaster molecular genetics to study inositol-lipid signaling and Transient Receptor Potential (TRP) channels at the single-molecule level. A handful of labs have mastered this powerful technique, which enables the analysis of the physiological responses to light under highly controlled conditions. This technique allows control over the intracellular and extracellular media; the membrane voltage; and the fast application of pharmacological compounds, such as a variety of ionic or pH indicators, to the intra- and extracellular media. With an exceptionally high signal-to-noise ratio, this method enables the measurement of dark spontaneous and light-induced unitary currents (i.e. spontaneous and quantum bumps) and macroscopic Light-induced Currents (LIC) from single D. melanogaster photoreceptors. This protocol outlines, in great detail, all the key steps necessary to perform this technique, which includes both electrophysiological and optical recordings. The fly retina dissection procedure for the attainment of intact and viable ex vivo isolated ommatidia in the bath chamber is described. The equipment needed to perform whole-cell and fluorescence imaging measurements are also detailed. Finally, the pitfalls in using this delicate preparation during extended experiments are explained. PMID- 28654041 TI - Visualization of the Axonal Projection Pattern of Embryonic Motor Neurons in Drosophila. AB - The establishment of functional neuromuscular circuits relies on precise connections between developing motor axons and target muscles. Motor neurons extend growth cones to navigate along specific pathways by responding to a large number of axon guidance cues that emanate from the surrounding extracellular environment. Growth cone target recognition also plays a critical role in neuromuscular specificity. This work presents a standard immunohistochemistry protocol to visualize motor neuron projections of late stage-16 Drosophila melanogaster embryos. This protocol includes a few key steps, including a genotyping procedure, to sort the desired mutant embryos; an immunostaining procedure, to tag embryos with fasciclin II (FasII) antibody; and a dissection procedure, to generate filleted preparations from fixed embryos. Motor axon projections and muscle patterns in the periphery are much better visualized in flat preparations of filleted embryos than in whole-mount embryos. Therefore, the filleted preparation of fixed embryos stained with FasII antibody provides a powerful tool to characterize the genes required for motor axon pathfinding and target recognition, and it can also be applied to both loss-of-function and gain of-function genetic screens. PMID- 28654042 TI - A Unified Methodological Framework for Vestibular Schwannoma Research. AB - Vestibular schwannomas are the most common neoplasms of the cerebellopontine angle, making up 6-8% percent of all intracranial growths. Though these tumors cause sensorineural hearing loss in up to 95% of affected individuals, the molecular mechanisms underlying this hearing loss remain elusive. This article outlines the steps established in our laboratory to facilitate the collection and processing of various primary human tissue samples for downstream research applications integral to the study of vestibular schwannomas. Specifically, this work describes a unified methodological framework for the collection, processing, and culture of Schwann and schwannoma cells from surgical samples. This is integrated with parallel processing steps now considered essential for current research: the collection of tumor and nerve secretions, the preservation of RNA and the extraction of protein from collected tissues, the fixation of tissue for the preparation of sections, and the exposure of primary human cells to adeno associated viruses for application to gene therapy. Additionally, this work highlights the translabyrinthine surgical approach to collect this tumor as a unique opportunity to obtain human sensory epithelium from the inner ear and perilymph. Tips to improve experimental quality are provided and common pitfalls highlighted. PMID- 28654043 TI - Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development. AB - Kinase activity is crucial for a plethora of cellular functions, including cell proliferation, differentiation, migration, and apoptosis. During early embryonic development, kinase activity is highly dynamic and widespread across the embryo. Pharmacological and genetic approaches are commonly used to probe kinase activities. Unfortunately, it is challenging to achieve superior spatial and temporal resolution using these strategies. Furthermore, it is not feasible to control the kinase activity in a reversible fashion in live cells and multicellular organisms. Such a limitation remains a bottleneck for achieving a quantitative understanding of kinase activity during development and differentiation. This work presents an optogenetic strategy that takes advantage of a bicistronic system containing photoactivatable proteins Arabidopsis thaliana cryptochrome 2 (CRY2) and the N-terminal domain of cryptochrome-interacting basic helix-loop-helix (CIBN). Reversible activation of the mitogen-activated protein kinase (MAPK) signaling pathway is achieved through light-mediated protein translocation in live cells. This approach can be applied to mammalian cell cultures and live vertebrate embryos. This bicistronic system can be generalized to control the activity of other kinases with similar activation mechanisms and can be applied to other model systems. PMID- 28654045 TI - Rescue and Characterization of Recombinant Virus from a New World Zika Virus Infectious Clone. AB - Infectious cDNA clones allow for genetic manipulation of a virus, thus facilitating work on vaccines, pathogenesis, replication, transmission and viral evolution. Here we describe the construction of an infectious clone for Zika virus (ZIKV), which is currently causing an explosive outbreak in the Americas. To prevent toxicity to bacteria that is commonly observed with flavivirus-derived plasmids, we generated a two-plasmid system which separates the genome at the NS1 gene and is more stable than full-length constructs that could not be successfully recovered without mutations. After digestion and ligation to join the two fragments, full-length viral RNA can be generated by in vitro transcription with T7 RNA polymerase. Following electroporation of transcribed RNA into cells, virus was recovered that exhibited similar in vitro growth kinetics and in vivo virulence and infection phenotypes in mice and mosquitoes, respectively. PMID- 28654044 TI - Methods for the Extraction of Endosymbionts from the Whitefly Bemisia tabaci. AB - Bacterial symbionts form an intimate relationship with their hosts and confer advantages to the hosts in most cases. Genomic information is critical to study the functions and evolution of bacterial symbionts in their host. As most symbionts cannot be cultured in vitro, methods to isolate an adequate quantity of bacteria for genome sequencing are very important. In the whitefly Bemisia tabaci, a number of endosymbionts have been identified and are predicted to be of importance in the development and reproduction of the pests through multiple approaches. However, the mechanism underpinning the associations remains largely unknown. The obstacle partially comes from the fact that the endosymbionts in whitefly, mostly restrained in bacteriocytes, are hard to separate from the host cells. Here we report a step-by-step protocol for the identification, extraction and purification of endosymbionts from the whitefly B. tabaci mainly by dissection and filtration. Endosymbiont samples prepared by this method, although still a mixture of different endosymbiont species, are suitable for subsequent genome sequencing and analysis of the possible roles of endosymbionts in B. tabaci. This method may also be used to isolate endosymbionts from other insects. PMID- 28654046 TI - Hypoxic Preconditioning of Marrow-derived Progenitor Cells As a Source for the Generation of Mature Schwann Cells. AB - This manuscript describes a means to enrich for neural progenitors from the marrow stromal cell (MSC) population and thereafter to direct them to the mature Schwann cell fate. We subjected rat and human MSCs to transient hypoxic conditions (1% oxygen for 16 h) followed by expansion as neurospheres upon low attachment substratum with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) supplementation. Neurospheres were seeded onto poly-D lysine/laminin-coated tissue culture plastic and cultured in a gliogenic cocktail containing beta-Heregulin, bFGF, and platelet-derived growth factor (PDGF) to generate Schwann cell-like cells (SCLCs). SCLCs were directed to fate commitment via coculture for 2 weeks with purified dorsal root ganglia (DRG) neurons obtained from E14-15 pregnant Sprague Dawley rats. Mature Schwann cells demonstrate persistence in S100beta/p75 expression and can form myelin segments. Cells generated in this manner have potential applications in autologous cell transplantation following spinal cord injury, as well as in disease modeling. PMID- 28654047 TI - Neonatal Murine Cochlear Explant Technique as an In Vitro Screening Tool in Hearing Research. AB - While there have been remarkable advances in hearing research over the past few decades, there is still no cure for Sensorineural Hearing Loss (SNHL), a condition that typically involves damage to or loss of the delicate mechanosensory structures of the inner ear. Sophisticated in vitro and ex vivo assays have emerged in recent years, enabling the screening of an increasing number of potentially therapeutic compounds while minimizing resources and accelerating efforts to develop cures for SNHL. Though homogenous cultures of certain cell types continue to play an important role in current research, many scientists now rely on more complex organotypic cultures of murine inner ears, also known as cochlear explants. The preservation of organized cellular structures within the inner ear facilitates the in situ evaluation of various components of the cochlear infrastructure, including inner and outer hair cells, spiral ganglion neurons, neurites, and supporting cells. Here we present the preparation, culture, treatment, and immunostaining of neonatal murine cochlear explants. The careful preparation of these explants facilitates the identification of mechanisms that contribute to SNHL and constitutes a valuable tool for the hearing research community. PMID- 28654048 TI - Combining Raman Imaging and Multivariate Analysis to Visualize Lignin, Cellulose, and Hemicellulose in the Plant Cell Wall. AB - The application of Raman imaging to plant biomass is increasing because it can offer spatial and compositional information on aqueous solutions. The analysis does not usually require extensive sample preparation; structural and chemical information can be obtained without labeling. However, each Raman image contains thousands of spectra; this raises difficulties when extracting hidden information, especially for components with similar chemical structures. This work introduces a multivariate analysis to address this issue. The protocol establishes a general method to visualize the main components, including lignin, cellulose, and hemicellulose within the plant cell wall. In this protocol, procedures for sample preparation, spectral acquisition, and data processing are described. It is highly dependent upon operator skill at sample preparation and data analysis. By using this approach, a Raman investigation can be performed by a non-specialist user to acquire high-quality data and meaningful results for plant cell wall analysis. PMID- 28654049 TI - Chondrogenic Pellet Formation from Cord Blood-derived Induced Pluripotent Stem Cells. AB - Human articular cartilage lacks the ability to repair itself. Cartilage degeneration is thus treated not by curative but by conservative treatments. Currently, efforts are being made to regenerate damaged cartilage with ex vivo expanded chondrocytes or bone marrow-derived mesenchymal stem cells (BMSCs). However, the restricted viability and instability of these cells limit their application in cartilage reconstruction. Human induced pluripotent stem cells (hiPSCs) have received scientific attention as a new alternative for regenerative applications. With unlimited self-renewal ability and multipotency, hiPSCs have been highlighted as a new replacement cell source for cartilage repair. However, obtaining a high quantity of high-quality chondrogenic pellets is a major challenge to their clinical application. In this study, we used embryoid body (EB)-derived outgrowth cells for chondrogenic differentiation. Successful chondrogenesis was confirmed by PCR and staining with alcian blue, toluidine blue, and antibodies against collagen types I and II (COL1A1 and COL2A1, respectively). We provide a detailed method for the differentiation of cord blood mononuclear cell-derived iPSCs (CBMC-hiPSCs) into chondrogenic pellets. PMID- 28654050 TI - DiI Perfusion as a Method for Vascular Visualization in Ambystoma mexicanum. AB - Perfusion techniques have been used for centuries to visualize the circulation of tissues. Axolotl (Ambystoma mexicanum) is a species of salamander that has emerged as an essential model for regeneration studies. Little is known about how revascularization occurs in the context of regeneration in these animals. Here we report a simple method for visualization of the vasculature in axolotl via perfusion of 1,1'-Dioctadecy-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). DiI is a lipophilic carbocyanine dye that inserts into the plasma membrane of endothelial cells instantaneously. Perfusion is done using a peristaltic pump such that DiI enters the circulation through the aorta. During perfusion, dye flows through the axolotl's blood vessels and incorporates into the lipid bilayer of vascular endothelial cells upon contact. The perfusion procedure takes approximately one hour for an eight-inch axolotl. Immediately after perfusion with DiI, the axolotl can be visualized with a confocal fluorescent microscope. The DiI emits light in the red-orange range when excited with a green fluorescent filter. This DiI perfusion procedure can be used to visualize the vascular structure of axolotls or to demonstrate patterns of revascularization in regenerating tissues. PMID- 28654051 TI - Experimental Protocol of a Three-minute, All-out Arm Crank Exercise Test in Spinal-cord Injured and Able-bodied Individuals. AB - Reliable exercise protocols are required to test changes in exercise performance in elite athletes. Performance improvements in these athletes may be small; therefore, sensitive tools are fundamental to exercise physiology. There are currently many exercise tests that allow for the examination of exercise capacity in able-bodied athletes, with protocols mainly for lower-body or whole-body exercise. There is a trend to test athletes in a sport-specific setting that closely resembles the actions that the participants are used to performing. Only a few protocols test short-term, high-intensity exercise capacity in participants with an impairment of the lower body. Most of these protocols are very sport specific and are not applicable to a wide range of athletes. One well-known test protocol is the 30 s Wingate test, which is well-established in cycling and in arm crank exercise testing. This test analyzes high-intensity exercise performance over a 30 s time duration. In order to monitor exercise performance over a longer duration, a different method was modified for application to the upper body. The 3 min, all-out arm crank ergometer test allows athletes to be tested in a manner specific to 1,500 m wheelchair racing (in terms of exercise duration), as well as to upper body exercises such as rowing or hand-cycling. In order to increase the reliability with identical test conditions, it is crucial to precisely replicate settings such as the resistance (i.e., torque factor) and the position of the participants (i.e., the height of the crank, the distance between the crank and the participant, and the fixation of the participant). Another important issue concerns the beginning of the exercise test. Fixed revolutions per minute are required to standardize the test conditions for the start of the exercise test. This exercise protocol shows the importance of accurate operations to reproduce identical test conditions and settings. PMID- 28654052 TI - Flow-sorting and Exome Sequencing of the Reed-Sternberg Cells of Classical Hodgkin Lymphoma. AB - The Hodgkin Reed-Sternberg cells of classical Hodgkin lymphoma are sparsely distributed within a background of inflammatory lymphocytes and typically comprise less than 1% of the tumor mass. Material derived from bulk tumor contains tumor content at a concentration insufficient for characterization. Therefore, fluorescence activated cell sorting using eight antibodies, as well as side- and forward-scatter, is described here as a method of rapidly separating and concentrating with high purity thousands of HRS cells from the tumor for subsequent study. At the same time, because standard protocols for exome sequencing typically require 100-1,000 ng of input DNA, which is often too high, even with flow sorting, we also provide an optimized, low-input library construction protocol capable of producing high-quality data from as little as 10 ng of input DNA. This combination is capable of producing next-generation libraries suitable for hybridization capture of whole-exome baits or more focused targeted panels, as desired. Exome sequencing of the HRS cells, when compared against healthy intratumor T or B cells, can identify somatic alterations, including mutations, insertions and deletions, and copy number alterations. These findings elucidate the molecular biology of HRS cells and may reveal avenues for targeted drug treatments. PMID- 28654053 TI - Assembly and Tracking of Microbial Community Development within a Microwell Array Platform. AB - The development of microbial communities depends on a combination of complex deterministic and stochastic factors that can dramatically alter the spatial distribution and activities of community members. We have developed a microwell array platform that can be used to rapidly assemble and track thousands of bacterial communities in parallel. This protocol highlights the utility of the platform and describes its use for optically monitoring the development of simple, two-member communities within an ensemble of arrays within the platform. This demonstration uses two mutants of Pseudomonas aeruginosa, part of a series of mutants developed to study Type VI secretion pathogenicity. Chromosomal inserts of either mCherry or GFP genes facilitate the constitutive expression of fluorescent proteins with distinct emission wavelengths that can be used to monitor community member abundance and location within each microwell. This protocol describes a detailed method for assembling mixtures of bacteria into the wells of the array and using time-lapse fluorescence imaging and quantitative image analysis to measure the relative growth of each member population over time. The seeding and assembly of the microwell platform, the imaging procedures necessary for the quantitative analysis of microbial communities within the array, and the methods that can be used to reveal interactions between microbial species area all discussed. PMID- 28654054 TI - Construction and Setup of a Bench-scale Algal Photosynthetic Bioreactor with Temperature, Light, and pH Monitoring for Kinetic Growth Tests. AB - The optimal design and operation of photosynthetic bioreactors (PBRs) for microalgal cultivation is essential for improving the environmental and economic performance of microalgae-based biofuel production. Models that estimate microalgal growth under different conditions can help to optimize PBR design and operation. To be effective, the growth parameters used in these models must be accurately determined. Algal growth experiments are often constrained by the dynamic nature of the culture environment, and control systems are needed to accurately determine the kinetic parameters. The first step in setting up a controlled batch experiment is live data acquisition and monitoring. This protocol outlines a process for the assembly and operation of a bench-scale photosynthetic bioreactor that can be used to conduct microalgal growth experiments. This protocol describes how to size and assemble a flat-plate, bench scale PBR from acrylic. It also details how to configure a PBR with continuous pH, light, and temperature monitoring using a data acquisition and control unit, analog sensors, and open-source data acquisition software. PMID- 28654055 TI - Chromatin Immunoprecipitation (ChIP) in Mouse T-cell Lines. AB - Signaling pathways regulate gene expression programs via the modulation of the chromatin structure at different levels, such as by post-translational modifications (PTMs) of histone tails, the exchange of canonical histones with histone variants, and nucleosome eviction. Such regulation requires the binding of signal-sensitive transcription factors (TFs) that recruit chromatin-modifying enzymes at regulatory elements defined as enhancers. Understanding how signaling cascades regulate enhancer activity requires a comprehensive analysis of the binding of TFs, chromatin modifying enzymes, and the occupancy of specific histone marks and histone variants. Chromatin immunoprecipitation (ChIP) assays utilize highly specific antibodies to immunoprecipitate specific protein/DNA complexes. The subsequent analysis of the purified DNA allows for the identification the region occupied by the protein recognized by the antibody. This work describes a protocol to efficiently perform ChIP of histone proteins in a mature mouse T-cell line. The presented protocol allows for the performance of ChIP assays in a reasonable timeframe and with high reproducibility. PMID- 28654056 TI - Multi-layer Cortical Ca2+ Imaging in Freely Moving Mice with Prism Probes and Miniaturized Fluorescence Microscopy. AB - In vivo circuit and cellular level functional imaging is a critical tool for understanding the brain in action. High resolution imaging of mouse cortical neurons with two-photon microscopy has provided unique insights into cortical structure, function and plasticity. However, these studies are limited to head fixed animals, greatly reducing the behavioral complexity available for study. In this paper, we describe a procedure for performing chronic fluorescence microscopy with cellular-resolution across multiple cortical layers in freely behaving mice. We used an integrated miniaturized fluorescence microscope paired with an implanted prism probe to simultaneously visualize and record the calcium dynamics of hundreds of neurons across multiple layers of the somatosensory cortex as the mouse engaged in a novel object exploration task, over several days. This technique can be adapted to other brain regions in different animal species for other behavioral paradigms. PMID- 28654057 TI - Murine Aortic Crush Injury: An Efficient In Vivo Model of Smooth Muscle Cell Proliferation and Endothelial Function. AB - Arterial reconstruction, whether angioplasty or bypass surgery, involves iatrogenic trauma causing endothelial disruption and vascular smooth muscle cell (VSMC) proliferation. Common murine models study small vessels such as the carotid and femoral arteries. Herein we describe an in vivo system in which both VSMC proliferation and endothelial barrier function can be simultaneously assessed in a large vessel. We studied the infrarenal aortic response to injury in C57BL/6 mice. The aorta was injured from the left renal vein to the aortic bifurcation by 30 transmural crushes of 5-seconds duration with a cotton-tipped applicator. Morphological changes were assessed with conventional histology. Aorta wall thickness was measured from the luminal surface to the adventitia. EdU integration and counter staining with DAPI and alpha-actin was used to demonstrate VSMC proliferation. Activation of ERK1/2, a known moderator of intimal hyperplasia formation, was determined by Western Blot analysis. The effect of inflammation was determined by immunohistochemistry for B-cells, T cells, and macrophages. En face sections of endothelium were visualized with scanning electron microscopy (SEM). Endothelial barrier function was determined with Evans Blue staining. Transmural injury resulted in aortic wall thickening. This injury induced VSMC proliferation, most prominently at 3 days after injury, and early activation of ERK1/2 and decreased p27kip1 expression. Injury did not result in increased B-cells, T-cells, or macrophages infiltration in the vessel wall. Injury caused partial endothelial cell denudation and loss of cell-cell contact. Injury resulted in a significant loss of endothelial barrier function, which returned to baseline after seven days. The murine transmural blunt aortic injury model provides an efficient system to simultaneously study both VSMC proliferation and endothelial barrier function in a large vessel. PMID- 28654058 TI - In Vitro Assays to Assess Blood-brain Barrier Mesh-like Vessel Formation and Disruption. AB - Blood-brain barrier (BBB) coverage plays a central role in the homeostasis of the central nervous system (CNS). The BBB is dynamically maintained by astrocytes, pericytes and brain endothelial cells (BECs). Here, we detail methods to assess BBB coverage using single cultures of immortalized human BECs, single cultures of primary mouse BECs, and a humanized triple culture model (BECs, astrocytes and pericytes) of the BBB. To highlight the applicability of the assays to disease states, we describe the effect of oligomeric amyloid-beta (oAbeta), which is an important contributor to Alzheimer's disease (AD) progression, on BBB coverage. Further, we utilize the epidermal growth factor (EGF) to illuminate the drug screening potential of the techniques. Our results show that single and triple cultured BECs form meshwork-like structures under basal conditions, and that oAbeta disrupts this cell meshwork formation and degenerates the preformed mesh structures, but EGF blocks this disruption. Thus, the techniques described are important for dissecting fundamental and disease-relevant processes that modulate BBB coverage. PMID- 28654059 TI - Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture based Method in Chronic Lymphocytic Leukemia Patients. AB - The role of long noncoding RNAs (lncRNAs) in cancer is coming to the forefront due to growing interest in understanding their mechanistic functions during cancer development and progression. Despite this, the global epigenetic regulation of lncRNAs and repetitive sequences in cancer has not been well investigated, particularly in chronic lymphocytic leukemia (CLL). This study focuses on a unique approach: the immunoprecipitation-based capture of double stranded, methylated DNA fragments using methyl-binding domain (MBD) proteins, followed by next-generation sequencing (MBD-seq). CLL patient samples belonging to two prognostic subgroups (5 IGVH mutated samples + 5 IGVH unmutated samples) were used in this study. Analysis revealed 5,800 hypermethylated and 12,570 hypomethylated CLL-specific differentially methylated genes (cllDMGs) compared to normal healthy controls. Importantly, these results identified several CLL specific, differentially methylated lncRNAs, repetitive elements, and protein coding genes with potential prognostic value. This work outlines a detailed protocol for an MBD-seq and bioinformatics pipeline developed for the comprehensive analysis of global methylation profiles in highly CpG-rich regions using CLL patient samples. Finally, a protein-coding gene and an lncRNA were validated using pyrosequencing, which is a highly quantitative method to analyze CpG methylation levels to further corroborate the findings from the MBD-seq protocol. PMID- 28654060 TI - Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity. AB - Macrophage accumulation in transplanted organs has long been recognized as a feature of allograft rejection1. Immunogenic monocytes infiltrate the allograft early after transplantation, mount a graft reactive response against the transplanted organ, and initiate organ rejection2. Recent data suggest that suppressive macrophages facilitate successful long-term transplantation3 and are required for the induction of transplantation tolerance4. This suggests a multidimensional concept of macrophage ontogeny, activation, and function, which demands a new roadmap for the isolation and analysis of macrophage function5. Due to the plasticity of macrophages, it is necessary to provide a methodology to isolate and characterize macrophages, depending on the tissue environment, and to define their functions according to different scenarios. Here, we describe a protocol for immune characterization of graft-infiltrating macrophages and the methods we used to functionally evaluate their capacity to inhibit CD8+ T proliferation and to promote CD4+Foxp3+ Treg expansion in vitro. PMID- 28654061 TI - The Inverted Heart Model for Interstitial Transudate Collection from the Isolated Rat Heart. AB - The present protocol describes a unique approach that enables the collection of cardiac transudate (CT) from the isolated, saline-perfused rat heart. After isolation and retrograde perfusion of the heart according to the Langendorff technique, the heart is inverted into an upside-down position and is mechanically stabilized by a balloon catheter inserted into the left ventricle. Then, a thin latex cap - previously cast to match the average size of the rat heart - is placed over the epicardial surface. The outlet of the latex cap is connected to silicon tubing, with the distal opening 10 cm below the base level of the heart, creating slight suction. CT continuously produced on the epicardial surface is collected in ice-cooled vials for further analysis. The rate of CT formation ranged from 17 to 147 uL/min (n = 14) in control and infarcted hearts, which represents 0.1-1% of the coronary venous effluent perfusate. Proteomic analysis and high performance liquid chromatography (HPLC) revealed that the collected CT contains a wide spectrum of proteins and purinergic metabolites. PMID- 28654062 TI - Using a Whole-mount Immunohistochemical Method to Study the Innervation of the Biliary Tract in Suncus murinus. AB - This work describes the whole-mount immunohistochemistry staining method in detail, using neurofilament protein antibody to label the innervation of the biliary tract in Suncus murinus (S. murinus ). First, the specimen was dissected from S. murinus and fixed in 4% paraformaldehyde (PFA). Second, an enzymatic treatment and potential endogenous peroxidase inactivation were performed. The specimen was then exposed to the primary antibody, anti-neurofilament protein antibody, for 3-6 days. It was then incubated with the secondary antibody conjugated with horseradish peroxidase. The color reaction was revealed by reacting the specimen with a 3,3'-diaminobenzidine (DAB) substrate. This method can be applied to analyze the innervation of all visceral organs. Furthermore, this protocol can also be adapted to test other neuronal antibodies, but optimization of the antibodies should be done first. This method was originally introduced by Kuratani and Tanaka1,2,3. PMID- 28654063 TI - A Tissue Displacement-based Contusive Spinal Cord Injury Model in Mice. AB - Producing a consistent and reproducible contusive spinal cord injury (SCI) is critical to minimizing behavioral and histological variabilities between experimental animals. Several contusive SCI models have been developed to produce injuries using different mechanisms. The severity of the SCI is based on the height that a given weight is dropped, the injury force, or the spinal cord displacement. In the current study, we introduce a novel mouse contusive SCI device, the Louisville Injury System Apparatus (LISA) impactor, which can create a displacement-based SCI with high injury velocity and accuracy. This system utilizes laser distance sensors combined with advanced software to produce graded and highly-reproducible injuries. We performed a contusive SCI at the 10th thoracic vertebral (T10) level in mice to demonstrate the step-by-step procedure. The model can also be applied to the cervical and lumbar spinal levels. PMID- 28654064 TI - Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay. AB - The DNA damage response orchestrates the repair of DNA lesions that occur spontaneously, are caused by genotoxic stress, or appear in the context of programmed DNA breaks in lymphocytes. The Ataxia-Telangiectasia Mutated kinase (ATM), ATM- and Rad3-Related kinase (ATR) and the catalytic subunit of DNA dependent Protein Kinase (DNA-PKcs) are among the first that are activated upon induction of DNA damage, and are central regulators of a network that controls DNA repair, apoptosis and cell survival. As part of a tumor-suppressive pathway, ATM and ATR activate p53 through phosphorylation, thereby regulating the transcriptional activity of p53. DNA damage also results in the formation of so called ionizing radiation-induced foci (IRIF) that represent complexes of DNA damage sensor and repair proteins that accumulate at the sites of DNA damage, which are visualized by fluorescence microscopy. Co-localization of proteins in IRIFs, however, does not necessarily imply direct protein-protein interactions, as the resolution of fluorescence microscopy is limited. In situ Proximity Ligation Assay (PLA) is a novel technique that allows the direct visualization of protein-protein interactions in cells and tissues with unprecedented specificity and sensitivity. This technique is based on the spatial proximity of specific antibodies binding to the proteins of interest. When the interrogated proteins are within ~40 nm an amplification reaction is triggered by oligonucleotides that are conjugated to the antibodies, and the amplification product is visualized by fluorescent labeling, yielding a signal that corresponds to the subcellular location of the interacting proteins. Using the established functional interaction between ATM and p53 as an example, it is demonstrated here how PLA can be used in suspension cell cultures to study the direct interactions between proteins that are integral parts of the DNA damage response. PMID- 28654065 TI - Analysis of the Gap Junction-dependent Transfer of miRNA with 3D-FRAP Microscopy. AB - Small antisense RNAs, like miRNA and siRNA, play an important role in cellular physiology and pathology and, moreover, can be used as therapeutic agents in the treatment of several diseases. The development of new, innovative strategies for miRNA/siRNA therapy is based on an extensive knowledge of the underlying mechanisms. Recent data suggest that small RNAs are exchanged between cells in a gap junction-dependent manner, thereby inducing gene regulatory effects in the recipient cell. Molecular biological techniques and flow cytometric analysis are commonly used to study the intercellular exchange of miRNA. However, these methods do not provide high temporal resolution, which is necessary when studying the gap junctional flux of molecules. Therefore, to investigate the impact of miRNA/siRNA as intercellular signaling molecules, novel tools are needed that will allow for the analysis of these small RNAs at the cellular level. The present protocol describes the application of three-dimensional fluorescence recovery after photobleaching (3D-FRAP) microscopy to elucidating the gap junction-dependent exchange of miRNA molecules between cardiac cells. Importantly, this straightforward and non-invasive live-cell imaging approach allows for the visualization and quantification of the gap junctional shuttling of fluorescently labeled small RNAs in real time, with high spatio-temporal resolution. The data obtained by 3D-FRAP confirm a novel pathway of intercellular gene regulation, where small RNAs act as signaling molecules within the intercellular network. PMID- 28654066 TI - A Mouse Model of Single and Repetitive Mild Traumatic Brain Injury. AB - Mild Traumatic Brain Injury (mTBI) can result in the acute loss of brain function, including a period of confusion, a loss of consciousness (LOC), focal neurological deficits and even amnesia. Athletes participating in contact sports are at high risk of exposure to large number of mTBIs. In terms of the level of injury in a sporting athlete, a mTBI is defined as a mild injury that does not cause gross pathological changes, but does cause short-term neurological deficits that are spontaneously resolved. Despite previous attempts to model mTBI in mice and rats, many have reported gross adverse effects including skull fractures, intracerebral bleeding, axonal injury and neuronal cell death. Herein, we describe our highly reproducible animal model of mTBI that reproduces clinically relevant symptoms. This model uses a custom made pneumatic impactor device to deliver a closed-head trauma. This impact is made under precise velocity and deformation parameters, creating a reliable and reproducible model to examine the mechanisms that contribute to effects of single or repetitive concussive mTBI. PMID- 28654067 TI - Bidirectional Retroviral Integration Site PCR Methodology and Quantitative Data Analysis Workflow. AB - Integration Site (IS) assays are a critical component of the study of retroviral integration sites and their biological significance. In recent retroviral gene therapy studies, IS assays, in combination with next-generation sequencing, have been used as a cell-tracking tool to characterize clonal stem cell populations sharing the same IS. For the accurate comparison of repopulating stem cell clones within and across different samples, the detection sensitivity, data reproducibility, and high-throughput capacity of the assay are among the most important assay qualities. This work provides a detailed protocol and data analysis workflow for bidirectional IS analysis. The bidirectional assay can simultaneously sequence both upstream and downstream vector-host junctions. Compared to conventional unidirectional IS sequencing approaches, the bidirectional approach significantly improves IS detection rates and the characterization of integration events at both ends of the target DNA. The data analysis pipeline described here accurately identifies and enumerates identical IS sequences through multiple steps of comparison that map IS sequences onto the reference genome and determine sequencing errors. Using an optimized assay procedure, we have recently published the detailed repopulation patterns of thousands of Hematopoietic Stem Cell (HSC) clones following transplant in rhesus macaques, demonstrating for the first time the precise time point of HSC repopulation and the functional heterogeneity of HSCs in the primate system. The following protocol describes the step-by-step experimental procedure and data analysis workflow that accurately identifies and quantifies identical IS sequences. PMID- 28654068 TI - Fabrication of 3D Carbon Microelectromechanical Systems (C-MEMS). AB - A wide range of carbon sources are available in nature, with a variety of micro /nanostructure configurations. Here, a novel technique to fabricate long and hollow glassy carbon microfibers derived from human hairs is introduced. The long and hollow carbon structures were made by the pyrolysis of human hair at 900 degrees C in a N2 atmosphere. The morphology and chemical composition of natural and pyrolyzed human hairs were investigated using scanning electron microscopy (SEM) and electron-dispersive X-ray spectroscopy (EDX), respectively, to estimate the physical and chemical changes due to pyrolysis. Raman spectroscopy was used to confirm the glassy nature of the carbon microstructures. Pyrolyzed hair carbon was introduced to modify screen-printed carbon electrodes ; the modified electrodes were then applied to the electrochemical sensing of dopamine and ascorbic acid. Sensing performance of the modified sensors was improved as compared to the unmodified sensors. To obtain the desired carbon structure design, carbon micro-/nanoelectromechanical system (C-MEMS/C-NEMS) technology was developed. The most common C-MEMS/C-NEMS fabrication process consists of two steps: (i) the patterning of a carbon-rich base material, such as a photosensitive polymer, using photolithography; and (ii) carbonization through the pyrolysis of the patterned polymer in an oxygen-free environment. The C MEMS/NEMS process has been widely used to develop microelectronic devices for various applications, including in micro-batteries, supercapacitors, glucose sensors, gas sensors, fuel cells, and triboelectric nanogenerators. Here, recent developments of a high-aspect ratio solid and hollow carbon microstructures with SU8 photoresists are discussed. The structural shrinkage during pyrolysis was investigated using confocal microscopy and SEM. Raman spectroscopy was used to confirm the crystallinity of the structure, and the atomic percentage of the elements present in the material before and after pyrolysis was measured using EDX. PMID- 28654069 TI - Optimized Protocol for the Extraction of Proteins from the Human Mitral Valve. AB - Analysis of the cellular proteome can help to elucidate the molecular mechanisms underlying diseases due to the development of technologies that permit the large scale identification and quantification of the proteins present in complex biological systems.The knowledge gained from a proteomic approach can potentially lead to a better understanding of the pathogenic mechanisms underlying diseases, allowing for the identification of novel diagnostic and prognostic disease markers, and, hopefully, of therapeutic targets. However, the cardiac mitral valve represents a very challenging sample for proteomic analysis because of the low cellularity in proteoglycan and collagen-enriched extracellular matrix. This makes it challenging to extract proteins for a global proteomic analysis. This work describes a protocol that is compatible with subsequent protein analysis, such as quantitative proteomics and immunoblotting. This can allow for the correlation of data concerning protein expression with data on quantitative mRNA expression and non-quantitative immunohistochemical analysis. Indeed, these approaches, when performed together, will lead to a more comprehensive understanding of the molecular mechanisms underlying diseases, from mRNA to post translational protein modification. Thus, this method can be relevant to researchers interested in the study of cardiac valve physiopathology. PMID- 28654070 TI - Generation of Genetically Modified Mice through the Microinjection of Oocytes. AB - The use of genetically modified mice has significantly contributed to studies on both physiological and pathological in vivo processes. The pronuclear injection of DNA expression constructs into fertilized oocytes remains the most commonly used technique to generate transgenic mice for overexpression. With the introduction of CRISPR technology for gene targeting, pronuclear injection into fertilized oocytes has been extended to the generation of both knockout and knockin mice. This work describes the preparation of DNA for injection and the generation of CRISPR guides for gene targeting, with a particular emphasis on quality control. The genotyping procedures required for the identification of potential founders are critical. Innovative genotyping strategies that take advantage of the "multiplexing" capabilities of CRISPR are presented herein. Surgical procedures are also outlined. Together, the steps of the protocol will allow for the generation of genetically modified mice and for the subsequent establishment of mouse colonies for a plethora of research fields, including immunology, neuroscience, cancer, physiology, development, and others. PMID- 28654071 TI - Protocols for C-Brick DNA Standard Assembly Using Cpf1. AB - CRISPR-associated protein Cpf1 cleaves double-stranded DNA under the guidance of CRISPR RNA (crRNA), generating sticky ends. Because of this characteristic, Cpf1 has been used for the establishment of a DNA assembly standard called C-Brick, which has the advantage of long recognition sites and short scars. On a standard C-Brick vector, there are four Cpf1 recognition sites - the prefix (T1 and T2 sites) and the suffix (T3 and T4 sites) - flanking biological DNA parts. The cleavage of T2 and T3 sites produces complementary sticky ends, which allow for the assembly of DNA parts with T2 and T3 sites. Meanwhile, a short "GGATCC" scar is generated between parts after assembly. As the newly formed plasmid once again contains the four Cpf1 cleavage sites, the method allows for the iterative assembly of DNA parts, which is similar to those of BioBrick and BglBrick standards. A procedure outlining the use of the C-Brick standard to assemble DNA parts is described here. The C-Brick standard can be widely used by scientists, graduate and undergraduate students, and even amateurs. PMID- 28654072 TI - Subcutaneous Neurotrophin 4 Infusion Using Osmotic Pumps or Direct Muscular Injection Enhances Aging Rat Laryngeal Muscles. AB - Laryngeal dysfunction in the elderly is a major cause of disability, from voice disorders to dysphagia and loss of airway protective reflexes. Few, if any, therapies exist that target age-related laryngeal muscle dysfunction. Neurotrophins are involved in muscle innervation and differentiation of neuromuscular junctions (NMJs). It is thought that neurotrophins enhance neuromuscular transmission by increasing neurotransmitter release. The neuromuscular junctions (NMJs) become smaller and less abundant in aging rat laryngeal muscles, with evidence of functional denervation. We explored the effects of NTF4 for future clinical use as a therapeutic to improve function in aging human laryngeal muscles. Here, we provide the detailed protocol for systemic application and direct injection of NTF4 to investigate the ability of aging rat laryngeal muscle to remodel in response to NTF4 application. In this method, rats either received NTF4 either systemically via osmotic pump or by direct injection through the vocal folds. Laryngeal muscles were then dissected and used for histological examination of morphology and age-related denervation. PMID- 28654073 TI - Rapid Deletion Production in Fungi via Agrobacterium Mediated Transformation of OSCAR Deletion Constructs. AB - Precise deletion of gene(s) of interest, while leaving the rest of the genome unchanged, provides the ideal product to determine that particular gene's function in the living organism. In this protocol the OSCAR method of precise and rapid deletion plasmid construction is described. OSCAR relies on the cloning system in which a single recombinase reaction is carried out containing the purified PCR-amplified 5' and 3' flanks of the gene of interest and two plasmids, pA-Hyg OSCAR (the marker vector) and pOSCAR (the assembly vector). Confirmation of the correctly assembled deletion vector is carried out by restriction digestion mapping followed by sequencing. Agrobacterium tumefaciens is then used to mediate introduction of the deletion construct into fungal spores (referred to as ATMT). Finally, a PCR assay is described to determine if the deletion construct integrated by homologous or non-homologous recombination, indicating gene deletion or ectopic integration, respectively. This approach has been successfully used for deletion of numerous genes in Verticillium dahliae and in Fusarium verticillioides among other species. PMID- 28654074 TI - A Chronic Autoimmune Dry Eye Rat Model with Increase in Effector Memory T Cells in Eyeball Tissue. AB - Dry eye disease is a very common condition that causes morbidity and healthcare burden and decreases the quality of life. There is a need for a suitable dry eye animal model to test novel therapeutics to treat autoimmune dry eye conditions. This protocol describes a chronic autoimmune dry eye rat model. Lewis rats were immunized with an emulsion containing lacrimal gland extract, ovalbumin, and complete Freund's adjuvant. A second immunization with the same antigens in incomplete Freund's adjuvant was administered two weeks later. These immunizations were administered subcutaneously at the base of the tail. To boost the immune response at the ocular surface and lacrimal glands, lacrimal gland extract and ovalbumin were injected into the forniceal subconjunctiva and lacrimal glands 6 weeks after the first immunization. The rats developed dry eye features, including reduced tear production, decreased tear stability, and increased corneal damage. Immune profiling by flow cytometry showed a preponderance of CD3+ effector memory T cells in the eyeball. PMID- 28654075 TI - Clock Scan Protocol for Image Analysis: ImageJ Plugins. AB - The clock scan protocol for image analysis is an efficient tool to quantify the average pixel intensity within, at the border, and outside (background) a closed or segmented convex-shaped region of interest, leading to the generation of an averaged integral radial pixel-intensity profile. This protocol was originally developed in 2006, as a visual basic 6 script, but as such, it had limited distribution. To address this problem and to join similar recent efforts by others, we converted the original clock scan protocol code into two Java-based plugins compatible with NIH-sponsored and freely available image analysis programs like ImageJ or Fiji ImageJ. Furthermore, these plugins have several new functions, further expanding the range of capabilities of the original protocol, such as analysis of multiple regions of interest and image stacks. The latter feature of the program is especially useful in applications in which it is important to determine changes related to time and location. Thus, the clock scan analysis of stacks of biological images may potentially be applied to spreading of Na+ or Ca++ within a single cell, as well as to the analysis of spreading activity (e.g., Ca++ waves) in populations of synaptically-connected or gap junction-coupled cells. Here, we describe these new clock scan plugins and show some examples of their applications in image analysis. PMID- 28654076 TI - A Method to Test the Efficacy of Handwashing for the Removal of Emerging Infectious Pathogens. AB - Handwashing is widely recommended to prevent infectious disease transmission. However, little comparable evidence exists on the efficacy of handwashing methods in general. Additionally, little evidence exists comparing handwashing methods to determine which are most efficacious at removing infectious pathogens. Research is needed to provide evidence for the different approaches to handwashing that may be employed during infectious disease outbreaks. Here, a laboratory method to assess the efficacy of handwashing methods at removing microorganisms from hands and their persistence in rinse water is described. Volunteers' hands are first spiked with the test organism and then washed with each handwashing method of interest. Generally, surrogate microorganisms are used to protect human subjects from disease. The number of organisms remaining on volunteers' hands after washing is tested using a modified "glove juice" method: the hands are placed in gloves with an eluent and are scrubbed to suspend the microorganisms and make them available for analysis by membrane filtration (bacteria) or plaque assay (viruses/bacteriophages). Rinse water produced from the handwashing is directly collected for analysis. Handwashing efficacy is quantified by comparing the log reduction value between samples taken after handwashing to samples with no handwashing. Rinse water persistence is quantified by comparing rinse water samples from various handwashing methods to samples collected after handwashing with just water. While this method is limited by the need to use surrogate organisms to preserve the safety of human volunteers, it captures aspects of handwashing that are difficult to replicate in an in vitro study and fills research gaps on handwashing efficacy and the persistence of infectious organisms in rinse water. PMID- 28654077 TI - Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing. AB - Human pluripotent stem cells can differentiate into various cell types that can be applied to human-based in vitro toxicity assays. One major advantage is that the reprogramming of somatic cells to produce human induced pluripotent stem cells (hiPSCs) avoids the ethical and legislative issues related to the use of human embryonic stem cells (hESCs). HiPSCs can be expanded and efficiently differentiated into different types of neuronal and glial cells, serving as test systems for toxicity testing and, in particular, for the assessment of different pathways involved in neurotoxicity. This work describes a protocol for the differentiation of hiPSCs into mixed cultures of neuronal and glial cells. The signaling pathways that are regulated and/or activated by neuronal differentiation are defined. This information is critical to the application of the cell model to the new toxicity testing paradigm, in which chemicals are assessed based on their ability to perturb biological pathways. As a proof of concept, rotenone, an inhibitor of mitochondrial respiratory complex I, was used to assess the activation of the Nrf2 signaling pathway, a key regulator of the antioxidant-response-element-(ARE)-driven cellular defense mechanism against oxidative stress. PMID- 28654078 TI - Selection-dependent and Independent Generation of CRISPR/Cas9-mediated Gene Knockouts in Mammalian Cells. AB - The CRISPR/Cas9 genome engineering system has revolutionized biology by allowing for precise genome editing with little effort. Guided by a single guide RNA (sgRNA) that confers specificity, the Cas9 protein cleaves both DNA strands at the targeted locus. The DNA break can trigger either non-homologous end joining (NHEJ) or homology directed repair (HDR). NHEJ can introduce small deletions or insertions which lead to frame-shift mutations, while HDR allows for larger and more precise perturbations. Here, we present protocols for generating knockout cell lines by coupling established CRISPR/Cas9 methods with two options for downstream selection/screening. The NHEJ approach uses a single sgRNA cut site and selection-independent screening, where protein production is assessed by dot immunoblot in a high-throughput manner. The HDR approach uses two sgRNA cut sites that span the gene of interest. Together with a provided HDR template, this method can achieve deletion of tens of kb, aided by the inserted selectable resistance marker. The appropriate applications and advantages of each method are discussed. PMID- 28654079 TI - In Situ Immunofluorescent Staining of Autophagy in Muscle Stem Cells. AB - Increasing evidence points to autophagy as a crucial regulatory process to preserve tissue homeostasis. It is known that autophagy is involved in skeletal muscle development and regeneration, and the autophagic process has been described in several muscular pathologies and age-related muscle disorders. A recently described block of the autophagic process that correlates with the functional exhaustion of satellite cells during muscle repair supports the notion that active autophagy is coupled with productive muscle regeneration. These data uncover the crucial role of autophagy in satellite cell activation during muscle regeneration in both normal and pathological conditions, such as muscular dystrophies. Here, we provide a protocol to monitor the autophagic process in the adult Muscle Stem Cell (MuSC) compartment during muscle regenerative conditions. This protocol describes the setup methodology to perform in situ immunofluorescence imaging of LC3, an autophagy marker, and MyoD, a myogenic lineage marker, in muscle tissue sections from control and injured mice. The methodology reported allows for monitoring the autophagic process in one specific cell compartment, the MuSC compartment, which plays a central role in orchestrating muscle regeneration. PMID- 28654080 TI - Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols. AB - The gene expression program of the cell cycle represents a critical step for understanding cell cycle-dependent processes and their role in diseases such as cancer. Cell cycle-regulated gene expression analysis depends on cell synchronization into specific phases. Here we describe a method utilizing two complementary synchronization protocols that is commonly used for studying periodic variation of gene expression during the cell cycle. Both procedures are based on transiently blocking the cell cycle in one defined point. The synchronization protocol by hydroxyurea (HU) treatment leads to cellular arrest in late G1/early S phase, and release from HU-mediated arrest provides a cellular population uniformly progressing through S and G2/M. The synchronization protocol by thymidine and nocodazole (Thy-Noc) treatment blocks cells in early mitosis, and release from Thy-Noc mediated arrest provides a synchronized cellular population suitable for G1 phase and S phase-entry studies. Application of both procedures requires monitoring of the cell cycle distribution profiles, which is typically performed after propidium iodide (PI) staining of the cells and flow cytometry-mediated analysis of DNA content. We show that the combined use of two synchronization protocols is a robust approach to clearly determine the transcriptional profiles of genes that are differentially regulated in the cell cycle (i.e. E2F1 and E2F7), and consequently to have a better understanding of their role in cell cycle processes. Furthermore, we show that this approach is useful for the study of mechanisms underlying drug-based therapies (i.e. mitomycin C, an anticancer agent), because it allows to discriminate genes that are responsive to the genotoxic agent from those solely affected by cell cycle perturbations imposed by the agent. PMID- 28654081 TI - Aging affects the balance of neural entrainment and top-down neural modulation in the listening brain. AB - Healthy aging is accompanied by listening difficulties, including decreased speech comprehension, that stem from an ill-understood combination of sensory and cognitive changes. Here, we use electroencephalography to demonstrate that auditory neural oscillations of older adults entrain less firmly and less flexibly to speech-paced (~3 Hz) rhythms than younger adults' during attentive listening. These neural entrainment effects are distinct in magnitude and origin from the neural response to sound per se. Non-entrained parieto-occipital alpha (8-12 Hz) oscillations are enhanced in young adults, but suppressed in older participants, during attentive listening. Entrained neural phase and task-induced alpha amplitude exert opposite, complementary effects on listening performance: higher alpha amplitude is associated with reduced entrainment-driven behavioural performance modulation. Thus, alpha amplitude as a task-driven, neuro-modulatory signal can counteract the behavioural corollaries of neural entrainment. Balancing these two neural strategies may present new paths for intervention in age-related listening difficulties. PMID- 28654083 TI - Targeted metagenomic sequencing data of human gut microbiota associated with Blastocystis colonization. AB - In the past decade, metagenomics studies have become widespread due to the arrival of second-generation sequencing platforms characterized by low costs, high throughput and short read lengths. Today, although benchtop sequencers are considered to be accurate platforms to deliver data for targeted metagenomics studies, the limiting factor has become the analysis of these data. In a previous paper, we performed an Ion Torrent PGM 16S rDNA gene sequencing of faecal DNAs from 48 Blastocystis-colonized patients and 48 Blastocystis-negative subjects, in order to decipher the impact of this widespread protist on gut microbiota composition and diversity. We report here on the Ion Torrent targeted metagenomic sequencing and analysis of these 96 human faecal samples, and the complete datasets from raw to analysed data. We also provide the key steps of the bioinformatic analyses, from library preparation to data filtering and OTUs tables generation. This data represents a valuable resource for the scientific community, enabling re-processing of these targeted metagenomic datasets through various pipelines and a comparative evaluation of microbiota analysis methods. PMID- 28654084 TI - Corrigendum: Image-based siRNA screen to identify kinases regulating Weibel Palade body size control using electroporation. AB - This corrects the article DOI: 10.1038/sdata.2017.22. PMID- 28654082 TI - A mitogenomic timetree for Darwin's enigmatic South American mammal Macrauchenia patachonica. AB - The unusual mix of morphological traits displayed by extinct South American native ungulates (SANUs) confounded both Charles Darwin, who first discovered them, and Richard Owen, who tried to resolve their relationships. Here we report an almost complete mitochondrial genome for the litoptern Macrauchenia. Our dated phylogenetic tree places Macrauchenia as sister to Perissodactyla, but close to the radiation of major lineages within Laurasiatheria. This position is consistent with a divergence estimate of ~66 Ma (95% credibility interval, 56.64 77.83 Ma) obtained for the split between Macrauchenia and other Panperissodactyla. Combined with their morphological distinctiveness, this evidence supports the positioning of Litopterna (possibly in company with other SANU groups) as a separate order within Laurasiatheria. We also show that, when using strict criteria, extinct taxa marked by deep divergence times and a lack of close living relatives may still be amenable to palaeogenomic analysis through iterative mapping against more distant relatives. PMID- 28654085 TI - The increasing threat to stratospheric ozone from dichloromethane. AB - It is well established that anthropogenic chlorine-containing chemicals contribute to ozone layer depletion. The successful implementation of the Montreal Protocol has led to reductions in the atmospheric concentration of many ozone-depleting gases, such as chlorofluorocarbons. As a consequence, stratospheric chlorine levels are declining and ozone is projected to return to levels observed pre-1980 later this century. However, recent observations show the atmospheric concentration of dichloromethane-an ozone-depleting gas not controlled by the Montreal Protocol-is increasing rapidly. Using atmospheric model simulations, we show that although currently modest, the impact of dichloromethane on ozone has increased markedly in recent years and if these increases continue into the future, the return of Antarctic ozone to pre-1980 levels could be substantially delayed. Sustained growth in dichloromethane would therefore offset some of the gains achieved by the Montreal Protocol, further delaying recovery of Earth's ozone layer. PMID- 28654086 TI - A multiscale dataset for understanding complex eco-hydrological processes in a heterogeneous oasis system. AB - We introduce a multiscale dataset obtained from Heihe Watershed Allied Telemetry Experimental Research (HiWATER) in an oasis-desert area in 2012. Upscaling of eco hydrological processes on a heterogeneous surface is a grand challenge. Progress in this field is hindered by the poor availability of multiscale observations. HiWATER is an experiment designed to address this challenge through instrumentation on hierarchically nested scales to obtain multiscale and multidisciplinary data. The HiWATER observation system consists of a flux observation matrix of eddy covariance towers, large aperture scintillometers, and automatic meteorological stations; an eco-hydrological sensor network of soil moisture and leaf area index; hyper-resolution airborne remote sensing using LiDAR, imaging spectrometer, multi-angle thermal imager, and L-band microwave radiometer; and synchronical ground measurements of vegetation dynamics, and photosynthesis processes. All observational data were carefully quality controlled throughout sensor calibration, data collection, data processing, and datasets generation. The data are freely available at figshare and the Cold and Arid Regions Science Data Centre. The data should be useful for elucidating multiscale eco-hydrological processes and developing upscaling methods. PMID- 28654087 TI - Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice. AB - Caffeine, an antagonist of the adenosine receptor A1R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A1R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A1R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A1Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice. PMID- 28654089 TI - Prostate cancer: Microbiome - the 'unforeseen organ'. PMID- 28654090 TI - Prostate cancer: ETS factors in the balance. PMID- 28654088 TI - Coherent soft X-ray diffraction imaging of coliphage PR772 at the Linac coherent light source. AB - Single-particle diffraction from X-ray Free Electron Lasers offers the potential for molecular structure determination without the need for crystallization. In an effort to further develop the technique, we present a dataset of coherent soft X ray diffraction images of Coliphage PR772 virus, collected at the Atomic Molecular Optics (AMO) beamline with pnCCD detectors in the LAMP instrument at the Linac Coherent Light Source. The diameter of PR772 ranges from 65-70 nm, which is considerably smaller than the previously reported ~600 nm diameter Mimivirus. This reflects continued progress in XFEL-based single-particle imaging towards the single molecular imaging regime. The data set contains significantly more single particle hits than collected in previous experiments, enabling the development of improved statistical analysis, reconstruction algorithms, and quantitative metrics to determine resolution and self-consistency. PMID- 28654091 TI - Variation in clinical practice: forests and trees revisited. AB - Variations in clinical practice are commonly viewed as a sign of uneven quality of care and attributed to provider self-interest. However, patient preferences, physician practice patterns, and diagnostic and therapeutic uncertainty also cause variations. Greater attention to both doctor-patient interactions and limits to the available evidence might enable more effective assessment and improvement of health-care quality. PMID- 28654093 TI - An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders. AB - Previous epigenome-wide association studies (EWAS) of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) have been inconsistent. This may be due to small sample sizes, and measurement and tissue differences. The current two EWA analyses of 473 World Trade Center responders are the largest to date for both PTSD and MDD. These analyses investigated DNA methylation patterns and biological pathways influenced by differentially methylated genes associated with each disorder. Methylation was profiled on blood samples using Illumina 450 K Beadchip. Two EWA analyses compared current versus never PTSD, and current versus never MDD, adjusting for cell types and demographic confounders. Pathway and gene set enrichment analyses were performed to understand the complex biological systems of PTSD and MDD. No significant epigenome-wide associations were found for PTSD or MDD at an FDR P<0.05. The majority of genes with differential methylation at a suggestive threshold did not overlap between the two disorders. Pathways significant in PTSD included a regulator of synaptic plasticity, oxytocin signaling, cholinergic synapse and inflammatory disease pathways, while only phosphatidylinositol signaling and cell cycle pathways emerged in MDD. The failure of the current EWA analyses to detect significant epigenome-wide associations is in contrast with disparate findings from previous, smaller EWA and candidate gene studies of PTSD and MDD. Enriched gene sets involved in several biological pathways, including stress response, inflammation and physical health, were identified in PTSD, supporting the view that multiple genes play a role in this complex disorder. PMID- 28654098 TI - Oxaliplatin reacts with DMSO only in the presence of water. AB - Herein we show that oxaliplatin reacts rapidly with DMSO in aqueous solutions, despite being stable in pure DMSO and pure water. Furthermore, the reactivity of the clinically applied Pt(ii) drugs in water/DMSO and PBS/DMSO mixtures, and the nature of the species formed were investigated by MS, NMR and RP-HPLC techniques. PMID- 28654092 TI - Risk factors for cryptorchidism. AB - Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to descend permanently is probably caused by disruptions to one or both of these phases, but the causes and mechanisms of such disruptions are still unclear. A broad range of putative risk factors have been evaluated in relation to the development of cryptorchidism but their plausibility is still in question. Consistent evidence of an association with cryptorchidism exists for only a few factors, and in those cases in which evidence seems unequivocal the factor is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor could vary considerably between mother-son pairs depending on an array of genetic, maternal, placental and fetal factors - all of which could vary between regions. Thus, the role of causative factors in aetiology of cryptorchidism requires further research. PMID- 28654094 TI - Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress. AB - During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, we used nonbiased analyses of microRNAs in the ventral hippocampus (vHPC) to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat. In the vHPC of active coping rats, miR-455-3p level was increased, while miR-30e-3p level was increased in the vHPC of passive coping rats. Pathway analyses identified inflammatory and vascular remodeling pathways as enriched by genes targeted by these microRNAs. Utilizing several independent markers for blood vessels, inflammatory processes and neural activity in the vHPC, we found that SL/vulnerable rats exhibit increased neural activity, vascular remodeling and inflammatory processes that include both increased blood-brain barrier permeability and increased number of microglia in the vHPC relative to control and resilient rats. To test the relevance of these changes for the development of the vulnerable phenotype, we used pharmacological approaches to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. Collectively, these results show that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the vHPC. These results suggest that dampening inflammatory processes by administering anti-inflammatory agents reduces vulnerability to stress. These results have translational relevance as they suggest that administration of anti inflammatory agents may reduce the impact of stress or trauma in vulnerable individuals. PMID- 28654100 TI - Chiral N,N'-dioxide/Co(ii)-promoted asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones. AB - A chiral N,N'-dioxide/Co(BF4)2.6H2O complex catalytic system has been developed to efficiently catalyze the asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones. The corresponding chiral multisubstituted spiroisoxazolidines with three contiguous quaternary-tertiary stereocenters were obtained in moderate to high yields with excellent dr and ee values (up to 97% yield, >19 : 1 dr and 98% ee). PMID- 28654095 TI - Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi episode schizophrenia. AB - Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia. PMID- 28654101 TI - A highly emissive and stable zinc(ii) metal-organic framework as a host-guest chemopalette for approaching white-light-emission. AB - A new adenine-containing metal-organic framework (MOF), [Zn4O(adenine)4(benzene 1,3-dicarboxylate)4Zn2] (named as ZnBDCA), was synthesized solvothermally. ZnBDCA possesses high quantum yield (>50%) and nano-channels that can encapsulate acriflavine molecules to build a host-guest chemopalette for approaching white light emission. PMID- 28654105 TI - Facile detection of glucose in human serum employing silver-ion-guided surface enhanced Raman spectroscopy signal amplification. AB - A facile surface-enhanced Raman scattering (SERS) sensor based on a silver-ion mediated amplification effect was designed for the determination of glucose concentration. In this approach, 4-aminothiophenol (4-ATP) molecules assembled on the surface of a gold wafer (Au wafer@4-ATP) act not only as Raman tags but also as linkage agents. Silver nanoparticles marked with cysteamine (AgNP@cys) were used as the SERS enhancement components because they could be bound to the Au wafer@4-ATP in the presence of silver ions through the formation of N -> Ag+ <- N coordination compounds. Here, the Ag+ ions were obtained by using glucose oxidase to catalyze the oxidation of glucose, producing hydrogen peroxide (H2O2) to etch the AgNPs. Therefore, we recorded the SERS intensity of 4-ATP to determine the concentration of glucose in a phosphate buffer as low as 0.1 mM and further achieved a lowest detection of 0.5 mM glucose in human serum. These results show that the proposed approach has strong potential for practical applications. PMID- 28654106 TI - High-index faceted CuFeS2 nanosheets with enhanced behavior for boosting hydrogen evolution reaction. AB - A rational design of highly active and robust catalysts based on earth-abundant elements for hydrogen evolution reaction (HER) is essential for future renewable energy applications. Herein, we report the synthesis of a new class of ultrathin metallic CuFeS2 nanosheets (NSs) with abundant exposed high-index {02[combining macron]4} facets. They serve as a robust catalyst for the HER with a lower onset potential of 28.1 mV, an overpotential of only 88.7 mV (at j = 10 mA cm-2) and remarkable long-term stability in 0.5 M H2SO4, which make them the best system among all the reported non-noble metal catalysts. The theoretical calculations reveal that the mechanistic origin for such a high HER activity should be attributed to the excess S2- active sites on the exposed {02[combining macron]4} high-index facets of CuFeS2 NSs, which have a rather favorable Gibbs free energy for atomic hydrogen adsorption. The present work highlights the importance of designing ultrathin metallic chalcopyrite nanosheets with high-index facets in order to increase the number of active sites for boosting the HER performance. PMID- 28654107 TI - In situ cathodic activation of V-incorporated NixSy nanowires for enhanced hydrogen evolution. AB - In situ cathodic activation (ISCA) of V-incorporated NixSy nanowires supported on nickel foam (VS/NixSy/NF) can be realized in an alkaline hydrogen evolution reaction (HER) process, which provides not only clearly enhanced activity but also ultrahigh stability for HER. The ISCA process is continuous linear sweep voltammetry (LSV) on VS/NixSy/NF as a cathodic electrode with gradually enhanced HER activity. The activated VS/NixSy/NF (A-VS/NixSy/NF) demonstrates enhanced HER activity with an overpotential of 125 mV to drive 10 mA cm-2, which is much lower than that of other samples. It may be predicted that the ISCA-derived amorphous VOOH film covering on A-VS/NixSy/NF accelerates the HER process, and NiOOH may protect active sites from decaying, leading to excellent activity and structural stability. However, for single metal sulfides, the ISCA process of nickel or vanadium sulfides is not available, implying that the synergistic effect between Ni and V of VS/NixSy/NF may be the key to drive ISCA in alkaline HER. In addition, its ultra-high stability confirms that the stable active sites and nanostructures of A-VS/NixSy/NF are derived from ISCA. Therefore, the ISCA of V incorporated transition metal sulfides in the alkaline HER process may be a facile and promising method to obtain efficient electrocatalysts. PMID- 28654108 TI - Spectral and spatial characterization of upconversion luminescent nanocrystals as nanowaveguides. AB - Lanthanide upconversion (UC) luminescent nanocrystals exhibit a uniquely sharp multiband emission over a broad spectral bandwidth covering the ultraviolet region to the near-infrared (NIR) region when subjected to NIR excitation, which is vital for multichannel optical communication using wavelength-division multiplexing to achieve high transmission rates. In this study, we experimentally and theoretically investigated the spectral and spatial characterization of a single NaYF4:Yb3+,Tm3+(Yb3+,Er3+) UC nanocrystal as a nanowaveguide. We suggest that a UC nanocrystal can be used as a nanowaveguide because it produces a range of output colors simultaneously and provides unaltered emission bands during propagation. Via the observation of single NaYF4:Yb3+,Tm3+(Yb3+,Er3+) UC nanocrystals, we found, for the first time, that a single UC nanocrystal exhibited wavelength- and position-dependent UC emissions. In addition, by adding Ag coating to the UC nanocrystal to act as a plasmonic waveguide and introducing a photonic crystal, the scattering loss of the UC emissions was significantly suppressed in the middle of the NaYF4 nanocrystal, indicating efficient light guiding through the UC nanocrystal. Our discovery provides a basic understanding of the use of UC nanocrystals as nanowaveguides at the single-nanoparticle level, expanding our knowledge of the performance optimization of UC nanomaterials. PMID- 28654110 TI - Copper-catalyzed decarboxylative methylthiolation of aromatic carboxylate salts with DMSO. AB - A novel copper-catalyzed decarboxylative methylthiolation of arenecarboxylate salts has been realized using DMSO as the methylthiolation source. Various potassium aryl carboxylates underwent decarboxylative methylthiolation under air to furnish the corresponding aryl methyl thioethers in moderate to excellent yields. The reaction tolerated a wide variety of functional groups. Notably, the synthesis of ethylthioethers was also successfully achieved directly from diethyl sulfoxide under similar reaction conditions. PMID- 28654103 TI - The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials. AB - Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems. PMID- 28654111 TI - Direct access to isoxazolino and isoxazolo benzazepines from 2 ((hydroxyimino)methyl)benzoic acid via a post-Ugi heteroannulation. AB - A diversity-oriented access to isoxazolino and isoxazolo benzazepines is elaborated via a post-Ugi heteroannulation involving intramolecular 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes and alkynes. This sequence offers an interesting multicomponent entry to a library of isoxazolino and isoxazolo benzazepines under mild reaction conditions in good to excellent yields. PMID- 28654112 TI - Distinguishing d- and l-aspartic and isoaspartic acids in amyloid beta peptides with ultrahigh resolution ion mobility spectrometry. AB - While alpha-linked amino acids in the l-form are exclusively utilized in mammalian protein building, beta-linked and d-form amino acids also have important biological roles. Unfortunately, the structural elucidation and separation of these different amino acid types in peptides has been analytically challenging to date due to the numerous isomers present, limiting our knowledge about their existence and biological roles. Here, we utilized an ultrahigh resolution ion mobility spectrometry platform coupled with mass spectrometry (IMS MS) to separate amyloid beta (Abeta) peptides containing l-aspartic acid, d aspartic acid, l-isoaspartic acid, and d-isoaspartic acid residues which span alpha- and beta-linked amino acids in both d- and l-forms. The results illustrate how IMS-MS could be used to better understand age-related diseases or protein folding disorders resulting from amino acid modifications. PMID- 28654113 TI - Organic waste as a sustainable feedstock for platform chemicals. AB - Biorefineries have been established since the 1980s for biofuel production, and there has been a switch lately from first to second generation feedstocks in order to avoid the food versus fuel dilemma. To a lesser extent, many opportunities have been investigated for producing chemicals from biomass using by-products of the present biorefineries, simple waste streams. Current facilities apply intensive pre-treatments to deal with single substrate types such as carbohydrates. However, most organic streams such as municipal solid waste or algal blooms present a high complexity and variable mixture of molecules, which makes specific compound production and separation difficult. Here we focus on flexible anaerobic fermentation and hydrothermal processes that can treat complex biomass as a whole to obtain a range of products within an integrated biorefinery concept. PMID- 28654114 TI - Functionalized metal organic frameworks for effective capture of radioactive organic iodides. AB - Highly efficient capture of radioactive organic iodides (ROIs) from off-gas mixtures remains a substantial challenge for nuclear waste treatment. Current materials utilized for ROI sequestration suffer from low capacity, high cost (e.g. use of noble metals), and poor recyclability. Recently, we have developed a new strategy to tackle this challenge by functionalizing MOF materials with tertiary amines to create molecular traps for the effective capture and removal of ROIs (e.g. radioactive methyl iodide) from nuclear wastes. To further enhance the uptake capacity and performance of CH3I capture by ROI molecular traps, herein, we carry out a systematic study to investigate the effect of different amine molecules on ROI capture. The results demonstrate a record-high CH3I saturation uptake capacity of 80% for MIL-101-Cr-DMEDA at 150 degrees C, which is 5.3 times that of Ag0@MOR (15 wt%), a leading adsorbent material for capturing ROIs during nuclear fuel reprocessing. Furthermore, the CH3I decontamination factors (DFs) for MIL-101-Cr-DMEDA are as high as 5000 under simulated reprocessing conditions, largely exceeding that of facility regulatory requirements (DF = 3000). In addition, MIL-101-Cr-DMEDA can be recycled without loss of capacity, illustrating yet another advantage compared to known industrial adsorbents, which are typically of a "single-use" nature. Our analysis also shows that both physisorption and chemisorption of CH3I occur at the three amine grafted MOFs. While chemisorption takes place at the amine functionalized sites, the amount of physisorption correlates with the MOF porosity. A possible binding site of amine-CH3I interaction has been identified via an in situ IR spectroscopic study. The results suggest that CH3I interacts strongly and directly with the tertiary nitrogen of the amine molecules. The CH3I uptake amount decreases as the amine chain length increases, in trend with the decreasing pore space of the corresponding framework. The strategy to build MOF based molecular traps developed in this work not only leads to a new record-high performance for ROI capture, but also offers an effective way of systematically tuning the porosity by varying the length of functionalized amine molecules. This study also demonstrates that MOFs represent a promising new platform for selective capture and removal of radioactive nuclear waste. PMID- 28654116 TI - From mixed to three-layer core/shell PtCu nanoparticles: ligand-induced surface segregation to enhance electrocatalytic activity. AB - Core-shell segregated bimetallic nanoparticles (NPs) exhibit increased enhanced catalytic performance compared to that of mixed bimetallic NPs. Here, we report a simple, yet efficient, one-pot synthetic strategy to synthesize uniform three layer core/shell PtCu NPs by adding benzyl ether (BE) in the synthesis process of mixed PtCu NPs. In comparison with commercial Pt/C and also mixed PtCu NPs, the three-layer core/shell PtCu NPs exhibit superior activity in catalyzing the oxygen reduction reaction (ORR), formic acid oxidation reaction (FAOR), methanol oxidation reaction (MOR), and ethanol oxidation reaction (EOR), mainly due to the ligand (BE)-induced surface segregation of Pt on the surface of the NPs. PMID- 28654115 TI - Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia. AB - Datasets comprising simultaneous measurements of many essential metals in Alzheimer's disease (AD) brain are sparse, and available studies are not entirely in agreement. To further elucidate this matter, we employed inductively-coupled plasma mass spectrometry to measure post-mortem levels of 8 essential metals and selenium, in 7 brain regions from 9 cases with AD (neuropathological severity Braak IV-VI), and 13 controls who had normal ante-mortem mental function and no evidence of brain disease. Of the regions studied, three undergo severe neuronal damage in AD (hippocampus, entorhinal cortex and middle-temporal gyrus); three are less-severely affected (sensory cortex, motor cortex and cingulate gyrus); and one (cerebellum) is relatively spared. Metal concentrations in the controls differed among brain regions, and AD-associated perturbations in most metals occurred in only a few: regions more severely affected by neurodegeneration generally showed alterations in more metals, and cerebellum displayed a distinctive pattern. By contrast, copper levels were substantively decreased in all AD-brain regions, to 52.8-70.2% of corresponding control values, consistent with pan-cerebral copper deficiency. This copper deficiency could be pathogenic in AD, since levels are lowered to values approximating those in Menkes' disease, an X-linked recessive disorder where brain-copper deficiency is the accepted cause of severe brain damage. Our study reinforces others reporting deficient brain copper in AD, and indicates that interventions aimed at safely and effectively elevating brain copper could provide a new experimental-therapeutic approach. PMID- 28654117 TI - Synthesis and biological evaluation of novel acyclic and cyclic glyoxamide based derivatives as bacterial quorum sensing and biofilm inhibitors. AB - Bacteria regulate the expression of various virulence factors and processes such as biofilm formation through a chemically-mediated communication mechanism called quorum sensing. Bacterial biofilms contribute to antimicrobial resistance as they can protect bacteria embedded in their matrix from the effects of antibiotics. Thus, developing novel quorum sensing inhibitors, which can inhibit biofilm formation, is a viable strategy to combat antimicrobial resistance. We report herein the synthesis of novel acyclic and cyclic glyoxamide derivatives via ring opening reactions of N-acylisatins. These compounds were evaluated for their quorum sensing inhibition activity against P. aeruginosa MH602 and E. coli MT102. Compounds 20, 21 and 30 displayed the greatest quorum sensing inhibition activity against P. aeruginosa MH602, with 71.5%, 71.5%, and 74% inhibition, respectively, at 250 MUM. Compounds 18, 20 and 21 exhibited the greatest QSI activity against E. coli MT102, with 71.5%, 72.1% and 73.5% quorum sensing inhibition activity, respectively. In addition, the biofilm inhibition activity was also investigated against P. aeruginosa and E. coli at 250 MUM. The glyoxamide compounds 16, 18 and 19 exhibited 71.2%, 66.9%, and 66.5% inhibition of P. aeruginosa biofilms, respectively; whereas compounds 12, 20, and 22 showed the greatest inhibitory activity against E. coli biofilms with 87.9%, 90.8% and 89.5%, respectively. Finally, the determination of the in vitro toxicity against human MRC-5 lung fibroblast cells revealed that these novel glyoxamide compounds are non-toxic to human cells. PMID- 28654118 TI - Camphyl-based alpha-diimine palladium complexes: highly efficient precatalysts for direct arylation of thiazoles in open-air. AB - Based on the strategy of the development of phosphine-free palladium-catalyzed direct C-H arylation, a series of camphyl-based alpha-diimine palladium complexes bearing sterically bulky substituents were synthesized and characterized. The palladium complexes were applied for the cross-coupling of thiazole derivatives with aryl bromides. The effect of the sterically bulky substituent on the N-aryl moiety as well as the reaction conditions was screened. Under the optimal protocols, a wide range of aryl bromides can be smoothly coupled with thiazoles in good to excellent yields in the presence of a low palladium loading of 0.2 mol% under open-air conditions. PMID- 28654119 TI - Environmentally sensitive molecular probes reveal mutations and epigenetic 5 methyl cytosine in human oncogenes. AB - There is currently an unmet need for reliable tools that allow for direct detection and quantification of modifications in genomic DNA. For example, in cancer research and clinical diagnostics, target DNA has to be amplified and sequenced in order to reveal mutations. For 5-methylcytosine detection, bisulfite treatment of DNA is applied for the analysis, which often leads to poor specificity and reproducibility of the results. Herein we describe a simple approach that specifically detects clinically significant modifications in the human oncogenes BRAF and KRAS. We prove that this can be done using a fast and reliable hybridization assay applying novel internally labelled oligonucleotide probes and optical detection methods. PMID- 28654120 TI - Sophopterocarpan A, a novel pterocarpine derivative with a benzotetrahydrofuran fused bicyclo [3.3.1] nonane from Sophora flavescens. AB - Sophopterocarpan A (1), with a novel benzotetrahydrofuran-fused bicyclo [3.3.1] nonane ring, was isolated from the roots of Sophora flavescens Ait. Its unusual structure, including its stereochemistry, was determined on the basis of a comprehensive spectroscopic data analysis. A plausible biogenetic pathway for 1 is presented. Sophopterocarpan A was identified as a potential autophagy activator. Additionally, it was found that 1 exhibited cytotoxic activity in MCF 7 cells with an IC50 of 29.36 MUM. PMID- 28654122 TI - Dissipation of self-assemblies by fusion of complementary gels: an elegant strategy for programmed enzymatic reactions. AB - Cholesterol based phenylboronic acid and glucose tailored complementary gels were developed which underwent mutual self-destruction upon mixing due to the formation of a boronate-diol adduct. This dissipation of the complementary gels was employed in a programmed enzymatic reaction and in pro-drug activation. PMID- 28654123 TI - Chemical physics of electroactive materials - the oft-overlooked faces of electrochemistry. AB - Electroactive materials and their applications are enjoying renewed attention, in no small part motivated by the advent of nanoscale tools for their preparation and study. While the fundamentals of charge and mass transport in electrolytes on this scale are by and large well understood, their interplay can have subtle manifestations in the more complex situations typical of, for example, integrated microfluidics-based applications. In particular, the role of faradaic processes is often overlooked or, at best, purposefully suppressed via experimental design. In this introductory article we discuss, using simple illustrations from our laboratories, some of the manifestations of electrochemistry in electroactive materials. PMID- 28654124 TI - Curving silver nanowires using liquid droplets for highly stretchable and durable percolation networks. AB - Silver (Ag) nanowires (NWs) are promising building blocks for the fabrication of stretchable electrodes, but they may undergo mechanical fracture at low tensile strains, which leads to degradation in electrical performance of Ag NW-based stretchable electrodes. Here we report on a simple route to create the percolation networks of Ag NW rings via a conventional spray coating process. We discovered that Ag NWs can be bent into curved shapes within micrometer-sized liquid droplets generated during the spraying process due to elasto-capillary interaction. This curving phenomenon allowed the deposition of Ag NW rings directly on a desired substrate without the need for any complicated process. The network of Ag NW rings effectively releases the applied tensile strains thanks to curved shapes of the constituent NWs, enabling the achievement of excellent electromechanical stability as well as high stretchability. Our approach not only provides a simple, low cost, and scalable route to the fabrication of high performance Ag NW-based stretchable electrodes, but also opens a new and useful way of engineering the structure of NWs for various applications. PMID- 28654125 TI - Palladium-catalyzed allylation of tautomerizable heterocycles with alkynes. AB - A method for the allylic amidation of tautomerizable heterocycles was developed by a palladium catalyzed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted heterocycles can be synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions. PMID- 28654126 TI - Electrocatalytic activity of silver decorated ceria microspheres for the oxygen reduction reaction and their application in aluminium-air batteries. AB - Nanosheet-constructing porous CeO2 microspheres with silver nanoparticles anchored on the surface were developed as a highly efficient oxygen reduction reaction (ORR) catalyst. The aluminum-air batteries applying Ag-CeO2 as the ORR catalyst exhibit a high output power density and low degradation rate of 345 mW cm-2 and 2.6% per 100 h, respectively. PMID- 28654127 TI - Bio-camouflage of anatase nanoparticles explored by in situ high-resolution electron microscopy. AB - While titanium is the metal of choice for most prosthetics and inner body devices due to its superior biocompatibility, the discovery of Ti-containing species in the adjacent tissue as a result of wear and corrosion has been associated with autoimmune diseases and premature implant failures. Here, we utilize the in situ liquid cell transmission electron microscopy (TEM) in a liquid flow holder and graphene liquid cells (GLCs) to investigate, for the first time, the in situ nano bio interactions between titanium dioxide nanoparticles and biological medium. This imaging and spectroscopy methodology showed the process of formation of an ionic and proteic bio-camouflage surrounding Ti dioxide (anatase) nanoparticles that facilitates their internalization by bone cells. The in situ understanding of the mechanisms of the formation of the bio-camouflage of anatase nanoparticles may contribute to the definition of strategies aimed at the manipulation of these NPs for bone regenerative purposes. PMID- 28654128 TI - Investigation into the structural features and microwave absorption of doped barium hexaferrites. AB - BaFe12-xGaxO19 (x <= 1.2) hexaferrites were synthesized via the usual ceramic technology. It has been established that with an increase in x, the unit cell and magnetic parameters monotonically decrease. The frequency of natural ferromagnetic resonance firstly decreases from 49.6 GHz down to 49.1 GHz when x = 0.6, and then it increases up to 50.5 GHz. The line width monotonically increases from 3.5 GHz up to 5 GHz. The peak amplitude of the resonant curve changes slightly with the exception of when x = 0.9, when it reaches -16 dB. The 1.3 GHz kOe-1 frequency shift in the bias field is more intensive for small values, when x = 0.3. The decreasing values of the magnetic parameters are a result of the dilution of Fe3+-O2--Fe3+ superexchange interactions. The behavior of the amplitude-frequency characteristics is largely determined through the reduction of uniaxial exchange anisotropy. The prospects of Ga-substituted hexaferrites acting as a material that effectively absorbs the high-frequency electromagnetic radiation are shown. PMID- 28654129 TI - Nanotopography featured polycaprolactone/polyethyleneoxide microfibers modulate endothelial cell response. AB - Among many physical properties, surface nanotopography has been found to strongly affect cell adhesion, migration and other functions. Accurate biological interpretation requires the nanotopography to be presented in a three-dimensional (3D) micro-environment. Herein, immiscible blends of polycaprolactone (PCL)/polyethyleneoxide (PEO) were electrospun into a grounded coagulation bath, resulting in macroporous microfibers with nanotopography featured surfaces. Variations in PCL/PEO ratios enabled tunable surface nanotopographic structures, from longitudinal submicron grooves to transverse nano-lamellae. Chemical composition, crystallinity and quantitative nanomechanical analysis confirmed that the interplay of the two semi-crystalline immiscible polymers and the pairing of miscible solvents/non-solvents in both the electrospinning solution and the bath solution were critical for the formation of the secondary structure. It was found that the nanotopography features promoted the proliferation of human umbilical vein endothelial cells (HUVECs) compared with their smooth film counterparts. An analysis of the cell adhesion related markers, vinculin and phosphorylated focal adhesion kinase (pFAK), further revealed that the nanotopographies enhanced the nascent adhesion complex formation compared with smooth PCL fibers, even in the scaffolds with a high PEO content, which is often considered as a non-adhesive material. PMID- 28654130 TI - Concurrent Double Fungal Infections of the Skin Caused by Phialemoniopsis endophytica and Exophiala jeanselmei in a Patient with Microscopic Polyangiitis. AB - is missing (Short communication). PMID- 28654131 TI - Topical Oxybutynin 10% Gel for the Treatment of Primary Focal Hyperhidrosis: A Randomized Double-blind Placebo-controlled Split Area Study. AB - Limited efficacy, costs, side-effects and complications are issues of concern for most current therapeutic modalities for focal hyperhidrosis. This study evaluated the efficacy of topical oxybutynin 10% gel in treating 61 patients with primary focal hyperhidrosis. The gel was applied to the right or left axilla, palms or soles vs. a placebo compound to the contralateral side for 30 days. A blinded visual grading of the change in starch-iodine tests was performed by 2 non involved physicians. The Hyperhidrosis Disease Severity Scale (HDSS) and Dermatology Life Quality Index (DLQI) questionnaires were administered before and after treatment. The patients rated their satisfaction with treatment. Fifty three patients completed the 4-week treatment. Sweat reduction in the drug treated sweating areas was higher than in the control-treated areas. There was a significant mean improvement in pre- and post-treatment HDSS and DQLI (p = 0.001 for both). Thirty-nine subjects (74%) reported moderate-to-high satisfaction. Twice-daily topical application of oxybutynin 10% gel appears to be an effective, safe and well-tolerated treatment for focal primary hyperhidrosis. PMID- 28654132 TI - Henoch-Schonlein Purpura: A Literature Review. AB - Henoch-Schonlein purpura is the most common childhood vasculitis, but may also affect adults. This article reviews the literature since 2011 on advances in diagnosis, clinical disease manifestations, pathophysiology and treatment of Henoch-Schonlein purpura. The clinical manifestations are thought to arise from IgA depositions in blood vessel walls in the affected organs, mostly skin, gastrointestinal tract, joints and kidneys. Corticosteroids may be effective in rapid resolution of renal manifestations and treating joint and abdominal pain, but they are not proven effective for treating organ manifestations and complications, such as glomerulonephritis, bowel infarction or intussusception. Mycophenolate mofetil or cyclosporine A may be better treatment choices in case of renal involvement. Other immunosuppressive and immunomodulating drugs, such as rituximab and dapsone, are promising, but larger studies are needed to confirm these findings. Cancer screening should be considered in older males diagnosed with Henoch-Schonlein purpura. PMID- 28654133 TI - Distraction From Itch Shows Brainstem Activation Without Reduction in Experimental Itch Sensation. AB - The central processing of itch is not completely understood. This is the first study to use functional magnetic resonance imaging (fMRI) to examine the central modulation by distraction of experimentally induced itch. A total of 33 healthy volunteers were examined with fMRI. Periods of itch induction without distraction and itch with distraction by a Stroop task (psychological test, where the participants have to decide if the colour of the writing corresponds to the written word, for example if "red" is written in red or not) were counterbalanced during the scanning to examine task-specific changes in blood oxygenation level dependent-signal. The intensity of the subjects' itch sensation, desire to scratch and pain sensation were evaluated. Distraction by a Stroop task did not reduce itch intensity or urge to scratch. However, the Stroop task led to significantly higher activation of the left brainstem when it followed the "pure" itch sensation. Itch and pain seem to have similar inhibition pathways, particularly concerning brainstem activation during distraction. But as itch sensation, in contrast to pain, could not be sufficiently reduced by distraction, both entities might have different modulation systems. PMID- 28654134 TI - ? PMID- 28654135 TI - ? PMID- 28654136 TI - ? PMID- 28654137 TI - ? PMID- 28654138 TI - A prospective cohort study of awake fibreoptic intubation practice at a tertiary centre. AB - Contemporary data are lacking for procedural practice, training provision and outcomes for awake fibreoptic intubation in the UK. We performed a prospective cohort study of awake fibreoptic intubations at a tertiary centre to assess current practice. Data from 600 elective or emergency awake fibreoptic intubations were collected to include information on patient and operator demographics, technical performance and complications. This comprised 1.71% of patients presenting for surgery requiring a general anaesthetic, with the majority occurring in patients presenting for head and neck surgery. The most common indication was reduced mouth opening (26.8%), followed by previous airway surgery or head and neck radiotherapy (22.5% each). Only five awake fibreoptic intubations were performed with no sedation, but the most common sedative technique was combined target-controlled infusions of remifentanil and propofol. Oxygenation was achieved with high-flow, heated and humidified oxygen via nasal cannula in 49.0% of patients. Most operators had performed awake fibreoptic intubation more than 20 times previously, but trainees were the primary operator in 78.6% of awake fibreoptic intubations, of which 86.8% were directly supervised by a consultant. The failure rate was 1.0%, and 11.0% of awake fibreoptic intubations were complicated, most commonly by multiple attempts (4.2%), over sedation (2.2%) or desaturation (1.5%). The only significant association with complications was the number of previous awake fibreoptic intubations performed, with fewer complications occurring in the hands of operators with more awake fibreoptic intubation experience. Our data demonstrate that awake fibreoptic intubation is a safe procedure with a high success rate. Institutional awake fibreoptic intubation training can both develop and maintain trainee competence in performing awake fibreoptic intubation, with a similar incidence of complications and success compared with consultants. PMID- 28654139 TI - Radiation safety for anaesthesia providers. PMID- 28654140 TI - Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity. OBJECTIVES: To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed. SELECTION CRITERIA: We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type). MAIN RESULTS: We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression free survival: I2 = 76%; overall survival: I2 = 40%; and response rate: I2 = 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I2 = 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I2 = 51%), likely due to the pooling of first-line and second line studies.The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.Scant information on quality of life was reported in the identified studies. AUTHORS' CONCLUSIONS: The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data. PMID- 28654141 TI - Current practice for awake fibreoptic intubation - some unanswered questions. PMID- 28654142 TI - Artefactual ST elevation with Mindray monitors. PMID- 28654143 TI - Dexamethasone, blood glucose and CONSORT guidelines. PMID- 28654144 TI - Misaligned bupivacaine ampoule labels obscuring the expiry date - manufacturer's reply. PMID- 28654145 TI - Preparation for the difficult airway. PMID- 28654146 TI - Sugammadex: economic and practical considerations. PMID- 28654147 TI - Clinical skill or statistical tests when predicting the difficult airway? PMID- 28654148 TI - Misaligned bupivacaine ampoule labels obscuring the expiry date. PMID- 28654150 TI - Severe hidradenitis suppurativa responding to treatment with secukinumab: a case report. AB - An inappropriate immunological response to an unknown antigen has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Studies have identified elevated levels of several proinflammatory cytokines, including interleukin (IL)-17A and tumour necrosis factor-alpha, nominating these as possible therapeutic targets.1 Secukinumab is an IL-17A monoclonal antibody, which binds to IL-17A and inhibits the cytokine interaction with the IL-17 receptors, inhibiting the inflammatory cascade. Here we report a case of a 47 year-old man, with Hurley stage III lesions on the neck, axillae, breasts, genital skin and buttocks, who had experienced only temporary benefit from different medical treatments over several years. After 12 weeks of treatment with secukinumab, the number of lesions reported by the patient within the period of the last 4 weeks was reduced from 23 to seven, his pain visual analogue scale (VAS) score was reduced from 5 to 3 and pain/utility/handicap VAS score was reduced from 7 to 4. These results may be taken to imply that IL-17 blockade could provide a possible therapeutic approach in the treatment of HS. PMID- 28654149 TI - Young adult survivors of childhood acute lymphoblastic leukemia show evidence of chronic inflammation and cellular aging. AB - BACKGROUND: Large epidemiologic studies have reported the premature onset of age related conditions, such as ischemic heart disease and diabetes mellitus, in childhood cancer survivors, decades earlier than in their peers. The authors investigated whether young adult survivors of childhood acute lymphoblastic leukemia (ALL) have a biologic phenotype of cellular ageing and chronic inflammation. METHODS: Plasma inflammatory cytokines were measured using a cytometric bead array in 87 asymptomatic young adult survivors of childhood ALL (median age, 25 years; age range, 18-35 years) who attended annual follow-up clinic and compared with healthy, age-matched and sex-matched controls. Leukocyte telomere length (LTL) was measured using Southern blot analysis. RESULTS: Survivors had significant elevation of plasma interleukin-2 (IL-2), IL-10, IL 17a, and high-sensitivity C-reactive protein levels (all P < .05). A raised high sensitivity C-reactive protein level (>0.8 mg/dL) was related to increased odds of having metabolic syndrome (odds ratio, 7.256; 95% confidence interval, 1.501 35.074). Survivors also had significantly shorter LTL compared with controls (median, 9866 vs 10,392 base pairs; P = .021). Compared with published data, LTL in survivors was similar to that in healthy individuals aged 20 years older. Survivors who received cranial irradiation had shorter LTL compared with those who had not (P = .013). CONCLUSIONS: Asymptomatic young adult survivors of childhood ALL demonstrate a biologic profile of chronic inflammation and telomere attrition, consistent with an early onset of cellular processes that drive accelerated aging. These processes may explain the premature development of age related chronic conditions in childhood cancer survivors. Understanding their molecular basis may facilitate targeted interventions to disrupt the accelerated aging process and its long-term impact on overall health. Cancer 2017;123:4207 4214. (c) 2017 American Cancer Society. PMID- 28654151 TI - Who should read cognitive aid prompts? PMID- 28654153 TI - Survivorship and the chronic cancer patient: Patterns in treatment-related effects, follow-up care, and use of survivorship care plans. AB - BACKGROUND: The survivorship needs of patients living with chronic cancer (CC) and their use of survivorship care plans (SCPs) have been overlooked and underappreciated. METHODS: A convenience sample of 39,088 SCPs completed for cancer survivors with an Internet-based SCP tool was examined; it included 5847 CC survivors (15%; CC was defined as chronic leukemia and/or recurrent/metastatic cancer of another nature). Patient-reported treatment effects and follow-up care patterns were compared between CC survivors and survivors treated with curative intent (CI). Responses from a follow-up survey regarding SCP satisfaction and use were reviewed. RESULTS: CC survivors had greater odds of experiencing multiple treatment-related effects than survivors treated with CI; these effects included fatigue, cognitive changes, dyspnea, peripheral neuropathy, lymphedema, and erectile dysfunction. Nearly half of CC survivors were managed by an oncologist alone, and they were less likely than CI patients to be comanaged by a primary care provider and an oncologist. Fewer SCPs were generated by health care providers (HCPs) for CC survivors versus CI survivors. A smaller proportion of CC users versus CI users rated their experience and satisfaction with the SCP tool as very good or excellent, and CC users were less likely to share the HCP summary with their health care team. CONCLUSIONS: A substantial number of CC survivors, often considered incurable but treatable, seek survivorship support. Tools to facilitate participation, communication, and coordination of care are valuable for these patients, and future iterations of SCPs should be designed to address the particular circumstances of living with CC. Cancer 2017;123:4268-4276. (c) 2017 American Cancer Society. PMID- 28654152 TI - Race-specific molecular alterations correlate with differential outcomes for black and white endometrioid endometrial cancer patients. AB - BACKGROUND: The objective of this study was to identify molecular alterations associated with disease outcomes for white and black patients with endometrioid endometrial cancer (EEC). METHODS: EEC samples from black (n = 17) and white patients (n = 13) were analyzed by proteomics (liquid chromatography-tandem mass spectrometry) and transcriptomics (RNA-seq). Coordinate alterations were validated with RNA-seq data from black (n = 49) and white patients (n = 216). Concordantly altered candidates were further tested for associations with race specific progression-free survival (PFS) in black (n = 64) or white patients (n = 267) via univariate and multivariate Cox regression modeling and log-rank testing. RESULTS: Discovery analyses revealed significantly altered candidate proteins and transcripts between black and white patients, suggesting modulation of tumor cell viability in black patients and cell death signaling in black and white patients. Eighty-nine candidates were validated as altered between these patient cohorts, and a subset significantly correlated with differential PFS. White-specific PFS candidates included serpin family A member 4 (SERPINA4; hazard ratio [HR], 0.89; Wald P value = .02), integrin subunit alpha3 (ITGA3; HR, 0.76; P = .03), and Bet1 Golgi vesicular membrane trafficking protein like (BET1L; HR, 0.48; P = .04). Black-specific PFS candidates included family with sequence similarity 228 member B (FAM228B; HR, 0.13; P = .001) and HEAT repeat containing 6 (HEATR6; HR, 4.94; P = .047). Several candidates were also associated with overall survival (SERPINA4 and ITGA3) as well as PFS independent of disease stage, grade and myometrial invasion (SERPINA4, BET1L and FAM228B). CONCLUSIONS: This study has identified and validated molecular alterations in tumors from black and white EEC patients, including candidates significantly associated with altered disease outcomes within these patient cohorts. Cancer 2017;123:4004-12. (c) 2017 American Cancer Society. PMID- 28654154 TI - Commentary: Should Pharmacogenomic Evidence Be Considered in Clinical Decision Making? Focus on Select Cardiovascular Drugs. AB - Despite advances in technology and guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) that focus on how to use pharmacogene test results, hurdles remain that have delayed the widespread application of pharmacogenomics in clinical practice. These hurdles include a lack of prospective randomized controlled trials to address the utility of pharmacogenomics on clinical outcomes, what the clinical algorithm for pharmacogenomics should be, and whether pharmacogenomics is cost-effective. However, the implementation of clinical practice guidelines, such as those from professional organizations, is commonplace and often termed the application of evidence-based medicine. Here, we draw an analogy between the evidence supporting many commonly cited clinical practice guidelines and U.S. Food and Drug Administration-approved labeling recommendations and the evidence supporting recommendations from CPIC. Although many clinical practice guideline recommendations are supported by the results of randomized controlled clinical trials, we cite examples of common clinical practices that are supported by levels and types of evidence similar to the evidence supporting many of the CPIC recommendations. Specifically, we discuss clinical recommendations for guidance related to drug-drug interactions, drug-gene interactions, therapeutic range selection, and dosage adjustments based on patient-specific factors within the context of a select set of cardiovascular therapeutic topics. PMID- 28654156 TI - Is Plan A OK in the 'plausibly difficult' airway? A reply. PMID- 28654155 TI - Incidence of hematologic malignancy and cause-specific mortality in the Women's Health Initiative randomized controlled trial of calcium and vitamin D supplementation. AB - BACKGROUND: Prior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists. METHODS: The authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan-Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM-specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses. RESULTS: A total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65-0.99) but not HM-specific mortality (HR, 0.77 [95% CI, 0.53-1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70-1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59 1.01) and 0.46 (95% CI, 0.24-0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation. CONCLUSIONS: The current post hoc analysis of data from a large and well-executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168-4177. (c) 2017 American Cancer Society. PMID- 28654157 TI - Predictive accuracy of difficult mask ventilation assessment methods. PMID- 28654158 TI - An adjustable multi-scale single beam acoustic tweezers based on ultrahigh frequency ultrasonic transducer. AB - This paper reports the fabrication, characterization, and microparticle manipulation capability of an adjustable multi-scale single beam acoustic tweezers (SBAT) that is capable of flexibly changing the size of "tweezers" like ordinary metal tweezers with a single-element ultrahigh frequency (UHF) ultrasonic transducer. The measured resonant frequency of the developed transducer at 526 MHz is the highest frequency of piezoelectric single crystal based ultrasonic transducers ever reported. This focused UHF ultrasonic transducer exhibits a wide bandwidth (95.5% at -10 dB) due to high attenuation of high-frequency ultrasound wave, which allows the SBAT effectively excite with a wide range of excitation frequency from 150 to 400 MHz by using the "piezoelectric actuator" model. Through controlling the excitation frequency, the wavelength of ultrasound emitted from the SBAT can be changed to selectively manipulate a single microparticle of different sizes (3-100 MUm) by using only one transducer. This concept of flexibly changing "tweezers" size is firstly introduced into the study of SBAT. At the same time, it was found that this incident ultrasound wavelength play an important role in lateral trapping and manipulation for microparticle of different sizes. Biotechnol. Bioeng. 2017;114: 2637-2647. (c) 2017 Wiley Periodicals, Inc. PMID- 28654159 TI - Acute Alcohol Exposure and Risk of Mortality of Patients with Traumatic Brain Injury: A Systematic Review and Meta-Analysis. AB - After traumatic brain injury (TBI), patients usually live with significant disability and socioeconomic burdens. Acute exposure to alcohol is considered a major risk factor for TBI. Numerous studies have examined whether alcohol exposure is related to the risk of mortality in patients with TBI, yet the results remain inconsistent. We performed a meta-analysis to assess whether acute alcohol exposure affects the mortality rate of TBI patients. We searched PubMed, EMBASE, and the Cochrane Library up to November 2015 for relevant studies. We screened studies based on their inclusion criteria and selected the studies that reported mortality rate, which included 18 observational studies. We used R to analyze the included data. An initial result showed that the presence of a positive blood alcohol concentration (BAC) had no significant relation with mortality rate (OR = 0.92, 95% CI = 0.83 to 1.01), but there was notable heterogeneity along with variable results according to sensitivity analysis. For the BAC-positive population, low BAC (1 to 100 mg/dl) carried a higher risk of mortality than moderate BAC (100 to 230 mg/dl) (OR = 1.40, 95% CI = 1.09 to 1.81), moderate and high BAC as a single category (>100 mg/dl) (OR = 1.57, 95% CI = 1.28 to 1.94), or high BAC (>230 mg/dl) (OR = 1.76, 95% CI = 1.34 to 2.30). However, moderate BAC did not increase the mortality risk when compared with high BAC (OR = 1.20, 95% CI = 0.89 to 1.63). Whether positive BAC at the time of admission after TBI reduces mortality rate compared with the rate under negative BAC remains unknown. In addition, low BAC (1 to 100 mg/dl) poses a risk of mortality compared with higher BAC. Further studies assessing the effect of alcohol between the BAC-positive group and the BAC-negative group are still needed. PMID- 28654160 TI - Pontamine fast scarlet 4B bifluorescence and measurements of cellulose microfibril angles. AB - Pontamine fast scarlet 4B is a red paper and textiles dye that has recently been introduced as a fluorescent probe for plant cell walls. Pontamine exhibits bifluorescence, or fluorescence dependent on the polarization of the excitation light: Because cellulose is aligned within the cell wall, pontamine-labelled cell walls exhibit variable fluorescence as the excitation polarization is modulated. Thus, bifluorescence measurements require polarized excitation that can be directly or indirectly modulated. In our confocal microscopy observations of various cellulose samples labelled with pontamine, we modulated excitation polarization either through sample rotation or by the confocal's scanfield rotation function. This variably rotated laser polarizations on Leica confocal microscopes, but not those from other makers. Beginning with samples with directly observable microfibril orientations, such as purified bacterial cellulose, the velamen of orchid roots and the inner S2 layer of radiata pine compression wood, we demonstrate that modelling the variations in pontamine fluorescence with a sine curve can be used to measure the known microfibril angles. We then measured average local microfibril angles in radiata pine samples, and showed similar microfibril angles in compression and normal (opposite) wood. Significantly, bifluorescence measurements might also be used to understand the degree of local cellulose alignment within the cell wall, as opposed to variations in the overall cellulose angle. PMID- 28654161 TI - Protocol for improved resolution of plasma cell subpopulations by flow cytometry. AB - Plasma cells are rare cells that have been notoriously difficult to detect by flow cytometry. New advances have described B220+ CD138+ plasma cells in the bone marrow that are particularly difficult to distinguish between CD138 intermediate B220+ developing B cells. Herein we describe a novel method for detecting plasma cells in the bone marrow using a combination of CD138 and Sca-1 staining. PMID- 28654162 TI - The importance of person-centred care and co-creation of care for the well-being and job satisfaction of professionals working with people with intellectual disabilities. AB - BACKGROUND: Person-centred care and co-creation of care (productive interactions between clients and professionals) are expected to lead to better outcomes for clients. Professionals play a prominent role in the care of people with intellectual disabilities at residential care facilities. Thus, person-centred care and co-creation of care may be argued to lead to better outcomes for professionals as well. This study aimed to identify relationships of person centred care and co-creation of care with the well-being and job satisfaction of professionals working with people with intellectual disabilities (PWID). METHODS: A cross-sectional survey was conducted in 2015 among professionals working at a disability care organisation in the Netherlands. All 1146 professionals involved in the care of people with intellectual disabilities who required 24-hours care were invited to participate. The response rate was 41% (n = 466). RESULTS: Most respondents (87%) were female, and the mean age was 42.8 +/- 11.5 years (22-65). The majority of respondents (70%) worked >=22 hours per week and had worked for the organisation for >=5 years (88%). Most of the respondents (76.8%) were direct care workers either in residential homes (59.3%) or in day activities (17.5%). After controlling for background variables, person-centred care and co-creation of care were associated positively with job satisfaction and well-being of professionals. CONCLUSIONS: The provision of person-centred care and co-creation of care may lead to better well-being and job satisfaction among professionals working with PWID. This finding is important, as such professionals often experience significant levels of work stress and burnout. PMID- 28654164 TI - Calculating oxygen consumption during low-flow anaesthesia. PMID- 28654163 TI - Homo- and Heterobinuclear Cu and Pd Complexes with a Bridging Redox-Active Bisguanidino-Substituted Dioxolene Ligand: Electronic Structure and Metal-Ligand Electron-Transfer. AB - A new redox-active 4,5-bisguanidino-substituted o-benzoquinone ligand L is synthesized, which allows rational access to heterobinuclear complexes through the sequential coordination of two metals. In the examples discussed in this work, mononuclear Cu and Pd complexes are prepared in a first coordination step, and these complexes are then used as precursors to homobinuclear [CuII -L0 -CuII ] and heterobinuclear [PdII -L0 -CuII ] complexes. In the heterobinuclear complex, the PdII is coordinated by the softer bisguanidine side of L and the CuII by the harder dioxolene side (in line with the HSAB concept). The heterobinuclear complex is in a temperature-dependent equilibrium with its dimer, with two unsymmetrical Cu-Cl-Cu bridges. The redox-chemistry of the [CuII -L-CuII ] and [PdII -L-CuII ] complexes is studied. One-electron oxidation of both complexes was found to be quasi-reversible in CV experiments, and chemical one electron oxidation was achieved with NO+ (SbF6- ). In the case of the homobinuclear complex [L(CuCl2 )2 ]+ , intramolecular ligand-metal electron transfer, triggered by coordination of a CH3 CN solvent molecule, leads to a temperature-dependent equilibrium between the form [CuII -L0 -CuIII ] at low temperatures (with CH3 CN coordinated to the CuIII atom) and [CuII -L?+ -CuII ] at higher temperatures (without CH3 CN). PMID- 28654165 TI - Using Personalized Medicine in the Management of Diabetes Mellitus. AB - Diabetes mellitus is a worldwide problem with an immense pharmacoeconomic burden. The multifactorial and complex nature of the disease lends itself to personalized pharmacotherapeutic approaches to treatment. Variability in individual risk and subsequent development of diabetes has been reported in addition to differences in response to the many oral glucose lowering therapies currently available for diabetes pharmacotherapy. Pharmacogenomic studies have attempted to uncover the heritable components of individual variability in risk susceptibility and response to pharmacotherapy. We review the current pharmacogenomics evidence as it relates to common oral glucose lowering therapies and how they can be utilized in the management of polygenic and monogenic forms of diabetes. Evidence supports the use of genetic testing and personalized approaches to the treatment of monogenic diabetes of the young. The data are not as robust for the current application of pharmacogenetic approaches to the treatment of polygenic type 2 diabetes mellitus, but there are suggestions as to future applications in this regard. We reviewed pertinent primary literature sources as well as current evidence-based guidelines on diabetes management. PMID- 28654166 TI - Lesions in the Splenium of the Corpus Callosum on MRI in Children: A Review. AB - A wide variety of conditions may involve the splenium of the corpus callosum on magnetic resonance imaging in children. A single cause may present with different patterns of splenial involvement, and multiple diseases may have similar imaging findings. Keeping this limitation in mind, the goal of this text is to assist in the diagnostic process of pediatric neurological diseases that are characterized by prominent involvement of the splenium of the corpus callosum on imaging. The various pathologies will be reviewed and categorized based on etiology, reversibility, and pattern of additional or associated findings. Transient splenial lesions in children are an uncommon radiologic finding of unknown etiology in a long list of conditions that may present with altered consciousness, and it usually carries a favorable prognosis. The discussion continues with the presentation of diseases inflicting irreversible damage on the splenium. Familiarity with the various causes implicated in splenial injury may assist in the formulation of differential diagnosis in the appropriate clinical setting using an easily recognizable imaging finding. PMID- 28654167 TI - Age is associated with asthma phenotypes. AB - BACKGROUND AND OBJECTIVE: The relationship between age and asthma phenotypes is important as population is ageing, asthma is becoming common in older ages and recently developed treatments for asthma are guided by phenotypes. The aim of this study is to evaluate whether age is associated with specific asthma phenotypes. METHODS: This is a cross-sectional study. We included subjects with asthma of varied degrees of severity. Subjects underwent spirometry, skin prick test to aeroallergens, answered the Asthma Control Questionnaire and had blood samples collected. We performed binary logistic regression analysis to evaluate whether age is associated with asthma phenotypes. RESULTS: We enrolled 868 subjects. In comparison with subjects <= 40 years, older subjects had high odds of irreversible airway obstruction (from 41 to 64 years, OR: 1.83 (95% CI: 1.32 2.54); >=65 years, OR: 3.45 (2.12-5.60)) and severe asthma phenotypes (from 41 to 64 years, OR: 3.23 (2.26-4.62); >=65 years, OR: 4.55 (2.39-8.67)). Older subjects had low odds of atopic (from 41 to 64 years, OR: 0.56 (0.39-0.79); >=65 years, OR: 0.47 (0.27-0.84)) and eosinophilic phenotypes (from 41 to 64 years, OR: 0.63 (0.46-0.84); >=65 years, OR: 0.39 (0.24-0.64)). CONCLUSION: Older subjects with asthma have low odds of atopic and eosinophilic phenotypes, whereas they present high odds of irreversible airway obstruction and severe asthma. PMID- 28654169 TI - Inter-rater agreement-Agreeing to disagree, again! PMID- 28654168 TI - Dexamethasone, blood glucose and CONSORT guidelines - a reply. PMID- 28654170 TI - From Electrons and Nuclei to Assemblies of Correlated Atoms. AB - What constitutes an atom? The answer may depend on whether you ask a physicist or a chemist. But the complementary views lead to productive overlap in atomic theory. Limiting cases, under high pressures and temperatures, have had a profound impact in a wider context. PMID- 28654172 TI - Is Plan A OK in the 'plausibly difficult' airway? PMID- 28654171 TI - Strongly Reducing, Visible-Light Organic Photoredox Catalysts as Sustainable Alternatives to Precious Metals. AB - Photoredox catalysis is a versatile approach for the construction of challenging covalent bonds under mild reaction conditions, commonly using photoredox catalysts (PCs) derived from precious metals. As such, there is need to develop organic analogues as sustainable replacements. Although several organic PCs have been introduced, there remains a lack of strongly reducing, visible-light organic PCs. Herein, we establish the critical photophysical and electrochemical characteristics of both a dihydrophenazine and a phenoxazine system that enables their success as strongly reducing, visible-light PCs for trifluoromethylation reactions and dual photoredox/nickel-catalyzed C-N and C-S cross-coupling reactions, both of which have been historically exclusive to precious metal PCs. PMID- 28654173 TI - Rocuronium vs. succinylcholine for rapid sequence intubation: a Cochrane systematic review. AB - This systemic review was performed to determine whether rocuronium creates intubating conditions comparable to those of succinylcholine during rapid sequence intubation of the trachea. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 2), MEDLINE (1966 to February Week 2 2015), and EMBASE (1988 to February 14 2015) for any randomised controlled trials or controlled clinical trials that reported intubating conditions comparing rocuronium and succinylcholine for rapid or modified rapid sequence intubation. The dose of rocuronium was at least 0.6 mg.kg-1 and succinylcholine was at least 1 mg.kg-1 . Sixty-six studies were identified and 50 included, representing 4151 participants. Overall, succinylcholine was superior to rocuronium for achieving excellent intubating conditions (risk ratio (95%CI) 0.86 (0.81 to 0.92), n = 4151) and clinically acceptable intubation conditions (risk ratio (95%CI) 0.97 (0.95-0.99), n = 3992). A high incidence of detection bias amongst the trials coupled with significant heterogeneity means that the quality of evidence was moderate for these conclusions. Succinylcholine was more likely to produce excellent intubating conditions when using thiopental as the induction agent: risk ratio (95%CI) 0.81 (0.73-0.88), n = 2302) with or without the use of opioids (risk ratio (95%CI) 0.85 (0.78-0.93), n = 2292 or 0.85 (0.76-0.95), n = 1428). PMID- 28654174 TI - Artefactual ST elevation with Mindray monitors - manufacturer's reply. PMID- 28654175 TI - Identification and occurrence of the hydroxamate siderophores aerobactin, putrebactin, avaroferrin and ochrobactin C as virulence factors from entomopathogenic bacteria. AB - Effective iron acquisition and fine-tuned intracellular iron storage systems are the main prerequisites for a successful host invasion by a pathogen. Bacteria have developed several different strategies to sequester this essential element from their environment, one relies on the secretion of low molecular weight compounds with high affinity for ferric iron, the so-called siderophores. Here, we report hydroxamate siderophore structures produced by entomopathogenic bacteria of the species Xenorhabdus and Photorhabdus, which are known for their potential to produce bioactive natural products, required for their role as nematode symbiont and insect pathogen. Four siderophores could be identified, namely aerobactin, putrebactin, avaroferrin and ochrobactin C, which was found previously only in marine bacteria. While the putrebactin and avaroferrin producing biosynthesis gene cluster (BGC) is more widespread and most likely was present in a common ancestor of these bacteria, the aerobactin and ochrobactin producing BGC was probably taken up by a few strains individually. For aerobactin a role in virulence towards Galleria mellonella larvae is shown. PMID- 28654176 TI - Multiple Pseudomonas species secrete exolysin-like toxins and provoke Caspase-1 dependent macrophage death. AB - Pathogenic bacteria secrete protein toxins that provoke apoptosis or necrosis of eukaryotic cells. Here, we developed a live-imaging method, based on incorporation of a DNA-intercalating dye into membrane-damaged host cells, to study the kinetics of primary bone marrow-derived macrophages (BMDMs) mortality induced by opportunistic pathogen Pseudomonas aeruginosa expressing either Type III Secretion System (T3SS) toxins or the pore-forming toxin, Exolysin (ExlA). We found that ExlA promotes the activation of Caspase-1 and maturation of interleukin-1beta. BMDMs deficient for Caspase-1 and Caspase-11 were resistant to ExlA-induced death. Furthermore, by using KO BMDMs, we determined that the upstream NLRP3/ASC complex leads to the Caspase-1 activation. We also demonstrated that Pseudomonas putida and Pseudomonas protegens and the Drosophila pathogen Pseudomonas entomophila, which naturally express ExlA-like toxins, are cytotoxic toward macrophages and provoke the same type of pro-inflammatory death as does ExlA+ P. aeruginosa. These results demonstrate that ExlA-like toxins of two-partner secretion systems from diverse Pseudomonas species activate the NLRP3 inflammasome and provoke inflammatory pyroptotic death of macrophages. PMID- 28654177 TI - Highly Emissive Organic Single-Molecule White Emitters by Engineering o-Carborane Based Luminophores. AB - The development of organic single-molecule solid-state white emitters holds a great promise for advanced lighting and display applications. Highly emissive single-molecule white emitters were achieved by the design and synthesis of a series of o-carborane-based luminophores. These luminophores are able to induce multiple emissions to directly emit high-purity white light in solid state. By tuning both molecular and aggregate structures, a significantly improved white light efficiency has been realized (absolute quantum yield 67 %), which is the highest value among the known organic single-molecule white emitters in the solid state. The fine-tuning of the packing modes from H- to J- and cross-stacking aggregates as well as intermolecular hydrogen bonds are successful in one molecular skeleton. These are crucial for highly emissive white-light emission in the solid state. PMID- 28654178 TI - Dual Catalytic Activity of a Cytochrome P450 Controls Bifurcation at a Metabolic Branch Point of Alkaloid Biosynthesis in Rauwolfia serpentina. AB - Plants create tremendous chemical diversity from a single biosynthetic intermediate. In plant-derived ajmalan alkaloid pathways, the biosynthetic intermediate vomilenine can be transformed into the anti-arrhythmic compound ajmaline, or alternatively, can isomerize to form perakine, an alkaloid with a structurally distinct scaffold. Here we report the discovery and characterization of vinorine hydroxylase, a cytochrome P450 enzyme that hydroxylates vinorine to form vomilenine, which was found to exist as a mixture of rapidly interconverting epimers. Surprisingly, this cytochrome P450 also catalyzes the non-oxidative isomerization of the ajmaline precursor vomilenine to perakine. This unusual dual catalytic activity of vinorine hydroxylase thereby provides a control mechanism for the bifurcation of these alkaloid pathway branches. This discovery highlights the unusual catalytic functionality that has evolved in plant pathways. PMID- 28654179 TI - Exploiting the Evolutionary Relationship between Malarial Parasites and Plants To Develop New Herbicides. AB - Herbicide resistance is driving a need to develop new herbicides. The evolutionary relationship between apicomplexan parasites, such as those causing malaria, and plants is close enough that many antimalarial drugs are herbicidal and so represent novel scaffolds for herbicide development. Using a compound library from the Medicines for Malaria Venture, the model plant Arabidopsis thaliana, and a physicochemical database of known herbicides, a compound was discovered that showed post-emergence herbicidal activity equal to commercial herbicides. Using structure-activity analysis, important points for its potency were found. The compound was also tested and found to be active against common crop weeds. Physiological profiling suggested the compound was a photosystem II inhibitor, representing a new scaffold for herbicide development. Overall this approach demonstrates the viability of using antimalarial compounds as lead compounds for the development of much needed new herbicides. PMID- 28654180 TI - Hydrometeorology organizes intra-annual patterns of tree growth across time, space and species in a montane watershed. AB - Tree radial growth is often systematically limited by water availability, as is evident in tree ring records. However, the physiological nature of observed tree growth limitation is often uncertain outside of the laboratory. To further explore the physiology of water limitation, we observed intra-annual growth rates of four conifer species using point dendrometers and microcores, and coupled these data to observations of water potential, soil moisture, and vapor pressure deficit over 2 yr in the Northern Rocky Mountains, USA. The onset of growth limitation in four species was well explained by a critical balance between soil moisture supply and atmospheric demand representing relatively mesic conditions, despite the timing of this threshold response varying by up to 2 months across topographic and elevation gradients, growing locations, and study years. Our findings suggest that critical water deficits impeding tissue growth occurred at relatively high water potential values, often occurring when hydrometeorological conditions were relatively wet during the growing season (e.g. in early spring in some cases). This suggests that species-specific differences in water use strategies may not necessarily affect tree growth, and that tissue growth may be more directly linked to environmental moisture conditions than might otherwise be expected. PMID- 28654181 TI - Photoelectrochemical H2 Generation from Suboxide TiO2 Nanotubes: Visible-Light Absorption versus Conductivity. AB - In the present work we report on the key factors dictating the photoelectrochemical (PEC) performance of suboxide titania (TiOx ) nanotubes. TiOx nanotubes were produced by a systematic variation of reduction heat treatments of TiO2 in Ar/H2 . The properties of the TiOx tubes were investigated by electron paramagnetic resonance (EPR), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), solid-state conductivity, reflectivity measurements, photocurrent spectroscopy, and photoelectrochemical hydrogen evolution. In line with earlier literature, these suboxide tubes show a drastically improved photoelectrochemical water-splitting performance compared to non-reduced anatase TiO2 tubes. In this work we show that the key improvement in water-splitting performance is due to the strongly improved conductivity of TiOx semimetalic tubes, reaching 13.5 KOmega per tube compared to 70 MOmega (for non reduced anatase), and is not due to the enhanced visible-light absorbance. PMID- 28654182 TI - The D-lactate dehydrogenase MoDLD1 is essential for growth and infection-related development in Magnaporthe oryzae. AB - Rice blast disease caused by Magnaporthe oryzae is initiated by the attachment of conidia to plant surfaces. Germ tubes emerging from conidia develop melanized appressoria to physically penetrate the host surface. Previous studies revealed that appressorium development requires the breakdown of storage lipids and glycogen that occur in peroxisomes and the cytosol respectively, culminating in production of pyruvate. However, the downstream product(s) entering the mitochondria for further oxidation is unclear. In this study, we aimed to investigate the molecular basis underlying the metabolic flux towards the mitochondria associated with the infectious-related development in M. oryzae. We showed that D-lactate is a key intermediate metabolite of the mobilization of lipids and glycogen, and its oxidative conversion to pyruvate is catalysed by a mitochondrial D-lactate dehydrogenase MoDLD1. Deletion of MoDLD1 caused defects in conidiogenesis and appressorium formation, and subsequently the loss of fungal pathogenicity. Further analyses demonstrated that MoDLD1 activity is involved in the maintenance of redox homeostasis during conidial germination. Thus, MoDLD1 is a critical modulator that channels metabolite flow to the mitochondrion coupling cellular redox state, and contributes to development and virulence of M. oryzae. PMID- 28654183 TI - Impact of drinking water treatment and distribution on the microbiome continuum: an ecological disturbance's perspective. AB - While microbes are known to be present at different stages of a drinking water system, their potential functions and ability to grow in such systems are poorly understood. In this study, we demonstrated that treatment and distribution processes could be viewed as ecological disturbances exhibited over space on the microbiome continuum in a groundwater-derived system. Results from 16S rRNA gene amplicon analysis and metagenomics suggested that disturbances in the system were intense as the community diversity was substantially reduced during the treatment steps. Specifically, syntrophs and methanogens dominant in raw water (RW) disappeared after water abstraction, accompanied by a substantial decrease in both the abundance and number of functional genes related to methanogenesis. The softening effluent was dominated by an Exiguobacterium-related population, likely due to its ability to use the phosphotransferase system (PTS) as regulatory machinery to control the energy conditions of the cell. After disinfection and entering the distribution system, community-level functionality remained relatively stable, whereas the community structure differed from those taken in the treatment steps. The diversity and high abundance of some eukaryotic groups in the system suggested that predation could be a disturbance to the bacterial microbiome, which could further drive the diversification of the bacterial community. PMID- 28654184 TI - Recycling of glucagon receptor to plasma membrane increases in adipocytes of obese rats by soy protein; implications for glucagon resistance. AB - SCOPE: Hyperglucagonemia contributes to hyperglycemia in type 2 diabetes (T2D). Previously, we have found that soy protein normalized fasting hyperglucagonemia in obese Zucker (fa/fa) rats, sensitizing the HSL-lipolytic signaling pathway in white adipose tissue (WAT), however the mechanism remains unknown. METHODS AND RESULTS: Zucker (fa/fa) rats were fed casein or soy protein diet in combination with soybean or coconut oil. Glucagon receptor (GR) was increased at the plasma membrane of adipocytes of rats fed soy protein compared to those fed casein, without changes in total GR abundance. The protein abundance of Rab4, a GTPase involved in GR fast recycling, was dramatically up-regulated in adipocytes of rats fed soy protein. The proportion of GR bound to Rab4 or to RAMP2, involved in promoting GR ligand-binding and G protein selectivity, increased when soy protein was combined with soybean oil as fat source. In rats fed soy protein with coconut oil, Rab11 levels, a protein involved in the slow recycling of GR, was also increased. CONCLUSION: Soy protein increases GR recycling to the membrane of adipocytes and its ligand-binding and G protein selectivity, suggesting, it could be used in T2D dietary treatment to reestablish glucagon sensitivity in WAT, leading to the regulation of circulating glucagon levels. PMID- 28654185 TI - Identification and characterisation of isoprene-degrading bacteria in an estuarine environment. AB - Approximately one-third of volatile organic compounds (VOCs) emitted to the atmosphere consists of isoprene, originating from the terrestrial and marine biosphere, with a profound effect on atmospheric chemistry. However, isoprene provides an abundant and largely unexplored source of carbon and energy for microbes. The potential for isoprene degradation in marine and estuarine samples from the Colne Estuary, UK, was investigated using DNA-Stable Isotope Probing (DNA-SIP). Analysis at two timepoints showed the development of communities dominated by Actinobacteria including members of the genera Mycobacterium, Rhodococcus, Microbacterium and Gordonia. Representative isolates, capable of growth on isoprene as sole carbon and energy source, were obtained from marine and estuarine locations, and isoprene-degrading strains of Gordonia and Mycobacterium were characterised physiologically and their genomes were sequenced. Genes predicted to be required for isoprene metabolism, including four component isoprene monooxygenases (IsoMO), were identified and compared with previously characterised examples. Transcriptional and activity assays of strains growing on isoprene or alternative carbon sources showed that growth on isoprene is an inducible trait requiring a specific IsoMO. This study is the first to identify active isoprene degraders in estuarine and marine environments using DNA SIP and to characterise marine isoprene-degrading bacteria at the physiological and molecular level. PMID- 28654186 TI - Haloperidol Decreases Hyperalgesia and Allodynia Induced by Chronic Constriction Injury. AB - Neuropathic pain has proven to be a difficult condition to treat, so investigational therapy has been sought that may prove useful, such as the use of sigma-1 antagonists. Haloperidol (HAL) is a compound that shows a high affinity with these receptors, acting as an antagonist. Therefore, the objective of this study was to demonstrate its effect in an experimental model of neuropathic pain and corroborate its antagonistic action of the sigma-1 receptors under these conditions. BD-1063 was used as a sigma-1 antagonist control, and gabapentin (Gbp) was used as a positive control. The antihyperalgesic and anti-allodynic effects of the drugs were determined after single-dose trials. In every case, the effects increased in a dose-dependent manner. HAL had the same efficacy as both BD-1063 and Gbp. In the analysis of pharmacological potency, in which the ED50 were compared, HAL was the most potent drug of all. The effect of HAL on chronic constriction injury (CCI) rats was reversed by the sigma-1 agonist (PRE-084). HAL reversed the hyperalgesic and allodynic effects of PRE-084 in naive rats. The dopamine antagonist, (-)-sulpiride, showed no effect in CCl rats. These results suggest that HAL presents an antinociceptive effect via sigma-1 receptor antagonism at the spinal level in the CCl model. PMID- 28654187 TI - Silver-Catalyzed Oxidative C(sp3 )-P Bond Formation through C-C and P-H Bond Cleavage. AB - The silver-catalyzed oxidative C(sp3 )-H/P-H cross-coupling of 1,3-dicarbonyl compounds with H-phosphonates, followed by a chemo- and regioselective C(sp3 ) C(CO) bond-cleavage step, provided heavily functionalized beta-ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional-group tolerance, and exclusive selectivity. PMID- 28654188 TI - Invited Response to "Potential Disadvantages of Over Centralization of Organ Recovery Centers: Response to Marsolais et al." PMID- 28654190 TI - Interobserver Variability in Scoring Liver Biopsies with a Diagnosis of Alcoholic Hepatitis. AB - BACKGROUND: Alcoholic hepatitis (AH) is one of the most severe forms of alcoholic liver disease. Recently, a histologic scoring system for predicting prognosis in this patient cohort was proposed as Alcoholic Hepatitis Histologic Score (AHHS). We aimed to assess interobserver variability in recognizing histologic features of AH and the effect of this variability on the proposed AHHS categories. METHODS: Hematoxylin-eosin- and trichrome-stained slides from 32 patients diagnosed with AH with liver biopsies within 1 month of presentation (2000 to 2015) were reviewed by 5 pathologists including 3 liver pathologists and 2 gastrointestinal (GI) pathologists masked to the clinical findings or outcome. Histologic features of AH were assessed, the AHHS was calculated, and an AHHS category (mild, moderate, severe) was assigned. The Fleiss' kappa coefficient (kappa) analysis was performed to determine the interobserver agreement. RESULTS: A slight-to-moderate level of interobserver agreement existed among 5 reviewers on histopathologic features of AH with kappa value ranging from 0.20 (95% confidence interval (CI): 0.03 to 0.46, megamitochondria) to 0.52 [95% CI: 0.40 to 0.68, polymorphonuclear leukocyte (PMN) infiltration]. There was only a fair level of agreement in assigning AHHS category (kappa = 0.33, 95% CI: 0.20 to 0.51). While overall fibrosis and neutrophilic inflammation were comparably evaluated by 3 liver pathologists and 2 GI pathologists, bilirubinostasis and megamitochondria were more consistently diagnosed by liver pathologists. Overall, 18 of 32 (56%) were uniformly assigned to an AHHS category by all liver pathologists with a kappa value of 0.40 (95% CI: 0.22 to 0.60). CONCLUSIONS: In general, features of AH can be recognized with a slight-to-moderate level of interobserver agreement and there was fair interobserver agreement on assigning an AHHS category. Significant interobserver variability among pathologists revealed by the current study can limit its usefulness in everyday clinical practice. PMID- 28654189 TI - The Hospital Anxiety and Depression Scale (HADS) and the 9-item Patient Health Questionnaire (PHQ-9) as screening instruments for depression in patients with cancer. AB - BACKGROUND: Depression screening in patients with cancer is recommended by major clinical guidelines, although the evidence on individual screening tools is limited for this population. Here, the authors assess and compare the diagnostic accuracy of 2 established screening instruments: the depression modules of the 9 item Patient Health Questionnaire (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS-D), in a representative sample of patients with cancer. METHODS: This multicenter study was conducted with a proportional, stratified, random sample of 2141 patients with cancer across all major tumor sites and treatment settings. The PHQ-9 and HADS-D were assessed and compared in terms of diagnostic accuracy and receiver operating characteristic (ROC) curves for Diagnostic and Statistical Manual of Mental Disorders, 4th edition diagnosis of major depressive disorder using the Composite International Diagnostic Interview for Oncology as the criterion standard. RESULTS: The diagnostic accuracy of the PHQ-9 and HADS-D was fair for diagnosing major depressive disorder, with areas under the ROC curves of 0.78 (95% confidence interval, 0.76-0.79) and 0.75 (95% confidence interval, 0.74 0.77), respectively. The 2 questionnaires did not differ significantly in their areas under the ROC curves (P = .15). The PHQ-9 with a cutoff score >=7 had the best screening performance, with a sensitivity of 83% (95% confidence interval, 78%-89%) and a specificity of 61% (95% confidence interval, 59%-63%). The American Society of Clinical Oncology guideline screening algorithm had a sensitivity of 44% (95% confidence interval, 36%-51%) and a specificity of 84% (95% confidence interval, 83%-85%). CONCLUSIONS: In patients with cancer, the screening performance of both the PHQ-9 and the HADS-D was limited compared with a standardized diagnostic interview. Costs and benefits of routinely screening all patients with cancer should be weighed carefully. Cancer 2017;123:4236-4243. (c) 2017 American Cancer Society. PMID- 28654191 TI - Experimental Determination of the Molar Absorption Coefficient of n-Hexane Adsorbed on High-Silica Zeolites. AB - Determination of the molar absorption coefficients of the CH3 bending mode at nu~ =1380 cm-1 (epsilon1380 ) of n-hexane adsorbed from the gas phase on two different dealuminated zeolites is derived by a combination of IR spectroscopy and microgravimetric analysis. High-silica zeolite Y (HSZ-Y) and zeolite ZSM-5 (with SiO2 /Al2 O3 ratios of 200 and 280, respectively) with different textural and surface features are selected to evaluate the effect of the pore structure and architecture on the value of epsilon1380 of the adsorbed n-hexane. Experimental data indicate that the molecule experiences a different adsorption environment inside zeolites; thus resulting in a significant change of the dipole moment and very different epsilon1380 values: (0.278+/-0.018) cm MUmol-1 for HSZ Y and (0.491+/-0.032) cm MUmol-1 for ZSM-5. Experimental data are also supported by computational modeling, which confirms the effect of different matrices on the IR absorption intensity. This study reveals that the use of probe molecules for quantitative measurements of surface sites has to be judiciously adopted, especially if adsorption occurs in the restricted spaces of microporous materials. PMID- 28654193 TI - Serotonin Transporter Gene Polymorphisms and Selective Serotonin Reuptake Inhibitor Tolerability: Review of Pharmacogenetic Evidence. AB - Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5-HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability. This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes. Four online databases (PubMed, Cochrane CENTRAL, PsycINFO, and PharmGKB) were searched for articles on polymorphisms of SLC6A4 including 5-HTTLPR and STin2 by using a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references. Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5-HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings. In conclusion, the S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence include assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs. PMID- 28654192 TI - Problematic Drinking Mediates the Association Between Urgency and Intimate Partner Aggression During Acute Intoxication. AB - BACKGROUND: This study tested a moderated-mediation model whereby dimensions of impulsivity (i.e., negative urgency, positive urgency, sensation seeking, lack of premeditation, and lack of perseverance) differentially predict perpetration of physical intimate partner aggression (IPA) through problematic drinking in intoxicated and nonintoxicated heavy drinkers. METHODS: Participants were 249 heavy drinkers (148 men and 101 women) with a recent history of psychological and/or physical IPA perpetration toward their current partner recruited from 2 metropolitan U.S. cities. Participants completed questionnaires that assessed impulsivity and problematic drinking, consumed an Alcohol or No-Alcohol Control beverage, and completed a shock-based aggression task in which they were ostensibly provoked by their intimate partner. RESULTS: Results indicated an indirect effect of urgency on IPA through problematic drinking that was significantly more positive in intoxicated individuals. CONCLUSIONS: These findings implicate a tendency to act rashly in response to emotions as the specific dimension of impulsivity associated with problematic drinking, which in turn exacerbates risk for IPA perpetration. Results also suggest acute effects of alcohol are key in facilitating this mechanism. PMID- 28654194 TI - EcoGenetics: An R package for the management and exploratory analysis of spatial data in landscape genetics. AB - The integration of ecology and genetics has become established in recent decades, in hand with the development of new technologies, whose implementation is allowing an improvement of the tools used for data analysis. In a landscape genetics context, integrative management of population information from different sources can make spatial studies involving phenotypic, genotypic and environmental data simpler, more accessible and faster. Tools for exploratory analysis of autocorrelation can help to uncover the spatial genetic structure of populations and generate appropriate hypotheses in searching for possible causes and consequences of their spatial processes. This study presents EcoGenetics, an R package with tools for multisource management and exploratory analysis in landscape genetics. PMID- 28654195 TI - Dynamics of the oral microbiota as a tool to estimate time since death. AB - The oral cavity harbors one of the most diverse microbiomes in the human body. It has been shown to be the second most complex in the body after the gastrointestinal tract. Upon death, the indigenous microorganisms lead to the decomposition of the carcass. Therefore, the oral cavity and gastrointestinal tract microbiomes play a key role in human decomposition. The aim of the present study is to monitor the microbiome of decaying bodies on a daily basis and to identify signature bacterial taxa, that can improve postmortem interval estimation. Three individuals (one male and two female) donated to the University of Tennessee Forensic Anthropology Center for the W.M. Bass Donated Skeletal Collection were studied. Oral swab samples were taken daily throughout the different stages of cadaveric putrefaction. DNA was extracted and analyzed by next-generation sequencing techniques. The three cadavers showed similar overall successional changes during the decomposition process. Firmicutes and Actinobacteria are the predominant phyla in the fresh stage. The presence of Tenericutes corresponds to bloat stage. Firmicutes is the predominant phylum in advanced decay, but the Firmicutes community is a different one from the predominant Firmicutes of the fresh stage. This study depicts the thanatomicrobiome successional changes in the oral cavity, and highlights its potential use in forensic cases as a quantitative and objective approach to estimate postmortem interval, from an ecological rationale. PMID- 28654196 TI - Compositional and functional dynamics of the bovine rumen methanogenic community across different developmental stages. AB - Methanogenic archaea in the bovine rumen are responsible for the reduction of carbon molecules to methane, using various electron donors and driving the electron flow across the microbial food webs. Thus, methanogens play a key role in sustaining rumen metabolism and function. Research of rumen methanogenic archaea typically focuses on their composition and function in mature animals, while studies of early colonization and functional establishment remain scarce. Here, we investigated the metabolic potential and taxonomic composition of the methanogenic communities across different rumen developmental stages. We discovered that the methanogenesis process changes with age and that the early methanogenic community is characterized by a high activity of methylotrophic methanogenesis, likely performed by members of the order Methanosarcinales, exclusively found in young rumen. In contrast, higher hydrogenotrophic activity was observed in the mature rumen, where a higher proportion of exclusively hydrogenotrophic taxa are found. These findings suggest that environmental filtering acts on the archaeal communities and select for different methanogenic lineages during different growth stages, affecting the functionality of this ecosystem. This study provides a better understanding of the compositional and metabolic changes that occur in the rumen microbiome from its initial stages of colonization and throughout the animals' life. PMID- 28654197 TI - Allergic risks of consuming edible insects: A systematic review. AB - The expected future demand for food and animal-derived protein will require environment-friendly novel food sources with high nutritional value. Insects may be one of such novel food sources. However, there needs to be an assessment of the risks associated with their consumption, including allergic risks. Therefore, we performed a systematic review aiming to analyse current data available regarding the allergic risks of consuming insects. We reviewed all reported cases of food allergy to insects, and studied the possibility of cross-reactivity and co-sensitisation between edible insects, crustaceans and house dust mites. We analysed a total of 25 articles - eight assessing the cross-reactivity/co sensitisation between edible insects, crustaceans and house dust mites; three characterizing allergens in edible insects and 14 case reports, describing case series or prevalence studies of food allergy caused by insects. Cross reactivity/co-sensitisation between edible insects and crustaceans seems to be clinically relevant, while it is still unknown if co-sensitisation between house dust mites and edible insects can lead to a food allergy. Additionally, more information is also needed about the molecular mechanisms underlying food allergy to insects, although current data suggest that an important role is played by arthropod pan-allergens such as tropomyosin or arginine kinase. PMID- 28654198 TI - Predictive accuracy of difficult mask ventilation assessment methods - a reply. PMID- 28654199 TI - Imidacloprid is hydroxylated by Laodelphax striatellus CYP6AY3v2. AB - Laodelphax striatellus (Fallen) is one of the most destructive pests of rice, and has developed high resistance to imidacloprid. Our previous work indicated a strong association between imidacloprid resistance and the overexpression of a cytochrome P450 gene CYP6AY3v2 in a L. striatellus imidacloprid resistant strain (Imid-R). In this study, a transgenic Drosophila melanogaster line that overexpressed the L. striatellus CYP6AY3v2 gene was established and was found to confer increased levels of imidacloprid resistance. Furthermore, CYP6AY3v2 was co expressed with D. melanogaster cytochrome P450 reductase (CPR) in Spodoptera frugiperda 9 (SF9) cells. A carbon monoxide difference spectra analysis indicated that CYP6AY3v2 was expressed predominately in its cytochrome P450 (P450) form, which is indicative of a good-quality functional enzyme. The recombinant CYP6AY3v2 protein efficiently catalysed the model substrate P-nitroanisole to p nitrophenol with a maximum velocity (Vmax ) of 60.78 +/- 3.93 optical density (mOD)/min/mg protein. In addition, imidacloprid itself was metabolized by the recombinant CYP6AY3v2/nicotinamide adenine dinucleotide 2'-phosphate reduced tetrasodium salt (NADPH) CPR microsomes in in vitro assays (catalytic constant (Kcat ) = 0.34 pmol/min/pmol P450, michaelis constant (Km ) = 41.98 MUM), and imidacloprid depletion and metabolite peak formation were with a time dependence. The data provided direct evidence that CYP6AY3v2 is capable of hydroxylation of imidacloprid and conferring metabolic resistance in L. striatellus. PMID- 28654200 TI - Preparation and Evaluation of Potent Pentafluorosulfanyl-Substituted Anti Tuberculosis Compounds. AB - The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub micromolar potency, and four displayed MICs <100 nm. Seven compounds were evaluated against non-replicating and mono-drug-resistant Mtb, and for their ability to inhibit Mtb within the macrophage. The greatest potency was observed against intracellular Mtb (MIC <10 nm for three compounds), which is often the most challenging to target. In general, the SF5 -bearing compounds were very similar to their CF3 counterparts, with the major differences observed being their in vitro ADME properties. Two SF5 -bearing compounds were found to have greater protein binding than their corresponding CF3 counterparts, but were also less metabolized in human microsomes, resulting in longer half-lives. PMID- 28654201 TI - Long-acting beta2-agonists versus long-acting muscarinic antagonists in patients with stable COPD: A systematic review and meta-analysis of randomized controlled trials. AB - Several long-acting bronchodilators have been developed and are widely used as first-line treatment in patients with stable chronic obstructive pulmonary disease (COPD). However, the initial choice of therapy is still uncertain. The aim of this study was to examine the clinical efficacy and safety of long-acting muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA) in patients with stable COPD. We searched several databases and manufacturers' websites to identify relevant randomized clinical trials for meta-analysis. Outcomes of interest were trough forced expiratory volume in 1 s (FEV1 ), acute exacerbations, transitional dyspnoea index (TDI) score, St George's Respiratory Questionnaire (SGRQ) score and adverse events. Sixteen trials with a total of 22 872 patients were included in this study. Compared with LABA, LAMA were associated with a greater reduction in acute exacerbations (OR: 0.84, 95% CI: 0.74-0.94, P = 0.003) and fewer adverse events (OR: 0.92, 95% CI: 0.86-0.97, P = 0.005). There were no significant differences in trough FEV1 , TDI and SGRQ scores. In patients with stable COPD, LAMA were associated with a greater reduction in acute exacerbations and fewer adverse effects compared with LABA. PMID- 28654202 TI - Socioeconomic factors affect the selection of proton radiation therapy for children. AB - BACKGROUND: Proton radiotherapy remains a limited resource despite its clear potential for reducing radiation doses to normal tissues and late effects in children in comparison with photon therapy. This study examined the impact of race and socioeconomic factors on the use of proton therapy in children with solid malignancies. METHODS: This study evaluated 12,101 children (age <= 21 years) in the National Cancer Data Base who had been diagnosed with a solid malignancy between 2004 and 2013 and had received photon- or proton-based radiotherapy. Logistic regression analysis was used to evaluate patient, tumor, and socioeconomic variables affecting treatment with proton radiotherapy versus photon radiotherapy. RESULTS: Eight percent of the patients in the entire cohort received proton radiotherapy, and this proportion increased between 2004 (1.7%) and 2013 (17.5%). Proton therapy was more frequently used in younger patients (age <= 10 years; odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and in patients with bone/joint primaries and ependymoma, medulloblastoma, and rhabdomyosarcoma histologies (P < .05). Patients with metastatic disease were less likely to receive proton therapy (OR, 0.4; 95% CI, 0.3-0.6). Patients with private/managed care were more likely than patients with Medicaid or no insurance to receive proton therapy (P < .0001). A higher median household income and educational attainment were also associated with increased proton use (P < .001). Patients treated with proton therapy versus photon therapy were more likely to travel more than 200 miles (13% vs 5%; P < .0001). CONCLUSIONS: Socioeconomic factors affect the use of proton radiotherapy in children. Whether this disparity is related to differences in the referral patterns, the knowledge of treatment modalities, or the ability to travel for therapy needs to be further clarified. Improving access to proton therapy in underserved pediatric populations is essential. Cancer 2017;123:4048-56. (c) 2017 American Cancer Society. PMID- 28654203 TI - Effects of storage temperature on bacterial growth rates and community structure in fresh retail sushi. AB - AIMS: This study was conducted to assess the effects of different storage temperatures (4-20 degrees C), on bacterial concentrations, growth rates and community structure in fresh retail sushi, a popular retail product with a claimed shelf life of 2-3 days. METHODS AND RESULTS: The maximum specific growth rate based on aerobic plate count (APC) at 4 degrees C was 0.06 h-1 and displayed a sixfold increase (0.37 h-1 ) at 20 degrees C. Refrigeration resulted in no growth of hydrogen sulphide (H2 S)-producing bacteria, but this group had the strongest temperature response. The bacterial community structure was determined by PCR/DGGE (denaturing gradient gel electrophoresis). Multivariate analysis based on Bray-Curtis similarities demonstrated that temperature alone was not the major determinant for the bacterial community structure. The total concentration of aerobic bacteria was the variable that most successfully explained the differences between the communities. The dominating organisms, detected by sequencing of DNA bands excised from the DGGE gel, were Brochothrix thermosphacta and genera of lactic acid bacteria (LAB). CONCLUSION: The relationship between growth rates and storage temperatures clearly demonstrates that these products are sensitive to deviations from optimal storage temperature, possibly resulting in loss of quality during shelf life. Regardless of the storage temperature, the bacterial communities converged towards a similar structure and density, but the storage temperature determined how fast the community reached its carrying capacity. SIGNIFICANCE AND IMPACT OF THE STUDY: Little information is available on the microbial composition of ready-to-eat food that are prepared with raw fish, subjected to contamination during handling, and susceptible to microbial growth during cold storage. Moreover, the data are a good first possibility to simulate growth of APC, H2 S-producing bacteria and LAB under different temperature scenarios that might occur during production, distribution or storage. PMID- 28654204 TI - Race and risk of metastases and survival after radical prostatectomy: Results from the SEARCH database. AB - BACKGROUND: Black race is associated with prostate cancer (PC) diagnosis and poor outcome. Previously, the authors reported that black men undergoing radical prostatectomy (RP) in equal-access hospitals had an increased risk of biochemical disease recurrence (BCR), but recurrences were equally aggressive as those occurring in white men. The authors examined the association between race and long-term outcomes after RP. METHODS: Data regarding 1665 black men (37%) and 2791 white men (63%) undergoing RP were analyzed. Using Cox models, the authors tested the association between race and BCR, BCR with a prostate-specific antigen (PSA) doubling time <9 months (aggressive disease recurrence), metastases, PC specific death, and overall death. RESULTS: At a median follow-up of 102 months, 1566 men (35%) developed BCR, 217 men (5%) experienced aggressive disease recurrence, 193 men (4%) developed metastases, and 1207 men (27%) had died, 107 of whom (2%) died of PC. White men were older and had a lower preoperative PSA level, a lower biopsy and pathological grade group, and more capsular penetration but less seminal vesicle invasion and positive surgical margins versus black men (all P<.05). Black men were found to have a more recent surgery year (P<.001). On univariable analysis, black race was associated with increased BCR (P = .003) and reduced overall death (P = .017). On multivariable analysis, black race was not found to be associated with BCR (hazard ratio [HR], 1.07; P = .26), aggressive recurrence (HR, 1.14; P = .42), metastasis (HR, 1.24; P = .21), PC-specific death (HR, 1.03; P = .91), or overall death (HR, 1.03; P = .67). CONCLUSIONS: Among men undergoing RP at equal-access centers, although black men were found to have an increased risk of BCR, they had similar risks of aggressive disease recurrence, metastasis, and PC-specific death compared with white men, and the risk of BCR was found to be similar after controlling for risk parameters. Longer follow-up is needed to confirm these findings. Cancer 2017;123:4199-4206. (c) 2017 American Cancer Society. PMID- 28654205 TI - Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet? AB - Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARalpha for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer. PMID- 28654206 TI - Cognitive aids and 'behavioural anaesthesia'. PMID- 28654208 TI - Inferring past demographic changes from contemporary genetic data: A simulation based evaluation of the ABC methods implemented in diyabc. AB - Inferring the demographic history of species and their populations is crucial to understand their contemporary distribution, abundance and adaptations. The high computational overhead of likelihood-based inference approaches severely restricts their applicability to large data sets or complex models. In response to these restrictions, approximate Bayesian computation (ABC) methods have been developed to infer the demographic past of populations and species. Here, we present the results of an evaluation of the ABC-based approach implemented in the popular software package diyabc using simulated data sets (mitochondrial DNA sequences, microsatellite genotypes and single nucleotide polymorphisms). We simulated population genetic data under five different simple, single-population models to assess the model recovery rates as well as the bias and error of the parameter estimates. The ability of diyabc to recover the correct model was relatively low (0.49): 0.6 for the simplest models and 0.3 for the more complex models. The recovery rate improved significantly when reducing the number of candidate models from five to three (from 0.57 to 0.71). Among the parameters of interest, the effective population size was estimated at a higher accuracy compared to the timing of events. Increased amounts of genetic data did not significantly improve the accuracy of the parameter estimates. Some gains in accuracy and decreases in error were observed for scaled parameters (e.g., Ne MU) compared to unscaled parameters (e.g., Ne and MU). We concluded that diyabc-based assessments are not suited to capture a detailed demographic history, but might be efficient at capturing simple, major demographic changes. PMID- 28654207 TI - The effect of obesity and repeated exposure on pharmacokinetic response to grape polyphenols in humans. AB - SCOPE: Evidence suggests that dietary pattern may affect polyphenol absorption and/or metabolism. Further, obesity is associated with lower circulating nutrients, though the reason is unclear. We investigated the pharmacokinetic (PK) response of polyphenols in obese/overweight versus lean individuals before and after repeated dosing of grape polyphenols. METHODS AND RESULTS: A pilot study was conducted in which PK challenges were administered before and after 10 days of repeated dosing with polyphenols. Volunteers (6 lean, 6 overweight/obese) consumed resveratrol, grape seed extract, and grape juice (2125 mg total polyphenols) daily. On days 1 and 11, blood samples were collected for 6 h after the polyphenol dose and analyzed for deconjugated catechin, epicatechin, resveratrol, and quercetin. Area under the plasma polyphenol mass by time curves (AUCs) were greater for catechin, epicatechin, and quercetin on day 11 versus day 1 for low BMI individuals (p = 0.039) but not high BMI individuals. Further, AUCs were greater for epicatechin and resveratrol for low versus high BMI individuals (p = 0.041), with a similar trend for catechin (p = 0.065), on day 11 but not day 1. CONCLUSION: These results suggest that that obesity and repeated exposure may modify polyphenol absorption and/or metabolism in humans. PMID- 28654209 TI - Sensitivity and Reliability of Halothane-anaesthetized Microminipigs to Assess Risk of Drug-induced Long QT Syndrome. AB - Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 MUg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals. PMID- 28654210 TI - Do plant-eating insect lineages pass through phases of host-use generalism during speciation and host switching? Phylogenetic evidence. AB - The Oscillation Hypothesis posits that plant-eating insect diversity is generated by cycles of diet breadth expansion and contraction. Although at any given time most plant-eating insect species are host specialists, host-use evolution and speciation tend to entail a phase of generalism. The main evidence for this comes from comparative phylogenetic studies, but with mixed support. Here, I review and add to this evidence. I show that some of the original work that inspired the Oscillation Hypothesis is flawed in a way that leads to spurious inferences about trends in the evolution of diet diversity. And I present a new analysis which fails to support its predictions about patterns of species diversity. On the other hand, some of the published work that claims to reject the Oscillation Hypothesis may actually provide some of the strongest support for it, and I present new analyses which support its prediction that host-use generalism facilitates host-use evolution. In summary, the Oscillation Hypothesis successfully predicts some phylogenetic patterns but not others. Generalism appears to facilitate host-use evolution, but it does not appear to be inevitably chased by host-use specialization and speciation. PMID- 28654211 TI - Cleaning lateral morphological features of the root canal: the role of streaming and cavitation. AB - AIM: To investigate the effects of ultrasonic activation file type, lateral canal location and irrigant on the removal of a biofilm-mimicking hydrogel from a fabricated lateral canal. Additionally, the amount of cavitation and streaming was quantified for these parameters. METHODOLOGY: An intracanal sonochemical dosimetry method was used to quantify the cavitation generated by an IrriSafe 25 mm length, size 25 file inside a root canal model filled with filtered degassed/saturated water or three different concentrations of NaOCl. Removal of a hydrogel, demonstrated previously to be an appropriate biofilm mimic, was recorded to measure the lateral canal cleaning rate from two different instruments (IrriSafe 25 mm length, size 25 and K 21 mm length, size 15) activated with a P5 Suprasson (Satelec) at power P8.5 in degassed/saturated water or NaOCl. Removal rates were compared for significant differences using nonparametric Kruskal-Wallis and/or Mann-Whitney U-tests. Streaming was measured using high-speed particle imaging velocimetry at 250 kfps, analysing both the oscillatory and steady flow inside the lateral canals. RESULTS: There was no significant difference in amount of cavitation between tap water and oversaturated water (P = 0.538), although more cavitation was observed than in degassed water. The highest cavitation signal was generated with NaOCl solutions (1.0%, 4.5%, 9.0%) (P < 0.007) and increased with concentration (P < 0.014). The IrriSafe file outperformed significantly the K-file in removing hydrogel (P < 0.05). Up to 64% of the total hydrogel volume was removed after 20 s. The IrriSafe file typically outperformed the K-file in generating streaming. The oscillatory velocities were higher inside the lateral canal 3 mm compared to 6 mm from WL and were higher for NaOCl than for saturated water, which in turn was higher than for degassed water. CONCLUSIONS: Measurements of cavitation and acoustic streaming have provided insight into their contribution to cleaning. Significant differences in cleaning, cavitation and streaming were found depending on the file type and size, lateral canal location and irrigant used. In general, the IrriSafe file outperformed the K-file, and NaOCl performed better than the other irrigants tested. The cavitation and streaming measurements revealed that both contributed to hydrogel removal and both play a significant role in root canal cleaning. PMID- 28654212 TI - Growth-independent cross-feeding modifies boundaries for coexistence in a bacterial mutualism. AB - Nutrient cross-feeding can stabilize microbial mutualisms, including those important for carbon cycling in nutrient-limited anaerobic environments. It remains poorly understood how nutrient limitation within natural environments impacts mutualist growth, cross-feeding levels and ultimately mutualism dynamics. We examined the effects of nutrient limitation within a mutualism using theoretical and experimental approaches with a synthetic anaerobic coculture pairing fermentative Escherichia coli and phototrophic Rhodopseudomonas palustris. In this coculture, E. coli and R. palustris resemble an anaerobic food web by cross-feeding essential carbon (organic acids) and nitrogen (ammonium) respectively. Organic acid cross-feeding stemming from E. coli fermentation can continue in a growth-independent manner during nitrogen limitation, while ammonium cross-feeding by R. palustris is growth-dependent. When ammonium cross feeding was limited, coculture trends changed yet coexistence persisted under both homogenous and heterogenous conditions. Theoretical modelling indicated that growth-independent fermentation was crucial to sustain cooperative growth under conditions of low nutrient exchange. In contrast to stabilization at most cell densities, growth-independent fermentation inhibited mutualistic growth when the E. coli cell density was adequately high relative to that of R. palustris. Thus, growth-independent fermentation can conditionally stabilize or destabilize a mutualism, indicating the potential importance of growth-independent metabolism for nutrient-limited mutualistic communities. PMID- 28654213 TI - Novel Alkoxy-Substituted Dipyrrins and Near-IR BODIPY Dyes-Preparation and Photophysical Properties. AB - Starting from 3-alkoxy-2-aryl-substituted pyrroles and aromatic aldehydes, a collection of new dipyrrins was prepared. Under the standard conditions of Treibs, these were converted into the corresponding boron dipyrrins (BODIPYs). Compounds of this type with alkoxy groups at C-3 position of both pyrrole subunits are new and hence the photophysical properties of this collection of novel dipyrrins and BODIPY dyes were investigated. The dipyrrins show absorption maxima up to 596 nm and emissions of up to 677 nm. For the BODIPY series a remarkable effect of the alkoxy groups was identified, resulting in red shifts for absorptions and emissions. The compound substituted with two 2-thien-2-yl groups and a meso-C6 F5 substituent shows an absorption maximum at 725 nm and emits at 754 nm and thus is a new representative of a near-IR BODIPY dye related to certain aza-BODIPYs. Our results demonstrate the influence of the alkoxy groups on the spectroscopic data and reveal the potential of 3-alkoxy-2-aryl substituted pyrroles for the design of new fluorophores. PMID- 28654214 TI - Locking the Coplanar Conformation of pi-Conjugated Molecules and Macromolecules Using Dynamic Noncovalent Bonds. AB - Torsional conformation of the backbone of a pi-conjugated molecule or macromolecule shapes its solubility, optoelectronic characteristics, rheological behaviors, and ultimately solid-state functions. In order to tailor these molecular, supramolecular, and materials properties, the desired coplanar conformation in pi-conjugated systems can be locked by using dynamic noncovalent bonds. In this article, the syntheses, characterizations, and unique properties of conjugated molecules/polymers involving a variety of bridging noncovalent bonds are disussed in the context of coplanar backbone conformation. In addition, challenges in this specific field are identified and discussed for future breakthroughs in exploiting the promising potential of noncovalent-bond-bridged, pi-conjugated organic materials. PMID- 28654215 TI - The FgSRP1 SR-protein gene is important for plant infection and pre-mRNA processing in Fusarium graminearum. AB - The versatile functions of SR (serine/arginine-rich) proteins in pre-mRNA splicing and processing are modulated by reversible phosphorylation. Previous studies showed that FgPrp4, the only protein kinase among spliceosome components, is important for intron splicing and the FgSrp1 SR protein is phosphorylated at five conserved sites in Fusarium graminearum. In this study, we showed that the Fgsrp1 deletion mutant rarely produced conidia and caused only limited symptoms on wheat heads and corn silks. Deletion of FgSRP1 also reduced ascospore ejection and deoxynivalenol (DON) production. Interestingly, FgSRP1 had two transcript isoforms due to alternative splicing and both of them were required for its normal functions in growth and DON biosynthesis. FgSrp1 localized to the nucleus and interacted with FgPrp4 in vivo. Deletion of all four conserved phosphorylation sites but not individual ones affected the FgSRP1 function, suggesting their overlapping functions. RNA-seq analysis showed that the expression of over thousands of genes and splicing efficiency in over 140 introns were affected. Taken together, FgSRP1 is important for conidiation, and pathogenesis and alternative splicing is important for its normal functions. The FgSrp1 SR protein is likely important for pre-mRNA processing or splicing of various genes in different developmental and infection processes. PMID- 28654216 TI - Mechanistic Sharing Between NK Cells in ABMR and Effector T Cells in TCMR. AB - Human organ allograft rejection depends on effector lymphocytes: NK cells in antibody-mediated rejection (ABMR) and effector T cells in T cell-mediated rejection (TCMR). We hypothesized that NK cell CD16a stimulation and CD8 T cell TCR/CD3 stimulation represent highly similar effector systems, and should lead to shared molecular changes between ABMR and TCMR. We studied similarity between soluble proteins and the transcripts induced in CD16a stimulated NK cells and TCR/CD3-stimulated T cells in vitro. Of 30 soluble mediators tested, CD16a activated NK cells and CD3/TCR activated T cells produced the same limited set of five mediators-CCL3, CCL4, CSF2, IFNG, and TNF-and failed to produce 25 others. Many transcripts increased in stimulated NK cells were also increased in CD3 stimulated CD8 T cells (FDR < 0.05), including IFNG, CSF2, CCL3, CCL4, and XCL1. We hypothesized that shared transcripts not produced by other cell types should be expressed both in ABMR and TCMR kidney transplant biopsies. CD160, XCL1, TNFRSF9, and IFNG were selective for TCR/CD3-activated T cells and CD16a-NK cells and all were strongly increased in ABMR and TCMR. The molecules such as CD160 and XCL1 shared between NK cells in ABMR and effector T cells in TCMR may hold insights into important rejection mechanisms. PMID- 28654218 TI - Unlocking the Potential of Organ Donation. PMID- 28654217 TI - Dual-labelled antibodies for flow and mass cytometry: A new tool for cross platform comparison and enrichment of target cells for mass cytometry. AB - Antibody conjugates applicable in both conventional flow and mass cytometry would offer interesting options for cross-platform comparison, as well as the enrichment of rare target cells by conventional flow cytometry (FC) sorting prior to deep phenotyping by mass cytometry (MC). Here, we introduce a simple method to generate dual fluorochrome/metal-labelled antibodies by consecutive orthogonal labelling. First, we compared different fluorochrome-conjugated antibodies specific for CD4, such as FITC, Vio667, VioGreen or VioBlue for their compatibility with the conventional secondary MAXPAR(r) labelling protocol. After labelling with 141 Pr, the fluorescence emission spectra of all fluorochromes investigated retained their characteristics, and CD4 dual conjugates (DCs) provided consistent results in immune phenotyping assays performed by FC and MC. The phenotypical composition of CD4+ T-cells was maintained after enrichment by FC sorting using different CD4 DCs. Finally, magnetic cell depletion was combined with FC sorting using CD19-VioBlue-142 Nd, CD20-VioGreen-147 Sm, CD27-Cy5-167 Er and CD38-Alexa488-143 Nd DC to enrich rare human plasmablasts to purities >80%, which allowed a subsequent deep phenotyping by MC. In conclusion, DCs have been successfully established for direct assay comparison between FC and MC, and help to minimise MC data acquisition time for deep phenotyping of rare cell subsets. PMID- 28654219 TI - A comparative study of hepatitis B virus X protein mutants K130M, V131I and KV130/131MI to investigate their roles in fibrosis, cirrhosis and hepatocellular carcinoma. AB - Hepatitis B virus (HBV) genomic mutations A1762T, G1764A and AG1762/1764TA cause production of HBV X protein (HBx) mutants, namely K130M, V131I and KV130/131MI. These mutations are important biomarkers for the development of cirrhosis and hepatocellular carcinoma (HCC) in chronic HBV patients. This study comparatively analyses the impact of intracellular expression of HBx mutants on HCC cell line Huh7. It was found that expression of KV130/131MI induced: cell proliferation, altered expression of cell cycle regulatory genes in favour of cell proliferation, intracellular reactive oxygen species (ROS) production and mitochondrial depolarization. KV130/131MI may be directly involved in host cell proliferation and hepatocarcinogenesis via altering expression of cell cycle regulatory genes. KV130/131MI may also play pivotal roles in fibrosis and cirrhosis via inducing ROS production and mitochondrial depolarization. Furthermore, these might be the possible reasons for higher occurrence of AG1762/1764TA as compared to A1762T and G1764A in cirrhosis and HCC patients. PMID- 28654220 TI - Temperature drives the assembly of endophytic communities' seasonal succession. AB - Endophytic microorganisms asymptomatically colonise plant tissues. Exploring the assembly dynamics of bacterial endophytic communities is essential to understand the functioning of the plant holobiont and to optimise their possible use as biopesticides or plant biostimulants. The variation in endophytic communities in above and below-ground organs in Vitis vinifera in the field were studied. To understand the specific effect of temperature on endophytic communities, a separate experiment was set up where grapevine cuttings were grown under controlled conditions at three different temperatures. The findings revealed the succession of endophytic communities over the year. Endophytic communities of roots and stems differ in terms of composition and dynamic response to temperature. Noticeably, compositional differences during the seasons affected bacterial taxa more in stems than in roots, suggesting that roots offer a more stable and less easily perturbed environment. Correlation abundance networks showed that the presence of several taxa (including Bradyrhizobium, Burkholderia, Dyella, Mesorhizobium, Propionibacterium and Ralstonia) is linked in both the field and the greenhouse. PMID- 28654222 TI - Imprint cytology-based breast malignancy screening: an efficient nuclei segmentation technique. AB - Imprint cytology (IC) refers to one of the most reliable, rapid and affordable techniques for breast malignancy screening; where shape variation of H&E stained nucleus is examined by the pathologists. This work aims at developing an automated and efficient segmentation algorithm by integrating Lagrange's interpolation and superpixels in order to delineate overlapped nuclei of breast cells (normal and malignant). Subsequently, a computer assisted IC tool has been designed for breast cancer (BC) screening. The proposed methodology consists of mainly three subsections: gamma correction for preprocessing, single nuclei segmentation and segmentation of overlapping nuclei. Single nuclei segmentation combines histogram-based thresholding and morphological operations; where segmentation of overlapping nuclei includes concave point detection, Lagrange's interpolation for overlapping arc area detection and the fine segmentation of overlapped arc area by superpixels. Total 16 significant features (p < 0.05) quantifying shape and texture of nucleus were extracted, and random forest (RF) classifier was skilled for automated screening. The proposed methodology has been tested on 120 IC images (approximately 12 000 nuclei); where 98% segmentation accuracy and 99% classification accuracy were achieved. Besides, performance evaluation was studied by using Jaccard's index (= 94%), correlation coefficient (= 95%), Dice similarity coefficient (= 97%) and Hausdorff distance (= 43%). The proposed approach could offer benefit to the pathologists for confirmatory BC screening with improved accuracy and could potentially lead to a better shape understanding of malignant nuclei. PMID- 28654221 TI - High salt diet impairs memory-related synaptic plasticity via increased oxidative stress and suppressed synaptic protein expression. AB - SCOPE: A high salt (HS) diet is detrimental to cognitive function, in addition to having a role in cardiovascular disorders. However, the method by which an HS diet impairs cognitive functions such as learning and memory remains open. METHODS AND RESULTS: In this study, we found that mice on a 7 week HS diet demonstrated disturbed short-term memory in an object-place recognition task, and both 4 week and 7 week HS treatments impaired long-term memory, as evidenced in a fear conditioning test. Mechanistically, the HS diet inhibited memory-related long-term potentiation (LTP) in the hippocampus, while also increasing the levels of reactive oxygen species (ROS) in hippocampal cells and downregulating the expression of synapsin I, synaptophysin, and brain-derived neurotrophic factor in specific encephalic region. CONCLUSION: This suggests that oxidative stress or synaptic protein/neurotrophin deregulation was involved in the HS diet-induced memory impairment. Thus, the present study provides novel insights into the mechanisms of memory impairment caused by excessive dietary salt, and underlined the importance of controlling to salt absorb quantity. PMID- 28654223 TI - The pomegranate (Punica granatum L.) genome and the genomics of punicalagin biosynthesis. AB - Pomegranate (Punica granatum L.) is a perennial fruit crop grown since ancient times that has been planted worldwide and is known for its functional metabolites, particularly punicalagins. We have sequenced and assembled the pomegranate genome with 328 Mb anchored into nine pseudo-chromosomes and annotated 29 229 gene models. A Myrtales lineage-specific whole-genome duplication event was detected that occurred in the common ancestor before the divergence of pomegranate and Eucalyptus. Repetitive sequences accounted for 46.1% of the assembled genome. We found that the integument development gene INNER NO OUTER (INO) was under positive selection and potentially contributed to the development of the fleshy outer layer of the seed coat, an edible part of pomegranate fruit. The genes encoding the enzymes for synthesis and degradation of lignin, hemicelluloses and cellulose were also differentially expressed between soft- and hard-seeded varieties, reflecting differences in their accumulation in cultivars differing in seed hardness. Candidate genes for punicalagin biosynthesis were identified and their expression patterns indicated that gallic acid synthesis in tissues could follow different biochemical pathways. The genome sequence of pomegranate provides a valuable resource for the dissection of many biological and biochemical traits and also provides important insights for the acceleration of breeding. Elucidation of the biochemical pathway(s) involved in punicalagin biosynthesis could assist breeding efforts to increase production of this bioactive compound. PMID- 28654224 TI - Comparing Inference Approaches for RD Designs: a Reexamination of the Effect of Head Start on Child Mortality. AB - The regression discontinuity (RD) design is a popular quasi-experimental design for causal inference and policy evaluation. The most common inference approaches in RD designs employ "flexible" parametric and nonparametric local polynomial methods, which rely on extrapolation and large-sample approximations of conditional expectations using observations somewhat near the cutoff that determines treatment assignment. An alternative inference approach employs the idea of local randomization, where the very few units closest to the cutoff are regarded as randomly assigned to treatment and finite-sample exact inference methods are used. In this paper, we contrast these approaches empirically by re analyzing the influential findings of Ludwig and Miller (2007), who studied the effect of Head Start assistance on child mortality employing parametric RD methods. We first review methods based on approximations of conditional expectations, which are relatively well developed in the literature, and then present new methods based on randomization inference. In particular, we extend the local randomization framework to allow for parametric adjustments of the potential outcomes; our extended framework substantially relaxes strong assumptions in prior literature and better resembles other RD inference methods. We compare all these methods formally, focusing on both estimands and inference properties. In addition, we develop new approaches for randomization-based sensitivity analysis specifically tailored to RD designs. Applying all these methods to the Head Start data, we find that the original RD treatment effect reported in the literature is quite stable and robust, an empirical finding that enhances the credibility of the original result. All the empirical methods we discuss are readily available in general purpose software in R and Stata; we also provide the dataset and software code needed to replicate all our results. PMID- 28654229 TI - Tung Oil Wood Finishes with Improved Weathering, Durability, and Scratch Performance by Addition of Cellulose Nanocrystals. AB - The main aim of this study is to verify whether cellulose nanocrystal (CNCs) reinforced tung oil (TO) composites are effective for wood finishes and offer enhanced mechanical and weathering performance owing to the high strength, stiffness, and barrier properties of CNCs. To achieve even dispersion of CNC particles in a polymeric coating film, surface hydrophobization of the CNCs was carried out by grafting poly(lactic acid) oligomers and oleic acid. These new TO coating formulations contain 0 (controlled sample) to 10 wt % of hydrophobized cellulose nanocrystals (hCNCs). The coating performance (degree of wrinkle, leveling, and instantaneous filling) of the hCNC-TO finishes as well as their coating properties (topography, optical properties, mechanical properties, and gas permeability) were investigated in this study. The influence of the hCNC content in the tung oil composite coatings was examined using scratch/impact resistance tests and oxygen transmission rate (OTR) measurements. An increase in the hCNC content led to an increase in scratch/impact resistance as well as a slight decrease in the color-b change, gloss, surface roughness, and OTR value of their film coatings. The hCNC-TO composites for wood coatings presented here showed enhanced performance for utilization in wood-working processes in terms of desired mechanical properties (scratch and impact resistance), weathering performance (color stability), and easy production without any deterioration in surface gloss and roughness after the addition of hCNC to a TO matrix. The hCNC enhanced coating system is a promising candidate for substantial protection of wood surfaces in demanding settings. PMID- 28654230 TI - Synthesis of Multifunctional Electrically Tunable Fluorine-Doped Reduced Graphene Oxide at Low Temperatures. AB - Doping with heteroatoms is a well-established method to tune the electronic properties and surface chemistry of graphene. Herein, we demonstrate the synthesis of a fluorine-doped reduced graphene oxide (FrGO) at low temperatures that offers multiple opportunities in applied fields. The as-synthesized FrGO product shows a better electrical conductivity of 750 S m-1 than that of undoped rGO with an electrical conductivity of 195 S m-1. To demonstrate the multifunctional applications of the as-synthesized FrGO, it was examined for electromagnetic interference shielding and electrochemical sensing of histamine as an important food biomarker. A laminate of FrGO delivered an EMI shielding effectiveness value of 22 dB in Ku band as compared with 11.2 dB for an rGO laminate with similar thickness. On the other hand, an FrGO modified sensor offered an excellent sensitivity (~7 nM), wide detection range, and good selectivity in the presence of similar biomarkers. This performance originates from the better catalytic ability of FrGO as compared with rGO, where fluorine atoms play the role of catalytic active sites owing to their high electronegativity. The fluorination reaction also helps to improve the reduction degree of the chemically synthesized graphene, consequently enhancing the electrical conductivity, which is a prime requirement for increasing the electromagnetic and electrochemical properties of graphene. PMID- 28654231 TI - Enhanced Adhesion of Mosquitoes to Rough Surfaces. AB - Insects and small animals capable of adhering reversibly to a variety of surfaces employ the unique design of the distal part of their legs. In the case of mosquitoes, their feet are composed of thousands of micro- and nanoscale protruding structures, which impart superhydrophobic properties. Previous research has shown that the superhydrophobic nature of the feet allows mosquitoes to land on water, which is necessary for their reproduction cycle. Here, we show that van der Waals interactions are the main adhesion mechanism employed by mosquitoes to adhere to various surfaces. We further demonstrate that the judicious creation of surface roughness on an opposing surface can increase the adhesion strength because of the increased number of surface elements interacting with the setae through multiple contact points. Although van der Waals forces are shown to be the predominant mechanism by which mosquitoes adhere to surfaces, capillary forces can also contribute to the total adhesion force when the opposing surface is hydrophilic and under humid conditions. These fundamental properties can potentially be applied in the development of superior Long Lasting Insecticidal Nets (LLINs), which represent one of the most effective methods to mitigate mosquito-transmitted infectious diseases such as Malaria, Filaria, Zika, and Dengue. PMID- 28654232 TI - Cellulose Aerogel Membranes with a Tunable Nanoporous Network as a Matrix of Gel Polymer Electrolytes for Safer Lithium-Ion Batteries. AB - Cellulose aerogel membranes (CAMs) are proposed as a matrix for gel polymer electrolyte to the fabrication of lithium-ion batteries (LIBs) with superior thermal stability. The CAMs are obtained from a cellulose-ionic liquid solution via a dissolution-regeneration-supercritical drying route. The presence of high porosity, the nanoporous network structure, and numerous polar hydroxyl groups benefits the quick absorption of liquid electrolytes for gelation of the CAMs and improves the ionic conductivity of the gelled CAMs. LIBs assembled with the gelled CAMs display excellent electrochemical performance at room temperature, and more importantly, the intrinsic thermal resistance of cellulose allows the LIBs to run stably for at least 30 min at working temperatures as high as 120 degrees C. The CAMs, with their excellent thermal stability, are promising for the development of highly safe, cost-effective, and high-performance LIBs. PMID- 28654233 TI - Interfacial Manipulation by Rutile TiO2 Nanoparticles to Boost CO2 Reduction into CO on a Metal-Complex/Semiconductor Hybrid Photocatalyst. AB - Metal-complex/semiconductor hybrids have attracted attention as photocatalysts for visible-light CO2 reduction, and electron transfer from the metal complex to the semiconductor is critically important to improve the performance. Here rutile TiO2 nanoparticles having 5-10 nm in size were employed as modifiers to improve interfacial charge transfer between semiconducting carbon nitride nanosheets (NS C3N4) and a supramolecular Ru(II)-Re(I) binuclear complex (RuRe). The RuRe/TiO2/NS-C3N4 hybrid was capable of photocatalyzing CO2 reduction into CO with high selectivity under visible light (lambda > 400 nm), outperforming an analogue without TiO2 by a factor of 4, in terms of both CO formation rate and turnover number (TON). The enhanced photocatalytic activity was attributed primarily to prolonged lifetime of free and/or shallowly trapped electrons generated in TiO2/NS-C3N4 under visible-light irradiation, as revealed by transient absorption spectroscopy. Experimental results also indicated that the TiO2 modifier served as a good adsorption site for RuRe, which resulted in the suppression of undesirable desorption of the complex, thereby contributing to the improved photocatalytic performance. This study presents the first successful example of interfacial manipulation in a metal-complex/semiconductor hybrid photocatalyst for improved visible-light CO2 reduction to produce CO. PMID- 28654234 TI - Single and Networked ZnO-CNT Hybrid Tetrapods for Selective Room-Temperature High Performance Ammonia Sensors. AB - Highly porous hybrid materials with unique high-performance properties have attracted great interest from the scientific community, especially in the field of gas-sensing applications. In this work, tetrapodal-ZnO (ZnO-T) networks were functionalized with carbon nanotubes (CNTs) to form a highly efficient hybrid sensing material (ZnO-T-CNT) for ultrasensitive, selective, and rapid detection of ammonia (NH3) vapor at room temperature. By functionalizing the ZnO-T networks with 2.0 wt % of CNTs by a simple dripping procedure, an increase of 1 order of magnitude in response (from about 37 to 330) was obtained. Additionally, the response and recovery times were improved (by decreasing them from 58 and 61 s to 18 and 35 s, respectively). The calculated lowest detection limit of 200 ppb shows the excellent potential of the ZnO-T-CNT networks as NH3 vapor sensors. Room temperature operation of such networked ZnO-CNT hybrid tetrapods shows an excellent long-time stability of the fabricated sensors. Additionally, the gas sensing mechanism was identified and elaborated based on the high porosity of the used three-dimensional networks and the excellent conductivity of the CNTs. On top of that, several single hybrid microtetrapod-based devices were fabricated (from samples with 2.0 wt % CNTs) with the help of the local metal deposition function of a focused ion beam/scanning electron microscopy instrument. The single microdevices are based on tetrapods with arms having a diameter of around 0.35 MUm and show excellent NH3 sensing performance with a gas response (Igas/Iair) of 6.4. Thus, the fabricated functional networked ZnO-CNT hybrid tetrapods will allow to detect ammonia and to quantify its concentration in automotive, environmental monitoring, chemical industry, and medical diagnostics. PMID- 28654235 TI - Ink-Jet Printing of High-Molecular-Weight Polymers in Oil-in-Water Emulsions. AB - Ink-jet printing of high-molecular-weight polymers is inhibited by the extensional elasticity of the polymer chains. This article describes how emulsions can be used to print high-molecular-weight polymers at much higher concentrations than is possible in a binary solution. The polymers are dissolved in the dispersed phase of an oil-in-water emulsion. The surface tension of the oil-water interface opposes deformation of the oil droplets during ejection from the nozzle and leads to the extensional strain occurring in the polymer-free continuous phase. We show that a solution of polystyrene (PS) (Mn = 419 kDa, polydispersity index = 1.21) can be printed at an overall concentration of 3.8 wt % in a sodium dodecyl sulfate-stabilized emulsion of methyl benzoate in water, an order of magnitude higher in concentration than previously reported for PS dissolved in binary solutions [ Hoath , S. D. , Harlen , O. G. , and Hutchings , I. M. J. Rheol. 2012 , 56 ( 5 ), 1109 - 1127 ]. Factors influencing the formulation of emulsions for ink-jet printing of polymers are discussed. PMID- 28654236 TI - Closed Bipolar Electrodes for Spatial Separation of H2 and O2 Evolution during Water Electrolysis and the Development of High-Voltage Fuel Cells. AB - Electrolytic water splitting could potentially provide clean H2 for a future "hydrogen economy". However, as H2 and O2 are produced in close proximity to each other in water electrolyzers, mixing of the gases can occur during electrolysis, with potentially dangerous consequences. Herein, we describe an electrochemical water-splitting cell, in which mixing of the electrogenerated gases is impossible. In our cell, separate H2- and O2-evolving cells are connected electrically by a bipolar electrode in contact with an inexpensive dissolved redox couple (K3Fe(CN)6/K4Fe(CN)6). Electrolytic water splitting occurs in tandem with oxidation/reduction of the K3Fe(CN)6/K4Fe(CN) redox couples in the separate compartments, affording completely spatially separated H2 and O2 evolution. We demonstrate operation of our prototype cell using conventional Pt electrodes for each gas-evolving reaction, as well as using earth-abundant Ni2P electrocatalysts for H2 evolution. Furthermore, we show that our cell can be run in reverse and operate as a H2 fuel cell, releasing the energy stored in the electrogenerated H2 and O2. We also describe how the absence of an ionically conducting electrolyte bridging the H2- and O2-electrode compartments makes it possible to develop H2 fuel cells in which the anode and cathode are at different pH values, thereby increasing the voltage above that of conventional fuel cells. The use of our cell design in electrolyzers could result in dramatically improved safety during operation and the generation of higher-purity H2 than available from conventional electrolysis systems. Our cell could also be readily modified for the electrosynthesis of other chemicals, where mixing of the electrochemical products is undesirable. PMID- 28654237 TI - Light-Induced Proton Pumping with a Semiconductor: Vision for Photoproton Lateral Separation and Robust Manipulation. AB - Energy-transfer reactions are the key for living open systems, biological chemical networking, and the development of life-inspired nanoscale machineries. It is a challenge to find simple reliable synthetic chemical networks providing a localization of the time-dependent flux of matter. In this paper, we look to photocatalytic reaction on TiO2 from different angles, focusing on proton generation and introducing a reliable, minimal-reagent-consuming, stable inorganic light-promoted proton pump. Localized illumination was applied to a TiO2 surface in solution for reversible spatially controlled "inorganic photoproton" isometric cycling, the lateral separation of water-splitting reactions. The proton flux is pumped during the irradiation of the surface of TiO2 and dynamically maintained at the irradiated surface area in the absence of any membrane or predetermined material structure. Moreover, we spatially predetermine a transient acidic pH value on the TiO2 surface in the irradiated area with the feedback-driven generation of a base as deactivator. Importantly we describe how to effectively monitor the spatial localization of the process by the in situ scanning ion-selective electrode technique (SIET) measurements for pH and the scanning vibrating electrode technique (SVET) for local photoelectrochemical studies without additional pH-sensitive dye markers. This work shows the great potential for time- and space-resolved water-splitting reactions for following the investigation of pH-stimulated processes in open systems with their flexible localization on a surface. PMID- 28654238 TI - Correction to "Advancing Homogeneous Antimicrobial Glycoconjugate Vaccines". PMID- 28654239 TI - Response to Comment on "Polychlorinated Biphenyls in Tree Bark near Former Manufacturing and Incinerator Facilities in Sauget, Illinois, United States". PMID- 28654240 TI - Enhanced Catalytic Activity of Aluminum Complexes for the Ring-Opening Polymerization of epsilon-Caprolactone. AB - A series of dinuclear aluminum (Al2Pyr2) complexes bridged by two pyrazole ligands were synthesized, and their catalytic activity toward ring-opening polymerization of epsilon-caprolactone (CL) was investigated. Different types of the Al-N-N-Al-N-N skeletal ring were found among these Al2Pyr2 complexes. The butterfly form, LThio2Al2Me4, exerted the highest catalytic activity for CL polymerization. kappa2-CL coordination with both Al centers within the butterfly form LThio2Al2Me4 facilitates the initiation process. Generally speaking, the Al2Pyr2 complexes exhibited substantially higher catalytic activity for CL polymerization than literature examples such as beta-diketiminate- or traiaza bearing aluminum complexes. In fact, the Al2Pyr2 complexes can even carry out CL polymerization at room temperature. PMID- 28654241 TI - Heavy-Metal-Free Fluorescent ZnTe/ZnSe Nanodumbbells. AB - For visible range emitting particles, which are relevant for display and additional applications, Cd-chalcogenide nanocrystals have reached the highest degree of control and performance. Considering potential toxicity and regulatory limitations, there is a challenge to successfully develop Cd-free emitting nanocrystals and, in particular, heterostructures with desirable properties. Herein, we report a colloidal synthesis of fluorescent heavy-metal-free Zn chalcogenide semiconductor nanodumbbells (NDBs), in which ZnSe tips were selectively grown on the apexes of ZnTe rods, as evidenced by a variety of methods. The fluorescence of the NDBs can be tuned between ~500 and 585 nm by changing the ZnSe tip size. The emission quantum yield can be greatly increased through chloride surface treatment and reaches more than 30%. Simulations within an effective-mass-based model show that the hole wave function is spread over the ZnTe nanorods, while the electron wave function is localized on the ZnSe tips. Quantitative agreement for the red-shifted emission wavelength is obtained between the simulations and the experiments. Additionally, the changes in radiative lifetimes correlate well with the calculated decrease in electron-hole overlap upon growth of larger ZnSe tips. The heavy-metal-free ZnTe/ZnSe NDBs may be relevant for optoelectronic applications such as displays or light-emitting diodes. PMID- 28654242 TI - Global Cryptosporidium Loads from Livestock Manure. AB - Understanding the environmental pathways of Cryptosporidium is essential for effective management of human and animal cryptosporidiosis. In this paper we aim to quantify livestock Cryptosporidium spp. loads to land on a global scale using spatially explicit process-based modeling, and to explore the effect of manure storage and treatment on oocyst loads using scenario analysis. Our model GloWPa Crypto L1 calculates a total global Cryptosporidium spp. load from livestock manure of 3.2 * 1023 oocysts per year. Cattle, especially calves, are the largest contributors, followed by chickens and pigs. Spatial differences are linked to animal spatial distributions. North America, Europe, and Oceania together account for nearly a quarter of the total oocyst load, meaning that the developing world accounts for the largest share. GloWPa-Crypto L1 is most sensitive to oocyst excretion rates, due to large variation reported in literature. We compared the current situation to four alternative management scenarios. We find that although manure storage halves oocyst loads, manure treatment, especially of cattle manure and particularly at elevated temperatures, has a larger load reduction potential than manure storage (up to 4.6 log units). Regions with high reduction potential include India, Bangladesh, western Europe, China, several countries in Africa, and New Zealand. PMID- 28654244 TI - Monolithically Integrated Flexible Black Phosphorus Complementary Inverter Circuits. AB - Two-dimensional (2D) inverters are a fundamental building block for flexible logic circuits which have previously been realized by heterogeneously wiring transistors with two discrete channel materials. Here, we demonstrate a monolithically integrated complementary inverter made using a homogeneous black phosphorus (BP) nanosheet on flexible substrates. The digital logic inverter circuit is demonstrated via effective threshold voltage tuning within a single BP material, which offers both electron and hole dominated conducting channels with nearly symmetric pinch-off and current saturation. Controllable electron concentration is achieved by accurately modulating the aluminum (Al) donor doping, which realizes BP n-FET with a room-temperature on/off ratio >103. Simultaneously, work function engineering is employed to obtain a low Schottky barrier contact electrode that facilities hole injection, thus enhancing the current density of the BP p-FET by 9.4 times. The flexible inverter circuit shows a clear digital logic voltage inversion operation along with a larger-than-unity direct current voltage gain, while exhibits alternating current dynamic signal switching at a record high frequency up to 100 kHz and remarkable electrical stability upon mechanical bending with a radii as small as 4 mm. Our study demonstrates a practical monolithic integration strategy for achieving functional logic circuits on one material platform, paving the way for future high-density flexible electronic applications. PMID- 28654245 TI - Effects of in Utero PFOS Exposure on Transcriptome, Lipidome, and Function of Mouse Testis. AB - Transcriptomic and LC-MS/MS-based targeted lipidomic analyses were conducted to identify the effects of in utero PFOS exposure on neonatal testes and its relation to testicular dysfunction in adult offspring. Pregnant mice were orally administered 0.3 and 3 MUg PFOS/g body weight until term. Neonatal testes (P1) were collected for the detection of PFOS, and were subjected to omics study. Integrated pathway analyses using DAVID, KEGG, and IPA underlined the effects of PFOS exposure on lipid metabolism, oxidative stress and cell junction signaling in testes. LC-MS/MS analysis showed that the levels of adrenic acid and docosahexaenoic acid (DHA) in testes were significantly reduced in the PFOS treatment groups. A significant linear decreasing trend in eicosapentaenoic acid and DHA with PFOS concentrations was observed. Moreover, LOX-mediated 5 hydroxyeicosatetraenoic acids (HETE) and 15-HETE from arachidonic acid in the testes were significantly elevated and a linear increasing trend of 15-HETE concentrations was detected with doses of PFOS. The perturbations of lipid mediators suggested that PFOS has potential negative impacts on testicular functions. Postnatal analysis of male offspring at P63 showed significant reductions in serum testosterone and epididymal sperm count. This study sheds light into the as yet unrevealed action of PFOS on lipid mediators in affecting testicular functions. PMID- 28654246 TI - Copper(II) Dihalotetracyanoplatinate(IV) Coordination Polymers and Their Vapochromic Behavior. AB - The coordination polymers [Cu(H2O)2(MU2-NC)4PtX2] (X = Cl, Br) form networks of square grid sheets that align in a staggered manner with one another via weak X...X interactions. Upon stepwise dehydration, the layers fuse, forming a 3-D network of distorted cubes. The materials were tested for visible vapochromic, Raman, and IR response to dimethyl sulfoxide, N,N-dimethylformamide, and pyridine. Analyte-bound coordination polymers of the form Cu(analyte)2[PtX2(CN)4] were structurally characterized by PXRD and found to form layers of square grids that align through X...X interactions. The reaction of [Cu(H2O)2(MU2-NC)4PtX2] with concentrated aqueous NH3 generated [PtBr(CN)4(NH3)]- and [PtCl(CN)4(OH)]2- anions that were incorporated into 1-D chain structures. UV-visible reflectance data show that a combination of shifting d-d transitions and the visible Br-Pt LMCT absorption band in [Cu(H2O)2(MU2-NC)4PtBr2] results in a greater vapochromic effect in comparison to that in chlorine-containing analogues. PMID- 28654247 TI - Response to Comment on "Chromosomal Aberrations in Large Japanese Field Mice (Apodemus speciosus) Captured near Fukushima Dai-ichi Nuclear Power Plant". PMID- 28654248 TI - Multiplexed Sequence-Specific Capture of Chromatin and Mass Spectrometric Discovery of Associated Proteins. AB - Comprehensive understanding of a gene's expression and regulation at the molecular level requires identification of all proteins interacting with the gene. HyCCAPP (Hybridization Capture of Chromatin Associated Proteins for Proteomics) is an approach that uses single-stranded DNA oligonucleotides to capture specific genomic sequences in cross-linked chromatin fragments and identify associated proteins by mass spectrometry. Previous studies have shown HyCCAPP to provide useful information on protein-DNA interactions, revealing the proteins associated with the GAL1-10 region in yeast. We present here a multiplexed version of HyCCAPP. Utilizing a toehold-mediated capture/release strategy, HyCCAPP is targeted to multiple genomic loci in parallel, and the protein binders at each locus are eluted in a programmable and selective fashion. Multiplexed HyCCAPP was applied to four genes (25S rDNA, ARX1, CTT1, and RPL30) in S. cerevisiae under normal and stressed conditions. Capture and release efficiencies and specificities were comparable to those obtained without multiplexing. Using mass spectrometry-based bottom-up proteomics, hundreds of proteins were discovered at each locus in each condition. Statistical analysis revealed 34-88 enriched proteins in each gene capture. Many of these proteins had expected functions, including DNA-related and ribosome biogenesis-associated activities. Multiplexed HyCCAPP provides a useful strategy for the identification of proteins interacting with specific chromatin regions. PMID- 28654249 TI - Comment on "Chromosomal Aberrations in Large Japanese Field Mice (Apodemus speciosus) Captured Near Fukushima Dai-ichi Nuclear Power Plant". PMID- 28654250 TI - Pressure-Induced Phase Transitions in GeTe-Rich Ge-Sb-Te Alloys across the Rhombohedral-to-Cubic Transitions. AB - We demonstrate that pressure-induced amorphization in Ge-Sb-Te alloys across the ferroelectric-paraelectric transition can be represented as a mixture of coherently distorted rhombohedral Ge8Sb2Te11 and randomly distorted cubic Ge4Sb2Te7 and high-temperature Ge8Sb2Te11 phases. While coherent distortion in Ge8Sb2Te11 does not prevent the crystalline state from collapsing into its amorphous counterpart in a similar manner to pure GeTe, the pressure-amorphized Ge8Sb2Te11 phase begins to revert to the crystalline cubic phase at ~9 GPa in contrast to Ge4Sb2Te7, which remains amorphous under ambient conditions when gradually decompressed from 40 GPa. Moreover, experimentally, it was observed that pressure-induced amorphization in Ge8Sb2Te11 is a temperature-dependent process. Ge8Sb2Te11 transforms into the amorphous phase at ~27.5 and 25.2 GPa at room temperature and 408 K, respectively, and completely amorphizes at 32 GPa at 408 K, while some crystalline texture could be seen until 38 GPa (the last measurement point) at room temperature. To understand the origins of the temperature dependence of the pressure-induced amorphization process, density functional theory calculations were performed for compositions along the (GeTe)x (Sb2Te3)1-x tie line under large hydrostatic pressures. The calculated results agreed well with the experimental data. PMID- 28654251 TI - Quantitative Assessment of Substitution NMR Effects in the Model Series of o Carborane Derivatives: alpha-Shift Correlation Method. AB - The principles of a new alpha-shift correlation (ASC) NMR method are demonstrated on a model series of substituted derivatives of o-carborane for which reliable NMR data are available. This graphical method revealed an acceptable linear correlation between alpha(11B) or alpha(13C) shifts and those induced by substituents in unsubstituted (u) positions of the carborane cluster. The linearity holds for all nuclei involved in skeletal bonding: Deltadelta(N)u = g * alpha (where N = 11B, 13C, and 1H). The factor g (slope of the correlation line * 102) becomes an important measure of sensitivity of a given cage position to substituent changes. The beta, gamma, and delta = A (= antipodal) shifts can be therefore derived from the alpha-shift, are linearly proportional, and reflect additive character in double substitution. The ASC method appears to be an important tool for quantitative assessment of substituent NMR effects in all exo substituted boron-cluster systems. PMID- 28654252 TI - Synthetic Biology Parts for the Storage of Increased Genetic Information in Cells. AB - To bestow cells with novel forms and functions, the goal of synthetic biology, we have developed the unnatural nucleoside triphosphates dNaMTP and dTPT3TP, which form an unnatural base pair (UBP) and expand the genetic alphabet. While the UBP may be retained in the DNA of a living cell, its retention is sequence-dependent. We now report a steady-state kinetic characterization of the rate with which the Klenow fragment of E. coli DNA polymerase I synthesizes the UBP and its mispairs in a variety of sequence contexts. Correct UBP synthesis is as efficient as for a natural base pair, except in one sequence context, and in vitro performance is correlated with in vivo performance. The data elucidate the determinants of efficient UBP synthesis, show that the dNaM-dTPT3 UBP is the first generally recognized natural-like base pair, and importantly, demonstrate that dNaMTP and dTPT3TP are well optimized and standardized parts for the expansion of the genetic alphabet. PMID- 28654253 TI - Comment on "Polychlorinated Biphenyls in Tree Bark near Former Manufacturing and Incinerator Facilities in Sauget, Illinois, United States". PMID- 28654254 TI - Development Strategies and Prospects of Nano-based Smart Pesticide Formulation. AB - Pesticides are important inputs for enhancing crop productivity and preventing major biological disasters. However, more than 90% of pesticides run off into the environment and reside in agricultural products in the process of application as a result of the disadvantages of conventional pesticide formulation, such as the use of a harmful solvent, poor dispersion, dust drift, etc. In recent years, using nanotechnology to create novel formulations has shown great potential in improving the efficacy and safety of pesticides. The development of nano-based pesticide formulation aims at precise release of necessary and sufficient amounts of their active ingredients in responding to environmental triggers and biological demands through controlled release mechanisms. This paper discusses several scientific issues and strategies regarding the development of nano-based pesticide formulations: (i) construction of water-based dispersion pesticide nanoformulation, (ii) mechanism on leaf-targeted deposition and dose transfer of pesticide nanodelivery system, (iii) mechanism on increased bioavailability of nano-based pesticide formulation, and (iv) impacts of nanoformulation on natural degradation and biosafety of pesticide residues. PMID- 28654255 TI - Growth Inhibition of Colon Cancer and Melanoma Cells by Versiol Derivatives from a Paraconiothyrium Species. AB - Bioassay-guided fractionation of a colon cancer growth inhibitory extract of the fungus Paraconiothyrium sp. led to the isolation of eight new versiol derivatives (1, 3-8, 10) along with two known compounds. The structures were elucidated by interpretation of combined MS and 2D NMR spectroscopic data. Compounds 8, 9, and 10 showed cell growth inhibition against COLO205 and KM12 cells, and both 8 and 9 displayed selectivity in their inhibition of melanoma cell lines in the NCI 60 one-dose test. In addition, compound 8 and the crude Paraconiothyrium sp. extract showed potent dose-dependent inhibitory effects in the five-dose NCI 60 cell line assay. PMID- 28654256 TI - Structurally Diverse Diterpenoids from Isodon scoparius and Their Bioactivity. AB - Fourteen new diterpenoids (1-14) based on four skeletal types and two known analogues (15 and 16) were isolated from the aerial parts of Isodon scoparius. Compound 2 is the first ent-kaurane diterpenoid featuring a 1,11-ether bridge, and the structures of these new compounds were established mainly by NMR and MS methods. The absolute configurations of 1 and 5 and the relative configuration of 3 were determined using single-crystal X-ray diffraction. The absolute configuration of 14 was determined by comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1, 4, and 15 were active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and they also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values of 1.0, 3.1, and 1.8 MUM, respectively. PMID- 28654258 TI - Pd-PEPPSI: Pd-NHC Precatalyst for Suzuki-Miyaura Cross-Coupling Reactions of Amides. AB - Pd-PEPPSI-IPr serves as a highly reactive precatalyst in the direct Suzuki Miyaura cross-coupling of amides. An array of amides can be cross-coupled with a range of arylboronic acids in very good yields using a single, operationally simple protocol. The studies described represent the first use of versatile PEPPSI type of Pd-NHC complexes as catalysts for the cross-coupling of amides by N-C bond activation. The method is user-friendly, since it employs a commercially available, air- and moisture-stable Pd-PEPPSI-IPr complex. Pd-PEPPSI-IPr provides a significant improvement over all current Pd/phosphane catalysts for amide N-C bond activation. Mechanistic studies provide insight into the reaction rates of Pd-NHC-catalyzed cross-coupling of different amides, with Pd-PEPPSI-IPr being particularly effective for the cross-coupling of N-Boc carbamates under the developed conditions. PMID- 28654257 TI - Lipophosphonoxins II: Design, Synthesis, and Properties of Novel Broad Spectrum Antibacterial Agents. AB - The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and -negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action-plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we demonstrate LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals. PMID- 28654259 TI - New Inhibitor Targeting Signal Transducer and Activator of Transcription 5 (STAT5) Signaling in Myeloid Leukemias. AB - Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias. PMID- 28654260 TI - Highly Enantioselective Cobalt-Catalyzed Hydrosilylation of Alkenes. AB - A cobalt-catalyzed highly Markovnikov-type and enantioselective hydrosilylation of alkenes is developed for the efficient synthesis of valuable chiral dihydrosilanes. This protocol is operationally simple and atom-economy, and using relatively simple and readily available starting materials. The reaction is suitable for both aryl and aliphatic alkenes with excellent functional group tolerability. The reaction could be easily carried out in a gram-scale. The TOF and TON is up to 1800 and 860, respectively. PMID- 28654243 TI - Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. AB - Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases. PMID- 28654261 TI - Astragalin Reduces Hexokinase 2 through Increasing miR-125b to Inhibit the Proliferation of Hepatocellular Carcinoma Cells in Vitro and in Vivo. AB - Astragalin (ASG) can be found in a variety of food components. ASG exhibits cytotoxic effects on several different types of malignant cells. However, its effects on hepatocellular carcinoma (HCC) cells and the underlying molecular mechanisms have remained to be fully elucidated. Here, we revealed that ASG remarkably suppressed the proliferation of HCC cells. In HCC cells, ASG inhibited glucose glycolysis and promoted oxidative phosphorylation, resulting in a surge of reactive oxygen species (ROS). Mechanistically, ASG suppressed the expression of hexokinase 2 (HK2). This event was indispensible for ASG-mediated metabolic reprogramming, ROS accumulation, and subsequent growth arrest. Our further investigations unveiled that ASG repressed HK2 expression via increasing miR 125b. In vivo experiments showed that gavage of ASG decreased the proliferation of Huh-7 HCC xenografts in nude mice and inhibited the growth of transplanted H22 HCC cells in Kunming mice. Declined HCC tumor growth in vivo was associated with boosted miR-125b and reduced expression of HK2 in tumor tissues. Collectively, our results demonstrated that ASG is able to suppress the proliferation of HCC cells both in vitro and in vivo. Inhibition of HK2 through upregulating miR-125b and subsequent metabolic reprogramming is implicated in the antiproliferative effects of ASG on HCC cells. PMID- 28654262 TI - Machine Learning Consensus Scoring Improves Performance Across Targets in Structure-Based Virtual Screening. AB - In structure-based virtual screening, compound ranking through a consensus of scores from a variety of docking programs or scoring functions, rather than ranking by scores from a single program, provides better predictive performance and reduces target performance variability. Here we compare traditional consensus scoring methods with a novel, unsupervised gradient boosting approach. We also observed increased score variation among active ligands and developed a statistical mixture model consensus score based on combining score means and variances. To evaluate performance, we used the common performance metrics ROCAUC and EF1 on 21 benchmark targets from DUD-E. Traditional consensus methods, such as taking the mean of quantile normalized docking scores, outperformed individual docking methods and are more robust to target variation. The mixture model and gradient boosting provided further improvements over the traditional consensus methods. These methods are readily applicable to new targets in academic research and overcome the potentially poor performance of using a single docking method on a new target. PMID- 28654263 TI - Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography. AB - Aggregates of tau and beta amyloid (Abeta) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5 c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Abeta plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates. PMID- 28654264 TI - Phytol Promotes the Formation of Slow-Twitch Muscle Fibers through PGC 1alpha/miRNA but Not Mitochondria Oxidation. AB - Phytol is a side chain of chlorophyll belonging to the side-chain double terpenoid. When animals consume food rich in chlorophyll, phytol can be broken down to phytanic acid after digestion. It was reported that feeding animals with different varieties and levels of forage could significant improve pH and marbling score of steer and lamb carcasses, but the internal mechanism for this is still not reported. The marbling score and pH of muscle was mainly determined by skeletal muscle fiber type, which is due to expression of different myosin heavy-chain (MHC) isoforms. Here, we provide evidence that phytol can indeed affect the diversity of muscle fiber types both in vitro and in vivo and demonstrate that phytol can increase the expression of MHC I (p < 0.05), likely by upgrading the expression of PPARdelta, PGC-1alpha, and related miRNAs. This fiber-type transformation process may not be caused by activated mitochondrial metabolism but by the structural changes in muscle fiber types. PMID- 28654265 TI - Polyphenolic Phytochemicals in Cancer Prevention and Therapy: Bioavailability versus Bioefficacy. AB - Natural polyphenols are organic chemicals which contain phenol units in their structures. They show antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The most common discrepancy between experimental and clinical observations is the use of nonphysiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how applicable underlying mechanisms are with bioavailable concentrations and biological half-life. The present Perspective analyses proposed antitumor mechanisms, in vivo reported antitumor effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in oncotherapy. PMID- 28654267 TI - Ternary Silver Halide Nanocrystals. AB - Nanocrystalline silver halides (AgX) such as AgCl, AgBr, and AgI, a class of semiconductor materials with characteristics of both direct and indirect band gaps, represent the most crucial components in traditional photographic processing. The nanocrystal surfaces provide sensitivity specks that can turn into metallic silver, forming an invisible latent image, upon exposure to light. The photographic processing implies that the AgX nanoparticles possess unique properties. First, pristine AgX nanoparticles absorb light only at low efficiency to convert surface AgX into tiny clusters of silver atoms. Second, AgX nanoparticles represent an excellent class of materials to capture electrons efficiently. Third, small metallic silver clusters can catalyze the reduction of AgX nanoparticles to Ag nanoparticles in the presence of mild reducing reagents, known as self-catalytic reduction. These properties indicate that AgX nanoparticles can be partially converted to metallic silver with high precision, leading to the formation of hybrid AgX/Ag nanoparticles. The nanosized metallic Ag usually exhibit intense absorption bands in the visible spectral region due to their strong surface plasmon resonances, which make the AgX/Ag nanoparticles a class of promising visible-light-driven photocatalysts for environmental remediation and CO2 reduction. Despite the less attention paid to their ability of capturing electrons, AgX nanoparticles might be a class of ideal electron shuttle materials to bridge light absorbers and catalysts on which electrons can drive chemical transformations. In this Account, we focus on ternary silver halide alloy (TSHA) nanoparticles, containing two types of halide ions, which increase the composition complexity of the silver halide nanoparticles. Interdiffusion of halide ions between two types of AgX at elevated temperatures has been developed for fabricating ternary silver halide alloy crystals, such as silver chlorobromide optical fibers for infrared communications. This solid state process is not feasible for synthesizing TSHA nanoparticles since it is hard to form two different types of AgX nanoparticles in direct contact. In contrast, coprecipitation of silver ions with different halide ions via colloidal chemistry represents the most promising strategy to synthesize TSHA nanoparticles. Forming uniform and phase-pure ternary silver halide nanocrystals requires that the rate ratio for precipitating both halide ions remains constant throughout the synthesis. However, the significant difference in solubility among different AgX usually leads to a nonuniform compositional distribution in the resulting nanoparticles because the halide ions corresponding to the less soluble AgX precipitate faster at the early reaction stage. This Account summarizes the methods recently developed for the successful synthesis of phase-pure TSHA nanoparticles with uniform sizes and morphologies, which involve precise control over the balanced diffusion of different halide ions to react with silver ions. Typical methods include the use of microemulsion capsules and high-viscosity solvents to lower and even the diffusion coefficients of various halide ions, thus maintaining the precipitation rates of both AgX in single nanoparticles at a constant ratio. The availability of high-quality TSHA nanoparticles provides promising opportunities to explore their new properties and applications. PMID- 28654266 TI - Unexpected Interactions between Alkyl Straps and Pyridine Ligands in Sulfur Strapped Porphyrin Nanorings. AB - Strapped or "basket-handle" porphyrins have been investigated previously as hemoglobin mimics and catalysts. The facial selectivity of their interactions with axial ligands is a sensitive test for noncovalent bonding. Here the binding of pyridyl ligands to zinc porphyrins with thioester-linked alkyl straps is investigated in solution by NMR spectroscopy and UV-vis titration, and in the solid state by X-ray crystallography. We expected that coordination of the axial ligand would occur on the less hindered face of the porphyrin, away from the strap. Surprisingly, attractive interactions between the strap and the ligand direct axial coordination to the strapped face of the porphyrin, except when the strap is short and tight. The strapped porphyrins were incorporated into pi conjugated cyclic porphyrin hexamers using template-directed synthesis. The strap and the sulfur substituents are located either inside or outside the porphyrin nanoring, depending on the length of the strap. Six-porphyrin nanorings with outwardly pointing sulfur anchors were prepared for exploring quantum interference effects in single-molecule charge transport. PMID- 28654268 TI - Electroactive and High Dielectric Folic Acid/PVDF Composite Film Rooted Simplistic Organic Photovoltaic Self-Charging Energy Storage Cell with Superior Energy Density and Storage Capability. AB - Herein we report a simplistic prototype approach to develop an organic photovoltaic self-charging energy storage cell (OPSESC) rooted with biopolymer folic acid (FA) modified high dielectric and electroactive beta crystal enriched poly(vinylidene fluoride) (PVDF) composite (PFA) thin film. Comprehensive and exhaustive characterizations of the synthesized PFA composite films validate the proper formation of beta-polymorphs in PVDF. Significant improvements of both beta-phase crystallization (F(beta) ~ 71.4%) and dielectric constant (epsilon ~ 218 at 20 Hz for PFA of 7.5 mass %) are the twosome realizations of our current study. Enhancement of beta-phase nucleation in the composites can be thought as a contribution of the strong interaction of the FA particles with the PVDF chains. Maxwell-Wagner-Sillars (MWS) interfacial polarization approves the establishment of thermally stable high dielectric values measured over a wide temperature spectrum. The optimized high dielectric and electroactive films are further employed as an active energy storage material in designing our device named as OPSESC. Self-charging under visible light irradiation without an external biasing electrical field and simultaneous remarkable self-storage of photogenerated electrical energy are the two foremost aptitudes and the spotlight of our present investigation. Our as fabricated device delivers an impressively high energy density of 7.84 mWh/g and an excellent specific capacitance of 61 F/g which is superior relative to the other photon induced two electrode organic self-charging energy storage devices reported so far. Our device also proves the realistic utility with good recycling capability by facilitating commercially available light emitting diode. PMID- 28654269 TI - Versatile DNA Origami Nanostructures in Simplified and Modular Designing Framework. AB - We introduce a simplified and modular architecture for design and construction of complex origami nanostructures. A series of basic two-dimensional and three dimensional structures are presented. As the resulting structures can be virtually divided into blocks, modular remodeling such as translocation, contraction/extension, and bending is carried out. Structures under such a designing framework are morphable. Local conformational changes can propagate to the entire structure to reshape the global conformation. PMID- 28654270 TI - Ultralong Hydroxyapatite Nanowires-Based Paper Co-Loaded with Silver Nanoparticles and Antibiotic for Long-Term Antibacterial Benefit. AB - Hydroxyapatite is a kind of biocompatible, environmentally friendly, and versatile inorganic biomaterial. Herein, the preparation of ultralong hydroxyapatite nanowires (HAPNWs)-based antibacterial paper co-loaded with silver nanoparticles (AgNPs) and antibiotic is reported. HAPNWs are used to prepare AgNPs in situ using an aqueous solution containing AgNO3 under the sunlight without added reducing agent at room temperature. Subsequently, ciprofloxacin (CIP) as an antibiotic is loaded on the HAPNWs@AgNPs. The resultant HAPNWs@AgNPs CIP paper possesses several unique properties, including high flexibility, high Brunauer-Emmett-Teller (BET) specific surface area (47.9 m2 g-1), high drug loading capacity (447.4 mg g-1), good biocompatibility, sustained and pH responsive drug release behavior (5.40-6.75% of Ag+ ions and 37.7-76.4% of CIP molecules at pH values of 7.4-4.5 at day 8, respectively), and reusable recycling. In the antibacterial tests against Escherichia coli and Staphylococcus aureus, the HAPNWs@AgNPs-CIP paper exhibits large diameters of inhibition zones and low minimum inhibitory concentrations (30 and 40 MUg mL-1), revealing the high antibacterial activity. Besides, the consecutive agar diffusion tests (8 cycles), long-term stability tests (over 56 days), and continuous contamination tests (5 cycles) demonstrate the excellent recycling performance and long-term antibacterial activity of the HAPNWs@AgNPs-CIP paper. These results indicate a promising potential of the HAPNWs@AgNPs-CIP bactericidal paper for tackling public health issues related to bacterial infections. PMID- 28654271 TI - Microstructure and Elastic Properties of Colloidal Gel Foams. AB - Colloidal gel foams are composed of a continuous, attractive particle network that surrounds and interconnects dispersed bubbles. Here, we investigate their stability, morphology, and elasticity as a function of foaming intensity, surfactant concentration and hydrophobicity, pH, and colloid volume fraction. Upon optimizing these parameters, highly stable colloidal gel foams are created. Within this stability region, the specific interfacial area between the continuous (colloidal gel) and dispersed (bubble) phase can be varied over 2 orders of magnitude leading to a concomitant increase in storage modulus, which scales nearly linearly with specific interfacial area. Our observations provide design guidelines for attractive-particle stabilized foams that enable the programmable assembly of architected porous materials. PMID- 28654272 TI - Branched Amphipathic Peptide Capsules: Different Ratios of the Two Constituent Peptides Direct Distinct Bilayer Structures, Sizes, and DNA Transfection Efficiency. AB - Branched amphipathic peptide capsules (BAPCs) are biologically derived, bilayer delimited, nanovesicles capable of being coated by or encapsulating a wide variety of solutes. The vesicles and their cargos are readily taken up by cells and become localized in the perinuclear region of cells. When BAPCs are mixed with DNA, the BAPCs act as cationic nucleation centers around which DNA winds. The BAPCs-DNA nanoparticles are capable of delivering plasmid DNA in vivo and in vitro yielding high transfection rates and minimal cytotoxicity. BAPCs share several biophysical properties with lipid vesicles. They are however considerably more stable-resisting disruption in the presence of chaotropes such as urea and guanidinium chloride, anionic detergents, proteases, and elevated temperature (~95 degrees C). To date, all of our published results have utilized BAPCs that are composed of equimolar concentrations of the two branched sequences (Ac FLIVI)2-K-K4-CO-NH2 and (Ac-FLIVIGSII)2-K-K4-CO-NH2. The mixture of sizes was utilized to relieve potential curvature strain in the spherical capsule. In this article, different molar ratios of the two peptides were studied to test whether alternate ratios produced BAPCs with different biological and biophysical properties. Additionally, preparation (annealing) temperature was included as a second variable. PMID- 28654273 TI - Luminescent Dinuclear Ruthenium Terpyridine Complexes with a Bis Phenylbenzimidazole Spacer. AB - A conjugated bis-terpyridine bridging ligand, 2-(4-(2,6-di(pyridin-2-yl)pyridin-4 yl)phenyl)-6-(2-(4-(2,6-di(pyridin-2-yl)pyridin-4-yl)phenyl)-1H-benzo[d]imidazol 6-yl)-1H-benzo[d] imidazole (tpy-BPhBzimH2-tpy), was designed in this work by covalent coupling of 3,3'-diaminobenzidine and two 4'-(p-formylphenyl)-2,2':6',2" terpyridine units to synthesize a new series of bimetallic Ru(II)-terpyridine light-harvesting complexes. Photophysical and electrochemical properties were modulated by the variation of the terminal ligands in the complexes. The new compounds were thoroughly characterized by 1H NMR spectroscopy, high-resolution mass spectrometry, and elemental analysis. Absorption spectra of the complexes consist of very strong ligand-centered pi-pi* and n-pi* transitions in the UV, metal-to-ligand, and intraligand charge transfer bands in the visible regions. Steady-state and time-resolved emission spectral measurements indicate that the complexes exhibit moderately intense luminescence at room temperature within the spectral domain of 653-687 nm having luminescence lifetimes in the range between 6.3 and 55.2 ns, depending upon terminal tridentate ligand and solvent. Variable temperature luminescence measurements suggest substantial increase of the energy gap between luminescent 3metal-to-ligand charge transfer state and nonluminescent 3metal centered in the complexes compared to the parent [Ru(tpy)2]2+. Each of the three bimetallic complexes exhibits only one reversible couple in the positive potential window with almost no detectable splitting corresponding to simultaneous oxidation of the two remote Ru centers. All the complexes possess a number of imidazole NH protons, which became sufficiently acidic upon metal ion coordination. By utilizing these NH protons, we thoroughly studied anion recognition properties of the complexes in pure organic as well as predominantly aqueous media through multiple optical channels and spectroscopic methods. Finally computation investigations employing density functional theory (DFT) and time-dependent DFT were done to examine the electronic structures of the complexes and accurate assignment of experimentally observed optical spectral bands. PMID- 28654274 TI - Studies on the Behavior of Eucalyptol and Terpinen-4-ol-Natural Food Additives and Ecological Pesticides-in Model Lipid Membranes. AB - Effective application of the essential oils requires detailed exploration of their mechanism of action and the origin of diverse activity of their components. In this work, the influence of eucalyptol and terpinen-4-ol on artificial membranes was studied to verify whether the differences in the activity of these compounds are related to their effect on membranes. The properties of monolayers formed from structurally different lipids in the presence of terpenes were examined based on the results of the surface pressure-area measurements, penetration studies, and Brewster angle microscopy experiments. Both compounds were able to incorporate into the membrane and alter lipid/lipid interactions, making the monolayer less stable and more fluid. These effects were determined by monolayer composition (but not by its condensation per se) and the resulting rheological properties and were stronger in the presence of terpinen-4-ol. These findings confirm the hypothesis that differences in the antimicrobial potency of these terpenes are membrane-related, and membrane composition may determine their selectivity. PMID- 28654275 TI - Accurate Quasiparticle Spectra from the T-Matrix Self-Energy and the Particle Particle Random Phase Approximation. AB - The GW self-energy, especially G0W0 based on the particle-hole random phase approximation (phRPA), is widely used to study quasiparticle (QP) energies. Motivated by the desirable features of the particle-particle (pp) RPA compared to the conventional phRPA, we explore the pp counterpart of GW, that is, the T matrix self-energy, formulated with the eigenvectors and eigenvalues of the ppRPA matrix. We demonstrate the accuracy of the T-matrix method for molecular QP energies, highlighting the importance of the pp channel for calculating QP spectra. PMID- 28654276 TI - Mercouri G. Kanatzidis: Excellence and Innovations in Inorganic and Solid-State Chemistry. AB - Over the last 3-4 decades, solid-state chemistry has emerged as the forefront of materials design and development. The field has revolutionized into a multidisciplinary subject and matured with a scope of new synthetic strategies, new challenges, and opportunities. Understanding the structure is very crucial in the design of appropriate materials for desired applications. Professor Mercouri G. Kanatzidis has encountered both challenges and opportunities during the course of the discovery of many novel materials. Throughout his scientific career, Mercouri and his group discovered several inorganic compounds and pioneered structure-property relationships. We, a few Ph.D. and postdoctoral students, celebrate his 60th birthday by providing a Viewpoint summarizing his contributions to inorganic solid-state chemistry. The topics discussed here are of significant interest to various scientific communities ranging from condensed matter to green energy production. PMID- 28654277 TI - Reversible Hydride Transfer to N,N'-Diarylimidazolinium Cations from Hydrogen Catalyzed by Transition Metal Complexes Mimicking the Reaction of [Fe] Hydrogenase. AB - [Fe]-hydrogenase is a key enzyme involved in methanogenesis and facilitates reversible hydride transfer from H2 to N5,N10-methenyltetrahydromethanopterin (CH H4MPT+). In this study, a reaction system was developed to model the enzymatic function of [Fe]-hydrogenase by using N,N'-diphenylimidazolinium cation (1+) as a structurally related alternative to CH-H4MPT+. In connection with the enzymatic mechanism via heterolytic cleavage of H2 at the single metal active site, several transition metal complex catalysts capable of such activation were utilized in the model system. Reduction of 1[BF4] to N,N'-diphenylimidazolidine (2) was achieved under 1 atm H2 at ambient temperature in the presence of an equimolar amount of NEt3 as a proton acceptor. The proposed catalytic pathways involved the generation of active hydride complexes and subsequent intermolecular hydride transfer to 1+. The reverse reaction was accomplished by treatment of 2 with HNMe2Ph+ as the proton source, where [(eta5-C5Me5)Ir{(p-MeC6H4SO2)NCHPhCHPhNH}] was found to catalyze the formation of 1+ and H2 with high efficiency. These results are consistent with the fact that use of 2,6-lutidine in the forward reaction or 2,6-lutidinium in the reverse reaction resulted in incomplete conversion. By combining these reactions using the above Ir amido catalyst, the reversible hydride transfer interconverting 1+/H2 and 2/H+ was performed successfully. This system demonstrated the hydride-accepting and hydride-donating modes of biologically relevant N-heterocycles coupled with proton concentration. The influence of substituents on the forward and reverse reactivities was examined for the derivatives of 1+ and 2 bearing one para-substituted N-phenyl group. PMID- 28654278 TI - Self-Assembly of InAs Nanostructures on the Sidewalls of GaAs Nanowires Directed by a Bi Surfactant. AB - Surface energies play a dominant role in the self-assembly of three-dimensional (3D) nanostructures. In this Letter, we show that using surfactants to modify surface energies can provide a means to externally control nanostructure self assembly, enabling the synthesis of novel hierarchical nanostructures. We explore Bi as a surfactant in the growth of InAs on the {110} sidewall facets of GaAs nanowires. The presence of surface Bi induces the formation of InAs 3D islands by a process resembling the Stranski-Krastanov mechanism, which does not occur in the absence of Bi on these surfaces. The InAs 3D islands nucleate at the corners of the {110} facets above a critical shell thickness and then elongate along ?110? directions in the plane of the nanowire sidewalls. Exploiting this growth mechanism, we realize a series of novel hierarchical nanostructures, ranging from InAs quantum dots on single {110} nanowire facets to zigzag-shaped nanorings completely encircling nanowire cores. Photoluminescence spectroscopy and cathodoluminescence spectral line scans reveal that small surfactant-induced InAs 3D islands behave as optically active quantum dots. This work illustrates how surfactants can provide an unprecedented level of external control over nanostructure self-assembly. PMID- 28654279 TI - Access to Amide from Aldimine via Aerobic Oxidative Carbene Catalysis and LiCl as Cooperative Lewis Acid. AB - Herein, an efficient route to amides from aldimines via aza-Breslow intermediates through aerobic oxidative carbene catalysis with LiCl as a cooperative Lewis acid is described. Many of the obtained N-heteroarylamides feature biological activity. Ambient air was used as the sole oxidant and source of oxygen in this catalytically oxidative amidation. This method allows for a broad substrate scope and mild conditions. The aza-Breslow intermediate derivative was isolated and its crystal structure confirmed. PMID- 28654280 TI - Molecular Beam Epitaxy of GaN Nanowires on Epitaxial Graphene. AB - We demonstrate an all-epitaxial and scalable growth approach to fabricate single crystalline GaN nanowires on graphene by plasma-assisted molecular beam epitaxy. As substrate, we explore several types of epitaxial graphene layer structures synthesized on SiC. The different structures differ mainly in their total number of graphene layers. Because graphene is found to be etched under active N exposure, the direct growth of GaN nanowires on graphene is only achieved on multilayer graphene structures. The analysis of the nanowire ensembles prepared on multilayer graphene by Raman spectroscopy and transmission electron microscopy reveals the presence of graphene underneath as well as in between nanowires, as desired for the use of this material as contact layer in nanowire-based devices. The nanowires nucleate preferentially at step edges, are vertical, well aligned, epitaxial, and of comparable structural quality as similar structures fabricated on conventional substrates. PMID- 28654281 TI - Differential Depth Sensing Reduces Cancer Cell Proliferation via Rho-Rac Regulated Invadopodia. AB - Bone, which is composed of a porous matrix, is one of the principal secondary locations for cancer. However, little is known about the effect of this porous microenvironment in regulating cancer cell proliferation. Here, we examine how the depth of the pores can transduce a mechanical signal and reduce the proliferation of noncancer breast epithelial cells (MCF-10A) and malignant breast cancer cells (MDA-MB-231 and MCF-7) using micrometer-scale topographic features. Interestingly, cells extend actin-rich protrusions, such as invadopodia, to sense the depth of the matrix pore and activate actomyosin contractility to decrease MCF-10A proliferation. However, in MDA-MB-231, depth sensing inactivates Rho-Rac regulated actomyosin contractility and phospho-ERK signaling. Inhibiting contractility on this porous matrix using blebbistatin further reduces MDA-MB-231 proliferation. Our findings support the notion of mechanically induced dormancy through depth sensing, where invadopodia-mediated depth sensing can inhibit the proliferation of noncancer and malignant breast cancer cells through differential regulation of actomyosin contractility. PMID- 28654282 TI - The Reduction in the IgE-Binding Ability of beta-Lactoglobulin by Dynamic High Pressure Microfluidization Coupled with Glycation Treatment Revealed by High Resolution Mass Spectrometry. AB - Our previous study indicated that pretreatment by dynamic high-pressure microfluidization (DHPM) and glycation with galactose was a promising method for decreasing the immunoglobulin E (IgE)-binding ability of beta-lactoglobulin (beta LG). In this work, the conformational alteration of beta-LG subjected to DHPM and glycation treatment was investigated in relation to IgE-binding ability by orbitrap mass spectrometry. After DHPM pretreatment, lower IgE-binding ability of glycated beta-LG was observed with increasing pressures. Prior to DHPM pretreatment, 11 glycated sites were identified, while the number of glycation sites was increased to 12 after pretreatment. However, there was no significant difference of the glycation sites at the pressures of 50, 100, and 200 MPa, respectively. Average degree of substitution per peptide molecule of beta-LG (DSP) was investigated to assess the degree of glycation per glycation site. All of the samples pretreated by DHPM exhibited a higher glycation level than those without DHPM pretreatment. The shielding effects of epitopes owing to glycation contributed to the reduction of IgE-binding capacity. Orbitrap mass spectrometry could provide a comprehensive understanding of the nature of protein glycation. PMID- 28654283 TI - Carrier Localization in GaN/AlN Quantum Dots As Revealed by Three-Dimensional Multimicroscopy. AB - The localization of carrier states in GaN/AlN self-assembled quantum dots (QDs) is studied by correlative multimicroscopy relying on microphotoluminescence, electron tomography, and atom probe tomography (APT). Optically active field emission tip specimens were prepared by focused ion beam from an epitaxial film containing a stack of quantum dot layers and analyzed with different techniques applied subsequently on the same tip. The transition energies of single QDs were calculated in the framework of a 6-bands k.p model on the basis of APT and scanning transmission electron microscopy characterization showing that a good agreement between experimental and calculated energies can be obtained, overcoming the limitations of both techniques. The results indicate that holes effectively localize at interface fluctuations at the bottom of the QD, decreasing the extent of the wave function and the band-to-band transition energy. They also represent an important step toward the correlation of the three dimensional atomic scale structural information with the optical properties of single light emitters based on quantum confinement. PMID- 28654284 TI - PEGylated, Water-Soluble, Stable Aminyl Radical. AB - We report the synthesis and kinetic study of PEGylated, water-soluble aminyl radical 2. The radical possesses four mPEG-3 groups replacing four methyl groups in the tert-butyl groups at the 3- and 6-positions of 1,3,6,8-tetra-tert-butyl carbazyl (TTBC). This structure is designed to mitigate the rapid decomposition of the radical via intramolecular 1,5-hydrogen atom transfer (1,5-HAT) that was observed in its constitutional isomer 1-H with four mPEG-3 groups in the vicinity of the nitrogen-centered radical (1- and 8-positions of TTBC). In dry, degassed acetone at 295 K, the radical 2 has a half-life, tau1/2 = 49 h (DeltaH? = 17.9 +/ 0.8 kcal mol-1), which is 3 orders of magnitude longer than that for 1-H, which decays via 1,5-HAT (tau1/2 = 48 s, DeltaH? = 10.0 +/- 0.3 kcal mol-1). Aminyl radical 2 aggregates at ambient conditions in water and has a half-life, tau1/2 = 2 h. PMID- 28654285 TI - Computational Discovery of Potent and Bioselective Protoporphyrinogen IX Oxidase Inhibitor via Fragment Deconstruction Analysis. AB - Tuning the binding selectivity through appropriate ways is a primary goal in the design and optimization of a lead toward agrochemical discovery. However, how to achieve rational design of selectivity is still a big challenge. Herein, we developed a novel computational fragment generation and coupling (CFGC) strategy that led to a series of highly potent and bioselective inhibitors targeting protoporphyrinogen IX oxidase. This enzyme plays a vital role in heme and chlorophyll biosynthesis, which has been proven to be associated with many drugs and agrochemicals. However, existing agrochemicals are nonbioselective, resulting in a great threat to nontargeted organisms. To the best of our knowledge, this is the first bioselective inhibitor targeting the tetrapyrrole biosynthesis pathway. In addition, the candidate showed excellent in vivo bioactivity and much better safety toward humans. PMID- 28654286 TI - Unusual C-N Coupling Reactivity of Thiopyridazines: Efficient Synthesis of Iron Diorganotrisulfide Complexes. AB - The reaction of iron(II) triflate with 6-tert-butyl-3-thiopyridazine (PnH) and 4 methyl-6-tert-butyl-3-thiopyridazine (MePnH) respectively led to iron bis(diorganotrisulfide) complexes [Fe(RPnS3PnR)2](OTf)2 [R = H (1a) and Me (2a)]. The corresponding perchlorate complexes were prepared by using the iron(II) chloride precursor and the subsequent addition of 2 equiv of NaClO4, giving [Fe(RPnS3PnR)2](ClO4)2 [R = H (1b) and Me (2b)]. The compounds were fully characterized including single-crystal X-ray diffraction analysis. All four compounds exhibit nearly perfect octahedral geometries with an iron center coordinated by four nitrogen atoms from two RPnS3PnR ligands and by two sulfur atoms of the central atom in the S3 unit. The diamagnetic complexes exhibit unusually high redox potentials for the Fe2+/3+ couple at E1/2 = 1.15 V (for 1a and 1b) and 1.08 V (for 2a and 2b) versus Fc/Fc+, respectively, as determined by cyclic voltammetry. Furthermore, the source of the extra sulfur atom within the S3 unit was elucidated by isolation of C-N-coupled pyridazinylthiopyridazine products. PMID- 28654287 TI - Near-Infrared and Two-Wavelength Electrochromism Based on Nanocrystalline TiO2 Films Functionalized with Ruthenium-Amine Conjugated Complexes. AB - Two cyclometalated ruthenium complexes 2 and 4 containing a redox-active amine substituent and three carboxylic acid groups were synthesized, where the ruthenium ion and the amine site were separated by a phenyl or biphenyl bridge for 2 and 4, respectively. Nanocrystalline TiO2 films on fluorine doped SnO2 (FTO)/glass substrates anchored with 2 or 4 were prepared. These films display two consecutive anodic waves in the potential region between +0.1 and +1.0 V vs Ag/AgCl. Among four organic solvents examined, the FTO/TiO2/2 film displays the best cyclic electrochemical stability in ClCH2CH2Cl. Both films exhibit promising two-step electrochromism in the near infrared region. A contrast ratio (DeltaT%) of 42% at 1000 nm and 40% at 680 nm was achieved for the FTO/TiO2/2 film in the single- and double-oxidation process, respectively. In contrast, the FTO/TiO2/4 film shows electrochromism at 1300 nm (DeltaT% = 58%) and 780 nm (DeltaT% = 59%) in the single- and double-oxidation process, respectively. The coloration efficiency of these processes varies in a range of 150-270 cm2/C. These films are potentially useful as variable optical attenuators for telecommunications. PMID- 28654288 TI - A General Strategy Toward Highly Fluorogenic Bioprobes Emitting across the Visible Spectrum. AB - A general approach toward highly fluorogenic probes across the visible spectrum for various analytes offers significant potential for engineering a wide range of bioprobes with diverse sensing and imaging functions. Here we show a facile and general strategy that involves introducing a new fluorogenic mechanism in boron dipyrromethene (BODIPY) dyes, based on the principle of stimuli-triggered dramatic reduction in the electron-withdrawing capabilities of the meso substituents of BODIPYs. The fluorogenic mechanism has been demonstrated to be applicable in various BODIPYs with emission maxima ranging from green to far red (509, 585, and 660 nm), and the synthetic strategy allows access to a panel of highly fluorogenic bioprobes for various biomolecules and enzymes (H2O2, H2S, and protease) via introducing specific triggering motifs. The potency of the general design strategy is exemplified by its application to develop a mitochondria targeting far-red probe capable of imaging of endogenous H2O2 in living cells. PMID- 28654289 TI - Oxidation of Natural Bioactive Flavonolignan 2,3-Dehydrosilybin: An Electrochemical and Spectral Study. AB - The electrochemical oxidation of the natural antioxidant 2,3-dehydrosilybin (DHS) was investigated in acetonitrile. The spectral changes during two electron and two proton oxidation registered by in situ IR spectroelectrochemistry show that the electron transfer is followed by a subsequent chemical reaction with traces of water. A benzofuranone derivative (BF) is formed by ECEC (electron transfer chemical reaction-electron transfer-chemical reaction) process at the potential of the first oxidation wave. A minor difference in the chemical structures of flavonolignans DHS and silybin, the presence of a double bond between atoms C-2 and C-3 in the DHS molecule, causes the formation of completely different oxidation products. BF was for the first time identified as the product of the oxidation of flavonolignan DHS. Its formation was proved by electroanalytical, chromatographic, and spectroelectrochemical techniques. Molecular orbital calculations support the experimental findings. PMID- 28654290 TI - Effect of Surface Crowding and Surface Hydrophilicity on the Activity, Stability and Molecular Orientation of a Covalently Tethered Enzyme. AB - We have investigated two surface properties that are generally thought to have an important influence of enzyme activity and stability: surface hydrophobicity and surface crowding. Here two variants of an engineered bacterial nitro-reductase were covalently tethered to orient the protein's pseudo-2-fold symmetry axis either parallel or perpendicular to the surface. The surface hydrophobicity was systematically varied by changing the ratio of methyl- to hydroxyl-groups displayed on the SAM surface, and the effects on enzyme activity, thermal stability, and structure investigated. Increasing surface hydrophobicity progressively decreased enzyme activity, but had no effect on thermal stability. Surface-sensitive sum frequency generation and attenuated total reflectance Fourier transform IR spectroscopies indicated that the enzyme is not denatured by the more hydrophobic surface, but is more likely trapped in less active conformations by transient hydrophobic interactions. In contrast, increasing enzyme surface concentration increased the specific activity of the parallel oriented enzyme, but had no effect on the activity of the perpendicularly oriented enzyme, suggesting that crowding effects are highly context dependent. PMID- 28654291 TI - Photocatalytic E -> Z Isomerization of Polarized Alkenes Inspired by the Visual Cycle: Mechanistic Dichotomy and Origin of Selectivity. AB - Iteratively executed with exquisite spatial and temporal control, the selective isomerization of polarized alkenes underpins a plethora of complex biological processes ranging from natural product biosynthesis through to the mammalian visual cycle. However, nature's proficiency conceals the inherent difficulties in replicating this contra-thermodynamic transformation in the laboratory. Recently, we disclosed the first highly Z-selective isomerization of polarized alkenes, employing the cinnamoyl chromophore as a retinal surrogate under UV-irradiation (402 nm) with (-)-riboflavin (vitamin B2) as an inexpensive, organic photocatalyst (J. Am. Chem. Soc. 2015, 137, 11254-11257). This study was inspired by the propensity of crystalline (-)-riboflavin in the eyes of vertebrates to invert the intrinsic directionality of retinal isomerization. Herein, we extend this methodology to include a bioinspired, catalytic E -> Z isomerization of alpha,beta-unsaturated nitriles, thereby mimicking the intermediate Opsin derived, protonated Schiff base in the visual cycle with simple polarized alkenes. Replacement of the iminium motif by a cyano group is well tolerated and gives an additional degree of versatility for postisomerization functionalization. Broad substrate scope is demonstrated (up to 99:1 Z:E) together with evidence of mechanistic dichotomy via both singlet and triplet energy transfer mechanisms. Kinetic studies, temperature dependent photostationary state correlations and investigation of substituent-based electronic perturbation of the alkene identified polarization combined with increased Z-isomer activation barriers as the selectivity governing factors in catalysis. This investigation demonstrates the importance of internal structural preorganization on photostationary composition and explicates the augmented Z selectivity upon hydrogen-alkyl exchange at the beta-position of the alkene. PMID- 28654292 TI - Broadband Absorbing Semiconducting Polymer Nanoparticles for Photoacoustic Imaging in Second Near-Infrared Window. AB - Photoacoustic (PA) imaging holds great promise for preclinical research and clinical practice. However, most studies rely on the laser wavelength in the first near-infrared (NIR) window (NIR-I, 650-950 nm), while few studies have been exploited in the second NIR window (NIR-II, 1000-1700 nm), mainly due to the lack of NIR-II absorbing contrast agents. We herein report the synthesis of a broadband absorbing PA contrast agent based on semiconducting polymer nanoparticles (SPN-II) and apply it for PA imaging in NIR-II window. SPN-II can absorb in both NIR-I and NIR-II regions, providing the feasibility to directly compare PA imaging at 750 nm with that at 1064 nm. Because of the weaker background PA signals from biological tissues in NIR-II window, the signal-to noise ratio (SNR) of SPN-II resulted PA images at 1064 nm can be 1.4-times higher than that at 750 nm when comparing at the imaging depth of 3 cm. The proof-of concept application of NIR-II PA imaging is demonstrated in in vivo imaging of brain vasculature in living rats, which showed 1.5-times higher SNR as compared with NIR-I PA imaging. Our study not only introduces the first broadband absorbing organic contrast agent that is applicable for PA imaging in both NIR-I and NIR-II windows but also reveals the advantages of NIR-II over NIR-I in PA imaging. PMID- 28654293 TI - Optical Emission in Hexagonal SiGe Nanowires. AB - Recent advances in the synthetic growth of nanowires have given access to crystal phases that in bulk are only observed under extreme pressure conditions. Here, we use first-principles methods based on density functional theory and many-body perturbation theory to show that a suitable mixing of hexagonal Si and hexagonal Ge yields a direct bandgap with an optically permitted transition. Comparison of the calculated radiative lifetimes with typical values of nonradiative recombination mechanisms indicates that optical emission will be the dominant recombination mechanism. These findings pave the way to the development of silicon-based optoelectronic devices, thus far hindered by the poor light emission efficiency of cubic Si. PMID- 28654294 TI - Trialkylphosphine-Mediated Synthesis of 2-Acyl Furans from Ynenones. AB - A novel reaction for the synthesis of 2-acyl furans is reported. The reaction is believed to proceed by sequential addition of a trialkylphosphine to an ynenone, 5-exo-dig cyclization to form the furan, and oxidation of the resulting phosphonium ylide with molecular oxygen. Many common functional groups are tolerated during the reaction, and the products are obtained in good to excellent yield under the mild conditions. This methodology offers efficient access to biologically important compounds, including fused polycyclic compounds and furaldehydes, from simple starting materials. PMID- 28654295 TI - Liposomes in Polymersomes: Multicompartment System with Temperature-Triggered Release. AB - Multicompartmentalization is a key feature of eukaryotic cells, allowing separation and protection of species within the membrane walls. During the last years, several methods have been reported to afford synthetic multicompartment lipidic or polymeric vesicles that mimic biological cells and that allow cascade chemical or enzymatic reactions within their lumen. We hereby report on the preparation and study of liposomes in polymersomes (LiPs) systems. We discuss on the loading and coloading of lipidic nanovesicles made of 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine (diC15-PC), or 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) inside the lumen of giant poly(butadiene)-b-poly(ethylene oxide) (PBut-b-PEO) polymersomes. These LiPs systems were characterized by confocal microscopy and UV-visible spectroscopy. We further demonstrate that we can achieve controlled sequential release of dyes from diC15-PC and DPPC liposomes at defined temperatures inside the giant PBut-b PEO polymersomes. This controlled release could be used as a means to initiate cascade reactions on demand in confined microreactors. PMID- 28654296 TI - Wurtzite ZnTe Nanotrees and Nanowires on Fluorine-Doped Tin Oxide Glass Substrates. AB - ZnTe nanotrees and nanowires were grown on fluorine-doped tin oxide glass by physical vapor transport. Sn from a fluorine-doped tin oxide layer catalyzed the growth at a growth temperature of 320 degrees C. Both the stem and branch nanowires grew along ?0001? in the rarely observed wurtzite structure. SnTe nanostructures were formed in the liquid catalyst and simultaneously ZnTe nanowire grew under Te-limited conditions, which made the formation of the wurtzite structure energetically favorable. Through polarization-dependent and power-dependent microphotoluminescence measurements from individual wurtzite nanowires at room temperature, we could determine the so far unknown fundamental bandgap of wurtzite ZnTe, which was 2.297 eV and thus 37 meV higher than that of zinc-blend ZnTe. From the analysis of doublet photoluminescence spectra, the valence band splitting energy between heavy hole and light hole bands is estimated to be 69 meV. PMID- 28654298 TI - Direct Neutron Spectroscopy Observation of Cerium Hydride Species on a Cerium Oxide Catalyst. AB - Ceria has recently shown intriguing hydrogenation reactivity in catalyzing alkyne selectively to alkenes. However, the mechanism of the hydrogenation reaction, especially the activation of H2, remains experimentally elusive. In this work, we report the first direct spectroscopy evidence for the presence of both surface and bulk Ce-H species upon H2 dissociation over ceria via in situ inelastic neutron scattering spectroscopy. Combined with in situ ambient-pressure X-ray photoelectron spectroscopy, IR, and Raman spectroscopic studies, the results together point to a heterolytic dissociation mechanism of H2 over ceria, leading to either homolytic products (surface OHs) on a close-to-stoichiometric ceria surface or heterolytic products (Ce-H and OH) with the presence of induced oxygen vacancies in ceria. The finding of this work has significant implications for understanding catalysis by ceria in both hydrogenation and redox reactions where hydrogen is involved. PMID- 28654297 TI - Eriodictyol, Not Its Glucuronide Metabolites, Attenuates Acetaminophen-Induced Hepatotoxicity. AB - Acetaminophen (APAP) is one of the most commonly used oral analgesics and antipyretics, but hepatotoxicity including liver failure may occur after overdose. The therapeutic options for treating APAP hepatotoxicity are limited. Eriodictyol, a dietary flavonoid with anti-inflammatory and antioxidant properties, was used here to determine its protective effects against APAP induced hepatotoxicity in mice. Various administration routes and pharmacokinetics-pharmacodynamics (PK-PD) analyses were used to determine these effects. Protective effects were observed in intravenously and intraperitoneally but not in intragastrically administered eriodictyol. LC-MS/MS analysis revealed two monoglucuronide metabolites of eriodictyol in liver and intestine microsomes. Recombinant human uridine-5'-diphospho -glucuronosyltransferase (UGT) isoforms and chemical inhibition studies demonstrated that UGT1As (mainly UGT1A1, UGT1A9, UGT1A10) and UGT2B7 were likely the main contributors to eriodictyol glucuronidation. Intragastric administration of eriodictyol, which displayed lower parent and higher metabolite concentrations in the plasma, did not elicit protective effects against APAP hepatotoxicity, when compared to the intraperitoneal injection of eriodictyol. The relative bioavailability of eriodictyol was increased to 216.84% with the coadministration of glycyrrhetinic acid (GA), an inhibitor of UGT1As. Intragastric administration of eriodictyol in combination with GA also induced protective effects against APAP hepatotoxicity. Furthermore, intragastric administration of eriodictyol attenuated APAP hepatotoxicity in heterozygous Ugt1 (Ugt1+/-) mice but not in its wild-type littermates. Thus, UGT1A-mediated metabolic inactivation reduced the protective effect of eriodictyol. Eriodictyol attenuated APAP hepatotoxicity via inhibition of hepatic cytochrome P450 (cyp) 2e1 and cyp3a11 activities; reserve of glutathione (GSH) by improvement of glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glutathione S-transferase (GST) activities; elevation of superoxide dismutase (SOD) activity; and reduction of malondialdehyde (MDA) level. Our findings indicate that parenterally administered eriodictyol may be used to treat APAP-induced hepatotoxicity, and its efficacy can be enhanced by UGT1As down-regulation. PMID- 28654299 TI - Carrier Recombination Processes in Gallium Indium Phosphide Nanowires. AB - Understanding of recombination and photoconductivity dynamics of photogenerated charge carriers in GaxIn1-xP NWs is essential for their optoelectronic applications. In this letter, we have studied a series of GaxIn1-xP NWs with varied Ga composition. Time-resolved photoinduced luminescence, femtosecond transient absorption, and time-resolved THz transmission measurements were performed to assess radiative and nonradiative recombination and photoconductivity dynamics of photogenerated charges in the NWs. We conclude that radiative recombination dynamics is limited by hole trapping, whereas electrons are highly mobile until they recombine nonradiatively. We also resolve gradual decrease of mobility of photogenerated electrons assigned to electron trapping and detrapping in a distribution of trap states. We identify that the nonradiative recombination of charges is much slower than the decay of the photoluminescence signal. Further, we conclude that trapping of both electrons and holes as well as nonradiative recombination become faster with increasing Ga composition in GaxIn1-xP NWs. We have estimated early time electron mobility in GaxIn1-xP NWs and found it to be strongly dependent on Ga composition due to the contribution of electrons in the X-valley. PMID- 28654301 TI - An Integrative Review of Scientific Evidence for Reconnective Healing. AB - BACKGROUND: Biofield therapies offer a novel, non-invasive approach to treating chronic diseases based on assessing and adjusting an individual's physiological and emotional responses through their bio-energetic field. Reconnective HealingTM (RH) is defined as: "...not just energy healing, but instead a more comprehensive spectrum of healing composed of energy, light, and information." OBJECTIVES: Several biofield therapies, such as Reiki, Therapeutic Touch and Johrei, have already been reviewed in the literature but RH has received little attention even though it is taught and practiced worldwide. This review provides a critical assessment of RH as a healing modality. METHODS: Scientific research articles published in peer-reviewed journals addressing RH were identified using relevant databases and archives. Information was extracted from each article that met selection criteria for evaluation of quality of reporting and design. This review summarizes and critically evaluates the five currently published peer-reviewed research papers involving RH and assesses whether RH provides consistent physiological outcomes between the studies. RESULTS: These results, taken together, suggest: (i) exposure of a healer or healee to RH, either directly or indirectly, amplifies their degree of autonomic arousal and energy, (ii) RH can reduce pain and improve range of motion in people with shoulder limitations, and (iii) when individuals experience RH as a group, their autonomic nervous systems simultaneously show sudden similar responses consistent with the idea that RH is mitigated by entrainment of biofields. CONCLUSIONS: Since these studies are extremely varied in design it is not possible at this point to reach conclusions about the general effectiveness of RH. More clinical and physiological research performed on different populations under a range of conditions is needed in order to support this healthcare approach. PMID- 28654302 TI - Evaluation of the Feasibility of a Home-Based TeleYoga Intervention in Participants with Both Chronic Obstructive Pulmonary Disease and Heart Failure. AB - OBJECTIVE: Test the feasibility and clinical outcomes of a home-based videoconferencing yoga intervention in participants diagnosed with both Chronic Obstructive Pulmonary Disease (COPD) and heart failure (HF). BACKGROUND: Yoga has potential benefit for symptom relief in participants with COPD and with HF; however, functional impairment and transportation issues can hinder access to typical yoga classes. METHODS: A controlled, nonrandomized trial was conducted of an 8-week TeleYoga intervention versus an educational control (information leaflets mailed to participants with one weekly phone call). One-hour TeleYoga classes were implemented twice weekly via multipoint videoconferencing, which connected participants to live classes via an Internet connection to their televisions. RESULTS: Fourteen participants with COPD and HF took part in the pilot study (7 in the intervention group and 8 in the control). Intervention participants were adherent to classes, able to safely participate, and found the classes enjoyable after the 8-week program. Dyspnea after exercise improved in the intervention group. CONCLUSIONS: Despite their frailty, patients diagnosed with both COPD and HF were able to perform yoga safely in the home setting. TeleYoga was acceptable and adherence was good; however, technical issues were an important hindrance to participation. PMID- 28654300 TI - A New Optimized Percutaneous Access System for CIPII. AB - In recent years, continuous intraperitoneal insulin infusion (CIPII) has become a favored treatment alternative for patients with subcutaneous insulin resistance, mainly due to its ability of mimicking physiological conditions of insulin absorption. CIPII has been shown to improve glycemic control as well as to reduce hypoglycemic events and to lead to increased patient satisfaction and quality of life (QoL). Among CIPII delivery systems, Diaport stands out due to its low side effects, its demonstrated clinical efficacy and the potential for integration into closed-loop systems. PMID- 28654303 TI - Imaging and dosimetry for radium-223: the potential for personalized treatment. AB - Radium-223 (223Ra) offers a new option for the treatment of bone metastases from prostate cancer. As cancer treatment progresses towards personalization, the potential for an individualized approach is exemplified in treatments with radiotherapeutics due to the unique ability to image in vivo the uptake and retention of the therapeutic agent. This is unmatched in any other field of medicine. Currently, 223Ra is administered according to standard fixed administrations, modified according to patient weight. Although gamma emissions comprise only 1% of the total emitted energy, there are increasing reports that quantitative imaging is feasible and can facilitate patient-specific dosimetry. The aim of this article is to review the application of imaging and dosimetry for 223Ra and to consider the potential for treatment optimization accordingly, in order to ensure clinical and cost effectiveness of this promising agent. PMID- 28654305 TI - Commentary Regarding Shapiro, "Nonadjunctive Use of Continuous Glucose Monitors for Insulin Dosing: Is It Safe?" AB - The FDA recently expanded the approved use of Dexcom's G5 Mobile continuous glucose monitoring (CGM) system to allow for diabetes treatment decisions. This decision is expected to reduce the burden of SMBG testing and increase the adoption and persistent use of CGM. The safety of nonadjunctive CGM use was questioned because of sporadic large discrepancies between CGM and SMBG values. These data were viewed in the context of complaints found in the FDA MAUDE database and social media postings. This commentary provides additional perspective on the inferences that can be drawn from these reports and the risk of nonadjunctive use of CGM data. PMID- 28654304 TI - A Prospective, Randomized, Double-Blind Multicenter Study Comparing Continuous Diffusion of Oxygen Therapy to Sham Therapy in the Treatment of Diabetic Foot Ulcers. AB - BACKGROUND: Over the past generation, preclinical data have suggested that there is a potential physiologic benefit to applying oxygen topically to wounds. However, we are unaware of any studies in the literature that have robustly assessed whether this would lead to a higher proportion of healing in similarly treated people without oxygen. Therefore, the purpose of this study was to assess this in people being treated for chronic diabetic foot ulcers (DFUs). METHODS: We enrolled and randomized 100 subjects with DFUs (79% male, aged 58.3 +/- 12.1 years) to receive either active continuous diffusion of oxygen (CDO) therapy using an active CDO device, or an otherwise fully operational sham device that provided moist wound therapy (MWT) without delivering oxygen. Patients were followed until closure or 12 weeks, whichever was sooner. Patients, treating physicians and independent evaluators were blinded to the study arm. All patients received identical offloading, dressings and follow-up. RESULTS: There were no significant differences in assessed descriptive characteristics between the treatment arms ( P > .05 for all). A significantly higher proportion of people healed in the active arm compared to sham (46% vs 22%, P = .02). This relative effect became greater in more chronic wounds (42.5% vs 13.5%, P = .006). Patients randomized to the active device experienced significantly faster rates of closure relative to the sham ( P < .001). CONCLUSIONS: The results of this study suggest that continuously diffused oxygen over a wound leads to significantly higher rates of closure, and faster time to closure, compared to similarly treated patients receiving standard therapy coupled with a sham device. Furthermore, the relative efficacy appears to improve the more the therapy may be needed (more chronic and larger wounds). PMID- 28654306 TI - Gene Expression Profile of Peripheral Blood Mononuclear Cells in Response to Intracerebral Hemorrhage. AB - RNA-sequencing, a powerful tool, yields a comprehensive view of whole transcriptome. Intracerebral hemorrhage (ICH) is a devastating form of stroke. To date, RNA-sequencing analysis of ICH has not been reported. Peripheral blood mononuclear cells (PBMCs) were used as a source of mRNA for gene expression profile analysis in stroke. In this study, we performed transcriptome analyses for PBMCs from four ICH patients and four healthy volunteers on Illumina platform. We identified 4040 significantly differentially expressed genes (DEGs). Functional annotation of DEGs with DAVID Bioinformatics Resources indicated that genes associated with cell apoptosis, autophagy, cell-cell adhesion, inflammatory response, protein binding, positive regulation of gene expression, and signal transduction were most significantly enriched by DEGs. Gene set enrichment analysis identified 40 significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including chemokine signaling, cytokine-cytokine receptor interaction, oxidative phosphorylation, and glutathione metabolism processes. These data point to a complex mechanism for ICH pathogenesis. Overall, the present study demonstrated an altered gene expression profile of PBMCs in response to acute ICH. Our study provided important information for understanding the molecular mechanisms of ICH pathogenesis at system-wide levels. PMID- 28654307 TI - Mangosteen Extract Prevents Dextran Sulfate Sodium-Induced Colitis in Mice by Suppressing NF-kappaB Activation and Inflammation. AB - In this study, the anti-inflammatory effects of mangosteen extract (MGE) on dextran sulfate sodium (DSS)-induced colitis in mice and nuclear factor (NF) kappaB pathway modulation were investigated. Acute colitis was induced by administering 3% DSS in drinking water for 7 days, and three groups of Institute of Cancer Research mice were treated with 30 and 120 mg/kg MGE or 5 aminosalicylic acid for 7 days; an additional two groups of mice served as healthy and disease controls. The results indicated that MGE significantly prevented weight loss, reduced disease activity index scores, and preserved colon length compared with the findings in the untreated colitis group. MGE downregulated the NF-kappaB pathway by inhibiting the phosphorylation of IkappaB and IKK in a dose-dependent manner. These findings suggest that MGE alleviates ulcerative colitis by modulating the NF-kappaB pathway. PMID- 28654308 TI - Does Parenteral Nutrition Increase the Risk of Catheter-Related Bloodstream Infection? A Systematic Literature Review. AB - BACKGROUND: Central venous access devices (CVADs) are used for parenteral nutrition (PN) delivery. We systematically reviewed research-based publications that reported comparative rates of catheter-related bloodstream infection (CRBSI) in patients with CVADs who received PN vs those who did not receive PN therapy. MATERIALS AND METHODS: The literature search included the Cochrane Library, MEDLINE, CINAHL, and PubMed up to July 14, 2015, to identity studies that compared patients with a CVAD who did and did not have PN therapy. RESULTS: Eleven observational studies were identified, comprising 2854 participants with 6287 CVADs. Six studies produced significant results in favor of non-PN, 4 studies showed no evidence of a difference between PN and non-PN, and 1 study produced significant results in favor of PN when analyzed per patient with multiple CVADs. Incidence ranged from 0 to 6.6 CRBSIs per 1000 CVAD days in the PN patients and 0.39 to 3.6 CRBSIs per 1000 CVAD days in the non-PN patients. The Cochrane risk of bias assessment tool for nonrandomized studies of interventions was used. Eight studies were rated as moderate risk of bias, 2 as serious, and 1 as critical. CONCLUSION: The data presented in this systematic review are not sufficient to establish whether patients receiving PN are more at risk of developing CRBSI than those who do not. Future PN studies needs to adjust for baseline imbalances and improve quality and reporting. PMID- 28654309 TI - Effect of Oral Branched-Chain Amino Acid Supplementation on Postoperative Blood Lactate Levels in Patients Undergoing Pancreatoduodenectomy. AB - BACKGROUND: Elevations in blood lactate levels have been associated with poor postoperative outcome. The aim of the present study was to determine if preoperative supplementation with branched-chain amino acids (BCAA) decreases postoperative blood lactate levels in patients undergoing pancreatoduodenectomy. METHODS: The cases of 223 consecutive patients who underwent pancreatoduodenectomy were retrospectively reviewed. Postoperative blood lactate levels in patients who were treated with BCAA supplementation before pancreatoduodenectomy (December 2011-December 2014) were compared with levels in patients who were not pretreated (January 2008-November 2011). RESULTS: Postoperative lactate levels were significantly lower in patients who received preoperative BCAA supplementation than in patients who did not (2.6 vs 3.1 mmol/L, P = .005), although preoperative blood lactate levels were statistically equivalent between the groups. In the univariate analysis, preoperative BCAA supplementation, preoperative lactate levels, operation time, and postoperative glucose levels were associated with postoperative lactate levels. A multiple regression analysis was performed among the 4 factors, and the preoperative use of BCAA supplementation was independently correlated with postoperative lactate levels ( P = .046). CONCLUSIONS: Preoperative BCAA supplementation decreased postoperative blood lactate levels. These results suggest that preoperative BCAA supplementation may help patients recover after surgery. PMID- 28654310 TI - Unique Infectious Strategy of H5N1 Avian Influenza Virus Is Governed by the Acid Destabilized Property of Hemagglutinin. AB - Highly pathogenic avian influenza (HPAI) H5N1 virus emerged in 1997 as a zoonotic disease in Hong Kong. It has since spread to Asia and Europe and is a serious threat to both the poultry industry and human health. For effective surveillance and possible prevention/control of HPAI H5N1 viruses, it is necessary to understand the molecular mechanism underlying HPAI H5N1 pathogenesis. The hemagglutinin (HA) protein of influenza A viruses (IAVs) is one of the major determinants of host adaptation, transmissibility, and viral virulence. The main function of the HA protein is to facilitate viral entry and viral genome release within host cells before infection. To achieve viral infection, IAVs belonging to different subtypes or strains induce viral-cell membrane fusion at different endosomal pH levels after internalization through endocytosis. However, host specific endosomal pH also affects induction of membrane fusion followed by infection. The HA protein of HPAI H5N1 has a higher pH threshold for membrane fusion than the HA protein of classical avian influenza viruses. Although this particular property of HA (which governs viral infection) is prone to deactivation in the avian intestine or in an ambient environment, it facilitates efficient infection of host cells, resulting in a broad host tropism, regardless of the pH in the host endosome. Accumulated knowledge, together with further research, about the HA-governed mechanism underlying HPAI H5N1 virulence (i.e., receptor tropism and pH-dependent viral-cell membrane fusion) will be helpful for developing effective surveillance strategies and for prevention/control of HPAI H5N1 infection. PMID- 28654311 TI - Effects of the Contextual Variables of Racing Games on Risky Driving Behavior. AB - OBJECTIVE: This research conducted experimental studies to investigate the effects of the contextual variables of racing games on risky driving behavior. MATERIALS AND METHODS: Three experiments were conducted. In Experiment 1, the effect of racing game violence on the driving-related risk-taking inclination of racing game players was examined. Experiment 2 investigated the impact of the competitiveness of racing games on risk-taking inclination, and Experiment 3 investigated the impact of the rewarded/punitive characteristics of racing games on the risk-taking inclination of racing game players. The Vienna Risk-Taking Test was used to measure risk-taking inclination of participants. RESULTS: The game violence, competitiveness, and the reward characteristics of racing games, all had significant impacts in increasing risky driving behavior. The punitive characteristics of racing games had a significant effect, which decreases risky driving behavior. CONCLUSION: The contextual variables of game violence, competitiveness, and rewarded/punitive characteristics of racing games investigated in this study were all shown to influence the risk-taking inclination of game players, which increased risky driving behavior. This study provides a useful reference for the classification and graded management of racing games. PMID- 28654312 TI - Effects of a T'ai Chi-Based Health Promotion Program on Metabolic Syndrome Markers, Health Behaviors, and Quality of Life in Middle-Aged Male Office Workers: A Randomized Trial. AB - OBJECTIVES: To determine the effects of a t'ai chi-applied worksite health promotion program on metabolic syndrome markers, health behaviors, and quality of life in middle-aged male office workers at a high risk of metabolic syndrome. DESIGN: A prospective randomized controlled study. SETTING: Health center of a government office building in Korea. SUBJECTS: Forty-three male office workers with two or more metabolic syndrome markers. INTERVENTIONS: The office workers were randomly assigned either to an experimental group that received t'ai chi combined with health education twice weekly for 12 weeks, or to a control group that received health education only. OUTCOME MEASURES: Blood sampling for metabolic syndrome markers and structured questionnaires for health behaviors and quality of life. RESULTS: The experimental group showed significant reductions in systolic (t = -3.103, p = 0.003) and diastolic (t = -2.159, p = 0.037) blood pressures and the triglyceride level (t = -2.451, p = 0.019) compared with the control group. Those in the experimental group also performed health behaviors more frequently (t = 4.047, p < 0.001) and reported a significantly better quality of life (t = 3.193, p = 0.003) than those in the control group. CONCLUSION: The study findings show that t'ai chi was an effective adjunctive intervention in a worksite health promotion program for middle-aged office workers at a high risk of metabolic syndrome. Future studies should examine the long-term effects of t'ai chi-applied worksite health promotion programs in individuals with confirmed metabolic syndrome. PMID- 28654313 TI - Oral Insulin Delivery in a Physiologic Context: Review. AB - Insulin remains indispensable to the treatment of diabetes, but its availability in injectable form only has hampered its timely and broader use. The development of an oral insulin remains an ultimate goal to both enhance ease of use, and to provide therapeutic advantages rooted in its direct delivery to the portal vein and liver. By mimicking the physiological path taken by pancreatic insulin, oral insulin is expected to have a distinct effect on the hepatic aspect of carbohydrate metabolism, hepatic insulin resistance, and, at the same time, avoid hyperinsulinemia and minimize the risk of hypoglycemia. With oral insulin approaching late stages of development, the goal of this review is to examine oral insulin in a physiological context and report on recent progress in its development. PMID- 28654315 TI - The Development of an Anthroposophic, Whole Medical System, Healthcare Program for Patients with Depressive Disorders. AB - OBJECTIVES: The aim of the study was to develop a whole medical system healthcare program as an alternative for group-oriented guidelines and as a basis for future studies on safety and (cost) effects. Mild to moderately severe depressive disorders were chosen as an illustrative example. DESIGN: Literature surveys, monodisciplinary expert interviews, and multidisciplinary panel discussions were employed to describe the whole medical system, its important elements, and the way the important elements are integrated in daily practice. RESULTS: The treatment of depressive disorders consists of four separate treatment phases in which 10 specific treatment goals are identified. Different disciplines may contribute to each goal. This gives an opportunity for the individualization of care. Within each discipline multiple options per goal are identified which leads to additional possibilities to individualize care. CONCLUSIONS: Individualized healthcare for patients with mild to moderately severe depressive disorders can be described in terms of treatment goals and treatment options to allow for personalization. The program may serve as the basis for future measurement of quality, cost effectiveness, and safety of provided care. PMID- 28654314 TI - Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes. AB - BACKGROUND: Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon. METHODS: Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 ug of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE). RESULTS: Assuming constant variables in a subject across nonoutlier visits and using thresholds of +/-15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients. CONCLUSIONS: The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia. PMID- 28654316 TI - Active Gaming as a Form of Exercise to Induce Hypoalgesia. AB - OBJECTIVE: An acute bout of moderate-to-vigorous exercise temporarily reduces pain sensitivity in healthy adults. Recently, active gaming has been rising in popularity as a means of light-to-moderate exercise and may be particularly suitable for deconditioned individuals. Whether the physical activity elicited in active games can produce a hypoalgesic effect remains unknown. The purpose of this study was to determine whether active videogames can reduce pressure and heat pain sensitivity in healthy adults. We also evaluated the relationship between the physical activity elicited by the games and the magnitude of the hypoalgesic response. MATERIALS AND METHODS: Twenty-one healthy adults played four different active games on separate days, including Microsoft(r) Kinect Xbox(r) One's Fighter Within and Sports Rival's Tennis, and Nintendo(r) WiiTM Sports' Boxing and Tennis. Heat pain thresholds on the forearm and pressure pain thresholds (PPTs) on the trapezius and forearm were assessed immediately before and after a 15-minute active gaming or control session. Minutes spent in sedentary time and moderate-to-vigorous physical activity (MVPA) during active gaming were measured with an accelerometer. RESULTS: The analyses revealed that PPTs at the forearm and trapezius significantly increased from pretest to posttest following Kinect Fighter Within. PPTs at the trapezius also significantly increased from pretest to posttest following Wii Boxing. The magnitude of the hypoalgesic response was significantly correlated with MVPA and sedentary time during gameplay. CONCLUSION: These results suggest that an active gaming session played at a moderate intensity is capable of temporarily reducing pain sensitivity. PMID- 28654317 TI - Federal Funding for Health Security in FY2018. AB - This article is the latest in an annual series analyzing federal funding for health security programs. It examines proposed funding in the President's Budget Request for FY2018 and provides updated amounts for FY2017 and actual funding for FY2010 through FY2016. The proposed FY2018 budget for health security-related programs represents a significant decrease in funding from prior years and previous administrations. In total, the President's proposed FY2018 budget includes $12.45 billion for health security-related programs, an estimated decrease in funding of $1.25 billion, or 9%, from the estimated $13.71 billion in FY2017 and an 11% decrease from the FY2016 actual funding level of $13.99 billion. Most FY2018 health security funding ($6.67 billion, 54%) would go to programs with multiple-hazard and preparedness goals and missions, representing a 14% decrease in this funding compared to FY2017. Radiological and nuclear security programs would receive 20% ($2.48 billion) of all health security funding, a slight decrease of 2% from the prior year. Biosecurity programs would be funded at $1.53 billion (12% of health security funding) in FY2018, a decrease of 6% compared to FY2017. Chemical security programs would represent 3% ($389.7 million) of all health security funding in FY2018, a 9% decrease from the prior year. Finally, 11% of health security funding ($1.39 billion) would be dedicated to pandemic influenza and emerging infectious diseases programs, the only category of funding to see an increase (3%) above FY2017. PMID- 28654318 TI - A Novel Technique for Parastomal Hernia Repair Combining a Laparoscopic and Ostomy-Opening Approach. AB - INTRODUCTION: The aim of this study was to evaluate a new method of parastomal hernia (PSH) repair by using a hybrid approach with a cylindrical-shaped mesh of 4 cm funnel length. MATERIALS AND METHODS: In a pilot prospective case series, 12 patients underwent surgical repair of PSHs with a combined laparoscopic and ostomy-opening approach. After laparoscopic adhesiolysis, the ostomy opening was excised from outside and the bowel was closed. The hernia sac was excised after reduction of its content. Then, the bowel was guided through the funnel of the mesh and the implant was manually transferred into the peritoneal cavity through the hernia defect. Next, the fascial margins were narrowed with sutures. Laparoscopy was continued, and the mesh was placed and fixed with absorbable tacks in the proper position. Finally, the diverted bowel was shortened outside of the abdomen and the stoma was matured in its original location. RESULTS: We documented no mesh-associated complications. Only one superficial peristomal wound defect occurred. No unplanned conversions were needed, and median duration of the operations was 72 minutes. There was no recurrence during the short-term follow-up of median 4 months (ranged from 3 to 8 months). DISCUSSION: The technique described gives several advantages, such as a minimally invasive hybrid approach creating a real three-dimensional mesh-covered barrier between the trephine and stomal limb and optional shortening of a concomitant prolapse. When needed due to a concomitant incisional hernia, a second flat mesh can be laparoscopically placed in an intraperitoneal position. PMID- 28654320 TI - Letter to the Editor: Re: Increased Periodontal Attachment Loss in Patients With Systemic Sclerosis. PMID- 28654319 TI - Partial Characterization of Tick-Borne Encephalitis Virus Isolates from Ticks of Southern Ukraine. AB - Tick-borne encephalitis (TBE) is the most common tick-borne viral infection in Eurasia; thousands of human cases are annually reported from several European countries. Several tick species are vectors of the tick-borne encephalitis virus (TBEV), while TBE appears to be spreading from the Eurasian continent westward to Europe. Fifteen study sites were chosen from five territories of southern Ukraine, including Odessa, Mykolaiv, Kherson Oblast, the Autonomous Republic of Crimea, and Sevastopol. Tick collection was performed in spring season of three consecutive years (1988-1990) using either flagging technique or direct collection of specimens feeding on cattle. A total of 15,243 tick imagoes and nymphs were collected from nine species, including Dermacentor marginatus, D. reticulatus, Haemaphysalis parva, H. punctata, Hyalomma marginatum, Ixodes ricinus, Rhipicephalus bursa, R. rossicus, and R. sanguineus, pooled in 282 monospecific samples. Supernatant of grinded pool was used for inoculation to suckling mice for virus isolation. Eight TBEV isolates were identified from ticks among six study sites. Ticks showed a minimum infection rate from 0.11% to 0.81%. Phylogenetic analysis of the envelope (E) protein gene of seven isolates, assigned all to the European subtype (TBEV-Eu) showing a maximum identity of 97.17% to the "Pan" TBEV-Eu reference strain. Compared to 104 TBEV-Eu isolates they clustered within the same clade as the Pan reference strain and distinguished from other TBEV-Eu isolates. Amino acid sequence analysis of the South Ukrainian TBEV-Eu isolates revealed the presence of four amino acid substitutions 67 (N), 266 (R), 306 (V), and 407 (R), in the ectodomains II and III and in the stem-anchor region of the E protein gene. This study confirmed TBEV-Eu subtype distribution in the southern region of Ukraine, which eventually overlaps with TBEV-FE (Far Eastern subtype) and TBEV-Sib (Siberian subtype) domains, showing the heterogeneity of TBEV circulating in Ukraine. PMID- 28654321 TI - Redox-Based Regulation of Bacterial Development and Behavior. AB - Severe changes in the environmental redox potential, and resulting alterations in the oxidation states of intracellular metabolites and enzymes, have historically been considered negative stressors, requiring responses that are strictly defensive. However, recent work in diverse organisms has revealed that more subtle changes in the intracellular redox state can act as signals, eliciting responses with benefits beyond defense and detoxification. Changes in redox state have been shown to influence or trigger chromosome segregation, sporulation, aerotaxis, and social behaviors, including luminescence as well as biofilm establishment and dispersal. Connections between redox state and complex behavior allow bacteria to link developmental choices with metabolic state and coordinate appropriate responses. Promising future directions for this area of study include metabolomic analysis of species- and condition-dependent changes in metabolite oxidation states and elucidation of the mechanisms whereby the redox state influences circadian regulation. PMID- 28654322 TI - Site-Specific Self-Catalyzed DNA Depurination: A Biological Mechanism That Leads to Mutations and Creates Sequence Diversity. AB - Self-catalyzed DNA depurination is a sequence-specific physiological mechanism mediated by spontaneous extrusion of a stem-loop catalytic intermediate. Hydrolysis of the 5'G residue of the 5'GA/TGG loop and of the first 5'A residue of the 5'GAGA loop, together with particular first stem base pairs, specifies their hydrolysis without involving protein, cofactor, or cation. As such, this mechanism is the only known DNA catalytic activity exploited by nature. The consensus sequences for self-depurination of such G- and A-loop residues occur in all genomes examined across the phyla, averaging one site every 2,000-4,000 base pairs. Because apurinic sites are subject to error-prone repair, leading to substitution and short frameshift mutations, they are both a source of genome damage and a means for creating sequence diversity. Their marked overrepresentation in genomes, and largely unchanging density from the lowest to the highest organisms, indicate their selection over the course of evolution. The mutagenicity at such sites in many human genes is associated with loss of function of key proteins responsible for diverse diseases. PMID- 28654324 TI - Conceptual and Experimental Tools to Understand Spatial Effects and Transport Phenomena in Nonlinear Biochemical Networks Illustrated with Patchy Switching. AB - Many biochemical systems are spatially heterogeneous and exhibit nonlinear behaviors, such as state switching in response to small changes in the local concentration of diffusible molecules. Systems as varied as blood clotting, intracellular calcium signaling, and tissue inflammation are all heavily influenced by the balance of rates of reaction and mass transport phenomena including flow and diffusion. Transport of signaling molecules is also affected by geometry and chemoselective confinement via matrix binding. In this review, we use a phenomenon referred to as patchy switching to illustrate the interplay of nonlinearities, transport phenomena, and spatial effects. Patchy switching describes a change in the state of a network when the local concentration of a diffusible molecule surpasses a critical threshold. Using patchy switching as an example, we describe conceptual tools from nonlinear dynamics and chemical engineering that make testable predictions and provide a unifying description of the myriad possible experimental observations. We describe experimental microfluidic and biochemical tools emerging to test conceptual predictions by controlling transport phenomena and spatial distribution of diffusible signals, and we highlight the unmet need for in vivo tools. PMID- 28654325 TI - A Bright Future for Antibiotics? AB - Multidrug resistance is a global threat as the clinically available potent antibiotic drugs are becoming exceedingly scarce. For example, increasing drug resistance among gram-positive bacteria is responsible for approximately one third of nosocomial infections. As ribosomes are a major target for these drugs, they may serve as suitable objects for novel development of next-generation antibiotics. Three-dimensional structures of ribosomal particles from Staphylococcus aureus obtained by X-ray crystallography have shed light on fine details of drug binding sites and have revealed unique structural motifs specific for this pathogenic strain, which may be used for the design of novel degradable pathogen-specific, and hence, environmentally friendly drugs. PMID- 28654326 TI - The Ubiquitin System, Autophagy, and Regulated Protein Degradation. AB - This brief disquisition about the early history of studies on regulated protein degradation introduces several detailed reviews about the ubiquitin system and autophagy. PMID- 28654323 TI - Metabolite Measurement: Pitfalls to Avoid and Practices to Follow. AB - Metabolites are the small biological molecules involved in energy conversion and biosynthesis. Studying metabolism is inherently challenging due to metabolites' reactivity, structural diversity, and broad concentration range. Herein, we review the common pitfalls encountered in metabolomics and provide concrete guidelines for obtaining accurate metabolite measurements, focusing on water soluble primary metabolites. We show how seemingly straightforward sample preparation methods can introduce systematic errors (e.g., owing to interconversion among metabolites) and how proper selection of quenching solvent (e.g., acidic acetonitrile:methanol:water) can mitigate such problems. We discuss the specific strengths, pitfalls, and best practices for each common analytical platform: liquid chromatography-mass spectrometry (LC-MS), gas chromatography mass spectrometry (GC-MS), nuclear magnetic resonance (NMR), and enzyme assays. Together this information provides a pragmatic knowledge base for carrying out biologically informative metabolite measurements. PMID- 28654327 TI - A New Facet of Vitamin B12: Gene Regulation by Cobalamin-Based Photoreceptors. AB - Living organisms sense and respond to light, a crucial environmental factor, using photoreceptors, which rely on bound chromophores such as retinal, flavins, or linear tetrapyrroles for light sensing. The discovery of photoreceptors that sense light using 5'-deoxyadenosylcobalamin, a form of vitamin B12 that is best known as an enzyme cofactor, has expanded the number of known photoreceptor families and unveiled a new biological role of this vitamin. The prototype of these B12-dependent photoreceptors, the transcriptional repressor CarH, is widespread in bacteria and mediates light-dependent gene regulation in a photoprotective cellular response. CarH activity as a transcription factor relies on the modulation of its oligomeric state by 5'-deoxyadenosylcobalamin and light. This review surveys current knowledge about these B12-dependent photoreceptors, their distribution and mode of action, and the structural and photochemical basis of how they orchestrate signal transduction and control gene expression. PMID- 28654328 TI - Biochemistry of Catabolic Reductive Dehalogenation. AB - A wide range of phylogenetically diverse microorganisms couple the reductive dehalogenation of organohalides to energy conservation. Key enzymes of such anaerobic catabolic pathways are corrinoid and Fe-S cluster-containing, membrane associated reductive dehalogenases. These enzymes catalyze the reductive elimination of a halide and constitute the terminal reductases of a short electron transfer chain. Enzymatic and physiological studies revealed the existence of quinone-dependent and quinone-independent reductive dehalogenases that are distinguishable at the amino acid sequence level, implying different modes of energy conservation in the respective microorganisms. In this review, we summarize current knowledge about catabolic reductive dehalogenases and the electron transfer chain they are part of. We review reaction mechanisms and the role of the corrinoid and Fe-S cluster cofactors and discuss physiological implications. PMID- 28654329 TI - Effects of Prior Experience on Shelter-Seeking Behavior of Juvenile American Lobsters. AB - Shelter-seeking behaviors are vital for survival for a range of juvenile benthic organisms. These behaviors may be innate or they may be affected by prior experience. After hatching, American lobsters Homarus americanus likely first come into contact with shelter during the late postlarval (decapodid) stage, known as stage IV. After the subsequent molt to the first juvenile stage (stage V), they are entirely benthic and are thought to be highly cryptic. We hypothesized that postlarval (stage IV) experience with shelter would carry over into the first juvenile stage (stage V) and reduce the time needed for juveniles to locate and enter shelters (sheltering). We found some evidence of a carryover effect, but not the one we predicted: stage V juveniles with postlarval shelter experience took significantly longer to initiate sheltering. We also hypothesized that stage V juveniles would demonstrate learning by relocating shelters more quickly with immediate prior experience. Our findings were mixed. In a maze, juveniles with immediate prior experience were faster to regain visual contact with shelter, suggesting that they had learned the location of the shelter. In contrast, there was no significant effect of immediate prior experience on time to initiate sheltering in an open arena, or in the maze after juveniles had regained visual contact. We conclude that very young (stage V) juvenile lobsters modify their shelter-seeking behavior based on prior experiences across several timescales. Ecologically relevant variation in habitat exposure among postlarval and early juvenile lobsters may influence successful recruitment in this culturally and commercially important fishery species. PMID- 28654330 TI - Early Transcriptional Responses during Heat Stress in the Coral Acropora hyacinthus. AB - Corals respond to heat pulses that cause bleaching with massive transcriptional change, but the immediate responses to stress that lead up to these shifts have never been detailed. Understanding these early signals could be important for identifying the regulatory mechanisms responsible for bleaching and how these mechanisms vary between more and less resilient corals. Using RNA sequencing (RNAseq) and sampling every 30 minutes during a short-term heat shock, we found that components of the transcriptome were significantly upregulated within 90 min and after a temperature increase of +2 degrees C. The developmental transcription factor, Kruppel-like factor 7, was highly expressed within 60 min, and stress-related transcription factors such as Elk-3 were highly expressed starting at 240 min. The sets of genes enriched for early transcriptional response to heat stress included heat shock proteins, small GTPases, and proteasome genes. Retrovirus-related Pol polyproteins from transposons were significantly expressed throughout the whole experiment. Lastly, we propose a model for early transcriptional regulation of protein degradation and cell adhesion response that may ultimately lead to the bleaching and stress response. PMID- 28654332 TI - Errata. PMID- 28654331 TI - Effects of Temperature and pCO2 on Population Regulation of Symbiodinium spp. in a Tropical Reef Coral. AB - This study tested the bleaching response of the Pacific coral Seriatopora caliendrum to short-term exposure to high temperature and elevated partial pressure of carbon dioxide (pCO2). Juvenile colonies collected from Nanwan Bay, Taiwan, were used in a factorial experimental design in which 2 temperatures (~27.6 degrees C and ~30.4 degrees C) and 2 pCO2 values (~47.2 Pa and ~90.7 Pa) were crossed to evaluate, over 12 days, the effects on the densities and physiology of the symbiotic dinoflagellates (Symbiodinium) in the corals. Thermal bleaching, as defined by a reduction of Symbiodinium densities at high temperature, was unaffected by high pCO2. The division, or mitotic index (MI), of Symbiodinium remaining in thermally bleached corals was about 35% lower than in control colonies, but they contained about 53% more chlorophyll. Bleaching was highly variable among colonies, but the differences were unrelated to MI or pigment content of Symbiodinium remaining in the coral host. At the end of the study, all of the corals contained clade C Symbiodinium (either C1d or C15), and the genetic variation of symbionts did not account for among-colony bleaching differences. These results showed that high temperature causes coral bleaching independent of pCO2, and underscores the potential role of the coral host in driving intraspecific variation in coral bleaching. PMID- 28654333 TI - Identification of Genes for Synthesis of the Blue Pigment, Biliverdin IXalpha, in the Blue Coral Heliopora coerulea. AB - Heliopora coerulea is the only species in the subclass Octocorallia that has a crystalline aragonite skeleton. The skeleton has been reported to contain the blue pigment, biliverdin IXalpha, which is formed by heme oxygenase (HO) during heme decomposition. There is little information regarding gene expression in H. coerulea; therefore, the biosynthesis pathway for biliverdin IXalpha is poorly understood. To identify the genes related to heme synthesis and degradation, metatranscripts of H. coerulea and its symbiont Symbiodinium spp. were sequenced and separated from the host- and symbiont-derived sequences. From the metatranscriptome analyses, all genes for heme synthesis and three HOs were isolated from the host and symbiont. From our phylogenetic and amino acid analysis, we noted that one of the HO isoforms in the host coral was predicted to possess HO activity. However, biliverdin reductase, which reduces biliverdin to bilirubin, was not identified in the present study. Similarly, biliverdin reductase was not identified in the transcripts of the red coral Corallium rubrum, a species that also belongs to Octocorallia. However, genes related to heme synthesis and HO were found in C. rubrum. We speculate that Heliopora coerulea can produce biliverdin and accumulate it in the skeleton, while red corals and other Octocorallia species cannot. Further information from molecular studies of H. coerulea will provide insights into the synthesis of biliverdin IXalpha, the blue pigment in the hard crystalline aragonite skeleton, and will be fundamental to future ecological and physiological studies. PMID- 28654334 TI - Antennular Morphology and Contribution of Aesthetascs in the Detection of Food related Compounds in the Shrimp Palaemon adspersus Rathke, 1837 (Decapoda: Palaemonidae). AB - Shrimp are an essential ecological component of marine ecosystems, and have commercial importance for human consumption and aquaculture. Like other decapod crustaceans, shrimp rely on chemical senses to detect and localize food resources by means of chemosensilla that are located mainly on the cephalothoracic appendages. Using the shrimp Palaemon adspersus, a model organism with omnivorous feeding behavior, we aimed to provide comparative information on the role of aesthetascs, antennular sensilla, and flicking behavior in food detection. To this end, we examined i) the morphology of antennular sensilla by field emission scanning electron microscopy, ii) the shrimp's sensitivity to a number of food related compounds (amino acids and sugars) by means of whole-animal bioassays, and iii) the contribution of the aesthetasc sensilla to food detection. Our results showed that, aside from the aesthetascs, only three other main morphotypes of setae with chemoreceptive features were present in the antennules, thus accounting for relatively simple sensillar equipment. Nevertheless, we found broad-spectrum sensitivity of the shrimp to a number of amino acids (i.e., isoleucine, leucine, methionine, phenylalanine, glycine, tryptophan, cysteine, and tyrosine) and carbohydrates (trehalose, maltose, cellobiose, and fructose) that was consistent with the omnivorous or scavenging habits of the animal. Although aesthetasc ablation attenuated flicking behavior in a chemical stimulus independent manner, success in detection and short-range localization of food did not rely on the presence of aesthetasc sensilla. This finding confirms the existence of a non-aesthetasc alternative pathway for feeding, with functional redundancy in simple generalist feeder models such as shrimp. PMID- 28654335 TI - Temperature-related Intraspecific Variability in the Behavioral Manipulation of Acanthocephalan Parasites on Their Gammarid Hosts. AB - Understanding the effect of temperature on ecologically important species has become a major challenge in the context of global warming. However, the consequences of climate change cannot be accurately predicted without taking into consideration biotic interactions. Parasitic infection, in particular, constitutes a widespread biotic interaction, and parasites impact their hosts in multiple ways, eventually leading to consequences for communities and ecosystems. We explored the effect of temperature on the anti-predator behavior of a keystone freshwater invertebrate, the amphipod Gammarus fossarum. Gammarids regularly harbor manipulative acanthocephalan parasites that modify their anti-predator behavior in ways that potentially increase the probability of trophic transmission to their definitive hosts. We investigated the impact of temperature on gammarids infected by two acanthocephalan parasites, Pomphorhynchus tereticollis and Polymorphus minutus. Uninfected and naturally infected gammarids were acclimatized to different temperatures, and their behavior was measured. Our results showed that the effect of infection on the phototaxis of gammarids increased with increasing temperature, with a stronger effect induced by P. tereticollis. In contrast, temperature had no effect on the alteration of refuge use or geotaxis observed in infected gammarids. Our results provide the first direct evidence that temperature can affect the extent of behavioral alteration brought about by certain parasite species. However, the consequences of increased trophic transmission remain elusive; the supposedly key anti-predatory behavior was not significantly affected by exposure of gammarids to different temperatures. PMID- 28654336 TI - Focal Therapy for Prostate Cancer with In-Bore MR-guided Focused Ultrasound: Two Year Follow-up of a Phase I Trial-Complications and Functional Outcomes. AB - Purpose To report the safety profile and 2-year functional outcomes of in-bore magnetic resonance (MR)-guided focused ultrasound on single cancer foci in men with prostate cancer. Materials and Methods Ethics approval was obtained from the centralized institutional review board for this prospective single-arm study, and patients provided informed consent. Patients with untreated low-volume low-grade prostate cancer (clinical stage T2a or lower; Gleason score, 3+3; index tumor <=10 mm3) underwent MR-guided focused ultrasound between July 2011 and February 2013. All patients underwent robotic transperineal mapping biopsy and multiparametric MR imaging. Only those with a maximum of two lesions smaller than 10 mm at mapping biopsy were included. Target areas were sonicated with real-time MR thermometry monitoring, excluding critical areas from the beam path. Serum prostate-specific antigen (PSA) and Expanded Prostate Index Composite (EPIC) scores were obtained at baseline and at 1, 3, 6, 12, 18, and 24 months and were plotted to observe their trend. Mean EPIC subdomain score changes at each serial time point were compared with the baseline score by using paired t tests (level of significance, P < .007). Repeat transperineal biopsy was performed at 6 and 24 months. Results Fourteen men (mean age, 62.8 years; median PSA level, 8.3 ng/mL) underwent treatment, with 12 men completing 2-year follow-up. A median reduction of PSA level by 2.9 ng/mL was observed at 6 months. Seven men had Clavien-Dindo grade 1-2 complications. There was a slight insignificant deterioration of EPIC urinary symptom score (mean increase of 7.8 points compared with baseline, P = .012) noted at 1 month, but it returned to baseline by 3 months. There was a trend to deterioration in sexual function score (mean decrease, 4.4 points; P = .04 [not significant]) that normalized at 3 months. There was no significant change in EPIC subdomain scores from baseline over the 24 months. At 6-month template biopsy, one man had cancer with a Gleason score greater than 6; at 24 months, three men had cancer with a Gleason score greater than 6. Conclusion MR guided focused ultrasound is technically feasible for focal prostate ablation and appears to have a favorable early safety and functional profile. Further clinical trials are necessary to establish oncologic efficacy. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28654337 TI - Newly Diagnosed Breast Cancer: Comparison of Contrast-enhanced Spectral Mammography and Breast MR Imaging in the Evaluation of Extent of Disease. AB - Purpose To compare the diagnostic performances of contrast material-enhanced spectral mammography and breast magnetic resonance (MR) imaging in the detection of index and secondary cancers in women with newly diagnosed breast cancer by using histologic or imaging follow-up as the standard of reference. Materials and Methods This institutional review board-approved, HIPAA-compliant, retrospective study included 52 women who underwent breast MR imaging and contrast-enhanced spectral mammography for newly diagnosed unilateral breast cancer between March 2014 and October 2015. Of those 52 patients, 46 were referred for contrast enhanced spectral mammography and targeted ultrasonography because they had additional suspicious lesions at MR imaging. In six of the 52 patients, breast cancer had been diagnosed at an outside institution. These patients were referred for contrast-enhanced spectral mammography and targeted US as part of diagnostic imaging. Images from contrast-enhanced spectral mammography were analyzed by two fellowship-trained breast imagers with 2.5 years of experience with contrast enhanced spectral mammography. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated for both imaging modalities and compared by using the Bennett statistic. Results Fifty-two women with 120 breast lesions were included for analysis (mean age, 50 years; range, 29 73 years). Contrast-enhanced spectral mammography had similar sensitivity to MR imaging (94% [66 of 70 lesions] vs 99% [69 of 70 lesions]), a significantly higher PPV than MR imaging (93% [66 of 71 lesions] vs 60% [69 of 115 lesions]), and fewer false-positive findings than MR imaging (five vs 45) (P < .001 for all results). In addition, contrast-enhanced spectral mammography depicted 11 of the 11 secondary cancers (100%) and MR imaging depicted 10 (91%). Conclusion Contrast enhanced spectral mammography is potentially as sensitive as MR imaging in the evaluation of extent of disease in newly diagnosed breast cancer, with a higher PPV. (c) RSNA, 2017. PMID- 28654347 TI - Molecular Imaging of the Human Pulmonary Vascular Endothelium Using an Adrenomedullin Receptor Ligand. AB - This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans ( N = 20) were included into escalating groups of 5 mCi ( n = 5), 10 mCi ( n = 5), or 15 mCi ( n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% +/- 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension. PMID- 28654338 TI - Small Intracranial Aneurysms: Diagnostic Accuracy of CT Angiography. AB - Purpose To assess the accuracy of computed tomographic (CT) angiography for diagnosis of cerebral aneurysms 5 mm or smaller, with digital subtraction angiography (DSA) as the reference standard, in a large patient cohort Materials and Methods This retrospective study was approved by the local institutional review board with a waiver of written informed consent. A total of 1366 patients who underwent cerebral CT angiography followed by DSA were included. The performance of CT angiography for depiction of aneurysms was evaluated by two readers on a per-patient and per-aneurysm basis and based on size of aneurysm, location, and status of rupture. The performance of CT angiography for diagnosis of aneurysms of different size, location, and rupture status was compared by using chi2 test. kappa statistic was used to assess interreader agreement for diagnosis of aneurysms. Results Of 1366 patients, 579 patients had 711 small aneurysms at DSA. By using DSA as the reference standard, the respective sensitivity, specificity, and accuracy of CT angiography for readers 1 and 2 for detection of small aneurysms on a per-patient basis were 97.1% (562 of 579) and 97.4% (564 of 579), 98.5% (451 of 458) and 99.1% (454 of 458), and 97.7% (1013 of 1037) and 98.2% (1018 of 1037) and those on a per-aneurysm basis were 95.2% (677 of 711) and 95.4% (678 of 711), 96.6% (451 of 467) and 97.0% (454 of 468), and 95.8% (1128 of 1178) and 96.0% (1132 of 1179). The sensitivities of CT angiography were lower for detection of aneurysms smaller than 3 mm and unruptured compared with aneurysms that were 3-5 mm and ruptured (P < .001). No difference existed for the sensitivities of CT angiography for diagnosis of aneurysms in the anterior versus posterior circulation (P > .0167). Excellent or good interreader agreement was found for detection of intracranial aneurysms on a per-patient (kappa = 0.982) and per-aneurysm (kappa = 0.748) basis. Conclusion This large cohort study demonstrated that CT angiography had high accuracy for detection of small cerebral aneurysms, including those smaller than 3 mm. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28654350 TI - Use of Telehealth Videoconferencing in Pediatric Type 1 Diabetes in Oregon. AB - INTRODUCTION: We reviewed the impact of telehealth videoconferencing clinics on outcomes of care in pediatric patients with type 1 diabetes in rural Oregon. METHODS: We performed a chart review as well as the review of patient satisfaction questionnaires from 27 patients seen in the first year of the program. RESULTS: The number of yearly visits to diabetes clinic increased from average 1.5 to 2.7, which was statistically significant (p < 0.0001). Glycemic control remained stable, and there was no difference in the amount of emergency department visits or hospitalizations related to diabetes. Patients expressed high satisfaction with the service and majority considered it equal to in-person visits. CONCLUSION: We conclude that telehealth videoconferencing visits have the potential to improve care in pediatric diabetes patients, particularly the patients living in areas distant from subspecialty centers. PMID- 28654351 TI - ZZ/Z0: The New System of Sex Chromosomes in Eigenmannia aff. trilineata (Teleostei: Gymnotiformes: Sternopygidae) Characterized by Molecular Cytogenetics and DNA Barcoding. AB - The cytogenetic characteristics of Eigenmannia aff. trilineata were analyzed by basic and molecular cytogenetics, applying fluorescent in situ hybridization, with 18S and 5S rDNA and U2 snRNA probes. The species revealed a kind of polymorphism associated to ZZ/Z0 type sex chromosomes, with 2n = 32 (8m+2sm+22a, NF = 42) in all males under analysis, whereas females evidenced 2n = 31 (8m+1sm+22a, NF = 40). C-banding showed constitutive heterochromatin restricted to the pericentromeric region of all chromosomes and single-nucleolus organized regions on pair 11. A site for rDNA 5S was synthetic with a cluster of rDNA 18S near the centromere on the long arm of only one homologue of pair 11. Other clusters for 5S rDNA were sited on pairs 7, 10, 12, 13, and 16. Further, 5S rDNA was co-located with U2 cluster in the pericentromeric region of pair 12. Joint analysis of DNA barcoding from cytochrome c oxidase subunit I (COI) sequences, generated from the karyotyped samples of E. aff. trilineata, and sequences of other Gymnotiforms recognized E. aff. trilineata as an Operational Taxonomic Unit. Results foreground the hypothesis that cytotypes are independent evolution units as cryptic species with a low morphological differentiation level, although with high genetic/karyotype differentiation rates. PMID- 28654355 TI - A Prognostic Scoring Tool for Cesarean Organ/Space Surgical Site Infections: Derivation and Internal Validation. AB - BACKGROUND: Organ/space surgical site infections (SSIs) are serious complications after cesarean delivery. However, no scoring tool to predict these complications has yet been developed. This study sought to develop and validate a prognostic scoring tool for cesarean organ/space SSIs. METHODS: Data for case and non-case of cesarean organ/space SSI between January 1, 2007 and December 31, 2012 from a tertiary care hospital in Thailand were analyzed. Stepwise multivariable logistic regression was used to select the best predictor combination and their coefficients were transformed to a risk scoring tool. The likelihood ratio of positive for each risk category and the area under receiver operating characteristic (AUROC) curves were analyzed on total scores. Internal validation using bootstrap re-sampling was tested for reproducibility. RESULTS: The predictors of 243 organ/space SSIs from 4,988 eligible cesarean delivery cases comprised the presence of foul-smelling amniotic fluid (four points), vaginal examination five or more times before incision (two points), wound class III or greater (two points), being referred from local setting (two points), hemoglobin less than 11 g/dL (one point), and ethnic minorities (one point). The likelihood ratio of cesarean organ/space SSIs with 95% confidence interval among low (total score of 0-1 point), medium (total score of 2-5 points), and high risk (total score of >=6 points) categories were 0.11 (0.07-0.19), 1.03 (0.89-1.18), and 13.25 (10.87-16.14), respectively. Both AUROCs of the derivation and validation data were comparable (87.57% versus 86.08%; p = 0.418). CONCLUSIONS: This scoring tool showed a high predictive ability regarding cesarean organ/space SSIs on the derivation data and reproducibility was demonstrated on internal validation. It could assist practitioners prioritize patient care and management depending on risk category and decrease SSI rates in cesarean deliveries. PMID- 28654356 TI - Health, Wealth, and the U.S. Senate. PMID- 28654357 TI - Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An Italian collaborative study. AB - BACKGROUND: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. OBJECTIVE: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). METHODS: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ?2 cognitive domains. RESULTS: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS ( p = 0.03) compared with AOMS patients. CONCLUSION: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed. PMID- 28654358 TI - Predicting Motivation: Computational Models of PFC Can Explain Neural Coding of Motivation and Effort-based Decision-making in Health and Disease. AB - Human behavior is strongly driven by the pursuit of rewards. In daily life, however, benefits mostly come at a cost, often requiring that effort be exerted to obtain potential benefits. Medial PFC (MPFC) and dorsolateral PFC (DLPFC) are frequently implicated in the expectation of effortful control, showing increased activity as a function of predicted task difficulty. Such activity partially overlaps with expectation of reward and has been observed both during decision making and during task preparation. Recently, novel computational frameworks have been developed to explain activity in these regions during cognitive control, based on the principle of prediction and prediction error (predicted response outcome [PRO] model [Alexander, W. H., & Brown, J. W. Medial prefrontal cortex as an action-outcome predictor. Nature Neuroscience, 14, 1338-1344, 2011], hierarchical error representation [HER] model [Alexander, W. H., & Brown, J. W. Hierarchical error representation: A computational model of anterior cingulate and dorsolateral prefrontal cortex. Neural Computation, 27, 2354-2410, 2015]). Despite the broad explanatory power of these models, it is not clear whether they can also accommodate effects related to the expectation of effort observed in MPFC and DLPFC. Here, we propose a translation of these computational frameworks to the domain of effort-based behavior. First, we discuss how the PRO model, based on prediction error, can explain effort-related activity in MPFC, by reframing effort-based behavior in a predictive context. We propose that MPFC activity reflects monitoring of motivationally relevant variables (such as effort and reward), by coding expectations and discrepancies from such expectations. Moreover, we derive behavioral and neural model-based predictions for healthy controls and clinical populations with impairments of motivation. Second, we illustrate the possible translation to effort-based behavior of the HER model, an extended version of PRO model based on hierarchical error prediction, developed to explain MPFC-DLPFC interactions. We derive behavioral predictions that describe how effort and reward information is coded in PFC and how changing the configuration of such environmental information might affect decision-making and task performance involving motivation. PMID- 28654360 TI - Interhemispheric Binding of Ambiguous Visual Motion Is Associated with Changes in Beta Oscillatory Activity but Not with Gamma Range Synchrony. AB - In vision, perceptual features are processed in several regions distributed across the brain. Yet, the brain achieves a coherent perception of visual scenes and objects through integration of these features, which are encoded in spatially segregated brain areas. How the brain seamlessly achieves this accurate integration is currently unknown and is referred to as the "binding problem." Among the proposed mechanisms meant to resolve the binding problem, the binding by-synchrony hypothesis proposes that binding is carried out by the synchronization of distant neuronal assemblies. This study aimed at providing a critical test to the binding-by-synchrony hypothesis by evaluating long-range connectivity using EEG during a motion integration visual task that entails binding across hemispheres. Our results show that large-scale perceptual binding is not associated with long-range interhemispheric gamma synchrony. However, distinct perceptual interpretations were found to correlate with changes in beta power. Increased beta activity was observed during binding under ambiguous conditions and originates mainly from parietal regions. These findings reveal that the visual experience of binding can be identified by distinct signatures of oscillatory activity, regardless of long-range gamma synchrony, suggesting that such type of synchrony does not underlie perceptual binding. PMID- 28654359 TI - Differential Tuning of Ventral and Dorsal Streams during the Generation of Common and Uncommon Tool Uses. AB - Our use of tools is situated in different contexts. Prior evidence suggests that diverse regions within the ventral and dorsal streams represent information supporting common tool use. However, given the flexibility of object concepts, these regions may be tuned to different types of information when generating novel or uncommon uses of tools. To investigate this, we collected fMRI data from participants who reported common or uncommon tool uses in response to visually presented familiar objects. We performed a pattern dissimilarity analysis in which we correlated cortical patterns with behavioral measures of visual, action, and category information. The results showed that evoked cortical patterns within the dorsal tool use network reflected action and visual information to a greater extent in the uncommon use group, whereas evoked neural patterns within the ventral tool use network reflected categorical information more strongly in the common use group. These results reveal the flexibility of cortical representations of tool use and the situated nature of cortical representations more generally. PMID- 28654362 TI - Optimal Use of Adjuvant Bisphosphonates and Breast Cancer. PMID- 28654361 TI - Enhancing Spatial Attention and Working Memory in Younger and Older Adults. AB - Daily experiences demand both focused and broad allocation of attention for us to interact efficiently with our complex environments. Many types of attention have shown age-related decline, although there is also evidence that such deficits may be remediated with cognitive training. However, spatial attention abilities have shown inconsistent age-related differences, and the extent of potential enhancement of these abilities remains unknown. Here, we assessed spatial attention in both healthy younger and older adults and trained this ability in both age groups for 5 hr over the course of 2 weeks using a custom-made, computerized mobile training application. We compared training-related gains on a spatial attention assessment and spatial working memory task to age-matched controls who engaged in expectancy-matched, active placebo computerized training. Age-related declines in spatial attention abilities were observed regardless of task difficulty. Spatial attention training led to improved focused and distributed attention abilities as well as improved spatial working memory in both younger and older participants. No such improvements were observed in either of the age-matched control groups. Note that these findings were not a function of improvements in simple response time, as basic motoric function did not change after training. Furthermore, when using change in simple response time as a covariate, all findings remained significant. These results suggest that spatial attention training can lead to enhancements in spatial working memory regardless of age. PMID- 28654364 TI - Practical Implications of the 2016 Revision of the World Health Organization Classification of Lymphoid and Myeloid Neoplasms and Acute Leukemia. AB - A major revision of the WHO classification of lymphoid and myeloid neoplasms and acute leukemia was released in 2016. A key motivation for this update was to include new information available since the 2008 version with clinical relevance for the diagnosis, prognosis, and therapy of patients. With > 100 entities described, it is important for the clinician to understand features that may be important in daily practice, whereas researchers need to incorporate the new classification scheme into study development and analysis. In this review, we highlight the key aspects of the 2016 update with particular importance to routine patient care and clinical trial design. PMID- 28654363 TI - Low-Fat Dietary Pattern and Breast Cancer Mortality in the Women's Health Initiative Randomized Controlled Trial. AB - Purpose Earlier Women's Health Initiative Dietary Modification trial findings suggested that a low-fat eating pattern may reduce breast cancers with greater mortality. Therefore, as a primary outcome-related analysis from a randomized prevention trial, we examined the long-term influence of this intervention on deaths as a result of and after breast cancer during 8.5 years (median) of dietary intervention and cumulatively for all breast cancers diagnosed during 16.1 years (median) of follow-up. Patients and Methods The trial randomly assigned 48,835 postmenopausal women with normal mammograms and without prior breast cancer from 1993 to 1998 at 40 US clinical centers to a dietary intervention with goals of a reduction of fat intake to 20% of energy and an increased intake of fruits, vegetables, and grains (40%; n = 19,541) or to a usual diet comparison (60%; n = 29,294). Results In the dietary group, fat intake and body weight decreased (all P < .001). During the 8.5-year dietary intervention, with 1,764 incident breast cancers, fewer deaths occurred as a result of breast cancer in the dietary group, which was not statistically significant (27 deaths [0.016% per year] v 61 deaths [0.024% per year]; hazard ratio [HR], 0.67; 95% CI, 0.43 to 1.06; P = .08). During the same period, deaths after breast cancer (n = 134) were significantly reduced (40 deaths [0.025% per year] v 94 deaths [0.038% per year]; HR, 0.65; 95% CI, 0.45 to 0.94; P = .02) by the dietary intervention. During the 16.1-year follow-up, with 3,030 incident breast cancers, deaths after breast cancer also were significantly reduced (234 deaths [0.085% per year] v 443 deaths [0.11% per year]; HR, 0.82; 95% CI, 0.70 to 0.96; P = .01) in the dietary group. Conclusion Compared with a usual diet comparison group, a low-fat dietary pattern led to a lower incidence of deaths after breast cancer. PMID- 28654367 TI - Reply to T.J. Powles et al. PMID- 28654365 TI - Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials. AB - Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2 negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (>= 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women. PMID- 28654366 TI - Quantitative Assessment of Early [18F]Sodium Fluoride Positron Emission Tomography/Computed Tomography Response to Treatment in Men With Metastatic Prostate Cancer to Bone. AB - Purpose [18F]Sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) is a promising radiotracer for quantitative assessment of bone metastases. This study assesses changes in early NaF PET/CT response measures in metastatic prostate cancer for correlation to clinical outcomes. Patients and Methods Fifty-six patients with metastatic castration-resistant prostate cancer (mCRPC) with osseous metastases had NaF PET/CT scans performed at baseline and after three cycles of chemotherapy (n = 16) or androgen receptor pathway inhibitors (n = 40). A novel technology, Quantitative Total Bone Imaging, was used for analysis. Global imaging metrics, including maximum standardized uptake value (SUVmax) and total functional burden (SUVtotal), were extracted from composite lesion-level statistics for each patient and tracked throughout treatment. Progression-free survival (PFS) was calculated as a composite end point of progressive events using conventional imaging and/or physician discretion of clinical benefit; NaF imaging was not used for clinical evaluation. Cox proportional hazards regression analyses were conducted between imaging metrics and PFS. Results Functional burden (SUVtotal) assessed midtreatment was the strongest univariable PFS predictor (hazard ratio, 1.97; 95% CI, 1.44 to 2.71; P < .001). Classification of patients based on changes in functional burden showed stronger correlation to PFS than did the change in number of lesions. Various global imaging metrics outperformed baseline clinical markers in predicting outcome, including SUVtotal and SUVmean. No differences in imaging response or PFS correlates were found for different treatment cohorts. Conclusion Quantitative total bone imaging enables comprehensive disease quantification on NaF PET/CT imaging, showing strong correlation to clinical outcomes. Total functional burden assessed after three cycles of hormonal therapy or chemotherapy was predictive of PFS for men with mCRPC. This supports ongoing development of NaF PET/CT-based imaging biomarkers in mCRPC to bone. PMID- 28654368 TI - Evaluation of Carbapenem Resistance Mechanisms and Its Association with Pseudomonas aeruginosa Infections in the Northwest of Iran. AB - The aims of this study were to determine carbapenem resistance mechanisms, molecular epidemiological relationship, clinical impact, and patient outcome of carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections. A total of 42 nonduplicated CRPA were recovered from Urmia, Iran. Antimicrobial susceptibility tests were carried out using phenotypic methods. The carbapenem resistance mechanisms such as carbapenemase genes, efflux pump hyperexpression, AmpC overproduction, and OprD gene downregulation were determined by phenotypic and molecular methods. Eighteen metallo-beta-lactamase (MBL) producer isolates were found to be sensitive to amikacin. Among the CRPA, 52.3%, 26.1%, 26.1%, and 59.5% were identified as carbapenemase, efflux pump hyperexpression, AmpC overproduction, and reduced expression OprD gene, respectively. Random Amplified Polymorphic DNA analysis yielded 25 distinct profiles. Most MBL-positive isolates were recovered from patients hospitalized in urology and internal wards with urinary tract infections. Most of the strains showed downregulation of porin. The clonal distribution of the strains was related to carbapenem resistance mechanisms (most of MBL producers belong to the same clones) and the same hospital wards where the isolates were collected. The study demonstrates that the main risk factor of MBL-related infections was hospitalization in non-intensive wards. Amikacin was considered a very efficient antibiotic to treatment of MBL producing CRPA isolates. Our results showed that OprD downregulation and IMP-type MBL are the main carbapenem resistance mechanisms in CRPA isolates from northwest of Iran. PMID- 28654369 TI - Gymnotus coatesi (Gymnotiformes): A Case of Colocation of Multiple Sites of 18S rDNA with Telomeric Sequences. AB - Gymnotus coatesi is a small and rare species of banded knife fish that was originally described by LaMonte in 1935, found along the main stretch of the Amazon River. There is no described cytogenetic data on this species. We analyzed the karyotype of five specimens of G. coatesi collected from Cururutuia Stream in Braganca, Para, Brazil. The obtained diploid number is 50 and the karyotypic formula is 24 m/sm +26 st/a. The constitutive heterochromatin is DAPI positive and distributed mainly in the centromeric and pericentromeric regions of the chromosomes. Ag-nucleolus organizer regions staining showed nine active sites. The 5S rDNA probe hybridized chromosome pair 17 in the interstitial part of the long arm. Fluorescence in situ hybridization (FISH) with telomeric probes revealed signals only at terminal regions of the chromosomes. The 18S rDNA probe hybridized to 21 sites, and these signals colocalized with the telomeric sequences. This relatively high number of 18S rDNA sites may reflect gene duplication mediated by transposable elements. These results indicate that although the diploid number of G. coatesi is within the range previously observed for other members of the genus, various karyotypic characteristics distinguish G. coatesi from the other species of the genus and members of the Gymnotiform order. PMID- 28654374 TI - Severe Fever with Thrombocytopenia Syndrome Virus Infection in Minks in China. AB - We analyzed the seroprevalence of tick-borne severe fever with thrombocytopenia syndrome virus (SFTSV) in farm-raised minks using double antigen ELISA (enzyme linked immunosorbent assay) kit and indicated that 8.4% (15/178) of the minks had antibodies to the nucleoprotein of SFTSV and 72.7% (8/11) of mink farms had minks positive to SFTSV. The ELISA results were further confirmed by presence of neutralization to SFTSV in the mink sera. Our results suggested that minks were widely infected with SFTSV in China. PMID- 28654375 TI - Re: Effect of the endOclear(r) Device on Biofilm in Endotracheal Tubes. PMID- 28654376 TI - Preclinical Evaluation of 18F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors. AB - PURPOSE: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. PROCEDURES: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. RESULTS: Treated mice demonstrated increased 18F ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. CONCLUSION: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment. PMID- 28654377 TI - Image-Based Analysis of Tumor Localization After Intra-Arterial Delivery of Technetium-99m-Labeled SPIO Using SPECT/CT and MRI. AB - The aim of this study is to evaluate the localization of 99mTc-labeled dextran coated superparamagnetic iron oxide (SPIO) nanoparticles to the liver tumor using image-based analysis. We delivered 99mTc-SPIO intravenously or intra-arterially (IA) with/without Lipiodol to compare the tumor localization by gamma scintigraphy, single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) in a rabbit liver tumor. The gamma and SPECT image-based analysis shows that the uptake ratio of the tumor to the normal liver parenchyma is highest after delivery of 99mTc-SPIO with Lipiodol IA and that well correlates with the trend of the signal decrease in the liver MRIs. Intra-arterial delivery of SPIO with Lipiodol might be a good drug delivery system targeting the hepatic tumors, as confirmed by image-based analysis. PMID- 28654378 TI - PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury. AB - Sphingosine-1-phosphate receptor (S1PR) activation plays a key role in vascular inflammatory response. Here, we report in vivo validation of [11C]TZ3321, a potent S1PR1 radioligand, for imaging vascular inflammation in a rat model of carotid injury. The right common carotid artery of male adult Sprague-Dawley rats was injured by balloon overinflation that denuded the endothelium and distended the vessel wall. Animals received a 60-minute micro-positron emission tomography (micro PET) scan with [11C]TZ3321 at 72 hours after injury. Ex vivo autoradiography was also conducted. The expression and cellular location of S1PR1 were examined by immunohistological analysis. Three-dimensional (3D) reconstruction of the first 100-second microPET/computed tomography (CT) image indicated the location of bilateral common carotid arteries. [11C]TZ3321 displayed significantly higher accumulation (standardized uptake values: 0.93 +/- 0.07 vs 0.78 +/- 0.09, n = 6, P = .001) in the injured carotid artery than in the contralateral side. Increased tracer uptake in the injured artery was confirmed by autoradiography (photostimulated luminescence measures: 85.5 +/- 0.93 vs 71.48 +/- 6.22, n = 2). Concordantly, high S1PR1expression was observed in infiltrated inflammatory cells in the injured artery. Our studies demonstrate [11C]TZ3321 microPET is able to detect the acute upregulation of S1PR1 expression in inflamed carotid artery. Therefore, [11C]TZ3321 has potential to be a PET radiotracer for detecting early inflammatory response and monitoring therapeutic efficacy of vascular inflammation. PMID- 28654379 TI - Multimodal Imaging of Patients With Gliomas Confirms 11C-MET PET as a Complementary Marker to MRI for Noninvasive Tumor Grading and Intraindividual Follow-Up After Therapy. AB - The value of combined L-( methyl-[11C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n = 65 patients with histologically verified brain lesions n = 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2 weighted [FLAIR/T2w]) examinations were performed. The computer software "visualization and analysis framework volume rendering engine (Voreen)" was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined by MET-PET (21.6 +/- 36.8 cm3), T1w-Gd-MRI (3.9 +/- 7.8 cm3), and FLAIR/T2-MRI (64.8 +/- 60.4 cm3; P < .001). The MET-PET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8 +/- 35.0 cm3 and without changes in FLAIR/T2 10.3 +/- 25.7 cm3. FLAIR/T2-MRI visualized greatest tumor extent with differences to MET-PET being greater in posttherapy (64.6 +/- 62.7 cm3) than in newly diagnosed patients (20.5 +/- 52.6 cm3). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n = 10 from other gliomas n = 16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management. PMID- 28654380 TI - Targeted Imaging of Tumor-Associated Macrophages by Cyanine 7-Labeled Mannose in Xenograft Tumors. AB - Mannose receptor is considered as a hallmark of M2-oriented tumor-associated macrophages (TAMs), but its utility in TAMs was rarely reported. Therefore, deoxymannose (DM), a high-affinity ligand of mannose receptor, was labeled with near-infrared dye cyanine 7 (Cy7), and its feasibility of targeted imaging on TAMs was evaluated in vitro and in vivo. The Cy7-DM was synthesized, and its binding affinity with induced TAMs in vitro, whole-body imaging in xenograft tumor mouse model in vivo, and the cellular localization in dissected tissues were evaluated. We demonstrated a high uptake of Cy7-DM by induced M2 macrophages and TAMs in tumor tissues. In vivo near-infrared live imaging visualized abundant TAMs in tumor lesions instead of inflammatory sites by Cy7-DM imaging, and the quantity of Cy7-DM signals in tumors was significantly higher than that shown in inflammatory sites from 1 to 8 hours of imaging. Our results suggest that mannose could rapidly and specifically target TAMs and is a promising candidate for targeted diagnosis of tumor with rich TAMs. PMID- 28654381 TI - Preclinical Multimodal Molecular Imaging Using 18F-FDG PET/CT and MRI in a Phase I Study of a Knee Osteoarthritis in In Vivo Canine Model. AB - The aim of this study was to use a multimodal molecular imaging approach to serially assess regional metabolic changes in the knee in an in vivo anterior cruciate ligament transection (ACLT) canine model of osteoarthritis (OA). Five canine underwent ACLT in one knee and the contralateral knee served as uninjured control. Prior, 3, 6, and 12 weeks post-ACLT, the dogs underwent 18F-fluoro-d glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The MRI was coregistered with the PET/CT, and 3 dimensional regions of interest (ROIs) were traced manually and maximum standardized uptake values (SUVmax) were evaluated. 18F-fluoro-d-glucose SUVmax in the ACLT knee ROIs was significantly higher compared to the uninjured contralateral knees at 3, 6, and 12 weeks. Higher 18F-FDG uptake observed in ACLT knees compared to the uninjured knees reflects greater metabolic changes in the injured knees over time. Knee 18F-FDG uptake in an in vivo ACLT canine model using combined PET/CT and MRI demonstrated to be highly sensitive in the detection of metabolic alterations in osseous and nonosteochondral structures comprising the knee joint. 18F-fluoro-d-glucose appeared to be a capable potential imaging biomarker for early human knee OA diagnosis, prognosis, and management. PMID- 28654382 TI - Imaging of Myocardial Ischemia-Reperfusion Injury Using Sodium [18F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans. AB - Positron emission tomography (PET)/computed tomography (CT) using sodium [18F]fluoride (Na[18F]F) has been proven to be a promising hot-spot imaging modality for myocardial infarction (MI). We investigated Na[18F]F uptake in ischemia-reperfusion injury (IRI) of rats and humans. Sodium [18F]fluoride PET/CT was performed in Sprague-Dawley rats that had IRI surgery, and it readily demonstrated prominent Na[18F]F uptake in the infarct area post-IRI. Sodium [18F]fluoride uptake was matched with negative 2,3,5-triphenyl-2 H-tetrazolium chloride staining results, accompanied by myocardial apoptosis and associated with positive calcium staining results. Furthermore, area at risk was negative for Na[18F]F uptake. Cyclosporine A (CysA) treatment reduced standardized uptake value of 18F over the infarct area, and a significant decrease in infarct size was also observed by the CysA treatment. In humans, Na[18F]F PET/CT readily demonstrated increased Na[18F]F uptake in the 2 patients with MI post percutaneous coronary intervention. In conclusion, this study sheds light on the potential utility of Na[18F]F PET/CT as a hot-spot imaging modality for myocardial IRI. PMID- 28654383 TI - Brain and Brown Adipose Tissue Metabolism in Transgenic Tg2576 Mice Models of Alzheimer Disease Assessed Using 18F-FDG PET Imaging. AB - OBJECTIVE: Imaging animal models of Alzheimer disease (AD) is useful for the development of therapeutic drugs and understanding AD. Transgenic Swedish hAPPswe Tg2576 mice are a good model of beta-amyloid plaques. We report 18F-fluoro-2 deoxyglucose (18F-FDG) positron emission tomography (PET) imaging of brain and intrascapular brown adipose tissue (IBAT) in transgenic mice 2576 (Tg2576) and wild-type (WT) mice. METHODS: Transgenic Tg2576 mice and WT mice, >18 months were injected intraperitonally with ~ 25 to 30 MBq 18F-FDG while awake. After 60 minutes, they were anesthetized with isoflurane (2.5%) and imaged with Inveon MicroPET. Select mice were killed, imaged ex vivo, and 20 um sections cut for autoradiography. 18F-FDG uptake in brain and IBAT PET and brain autoradiographs were analyzed. RESULTS: Fasting blood glucose levels averaged 120 mg/dL for WT and 100 mg/dL for Tg2576. Compared to WT, Tg2576 mice exhibited a decrease in SUVglc in the various brain regions. Average reductions in the cerebrum regions were as high as -20%, while changes in cerebellum were -3%. Uptake of 18F-FDG in IBAT decreased by -60% in Tg2576 mice and was found to be significant. Intrascapular brown adipose tissue findings in Tg2576 mice are new and not previously reported. Use of blood glucose for PET data analysis and corpus callosum as reference region for autoradiographic analysis were important to detect change in Tg2576 mice. CONCLUSION: Our results suggest that 18F-FDG uptake in the Tg2576 mice brain show 18F-FDG deficits only when blood glucose is taken into consideration. PMID- 28654384 TI - Fluorescent, Plasmonic, and Radiotherapeutic Properties of the 177Lu-Dendrimer AuNP-Folate-Bombesin Nanoprobe Located Inside Cancer Cells. AB - The integration of fluorescence and plasmonic properties into one molecule is of importance in developing multifunctional imaging and therapy nanoprobes. The aim of this research was to evaluate the fluorescent properties and the plasmonic photothermal, therapeutic, and radiotherapeutic potential of 177Lu-dendrimer conjugated to folate and bombesin with gold nanoparticles in the dendritic cavity (177Lu-DenAuNP-folate-bombesin) when it is internalized in T47D breast cancer cells. The intense near-Infrared (NIR) fluorescence emitted at 825 nm from the conjugate inside cells corroborated the usefulness of DenAuNP-folate-bombesin for optical imaging. After laser irradiation, the presence of the nanosystem in cells caused a significant increase in the temperature of the medium (46.8 degrees C, compared to 39.1 degrees C without DenAuNP-folate-bombesin, P < 0.05), resulting in a significant decrease in cell viability (down to 16.51% +/- 1.52%) due to the 177Lu-DenAuNP-folate-bombesin plasmonic properties. After treatment with 177Lu DenAuNP-folate-bombesin, the T47D cell viability decreased 90% because of the radiation-absorbed dose (63.16 +/- 4.20 Gy) delivered inside the cells. The 177Lu DenAuNP-folate-bombesin nanoprobe internalized in cancer cells exhibited properties suitable for optical imaging, plasmonic-photothermal therapy, and targeted radiotherapy. PMID- 28654385 TI - 3D Fusion Framework for Infarction and Angiogenesis Analysis in a Myocardial Infarct Minipig Model. AB - The combination of different modality images can provide detailed and comprehensive information for the prognostic assessment and therapeutic strategy of patients with ischemic heart disease. In this study, a 3D fusion framework is designed to integrate coronary computed tomography (CT) angiography (CTA), 2 deoxy-2-[18F]fluoro-D-glucose ([18F]DG) positron emission tomography (PET)/CT, and [68Ga]-1,4,7-triazacyclononane-1,4,7-triacetic acid-(Arg-Gly-Asp)2 ([68Ga] NOTA-PRGD2) PET/CT images of the myocardial infarction model in minipigs. First, the structural anatomy of the heart in coronary CTA and CT is segmented using a multi-atlas-based method. Then, the hearts are registered using the B-spline based free form deformation. Finally, the [18F]DG and [68Ga]-NOTA-PRGD2 signals are mapped into the heart in coronary CTA, which produces a single fusion image to delineate both the cardiac structural anatomy and the functional information of myocardial viability and angiogenesis. Heart segmentation demonstrates high accuracy with good agreement between manual delineation and automatic segmentation. The fusion result intuitively reflects the extent of the [18F]DG uptake defect as well as the location where the [68Ga]-NOTA-PRGD2 signal appears. The fusion result verified the occurrence of angiogenesis based on the in vivo noninvasive molecular imaging approach. The presented framework is helpful in facilitating the study of the relationship between infarct territories and blocked coronary arteries as well as angiogenesis. PMID- 28654386 TI - Dual-Energy SPECT and the Development of Peptide p5+14 for Imaging Amyloidosis. AB - Amyloidosis is associated with a number of rare diseases and is characterized by the deposition, in abdominothoracic organs and peripheral nerves, of extracellular protein fibrils, which leads to dysfunction and severe morbidity. Effective clinical evaluation and management of patients with systemic amyloidosis are hampered by the lack of a noninvasive, quantitative method for detecting whole-body amyloid load. We have used a battery of assays including dual-energy SPECT imaging and comparative effectiveness studies in support of translation of a synthetic polybasic peptide, p5+14, as a novel radiotracer for visualization of amyloidosis by molecular imaging. These data provide support for a phase 1 positron emission tomography/computed tomography imaging trial of this reagent, labeled with iodine-124, in patients with all forms of systemic amyloidosis. PMID- 28654388 TI - Commentary on "A Microfluidic Platform to Design Crosslinked Hyaluronic Acid Nanoparticles (cHANPs) for Enhanced MRI". AB - Strategies to enhance the relaxometric properties of gadolinium (Gd)-based contrast agents (CAs) for magnetic resonance imaging (MRI), without the chemical modification of chelates, have recently had a strong impact on the diagnostic field. We have taken advantage of the interaction between Gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) and the hydrogel structure of hyaluronic acid to design cross-linked hyaluronic acid nanoparticles down to 35 nm for use in MRI applications. The proposed bioformulations enable the control of the relaxometric properties of CAs, thus boosting the relaxation rate of T1. Our results led us to identify this approach as an adjustable scenario to design intravascularly injectable hydrogel nanoparticles entrapping Gd-DTPA. This approach overcomes the general drawbacks of clinically approved CAs having poor relaxivity and toxic effects. PMID- 28654410 TI - Audiologic Assessment in Adults With Down Syndrome. AB - Increased life expectancy in persons with Down syndrome (DS) is associated with premature age-related changes. The aim of this study was to assess auditory function in adults with DS and to evaluate the prevalence of hearing loss in this population. Audiometric tests were performed in 72 adults with DS (mean age 37.3+/-10.1 years, 51.4% females). Air conduction pure tone average (PTA) thresholds at frequencies 0.5-1-2-4 kHz were calculated to assess hearing function. Hearing loss was present if the PTA threshold was > 20 dB hearing level. Higher frequencies of 4 and 8 kHz were also assessed. Hearing loss was shown in 47 (65.3%) participants. The prevalence of hearing loss increased with age, ranging from 42.86% in the 20-29 years group to 90.91% in the 50-59 years group. High frequencies (4 and 8 kHz) were more often impaired than other frequencies used to measure PTA. Thus, the study concluded hearing loss is common in adults with DS and shows a pattern compatible with precocious aging of the hearing system. Auditory evaluation is strongly recommended in adults with DS. PMID- 28654387 TI - Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential. AB - Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood-brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors. PMID- 28654412 TI - Resumenes al Espanol. PMID- 28654411 TI - A Multi-Method Investigation of Pragmatic Development in Individuals With Down Syndrome. AB - This longitudinal study examined pragmatic language in boys and girls with Down syndrome (DS) at up to three time points, using parent report, standardized and direct assessments. We also explored relationships among theory of mind, executive function, nonverbal mental age, receptive and expressive vocabulary, grammatical complexity, and pragmatic competence. Controlling for cognitive and language abilities, children with DS demonstrated greater difficulty than younger typically developing controls on parent report and standardized assessments, but only girls with DS differed on direct assessments. Further, pragmatic skills of individuals with DS developed at a delayed rate relative to controls. Some sex specific patterns of pragmatic impairments emerged. Theory of mind and executive function both correlated with pragmatic competence. Clinical and theoretical implications are discussed. PMID- 28654413 TI - Introduction to the Special Issue on the Development of People With Down Syndrome Throughout the Lifespan (Part 2). PMID- 28654414 TI - Handwriting in Children and Adults With Down Syndrome: Developmental Delay or Specific Features? AB - While there is a long history and tradition of behavioral research on basic motor skills in Down syndrome (DS), there has been only limited research on handwriting ability. We analyzed the spatiotemporal features of handwriting produced by children and adults with DS (n = 24), and compared their productions with those of comparison groups matched for developmental (n = 24) or chronological (n = 24) age. Results indicated that the participants with DS performed an alphabet letter writing task just as efficiently as the children of the same developmental age, in terms of the length, duration and speed of their handwriting, and the number and duration of their pauses. Our study highlights a substantial delay in the stages of writing acquisition. PMID- 28654415 TI - Resumes en Francais. PMID- 28654416 TI - The Evaluation of a Personal Narrative Language Intervention for School-Age Children With Down Syndrome. AB - The purpose of this study was to evaluate the feasibility of an intervention focused on improving personal narrative skills of school-age children with Down syndrome (DS) using an approach involving visual supports. Four females with DS, ages 10 through 15 years, participated in this multiple baseline across participants single-subject experimental design study. Participants completed 18 intervention sessions that targeted personal narrative goals. Parents completed a survey regarding their perspectives of the intervention. Two participants made small treatment gains in mean length of utterance. One participant had small to medium gains on all macrostructural measures. Parent perspectives were positive. Results support the feasibility of personal narrative interventions for individuals with DS when visual support is provided. PMID- 28654417 TI - Imaging Bone-Cartilage Interactions in Osteoarthritis Using [18F]-NaF PET-MRI. AB - PURPOSE: Simultaneous positron emission tomography-magnetic resonance imaging (PET-MRI) is an emerging technology providing both anatomical and functional images without increasing the scan time. Compared to the traditional PET/computed tomography imaging, it also exposes the patient to significantly less radiation and provides better anatomical images as MRI provides superior soft tissue characterization. Using PET-MRI, we aim to study interactions between cartilage composition and bone function simultaneously, in knee osteoarthritis (OA). PROCEDURES: In this article, bone turnover and remodeling was studied using [18F] sodium fluoride (NaF) PET data. Quantitative MR-derived T1rho relaxation times characterized the biochemical cartilage degeneration. Sixteen participants with early signs of OA of the knee received intravenous injections of [18F]-NaF at the onset of PET-MR image acquisition. Regions of interest were identified, and kinetic analysis of dynamic PET data provided the rate of uptake ( Ki) and the normalized uptake (standardized uptake value) of [18F]-NaF in the bone. Morphological MR images and quantitative voxel-based T1rho maps of cartilage were obtained using an atlas-based registration technique to segment cartilage automatically. Voxel-by-voxel statistical parameter mapping was used to investigate the relationship between bone and cartilage. RESULTS: Increases in cartilage T1rho, indicating degenerative changes, were associated with increased turnover in the adjoining bone but reduced turnover in the nonadjoining compartments. Associations between pain and increased bone uptake were seen in the absence of morphological lesions in cartilage, but the relationship was reversed in the presence of incident cartilage lesions. CONCLUSION: This study shows significant cartilage and bone interactions in OA of the knee joint using simultaneous [18F]-NaF PET-MR, the first in human study. These observations highlight the complex biomechanical and biochemical interactions in the whole knee joint in OA, which potentially could help assess therapeutic targets in treating OA. PMID- 28654418 TI - A New Bat-HKU2-like Coronavirus in Swine, China, 2017. AB - We identified from suckling piglets with diarrhea in China a new bat-HKU2-like porcine coronavirus (porcine enteric alphacoronavirus). The GDS04 strain of this coronavirus shares high aa identities (>90%) with the reported bat-HKU2 strains in Coronaviridae-wide conserved domains, suggesting that the GDS04 strain belongs to the same species as HKU2. PMID- 28654420 TI - Lineage commitment of embryonic cells involves MEK1-dependent clearance of pluripotency regulator Ventx2. AB - During early embryogenesis, cells must exit pluripotency and commit to multiple lineages in all germ-layers. How this transition is operated in vivo is poorly understood. Here, we report that MEK1 and the Nanog-related transcription factor Ventx2 coordinate this transition. MEK1 was required to make Xenopus pluripotent cells competent to respond to all cell fate inducers tested. Importantly, MEK1 activity was necessary to clear the pluripotency protein Ventx2 at the onset of gastrulation. Thus, concomitant MEK1 and Ventx2 knockdown restored the competence of embryonic cells to differentiate. Strikingly, MEK1 appeared to control the asymmetric inheritance of Ventx2 protein following cell division. Consistently, when Ventx2 lacked a functional PEST-destruction motif, it was stabilized, displayed symmetric distribution during cell division and could efficiently maintain pluripotency gene expression over time. We suggest that asymmetric clearance of pluripotency regulators may represent an important mechanism to ensure the progressive assembly of primitive embryonic tissues. PMID- 28654421 TI - Correction: TRAF2 regulates TNF and NF-kappaB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. PMID- 28654419 TI - Affimer proteins are versatile and renewable affinity reagents. AB - Molecular recognition reagents are key tools for understanding biological processes and are used universally by scientists to study protein expression, localisation and interactions. Antibodies remain the most widely used of such reagents and many show excellent performance, although some are poorly characterised or have stability or batch variability issues, supporting the use of alternative binding proteins as complementary reagents for many applications. Here we report on the use of Affimer proteins as research reagents. We selected 12 diverse molecular targets for Affimer selection to exemplify their use in common molecular and cellular applications including the (a) selection against various target molecules; (b) modulation of protein function in vitro and in vivo; (c) labelling of tumour antigens in mouse models; and (d) use in affinity fluorescence and super-resolution microscopy. This work shows that Affimer proteins, as is the case for other alternative binding scaffolds, represent complementary affinity reagents to antibodies for various molecular and cell biology applications. PMID- 28654423 TI - Daily wrist activity classification using a smart band. AB - OBJECTIVE: In this letter, we propose a novel method for classifying daily wrist activities by using a smart band. APPROACH: Triaxial acceleration data are collected by built-in sensors of the smart band during experiments regarding five activities, i.e. texting, calling, placing a hand in a pocket, carrying a suitcase, and swinging a hand. We analyze patterns in the sensor signals during these activities based on three types of features, i.e. norm, norm-variance, and frequency-domain features. After extracting the significant features, a multi class support vector machine algorithm is applied to classify these activities. MAIN RESULTS: We obtained recognition error rates of approximately 2.7% by applying the proposed method to the experimental dataset. PMID- 28654422 TI - PARP1 expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma. AB - Overexpression of PARP1 exists in various cancers, including glioblastoma (GBM). Although PARP1 inhibition is a promising therapeutic target, no comprehensive study has addressed PARP1's expression characteristics and prognostic role regarding molecular heterogeneity in astrocytomas including GBM. Our aim was to evaluate PARP1's associations with survival, WHO grade, lineage specific markers, and GBM transcriptomic subtypes. We collected genomic and clinical data from the latest glioma datasets of The Cancer Genome Atlas and performed PARP1, ATRX, IDH1, and p53 immunohistochemistry on GBM tissue samples. We demonstrated that PARP1 gain and increased mRNA expression are characteristics of high-grade astrocytomas, particularly of Proneural and Classical GBM subtypes. Additionally, higher PARP1 levels exhibited an inverse correlation with patient survival (p<0.005) in the Classical subgroup. ATRX (p=0.006), and TP53 (p=0.015) mutations were associated with increased PARP1 expression and PARP1 protein level correlated with ATRX loss and p53 overexpression. Furthermore, higher PARP1 expression together with wildtype TP53 indicated shorter survival (p=0.039). Therefore, due to subtype specificity, PARP1 expression level and TP53 mutation status are reliable marker candidates to distinguish Proneural and Classical subtypes, with prognostic and therapeutic implications in GBM. PMID- 28654424 TI - Earliest English Definitions of Anaisthesia and Anaesthesia. AB - The earliest identified English definition of the word anaisthesia was discovered in the first edition (1684) of A Physical Dictionary, an English translation of Steven Blankaart's medical dictionary, Lexicon Medicum Graeco-Latinum. This definition was almost certainly the source of the definition of anaesthesia which appeared in Dictionarium Anglo-Britannicum (1708), a general-purpose English dictionary compiled by the lexicographer John Kersey. The words anaisthesia and anaesthesia have not been identified in English medical or surgical publications that antedate the earliest English dictionaries in which they are known to have been defined. PMID- 28654425 TI - Association between gene polymorphisms and clinical features in idiopathic thrombocytopenic purpura patients. AB - : Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which increased platelet destruction and thrombocytopenia are diagnostic features. In fact, the exact pathogenesis of this disease is still unknown, but genetic changes can be a potential factor in the development of ITP. In this study, the relationship between polymorphisms with platelet destruction has been studied, which leads to decreased platelet count. Relevant literature was identified by a PubMed search (2000-2016) of English language papers using the terms 'ITP', 'polymorphism,' and 'immune system'. The majority of genetic changes (polymorphisms) occur in immune system genes, including interferon (IFN)-gamma gene. These changes lead to the dysfunction of immune system and production of pathogenic antibodies against platelet surface glycoproteins such as glycoprotein IIb/IIIa, which eventually result in the destruction of platelets and increasing disease severity. In addition, IFN-gamma as well as factors and cytokines involved in megakaryopoiesis, including stem cell factor and interleukin-3 (IL 3), leads to the differentiation of megakaryocytes and platelet release. Considering the fact that IFN-gamma is a factor of inflammation and thrombocytopenia, coexistence of this cytokine with thrombopoietin, stem cell factor, and IL-3 results in megakaryocytes differentiation and platelet production, which can be effective to reduce disease severity and increase the platelet counts. PMID- 28654427 TI - DICER1 Mutations Are Consistently Present in Moderately and Poorly Differentiated Sertoli-Leydig Cell Tumors. AB - Ovarian Sertoli-Leydig cell tumors (SLCTs) are uncommon sex cord-stromal tumors associated with both germ-line and somatic DICER1 mutations, the frequency of which has varied widely in different studies (0% to 62.5%). The current World Health Organization Classification includes 3 histologic types of SLCTs (well differentiated, moderately differentiated, and poorly differentiated); heterologous elements and/or retiform patterns may be present in moderately and poorly differentiated neoplasms. We investigated the frequency of DICER1 mutations in a series of 38 ovarian tumors initially diagnosed as SLCTs, and explored whether identified mutations were associated with specific morphologic features. Specialist pathology review performed blinded to molecular results confirmed 34 tumors to be SLCTs (22 moderately differentiated, 8 poorly differentiated; 4 well-differentiated), while the remaining 4 neoplasms were considered not to represent SLCTs. Of the 34 cases diagnosed as SLCTs, 30 (88%) harbored >=1 DICER1 mutation. All 30 moderately differentiated/poorly differentiated SLCTs contained mutations, but we did not find deleterious DICER1 mutations in the 4 well-differentiated SLCTs. Our study reports the highest DICER1 mutation frequency to date in SLCTs, with 100% of moderately differentiated and poorly differentiated tumors being DICER1-mutated. This suggests that DICER1 mutation may be a defining feature of these neoplasms. Although the number of cases is limited, well-differentiated SLCTs appear to be DICER1-independent. Moderately differentiated and poorly differentiated SLCT components often coexist with each other and form part of a spectrum, while well differentiated SLCTs usually occur in pure form, suggesting that fundamentally, these represent 2 separate and independent tumor types with a different pathogenesis. We suggest that all patients with ovarian SLCTs undergo germ-line DICER1 mutation testing. PMID- 28654426 TI - Use of three procoagulants in improving bleeding outcomes in the warfarin patient with intracranial hemorrhage. AB - : When patients on anticoagulation present with intracranial bleeding, stopping the bleeding is paramount. Despite the availability of multiple options to reverse anticoagulation, no study has directly compared the effectiveness of the procoagulants recombinant activated factor VII (rFVIIa), the rFVIIa and 3-factor prothrombin complex concentrate (PCC) combination, and 4-factor PCC on improving patient outcomes compared with a control. This study examined the medical records of 197 warfarin patients with intracranial hemorrhage, an initial international normalized ratio (INR) greater than 1.5, and who received rFVIIa (26), the combination (84), 4-PCC (50), or no procoagulant, the control group (37). Mortality, length of stay, location discharged, change in INR prior to and postdrug administration, plasma use, and number of thromboembolic complications were used to assess effectiveness. Although INR decreased in all groups (1.31 rFVIIa vs. 2.04 combination vs. 1.41 4-PCC vs. 1.20 control, P = 0.07), the combination group had the greatest percentage to reach an INR of less than 1.3 (46.2 vs. 73.8 vs. 58.0 vs. 43.2%, P = 0.004). The combination and control groups experienced a high, though nonsignificant, number of thromboembolic complications (5.6 vs. 19.0 vs. 7.7 vs. 12.9%, P = 0.533). The rFVIIa group used the most plasma and had the longest length of stay. Mortality did not differ significantly among groups. Although the combination improved INR compared with control, this had a high number of complications. Judicious use of procoagulants is recommended due to their expense and lack of significant improvement in outcomes compared with control. PMID- 28654428 TI - Residual Pure Intralymphatic Breast Carcinoma Following Neoadjuvant Chemotherapy Is Indicative of Poor Clinical Outcome, Even in Node-Negative Patients. AB - Residual carcinoma confined to lymphovascular spaces following neoadjuvant chemotherapy (NAC) for invasive breast carcinoma is an uncommon finding. We studied pathologic features and outcome for patients with pure intralymphatic carcinoma (PIC) following NAC, a pattern of residual disease reported to have a poor outcome in the only previously published series of this entity. Six of 284 (2.1%) patients treated with NAC were studied. All 6 patients had axillary lymph node involvement before NAC. Tumors were triple-negative (n=3) and HER2+ (n=3: 2 ER+, 1 ER-). Two patients presented with clinical findings of inflammatory carcinoma. Three of 5 pre-NAC core biopsies showed lymphovascular invasion. Three patients showed complete clinical response to NAC, and 3 showed partial response. Post-NAC surgical specimens showed foci of intralymphatic carcinoma in the breast spanning an extent of 0.5 mm to 0.5 cm. Residual ductal carcinoma in situ was present in 2 cases. Four of 6 patients converted to node-negative following NAC. One patient had distant metastasis at presentation and 1 patient died of pulmonary embolism 2 months after surgery. Three of the 4 remaining patients developed distant metastasis, of which 2 first recurred locally (in mean follow up of 46.5 mo). Patients with PIC had significant greater risk for relapse (hazard ratio, 10.18 [1.97, 52.58]; P=0.006) compared with other NAC-treated patients, after controlling for residual lymph node involvement, tumor size, tumor subtype, histologic grade, and age. Residual PIC following NAC is associated with poor outcome, including in patients that are node-negative following NAC. PMID- 28654429 TI - Quadratus Lumborum Spares Paravertebral Space in Fresh Cadaver Injection. PMID- 28654430 TI - To the Editor. PMID- 28654431 TI - In Response. PMID- 28654432 TI - In Response. PMID- 28654433 TI - To the Editor. PMID- 28654434 TI - In Response. PMID- 28654435 TI - Myasthenia gravis: new developments in research and treatment. AB - PURPOSE OF REVIEW: Myasthenia gravis, a rare disorder of the neuromuscular transmission, is increasingly acknowledged as a syndrome more than as a single disease. This review summarizes recent advances in pathophysiology which confirm the disease heterogeneity, and may help find disease-targeted and patient targeted therapies. RECENT FINDINGS: Antibodies to the acetylcholine receptor, the muscle-specific tyrosine kinase and the lipoprotein receptor protein 4, characterize disease subtypes with distinct clinical traits and immune-pathogenic mechanisms. Genome-wide approaches have identified susceptibility loci within genes that participate in the immune response. Regulatory T and B cells appear to be defective in myasthenia gravis. In patients with acetylcholine receptor antibodies, thymectomy associated with prednisone proved more effective than prednisone alone in a multicenter randomized trial. New therapeutic options target B cells, B-cell growth factors and complement inhibition, and are currently reserved for patients with refractory disease. SUMMARY: In the recent past, there has been an active search for new antigens in myasthenia gravis, whereas clinical and experimental studies have provided new insights of crucial pathways in immune regulation, which might become the targets of future therapeutic interventions. PMID- 28654436 TI - Variability of cancer risk within an area: time to complement the incidence rate. AB - The aim of this study was to show that age-adjusted cancer incidence rates for an area may not be representative of the incidence in subareas. We propose a simple measure to show the amount of geographical variability. European age-standardized incidence rates (ASRs) for 'all sites excluding nonmelanoma skin cancer', for men, in 2014, for Nordic countries as a whole, for each country (Denmark, Faroe Islands, Finland, Greenland, Iceland, Sweden and Norway) and for their regions, were retrieved from the Nordcan with corresponding standard errors SEs. We compared the ASR for Nordic countries versus single country and single country versus specific regions. The overlapping of 95% confidence intervals was used for ASRs comparisons. As a measure of variability, we computed the range between the highest and the lowest ASR within an area and the ratio between this range and the ASR of the overall area, r/R=(range/ASR)*100. The 95% confidence interval of the ASR for Nordic countries as a whole did not overlap those of the majority of the single countries; in fact, the r/R - which provides a clue for the amount of underlying geographical variability - was rather large (57.1%). Within countries, the variability was negligible in Iceland (r/R=9.6%), whereas the highest value was found in Sweden (37.1%). The ASR does not provide any information on underlying geographical variability. Therefore, its interpretation could be misleading. When data for subareas are available, the r/R, which is simple to compute and to understand, should be added to the ASR for providing more truthful information. PMID- 28654437 TI - Self-Reported Physical Activity Level in Student Athletes at Preparticipation Physical Evaluations. AB - OBJECTIVE: Quantify physical activity in healthy student athletes. DESIGN: Cross sectional survey. SETTING: Five Central Ohio schools during mass preparticipation physicals. PARTICIPANTS: Three hundred sixty-five children between the ages 10 and 18 years. INDEPENDENT VARIABLES: Days per week of moderate to vigorous physical activity (MVPA), minutes per day of MVPA, and number of activities. MAIN OUTCOME MEASURES: Minutes per week of MVPA. RESULTS: One hundred eighty high school and 177 middle school subjects responded to the survey. There were 198 male and 162 female respondents. Mean age recorded 14.2 +/- 1.7 years. There were no differences in activity volume based on sex. Mean minutes per week of MVPA reported 316.0 +/- 231.0. High school subjects reported fewer activities than middle school cohort 2.7 +/- 1.2 versus 3.2 +/- 1.5 (P < 0.05). CONCLUSION: Only 7% of respondents reported exercising 60 minutes daily. Twenty-seven percent of respondents met minutes per week (420 minutes of MVPA) by training in large volumes on fewer days. Surprisingly, this physically active population did not meet the national standards of daily MVPA. In addition, middle school athletes reported more variety of activities compared with high school athletes surveyed which reached statistical significance. Screening for daily physical activity is important in the athletic population because young athletes may not meet daily MVPA recommendations. PMID- 28654438 TI - Differences in Athletic Performance Between Sportsmen With Symptomatic Femoroacetabular Impingement and Healthy Controls. AB - OBJECTIVE: Femoroacetabular impingement (FAI) is a commonly recognized condition in athletes characterized by activity-related hip pain and stiffness, which if left untreated can progress to hip osteoarthritis. The aim of the study was to determine the effect of symptomatic FAI on performance in young athletes based on the hypothesis that athletes with FAI would show deficits in performance compared with healthy controls. DESIGN: The functional performance of a cohort of preoperative, competitive sportsmen with symptomatic FAI (FAI group, n = 54), was compared with that of a group of age, sex and activity-level matched controls (n = 66). OUTCOME MEASURES: Participants performed functional tests including a 10-m sprint, a modified agility T-test, a maximal deep squat test and a single-leg drop jump (reactive strength index). Hip range of motion was assessed by measuring maximal hip flexion, abduction, and internal rotation (at 90 degree hip flexion). RESULTS: The FAI group was significantly slower during the 10-m sprint (3%, P = 0.002) and agility T-test (8%, P < 0.001); flexion, abduction, and internal rotation values for the FAI group were reduced compared with controls (P < 0.001). No significant differences between groups were identified for squat depth or reactive strength index. The FAI group also reported higher levels of anterior groin pain during the 10-m sprint, modified agility T-test, and while squatting. CONCLUSIONS: Many sportsmen with confirmed FAI continue sports participation up to and after diagnosis, despite issues with activity-related pain and stiffness. This study highlights the functional limitations in speed, agility, and flexibility that are likely to be present in this group of FAI patients. PMID- 28654439 TI - Unusual Cause of Thoracic Wall Pain in a Kayaker: A Case Report. AB - Chest wall injuries are common in paddle-based sports such as kayaking. We present the case of a 46-year-old amateur kayaker who presented with signs and symptoms in keeping with a rib stress response or fracture. The patient failed to respond to conservative management and subsequent imaging revealed an obstructed left kidney with associated hydronephrosis. This case report highlights the importance of considering the wider differential diagnoses when managing athletes participating in paddle-based sports, especially when symptoms fail to settle with appropriate conservative management. PMID- 28654440 TI - Quadriceps Tendon-Bone or Patellar Tendon-Bone Autografts When Reconstructing the Anterior Cruciate Ligament: A Meta-analysis. AB - OBJECTIVE: We aimed to quantitatively assess the outcomes of studies, comparing the use of Bone-patellar tendon-bone (BPTB) and the quadriceps tendon-bone (QTB) autografts when reconstructing the anterior cruciate ligament (ACL). DATA SOURCES: MEDLINE, Embase, and CINAHL databases were searched for relevant articles published between January 1980 and January 2015 for the purpose of identifying studies comparing BPTB and QTB autografts for ACL reconstruction. Included studies were assessed regarding their methodological quality before analysis. Outcomes analyzed were graft failure rates, objective and subjective stability assessments, as well as the presence and severity of donor site morbidity. MAIN RESULTS: Five studies contributed to the quantitative analysis of 806 patients with 452 patients included in the BPTB group and 354 patients in the QTB group. Graft failure rates were similar between the 2 groups [odds ratio (OR) = 0.61; confidence interval (CI) = 0.17-2.15; Z = 0.78, P = 0.44]. There were no significant differences between the 2 groups when testing anteroposterior stability using an arthrometer (standardized mean difference = 0.07; CI = -0.12 0.25; Z = 0.70, P = 0.48). At 1 year postoperatively, there was no difference in the percentage of patients with a positive pivot shift test between the 2 groups (OR = 1.0; CI = 0.85-1.18; Z = 0.01, P = 0.99). However, significantly less patients had graft site pain 1 year after surgery in the QTB group (OR = 0.10; CI = 0.02-0.43; Z = 3.12, P = 0.002). Similarly, fewer patients reported moderate to severe pain while kneeling, in the QTB group (OR = 0.16; CI = 0.07-0.37; Z = 4.26, P < 0.001). CONCLUSIONS: This study demonstrates comparable survival rates and joint stability when BPTB and QTB grafts are used. However, fewer adverse donor site symptoms are evident with QTB grafts. LEVEL OF EVIDENCE: III. PMID- 28654441 TI - Multidisciplinary Assessment of 100 Athletes With Groin Pain Using the Doha Agreement: High Prevalence of Adductor-Related Groin Pain in Conjunction With Multiple Causes. AB - OBJECTIVE: To examine the prevalence of different causes of groin pain in athletes using the recent Doha consensus classification of terminology and definitions of groin pain in athletes. DESIGN: Descriptive epidemiological study. SETTING: Multidisciplinary sports groin pain clinic at Aspetar Orthopedic and Sports Medicine Hospital, Doha, Qatar. PATIENTS: The clinical records of 100 consecutive athletes with complaints of groin pain who attended the multidisciplinary sports groin pain clinic between January and December 2014 were analyzed. MAIN OUTCOME MEASURES: The causes of groin pain were categorized according to terminology and definitions agreed upon at the Doha consensus meeting on groin pain classification in athletes. The classification system has 3 main subheadings; defined clinical entities for groin pain (adductor-related, iliopsoas-related, inguinal-related, and pubic-related groin pain), hip-related groin pain, and other causes of groin pain in athletes. RESULTS: The majority of athletes were male (98%) soccer players (60%). Multiple causes for groin pain were found in 44% of the athletes. Adductor-related groin pain was the most prevalent defined clinical entity (61% of athletes), and pubic-related groin pain was the least prevalent (4% of athletes). CONCLUSIONS: Adductor-related groin pain is the most commonly occurring clinical entity in this athlete population in mainly kicking and change of direction sports and frequently, multiple causes are found. CLINICAL RELEVANCE: This is the first study to use the Doha agreement classification system and highlights the prevalence of adductor-related groin pain and that often multiple clinical entities contribute to an athlete's groin pain. Consequently, prevention programs should be implemented with these factors in mind. PMID- 28654442 TI - Low-Intensity Pulsed Ultrasound Therapy for a Symptomatic Persistent Olecranon Physis in an Adolescent Baseball Pitcher. AB - A 15-year-old competitive right-handed high school baseball pitcher experienced an acute onset of right elbow pain when throwing. He initially treated it conservatively with rest alone for 3 months, but on return to throwing, he was still experiencing pain. Radiographs revealed that he had a persistent olecranon physis. He proceeded with a trial of low-intensity pulsed ultrasound therapy and attained radiographic evidence of bony union at 7 months postinjury, thus avoiding surgical intervention. He returned to pitching competitively 9 months after injury without elbow pain. This is the first reported case of using ultrasound bone stimulation for treatment of a symptomatic persistent olecranon physis in a baseball pitcher. PMID- 28654443 TI - Application and interpretation of histocompatibility data in thoracic (heart and lung) transplantation. AB - PURPOSE OF REVIEW: The purpose of the review is to update our current understanding and utilization of immunogenetic tools in heart and lung transplant. RECENT FINDINGS: Increasingly, complex patients have been managed perioperatively for heart and lung transplant using a variety of tests and techniques. Recent treatment regimens and listing strategies have exploited recent laboratory advances. However, the better characterization has led to an even more complex description of sensitized heart and lung candidates. Several recent studies have examined antibody strengths and behavior to guide clinical decision-making and examine postoperative outcomes. Finally, non-human leukocyte antigen antibodies have emerged as possible determinants of allograft outcome in heart and lung transplant. SUMMARY: Heart and lung transplant candidates with preformed and de-novo posttransplant antibodies continue to represent a challenging and high-risk group of patients. Modern immunogenetic techniques have broadened our understanding and have revealed an even more complex relationship between antibodies, allografts, and outcomes. PMID- 28654444 TI - Lichenoid Dermatitis of the Vulva: Diagnosis and Differential Diagnosis for the Gynecologic Pathologist. AB - Inflammatory processes affecting the vulva may present a unique challenge due to location specific changes. Different factors are behind the intricacy in the presentation of vulvar dermatoses. First, the vulva is lined by different epithelia (hair-bearing keratinized epithelium, modified mucosa, and mucosa). Furthermore, among other factors, this organ is exposed to friction, occlusion, and trauma. Lastly, as there is a tendency to look for health care advice at an advanced stage of the disease, the lesion may be modified by secondary changes due to self-treatment. This article describes the clinical presentation and pathologic features of vulvar dermatoses with a lichenoid pattern and highlights practical points for their diagnoses. PMID- 28654445 TI - Sepsis in Obstetrics. PMID- 28654446 TI - Sepsis in Obstetrics: Pathophysiology and Diagnostic Definitions. AB - In spite of many medical breakthroughs, sepsis continues to be challenging to identify, treat, and successfully resolve, including among the obstetric population. Sepsis is the result of an overactive, complex inflammatory response that is not completely understood. Currently there are no nationally agreed-upon criteria for systemic inflammatory response syndrome or sepsis in pregnant or peripartum women, as the physiologic changes of pregnancy have not been taken into consideration.This article is the first in a series of three that discuss the importance of sepsis and septic shock in pregnancy. The focus of this article is to understand the proposed pathophysiology of sepsis and new definitions associated with sepsis and septic shock. Knowledge of these conditions can assist in better identification of sepsis in the obstetric population. PMID- 28654448 TI - Delayed Umbilical Cord Clamping at Birth: Beneficial for All Babies. PMID- 28654447 TI - Understanding and Promoting Birth Satisfaction in New Mothers. AB - PURPOSE: The purpose of this study was to examine the impact of select maternal psychosocial and experiential factors on birth satisfaction of new mothers during early postpartum. STUDY DESIGN AND METHODS: This is a descriptive correlational study exploring the relationships among birth satisfaction, breastfeeding self efficacy, and perceived stress in 107 new mothers in the first 4 days postpartum. Instruments used included the Birth Satisfaction Scale-Revised, the Perceived Stress Scale, the Breastfeeding Self-Efficacy Scale-Short Form, and a researcher generated demographic form. Quantitative analysis included descriptive statistics, correlation, one-way Analysis of Variance, and multiple linear regression. RESULTS: Birth satisfaction was negatively correlated with perceived stress (r = -.299, p < .05) and positively correlated with feeling prepared for birth (rho = .243, p < .05) and breastfeeding self-efficacy (r = .226, p < .05). The predictive model for birth satisfaction was significant (R = .204, F [6, 99] = 4.225, p = .001), explaining approximately 20.4% of variance in birth satisfaction in the sample. CLINICAL IMPLICATIONS: Stress reduction and management, establishment of realistic expectations for labor and birth, and promotion of togetherness with newborn immediately after birth are nursing priorities to promote birth satisfaction. PMID- 28654449 TI - Neonatal Male Circumcision: Still a Controversy. PMID- 28654450 TI - Say No to Success-Say Yes to Goal Setting. PMID- 28654451 TI - Caring Hearts Coupled with Helping Hands: Making a Difference for Children with Medical Hair Loss. PMID- 28654453 TI - Minimizing Unnecessary Interventions During Labor and Birth. PMID- 28654456 TI - Diagnostic and Therapeutic Challenges. PMID- 28654457 TI - EFFECT OF DARK ADAPTATION AND BLEACHING ON BLUE LIGHT REFLECTANCE IMAGING IN MACULAR TELANGIECTASIA TYPE 2. AB - PURPOSE: In patients with macular telangiectasia Type 2, blue light reflectance imaging reveals an oval, parafoveal area in the macula that has increased reflectance compared with its surrounding. Here, we examine how dark adaptation and photobleaching can affect the blue light reflectance imaging pattern. METHODS: Prospective study of patients with macular telangiectasia enrolled in the MacTel Natural History Observation Study. After dark adaptation, a sequence of images was obtained with a confocal scanning laser ophthalmoscope at 488 nm. Change of reflectance patterns was analyzed over time. RESULTS: Eighteen eyes from 16 patients were analyzed. Initially, increased reflectivity in the parafoveal area resulted in higher gray values compared with the paramacular surrounding on blue light reflectance imaging. The difference between parafoveal and paramacular reflectance intensity decreased steadily during imaging, from 17.7 gray-value units (95% confidence interval: 12.1-23.2) down to 2.8 (95% confidence interval: -0.8 to 6.5) after around 30 seconds, and recovered after 5 minutes of dark adaptation. CONCLUSION: A bleaching effect was evident in our study. Understanding these changes is important for both diagnosis and assessment of blue light reflectance phenotype in patients with macular telangiectasia and could also provide further insights into the pathophysiology of this disease. PMID- 28654458 TI - ELECTROPHYSIOLOGICAL CHARACTERIZATION OF MACULAR TELANGIECTASIA TYPE 2 AND STRUCTURE-FUNCTION CORRELATION. AB - PURPOSE: To investigate the electrophysiological features of macular telangiectasia Type 2 and their relationship to structure as determined by optical coherence tomography imaging. METHODS: Forty-two eyes from 21 patients enrolled in the Macular Telangiectasia Natural History Observation Study were reviewed. All patients had full-field and pattern electroretinography (ERG; PERG) with some patients additionally having multifocal electroretinography (mfERG; N = 15) or electrooculography (N = 12). Multiple linear regression modeling assessed the relationship between the ellipsoid zone break size on optical coherence tomography and the central mfERG response. RESULTS: Full-field ERG and electrooculography were normal in all eyes. Six eyes (14%) from five patients had subnormal PERG P50 amplitudes. Twenty-two of 30 eyes (73%) had reduced central or paracentral stimulus on mfERG. There was a significant correlation between ellipsoid zone break size and both the P1 amplitude (R = 0.37, P = 0.002) and P1:N1 ratio (R = 0.32, P = 0.002) of the central response on mfERG. CONCLUSION: The electrophysiological findings in macular telangiectasia Type 2 are those of localized central dysfunction and are consistent with the structural data available from imaging and histologic studies. The ellipsoid zone break size correlates with mfERG reduction. The reduced mfERG P1:N1 ratio is consistent with inner retinal dysfunction. PMID- 28654459 TI - Hodgkin Lymphoma in a Patient With IFAP Syndrome: A Case Report and Review of Literature. AB - The IFAP syndrome is a rare X-linked recessive inheritance disorder with defect of the MBTPS2 gene defined by the triad of follicular ichthyosis, alopecia, and photophobia. A total of 40 cases has been reported, but no correlation with Hodgkin lymphoma has been reported yet. A 3.5-year-old boy was diagnosed with IFAP syndrome confirmed by Next Generation Sequencing. He was on regular follow up when he developed prolonged fever and lymphadenopathy. His lymph node biopsy showed Hodgkin lymphoma with mixed cellularity subtype. This case is the first report on IFAP syndrome associated with malignancy. IFAP syndrome could be a risk factor in developing malignancy. PMID- 28654460 TI - Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model. AB - Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg*4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 MUM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse. PMID- 28654461 TI - Natural History, Pathogenesis, and Treatment of Evans Syndrome in Children. AB - Primary Evans syndrome (ES) is defined by the concurrent or sequential occurrence of immune thrombocytopenia and autoimmune hemolytic anemia in the absence of an underlying etiology. The syndrome is characterized by a chronic, relapsing, and potentially fatal course requiring long-term immunosuppressive therapy. Treatment of ES is hardly evidence-based. Corticosteroids are the mainstay of therapy. Rituximab has emerged as the most widely used second-line treatment, as it can safely achieve high response rates and postpone splenectomy. An increasing number of new genetic defects involving critical pathways of immune regulation identify specific disorders, which explain cases of ES previously reported as "idiopathic". PMID- 28654462 TI - Depressed gut? The microbiota-diet-inflammation trialogue in depression. AB - PURPOSE OF REVIEW: According to the WHO reports, around 350 million people worldwide suffer from depression. Despite its high prevalence, the complex interaction of multiple mechanisms underlying depression still needs to be elucidated. RECENT FINDINGS: Over the course of the last few years, several neurobiological alterations have been linked to the development and maintenance of depression. One basic process that seems to link many of these findings is inflammation. Chronic inflammation has been associated with both biological factors such as excessive neurotransmitter concentrations as well as psychological processes such as adult stress reactivity and a history of childhood trauma. As a balanced microbial community, modulated by diet, is a key regulator of the host physiology, it seems likely that gut microbiota plays a role in depression. SUMMARY: The review summarizes the existent literature on this emerging research field and provides a comprehensive overview of the multifaceted links between the microbiota, diet, and depression. Several pathways linking early life trauma, pharmacological treatment effects, and nutrition to the microbiome in depression are described aiming to foster the psychotherapeutic treatment of depressed patients by interventions targeting the microbiota. PMID- 28654463 TI - Fatty Acid Synthase and Acetyl-CoA Carboxylase Are Expressed in Nodal Metastatic Melanoma But Not in Benign Intracapsular Nodal Nevi. AB - BACKGROUND: Melanoma is a potentially lethal form of skin cancer for which the current standard therapy is complete surgical removal of the primary tumor followed by sentinel lymph node biopsy when indicated. Histologic identification of metastatic melanoma in a sentinel node has significant prognostic and therapeutic implications, routinely guiding further surgical management with regional lymphadenectomy. While melanocytes in a lymph node can be identified by routine histopathologic and immunohistochemical examination, the distinction between nodal nevus cells and melanoma can be morphologically problematic. Previous studies have shown that malignant melanoma can over-express metabolic genes such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). This immunohistochemical study aims to compare the utility of FASN and ACC in differentiating sentinel lymph nodes with metastatic melanomas from those with benign nodal nevi in patients with cutaneous melanoma. MATERIALS AND METHODS: Using antibodies against FASN and ACC, 13 sentinel lymph nodes from 13 patients with metastatic melanoma and 14 lymph nodes harboring benign intracapsular nevi from 14 patients with cutaneous malignant melanoma were examined. A diagnosis of nodal melanoma was based on cytologic atypia and histologic comparison with the primary melanoma. All nodal nevi were intracapsular and not trabecular. Immunohistochemistry for Melan-A, S100, human melanoma black 45 (HMB45), FASN, and ACC were performed. The percentage of melanocytes staining with HMB45, FASN, and ACC was determined and graded in 25% increments; staining intensity was graded as weak, moderate, or strong. RESULTS: All metastatic melanomas tested had at least 25% tumor cell staining for both FASN and ACC. Greater than 75% of the tumor cells stained with FAS in 7/13 cases and for ACC in 5/12 cases. Intensity of staining was variable; strong staining for FASN and ACC was observed in 69% and 50% of metastatic melanoma, respectively. HMB45 was negative in 40% of nodal melanoma cases all of which stained with FASN and ACC. Capsular nevi were uniformly negative for FASN, ACC, and HMB45 immunoreactivity. CONCLUSIONS: All metastatic melanoma cases involving sentinel lymph nodes were positive for FASN and ACC while no staining was observed in intracapsular nevi. These findings suggest that FASN and ACC could be used as valuable ancillary stains in the distinction between nodal nevi and metastatic melanoma. PMID- 28654464 TI - Lichenoid Granulomatous Mycosis Fungoides. AB - The presence of a granulomatous reaction in cutaneous lymphomas has been described in the past, especially in mycosis fungoides (MF), where a "granulomatous" variant of the disease is well known. We describe a patient with granulomatous MF (GMF) who has been followed for 13 years presenting with erythematosquamous plaques on his fingers and toes, ankles, heels, and abdomen, which on microscopic examination showed a lichenoid granulomatous reaction admixed with a neoplastic proliferation of small-sized, atypical CD4 lymphocytes. GMF is characterized by a granulomatous reaction intermingled with the dermal infiltrate of MF which may even reach the subcutaneous tissue. Only 7 cases of GMF in which the granulomas were located within the papillary or superficial dermis have been described to date. We report for the first time a unique case of lichenoid GMF where the granulomatous reaction obscures the interface between the epidermis and dermis. Sequential biopsies and complete phenotypic studies were necessary to get an accurate diagnosis. PMID- 28654465 TI - High-Velocity Paint Gun Injuries. AB - Cutaneous injuries due to industrial high-pressure paint guns are well-documented in the literature; however, the histologic characteristics are uncommonly described, and facial involvement has not been previously reported. Histopathologic features of paint gun injuries vary depending on the time since injection and type of material. Early lesions display an acute neutrophilic infiltrate, edema, and thrombosis, with varying degrees of skin, fat, and muscle necrosis. More developed lesions (120-192 hours after injury) have prominent histiocytes and fibrosis around necrotic foci, possibly with the pitfall of muscle regenerative giant cells that could be mistaken for sarcoma. Continuing inflammation, swelling, and resultant vascular compression could explain ongoing necrosis months after the accident. The histopathologic differential diagnosis in the absence of clinical history includes paint in an abrasion, foreign body reaction to tattoo, giant cell tumor of tendon sheath, and various neoplasms. If available, radiologic studies can substitute for clinical photographs to indicate the extent of injury. The radiologic differential, uninformed by history, may include calcific periarthritis, gouty tophus, and tumoral calcinosis. Seven cases of injury due to high-velocity paint guns are presented with 4 additional cases mimicking paint gun injury and with review of the literature. PMID- 28654466 TI - Detection of Beta-Human Papillomavirus in a Child With Polyomavirus-Associated Trichodysplasia Spinulosa. AB - Viral associated trichodysplasia spinulosa (VATS) is a rare cutaneous eruption characterized by folliculocentric papules, keratin spicules, and alopecia associated with trichodysplasia spinulosa-associated polyomavirus (TSPyV) infection. We report a case of a 6-year-old male child who presented with a generalized papular eruption during chemotherapy for acute lymphoblastic leukemia. The papules were tested for human papillomavirus (HPV) DNA by nested polymerase chain reaction (PCR) and TSPyV using PCR and gene sequencing studies. The lesions were positive for TSPyV by PCR combined with sequencing and showed high copy number with real-time PCR, and beta-papillomavirus was identified by PCR and sequencing. Immunohistochemistry revealed inner root sheath keratinocytes expressing nuclear HPV L1 capsid antigen. To our knowledge, this is the first case of concomitant productive HPV and TSPyV infection in a VATS-affected patient. The presence of HPV may be coincidental, however, further studies are needed to establish whether specific HPV genotypes influence the development of abnormal inner root sheath trichohyalin granules found in VATS. PMID- 28654467 TI - A Young Woman With an Erythematous Rash, Fever, Tachycardia, and Pancytopenia. PMID- 28654468 TI - Bullous Pemphigoid: Use of C4d Immunofluorescent Staining in a Case With Repeated Negative Conventional Direct Immunofluorescence Studies. AB - Direct immunofluorescence (DIF) using frozen section material from a fresh/preserved perilesional biopsy is the gold standard for the immunopathologic diagnosis of bullous pemphigoid (BP). DIF in BP shows linear dermoepidermal junction (DEJ) staining for C3, with or without staining for IgG. In some situations, only a formalin-fixed lesional biopsy is obtained (with no fresh/preserved perilesional biopsy for DIF). In this setting, paraffin section C4d immunohistochemistry has proven to be diagnostically useful, demonstrating linear DEJ positivity for C4d. We present a novel use of C4d staining for the diagnosis of BP, specifically analyzing C4d perilesional frozen section DIF in a case where standard perilesional frozen section DIF for IgG/C3 was available, but was negative. An 80-year-old woman presented with a pruritic bullous lesion on her left upper extremity, clinically thought to represent BP. Lesional histologic findings were typical for BP, but perilesional frozen section DIF staining was negative for IgG and C3. A second set of biopsies processed at a different laboratory yielded the same result. A diagnosis of bullous scabies was considered. Subsequently, perilesional frozen section DIF for C4d was obtained, which showed strong linear DEJ positivity, confirming the diagnosis of BP. DIF for C4d is widely used in transplant pathology, since C4d is persistent in tissue, versus C3. Our case demonstrates that perilesional frozen section DIF staining for C4d may be positive and diagnostic in BP, even when conventional DIF staining for IgG and C3 is negative. PMID- 28654469 TI - The Histopathological Spectrum of Pseudolymphomatous Infiltrates in Cutaneous Lupus Erythematosus. AB - The occurrence of pseudolymphomatous infiltrates in cutaneous lupus erythematosus (cLE) is described mainly in lupus panniculitis and lupus tumidus/lymphocytic infiltration of the skin (Jessner-Kanof). We collected 15 cases of pseudolymphomatous cLE other than lupus panniculitis and lupus tumidus (M:F = 4:11; age range: 23-79 years; mean age: 50.9 years; median age: 57 years). Of the 15 cases, 9 (60%) were characterized by dense nodular infiltrates. Three cases (20%) showed an angiocentric pattern with cytological atypia of lymphoid cells; 2 cases (13.3%) showed a band-like infiltrate mimicking mycosis fungoides, and 1 case had mixed features of the band-like and angiocentric patterns. Clues to the histopathological diagnosis of cLE were presence of interface dermatitis, clusters of plasmacytoid dendritic cells, and dermal mucin deposition. Our study shows that the spectrum of pseudolymphomatous presentations of cLE is broader than previously described, including band-like cases that may be misconstrued as mycosis fungoides, and angiocentric cases that may be misinterpreted as an aggressive lymphoma. Recognition of such cases is possible only on careful clinicopathologic correlation and requires a high level of histopathological suspicion to allow a correct diagnosis and the proper management of the patients. PMID- 28654470 TI - Team Approach: Pyomyositis. PMID- 28654471 TI - State of Our Profession Over the Decades. PMID- 28654472 TI - The Past, Present, and Future of Neurorehabilitation: From NUSTEP Through IV STEP and Beyond. AB - PURPOSES: To present the history and aims of the STEP conferences; describe the interdependence of prevention, prediction, plasticity, and participation; reflect on where we stand today regarding those 4 Ps; and discuss how future neurorehabilitation should look for individuals with movement disorders. KEY POINTS: Physical therapists have focused primarily on tertiary prevention, emphasizing primary/secondary prevention far less. Predicting optimal response to intervention is essential for primary prevention. Research examining neurorehabilitation effects mediated by brain plasticity is evolving from an emphasis on impairment outcomes toward examination of participation outcomes. CLINICAL PRACTICE RECOMMENDATIONS:: (1) Capitalize on primary and secondary prevention. (2) Administer simple, environmentally relevant predictive measures. (3) Partner with researchers to examine exercise-induced brain plasticity effects via neuroimaging. (4) Encourage physical activity to promote secondary prevention of lifestyle-related diseases and enhance participation. (5) Integrate psychological/social sciences with physiological sciences to move forward with advances in mindful health and patient-centered practices. PMID- 28654473 TI - Regenerative Rehabilitation: Combining Stem Cell Therapies and Activity-Dependent Stimulation. AB - The number of clinical trials in regenerative medicine is burgeoning, and stem cell/tissue engineering technologies hold the possibility of becoming the standard of care for a multitude of diseases and injuries. Advances in regenerative biology reveal novel molecular and cellular targets, with potential to optimize tissue healing and functional recovery, thereby refining rehabilitation clinical practice. The purpose of this review is to (1) highlight the potential for synergy between the fields of regenerative medicine and rehabilitation, a convergence of disciplines known as regenerative rehabilitation; (2) provide translational examples of regenerative rehabilitation within the context of neuromuscular injuries and diseases; and (3) offer recommendations for ways to leverage activity dependence via combined therapy and technology, with the goal of enhancing long-term recovery. The potential clinical benefits of regenerative rehabilitation will likely become a critical aspect in the standard of care for many neurological and musculoskeletal disorders. PMID- 28654474 TI - Excellence in Promoting Participation: Striving for the 10 Cs-Client-Centered Care, Consideration of Complexity, Collaboration, Coaching, Capacity Building, Contextualization, Creativity, Community, Curricular Changes, and Curiosity. AB - Participation of children with physical disabilities is critical to optimizing their life roles and lived experiences. This perspective explores the complex and multidimensional construct of participation and presents recommendations for practice, education, and research to transform pediatric physical therapy service delivery. Two models are reviewed of participation-based service delivery grounded in client-centered care and the principles of coaching to engage clients in their rehabilitation. The roles and responsibilities of the physical therapist and the importance of team collaboration are emphasized. Considerations are presented for ecological measurements and interventions to support client participation goals for children of all ages in home and community settings. Practitioners, educators, and researchers are encouraged to be advocates and change agents to ensure that services support meaningful participation for children in real-life contexts. PMID- 28654477 TI - Use of Lower-Limb Robotics to Enhance Practice and Participation in Individuals With Neurological Conditions. AB - PURPOSE: To review lower-limb technology currently available for people with neurological disorders, such as spinal cord injury, stroke, or other conditions. We focus on 3 emerging technologies: treadmill-based training devices, exoskeletons, and other wearable robots. SUMMARY OF KEY POINTS: Efficacy for these devices remains unclear, although preliminary data indicate that specific patient populations may benefit from robotic training used with more traditional physical therapy. Potential benefits include improved lower-limb function and a more typical gait trajectory. STATEMENT OF CONCLUSIONS: Use of these devices is limited by insufficient data, cost, and in some cases size of the machine. However, robotic technology is likely to become more prevalent as these machines are enhanced and able to produce targeted physical rehabilitation. RECOMMENDATIONS FOR CLINICAL PRACTICE: Therapists should be aware of these technologies as they continue to advance but understand the limitations and challenges posed with therapeutic/mobility robots. PMID- 28654476 TI - Coupling Timing of Interventions With Dose to Optimize Plasticity and Participation in Pediatric Neurologic Populations. AB - PURPOSE: The purpose of this article is to propose that coupling of timing of interventions with dosing of interventions optimizes plasticity and participation in pediatric neurologic conditions, specifically cerebral palsy. Dosing includes frequency, intensity, time per session, and type of intervention. Interventions focus on body structures and function and activity and participation, and both are explored. Known parameters for promoting bone, muscle, and brain plasticity and evidence supporting critical periods of growth during development are reviewed. Although parameters for dosing participation are not yet established, emerging evidence suggests that participation at high intensities has the potential for change. Participation interventions may provide an additional avenue to promote change through the life span. Recommendations for research and clinical practice are presented to stimulate discussions and innovations in research and practice. PMID- 28654478 TI - Research Design Options for Intervention Studies. AB - PURPOSE: To review research designs for rehabilitation. SUMMARY OF KEY POINTS: Single-case, observational, and qualitative designs are highlighted in terms of recent advances and ability to answer important scientific questions about rehabilitation. STATEMENT OF CONCLUSIONS: Single-case, observational, and qualitative designs can be conducted in a systematic and rigorous manner that provides important information that cannot be acquired using more common designs, such as randomized controlled trials. These less commonly used designs may be more feasible and effective in answering many research questions in the field of rehabilitation. RECOMMENDATIONS FOR CLINICAL PRACTICE: Researchers should consider these designs when selecting the optimal design to answer their research questions. We should improve education about the advantages and disadvantages of existing research designs to enable more critical analysis of the scientific literature we read and review to avoid undervaluing studies not within more commonly used categories. PMID- 28654479 TI - Knowledge Translation in Rehabilitation: A Shared Vision. AB - PURPOSE: Advances in rehabilitation provide the infrastructure for research and clinical data to improve care and patient outcomes. However, gaps between research and practice are prevalent. Knowledge translation (KT) aims to decrease the gap between research and its clinical use. This special communication summarizes KT-related proceedings from the 2016 IV STEP conference, describes current KT in rehabilitation science, and provides suggestions for its application in clinical care. SUMMARY OF KEY POINTS: We propose a vision for rehabilitation clinical practice and research that includes the development, adaptation, and implementation of evidence-based practice recommendations, which will contribute to a learning health care system. A clinical research culture that supports this vision and methods to engage key stakeholders to innovate rehabilitation science and practice are described. CONCLUSIONS: Through implementation of this vision, we can lead an evolution in rehabilitation practice to ultimately prevent disabilities, predict better outcomes, exploit plasticity, and promote participation. PMID- 28654475 TI - Virtual Reality and Serious Games in Neurorehabilitation of Children and Adults: Prevention, Plasticity, and Participation. AB - Use of virtual reality (VR) and serious games (SGs) interventions within rehabilitation as motivating tools for task specific training for individuals with neurological conditions are fast-developing. Within this perspective paper we use the framework of the IV STEP conference to summarize the literature on VR and SG for children and adults by three topics: Prevention; Outcomes: Body Function-Structure, Activity and Participation; and Plasticity. Overall the literature in this area offers support for use of VR and SGs to improve body functions and to some extent activity domain outcomes. Critical analysis of clients' goals and selective evaluation of VR and SGs are necessary to appropriately take advantage of these tools within intervention. Further research on prevention, participation, and plasticity is warranted. We offer suggestions for bridging the gap between research and practice integrating VR and SGs into physical therapist education and practice. PMID- 28654480 TI - Overweight and Obesity in Children: More Than Just the Kilos. AB - A new model of diagnostics and treatment for overweight in children is used for implementation of a new approach toward childhood obesity. Although based in a hospital setting, it is part of a cure and care network with other professionals. By psycho-education about the body at a 6-year-old level, parents and children become informed and competent partners. This knowledge increases their autonomy and ability to make choices. Collaboration with the family's support group or network reduces isolation and increases the feeling of being connected and supported. Together with their support network, they can maintain this healthier lifestyle or adjust it where needed. Family workbooks and worksheets support the child and parents and increase their autonomy, self management skills, and motivation to take part in the cure and care network. The approach is a based on the three basic needs that determine motivation, namely autonomy, competence, and connectedness. PMID- 28654482 TI - Global Reach. PMID- 28654481 TI - Stepping Up to Rethink the Future of Rehabilitation: IV STEP Considerations and Inspirations. AB - BACKGROUND AND PURPOSE: The IV STEP conference challenged presenters and participants to consider the state of science in rehabilitation, highlighting key area of progress since the previous STEP conference related to prediction, prevention, plasticity, and participation in rehabilitation. KEY POINTS: Emerging from the thought-provoking discussions was recognition of the progress we have made as a profession and a call for future growth. In this summary article, we present a recap of the key points and call for action. We review the information presented and the field at large as it relates to the 4 Ps: prediction, prevention, plasticity, and participation. RECOMMENDATIONS FOR PRACTICE: Given that personalized medicine is an increasingly important approach that was clearly woven throughout the IV STEP presentations, we took the liberty of adding a fifth "P," Personalized, in our discussion of the future direction of the profession. PMID- 28654484 TI - Commentary on "Therapy Use for Children With Developmental Conditions: Analysis of Colorado Medicaid Data". PMID- 28654483 TI - Therapy Use for Children With Developmental Conditions: Analysis of Colorado Medicaid Data. AB - STUDY PURPOSE: To examine therapy use and spending for Medicaid-enrolled infants and toddlers with developmental conditions. METHODS: Sample infants and toddlers had a diagnosis (eg, cerebral palsy) or developmental delay (DD). Colorado Children's Medicaid administrative outpatient therapy claims (2006-2008) were used to estimate differences, by condition type and number of comorbid chronic conditions (CCCs), of any physical therapy (PT)/occupational therapy (OT) and Medicaid PT/OT spending. RESULTS: The sample included 20 959 children. Children with at least 2 CCCs had higher odds of PT/OT than children with no CCC. Children with DD had 12-fold higher odds of having any PT/OT compared with children with diagnosis. Children with a DD and 2 CCCs had the highest PT/OT spending. CONCLUSIONS: Medicaid PT/OT use and spending are higher for children with more CCCs and those with DD because children with DD receive more specialized PT/OT. PMID- 28654485 TI - Commentary on "Physical Activity Patterns in Infants With and Without Down Syndrome". PMID- 28654486 TI - Ride-On Car Training for Behavioral Changes in Mobility and Socialization Among Young Children With Disabilities. AB - PURPOSE: To characterize behavioral changes in mobility and socialization in children with disabilities aged 1 to 3 years while they are receiving ride-on car training in the hospital environment. METHODS: Ten young children with motor disabilities received ride-on car training for 9 weeks (2 hours per session, 2 sessions per week). The driving and socialization behaviors were videotaped for 20 minutes per session (1 session per week) within the same period. RESULTS: Independent mobility, visual attention to the switch, and positive facial expressions during the training period were significantly improved. CONCLUSIONS: Ride-on car training has positive effects on behavioral changes in mobility and socialization among young children with motor disabilities. This provides clinicians a novel option for implementing early mobility training in a hospital based environment. PMID- 28654487 TI - Commentary on "Ride-On Car Training for Behavioral Changes in Mobility and Socialization Among Young Children With Disabilities". PMID- 28654488 TI - Goal Attainment Scaling to Evaluate Intervention on Individual Gains for Children Born Extremely Preterm. AB - PURPOSE: To investigate the effect of group-based physical therapy on individual gains among preterm and/or extremely low-birth-weight children with minimal or mild impairment at 4 years using Goal Attainment Scaling (GAS). To explore the relationship between GAS with motor and postural outcomes and effect of gender on GAS scores. METHODS: Twenty-four 4-year-old children (born <28 weeks' gestation and/or birth weight <1000 g) with minimal or mild motor impairment completed 6 group-based weekly intervention sessions and a goal-based home program. Assessments included GAS, Movement Assessment Battery for Children-Second Edition (MABC-2), postural stability, and limb strength after intervention. RESULTS: GAS group T score improved, exceeding expected goal of "0" score after intervention (mean = 58.2, standard deviation = 0.82). GAS mean T-score and MABC-2 percentile were moderately correlated (r = 0.42, P = .04). Females improved more than males (P = .05). CONCLUSIONS: Goals were achieved above expected level after intervention and were related to motor coordination. Male gender is a risk factor for less favorable outcomes. PMID- 28654489 TI - Commentary on "Goal Attainment Scaling to Evaluate Intervention on Individual Gains for Children Born Extremely Preterm". PMID- 28654490 TI - A Home-Based Body Weight-Supported Treadmill Program for Children With Cerebral Palsy: A Pilot Study. AB - PURPOSE: The purpose of this pilot study was to explore the effect and feasibility of a home-based body weight-supported treadmill training (BWSTT) program on walking capacity and functional mobility in children with cerebral palsy (CP). METHODS: A within-subjects, repeated-measures design was used. Ten children with CP ages 6 to 16 years participated in pre- and postintervention testing sessions, an initial home training session, and a 12-week home-based BWSTT program conducted 3 to 4 times per week by a parent or caregiver for up to 20 minutes each session. Multiple outcome measures for walking capacity and functional mobility were used. RESULTS: As a group, participants demonstrated significant improvements in walking capacity and functional mobility at the completion the 12-week intervention program. CONCLUSIONS: Additional research regarding home-based BWSTT programs in children with CP is warranted and should focus on identifying specific parameters that promote achievement of optimal functional outcomes. PMID- 28654491 TI - Commentary on "A Home-Based Body Weight-Supported Treadmill Program for Children With Cerebral Palsy: A Pilot Study". PMID- 28654492 TI - A Range of Service Delivery Modes for Children With Developmental Coordination Disorder Are Effective: A Randomized Controlled Trial. AB - PURPOSE: To investigate whether the environment and personnel providing intervention to children with developmental coordination disorder make a difference in motor outcomes and perceived competency. METHODS: Ninety-three children (66 males), aged 5 years 1 month to 8 years 11 months, with developmental coordination disorder were randomized to receive a 13-week group based task-oriented intervention, either at school by a school assistant or physical therapist, or in a health clinic by a physical therapist. The Movement Assessment Battery for Children (MABC) assessed motor skills pre- and postintervention. Self-perception and cost-effectiveness were also assessed. RESULTS: Participants demonstrated a significant improvement in motor skills following intervention for all modes of delivery up to 6 months postintervention, MABC mean difference 7.20 (95% confidence interval, 5.89-8.81), effect size = 0.98. CONCLUSION: Group intervention programs for developmental coordination disorder can be run by either a health professional or a school assistant (supported by physical therapist) in either the school or clinic environment and provide successful outcomes. PMID- 28654493 TI - Commentary on "A Range of Service Delivery Modes for Children With Developmental Coordination Disorder Are Effective: A Randomized Controlled Trial". PMID- 28654494 TI - Reliability and Validity of the 50-ft Walk Test for Idiopathic Toe Walking. AB - PURPOSE: To evaluate interrater reliability and concurrent validity of the 50-ft walk test (FWT) for children with idiopathic toe walking (ITW). METHODS: Thirty children, 6 to 13 years old, with ITW participated. During the 50-FWT, an accelerometer counted total steps. A physical therapist counted the number of toe walking steps. The number of toe-walking steps was divided by the total steps to calculate a toe-walking percentage. Interrater reliability was assessed by correlating the toe-walking percentage obtained by 2 raters using an intraclass correlation coefficient. Concurrent validity was evaluated by correlating the toe walking percentage calculated by the GAITRite and therapist using a Spearman rho. RESULTS: There was excellent interrater reliability and concurrent validity. Experience level did not impact the therapist's ability to identify a toe-walking step. CONCLUSIONS: The 50-FWT demonstrated excellent interrater reliability and concurrent validity. It can be used to obtain a percentage of toe walking in children 6-13 years of age with ITW. PMID- 28654495 TI - Commentary on "Reliability and Validity of the 50-ft Walk Test for Idiopathic Toe Walking". PMID- 28654496 TI - Psychometric Properties of a Standardized Observation Protocol to Quantify Pediatric Physical Therapy Actions. AB - PURPOSE: Pediatric physical therapy (PPT) is characterized by heterogeneity. This blurs the evaluation of effective components of PPT. The Groningen Observation Protocol (GOP) was developed to quantify contents of PPT. This study assesses the reliability and completeness of the GOP. METHODS: Sixty infant PPT sessions were video-taped. Two random samples of 10 videos were used to determine interrater and intrarater reliability using interclass correlation coefficients (ICCs) with 95% confidence intervals. Completeness of GOP 2.0 was based on 60 videos. RESULTS: Interrater reliability of quantifying PPT actions was excellent (ICC, 0.75-1.0) in 71% and sufficient to good (ICC, 0.4-0.74) in 24% of PPT actions. Intrarater reliability was excellent in 94% and sufficient to good in 6% of PPT actions. Completeness was good for greater than 90% of PPT actions. CONCLUSIONS: GOP 2.0 has good reliability and completeness. After appropriate training, it is a useful tool to quantify PPT for children with developmental disorders. PMID- 28654497 TI - Commentary on "Psychometric Properties of a Standardized Observation Protocol to Quantify Pediatric Physical Therapy Actions". PMID- 28654498 TI - Cross-cultural Translation and Adaptation of the Lifestyle Assessment Questionnaire (LAQ-CP) Into Dutch: A Brief Report. AB - PURPOSE: To produce a Dutch translation of the Lifestyle Assessment Questionnaire for children with cerebral palsy (LAQ-CP), adapted for cross-cultural differences. METHODS: The translation process consisted of 6 stages, following a guideline for cross-cultural adaptations including duplicate forward- and back translations, expert group review, pilot-testing, and a process audit. RESULTS: Several adaptations to the questionnaire were required due to cross-cultural differences. As a result of the pilot-test, the layout was adapted to the desires of the users. The process auditor stated that the process had been comprehensive and valued the quality of the work. CONCLUSION: The project resulted in a Dutch translation of the LAQ-CP, adapted for cross-cultural differences. Validation of the translated questionnaire is required before use in clinical practice and research is recommended (Dutch abstract, Supplemental Digital Content 1, available at: http://links.lww.com/PPT/A164). PMID- 28654499 TI - Physical Exercise and Physical Activity for Children and Adolescents With Juvenile Idiopathic Arthritis: A Literature Review. AB - PURPOSE: This is a review of studies that investigate the efficacy of exercise therapy and physical activity for children with juvenile idiopathic arthritis since the 2008 Cochrane Review. METHOD: Studies were identified that investigated the use of physical activity and exercise therapy in the treatment of children and adolescents with juvenile idiopathic arthritis, excluding the Cochrane Review. Two reviewers individually analyzed the results of the search to determine the eligibility of studies. The randomized controlled trial study designs were evaluated using PEDro scales. CONCLUSIONS AND RECOMMENDATIONS FOR CLINICAL PRACTICE: Recent literature supports the importance of the combination of strengthening, stretching, proprioceptive, and balance exercises and activities in water. Many of the reviewed studies proposed an intensive program of physical activity and exercise therapy, conducted 3 times a week for 12 weeks. PMID- 28654500 TI - Commentary on "Physical Exercise and Physical Activity for Children and Adolescents With Juvenile Idiopathic Arthritis: A Literature Review". PMID- 28654501 TI - Developing Overhand Throwing Skills for a Child With Autism With a Collaborative Approach in School-Based Therapy. AB - PURPOSE: This case report presents an interdisciplinary approach in school-based therapy, combining physical therapy and applied behavior analysis to improve the motor skills and the participation in recreational activities of a child with autism spectrum disorder. METHODS: A 9-year-old child with autism spectrum disorder participated in a 20-week gross motor intervention designed to improve the child's overhand throwing ability, which included weekly physical therapy instruction and daily throwing trials using applied behavior analysis approaches. RESULTS: The child demonstrated gains in throwing accuracy, significant gains on measures of the Bruininks-Oseretsky Test of Motor Proficiency-2, the Test of Gross Motor Development-2, and the School Function Assessment. CONCLUSION: This unique approach in school-based therapy demonstrates effective strategies for a multidisciplinary intervention to improve motor learning skills and participation in recreational activities in the school setting. PMID- 28654502 TI - Kinematic Gait Changes Following Serial Casting and Bracing to Treat Toe Walking in a Child With Autism. AB - PURPOSE: To evaluate the effectiveness of serial casting in a child with autism spectrum disorder (ASD) exhibiting a toe-walking gait pattern with equinus contractures. SUMMARY OF KEY POINTS: Although many children with ASD toe walk, little research on physical therapy interventions exists for this population. Serial casting has been validated for use in idiopathic toe walking to increase passive dorsiflexion and improve gait, but not for toe walking in children with ASD. Serial casting followed by ankle-foot orthosis use was implemented to treat a child with ASD who had an obligatory equinus gait pattern. Gait analysis supported improvements in kinematic, spatial, and temporal parameters of gait, and the child maintained a consistent heel-toe gait at 2-year follow-up. STATEMENT OF CONCLUSION AND RECOMMENDATIONS FOR CLINICAL PRACTICE:: Serial casting followed by ankle-foot orthosis use is a viable treatment option for toe walking in children with ASD. PMID- 28654503 TI - Effectiveness of Functional Power Training on Walking Ability in Young Children With Cerebral Palsy: Study Protocol of a Double-Baseline Trial. AB - PURPOSE: To evaluate the effect of functional high-velocity resistance (power) training to improve walking ability of young children with cerebral palsy. METHODS: Twenty-two children with bi- or unilateral spastic cerebral palsy, Gross Motor Function Classification System levels I and II, aged 4 to 10 years will be recruited. A double-baseline design will be used to compare a 14-week functional power training (3 times a week) program with a 14-week usual care period and a 14 week follow-up period. The power exercises will be loaded and performed at 50% to 70% of the maximum unloaded speed. Load will be increased when exercises are performed faster than 70% of the unloaded speed. Primary outcomes will be sprinting capacity (15-m Muscle Power Sprint Test) and goal attainment scaling score of walking-related treatment goals. Secondary outcomes will be walking speed (1-min walk test), endurance (10-m shuttle run test), gross motor function, lower-limb strength, and parent-reported mobility. PMID- 28654504 TI - How Accurately Do Both Parents and Health Professionals Assess Overweight in Children? AB - BACKGROUND: An accurate perception of weight status is important to prevent childhood obesity. OBJECTIVE: We investigated whether parents and health professionals accurately identify children's weight status. METHODS: On the 2012 National Health and Nutrition Examination Survey: National Youth Fitness Survey, parents and health professionals rated the same child's weight status as overweight or healthy. The sensitivity and specificity of their answers were computed by comparing parents' and health professionals' ratings to the age growth chart from the US Centers for Disease Control and Prevention. RESULTS: Participants were 1571 children. Parents' sensitivity and specificity were 0.386 and 0.992, respectively. Health professionals' sensitivity and specificity were 0.343 and 0.981, respectively. CONCLUSIONS: Parents and health professionals demonstrate low sensitivity in identifying children's weight status. Health professionals should use the Centers for Disease Control and Prevention categories to more accurately identify children who are overweight. PMID- 28654505 TI - Avulsion of the Anterior Inferior Iliac Spine Rehabilitation in a Rural Private Practice. AB - An unusual case is presented of an 11-year-old girl presenting for treatment to a semirural private physical therapy practice, not specializing in pediatric care, following an avulsion fracture of the anterior inferior iliac spine. The patient presented initially non-weight-bearing, with little hip movement due to pain. Following treatment, the patient returned to preinjury status including return to full participation in netball. A review of the literature regarding healing and rehabilitation is described. Concepts of neuromuscular retraining were integrated in the rehabilitation program. Recent evidence demonstrates deficiencies in hip and knee control for girls between 11 and 15 years of age. Evidence suggests that these deficiencies may be a precursor to injury and poor outcomes in lower extremity injuries in this patient group. PMID- 28654506 TI - A Progressive Running Program for an Adolescent With Cerebral Palsy. AB - PURPOSE: To describe the physical therapy intervention and outcomes for a 20-week progressive running program. SUMMARY OF KEY POINTS: A 12-year-old boy with spastic diplegic cerebral palsy, Gross Motor Function Classification System level II, participated in a 20-week running program. The 6-minute walk test and the 88 item and 66-item versions of the Gross Motor Function Measure (GMFM) were administered at baseline and program completion. After completion of the program, the participant exceeded thresholds for minimally clinically important differences on the GMFM-66 total score and GMFM-88 Dimension D and E scores. He improved gait speed and distance walked during the 6-minute walk test. CONCLUSIONS AND RECOMMENDATIONS FOR CLINICAL PRACTICE: Participation in a progressive running program is a feasible intervention to promote improvements in walking speed and gross motor function in some adolescents with spastic diplegic cerebral palsy in Gross Motor Function Classification System level II. PMID- 28654507 TI - Effect of Sleeve Gastrectomy on Thyroid Function in Chinese Euthyroid Obese Patients. AB - BACKGROUND: Changes in thyroid function following bariatric surgery in euthyroid obese patients have yielded inconsistent results. Nevertheless, no data exist on changes in thyroid function after bariatric surgery in Chinese obese subjects. OBJECTIVES: The objective of this study is to evaluate the influence of weight reduction on thyroid function following laparoscopic sleeve gastrectomy (LSG) in patients with normal thyroid function. PATIENTS AND METHODS: Serum free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) levels were retrospectively analyzed before and 12 months after LSG in euthyroid patients with morbid obesity. Correlation between weight loss after LSG and changes in thyroid function were investigated. RESULTS: In total, 16 patients who underwent LSG were included in the study. Mean BMI change from 35.78 to 23.66 kg/m (P<0.000) after LSG was associated with a mean reduction in the TSH from 2.31 to 1.54 mU/L (P=0.022), whereas FT4 (15.19+/-0.33 pmol/L at baseline and 14.85+/-0.58 pmol/L at 12 mo after LSG; P=0.583) and FT3 (4.98+/-0.15 pmol/L at baseline and 4.77+/-0.60 pmol/L at 12 mo after surgery; P=0.406) levels remained steady. Decrease in TSH was significantly correlated with decrease in BMI at 12 months after surgery but did not correlate with excess weight loss and total weight loss. CONCLUSIONS: Weight loss after LSG is accompanied by significant decrease in serum TSH level but no change in serum FT4 and FT3 levels. However, further work is required to elucidate the mechanism. PMID- 28654508 TI - How to Successfully Manage Residual Gallbladders Laparoscopically Following Open Techniques? AB - PURPOSE: This study aimed to explore the feasibility and safety of laparoscopic retreatment for residual gallbladders following open techniques, and outline strategies for successful reintervention. PATIENTS AND METHODS: From January 2008 to December 2015, the clinical and follow-up data of 32 patients who underwent laparoscopic reintervention for residual gallbladders following open techniques were retrospectively analyzed and summarized. RESULTS: Of all patients, 4 underwent 2 laparotomic surgeries; 6 had choledocholithiasis and underwent endoscopic retrograde cholangiopancreatography. All procedures for residual gallbladders, except 1, were successfully completed by laparoscopy using 3 to 6 trocars. The mean operative time, mean blood loss, and duration of hospital stay were 51.9+/-14.6 minutes, 30 mL, and 3 to 8 days, respectively. One patient had bilious drainage, lasting up to day 8. All patients remained symptom free, and no mortality and major morbidity were observed on a mean follow-up of at least 6 months. CONCLUSIONS: Laparoscopic management is feasible and safe for residual gallbladders following open techniques, subject to availability of expertise with well-defined strategies. PMID- 28654509 TI - PI3Ks in Diabetic Cardiomyopathy. AB - Diabetic cardiomyopathy is a heart disease in diabetic patients, identified as ventricular dysfunction in the absence of coronary artery disease and hypertension. The molecular mechanisms underlying diabetic cardiomyopathy are still poorly understood. The protein and lipid kinase phosphoinositide 3-kinases (PI3Ks) have been suggested to regulate cardiac injury during diabetes. In this review, we will summarize the role of different PI3K isoforms and of their downstream signaling in the pathogenesis of diabetic cardiomyopathy, including the regulation of cardiac metabolism, contractility, hypertrophy, myocardial cell death, and inflammation. PMID- 28654510 TI - Late INa Inhibition as an Antiarrhythmic Strategy. AB - Late sodium channel current (late INa) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late INa inhibition have been suggested to be (1) suppression of intracellular calcium [Cai]-mediated rhythmic activity (through reduction in Cai secondary to the decrease in intracellular sodium [Nai]) and (2) normalization of repolarization. Endogenous late INa is a small current and acceleration of the heart rate decreases late INa density. Late INa influx may significantly contribute to Nai loading, but it seems to largely occur under the combined conditions of augmented late INa density, bradycardia, and prolonged repolarization. At the same time, the relative contribution of late INa (including endogenous) in any type of prolonged cardiac repolarization is critical. Sodium channel blockers inhibit both late INa and peak INa, and a specific block of late INa might be achieved at slow and normal but seems not at rapid activation rates, at which peak INa, a much greater current, is also likely to be inhibited. The antiarrhythmic potential of a specific inhibition of late INa seems to best fit for, or may be limited to, the prevention of arrhythmias associated with prolonged repolarization, but it seems to be applicable to all types of arrhythmic abnormalities with elongated cardiac repolarization. PMID- 28654511 TI - Changing the Medical Malpractice System to Align With What We Know About Patient Safety and Quality Improvement. PMID- 28654512 TI - Improving Wellness by Improving Autonomy Through Physician Leadership Development. PMID- 28654513 TI - In Reply to Khan. PMID- 28654514 TI - More Transparency Is Needed to Curb Excessive Residency Applications. PMID- 28654515 TI - In Reply to Deng et al. PMID- 28654516 TI - A Proposal to Address the Increasing Number of Residency Applications. PMID- 28654517 TI - A Trainee's Perspective: Delay the Fellowship Start Date. PMID- 28654518 TI - Addressing Digital Wellness in Contemporary Training and Practice. PMID- 28654519 TI - Preparing Medical Schools for Tragedy. PMID- 28654521 TI - Resilience Through Grieving Rounds. PMID- 28654522 TI - Wellness: A Surgical Resident's Perspective. PMID- 28654520 TI - Wellness Programs in Medical School: Reevaluating the Current Paradigm. PMID- 28654523 TI - The Culture of Perfection: A Barrier to Medical Student Wellness and Development. PMID- 28654524 TI - Nonmedical Use of Prescription Stimulants by Medical Students: A Call to Action. PMID- 28654525 TI - The Shadow of Shame. PMID- 28654526 TI - Mindfulness in Residency: Making a Case for More Research. PMID- 28654527 TI - Moral of the Story: Combating Burnout and Apathy. PMID- 28654528 TI - Connection Is the Key: A Military Anecdote. PMID- 28654529 TI - Using Hobbies as a Benchmark for Wellness in Medical Students. PMID- 28654530 TI - Inspiration Repletion: A Missing Ingredient in Resident Wellness. PMID- 28654531 TI - Resident Burnout: Not Just for the "Long Hours" Specialties. PMID- 28654532 TI - Incorporating Advocacy Training to Decrease Burnout. PMID- 28654533 TI - Why I Don't Want a "Work-Life Balance". PMID- 28654534 TI - Burnout Among MD/PhD Trainees: The Forgotten Subgroup. PMID- 28654535 TI - Artist's Statement: Trapped. PMID- 28654536 TI - The Five Stages of Grief. PMID- 28654537 TI - Commentary on "The Five Stages of Grief". PMID- 28654538 TI - Our First Simulator: A Fond Farewell. PMID- 28654539 TI - From Reflex to Reflection: A Resident's Perspective on Learning in a Clinical Setting. PMID- 28654540 TI - Chest Wall Resection for Recurrent Breast Cancer in the Modern Era: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To review the literature on chest wall resection for recurrent breast cancer and evaluate overall survival (OS) and quality-of-life (QOL) outcomes. BACKGROUND: Full-thickness chest wall resection for recurrent breast cancer is controversial, as historically these recurrences have been thought of as a harbinger of systemic disease. METHODS: A systematic search in MEDLINE, EMBASE, and Cochrane CENTRAL identified 48 eligible studies, all retrospective, accounting for 1305 patients. The review is reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Primary end points were patient-centered QOL outcomes and OS; secondary outcomes included disease-free survival (DFS) and 30-day morbidity. Risk of bias was assessed using the Methodological Index for Non-Randomized Studies instrument and the Oxford Centre for Evidence-Based Medicine's levels of evidence tool. Random-effects meta analysis was used to create pooled estimates. Meta-regressions and sensitivity analyses were used to explore study heterogeneity by age, year of publication, risk of bias, and surgical intent (curative vs palliative). RESULTS: Studies consistently reported excellent OS and DFS in properly selected patients. Pooled estimates for 5-year OS in all studies and those from the past 15 years were 40.8% [95% confidence interval (CI) 35.2-46.7) and 43.1% (95% CI 35.8-50.7), whereas pooled 5-year DFS was 27.1% (95% CI 16.6-41.0). Eight studies reported excellent outcomes related to QOL. Mortality was consistently low (<1%) and 30 day pooled morbidity was 20.2% (95% CI 15.3%-26.3%). Study quality varied, and risk of selection bias in included studies was high. CONCLUSIONS: Full-thickness chest wall resection can be performed with excellent survival and low morbidity. Few studies report on QOL; prospective studies should focus on patient-centered outcomes in this population. PMID- 28654541 TI - Caring for Older Surgical Patients: Contemporary Attitudes, Knowledge, Practices, and Needs of General Surgeons and Residents. AB - OBJECTIVE: To gain contemporary insights from residents and surgeons regarding the care of older surgical patients. BACKGROUND DATA: With worldwide aging, efforts over the past decade have attempted to increase surgeons' abilities to care for older adults, but a current understanding of attitudes, knowledge, practices, and needs is missing. METHODS: Between July 2016 and September 2016 we conducted a national Web-based survey sampling all general surgery residents and academic general surgeons using a questionnaire designed and tested for this purpose. Summative scales within each domain (attitudes, knowledge, practices, and needs) were created and compared between groups. Open-ended responses were analyzed with thematic analysis. RESULTS: Ninety-four of 172 invited residents (55%) and 80 of 243 invited surgeons (33%) across 14 general surgery programs responded with no missing data. Both groups had favorable attitudes (83% vs 68%, P = 0.02). However, 80% of residents and 76% of surgeons had medium-level knowledge test scores, and few had prior training. Most respondents reported only sometimes performing guideline-recommended practices (71% vs 73%, P = 0.55). Gaps in training and care delivery were identified. Residents wanted focused, high yield materials and case-oriented practical skills training. Respondents reported further improvements may come from building surgeons' capacity, enhancing collaboration including perioperative geriatric services, better preoperative assessment, increased adherence to perioperative guidelines, and greater community-based supports to recovery. CONCLUSIONS: Residents and surgeons have favorable attitudes, but only moderate geriatric-specific knowledge and only some guideline-adherent practices. We identified gaps in training and care delivery with targets for future knowledge translation and quality improvement initiatives. PMID- 28654542 TI - Percutaneous Vascular Interventions Versus Bypass Surgeries in Patients With Critical Limb Ischemia: A Comprehensive Meta-analysis. AB - OBJECTIVE: The aim of our study was to compare percutaneous vascular interventions (PVI) versus bypass surgeries (BSX) in patients with critical limb ischemia (CLI). BACKGROUND: Previous relevant reviews with limited numbers of included studies did not strictly confine the inclusion criteria to CLI, also involving patients with severe claudication, which may introduce bias in the decision-making of CLI revascularization. Current treatment strategies for CLI still remain controversial. METHODS: We performed a meta-analysis of all available randomized controlled trials and observational clinical studies comparing PVI with BSX in CLI patients. Primary endpoints included overall survival, amputation-free survival, 30-day mortality, and major adverse cardiovascular and cerebrovascular events. RESULTS: We identified 45 cohorts and 1 RCT in over 20,903 patients. In overall population, PVI reduced the risks of 30 day mortality [odds ratio (OR) 0.69, 95% confidence interval (CI) 0.51-0.95), major adverse cardiovascular and cerebrovascular events (OR 0.42, 95% CI 0.29 0.61), and surgical site infection (OR 0.31, 95% CI 0.19-0.51), but increased the risks of long-term all-cause mortality [hazard ratio (HR) 1.16, 95% CI 1.05-1.27) and primary patency failure (HR 1.31, 95% CI 1.08-1.58). When compared with autogenous BSX, PVI was also associated with additional increased risks of long term death or amputation (HR 1.41, 95% CI 1.02-1.94) and secondary patency failure (HR 1.51, 95% CI 1.17-1.95). In patients with infrapopliteal lesions, we found PVI had inferior primary patency (HR 1.39, 95% CI 1.10-1.75) compared with BSX. CONCLUSION: For patients in good physical condition with long life expectancy, BSX may represent a better choice compared with PVI, particularly when autogenous bypass is available. While enhanced perioperative care for cardiovascular events and surgical site should be considered in patients underwent BSX to achieve comparable short-term outcomes provided by PVI. PMID- 28654543 TI - Extended Versus Narrow-spectrum Antibiotics in the Management of Uncomplicated Appendicitis in Children: A Propensity-matched Comparative Effectiveness Study. AB - OBJECTIVE: The aim of this study was to compare the effectiveness of extended versus narrow spectrum antibiotics in preventing surgical site infections (SSIs) and hospital revisits in children with uncomplicated appendicitis. SUMMARY OF BACKGROUND DATA: There is a paucity of high-quality evidence in the pediatric literature comparing the effectiveness of extended versus narrow-spectrum antibiotics in the prevention of SSIs associated with uncomplicated appendicitis. METHODS: Clinical data from the ACS NSQIP-Pediatric Appendectomy Pilot Project were merged with antibiotic utilization data from the Pediatric Health Information System database for patients undergoing appendectomy for uncomplicated appendicitis at 17 hospitals from January 1, 2013 to June 30, 2015. Patients who received piperacillin/tazobactam (extended spectrum) were compared with those who received either cefoxitin or ceftriaxone with metronidazole (narrow spectrum) after propensity matching on demographic and severity characteristics. Study outcomes were 30-day SSI and hospital revisit rates. RESULTS: Of the 1389 patients included, 39.1% received piperacillin/tazobactam (range by hospital: 0% to 100%), and the remainder received narrow-spectrum agents. No differences in demographics or severity characteristics were found between groups following matching. In the matched analysis, the rates of SSI were similar between groups [extended spectrum: 2.4% vs narrow spectrum 1.8% (odds ratio, OR: 1.05, 95% confidence interval, 95% CI 0.34-3.26)], as was the rate of revisits [extended spectrum: 7.9% vs narrow spectrum 5.1% (OR: 1.46, 95% CI 0.75 2.87)]. CONCLUSIONS: Use of extended-spectrum antibiotics was not associated with lower rates of SSI or hospital revisits when compared with narrow-spectrum antibiotics in children with uncomplicated appendicitis. Our results challenge the routine use of extended-spectrum antibiotics observed at many hospitals, particularly given the increasing incidence of antibiotic-resistant organisms. PMID- 28654544 TI - Cytolytic Induction Therapy Improves Clinical Outcomes in African-American Kidney Transplant Recipients. AB - OBJECTIVE: Determine the impact of cytolytic versus IL-2 receptor antibody (IL 2RA) induction on acute rejection, graft loss and death in African-American (AA) kidney transplant (KTX) recipients. BACKGROUND: AAs are underrepresented in clinical trials in transplantation; thus, there is controversy regarding the optimal choice of perioperative antibody induction in KTX to improve outcomes. METHODS: National cohort study using US transplant registry data from January 1, 2000 to December 31, 2009 in adult solitary AA KTX recipients, with at least 5 years of follow-up. Multivariable logistic and Cox regression were utilized to assess the outcomes of acute rejection, graft loss, and mortality, with interaction terms to assess effect modification. RESULTS: Twenty-five thousand eighty-four adult AAs receiving solitary KTX were included, 16,927 (67.5%) received cytolytic induction and 8157 (32.5%) received IL-2RA induction. After adjustment for recipient sociodemographics, donor, and transplant characteristics, the use of cytolytic induction therapy reduced the risk of acute rejection by 32% (OR 0.68, 0.62-0.75), graft loss by 9% (HR 0.91, 0.86-0.97), and death by 12% (HR 0.88, 0.83-0.94). There were a number of significant effect modifiers, including public insurance, panel reactive antibody, delayed graft function, and steroid withdrawal; in these groups, cytolytic induction substantially improved clinical outcomes. CONCLUSIONS: These data demonstrate that cytolytic induction therapy, as compared with IL-2RA, reduces the risk of rejection, graft loss, and death in adult AA KTX recipients, particularly in those who are sensitized, receive public insurance, develop delayed graft function, or undergo steroid withdrawal. PMID- 28654545 TI - Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium. AB - OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates. PMID- 28654546 TI - Sex-specific effect of RNASEL rs486907 and miR-146a rs2910164 polymorphisms' interaction as a susceptibility factor for melanoma skin cancer. AB - The genetics of melanoma is complex and, in addition to environmental influences, numerous genes are involved or contribute toward melanoma predisposition. In this study, we evaluated the possible interaction between miR-146a and one of its putative targets ribonuclease L (RNASEL) in the risk of sporadic melanoma. Polymorphisms rs2910164 in miR-146a and rs486907 in the RNASEL gene have both independently been associated with the risk of different cancers, and an interaction between them has been observed in nonmelanoma skin cancer. Polymorphisms rs2910164 G/C and rs486907 A/G were genotyped by restriction fragment length polymorphism analysis in 304 sporadic melanoma patients and 314 control individuals. Genotype distribution between cases and controls for each of the two polymorphisms was compared using Fisher's exact test. Epistasis between the two polymorphisms was tested by a logistic regression model. In the present study, we observed a sex-specific effect of the miR-146a rs2910164 C allele restricted to individuals carrying the RNASEL rs486907 A allele as well. Men carrying this allelic combination have the highest risk of melanoma, whereas it seems to have no effect or even an opposite relationship to melanoma risk in the female population. The results reported in the present study suggest a sex specific interaction between miR-146a and RNASEL genes in melanoma skin cancer susceptibility, and could account for possible discordant results in association studies when stratification according to sex is not performed. PMID- 28654547 TI - Dendritic cell vaccination for metastatic melanoma: a 14-year monoinstitutional experience. AB - Although immunomodulating antibodies are highly effective in metastatic melanoma, their toxicity, related to the activation of T lymphocytes, can be severe. Anticancer vaccines promote a fairly specific response and are very well tolerated, but their effectiveness has yet to be demonstrated. We have been treating patients with advanced melanoma with an autologous dendritic cell vaccine since 2001; to better characterize the safety and efficacy of our product, we designed a retrospective study on all of our patients treated with the vaccine to date. We retrospectively reviewed both case report forms of patients included in clinical trials and medical records of those treated within a compassionate use program. Response was assessed according to the Response Evaluation Criteria In Solid Tumors criteria and toxicity has been graded according to CTCAE 4.0. Although the response rate has been rather low, the median overall survival of 11.4 months and the 1-year survival rate of 46.9% are encouraging, especially considering the fact that data were obtained in a heavily pretreated population and only about one quarter of the patients had received ipilimumab and/or BRAF inhibitors. Multivariate analysis confirmed that the development of an immune response was significantly correlated with a better prognosis (hazard ratio 0.54; P=0.019). The adverse events observed were generally mild and self-limiting. Our analysis confirms the excellent tolerability of our vaccine, making it a potential candidate for combination therapies. As efficacy seems largely restricted to immunoresponsive patients, future strategies should aim to increase the number of these patients. PMID- 28654548 TI - Histopathologic review of negative sentinel lymph node biopsies in thin melanomas: an argument for the routine use of immunohistochemistry. AB - Sentinel lymph node biopsy (SLNB) is performed for some thin melanomas in the presence of concerning histopathological features. There are no defined standards for how sentinel nodes should be processed to detect microscopic metastases. We compared our method of serially sectioning nodes at 2-3 mm intervals and performing one hematoxylin and eosin (H&E) slide versus multiple H&E levels and utilizing immunohistochemistry (IHC). This was a retrospective review of a prospectively collected database identified patients with thin melanomas treated with wide local excision and SLNB between 1995 and 2010. Two patients had positive nodes. Out of 95 patients with negative SLNBs, 48 (49 nodes) patients were evaluable. Additional sections of each SLNB tissue block were stained with H&E (*2), Melan-A (*2) and HMB45 (*2), and reviewed by two pathologists. Additional histopathological sections showed that 1/49 (2.0%) nodes originally called negative had evidence of metastasis, which was evident both on additional H&E levels and by IHC; 3/49 (6.1%) nodes had benign nodal rests. All other nodes (45/49, 91.8%) were negative by H&E and IHC for metastatic disease. This study supports previous work suggesting the value of IHC in detecting micrometastases in melanoma sentinel nodes. Especially for thin melanomas where metastases are uncommon, but where detection of the metastasis upstages considerably from stage IA to IIIA, evaluation of nodes may be enhanced by combining breadloafing at 2-3 mm intervals with multiple H&E sections and IHC analysis. PMID- 28654549 TI - Workload of Team Leaders and Team Members During a Simulated Sepsis Scenario. AB - OBJECTIVES: Crisis resource management principles dictate appropriate distribution of mental and/or physical workload so as not to overwhelm any one team member. Workload during pediatric emergencies is not well studied. The National Aeronautics and Space Administration-Task Load Index is a multidimensional tool designed to assess workload validated in multiple settings. Low workload is defined as less than 40, moderate 40-60, and greater than 60 signify high workloads. Our hypothesis is that workload among both team leaders and team members is moderate to high during a simulated pediatric sepsis scenario and that team leaders would have a higher workload than team members. DESIGN: Multicenter observational study. SETTING: Nine pediatric simulation centers (five United States, three Canada, and one United Kingdom). PATIENTS: Team leaders and team members during a 12-minute pediatric sepsis scenario. INTERVENTIONS: National Aeronautics and Space Administration-Task Load Index. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-seven teams were recruited from nine sites. One hundred twenty-seven team leaders and 253 team members completed the National Aeronautics and Space Administration-Task Load Index. Team leader had significantly higher overall workload than team member (51 +/- 11 vs 44 +/- 13; p < 0.01). Team leader had higher workloads in all subcategories except in performance where the values were equal and in physical demand where team members were higher than team leaders (29 +/- 22 vs 18 +/- 16; p < 0.01). The highest category for each group was mental 73 +/- 13 for team leader and 60 +/- 20 for team member. For team leader, two categories, mental (73 +/- 17) and effort (66 +/- 16), were high workload, most domains for team member were moderate workload levels. CONCLUSIONS: Team leader and team member are under moderate workloads during a pediatric sepsis scenario with team leader under high workloads (> 60) in the mental demand and effort subscales. Team leader average significantly higher workloads. Consideration of decreasing team leader responsibilities may improve team workload distribution. PMID- 28654550 TI - Promoters and Barriers to Implementation of Tracheal Intubation Airway Safety Bundle: A Mixed-Method Analysis. AB - OBJECTIVES: To describe promoters and barriers to implementation of an airway safety quality improvement bundle from the perspective of interdisciplinary frontline clinicians and ICU quality improvement leaders. DESIGN: Mixed methods. SETTING: Thirteen PICUs of the National Emergency Airway Registry for Children network. INTERVENTION: Remote or on-site focus groups with interdisciplinary ICU staff. Two semistructured interviews with ICU quality improvement leaders with quantitative and qualitative data-based feedbacks. MEASUREMENTS AND MAIN RESULTS: Bundle implementation success (compliance) was defined as greater than or equal to 80% use for tracheal intubations for 3 consecutive months. ICUs were classified as early or late adopters. Focus group discussions concentrated on safety concerns and promoters and barriers to bundle implementation. Initial semistructured quality improvement leader interviews assessed implementation tactics and provided recommendations. Follow-up interviews assessed degree of acceptance and changes made after initial interview. Transcripts were thematically analyzed and contrasted by early versus late adopters. Median duration to achieve success was 502 days (interquartile range, 182-781). Five sites were early (median, 153 d; interquartile range, 146-267) and eight sites were late adopters (median, 783 d; interquartile range, 773-845). Focus groups identified common "promoter" themes-interdisciplinary approach, influential champions, and quality improvement bundle customization-and "barrier" themes-time constraints, competing paperwork and quality improvement activities, and poor engagement. Semistructured interviews with quality improvement leaders identified effective and ineffective tactics implemented by early and late adopters. Effective tactics included interdisciplinary quality improvement team involvement (early adopter: 5/5, 100% vs late adopter: 3/8, 38%; p = 0.08); ineffective tactics included physician-only rollouts, lack of interdisciplinary education, lack of data feedback to frontline clinicians, and misconception of bundle as research instead of quality improvement intervention. CONCLUSIONS: Implementation of an airway safety quality improvement bundle with high compliance takes a long time across diverse ICUs. Both early and late adopters identified similar promoter and barrier themes. Early adopter sites customized the quality improvement bundle and had an interdisciplinary quality improvement team approach. PMID- 28654551 TI - Assuring Sustainable Gains in Interdisciplinary Performance Improvement: Creating a Shared Mental Model During Operating Room to Cardiac ICU Handoff. AB - OBJECTIVE: To understand sustainability and assure long-term gains in multidisciplinary performance improvement using an operating room to cardiac ICU handoff process focused on creation of a shared mental model. DESIGN: Performance improvement cohort project with pre- and postintervention assessments spanning a 4-year period. SETTING: Twenty-six bed pediatric cardiac ICU in a tertiary care children's hospital. PATIENTS: Cardiac surgery patients admitted to cardiac ICU from the operating room following cardiac surgery. INTERVENTIONS: An interdisciplinary workgroup overhauled our handoff process in 2010. The new algorithm emphasized role delineation, standardized communication, and creation of a shared mental model. Our "I-5" mnemonic allowed validation and verification of a shared mental model between multidisciplinary teams. Staff orientation and practice guidelines were revised to incorporate the new process, visual aids were distributed and posted at each patient's bedside, and lapses/audit data were discussed in multidisciplinary forum. MEASUREMENTS AND MAIN RESULTS: Audits assessing equipment and information transfer during handoff were performed 8 weeks following implementation (n = 29), repeated at 1 year (n = 37), 3 years (n = 15), and 4 years (n = 50). Staff surveys prior to implementation, at 8 weeks, and 4 years postintervention assessed satisfaction. Comprehensiveness of information transfer improved in the 4 years following implementation, and staff satisfaction was maintained. At 4 years, discussion of all elements of information transfer was 94%, increased from 85% 8 weeks following implementation and discussion of four or more information elements was 100% increased from 93%. Of the 73% of staff who completed the survey at 4 years, 91% agreed that they received all necessary information, and 87% agreed that the handoff resulted in a shared mental model. CONCLUSIONS: Our methods were effective in creating and sustaining high levels of staff communication and adherence to the new process, thus achieving sustainable gains. Performance improvement initiatives require proactive interdisciplinary maintenance to be successful long term. PMID- 28654552 TI - Severe Upper Airway Obstruction After Intraoperative Transesophageal Echocardiography in Pediatric Cardiac Surgery: A Retrospective Analysis. AB - OBJECTIVES: The aim of this study was to evaluate if there is a correlation between the use of intraoperative transesophageal echocardiography and an increased rate of extubation failure and to find other risk factors for severe upper airway obstructions after pediatric cardiac surgery. DESIGN: Retrospective analysis. SETTING: Cardiac PICU. PATIENTS: Patients 24 months old or younger who underwent surgery for congenital heart disease with cardiopulmonary bypass were retrospectively enrolled and divided into two groups depending on whether they received an intraoperative transesophageal echocardiography or not. We analyzed all cases of early reintubations within 12 hours after extubation due to a documented upper airway obstruction. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: From a total of 424 patients, 12 patients (2.8%) met our criteria of early reintubation due to upper airway obstruction. Ten of 207 children in the transesophageal echocardiography group had to be reintubated, whereas only two of the 217 children in the control group had to be reintubated (4.8% vs 0.9%; p = 0.018). Logistic regression analysis showed a significant correlation between use of intraoperative transesophageal echocardiography and extubation failure (odds ratio, 5.64; 95% CI, 1.18-27.05; p = 0.030). There was no significant relationship among sex (odds ratio, 4.53; 95% CI, 0.93-22.05; p = 0.061), weight (odds ratio, 1.07; 95% CI, 0.82-1.40; p = 0.601), duration of surgery (odds ratio, 1.04; 95% CI, 0.74-1.44; p = 0.834), duration of mechanical ventilation (odds ratio, 1.00; 95% CI, 0.99-1.00; p = 0.998), and occurrence of trisomy 21 (odds ratio, 3.47; 95% CI, 0.83-14.56; p = 0.089). CONCLUSIONS: Although the benefits of intraoperative transesophageal echocardiography during pediatric cardiac surgery are undisputed, it may be one factor which could increase the rate of severe upper airway obstruction after extubation with the need for reintubation. We suggest to take precautions before extubating high-risk patients, especially in young male children with genetic abnormalities after cardiac surgery with cardiopulmonary bypass. PMID- 28654553 TI - Clinical and Histopathologic Features of Colorectal Adenocarcinoma in Crohn's Disease. AB - GOALS: The aim of this study was to assess the histopathologic characteristics of colorectal carcinomas (CRC) in patients with Crohn's disease (CD). BACKGROUND: A higher frequency of microsatellite instability (MSI) is seen in mucinous compared with nonmucinous CRC which suggests that its pathogenesis involves distinct molecular pathways. Several publications reported a higher percentage of mucinous adenocarcinoma in CD patients with CRC. So far, there has been no investigation of MSI in CD patients with mucinous CRC. STUDY: The medical records of patients who underwent surgery for CRC were reviewed and those with a history of CD identified. The data of histologic classification and MSI status of the tumor were investigated. RESULTS: Fourteen patients with CD-associated CRC were identified (5 female, 9 male) resulting in 20 CRC in total. Histologic investigation revealed 7 adenocarcinomas without a mucinous or signet ring cell component. All other CRCs harbored a mucinous (n=11) and/or signet ring cell (n=6) component. All tumors assessed for MSI were found to be microsatellite stable. CONCLUSIONS: Our data indicate that CRCs with signet ring cell and mucinous components were much more common in patients with CD than in patients with sporadic CRC. This observation suggests that CRC in CD represent an own entity with distinct histopathologic and molecular features. This may implicate potential consequences for diagnosis and therapy of CRC in CD in the future as well as new factors to identify patients with an increased risk for developing CRC in CD. PMID- 28654554 TI - Baseline Hepatitis B Virus Titer Predicts Initial Postpartum Hepatic Flare: A Multicenter Prospective Study. AB - BACKGROUND AND GOALS: A series of changes in the immune system occur during pregnancy and puerperium. Currently, we aim to characterize both the natural changes in liver inflammation and its association with hepatitis B viremia during this special period. PATIENTS AND METHODS: Chronic hepatitis B (CHB) gravidas were recruited and followed up to 52 weeks postpartum. Virological and biochemical parameters were assessed throughout the period. RESULTS: A total of 1097 CHB mothers had finished the entire follow-up including 451 accepting telbivudine, 178 accepting tenofovir, and 468 without antiviral therapy. Among the mothers, 11.94% went through hepatic flare in the first trimester and the rate decreased to 2.1% at the time of delivery. Nevertheless, a much higher frequency (19.78%) was observed in the early postpartum. Interestingly, alanine aminotransferase level decreased along with the development of pregnancy and then suddenly increased in the first month of puerperium. In addition, a downward trend was observed on the titer of HBsAg and HBeAg after delivery. Of note, an obvious higher frequency of alanine aminotransferase flare was revealed in mothers with high viremia (>6 log10 IU/mL). With multivariate analysis, only hepatitis B virus titer at baseline was strongly associated with hepatic flare during early postpartum (95% confidence interval, 1.012-3.049, P=0.045). The predictive rates of hepatic flare at baseline viral load of 6, 7, and 8 log10 IU/mL were 16.67%, 28.30%, and 30.60%, respectively. CONCLUSIONS: CHB gravidas with high viremia should be monitored closely during entire pregnancy, and extended antiviral therapy is recommend to those mothers with baseline viremia >7 log10 IU/mL. PMID- 28654555 TI - The Experience of Pain Dismissal in Adolescence. AB - CONTEXT: Pain in adolescence has psychosocial effects lasting into adulthood, including increased likelihood of pain in adulthood and higher rates of depression and anxiety. Many adolescents with chronic pain describe skepticism of pain reports, but this has not yet been evaluated in a sample of typically developing adolescents. OBJECTIVE: The current study sought to describe the experience of perceived pain dismissal during adolescence in a community sample. METHOD: Nearly 2000 (1931) emerging adults were recruited from the community and answered open-ended questions regarding whether they had experienced dismissal of their pain in adolescence, who dismissed their pain, characteristics of the dismisser, and what that experience was like. Qualitative responses were coded using a Delphi method. RESULTS: One in 10 young adults reported an experience of pain dismissal during adolescence. Young adults reported that dismissals by parents and physicians were the most distressing. Often, this experience was associated with a lasting sense of hostility toward the person who dismissed their pain, as well as anger, self-directed negativity, damage to the relationship, and feelings of isolation. CONCLUSIONS: One in 10 young adults reported at least one instance of dismissed pain and half of these instances involved a parent or medical provider. Results suggest a lasting negative impact of perceived dismissal. Pain in adolescence is a complicated experience and the current study indicates that parents and physicians need further guidance on how best to respond to reports of pain. PMID- 28654556 TI - Patient-controlled Intravenous Analgesia With Combination of Dexmedetomidine and Sufentanil on Patients After Abdominal Operation: A Prospective, Randomized, Controlled, Blinded, Multicenter Clinical Study. AB - OBJECTIVE: To investigate the effect of combination of dexmedetomidine and sufentanil on patient-controlled intravenous analgesia (PCIA) in patients after abdominal operation and to assess the safety and validity of this treatment. METHODS: This is a prospective, randomized controlled, blinded, multicenter clinical study. A total of 210 patients from 9 clinical research centers underwent selective abdominal operation with general anesthesia were enrolled in the study, including laparoscopic-assisted abdominal operation on stomach, intestines or open surgery on stomach, intestines, kidneys and liver, the American Society of Anesthesiologists status I to II. Patients were randomly assigned into 2 groups: control group (group C) sufentanil 100 MUg+normal saline 100 mL in total and test group (group D) sufentanil 100 MUg+ dexmedetomidine 200 MUg+normal saline 100 mL in total. PCIA was set as follow: background infusion of sufentanil 2 MUg/h, bolus dose of sufentanil 2 MUg, lockout interval 5 minutes. Main measure indices were analgesic consumption, pressing times and effective pressing times of analgesic pump, usage count, and consumption of remedy drug. Validity indices were visual analog scale (VAS) scores and patient satisfaction. Drug safety indices were hemodynamic parameters, drug side effects, and anal exhaust time. RESULTS: In total, 203 cases were analyzed. Seven cases were eliminated for incomplete data record. The total consumption of sufentanil (MUg) in 24 hours after operation of group C and group D were 56.9+/-21.5 and 49.8+/ 15.5, respectively, and the difference was statistically significant (P<0.05). Pressing times of analgesic pump in 24 hours after operation of group C and group D were 9.47+/-16.07 and 5.02+/-5.56 times, respectively, and the difference was statistically significant (P<0.05). Effective pressing times of analgesic pump in 24 hours after operation of group C and group D were 7.8+/-9.7 and 4.57+/-5.02 times, respectively, and the difference was statistically significant (P<0.05). Resting VAS scores and movement VAS scores at 2, 4, 8, and 24 hours postoperatively were statistically different (P<0.05). Usage times of rescue drug (pethidine) of group C and group D were 9 and 1, mean rank 118.13 and 85.71, respectively, and the difference was statistically significant (P<0.05). Mean rank of general satisfaction of group C and group D were 98.99 and 105.04, respectively, and the difference was statistically significant (P<0.05). Incidence rate of nausea in group C and group D within 24 hours after surgery was 25% and 12.5%, and of vomiting 18.2% and 6.25%, respectively and of vomiting and the difference was statistically significant. CONCLUSIONS: Compared with sufentanil PCIA alone, the combination of dexmedetomidine and sufentanil for PCIA after abdominal operation could reduce sufentanil consumption, decrease VAS scores, lower the rate of nausea and vomiting, and improve patient satisfaction. PMID- 28654557 TI - The Effectiveness of Transcranial Direct Current Stimulation as an Add-on Modality to Graded Motor Imagery for Treatment of Complex Regional Pain Syndrome: A Randomized Proof of Concept Study. AB - BACKGROUND: The efficacy of Graded Motor Imagery (GMI) for the management of Complex Regional Pain Syndrome (CRPS) is supported by evidence, but its treatment effect remains generally modest. Transcranial Direct Current Stimulation (tDCS) has been advocated as an adjunct intervention to enhance the effect of motor imagery approaches in pain populations. OBJECTIVE: The purpose of this study was to investigate the effectiveness of GMI+active tDCS compared with the GMI+sham tDCS in the treatment of CRPS type I. METHODS: A total of 22 patients (n=11/group) were randomly assigned to the experimental (GMI+tDCS) or placebo (GMI+sham tDCS) group. GMI treatments lasted 6 weeks; anodal tDCS was applied over the motor cortex for 5 consecutive days during the first 2 weeks and once a week thereafter. Changes in pain perception, quality of life, kinesiophobia, pain catastrophizing, anxiety and mood were monitored after 6 weeks of treatment (T1) and 1-month posttreatment (T2). RESULTS: GMI+tDCS induced no statistically significant reduction in pain compared with GMI+sham tDCS. Although we observed significant group differences in kinesiophobia (P=0.012), pain catastrophizing (P=0.049), and anxiety (P=0.046) at T1, these improvements were not maintained at T2 and did not reached a clinically significant difference. DISCUSSION: We found no added value of tDCS combined with GMI treatments for reducing pain in patients with chronic CRPS. However, given that GMI+sham tDCS induced no significant change, further studies comparing GMI+tDCS and tDCS alone are needed to further document tDCS's effect in CRPS. PMID- 28654558 TI - The Efficacy of Ultrasound-guided Type II Pectoral Nerve Blocks in Perioperative Pain Management for Immediate Reconstruction After Modified Radical Mastectomy: A Prospective, Randomized Study. AB - OBJECTIVES: The pectoral nerves (Pecs) II block is a technique that places local anesthetic between the thoracic muscles to block the axillary and breast regions. This study aimed to compare the quality of perioperative analgesia and side effects of the Pecs II block under general anesthesia versus general anesthesia alone in immediate unilateral breast reconstruction with an implant and latissimus dorsi flap after modified radical mastectomy. MATERIALS AND METHODS: Sixty-four patients scheduled for immediate breast reconstruction after modified radical mastectomy were randomly allocated into the Pecs II block under general anesthesia group (group P, n=32) or the general anesthesia alone group (group G, n=32). After anesthesia induction, patients in group P underwent a Pecs II block. The primary endpoint was postoperative morphine consumption in the first 24 hours in postoperative intensive care unit. Intraoperative fentanyl consumption, visual analog scale scores, shoulder range of motion, and postoperative nausea and vomiting were also assessed. RESULTS: Sixty patients completed the study. There was a significant reduction in postoperative morphine consumption (3.67 mg; 95% confidence interval, 2.91-4.51 mg) and intraoperative fentanyl consumption in group P patients compared with group G patients. Less postoperative nausea and vomiting (relative risk 0.22; 95% confidence interval, 0.05-0.94) and lower visual analog scale scores were also observed in group P. No block-related complications were recorded. DISCUSSION: When patients underwent immediate breast reconstruction with an implant and latissimus dorsi flap, the Pecs II block offers a comprehensive block of associated nerves in the surgical area, and therefore can provide superior analgesia and reduced perioperative opioids use without obvious block-related complications. PMID- 28654559 TI - The Role of Preoperative Radiologic Severity, Sensory Testing, and Temporal Summation on Chronic Postoperative Pain Following Total Knee Arthroplasty. AB - OBJECTIVES: Knee osteoarthritis (KOA) can be associated with local and central sensitization. As an indicator of the central gain, facilitated temporal summation of pain (TSP) has been found in KOA patients. This facilitation is predictive of the development of chronic postoperative pain after total knee arthroplasty (TKA). Other studies have suggested hypoesthesia/hypoalgesia to thermal stimuli as a feature in KOA. This study investigated associations between preoperative TSP, thermal sensitivity, and radiologic severity for the development of chronic postoperative pain after TKA. METHODS: Radiologic KOA (Kellgren and Lawrence), TSP, and thermal stimuli were collected, preoperatively. Clinical knee pain intensity (VAS 0-10) was assessed before and 12 months following TKA. Patients were categorized into a chronic postoperative pain group if they experienced <30% pain reduction of the initial pain after 12 months. RESULTS: In total, 19% of the patients were categorized as chronic pain patients and presented facilitated preoperative TSP (P<0.05) and a trend towards increased heat pain threshold (P=0.077) compared with patients with normal recovery. Pearson correlations found that preoperative TSP (R=0.193; P=0.013), Kellgren and Lawrence (R=-0.168; P=0.027), warm detection threshold (R=0.195; P=0.012), and heat pain threshold (R=0.196; P=0.012) were associated with pain intensity 12 months after TKA where TSP was identified as an independent factor. DISCUSSION: This study showed that preoperatively facilitated TSP in KOA patients was predictive of the development of chronic postoperative pain following TKA. Furthermore, this study is the first to find an association between preoperative hypoalgesia to heat and the development of chronic postoperative pain following TKA. PMID- 28654560 TI - Ochrobactrum anthropi Fulminant Early-onset Neonatal Sepsis: A Case Report and Review of Literature. AB - Ochrobactrum anthropi is Gram-negative bacteria that cause infection in humans, particularly immunocompromised patients and those with indwelling central venous catheters. O. anthropi is unlikely to cause fulminant sepsis in infected patients. A few cases of late-onset neonatal sepsis have been reported in preterm infants with congenital anomalies. We hereby present the first published case of fulminant early-onset neonatal sepsis in a premature newborn. PMID- 28654561 TI - Influenza-associated Encephalitis/Encephalopathy Identified by the Australian Childhood Encephalitis Study 2013-2015. AB - BACKGROUND: Influenza-associated encephalitis/encephalopathy (IAE) is an important cause of acute encephalitis syndrome in children. IAE includes a series of clinicoradiologic syndromes or acute encephalopathy syndromes that have been infrequently reported outside East Asia. We aimed to describe cases of IAE identified by the Australian Childhood Encephalitis study. METHODS: Children <= 14 years of age with suspected encephalitis were prospectively identified in 5 hospitals in Australia. Demographic, clinical, laboratory, imaging, and outcome at discharge data were reviewed by an expert panel and cases were categorized by using predetermined case definitions. We extracted cases associated with laboratory identification of influenza virus for this analysis; among these cases, specific IAE syndromes were identified where clinical and radiologic features were consistent with descriptions in the published literature. RESULTS: We identified 13 cases of IAE during 3 southern hemisphere influenza seasons at 5 tertiary children's hospitals in Australia; 8 children with specific acute encephalopathy syndromes including: acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late diffusion restriction, mild encephalopathy with reversible splenial lesion, and hemiconvulsion-hemiplegia syndrome. Use of influenza-specific antiviral therapy and prior influenza vaccination were infrequent. In contrast, death or significant neurologic morbidity occurred in 7 of the 13 children (54%). CONCLUSIONS: The conditions comprising IAE are heterogeneous with varied clinical features, magnetic resonance imaging changes, and outcomes. Overall, outcome of IAE is poor emphasizing the need for optimized prevention, early recognition, and empiric management. PMID- 28654562 TI - Cardio-respiratory Events and Inflammatory Response After Primary Immunization in Preterm Infants < 32 Weeks Gestational Age: A Randomized Controlled Study. AB - BACKGROUND: Inflammation may depress respiration in neonates. This study aimed to establish a link between postimmunization inflammation and cardio-respiratory events (CREs). METHODS: Randomized double-blind controlled study of infants born < 32 weeks gestation receiving the 2 months vaccine, which comprised diphtheria and tetanus toxoids and acellular pertussis adsorbed combined with inactivated poliomyelitis vaccines and Haemophilus b conjugate and the pneumococcal conjugate 10-valent vaccines. Infants were randomized to ibuprofen treatment or a placebo group (n = 28/group). C-reactive protein (CRP) and prostaglandins E2 (PgE2) levels were assessed before and after immunization. CREs were recorded for 72 hours. Heart rate variability was assessed by polysomnography. RESULTS: In the placebo group, immunization was associated with significantly increased CRP levels and an increase in CRE (8.6 +/- 11.1 before versus 14.0 +/- 12.8 after), which did not reach statistical significance (P = 0.08), and no change in PgE2. The increase in CRP was correlated with changes in CRE (r = 0.4: P < 0.05). In the ibuprofen group, immunization significantly increased CRP levels but was not associated with change in CRE (6.7 +/- 7.7 before versus 6.8 +/- 9.7 after) and PgE2 levels. Comparing the groups, variation in CRE (DeltaCRE before versus after immunization) was significantly lower in the ibuprofen group (0.1 +/- 7.9 versus 5.4 +/- 10.0 DeltaCRE; P < 0.05). CONCLUSION: The first immunization of infants born < 32 weeks was associated with an increase in CRP. Ibuprofen treatment significantly attenuated the variation (Delta) in CRE following first immunization in these infants but the current study could not demonstrate an impact on CRP and PgE2 levels. The impact of anti-inflammatory treatment on antigenicity must be evaluated before their clinical use aiming at reducing CRE after immunization in preterm infants. PMID- 28654563 TI - Neuroborreliosis in Swedish Children: A Population-based Study on Incidence and Clinical Characteristics. AB - BACKGROUND: Borrelia burgdorferi is a common cause of bacterial meningitis, but there are very few studies on incidence in Europe. The aim of this study was to report the incidence and symptoms of neuroborreliosis in Swedish children. METHODS: Medical records of children (< 15 years) treated for neuroborreliosis 2002-2014 were studied retrospectively. The patients were identified in the computerized registers of discharge diagnoses at the Departments of Pediatrics and Infectious Diseases in Gothenburg, Boras, Trollhattan and Halmstad using International Classification of Diseases 10 diagnosis codes G51.0, G01.9 and/or A69.1. Of those, patients with symptoms compatible with neuroborreliosis and a white blood cell count in cerebrospinal fluid >= 7 cells/mm with >= 80% mononuclear cells were included. Only children living in the city of Gothenburg and 10 surrounding municipalities were included. RESULTS: Five hundred forty eight children were included. The median age was 7 (1-14) years. The total incidence for the 13-year-period was 2.8/10,000 and remained unchanged during the period. The incidence was significantly higher in rural (4.0/10,000) than in urban municipalities (2.1/10,000). The most common presenting symptoms were headache (n = 335), fatigue (n = 330) and cranial nerve palsies (n = 329). The median duration of symptoms before admittance was 4.0 days for facial palsy and 14.0 days for other symptoms (P < 0.001). The median white blood cell count in cerebrospinal fluid was 129 (7-1069) cells/mm. CONCLUSIONS: This study is the largest so far in a pediatric population. The incidence of neuroborreliosis was higher than in previous European reports. This might be explained by increased Borrelia awareness, the distribution of tick population in Sweden, and the possibility that Swedish children more frequently play outdoors. PMID- 28654564 TI - Post-Malaria Neurologic Syndrome: A Rare Pediatric Case Report. AB - Post-malaria neurologic syndrome (PMNS) is a rare complication following a Plasmodium falciparum infection and its pathophysiology remains unclear. This is the first report of a pediatric PMNS following an infection acquired in Africa and the fourth description of pediatric PMNS overall. Neither intrathecal synthesis of Immunoglobin G nor specific P. falciparum antibodies were found in the cerebrospinal fluid. PMID- 28654565 TI - Coauthors and Collaboration in Scientific Publication. PMID- 28654566 TI - Prospective State and Trait Predictors of Daily Medication Adherence Behavior in HIV. AB - BACKGROUND: Many persons living with HIV (PLWH) are nonadherent to medication. Trait level measures that ask about predictors of adherence in the abstract may not adequately capture state level daily variability that more directly impacts adherence. OBJECTIVES: This preliminary study was designed to test six predictors of electronically monitored adherence at both the state and trait levels and to compare their relative effects. METHODS: Using a smartphone, 87 PLWH completed randomly cued daily surveys on thoughts, mood, stress, coping, social support, and treatment motivation. All participants also completed baseline surveys on each construct. These state and trait variables were tested as prospective predictors of next-day adherence in multilevel models, and their relative importance was quantified. The analysis sample consisted of 53 PLWH who stored their most frequent antiretroviral medication in a bottle that time-stamped openings to measure adherence. RESULTS: Higher state level motivation, OR = 1.55, 95% CI [1.07, 2.24], and negative mood, OR = 1.33, 95% CI [1.07, 1.63], predicted greater adherence the following day. Importantly, these effects were only found at the state level. Trait level control beliefs predicted greater adherence, OR = 1.65, 95% CI [1.17, 2.35], but contrary to prediction, validated trait level measures of mood, stress, coping, social support, and motivation did not. DISCUSSION: Trait and state level measures predicted adherence, but there were differences between them. Motivation for treatment and negative mood predicted adherence when measured the preceding day, but not as aggregate measures. At the trait level, only control beliefs predicted adherence. Researchers should consider state level variations in mood and motivation as possible explanations for nonadherence. Interventions could be developed to target state level variables. PMID- 28654567 TI - Worry in Head and Neck Cancer Caregivers: The Role of Survivor Factors, Care Related Stressors, and Loneliness in Predicting Fear of Recurrence. AB - BACKGROUND: Fear of recurrence (FOR) is a primary concern for both cancer survivors and their caregivers, yet little is known about what care-related factors exacerbate this worry. OBJECTIVES: This study aimed to establish the role of care-related stressors-as distinct from survivor characteristics-in predicting FOR in head and neck cancer caregivers. METHODS: HNC survivor-caregiver dyads took part in a mailed survey. Survivors provided information on health and quality of life (using the Functional Assessment of Cancer Therapy Questionnaire). Caregivers provided sociodemographic information, impact of caring on their time and finances, as well as their level of social support (Oslo Support Scale), loneliness (3-point loneliness scale), and completed the Worry of Cancer Scale (to measure FOR). RESULTS: Data from 180 dyads were available for analysis. Multiple regression analysis was used to examine the role of caregiver stressors, social support, and loneliness while controlling for caregiver and survivor characteristics. The model explained 28% of the variance in Worry of Cancer scores (FOR). Caregivers who reported more loneliness, spent more time caring, and had greater financial stress from caring had higher scores on Worry of Cancer (FOR). Female caregivers, those caring for younger survivors, and those with survivors who had undergone less extensive forms of surgery also reported higher FOR. DISCUSSION: A combination of factors place caregivers at greater risk of cancer-related worry, paving the way for designing interventions aimed at reducing FOR in caregivers of patients with head and neck cancers. PMID- 28654568 TI - Elders' Experiences During Return Visits to the Emergency Department: A Phenomenographic Study in Taiwan. AB - BACKGROUND: Elders often experience multiple chronic diseases associated with frequent early return visits to emergency departments (EDs). There is limited knowledge of the experiences and concerns of elders during ED return visits. OBJECTIVES: The purpose of the research was to explore the experiences of elders during ED return visits, with a view toward identifying factors that contribute to return visits. METHODS: The qualitative approach of phenomenography was used. Data were collected at one ED in a 3,000-bed medical center in Taiwan. Inclusion criteria were aged 65 or above and return visits to the ED within 72 hours of discharge from an index ED visit. The seven steps of qualitative data analysis for a phenomenographic study were employed to develop understanding of participants' experiences. RESULTS: Thirty return-visit elders were interviewed in 2014. Four categories of description were established from the participants' accounts. These were "being tricked by ED staff," "doctor shopping," "a sign of impending death," and "feeling fatalistic." The outcome space of elders with early return visits to ED was characterized as "seeking the answer." CONCLUSION: Index ED visits are linked to return visits for Taiwanese elders through physiological, psychological, and social factors. PMID- 28654569 TI - Maintaining Interrater Agreement of Core Assessment Instruments in a Multisite Randomized Controlled Clinical Trial: The Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) Trial. AB - BACKGROUND: RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) was a cluster randomized clinical trial evaluating a sedation strategy in children 2 weeks to <18 years of age with acute respiratory failure supported on mechanical ventilation. A total of 31 U.S. pediatric intensive care units (PICUs) participated in the trial. Staff nurse rater agreement on measures used to assess a critical component of treatment fidelity was essential throughout the 4-year data collection period. OBJECTIVE: The purpose of the study is to describe the method of establishing and maintaining interrater agreement (IRA) of two core clinical assessment instruments over the course of the clinical trial. METHODS: IRA cycles were carried out at all control and intervention sites and included a minimum of five measurements of the State Behavioral Scale (SBS) and Withdrawal Assessment Tool-Version 1 (WAT-1). Glasgow Coma Scale scores were also obtained. PICUs demonstrating <80% agreement repeated their IRA cycle. Fleiss's kappa coefficient was used to assess IRA. RESULTS: Repeated IRA cycles were required for 8% of 226 SBS cycles and 2% of 222 WAT-1 cycles. Fleiss's kappa coefficients from more than 1,350 paired assessments were .86 for SBS and .92 for WAT-1, demonstrating strong agreement and similar to .91 for the Glasgow Coma Scale. There was no difference in Fleiss's kappa for any of the instruments based on unit size or timing of assessment (earlier or later in the study). For SBS scores, Fleiss's kappa was significantly different in larger and smaller PICUs (.82 vs. .92, p = .003); however, Fleiss's kappa for both groups indicated excellent agreement. CONCLUSION: Monitoring measurement reliability is an essential step in ensuring treatment fidelity and, thus, the validity of study results. Standardization on the use of these core assessment instruments among participating sites was achieved and maintained throughout the trial. PMID- 28654571 TI - Radiotherapy Alone or With Chemotherapy in the Management of Carcinoma of the Supraglottic Larynx: A 25-Year Community Hospital Experience. AB - OBJECTIVES: The purpose of this study was to retrospectively review outcomes for patients treated with definitive radiotherapy for carcinoma of the supraglottic larynx at a community hospital and to compare our results with the literature. MATERIALS AND METHODS: Treatment records of 46 patients with localized carcinoma of the supraglottic larynx treated from January 1987 through January 2012 were reviewed. Overall, 18 (39%) presented with stage I or II disease, whereas 28 (61%) presented with stage III to IV. In total, 30 patients (65%) were treated using hyperfractionation, whereas 16 (35%) received once-daily fractionation. Twelve patients (26%) received concurrent chemotherapy with weekly cisplatin. The Kaplan-Meier method was used to assess outcomes. RESULTS: The median follow-up for the living patients was 6.7 years (range, 1.7 to 23.1 y). At 5 years, the local-regional control (LRC), ultimate LRC, laryngeal preservation, and overall survival (OS) rates were 70%, 82%, 65%, and 53%, respectively. At 5 years, disease-free survival and cause-specific survival rates were 75% and 76%, respectively. The 5-year OS rates by American Joint Committee on Cancer stage were as follows: I to II, 61%; III, 51%; and IV, 44%. For those receiving concurrent chemotherapy, there was no improvement in 5-year LRC (83% vs. 66%; P=0.4081) or OS (55% vs. 50%; P=0.7697). For those receiving hyperfractionation, there was no improvement in 5-year LRC (75% vs. 63%; P=0.3369) or OS (55% vs. 50%; P=0.4161). CONCLUSIONS: Our outcomes are similar to those reported in the literature. Neither hyperfractionation nor chemotherapy appeared to confer a benefit for disease control or OS possibly owing to small sample size and the inherent bias of a retrospective review. PMID- 28654570 TI - Fear and Risk of Falling, Activities of Daily Living, and Quality of Life: Assessment When Older Adults Receive Emergency Department Care. AB - BACKGROUND: Falls tend to create fear and concern in older adults who also seek care in emergency departments (EDs) at high rates. AIM: The purposes of this study were to (a) describe risk and fear of falling in older adults seeking care in the ED and (b) explore relationships between risk and fear of falling with activities of daily living and quality of life. METHODS: The study was conducted in the ED of Ondokuz Mayis University Hospital in Samsun, Turkey. Data were collected for 7 months in 2013-2014. Adults aged 65 years and above who scored at least 20 on the Standardized Mini-Mental Test and who presented for care in the ED were eligible to take part. Patients self-reported demographic information and completed the Tinetti Falls Efficacy Scale, the Morse Fall Scale, the Nottingham Health Profile (NHP), and the Modified Barthel Index (MBI). RESULTS: A total of 151 older adults took part. Prevalence of falls was high (48.3%), as well as fear of falling (63.6%). Risk of falling (Morse Fall Scale scores) was negatively correlated with the ability to carry out activities of daily living (MBI scores; r = -.50, p < .001) and positively related to scores on the NHP (r = .45, p < .001); likewise, fear of falling (Falls Efficacy Scale scores) was negatively correlated with the ability to carry out activities of daily living (MBI scores; r = -.79, p < .001) and positively correlated with NHP scores (r = .64, p < .001). DISCUSSION: Older adults seeking care in the ED who have a higher risk of falling are more dependent in daily living activities and experience lower quality of life. Care seeking in the ED offers an opportunity to assess fall risk and fear of falling and provide guidance on prevention and management of falls in older adults. PMID- 28654572 TI - Quantifying Decreased Radiation Exposure From Modern CT Scan Technology and Surveillance Programs of Germ Cell Tumors. AB - INTRODUCTION: Upgrading computerized tomography (CT) scanners to iterative reconstruction techniques (IRT) decreases radiation dose. This reduction, combined with changes in surveillance protocols in clinical stage I testicular cancer (CS1TC) measurably decrease the lifetime attributable risk (LAR) of dying of radiation-associated cancer. MATERIALS AND METHODS: This IRB-approved study enrolled 24 CS1TC patients who had CT scans on the same Toshiba Aquilion 64 CT before and after IRT software installation. Dose-length product and CT dose index volume were recorded. A physicist calculated effective doses. Radiation doses were compared using the Wilcoxon signed rank test. Median effective dose per scan was multiplied by scan number based on 16 versus 7 scans in 5-year AS protocols to calculate estimated cumulative dose (ECD). LAR of dying of radiation associated solid tumor was estimated using ECD for a single exposure at age 35 with the excess absolute risk transport model from the BEIR VII analysis of long term atomic bomb survivors. RESULTS: Median preupgrade and postupgrade effective doses were 12.5 and 7.7 mSv, respectively (P<0.0001). A linear regression model with a constrained zero intercept fit to the data found that IRT dose was estimated as 61% of filtered back projection dose (95% confidence interval, 0.56 0.66). The IRT upgrade reduced the LAR of the 16-scan protocol 35%. Combination of IRT upgrade and 7-scan protocol reduced surveillance LAR 72%. CONCLUSIONS: Modern CT technology combined with reduced scanning strategies can markedly decrease lifetime radiation exposure, further lowering the already small potential mortality of imaging-associated cancers. PMID- 28654573 TI - Patterns of Adjuvant Therapy Utilization in Uterine Carcinosarcoma Stages I to III: A National Cancer Database Analysis. AB - OBJECTIVE: The objective of this study is to characterize patterns of utilization of adjuvant chemotherapy (CT) and radiotherapy (RT) in the posthysterectomy management of uterine carcinosarcoma (UCS) in the United States. MATERIALS AND METHODS: We queried the National Cancer Database for women diagnosed with UCS between 2004 and 2012 and undergoing hysterectomy. Logistic regression was performed to identify sociodemographic, facility-specific, and treatment-related predictors of receiving multiagent chemotherapy, external beam radiotherapy (EBRT), or brachytherapy (BT). RESULTS: In total 4272 patients were included, with 2 in 5 (40.5%) receiving no adjuvant therapy. Regarding RT, 2357 (55.1%) received neither EBRT nor BT, 929 (21.7%) received EBRT alone, 518 (12.1%) received BT alone, and 468 (11.0%) received EBRT+BT. Most women (70.8%) received no CT, a minority (1.5%) received single-agent CT, and the rest (27.8%) received multiagent chemotherapy. Logistic regression demonstrated disparities in receipt of adjuvant therapies by age, diagnosis year, insurance, facility volume, facility type, stage, and margin status, with patients with positive surgical margins less likely to receive BT. CONCLUSIONS: Following hysterectomy for UCS, a large proportion of women receives no CT and no RT in the United States. Multispecialty evaluation is critical for individualization of therapy and may address disparities in this aggressive disease. PMID- 28654574 TI - Capecitabine and Celecoxib as a Promising Therapy for Thymic Neoplasms. AB - OBJECTIVES: For patients with unresectable or metastatic thymic epithelial neoplasms, few therapy options are available and outcomes are poor. This case series demonstrates that the combination of capecitabine and celecoxib may be a promising therapeutic option for these patients. MATERIALS AND METHODS: The current report describes the outcomes of 5 patients with thymic neoplasms treated on a drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies (NCT01705106) conducted at the University of Chicago, plus a sixth patient treated with the same regimen outside of the protocol. RESULTS: Six patients with thymic neoplasms were treated with capecitabine 1000 mg/m twice daily and celecoxib 200 mg twice daily, day 1 to day 14 on a 21-day cycle. This included 3 patients with thymic carcinoma, 1 with thymic neuroendocrine tumor, and 2 with thymomas. Objective response rates were noted in 3 of 6 patients. Two of the 3 thymic carcinoma patients had complete responses, and the third had a partial response. Best response for the other patients included stable disease for both thymoma patients and progressive disease for the thymic neuroendocrine patient. Other than grade 3 palmar-plantar erythrodysesthesia, which developed in 4 of 6 patients and required dose reductions, the regimen was well tolerated. CONCLUSIONS: This case series suggests that capecitabine plus celecoxib may be an effective and well-tolerated treatment option for patients with thymic carcinoma. Further studies should be carried out to establish the efficacy of capecitabine plus celecoxib in thymic carcinoma, and to determine whether monotherapy with capecitabine would be similarly effective. PMID- 28654575 TI - Update on classification and diagnosis of vascular malformations. AB - PURPOSE OF REVIEW: This review provides an update of the classification in the classification of vascular anomalies since April 2014 at the International Society for the Study of Vascular Anomalies meeting in Melbourne, Australia. RECENT FINDINGS: The reader will become familiar with how to diagnose the major vascular malformations, including capillary, venous, arteriovenous, and lymphatic and combinations thereof. In addition, vascular malformation syndromes, including those with overgrowth, will be clarified. SUMMARY: Vascular malformations are common. Capillary malformations are now better understood through an updated classification. Verrucous hemangioma is truly a venulocapillary malformation that extends into the subcutis. PIK3Ca-Related Overgrowth Syndromes encompass Klippel Trenaunay, Congenital Lipomatous Asymmetric Overgrowth of the Trunk with Lymphatic, Capillary, Venous, and Combined-Type Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal Anomalies, Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome (M-CAP), fibroadipose hyperplasia, and macrodactyly. Yet another syndrome should be highlighted: Capillary Malformation of the Lower Lip, Lymphatic Malformation of the Face and Neck, Asymmetry and Partial/Generalized Overgrowth. Knowledge of the genetic basis of vascular malformations will lead to future treatments. PMID- 28654576 TI - Effect of Postoperative Dressing on Excisions Performed on the Leg: A Comparison Between Zinc Oxide Compression Dressings Versus Standard Wound Care. AB - BACKGROUND: Wound healing on the legs may be complicated by delayed healing and other postoperative problems. Two potential postoperative wound care regimens for sutured excisions on the legs include a standard pressure dressing and zinc oxide compression dressings. Limited data exist comparing the efficacy of these 2 options. OBJECTIVE: To compare outcomes of standard postoperative wound care dressing versus postoperative use of a zinc oxide compression dressings for sutured repairs on the legs. METHODS: In this retrospective cohort study, healing time and complication rate of 44 patients treated with standard dressing and 36 patients treated with zinc oxide compression dressings were compared. RESULTS: At 19 days, 91.7% of patients receiving zinc oxide dressing were fully healed, whereas only 65.9% of patients receiving standard wound care were healed. Complications were noted in 6 of the patients receiving standard dressing (13.6%); no complications occurred in the zinc oxide dressing group. CONCLUSION: Zinc oxide compression dressings were a practical option for postoperative wound care, with decreased incidence of delayed wound healing, and fewer complications versus standard postoperative wound dressing. PMID- 28654577 TI - Small Intestinal Submucosal Matrix as a Novel Reconstructive Option for Large Scrotal Defects. PMID- 28654578 TI - Microcystic Adnexal Carcinoma: A Review of the Literature. AB - BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare, locally aggressive cutaneous neoplasm that commonly occurs on the face. OBJECTIVE: The purpose of this article is to comprehensively review the current literature on MAC pertaining to epidemiology, pathogenesis, clinical presentation, histology, immunohistochemistry, prognosis, follow-up, and treatment. MATERIALS AND METHODS: An extensive literature review was conducted using OVID MEDLINE and PubMed to identify articles relating to MAC. RESULTS: Microcystic adnexal carcinoma typically presents as a skin-colored nodule on the face. The pathogenesis is mostly related to pilar and eccrine differentiation. Histologically, MAC can mimic syringoma, desmoplastic trichoepithelioma, and infiltrative basal cell carcinoma. Diagnosis is challenging because superficial shave biopsies may reveal only benign findings that do not warrant further management. A deep biopsy is mandatory for the correct diagnosis, and Mohs micrographic surgery provides the highest cure rate. CONCLUSION: Microcystic adnexal carcinoma is a locally aggressive disease with histological margins that often far surpass what is clinically suspected. Mohs micrographic surgery is the standard of care for removal of these lesions. Patients with a history of MAC should be examined at least every 6 months for recurrence, metastasis, and development of additional skin cancers. PMID- 28654579 TI - Detection of High-Risk Histologic Features and Tumor Upstaging of Nonmelanoma Skin Cancers on Debulk Analysis: A Quantitative Systematic Review. AB - BACKGROUND: Histologic analysis of tumor debulks from Mohs micrographic surgery (MMS) or wide local excision may lead to the detection of adverse features missed on initial biopsy. OBJECTIVE: Determine the incidence of (1) high-risk features on debulk analysis compared with initial biopsy and (2) upstaging of tumors on debulk analysis according to the American Joint Committee of Cancer-7th Edition (AJCC-7) and the Brigham and Women's Alternative (BWH) staging criteria. MATERIALS AND METHODS: A comprehensive search strategy using PubMed/MEDLINE, Web of Science, and EMBASE was conducted to identify articles published from 1960 to present that detail histology of initial biopsy and debulked tumor. RESULTS: Fourteen studies, encompassing 2,565 cases of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were included in the data extraction process. BCCs (30.9%) were reclassified from a low-risk histologic subtype to a high-risk subtype on debulk analysis (p < .001). Cases with perineural invasion (89.4%) were detected on debulk analysis. SCC tumors (9.1% and 11.1%) were upstaged according to the AJCC-7 and BWH Alternative criteria, respectively. Ninety percent of high-risk BWH T2b SCCs were inaccurately staged lower on initial biopsy. CONCLUSION: Tumor debulk analysis in MMS may aid in the identification of additional high-risk features, thereby improving staging accuracy, treatment decisions and patient outcomes. PMID- 28654580 TI - Mohs Mapping Fidelity: Optimizing Orientation, Accuracy, and Tissue Identification in Mohs Surgery. AB - BACKGROUND: Mohs micrographic surgery (MMS) is a highly effective process that requires consistent accuracy in resection, mapping, and histologic interpretation. Although the general sequence in MMS is similar, there are numerous variations among Mohs surgeons as to how this process is performed. OBJECTIVE: This article aims to review the process of MMS, with the intent to identify and mitigate the potential errors at each step. Existing variations will be discussed and protocols offered to minimize error and optimize accuracy. METHODS: A Pubmed search was performed for publications on methods of tissue mapping, orienting, and processing in MMS. RESULTS: Our literature review highlights various techniques for tissue orientation, transfer, flattening, inking, mapping, and processing of later stages and multiple specimens. We discuss our system, which reduces error during tissue transfer, tissue identification in vivo and ex vivo, and tissue flattening. Furthermore, we discuss adaptations to increase the accuracy during reexcisions of subsequent Mohs layers. CONCLUSION: Variations in MMS reflects the diverse training and creativity among Mohs surgeons. Unless potential errors are addressed, however, false negatives will occur and undermine the superior cure rate of MMS. PMID- 28654581 TI - Improved Rates of Immediate Breast Reconstruction at Safety Net Hospitals. AB - BACKGROUND: Substantial federal resources have been directed toward ensuring the delivery of high-quality care at safety net hospitals. Although disparities in receipt of breast reconstruction persist at the patient level, the extent to which hospital factors contribute to these differences remains unclear. The rates of immediate breast reconstruction across safety net and non-safety net hospitals were investigated. METHODS: Women 21 years and older with breast cancer or increased risk of breast cancer undergoing immediate post-mastectomy reconstruction were identified in the Nationwide Inpatient Sample database. Safety net hospitals were defined as hospitals with the highest tertile of Medicaid disproportionate share hospital payment adjustments. Adjusted odds ratios of undergoing reconstruction were calculated. RESULTS: Thirty-one percent of patients (n = 10,910) at safety net hospitals underwent immediate reconstruction compared with 46 percent of patients (n = 14,619) at non-safety net hospitals (p < 0.001). Logistic regression revealed that women at non-safety net hospitals were significantly more likely to undergo reconstruction (OR, 1.89; 95 percent CI, 1.65 to 2.16). However, analysis by study year revealed that rates of reconstruction at safety net hospitals increased over time. CONCLUSIONS: After accounting for sociodemographic factors, women undergoing mastectomies at safety net hospitals remain less likely to undergo immediate breast reconstruction. However, the differences in rates of reconstruction between safety net and non safety net hospitals have narrowed over time. The availability of immediate reconstruction lessens the psychological trauma of mastectomy, and it is critical to continue redirecting federal efforts toward this valuable component of breast cancer care. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 28654582 TI - Predictors, Classification, and Management of Umbilical Complications in DIEP Flap Breast Reconstruction. AB - BACKGROUND: In recent years, the deep inferior epigastric perforator (DIEP) flap has become the workhorse flap for autologous breast reconstruction. Despite increased reports on DIEP flaps, umbilical complications have not been previously studied. The aesthetics of the umbilicus dictates the beauty of the abdomen, and it is critical for plastic surgeons to minimize the scarring of the umbilicus. In this study, we retrospectively reviewed patients who underwent DIEP flaps to determine the predictors of umbilical complications, and created a classification system of these wounds. METHODS: Retrospective review of 323 patients who underwent DIEP flap surgery from 2009 to 2016 was performed. Umbilical stalk heights, widths of fascial diastasis, and abdominal wall thicknesses were measured from computed tomographic scans. Data regarding demographic and patient characteristics were collected. RESULTS: Of the 323 patients, there were 58 patients that had umbilical complications (18 percent). These patients had statistically higher body mass indexes, heavier flaps, and thicker abdominal walls (p < 0.05). Also, they had statistically higher umbilical stalk heights (29.3 mm versus 18.7 mm), and analysis showed that the likelihood ratio of having umbilical complications was 2.05 at 20.1 mm, 3.05 at 25.4 mm, and 6.43 at 30 mm. Logistic regression analysis revealed that umbilical stalk height, fascial diastasis, age, procedure time, and flap weight were significant predictors (p < 0.05). CONCLUSIONS: Umbilical complications in patients undergoing DIEP flap surgery for breast reconstruction have not been previously studied. Our study shows that the umbilical stalk height plays a significant role, and umbilical wounds can be classified into five types: no wound, minor wound, wound dehiscence, partial necrosis, and total necrosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28654583 TI - Tumor-to-Nipple Distance as a Predictor of Nipple Involvement: Expanding the Inclusion Criteria for Nipple-Sparing Mastectomy. AB - BACKGROUND: A tumor-to-nipple distance of greater than 2 cm has traditionally been considered a criterion for nipple-sparing mastectomy. This study evaluates whether magnetic resonance imaging and sonographic measurements of tumor-to nipple distance accurately reflect the risk of nipple involvement by disease. METHODS: All nipple-sparing mastectomy cases with implant-based reconstruction performed by the senior author between July 2006 and December 2014 were retrospectively reviewed. Therapeutic cases with preoperative magnetic resonance imaging or sonography were included. RESULTS: One hundred ninety-five cases were included. Preoperative imaging consisted of sonography (n = 169), magnetic resonance imaging (n = 152), or both (n = 126). With sonography, nipple involvement did not differ between nipple-sparing mastectomy candidates and noncandidates using a tumor-to-nipple distance cutoff of 2 cm (10.7 percent versus 10.6 percent; p = 0.988) or 1 cm (9.3 percent versus 15.0 percent; p = 0.307). With magnetic resonance imaging, nipple involvement did not differ between candidates and noncandidates using a cutoff of 2 cm (11.6 percent versus 12.5 percent; p = 0.881) or 1 cm (11.4 percent versus 13.8 percent; p = 0.718). When sonography and magnetic resonance imaging findings were both available and concordant, nipple involvement still did not differ between candidates and noncandidates using a cutoff of 2 cm (8.8 percent versus 11.8 percent; p = 0.711) or 1 cm (7.6 percent versus 14.3 percent; p = 0.535). CONCLUSION: A tumor-to nipple distance as small as 1 cm, as measured by sonography or magnetic resonance imaging, should not be considered a contraindication to nipple-sparing mastectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 28654584 TI - A Novel Noncontact Diffuse Correlation Spectroscopy Device for Assessing Blood Flow in Mastectomy Skin Flaps: A Prospective Study in Patients Undergoing Prosthesis-Based Reconstruction. AB - : A new advanced technology, noncontact diffuse correlation spectroscopy, has been recently developed for the measurement of tissue blood flow through analyzing the motions of red blood cells in deep tissues. This technology is portable, inexpensive, and noninvasive, and can measure up to 1.5-cm tissue depth. In this prospective study, the authors aimed to explore the use of this novel device in the prediction of mastectomy skin flap necrosis. The noncontact diffuse correlation spectroscopy device was used to measure mastectomy skin flap flow in patients undergoing mastectomy and immediate implant-based breast reconstruction before and immediately after mastectomy, and after placement of the prosthesis. Patients were tracked for the development of complications, including skin necrosis and the need for further surgery. Nineteen patients were enrolled in the study. Four patients (21 percent) developed skin necrosis, one of which required additional surgery. The difference in relative blood flow levels immediately after mastectomy in patients with or without necrosis was statistically significant, with values of 0.27 +/- 0.11 and 0.66 +/- 0.22, respectively (p = 0.0005). Relative blood flow measurements immediately after mastectomy show a significant high accuracy in prediction of skin flap necrosis, with an area under the receiver operating characteristic curve of 0.95 (95 percent confidence interval, 0.81 to 1). The noncontact diffuse correlation spectroscopy device is a promising tool that provides objective information regarding mastectomy skin flap viability intraoperatively, allowing surgeons early identification of those compromised and ischemic flaps with the hope of potentially salvaging them. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 28654585 TI - Discussion: Vertical Midface Lifting with Periorbital Anchoring in the Management of Lower Eyelid Retraction: A 10-Year Clinical Retrospective Study. PMID- 28654586 TI - Botulinum Toxin for Neck Rejuvenation: Assessing Efficacy and Redefining Patient Selection. AB - BACKGROUND: The "Nefertiti lift" consists of injecting the platysmal bands and the inferior border of the mandible with botulinum toxin. No clinical trial has evaluated its effect on the different lower face and neck aging components, and little is known about the clinical characteristics that predict treatment success. METHODS: Patients were injected with abobotulinumtoxinA along the inferior border of the mandible and into the platysmal bands. Using standardized preinjection and postinjection photographs, the jowls, marionette lines, oral commissures, neck volume, and platysmal bands at maximal contraction and at rest were assessed with validated photonumeric scales. In addition, the overall appearance of the lower face and neck was evaluated by the Investigators and Subjects Global Aesthetic Improvement Score. Pain and patient satisfaction rates were also evaluated. RESULTS: Thirty patients were injected with a mean dose of 124.9 U of abobotulinumtoxinA per patient. Platysmal bands at rest and with maximal tension reached a statistically significant improvement. The other components showed a tendency for improvement but did not reach statistical significance; 93.3 percent of investigators and patients rated the overall results as improved, and 96.6 percent of patients were satisfied with their results. When comparing the patients who improved the most to all the other patients, they had lower preinjection region-specific scores. CONCLUSIONS: The Nefertiti lift can be used on its own or in conjunction with other rejuvenating procedures. It is particularly helpful in younger patients with platysma muscle hyperactivity and retained skin elasticity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28654587 TI - Discussion: Botulinum Toxin for Neck Rejuvenation: Assessing Efficacy and Redefining Patient Selection. PMID- 28654588 TI - Assessment of the Efficacy of Cryolipolysis on Saddlebags: A Prospective Study of 53 Patients. AB - BACKGROUND: Cryolipolysis is a noninvasive subcutaneous fat removal technique. Its efficacy has been demonstrated on various fatty areas but not yet on saddlebags. The main objective of this study was to demonstrate the efficacy, patient tolerance, and safety of cryolipolysis on the saddlebags. METHODS: This prospective study enrolled 53 patients with saddlebags. Patients with a history of liposuction or other surgical procedure on the saddlebag area and those on diet pills were excluded. The primary endpoint was a decrease in fat thickness at 3 and 6 months, as assessed by thigh circumference measurement and by ultrasound evaluation of subcutaneous fat. Pain associated with cryolipolysis was assessed using a visual analogue scale. Body mass index at the different time points and adverse events were recorded. All patients completed a satisfaction questionnaire at the end of the study. RESULTS: At 6 months, there was a mean decrease of 5.63 cm in thigh circumference; the mean decrease in fat layer thickness measured by ultrasound was 1.31 cm. The satisfaction questionnaire showed that 93.75 percent of patients were satisfied with the results. The mean visual analogue scale score was 1.66 of 10 after the session. Reversible skin changes such as postprocedure postinflammatory hyperpigmentation were observed in 8.33 percent of patients. CONCLUSIONS: Cryolipolysis is an effective technique for reducing saddlebag fat and is well tolerated by patients. A substantial risk of skin lesions, including postinflammatory hyperpigmentation that resolved after a few months, was observed. Cryolipolysis is a good alternative to liposuction in women with moderate, well-localized saddlebags. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28654589 TI - Discussion: Assessment of the Efficacy of Cryolipolysis on Saddlebags: A Prospective Study of 53 Patients. PMID- 28654590 TI - The Ideal Buttock Size: A Sociodemographic Morphometric Evaluation. AB - BACKGROUND: Perception of beauty is influenced by geographic, ethnic, cultural, and demographic factors. However, objective measurements remain the foundation for aesthetic evaluations. In the quest to better define the "ideal" female buttock, this study assumes interdependence among variables such as country of residence, sex, age, occupation, and aesthetic perception, yielding a waist-to hip ratio that appears most pleasing across most cultures and geographic locations. METHODS: An online survey was designed. Modifiable ranges of buttock sizes were achieved by means of digital alteration, enabling participants to interactively change the size and waist-to-hip ratio of a single model's buttocks. The questionnaire was translated into multiple languages and sent to more than 9000 plastic surgeons and to the general public worldwide. Demographic data were collected, and analysis of variance was used to elucidate buttock shape preferences. RESULTS: A total of 1032 responses were gathered from over 40 different countries. Significant differences regarding preferences for buttock size were identified across the respondents. Overall, 404 of 1032 of survey takers (39 percent) chose the 0.7 waist-to-hip ratio to be their ideal. Significant relationships were distilled between sex, age, self-reported ethnicity, plastic surgeons' country of residence, and ethnic background. For example, surgeons in Latin America preferred the largest buttocks, followed by surgeons in Asia, North America, and Europe, with non-Caucasians preferring larger buttocks than Caucasians. CONCLUSION: There seems to exist a global consensus regarding the ideal waist-to-hip ratio; however, multiple other factors impact the aesthetic perception of the buttocks significantly. PMID- 28654591 TI - The Classification and Prognosis of Periocular Complications Related to Blindness following Cosmetic Filler Injection. AB - : Common side effects during hyaluronic acid filler injections are typically mild and reversible, but several reports of blindness have received attention. The present study focused on orbital symptoms combined with blindness, aiming to classify affected patients and predict their disease course and prognosis. From September of 2012 to August of 2015, nine patients with vision loss after filler injection were retrospectively reviewed. Ptosis, ophthalmoplegia, and enophthalmos were recorded over a 6-month follow-up, and patients were classified into four types according to periocular symptom manifestation. Two patients were categorized as type I (blindness without ptosis or ophthalmoplegia), two patients as type II (blindness and ptosis without ophthalmoplegia), two patients as type III (blindness and ophthalmoplegia without ptosis), and three patients as type IV (blindness with ptosis and ophthalmoplegia). The present study includes previously unpublished information about orbital symptom manifestations and prognosis combined with blindness caused by retinal artery occlusion after cosmetic filler injection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 28654592 TI - Preventing Soft-Tissue Triangle Collapse in Modern Rhinoplasty. AB - The unique anatomy of the soft-tissue triangle makes it prone to notching in primary, secondary, and reconstructive rhinoplasty. Understanding the anatomy of the region is critical to appropriate treatment. This article is meant to further clarify the anatomy of the soft-tissue triangle and to present the senior author's (R.J.R.) approach to proactive correction and prevention of soft-tissue triangle notching through five key steps: (1) precise dissection and incision placement, (2) providing internal support with cartilage grafting if needed, (3) closure of dead space, (4) avoiding undue tension during closure, and (5) providing external support postoperatively. PMID- 28654593 TI - Population Health Implications of Medical Tourism. AB - BACKGROUND: Fifteen million U.S. patients each year seek medical care abroad; however, there are no data on outcomes and follow-up of these procedures. This study aims to identify, evaluate, and survey patients presenting with complications from aesthetic procedures abroad and estimate their cost to the U.S. health care system. METHODS: A single-center retrospective review was conducted. A cohort of patients presenting with complications from aesthetic procedures performed abroad was generated. Demographic, complication, and cost data were compiled. Patients were surveyed to assess their overall experience. RESULTS: Over a 36-month period, 42 patients met inclusion criteria (one man and 41 women), with an average age of 35 +/- 11.4 years (range, 20 to 60 years). Comorbidities included four active smokers, two patients with hypertension, and one patient with diabetes. Average body mass index was 29 +/- 4.4 kg/m (range, 22 to 38 kg/m). Procedures performed abroad included abdominoplasty (n = 28), liposuction (n = 20), buttock augmentation (n = 10), and breast augmentation (n = 7), with several patients undergoing combined procedures. Eleven patients presented with abscesses and eight presented with wound dehiscence. Eight of the 18 patients who were surveyed were not pleased with their results and 11 would not go abroad again for subsequent procedures. Average cost of treating the complications was $18,211, with an estimated cost to the U.S. health care system of $1.33 billion. The main payer group was Medicaid. CONCLUSIONS: Complications from patients seeking aesthetic procedures abroad will continues to increase. Patients should be encouraged to undergo cosmetic surgery in the United States to improve patient outcomes and satisfaction and because it is economically advantageous. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28654594 TI - Comparison of Steroid and Botulinum Toxin Type A Monotherapy with Combination Therapy for Treating Human Hypertrophic Scars in an Animal Model. AB - BACKGROUND: The authors evaluated the efficacy of a combined regimen of botulinum toxin type A (Botox) and a steroid (triamcinolone acetonide) for treating hypertrophic scars in comparison with the treatment with each drug alone. METHODS: Twenty excised human hypertrophic scar fragments obtained from surgically treated burn patients were divided into four groups: negative control (group A), triamcinolone alone (group B), Botox alone (group C), and a combination of triamcinolone and Botox (group D). These specimens were implanted into the backs of nude mice after intralesional injection from each group and were observed for 4 weeks. In total, 12 mice and 48 scars were studied. After 4 weeks, the hypertrophic scars were removed from the backs. The authors compared the scar weights, decorin staining, and the Cell Counting Kit-8 assay to evaluate treatment efficacy. RESULTS: Significant differences in scar weight reduction were observed among the four groups (group A, 10 percent; group B, 17 percent; group C, 23 percent; and group D, 30 percent; p < 0.05). Treatment groups (groups B, C, and D) showed strong decorin staining. Significant differences in reduction of fibroblast proliferation were observed among the four groups (group A, 0.58; group B, 0.44; group C, 0.21; and group D, 0.08; p < 0.05). Botox or triamcinolone intralesional monotherapy showed significant therapeutic efficacy compared with the control group. The combined therapy further exhibited a significant therapeutic effect compared with monotherapy. CONCLUSION: This study indicates the potential of Botox and triamcinolone when combined for intralesional therapy in treating hypertrophic scars. PMID- 28654595 TI - Oxygen-Sensing Paint-On Bandage: Calibration of a Novel Approach in Tissue Perfusion Assessment. AB - BACKGROUND: Knowledge of tissue oxygenation status is fundamental in the prevention of postoperative flap failure. Recently, the authors introduced a novel oxygen-sensing paint-on bandage that incorporated an oxygen-sensing porphyrin with a commercially available liquid bandage matrix. In this study, the authors extend validation of their oxygen-sensing bandage by comparing it to the use of near-infrared tissue oximetry in addition to Clark electrode measurements. METHODS: The oxygen-sensing paint-on bandage was applied to the left hind limb in a rodent model. Simultaneously, a near-infrared imaging device and Clark electrode were attached to the right and left hind limbs, respectively. Tissue oxygenation was measured under normal, ischemic (aortic ligation), and reperfused conditions. RESULTS: On average, the oxygen-sensing paint-on bandage measured a decrease in transdermal oxygenation from 85.2 mmHg to 64.1 mmHg upon aortic ligation. The oxygen-sensing dye restored at 81.2 mmHg after unclamping. Responses in both control groups demonstrated a similar trend. Physiologic changes from normal to ischemic and reperfused conditions were statistically significantly different in all three techniques (p < 0.001). CONCLUSIONS: The authors' newly developed oxygen-sensing paint-on bandage exhibits a comparable trend in oxygenation recordings in a rat model similar to conventional oxygenation assessment techniques. This technique could potentially prove to be a valuable tool in the routine clinical management of flaps following free tissue transfer. Incorporating oxygen-sensing capabilities into a simple wound dressing material has the added benefit of providing both wound protection and constant wound oxygenation assessment. PMID- 28654596 TI - A Microbiological and Ultrastructural Comparison of Aseptic versus Sterile Acellular Dermal Matrix as a Reconstructive Material and a Scaffold for Stem Cell Ingrowth. AB - BACKGROUND: Recent data suggest an increased risk for infection when acellular dermal matrix is used in breast reconstruction. This may be because some acellular dermal matrices are actually not terminally sterilized but are instead "aseptically processed." This study evaluates aseptic and sterile matrices for evidence of bacterial contamination and whether or not terminal sterilization affects matrix collagen architecture and stem cell ingrowth. METHODS: Five separate samples of 14 different matrices were analyzed by fluorescent in situ hybridization using a bacterial DNA probe to detect bacterial DNA on the matrices. Separate samples were incubated for bacteria, acid-fast bacilli, and fungi for 2 to 6 weeks to detect living organisms. The impact of terminal sterilization on the collagen network and stem cell ingrowth on the matrices was then assessed. RESULTS: Traces of bacterial DNA were encountered on all matrices, with more bacteria in the aseptic group compared with the sterile group (3.4 versus 1.6; p = 0.003). The number of positive cultures was the same between groups (3.8 percent). Electron microscopy demonstrated decreased collagen organization in the sterile group. Stem cell seeding on the matrices displayed a wide variation of cellular ingrowth between matrices, with no difference between aseptic and sterile groups (p = 0.2). CONCLUSIONS: Although there was more evidence of prior bacterial contamination on aseptically processed matrices compared with sterile matrices; clinical cultures did not differ between groups. Terminal sterilization does not appear to affect stem cell ingrowth but may come at the cost of damaging the collagen network. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 28654597 TI - Involvement of the Interosseous and Lumbrical Muscle-Tendon Units in the Lateral and Spiral Cords in Dupuytren's Disease of the Middle Fingers. AB - BACKGROUND: The nature of intrinsic muscle involvement in Dupuytren's disease of the middle fingers (long and ring) remains poorly characterized. Over the years, the authors have observed that both the spiral and lateral digital cords in the middle fingers receive contribution from intrinsic muscle-tendon units. This report describes the anatomical characteristics and frequency of intrinsic muscle tendon unit involvement in Dupuytren's disease of the middle fingers. METHODS: Intrinsic muscle involvement in the middle digits was recorded in the operative reports of patients undergoing Dupuytren's surgery between October of 2013 and February of 2016. The anatomical variations of diseased fascia were delineated and classified. RESULTS: Of the 113 digits with Dupuytren's contracture operated on during this period, 52 involved the middle fingers (12 long and 40 ring fingers). Intrinsic muscles were found to be involved in the contracture of 14 of these digits. Two unique contracture patterns were identified: type I contracture, which involves a lateral digital cord originating from intrinsic muscle-tendon units and contracting only the proximal interphalangeal joint; and type II contracture, which involves a spiral cord receiving contribution from intrinsic muscle-tendon units and contracting both the metacarpophalangeal and proximal interphalangeal joints. The frequency of type I and type II contractures was 6 percent and 12 percent, respectively. CONCLUSION: Intrinsic hand muscles may contribute to Dupuytren's disease in the middle digits, and the authors suggest resecting cords as close as possible to their musculotendinous origin to improve postoperative outcomes. PMID- 28654598 TI - Discussion: Spring-Assisted Cranioplasty for the Correction of Nonsyndromic Scaphocephaly: A Quantitative Analysis of 100 Consecutive Cases. PMID- 28654599 TI - Predictors of Autologous Free Fat Graft Retention in the Management of Craniofacial Contour Deformities. AB - BACKGROUND: Autologous free fat graft outcomes are not always predictable, and variables that can potentially influence fat graft retention are still not well understood or investigated. The purposes of this study were to assess fat graft retention in the management of craniofacial contour deformities and to identify possible predictive factors of this retention. METHODS: A prospective analysis was conducted using consecutive patients with unilateral craniofacial contour deformities who underwent autologous free fat grafting between 2012 and 2015. Standardized ultrasonographic craniofacial soft-tissue thickness measurements were adopted to determine the fat graft retention. Bivariate and multivariate analyses were performed to identify independent predictors of 12-month postoperative fat graft retention. RESULTS: One hundred forty-two patients were enrolled. There was significant (all p < 0.05) and progressive reduction in fat graft retention within the first 3 postoperative months, and the retained fat graft was maintained (all p > 0.05) from 3 to 12 months postoperatively, with a 12-month fat graft retention rate of 67.7 percent. Age, Parry-Romberg syndrome, previous craniofacial bone surgery, grafted volume, and forehead unit were independently negative (all p < 0.05) predictors of fat graft retention, whereas cheek unit was an independently positive (all p < 0.05) predictor of retention. CONCLUSION: Craniofacial fat graft retention is achievable but remains somewhat unpredictable, with age, Parry-Romberg syndrome, previous bone surgical intervention, grafted volume, and recipient sites affecting retention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 28654600 TI - An Appraisal of the Cephalic Index in Sagittal Craniosynostosis, and the Unseen Third Dimension. AB - BACKGROUND: The cephalic index is often used to evaluate sagittal craniosynostosis corrections; however, validation of this measure remains untested. METHODS: A three-part study was designed to (1) determine the normal distribution of cephalic indices in untreated sagittal craniosynostosis; (2) examine index values in treated children, subsequently determined to require secondary surgery; and (3) explore the correlation between a photography-based assessment of scaphocephaly severity and the cephalic index. RESULTS: Of 392 preoperatively measured patients (mean cephalic index, 70.7; 95 percent CI, 57.4 to 89.5), 343 (87.5 percent) had Z scores falling within 2 SD of the mean; only 49 (12.5 percent) fell more than 2 SD below the mean, whereas 13 percent exceeded the mean. For 10 patients requiring secondary surgery (mean cephalic index, 74.8; 95 percent CI, 68.1 to 83.4), the mean Z score was -0.5 (range, -2.5 to 1.6). The polled results of 10 observers revealed no significant correlation between subjectively ranked severity scores and cephalic indices. CONCLUSIONS: Although the average preoperative cephalic index in children with sagittal craniosynostosis was below normal, the majority of measurements fell within a statistically normal distribution. Furthermore, many children requiring secondary corrections were found to have relatively normal indices, suggesting that normal values are not necessarily predictive of satisfactory outcomes. We also found no correlation between this index and a subjective assessment of severity. These findings suggest that the cephalic index is not a reliable outcome measure, perhaps because of the inability for this ratio to capture the amount of correction of the reduced posterior skull height associated with sagittal craniosynostosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 28654601 TI - Nonsyndromic Craniosynostosis and Associated Abnormal Speech and Language Development. AB - BACKGROUND: Although many metrics for neurodevelopment in children with nonsyndromic craniosynostosis have been analyzed, few have directly examined early language acquisition and speech development. The authors characterized language acquisition and speech development in children with nonsyndromic craniosynostosis. METHODS: The authors' institutional database was queried for nonsyndromic craniosynostosis from 2000 to 2014. Patients with an identified syndrome were excluded. Specific data elements included age, gender, velopharyngeal adequacy by means of the Pittsburgh Weighted Speech Scale, evaluation for anatomical motor delay, language acquisition delay/disorder, articulation or speech sound production delays/disorders, and whether speech therapy was recommended. Diagnosis of a submucous cleft palate was noted. RESULTS: One hundred one patients met inclusion criteria, of which 57.4 percent were male. Average age at the time of the most recent speech evaluation was 6.1 years (range, 2.31 to 17.95 years); 43.6 percent had normal speech/language metrics and 56.4 percent had one or more abnormalities, including anatomical motor delay/disorder (29.7 percent), language acquisition delay/disorder (21.8 percent), articulation or speech production delay/disorder (4.0 percent), hypernasality (15.8 percent), and velopharyngeal insufficiency or borderline competency (23.8 percent). Average Pittsburgh Weighted Speech Scale score was 1.3 (range, 0 to 5), and 29.7 percent (n = 30) of patients were recommended to have speech therapy. In addition, 25.8 percent of patients were diagnosed with a submucous cleft palate. CONCLUSIONS: One in four patients with nonsyndromic craniosynostosis carried a diagnosis of submucous cleft palate. The authors found that abnormal speech and language development occurs in one in 1.7 patients with nonsyndromic craniosynostosis, and that speech therapy for such abnormal development is warranted in one in 3.4 of them-a prevalence two to five times higher compared with the general pediatric population. PMID- 28654602 TI - A Morphometric Study of the Newborn Ear and an Analysis of Factors Related to Congenital Auricular Deformities. AB - BACKGROUND: The incidence of neonatal ear deformities varies widely in the literature, and the incidence of those that correct spontaneously is largely unknown. To address these questions, the authors analyzed the auricles of 1500 newborns from the Pearl River Delta within the first 7 days of life and again at 30 days of age. METHODS: Using a combination of direct measurement and digital image measurement, the authors measured physiognomic ear length, physiognomic ear breadth, morphologic ear length, vertical distance between head and ear, and auriculocephalic angle of the newborns. The first measurement was within 1 week of birth, whereas the second measurement was performed for the same newborns 1 month after birth. RESULTS: Among 1500 newborns, 862 had various forms of auricular deformities. The incidence of neonatal auricular deformity in the Pearl River Delta area was 57.46 percent, and the self-healing rate was 31.55 percent by the 30-day follow-up. Seven factors were found to be statistically significant: mother's delivery situation, mother's hepatitis history, abnormal pregnancy, abnormal labor, cephalopelvic disproportion, premature rupture of membranes, and neonatal weight. Birth by cesarean delivery and mother with no abnormal pregnancy or no history of hepatitis were protective factors against the newborn's auricular deformity. CONCLUSIONS: Newborns have a high incidence of auricular deformities, and different types of auricular deformities have distinct incidences. Auricular deformities are caused by the interactions of a number of factors. There were large differences in the self-healing rates of different types of auricular deformities. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 28654603 TI - Discussion: A Morphometric Study of the Newborn Ear and an Analysis of Factors Related to Congenital Auricular Deformities. PMID- 28654604 TI - Discussion: First Lower Two-Thirds Osteomyocutaneous Facial Allograft Perfused by a Unilateral Facial Artery: Outcomes and Vascularization at 1 Year after Transplantation. PMID- 28654605 TI - Selective Intraoperative Vasopressor Use Is Not Associated with Increased Risk of DIEP Flap Complications. AB - BACKGROUND: During deep inferior epigastric perforator (DIEP) flap cases, anesthesiologists commonly avoid intravenous vasopressor administration because of the theoretical concern of inducing vasospasm, thrombosis, or congestion in the vessels of the anastomosis, potentially resulting in poor flap perfusion and ischemia and necessitating revision. In the setting of hypotension, however, vasopressor administration may actually improve outcomes by augmenting flap perfusion by means of increased mean arterial pressure. METHODS: The authors reviewed 475 consecutive DIEP flap cases in 333 patients at a single large academic medical center over a 3-year period, addressing potential confounders using univariate analyses. RESULTS: Ephedrine administration was significantly associated with decreased risk of intraoperative flap complications (OR, 0.88), including vasospasm, thrombosis, and congestion requiring revision, compared with controls, after controlling for the severity and duration of hypotension. Phenylephrine had no significant association with complication rates. Vasopressor administration was not associated with an increased risk of reoperation in the setting of necrosis within 60 days. CONCLUSIONS: Ephedrine treatment for hypotension during DIEP flap cases is associated with decreased intraoperative flap complication rates compared with controls who did not receive vasopressors, whereas phenylephrine has no significant association. The common clinical practice of complete abstinence from vasopressors out of concern for worsening DIEP flap outcomes is not supported by this study. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28654606 TI - Discussion: Selective Intraoperative Vasopressor Use Is Not Associated with Increased Risk of DIEP Flap Complications. PMID- 28654607 TI - Discussion: Selective Intraoperative Vasopressor Use Is Not Associated with Increased Risk of DIEP Flap Complications. PMID- 28654608 TI - The Efficacy of Perforator Flaps in the Treatment of Chronic Osteomyelitis. AB - BACKGROUND: Treatment of chronic osteomyelitis involves aggressive debridement followed by soft-tissue coverage. The dictum of muscle coverage being superior has been challenged by successful reports of coverage with skin flaps. The objective of this article is to evaluate the efficacy of perforator flaps for reconstruction of chronic osteomyelitis defects. METHODS: A retrospective review of 120 patients with chronic osteomyelitis who underwent debridement and reconstruction using perforator flaps from April of 2000 to November of 2015 was conducted. Inclusion criteria were cases with chronic osteomyelitis for a minimum of 6 weeks and with a follow-up of at least 2 years after surgery. Correlation between recurrence and the following factors was analyzed: comorbidities, frequency of debridement, duration of chronic osteomyelitis, limb vascular status, and method of dead space obliteration. The outcomes analyzed were flap loss, recurrence rate, primary remission rate, secondary remission rate, and amputation rate. RESULTS: The flap loss rate was 4.2 percent flap, the recurrence rate was 8.3 percent, the primary remission rate was 91.6 percent, the secondary remission rate was 98.3 percent, and the amputation rate was 1 percent. Significant predictors of recurrence were peripheral vascular disease and major vessel compromise, which had 5.1 times higher odds of recurrence (p < 0.05). CONCLUSIONS: Used with adequate debridement, bone reconstruction, and obliteration of dead space, a primary remission rate of 91.6 percent and a secondary remission rate of 98.3 percent were achieved using perforator flap. The predictors of chronic osteomyelitis recurrence were peripheral vascular disease and major vascular compromise. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28654609 TI - Discussion: The Efficacy of Perforator Flaps in the Treatment of Chronic Osteomyelitis. PMID- 28654610 TI - What's New in Syndromic Craniosynostosis Surgery? AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the role of prenatal screening and counseling of parents of unborn children with syndromic craniosynostosis. 2. Recognize the genetic abnormalities, craniofacial phenotype, associated anomalies, and challenges associated with each of the five major forms of syndromic craniosynostosis. 3. Identify the pros and cons associated with timing and types of cranial vault remodeling techniques in this patient population. 4. Understand the risks and benefits associated with midface advancement with Le Fort III, Le Fort II plus zygomatic repositioning, monobloc, and facial bipartition. 5. Understand the important role of psychological counseling throughout childhood in this at-risk group. SUMMARY: Crouzon, Apert, Pfeiffer, Muenke, and Saethre-Chotzen syndromes are the five most common forms of syndromic craniosynostosis. Although each has different genetic underpinnings and associated anomalies, their hallmark finding is turribrachycephaly most often associated with bicoronal craniosynostosis. The role of prenatal screening and counseling is growing, with caregivers becoming involved before birth. Multidisciplinary care from birth onward involves craniofacial plastic surgeons, neurosurgeons, otolaryngologists, ophthalmologists, orthodontists, anesthesiologists, psychologists, speech therapists, and geneticists. Early partial, or regional, craniectomy may be urgently indicated in multisuture cases with signs of increased intracranial pressure. Others may be managed successfully with posterior cranial vault distraction, middle vault expansion, or fronto-orbital advancement. Some authors have advocated early monobloc advancement for those patients who require acute airway intervention and globe protection, although the risks of these procedures are high. Many patients will require midfacial advancement with a Le Fort III, Le Fort II plus zygomatic repositioning, monobloc, or facial bipartition. The indications, risks, and benefits for each midfacial procedure must be considered, as this step in the treatment algorithm may carry the greatest functional and aesthetic benefits but also the potential for the greatest morbidity. At the culmination of facial growth, it is not uncommon for patients to require conventional orthognathic surgery and other bony contouring and soft-tissue procedures. Finally, an understanding of the psychological aspects of craniofacial difference, both in affected individuals and in their families, is essential to a successful, holistic approach. PMID- 28654611 TI - Evidence-Based Medicine: Alloplastic Breast Reconstruction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the different advances that have resulted in improved outcomes in implant-based reconstruction. 2. Gain knowledge about specific techniques that have evolved rapidly in recent years and how to implement these. 3. Gain an understanding of controversies associated with alloplastic reconstruction. 4. Recognize undesirable outcomes in implant-based breast reconstruction and understand strategies for correction. SUMMARY: There have been multiple advances in implant-based breast reconstruction. Many of these have resulted in improvements in patient outcomes and care. Understanding new techniques and technologies ensures competence in providing care for the alloplastic breast reconstruction patient. This article was prepared to accompany practice-based assessment with ongoing surgical education for the Maintenance of Certification for the American Board of Plastic Surgery. It is structured to outline the care of the patient with the postmastectomy breast deformity. PMID- 28654612 TI - Evidence-Based Medicine: Breast Augmentation. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the key decisions in patient evaluation for cosmetic breast augmentation. 2. Cite key decisions in preoperative planning. 3. Discuss the risks and complications, and key patient education points in breast augmentation. SUMMARY: Breast augmentation remains one of the most popular procedures in plastic surgery. The integral information necessary for proper patient selection, preoperative assessment, and surgical approaches are discussed. Current data regarding long term safety and complications are presented to guide the plastic surgeon to an evidence-based approach to the patient seeking breast enhancement to obtain optimal results. PMID- 28654613 TI - Evidence-Based Medicine: Current Evidence in the Diagnosis and Management of Carpal Tunnel Syndrome. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Create a safe and effective plan for management of carpal tunnel syndrome. 2. Support his or her rationale for the use of diagnostic tests. 3. Discuss elements of management that have been controversial, including anesthesia, the use of a tourniquet, postoperative pain control, and cost of care. SUMMARY: This is the fourth MOC-PS CME article on carpal tunnel syndrome. Each of the prior three has had a slightly different focus, and the reader is invited to review all to generate a comprehensive view of the management of this common, and often controversial, topic. The operative goal-to release the transverse carpal ligament-is straightforward: diagnosis, cause, and technique have generated more vibrant discussions. PMID- 28654614 TI - Evidence-Based Medicine: Surgical Management of Flexor Tendon Lacerations. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Accurately diagnose a flexor tendon injury. 2. Develop a surgical approach with regard to timing, tendon repair technique, and rehabilitation protocol. 3. List the potential complications following tendon repair. SUMMARY: Flexor tendon lacerations are complex injuries that require a thorough history and physical examination for accurate diagnosis and management. Knowledge of operative approaches and potential concomitant injuries allows the surgeon to be prepared for various findings during exploration. Understanding the biomechanical principles behind tendon lacerations and repair techniques aids the surgeon in selecting the optimal repair technique and postoperative rehabilitation. PMID- 28654615 TI - Evidence-Based Medicine: Management of Metacarpal Fractures. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand metacarpal anatomy and its role in fracture pathology. 2. Determine when surgical intervention is needed for metacarpal fractures. 3. Understand the various treatment options for surgical fixation of metacarpal fractures. 4. Describe the role for external fixation in managing difficult metacarpal fractures. BACKGROUND: Metacarpal fractures are common injuries that plastic surgeons should be able to evaluate and treat. The goal of this review is to highlight current evidence for managing metacarpal fractures. This Continuing Medical Education article consists of a literature review, illustrations, videos, and an online Continuing Medical Education examination. METHODS: The authors reviewed the scientific literature from 2000 to 2015 regarding treatment of metacarpal fractures. Cadaver models were used for instructional videography demonstrating common surgical techniques. Multiple-choice questions were created to review pertinent topics. A discussion and references are provided. RESULTS: Numerous treatment options have been described for metacarpal fractures, including splinting, percutaneous fixation, open reduction with internal fixation, and external fixation. All modalities are acceptable strategies for treating metacarpal fractures. The ultimate goal is to maximize hand function with minimal morbidity. CONCLUSIONS: A thorough understanding of treatment modalities is helpful in evaluating and managing metacarpal fractures. Although the current literature supports a wide array of treatment strategies, high-level evidence to guide fracture management remains lacking. PMID- 28654616 TI - Evidence-Based Medicine: The Bilateral Cleft Lip Repair. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the epidemiology, abnormal embryology, anatomy, and etiopathogenesis of cleft lip. 2. Be able to classify and describe bilateral cleft lip. 3. Recognize the importance of preoperative management of bilateral cleft lip. 4. Recognize the large breadth of differing management options. 5. Describe key steps and tenets of the surgical repair. SUMMARY: This fourth Maintenance of Certification/Continuing Medical Education article on cleft lip focuses on the topic of bilateral cleft lip. Previous articles placed an emphasis on the unilateral cleft lip, velopharyngeal insufficiency, or cleft lip and palate management. The authors focus on summarizing key points from previous articles and describing the importance of preoperative management and surgical repair of the bilateral cleft lip. PMID- 28654618 TI - Evidence-Based Medicine: Nonsyndromic Craniosynostosis. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the craniofacial dysmorphology associated with nonsyndromic craniosynostosis. 2. Understand the functional concerns and preoperative considerations when treating patients with nonsyndromic craniosynostosis. 3. Understand the various treatment options available to address patients with nonsyndromic craniosynostosis. 4. Recognize the current debate with regard to timing and type of surgical intervention, and their impact on patient outcome, for patients with nonsyndromic craniosynostosis. SUMMARY: Craniosynostosis is a pathologic condition associated with the premature fusion of one or more cranial sutures. When the cranial sutures fuse prematurely, the skull and the growing brain beneath the suture are restricted, leading to a compensatory expansion into regions of the skull that are not affected. Craniosynostosis can occur in isolation (nonsyndromic) or can be associated with other extracranial anomalies. When anomalies outside the skull are present, craniosynostosis is often part of a syndrome and usually involves multiple sutures (syndromic craniosynostosis). This article focuses on nonsyndromic craniosynostosis, and describes the current state of knowledge regarding its diagnosis, surgical management, and outcomes. PMID- 28654617 TI - Evidence-Based Medicine: Secondary Correction of Cleft Lip Nasal Deformity. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the components of unilateral and bilateral cleft lip nasal deformity. 2. Assess the deformity. 3. Design a treatment plan for secondary correction of cleft lip nasal deformity. 4. Discuss methods for managing suboptimal outcomes. SUMMARY: Correction of cleft lip nasal deformity has been addressed in this Maintenance of Certification/Continuing Medical Education series a number of times-a testament to the complexity of the topic. In this addition to the series, the authors provide a principle-based approach toward management of unilateral and bilateral cleft lip nasal deformity with an emphasis on timing intervention, role for intermediate correction, and methods for cleft rhinoplasty after completion of nasal growth. PMID- 28654619 TI - Evidence-Based Medicine: Mandible Fractures. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Explain the epidemiology of mandible fractures. 2. Discuss preoperative evaluation of the patient with a mandible fracture. 3. Compare the various modalities of fracture fixation. 4. Identify common complications after fracture repair. SUMMARY: In this Maintenance of Certification/Continuing Medical Education article, the reader is provided with a review of the epidemiology, preoperative evaluation, perioperative management, and surgical outcomes of mandible fractures. The objective of this series is to present a review of the literature so that the practicing physician can remain up-to-date on key evidence based guidelines to enhance management and improve outcomes. The physician can also seek further in-depth study of the topic through the references provided. PMID- 28654620 TI - Evidence-Based Medicine: Wound Management. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Describe the basic science of chronic wounds. 2. Discuss the general and local factors that should be considered in any patient with a chronic wound. 3. Discuss the rationale of converting a chronic wound into an acute wound. 4. Describe techniques used to prepare chronic wounds. 5. Discuss the appropriate use of different dressings presented in this article. 6. Discuss the pros and cons of the adjuncts to wound healing discussed in this article. SUMMARY: This is the second Maintenance of Certification article on wound healing. In the first, Buchanan, Kung, and Cederna dealt with the mechanism and reconstructive techniques for closing wounds. In this article, the authors have concentrated on the chronic wound. The authors present a summary of the basic science of chronic wounds and the general and local clinical factors important in assessing any chronic wound. The evidence for interventions of these conditions is presented. The surgical and nonsurgical methods of wound preparation and the evidence supporting the use of the popular wound dressings are presented. The authors then present the evidence for some of the popular adjuncts for wound healing, including hyperbaric oxygen, electrotherapy, and ultrasound. A number of excellent articles on negative-pressure wound therapy have been written, and are not covered in this article. PMID- 28654621 TI - Measuring Provider Performance for Physicians Participating in the Merit-Based Incentive Payment System. AB - In 2017, the Centers for Medicare and Medicaid Services began requiring all eligible providers to participate in the Quality Payment Program or face financial reimbursement penalty. The Quality Payment Program outlines two paths for provider participation: the Merit-Based Incentive Payment System and Advanced Alternative Payment Models. For the first performance period beginning in January of 2017, the Centers for Medicare and Medicaid Services estimates that approximately 83 to 90 percent of eligible providers will not qualify for participation in an Advanced Alternative Payment Model and therefore must participate in the Merit-Based Incentive Payment System program. The Merit-Based Incentive Payment System path replaces existing quality-reporting programs and adds several new measures to evaluate providers using four categories of data: (1) quality, (2) cost/resource use, (3) improvement activities, and (4) advancing care information. These categories will be combined to calculate a weighted composite score for each provider or provider group. Composite Merit-Based Incentive Payment System scores based on 2017 performance data will be used to adjust reimbursed payment in 2019. In this article, the authors provide relevant background for understanding value-based provider performance measurement. The authors also discuss Merit-Based Incentive Payment System reporting requirements and scoring methodology to provide plastic surgeons with the necessary information to critically evaluate their own practice capabilities in the context of current performance metrics under the Quality Payment Program. PMID- 28654624 TI - Reply: The Lipo-Body Lift: A New Circumferential Body-Contouring Technique Useful after Bariatric Surgery. PMID- 28654625 TI - Separation, Aspiration, and Fat Equalization: SAFE Liposuction Concepts for Comprehensive Body Contouring. PMID- 28654626 TI - Patient-Reported Outcomes in Gender Confirming Surgery. PMID- 28654627 TI - Effect of programmed exercise on insulin sensitivity in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effect of programmed exercise for at least 12 weeks, in postmenopausal women on insulin sensitivity-related outcomes (ISROs), including fasting insulin, C-peptide, insulin growth factor (IGF-1) and IGF-binding protein (IGFBP-3), Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), and anthropometric variables. METHODS: Searches were conducted in PubMed-Medline, Embase, Scopus, Web of Science, and Cochrane Library from inception through May 3, 2016, for studies published in all languages. Extracted data included characteristics of the study design, study participants, intervention, and outcome measures. Types of exercise were classified into "mid term exercise intervention" (MTEI, 3-4 months exercise duration) and a "long-term exercise intervention" (LTEI, 6-12 months exercise duration). Risk of bias in RCTs was evaluated with the Cochrane tool. We used random-effects models for meta analyses. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Seven RCTS (n = 580) evaluating the effects of programmed exercise on ISROs were included. In three RCTs, MTEI significantly lowered insulin levels (mean difference [MD] -6.50 pmol/L, 95% confidence interval [CI] -11.19, -1.82, P = 0.006) and HOMA-IR values (MD -0.18, 95% CI 0.34, -0.03, P = 0.02) when compared with controls. LTEI had no significant effect on insulin levels (P = 0.19) or HOMA-IR values (P = 0.68) in four and three RCTs, respectively. There were no significant differences between exercise intervention versus controls in circulating IGF-1, glucose, triglycerides with both MTEI and LTEI, and in IGFBP-3 with LTEI. There were significant reductions in body mass index (BMI, kg/m) (MD -1.48, 95% CI -2.48, -0.48, P = 0.004) and in body fat percentage (MD -2.99, 95% CI -4.85, -1.14, P = 0.01) after MTEI; and in waist circumference after both MTEI (MD -1.87, 95% CI -3.02, -0.72, P = 0.001) and LTEI (MD -3.74, 95% CI -6.68, -0.79). Heterogeneity of effects among studies was moderate to low. CONCLUSION: Exercising for 3 to 4 months significantly lowered insulin levels and HOMA-IR values, BMI waist circumference, and percentage body fat mass; exercising for 6 to 12 months lowered waist circumference in postmenopausal women. PMID- 28654628 TI - Hot flush frequency and severity at baseline as predictors of time to transient and stable treatment success: pooled analysis of two CE/BZA studies. AB - OBJECTIVE: To evaluate the impact of baseline hot flush frequency and severity on time to symptom improvement during treatment with conjugated estrogens/bazedoxifene (CE/BZA). METHODS: Data were pooled through week 12 from two randomized placebo-controlled trials (SMART-1 and SMART-2) of nonhysterectomized postmenopausal women with hot flushes treated with CE 0.45 mg/BZA 20 mg or CE 0.625 mg/BZA 20 mg. Time to transient and stable improvement (>= 50% reduction in hot flush frequency/severity) was estimated using nonparametric models. RESULTS: Transient improvement in hot flush frequency occurred earlier in women treated with CE 0.45 mg/BZA 20 mg with less frequent versus more frequent baseline hot flushes per day: median time to transient improvement was 2, 7, and 11 days for women with < 3, 3 to < 8, and >= 8 hot flushes per day at baseline, respectively (P = 0.0009). Transient improvement in severity occurred earlier for women with less severe versus more severe baseline hot flushes: median time to transient improvement was 2, 6, and 16 days for women with mild, moderate, and severe hot flushes at baseline, respectively (P < 0.0001). Stable improvement typically occurred 2 to 3 days after the transient event and was less influenced by baseline status. A similar pattern was observed with CE 0.625 mg/BZA 20 mg treatment, though improvement occurred a few days earlier than with CE 0.45 mg/BZA 20 mg. CONCLUSION: Women with more frequent/severe hot flushes take longer to achieve transient improvements with CE/BZA and should be encouraged to continue treatment, as it may take longer than a few weeks to achieve significant improvement. PMID- 28654629 TI - PREDICTORS OF ONE-YEAR VISUAL OUTCOMES AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To determine predictors of best-corrected visual acuity (BCVA) outcomes 1 year after ranibizumab or bevacizumab treatment for neovascular age-related macular degeneration, within the French Study Group Avastin versus Lucentis for neovascular age-related macular degeneration (GEFAL). METHODS: Patients aged >=50 years presenting subfoveal neovascular age-related macular degeneration were randomized to receive ranibizumab or bevacizumab (3 monthly intravitreal injections followed by an as-needed regimen). The main outcome measures were BCVA and its change from baseline at 1 year. Variables with a P value <0.20 in the univariate model and/or which were clinically relevant were included in the multivariate analysis. RESULTS: The following baseline factors were associated with a lower BCVA score at 1 year and with less improvement in BCVA (multivariate analysis): intraretinal fluid, thickness of central subfield macular <=277 MUm, predominantly classic choroidal neovascularization, and total area of choroidal neovascularization (all P <= 0.01). Pigment epithelium detachment and high baseline BCVA were associated with less improvement in BCVA (P = 0.03, P = 0.05, respectively). Patients who met retreatment criteria but did not receive the corresponding injection had significantly poorer outcomes (only tested in the univariate analysis). CONCLUSION: This study confirms the predictors of BCVA score at 1 year posttreatment; the presence of intraretinal fluid was associated with a poor prognosis. PMID- 28654630 TI - PROGNOSTIC VALUE OF SUBRETINAL HYPERREFLECTIVE MATERIAL IN NEOVASCULAR AGE RELATED MACULAR DEGENERATION TREATED WITH BEVACIZUMAB. AB - PURPOSE: To study the correlation between subretinal hyperreflective material (SHRM) seen on spectral domain optical coherence tomography at baseline and visual outcomes after intravitreal bevacizumab injection in neovascular age related macular degeneration. METHODS: Consecutive patient charts with treatment naive center-involved neovascular age-related macular degeneration treated with 3 monthly intravitreal bevacizumab's, continued as needed, from 2011 to 2014 were reviewed. Baseline spectral domain optical coherence tomography SHRM parameters (height, width, area, reflectivity, border definition, and homogeneity) and established optical coherence tomography biomarkers of neovascular activity (intraretinal fluid, subretinal fluid, retinal volume, central retinal thickness, and pigment epithelial detachment presence) were collected. These baseline parameters were correlated with visual acuity at baseline, 3 and 12 months. RESULTS: Seventy-three eyes of 73 patients, 47 (64.4%) having central SHRM at baseline, were studied. Mean age was 79.2 +/- 8.9 years. Mean best-corrected visual acuity was 0.70 +/- 0.57 logarithm of the minimum angle of resolution (20/100), 0.73 +/- 0.55 (20/107), and 0.76 +/- 0.63 (20/115) at baseline, 3 and 12 months, respectively. Baseline parameters with a significant predictive value of 12-month visual acuity by univariate analysis were presence of intraretinal fluid, presence of SHRM, highly reflective SHRM, well-defined SHRM borders, and thick SHRM. These parameters, with the exception of high reflectivity, were significant on multivariate regression analysis. The most predictive baseline parameter was well-defined SHRM borders. CONCLUSION: This study supports the use of SHRM as a prognostic biomarker when interpreting optical coherence tomography in neovascular age-related macular degeneration. Baseline parameters predicting poorer vision 1 year after intravitreal bevacizumab treatment were as follows: presence of central SHRM, well-defined SHRM borders, intraretinal fluid, and thicker SHRM. PMID- 28654631 TI - CHANGES IN CHOROIDAL THICKNESS IN CLINICALLY SIGNIFICANT PSEUDOPHAKIC CYSTOID MACULAR EDEMA. AB - PURPOSE: To investigate choroidal thickness in eyes with clinically significant pseudophakic cystoid macular edema (PCME) during the acute phase and following resolution of the edema, using enhanced depth imaging spectral domain optical coherence tomography (EDI-OCT). METHODS: This is a retrospective, observational clinical study. Patients' records were reviewed for cases of clinically significant PCME after uneventful phacoemulsification surgery. Choroidal thickness was measured at time of PCME diagnosis in both eyes and after CME resolution in the affected eye using enhanced depth imaging spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering). Measurements were taken subfoveal and 1.5 mm nasal, temporal, inferior, and superior from the center of the fovea. Statistical analysis was performed using paired t-test and Pearson correlation. RESULTS: Mean subfoveal choroidal thickness in 34 eyes with PCME measured 258 +/- 83 MUm at baseline and decreased to 215 +/- 79 MUm after CME resolution (P < 0.001). Mean subfoveal choroidal thickness measured at baseline in fellow eyes was significantly lower (194 +/- 77 MUm) compared to acute PCME (P < 0.001) and after CME resolution (P = 0.011). CONCLUSION: Choroidal thickness is increased in eyes with PCME and decreases following edema resolution. These findings may strengthen the hypothesis of an inflammatory pathogenesis in PCME. PMID- 28654632 TI - P53 and Protein Phosphorylation Regulate the Oncogenic Role of Epithelial Cell Transforming 2 (ECT2). AB - BACKGROUND Gastric cancer (GC) is the second leading cause of cancer-related death worldwide, but little progress has been achieved in the treatment of advanced or metastatic GC. GC is highly heterogeneous and more studies are needed to elucidate the metastatic mechanisms. Epithelial cell transforming 2 (ECT2) has been reported to be up-regulated in GC tissues, but its signaling mechanisms remain unclear. MATERIAL AND METHODS In this study, we used Western blot analysis to compare the expression level of ECT2 in 2 GC cell lines: MKN1 and MKN45. Mutagenesis and transfections were conducted to investigate the oncogenic mechanisms of ECT2 in GC cells. RESULTS ECT2 was expressed at higher levels in MKN1 than in MKN45. Immunoblotting results showed that MKN1 expression was suppressed by p53-WT but was enhanced by p53-mutant. In addition, in vitro experiments showed that ECT2 positively regulated the proliferation and invasion of GC cells. To better explore the mechanisms of ECT2 in promoting GC progression, we introduced site-directed mutants of ECT2, and found that the phosphor-mimic mutant T359D enhanced its oncogenic activity. In contrast, activation of RhoA was inhibited in cells transfected with ECT2 phosphor deficient mutant T359A. We found that the epithelial cell biomarker E-cadherin was down-regulated by ECT2-T359D, highlighting the role of phosphorylation in regulating epithelial-mesenchymal transition. CONCLUSIONS Our results identified p53 as a novel up-stream signaling molecule of ECT2 in GC cells, and the post translational modifications of ECT2 play important roles in regulating cancer development and progression. PMID- 28654633 TI - Chemotherapy with radiotherapy influences time-to-development of radiation induced sarcomas: a multicenter study. AB - BACKGROUND: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present a multi-centre collaborative study to validate this association. METHODS: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between 1 January 2000 to 31 December 2014. The primary endpoint was time to development of RIS. RESULTS: We identified 419 patients with RIS. Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1.37; 95% CI: 1.08-1.72; P=0.009). In the multi-variable model, older age (HR 2.11; 95% CI 1.83-2.43; P<0.001) and chemotherapy for the first malignancy (HR 1.61; 95% CI 1.26-2.05; P<0.001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect. CONCLUSIONS: This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of RIS. PMID- 28654634 TI - Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer. AB - BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAFV600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown. METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data. RESULTS: We identified in plasma MET gene hyper amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition. CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition. PMID- 28654635 TI - Two different mechanisms support selective attention at different phases of training. AB - Selective attention supports the prioritized processing of relevant sensory information to facilitate goal-directed behavior. Studies in human subjects demonstrate that attentional gain of cortical responses can sufficiently account for attention-related improvements in behavior. On the other hand, studies using highly trained nonhuman primates suggest that reductions in neural noise can better explain attentional facilitation of behavior. Given the importance of selective information processing in nearly all domains of cognition, we sought to reconcile these competing accounts by testing the hypothesis that extensive behavioral training alters the neural mechanisms that support selective attention. We tested this hypothesis using electroencephalography (EEG) to measure stimulus-evoked visual responses from human subjects while they performed a selective spatial attention task over the course of ~1 month. Early in training, spatial attention led to an increase in the gain of stimulus-evoked visual responses. Gain was apparent within ~100 ms of stimulus onset, and a quantitative model based on signal detection theory (SDT) successfully linked the magnitude of this gain modulation to attention-related improvements in behavior. However, after extensive training, this early attentional gain was eliminated even though there were still substantial attention-related improvements in behavior. Accordingly, the SDT-based model required noise reduction to account for the link between the stimulus-evoked visual responses and attentional modulations of behavior. These findings suggest that training can lead to fundamental changes in the way attention alters the early cortical responses that support selective information processing. Moreover, these data facilitate the translation of results across different species and across experimental procedures that employ different behavioral training regimes. PMID- 28654637 TI - Pathways and progress to enhanced global sexually transmitted infection surveillance. AB - Melanie Taylor and colleagues discuss global initiatives for surveillance of sexually transmitted diseases. PMID- 28654636 TI - Human cyclophilin 40 unravels neurotoxic amyloids. AB - The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids. PMID- 28654638 TI - Increased inspiratory resistance affects the dynamic relationship between blood pressure changes and subarachnoid space width oscillations. AB - BACKGROUND AND OBJECTIVE: Respiration is known to affect cerebrospinal fluid (CSF) movement. We hypothesised that increased inspiratory resistance would affect the dynamic relationship between blood pressure (BP) changes and subarachnoid space width (SAS) oscillations. METHODS: Experiments were performed in a group of 20 healthy volunteers undergoing controlled intermittent Mueller Manoeuvres (the key characteristic of the procedure is that a studied person is subjected to a controlled, increased inspiratory resistance which results in marked potentiation of the intrathoracic negative pressure). BP and heart rate (HR) were measured using continuous finger-pulse photoplethysmography; oxyhaemoglobin saturation with an ear-clip sensor; end-tidal CO2 with a gas analyser; cerebral blood flow velocity (CBFV), pulsatility and resistive indices with Doppler ultrasound. Changes in SAS were recorded with a new method i.e. near infrared transillumination/backscattering sounding. Wavelet transform analysis was used to assess the BP and SAS oscillations coupling. RESULTS: Initiating Mueller manoeuvres evoked cardiac SAS component decline (-17.8%, P<0.001), systolic BP, diastolic BP and HR increase (+6.3%, P<0.001; 6.7%, P<0.001 and +2.3%, P<0.05, respectively). By the end of Mueller manoeuvres, cardiac SAS component and HR did not change (+2.3% and 0.0%, respectively; both not statistically significant), but systolic and diastolic BP was elevated (+12.6% and +8.9%, respectively; both P<0.001). With reference to baseline values there was an evident decrease in wavelet coherence between BP and SAS oscillations at cardiac frequency in the first half of the Mueller manoeuvres (-32.3%, P<0.05 for left hemisphere and -46.0%, P<0.01 for right hemisphere) which was followed by subsequent normalization at end of the procedure (+3.1% for left hemisphere and +23.1% for right hemisphere; both not statistically significant). CONCLUSIONS: Increased inspiratory resistance is associated with swings in the cardiac contribution to the dynamic relationship between BP and SAS oscillations. Impaired cardiac performance reported in Mueller manoeuvres may influence the pattern of cerebrospinal fluid pulsatility. PMID- 28654639 TI - Improvement of atropine on esophagogastric junction observation during sedative esophagogastroduodenoscopy. AB - BACKGROUND AND STUDY AIMS: Although sedation esophagogastroduodenoscopy (EGD) is now widely used, previous research has reported that sedation during EGD exhibits a negative effect on esophagogastric junction (EGJ) exposure. Atropine might improve EGJ exposure, as noted in clinical practice. The aim of this study was to examine whether sedation had a negative effect on EGJ observation in the Chinese population, and whether atropine had some ability to act as an antidote to this unexpected secondary effect of sedation. PATIENTS AND METHODS: In this cross sectional study, subjects were divided into the following three groups according to the methods of EGD examination: the non-sedation group, the propofol-fentanyl combined sedation group and the combined sedation with atropine administration group. The EGJ observation was assessed by a key photograph taken with the endoscopic camera 1 cm from the EGJ, which was rated on the following four-degree scale: excellent (score = 4), good (score = 3), fair (score = 2) and poor (score = 1). RESULTS: The EGJ exposure was better in the sedation group administered atropine (score = 2.64+/-1.05) than in the sedation group (score = 1.99+/-1.08, P<0.05) but not as good as in the non-sedation group (score = 3.24+/-1.12, P<0.05). Reduced detection of EGJ diseases in the sedation group was also found, compared to the non-sedation group (P<0.05). Only the use of atropine (OR = 2.381, 95%CI: 1.297-4.371, P = 0.005) was independently associated with excellent observation of the EGJ during sedation EGD. CONCLUSIONS: Combined propofol fentanyl sedation reduces the extent of exposure of the EGJ during EGD and reduces the detection of EGJ diseases. The application of atropine in the sedation endoscopy examination helped to achieve better EGJ observation, but still cannot achieve an equal extent of exposure compared to non-sedation EGD. PMID- 28654640 TI - Vaccination to prevent human papillomavirus infections: From promise to practice. AB - In an essay, Paul Bloem and Ikechukwu Ogbuanu discuss the public health implications of HPV vaccination. PMID- 28654642 TI - Monitoring of noble, signal and narrow-clawed crayfish using environmental DNA from freshwater samples. AB - For several hundred years freshwater crayfish (Crustacea-Decapoda-Astacidea) have played an important ecological, cultural and culinary role in Scandinavia. However, many native populations of noble crayfish Astacus astacus have faced major declines during the last century, largely resulting from human assisted expansion of non-indigenous signal crayfish Pacifastacus leniusculus that carry and transmit the crayfish plague pathogen. In Denmark, also the non-indigenous narrow-clawed crayfish Astacus leptodactylus has expanded due to anthropogenic activities. Knowledge about crayfish distribution and early detection of non indigenous and invasive species are crucial elements in successful conservation of indigenous crayfish. The use of environmental DNA (eDNA) extracted from water samples is a promising new tool for early and non-invasive detection of species in aquatic environments. In the present study, we have developed and tested quantitative PCR (qPCR) assays for species-specific detection and quantification of the three above mentioned crayfish species on the basis of mitochondrial cytochrome oxidase 1 (mtDNA-CO1), including separate assays for two clades of A. leptodactylus. The limit of detection (LOD) was experimentally established as 5 copies/PCR with two different approaches, and the limit of quantification (LOQ) were determined to 5 and 10 copies/PCR, respectively, depending on chosen approach. The assays detected crayfish in natural freshwater ecosystems with known populations of all three species, and show promising potentials for future monitoring of A. astacus, P. leniusculus and A. leptodactylus. However, the assays need further validation with data 1) comparing traditional and eDNA based estimates of abundance, and 2) representing a broader geographical range for the involved crayfish species. PMID- 28654641 TI - Biological effects of the hypomagnetic field: An analytical review of experiments and theories. AB - During interplanetary flights in the near future, a human organism will be exposed to prolonged periods of a hypomagnetic field that is 10,000 times weaker than that of Earth's. Attenuation of the geomagnetic field occurs in buildings with steel walls and in buildings with steel reinforcement. It cannot be ruled out also that a zero magnetic field might be interesting in biomedical studies and therapy. Further research in the area of hypomagnetic field effects, as shown in this article, is capable of shedding light on a fundamental problem in biophysics-the problem of primary magnetoreception. This review contains, currently, the most extensive bibliography on the biological effects of hypomagnetic field. This includes both a review of known experimental results and the putative mechanisms of magnetoreception and their explanatory power with respect to the hypomagnetic field effects. We show that the measured correlations of the HMF effect with HMF magnitude and inhomogeneity and type and duration of exposure are statistically absent. This suggests that there is no general biophysical MF target similar for different organisms. This also suggests that magnetoreception is not necessarily associated with evolutionary developed specific magnetoreceptors in migrating animals and magnetotactic bacteria. Independently, there is nonspecific magnetoreception that is common for all organisms, manifests itself in very different biological observables as mostly random reactions, and is a result of MF interaction with magnetic moments at a physical level-moments that are present everywhere in macromolecules and proteins and can sometimes transfer the magnetic signal at the level of downstream biochemical events. The corresponding universal mechanism of magnetoreception that has been given further theoretical analysis allows one to determine the parameters of magnetic moments involved in magnetoreception-their gyromagnetic ratio and thermal relaxation time-and so to better understand the nature of MF targets in organisms. PMID- 28654643 TI - Elimination of mother-to-child transmission of HIV and Syphilis (EMTCT): Process, progress, and program integration. AB - Melanie Taylor and colleagues discuss progress towards eliminating vertical transmission of HIV and syphilis. PMID- 28654644 TI - Net profit flow per country from 1980 to 2009: The long-term effects of foreign direct investment. AB - AIM OF THE PAPER: The paper aims at describing and explaining net profit flows per country for the period 1980-2009. Net profit flows result from Foreign Direct Investment (FDI) stock and profit repatriation: inward stock creating a profit outflow and outward FDI stock a profit inflow. Profit flows, especially 'normal' ones are not commonly researched. THEORETICAL BACKGROUND: According to world system theory, countries are part of a system characterised by a core, semi periphery and periphery, as shown by network analyses of trade relations. Network analyses based on ownership relations of TransNational Corporations (TNCs) show that the top 50 firms that control about 40% of the world economy are almost exclusively located in core countries. So, we may expect a hierarchy in net profit flows with core countries on top and the periphery at the bottom. FDI outflows from the core countries especially rose in the 1990s, so we may expect that the difference has grown in time. DATA AND RESULTS: A dataset on 'net profit flow' per country is developed. There are diverging developments in net profit flows since the 1980s, as expected: ever more positive for core countries, negative and ever lower for semi-peripheral and peripheral countries, in particular from the 1990s onwards. A fixed effects quantile regression using publicly available data confirms the prediction that peripheral countries share a unique characteristic: their outward investments do not have a positive influence on net profit flow as is the case with semi-peripheral and core countries. The most probable explanation is that peripheral outward investments are indirectly owned by firms located in core and semi-peripheral countries, so all peripheral profit inflows end up in those countries. PMID- 28654645 TI - Correction: Cortical maturation in children with cochlear implants: Correlation between electrophysiological and behavioral measurement. AB - [This corrects the article DOI: 10.1371/journal.pone.0171177.]. PMID- 28654646 TI - Developing and validating a scale to measure Food and Nutrition Literacy (FNLIT) in elementary school children in Iran. AB - BACKGROUND: Food and nutrition literacy is an emerging term which is increasingly used in policy and research. Though research in this area is growing, progression is limited by the lack of an accepted method to measure food and nutrition literacy. The aim of this study is to develop a valid and reliable questionnaire to assess food and nutrition literacy in elementary school children in the city of Tehran. METHODS: The study was conducted in three phases. To develop Food and Nutrition Literacy (FNLIT) questionnaire, a comprehensive literature review and a qualitative study were initially performed to identify food and nutrition literacy dimensions and its components. Content and face validity of the questionnaire were evaluated by an expert panel as well as students. In the second phase, construct validity of the scale was evaluated using Explanatory Factor Analyses (EFA) and Confirmatory Factor Analyses (CFA). In the last phase (confirmatory phase), the final version of the questionnaire was evaluated on 400 students. RESULTS: Findings show Content Validity Ratio (CVR) and Content Validity Index (CVI) of the 62-item questionnaire at acceptable levels of 0.87 and 0.92, respectively. EFA suggested a six-factor construct, namely, understanding food and nutrition information, knowledge, functional, interactive, food choice, and critical. The results of CFA indicated acceptable fit indices for the proposed models. All subscales demonstrated satisfactory internal consistency (Cronbach's alpha>=0.70), except for critical skill subscale (0.48). The intraclass correlation coefficient (ICC = 0.90, CI: 0.83-0.94) indicated that Food and Nutrition Literacy (FNLIT) scale had satisfactory stability. Each phase of development progressively improved the questionnaire, which resulted in a 46 item (42 likert-type items and 4 true-false items) Food and Nutrition Literacy (FNLIT) scale. The questionnaire measured two domains with 6 subscales, including: 1) cognitive domain: understanding and knowledge; 2) skill domain: functional, food choice, interactive, and critical skills. CONCLUSION: The developed food and nutrition literacy scale is a valid and reliable instrument to measure food and nutrition literacy in children. This measure lays a solid empirical and theoretical foundation for future research and tailored interventions to promote food and nutrition literacy in this age group. PMID- 28654648 TI - A Collection on the prevention, diagnosis, and treatment of sexually transmitted infections: Call for research papers. AB - Nicola Low and colleagues announce a call for research papers on sexually transmitted infections, to accompany a Collection on the topic. PMID- 28654649 TI - Optimal specific wavelength for maximum thrust production in undulatory propulsion. AB - What wavelengths do undulatory swimmers use during propulsion? In this work we find that a wide range of body/caudal fin (BCF) swimmers, from larval zebrafish and herring to fully-grown eels, use specific wavelength (ratio of wavelength to tail amplitude of undulation) values that fall within a relatively narrow range. The possible emergence of this constraint is interrogated using numerical simulations of fluid-structure interaction. Based on these, it was found that there is an optimal specific wavelength (OSW) that maximizes the swimming speed and thrust generated by an undulatory swimmer. The observed values of specific wavelength for BCF animals are relatively close to this OSW. The mechanisms underlying the maximum propulsive thrust for BCF swimmers are quantified and are found to be consistent with the mechanisms hypothesized in prior work. The adherence to an optimal value of specific wavelength in most natural hydrodynamic propulsors gives rise to empirical design criteria for man-made propulsors. PMID- 28654647 TI - Ancient female philopatry, asymmetric male gene flow, and synchronous population expansion support the influence of climatic oscillations on the evolution of South American sea lion (Otaria flavescens). AB - The South American sea lion (Otaria flavescens) is widely distributed along the southern Atlantic and Pacific coasts of South America with a history of significant commercial exploitation. We aimed to evaluate the population genetic structure and the evolutionary history of South American sea lion along its distribution by analyses of mitochondrial DNA (mtDNA) and 10 nuclear microsatellites loci. We analyzed 147 sequences of mtDNA control region and genotyped 111 individuals of South American sea lion for 10 microsatellite loci, representing six populations (Peru, Northern Chile, Southern Chile, Uruguay (Brazil), Argentina and Falkland (Malvinas) Islands) and covering the entire distribution of the species. The mtDNA phylogeny shows that haplotypes from the two oceans comprise two very divergent clades as observed in previous studies, suggesting a long period (>1 million years) of low inter-oceanic female gene flow. Bayesian analysis of bi-parental genetic diversity supports significant (but less pronounced than mitochondrial) genetic structure between Pacific and Atlantic populations, although also suggested some inter-oceanic gene flow mediated by males. Higher male migration rates were found in the intra-oceanic population comparisons, supporting very high female philopatry in the species. Demographic analyses showed that populations from both oceans went through a large population expansion ~10,000 years ago, suggesting a very similar influence of historical environmental factors, such as the last glacial cycle, on both regions. Our results support the proposition that the Pacific and Atlantic populations of the South American sea lion should be considered distinct evolutionarily significant units, with at least two managements units in each ocean. PMID- 28654650 TI - Risk factors for prevalent hepatitis C virus-infection among inmates in a state prison system in Mexico. AB - OBJECTIVES: To estimate the prevalence of HCV-infection and identify associated factors among inmates in the State Prison System of Guanajuato in Mexico (Sep 2011 to Feb-2012). METHODS: Cross-sectional, observational study in 10 prisons in the State of Guanajuato in Mexico (2011-2012). We offered HCV-testing and applied audio computer-assisted self-interviews to all adults imprisoned in the State Prison System. We used a complex survey analysis to estimate the distribution of variables and its corresponding 95% confidence intervals, taking into consideration the expected cluster effect by common characteristics within prisons. Inverse probability weights were applied to correct potential biased estimates arising from non-participation in accrual activities and non-response rates. We fitted multivariate logistic regression models to identify risk behaviors associated to HCV-infection. RESULTS: We included data of 2,519 participating inmates. Prevalence of HCV-infection was 4.9 (95%CI = 3.6-5.9). Most HCV-infected inmates were male (99%). Before being incarcerated, inmates with HCV-infection were more frequently tattooed, used and injected drugs more frequently, and were more likely to share materials for injecting, when compared with those non-infected. During incarceration, HCV-infected inmates got tattoos and used drugs more often than non-infected, including injecting-drugs and sharing materials. Injecting-drug use (OR = 7.6, 95%CI, 2.5-23.4), sharing materials for injecting-drugs (OR = 19.6, 95%CI, 4.7-81.7) and being tattooed at least once before incarceration (OR = 2.1, 95%CI, 1.1-3.9), but not during incarceration, were independently associated to HCV-infection. CONCLUSIONS: The prevalence of HCV-infection among inmates in the State of Guanajuato in Mexico is considerably higher than in the general population. The most important risk factors for HCV in this inmate population were injecting-drugs and sharing materials for injections before incarceration. High-risk behaviors during imprisonment are very high particularly among those already infected. HCV diagnostic and treatment services, and harm-reduction programs for incarcerated injecting-drug users in Mexico should be integrated to control the HCV epidemic in Mexico. PMID- 28654651 TI - Herpes simplex virus 1 and 2 educational assessment of young adults in rural southwest Virginia. AB - PURPOSE: Herpes simplex virus 2 (HSV-2) causes genital herpes, one of the most common sexually transmitted infections (STIs) in the U.S. HSV-1, commonly associated with cold sores, is increasing as a cause of genital herpes. Abstinence-only sexual health classes, commonly taught in Virginia, generate young adults who are under-educated in sexual health, increasing STI risks. College students in southwest Virginia were surveyed to assess comprehensiveness of high school health education regarding HSV-1 and HSV-2 and to identify students' preferred methods for STI education. METHODS: To obtain data on knowledge of HSV, comprehensiveness of sexual health education in high school, and preferred learning methods, 237 college students participated in an online questionnaire and 28 students were interviewed using structured interviews. RESULTS: Questionnaire and interview data indicated that Family Life Education classes need to include more comprehensive information on prevention, viral transmission, and differences between HSV-1 and HSV-2. The majority of total respondents (both the questionnaire and interview) (65%) reported non comprehensive high school sexual health education. The majority of interview (79%) and questionnaire (55%) respondents wished they had learned more about herpes and other STIs in high school. Education preferences of both interviewed and surveyed respondents included interactive internet programs or games, more realistic lectures, and learning about STIs later in high school when students reported greater sexual activity. CONCLUSION: Our results indicate that more comprehensive sexual health education is needed and wanted by students in southwest Virginia. More relevant educational programs should be implemented for VA high school students utilizing technology and interactive methods to improve student engagement in sexual health education. IMPLICATIONS AND CONTRIBUTION: These studies provide information on knowledge of herpes simplex viruses among college students, comprehensiveness of sexual health education received in high schools, and preferred methods to learn about HSV and other STIs. These studies inform the facilitation of improved health education practices and programs for high school and college students. PMID- 28654652 TI - Alleviation of the effects of saline-alkaline stress on maize seedlings by regulation of active oxygen metabolism by Trichoderma asperellum. AB - This study investigated the influence of Trichoderma asperellum on active oxygen production in maize seedlings under saline-alkaline stress conditions. Two maize cultivars were tested: 'Jiangyu 417' ('JY417'), which can tolerate saline alkaline stress; and, 'Xianyu 335' ('XY335'), which is sensitive to saline alkaline stress. The seedlings were grown on natural saline-alkaline soil (pH 9.30) in plastic pots. To each liter of saline-alkaline soil, 200 mL of T. asperellum spore suspension was applied; three fungal suspensions were used, namely, 1 * 103, 1 * 106, and 1 * 109 spores/L. A control with only the vehicle applied was also established, along with a second control in which untreated meadow soil (pH 8.23) was used. Root and leaf samples were collected when the seedlings had three heart-shaped leaves and the fourth was in the developmental phase. Physical and biochemical parameters related to oxidation resistance were assessed. The results indicated that the 'JY417' and 'XY335' seedlings showed different degrees of oxidative damage and differences in their antioxidant defense systems under saline-alkaline stress. As the spore density of the fungal suspension increased, the K+ and Ca2+ contents in the seedlings increased, but Na+ content decreased. Moreover, fungal treatment promoted the synthesis or accumulation of osmolytes, which enhanced the water absorbing capacity of the cells, increased antioxidant enzyme activities, enhanced the content of non enzyme antioxidants, and reduced the accumulation of reactive oxygen species. Fungal treatment alleviated oxidative damage caused by the saline-alkaline stress in roots and leaves of the seedlings. The application of T. asperellum overcame the inhibitory effect of saline-alkaline soil stress on the growth of maize seedlings. In the present experiment, application with 1 * 109 spores/L gave the optimal results. PMID- 28654653 TI - Validity of using multiple imputation for "unknown" stage at diagnosis in population-based cancer registry data. AB - BACKGROUND: The multiple imputation approach to missing data has been validated by a number of simulation studies by artificially inducing missingness on fully observed stage data under a pre-specified missing data mechanism. However, the validity of multiple imputation has not yet been assessed using real data. The objective of this study was to assess the validity of using multiple imputation for "unknown" prostate cancer stage recorded in the New South Wales Cancer Registry (NSWCR) in real-world conditions. METHODS: Data from the population based cohort study NSW Prostate Cancer Care and Outcomes Study (PCOS) were linked to 2000-2002 NSWCR data. For cases with "unknown" NSWCR stage, PCOS-stage was extracted from clinical notes. Logistic regression was used to evaluate the missing at random assumption adjusted for variables from two imputation models: a basic model including NSWCR variables only and an enhanced model including the same NSWCR variables together with PCOS primary treatment. Cox regression was used to evaluate the performance of MI. RESULTS: Of the 1864 prostate cancer cases 32.7% were recorded as having "unknown" NSWCR stage. The missing at random assumption was satisfied when the logistic regression included the variables included in the enhanced model, but not those in the basic model only. The Cox models using data with imputed stage from either imputation model provided generally similar estimated hazard ratios but with wider confidence intervals compared with those derived from analysis of the data with PCOS-stage. However, the complete-case analysis of the data provided a considerably higher estimated hazard ratio for the low socio-economic status group and rural areas in comparison with those obtained from all other datasets. CONCLUSIONS: Using MI to deal with "unknown" stage data recorded in a population-based cancer registry appears to provide valid estimates. We would recommend a cautious approach to the use of this method elsewhere. PMID- 28654654 TI - Identification and characterization of AckA-dependent protein acetylation in Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae, the causative agent of gonorrhea, has a number of factors known to contribute to pathogenesis; however, a full understanding of these processes and their regulation has proven to be elusive. Post-translational modifications (PTMs) of bacterial proteins are now recognized as one mechanism of protein regulation. In the present study, Western blot analyses, with an anti acetyl-lysine antibody, indicated that a large number of gonococcal proteins are post-translationally modified. Previous work has shown that Nepsilon-lysine acetylation can occur non-enzymatically with acetyl-phosphate (AcP) as the acetyl donor. In the current study, an acetate kinase mutant (1291ackA), which accumulates AcP, was generated in N. gonorrhoeae. Broth cultures of N. gonorrhoeae 1291wt and 1291ackA were grown, proteins extracted and digested, and peptides containing acetylated-lysines (K-acetyl) were affinity-enriched from both strains. Mass spectrometric analyses of these samples identified a total of 2686 unique acetylation sites. Label-free relative quantitation of the K-acetyl peptides derived from the ackA and wild-type (wt) strains demonstrated that 109 acetylation sites had an ackA/wt ratio>2 and p-values <0.05 in at least 2/3 of the biological replicates and were designated as "AckA-dependent". Regulated K acetyl sites were found in ribosomal proteins, central metabolism proteins, iron acquisition and regulation proteins, pilus assembly and regulation proteins, and a two-component response regulator. Since AckA is part of a metabolic pathway, comparative growth studies of the ackA mutant and wt strains were performed. The mutant showed a growth defect under aerobic conditions, an inability to grow anaerobically, and a defect in biofilm maturation. In conclusion, the current study identified AckA-dependent acetylation sites in N. gonorrhoeae and determined that these sites are found in a diverse group of proteins. This work lays the foundation for future studies focusing on specific acetylation sites that may have relevance in gonococcal pathogenesis and metabolism. PMID- 28654655 TI - The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki 67 tissue markers in localized renal cell carcinoma: A retrospective study of tissue microarrays using immunohistochemistry. AB - OBJECTIVE: To assess the prognostic roles of BAP1, PBRM1, pS6, PTEN, TGase2, PD L1, CA9, PSMA, and Ki-67 tissue biomarkers in localized renal cell carcinoma (RCC). METHODS: Patients who underwent a nephrectomy during 1992-2015 and had a primary specimen of their kidney tumor were included. The nine tissue biomarkers were immunohistochemically stained on tissue microarrays of RCC, and the semi quantitative H-score, including intensity score, was used to grade the sample. The Cox proportional hazards model was used to evaluate tissue markers significant for overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) after adjusting for significant clinicopathological parameters. RESULTS: Samples from 351 RCC patients were included. The mean age of the patients was 53.9 years; the rates of pathologic T1 2/>=T3 stage, Fuhrman 1+2/3+4 grade, recurrence, and death were 269/65(80.5/19.5%), 222/107 (67.5/32.5%), 6.6%, and 10.5%, respectively. Median OS, CSS, and RFS were 220.6, 220.6, and 147.1 months, respectively. The multivariable analysis showed that pathologic T stage and Fuhrman nuclear grade were significantly associated with OS and CSS. Pathologic T stage and tumor size were associated with RFS. After adjusting for these significant prognostic clinicopathological factors, Ki-67 was significantly associated with OS (hazard ratio [HR], 2.7), CSS (HR, 3.82), and RFS (HR, 4.85) and pS6 was associated with CSS (HR, 8.63) and RFS (HR, 8.51) in the multivariable model (p<0.05). CONCLUSION: pS6 and Ki-67 are significant prognostic factors of RCC; however, BAP1, PBRM1, TGase 2, PD-L1, CA9, PTEN loss, and PSMA markers did not show this association. PMID- 28654656 TI - Developmental trajectory of the corpus callosum from infancy to the juvenile stage: Comparative MRI between chimpanzees and humans. AB - How brains develop during early life is one of the most important topics in neuroscience because it underpins the neuronal functions that mature during this period. A comparison of the neurodevelopmental patterns among humans and nonhuman primates is essential to infer evolutional changes in neuroanatomy that account for higher-order brain functions, especially those specific to humans. The corpus callosum (CC) is the major white matter bundle that connects the cerebral hemispheres, and therefore, relates to a wide variety of neuronal functions. In humans, the CC area rapidly expands during infancy, followed by relatively slow changes. In chimpanzees, based on a cross-sectional study, slow changes in the CC area during the juvenile stage and later have also been reported. However, little is known about the developmental changes during infancy. A longitudinal study is also required to validate the previous cross-sectional observations about the chimpanzee CC. The present longitudinal study of magnetic resonance imaging scans demonstrates that the CC development in chimpanzees and humans is characterized by a rapid increase during infancy, followed by gradual increase during the juvenile stage. Several differences between the two species were also identified. First, there was a tendency toward a greater increase in the CC areas during infancy in humans. Second, there was a tendency toward a greater increase in the rostrum during the juvenile stage in chimpanzees. The rostral body is known to carry fibers between the bilateral prefrontal and premotor cortices, and is involved in behavior planning and control, verbal working memory, and number conception. The rostrum is known to carry fibers between the prefrontal cortices, and is involved in attention control. The interspecies differences in the developmental trajectories of the rostral body and the rostrum might be related to evolutional changes in the brain systems. PMID- 28654657 TI - HEK293T cell lines defective for O-linked glycosylation. AB - Here we describe derivatives of the HEK293T cell line that are defective in their ability to generate mucin-type O-linked glycosylation. Using CRISPR/Cas9 and a single-cell GFP-sorting procedure, the UDP-galactose-4-epimerase (GALE), galactokinase 1 (GALK1), and galactokinase 2 (GALK2) genes were knocked out individually and in combinations with greater than 90% of recovered clones having the desired mutations. Although HEK293T cells are tetraploid, we found this approach to be an efficient method to target and disrupt all 4 copies of the target gene. Deficient glycosylation in the GALE knockout cell line could be rescued by the addition of galactose and N-acetylgalactosamine (GalNAc) to the cell culture media. However, when key enzymes of the galactose/GalNAc salvage pathways were disrupted in tandem (GALE+GALK1 or GALE+GALK2), O-glycosylation was eliminated and could not be rescued by the addition of either galactose plus GalNAc or UDP-galactose plus UDP-GalNAc. GALK1 and GALK2 are key enzymes of the galactose/GalNAc salvage pathways. Mass spectrometry was performed on whole cell lysate of the knockout cell lines to verify the glycosylation phenotype. As expected, the GALE knockout was almost completely devoid of all O-glycosylation, with minimal glycosylation as a result of functional salvage pathways. However, the GALE+GALK1 and GALE+GALK2 knockout lines were devoid of all O-glycans. Mass spectrometry analysis revealed that the disruption of GALE, GALK1, and GALE+GALK2 had little effect on the N-glycome. But when GALE was knocked out in tandem with GALK1, N-glycans were exclusively of the high mannose type. Due to the well characterized nature of these five knockout cell lines, they will likely prove useful for a wide variety of applications. PMID- 28654658 TI - Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway. AB - The intestinal epithelial barrier, composed of epithelial cells, tight junction proteins and intestinal secretions, prevents passage of luminal substances and antigens through the paracellular space. Dysfunction of the intestinal barrier integrity induced by toxins and pathogens is associated with a variety of gastrointestinal disorders and diseases. Although butyrate is known to enhance intestinal health, its role in the protection of intestinal barrier function is poorly characterized. Therefore, we investigated the effect of butyrate on intestinal epithelial integrity and tight junction permeability in a model of LPS induced inflammation in IPEC-J2 cells. Butyrate dose-dependently reduced LPS impairment of intestinal barrier integrity and tight junction permeability, measured by trans-epithelial electrical resistance (TEER) and paracellular uptake of fluorescein isothiocyanate-dextran (FITC-dextran). Additionally, butyrate increased both mRNA expression and protein abundance of claudins-3 and 4, and influenced intracellular ATP concentration in a dose-dependent manner. Furthermore, butyrate prevented the downregulation of Akt and 4E-BP1 phosphorylation by LPS, indicating that butyrate might enhance tight junction protein abundance through mechanisms that included activation of Akt/mTOR mediated protein synthesis. The regulation of AMPK activity and intracellular ATP level by butyrate indicates that butyrate might regulate energy status of the cell, perhaps by serving as a nutrient substrate for ATP synthesis, to support intestinal epithelial barrier tight junction protein abundance. Our findings suggest that butyrate might protect epithelial cells from LPS-induced impairment of barrier integrity through an increase in the synthesis of tight junction proteins, and perhaps regulation of energy homeostasis. PMID- 28654660 TI - Isolation and characterization of GmMYBJ3, an R2R3-MYB transcription factor that affects isoflavonoids biosynthesis in soybean. AB - Isoflavonoids are secondary metabolites that play a variety of roles in plant microbe interactions and plant defenses against abiotic stresses. Here we report a new MYB transcription factor (TF) gene, GmMYBJ3, that is involved in the isoflavonoids biosynthesis. The GmMYBJ3 gene is 1,002 bp long and encodes a protein of 333 amino acids. Amino acid sequence analysis showed that GmMYBJ3 is a typical R2R3 MYB TF. Yeast expression experiment demonstrated that GmMYBJ3 has its transcription activity in the nucleus and is transiently expressed in onion epidermal cells. The GmMYBJ3 gene was transformed into soybean and the expression activity of the GmMYBJ3 gene was significantly positively correlated with total isoflavonoid accumulation in soybean. Transient expression assays indicated that GmMYBJ3 can activate CHS8 expression. Furthermore, we analyzed the expressions of several genes known involved in the isoflavonoid biosynthesis, including CHS8, CHI1A, PAL1, IFS2 and F3H, in the GmMYBJ3 transgenic plants. The results showed that the expression levels of CHS8 and CHI1A were significantly increased in the transgenic plants compared to wild-type plants, but those of PAL1, IFS2 and F3H remained similar between the transgenic and wild-type plants. These results suggest that GmMYBJ3 participates in the isoflavonoid biosynthesis through regulation of CHS8 and CHI1A in soybean. PMID- 28654659 TI - Environmental change drives accelerated adaptation through stimulated copy number variation. AB - Copy number variation (CNV) is rife in eukaryotic genomes and has been implicated in many human disorders, particularly cancer, in which CNV promotes both tumorigenesis and chemotherapy resistance. CNVs are considered random mutations but often arise through replication defects; transcription can interfere with replication fork progression and stability, leading to increased mutation rates at highly transcribed loci. Here we investigate whether inducible promoters can stimulate CNV to yield reproducible, environment-specific genetic changes. We propose a general mechanism for environmentally-stimulated CNV and validate this mechanism for the emergence of copper resistance in budding yeast. By analysing a large cohort of individual cells, we directly demonstrate that CNV of the copper resistance gene CUP1 is stimulated by environmental copper. CNV stimulation accelerates the formation of novel alleles conferring enhanced copper resistance, such that copper exposure actively drives adaptation to copper-rich environments. Furthermore, quantification of CNV in individual cells reveals remarkable allele selectivity in the rate at which specific environments stimulate CNV. We define the key mechanistic elements underlying this selectivity, demonstrating that CNV is regulated by both promoter activity and acetylation of histone H3 lysine 56 (H3K56ac) and that H3K56ac is required for CUP1 CNV and efficient copper adaptation. Stimulated CNV is not limited to high-copy CUP1 repeat arrays, as we find that H3K56ac also regulates CNV in 3 copy arrays of CUP1 or SFA1 genes. The impact of transcription on DNA damage is well understood, but our research reveals that this apparently problematic association forms a pathway by which mutations can be directed to particular loci in particular environments and furthermore that this mutagenic process can be regulated through histone acetylation. Stimulated CNV therefore represents an unanticipated and remarkably controllable pathway facilitating organismal adaptation to new environments. PMID- 28654661 TI - Structure, dynamics and kinetics of two-component Lantibiotic Lichenicidin. AB - Two variants of the two-component Lantibiotic Lichenicidin, produced by the strains B. Licheniformis VK21 and I89 (Lchalpha/ Lchbeta and Blialpha/ Blibeta peptides, respectively) have been investigated by means of 2 MUs-long all-atom molecular dynamics simulations combined with Markov State Models. This rigorous statistical analysis enabled to evaluate the dynamic and kinetic properties of the aforementioned systems which are not accessible via experimental techniques. The structural flexibility characteristic of these small peptides is understood by a delicate equilibrium between random coil, alpha-helices and beta-sheet structures. The undergoing secondary structure transitions from an alpha-helix to a beta-sheet observed for Lchalpha and Lchbeta peptides, were not present in the Blialpha component and provide new insights to understand their mechanism of action. PMID- 28654662 TI - Generation of a rabbit single-chain fragment variable (scFv) antibody for specific detection of Bradyrhizobium sp. DOA9 in both free-living and bacteroid forms. AB - A simple and reliable method for the detection of specific nitrogen-fixing bacteria in both free-living and bacteroid forms is essential for the development and application of biofertilizer. Traditionally, a polyclonal antibody generated from an immunized rabbit was used for detection. However, the disadvantages of using a polyclonal antibody include limited supply and cross-reactivity to related bacterial strains. This is the first report on the application of phage display technology for the generation of a rabbit recombinant monoclonal antibody for specific detection and monitoring of nitrogen-fixing bacteria in both free living form and in plant nodules. Bradyrhizobium sp. DOA9, a broad host range soil bacteria, originally isolated from the root nodules of Aeschynomene americana in Thailand was used as a model in this study. A recombinant single chain fragment variable (scFv) antibody library was constructed from the spleen of a rabbit immunized with DOA9. After three rounds of biopanning, one specific phage-displayed scFv antibody, designated bDOA9rb8, was identified. Specific binding of this antibody was confirmed by phage enzyme-linked immunosorbent assay (phage ELISA). The phage antibody could bind specifically to DOA9 in both free living cells (pure culture) and bacteroids inside plant nodules. In addition to phage ELISA, specific and robust immunofluorescence staining of both free-living and bacteroid forms could also be observed by confocal-immunofluorescence imaging, without cross-reactivity with other tested bradyrhizobial strains. Moreover, specific binding of free scFv to DOA9 was also demonstrated by ELISA. This recombinant antibody can also be used for the study of the molecular mechanism of plant-microbe interactions in the future. PMID- 28654663 TI - Two sides of a coin: Effects of climate change on the native and non-native distribution of Colossoma macropomum in South America. AB - Climate change and species invasions interact in nature, disrupting biological communities. Based on this knowledge, we simultaneously assessed the effects of climate change on the native distribution of the Amazonian fish Colossoma macropomum as well as on its invasiveness across river basins of South America, using ecological niche modeling. We used six niche models within the ensemble forecast context to predict the geographical distribution of C. macropomum for the present time, 2050 and 2080. Given that this species has been continuously introduced into non-native South American basins by fish farming activities, we added the locations of C. macropomum farms into the modeling process to obtain a more realistic scenario of its invasive potential. Based on modelling outputs we mapped climate refuge areas at different times. Our results showed that a plenty of climatically suitable areas for the occurrence of C. macropomum occurrence are located outside the original basins at the present time and that its invasive potential is greatly amplified by fish farms. Simulations of future geographic ranges revealed drastic range contraction in the native region, implying concerns not only with respect to the species conservation but also from a socio-economic perspective since the species is a cornerstone of artisanal and commercial fisheries in the Amazon. Although the invasive potential is projected to decrease in the face of climate change, climate refugia will concentrate in Parana River, Southeast Atlantic and East Atlantic basins, putting intense, negative pressures on the native fish fauna these regions. Our findings show that short and long term management actions are required for: i) the conservation of natural stocks of C. macropomum in the Amazon, and ii) protecting native fish fauna in the climate refuges of the invaded regions. PMID- 28654664 TI - Functional group diversity is key to Southern Ocean benthic carbon pathways. AB - High latitude benthos are globally important in terms of accumulation and storage of ocean carbon, and the feedback this is likely to have on regional warming. Understanding this ecosystem service is important but difficult because of complex taxonomic diversity, history and geography of benthic biomass. Using South Georgia as a model location (where the history and geography of benthic biology is relatively well studied) we investigated whether the composition of functional groups were critical to benthic accumulation, immobilization and burial pathway to sequestration-and also aid their study through simplification of identification. We reclassified [1], [2]) morphotype and carbon mass data to 13 functional groups, for each sample of 32 sites around the South Georgia continental shelf. We investigated the influence on carbon accumulation, immobilization and sequestration estimate by multiple factors including the compositions of functional groups. Functional groups showed high diversity within and between sites, and within and between habitat types. Carbon storage was not linked to a functional group in particular but accumulation and immobilization increased with the number of functional groups present and the presence of hard substrata. Functional groups were also important to carbon burial rate, which increased with the presence of mixed (hard and soft substrata). Functional groups showed high surrogacy for taxonomic composition and were useful for examining contrasting habitat categorization. Functional groups not only aid marine carbon storage investigation by reducing time and the need for team size and speciality, but also important to benthic carbon pathways per se. There is a distinct geography to seabed carbon storage; seabed boulder-fields are hotspots of carbon accumulation and immobilization, whilst the interface between such boulder-fields and sediments are key places for burial and sequestration. PMID- 28654666 TI - Correction: An instrument to measure nurses' knowledge in palliative care: Validation of the Spanish version of Palliative Care Quiz for Nurses. AB - [This corrects the article DOI: 10.1371/journal.pone.0177000.]. PMID- 28654665 TI - Probing the potential of CnaB-type domains for the design of tag/catcher systems. AB - Building proteins into larger, post-translational assemblies in a defined and stable way is still a challenging task. A promising approach relies on so-called tag/catcher systems that are fused to the proteins of interest and allow a durable linkage via covalent intermolecular bonds. Tags and catchers are generated by splitting protein domains that contain intramolecular isopeptide or ester bonds that form autocatalytically under physiological conditions. There are already numerous biotechnological and medical applications that demonstrate the usefulness of covalent linkages mediated by these systems. Additional covalent tag/catcher systems would allow creating more complex and ultra-stable protein architectures and networks. Two of the presently available tag/catcher systems were derived from closely related CnaB-domains of Streptococcus pyogenes and Streptococcus dysgalactiae proteins. However, it is unclear whether domain splitting is generally tolerated within the CnaB-family or only by a small subset of these domains. To address this point, we have selected a set of four CnaB domains of low sequence similarity and characterized the resulting tag/catcher systems by computational and experimental methods. Experimental testing for intermolecular isopeptide bond formation demonstrated two of the four systems to be functional. For these two systems length and sequence variations of the peptide tags were investigated revealing only a relatively small effect on the efficiency of the reaction. Our study suggests that splitting into tag and catcher moieties is tolerated by a significant portion of the naturally occurring CnaB-domains, thus providing a large reservoir for the design of novel tag/catcher systems. PMID- 28654667 TI - Development and initial implementation of the Dynamic Assessment Treatment Algorithm (DATA). AB - Given the recent increase in transdiagnostic research, it is important to discern how dimensional models of psychopathology could be used to guide personalized, dynamic assessment and treatment of symptoms. Using the person-specific approach described by Fisher (2015), we devised an initial 4-step algorithm for devising a treatment plan based on modular cognitive behavioral therapy using results obtained from within-person factor analyses and dynamic factor models. Then, we describe the improvement and digitization of the algorithm, termed Dynamic Assessment Treatment Algorithm (DATA). The development, structure, and clinical implications of DATA are discussed. PMID- 28654668 TI - Influence of the way of reporting alpha-Amylase values in saliva in different naturalistic situations: A pilot study. AB - The objective of this pilot study was to compare the different ways of measuring salivary alpha-amylase (sAA, enzymatic vs. concentration) and to evaluate the influence that the different ways of reporting the results can have in sAA interpretation. For this purpose, sAA was measured by direct quantification and also by an enzymatic assay in three different naturalistic situations, a physical stressor (situation 1) and two mental stressors of different intensity (situations 2 and 3). The results were expressed in three different ways (without correction, multiplied by flow rate and divided by protein concentration). sAA concentration and activity increased just after situations 1 and 3. When values were multiplied by the flow rate, significant changes after situation 1 were detected only for sAA activity but not for sAA concentration, being these changes of lower significance and magnitude that those observed for sAA activity without any correction. In addition, a significant increase in sAA activity was found at T+15 in situation 2. In situation 3 the significant decrease in sAA at T+15 disappeared. When values were divided by protein concentration, there were no significant changes in situations 1 or 3, but a decrease in situation 2 at T+0 and an increase at T+15. sAA activity and concentration showed a significant correlation in all situations. This pilot study points out that the way of expressing sAA can influence the results obtained in different stress models and also their interpretation. Therefore, how sAA is reported and the factors involved in the different ways of expressing sAA, should be taken into consideration for an objective interpretation of sAA values. PMID- 28654670 TI - Assessing process, content, and politics in developing the global health sector strategy on sexually transmitted infections 2016-2021: Implementation opportunities for policymakers. AB - Andrew Seale and colleagues discuss the development of a global strategy to counter sexually transmitted infections. PMID- 28654669 TI - Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. AB - Current treatment options for depression are limited by efficacy, cost, availability, side effects, and acceptability to patients. Several studies have looked at the association between magnesium and depression, yet its role in symptom management is unclear. The objective of this trial was to test whether supplementation with over-the-counter magnesium chloride improves symptoms of depression. An open-label, blocked, randomized, cross-over trial was carried out in outpatient primary care clinics on 126 adults (mean age 52; 38% male) diagnosed with and currently experiencing mild-to-moderate symptoms with Patient Health Questionnaire-9 (PHQ-9) scores of 5-19. The intervention was 6 weeks of active treatment (248 mg of elemental magnesium per day) compared to 6 weeks of control (no treatment). Assessments of depression symptoms were completed at bi weekly phone calls. The primary outcome was the net difference in the change in depression symptoms from baseline to the end of each treatment period. Secondary outcomes included changes in anxiety symptoms as well as adherence to the supplement regimen, appearance of adverse effects, and intention to use magnesium supplements in the future. Between June 2015 and May 2016, 112 participants provided analyzable data. Consumption of magnesium chloride for 6 weeks resulted in a clinically significant net improvement in PHQ-9 scores of -6.0 points (CI 7.9, -4.2; P<0.001) and net improvement in Generalized Anxiety Disorders-7 scores of -4.5 points (CI -6.6, -2.4; P<0.001). Average adherence was 83% by pill count. The supplements were well tolerated and 61% of participants reported they would use magnesium in the future. Similar effects were observed regardless of age, gender, baseline severity of depression, baseline magnesium level, or use of antidepressant treatments. Effects were observed within two weeks. Magnesium is effective for mild-to-moderate depression in adults. It works quickly and is well tolerated without the need for close monitoring for toxicity. PMID- 28654671 TI - Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients' experiences. AB - Elucidating patients' experiences of living with chronic progressive hereditary ataxia and the symptomatic treatment with intrathecal baclofen (ITB) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants' experiences through semi structured interviews. The transcribed text was analyzed according to content analysis guidelines. Overall we identified living in the present/ taking one day at a time as the main theme covering the following categories: 1) Uncertainty about the future as a consequence of living with a hereditary disease; The disease; 2) Impact on life as a whole, 3) Influence on personal life in terms of feeling forced to terminate employment, 4) Limiting daily activities, and 5) ITB therapy, advantages, and disadvantages. Uncertainty about the future was the category that affected participants' personal life, employment, and daily activities. The participants' experience of receiving ITB therapy was expressed in terms of improved quality of life due to better body position and movement as well as better sleep and pain relief. PMID- 28654672 TI - Cost-effectiveness analysis of oral fentanyl formulations for breakthrough cancer pain treatment. AB - Breakthrough cancer Pain (BTcP) has a high prevalence in cancer population. Patients with BTcP reported relevant health care costs and poor quality of life. The study assessed the cost-effectiveness of the available Oral Fentanyl Formulations (OFFs) for BTcP in Italy. A decision-analytical model was developed to estimate costs and benefits associated with treatments, from the Italian NHS perspective. Expected reductions in pain intensity per BTcP episodes were translated into, percentage of BTcP reduction, resource use and Quality-Adjusted Life-Years (QALYs). Relative efficacy, resources used and unit costs data were derived from the literature and validated by clinical experts. Probabilistic and deterministic sensitivity analyses were performed. At base-case analysis, Sublingual Fentanyl Citrate (FCSL) compared to other oral formulations reported a lower patient's cost (?1,960.8) and a higher efficacy (18.7% of BTcP avoided and 0.0507 QALYs gained). The sensitivity analyses confirmed the main results in all tested scenarios, with the highest impact reported by BTcP duration and health care resources consumption parameters. Between OFFs, FCSL is the cost-effective option due to faster reduction of pain intensity. However, new research is needed to better understand the economic and epidemiologic impact of BTcP, and to collect more robust data on economic and quality of life impact of the different fentanyl formulations. Different fentanyl formulations are available to manage BTcP in cancer population. The study is the first that assesses the different impact in terms of cost and effectiveness of OFFs, providing new information to better allocate the resources available to treat BTcP and highlighting the need of better data. PMID- 28654673 TI - Double hit of NEMO gene in preeclampsia. AB - The precise etiology of preeclampsia is unknown. Family studies indicate that both genetic and environmental factors influence its development. One of these factors is NFkB, whose activation depends on NEMO (NFkB essential modulator. This is the first study to investigate the association between the existence of single nucleotide variant of the NEMO gene and the appearance of preeclampsia. A total of 151 women (72 preeclamptic women and 79 controls) and their children were examined. Sanger sequencing was performed to identify variants in the NEMO gene in the preeclamptic mothers. The maternal identified variants were then sought in the studied groups of children, and in the maternal and child controls, using RFLP-PCR. Real-time RT-PCR was performed to assess NEMO gene expression in maternal blood, umbilical cord blood and placentas. The sequencing process indicated the existence of two different variants in the 3'UTR region of the NEMO gene of preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T). The simultaneous occurrence of the TT genotype in the mother and the TT genotype in the daughter or a T allele in the son increased the risk of preeclampsia development 2.59 fold. Additionally, we found that the configuration of maternal/fetal genotypes (maternal TT/ daughter TT or maternal TT/son T) of IKBKG:c.*402C/T variant is associated with the level of NEMO gene expression. Our results showed that, the simultaneous occurrence of the maternal TT genotype (IKBKG:c.*402C>T variants) and TT genotype in the daughter or T allele in the son correlates with the level of NEMO gene expression and increases the risk of preeclampsia development. Our observations may offer a new insight into the genetic etiology and pathogenesis of preeclampsia. PMID- 28654674 TI - Practices and promises of Facebook for science outreach: Becoming a "Nerd of Trust". AB - Arguably, the dissemination of science communication has recently entered a new age in which science must compete for public attention with fake news, alternate facts, and pseudoscience. This clash is particularly evident on social media. Facebook has taken a prime role in disseminating fake news, alternate facts, and pseudoscience, but is often ignored in the context of science outreach, especially among individual scientists. Based on new survey data, scientists appear in large Facebook networks but seldom post information about general science, their own scientific research, or culturally controversial topics in science. The typical individual scientist's audience is large and personally connected, potentially leading to both a broad and deep engagement in science. Moreover, this media values individual expertise, allowing scientists to serve as a "Nerd of Trust" for their online friend and family networks. Science outreach via social media demands a renewed interest, and Facebook may be an overlooked high-return, low-risk science outreach tool in which scientists can play a valuable role to combat disinformation. PMID- 28654675 TI - Estimating the disease burden of methicillin-resistant Staphylococcus aureus in Japan: Retrospective database study of Japanese hospitals. AB - OBJECTIVES: The nationwide impact of antimicrobial-resistant infections on healthcare facilities throughout Japan has yet to be examined. This study aimed to estimate the disease burden of methicillin-resistant Staphylococcus aureus (MRSA) infections in Japanese hospitals. DESIGN: Retrospective analysis of inpatients comparing outcomes between subjects with and without MRSA infection. DATA SOURCE: A nationwide administrative claims database. SETTING: 1133 acute care hospitals throughout Japan. PARTICIPANTS: All surgical and non-surgical inpatients who were discharged between April 1, 2014 and March 31, 2015. MAIN OUTCOME MEASURES: Disease burden was assessed using hospitalization costs, length of stay, and in-hospital mortality. Using a unique method of infection identification, we categorized patients into an anti-MRSA drug group and a control group based on anti-MRSA drug utilization. To estimate the burden of MRSA infections, we calculated the differences in outcome measures between these two groups. The estimates were extrapolated to all 1584 acute care hospitals in Japan that have adopted a prospective payment system. RESULTS: We categorized 93 838 patients into the anti-MRSA drug group and 2 181 827 patients into the control group. The mean hospitalization costs, length of stay, and in-hospital mortality of the anti-MRSA drug group were US$33 548, 75.7 days, and 22.9%, respectively; these values were 3.43, 2.95, and 3.66 times that of the control group, respectively. When extrapolated to the 1584 hospitals, the total incremental burden of MRSA was estimated to be US$2 billion (3.41% of total hospitalization costs), 4.34 million days (3.02% of total length of stay), and 14.3 thousand deaths (3.62% of total mortality). CONCLUSIONS: This study quantified the approximate disease burden of MRSA infections in Japan. These findings can inform policymakers on the burden of antimicrobial-resistant infections and support the application of infection prevention programs. PMID- 28654676 TI - Silver, bighead, and common carp orient to acoustic particle motion when avoiding a complex sound. AB - Behavioral responses of silver carp (Hypopthalmichthys molitrix), bighead carp (H. nobilis), and common carp (Cyprinus carpio) to a complex, broadband sound were tested in the absence of visual cues to determine whether these species are negatively phonotaxic and the roles that sound pressure and particle motion might play mediating this response. In a dark featureless square enclosure, groups of 3 fish were tracked and the distance of each fish from speakers and their swimming trajectories relative to sound pressure and particle acceleration were analyzed before, and then while an outboard motor sound was played. All three species exhibited negative phonotaxis during the first two exposures after which they ceased responding. The median percent time fish spent near the active speaker for the first two trials decreased from 7.0% to 1.3% for silver carp, 7.9% to 1.1% for bighead carp, and 9.5% to 3% for common carp. Notably, when close to the active speaker fish swam away from the source and maintained a nearly perfect 0 degrees orientation to the axes of particle acceleration. Fish did not enter sound fields greater than 140 dB (ref. 1 MUPa). These results demonstrate that carp avoid complex sounds in darkness and while initial responses may be informed by sound pressure, sustained oriented avoidance behavior is likely mediated by particle motion. This understanding of how invasive carp use particle motion to guide avoidance could be used to design new acoustic deterrents to divert them in dark, turbid river waters. PMID- 28654677 TI - EcoBLMcrX, a classical modification-dependent restriction enzyme in Escherichia coli B: Characterization in vivo and in vitro with a new approach to cleavage site determination. AB - Here we characterize the modification-dependent restriction enzyme (MDE) EcoBLMcrX in vivo, in vitro and in its genomic environment. MDE cleavage of modified DNAs protects prokaryote populations from lethal infection by bacteriophage with highly modified DNA, and also stabilizes lineages by reducing gene import when sparse modification occurs in the wrong context. The function and distribution of MDE families are thus important. Here we describe the properties of EcoBLMcrX, an enzyme of the E. coli B lineage, in vivo and in vitro. Restriction in vivo and the genome location of its gene, ecoBLmcrX, were determined during construction and sequencing of a B/K-12 hybrid, ER2566. In classical restriction literature, this B system was named r6 or rglAB. Like many genome defense functions, ecoBLmcrX is found within a genomic island, where gene content is variable among natural E. coli isolates. In vitro, EcoBLMcrX was compared with two related enzymes, BceYI and NhoI. All three degrade fully cytosine-modified phage DNA, as expected for EcoBLMcrX from classical T4 genetic data. A new method of characterizing MDE specificity was developed to better understand action on fully-modified targets such as the phage that provide major evolutionary pressure for MDE maintenance. These enzymes also cleave plasmids with m5C in particular motifs, consistent with a role in lineage-stabilization. The recognition sites were characterized using a site-ranking approach that allows visualization of preferred cleavage sites when fully-modified substrates are digested. A technical constraint on the method is that ligation of one nucleotide 5' extensions favors G:C over A:T approximately five-fold. Taking this bias into account, we conclude that EcoBLMcrX can cleave 3' to the modified base in the motif Rm5C|. This is compatible with, but less specific than, the site reported by others. Highly-modified site contexts, such as those found in base substituted virulent phages, are strongly preferred. PMID- 28654678 TI - Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples. AB - Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection. To test this hypothesis, we retrieved whole-genome sequenced EBV mapping reads from 1,753 LCL samples derived from 19 populations worldwide that were sequenced within the context of the 1000 Genomes Project. An in silico methodology was developed to estimate the number of EBV copy number in LCLs and validated these estimations by real-time PCR. After experimentally confirming that EBV relative copy number remains stable over cell passages, we performed a genome wide association analysis (GWAS) to try detecting genetic variants of the host that may be associated with EBV copy number. Our GWAS has yielded several genomic regions suggestively associated with the number of EBV genomes per cell in LCLs, unraveling promising candidate genes such as CAND1, a known inhibitor of EBV replication. While this GWAS does not unequivocally establish the degree to which genetic makeup of individuals determine viral levels within their derived LCLs, for which a larger sample size will be needed, it potentially highlighted human genes affecting EBV-related processes, which constitute interesting candidates to follow up in the context of EBV related pathologies. PMID- 28654679 TI - Increased risk of thyroid diseases in patients with systemic lupus erythematosus: A nationwide population-based Study in Korea. AB - We investigated the association between autoimmune thyroid disease and systemic lupus erythematosus (SLE) using nationwide insurance claims data for the entire Korean population. Claims data for the period 2009-2013 were retrieved from the National Health Insurance System database. SLE and thyroid disease were identified using the International Classification of Diseases codes and medication information. Logistic regression analyses were used to evaluate the association between SLE and thyroid disease. The study used records from 17,495 patients with SLE and 52,485 age- and sex-matched control subjects. A greater prevalence of Graves' disease (0.94% vs. 0.46%, P < 0.001), Hashimoto's thyroiditis (2.68% vs. 0.80%, P < 0.001), and thyroid cancer (1.81% vs. 1.30%, P < 0.001) was observed in SLE patients than in control subjects. Multivariate regression analyses demonstrated that SLE was significantly associated with an increased risk of both autoimmune thyroid disease and thyroid cancer (Graves' disease: odds ratio [OR] 2.07, 95% confidence interval [CI] 1.70-2.53; Hashimoto's thyroiditis: OR 3.42, 95% CI 3.00-3.91; thyroid cancer: OR 1.40, 95% CI 1.22-1.60). Age- and sex- stratified analyses revealed that the risk of autoimmune thyroid disease in SLE patients was increased for all age groups and the female group. An association between thyroid cancer and SLE was identified only in the 20- to 59-year-old age group and in the female group. Using a large population-based study, we demonstrated that patients with SLE are at a greater risk of developing thyroid disease than matched control individuals. PMID- 28654680 TI - Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study. AB - Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and beta cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls. We recruited 30 participants (12 T2DM and 18 non-diabetic healthy controls). Participants underwent a meal tolerance test during which plasma glucose, insulin and serum C-peptide immunoreactivity were measured. We performed a hyperinsulinemic-euglycemic clamp and measured the glucose-disposal rate (GDR). The fasting serum levels of adiponectin, insulin-like growth factor 1, irisin, autotaxin, FABP4 and interleukin-6 were measured by ELISA. We found a strong negative correlation between FABP4 concentration and GDR in T2DM (r = 0.657, p = 0.020). FABP4 also was positively correlated with insulin secretion during the meal tolerance test in T2DM (IRI (120): r = 0.604, p = 0.038) and was positively related to the insulinogenic index in non-DM subjects (r = 0.536, p = 0.022). Autotaxin was also related to GDR. However, there was no relationship with insulin secretion. We found that serum FABP4 concentration were associated with insulin resistance and secretion in T2DM. This suggests that FABP4 may play an important role in glucose homeostasis. PMID- 28654681 TI - Abnormal neurofilament inclusions and segregations in dorsal root ganglia of a Charcot-Marie-Tooth type 2E mouse model. AB - Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is the most prevalent inherited peripheral neuropathy and is associated with over 90 causative genes. Mutations in neurofilament light polypeptide gene, NEFL cause CMT2E, an axonal form of CMT that results in abnormal structures and/or functions of peripheral axons in spinal cord motor neurons and dorsal root ganglion neurons. We have previously generated and characterized a knock-in mouse model of CMT2E with the N98S mutation in Nefl that presented with multiple inclusions in spinal cord neurons. In this report, we conduct immunofluorescence studies of cultured dorsal root ganglia (DRG) from NeflN98S/+ mice, and show that inclusions found in DRG neurites can occur in embryonic stages. Ultrastructural analyses reveal that the inclusions are disordered neurofilaments packed in high density, segregated from other organelles. Immunochemical studies show decreased NFL protein levels in DRG, cerebellum and spinal cord in NeflN98S/+ mice, and total NFL protein pool is shifted toward the triton-insoluble fraction. Our findings reveal the nature of the inclusions in NeflN98S/+ mice, provide useful information to understand mechanisms of CMT2E disease, and identify DRG from NeflN98S/+ mice as a useful cell line model for therapeutic discoveries. PMID- 28654682 TI - Low-intensity cognitive-behaviour therapy interventions for obsessive-compulsive disorder compared to waiting list for therapist-led cognitive-behaviour therapy: 3-arm randomised controlled trial of clinical effectiveness. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is prevalent and without adequate treatment usually follows a chronic course. "High-intensity" cognitive-behaviour therapy (CBT) from a specialist therapist is current "best practice." However, access is difficult because of limited numbers of therapists and because of the disabling effects of OCD symptoms. There is a potential role for "low-intensity" interventions as part of a stepped care model. Low-intensity interventions (written or web-based materials with limited therapist support) can be provided remotely, which has the potential to increase access. However, current evidence concerning low-intensity interventions is insufficient. We aimed to determine the clinical effectiveness of 2 forms of low-intensity CBT prior to high-intensity CBT, in adults meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for OCD. METHODS AND FINDINGS: This study was approved by the National Research Ethics Service Committee North West-Lancaster (reference number 11/NW/0276). All participants provided informed consent to take part in the trial. We conducted a 3-arm, multicentre randomised controlled trial in primary- and secondary-care United Kingdom mental health services. All patients were on a waiting list for therapist-led CBT (treatment as usual). Four hundred and seventy-three eligible patients were recruited and randomised. Patients had a median age of 33 years, and 60% were female. The majority were experiencing severe OCD. Patients received 1 of 2 low-intensity interventions: computerised CBT (cCBT; web-based CBT materials and limited telephone support) through "OCFighter" or guided self-help (written CBT materials with limited telephone or face-to-face support). Primary comparisons concerned OCD symptoms, measured using the Yale-Brown Obsessive Compulsive Scale-Observer-Rated (Y-BOCS OR) at 3, 6, and 12 months. Secondary outcomes included health-related quality of life, depression, anxiety, and functioning. At 3 months, guided self-help demonstrated modest benefits over the waiting list in reducing OCD symptoms (adjusted mean difference = -1.91, 95% CI -3.27 to -0.55). These effects did not reach a prespecified level of "clinically significant benefit." cCBT did not demonstrate significant benefit (adjusted mean difference = -0.71, 95% CI -2.12 to 0.70). At 12 months, neither guided self-help nor cCBT led to differences in OCD symptoms. Early access to low-intensity interventions led to significant reductions in uptake of high-intensity CBT over 12 months; 86% of the patients allocated to the waiting list for high-intensity CBT started treatment by the end of the trial, compared to 62% in supported cCBT and 57% in guided self-help. These reductions did not compromise longer-term patient outcomes. Data suggested small differences in satisfaction at 3 months, with patients more satisfied with guided self-help than supported cCBT. A significant issue in the interpretation of the results concerns the level of access to high-intensity CBT before the primary outcome assessment. CONCLUSIONS: We have demonstrated that providing low intensity interventions does not lead to clinically significant benefits but may reduce uptake of therapist-led CBT. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) Registry ISRCTN73535163. PMID- 28654683 TI - A data analysis framework for biomedical big data: Application on mesoderm differentiation of human pluripotent stem cells. AB - The development of high-throughput biomolecular technologies has resulted in generation of vast omics data at an unprecedented rate. This is transforming biomedical research into a big data discipline, where the main challenges relate to the analysis and interpretation of data into new biological knowledge. The aim of this study was to develop a framework for biomedical big data analytics, and apply it for analyzing transcriptomics time series data from early differentiation of human pluripotent stem cells towards the mesoderm and cardiac lineages. To this end, transcriptome profiling by microarray was performed on differentiating human pluripotent stem cells sampled at eleven consecutive days. The gene expression data was analyzed using the five-stage analysis framework proposed in this study, including data preparation, exploratory data analysis, confirmatory analysis, biological knowledge discovery, and visualization of the results. Clustering analysis revealed several distinct expression profiles during differentiation. Genes with an early transient response were strongly related to embryonic- and mesendoderm development, for example CER1 and NODAL. Pluripotency genes, such as NANOG and SOX2, exhibited substantial downregulation shortly after onset of differentiation. Rapid induction of genes related to metal ion response, cardiac tissue development, and muscle contraction were observed around day five and six. Several transcription factors were identified as potential regulators of these processes, e.g. POU1F1, TCF4 and TBP for muscle contraction genes. Pathway analysis revealed temporal activity of several signaling pathways, for example the inhibition of WNT signaling on day 2 and its reactivation on day 4. This study provides a comprehensive characterization of biological events and key regulators of the early differentiation of human pluripotent stem cells towards the mesoderm and cardiac lineages. The proposed analysis framework can be used to structure data analysis in future research, both in stem cell differentiation, and more generally, in biomedical big data analytics. PMID- 28654684 TI - Intravenous immunoglobulin therapy in kidney transplant recipients with de novo DSA: Results of an observational study. AB - BACKGROUND: Approximately 25% of kidney transplant recipients develop de novo anti-HLA donor-specific antibodies (dnDSA) leading to acute antibody-mediated rejection (ABMR) in 30% of patients. Preemptive therapeutic strategies are not available. METHODS: We conducted a prospective observational study including 11 kidney transplant recipients. Inclusion criteria were dnDSA occurring within the first year after transplant and normal allograft biopsy. All patients were treated with high-dose IVIG (2 g/kg 0, 1 and 2 months post-dnDSA). The primary efficacy outcome was incidence of clinical and subclinical acute ABMR within 12 months after dnDSA detection as compared to a historical control group (IVIG-). RESULTS: Acute ABMR occurred in 2 or 11 patients in the IVIG+ group and in 1 of 9 patients in the IVIG- group. IVIG treatment did not affect either class I or class II DSA, as observed at the end of the follow-up. IVIG treatment significantly decreased FcgammaRIIA mRNA expression in circulating leukocytes, but did not affect the expression of any other markers of B cell activation. CONCLUSIONS: In this first pilot study including kidney allograft recipients with early dnDSA, preemptive treatment with high-dose IVIG alone did not prevent acute ABMR and had minimal effects on DSA outcome and B cell phenotype. PMID- 28654685 TI - Spatial variability of Spanish sardine (Sardinella aurita) abundance as related to the upwelling cycle off the southeastern Caribbean Sea. AB - The Sardinella aurita fishery off northeastern Venezuela, region of seasonal wind driven coastal-upwelling, accounts for 90% of the Caribbean Sea small pelagic catch. This law-protected artisanal fishery takes place up to ~10 km offshore. The spatial distribution, number of schools, and biomass of S. aurita were studied using eight hydro-acoustic surveys (1995-1998). The study included the analysis of satellite-derived sea surface temperature and chlorophyll-a. Surveys were grouped by strong, weak, and transitional upwelling seasons. Relationships between these observations were analyzed using Generalized Additive Models. Results show that during the primary upwelling season (January-May) sardines were widely distributed in upwelling plumes that extended up to 70 km offshore. In the other hand, during the weak upwelling season (September-October) higher sardine densities were found within 10 Km off the coastal upwelling foci. The number of small pelagic schools was directly correlated with small pelagic densities; however, regardless of the season, higher numbers of small pelagic schools were always closer to the shoreline, especially during warm conditions. These two behaviors increase the availability and catchability of sardines for the artisanal fishery during the warm season, regardless of the total stock size. Using this evidence, we pose the hypothesis that the collapse of the regional S. aurita fishery in 2005 was due to a combination of stressful habitat conditions sustained since 2004. These included bottom-up factors due to food scarcity caused by weak upwelling, combined with top-down stress due to overfishing, as sardines accumulated in narrow diminished upwelling plumes located close to the coast. The increased catchability within easily accessible upwelling foci led to the demise of this biological resource, which as of 2014 had not yet recovered. Environmental conditions affecting the sardine habitat needs to be taken into account for the management of this stock. For example, during years with weak upwelling, special measures should be taken during the warm season on the second half of the year to avoid further pressure on the stock. PMID- 28654686 TI - The role of Patient Health Engagement Model (PHE-model) in affecting patient activation and medication adherence: A structural equation model. AB - BACKGROUND: Increasing bodies of scientific research today examines the factors and interventions affecting patients' ability to self-manage and adhere to treatment. Patient activation is considered the most reliable indicator of patients' ability to manage health autonomously. Only a few studies have tried to assess the role of psychosocial factors in promoting patient activation. A more systematic modeling of the psychosocial factors explaining the variance of patient activation is needed. OBJECTIVE: To test the hypothesized effect of patient activation on medication adherence; to test the the hypothesized effects of positive emotions and of the quality of the patient/doctor relationship on patient activation; and to test the hypothesized mediating effect of Patient Health Engagement (PHE-model) in this pathway. MATERIAL AND METHODS: This cross sectional study involved 352 Italian-speaking adult chronic patients. The survey included measures of i) patient activation (Patient Activation Measure 13 -short form); ii) Patient Health Engagement model (Patient Health Engagement Scale); iii) patient adherence (4 item-Morinsky Medication Adherence Scale); iv) the quality of the patients' emotional feelings (Manikin Self Assessment Scale); v) the quality of the patient/doctor relationship (Health Care Climate Questionnaire). Structural equation modeling was used to test the hypotheses proposed. RESULTS: According to the theoretical model we hypothesized, research results confirmed that patients' activation significantly affects their reported medication adherence. Moreover, psychosocial factors, such as the patients' quality of the emotional feelings and the quality of the patient/doctor relationship were demonstrated to be factors affecting the level of patient activation. Finally, the mediation effect of the Patient Health Engagement model was confirmed by the analysis. CONCLUSIONS: Consistently with the results of previous studies, these findings demonstrate that the Patient Health Engagement Model is a critical factor in enhancing the quality of care. The Patient Health Engagement Model might acts as a mechanism to increase patient activation and adherence. PMID- 28654687 TI - Combined single-cell quantitation of host and SIV genes and proteins ex vivo reveals host-pathogen interactions in individual cells. AB - CD4 T cells harboring HIV-1/SIV represent a formidable hurdle to eradicating infection, and yet their detailed phenotype remains unknown. Here we integrate two single-cell technologies, flow cytometry and highly multiplexed quantitative RT-PCR, to characterize SIV-infected CD4 T cells directly ex vivo. Within individual cells, we correlate the cellular phenotype, in terms of host protein and RNA expression, with stages of the viral life cycle defined by combinatorial expression of viral RNAs. Spliced RNA+ infected cells display multiple memory and activation phenotypes, indicating virus production by diverse CD4 T cell subsets. In most (but not all) cells, progressive infection accompanies post transcriptional downregulation of CD4 protein, while surface MHC class I is largely retained. Interferon-stimulated genes were also commonly upregulated. Thus, we demonstrate that combined quantitation of transcriptional and post transcriptional regulation at the single-cell level informs in vivo mechanisms of viral replication and immune evasion. PMID- 28654688 TI - Modelled health benefits of a sugar-sweetened beverage tax across different socioeconomic groups in Australia: A cost-effectiveness and equity analysis. AB - BACKGROUND: A sugar-sweetened beverage (SSB) tax in Mexico has been effective in reducing consumption of SSBs, with larger decreases for low-income households. The health and financial effects across socioeconomic groups are important considerations for policy-makers. From a societal perspective, we assessed the potential cost-effectiveness, health gains, and financial impacts by socioeconomic position (SEP) of a 20% SSB tax for Australia. METHODS AND FINDINGS: Australia-specific price elasticities were used to predict decreases in SSB consumption for each Socio-Economic Indexes for Areas (SEIFA) quintile. Changes in body mass index (BMI) were based on SSB consumption, BMI from the Australian Health Survey 2011-12, and energy balance equations. Markov cohort models were used to estimate the health impact for the Australian population, taking into account obesity-related diseases. Health-adjusted life years (HALYs) gained, healthcare costs saved, and out-of-pocket costs were estimated for each SEIFA quintile. Loss of economic welfare was calculated as the amount of deadweight loss in excess of taxation revenue. A 20% SSB tax would lead to HALY gains of 175,300 (95% CI: 68,700; 277,800) and healthcare cost savings of AU$1,733 million (m) (95% CI: $650m; $2,744m) over the lifetime of the population, with 49.5% of the total health gains accruing to the 2 lowest quintiles. We estimated the increase in annual expenditure on SSBs to be AU$35.40/capita (0.54% of expenditure on food and non-alcoholic drinks) in the lowest SEIFA quintile, a difference of AU$3.80/capita (0.32%) compared to the highest quintile. Annual tax revenue was estimated at AU$642.9m (95% CI: $348.2m; $1,117.2m). The main limitations of this study, as with all simulation models, is that the results represent only the best estimate of a potential effect in the absence of stronger direct evidence. CONCLUSIONS: This study demonstrates that from a 20% tax on SSBs, the most HALYs gained and healthcare costs saved would accrue to the most disadvantaged quintiles in Australia. Whilst those in more disadvantaged areas would pay more SSB tax, the difference between areas is small. The equity of the tax could be further improved if the tax revenue were used to fund initiatives benefiting those with greater disadvantage. PMID- 28654689 TI - A high-density intraspecific SNP linkage map of pigeonpea (Cajanas cajan L. Millsp.). AB - Pigeonpea (Cajanus cajan (L.) Millsp.) is a major food legume cultivated in semi arid tropical regions including the Indian subcontinent, Africa, and Southeast Asia. It is an important source of protein, minerals, and vitamins for nearly 20% of the world population. Due to high carbon sequestration and drought tolerance, pigeonpea is an important crop for the development of climate resilient agriculture and nutritional security. However, pigeonpea productivity has remained low for decades because of limited genetic and genomic resources, and sparse utilization of landraces and wild pigeonpea germplasm. Here, we present a dense intraspecific linkage map of pigeonpea comprising 932 markers that span a total adjusted map length of 1,411.83 cM. The consensus map is based on three different linkage maps that incorporate a large number of single nucleotide polymorphism (SNP) markers derived from next generation sequencing data, using Illumina GoldenGate bead arrays, and genotyping with restriction site associated DNA (RAD) sequencing. The genotyping-by-sequencing enhanced the marker density but was met with limited success due to lack of common markers across the genotypes of mapping population. The integrated map has 547 bead-array SNP, 319 RAD-SNP, and 65 simple sequence repeat (SSR) marker loci. We also show here correspondence between our linkage map and published genome pseudomolecules of pigeonpea. The availability of a high-density linkage map will help improve the anchoring of the pigeonpea genome to its chromosomes and the mapping of genes and quantitative trait loci associated with useful agronomic traits. PMID- 28654690 TI - Effectiveness and equity of sugar-sweetened beverage taxation. AB - Sanjay Basu and Kristine Madsen discuss the effects of taxes on sugar-sweetened beverages in both Australia and Berkeley, USA. PMID- 28654691 TI - Whole-gene analysis of two groups of hepatitis B virus C/D inter-genotype recombinant strains isolated in Tibet, China. AB - Tibet is a highly hepatitis B virus (HBV) endemic area. Two types of C/D recombinant HBV are commonly isolated in Tibet and have been previously described. In an effort to better understand the molecular characteristic of these C/D recombinant strains from Tibet, we undertook a multistage random sampling project to collect HBsAg positive samples. Molecular epidemiological and bio-informational technologies were used to analyze the characteristics of the sequences found in this study. There were 60 samples enrolled in the survey, and we obtained 19 whole-genome sequences. 19 samples were all C/D recombinant, and could be divided into two sub-types named C/D1 and C/D2 according to the differences in the location of the recombinant breakpoint. The recombination breakpoint of the 10 strains belonging to the C/D1 sub-type was located at nt750, while the 9 stains belonging to C/D2 had their recombination break point at nt1530. According to whole-genome sequence analysis, the 19 identified strains belong to genotype C, but the nucleotide distance was more than 5% between the 19 strains and sub-genotypes C1 to C15. The distance between C/D1with C2 was 5.8+/ 2.1%, while the distance between C/D2 with C2 was 6.4+/-2.1%. The parental strain was most likely sub-genotype C2. C/D1 strains were all collected in the middle and northern areas of Tibet including Lhasa, Linzhi and Ali, while C/D2 was predominant in Shannan in southern Tibet. This indicates that the two recombinant genotypes are regionally distributed in Tibet. These results provide important information for the study of special HBV recombination events, gene features, virus evolution, and the control and prevention policy of HBV in Tibet. PMID- 28654692 TI - Heart rate variability as predictor of mortality in sepsis: A prospective cohort study. AB - BACKGROUND: Sepsis is a serious medical condition with increasing prevalence and high mortality. The role of the autonomic nervous system in pathophysiology of sepsis has been increasingly researched. The objective of this study is to evaluate the Heart rate variability (HRV) as a predictor of mortality in septic patients. METHODS: This was a prospective cohort of patients diagnosed with sepsis. Patient recruitment was carried out at ICU in tertiary university hospital between March 2012 and February 2014. Clinical data and laboratory exams were collected at admission. Each patient underwent a 20-minute Holter and a 24 hour Holter on the first day of enrollment. The primary outcome was the 28-day all-cause mortality. RESULTS: A total of 63 patients were included. Patients were categorized into nonsurvivor group (n = 16) or survivor group (n = 47) depending on this endpoint. Survivors were younger (48.6 years vs. 63.0 years), had better renal function and lower values in severity scores (APACHE II and SOFA) compared to nonsurvivors. In the 20-minute Holter, SDNN, Total Power, VLF Power, LF Power and LF/HF of nonsurvivors were significantly lower than those of survivors (p = <0.001, p = 0.003, p = 0.002, p = 0.006, p = 0.009 respectively). ROC curve of SDNN was built, showing area under the curve of 0.772 (0.638-0.906) for mortality. The value of 17ms was chosen as best SDNN cutoff to discriminate survivors and nonsurvivors. In the Cox proportional regression, adjusted for SOFA score and for APACHE II, a SDNN <= 17ms was associated with a greater risk of death, with hazard ratios of 6.3 (1.4-28.0; p = 0.015) and 5.5 (1,2-24,8; p = 0.027), respectively. The addition of the dichotomized SDNN to the SOFA model reduced AIC and increased the concordance statistic and the R2, indicating that predictive power of the SDNN + SOFA model is better than predictive power of SOFA only. CONCLUSIONS: Several HRV parameters are reduced in nonsurviving septic patients. SDNN <=17 is a risk factor for death in septic patients, even after adjusting for severity scores. PMID- 28654693 TI - Fatty acid synthase reprograms the epigenome in uterine leiomyosarcomas. AB - SK-UT-1 uterine leiomyosarcomas (Ut-LMS) cells were transduced with a fatty acid synthase (FASN)-containing retroviral vector to recapitulate the "lipogenic phenotype of cancer." Consistent with this model, forced expression of FASN enhanced SK-UT-1 proliferation, migration, and cellular motion. Further investigation showed FASN promotes trimethylation of H3K9 (H3K9me3) and acetylation of H3K27 (H3K27ac) in SK-UT-1 cells. In contrast, siRNA targeting of FASN in high endogenous FASN expressing SK-LMS-1 Ut-LMS cells inhibits trimethylation of H3K9 and acetylation of H3K27. Palmitate, the predominant fatty acid product of FASN, increased H3K9me3, H3K27ac and H3K27me3 detection in SK-UT 1 cells. FASN promoted histone 3 methylation and acetylation through alteration of histone 3-modifying enzymatic activities (HDAC, HDM, HMT and HAT). ChIP-seq in SK-UT-1-FASN cells with anti-H3K9me3 antibody identified regions of enriched binding compared to vector-only cells. One differentially-enriched gene, CRISP1, was investigated further by ChIP-PCR. The transcriptionally repressive function of H3K9me3 was confirmed in CRISP1. Our results provide mechanistic insight into the pathobiology of the "lipogenic phenotype of cancer." Here, FASN reprograms the Ut-LMS epigenome through chromatin remodeling to promote the "malignant phenotype." PMID- 28654694 TI - Ethnic differences in lens parameters measured by ocular biometry in a cataract surgery population. AB - PURPOSE: To investigate whether differences exist in lens position and other lens parameters among major ethnic groups with cataractous eyes, which may help explain racial differences in angle closure risk. METHODS: This retrospective, cross-sectional study included 807 adult patients who had cataract surgery between years 2014 and 2016 at the University of California, San Francisco (UCSF). Adult patients of white, Asian, Hispanic and African-American ethnicity were included. Lens position (LP), defined as anterior chamber depth (ACD) + 1/2 lens thickness (LT), was assessed using measurements from optical biometry. Other assessed biometric parameters included axial length (AL), relative lens position (RLP) (defined as LP/AL), and anterior chamber depth (ACD). RESULTS: A total of 807 patients and 1361 eyes were included in this study from a database of patients having cataract surgery. Mean age was 69.2 years (age range from 18 to 101 years old), and 60.3% of patients were women. The mean LP measurements were 5.54+/-0.32 mm for white, 5.38+/-0.32 mm for Asian, 5.32+/-0.30 mm for Hispanic, and 5.40+/-0.28 mm for African-American participants. After adjusting for age, sex, and AL, significant differences were found when comparing LP in paired comparisons among White cohort with Asians (P<0.001), Hispanics (P<0.001) and African-Americans (P = 0.003). Additionally, when comparing RLP, similar significant results were found when comparing Whites with Asians (P<0.001), Hispanics (P<0.001) and African-Americans (P = 0.002). Lastly, pair-wise comparison of LT between ethnic groups showed significant differences while comparing Asians with Whites (P = 0.001) and Asians with African-Americans (P<0.001). CONCLUSION: The results of this study suggest that the LP of Hispanic, Asian, and African-American patients are significantly smaller than that of White patients, and among all ethnic groups, Hispanics and after Asians have the smallest LP (P<0.001) and RLP (P<0.001). These findings may have implications for the relative risk of angle closure and the potential IOP response after cataract surgery among different ethnic groups. PMID- 28654695 TI - Fate of tenogenic differentiation potential of human bone marrow stromal cells by uniaxial stretching affected by stretch-activated calcium channel agonist gadolinium. AB - The role for mechanical stimulation in the control of cell fate has been previously proposed, suggesting that there may be a role of mechanical conditioning in directing mesenchymal stromal cells (MSCs) towards specific lineage for tissue engineering applications. Although previous studies have reported that calcium signalling is involved in regulating many cellular processes in many cell types, its role in managing cellular responses to tensile loading (mechanotransduction) of MSCs has not been fully elucidated. In order to establish this, we disrupted calcium signalling by blocking stretch-activated calcium channel (SACC) in human MSCs (hMSCs) in vitro. Passaged-2 hMSCs were exposed to cyclic tensile loading (1 Hz + 8% for 6, 24, 48, and 72 hours) in the presence of the SACC blocker, gadolinium. Analyses include image observations of immunochemistry and immunofluorescence staining from extracellular matrix (ECM) production, and measuring related tenogenic and apoptosis gene marker expression. Uniaxial tensile loading increased the expression of tenogenic markers and ECM production. However, exposure to strain in the presence of 20 MUM gadolinium reduced the induction of almost all tenogenic markers and ECM staining, suggesting that SACC acts as a mechanosensor in strain-induced hMSC tenogenic differentiation process. Although cell death was observed in prolonged stretching, it did not appear to be apoptosis mediated. In conclusion, the knowledge gained in this study by elucidating the role of calcium in MSC mechanotransduction processes, and that in prolonged stretching results in non apoptosis mediated cell death may be potential useful for regenerative medicine applications. PMID- 28654696 TI - Novel insight into the origin of the growth dynamics of sauropod dinosaurs. AB - Sauropod dinosaurs include the largest terrestrial animals and are considered to have uninterrupted rapid rates of growth, which differs from their more basal relatives, which have a slower cyclical growth. Here we examine the bone microstructure of several sauropodomorph dinosaurs, including basal taxa, as well as the more derived sauropods. Although our results agree that the plesiomorphic condition for Sauropodomorpha is cyclical growth dynamics, we found that the hypothesized dichotomy between the growth patterns of basal and more derived sauropodomorphs is not supported. Here, we show that sauropod-like growth dynamics of uninterrupted rapid growth also occurred in some basal sauropodomorphs, and that some basal sauropods retained the plesiomorphic cyclical growth patterns. Among the sauropodomorpha it appears that the basal taxa exploited different growth strategies, but the more derived Eusauropoda successfully utilized rapid, uninterrupted growth strategies. PMID- 28654697 TI - Correction: A Physically-Modified Saline Suppresses Neuronal Apoptosis, Attenuates Tau Phosphorylation and Protects Memory in an Animal Model of Alzheimer's Disease. AB - [This corrects the article DOI: 10.1371/journal.pone.0103606.]. PMID- 28654698 TI - The future of the London Buy-To-Let property market: Simulation with temporal Bayesian Networks. AB - In 2015 the British government announced a number of major tax reforms for individual landlords. To give landlords time to adjust, some of these tax measures are being introduced gradually from April 2017, with full effect in tax year 2020/21. The changes in taxation have received much media attention since there has been widespread belief that the new measures were sufficiently skewed against landlords that they could signal the end of the Buy-To-Let (BTL) investment era in the UK. This paper assesses the prospective performance of BTL investments in London from the investor's perspective, and examines the impact of incoming tax reforms using a novel Temporal Bayesian Network model. The model captures uncertainties of interest by simulating the impact of changing circumstances and the interventions available to an investor at various time steps of a BTL investment portfolio. The simulation results suggest that the new tax reforms are likely to have a detrimental effect on net profits from rental income, and this hits risk-seeking investors who favour leverage much harder than risk-averse investors who do not seek to expand their property portfolio. The impact on net profits also poses substantial risks for lossmaking returns excluding capital gains, especially in the case of rising interest rates. While this makes it less desirable or even non-viable for some to continue being a landlord, based on the current status of all factors taken into consideration for simulation, investment prospects are still likely to remain good within a reasonable range of interest rate and capital growth rate variations. The results also suggest that the recent trend of property prices in London increasing faster than rents will not continue for much longer; either capital growth rates will have to decrease, rental growth rates will have to increase, or we shall observe a combination of the two events. PMID- 28654699 TI - Early mobilisation after total hip or knee arthroplasty: A multicentre prospective observational study. AB - OBJECTIVE: Early mobilisation is recommended following total hip arthroplasty (THA) or total knee arthroplasty (TKA) to prevent venous thromboembolism (VTE). We sought to determine the proportions of patients that first mobilised on post operative day 0 (POD 0) and factors associated with earlier time to mobilisation. METHODS: A prospective cohort study was conducted involving patients with hip or knee osteoarthritis who had undergone primary unilateral THA (n = 818) and TKA (n = 989) at 19 Australian hospitals. Patient-related (e.g. age, gender, body mass index), treatment-related (e.g. hospital site, presence of indwelling catheter) and mobilisation-related variables were collected on standardised forms. Time was measured by post-operative days, where POD 0 was defined as the day of surgery ending at midnight. Multivariate Poisson regression analysis identified associations between patient- and treatment-related covariates and time to mobilisation. RESULTS: Inter-hospital variation was evident, but overall, only 9.4% of THA and 5.6% of TKA patients mobilised on POD 0. For THA patients, earlier time to mobilisation was associated with hospital site and absences of an indwelling catheter and acute complications. For TKA patients, earlier time to mobilisation was associated with hospital site and absence of donor blood transfusion. CONCLUSIONS: Few THA and TKA patients mobilise POD 0, although some hospitals appear more aggressive with their mobilisation attempts than others. Treatment-related factors, not patient-related, are associated with post operative day of mobilisation, indicating the potentially pivotal role of service providers in promoting early mobilisation to improve health outcomes and reduce rates of VTE. PMID- 28654701 TI - Correction: Comparison of French and Worldwide Bacillus anthracis Strains Favors a Recent, Post-Columbian Origin of the Predominant North-American Clade. AB - [This corrects the article DOI: 10.1371/journal.pone.0146216.]. PMID- 28654700 TI - Both absolute and relative quantification of urinary mRNA are useful for non invasive diagnosis of acute kidney allograft rejection. AB - Urinary mRNA analysis with three-gene set (18S rRNA, CD3epsilon, and IP-10) has been suggested as a non-invasive biomarker of acute rejection (AR) in kidney transplant recipients using quantitative real-time PCR (qPCR). Application of droplet digital PCR (ddPCR), which has been suggested to provide higher sensitivity, accuracy, and absolute quantification without standard curves, could be a useful method for the quantifying low concentration of urinary mRNA. We investigated the urinary expression of these three genes in Korean patients with kidney transplantation and also evaluated the usefulness of ddPCR. 90 urine samples were collected at time of allograft biopsy in kidney recipients (n = 67) and from patients with stable renal function more than 10 years (n = 23). Absolute quantification with both PCR system showed significant higher mRNA levels of CD3epsilon and IP-10 in AR patients compared with stable transplants (STA), but there was no difference in 18S rRNA expression across the patient groups. To evaluate discrimination between AR and STA, ROC curve analyses of CTOT 4 formula yielded area under the curve values of 0.72 (95% CI 0.60-0.83) and 0.77 (95% CI 0.66-0.88) for qPCR and ddPCR, respectively. However, 18S normalization of absolute quantification and relative quantification with 18S showed better discrimination of AR from STA than those of the absolute method. Our data indicate that ddPCR system without standard curve would be useful to determine the absolute quantification of urinary mRNA from kidney transplant recipients. However, comparative method also could be useful and convenient in both qPCR and ddPCR analysis. PMID- 28654702 TI - Stomatin-like protein 2 deficiency results in impaired mitochondrial translation. AB - Mitochondria translate the RNAs for 13 core polypeptides of respiratory chain and ATP synthase complexes that are essential for the assembly and function of these complexes. This process occurs in close proximity to the mitochondrial inner membrane. However, the mechanisms and molecular machinery involved in mitochondrial translation are not fully understood, and defects in this process can result in severe diseases. Stomatin-like protein (SLP)-2 is a mainly mitochondrial protein that forms cardiolipin- and prohibitin-enriched microdomains in the mitochondrial inner membrane that are important for the formation of respiratory supercomplexes and their function. Given this regulatory role of SLP-2 in processes closely associated with the mitochondrial inner membrane, we hypothesized that the function of SLP-2 would have an impact on mitochondrial translation. 35S-Methionine/cysteine pulse labeling of resting or activated T cells from T cell-specific Slp-2 knockout mice showed a significant impairment in the production of several mitochondrial DNA-encoded polypeptides following T cell activation, including Cytb, COXI, COXII, COXIII, and ATP6. Measurement of mitochondrial DNA stability and mitochondrial transcription revealed that this impairment was at the post-transcriptional level. Examination of mitochondrial ribosome assembly showed that SLP-2 migrated in sucrose-density gradients similarly to the large ribosomal subunit but that its deletion at the genetic level did not affect mitochondrial ribosome assembly. Functionally, the impairment in mitochondrial translation correlated with decreased interleukin-2 production in activated T cells. Altogether, these data show that SLP-2 acts as a general regulator of mitochondrial translation. PMID- 28654703 TI - Development of a forecasting model for brucellosis spreading in the Italian cattle trade network aimed to prioritise the field interventions. AB - Brucellosis caused by Brucella abortus is an important zoonosis that constitutes a serious hazard to public health. Prevention of human brucellosis depends on the control of the disease in animals. Livestock movement data represent a valuable source of information to understand the pattern of contacts between holdings, which may determine the inter-herds and intra-herd spread of the disease. The manuscript addresses the use of computational epidemic models rooted in the knowledge of cattle trade network to assess the probabilities of brucellosis spread and to design control strategies. Three different spread network-based models were proposed: the DFC (Disease Flow Centrality) model based only on temporal cattle network structure and unrelated to the epidemiological disease parameters; a deterministic SIR (Susceptible-Infectious-Recovered) model; a stochastic SEIR (Susceptible-Exposed-Infectious-Recovered) model in which epidemiological and demographic within-farm aspects were also modelled. Containment strategies based on farms centrality in the cattle network were tested and discussed. All three models started from the identification of the entire sub-network originated from an infected farm, up to the fifth order of contacts. Their performances were based on data collected in Sicily in the framework of the national eradication plan of brucellosis in 2009. Results show that the proposed methods improves the efficacy and efficiency of the tracing activities in comparison to the procedure currently adopted by the veterinary services in the brucellosis control, in Italy. An overall assessment shows that the SIR model is the most suitable for the practical needs of the veterinary services, being the one with the highest sensitivity and the shortest computation time. PMID- 28654704 TI - 2,5-hexanedione downregulates nerve growth factor and induces neuron apoptosis in the spinal cord of rats via inhibition of the PI3K/Akt signaling pathway. AB - 2,5-hexanedione (2,5-HD) is the main active metabolite of n-hexane and induces apoptosis in nerve tissue, however, the mechanism of which remains unclear. In the present study, neuropathic animal models were successfully constructed in rats by injecting 100, 200 and 400 mg/kg 2,5-HD intraperitoneally for 5 weeks. Rats exposed to 2,5-HD exhibited progressive gait abnormalities and slower motor neural response in a dose-dependent manner. TUNEL analysis and immunofluorescence dual labeling revealed that the spinal cord of the 2,5-HD treated rats underwent significantly more apoptosis in the cells of spinal cord than that of the control group. The neuron apoptosis index in spinal cord was 4.1%, 6.7%, 9.8% respectively in rats exposed to 100, 200 and 400 mg/kg 2,5-HD, compared with 1.1% in the control group (p < 0.05). Biochemical analysis showed that 2,5-HD exposure downregulated NGF expression in the spinal cord of the intoxicated rats; inhibited the phosphorylation of Akt and Bad, two key players in PI3K/Akt pathway downstream of NGF; increased the dimerization of Bad with Bcl-xL in the mitochondrial fraction, followed by the release of cytochrome c and activation of caspase-3 in the spinal cord of rats. In vitro study showed that the NGF expression decreased significantly in VSC4.1 cells dosed with 5.0, 10.0 mM 2,5-HD in comparison with the control group. It was also found that NGF supplement repressed the induced apoptosis, and increased p-Akt and p-Bad level in 2,5-HD treated VSC4.1 cells, which could be antagonized by PI3K kinase (the upstream member of Akt) inhibitor LY294002. Taken together, our experimental results indicate that 2,5-HD may induce apoptosis in the spinal cord of rats via downregulating NGF expression and subsequently repressing PI3K/Akt signaling pathway. PMID- 28654705 TI - Effective new membrane for preventing postthoracotomy pleural adhesion by surface water induction technology. AB - BACKGROUND: After thoracic surgery, adhesions between the pleura can cause substantial complications. This study investigated the effectiveness of a novel membrane utilizing surface water induction technology to prevent adhesions. METHODS: Eight beagles were divided into an experimental group (five males) and a control group (three females). The experimental group underwent thoracotomy on both the left and right sides of the chest. Both sides received the membrane, and the membrane on one side was glued to the pleura using tissue adhesive. The control group underwent thoracotomy only on the left side. Two weeks postoperatively, all dogs were sacrificed and adhesions were evaluated macroscopically and microscopically. RESULTS: Severe adhesion was seen between the parietal and visceral pleura in all control dogs, whereas the experimental group showed minor adhesion in only one dog on one side. CONCLUSIONS: Our novel anti-adhesive membrane appeared highly effective in preventing postthoracotomy pleural adhesions. PMID- 28654706 TI - Differential effects of heat shock protein 90 and serine 1179 phosphorylation on endothelial nitric oxide synthase activity and on its cofactors. AB - Endothelial nitric oxide synthase (eNOS) is responsible for maintaining systemic blood pressure, vascular remodeling and angiogenesis. Previous studies showed that bovine eNOS serine 1179 (Serine 1177 for human eNOS) phosphorylation enhanced NO synthesis. Meanwhile, heat shock protein 90 (Hsp90) plays a critical role in maintenance of eNOS structure and function. However, the regulatory difference and importance between Serine 1179 phosphorylation and Hsp90 on eNOS activity have not been evaluated. In current studies, S1179D eNOS was employed to mimic phospho-eNOS and exhibited markedly increased enzyme activity than wild type eNOS (WT eNOS). Hsp90 showed a dose-dependent increase for both WT eNOS and S1179D eNOS activity at the presence of all eNOS cofactors, such as Calcium/Calmodulin (Ca2+ /CaM), BH4, and NADPH etc. The enhancement effects were abolished by dominant-negative mutant Hsp 90 protein. ENOS-cofactors dynamic assay showed that Hsp90 enhanced WT eNOS affinity to NADPH, L-arginine, and CaM but not to Ca2+ and BH4. The impact of eNOS Serine 1179 phosphorylation and Hsp90 on eNOS affinity to cofactors has also been compared. Different from the effect of Hsp90 on eNOS affinity to specific cofactors, Serine 1179 phosphorylation significantly increased eNOS affinity to all cofactors. Moreover, VEGF-induced eNOS phosphorylation in bovine aortic endothelial cells (BAECs) and more NO generation from eNOS compared to control. Inhibition of Hsp90 by geldanamycin decreased eNOS activity and decreased endothelial viability. In conclusion, by changing eNOS structure, Hsp90 profoundly affected eNOS functions, including change of affinity of eNOS to cofactors like Ca2+, L-arginine, BH4 and further affecting NO generation capability. These specific cofactors regulated by Hsp 90 could become potential therapeutic targets of the eNOS-related diseases in future. PMID- 28654707 TI - Meeting the challenge of atopic dermatitis from infancy to adulthood, introduction. PMID- 28654708 TI - Practical strategies for the diagnosis and assessment of atopic dermatitis. AB - Atopic dermatitis (AD) has a significant, lifelong clinical impact on affected individuals and has profound effects on quality of life both for patients and their families. The diagnosis usually can be reliably established on the basis of the history and physical examination. In patients with skin of color, blanching of the skin may be helpful to detect erythema, lichenification, follicular accentuation, and hypopigmentation (all of which are more common than in lighter skinned patients). Once the diagnosis of AD is established, an assessment of severity, persistence, and impact on the patient's and family's life is important as a guide to treatment decisions. PMID- 28654709 TI - Atopic dermatitis progression: evaluating intervention strategies. AB - Several risk factors have been identified that appear to be consistently and strongly associated with the development of atopic dermatitis (AD): a family history of atopy, an inherited genetic predisposition, and active and passive exposure to tobacco smoke. Recent studies also have demonstrated that a simple intervention from birth-the daily application of an emollient moisturizer-seems to protect susceptible infants from the development of AD. PMID- 28654710 TI - Nonpharmacologic strategies and topical agents for treating atopic dermatitis: an update. AB - The signs and symptoms of atopic dermatitis can be safely and effectively controlled in most patients; in many cases, the disease can be improved to the point that signs and symptoms are absent or minimal. In addition, flares can be effectively controlled and, in some cases, prevented. New topical medications, improved strategies for the use of topical corticosteroids and topical calcineurin inhibitors, and judicious use of nonpharmacologic regimens-including bathing, bleach baths, and early use of emollients-have led to better disease management and improved quality of life for patients and their families. PMID- 28654711 TI - Addressing the immunopathogenesis of atopic dermatitis: advances in topical and systemic treatment. AB - Several immunologic mediators-phosphodiesterase (PDE), interleukin (IL), small molecules, and Janus kinase-have been implicated in the pathogenesis of atopic dermatitis, and evidence has shown that blocking these mediators can help modify the disease process. Several new topical medications have been developed that target the enzyme PDE; crisaborole was recently approved by the US Food and Drug Administration (FDA) for the treatment of atopic dermatitis, and phase II studies have been completed on OPA-15406. The phase III clinical trial results of the systemic medication dupilumab, an inhibitor of the IL-4 receptor alpha subunit (which inhibits both IL-4 and IL-13 signaling), are currently being reviewed by the FDA. PMID- 28654712 TI - Identifying Significantly Impacted Pathways and Putative Mechanisms with iPathwayGuide. AB - iPathwayGuide is a gene expression analysis tool that provides biological context and inferences from data generated by high-throughput sequencing. iPathwayGuide utilizes a systems biology approach to identify significantly impacted signaling pathways, Gene Ontology terms, disease processes, predicted microRNAs, and putative mechanisms based on the given differential expression signature. By using a novel analytical approach called Impact Analysis, iPathwayGuide considers the role, position, and relationships of each gene within a pathway, which results in a significant reduction in false positives, as well as a better ability to identify the truly impacted pathways and putative mechanisms that can explain all measured gene expression changes. It is a Web-based, user-friendly, interactive tool that does not require prior training in bioinformatics. The protocols in this unit describe how to use iPathwayGuide to analyze a single contrast between two phenotypes (any number of samples), and provide guidance on how to interpret the results obtained from iPathwayGuide. Even though iPathwayGuide has powerful meta-analysis capabilities, these are not covered in this unit. (c) 2017 by John Wiley & Sons, Inc. PMID- 28654713 TI - How Could Nurse Researchers Apply Theory to Generate Knowledge More Efficiently? AB - BACKGROUND: Reports of nursing research often do not provide adequate information about whether, and how, researchers applied theory when conducting their studies. Unfortunately, the lack of adequate application and explication of theory in research impedes development of knowledge to guide nursing practice. OBJECTIVES: To clarify and exemplify how to apply theory in research. METHODS: First we describe how researchers can apply theory in phases of research. Then we share examples of how three research teams applied one theory to these phases of research in three different studies of preventive behaviors. CONCLUSIONS: Nurse researchers can review and refine ways in which they apply theory in guiding research and writing publications. Scholars can appreciate how one theory can guide researchers in building knowledge about a given condition such as preventive behaviors. Clinicians and researchers can collaborate to apply and examine the usefulness of theory. CLINICAL RELEVANCE: If nurses had improved understanding of theory-guided research, they could better assess, select, and apply theory-guided interventions in their practices. PMID- 28654714 TI - Reactions of Donor-Acceptor Cyclopropanes with Naphthoquinones: Redox and Lewis Acid Catalysis Working in Concert. AB - Reactions of 2-arylcyclopropane dicarboxylates with naphthoquinones are reported. The key feature was the use of catalytic amounts of SnCl2 , which acts as both an electron donor and a Lewis acid. By an in situ umpolung of naphthoquinone the formerly electrophilic species is converted into a nucleophile that is able to trigger the ring-opening of the three-membered ring with formation of a new C-C bond. Treatment of these products with base under oxidative conditions resulted through loss of methyl formate-in cyclopentannulated products with fully conjugated pi systems exhibiting intensive absorptions in the visible range. PMID- 28654715 TI - A Secondary Structural Element in a Wide Range of Fucosylated Glycoepitopes. AB - The increasing understanding of the essential role of carbohydrates in development, and in a wide range of diseases fuels a rapidly growing interest in the basic principles governing carbohydrate-protein interactions. A still heavily debated issue regarding the recognition process is the degree of flexibility or rigidity of oligosaccharides. Combining NMR structure determination based on extensive experimental data with DFT and database searches, we have identified a set of trisaccharide motifs with a similar conformation that is characterized by a non-conventional C-H???O hydrogen bond. These motifs are present in numerous classes of oligosaccharides, found in everything from bacteria to mammals, including Lewis blood group antigens but also unusual motifs from amphibians and marine invertebrates. The set of trisaccharide motifs can be summarized with the consensus motifs X-beta1,4-[Fucalpha1,3]-Y and X-beta1,3-[Fucalpha1,4]-Y-a secondary structure we name [3,4]F-branch. The wide spectrum of possible modifications of this scaffold points toward a large variety of glycoepitopes, which nature generated using the same underlying architecture. PMID- 28654716 TI - Cation Dependence of the Dimerization Enthalpy for A2 [tetracyanoethylene]2 (A=NMe4 , Mepy, NEt4 ) Possessing a Long, Multicenter Bond. AB - [TCNE].- (TCNE=tetracyanoethylene) has been isolated as D2h pi-[TCNE]22- possessing a long, 2.9 A multicenter 2-electron-4-center (2e- /4c) C-C bond, and as C2 pi-[TCNE]22- possessing a longer, 3.04 A multicenter 2e- /6c (4 C+2 N atoms) bond. Temperature-dependent UV/Vis spectroscopic measurements in 2 methyltetrahydrofuran (MeTHF) has led to the determination of the dimerization, 2[TCNE].- ?pi-[TCNE]22- , equilibrium constants, Keq (T), [[TCNE]22- ]/[[TCNE].- ]2 , enthalpy, DeltaH, and entropy, DeltaS, of dimerization for [Mepy]2 [TCNE]2 (Mepy=N-methylpyridinium, H3 CNC5 H5+ ) possessing D2h pi-[TCNE]22- and [NMe4 ]2 [TCNE]2 possessing C2 pi-[TCNE]22- conformations in the solid state; however, both form D2h pi-[TCNE]22- in MeTHF solution. Based on DeltaH=-3.6+/-0.1 kcal mol 1 (-15.2 kJ mol-1 ), and DeltaS=-11+/-1 eu (-47 J mol-1 K-1 ) and DeltaH=-2.4+/ 0.2 kcal mol-1 (-10.2 kJ mol-1 ), and DeltaS=-8+/-1 eu (-32 J mol-1 K-1 ) in MeTHF for [NMe4 ]2 [TCNE]2 and [Mepy]2 [TCNE]2 , respectively, the calculated Keq (298 K) are 1.6 and 1.3 m-1 , respectively. The observed Keq (145 K) are 3 and 2 orders of magnitude greater for [NMe4 ]2 [TCNE]2 and [Mepy]2 [TCNE]2 , respectively. The Keq (130 K) is 4470, 257, ~0.8, and ?0.1 m-1 for [NMe4 ]2 [TCNE]2 , [Mepy]2 [TCNE]2 , [NEt4 ]2 [TCNE]2 , and [N(nBu)4 ]2 [TCNE]2 , respectively, decreasing with increasing cation size. At standard conditions and below ambient temperature the equilibrium favors the dimer for the NMe4+ and Mepy+ cations. From the decreasing enthalpy, NMe4+ >Mepy+ , along with the decrease in dimer formation Keq (T) as NMe4+ >Mepy+ >NEt4+ >N(nBu)4+ , the dimer bond energy decreases with increasing cation size in MeTHF. This is attributed to a decrease in the [A]+ ???[TCNE]- attractive interactions with increasing cation size. Solid state UV/Vis spectroscopic determinations of [NMe4 ]2 [TCNE]2 are reported and compared to D2h pi-[TCNE]22- conformers. The feasibility and limitations of temperature-dependent electron paramagnetic resonance (EPR) measurements for the determination of Keq (T) are also discussed. PMID- 28654718 TI - Building connectomes using diffusion MRI: why, how and but. AB - Why has diffusion MRI become a principal modality for mapping connectomes in vivo? How do different image acquisition parameters, fiber tracking algorithms and other methodological choices affect connectome estimation? What are the main factors that dictate the success and failure of connectome reconstruction? These are some of the key questions that we aim to address in this review. We provide an overview of the key methods that can be used to estimate the nodes and edges of macroscale connectomes, and we discuss open problems and inherent limitations. We argue that diffusion MRI-based connectome mapping methods are still in their infancy and caution against blind application of deep white matter tractography due to the challenges inherent to connectome reconstruction. We review a number of studies that provide evidence of useful microstructural and network properties that can be extracted in various independent and biologically relevant contexts. Finally, we highlight some of the key deficiencies of current macroscale connectome mapping methodologies and motivate future developments. PMID- 28654717 TI - Similar reliability and equivalent performance of female and male mice in the open field and water-maze place navigation task. AB - Although most nervous system diseases affect women and men differentially, most behavioral studies using mouse models do not include subjects of both sexes. Many researchers worry that data of female mice may be unreliable due to the estrous cycle. Here, we retrospectively evaluated sex effects on coefficient of variation (CV) in 5,311 mice which had performed the same place navigation protocol in the water-maze and in 4,554 mice tested in the same open field arena. Confidence intervals for Cohen's d as measure of effect size were computed and tested for equivalence with 0.2 as equivalence margin. Despite the large sample size, only few behavioral parameters showed a significant sex effect on CV. Confidence intervals of effect size indicated that CV was either equivalent or showed a small sex difference at most, accounting for less than 2% of total group to group variation of CV. While female mice were potentially slightly more variable in water-maze acquisition and in the open field, males tended to perform less reliably in the water-maze probe trial. In addition to evaluating variability, we also directly compared mean performance of female and male mice and found them to be equivalent in both water-maze place navigation and open field exploration. Our data confirm and extend other large scale studies in demonstrating that including female mice in experiments does not cause a relevant increase of data variability. Our results make a strong case for including mice of both sexes whenever open field or water-maze are used in preclinical research. PMID- 28654719 TI - Everolimus-Based Immunosuppression in Liver Transplant Recipients. PMID- 28654720 TI - Comparing triggers to visual disturbances among individuals with positive vs negative experiences of hallucinogen-persisting perception disorder (HPPD) following LSD use. AB - BACKGROUND AND OJECTIVE: Exploring differences in visual disturbances and triggers between Hallucinogen-Persisting-Perceptual-Disorder (HPPD) Type I ("positive/benign") and II ("negative/distressing"). METHODS: Forty individuals with HPPD and prior LSD use completed clinical questionnaires. RESULTS: The most common type of visual disturbances among individuals with HPPD I and II was slow movement of still objects and trailing phenomena, respectively. Those with HPPD I were more likely to report experiencing disturbances in dark environment, while looking at a still or moving object and during sexual intercourse. DISCUSSION AND CONCLUSIONS: HPPD I and II differ in terms of visual disturbances and triggers, possibly representing different phenomena existing on the same spectrum. SCIENTIFIC SIGNIFICANCE: Our study indicating differences in triggers to HPPD I and II adds to existing literature on differences in visual disturbances between the two subtypes. Further research elucidating additional differences between the subtypes of HPPD is needed. (Am J Addict 2017;26:568-571). PMID- 28654721 TI - Comparative evaluation of esthetic changes in nonpitted fluorosis stains when treated with resin infiltration, in-office bleaching, and combination therapies. AB - OBJECTIVES: Dental fluorosis leads to esthetic deviation and varies from nonpitted white opacities, dark brown stains to pitting or structural breakdown of enamel surface. Treatment for fluorosis depends on the severity of condition and includes both noninvasive methods and invasive methods. Recently resin infiltration has been proposed as an alternative treatment for nonpitted fluorosis. This study was done to evaluate the esthetic changes in nonpitted fluorosis stains when treated with resin infiltration, in-office bleaching and combination therapies. MATERIALS AND METHODS: The present study is a randomized, single blinded controlled trial with four parallel arms with 1:1 allocation ratio. The intervention arms included bleaching with 35% hydrogen peroxide, resin infiltration, resin infiltration with increased infiltration time and a combination approach of bleaching and infiltration. Immediate esthetic changes were evaluated for two parameters including, 'Change in esthetics' and 'Improvement in opacities/stains' using a VAS scale by two independent observers. Kruskal-Wallis test and Mann-Whitney U-test were done for intergroup comparisons. RESULTS: Best results for both the parameters were observed among patients treated with resin infiltration with increased infiltration time. Mann-Whitney U test revealed significantly better results for resin infiltration groups (alone or combination with bleaching) as compared to bleaching alone (P < .001). CONCLUSIONS: Resin infiltration procedure with tailored etching times and increased infiltration time exhibited best results in terms of change in esthetics and improvement in stains. CLINICAL SIGNIFICANCE: White and brown opacities due to fluorosis have always been a concern for esthetics. In our study, resin infiltration technique with tailored etching times and increased infiltration time exhibited best immediate esthetic improvement for nonpitted fluorotic opacities and stains. These esthetic outcomes reaffirm the applicability of RI technique for nonpitted fluorosis, which was originally advocated only for white spot lesions due to early caries. This will in turn help the dentists to plan the esthetic management of nonpitted fluorosis in a micro invasive manner. PMID- 28654722 TI - Synthesis of Ultra-Small Palladium Nanoparticles Deposited on CdS Nanorods by Pulsed Laser Ablation in Liquid: Role of Metal Nanocrystal Size in the Photocatalytic Hydrogen Production. AB - It is imperative to suppress the rate of recombination of photogenerated carriers to improve the semiconductor-catalyzed solar-driven production of hydrogen. To this end, photocatalysts comprising active sunlight-harvesting photo-absorbers and stable metal co-catalysts have attracted significant attention. However, the size, clean surface, and highly dispersed nature of the metal co-catalysts are crucial factors affecting catalyst performance and reaction rate. Nevertheless, most of the available metal nanocrystals have been synthesized by complex procedures using harmful organic templates and stabilizers, affording high-purity compounds with difficulty and high cost. To overcome these problems, in this study, the pulsed laser ablation in liquid approach was utilized to generate palladium and bimetallic palladium-platinum nanoparticles with an average size and distribution by adjusting the laser wavelength and fluence. A high rate of evolution of hydrogen of 130.33 mmol g-1 h-1 was obtained by using the optimized CdS-PdPt catalyst under simulated sunlight irradiation. This value is 51.31 times greater than that observed for bare CdS nanostructures. Furthermore, the amount of hydrogen evolved was significantly better than that obtained by using several other noble-metal co-catalysts deposited on CdS. This proposed strategy is thought to open new avenues for the design of advanced photocatalytic materials for efficient solar-driven production of hydrogen. PMID- 28654723 TI - Comparison of two species-specific oscillometric blood pressure monitors with direct blood pressure measurement in anesthetized cats. AB - OBJECTIVE: To compare the performance of 2 species-specific oscillometric blood pressure (OBP) monitors (petMAPclassic and petMAPgraphic ) with direct blood pressure measurement in anesthetized cats. DESIGN: Prospective, experimental study. SETTING: Veterinary teaching hospital. ANIMALS: Eight adult cats (3.2-5.5 kg). INTERVENTIONS: During isoflurane anesthesia, OBP cuffs were placed on the thoracic limb and on the base of the tail while invasive blood pressure (IBP) was recorded from a dorsal pedal artery. End-tidal isoflurane concentrations, with or without intravenous dopamine (n = 8), norepinephrine (n = 1), or phenylephrine (n = 1) were adjusted to change invasive mean arterial pressure (MAP) between 40 to 100 mm Hg. Data were analyzed by the Bland-Altman method and 4-quadrant plots. MEASUREMENTS AND MAIN RESULTS: Mean biases and limits of agreement (LOA: +/- 1.96 SD) (mm Hg) recorded between the petMAPclassic (thoracic limb) and IBP for systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and MAP were 4.2 +/- 28.5, -6.1 +/- 13.2, and -1.9 +/- 14.6, respectively; mean biases and LOA (mm Hg) recorded with the tail cuff were 7.2 +/- 31.3 (SAP), -6.1 +/- 11.6 (DAP), and -1.1 +/- 11.7 (MAP). Mean biases and LOA (mm Hg) between petMAPgraphic (thoracic limb) and IBP were 7.7 +/- 27.0 (SAP), -4.3 +/- 11.5 (DAP), 0.2 +/- 13.0 (MAP); values recorded with the tail cuff were 10.9 +/- 29.6 (SAP), -4.4 +/- 11.7 (DAP), and -0.1 +/- 12.1 (MAP). Concordance rates after excluding arterial pressure changes <= 5 mm Hg was >= 93% for both devices. CONCLUSIONS: Although both OBP monitors provide unacceptable SAP estimations, MAP values derived from both monitors and DAP measured by the petMAPgraphic result in acceptable agreement with the reference method according to the Association for the Advancement of Medical Instrumentation (mean bias <= 5 mm Hg with LOA <= +/- 16 mm Hg). Both monitors provide acceptable trending ability for SAP, DAP, and MAP. PMID- 28654724 TI - Metal-Free Oxidation of Glycerol over Nitrogen-Containing Carbon Nanotubes. AB - Nitrogen rich carbon nanotubes have been used as a metal free catalyst for the conversion of glycerol into dihydroxyacetone using tert-butyl hydroperoxide as an oxidant. Pyridine nitrogen groups embedded in a carbon matrix are identified as active sites for the reaction. Computational studies have demonstrated that oxidation of pyridine groups to pyridine oxime followed by hydrogen abstraction from secondary alcohol is likely responsible for the oxidation process. PMID- 28654725 TI - Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes. AB - Online Mendelian Inheritance in Man (OMIM) at OMIM.org is the primary repository of comprehensive, curated information on genes and genetic phenotypes and the relationships between them. This unit provides an overview of the types of information in OMIM and optimal strategies for searching and retrieving the information. OMIM.org has links to many related and complementary databases, providing easy access to more information on a topic. The relationship between genes and genetic disorders is highlighted in this unit. The basic protocol explains searching OMIM both from a gene perspective and a clinical features perspective. Two alternate protocols provide strategies for viewing gene phenotype relationships: a gene map table and Quick View or Side-by-Side format for clinical features. OMIM.org is updated nightly, and the MIMmatch service, described in the support protocol, provides a convenient way to follow updates to entries, gene-phenotype relationships, and collaborate with other researchers. (c) 2017 by John Wiley & Sons, Inc. PMID- 28654726 TI - Exploring Short Linear Motifs Using the ELM Database and Tools. AB - The Eukaryotic Linear Motif (ELM) resource is dedicated to the characterization and prediction of short linear motifs (SLiMs). SLiMs are compact, degenerate peptide segments found in many proteins and essential to almost all cellular processes. However, despite their abundance, SLiMs remain largely uncharacterized. The ELM database is a collection of manually annotated SLiM instances curated from experimental literature. In this article we illustrate how to browse and search the database for curated SLiM data, and cover the different types of data integrated in the resource. We also cover how to use this resource in order to predict SLiMs in known as well as novel proteins, and how to interpret the results generated by the ELM prediction pipeline. The ELM database is a very rich resource, and in the following protocols we give helpful examples to demonstrate how this knowledge can be used to improve your own research. (c) 2017 by John Wiley & Sons, Inc. PMID- 28654727 TI - Using the NONCODE Database Resource. AB - NONCODE is a comprehensive database that aims to present the most complete collection and annotation of non-coding RNAs, especially long non-coding RNAs (lncRNA genes), and thus NONCODE is essential to modern biological and medical research. Scientists are producing a flood of new data from which new lncRNA genes and lncRNA-disease relationships are continually being identified. NONCODE assimilates such information from a wide variety of sources including published articles, RNA-seq data, micro-array data and databases on genetic variation (dbSNP) and genome-wide associations (GWAS). NONCODE organizes all this information and makes it freely available to the public via the Internet. The NONCODE protocol provides step-by-step instructions on how to browse and search lncRNA information such as sequence, expression, and disease relationships, how to use the tools for functional prediction, species conservation assays, blast analysis, identifier conversion, and, finally, how to submit sequences to identify lncRNA genes. As of Dec 2016, NONCODE has cataloged 487,851 lncRNA genes sequenced from 16 species. (c) 2017 by John Wiley & Sons, Inc. PMID- 28654728 TI - Finding Similar Nucleotide Sequences Using Network BLAST Searches. AB - The Basic Local Alignment Search Tool (BLAST) is the first tool in the annotation of nucleotide or amino acid sequences. BLAST is a flagship of bioinformatics due to its performance and user-friendliness. Beginners and intermediate users will learn how to design and submit blastn and Megablast searches on the Web pages at the National Center for Biotechnology Information. We map nucleic acid sequences to genomes, find identical or similar mRNAs, expressed sequence tag, and noncoding RNA sequences, and run Megablast searches, which are much faster than blastn. Understanding results is assisted by taxonomy reports, genomic views, and multiple alignments. We interpret expected frequency thresholds, biological significance, and statistical significance. Weak hits provide no evidence, but indicate hints for further analyses. We find genes that may code for homologous proteins by translated BLAST. We reduce false positives by filtering out low complexity regions. Parsed BLAST results can be integrated into analysis pipelines. Links in the output connect to Entrez and PubMed, as well as structural, sequence, interaction, and expression databases. This facilitates integration with a wide spectrum of biological knowledge. (c) 2017 by John Wiley & Sons, Inc. PMID- 28654729 TI - SIGNOR: A Database of Causal Relationships Between Biological Entities-A Short Guide to Searching and Browsing. AB - SIGNOR (http://signor.uniroma2.it), the SIGnaling Network Open Resource, is a database designed to store experimentally validated causal interactions, i.e., interactions where a source entity has a regulatory effect (up-regulation, down regulation, etc.) on a second target entity. SIGNOR acts both as a source of signaling information and a support for data analysis, modeling, and prediction. A user-friendly interface features the ability to search entries for any given protein or group of proteins and to display their interactions graphically in a network view. At the time of writing, SIGNOR stores approximately 16,000 manually curated interactions connecting more than 4,000 biological entities (proteins, chemicals, protein complexes, etc.) that play a role in signal transduction. SIGNOR also offers a collection of 37 signaling pathways. SIGNOR can be queried by three search tools: "single-entity" search, "multiple-entity" search, and "pathway" search. This manuscript describes two basic protocols detailing how to navigate and search the SIGNOR database and how to download the annotated dataset for local use. Finally, the support protocol reviews the utilities of the graphic visualizer. (c) 2017 by John Wiley & Sons, Inc. PMID- 28654731 TI - Editorial. PMID- 28654730 TI - Promises, pitfalls and practicalities of prenatal whole exome sequencing. AB - Prenatal genetic diagnosis provides information for pregnancy and perinatal decision-making and management. In several small series, prenatal whole exome sequencing (WES) approaches have identified genetic diagnoses when conventional tests (karyotype and microarray) were not diagnostic. Here, we review published prenatal WES studies and recent conference abstracts. Thirty-one studies were identified, with diagnostic rates in series of five or more fetuses varying between 6.2% and 80%. Differences in inclusion criteria and trio versus singleton approaches to sequencing largely account for the wide range of diagnostic rates. The data suggest that diagnostic yields will be greater in fetuses with multiple anomalies or in cases preselected following genetic review. Beyond its ability to improve diagnostic rates, we explore the potential of WES to improve understanding of prenatal presentations of genetic disorders and lethal fetal syndromes. We discuss prenatal phenotyping limitations, counselling challenges regarding variants of uncertain significance, incidental and secondary findings, and technical problems in WES. We review the practical, ethical, social and economic issues that must be considered before prenatal WES could become part of routine testing. Finally, we reflect upon the potential future of prenatal genetic diagnosis, including a move towards whole genome sequencing and non invasive whole exome and whole genome testing. (c) 2017 John Wiley & Sons, Ltd. PMID- 28654732 TI - Age-based differences in the predictive accuracy of a one-size-fits-all risk cutoff value in prenatal integrated screening for Down syndrome. AB - OBJECTIVE: The objective of this study is to assess variation in detection and false positive rates and adverse pregnancy outcomes across different age groups when a one-size-fits-all risk-cutoff value, such as 1/270, is used in integrated screening for Down syndrome. METHOD: A Monte Carlo simulation was utilized to estimate the detection and false positive rates as well as adverse pregnancy outcomes. RESULTS: Using a one-size-fits-all risk-cutoff value, such as 1/270, can result in considerably high variations in detection and false positive rates across maternal ages and lead to a higher than the minimum possible total number of adverse outcomes. CONCLUSION: Our findings indicate that the one-size-fits-all risk-cutoff value of 1/270, commonly used in DS screening, should be revisited and alternative (possibly age-based) cutoff values and strategies should be considered. (c) 2017 John Wiley & Sons, Ltd. PMID- 28654733 TI - Target-directed Dynamic Combinatorial Chemistry: A Study on Potentials and Pitfalls as Exemplified on a Bacterial Target. AB - Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors of pharmacologically relevant targets. In this contribution, we present an application for a bacterial target, the lectin FimH, a crucial virulence factor of uropathogenic E. coli being the main cause of urinary tract infections. A small dynamic library of acylhydrazones was formed from aldehydes and hydrazides and equilibrated at neutral pH in presence of aniline as nucleophilic catalyst. The major success factors turned out to be an accordingly adjusted ratio of scaffolds and fragments, an adequate sample preparation prior to HPLC analysis, and the data processing. Only then did the ranking of the dynamic library constituents correlate well with affinity data. Furthermore, as a support of DCC applications especially to larger libraries, a new protocol for improved hit identification was established. PMID- 28654735 TI - Controlling Regioselectivity in the Enantioselective N-Alkylation of Indole Analogues Catalyzed by Dinuclear Zinc-ProPhenol. AB - The enantioselective N-alkylation of indole and its derivatives with aldimines is efficiently catalyzed by a zinc-ProPhenol dinuclear complex under mild conditions to afford N-alkylated indole derivatives in good yield (up to 86 %) and excellent enantiomeric ratio (up to 99.5:0.5 e.r.). This method tolerates a wide array of indoles, as well as pyrrole and carbazole, to afford the corresponding N alkylation products. The reaction can be run on a gram scale with reduced catalyst loading without impacting the efficiency. The chiral aminals were further elaborated into various chiral polyheterocyclic derivatives. The surprising stability of the chiral N-alkylation products will open new windows for asymmetric catalysis and medicinal chemistry. PMID- 28654736 TI - Maternal chromosome Xp deletion identified by prenatal cell-free DNA screening. PMID- 28654734 TI - Can a rapid measure of self-exposure to drugs of abuse provide dimensional information on depression comorbidity? AB - BACKGROUND AND OBJECTIVES: Addictions to heroin or to cocaine are associated with substantial psychiatric comorbidity, including depression. Poly-drug self exposure (eg, to heroin, cocaine, cannabis, or alcohol) is also common, and may further affect depression comorbidity. METHODS: This case-control study examined the relationship of exposure to the above drugs and depression comorbidity. Participants were recruited from methadone maintenance clinics, and from the community. Adult male and female participants (n = 1,201) were ascertained consecutively by experienced licensed clinicians. The instruments used were the SCID-I, and Kreek-McHugh-Schluger-Kellogg (KMSK) scales, which provide a rapid dimensional measure of maximal lifetime self-exposure to each of the above drugs. This measure ranges from no exposure to high unit dose, high frequency, and long duration of exposure. RESULTS: A multiple logistic regression with stepwise variable selection revealed that increasing exposure to heroin or to cocaine was associated greater odds of depression, with all cases and controls combined. In cases with an opioid dependence diagnosis, increasing cocaine exposure was associated with a further increase in odds of depression. However, in cases with a cocaine dependence diagnosis, increasing exposure to either cannabis or alcohol, as well as heroin, was associated with a further increase in odds of depression. DISCUSSION AND CONCLUSIONS: This dimensional analysis of exposure to specific drugs provides insights on depression comorbidity with addictive diseases, and the impact of poly-drug exposure. SCIENTIFIC SIGNIFICANCE: A rapid analysis of exposure to drugs of abuse reveals how specific patterns of drug and poly-drug exposure are associated with increasing odds of depression. This approach detected quantitatively how different patterns of poly-drug exposure can result in increased odds of depression comorbidity, in cases diagnosed with opioid versus cocaine dependence. (Am J Addict 2017;26:632-639). PMID- 28654737 TI - The problem of elimination of HCV infections in Poland AB - The article concerns abbreviated presentation of the results obtained in the Project KIK / 35 "Prevention of HCV infection," sponsored by the Government of the Swiss Federation and the Ministry of Health of the Republic of Poland. The Project concerned the analysis of the prevalence of HCV infection in the adult population in Poland, the risk factors and groups at risk of these infections. Two sub-projects were related to separate subpopulations: pregnant women and drug users. Research in one sub-project focused on the hazards of HCV infections in medical institutions and non-medical facilities, where the procedures are performed with the interruption of tissue. In all sub-projects were carried out surveys, which served to check the knowledge ofn HCV infections, but also practical measures aimed at preventing these infections. One of the sub projects KIK / 35 "Education of medical staff and nonmedical as a key element in the prevention of blood-borne infections" was devoted entirely to the education of professionals responsible for the proper, safety, performance of procedures running withinterruption of tissues."The results of these studies revealed significant shortcomings in the detection of existing infections and large gaps in knowledge about prevention. Taking into account the range of expertise needed, it turned out that the lack of information applies to both the general public and to many professionals. The project KIK / 35 in its summary refers to the risks of HCV infection, both known from the literature and disclosed the specificity of our country. The ultimate result of the Project NCI / 35 is to develop a strategy for the elimination of HCV infections in Poland. This strategy, strongly linked to the WHO strategy includes integrated, permanent preventive measures related tot he introduction of screening programs for early detection of HCV infections and treat them as important element in prevention. Special emphasis was put on universal access to diagnosis and treatment for all social groups. PMID- 28654738 TI - Measles elimination - review of event notifications sent to National IHR Focal Point between 2010 and 2016 AB - The Member States of the World Health Organization (WHO) in accordance with International Health Regulations (2005) were obliged to appoint National IHR Focal Points (N IHR FP), of which tasks include obtaining information concerning public health emergencies of international concern which occurred abroad or within the country.The aim of this work is the review of WHO, ECDC, National IHR Focal Points from the WHO Member States and The State Sanitary Inspection notifications related to measles received by National IHR Focal Point in Poland in the period from 2010 to 2016.During this period N IHR FP was informed about 79 events related to measles. These events include: 36 related to the outbreaks in different countries, 27 concerning individual cases, 14 related to the exposure in contact with a measles case during air travel and two concerning the implementation of the MMR vaccination programs. Despite the progress in implementing the measures included in the elimination of measles programs in Europe, there was a significant increase in the number of measles cases and outbreaks particularly in years 2010-2011. PMID- 28654739 TI - Poliomyelitis eradication - the review of notifications from the years 2010-2016 sent to National IHR Focal Point AB - Polio eradication programme was launched after World Health Assembly in 1988. Despite considerable decrease in reported cases it still constitutes a significant public health threat. All WHO member state is bound to appoint National IHR Focal Point, which operates based on International Health Regulations (2005), which were enacted during the World Health Assembly in 2005. In Poland National IHR Focal Point (IHR NFP in Poland) operates since 2007, and is located in the Department of Epidemiology, in National Institute of Public Health - National Institute of Hygiene. Its aim is to acquire, assess and to transfer information on events which may constitute an international threat for the public health. IHR NFP in Poland has an access to WHO's Event Information Site (EIS) as well as Early Warning and Response System (EWRS) with reading-only credentials. Both platforms are of limited access (1). Among recipients of IHR NFP notifications and information are experts from many fields such as epidemiology, virology, bacteriology and others- related to specific type of notification, as well as specific and appointed members of state's administration and authorities in the field of public health. In this paper a review of notifications on the subject of poliomyelitis, sent to IHR NFP in Poland in the years 2010-2016 is presented, as well as references to poliomyelitis epidemiological situation were made based on the date from Global Polio Eradication Initiative. PMID- 28654740 TI - Evaluation of knowledge and use of the malaria prevention measures among the patients of the Department of Tropical and Parasitic Diseases University Center of Maritime and Tropical Medicine, Gdynia, based on a questionnaire performed in the years 2012-20 AB - INTRODUCTION: Every year, approximately 125 million travelers visit areas where malaria prevails, located in over 100 countries. Over 10,000 of them suffer from malaria annually. Visitors to these areas may protect themselves against infection by using chemoprophylaxis, insect repellents, appropriate clothing, sleeping in airconditioned and well-screened quarters or using mosquito nets impregnated with insecticides. AIM OF THE STUDY: The aim of this study was to gather and analyze the data about knowledge and usage of pharmacological and non pharmacological malaria prevention methods among the patients of the University Centre for Maritime and Tropical Medicine (UCMMiT), Gdynia, Poland, in 2012-2013. MATERIAL AND METHODS: A survey was conducted among 245 patients hospitalized in the Department of Tropical and Parasitic Diseases, UCMMiT in Gdynia, Poland in 2012 - 2013. The only criterion for inclusion was a sojourn and consent for participation in the study. The questionnaire included questions concerning mainly the use of chemoprophylaxis, opinion on the medication used for prophylaxis, side effects during its usage, the non-pharmacological prevention methods used against insect bites. RESULTS: Due to travel destination, malaria chemoprophylaxis should have been recommended for 73 (30%) individuals prior to the travel. It should not have been recommended for the group of 129 patients reporting long-term sojourns (over a year) and for 43 persons (17%) due to their travel to non-endemic countries. In fact, chemoprophylaxis in the "recommended" group was used by 32 persons which constituted 44%, while in the "long sojourn" group prophylaxis was used by 7 persons and in the "not recommended group" by 1 person. The number of people who reported proper use of chemoprophylaxis (an appropriate drug and mode of usage) amounted to 26 (36%) in the "recommended" group. Among bite prevention methods, usage of window mosquito nets was reported by 154 people (63%), bed mosquitonets by 39 (16%), insect repellents by 52 (21%) and insecticides by 52 (21%) patients. Adverse effects associated with chemoprophylaxis were reported by 10 persons (26%) but none of them stopped taking the medication. CONCLUSIONS: In spite of the availability of information on the Internet and the access to pre-travel medical counseling, the knowledge of correct prophylaxis against malaria among the people traveling to tropical countries is still unsatisfactory, leading to increased risk of Plasmodium infections. Better understanding of prophylaxis rules among travelers may increase usage of non-pharmacological methods and highlight the factors affecting usage of prevention methods. PMID- 28654741 TI - Intestinal parasites in stool samples and perianal swabs examined by The Voivodeship Sanitary-Epidemiological Station in Bydgoszcz between 2000-2014 AB - INTRODUCTION: Epidemiological conditions are changing due to the modifications in human behavior and environment. Parasitic diseases are most often caused by intestinal parasites. The frequency of Echinococcus multilocularis and tropical diseases increases in Poland. AIM OF STUDY: Analysis of intestinal parasites' occurrence in stool samples and perianal swabs tested in Medical Diagnostics Department of The Voivodeship Sanitary-Epidemiological Station in Bydgoszcz between 2000-2014. MATERIAL AND METHODS: 24 609 fecal samples and perianal swabs were tested using microscopic method for intestinal parasites' presence and immunoenzymatic method (ELISA) for Giardia intestinalis presence. The study population was sorted into four groups according to age. RESULTS: Prevalence of intestinal parasites in persons tested over 2000-2014 period ranged between 2.15% - 7.04%. The most common invasive parasite was Enterobius vermicularis, especially among children between 3-7 years (64.58%). In the same time period the most prevalent pathogenic intestinal parasite in adults (>16 years) was Giardia intestinalis (65.81%). CONCLUSIONS: 1. The prevalence of intestinal parasites infection changes depending on the number of tests carried out. The number of infections may be underestimated given that the testing encompassed only a part of population. A need for more thorough examination exists. 2. Enterobius vermicularis infection was most often found in children between 3-7 years, mainly from specific communities (kindergartens, orphanages). PMID- 28654742 TI - The safety and effectiveness of vaccination against influenza and pertussis in pregnant women AB - In recent years a large amount of data has become available with regard to vaccinating women during pregnancy against influenza and against pertussis. The data comes from observational studies conducted when vaccine was administered as a part of a vaccination campaign, retrospective evaluations of databases and surveillance of the adverse post-vaccination events. Popularization of knowledge about the importance of immunization in this group and educating pregnant women about vaccination should be an essential element of health promotion and prevention programs. PMID- 28654743 TI - Territorial differences in years of life lost due to premature mortality in inhabitants of Poland AB - INTRODUCTION: Reduction of social and territorial differences with regards to health of a population is one of the most crucial global problems of public health. An analysis of years of life lost focuses on social and economic aspects of premature mortality. AIM: The aim of the study is to analyze territorial differences in years of life lost due to premature mortality in inhabitants of various regions of Polan d, according to the most important causes of death, with consideration given to classification categories of ICD-10. METHODS: The study material included a database which contained information gathered from 387,312 death certificates of inhabitants of Poland in 2013. The SEYLLp index (Standard Expected Years of Life Lost per living person) was used to calculate standard expected years of life lost. RESULTS: The absolute number of years of life lost in inhabitants of Poland for the year 2013 was 4,168,256 in males and 2,536,447 in females, which corresponded to 2,237 years per 10,000 males and 1,277 per 10,000 females. Inhabitants of the Lodz Province are characterized with the highest number of years of life lost (2,858 years per 10,000 males and 1,544 per 10,000 females), whereas inhabitants of the Subcarpathian Province are characterized with the lowest number of years of life lost (1,833 years per 10,000 males and 1,039 per 10,000 females). In the male group, the highest SEYLLp values were contributed by: ischemic heart disease (217 years), malignant neoplasms of the trachea, bronchi and lungs (175 years) and cardiac insufficiency (156 years), whereas in the female group, the causes included: cerebral diseases (106 years), cardiac insufficiency (105 years) and ischemic heart disease (103 years) CONCLUSIONS: There are huge territorial differences in Poland with regards to a number of years of life lost. Thus, there is a need to continue studies in order to find an explanation for these differences and gradually eliminate them. PMID- 28654744 TI - Mimicking an Enzyme-Based Colorimetric Aptasensor for Antibiotic Residue Detection in Milk Combining Magnetic Loop-DNA Probes and CHA-Assisted Target Recycling Amplification. AB - A mimicking-enzyme-based colorimetric aptasensor was developed for the detection of kanamycin (KANA) in milk using magnetic loop-DNA-NMOF-Pt (m-L-DNA) probes and catalytic hairpin assembly (CHA)-assisted target recycling for signal amplification. The m-L-DNA probes were constructed via hybridization of hairpin DNA H1 (containing aptamer sequence) immobilized magnetic beads (m-H1) and signal DNA (sDNA, partial hybridization with H1) labeled nano Fe-MIL-88NH2-Pt (NMOF-Pt sDNA). In the presence of KANA and complementary hairpin DNA H2, the m-L-DNA probes decomposed and formed an m-H1/KANA intermediate, which triggered the CHA reaction to form a stable duplex strand (m-H1-H2) while releasing KANA again for recycling. Consequently, numerous NMOF-Pt-sDNA as mimicking enzymes can synergistically catalyze 3,3',5,5'-tetramethylbenzidine (TMB) for color development. The aptasensor exhibited high selectivity and sensitivity for KANA in milk with a detection limit of 0.2 pg mL-1 within 30 min. The assay can be conveniently extended for on-site screening of other antibiotics in foods by simply changing the base sequence of the probes. PMID- 28654745 TI - Efficient Cancer Regression by a Thermosensitive Liposome for Photoacoustic Imaging-Guided Photothermal/Chemo Combinatorial Therapy. AB - The capacity to specifically destroy cancer cells while avoiding normal tissue is urgently desirable in cancer treatment. Herein, a photothermal-trigger-released system serves as a photoacoustic imaging agent constructed by entrapping diketopyrrolopyrrole-based conjugated polymers and curcumin in a poly(ethylene glycol) (PEG)-protected thermoresponsive liposomal phospholipid bilayer. This lipid nanostructure can improve the bioavailability of hydrophobic agents for photothermal treatment with high efficiency and deliver the anticancer drug curcumin to the tumor site actuated by near-infrared (NIR) irradiation. A significantly enhanced combined therapeutic effect to HepG2 tumor-bearing mice was acquired in contrast to the result of single therapy alone. These liposomes with the capability of photoacoustic imaging, greater EPR-induced accumulation in tumor sites, and hyperthermia ablation for photothermal chemotherapy show potential for photoacoustic imaging-guided photothermal/chemo combined therapeutic applications. PMID- 28654746 TI - Single Electron Delivery to Lewis Pairs: An Avenue to Anions by Small Molecule Activation. AB - Single electron transfer (SET) reactions are effected by the combination of a Lewis acid (e.g., E(C6F5)3 E = B or Al) with a small molecule substrate and decamethylferrocene (Cp*2Fe). Initially, the corresponding reactions of (PhS)2 and (PhTe)2 were shown to give the species [Cp*2Fe][PhSB(C6F5)3] 1 and [Cp*2Fe][(MU-PhS)(Al(C6F5)3)2] 2 and [Cp*2Fe][(MU-PhTe)(Al(C6F5)3)2] 3, respectively. Analogous reactions with di-tert-butyl peroxide yielded [Cp*2Fe][(MU-HO)(B(C6F5)3)2] 4 with isobutene while with benzoyl peroxide afforded [Cp*2Fe][PhC(O)OE(C6F5)3] (E = B 5, Al 6). Evidence for a radical pathway was provided by the reaction of Ph3SnH and p-quinone afforded [Cp*2Fe][HB(C6F5)3] 7 and [Cp*2Fe]2[(MU-O2C6H4)(E(C6F5)3)2] (E = B 8, Al 9). In addition, the reaction of TEMPO with Lewis acid and Cp*2Fe afforded [Cp*2Fe][(C5H6Me4NOE(C6F5)3] (E = B 10, Al 11). Finally, reactions with O2, Se, Te and S8 gave [Cp*2Fe]2[((C6F5)2Al(MU-O)Al(C6F5)3)2]2 12, [Cp*2Fe]2[((C6F5)2Al(MU-Se)Al(C6F5)3)2]2 13, [Cp*2Fe][(MU-Te)2(Al(C6F5)2)3] 14 and [Cp*2Fe]2[(MU-S7)B(C6F5)3)2] 15, respectively. The mechanisms of these SET reactions are discussed, and the ramifications are considered. PMID- 28654747 TI - Confining Sulfur in N-Doped Porous Carbon Microspheres Derived from Microalgaes for Advanced Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) battery is one of the most attractive candidates for the next-generation energy storage system. However, the intrinsic insulating nature of sulfur and the notorious polysulfide shuttle are the major obstacles, which hinder the commercial application of Li-S battery. Confining sulfur into conductive porous carbon matrices with designed polarized surfaces is regarded as a promising and effective strategy to overcome above issues. Herein, we propose to use microalgaes (Schizochytrium sp.) as low-cost, renewable carbon/nitrogen precursors and biological templates to synthesize N-doped porous carbon microspheres (NPCMs). These rational designed NPCMs can not only render the sulfur-loaded NPCMs (NPCSMs) composites with high electronic conductivity and sulfur content, but also greatly suppress the diffusion of polysulfides by strongly physical and chemical adsorptions. As a result, NPCSMs cathode demonstrates a superior reversible capacity (1030.7 mA h g-1) and remarkable capacity retention (91%) at 0.1 A g-1 after 100 cycles. Even at an extremely high current density of 5 A g-1, NPCSMs still can deliver a satisfactory discharge capacity of 692.3 mAh g-1. This work reveals a sustainable and effective biosynthetic strategy to fabricate N-doped porous carbon matrices for high performance sulfur cathode in Li-S battery, as well as offers a fascinating possibility to rationally design and synthesize novel carbon-based composites. PMID- 28654748 TI - Preparation of Poly(styrene)-b-poly(acrylic acid)-Coupled Carbon Dots and Their Applications. AB - Carbon dots (CDs) are covalently coupled to the poly(acrylic acid) (PAA) block of polystyrene-b-poly(acrylic acid) (PS-b-PAA). The produced amphiphilic PS-b-PAA-CD shows excellent solubility and micellar formation in selective solvents. Transmission electron microscopy study shows that the micelle of PS-b-PAA-CD in water (a PAA-selective solvent) has a strawberry-like shape with the CDs as patches on the PAA corona surface although that in toluene (a PS-selective solvent) has a reversed shape with the CDs in the core. The fluorescence intensity of PS-b-PAA-CD in water is approximately twice that in toluene because the close contacts between the CDs in the core of the micelle lead to decreased fluorescence intensity due to pi-pi interactions. Thus, PS-b-PAA-CD can be used in sensors via fluorescence quenching through morphology control of micelle by solvent selectivity. The PS-b-PAA-CD aqueous solution is successfully used as an fluorescent ink for inkjet printing and fluorescent fillers for poly(methyl methacrylate) (PMMA) composites. The quantum yields of the CDs in pure CD, PS-b PAA-CD, and a PMMA/PS-b-PAA-CD composite were almost the same (~41%). Because of its good solubility in organic solvents and self-assembly property in solution, the application scope of PS-b-PAA-CD can be further expanded in the future. PMID- 28654749 TI - A General Route for Nanoemulsion Synthesis Using Low-Energy Methods at Constant Temperature. AB - The central dogma of nanoemulsion formation using low-energy methods at constant temperature-popularly known as the emulsion inversion point (EIP) method-is that to create O/W nanoemulsions, water should be added to a mixture of an oil and surfactant. Here, we demonstrate that the above order of mixing is not universal and a reverse order of mixing could be superior, depending on the choice of surfactant and liquid phases. We propose a more general methodology to make O/W as well as W/O nanoemulsions by studying the variation of droplet size with the surfactant hydrophilic-lypophilic balance for several model systems. Our analysis shows that surfactant migration from the initial phase to the interface is the critical step for successful nanoemulsion synthesis of both O/W and W/O nanoemulsions. On the basis of our understanding and experimental results, we utilize the reverse order of mixing for two applications: (1) crystallization and formulation of pharmaceutical drugs with faster dissolution rates and (2) synthesis of alginate-based nanogels. The general route provides insights into nanoemulsion formation through low-energy methods and also opens up possibilities that were previously overlooked in the field. PMID- 28654750 TI - Combining Static and Dynamical Approaches for Infrared Spectra Calculations of Gas Phase Molecules and Clusters. AB - Four models for the calculation of the IR spectrum of gas phase molecules and clusters from molecular dynamics simulations are presented with the aim to reduce the computational cost of the usual Fourier transform (FT) of the time correlation function of the dipole moment. These models are based on the VDOS, FT of time correlation function of velocities, and atomic polar tensors (APT). The models differ from each other by the number of APTs inserted into the velocities correlation function. Excellent accuracy is achieved by the model adopting a weighted linear combination of a few selected APTs adapted for the rotation of the molecule (model D). The achieved accuracy relates to band positions, band shapes, and band intensities. Depending on the degree of actual dynamics of the molecule, rotational motion, conformational isomerization, and large amplitude motions that can be seen during the finite temperature trajectory, one could also apply one of the other models (models A, B, or C), but with caution. Model D is therefore found simple and accurate, with appealing computational cost and should be systematically applied. Its generalization to condensed phase systems should be straightforward. PMID- 28654751 TI - Substrate Recognition Mechanism of the Putative Yeast Carnosine N methyltransferase. AB - Anserine (beta-alanyl-N(Pi)-methyl-l-histidine) is a natural metabolite present in skeletal muscle and the central nervous system of vertebrates and plays important physiological roles in living organisms. The production of anserine is catalyzed by carnosine N-methyltransferases, which transfer a methyl group to carnosine (beta-alanyl-l-histidine). However, the structural basis of the substrate recognition for the enzymes is unknown. We present the crystal structure of the putative carnosine N-methyltransferase from yeast named YNL092W in complex with SAH, solved by the single-wavelength anomalous dispersion (SAD) method. The protein contains a typical Rossmann domain and a characteristic N terminal helical domain. At the cofactor-binding site, SAH forms an extensive interaction network with the enzyme. The individual contribution of each residue to ligand affinity and enzyme activity was assessed by ITC and methyltransferase assays after mutagenesis of the key residues. Additionally, docking studies and activity assays were conducted in order to identify the binding site for carnosine, and a plausible complex model was proposed. Furthermore, we discovered that two disulfide bridges might be functionally important to the enzyme. By comparison to structure- and sequence-similar methyltransferases, we deduce that the enzyme most likely acts on a protein substrate. Our structural analyses shed light on the catalytic mechanism and substrate recognition by YNL092W. PMID- 28654752 TI - In Silico Prediction of the Toxic Potential of Lupeol. AB - Lupeol is a natural triterpenoid found in many plant species such as mango. This compound is the principal active component of many traditional herbal medicines. In the past decade, a considerable number of publications dealt with lupeol and its analogues due to the interest in their pharmacological activities against cancer, inflammation, arthritis, diabetes, and heart disease. To identify further potential applications of lupeol and its analogues, it is necessary to investigate their mechanisms of action, particularly their interaction with off target proteins that may trigger adverse effects or toxicity. In this study, we simulated and quantified the interaction of lupeol and 11 of its analogues toward a series of 16 proteins known or suspected to trigger adverse effects employing the VirtualToxLab. This software provides a thermodynamic estimate of the binding affinity, and the results were challenged by molecular-dynamics simulations, which allow probing the kinetic stability of the underlying protein-ligand complexes. Our results indicate that there is a moderate toxic potential for lupeol and some of its analogues, by targeting and binding to nuclear receptors involved in fertility, which could trigger undesired adverse effects. PMID- 28654753 TI - Surface Inclusion of Unidirectional Molecular Motors in Hexagonal Tris(o phenylene)cyclotriphosphazene. AB - A new unidirectional light-driven molecular motor suitable for host-guest surface inclusion complexes with tris(o-phenylene)cyclotriphosphazene (TPP) was synthesized. The motor molecules formed regular two-dimensional trigonal arrays covering the large facets of disc-shaped TPP nanocrystals. Photochemical and thermal isomerization studies demonstrated that the light-driven rotation of the anchored motors is similar to that observed in solution and is not compromised neither by either the surface confinement or the density of surface coverage (50 vs 100%). PMID- 28654754 TI - Potential Strategies to Target Protein-Protein Interactions in the DNA Damage Response and Repair Pathways. AB - This review article discusses some insights about generating novel mechanistic inhibitors of the DNA damage response and repair (DDR) pathways by focusing on protein-protein interactions (PPIs) of the key DDR components. General requirements for PPI strategies, such as selecting the target PPI site on the basis of its functionality, are discussed first. Next, on the basis of functional rationale and biochemical feasibility to identify a PPI inhibitor, 26 PPIs in DDR pathways (BER, MMR, NER, NHEJ, HR, TLS, and ICL repair) are specifically discussed for inhibitor discovery to benefit cancer therapies using a DNA damaging agent. PMID- 28654757 TI - Overthrowing barriers to empathy in healthcare: empathy in the age of the Internet. PMID- 28654756 TI - Hydrogels with a Memory: Dual-Responsive, Organometallic Poly(ionic liquid)s with Hysteretic Volume-Phase Transition. AB - We report on the synthesis and structure-property relations of a novel, dual responsive organometallic poly(ionic liquid) (PIL), consisting of a poly(ferrocenylsilane) backbone of alternating redox-active, silane-bridged ferrocene units and tetraalkylphosphonium sulfonate moieties in the side groups. This PIL is redox responsive due to the presence of ferrocene in the backbone and also exhibits a lower critical solution temperature (LCST)-type thermal responsive behavior. The LCST phase transition originates from the interaction between water molecules and the ionic substituents and shows a concentration dependent, tunable transition temperature in aqueous solution. The PIL's LCST type transition temperature can also be influenced by varying the redox state of ferrocene in the polymer main chain. As the polymer can be readily cross-linked and is easily converted into hydrogels, it represents a new dual-responsive materials platform. Interestingly, the as-formed hydrogels display an unusual, strongly hysteretic volume-phase transition indicating useful thermal memory properties. By employing the dispersing abilities of this cationic PIL, CNT hydrogel composites were successfully prepared. These hybrid conductive composite hydrogels showed bi-stable states and tunable resistance in heating-cooling cycles. PMID- 28654755 TI - Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C-H Bonds. AB - The use of copper in directed C-H oxidation has been relatively underexplored. In a seminal example, Schonecker showed that copper and O2 promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu2O2 intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCuII(OOR) intermediate undergoes homolytic O-O cleavage to generate reactive RO* species, which are responsible for key C-H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield. PMID- 28654758 TI - Looking into a whale's heart: investigating a genetic basis for cardiomyopathy in a non-model species. AB - Understanding the pathogenesis of complex diseases can benefit from multi-species comparative studies. Yet these studies rarely include natural populations of non model species. Here, we focused on the cause of a heart muscle disease, cardiomyopathy (CM), affecting multiple mammalian species including humans, cats, dogs, and certain species of whales. Mutations in genes coding for sarcomeric proteins have been identified as a leading cause for CM in humans, and some were also revealed to be responsible for CM in cats. We investigated whether similar mutations could be detected in the deep-diving pygmy sperm whale (Kogia breviceps), which is one of two cetacean species known to display CM. We sequenced portions of two candidate genes (MYH7: 3153 bp and MYBPC3: 3019 bp) in 55 whales including affected and unaffected individuals. Mutation screening revealed six nonsynonymous substitutions that were predicted to have an effect on protein function. However, the etiology of CM is likely complex and probably multi-factorial as three of these mutations were observed in unaffected individuals from our control group. This incomplete penetrance could be partly age-related and could also be due to the influence of environmental factors on the development of CM, as seen in humans. PMID- 28654759 TI - Taurine reverses sodium fluoride-mediated increase in inflammation, caspase-3 activity, and oxidative damage along the brain-pituitary-gonadal axis in male rats. AB - Excessive exposure to fluoride is associated with male reproductive dysfunction in humans and animals. Taurine (2-aminoethane sulfonic acid) is a free intracellular beta-amino acid with antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of taurine on fluoride-induced reproductive toxicity has not been reported. The present study investigated the influence of taurine on sodium fluoride (NaF)-induced functional changes along the brain-pituitary-gonadal axis in male rats. NaF was administered singly in drinking water at 15 mg.L-1 alone or orally co-administered by gavage with taurine at 100 and 200 mg.(kg body mass)-1 for 45 consecutive days. Results showed that taurine significantly prevented NaF-induced increase in oxidative stress indices as well as augmented antioxidant enzymes activities and glutathione level in the brain, testes, and epididymis of the treated rats. Moreover, taurine reversed NaF-induced elevation in inflammatory biomarkers and caspase-3 activity as well as histological damage in the brain, testes, and epididymis of the treated rats. The significant reversal of NaF-induced decreases in testosterone level and testicular activities of acid phosphatase, alkaline phosphatase, and lactate dehydrogenase by taurine was accompanied by enhancement of sperm functional characteristics in the treated rats. Taurine may be a possible chemopreventive candidate against reproductive dysfunction resulting from fluoride exposure. PMID- 28654760 TI - Gametocidal genes of Aegilops: segregation distorters in wheat-Aegilops wide hybridization. AB - Aegilops is a genus belonging to the family Poaceace, which have played an indispensible role in the evolution of bread wheat and continues to do so by transferring genes by wide hybridization. Being the secondary gene pool of wheat, gene transfer from Aegilops poses difficulties and segregation distortion is common. Gametocidal genes are the most well characterized class of segregation distorters reported in interspecific crosses of wheat with Aegilops. These "selfish" genetic elements ensure their preferential transmission to progeny at the cost of gametes lacking them without providing any phenotypic benefits to the plant, thereby causing a proportional reduction in fertility. Gametocidal genes (Gc) have been reported in different species of Aegilops belonging to the sections Aegilops (Ae. geniculata and Ae. triuncialis), Cylindropyrum (Ae. caudata and Ae. cylindrica), and Sitopsis (Ae. longissima, Ae. sharonensis, and Ae. speltoides). Gametocidal activity is mostly confined to 2, 3, and 4 homeologous groups of C, S, S1, Ssh, and Mg genomes. Removal of such genes is necessary for successful alien gene introgression and can be achieved by mutagenesis or allosyndetic pairing. However, there are some instances where Gc genes are constructively utilized for development of deletion stocks in wheat, improving genetic variability and chromosome engineering. PMID- 28654761 TI - Obstructive Post-tracheotomy Granulation Tissue. PMID- 28654762 TI - Jatropha-6(17),11E-diene class derivatives induce apoptosis effects in OVCAR-3 and Caov-4 ovarian cancer cell lines via a mitochondrial pathway. AB - We investigated the molecular mechanism of apoptosis induced by novel jatropha 6(17),11E-diene class derivatives, compounds A, B, and C that were extracted from Euphorbia osyridea Boiss, in the ovarian cancer cell lines Caov-4 and OVCAR-3. The OVCAR-3 and Caov-4 cell lines were treated with different concentrations of these compounds. Cytotoxicity was evaluated using MTT, clonogenic survival assay, and flow cytometry assays. The production of reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsim), and the activity of caspase 3 and 9 were evaluated. Compounds A, B, and C reduced cell viability in a dose-dependent manner (P < 0.05). The IC50 values were calculated as 46.27 +/- 3.86, and 38.81 +/- 3.30 MUmol/L for compound A, 36.48 +/- 3.18 and 42.59 +/- 4.50 MUmol/L for compound B, and 85.86 +/- 6.75 and 75.65 +/- 2.56 MUmol/L for compound C against the Caov-4 and OVCAR-3 cell lines, respectively. Apoptosis evaluation showed that jatrophane derivatives increase both early and late apoptosis (P < 0.01). These compounds also increased ROS generation, DeltaPsim, and the activity of caspase 3 and 9 in the treated cells. These results showed that compounds A and B have significant inhibitory effects on OVCAR-3 and Caov-4 proliferation and induction of apoptosis. PMID- 28654763 TI - Effect of tolbutamide on tetraethylammonium-induced postsynaptic zinc signals at hippocampal mossy fiber-CA3 synapses. AB - The application of tetraethylammonium (TEA), a blocker of voltage-dependent potassium channels, can induce long-term potentiation (LTP) in the synaptic systems CA3-CA1 and mossy fiber-CA3 pyramidal cells of the hippocampus. In the mossy fibers, the depolarization evoked by extracellular TEA induces a large amount of glutamate and also of zinc release. It is considered that zinc has a neuromodulatory role at the mossy fiber synapses, which can, at least in part, be due to the activation of presynaptic ATP-dependent potassium (KATP) channels. The aim of this work was to study properties of TEA-induced zinc signals, detected at the mossy fiber region, using the permeant form of the zinc indicator Newport Green. The application of TEA caused a depression of those signals that was partially blocked by the KATP channel inhibitor tolbutamide. After the removal of TEA, the signals usually increased to a level above baseline. These results are in agreement with the idea that intense zinc release during strong synaptic events triggers a negative feedback action. The zinc depression, caused by the LTP-evoking chemical stimulation, turns into potentiation after TEA washout, suggesting the existence of a correspondence between the observed zinc potentiation and TEA-evoked mossy fiber LTP. PMID- 28654764 TI - Deep Proteome Profiling Reveals Common Prevalence of MZB1-Positive Plasma B Cells in Human Lung and Skin Fibrosis. AB - RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets. OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across end-stage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis. METHODS: We collected samples of ILD tissue (n = 45) and healthy donor control samples (n = 10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n = 6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging. MEASUREMENTS AND MAIN RESULTS: We determined the abundance of more than 7,900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteomic comparison of lung and skin fibrosis identified a common upregulation of marginal zone B- and B1-cell-specific protein (MZB1), the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG and negatively with diffusing capacity of the lung for carbon monoxide. CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1-positive plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis. PMID- 28654765 TI - A Traffic Light Grading System of Hip Dysplasia to Predict the Success of Arthroscopic Hip Surgery. AB - BACKGROUND: The role of hip arthroscopic surgery in dysplasia is controversial. PURPOSE: To determine the 7-year joint preservation rate after hip arthroscopic surgery in hip dysplasia and identify anatomic and intraoperative features that predict the success of hip preservation with arthroscopic surgery, allowing the formulation of an evidence-based classification system. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Between 2008 and 2013, 111 hips with dysplastic features (acetabular index [AI] >10 degrees and/or lateral center-edge angle [LCEA] <25 degrees ) that underwent arthroscopic surgery were identified. Clinical, radiological, and operative findings and the type of procedure performed were reviewed. Radiographic evaluations of the operated hip (AI, LCEA, extrusion index) were performed. Outcome measures included whether the hip was preserved (ie, did not require arthroplasty) at follow-up and the preoperative and postoperative Non-Arthritic Hip Score (NAHS) and Hip disability and Osteoarthritis Outcome Score (HOOS). The AI and LCEA were calculated, factored by a measure of articular wear (AIf and LCEAf, respectively), according to the University College Hospital, London (UCL) grading system as follows: AIf = AI * (number of UCL wear zones + 1), and LCEAf = LCEA / (number of UCL wear zones + 1). A contour plot of the resulting probability value of failure for every combination of AIf and LCEAf allowed for the determination of the zones with the lowest and highest incidences of failure to preserve the hip. RESULTS: The mean AI and LCEA were 9.8 degrees and 18.0 degrees , respectively. At a mean follow up of 4.5 years (range, 0.4-8.3 years), 33 hips had failed, requiring hip arthroplasty. The 7-year joint survival rate was 68%. The mean improvements in the NAHS and HOOS were 11 ( P = .001) and 22.8 ( P < .001) points, respectively. The zone with the greatest chance of joint preservation (odds ratio, 10; P < .001) was the green zone, with an AIf of 0 degrees to 15 degrees and an LCEAf of 15 degrees to 25 degrees ; in contrast, the zone with the greatest chance of failure (odds ratio, 10; P < .001) was the red zone, with an AIf of 20 degrees to 100 degrees and an LCEAf of 0 degrees to 10 degrees . CONCLUSION: Overall, the 7-year hip survival rate in hip dysplasia appears inferior compared with that reported in femoroacetabular impingement (78%). Hip arthroscopic surgery is associated with an excellent chance of hip preservation in mild dysplasia (green zone: AI = 0 degrees -15 degrees , LCEA = 15 degrees -25 degrees ) and no articular wear. The authors advise that the greatest caution should be used when considering arthroscopic options in cases of severe dysplasia (red zone: AI >20 degrees and/or LCEA <10 degrees ). PMID- 28654766 TI - Methotrexate-Related Lymphoproliferative Disorder in Patients With Osteonecrosis of the Jaw: A 3-Case Report and Literature Review. AB - Patients with immunodeficiency or immunosuppression are at risk of developing a lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD, which in up to 50% cases occurs in extranodal sites. The occurrence of MTX related LPD with osteonecrosis of the jaw (ONJ) has rarely been reported. Moreover, there are no clear diagnostic criteria and treatment strategies for management of these lesions. In the present cases, discontinuing MTX and debridement of the necrotic bone were effective. This report describes 3 cases of MTX-related LPD in patients with longstanding rheumatoid arthritis (RA) who presented with ONJ. The first patient was a 74-year-old man with RA who had received treatment with MTX for 7 years before presenting with ONJ and submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient was a 67-year old man who had been treated with MTX for more than 15 years. In all 3 cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (Epstein-Barr virus [EBV], CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV-driven T-cell, B-cell, and Hodgkin-like LPD. All 3 patients recovered after cessation of MTX and surgical debridement. Biopsy examination, diagnostic immunohistochemistry using lymphoid immune markers, and imaging studies using computed tomography, magnetic resonance imaging, and positron emission tomographic computed tomography were useful for the correct diagnosis of this condition. PMID- 28654767 TI - Melanoma Metastasis to the Mandible-Case Report and Comprehensive Literature Review. AB - With the incidence of melanoma increasing yearly, there is a need for heightened awareness of its metastatic potential and for screening with appropriate referral for identification of pre-metastatic lesions. Melanoma has a 16- to 25-month period to metastasize from a localized disease to one with a median survival no longer than 12 months once metastasis occurs. Nearly one third of oral metastases are found to be the first indication of occult malignancy from a distant site. This report describes the case of a 54-year-old woman with a longstanding undiagnosed acral lentiginous melanoma with metastasis to the maxillofacial region. She underwent resection and died 7 months later. The authors analyzed case reports and the current literature for biological mechanisms of metastasis, risk factors, clinical presentation, classifications, staging, treatment modalities, prognosis, and current therapy modalities. PMID- 28654768 TI - Systematic Review of Sexual and Reproductive Health Care Content in Nursing Curricula. AB - OBJECTIVE: To examine whether and to what extent pre-licensure nursing programs include sexual and reproductive health (SRH) content in their curricula. DATA SOURCES: Electronic databases, including CINAHL, MEDLINE, PubMed, Web of Science, Science Direct, Google Scholar, ProQuest, and CAB Direct were searched for relevant literature. We also reviewed the reference lists of all studies, nursing organization Web sites, and the personal files of the authors. STUDY SELECTION: Inclusion criteria were studies focused on SRH content in pre-licensure nursing education, written in English, and published between January 1990 and November 2016. We identified 632 articles, and of these, 22 met the inclusion criteria. Duplicates were discarded, and 13 articles were reviewed (9 quantitative descriptive, 2 modified Delphi, 2 mixed methods). DATA EXTRACTION: Data extraction and subsequent analysis were guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted and organized under the following headings: author and year to establish a historical timeline, study purpose and design, sample size, data collection methods, main study findings, and limitations. DATA SYNTHESIS: We found the following: (a) most studies focused on baccalaureate education; if associated degree programs were reviewed, findings were not reported separately; (b) definitions were not consistent, which affected the scope of study results; (c) the SRH topics taught were similar; (d) there is a recent interest in sexual orientation and gender identity curriculum; (e) barriers to including content were time constraints, competing demands with other curriculum priorities, and a need for creative curriculum tools. CONCLUSION: Documentation of SRH content in pre-licensure nursing education is limited. Faculty should conduct ongoing evaluation of their curricular strategies and clinical experiences and publish results in the literature. PMID- 28654769 TI - Structural and functional characterization of the triticale (x Triticosecale Wittm.) phytocystatin TrcC-8 and its dimerization-dependent inhibitory activity. AB - Phytocystatins are a group of proteins with significant potential to regulate activities of cysteine proteinases of native and pest/pathogen origins. The two domain triticale (x Triticosecale Wittm.) phytocystatin TrcC-8 was characterized in this study. This protein belongs to the second group of phytocystatins and contains all the conserved sequences and motifs as well as both N-terminal (CY) and C-terminal (CY-L) domains that are characteristic of phytocystatins with the C-terminal extension. We demonstrated that TrcC-8 forms stable dimers with a significantly reduced inhibitory activity against papain compared to the activity of monomers, indicating the regulatory nature of the oligomerization. Moreover, according to our research, only the N-terminal domain possesses the ability to form dimers, indicating that this part of TrcC-8 is involved in the dimerization of the full-length protein. Homology modelling of TrcC-8 strongly suggests distinct specificities for the CY and CY-L domains, confirmed in experiments with inhibition of the papain. Our results suggest that the CY domain of TrcC-8 may, although markedly weakly and suboptimally, interact with papain in an analogous mode to tarocystatin, while the CY-L domain of TrcC-8 has distinct specificity than tarocystatin. PMID- 28654770 TI - MD-2 regulates LPS-induced NLRP3 inflammasome activation and IL-1beta secretion by a MyD88/NF-kappaB-dependent pathway in alveolar macrophages cell line. AB - Myeloid differentiation protein 2 (MD-2) is required in the recognition of lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and participates in LPS induced alveolar macrophage (AM) inflammation during acute lung injury (ALI). Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome aggravates inflammation in LPS-induced ALI. However, there is currently little known about the relationship between MD-2 signaling and the NLRP3 inflammasome. This study showed that NLRP3 expression, IL-1beta (IL-1beta) secretion, and pyroptosis were up-regulated after LPS stimulation in the NR8383 AM cell-line. MD-2 gene knock-down reduced LPS-induced mRNA and protein expression of NLRP3 and IL-1beta secretion in NR8383 cells, and inhibited the MyD88/NF-kappaB signaling pathway. Conversely, over-expression of MD-2 not only heightened NLRP3, MyD88, and NF-kappaB p65 protein expression, it also aggravated the LPS-induced inflammatory response. Furthermore, the NF-kappaB inhibitor SN50 had a beneficial role in decreasing NLRP3 and caspase-1 mRNA and protein expression. The observations suggest that MD-2 helps to regulate LPS-induced NLRP3 inflammasome activation and the inflammatory response in NR8383 cells, and likely does so by affecting MyD88/NF-kappaB signaling. PMID- 28654771 TI - Trajectories of social anxiety, cognitive reappraisal, and mindfulness during an RCT of CBGT versus MBSR for social anxiety disorder. AB - : Cognitive-Behavioral Group Therapy (CBGT) and Mindfulness-Based Stress Reduction (MBSR) are efficacious in treating social anxiety disorder (SAD). It is not yet clear, however, whether they share similar trajectories of change and underlying mechanisms in the context of SAD. This randomized controlled study of 108 unmedicated adults with generalized SAD investigated the impact of CBGT vs. MBSR on trajectories of social anxiety, cognitive reappraisal, and mindfulness during 12 weeks of treatment. CBGT and MBSR produced similar trajectories showing decreases in social anxiety and increases in reappraisal (changing the way of thinking) and mindfulness (mindful attitude). Compared to MBSR, CBGT produced greater increases in disputing anxious thoughts/feelings and reappraisal success. Compared to CBGT, MBSR produced greater acceptance of anxiety and acceptance success. Granger Causality analyses revealed that increases in weekly reappraisal and reappraisal success predicted subsequent decreases in weekly social anxiety during CBGT (but not MBSR), and that increases in weekly mindful attitude and disputing anxious thoughts/feelings predicted subsequent decreases in weekly social anxiety during MBSR (but not CBGT). This examination of temporal dynamics identified shared and distinct changes during CBGT and MBSR that both support and challenge current conceptualizations of these clinical interventions. CLINICALTRIALS. GOV IDENTIFIER: NCT02036658. PMID- 28654772 TI - Evidence for the presence of cell-surface-bound and intracellular bactericidal toxins in the dinoflagellate Heterocapsa circularisquama. AB - Heterocapsa circularisquama, a harmful dinoflagellate, has multiple haemolytic toxins that are considered to be involved in the toxic mechanism against shellfish and certain species of zooplankton. To evaluate the further nature of the toxins of H. circularisquama, we investigated its effects on several species of bacteria. By colony formation assay, we found that H. circularisquama had antibacterial activity toward the marine bacterium Vibrio alginolyticus in a cell density-dependent manner. When the inoculated bacterial cells were co-cultured with H. circularisquama under dinoflagellate cell culture conditions, the bacterial growth was significantly suppressed, whereas the number of live bacterial cells increased when cultured in the medium alone. Since the cell-free culture supernatant and the ruptured dinoflagellate cell suspension showed no toxic effects on V. alginolyticus, it is speculated that direct cell-to-cell contact mediated by the live dinoflagellate cells may be the major toxic mechanism. The decrease in bactericidal activity of theca-removed dinoflagellate cells may further support this speculation. H. circularisquama also showed bactericidal activities towards Escherichia coli and Staphylococcus aureus. In the dinoflagellate/bacteria co-culture system, the number of live bacterial cells declined with increasing incubation time. Light-dependent antibacterial activity of the ruptured dinoflagellate cells against S. aureus was observed, whereas no such activity was detected against E. coli. These results suggest that intracellular photosensitising bactericidal toxins, which were previously found to be porphyrin derivatives, may have specificity towards gram-positive bacteria. Based on these results together with previous studies, it is obvious that H. circularisquama possesses antibacterial activity, which may be mediated through toxins located on its cell surface. It is likely that such toxins play a role in the defence mechanism against predators and infectious bacteria. Although the exact biological significance of intracellular photosensitising toxins is still unclear, such toxins may have potential to be developed as novel photo controllable antibiotics. PMID- 28654773 TI - Increased anxiety and fear memory in adult mice lacking type 2 deiodinase. AB - A euthyroid state in the brain is crucial for its adequate development and function. Impairments in thyroid hormones (THs; T3 or 3,5,3'-triiodothyronine and T4 or thyroxine) levels and availability in brain can lead to neurological alterations and to psychiatric disorders, particularly mood disorders. The thyroid gland synthetizes mainly T4, which is secreted to circulating blood, however, most actions of THs are mediated by T3, the transcriptionally active form. In the brain, intracellular concentrations of T3 are modulated by the activity of type 2 (D2) and type 3 (D3) deiodinases. In the present work, we evaluated learning and memory capabilities and anxiety-like behavior at adult stages in mice lacking D2 (D2KO) and we analyzed the impact of D2-deficiency on TH content and on the expression of T3-dependent genes in the amygdala and the hippocampus. We found that D2KO mice do not present impairments in spatial learning and memory, but they display emotional alterations with increased anxiety-like behavior as well as enhanced auditory-cued fear memory and spontaneous recovery of fear memory following extinction. D2KO mice also presented reduced T3 content in the hippocampus and decreased expression of the T3-dependent gene Dio3 in the amygdala suggesting a hypothyroid status in this structure. We propose that the emotional dysfunctions found in D2KO mice can arise from the reduced T3 content in their brain, which consequently leads to alterations in gene expression with functional consequences. We found a downregulation in the gene encoding for the calcium-binding protein calretinin (Calb2) in the amygdala of D2KO mice that could affect the GABAergic transmission. The current findings in D2KO mice can provide insight into emotional disorders present in humans with DIO2 polymorphisms. PMID- 28654774 TI - FKBP5 moderation of the relationship between childhood trauma and maladaptive emotion regulation strategies in adolescents. AB - Maladaptive emotion regulation strategies, such as rumination and catastrophizing, are transdiagnostic risk factors for psychopathology. FK506 binding protein 51 (FKBP5) has been found to moderate the relationship between stressful life events and various psychiatric disorders. Given the cross-disorder moderation effect of FKBP5 at the diagnostic level, the aim of the current study was to examine whether the relationship between exposure to childhood trauma and transdiagnostic maladaptive emotion regulation processes would also be moderated by genetic FKBP5 variation in a community sample of adolescents. We hypothesized that adolescent carriers of the FKBP5 CATT haplotype composed of rs9296158, rs3800373, rs1360780, and rs9470080, that has been associated with increased risk for psychiatric disorders in adulthood, would also show higher levels of rumination and catastrophizing. Participants included 1345 genotyped adolescents (Mage=13.95, 64.2% female; 100% European Caucasians of Portuguese descent) who completed self-report measures on exposure to childhood trauma and emotion regulation strategies. Genotypes of rs9296158, rs3800373, rs1360780, and rs9470080 were used to estimate the CATT haplotype (carriers versus non carriers). Consistent with our hypotheses and previous findings, adolescent CATT haplotype carriers with higher levels of childhood trauma endorsed higher levels of both rumination and catastrophizing compared to non-carriers. Given the association of these maladaptive emotion regulation processes and psychiatric disorders, the findings suggest possible psychological mechanisms why FKBP5 haplotype carriers exposed to childhood trauma are more vulnerable to developing a psychiatric disorder later in life. PMID- 28654775 TI - Hepatitis B virus reactivation among hepatitis C patients treated with direct acting antiviral therapies in routine clinical practice. AB - BACKGROUND: Hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients treated with IFN-free direct acting antiviral (DAA) therapies has recently emerged as a potential risk. Given the potential burden of this issue, further data are needed to establish its actual clinical impact. OBJECTIVES: The aim of the present study was to analyze the occurrence of HBV reactivation in a cohort of CHC patient treated with DAAs in routine clinical practice. STUDY DESIGN: Consecutive CHC patients with different genotypes, treated with DAA between January 2015 and January 2016 were included in the study. Subjects had been tested for HBsAg and anti-HBc antibodies before antiviral therapy. HBV-DNA levels were examined in anti-HBc positive patients at baseline and 24 weeks after the end of treatment. Post-treatment HBsAg determination was performed in case of HBV DNA positivity. Serum anti-HBs kinetics was analysed in anti-HBs and anti-HBc positive subjects. RESULTS: A cohort of 137 consecutive HCV patients treated with IFN-free regimens in routine clinical practice was evaluated. From this cohort, plasma samples of 44 subjects with positive serology for HBV (anti-HBc positive) were tested for HBV-DNA levels at baseline and 24 weeks after the end of treatment. Two of them were HBsAg-positive, while the others had signs of a past HBV exposure (HBsAg-negative+/-HBsAb-positive). No reactivation was found in HBcAb-positive and HBsAg-negative subjects. In the two HBsAg-positive, one experienced an increase in HBV-DNA levels of >=2 log10 IU/mL during treatment. However, the reactivation was without clinical impact and, most important, was followed by HBsAg loss. CONCLUSIONS: Based on our experience, a past HBV infection seems not to be a condition predisposing to HBV reactivation. On the contrary, in HBsAg-positive subjects not in suppressive treatment with nucleos(t)ide analogs, regular monitoring of HBV-DNA during and after DAA treatment should be considered. PMID- 28654776 TI - Proximity alert! Distance related cuneus activation in military veterans with anger and aggression problems. AB - Problems involving anger and aggression are common after military deployment, and may involve abnormal responses to threat. This study therefore investigated effects on neural activation related to threat and escapability among veterans with deployment experience. Twenty-seven male veterans with anger and aggression problems (Anger group) and 30 Control veterans performed a virtual predator-task during fMRI measurement. In this task, threat and proximity were manipulated. The distance of cues determined their possibility for escape. Cues signaled impending attack by zooming in towards the participant. If Threat cues, but not Safe cues, reached the participants without being halted by a button press, an aversive noise (105dB scream) was presented. In both the Threat and the Safe condition, closer proximity of the virtual predator resulted in stronger activation in the cuneus in the Anger versus Control group. The results suggest that anger and aggression problems are related to a generalized sensitivity to proximity rather than preparatory processes related to task-contingent aversive stimuli. Anger and aggression problems in natural, dynamically changing environments may be related to an overall heightened vigilance, which is non-adaptively driven by proximity. PMID- 28654778 TI - A new platform for serological analysis based on porous 3-dimensional polyethylene sinter bodies. AB - A new sensitive and selective platform, three-dimensional immunosensor, has been developed for a rapid serological diagnosis; detection of a Borrelia infection was considered as a model assay. The immunosensor is based on a 3-dimensional (3D) porous solid surface (sinter body) with dimensions of 2*2.5mm where a recombinant variable lipoprotein surface-exposed protein (VlsE; Borrelia-antigen) is immobilized by different techniques. The sinter body served as a robust and inexpensive carrier, which facilitated a successful hydrophobic adsorption as well as covalent immobilization of the antigen with sufficient amounts of on the surface. Because of sinter body's porosity, the detection could be performed in an immune affinity flow system based on a little disposable plastic column. The flow of reagents through the column is advantageous in terms of reducing the non specific interaction and shortening the test time. Furthermore, three labels were tested for a colorimetric detection: i) a horseradish peroxidase (HRP) labeled secondary antibody, ii) nanoparticles based on Sudan IV, and iii) gold nanoparticles modified with protein A. HRP secondary labeled antibody provides the most sensitive test, 1000 fold dilution of serum sample can be clearly detected in only 20min. Gold nanoparticles modified with protein A were used as a direct label or as a catalyst for reduction of silver ions. Direct detection with gold nanoparticles provides short time of analysis (5min) while detection of metallic silver required longer time (12min) but with improved sensitivity. Nanoparticles based on Sudan IV showed high background and were less favorable. The assay is distinctive because of the rapid analysis time with all used labels, longest 20min. Compared to classical serological methods for Borrelia diagnosis, the developed method offers a simple, rapid and reliable tool of analysis with minimal cost and can be easily transferred to other infectious diseases. PMID- 28654777 TI - A study of associations among attachment patterns, maltreatment, and behavior problem in institutionalized children in Japan. AB - The present study investigates the relationships among children's history of maltreatment, attachment patterns, and behavior problems in Japanese institutionalized children. Twenty-nine children (12 boys and 17 girls) from three different institutions in the Kinki area (Western part of Japan) participated in this study. Their average age was 6. 41-years (ranging from 4 to 10). Thirteen of the children (44.8%) had history of maltreatment before they were institutionalized. Children's attachment was assessed by the Attachment Doll Play Assessment (George & Solomon, 1990, 1996, 2000). The child's main caregiver answered the Child Behavior Checklist (CBCL; Archenbach, 1991) to identify children's behavior problems. Results indicated a significant relationship between maltreatment history and attachment pattern. The relationship between attachment pattern and behavior problem was also confirmed. Implications and limitations of this study were discussed. PMID- 28654779 TI - Liquid chromatographic enantioseparation of carbocyclic beta-amino acids possessing limonene skeleton on macrocyclic glycopeptide-based chiral stationary phases. AB - Polar-ionic and reversed-phase high-performance liquid chromatographic separations of limonene-based cyclic beta-amino acid enantiomers were carried out by using macrocyclic glycopeptide-based chiral selectors applying Chirobiotic T, TAG and R columns. The effects of additives, concentration of the co- and counter ions and the temperature in polar-ionic mobile phase systems were studied. The influence of pH, MeOH content and alcohol additives were investigated in the reversed-phase mode. The difference in the change in standard enthalpy Delta(DeltaH degrees ), entropy Delta(DeltaS degrees ), and free energy Delta(DeltaG degrees ) was calculated from the linear van't Hoff plots derived from the ln alpha vs 1/T curves in the temperature range 5-40 degrees C. Unusual temperature behavior was observed on Chirobiotic TAG for most of the analytes: decreased retention times were accompanied with increased separation factors with increasing temperature, and separation was entropically-driven. For two of the studied analytes enthalpically-driven enantioseparations were observed. The elution sequence was determined in all cases, but no general rule could be established. PMID- 28654780 TI - Development and validation of an ICP-MS method for the determination of elemental impurities in TP-6076 active pharmaceutical ingredient (API) according to USP <232>/<233>. AB - The new guidelines of the United States pharmacopeia (USP), European pharmacopeia (EP) and international conference on harmonization (ICH) regulating elemental impurities limits in pharmaceuticals signify the end of unspecific analysis of metals as outlined in USP <231>. The new guidelines specify both daily doses and concentration/limits of elemental impurities in pharmaceutical final products, active pharmaceutical ingredients (API) and excipients. In chapter USP <233> method implementation, validation and quality control during the analytical process are described. We herein report the use of a stabilising matrix that overcomes low spike recovery problem encountered with Os and allows the determination of all USP required elemental impurities (As, Cd, Hg, Pb, V, Cr, Ni, Mo, Cu, Pt, Pd, Ru, Rh, Os and Ir) in a single analysis. The matrix was used in the validation of a method to determine elemental impurities in TP-6076 active pharmaceutical ingredient (API) by ICP-MS according to the procedures defined in USP<233> and to GMP requirements. This validation will support the regulatory submission of TP-6076 which is a novel tetracycline analogue effective against the most urgent multidrug-resistant gram-negative bacteria. Evaluation of TP-6076 in IND-enabling toxicology studies has led to the initiation of a phase 1 clinical trial. PMID- 28654781 TI - Comparison of SEC and CE-SDS methods for monitoring hinge fragmentation in IgG1 monoclonal antibodies. AB - Fragmentation of monoclonal antibodies is a critical quality attribute routinely monitored to assess the purity and integrity of the product from development to commercialization. Cleavage in the upper hinge region of IgG1 monoclonal antibodies is a common fragmentation pattern widely studied by size exclusion chromatography (SEC). Capillary electrophoresis with sodium dodecylsulfate (CE SDS) is a well-established technique commonly used for monitoring antibody fragments as well, but its comparability to SEC in monitoring hinge fragments has not been established until now. We report a characterization strategy that establishes the correlation between hinge region fragments analyzed by SEC and CE SDS. Monoclonal antibodies with elevated hinge fragments were generated under low pH stress conditions and analyzed by SEC and CE-SDS. The masses of the fragments generated were determined by LC-MS. Electrophoretic migration of the hinge fragmentation products in CE-SDS were determined based on their mass values. Comparative assessment of fragments by SEC, and CE-SDS showed similar correlation with incubation time. This study demonstrates that CE-SDS can be employed as a surrogate technique to SEC for monitoring hinge region fragments. Most importantly, combination of these techniques can be used to obtain comprehensive understanding of fragment related characteristics of therapeutic protein products. PMID- 28654782 TI - Revisiting blood-brain barrier: A chromatographic approach. AB - Drugs designed to reach a pharmacological CNS target must be effectively transported across the blood-brain barrier (BBB), a thin monolayer of endothelial cells tightly attached together between the blood and the brain parenchyma. Because of the lipidic nature of the BBB, several physicochemical partition models have been studied as surrogates for the passive permeation of potential drug candidates across the BBB (octanol-water, alkane-water, PAMPA...). In the last years, biopartition chromatography is gaining importance as a noncellular system for the estimation of biological properties in early stages of drug development. Microemulsions (ME) are suitable mobile phases, because of their ease of formulation, stability and adjustability to a large number of compositions mimicking biological structures. In the present work, several microemulsion liquid chromatographic (MELC) systems have been characterized by means of the Abraham's solvation parameter model, in order to assess their suitability as BBB distribution or permeability surrogates. In terms of similarity between BBB and MELC systems (dispersion forces arising from solute non-bonded electrons, dipolarity/polarizability, hydrogen-bond acidity and basicity, and molecular volume), the passive permeability surface area product (log PS) for neutral (including zwitterions), fully and partially ionized drugs was found to be well correlated with the ME made of 3.3% SDS (w/v; surfactant) 0.8% heptane (w/v; oil phase) and 6.6% 1-butanol (w/v; co-surfactant) in 50mM aqueous phosphate buffer, pH 7.4. PMID- 28654783 TI - Fibulins and matrilins are novel structural components of the periodontium in the mouse. AB - Periodontitis refers to inflammatory disease of the periodontal structures (the gingiva, dental cementum, periodontal ligament (PDL) and alveolar bone) that ultimately leads to their destruction. Whereas collagens are well-examined main components of the periodontium, little is known about the other structural proteins that make up this tissue. The aim of this study was to identify new extracellular matrix (ECM) components, including fibulins and matrilins, in the periodontium of mice. After sacrificing 14 mice (Sv/129 strain), jaws were prepared. Each tissue sample contained a molar and its surrounding alveolar bone. Immunohistochemistry was carried out on paraffin-embedded sections. Our results show that mice exhibit fibulin-3, -4 and -5 and matrilin-1, -2, -3 and -4 in PDL and in blood vessels of alveolar bone and PDL as well as in the pericellular matrix of osteocytes and cementocytes. In dental cementum, only fibulin-4 is expressed. For the first time, we show that fibulin-3, -4 and -5 and matrilin-1, 2, -3 and -4 are essential components of the periodontal tissues. Our findings indicate an association of these proteins with collagens and oxytalan fibers that might be of future interest in regenerative periodontitis therapy. PMID- 28654784 TI - Generation and characterization of a human oral squamous carcinoma cell line SCC 9 with CRISPR/Cas9-mediated deletion of the p75 neurotrophin receptor. AB - OBJECTIVE: To investigate the importance of the p75 neurotrophin receptor (p75NTR) in human tongue squamous carcinoma cells, we exploited the CRISPR/Cas9 technology to establish a p75NTR-knockout SCC-9 cell line and to explore the effect on biological functions. MATERIALS AND METHODS: The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas9) system was used to generate genomic deletion mutants of p75NTR in the tongue squamous carcinoma cell lines SCC-9. Single-guide RNA (sgRNA) sequences were designed to target the p75NTR genomic sequence and were cloned into plasmid pGK1.1. The linearized vector was electroporated into SCC-9 cells and p75NTR deletion was confirmed using CruiserTM enzyme digestion and PCR amplification. SCC-9 clones with successful deletion of p75NTR were identified and verified by sequencing and selected for functional testing in cell proliferation, invasion, migration, and colony-forming assays. RESULTS: Compared with control cells, p75NTR-knockout SCC-9 cells showed significantly diminished abilities to proliferate, invade, migrate, and form colonies, indicating a reduction in pro tumorigenic behavior. CONCLUSION: These data demonstrate, first, that the CRISPR/Cas9 system is a simplified method for generating p75NTR knockouts with relatively high efficiency, and second, that deletion of p75NTR suppresses several tumor-promoting properties of SCC-9 cells, suggesting that p75NTR is a potential target for the development of novel therapies for tongue cancer. PMID- 28654785 TI - Global incidence of oral and oropharynx cancer in patients younger than 45 years versus older patients: A systematic review. AB - Head and neck squamous cell carcinoma (HNSCC) is typically regarded as a disease of elderly people. However, increasing numbers of patients worldwide with HNSCC at younger age (defined as <45 years old) have been reported in recent years. To assess geographical variations and trends worldwide in incidence of oral and oropharyngeal cancer in young patients, a systematic review was conducted in PubMed and Google scholar databases from 1975 to June 2016. Seventy-eight studies were selected for further study. Nineteen population-based studies on incidence rate were available from 13 countries, showing a prominent increase over time except for the Netherlands. A notable rise of oral (mobile) tongue cancer among white women and oropharyngeal cancer in white men was observed. Data suggest that cancer in young patients may be a distinct clinical entity and characterised by different aetiology and pathogenesis. Additionally, the relative proportion of oral and oropharyngeal cancer in young patients to total incidence revealed a significant difference between estimates from North America (5.5%) and both Africa (17.2%) and Middle East (14.5%). It is concluded that (i) a rising trend in oral and oropharynx cancers is observed in young patients worldwide; (ii) incidence studies should properly define outcomes in age cohorts and use a consensus cut-off for young patients; (iii) more population-based studies should be performed in non-Western regions to get accurate global measures of incidence for these cancers in young subpopulations and (iv) there is an urge to identify new aetiological factors in these young patients. PMID- 28654786 TI - L-proline-based deep eutectic solvents (DESs) for deep catalytic oxidative desulfurization (ODS) of diesel. AB - A series of L-proline-based DESs was prepared through an atom economic reaction between L-proline (L-Pro) and four different kinds of organic acids. The DESs were characterized by Fourier transform infrared spectroscopy (FT-IR), H nuclear magnetic resonance (1HNMR), cyclic voltammogram (CV) and the Hammett method. The synthesized DESs were used for the oxidative desulfurization and the L-Pro/p toluenesultonic acid (L-Pro/p-TsOH) system shows the highest catalytic activity that the removal of dibenzothiophene (DBT) reached 99% at 60 degrees C in 2h, which may involve the dual activation of the L-Pro/p-TsOH. The acidity of four different L-proline-based DESs was measured and the results show that it could not simply conclude that the correlation between the acidity of DESs and desulfurization capability was positive or negative. The electrochemical measurements evidences and recycling experiment indicate a good stability performance of L-Pro/p-TsOH in desulfurization. This work will provide a novel and potential method for the deep oxidation desulfurization. PMID- 28654787 TI - Remediation of soils polluted with lindane using surfactant-aided soil washing and electrochemical oxidation. AB - In this work the complete treatment of soil spiked with lindane is studied using surfactant-aided soil-washing (SASW) to exhaust lindane from soil and electrolysis with diamond anodes to mineralize lindane from the soil washing fluid (SWF) waste. Results demonstrated that this technological approach is efficient and allow to remove this hazardous pollutant from soil. They also pointed out the significance of the ratio surfactant/soil in the efficiency of the SASW process and in the performance of the later electrolysis used to mineralize the pollutant. Larger values of this parameter lead to effluents that undergo a very efficient treatment which allows the depletion of lindane for applied charges lower than 15AhL-1 and the recovery of more than 70% of the surfactant for the regeneration of the SWF. PMID- 28654788 TI - Highly selective and efficient removal of arsenic(V), chromium(VI) and selenium(VI) oxyanions by layered double hydroxide intercalated with zwitterionic glycine. AB - In this study, a new strategy for highly selective and extremely efficient removal of toxic oxyanions (Cr(VI), Se(VI), and As(V)) from aqueous solutions using zwitterionic glycine intercalated layered double hydroxide (Gly-LDH) was reported. Hence, to investigate the effect of zwitterionic glycine on the adsorption capacity, selectivity factor and adsorption mechanism of LDHs, two NiAl LDHs intercalated with different inter-layer anions, including NO3- and glycine, were synthesized. The obtained results show that the adsorption capacity and selectivity factor of oxyanions through ion exchange mechanism in NO3-LDH is lower than Gly-LDH. Gly-LDH displayed a selectivity order of Se(VI)0.14MUg/L) was higher than the local reference values at all sampling points and in both seasons. Ordination analysis (PCA) highlighted As and Cu elements in the water. PERMANOVA showed that the metals behaved differently in the water throughout the monitored season and between sampling points. The sites with mining activity were the regions that were the most contaminated by metals. Samples of sediment (Ni>18mg/kg and Cr>37.30mg/kg) and soil (Pb>72mg/kg, Cr>75mg/kg and Ni>30mg/Kg) showed concentrations above the recommended by local legislation. Metal values in the muscle of both fish species were relatively low at all sampling points and in both monitored seasons. Concentrations in water, sediment, and soil showed that some points of the Xingu River, Fresco River and mining pits are contaminated by trace elements, mainly As, Hg, Cr, Pb, and Ni. This was the first study about trace elements in the Middle Xingu River, which leads us to conclude that rainfall and cassiterite mining activities strongly influence the mobilization of metals, especially in abiotic compartments. However, the fish analyzed did not exhibit relevant levels of contamination. This indicates low risk for human consumption. Additionally, results highlight the need to establish local criteria to define contamination limits for different metals while taking into account local geochemistry particularities and biome diversity. PMID- 28654811 TI - Return to running following knee osteochondral repair using an anti-gravity treadmill: A case report. AB - BACKGROUND: The purpose of this study was to assess the impact of an anti-gravity treadmill return to running programme on self-efficacy and subjective knee function following knee osteochondral surgery. CASE DESCRIPTION: A 39-year-old otherwise healthy female endurance runner with a left knee femoral cartilage grade 3-4 defect 3 cm2. The patient underwent single step arthroscopic microfracture with Bone Marrow Aspirate Concentrate. An AlterG(r) anti-gravity treadmill was used to manipulate loading during a graduated phased return to running over 8 weeks. Self-efficacy was evaluated using the Self-Efficacy for Rehabilitation outcomes scale (SER) and the Knee Self-Efficacy Scale (K-SES). Subjective knee function was evaluated using the Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee Subjective Knee Form (IKDC). OUTCOMES: The programme resulted in improvements in SER (57%), K-SES present (89%) and K-SES future (65%) self-efficacy domains. The IKDC score demonstrated a clinically important improvement with an increase from 62.1 in week 1-86.2 in week 8 (39%). Only the KOOS Sport/Rec subscale showed a clinically important improvement from week 1 to week 8. DISCUSSION: The programme resulted in improved knee and rehabilitation self-efficacy and subjective knee function following osteochondral repair of the knee. This case report illustrates the importance of considering self-efficacy in rehabilitation after knee osteochondral surgery and highlights the potential role for anti-gravity treadmills in enhancing self-efficacy and subjective knee function in preparation for a return to sport. PMID- 28654812 TI - The L for lb. Challenge. Evaluation of a novel, workplace-based peer-led weight management programme, 2014-2016. AB - OBJECTIVES: To evaluate the L for lb. Challenge, a novel country-wide, workplace based, peer-led weight management programme with participants from a range of private and public organisations in Northern Ireland. STUDY DESIGN: Pre- and post intervention studies. METHODS: The intervention was workplace-based, led by volunteer co-worker champions and based on the NHS Choices 12-week weight loss guide which incorporates dietary advice, physical activity, behaviour change methods and weekly weight monitoring. It operated from January to April in three consecutive years (2014-16). Overweight and obese adult workers were eligible. Training of peer champions involved two half-day workshops delivered by dieticians and physical activity professionals. Employers and/or participants pledged L1 to charity for every pound of weight lost. Weight was reported at enrolment and at either 12 weeks (2014) or at 12 weekly intervals (2015-16). Changes in weight and % weight, and body mass index were determined for all the participants and for gender and deprivation subgroups. RESULTS: There were 734, 1559 and 1513 eligible participants, and 21, 31 and 35 participating companies in 2014, 2015 and 2016, respectively. Engagement rates were 94% and 96% and completion rates were 70% and 71% in 2015 and 2016, respectively. Mean weight loss was 1.9 kg (2.2%; 2014), 2.5 kg (2.8%; 2015) and 2.4 kg (2.7%; 2016). The proportions losing >=5% initial bodyweight were 21% (2014), 24% (2015) and 26% (2016). Male participants were more than twice as likely as women to complete the programme (odds ratio: 2.5 [2015]; 2.2 [2016]) and to lose >=5% bodyweight (odds ratio: 2.5 [2015]; 3.7 [2016]). CONCLUSIONS: The L for lb. Challenge was an effective, low-cost health improvement intervention with meaningful weight loss for many participants, particularly male workers. With high levels of engagement and ownership, and successful collaboration between public health, voluntary bodies, private companies and public organisations, it is a novel workplace-based model with potential to expand. PMID- 28654813 TI - Conformational flexibility and base-pairing tendency of the tobacco carcinogen O6 [4-oxo-4-(3-pyridyl)butyl]guanine. AB - The present work uses DFT calculations to characterize the conformational and hydrogen-bonding properties of O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G), a DNA adduct caused by tobacco. POB-G is found to adopt many isoenergetic conformations that allow for discrete interactions between the bulky moiety and the adducted G and/or pairing base. The calculated structure and stability of the hydrogen-bonded pairs between the Watson-Crick or Hoogsteen face of POB-G and the canonical DNA nucleobases fully rationalize the previously reported mutational spectra. Specifically, the stable, non-distorted pseudo-Watson-Crick POB-G:T pair explains the predominant G?A mutations, while the stable, yet marginally distorted pairs between the Watson-Crick face of POB-G and A or C clarify the G?T mutations and non-mutagenic replication. Finally, the stable, yet highly distorted Hoogsteen POB-G:G pair rationalizes the experimentally-observed insertion but lack of persistence of G opposite POB-G in DNA. Overall, these structural insights are critical for guiding future studies that strive to fully understand the adduct mutagenicity, including the accessible conformations and the replication of POB-G-adducted DNA. PMID- 28654814 TI - An overview of the outcomes and impact of specialist and advanced nursing and midwifery practice, on quality of care, cost and access to services: A narrative review. AB - OBJECTIVES: This paper presents the results of a systematic rapid review and narrative synthesis of the literature of the outcomes and impact of specialist and advanced nursing and midwifery practice regarding quality of care, cost and access to services. DESIGN: A rapid review was undertaken of the relevant national and international literature, regulatory and policy documents relating to the establishment and definition of nurses' and midwives' specialist and advanced practice roles. DATA SOURCES: A search of the Cumulative Index to the Nursing and Allied Health Literature (CINAHL), PubMed (MEDLINE) was undertaken from 2012 to 2015. The study also included primary data collection on the perceived impact of specialist and advanced practice nursing and midwifery roles and enablers and barriers to these roles using semi-structured interviews. These are not included in this paper. REVIEW METHOD: To facilitate a systematic approach to searching the literature, the PICO framework, was adapted. RESULTS: The database search yielded 437 articles relevant to the analysis of specialist and advanced practice in relation to quality care, cost and access to services with additional articles added in a manual review of reference lists. In the final review a total of 86 articles were included as they fulfilled the eligibility criteria. CONCLUSION: The evidence presented in the 86 articles indicates that nursing and midwifery practitioners continue to be under-utilised despite the evidence that greater reliance on advanced nurse practitioners could improve accessibility of primary care services while also saving on cost. Results point to continued difficulties associated with accurate measurement of the impact of these roles on patient outcomes. This review demonstrates that there is a need for robust measurement of the impact of these roles on patient outcomes. PMID- 28654815 TI - Flipping around the classroom: Accelerated Bachelor of Science in Nursing students' satisfaction and achievement. AB - BACKGROUND: The flipped classroom approach is based on shared responsibility for learning by students and teachers, and empowers students to take an active role in the learning process. While utilization of this approach has resulted in higher exam scores compared to traditional approaches in prior studies, the flipped classroom has not included learners in Accelerated Bachelor of Science in Nursing (ABSN) programs. OBJECTIVE: To examine differences on exam scores and satisfaction of teaching between a 3-week flipped and traditional classroom approach. DESIGN: Mixed methods, crossover repeated measures design. SETTINGS: Private school of nursing located in the eastern United States. PARTICIPANTS: 76 ABSN students. METHODS: Two separate sections of a Pharmacology course received either 3-weeks of flipped or traditional classroom during Period 1, then switched approaches during Period 2. Two exam scores measuring knowledge and a questionnaire assessing satisfaction of teaching were collected. Focus groups were conducted to learn about students' experience in the flipped classroom. Descriptive statistics, Wilcoxon rank sum test, and stepwise linear mixed model were used to analyze quantitative data. Focus group data were transcribed, coded, and categorized in themes. RESULTS: Students in the flipped classroom achieved significantly higher scores on the first Pharmacology exam than students in the traditional classroom, but there was no significant difference on the second exam. Three themes emerged from focus groups on student perception of integrating the flipped approach: don't fix what isn't broken; treat me as an adult; and remember the work is overwhelming. CONCLUSIONS: Both traditional and flipped classroom approaches successfully prepared students for the Pharmacology exams. While results support the use of the flipped approach, judicious use of this instructional pedagogy with dense or difficult content, particularly in accelerated programs, is recommended. Instructors should also provide students with enough information and rationale for using the flipped classroom approach. PMID- 28654817 TI - The role of the hippocampus in recognition memory. AB - Many theories of declarative memory propose that it is supported by partially separable processes underpinned by different brain structures. The hippocampus plays a critical role in binding together item and contextual information together and processing the relationships between individual items. By contrast, the processing of individual items and their later recognition can be supported by extrahippocampal regions of the medial temporal lobes (MTL), particularly when recognition is based on feelings of familiarity without the retrieval of any associated information. These theories are domain-general in that "items" might be words, faces, objects, scenes, etc. However, there is mixed evidence that item recognition does not require the hippocampus, or that familiarity-based recognition can be supported by extrahippocampal regions. By contrast, there is compelling evidence that in humans, hippocampal damage does not affect recognition memory for unfamiliar faces, whilst recognition memory for several other stimulus classes is impaired. I propose that regions outside of the hippocampus can support recognition of unfamiliar faces because they are perceived as discrete items and have no prior conceptual associations. Conversely, extrahippocampal processes are inadequate for recognition of items which (a) have been previously experienced, (b) are conceptually meaningful, or (c) are perceived as being comprised of individual elements. This account reconciles findings from primate and human studies of recognition memory. Furthermore, it suggests that while the hippocampus is critical for binding and relational processing, these processes are required for item recognition memory in most situations. PMID- 28654816 TI - Successful non-native speech perception is linked to frequency following response phase consistency. AB - Some people who attempt to learn a second language in adulthood meet with greater success than others. The causes driving these individual differences in second language learning skill continue to be debated. In particular, it remains controversial whether robust auditory perception can provide an advantage for non native speech perception. Here, we tested English speech perception in native Japanese speakers through the use of frequency following responses, the evoked gamma band response, and behavioral measurements. Participants whose neural responses featured less timing jitter from trial to trial performed better on perception of English consonants than participants with more variable neural timing. Moreover, this neural metric predicted consonant perception to a greater extent than did age of arrival and length of residence in the UK, and neural jitter predicted independent variance in consonant perception after these demographic variables were accounted for. Thus, difficulties with auditory perception may be one source of problems learning second languages in adulthood. PMID- 28654818 TI - High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth. AB - Myxoid liposarcoma (MLS) is a soft tissue sarcoma characterized by a recurrent t(12;16) translocation. Although tumors are initially radio- and chemosensitive, the management of inoperable or metastatic MLS can be challenging. Therefore, our aim was to identify novel targets for systemic therapy. We performed an in vitro high-throughput drug screen using three MLS cell lines (402091, 1765092, DL-221), which were treated with 273 different drugs at four different concentrations. Cell lines and tissue microarrays were used for validation. As expected, all cell lines revealed a strong growth inhibition to conventional chemotherapeutic agents, such as anthracyclines and taxanes. A good response was observed to compounds interfering with Src and the mTOR pathway, which are known to be affected in these tumors. Moreover, BIRC5 was important for MLS survival because a strong inhibitory effect was seen at low concentration using the survivin inhibitor YM155, and siRNA for BIRC5 decreased cell viability. Immunohistochemistry revealed abundant expression of survivin restricted to the nucleus in all 32 tested primary tumor specimens. Inhibition of survivin in 402 91 and 1765-92 by YM155 increased the percentage S-phase but did not induce apoptosis, which warrants further investigation before application in the treatment of metastatic MLS. Thus, using a 273-compound drug screen, we confirmed previously identified targets (mTOR, Src) in MLS and demonstrate survivin as essential for MLS survival. PMID- 28654819 TI - The Expression of Connexins and SOX2 Reflects the Plasticity of Glioma Stem-Like Cells. AB - Glioblastoma (GBM) is the most malignant primary brain tumor, with an average survival rate of 15 months. GBM is highly refractory to therapy, and such unresponsiveness is due, primarily, but not exclusively, to the glioma stem-like cells (GSCs). This subpopulation express stem-like cell markers and is responsible for the heterogeneity of GBM, generating multiple differentiated cell phenotypes. However, how GBMs maintain the balance between stem and non-stem populations is still poorly understood. We investigated the GBM ability to interconvert between stem and non-stem states through the evaluation of the expression of specific stem cell markers as well as cell communication proteins. We evaluated the molecular and phenotypic characteristics of GSCs derived from differentiated GBM cell lines by comparing their stem-like cell properties and expression of connexins. We showed that non-GSCs as well as GSCs can undergo successive cycles of gain and loss of stem properties, demonstrating a bidirectional cellular plasticity model that is accompanied by changes on connexins expression. Our findings indicate that the interconversion between non GSCs and GSCs can be modulated by extracellular factors culminating on differential expression of stem-like cell markers and cell-cell communication proteins. Ultimately, we observed that stem markers are mostly expressed on GBMs rather than on low-grade astrocytomas, suggesting that the presence of GSCs is a feature of high-grade gliomas. Together, our data demonstrate the utmost importance of the understanding of stem cell plasticity properties in a way to a step closer to new strategic approaches to potentially eliminate GSCs and, hopefully, prevent tumor recurrence. PMID- 28654820 TI - The Potential Value of Preoperative MRI Texture and Shape Analysis in Grading Meningiomas: A Preliminary Investigation. AB - OBJECT: Preoperative knowledge of meningioma grade is essential for planning treatment and surgery. The purpose of this study was to investigate the diagnostic value of MRI texture and shape analysis in grading meningiomas. METHODS: A surgical database was reviewed to identify meningioma patients who had undergone tumor resection between January 2015 and December 2016. Preoperative MR images were retrieved and analyzed. Texture and shape analysis was conducted to quantitatively evaluate tumor heterogeneity and morphology. Three machine learning classifiers were trained with these features to build classification models. The performance of the features and classification models was assessed. RESULTS: A total of 131 patients were included in this study: 21 with high-grade meningiomas and 110 with low-grade meningiomas. Three texture features were selected: Horzl_RLNonUni, S(2,2)SumOfSqs, and WavEnHL_s-3; three shape features were selected: GeoFv, GeoW4, and GeoW5b. The Mann-Whitney test indicated that all six features were significantly different between high-grade and low-grade meningiomas. AUC values were generally greater than 0.50 (range, 0.73 to 0.88). Sensitivities and specificities ranged from 47.62% to 90.48% and 69.09% to 96.36%, respectively. Among the nine classification models obtained, the one built by training the SVM classifier with all six features achieved the best performance, with a sensitivity, specificity, diagnostic accuracy, and AUC of 0.86, 0.87, 0.87, and 0.87, respectively. CONCLUSIONS: Texture and shape analysis, especially when combined with a SVM classifier, can provide satisfactory performance in the preoperative determination of meningioma grade and is thus potentially useful for clinical application. PMID- 28654821 TI - Table talk: How mothers and adolescents across socioeconomic status discuss food. AB - This article reports findings from a qualitative study of food practices among families of differing socioeconomic circumstances. Using in-depth interviews from sixty-two families in the San Francisco Bay Area in 2015-2016, we find socioeconomic differences in how mothers and adolescents talk about food. Across SES, mothers and adolescents engage in discussions about healthy eating. However, these conversations are more commonplace and embedded within high-SES family life than among low-SES families. Beyond conversations about 1) healthy eating, the topics of 2) food quality and 3) price are discussed to varying degrees across SES. Within high-SES families, frequent discussions of healthy eating are paired with dialogue highlighting the importance of consuming higher quality food. Price is largely absent as a topic of conversation among high-SES families. On the other end of the socioeconomic spectrum, low-SES mothers and adolescents frequently engage in conversations about price when discussing food. Mentions of food quality are rare, but when they do occur, they underscore important trade offs between food's healthiness, quality and price. Given prior research showing the impact of dialogue between parents and adolescents on adolescents' dietary behaviors, these findings help us understand how family discussions contribute to shaping adolescents' approaches to food. An important implication is that high SES families' discussions of food quality may strengthen messages about healthy eating, while conversations about affordability within low-SES families may highlight financial barriers to healthy eating. PMID- 28654822 TI - Gender and the structure of self-rated health across the adult life span. AB - Despite the widespread use of self-rated health (SRH) in population health studies, the meaning of this holistic health judgment remains an open question. Gender differences in health, an issue of utmost importance in population research and policy, are often measured with SRH; the comparisons could be biased if men and women differ in how they form their health judgment. The aim of this study is to examine whether men and women differ in how health inputs predict their health rating across the adult life span. We use the 2002-2015 National Health Interview Survey data from US-born respondents aged 25-84. Ordered logistic models of SRH as a function of 24 health measures including medical conditions and symptoms, mental health, functioning, health care utilization, and health behaviors, all interacted with gender, test how the measures influence health ratings and the extent to which these influences differ by gender. Using a Bayesian approach, we then compare how closely a select health measure (K6 score) corresponds to SRH levels among men and women. We find little systematic gender difference in the structure of SRH: men and women use wide-ranging health-related frames of reference in a similar way when making health judgments, with some exceptions: mid-life and older men weigh physical functioning deficits and negative health behaviors more heavily than women. Women report worse SRH than men on average but this only holds through mid-adulthood and is reversed at older ages; moreover, the female disadvantage disappears when differences in socio economic and health covariates are considered. Our findings suggest that the meaning of SRH is similar for women and men. Both groups use a broad range of health-related information in forming their health judgment. This conclusion strengthens the validity of SRH in measuring gender differences in health. PMID- 28654823 TI - Supporting the role of community members employed as research staff: Perspectives of community researchers working in addiction research. AB - Community researchers are laypersons who conduct research activities in their own communities. In addiction and HIV research, community researchers are valued for their insider status and knowledge. At the same time, their presence on the research team raises concerns about coercion and confidentiality when community researchers and participants know each other personally, and the work of navigating between the worlds of research and community leads to moral distress and burnout for some community researchers. In this paper, we draw upon the concept of 'moral experience' to explore the local moral worlds of community researchers in the context of addiction research. In February and March 2010, we conducted focus groups with 36 community researchers employed on community-based addiction studies in the United States to elicit perspectives on ethical and moral challenges they face in their work and insights on best practices to support their role in research. Community researchers described how their values were realized or thwarted in the context of research, and their strategies for coping with shifting identities and competing priorities. They delineated how their knowledge could be used to inform development of research protocols and help principal investigators build and maintain trust with the community researchers on their teams. Our findings contribute to current understandings of the moral experiences of community members employed in research, and inform policies and practices for the growing field of community-engaged research. Funders, research organizations, and research ethics boards should develop guidelines and standards to ensure studies have key resources in place to support community researchers and ensure quality and integrity of community-engaged work. Investigators who work with community researchers should ensure channels for frontline staff to provide input on research protocols and to create an atmosphere where challenges and concerns can be openly and safely discussed. PMID- 28654824 TI - Visceral sensitivity, anxiety, and smoking among treatment-seeking smokers. AB - It is widely recognized that smoking is related to abdominal pain and discomfort, as well as gastrointestinal disorders. Research has shown that visceral sensitivity, experiencing anxiety around gastrointestinal sensations, is associated with poorer gastrointestinal health and related health outcomes. Visceral sensitivity also increases anxiety symptoms and mediates the relation with other risk factors, including gastrointestinal distress. No work to date, however, has evaluated visceral sensitivity in the context of smoking despite the strong association between smoking and poor physical and mental health. The current study sought to examine visceral sensitivity as a unique predictor of cigarette dependence, threat-related smoking abstinence expectancies (somatic symptoms and harmful consequences), and perceived barriers for cessation via anxiety symptoms. Eighty-four treatment seeking adult daily smokers (Mage=45.1years [SD=10.4]; 71.6% male) participated in this study. There was a statistically significant indirect effect of visceral sensitivity via general anxiety symptoms on cigarette dependence (b=0.02, SE=0.01, Bootstrapped 95% CI [0.006, 0.05]), smoking abstinence somatic expectancies (b=0.10, SE=0.03, Bootstrapped 95% CI [0.03, 0.19]), smoking abstinence harmful experiences (b=0.13, SE=0.05, Bootstrapped 95% CI [0.03, 0.25]), and barriers to cessation (b=0.05, SE=0.06, Bootstrapped 95% CI [0.01, 0.13]). Overall, the present study serves as an initial investigation into the nature of the associations between visceral sensitivity, anxiety symptoms, and clinically significant smoking processes among treatment-seeking smokers. Future work is needed to explore the extent to which anxiety accounts for relations between visceral sensitivity and other smoking processes (e.g., withdrawal, cessation outcome). PMID- 28654825 TI - Post-transcriptional regulation of the pluripotent state. AB - Pluripotency describes the developmental capacity to give rise to all cell types in the adult body. A comprehensive understanding of the molecular mechanisms that regulate pluripotency is important for both basic and translational research. While earlier studies mostly focused on signaling pathways, transcriptional regulation, and epigenetic modifications, recent investigations showed that RNA binding proteins, RNA processing machineries, and regulatory RNA molecules also play essential roles. Here, we provide a concise review on the latest findings and developments in post-transcriptional regulation of the pluripotent state. PMID- 28654826 TI - Idealised media images: The effect of fitspiration imagery on body satisfaction and exercise behaviour. AB - Recent studies have documented a shift in the cultural ideal of physical attractiveness, with women subscribing to a visibly toned ideal that emphasises health and fitness. The present study experimentally investigated the impact of athletic and muscular fitness-idealised images compared to traditional thin ideal images on women's body dissatisfaction and exercise behaviour, under the framework of Social Comparison Theory. Participants were 106 female undergraduate students randomly assigned to view one of three sets of images (thin ideal, athletic ideal, or muscular ideal) followed by a bout of exercise. Acute exposure to athletic ideal and thin ideal images led to increased body dissatisfaction, but exposure to muscular ideal images did not. Relative to thin ideal images, fitness-idealised images did not motivate participants to engage in higher levels of exercise suggesting that this type of fitness inspiration might not motivate actual exercise behaviour. PMID- 28654827 TI - Characterisation of the Medipix3 detector for 60 and 80keV electrons. AB - In this paper we report quantitative measurements of the imaging performance for the current generation of hybrid pixel detector, Medipix3, used as a direct electron detector. We have measured the modulation transfer function and detective quantum efficiency at beam energies of 60 and 80keV. In single pixel mode, energy threshold values can be chosen to maximize either the modulation transfer function or the detective quantum efficiency, obtaining values near to, or exceeding those for a theoretical detector with square pixels. The Medipix3 charge summing mode delivers simultaneous, high values of both modulation transfer function and detective quantum efficiency. We have also characterized the detector response to single electron events and describe an empirical model that predicts the detector modulation transfer function and detective quantum efficiency based on energy threshold. Exemplifying our findings we demonstrate the Medipix3 imaging performance recording a fully exposed electron diffraction pattern at 24-bit depth together with images in single pixel and charge summing modes. Our findings highlight that for transmission electron microscopy performed at low energies (energies <100keV) thick hybrid pixel detectors provide an advantageous architecture for direct electron imaging. PMID- 28654828 TI - Gated interference for time-resolved electron holography. AB - Pump-probe measurements of periodic processes require a temporal gating for the time-dependent signal. For this purpose we propose to take advantage of the sensitivity of interferometric techniques like electron holography to instabilities. We have realized such a gating by synchronized disturbances of the measurement setup and successfully conducted measurements of electric fields with microsecond time resolution. PMID- 28654829 TI - Fructose intake exacerbates the contractile response elicited by norepinephrine in mesenteric vascular bed of rats via increased endothelial prostanoids. AB - Chronic fructose intake induces major cardiovascular and metabolic disturbances and is associated with the development of hypertension due to changes in vascular function. We hypothesized that high fructose intake for 6 weeks would cause metabolic syndrome and lead to initial vascular dysfunction. Male Wistar rats were assigned to receive fructose (FRU, 10%) or drinking water (CON) for 6 weeks. Systolic blood pressure was evaluated by tail plethysmography. Fasting glucose, insulin and glucose tolerance were measured at the end of the follow-up. Mesenteric vascular bed reactivity was tested before and after pharmacological blockade. Western blot analysis was performed for iNOS, eNOS, Nox2 and COX-2. DHE staining was used for vascular superoxide anion detection. Vessel structure was evaluated by optical and electronic microscopy. Fructose intake did not alter blood pressure, but did increase visceral fat deposition and fasting glucose as well as impair insulin and glucose tolerance. Fructose increased NE-induced vasoconstriction compared with CON, and this difference was abrogated by indomethacin perfusion as well as endothelium removal. ACh-induced relaxation was preserved, and the NO modulation tested after L-NAME perfusion was similar between groups. SNP-induced relaxation was not altered. Inducible NOS was increased; however, there were no changes in eNOS, Nox2 or COX-2 protein expression. Basal or stimulated superoxide anion production was not changed by fructose intake. In conclusion, high fructose intake increased NE-induced vasoconstriction through the endothelial prostanoids even in the presence of a preserved endothelium-mediated relaxation. No major changes in vessel structure were detected. PMID- 28654830 TI - Analysis of variations of correlation dimension and nonlinear interdependence for the prediction of pediatric myoclonic seizures - A preliminary study. AB - In this preliminary study, we evaluated the predictive ability of Correlation Dimension (CD) and Nonlinear Interdependence (NI) for seizures in pediatric myoclonic epilepsy patients. Scalp EEG recordings of eight diagnosed cases of myoclonic epilepsy were analyzed using Receiver Operating Curve (ROC) for discriminating the preictal period from interictal period. Furthermore, based on clinical seizure characteristics and EEG data, the spatiotemporal patterns of measures in clinically relevant areas of the brain were compared with other areas for each patient. CD showed a dominant increasing behavior in both all of the individual channels and channels of clinical interest for 75% of patients. For NI, the dominant direction was also increasing in 62.5% of patients for all of the individual channels and in 75% of patients for channels of clinical interest. However, there was no consistent general behavior in the timing of the preictal change amongst patients and within individual patient. Nonlinear measures of CD and NI can differentiate the preictal phase from the corresponding interictal phase. However, due to high variability, patient-wise tuning of possible automated systems for seizure prediction is suggested. This is the first study to employ nonlinear analysis for seizure prediction in pediatric myoclonic epilepsy. PMID- 28654831 TI - Immune response mechanism of mouse monocytes/macrophages treated with kappa carrageenan polysaccharide. AB - This study investigated the function of kappa-carrageenan polysaccharide in immune regulation. The immune response of RAW 264.7 cells treated with kappa carrageenan polysaccharide was explored by MTT assay, general morphological observation, neutral red phagocytosis assay, Griess method, fluorescence method, and enzyme-linked immunosorbent assay. In addition, TLR4 blocking experiment and double-fluorescence immunostaining were performed on cells to demonstrate their immune response mechanism. Results show that kappa-carrageenan polysaccharide not only promotes cell proliferation but also activates RAW 264.7 cells, thereby improving the cells' phagocytic capability, NO production, and tumor necrosis factor-alpha (TNF-alpha) secretion. In addition, the use of TLR4-specific inhibitors can significantly mediate the increased TNF-alpha secretion induced by kappa-carrageenan polysaccharide. The RAW 264.7 cells treated with kappa carrageenan polysaccharide show upregulated TLR4 expression, and the main subunit of NF-kappaB (p65) is translocated. These results support the immunomodulatory function of kappa-carrageenan polysaccharide in RAW 264.7 cells. PMID- 28654832 TI - Dyslipdemia induced by chronic low dose co-exposure to lead, cadmium and manganese in rats: the role of oxidative stress. AB - Lead (Pb), cadmium (Cd) and manganese (Mn) have many potential adverse health effects in vitro and in animal models of clinical toxicity. The current study investigated the dyslipidaemic and oxidative stress effects of chronic low-dose oral exposure to Pb, Cd and Mn and the combination (Pb+Cd+Mn) in rats for 15 weeks. Chronic exposure to the metals did not significantly (P>0.05) alter serum lipid profiles. However, the atherogenic index decreased by 32.2% in the Pb+Cd+Mn group, relative to the control. The triglyceride/high-density lipoprotein cholesterol ratio decreased by 39.4% in the Pb+Cd+Mn group, relative to the control, and elevated by 81.8, 94.8 and 20.8%, relative to the Pb, Cd and Mn groups, respectively. While the serum concentrations of malondialdehyde significantly increased in the Mn and Pb+Cd+Mn groups, that of glutathione peroxidase-1 decreased in the Pb+Cd+Mn group, and metallothionein-1 and zinc concentrations markedly decreased in all the metal treatment groups. The results suggest that long-term exposure of rats to Pb+Cd+Mn may result in hypolipidaemia, mediated via oxidative stress and metal interactions. Individuals who are constantly exposed to environmentally relevant levels of the metals may be at risk of hypolipidaemia. PMID- 28654833 TI - Novel and economic acid-base indicator based on (p-toluidine) oligomer: Synthesis; characterization and solvatochromism applications. AB - A new (p-toluidine) oligomer (PTO) was facile synthesized and economically routed via chemical oxidative polymerization by potassium dichromate as an initiator in an acidic aqueous medium at room temperature. The characterization of (p toluidine) oligomer (PTO) has been described by various techniques including Fourier transform infra-red (FTIR), UV-Visible measurements, Mass spectra, H NMR, and thermal gravimetric analysis (TGA). Solvatochromism of PTO was studied in different polaritiy solvents such as acetic acid, acetone, dimethyl formamide, ethanol, isopropanol, chloroform, p-xylene, dichloromethane and carbon teterachloride. The absorption bands were bathochromically shifted with increased polarity of the solvent (positive solvatochromism). PTO shows three isosbestic points at 333, 388 and 472nm in a binary mixture of acetone and chloroform. The deprotonation constants of PTO were found to be 3.1 and 5.8, based on spectrophotometric calculations. PTO was successfully used as an acid-base indicator; the acid solution color sharply turned from pink (acidic medium) to yellow (basic medium) at the end point. PMID- 28654834 TI - Hydrogen bond strengthening induces fluorescence quenching of PRODAN derivative by turning on twisted intramolecular charge transfer. AB - Researchers have proposed different effective mechanisms of hydrogen bonding (HB) on the fluorescence of 6-propionyl-2-dimethylaminonaphthalene (PRODAN) and its derivatives. Herein, excited state transition and dynamics analysis confirm that the fluorescence of PD (a derivative of PRODAN with ethyl replaced by 3-hydroxy 2,2-dimethylpropan) emits from the planar intramolecular charge transfer (PICT) state rather than twist ICT (TICT) state, because the fluorescence emission and surface hopping from the TICT state to the twist ground (T-S0) state is energy forbidden. Nevertheless, the strengthening of intramolecular-HB (intra-HB) and intermolecular-HB (inter-HB) of PD-(methanol)2 smooth the pathway of surface hopping from TICT to T-S0 state and the external conversion going to planar ground state by decreasing the energy difference of the two states. This smoothing changes the fluorescence state of PD-(methanol)2 to the TICT state in which fluorescence emission does not occur but surface hopping, leading to the partial fluorescence quenching of PD in methanol solvent. This conclusion is different from previous related reports. Moreover, the inter-HB strengthening of PD-methanol in PICT state induces the cleavage of intra-HB and a fluorescence red shift of 54nm compared to PD. This red-shift increases to 66nm for PD-(methanol)2 for the strengthening of the one intra-HB and two inter-HBs. The dipole moments of PD-methanol and PD-(methanol)2 respectively increase about 10.3D and 8.1D in PICT state compared to PD. The synergistic effect of intra-HB and inter-HB induces partial quenching of PD in methanol solvent by turning on the TICT state and fluorescence red-shift. This work gives a reasonable description on the fluorescence red-shift and partial quenching of PD in methanol solvent, which will bring insight into the study of spectroscopic properties of molecules owning better spectral characteristics. PMID- 28654835 TI - Sensitized green emission of terbium with dibenzoylmethane and 1, 10 phenanthroline in polyvinyl alcohol and polyvinyl pyrrolidone blends. AB - Tb doped polyvinyl alcohol: polyvinyl pyrrolidone blends with dibenzoylmethane (DBM) and 1, 10 Phenanthroline (Phen) have been prepared by solution cast technique. Bond formation amongst the ligands and Tb3+ ions in the doped polymer has been confirmed employing Fourier Transform Infrared (FTIR) techniques. Optical properties of the Tb3+ ions have been investigated using UV-Vis absorption, excitation and fluorescence studies excited by different radiations. Addition of dimethylbenzoate and 1, 10 Phenanthroline to the polymer blend increases the luminescence from Tb3+ ions along with energy transfer from the polymer blend itself. Luminescence decay curve analysis affirms the non-radiative energy transfer from DBM and Phen to Tb3+ ions, which is identified as the reason behind this enhancement. The fluorescence decay time of PVA-PVP host decreases from 6.02ns to 2.31ns showing an evidence of energy transfer from the host blend to the complexed Tb ions. Similarly the lifetime of DBM and Phen and both in the blend reduces in the complexed system showing the feasibility of energy transfer from these excited DBM and Phen to Tb3+ and is proposed as the cause of the above observations. These entire phenomena have been explained by the energy level diagram. PMID- 28654836 TI - Addition of seaweed and bentonite accelerates the two-stage composting of green waste. AB - Green waste (GW) is an important recyclable resource, and composting is an effective technology for the recycling of organic solid waste, including GW. This study investigated the changes in physical and chemical characteristics during the two-stage composting of GW with or without addition of seaweed (SW, Ulva ohnoi) (at 0, 35, and 55%) and bentonite (BT) (at 0.0, 2.5%, and 4.5%). During the bio-oxidative phase, the combined addition of SW and BT improved the physicochemical conditions, increased the respiration rate and enzyme activities, and decreased ammonia and nitrous oxide emissions. The combination of SW and BT also enhanced the quality of the final compost in terms of water-holding capacity, porosity, particle-size distribution, water soluble organic carbon/organic nitrogen ratio, humification, nutrient content, and phytotoxicity. The best quality compost, which matured in only 21days, was obtained with 35% SW and 4.5% BT. PMID- 28654837 TI - Application of agar liquid-gel transition in cultivation and harvesting of microalgae for biodiesel production. AB - In order to increase microalgal biomass productivity efficient cultivation and harvesting methods are needed against the available traditional methods. The present study focuses on the same by harvesting microalgae using agar gel. Agar medium containing bold's basal medium (BBM) undergoes a thermoreversible gel transition. As compared to the traditional protocols, this gel is used to cultivate microalgae without even affecting the total productivity. To develop the gel for microalgae cultivation, agar was boiled in BBM. Then the agar was cooled to 35 degrees C and microalgae culture was added to it. After seeding the microalgae the temperature of the agar was further decreased by 10 degrees C to induce gelation. Instead of isolated cells microalgae were grown in clusters within the agar gel. Microalgal clusters gravimetrically settle at the bottom within 2h. In this method agar can be reused. PMID- 28654839 TI - Dissociating contributions of head and torso to spatial reference frames: The misalignment paradigm. AB - When we represent someone's view of a scene as egocentrically structured, where do we represent the origin of the reference frame? By analysing responses in a spatial perspective-taking task as a function of spatial location with respect to both head and torso, we isolated the respective contribution of each part to spatial judgments. Both the head and the torso contributed to judgements, though with greater contributions from the torso. A second experiment manipulating visual contrast of the torso showed that this does not reflect low-level differences in visual salience between body parts. Our results demonstrate that spatial perspective-taking relies on a weighted combination of reference frames centred on different parts of the body. PMID- 28654838 TI - Callous-unemotional traits moderate executive function in children with ASD and ADHD: A pilot event-related potential study. AB - Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are associated with varied executive function (EF) difficulties. Callous unemotional (CU) traits, a proposed antecedent of adult psychopathy, are often associated with intact or enhanced EF. Here we test whether CU traits may therefore modulate EF in ASD and ADHD, in which EF is typically impaired. We collected CU traits and measured event-related potentials (ERPs) that index EF during a cued-continuous performance test (CPT-OX) in boys with ASD, ADHD, comorbid ASD+ADHD and typical controls. We examined attentional orienting at cues (Cue-P3), inhibitory processing at non-targets (NoGo-P3) and conflict monitoring between target and non-target trials (Go-N2 vs. NoGo-N2). In children with ASD, higher CU traits were associated with an enhanced increase in N2 amplitude in NoGo trials compared to Go trials, which suggests relatively superior conflict monitoring and a potential cognitive strength associated with CU traits. The results emphasise the importance of considering the effects of co-occurring traits in the assessment of heterogeneity of EF profiles in neurodevelopmental disorders. PMID- 28654840 TI - An emotional Stroop task with faces and words. A comparison of young and older adults. AB - ANTECEDENTS: Given the contradictions of previous studies on the changes in attentional responses produced in aging a Stroop emotional task was proposed to compare young and older adults to words or faces with an emotional valence. METHOD: The words happy or sad were superimposed on faces that express the emotion of happiness or sadness. The emotion expressed by the word and the face could agree or not (cued and uncued trials, respectively). 85 young and 66 healthy older adults had to identify both faces and words separately, and the interference between the two types of stimuli was examined. RESULTS: An interference effect was observed for both types of stimuli in both groups. There was more interference on positive faces and words than on negative stimuli. CONCLUSIONS: Older adults had more difficulty than younger in focusing on positive uncued trials, whereas there was no difference across samples on negative uncued trials. PMID- 28654841 TI - Exposure to particulate matter 2.5 (PM2.5) induced macrophage-dependent inflammation, characterized by increased Th1/Th17 cytokine secretion and cytotoxicity. AB - Particulate matter PM2.5 is a class of airborne particles and droplets with sustained high levels in many developing countries. Epidemiological studies have shown the association between sustained high level of PM2.5 and the risk of many diseases in the respiratory system, including lung cancer. However, the precise mechanisms through which PM2.5 induces respiratory diseases are still unclear. In this study, we demonstrated that CD4+ and CD8+ T cells following PM2.5 treatment demonstrated significantly elevated mRNA and protein levels of interferon (IFN) gamma, interleukin (IL)-10, IL-17, and IL-21 production. This increase in cytokines required the presence of macrophages, such that CD4+ and CD8+ T cells treated with PM2.5 in the absence of macrophages did not present higher IFN gamma, IL-10, or IL-21 expression. In contrast, PM2.5-treated macrophages could significantly upregulate T cell cytokine secretion, even when excess PM2.5 was removed from cell culture. We also observed a macrophage-dependent upregulation of granzyme A and granzyme B expression by CD4+ and CD8+ T cells following PM2.5 treatment. These PM2.5-stimulated CD4+ and CD8+ T cells potently induced the death of human bronchial epithelial (HBE) cells. Interestingly, the CD4+ and CD8+ T cells presented synergistic effects at inducing HBE cytotoxicity, such that CD4+ T cells and CD8+ T cells combined resulted in higher HBE cell death than the sum of the separate effects of CD4+ T cells and CD8+ T cells. While blocking cytotoxic molecule release significantly compromised the T cell-mediated cytotoxicity against HBE cells, blocking IFN-gamma, but not IL-10, could also slightly but significantly reduce T cell-mediated cytotoxicity. Together, these data demonstrated that PM2.5 could promote the inflammation of cytotoxicity of T cells in a macrophage-dependent manner. In addition, PM2.5-treated macrophages presented long-lasting proinflammatory effects on T cells. PMID- 28654842 TI - Haploidentical hematopoietic stem cell transplantation for pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia in the imatinib era. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important curative option for children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have a poor response to chemotherapy plus imatinib. For such children, if there are no matched related or unrelated donors, alternative donor transplantation may be a choice. The role of haploidentical donor (HID) HSCT in pediatric patients with Ph+ ALL has not been reported. The study population included pediatric patients with Ph+ ALL who underwent HID-HSCT. BCR-ABL transcript levels were analyzed using real-time quantitative reverse transcription polymerase chain reaction. At a median follow up of 34 months, the 5-year probabilities of event-free survival (EFS) and overall survival (OS) were 61.0% and 70.0%, respectively in HID HSCT. The 3-year incidence of relapse and non-relapse mortality was 22.7% and 16.4%. Multivariate analysis showed that the post-HSCT BCR-ABL transcript level on +30day was a significant factor affecting relapse rate. HID HSCT for the treatment of pediatric patients with Ph+ ALL yielded promising long-term survival. Post-HSCT BCR-ABL transcript positivity was a significant factor for clinical relapse after allo-HSCT in the imatinib era. PMID- 28654843 TI - Naturalistic assessment of the learner license period. AB - The purpose of this study was to describe the characteristics and progression of practice driving during the learner license period in a sample of teenagers. During the first and last 10h of practice driving, we examined (1) the amount, variety and complexity of conditions of practice; (2) the nature of parental instruction; and (3) errors that teens made while driving. Data were collected from 90 teens and 131 parents living in Virginia, USA, using in-vehicle cameras, audio recorders, GPS and trip recorders. Based on data collected from the instrumented vehicles, teens practiced for 46.6h on average, slightly higher than the GDL requirement for their jurisdiction, though half did not complete the required 45h of practice and only 17% completed the required 15h of night time driving. Exposure to diverse roadways increased over the practice driving period, which averaged 10.6 months. Most driving instruction occurred in reaction to specific driving situations, such as navigating and identifying hazards, and could be characterized as co-driving. Higher order instruction, which relates to the tactics or strategies for safe driving, was less frequent, but remained stable through the practice driving period. Instruction of all forms was more likely following an elevated gravitational force (g-force) event. Errors decreased over time, suggesting improvements in manual and judgment skills, but engagement in potentially distracting secondary tasks increased (when an adult was in the vehicle). A small percentage of trips occurred with no passenger in the front seat, and the g-force rate during these trips was almost 5 times higher than trips with an adult front-seat passenger. Taken collectively, these findings indicate (1) most teens got at least the required amount of supervised practice, but some did not; (2) instruction was mainly reactive and included some higher order instruction; (3) teens driving skills improved despite increased exposure to complex driving conditions, but secondary tasks also increased. Opportunities remained for improving the quality and variability in supervision and enhancing the development of skills during the lengthy period of practice. PMID- 28654844 TI - Exploring the mechanisms of vehicle front-end shape on pedestrian head injuries caused by ground impact. AB - In pedestrian-vehicle accidents, pedestrians typically suffer from secondary impact with the ground after the primary contact with vehicles. However, information about the fundamental mechanism of pedestrian head injury from ground impact remains minimal, thereby hindering further improvement in pedestrian safety. This study addresses this issue by using multi-body modeling and computation to investigate the influence of vehicle front-end shape on pedestrian safety. Accordingly, a simulation matrix is constructed to vary bonnet leading edge height, bonnet length, bonnet angle, and windshield angle. Subsequently, a set of 315 pedestrian-vehicle crash simulations are conducted using the multi body simulation software MADYMO. Three vehicle velocities, i.e., 20, 30, and 40km/h, are set as the scenarios. Results show that the top governing factor is bonnet leading-edge height. The posture and head injury at the instant of head ground impact vary dramatically with increasing height because of the significant rise of the body bending point and the movement of the collision point. The bonnet angle is the second dominant factor that affects head-ground injury, followed by bonnet length and windshield angle. The results may elucidate one of the critical barriers to understanding head injury caused by ground impact and provide a solid theoretical guideline for considering pedestrian safety in vehicle design. PMID- 28654845 TI - Alcohol-related cognitions in children (aged 2-10) and how they are shaped by parental alcohol use: A systematic review. AB - BACKGROUND: This systematic review aims to summarize the evidence of the impact of parental alcohol use on the acquisition of children's alcohol-related cognitions (alcohol-related knowledge, alcohol-related norms, alcohol expectancies) in the developmental period from age two to ten. METHODS: A computer-assisted systematic literature search was performed in PubMed, PsychINFO, ERIC, and EMBASE. Overall, 20 out of the 3406 unique articles identified in the first screening were included. RESULTS: The results revealed that children acquire knowledge about alcohol already at age two and from age four on, they understand its use in adult culture. By the age of four, children have certain alcohol expectancies. The evidence of the impact of parental alcohol use on the acquisition of children's alcohol-related cognitions is inconsistent so far with studies showing positive and no effects. Unfortunately, the existing evidence is limited because most studies a) were conducted exclusively in the United States and more than two decades ago, b) used cross-sectional study designs, and c) used non-representative samples recruited using convenience sampling strategies. CONCLUSIONS: Research on children's alcohol-related cognitions is underdeveloped. To elucidate the conclusions about alcohol involvement in early life, studies with longitudinal study designs need to be conducted among representative samples of children and early adolescents by using age-appropriate measurement tools in a broader cultural context. PMID- 28654846 TI - Diabetes mellitus is associated with late-onset post-stroke depression. AB - OBJECTIVE: To explore the associated factors of late-onset post-stroke depression (PSD). METHODS: A total of 251 patients with acute ischemic stroke were recruited. The evaluation of depression was performed 2 weeks after ischemia. 206 patients showing no depression in 2 weeks were followed up. They were divided into late-onset PSD group and non-depressed group by clinical interview with Hamilton depression scale score 3 months after stroke. On the first day following hospitalization, the clinical data including age, gender, educational level and vascular risk factors were recorded. The severity, etiological subtype and location of stroke were evaluated. The inflammatory mediators, glucose and lipid levels were recorded on the day of admission. The association between clinical factors and late-onset PSD was explored by logistic regression analysis. The ROC analysis was performed to evaluate the predicting power of the clinical factors. RESULTS: 187 of 206 patients completed the assessment 3 months after stroke. 19 (10.16%) patients were diagnosed as late onset PSD. Diabetes mellitus was an independent risk factor for late-onset PSD (OR 2.675, p = 0.047). ROC analysis demonstrated that glucose and HbA1C could predict late-onset PSD with specificity of 84.4%. LIMITATIONS: The sample of our study was small. The results should be further confirmed in a larger cohort of patients with acute ischemic stroke. CONCLUSIONS: The acute ischemic stroke patients with diabetes mellitus were more tendered to suffer late-onset PSD. PMID- 28654847 TI - A model comparison approach to trauma-related guilt as a mediator of the relationship between PTSD symptoms and suicidal ideation among veterans. AB - BACKGROUND: Suicidal ideation (SI) is a serious issue affecting U.S. veterans, and those with posttraumatic stress disorder (PTSD) are at an especially high risk of SI. Guilt has been associated with both PTSD and SI and may therefore be an important link between these constructs. METHODS: The present study compared models of trauma-related guilt and used path analysis to examine the direct and indirect effects of PTSD and trauma-related guilt on SI among a sample of 988 veterans receiving outpatient PTSD treatment at a Veterans Affairs (VA) specialty clinic. RESULTS: Results showed that a model of trauma-related guilt including guilt-cognitions and global guilt (but not distress) provided the best model fit for the data. PTSD and trauma-related guilt had direct effects on SI, and PTSD exhibited indirect effects on SI via trauma-related guilt. LIMITATIONS: The use of cross-sectional data limits the ability to make causal inferences. A treatment seeking sample composed primarily of Vietnam veterans limits generalizability to other populations. CONCLUSIONS: Trauma-related guilt, particularly guilt cognitions, may be an effective point of intervention to help reduce SI among veterans with PTSD. This is an important area of inquiry, and suggestions for future research are discussed. PMID- 28654848 TI - Gender differences in the association between physical activity and cognitive function in individuals with bipolar disorder. AB - INTRODUCTION: Bipolar disorder (BD) is accompanied by a high number of comorbidities and associated with an overall increased mortality. Especially obesity, systemic inflammatory processes and cognitive deficits are highly prevalent and increase with the course of illness. Physical activity (PA) is associated with beneficial effects on somatic comorbidities such as obesity or cardiovascular disease in individuals without psychiatric disorder. Furthermore, PA might increase neurocognitive performance and reduce systemic inflammation. OBJECTIVE: The aim of the study was to investigate the association between PA and neurocognitive function in euthymic individuals suffering from BD. METHODS AND PARTICIPANTS: 120 individuals with BD, euthymic at test time, completed the self reported International Physical Activity Questionnaire (IPAQ) assessing PA of the past seven days and were accordingly assigned to a specific activity category (low, moderate or vigorous). Furthermore, clinical parameters were gathered and cognitive tests analysing verbal-dependent intelligence, attention, executive functioning as well as memory were administered. RESULTS: Female individuals in the vigorous PA group performed significantly higher in most of the cognitive domains compared to females with moderate or low PA. In males, we only found a significant difference in one test for attention between moderate/vigorous and the low activity group. CONCLUSION: Differences between PA groups in cognitive performance in female individuals with BD were obvious in almost all cognitive domains. As cognitive deficits are strongly associated with a worse course of disease and outcome, PA might offer a concomitant therapy targeting not only somatic comorbidities such as obesity and cardiovascular disease, but also neurocognition. PMID- 28654849 TI - Factors associated with post-traumatic stress symptoms (PTSS) 4-6 weeks and 6 months after birth: A longitudinal population-based study. AB - BACKGROUND: Identifying factors that precipitate and maintain post-traumatic stress symptoms (PTSS) after birth is important to inform clinical and research practice; yet, prospective longitudinal studies on the predictors of PTSS are limited. This study aimed to determine the pregnancy and postpartum factors associated with PTSS at 4-6 weeks and 6-months postpartum. METHOD: A systematic sample of 950 pregnant women were recruited from three maternity hospitals in Turkey. Participants completed assessments of depression, anxiety, PTSS and social support in pregnancy, 4-6 weeks and 6-months postpartum. Fear of childbirth was assessed in pregnancy and 4-6 weeks after birth. RESULTS: Regression models showed that PTSS six months after birth were associated with anxiety and PTSS in pregnancy, complications during birth, satisfaction with health professionals, fear of childbirth 4-6 weeks after birth, PTSS and depression 4-6 weeks after birth, social support 4-6 weeks after birth, traumatic events after birth, need for psychological help, and social support 6-months after birth. PTSS was highly comorbid with depression and anxiety at all-time points. The most robust predictor of PTSS at 6-months postpartum was PTSS at 4-6 weeks postpartum. Intra-partum complications were not associated with PTSS 4-6 weeks after birth. No socio-demographic variables were correlated with PTSS postpartum. LIMITATIONS: Self-report questionnaires were used to measure outcomes. This study is based on sampling from public hospitals so may not represent women treated in private hospitals. CONCLUSIONS: Associated risk factors may help to identify women at risk of PTSS after birth and to inform targeted early intervention. PMID- 28654850 TI - Wound management with negative pressure wound therapy in postoperative infection after open reconstruction of chronic Achilles tendon rupture. AB - INTRODUCTION: Deep infection after reconstruction of chronic Achilles tendon rupture is a major and intractable complication. CASE REPORT: We report a case of late deep infection following a surgery for chronic Achilles tendon rupture, and its simple and successful treatment with negative pressure wound therapy (NPWT). Six months following the reconstruction of chronic Achilles tendon rupture, a deep infection developed and reconstructed part of the tendon ruptured again. After appropriate debridement. DISCUSSION: There is no definitive treatment strategy for postoperative infection following open Achilles tendon repair. NPWT was applied to the wound, to promote wound healing and healthy granulation. In our case, NPWT promoted the wound healing and the infected Achilles tendon with tendon loss formed a healthy bridge with granulation tissue spontaneously. The patient resumed her normal activities of daily living, without requiring tendon transfer surgery. NPWT seems to be a simple and successful candidate for this situation. CONCLUSION: NPWT seems to be effective for the treatment of postoperative infection following Achilles tendon repair, even in cases of tendon loss. PMID- 28654851 TI - A colovesical fistula with a persistent descending mesocolon due to partial situs inversus: A case report. AB - INTRODUCTION: Situs inversus viscerum, a congenital condition in which the visceral organs are a mirror image of their normal physiological positions, could be total or partial. Persistent descending mesocolon (PDM) is a congenital anomaly that is asymptomatic because of its short length. PDM causing intestinal obstruction is a known clinical complication. PRESENTATION OF CASE: A 74-year-old woman presented with pneumaturia and enteruria for two months, and recurrent cystitis for a month. An enhanced computed tomography (CT) showed air in the bladder along with sigmoid colonic diverticula adherent to it, suspecting a fistula. The CT also showed partial situs inversus with the common hepatic artery, and left colic artery arising abnormally from the superior mesenteric artery (SMA). Minimally invasive endoscopic closure using the over-the-scope clipping system was difficult because of thickening and scar tissue due to chronic inflammation from diverticulitis. Thus, a sigmoidectomy was performed to close the fistula. Intraoperatively, we noted an abnormally fixed descending mesocolon. An emergency reoperation was performed on the sixth postoperative day owing to an anastomotic leak. Suture failure was attributed to these congenital abnormalities due to insufficient blood flow from an absent marginal vessel and a high endocolonic pressure by adhesions. Sigmoid colon re-resection and maturation of an ileostomy was performed. The patient had no specific postoperative complications, and the ileostomy was closed after three months. CONCLUSION: We report an extremely rare case of colovesical fistula due to a PDM in a patient having partial situs inversus with abnormal branches originating from the SMA. PMID- 28654852 TI - Adductor canal compression syndrome in an 18-year-old female patient leading to acute critical limb ischemia: A case report. AB - BACKGROUND: Adductor canal compression syndrome is a rare non-atherosclerotic cause of arterial occlusion and limb ischemia. PRESENTATION OF CASE: The patient is an 18-year-old healthy female who presented to the emergency department with acute left lower extremity ischemia. Her symptoms began as sudden onset mild foot pain approximately two months ago. Over the 72h prior to presentation, she developed severe pain, pallor, paralysis, loss of pedal pulses, paresthesia, and poikilothermia. Due to her advanced ischemia, she was taken immediately to the operating room for angiography and intervention. Initial angiography demonstrated distal superficial femoral and popliteal artery occlusions along with lack of tibial or pedal artery blood flow. She underwent percutaneous mechanical thrombectomy and initiation of catheter directed thrombolysis. After 48h of catheter directed thrombolysis and repeat mechanical thrombectomy, computed tomography (CT) was performed and demonstrated external compression of the superficial femoral artery in the adductor canal and residual chronic thrombus. Echocardiography and CT of the thoracic aorta was also performed, and were negative, therefore excluding other potential sources of arterial embolism. She next underwent surgical exploration, division of an anomalous musculotendinous band compressing the left superficial femoral artery and thromboendarterectomy of the distal left superficial femoral artery. The patient recovered well without any post-operative complications and could return to her daily activities 3 weeks following surgery. CONCLUSION: Knowledge of rare non-atherosclerotic vascular disorders, such as adductor canal compression syndrome, is paramount when treating patients who present with limb ischemia and lack traditional risk factors. PMID- 28654853 TI - Association of matrix gamma-carboxyglutamic acid protein levels with insulin resistance and Lp(a) in diabetes: A cross-sectional study. AB - AIMS: The risk of cardiovascular disease (CVD) and mortality is increased in patients with chronic kidney disease (CKD), with a background role of vascular calcification in the development of CVD also reported. Studies have demonstrated that high lipoprotein(a) (Lp(a)) levels accelerate the development of atherosclerolsis and are potentially involved in the vascular calcification. Matrix Gla Protein (MGP) seems to play an important role in vascular calcification. The aim of the study was to examine the potential association of MGP concentrations with Lp(a) and insulin resistance. METHODS: The study involved 100patients divided in four groups: 25 with both CKD stage 4 and Type2 Diabetes (DM) (Group-A), 25 with CKD4 without DM (Group-B), 25 non uremic patients with DM (Group-C) and 25 healthy subjects (Group-D). Serum glucose, Lp(a), MGP, plasma HBA1c and insulin were measured in all patients. Insulin resistance was estimated by the homeostasis model assessment equation (HOMA-IR). RESULTS: A significant positive linear association between MGP and Lp(a) levels (r=0.272, p=0.006) was noted, as well as between MGP and HOMA-IR levels (r=0.308, p=0.002). However, no significant linear association between Lp(a) and HOMA-IR levels was recorded. A similar positive association between MGP and insulin levels (r=0.204, p=0.042) was also found. CONCLUSION: This study concluded that diabetes coexisting with renal disease leads to extreme vascular calcification expressed by elevated MGP levels, resulting in higher frequency of cardiovascular disease in comparison to CKD patients without diabetes. The detected Lp(a) and MGP association in CKD4 patients may also represent the key to the complicated mechanism of their coexisting accelerated atherosclerosis and vascular calcification. PMID- 28654854 TI - Viscoelastic power law parameters of in vivo human brain estimated by MR elastography. AB - The noninvasive imaging technique of magnetic resonance elastography (MRE) was used to estimate the power law behavior of the viscoelastic properties of the human brain in vivo. The mechanical properties for four volunteers are investigated using shear waves induced over a frequency range of 10-50Hz to produce a displacement field measured by magnetic resonance motion-encoding gradients. The average storage modulus (MUR) reconstructed with non-linear inversion (NLI) increased from approximately 0.95 to 2.58kPa over the 10-50Hz span; the average loss modulus (MUI) also increased from 0.29 to 1.25kPa over the range. These increases were modeled by independent power law (PL) relations for MUR and MUI returning whole brain, group mean exponent values of 0.88 and 1.07 respectively. Investigation of these exponents also showed distinctly different behavior in the region of the cerebral falx compared to other brain structures. PMID- 28654855 TI - Clinical profile and neurodevelopmental outcome of new-onset acute symptomatic seizures in children. AB - PURPOSE: To study clinical profile, neurodevelopmental outcome and its predictors in children with acute symptomatic seizures (ASS). METHODS: Short-term neurodevelopmental outcome and predictors of poor outcomes were prospectively assessed in 105 consecutive children with ASS aged 3 months-12 years RESULTS: Mean age was 51.2+42.2months (3-144 months); 67.2% were males. Central nervous system (CNS) infection in 82%, status epilepticus in 15.2%, abnormal neuroimaging in 62.8% and abnormal electroencephalography in 22.3% were noted. At discharge, 27.6% had poor outcome including death (13%); CNS infections were significantly associated with poor outcome compared to ASS of other aetiologies (32.6% vs 5.2%, p=0.02). Low GCS (OR 4.9, 95%CI 1.2-20.7), abnormal electroencephalograph (OR 4.3, 95%CI 1-16.9) and neuroimaging (OR 12.1, 95%CI 1.4-105.2) were independent predictors of poor outcome. After 6 months, 16% children had delayed neurodevelopment and cognition; 6% had seizure recurrences. Abnormal electroencephalograph (p=0.002; OR 6.8, 95%CI 2.0-23.1), abnormal neuroimaging (p=0.015; OR 9.47, 95%CI 1.18-75.8),>1 anti-epileptic (p=0.00; OR 9.9, 95%CI 2.88 33.9), intubation (p=0.004; OR 6.25, 95%CI 1.79-21.7) and poor outcome at discharge (p=0.02; OR 4.44, 95%CI1.38-14.2) predicted abnormal neurodevelopment. CONCLUSIONS: CNS infections are the most common cause of ASS in children from developing countries. Abnormal neurodevelopment and seizure recurrences on short term follow-up are seen in a minority of children. PMID- 28654856 TI - Evaluation of a self-regulation based psycho-educational pilot intervention targeting children and adolescents with epilepsy in Greece. AB - PURPOSE: The purpose of this study is to describe the development and initial evaluation of a minimal structured psycho-educational intervention for children and adolescents with epilepsy. The intervention aimed at increasing the understanding and personal control (self-management) of epilepsy, and at reducing psychological distress, sleep problems and somatic complaints. METHOD: Twelve patients participated in our intervention and another 12, matched on age and gender, served as the control group. Data were obtained at baseline (prior to the intervention) and 3 months later in the context of an interview based on several validated questionnaires. The intervention was limited to one 4-h session using Cognitive Behavioural Therapy techniques, relaxation techniques, video and storytelling. Effects of the intervention on primary and secondary outcomes were examined using 2 (baseline, T1 vs. post-treatment, T2)*2 (intervention vs. control) mixed model repeated measures analysis of covariance (ANCOVA), controlling for epilepsy severity. RESULTS: The analysis revealed that over the three months of the study, significant main effects (group x time) were observed on coherence (F(1,21)=6.12; p=0.02) with important changes in favour of the intervention group. Significant main effects were also observed on psychological distress levels (F(1,21)=10.08; p=0.005) and sleep problems (F(1,21)=11.40; p=0.003). CONCLUSION: The results of this study show that a brief self-regulation based intervention may have beneficial effects for children and adolescents suffering from epilepsy by inciting improvements in coherence, psychological distress and sleep problems. PMID- 28654857 TI - Long-term outcome of a 26-year-old woman with West syndrome and an nuclear receptor subfamily 2 group F member 1 gene (NR2F1) mutation. AB - Long-term outcome of West syndrome with a NR2F1 mutation. PMID- 28654858 TI - Reference values of lithium in postmortem femoral blood. AB - INTRODUCTION: The main recipients of lithium, people diagnosed with bipolar disorder, show an increased mortality in both natural and unnatural causes of death. Based on international data persons diagnosed with bipolar disorder comprise 2.3-9.6% of all suicidal deaths. In cases of suicide among those suffering from bipolar disorder, 17-53% are due to fatal intoxications. Diagnosing fatal intoxications is often challenging, particularly when the reference information needed to interpret the concentration of a drug is lacking or scarce. AIM: The aim of this study was to establish postmortem femoral blood reference concentrations of lithium, providing both fatal and "normal" postmortem concentrations, as well as to investigate the impact of the mode of intoxication and to study the co-detection of lithium and antidepressant drugs in intoxications and controls. METHOD: In Sweden, forensic autopsies are performed in unnatural and obscure deaths. This study included all autopsies in which lithium was found during the study period (1992-2010). Lithium was not included in the regular drug screen, but analysed upon request using flame photometry, ion selective electrode detection or atomic absorption spectrophotometry. Each case was evaluated according to an established strategy, with strict inclusion and exclusion criteria followed by a multi-observer manual review (Fig. 1, Table 1). The cases included were classified as single intoxications (group A), multi-drug intoxications (group B) or controls (group C). The control group only included cases where death by intoxication and antemortem incapacitation by drugs could be ruled out. RESULTS AND DISCUSSION: During the study period, lithium was found in 124 cases. After application of inclusion and exclusion criteria and the subsequent manual review, 21 cases were classified as group A (n=4), group B, (n=7) and group C (n=10). The femoral blood lithium concentrations in group A (median 2.69mmol/l) and group B (median 2.10mmol/l) were significantly different (p=0.01) compared to group C (median 0.2mmol/l). There were however no statistically significant difference between the concentrations in groups A and B. The most common mode of death in intoxications was acute-on-chronic (n=10), but the impact of chronic use on the fatal blood concentrations could not be evaluated since there was just one case without previous use. There was no difference in the proportion of co-detections of lithium and antidepressants between intoxication cases and controls. PMID- 28654859 TI - A Comparison of Methods to Analyze Aquatic Heterotrophic Flagellates of Different Taxonomic Groups. AB - Heterotrophic flagellates contribute significantly to the matter flux in aquatic and terrestrial ecosystems. Still today their quantification and taxonomic classification bear several problems in field studies, though these methodological problems seem to be increasingly ignored in current ecological studies. Here we describe and test different methods, the live-counting technique, different fixation techniques, cultivation methods like the liquid aliquot method (LAM), and a molecular single cell survey called aliquot PCR (aPCR). All these methods have been tested either using aquatic field samples or cultures of freshwater and marine taxa. Each of the described methods has its advantages and disadvantages, which have to be considered in every single case. With the live-counting technique a detection of living cells up to morphospecies level is possible. Fixation of cells and staining methods are advantageous due to the possible long-term storage and observation of samples. Cultivation methods (LAM) offer the possibility of subsequent molecular analyses, and aPCR tools might complete the deficiency of LAM in terms of the missing detection of non cultivable flagellates. In summary, we propose a combination of several investigation techniques reducing the gap between the different methodological problems. PMID- 28654860 TI - Transcriptome-wide piRNA profiling in human brains of Alzheimer's disease. AB - Discovered in the brains of multiple animal species, piRNAs may contribute to the pathogenesis of neuropsychiatric illnesses. The present study aimed to identify brain piRNAs across transcriptome that are associated with Alzheimer's disease (AD). Prefrontal cortical tissues of 6 AD cases and 6 controls were examined for piRNA expression levels using an Arraystar HG19 piRNA array (containing 23,677 piRNAs) and genotyped for 17 genome-wide significant and replicated risk SNPs. We examined whether piRNAs are expressed differently between AD cases and controls and explored the potential regulatory effects of risk SNPs on piRNA expression levels. We identified a total of 9453 piRNAs in human brains, with 103 nominally (p < 0.05) differentially (>1.5 fold) expressed in AD cases versus controls and most of the 103 piRNAs nominally correlated with genome-wide significant risk SNPs. We conclude that piRNAs are abundant in human brains and may represent risk biomarkers of AD. PMID- 28654862 TI - Biopolymer zein-coated gold nanoparticles: Synthesis, antibacterial potential, toxicity and histopathological effects against the Zika virus vector Aedes aegypti. AB - The control of multidrug-resistant bacteria as well as insect pests and vectors is timely and important now a days. The present study was designed to evaluate the in vitro antibacterial, antibiofilm and mosquito larvicidal effects of gold nanoparticles synthesized using the zein biopolymer (Ze-AuNPs) against Gram positive (Bacillus pumilus and Bacillus subtilis), Gram negative (Shigella sonnei and Pseudomonas aeruginosa) bacteria and third instar larvae of the dengue and Zika virus vector Aedes aegypti. The synthesized Ze-AuNPs were characterized by UV-vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The antibacterial assays testing Ze-AuNPs at 100MUg/ml showed that the zones of inhibition against Gram positive species B. pumilus and B. subtilis were 13.9 and 14.2mm, respectively, while for Gram negative S. sonnei and P. aeruginosa they were 18.1 and 18.4mm, respectively. Light and confocal laser scanning microscopy (CLSM) confirmed the interruption and disintegration of bacterial biofilm post-treatment with Ze-AuNPs at 100MUg/ml. In larvicidal assays on A. aegypti, HAuCl4 and Ze-AuNPs treated third instar larvae of A. aegypti showed LC50 of 26.6 and 6.81mg/L, respectively, and LC90 of 81.1 and 13.6mg/L respectively. The histopathological analysis of A. aegypti treated with Ze-AuNPs showed complete disintegration of abdominal region, particularly the midgut and caeca, with loss of lateral and caudal hairs. The stereomicroscopic visualization of A. aegypti treated with Ze-AuNPs showed the loss of upper head hair, lower head hair, antenna hair, lateral hair and caudal hair. Overall, the study concludes that Ze-AuNPs have excellent antibacterial, antibiofilm effects and has ability to control the larval populations of A. aegypti mosquitoes. PMID- 28654861 TI - Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier. AB - Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Abeta) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Abeta transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Abeta receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Abeta accumulation. PMID- 28654863 TI - Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response. AB - Intestinal tumorigenesis in the ApcMin/+ model is initiated by aberrant activation of Wnt pathway. Increased IL-4 expression in human colorectal cancer tissue and growth of colon cancer cell lines implied that IL-4-induced Stat6 mediated tumorigenic signaling likely contributes to intestinal tumor progression in ApcMin/+ mice. Stat6 also appears to promote expansion of myeloid-derived suppressor cells (MDSCs) cells. MDSCs promote polyp formation in the ApcMin/+ model. Hence, Stat6 could have a broad role in coordinating both polyp cell proliferation and MDSC expansion. We found that IL-4-induced Stat6-mediated proliferation of intestinal epithelial cells is augmented by platelet-derived growth factor-BB, a tumor-promoting growth factor. To determine whether polyp progression in ApcMin/+ mice is dependent on Stat6 signaling, we disrupted Stat6 in this model. Total polyps in the small intestine were fewer in ApcMin/+ mice lacking Stat6. Furthermore, proliferation of polyp epithelial cells was reduced, indicating that Stat6 in part controlled polyp formation. Stat6 also promoted expansion of MDSCs in the spleen and lamina propria of ApcMin/+ mice, implying regulation of antitumor T-cell response. More CD8 cells and reduced PD-1 expression on CD4 cells correlated with reduced polyps. In addition, a strong CD8 mediated cytotoxic response led to killing of tumor cells in Stat6-deficient ApcMin/+ mice. Therefore, these findings show that Stat6 has an oncogenic role in intestinal tumorigenesis by promoting polyp cell proliferation and immunosuppressive mediators, and preventing an active cytotoxic process. PMID- 28654864 TI - Wolf-Hirschhorn Syndrome Candidate 1 (whsc1) Functions as a Tumor Suppressor by Governing Cell Differentiation. AB - Wolf-Hirschhorn syndrome candidate 1 (WHSC1) is a histone 3 lysine 36 (H3K36) specific methyltransferase that is frequently deleted in Wolf-Hirschhorn syndrome (WHS). Whsc1 is also found mutated in a subgroup of B-cell derived malignant diseases by genomic translocation or point mutation, both of which resulted in hyperactivity of WHSC1 mediated H3K36 methylation and uncontrolled cell proliferation, suggesting that whsc1 functions as an oncogene. However, here we provided evidences to show that whsc1 also has tumor suppressor functions. We used zebrafish as an in vivo model and generated homozygous whsc1 mutant lines via clustered regularly interspaced short palindromic repeats-associated protein Cas9 (CRISPR/Cas9) technology. Then western-blot (WB) and immunofluorescence (IF) were performed to analysis the expression level of H3K36Me2 and H3K36Me3, and we identified the diseased tissue via hematoxylin-eosin (HE) staining, IF staining or immunohistochemistry (IHC). Whsc1 lose-of-function led to significant decrease in di- and tri-methylation of H3K36. A series of WHS related phenotypes were found in whsc1-/- zebrafish, including growth retardation, neural development defects and heart failure. In addition, loss of function of whsc1 led to defects in the development of swim bladder, possibly through the dis-regulation of key genes in swim bladder organogenesis and inhibition of progenitor cell differentiation, which was correlated with its expression in this organ during embryonic development. At later stage, these whsc1-/- zebrafishes are inclined to grow tumors in the swim bladder. Our work suggested that whsc1 may function as a tumor suppressor by governing progenitor cell differentiation. PMID- 28654866 TI - Magnetic particles for in vitro molecular diagnosis: From sample preparation to integration into microsystems. AB - Colloidal magnetic particles (MPs) have been developed in association with molecular diagnosis for several decades. MPs have the great advantage of easy manipulation using a magnet. In nucleic acid detection, these particles can act as a capture support for rapid and simple biomolecule separation. The surfaces of MPs can be modified by coating with various polymer materials to provide functionalization for different applications. The use of MPs enhances the sensitivity and specificity of detection due to the specific activity on the surface of the particles. Practical applications of MPs demonstrate greater efficiency than conventional methods. Beyond traditional detection, MPs have been successfully adopted as a smart carrier in microfluidic and lab-on-a-chip biosensors. The versatility of MPs has enabled their integration into small single detection units. MPs-based biosensors can facilitate rapid and highly sensitive detection of very small amounts of a sample. In this review, the application of MPs to the detection of nucleic acids, from sample preparation to analytical readout systems, is described. State-of-the-art integrated microsystems containing microfluidic and lab-on-a-chip biosensors for the nucleic acid detection are also addressed. PMID- 28654865 TI - Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer. AB - Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS) detected total choline (tCho) signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC), phosphocholine (PC) and free choline (Cho), before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase alpha (ChKalpha), which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKalpha protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA MB-231 cell migration. GDPD6, but not PLD1 or ChKalpha, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKalpha mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually. PMID- 28654867 TI - Cholesterol-rich lipid rafts play a critical role in bovine parainfluenza virus type 3 (BPIV3) infection. AB - Lipid rafts are specialized lipid domains enriched in cholesterol and sphingolipid, which can be utilized in the lifecycle of numerous enveloped viruses. Bovine parainfluenza virustype3 (BPIV3) entry to cell is mediated by receptor binding and membrane fusion, but how lipid rafts in host cell membrane and BPIV3 envelope affect virus infection remains unclear. In this study, we investigated the role of lipid rafts in the different stages of BPIV3 infection. The MDBK cells were treated by methyl-beta-cyclodextrin (MbetaCD) to disrupt cellular lipid raft, and the virus infection was determined. The results showed that MbetaCD significantly inhibited BPIV3 infection in a dose-dependent manner, but didn't block the binding of virus to the cell membrane. Whereas, the MDBK cells treated by MbetaCD after virus-entry had no effects on the virus infection, to suggest that BPIV3 infection was associated with lipid rafts in cell membrane during viral entry stage. To further confirm lipid rafts in viral envelope also affected BPIV3 infection, we treated BPIV3 with MbetaCD to determine the virus titer. We found that disruption of the viral lipid raft caused a significant reduction of viral yield. Cholesterol reconstitution experiment showed that BPIV3 infection was successfully restored by cholesterol supplementation both in cellular membrane and viral envelope, which demonstrated that cholesterol-rich lipid rafts played a critical role in BPIV3 infection. These findings provide insights on our understanding of the mechanism of BPIV3 infection and imply that lipid raft might be a good potential therapeutic target to prevent virus infection. PMID- 28654868 TI - Simultaneous assessment of absorption characteristics of coumarins from Angelicae Pubescentis Radix: In vitro transport across Caco-2 cell and in vivo pharmacokinetics in rats after oral administration. AB - Angelicae Pubescentis Radix (APR), a well-known traditional Chinese medicine, is widely used for the treatments of rheumatism and headache for centuries. To assess the absorption characteristics of coumarins from APR, a sensitive and reliable UPLC-MS/MS method was established for the simultaneous determination of sixteen coumarins from APR, including psoralen, xanthotoxin, bergapten, bergaptol, isoimperatorin, imperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, umbelliferone, scopoletin, osthole, meranzin hydrate and nodakenetin. The specificity, linearity, sensitivity, precision, accuracy, recovery, matrix effect and stability of the method were all validated to be satisfactory. The method was then applied to the in vitro transport of APR extract (APRE) across human intestinal epithelial Caco 2 cell and in vivo pharmacokinetics in rats after oral administration of APRE. All of the tested coumarins were well or moderately absorbed across Caco-2 monolayers, and could be quickly absorbed into rat blood circulation after oral administration. Columbianetin was the most easily absorbed compound across Caco-2 cell, and also had extremely highest plasma concentration in vivo. Excellent correlation between in vitro absorption across Caco-2 cell monolayers and in vivo pharmacokinetics of coumarins from APRE was well verified. The results provided valuable information for the overall absorption characteristics of the coumarins from APR, as well as for its further studies of in vivo active substances in the further. PMID- 28654869 TI - A review of high performance liquid chromatographic-mass spectrometric urinary methods for anticancer drug exposure of health care workers. AB - This review describes published high performance liquid chromatography/mass spectrometry (HPLC-MS) methods for the determination of anticancer drugs in human urine as non-invasive tool for monitoring of health care worker exposure to antineoplastic and cytotoxic drugs. HPLC-MS is a sensitive and specific method for analysis of anticancer drugs and their metabolites in biological fluids. In this review, a tabular summary and overview of published HPLC-MS methods are presented, as well as future trends and limitations in this area of research. PMID- 28654870 TI - Twenty years of take-home naloxone for the prevention of overdose deaths from heroin and other opioids-Conception and maturation. AB - BACKGROUND: Opioid overdose is a major cause of mortality, but injury and fatal outcomes can be prevented by timely administration of the opioid antagonist naloxone. Pre-provision of naloxone to opioid users and family members (take-home naloxone, THN) was first proposed in 1996, and WHO Guidelines were issued in 2014. While widespread in some countries, THN is minimally available or absent elsewhere. This review traces the development of THN over twenty years, from speculative harm reduction proposal to public health strategy. METHOD: Medline and PsycINFO were searched for peer-reviewed literature (1990-2016) using Boolean queries: 1) "naloxone OR Narcan"; 2) "(opioid OR opiate) AND overdose AND prevention". Grey literature and specialist websites were also searched. Data were extracted and synthesized as narrative review, with key events presented as chronological timeline. RESULTS: Results are presented in 5-year intervals, starting with the original proposal and THN pilots from 1996 to 2001. Lack of familiarity with THN challenged early distribution schemes (2001-2006), leading to further testing, evaluation, and assessment of challenges and perceived medicolegal barriers. From 2006-2011, response to social and legal concerns led to the expansion of THN programs; followed by high-impact research and efforts to widen THN availability from 2011 to 2016. CONCLUSIONS: Framed as a public health tool for harm reduction, THN has overcome social, clinical, and legal barriers in many jurisdictions. Nonetheless, the rising death toll of opioid overdose illustrates that current THN coverage is insufficient, and greater public investment in overdose prevention will be required if THN is to achieve its full potential impact. PMID- 28654871 TI - The spatial accuracy of geographic ecological momentary assessment (GEMA): Error and bias due to subject and environmental characteristics. AB - BACKGROUND: Geographic ecological momentary assessment (GEMA) combines ecological momentary assessment (EMA) with global positioning systems (GPS) and geographic information systems (GIS). This study evaluates the spatial accuracy of GEMA location data and bias due to subject and environmental data characteristics. METHODS: Using data for 72 subjects enrolled in a study of urban adolescent substance use, we compared the GPS-based location of EMA responses in which the subject indicated they were at home to the geocoded home address. We calculated the percentage of EMA locations within a sixteenth, eighth, quarter, and half miles from the home, and the percentage within the same tract and block group as the home. We investigated if the accuracy measures were associated with subject demographics, substance use, and emotional dysregulation, as well as environmental characteristics of the home neighborhood. RESULTS: Half of all subjects had more than 88% of their EMA locations within a half mile, 72% within a quarter mile, 55% within an eighth mile, 50% within a sixteenth of a mile, 83% in the correct tract, and 71% in the correct block group. There were no significant associations with subject or environmental characteristics. CONCLUSIONS: Results support the use of GEMA for analyzing subjects' exposures to urban environments. Researchers should be aware of the issue of spatial accuracy inherent in GEMA, and interpret results accordingly. Understanding spatial accuracy is particularly relevant for the development of 'ecological momentary interventions' (EMI), which may depend on accurate location information, though issues of privacy protection remain a concern. PMID- 28654872 TI - The effects of using answer sheets on reported drug use and data quality in a classroom survey: A cluster-randomized study. AB - BACKGROUND: We compare self-reported prevalence of drug use and indicators of data quality from two different response modes (with and without an independent answer sheet for recording responses) in a survey conducted in 2015 among secondary school students. METHODS: Stratified cluster-randomized study conducted among students in grades 8-12 from public, private and subsidized schools in Chile (N=2317 students in 122 classes). Measurements included were: percentage reporting substance use (tobacco, alcohol, marijuana, cocaine, ecstasy); number of inconsistent responses; number of item nonresponses; percentage of extreme reports of drug use; percentage reporting using the nonexistent drug, relevon; and completion times. RESULTS: Compared with those who responded directly in the questionnaire booklet, students who used a separate answer sheet took 17.6 more minutes (95% confidence interval [CI]: 14.4-20.8) to complete the survey and had on average 1.5 more inconsistent responses (95%CI: 0.91-2.14). The prevalence and variance of drug use was higher among those who used an answer sheet for all substances except tobacco; the prevalence ratio (PR) of reported substance use for low-prevalence substances during the past year were: cocaine PR=2.5 (95%CI: 1.6-4.1); ecstasy PR=5.0 (95%CI: 2.4-10.5); relevon PR=4.8 (95%CI: 2.5-9.3). CONCLUSIONS: Using an answer sheet for a self-administered paper-and-pencil survey of drug use among students result in lower quality data and higher reports of drug use. International comparison of adolescent drug use from school-based surveys should be done with caution. The relative ranking of a country could be misleading if different mode of recording answers are used. PMID- 28654873 TI - Seller's reputation and capacity on the illicit drug markets: 11-month study on the Finnish version of the Silk Road. AB - AIMS: This 11-month study analyzed illicit drug sales on the anonymous Tor network, with a focus on investigating whether a seller's reputation and capacity increased daily drug sales. DESIGN AND SETTING: The data were gathered from Silkkitie, the Finnish version of the Silk Road, by web crawling the site on a daily basis from (November 2014 to September 2015). The data include information on sellers (n=260) and products (n=3823). MEASUREMENTS: The measurements include the sellers' reputation, the sale amounts (in euros), the number of available products and the types of drugs sold. The sellers' capacity was measured using their full sales potential (in euros). Fixed-effects regression models were used to estimate the effects of sellers' reputation and capacity; these models were adjusted for the types of drugs sold. FINDINGS: Overall, illicit drug sales totalled over 2 million euros during the study, but many products were not sold at all, and sellers were active for only a short time on average (mean=62.8days). Among the products sold, stimulants were most widely purchased, followed by cannabis, MDMA, and psychedelics. A seller's reputation and capacity were both associated with drug sales. CONCLUSION: The Tor network has enabled a transformation in drug sales. Due to the network's anonymity, the seller's reputation and capacity both have an impact on sales. PMID- 28654874 TI - Aquatic toxicity of ivermectin in cattle dung assessed using microcosms. AB - Ivermectin (IVM) is a parasiticide widely used for livestock. It is a semisynthetic derivative of avermectin, a macrocyclic lactone produced by Streptomyces avermitilis. This drug is only partly metabolized by livestock; considerable amounts of parent drug are excreted mostly via feces. To simulate exposure of aquatic invertebrates and macrophytes to direct excretion of cattle dung into surface waters, a microcosm experiment with IVM spiked in cattle dung was conducted. The objectives of this study were to characterize accumulation of IVM in water, sediment+dung, roots of the floating fern Salvinia and the zooplankton Ceriodaphnia dubia, the amphipod Hyalella and the apple snail Pomacea; to determine the effect of this drug spiked in cattle dung on life history traits of these invertebrates; and to evaluate the influence of IVM on aquatic nutrient cycling. Dung was spiked with IVM to attain concentrations of 1150, 458, 50 and 22ugkg-1dung fresh weight, approximating those found in cattle dung at days 3, 7, 16 and 29 following subcutaneous injection. Concentrations found in dung during the first week of excretion were lethally toxic to Ceriodaphnia dubia and Hyalella, whereas no mortality was observed in Pomacea. Concentrations of IVM in roots, sediment + dung and Pomacea increased significantly from the lowest to the highest treatment level. The effect of this drug on decomposition and release of nutrients from dung would have negative consequences for nutrient cycling in water. Increasing concentrations in sediment + dung with days of the experiment suggested that toxic concentrations would persist for an extended period in the water-sediment system. IVM represents an ecological risk for aquatic ecosystems, underscoring the need for livestock management strategies to limit its entry into water bodies. PMID- 28654875 TI - Temporal focus clusters differ meaningfully in terms of anxiety and depressive symptomatology. AB - The present study examined the relationship between temporal focus profiles and scores on psychiatric symptomatology. Participants were recruited by undergraduate students in a university in the United Kingdom (N = 372; 46% male). Five clusters emerged from hierarchical cluster analysis and were labelled, No Focus, Multi Focus, Past Focus, Future Focus, and Current Focus. The worst outcomes in terms of psychiatric symptomatology were observed for those belonging to the Past Focus cluster. These results build on the only previous study using cluster analysis of Temporal Focus Scale scores, where being past focussed was associated with lower self-esteem in adolescents. PMID- 28654876 TI - Interaction between behavioral inhibition and emotional processing in borderline personality disorder using a pictorial emotional go/no-go paradigm. AB - Borderline personality disorder (BPD) is characterized by difficulties in emotional regulation and impulse control. In this study, we presented a novel picture-based emotional go/no-go task with distracting emotional faces in the background, which was administered to 16 patients with BPD and 16 age-matched healthy controls. The faces displayed different emotional content (angry, neutral, or happy). Results showed differences in sensitivity between patients and the control group, with patients exhibiting less sensitivity in the task, and also showed influences of emotional content represented in the distracting faces in both groups. Specifically, happy faces decreased sensitivity compared to angry faces. It seemed as though processing of a positive emotional stimulus led to a more relaxed state and thereby to decreased sensitivity, while a negative emotional stimulus induced more alertness and tension, leading to higher sensitivity. Thus, this paradigm is suitable to investigate the interplay between emotion processing and impulse control in patients with BPD. PMID- 28654877 TI - Highlighting the complexities of a groundwater pilot study during an avian influenza outbreak: Methods, lessons learned, and select contaminant results. AB - The highly pathogenic avian influenza (H5N2) outbreak in the Midwestern United States (US) in 2015 was historic due to the number of birds and poultry operations impacted and the corresponding economic loss to the poultry industry and was the largest animal health emergency in US history. The U.S. Geological Survey (USGS), with the assistance of several state and federal agencies, aided the response to the outbreak by developing a study to determine the extent of virus transport in the environment. The study goals were to: develop the appropriate sampling methods and protocols for measuring avian influenza virus (AIV) in groundwater, provide the first baseline data on AIV and outbreak- and poultry-related contaminant occurrence and movement into groundwater, and document climatological factors that may have affected both survival and transport of AIV to groundwater during the months of the 2015 outbreak. While site selection was expedient, there were often delays in sample response times due to both relationship building between agencies, groups, and producers and logistical time constraints. This study's design and sampling process highlights the unpredictable nature of disease outbreaks and the corresponding difficulty in environmental sampling of such events. The lessons learned, including field protocols and approaches, can be used to improve future research on AIV in the environment. PMID- 28654878 TI - Development of a semi-quantitative risk assessment model for evaluating environmental threat posed by the three first EU watch-list pharmaceuticals to urban wastewater treatment plants: An Irish case study. AB - Contamination of receiving waters with pharmaceutical compounds is of pressing concern. This constitutes the first study to report on the development of a semi quantitative risk assessment (RA) model for evaluating the environmental threat posed by three EU watch list pharmaceutical compounds namely, diclofenac, 17-beta estradiol and 17-alpha-ethinylestradiol, to aquatic ecosystems using Irish data as a case study. This RA model adopts the Irish Environmental Protection Agency Source-Pathway-Receptor concept to define relevant parameters for calculating low, medium or high risk score for each agglomeration of wastewater treatment plant (WWTP), which include catchment, treatments, operational and management factors. This RA model may potentially be used on a national scale to (i) identify WWTPs that pose a particular risk as regards releasing disproportionally high levels of these pharmaceutical compounds, and (ii) help identify priority locations for introducing or upgrading control measures (e.g. tertiary treatment, source reduction). To assess risks for these substances of emerging concern, the model was applied to 16 urban WWTPs located in different regions in Ireland that were scored for the three different compounds and ranked as low, medium or high risk. As a validation proxy, this case study used limited monitoring data recorded at some these plants receiving waters. It is envisaged that this semi quantitative RA approach may aid other EU countries investigate and screen for potential risks where limited measured or predicted environmental pollutant concentrations and/or hydrological data are available. This model is semi quantitative, as other factors such as influence of climate change and drug usage or prescription data will need to be considered in a future point for estimating and predicting risks. PMID- 28654879 TI - Geochemical phase and particle size relationships of metals in urban road dust. AB - Detailed knowledge of the processes that metals undergo during dry weather periods whilst deposited on urban surfaces and their environmental significance is essential to predict the potential influence of metals on stormwater quality in order to develop appropriate stormwater pollution mitigation measures. However, very limited research has been undertaken in this area. Accordingly, this study investigated the geochemical phase and particle size relationships of seven metals which are commonly associated with urban road dust, using sequential extraction in order to assess their mobility characteristics. Metals in the sequentially extracted fractions of exchangeable, reducible, oxidisable and residual were found to follow a similar trend for different land uses even though they had variable accumulation loads. The high affinity of Cd and Zn for exchangeable reactions in both, bulk and size-fractionated solid samples confirmed their high mobility, while the significant enrichment of Ni and Cr in the stable residual fraction indicated a low risk of mobility. The study results also confirmed the availability of Cu, Pb and Mn in both, stable and mobile fractions. The fine fraction of solids (<150 MUm) and antecedent dry days can be highlighted as important parameters when determining the fate of metals associated with urban road dust. The outcomes from this study are expected to contribute to the development of effective stormwater pollution mitigation strategies by taking into consideration the metal-particulate relationships. PMID- 28654880 TI - Fine particulate air pollution and hospital visits for asthma in Beijing, China. AB - Data on fine particulate matter (PM2.5) in China were first announced in 2013. The primary objective of this study was to evaluate the acute effects of PM2.5 on asthma morbidity in Beijing, China. A total of 978,658 asthma hospital visits consisting of 928,607 outpatient visits, 40,063 emergency room visits and 9988 hospital admissions from January 1, 2010, to June 30, 2012, were identified from the Beijing Medical Claim Data for Employees. A generalized additive Poisson model was applied to explore the association between PM2.5 and health service use. The mean daily PM2.5 concentration was 99.5 MUg/m3 with a range from 7.2 MUg/m3 to 492.8 MUg/m3. Ambient PM2.5 concentration was significantly associated with increased use of asthma-related health services. Every 10 MUg/m3 increase in PM2.5 concentration on the same day was significantly associated with a 0.67% (95% CI, 0.53%-0.81%), 0.65% (95% CI, 0.51%-0.80%), and 0.49% (95% CI, 0.35% 0.64%) increase in total hospital visits, outpatient visits and emergency room visits, respectively. The exposure-response association between PM2.5 concentration and hospital visits for asthma exacerbations was approximately linear. In conclusion, this study found that short-term elevations in PM2.5 concentration may increase the risk of asthma exacerbations. Our findings contribute to the limited scientific literature concerning the acute effects of PM2.5 on asthma morbidity outcomes in developing countries. PMID- 28654881 TI - Association between ambient air pollution and hospitalization for ischemic and hemorrhagic stroke in China: A multicity case-crossover study. AB - There is growing interest in the association between ambient air pollution and stroke, but few studies have investigated the association in developing countries. The primary objective of this study was to examine the association between levels of ambient air pollutants and hospital admission for stroke in China. A time-stratified case-crossover analysis was conducted between 2014 and 2015 in 14 large Chinese cities among 200,958 ischemic stroke and 41,746 hemorrhagic stroke hospitalizations. We used conditional logistic regression to estimate the percentage changes in stroke admissions in relation to interquartile range increases in air pollutants. Air pollution was positively associated with ischemic stroke. A difference of an interquartile range of the 6-day average for particulate matter less than 10 MUm in aerodynamic diameter, sulfur dioxide, nitrogen dioxide, carbon monoxide, and ozone corresponded to 0.7% (95% CI: 0%, 1.4%), 1.6% (95% CI: 1.0%, 2.3%), 2.6% (95% CI: 1.8%, 3.5%), 0.5% (95% CI: -0.2%, 1.1%), and 1.3% (95% CI: 0.3%, 2.3%) increases in ischemic stroke admissions, respectively. For hemorrhagic stroke, we observed the only significant association in relation to nitrogen dioxide on the current day (percentage change: 1.6%; 95% CI: 0.3%, 2.9%). Our findings contribute to the limited scientific literature concerning the effect of ambient air pollution on stroke in developing countries. Our findings may have significant public health implications for primary prevention of stroke in China. PMID- 28654882 TI - Synthesis and characterisation of robust emulsion-templated silica microcapsules. AB - Robust silica microcapsules were synthesised using an emulsion template via a seeded growth strategy. Multiple additions of the silica precursor tetraethyl orthosilicate (TEOS) were observed to result in a number of physical and property changes of the capsule shells as compared to a single coating. Scanning electron microscopy indicated a morphological transition from a smooth to a roughened surface. Improved cargo retention and consolidation of the pore structure of the silica shells were observed using dye release experiments and nitrogen porosimetry respectively. In comparison to a typical hollow silica shell synthesis procedure, this one-pot loading and synthesis allows the simple production of robust capsules that are capable of sustained release, using mild conditions and reagents. PMID- 28654883 TI - Removal of chromium (VI) from aqueous solutions using surface modified composite nanofibers. AB - A novel material composite nanofibers (PAN-CNT/TiO2-NH2) based on adsorption of Cr(VI) ions, was applied. Polyacrylonitrile (PAN) and carbon nanotube (CNTs)/titanium dioxide nanoparticles (TiO2) functionalized with amine groups (TiO2-NH2) composite nanofibers have been fabricated by electrospinning. The nanostructures and the formation process mechanism of the obtained PAN-CNT/TiO2 NH2 composite nanofibers are investigated using FTIR, XRD, XPS, SEM, and TEM. The composite nanofibers were used as a novel adsorbent for removing toxic chromium Cr(VI) in aqueous solution. The kinetic study, adsorption isotherm, pH effect, initial concentration, and thermodynamic study were investigated in batch experiments. The composite nanofibers had a positive effect on the absorption of Cr(VI) ions under neutral and acidic conditions, and the saturated adsorption reached the highest when pH was 2. The adsorption equilibrium reached within 30 and 180min with an initial solution concentration increasing from 10 to 300mg/L, and the process can be better described using nonlinear pseudo first than nonlinear pseudo second order model and Intra-particle diffusion. Isotherm data fitted well using linear and nonlinear Langmuir, Freundlich, Redlich-Peterson, and Temkin isotherm adsorption model. Thermodynamic study showed that the adsorption process is exothermic. The adsorption capacity can remain up to 80% after 5 times usage, which show good durability performance. The adsorption mechanism was also studied by UV-vis and XPS. PMID- 28654884 TI - Specific and selective probes for Staphylococcus aureus from phage-displayed random peptide libraries. AB - Staphylococcus aureus is a major human pathogen causing health care-associated and community-associated infections. Early diagnosis is essential to prevent disease progression and to reduce complications that can be serious. In this study, we selected, from a 9-mer phage peptide library, a phage clone displaying peptide capable of specific binding to S. aureus cell surface, namely St.au9IVS5 (sequence peptide RVRSAPSSS).The ability of the isolated phage clone to interact specifically with S. aureus and the efficacy of its bacteria-binding properties were established by using enzyme linked immune-sorbent assay (ELISA). We also demonstrated by Western blot analysis that the most reactive and selective phage peptide binds a 78KDa protein on the bacterial cell surface. Furthermore, we observed selectivity of phage-bacteria-binding allowing to identify clinical isolates of S. aureus in comparison with a panel of other bacterial species. In order to explore the possibility of realizing a selective bacteria biosensor device, based on immobilization of affinity-selected phage, we have studied the physisorbed phage deposition onto a mica surface. Atomic Force Microscopy (AFM) was used to determine the organization of phage on mica surface and then the binding performance of mica-physisorbed phage to bacterial target was evaluated during the time by fluorescent microscopy. The system is able to bind specifically about 50% of S. aureus cells after 15' and 90% after one hour. Due to specificity and rapidness, this biosensing strategy paves the way to the further development of new cheap biosensors to be used in developing countries, as lab-on-chip (LOC) to detect bacterial agents in clinical diagnostics applications. PMID- 28654885 TI - Fabrication of PLA/CaCO3 hybrid micro-particles as carriers for water-soluble bioactive molecules. AB - We propose the use of polylactic acid/calcium carbonate (PLA/CaCO3) hybrid micro particles for achieving improved encapsulation of water-soluble substances. Biodegradable porous CaCO3 microparticles can be loaded with wide range of bioactive substance. Thus, the formation of hydrophobic polymeric shell on surface of these loaded microparticles results on encapsulation and, hence, sealing internal cargo and preventing their release in aqueous media. In this study, to encapsulate proteins, we explore the solid-in-oil-in-water emulsion method for fabricating core/shell PLA/CaCO3 systems. We used CaCO3 particles as a protective core for encapsulated bovine serum albumin, which served as a model protein system. We prepared a PLA coating using dichloromethane as an organic solvent and polyvinyl alcohol as a surfactant for emulsification; in addition, we varied experimental parameters such as surfactant concentration and polymer-to CaCO3 ratio to determine their effect on particle-size distribution, encapsulation efficiency and capsule permeability. The results show that the particle size decreased and the size distribution narrowed as the surfactant concentration increased in the external aqueous phase. In addition, when the CaCO3/PLA mass ratio dropped below 0.8, the hybrid micro-particles were more likely to resist treatment by ethylenediaminetetraacetic acid and thus retained their bioactive cargos within the polymer-coated micro-particles. PMID- 28654886 TI - Bimetallic Pt-Au nanocatalysts electrochemically deposited on boron-doped diamond electrodes for nonenzymatic glucose detection. AB - The enormous demand for medical diagnostics has encouraged the fabrication of high- performance sensing platforms for the detection of glucose. Nonenzymatic glucose sensors are coming ever closer to being used in practical applications. Bimetallic catalysts have been shown to be superior to single metal catalysts in that they have greater activity and selectivity. Here, we demonstrate the preparation, characterization, and electrocatalytic characteristics of a new bimetallic Pt/Au nanocatalyst. This nanocatalyst can easily be synthesized by electrodeposition by sequentially depositing Au and Pt on the surface of a boron doped diamond (BDD) electrode. We characterized the nanocatalyst by scanning electron microscopy (SEM), X-ray diffraction (XRD), and voltammetry. The morphology and composition of the nanocatalyst can be easily controlled by adjusting the electrodeposition process and the molar ratio between the Pt and Au precursors. The electrocatalytic characteristics of a Pt/Au/BDD electrode for the nonenzymatic oxidation of glucose were systematically investigated by cyclic voltammetry. The electrode exhibits higher catalytic activity for glucose oxidation than Pt/BDD and Au/BDD electrodes. The best catalytic activity and stability was obtained with a Pt:Au molar ratio of 50:50. Moreover, the presence of Au can significantly enhance the long-term stability and poisoning tolerance during the electro-oxidation of glucose. Measurements of glucose using the Pt/Au/BDD electrode were linear in the range from 0.01 to 7.5mM, with a detection limit of 0.0077mM glucose. The proposed electrode performs selective electrochemical analysis of glucose in the presence of common interfering species (e.g., acetaminophen, uric and ascorbic acids), avoiding the generation of overlapping signals from such species. PMID- 28654887 TI - Glucose oxidase-initiated cascade catalysis for sensitive impedimetric aptasensor based on metal-organic frameworks functionalized with Pt nanoparticles and hemin/G-quadruplex as mimicking peroxidases. AB - Based on cascade catalysis amplification driven by glucose oxidase (GOx), a sensitive electrochemical impedimetric aptasensor for protein (carcinoembryonic antigen, CEA as tested model) was proposed by using Cu-based metal-organic frameworks functionalized with Pt nanoparticles, aptamer, hemin and GOx (Pt@CuMOFs-hGq-GOx). CEA aptamer loaded onto Pt@CuMOFs was bound with hemin to form hemin@G-quadruplex (hGq) with mimicking peroxidase activity. Through sandwich-type reaction of target CEA and CEA aptamers (Apt1 and Apt2), the obtained Pt@CuMOFs-hGq-GOx as signal transduction probes (STPs) was captured to the modified electrode interface. When 3,3-diaminobenzidine (DAB) and glucose were introduced, the cascade reaction was initiated by GOx to catalyze the oxidation of glucose, in situ generating H2O2. Simultaneously, the decomposition of the generated H2O2 was greatly promoted by Pt@CuMOFs and hGq as synergistic peroxide catalysts, accompanying with the significant oxidation process of DAB and the formation of nonconductive insoluble precipitates (IPs). As a result, the electron transfer in the resultant sensing interface was effectively hindered and the electrochemical impedimetric signal (EIS) was efficiently amplified. Thus, the high sensitivity of the proposed CEA aptasensor was successfully improved with 0.023pgmL-1, which may be promising and potential in assaying certain clinical disease related to CEA. PMID- 28654893 TI - Aberrant patterns of local and long-range functional connectivity densities in schizophrenia. AB - Schizophrenia is a disorder of brain dysconnectivity, and both the connection strength and connection number are disrupted in patients with schizophrenia. The functional connectivity density (FCD) can reflect alterations in the connection number. Alterations in the global FCD (gFCD) in schizophrenia were previously demonstrated; however, alterations in two other indices of the pathological characteristics of the brain, local FCD (lFCD) and long-range FCD (lrFCD), have not been revealed. To investigate lFCD and lrFCD alterations in patients with schizophrenia, 95 patients and 93 matched healthy controls were examined using structural and resting-state functional magnetic resonance imaging scanning. lFCD and lrFCD were measured using FCD mapping, and differences were identified using a two-sample t-test in a voxel-wise manner, with age and gender considered to increase variability. Multiple comparisons were performed using a false discovery rate method with a corrected threshold of P<0.05. Our analysis showed that lFCD was primarily decreased in the postcentral gyrus, right calcarine sulcus, and inferior occipital gyrus lobule, but increased in the bilateral subcortical regions. The differences in lFCD were more pronounced and complicated than those in lrFCD. In summary, in contrast with previous studies that focused on the connection strength, our findings, from the perspective of connection number, indicate that schizophrenia is a disorder of brain dysconnectivity, particularly affecting the local functional connectivity network, and support the hypothesis that schizophrenia is associated with a widespread cortical functional connectivity/activity deficit, with hyper- and/or hypo-connectivity/activity coexisting in some cortical or subcortical regions. PMID- 28654895 TI - Preoperative albumin/globulin ratio has predictive value for patients with laryngeal squamous cell carcinoma. AB - This study evaluated the predictive value of the preoperative albumin/globulin ratio (AGR) in laryngeal squamous cell carcinoma (LSCC) retrospectively, which has not been reported before. The current study enrolled 241 newly diagnosed LSCC patients in the Second Affiliated Hospital of Nanchang University between January 2005 and December 2010. The optimal AGR cut-off value for overall survival (OS) was determined to be 1.28. Univariate survival analysis identified sex, low AGR, T classification, histological grade and nodal metastasis as factors associated with poor OS. Additionally, a low AGR, T classification, nodal metastasis, and histological grade were associated with poor disease-free survival (DFS) in LSCC patients. In multivariate survival analysis, nodal metastasis and a low AGR remained significant for OS and DFS. Our preliminary study revealed that low preoperative AGR could serve as a valuable and easily-assessed blood-based indicator to predict the prognosis of LSCC patients. PMID- 28654894 TI - Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer. AB - Ovarian cancer is the deadliest of all gynecologic cancers. Despite success with initial chemotherapy, the majority of patients relapse with an incurable disease. Development of chemotherapy resistance is a major factor for poor long-term survival in ovarian cancer. The biological effects of estrogens are mediated by estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). Emerging evidence suggests that ovarian cancer cells express ERbeta that functions as a tumor suppressor; however, the clinical utility of ERbeta agonists in ovarian cancer remains elusive. We tested the utility of two natural ERbeta agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer. Both natural ERbeta ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERbeta agonists showed tumor suppressive functions in therapy-resistant ovarian cancer model cells and sensitized ovarian cancer cells to cisplatin and paclitaxel treatment. Global RNA-Seq analysis revealed that ERbeta agonists modulate several tumor suppressive pathways, including downregulation of the NF kappaB pathway. Immunoprecipitation assays revealed that ERbeta interacts with p65 subunit of NF-kappaB and ERbeta overexpression reduced the expression of NF kappaB target genes. In xenograft assays, ERbeta agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERbeta agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERbeta agonists represent novel therapeutic agents for the management of ovarian cancer. PMID- 28654902 TI - Cryptotanshinone inhibits proliferation yet induces apoptosis by suppressing STAT3 signals in renal cell carcinoma. AB - It has been established that signal transducer and activator of transcription 3 serves as an oncoprotein in various human cancers; targeting it is therefore a reasonable approach for emerging cancer therapies. Cryptotanshinone, a natural compound extracted from the root of Salvia miltiorrhiza Bunge, has been identified as a potential STAT3 inhibitor. However, its functional role in renal cell carcinomas remains largely unknown. Therefore, we investigated the mode of action for cryptotanshinone. We found that cryptotanshinone substantially suppressed cancer cell growth while it promoted cell apoptosis by inhibiting the phosphorylation of STAT3 at Tyr705 and its blocking nuclear translocation. Coordinately, P-AKT, CyclinD1, C-MYC, MEKK2, and HGF were down-regulated and cell cycle progression was arrested at the G0/G1 phase, thereby attenuating cell proliferation. Moreover, the level of Cleaved-Caspase-3 was elevated while Bcl-2 and Survivin were down-regulated, accounting for the increased apoptosis. Furthermore, in vivo results revealed that cryptotanshinone effectively inhibits tumorigenesis in an A498-xenografted mouse model. Taken together, our data gives a more comprehensive understanding of how cryptotanshinone functions in renal cell carcinomas and demonstrates its potential as a powerful therapeutic approach to treat renal cell carcinomas. PMID- 28654918 TI - Serum Human Beta-Defensin-2 Is a Possible Biomarker for Monitoring Response to JAK Inhibitor in Psoriasis Patients. AB - AIMS: To analyse the correlation between serum human beta-defensin-2 (hBD-2) levels and response to JAK inhibitor in psoriasis. METHODS: We evaluated the psoriasis area and severity index (PASI) and serum hBD-2 levels of 18 psoriasis patients randomized to receive placebo or tofacitinib 5 or 10 mg b.i.d. at baseline, week 8, and week 16. Serum hBD-2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The PASI achieved a dramatic reduction after tofacitinib 5 or 10 mg b.i.d. treatment for 16 weeks (p < 0.05). Serum hBD 2 levels significantly decreased in patients treated with tofacitinib 10 mg b.i.d. compared with baseline and the placebo-treated patients (p < 0.05). A significant correlation was found between hBD-2 levels and PASI (r = 0.52, p < 0.01). A serum hBD-2 level of 1,255.45 pg/mL was a cut-off between mild and moderate-to-severe psoriasis in ROC analysis. CONCLUSIONS: Serum hBD-2 level might be a possible biomarker for monitoring psoriasis treatment response and differentiating mild from moderate-to-severe psoriasis. PMID- 28654919 TI - A Clinical Score for Predicting Atrial Fibrillation in Patients with Cryptogenic Stroke or Transient Ischemic Attack. AB - OBJECTIVES: Detection of atrial fibrillation (AF) in post-cryptogenic stroke (CS) or transient ischemic attack (TIA) patients carries important therapeutic implications. METHODS: To risk stratify CS/TIA patients for later development of AF, we conducted a retrospective cohort study using data from 1995 to 2015 in the Stanford Translational Research Integrated Database Environment (STRIDE). RESULTS: Of the 9,589 adult patients (age >=40 years) with CS/TIA included, 482 (5%) patients developed AF post CS/TIA. Of those patients, 28.4, 26.3, and 45.3% were diagnosed with AF 1-12 months, 1-3 years, and >3 years after the index CS/TIA, respectively. Age (>=75 years), obesity, congestive heart failure, hypertension, coronary artery disease, peripheral vascular disease, and valve disease are significant risk factors, with the following respective odds ratios (95% CI): 1.73 (1.39-2.16), 1.53 (1.05-2.18), 3.34 (2.61-4.28), 2.01 (1.53-2.68), 1.72 (1.35-2.19), 1.37 (1.02-1.84), and 2.05 (1.55-2.69). A risk-scoring system, i.e., the HAVOC score, was constructed using these 7 clinical variables that successfully stratify patients into 3 risk groups, with good model discrimination (area under the curve = 0.77). CONCLUSIONS: Findings from this study support the strategy of looking longer and harder for AF in post-CS/TIA patients. The HAVOC score identifies different levels of AF risk and may be used to select patients for extended rhythm monitoring. PMID- 28654920 TI - Greater Real-Life Diagnostic Efficacy of Allergen Molecule-Based Diagnosis for Prescription of Immunotherapy in an Area with Multiple Pollen Exposure. AB - BACKGROUND: Allergen molecule-based diagnosis has been suggested to facilitate the identification of disease-causing allergen sources and the prescription of allergen-specific immunotherapy (AIT). The aim of the current study was to compare allergen molecule-based IgE serology with allergen extract-based skin testing for the identification of the disease-causing allergen sources. The study was conducted in an area where patients are exposed to pollen from multiple sources (trees, grasses, and weeds) at the same time to compare the diagnostic efficiency of the 2 forms of diagnosis. METHODS: Patients from Astana, Kazakhstan, who suffered from pollen-induced allergy (n = 95) were subjected to skin prick testing (SPT) with a local panel of tree pollen, grass pollen, and weed pollen allergen extracts and IgE antibodies specific for marker allergen molecules (nArt v 1, nArt v 3, rAmb a 1, rPhl p 1, rPhl p 5, rBet v 1) were measured by ImmunoCAP. Direct and indirect costs for diagnosis based on SPT and marker allergen-based IgE serology as well as direct costs for immunotherapy depending on SPT and serological test results were calculated. RESULTS: The costs for SPT-based diagnosis per patient were lower than the costs for allergen molecule-based IgE serology. However, allergen molecule-based serology was more precise in detecting the disease-causing allergen sources. A lower number of immunotherapy treatments (n = 119) was needed according to molecular diagnosis as compared to extract-based diagnosis (n = 275), which considerably reduced the total costs for diagnosis and for a 3-year treatment from EUR 1,112.30 to 521.77 per patient. CONCLUSIONS: The results from this real-life study show that SPT is less expensive than allergen molecule-based diagnostic testing, but molecular diagnosis allowed more precise prescription of immunotherapy which substantially reduced treatment costs and combined costs for diagnosis and treatment. PMID- 28654923 TI - Antibakterielle In-vitro-Wirksamkeit atherischer Ole gegen veterinarmedizinisch relevante Keime klinischer Isolate von Hunden, Katzen und Pferden. AB - Einleitung: Atherische Ole sind die Grundlage der Aromatherapie. Unter anderem wird ihnen eine antibakterielle Wirkung zugeschrieben. In dieser Studie sollte die In-vitro-Wirksamkeit atherischer Ole gegen ein breites Spektrum veterinarmedizinisch relevanter Erreger getestet werden. Methoden: Die antibakterielle Aktivitat von 16 atherischen Olen wurde mittels Agardiffusionstest bestimmt. Getestet wurden grampositive und gramnegative Erreger, die aus klinischen Isolaten von Hunden, Katzen und Pferden aus der veterinarmedizinischen Routinediagnostik stammten. Die Einteilung der Wirksamkeit in nicht, gering-, mittel- und hochgradig wirksam erfolgte anhand der Grobetae der Hemmhofradien des Bakterienwachstums. Ergebnisse: Generell zeigten sich sowohl grampositive als auch gramnegative Erreger empfindlich gegen einige der getesteten atherischen Ole. Nicht nur gegen Staphylokokken, sondern auch gegen Methicillin-resistente Stamme der Staphylokokken wiesen die atherischen Ole in vitro eine nicht zu vernachlassigende Wirkung auf. Pasteurella multocida stellte sich als eher sensibler Keim heraus, wahrend Pseudomonas aeruginosa als vollkommen resistenter Keim eine Ausnahme bildete. Teebaum-, Oregano-, und Bergbohnenkrautol waren die potentesten Ole. Zusatzlich zeigten sich bei den grampositiven Erregern Lemongrasol und bei den gramnegativen Erregern Thymianol als gut wirksam. Schlussfolgerung: Atherische Ole verfugen in vitro uber eine antibakterielle Aktivitat gegen klinische Isolate von Hunden, Katzen und Pferden. Diese Studie bietet eine Grundlage fur die Anwendung atherischer Ole in der Veterinarmedizin. Es zeichneten sich Tendenzen im Wirkspektrum einzelner atherischer Ole bzw. im Grad der Wirksamkeit atherischer Ole hinsichtlich einzelner Erregerspezies ab, allerdings lasst sich keine sichere Vorhersage uber ihre Wirksamkeit gegen einen spezifischen Keim eines individuellen Patienten treffen. Deswegen sollte vor einer Therapie mit atherischen Olen deren individuelle Wirksamkeit mittels Aromatogramm getestet werden. PMID- 28654921 TI - Effect of Maternal Dietary Patterns during Pregnancy on Self-Reported Allergic Diseases in the First 3 Years of Life: Results from the GUSTO Study. AB - BACKGROUND: Maternal diet during pregnancy has been suggested to be an important early-life exposure that influences immune tolerance and the development of allergic diseases in offspring. METHODS: We examined the relationship between maternal dietary patterns assessed using 24-h recalls and food diaries at 26-28 weeks of pregnancy and the subsequent development of allergic outcomes in the offspring in the Growing Up in Singapore towards Healthy Outcomes (GUSTO) birth cohort. Exploratory factor analysis was used to characterize maternal dietary patterns during pregnancy. During repeated visits in the first 36 months of life, questionnaires were administered to ascertain allergic symptoms, namely, eczema, rhinitis, and wheeze. At ages 18 and 36 months, we administered skin-prick testing to inhalant and food allergens. RESULTS: Of the 3 maternal dietary patterns that emerged, the seafood and noodles pattern was associated with a reduced risk of developing allergen sensitization at both 18 months (odds ratio [95% confidence interval]: 0.7 [0.5-0.9]) and 36 months (0.7 [0.6-0.9]) after adjustment for a family history of allergy, and ethnicity, sex, and maternal education levels. No associations between the patterns vegetables, fruit, and white rice or pasta, cheese, and processed meat were observed with any of the allergic outcomes in the first 18 and 36 months of life. CONCLUSION: Maternal diet during pregnancy can influence the subsequent development of allergic outcomes in offspring. PMID- 28654924 TI - Influence of Intrinsic and Lifestyle Factors on the Development of IgE Sensitization. AB - BACKGROUND: IgE sensitization is a prerequisite for the development of allergic symptoms. The investigation of factors influencing the development of IgE is therefore crucial for understanding the onset of allergic diseases. METHODS: This epidemiological study investigated personal, intrinsic, and lifestyle factors in a nonselected cohort of 501 Austrian adolescents (aged 12-21 years). IgE levels to 112 allergen molecules were analyzed in the serum of participants using the ImmunoCAP ISAC(r). Allergic sensitization, IgE levels to single allergens, and ISAC score sums were correlated with results obtained from a questionnaire. RESULTS: In this adolescent cohort, male participants showed a higher sensitization frequency (56.8%) compared to females (50.9%) and significantly increased IgE levels to profilins. Underweight subjects demonstrated a stronger IgE sensitization. Family size inversely correlated with IgE levels to PR-10 allergens, and predominately paternal allergies were a predictive factor for IgE sensitization in the children. Vaccination, breastfeeding, and delivery mode showed no influence, while a highly protective effect was observed for growing up on a farm. Of all of the investigated lifestyle factors, only smoking significantly influenced the risk for IgE development. Participants with moderate frequencies of colds showed increased sensitization levels. CONCLUSION: A hereditary predisposition and lifestyle factors such as a farming environment, smoking, family size, body weight, or frequency of colds significantly influenced the development of allergen-specific IgE in this cohort of adolescents. PMID- 28654925 TI - Cardiovascular Oncologic Emergencies. AB - Oncologic emergencies can present either as a progression of a known cancer or as the initial presentation of a previously undiagnosed cancer. In most of these situations, a very high degree of suspicion is required to allow prompt assessment, diagnosis, and treatment. In this article, we review the presentation and management of cardiovascular oncologic emergencies from primary and metastatic tumors of the heart and complications such as pericardial tamponade, superior vena cava syndrome, and hyperviscosity syndrome. We have included the cardiovascular complications from radiation therapy, chemotherapeutic agents, and biologic agents used in modern cancer treatment. PMID- 28654926 TI - Are There Indications for Isotretinoin Treatment of Hidradenitis Suppurativa? PMID- 28654927 TI - Acute Diverticulitis and Subsequent Colonoscopy: Instigating an Old Discussion. PMID- 28654928 TI - Risk Stratification of Patients with Crohn's Disease: A Retrospective Analysis of Clinical Decision Making and Its Impact on Long-Term Outcome. AB - BACKGROUND AND AIMS: Complications such as need for bowel resections and hospitalization due to Crohn's disease (CD) occur when disease activity persists due to ineffective therapy. Certain "high-risk" features require an early introduction of anti-tumor necrosis factor-alpha therapy to prevent such complications. We aim to evaluate the prevalence of "high-risk" features among a cohort of patients with CD and examine the association between discordance of early therapy with baseline risk stratification and disease outcome. PATIENTS AND METHODS: All adult patients with CD were retrospectively identified and their medical records were reviewed. Clinical, endoscopic, laboratory, and radiological data were collected. Patients were divided into "low" and "high" risk groups according to the presence or absence of penetrating disease, perianal involvement, foregut involvement, extensive disease seen on endoscopy or cross sectional imaging, young age at the time of diagnosis (<40), persistent cigarette smoking and frequent early requirements for corticosteroid therapy. Initial treatment selection and treatment approach ("step-up" vs. "accelerated step-up" vs. "top-down") within 6 months of diagnosis were recorded. Rates of CD-related bowel resections and hospitalization within 5 years of diagnosis were calculated. Logistic regression analysis was used to examine the association between "discordance" of early treatment selections and risk stratification categories with outcomes. RESULTS: Eighty-five CD patients were included. The median age and duration of disease were 25 (interquartile range [IQR] 19-32) and 5 (IQR 4-6) years, respectively. Sixty five percent were females and 66% were native Saudis. Smoking was reported in 12% of patients and perianal disease in 18%. "High-risk" features were identified in 43 (51%) patients, of which only 6 (14%) were treated with "top-down" therapy and 7 (16%) with "accelerated step-up" care. The risk of requiring a bowel resection, and hospitalization was higher for "high-risk" patients compared to "low-risk" patients (risk ratio [RR] 13.67, 95% CI 1.88 99.41; p = 0.003, and RR 1.86, 95% CI 0.03-0.43; p = 0.0312, respectively). "Discordance" occurred in 34% of cases. Bowel resection was required in 15/85 (18%) patients and 32/85 (38%) required at least one hospitalization within 5 years of diagnosis. Logistic regression analysis identified a statistically significant association between "discordance" and need for bowel resections (OR 6.50, 95% CI 1.59-26.27, p = 0.009), and hospitalizations (OR 3.01, 95% CI 1.08 8.39, p = 0.035) within 5 years of diagnosis. CONCLUSIONS: "Discordance" between patient risk-profile and treatment selection early in the course of CD has a significant impact on disease outcome, specifically need for bowel resection and hospitalization, which are more likely to occur in the presence of "high-risk" features. Early identification of "high-risk" features could help prevent long term complications. PMID- 28654929 TI - Temperature effects on life history traits of two sympatric branchiopods from an ephemeral wetland. AB - Temperature effects on organisms are of multiple scientific interests, such as for their life history performance and for the study of evolutionary strategies. We have cultured two sympatric branchiopod species from an ephemeral pond in northern Taiwan, Branchinella kugenumaensis and Eulimnadia braueriana, and compared their hatching rate, maturation time, sex ratio, growth of body length, survivorship, clutch size, net reproductive rate R0, generation time TG, and intrinsic rate of natural increase r in relation to temperature (15, 20, 25 and 30 degrees C). We found that E. braueriana had a significantly higher temperature dependent fecundity and intrinsic population growth pattern (R0 and r). In contrast, B. kugenumaensis reproduced much slower than E. braueriana with much lower R0 (90-100 folds less) and r (about 10 folds less) at 15, 20 and 25 degrees C and with a double as long TG at 20 and 25 degrees C. In addition, E. braueriana increased its chance of hermaphroditic sexual reproductive mode at higher temperature because of a significantly delayed maturation of males from hermaphrodites. In contrast, B. kugenumaensis showed no significant change in reproductive mode with temperature. This is the first study indicating a significant differentiation in life history parameters of two sympatric branchiopods mediated by temperature. PMID- 28654934 TI - Risk of Primary Tumor Sidedness as a Criterion for Screening, Diagnostic Colonoscopy, and Surveillance Intervals. PMID- 28654930 TI - Understanding the (inter)disciplinary and institutional diversity of citizen science: A survey of current practice in Germany and Austria. AB - Citizen science has become more popular in recent years, quickly taking on a variety of potentially conflicting characteristics: a way to collect massive data sets at relatively low cost, a way to break science out of the ivory tower and better engage the public, an approach to educate lay people in scientific methods. But the extent of current citizen science practice-the types of actors and scientific disciplines who take part-is still poorly understood. This article builds on recent surveys of citizen science in PLOS One by analyzing citizen science practice in Germany and Austria through the projects on two online platforms. We find evidence supporting previous findings that citizen science is a phenomenon strongest in biodiversity and environmental monitoring research, but at home in a number of scientific fields, such as history and geography. In addition, our survey method yields new insights into citizen science projects initiated by non-scientific actors. We close by discussing additional methodological considerations in attempting to present a cross-disciplinary overview of citizen science. PMID- 28654935 TI - Prenatally Diagnosed Trisomy 21. PMID- 28654936 TI - An Objective Drug-Induced Sedation Endoscopy Data Capture and Analysis System Reply. PMID- 28654938 TI - Numerical Study of Bubble Area Evolution During Acoustic Droplet Vaporization Enhanced HIFU Treatment. AB - Acoustic droplet vaporization has the potential to shorten treatment time of high intensity focused ultrasound (HIFU) while minimizing the possible effects of microbubbles along the propagation path. Distribution of the bubbles formed from the droplets during the treatment is the major factor shaping the therapeutic region. A numerical model was proposed to simulate the bubble area evolution during this treatment. Using a linear acoustic equation to describe the ultrasound field, a threshold range was defined that determines the amount of bubbles vaporized in the treated area. Acoustic parameters, such as sound speed, acoustic attenuation coefficient, and density, were treated as a function of the bubble size distribution and the gas void fraction, which were related to the vaporized bubbles in the medium. An effective pressure factor was proposed to account for the influence of the existing bubbles on the vaporization of the nearby droplets. The factor was obtained by fitting one experimental result and was then used to calculate bubble clouds in other experimental cases. Comparing the simulation results to these other experiments validated the model. The dynamic change of the pressure and the bubble distribution after exposure to over 20 pulses of HIFU are obtained. It is found that the bubble area grows from a grainlike shape to a "tadpole," with comparable dimensions and shape to those observed in experiments. The process was highly dynamic with the shape of the bubble area changing with successive HIFU pulses and the focal pressure. The model was further used to predict the shape of the bubble region triggered by HIFU when a bubble wall pre-exists. The results showed that the bubble wall helps prevent droplet vaporization on the distal side of the wall and forms a particularly shaped region with bubbles. This simulation model has predictive potential that could be beneficial in applications, such as cancer treatment, by parametrically studying conditions associated with these treatments and designing treatment protocols. PMID- 28654937 TI - Handheld In Vivo Reflectance Confocal Microscopy for the Diagnosis of Eyelid Margin and Conjunctival Tumors. AB - Importance: The clinical diagnosis of conjunctival and eyelid margin tumors is challenging, and new noninvasive imaging techniques could be valuable in this field. Objective: To assess the diagnostic accuracy of handheld in vivo reflectance confocal microscopy (IVCM) for the diagnosis of eyelid margin and conjunctival tumors. Design: A prospective observational study was conducted at University Hospital of Saint-Etienne from January 2, 2011, to December 31, 2016 (inclusion of patients until December 31, 2015, and follow-up until December 31, 2016). A total of 278 consecutive patients with eyelid margin or conjunctival lesions were included. Conjunctival lesions were diagnosed with a conventional clinical examination using a slitlamp and by handheld IVCM. Final diagnoses were established by histopathologic examination for 155 neoformations suspicious for being malignant through clinical and/or IVCM examination that were excised and on follow-up of 12 months or longer for the remaining 140 lesions. Main Outcomes and Measures: Sensitivity, specificity, and positive and negative predictive values for malignant tumors of the conjunctiva and eyelid margin were calculated using clinical examination with slitlamp and handheld IVCM. Results: In the 278 patients (136 [48.9%] females; mean [SD] age, 59 [21] years), a total of 166 eyelid margin and 129 conjunctival lesions were included in the analysis. Of the 155 excised neoformations with a histopathologic diagnosis, IVCM showed higher sensitivity compared with clinical examination conducted with the slitlamp for malignant tumors of the eyelid margin (98% vs 92%) and conjunctiva (100% vs 88%). The specificity for malignant eyelid margin tumors was higher for IVCM than for slitlamp examination (74% vs 46%), but slightly less for malignant conjunctival tumors (78% vs 88%). Analysis of all neoformations (155 excised and 140 in follow up) confirmed these differences in the diagnostic accuracy of the clinical examination and IVCM. The presence of hyperreflective Langerhans cells mimicking malignant melanocytes was the main cause for misdiagnosis of malignant conjunctival tumors with IVCM. Conclusions and Relevance: Handheld IVCM could be a useful tool for the identification of malignant conjunctival tumors. Further studies are required to confirm the usefulness of this device and identify possible features that can differentiate Langerhans cells from malignant melanocytes to prevent the misdiagnosis of melanoma using IVCM. PMID- 28654939 TI - Speech Versus Speaking: The Experiences of People With Parkinson's Disease and Implications for Intervention. AB - Purpose: In this project, we explore the experiences of people who report speech changes associated with Parkinson's disease as they describe taking part in everyday communication situations and report impressions related to speech treatment. Method: Twenty-four community-dwelling adults with Parkinson's disease took part in face-to-face, semistructured interviews. Qualitative research methods were used to code and develop themes related to the interviews. Results: Two major themes emerged. The first, called "speaking," included several subthemes: thinking about speaking, weighing value versus effort, feelings associated with speaking, the environmental context of speaking, and the impact of Parkinson's disease on speaking. The second theme involved "treatment experiences" and included subthemes: choosing not to have treatment, the clinician, drills and exercise, and suggestions for change. Conclusions: From the perspective of participants with Parkinson's disease, speaking is an activity requiring both physical and cognitive effort that takes place in a social context. Although many report positive experiences with speech treatment, some reported dissatisfaction with speech drills and exercises and a lack of focus on the social aspects of communication. Suggestions for improvement include increased focus on the cognitive demands of speaking and on the psychosocial aspects of communication. PMID- 28654940 TI - Consonant Acoustics in Parkinson's Disease and Multiple Sclerosis: Comparison of Clear and Loud Speaking Conditions. AB - Purpose: The impact of clear speech or an increased vocal intensity on consonant spectra was investigated for speakers with mild dysarthria secondary to multiple sclerosis or Parkinson's disease and healthy controls. Method: Sentences were read in habitual, clear, and loud conditions. Spectral moment coefficients were obtained for word-initial and word-medial /s/, /?/, /t/, and /k/. Global production differences among conditions were confirmed with measures of vocal intensity and articulation rate. Results: Static or slice-in-time first moments (M1) for loud differed most frequently from habitual, but neither loud nor clear enhanced M1 contrast for consonant pairs. In several instances, the clear and loud conditions yielded stable or nonvarying fricative M1 time histories. Spectral contrast was reduced for word-medial versus word-initial consonant pairs. Conclusion: The finding that the loud and especially clear condition yielded fairly subtle changes in consonant spectra suggests these global techniques may minimally enhance consonant segmental production or contrast in mild dysarthria. The robust effect of word position on consonant spectra indicates that this variable deserves consideration in future studies. Future research also is needed to investigate how or whether consonant production bears on the improved intelligibility previously reported for these global dysarthria treatment techniques. PMID- 28654942 TI - Jaw Rotation in Dysarthria Measured With a Single Electromagnetic Articulography Sensor. AB - Purpose: This study evaluated a novel method for characterizing jaw rotation using orientation data from a single electromagnetic articulography sensor. This method was optimized for clinical application, and a preliminary examination of clinical feasibility and value was undertaken. Method: The computational adequacy of the single-sensor orientation method was evaluated through comparisons of jaw rotation histories calculated from dual-sensor positional data for 16 typical talkers. The clinical feasibility and potential value of single-sensor jaw rotation were assessed through comparisons of 7 talkers with dysarthria and 19 typical talkers in connected speech. Results: The single-sensor orientation method allowed faster and safer participant preparation, required lower data acquisition costs, and generated less high-frequency artifact than the dual sensor positional approach. All talkers with dysarthria, regardless of severity, demonstrated jaw-rotation histories with more numerous changes in movement direction and reduced smoothness compared with typical talkers. Conclusions: Results suggest that the single-sensor orientation method for calculating jaw rotation during speech is clinically feasible. Given the preliminary nature of this study and the small participant pool, the clinical value of such measures remains an open question. Further work must address the potential confound of reduced speaking rate on movement smoothness. PMID- 28654941 TI - Internally Versus Externally Cued Speech in Parkinson's Disease and Cerebellar Disease. AB - Purpose: The purpose of this study was to examine the effects of an internally versus externally cued speech task on perceived understandability and naturalness in speakers with Parkinson's disease (PD) and cerebellar disease (CD). Method: Sentences extracted from a covertly recorded conversation (internally cued) were compared to the same sentences read aloud (externally cued) by speakers with PD and a clinical comparison group of speakers with CD. Experienced listeners rated the speech samples using a visual analog scale for the perceptual dimensions of understandability and naturalness. Results: Results suggest that experienced listeners rated the speech of participants with PD as significantly more natural and more understandable during the reading condition. Participants with CD were also rated as significantly more understandable during the reading condition, but ratings of naturalness did not differ between conversation and reading. Conclusions: Speech tasks can have a pronounced impact on perceived speech patterns. For individuals with PD, both understandability and naturalness can improve during reading tasks versus conversational tasks. The speech benefits from reading may be attributed to several mechanisms, including possible improvement from an externally cued speech task. These findings have implications for speech task selection in evaluating individuals with dysarthria. PMID- 28654943 TI - The Nature of Error Consistency in Individuals With Acquired Apraxia of Speech and Aphasia. AB - Purpose: The primary characteristics used to define acquired apraxia of speech (AOS) have evolved to better reflect a disorder of motor planning/programming. However, there is debate regarding the feature of relatively consistent error location and type. Method: Ten individuals with acquired AOS and aphasia and 11 individuals with aphasia without AOS participated in this study. In the context of a 2-group experimental design, error consistency was examined via 5 repetitions of 30 multisyllabic words. The influence of error rate, severity of impairment, and stimulus presentation condition (blocked vs. random) on error consistency was also explored, as well as between-groups differences in the types of errors produced. Results: Groups performed similarly on consistency of error location; however, adults with AOS demonstrated greater variability of error type in a blocked presentation condition only. Stimulus presentation condition, error rate, and severity of impairment did not influence error consistency in either group. Groups differed in the production of phonetic errors (e.g., sound distortions) but not phonemic errors. Conclusions: Overall, findings do not support relatively consistent errors as a differentiating characteristic of AOS. PMID- 28654944 TI - Perceptually Salient Sound Distortions and Apraxia of Speech: A Performance Continuum. AB - Purpose: We sought to characterize articulatory distortions in apraxia of speech and aphasia with phonemic paraphasia and to evaluate the diagnostic validity of error frequency of distortion and distorted substitution in differentiating between these disorders. Method: Study participants were 66 people with speech sound production difficulties after left-hemisphere stroke or trauma. They were divided into 2 groups on the basis of word syllable duration, which served as an external criterion for speaking rate in multisyllabic words and an index of likely speech diagnosis. Narrow phonetic transcriptions were completed for audio recorded clinical motor speech evaluations, using 29 diacritic marks. Results: Partial voicing and altered vowel tongue placement were common in both groups, and changes in consonant manner and place were also observed. The group with longer word syllable duration produced significantly more distortion and distorted-substitution errors than did the group with shorter word syllable duration, but variations were distributed on a performance continuum that overlapped substantially between groups. Conclusions: Segment distortions in focal left-hemisphere lesions can be captured with a customized set of diacritic marks. Frequencies of distortions and distorted substitutions are valid diagnostic criteria for apraxia of speech, but further development of quantitative criteria and dynamic performance profiles is necessary for clinical utility. PMID- 28654945 TI - Quantification and Systematic Characterization of Stuttering-Like Disfluencies in Acquired Apraxia of Speech. AB - Purpose: The purpose of this article is to quantify and describe stuttering-like disfluencies in speakers with acquired apraxia of speech (AOS), utilizing the Lidcombe Behavioural Data Language (LBDL). Additional purposes include measuring test-retest reliability and examining the effect of speech sample type on disfluency rates. Method: Two types of speech samples were elicited from 20 persons with AOS and aphasia: repetition of mono- and multisyllabic words from a protocol for assessing AOS (Duffy, 2013), and connected speech tasks (Nicholas & Brookshire, 1993). Sampling was repeated at 1 and 4 weeks following initial sampling. Stuttering-like disfluencies were coded using the LBDL, which is a taxonomy that focuses on motoric aspects of stuttering. Results: Disfluency rates ranged from 0% to 13.1% for the connected speech task and from 0% to 17% for the word repetition task. There was no significant effect of speech sampling time on disfluency rate in the connected speech task, but there was a significant effect of time for the word repetition task. There was no significant effect of speech sample type. Conclusions: Speakers demonstrated both major types of stuttering like disfluencies as categorized by the LBDL (fixed postures and repeated movements). Connected speech samples yielded more reliable tallies over repeated measurements. Suggestions are made for modifying the LBDL for use in AOS in order to further add to systematic descriptions of motoric disfluencies in this disorder. PMID- 28654946 TI - Fricative Contrast and Coarticulation in Children With and Without Speech Sound Disorders. AB - Purpose: The purpose of this study was, first, to expand our understanding of typical speech development regarding segmental contrast and anticipatory coarticulation, and second, to explore the potential diagnostic utility of acoustic measures of fricative contrast and anticipatory coarticulation in children with speech sound disorders (SSD). Method: In a cross-sectional design, 10 adults, 17 typically developing children, and 11 children with SSD repeated carrier phrases with novel words with fricatives (/s/, /?/). Dependent measures were 2 ratios derived from spectral mean, obtained from perceptually accurate tokens. Group analyses compared adults and typically developing children; individual children with SSD were compared to their respective typically developing peers. Results: Typically developing children demonstrated smaller fricative acoustic contrast than adults but similar coarticulatory patterns. Three children with SSD showed smaller fricative acoustic contrast than their typically developing peers, and 2 children showed abnormal coarticulation. The 2 children with abnormal coarticulation both had a clinical diagnosis of childhood apraxia of speech; no clear pattern was evident regarding SSD subtype for smaller fricative contrast. Conclusions: Children have not reached adult-like speech motor control for fricative production by age 10 even when fricatives are perceptually accurate. Present findings also suggest that abnormal coarticulation but not reduced fricative contrast is SSD-subtype-specific. Supplemental Materials: S1: https://doi.org/10.23641/asha.5103070. S2 and S3: https://doi.org/10.23641/asha.5106508. PMID- 28654947 TI - Acquired Apraxia of Speech: The Relationship Between Awareness of Errors in Word Productions and Treatment Outcomes. AB - Purpose: Awareness of errors has been considered a clinical feature of acquired apraxia of speech (AOS). However, there is limited research examining error awareness in speakers with AOS. The purpose of this investigation was to examine awareness of errors and explore the relationship between awareness of errors and treatment outcomes in speakers with AOS. Method: Twenty speakers with AOS and aphasia produced mono- and multisyllabic words in a repetition task. Following each production, speakers were asked to judge the accuracy of their production (i.e., correct or incorrect). Then, speakers received Sound Production Treatment. Results: Judgment accuracy of productions for the group ranged from 20% to 96%. There was a weak relationship between judgment accuracy and probe performance at posttreatment (r = .47) and a moderate relationship between judgment accuracy and probe performance at follow-up (r = .53). Conclusion: Findings indicate that speakers with AOS varied in their ability to judge the accuracy of their productions. For some speakers, the ability to judge the accuracy of their productions did not coincide with their production accuracy of treatment stimuli at posttreatment and at follow-up. Further research is needed to explore the relationship between error awareness and treatment outcomes. PMID- 28654948 TI - Self-Rated Communication-Related Quality of Life of Individuals With Oromandibular Dystonia Receiving Botulinum Toxin Injections. AB - Purpose: In this preliminary study, we examined self-rated communication-related quality of life (CR-QoL) of 10 control participants and 10 individuals with oromandibular dystonia (OMD) and dysarthria receiving therapeutic botulinum toxin (BoNT-A) injections. Method: Participants with OMD and associated dysarthria self rated CR-QoL pre- and post- BoNT-A injection using the American Speech-Language Hearing Association's Quality of Communication Life Scale (ASHA QCL; Paul et al., 2004). Control participants self-rated CR-QoL during a single experimental visit. Results: Significant differences were found between control participants and participants with OMD on ratings of CR-QoL across all 5 domains and subdomains of the ASHA QCL. No significant differences in CR-QoL were found over the course of the BoNT-A treatment cycle. Conclusions: CR-QoL was rated lower by participants with OMD as compared with control participants across all ASHA QCL domains/subdomains with "socialization/activities" and "confidence/self-concept" having the largest effect sizes. No differences in CR-QoL were found over the course of the treatment cycle. We advocate for outcome measures that include patient report. The use of patient-reported outcome measures in conjunction with objective or impairment-based outcome measures can help inform meaningful clinical indicators of treatment success. This study adds novel information that may aid our understanding of the experience of living with OMD in this underserviced clinical population. PMID- 28654949 TI - The Effects of Lip-Closure Exercise on Lip Strength and Function Following Full Facial Transplantation: A Case Report. AB - Purpose: Facial transplantation is a relatively new option for individuals with severe facial disfigurements. Clinical case studies on existing patients indicate many instances of persistent facial motor impairment for facial expression, speech, and swallowing. These preliminary findings motivate additional research on the impact of lip-strengthening exercises following facial transplantation. Method: In this study, we assessed the efficacy of an 8-week, biofeedback-driven, lip closure-strengthening exercise program in a single patient 1-year status post full facial transplantation. Exercise was at 60% of peak strength. Outcome measures included instrumental measures of lip strength and mobility, clinical measures of speech, and patient-reported outcomes in feeding and facial expression. Results: Results revealed improvements in labial strength, speed of lip movement, and range of motion during speech. A 3-point improvement in sentence speech intelligibility was also observed following strength-training exercise. The patient reported improvements in her ability to drink from a straw and communicate via facial expression. Conclusion: These preliminary findings motivate additional research on the efficacy of lip-strengthening exercises following facial transplantation. PMID- 28654951 TI - Re-Enchanting Medicine. PMID- 28654952 TI - Are Antiplatelet Agents Beneficial in Essential Thrombocythemia? Maybe Yes, Probably No. PMID- 28654953 TI - Adverse Events Reported to the US Food and Drug Administration for Cosmetics and Personal Care Products. PMID- 28654955 TI - Circumscribed Iris Elevation in a Middle-Aged Woman. PMID- 28654954 TI - Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy: The EQUIGEN Randomized Clinical Trial. AB - Importance: Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. Objective: To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. Design, Setting, and Participants: The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (>=18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to treat analyses. Interventions: Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. Main Outcomes and Measures: The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Results: Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, chi22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-infinity, 4.05; P >= .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject * formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0 infinity, 0.36; P >= .76). Conclusions and Relevance: This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs. Trial Registration: clinicaltrials.gov Identifier: NCT01733394. PMID- 28654956 TI - Rubella and Zika Vaccine Research-A Cautionary Tale About Caution. PMID- 28654957 TI - CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Simplified Chinese Version). AB - Editors' Note: This article is the simplified Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. (Cheng C, Wu T, Shang H, Li, Y, Altman D, Moher D; CONSORT-CHM Formulas 2017 Group. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;167:112-21. [Epub 27 June 2017]. doi:10.7326/M16-2977). PMID- 28654958 TI - The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized Trial. AB - Background: Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value. Objective: To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design: Pilot randomized trial. (ClinicalTrials.gov: NCT01736566). Setting: Academic primary care practices. Participants: 9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years. Intervention: Patients were randomly assigned to receive a family history report alone (FH group) or in combination with an interpreted WGS report (FH + WGS group), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her PCP to discuss the report. Measurements: Clinical outcomes and health care use through 6 months were obtained from medical records and audio-recorded discussions between PCPs and patients. Patients' health behavior changes were surveyed 6 months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results. Results: Mean age was 55 years; 58% of patients were female. Eleven FH + WGS patients (22% [95% CI, 12% to 36%]) had new MDR results. Only 2 (4% [CI, 0.01% to 15%]) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). Primary care physicians recommended new clinical actions for 16% (CI, 8% to 30%) of FH patients and 34% (CI, 22% to 49%) of FH + WGS patients. Thirty percent (CI, 17% to 45%) and 41% (CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after 6 months. Geneticists rated PCP management of 8 MDR results (73% [CI, 39% to 99%]) as appropriate and 2 results (18% [CI, 3% to 52%]) as inappropriate. Limitation: Limited sample size and ancestral and socioeconomic diversity. Conclusion: Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Nongeneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value. Primary Funding Source: National Institutes of Health. PMID- 28654959 TI - Cardiovascular Testing and Clinical Outcomes in Emergency Department Patients With Chest Pain. AB - Importance: Noninvasive testing and coronary angiography are used to evaluate patients who present to the emergency department (ED) with chest pain, but their effects on outcomes are uncertain. Objective: To determine whether cardiovascular testing-noninvasive imaging or coronary angiography-is associated with changes in the rates of coronary revascularization or acute myocardial infarction (AMI) admission in patients who present to the ED with chest pain without initial findings of ischemia. Design, Setting, and Participants: This retrospective cohort analysis used weekday (Monday-Thursday) vs weekend (Friday-Sunday) presentation as an instrument to adjust for unobserved case-mix variation (selection bias) between 2011 and 2012. National claims data (Truven MarketScan) was used. The data included a total of 926 633 privately insured patients ages 18 to 64 years who presented to the ED with chest pain without initial diagnosis consistent with acute ischemia. Exposures: Noninvasive testing or coronary angiography within 2 days or 30 days of presentation. Main Outcomes and Measures: The primary end points were coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) and AMI admission at 7, 30, 180, and 365 days. The secondary end points were coronary angiography and coronary artery bypass grafting in those who underwent angiography. Results: The patients were ages 18 to 64 years with an average age of 44.4 years. A total of 536 197 patients (57.9%) were women. Patients who received testing (224 973) had increased risk at baseline and had greater risk of AMI admission than those who did not receive testing (701 660) (0.35% vs 0.14% at 30 days). Weekday patients (571 988) had similar baseline comorbidities to weekend patients (354 645) but were more likely to receive testing. After risk factor adjustment, testing within 30 days was associated with a significant increase in coronary angiography (36.5 per 1000 patients tested; 95% CI, 21.0-52.0) and revascularization (22.8 per 1000 patients tested; 95% CI, 10.6-35.0) at 1 year but no significant change in AMI admissions (7.8 per 1000 patients tested; 95% CI, -1.4 to 17.0). Testing within 2 days was also associated with a significant increase in coronary revascularization but no difference in AMI admissions. Conclusions and Relevance: Cardiac testing in patients with chest pain was associated with increased downstream testing and treatment without a reduction in AMI admissions, suggesting that routine testing may not be warranted. Further research into whether specific high-risk subgroups benefit from testing is needed. PMID- 28654960 TI - The cost of making an eye movement: A direct link between visual working memory and saccade execution. AB - To facilitate visual continuity across eye movements, the visual system must presaccadically acquire information about the future foveal image. Previous studies have indicated that visual working memory (VWM) affects saccade execution. However, the reverse relation, the effect of saccade execution on VWM load is less clear. To investigate the causal link between saccade execution and VWM, we combined a VWM task and a saccade task. Participants were instructed to remember one, two, or three shapes and performed either a No Saccade-, a Single Saccade- or a Dual (corrective) Saccade-task. The results indicate that items stored in VWM are reported less accurately if a single saccade-or a dual saccade task is performed next to retaining items in VWM. Importantly, the loss of response accuracy for items retained in VWM by performing a saccade was similar to committing an extra item to VWM. In a second experiment, we observed no cost of executing a saccade for auditory working memory performance, indicating that executing a saccade exclusively taxes the VWM system. Our results suggest that the visual system presaccadically stores the upcoming retinal image, which has a similar VWM load as committing one extra item to memory and interferes with stored VWM content. After the saccade, the visual system can retrieve this item from VWM to evaluate saccade accuracy. Our results support the idea that VWM is a system which is directly linked to saccade execution and promotes visual continuity across saccades. PMID- 28654961 TI - Labeled lines for image blur and contrast. AB - It has been suggested that blur and contrast discrimination thresholds are limited by a common stage of contrast energy transduction, and that this explains the characteristic "dipper" functions found for contrast and blur discrimination. To test this conjecture, thresholds for discriminating increments from decrements in sharpness/blur, and similarly for contrast, were measured using the same chessboard stimuli with the Method of Single Stimuli (Experiment 1). Using a generic human contrast sensitivity function (HCSF) to calculate energy, thresholds were significantly lower for blur than for contrast. They could be made more similar only by using an implausibly narrow band-pass version of the HCSF. In separate sessions (Experiment 2), observers also attempted to discriminate between blur and contrast changes when they were randomly interleaved (channel discrimination). Channel discrimination thresholds were similar to those predicted from noisy independent channels, consistent with separate labeled lines for the two channels. Experiment 3 measured subthreshold summation of contrast and blur signals, in either energy-add or energy-subtract modes with a two-alternative forced choice task. Both add and subtract modes lowered thresholds. Experiment 4 measured standard T versus C ("dipper") functions for blur, and compared these with T versus C functions when a contrast cue was added to keep energy constant. The finding of a "dipper" function in the latter case suggests that it does not arise from a common energy transduction stage. PMID- 28654962 TI - The contribution of nonrigid motion and shape information to object perception in pigeons and humans. AB - The ability to perceive and recognize objects is essential to many animals, including humans. Until recently, models of object recognition have primarily focused on static cues, such as shape, but more recent research is beginning to show that motion plays an important role in object perception. Most studies have focused on rigid motion, a type of motion most often associated with inanimate objects. In contrast, nonrigid motion is often associated with biological motion and is therefore ecologically important to visually dependent animals. In this study, we examined the relative contribution of nonrigid motion and shape to object perception in humans and pigeons, two species that rely extensively on vision. Using a parametric morphing technique to systematically vary nonrigid motion and three-dimensional shape information, we found that both humans and pigeons were able to rely solely on either shape or nonrigid motion information to identify complex objects when one of the two cues was degraded. Humans and pigeons also showed similar 80% accuracy thresholds when the information from both shape and motion cues were degraded. We argue that the use of nonrigid motion for object perception is evolutionarily important and should be considered in general theories of vision at least with respect to visually sophisticated animals. PMID- 28654963 TI - Visualizing fMRI BOLD responses to diverse naturalistic scenes using retinotopic projection. AB - To view brain activity in register with visual stimuli, a technique here referred to as "retinotopic projection," which translates functional measurements into retinotopic space, is employed. Retinotopic projection is here first applied to a previously acquired fMRI dataset in which a large set of grayscale photos of real scenes were presented to three subjects. A simple model of local contrast integration accounts for much of the data in early visual areas (V1 and V2). However, consistent discrepancies were discovered: Human faces tend to evoke stronger responses relative to other scene elements than predicted by the model, whereas periodic patterns evoke weaker responses than predicted by the model. Next, in new fMRI experiments, three subjects directed attention toward various elements of naturalistic scenes (Vermeer paintings). Retinotopic projection applied to these data showed that attending to an object increased activation in cortex corresponding to the location of that object. Together the results suggest that even during passive viewing, the visual system differentially processes natural scenes in a manner consistent with deployment of visual attention to salient elements. PMID- 28654965 TI - Mid-level perceptual features contain early cues to animacy. AB - While substantial work has focused on how the visual system achieves basic-level recognition, less work has asked about how it supports large-scale distinctions between objects, such as animacy and real-world size. Previous work has shown that these dimensions are reflected in our neural object representations (Konkle & Caramazza, 2013), and that objects of different real-world sizes have different mid-level perceptual features (Long, Konkle, Cohen, & Alvarez, 2016). Here, we test the hypothesis that animates and manmade objects also differ in mid-level perceptual features. To do so, we generated synthetic images of animals and objects that preserve some texture and form information ("texforms"), but are not identifiable at the basic level. We used visual search efficiency as an index of perceptual similarity, as search is slower when targets are perceptually similar to distractors. Across three experiments, we find that observers can find animals faster among objects than among other animals, and vice versa, and that these results hold when stimuli are reduced to unrecognizable texforms. Electrophysiological evidence revealed that this mixed-animacy search advantage emerges during early stages of target individuation, and not during later stages associated with semantic processing. Lastly, we find that perceived curvature explains part of the mixed-animacy search advantage and that observers use perceived curvature to classify texforms as animate/inanimate. Taken together, these findings suggest that mid-level perceptual features, including curvature, contain cues to whether an object may be animate versus manmade. We propose that the visual system capitalizes on these early cues to facilitate object detection, recognition, and classification. PMID- 28654966 TI - Randomized Trials of Chinese Herbal Medicine: A New Extension of the CONSORT Statement. PMID- 28654967 TI - Human Papillomavirus Triage of Women With Atypical Squamous Cells of Undetermined Significance-Reduction of Overtreatment Needed. PMID- 28654964 TI - Evidence for unlimited capacity processing of simple features in visual cortex. AB - Performance in many visual tasks is impaired when observers attempt to divide spatial attention across multiple visual field locations. Correspondingly, neuronal response magnitudes in visual cortex are often reduced during divided compared with focused spatial attention. This suggests that early visual cortex is the site of capacity limits, where finite processing resources must be divided among attended stimuli. However, behavioral research demonstrates that not all visual tasks suffer such capacity limits: The costs of divided attention are minimal when the task and stimulus are simple, such as when searching for a target defined by orientation or contrast. To date, however, every neuroimaging study of divided attention has used more complex tasks and found large reductions in response magnitude. We bridged that gap by using functional magnetic resonance imaging to measure responses in the human visual cortex during simple feature detection. The first experiment used a visual search task: Observers detected a low-contrast Gabor patch within one or four potentially relevant locations. The second experiment used a dual-task design, in which observers made independent judgments of Gabor presence in patches of dynamic noise at two locations. In both experiments, blood-oxygen level-dependent (BOLD) signals in the retinotopic cortex were significantly lower for ignored than attended stimuli. However, when observers divided attention between multiple stimuli, BOLD signals were not reliably reduced and behavioral performance was unimpaired. These results suggest that processing of simple features in early visual cortex has unlimited capacity. PMID- 28654969 TI - The Persisting Challenge of Socioeconomic Inequalities in Health Across the Life Course. PMID- 28654968 TI - Association of Electrochemical Therapy With Optical, Mechanical, and Acoustic Impedance Properties of Porcine Skin. AB - Importance: The classic management of burn scars and other injuries to the skin has largely relied on soft-tissue transfer to resurface damaged tissue with local tissue transfer or skin graft placement. In situ generation of electrochemical reactions using needle electrodes and an application of current may be a new approach to treat scars and skin. Objective: To examine the changes in optical, mechanical, and acoustic impedance properties in porcine skin after electrochemical therapy. Design, Setting, and Participants: This preclinical pilot study, performed from August 1, 2015, to November 1, 2016, investigated the effects of localized pH-driven electrochemical therapy of ex vivo porcine skin using 24 skin samples. Platinum-plated needle electrodes were inserted into fresh porcine skin samples. A DC power supply provided a voltage of 4 to 5 V with a 3 minute application time. Specimens were analyzed using optical coherence tomography, optical coherence elastography, and ultrasonography. Ultrasonography was performed under 3 conditions (n = 2 per condition), optical coherence tomography was performed under 2 conditions (n = 2 per condition), and optical coherence elastography was performed under 2 conditions (n = 2 per condition). The remaining samples were used for the positive and negative control groups (n = 10). Exposures: Platinum-plated needle electrodes were inserted into fresh porcine skin samples. A DC power supply provided a voltage of 4 to 5 V with a 3 minute application. Main Outcomes and Measures: Tissue softening was observed at the anode and cathode sites as a result of electrochemical modification. Volumetric changes were noted using each optical and acoustic technique. Results: A total of 24 ex vivo porcine skin samples were used for this pilot study. Optical coherence tomography measured spatial distribution of superficial tissue changes around each electrode site. At 4 V for 3 minutes, a total volumetric effect of 0.47 mm3 was found at the anode site and 0.51 mm3 at the cathode site. For 5 V for 3 minutes, a total volumetric effect of 0.85 mm3 was found at the anode site and 1.05 mm3 at the cathode site. Conclusions and Relevance: Electrochemical therapy is a low-cost technique that is on par with the costs of suture and scalpel. The use of electrochemical therapy to create mechanical and physiologic changes in tissue has the potential to locally remodel the soft tissue matrix, which ultimately may lead to an inexpensive scar treatment or skin rejuvenation therapy. Level of Evidence: NA. PMID- 28654970 TI - Probing the Role of Inflammation in Age-Related Macular Degeneration. PMID- 28654971 TI - Incorporating Whole-Genome Sequencing Into Primary Care: Falling Barriers and Next Steps. PMID- 28654973 TI - Erosive Rheumatoid Arthritis After Bilateral Hand Transplantation. PMID- 28654974 TI - The Role of Patient Engagement in Addressing Parents' Perceptions About Immunizations. PMID- 28654975 TI - Chemical Ocular Burn Epidemiology-Dealing with Missing Values-Reply. PMID- 28654972 TI - Effect of Electronic Reminders, Financial Incentives, and Social Support on Outcomes After Myocardial Infarction: The HeartStrong Randomized Clinical Trial. AB - Importance: Adherence to medications prescribed after acute myocardial infarction (AMI) is low. Wireless technology and behavioral economic approaches have shown promise in improving health behaviors. Objective: To determine whether a system of medication reminders using financial incentives and social support delays subsequent vascular events in patients following AMI compared with usual care. Design, Setting, and Participants: Two-arm, randomized clinical trial with a 12 month intervention conducted from 2013 through 2016. Investigators were blinded to study group, but participants were not. Design was a health plan-intermediated intervention for members of several health plans. We recruited 1509 participants from 7179 contacted AMI survivors (insured with 5 large US insurers nationally or with Medicare fee-for-service at the University of Pennsylvania Health System). Patients aged 18 to 80 years were eligible if currently prescribed at least 2 of 4 study medications (statin, aspirin, beta-blocker, antiplatelet agent), and were hospital inpatients for 1 to 180 days and discharged home with a principal diagnosis of AMI. Interventions: Patients were randomized 2:1 to an intervention using electronic pill bottles combined with lottery incentives and social support for medication adherence (1003 patients), or to usual care (506 patients). Main Outcomes and Measures: Primary outcome was time to first vascular rehospitalization or death. Secondary outcomes were time to first all-cause rehospitalization, total number of repeated hospitalizations, medication adherence, and total medical costs. Results: A total of 35.5% of participants were female (n = 536); mean (SD) age was 61.0 (10.3) years. There were no statistically significant differences between study arms in time to first rehospitalization for a vascular event or death (hazard ratio, 1.04; 95% CI, 0.71 to 1.52; P = .84), time to first all-cause rehospitalization (hazard ratio, 0.89; 95% CI, 0.73 to 1.09; P = .27), or total number of repeated hospitalizations (hazard ratio, 0.94; 95% CI, 0.60 to 1.48; P = .79). Mean (SD) medication adherence did not differ between control (0.42 [0.39]) and intervention (0.46 [0.39]) (difference, 0.04; 95% CI, -0.01 to 0.09; P = .10). Mean (SD) medical costs in 12 months following enrollment did not differ between control ($29 811 [$74 850]) and intervention ($24 038 [$66 915]) (difference, -$5773; 95% CI, -$13 682 to $2137; P = .15). Conclusions and Relevance: A compound intervention integrating wireless pill bottles, lottery-based incentives, and social support did not significantly improve medication adherence or vascular readmission outcomes for AMI survivors. Trial Registration: clinicaltrials.gov Identifier: NCT01800201. PMID- 28654977 TI - Chemical Ocular Burn Epidemiology-Dealing With Missing Values. PMID- 28654976 TI - Contact Precautions for Endemic MRSA and VRE: Time to Retire Legal Mandates. PMID- 28654978 TI - Cardiac Testing After Emergency Department Evaluation for Chest Pain: Time for a Paradigm Shift? PMID- 28654979 TI - Social Mission in Health Professions Education: Beyond Flexner. PMID- 28654980 TI - CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. AB - Chinese herbal medicine (CHM) formulas are the major components of traditional Chinese medicine (TCM) interventions. The general reporting quality of randomized controlled trials (RCTs) of CHM formulas is disappointing, although CONSORT (Consolidated Standards of Reporting Trials) Statement extensions for herbal medicinal interventions and acupuncture interventions are available. A group of TCM clinical experts, methodologists, epidemiologists, and editors has developed this CONSORT Extension for CHM Formulas (CONSORT-CHM Formulas 2017) through a comprehensive process, including publication of the draft version, solicitation of comments, revision, and finalization. The CONSORT 2010 Statement was extended by introducing the idea of TCM Pattern and the features of CHM formulas. One new checklist subitem, keywords, was added to facilitate indexing and data searching. Seven of the 25 CONSORT checklist items, namely title and abstract, background and objectives, participants, interventions, outcomes, generalizability, and interpretation, are now elaborated, and the explanation of harms specific to CHM formulas is revised. Illustrative examples and explanations are also provided. The group hopes that CONSORT-CHM Formulas 2017 can improve the reporting quality of RCTs of CHM formulas. PMID- 28654981 TI - Optic Nerve Tilt, Crescent, Ovality, and Torsion in a Multi-Ethnic Cohort of Young Adults With and Without Myopia. AB - Purpose: The purpose of this article is to evaluate optic nerve head (ONH) characteristics in an ethnically diverse cohort of young U.S. adults. Methods: In this study, 409 myopes and 206 nonmyopes (median age 22 years) completed measures including biometry and spectral domain optical coherence tomography from enface (ovality and torsion) and cross-sectional (tilt and crescent width) scans. Associated factors were evaluated using multivariable models. Results: In myopic versus nonmyopic right eyes, median tilt (6.0 degrees vs. 2.4 degrees ; P < 0.0001) and frequency of crescents (49% vs. 10%; P < 0.0001) were higher in myopes. Right eyes with crescents had higher median tilts (8.8 degrees [myopic], 9.0 degrees [nonmyopic]) than those without crescent (2.5 degrees [myopic], 2.1 degrees [nonmyopic]), irrespective of refractive group (both P < 0.0001). Torsion was similar between groups, with a slight difference in ovality (0.89 vs. 0.91; P < 0.03). Data in the left eyes were similar, and modeling was done only for the right myopic eyes. Multivariable models showed that an increased tilt was associated with ethnicity (P < 0.001), the presence of crescent (P < 0.001), and smaller ONH diameter (P < 0.0031), with interactions between ethnicity and crescent (P = 0.002). Specifically, ONH tilt was significantly higher in Asian eyes without crescent (P < 0.0001 for all comparisons), and crescent width was associated with increased tilt in non-Asian eyes (P < 0.02). Crescent width was associated with ethnicity (greatest in Asians) and disc tilt. Interactions were observed between tilt and ethnicity, whereby tilt had a greater effect on crescent width in non-Asian eyes, and crescent width was associated with increased tilt in non-Asian eyes. Conclusions: The data clarify the influence of ethnicity and myopia on ONH characteristics in young adults and may inform future studies of biomechanical properties or of retinal pathology of the myopic eye. PMID- 28654982 TI - Genetic African Ancestry Is Associated With Central Corneal Thickness and Intraocular Pressure in Primary Open-Angle Glaucoma. AB - Purpose: To unravel the relationship between African ancestry, central corneal thickness (CCT), and intraocular pressure (IOP) by estimating the genetic African ancestry (GAA) proportion in primary open-angle glaucoma (POAG) patients and controls from an admixed South African Colored (SAC) and a South African Black (SAB) population. Methods: In this case-control study, 268 POAG patients and 137 controls were recruited from a university clinic in Cape Town, South Africa. All participants were genotyped on the Illumina HumanOmniExpress beadchip or HumanOmni2.5Exome beadchip. ADMIXTURE was used to infer participant's GAA among 86,632 SNPs. Linear and logistic regression models were used to assess the relation between GAA, POAG, CCT, and IOP. Results: The median proportion of GAA was 60% in the study population. GAA was significantly associated with thinner CCT (P < 0.001) and IOP (P = 0.034) in POAG patients. The effect of GAA on CCT was marginally different among POAG patients versus controls (P = 0.066). In POAG patients, the CCT was significantly thinner compared to controls after adjusting for age and sex (P = 0.016). In a stratified analysis in participants with >60% GAA, CCT was not associated with POAG (P = 0.550). Conclusions: This study demonstrated that a higher proportion of GAA was associated with a thinner CCT and a higher IOP in POAG patients. Remarkably, at higher proportions of GAA, the difference in CCT between POAG and controls was reduced. This suggests that thinner CCT is not associated with POAG in Africans. PMID- 28654983 TI - The Effect of Systemic Hyperoxia on Optic Nerve Head Blood Flow in Primary Open Angle Glaucoma Patients. AB - Purpose: To assess the optic nerve head blood flow (ONH BF) response to hyperoxia in glaucoma patients using laser speckle flowgraphy (LSFG), and determine factors influencing vasoreactivity within the ONH. Methods: We performed oxygen provocation testing in 15 eyes of 15 primary open-angle glaucoma (POAG) patients and 15 eyes of 15 age-matched control subjects. During the test, LSFG-derived tissue mean blur rate (MBRT) and clinical variables, including blood pressure, were recorded. We evaluated differences in MBRT alteration during systemic hyperoxia between the groups. Additionally, we calculated the mean % change in MBRT against baseline and determined contributing factors. Results: Despite similar clinical variables during systemic hyperoxia in both groups, the mean % change in MBRT against baseline was significantly lower in the POAG than control subjects (P < 0.0001). Multiple regression analysis revealed that baseline MBRT and systolic blood pressure (SBP) were contributing factors to mean % change in MBRT (beta = 0.44, beta = -0.32, respectively). Additionally, baseline MBRT and SBP were strongly correlated to mean % change in MBRT only in the POAG group (r = 0.83, P < 0.0001; r = -0.60, P = 0.02, respectively). Conclusions: POAG patients had a weaker vasoreactive response to hyperoxia than controls, and this impaired response was associated with lower basal ONH BF and higher SBP. These findings suggest that pre-existing vasoconstriction in the ONH of eyes with glaucoma might reduce the capacity of the vasoconstrictive response to hyperoxia. Alternatively, the pathways that mediate hyperoxia-induced vasoconstriction could be altered in POAG. PMID- 28654984 TI - Osteoprotegerin Is a New Regulator of Inflammation and Angiogenesis in Proliferative Diabetic Retinopathy. AB - Purpose: Osteoprotegerin (OPG) is a novel regulator of endothelial cell function, angiogenesis, and vasculogenesis. We correlated expression levels of OPG with those of the angiogenic and inflammatory factors vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2) in proliferative diabetic retinopathy (PDR). We also examined expression of OPG in retinas from diabetic rats and diabetic patients and measured production of OPG by human retinal microvascular endothelial cells (HRMEC) and investigated its angiogenic activity. Methods: Vitreous samples from 47 PDR and 28 nondiabetic patients, epiretinal membranes from 14 patients with PDR, human retinas (10 from diabetic patients and 10 from nondiabetic subjects), and rat retinas and HRMEC were studied by using enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, Western blot analysis, and RT-PCR. In vitro and in vivo angiogenesis assays were performed. Results: We showed a significant increase in the expression of OPG, VEGF, and MCP-1/CCL2 in a comparison between vitreous samples from PDR patients and those from nondiabetic controls. Significant positive correlations were found between levels of OPG and levels of VEGF and MCP 1/CCL2. In epiretinal membranes, OPG was expressed in vascular endothelial cells and stromal cells. Significant increases of OPG mRNA and protein were detected in the retinas from diabetic patients. The proinflammatory cytokines TNF-alpha and IL-1beta, but not VEGF, MCP-1/CCL2 or thrombin, induced upregulation of OPG in HRMEC. Osteoprotegerin induced ERK1/2 and Akt phosphorylation in HRMEC and stimulated their migration. Osteoprotegerin potentiated the angiogenic effect of VEGF in the in vivo protein gelatin plug assay. Conclusions: These results suggest that OPG is involved in PDR angiogenesis. PMID- 28654987 TI - Women's Awareness and Perceived Importance of the Harms and Benefits of Mammography Screening: Results From a 2016 National Survey. PMID- 28654985 TI - Transcriptomic Profiling of Posterior Polymorphous Corneal Dystrophy. AB - Purpose: To investigate the molecular basis of posterior polymorphous corneal dystrophy (PPCD) by examining the PPCD transcriptome and the effect of decreased ZEB1 expression on corneal endothelial cell (CEnC) gene expression. Methods: Next generation RNA sequencing (RNA-seq) analyses of corneal endothelium from two PPCD affected individuals (one with PPCD3 and one of unknown genetic cause) compared with two age-matched controls, and primary human CEnC (pHCEnC) transfected with siRNA-mediated ZEB1 knockdown. The expression of selected differentially expressed genes was validated by quantitative polymerase chain reaction (qPCR) and/or assessed by in situ hybridization in the corneal endothelium of four independent cases of PPCD (one with PPCD3 and three of unknown genetic cause). Results: Expression of 16% and 46% of the 104 protein-coding genes specific to ex vivo corneal endothelium was lost in the endothelium of two individuals with PPCD. Thirty-two genes associated with ZEB1 and 3 genes (BMP4, CCND1, ZEB1) associated with OVOL2 were differentially expressed in the same direction in both individuals with PPCD. Immunohistochemistry staining and RNA-seq analyses demonstrated variable expression of type IV collagens in PPCD corneas. Decreasing ZEB1 expression in pHCEnC altered expression of 711 protein-coding genes, many of which are associated with canonical pathways regulating various cellular processes. Conclusions: Identification of the altered transcriptome in PPCD and in a cell-based model of PPCD provided insight into the molecular alterations characterizing PPCD. Further study of the differentially expressed genes associated with ZEB1 and OVOL2 is expected to identify candidate genes for individuals with PPCD and without a ZEB1 or OVOL2 mutation. PMID- 28654986 TI - Association Between Initial Use of e-Cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults: A Systematic Review and Meta-analysis. AB - Importance: The public health implications of e-cigarettes depend, in part, on whether e-cigarette use affects the risk of cigarette smoking. Objective: To perform a systematic review and meta-analysis of longitudinal studies that assessed initial use of e-cigarettes and subsequent cigarette smoking. Data Sources: PubMed, EMBASE, Cochrane Library, Web of Science, the 2016 Society for Research on Nicotine and Tobacco 22nd Annual Meeting abstracts, the 2016 Society of Behavioral Medicine 37th Annual Meeting & Scientific Sessions abstracts, and the 2016 National Institutes of Health Tobacco Regulatory Science Program Conference were searched between February 7 and February 17, 2017. The search included indexed terms and text words to capture concepts associated with e cigarettes and traditional cigarettes in articles published from database inception to the date of the search. Study Selection: Longitudinal studies reporting odds ratios for cigarette smoking initiation associated with ever use of e-cigarettes or past 30-day cigarette smoking associated with past 30-day e cigarette use. Searches yielded 6959 unique studies, of which 9 met inclusion criteria (comprising 17 389 adolescents and young adults). Data Extraction and Synthesis: Study quality and risk of bias were assessed using the Newcastle Ottawa Scale and the Risk of Bias in Non-randomized Studies of Interventions tool, respectively. Data and estimates were pooled using random-effects meta analysis. Main Outcomes and Measures: Among baseline never cigarette smokers, cigarette smoking initiation between baseline and follow-up. Among baseline non past 30-day cigarette smokers who were past 30-day e-cigarette users, past 30-day cigarette smoking at follow-up. Results: Among 17 389 adolescents and young adults, the ages ranged between 14 and 30 years at baseline, and 56.0% were female. The pooled probabilities of cigarette smoking initiation were 30.4% for baseline ever e-cigarette users and 7.9% for baseline never e-cigarette users. The pooled probabilities of past 30-day cigarette smoking at follow-up were 21.5% for baseline past 30-day e-cigarette users and 4.6% for baseline non-past 30-day e-cigarette users. Adjusting for known demographic, psychosocial, and behavioral risk factors for cigarette smoking, the pooled odds ratio for subsequent cigarette smoking initiation was 3.62 (95% CI, 2.42-5.41) for ever vs never e cigarette users, and the pooled odds ratio for past 30-day cigarette smoking at follow-up was 4.28 (95% CI, 2.52-7.27) for past 30-day e-cigarette vs non-past 30 day e-cigarette users at baseline. A moderate level of heterogeneity was observed among studies (I2 = 60.1%). Conclusions and Relevance: e-Cigarette use was associated with greater risk for subsequent cigarette smoking initiation and past 30-day cigarette smoking. Strong e-cigarette regulation could potentially curb use among youth and possibly limit the future population-level burden of cigarette smoking. PMID- 28654989 TI - Risk of Primary Tumor Sidedness as a Criterion for Screening, Diagnostic Colonoscopy, and Surveillance Intervals-Reply. PMID- 28654988 TI - CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Traditional Chinese Version). AB - Editors' Note: This article is the traditional Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. (Cheng C, Wu T, Shang H, Li, Y, Altman D, Moher D; CONSORT-CHM Formulas 2017 Group. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;167:112-21. [Epub 27 June 2017]. doi:10.7326/M16-2977). PMID- 28654991 TI - Incorrect Statement in Text. PMID- 28654990 TI - Venous vs Arterial Lactate and 30-Day Mortality in Pediatric Sepsis. PMID- 28654992 TI - Acupuncture and the Complex Connections Between the Mind and the Body. PMID- 28654993 TI - High-Intensity Statins: Guideline Expectations and Clinical Application. PMID- 28654994 TI - Hunt for an HIV Vaccine Intensifies. PMID- 28654995 TI - National Plan for COPD Care. PMID- 28654996 TI - Effort to Relax School Lunch Guidelines. PMID- 28654998 TI - Chromosomal Microarray Testing for Children With Unexplained Neurodevelopmental Disorders. PMID- 28654999 TI - Some Problems of Wartime Neurology. PMID- 28655000 TI - Assessment of Head Collision Events During the 2014 FIFA World Cup Tournament. PMID- 28655001 TI - Maternal Obesity and Cerebral Palsy in Offspring. PMID- 28655002 TI - Administration of Fibrinogen Concentrate During Cardiac Surgery. PMID- 28655003 TI - Administration of Fibrinogen Concentrate During Cardiac Surgery. PMID- 28655004 TI - Complications of Diabetes Diagnosed in Children and Adolescents. PMID- 28655005 TI - Complications of Diabetes Diagnosed in Children and Adolescents. PMID- 28655006 TI - Maternal Obesity and Cerebral Palsy in Offspring-Reply. PMID- 28655007 TI - Administration of Fibrinogen Concentrate During Cardiac Surgery-Reply. PMID- 28655009 TI - Neonatal Abstinence Syndrome Better Treated With Buprenorphine. PMID- 28655008 TI - Complications of Diabetes Diagnosed in Children and Adolescents-Reply. PMID- 28655010 TI - Nocebo Effect May Account for Statin Adverse Events. PMID- 28655011 TI - Teens Who Were Breastfed Are Heavier. PMID- 28655012 TI - Silk Offers No Relief From Eczema. PMID- 28655013 TI - Pill Reminders Don't Improve Adherence. PMID- 28655014 TI - Association Between Health Plan Exit From Medicaid Managed Care and Quality of Care, 2006-2014. AB - Importance: State Medicaid programs have increasingly contracted with insurers to provide medical care services for enrollees (Medicaid managed care plans). Insurers that provide these plans can exit Medicaid programs each year, with unclear effects on quality of care and health care experiences. Objective: To determine the frequency and interstate variation of health plan exit from Medicaid managed care and evaluate the relationship between health plan exit and market-level quality. Design, Setting, and Participants: Retrospective cohort of all comprehensive Medicaid managed care plans (N = 390) during the interval 2006 2014. Exposures: Plan exit, defined as the withdrawal of a managed care plan from a state's Medicaid program. Main Outcomes and Measures: Eight measures from the Healthcare Effectiveness Data and Information Set were used to construct 3 composite indicators of quality (preventive care, chronic disease care management, and maternity care). Four measures from the Consumer Assessment of Healthcare Providers and Systems were combined into a composite indicator of patient experience, reflecting the proportion of beneficiaries rating experiences as 8 or above on a 0-to-10-point scale. Outcome data were available for 248 plans (68% of plans operating prior to 2014, representing 78% of beneficiaries). Results: Of the 366 comprehensive Medicaid managed care plans operating prior to 2014, 106 exited Medicaid. These exiting plans enrolled 4 848 310 Medicaid beneficiaries, with a mean of 606 039 beneficiaries affected by plan exits annually. Six states had a mean of greater than 10% of Medicaid managed care recipients enrolled in plans that exited, whereas 10 states experienced no plan exits. Plans that exited from a state's Medicaid market performed significantly worse prior to exiting than those that remained in terms of preventive care (57.5% vs 60.4%; difference, 2.9% [95% CI, 0.3% to 5.5%]), maternity care (69.7% vs 73.6%; difference, 3.8% [95% CI, 1.7% to 6.0%]), and patient experience (73.5% vs 74.8%; difference, 1.3% [95% CI, 0.6% to 1.9%]). There was no significant difference between exiting and nonexiting plans for the quality of chronic disease care management (76.2% vs 77.1%; difference, 1.0% [95% CI, -2.1% to 4.0%]). There was also no significant change in overall market performance before and after the exit of a plan: 0.7-percentage point improvement in preventive care quality (95% CI, -4.9 to 6.3); 0.2-percentage point improvement in chronic disease care management quality (95% CI, -5.8 to 6.2); 0.7-percentage point decrease in maternity care quality (95% CI, -6.4 to 5.0]); and a 0.6-percentage point improvement in patient experience ratings (95% CI, -3.9 to 5.1). Medicaid beneficiaries enrolled in exiting plans had access to coverage for a higher quality plan, with 78% of plans in the same county having higher quality for preventive care, 71.1% for chronic disease management, 65.5% for maternity care, and 80.8% for patient experience. Conclusions and Relevance: Between 2006 and 2014, health plan exit from the US Medicaid program was frequent. Plans that exited generally had lower quality ratings than those that remained, and the exits were not associated with significant overall changes in quality or patient experience in the plans in the Medicaid market. PMID- 28655015 TI - Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial. AB - Importance: Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective: To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants: A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions: Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures: The primary outcome was live birth. Secondary outcomes included adverse events. Results: Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance: Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration: clinicaltrials.gov Identifier: NCT01573858. PMID- 28655018 TI - Groin Hernia. PMID- 28655016 TI - Effect of Electroacupuncture on Urinary Leakage Among Women With Stress Urinary Incontinence: A Randomized Clinical Trial. AB - Importance: Electroacupuncture involving the lumbosacral region may be effective for women with stress urinary incontinence (SUI), but evidence is limited. Objective: To assess the effect of electroacupuncture vs sham electroacupuncture for women with SUI. Design, Setting, and Participants: Multicenter, randomized clinical trial conducted at 12 hospitals in China and enrolling 504 women with SUI between October 2013 and May 2015, with data collection completed in December 2015. Interventions: Participants were randomly assigned (1:1) to receive 18 sessions (over 6 weeks) of electroacupuncture involving the lumbosacral region (n = 252) or sham electroacupuncture (n = 252) with no skin penetration on sham acupoints. Main Outcomes and Measures: The primary outcome was change from baseline to week 6 in the amount of urine leakage, measured by the 1-hour pad test. Secondary outcomes included mean 72-hour urinary incontinence episodes measured by a 72-hour bladder diary (72-hour incontinence episodes). Results: Among the 504 randomized participants (mean [SD] age, 55.3 [8.4] years), 482 completed the study. Mean urine leakage at baseline was 18.4 g for the electroacupuncture group and 19.1 g for the sham electroacupuncture group. Mean 72-hour incontinence episodes were 7.9 for the electroacupuncture group and 7.7 for the sham electroacupuncture group. At week 6, the electroacupuncture group had greater decrease in mean urine leakage (-9.9 g) than the sham electroacupuncture group (-2.6 g) with a mean difference of 7.4 g (95% CI, 4.8 to 10.0; P < .001). During some time periods, the change in the mean 72-hour incontinence episodes from baseline was greater with electroacupuncture than sham electroacupuncture with between-group differences of 1.0 episode in weeks 1 to 6 (95% CI, 0.2-1.7; P = .01), 2.0 episodes in weeks 15 to 18 (95% CI, 1.3-2.7; P < .001), and 2.1 episodes in weeks 27 to 30 (95% CI, 1.3-2.8; P < .001). The incidence of treatment-related adverse events was 1.6% in the electroacupuncture group and 2.0% in the sham electroacupuncture group, and all events were classified as mild. Conclusions and Relevance: Among women with stress urinary incontinence, treatment with electroacupuncture involving the lumbosacral region, compared with sham electroacupuncture, resulted in less urine leakage after 6 weeks. Further research is needed to understand long-term efficacy and the mechanism of action of this intervention. Trial Registration: clinicaltrials.gov Identifier: NCT01784172. PMID- 28655017 TI - Prevalence and Ethnic Pattern of Diabetes and Prediabetes in China in 2013. AB - Importance: Previous studies have shown increasing prevalence of diabetes in China, which now has the world's largest diabetes epidemic. Objectives: To estimate the recent prevalence and to investigate the ethnic variation of diabetes and prediabetes in the Chinese adult population. Design, Setting, and Participants: A nationally representative cross-sectional survey in 2013 in mainland China, which consisted of 170 287 participants. Exposures: Fasting plasma glucose and hemoglobin A1c levels were measured for all participants. A 2 hour oral glucose tolerance test was conducted for all participants without diagnosed diabetes. Main Outcomes and Measures: Primary outcomes were total diabetes and prediabetes defined according to the 2010 American Diabetes Association criteria. Awareness and treatment were also evaluated. Hemoglobin A1c concentration of less than 7.0% among treated diabetes patients was considered adequate glycemic control. Minority ethnic groups in China with at least 1000 participants (Tibetan, Zhuang, Manchu, Uyghur, and Muslim) were compared with Han participants. Results: Among the Chinese adult population, the estimated standardized prevalence of total diagnosed and undiagnosed diabetes was 10.9% (95% CI, 10.4%-11.5%); that of diagnosed diabetes, 4.0% (95% CI, 3.6%-4.3%); and that of prediabetes, 35.7% (95% CI, 34.1%-37.4%). Among persons with diabetes, 36.5% (95% CI, 34.3%-38.6%) were aware of their diagnosis and 32.2% (95% CI, 30.1%-34.2%) were treated; 49.2% (95% CI, 46.9%-51.5%) of patients treated had adequate glycemic control. Tibetan and Muslim Chinese had significantly lower crude prevalence of diabetes than Han participants (14.7% [95% CI, 14.6%-14.9%] for Han, 4.3% [95% CI, 3.5%-5.0%] for Tibetan, and 10.6% [95% CI, 9.3%-11.9%] for Muslim; P < .001 for Tibetan and Muslim compared with Han). In the multivariable logistic models, the adjusted odds ratios compared with Han participants were 0.42 (95% CI, 0.35-0.50) for diabetes and 0.77 (95% CI, 0.71-0.84) for prediabetes for Tibetan Chinese and 0.73 (95% CI, 0.63-0.85) for diabetes and 0.78 (95% CI, 0.71-0.86) for prediabetes in Muslim Chinese. Conclusions and Relevance: Among adults in China, the estimated overall prevalence of diabetes was 10.9%, and that for prediabetes was 35.7%. Differences from previous estimates for 2010 may be due to an alternate method of measuring hemoglobin A1c. PMID- 28655020 TI - Porous Boundaries. PMID- 28655023 TI - Drug-Resistant Fungus Arrives in US. PMID- 28655024 TI - Changing the Weight-loss Subject. PMID- 28655021 TI - The Diagnosis and Treatment of Prostate Cancer: A Review. AB - Importance: Prostate cancer is the most common cancer diagnosis made in men with more than 160 000 new cases each year in the United States. Although it often has an indolent course, prostate cancer remains the third-leading cause of cancer death in men. Observations: When prostate cancer is suspected, tissue biopsy remains the standard of care for diagnosis. However, the identification and characterization of the disease have become increasingly precise through improved risk stratification and advances in magnetic resonance and functional imaging, as well as from the emergence of biomarkers. Multiple management options now exist for men diagnosed with prostate cancer. Active surveillance (the serial monitoring for disease progression with the intent to cure) appears to be safe and has become the preferred approach for men with less-aggressive prostate cancer, particularly those with a prostate-specific antigen level of less than 10 ng/mL and Gleason score 3 + 3 tumors. Surgery and radiation continue to be curative treatments for localized disease but have adverse effects such as urinary symptoms and sexual dysfunction that can negatively affect quality of life. For metastatic disease, chemotherapy as initial treatment now appears to extend survival compared with androgen deprivation therapy alone. New vaccines, hormonal therapeutics, and bone-targeting agents have demonstrated efficacy in men with metastatic prostate cancer resistant to traditional hormonal therapy. Conclusions and Relevance: Advances in the diagnosis and treatment of prostate cancer have improved the ability to stratify patients by risk and allowed clinicians to recommend therapy based on cancer prognosis and patient preference. Initial treatment with chemotherapy can improve survival compared with androgen deprivation therapy. Abiraterone, enzalutamide, and other agents can improve outcomes in men with metastatic prostate cancer resistant to traditional hormonal therapy. PMID- 28655026 TI - Potential Influence of FDA-Sponsored Studies of Antiepilepsy Drugs on Generic and Brand-name Formulation Prescribing. PMID- 28655027 TI - Zolpidem for the Treatment of Neurologic Disorders: A Systematic Review. AB - Importance: Given its selective action on the omega1 subtype of the gamma aminobutyric acid A receptor, zolpidem tartrate presents a potential treatment mechanism for other neurologic disorders. Objective: To synthesize studies that used zolpidem to treat neurologic disorders. Evidence Review: Eligibility criteria included any published English-language article that examined the use of zolpidem for noninsomnia neurologic disorders in humans for all dates up to March 20, 2015. Searched databases included PubMed, Scopus, Web of Science Core Collection, the Cochrane Library, EMBASE, CENTRAL, and clinicaltrials.gov. Publication bias was mitigated by searching clinicaltrials.gov for unpublished studies. Two rounds of screening were performed based on title and then abstract, and coding was performed by 2 coders. All methods followed the PRISMA Reporting Guidelines for systematic reviews of the literature. Findings: The initial search produced 2314 articles after removing duplicates. After exclusion based on a review of abstracts, 67 articles remained for full manuscript review. Thirty-one studies treated movement disorders, 22 treated disorders of consciousness, and 14 treated other neurologic conditions, including stroke, traumatic brain injury, encephalopathy, and dementia. Study designs included case reports (n = 28), case series (n = 8), single-patient interventional (n = 13), pretest and posttest (n = 9), randomized clinical trials (n = 9), and crossover studies (n = 5). Only 11 studies had more than 10 participants. Effects of zolpidem were wide ranging (eg, improvement on the JFK Coma Recovery Scale-Revised, the Unified Parkinson Disease Rating Scale, and the Burke-Fahn-Marsden Dystonia Rating Scale) and generally lasted 1 to 4 hours before the participant returned to baseline. Sedation was the most common adverse effect. Conclusions and Relevance: Zolpidem has been observed to transiently treat a large variety of neurologic disorders, most often related to movement disorders and disorders of consciousness. Much of what is known comes from case reports and small interventional trials. These findings may represent a new treatment mechanism for these disorders. PMID- 28655025 TI - Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial. AB - Importance: Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation. Objective: To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment seeking individuals with OUD. Design, Setting, and Participants: This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit). Interventions: A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13). Main Outcomes and Measures: The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes. Results: A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P < .001, and CAM2038, 32 mg: effect size, 0.753; P < .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P < .001, and CAM2038, 32 mg: effect size, 0.751; P < .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg). Conclusions and Relevance: CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits. Trial Registration: Clinicaltrials.gov Identifier: NCT02611752. PMID- 28655028 TI - Hospital-Based End-of-Life Care and Costs for Older Patients With Malignant Brain Tumors. PMID- 28655030 TI - Call for Papers, JAMA Pediatrics Contest for Trainees. PMID- 28655031 TI - Evolving Technologies for Lid and Ocular Surface Neoplasias: Is Optical Biopsy a Reality? PMID- 28655029 TI - Breast Cancer Screening With Mammography Plus Ultrasonography or Magnetic Resonance Imaging in Women 50 Years or Younger at Diagnosis and Treated With Breast Conservation Therapy. AB - Importance: Younger women (aged <=50 years) who underwent breast conservation therapy may benefit from breast magnetic resonance imaging (MRI) screening as an adjunct to mammography. Objective: To prospectively determine the cancer yield and tumor characteristics of combined mammography with MRI or ultrasonography screening in women who underwent breast conservation therapy for breast cancers and who were 50 years or younger at initial diagnosis. Design, Setting, and Participants: This multicenter, prospective, nonrandomized study was conducted from December 1, 2010, to January 31, 2016, at 6 academic institutions. Seven hundred fifty-four women who were 50 years or younger at initial diagnosis and who had undergone breast conservation therapy for breast cancer were recruited to participate in the study. Reference standard was defined as a combination of pathology and 12-month follow-up. Interventions: Participants underwent 3 annual MRI screenings of the conserved and contralateral breasts in addition to mammography and ultrasonography, with independent readings. Main Outcomes and Measures: Cancer detection rate, sensitivity, specificity, interval cancer rate, and characteristics of detected cancers. Results: A total of 754 women underwent 2065 mammograms, ultrasonography, and MRI screenings. Seventeen cancers were diagnosed, and most of the detected cancers (13 of 17 [76%]) were stage 0 or stage 1. Overall cancer detection rate (8.2 vs 4.4 per 1000; P = .003) or sensitivity (100% vs 53%; P = .01) of mammography with MRI was higher than that of mammography alone. After the addition of ultrasonography, the cancer detection rate was higher than that by mammography alone (6.8 vs 4.4 per 1000; P = .03). The specificity of mammography with MRI or ultrasonography was lower than that by mammography alone (87% or 88% vs 96%; P < .001). No interval cancer was found. Conclusions and Relevance: After breast conservation therapy in women 50 years or younger, the addition of MRI to annual mammography screening improves detection of early-stage but biologically aggressive breast cancers at acceptable specificity. Results from this study can inform patient decision making on screening methods after breast conservation therapy. PMID- 28655033 TI - Venous vs Arterial Lactate and 30-Day Mortality in Pediatric Sepsis-Reply. PMID- 28655032 TI - Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms. AB - Importance: It has been suggested that systemic inflammation increases the risk of age-related macular degeneration (AMD). Given that chronic immune modulation is present in patients with myeloproliferative neoplasms (MPNs), the risk of AMD in these patients may be increased. Objective: To compare the risk of AMD in patients with MPNs with the risk of AMD in matched controls from the general population. Design, Setting, and Participants: A nationwide population-based cohort study using Danish registers was conducted of all patients in Denmark who received a diagnosis between January 1, 1994, and December 31, 2013, of essential thrombocythemia, polycythemia vera, myelofibrosis, or unclassifiable MPNs. For each patient, 10 age- and sex-matched controls were included. All patients without prior AMD were followed up from the date of diagnosis (or corresponding entry date for the controls) until the first AMD diagnosis, death or emigration, or December 31, 2013, whichever occurred first. Data analysis was performed from April 1, 2015, to October 31, 2016. Main Outcomes and Measures: Incidence of AMD recorded in specialized hospital-based care. The rates and absolute risk of AMD were calculated. Using Cox proportional hazards regression models, smoking and risk-time adjusted hazard ratios (HRs) between patients and controls were calculated. In addition, HRs of neovascular AMD after 2006 were calculated since antivascular endothelial growth factor treatment was introduced nationwide at hospitals thereafter. Results: A total of 7958 patients with MPNs (4279 women [53.8%] and 3679 men [46.2%]; mean [SD] age at diagnosis, 66.4 [14.3] years) were included in the study. The rate of AMD per 1000 person-years at risk was 5.2 (95% CI, 4.6-5.9) for patients with MPNs (2628 with essential thrombocythemia, 3063 with polycythemia vera, 547 with myelofibrosis, and 1720 with unclassifiable MPNs) and 4.3 (95% CI, 4.1-4.4) for the 77 445 controls, while the 10-year risk of AMD was 2.4% (95% CI, 2.1%-2.8%) for patients with MPNs and 2.3% (95% CI, 2.2% 2.4%) for the controls. The risk of AMD was increased overall for patients with MPNs (adjusted HR, 1.3; 95% CI, 1.1-1.5), with adjusted HRs for the subtypes of 1.2 (95% CI, 1.0-1.6) for essential thrombocythemia, 1.4 (95% CI, 1.2-1.7) for polycythemia vera, 1.7 (95% CI, 0.8-4.0) for myelofibrosis, and 1.5 (95% CI, 1.1 2.1) for unclassifiable MPNs. In addition, patients with MPNs had a higher risk of neovascular AMD (adjusted HR, 1.4; 95% CI, 1.2-1.6). Conclusions and Relevance: Our results suggest that patients with MPNs are at increased risk of AMD, supporting the possibility that systemic inflammation is involved in the pathogenesis of AMD. PMID- 28655034 TI - The Relationship of Health Insurance and Mortality: Is Lack of Insurance Deadly? AB - About 28 million Americans are currently uninsured, and millions more could lose coverage under policy reforms proposed in Congress. At the same time, a growing number of policy leaders have called for going beyond the Patient Protection and Affordable Care Act to a single-payer national health insurance system that would cover every American. These policy debates lend particular salience to studies evaluating the health effects of insurance coverage. In 2002, an Institute of Medicine review concluded that lack of insurance increases mortality, but several relevant studies have appeared since that time. This article summarizes current evidence concerning the relationship of insurance and mortality. The evidence strengthens confidence in the Institute of Medicine's conclusion that health insurance saves lives: The odds of dying among the insured relative to the uninsured is 0.71 to 0.97. PMID- 28655035 TI - Cosmetics, Regulations, and the Public Health: Understanding the Safety of Medical and Other Products. PMID- 28655036 TI - Objective and Subjective Measures of Simultaneous vs Sequential Bilateral Cochlear Implants in Adults: A Randomized Clinical Trial. AB - Importance: To date, no randomized clinical trial on the comparison between simultaneous and sequential bilateral cochlear implants (BiCIs) has been performed. Objective: To investigate the hearing capabilities and the self reported benefits of simultaneous BiCIs compared with those of sequential BiCIs. Design, Setting, and Participants: A multicenter randomized clinical trial was conducted between January 12, 2010, and September 2, 2012, at 5 tertiary referral centers among 40 participants eligible for BiCIs. Main inclusion criteria were postlingual severe to profound hearing loss, age 18 to 70 years, and a maximum duration of 10 years without hearing aid use in both ears. Data analysis was conducted from May 24 to June 12, 2016. Interventions: The simultaneous BiCI group received 2 cochlear implants during 1 surgical procedure. The sequential BiCI group received 2 cochlear implants with an interval of 2 years between implants. Main Outcomes and Measures: First, the results 1 year after receiving simultaneous BiCIs were compared with the results 1 year after receiving sequential BiCIs. Second, the results of 3 years of follow-up for both groups were compared separately. The primary outcome measure was speech intelligibility in noise from straight ahead. Secondary outcome measures were speech intelligibility in noise from spatially separated sources, speech intelligibility in silence, localization capabilities, and self-reported benefits assessed with various hearing and quality of life questionnaires. Results: Nineteen participants were randomized to receive simultaneous BiCIs (11 women and 8 men; median age, 52 years [interquartile range, 36-63 years]), and another 19 participants were randomized to undergo sequential BiCIs (8 women and 11 men; median age, 54 years [interquartile range, 43-64 years]). Three patients did not receive a second cochlear implant and were unavailable for follow-up. Comparable results were found 1 year after simultaneous or sequential BiCIs for speech intelligibility in noise from straight ahead (difference, 0.9 dB [95% CI, -3.1 to 4.4 dB]) and all secondary outcome measures except for localization with a 30 degrees angle between loudspeakers (difference, -10% [95% CI, -20.1% to 0.0%]). In the sequential BiCI group, all participants performed significantly better after the BiCIs on speech intelligibility in noise from spatially separated sources and on all localization tests, which was consistent with most of the participants' self-reported hearing capabilities. Speech intelligibility-in-noise results improved in the simultaneous BiCI group up to 3 years following the BiCIs. Conclusions and Relevance: This study shows comparable objective and subjective hearing results 1 year after receiving simultaneous BiCIs and sequential BiCIs with an interval of 2 years between implants. It also shows a significant benefit of sequential BiCIs over a unilateral cochlear implant. Until 3 years after receiving simultaneous BiCIs, speech intelligibility in noise significantly improved compared with previous years. Trial Registration: trialregister.nl Identifier: NTR1722. PMID- 28655037 TI - Monitoring Medical Devices: Missed Warning Signs Within Existing Data. PMID- 28655038 TI - Kinematic Analysis of Speech Sound Sequencing Errors Induced by Delayed Auditory Feedback. AB - Purpose: Delayed auditory feedback (DAF) causes speakers to become disfluent and make phonological errors. Methods for assessing the kinematics of speech errors are lacking, with most DAF studies relying on auditory perceptual analyses, which may be problematic, as errors judged to be categorical may actually represent blends of sounds or articulatory errors. Method: Eight typical speakers produced nonsense syllable sequences under normal and DAF (200 ms). Lip and tongue kinematics were captured with electromagnetic articulography. Time-locked acoustic recordings were transcribed, and the kinematics of utterances with and without perceived errors were analyzed with existing and novel quantitative methods. Results: New multivariate measures showed that for 5 participants, kinematic variability for productions perceived to be error free was significantly increased under delay; these results were validated by using the spatiotemporal index measure. Analysis of error trials revealed both typical productions of a nontarget syllable and productions with articulatory kinematics that incorporated aspects of both the target and the perceived utterance. Conclusions: This study is among the first to characterize articulatory changes under DAF and provides evidence for different classes of speech errors, which may not be perceptually salient. New methods were developed that may aid visualization and analysis of large kinematic data sets. Supplemental Material: https://doi.org/10.23641/asha.5103067. PMID- 28655039 TI - Speech Motor Sequence Learning: Effect of Parkinson Disease and Normal Aging on Dual-Task Performance. AB - Purpose: Everyday communication is carried out concurrently with other tasks. Therefore, determining how dual tasks interfere with newly learned speech motor skills can offer insight into the cognitive mechanisms underlying speech motor learning in Parkinson disease (PD). The current investigation examines a recently learned speech motor sequence under dual-task conditions. Method: A previously learned sequence of 6 monosyllabic nonwords was examined using a dual-task paradigm. Participants repeated the sequence while concurrently performing a visuomotor task, and performance on both tasks was measured in single- and dual task conditions. Results: The younger adult group exhibited little to no dual task interference on the accuracy and duration of the sequence. The older adult group exhibited variability in dual-task costs, with the group as a whole exhibiting an intermediate, though significant, amount of dual-task interference. The PD group exhibited the largest degree of bidirectional dual-task interference among all the groups. Conclusions: These data suggest that PD affects the later stages of speech motor learning, as the dual-task condition interfered with production of the recently learned sequence beyond the effect of normal aging. Because the basal ganglia is critical for the later stages of motor sequence learning, the observed deficits may result from the underlying neural dysfunction associated with PD. PMID- 28655040 TI - Factors Associated With Communicative Participation in Amyotrophic Lateral Sclerosis. AB - Purpose: People with amyotrophic lateral sclerosis frequently experience bulbar impairment and dysarthria that may restrict their ability to take part in everyday communication situations. The aim of this study is to examine selected variables that may contribute to restrictions in communicative participation. Method: Community-dwelling participants with amyotrophic lateral sclerosis (N = 70) who reported communication changes but continued to use natural speech completed a survey, including the Communicative Participation Item Bank, demographics (age, sex, living situation, employment status, education, and time since diagnosis), and self- reported symptom-related variables (physical activity, emotional problems, fatigue, pain, speech severity, speech usage, and cognitive and communication skills). To identify predictors of restrictions in communicative participation, these variables were entered into a backward stepwise multiple linear regression analysis. Results: Three variables (speech severity, swallowing severity, and speech usage) were included in the final model and accounted for 55% of the variability. Conclusions: Better speech and swallowing skills and higher speech usage are associated with better communicative participation in this sample. Thus, when making clinical decisions regarding intervention, clinicians should continue their efforts to target speech and swallow abilities, while recognizing other variables that have the potential of restricting communicative participation. PMID- 28655041 TI - Game-Based Augmented Visual Feedback for Enlarging Speech Movements in Parkinson's Disease. AB - Purpose: The purpose of this pilot study was to demonstrate the effect of augmented visual feedback on acquisition and short-term retention of a relatively simple instruction to increase movement amplitude during speaking tasks in patients with dysarthria due to Parkinson's disease (PD). Method: Nine patients diagnosed with PD, hypokinetic dysarthria, and impaired speech intelligibility participated in a training program aimed at increasing the size of their articulatory (tongue) movements during sentences. Two sessions were conducted: a baseline and training session, followed by a retention session 48 hr later. At baseline, sentences were produced at normal, loud, and clear speaking conditions. Game-based visual feedback regarding the size of the articulatory working space (AWS) was presented during training. Results: Eight of nine participants benefited from training, increasing their sentence AWS to a greater degree following feedback as compared with the baseline loud and clear conditions. The majority of participants were able to demonstrate the learned skill at the retention session. Conclusions: This study demonstrated the feasibility of augmented visual feedback via articulatory kinematics for training movement enlargement in patients with hypokinesia due to PD. Supplemental Materials: https://doi.org/10.23641/asha.5116840. PMID- 28655042 TI - A Novel Investigation of Generalized Motor Program Theory: Syllable Stress as a Motor-Class Variable. AB - Purpose: This experiment evaluated syllable-stress position as a motor class directed by a syllable-sized generalized motor program. Reaction times were predicted to be slower for stimuli with untrained stress patterns outside the trained motor class. Furthermore, reaction times were predicted to be stable for untrained stimuli within the same motor class regardless of phonetic similarity. Method: Twenty-three young adults with typical speech and hearing participated in a motor-learning study comprised of motor-class training and a judgment task. Reaction times derived from the judgment task were evaluated using a within subject repeated-measures design to evaluate the effects of syllable-stress position on stimulus type. Results: Reaction times were not significantly different across proposed syllable-stress motor-class boundaries. However, reaction times for the stimuli within the same motor class were significantly different. To be specific, slower reaction times were associated with untrained stimuli that were phonetically similar to the trained stimuli. Conclusions: The proposed hypotheses for syllable stress as a motor class were not met. Results indicate that multiple stimulus features, including syllable stress and phoneme similarity, may be encoded into memory during motor learning. Future research should evaluate how phonetic similarity of stimuli may influence motor-learning outcomes. Supplemental Material: https://doi.org/10.23641/asha.5116837. PMID- 28655043 TI - The Impact of Feedback Frequency on Performance in a Novel Speech Motor Learning Task. AB - Purpose: This study investigated whether whole nonword accuracy, phoneme accuracy, and acoustic duration measures were influenced by the amount of feedback speakers without impairment received during a novel speech motor learning task. Method: Thirty-two native English speakers completed a nonword production task across 3 time points: practice, short-term retention, and long term retention. During practice, participants received knowledge of results feedback according to a randomly assigned schedule (100%, 50%, 20%, or 0%). Changes in nonword accuracy, phoneme accuracy, nonword duration, and initial cluster duration were compared among feedback groups, sessions, and stimulus properties. Results: All participants improved phoneme and whole nonword accuracy at short-term and long-term retention time points. Participants also refined productions of nonwords, as indicated by a decrease in nonword duration across sessions. The 50% group exhibited the largest reduction in duration between practice and long-term retention for nonwords with native and nonnative clusters. Conclusions: All speakers, regardless of feedback schedule, learned new speech motor behaviors quickly with a high degree of accuracy and refined their speech motor skills for perceptually accurate productions. Acoustic measurements may capture more subtle, subperceptual changes that may occur during speech motor learning. Supplemental Materials: https://doi.org/10.23641/asha.5116324. PMID- 28655044 TI - Identification and Remediation of Phonological and Motor Errors in Acquired Sound Production Impairment. AB - Purpose: This study aimed to test whether an approach to distinguishing errors arising in phonological processing from those arising in motor planning also predicts the extent to which repetition-based training can lead to improved production of difficult sound sequences. Method: Four individuals with acquired speech production impairment who produced consonant cluster errors involving deletion were examined using a repetition task. We compared the acoustic details of productions with deletion errors in target consonant clusters to singleton consonants. Changes in accuracy over the course of the study were also compared. Results: Two individuals produced deletion errors consistent with a phonological locus of the errors, and 2 individuals produced errors consistent with a motoric locus of the errors. The 2 individuals who made phonologically driven errors showed no change in performance on a repetition training task, whereas the 2 individuals with motoric errors improved in their production of both trained and untrained items. Conclusions: The results extend previous findings about a metric for identifying the source of sound production errors in individuals with both apraxia of speech and aphasia. In particular, this work may provide a tool for identifying predominant error types in individuals with complex deficits. PMID- 28655045 TI - Effects of Blocked and Random Practice Schedule on Outcomes of Sound Production Treatment for Acquired Apraxia of Speech: Results of a Group Investigation. AB - Purpose: The purpose of this investigation was to compare the effects of schedule of practice (i.e., blocked vs. random) on outcomes of Sound Production Treatment (SPT; Wambaugh, Kalinyak-Fliszar, West, & Doyle, 1998) for speakers with chronic acquired apraxia of speech and aphasia. Method: A combination of group and single case experimental designs was used. Twenty participants each received SPT administered with randomized stimuli presentation (SPT-R) and SPT applied with blocked stimuli presentation (SPT-B). Treatment effects were examined with respect to accuracy of articulation as measured in treated and untreated experimental words produced during probes. Results: All participants demonstrated improved articulation of treated items with both practice schedules. Effect sizes were calculated to estimate magnitude of change for treated and untreated items by treatment condition. No significant differences were found for SPT-R and SPT-B relative to effect size. Percent change over the highest baseline performance was also calculated to provide a clinically relevant indication of improvement. Change scores associated with SPT-R were significantly higher than those for SPT B for treated items but not untreated items. Conclusion: SPT can result in improved articulation regardless of schedule of practice. However, SPT-R may result in greater gains for treated items. Supplemental Materials: https://doi.org/10.23641/asha.5116831. PMID- 28655046 TI - Acoustic and Perceptual Consequences of Speech Cues for Children With Dysarthria. AB - Purpose: Reductions in articulatory working space and vocal intensity have been linked to intelligibility deficits in children with dysarthria due to cerebral palsy. However, few studies have examined the outcomes of behavioral treatments aimed at these underlying impairments or investigated which treatment cues might best facilitate improved intelligibility. This study assessed the effects of cues targeting clear speech (i.e., "Speak with your big mouth") and greater vocal intensity (i.e., "Speak with your strong voice") on acoustic measures of speech production and intelligibility. Method: Eight children with spastic dysarthria due to cerebral palsy repeated sentence- and word-level stimuli across habitual, big mouth, and strong voice conditions. Acoustic analyses were conducted, and 48 listeners completed orthographic transcription and scaled intelligibility ratings. Results: Both cues resulted in significant changes to vocal intensity and speech rate although the degree of change varied by condition. In a similar manner, perceptual analysis revealed significant improvements to intelligibility with both cues; however, at the single-word level, big mouth outperformed strong voice. Conclusion: Children with dysarthria are capable of changing their speech styles differentially in response to cueing. Both the big mouth and strong voice cues hold promise as intervention strategies to improve intelligibility in this population. Supplemental Material: https://doi.org/10.23641/asha.5116843. PMID- 28655047 TI - Initial Observations of Lingual Movement Characteristics of Children With Cerebral Palsy. AB - Purpose: This preliminary study compared the speech motor control of the tongue and jaw between children with cerebral palsy (CP) and their typically developing (TD) peers. Method: Tongue tip and jaw movements of 4 boys with spastic CP and 4 age- and sex-matched TD peers were recorded using an electromagnetic articulograph during 10 repetitions of "Dad told stories today." The duration, path distance, average speed, and speech movement stability of the movements were calculated for each repetition. Results: The children with CP had longer durations than their TD peers. Children with CP had longer path distances and faster average speed as compared with their TD peers for both articulators. The TD group but not the CP group had longer path distances and faster average speeds for the tongue than the jaw. The CP group had reduced speech movement stability for the tongue as compared with their TD peers, but both groups had similar speech movement stability for the jaw. Conclusions: Children with CP had impaired speech motor control of the tongue and jaw as compared with their TD peers, and these speech motor control deficits were more pronounced in the tongue tip than the jaw. PMID- 28655048 TI - Cutting-Edge Technology for Speech Rehabilitation. AB - Purpose: The authors of this article introduce the technical reports of this special issue. PMID- 28655049 TI - Video Game Rehabilitation of Velopharyngeal Dysfunction: A Case Series. AB - Purpose: Video games provide a promising platform for rehabilitation of speech disorders. Although video games have been used to train speech perception in foreign language learners and have been proposed for aural rehabilitation, their use in speech therapy has been limited thus far. We present feasibility results from at-home use in a case series of children with velopharyngeal dysfunction (VPD) using an interactive video game that provided real-time biofeedback to facilitate appropriate nasalization. Method: Five participants were recruited across a range of ages, VPD severities, and VPD etiologies. Participants completed multiple weeks of individual game play with a video game that provides feedback on nasalization measured via nasal accelerometry. Nasalization was assessed before and after training by using nasometry, aerodynamic measures, and expert perceptual judgments. Results: Four participants used the game at home or school, with the remaining participant unwilling to have the nasal accelerometer secured to his nasal skin, perhaps due to his young age. The remaining participants showed a tendency toward decreased nasalization after training, particularly for the words explicitly trained in the video game. Conclusion: Results suggest that video game-based systems may provide a useful rehabilitation platform for providing real-time feedback of speech nasalization in VPD. Supplemental Material: https://doi.org/10.23641/asha.5116828. PMID- 28655050 TI - Enhancing Intervention for Residual Rhotic Errors Via App-Delivered Biofeedback: A Case Study. AB - Purpose: Recent research suggests that visual-acoustic biofeedback can be an effective treatment for residual speech errors, but adoption remains limited due to barriers including high cost and lack of familiarity with the technology. This case study reports results from the first participant to complete a course of visual-acoustic biofeedback using a not-for-profit iOS app, Speech Therapist's App for /r/ Treatment. Method: App-based biofeedback treatment for rhotic misarticulation was provided in weekly 30-min sessions for 20 weeks. Within treatment progress was documented using clinician perceptual ratings and acoustic measures. Generalization gains were assessed using acoustic measures of word probes elicited during baseline, treatment, and maintenance sessions. Results: Both clinician ratings and acoustic measures indicated that the participant significantly improved her rhotic production accuracy in trials elicited during treatment sessions. However, these gains did not transfer to generalization probes. Conclusions: This study provides a proof-of-concept demonstration that app-based biofeedback is a viable alternative to costlier dedicated systems. Generalization of gains to contexts without biofeedback remains a challenge that requires further study. App-delivered biofeedback could enable clinician-research partnerships that would strengthen the evidence base while providing enhanced treatment for children with residual rhotic errors. Supplemental Material: https://doi.org/10.23641/asha.5116318. PMID- 28655052 TI - Automatic detection and recognition of multiple macular lesions in retinal optical coherence tomography images with multi-instance multilabel learning. AB - Detection and recognition of macular lesions in optical coherence tomography (OCT) are very important for retinal diseases diagnosis and treatment. As one kind of retinal disease (e.g., diabetic retinopathy) may contain multiple lesions (e.g., edema, exudates, and microaneurysms) and eye patients may suffer from multiple retinal diseases, multiple lesions often coexist within one retinal image. Therefore, one single-lesion-based detector may not support the diagnosis of clinical eye diseases. To address this issue, we propose a multi-instance multilabel-based lesions recognition (MIML-LR) method for the simultaneous detection and recognition of multiple lesions. The proposed MIML-LR method consists of the following steps: (1) segment the regions of interest (ROIs) for different lesions, (2) compute descriptive instances (features) for each lesion region, (3) construct multilabel detectors, and (4) recognize each ROI with the detectors. The proposed MIML-LR method was tested on 823 clinically labeled OCT images with normal macular and macular with three common lesions: epiretinal membrane, edema, and drusen. For each input OCT image, our MIML-LR method can automatically identify the number of lesions and assign the class labels, achieving the average accuracy of 88.72% for the cases with multiple lesions, which better assists macular disease diagnosis and treatment. PMID- 28655053 TI - Quantitative assessment of neural outgrowth using spatial light interference microscopy. AB - Optimal growth as well as branching of axons and dendrites is critical for the nervous system function. Neuritic length, arborization, and growth rate determine the innervation properties of neurons and define each cell's computational capability. Thus, to investigate the nervous system function, we need to develop methods and instrumentation techniques capable of quantifying various aspects of neural network formation: neuron process extension, retraction, stability, and branching. During the last three decades, fluorescence microscopy has yielded enormous advances in our understanding of neurobiology. While fluorescent markers provide valuable specificity to imaging, photobleaching, and photoxicity often limit the duration of the investigation. Here, we used spatial light interference microscopy (SLIM) to measure quantitatively neurite outgrowth as a function of cell confluence. Because it is label-free and nondestructive, SLIM allows for long-term investigation over many hours. We found that neurons exhibit a higher growth rate of neurite length in low-confluence versus medium- and high confluence conditions. We believe this methodology will aid investigators in performing unbiased, nondestructive analysis of morphometric neuronal parameters. PMID- 28655054 TI - Label-free tissue scanner for colorectal cancer screening. AB - The current practice of surgical pathology relies on external contrast agents to reveal tissue architecture, which is then qualitatively examined by a trained pathologist. The diagnosis is based on the comparison with standardized empirical, qualitative assessments of limited objectivity. We propose an approach to pathology based on interferometric imaging of "unstained" biopsies, which provides unique capabilities for quantitative diagnosis and automation. We developed a label-free tissue scanner based on "quantitative phase imaging," which maps out optical path length at each point in the field of view and, thus, yields images that are sensitive to the "nanoscale" tissue architecture. Unlike analysis of stained tissue, which is qualitative in nature and affected by color balance, staining strength and imaging conditions, optical path length measurements are intrinsically quantitative, i.e., images can be compared across different instruments and clinical sites. These critical features allow us to automate the diagnosis process. We paired our interferometric optical system with highly parallelized, dedicated software algorithms for data acquisition, allowing us to image at a throughput comparable to that of commercial tissue scanners while maintaining the nanoscale sensitivity to morphology. Based on the measured phase information, we implemented software tools for autofocusing during imaging, as well as image archiving and data access. To illustrate the potential of our technology for large volume pathology screening, we established an "intrinsic marker" for colorectal disease that detects tissue with dysplasia or colorectal cancer and flags specific areas for further examination, potentially improving the efficiency of existing pathology workflows. PMID- 28655055 TI - Deep convolutional neural networks for classifying head and neck cancer using hyperspectral imaging. AB - Surgical cancer resection requires an accurate and timely diagnosis of the cancer margins in order to achieve successful patient remission. Hyperspectral imaging (HSI) has emerged as a useful, noncontact technique for acquiring spectral and optical properties of tissue. A convolutional neural network (CNN) classifier is developed to classify excised, squamous-cell carcinoma, thyroid cancer, and normal head and neck tissue samples using HSI. The CNN classification was validated by the manual annotation of a pathologist specialized in head and neck cancer. The preliminary results of 50 patients indicate the potential of HSI and deep learning for automatic tissue-labeling of surgical specimens of head and neck patients. PMID- 28655056 TI - Inactivation of Pseudomonas aeruginosa biofilm after ultraviolet light-emitting diode treatment: a comparative study between ultraviolet C and ultraviolet B. AB - The objective of this study was to test the inactivation efficiency of two different light-based treatments, namely ultraviolet B (UVB) and ultraviolet C (UVC) irradiation, on Pseudomonas aeruginosa biofilms at different growth stages (24, 48, and 72 h grown). In our experiments, a type of AlGaN light-emitting diodes (LEDs) was used to deliver UV irradiation on the biofilms. The effectiveness of the UVB at 296 nm and UVC at 266 nm irradiations was quantified by counting colony-forming units. The survival of less mature biofilms (24 h grown) was studied as a function of UV-radiant exposure. All treatments were performed on three different biological replicates to test reproducibility. It was shown that UVB irradiation was significantly more effective than UVC irradiation in inactivating P. aeruginosa biofilms. UVC irradiation induced insignificant inactivation on mature biofilms. The fact that the UVB at 296 nm exists in daylight and has such disinfection ability on biofilms provides perspectives for the treatment of infectious diseases. PMID- 28655057 TI - Evaluating Surgeon-Specific Performance for Endoscopic Sinus Surgery. AB - Importance: Several identified factors have raised questions concerning the quality of care for endoscopic sinus surgery (ESS), including the presence of large geographic variation in the rates and extent of surgery, poorly defined indications, and lack of ESS-specific quality metrics. Combined with the risk of major complications, ESS represents a high-value target for quality improvement. Objective: To evaluate differences in surgeon-specific performance for ESS using a risk-adjusted, 5-year ESS revision rate as a quality metric. Design, Setting, and Participants: This retrospective study used a population-based administrative database to study adults (>=18 years of age) with chronic rhinosinusitis (CRS) who underwent primary ESS in Alberta, Canada, between March 1, 2007, and March 1, 2010. The study period ended in 2015 to provide 5 years of follow-up. Interventions: Endoscopic sinus surgery for CRS. Main Outcomes and Measures: Primary outcomes were the 5-year observed and risk-adjusted ESS revision rate. Logistic regression was used to develop a risk adjustment model for the primary outcome. Results: A total of 43 individual surgeons performed primary ESS in 2168 patients with CRS. Within 5 years after the primary ESS procedure, 239 patients underwent revision ESS, and the mean crude 5-year ESS revision rate was 10.6% (range, 2.4%-28.6%). After applying the risk adjustment model and 95% CI to each surgeon, 7 surgeons (16%) had lower-than-expected performance and 2 surgeons (5%) had higher-than-expected performance. Three variables had significant associations with surgeon-specific, 5-year ESS revision rates: presence of nasal polyps (odds ratio [OR], 2.07; 95% CI, 1.59-2.70), more annual systemic corticosteroid courses (OR, 1.33; 95% CI, 1.19-1.48), and concurrent septoplasty (OR, 0.70; 95% CI, 0.55-0.89). Conclusions and Relevance: Evaluating surgeon specific performance for ESS may provide information to assist in quality improvement. Although most surgeons had comparable risk-adjusted, 5-year ESS revision rates, 16% of surgeons had lower-than-expected performance, indicating a potential to improve quality of care. Future studies are needed to evaluate more surgeon-specific variables and validate a risk adjustment model to provide appropriate feedback for quality improvement. PMID- 28655058 TI - Association of Socioeconomic Status in Childhood With Left Ventricular Structure and Diastolic Function in Adulthood: The Cardiovascular Risk in Young Finns Study. AB - Importance: Increased left ventricular (LV) mass and diastolic dysfunction are associated with cardiovascular disease. Prospective data on effects of childhood socioeconomic status (SES) on measures of LV structure and function are lacking. Objective: To examine whether family SES in childhood was associated with LV mass and diastolic function after adjustment for conventional cardiovascular disease risk factors in childhood and adulthood. Design, Setting, and Participants: The analyses were performed in 2016 using data gathered in 1980 and 2011 within the longitudinal population-based Cardiovascular Risk in Young Finns Study. The sample comprised 1871 participants who reported family SES at ages 3 to 18 years and were evaluated for LV structure and function 31 years later. Exposures: Socioeconomic status was characterized as annual income of the family and classified on a 3-point scale. Main Outcomes and Measures: Left ventricular mass indexed according to height at the allometric power of 2.7 and the E/e' ratio describing LV diastolic performance at ages 34 to 49 years. Results: The participants were aged 3 to 18 years at baseline (mean [SD], 10.8 [5.0] years), and the length of follow-up was 31 years. Family SES was inversely associated with LV mass (mean [SD] LV mass index, 31.8 [6.7], 31.0 [6.6], and 30.1 [6.4] g/m2.7 in the low, medium, and high SES groups, respectively; differences [95% CI], 1.7 [0.6 to 2.8] for low vs high SES; 0.8 [-0.3 to 1.9] for low vs medium; and 0.9 [0.1 to 1.6] for medium vs high; overall P = .001) and E/e' ratio (mean [SD] E/e' ratio, 5.0 [1.0], 4.9 [1.0], and 4.7 [1.0] in the low, medium, and high SES groups, respectively; differences [95% CI], 0.3 [0.1 to 0.4] for low vs high SES; 0.1 [-0.1 to 0.3] for low vs medium; and 0.2 [0 to 0.3] for medium vs high; overall P < .001) in adulthood. After adjustment for age, sex, and conventional cardiovascular disease risk factors in childhood and adulthood, and participants' own SES in adulthood, the relationship with LV mass (differences [95% CI], 1.5 [0.2 to 2.8] for low vs high SES; 1.3 [0 to 2.6] for low vs medium; and 0.2 [-0.6 to 1.0] for medium vs high; P = .03) and E/e' ratio (differences [95% CI], 0.2 [0 to 0.5] for low vs high SES; 0.1 [-0.1 to 0.4] for low vs medium; and 0.1 [0 to 0.3] for medium vs high; P = .02) remained significant. Conclusions and Relevance: Low family SES was associated with increased LV mass and impaired diastolic performance more than 3 decades later. These findings emphasize that approaches of cardiovascular disease prevention must be directed also to the family environment of the developing child. PMID- 28655059 TI - Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease. AB - Importance: Evidence suggests that development of autonomic dysfunction (AutD) may negatively affect disease course and survival in patients with synucleinopathies. However, the few available studies on Parkinson disease (PD) have conflicting results, comprise a small number of patients, have short follow up periods, and lack pathologic confirmation of the diagnosis. Objective: To examine the association of time of onset of AutD with disease progression and survival in PD. Design, Setting, and Participants: This retrospective review of clinical data from 100 consecutive patients with an autopsy-confirmed diagnosis of PD from the archives of the Queen Square Brain Bank in London, United Kingdom, from January 1, 2006, to June 3, 2016, included patients with PD regularly seen by hospital specialists (neurologists or geriatricians) in the United Kingdom throughout their disease until death. Patients with dementia before or within 1 year after onset of motor symptoms, monogenic forms of PD, comorbidities that affect autonomic function, a coexisting neuropathologic diagnosis, or insufficient clinical information were excluded. Main Outcomes and Measures: Survival and time from diagnosis to specific disease milestones were calculated to assess disease progression. Autonomic dysfunction was defined as autonomic failure at autonomic function testing or 2 of the following symptoms: urinary symptoms, constipation, upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, or erectile dysfunction. Multivariable Cox proportional hazards regression models on the risk of a disease milestone and death were used. Results: A total of 100 patients (60 [60.0%] male; mean [SD] age at diagnosis, 63.9 [10.3] years; mean [SD] disease duration, 14.6 [7.7] years) were studied. Autonomic dysfunction developed in 85 patients (mean [SD] time from diagnosis, 6.7 [7.7] years) and was associated with older age at diagnosis, male sex, poor initial levodopa treatment response, and postural instability and gait difficulty motor PD subtype in linear regression analysis, but staging of alpha synuclein pathologic changes was unrelated. Earlier AutD increased the risk of reaching the first milestone (hazard ratio, 0.86; 95% CI, 0.83-0.89; P < .001) and shortened survival (hazard ratio, 0.92; 95% CI, 0.88-0.96; P < .001). Older age at diagnosis and poorer levodopa treatment response were the other factors associated with shorter survival in adjusted multivariate analysis. Conclusions and Relevance: Earlier AutD is associated with a more rapid development of disease milestones and shorter survival in patients with PD. PMID- 28655060 TI - Biomarkers and Surrogate Endpoints in Uveitis: The Impact of Quantitative Imaging. AB - Purpose: Uveitis is a major cause of sight loss across the world. The reliable assessment of intraocular inflammation in uveitis ('disease activity') is essential in order to score disease severity and response to treatment. In this review, we describe how 'quantitative imaging', the approach of using automated analysis and measurement algorithms across both standard and emerging imaging modalities, can develop objective instrument-based measures of disease activity. Methods: This is a narrative review based on searches of the current world literature using terms related to quantitative imaging techniques in uveitis, supplemented by clinical trial registry data, and expert knowledge of surrogate endpoints and outcome measures in ophthalmology. Results: Current measures of disease activity are largely based on subjective clinical estimation, and are relatively insensitive, with poor discrimination and reliability. The development of quantitative imaging in uveitis is most established in the use of optical coherence tomographic (OCT) measurement of central macular thickness (CMT) to measure severity of macular edema (ME). The transformative effect of CMT in clinical assessment of patients with ME provides a paradigm for the development and impact of other forms of quantitative imaging. Quantitative imaging approaches are now being developed and validated for other key inflammatory parameters such as anterior chamber cells, vitreous haze, retinovascular leakage, and chorioretinal infiltrates. Conclusions: As new forms of quantitative imaging in uveitis are proposed, the uveitis community will need to evaluate these tools against the current subjective clinical estimates and reach a new consensus for how disease activity in uveitis should be measured. The development, validation, and adoption of sensitive and discriminatory measures of disease activity is an unmet need that has the potential to transform both drug development and routine clinical care for the patient with uveitis. PMID- 28655062 TI - An Objective Drug-Induced Sedation Endoscopy Data Capture and Analysis System. PMID- 28655061 TI - Outcomes in Women With Cytology Showing Atypical Squamous Cells of Undetermined Significance With vs Without Human Papillomavirus Testing. AB - Importance: Little is known about the long-term yield of high-grade cervical intraepithelial neoplasia (CIN) and the influence on biopsy and treatment rates of human papillomavirus (HPV) triage of cytology showing atypical squamous cells of undetermined significance (hereafter ASC-US cytology). Objective: To examine 5 year outcomes after ASC-US cytology with vs without HPV testing. Design, Setting, and Participants: In this observational study, all cervical cytology and HPV testing reports from January 1, 2007, to December 31, 2012, were obtained for women throughout New Mexico and linked to pathology reports. The dates of the analysis were May 4, 2015, to January 13, 2017. Main Outcomes and Measures: Influence of HPV testing on disease yield, time to histologically confirmed disease, and biopsy or loop electrosurgical excision procedure rates. Results: A total of 457 317 women (mean [SD] age, 39.8 [12.5] years) with a screening test were recorded between 2008 and 2012, and 20 677 (4.5%) of the first cytology results per woman were reported as ASC-US. CIN grade 3 or more severe (CIN3+) lesions were detected in 2.49% of women with HPV testing vs 2.15% of women without HPV testing (P = .23). Time to CIN3+ detection was much shorter in those with HPV testing vs those without testing (median, 103 vs 393 days; P < .001). CIN grade 1 was detected in 11.6% of women with HPV testing vs 6.6% without testing (relative risk, 1.76; 95% CI, 1.56-2.00; P < .001). Loop electrosurgical excision procedure rates within 5 years were 20.0% higher in those who underwent HPV testing, resulting in more CIN2+ and CIN3+ detection. Conclusions and Relevance: Human papillomavirus testing led to faster and more complete diagnosis of cervical disease, but 55.8% more biopsies and 20.0% more loop electrosurgical excision procedures were performed. In those tested, virtually all high-grade disease occurred in the 43.1% of women who were HPV positive, allowing clinical resources to be focused on women who need them most. These data provide essential information for cervical screening guidelines and public health policy. PMID- 28655063 TI - Prenatally Diagnosed Trisomy 21-Reply. PMID- 28655064 TI - Range and Precision of Formant Movement in Pediatric Dysarthria. AB - Purpose: This study aimed to improve understanding of speech characteristics associated with dysarthria in children with cerebral palsy by analyzing segmental and global formant measures in single-word and sentence contexts. Method: Ten 5 year-old children with cerebral palsy and dysarthria and 10 age-matched, typically developing children participated in this study. Vowel space area and second formant interquartile range were measured from children's elicited productions of single words and sentences. Results: Results showed that the children with dysarthria had significantly smaller vowel space areas than typically developing children in both word and sentence contexts; however, overall ranges of second formant movement did not differ between groups in word or sentence contexts. Additional analysis of single words revealed that, compared to typical children, children with dysarthria had smaller second formant interquartile ranges in single words with phonetic contexts requiring large changes in vocal tract configuration, but not in single words with monophthongs. Conclusions: Results of this study suggest that children with dysarthria may not have globally reduced ranges of articulatory movement compared to typically developing peers; however, they do exhibit reduced precision in producing phonetic targets. PMID- 28655066 TI - [Initial Experience with Uniportal Video-Assisted Thoracoscopic Surgery for Anatomical Lung Resections: A Propensity Score Study and an Observational Assessment of the Learning Curve]. AB - INTRODUCTION: Uniportal video-assisted thoracoscopic surgery (UVATS) for anatomical lung resections has gained popularity of late. This study aimed to elucidate the impediments to implementing the uniportal access method into the daily routine of VATS lung resections. To this end, we reviewed our initial experience and evaluated our progress. METHODS: From January to May 2016, 24 consecutive UVATS anatomical lung resections (UVATS group) were performed by a single surgeon without any previous experience in UVATS surgery. These cases were matched in a one-to-one fashion with a cohort of 102 patients who had undergone "classical" VATS anatomical lung resections (VATS group) in the past 2?years performed by the same surgeon, using the nearest estimated propensity score. Based on an initial analysis, the UVATS group was further divided into two subgroups, UVATS1 and UVATS2, consisting of the first and last 12 cases. RESULTS: No UVATS patient required conversion to thoracotomy or needed an additional port. The VATS group had a shorter mean operation time if compared with the UVATS1 subgroup (MVATS = 152, MUVATS1 = 191; p = 0.019), but not if compared with the UVATS2 subgroup (MVATS = 152, MUVATS2 = 152; p = 1). There was no difference between the groups in the number of lymph node stations sampled (MVATS = 7, MUVATS1 = 7, MUVATS2 = 7; p = 0.92), the average number of dissected lymph nodes (MVATS = 19, MUVATS1 = 15, MUVATS2 = 18; p = 0.659), and the number and type of postoperative complications. As demonstrated on an audio-analogue pain scale (AAS), the UVATS groups needed significantly less pain medication until discharge (p < 0.001). CONCLUSION: The adoption of uniportal VATS for anatomical lung resections can be accomplished without any impact on operative or clinical success, if performed by a surgeon already experienced in "classical" VATS. In our experience, there was no need for additional courses, proctored cases or modification of surgical instruments, although all options mentioned above may facilitate adoption. PMID- 28655065 TI - Impact of Acute Intestinal Ischemia and Reperfusion Injury on Hemodynamics and Remote Organs in a Rat Model. AB - BACKGROUND: Acute mesenteric ischemia following cardiovascular surgery is a rare but fatal complication. We established a new rat model for hemodynamic monitoring during mesenteric ischemia/reperfusion (I/R) and evaluated the impact of mesenteric I/R on hemodynamics and remote organ injury. METHODS: Mesenteric I/R was induced in male Wistar rats by superior mesenteric artery occlusion for 90 minutes, followed by 120 minutes of reperfusion. Before I/R, ventilation and hemodynamic monitoring including mean arterial blood pressure (MAP) and cardiac output (CO) were established. During reperfusion Geloplasma (I/R + Geloplasma, N = 6) and Ringer's solution (I/R + Ringer, N = 6) were titrated according to CO and compared with I/R without volume resuscitation (I/R only, N = 6) and a sham group (sham, N = 6). Blood samples were regularly taken for serum marker measurements. After reperfusion organs were harvested for histology studies. RESULTS: After acute mesenteric I/R, MAP and CO decreased (p < 0.01) while systemic and pulmonary vascular resistance increased (p < 0.01) continuously in the I/R group. Volume substitution according to CO initially stabilized hemodynamic parameters, but CO declined independently in the late stage. Compared with the I/R + Ringer group, the I/R + Geloplasma group required less volume for resuscitation (p < 0.01), experienced less metabolic acidosis. I/R groups had more organ injuries, more neutrophils sequestration, and higher creatine phosphokinase-MB levels than sham group. CONCLUSION: A new model for CO monitoring after mesenteric I/R injury demonstrated severe hypovolemic shock during reperfusion followed by remote myocardial and lung injury. Far less colloid volume is needed for hemodynamic stabilization after I/R compared with crystalloid volume. PMID- 28655067 TI - Fatal ulcerative enteritis of the small intestine in a patient with ulcerative colitis treated with vedolizumab. AB - Vedolizumab (VDZ) inhibits alpha4beta7 integrins and is used to target intestinal immune responses in patients with inflammatory bowel disease, which is considered to be relatively safe. Here we report on a fatal complication following VDZ administration. A 64-year-old female patient with ulcerative colitis (UC) refractory to tumor necrosis factor inhibitors was treated with VDZ. One week after the second VDZ infusion, she was admitted to hospital with severe diarrhea and systemic inflammatory response syndrome (SIRS). Blood stream infections were ruled out, and endoscopy revealed extensive ulcerations of the small intestine covered with pseudomembranes, reminiscent of invasive candidiasis or mesenteric ischemia. Histology confirmed subtotal destruction of small intestinal epithelia and colonization with Candida. Moreover, small mesenteric vessels were occluded by hyaline thrombi, likely as a result of SIRS, while perfusion of large mesenteric vessels was not compromised. Beta-D-glucan concentrations were highly elevated, and antimycotic therapy was initiated for suspected invasive candidiasis but did not result in any clinical benefit. Given the non responsiveness to anti-infective therapies, an autoimmune phenomenon was suspected and immunosuppressive therapy was escalated. However, the patient eventually died from multi-organ failure. This case should raise the awareness for rare but severe complications related to immunosuppressive therapy, particularly in high risk patients. PMID- 28655068 TI - Potential impact of screening for fatty liver disease by transient elastography with liver stiffness and controlled attenuation parameter measurements: a pilot study. AB - Background The prevalence of chronic liver diseases is high in developed countries, and the leading causes are amenable to prevention. The German Lebertag is to increase awareness of the burden of chronic liver diseases in the general public. We performed a pilot study using transient elastography with liver stiffness measurement (LSM) and the controlled attenuation parameter (CAP) as a screening tool for previously unrecognized liver diseases. Patients and methods LSM and CAP was performed in 60 individuals, and participants filled in a questionnaire reporting basic characteristics and past medical history. Results Median LSM and CAP values were within the normal range. Participants with self reported diabetes mellitus had significantly elevated LSM (p = 0.02) and CAP values (p = 0.002). Participants with a BMI > 30 kg/m2 or dyslipidemia had significantly elevated CAP values (p = 0.007 and p = 0.01, respectively) with normal LSM values. Overall, 35 % of participants had elevated CAP values, indicating a high prevalence of hepatic steatosis. Discussion In a German pilot study, diabetes mellitus was a key risk factor for increased LSM and CAP values. Prevalence of steatosis was high and comparable to other Western countries. Transient elastography is a valuable tool to identify patients with increased risk for metabolic liver diseases. In people without risk factors, LSM and CAP values were within the normal range, indicating that screening for chronic liver injury was not warranted. PMID- 28655070 TI - Inhibitory Effect of Carnosol on Phthalic Anhydride-Induced Atopic Dermatitis via Inhibition of STAT3. AB - Carnosol is a phenolic antioxidant present in rosemary (Rosmarinus officinalis). It is known for anti-inflammatory effects, analgesic activity and anti-cancer effects. However, no study has been dedicated yet to its effect on atopic dermatitis (AD). Here, we show that carnosol effectively inhibited LPS-induced nitric oxide (NO) generation and expression of inflammatory marker proteins (iNOS and COX-2) in RAW 264.7 cells. In addition, carnosol effectively inhibits the phosphorylation of STAT3 and DNA binding activity in RAW 264.7 cells. Pull down assay and docking model analysis showed that carnosol directly binds to the DNA binding domain (DBD) of STAT3. We next examined the anti-atopic activity of carnosol (0.05 ug/cm2) using 5% Phthalic anhydride (PA)-induced AD model in HR1 mice. Carnosol treatment significantly reduced 5% PA-induced AD like skin inflammation in skin tissues compared with control mice. Moreover, carnosol treatment inhibits the expression of iNOS and COX-2 in skin tissue. In addition, the levels of TNF-alpha, IL-1beta, and Immunoglobulin-E in blood serum was significantly decreased in carnosol treated mice compared with those of 5% PA treated group. Furthermore, the activation of STAT3 in skin tissue was decreased in carnosol treated mice compared with control mice. In conclusion, these findings suggest that carnosol exhibited a potential anti-AD activity by inhibiting pro-inflammatory mediators through suppression of STAT3 activation via direct binding to DBD of STAT3. PMID- 28655069 TI - Delivery of parasite Cdg7_Flc_0990 RNA transcript into intestinal epithelial cells during Cryptosporidium parvum infection suppresses host cell gene transcription through epigenetic mechanisms. AB - Cryptosporidial infection causes dysregulated transcription of host genes key to intestinal epithelial homeostasis, but the underlying mechanisms remain obscure. Previous studies demonstrate that several Cryptosporidium parvum (C. parvum) RNA transcripts are selectively delivered into epithelial cells during host cell invasion and may modulate gene transcription in infected cells. We report here that C. parvum infection suppresses the transcription of LRP5, SLC7A8, and IL33 genes in infected intestinal epithelium. Trans-suppression of these genes in infected host cells is associated with promoter enrichment of suppressive epigenetic markers (i.e., H3K9me3). Cdg7_FLc_0990, a C. parvum RNA that has previously demonstrated to be delivered into the nuclei of infected epithelial cells, is recruited to the promoter regions of LRP5, SLC7A8, and IL33 genes. Cdg7_FLc_0990 appears to be recruited to their promoter regions together with G9a, a histone methyltransferase for H3K9 methylation. The PR domain zinc finger protein 1, a G9a-interacting protein, is required for the assembly of Cdg7_FLc_0990 to the G9a complex and gene-specific enrichment of H3K9 methylation. Our data demonstrate that cryptosporidial infection induces epigenetic histone methylations in infected cells through nuclear transfer of parasite Cdg7_Flc_0990 RNA transcript, resulting in transcriptional suppression of the LRP5, SLC7A8, and IL33 genes. PMID- 28655071 TI - Melatonin Rescues Mesenchymal Stem Cells from Senescence Induced by the Uremic Toxin p-Cresol via Inhibiting mTOR-Dependent Autophagy. AB - p-Cresol, found at high concentrations in the serum of chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body. p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether p-cresol induces senescence of mesenchymal stem cells, and whether melatonin can ameliorate abnormal autophagy response caused by p-cresol. We found that p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with melatonin prevented pro-senescence effects of p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway, melatonin enhanced catalase activity and thereby inhibited the accumulation of reactive oxygen species induced by p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with melatonin counteracted other pro senescence changes caused by p-cresol, such as the increase in total 5'-AMP activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of rapamycin. Ultimately, we discovered that melatonin restored the expression of senescence marker protein 30, which is normally suppressed because of the induction of the autophagy pathway in chronic kidney failure patients by p-cresol. Our findings suggest that stem cell senescence in patients with chronic kidney failure could be potentially rescued by the administration of melatonin, which grants this hormone a novel therapeutic role. PMID- 28655072 TI - Oral Administration of Glycine and Leucine Dipeptides Improves Skin Hydration and Elasticity in UVB-Irradiated Hairless Mice. AB - Placenta is a special organ that contains many nutrients such as growth factors, minerals, and bioactive peptides. Dipeptides of glycine and leucine are major components of porcine placenta extracts (PPE) that has been used as an alternative of human placenta extracts. In this study, we investigated whether major peptides of PPE, Glycyl-L-Leucine (Gly-Leu), L-Leucyl-Glycine (Leu-Gly), and L-Leucyl-L-Leucine (Leu-Leu), affect skin hydration and elasticity in vitro and in vivo. We found that Gly-Leu and Leu-Gly dipeptides induced the expression of transglutaminase 1 in normal human epidermal keratinocytes (NHEKs) whereas Leu Leu dipeptides did not. Treatment with Gly-Leu or Leu-Gly significantly increased hyaluronan (HA) synthesis in NHEKs and the upregulation of hyaluronan synthase 2 (HAS2) mRNA level was confirmed. In addition, elastase activity was inhibited in NHEKs treated with Gly-Leu or Leu-Gly dipeptides. Oral administration of Gly-Leu or Leu-Gly dipeptides increased skin hydration and elasticity in UVB-irradiated hairless mice. The significant upregulation of HA in UVB-irradiated hairless mice was observed in response to oral administration of Gly-Leu or Leu-Gly. These results suggest that the major dipeptides of porcine placenta, Gly-Leu and Leu Gly, are potentially active ingredients for skin moisturization formulations. PMID- 28655073 TI - [Thought of the present application situation and the future trends of minimally invasive surgery in colorectal cancer]. AB - Laparoscopic surgery has been increasingly used in rectal cancer surgery. Though there are still some controversies, most of the research results support that the outcome is similar for rectal cancer patients with either laparoscopic or open surgery, in term of short-term such as safety and efficacy and long-term such as oncologic outcome. Standardization of laparoscopic training together with the comprehensive management concept are the prerequisites of laparoscopic rectal cancer surgery. Those doctors who do minimally invasive surgery should follow the rationale that smaller incision and sphincter preservation are secondary to safety and oncological result of the patients. It is the comprehensive management and personalized treatment that bring opportunities for the continuous development and innovation of innovative technologies and concepts, for example, non-operative treatment, endoscopic therapy, natural orifice transluminal endoscopic surgery, single incision laparoscopic surgery, and robotic surgery. And they may finally lead to better outcome and quality of life for the patients. PMID- 28655074 TI - [Single and reduced port laparoscopic surgery for colorectal cancer: current status and future perspectives]. AB - For further maximizing the minimally invasive benefits for colorectal cancer patients, laparoscopic surgeons have been dedicating to improve the surgery through single-port (SILES) or natural orifice transluminal endoscopic surgery (NOTES), which is supported by amount of single-port devices and flexible laparoscopic instruments.Many small sample studies of single institution have suggested that SILES for colorectal cancer has similar oncological outcomes with conventional laparoscopic surgery (CLS), could improve the cosmetic results, and is more minimally invasive than CLS. However, evidences of advantages for SILES are limited, because of there has been only 4 published studies of prospective randomized clinical trial so far. Due to the technical difficulties and long learning curves, SILES and NOTES are relatively hard to be widely promoted. Thus, a balance between minimally invasive pursuit and laparoscopic technical challenge should be sought. In this way, modified SILES and reduced-port laparoscopic surgery have emerged in recent years, which might be minimally invasive solutions with lower technical demanding for laparoscopic colorectal cancer surgeries. Adding a port as the surgeon's dominant operation channel improved the collisions or overlapping of instruments with movement to reduce the technical difficulties. SILS+ 1 is safe and feasible, would be supported by more and more evidences. PMID- 28655075 TI - [Surgical treatment of colorectal liver metastases]. AB - Surgical resection of the metastases offers the only opportunity for long-term survival in colorectal liver metastases. However, only 10% to 20% of patients present with resectable disease, and so how to increase surgical patients has been a clinical hotspot. In addition to expanding surgical indications, two-stage hepatectomy and convertible therapy are optional. In convertible therapy, initial treatment regimen decides long-term benefit, and it is important to select appropriate patient population in addition to Ras status when anti-epithelial growth factor receptor monoclonal antibody is used. Minimally invasive surgery can also be used for liver resection and simultaneous resection, and it is safe and effective. For patients with colorectal cancer and unresectable asymptomatic liver metastases, the debate continues over the efficacy of primary resection compared to chemotherapy alone, limited by lack of prospective evidence. Therefore, multidisciplinary team assessment is essential to optimize outcomes in colorectal liver metastases. PMID- 28655076 TI - [Diagnosis and treatment strategy for clinical complete responders after chemoradiotherapy for rectal cancer: is watch-and-wait policy safe?] AB - Neo-adjuvant chemoradiotherapy (NACRT) combined with total mesorectal excision (TME) surgery is the main treatment for locally advanced middle-low rectal cancer, and NACRT significantly improves the local control rate of rectal cancer. According to the current guidelines, patients who receive clinical complete response (cCR) after NACRT are recommended for treatment with TME surgery. A few studies have shown that the watch-and-wait (WAW) policy is safe and could ensure anorectal function and quality of life in patients with cCR. In addition, such patients must be closely observed and followed up so as to enable salvage surgery for long periods of tumor re-growth. However, there is not enough evidence to provide a clear answer to the oncological effect of the WAW policy. As a result, WAW policy is not widely available in clinical practice, and further prospective studies are needed to assess its risk and benefit for the patients. PMID- 28655077 TI - [Attach importance to standardized treatment of chronic radiation proctopathy]. AB - Radiation proctopathy represents the feared injury of rectum resulting from radiotherapy to pelvic malignancy. Interstitial fibrosis is the major histopathologic feature of chronic radiation proctopathy, whose symptoms may improve over time without any management. Treatment decisions should be based on the pattern and severity of symptoms and endoscopic findings. Non-surgical interventions are generally used to relieve major symptoms and prevent severe complications. Surgery is reserved for patients with refractory complications. Diverting stoma and restorative resection are suggested for selected patients to promote rehabilitation. Overall management should target on the improvement of patients' long-term quality-of-life. PMID- 28655078 TI - [Updates and analyzation of postoperative pancreatic fistula system of consensus statement on the diagnosis, treatment, and prevention of common complications after pancreatic surgery(2017)]. AB - In 2017, following many thorough discussions, considering Chinese actual situation, more than 20 distinguished pancreatic surgeons brought about an update of the previous 2010 Chinese experts' consensus on the prevention and treatment of common complications after pancreatic surgery. Referred to the latest update of the postoperative pancreatic fistula consensus statement by the International Study Group of Pancreatic Surgery, the postoperative pancreatic fistula system of 2017 version Chinese consensus divided pancreatic fistula into pure fistula and mixed fistula based on whether other digestive fluid is mixed or not. The new version also presents key points of pancreatic fistula prevention and surgical strategy. In the paper, the authors analyzed the necessity, essentials and controversy of the update. PMID- 28655079 TI - [Pathological insights of radiotherapy-related damage to surgical margin after preoperative radiotherapy in patients with rectal cancer]. AB - Objective: To investigate the effect of irradiation to anastomosis from preoperative radiotherapy for patients with rectal cancer by studying the pathological changes. Methods: In this retrospective study, patients enrolled in the FOWARC study from January 2011 to July 2014 in the Sixth Affiliated Hospital of Sun Yat-Sen University were included. In the FOWARC study, enrolled patients with local advanced rectal cancer were randomly assigned to receive either neoadjuvant chemo-radiotherapy or chemotherapy. Among these patients, 23 patients were selected as radiation proctitis (RP)group, who fulfilled these conditions: (1) received neoadjuvant chemo-radiotherapy followed by sphincter-preserving surgery; (2) developed radiation proctitis as confirmed by preoperative imaging diagnosis; (3) had intact clinical samples of surgical margins. Twenty-three patients who had received neoadjuvant chemo-radiotherapy but without development of radiation proctitis were selected as non-radiation proctitis (nRP) group. Meanwhile, 23 patients received neoadjuvant chemotherapy only were selected as neoadjuvant chemotherapy (CT) group. Both nRP and CT cases were selected by ensuring the basic characteristics such as sex, age, tumor site, lengths of proximal margin and distal margin all maximally matched to the RP group. Both proximal and distal margins were collected for further analysis for all selected cases. Microscopy slices were prepared for hematoxylin & eosin staining and Masson staining to show general pathological changes, and also for immunohistochemistry with anti-CD-34 as primary antibody to reveal the microvessel. Microvessel counting in submucosal layer and proportion of macrovessel with stenosis were used to evaluate the blood supply of the proximal and distal end of anastomosis. A modified semi-quantitative grading approach was used to evaluate the severity of radiation-induced injury. Either ANOVA analysis, Kruskal-Wallis rank-sum test or chi(2) test was used for comparison among three groups, and Mann-Whitney U test was used for comparison between two groups. Results: Compared to group of neoadjuvant chemotherapy only, patients receiving neoadjuvant chemo-radiotherapy had lower microvessel count in both proximal and distal margins (M(Q(R)): proximal, 25.5 (19.6) vs. 50.0 (25.0), Z=3.915, P=0.000; distal, 20.5 (17.5) vs. 49.0 (28.0), Z=3.558, P=0.000), higher proportions of macrovessel with stenosis (proximal, 9.5% (23.8%) vs. 0, Z=3.993, P=0.000; distal, 11.5%(37.3%) vs. 0 (2.0%), Z=2.893, P=0.004), higher histopathologic score (proximal, 4.0 (2.0) vs. 1.0 (2.0), Z=6.123, P=0.000; distal, 5.0 (3.0) vs. 2.0 (1.0), Z=4.849, P=0.000). In patients receiving neoadjuvant chemo radiotherapy, compared to nRP group, RP group had lower microvessel count in both proximal and distal margins (proximal, 19.0 (23.0) vs. 30.4 (38.0), Z=2.845, P=0.004; distal, 19.0 (13.0) vs. 30.0(29.1), Z=2.022, P=0.043), higher proportions of macrovessel with stenosis (proximal, 23.0% (40.0%) vs. 0(11.0%), Z=3.248, P=0.001; distal, 27.0% (45.0%) vs. 3.0% (19.0%), Z=2.164, P=0.030). Rate of anastomotic leakage for CT, nRP and RP group were 8.7% (2/23), 30.4% (7/23), and 52.2% (12/23), and the differences among three groups were statistically significant (chi(2)=10.268, P=0.007). Conclusion: Radiation-induced injury existed on both margins of the resected rectal site after preoperative radiotherapy, and those diagnosed as radiation proctitis had more severe microvascular injury. PMID- 28655080 TI - [A retrospective controlled clinical study of single-incision plus one port laparoscopic surgery for sigmoid colon and upper rectal cancer]. AB - Objective: To evaluate the short-term and oncologic outcomes of single-incision plus one port laparoscopic surgery (SILS+ 1) for sigmoid colon and upper rectal cancer. Methods: The clinic data of 46 patients with sigmoid colon and upper rectal cancer underwent SILS+ 1 at Department of General Surgery, Nanfang Hospital, Southern Medical University from September 2013 to September 2014 were retrospectively reviewed (SILS+ 1 group). After generating 1?1 ration propensity scores given the covariates of age, gender, body mass index, American Society of Anesthesiologists score, surgeons, tumor location, the distance of tumor from anal, tumor diameter, and pathologic TNM stage, 46 patients with sigmoid colon and upper rectal cancer underwent conventional laparoscopic surgery (CLS) in the same time were matched as CLS group. The baseline characteristics and short-term outcomes were compared using t test, chi(2) test or Wilcoxon signed ranks test. Kaplan-Meier survival curves and Log-rank tests demonstrated the distribution of disease free survival. Results: The two study groups were well balanced with respect to the baseline characteristics of the propensity score derivation model. As compared to the CLS group, patients in SILS+ 1 group had a smaller incision ((6.9+/-1.1) cm vs. (8.4+/-1.2) cm, t=6.502, P=0.000), less estimated blood loss (20(11) ml vs. 50(30) ml, Z=2.414, P=0.016), shorter intracorporeal operating time ((67.0+/-25.8) minutes vs. (75.5+/-27.7) minutes, t=2.062, P=0.042) and significantly faster recovery course including shorter time to first ambulation ((46.7+/-20.3) hours vs. (78.6+/-28.0) hours, t=6.255, P=0.000), shorter time to first oral diet ((64.7+/-28.8) hours vs. (77.1+/-30.0) hours, t=2.026, P=0.047), shorter time of postoperative hospital stay ((7.8+/-2.2) days vs. (6.5+/-2.2) days, t=2.680, P=0.009), and lower postoperative visual analogue scale scores (F=4.721, P=0.032). No significant difference was observed in total operating time, postoperative morbidity, first time to flatus and defecation, analgesic use, number of retrieved lymph nodes and resection margin. During the median follow-up period of 33 months (ranging from 7 to 39 months) , there was no significant difference between the two groups in terms of 3-year disease-free survival (SILS+ 1: 91.3%, CLS: 93.4%, P=1.000). The recurrence rates of SILS+ 1 group and CLS groups were 8.7% (4/46) and 6.5% (3/46), respectively. Conclusion: For experienced CLS surgeons, the SILS+ 1 for sigmoid colon and upper rectal cancer would be easiness, safe and efficient alternative. PMID- 28655081 TI - [Prognostic analysis of colorectal liver metastases treated by surgery combined with intraoperative radiofrequency ablation]. AB - Objective: To investigate the clinical value of intraoperative radiofrequency ablation (RFA) in the treatment of colorectal liver metastasis (CLM). Methods: A retrospectively analysis of 187 patients with CLM who underwent liver resection with or without RFA from January 2009 to August 2016 in Department of Hepatobiliary Surgery, Cancer Hospital, Chinese Academy of Medical Sciences was performed. According to whether RFA was used intraoperatively, patients were divided into resection only group and combined treatment group. The clinical and pathological characteristics of the two groups were compared to explore factors influencing survival and recurrence. Imbalance of background characteristics between the two groups was further overcome by propensity score matching method (PSM). Results: The number of liver metastases (267), simultaneous liver metastases (100%), bilobar involvement (73.3%) and preoperative chemotherapy (93.3%) rates were significantly higher in the combined treatment group than those in the resection only group(471, 74.7%, 42.0% and 63.1%)(all P<0.05). In the combined treatment group, median overall survival (OS) was 25.7 months; and 3 year and 5-year OS were 47.9% and 28.8%, respectively. In the resection only group, the median survival time was 46.9 months; and 3-year and 5-year OS rate was 59.1% and 42.4%, respectively (chi(2)=4.579, P=0.034). Median disease-free survival (DFS) was 5.4 months in the combined treatment group, and 10.1 months in the resection only group (chi(2)=5.399, P=0.023). In multivariate analysis, intraoperative RFA was not an independent prognostic factor for OS and DFS (HR=0.98, 95%CI: 0.47-2.08, P=0.965; HR=1.21, 95%CI: 0.71-2.07, P=0.465). After PSM, the median OS of the resection only and the combined treatment groups were 30.2 and 25.7 months (chi(2)=0.876, P=0.350). The median DFS in the two groups was 5.3 and 4.2 months, respectively (chi(2)=0.199, P=0.650). Conclusion: In patients with similar tumor burden, liver resection combined with intraoperative RFA for unresectable CLM can achieve long-term outcomes similar to hepatectomy alone for resectable CLM. PMID- 28655082 TI - [Impact of the 2016 new definition and classification system of pancreatic fistula on the evaluation of pancreatic fistula after pancreatic surgery]. AB - Objective: To discuss the impact of updated definition and classification system of pancreatic fistula published in 2016 on the postoperative classification of pancreatic fistula. Methods: Retrospective analysis was made on patients who underwent pancreatic surgery at ward 1 in Department of General Surgery, Peking Union Medical College Hospital from January 2015 to December 2016.A total of 408 patients were included in this retrospective study, male/female was 184/224, aged from 9 to 81 years with mean age of 51.6 years.One hundred and fifty-two cases were performed pancreaticoduodenectomy, 125 cases for distal pancreatectomy, 43 cases for spleen preservation distal pancreatectomy, 61 cases for partital pancreatectomy or enucleation, 8 cases for middle pancreatectomy, 6 cases for pancreaticojejunostomy and 13 cases for other procedures.Clinical data including postoperative drainage fluid volume, amylase concentration, duration of hospitalization and drainage were obtained, revaluated and re-analyzed, classified grounded on 2005 edition and 2016 edition, respectively.t-test was adopted for data analysis. Results: According to the previous standards, the incident rate of pancreatic fistula was 57.4%, and the incident rate of B-level plus C-level pancreatic fistula was 35.8%, which decreased to 13.7% based on 2016 edition.Nine patients who received percutaneous puncture or endoscopic drainage was regraded from C-level to B-level. The average duration of postoperative hospitalization of patients without pancreatic fistula was (12.5+/-6.0)days, demonstrating no significant difference compared to (14.1+/-7.7)days, duration of postoperative hospitalization of A-level(under 2005 edition of criteria) pancreatic fistula group(t=1.66, P=0.09) and (12.4+/-6.1)days, duration of postoperative hospitalization of biochemical leakage group(t=0.14, P=0.89). Nevertheless, there was statistical significant difference between the average postoperative duration of hospitalization(30.7+/-16.9) days of B-level(under 2016 criteria) pancreatic fistula patients and pancreatic fistula-free patients as well as the biochemical leakage group patients (t=7.10, 7.13; both P<0.01). Conclusions: Based on the new diagnostic criteria, the incidence of postoperative pancreatic fistula decreased dramatically.New classification system downgraded part of cases graded C-level pancreatic fistula to B-level and some B-level to biochemical fistula.The new diagnostic classification and criteria facilitated clinical practice, accomplished better conformity to clinical reality and potentially enacted clinical outcome. PMID- 28655083 TI - [Anatomic study and clinical practice of mesopancreas and total mesopancreatic excision]. AB - Objective: To explore the anatomical characteristics of the mesopancreas, to define the range of the total mesopancreas excision and to evaluate the feasibility, safety and effectiveness in the treatment of pancreatic cancer. Methods: A regional anatomical and pathological study was performed on 14 cadavers with large slices and paraffin sections. The clinical and pathological data of 58 consecutive patients underwent total mesopancreas excision for pancreatic head carcinoma from January 2013 to December 2015 were prospectively collected and analysed. The perioperative morbidity, mortality and clinical outcomes of patients underwent total mesopancreas excision were compared with the patients underwent conventional pancreaticoduodenectomy from January 2010 to December 2012. Results: The mesopancreas located in the retropancreatic area, extending from the head, neck, and uncinated process of pancreas to the aorto caval groove, in which there were loose areolar tissue, adipose tissue, nerve plexus, lymphatic and capillaries. Although no fibrous sheath or fascia like mesocolorectum was found around the structures, a relatively fixed extent could be defined according to its embryologic and anatomic characters. In clinical practice, total mesopancreas excision was classified into two levels according to the extent of resection in this series: level I was a"standard total mesopancreas excision" or"total mesopancreas excision in a narrow sense" , which was similar to the extent of standard resection from consensus statement of ISGPS. Level II was defined as any procedure extending the range of level I, called the"extended total mesopancreas excision" or"total mesopancreas excision in a broad sense". In TMpE group, the intraoperative blood loss( (461.4+/-184.5)ml vs. (532.2+/ 319.8)ml, P=0.301), operation time( (368.6+/-92.5)minutes vs. (397.1+/ 112.7)minutes, P=0.559), total complication rate (39.7% vs. 51.2%, P=0.250), fistula mortality (25.9% vs. 30.2%, P=0.628) were all reduced. There were significantly higher R0 rate (91.4% vs.76.7%, P=0.041) and more harvested lymph nodes (16.2 vs. 11.4, P=0.000) and lower total and local recurrence: rate (half year local recurrence rate: 7.8% vs. 23.7%, P=0.036; one-year local recurrence rate: 18.2% vs. 39.5%, P=0.018) and longer disease-free survival (16.9 months vs. 13.4 months, P=0.044) and overall survival(22.5 months vs. 19.9 months, P>0.05) were also found in the study group. Conclusions: Mesopancreas is different from mesorectum since it has no fascial envelop, which should be regarded as a surgical concept, rather than an anatomical structure. Total mesopancreas excision is safe and feasible for pancreatic head cancer and probably helps to increase the R0 resection rate and improve the clinical outcomes. PMID- 28655084 TI - [Therapeutic effect of a new hybrid technique which combined laparoscopic method and abdominal repair for parastomal hernia repair]. AB - Objective: To investigate the safety and effectiveness of a new hybrid technique which combined laparoscopic method and abdominal repair (Dual Lap) for parastomal herniarepair. Methods: The clinical and follow-up data of 27 cases who accepted Dual Lap procedure performed at Department of Hernia and Abdominal Wall Surgery, Wuhan Central Hospital, Tongji Medical College of Huazhong University from January 2010 to January 2015 were analyzed retrospectively. The data included 22 male patients and 5 female patients with mean age of 54 years. Of the patients, there were 19 cases of the left hernia and 8 cases of the right hernia, without ostomy hernia repair history. There were 4 cases of the occult hernial defects during the operation. There were 8 patients with ilealneobladder, 2 patients with ileostomyafter total colectomy for familial adenomatous polyposis, 3 patients with ileostomy and 14 patients with colostomy for ulcerative colitis. Results: All cases underwent hybrid technique successfully. The mean operation time was (108+/-16) minutes(ranging from 90 to 150 minutes) and the diameter of the hernial ring was (6.4+/-1.8)cm (ranging from 3 to 13 cm). There were no intestinal, kidney and ureteral obstructions in operations. Five cases need to use the analgesic adjuvant at 48-hour after operation. The time of postoperative defecations was (9.3+/-2.4) days (ranging from 7 to 16 days) and there were no intestinal leakage, local hematoma, wound infection and fat liquefaction after operations. All patients were followed up for (16.3+/-4.2) months (ranging from 12 to 48 months). There was no ileus, obvious seroma, hernia recurrence, chronic pain and mesh infection. Conclusion: The Dual Lap procedureis safe and effective for parastomal hernia repair with less complication. PMID- 28655085 TI - [Effects of robot-assisted minimally invasive transforaminal lumbar interbody fusion and traditional open surgery in the treatment of lumbar spondylolisthesis]. AB - Objective: To compare the clinical effects of robot-assisted minimally invasive transforaminal lumbar interbody fusion (TLIF) and traditional open TLIF in the treatment of lumbar spondylolisthesis. Methods: A total of 41 patients with lumbar spondylolisthesis accepted surgical treatment in Department of Spinal Surgery of Beijing Jishuitan Hospital From July 2015 to April 2016 were retrospectively analyzed. There were 16 cases accepted robot-assisted minimally invasive TLIF and 25 accepted traditional open TLIF. The operation time, X-ray radiation exposure time, perioperative bleeding, drainage volume, time of hospitalization, time for pain relief, time for ambulatory recovery, visual analogue scale (VAS), Oswestry disability index (ODI) and complications were compared. T test and chi(2) were used to analyze data. Results: There were no significant difference in gender, age, numbers, degrees, pre-operative VAS and ODI in spondylolisthesis (all P>0.05). Compared with traditional open TLIF group, the robot-assisted minimally invasive TLIF group had less perioperative bleeding ((187.5+/-18.4) ml vs. (332.1+/-23.5) ml), less drainage volume ((103.1+/-15.6) ml vs. (261.3+/-19.8) ml), shorter hospitalization ((7.8+/-1.9) days vs. (10.0+/ 1.6) days), shorter time for pain relief ((2.8+/-1.0) days vs. (5.2+/-1.1) days), shorter time for ambulatory recovery ((1.7+/-0.9) days vs. (2.9+/-1.3) days) and less VAS of the third day postoperatively (2.2+/-0.9 vs. 4.2+/-2.4) (t=2.762 16.738, all P<0.05), but need more operation time ((151.3+/-12.3) minutes vs. (102.2+/-7.1) minutes) and more X-ray radiation exposure ((26.1+/-3.3) seconds vs. (5.5+/-2.1) seconds) (t=6.125, 15.168, both P<0.01). In both groups ODI was significantly lower in final follow-up than that of the pre-operation (t=12.215, 14.036, P<0.01). Intervertebral disc height of the final follow-up in both groups were significantly larger than that of the preoperation (robot-assisted minimally invasive TLIF group: (11.8 +/- 2.8) mm vs. (7.5 +/- 1.9) mm, traditional open TLIF group: (12.7 +/- 2.5) mm vs. (7.9+/-2.0) mm), and so was the lumbar lordosis angle (robot-assisted minimally invasive TLIF group: (48.7+/-9.2) degrees vs. (39.6+/-7.9) degrees , traditional open TLIF group: (50.1+/-10.8) degrees vs. (41.4+/-8.8) degrees ), the lordosis angle of the slippage segment (robot assisted minimally invasive TLIF group: (18.7+/-5.6) degrees vs. (10.9+/-3.8) degrees , traditional open TLIF group: (17.6+/-6.1) degrees vs.(8.7+/-3.2) degrees ) (t=4.128-16.738, all P<0.01). Slippage rate of the final follow-up in both groups were significantly smaller than those of the pre-operation (robot assisted minimally invasive TLIF group: (5.3+/-2.3) % vs. (27.8+/-7.2) %, traditional open TLIF group: (6.6+/-2.8) % vs. (29.1+/-9.5) %) (t=11.410, 18.504, both P<0.01). There was no difference of the upper data between two groups (t=0.106-1.227, P>0.05). The results of the post-operative CT showed that the pedicle screws in the robot-assisted minimally invasive TLIF group were more precisely placed than traditional open TLIF group (chi(2)=4.247, P=0.039). The mean follow-up time was 8 months (ranging from 3 to 12 months). There were no significant difference in outcomes between the two groups (chi(2)=0.366, P=0.545). Conclusions: In the treatment of lumbar spondylolisthesis, Robot assisted minimally invasive TLIF can lead to less perioperative bleeding, less post-operative pain, and quicker recovery than traditional open TLIF surgery, but it needs more operation time and radiation exposure. PMID- 28655086 TI - [Clinical study of SMT-II video laryngoscope with difficult airway intubation in emergency department]. AB - Objective: To observe the clinical feasibility and security of SMT-II video laryngoscope in difficult airway intubation in emergency department. Methods: This study took 90 adults with difficult airway who were admitted to the rescue room of Jingxi court of Beijing Chao-Yang Hospital, Capital Medical University from January 2015 to December 2016.The patients were randomly divided into 2 groups(SMT-II video laryngoscope group: n=45, Macintosh direct laryngoscope group: n=45), which were treated with endotracheal intubation and ventilator assisted ventilation.The evaluation of difficult mask ventilation(DMV) independent risk factor score, Wlison score, Cormack-Lehane grade, mouth opening, thyromental distance, visualization of the glottis, time for laryngoscopy, time for tracheal intubation, first-pass success rate of intubation, complications, mean arterial pressure(MAP) and heart rate(HR) before induction, after laryngoscopy, after induction, after intubation 5 minutes, 10 minutes were recorded.ANOVA, t-test, Chi-square test was used to analyze differences data, respectively. Results: There was no significant difference between the two groups in terms of gender, age, height, weight and other general data, mouth opening, DMV independent risk factor score, Wlison score, and thyromental distance(chi(2)=0.045, t=-0.367, t=0.684, t=0.511, t=0.330, t=-0.724, t=1.219, t=1.034, all P>0.05). A Cormack-Lehane grade I or II view were 44 cases in SMT-II video laryngoscope group and 14 cases in Macintosh direct laryngoscope group. It significantly improved with the use of SMT- II video laryngoscope, compared with Macintosh direct laryngoscope(chi(2)=52.096, P<0.01). The time to best view was shorter in SMT-II video laryngoscope group compared to that in Macintosh direct laryngoscope group with (15.0+/-1.0) seconds vs. (24.2+/-3.4) seconds(t=-26.319, P<0.05). The tube passage time was shorter with SMT-II video laryngoscope (31.6+/ 4.3) seconds vs. (12.7+/-0.9) seconds(t=-21.698, P<0.05)). The first -pass success rates in SMT-II video laryngoscope group and Macintosh direct laryngoscope group were 100% and 84.4%, respectively(chi(2)=5.577, P<0.05). For complications, pharyngorrhagia at intubation occurred in 1 case in SMT-II video laryngoscope group and 9 cases in Macintosh direct laryngoscope group(chi(2)=5.513, P<0.05), dislocation of tooth at intubation occurred in 0 case in SMT- II video laryngoscope group and 6 cases in Macintosh direct laryngoscope group (chi(2)=4.464, P<0.05). The mean arterial pressure values before induction, after laryngoscopy, after induction and after intubation 5 minutes, 10 minutes were (84.8+/-3.3), (89.2+/-3.6), (90.8+/-3.6), (86.6+/-3.4), (85.4+/-3.6) mmHg(1 mmHg=0.133 kPa) in SMT-II video laryngoscope group and (85.8+/-3.1), (91.9+/-3.4), (96.1+/-2.9), (90.0+/-2.5), (86.5+/-2.9) mmHg in Macintosh direct laryngoscope group. There was a significant difference between the two groups at the 5-time points of MAP (F=16.619, P=0.000). The heart rate values before induction, after laryngoscopy, after induction and after intubation 5 minutes, 10 minutes were(77.4+/-4.3), (80.8+/-4.3), (83.3+/-4.9), (78.8+/-4.2), (76.9+/-4.2) rate/minutes in SMT-II video laryngoscope group and (75.7+/-4.0), (85.3+/-4.4), (90.7+/-4.4), (84.3+/-4.1), (78.3+/-4.2) rate/minutes in the Macintosh direct laryngoscope group.There was a significant difference between the two groups at the 5-time points of HR(F=15.857, P=0.000). Conclusions: SMT-II video laryngoscope uesd in difficult ariway enable better visualization of the glottic opening, short opertive time, enhance the success rate of intubation.It indicucates that SMT-II video laryngoscope is safer than Macintosh direct laryngoscope in patients with difficult airway. PMID- 28655087 TI - [How I treat young patients with multiple myeloma]. PMID- 28655088 TI - [How I treat immunoglobulin light chain amyloido-sis]. PMID- 28655089 TI - [Prognostic value of the revised international staging system for newly diagnosed multiple myeloma patients]. AB - Objective: To assess the prognostic value of revised international staging system (R-ISS) for multiple myeloma (MM) in real world. Methods: A total of 202 newly diagnosis symptomatic MM patients were enrolled from May 2010 to April 2015 and the clinical data were retrospectively analyzed. All the patients received at least four courses of bortezomib-based or thalidomide-based induction therapy. Results: With a median follow-up of 31 months, the cohort included 56 cases in R ISSI, 108 in R-ISS II, and 38 in R-ISS III, and the median OS was not reached/61/38 months, respectively (P=0.001). According to the ISS system, 62 patients were classified in ISS-I, 70 in ISS-II and 70 in ISS-III, with the median OS was 58, 52 and 40 months, respectively (P=0.001). The relative risk (HR) of R-ISS stage III vs I, II vs I were 9.606 (P=0.008) and 4.038 (P=0.029). The HR of III vs I, II vs I of ISS system were 4.127 (P=0.070) and 2.877 (P=0.005). In the subgroup analysis, R-ISS predicted survival for patients who were not transplanted (P=0.003) , receiving bortezomib-based therapy (P=0.010) , and patients younger than 65 years (P=0.001). Conclusion: R-ISS system could better predict prognosis for OS in unselected nonclinical trial myeloma patients than ISS system, especially for the younger patients, patients with bortezomib based therapy, and patients without transplantation. PMID- 28655090 TI - [Molecular mechanisms and relationship of M2-polarized macrophages with early response in multiple myeloma]. AB - Objective: To investigate the relationship between M2-polarized macrophages and early response in multiple myeloma and its molecular mechanism. Methods: Two hundred and forty bone marrow biopsy tissue were collected and M2-polarized macrophages were stained by anti-CD163 monoclonal antibody. In vitro M2-polarized macrophages were derived from human peripheral blood mononuclear cell or THP-1 cells and identified by flow cytometry. Two myeloma cell lines RPMI 8226 and U266 were co-cultured with M2 macrophages using a transwell system. We measured myeloma cells proliferation through CCK-8 method and the pro-inflammatory cytokines expression (TNF-alpha and IL-6) by ELISA. Real time PCR was applied to measure chemokines (CCL2 and CCL3) , chemokine receptors (CCR2, CCR5) , VEGF and their receptors. In addition, flow cytometry was used to analyze the apoptosis of myeloma cells induced by dexamethasone. Results: 1Patients with high percentage of M2 macrophage involvement in bone marrow showed poorer response (23.9% versus 73.0%, chi(2)=60.31, P<0.001). 2 In vitro the proliferation of RPMI 8226 cells (P=0.005 at 24 h, P=0.020 at 36 h) or U266 myeloma cells (P= 0.030 at 24h, P=0.020 at 36h) co-cultured with M2-polarized macrophages was higher than control group. 3In vitro the apoptotic rate of RPMI 8226 cells (29.0% versus 71.0%, t=4.97, P=0.008) or U266 myeloma cells (24.9% versus 67.7%, t=6.99, P=0.002) co cultured with M2-polarized macrophages was lower than control group. 4 In vitro M2-polarized macrophages promoted myeloma cells secreting higher level of IL-6, TNF-alpha and higher expression of CCL2, CCL3, CCR2, CCR5, VEGFA, VEGFR-1,-2 compared with the non-macrophage co-culture system. Conclusion: M2-polarized macrophages promote myeloma cells proliferation and inhibit apoptosis through a very complex mechanism involving pro-inflammatory cytokines IL-6 and TNF-alpha, chemokines and related receptors such as CCL2, CCL3, CCR2, CCR3, and VEGF as well as related VEGFR. PMID- 28655091 TI - [Outcomes of lenalidomide-based treatment for 57 patients of relapsed or refractory multiple myeloma]. AB - Objective: To investigate the clinical efficacy and safety of lenalidomide (Revlimid, R) -based chemotherapy in the treatment of relapsed/refractory multiple myeloma (MM) patients. Methods: 57 consecutively relapsed/refractory MM patients were retrospectively analyzed from June 2013 to February 2016. All the patients received lenalidomide-based chemotherapy. Results: 1 60.4% patients had international staging system (ISS) stage III, 37.9% patients had revised international staging system (R-ISS) stage III, and 53.3% patients harbored at least one of the high-risk cytogenetic abnormalities[del (17p) and/or t (4;14) and/or t (14;16) ]. 2The patients received median 6 cycles of R (range: 1-32). The overall response rate (ORR) was 58.9% (33/56) , among which 8.9% was complete response (CR) , 19.8% was very good partial response (VGPR) , and 30.4% was partial response (PR). In addition, 10.7% patients attained minor response (MR). Total clinical benefit was 69.6%. Patients with more than 1 line of prior therapy, or previously thalidomide-resistance, or R-ISS stage III disease showed significantly lower ORR. 3With a median follow-up of 27 months, the median progression free survival (PFS) , the median interval to PR, the median duration of response (DOR) , and the median overall survival (OS) was 8 months, 2 months, 8 months, and 19 months, respectively. Univariate prognostic analysis showed that abnormal karyotype, R-ISS stage III and response inferior to PR were negative prognostic factors for PFS and OS. While the multivariate prognostic analysis showed that abnormal karyotype and R-ISS stage III were independent prognostic factors. 4In the safety aspect, the most common grade 3-4 non-hematology adverse events (AEs) were infection (17.5%) , rash (1.8%) and thromboembolism (1.8%) , and the most common grade 3-4 hematology AEs were neutropenia (7.0%) and thrombocytopenia (3.5%). Totally 3 patients (5.3%) discontinued R because of AEs, and 2 cases (3.5%) of secondary primary malignancies were observed. Conclusion: The R-based treatment is effective and safe in the treatment of relapsed/refractory MM patients in China. Abnormal karyotype and R-ISS stage III were independent negative prognosis factors in this cohort. PMID- 28655092 TI - [Evaluation of clinical characteristics, MYD88(L265P) mutation, CXCR4(WHIM) mutation and prognosis in Waldenstrom macroglobulinemia: A single center retrospective study of 93 patients]. AB - Objective: To evaluate the clinical characteristics, MYD88(L265P) mutation, CXCR4(W)HIM mutation and prognosis in patients with Waldenstrom macroglobulinemia (WM). Methods: The clinical characteristics, International Prognostic Scoring System for symptomatic WM (WPSS) , and overall survival (OS) were retrospectively assayed in 93 patients with newly diagnosed WM at Peking Union Medical College Hospital during January 2000 to August 2016. The MYD88(L265P) mutation and CXCR4(W)HIM mutation were tested among 34 patients. Results: The median age of the 93 patients was 64 years (range, 33-85 years) with a male-to-female ratio of 2.44. According to WPSS, we included 16 (17.2%) low-risk, 44 (47.3%) intermediate risk and 33 (35.5%) high-risk patients. Eight patients had secondary amyloidosis. With a median follow-up of 44 (1-201) months, the median OS was 84 months. Cox regression multifactor analysis showed WPSS risk group (HR=2.342, 95% CI 1.111 4.950, P=0.025) , whether patients had secondary amyloidosis (HR=5.538, 95% CI 1.958-15.662, P=0.001) and whether patients received new drugs (HR=3.392, 95% CI 1.531-7.513, P=0.003) were independent factors associated with OS. We have investigated the presence of the MYD88(L265P) and CXCR4(WHIM) mutation in 34 patients and found that MYD88(L265P) mutation was occurred in 32 patients (94.1%) and CXCR4(WHIM) mutation was occurred in 8 patients (23.5%). Seven of 8 patients who harbored CXCR4(WHIM)-mutated also exhibited the MYD88(L)265P mutation. Patients with MYD88(L265P)CXCR4(WHIM) vs MYD88(L265P)CXCR4(WT) presented with more severe anemia, lower platelet level, higher M protein level and more hyper viscosity syndrome. Conclusion: WPSS risk group, whether patients had secondary amyloidosis or received new drugs are independent factors for OS in WM. MYD88(L265P) and CXCR4(WHIM) mutation, the most common somatic variants in WM, often occur together and impact the clinical presentation. PMID- 28655093 TI - [Long-term follow-up of multiple myeloma after autologous hematopoietic stem cell transplantation: a single center results]. AB - Objective: To evaluate the efficacy and long-term outcome of a combined protocol for multiple myeloma (MM) , including induction therapy, autologous hematopoietic stem cell transplantation (ASCT) and consolidation and maintenance therapy. Methods: Clinical records of 144 patients with MM from January 1, 2005 to February 1, 2016 were retrospectively analyzed. Results: The overall response rate (ORR) after ASCT was 100.0%, in which the complete remission (CR) was 64.1% and the best treatment response rate of superior to PR was 89.4%. During a median follow-up of 47 months, patients with an overall survival (OS) and progression free survival (PFS) was 120.9 and 56.9 months respectively. 5y-OS (73.7+/-4.7) %, 7y-OS (60.5+/-6.3) %; 3y-PFS (69.2+/-4.2) %, 5y-PFS (47.8+/-5.3) %. The median OS and PFS between the first line transplantation group and salvage transplantation group were 120.9 months vs 50.1 months and 60.2 months vs 16.7 months (all P=0.000). In 127 patients with R-ISS staging, the median survival of I, II, III stage was 120.9 months (n=43) , 88.4 months (n=64) , 35.6 months (n=20) , respectively (P=0.000). For subgroup analysis of survival in early and late ASCT, the median OS of patients with R-ISS stage III (35.6 months vs 15.8 months, P=0.031) and the median PFS of two groups (phase I: 72.1 months vs 18.9 months, P=0.000; II: 53.4 months vs 16.7 months, P=0.012; III: 28.5 months vs 5.9 months, P=0.001) were different. Multivariate analysis showed that only R-ISS and the degree of remission before transplantation had impact on OS (HR=8.486, 95% CI 2.549-28.255, P=0.003) and PFS (HR=2.412, 95% CI 1.364-4.266, P=0.002) , respectively. Conclusion: The combined protocol containing ASCT is effective for MM patients, improving remission rate and remission depth, prolonging PFS and OS. First line transplantation could significantly prolong the OS and PFS as compared with salvage transplantation. R-ISS and pre-transplantation remission depth are prognostic factors for survival. PMID- 28655094 TI - [A retrospective analysis of clinical characteristics and prognostic factors for 124 cases of primary gastric lymphomas]. AB - Objective: To analyze the clinical characteristics, treatment and prognosis of primary gastric lymphomas (PGL). Methods: A retrospective study was conducted in 124 cases of PGL from July 2009 to January 2016 in our hospital, and the clinical records, pathological and immunohistochemical features were analyzed. The relationship between different factors at diagnosis and prognosis were studied. Results: 124 cases of PGL included 93 diffuse large B cell lymphoma (DLBCL) patients, 25 mucosa associated lymphoid tissue (MALT) lymphoma cases, 1 mantle cell lymphoma, 4 peripheral T-cell lymphoma-not otherwise specified, and 1 extra nodal NK/T-cell lymphoma-nasal type. Of the 93 primary gastric DLBCL (PG-DLBCL) patients, the germinal center B cell-like (GCB) DLBCL were 45 cases, non-GCB DLBCL were 48 cases. 10 cases (10.8%) of 93 PG-DLBCL were transformed from gastric MALT, and 7 cases (7.5%) have bone marrow involvement. Evidence of Helicobacter pylori infection was detected in 21 cases (51.2%) of 41 DLBCL patients and in 10 cases (43.5%) of 23 MALT patients. Univariate analysis revealed that clinical stages (P=0.002) , B symptoms (P=0.001) , international prognostic index (IPI) score (P<0.001) , anemia (P<0.001) , low level of serum albumin level (P=0.001) , high level of lactate dehydrogenase (LDH) (P<0.001) , high beta2-microglobulin (P=0.003) , chemotherapy uncombined with rituximab (P=0.006) were factors affecting progression-free survival (PFS). Multivariate Cox regression analysis indicated that clinical stages (HR=5.113, 95% CI 1.087 24.048, P=0.039) and LDH (HR=5.111, 95%CI 1.651-15.827, P=0.005) were independent poor prognosis factors affecting PFS. In the non-GCB group, the PFS was significantly extended (P=0.013) , the OS has no statistical significance (P=0.764). The PFS was significantly shortened in MALT transformed to DLBCL compared with MALT lymphoma patients (P=0.016) , but have no statistical significance compared with DLBCL patients (P=0.373). Conclusions: The types of DLBCL and MALT are more common in PGL. PG-DLBCL is a highly heterogeneous malignant tumor, and advanced clinical stages and high LDH value are associated with poor outcome. PMID- 28655095 TI - [Efficacy and prognostic analysis of 98 cases of relapsed/refractory diffuse large B-cell lymphoma treated with second-line regimens]. AB - Objective: To evaluate the efficacy and prognostic factors of second-line regimens for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods: A retrospective analysis was performed in 98 patients with relapsed/refractory DLBCL who were treated with salvage regimens in Rui Jin Hospital from July 2004 to June 2016. Overall response rate (ORR) was evaluated after all treatment finished. Overall survival (OS) was analyzed by Kaplan-Meier method and multivariate by Cox proportional hazards models. Results: There were 60 males and 38 females with a median age of 55.5 (15-77) years. 48 (49.0%) patients responded to chemotherapy, and 32 (32.7%) patients achieved complete remission (CR). Factors affecting ORR were progression disease or refractory/relapse status less than 12 months after diagnosis (chi(2)=5.878, P=0.015) , IPI intermediate-high/high risk (chi(2)=5.930, P=0.015) and NCCN-IPI intermediate-high/high risk (chi(2)=4.961, P=0.026). No significance difference was observed in ORR between germinal-center B-cell type (GCB) and non-GCB (chi(2)=0.660, P=0.417). One-year and 2-year OS rates were 51.0% and 31.5%, with median OS at 13.17 months, respectively. Multivariate analysis indicated NCCN-IPI intermediate-high/high risk[HR=2.176 (95%CI 1.338-3.538) , P=0.002] and response to chemotherapy [HR=0.273 (95%CI 0.165-0.452) , P<0.001] were independent prognostic factors for survival. Conclusion: NCCN-IPI is a valid predictor of outcome for patients with relapse/refractory DLBCL. Response to chemotherapy is an independent prognostic factor for better survival. PMID- 28655096 TI - [A retrospective analysis of prognosis in favorable-risk acute myeloid leukemia patients with different consolidation regimens]. AB - Objective: To explore the impact on prognosis in favorable-risk acute myeloid leukemia (AML) patients with different consolidation regimens after first complete remission (CR(1)). Methods: A total of 107 cases of non-refractory adult AML from January 2010 to June 2015 in single center were enrolled in the study. HD-Ara-C group (38 cases) as the control group, we explore the prognosis in three consolidation regimens, including micro-transplantation (16 cases) , autologous transplantation (auto-PBSCT, 14 cases) , allogeneic transplantation (allo-HSCT, 39 cases). Results: Of 107 patients (59 males and 48 females) , with a median age of 33 (16-59) years old and a median follow-up of 36.5 (5.3-79.1) months, the overall relapse rate was 20.6% (22/107) , and overall mortality rate was 18.7% (20/107). The 5 years cumulative relapse rate (CIR) of HD-Ara-C, micro transplantation, auto-PBSCT and allo-HSCT group were 39.7%, 6.2%, 14.3% and 5.6%, respectively (P<0.001). The CIR of the observed group was lower than the HD-Ara-C group. The 5 years progression-free survival (PFS) rate of HD-Ara-C, micro transplantation, auto-PBSCT and allo-HSCT group were 44.7%, 93.8%, 85.7% and 78.1%, respectively (P=0.011). The PFS of observed groups were similar, but superior to that in HD-Ara-C group. The 5-year overall survival (OS) in four groups was 54.9%, 100%, 92.9% and 77.4%, respectively (P>0.05). Multiple factors analysis showed that compared to HD-Ara-C regimen, allo-HSCT could improve PFS (HR=0.376, P=0.031) , but not OS (P>0.05) ; micro-transplantation and auto-PBSCT could not improve the PFS or OS (P>0.05). Conclusion: As compared with HD-Ara-C regimen, allo-HSCT could obviously decrease CIR, improve PFS, but treatment related mortality is high. These results show that auto-PBSCT and micro transplantation have similar outcomes, compared to HD-Ara-C regimen, so both can be used as a option of consolidation treatment for favorable-risk AML. PMID- 28655097 TI - [Efficacy of combination of ATRA, ATO and anthracyclines induction therapy in patients with acute promyelocytic leukemia]. AB - Objective: To explore the efficacies of regimens of three-drug induction therapy (ATRA+ATO+anthracyclines) versus two-drug induction therapy (ATRA+ATO) in patients with acute promyelocytic leukemia (APL). Methods: Of 184 patients diagnosed with APL from January 2009 to March 2016, 58 patients underwent three drug induction therapy, while the rest were treated with two-drug induction therapy. Three-drug induction therapy was of ATRA (20 mg.m(-2).d(-1), d(1-28)) + ATO (0.16 mg.kg(-1).d(-1), d(1-28)) + Idarubicin (8 mg.m(-2).d(-1), d(3-5)) /daunorubicin (40 mg.m(-2).d(-1), d(3-5)) , while two-drug induction therapy ATRA+ATO with the same doses and methods as above. Of 184 cases, 69 cases accompanied with WBC counts>10*10(9)/L, 115 cases with WBC counts<=10*10(9)/L at onset. Results: 1Short-term efficacy: After one cycle induction therapy, the rates of hematologic remission, genetic remission, molecular remission and induced differentiation syndrome (DS) in three-drug regimen group were 98.3%, 87.9%, 72.4% and 0 respectively, while those in two-drug regimen group were 87.3%, 65.9%, 51.6% and 12.7% respectively. In patients with WBC >10*10(9)/L, DS rate and early mortality in three-drug regimen group were lower than in two-drug regimen group (0 vs 15.6%, 4.2% vs 15.6%, respectively). In patients with WBC<=10*10(9)/L, DS rate in three-drug regimen group was also lower than in two drug regimen group (0 vs 12.3%) , but there were no statistical differences in terms of relapse and early mortality. 2 Long-term efficacy: The relapse rate, overall survival (OS) and disease free survival (DFS) in three-drug regimen group were 0, 98.5%, 96.6% respectively, while those in two-drug regimen group were 8.6%, 86.5% and 84.1% respectively; the advantages of three-drug over two-drug regimen, especially in cases of WBC >10*10(9)/L were observed. 3 Side effects: the incidences of gastrointestinal reaction, liver dysfunction, myocardial damage and headache in three-drug regimen group hardly increased. Conclusion: The efficacies of three-drug induction therapy were superior to two-drug one. PMID- 28655098 TI - [Primary antifungal prophylaxis with posaconazole plays a pivotal role during chemotherapy of acute myeloid leukemia]. AB - Objective: To evaluate the incidence of invasive fungal infections (IFI) and usage of intravenous antifungal drugs during remission induction chemotherapy in patients with acute myeloid leukemia (AML) under primary antifungal prophylaxis with posaconazole. Methods: Clinical records from newly diagnosed AML patients above 15 years old in one single center from February 2014 to January 2016 were retrospectively reviewed and analyzed, excluding acute promyelocytic leukemia. The incidence of IFI and usage of intravenous antifungal drugs were investigated between control group (not receiving any broad spectrum antifungal prophylaxis) and treatment group (receiving posaconazole as primary prophylaxis). Results: A total of 147 newly diagnosed AML patients were enrolled. Of them, 81 received prophylaxis with posaconazole, and 66 did not receive broad-spectrum antifungal treatment. 7 IFI occurred in posaconazole group, and all were possible cases; 19 IFI occurred in control group (3 proven, 4 probable, 12 possible). The incidence of IFI was significantly lower in treatment group than that in control group (8.6% vs 28.8%, chi(2)=10.138, P=0.001). Usage of intravenous antifungal drugs was significantly decreased in posaconazole group (18.5% vs 50.0%, chi(2)=16.390, P<0.001). Conclusion: Prophylaxis with posaconazole coulf prevent IFI and reduce usage of intravenous antifungal drugs significantly during remission induction chemotherapy in AML patients. PMID- 28655099 TI - [Mononuclear cells of umbilical cord blood differentiation to granulocyte cell in vitro]. AB - Objective: To explore an optimal method for granulocyte cell production from umbilical cord blood mononuclear cells. Methods: Erythrocytes were precipitated by hydroxyethyl starch. Mononuclear cells were isolated through Ficoll density gradient centrifugation. Different media, additives and cultivation model were chosen for granulocyte induction. Cell morphology was observed by microscopy, and cell phenotype was detected by flow cytometry. The CD18 expression of granulocytes was tested by immunofluorescence assay, and phagocytosis test was executed as well. Results: Compared to fetal bovine serum (FBS) treatment group, cell viability, counts and differentiation rate of granulocytes induced by X VIVO(TM) 15 combined with TPO, SCF, G-CSF but without FBS were superior. And X VIVO(TM)15 medium was better than SCGM medium at effectiveness and cost. Using two-stage mode of hematopoietic stem cell expansion followed by granulocyte induction with X-VIVO(TM)15 combining TPO, SCF and G-CSF, cell proliferation was nearly 132 times at day 21. Flow cytometry showed that the differentiation was lagged in 2-stage mode than in direct induction mode, CD15 expression was (69.60+/- 1.06) % vs (97.73+/-0.39) %; Wright-Giemsa staining demonstrated mature granulocytes; immunofluorescence showed the expression of lysosomal proteins CD18. A strong phagocytic function of mature granulocytes was demonstrated by phagotrophic efficiency of (51.43+/-0.05) %. And granulocyte had chemotaxis ability under the role of chemotactic factor IL-8. Conclusion: Optimized culture media and cultivation mode are achieved for functional granulocytes induction in vitro. PMID- 28655101 TI - [Efficacy and safety of DVD and VAD regimens in patients with newly diagnosed multiple myeloma]. PMID- 28655100 TI - [Correlation of the degree of band 3 protein absence on erythrocyte membrane by eosin-5'-maleimide binding test and clinical phenotype in hereditary spherocytosis]. AB - Objective: To investigate the relationship between the eosin-5'-maleimide (EMA) binding test and the clinical severity of hereditary spherocytosis (HS). Methods: A total of 258 un-splenectomize HS patients were consecutively enrolled. Correlation of hemoglobin concentration, hemolytic parameters, compensating erythropoiesis and the EMA binding test were evaluated. Results: 258 (128 male and 130 female) patients were included in this study, including 91 compensatory hemolysis patients, 53 patients with mild anemia, 78 patients with moderate anemia and 36 patients with severe anemia. The median age at diagnosis was 23 (2 70) years. The median decreased fluorescence intensity of EMA binding test was 29.97% (16.09%-47.34%) and the average intensity was (29.70+/-6.28) % of 258 HS patients. The decreased EMA binding fluorescence intensity correlated with MCV (r=-0.343, P<0.001) and MCHC (r=0.223, P<0.001). There was no relationship between EMA fluorescence intensity and absolute reticulocyte count (r=0.080, P=0.198) , reticulocyte percentile (r=-0.015, P=0.813) , IBIL levels (r=-0.009, P=0.902) , HGB levels (r=-0.067, P=0.280). Evaluated as a quartile variable, EMA fluorescence intensity was not correlated with anemia severity (C=0.150, P=0.746). Conclusion: EMA binding test does not related to anemia levels and has no major clinical implications for disease severity in HS. PMID- 28655102 TI - [Myeloid-derived suppressor cells in peripheral blood of multiple myeloma]. PMID- 28655103 TI - [Dose-adjusted EPOCH/EDOCH plus rituximab in untreated double-protein expression lymphoma]. PMID- 28655104 TI - [Chronic lymphocytic leukemia misdiagnosed as immune thrombocytopenia: case report and literature review]. PMID- 28655105 TI - [Sensitivity of alternative spliceosomes of L-type PML-RARalpha fusion gene to ATO]. PMID- 28655106 TI - [Brothers with multiple myeloma: two cases report]. PMID- 28655107 TI - [Acute myeloid leukemia with inv (3) (q21;q26) and lymphoid antigen expression: one case report]. PMID- 28655108 TI - [Indirubin-the fruit of combination of Chinese traditional and Western medicine]. PMID- 28655111 TI - Capacitive deionization of arsenic-contaminated groundwater in a single-pass mode. AB - A single-pass-mode capacitive deionization (CDI) reactor was used to remove arsenic from groundwater in the presence of multiple ions. The CDI reactor involved an applied voltage of 1.2 V and six cell pairs of activated carbon electrodes, each of which was 20 * 30 cm2. The results indicate that this method achieved an effluent arsenic concentration of 0.03 mg L-1, which is lower than the arsenic concentration standard for drinking water and irrigation sources in Taiwan, during the charging stage. Additionally, the ability of the CDI to remove other coexisting ions was studied. The presence of other ions has a significant influence on the removal of arsenic from groundwater. From the analysis of the electrosorption selectivity, the preference for anion removal could be ordered as follows: NO3- > SO42- > F- > Cl- >As. The electrosorption selectivity for cations could be ordered as follows: Ca2+ > Mg2+ > Na+ ~ K+. Moreover, monovalent cations can be replaced by divalent cations at the electrode surface in the later period of the electrosorption stage. Consequently, activated carbon-based capacitive deionization is demonstrated to be a high-potential technology for remediation of arsenic-contaminated groundwater. PMID- 28655112 TI - Real-time monitoring of the degradation of Cu(II)-EDTA in H2O2/UV using illumination-assisted droplet spray ionization mass spectrometry. AB - Illumination-assisted droplet spray ionization (IA-DSI) mass spectrometry was developed for in situ analysis and real-time monitoring of photolysis reactions. In IA-DSI, a photolysis reaction occurs on a corner of a cover slip positioned in front of a mass spectrometer, and the generated reaction intermediates are ionized via the corner and are directed to the inlet and analyzed by a mass spectrometer. IA-DSI is contaminant-free, low-cost and simple, and was demonstrated for in situ analysis and real-time monitoring of the degradation of Cu(II)-EDTA in H2O2/UV. The reaction times varied from seconds to minutes, and three new reaction intermediates were detected and identified by tandem mass spectrometry. More importantly, the proposed initiation site of Cu(II)-EDTA at the carboxyl group by ?OH attack was verified for the first time. The degradation of Cu(II)-EDTA occurred through its chemical bonds broken at the carboxyl group, at the amino group, and between EDTA and Cu(II). By sampling in situ and monitoring in real time, IA-DSI provides advantages in simplifying the analysis process for photolysis reaction intermediates and products, and can detect photolysis reaction intermediates and products in less than a second. PMID- 28655113 TI - Application of enhanced gas chromatography/triple quadrupole mass spectrometry for monitoring petroleum weathering and forensic source fingerprinting in samples impacted by the Deepwater Horizon oil spill. AB - Accurate characterization of petroleum hydrocarbons in complex and weathered oil residues is analytically challenging. This is primarily due to chemical compositional complexity of both the oil residues and environmental matrices, and the lack of instrumental selectivity due to co-elution of interferences with the target analytes. To overcome these analytical selectivity issues, we used an enhanced resolution gas chromatography coupled with triple quadrupole mass spectrometry in Multiple Reaction Monitoring (MRM) mode (GC/MS/MS-MRM) to eliminate interferences within the ion chromatograms of target analytes found in environmental samples. This new GC/MS/MS-MRM method was developed and used for forensic fingerprinting of deep-water and marsh sediment samples containing oily residues from the Deepwater Horizon oil spill. The results showed that the GC/MS/MS-MRM method increases selectivity, eliminates interferences, and provides more accurate quantitation and characterization of trace levels of alkyl-PAHs and biomarker compounds, from weathered oil residues in complex sample matrices. The higher selectivity of the new method, even at low detection limits, provides greater insights on isomer and homolog compositional patterns and the extent of oil weathering under various environmental conditions. The method also provides flat chromatographic baselines for accurate and unambiguous calculation of petroleum forensic biomarker compound ratios. Thus, this GC/MS/MS-MRM method can be a reliable analytical strategy for more accurate and selective trace level analyses in petroleum forensic studies, and for tacking continuous weathering of oil residues. PMID- 28655114 TI - Establishment of thermophilic anaerobic terephthalic acid degradation system through one-step temperature increase startup strategy - Revealed by Illumina Miseq Sequencing. AB - Over recent years, thermophilic digestion was constantly focused owing to its various advantage over mesophilic digestion. Notably, the startup approach of thermophilic digester needs to be seriously considered as unsuitable startup ways may result in system inefficiency. In this study, one-step temperature increase startup strategy from 37 degrees C to 55 degrees C was applied to establish a thermophilic anaerobic system treating terephthalic acid (TA) contained wastewater, meanwhile, the archaeal and bacterial community compositions at steady periods of 37 degrees C and 55 degrees C during the experimental process was also compared using Illumina Miseq Sequencing. The process operation demonstrated that the thermophilic TA degradation system was successfully established at 55 degrees C with over 95% COD reduction. For archaea community, the elevation of operational temperature from 37 degrees C to 55 degrees C accordingly increase the enrichment of hydrogenotrophic methanogens but decrease the abundance of the acetotrophic ones. While for bacterial community, the taxonomic analysis suggested that Syntrophorhabdus (27.40%) was the dominant genus promoting the efficient TA degradation under mesophilic condition, whereas OPB95 (24.99%) and TA06 (14.01%) related populations were largely observed and probably take some crucial role in TA degradation under thermophilic condition. PMID- 28655115 TI - Characteristics and fate of natural organic matter during UV oxidation processes. AB - Advanced oxidation processes (AOPs) are widely used in water treatments. During oxidation processes, natural organic matter (NOM) is modified and broken down into smaller compounds that affect the characteristics of the oxidized NOM by AOPs. In this study, NOM was characterized and monitored in the UV/hydrogen peroxide (H2O2) and UV/persulfate (PS) processes using a liquid chromatography organic carbon detector (LC-OCD) technique, and a combination of excitation emission matrices (EEM) and parallel factor analysis (PARAFAC). The percentages of mineralization of NOM in the UV/H2O2 and UV/PS processes were 20.5 and 83.3%, respectively, with a 10 mM oxidant dose and a contact time of 174 s (UV dose: approximately 30,000 mJ). Low-pressure, Hg UV lamp (254 nm) was applied in this experiment. The steady-state concentration of SO4- was 38-fold higher than that of OH at an oxidant dose of 10 mM. With para-chlorobenzoic acid (pCBA) as a radical probe compound, we experimentally determined the rate constants of Suwannee River NOM (SRNOM) with OH (kOH/NOM = 3.3 * 108 M-1s-1) and SO4- (kSO4 /NOM = 4.55 * 106 M-1s-1). The hydroxyl radical and sulfate radical showed different mineralization pathways of NOM, which have been verified by the use of LC-OCD and EEM/PARAFAC. Consequently, higher steady-state concentrations of SO4-, and different reaction preferences of OH and SO4- with the NOM constituent had an effect on the mineralization efficiency. PMID- 28655116 TI - Phytotoxic effects of terrestrial dissolved organic matter on a freshwater cyanobacteria and green algae species is affected by plant source and DOM chemical composition. AB - Here we link plant source phylogeny to its chemical characteristics and determine parameters useful for predicting DOM phytotoxicity towards algal monocultures. We found that DOM characterised using UV-visible spectroscopic indices and elemental analysis is useful for distinguishing DOM plant sources. Specifically, combined values of absorbance at 440 nm and coefficients for the spectral slope ratio, were used to distinguish between gymnosperm-leached DOM and that from angiosperms. In our bioassays, DOM leached from 4 g leaf L-1 resulted in over 40% inhibition of photosynthetic yield for the cyanobacterium, Cylindrospermopsis raciborskii, for eight of the nine plants tested. Significant variables for predicting inhibition of yield were DOM exposure time and plant source, or using an alternate model, exposure time and spectroscopic and elemental measures. Our study proposes spectroscopic indices which can estimate a plant source's contribution to aquatic DOM, may provide insights into ecological outcomes, such as phytotoxicity to algae. The cyanobacterium (C. raciborskii) was more sensitive to DOM than a green algae (Monoraphidium spp.), as identified in a subsequent dose-response experiment with five different DOM plant sources. Low level additions of angiosperm derived-DOM (i.e. 0.5 g L-1) were slight phytotoxic to Monoraphidium spp. causing 30% inhibition of yield, while C. raciborskii was not affected. Higher DOM additions (i.e. 2 g L-1) caused 100% inhibition of yield for C. raciborskii, while Monoraphidium spp. inhibition remained under 30%. The divergence in algal sensitivity to DOM indicates that in aquatic systems, DOM derived from catchment vegetation has the potential to affect algal assemblages. PMID- 28655117 TI - The overall 5-year survival rate of breast cancer among Iranian women: A systematic review and meta-analysis of published studies. AB - INTRODUCTION: Breast Cancer (BC) is the most prevalent cancer and the second leading cause of cancer-related death among Iranian women. A valid estimation of the 5-year survival rate can improve the current BC treatment programs. The present study aimed to assess the 5-year survival rate through a systematic review of published studies. METHODS: A systematic search of Medline/PubMed, Scopus, and Science direct as well as Iranian databases was conducted to identify the original articles evaluating the 5-year survival rate of BC among women in Iran. Random effects model was used to estimate the pooled 5-year survival rate. The eligible articles were analyzed using the Stata software. RESULTS: Our comprehensive literature search identified 11 eligible articles 2 of which were excluded due to reporting the results of a single study. The remaining 9 articles that contained 4815 women diagnosed with BC during 1991-2014 were included in the meta-analysis. The combined 5-year survival rate of BC was estimated to be 67.60%. DISCUSSION/CONCLUSION: The survival rate of BC was relatively low in Iran compared to developed countries. Hence, more effective measures have to be taken to increase these patients' survival. PMID- 28655118 TI - Giant juvenile fibroadenoma in a 9-year-old: A case presentation and review of the current literature. AB - Juvenile fibroadenoma is the most common breast mass in adolescents accounting for 0.5-4% of all cases of fibroadenomas. Giant fibroadenomas are well circumscribed, firm breast masses characterized by proliferation of epithelial and connective tissue. They are defined as being larger than 5 cm or weighing more than 500 g. The peak age has been reported between the ages of 17 and 20, with less than 5% of these in patients less than 18-years-old.We present a 9-year old, pre-menstrual, Nigerian female with no known family history of breast masses or cancers who developed spontaneous giant fibroadenoma measuring approximately 13 cm * 13 cm. Rapid growth of a breast mass can be of great concern to such young patients whose breasts are in the early formative stages. It is important to promptly rule out malignant processes or phyllodes tumor, and educate young patients and their families on treatment options that fit their unique concerns and circumstances. PMID- 28655119 TI - Follow-up of granulomatous mastitis with monitoring versus surgery. AB - BACKGROUND: IGM (Idiopathic Granulomatous Mastitis) is a rare, chronic, non malignant and non-life-threatening breast disease. Clinically and radiologically, it has similar characteristics with other granulomatous diseases and breast carcinomas. METHODS: The patients whom diagnosed IGM according to pathology report were retrospectively evaluated between November 2014 and January 2016. The demographic properties, complaints during admission, diagnosis and treatment methods and clinical results were obtained via investigation of the patient files. The patients were called for follow-up and discussion. RESULTS: The patients whom diagnosed IGM were retrospectively evaluated and total number of patients were 19. The average following period was 11 months (4-13 months). Fourteen patients were in the reproductive period, five patients were in the postmenopausal period. Ultrasound imaging was performed on all patients, mammography was done on 6 patients over 40 years of age. The patients were not imaged by magnetic resonance imaging (MRI). Sixteen patients had IGM in a single breast, only three patient have an IGM history in bilateral breast, one or three years ago. Core biopsy was performed on all patients. One patient with bilateral IGM diagnosis performed a drainage and incisional biopsy due to a twice developing abscess clinic and recurrence. One patient had final diagnosis coexistence IGM and ductal carcinoma. CONCLUSIONS: Patients who followed-up by observation should be explained that IGM is a chronic disease and that it may recur in certain periods. Clinical, radiological and pathological examinations should be performed together for breast cancer developing due to the chronical progresses of IGM or concurrent breast cancer. PMID- 28655120 TI - A rare benign tumor of breast masquerading on fine needle aspiration cytology: A case report. AB - Pleomorphic adenoma is a common tumor encountered in major salivary gland and very rarely seen in breast. This matrix producing tumor can be confused with fibroadenoma, phyllodes tumor and metaplastic carcinoma on fine needle aspiration cytology(FNAC). Pre-operative diagnosis of pleomorphic adenoma helps in preventing surgical over or under treatment of the disease. We present an extremely rare case of pleomorphic adenoma of breast diagnosed on FNAC with histopathological confirmation. PMID- 28655121 TI - High-grade poorly differentiated neuroendocrine carcinoma of the breast with low oncotype Dx recurrence score: A case report. AB - Primary neuroendocrine carcinoma of the breast (NECB) is a rare malignant tumor with controversial biological behavior and a lack of data guiding treatment decisions due to its scarcity. Cancer gene-expression profiling tests provide a better indication of clinical prognosis and help determine the best clinical management versus the traditional clinical and pathological parameters. This is a report of a NECB with a genetic assay that showed a low-risk tumor despite high grade and poorly differentiated histopathological features. Patient outcomes correlate with the low risk classification without the need for adjuvant chemotherapy despite the standard clinical-pathologic approach. Analysis of cancer related genes expression and outcomes in historical NECB may elucidate new insight of this rare disease. PMID- 28655122 TI - The effect of surface instability on the differential activation of muscle activity in low back pain patients as compared to healthy individuals: A systematic review of the literature and meta-analysis. AB - BACKGROUND: Dynamic tasks over unstable surfaces are commonly done in daily activities. OBJECTIVE: A number of studies indicated positive effect of doing postural tasks over unstable surface on trunk muscle activities in patients with low back pain (LBP), while the others reported opposite effects. Due to lack of consensus in the findings in this area of research, we aimed to systematically review studies, which investigated the effect of surface instability on trunk muscle activity in patients with LBP as compared to healthy individuals. METHIDS: A literature search was performed using the PubMed, Science Direct, OVID, CINAHL, PEDro, Cochrane, Scopus and MEDLINE databases. Low back pain, unstable surface, posture or stability and trunk muscle activity were applied as keywords. The methodological quality was examined using valid assessment tools. RESULTS: The activity of superficial trunk muscles is impaired in patients with LBP during dynamic tasks over unstable surfaces. Differences in the methodology of included studies could be considered as reasons behind the inconsistencies in the findings in included studies. These studies included investigation of superficial or deep muscles, the timing of recorded muscle activity, the level of surface instability and the length of time over unstable surfaces. CONCLUSION: Dynamic tasks over unstable surfaces could decrease pre-program reaction (PPR) and increase voluntary reaction (VR) of superficial trunk muscles in patients with LBP, which may reduce the ratio of deep versus superficial muscles, compared to healthy individuals. PMID- 28655123 TI - Mechanical Low Back Pain in Elite Track and Field Athletes: An observational cohort study. AB - OBJECTIVE: The aim of the study was to gain information about the incidence of mechanical Low Back Pain (MLBP) injuries etiology in elite track and field athletes and to assess the recurrence rate. BACKGROUND: The prevalence and the etiology of Low Back Pain (LBP) in athletic populations at the elite level of competition lack of longitudinal studies focused on certain sport fields. The present study evaluates MLBP incidents in elite track and field athletes visiting National Track and Field Centre in Thessaloniki, Greece and classifies MLBP according to etiology. METHODS: One hundred and thirty Elite Track and Field Athletes with MLBP injuries were included in a 20-year observational cohort study recording the initial MLBP etiology according to a classification system based on mechanical diagnosis. It was examined if age, gender and sport category predispose the incidence of the initial MLBP etiology and if they consist risk factors for MLBP recurrence. RESULTS: Discogenic MLBP in elite track and field athletes was significantly higher at 46.9% (alpha= 0.05) compared with the other MLBP etiologies under consideration. Secondary findings of the present study regarding the incidence of MLBP etiology categories did not reveal significant associations with gender, age and contest categories (alpha= 0.05). Additionally, recurrence pathophysiology showed that discogenic MLBP obtained high recurrence rates at 0.48 (14 athletes from 29 athletes recurred) compared with other etiologies, followed by back elements injury recurrence rate at 0.24 (7 athletes out of 29). CONCLUSIONS: The study provided us with evidence of higher incidence of discogenic etiology of MLBP in elite track and field athletes. Further research is suggested in the use of etiology related LBP classification system in order to evaluate causes, prevalence and epidemiology of MLBP in athletic populations of specific sport categories. PMID- 28655124 TI - Evaluation in terms of dietary habits of rheumatic process: A clinical study. AB - OBJECTIVE: This study compared the dietary habits of patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). METHODS: The nutritional status of 56 patients, seen at the Rheumatology Outpatient Clinic and diagnosed with RA based on the ACR-2010 criteria, was compared with that of 28 patients diagnosed with AS using the modified New York criteria. Nutritional status was determined using a form that was filled out during face-to-face interviews with all patients. Patient demographics, disease activity, smoking and alcohol use, concomitant diseases, disease duration and nutritional status were determined using a questionnaire. RESULTS: RA patients consumed butter on 2 days a week, and AS patients on 1 day per month. Yoghurt was consumed by RA patients daily and by AS patients 3 days a week. CONCLUSIONS: Compared to the diet of AS patients, the diet of RA patients was richer in protein and lipids. The impact of diet on these two diseases remains to be determined in large-scale studies. PMID- 28655125 TI - Validation of the Korean version of the Spinal Appearance Questionnaire. AB - OBJECTIVE: To evaluate the reliability and validity of an adapted Korean version of the Spinal Appearance Questionnaire (SAQ). METHODS: Translation/retranslation of the English version of the SAQ was conducted, and all steps of the cross cultural adaptation process were performed. The Korean version of the SAQ (K-SAQ) and the previously validated appearance domain of the Korean version of the Scoliosis Research Society-22 Outcomes questionnaire (K-SRS-22) were mailed to 160 patients with adolescent idiopathic scoliosis (AIS). Reliability assessments were conducted using kappa statistics to assess item agreements, and intraclass correlation coefficients (ICC) and Cronbach's alpha values were calculated. Convergent validity was evaluated by comparing K-SAQ and K-SRS-22 appearance domain scores and discriminant validity by analyzing relationships between K-SAQ scores and patient characteristics. RESULTS: All items of the K-SAQ had kappa values of agreement of > 0.6. The K-SAQ showed excellent test/re-test reliability with an intraclass correlation coefficient of 0.922. Internal consistency of the K-SAQ was found to be very good (alpha= 0.883). Convergent validity testing demonstrated a moderate correlation between the K-SAQ and K-SRS-22 (r=-451). The correlation between the K-SAQ and major curve magnitude was significant (r= 0.812). Discriminant validity was confirmed by significant differences in K-SAQ scores and individual K-SAQ domain scores among patients requiring observation, bracing, or surgery. CONCLUSIONS: The adapted Korean version of the SAQ showed satisfactory reliability and validity, and thus, is considered suitable for the evaluation of spinal deformity appearance in Korean speaking patients with adolescent idiopathic scoliosis. PMID- 28655127 TI - Depression screening by physical therapists: Practices, beliefs, barriers. AB - BACKGROUND: Depression, a common comorbidity encountered in physical therapy (PT) practice, negatively impacts outcomes. There is limited knowledge of PT practice patterns relative to screening for depression. OBJECTIVE: Objectives were to describe beliefs regarding depression, and identify practice patterns and perceived barriers regarding screening for depression among APTA Board Certified Orthopedic Clinical Specialist (OCS) PTs. METHODS: Surveys were distributed to all PT OCSs in the US; 416 responses were analyzed. Descriptive, univariate and multiple regression analyses were performed. RESULTS: Ninety-five percent of respondents believed that depression has a moderate to high influence on PT outcomes, whereas 68% believed a pre-existing diagnosis of depression influences the plan of care. Most believed that 20% or more of their current patients presented with symptoms of depression. Nevertheless, only 18% formally screen for depression during the initial evaluation. Those with formal depression screening education were 2.3 times more likely to screen at initial examination. Common barriers to screening included lack of department policy, limited knowledge and lack of follow-up resources. CONCLUSIONS: Formal screening did not occur as frequently as expected, given the belief regarding depression's impact on plan of care and outcomes. Addressing barriers may assist in greater compliance with recommended screening guidelines. PMID- 28655126 TI - Peroneus Longus activity according to various angles of a ramp during cross-ramp walking and one-legged standing. AB - BACKGROUND: Ankle sprain are one of the most common injuries in sports and public health in general. Cross-slope may creat a risk for ankle sprain and are commonly found in both urban and rural environment. OBJECTIVE: The purpose of study was to clarify the environmental risk factor that can be easily occurred ankle sprain during walking (stance phase) and one leg standing at various ramp environment. METHODS: Participants was measured muscle activation on peroneus longus during both conditions (walk across the ramp and one leg stand in the transverse direction) of seven different angle (0?, 2?, 5?, 10?, 15?, 20?, 25?). The measured data were analyzed using one-way ANOVA to investigate the effect of muscle activation on the each condition. RESULTS: Ankle sprain can be easily occurred when cross walk and one-leg stand on a ramp from higher than 10?, and highest risk was angle of 25? or more. As a people with peroneus longus weakness walks a ramp, the ramp angle has a cross relationship with the sprain on the ankle. CONCLUSIONS: If people with peroneus longus weakness walk on the more than 10? of ramp angle, they will need a lot of attention for prevent ankle sprain. PMID- 28655128 TI - Clinical outcomes of kinesio taping applied in patients with knee osteoarthritis: A randomized controlled trial. AB - INTRODUCTION: The aim of this study was to compare kinesio taping along with conventional treatment to conventional treatment alone and to report the results of both a single and repetitive kinesio taping application applied on quadriceps femoris and hamstring muscles on pain, range of motion, muscle strength, and functional status in patients with knee osteoarthritis. METHODS: Fifty-four patients with knee osteoarthritis were randomly allocated to two groups. A total of 28 patients were included in kinesio taping group, others were included in the control group. Before and after intervention, pain was measured with visual analog scale, range of motion was measured with universal goniometer, muscle strength was measured with dynamometer, and functional status was measured with Knee Injury Osteoarthritis Outcome Score. RESULTS: There were statistically significant improvements in measures of pain, range of motion, quadriceps muscle strength and functional status between pre- and post-treatment in both groups (p< 0.05). In comparison, there were no significant differences with these parameters between groups (p> 0.05). It was also found that significant difference was observed in terms of range of motion, pain, functional status between pre treatment and post-taping in intervention group (p< 0.017). CONCLUSION: In conclusion, we could report that kinesio taping has significant immediate effects after a single kinesio taping application on range of motion, pain and functional status in patients with knee osteoarthritis. We could also report that KT in addition to conventional treatment is not superior to conventional treatment alone in terms of clinical outcomes over 3 weeks later. PMID- 28655129 TI - Pain-related fear of (re-)injury in patients with low back pain: Estimation or measurement in manual therapy primary care practice? A pilot study. AB - BACKGROUND: Manual physical therapists (MPTs) working in primary care get limited information about patient's courses of (chronic) low back pain (LBP). Identification of kinesiophobia is mostly based on clinical perception. OBJECTIVE: The aim of this study was to evaluate the association between the scores with which manual physical therapists in a primary care setting identify kinesiophobia in patients with low back pain, and the patients' self-reported measures of kinesiophobia. METHODS: The cross-sectional study comprised 104 patients with LBP and 17 MPTs. Patients first independently completed the Tampa Scale for Kinesiophobia (TSK-17). The therapists, blinded to the TSK-scores, rated their perception of a patient's kinesiophobia using the Visual Analogue Scale-Estimation (VAS-est) and the accuracy of their ratings using the Visual Analogue Scale-Accuracy (VAS-ac). Kendall's tau b was used to determine the level of correlation between scores on the TSK-17 and the VAS-est. PMID- 28655130 TI - Comparison of biochemical parameters of blood and urine in spinal cord injury patients and association with urinary stone formation. AB - OBJECTIVE: The aim of this study was to compare the biochemical parameters of the urine and blood in spinal cord injury (SCI) patients and healthy subjects. METHODS: Thirty male patients with SCI were enrolled. Biochemical features of the urine and blood of the SCI patients were compared to healthy subjects. Extracted stones were analyzed by X-ray diffraction. RESULTS: A total of 30 patients with SCI (mean age of 28.77 +/- 7.3 years) and 10 healthy subjects (mean age of 27.6 + 6.2 years) were included. Among the patients with SCI; 12 of them (40%) had urinary stones and 18 of them (60%) did not. Urinary stone was localized in the kidneys and bladder in 25% and 75% of the subjects, respectively. The mean duration of cord injury at diagnosis of urinary stone was 9.2 +/- 6 months. Urine cultures obtained on admission were negative for the control group, while the microorganism isolation rate was 73.3% in the SCI group. The urinary excretion of citrate and Mg were lower in the patient group compared with control group (p= 0.008, p= 0.001, respectively). As for the diffraction analysis of eight stones; five (62.5%) of the stones were calcium oxalate, two (25%) of them were calcium phosphate, and one (12.5%) was magnesium ammonium phosphate. CONCLUSION: Both infection and metabolic changes play an important role in stones formation in SCI patients. The urinary excretion of citrate and Mg was decreased and urinary PH was increased in SCI patients. PMID- 28655131 TI - Thrombospondin-I concentrations behavior in plasma of patients with ovarian cancer. AB - PURPOSE: To determine whether thrombospondin-1 might be used as a prognostic factor in ovarian cancer patients. METHOD: Ninety-six female subjects hospitalized in years 2011-2014 was included in the study. Transvaginal ultrasound examination was performed in all patients. In 39 cases of suspected ovarian cancer, CT scans were also performed. Each patient had been subjected to collection of a 5-mL blood sample before the laparoscopic procedure. Thrombospondin-1 concentrations were quantified in serum by multiplex fluorescent bead-based immunoassays (Luminex) at the Laboratory of the Department of General Pathology. RESULTS: Statistical analysis performed using the Kaplan-Meier survival curves and log-rank test revealed no statistically significant correlations between the median, 75th percentile and 95th percentile thrombospondin-1 levels with progression-free survival of patients (p= 0.47). In the univariate OS model, median thrombospondin-1 level was a significant variable. Correlation was demonstrated between baseline thrombospondin-1 levels and overall survival of patients (p= 0.04, HR = 0.99). The higher the baseline TSP1 level, the longer the overall survival of patients. CONCLUSION: In our study, we were the first to demonstrate correlation between the levels of thrombospondin-1 and overall survival of patients. Therefore, it appears that thrombospondin-1 may be used as a prognostic factor in ovarian cancer patients. PMID- 28655132 TI - FSTL1 contributes to tumor progression via attenuating apoptosis in a AKT/GSK 3beta - dependent manner in hepatocellular carcinoma. AB - BACKGROUND: Several investigations have demonstrated that follistatin-like 1 (FSTL1) is implicated in the initiation and progression of diverse cancers. It remains unclear whether FSTL1 acted as a cancer-promoting gene through its overexpression in HCC. PATIENTS AND METHODS: We detected FSTL1 protein expression in 210 consecutive HCC cases curatively resected in our hospital between 2004 and 2007. The correlation between FSTL1 expression in HCC tissues and post-surgical prognosis of HCCs was analyzed. The in vitro experiments including apoptosis assessment, MTT, BrdU incorporation ELISA assay, Western immunoblotting, and qRT PCR were performed to determine the impact of FSTL1 on apoptosis and proliferation abilities of HCC cells and the relevant mechanisms. RESULTS: FSTL1 protein was found aberrantly increased in 172 of 210 HCC tissues (81.9%) compared to adjacent liver tissues. FSTL1 overexpression was apparently associated with larger tumor size, advanced TNM staging, portal vein invasion, intra-hepatic metastases. Patients with higher FSTL1 expression in tumors suffered from the worse overall survival rate as assessed by comparison of Kaplan-Meier survival curves. Higher FSTL1 expression in HCC tissues was identified as a independent poor post-surgical prognostic predictor for HCC. Silencing FSTL1 by siRNA promoted cell apoptosis and leaded to suppression of cell viability and proliferation in MHCC97h cells. Furthermore, enforced expression of FSTL1 obtained the opposite results in Huh7 cells. Mechanistic investigation showed that FSTL1 repressed HCC cell apoptosis through AKT/GSK-3beta/Bcl2/BAX/Bim signaling. CONCLUSION: These data proved that FSTL1 contributed to unfavorable post-surgical outcome of HCC patients via inhibiting cell apoptosis. PMID- 28655134 TI - Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer's Disease: Testosterone as a Modifier. AB - Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-beta (Abeta) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal aging, and although there is no significant increase in cerebral Abeta deposition in T2DM, the extent of Abeta accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk. PMID- 28655135 TI - Home-Based Exercise Program Improves Balance and Fear of Falling in Community Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study. AB - BACKGROUND/OBJECTIVE: Balance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD. METHODS: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73+/-6.2 years) with mild AD. Home based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8 weeks post-intervention). RESULTS: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p < 0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p = 0.445). CONCLUSION: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD. PMID- 28655133 TI - The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer's Disease Dementia. AB - Traumatic brain injury (TBI) is thought to be a risk factor for dementia, including dementia due to Alzheimer's disease (AD). However, the influence of TBI history on the neuropsychological course of AD is unknown and, more broadly, the effect of TBI history on age-related cognitive change is poorly understood. We examined the relationship between history of TBI with loss of consciousness (LOC) history and cognitive change in participants with normal cognition and probable AD, stratified by APOEE4 allele status. The sample included 706 participants (432 with normal cognition; 274 probable AD) from the National Alzheimer's Coordinating Center (NACC) dataset that completed the Uniform Data Set evaluation between 2005 and 2014. Normal and probable AD participants with a history of TBI were matched to an equal number of demographically and clinically similar participants without a TBI history. In this dataset, TBI with LOC was defined as brain trauma with brief or extended unconsciousness. For the normal and probable AD cohorts, there was an average of 3.2+/-1.9 and 1.8+/-1.1 years of follow-up, respectively. 30.8% of the normal cohort were APOEE4 carriers, whereas 70.8% of probable AD participants were carriers. Mixed effects regressions showed TBI with LOC history did not affect rates of cognitive change in APOEE4 carriers and non carriers. Findings from this study suggest that TBI with LOC may not alter the course of cognitive function in older adults with and without probable AD. Future studies that better characterize TBI (e.g., severity, number of TBIs, history of subconconcussive exposure) are needed to clarify the association between TBI and long-term neurocognitive outcomes. PMID- 28655136 TI - Decreased Methylation of the Mitochondrial D-Loop Region in Late-Onset Alzheimer's Disease. AB - Mitochondrial impairment is a feature of neurodegeneration and many investigators have suggested that epigenetic modifications of the mitochondrial DNA (mtDNA) might be involved in late-onset Alzheimer's disease (LOAD), but evidence in humans is limited. We assessed the methylation levels of the mtDNA D-loop region in blood DNA from 133 LOAD patients and 130 controls, observing a significant 25% reduction of DNA methylation levels in the first group (2.3 versus 3.1%). Overall, the present data indicate that there is a decreased methylation of the D loop region in LOAD peripheral blood DNA, suggesting that mtDNA epimutations deserve further investigations in AD pathogenesis. PMID- 28655139 TI - Diagnostic work-up and rehabilitation of cerebral visual impairment in infancy: A case of epileptic perinatal encephalopathy due to KCNQ2-related channelopathy AB - BACKGROUND: There is evidence that channelopathies are the cause of many different neurological diseases. The epileptic perinatal encephalopathy due to mutation in the KCNQ2 gene is a rare disease involving severe tetraparesis and cerebral visual impairment. Diseases of this kind are associated with severe disability that involves multiple systems and requires accurate genetic diagnosis and early multidisciplinary care once clinical stability is reached. CASE REPORT: We describe a case of a baby girl with KCNQ2 encephalopathy who came to our observation for rehabilitation at age 2 years and 6 months. CLINICAL REHABILITATION IMPACT: We stress the importance of a correct clinical, pharmacological and visual diagnosis. Correct diagnosis made it possible to involve the baby girl and her care-giver in an early process of visual rehabilitation lasting 6 months, the effects of which proved to persist at follow up after more than a year, making it possible to start a useful inter professional rehabilitation plan. PMID- 28655137 TI - Alzheimer's Disease Genetics and ABCA7 Splicing. AB - Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer's disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ~1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended exon 41 is predicted to undergo nonsense mediated RNA decay, this was not supported by qPCR analyses, which showed relatively normal ABCA7 mRNA levels in the carrier of the rs200538373 minor C allele. In summary, rs200538373 is a functional polymorphism that alters ABCA7 exon 41 splicing without grossly altering the level of ABCA7 mRNA. PMID- 28655141 TI - Validity of CAVI measurements for diagnosing hypertension in middle-aged and elderly patients and correlations of these measurements with relevant factors. AB - BACKGROUND: The high risk of hypertension in middle-aged and elderly people has led to the development of the cardio-ankle vascular index (CAVI), a novel predictor of cardiovascular events. OBJECTIVE: This paper aimed to determine how reliably hypertension can be diagnosed in middle-aged and elderly people by measuring CAVI. METHODS: One hundred and ninety-five subjects (69 males/126 females; mean age of 56.06 +/- 2.08 years) were enrolled. CAVI were measured using a blood pressure and pulse monitor device. RESULTS: The CAVI was positively correlated with age, SBP, PP and PPI in the hypertension group (r= 0.656, 0.388, 0.445, 0.376; all P< 0.05). The mean CAVI was the significant difference between each age group. The ROC results showed that the best diagnostic point was 8.350, where the sensitivity was 72.2% and the specificity was 72.3%. The positive rate of the CAVI was higher than normal blood pressure for those over 60 years of age. CONCLUSION: Compared with normal blood pressure measurements, CAVI measurements are relatively reliable for predicting hypertension in those over the age of 60. More attention should be paid to the CAVI ? 8.350, which may be regarded as a simple and noninvasive reference index of hypertension diagnosis for middle-aged and elderly. PMID- 28655142 TI - Systematic reviews: guidance relevant for studies of older people. AB - Systematic reviews and meta-analyses are increasingly common. This article aims to provide guidance for people conducting systematic reviews relevant to the healthcare of older people. An awareness of these issues will also help people reading systematic reviews to determine whether the results will influence their clinical practice. It is essential that systematic reviews are performed by a team which includes the required technical and clinical expertise. Those performing reviews for the first time should ensure they have appropriate training and support. They must be planned and performed in a transparent and methodologically robust way: guidelines are available. The protocol should be written-and if possible published-before starting the review. Geriatricians will be interested in a table of baseline characteristics, which will help to determine if the studied samples or populations are similar to their patients. Reviews of studies of older people should consider how they will manage issues such as different age cut-offs; non-specific presentations; multiple predictors and outcomes; potential biases and confounders. Systematic reviews and meta analyses may provide evidence to improve older people's care, or determine where new evidence is required. Newer methodologies, such as meta-analyses of individual level data, network meta-analyses and umbrella reviews, and realist synthesis, may improve the reliability and clinical utility of systematic reviews. PMID- 28655144 TI - Up-regulation of carcinoembryonic antigen-related cell adhesion molecule 1 in gastrointestinal cancer and its clinical relevance. AB - Serum carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is dysregulated in various malignant tumors and has been associated with tumor progression. However, the expression and regulatory mechanisms of serum CEACAM1 in gastrointestinal cancer are still unclear. The expression ratio of the CEACAM1 L and CEACAM1-S isoforms has seldom been investigated in gastrointestinal cancer. In this study, we intended to explore the expression and diagnostic value of CEACAM1 in gastrointestinal cancer. Serum CEACAM1 levels were measured by enzyme linked immunosorbent assay. The protein expression and distribution of CEACAM1 in tumors were examined by immunohistochemical staining. The expression patterns and ratio of CEACAM1-L/S were analyzed by reverse transcription-polymerase chain reaction. The results showed that serum CEACAM1 levels were significantly higher in cancer patients than in healthy controls. CEACAM1 was found in secreted forms within the neoplastic glands, and its expression was more intense at the tumor invasion front. The CEACAM1-L/S (L:S) ratios were up-regulated during tumorigenesis. Our data suggest that the serum level of CEACAM1 may be used to discriminate gastrointestinal cancer patients from health controls. PMID- 28655143 TI - Air Pollution and Cardiometabolic Disease: An Update and Call for Clinical Trials. AB - Fine particulate matter <2.5 um (PM2.5) air pollution is a leading cause of global morbidity and mortality. The largest portion of deaths is now known to be due to cardiovascular disorders. Several air pollutants can trigger acute events (e.g., myocardial infarctions, strokes, heart failure). However, mounting evidence additionally supports that longer-term exposures pose a greater magnified risk to cardiovascular health. One explanation may be that PM2.5 has proven capable of promoting the development of chronic cardiometabolic conditions including atherosclerosis, hypertension, and diabetes mellitus. Here, we provide an updated overview of recent major studies regarding the impact of PM2.5 on cardiometabolic health and outline key remaining scientific questions. We discuss the relevance of emerging trials evaluating personal-level strategies (e.g., facemasks) to prevent the harmful effects of PM2.5, and close with a call for large-scale outcome trials to allow for the promulgation of formal evidence-base recommendations regarding their appropriate usage in the global battle against air pollution. PMID- 28655145 TI - Partitioned learning of deep Boltzmann machines for SNP data. AB - Motivation: Learning the joint distributions of measurements, and in particular identification of an appropriate low-dimensional manifold, has been found to be a powerful ingredient of deep leaning approaches. Yet, such approaches have hardly been applied to single nucleotide polymorphism (SNP) data, probably due to the high number of features typically exceeding the number of studied individuals. Results: After a brief overview of how deep Boltzmann machines (DBMs), a deep learning approach, can be adapted to SNP data in principle, we specifically present a way to alleviate the dimensionality problem by partitioned learning. We propose a sparse regression approach to coarsely screen the joint distribution of SNPs, followed by training several DBMs on SNP partitions that were identified by the screening. Aggregate features representing SNP patterns and the corresponding SNPs are extracted from the DBMs by a combination of statistical tests and sparse regression. In simulated case-control data, we show how this can uncover complex SNP patterns and augment results from univariate approaches, while maintaining type 1 error control. Time-to-event endpoints are considered in an application with acute myeloid leukemia patients, where SNP patterns are modeled after a pre screening based on gene expression data. The proposed approach identified three SNPs that seem to jointly influence survival in a validation dataset. This indicates the added value of jointly investigating SNPs compared to standard univariate analyses and makes partitioned learning of DBMs an interesting complementary approach when analyzing SNP data. Availability and implementation: A Julia package is provided at 'http://github.com/binderh/BoltzmannMachines.jl'. Contact: binderh@imbi.uni-freiburg.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28655146 TI - Ginseng saponin Rb1 enhances hematopoietic function and dendritic cells differentiation. PMID- 28655147 TI - Underlying Mechanism for Reduced Left Ventricular Mass by Physical Activity in Obese and Hypertensive Subjects. PMID- 28655148 TI - Genetic Variants in the Manganese Superoxide Dismutase 2 Gene and in the Catalase Gene are not Associated With Alcoholic Chronic Pancreatitis. AB - Aims: Oxidative stress may contribute to the development of chronic pancreatitis (CP). The enzymes manganese superoxide dismutase 2 (MnSOD, SOD2) and catalase (CAT) counteract free radical activity within the mitochondria and the cytosol. Moreover, CAT activity contributes to the transformation of ethanol to acetaldehyde, a toxic intermediate product of ethanol metabolism, which has been associated with pancreatic damage. Common functional polymorphisms have been described in the MnSOD gene [rs4880, NM_000636.3:c.47 T > C, alanine (ALA) to valine (Val)] and in the CAT promoter region [rs1001179, NG_013339.1:g.4760 C > T]. We investigated whether these polymorphisms are associated with alcoholic CP. Methods: We genotyped 470 patients with alcoholic CP for these MnSOD and CAT polymorphisms. We also analysed these variants in 357 healthy control subjects, and in an additional control group of 113 individuals with non-alcoholic CP. We used the age at onset of CP as marker of disease severity and investigated whether different genotypes are associated with different ages at onset. In patients with alcoholic CP, we investigated whether an interaction exists between smoking behaviour and genotypes by comparing genotype distributions in smokers and non-smokers. Results: We did not observe significant differences of genotype frequencies between patient groups and controls. In patient groups, we did not find significant differences in the ages at onset between different genotypes. We did not observe an interaction between these polymorphisms. We did not find an association of these variants with smoking behaviour. Conclusions: The investigated MnSOD and CAT polymorphisms do not predispose to the development of alcoholic CP. Short summary: Patients with alcoholic pancreatitis and controls were genotyped for polymorphisms in oxidative stress genes. There were no significant differences of genotype frequencies between patients and controls, and no association with the age at onset of disease was observed. The polymorphisms are not associated with the development of alcoholic pancreatitis. PMID- 28655149 TI - Neuromodulation of Axon Terminals. AB - Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long been speculated to be sensitive to polarization, but experimentally informed models for CNS stimulation are lacking. We conducted simultaneous intracellular recording from the neuron soma and axon terminal (blebs) during extracellular stimulation with weak sustained (DC) uniform electric fields in mouse cortical slices. Use of weak direct current stimulation (DCS) allowed isolation and quantification of changes in axon terminal biophysics, relevant to both suprathreshold (e.g., deep brain stimulation, spinal cord stimulation, and transcranial magnetic stimulation) and subthreshold (e.g., transcranial DCS and transcranial alternating current stimulation) neuromodulation approaches. Axon terminals polarized with sensitivity (mV of membrane polarization per V/m electric field) 4 times than somas. Even weak polarization (<2 mV) of axon terminals significantly changes action potential dynamics (including amplitude, duration, conduction velocity) in response to an intracellular pulse. Regarding a cellular theory of neuromodulation, we explain how suprathreshold CNS stimulation activates the action potential at terminals while subthreshold approaches modulate synaptic efficacy through axon terminal polarization. We demonstrate that by virtue of axon polarization and resulting changes in action potential dynamics, neuromodulation can influence analog-digital information processing. PMID- 28655150 TI - Is the frozen elephant trunk procedure superior to the conventional elephant trunk procedure for completion of the second stage? AB - OBJECTIVES: Our goal was to compare the results and outcomes of second-stage completion in patients who had previously undergone the elephant trunk (ET) or the frozen elephant trunk (FET) procedure for the treatment of complex aortic arch and descending aortic disease. METHODS: Between August 2001 and December 2014, 53 patients [mean age 61 +/- 13 years, 64% (n = 34) male] underwent a second-stage completion procedure. Of these patients, 32% (n = 17) had a previous ET procedure and 68% (n = 36) a previous FET procedure as a first-stage procedure. RESULTS: The median times to the second-stage procedure were 7 (0-78) months in the ET group and 8 (0-66) months in the FET group. The second-stage procedure included thoracic endovascular aortic repair in 53% (n = 28) of patients and open surgical repair in 47% (n = 25). More endovascular interventions were performed in FET patients (61%, n = 22) than in the ET group (35%, n = 6, P = 0.117). The in-hospital mortality rate was significantly lower in the FET (8%, n = 3) group compared with the ET group (29%, n = 5, P = 0.045). The median follow-up time after the second-stage operation for the entire cohort was 4.6 (0.4-10.4) years. The 5-year survival rate was 76% in the ET patients versus 89% in the FET patients (log-rank: P = 0.11). CONCLUSIONS: We observed a significantly lower in-hospital mortality rate in the FET group compared to the ET group. This result might be explained by the higher rate of endovascular completion in the FET group. We assume that the FET procedure offers the benefit of a more ideal landing zone, thus facilitating endovascular completion. PMID- 28655151 TI - Cardioversion of atrial fibrillation in a real-world setting: non-vitamin K antagonist oral anticoagulants ensure a fast and safe strategy compared to warfarin. AB - Aims: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used as thromboembolic prophylaxis in cardioversion. We examined the waiting time to cardioversion and the outcomes in patients with non-valvular atrial fibrillation (AF) of > 48 h of duration who were treated with either NOACs or warfarin. Methods and results: Anticoagulation was handled in a structured, multidisciplinary AF-clinic. The objectives were the waiting time to cardioversion, and thromboembolism and major bleeding events within 60 days. In total, 2150 electrical cardioversions were performed; 684 (31.8%) of patients were on NOACs and 1466 (68.2%) were on warfarin. The waiting time to non-TOE guided cardioversion was significantly shorter in the NOAC group compared with the warfarin group for all cardioversions (P < 0.001 for log-rank test) and for first-time cardioversions (P < 0.001 for log-rank test). For all non-TOE-guided cardioversions, 80% of procedures on NOACs and 67% of procedures on warfarin were performed within 25 days (P < 0.001). Thromboembolism occurred in one patient (0.15%) receiving NOAC and in two patients (0.14%) receiving warfarin (risk ratio (RR) 1.07; 95% confidence interval (CI) 0.10-11.81). Major bleeding events occurred in four patients (0.58%) in the NOAC group and 11 patients (0.75%) in the warfarin group (RR 0.78; 95% CI 0.25-2.43). Conclusion: In a real-world clinical setting with anticoagulation handled in a structured multidisciplinary AF clinic, the waiting time to cardioversion was shorter with NOACs compared to warfarin. The rates of thromboembolism and major bleeding events were low, with NOACs shown to be as effective and safe as warfarin. PMID- 28655153 TI - The KSEA App: a web-based tool for kinase activity inference from quantitative phosphoproteomics. AB - Summary: Computational characterization of differential kinase activity from phosphoproteomics datasets is critical for correctly inferring cellular circuitry and how signaling cascades are altered in drug treatment and/or disease. Kinase Substrate Enrichment Analysis (KSEA) offers a powerful approach to estimating changes in a kinase's activity based on the collective phosphorylation changes of its identified substrates. However, KSEA has been limited to programmers who are able to implement the algorithms. Thus, to make it accessible to the larger scientific community, we present a web-based application of this method: the KSEA App. Overall, we expect that this tool will offer a quick and user-friendly way of generating kinase activity estimates from high-throughput phosphoproteomics datasets. Availability and Implementation: the KSEA App is a free online tool: casecpb.shinyapps.io/ksea/. The source code is on GitHub: github.com/casecpb/KSEA/. The application is also available as the R package "KSEAapp" on CRAN: CRAN.R-project.org/package=KSEAapp/. Contact: mark.chance@case.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28655152 TI - Faulty Adaptation to Repeated Face-Name Associative Pairs in Mild Cognitive Impairment is Predictive of Cognitive Decline. AB - Objective: We examined BOLD (Blood-Oxygen-Level Dependent) activity reduction upon stimuli repetition of face-name pairs in older adults with amnestic (aMCI) and non-amnestic (naMCI) mild cognitive impairment diagnosed using a comprehensive actuarial method, and relationships between activity reduction and behavioral indices. Method: Twenty-nine cognitively healthy older adults (CHs) and 20 with MCI (n = 12 aMCI; n = 8 naMCI) underwent functional MRI event-related imaging, a comprehensive neuropsychological battery, and 1-year follow-up exam. During scanning, participants were shown face-name pairs 1-3 times and administered a post-scan recognition task. Results: The MCI group demonstrated less activity reduction upon repetition of face-name pairs within the MTL and other regions compared to CHs. Less activity reduction was associated with poorer Time 1 neuropsychological performance for the CH group and poorer post-scan recognition performance for the MCI group. Less activity reduction was related to poorer neuropsychological performance at Time 2 in the MCI group. Within MCIs, those with aMCI demonstrated less activity reduction upon repetition of face-name pairs than those with naMCI. Conclusions: Distinct patterns of brain activity were identified in the MCI group compared to CHs, and aMCI compared to naMCI. Activated regions were not restricted to traditional memory circuitry, implicating a wider network of regions involved in the encoding of associative tasks. Findings add support to the hypothesis that lack of reduced BOLD activity reflects "faulty adaptation" to repeated stimuli and that reduction in activity represents successful encoding processes. They also provide further support for use of the face-name paradigm as a marker of prodromal Alzheimer's disease, and method to distinguish between MCI subtypes. PMID- 28655154 TI - Risk model for deaths and renal replacement therapy dependence in patients with acute kidney injury after cardiac surgery. AB - OBJECTIVES: Acute kidney injury (AKI) is a serious complication after cardiac surgery and is associated with increased in-hospital deaths. Renal replacement therapy (RRT) is becoming a routine strategy for severe AKI. Our goal was to evaluate the risk factors for death and RRT dependence in patients with AKI after cardiac surgery. METHODS: We included 190 eligible adult patients who had AKI following cardiac surgery and who required RRT at our centre from November 2010 to March 2015. We collected preoperative, intraoperative, postoperative and RRT data for all patients. RESULTS: In this cohort, 87 patients had successful RRT in the hospital, whereas 103 patients had RRT that failed (70 deaths and 33 cases of RRT dependence). The multivariable logistic analysis identified old age [odds ratio (OR): 1.042, 95% confidence interval (CI): 1.012-1.074; P = 0.011], serum uric acid (OR: 1.015, 95% CI: 1.003-1.031; P = 0.024), intraoperative concentrated red blood cell transfusions (OR: 1.144, 95% CI: 1.006-1.312; P = 0.041), postoperative low cardiac output syndrome (OR: 3.107, 95% CI: 1.179 8.190; P = 0.022) and multiple organ failure (OR: 5.786, 95% CI: 2.115-15.832; P = 0.001) as factors associated with a higher risk for RRT failure. The prediction model (-4.3 + 0.002 * preuric acid + 0.10 * concentrated red blood cells + 0.04 * age + 1.12 * [low cardiac output syndrome = 1] + 1.67 * [multiple organ failure = 1]) based on the multivariate analysis had statistically significant different incriminatory power with an area under the curve of 0.786. CONCLUSIONS: The prediction model may serve as a simple, accurate tool for predicting in-hospital RRT failure for patients with AKI following cardiac surgery. PMID- 28655155 TI - Evolution of Cytochrome c Oxidase in Hypoxia Tolerant Sculpins (Cottidae, Actinopterygii). AB - Vertebrate hypoxia tolerance can emerge from modifications to the oxygen (O2) transport cascade, but whether there is adaptive variation to O2 binding at the terminus of this cascade, mitochondrial cytochrome c oxidase (COX), is not known. In order to address the hypothesis that hypoxia tolerance is associated with enhanced O2 binding by mitochondria we undertook a comparative analysis of COX O2 kinetics across species of intertidal sculpins (Cottidae, Actinopterygii) that vary in hypoxia tolerance. Our analysis revealed a significant relationship between hypoxia tolerance (critical O2 tension of O2 consumption rate; Pcrit), mitochondrial O2 binding affinity (O2 tension at which mitochondrial respiration was half maximal; P50), and COX O2-binding affinity (apparent Michaelis-Menten constant for O2 binding to COX; Km,app O2). The more hypoxia tolerant species had both a lower mitochondrial P50 and lower COX Km,app O2, facilitating the maintenance of mitochondrial function to a lower O2 tension than in hypoxia intolerant species. Additionally, hypoxia tolerant species had a lower overall COX Vmax but higher mitochondrial COX respiration rate when expressed relative to maximal electron transport system respiration rate. In silico analyses of the COX3 subunit postulated as the entry point for O2 into the COX protein catalytic core, points to variation in COX3 protein stability (estimated as free energy of unfolding) contributing to the variation in COX Km,app O2. We propose that interactions between COX3 and cardiolipin at four amino acid positions along the same alpha-helix forming the COX3 v-cleft represent likely determinants of interspecific differences in COX Km,app O2. PMID- 28655156 TI - Comparison of latest generation transfemoral self-expandable and balloon expandable transcatheter heart valves. AB - OBJECTIVES: We herein aimed to compare acute 30-day outcomes of latest-generation self-expandable and balloon-expandable transcatheter heart valves. METHODS: From 2012 through 2016, 104 consecutive patients (study group, 69.2% female, 81.7 +/- 5.5 years, logEuroSCORE I 15.9 +/- 9.3%) received transfemoral transcatheter aortic valve implantation using the Symetis ACURATE neo(r) transcatheter heart valve. A control group of patients after transfemoral transcatheter aortic valve implantation with the Edwards Sapien 3TM transcatheter heart valve was retrieved from our database and matched to the study group. Data were retrospectively analysed according to updated Valve Academic Research Consortium definitions. RESULTS: Device success was 94.2% (98 of 104) and 98.1% (102 of 104) in study and control groups, respectively (P = 0.157). All-cause 30-day mortality was 3.9 (4 of 104) vs 0.9% (1 of 104) (P = 0.317). Resultant transvalvular peak/mean gradients and effective orifice area were 14.2 +/- 5.7 vs 22.6 +/- 6.8 mmHg (P < 0.001)/7.3 +/- 2.8 vs 11.8 +/- 3.5 mmHg (P < 0.001) and 2.0 +/- 0.4 vs 1.7 +/- 0.4 cm2 (P = 0.063). Paravalvular leakage >=moderate was observed in 4.8% (5 of 104) and 1.9% (2 of 104) (P = 0.257). Rate of permanent pacemaker implantation was 10.6% (11 of 104) vs 16.4% (17 of 104) (P = 0.239). CONCLUSIONS: Next generation self-expandable transcatheter heart valves preserve superiority in terms of post-interventional haemodynamics without presenting former drawbacks: rate of postoperative permanent pacemaker implantation and severity of residual paravalvular leakage were similar to balloon-expandable transcatheter heart valves. PMID- 28655157 TI - Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy. AB - Sleep problems relate to brain changes in aging and disease, but the mechanisms are unknown. Studies suggest a relationship between beta-amyloid (Abeta) accumulation and sleep, which is likely augmented by interactions with multiple variables. Here, we tested how different cerebrospinal fluid (CSF) biomarkers for brain pathophysiology, brain atrophy, memory function, and depressive symptoms predicted self-reported sleep patterns in 91 cognitively healthy older adults over a 3-year period. The results showed that CSF levels of total- and phosphorylated (P) tau, and YKL-40-a marker of neuroinflammation/astroglial activation-predicted poor sleep in Abeta positive older adults. Interestingly, although brain atrophy was strongly predictive of poor sleep, the relationships between CSF biomarkers and sleep were completely independent of atrophy. A joint analysis showed that unique variance in sleep was explained by P-tau and the P tau * Abeta interaction, memory function, depressive symptoms, and brain atrophy. The results demonstrate that sleep relates to a range of different pathophysiological processes, underscoring the importance of understanding its impact on neurocognitive changes in aging and people with increased risk of Alzheimer's disease. PMID- 28655158 TI - CoreTracker: accurate codon reassignment prediction, applied to mitochondrial genomes. AB - Motivation: Codon reassignments have been reported across all domains of life. With the increasing number of sequenced genomes, the development of systematic approaches for genetic code detection is essential for accurate downstream analyses. Three automated prediction tools exist so far: FACIL, GenDecoder and Bagheera; the last two respectively restricted to metazoan mitochondrial genomes and CUG reassignments in yeast nuclear genomes. These tools can only analyze a single genome at a time and are often not followed by a validation procedure, resulting in a high rate of false positives. Results: We present CoreTracker, a new algorithm for the inference of sense-to-sense codon reassignments. CoreTracker identifies potential codon reassignments in a set of related genomes, then uses statistical evaluations and a random forest classifier to predict those that are the most likely to be correct. Predicted reassignments are then validated through a phylogeny-aware step that evaluates the impact of the new genetic code on the protein alignment. Handling simultaneously a set of genomes in a phylogenetic framework, allows tracing back the evolution of each reassignment, which provides information on its underlying mechanism. Applied to metazoan and yeast genomes, CoreTracker significantly outperforms existing methods on both precision and sensitivity. Availability and implementation: CoreTracker is written in Python and available at https://github.com/UdeM LBIT/CoreTracker. Contact: mabrouk@iro.umontreal.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28655160 TI - Corrigendum: Generating global political priority for urban health: the role of the urban health epistemic community. PMID- 28655159 TI - Two distinct metacommunities characterize the gut microbiota in Crohn's disease patients. AB - The inflammatory intestinal disorder Crohn's disease (CD) has become a health challenge worldwide. The gut microbiota closely interacts with the host immune system, but its functional impact in CD is unclear. Except for studies on a small number of CD patients, analyses of the gut microbiota in CD have used 16S rDNA amplicon sequencing. Here we employed metagenomic shotgun sequencing to provide a detailed characterization of the compositional and functional features of the CD microbiota, comprising also unannotated bacteria, and investigated its modulation by exclusive enteral nutrition. Based on signature taxa, CD microbiotas clustered into 2 distinct metacommunities, indicating individual variability in CD microbiome structure. Metacommunity-specific functional shifts in CD showed enrichment in producers of the pro-inflammatory hexa-acylated lipopolysaccharide variant and a reduction in the potential to synthesize short-chain fatty acids. Disruption of ecological networks was evident in CD, coupled with reduction in growth rates of many bacterial species. Short-term exclusive enteral nutrition elicited limited impact on the overall composition of the CD microbiota, although functional changes occurred following treatment. The microbiotas in CD patients can be stratified into 2 distinct metacommunities, with the most severely perturbed metacommunity exhibiting functional potentials that deviate markedly from that of the healthy individuals, with possible implication in relation to CD pathogenesis. PMID- 28655161 TI - Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma. AB - Little is known about how chronic inflammation contributes to the progression of hepatocellular carcinoma (HCC), especially the initiation of cancer. To uncover the critical transition from chronic inflammation to HCC and the molecular mechanisms at a network level, we analyzed the time-series proteomic data of woodchuck hepatitis virus/c-myc mice and age-matched wt-C57BL/6 mice using our dynamical network biomarker (DNB) model. DNB analysis indicated that the 5th month after birth of transgenic mice was the critical period of cancer initiation, just before the critical transition, which is consistent with clinical symptoms. Meanwhile, the DNB-associated network showed a drastic inversion of protein expression and coexpression levels before and after the critical transition. Two members of DNB, PLA2G6 and CYP2C44, along with their associated differentially expressed proteins, were found to induce dysfunction of arachidonic acid metabolism, further activate inflammatory responses through inflammatory mediator regulation of transient receptor potential channels, and finally lead to impairments of liver detoxification and malignant transition to cancer. As a c-Myc target, PLA2G6 positively correlated with c-Myc in expression, showing a trend from decreasing to increasing during carcinogenesis, with the minimal point at the critical transition or tipping point. Such trend of homologous PLA2G6 and c-Myc was also observed during human hepatocarcinogenesis, with the minimal point at high-grade dysplastic nodules (a stage just before the carcinogenesis). Our study implies that PLA2G6 might function as an oncogene like famous c-Myc during hepatocarcinogenesis, while downregulation of PLA2G6 and c Myc could be a warning signal indicating imminent carcinogenesis. PMID- 28655162 TI - The Role of Older Persons' Environment in Aging Well: Quality of Life, Illness, and Community Context in South Africa. AB - Purpose of the Study: This article evaluates the influence of local district conditions on subjective quality of life of older South African adults. Policymakers increasingly recognize that "successful" aging policies must not only address physical health needs but also factors that influence subjective well-being. Design and Methods: To investigate the influence of area-level distribution of "public goods" on well-being in a low- and middle-income setting, nationally representative WHO-Study of Global AGEing and Adult Health (WHO-SAGE) survey data is combined with district-level data that captures built resources and health system distribution. Multilevel regression modeling is utilized to explore how community context, including built resources and health infrastructure quality, influence older persons' quality of life and how chronic health conditions may moderate this relationship while controlling for important individual characteristics. Results: While controlling for individual and district level factors, it is found community level provision of built resources of basic services (i.e., water, sanitation, electricity, housing) has a modest but significant impact on older persons' subjective well-being. Further, this effect on older persons' perceptions of quality of life is moderated by individual chronic health status; individuals with a chronic health condition do not receive an equivalent benefit from district built condition like those without an illness do. Implications: This work adds to the literature concerning the effect of environments in low- and middle-income countries on older adults' subjective well-being. It also adds to the growing literature on the complex relationship between subjective well-being and health in diverse contexts. PMID- 28655163 TI - microRNA-21a-5p/PDCD4 axis regulates mesenchymal stem cell-induced neuroprotection in acute glaucoma. AB - Mesenchymal stem cells (MSCs) have been demonstrated to have promising therapeutic benefits for a variety of neurological diseases; however, the underlying mechanisms are poorly understood. Here, we showed that intravitreal infusion of MSCs promoted retinal ganglion cell (RGC) survival in a mouse model of acute glaucoma, with significant inhibition of microglial activation, production of TNF-alpha, IL-1beta, and reactive oxygen species, as well as caspase-8 and caspase-3 activation. In vitro, MSCs inhibited both caspase-8 mediated RGC apoptosis and microglial activation, partly via the action of stanniocalcin 1 (STC1). Furthermore, we found that microRNA-21a-5p (miR-21) and its target, PDCD4, were essential for STC1 production and the neuroprotective property of MSCs in vitro and in vivo. Importantly, miR-21 overexpression or PDCD4 knockdown augmented MSC-mediated neuroprotective effects on acute glaucoma. These data highlight a previously unrecognized neuroprotective mechanism by which the miR-21/PDCD4 axis induces MSCs to secrete STC1 and other factors that exert neuroprotective effects. Therefore, modulating the miR-21/PDCD4 axis might be a promising strategy for clinical treatment of acute glaucoma and other neurological diseases. PMID- 28655164 TI - Role of diastolic function indices in the risk stratification of patients with mixed aortic valve disease. AB - Aims: Determine the role of diastolic function indices in pre-operative and post operative risk stratification in patients with moderate mixed aortic valve disease (MAVD). Methods and results: A retrospective study was conducted of asymptomatic patients with moderate MAVD (a combination of moderate aortic stenosis and moderate aortic regurgitation) and an ejection fraction of 50% or more who were followed up at Mayo Clinic from 1 January 2004, to 31 December 2013. A pre-requisite for inclusion in the study was assessment of diastolic function involving at least three of the following indices: tissue Doppler early diastolic velocity (e'), mitral inflow early velocity (E), tricuspid regurgitation velocity, and left atrial volume index. Primary endpoints were aortic valve replacement (AVR) or cardiac death while secondary endpoints were cardiovascular adverse events (CAEs) after AVR. We defined CAEs as stroke, heart failure hospitalization, severe left ventricular dysfunction, and cardiac death. There were 214 patients (age 61 +/- 8 years, men 146 [68%]) followed for 6.1 +/- 2.3 years during which 162 (76%) AVRs and 11 (5%) cardiac deaths occurred. The multivariable risk factors for cardiac death or AVR were relative wall thickness (RWT) > 0.42 [hazard ratio (HR), 1.88 [95% CI, 1.28-2.59]; P = 0.001] and average E/e' >14 (HR, 1.94 [95% CI, 1.29-3.01]; P = 0.02). Freedom from CAE after AVR was significantly lower in the patients with baseline RWT >0.42 or mean E/e' >14 than the other patients: 79% (95% CI 74-83%) vs. 94% (95% CI 89-98%) at 3 years (P = 0.03). Conclusion: The presence of RWT >0.42 or E/e' >14 identifies a high-risk patient subset whose risk for cardiovascular morbidities persists even after AVR. PMID- 28655165 TI - INVESTIGATION OF NATURAL RADIOACTIVITY AS A POSSIBLE DRIVER OF CANCER INCIDENCE IN PARAIBA, NORTHEASTERN BRAZIL. AB - An increase of health problems has been reported in the city of Triunfo, Paraiba, NE Brazil. This pattern has been attributed to environmental radiation since there are uranium deposits in the neighboring municipalities. The present study aimed to carry a radiometric survey in Triunfo to determine effective dose from external outdoor radiation exposure. The results were obtained through 'in situ' measurements using a gamma spectrometry system. The results ranged from 0.06 to 0.38 mSv/y, mean of 0.20 mSv/y. Due to the low value of the effective dose rate, we concluded that the area is characterized by low background radiation. Therefore, natural radioactivity is probably not directly influencing the increase in cancer incidence in the region. However, there is a need for complementary studies in this area to evaluate the dose from potential exposure to ingested and inhaled natural radionuclides from natural radioactivity in soil, rocks, vegetation and water. PMID- 28655166 TI - Communication in Multiple Sclerosis: Pragmatic Deficit and its Relation with Cognition and Social Cognition. AB - Objective: Cognitive functions have been largely investigated in multiple sclerosis. Less attention has been paid to social communication abilities, despite their presumptive affect on quality of life. We run the first comprehensive assessment of pragmatic skills in multiple sclerosis, evaluating also the relationship between pragmatics and other cognitive domains. Methods: Forty-two multiple sclerosis patients and 42 controls were tested for pragmatic abilities, neuro-cognition, social cognition, depression, and fatigue. Results: Patients performed poorly in most pragmatic tasks compared to controls. Globally, 55% of patients performed below the 5th percentile in the total pragmatic score. Notably, pragmatic skills did not differ between cognitively impaired and unimpaired patients. However, an association was found between pragmatics and verbal fluency, as measured in the Word List Generation. Finally, we observed an association of pragmatic abilities with social cognition, and a trend with psychosocial functioning. Conclusion: Overall, the study shows a diffuse pragmatic impairment in multiple sclerosis, not associated with the patient's global neuropsychological profile. By contrast, our findings suggest a close relation between pragmatics and specific cognitive aspects such as executive functions, and between pragmatics and social cognition. This study underlines the need of looking beyond classical cognitive performance, to consider underestimated communicative disturbances of high clinical relevance. PMID- 28655167 TI - Identification of transcript regulatory patterns in cell differentiation. AB - Motivation: Studying transcript regulatory patterns in cell differentiation is critical in understanding its complex nature of the formation and function of different cell types. This is done usually by measuring gene expression at different stages of the cell differentiation. However, if the gene expression data available are only from the mature cells, we have some challenges in identifying transcript regulatory patterns that govern the cell differentiation. Results: We propose to exploit the information of the lineage of cell differentiation in terms of correlation structure between cell types. We assume that two different cell types that are close in the lineage will exhibit many common genes that are co-expressed relative to those that are far in the lineage. Current analysis methods tend to ignore this correlation by testing for differential expression assuming some sort of independence between cell types. We employ a Bayesian approach to estimate the posterior distribution of the mean of expression in each cell type, by taking into account the cell formation path in the lineage. This enables us to infer genes that are specific in each cell type, indicating the genes are involved in directing the cell differentiation to that particular cell type. We illustrate the method using gene expression data from a study of haematopoiesis. Availability and implementation: R codes to perform the analysis are available in http://www1.maths.leeds.ac.uk/~arief/R/CellDiff/. Contact: a.gusnanto@leeds.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28655168 TI - BMP4 uses several different effector pathways to regulate proliferation and differentiation in the epithelial and mesenchymal tissue compartments of the developing mouse ureter. AB - Heterozygous loss of Bmp4 results both in humans and mice in severe malformation of the urinary tract. These defects have at least partially been attributed to loss of expression of Bmp4 in the ureteric mesenchyme, yet the cellular and molecular function of this signal as well as its effector pathways in this tissue have remained incompletely resolved. Here, we show that mice with a conditional deletion of Bmp4 in the ureteric mesenchyme exhibited hydroureter and hydronephrosis at newborn stages due to functional and physical ureter obstruction. Proliferation in both the mesenchymal and epithelial progenitor pools was severely reduced and smooth muscle cell and urothelial differentiation programs were not activated. Epithelial expression of P-ERK1/2, P-AKT and P-P38, and mesenchymal expression of P-SMAD1/5/9, P-P38 and P-AKT were abrogated. Pharmacological inhibition and activation experiments in ureter cultures defined AKT as the most relevant downstream effector for epithelial and mesenchymal proliferation as well as for epithelial differentiation. Epithelial proliferation and differentiation were also influenced by P-38 and ERK1/2, while SMAD signaling, together with AKT and P-38, were required for smooth muscle cell differentiation. Our analysis suggests that BMP4 is the signal that couples the proliferation and differentiation programs in the epithelial and mesenchymal tissue compartments of the developing ureter by different downstream effectors, most importantly AKT and SMAD. PMID- 28655170 TI - Metabolic Balance and its Outcome: Deficiency of Vitamin B9 and Sucrose Supply Ectopically Induces Starch Synthesis in Etioplasts. PMID- 28655169 TI - Hospital-at-home Integrated Care Programme for the management of disabling health crises in older patients: comparison with bed-based Intermediate Care. AB - Objective: to analyse the clinical impact of a home-based Intermediate Care model in the Catalan health system, comparing it with usual bed-based care. Design: quasi-experimental longitudinal study. Setting: hospital Municipal de Badalona and El Carme Intermediate Care Hospital, Badalona, Catalonia, Spain. Participants: we included older patients with medical and orthopaedic disabling health crises in need of Comprehensive Geriatric Assessment (CGA) and rehabilitation. Methods: a CGA-based hospital-at-home Integrated Care Programme (acute care and rehabilitation) was compared with a propensity score matched cohort of contemporary patients attended by usual inpatient hospital care (acute care plus intermediate care hospitalisation), for the management of medical and orthopaedics processes. Main outcomes measures were: (a) Health crisis resolution (referral to primary care at the end of the intervention); (b) functional resolution: relative functional gain (functional gain/functional loss) >= 0.35; and (c) favourable crisis resolution (health + functional) = a + b. We compared between-groups outcomes using uni/multivariable logistic regression models. Results: clinical characteristics were similar between home-based and bed-based groups. Acute stay was shorter in home group: 6.1 (5.3-6.9) versus 11.2 (10.5 11.9) days, P < 0.001. The home-based scheme showed better results on functional resolution 79.1% (versus 75.2%), OR 1.62 (1.09-2.41) and on favourable crisis resolution 73.8% (versus 69.6%), OR 1.54 (1.06-2.22), with shorter length of intervention, with a reduction of -5.72 (-9.75 and -1.69) days. Conclusions: in our study, the extended CGA-based hospital-at-home programme was associated with shorter stay and favourable clinical outcomes. Future studies might test this intervention to the whole Catalan integrated care system. PMID- 28655172 TI - Learning From Our Failures in Smoking Cessation Research. PMID- 28655171 TI - Regulatory control and impulsivity relate to resting frontal activity. AB - Gray's Reinforcement Sensitivity Theory (RST) asserts three core personality systems: the behavioral approach system (BAS), the fight-flight-freeze system (FFFS) and the revised behavioral inhibition system (r-BIS). Past models of frontal activity link greater relative left frontal activity with Carver and White's (1994) BAS scale and trait impulsivity and greater relative right frontal activity with Carver and White's (1994) BIS scale. However, the original BIS scale assesses both FFFS and r-BIS. Past work linking the BIS scale and right frontal activity does not indicate which system is related to right frontal activity. The current study (n = 182) examined frontal asymmetric activity with personality traits associated with approach (BAS), withdrawal (FFFS-Fear), behavioral inhibition (BIS-Anxiety) and impulsivity (UPPS-P). Resting frontal cortical activity was recorded using electroencephalography (EEG), and the traditional alpha band was examined. Greater BIS-Anxiety related to greater relative right frontal activity. Impulsivity related to less relative right frontal activity. BAS and FFFS-Fear (approach and withdrawal motivation) did not relate to asymmetric frontal activity. Regulatory control processes associated with r-BIS and impulsivity, rather than withdrawal motivation associated with FFFS, may be more closely related to right frontal activity. PMID- 28655173 TI - Feasibility, Efficacy, and Cost Analysis of Promoting Smoking Cessation at Outdoor Smoking "Hotspots": A Pre-Post Study. AB - Introduction: To motivate smokers to quit, there is a need for enhanced smoking cessation (SC) recruitment and for innovative and proactive approaches to SC. This study evaluated the feasibility, efficacy, and cost of promoting SC in public outdoor areas where smokers gather to smoke (smoking hotspots). Methods: We selected 14 smoking hotspots in Hong Kong for SC promotion in 2015. University students were trained as SC ambassadors to deliver brief SC intervention, and to recruit smokers for telephone follow-up. The proportion of smokers accepting the intervention components was recorded. Self-reported abstinence in the past 7 days and knowledge of smoking and health were assessed at the 6-month follow-up. The average costs of each smoker receiving our intervention and quitting were also compared. Results: Of 3,080 smokers approached, 1,278 (41.5%) accepted the souvenir and 920 (29.9%) received brief advice. Of the 210 (6.8%) who consented to the follow-up, 24.5% were aged 15-29 and 46.4% were aged 30-49. Of the 151 smokers successfully contacted within 1 month after recruitment, 16 (10.6%; 1.3% of the 1,278 who received any form of intervention) reported abstinence, and their overall knowledge improved. The average costs for a smoker to receive brief advice, consent to follow up by telephone, attempt to quit, and quit successfully at the 6-month follow-up were US$30, US$132, US$601, and US$1,626, respectively. Conclusions: Promoting SC at smoking hotspots could be a feasible way to achieve satisfactory quitting outcomes at low cost and is useful in the absence of the strengthening of tobacco policies. Implications: Our study indicates that outdoor smoking hotspots are feasible platforms for promoting SC and recruiting smokers for cessation services; satisfactory outcomes can be achieved at a reasonable cost. Our promotion was particularly useful for recruiting young smokers and those who want to quit. It is feasible and efficacious to raise smokers' awareness of SC when other tobacco control policies not feasible. Indoor smoking bans or other substantial tobacco control policies could enhance the efficiency with which SC is promoted. PMID- 28655174 TI - Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. AB - Background: Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients. Methods: A modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system. Results: Consensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment. Conclusions: Scarcity of published studies on osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care. PMID- 28655175 TI - Associations of acetylcholinesterase inhibitor treatment with reduced mortality in Alzheimer's disease: a retrospective survival analysis. AB - Background: dementia is increasingly recognised as life-limiting condition. Although the benefits of acetylcholinesterase inhibitors (AChEIs) on cognition and function are well established, their effect on survival is less clear. Objective: to investigate associations between AChEI prescription and mortality in patients with Alzheimer's dementia (AD) in a naturalistic setting, using detailed baseline data on cognition, functioning, and mental and physical wellbeing. Methods: we used a large mental healthcare database in South London, linked to Hospital Episode Statistics and Office for National Statistics mortality data, to assemble a retrospective cohort. We conducted a survival analysis adjusting for a wide range of potential confounders using propensity scores to reduce the impact of confounding by indication. Results: of 2,464 patients with AD, 1,261 were prescribed AChEIs. We detected a strong association between AChEI receipt and lower mortality (hazard ratio = 0.57; 95% CI 0.51 0.64). This remained significant after controlling for a broad range of potential confounders including psychotropic co-prescription, symptom severity, functional status and hospital admissions (hazard ratio = 0.77; 95% CI 0.67-0.87). Conclusions: in a large cohort of patients with AD, AChEI prescription was associated with reduced risk of death by more than 20% in adjusted models. This has implications for individual care planning and service development. PMID- 28655176 TI - A systematic review and meta-analysis of the effectiveness of nudging to increase fruit and vegetable choice. AB - Background: Nudging refers to interventions that organize the choice architecture in order to alter people's behaviour in a predictable way without forbidding any options or significantly changing their economic incentives. As a strategy to encourage healthy behaviour, nudging can serve as a complement to health education. However, the empirical evidence regarding the effectiveness of nudging as a way to influence food choice remains contradictory. To address this issue, a systematic review and meta-analysis was conducted to test the effects of nudging to encourage people to select more fruit and vegetables. Methods: A systematic literature search was performed on PubMed, Medline, PsycInfo, Cochrane library, Scopus and Google Scholar. After quality assessment, 20 articles (23 studies) were retained for narrative synthesis. Twelve articles (14 studies) contained enough information to calculate effect-sizes for meta-analysis using Comprehensive Meta-analysis software. Results: The meta-analysis shows that nudging interventions that aim to increase fruit and/or vegetable choice/sales/servings have a moderately significant effect (d = 0.30), with the largest effect for altering placement (d = 0.39) and combined nudges (d = 0.28). Conclusion: The results of this review provide an indication of the effectiveness of nudging on fruit and vegetable choice in terms of actual effect-sizes, while also highlighting the problems that must be addressed before more definitive conclusions can be drawn. PMID- 28655177 TI - Stability-Indicating TLC-Densitometric Assay for Methyltestosterone and Quantum Chemical Calculations. AB - Methyltestosterone is a synthetic testosterone derivative commonly used for the treatment of testosterone deficiency in males and one the anabolic steroids whose use is banned by World Anti-Doping Agency (WADA). This study presents a simple, cost-effective and rapid stability-indicating assay for densitometric quantification of methyltestosterone in pharmaceutical formulation. The developed method employed pre-coated TLC plates with mobile phase hexane:acetone (6.5:3.5 v/v). Limit of detection and limit of quantitation were found to be 2.06 and 6.24 ng/spot, respectively. Stress degradation study of methyltestosterone was conducted by applying various stress conditions such as hydrolysis under acidic, basic and neutral conditions, heating in anhydrous conditions and exposure to light. Methyltestosterone was found to be susceptible to photodegradation, acidic and basic hydrolysis. Degraded products were well resolved with significantly different Rf values. Acid degraded product was identified as 17,17-dimethyl-18 norandrosta-4,13(14)-dien-3-one through spectroscopic methods. The reactivity of methyltestosterone under applied stress conditions was also explained by quantum chemical calculations. The developed method is found to be repeatable, selective and accurate for quantification of methyltestosterone and can be employed for routine analysis. PMID- 28655178 TI - Fournier's gangrene. PMID- 28655180 TI - Checklists, cognitive aids, and the future of patient safety. PMID- 28655179 TI - To err is (perfectly) human: behavioural and neural correlates of error processing and perfectionism. AB - The attitude towards one's own imperfection strongly varies between individuals. Here, we investigated variations in error-related activity depending on two sub traits of perfectionism, Personal Standard Perfectionism (PSP) and Evaluative Concern Perfectionism (ECP) in a large scale functional magnetic resonance imaging study (N = 75) using a digit-flanker task. Participants with higher PSP scores showed both more post-error slowing and more neural activity in the medial frontal gyrus including anterior cingulate cortex after errors. Interestingly, high-EC perfectionists with low PSP showed no post-error slowing and the highest activity in the middle frontal gyrus, whereas high-EC perfectionists with high PSP showed the lowest activity in this brain area and more post-error slowing. Our findings are in line with the hypothesis that perfectionists with high concerns but low standards avoid performance monitoring to avoid the worry inducing nature of detecting personal failure and the anticipation of poor evaluation by others. However, the stronger goal-oriented performance motivation of perfectionists with high concerns and high standards may have led to less avoidance of error processing and a more intense involvement with the imperfect behaviour, which is essential for improving future performance. PMID- 28655182 TI - Longitudinal Changes in Mean and Pulse Pressure, and All-Cause Mortality: Data From 71,629 Untreated Normotensive Individuals. AB - BACKGROUND: Blood pressure (BP) includes a steady (mean arterial pressure, MAP) and a pulsatile component that independently predict mortality. The association between longitudinal changes in central (c) pulse pressure (PP), brachial (b) PP, MAP, and incident mortality has never been investigated in this context. METHODS: Brachial MAP and PP were measured at 2 routine checkups (1st visit 1992; mean interval, 5.8 +/- 2.4 years) in 71,629 individuals, age 16-95 years, none on antihypertensive drugs. cPP was estimated with a validated algorithm. Each change (visit 2-1) in bPP, cPP, and MAP, expressed in mm Hg/year, was categorized as: increase, decrease, or no-change, with the latter representing the control-group. Follow-up data (6.9 +/- 3.3 years) on all-cause mortality (2,033 deaths) were documented. RESULTS: All-cause mortality Cox regression models adjusted for confounders showed that compared to the subgroup with steady BP at both visits, the subgroup with: (i) increased bPP or cPP had an approximately 200% increase in relative risk (RR); (ii) decreased cPP and bPP had a 15% reduction in RR; (iii) increased MAP had a 68% increase in RR; (iv) decreased MAP had a 7% increase in RR of mortality. Interaction analysis stratified by gender showed that annual increases in PP, but not MAP, were greater in younger than older men and lower in younger than older women. Age cutoff value was 55 years. CONCLUSIONS: MAP and PP have distinct characteristics affecting all-cause mortality. PP integrates the effects of age and gender on all-cause mortality more notably than MAP, thus impacting significantly on cardiovascular risk. PMID- 28655183 TI - Three-Year Follow-Up Comparing Cognitive Behavioral Therapy for Depression to Cognitive Behavioral Therapy for Insomnia, for Patients With Both Diagnoses. AB - This 3-year follow-up compared insomnia treatment to depression treatment for patients with both diagnoses. Forty-three participants were randomized to either treatment, in the form of Internet-delivered therapist-guided cognitive behavior therapy (CBT), and 37 (86%) participants provided primary outcome data at the 3 year follow-up. After 3 years, reductions on depression severity were similar in both groups (between-group effect size, d = 0.33, p = .45), while the insomnia treatment had superior effects on insomnia severity (d = 0.66, p < .05). Overall, insomnia treatment was thus more beneficial than depression treatment. The implication for practitioners, supported by previous research, is that patients with co-occurring depression and insomnia should be offered CBT for insomnia, in addition to medication or psychological treatment for depression. PMID- 28655181 TI - Pantothenate auxotrophy in Zymomonas mobilis ZM4 is due to a lack of aspartate decarboxylase activity. AB - The bacterium Zymomonas mobilis naturally produces ethanol at near theoretical maximum yields, making it of interest for industrial ethanol production. Zymomonas mobilis requires the vitamin pantothenate for growth. Here we characterized the genetic basis for the Z. mobilis pantothenate auxotrophy. We found that this auxotrophy is due to the absence of a single gene, panD, encoding aspartate-decarboxylase. Heterologous expression of Escherichia coli PanD in Z. mobilis or supplementation of the growth medium with the product of PanD activity, beta-alanine, eliminated the need for exogenous pantothenate. We also determined that Z. mobilis IlvC, an enzyme better known for branched-chain amino acid synthesis, is required for pantothenate synthesis in Z. mobilis, as it compensates for the absence of PanE, another pantothenate synthesis pathway enzyme. In addition to contributing to an understanding of the nutritional requirements of Z. mobilis, our results have led to the design of a more cost effective growth medium. PMID- 28655185 TI - Local knockdown of Nav1.6 relieves pain behaviors induced by BmK I. AB - Voltage-gated sodium channels (VGSCs) in peripheral nociceptive sensory neurons are critical to transmit pain signals. BmK I purified from the venom of scorpion Buthus martensi Karsch (BmK) has been demonstrated to be the primary contributor of envenomation-associated pain. However, the role of distinct VGSCs such as Nav1.6 in the induction and maintenance of pain behaviors induced by BmK I was ambiguous. Herein, using molecular and behavioral approaches we investigated the mRNA and protein expression profiles of Nav1.6 in rat DRG after intraplantar injection of BmK I and tested the pain behaviors after knockdown of Nav1.6 in BmK I-treated rats. It was shown that during induction and maintenance of pain responses induced by BmK I, the expression of Nav1.6 in DRG was found to be significantly increased at both mRNA and protein levels. The percentage of co localization of Nav1.6 and Isolectin B4, a molecular marker of small diameter non peptidergic DRG neurons, was increased at the maintenance phase of pain responses. Furthermore, spontaneous pain and mechanical allodynia, but not thermal hyperalgesia induced by BmK I, were significantly alleviated after knockdown of Nav1.6. These data strongly suggest that Nav1.6 plays an indispensable role in the peripheral pain hypersensitivity induced by BmK I. PMID- 28655184 TI - Characterization of a coupled DNA replication and translesion synthesis polymerase supraholoenzyme from archaea. AB - The ability of the replisome to seamlessly coordinate both high fidelity and translesion DNA synthesis requires a means to regulate recruitment and binding of enzymes from solution. Co-occupancy of multiple DNA polymerases within the replisome has been observed primarily in bacteria and is regulated by posttranslational modifications in eukaryotes, and both cases are coordinated by the processivity clamp. Because of the heterotrimeric nature of the PCNA clamp in some archaea, there is potential to occupy and regulate specific polymerases at defined subunits. In addition to specific PCNA and polymerase interactions (PIP site), we have now identified and characterized a novel protein contact between the Y-family DNA polymerase and the B-family replication polymerase (YB site) bound to PCNA and DNA from Sulfolobus solfataricus. These YB contacts are essential in forming and stabilizing a supraholoenzyme (SHE) complex on DNA, effectively increasing processivity of DNA synthesis. The SHE complex can not only coordinate polymerase exchange within the complex but also provides a mechanism for recruitment of polymerases from solution based on multiequilibrium processes. Our results provide evidence for an archaeal PCNA 'tool-belt' recruitment model of multienzyme function that can facilitate both high fidelity and translesion synthesis within the replisome during DNA replication. PMID- 28655186 TI - Catheter-related right internal jugular vein thrombosis after chest surgery. AB - Background: Central venous catheters (CVCs) are frequently used for monitoring haemodynamic status and rapidly delivering fluid therapy during the peri- and postoperative periods. Indwelling CVCs are typically used 7-14 days postoperatively for additional monitoring and treatment, but patients may develop asymptomatic catheter-related thrombosis, leading to life-threatening pulmonary embolism and death. Early detection helps to avoid such complications. Methods: This prospective observational study investigated the risk factors associated with catheter-related right internal jugular vein thrombosis in patients undergoing chest surgery. The study enrolled 24 patients who were scheduled to receive chest surgeries during which catheters were needed. To detect thrombus formation, Doppler ultrasound examinations from the thyroid cartilage level to the supraclavicular region were used after CVC placement and on each of the following days until the catheter was removed. Results: No thrombosis was found in patients before surgery, but it appeared in 75% (18/24) after surgery. The risks of thrombosis increased with a longer duration of anaesthesia, greater amounts of bleeding, and use of postoperative ventilator support. Conclusions: Earlier catheter removal may reduce the risk of catheter-related thrombosis and avoid possibly fatal complications after catheter-related thrombosis. PMID- 28655189 TI - Corrigenda. PMID- 28655187 TI - Nutrient availability affects floral scent much less than other floral and vegetative traits in Lithophragma bolanderi. AB - Background and Aims: Many plant-pollinator interactions are mediated by floral scents that can vary among species, among populations within species and even among individuals within populations. This variation could be innate and unaffected by the environment, but, because many floral volatiles have amino-acid precursors, scent variation also could be affected by differences in nutrient availability among environments. In plants that have coevolved with specific pollinators, natural selection is likely to favour low phenotypic plasticity in floral scent even under different conditions of nutrient availability if particular scents or scent combinations are important for attracting local pollinators. Methods: Clonal pairs of multiple seed-families of two Lithophragma bolanderi (Saxifragaceae) populations were subjected to a high and a low nutrient treatment. These plants are pollinated primarily by host-specific Greya moths. It was evaluated how nutrient treatment affected variation in floral scent relative to other vegetative and reproductive traits. Key Results: Floral scent strength (the per-flower emission rate) and composition were unaffected by nutrient treatment, but low-nutrient plants produced fewer and lighter leaves, fewer scapes and fewer flowers than high-nutrient plants. The results held in both populations, which differed greatly in the number and composition of floral scents produced. Conclusions: The results reveal a strong genetic component both to scent composition and emission level, and partly contrasts with the only previous study that has assessed the susceptibility of floral volatile signals to variation in the abundance of nutrients. These results, and the tight coevolutionary relationship between Lithophragma plants and their specialized Greya moth pollinators, indicate that reproductive traits important to coevolving interactions, such as the floral scent of L. bolanderi, may be locally specialized and more canalized than other traits important for plant fitness. PMID- 28655188 TI - Diversity and Persistence of the Gut Microbiome of the Giant Neotropical Bullet Ant. AB - Identifying the factors that structure host-associated microbiota is critical to understand the role these microbes may play in host ecology and evolutionary history. To begin to address this question we investigate the diversity and persistence of the bacterial community of the giant Neotropical bullet ant, Paraponera clavata. We included samples from four widely dispersed locations to address the role geography plays in shaping these communities. To understand how the digestive tract can filter bacterial communities, we sampled mouth and gut communities. To investigate the stability of community members we sampled wild caught and individuals kept on a sterile diet. Only a single bacterial taxon in the Firmicutes is consistently present across individuals, indicating a remarkably simple "core" bacterial community for the giant Neotropical bullet ant. Geography did not explain host bacterial diversity, but we did find significant reductions in diversity between the mouth and the gut tract. Lastly, our diet manipulations highlight the importance of controlled experiments to tease apart persistent microbial communities from environmental transients. PMID- 28655190 TI - Right ventricular function during exercise in children after heart transplantation. AB - Aims: Right ventricular (RV) dysfunction is a common problem after heart transplant (HTx). In this study, we used semi-supine bicycle ergometry (SSBE) stress echocardiography to evaluate RV systolic and diastolic reserve in paediatric HTx recipients. Methods and results: Thirty-nine pediatric HTx recipients and 23 controls underwent stepwise SSBE stress echocardiography. Colour tissue doppler imaging (TDI) peak systolic (s') and peak diastolic (e') velocities, myocardial acceleration during isovolumic contraction (IVA), and RV free wall longitudinal strain were measured at incremental heart rates (HR). The relationship with increasing HR was evaluated for each parameter by plotting values at each stage of exercise versus HR using linear and non-linear regression models. At rest, HTx recipients had higher HR with lower TDI velocities (s': 5.4 +/- 1.7 vs. 10.4 +/- 1.8 cm/s, P < 0.001; e': 6.4 +/- 2.2 vs.12 +/- 2.4 cm/s, P < 0.001) and RV IVA values (IVA: 1.2 +/- 0.4 vs. 1.6 +/- 0.8 m/s2, P = 0.04), while RV free wall longitudinal strain was similar between groups. At peak exercise, HR was higher in controls and all measurements of RV function were significantly lower in HTx recipients, except for RV free wall longitudinal strain. When assessing the increase in each parameter vs. HR, the slopes were not significantly different between patients and controls except for IVA, which was lower in HTx recipients. Conclusion: In pediatric HTx recipients RV systolic and diastolic functional response to exercise is preserved with a normal increase in TDI velocities and strain values with increasing HR. The blunted IVA response possibly indicates a mildly decreased RV contractile response but it requires further investigation. PMID- 28655191 TI - Iatrogenic Effect? Cautions when Utilizing an Early Health Education for Post concussion Symptoms. AB - Objective: Patients with mild traumatic brain injury (MTBI) usually suffer from the post-concussion symptoms (PCS). PCS could recover by 3 months post-injury, but some patients still persistently complain of those symptoms for years. Accordingly, the Chang-Gung University Brief Intervention for Post-Concussion Symptoms (CGU-BIPCS) was developed to intervene PCS based on the established advantages of health education. This prospective study thus aims to evaluate the effectiveness of CGU-BIPCS for patients with MTBI. Methods: A total of 130 participants, which included 53 healthy participants and 77 patients with MTBI. Patients were further subdivided as two groups: "regular intervention" (RI) and "health education intervention" (EI). PCS of patients with MTBI were respectively evaluated at 2 weeks and 3 months post-injury, and symptoms of healthy participants were also examined. Results: Both patients in RI and EI reported significantly more PCS than healthy participants did at 2 weeks and 3 months post injury but less PCS at 3 months than at 2 weeks post-injury. However, the PCS endorsement of patients in RI and EI were not significantly different. In addition, more patients in EI reported significantly PCS deterioration than patients in RI did at 3 months post-injury. Conclusions: Although establishing the effectiveness of CGU-BIPCS was unsuccessful in this study, it is further suggested that a potential iatrogenic effect from this kind of early interventions should never be overlooked. PMID- 28655192 TI - Right ventricular dysfunction after surgical left ventricular restoration: prevalence, risk factors and clinical implications. AB - OBJECTIVES: Surgical left ventricular (LV) restoration (SVR) induces changes in LV systolic and diastolic function that may affect postoperative right ventricular (RV) function. This study aimed to evaluate the long-term effect of SVR on RV function, with specific focus on determinants and prognostic implications of RV dysfunction. METHODS: Eighty-six patients (age 60 +/- 10 years, 73% male) with clinical and echocardiographic follow-up 2 years after SVR were included. RV dysfunction was defined as RV fractional area change <35%. The association between RV dysfunction at follow-up and clinical and echocardiographic characteristics and outcome was investigated. RESULTS: RV dysfunction at follow-up was present in 40% of patients and was associated with worse preoperative RV fractional area change (39 +/- 9 vs 46 +/- 7%, P < 0.01), pulmonary hypertension (18 vs 4%, P = 0.03) and higher follow-up LV filling pressures (E/E' ratio 23 +/- 8 vs 15 +/- 8, P = 0.02). At follow-up, patients with RV dysfunction were more frequently in New York Heart Association Class III or IV (30 vs 12%, P = 0.04) and 5-year mortality, heart transplantation and LV assist device implantation rate was increased (49 vs 17%, P < 0.01) as compared to patients with normal RV function. CONCLUSIONS: RV dysfunction after SVR was observed in 40% of patients and was associated with preoperative RV dysfunction, presence of pulmonary hypertension and an increase in LV filling pressures at follow-up. Patients with RV dysfunction after SVR had worse clinical functioning and outcome as compared to patients with normal RV function. PMID- 28655193 TI - The importance of fermentative conditions for the biotechnological production of lignin modifying enzymes from white-rot fungi. AB - White-rot fungi are the main natural producers of lignin-modifying enzymes, i.e. laccases and peroxidases, whose secretion and activity allows the depolymerization of lignin and the release of polysaccharides contained in lignocellulose. These enzymes are able to oxidize, in addition to lignin, a wide spectrum of natural and synthetic substrates, making their industrial and biotechnological application appealing. However, the complex regulation of the synthesis of lignin-modifying enzymes, as well as the heterogeneous physiology of fungi in response to nutrients, makes the use of white-rot fungi as production platforms challenging. Finally, yet importantly, analytical methods are not fully standardized, making evaluations and comparisons ambiguous. Consequently, robust and cost-effective fermentative processes for the production of lignin-modifying enzymes by fungi have not yet been fully established, limiting their industrial exploitation. In this review, we describe the importance of both the media composition and the fermentative conditions for leveraging the fungal potential in terms of production titer and enzymatic biodiversity of lignin-modifying enzymes. PMID- 28655194 TI - Predicting Indirect Effects of Predator-Prey Interactions. AB - SYNOPSIS: Predicting the effects of climate change on species and communities remains a pre-eminent challenge for biologists. Critical among this is understanding the indirect effects of climate change, which arise when the direct, physiological effects of climate on one species change the outcome of its interaction with a second species, altering the success of the second species. A diverse array of approaches to predicting indirect effects exists from mechanistic models, which attempt to build-up from physiological changes to ecological consequences, to ecological models that focus solely on the ecological scale. Here I review studies of the indirect effects of temperature on two predator-prey systems in rocky intertidal habitats. Laboratory and field studies have shown that temperature can indirectly affect interactions through both physiological and behavioral changes in predator and prey, but no model yet captures the full range of these effects. The three main categories of changes are metabolic rate effects, stress effects, and behavioral avoidance. Mechanistic models best capture the first two of these three dynamics, while ecological models have focused mainly on the last two. The challenge remains to correctly identify a species' vulnerability to climate change, which differs from its physiological sensitivity. The best approach may be to use detailed physiological scale studies of indirect effect in a few systems to ground truth simpler models that can be applied more broadly. Model development and testing is also hampered by the small number of field studies of indirect effects in natural systems, particularly studies that examine natural temporal or spatial variation in climate. PMID- 28655196 TI - Rocking makes the difference. PMID- 28655195 TI - Positive autobiographical memory retrieval reduces temporal discounting. AB - People generally prefer rewards sooner rather than later. This phenomenon, temporal discounting, underlies many societal problems, including addiction and obesity. One way to reduce temporal discounting is to imagine positive future experiences. Since there is overlap in the neural circuitry associated with imagining future experiences and remembering past events, here we investigate whether recalling positive memories can also promote more patient choice. We found that participants were more patient after retrieving positive autobiographical memories, but not when they recalled negative memories. Moreover, individuals were more impulsive after imagining novel positive scenes that were not related to their memories, showing that positive imagery alone does not drive this effect. Activity in the striatum and temporo parietal junction during memory retrieval predicted more patient choice, suggesting that to the extent that memory recall is rewarding and involves perspective-taking, it influences decision-making. Furthermore, representational similarity in the ventromedial prefrontal cortex between memory recall and decision phases correlated with the behavioral effect across participants. Thus, we have identified a novel manipulation for reducing temporal discounting-remembering the positive past-and have begun to characterize the psychological and neural mechanisms behind it. PMID- 28655197 TI - Effect of dose timing on the blood concentration of lapatinib in patients with breast cancer. PMID- 28655198 TI - Glycosylation of IgG-Fc: a molecular perspective. AB - Antibodies of the IgG class carry a pair of oligosaccharides (N-glycans) in the Fc region. The importance of the N-glycan is clearly demonstrated by its profound effect in the physicochemical and biological properties of antibodies. The term 'glycoengineering' has been coined to describe contemporary strategies to improve the performance of therapeutic monoclonal antibodies on the basis of modifications in the structure and composition of the N-glycan. These methodologies have resulted in the approval and commercialization of a new generation of antibodies with improved therapeutic efficacy. So far, these advances have been driven by herculean efforts in a process of trial-and-error. The collective work of researchers in this field is progressively revealing the molecular basis of N-glycans for the function of antibodies. This knowledge will ultimately be conducive to the application of rational approaches for the successful manipulation of antibodies using glycoengineering strategies. Herein, we review advances in our understanding of the role of the N-glycan in the structural and dynamic integrity, and biological activity, of antibodies. Since the N-glycan has a multifaceted effect in antibodies, in this review we have emphasized the importance of integrating various techniques that address this problem from multiple points of view. In particular, the combination of X-ray crystallography with nuclear magnetic resonance, molecular dynamics simulations and biophysical approaches based on thermodynamic principles, has emerged as a powerful combination that is deepened our understanding of this unique system with critical implications for human well-being. PMID- 28655199 TI - Proteins Involved in Endocytosis Are Upregulated by Ageing in the Normal Human Brain: Implications for the Development of Alzheimer's Disease. AB - The greatest risk factor for Alzheimer's disease (AD) is advanced age, but the reason for this association remains unclear. Amyloid-beta (Abeta) is produced from amyloid precursor protein (APP) primarily after APP is internalized by clathrin-mediated or clathrin-independent endocytosis. Changes in endocytosis in AD have been identified. We hypothesized that endocytic protein expression is altered during ageing, thus influencing the likelihood of developing AD by increasing Abeta production. We explored how levels of endocytic proteins, APP, its metabolites, secretase enzymes, and tau varied with age in cortical brain samples from men of three age ranges (young [20-30], middle aged [45-55], and old [70-90]) with no symptoms of dementia. Abeta40 and Abeta42 were significantly increased in old brains, while APP and secretase expression was unaffected by age. Phosphorylated GSK3beta increased significantly with age, a possible precursor for neurofibrillary tangle production, although phosphorylated tau was undetectable. Significant increases in clathrin, dynamin-1, AP180, Rab-5, caveolin-2, and flotillin-2 were seen in old brains. Rab-5 also increased in middle-aged brains prior to changes in Abeta levels. This age-related increase in endocytic protein expression, not described previously, suggests an age-related upregulation of endocytosis which could predispose older individuals to develop AD by increasing APP internalization and Abeta generation. PMID- 28655200 TI - Highly efficient preparation of single-stranded DNA rings by T4 ligase at abnormally low Mg(II) concentration. AB - Preparation of large amount of single-stranded circular DNA in high selectivity is crucial for further developments of nanotechnology and other DNA sciences. Herein, a simple but practically useful methodology to prepare DNA rings has been presented. One of the essential factors is to use highly diluted T4 ligase buffer for ligase reactions. This strategy is based on our unexpected finding that, in diluted T4 buffers, intermolecular polymerization of DNA fragments is greatly suppressed with respect to their intramolecular cyclization. This promotion of cyclization is attributable to abnormally low concentration of Mg2+ ion (0.5-1.0 mM) but not ATP in the media for T4 ligase reactions. The second essential factor is to add DNA substrate intermittently to the mixture and maintain its temporal concentration low. By combining these two factors, single-stranded DNA rings of various sizes (31-74 nt) were obtained in high selectivity (89 mol% for 66-nt DNA) and in satisfactorily high productivity (~0.2 mg/ml). A linear 72-nt DNA was converted to the corresponding DNA ring in nearly 100% selectivity. The superiority of this new method was further substantiated by the fact that small sized DNA rings (31-42 nt), which were otherwise hardly obtainable, were successfully prepared in reasonable yields. PMID- 28655201 TI - Unplanned Reoperation After Craniotomy for Tumor: A National Surgical Quality Improvement Program Analysis. AB - BACKGROUND: Reoperation has been increasingly utilized as a metric evaluating quality of care. OBJECTIVE: To evaluate the rate of, reasons for, and predictors of unplanned reoperation after craniotomy for tumor in a nationally accrued population. METHODS: Patients who underwent cranial tumor resection were extracted from the prospective National Surgical Quality Improvement Program registry (2012-2014). Multivariate logistic regression examined predictors of unplanned cranial reoperation. Predictors screened included patient age, sex, tumor location and histology, functional status, comorbidities, preoperative laboratory values, operative urgency, and time. RESULTS: Of the 11 462 patients included, 3.1% (n = 350) underwent an unplanned cranial reoperation. The most common reasons for cranial reoperation were intracranial hematoma evacuation (22.5%), superficial or intracranial surgical site infections (11.9%), re resection of tumor (8.4%), decompressive craniectomy (6.1%), and repair of cerebrospinal fluid leakage (5.6%). The strongest predictor of any cranial reoperation was preoperative thrombocytopenia (less than 100 000/MUL, odds ratio [OR] = 2.51, 95% confidence interval [CI]: 1.23-5.10, P = .01). Thrombocytopenia, hypertension, emergent surgery, and longer operative time were predictors of reoperation for hematoma (P <= .004), while dependent functional status, morbid obesity, leukocytosis, and longer operative time were predictors of reoperation for infection (P < .05). Although any unplanned cranial reoperation was not associated with differential odds of mortality (OR = 1.68, 95% CI: 0.94-3.00, P = .08), hematoma evacuation was significantly associated with thirty-day death (P = .04). CONCLUSION: In this national analysis, unplanned cranial reoperation was primarily associated with operative indices, rather than preoperative characteristics, suggesting that reoperation may have some utility as a quality indicator. However, hypertension and thrombocytopenia were potentially modifiable predictors of reoperation. PMID- 28655203 TI - Kronos: a workflow assembler for genome analytics and informatics. AB - Background: The field of next-generation sequencing informatics has matured to a point where algorithmic advances in sequence alignment and individual feature detection methods have stabilized. Practical and robust implementation of complex analytical workflows (where such tools are structured into "best practices" for automated analysis of next-generation sequencing datasets) still requires significant programming investment and expertise. Results: We present Kronos, a software platform for facilitating the development and execution of modular, auditable, and distributable bioinformatics workflows. Kronos obviates the need for explicit coding of workflows by compiling a text configuration file into executable Python applications. Making analysis modules would still require programming. The framework of each workflow includes a run manager to execute the encoded workflows locally (or on a cluster or cloud), parallelize tasks, and log all runtime events. The resulting workflows are highly modular and configurable by construction, facilitating flexible and extensible meta-applications that can be modified easily through configuration file editing. The workflows are fully encoded for ease of distribution and can be instantiated on external systems, a step toward reproducible research and comparative analyses. We introduce a framework for building Kronos components that function as shareable, modular nodes in Kronos workflows. Conclusions: The Kronos platform provides a standard framework for developers to implement custom tools, reuse existing tools, and contribute to the community at large. Kronos is shipped with both Docker and Amazon Web Services Machine Images. It is free, open source, and available through the Python Package Index and at https://github.com/jtaghiyar/kronos. PMID- 28655205 TI - Motor Issues in the Clinical High Risk Phase of Psychosis. PMID- 28655204 TI - TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis. AB - Aims: The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL cholesterol concentration. Methods and results: Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion: We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti atherosclerotic therapies. PMID- 28655202 TI - Small RNA Activity in Archeological Barley Shows Novel Germination Inhibition in Response to Environment. AB - The recovery of ancient RNA from archeological material could enable the direct study of microevolutionary processes. Small RNAs are a rich source of information because their small size is compatible with biomolecular preservation, and their roles in gene regulation make them likely foci of evolutionary change. We present here the small RNA fraction from a sample of archeological barley generated using high-throughput sequencing that has previously been associated with localized adaptation to drought. Its microRNA profile is broadly similar to 19 globally distributed modern barley samples with the exception of three microRNAs (miRNA159, miRNA319, and miR396), all of which are known to have variable expression under stress conditions. We also found retrotransposon activity to be significantly reduced in the archeological barley compared with the controls, where one would expect the opposite under stress conditions. We suggest that the archeological barley's conflicting stress signals could be the result of long term adaptation to its local environment. PMID- 28655207 TI - Gastrointestinal stromal tumor with synchronous colorectal adenocarcinoma. PMID- 28655206 TI - Deficient Emotion Processing is Associated with Everyday Functioning Capacity in HIV-associated Neurocognitive Disorder. AB - Objective: Emotion processing has received little research focus in HIV, but emerging evidence suggests that abilities such as facial affect discrimination may be features of HIV-associated neurocognitive disorder (HAND). The present study hypothesized that individuals with HAND would evidence an emotion processing deficit relative to cognitively unimpaired individuals with HIV and seronegative comparison participants on a task assessing these abilities. Moreover, it was expected that this deficit would be significantly associated with social aspects of everyday functioning. Method: To explore these hypotheses, 37 HIV+ individuals with HAND, 46 HIV+ without HAND, and 38 HIV-seronegative comparison participants were administered the CogState Social Emotional Cognition Task (SECT) and the UCSD Performance-based Skills Assessment-Brief (UPSA-B). Results: Results revealed that the HAND group was more likely to have impaired accuracy and slower reaction time relative to the comparison groups on the SECT task. In fact, individuals with HAND were almost 10 times more likely to be impaired on emotion processing accuracy than HIV+ without HAND. Among individuals with HIV, accuracy (but not reaction time) was independently related to a functional capacity measure tapping social ability, but not to a similar measure without a social component (UPSA-B Communication and Finances subscales, respectively). Conclusions: These results suggest that disruption of emotion processing may be an important feature of HAND that has clinical value as an independent predictor of real-world activities that involve social components. Future research should prospectively investigate this relationship, which may inform of intervention strategies for improving everyday functioning. PMID- 28655208 TI - Accuracy in Identifying the Source of Subarachnoid Hemorrhage in the Setting of Multiple Intracranial Aneurysms. AB - BACKGROUND: Subarachnoid hemorrhage cases with multiple cerebral aneurysms frequently demonstrate a hemorrhage pattern that does not definitively delineate the source aneurysm. In these cases, rupture site is ascertained from angiographic features of the aneurysm such as size, morphology, and location. OBJECTIVE: To examine the frequency with which such features lead to misidentification of the ruptured aneurysm. METHODS : Records of patients who underwent surgical clipping of a ruptured aneurysm at our institution between 2004 and 2014 and had multiple aneurysms were retrospectively reviewed. A blinded neuroendovascular surgeon provided the rupture source based on the initial head computed tomography scans and digital subtraction angiography images. Operative reports were then assessed to confirm or refute the imaging-based determination of the rupture source. RESULTS: One hundred fifty-one patients had multiple aneurysms. Seventy-one patients had definitive hemorrhage patterns on initial computed tomography scans and 80 patients had nondefinitive hemorrhage patterns. Thirteen (16.2%) of the cases with nondefinitive hemorrhage patterns had discordance between the imaging-based determination of the rupture source and intraoperative findings of the true ruptured aneurysm, yielding an imperfect positive predictive value of 83.8%. Of all multiple aneurysm cases with subarachnoid hemorrhage treated by surgical or endovascular means at our institution, 4.3% (13 of 303) were misidentified. CONCLUSION: Morphological features cannot reliably be used to determine rupture site in cases with nondefinitive subarachnoid hemorrhage patterns. Microsurgical clipping, confirming obliteration of the ruptured lesion, may be preferentially indicated in these patients unless, alternatively, all lesions can be contemporaneously and safely treated with endovascular embolization. PMID- 28655209 TI - Phylogenetic diversification and developmental implications of poly-(R)-3 hydroxyalkanoate gene cluster assembly in prokaryotes. AB - Many polyhydroxyalkanoates (PHAs) system genes, such as phaC, phaA, phaB, phaR, phaP and phaZ, are often found to be organised in the form of operon-like clusters. In this study, a genome survey was performed to identify such clustered PHA systems among 256 prokaryotic organisms. These data were then used to generate a comprehensive 16S rRNA species tree depicting the phylogenetic distribution of the observed clusters with diverse gene arrangements. In addition, the gene occurrences and physical linkages between PHA system genes were quantitatively estimated. From this, we identified a centrally connected hub gene, i.e. the phaC gene of PHA. Furthermore, a comparative investigation was performed between the clusters of PHA and glycogen, which decoded the role of the hub gene in the cluster organisation of both systems. Together, these findings suggest that the highly connected hub gene might contribute substantively towards the organisation and maintenance of the gene network connectivity in the clusters, particularly in the storage reserve systems. PMID- 28655211 TI - Corrigenda. PMID- 28655210 TI - Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. PMID- 28655212 TI - Do comorbidities influence help-seeking for cancer alarm symptoms? A population based survey in England. AB - Background: We examined associations between different chronic morbidities and help-seeking for possible cancer symptoms. Methods: Postal survey of individuals aged >50 years in England. Participants could report prior morbidities in respect of 12 pre-defined conditions. Among patients experiencing possible cancer symptoms we examined associations between specific morbidities and self-reported help-seeking (i.e. contacted versus not contacted a GP) for each alarm symptom using regression analyses. Results: Among 2042 respondents (42% response rate), 936 (46%) recently experienced 1 of 14 possible cancer symptoms considered in our analysis. Of them, 80% reported one or more morbidities, most frequently hypertension/hypercholesterolemia (40%), osteomuscular (36%) and heart diseases (21%). After adjustment for socio-demographic characteristics, patients with hypertension/hypercholesterolemia were more likely to report help-seeking for possible cancer symptoms, such as unexplained cough (OR = 2.0; 95% confidence interval (CI) 1.1-3.5), pain (OR = 2.2; 95% CI 1.0-4.5) and abdominal bloating (OR = 2.3; 95% CI 1.1-4.8). Urinary morbidity was associated with increased help seeking for abdominal bloating (OR = 5.4; 95% CI 1.2-23.7) or rectal bleeding (OR = 5.8; 95% CI 1.4-23.8). In contrast, heart problems reduced help-seeking for change in bowel habits (OR = 0.4; 95% CI 0.2-1.0). Conclusions: Comorbidities are common and may facilitate help-seeking for possible cancer symptoms, but associations vary for specific symptom-comorbidity pairs. The findings can contribute to the design of future cancer symptom awareness campaigns. PMID- 28655213 TI - From academia to industry: a road more travelled. PMID- 28655214 TI - Nutritional value, chemical composition and antioxidant activity of three Tuber species from China. AB - Nutritional value, chemical composition and antioxidant activity of the traditional edible truffles Tuber latisporum, T. subglobosum and T. pseudohimalayense, from China were evaluated. Powder formulations of the three truffles revealed the presence of essential nutrients, such as proteins, carbohydrates and unsaturated fatty acids, and T. latisporum presented the highest contents of total sugar (50.10 g/100 g) and monounsaturated fatty acids (265.19 mg/100 g dw); T. pseudohimalayense showed the highest content of polyunsaturated fatty acids (367.98 mg/100 g dw). They all presented a low fat content but high contents of proteins and unsaturated fatty acid, which is beneficial to human health. The methanol extract from T. pseudohimalayense showed a high radicals scavenging activity and the highest content of total phenols (735.01 mg/100 g dw); T. subglobosum presented the highest content of flavonoids (1355.43 mg/100 g dw). All these extracts could be used as potential antioxidant sources to prevent diseases related to oxidative damage. PMID- 28655215 TI - Development of a new method based on unmodified gold nanoparticles and peptide nucleic acids for detecting bovine viral diarrhea virus-RNA. AB - A simple colorimetric assay is presented for detecting bovine viral diarrhea virus (BVDV)-RNA based on aggregation of gold nanoparticles (AuNPs) in the presence of charge-neutral peptide nucleic acids (PNA). Free charge-neutral PNA oligomers tended to be adsorbed onto AuNPs and act as a coagulant, whereas hybridizing complementary RNA with PNA disrupted PNA-induced AuNP aggregation, and the NPs remained stable. However, non-complementary RNA did not have this effect, and PNA induced aggregation of the AuNPs that resulted in a color change of the reaction from red to blue. The label-free colorimetric assay developed was estimated to have a 10.48 ng/reaction BVDV-RNA detection limit for the visual assay and 1.05 ng/reaction BVDV-RNA using a spectrophotometer. Diagnostic sensitivity and specificity for the assay was in accordance with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and nested RT-PCR results were 98 and 100%, respectively. Absorption of the 520/620 nm ratio was linear, along with an increase in the target RNA concentration of 1.64-52.4 ng/reaction (R2 = 0.992), which showed a linear correlation for the quantitative assay. This study established a rapid visual label and enzyme-free diagnostic assay for detecting BVDV that is applicable in any clinical laboratory. PMID- 28655216 TI - Phenotypic and genomic survey on organic acid utilization profile of Pseudomonas mendocina strain S5.2, a vineyard soil isolate. AB - Root exudates are chemical compounds that are released from living plant roots and provide significant energy, carbon, nitrogen and phosphorus sources for microbes inhabiting the rhizosphere. The exudates shape the microflora associated with the plant, as well as influences the plant health and productivity. Therefore, a better understanding of the trophic link that is established between the plant and the associated bacteria is necessary. In this study, a comprehensive survey on the utilization of grapevine and rootstock related organic acids were conducted on a vineyard soil isolate which is Pseudomonas mendocina strain S5.2. Phenotype microarray analysis has demonstrated that this strain can utilize several organic acids including lactic acid, succinic acid, malic acid, citric acid and fumaric acid as sole growth substrates. Complete genome analysis using single molecule real-time technology revealed that the genome consists of a 5,120,146 bp circular chromosome and a 252,328 bp megaplasmid. A series of genetic determinants associated with the carbon utilization signature of the strain were subsequently identified in the chromosome. Of note, the coexistence of genes encoding several iron-sulfur cluster independent isoenzymes in the genome indicated the importance of these enzymes in the events of iron deficiency. Synteny and comparative analysis have also unraveled the unique features of D-lactate dehydrogenase of strain S5.2 in the study. Collective information of this work has provided insights on the metabolic role of this strain in vineyard soil rhizosphere. PMID- 28655217 TI - Preventing subclinical necrotic enteritis through Lactobacillus johnsonii BS15 by ameliorating lipid metabolism and intestinal microflora in broiler chickens. AB - Increasing studies have focused on the beneficial effects of Lactobacillus johnsonii in certain diseases. Here, we studied the prevention ability of a probiotic strain, L. johnsonii BS15 on subclinical necrotic enteritis (SNE), and its underlying mechanism. 180 male Cobb 500 chicks were randomly allotted into three groups and administrated with BS15 (1 * 106 cfu/g) or Man Rogosa Sharpe liquid medium throughout a 28-day experimental period. With the exception of the normal group, SNE infection was treated for the remaining experimental period after the chicks were fed with normal diet 14 days. Results showed that BS15 notably suppressed the SNE-induced loss of average daily gain and liver functional abnormality. Additionally, BS15 facilitated lipid metabolism of SNE boilers when the contents of peroxisome proliferator activated receptor gamma and adipose triglyceride lipase in adipose tissue and serum high-density lipoprotein cholesterol decreased. BS15 also attenuated the hepatic lipid accumulation of stricken chicks by suppressing the genes expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1c as well as stimulating the genes expression of peroxisome proliferator activated receptor alpha and carnitine palmitoyltransferase-1. Moreover, BS15 enhanced the development of SNE gut by improving the intestinal development and digestion as well as adjusting the gut microflora. Therefore, BS15 may provide a promising natural preventative strategy against SNE, which may be contributed to the amelioration of lipid metabolism and intestinal microflora. PMID- 28655219 TI - Ultra-narrow Band Perfect Absorber and Its Application as Plasmonic Sensor in the Visible Region. AB - We propose and numerically investigate a perfect ultra-narrowband absorber with an absorption bandwidth of only 1.82 nm and an absorption efficiency exceeding 95% in the visible region. We demonstrate that the perfect ultra-narrowband absorption is ascribed to the coupling effect induced by localized surface plasmon resonance. The influence of structural dimensions on the optical performance is also investigated, and the optimal structure is obtained with the extremely low reflectivity (0.001) of the resonance dip. The perfect absorber can be operated as a refractive index sensor with a sensitivity of around 425 nm/RIU and the figure of merit (FOM) reaching 233.5, which greatly improves the accuracy of the plasmonic sensors in visible region. Moreover, the corresponding figure of merit (FOM*) for this sensor is also calculated to describe the performance of the intensity change detection at a fixed frequency, which can be up to 1.4 * 105. Due to the high sensing performance, the metamaterial structure has great potential in the biological binding, integrated photodetectors, chemical applications and so on. PMID- 28655218 TI - Isolation and characterization of Burkholderia fungorum Gan-35 with the outstanding ammonia nitrogen-degrading ability from the tailings of rare-earth element mines in southern Jiangxi, China. AB - The exploitation of rare-earth-element (REE) mines has resulted in severe ammonia nitrogen pollution and induced hazards to environments and human health. Screening microorganisms with the ammonia nitrogen-degrading ability provides a basis for bioremediation of ammonia nitrogen-polluted environments. In this study, a bacterium with the outstanding ammonia nitrogen-degrading capability was isolated from the tailings of REE mines in southern Jiangxi Province, China. This strain was identified as Burkholderia fungorum Gan-35 according to phenotypic and phylogenetic analyses. The optimal conditions for ammonia-nitrogen degradation by strain Gan-35 were determined as follows: pH value, 7.5; inoculum dose, 10%; incubation time, 44 h; temperature, 30 degrees C; and C/N ratio, 15:1. Strain Gan-35 degraded 68.6% of ammonia nitrogen under the optimized conditions. Nepeta cataria grew obviously better in the ammonia nitrogen-polluted soil with strain Gan-35 than that without inoculation, and the decrease in ammonia-nitrogen contents of the former was also more obvious than the latter. Besides, strain Gan 35 exhibited the tolerance to high salinities. In summary, strain Gan-35 harbors the ability of both ammonia-nitrogen degradation at high concentrations and promoting plant growth. This work has reported a Burkholderia strain with the ammonia nitrogen-degrading capability for the first time and is also the first study on the isolation of a bacterium with the ammonia nitrogen-degrading ability from the tailings of REE mines. The results are useful for developing an effective method for microbial remediation of the ammonia nitrogen-polluted tailings of REE mines. PMID- 28655220 TI - Self-Catalyzed Growth of Vertical GaSb Nanowires on InAs Stems by Metal-Organic Chemical Vapor Deposition. AB - We report the first self-catalyzed growth of high-quality GaSb nanowires on InAs stems using metal-organic chemical vapor deposition (MOCVD) on Si (111) substrates. To achieve the growth of vertical InAs/GaSb heterostructure nanowires, the two-step flow rates of the trimethylgallium (TMGa) and trimethylantimony (TMSb) are used. We first use relatively low TMGa and TMSb flow rates to preserve the Ga droplets on the thin InAs stems. Then, the flow rates of TMGa and TMSb are increased to enhance the axial growth rate. Because of the slower radial growth rate of GaSb at higher growth temperature, GaSb nanowires grown at 500 degrees C exhibit larger diameters than those grown at 520 degrees C. However, with respect to the axial growth, due to the Gibbs-Thomson effect and the reduction in the droplet supersaturation with increasing growth temperature, GaSb nanowires grown at 500 degrees C are longer than those grown at 520 degrees C. Detailed transmission electron microscopy (TEM) analyses reveal that the GaSb nanowires have a perfect zinc-blende (ZB) crystal structure. The growth method presented here may be suitable for other antimonide nanowire growth, and the axial InAs/GaSb heterostructure nanowires may have strong potential for use in the fabrication of novel nanowire-based devices and in the study of fundamental quantum physics. PMID- 28655221 TI - What you didn't know that you needed to know. PMID- 28655222 TI - ? PMID- 28655223 TI - ? PMID- 28655224 TI - ? PMID- 28655225 TI - Why are autoimmune diseases more prevalent in women? PMID- 28655226 TI - ? PMID- 28655227 TI - [Planned home birth and proper health care]. PMID- 28655228 TI - [Assessment of mental status in acutely ill elderly]. PMID- 28655229 TI - [Mechanical thrombectomy in stroke - the prehospital phase is crucial]. PMID- 28655231 TI - ? PMID- 28655230 TI - ? PMID- 28655232 TI - ? PMID- 28655233 TI - [Silence is death - what the HIV activists taught us]. PMID- 28655234 TI - [Sterile or non-sterile gloves in minor surgery?]. PMID- 28655235 TI - [Incorrect diagnostic codes cause poorer management of health enterprises]. PMID- 28655236 TI - Harmonised reference ranges for antiepileptic drugs. PMID- 28655237 TI - ? PMID- 28655238 TI - [Provision of analgesics to children before and after the new recommendations on codeine]. PMID- 28655239 TI - ? PMID- 28655240 TI - ? PMID- 28655241 TI - ? PMID- 28655242 TI - ? PMID- 28655243 TI - ? PMID- 28655244 TI - [Low language requirements on foreign physicians]. PMID- 28655245 TI - [Numbers and medicine]. PMID- 28655246 TI - [Fat embolism syndrome]. PMID- 28655247 TI - The man who collapsed in the field. PMID- 28655248 TI - The poisonings chart. PMID- 28655250 TI - ? PMID- 28655249 TI - [The world's first p-value]. PMID- 28655251 TI - ? PMID- 28655252 TI - ? PMID- 28655253 TI - ? PMID- 28655254 TI - ? PMID- 28655255 TI - [Wada and WADA]. PMID- 28655256 TI - ? PMID- 28655257 TI - ? PMID- 28655258 TI - ? PMID- 28655259 TI - ? PMID- 28655260 TI - ? PMID- 28655261 TI - ? PMID- 28655262 TI - ? PMID- 28655263 TI - ? PMID- 28655264 TI - ? PMID- 28655265 TI - ? PMID- 28655266 TI - ? PMID- 28655267 TI - [Sterile or non-sterile gloves in minor surgical procedures in general practice]. AB - BACKGROUND: Minor surgical procedures are regularly performed in general practice. The practice with regard to routine use of sterile or non-sterile gloves varies. The purpose of this article was to review the scientific basis for choice and recommendation in this area. MATERIAL AND METHOD: A search was conducted in PubMed, Cochrane, Medline and Embase for clinical studies in English which had investigated the use of sterile or non-sterile gloves and the prevalence of wound infection related to minor surgery. This applied primarily to general practice, including accident and emergency departments, but also encompassed other fields of medicine. The reference lists for the relevant articles were also scrutinised. RESULTS: Three randomised prospective studies from general practice were found. These showed no difference in frequency of infection. Two of the studies were of moderately good quality. A further five randomised prospective studies and four observational studies were also found, which had examined the association between the use of sterile or non-sterile gloves and infection related to minor surgery. Common to all of these was that they came from fields of medicine other than general practice, namely dermatology and odontology. No difference was found in the majority of these (six out of nine). However, the scientific quality was low or very low. INTERPRETATION: The research data on the use of sterile or non-sterile gloves in minor surgery in general practice and the consequences for wound infection are very limited. No clear difference in infection frequency was demonstrated. PMID- 28655268 TI - Contacts with out-of-hours services because of poisonings in Norway 2006 - 15. AB - BACKGROUND: Poisonings constitute a serious health problem in Norway. The objective of the study was to analyse cases of poisoning reported to out-of-hours services and any changes that may have occurred over a ten-year period. MATERIAL AND METHOD: The material consists of reimbursement claims from all doctors on out of-hours duty in Norway in the period 2006 - 15. Poisonings were defined as ICPC diagnostic codes A84 (poisoning by medical agent), A86 (toxic effect non medicinal substance) or P16 (acute alcohol abuse). RESULTS: The contact rate due to poisonings increased from 221 per 100 000 inhabitants in 2006 to 297 per 100 000 inhabitants in 2015. For the age group 1 - 2 years, the contact rate per 100 000 inhabitants dropped from 469 to 223, for the age group 15 - 25 it rose from 523 to 719, and for the age group 53 - 59 it rose from 178 to 339. The highest contact rate was found among women aged 15 - 25 (785 per 100 000 inhabitants). This group also had the highest contact rate caused by poisoning by a medical agent (238 per 100 000 inhabitants). In the age group 15 - 25 years, altogether 63% of the poisonings occurred during the night. INTERPRETATION: The frequency of contact with out-of-hours services because of poisoning is generally increasing, although a strong decline is observed among small children. Adolescents, and young women in particular, stand out in suffering frequent cases of poisoning. PMID- 28655269 TI - [Screening for the individual and knowledge for all]. PMID- 28655270 TI - [Now I realize - after many years as a doctor...]. PMID- 28655271 TI - One year results of a randomized controlled trial on radial Extracorporeal Shock Wave Treatment, with predictors of pain, disability and return to work in patients with subacromial pain syndrome. AB - BACKGROUND: Radial Extracorporeal Shock Wave Therapy (rESWT) is increasingly used to treat patients with subacromial pain syndrome despite conflicting evidence of its effectiveness. Better knowledge regarding prognostic factors may contribute to the improvement in treatment and prognosis for the patients. AIM: The first aim of this study was to evaluate the effect of rESWT in addition to supervised exercises in patients with subacromial pain syndrome after one year. The second aim was to identify predictors of pain and disability and work status after one year in this patient group. DESIGN: A randomized, double-blind, sham-controlled trial. SETTING: An outpatient shoulder clinic of a University hospital. METHODS: Patients aged 25 to 70 years, with subacromial pain syndrome lasting at least three months were included and randomly assigned to receive either rESWT and supervised exercises or sham rESWT and supervised exercises. The Shoulder Pain and Disability Index (SPADI) and work status were assessed after one year. RESULTS: We screened 265 patients and enrolled 143; 74 were allocated to receive sham rESWT and exercises, and 69 were allocated to receive rESWT and exercises. After one year, no differences were found for the SPADI Score (mean difference 1.6, 95% confidence interval (CI) -10.2 to 7.0, P=0.71). Subgroup analysis of patients with calcification in the rotator cuff demonstrated no significant additional effect of rESWT to supervised exercises (mean difference -6.3, 95% CI 22.4 to 9.8, P=0.44). Marital status (single), frequent use of pain medication, not working at baseline, negative outcome expectations, low self-reported general health status and few supervised exercise sessions predicted a poor outcome on SPADI after one year. CONCLUSIONS: Radial ESWT was not superior to sham rESWT in addition to supervised exercises in the long term for patients with subacromial pain syndrome. The identified predictors for pain, disability and work should be assessed in future studies and addressed by clinicians in order to improve the effectiveness of supervised exercises. CLINICAL REHABILITATION IMPACT: Radial ESWT should not be recommended for patients with subacromial pain syndrome. Clinicians should assess patient's outcome expectations, and if possible reduce the use of pain medication and sick leave in this patient group. PMID- 28655272 TI - What health allied professions students know about physical medicine and rehabilitation: a perspective of physiotherapy students. PMID- 28655273 TI - Synthesis, Structures, and Photophysical Properties of Optically Stable 1,16 Diphenyl-3,14-diaryl-Substituted Tetrahydrobenzo[5]helicenediol Derivatives: Enantioselective Recognition toward Tryptophan Methyl Esters. AB - Starting from commercially available 7-methoxytetralone, 1,16-diphenyl-3,14 dibromotetrahydrobenzo[5]helicenediol (Br-H[5]HOL) was conveniently prepared, which underwent efficient resolution to give the optically stable enantiomeric diols in gram scale by HPLC with semipreparative chiral columns. The absolute configurations of the diols were determined by the circular dichroism (CD) spectra and X-ray crystal structure. By Suzuki-Miyaura cross-coupling reactions, a series of enantiopure pi-extended 1,16-diphenyl-3,14 diaryltetrahydrobenzo[5]helicenediol derivatives (Ar-H[5]HOL) were further synthesized in high yields. The enantiomeric Ar-H[5]HOL exhibited almost identical absorption and emission spectra but showed mirror-image CD spectra and mirror-image circularly polarized luminescence properties. Moreover, it was also found that aryl substituents at the 3,14-positions could extend the chiral environment of the helical skeletons, which led to efficient enantioselective recognition of the enantiomers of tryptophan methyl esters. PMID- 28655274 TI - Effect of Geometry on Electrokinetic Characterization of Solid Surfaces. AB - An analytical approach is presented to describe pressure-driven streaming current (Istr) and streaming potential (Ustr) generation in geometrically complex samples, for which the classical Helmholtz-Smoluchowski (H-S) equation is known to be inaccurate. The new approach is valid under the same prerequisite conditions that are used for the development of the H-S equation, that is, the electrical double layers (EDLs) are sufficiently thin and surface conductivity and electroviscous effects are negligible. The analytical methodology is developed using linear velocity profiles to describe liquid flow inside of EDLs and using simplifying approximations to describe macroscopic flow. At first, a general expression is obtained to describe the Istr generated in different cross sections of an arbitrarily shaped sample. Thereafter, assuming that the generated Ustr varies only along the pressure-gradient direction, an expression describing the variation of generated Ustr along the sample length is obtained. These expressions describing Istr and Ustr generation constitute the theoretical foundation of this work, which is first applied to a set of three nonuniform cross-sectional capillaries and thereafter to a square array of cylindrical fibers (model porous media) for both parallel and transverse fiber orientation cases. Although analytical solutions cannot be obtained for real porous substrates because of their random structure, the new theory provides useful insights into the effect of important factors such as fiber orientation, sample porosity, and sample dimensions. The solutions obtained for the model porous media are used to device strategies for more accurate zeta potential determination of porous fiber plugs. The new approach could be thus useful in resolving the long-standing problem of sample geometry dependence of zeta potential measurements. PMID- 28655276 TI - Modified Random Sequential Adsorption Model for Understanding Kinetics of Proteins Adsorption at a Liquid-Solid Interface. AB - In this Article, we experimentally measure the adsorption kinetics of human serum albumin (HSA) on a hydrophobic hexadecanethiolated gold surface. We use micromachined quartz crystal resonators with fundamental frequency of 83 MHz to accomplish these measurements in real time. In this work, we focus on two key results: (i) asymptotic behavior of the sensor responses upon HSA adsorption and (ii) the jamming limit of adsorbed layer formed by both single-injection and multi-injection experiments with the same value of final concentration. We develop a new interface-depletion modified random sequential adsorption (RSA) model to elucidate the adsorption kinetics and the transport properties of the protein molecules. Analysis of the experimentally measured data shows that the results can be explained on the basis of the exponentially depleting interfacial layer RSA model. To better understand the origin of the formation of the interfacial depletion region where the supply of protein molecules is dramatically reduced, we performed a series of molecular dynamics (MD) simulations using the ReaxFF method. These simulations predict that the resulting adsorption of the protein molecules on the thiolated surface results in a specific orientation at the interface and the diffusion constant of the protein molecules in this layer is significantly reduced. This interplay between the surface adsorption rate and the reduced diffusion coefficient leads to the depletion of the protein molecules in the interfacial layer where the concentration of the protein molecules is much less than the bulk concentration and explains the observed slowdown of the HSA adsorption characteristics on a hydrophobic surface. PMID- 28655275 TI - Nontransformed and Cancer Cells Can Utilize Different Endocytic Pathways To Internalize Dendritic Nanoparticle Variants: Implications on Nanocarrier Design. AB - Three hyperbranched polyglycerol nanoparticle (HPG NP) variants were synthesized and fluorescently labeled for the study of their cellular interactions. The polymeric nanoparticle that contains a hydrophobic core and a hydrophilic HPG shell, HPG-C10-HPG, is taken up faster by HT-29 cancer cells than nontransformed cells, while similar uptake rates are observed with both cell types for the nanoparticle HPG-C10-PEG that contains a hydrophobic core and a polyethylene glycol shell. The nanoparticle HPG-104, containing neither the hydrophobic core nor the polyethylene glycol shell, is taken up faster by nontransformed cells than HT-29 cells. Importantly, cancer and normal cells can utilize different endocytic mechanisms for the internalization of these HPG NPs. Both HPG-C10-HPG and HPG-C10-PEG are taken up by HT-29 cells through clathrin-mediated endocytosis and macropinocytosis. Nontransformed cells, however, take up HPG-C10-HPG and HPG 104 through macropinocytosis, while these cells utilize both clathrin-mediated endocytosis and macropinocytosis to internalize HPG-C10-PEG. PMID- 28655277 TI - Eavesdropping on Plant-Insect-Microbe Chemical Communications in Agricultural Ecology: A Virtual Issue on Semiochemicals. PMID- 28655279 TI - Solid state deuterium NMR study of LKalpha14 peptide aggregation in biosilica. AB - In nature, organisms including diatoms, radiolaria, and marine sponges use proteins, long chain polyamines, and other organic molecules to regulate the assembly of complex silica-based structures. Here, the authors investigate structural features of small peptides, designed to mimic the silicifying activities of larger proteins found in natural systems. LKalpha14 (Ac LKKLLKLLKKLLKL-C), an amphiphilic lysine/leucine repeat peptide with an alpha helical secondary structure at polar/apolar interfaces, coprecipitates with silica to form nanospheres. Previous 13C magic angle spinning studies suggest that the tetrameric peptide bundles that LKalpha14 is known to form in solution may persist in the silica-complexed form, and may also function as catalysts and templates for silica formation. To further investigate LKalpha14 aggregation in silica, deuterium solid-state nuclear magnetic resonance (2H ssNMR) was used to establish how leucine side-chain dynamics differ in solid LKalpha14 peptides isolated from aqueous solution, from phosphate-buffered solution, and in the silica-precipitated states. Modeling the 2H ssNMR line shapes probed the mechanisms of peptide preaggregation and silica coprecipitation. The resulting NMR data indicates that the peptide bundles in silica preserve the hydrophobic interior that they display in the hydrated solid state. However, NMR data also indicate free motion of the leucine residues in silica, a condition that may result from structural deformation of the aggregates arising from interactions between the surface lysine side chains and the surrounding silica matrix. PMID- 28655280 TI - Factors Associated With End-of-Life Planning in Huntington Disease. AB - OBJECTIVE: Knowledge of one's gene status for adult onset conditions provides opportunity to make advance end-of-life (EOL) plans. The purposes of these analyses were to (1) determine the prevalence of EOL plans, including advance directives (ADs) among persons across 3 stages of Huntington disease (HD) and (2) examine factors associated with having ADs in this sample. METHODS: Data are from 503 participants in the HD Quality of Life study. Participants completed an online health-related quality-of-life survey that included questions regarding EOL planning and self-reported HD symptoms. Frequencies were calculated for EOL planning by the HD stage. Bivariate analysis and logistic regression were used to identify variables associated with having ADs. RESULTS: A total of 38.2% of participants stated they had ADs and fewer than half had other EOL plans. Being older, increased HD stage, more years of education, lower anxiety, more swallowing symptoms, and higher meaning and purpose were associated with having ADs. CONCLUSION: The prevalence of ADs in our sample is comparable to the general US population, but surprisingly low, considering the severity and long disease course of HD. PRACTICE IMPLICATIONS: Health-care providers should develop specific interventions early in the disease process to increase ADs in this population. PMID- 28655281 TI - Development of poly(hydroxyethyl methacrylate) nanogel for effective oral insulin delivery. AB - Because of uncomfortable, painful and even deleterious effects of daily injection of insulin, extensive efforts are being made worldwide for developing noninvasive drug delivery systems, especially via the oral route. In this study, we synthesized hydroxyethyl methacrylate (HEMA) nanogel via emulsion polymerization method. The morphology and stability of the nanogel were characterized by scanning electronic microscope and dynamic light scattering. In vivo results showed the soft HEMA nanogel had longer half-live in the body circulation and exhibited almost negligible uptake by the macrophage cells as compared with blank cells. For the FITC-dextran tracking for intestinal penetration, the results indicated that the FITC-dextran in the soft nanogel penetrated faster from the inner side of the abdominal segment, which explained why the soft HEMA nanogel could promote intestinal absorption of encapsulated insulin. In vivo delivery of insulin encapsulated in the soft HEMA nanogel sustained blood glucose control for 12 h, and the overall bioavailability of administrated insulin was much higher than free insulin. Our results showed that the insulin-loaded HEMA nanogel was able to efficiently control blood glucose as a delivery system, suggesting the HEMA nanogel using emulsion polymerization could be an alternative carrier for oral insulin delivery. PMID- 28655282 TI - Causes of Death Among 379 Patients With Hemophilia: A Developing Country's Report. AB - There are steps to achieve an optimum life for patients with hemophilia in developing countries, and awareness of the pattern of death in patients with hemophilia is a prerequisite for any health-care program. Owing to the lack of any data on the pattern of death in patients with hemophilia from developing countries, the current study was done to address common causes of death, and the spectrum of causes of death among individuals with hemophilia A and B. To address the pattern of death in northeast of Iran, we retrospectively collected demographic data regarding deceased patients with hemophilia A and B. Overall, among 379 people with hemophilia A and B, there were 46 deaths. Thirty-two deaths happened in the severe forms of the diseases. The obtained results show the patterns of death in the patients studied are not as parallel as some reports from the developed countries. Traumatic and spontaneous bleeding events were the main causes of death. The trend of death shows a decrease in the current decade post better therapeutic facilities. Evaluation of causes of death in hemophilia can be a useful indicator for managing the efficacy of health care in the current patients. PMID- 28655283 TI - [Insight and Violent Behavior in a Cohort of Early Psychosis Patients]. PMID- 28655284 TI - Clozapine Response Rates among People with Treatment-Resistant Schizophrenia: Data from a Systematic Review and Meta-Analysis. AB - Clozapine is the most effective antipsychotic for the 25% to 33% of people with schizophrenia who are treatment resistant, but not all people achieve response. Using data from a previously published clozapine systematic review and meta analysis, we explored the proportion of people who achieved response and examined the absolute and percentage change in Positive and Negative Syndrome Scale (PANSS) scores. Overall, 40.1% (95% confidence interval [CI], 36.8%-43.4%) responded, with a mean reduction in PANSS of 22.0 points (95% CI, 20.9-23.1), a reduction of 25.8% (95% CI, 24.7%-26.9%) from baseline. These reductions are clinically meaningful. A 40% response rate to clozapine suggests that 12% to 20% of people with schizophrenia will be ultra-resistant. PMID- 28655285 TI - The Effects of a Health Partner Program on Improving Health Status Among Overweight/Obese Individuals With and Without Prediabetes. AB - The purpose of this study was to compare baseline health status in overweight/obese adults with and without prediabetes and to determine whether a health partner program improved health status at 1-year follow-up from 2010 to 2011. Sociodemographic information, body composition, blood work, and health status were obtained from both baseline and 1-year follow-up visit. Healthy overweight/obese participants with prediabetes were likely to self-report poorer physical functioning compared with those without prediabetes at baseline. At the 1-year follow-up visit, compared with participants without prediabetes, participants with prediabetes had the greatest improvements in physical functioning. Although participants without prediabetes had a significant improvement in mental functioning, there were no significant differences in changes in mental functioning between those with and without prediabetes. Early interventions to improve health status are important, and provider advice and preventive measures aimed at improving health status should be integrated into clinical practice. PMID- 28655286 TI - A group II metabotropic glutamate receptor 3 (mGlu3, GRM3) isoform implicated in schizophrenia interacts with canonical mGlu3 and reduces ligand binding. AB - As well as being expressed as a full-length transcript, the group II metabotropic glutamate receptor 3 (GRM3, mGlu3) gene is expressed as an mRNA isoform which lacks exon 4 (GRM3Delta4) and which is predicted to encode a protein with a novel C terminus (called mGlu3Delta4). This variant may contribute to the mechanism by which GRM3 acts as a schizophrenia risk gene. However, little is known about the properties or function of mGlu3Delta4. Here, using transiently transfected HEK293T/17 cells, we confirm that GRM3Delta4 cDNA is translated, with mGlu3Delta4 existing as a homodimer as well as a monomer, and localizing primarily to cell membranes including the plasma membrane. Co-immunoprecipitation shows that mGlu3Delta4 interacts with canonical mGlu3. mGlu3Delta4 does not bind the mGlu2/3 antagonist [3H]LY341495, but the presence of mGlu3Delta4 reduces binding of [3H]LY341495 to mGlu3, paralleled by a decrease in the abundance of membrane associated mGlu3. These experiments indicate that mGlu3Delta4 may negatively modulate mGlu3, and thereby impact on the roles of GRM3/mGlu3 in schizophrenia and as a therapeutic target. PMID- 28655287 TI - The influence of traumatic transfemoral amputation on metabolic cost across walking speeds. AB - BACKGROUND: Recent literature indicates equivalent costs of walking can be achieved after a transtibial amputation when the individual is young, active, and/or has extensive access to rehabilitative care. It is unknown if a similar cohort with transfemoral amputation can also achieve lower metabolic costs of walking than previously reported. OBJECTIVE: Compare metabolic cost in individuals with a transfemoral amputation to controls and to the literature across a range of walking speeds. STUDY DESIGN: Cross-sectional. METHODS: A total of 14 individuals with a unilateral transfemoral amputation (27 +/- 5 years, N = 4 mechanical knee, N = 10 microprocessor knee) and 14 able-bodied controls (26 +/ 6 years) walked at self-selected and four standardized speeds. Heart rate, metabolic rate (mL O2/kg/min), metabolic cost (mL O2/kg/m), and rating of perceived exertion were calculated. RESULTS: Self-selected speed was 8.6% slower in the transfemoral amputation group ( p = 0.031). Across standardized speeds, both metabolic rate and metabolic cost ranged from 44%-47% greater in the transfemoral amputation group ( p < 0.001), heart rate was 24%-33% greater ( p < 0.001), and perceived exertion was 24%-35% greater ( p < 0.009). CONCLUSION: Although the transfemoral amputation group was relatively young, physically fit, and had extensive access to rehabilitative care, the metabolic cost of walking fell within the ranges of the literature on older or presumably less fit individuals with transfemoral amputation. Clinical relevance Developments in prosthetic technology and/or rehabilitative care may be warranted and may reduce the metabolic cost of walking in individuals with a transfemoral amputation. PMID- 28655288 TI - Together They Stand: Interpreting Not-At-Issue Content. AB - Potts unified the account of appositives, parentheticals, expressives, and honorifics as 'Not- At-Issue' (NAI) content, treating them as a natural class semantically in behaving like root (unembedded) structures, typically expressing speaker commitments, and being interpreted independently of At-Issue content. We propose that NAI content expresses a complete speech act distinct from the speech act of the containing utterance. The speech act hypothesis leads us to expect the semantic properties Potts established. We present experimental confirmation of two intuitive observations made by Potts: first that speech act adverbs should be acceptable as NAI content, supporting the speech act hypothesis; and second, that when two speech acts are expressed as successive sentences, the comprehender assumes they are related by some discourse coherence relation, whereas an NAI speech act need not bear a restrictive discourse coherence relation to its containing utterance, though overall sentences containing relevant content are rated more acceptable than those that do not. The speech act hypothesis accounts for these effects, and further accounts for why judgments of syntactic complexity or evaluations of whether or not a statement is true interact with the at-issue status of the material being judged or evaluated. PMID- 28655290 TI - The Effect of Erythropoietin in Preventing Ischemia-Reperfusion Injury in Ovarian Tissue Transplantation. AB - : Condensation Erythropoietin improved the survival of follicles in ovarian grafts most likely by reducing ischemic injury, by improving neoangiogenesis, and by its antioxidant effects. OBJECTIVE: Ovarian tissue cryopreservation and transplantation are the only options accepted for prepubertal girls and women requiring immediate chemotherapy. Ischemia-reperfusion injury is the main obstacle for ovarian tissue transplantation. In the present study, we aimed to evaluate the effects of recombinant human erythropoietin (EPO) on tissue viability in autotransplanted rat ovaries. STUDY DESIGN: Seventeen female rats were randomized into 3 groups as sham control group (n = 5), EPO-treated group (n = 6), and EPO-untreated group (n = 6). Both ovaries were excised and transplanted into a subcutaneous pouch formed at the anterior abdominal wall in the EPO treated and untreated groups. In the EPO group, 5000 U/kg EPO was applied as local injection to the site that ovarian tissue was placed and the dose was repeated with the same route at the end of the fourth week. After 2 months, ovaries were removed and blood samples were obtained. Levels of estradiol (E2), vascular endothelial growth factor (VEGF), VEGF-C, and lipid hydroperoxidase (LPO) and the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) were measured both in blood and tissue samples. Histopathological and morphometric analyses were also performed on tissue samples. RESULTS: Considering serum levels, mean CAT was significantly higher ( P = .003) and mean SOD ( P = .033), LPO ( P = .050), VEGF ( P = .001), and VEGF-C ( P = .024) were significantly lower in the EPO-treated group than in the untreated group. Mean serum GPX levels were similar. Significantly higher levels of E2 were determined in the EPO group than in the untreated group. Highest serum E2 levels were found in the sham group ( P = .001). Tissue levels of GPX (1.23) and CAT (53.17) were significantly higher in the EPO group ( P = .002 and P = .001, respectively). However, tissue levels of SOD and LPO, VEGF, and VEGF-C levels were significantly lower in the EPO group than those in the untreated group ( P = .033, P = .050, P = .002, and P = .003, respectively). In tissue examination, the highest values of x, y axis and epithelial height were in the sham group. Mean value of the EPO group was found statistically significantly higher than that of the untreated group ( P <= .05). In terms of antral follicle count, ordering was found as sham > EPO-treated > EPO-untreated group. Follicle counts in the EPO group were significantly higher than those in the untreated group ( P <= 0.05). CONCLUSION: Erythropoietin improved the survival of follicles in ovarian grafts most likely by reducing ischemic injury, by improving neoangiogenesis, and by its antioxidant effects. PMID- 28655289 TI - The costs, resource use and cost-effectiveness of Clinical Nurse Specialist-led interventions for patients with palliative care needs: A systematic review of international evidence. AB - BACKGROUND: Patients with palliative care needs do not access specialist palliative care services according to their needs. Clinical Nurse Specialists working across a variety of fields are playing an increasingly important role in the care of such patients, but there is limited knowledge of the extent to which their interventions are cost-effective. OBJECTIVES: To present results from a systematic review of the international evidence on the costs, resource use and cost-effectiveness of Clinical Nurse Specialist-led interventions for patients with palliative care needs, defined as seriously ill patients and those with advanced disease or frailty who are unlikely to be cured, recover or stabilize. DESIGN: Systematic review following PRISMA methodology. DATA SOURCES: Medline, Embase, CINAHL and Cochrane Library up to 2015. Studies focusing on the outcomes of Clinical Nurse Specialist interventions for patients with palliative care needs, and including at least one economic outcome, were considered. The quality of studies was assessed using tools from the Joanna Briggs Institute. RESULTS: A total of 79 papers were included: 37 randomized controlled trials, 22 quasi experimental studies, 7 service evaluations and other studies, and 13 economic analyses. The studies included a wide variety of interventions including clinical, support and education, as well as care coordination activities. The quality of the studies varied greatly. CONCLUSION: Clinical Nurse Specialist interventions may be effective in reducing specific resource use such as hospitalizations/re-hospitalizations/admissions, length of stay and health care costs. There is mixed evidence regarding their cost-effectiveness. Future studies should ensure that Clinical Nurse Specialists' roles and activities are clearly described and evaluated. PMID- 28655291 TI - Naturally Acquired Canine Herpesvirus-Associated Meningoencephalitis. AB - Canid alphaherpesvirus 1 (CHV) causes morbidity and mortality in susceptible puppies. While the neuropathology of experimentally infected puppies has been detailed, characterization of naturally acquired infections is limited. The aim of this study was to describe the histologic, immunohistochemical, and in situ hybridization features of CHV encephalitis in the dog. Six female and 11 male puppies ranging in age from stillborn to 57 days old were included. Histologically, lesions included multifocal glial nodules (16/17, 94%), meningeal infiltrates (15/17, 88%), and cerebellar cortical necrosis (6/9, 67%); however, robust inflammation was not a significant feature in any of the cases. Immunohistochemistry for CD3, CD20, MAC387, and Iba1 was performed. Although T cells predominated over B cells, the overall number of cells was small in all cases both within the glial nodules and the meninges. In 16 of 16 (100%) cases, glial nodules were diffusely immunoreactive for Iba1; however, limited or no immunoreactivity for MAC387 was present. In situ hybridization directed at the CHV thymidine kinase gene revealed CHV nucleic acid in the granule neurons of the cerebellar folia (8/9; 89%), endothelial cells in the meninges and parenchyma (12/17, 71%), and individual randomly distributed neurons (6/17, 35%). These results clarify the pathology of naturally acquired CHV infection and indicate that developing cerebellar granule neurons are an important site of viral replication. PMID- 28655292 TI - Insertionally polymorphic sites of human endogenous retrovirus-K (HML-2) with long target site duplications. AB - BACKGROUND: Human endogenous retroviruses (HERVs) belong to the LTR retrotransposon family, where the complete HERV sequence contains two long terminal repeats (LTRs) located at each end. Intact LTRs possess highly conserved transcriptional promoter and enhancer sequences, so analyses of HERV insertional polymorphisms are expected to provide greater insights into human genomic variation compared with the conventional analysis of single nucleotide variations. High-throughput sequencing technology is developing but genome-wide investigations of HERVs are methodically challenging, and thus a comprehensive understanding of HERV insertional polymorphisms and target site duplications (TSDs) remains elusive. RESULTS: We identified five human-specific insertionally polymorphic sites in HERVK (HML-2), one of the HERV subgroups, by extracting HML 2-deleted sequences from the genomic structural variation database, which we successfully characterized and then updated the existing catalogue of HML-2 insertional polymorphisms. The insertionally polymorphic states were confirmed in a small Japanese population by genomic PCR analysis for four of the five sites identified. Sequencing of the preintegration sites clearly showed that the HML-2 site located at 7p21.2 had 250-base pair (bp) TSDs, which is one of the longest TSDs in HML-2. In addition to these five sites, another insertionally polymorphic site for a non-human-specific HML-2 site was also identified at 6p25.2, which was flanked by 111-bp TSDs and the corresponding ERV locus was also annotated in the genome of non-human primates. CONCLUSIONS: Our analysis demonstrated the existence of HERV insertions flanked by unconventionally long TSDs, including those with lengths as high as 250 bp. This suggests that the length range of retroviral TSDs is larger than considered previously, which might help to understand how retroviral integration occurs in the host genome. PMID- 28655293 TI - Plant manipulation through gall formation constrains amino acid transporter evolution in sap-feeding insects. AB - BACKGROUND: The herbivore lifestyle leads to encounters with plant toxins and requires mechanisms to overcome suboptimal nutrient availability in plant tissues. Although the evolution of bacterial endosymbiosis alleviated many of these challenges, the ability to manipulate plant nutrient status has evolved in lineages with and without nutritional symbionts. Whether and how these alternative nutrient acquisition strategies interact or constrain insect evolution is unknown. We studied the transcriptomes of galling and free-living aphidomorphs to characterize how amino acid transporter evolution is influenced by the ability to manipulate plant resource availability. RESULTS: Using a comparative approach we found phylloxerids retain nearly all amino acid transporters as other aphidomorphs, despite loss of nutritional endosymbiosis. Free living species show more transporters than galling species within the same genus, family, or infraorder, indicating plant hosts influence the maintenance and evolution of nutrient transport within herbivores. Transcript profiles also show lineage specificity and suggest some genes may facilitate life without endosymbionts or the galling lifestyle. CONCLUSIONS: The transcript abundance profiles we document across fluid feeding herbivores support plant host constraint on insect amino acid transporter evolution. Given amino acid uptake, transport, and catabolism underlie the success of herbivory as a life history strategy, this suggests that plant host nutrient quality, whether constitutive or induced, alters the selective environment surrounding the evolution and maintenance of endosymbiosis. PMID- 28655294 TI - Erratum to: OrthoFiller: utilising data from multiple species to improve the completeness of genome annotations. PMID- 28655296 TI - SparkBLAST: scalable BLAST processing using in-memory operations. AB - BACKGROUND: The demand for processing ever increasing amounts of genomic data has raised new challenges for the implementation of highly scalable and efficient computational systems. In this paper we propose SparkBLAST, a parallelization of a sequence alignment application (BLAST) that employs cloud computing for the provisioning of computational resources and Apache Spark as the coordination framework. As a proof of concept, some radionuclide-resistant bacterial genomes were selected for similarity analysis. RESULTS: Experiments in Google and Microsoft Azure clouds demonstrated that SparkBLAST outperforms an equivalent system implemented on Hadoop in terms of speedup and execution times. CONCLUSIONS: The superior performance of SparkBLAST is mainly due to the in memory operations available through the Spark framework, consequently reducing the number of local I/O operations required for distributed BLAST processing. PMID- 28655295 TI - Genome-wide identification and expression analysis of SBP-like transcription factor genes in Moso Bamboo (Phyllostachys edulis). AB - BACKGROUND: The SQUAMOSA promoter binding protein-like (SPL) proteins are plant specific transcription factors (TFs) that function in a variety of developmental processes including growth, flower development, and signal transduction. SPL proteins are encoded by a gene family, and these genes have been characterized in two model grass species, Zea mays and Oryza sativa. The SPL gene family has not been well studied in moso bamboo (Phyllostachys edulis), a woody grass species. RESULTS: We identified 32 putative PeSPL genes in the P. edulis genome. Phylogenetic analysis arranged the PeSPL protein sequences in eight groups. Similarly, phylogenetic analysis of the SBP-like and SBP proteins from rice and maize clustered them into eight groups analogous to those from P. edulis. Furthermore, the deduced PeSPL proteins in each group contained very similar conserved sequence motifs. Our analyses indicate that the PeSPL genes experienced a large-scale duplication event ~15 million years ago (MYA), and that divergence between the PeSPL and OsSPL genes occurred 34 MYA. The stress-response expression profiles and tissue-specificity of the putative PeSPL gene promoter regions showed that SPL genes in moso bamboo have potential biological functions in stress resistance as well as in growth and development. We therefore examined PeSPL gene expression in response to different plant hormone and drought (polyethylene glycol-6000; PEG) treatments to mimic biotic and abiotic stresses. Expression of three (PeSPL10, -12, -17), six (PeSPL1, -10, -12, -17, -20, -31), and nine (PeSPL5, -8, -9, -14, -15, -19, -20, -31, -32) genes remained relatively stable after treating with salicylic acid (SA), gibberellic acid (GA), and PEG, respectively, while the expression patterns of other genes changed. In addition, analysis of tissue-specific expression of the moso bamboo SPL genes during development showed differences in their spatiotemporal expression patterns, and many were expressed at high levels in flowers and leaves. CONCLUSIONS: The PeSPL genes play important roles in plant growth and development, including responses to stresses, and most of the genes are expressed in different tissues. Our study provides a comprehensive understanding of the PeSPL gene family and may enable future studies on the function and evolution of SPL genes in moso bamboo. PMID- 28655297 TI - Reduced egfr, elevated urine protein and low level of personal protective equipment compliance among artisanal small scale gold miners at Bibiani-Ghana: a cross-sectional study. AB - BACKGROUND: Mercury is a toxic metal with its effects on human health ranging from acute to chronic in a very short time of exposure. Artisanal and small-scale gold mining (ASGM) is the main source of direct human exposure to mercury. AIM: To access the effect of mercury exposure on the renal function and level of personal protective equipment (PPE) compliance among small-scale gold miners in Bibiani District of the Western Region of Ghana METHOD: 110 consenting male gold miners were purposively recruited for this study. A structured questionnaire was used to collect socio-demographic information from the participants. Work place assessment and interviews were conducted. Urine samples were analysed for protein; blood was analysed for mercury and creatinine. Estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. RESULTS: Of the 110 participants, 61(55.5%) exceeded the occupational exposure threshold (blood mercury <5MUg/L). Urine protein (41.72+/-68.34, P<0.0001), serum creatinine (2.24+/-1.19, P<0.0001) and blood mercury (18.37+/-10.47, P<0.0001) were significantly elevated among the exposed group compared to the non-exposed group. However, the exposed group had a significantly reduced eGFR (P<0.0001). There was a significant correlation (r=0.7338, p<0.0001) between blood mercury concentration and urine protein concentration. An increase in blood mercury correlated negatively (r = -0.8233, P<0.0001) with eGFR among the exposed group. High urine protein (P< 0.0001) and high serum creatinine (P< 0.0001) were significantly associated with increased mercury exposure. Increased mercury exposure was significantly associated with burning of amalgam (P=0.0196), sucking of excess mercury (P=0.0336), longer work duration (P=0.0314) and low educational background (P=0.0473). CONCLUSION: Small scale miners at the Bibiani work site are exposed to excess mercury. Proteinuria and reduced eGFR is common in mine workers exposed to excess mercury. We found poor PPE compliance among the study population. PMID- 28655298 TI - Assessment of Staphylococcus aureus along milk value chain and its public health importance in Sebeta, central Oromia, Ethiopia. AB - BACKGROUND: Staphylococcus aureus is one of the leading causes of gastroenteritis acquired from contaminated foods such as milk and milk products. However, such information is limited in Ethiopia. A cross-sectional study was conducted to assess the contamination of milk with S. aureus and knowledge, attitudes and practices (KAP) of actors along the milk value chain in Sebeta, Central Oromia, Ethiopia. A total of 291 samples collected from dairy farms, milk collection centers (MCCs) and processing plant were examined using standard microbiological techniques. The antimicrobial susceptibility profiles of the isolates were also investigated. The KAP of actors in milk value chain were evaluated through a structured questionnaire. RESULTS: Overall, 23.4% (n = 68) of the samples were positive for S. aureus. The prevalence of S. aureus was 19.6% (95% CI: 14.5-25.6) and 80.0% (95% CI: 14.5-25.6) at farm level and MCCs, respectively. Higher isolation rate was observed in the MCCs (p = 0.000) than the farms. The contamination rates of hands of milkers' and milking buckets with S. aureus were 32% and 11.1%, respectively. S. aureus was not isolated from pasteurized milk samples. The isolates were found to be resistant to cefoxitin (100%), penicillin G (98.5%), and streptomycin (77.9%). Among 23 interviewed farmers, 35% of them consumed raw milk, none of them wash their hands and 82.6% did not wash udder and teat before milking. Six percent of consumers had the habit of raw milk consumption. Eighty seven percent of dairy farmers and 54% of consumers had no awareness about milk borne diseases and staphylococcal food poisoning. CONCLUSIONS: The study revealed a high prevalence of S. aureus along the milk value chain, poor milk handling practices, raw milk consumption behavior, lack of awareness about milk borne diseases and occurrence of antimicrobials resistant S. aureus. S. aureus seems to pose a public health risk in Sebeta. Authors recommended the urgent need of public awareness creation about the importance of hygienic milk production and proper handling and adequate heat treatment of milk before consumption and further study to assess cost-effective preventive and control options. PMID- 28655299 TI - Implementing technology in healthcare: insights from physicians. AB - BACKGROUND: Technology has significantly changed the way health organizations operate. However, the role it plays in healthcare systems remains unclear. This aim of this study was to evaluate the opinion of physicians regarding e-health and determine what factors influence their opinion and describe the advantages, inconveniences and threats they may perceive by its use. METHODS: A cross sectional questionnaire-based study. A questionnaire which had been previously designed and validated by the authors was used to interview physicians from the Barcelona Medical Association. 930 physicians were contacted by phone to participate in the study. RESULTS: Seven hundred sixty physicians responded to the questionnaire (response rate: 82%). The usefulness of telemedicine scored 7.4 (SD 1.8) on a scale from 1-10 (from the lowest to the highest) and the importance of the Internet in the workplace was 8.2 points (SD 1.8). Therapeutic compliance (7.0 -SD 1.8-) and patient health (7.0 -SD 1.7-) showed the best scores, and there were differences between professionals who had and had not previously participated in a telemedicine project (p < 0.05). The multivariate regression model explained the 41% of the variance for 7 factors: participation in telemedicine project (p < 0.001), quality of clinical practice (p < 0.001), patient health (p < 0.001), professional workload (p = 0.005), ease-of-use of electronic device (p = 0.007), presence of incentives for telemedicine (p = 0.011) and patient preference for in-person visits (p = 0.05). CONCLUSIONS: Physicians believe in the usefulness of e-health. Professionals with previous experience with it are more open to its implementation and consider that the benefits of technology outweigh its possible difficulties and shortcomings. Physicians demanded projects with appropriate funding and technology, as well as specific training to improve their technological abilities. The relationship of users with technology differs according to their personal or professional life. Although a 2.0 philosophy has been incorporated into many aspects of our lives, healthcare systems still have a long way to go in order to adapt to this new understanding of the relationship between patients and their health. PMID- 28655300 TI - Dynamic high-sensitivity troponin elevations in atrial fibrillation patients might not be associated with significant coronary artery disease. AB - BACKGROUND: Since the introduction of high-sensitivity troponin assays a greater proportion of atrial fibrillation (AF) patients present with dynamic troponin elevations. We hypothesize that significant coronary artery disease (CAD) causes relative ischemia in the setting of a rapid heart rate resulting in dynamic troponin elevation. The aim of this study was to examine if patients without known CAD who present with AF, tachycardia and dynamic high-sensitivity troponin T (hsTnT) change have an increased risk of cardiac events. METHODS: We retrospectively included AF patients presenting with tachycardia during one year. The primary endpoint was acute coronary syndrome, revascularization or death due to ischemic heart disease during 30 months follow-up. RESULTS: Five hundred twenty-two patients without known CAD were included, 300 (57%) had normal hsTnT and 49 (9.5%) had dynamic hsTnT elevation. During follow-up 12 (4%) patients with normal hsTnT reached the primary endpoint and a total of 14 (4.7%) patients died. In the group with dynamic hsTnT the results were 4 (8.2%) and 12 (25%) respectively. The age-adjusted hazard ratio (HR) for the primary endpoint in patients with dynamic hsTnT was 1.9 (95% CI: 0.6 to 6.2; p = 0.28) and for all cause mortality 3.8 (95% CI: 1.7 to 8.5; p = 0.001). CONCLUSIONS: Dynamic hsTnT elevation in connection with AF might not be associated with any major increased risk of coronary events, but indicates increased all-cause mortality. PMID- 28655301 TI - Recurrence of cystic echinococcosis in an endemic area: a retrospective study. AB - BACKGROUND: Cystic echinococcosis (CE) is a chronic, complex and neglected zoonotic disease. CE occurs worldwide. In humans, it may result in a wide spectrum of clinical manifestations, ranging from asymptomatic infection to fatal disease. Clinical management procedures have evolved over decades without adequate evaluation. Despite advances in surgical techniques and the use of chemotherapy, recurrence remains one of the major problems in the management of hydatid disease. The aim of this study was to determine the frequency of CE recurrence and the risk factors involved in recurrence. METHODS: A descriptive longitudinal-retrospective study was designed. We reviewed all patients diagnosed with CE according to ICD-9 (code 122-0 to 122-9) criteria admitted at Complejo Asistencial Universitario de Salamanca, Spain, between January 1998 and December 2015. RESULTS: Among the 217 patients studied, 25 (11.5%) had a hydatid recurrence after curative intention treatment. Median duration of recurrence's diagnosis was 12.35 years (SD: +/-9.31). The likelihood of recurrence was higher [OR = 2.7; 95% CI, 1.1-7.1; p < 0.05] when the cyst was located in organs other than liver and lung, 22.6% (7/31) vs 14.2% (31/217) in the cohort. We detected a chance of recurrence [OR = 2.3; 95% CI, 1.4-6.5; p > 0.05] that was two times higher in those patients treated with a combination of antihelminthic treatments and surgical intervention (20/141, 14.2%) than in patients treated with surgical intervention alone (5/76, 6.6%). CONCLUSIONS: Despite advances in diagnosis and therapeutic techniques in hydatid disease, recurrence remains one of the major problems in the management of hydatid disease. The current management and treatment of recurrences is still largely based on expert opinion and moderate-to poor quality of evidence. Consequently, large prospective and multicenter studies will be needed to provide definitive recommendations for its clinical management. PMID- 28655302 TI - A qualitative understanding of the effects of reusable sanitary pads and puberty education: implications for future research and practice. AB - BACKGROUND: The management of menstruation has come to the fore as a barrier to girls' education attainment in low income contexts. Interventions have been proposed and piloted, but the emerging nature of the field means limited evidence is available to understand their pathways of effect. METHODS: This study describes and compares schoolgirls' experiences of menstruation in rural Uganda at the conclusion of a controlled trial of puberty education and sanitary pad provision to elucidate pathways of effect in the interventions. Semi-structured interviews were undertaken with schoolgirls who participated in the Menstruation and the Cycle of Poverty trial concurrent with the final set of quantitative surveys. A framework approach and cross-case analysis were employed to describe and compare the experiences of 27 menstruating girls across the four intervention conditions; education (n = 8), reusable sanitary pads (n = 8), education with reusable sanitary pads (n = 6), and control (n = 5). RESULTS: Themes included: menstrual hygiene, soiling, irritation and infection, physical experience, knowledge of menstruation, psychological, social and cultural factors, and support from others. Those receiving reusable pads experienced improvements in comfort and reliability. This translated into reduced fears around garment soiling and related school absenteeism. Other menstrual hygiene challenges of washing, drying and privacy remained prominent. Puberty education improved girls' confidence to discuss menstruation and prompted additional support from teachers and peers. CONCLUSIONS: Findings have important implications for the development and evaluation of future interventions. Results suggest the provision of menstrual absorbents addresses one core barrier to menstrual health, but that interventions addressing broader needs such as privacy may improve effectiveness. Puberty education sessions should increase attention to body awareness and include strategies to address a wider range of practical menstrual challenges, including pain management. Interviews revealed possibilities for improving quantitative surveys in future research. TRIAL REGISTRATION: Pan-African Clinical Trials Registry PACTR201503001044408. PMID- 28655303 TI - Knowledge, attitudes, and values among physicians working with clinical genomics: a survey of medical oncologists. AB - BACKGROUND: It has been over a decade since the completion of the Human Genome Project (HGP), genomic sequencing technologies have yet to become parts of standard of care in Canada. This study investigates medical oncologists' (MOs) genomic literacy and their experiences based on their participation in a cancer genomics trial in British Columbia, Canada. METHODS: The authors conducted a survey of MOs from British Columbia, Canada (n = 31, 52.5% response rate), who are actively involved in a clinical genomics trial called Personalized Onco Genomics (POG). The authors also measured MOs' level of genomic knowledge and attitudes about clinical genomics in cancer medicine. RESULTS: The findings show a low to moderate level of genomic literacy among MOs. MOs located outside the Vancouver area (the major urban center) reported less knowledge about new genetics technologies compared to those located in the major metropolitan area (26.7 vs 73.3%, P < 0.07, Fisher exact test). Forty-two percent of all MOs thought medical training programs do not offer enough genomic training. The majority of the respondents thought genomics will have major impact on drug discovery (67.7%), and treatment selection (58%) in the next 5 years. They also thought the major challenges are cost (61.3%), patient genomic literacy (48.3%), and clinical utility of genomics (42%). CONCLUSIONS: The data suggest a high need to increase genomic literacy among MOs and other doctors in medical school training programs and beyond, especially to physicians in regional areas who may need more educational interventions. Initiatives like POG play a critical role in the education of MOs and the integration of big data clinical genomics into cancer care. PMID- 28655304 TI - Assessment of client satisfaction on emergency department services in Hawassa University Referral Hospital, Hawassa, Southern Ethiopia. AB - BACKGROUND: Satisfaction refers to a state of pleasure or contentment with an action, event or service, especially one that was previously desired. Regarding to client, satisfaction is the level of happiness that clients experience having used a service. It therefore reflects the gap between the expected service and the experience of the service, from the client's point of view. Information was unavailable regarding the level of satisfaction of patients towards emergency health care servicesat Hawassa University Referral Hospital thatserve a huge catchment area; and this study addressed this gap. METHOD: Cross-sectional study was conducted from March 13 to May 15/2014. Systematic sampling method was used to enroll study participants. The data was collected by trained data collectors using pre-structured questionnaire. RESULTS: A total 407 clients were enrolled under this study with respondent rate of 96.9%. Nearly two third of study participants were male, 270 (66.3%). 86.7% of study participants were satisfied by services provided in Emergency Out Patient Department (OPD). The percentage of study satisfaction with physical examination by Doctor, nursing, laboratory and pharmacy services were 95.6%, 89.9%, 84.7% and 67.6%, respectively. Only 31.9% were satisfied with availability of drugs in the pharmacy. Regarding to staff courtesy, 91.7% of study participants were satisfied by the manner shown by the staffs working in Emergency OPD. The vast majority of the participants (97%) were satisfied with the courtesy of Medical laboratory personnel and the least satisfaction (79.4%) was recorded for security guards. CONCLUSION: This study showed low level of patient satisfaction in pharmacy services specifically due to unavailability of drugs due to lack of sustained supply of drugs. PMID- 28655305 TI - Effect of pomegranate extracts on brain antioxidant markers and cholinesterase activity in high fat-high fructose diet induced obesity in rat model. AB - BACKGROUND: To investigate beneficial effects of Pomegranate seeds oil (PSO), leaves (PL), juice (PJ) and (PP) on brain cholinesterase activity, brain oxidative stress and lipid profile in high-fat-high fructose diet (HFD) induced obese rat. METHODS: In vitro and in vivo cholinesterase activity, brain oxidative status, body and brain weight and plasma lipid profile were measured in control rats, HFD-fed rats and HFD-fed rats treated by PSO, PL, PJ and PP. RESULTS: In vitro study showed that PSO, PL, PP, PJ inhibited cholinesterase activity in dose dependant manner. PL extract displayed the highest inhibitory activity by IC50 of 151.85 mg/ml. For in vivo study, HFD regime induced a significant increase of cholinesterase activity in brain by 17.4% as compared to normal rats. However, the administration of PSO, PL, PJ and PP to HDF-rats decreased cholinesterase activity in brain respectively by 15.48%, 6.4%, 20% and 18.7% as compared to untreated HFD-rats. Moreover, HFD regime caused significant increase in brain stress, brain and body weight, and lipid profile disorders in blood. Furthermore, PSO, PL, PJ and PP modulated lipid profile in blood and prevented accumulation of lipid in brain and body evidenced by the decrease of their weights as compared to untreated HFD-rats. In addition administration of these extract protected brain from stress oxidant, evidenced by the decrease of malondialdehyde (MDA) and Protein carbonylation (PC) levels and the increase in superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. CONCLUSION: These findings highlight the neuroprotective effects of pomegranate extracts and one of mechanisms is the inhibition of cholinesterase and the stimulation of antioxidant capacity. PMID- 28655306 TI - Multi-state models for the analysis of time-to-treatment modification among HIV patients under highly active antiretroviral therapy in Southwest Ethiopia. AB - BACKGROUND: Highly active antiretroviral therapy (HAART) has shown a dramatic change in controlling the burden of HIV/AIDS. However, the new challenge of HAART is to allow long-term sustainability. Toxicities, comorbidity, pregnancy, and treatment failure, among others, would result in frequent initial HAART regimen change. The aim of this study was to evaluate the durability of first line antiretroviral therapy and to assess the causes of initial highly active antiretroviral therapeutic regimen changes among patients on HAART. METHODS: A Hospital based retrospective study was conducted from January 2007 to August 2013 at Jimma University Hospital, Southwest Ethiopia. Data on the prescribed ARV along with start date, switching date, and reason for change was collected. The primary outcome was defined as the time-to-treatment change. We adopted a multi state survival modeling approach assuming each treatment regimen as state. We estimate the transition probability of patients to move from one regimen to another. RESULT: A total of 1284 ART naive patients were included in the study. Almost half of the patients (41.2%) changed their treatment during follow up for various reasons; 442 (34.4%) changed once and 86 (6.69%) changed more than once. Toxicity was the most common reason for treatment changes accounting for 48.94% of the changes, followed by comorbidity (New TB) 14.31%. The HAART combinations that were robust to treatment changes were tenofovir (TDF) + lamivudine (3TC)+ efavirenz (EFV), tenofovir + lamivudine (3TC) + nevirapine (NVP) and zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP) with 3.6%, 4.5% and 11% treatment changes, respectively. CONCLUSION: Moving away from drugs with poor safety profiles, such as stavudine(d4T), could reduce modification rates and this would improve regimen tolerability, while preserving future treatment options. PMID- 28655307 TI - Short-term efficacy of intravitreal Aflibercept injections for retinal angiomatous proliferation. AB - BACKGROUND: To evaluate the short-term efficacy of intravitreal injections of aflibercept (IVA) to treat retinal angiomatous proliferation (RAP) and identify factors related to functional outcomes. METHODS: This retrospective case series consisted of 19 eyes in 19 patients with RAP. All 19 eyes received 3 monthly consecutive IVA. The primary outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) after the last IVA. RESULTS: Of the 19 treated eyes, 8 (42%) were pre-treated with 1 dose of bevacizumab one month prior to the initiation of treatment with aflibercept. BCVA was significantly improved and CRT was significantly reduced after 3 consecutive IVAs (P = 0.014 and P = 0.0002, respectively). Stabilization or improvement in BCVA was observed in 17 eyes (90%) treated with IVA. Eyes with baseline fibrovascular pigment epithelial detachment (PED) showed no significant gain in BCVA, and fibrovascular PED was negatively correlated with final BCVA (Spearman's correlation coefficient = - 0.481, P = 0.037). The mean follow-up was 3.5 +/- 0.5 months. CONCLUSIONS: In this short-term study, three consecutive IVAs showed efficacy for improving vision and reducing retinal edema in RAP patients. Eyes with fibrovascular PED showed poorer responses, and the presence of fibrovascular PED at baseline was negatively correlated with visual outcomes. PMID- 28655308 TI - A systematic literature review of time to return to work and narcotic use after lumbar spinal fusion using minimal invasive and open surgery techniques. AB - BACKGROUND: Chronic low back pain is a common health problem for adult workers and causes an enormous economic burden. With the improvement of minimally invasive surgical techniques (MIS) in spinal fusion and the development of fusion devices, more lumbar operations are today being performed through a less invasive technique. When compared with open surgeries (OS), MIS has demonstrated better clinical outcomes including operation time, blood loss, complication rates and length of hospital stay. The aim of this review was to identify and summarize evidence on the time to return to work and the duration of post-operation narcotic use for patients who had lumbar spinal fusion operations using MIS and OS techniques. METHODS: A systematic literature review was performed including studies identified from PubMed, EMBASE, the Cochrane Collaboration, and the Centre for Review and Dissemination (CRD) (January 2004-April 2014) for publications reporting on time to return to work and post-operation narcotic use after MIS or OS lumbar spinal fusion surgeries. RESULTS: Out of a total of 36 included studies, 28 reported on the time to return to work and 17 on the narcotic useafter MIS or OS. Four studies described the time to return to work directly comparing MIS and OS. Three studies, from the US, directly compared the duration of narcotic use between MIS- transforaminal lumbar interbody fusion (TLIF) and OS-TLIF. In addition to the time to return to work, 23 studies reported on the rate of return to work and the employment rate before and after surgery, and two Swedish studies presented sick leave data. CONCLUSION: There is a gap of good quality data describing the time to return to work and narcotic use after lumbar spinal fusion operations using MIS or OS techniques. However, the current systematic literature review indicates that patients who have lumbar spinal fusion operations, with the MIS procedure, generally return to work after surgery more quickly and require less post-operation narcotics for pain control compared to patients who have OS. PMID- 28655309 TI - The effectiveness of emergency nurse practitioner service in the management of patients presenting to rural hospitals with chest pain: a multisite prospective longitudinal nested cohort study. AB - BACKGROUND: Health reforms in service improvement have included the use of nurse practitioners. In rural emergency departments, nurse practitioners work to the full scope of their expanded role across all patient acuities including those presenting with undifferentiated chest pain. Currently, there is a paucity of evidence regarding the effectiveness of emergency nurse practitioner service in rural emergency departments. Inquiry into the safety and quality of the service, particularly regarding the management of complex conditions is a priority to ensure that this service improvement model meets health care needs of rural communities. METHODS: This study used a prospective, longitudinal nested cohort study of rural emergency departments in Queensland, Australia. Sixty-one consecutive adult patients with chest pain who presented between November 2014 and February 2016 were recruited into the study cohort. A nested cohort of 41 participants with suspected or confirmed acute coronary syndrome were identified. The primary outcome was adherence to guidelines and diagnostic accuracy of electrocardiograph interpretation for the nested cohort. Secondary outcomes included service indicators of waiting times, diagnostic accuracy as measured by unplanned representation rates, satisfaction with care, quality-of-life, and functional status. Data were examined and compared for differences for participants managed by emergency nurse practitioners and those managed in the standard model of care. RESULTS: The median waiting time was 8.0 min (IQR 20) and length-of-stay was 100.0 min (IQR 64). Participants were 2.4 times more likely to have an unplanned representation if managed by the standard service model. The majority of participants (91.5%) were highly satisfied with the care that they received, which was maintained at 30-day follow-up measurement. In the evaluation of quality of life and functional status, summary scores for the SF-12 were comparable with previous studies. No differences were demonstrated between service models. CONCLUSIONS: There was a high level of adherence to clinical guidelines for the emergency nurse practitioner service model and a concomitant high level of diagnostic accuracy. Nurse practitioner service demonstrated comparable effectiveness to that of the standard care model in the evaluation of the service indicators and patient reported outcomes. These findings provide a foundation for the beginning evaluation of rural emergency nurse practitioner service in the delivery of safe and effective beyond the setting of minor injury and illness presentations. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000823471 (Retrospectively registered). PMID- 28655310 TI - Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1beta. AB - BACKGROUND: The cause of neurodegeneration in progressive forms of multiple sclerosis is unknown. We investigated the impact of specific neuroinflammatory markers on human neurons to identify potential therapeutic targets for neuroprotection against chronic inflammation. METHODS: Surface immunocytochemistry directly visualized protease-activated receptor-1 (PAR1) and interleukin-1 (IL-1) receptors on neurons in human postmortem cortex in patients with and without neuroinflammatory lesions. Viability of cultured neurons was determined after exposure to cerebrospinal fluid from patients with progressive multiple sclerosis or purified granzyme B and IL-1beta. Inhibitors of PAR1 activation and of PAR1-associated second messenger signaling were used to elucidate a mechanism of neurotoxicity. RESULTS: Immunohistochemistry of human post-mortem brain tissue demonstrated cells expressing higher amounts of PAR1 near and within subcortical lesions in patients with multiple sclerosis compared to control tissue. Human cerebrospinal fluid samples containing granzyme B and IL 1beta were toxic to human neuronal cultures. Granzyme B was neurotoxic through activation of PAR1 and subsequently the phospholipase Cbeta-IP3 second messenger system. Inhibition of PAR1 or IP3 prevented granzyme B toxicity. IL-1beta enhanced granzyme B-mediated neurotoxicity by increasing PAR1 expression. CONCLUSIONS: Neurons within the inflamed central nervous system are imperiled because they express more PAR1 and are exposed to a neurotoxic combination of both granzyme B and IL-1beta. The effects of these inflammatory mediators may be a contributing factor in the progressive brain atrophy associated with neuroinflammatory diseases. Knowledge of how exposure to IL-1beta and granzyme B act synergistically to cause neuronal death yields potential novel neuroprotective treatments for neuroinflammatory diseases. PMID- 28655311 TI - Diagnostic delay for giant cell arteritis - a systematic review and meta analysis. AB - BACKGROUND: Giant cell arteritis (GCA), if untreated, can lead to blindness and stroke. The study's objectives were to (1) determine a new evidence-based benchmark of the extent of diagnostic delay for GCA and (2) examine the role of GCA-specific characteristics on diagnostic delay. METHODS: Medical literature databases were searched from inception to November 2015. Articles were included if reporting a time-period of diagnostic delay between onset of GCA symptoms and diagnosis. Two reviewers assessed the quality of the final articles and extracted data from these. Random-effects meta-analysis was used to pool the mean time period (95% confidence interval (CI)) between GCA symptom onset and diagnosis, and the delay observed for GCA-specific characteristics. Heterogeneity was assessed by I 2 and by 95% prediction interval (PI). RESULTS: Of 4128 articles initially identified, 16 provided data for meta-analysis. Mean diagnostic delay was 9.0 weeks (95% CI, 6.5 to 11.4) between symptom onset and GCA diagnosis (I 2 = 96.0%; P < 0.001; 95% PI, 0 to 19.2 weeks). Patients with a cranial presentation of GCA received a diagnosis after 7.7 (95% CI, 2.7 to 12.8) weeks (I 2 = 98.4%; P < 0.001; 95% PI, 0 to 27.6 weeks) and those with non-cranial GCA after 17.6 (95% CI, 9.7 to 25.5) weeks (I 2 = 96.6%; P < 0.001; 95% PI, 0 to 46.1 weeks). CONCLUSIONS: The mean delay from symptom onset to GCA diagnosis was 9 weeks, or longer when cranial symptoms were absent. Our research provides an evidence-based benchmark for diagnostic delay of GCA and supports the need for improved public awareness and fast-track diagnostic pathways. PMID- 28655312 TI - Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem. OBJECTIVE: To evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM. METHODS: Pancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCbeta), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD). RESULTS: Islet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCbeta became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined. CONCLUSIONS: DN may be reversed by transplantation of human fetal pancreatic progenitor cell derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy. PMID- 28655313 TI - Lipids characterization of ultrasound and microwave processed germinated sorghum. AB - BACKGROUND: Cereal crops and oilseeds provide diverse pool of fatty acids with characteristic properties. Sorghum (Sorghum bicolor (L.) Moench) provides the staple food with serving as main source of energy and protein. Germination of sorghum generally increases the nutritive value of seeds and the effects of germination on lipids composition of seeds vary greatly with processing conditions. Therefore, the current study was conducted to compare the effect of emerging processing techniques such as ultrasound (US) and microwave (MW) on fatty acids composition and oil yield of sorghum seeds before and after germination. METHODS: Initially sorghum grains were soaked with 5% NaOCl (sodium hypochlorite) for surface sterilization. Afterwards, grains were soaked in excess water for 22 h at room temperature and were divided into four portions. The first portion (100 g grains) was subjected to germination without applying any microwave and ultrasonic treatment (T0). Second portion was further divided into four groups (T1, T2, T3, T4) (100 g of each group) and grains were subjected to ultrasonic treatments using two different ultrasonic intensities (US1: 40%; US2: 60%) within range of 0-100% and with two different time durations (tUS1: 5 min; tUS2: 10 min) at constant temperature. Third portion was also divided into four groups (T1, T2, T3, T4) (100 g of each group) and exposed to microwave treatments at two different power levels (MW1: 450 watt; MW2: 700 watt) within the range of 100-900 W for two different time durations (tMW1: 15 s; tMW2: 30s). Similarly, fourth portion was divided into four groups (T1, T2, T3, T4) (100 g of each group). Each group was exposed to both MW (MW1, MW2) (100-900 watt power) & US (US1, US2) (0-100% intensity) treatments at two different time levels (tUS, tMW). Then, germination was carried out and pre-treated raw and pre-treated germinated sorghum grains were analyzed for total oil yield, fatty acid composition and unsaturated fatty acids (Un-SFA)/saturated fatty acids (SFA) ratio by gas chromatography. RESULTS: The results revealed that oil yield in sorghum before and after germination ranged from 6.55 to 7.84% and 6.28 to 7.57%, respectively. All the microwave and ultrasound processed samples showed significant difference in oil yield than the raw sorghum grains. The highest tested yield was 7.84 +/- 0.31% when combination of microwave power (700 W) and ultrasound intensity (60%) was applied for 30s and 10 min, respectively. The results further demonstrate that the raw sorghum contained palmitic (13.73 +/- 0.10%), palmitoleic (0.43 +/- 0.02%), stearic (1.07 +/- 0.04%), oleic (37.15 +/- 0.10%), linoleic (43.33 +/- 0.21%), linolenic (1.55 +/- 0.04%), arachidic acid (0.13 +/- 0.01%) and eicosenoic acid (0.37 +/- 0.02%), respectively. The highest fatty acid percentage for palmitic, stearic and arachidic acid was 13.75 +/- 0.07%, 1.11 +/- 0.09% and 0.15 +/- 0.03% at 60% US intensity for 10 min (T4), respectively. Maximum amount observed was 1.60 +/- 0.09% of linolenic acid while amount of eicosenoic acid decreased from 0.37 +/- 0.02% to 0.31 +/- 0.01% after processing. In case of applying combination of microwave and sonication treatments, the change in eicosenoic acid increased from 0.35 +/- 0.02% to 0.40 +/- 0.04% while there was no significant change in other fatty acids. The ungerminated sorghum oil possessed 14.93-15.05% and 82.83-83.12% of SFA and Un-SFA, respectively. After germination, percentage of saturated fatty acids increased (16.4-16.55%) while decreased for unsaturated fatty acids (80.13-80.56%) were noted. CONCLUSIONS: The results of the present study conclude that the yield of oil from sorghum grains increased by emerging processing. Fatty acid analysis of sorghum oil suggested that pre-treatment strategies will not affect the quality of the oil with respect to essential fatty acids content. Overall, the composition of saturated fatty acid in germinated grain is improved than ungerminated grains after processing. PMID- 28655314 TI - Greater involvement of HIV-infected peer-mothers in provision of reproductive health services as "family planning champions" increases referrals and uptake of family planning among HIV-infected mothers. AB - BACKGROUND: In 2012, Makerere University Johns - Hopkins University, and Mulago National Referral Hospital, with support from the National Institute of Health (under Grant number: NOT AI-01-023) undertook operational research at Mulago National Hospital PMTCT/PNC clinics. The study employed Peer Family Planning Champions to offer health education, counselling, and triage aimed at increasing the identification, referral and family planning (FP) uptake among HIV positive mothers attending the clinic. METHODS: The Peer Champion Intervention to improve FP uptake was introduced into Mulago Hospital PMTCT/PNC clinic, Kampala Uganda. During the intervention period, peers provided additional FP counselling and education; assisted in identification and referral of HIV Positive mothers in need of FP services; and accompanied referred mothers to FP clinics. We compiled and compared the average proportions of mothers in need that were referred and took up FP in the pre-intervention (3 months), intervention (6 months), and post intervention(3 months) periods using interrupted time series with segmented regression models with an autoregressive term of one. RESULTS: Overall, during the intervention, the proportion of referred mothers in need of FP increased by 30.4 percentage points (P < 0.001), from 52.7 to 83.2 percentage points. FP uptake among mothers in need increased by over 31 percentage points (P < 0.001) from 47.2 to 78.5 percentage points during the intervention. There was a positive non-significant change in the weekly trend of referral beta3 = 2.9 percentage points (P = 0.077) and uptake beta3 = 1.9 percentage points (P = 0.176) during the intervention as compared to the pre-intervention but this was reversed during the post intervention. Over 57% (2494) mothers took up Depo-Provera injectable-FP method during the study. CONCLUSIONS: To support overstrained health care work force in post-natal clinics, peers in trained effective family planning can be a valuable addition to clinic staff in limited-resource settings. The study provides additional evidence on the utilization of peer mothers in HIV care, improves health services uptake including family planning which is a common practice in many donor supported programs. It also provides evidence that may be used to advocate for policy revisions in low-income countries to include peers as support staff especially in busy clinic settings with poor services uptake. PMID- 28655315 TI - Comparison of apoptosis in human primary pulmonary endothelial cells and a brain microvascular endothelial cell line co-cultured with Plasmodium falciparum field isolates. AB - BACKGROUND: Plasmodium falciparum infection can progress unpredictably to severe forms including respiratory distress and cerebral malaria. The mechanisms underlying the variable natural course of malaria remain elusive. METHODS: The cerebral microvascular endothelial cells-D3 and lung endothelial cells both from human were cultured separately and challenged with P. falciparum field isolates taken directly from malaria patients or 3D7 strain (in vitro maintained culture). The capacity of these P. falciparum isolates to induce endothelial cell apoptosis via cytoadherence or not was then assessed. RESULTS: Overall, 27 P. falciparum isolates were collected from patients with uncomplicated malaria (n = 25) or severe malaria (n = 2). About half the isolates (n = 17) were able to bind brain endothelial cells (12 isolates, 44%) or lung endothelial cells (17 isolates, 63%) or both (12 isolates, 44%). Sixteen (59%) of the 27 isolates were apoptogenic for brain and/or lung endothelial cells. The apoptosis stimulus could be cytoadherence, direct cell-cell contact without cytoadherence, or diffusible soluble factors. While some of the apoptogenic isolates used two stimuli (direct contact with or without cytoadherence, plus soluble factors) to induce apoptosis, others used only one. Among the 16 apoptogenic isolates, eight specifically targeted brain endothelial cells, one lung endothelial cells, and seven both. CONCLUSION: These results indicate that the brain microvascular cell line was more susceptible to apoptosis triggered by P. falciparum than the primary pulmonary endothelial cells and may have relevance to host-parasite interaction. PMID- 28655316 TI - Reconstruction of fluorescence molecular tomography with a cosinoidal level set method. AB - BACKGROUND: Implicit shape-based reconstruction method in fluorescence molecular tomography (FMT) is capable of achieving higher image clarity than image-based reconstruction method. However, the implicit shape method suffers from a low convergence speed and performs unstably due to the utilization of gradient-based optimization methods. Moreover, the implicit shape method requires priori information about the number of targets. METHODS: A shape-based reconstruction scheme of FMT with a cosinoidal level set method is proposed in this paper. The Heaviside function in the classical implicit shape method is replaced with a cosine function, and then the reconstruction can be accomplished with the Levenberg-Marquardt method rather than gradient-based methods. As a result, the priori information about the number of targets is not required anymore and the choice of step length is avoided. RESULTS: Numerical simulations and phantom experiments were carried out to validate the proposed method. Results of the proposed method show higher contrast to noise ratios and Pearson correlations than the implicit shape method and image-based reconstruction method. Moreover, the number of iterations required in the proposed method is much less than the implicit shape method. CONCLUSIONS: The proposed method performs more stably, provides a faster convergence speed than the implicit shape method, and achieves higher image clarity than the image-based reconstruction method. PMID- 28655317 TI - Intraoperative and postoperative feasibility and safety of total tubeless, tubeless, small-bore tube, and standard percutaneous nephrolithotomy: a systematic review and network meta-analysis of 16 randomized controlled trials. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) is performed to treat relatively large renal stones. Recent publications indicate that tubeless and total tubeless (stentless) PCNL is safe in selected patients. We performed a systematic review and network meta-analysis to evaluate the feasibility and safety of different PCNL procedures, including total tubeless, tubeless with stent, small-bore tube, and large-bore tube PCNLs. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and EMBASETM databases were searched to identify randomized controlled trials published before December 30, 2013. One researcher examined all titles and abstracts found by the searches. Two investigators independently evaluated the full-text articles to determine whether those met the inclusion criteria. Qualities of included studies were rated with Cochrane's risk-of-bias assessment tool. RESULTS: Sixteen studies were included in the final syntheses including pairwise and network meta-analyses. Operation time, pain scores, and transfusion rates were not significantly different between PCNL procedures. Network meta-analyses demonstrated that for hemoglobin changes, total tubeless PCNL may be superior to standard PCNL (mean difference [MD] 0.65, 95% CI 0.14 1.13) and tubeless PCNLs with stent (MD -1.14, 95% CI -1.65--0.62), and small bore PCNL may be superior to tubeless PCNL with stent (MD 1.30, 95% CI 0.27 2.26). Network meta-analyses also showed that for length of hospital stay, total tubeless (MD 1.33, 95% CI 0.23-2.43) and tubeless PCNLs with stent (MD 0.99, 95% CI 0.19-1.79) may be superior to standard PCNL. In rank probability tests, small bore tube and total tubeless PCNLs were superior for operation time, pain scores, and hemoglobin changes. CONCLUSIONS: For hemoglobin changes, total tubeless and small-bore PCNLs may be superior to other methods. For hospital stay, total tubeless and tubeless PCNLs with stent may be superior to other procedures. PMID- 28655318 TI - Harnessing opportunities for good governance of health impacts of mining projects in Mongolia: results of a global partnership. AB - BACKGROUND: The Sustainable Development Goals call for the effective governance of shared natural resources in ways that support inclusive growth, safeguard the integrity of the natural and physical environment, and promote health and well being for all. For large-scale resource extraction projects -- e.g. in the mining sector -- environmental regulations and in particular environmental impact assessments (EIA) provide an important but insufficiently developed avenue to ensure that wider sustainable development issues, such as health, have been considered prior to the permitting of projects. METHODS: In recognition of the opportunity provided in EIA to influence the extent to which health issues would be addressed in the design and delivery of mining projects, an international and intersectoral partnership, with the support of WHO and public funds from Canadian sources, engaged over a period of six years in a series of capacity development activities and knowledge translation/dissemination events aimed at influencing policy change in the extractives sector so as to include consideration of human health impacts. RESULTS: Early efforts significantly increased awareness of the need to include health considerations in EIAs. Coupling effective knowledge translation about health in EIA with the development of networks that fostered good intersectoral partnerships, this awareness supported the development and implementation of key pieces of legislation. These results show that intersectoral collaboration is essential, and must be supported by an effective conceptual understanding about which methods and models of impact assessment, particularly for health, lend themselves to integration within EIA. CONCLUSIONS: The results of our partnership demonstrate that when specific conditions are met, integrating health into the EIA system represents a promising avenue to ensure that mining activities contribute to wider sustainable development goals and objectives. PMID- 28655319 TI - Chronic disease self-management education courses: utilization by low-income, middle-aged participants. AB - BACKGROUND: Individuals living in lower-income areas face an increased prevalence of chronic disease and, oftentimes, greater barriers to optimal self-management. Disparities in disease management are seen across the lifespan, but are particularly notable among middle-aged adults. Although evidence-based Chronic Disease Self-management Education courses are available to enhance self management among members of this at-risk population, little information is available to determine the extent to which these courses are reaching those at greatest risk. The purpose of this study is to compare the extent to which middle aged adults from lower- and higher-income areas have engaged in CDSME courses, and to identify the sociodemographic characteristics of lower-income, middle aged participants. METHODS: The results of this study were produced through analysis of secondary data collected during the Communities Putting Prevention to Work: Chronic Disease Self-Management Program initiative. During this initiative, data was collected from 100,000 CDSME participants across 45 states within the United States, the District of Columbia, and Puerto Rico. RESULTS: Of the entire sample included in this analysis (19,365 participants), 55 people lived in the most impoverished counties. While these 55 participants represented just 0.3% of the total study sample, researchers found this group completed courses more frequently than participants from less impoverished counties once enrolled. CONCLUSION: These results signal a need to enhance participation of middle-aged adults from lower-income areas in CDSME courses. The results also provide evidence that can be used to inform future program delivery choices, including decisions regarding recruitment materials, program leaders, and program delivery sites, to better engage this population. PMID- 28655320 TI - Functional Annotation of All Salmonid Genomes (FAASG): an international initiative supporting future salmonid research, conservation and aquaculture. AB - We describe an emerging initiative - the 'Functional Annotation of All Salmonid Genomes' (FAASG), which will leverage the extensive trait diversity that has evolved since a whole genome duplication event in the salmonid ancestor, to develop an integrative understanding of the functional genomic basis of phenotypic variation. The outcomes of FAASG will have diverse applications, ranging from improved understanding of genome evolution, to improving the efficiency and sustainability of aquaculture production, supporting the future of fundamental and applied research in an iconic fish lineage of major societal importance. PMID- 28655321 TI - Stratified analysis and clinical significance of elevated serum triglyceride levels in early acute pancreatitis: a retrospective study. AB - BACKGROUND: Hypertriglyceridemia is one of the three most common causes of AP, which is associated with the AP prognosis that has not been clearly defined. METHODS: In this retrospective study, 1539 AP patients, who had serum triglyceride (TG) levels measured within the first 72 h, were assessed. The study groups consisted of patients with normal, mild, moderate, and severe/very severe HTG levels based on the Endocrine Society Clinical Practice Guidelines. We collected baseline demographic information, laboratory values, complications, and clinical outcome data in different HTG severity groups to analyze the clinical significance of elevated TG levels in AP. RESULTS: Our study included 1539 AP patients; of these, 1078 (70%) had a normal TG levels, and 461 (30%) had elevated TG levels. The rates of severe AP increased in HTG groups of increasing severity (4% vs. 8% vs. 12%; P trend < 0.001). acute necrotic collection (ANC) and pancreatic necrosis developed in 32 and 39 of 112 patients (29% and 35%) (P trend = 0.001; P trend = 0.001) in the severe/very severe HTG group, respectively. The proportion of persistent organ failure (POF), multiple organ failure (MOF), and persistent Systemic Inflammatory Response Syndrome (SIRS) increased with higher grades of HTG (P trend < 0.001; P trend < 0.001; P trend < 0.001). The ICU admission rate was higher in the severe/very severe HTG group (57/112 patients; 51%; P trend < 0.001). A logistic multivariate regression analysis showed a positive correlation between HTG and certain AP complications. CONCLUSION: In addition to other factors, an elevated TG level could be associated with the severity and prognosis of AP, including pancreatic necrosis, POF, MOF, persistent SIRS, ICU admission, and mortality. PMID- 28655323 TI - Epidemiological and economic consequences of purchasing livestock infected with Mycobacterium avium subsp. paratuberculosis. AB - BACKGROUND: Paratuberculosis (PTB) is a chronic disease which may lead to reduced milk yield, lower animal welfare and death in cattle. The causative agent is Mycobacterium avium subsp. paratuberculosis (MAP). The economic consequences are particularly important incentives in the control and eradication of the infection. One strategy to control PTB in a herd is to purchase animals from farms with a low risk of MAP infection. We wanted to investigate the epidemiological and economic consequences of buying livestock from different supplier farms of low, medium or high risk, as well as farms with unknown status. We also wanted to estimate the probability of spontaneous fadeout if the farmer of an initially MAP-free herd bought a specified number of infected animals in a single year, or continually bought infected animals. This was achieved through simulation modeling, and the effects of consistently introducing one, five or ten infected animals annually into an initially infection-free herd was also modeled. RESULTS: Our findings show that once infected, a farm can relatively safely purchase animals from other low and medium-risk farms without experiencing an increase in the prevalence, highlighting the importance of certification programmes. Furthermore, farms free of MAP are highly susceptible and cannot purchase more than a small number of animals per year without having a high risk of being infected. The probability of spontaneous fadeout after 10 years was 82% when introducing a single infected animal into an initially MAP-free herd. When purchasing ten infected animals, this probability was 46%. The continual purchase of infected animals resulted in very low probabilities of spontaneous fadeout. CONCLUSIONS: We demonstrated that MAP-free farms can purchase a small number of animals, preferably from certified farms, each year and still remain free of MAP. Already infected farms have little risk of increasing the prevalence on a farm when purchasing animals from other farms. PMID- 28655322 TI - Interaction of primary mast cells with Borrelia burgdorferi (sensu stricto): role in transmission and dissemination in C57BL/6 mice. AB - BACKGROUND: Borrelia burgdorferi (sensu lato), the causative agent of Lyme borreliosis is a bacterium transmitted by hard ticks, Ixodes spp. Bacteria are injected into the host skin during the tick blood meal with tick saliva. There, Borrelia and saliva interact together with skin cells such as keratinocytes, fibroblasts, mast cells and other specific immune cells before disseminating to target organs. METHODS: To study the role of mast cells in the transmission of Lyme borreliosis, we isolated mouse primary mast cells from bone marrow and incubated them in the presence of Borrelia burgdorferi (sensu stricto) and tick salivary gland extract. We further analyzed their potential role in vivo, in a mouse model of deficient in mast cells (Kit wsh-/- mice). RESULTS: To our knowledge, we report here for the first time the bacteria ability to induce the inflammatory response of mouse primary mast cells. We show that OspC, a major surface lipoprotein involved in the early transmission of Borrelia, induces the degranulation of primary mast cells but has a limited effect on the overall inflammatory response of these cells. In contrast, whole bacteria have an opposite effect. We also show that mast cell activation is significantly inhibited by tick salivary gland extract. Finally, we demonstrate that mast cells are likely not the only host cells involved in the early transmission and dissemination of Borrelia since the use of mast cell deficient Kit wsh-/- mice shows a limited impact on these two processes in the context of this mouse genetic background. CONCLUSIONS: The absence of mast cells did not change the replication rate of Borrelia in the skin. However, in the absence of mast cells, Borrelia dissemination to the joints was faster. Mast cells do not control skin bacterial proliferation during primary infection and the establishment of the primary infection, as shown in the C57BL/6 mouse model studied. Nevertheless, the Borrelia induced cytotokine modulation on mast cells might be involved in long term and/or repeated infections and protect from Lyme borreliosis due to the development of a hypersensitivity to tick saliva. PMID- 28655324 TI - The topical application of low-temperature argon plasma enhances the anti inflammatory effect of Jaun-ointment on DNCB-induced NC/Nga mice. AB - BACKGROUND: Jaun-ointment (JO), also known as Shiunko in Japan, is one of the most popular medicinal formulae used in Korean traditional medicine for the external treatment of skin wound and inflammatory skin conditions. Since JO is composed of crude mixture of two herbal extracts (radix of Lithospermum erythrorhizon Siebold & Zucc and Angelica gigas Nakai), those been proved its anti-inflammatory activities in-vitro and in-vivo, JO has been expected as a good alternative treatment option for atopic dermatitis (AD). However, due to the lack of strategies for the penetrating methods of JO's various anti-inflammatory elements into the skin, an effective and safe transdermal drug delivery system needs to be determined. Here, low-temperature argon plasma (LTAP) was adopted as an ancillary partner of topically applied JO in a mice model of AD and the effectiveness was examined. METHODS: Dorsal skins of NC/Nga mice were challenged with DNCB (2,4-dinitrochlorobenzene) to induce AD. AD-like skin lesions were treated with JO alone, or in combination with LTAP. Inflammatory activity in the skin tissues was evaluated by histological analysis and several molecular biological tests. RESULTS: LTAP enhanced the effect of JO on AD-like skin lesion. Topical application of JO partially inhibited the development of DNCB-induced AD, shown by the moderate reduction of eosinophil homing and pro-inflammatory cytokine level. Combined treatment of JO and LTAP dramatically inhibited AD phenotypes. Interestingly, treatment with JO alone did not affect the activity of nuclear factor (NF)kappaB/RelA in the skin, but combined treatment of LTAP-JO blocked DCNB-mediated NFkappaB/RelA activation. CONCLUSIONS: LTAP markedly enhanced the anti-inflammatory activity of JO on AD-like skin lesions. The effect of LTAP may be attributed to enhancement of drug penetration and regulation of NFkappaB activity. Therefore, the combination treatment of JO and LTAP could be a potential strategy for the treatment of AD. PMID- 28655325 TI - Injury to infrapatellar branch of saphenous nerve in anterior cruciate ligament reconstruction using vertical skin incision for hamstring harvesting: risk factors and the influence of treatment outcome. AB - BACKGROUND: Injury to the infrapatellar branch of the saphenous nerve (IPBSN) is a high-frequency complication in anterior cruciate ligament (ACL) reconstruction. We analyzed the risk factor of IPBSN injury in ACL reconstruction. Moreover, we investigated the influence on treatment outcome by this complication. METHODS: One hundred twenty-three patients who underwent ACL reconstruction using semitendinosus tendon graft were studied. Gender, age, BMI, and additional use of gracilis tendon were recorded. Treatment outcome was assessed by Lysholm score, visual analog scale (VAS) pain score, anterior knee pain, knee range of motion (ROM), and the patient-based SF-36. Patients who developed sensory disturbance at 24 months after reconstruction were compared with those without sensory disturbance. RESULTS: Twenty-six of 123 patients (21.1%) developed postoperative sensory disturbance caused by IPBSN injury. Baseline parameters were not significantly different compared to those in the non-sensory disturbance group. In the sensory disturbance group, treatment outcome evaluated at 24 months post reconstruction showed Lysholm score of 94.1, VAS of 9.8 mm, anterior knee pain in 7.7%, and limitation of knee extension of 5 degrees in 7.7%. SF-36 scores in all subscales were above the mean national standard scores. Treatment outcome parameters were also not significantly different compared to those in the non sensory disturbance group, and none of the patients had serious impairment of knee function and activities of daily living. CONCLUSION: Injury to IPBSN in ACL reconstruction was not related to age, gender, and physique, and injury frequency did not increase. Evaluation of postoperative treatment outcome showed that IPBSN injury was not related to anterior knee pain or knee ROM limitation, and patients' subjective evaluation confirmed no serious impact on physical and mental health. PMID- 28655326 TI - Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials. AB - BACKGROUND: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs. METHODS: A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened. RESULTS: From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27-100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened. CONCLUSION: Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs. PMID- 28655329 TI - Erratum to: Analgesic use in a Norwegian general population: change over time and high-risk use - The Tromso Study. PMID- 28655327 TI - Advances in the delivery of RNA therapeutics: from concept to clinical reality. AB - The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic. PMID- 28655330 TI - NicE-seq: high resolution open chromatin profiling. AB - Open chromatin profiling integrates information across diverse regulatory elements to reveal the transcriptionally active genome. Tn5 transposase and DNase I sequencing-based methods prefer native or high cell numbers. Here, we describe NicE-seq (nicking enzyme assisted sequencing) for high-resolution open chromatin profiling on both native and formaldehyde-fixed cells. NicE-seq captures and reveals open chromatin sites (OCSs) and transcription factor occupancy at single nucleotide resolution, coincident with DNase hypersensitive and ATAC-seq sites at a low sequencing burden. OCSs correlate with RNA polymerase II occupancy and active chromatin marks, while displaying a contrasting pattern to CpG methylation. Decitabine-mediated hypomethylation of HCT116 displays higher numbers of OCSs. PMID- 28655328 TI - Epigenetic and chromatin-based mechanisms in environmental stress adaptation and stress memory in plants. AB - Plants frequently have to weather both biotic and abiotic stressors, and have evolved sophisticated adaptation and defense mechanisms. In recent years, chromatin modifications, nucleosome positioning, and DNA methylation have been recognized as important components in these adaptations. Given their potential epigenetic nature, such modifications may provide a mechanistic basis for a stress memory, enabling plants to respond more efficiently to recurring stress or even to prepare their offspring for potential future assaults. In this review, we discuss both the involvement of chromatin in stress responses and the current evidence on somatic, intergenerational, and transgenerational stress memory. PMID- 28655331 TI - BRIE: transcriptome-wide splicing quantification in single cells. AB - Single-cell RNA-seq (scRNA-seq) provides a comprehensive measurement of stochasticity in transcription, but the limitations of the technology have prevented its application to dissect variability in RNA processing events such as splicing. Here, we present BRIE (Bayesian regression for isoform estimation), a Bayesian hierarchical model that resolves these problems by learning an informative prior distribution from sequence features. We show that BRIE yields reproducible estimates of exon inclusion ratios in single cells and provides an effective tool for differential isoform quantification between scRNA-seq data sets. BRIE, therefore, expands the scope of scRNA-seq experiments to probe the stochasticity of RNA processing. PMID- 28655332 TI - Conditional knock-out of lipoic acid protein ligase 1 reveals redundancy pathway for lipoic acid metabolism in Plasmodium berghei malaria parasite. AB - BACKGROUND: Lipoic acid is a cofactor for alpha-keto acid dehydrogenase system that is involved in the central energy metabolism. In the apicomplexan parasite, Plasmodium, lipoic acid protein ligase 1 (LplA1) and LplA2 catalyse the ligation of acquired lipoic acid to the dehydrogenase complexes in the mitochondrion. The enzymes LipB and LipA mediate lipoic acid synthesis and ligation to the enzymes in the apicoplast. These enzymes in the lipoic acid metabolism machinery have been shown to play important roles in the biology of Plasmodium parasites, but the relationship between the enzymes is not fully elucidated. METHODS: We used an anhydrotetracycline (ATc)-inducible transcription system to generate transgenic P. berghei parasites in which the lplA1 gene was conditionally knocked out (LplA1 cKO). Phenotypic changes and the lplA1 and lplA2 gene expression profiles of cloned LplA1-cKO parasites were analysed. RESULTS: LplA1-cKO parasites showed severely impaired growth in vivo in the first 8 days of infection, and retarded blood-stage development in vitro, in the absence of ATc. However, these parasites resumed viability in the late stage of infection and mounted high levels of parasitemia leading to the death of the hosts. Although lplA1 mRNA expression was regulated tightly by ATc during the whole course of infection, lplA2 mRNA expression was significantly increased in the late stage of infection only in the LplA1-cKO parasites that were not exposed to ATc. CONCLUSIONS: The lplA2 gene can be activated as an alternative pathway to compensate for the loss of LplA1 activity and to maintain lipoic acid metabolism. PMID- 28655333 TI - Deworming of stray dogs and wild canines with praziquantel-laced baits delivered by an unmanned aerial vehicle in areas highly endemic for echinococcosis in China. AB - BACKGROUND: Canines, the definitive hosts for the parasites causing alveolar (AE) and cystic echinococcosis (CE), are the main source of this infections playing the key role in the transmission. The ten-year mortality rate of AE is extremely high (94%) if the patients are not given sustained treatment. The aim of this field study is to explore the possibility of delivery of praziquantel-laced baits using unmanned aerial vehicles (UAVs) aimed at deworming wild canines in the endemic areas. METHODS: UAVs were compared to manual bait delivery in the 1-km2 test areas followed by testing of canine faeces using an Echinococcus coproantigen ELISA test in the ensuing year. The outcomes of the two approaches were compared with respect to time of delivery and overall cost. FINDINGS: Compared to manual bait delivery, delivery by UAVs saved up to 67% of the overall cost. Three times more staff was needed for the former approach compared to the latter and, time wise, UAV bait delivery saved 350% compared to manual bait delivery on average. With regard to investment needed, the use of UAVs showed an efficiency 2.5 times better than manual bait delivery. Compared to the area served by UAVs, the average positive rate for the canine faecal samples was more than 38% higher in the area served manually. CONCLUSION: The technique of bait delivery with praziquantel using UAVs for canine deworming has a strong potential with regard to savings of manpower, time and overall cost in areas highly endemic for echinococcosis. PMID- 28655334 TI - Growth-dependent activity of the cold shock cspA promoter + 5' UTR and production of the protein CspA in Staphylococcus aureus Newman. AB - BACKGROUND: Research involving the cold shock gene cspA of the medically important bacterium Staphylococcus aureus is steadily increasing as the relationships between the activity of this gene at 37 degrees C and a spectrum of virulence factors (e.g., biofilm formation, capsule production) as well as stress-related genes (e.g., alkaline shock protein, asp-23 and the alternative sigma factor, sigB) are distinguished. Fundamental to each of these discoveries is defining the regulation of cspA and the production of its protein product CspA. RESULTS: In this paper, primer extension analysis was used to identify a transcriptional start point at 112 bp upstream of the initiation codon of the cspA coding sequence from S. aureus Newman RNA collected at 37 degrees C. Based on the location of the putative -10 and -35 sites as well as putative cold shock protein binding sites, a 192 bp sequence containing an 80 bp promoter + a 112 bp 5' UTR was generated by polymerase chain reaction. The activity of this 192 bp sequence was confirmed in a pLL38 promoter::xylE reporter gene construct. In addition, Western blots were used to confirm the production of CspA at 37 degrees C and demonstrated that production of the protein was not constitutive but showed growth-dependent production with a significant increase at the 6 h time point. CONCLUSIONS: The results presented identify another regulatory region for the cold shock gene cspA of S. aureus and show growth-dependent activity of both this cspA regulatory sequence, presented as a 192 bp sequence of promoter + 5' UTR and the production of the CspA protein at 37 degrees C. The presence of two active transcription start points, a -112 bp sequence defined in this work and a second previously defined at -514 bp upstream of the cspA initiation codon, suggests the possibility of interactions between these two regions in the regulation of cspA. The growth-dependent production of the cold shock protein CspA supports the availability of this protein to be a modulator of virulence and stress factor genes at 37 degrees C. PMID- 28655335 TI - Identification of G-quadruplex structures that possess transcriptional regulating functions in the Dele and Cdc6 CpG islands. AB - BACKGROUND: G-quadruplex is a DNA secondary structure that has been shown to play an important role in biological systems. In a previous study, we identified 1998 G-quadruplex-forming sequences using a mouse CpG islands DNA microarray with a fluorescent-labeled G-quadruplex ligand. Among these putative G-quadruplex forming sequences, G-quadruplex formation was verified for 10 randomly selected sequences by CD spectroscopy and DMS footprinting analysis. In this study, the biological function of the 10 G-quadruplex-forming sequences in the transcriptional regulation has been analyzed using a reporter assay. RESULTS: When G-quadruplex-forming sequences from the Dele and Cdc6 genes have been cloned in reporter vectors carrying a minimal promoter and the luciferase gene, luciferase expression is activated. This has also been detected in experiments applying a promoterless reporter vector. Mutational analysis reveals that guanine bases, which form the G-tetrads, are important in the activation. In addition, the activation has been found to decrease by the telomestatin derivative L1H1 7OTD which can bind to the G-quadruplex DNA. When Dele and Cdc6 CpG islands, containing the G-quadruplex-forming sequence, have been cloned in the promoterless reporter vector, the luciferase expression is activated. Mutational analysis reveals that the expression level is decreased by mutation on Dele G quadruplex; however, increased by mutation on Cdc6 G-quadruplex. CONCLUSION: Dele and Cdc6 G-quadruplex formation is significant in the transcriptional regulation. Dele and Cdc6 G-quadruplex DNA alone possess enhancer and promotor function. When studied in more complex CpG islands Dele G-quadruplex also demonstrates promotor activity, whereas Cdc6 G-quadruplex may possess a dual function of transcriptional regulation. PMID- 28655336 TI - A survey of current state of training of plastic surgery residents. AB - BACKGROUND: Plastic surgery training is undergoing major changes however there is paucity of data detailing the current state of training as perceived by plastic surgical trainees. Our aim was to determine the quality of training as perceived by the current trainee pool and their future plans. METHODS: A 25-item anonymous survey with three discrete sections (demographics, quality of training, and post graduate career plans) was developed and distributed to plastic surgery residents during the academic year 2013. With the confidence interval of 95% and margin of error of 10%, our target response rate was 87 responders. RESULTS: We received a total of 114 respondents with all levels of Post Graduate Year in training represented. Upon comparison of residents with debt of <100,000 to residents with a debt of >250,000, those with higher debt were significantly less interested in fellowship training (p value 0.05) and were more likely to pursue private practice (p value <0.01). Disciplines within plastic surgery least offered as a separate rotation were microsurgery (45%) followed by aesthetic surgery (33%). 53.7% of the residents felt that they were least trained in aesthetic surgery followed by burn surgery 45.4%. Of note 56.4% intended to seek additional training after residency. Moreover residents with an average of 6.4 months of experience in an individual subspecialty were more likely to feel comfortable with that specialty. CONCLUSIONS: This survey highlights the areas and subspecialties that deserve attention as perceived by the current trainee pool. PMID- 28655338 TI - Tapping the biotechnological potential of insect microbial symbionts: new insecticidal porphyrins. AB - BACKGROUND: The demand for sustainable agricultural practices and the limited progress toward newer and safer chemicals for use in pest control maintain the impetus for research and identification of new natural molecules. Natural molecules are preferable to synthetic organic molecules because they are biodegradable, have low toxicity, are often selective and can be applied at low concentrations. Microbes are one source of natural insecticides, and microbial insect symbionts have attracted attention as a source of new bioactive molecules because these microbes are exposed to various selection pressures in their association with insects. Analytical techniques must be used to isolate and characterize new compounds, and sensitive analytical tools such as mass spectrometry and high-resolution chromatography are required to identify the least-abundant molecules. RESULTS: We used classical fermentation techniques combined with tandem mass spectrometry to prospect for insecticidal substances produced by the ant symbiont Streptomyces caniferus. Crude extracts from this bacterium showed low biological activity (less than 10% mortality) against the larval stage of the fall armyworm Spodoptera frugiperda. Because of the complexity of the crude extract, we used fractionation-guided bioassays to investigate if the low toxicity was related to the relative abundance of the active molecule, leading to the isolation of porphyrins as active molecules. Porphyrins are a class of photoactive molecules with a broad range of bioactivity, including insecticidal. The active fraction, containing a mixture of porphyrins, induced up to 100% larval mortality (LD50 = 37.7 MUg.cm-2). Tandem mass-spectrometry analyses provided structural information for two new porphyrin structures. Data on the availability of porphyrins in 67 other crude extracts of ant ectosymbionts were also obtained with ion-monitoring experiments. CONCLUSIONS: Insect-associated bacterial symbionts are a rich source of bioactive compounds. Exploring microbial diversity through mass-spectrometry analyses is a useful approach for isolating and identifying new compounds. Our results showed high insecticidal activity of porphyrin compounds. Applications of different experiments in mass spectrometry allowed the characterization of two new porphyrins. PMID- 28655339 TI - India Allele Finder: a web-based annotation tool for identifying common alleles in next-generation sequencing data of Indian origin. AB - OBJECTIVE: We built India Allele Finder, an online searchable database and command line tool, that gives researchers access to variant frequencies of Indian Telugu individuals, using publicly available fastq data from the 1000 Genomes Project. Access to appropriate population-based genomic variant annotation can accelerate the interpretation of genomic sequencing data. In particular, exome analysis of individuals of Indian descent will identify population variants not reflected in European exomes, complicating genomic analysis for such individuals. RESULTS: India Allele Finder offers improved ease-of-use to investigators seeking to identify and annotate sequencing data from Indian populations. We describe the use of India Allele Finder to identify common population variants in a disease quartet whole exome dataset, reducing the number of candidate single nucleotide variants from 84 to 7. India Allele Finder is freely available to investigators to annotate genomic sequencing data from Indian populations. Use of India Allele Finder allows efficient identification of population variants in genomic sequencing data, and is an example of a population-specific annotation tool that simplifies analysis and encourages international collaboration in genomics research. PMID- 28655337 TI - Long-term cognitive outcome of Alzheimer's disease and dementia with Lewy bodies: dual disease is worse. AB - BACKGROUND: Longitudinal studies of dementia with Lewy bodies (DLB) are rare. Clinically, DLB is usually considered to worsen into Alzheimer's disease (AD). The aim of our study was to compare the rate of the cognitive decline in DLB, AD, and the association of the two diseases (AD + DLB). METHODS: Using the Regional Network for Diagnostic Aid and Management of Patients with Cognitive Impairment database, which includes all the patients seen at all memory clinics (medical consultation and day hospitals) in four French regions, and beta regression, we compared the longitudinal the Mini-Mental State Examination scores of 1159 patients with AD (n = 1000), DLB (n = 131) and AD + DLB (association of the two) (n = 28) during follow-up of at least 4 years. RESULTS: The mean follow-up of the patients was 5.88 years. Using beta regression without propensity scores, the comparison of the decline of patients with AD and patients with DLB did not show a significant difference, but the decline of patients with AD + DLB was worse than that of either patients with DLB (P = 0.006) or patients with AD (P < 0.001). Using beta regression weighted by a propensity score, comparison of patients with AD and patients with DLB showed a faster decline for patients with DLB (P < 0.001). The comparison of the decline of patients with AD + DLB with that of patients with DLB (P < 0.001) and patients with AD (P < 0.001) showed that the decline was clearly worse in the patients with dual disease. CONCLUSIONS: Whatever the analysis, the rate of decline is faster in patients with AD + DLB dual disease. The identification of such patients is important to enable clinicians to optimise treatment and care and to better inform and help patients and caregivers. PMID- 28655340 TI - HIV care-seeking behaviour after HIV self-testing among men who have sex with men in Beijing, China: a cross-sectional study. AB - BACKGROUND: Men who have sex with men (MSM) has become the group with the fastest growing HIV epidemic in China. Since many Chinese MSM are conducting HIV self testing, we aimed to determine the rate of HIV care seeking after self-testing, examine characteristics of "seekers" compared to "non-seekers," and explore factors associated with HIV care-seeking behaviour. METHODS: A cross-sectional study design was used and an online survey was conducted in Beijing, China in 2016, among users of a popular Chinese gay networking smart phone application. Chi-square test was used to compare characteristics of those who sought HIV care ("seekers") and those who did not ("non-seekers"). Univariate and multivariate logistic regression analyses were conducted to assess factors associated with HIV care seeking. RESULTS: Among 21,785 screened, 2383 participants (10.9%) were included in the study. A total of 380 participants (15.9%) reported seeking HIV care after HIV self-testing while 2003 (84.1%) did not. Lack of knowledge of the "window period" (adjusted odds ratio [AOR] = 0.68, 95% confidence interval [95% CI] = 0.47-0.97, P = 0.04) was associated with reduced odds of seeking HIV care, while lower monthly income (AOR = 1.29, 95% CI = 1.03-1.62, P = 0.03) and obtaining HIV self-testing kits from health facilities (AOR = 2.40, 95% CI = 1.81 3.17, P < 0.001), and non-governmental organizations (AOR = 2.44, 95% CI = 1.79 3.34, P < 0.001) was associated with increased odds of seeking HIV care. Among those who sought HIV care, a large majority (92.4%) had non-reactive HIV self testing results. Only 29 out of 265 with reactive, uncertain, or unknown results sought HIV care. CONCLUSIONS: We found a very low rate of HIV care seeking among our sample of urban Chinese MSM. The observation that most with reactive, uncertain, or unknown results did not seek HIV care is a cause for concern. These people should be paid more attention and helped to enter the care cascade. Our findings highlight that interventions aimed at improving linkage to care after HIV self-testing are urgently needed. However, further study is required to inform the design and implementation of future interventions aiming to encourage HIV care-seeking behaviour. PMID- 28655342 TI - The complete mitochondrial DNA of three monozoic tapeworms in the Caryophyllidea: a mitogenomic perspective on the phylogeny of eucestodes. AB - BACKGROUND: External segmentation and internal proglottization are important evolutionary characters of the Eucestoda. The monozoic caryophyllideans are considered the earliest diverging eucestodes based on partial mitochondrial genes and nuclear rDNA sequences, yet, there are currently no complete mitogenomes available. We have therefore sequenced the complete mitogenomes of three caryophyllideans, as well as the polyzoic Schyzocotyle acheilognathi, explored the phylogenetic relationships of eucestodes and compared the gene arrangements between unsegmented and segmented cestodes. RESULTS: The circular mitogenome of Atractolytocestus huronensis was 15,130 bp, the longest sequence of all the available cestodes, 14,620 bp for Khawia sinensis, 14,011 bp for Breviscolex orientalis and 14,046 bp for Schyzocotyle acheilognathi. The A-T content of the three caryophyllideans was found to be lower than any other published mitogenome. Highly repetitive regions were detected among the non-coding regions (NCRs) of the four cestode species. The evolutionary relationship determined between the five orders (Caryophyllidea, Diphyllobothriidea, Bothriocephalidea, Proteocephalidea and Cyclophyllidea) is consistent with that expected from morphology and the large fragments of mtDNA when reconstructed using all 36 genes. Examination of the 54 mitogenomes from these five orders, revealed a unique arrangement for each order except for the Cyclophyllidea which had two types that were identical to that of the Diphyllobothriidea and the Proteocephalidea. When comparing gene order between the unsegmented and segmented cestodes, the segmented cestodes were found to have the lower similarities due to a long distance transposition event. All rearrangement events between the four arrangement categories took place at the junction of rrnS-tRNA Arg (P1) where NCRs are common. CONCLUSIONS: Highly repetitive regions are detected among NCRs of the four cestode species. A long distance transposition event is inferred between the unsegmented and segmented cestodes. Gene arrangements of Taeniidae and the rest of the families in the Cyclophyllidea are found be identical to those of the sister order Proteocephalidea and the relatively basal order Diphyllobothriidea, respectively. PMID- 28655341 TI - Hi-C as a tool for precise detection and characterisation of chromosomal rearrangements and copy number variation in human tumours. AB - Chromosomal rearrangements occur constitutionally in the general population and somatically in the majority of cancers. Detection of balanced rearrangements, such as reciprocal translocations and inversions, is troublesome, which is particularly detrimental in oncology where rearrangements play diagnostic and prognostic roles. Here we describe the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumour samples, with the potential to define chromosome breakpoints to bp resolution. In addition, we show copy number profiles can also be obtained from the same data, all at a significantly lower cost than standard sequencing approaches. PMID- 28655344 TI - Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound. AB - BACKGROUND: The use of neurotrophic factors to treat Alzheimer's disease (AD) is hindered by their blood-brain barrier impermeability, short half-life, and severe side effects. Peptide 021 (P021) is a neurotrophic/neurogenic tetra-peptide that was derived from the most active region of the ciliary neurotrophic factor (CNTF) by epitope mapping. Admantylated glycine was added to its C-terminal to increase its blood-brain barrier permeability and decrease its degradation by exopeptidases to make it druggable. Here, we report on the preventive effect of P021 in 3 * Tg-AD, a transgenic mouse model of AD. METHODS: P021 was administered in the diet at 3 months, i.e., 6-9 months before any overt amyloid beta (Abeta) or tau pathology, and during the period of synaptic compensation, and was continued until 21 months in 3 * Tg-AD mice. The 3 * Tg-AD mice and wild-type (WT) mice were treated identically but with a vehicle-only diet serving as controls. The effects of P021 on neurogenesis, dendritic and synaptic markers, and cognitive performance were investigated. RESULTS: We found that P021 treatment was able to rescue dendritic and synaptic deficits, boost neurogenesis, and reverse cognitive impairment in 3 * Tg-AD mice. CONCLUSIONS: Availability of appropriate neurotrophic support during the period of synaptic compensation can prevent synaptic deficit and cognitive impairment, and P021 is a promising neurotrophic compound for this purpose. PMID- 28655345 TI - Methotrexate-induced Hypersensitivity Pneumonitis appearing after 30 years of use: a case report. AB - BACKGROUND: Methotrexate has been implicated in a variety of lung complications, one of which is hypersensitivity pneumonitis. Hypersensitivity pneumonitis most often occurs within the first year of starting low-dose orally administered methotrexate. We present a case of methotrexate-induced hypersensitivity pneumonitis after 30 years of methotrexate use, which is the first case to be reported so far. CASE PRESENTATION: A 77-year-old African American woman with a history of rheumatoid arthritis presented with progressively worsening shortness of breath and nonproductive cough. She was on a daily dose of 2.5 mg of methotrexate that had been orally administered for the last 30 years. A physical examination was significant for fever of 38.2 degrees C (100.8 degrees F), tachycardia, bilateral basal crackles, and oxygen saturation of 88% on room air. A laboratory work up was significant for normal white blood cell count, increased eosinophil count of 18.3%, and erythrocyte sedimentation rate of 111 mm/hour. Sputum cultures were negative for any bacterial pathogens including acid-fast bacilli. Influenza and respiratory syncytial viral infection were ruled out. A (1 3)-B-D-glucan assay (Fungitell(r)) was within normal limits. Pulmonary embolism was ruled out and echocardiography was normal. A chest X-ray showed hazy opacity with prominent reticulation within the upper lung fields bilaterally, right greater than the left with no pleural effusion. Lung computed tomography revealed nonspecific bilateral upper lung opacification. A pulmonary function test was significant for no obstruction, normal maximum voluntary ventilation, and no restriction, with mildly decreased diffusion. Methotrexate was stopped, and our patient was started on prednisone 60 mg orally administered daily with dramatic clinical and radiologic improvement. CONCLUSIONS: Methotrexate-induced hypersensitivity pneumonitis usually occurs in the initial few weeks to months of starting treatment with methotrexate; however, it can occur late during therapy too, and prompt diagnosis is crucial as it is a reversible condition when diagnosed early. PMID- 28655346 TI - Different dissecting orders of the pulmonary bronchus and vessels during right upper lobectomy are associated with surgical feasibility and postoperative recovery for lung cancer patients. AB - BACKGROUND: Right upper lobectomy (RUL) for lung cancer with different dissecting orders involves the most variable anatomical structures, but no studies have analyzed its effects on postoperative recovery. This study compared the conventional surgical approach, VAB (dissecting pulmonary vessels first, followed by the bronchus), and the alternative surgical approach, aBVA (dissecting the posterior ascending arterial branch first, followed by the bronchus and vessels) on improving surgical feasibility and postoperative recovery for lung cancer patients. METHODS: According to the surgical approach, consecutive lung cancer patients undergoing RUL were grouped into aBVA and VAB cohorts. Their clinical, pathologic, and perioperative characteristics were collected to compare perioperative outcomes. RESULTS: Three hundred one patients were selected (109 in the aBVA cohort and 192 in the VAB cohort). The mean operation time was shorter in the aBVA cohort than in the VAB cohort (164 vs. 221 min, P < 0.001), and less blood loss occurred in the aBVA cohort (92 vs. 141 mL, P < 0.001). The rate of conversion to thoracotomy was lower in the aBVA cohort than in the VAB cohort (0% vs. 11.5%, P < 0.001). The mean duration of postoperative chest drainage was shorter in the aBVA cohort than in the VAB cohort (3.6 vs. 4.5 days, P = 0.001). The rates of postoperative complications were comparable (P = 0.629). The median overall survival was not arrived in both cohorts (P > 0.05). The median disease free survival was comparable for all patients in the two cohorts (not arrived vs. 41.97 months) and for patients with disease recurrences (13.25 vs. 9.44 months) (both P > 0.05). The recurrence models in two cohorts were also comparable for patients with local recurrences (6.4% vs. 7.8%), distant metastases (10.1% vs. 8.3%), and both (1.8% vs. 1.6%) (all P > 0.05). CONCLUSIONS: Dissecting the right upper bronchus before turning over the lobe repeatedly and dissecting veins via the aBVA approach during RUL would promote surgical feasibility and achieve comparable postoperative recovery for lung cancer patients. PMID- 28655347 TI - Helicobacter pylori cagA and vacA genes in dyspeptic Ghanaian patients. AB - BACKGROUND: Helicobacter pylori infection is prevalent in Ghana. The development of gastro-duodenal disease is dependent on virulence of the infecting strain, host susceptibility and environmental factors. Helicobacter pylori cagA and vacA strains induce more inflammation, ulceration and oncogenesis. Here, for the first time we present data on H. pylori cagA and vacA genes and their association with gastro-duodenal disease in Ghana. A total of 159 patients with dyspepsia at Korle Bu Teaching Hospital, Accra, were investigated for H. pylori with urease-CLO, of which 113 (71.1%) were positive. Genomic DNA was extracted from antral biopsies using QIAGEN DNeasy kit. Detection of H. pylori vacA and cagA genes were determined by PCR as previously described. RESULTS: In total, 110 (69.2%) vacAs1, 71 (44.7%) vacAm1, 35 (22.0%) vacAm2, 77 (48.4%) cagA-(hydrophilic region) and 109 (68.6%) cagA-(internal duplication region) were detected. In multivariate analysis, duodenal ulcer was more likely than other diagnoses to have detectable cagA-(hydrophilic region) (OR 3.1 CI 1.2-7.9) or vacAs1m1 (OR 6.5 CI 1.2-34.0). CONCLUSIONS: Majority of biopsies were colonized with H. pylori harboring both cagA and vacA. H. pylori cagA-(internal duplication region) was more prevalent than cagA-(hydrophilic region). Duodenal ulcer was more likely than other diagnoses to have detectable cagA-(hydrophilic region) or vacAs1m1. PMID- 28655348 TI - The Carbon monoxide releasing molecule ALF-186 mediates anti-inflammatory and neuroprotective effects via the soluble guanylate cyclase beta1 in rats' retinal ganglion cells after ischemia and reperfusion injury. AB - BACKGROUND: The endogenously produced gaseous molecule carbon monoxide is able to promote organ protection after ischemia-reperfusion injuries (IRI). The impact of carbon monoxide releasing molecules (CORM) regarding inflammation in neuronal tissues has not been studied in detail. In this investigation, we aimed to analyze the effects of the CORM ALF-186 on neuro-inflammation and hypothesized that the soluble guanylate cyclase (sGC) is playing a decisive role. METHODS: Retinal ischemia-reperfusion injury was performed for 60 min in Sprague-Dawley rats. Thereafter, the CORM ALF-186 (10 mg/kg) in the presence or absence of the sGC inhibitor ODQ was injected via a tail vein. Retinal tissue was harvested 24 h later to analyze mRNA or protein expression of sGC-beta1 subunit, transcription factors NF-kappaB and CREB, the inflammatory cytokines TNF-alpha and IL-6, as well as the heat shock proteins (HSP) HSP-70 and HSP-90. Immunohistochemistry was performed on frozen sections of the retina. The overall neuroprotective effect of ALF-186 was assessed by counting fluorogold-pre-labeled retinal ganglion cells (RGC) 7 days after IRI. RESULTS: Ischemia-reperfusion mediated loss of vital RGC was attenuated by the administration of ALF-186 after injury. ALF-186 treatment after IRI induced sGC-beta1 leading to a decreased NF-kappaB and CREB phosphorylation. Consecutively, ALF-186 mitigated IRI induced TNF-alpha and IL-6 expression in the retina and in the rats' serum. Moreover, ALF-186 attenuated heat shock protein 70 (Hsp-70) while increasing Hsp-90. The sGC-inhibitor ODQ attenuated the anti-inflammatory effects of ALF-186 and increased retinal loss of ganglion cells. These results were confirmed by immunohistochemistry. CONCLUSION: The CORM ALF-186 protected RGC from IRI induced loss. Furthermore, ALF-186 reduced IRI mediated neuroinflammation in the retina and in the serum by activating sGC. Inhibition of sGC stopped the beneficial and protective effects of ALF-186. ALF-186 may present a promising therapeutic alternative in treating inflammation after neuronal IRI. PMID- 28655349 TI - Oligomeric tau-targeted immunotherapy in Tg4510 mice. AB - BACKGROUND: Finding ways to reverse or prevent the consequences of pathogenic tau in the brain is of considerable importance for treatment of Alzheimer's disease and other tauopathies. Immunotherapy against tau has shown promise in several mouse models. In particular, an antibody with selectivity for oligomeric forms of tau, tau oligomer monoclonal antibody (TOMA), has shown rescue of the behavioral phenotype in several murine models of tau deposition. METHODS: In this study, we examined the capacity of TOMA to rescue the behavioral, histological, and neurochemical consequences of tau deposition in the aggressive Tg4510 model. We treated mice biweekly with 60 MUg TOMA i.p. from 3.5 to 8 months of age. RESULTS: Near the end of the treatment, we found that oligomeric tau was elevated in both the CSF and in plasma. Further, we could detect mouse IgG in Tg4510 mouse brain after TOMA treatment, but not after injection with mouse IgG1 as control. However, we did not find significant reductions in behavioral deficits or tau deposits by either histological or biochemical measurements. CONCLUSIONS: These data suggest that there is some exposure of the Tg4510 mouse brain to TOMA, but it was inadequate to affect the phenotype in these mice at the doses used. These data are consistent with other observations that the rapidly depositing Tg4510 mouse is a challenging model in which to demonstrate efficacy of tau-lowering treatments compared to some other preclinical models of tau deposition/overexpression. PMID- 28655350 TI - Serum biochemical parameters and cytokine profiles associated with natural African trypanosome infections in cattle. AB - BACKGROUND: Animal African trypanosomiasis (AAT) greatly affects livestock production in sub-Saharan Africa. In Ghana prevalence of AAT is estimated to range between 5 and 50%. Studies have reported serum biochemical aberrations and variability in cytokine profiles in animals during infection. However, information regarding the biochemical parameters and cytokine profiles associated with natural infections are limited. This study was therefore aimed at investigating changes in the levels of serum biochemical parameters and inflammatory cytokines during a natural infection. METHODS: Nested internal transcribed spacer (ITS)-based PCR and sequencing were used to characterise trypanosome infection in cattle at two areas in Ghana (Adidome and Accra) of different endemicities. The cattle were sampled at four to five-week intervals over a period of six months. Levels of serum biochemical parameters, including creatinine, cholesterol, alkaline phosphatase (ALP), alanine aminotransferase (ALT), total bilirubin and total protein and cytokines (interleukin 10, interleukin 4, interleukin 12, interferon gamma and tumor necrosis factor alpha) were measured in serum samples and then compared between infected cattle and uninfected controls. RESULTS: The predominant trypanosome species detected in Accra (non-endemic) and Adidome (endemic) were Trypanosoma theileri and Trypanosoma vivax, respectively. Serum biochemical parameters were similar between infected and uninfected cattle in Accra. Infected cattle at Adidome however, had significantly higher levels of ALP, creatinine, total protein and total bilirubin (P < 0.05) and significantly lower levels of cholesterol (P < 0.05) at specific time points. At basal levels and during infection, significantly higher pro-inflammatory to anti-inflammatory (Th1/Th2) cytokine ratios were observed in cattle at Adidome compared to Accra (P < 0.05), indicating a shift towards Th1 immune response in Adidome. Levels of IL-10 were, however, significantly elevated in infected cattle in Accra (P < 0.05), suggesting high anti-inflammatory cytokine response in Accra. CONCLUSION: These results suggests that cattle in an endemic area repeatedly infected with trypanosomes of different species or different antigenic types demonstrate high pro-inflammatory (Th1) immune response and biochemical alterations whereas cattle in a non-endemic area with predominantly chronic T. theileri infections demonstrate high anti-inflammatory response and no biochemical alterations. PMID- 28655351 TI - Digitally translated Self-Administered Gerocognitive Examination (eSAGE): relationship with its validated paper version, neuropsychological evaluations, and clinical assessments. AB - BACKGROUND: The original paper Self-Administered Gerocognitive Examination (SAGE) is a valid and reliable cognitive assessment tool used to identify individuals with mild cognitive impairment (MCI) or early dementia. We evaluated identical test questions in a digital format (eSAGE) made for tablet use with the goals of calibrating it against SAGE and establishing its association with other neuropsychological tests and clinical assessments of cognitive impairment. METHODS: Subjects aged 50 and over who had taken SAGE were recruited from community and clinic settings. Subjects were randomly selected to participate in a clinical evaluation including neuropsychological evaluations. SAGE and eSAGE were administered using a crossover design. Subjects were identified as dementia, MCI, or normal based on standard clinical criteria. Associations were investigated using Spearman correlations, linear regression, and sensitivity and specificity measures. RESULTS: Of the 426 subjects screened, 66 completed the evaluation. eSAGE score correlation to a battery of neuropsychological tests was 0.73 (p < 0.0001) with no significant difference between the paper and digital format. Spearman correlation of SAGE versus eSAGE was 0.88 (p < 0.0001), and they are related by the formula: eSAGE score = -1.05 + 0.99 * SAGE score. Since the slope is very close to 1 (p = 0.86) there is strong evidence that the scaling is identical between eSAGE and SAGE, with no scale bias. Overall, eSAGE scores are lower by an average of 1.21 and the decrease is statistically significant (p < 0.0001). For those subjects familiar with smartphones or tablets (one measure of digital proficiency), eSAGE scores are lower by an average of 0.83 points (p = 0.029). With a score 16 and higher being classified as normal, eSAGE had 90% specificity and 71% sensitivity in detecting those with cognitive impairment from normal subjects. CONCLUSIONS: Tablet-based eSAGE shows a strong association with the validated paper SAGE and a neuropsychological battery. It shows no scale bias compared to SAGE. Both have the advantage of self-administration, brevity, four interchangeable forms, and high sensitivity and specificity in detecting cognitive impairment from normal subjects. Their potential widespread availability will be a major factor in overcoming the many obstacles in identifying early cognitive changes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02544074 . Registered on 18 March 2015. PMID- 28655352 TI - Evaluation of early antimicrobial therapy adaptation guided by the BetaLACTA(r) test: a case-control study. AB - BACKGROUND: Rapid diagnostic tests detecting microbial resistance are needed for limiting the duration of inappropriateness of empirical antimicrobial therapy (EAT) in intensive care unit patients, besides reducing the use of broad-spectrum antibiotics. We hypothesized that the betaLACTA(r) test (BLT) could lead to early increase in the adequacy of antimicrobial therapy. METHODS: This was a case control study. Sixty-one patients with BLT-guided adaptation of EAT were prospectively included, and then matched with 61 "controls" having similar infection characteristics (community or hospital-acquired, and source of infection), in whom EAT was conventionally adapted to antibiogram results. Endpoints were to compare the proportion of appropriate (primary endpoint) and optimal (secondary endpoint) antimicrobial therapies with each of the two strategies, once microbiological sample culture results were available. RESULTS: Characteristics of patients, infections and EAT at inclusion were similar between groups. Nine early escalations of EAT occurred in the BLT-guided adaptation group, reaching 98% appropriateness vs. 77% in the conventional adaptation group (p < 0.01). The BLT reduced the time until escalation of an inappropriate EAT from 50.5 (48-73) to 27 (24-28) hours (p < 0.01). Seventeen early de-escalations occurred in the BLT-guided adaptation group, compared to one in the conventional adaptation group, reducing patients' exposure to broad-spectrum beta-lactam such as carbapenems. In multivariate analysis, use of the BLT was strongly associated with early appropriate (OR = 18 (3.4-333.8), p = 0.006) and optimal (OR = 35.5 (9.6-231.9), p < 0.001) antimicrobial therapies. Safety parameters were similar between groups. CONCLUSIONS: Our study suggests that a BLT-guided adaptation strategy may allow early beta-lactam adaptation from the first 24 hours following the beginning of sepsis management. PMID- 28655353 TI - XC_0531 encodes a c-type cytochrome biogenesis protein and is required for pathogenesis in Xanthomonas campestris pv. campestris. AB - BACKGROUND: The phytopathogenic Xanthomonas campestris pv.campestris is a gram negative bacterium and the causal agent of black-rot disease of cruciferous crops. Many gram-negative bacteria possess a family of proteins, called Dsbs, which are involved in disulfide bond formation in certain periplasmic proteins. In our preliminary screening of the virulence to the plants we identified that gene XC_0531 which annotated gene dsbD of Xanthomonas campestris pv. campestris (Xcc) is related to the virulence to the host plants. RESULTS: Here, we found XC_0531 encoded a DsbD like protein. Its deletion is sensitive to DTT and copper, decreased accumulation of free thiols in periplasm. Its deletion also affected heme synthesis, position of Soret band and the production of peak c550. This suggests that XC_0531 is related to c-type cytochromes biogenesis. XC_0531 mutation decreased the utilization of different carbon sources (such as galactose, xylose, maltose, saccharose and glucose), reduced extracellular polysaccharide (EPS) production, decreased extracellular enzyme activities (protease, cellulose and amylase), slowed down growth rate of Xcc and weakened virulence to the plants. These results suggest that these phenotypes caused by XC_0531 mutation is possibly due to deficient biosynthesis of c-type cytochromes in respiration chain and the formation of disulfide bonds. Our work confirmed the function of XC_0531 and provide theory basis for scientists working on molecular mechanisms of cytochrome c biogenesis, pathogenesis of Xcc, development of EPS commercial values and protecting plant from black rot. CONCLUSION: We confirmed the function of gene XC_0531, which encodes a DsbD like protein, a protein correlated with c-type cytochrome biogenesis. This gene is related to the virulence to plants by affecting funtion of cytochromes c and probably disulfide bonds modification of proteins in type II secretion system (T2SS). PMID- 28655354 TI - Perioperative systemic steroid for rapid recovery in total knee and hip arthroplasty: a systematic review and meta-analysis of randomized trials. AB - BACKGROUND: Perioperative systemic steroid administration for rapid recovery in total knee and hip arthroplasty (TKA/THA) is an important and controversial topic. We conducted this systematic review and meta-analysis to evaluate the overall benefits and harms of perioperative systemic steroid in patients undergoing TKA and THA. METHODS: A comprehensive search was performed on PubMed, OVID, and Web of Science databases, and a systematic approach was carried out starting from the PRISMA recommendations. Relevant randomized controlled trials (RCTs) were selected. The risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions version. Data were extracted and meta-analyzed or qualitatively synthesized for all the outcomes. RESULTS: Data were extracted from 11 trials involving 774 procedures. Meta-analysis showed that high-dose systemic steroid (dexamethasone > 0.1 mg/kg) rather than low dose is effective to reduce postoperative nausea and vomiting and postoperative acute pain (within 24 h). In addition, systemic steroid is associated within faster functional rehabilitation and greater inflammation control. On the other hand, systemic steroid is associated with a higher level of postoperative serum glucose on the operation day. The complications between groups are similarly low. CONCLUSIONS: Our study suggests that by providing lower incidence of postoperative nausea and vomiting and less postoperative acute pain, high-dose systemic steroid plays a critical role in rapid recovery to TKA and THA. The preliminary results also show the superior possibility of systemic steroid in functional rehabilitation and inflammation control. More large, high-quality studies that investigate the safety and dose-response relationship are necessary. PMID- 28655355 TI - Genomic, proteomic and bioinformatic analysis of two temperate phages in Roseobacter clade bacteria isolated from the deep-sea water. AB - BACKGROUND: Marine phages are spectacularly diverse in nature. Dozens of roseophages infecting members of Roseobacter clade bacteria were isolated and characterized, exhibiting a very high degree of genetic diversity. In the present study, the induction of two temperate bacteriophages, namely, vB_ThpS-P1 and vB_PeaS-P1, was performed in Roseobacter clade bacteria isolated from the deep sea water, Thiobacimonas profunda JLT2016 and Pelagibaca abyssi JLT2014, respectively. Two novel phages in morphological, genomic and proteomic features were presented, and their phylogeny and evolutionary relationships were explored by bioinformatic analysis. RESULTS: Electron microscopy showed that the morphology of the two phages were similar to that of siphoviruses. Genome sequencing indicated that the two phages were similar in size, organization, and content, thereby suggesting that these shared a common ancestor. Despite the presence of Mu-like phage head genes, the phages are more closely related to Rhodobacter phage RC1 than Mu phages in terms of gene content and sequence similarity. Based on comparative genomic and phylogenetic analysis, we propose a Mu-like head phage group to allow for the inclusion of Mu-like phages and two newly phages. The sequences of the Mu-like head phage group were widespread, occurring in each investigated metagenomes. Furthermore, the horizontal exchange of genetic material within the Mu-like head phage group might have involved a gene that was associated with phage phenotypic characteristics. CONCLUSIONS: This study is the first report on the complete genome sequences of temperate phages that infect deep-sea roseobacters, belonging to the Mu-like head phage group. The Mu-like head phage group might represent a small but ubiquitous fraction of marine viral diversity. PMID- 28655356 TI - Ultrasonography helps emergency physician identify the best lumbar puncture site under the conus medullaris. AB - BACKGROUND: Ultrasonography - assisted lumbar puncture helps physicians identify traditional anatomical landmarks. However, it could help to overcome the anatomical dogmas and thus identify the best interspinous space under the medullary cone. METHODS: Traditional anatomical landmarks were reported on a tracing paper in patients with an indication for lumbar puncture. Then, ultrasonography was used to locate the optimal interspinous level defined as the widest subarachnoid space located below the conus medullaris. Primary endpoint was the distance between traditional and ultrasound landmarks. RESULTS: Fifty seven patients were included. Seven emergency physicians practiced the procedure. The median absolute distance between traditional anatomical landmarks and ultrasound marking was 32 [interquartile (IQR) 27 - 37] mm. The inter-spinous space identified in the two procedures was different in 68% of the cases. CONCLUSIONS: Ultrasound not only allows us to better identify anatomical structures before lumbar puncture, but it also allows us to choose a site of puncture different from recommendations. PMID- 28655357 TI - Drug-related problems and medication reviews among old people with dementia. AB - BACKGROUND: Drug-related problems, including medication errors and adverse drug events, are common among old people. Due to, for example, greater susceptibility to side effects, people with dementia are even more at risk of drug-related problems. The objectives of this study were to assess the occurrence and character of drug-related problems found among old people with dementia or cognitive impairment. METHODS: Data from a randomized controlled clinical trial exploring the effects of a pharmacist intervention as part of a hospital ward team in patients 65 years and older with dementia or cognitive impairment were used. The study was conducted between 2012 and 2014 in the orthopedic and medicine wards in two hospitals located in Northern Sweden. Drug-related problems identified in this patient group were classified and described, and associations with different factors were investigated. RESULTS: Clinical pharmacists identified at least one DRP in 66% (140/212) of participants in the intervention group, for a total of 310 DRPs. Ineffective drug/inappropriate drug and unnecessary drug therapy were the most common drug-related problems. Discontinuation of drug therapy was the most common action carried out. Drug related problems were more common among people prescribed a larger number of drugs and among people with an earlier stroke. CONCLUSIONS: Drug-related problems are common among people with dementia and cognitive impairment. Comprehensive medication reviews conducted by clinical pharmacists as part of a health care team might be important to prevent, identify and solve these problems. PMID- 28655359 TI - On the appropriate use and interpretation of dietary diversity scores. Response to: 'Farm production diversity and individual-level dietary diversity' by Koppmair and Qaim. PMID- 28655358 TI - The association between interleukin-28B gene polymorphisms as a potential biomarker and the risk of chronic Periodontitis in an Iranian population. AB - BACKGROUND: Chronic Periodontitis (CP) is a common inflammatory disease affects supporting tissues of the teeth and can lead to tooth loss. The objective of this study was to determine the relationship between polymorphisms in the IL-28B gene and chronic periodontitis in an Iranian population. METHODS: Two hundred and ten CP patients and one hundred healthy subjects were enrolled in the present case control study. The rs12979860 and rs8099917 SNPs were identified using RFLP and T ARMS-PCR methods respectively. RESULTS: SNP analysis revealed that the G allele of rs8099917 SNP and T allele of rs12979860 SNP increased susceptibility to CP compared to the A allele and C allele (p < 0.0001, OR = 2.712, CI = 1.783-4.126; p < 0.0001, OR = 2.538, CI = 1.784-3.613 respectively). In addition, the CT/GT, TT/GG and TT/GT haplotypes were predominant in CP patients and significantly associated with the increased risk of CP. CONCLUSION: IL-28B polymorphisms may be useful predictive factors for chronic periodontitis and correlated to the susceptibility to CP infection in our population. PMID- 28655360 TI - Tobacco smoking is associated with psychotic experiences in the general population of South London. AB - BACKGROUND: The association between cigarette smoking and psychosis remains unexplained, but could relate to causal effects in both directions, confounding by socioeconomic factors, such as ethnicity, or use of other substances, including cannabis. Few studies have evaluated the association between cigarettes and psychotic experiences (PEs) in diverse, inner-city populations, or relationships with number of cigarettes consumed. METHODS: We assessed associations and dose-response relationships between cigarette smoking and PEs in a cross-sectional survey of household residents (n = 1680) in South East London, using logistic regression to adjust for cannabis use, other illicit substances, and socioeconomic factors, including ethnicity. RESULTS: We found association between any PEs and daily cigarette smoking, which remained following adjustment for age, gender, ethnicity, cannabis and use of illicit stimulant drugs (fully adjusted odds ratio 1.47, 95% confidence interval 1.01-2.15). Fully adjusted estimates for the association, and with number of PEs, increased with number of cigarettes smoked daily, implying a dose-response effect (p = 0.001 and <0.001, respectively). Odds of reporting any PEs in ex-smokers were similar to never smokers. CONCLUSIONS: In this diverse epidemiological sample, association between smoking and PEs was not explained by confounders such as cannabis or illicit drugs. Daily cigarette consumption showed a dose-response relationship with the odds of reporting PEs, and of reporting a greater number of PEs. There was no difference in odds of reporting PEs between ex-smokers and never-smokers, raising the possibility that the increase in PEs associated with smoking may be reversible. PMID- 28655361 TI - Long hair. PMID- 28655362 TI - Measuring depressive symptoms during adolescence: what is the role of gender? AB - AIMS: The higher prevalence of depressive symptoms among females is well recognised but the reasons for this gender difference are not fully understood. There is growing evidence that current diagnostic criteria and instruments used to assess depression are less sensitive to depression in men, but studies about this issue among adolescents are scarce, especially in Latin countries. Our aim was to assess sex differences in the intensity of depressive symptoms, measured using the Beck Depression Inventory second edition (BDI-II), among Portuguese adolescents, at 13 and 17 years of age. METHODS: Urban adolescents born in 1990 and enrolled in schools of Porto, Portugal, in 2003-2004 (EPITeen study) completed the BDI-II at 13 and 17 years of age. The final sample included 1988 (52.2% girls) and 2131 (53.0% girls) adolescents at 13 and 17 years, respectively. Sex differences in the frequency of endorsing the statements on the 21 items of the BDI-II were examined using the chi2 test and effect sizes were estimated (Cohen's w). To examine whether responses were linked systematically to sex, we used a differential item functioning (DIF), based on the logistic regression approach. Option characteristic curves were estimated for items with differential endorsement and a new BDI-II score was computed excluding those items. RESULTS: Girls and boys at the same level of depression expressed similar severity ratings for most of the depressive symptoms. We had four items with DIF at 13 and 17 years of age. At 13 years, two items provided lower scores (sadness and crying items) and two higher scores (punishment feelings and loss of interest in sex items) among boys, comparing with equally depressed girls. At 17 years, the four items with DIF provided lower scores among boys (sadness, crying, self dislike and tiredness or fatigue items). After excluding these items the prevalence of depression remained higher among girls but at 17 years the difference between sexes was attenuated. CONCLUSIONS: Sex differences were found in the functioning of the BDI-II, more relevant at 17 years of age, which may lead to an overestimation of symptoms among girls as well as to lower reported rates of depression among boys. For a higher diagnostic accuracy it is important that the criteria and instruments used to assess depression adequately reflect female and male common symptoms and experiences of depression. PMID- 28655363 TI - A scoping research literature review to assess the state of existing evidence on the "bad" death. AB - OBJECTIVE: A scoping research literature review on "bad death" was undertaken to assess the overall state of the science on this topic and to determine what evidence exists on how often bad deaths occur, what contributes to or causes a bad death, and what the outcomes and consequences of bad deaths are. METHOD: A search for English-language research articles was conducted in late 2016, with 25 articles identified and all retained for examination, as is expected with scoping reviews. RESULTS: Only 3 of the 25 articles provided incidence information, specifying that 7.8 to 23% of deaths were bad and that bad deaths were more likely to occur in hospitals than in community-care settings. Many different factors were associated with bad deaths, with unrelieved pain being the most commonly identified. Half of the studies provided information on the possible consequences or outcomes of bad deaths, such as palliative care not being initiated, interpersonal and team conflict, and long-lasting negative community effects. SIGNIFICANCE OF RESULTS: This review identified a relatively small number of research articles that focused in whole or in part on bad deaths. Although the reasons why people consider a death to be bad may be highly individualized and yet also socioculturally based, unrelieved pain is a commonly held reason for bad deaths. Although bad and good deaths may have some opposing causative factors, this literature review revealed some salient bad death attributes, ones that could be avoided to prevent bad deaths from occurring. A routine assessment to allow planning so as to avoid bad deaths and enhance the probability of good deaths is suggested. PMID- 28655364 TI - Systematic review of the use of low-dose ketamine for analgesia in the emergency department. AB - OBJECTIVES: The aim of the study is to determine the performance of low-dose ketamine (LDK) as an analgesic for acute pain management in adult patients in the emergency department (ED). METHODS: We systematically reviewed electronic databases, grey literature, conference abstracts, and clinical trial registries. Two independent reviewers identified eligible studies. These selections were subsequently reviewed by one reviewer who identified the final eligible studies, using refined inclusion and exclusion criteria. Our outcome measures included the analgesic effect of LDK, need for rescue analgesia, and neuropsychological adverse events secondary to LDK use. We assessed inter-rater agreement using kappa statistics and proposed a treatment recommendation using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) software. Heterogeneity among studies precluded meta-analysis. RESULTS: Our electronic search identified 1,408 records; 44 were selected for full evaluation (kappa=0.70), and 8 were included after the final review. All six randomized controlled trials and two observational studies were set in the ED where LDK was administered to adult patients ( >18 years old) exclusively for pain management. All studies had an overall low risk of bias. There was extensive variation in the dose and route of LDK used (0.1-0.7 mg/kg SC/IV/IM), administration protocols, and use of adjunct analgesia. Overall, most studies reported a significant analgesic effect of LDK with occasional need for rescue analgesia and mild-to moderate adverse events (dizziness, dysphoria, and confusion). CONCLUSION: There are moderate to low quality data supporting LDK as an alternative analgesic in the ED with the potential for minimal requirement of rescue analgesia and self limited neuropsychological adverse events. PMID- 28655365 TI - GRADE EVIDENCE TO DECISION (EtD) FRAMEWORK FOR COVERAGE DECISIONS. AB - OBJECTIVES: Coverage decisions are decisions by third party payers about whether and how much to pay for technologies or services, and under what conditions. Given their complexity, a systematic and transparent approach is needed. The DECIDE (Developing and Evaluating Communication Strategies to Support Informed Decisions and Practice Based on Evidence) Project, a GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group initiative funded by the European Union, has developed GRADE Evidence to Decision (EtD) framework for different types of decisions, including coverage ones. METHODS: We used an iterative approach, including brainstorming to generate ideas, consultation with stakeholders, user testing, and pilot testing of the framework. RESULTS: The general structure of the EtD includes formulation of the question, an assessment using twelve criteria, and conclusions. Criteria that are relevant for coverage decisions are similar to those for clinical recommendations from a population perspective. Important differences between the two include the decision-making processes, accountability, and the nature of the judgments that need to be made for some criteria. Although cost-effectiveness is a key consideration when making coverage decisions, it may not be the determining factor. Strength of recommendation is not directly linked to the type of coverage decisions, but when there are important uncertainties, it may be possible to cover an intervention for a subgroup, in the context of research, with price negotiation, or with restrictions. CONCLUSIONS: The EtD provides a systematic and transparent approach for making coverage decisions. It helps ensure consideration of key criteria that determine whether a technology or service should be covered and that judgments are informed by the best available evidence. PMID- 28655366 TI - Cardiovascular fitness in late adolescent males and later risk of serious non affective mental disorders: a prospective, population-based study. AB - BACKGROUND: Cardiovascular fitness in late adolescence is associated with future risk of depression. Relationships with other mental disorders need elucidation. This study investigated whether fitness in late adolescence is associated with future risk of serious non-affective mental disorders. Further, we examined how having an affected brother might impact the relationship. METHOD: Prospective, population-based cohort study of 1 109 786 Swedish male conscripts with no history of mental illness, who underwent conscription examinations at age 18 between 1968 and 2005. Cardiovascular fitness was objectively measured at conscription using a bicycle ergometer test. During the follow-up (3-42 years), incident cases of serious non-affective mental disorders (schizophrenia and schizophrenia-like disorders, other psychotic disorders and neurotic, stress related and somatoform disorders) were identified through the Swedish National Hospital Discharge Register. Cox proportional hazards models were used to assess the influence of cardiovascular fitness at conscription and risk of serious non affective mental disorders later in life. RESULTS: Low fitness was associated with increased risk for schizophrenia and schizophrenia-like disorders [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.29-1.61], other psychotic disorders (HR 1.41, 95% CI 1.27-1.56), and neurotic or stress-related and somatoform disorders (HR 1.45, 95% CI 1.37-1.54). Relationships persisted in models that included illness in brothers. CONCLUSIONS: Lower fitness in late adolescent males is associated with increased risk of serious non-affective mental disorders in adulthood. PMID- 28655367 TI - EXPLORING PATENT ACTIVITY AND ITS POTENTIAL ASSOCIATION WITH HEALTHCARE OUTCOMES: A CASE STUDY OF OSTOMY PRODUCTS IN SWEDEN. AB - OBJECTIVES: The aim of this study was to evaluate whether ostomy industry patent activity (PA) is associated with patient outcomes and healthcare costs. METHODS: Two groups of ostomy pouch users based on manufacturer PA (low or high) were compared in terms of ostomy-related wear patterns, adverse events, and healthcare expenditure. Using Swedish registry data, all patients with newly formed stomas were divided between each group and were followed during a 2-year period (2011 12). Propensity score matching and parametric duration analysis were used to compare outcomes between patients of similar characteristics such as sex, age, and ostomy surgery type. RESULTS: In both one- and two-piece systems, the high PA group had significantly lower monthly ostomy-related expenditure than the low PA group (one-piece: 197.47 EUR versus 233.34 EUR; two-piece: 164.00 EUR versus 278.98 EUR). Fewer pouch and skin wafer purchases per month were an important driver of cost differences. Both groups had similar likelihood of purchasing dermatological products for skin complications over time. CONCLUSIONS: PA in the ostomy care industry was associated with reduced healthcare costs, but not necessarily with fewer skin complications. It suggests that there is a health economic benefit from products made by patent intensive companies which may differentiate them from generic comparators, but more research is needed to understand the impact of activities conducive to medical innovation on health outcomes. PMID- 28655368 TI - Host mating system and coevolutionary dynamics shape the evolution of parasite avoidance in Caenorhabditis elegans host populations. AB - Hosts exhibit a variety of defence mechanisms against parasites, including avoidance. Both host-parasite coevolutionary dynamics and the host mating system can alter the evolutionary trajectories of populations. Does the nature of host parasite interactions and the host mating system affect the mechanisms that evolve to confer host defence? In a previous experimental evolution study, mixed mating and obligately outcrossing Caenorhabditis elegans host populations adapted to either coevolving or static Serratia marcescens parasite populations. Here, we assessed parasite avoidance as a mechanism underlying host adaptation. We measured host feeding preference for the coevolved and static parasites vs preference for Escherichia coli, to assess the evolution of avoidance behaviour within our experiment. We found that mixed mating host populations evolved a preference for E. coli relative to the static parasite strain; therefore, the hosts evolved parasite avoidance as a defence. However, mixed mating hosts did not exhibit E. coli preference when exposed to coevolved parasites, so avoidance cannot account for host adaptation to coevolving parasites. Further, the obligately outcrossing host populations did not exhibit parasite avoidance in the presence of either static or coevolved parasites. Therefore, both the nature of host-parasite interactions and the host mating system shaped the evolution of host defence. PMID- 28655369 TI - Controlling the Use of Antibiotics: Are You Ready? PMID- 28655370 TI - Antibiotic Stewardship in Long-Term Care: A Call to Action. AB - The Centers for Medicare & Medicaid Services and the Centers for Disease Control and Prevention are focused heavily on curbing the misuse of antibiotics in health care facilities. Regulations governing the management of antibiotics in the nursing facility will likely be changing in the near future, which will put the pharmacist at the forefront of a clinical team that is dedicated to proper antibiotic utilization. Savvy pharmacists are embracing this opportunity to engage long-term care facility staff to improve the care of their residents. PMID- 28655371 TI - Implementing an Antimicrobial Stewardship Program. AB - The Centers for Medicare & Medicaid Services is expected to expand requirements for antimicrobial stewardship in nursing facilities during 2016. Many facilities are looking to pharmacists to help them take the initial steps toward developing these coordinated programs to promote the appropriate use of antimicrobials. PMID- 28655372 TI - Antibiotic Stewardship: New Frontier, Familiar Journey. AB - Recent changes in regulations by the Centers for Medicare & Medicaid Services require long-term care facilities to meet specific requirements on antibiotic stewardship, promoting the appropriate use of antibiotics and antimicrobials. The goal is to improve patient outcomes and decrease the spread of infections caused by multi-drug-resistant organisms. Consultant pharmacists can help facility personnel implement policies and procedures for effective antibiotic stewardship, assist prescribers and facility staff in understanding how to use the facility's antibiogram, find appropriate resources, and provide facility personnel with feedback on their antimicrobial stewardship efforts. PMID- 28655375 TI - Acute Pulmonary Embolism. PMID- 28655373 TI - The Pathogenesis, Assessment and Treatment of Speech Fluency Disorders. AB - BACKGROUND: Approximately 1% of children and adolescents, 0.2% of women, and 0.8% of men suffer from stuttering, and lesser numbers from cluttering. Persistent speech fluency disorders often cause lifelong problems in communication and social participation. METHODS: In an interdisciplinary, evidence and consensus based clinical practice guideline, the current understanding of the nature, identification, diagnosis, and treatment of stuttering and cluttering was summarized. A systematic review of the literature was carried out to assess the efficacy and effectiveness of treatments for stuttering. Evidence is lacking on the etiology, pathogenesis, evaluation, and treatment of cluttering. RESULTS: In view of the fact that common (developmental, idiopathic) stuttering is associated with structural and functional changes of the brain, the guideline recommends that it should be called "originary neurogenic non-syndromic stuttering." Heritability estimates for this disorder range from 70% to over 80%. For preschool children, the Lidcombe therapy has the best evidence of efficacy (Cohen's d = 0.72-1.00). There is also strong evidence for an indirect treatment approach. For children aged 6 to 12, there is no solid evidence for the efficacy of any treatment. For adolescents and adults, there is good evidence with high effect sizes (Cohen's d = 0.75-1.63) for speech restructuring methods such as fluency shaping; weak evidence with intermediate effect sizes for stuttering modification (Cohen's d = 0.56-0.65); and weak evidence for combined speech restructuring and stuttering modification. The evidence does not support the efficacy of pharmacotherapy, rhythmic speaking, or breathing regulation as the sole or main form of treatment, or that of hypnosis or eclectic, unspecified stuttering therapies. CONCLUSION: Stuttering is often treated in Germany with therapies for which there is inadequate evidence, and the initiation of treatment is often unnecessarily delayed. The guideline presents treatment methods whose efficacy is supported by the current evidence. PMID- 28655374 TI - Incidence, Treatment and Mortality in Patients with Abdominal Aortic Aneurysms. AB - BACKGROUND: Aim of this study was to analyze hospital incidence, type of treatment, and hospital mortality rates of patients with abdominal aortic aneurysm (AAA) in Germany from 2005 to 2014. METHODS: Microdata of the diagnosis related group (DRG) statistics compiled by the German Federal Statistical Office for the years 2005-2014 were analyzed. Patients who were hospitalized for a ruptured AAA (rAAA, ICD-10 code I71.3, treated either surgically or conservatively) or received surgical treatment for an unruptured AAA (nrAAA, ICD 10-Code I71.4, treated either with open surgery or an endovascular procedure) were included in the analysis. The "European Standard Population 2013" was used for direct standardization of the hospital incidences. In-hospital mortality was calculated with standardization for age and risk. RESULTS: The standardized overall hospital incidence of AAA was 27.9 and 3.3 cases per 100 000 people for men and women, respectively; over the period of the study, the incidence of rAAA fell by 30% in both sexes and that of nrAAA rose by 16% in men and 42% in women. The percentage of patients receiving endovascular treatment rose from 29% to 75% in patients with nrAAA and from 8% to 36% in patients with rAAA. The age- and risk-standardized in-hospital mortality of nrAAA was 3.3% in men and 5.3% in women. The in-hospital mortality of surgically treated rAAA was 39% in men and 48% in women. CONCLUSION: The hospital incidence of AAA rose from 2005 to 2014, while that of rAAA fell. Endovascular treatment became more common for nrAAA as well as rAAA, and in-hospital mortality fell for both. PMID- 28655376 TI - Treat Foot Ulcers Conservatively. PMID- 28655377 TI - Podological Treatment Has a Protective Effect. PMID- 28655378 TI - Interdisciplinary collaboration is important in peripheral arterial disease. PMID- 28655379 TI - In Reply. PMID- 28655380 TI - Clinical Neuropathology image 4-2017: High-resolution 7 Tesla MRI of postmortem brain specimens: improving neuroimaging-neuropathology correlations. PMID- 28655381 TI - Evaluation of factors associated with the achievement of an optimal teicoplanin trough concentration?. AB - OBJECTIVE: Because teicoplanin has a long serum half-life, a longer period of time is needed to achieve a steady-state concentration compared with vancomycin. The administration of an initial loading dose has been recommended to reach an effective teicoplanin serum concentration for the treatment of methicillin resistant Staphylococcus aureus (MRSA). However, little is known regarding factors that affect teicoplanin concentration. This study aimed to retrospectively determine which factors are associated with achieving an optimal teicoplanin trough level. METHODS: We analyzed patients with MRSA infections who were treated with teicoplanin intravenously between January 2010 and July 2014. The effect of loading dose administration was evaluated in patients treated with 1,200 mg or 1,600 mg of teicoplanin, respectively. RESULTS: Approximately 32% (31/97) of patients achieved the trough concentration target (>= 15 ug/mL) on the 3rd or 4th day. Multivariate analysis showed that loading doses and body surface area (BSA) were associated with trough concentration > 15 ug/mL on the 3rd or 4th day. Moreover, patients treated with the 2-day loading dose (1,600 mg group: 800 mg/day on 2 days) promptly achieved a trough concentration > 15 ug/mL on the 3rd or 4th day compared with those receiving a 1-day loading dose (1,200 mg group: 800 mg/day on only 1 day). The receiver operating characteristic curve showed that the optimal cut-off point of estimated glomerular filtration rate (eGFR) was 56 mL/min with 1-day loading dose to achieve a trough concentration target > 15 ug/mL. CONCLUSION: These results suggested that patients with decreased renal function (eGFR < 56 mL/min) can safely achieve an optimal trough level with the 1-day loading dose. In patients with normal renal function (eGFR >= 56 mL/min), administration of a 2-day loading dose may be needed to rapidly achieve a trough concentration >= 15 ug/mL.?. PMID- 28655382 TI - Novel clinical trial designs for targeted therapies?. PMID- 28655383 TI - Mixed isopropanol-methanol intoxication following ingestion of alcohol-based hand rub solution?. AB - Traditionally, ingestion of alcohol-based hand rub solution results in isopropanol poisoning, which has a low toxicity. We describe a case of combined methanol and isopropanol intoxication by ingestion of alcohol-based hand rub solution. Metabolic acidosis was absent in our patient, presumably because formic acid production is blocked by isopropanol, which inhibits alcohol dehydrogenase. Our case highlights the importance of considering methanol intoxication in patients who ingested alcohol-based hand rub solution, even when there is no metabolic acidosis, and timely removal of the toxic alcohols by dialysis in these patients would prevent permanent retinal damage.?. PMID- 28655385 TI - No impact of surviving sepsis campaign care bundles in reducing sepsis-associated acute kidney injury?. AB - BACKGROUND: The impact of Surviving Sepsis Campaign (SSC) care bundles in reducing sepsis-associated acute kidney injury (SA-AKI) was evaluated. METHODS: We conducted an observational single-center cohort study. Accomplishment of SSC care bundles was registered in all patients with severe sepsis admitted to the critical care department of a university hospital during three different periods. The main outcome measured was SA-AKI incidence defined as any worsening of AKI stage within the first 7 days from onset of sepsis. RESULTS: Among 260 patients with severe sepsis or septic shock finally meeting inclusion criteria, 82 (31.5%) patients developed SA-AKI. None of the SSC care tasks significantly decreased SA AKI incidence, although a trend was observed with an initial better blood glucose control as well as with a more protective ventilation strategy. Hypotension requiring fluid challenge (hazard ratio (HR), 2.3; 95% confidence interval (CI), 1.2 - 4.2) and the presence of an abdominal sepsis etiology (HR, 1.8; 95% CI, 1.1 - 3.1) were independently associated with SA-AKI. Patients who developed SA-AKI had a higher 90-day mortality rate (62.2 vs. 40.4%). CONCLUSION: In a cohort of septic patients, none of the SSC care tasks significantly decreased SA-AKI incidence within the first week after onset of sepsis.?. PMID- 28655384 TI - Altered basophil function in patients with chronic kidney disease on hemodialysis?. AB - AIMS: Chronic kidney disease (CKD) leads to impairment of immune cell function. Given the potential role of basophils in the pathogenesis of CKD, we aimed to study the basophil responsiveness towards microbial antigen exposure, judged as adhesion molecule expression and degranulation, in CKD patients on hemodialysis. MATERIALS AND METHODS: We selected markers linked to two crucial biological phases: the transmigration and degranulation processes, respectively. For the transmigration process, we selected the adhesion molecules CD11b, active CD11b epitope, and CD62L and for the degranulation process CD203c (piecemeal degranulation marker), CD63 (degranulation marker), and CD300a (inhibitory marker of degranulation). We measured basophil responsiveness after stimulation of different activation pathways in basophils using lipopolysaccharide (LPS), peptidoglycan (PGN), formyl-methyinoyl-leucyl-phenylalanine (fMLP), and anti FcepsilonRI-ab. RESULTS: The expression of CD63 in basophils following activation by fMLP was significantly higher in the patient group compared to matched healthy controls, but no differences were observed after activation by anti-FcEI. CD300a expression was significantly higher in patients following activation by fMLP and anti-FcEI, and the active epitope CD11b expression was significantly higher in patients after LPS activation. In addition, we found that CD62L was not shed from the cell surface after activation with LPS and fMLP. A slight downregulation was noted after activation with anti-FcEI in healthy controls. CONCLUSION: Together, these data demonstrate that basophil functions related to adhesion and degranulation are altered in CKD patients on hemodialysis, which indicates a potential role for the basophil in the pathogenesis of complications related to infections. PMID- 28655386 TI - Rhabdomyolysis and interferon-beta: case report and short review. AB - BACKGROUND: We present a case of acute rhabdomyolysis in the setting of interferon-beta treatment and concomitant pomelo juice ingestion, with concern of possible pharmacological interaction, which has not yet been described in the literature. CASE PRESENTATION: A young Caucasian female with multiple sclerosis on chronic therapy with interferon-beta presented with acute rhabdomyolysis after mild exercise and concomitant ingestion of pomelo extract. After stopping the suspected drugs, the signs of rhabdomyolysis diminished, the subsequent course was favorable. CONCLUSIONS: The most probable cause of rhabdomyolysis in our patient could have been the combination of interferon effect, which down regulates P450 expression, with inhibition of the P450 activity by furanocoumarin derivatives from pomelo juice. Therefore, patients treated with drugs that have a possible interaction with inhibitors of cytochrome P450 should be warned against pomelo ingestion.?. PMID- 28655387 TI - Hemodialysis treatment of cardiorenal syndrome. AB - AIMS: We evaluated the impact of hemodialysis on mortality and hospital readmission in patients with cardiorenal syndrome. METHODS: All patients were NYHA IV functional class and underwent laboratory testing, echocardiography, and cardiac functional testing. Hemodialysis was indicated in patients with progressive decline of kidney function and consequent failure to titrate heart failure medication as well as in patients with hypervolemia that was resistant to conservative treatment with more than 4 annual hospitalizations due to heart failure and/or concomitant chronic kidney disease stage III - IV. Patients were treated with low-efficacy bicarbonate hemodialysis with permanent central venous catheter used as vascular access. RESULTS: Since 2004, 67 patients were started on hemodialysis because of cardiorenal syndrome. Hospital readmission rate due to heart failure decreased (1 year before dialysis vs. 1 year after dialysis: 0.79 +/- 1.32 vs. 0.22 +/- 0.65 hospitalizations per year, p = 0.001) together with the duration of annual hospital stay (11.4 +/- 21.4 vs. 3.7 +/- 10.4 days, p = 0.011). 1-, 2-, 3-, 4- and 5-year survival for our patients was 81%, 61%, 52%, 47%, and 39%, respectively. CONCLUSIONS: Chronic renal replacement therapy with hemodialysis and strict uremic, electrolyte, and volume control may be more beneficial for patients with advanced heart failure with preserved or reduced LVEF than ultrafiltration alone. We have observed better survival of terminal cardiorenal patients treated with hemodialysis than in the general NYHA IV population, with lower hospital readmission rate and less hospitalized days for heart failure.?. PMID- 28655388 TI - Ultrasound-guided percutaneous endovascular treatment of arteriovenous fistula/graft. AB - BACKGROUND: Ultrasound-guided percutaneous endovascular treatment of arteriovenous fistula (AVF) or graft failure is an alternative to radiologically guided angioplastic methods. Its main advantages are that it can be used with open or percutaneous access, using no contrast media and no radiation. The aim of this study was to analyze the results of ultrasound-guided endovascular treatment of arteriovenous access failure. MATERIAL AND METHODS: Preoperative ultrasound was used to determine the degree of stenosis and the size of balloon used in angioplasty. Angioplasty was performed as open procedure or by using a 4 - 6 French percutaneous sheath. Indications for angioplasty were significant stenosis of native vein or polytetrafluoroethylene (PTFE) graft with or without AVF thrombosis. Stenosis was considered significant if it narrowed the lumen of AVF for more than 50% and changed the shape of the flow curve. Balloon inflation was controlled by ultrasound. Procedural success was assessed with repeated postprocedural ultrasound. RESULTS: In the period from August 2012 until August 2016, 228 ultrasound-guided open or percutaneous transluminal angioplasties (PTA) were performed (61% men, mean age 66.6 +/- 12.0 years), success rate was 93%. In 19 (8%) cases, ultrasound-guided PTA was used in conjunction with surgical reconstruction of arteriovenous fistula/graft and in 27 (12%) cases with thromboendarterectomy. Main complications were recoil, phlebitic vein rupture, and guidewire false route in thrombotic vessels. The main cause of access failure was perianastomotic stenosis (25%). 46% of patients required repeated PTA after the first one (after a mean time of 20.8 +/- 22.8 weeks, mean number of repeated PTA 2.1 +/- 1.7). Repeated PTA was done intentionally as stepped dilatation or because of rethrombosis/restenosis. Ultrasound-guided stent placement was done in 8% of PTA. CONCLUSIONS: Ultrasound-guided endovascular treatment of arteriovenous fistula or graft is a feasible and safe method of reestablishing or maintaining a functional vascular access.?. PMID- 28655389 TI - Role of dry lean body mass for estimation of glomerular filtration rate in kidney transplant recipients. AB - BACKGROUND: The use of equations that predict glomerular filtration rate (GFR) in patients with a kidney graft is still a matter of debate. The purpose of this study was to determine the level of accuracy of GFR equations and the relevance of dry lean body mass in the assessment of GFR. METHODS: In a prospective clinical study, 100 patients with a kidney graft were included. Estimated GFR with Modification of Diet in Renal Disease equation (MDRD), Chronic Kidney Disease Epidemiology Collaboration equation (CKD EPI) with serum creatinine concentration (CKD EPI Cr), serum cystatin C concentration (CKD EPI CysC) or both (CKD EPI Cr-CysC), and creatinine clearance calculated with Cockcroft-Gault equation (CG) was compared with GFR measured by 51Cr-EDTA clearance (mGFR 51Cr-EDTA). Dry lean body mass (body mass without fat mass and body water) was measured with bioimpedance analysis. RESULTS: All of the estimating equations overestimated mGFR 51Cr-EDTA by a significant degree (bias +/- SD in mL/min/1.73m2, 30% accuracy in brackets): CG 16.8 +/- 14.1 (44%), MDRD 12.5 +/- 15.3 (54%), CKD EPI Cr 15.1 +/- 15.3 (50%), CKD EPI CysC 8.0 +/- 16.6 (56%), CKD EPI Cr-CysC 10.3 +/- 13.4 (55%). Dry lean body mass significantly correlated with mGFR 51Cr-EDTA, but not with estimated GFRs. CONCLUSION: The estimating GFR equations are neither accurate nor precise in renal transplant recipients. Dry lean body mass is an important parameter that could potentially improve the GFR estimation in this population.?. PMID- 28655390 TI - Acute granulomatous interstitial nephritis and acute rejection in a kidney transplant recipient after zoledronic acid therapy - a case report and review of the literature. AB - BACKGROUND: Acute granulomatous interstitial nephritis (AGIN) in native kidneys is most commonly linked to drugs. In allografts, it is a rare complication, and it occurs mostly with infections. CASE PRESENTATION: Our case report presents AGIN with simultaneous acute cellular rejections and acute tubular necrosis in a kidney transplant patient 2 weeks after intravenous application of zoledronic acid. A kidney biopsy showed signs of destructive AGIN with acute cellular rejection. After treatment with methylprednisolone pulses and immunosuppressive therapy modification, rebiopsy confirmed complete regression of AGIN with less intense persistent acute cellular rejection and acute tubular necrosis. Kidney function improved after glucocorticoid and intravenous immunoglobulin G therapy. CONCLUSION: To our knowledge, this is the first case of AGIN related to bisphosphonate zoledronate in a kidney transplant patient with consequent acute cellular rejection. In using intravenous zoledronate infusion in a kidney transplant recipient, we should be aware that it could potentially induce acute granulomatous tubulointerstitial nephritis and acute rejection.?. PMID- 28655391 TI - Prevalence and risk factors for nonvertebral bone fractures in kidney transplant recipients - a single-center retrospective analysis. AB - BACKGROUND: Complex and longstanding bone disease superimposed by harmful influences of immunosuppression is the reason for increased risk of bone fracture in kidney transplant recipients. The aim of our study was to analyze the incidence and prevalence of nonvertebral bone fractures and early (in the first post-transplant year) clinical and laboratory risk factors for suffering bone fracture in the long-term post-transplant period. METHODS: Clinical and laboratory data as well as bone mineral density (BMD) measurements of 507 first kidney transplant recipients who were transplanted in the period from 1976 to 2011 were analyzed. RESULTS: The mean age of included patients was 54.3 +/- 12.0 years, there were 45% females, and mean time on renal replacement treatment prior to transplantation was 63.4 +/- 43.6 months. The average observation time post transplant was 9.7 years (1.4 - 36.3 years). Post-transplant, 64 (12.6%) patients suffered 89 nonvertebral fractures (44 patients suffered 1 fracture, 15 patients 2 fractures, and 5 patients 3 fractures). Patients with fractures had significantly lower late BMD of femoral neck in the period of 1 - 10 years post transplant, had osteopenia and osteoporosis more frequently in the same time period, and higher serum alkaline phosphatase in the first year post-transplant. 13 patients (13/64, 20.3%) had major fractures. Patients with major fractures were significantly older than patients with no major fractures and had lower serum albumin. Frequency of treatment with bisphosphonate, calcium, or phosphate did not differ between the groups. Vitamin D supplement (active form in 98% of cases) was prescribed more frequently in the group without fractures, but this was not statistically significant. CONCLUSION: Fracture rate in our transplant patient population was comparable to that reported in the literature. Except for a higher level of serum total alkaline phosphatase in the fracture group, we found no other early laboratory risk factors for bone fractures. BMD at the femoral region 1 - 10 years after kidney transplantation but not BMD at the time of transplantation was a risk factor for nonvertebral fractures. Osteopenia and osteoporosis in the post-transplant period were found to be a fracture risk factor.?. PMID- 28655392 TI - Outcome of polyomavirus nephropathy in renal transplant patients: a single-center experience. AB - BACKGROUND: Reduction of immunosuppression is a common therapeutic strategy in patients with polyomavirus nephropathy (PVN) but may be associated with acute rejection. This study aimed to evaluate the morphology of PVN in renal biopsies after reduction of immunosuppression. METHODS: Eight of 241 patients who received a kidney transplant between January 2012 and December 2015 presented with BK viremia and biopsy-proven PVN. Morphological evaluation according to Banff criteria and correlation with viremia and kidney function after immunosuppression reduction was performed. RESULTS: PVN grades A and B were diagnosed on average 4.7 months post-transplant in 1 and 7 patients, respectively. Indication biopsies after immunosuppression reduction showed an increase in tubulitis and interstitial inflammation score compared to those at the time of the PVN diagnosis. Surveillance biopsies 1 year after transplantation revealed resolution of interstitial inflammation and tubulitis accompanied by clearance of BK viremia in 4 patients (50%), including 1 patient with rejection. One patient showed residual interstitial inflammation after viral clearance. In these patients, renal function returned to baseline. One patient with persisting low BK virus (BKV) in serum and kidney showed a decrease of tubulointerstitial inflammation but scarring was seen. Rejection occurred in 3 patients (38%). CONCLUSION: PVN associated interstitial inflammation and tubulitis cannot be differentiated morphologically from T-cell-mediated tubulointerstitial rejection. Significant interstitial inflammation and tubulitis in PVN under low-dose immunosuppression might represent immune reconstitution injury, which is reduced after successful BKV clearance from the serum and kidney. Concomitant rejection in PVN patients on low immunosuppression might be efficiently treated with transient pulse immunosuppressive therapy.?. PMID- 28655393 TI - The role of single nucleotide polymorphisms of CYP3A and ABCB1 on tacrolimus predose concentration in kidney transplant recipients. AB - BACKGROUND: Tacrolimus has a narrow therapeutic drug window but high inter- and intrapatient variability. Our aim is to construct a model able to predict optimal maintenance tacrolimus predose concentration (C0) in kidney transplant patients. Here we present our study design and genotype and variant allele frequencies for the selected single nucleotide polymorphisms of genes involved in tacrolimus metabolism in our national cohort of kidney transplant recipients. METHODS: In the observational part of the study, we intend to determine allelic variants of CYP3A4, CYP3A5, and ABCB1 gene in a national cohort of 700 kidney transplants recipients. Clinical and laboratory data of this historic cohort will be added to assess patient's immunologic risk. Based on these data, a prediction model will be constructed that will be validated in a prospective randomized study in 60 de novo kidney transplant recipients. RESULTS: Our interim cross-sectional observational results show higher variability of ABCB1 genotypes when compared to CYP3A genes, with more than two thirds of the population carrying at least one polymorphic allele. On the other hand, less than 1% of our transplant recipients possess the CYP3A genotype, which requires high daily tacrolimus dose. CONCLUSIONS: Due to high inter- and intrapatient tacrolimus variability, a patient-tailored approach to define the optimal maintenance tacrolimus C0 for each individual patient is needed. Our model will rely on individual pharmacogenomic and clinical data to cover different patient-specific risk factors for adverse outcomes.?. PMID- 28655394 TI - Orientation of monoclonal antibodies in ion-exchange chromatography: A predictive quantitative structure-activity relationship modeling approach. AB - Chromatographic separation of biopharmaceuticals in general and monoclonal antibodies (mAbs) specifically is the bottleneck in terms of cost and throughput in preparative purification. Still, generalized platform processes are used, neglecting molecule specific characteristics, defining protein-resin interaction terms. Currently used in silico modeling approaches do not consider the orientation of the molecule towards the chromatographic resins as a result of the structural features on an atomic level. This paper describes a quantitative structure-activity relationship (QSAR) approach to model the orientation of mAbs on ion exchange chromatographic matrices as a function of property distribution and mobile phase characteristics. 6 mAbs were used to build a predictive QSAR model and to investigate the preferred binding orientations and resulting surface shielding on resins. Thereby different dominating orientations, caused by composition of Fab fragments of the mAbs, could be identified. The presented methodology is suitable to gain extended insight in molecule orientation on chromatographic resins and to tailor purification strategies based on molecule structure. PMID- 28655395 TI - Event-triggered Kalman-consensus filter for two-target tracking sensor networks. AB - This paper is concerned with the problem of event-triggered Kalman-consensus filter for two-target tracking sensor networks. According to the event-triggered protocol and the mean-square analysis, a suboptimal Kalman gain matrix is derived and a suboptimal event-triggered distributed filter is obtained. Based on the Kalman-consensus filter protocol, all sensors which only depend on its neighbors' information can track their corresponding targets. Furthermore, utilizing Lyapunov method and matrix theory, some sufficient conditions are presented for ensuring the stability of the system. Finally, a simulation example is presented to verify the effectiveness of the proposed event-triggered protocol. PMID- 28655396 TI - On the Use of Phototherapy in the Management of Photodermatoses. PMID- 28655397 TI - Patient survival and surgical re-intervention predictors for intracapsular hip fractures. AB - BACKGROUND: Choosing between total hip replacement (THR) and partial hip replacement (PHR) for patients with intracapsular hip fractures is often based on subjective factors. Predicting the survival of these patients and risk of surgical re-intervention is essential to select the most adequate implant. METHODS: We conducted a retrospective cohort study on mortality of patients over 70 years with intracapsular hip fractures who were treated between January 2010 and December 2013, with either PHR or THR. Patients' information was withdrawn from our local computerized database. The age-adjusted Charlson comorbidity index (ACCI) and American Society of Anesthesiologists (ASA) score were calculated for all patients. The patients were followed for 2 years after surgery. Survival and surgical re-intervention rates were compared between the two groups using a Multivariate Cox proportional hazard model. RESULTS: A total of 356 individuals were included in this study. At 2 years of follow-up, 221 (74.4%) of the patients with ACCI score<=7 were still alive, in contrast to only 20 (29.0%) of those with ACCI score>7. In addition, 201 (76.2%) of the patients with ASA score<=3 were still alive after 2 years, compared to 30 (32.6%) of individuals with ASA >3. Patients with the ACCI score>7, and ASA score>3 had a significant increase in all cause 2-year mortality (adjusted hazard ratio of 3.2, 95% CI 2.2-4.6; and 3.12, 95% CI 2.2-4.5, respectively). Patients with an ASA score>3 had a quasi significant increase in the re-intervention risk (adjusted hazard ratio 2.2, 95% CI 1.0-5.1). The sensitivity, specificity, positive predictive value and negative predictive values of ACCI in predicting 2-year mortality were 39.2%, 91.1%, 71%, and 74.4%, respectively. On the other hand, the sensitivity, specificity, positive predictive value and negative predictive values of ASA score in predicting 2-year mortality were 49.6%, 79.1%, 67.4%, and 76.1%, respectively. CONCLUSIONS: Both ACCI and ASA scales were able to predict the 2-year survival of patients with intracapsular hip fractures. The ASA scale was also able to predict the risk of re-intervention in these patients. PMID- 28655398 TI - A survey of pediatric surgeons' practices with enhanced recovery after children's surgery. AB - PURPOSE: Enhanced Recovery After Surgery (ERAS) protocols have been shown to improve outcomes in adult abdominal surgical populations. Our purpose was to survey pediatric surgeons' opinions regarding applicability of individual ERAS elements to children's surgery. METHODS: A survey of the American Pediatric Surgical Association was conducted electronically. Using a 5-point Likert scale, respondents rated their willingness to implement 21 adult ERAS elements in an adolescent undergoing elective colorectal surgery. RESULTS: Of an estimated 1052 members, 257 completed the survey (24%). The majority of the respondents (n=175, 68.4%) rated their familiarity with ERAS as "moderately", "very", or "extremely familiar". However only 19.2% (n=49) replied that they were "already implementing" an ERAS protocol in their practice. Most respondents replied that they were "already doing" or "definitely willing" to implement 14 of the 21 (67%) ERAS elements. For the remaining 7 elements, >10% of surgeons answered that they were only "somewhat willing" to, "uncertain" about or "unwilling" to implement these interventions. CONCLUSIONS: Most respondents were willing to implement the majority of adult ERAS concepts in children undergoing abdominal surgery. However, we identified 7 elements that remain contentious. Further investigation regarding the safety and feasibility of these elements is warranted before applying them to children's surgery. LEVEL OF EVIDENCE: Level V. PMID- 28655399 TI - Sonochemical synthesis of highly crystalline photocatalyst for industrial applications. AB - Highly photo active pure anatase form of TiO2 nanoparticles with average particle size 4nm have been successfully synthesized by ultrasonic acoustic method (UAM). The effects of process variables i.e. precursors concentration and sonication time were investigated based on central composite design and response surface methodology. The characteristics of the resulting nanoparticles (RNP) were analyzed by scanning electron microscopy, dynamic light scattering, transmission electron microscopy, X-ray diffractometry and Raman spectroscopy. Photocatalytic experiments were performed with methylene blue dye which is considered as model organic pollutant in textile industry. A comparative analysis between the RNP and commercially available Degussa P25 for photocatalytic performance against dye removal efficiency was performed. The rapid removal of methylene blue in case of RNP indicates their higher photocatalytic activity than P25. Maximum dye removal efficiency 98.45% was achieved with optimal conditions i.e. TTIP conc. 10mL, EG conc. 4mL and sonication time 1h. Interestingly, no significant difference was found in the photocatalytic performance of RNP after calcination. Moreover, self cleaning efficiency of RNP deposited on cotton was evaluated in RGB color space. The obtained results indicate the significant impact of ultrasonic irradiations on the photocatalytic performance of pure anatase form than any other hybrid type of TiO2 nanoparticles. PMID- 28655400 TI - Intraoperative sialendoscopy to assist with and confirm repair of Stensen's duct. PMID- 28655401 TI - Pseudomonas mendocina: the first case of peritonitis on peritoneal dialysis. PMID- 28655402 TI - Mucinous appendiceal neoplasms: Incidence, diagnosis and surgical treatment. AB - INTRODUCTION: Mucinous tumors of the appendix are a rare pathology, with a prevalence below 0.5%. Clinical presentation usually occurs during the sixth decade of life, and mucinous tumors can clinically mimic acute appendicitis. The aim of this study is to describe the clinical and demographic variables, therapeutic procedure and diagnosis of these tumors. We analyze the association between mucinous tumors and pseudomyxoma peritonei (PP), as well as the association with colorectal and ovarian tumors. METHODS: A retrospective study was performed including patients who underwent an appendectomy between December 2003 and December 2014. RESULTS: Seventy-two mucinous tumors of the appendix were identified among 7.717 patients reviewed, resulting in a prevalence of 0.9%. Mean age at presentation was 64 years, 62% patients were female and 38% males. An incidental diagnosis was made in 43% of patients. Mucinous tumors of low malignant potential were significantly related to the presence of pseudomyxoma peritonei, identified in 16 (22%) of the cases. We also observed an increased risk of ovarian mucinous tumors in patients with a diagnosis of appendiceal mucinous neoplasm. In our sample, 22 (30.5%) patients showed a synchronous or metachronous colorectal cancer. CONCLUSIONS: Appendiceal mucinous tumors are frequently an incidental finding. The diagnosis of mucinous tumors of low malignant potential is a factor associated with the development of pseudomyxoma peritonei. Histologic tumor grade and the presence of peritoneal dissemination will determine surgical treatment that can vary, from appendectomy to cytoreductive surgery. PMID- 28655403 TI - Yuan Longping, Hybrid Rice, and the Meaning of Science in the Cultural Revolution and Beyond. AB - This paper uses the case of hybrid rice to chart changes in the meanings science has carried in China from the Mao era to today. It begins by using Chinese journal articles to reconstruct the 1970s development of hybrid rice technology by a network of diverse historical actors. It then documents the emergence during the Hua Guofeng era (1976-1978) of a historical narrative of hybrid rice centered on the figures of Yuan Longping and Hua Guofeng. Finally, it surveys post-1978 biographies of Yuan Longping to identify changes and continuities in scientific values. The paper demonstrates that, although the reform era has witnessed the replacement of most of the Maoist vision of mass (or tu) science with a vision far more consistent with the values of international, professional (yang) science, the legacy of the Mao era can still be seen in a continued emphasis on certain aspects of Mao Zedong Thought, a strong narrative of nationalist triumphalism, and a celebration of Yuan Longping as an "intellectual peasant." PMID- 28655404 TI - The "cluster of black pearls" sign of sarcoid lymphadenopathy: a new sign on thin section contrast-enhanced multidetector CT. AB - AIM: To identify a specific diagnostic sign for sarcoid adenopathy on contrast enhanced multidetector computed tomography (MDCT) based on nodal morphology. MATERIALS AND METHODS: A prospective study was performed on 105 patients with 1654 nodes. Of this, 18 patients with sarcoidosis formed the study group. The control group consisted of the remaining 87 patients with other proven disease entities of metastatic adenocarcinoma, lymphoma, tuberculosis, and reactive adenopathy for comparison. CT examinations were undertaken using a 64-section helical mode in the arterial and venous phases with a 0.5-mm section thickness. The lymph nodes were evaluated for various morphological criteria and the presence of the "cluster of black pearls" (CBP) sign. The CBP sign was considered present when tiny round nodules each measuring 1-2 mm were seen distributed uniformly within the whole or part of the lymph node. RESULTS: The CBP sign had a significance of p<0.001, 83% sensitivity, 98% specificity, 91% positive predictive value, and 96% negative predictive value on a per node basis and a sensitivity of 100% on a per patient basis. CONCLUSION: The CBP sign is an accurate morphological sign differentiating sarcoid from other adenopathy. PMID- 28655405 TI - Commentary on: The "cluster of black pearls" sign of sarcoid lymphadenopathy: a new sign on thin-section contrast-enhanced multidetector CT. PMID- 28655406 TI - State of the art MRI in head and neck cancer. AB - Head and neck cancer affects more than 11,000 new patients per year in the UK1 and imaging has an important role in the diagnosis, treatment planning, and assessment, and post-treatment surveillance of these patients. The anatomical detail produced by magnetic resonance imaging (MRI) is ideally suited to staging and follow-up of primary tumours and cervical nodal metastases in the head and neck; however, anatomical images have limitations in cancer imaging and so increasingly functional-based MRI techniques, which provide molecular, metabolic, and physiological information, are being incorporated into MRI protocols. This article reviews the state of the art of these functional MRI techniques with emphasis on those that are most relevant to the current management of patients with head and neck cancer. PMID- 28655407 TI - Turner syndrome as a cause of liver cirrhosis. PMID- 28655408 TI - Autoimmune Hepatitis (Immune-Mediated Liver Injury) Induced By Rosuvastatin. PMID- 28655409 TI - Concurrent inflammatory bowel disease and gastrointestinal stromal tumor. PMID- 28655411 TI - Pancreatectomy with duodenal preservation in a intraductal papillary mucinosus neoplasia case. PMID- 28655410 TI - Update on acute-on-chronic liver failure. AB - Acute-on-chronic liver failure (ACLF) is a recently defined syndrome characterised by acute decompensation of chronic liver disease, associated with organ failures and high mortality. ACLF is a common condition and may affect up to 30% of patients admitted to hospital for cirrhosis complications. Bacterial infections, alcoholism and reactivation of viral hepatitis are the most common precipitating factors in ACLF, although in up to 40% of patients no precipitating factor can be identified. Although the pathophysiology of ACLF is not completely understood, the presence of an excessive inflammatory response appears to play a key role. There is no specific treatment for patients with ACLF and management is based on organ support and liver transplantation. New treatment strategies based on liver support systems and immunomodulatory treatments are being evaluated but existing data are still limited. PMID- 28655412 TI - Paraneoplastic syndromes associated with gynecological cancers: A systematic review. AB - A number of paraneoplastic syndromes have been described with gynecological cancers. These syndromes are induced by substances secreted by the tumor or by an immune response triggered by the cancer. Each system of the human body can be affected by different syndromes. Indeed, paraneoplastic syndromes occurring from tumors of the gynecologic tract were found to involve the nervous, ophthalmologic, dermatologic, rheumatologic, endocrine, hematologic and renal systems. These syndromes can manifest before, at the time, or after the diagnosis of cancer. They can also occur at the time of a recurrence. Knowledge about these syndromes is important for physicians caring for patients with cancers, as they can result in severe morbidity and must be treated appropriately. Literature regarding paraneoplastic syndromes associated with tumors of the female genital tract is scattered and the subject has not been reviewed recently. A systematic literature search was thus conducted to identify paraneoplastic syndromes associated with gynecologic cancers. This review focuses on the cancers involved with each paraneoplastic syndrome, and on their pathophysiology, clinical manifestations, possible complications, outcomes, and treatments. As the mainstay of treatment in these conditions is often to address the underlying tumor, it is of upmost importance that physicians be aware of these rare cancer manifestations. PMID- 28655413 TI - The impact of physician burnout on clinical and academic productivity of gynecologic oncologists: A decision analysis. AB - OBJECTIVE: Physician burnout is associated with mental illness, alcohol abuse, and job dissatisfaction. Our objective was to estimate the impact of burnout on productivity of gynecologic oncologists during the first half of their career. METHODS: A decision model evaluated the impact of burnout on total relative value (RVU) production during the first 15years of practice for gynecologic oncologists entering the workforce from 2011 to 2015. The SGO practice survey provided physician demographics and mean annual RVUs. Published data were used to estimate probability of burnout for male and female gynecologic oncologists, and the impact of depression, alcohol abuse, and early retirement. Academic productivity was defined as annual PubMed publications since finishing fellowship. RESULTS: Without burnout, RVU production for the cohort of 250 gynecologic oncologists was 26.2 million (M) RVUs over 15years. With burnout, RVU production decreased by 1.6 M (5.9% decrease). Disproportionate rates of burnout among females resulted in 1.1 M lost RVUs for females vs. 488 K for males. Academic production without burnout was estimated at 9277 publications for the cohort. Burnout resulted in 1383 estimated fewer publications over 15years (14.9%). CONCLUSIONS: The impact of burnout on clinical and academic productivity is substantial across all specialties. As health care systems struggle with human resource shortages, this study highlights the need for effective burnout prevention and wellness programs for gynecologic oncologists. Unless significant resources are designated to wellness programs, burnout will increasingly affect the care of our patients and the advancement of our field. PMID- 28655414 TI - Heart and heart-liver transplantation in patients with hemochromatosis. AB - BACKGROUND: Hemochromatosis predisposes to dilated or restrictive cardiomyopathy which can progress to end-stage heart failure, requiring the use of advanced heart therapies including heart (HT) and heart liver (HLT) transplantation. Little is known about the characteristics and outcomes of these patients. METHODS AND RESULTS: We queried the United Network for Organ Sharing (UNOS) registry for all patients listed for HT or HLT for a diagnosis of 'hemochromatosis' between 1987 and 2014. Waitlist and post-transplantation outcomes were compared between patients with hemochromatosis (HT vs HLT) and other etiologies. Of the 81,356 adults listed for heart transplantation, 23 patients with hemochromatosis were identified (16 listed for HLT; and 7 listed for HT). Compared with other etiologies, HC patients were younger (39 vs 51years, p<0.0001), and more likely to need inotropes (56.5% vs 25.6%, p=0.003) and mechanical ventilation (13% vs 3.4%, p=0.041). Cumulative hazards of waitlist mortality or delisting were higher in hemochromatosis patients than for other etiologies of heart failure (p<0.001). There were 4 HT and 4 HLT during the study period. Post-transplantation, patients with HC had a 1- and 2-year cumulative survival of 88% and 75%, respectively. CONCLUSIONS: Both HT and HLT are viable options for patients with hemochromatosis. Patients with hemochromatosis are younger with increased wait list mortality compared with other etiologies. PMID- 28655415 TI - Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy. AB - BACKGROUND: In biliary atresia mechanisms of progressive liver injury leading to need of liver transplantation after successful portoenterostomy remain unknown. A better understanding is a prerequisite for development of novel therapies to extend native liver survival, and we aimed to unravel molecular characteristics of liver injury after successful portoenterostomy. METHODS: Liver biopsies obtained from 28 biliary atresia children during successful portoenterostomy and at median age 3.0 years were studied. Biopsies were analyzed for histology and immunohistochemical expression of collagen 1, myofibroblast marker alpha-smooth muscle actin, and cytokeratin-7 positive ductal reactions. Hepatic ribonucleic acid (RNA) expression of growth factors and inflammatory cytokines was evaluated. Intestinal failure patients with comparable liver fibrosis and nonfibrotic gallstone patients and donor livers were controls. RESULTS: After successful portoenterostomy, histologic cholestasis resolved and portal inflammation reduced, while fibrosis along with ductal reactions and overexpression of collagen and alpha-smooth muscle actin persisted. At follow-up, liver RNA expression of collagen and platelet-derived growth factor was increased, whereas RNA expression of various inflammatory cytokines remained low. Disappearance of periductal alpha-smooth muscle actin expression after successful portoenterostomy (36% of patients) associated with contracted ductal reactions and reduced progression of fibrosis, collagen accumulation, platelet-derived growth factor RNA expression, and serum levels of bile acids and bilirubin. Fibrosis progressed less rapidly in syndromic than in isolated biliary atresia patients. CONCLUSION: These findings suggest that instead of inflammation, molecular signature of active fibrogenesis in association with ductal reactions prevails in long-term native liver survivors with biliary atresia. Patients should be stratified for isolated and syndromic disease forms in interventional studies. PMID- 28655416 TI - Evaluation and proposal of novel resectability criteria for pancreatic cancer established by the Japan Pancreas Society. AB - BACKGROUND: The guidelines for the classification of the resectability of pancreatic cancer established by the National Comprehensive Cancer Network can be difficult to utilize in clinical practice. We evaluated novel criteria proposed by the Japan Pancreas Society. METHODS: We analyzed 382 patients with pancreatic cancer between 2001 and 2015 for survival differences among subgroups classified according to the Japan Pancreas Society classification. Overall survival and disease-free survival were expressed as median values and compared with data based on the National Comprehensive Cancer Network classification, and differences in initial patterns of recurrence were analyzed. RESULTS: Overall survival times according to the Japan Pancreas Society criteria were 34.2, 29.7, 17.3, 14.3, and 15.8 months for the groups defined as resectable, resectable with portal vein invasion, borderline resectable with portal vein invasion, borderline resectable with arterial invasion, and unresectable by locally advanced disease respectively. The overall survival of the resectable group was better than those of the borderline resectable with portal vein invasion or borderline resectable with arterial invasion groups (P < .0001); however, the borderline resectable with portal vein invasion, borderline resectable with arterial invasion, and unresectable by locally advanced groups showed no differences in overall survival. The resectable group showed a tendency toward better survival than the resectable with portal vein invasion group (P = .058). The median overall survival times according to the classic 2012 National Comprehensive Cancer Network criteria were 30.5, 20.5, 15.8, and 13.8 months for the resectable, portal invasion, common hepatic artery and superior mesenteric artery invasion groups, respectively. Each survival curve was clearly separate. The borderline resectable with arterial invasion and unresectable by locally advanced groups exhibited high local recurrence rates (42.0% and 44.8%, respectively). CONCLUSION: The Japan Pancreas Society criteria, which are simpler, predicted survival differences between the resectable group and the other subgroups. Our data suggest that cancer patients with borderline resectable pancreatic cancer (borderline resectable with portal vein invasion and borderline resectable with arterial invasion) can be managed as a single subset. PMID- 28655417 TI - [Functional impairment associated with cognitive impairment in hospitalised elderly]. AB - INTRODUCTION: The aim of this study was to analyse the effect of cognitive impairment on functional decline in hospitalised patients aged >=60 years. METHODS: Measurements at admission included demographic data, Charlson's comorbidity index, and cognitive impairment (according to education level). Data were also collected on hospital length of stay, depression, and delirium developed during hospitalisation. The outcome, Barthel Index (BI), was measured at admission, discharge, and 1-month post-discharge. Patients with BI<=75 at admission (n=54) or with a missing BI value were excluded (n=1). Multivariate logistic regression analyses were conducted to explore predictive factors with functional decline (BI<=75) from admission to discharge, and 1-month later. RESULTS: Of the 133 patients included, 24.8% and 19.6% had a BI<=75 at discharge and at 1-month, respectively. Compared with men, women had more than double risk for functional decline at discharge and 1-month (P<.05). Compared with those without delirium and without cognitive impairment, those with delirium and cognitive impairment had an increased risk for functional decline (BI<=75) at discharge (OR 5.15, 95% CI; 1.94-13.67), and at 1-month (OR 6.26, 95% CI; 2.30 17.03). Similarly, those with comorbidity (>=2) had increased functional decline at discharge (OR 2.36, 95% CI; 1.14-4.87), and at 1-month after discharge (OR 2.71, 95% CI; 1.25-5.89). CONCLUSION: Delirium during hospitalisation, together with cognitive impairment on admission, was a strong predictor of functional decline. PMID- 28655418 TI - Synthesis and characterization of monophosphinic acid DOTA derivative: A smart tool with functionalities for multimodal imaging. AB - A new facile synthetic strategy was developed to prepare bifunctional monophosphinic acid Ln-DOTA derivatives, Gd-DO2AGAPNBn and Gd- DO2AGAPABn. The relaxivities of the Gd-complexes are enhanced compared to Gd-DOTA. Monophosphinic acid arm of these Gd-complexes affords enhancement of inner sphere water exchange rate due to its steric bulkiness. The different functionalities of DO2AGAPNBn were appended in trans positions and are designed to conjugate identical or different vectors according to the potential applications. The conjugation of Gd DO2AGAPABn with E3 peptide known to target apoptosis was successfully performed and in vivo MRI allowed cell death detection in a mouse model. PMID- 28655419 TI - Neural representations of concurrent sounds with overlapping spectra in rat inferior colliculus: Comparisons between temporal-fine structure and envelope. AB - Perceptual segregation of multiple sounds, which overlap in both time and spectra, into individual auditory streams is critical for hearing in natural environments. Some cues such as interaural time disparities (ITDs) play an important role in the segregation, especially when sounds are separated in space. In this study, we investigated the neural representation of two uncorrelated narrowband noises that shared the identical spectrum in the rat inferior colliculus (IC) using frequency-following-response (FFR) recordings, when the ITD for each noise stimulus was manipulated. The results of this study showed that recorded FFRs exhibited two distinctive components: the fast-varying temporal fine structure (TFS) component (FFRTFS) and the slow-varying envelope component (FFRENV). When a single narrowband noise was presented alone, the FFRTFS, but not the FFRENV, was sensitive to ITDs. When two narrowband noises were presented simultaneously, the FFRTFS took advantage of the ITD disparity that was associated with perceived spatial separation between the two concurrent sounds, and displayed a better linear synchronization to the sound with an ipsilateral leading ITD. However, no effects of ITDs were found on the FFRENV. These results suggest that the FFRTFS and FFRENV represent two distinct types of signal processing in the auditory brainstem and contribute differentially to sound segregation based on spatial cues: the FFRTFS is more critical to spatial release from masking. PMID- 28655420 TI - Comparison of the effects of esomeprazole plus mosapride citrate and botulinum toxin A on vocal process granuloma. AB - OBJECTIVES: Vocal process granulomas have a high tendency for persistence despite many treatment alternatives. Anti-reflux medications or botulinum toxin A injections are the main current therapies. There are no studies that compare the effects on vocal process granuloma of proton pump inhibitors plus prokinetic agents with botulinum toxin A injections. STUDY DESIGN: Prospective cohort study. METHODS: Adult patients reporting to our outpatient department complaining of trachyphonia and/or abnormal pharyngeal sensations who were found to have contact granulomas. Patients were divided into two groups according to the treatment: esomeprazole with mosapride citrate (n=26) or botulinum toxin A injection (n=20). The reflux symptom index and reflux finding score determined by electronic fibrolaryngoscopy were utilized to assess efficacy. RESULTS: Forty-six patients were recruited (43 male; 3 female). The mean age (range) was 48.3years (38-69) and the body mass index was 23.51kg/m2 (19.13-27.89). Laryngopharyngeal reflux disease diagnosed by RSI or RFS was found in 18 and 27 patients, respectively, and 18 diagnosed without laryngopharyneal reflux disease. Twenty patients (95%) were cured in the esomeprazole with mosapride citrate group and nine (45%) in the botulinum toxin A group. Eleven (55%) patients had recurrence after botulinum toxin A injection, with an average interval of 3.1months (range 1-6). The recorded symptoms after therapy resolved within 6months with a statistically significant improvement in the esomeprazole with mosapride citrate group. CONCLUSIONS: Combined proton pump inhibitor plus prokinetic drug therapy plays a significant role in the treatment of vocal process granulomas or after surgery. PMID- 28655421 TI - Synthesis and evaluation of hydroxychalcones as multifunctional non-purine xanthine oxidase inhibitors for the treatment of hyperuricemia. AB - A series of hydroxychalcone derivatives have been designed, synthesized and evaluated for human xanthine oxidase (XO) inhibitory activity. Most of the tested compounds acted moderate XO inhibition with IC50 values in the micromolar rang. Molecular docking and kinetic studies have been performed to explain the binding modes of XO with the selected compounds. In addition, in vitro antioxidant screening results indicated that some of the hydroxychalcones possessed good anti free radical activities. Furthermore, the preferred compounds 16 and 18 were able to significantly inhibit hepatic xanthine oxidase activity and reduced serum uric acid level of hyperuricemic mice in vivo. In summary, compounds 16 and 18 with balanced activities of antioxidant, XO inhibition and serum uric acid reduction, which are promising candidates for the treatment of hyperuricemia and gout. PMID- 28655422 TI - Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2: Pyridone- and pyrimidinone-derived systems. AB - Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE). PMID- 28655423 TI - Synthesis and antibacterial activity of novel 4"-O-(1-aralkyl-1,2,3-triazol-4 methyl-carbamoyl) azithromycin analogs. AB - Three novel structural series of 4"-O-(1-aralkyl-1,2,3-triazol-4-methyl carbamoyl) azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activity. All the target compounds exhibited excellent activity against erythromycin-susceptible Streptococcus pyogenes, and significantly improved activity against three phenotypes of erythromycin resistant Streptococcus pneumoniae compared with clarithromycin and azithromycin. Among the three series of azithromycin analogs, the novel series of 11,4" disubstituted azithromycin analogs 9a-k exhibited the most effective and balanced activity against susceptible and resistant bacteria. Among them, compound 9j showed the most potent activity against Staphylococcus aureus ATCC25923 (0.008ug/mL) and Streptococcus pyogenes R2 (1ug/mL). Besides, all the 11,4" disubstituted azithromycin analogs 9a-k except 9f shared the identical activity with the MIC value <0.002ug/mL against Streptococcus pyogenes S2. Furthermore, compounds 9g, 9h, 9j and 9k displayed significantly improved activity compared with the references against all the three phenotypes of resistant S. pneumoniae. Particularly, compound 9k was the most effective (0.06, 0.03 and 0.125ug/mL) against all the erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, exhibiting 2133, 133 and 2048-fold more potent activity than azithromycin, respectively. PMID- 28655424 TI - Risk factors for early return visits to the emergency department in patients with urinary tract infection. AB - BACKGROUND: Optimal management of urinary tract infections (UTIs) in the emergency department (ED) is challenging due to high patient turnover, decreased continuity of care, and treatment decisions made in the absence of microbiologic data. We sought to identify risk factors for return visits in ED patients treated for UTI. METHODS: A random sample of 350 adult ED patients with UTI by ICD 9/10 codes was selected for review. Relevant data was extracted from medical charts and compared between patients with and without ED return visits within 30days (ERVs). RESULTS: We identified 51 patients (15%) with 59 ERVs, of whom 6% returned within 72h. Nearly half of ERVs (47%) were UTI-related and 33% of ERV patients required hospitalization. ERVs were significantly more likely (P<0.05) in patients with the following: age>=65years; pregnancy; skilled nursing facility residence; dementia; psychiatric disorder; obstructive uropathy; healthcare exposure; temperature>=38 degrees C heart rate>100; and bacteremia. Escherichia coli was the most common uropathogen (70%) and susceptibility rates to most oral antibiotics were below 80% in both groups except nitrofurantoin (99% susceptible). Cephalexin was the most frequently prescribed antibiotic (51% vs. 44%; P=0.32). Cephalexin bug-drug mismatches were more common in ERV patients (41% vs. 15%; P=0.02). Culture follow-up occurred less frequently in ERV patients (75% vs. 100%; P<0.05). CONCLUSIONS: ERV in UTI patients may be minimized by using ED-source specific antibiogram data to guide empiric treatment decisions and by targeting at-risk patients for post-discharge follow-up. PMID- 28655425 TI - Glasgow coma scale versus computed tomography in prognostication. PMID- 28655426 TI - In reply: GCS in prognostication after traumatic brain injury. PMID- 28655427 TI - The development and efficacy of a group intervention program for individuals with serious mental illness in jail. AB - Providing cost-effective means to treat the influx of individuals with serious mental illness entering the correctional system is a major challenge. Failure to provide appropriate mental health treatment may lead to poor outcomes, including recidivism and suicide. Group intervention is an effective and cost efficient way to provide mental health treatment. However, it has been understudied in jail settings. To meet the needs of jail-inmates with serious mental illness, an eight week group-based module curriculum was developed and studied through analyses of perceived usefulness, retention of key material, and associations with cognitive ability, improvement in psychiatric symptoms, and level of motivation. One week after the completion of a group session, the participants remembered the group topic and at least one key point from the group the majority of the time. Better recall of group material was associated with better overall cognitive ability and motivation at discharge. Participants found the groups to be somewhat to extremely useful 88.4% of the time. Higher levels of usefulness were associated with reduced psychopathology and psychiatric improvement, as well as higher motivation at discharge. The findings provide support for the group intervention and implementation in a jail setting. Further implications are discussed. PMID- 28655428 TI - Balancing autonomy and protection: A qualitative analysis of court hearings dealing with protective measures. AB - Respect for individual autonomy is at the core of the Convention on the Rights of Persons with Disabilities (CRPD). However, the need to protect persons with disabilities, especially those with cognitive impairments and psychosocial conditions, from outright exploitation, violence and abuse is explicitly provided for in article 16. Legal authorities still decide on a daily basis upon the institution of measures, which aim to protect vulnerable persons and unavoidably impact on the autonomy of persons concerned, known as guardianship, curatorship or administration. Observations of court hearings, interviews with judges and analysis of written materials from the cantons of Geneva and Vaud in Switzerland as well as from Belgium - which all have differently composed authorities - were carried out in order to identify what influences authorities in decision-making processes regarding protective measures, and to explore how autonomy and protection can be balanced. We suggest pragmatic considerations that should not be ignored when trying to reach a balance between autonomy and protection from abuse, in line with the CRPD. PMID- 28655429 TI - A study of the correlation between ultrafine particle emissions in motorcycle smoke and mice erythrocyte damages. AB - Sharply increasing of motor vehicles every year contributes to amounts of ultrafine particles (UFPs) in the air. Besides, the existence of UFPs in the blood may cause erythrocyte damages that subject to shape deformation. This study was aimed to investigate the influence of UFPs in the motorcycle smoke exposed to mice in different concentrations to the erythrocyte damages. The experiments were conducted by injecting the motorcycle smoke with the varied amounts in an experimental chamber (dimension of 30*20*20cm3) where the mice were put in advance for exposuring twice a day (100s). Total numbers of UFPs in the smoke were calculated by measuring the total concentrations multiplied by the smoke debit. They were measured using a TSI 8525 P-Trak UPC. The effects of the smoke exposures in the mice's erythrocytes related to the UFPs in the smoke were observed by a binocular CX-31 Computer Microscope after the 2nd, 4th, 6th, 8th, and 10th exposure days. The erythrocyte damages were calculated from the total abnormal erythrocytes divided by the total erythrocytes. Our results showed that more UFPs exposed to mice resulted in more the erythrocytes damages. Longer exposures caused more damages of the mice erythrocytes. This study found significant correlations between the numbers of UFPs exposed to mice and the erythrocyte damages. Our finding gives important evidence that motorcycle emissions especially UFPs affect on health. PMID- 28655430 TI - Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia. AB - BACKGROUND AND AIMS: Oxidative modification of lipoproteins is a crucial step in atherosclerosis development. Isotopic-reinforced polyunsaturated fatty acids (D PUFAs) are more resistant to reactive oxygen species-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-)PUFAs. We aimed at investigating the effect of D-PUFA treatment on lipid peroxidation, hypercholesterolemia and atherosclerosis development. METHODS: Transgenic APOE*3-Leiden.CETP mice, a well established model for human-like lipoprotein metabolism, were pre-treated with D PUFAs or control H-PUFAs-containing diet (1.2%, w/w) for 4 weeks. Thereafter, mice were fed a Western-type diet (containing 0.15% cholesterol, w/w) for another 12 weeks, while continuing the D-/H-PUFA treatment. RESULTS: D-PUFA treatment markedly decreased hepatic and plasma F2-isoprostanes (approx. -80%) and prostaglandin F2alpha (approx. -40%) as compared to H-PUFA treatment. Moreover, D PUFAs reduced body weight gain during the study (-54%) by decreasing body fat mass gain (-87%) without altering lean mass. D-PUFAs consistently reduced plasma total cholesterol levels (approx. -25%), as reflected in reduced plasma non-HDL cholesterol (-28%). Additional analyses of hepatic cholesterol metabolism indicated that D-PUFAs reduced the hepatic cholesterol content (-21%). Sterol markers of intestinal cholesterol absorption and cholesterol breakdown were decreased. Markers of cholesterol synthesis were increased. Finally, D-PUFAs reduced atherosclerotic lesion area formation throughout the aortic root of the heart (-26%). CONCLUSIONS: D-PUFAs reduce body weight gain, improve cholesterol handling and reduce atherosclerosis development by reducing lipid peroxidation and plasma cholesterol levels. D-PUFAs, therefore, represent a promising new strategy to broadly reduce rates of lipid peroxidation, and combat hypercholesterolemia and cardiovascular diseases. PMID- 28655431 TI - Canadian Association of Radiologists: Guide on Computed Tomography Screening for Lung Cancer. PMID- 28655432 TI - Diagnostic accuracy of different magnetic resonance imaging sequences for detecting local tumor progression after radiofrequency ablation of hepatic malignancies. AB - OBJECTIVE: To evaluate the diagnostic accuracy of the individual sequences of a clinical routine liver MRI protocol for the detection of local tumour progression after radiofrequency (RF) ablation of hepatic malignancies. MATERIAL AND METHODS: A cohort of 93 patients treated for 140 primary and secondary hepatic malignancies with RF ablation was assembled for this retrospective study. The cohort contained 31 cases of local tumour progression, which occurred 8.3+/ 6.2months (range: 4.0-28.2 months) after treatment. All patients underwent clinical routine follow-up MRI at 1.5T including following sequences: unenhanced T1-weighted fast low angle shot (FLASH-2D), T2-weighted turbo-spin-echo sequence, contrast-enhanced (CE) T1-weighted volume-interpolated breath-hold examination (VIBE), diffusion-weighted imaging (DWI). Follow-up was 32.7+/-22.5months (range: 4.0-138.3 months). Two readers independently evaluated the individual sequences separately for signs of local tumour progression. Diagnostic confidence was rated on a 4-point scale. Inter-reader agreement was assessed with Cohens kappa. Long term follow-up and histological specimen served as standard of reference. RESULTS: Both readers reached the highest sensitivity for detection of local tumour progression with unenhanced T1-FLASH 2D (88.2% and 94.1%, respectively) and the highest specificity with CE T1-VIBE (96.2% and 97.2%, respectively). Highest inter-reader agreement was reached with T1-FLASH-2D (kappa=0.83). Typical pitfalls for false-positive diagnoses were focal cholestasis and vasculature adjacent to the ablation zone. Diagnostic confidence was highest with CE T1-VIBE for reader 1 and DWI for reader 2. CONCLUSION: Unenhanced T1-FLASH-2D is an essential sequence for follow-up imaging after tumour ablation with a high sensitivity for detection of local progression and a high inter-reader agreement. PMID- 28655433 TI - Role of chemical shift and Dixon based techniques in musculoskeletal MR imaging. AB - Fat suppression technique is a valuable resource in musculoskeletal magnetic resonance (MR) imaging that is helpful in the diagnosis and differentiation of various pathologies. Multiple different techniques are available for fat suppression, including frequency selective pulse sequence, inversion recovery, hybrid technique, chemical shift imaging (CSI) and the related Dixon based approach. The utility of CSI and Dixon approach is not well recognized in the domain of musculoskeletal MR imaging. The aim of this article is to review the various options for fat suppression and present focused discussion of the role of CSI and Dixon techniques for musculoskeletal MR imaging. PMID- 28655434 TI - Immediate full-arch rehabilitation of the severely atrophic maxilla supported by zygomatic implants: a prospective clinical study with minimum follow-up of 6 years. AB - The aim of this study was to evaluate the outcomes of immediate full-arch prostheses supported by zygomatic implants alone or in combination with standard fixtures after a minimum of 6 years of loading. From October 2008 to April 2010, 15 patients with severely atrophic maxillae were treated using four zygomatic implants or two zygomatic implants in conjunction with two conventional fixtures. All subjects received a fixed screw-retained prosthesis within 3hours of surgery, while the final restoration was delivered after 6 months. Follow-up examinations were scheduled to evaluate zygomatic implant survival, conventional dental implant success, prosthetic success, plaque and bleeding scores, marginal bone loss for conventional dental implants, and patient satisfaction. Forty-two zygomatic fixtures and 18 standard implants were placed. Patients were followed up for a minimum of 79 months (range 79-97 months, average 90.61 months). No implant was lost, leading to implant and prosthetic survival rates of 100%. Bone loss for conventional implants averaged 1.39+/-0.10mm after 6 years of function, leading to a 100% implant success rate. High levels of patient satisfaction were recorded. These medium-term results indicate that immediate full-arch rehabilitation supported by zygomatic implants could be considered a viable treatment modality for the severely atrophic maxilla. PMID- 28655435 TI - Primary epithelial salivary gland tumours in children and adolescents. AB - Primary epithelial tumours of the salivary glands are very rare in paediatric patients. The aim of this study was to evaluate the clinical course, treatment, and outcomes of these uncommon neoplasms based on the authors' experience and the recent literature. The medical charts of 12 female patients and seven male patients with primary epithelial salivary gland tumours were reviewed. All were under 19 years of age and underwent surgical treatment between 1994 and 2016. The results of this group of paediatric patients were compared with those of 621 adult patients. The two most common tumours in the paediatric patients were pleomorphic adenoma and mucoepidermoid carcinoma (89.4%; P=0.004). The incidence of facial nerve palsy following surgery of the parotid tumours was similar in the two groups (P=1.000). The most common primary cancer in the paediatric group was mucoepidermoid carcinoma (77.8%), while in the adult group, adenoid cystic carcinoma was most common (P<0.001). The paediatric group had only low-grade cancers in early stages (P<0.001), with an overall 5-year survival rate of 100%. These results show that the incidence of malignant salivary gland tumours is higher in paediatric patients than in adult patients. This should be taken into account during diagnosis and therapy. PMID- 28655436 TI - Non-infectious genital ulcer: The relevance of anamnesis. PMID- 28655437 TI - Erythemato-violaceous plaques on the shin of a trasplanted lung host. PMID- 28655438 TI - Reply. PMID- 28655439 TI - [Blood-filled blister on tongue]. PMID- 28655440 TI - iACP-GAEnsC: Evolutionary genetic algorithm based ensemble classification of anticancer peptides by utilizing hybrid feature space. AB - Cancer is a fatal disease, responsible for one-quarter of all deaths in developed countries. Traditional anticancer therapies such as, chemotherapy and radiation, are highly expensive, susceptible to errors and ineffective techniques. These conventional techniques induce severe side-effects on human cells. Due to perilous impact of cancer, the development of an accurate and highly efficient intelligent computational model is desirable for identification of anticancer peptides. In this paper, evolutionary intelligent genetic algorithm-based ensemble model, 'iACP-GAEnsC', is proposed for the identification of anticancer peptides. In this model, the protein sequences are formulated, using three different discrete feature representation methods, i.e., amphiphilic Pseudo amino acid composition, g-Gap dipeptide composition, and Reduce amino acid alphabet composition. The performance of the extracted feature spaces are investigated separately and then merged to exhibit the significance of hybridization. In addition, the predicted results of individual classifiers are combined together, using optimized genetic algorithm and simple majority technique in order to enhance the true classification rate. It is observed that genetic algorithm-based ensemble classification outperforms than individual classifiers as well as simple majority voting base ensemble. The performance of genetic algorithm-based ensemble classification is highly reported on hybrid feature space, with an accuracy of 96.45%. In comparison to the existing techniques, 'iACP-GAEnsC' model has achieved remarkable improvement in terms of various performance metrics. Based on the simulation results, it is observed that 'iACP-GAEnsC' model might be a leading tool in the field of drug design and proteomics for researchers. PMID- 28655441 TI - Resolution enhancement in proton double quantum magic-angle spinning spectra by constant-time acquisition. AB - Although very fast MAS rate (>60 kHz) paves a way to obtain a sufficient resolution in the 1H double-quantum magic-angle spinning (DQMAS) experiments to probe 1H proximities, the 1H resolution still limits wider applications below its potential use. Here, the combination of the DQMAS experiment with the constant time (CT) acquisition approach is demonstrated, giving an increased peak separation power in the DQ dimension. The advantages and disadvantages in terms of sensitivity and resolution of the conventional and CT approaches are discussed. PMID- 28655442 TI - Effects of common functional MMP12 gene polymorphisms on PD in a Polish population. AB - The present study investigated associations of two functional MMP12 polymorphisms with PD risk and cognitive impairment in PD. A total of 478 study subjects (241 PD and 237 age and sex matched controls) were included in the study. UPDRS score, Hoehn-Yahr staging and Schwab-England scale were used to assess motor abilities and activity during daily life. All patients were classified into groups with dementia (PDD, n=72) and without dementia (nPDD, n=159) based on the neuropsychological assessment. The two most common functional single nucleotide polymorphisms (SNPs) in MMP12 gene were determined using TaqMan real-time PCR assays. Frequencies of evaluated MMP12 rs2276109 alleles and genotypes were similar in PD and the controls, whereas rs652438G allele genotypes were significantly more frequent among healthy individuals (p=0.013, OR 0.47 (0.26 0.85). The rs2276109 and rs652438 allele and genotype frequencies were not associated with dementia in PD patients. The current results suggest that MMP12 rs652438 but not MMP12 rs2276109 may affect the risk for PD, as the minor G allele genotypes might be a protective factor. PMID- 28655444 TI - Mediating effect of emotional/behavioral problems and academic competence between parental abuse/neglect and school adjustment. AB - The current study examined the mediating effects of emotional/behavioral problems and academic competence between parental abuse/neglect and a child's school adjustment by investigating 2070 student surveys from the Korean Child Youth Panel Study (KCYPS). A path analysis yielded the following key findings. Firstly, childhood abuse and neglect showed a significant negative and direct effect on school adjustment. It is particularly important to note that the effect of neglect was bigger than that of abuse in this study. Secondly, emotional/behavioral problems were found to partially mediate between abuse/neglect and school adjustment. Thirdly, academic competence partially mediated the effect of neglect on school adjustment, while it did not mediate the effect of abuse on school adjustment. The indirect effect of parental neglect via emotional/behavioral problems and academic competence was stronger than that of parental abuse. The influence of parental abuse and neglect on children's school adjustments was discussed in terms of emotional/behavioral problems and academic competence considering unique Korean cultural context. PMID- 28655443 TI - Different hypersensitivities against homologous proteins of MGL_1304 in patients with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is exacerbated by sweating, and the skin of most patients with AD are resided by Malassezia (M.) fungi. Recently, MGL_1304 produced by Malassezia globosa was identified as the major histamine releasing antigen in human sweat. METHODS: The full length cDNA of the counterpart of MGL_1304 in Malassezia restricta (Mala r 8), was cloned by degenerate PCR and rapid identification of cDNA ends (RACE). Recombinant MGL_1304, and its counterparts, Mala s 8 (produced by Malassezia sympodialis) and Mala r 8 were prepared, and compared in their allergenicities by dot blot analysis and histamine release tests with sera and basophils of patients with AD. RESULTS: The identities between MGL_1304 and Mala s 8, MGL_1304 and Mala r 8, and Mala s 8 and Mala r 8 were 68%, 78%, and 76%, respectively, in protein sequences. Dot blot analysis revealed that the level of IgE binding to Mala s 8 was higher than that of MGL_1304. However, histamine release tests revealed that MGL_1304 and Mala r 8 possessed higher activity than Mala s 8. In addition, the crude lysate of M. globosa showed higher histamine release ability than that of M. sympodialis. CONCLUSIONS: Patients with AD showed hypersensitivities against MGL_1304 and its homologs. However, the allergenicities of the homologs are variable and the histamine release activities may be different from the solid-phase binding activities for IgE. Sweat allergy should be carefully evaluated with biological activities of MGL_1304 and its homologs of other Malassezia fungi residing on the skin. PMID- 28655445 TI - Intraoperative transprosthetic leakage of a bovine prosthetic valve after aortic valve replacement. PMID- 28655446 TI - Cerebral autoregulation: Making sense of the nonsensical. PMID- 28655447 TI - There's no fun like work. PMID- 28655448 TI - Methylene blue-induced serotonin syndrome after left ventricular assist device implantation: A case report and literature review. PMID- 28655449 TI - Chimney reconstruction of the aortic arch in the Norwood procedure. PMID- 28655450 TI - Dr Blalock's unfinished business. PMID- 28655451 TI - Rationale for two influenza B lineages in seasonal vaccines: A meta-regression study on immunogenicity and controlled field trials. AB - B lineage mismatch prompted introduction of quadri-valent influenza vaccines (QIV) with two influenza B viruses representing distinct antigenic lineages. To explore the impact on antibody induction and vaccine effectiveness predicted from antibody (VEab), we performed a systematic literature search on immunogenicity studies conducted to assess antibody superiority of QIV over trivalent influenza vaccine (TIV). Thirteen relevant articles described 31 trials from 2007 and 2013. Log-transformed GMT trial estimates and their variances were converted to clinical protection rates predicted from antibody (PRab). VEab estimates were calculated from pre- and post-vaccination PRab. Without specific pre-vaccination immunity, average VEab was 69% for match, and -4% for lineage mismatch. With increasing pre-vaccination seropositivity, mismatch impact declined to 2%. We also performed an umbrella literature search for randomised controlled trials and test-negative case-control trials with TIV, and estimated vaccine effectiveness against laboratory-confirmed influenza B (VEf). Sixty-eight eligible clinical articles described 110 season-trials from 1965 to 2012, covering seasons with B lineage match (n=52), lineage drift (n=15) and lineage mismatch (n=43). With no pre-vaccination antibody levels determined, we used chance of previous exposure to influenza B (Ppe) as pre-seasonal immunity measure. When Ppe was 0%, average VEf for matched seasons was 67%, and for mismatched seasons 35%, indicating a moderate, yet significant mismatch impact on VEf. With increasing Ppe, mismatch impact declined to 3%. Thus serological and field trials indicate that B lineage mismatch impact is negatively related to pre-seasonal immunity and that the gain of QIV over TIV most benefits infants and children not yet exposed to influenza B. PMID- 28655453 TI - Cannabis for restless legs syndrome: a report of six patients. PMID- 28655452 TI - High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer. AB - BACKGROUND: Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open-label, single-arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard-dose therapy. PATIENTS AND METHODS: Eligible patients had progressive mCRPC and started AA 1000 mg daily and P 5 mg twice daily. Patients who achieved any prostate-specific antigen (PSA) decline after 12 weeks of therapy continued AA with P until PSA or radiographic progression. At progression, AA was increased to 1000 mg twice daily with unchanged P dosing. Patients were monitored for response to therapy for a minimum of 12 weeks or until PSA or radiographic progression. The primary end point was PSA decline of at least 30% after 12 weeks of therapy at the increased dose of AA. RESULTS: Forty-one patients were enrolled from March 2013 through March 2014. Thirteen men experienced disease progression during standard-dose therapy and were subsequently treated with AA 1000 mg twice per day. Therapy was well tolerated. No PSA declines >= 30% nor radiographic responses were observed after 12 weeks of dose-escalated therapy. Higher baseline dehydroepiandrosterone levels, lower circulating tumor cell burden, and higher pharmacokinetic levels of abiraterone and abiraterone metabolites were associated with response to standard-dose therapy. CONCLUSION: Increasing the dose of abiraterone at the time of resistance has limited clinical utility and cannot be recommended. Lower baseline circulating androgen levels and interpatient pharmacokinetic variance appear to be associated with primary resistance to AA with P. PMID- 28655454 TI - MLC tracking for lung SABR reduces planning target volumes and dose to organs at risk. AB - PURPOSE: Assess the dosimetric impact of multi-leaf collimator (MLC) tracking and mid-ventilation (midV) planning compared with the internal target volume (ITV) based planning approach for lung Stereotactic Ablative Body Radiotherapy (SABR). METHOD: Ten lung SABR patients originally treated with an ITV-based plan were re planned according to MLC tracking and midV planning schemes. All plans were delivered on a linac to a motion phantom in a simulated treatment with real lung motions. Delivered dose was reconstructed in patient planning scans. ITV-based, tracking and midV regimes were compared at the planning and delivered stages based on PTV volume and dose metrics for the GTV and OAR. RESULTS: MLC tracking and midV schemes yielded favourable outcomes compared with ITV-based plans. Average reduction in PTV volume was (MLC tracking/MidV) 33.9%/22%. GTV dose coverage performed better with MLC tracking than the other regimes. Reduction in dose to OAR were for the lung (mean lung dose, 0.8Gy/0.2Gy), oesophagus (D3cc, 1.9Gy/1.4Gy), great vessels (D10cc, 3.2Gy/1.3Gy), trachea (D4cc, 1.1Gy/0.9Gy), heart (D1cc, 2.0Gy/0.5Gy) and spinal cord (D0.03cc, 0.5Gy/-0.1Gy). CONCLUSION: MLC tracking showed reduction in PTV volume, superior GTV dose coverage and organ dose sparing than MidV and ITV-based strategies. PMID- 28655456 TI - Reflections on multiple strategies to reduce transfusion in cancer patients: A joint narrative. AB - Transfusion of red blood cells, platelets and plasma is widely used in the management of anemia and coagulopathy in cancer patients undergoing surgery, chemotherapy, and radiation. The decision to transfuse should not be made lightly as exposure to transfused blood, whether from an allogeneic or even autologous source, is not without risk and the long-term effect of blood transfusion on cancer outcomes remains questionable. Recognition of anemia associated with nutritional deficiency should be promptly corrected while avoiding the use of erythropoiesis stimulating agents. Minimizing blood loss and the prompt control of bleeding, coupled with a restrictive transfusion strategy, seem to be a reasonable approach that does not appear to be associated with long-term sequelae. Limiting platelet transfusion to patients with severe hypo proliferative thrombocytopenia, and implementation of local hemostatic measures, together with the use of fractionated coagulation factor concentrates, as an alternative to frozen plasma transfusion, may reduce the exposure of cancer patients to potentially harmful thrombogenic and pro-inflammatory cellular microparticles. This joint narrative highlights current opinions for minimizing blood usage in patients with cancer. PMID- 28655455 TI - Attention, processing speed, and executive functioning in pediatric brain tumor survivors treated with proton beam radiation therapy. AB - BACKGROUND AND PURPOSE: This study examines attention, processing speed, and executive functioning in pediatric brain tumor survivors treated with proton beam radiation therapy (PBRT). MATERIAL AND METHODS: We examined 39 survivors (age 6 19years) who were 3.61years post-PBRT on average. Craniospinal (CSI; n=21) and focal (n=18) subgroups were analyzed. Attention, processing speed, and executive functioning scores were compared to population norms, and clinical/demographic risk factors were examined. RESULTS: As a group, survivors treated with focal PBRT exhibited attention, processing speed, and executive functioning that did not differ from population norms (all p>0.05). Performance in the CSI group across attention scales was normative (all p>0.05), but areas of relative weakness were identified on one executive functioning subtest and several processing speed subtests (all p<0.01). CONCLUSIONS: Survivors treated with PBRT may exhibit relative resilience in cognitive domains traditionally associated with radiation late effects. Attention, processing speed, and executive functioning remained intact and within normal limits for survivors treated with focal PBRT. Among survivors treated with CSI, a score pattern emerged that was suggestive of difficulties in underlying component skills (i.e., processing speed) rather than true executive dysfunction. No evidence of profound cognitive impairment was found in either group. PMID- 28655457 TI - [Occupational hazards, DNA damage, and oxidative stress on exposure to waste anesthetic gases]. AB - BACKGROUND AND OBJECTIVES: The waste anesthetic gases (WAGs) present in the ambient air of operating rooms (OR), are associated with various occupational hazards. This paper intends to discuss occupational exposure to WAGs and its impact on exposed professionals, with emphasis on genetic damage and oxidative stress. CONTENT: Despite the emergence of safer inhaled anesthetics, occupational exposure to WAGs remains a current concern. Factors related to anesthetic techniques and anesthesia workstations, in addition to the absence of a scavenging system in the OR, contribute to anesthetic pollution. In order to minimize the health risks of exposed professionals, several countries have recommended legislation with maximum exposure limits. However, developing countries still require measurement of WAGs and regulation for occupational exposure to WAGs. WAGs are capable of inducing damage to the genetic material, such as DNA damage assessed using the comet assay and increased frequency of micronucleus in professionals with long-term exposure. Oxidative stress is also associated with WAGs exposure, as it induces lipid peroxidation, oxidative damage in DNA, and impairment of the antioxidant defense system in exposed professionals. CONCLUSIONS: The occupational hazards related to WAGs including genotoxicity, mutagenicity and oxidative stress, stand as a public health issue and must be acknowledged by exposed personnel and responsible authorities, especially in developing countries. Thus, it is urgent to stablish maximum safe limits of concentration of WAGs in ORs and educational practices and protocols for exposed professionals. PMID- 28655458 TI - Phospholipid fatty acid (PLFA) analysis for profiling microbial communities in offshore produced water. AB - A method based on phospholipid fatty acid (PLFA) analysis for profiling microbial communities in offshore produced water was optimized. The operation parameters affecting final PLFA profiling performance from the solid phase extraction (SPE) purification and fatty acid methyl esters (FAMEs) yielding process were investigated. Under the selected conditions, 92.9%, 96.3% and 92.8% of the spiked phospholipid standards C16:1 (cis-9) PC, C18:1 (cis-9) PC, and C19:0 PC were recovered, respectively, using 10mL methanol as elution solvent on a non commercial SPE column. Over 90% of spiked C19:0 PC was recovered before sample transesterification. Four parameters including alkaline reagent, volume of acid for neutralization, time and temperature for FAMEs derivatization were examined. Gas Chromatography-Mass Spectrometry (GC-MS) was used to analyze FAMEs and the method linearities, recoveries of 29 FAMEs during transesterification, detection limits, relative standard deviations were presented. The results provided valuable information for biological reservoir souring control. PMID- 28655459 TI - Detection of low numbers of microplastics in North Sea fish using strict quality assurance criteria. AB - We investigated 400 individual fish of four North Sea species: Atlantic Herring, Sprat, Common Dab, and Whiting on ingestion of >20MUm microplastic. Strict quality assurance criteria were followed in order to control contamination during the study. Two plastic particles were found in only 1 (a Sprat) out of 400 individuals (0.25%, with a 95% confidence interval of 0.09-1.1%). The particles were identified to consist of polymethylmethacrylate (PMMA) through FTIR spectroscopy. No contamination occurred during the study, showing the method applied to be suitable for microplastic ingestion studies in biota. We discuss the low particle count for North Sea fish with those in other studies and suggest a relation between reported particle count and degree of quality assurance applied. Microplastic ingestion by fish may be less common than thought initially, with low incidence shown in this study, and other studies adhering to strict quality assurance criteria. PMID- 28655460 TI - Bioaccumulation of metals and biomarkers of environmental stress in Parablennius sanguinolentus (Pallas, 1814) sampled along the Italian coast. AB - Heavy metal pollution is one of the greatest threats to the ecosystems because it degrades the habitat and is potentially toxic to wildlife and human populations. In the last few decades, bioaccumulation studies performed with a multimarker approach have been a valuable tool for the investigation of environmental and animal safety. We perform an analysis of a benthic teleost fish species - Parablennius sanguinolentus - sampled at several Italian coastal sites with different degrees of anthropogenic pressure. Our integrative analysis encompasses bioaccumulation of 10 metals, biomarkers of environmental stress (micronuclei and nuclear abnormalities) and neutral genetic variation (using sequences of the mtDNA control region). We find a clear and significant correlation of metal bioaccumulation with micronuclei and nuclear abnormalities, especially with undisputed genotoxic metals, such as Cd, Cr, Hg and Pb. Furthermore, the molecular genetic analysis revealed a decrease of genetic variability in the populations more subjected to anthropic pressure. PMID- 28655461 TI - Intraspecific variations in responses to ocean acidification in two branching coral species. AB - Ocean acidification is widely recognised to have a negative impact on marine calcifying organisms by reducing calcifications, but controversy remains over whether such organisms could cope with ocean acidification within a range of phenotypic plasticity and/or adapt to future acidifying ocean. We performed a laboratory rearing experiment using clonal fragments of the common branching corals Montipora digitata and Porites cylindrica under control and acidified seawater (lower pH) conditions (approximately 400 and 900MUatm pCO2, respectively) and evaluated the intraspecific variations in their responses to ocean acidification. Intra- and interspecific variations in calcification and photosynthetic efficiency were evident according to both pCO2 conditions and colony, indicating that responses to acidification may be individually variable at the colony level. Our results suggest that some corals may cope with ocean acidification within their present genotypic composition by adaptation through phenotypic plasticity, while others may be placed under selective pressures resulting in population alteration. PMID- 28655462 TI - Evaluation of the antibiotics effects on the physical and chemical parameters during the co-composting of sewage sludge with palm wastes in a bioreactor. AB - The objective of this study was to investigate thermal and physicochemical parameters of sewage sludge-palm waste mixtures contaminated by different families of antibiotics (tetracyclines, macrolides and fluoroquinolones) during co-composting. Sludge was spiked with chlortetracycline (CTC), oxytetracycline (OTC), roxithromycin (RXY), enrofloxacin (ENR) and ciprofloxacin (CIP). Antibiotics were spiked at a low level, medium level, high level and a control without antibiotics was conducted. The results showed that the organic matter degradation was delayed and the carbon/nitrogen (C/N) ratio was affected by an increase of the antibiotics concentration. The presence of antibiotics, especially at high level, delayed the coming of the temperature maxima, and disturbed the thermophilic phase. The calorific model showed that the heat release is affected during the thermophilic phase when high antibiotics concentrations were used. In addition, the microbiological approach showed that the adsorption of antibiotics on the rachis could be probably responsible of the fungi inhibition especially during the maturation phase. Therefore, the medium and high levels of antibiotics affected the thermal, physical and chemical parameters as well as the compost quality. PMID- 28655463 TI - Further steps in the standardization of BOD5/COD ratio as a biological stability index for MSW. AB - In recent decades the definition of standard test methodologies suitable for use in assessing the biological stability of solid waste has become increasingly imperative. To meet this requirement, the BOD5/COD ratio, measured on waste eluate, has been proposed by Cossu et al. (2012) as a more appropriate parameter than the traditional respirometric indices and biogas production measured directly on solid samples. However, to ensure reproducibility, the parameter should undergo standardization of operational conditions. Previous studies have demonstrated that: the testing mode (static or dynamic) does not influence test representativeness; the long testing time (>6h) does not influence BOD5/COD ratio; COD measured on unfiltered or filtered samples is consistent and significant in both cases. The main aim of this study was to further promote the standardization of this parameter. A series of static leaching tests on representative samples of five types of waste was carried out under different operative conditions: contact time, liquid to solid ratio and pretreatment. The results obtained demonstrate: the apparent adequacy of a short contact time (2h), which is highly preferable and would speed up the procedure; a low liquid to solid ratio (5 l/kgTS) which is recommended as a water saving strategy; the applicability of centrifugation of the eluate prior to analysis which is faster that filtration method. PMID- 28655464 TI - Effect of water-washing on the co-removal of chlorine and heavy metals in air pollution control residue from MSW incineration. AB - The present study systemically investigated the effect of a water-washing process on the removal of harmful chlorides, sulfates, and heavy metals in the air pollution control (APC) residue from municipal solid wastes incineration (MSWI), for sake of a better reuse and disposal of this kind of waste. In addition, the kinetic study was conducted to reveal the releasing mechanism of relevant element in the residue. The results show that, over 70wt.% of chlorides and nearly 25wt.% of sulfates in the residue could be removed by water washing. Based on an economical consideration, the optimal operation conditions for water washing of APC residue was at liquid/solid (L/S) ratio of 3mL:1g and extracting time of 5min. As expected, the concentrations of Co, Cr, Fe, Ni, V and Cu in the washing effluent increased with time during the washing process. However, the extracting regime differs among different heavy metals. The concentrations of Ba and Mn increased firstly but declined afterwards, and concentrations of Pb and Zn gradually declined while Cd and As kept constant with the increase of extracting time. It is worth mentioning that the bubbling of CO2 into the washing effluent is promisingly effective for a further removal of Pb, Cu and Zn. Furthermore, kinetic study of the water washing process reveals that the extracting of heavy metals during water washing follows a second-order model. PMID- 28655465 TI - Hydrothermal post-treatment of digestate to maximize the methane yield from the anaerobic digestion of microalgae. AB - As an alternative to applying the hydrothermal treatment to the raw algal feedstock before the anaerobic digestion (i.e. pre-treatment), one considered a post-treatment scenario where anaerobic digestion is directly used as the primary treatment while the hydrothermal treatment is thereafter applied to the digestate. Hydrothermal treatments such as wet oxidation (WetOx) and hydrothermal carbonization (HTC) were compared at a temperature of 200 degrees C, for initial pressure of 0.1 and 0.82MPa, and no holding time after the process had reached the temperature setpoint. Both WetOx and HTC resulted in a substantial solids conversion (47-62% with HTC, 64-83% with WetOx, both at 0.82MPa) into soluble products, while some total chemical oxygen demand-based carbon loss from the solid-liquid phases was observed (20-39%). This generated high soluble products concentrations (from 6.2 to 10.9g soluble chemical oxygen demand/L). Biomethane potential tests showed that these hydrothermal treatments allowed for a 4-fold improvement of the digestate anaerobic biodegradability. The hydrothermal treatments increased the methane yield to about 200 LSTP CH4/kg volatile solids, when related to the untreated digestate, compared to 66 LSTP CH4/kg volatile solids, without treatment. PMID- 28655466 TI - Three-Dimensional Echocardiography-Derived Non-Invasive Right Ventricular Pressure-Volume Analysis. AB - In patients with pulmonary hypertension, repeated evaluations of right ventricular (RV) function are still required for clinical decision making, but the invasive nature of current pressure-volume analysis makes conducting regular follow-ups in a clinical setting infeasible. We enrolled 12 patients with pulmonary arterial hypertension (PAH) and 10 with pulmonary venous hypertension (PVH) May 2016-October 2016. All patients underwent a clinically indicated right heart catheterization (RHC), from which the yielded right ventricular pressure recordings were conjugated with RV volume by 3-D echocardiography to generate a pressure-volume loop. A continuous-wave Doppler envelope of tricuspid regurgitation was transformed into a pressure gradient recording by the simplified Bernoulli equation, and then a systolic pressure gradient-volume (PG V) diagram was generated from similar methods. The area enclosed by the pressure volume loop was calculated to represent semi-invasive right ventricular stroke work (RVSWRHC). The area between the PG-V diagram and x-axis was calculated to estimate non-invasive RVSW (RVSWecho). Patients with PAH have higher RV pressure, lower pulmonary arterial wedge pressure and larger RV volume that was contributed by the dilation of RV mid-cavity minor dimension. We found no significant difference of traditional parameters between these two groups, but RVSW values were significantly higher in PAH patients. The RVSW values of these two methods were significantly correlated by the equation RVSWecho = 0.8447 RVSWRHC + 129.38 (R2 = 0.9151, p < 0.001). The linearity remained satisfactory in both groups. We conclude that a PG-V diagram is a reliable method to estimate RVSW and to depict pathophysiological status. PMID- 28655467 TI - Determination of Skeletal Muscle Microvascular Flowmotion with Contrast-Enhanced Ultrasound. AB - Most methods of assessing flowmotion (rhythmic oscillation of blood flow through tissue) are limited to small sections of tissue and are invasive in tissues other than skin. To overcome these limitations, we adapted the contrast-enhanced ultrasound (CEUS) technique to assess microvascular flowmotion throughout a large region of tissue, in a non-invasive manner and in real time. Skeletal muscle flowmotion was assessed in anaesthetised Sprague Dawley rats, using CEUS and laser Doppler flowmetry (LDF) for comparison. Wavelet transformation of CEUS and LDF data was used to quantify flowmotion. The alpha-adrenoceptor antagonist phentolamine was infused to predictably blunt the neurogenic component of flowmotion. Both techniques identified similar flowmotion patterns, validating the use of CEUS to assess flowmotion. This study demonstrates for the first time that the novel technique of CEUS can be adapted for determination of skeletal muscle flowmotion in large regions of skeletal muscle. PMID- 28655468 TI - Revisiting the Cramer Rao Lower Bound for Elastography: Predicting the Performance of Axial, Lateral and Polar Strain Elastograms. AB - We derived the Cramer Rao lower bound for 2-D estimators employed in quasi-static elastography. To illustrate the theory, we modeled the 2-D point spread function as a sinc-modulated sine pulse in the axial direction and as a sinc function in the lateral direction. We compared theoretical predictions of the variance incurred in displacements and strains when quasi-static elastography was performed under varying conditions (different scanning methods, different configuration of conventional linear array imaging and different-size kernels) with those measured from simulated or experimentally acquired data. We performed studies to illustrate the application of the derived expressions when performing vascular elastography with plane wave and compounded plane wave imaging. Standard deviations in lateral displacements were an order higher than those in axial. Additionally, the derived expressions predicted that peak performance should occur when 2% strain is applied, the same order of magnitude as observed in simulations (1%) and experiments (1%-2%). We assessed how different configurations of conventional linear array imaging (number of active reception and transmission elements) influenced the quality of axial and lateral strain elastograms. The theoretical expressions predicted that 2-D echo tracking should be performed with wide kernels, but the length of the kernels should be selected using knowledge of the magnitude of the applied strain: specifically, longer kernels for small strains (<5%) and shorter kernels for larger strains. Although the general trends of theoretical predictions and experimental observations were similar, biases incurred during beamforming and subsample displacement estimation produced noticeable differences. PMID- 28655469 TI - Transcutaneous immunization with a novel imiquimod nanoemulsion induces superior T cell responses and virus protection. AB - BACKGROUND: Transcutaneous immunization (TCI) is a novel vaccination strategy utilizing the skin associated lymphatic tissue to induce immune responses. TCI using a cytotoxic T lymphocyte (CTL) epitope and the Toll-like receptor 7 (TLR7) agonist imiquimod mounts strong CTL responses by activation and maturation of skin-derived dendritic cells (DCs) and their migration to lymph nodes. However, TCI based on the commercial formulation Aldara only induces transient CTL responses that needs further improvement for the induction of durable therapeutic immune responses. OBJECTIVE: Therefore we aimed to develop a novel imiquimod solid nanoemulsion (IMI-Sol) for TCI with superior vaccination properties suited to induce high quality T cell responses for enhanced protection against infections. METHODS: TCI was performed by applying a MHC class I or II restricted epitope along with IMI-Sol or Aldara (each containing 5% Imiquimod) on the shaved dorsum of C57BL/6, IL-1R, Myd88, Tlr7 or Ccr7 deficient mice. T cell responses as well as DC migration upon TCI were subsequently analyzed by flow cytometry. To determine in vivo efficacy of TCI induced immune responses, CTL responses and frequency of peptide specific T cells were evaluated on day 8 or 35 post vaccination and protection in a lymphocytic choriomeningitis virus (LCMV) infection model was assessed. RESULTS: TCI with the imiquimod formulation IMI-Sol displayed equal skin penetration of imiquimod compared to Aldara, but elicited superior CD8+ as well as CD4+ T cell responses. The induction of T-cell responses induced by IMI-Sol TCI was dependent on the TLR7/MyD88 pathway and independent of IL-1R. IMI-Sol TCI activated skin-derived DCs in skin-draining lymph nodes more efficiently compared to Aldara leading to enhanced protection in a LCMV infection model. CONCLUSION: Our data demonstrate that IMI-Sol TCI can overcome current limitations of previous imiquimod based TCI approaches opening new perspectives for transcutaneous vaccination strategies and allowing the use of this enhanced cutaneous drug-delivery system to be tailored for the improved prevention and treatment of infectious diseases and cancers. PMID- 28655470 TI - Keratinocytes in atopic dermatitis express abundant DeltaNp73 regulating thymic stromal lymphopoietin production via NF-kappaB. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that often cannot be completely controlled by modern medicine. Since multiple factors are intricately involved in the pathogenesis of AD, wide-ranging research is required for further advancement of AD treatment. Epidermal keratinocytes are the forefront to the external environment and play a pivotal role in the initiation of immune reaction against exogenous invasion. OBJECTIVE: Thymic stromal lymphopoietin (TSLP) is a keratinocyte-derived cytokine that induces differentiation and activation of type 2 helper T cells and innate lymphoid cells, cardinal effectors in pathophysiology of AD. We previously reported that DeltaNp63, a p53-related molecule, regulates the expression of TSLP receptors and suggested the entity of a potential TSLP autocrine loop in the AD epidermis. In this study, we further explored the significance of p53 family transcription factors in TSLP production from human keratinocytes. METHOD: Expression profile of p73, a p53-related molecule, was evaluated in human AD tissue by immunohistochemistry. In addition, the function of p73 in producing TSLP was investigated with in vitro cultured keratinocytes via molecular biological analysis. RESULTS: DeltaNp73 was abundantly expressed in the AD epidermis and increased the release of TSLP via NF-kappaB activation. Furthermore, the Toll like receptor 3 signal enhanced DeltaNp73 expression and thereby induced TSLP expression. CONCLUSION: Our results indicate that DeltaNp73 is an additional participant in the mechanism of TSLP production. Amending the aberrant state of keratinocytes, represented by overexpression of DeltaNp73, can be a novel therapeutic target of AD. PMID- 28655471 TI - Early inflammatory players in cutanous fibrosis. AB - Systemic sclerosis (SSc) is one of the most complex systemic autoimmune diseases with multi-organ involvement and heterogeneous clinical manifestations. The exact etiology of SSc is still unknown. However, identified target structures are components of endothelial cells, the innate/adaptive immune systems and fibroblasts, resulting in the hallmarks of the disease in form of inflammation/autoimmunity, vasculopathy and fibrosis of the skin and internal organs. There has been a large body of evidence that the adaptive immune system with autoreactive T and B cells producing autoantibodies plays a central role in the pathogenesis of SSc but the role of earlier pathogenic processes involving the innate immune system, is far from being understood. There is strong evidence that a dysregulation of innate lymphoid cells and myeloid cells critically contributes to early pathogenic events in SSc. As disruption of vascular homeostasis and a fibroproliferative vasculopathy are hallmarks of early SSc, intravascular processes including platelet activation and interaction with neutrophils and monocytes, may even be upstream of innate immune deviation. Therefore, further studies of the dysregulated innate immune system may provide insights into novel and potentially curative treatments of SSc. In this review, we highlight the most relevant findings regarding the involvement of innate immune cells during the early stage of cutaneous fibrosis in SSc, with emphasis on the role of neutrophils, myeloid cells and innate lymphoid/NK cells in the pathogenesis of SSc and their potential as therapeutic targets for this difficult to-treat autoimmune disease. PMID- 28655472 TI - Induction of skin-pathogenic Th22 cells by epicutaneous allergen exposure. AB - BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with dysfunction of the skin barrier, an abnormal immune response and frequent allergies to environmental antigens like food antigens. Clinical observations suggest that certain diets can influence the course of AD. OBJECTIVE: Here we compared the phenotype of food allergen-specific T cells activated through skin or gut allergen exposure to transfer skin inflammation into naive recipients upon epicutaenous allergen challenge. METHODS: Ovalbumin (OVA) TCR-transgenic mice were treated epicutaneously with OVA or were fed OVA. CD4+ T cells from skin lymph nodes or mesenteric lymph nodes were transferred into naive BALB/c mice, which were challenged with OVA epicutaneously. Skin inflammation was determined by histological parameters. In addition, we analyzed the phenotype of the immune response in lymphoid tissues and in skin tissue. RESULTS: TCR-transgenic T cells activated through epicutaneous or oral OVA exposure both migrate to skin lymph nodes after adoptive transfer and epicutaenous OVA exposure. AD-like skin inflammation could only be induced by the transfer of epicutaneously primed OVA T cells. Analysis of the immune phenotype demonstrated an IL-22/IL-17A-dominated immune phenotype of skin-pathogenic T cells. CONCLUSION: IL-22 seems to be the critical cytokine for the development of AD and is induced in this model by epicutaneous sensitization with OVA. PMID- 28655473 TI - Keratinocytes as sensors and central players in the immune defense against Staphylococcus aureus in the skin. AB - Healthy human skin provides an effective mechanical as well as immunologic barrier against pathogenic microorganisms with keratinocytes as the main cell type in the epidermis actively participating and orchestrating the innate immune response of the skin. As constituent of the outermost layer encountering potential pathogens they have to sense signals from the environment and must be able to initiate a differential immune response to harmless commensals and harmful pathogens. Staphylococci are among the most abundant colonizers of the skin: Whereas Staphylococcus epidermidis is part of the skin microbiota and ubiquitously colonizes human skin, Staphylococcus aureus is only rarely found on healthy human skin, but frequently colonizes the skin of atopic dermatitis (AD) patients. This review highlights recent advances in understanding how keratinocytes as sessile innate immune cells orchestrate an effective defense against S. aureus in healthy skin and the mechanisms leading to an impaired keratinocyte function in AD patients. PMID- 28655474 TI - Quantification of hand function by power grip and pinch strength force measurements in ulnar nerve lesion simulated by ulnar nerve block. AB - INTRODUCTION: In the assessment of hand and upper limb function, grip strength is of the major importance. The measurement by dynamometers has been established. PURPOSE OF THE STUDY: In this study, the effect of a simulated ulnar nerve lesion on different grip force measurements was evaluated. METHODS: In 25 healthy volunteers, grip force measurement was done by the JAMAR dynamometer (Fabrication Enterprises Inc, Irvington, NY) for power grip and by a pinch strength dynamometer for tip pinch strength, tripod grip, and key pinch strength. STUDY DESIGN: A within-subject research design was used in this prospective study. Each subject served as the control by preinjection measurements of grip and pinch strength. Subsequent measurements after ulnar nerve block were used to examine within-subject change. RESULTS: In power grip, there was a significant reduction of maximum grip force of 26.9% with ulnar nerve block compared with grip force without block (P < .0001). Larger reductions in pinch strength were observed with block: 57.5% in tip pinch strength (P < .0001), 61.0% in tripod grip (P < .0001), and 58.3% in key pinch strength (P < .0001). DISCUSSION: The effect of the distal ulnar nerve block on grip and pinch force could be confirmed. However, the assessment of other dimensions of hand strength as tip pinch, tripod pinch and key pinch had more relevance in demonstrating hand strength changes resulting from an distal ulnar nerve lesion. CONCLUSIONS: The measurement of tip pinch, tripod grip and key pinch can improve the follow-up in hand rehabilitation. LEVEL OF EVIDENCE: II. PMID- 28655475 TI - Preoperative Performance of the Patient-Reported Outcomes Measurement Information System in Patients With Rotator Cuff Pathology. AB - PURPOSE: To evaluate the Patient-Reported Outcomes Measurement Information System upper extremity item bank (PROMIS UE) and physical function computerized adaptive test (PROMIS PF CAT) in patients with rotator cuff (RC) pathology at their preoperative clinic visit. METHODS: Patient data were collected from January 2015 to September 2015. Patients with a preoperative diagnosis of RC pathology were prospectively enrolled at the time of their surgical indication for RC repair. Each patient was asked to fill out the Western Ontario Rotator Cuff Index (WORC), American Shoulder and Elbow Surgeons Shoulder Assessment Form, Marx Shoulder Activity Scale, Short Form 36 Health Survey Physical Function and General Health (SF-36 PF and GH), EuroQol-5 Dimension (EQ-5D), PROMIS PF CAT, and PROMIS UE. Correlation was defined as excellent (>0.7), excellent-good (0.61-0.7), good (0.4 0.6), and poor (0.2-0.3). RESULTS: Patient data were collected from January 2015 to September 2015. No patients were excluded from participation in the study. In 82 patients with preoperative RC pathology, the PROMIS UE showed excellent correlation with American Shoulder and Elbow Surgeons Shoulder Assessment Form (r = 0.77, P < .01), WORC (r = 0.73, P < .01), and the EQ-5D (r = 0.73, P < .01); there was excellent-good correlation with the SF-36 PF (r = .66, P < .01) and PROMIS PF CAT (r = .70, P < .01). The PROMIS PF CAT showed excellent correlation with the SF-36 PF (r = 0.77, P < .01); there was excellent-good correlation with EQ-5D (r = 0.65, P < .01) and WORC (r = 0.61, P < .01). There were no significant floor or ceiling effects using the PROMIS UE item bank or PROMIS PF CAT. CONCLUSIONS: We report that in a patient population with preoperative RC pathology, the PROMIS UE and PROMIS CAT are valid patient-reported outcome alternatives that have high correlation with traditional shoulder and upper extremity patient-reported outcomes. We find a decreased question burden using the PROMIS PF CAT. We find no significant floor or ceiling effects present in the PROMIS UE or PROMIS PF CAT. LEVEL OF EVIDENCE: Level II, prospective diagnostic study. PMID- 28655476 TI - Quality Measures in Orthopaedic Sports Medicine: A Systematic Review. AB - PURPOSE: To report the current quality measures that are applicable to orthopaedic sports medicine physicians. METHODS: Six databases were searched with a customized search term to identify quality measures relevant to orthopaedic sports medicine surgeons: MEDLINE/PubMed, EMBASE, the National Quality Forum (NQF) Quality Positioning System (QPS), the Agency for Healthcare Research and Quality (AHRQ) National Quality Measures Clearinghouse (NQMC), the Physician Quality Reporting System (PQRS) database, and the American Academy of Orthopaedic Surgeons (AAOS) website. Results were screened by 2 Board-certified orthopaedic surgeons with fellowship training in sports medicine and dichotomized based on sports medicine-specific or general orthopaedic (nonarthroplasty) categories. Hip and knee arthroplasty measures were excluded. Included quality measures were further categorized based on Donabedian's domains and the Center for Medicare and Medicaid (CMS) National Quality Strategy priorities. RESULTS: A total of 1,292 quality measures were screened and 66 unique quality measures were included. A total of 47 were sports medicine-specific and 19 related to the general practice of orthopaedics for a fellowship-trained sports medicine specialist. Nineteen (29%) quality measures were collected within PQRS, with 5 of them relating to sports medicine and 14 relating to general orthopaedics. AAOS Clinical Practice Guidelines (CPGs) comprised 40 (60%) of the included measures and were all within sports medicine. Five (8%) additional measures were collected within AHRQ and 2 (3%) within NQF. Most quality measures consist of process rather than outcome or structural measures. No measures addressing concussions were identified. CONCLUSIONS: There are many existing quality measures relating to the practice of orthopaedic sports medicine. Most quality measures are process measures described within PQRS or AAOS CPGs. CLINICAL RELEVANCE: Knowledge of quality measures are important as they may be used to improve care, are increasingly being used to determine physician reimbursement, and can inform future quality measure development efforts. PMID- 28655477 TI - Systematic Review of the Long-term Surgical Outcomes of Discoid Lateral Meniscus. AB - PURPOSE: To evaluate the surgical treatment of the discoid lateral meniscus (DLM) with long-term follow-up and to search which factors are related to good clinical or radiological outcomes. METHODS: Search was performed using a MEDLINE, EMBASE, and Cochrane database, and each of the selected studies was evaluated for methodological quality using a risk of bias (ROB) covering 7 criteria. Clinical and radiological outcomes with more than 5 years of follow-up were evaluated after surgical treatment of DLM. They were analyzed according to the age, follow up period, kind of surgery, DLM type, and alignment. RESULTS: Eleven articles (422 DLM cases) were included in the final analysis. Among 7 criteria, 3 criteria showed little ROB in all studies. However, 4 criteria showed some ROB ("Yes" in 63.6% to 81.8%). The minimal follow-up period was 5.5 years (weighted mean follow up: 9.1 years). Surgical procedures were performed with open or arthroscopic partial central meniscectomy, subtotal meniscectomy, total meniscectomy, or partial meniscectomy with repair. The majority of the studies showed good clinical results. Mild joint space narrowing was reported in the lateral compartment, but none of the knees demonstrated moderate or advanced degenerative changes. Increased age at surgery, longer follow-up period, and subtotal or total meniscectomy could be related to degenerative change. The majority of the complications was osteochondritis dissecans at the lateral femoral condyle (13 cases) and reoperation was performed by osteochondritis dissecans (4 cases), recurrent swelling (2 cases), residual symptom (1 case), stiffness (1 case), and popliteal stenosis (1 case). CONCLUSIONS: Good clinical results were obtained with surgical treatment of symptomatic DLM. The progression of degenerative change was minimal and none of the knees demonstrated moderate or advanced degenerative changes. Increased age at surgery, longer follow-up period, and subtotal or total meniscectomy were possible risk factors for degenerative changes. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 28655478 TI - The impact of argon/oxygen low-pressure plasma on shear bond strength between a veneering composite and different PEEK materials. AB - OBJECTIVE: The aim of the study was to evaluate the impact of low-pressure argon/oxygen plasma with and without previous sandblasting on the shear bond strength (SBS) between dental PEEK compounds and a veneering composite. METHODS: Of one type of unfilled PEEK and two pigment powder filled PEEK compounds, forty rectangular plates each were prepared and polished up to 4000 grit. The samples were randomly assigned to four surface pre-treatment groups, each consisting of ten specimens (1. Untreated; 2. Plasma treatment; 3. Sandblasting; 4. Sandblasting+plasma treatment). Plasma treatment was performed for 35min using a low-pressure plasma system with a 1:1 mixture of the process gases argon and oxygen. Surface roughness and water contact angles were recorded. An adhesive (Visio.link, Bredent GmbH & Co KG, Senden, Germany) was applied onto the specimen surfaces and light cured. A mold was used to shape the veneering composite (Vita VM LC, Vita Zahnfabrik, Bad Sackingen, Germany) into a cylindrical form on the sample surface before light curing. SBS was measured after 24h incubation at 37 degrees C in distilled water using a universal testing machine. RESULTS: The samples pre-treated according to group 4 (sandblasting and plasma treatment) showed the highest SBS overall, whereas the unfilled PEEK showed the highest SBS (19.8+/-2.46MPa) compared to the other PEEK materials (15.86+/-4.39MPa and 9.06+/ 3.1MPa). SIGNIFICANCE: Sandblasting and surface activation with low-pressure argon/oxygen plasma in combination with an adhesive causes a favorable increase in shear bond strength, especially on unfilled PEEK material. PMID- 28655479 TI - The pathology of pulmonary bacterial infection. PMID- 28655481 TI - Arnstein Finset's legacy. PMID- 28655480 TI - Associations of suicidality with cognitive ability and cognitive insight in outpatients with Schizophrenia. AB - BACKGROUND: Previous literature suggests that better cognitive ability and insight are associated with greater lifetime risk of suicide attempts in schizophrenia, counter to the direction of association in the general population. However, the conjoint association between distinct cognitive domains, insight, and suicidality has not been assessed. METHOD: In a cross-sectional study, 162 adults with schizophrenia or schizoaffective disorder completed cognitive testing via the MATRICS battery, symptom and cognitive insight assessments, along with the Columbia Suicide Severity Rating Scale. We then contrasted participants based on history of suicidality by cognitive domains and insight measures and conducted multivariate analyses. RESULTS: Although a history of any passive ideation was not associated with cognitive ability or insight, verbal learning was positively associated with a greater history of suicidal attempt and prior ideation with a plan and intent. Higher cognitive insight, and the self-reflectiveness subscale insight, was also associated with history of passive or active suicidal ideation. Cognitive insight and cognitive ability were independent from each other, and there were no moderating influences of insight on the effect of cognitive ability on suicide related history. Exploratory analyses revealed that history of planned attempts were associated with greater verbal learning, whereas histories of aborted attempts were associated with poorer reasoning and problem-solving. IMPLICATIONS: Although cross-sectional and retrospective, this study provides support that greater cognitive ability, specifically verbal learning, along with self-reflectiveness, may confer elevated risk for more severe suicidal ideation and behavior in an independent fashion. Interestingly, poorer problem-solving was associated with aborted suicide attempts. PMID- 28655482 TI - Editorial. PMID- 28655483 TI - The impact of pre- and post-operative weight loss and body mass index on prognosis in patients with oesophageal cancer. AB - BACKGROUND: Weight loss is a cardinal symptom of oesophageal cancer and is often continued after surgery. High body mass index (BMI) is a strong risk factor for oesophageal adenocarcinoma. This study aimed to assess the impact of pre- and post-operative weight loss and BMI on long-term mortality after resection for oesophageal cancer. METHODS: This prospective and nationwide cohort study included 390 patients, operated on for oesophageal cancer in Sweden in 2001-2005 with follow-up until 2016, who responded to a questionnaire on weight history 6 months after surgery. Multivariable Cox proportional hazard models provided hazard ratios (HRs) and 95% confidence intervals (95% CIs) of mortality while adjusting for several prognostic factors, including tumour stage. RESULTS: Compared to weight stable patients, pre-surgery weight loss indicated increased HRs of overall all-cause mortality (HR = 1.32, 95% CI 0.94-1.86) and disease specific mortality (HR = 1.36, 95% CI 0.93-1.98). Patients with >20% weight loss post-surgery had worse overall all-cause mortality (HR = 1.71, 95% CI 1.01-2.88) and disease-specific mortality (HR = 2.20, 95% CI 1.24-3.89). Compared to patients with normal BMI, decreased HRs were indicated for patients who were obese at the time of surgery (overall all-cause mortality HR 0.87 95% CI, 0.58 1.31 and disease-specific mortality HR = 0.89, 95% CI 0.57-1.40), while patients with BMI <=19.9 at 6 months post-surgery had increased all-cause mortality (HR = 1.41, 95% CI 1.03-1.95) and disease-specific mortality (HR = 1.55, 95% CI 1.09 2.21). CONCLUSION: Post-operative weight loss and low BMI at 6 months post surgery are independent markers of poor prognosis in patients who undergo surgery for oesophageal cancer. PMID- 28655484 TI - [Anterior skull-base schwannoma]. AB - Schwannomas are nerve sheath tumours that originate in Schwann cells. They are usually solitary and sporadic and manifest on peripheral, spinal or cranial nerves. Intracranial schwannomas tend to manifest on the eighth cranial nerve, particularly in patients with neurofibromatosis type2. Anterior skull-base schwannomas represent less than 1% of all intracranial schwannomas. They are more frequent in young people and are typically benign. These tumours represent a diagnostic challenge due to their rarity and difficult differential diagnosis, and numerous theories have been postulated concerning their origin and development. In this article, we present the case of a 13-year-old male with a single anterior cranial-base tumour not associated with neurofibromatosis who presented with headache, papilloedema, eye pain and loss of visual acuity. Complete resection of the tumour was performed, which was histopathologically diagnosed as a schwannoma. The patient made a complete clinical recovery with abatement of all symptoms. We conducted a review of the literature and found 66 cases worldwide with this diagnosis. We describe the most relevant epidemiological and clinical characteristics of this kind of tumour and its relation with the recently discovered and similar olfactory schwannoma. PMID- 28655485 TI - The low-dose benzene debate needs a sharp blade. PMID- 28655486 TI - Vaginal Atrophy in Breast Cancer Survivors: Attitude and Approaches Among Oncologists. AB - BACKGROUND: Vulvovaginal atrophy (VVA) is a relevant problem for breast cancer survivors (BCSs), in particular for those who receive aromatase inhibitors (AIs). We conducted a survey, to assess the attitude of oncologists toward the diagnosis and treatment of VVA in BCSs. MATERIALS AND METHODS: In 2015, 120 computer assisted Web interviews were performed among breast oncologists. RESULTS: According to oncologists' perceptions, 60% of postmenopausal BCSs and 39.4% of premenopausal BCSs will suffer from VVA. Despite that none of the physicians considered VVA as a transient event or a secondary problem in BCSs, only half of the oncologists (48%) directly illustrated VVA to the patients as a possible consequence. Forty-one percent of the oncologists refer BCSs to gynaecologist to define VVA treatment, whereas 35.1% manages it alone. Nonhormonal treatments are preferred by most oncologists (71%). The main reason not to prescribe vaginal estrogen therapy in BCSs is the fear of increased cancer recurrence, the possible interference with tamoxifen, or AIs and the fear of medical litigation. CONCLUSION: VVA is a relevant problem for BCSs. Great effort should be done to correctly inform health care providers about VVA problems and on the different possible available treatments. PMID- 28655487 TI - Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals. AB - Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufacturing. The fate of this emerging technology will rely, in large part, on the regulatory implementation of this novel technology. This paper, which is based on the 2nd International Symposium on the Continuous Manufacturing of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufacturing of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufacturing. Collaborative efforts, among academia, industry, and regulatory agencies, are the optimal solution for ensuring a solid future for this promising manufacturing technology. PMID- 28655488 TI - Acute Superior Vena Cava Syndrome After Thoracic Surgery. PMID- 28655489 TI - The spillover effects of health insurance benefit mandates on public insurance coverage: Evidence from veterans. AB - This study examines how regulations in private health insurance markets affect coverage of public insurance. We focus on mental health parity laws, which mandate private health insurance to provide equal coverage for mental and physical health services. The implementation of mental health parity laws may improve a quality dimension of private health insurance but at increased costs. We graphically develop a conceptual framework and then empirically examine whether the regulations shift individuals from private to public insurance. We exploit state-by-year variation in policy implementation in 1999-2008 and focus on a sample of veterans, who have better access to public insurance than non veterans. Using data from the Current Population Survey, we find that the parity laws reduce employer-sponsored insurance (ESI) coverage by 2.1% points. The drop in ESI is largely offset by enrollment gains in public insurance, namely through the Veterans Affairs (VA) benefit and Medicaid/Medicare programs. PMID- 28655490 TI - Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment - a clinical appraisal. AB - AIM: A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes. METHOD: A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel. RESULTS: Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature. CONCLUSIONS: While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies. PMID- 28655491 TI - Effects of the Affordable Care Act's contraceptive coverage requirement on the utilization and out-of-pocket costs of prescribed oral contraceptives. AB - BACKGROUND: The Affordable Care Act (ACA) mandated that private health insurance plans cover prescribed contraceptive services for women, including oral contraceptives (OCs), without charging a patient any cost-sharing beginning in August 2012. OBJECTIVE: To evaluate the effects of the ACA's contraceptive coverage requirement on the utilization and out-of-pocket costs of prescribed OCs after two years of implementation. METHODS: A retrospective, cross-sectional study was designed using data from the 2010 to 2014 waves of the Medical Expenditure Panel Survey. The sample consisted of reproductive-aged women who have either private health insurance or Medicaid. Utilization of OCs was evaluated using 1) the proportion of women who purchased any OCs and 2) the mean annual number of cycles prescribed per woman. Out-of-pocket costs for OCs were evaluated using 1) the proportion of women who had any OC purchase with $0 out-of pocket costs, 2) the mean annual out-of-pocket costs per woman, and 3) the mean out-of-pocket costs per cycle. Descriptive analyses and a difference-in difference linear regression approach were used. MAIN FINDINGS: No substantial changes were seen in the utilization of OCs after the ACA requirement became effective. The difference-in-difference regression showed that the proportion of women who had any OC purchase with $0 out-of-pocket costs increased significantly by 54.0 percentage points after the ACA requirement in the private insurance group relative to the Medicaid group. Mean annual out-of-pocket costs in the private insurance group dropped by 37% in the first year and an additional 52% decrease was found in the second year of the policy. Mean out-of-pocket costs per cycle also decreased substantially in the private insurance group by 39% in the first year and an additional decrease of 44% was seen in the second year. CONCLUSIONS: The ACA's contraceptive coverage requirement markedly reduced out-of pocket costs of prescribed OCs for women with private health insurance. PMID- 28655492 TI - Medication adherence beliefs of U.S community pharmacists. AB - BACKGROUND: There is increasing attention on the role of community pharmacists in improving medication adherence. There is a need to better understand pharmacist attitudes and experiences related to this role. OBJECTIVE: To assess community pharmacist perceptions of patient reasons for non-adherence, characterize the adherence beliefs of community pharmacists, and test if there are demographic predictors of pharmacists' self-efficacy, outcome expectations, and role beliefs related to intervening on medication non-adherence. METHODS: A cross-sectional survey was mailed using a 4-contact approach to 1000 pharmacists practicing in 5 Midwestern U.S. States. The survey included seven domains to address the study objectives. Descriptive statistics were calculated for demographic items, coefficient alphas tested the internal consistency of scales, and multiple regression was used to test the relationship between demographics and scale means. RESULTS: There were 261 usable responses giving a 29% response rate. Pharmacists perceived forgetting and instructions changing without a new prescription to be the most common reasons for late refills. A minority of pharmacists agreed that non-adherence involves a deliberate decision or that negative medication beliefs were common reasons for late refills. Pharmacists were confident, had positive outcome expectations, and positive role beliefs related to interacting with patients who have adherence issues. Barriers to adherence intervention included difficulties with follow-up and documentation. Also, over half of the pharmacists reported that discussing adherence makes patients defensive. CONCLUSIONS: Pharmacists had positive attitudes toward intervening on medication non-adherence although barriers to intervention are present. Pharmacists perceived non-intentional reasons for late refills to be more prevalent than intentional reasons. Pharmacists may benefit from additional non-adherence communication training and support targeted at identifying a broader range of non-adherence reasons. PMID- 28655493 TI - EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement. AB - Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX neurotoxicity, we observed an electroencephalographic (EEG) with extreme delta brush. Extreme delta brush is an EEG pattern previously described in patients with NMDAR autoimmune encephalitis. The observations suggest that the mechanism of this neurotoxicity may be mediated by the NMDAR. Furthermore, extreme EEG delta brush should suggest a diagnosis of MTX associated subacute neurotoxicity. PMID- 28655495 TI - Tranylcypromine in mind (Part I): Review of pharmacology. AB - It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: Part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and Part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. Pharmacological data of this review part I characterize TCP as an irreversible and nonselective MAO-A/B inhibitor at low therapeutic doses of 20mg/day with supplementary norepinephrine reuptake inhibition at higher doses of 40-60mg/day. Serotonin, norepinephrine, dopamine, and trace amines, such as the "endogenous amphetamine" phenylethylamine, are increased in brain, which leads to changes in neuroplasticity by e.g. increased neurotrophic growth factors and translates to reduced stress-induced hypersecretion of corticotropin releasing factor (CRF) and positive testing in animal studies of depression. TCP has a pharmacokinetic half life (t1/2) of only 2h which is considerably lower than for most other antidepressant drugs. However, a very long pharmacodynamic half-life of about one week is found because of the irreversible MAO inhibition. New studies show that, except for cytochrome P450 (CYP) 2A6, no other drug metabolizing CYP-enzymes are inhibited by TCP at therapeutic doses which defines a low potential of pharmacokinetic interactions in the direction from TCP to other drugs. Insufficient information is available, however, for plasma concentrations of TCP influenced by comedication. More quantitative data are also needed for TCP metabolites such as p-hydroxytranylcypromine and N-acetyltranylcypromine. Pharmacodynamic drug interactions comprise for instance severe serotonin toxicity (SST) with serotonergic drugs and hypertensive crisis with indirect sympathomimetics. Because of the risk of severe food interaction, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet. Toxicity in overdose is similar to amitriptyline and imipramine according to the distance of therapeutic to toxic doses. In conclusion, TCP is characterized by an exceptional pharmacology which is different to most other antidepressant drugs, and a more special evaluation of clinical efficacy and safety may therefore be needed. PMID- 28655496 TI - Mosquito aging modulates the heart rate and the proportional directionality of heart contractions. AB - Mosquito aging impacts a myriad of physiological processes, including digestion, flight, mating, reproductive success, and immunity. In the present study, we conducted intravital video imaging in 1, 3, 5, 10, 15 and 20-day-old Anopheles gambiae female adults to assess whether aging impacts mosquito heart physiology. We found that the heart contraction rate increases over the first 15days of adulthood and then decreases. These changes occur for both contraction directions, although aging results in a relative change in the anterograde versus retrograde contraction rates. That is, whereas for the first 5days of life the anterograde and retrograde contraction rates are similar, from day 10 to day 20 the retrograde contraction rate is higher than the anterograde contraction rate. Aging also biases the proportional directionality of heart contractions, from approximately two thirds of the time being spent contracting in the anterograde direction and two thirds of the contractions propagating anterograde during the first 5days of life to an approximately even split between anterograde and retrograde when the mosquitoes have reached 10 to 20days of age. Transcriptional analyses of crustacean cardioactive peptide (CCAP), FMRFamide, calcium-calmodulin dependent kinase II (CaMKII), pygopus, manganese-iron superoxide dismutase (MnSOD1) and vinculin by quantitative RT-PCR revealed age-associated changes in gene expression, with MnSOD1 and vinculin expression showing a declining trend with age. RNAi-based knockdown of MnSOD1 or vinculin resulted in heart physiology that trended toward the aging phenotype for every parameter that was measured, suggesting that these two genes are involved in cardiac aging. PMID- 28655497 TI - Pharmacokinetics of dexmedetomidine in isoflurane-anesthetized New Zealand White rabbits. AB - OBJECTIVE: To characterize the pharmacokinetics of dexmedetomidine when administered as a short intravenous (IV) infusion to isoflurane-anesthetized rabbits. STUDY DESIGN: Experimental study. ANIMALS: A total of six healthy adult female New Zealand White rabbits. METHODS: Rabbits were anesthetized with isoflurane in oxygen. Following determination of isoflurane minimum alveolar concentration (MAC), the anesthetic dose was reduced to 0.7 * MAC, and dexmedetomidine hydrochloride (20 MUg kg-1) was infused IV over 5 minutes. Arterial blood samples were obtained immediately before and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240 and 360 minutes following termination of the infusion. Samples were transferred into tubes containing ethylenediaminetetraacetic acid and centrifuged immediately. The plasma was harvested and stored at -80 degrees C until analyzed. Concentrations of dexmedetomidine in plasma were determined by liquid chromatography mass spectrometry. Compartment models were fitted to the time and concentration data using nonlinear regression. RESULTS: A three compartment model best fit the data set. Median volume of distribution at steady state and terminal half-life were 3169 mL kg-1 (range, 2182-3859 mL kg-1) and 80 minutes (range, 72-88 minutes), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of dexmedetomidine in isoflurane-anesthetized, healthy, New Zealand White rabbits were characterized in this study. Data from this study can be used to determine dosing regimens for dexmedetomidine in isoflurane anesthetized rabbits. PMID- 28655498 TI - Mind Games: Game Engines as an Architecture for Intuitive Physics. AB - We explore the hypothesis that many intuitive physical inferences are based on a mental physics engine that is analogous in many ways to the machine physics engines used in building interactive video games. We describe the key features of game physics engines and their parallels in human mental representation, focusing especially on the intuitive physics of young infants where the hypothesis helps to unify many classic and otherwise puzzling phenomena, and may provide the basis for a computational account of how the physical knowledge of infants develops. This hypothesis also explains several 'physics illusions', and helps to inform the development of artificial intelligence (AI) systems with more human-like common sense. PMID- 28655499 TI - Continuous exposure to low-frequency noise and carbon disulfide: Combined effects on hearing. AB - Carbon disulfide (CS2) is used in industry; it has been shown to have neurotoxic effects, causing central and distal axonopathies.However, it is not considered cochleotoxic as it does not affect hair cells in the organ of Corti, and the only auditory effects reported in the literature were confined to the low-frequency region. No reports on the effects of combined exposure to low-frequency noise and CS2 have been published to date. This article focuses on the effects on rat hearing of combined exposure to noise with increasing concentrations of CS2 (0, 63,250, and 500ppm, 6h per day, 5 days per week, for 4 weeks). The noise used was a low-frequency noise ranging from 0.5 to 2kHz at an intensity of 106dB SPL. Auditory function was tested using distortion product oto-acoustic emissions, which mainly reflects the cochlear performances. Exposure to noise alone caused an auditory deficit in a frequency area ranging from 3.6 to 6 kHz. The damaged area was approximately one octave (6kHz) above the highest frequency of the exposure noise (2.8kHz); it was a little wider than expected based on the noise spectrum.Consequently, since maximum hearing sensitivity is located around 8kHz in rats, low-frequency noise exposure can affect the cochlear regions detecting mid-range frequencies. Co-exposure to CS2 (250-ppm and over) and noise increased the extent of the damaged frequency window since a significant auditory deficit was measured at 9.6kHz in these conditions.Moreover, the significance at 9.6kHz increased with the solvent concentrations. Histological data showed that neither hair cells nor ganglion cells were damaged by CS2. This discrepancy between functional and histological data is discussed. Like most aromatic solvents, carbon disulfide should be considered as a key parameter in hearing conservation regulations. PMID- 28655500 TI - Finite-element design and optimization of a three-dimensional tetrahedral porous titanium scaffold for the reconstruction of mandibular defects. AB - Reconstruction of segmental defects in the mandible remains a challenge for maxillofacial surgery. The use of porous scaffolds is a potential method for repairing these defects. Now, additive manufacturing techniques provide a solution for the fabrication of porous scaffolds with specific geometrical shapes and complex structures. The goal of this study was to design and optimize a three dimensional tetrahedral titanium scaffold for the reconstruction of mandibular defects. With a fixed strut diameter of 0.45mm and a mean cell size of 2.2mm, a tetrahedral structural porous scaffold was designed for a simulated anatomical defect derived from computed tomography (CT) data of a human mandible. An optimization method based on the concept of uniform stress was performed on the initial scaffold to realize a minimal-weight design. Geometric and mechanical comparisons between the initial and optimized scaffold show that the optimized scaffold exhibits a larger porosity, 81.90%, as well as a more homogeneous stress distribution. These results demonstrate that tetrahedral structural titanium scaffolds are feasible structures for repairing mandibular defects, and that the proposed optimization scheme has the ability to produce superior scaffolds for mandibular reconstruction with better stability, higher porosity, and less weight. PMID- 28655501 TI - Osteoporosis Knowledge and Health Beliefs Among Men in Midlife Years. AB - OBJECTIVE: To examine the role of socioeconomic variables on middle-aged adult men's knowledge and health beliefs about osteoporosis. METHODS: An anonymous survey used validated scales to assess osteoporosis knowledge and health beliefs in a sample of 262 men aged 36-55 years. Descriptive and group-differences statistics (MANOVA and ANOVA) were used. RESULTS: Total osteoporosis knowledge was low (mean, 11.1 of 22) and mean scores on perceived susceptibility and seriousness health belief domains were also low: 13.2 and 17.2, respectively out of 30. Multivariate ANOVA revealed that perceived seriousness, barriers to calcium intake, and health motivation varied significantly with level of formal education attained (P < .05). There was no significant difference with income. CONCLUSIONS AND IMPLICATIONS: Results of this convenience sample of predominantly white men found that level of osteoporosis knowledge and perceived susceptibility were low. Given the increased prevalence of osteoporosis-related fracture in men, methods to increase knowledge and awareness are needed. PMID- 28655502 TI - Genetic diversity of pvl-positive community-onset methicillin-resistant Staphylococcus aureus isolated at a university hospital in Japan. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is pathogenic to healthy individuals and a significant issue throughout the world. Panton-Valentine leukocidin gene (pvl)-positive sequence type (ST) 8 staphylococcal cassette chromosome (SCC) mec type IV (ST8-IV) as represented by the USA300 clone, is the most prevalent CA-MRSA in many countries. However, the prevalence of pvl-positive CA-MRSA was limited in Japan. Here, we report the incidence of pvl-positive community-onset MRSA (CO-MRSA) isolated from 10 patients seen between 2009 and 2014 at a Japanese university hospital. All patients were Japanese and eight cases involved severe skin infections. Antimicrobial susceptibility patterns of the pvl-positive isolates were consistent with those of a typical CA-MRSA clone. Detailed molecular epidemiological analyses showed that three isolates were ST8-IV USA300 clones, whereas the other seven were ST30-IV (three isolates), ST30-I (one isolate), ST59 V (two isolates), and ST1-V (one isolate) clones. No clear difference of infection severity was found between the patients associated with the USA300 clone and those with the other clones. Our findings show that, not only the USA300 clone, but also diverse pvl-positive CO-MRSA clones exist in the community and cause severe skin infections in Japan. PMID- 28655503 TI - In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2015-16 season: Comparison with the 2010-11 to 2014-15 seasons. AB - To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2015-2016 influenza season in Japan, we measured the 50% inhibitory concentration (IC50) of NAIs for influenza virus isolates and compared them with the results from the 2010-11 to 2014-15 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Influenza viruses were isolated: 210 influenza A(H1N1)pdm09 (67.3%), 20 A(H3N2) (6.4%), and 82 B (26.3%), and for the Victoria and Yamagata lineages the numbers were 53 (64.6%) and 28 (34.1%), respectively, with one unknown. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM). No isolate showed a very high IC50 for A(H3N2) or B. The ratios of geometric mean IC50 of the 2015-2016 influenza season to those of the 2010-2011 to 2014-2015 influenza seasons ranged from 0.62 to 1.78 for A(H1N1) pdm09. The range was 0.73-1.35 for A(H3N2) and 0.48-1.12 for B. No significant trend of increase or decrease in IC50 was found for any of the four NAIs. Although some isolates showed highly reduced sensitivity to oseltamivir among the A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2), and B viruses are susceptible to all four NAIs, with no trend toward decreased sensitivity. PMID- 28655505 TI - Role of ethnopharmacologists in the conservation of endangered animal species. PMID- 28655504 TI - Early life factors and dental caries in 5-year-old children in China. AB - OBJECTIVES: This study aimed to explore the association between early life factors and dental caries among 5-year-old Chinese children. METHODS: Data from 9722 preschool children who participated in the third National Oral Health Survey of China were analysed. Information on early life (birth weight, breastfeeding and age when toothbrushing started), child (sex, ethnicity, birth order and dental behaviours) and family factors (parental education, household income, place of residence, number of children in the family, respondent's age and relation to the child) were obtained from parental questionnaires. Children were also clinically examined to assess dental caries experience using the decayed, missing and filled teeth (dmft) index. The association of early life factors with dmft was evaluated in negative binomial regression models. RESULTS: We found that birth weight was not associated with dental caries experience; children who were exclusively and predominantly formula-fed had lower dmft values than those exclusively breastfed; and children who started brushing later in life had higher dmft values than those who were brushing within the first year. Only one in seven of all children received regular toothbrushing twice per day, and only 34.7% had commenced toothbrushing by the age of 3 years. CONCLUSIONS: This study shows certain early life factors play a role in dental caries among Chinese preschool children and provides important insights to shape public health initiatives on the importance of introducing early toothbrushing. CLINICAL SIGNIFICANCE: The early environment, especially the age when parents introduce toothbrushing to their children, can be an important factor to prevent childhood dental caries. PMID- 28655506 TI - In Silico Shear and Intramural Stresses are Linked to Aortic Valve Morphology in Dilated Ascending Aorta. AB - OBJECTIVE/BACKGROUND: The development of ascending aortic dilatation in patients with bicuspid aortic valve (BAV) is highly variable, and this makes surgical decision strategies particularly challenging. The purpose of this study was to identify new predictors, other than the well established aortic size, that may help to stratify the risk of aortic dilatation in BAV patients. METHODS: Using fluid-structure interaction analysis, both haemodynamic and structural parameters exerted on the ascending aortic wall of patients with either BAV (n = 21) or tricuspid aortic valve (TAV; n = 13) with comparable age and aortic diameter (42.7 +/- 5.3 mm for BAV and 45.4 +/- 10.0 mm for TAV) were compared. BAV phenotypes were stratified according to the leaflet fusion pattern and aortic shape. RESULTS: Systolic wall shear stress (WSS) of BAV patients was higher than TAV patients at the sinotubular junction (6.8 +/- 3.3 N/m2 for BAV and 3.9 +/- 1.3 N/m2 for TAV; p = .006) and mid-ascending aorta (9.8 +/- 3.3 N/m2 for BAV and 7.1 +/- 2.3 N/m2 for TAV; p = .040). A statistically significant difference in BAV versus TAV was also observed for the intramural stress along the ascending aorta (e.g., 2.54 * 105 +/- 0.32 * 105 N/m2 for BAV and 2.04 * 105 +/- 0.34 * 105 N/m2 for TAV; p < .001) and pressure index (0.329 +/- 0.107 for BAV and 0.223 +/- 0.139 for TAV; p = .030). Differences in the BAV phenotypes (i.e., BAV type 1 vs. BAV type 2) and aortopathy (i.e., isolated tubular vs. aortic root dilatations) were associated with asymmetric WSS distributions in the right anterior aortic wall and right posterior aortic wall, respectively. CONCLUSION: These findings suggest that valve mediated haemodynamic and structural parameters may be used to identify which regions of aortic wall are at greater stress and enable the development of a personalised approach for the diagnosis and management of aortic dilatation beyond traditional guidelines. PMID- 28655507 TI - Hyperplasia of Interstitial Cells of Cajal Leads to Rapid Gastric Emptying in Diabetes. PMID- 28655508 TI - A Penetrating Look at Eosinophilic Esophagitis Pathogenesis: Direct Antigen Exposure in the Esophagus? PMID- 28655509 TI - Filgotinib in Crohn's Disease: JAK Is Back. PMID- 28655510 TI - Collagen XIV and a related recombinant fragment protect human vascular smooth muscle cells from calcium-/phosphate-induced osteochondrocytic transdifferentiation. AB - Transdifferentiation of vascular smooth muscle cells (VSMC) promotes the development of vascular calcifications such as arteriosclerosis. The aim was to investigate effects of specific extracellular matrix (ECM) components on transdifferentiation of VSMC to identify novel ECM-based therapeutic tools. Human collagens I & IV (CI, CIV) along with collagen XIV (CXIV) and a CXIV-derived fragment (CXIV-F), both of which induce differentiation, were applied in an in vitro model of calcium-/phosphate (Ca/P)-induced osteochondrocytic transdifferentiation of human and murine VSMC. Transdifferentiation was determined by RT-PCR and calcium contents of VSMC cultures. Signaling pathways involved were determined by western-blot and luciferase reporter plasmid assays. Under normal culture conditions, CI induced VSMC proliferation and a more epithelioid/synthetic phenotype while CIV and predominantly CXIV provoked opposite effects. CIV and CXIV further blocked Ca/P-induced osteochondrocytic transdifferentiation of VSMC displayed e.g. by reduced gene expressions of Runx2, Sox9, osterix and increased expressions of alphaSMA and SM22alpha. This involved impaired activation of ERK1/2, NF-KB and Wnt-signaling. Similar preventive effects were achieved by applying CXIV-F. Impaired preventive effects of CXIV by co-treatment with a cluster of differentiation (CD)44 agonist propose CD44 as a CXIV-target structure on VSMC. In conclusion, CXIV and CXIV-F interfere with osteochondrocytic transdifferentiation of VSMC and should be further explored as potential therapeutic tools in vascular calcification. PMID- 28655512 TI - Reply to: 'Patients with low-risk cutaneous squamous cell carcinoma do not require extended out-patient follow-up'. PMID- 28655511 TI - Tobacco use as a screener for Clostridium difficile infection outcomes. AB - A retrospective cohort study was conducted to evaluate the utility of self reported tobacco use for developing a clinical prediction rule for poor outcomes of Clostridium difficile infection. Patients with any history of smoking were significantly less likely than never smokers to be cured of their infection within two weeks. Disease recurrence, readmission within 30 days, death before treatment completion, and the severity of Clostridium difficile infection were not associated with smoking status. PMID- 28655513 TI - Measuring the carbon footprint of plastic surgery: A preliminary experience in a Chilean teaching hospital. PMID- 28655514 TI - Incidence and risk factors for venous thromboembolism in bilateral breast reduction surgery: An analysis of the National Surgical Quality Improvement Program. AB - BACKGROUND: The risk of venous thromboembolism (VTE) in patients undergoing bilateral breast reduction surgery remains unknown. This study aimed to determine VTE incidence and risk factors in this patient cohort. METHODS: American College of Surgeons National Surgical Quality Improvement Program (2010-2014) was used to identify women undergoing bilateral breast reduction. Demographic factors, comorbidities, and incidence of postoperative VTE were evaluated. Bivariate and risk-adjusted multivariate logistic regressions were performed to determine factors associated with the development of postoperative VTE. RESULTS: A total of 5371 cases were identified. The mean age was 43.7 years (SD +/- 13.9 years). The rate of VTE was 0.22%, with 0.17% rate of pulmonary embolism and 0.07% rate of deep venous thrombosis requiring treatment. Patients who suffered VTE were older (52.4 +/- 12.8 vs. 43.7 +/- 13.9 years, p < 0.05), had longer length of stay (1.7 +/- 2.9 vs. 0.4 +/- 2.1 days, p < 0.05), and had higher rates of blood transfusion (8.3% vs. 0.4%, p < 0.01) and reoperation (16.7% vs. 2.0%, p < 0.01). Risk-adjusted multivariate analysis demonstrated that older age (OR 1.05, 95% CI 1.01-1.10), postoperative blood transfusion (OR 12.1, 95% CI 1.3-112.0) and unplanned return to the operating room (OR 6.7, 95% CI 1.3-34.8) were independent risk factors for developing postoperative VTE. CONCLUSION: In bilateral breast reduction surgery, older patients, patients requiring blood transfusion, and patients who have unplanned return to the operating room are at an increased risk of developing postoperative VTE. These factors can be considered for patient risk stratification and perioperative decision-making regarding VTE prevention. PMID- 28655515 TI - Early-life lipopolysaccharide exposure potentiates forebrain expression of NLRP3 inflammasome proteins and anxiety-like behavior in adolescent rats. AB - BACKGROUND: Neonatal inflammation may affect brain development and lead to cognitive and emotional deficits at adolescence and adulthood. The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) is the core component of NLRP3 inflammasome, which may involve in neuroinflammation. We explored if early-life exposure to the bacterial endotoxin lipopolysaccharide (LPS) could promote the expression of proteins related to NLRP3 inflammasome, including NLRP3, the apoptosis-associated speck-like protein (ASC) and cysteiny aspartate-specific protease (Caspase-1) in the forebrain, and behavioral alteration in adolescent rats. METHODS: Two-week old Sprague Dawley rats were divided into naive control, vehicle (phosphate buffered saline, PBS) control and LPS (100MUg/kg, i.p.) treatment groups. Anxiety and depression-like behaviors were examined around 1month age, with the expression of NLRP3, ASC and Caspase-1 in the prefrontal cortex (PFC) and hippocampus analyzed by means of immunohistochemistry and western blot. RESULTS: LPS-treated rats exhibited anxiety but not depressive-like behavior as indicated by results of open field, elevated plus maze, dark-light box, sucrose preference and forced swimming tests. Increased immunolabeling of NLRP3, ASC and Caspase-1 in neurons and/or microglia occurred in the PFC and hippocampus in LPS-treated adolescents relative to controls, with immunoblot shown elevated levels of these proteins. CONCLUSION: Early-life inflammatory stress promotes the expression of NLRP3 inflammasome proteins in the brain and the occurrence of anxiety-like behavior in adolescent rats. PMID- 28655516 TI - Characterization of Autoantigen Presentation by HLA-C*06:02 in Psoriasis. PMID- 28655517 TI - Safety assessment of green tea based beverages and dried green tea extracts as nutritional supplements. AB - The safety of green tea infusions and green tea extract (GTE)-based products is reviewed regarding catechins. Epigallocatechin 3-gallate (EGCG), the major catechin present in green tea, is suspected of being responsible for liver toxicity reported in humans consuming food supplements. Intake of EGCG with green tea infusions and GTE-based beverages is up to about 450mg EGCG/person/day in Europe and higher in Asia. Consumption of green tea is not associated with liver damage in humans, and green tea infusion and GTE-based beverages are considered safe in the range of historical uses. In animal studies, EGCG's potency for liver effects is highly dependent on conditions of administration. Use of NOAELs from bolus administration to derive a tolerable upper intake level applying the margin of safety concept results in acceptable EGCG-doses lower than those from one cup of green tea. NOAELs from toxicity studies applying EGCG with diet/split of the daily dose are a better point of departure for risk characterization. In clinical intervention studies, liver effects were not observed after intakes below 600mg EGCG/person/day. Thus, a tolerable upper intake level of 300mg EGCG/person/day is proposed for food supplements; this gives a twofold safety margin to clinical studies that did not report liver effects and a margin of safety of 100 to the NOAELs in animal studies with dietary administration of green tea catechins. PMID- 28655518 TI - Effects of long non-coding RNA H19 and microRNA let7a expression on thyroid cancer prognosis. AB - This study aims to explore the effects of long non-coding RNA H19 (lncRNA H19) and microRNA let7a (miRNA let7a) expression on the prognosis of thyroid cancer (TC). This may aid in the discovery of more effective treatment and prognosis approaches for TC. Between January 2008 and January 2011, 131 TC tissues and adjacent tissues were obtained from TC patients. An additional 122 normal thyroid tissues were also collected as normal controls from patients with benign thyroid lesions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect lncRNA H19 and miRNA let7a mRNA expression. Five-year follow-ups were conducted. A Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of lncRNA H19 and miRNA let7a in TC. The Kaplan-Meier method was applied to analyze the 5-year survival rate of TC patients. Univariate and multivariate factor analyses were employed to analyze the prognostic factors of TC. The lncRNA H19 mRNA expression was higher while the miRNA let7a mRNA expression was lower in TC tissues than, in the normal thyroid tissues and adjacent tissues. The area under the ROC curve (AUC) of lncRNA H19 and miRNA let7a were 0.801 and 0.116, with sensitivity at 72.5% and 84%, as well as specificity 75.4% and 77%, respectively. In TC patients with tumor diameters>=1.0cm, lncRNA H19 mRNA expression was elevated, but miRNA let7a mRNA expression was reduced. This was also evident in TC patients with TNM stages III+IV and those with lymph node metastasis. TC patients with a lower 5-year survival rate showed upregulated levels of lncRNA H19 expression and, downregulated levels of miRNA let7a expression. LncRNA H19 and miRNA let7a expression, tumor diameter, TNM stage and lymph node metastasis were independent prognostic factors of TC. This study demonstrated that increased lncRNA H19 and decreased miRNA let7a expression levels are associated with poor prognosis in TC patients. An inverse relationship between lncRNA H19 and miRNA let7a expression levels was exhibited. PMID- 28655519 TI - Omega-3 polyunsaturated fatty acids ameliorates testicular ischemia-reperfusion injury through the induction of Nrf2 and inhibition of NF-kappaB in rats. AB - OBJECTIVE: This study was designed to investigate the protective effect of Omega 3 polyunsaturated fatty acids (n-3 PUFAs) on testicular ischemia-reperfusion (I/R) injury in rats. METHODS: A total of 24 rats were randomly divided into the following three groups: Group A (Control group, n=8), Group B (I/R group, n=8), Group C (I/R group treated with n-3 PUFAs, n=8). Histological examination was used to assess changes in testicular structure. Tissue oxidative stress biomarkers, malondialdehyde (MDA) as well as Superoxide, and antioxidant indexes, including total antioxidant capacity (T-AOC); catalase (CAT); glutathione (GSH); glutathione/glutathione disulfide ratio (GSH/GSSG); superoxide dismutase (SOD) were determined. In addition, nuclear transcription factor erythroid 2-related factor 2 (Nrf2), Nrf2-dependent antioxidant enzymes, such as heme oxygenase-1 (HO 1) and NADPH quinine oxidoreductase-1 (NQO-1), and nuclear factor kappa B (NF kappaB) were detected. RESULTS: Compared to I/R group, n-3 PUFAs could obviously increase the mean seminiferous tubular diameter in the histological examination. After n-3 PUFAs treatment, the level of tissue MDA and Superoxide were significantly decreased, while tissue T-AOC, CAT, GSH, GSH/GSSG and SOD levels were significantly increased, compared to I/R group (P<0.05). Besides, the expression levels of Nrf2, HO-1, and NQO-1 were significantly higher and the NF kappaB expression level was significantly lower in the n-3 PUFAs treated group than that in I/R group (P<0.05). CONCLUSIONS: These results provided evidences that n-3 PUFAs ameliorated testes damage caused by testicular I/R injury through its antioxidative capacity and anti-inflammatory effects, involving the activation of Nrf2 and the inhibition of NF-kappaB. PMID- 28655520 TI - The mitochondrial dynamics in cancer and immune-surveillance. AB - Mitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence. PMID- 28655521 TI - It takes a village: Exploring the impact of social determinants on delivery system outcomes for heart failure patients. AB - BACKGROUND: Local social determinants may act as effect modifiers for the impact of neighborhood material deprivation on patient-level healthcare outcomes. The objective of this study was to understand the mediating effect of local social determinants on neighborhood material deprivation and delivery outcomes in heart failure (HF) patients. MATERIAL AND METHODS: A retrospective cohort study was conducted using 4737 HF patients receiving inpatient care (n=6065 encounters) from an integrated healthcare delivery system from 2010 to 2014. Outcomes included post-discharge mortality, readmission risk and length of stay. Deprivation was measured using an area deprivation index by address of residence. Effect modifications measured included urban-rural residency and faith identification using generalized linear regression models. Patient-level data was drawn from the delivery system data warehouse. RESULTS: Faith identification had a significant protective effect on HF patients from deprived areas, lowering 30 day mortality odds by one-third over patients who did not identify with a faith (OR 0.35 95%CI:0.12-0.98;p=0.05). Significant effects persisted at the 90 and 180 day timeframes. In rural areas, lack of faith identification had a multiplicative effect on 30-day mortality for deprived patients (OR 14.0 95%CI:1.47 132.7;p=0.02). No significant effects were noted for other healthcare outcomes. CONCLUSIONS: The lack of expected association between area deprivation and healthcare outcomes in some communities may be explained by the presence of effect modifiers. IMPLICATIONS: Understanding existing effect modifiers for area deprivation in local communities that delivery systems serve can inform targeted quality improvement. These factors should also be considered when comparing delivery system performance for reimbursement and in population health management. PMID- 28655523 TI - In reply to Korean translation and validation of the WHOQOL-DIS for people with spinal cord injury and stroke: Methodological issues. PMID- 28655522 TI - Preventive effect of pravastatin on the development of hypertension in patients with hypercholesterolemia: A post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study. AB - BACKGROUND: It remains unclear whether treatment of dyslipidemia with 3-hydroxy-3 methyl-glutaryl-coenzyme A reductase inhibitors (statins) reduces the risk of developing hypertension. OBJECTIVE: In this post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, a large-scale primary prevention trial with pravastatin, we examined the preventive effect of pravastatin on the future development of hypertension in patients with hypercholesterolemia. METHODS: Of the overall (MEGA) Study population, 3397 nonhypertensive patients at baseline were enrolled in this study. The patients were randomly assigned to either the diet alone group (n = 1722) or the diet plus pravastatin group (n = 1675) and then were followed-up for a median of 36 months to determine new-onset hypertension. RESULTS: During the follow-up period, 1595 patients developed hypertension (49.1% in the diet alone group and 44.7% in the diet plus pravastatin group). After adjusting for multiple covariates, the diet plus pravastatin group showed a 10% reduction in the risk of developing hypertension (hazard ratio 0.90, 95% confidence interval 0.81-0.998), compared with the diet alone group. Subgroup analyses revealed that the preventive effect of pravastatin on the development of hypertension was pronounced in patients aged >=60 years, men, those with chronic kidney disease or diabetes mellitus and those without obesity. CONCLUSIONS: Pravastatin reduced the risk of developing hypertension in Japanese patients with hypercholesterolemia. The risk reduction of cardiovascular disease with statins could be partly explained by their preventive effect on the development of hypertension. PMID- 28655525 TI - Ewing's Sarcoma of the maxillofacial region: A case report. AB - Ewing's sarcoma (ES) is an uncommon malignancy, especially in the head and neck region, with only 30 cases reported so far. The mandible is more affected than the maxilla. It represents the most frequent small round cell bone tumor of childhood and adolescence. This report presented a case of 19-year-old male with primary ES in the right side of maxilla, maxillary sinus, zygoma and temporal fossa areas. The clinical, radiographic, histopathologic features and main histopathologic differential diagnosis of ES were reviewed to avoid potential diagnostic pitfalls. PMID- 28655524 TI - 25 (OH) D3 levels, incidence and recurrence of different clinical forms of benig paroxysmal positional vertigo. AB - INTRODUCTION: Benign paroxysmal positional vertigo is the most common cause of dizziness in the general population. It is a condition with potential impact of reduced levels of vitamin D on its recurrent attacks. OBJECTIVES: The aim of this study was to measure the serum levels of 25-hydroxyvitamin D3 (25-OH D3) in patients with benign paroxysmal positional vertigo and determine whether there is a difference in the serum levels of vitamin D3 between patients with and without recurrence, as well as between the different clinical forms of benign paroxysmal positional vertigo. METHODS: The study included 40 patients who came to the regular medical examination, diagnosed with posterior canal-benign paroxysmal positional vertigo based on the positive Dix-Hallpike's test. All patients underwent Epley manoeuvre after the diagnosis. Patients were classified according to current guidelines for levels of vitamin D3 in the serum in three groups: the deficiency, insufficiency and adequate level. RESULTS: The average serum level of 25-OH D3 among respondents was 20.78ng/mL, indicating a lack or insufficiency of the aforementioned 25-OH D3. According to the levels of 25-OH D3, most patients suffer from deficiency (47.5%). 7 (17.5%) respondents had adequate blood level of 25-OH D3, and 14 (35%) respondents suffer from insufficiency. A significant difference was not found in the serum level of 25-OH D3 between patients with and without benign paroxysmal positional vertigo recurrence. There was a significant difference in the serum levels of 25-OH D3 in comparison to the clinical form of the disease. Lower 25-OH D3 values were found in patients with canalithiasis compared to those with cupulolithiasis. CONCLUSIONS: There were no significant differences in the vitamin D3 serum level in patients with and without recurrence. The study showed a low level of serum vitamin D3 in most patients, indicating the need for supplemental therapy. PMID- 28655526 TI - Agreement between electronic medical records and self-reported urologic domains in the National Spina Bifida Patient Registry (NSBPR): Implications for future research. AB - BACKGROUND: Self-report (SR) is an efficient data collection method. However, SR data have been shown to be discrepant with medical record (MR) documentation, which raises questions about using SR to supplement retrospective chart review in research. In this study, pediatric spina bifida (SB) patients who completed SR interviews about continence status and personal bladder/bowel management were identified. We examined agreement between SR data and Urology provider notes in MRs. OBJECTIVE: This study aimed to (1) identify demographic, medical, or methodological factors that might contribute to SR/MR disagreement; (2) postulate how these findings might be significant clinically; and (3) recommend improvements to SR data collection and MR documentation. STUDY DESIGN: Our institution participates in the National Spina Bifida Patient Registry (NSBPR). NSBPR-enrolled subjects typically complete annual interviews about their urologic outcomes; we consider this to be a form of SR. After identifying patients who interviewed within 1 month of an encounter with a urology provider, we systematically reviewed and compared their SR responses to the MR. Overall SR/MR agreement (no. of agreeing data pairs/no. of complete data pairs) and strength of agreement (kappa, kappa) were assessed. Agreement about daytime continence status was assessed for children >=5 years or in younger children who were toilet trained. Analyses were also stratified by diagnosis, type of bladder management, and ethnicity. RESULTS: Eleven urologic domains were analyzed for 176 patients. Overall SR/MR agreement was >=90% for nine out of 11 domains (figure). Daytime urinary and stool incontinence (DUSI) domains demonstrated the lowest overall agreement, at 69% and 74% respectively. Patients with myelomeningocele (MM) and those on clean intermittent catheterization demonstrated twice as much SR/MR disagreement about DUSI than patients without MM and those who void. There was no significant difference in rates of SR/MR agreement about DUSI when analyzed by ethnicity, race, and ambulatory function status. Among cases of SR/MR disagreement about DUSI, the SR and MR had a roughly equal percentage of better outcomes reported for both UI and SI. DISCUSSION: There was strong SR/MR agreement for the majority of urologic data we analyzed. Medically complex patients faced lower SR/MR agreement, which is consistent with findings in other patient populations. Biased reporting by patients/families or providers was not found. CONCLUSION: Minimizing SR/MR disagreement through standardized data collection methods and tools, improved definitions of patient outcomes, and documentation of respondent identity will improve large, multisite studies that utilize SR and MR concurrently. PMID- 28655527 TI - Changes in Adenosine Triphosphate and Nitric Oxide in the Urothelium of Patients with Benign Prostatic Hyperplasia and Detrusor Underactivity. AB - PURPOSE: We investigated changes in the levels of adenosine triphosphate and nitric oxide in the urothelium of men with detrusor underactivity and benign prostatic hyperplasia. MATERIALS AND METHODS: We prospectively enrolled in study 30 men who planned to undergo surgical treatment for benign prostatic hyperplasia. The 15 patients with a bladder contractility index less than 100 were assigned to the detrusor underactivity group while the 15 with a bladder contractility index more than 100 were assigned to the no detrusor underactivity group. Bladder mucosal specimens were collected at surgical prostate resection, and adenosine triphosphate and endothelial nitric oxide synthase were analyzed in these specimens. The levels of adenosine triphosphate and endothelial nitric oxide synthase were compared between the 2 groups. The correlation of urodynamic parameters with adenosine triphosphate and endothelial nitric oxide synthase was assessed in all patients. RESULTS: Mean +/- SEM endothelial nitric oxide synthase did not significantly differ between the detrusor underactivity and no underactivity groups (3.393 +/- 0.969 vs 1.941 +/- 0.377 IU/ml, p = 0.247). However, the mean level of adenosine triphosphate in the detrusor underactivity group was significantly lower than in the no detrusor underactivity group (1.289 +/- 0.320 vs 9.262 +/- 3.285 pmol, p = 0.011). In addition, in all patients adenosine triphosphate positively correlated with the bladder contractility index (r = 0.478, p = 0.018) and with detrusor pressure on maximal flow (r = 0.411, p = 0.046). CONCLUSIONS: Adenosine triphosphate was significantly decreased in the urothelium in men with detrusor underactivity and benign prostatic hyperplasia, reflecting the change in detrusor function. PMID- 28655528 TI - The Null Effect of Bladder Neck Size on Incontinence Outcomes after Radical Prostatectomy. AB - PURPOSE: We sought to determine whether bladder neck size is associated with incontinence scores after robot-assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS: Consecutive eligible patients undergoing robot-assisted laparoscopic radical prostatectomy between July 19 and December 28, 2016 were enrolled in a prospective, longitudinal, observational cohort study. The primary outcome was patient reported urinary incontinence on the EPIC (Expanded Prostate Cancer Index Composite) scale 6 and 12 weeks postoperatively. The relationship between the EPIC score of urinary incontinence and bladder neck size was evaluated by multiple regression. Predicted EPIC scores for incontinence were displayed graphically after using restricted cubic splines to model bladder neck size. RESULTS: A total of 107 patients were enrolled. The response rate was 98% and 87% at 6 and 12 weeks, respectively. Bladder neck size was not significantly associated with incontinence scores at 6 and 12 weeks. Comparing the 90th percentile for bladder neck size (18 mm) with the 10th percentile (7 mm) revealed no significant difference in adjusted EPIC scores for incontinence at 6 weeks (beta coefficient 0.88, 95% CI -10.92-12.68, p = 0.88) or at 12 weeks (beta coefficient 5.80, 95% CI -7.36-18.97, p = 0.39). CONCLUSIONS: These findings question the merit of creating an extremely small bladder neck during robot assisted laparoscopic radical prostatectomy. We contend that doing so increases the risk of positive margins at the bladder neck without facilitating early recovery of continence. PMID- 28655529 TI - Telementoring and Telesurgery for Minimally Invasive Procedures. AB - PURPOSE: Tremendous interest and need lie at the intersection of telemedicine and minimally invasive surgery. Robotics provides an ideal environment for surgical telementoring and telesurgery given its endoscopic optics and mechanized instrument movement. We review the present status, current challenges and future promise of telemedicine in endoscopic and minimally invasive surgery with a focus on urological applications. MATERIALS AND METHODS: Two paired investigators screened PubMed(r), Scopus(r) and Web of Science(r) databases for all full text English language articles published between 1995 and 2016 using the key words "telemedicine," "minimally invasive surgical procedure," "robotic surgical procedure," "education" and "distance." We categorized and included studies of level of interaction between proctors and trainees. Research design, special equipment, telecommunication network bandwidth and research outcomes of each study were ascertained and analyzed. RESULTS: Of 65 identified reports 38 peer reviewed studies qualified for inclusion. Series were categorized into 4 advancing levels, ie verbal guidance, guidance with telestration, guidance with tele-assist and telesurgery. More advanced levels of surgical telementoring provide more effective and experiential teaching but are associated with increased telecommunication network bandwidth requirements and expenses. Concerns regarding patient safety and legal, financial, economic and ethical issues remain to be reconciled. CONCLUSIONS: Telementoring and telesurgery in minimally invasive surgery are becoming more practical and cost effective in facilitating teaching of advanced surgical skills worldwide and delivery of surgical care to underserved areas, yet many challenges remain. Maturity of these modalities depends on financial incentives, favorable legislation and collaboration with cybersecurity experts to ensure safety and cost-effectiveness. PMID- 28655530 TI - Variation in the Diagnostic Evaluation among Persons with Hematuria: Influence of Gender, Race and Risk Factors for Bladder Cancer. AB - PURPOSE: We sought to determine whether race, gender and number of bladder cancer risk factors are significant predictors of hematuria evaluation. MATERIALS AND METHODS: We used self-reported data from SCCS (Southern Community Cohort Study) linked to Medicare claims data. Evaluation of subjects diagnosed with incident hematuria was considered complete if imaging and cystoscopy were performed within 180 days of diagnosis. Exposures of interest were race, gender and risk factors for bladder cancer. RESULTS: Of the 1,412 patients evaluation was complete in 261 (18%). On our adjusted analyses African American patients were less likely than Caucasian patients to undergo any aspect of evaluation, including urology referral (OR 0.72, 95% CI 0.56-0.93), cystoscopy (OR 0.67, 95% CI 0.50-0.89) and imaging (OR 0.75, 95% CI 0.59-0.95). Women were less likely than men to be referred to a urologist (OR 0.59, 95% CI 0.46-0.76). Also, although all patients with 2 or 3 risk factors had 31% higher odds of urology referral (OR 1.31, 95% CI 1.02-1.69), adjusted analyses indicated that this effect was only apparent among men. CONCLUSIONS: Only 18% of patients with an incident hematuria diagnosis underwent complete hematuria evaluation. Gender had a substantial effect on referral to urology when controlling for socioeconomic factors but otherwise it had an unclear role on the quality of evaluation. African American patients had markedly lower rates of thorough evaluation than Caucasian patients. Number of risk factors predicted referral to urology among men but it was otherwise a poor predictor of evaluation. There is opportunity for improvement by increasing the completion of hematuria evaluations, particularly in patients at high risk and those who are vulnerable. PMID- 28655531 TI - Results of the Third AIEOP Cooperative Protocol on Wilms Tumor (TW2003) and Related Considerations. AB - PURPOSE: TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review. MATERIALS AND METHODS: TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease. RESULTS: We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95% CI 83.6-94.9) and 97.0% (93.7-100) for stage I; 85.1% (79.6-91.1) and 94.0% (90.1-98.1) for stage II (160); 82.7% (75.3-90.8) and 90.9% (85.0-97.1) for stage III (101); and 72.1% (61.9-84.0) and 82.5% (73.1 93.1) for stage IV (69), respectively. On multivariable analysis only anaplasia was significant for event-free survival (HR 2.68, 95% CI 1.48-4.86, p=0.001; bias corrected c-index 0.580) and overall survival (HR 5.29, 95% CI 2.52-11.12, p <0.001; bias corrected c-index 0.697). CONCLUSIONS: The survival rates achieved and the proposed risk stratification schema provide a basis for future comparisons of Wilms tumor treatment burden and patient outcome. PMID- 28655532 TI - Surgical Relief of Left Ventricular Outflow Tract Obstruction in Adults With Congenital Aortic Stenosis and Associated Aortic Annulus Hypoplasia and/or Subaortic Obstruction. AB - BACKGROUND: In children and adolescents, a Ross/Konno operation is commonly done to both enlarge the aortic root and provide a competent aortic valve with relief of left ventricular outflow tract obstruction (LVOTO). Optimum management is not so straightforward in adults. METHODS: Between 1995 and 2014, 16 patients of mean age 39.4 years (18-57 years) with hypoplastic aortic annulus (AA) measuring 20mm and less, and mean aortic valve/LVOT gradient of 61mmHg (30-70mmHg) presented for surgery. RESULTS: Eight patients with mean LVOT/AA diameter 19.6mm (18-20mm) underwent an "inclusion-cylinder" type Ross procedure (RP). Eight patients with more severe LVOT/AA obstruction, with mean diameter of 17.4mm (16-19mm) underwent mechanical aortic valve replacement (AVR) with standard Konno-type aortoventriculoplasty. There was zero early and late mortality; with mean follow up of 11.6 years (3-21 years) in the Ross group and 6 years (2-10 years) in the Konno-AVR group. One patient in the Konno-AVR group had reoperation after 2 years for RVOT obstruction. The postoperative echocardiograms of these patients at last follow-up show residual mean gradient across LVOT/AA of 4.4mmHg (2-6mmHg) after RP, and 11.9mmHg (8-17mmHg) after Konno-AVR. CONCLUSIONS: In adults, the "inclusion-cylinder" Ross-procedure is a good alternative for mild to moderate aortic root hypoplasia. However, for cases with severe LVOT obstruction, a Ross Konno is not possible with the same method of autologous support used in a non Konno RP, and this could be expected to have an impact on late durability and the need for further intervention, in a group that has already undergone multiple procedures in childhood. Both methods of RP and Konno-AVR lead to excellent early and late results. PMID- 28655533 TI - A Unique Hybrid Approach to Complex Re-Do Aortic Root Surgery. AB - BACKGROUND: We present the case of a 23-year-old male with ventriculo-aortic dehiscence and a retrosternal false aneurysm communicating to the left ventricular outflow tract (LVOT) and ascending aorta. His history included aortic valve replacement (AVR) and mitral valve (MV) repair remotely, followed by two further operations for endocarditis and aortic root abscess. METHODS: The risk associated with the redo surgery required detailed planning and innovative techniques to allow it to be performed safely. These included femoral cannulation for cardiopulmonary bypass, venting the left ventricular apex via a small left anterior thoracotomy, use of a CODA(r) (COOK Medical, Bloomington USA) balloon to occlude the distal ascending aorta (placed via left brachial artery) and finally, the use of a PROPLEGE(r) (Edwards Lifesciences, Irvine, USA) retrograde cardioplegia cannula (placed via right internal jugular vein). PMID- 28655534 TI - Position Statement on the Diagnosis and Management of Familial Dilated Cardiomyopathy. PMID- 28655535 TI - Adenosine Testing After Atrial Fibrillation Ablation: Systematic Review and Meta Analysis. AB - BACKGROUND: Adenosine can be used to reveal dormant pulmonary vein (PV) conduction after pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF). We performed a systematic review and meta-analysis to assess the impact of adenosine administration in patients undergoing PVI for AF. METHODS: Meta-analysis of 22 studies was performed to assess the rates of freedom from AF in 1) patients with dormant PV conduction versus patients without dormant PV conduction, and 2) patients given routine adenosine post PVI versus patients not given adenosine. Relative-risks (RR) were calculated using random effects modelling. RESULTS: In 18 studies, 3038 patients received adenosine and freedom from AF in those patients with dormant PV reconnection was significantly lower (62.9%) compared to patients without PV reconnection (67.2%) (RR 0.87; 95% CI: 0.78-0.98). In seven studies with 3049 patients, the freedom from AF was significantly higher in patients who received adenosine (67%) versus those patients who did not receive adenosine (63%) (RR: 1.11; 95% CI: 1.01-1.22). CONCLUSIONS: The present study showed clear benefits of adenosine testing for freedom from AF recurrence. Adenosine-guided dormant conduction is associated with higher AF recurrence despite further ablation. Future studies should investigate the optimal methodology, including dosage and waiting time between PVI and adenosine administration. PMID- 28655536 TI - B-cell identity as a metabolic barrier against malignant transformation. AB - B-lineage and myeloid leukemia cells are often transformed by the same oncogenes, but have different biological and clinical characteristics. Although B-lineage acute lymphoblastic leukemia (B-ALL) cells are characterized by a state of chronic energy deficit, myeloid leukemia cells show abundant energy reserve. Interestingly, fasting has been demonstrated to inhibit selectively the development of B-ALL but not myeloid leukemia, further suggesting that lineage identity may be linked to divergent metabolic states in hematopoietic malignancies. The B-lymphoid transcription factors IKZF1, EBF1, and PAX5 are essential for early B-cell development and commitment to B-cell identity. However, in >80% of human pre-B-ALL cases, the leukemic clones harbor genetic lesions of these transcription factors. The significance of these defects has only recently been investigated. Here, we discuss the unexpected function of a B lymphoid transcriptional program as a metabolic barrier against malignant transformation of B-cell precursor cells. The metabolic gatekeeper function of B lymphoid transcription factors may force silent preleukemic clones carrying potentially oncogenic lesions to remain in a latent state. In addition, this program sets the threshold for responses to glucocorticoids in pre-B-ALL. Finally, the link between the tumor-suppressor and metabolic functions of B lymphoid transcription factors is matched by observations in clinical trials: obesity and hyperglycemia are associated with poor clinical outcome in patients with pre-B-ALL. PMID- 28655537 TI - Not All Seeds Are Created Equal: Seed Classification Is Predictive of Outcomes in Retinoblastoma. AB - OBJECTIVE: Intravitreal chemotherapy has emerged as an important modality for treating vitreous seeding in retinoblastoma. A classification system has been described as predictive of response to intravitreal melphalan (IVM) in patients treated predominantly with primary intra-arterial chemotherapy. The objective of this study is to evaluate the outcomes of retinoblastoma treated with intravenous chemotherapy and IVM as salvage for vitreous seeding, and further to determine whether vitreous seed classification (dust, spheres, cloud) is predictive of the total number and dose of IVM injections required for treatment in this cohort. DESIGN: A nonrandomized retrospective review. PARTICIPANTS: Retinoblastoma patients treated at a single center with intravenous chemotherapy and IVM. METHODS: Retrospective review of patients with vitreous seeding from retinoblastoma treated with intravenous chemotherapy and IVM from 2012 to 2016. MAIN OUTCOME MEASURES: Primary outcome measure was eradication of seeds and globe salvage. Secondary measures included IVM-associated toxicity and complications. RESULTS: Overall, 28 eyes of 25 patients were included, with a total of 110 IVM injections. By seed classification, eyes with dust (n = 15) required a median of 3 injections, spheres (n = 8) required 4 injections, and clouds (n = 5) required 6 injections. Spherical seeds were only seen in recurrent vitreous seeding. Of the 28 treated eyes, 9 were enucleated, 6 for recurrent retinal disease, resulting in an overall globe salvage rate of 68%. The salvage rate secondary to active retinoblastoma was 79%. Dust classification was the most prevalent seeding type of the 9 enucleated eyes. There was 100% regression of vitreous seeds after intravitreal injection and no eye was treated with radiation or enucleated for seeding. Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean follow-up was 33 months (range, 9 51 months). CONCLUSIONS: IVM is an effective treatment for vitreous seeding after intravenous chemotherapy for retinoblastoma. As with eyes treated with intra arterial chemotherapy, seed classification is predictive of the total number and dose of IVM injections in eyes treated with intravenous chemotherapy. Eyes with clouds required significantly more injections than eyes with dust or spheres. PMID- 28655539 TI - Myopic Choroidal Neovascularization: Review, Guidance, and Consensus Statement on Management. AB - TOPIC: The aim of this article is to review and compile available information on the classification, pathophysiology, and clinical features of myopic choroidal neovascularization (CNV); to describe the latest data on the management of this disease; and to present guidance. CLINICAL RELEVANCE: In the United States, myopia affects approximately 34 million people (2010), and similar figures have been reported in Europe. Pathologic myopia (PM), a possible consequence of myopia, is estimated to affect up to 3% of the global population. One of the most serious complications of PM is myopic CNV, which often leads to a sudden onset but progressive decline in central vision and is associated with a poor prognosis unless treated. Furthermore, 35% of patients with myopic CNV develop bilateral disease in the fellow eye within 8 years. Although intravitreal anti-vascular endothelial growth factor (VEGF) therapies have had a major impact on the management of patients with myopic CNV, there remain significant gaps in our understanding of this condition and how to best administer treatment. Additionally, the long-term safety and efficacy of these treatments are largely unknown. METHODS: We carried out a literature review (September 2015) of all English-language articles in PubMed resulting from searches of the following terms: "choroidal neovascularization" AND "myopia" OR "myopic macular degeneration" OR "degenerative myopia" OR "myopic maculopathy" OR "myopic retinopathy" OR "pathological myopia" OR "pathologic myopia." RESULTS: We screened a total of 566 abstracts, and 250 articles were deemed relevant for full publication review. We excluded a further 71, but an additional 44 articles were identified. This resulted in 223 articles being used to develop this review. CONCLUSIONS: Highly myopic patients experiencing a sudden loss of central vision should be referred for further examination. Once a diagnosis of myopic CNV has been confirmed, after fluorescein angiography, treatment initiation should be prompt and anti-VEGF agents considered as first-line therapy, unless contraindicated. Continued monitoring of patients is required to assess any progression or recurrence of the condition. PMID- 28655538 TI - U.S. Multicenter Clinical Trial of Corneal Collagen Crosslinking for Treatment of Corneal Ectasia after Refractive Surgery. AB - PURPOSE: To evaluate the safety and efficacy of corneal collagen crosslinking (CXL) for the treatment of corneal ectasia after laser refractive surgery. DESIGN: Prospective, randomized, multicenter, controlled clinical trial. PARTICIPANTS: One hundred seventy-nine subjects with corneal ectasia after previous refractive surgery. METHODS: The treatment group underwent standard CXL, and the sham control group received riboflavin alone without removal of the epithelium. MAIN OUTCOME MEASURES: The primary efficacy criterion was the change over 1 year of topography-derived maximum keratometry (K), comparing treatment with control groups. Secondary outcomes evaluated were corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), manifest refraction spherical equivalent, endothelial cell count, and adverse events. RESULTS: In the crosslinking treatment group, the maximum K value decreased by 0.7 diopters (D) from baseline to 1 year, whereas there was continued progression in the control group (1.3 D difference between treatment and control, P < 0.0001). In the treatment group, the maximum K value decreased by 2.0 D or more in 14 eyes (18%) and increased by 2.0 D or more in 3 eyes (4%). The CDVA improved by an average of 5.0 logarithm of the minimum angle of resolution (logMAR) letters. Twenty-three eyes (32%) gained and 3 eyes (4%) lost 10 or more logMAR letters. The UDVA improved 4.5 logMAR letters. Corneal haze was the most frequently reported crosslinking-related adverse finding. CONCLUSIONS: Corneal collagen crosslinking was effective in improving the maximum K value, CDVA, and UDVA in eyes with corneal ectasia 1 year after treatment, with an excellent safety profile. CXL is the first approved procedure to diminish progression of this ectatic corneal process. PMID- 28655540 TI - Cloning, expression pattern and promoter functional analysis of cyp19a1a gene in miiuy croaker. AB - Gonadal-specific aromatase encoded by cyp19a1a is the important enzyme controlling estrogen biosynthesis in teleosts. In the present study, the cDNA sequence of cyp19a1a was cloned and characterized from miiuy croaker Miichthys miiuy. The cDNA encoded a protein of 519 amino acids with five structural regions. Higher identities of amino acid sequences and conserved structural regions were found between Mmcyp19a1a and other cyp19a1a genes. In addition, Mmcyp19a1a was clustered together with other seawater fishes. Immunohistochemical analysis revealed that Mmcyp19a1a was localized exclusively in the cytoplasmic of thecal and granulosa cells surrounding the oocytes. Both the protein and mRNA levels of Mmcyp19a1a were increased significantly at the stage III follicles (mid vitellogenic) and then decreased along with vitellogenesis. Interestingly, strong immunoreactive signals were also detected in the supporting cells of connective tissues during ovarian development. A 1777bp promoter fragment of Mmcyp19a1a was also isolated, and functional analysis using an EGFP reporter fusion in zebrafish larvae presented positive signals in the above of yolk sac, where is the region of pronephros and germ plasm occur. The Mmcyp19a1a:EGFP expression pattern was generally consistent with the endogenous cyp19a1a genesis. These results indicate that the Mmcyp19a1a gene plays an important role during vitellogenesis and oocyte maturation. The constructor of Mmcyp19a1a:EGFP may provide a useful tool for genetic analysis of gonad development in teleost. PMID- 28655542 TI - Re: Multi-institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy. PMID- 28655543 TI - Health-Related Quality of Life and Costs Associated With Eosinophilic Esophagitis: A Systematic Review. AB - BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by esophageal inflammation and dysfunction. Little is known about the humanistic and economic burden of the disease on patients, their caregivers, and the health care system. A systematic review was conducted to evaluate the existing literature on the disease burden of EoE for patients and their caregivers. METHODS: The MEDLINE, Embase, and Evidence-Based Medicine Reviews databases and recent congresses were searched on March 23, 2017, for English-language publications describing the impact of EoE on health-related quality of life (HRQoL) in children and adults, and the economic burden associated with the disease. RESULTS: Of 676 articles identified, 22 met the inclusion criteria and were included in this analysis (HRQoL, 13; economic burden, 7; cost effectiveness, 2). The included studies showed that EoE is associated with a significant impact on HRQoL, resulting in disruption to and restrictions on daily life for patients, their caregivers, and, in some instances, their families. Treatment with topical corticosteroids, the 6-food elimination diet, or the cow's milk elimination diet significantly improved the HRQoL of patients with EoE. Symptom severity was associated strongly with the impact of EoE on HRQoL. Medical resource utilization costs for patients with EoE were significantly higher than those for healthy controls. CONCLUSIONS: EoE negatively impacts the HRQoL of patients and their families, and is a burden to the health care system. Although data are sparse, currently available treatments appear to improve HRQoL. PMID- 28655541 TI - Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. AB - BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naive and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process. PMID- 28655544 TI - Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants. AB - The mitochondrial DNA (mtDNA) is a closed circular molecule that encodes, in humans, 13 polypeptides components of the oxidative phosphorylation complexes. Integrity of the mitochondrial genome is essential for mitochondrial function and cellular homeostasis, and mutations and deletions in the mtDNA lead to oxidative stress, mitochondrial dysfunction and cell death. In vitro and in situ studies suggest that when exposed to certain genotoxins, mtDNA accumulates more damage than nuclear DNA, likely owing to its organization and localization in the mitochondrial matrix, which tends to accumulate lipophilic, positively charged molecules. In that regard, several relevant environmental and occupational contaminants have physical-chemical characteristics that indicate that they might accumulate in mitochondria and target mtDNA. Nonetheless, very little is known so far about mtDNA damage and mitochondrial dysfunction due to environmental exposure, either in model organisms or in humans. In this article, we discuss some of the characteristics of mtDNA which render it a potentially relevant target for damage by environmental contaminants, as well as possible functional consequences of damage/mutation accumulation. In addition, we review the data available in the literature focusing on mitochondrial effects of the most common classes of environmental pollutants. From that, we conclude that several lines of experimental evidence support the idea that mitochondria and mtDNA are susceptible and biologically relevant targets for pollutants, and more studies, including mechanistic ones, are needed to shed more light into the contribution of mitochondrial dysfunction to the environmental and human health effects of chemical exposure. PMID- 28655546 TI - Optimised NLC: a nanotechnological approach to improve the anaesthetic effect of bupivacaine. AB - The short time of action and systemic toxicity of local anaesthetics limit their clinical application. Bupivacaine is the most frequently used local anaesthetic in surgical procedures worldwide. The discovery that its S(-) enantiomeric form is less toxic than the R(+) form led to the introduction of products with enantiomeric excess (S75:R25 bupivacaine) in the market. Nevertheless, the time of action of bupivacaine is still short; to overcome that, bupivacaine S75:R25 (BVCS75) was encapsulated in nanostructured lipid carriers (NLC). In this work, we present the development of the formulation using chemometric tools of experimental design to study the formulation factors and Raman mapping associated with Classical Least Squares (CLS) to study the miscibility of the solid and the liquid lipids. The selected formulation of the nanostructured lipid carrier containing bupivacaine S75:R25 (NLCBVC) was observed to be stable for 12 months under room conditions regarding particle size, polydispersion, Zeta potential and encapsulation efficiency. The characterisation by DSC, XDR and TEM confirmed the encapsulation of BVCS75 in the lipid matrix, with no changes in the structure of the nanoparticles. The in vivo analgesic effect elicited by NLCBVC was twice that of free BVCS75. Besides improving the time of action, no statistical difference in the blockage of the sciatic nerve of rats was found between 0.125% NLCBVC and 0.5% free BVCS75. Therefore, the formulation allows a reduction in the required anaesthesia dose, decreasing the systemic toxicity of bupivacaine, and opening up new possibilities for different clinical applications. PMID- 28655545 TI - Mitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival. AB - Mitochondrial dysfunction is central to the pathogenesis of neurological disorders. Neurons rely on oxidative phosphorylation to meet their energy requirements and thus alterations in mitochondrial function are linked to energy failure and neuronal cell death. Furthermore, in neurons, dysfunctional mitochondria are reported to increase the steady-state levels of reactive oxygen species derived from the leakage of electrons from the electron transport chain. Research aimed at understanding mitochondrial dysfunction and its role in neurological disorders has been primarily geared towards neurons. In contrast, the effects of mitochondrial dysfunction in glial cells' function and its implication for neuronal homeostasis and brain function has been largely understudied. Unlike neurons and oligodendrocytes, astrocytes and microglia do not degenerate upon the impairment of mitochondrial function, as they rely primarily on glycolysis to produce energy and have a higher antioxidant capacity than neurons. However, recent evidence highlights the role of mitochondrial metabolism and signaling in glial cell function. In this work, we review the functional role of mitochondria in glial cells and the evidence regarding its potential role regulating neuronal homeostasis and disease progression. PMID- 28655547 TI - Breast cancer screening outreach effectiveness: Mammogram-specific reminders vs. comprehensive preventive services birthday letters. AB - We compared the effectiveness of two outreach strategies on timely mammography adherence: a mammogram-specific reminder letter (sent just before a woman was due) to a birthday letter (addresses multiple preventive services and not timed around due dates). We evaluated screening mammography adherence following 79,848 mammogram-specific and 151,626 birthday letters mailed between 2002 and 2012 to women aged 40-74years enrolled in Kaiser Permanente Washington. Screening mammogram adherence was specifically tied to due date and was evaluated separately by age group and up-to-date or overdue status at the time of mailing. We used generalized estimating equations to account for correlation between repeated observations, to model the odds of screening mammography adherence by letter type. Among women up-to-date, adherence following birthday letters was 22 76% lower compared to the mammogram-specific reminders, with the greatest decreases in adherence in women aged 70-74. Birthday letters were more effective at activating screening uptake among some subgroups of overdue women aged 50-69 and most overdue women aged 70-74, but universally low adherence rates were observed in overdue women. Increasing number of recommended services for women aged 50-74 who were up-to-date resulted in 12-17% lower mammography adherence, but had no effect in women aged 40-49 or in overdue women. Birthday letters are less effective than mammogram-specific reminder letters at prompting women to undergo timely breast cancer screening, particularly among women up-to-date with screening. Birthday letters may be effective at increasing overall preventive care; however, supplemental outreach may be needed around the due date to increase timely preventive services receipt. PMID- 28655548 TI - Recent advances in understanding the adaptive immune response to Zika virus and the effect of previous flavivirus exposure. AB - Zika virus (ZIKV) caused explosive epidemics across the Americas, starting in Brazil in 2015, and has been associated with severe manifestations such as microcephaly in babies born to infected mothers and Guillain-Barre syndrome in adults. As the underlying mechanisms of pathogenesis remain largely unknown, diverse investigations have focused on a potential role for flavivirus cross reactive antibodies in enhancing ZIKV infection. Antibody-dependent enhancement is especially concerning due to structural similarities between ZIKV and other flaviviruses, especially dengue virus (DENV), that co-circulate in areas affected by ZIKV. Conversely, investigating cross-neutralizing antibodies is important for understanding protection among flaviviruses, including ZIKV. In this review, we discuss the latest findings regarding ZIKV-induced adaptive immunity, such as monoclonal and polyclonal antibody responses, structural immunology, and T cell mediated responses. Much progress has been made in a short amount of time, but many questions remain. Fully understanding the specificity, magnitude, and kinetics of B cell/antibody and T cell responses in ZIKV-infected individuals with or without prior exposure to flaviviruses is of great relevance for diagnostics and vaccine development. PMID- 28655549 TI - Lower extremity bypass for critical limb ischemia decreases major adverse limb events with equivalent cardiac risk compared with endovascular intervention. AB - OBJECTIVE: Lower extremity bypass (LEB) has traditionally been the "gold standard" in the treatment of critical limb ischemia (CLI). Infrainguinal endovascular intervention (IEI) has become more commonly performed than LEB, but comparative outcomes are limited. We sought to compare rates of major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) after LEB and IEI in a propensity score-matched, national cohort of patients with CLI. METHODS: The National Surgical Quality Improvement Program (NSQIP) vascular targeted files (2011-2014) for LEB and IEI were merged. CLI patients were identified by ischemic rest pain or tissue loss. Patients were matched on a 1:1 basis for propensity to undergo LEB or IEI. Primary outcomes were 30-day MALEs and MACEs. Within the propensity-matched cohort, multivariate logistic regression was used to identify independent predictors of MALEs and MACEs. RESULTS: A total of 13,294 LEBs and IEIs were identified, with 8066 cases performed for CLI. Propensity matching identified 3848 cases (1924 per group). There were no differences in preoperative variables between the propensity-matched LEB and IEI groups (all P > .05). At 30 days, rates of MALEs were significantly lower in the LEB group (9.2% LEB vs IEI 12.2%; P = .003). On multivariate logistic regression, bypass with single-segment saphenous vein vs IEI (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.54 0.92; P = .01), bypass with alternative conduit (prosthetic, spliced vein, or composite) vs IEI (OR, 0.7; 95% CI, 0.56-0.98; P = .04), antiplatelet therapy (OR, 0.8; 95% CI, 0.58-1.00; P = .049), and statin therapy (OR, 0.8; 95% CI, 0.62 0.99; P = .04) were protective against MALEs, whereas infrageniculate intervention (OR, 1.4; 95% CI, 1.09-1.72; P = .01) and a history of prior bypass of the same arterial segment (OR, 1.8; 95% CI, 1.41-2.41; P <. 0001) were predictive. Rates of 30-day MACEs were not significantly different (4.9% LEB vs 3.7% IEI; P = .07) between the groups. Independent predictors of MACEs included age (OR, 1.02; 95% CI, 1.01-1.04; P = .01), steroid use (OR, 1.8; 95% CI, 1.08 2.99; P = .03), congestive heart failure (OR, 1.7; 95% CI, 1.00-1.96; P = .02), beta blocker use (OR, 1.6; 95% CI, 1.09-1.43; P = .01), dialysis (OR, 2.3; 95% CI, 1.55-3.45; P < .0001), totally dependent functional status (OR, 3.1; 95% CI, 1.25-7.58; P = .02), and suboptimal conduit for LEB compared with IEI (OR, 1.6; 95% CI, 1.08-2.36; P = .02). CONCLUSIONS: Within this large, propensity-matched, national cohort, LEB predicted lower risk-adjusted 30-day MALE rate compared with IEI. Furthermore, there was no difference in 30-day MACE rate between the groups despite higher inherent risk with open surgical procedures. Therefore, this study supports the effectiveness and primacy of LEB for revascularization in CLI. PMID- 28655550 TI - Skin accumulation of advanced glycation end products is increased in patients with an abdominal aortic aneurysm. AB - OBJECTIVE: Advanced glycation end products (AGEs) are implicated in the pathogenesis of cardiovascular disease. Accumulation of AGEs is driven by oxidative or glycemic stress and can be assessed by skin autofluorescence (SAF). SAF is increased in patients with peripheral artery disease (PAD) and independently associated with mortality and major adverse cardiovascular events in these patients. PAD and abdominal aortic aneurysm (AAA) share several risk factors. Inflammation is an important process in AAA formation and increases levels of oxidative stress. We therefore hypothesized that SAF would be increased in AAA patients compared with controls. METHODS: A case-control study was performed in 248 AAA patients and 124 controls without AAA or PAD matched for age and presence of diabetes mellitus. SAF was noninvasively assessed with the AGE Reader (Diagnoptics Technologies BV, Groningen, The Netherlands). RESULTS: SAF was higher in AAA patients than in controls: 2.89 +/- 0.63 vs 2.68 +/- 0.63 arbitrary units (P = .003). PAD comorbidity was associated with increased SAF within the AAA patient group (P = .01). After correction for known factors influencing SAF (age, current smoking, hypertension, and estimated glomerular filtration rate), PAD comorbidity remained an independent determinant of SAF. Logistic regression analysis of the total cohort showed an unadjusted odds ratio (OR) of 1.74 (95% confidence interval [CI], 1.20-2.51) for the presence of AAA with each unit increase of SAF and an adjusted OR of 1.78 (95% CI, 1.22-2.60) after correction for cardiovascular comorbidity (cerebrovascular disease and coronary artery disease). After additional correction for sex, current smoking, hypertension, and use of lipid-lowering drugs, this significance was lost (adjusted OR, 1.53; 95% CI, 0.94-2.48). CONCLUSIONS: Skin accumulation of AGEs, measured by SAF, is increased in patients with AAA compared with controls without AAA or PAD, independent of the presence of coronary artery disease and cerebrovascular disease. In AAA patients, SAF is closely associated with the presence of PAD and cardiovascular risk factors. PMID- 28655551 TI - Adult venous endothelium is a niche for highly proliferative and vasculogenic endothelial colony-forming cells. AB - OBJECTIVE: Postnatal resident endothelium of blood vessels has been proposed to represent terminally differentiated tissue that does not replicate. We previously isolated endothelial colony-forming cells (ECFCs) from human umbilical cord blood (CB) and term placenta by using colony-forming assays and immunocytochemistry. We showed that ECFCs are highly proliferative and form functioning vessels in vivo, the defining characteristics of a true endothelial progenitor cell. This exploratory investigation was conducted to determine whether the endothelium of healthy adult blood vessels contained resident ECFCs. METHODS: The endothelium of great saphenous vein (GSV) obtained from vein stripping procedures was collected with mechanical scraping, and ECFCs were isolated according to established protocols. RESULTS: GSV ECFCs incorporated acetylated low-density lipoprotein, formed tubules in Matrigel (BD Biosciences, San Jose, Calif) at 24 hours, and expressed endothelial antigens cluster of differentiation (CD) 144, CD31, CD105, and kinase insert domain receptor but not hematopoietic antigen CD45. Using cumulative population doublings and single-cell assays, we demonstrated that GSV ECFCs exhibited comparable proliferative capacities compared with CB ECFCs, including similar numbers of highly proliferative cells. When injected in collagen/fibronectin gels implanted in nonobese diabetic/severe combined immune deficiency mice, GSV ECFCs formed blood vessels with circulating murine red blood cells, demonstrating their vasculogenic potential. CONCLUSIONS: The ECFCs of the GSV contain a hierarchy of progenitor cells with a comparable number of highly proliferative clones as ECFCs of CB. The results of this investigation demonstrate that the adult endothelium contains resident progenitor cells that may have a critical role in vascular homeostasis and repair and could potentially be used as a source of autologous cells for cell therapies focusing on vasculogenesis. PMID- 28655552 TI - The impact of contralateral carotid artery stenosis on outcomes after carotid endarterectomy. AB - OBJECTIVE: Patients with contralateral carotid occlusion (CCO) have been excluded from randomized clinical trials because of a deemed high risk for adverse neurologic outcomes with carotid endarterectomy (CEA). Evidence for this rationale is limited and conflicting. Therefore, we aimed to compare outcomes after CEA between patients with and without CCO and varying degrees of contralateral carotid stenosis (CCS). METHODS: We identified patients undergoing CEA from 2003 to 2015 in the Vascular Study Group of New England (VSGNE) registry. Patients were stratified by preoperative symptom status and presence of CCO. Multivariable analysis was used to account for differences in demographics and comorbidities. Our primary outcome was 30-day stroke/death risk. RESULTS: Of 15,487 patients we identified who underwent CEA, 10,377 (67%) were asymptomatic. CCO was present in 914 patients, of whom 681 (75%) were asymptomatic. Overall, the 30-day stroke/death was 2.0% for symptomatic patients (CCO: 2.6%) and 1.1% for asymptomatic patients (CCO: 2.3%). After adjustment, including symptom status, CCO was associated with higher 30-day stroke/death (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4-3.3; P = .001), any in-hospital stroke (OR, 2.8; 95% CI, 1.7-4.6; P < .001), in-hospital ipsilateral stroke (OR, 2.2; 95% CI, 1.2-4.0; P = .02), in-hospital contralateral stroke (OR, 5.1; 95% CI, 2.2-11.4; P < .001), and prolonged length of stay (OR, 1.6; 95% CI, 1.3-1.9; P < .001). CCS of 80% to 99% was only associated with a prolonged length of stay (OR, 1.3; 95% CI, 1.1-1.6; P = .01), not with in-hospital stroke. Neither CCO nor CCS was associated with 30-day mortality. CONCLUSIONS: Although CCO increases the risk of 30-day stroke/death, in-hospital strokes, and prolonged length of stay after CEA, the 30-day stroke/death rates in symptomatic and asymptomatic patients with CCO remain within the recommended thresholds set by the 14 societies' guideline document. Thus, CCO should not qualify as a high-risk criterion for CEA. Moreover, there is no evidence that patients with CCO have lower stroke/death rates after carotid artery stenting than after CEA. We believe that CEA remains a valid and safe option for patients with CCO and that CCO should not be applied as a criterion to promote carotid artery stenting per se. PMID- 28655553 TI - Variant discovery in patients with Mendelian vascular anomalies by next generation sequencing and their use in patient clinical management. AB - OBJECTIVE: An accurate "molecular" diagnosis and classification of similar but distinct diseases is sometime challenging but often crucial for the definition of the appropriate patient medical management and treatment as well as for genetic counseling and risk assessment in families. The advent of next-generation sequencing (NGS), which analysed all known disease-associated genes in parallel in a cost- and time-effective manner, eased this process of disease definition and also for vascular anomalies that are a heterogeneous group of vascular tumors and congenital circulatory malformations and often characterized by overlapping phenotypes. METHODS: We designed a NGS-based screening of the 25 currently most prevalent genes identified in patients with vascular anomalies with Mendelian inheritance and applied this panel to study the DNA of 150 patients affected with vascular anomalies for autosomal recessive and autosomal dominant variants and to analyse the paired blood and DNA from intralesional biopsy specimens in 17 patients for somatic unbalance. Results were confirmed with Sanger sequencing. RESULTS: We identified 14 pathogenic variants in 13 of 150 patients. Eight variants were previously reported as a disease-causing variant, and six were new. In 55 additional probands we detected 75 variants with unknown significance. Moreover, a previously reported somatic variant was detected in five of 17 available tissue biopsy specimens. CONCLUSIONS: Our results show that many genes can cause a wide variety of syndromic and nonsyndromic disorders, confirming that genetic testing by NGS is the approach of choice to diagnose heritable vascular anomalies, especially, but not only, when an intralesional biopsy specimen is available. The identification of the causative genes and the possibility of tracing somatic variants in tissues provide important information about etiology, patient clinical management, and treatment, and it could highlight otherwise unsuspected clinical situations. PMID- 28655555 TI - Impaired reversal learning in an animal model of anorexia nervosa. AB - BACKGROUND: Clinical investigations indicate that anorexia nervosa (AN) is associated with impaired cognitive flexibility. Activity-based anorexia (ABA), a rodent behavioral model of AN, is characterized by compulsive wheel running associated with voluntary food restriction and progressive weight loss. The goal of this study was to test whether ABA is associated with impaired cognitive flexibility. METHODS: Female Sprague-Dawley rats were trained to perform the attentional set-shifting test (ASST) to assess cognitive flexibility, including capacity for set-shifting and reversal learning. Rats were assigned to ABA or weight-loss paired control (WPC) conditions. Following baseline testing, the ABA group had access to food for 1h/d and access to running wheels 23h/d until 20% weight loss was voluntarily achieved. For the WPC group, running wheels were locked and access to food was restricted to reduce body weight at the same rate as the ABA group. ASST performance was assessed after weight loss, and again following weight recovery. RESULTS: Compared to baseline, the ABA group (but not the WPC group) showed a significant decrement in reversal learning at low weight, with return to baseline performance following weight restoration. The other components of ASST were not affected. CONCLUSIONS: Impaired reversal learning, indicative of increased perseverative responding, in the ABA model reveals its potential to recapitulate selective components of cortical dysfunction in AN. This finding supports the utility of the ABA model for investigations of the neural mechanisms underlying such deficits. Reversal learning relies on neural circuits involving the orbitofrontal cortex and thus the results implicate orbitofrontal abnormalities in AN-like state. PMID- 28655554 TI - T-type Ca2+ channels elicit pro-proliferative and anti-apoptotic responses through impaired PP2A/Akt1 signaling in PASMCs from patients with pulmonary arterial hypertension. AB - Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca2+ channel blockers have been shown to reduce experimental pulmonary hypertension, although the impact of T-type channel inhibition remains unexplored in PASMCs from iPAH patients. Here we show that T type channels Cav3.1 and Cav3.2 are present in the lung and PASMCs from iPAH patients and control subjects. The blockade of T-type channels by the specific blocker, TTA-A2, prevents cell cycle progression and PASMCs growth. In iPAH cells, T-type channel signaling fails to activate phosphatase PP2A, leading to an increase in ERK1/2, P38 activation. Moreover, T-type channel signaling is redirected towards the activation of the kinase Akt1, leading to increased expression of the anti-apoptotic protein survivin, and a decrease in the pro apoptotic mediator FoxO3A. Finally, in iPAH cells, Akt1 is no longer able to regulate caspase 9 activation, whereas T-type channel overexpression reverses PP2A defect in iPAH cells but reinforces the deleterious effects of Akt1 activation. Altogether, these data highlight T-type channel signaling as a strong trigger of the pathological phenotype of PASMCs from iPAH patients (hyper proliferation/cells survival and apoptosis resistance), suggesting that both T type channels and PP2A may be promising therapeutic targets for pulmonary hypertension. PMID- 28655557 TI - Rapid identification of ST131 Escherichia coli by a novel multiplex real-time allelic discrimination assay. AB - Escherichia coli sequence type 131 is increasingly described in severe hospital infections. We developed a rapid real-time allelic discrimination assay for the rapid identification of E. coli ST131 isolates. This rapid assay represents an affordable alternative to sequence-based strategies before completing characterization of potentially highly virulent isolates of E. coli. PMID- 28655556 TI - Comparison of two bioinformatics tools used to characterize the microbial diversity and predictive functional attributes of microbial mats from Lake Obersee, Antarctica. AB - In this study, using NextGen sequencing of the collective 16S rRNA genes obtained from two sets of samples collected from Lake Obersee, Antarctica, we compared and contrasted two bioinformatics tools, PICRUSt and Tax4Fun. We then developed an R script to assess the taxonomic and predictive functional profiles of the microbial communities within the samples. Taxa such as Pseudoxanthomonas, Planctomycetaceae, Cyanobacteria Subsection III, Nitrosomonadaceae, Leptothrix, and Rhodobacter were exclusively identified by Tax4Fun that uses SILVA database; whereas PICRUSt that uses Greengenes database uniquely identified Pirellulaceae, Gemmatimonadetes A1-B1, Pseudanabaena, Salinibacterium and Sinobacteraceae. Predictive functional profiling of the microbial communities using Tax4Fun and PICRUSt separately revealed common metabolic capabilities, while also showing specific functional IDs not shared between the two approaches. Combining these functional predictions using a customized R script revealed a more inclusive metabolic profile, such as hydrolases, oxidoreductases, transferases; enzymes involved in carbohydrate and amino acid metabolisms; and membrane transport proteins known for nutrient uptake from the surrounding environment. Our results present the first molecular-phylogenetic characterization and predictive functional profiles of the microbial mat communities in Lake Obersee, while demonstrating the efficacy of combining both the taxonomic assignment information and functional IDs using the R script created in this study for a more streamlined evaluation of predictive functional profiles of microbial communities. PMID- 28655558 TI - Now you see it, now you don't: A case of covert (invisible) IgM. PMID- 28655559 TI - Gym-based exercise and home-based exercise with telephone support have similar outcomes when used as maintenance programs in adults with chronic health conditions: a randomised trial. AB - QUESTION: What is the effectiveness of gym-based exercise versus home-based exercise with telephone follow-up amongst adults with chronic conditions who have completed a short-term exercise program supervised by a health professional? DESIGN: A randomised, controlled trial with concealed allocation, intention-to treat analysis, and blinded outcome assessment at baseline and 3, 6, 9 and 12 months. PARTICIPANTS: The participants were recruited following a 6-week exercise program at a community health service. INTERVENTION: One group of participants received a gym-based exercise program for 12 months (gym group). The other group received a home-based exercise program for 12 months with telephone follow-up for the first 10 weeks (home group). OUTCOME MEASURES: Outcome measures included European Quality of Life Instrument (EQ-5D), the Friendship Scale, the Hospital and Anxiety and Depression Scale, Phone-FITT, 6-minute walk test, body mass index and 15-second sit-to-stand test. RESULTS: There was no significant difference between study groups in the primary outcome (EQ-5D visual analogue scale, 0 to 100) across the 12-month intervention period, with an estimate (adjusted regression coefficient) of the difference in effects of 0 (95% CI -5 to 4). The gym group demonstrated slightly fewer symptoms of depression over the 12-month period compared to the home group (mean difference 0.8 points on a 21-point scale, 95% CI 0.1 to 1.6). CONCLUSION: Similar long-term clinical outcomes and long-term exercise adherence are achieved with the two approaches examined in this study. Participation in gym-based group exercise may improve mental health outcomes slightly more, although the mechanisms for this are unclear because there was no change in the selected measure of social isolation or other measures of health and wellbeing. This finding may also be a Type 1 error. Further research to reproduce these results and that investigates the economic efficiency of these models of care is indicated. TRIAL REGISTRATION: ACTRN12610001035011. [Jansons P, Robins L, O'Brien L, Haines T (2017) Gym-based exercise and home based exercise with telephone support have similar outcomes when used as maintenance programs in adults with chronic health conditions: a randomised trial. Journal of Physiotherapy 63: 154-160]. PMID- 28655560 TI - Patients with uncomplicated total knee arthroplasty may not benefit from referral to inpatient rehabilitation [synopsis]. PMID- 28655561 TI - Patients with uncomplicated total knee arthroplasty may not benefit from referral to inpatient rehabilitation [commentary]. PMID- 28655562 TI - Physiotherapists' beliefs and attitudes influence clinical practice in chronic low back pain: a systematic review of quantitative and qualitative studies. AB - QUESTION: What influence do physiotherapists' beliefs and attitudes about chronic low back pain have on their clinical management of people with chronic low back pain? DESIGN: Systematic review with data from quantitative and qualitative studies. Quantitative and qualitative studies were included if they investigated an association between physiotherapists' attitudes and beliefs about chronic low back pain and their clinical management of people with chronic low back pain. RESULTS: Five quantitative and five qualitative studies were included. Quantitative studies used measures of treatment orientation and fear avoidance to indicate physiotherapists' beliefs and attitudes about chronic low back pain. Quantitative studies showed that a higher biomedical orientation score (indicating a belief that pain and disability result from a specific structural impairment, and treatment is selected to address that impairment) was associated with: advice to delay return to work, advice to delay return to activity, and a belief that return to work or activity is a threat to the patient. Physiotherapists' fear avoidance scores were positively correlated with: increased certification of sick leave, advice to avoid return to work, and advice to avoid return to normal activity. Qualitative studies revealed two main themes attributed to beliefs and attitudes of physiotherapists who have a relationship to their management of chronic low back pain: treatment orientation and patient factors. CONCLUSION: Both quantitative and qualitative studies showed a relationship between treatment orientation and clinical practice. The inclusion of qualitative studies captured the influence of patient factors in clinical practice in chronic low back pain. There is a need to recognise that both beliefs and attitudes regarding treatment orientation of physiotherapists, and therapist patient factors need to be considered when introducing new clinical practice models, so that the adoption of new clinical practice is maximised. [Gardner T, Refshauge K, Smith L, McAuley J, Hubscher M, Goodall S (2017) Physiotherapists' beliefs and attitudes influence clinical practice in chronic low back pain: a systematic review of quantitative and qualitative studies. Journal of Physiotherapy 63: 132-143]. PMID- 28655563 TI - Pathogenic characteristics of Candida albicans isolated from oral cavities of denture wearers and cancer patients wearing oral prostheses. AB - Candida albicans cause opportunistic infections including oral candidiasis in immunocompromised patients. It has an ability to cause infection due to its virulence factors. This study investigated the pathogenic characteristics of C. albicans isolated from the oral cavities of healthy subjects and two vulnerable groups, denture wearers and cancer patients wearing oral prostheses. Oral rinse samples were collected and cultured for the quantitative and qualitative analysis of Candida. Twenty strains of C. albicans isolated from the healthy individuals and denture wearers and, 14 strains isolated from the cancer patients were selected and their pathogenic characteristics were measured. The results of the study groups were compared using a Scheffe test for pairwise comparison and a chi square test. Denture wearer and cancer patients with prostheses carried significantly higher number (p < 0.01) and a variety of Candida than the normal individuals. Denture wearer and cancer patients carried several Candida species. The adherence abilities (p = 0.01) as well as phospholipase (p < 0.01) and proteinase (p = 0.03) production were significantly higher in the strains from denture wearers. In addition, high number of isolates from the denture wearers produced phospholipase and proteinase (85% and 80% respectively) compared to the strains from normal subjects (25% and 60% respectively). Only the germ tube formation and adherence ability were significantly higher in the strains from the cancer patients with prostheses (p = 0.05 and p < 0.01 respectively). In conclusion, during the commensal state, the increased expression of virulence factors in the denture wearers suggests the readiness of these strains to cause infection in this group. The high number of C. albicans and their increased adherence ability in the two study groups suggest that hygiene of oral cavity and prostheses is important in the prevention of colonization of Candida and the development of oral candidiasis. PMID- 28655564 TI - Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model. AB - Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats. PMID- 28655565 TI - Environmental enrichment attenuates behavioral abnormalities in valproic acid exposed autism model mice. AB - We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function. PMID- 28655566 TI - Determination of suitable reference genes for RT-qPCR analysis of murine Cytomegalovirus in vivo and in vitro. AB - Reverse transcription quantitative PCR (RT-qPCR) is the most commonly used method to evaluate gene expression. Reliable qPCR results are highly dependent on accurate normalization using suitable reference genes. We investigated expression of commonly used reference genes during murine Cytomegalovirus (mCMV) infection and latency to determine those genes least perturbed by infection. Following mCMV infection in BALB/c mice, lung, salivary gland, liver, spleen and kidney were evaluated. Liver sinusoidal endothelial cells and NIH-3T3 cells were also evaluated. RT-qPCR was performed during acute and latent mCMV infection for 11 commonly used reference genes with comparisons made to uninfected samples. Normfinder, BestKeeper, GeNorm and the comparative delta CT method produced comparable analyses that were combined in RefFinder to generate an overall ranking. Ppia, B2m and Gapdh are the most stable reference genes for in vitro infection studies. For in vivo studies the most suitable reference genes were highly tissue and cell type dependent. Comparing infected and uninfected groups revealed viral influence on transcription of some genes. We provide reference gene guidelines for investigations of gene expression for mCMV Smith strain infection of Balb/cJ mice or NIH-3T3 cells. These results also suggest careful consideration of reference genes for different host tissues evaluated. PMID- 28655568 TI - Corrigendum to "Physical Activity Promotes Gait Improvement in Patients With Total Knee Arthroplasty" [Journal of Arthroplasty 31(2016) 984-988]. PMID- 28655567 TI - Total Knee Replacement in Young Patients: Survival and Causes of Revision in a Registry Population. AB - BACKGROUND: The incidence of total knee replacements (TKRs) in young patients is increasing. Few reports described encouraging results and acceptable survival rates. However, many concerns still persist, in particular about the high rates of infection and aseptic loosening. Aim of this article was to investigate the survival of TKRs in patients aged 45 years or younger in a registry population. METHODS: The Emilia-Romagna registry RIPO was enquired about TKRs in patients <=45 years; 238 TKRs were evaluated at a mean follow-up of 5.4 years (range 0 15.6 years), examining the features of the patients involved, the survival rate, and the reasons for revision of the knee implants. RESULTS: The TKRs were generally performed in men, in private hospitals, and almost in half of the cases for other causes rather than primary osteoarthritis. The mean age was 40 years. Bicompartmental, cemented posterior-stabilized implants with fixed bearing were preferred. The survival rate was higher than 90% in the first 7 years, and then it decremented. The choice of implant did not apparently influence the survivorship. The final outcomes were acceptable, substantially in line with the previous literature about young patients. Twenty-one revisions occurred (8.8%), in particular 8 cases for aseptic loosening and 7 TKRs for infection. The rate of revision was higher than in overall population and even in some young cohorts. CONCLUSION: TKRs in patients aged 45 years or younger seem a promising procedure, although the high rates of septic and aseptic loosening should be carefully evaluated. Prospective, well-designed studies are required to confirm and investigate these preliminary findings. PMID- 28655569 TI - The hypaxial origin of the epaxially located rhomboid muscles. AB - In vertebrates, skeletal muscles of the body are made up of epaxial and hypaxial muscles based on their innervation and relative position to the vertebral column. The epaxial muscles are innervated by the dorsal branches of the spinal nerves and comprise the intrinsic (deep) back muscles, while the hypaxial muscles are innervated by the ventral branches of the spinal nerves including the plexus and consist of a heterogeneous group of intercostal, abdominal, and limb as well as girdle muscles. The canonical view holds that the epaxial muscles are derived from the medial halves of the somites, whereas the hypaxial muscles are all derived from the lateral somitic halves. The rhomboid muscles are situated dorsal to the vertebral column and therefore in the domain typically occupied by epaxial muscles. However, they are innervated by a ventral branch of the brachial plexus called the N. dorsalis scapulae. Due to the apparent inappropriate position of the muscle in relation to its innervation we investigated its origin to help clarify this issue. To study the embryonic origin of the rhomboid muscles, we followed derivatives of the medial and lateral somite halves using quail-chick chimeras. Our results showed that the rhomboid muscles are made up of cells derived mainly from the lateral portion of the somite. Therefore the rhomboid muscles which lie within the epaxial domain of the body, originate from the hypaxial domain of the somites. However their connective tissue is derived from both medial and lateral somites. PMID- 28655570 TI - New nano-hydroxyapatite in bone defect regeneration: A histological study in rats. AB - Many types of bone substitute materials are available on the market. Researchers are refining new bone substitutes to make them comparable to autologous grafting materials in treatment of bone defects. The purpose of the study was to evaluate the osseoconductive potential and bone defect regeneration in rat calvaria bone defects treated with new synthetic nano-hydroxyapatite. The study was performed on 30 rats divided into 5 equal groups. New preproduction of experimental nano hydroxyapatite material by NanoSynHap (Poznan, Poland) was tested and compared with commercially available materials. Five mm critical size defects were created and filled with the following bone grafting materials: 1) Geistlich Bio-Oss(r); 2) nano-hydroxyapatite+beta-TCP; 3) nano-hydroxyapatite; 4) nano hydroxyapatite+collagen membrane. The last group served as controls without any augmentation. Bone samples from calvaria were harvested for histological and micro-ct evaluation after 8 weeks. New bone formation was observed in all groups. Histomorphometric analysis revealed an amount of regenerated bone between 34.2 and 44.4% in treated bone defects, whereas only 13.0% regenerated bone was found in controls. Interestingly, in group 3, no significant particles of the nano-HA material were found. In contrast, residual bone substitute material could be detected in all other test groups. Micro-CT study confirmed the results of the histological examinations. The new nano-hydroxyapatite provides comparable results to other grafts in the field of bone regeneration. PMID- 28655571 TI - Zoonotic potential of Helicobacter spp. AB - The genus Helicobacter contains more than 35 species. Helicobacter pylori is the most important in terms of human health. Discovery of these helicobacters gives opportunity to understand the relationship between these bacteria which colonise the animal and human gut and their effect on the host. Infection with Helicobacter spp. and the associated diseases in their hosts allow us to study the pathogenic mechanisms. The potential zoonotic pathway for the transmission of Helicobacter spp. and epidemiology of this genus, deserve more attention to these emerging pathogens. PMID- 28655572 TI - A rarely considered diagnosis of unknown fever, disseminated lymphadenopathy and chronic peritonitis in Taiwan: Whipple's disease. PMID- 28655573 TI - Identification of a panel of serum protein markers in early stage of sepsis and its validation in a cohort of patients. AB - BACKGROUND: Sepsis is a life-threatening illness with a challenging diagnosis. Current serum biomarkers are not sensitive enough for diagnosis. With the aim of finding proteins associated with sepsis, serum protein profile was compared between patients and healthy donors and serum classical inflammatory proteins were analyzed in both groups. METHODS: Serum protein profiles were characterized by two-dimensional electrophoresis (2DE). Identification of the proteins was carried out by mass spectrophotometry and their validation was performed by Enzyme-Linked-ImmunoSorbent Assay (ELISA) in a cohort of 85 patients and 67 healthy donors. Seven classical inflammatory proteins were analyzed in the same cohort by ELISA: interleukin-2 receptor alpha-chain (sCD25), scavenger receptor cysteine-rich-type-1 (sCD163), tumor-necrosis factor receptor superfamily-member 6 (sFas), hemeoxigenase-1 decycling (HO-1), interleukin-6 (IL-6), interleukin-18 (IL-18) and intercellular adhesion-molecule-1 (sICAM-1). RESULTS: After 2DE, 20 significantly differently expressed spots were identified by mass spectrometry analysis, revealing deregulation of six different proteins upon sepsis and 50% were validated by ELISA: Antithrombin-III (AT-III), Clusterin (CLUS) and Serum amyloid A-1 (SAA-1). Serum concentration of AT-III and CLUS was significantly lower in patients' serum, whereas SAA-1 showed higher values in septic patients. Serum concentration of the seven inflammatory proteins was significantly increased in septic patients. Functional analysis of the ten deregulated proteins revealed an enrichment of proteins related mainly to the activation of the immune response. CONCLUSION: We have identified a panel of ten potential sepsis marker proteins biologically connected and validated in a large number of patients, whose analysis could be considered as a complementary tool for the diagnosis of sepsis. PMID- 28655574 TI - Cisplatin along with herbal drug treatment reduces the percentage of regulatory T cells and decreased the severity of experimental visceral leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis is the most alarming and devastating amongst the various forms of leishmaniases. It is caused by Leishmania donovani, an obligate intracellular parasite of macrophages that survives through immunosuppression. Absence of T regulatory cells provides complete clearance of the parasite. A few immunoprophylactics have been sought to battle instinctive leishmaniasis, with fluctuating achievement. Our previous studies have shown that treatment of L. donovani infected mice with cisplatin along with herbal drugs resulted in decreased parasite load with heightened delayed type hypersensitivity responses (DTH), increased levels of IgG2a, IFN-gamma, IL-2, CD4+ cells, NK 1.1 cells over that of IgG1, IL-4, 1L-10, CD8+ and CD19 in infected mice. METHODS: Along the above lines, the present study further evaluated the percentage of CD4+ CD25+ FoxP3+ T regulatory cells and ultra structural changes in kidney, liver and spleen. Cisplatin (5 mg/kg b.wt. daily for 5 days, i.p.) along with Tinosporacordifolia (100 mg/kg b.wt. daily for 15 days, p.o.) or Withaniasomnifera (350 mg/kg b.wt. daily for 15 days, p.o.) or Asparagusracemosus (650 mg/kg b.wt. daily for 15 days, p.o.) was administered to L. donovani infected BALB/c and after 30 days post treatment mice were sacrificed. RESULTS: The findings uncover a significant reduction in parasite load coupled with decreased percentage of Treg cells and no pathological changes at ultra structural level. CONCLUSION: In this manner, results acquired recommend that the decrease in percentage of T reg cells may further help the antileishmanial remedial impact of cisplatin alongside natural medications. PMID- 28655575 TI - Cell-free DNA in a three-dimensional spheroid cell culture model: A preliminary study. AB - BACKGROUND: Investigating the biological functions of cell-free DNA (cfDNA) is limited by the interference of vast numbers of putative sources and causes of DNA release into circulation. Utilization of three-dimensional (3D) spheroid cell cultures, models with characteristics closer to the in vivo state, may be of significant benefit for cfDNA research. METHODS: CfDNA was isolated from the growth medium of C3A spheroid cultures in rotating bioreactors during both normal growth and treatment with acetaminophen. Spheroid growth was monitored via planimetry, lactate dehydrogenase activity and glucose consumption and was related to isolated cfDNA characteristics. RESULTS: Changes in spheroid growth and stability were effectively mirrored by cfDNA characteristics. CfDNA characteristics correlated with that of previous two-dimensional (2D) cell culture and human plasma research. CONCLUSIONS: 3D spheroid cultures can serve as effective, simplified in vivo-simulating "closed-circuit" models since putative sources of cfDNA are limited to only the targeted cells. In addition, cfDNA can also serve as an alternative or auxiliary marker for tracking spheroid growth, development and culture stability. BIOLOGICAL SIGNIFICANCE: 3D cell cultures can be used to translate "closed-circuit" in vitro model research into data that is relevant for in vivo studies and clinical applications. In turn, the utilization of cfDNA during 3D culture research can optimize sample collection without affecting the stability of the growth environment. Combining 3D culture and cfDNA research could, therefore, optimize both research fields. PMID- 28655576 TI - Involvement of a tachylectin-like gene and its protein in pathogenesis of acute hepatopancreatic necrosis disease (AHPND) in the shrimp, Penaeus monodon. AB - A shrimp disease, the so-called acute hepatopancreatic necrosis disease (AHPND) is caused by a specific strain of Vibrio parahaemolyticus (VP) and it has resulted in significant losses to the global shrimp farming industry. In our previous study, three of tachylectin-like genes were cloned and characterized from the intestine of Penaeus monodon, designated as Penlectin5-1 (PL5-1), Penlectin5-2 (PL5-2) and Penlectin5-3 (PL5-3). These three genes all contain fibrinogen-related domain (FReD). The expression level of PL5-1, PL5-2 and PL5-3 was elevated in the stomach after oral administration with AHPND-causing V. parahaemolyticus 3HP (VP3HP). A polyclonal antibody to PL5-2 was successfully produced in a rabbit using the purified recombinant PL5-2 as an immunogen, and this because only the predominant protein PL5-2 could be successfully purified from shrimp plasma by affinity chromatography using a N-Acetyl-d-glucosamine column allowed us to perform functional studies of this lectin. The native purified PL5-2 protein had binding and agglutination activities towards VP3HP. To further understand the functions and the involvements of this lectin in response to AHPND in shrimp, RNAi-mediated knockdown of PL5-1, PL5-2 or PL5-3 was performed prior to an oral administration of VP3HP. As a result, Penlectin5 silencing in shrimp challenged with VP3HP showed higher mortality and resulted in more severe histopathological changes in the hepatopancreas with typical signs of AHPND. These results therefore suggest a role for crustacean fibrinogen-related proteins (FRePs) in innate immune response during the development of AHPND, and maybe also during other infections. PMID- 28655577 TI - NOD1 is the innate immune receptor for iE-DAP and can activate NF-kappaB pathway in teleost fish. AB - The innate immune system is the first line for organisms defense against microbial infection, and NOD-like receptors (NLRs) protein family is an important member of innate immunity effector molecules. It has been proved that NLRs are located in the endochylema and can senses of microbial products. NOD1 is one of the representatives of this family, it has been proved that in mammals, NOD1 can distinguish a specific muropeptide (G-d-glutamyl-meso-diaminopimelic acid, iE DAP) which was derived from bacterial peptidoglycans. However, the NOD-mediated intracellular recognition of microorganisms remains largely uncharacterized in teleost fishes. In this study, we use miiuy croaker (Miichthys miiuy) as a model to determine NOD1 can response to the infection of Gram-negative bacteria and it is the receptor that can recognize of iE-DAP by LRRs domain, it can activate the NF-kappaB signaling pathway through recruit RIP2 to induce inflammatory response in teleost fishes. Results showed that NOD1 can recognize the components of Gram negative bacteria and activate inflammatory response to resistance of bacterial infection. Our study can improve the knowledge on immune system of fishes and provide a theoretical basis for the study of prevention and treatment of fish diseases. PMID- 28655578 TI - Unusual tissue distribution of carcinin, an antibacterial crustin, in the crab, Carcinus maenas, reveals its multi-functionality. AB - Crustins are whey acidic four-disulphide core (WFDSC) domain-containing proteins in decapods that are widely regarded as antimicrobial agents that contribute to host defence. Whilst there have been many analyses of crustin gene expression in tissues, few studies have been made of the distribution of the natural proteins. Here we report an immunostaining investigation of carcinin, a native crustin from Carcinus maenas, in the body organs. The results show that the protein is largely confined to the haemocytes with only a weak signal detected in the heart, hepatopancreas and midgut caecum where it is restricted to the outer surfaces. Importantly, carcinin was seen to be deposited by the haemocytes on these surfaces. Higher levels of staining were detected in the gonads with carcinin particularly abundant in the capsule of ovary as well as some oocytes. Conspicuous staining was further evident in the cuticle of the eyestalk peduncles. Ablation of the eyestalks resulted in a reduction of carcinin in the maturing ovary with the mature eggs rarely displaying a strong signal for the protein. Interestingly, the degree of carcinin also strongly increased in the healing peduncle, indicating that the protein may be associated with wounding, cell damage and/or tissue regeneration. PMID- 28655579 TI - The interbranchial lymphoid tissue likely contributes to immune tolerance and defense in the gills of Atlantic salmon. AB - Central and peripheral immune tolerance is together with defense mechanisms a hallmark of all lymphoid tissues. In fish, such tolerance is especially important in the gills, where the intimate contact between gill tissue and the aqueous environment would otherwise lead to continual immune stimulation by innocuous antigens. In this paper, we focus on the expression of genes associated with immune regulation by the interbranchial lymphoid tissue (ILT) in an attempt to understand its role in maintaining immune homeostasis. Both healthy and virus challenged fish were investigated, and transcript levels were examined from laser dissected ILT, gills, head kidney and intestine. Lack of Aire expression in the ILT excluded its involvement in central tolerance and any possibility of its being an analogue to the thymus. On the other hand, the ILT appears to participate in peripheral immune tolerance due to its relatively high expression of forkhead box protein 3 (Foxp3) and other genes associated with regulatory T cells (Tregs) and immune suppression. PMID- 28655580 TI - Cognitive behavioral therapy for insomnia (CBT-I): What is known, and advancing the science by avoiding the pitfalls of the placebo effect. PMID- 28655581 TI - Clinical and molecular characteristics of community-acquired Clostridium difficile infections in comparison with those of hospital-acquired C. difficile. AB - Community-acquired Clostridium difficile infection (CA-CDI) is a growing concern. CA-CDI differs from hospital-acquired C. difficile infection (HA-CDI) in its epidemiology, risk factors, severity, and outcomes. In this study, we investigated C. difficile infections in a tertiary care hospital in Seoul, Korea, and compared the CA-CDI and HA-CDI cases diagnosed in the same period. Total 593 cases were confirmed as CDI in 2014, of which CA-CDI accounted for 68 (11.5%) of the total CDI cases. Compared with HA-CDI, the mean age of CA-CDI cases was lower than that of HA-CDI (42.7 vs 60.4). In CA-CDI, antibiotic and proton pump inhibitor (PPI) use in the 12 preceding weeks and concurrent chemotherapy and tube feeding were less frequent compared with HA-CDI. In most cases (63/68, 92.6%), patients with CA-CDI recovered without any complications or recurrence. The most prevalent C. difficile type in CA-CDI cases was PCR-ribotype 012, accounting for 18.3% of the total, followed by PCR-ribotype 018 (16.7%). PMID- 28655582 TI - Prevalence of Clostridium perfringens toxin in patients suspected of having antibiotic-associated diarrhea. AB - BACKGROUND: Although Clostridium perfringens has been reported as a cause of antibiotic-associated diarrhea (AAD), it is uncommon to detect this pathogen in clinical microbiology laboratories in Korea. The aim of this study was to investigate the prevalence of C. perfringens toxin in patients suspected of having AAD. METHODS: A total of 135 stool specimens submitted to a clinical microbiology laboratory for C. difficile toxin assay were tested. We tried to detect both C. difficile and C. perfringens toxins using the Seeplex Diarrhea ACE Detection kit (Seegene, Seoul, Korea). We evaluated the prevalence of 10 bacteria and 5 viruses. RESULTS: A total of 40 Clostridium spp. were detected in 34 specimens (29.6%). The C. perfringens toxin was detected in 14 of 135 specimens (10.4%), while C. difficile toxin was detected in 26 specimens (19.3%). Other bacteria and viruses, including 8 Aeromonas spp., were detected in 15 specimens. All tests were negative in 92 of the 135 specimens (68.1%). CONCLUSION: Clostridium perfringens toxin is relatively common, and we should consider the possibility of its presence in patients suspected of having AAD, especially if C. difficile tests are negative. PMID- 28655583 TI - Evaluation of the inhibitory effect of N-acetyl-L-cysteine on Babesia and Theileria parasites. AB - N-acetyl-L-cysteine is known to have antibacterial, antiviral, antimalarial, and antioxidant activities. Therefore, the in vitro inhibitory effect of this hit was evaluated in the present study on the growth of Babesia and Theileria parasites. The in vitro growth of Babesia bovis, Babesia bigemina, Babesia divergens, Theileria equi, and Babesia caballi that were tested was significantly inhibited (P < 0.05) by micromolar concentrations of N-acetyl-L-cysteine. The inhibitory effect of N-acetyl-L-cysteine was synergistically potentiated when used in combination with diminazene aceturate on B. bovis and B. caballi cultures. These results indicate that N-acetyl-L-cysteine might be used as a drug for the treatment of babesiosis, especially when used in combination with diminazene aceturate. PMID- 28655584 TI - Biological, biochemical and histological features of Bradybaena similaris (Gastropoda: Pulmonata) infected by Heterorabditis indica (Rhabditida: Heterorhabditidae) strain LPP1. AB - This study investigated the possible biological, biochemical and histological changes in Bradybaena similaris(Gastropoda: Pulmonata) infected by Heterorhabditis indica (Rhabditida: Heterorhabditidae), strain LPP1. Two groups of 16 snails were formed: the control group (unexposed) and the treated group, which was exposed for three weeks to infective juveniles (J3) of H. indica LPP1. The experiment was conducted in duplicate, using a total of 64 snails. After the exposure period, the snails were dissected to collect the hemolymph and tissues, for evaluation of the physiological changes caused by the infection. The number of eggs laid/snail and the viability of these eggs were also assessed as indicators of the reproductive activity of B. similaris. Intense glycogenolysis was accompanied by a significant reduction (p < 0.05) in the glucose content of the hemolymph of the exposed snails, indicating that infection by H. indica induces breakdown of the host's glycemic homeostasis. Significant variations (p < 0.05) in the lactate dehydrogenase activity occurred together with changes in the concentration of pyruvic and lactic acid in the hemolymph of the infected B. similaris snails, corroborating the transition from aerobic to anaerobic metabolism in the hosts. These metabolic alterations reflect the parasitic castration process in this interface. The results suggest that the use of H. indica LPP1 is a potential alternative for biological control of B. similaris. PMID- 28655585 TI - IgM and IgG responses in Schistosoma mansoni-infected mice using egg and worm antigens: Does response vary with parasitic burden and phase of infection? AB - Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma, endemic in tropical and subtropical regions. The hepatic pathology of this parasitic disease could develop complications, such as fibrosis and cirrhosis, which can be fatal. The Venezuelan endemic area is considered as one of low transmission, which complicates the detection of infected individuals and signals the importance of improving the sensitivity of immunodiagnostic methods. Using ELISA, an evaluation was conducted of IgM and IgG responses to soluble antigens of eggs and female worms (SEA and SFWA) and excretion-secretion products of eggs and female worms (ESPE and ESPAW) in infected Balb/c mice with different parasitic burden and infection times. A high positivity rate by IgM detection was observed for all antigen preparations in 7-week infections (100% by SEA, SFWA, ESPE, and ESPWA in high parasitic burden) as well as a reduction of this immunoglobulin in chronic infection. Positivity rate for IgG detection was higher in 20-week infections (100% by ESPE in low burden, 100% by SEA and ESPE in medium burden, and 100% by ESPE and ESPAW in high burden conditions). The potential use of combined or unique antigenic preparations associated with IgM or IgG for detection of active infection, regardless the parasitic burden, was demonstrated. Differences between immunoglobulin responses show its application for phase specific diagnosis. PMID- 28655586 TI - Screening study of TUBB4A in isolated dystonia. AB - Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum ranging from hereditary generalized dystonia with whispering dysphonia (DYT4) to the leukodystrophy hypomyelination syndrome with atrophy of the basal ganglia and cerebellum (H-ABC). To test for the contribution of TUBB4A mutations in different ethnicities (Spanish, Italian, Korean, Japanese), we screened 492 isolated dystonia cases for mutations in this gene and for the first time determined TUBB4A copy number variations in 336 dystonia patients. A potentially pathogenic rare 3bp-in-frame deletion was found in a patient with cervical dystonia but no copy number variations were detected in this study, suggesting that TUBB4A mutations exceedingly rarely contribute to the etiology of isolated dystonia. PMID- 28655587 TI - Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses. AB - Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (KO) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120ug/kg; HPA-axis: 120ug/kg), but showed attenuated but not extinguished fever (120ug/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-alpha (TNFalpha) inhibitor etanercept nor the IL-6 receptor antibody tocilizumab abolished the LPS induced fever in IL-1R1 KO mice. Deletion of IL-1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFalpha, but by some yet unidentified pyrogenic factor. PMID- 28655588 TI - Gaseous ligand selectivity of the H-NOX sensor protein from Shewanella oneidensis and comparison to those of other bacterial H-NOXs and soluble guanylyl cyclase. AB - To delineate the commonalities and differences in gaseous ligand discrimination among the heme-based sensors with Heme Nitric oxide/OXygen binding protein (H NOX) scaffold, the binding kinetic parameters for gaseous ligands NO, CO, and O2, including KD, kon, and koff, of Shewanella oneidensis H-NOX (So H-NOX) were characterized in detail in this study and compared to those of previously characterized H-NOXs from Clostridium botulinum (Cb H-NOX), Nostoc sp. (Ns H NOX), Thermoanaerobacter tengcongensis (Tt H-NOX), Vibrio cholera (Vc H-NOX), and human soluble guanylyl cyclase (sGC), an H-NOX analogue. The KD(NO) and KD(CO) of each bacterial H-NOX or sGC follow the "sliding scale rule"; the affinities of the bacterial H-NOXs for NO and CO vary in a small range but stronger than those of sGC by at least two orders of magnitude. On the other hand, each bacterial H NOX exhibits different characters in the stability of its 6c NO complex, reactivity with secondary NO, stability of oxyferrous heme and autoxidation to ferric heme. A facile access channel for gaseous ligands is also identified, implying that ligand access has only minimal effect on gaseous ligand selectivity of H-NOXs or sGC. This comparative study of the binding parameters of the bacterial H-NOXs and sGC provides a basis to guide future new structural and functional studies of each specific heme sensor with the H-NOX protein fold. PMID- 28655589 TI - Identification of Seniors at Risk (ISAR) in the emergency room: A prospective study. AB - INTRODUCTION: The Identification of Seniors at Risk (ISAR) is one of the most frequently utilized risk screening tools in emergency departments (ED). The goal of this study was to evaluate the predictive validity of the ISAR screening tool for adverse outcomes in an ED. METHODS: This was a prospective single-center observational study in a Portuguese urban university hospital ED, and included 402 older adults (OA). After triage, baseline sociodemographic and clinic data were collected by the researcher and the ISAR was administered. Baseline ISAR, adverse outcomes (ED revisits and hospital admission) at 30 (early) and 180 (late) days were evaluated. RESULTS: ISAR screening showed that 308 (76.62%) OAs were at risk (cutoff>=2). High-risk patients were more like to be older, take more medication, have urgent or very urgent ED visits and have longer ED lengths of stay. The high-risk group were more likely to demonstrate both early (OR=2.43, 95% CI 1.35-4.35, p<0.01) and late returns to the ED (AO=1.70, 95% CI 1.04-2.79, p<0.05). The ISAR did not predict any significant variable for hospital admission in 30 or 180days. DISCUSSION: The ISAR predicted returns to EDs at 30 and 180days for OAs at risk, but was unable to predict early or late hospital readmission. PMID- 28655590 TI - Emergency nurses' knowledge and experience with the triage process in Hunan Province, China. AB - INTRODUCTION: Triage is implemented to facilitate timely and appropriate treatment of patients, and is typically conducted by senior nurses. Triage accuracy and consistency across emergency departments remain a problem in mainland China. This study aimed to investigate the current status of triage practice and knowledge among emergency nurses in Changsha, Hunan Province, China. METHOD: A sample of 300 emergency nurses was selected from 13 tertiary hospitals in Changsha and a total of 193 completed surveys were returned (response rate=64.3%). Surveys were circulated to head nurses, who then distributed them to nurses who met the selection criteria. Nurses were asked to complete the surveys and return them via dedicated survey return boxes that were placed in discreet locations to ensure anonymity. RESULTS: Just over half (50.8%) of participants reported receiving dedicated triage training, which was provided by their employer (38.6%), an education organisation (30.7%) or at a conference (26.1%). Approximately half (53.2%) reported using formal triage scales, which were predominantly 4-tier (43%) or 5-tier (34%). CONCLUSIONS: The findings highlight variability in triage practices and training of emergency nurses in Changsha. This has implications for the comparability of triage data and transferability of triage skills across hospitals. PMID- 28655591 TI - Promoting dignified end-of-life care in the emergency department: A qualitative study. AB - BACKGROUND: Preservation of a dying person's dignity in the emergency department (ED) is fundamental for the patient, his/her relatives and healthcare professionals. The aim of this study was to explore and interpret physicians' and nurses' experiences regarding conservation of dignity in end-of-life care in dying patients in the ED. METHODS: A qualitative study based on the hermeneutic phenomenological approach, was carried out in the emergency department of two general hospitals. A total of 16 nurses and 10 physicians participated in the study. Data collection included 12 individual in-depth interviews and 2 focus groups. RESULTS: The findings revealed that two themes represent the practices and proposals for the conservation of dignity in the emergency department: dignified care in hostile surroundings and the design of a system focused on the person's dignity. CONCLUSION: Dignifying treatment, redesigning environmental conditions, and reorienting the healthcare system can contribute to maintaining dignity in end-of-life care in the ED. PMID- 28655592 TI - Prognostic Value of Radiation Pneumonitis After Stereotactic Body Radiotherapy: Effect of Pulmonary Emphysema Quantitated Using CT Images. AB - BACKGROUND: The aim of this study was to determine the prognostic factors of radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: A total of 50 patients (36 male and 14 female) were treated with SBRT for 42 primary lung cancers and 8 metastatic lung cancers. SBRT was performed with 48 Gy in 4 fractions to the isocenter or with 40 Gy in 4 fractions covering 95% of the planning target volume. Percentage of low attenuation area (%LAA) was defined as percentage of the lung area with attenuation of -860 Hounsfield units (HU) or lower (%LAA-860) or of -960 HU or lower (%LAA-960). The dosimetric parameter of V20 Gy, which means percentage volume of the lung receiving 20 Gy or more, was recalculated. RP was assessed using Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow up period was 39.0 months (range, 7.2-94.5 months). RP of Grade 0, Grade 1, and Grade 2 to 3 was diagnosed in 11, 29, and 10 patients, respectively. Multivariate analyses (MVA) for Grade 1 showed that higher %LAA-860 and higher %LAA-960 were significantly associated with a lower rate of Grade 1 RP. MVA for Grade 2 to 3 showed that lower Brinkman index and lower lung V20 Gy were significantly associated with a lower rate of Grade 2 to 3 RP, and, in contrast, %LAA-860 and %LAA-960 had no association with Grade 2 to 3 RP. CONCLUSION: This result suggests that high %LAA is associated with radiological changes (Grade 1) but that %LAA has no correlation with Grade 2 to 3 RP because symptomatic RP might also be affected by other factors. PMID- 28655593 TI - Collagen fibril organization within rat vertebral bone modified with metastatic involvement. AB - Metastatic involvement diminishes the mechanical integrity of vertebral bone, however its specific impact on the structural characteristics of a primary constituent of bone tissue, the collagen-I fibril matrix, has not been adequately characterized. Female athymic rats were inoculated with HeLa or Ace-1 cancer cells lines producing osteolytic or mixed (osteolytic & osteoblastic) metastases respectively. A maximum of 21days was allowed between inoculation and rat sacrifice for vertebrae extraction. Linear polarization-in, polarization-out (PIPO) second harmonic generation (SHG) and transmission electron microscopy (TEM) imaging was utilized to assess the impact of metastatic involvement on collagen fibril organization. Increased observations of deviations in the typical plywood motif or a parallel packing structure and an increased average measured susceptibility ratio (related to relative degree of in-plane vs. out-plane fibrils in the analyzed tissue area) in bone adjacent to metastatic involvement was indicative of change in fibrilar organization compared to healthy controls. In particular, collagen-I fibrils in tumour-induced osteoblastic bone growth showed no adherence to the plywood motif or parallel packing structure seen in healthy lamellar bone, exhibiting a much higher susceptibility ratio and degree of fibril disorder. Negative correlations were established between measured susceptibility ratios and the hardness and modulus of metastatic bone tissue assessed in a previous study. Characterizing modifications in tissue level properties is key in defining bone quality in the presence of metastatic disease and their potential impact on material behaviour. PMID- 28655594 TI - Transcriptome profiling and expression analysis of immune responsive genes in the liver of Golden mahseer (Tor putitora) challenged with Aeromonas hydrophila. AB - Transcriptome profiling has been used to decipher the novel mechanisms behind immune responses of the fishes. However, the molecular mechanism underlining immune response in mahseer is not studied so far. Fishes are greatly affected by bacterial pathogens such as Aeromonas hydrophila. In this study, transcriptome response of golden mahseer (Tor putitora) infected with A. hydrophila was examined using paired end Illumina sequencing of liver tissue to understand the immune response of the fish. The de novo assembly generated 61,042 unigenes ranging from 200 to 9322 bp in length and an average length of 463 bp. The gene ontology annotations resulted a total of 131,826 term assignments to the annotated transcriptome including 60,846 (46.16%) allocations from the biological process; 21,603 (16.39%) from molecular function and 49,377 (37.46%) from cellular components. Differential gene expression analysis of the transcriptome data from challenged and control group revealed 1104 upregulated and 1304 down regulated unigenes. The differentially expressed genes were mainly involved in the pathways including cell surface receptor signaling, TH1 and TH2 cell differentiation, pathogen recognition, and immune system process/defense response especially complement cascade. Twelve unigenes including ankyrin, serum amyloid, hsp4b, STAT3, complement factor c3 and c7 were validated using qPCR and found differentially expressed in accordance with in silico expression analysis. The results obtained in this study will provide the first and crucial information on the molecular mechanism of mahseer fishes against bacterial infection. PMID- 28655595 TI - Diabetes of the exocrine pancreas: American Diabetes Association-compliant lexicon. AB - Multidisciplinary teams, including gastroenterologists, endocrinologists, surgeons, dietitians, primary care physicians, and other health professionals, are involved in management of individuals with diabetes of the exocrine pancreas (DEP). This necessitates introduction of a uniform terminology to ensure proper communication and reporting. Because DEP is a form of secondary diabetes mellitus, it makes sense to align the evolving DEP lexicon with nomenclature and diagnostic standards advocated by a world leading professional body in the field of diabetes such as the American Diabetes Association. This Editorial offers a historical excursus on the terms used and proposes a new concise nomenclature and diagnostic criteria. This new taxonomy of DEP, compliant with the American Diabetes Association standards of diagnosis and care for patients with diabetes mellitus, will ensure standardisation of reporting in future clinical studies on DEP and enable a dynamic incorporation of glucose dysregulation mechanisms related specifically to diseases of the exocrine pancreas as new evidence emerges. PMID- 28655596 TI - Effects of Macronutrient Distribution on Weight and Related Cardiometabolic Profile in Healthy Non-Obese Chinese: A 6-month, Randomized Controlled-Feeding Trial. PMID- 28655597 TI - Identification of Host Proteins Predictive of Early Stage Mycobacterium tuberculosis Infection. AB - The objective of this study was to identify blood-based protein biomarkers of early stage Mycobacterium tuberculosis (Mtb) infection. We utilized plasma and serum specimens from TB patients and their contacts (age>=12) enrolled in a household contact study in Uganda. In the discovery phase cross-sectional samples from 104 HIV-uninfected persons classified as either active TB, latent Mtb infection (LTBI), tuberculin skin test (TST) converters, or persistent TST negative were analyzed. Two hundred eighty-nine statistically significant (false discovery rate corrected p<0.05) differentially expressed proteins were identified across all comparisons. Proteins associated with cellular immunity and lipid metabolism were induced early after Mtb infection. One hundred and fifty nine proteins were selected for a targeted mass spectrometry assay. A set of longitudinal samples from 52 TST-negative subjects who converted to TST-positive or remained TST-negative were analyzed, and multivariate logistic regression was used to identify unique protein panels able to predict TST conversion with cross validated AUC>0.85. Panel performance was confirmed with an independent validation set of longitudinal samples from 16 subjects. These candidate protein biomarkers may allow for the identification of recently Mtb infected individuals at highest risk for developing active TB and most likely to benefit from preventive therapy. PMID- 28655598 TI - Annual Facility Treatment Volume and Patient Survival for Mycosis Fungoides and Sezary Syndrome. AB - BACKGROUND: Management of mycosis fungoides and Sezary syndrome (MF/SS) is complex, and randomized evidence to guide treatment is lacking. The institutional treatment volumes for MF/SS might vary widely nationally and influence patient survival. PATIENTS AND METHODS: Using the National Cancer Database, we identified patients with a diagnosis of MF/SS from 2004 to 2011 in the United States who had received treatment at a reporting facility. The patients were grouped into quintiles according to their treatment facility's average annual treatment volume (ATV). The characteristics associated with ATV were identified and compared using chi2 tests. Overall survival (OS) was compared among the ATV quintiles using the Kaplan-Meier method with log-rank tests and multivariable Cox regression with hazard ratios (HRs). OS was also analyzed using the annual patient volume as a continuous variable. RESULTS: A total of 2205 patients treated at 374 facilities were included for analysis. The ATV quintile cutoffs were 1, 3, 6, and 9 patients. With a median follow-up period of 59 months, the 5-year estimated OS survival increased with ATV from 56.7% in the lowest quintile (<= 1 patient annually) to 83.8% in the highest quintile (> 9 patients annually; P < .001). On multivariable analysis, greater ATV was associated with improved survival when analyzed as a continuous variable (HR, 0.96 per patient per year; 95% confidence interval, 0.94-0.98; P < .001) and when comparing the highest quintile to the lowest quintile (HR, 0.46; 95% confidence interval, 0.39-0.55). CONCLUSION: The present national database analysis demonstrated that higher facility ATV is associated with improved OS for patients with MF/SS. Further study is needed to determine the underlying reasons for improved survival with higher facility ATV. PMID- 28655599 TI - Final Results of a Phase 1 Study of Vorinostat, Pegylated Liposomal Doxorubicin, and Bortezomib in Relapsed or Refractory Multiple Myeloma. AB - INTRODUCTION/BACKGROUND: Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in preclinical models of multiple myeloma (MM). We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in relapsed/refractory MM. PATIENTS AND METHODS: Thirty-two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14. RESULTS: The maximum tolerated dose of vorinostat was 400 mg on days 4 to 11. Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59% and 94% of patients, of which 37% and 47% were of grade 3 or higher severity, respectively. Constitutional and gastrointestinal adverse events of all grades were common, the majority of which were less than grade 3 in severity. The overall response rate (partial response rate or better) was 65% and the clinical benefit rate (minimal response rate or better) 74%. The overall response rate was 83%, 71%, and 45% for patients with bortezomib-naive, -sensitive, and -refractory MM, respectively. The median progression-free survival was 13.9 months and the 3-year overall survival 77%. Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic-like activity of the proteasome. CONCLUSION: Further evaluation of PLD, bortezomib, and deacetylase inhibitor combinations is warranted, with special attention directed toward strategies to improve tolerability. PMID- 28655600 TI - Cellular mechanisms of peroxynitrite-induced neuronal death. AB - Peroxynitrite (ONOO-) is a strong biological oxidant formed by the diffusion limited reaction of nitric oxide (NO-) and superoxide anion (O2-). It has long been theorized that peroxynitrite generation could be the cause in a number of pathological conditions ranging from atherosclerosis to inflammatory, autoimmune, heart and neurodegenerative diseases. Its relatively long biological half-life and high reactivity allows peroxynitrite to oxidize a number of different targets in the cell. In physiologically relevant conditions peroxynitrite can directly react with thiols, or the radical products of peroxynitrite decomposition may indirectly oxidize other cellular components such as lipids, proteins and DNA. Downstream, oxidative modifications caused by peroxynitrite trigger cell death by a variety of mechanisms depending on the concentration of the oxidant. Peroxynitrite stimulates necrosis, apoptosis, autophagy, parthanatos and necroptosis. Here we review the mechanisms activated by peroxynitrite to cause neuronal death. PMID- 28655601 TI - The effect of monascin on hematoma clearance and edema after intracerebral hemorrhage in rats. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a particularly devastating form of stroke with high mortality and morbidity. Hematomas are the primary cause of neurologic deficits associated with ICH. The products of hematoma are recognized as neurotoxins and the main contributors to edema formation and tissue damage after ICH. Finding a means to efficiently promote absorption of hematoma is a novel clinical challenge for ICH. Peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor erythroid 2 related factor 2 (Nrf2), had been shown that, can take potential roles in the endogenous hematoma clearance. However, monascin, a novel natural Nrf2 activator with PPARgamma agonist, has not been reported to play a role in ICH. This study was designed to evaluate the effect of monascin on neurological deficits, hematoma clearance and edema extinction in a model of ICH in rats. METHODS: 164 adult male Sprague-Dawley (SD) rats were randomly divided into sham; vehicle; monascin groups with low dosages (1mg/kg/day), middle dosages (5mg/kg/day) and high dosages (10mg/kg/day) respectively. Animals were euthanized at 1, 3 and 7days following neurological evaluation after surgery. We examined the effect of monascin on the brain water contents, blood brain barrier (BBB) permeability and hemoglobin levels, meanwhile reassessed the volume of hematoma and edema around the hematoma by Magnetic Resonance Imaging (MRI) in each group. RESULTS: The high dosage of monascin significantly improved neurological deficits, reduced the volume of hematoma in 1-7days after ICH, decreased BBB permeability and edema formation in 1-3days following ICH. CONCLUSION: Our study demonstrated that the high dosage of monascin played a neuroprotective role in ICH through reducing BBB permeability, edema and hematoma volume. PMID- 28655602 TI - The journey from pain to power: A meta-ethnography on women's experiences of vaginal birth after caesarean. AB - BACKGROUND: Vaginal birth after caesarean can be a safe and satisfying option for many women who have had a previous caesarean, yet rates of vaginal birth after caesarean remain low in the majority of countries. Exploring women's experiences of vaginal birth after caesarean can improve health practitioners' understanding of the factors that facilitate or hinder women in the journey to have a vaginal birth after caesarean. METHODS: This paper reports on a meta-ethnographic review of 20 research papers exploring women's experience of vaginal birth after caesarean in a variety of birth locations. Meta-ethnography utilises a seven stage process to synthesise qualitative research. RESULTS: The overarching theme was 'the journey from pain to power'. The theme 'the hurt me' describes the previous caesarean experience and resulting feelings. Women experience a journey of 'peaks and troughs' moving from their previous caesarean to their vaginal birth after caesarean. Achieving a vaginal birth after caesarean was seen in the theme 'the powerful me,' and the resultant benefits are described in the theme 'the ongoing journey'. CONCLUSION: Women undergo a journey from their previous caesarean with different positive and negative experiences as they move towards their goal of achieving a vaginal birth after caesarean. This 'journey from pain to power' is strongly influenced by both negative and positive support provided by health care practitioners. Positive support from a health care professional is more common in confident practitioners and continuity of care with a midwife. PMID- 28655603 TI - Fracture during oral bisphosphonate therapy is associated with deteriorated bone material strength index. AB - BACKGROUND: Some patients experience fractures while receiving oral bisphosphonates (BPs) treatment. Clinical risk factors, advanced bone density loss, and microarchitecture deterioration have been associated with such fractures but bone tissue properties other than bone mineral density (BMD) have not been assessed. METHODS: In a cross-sectional study of postmenopausal women on bisphosphonates for at least 4years with good adherence to treatment, 21 patients with incident fractures were compared with 18 treated patients without new fractures. Demographic and clinical variables, BMD, laboratory tests, and bone material strength index (BMSi) assessed by impact microindentation at the tibial diaphysis were recorded for all participants. RESULTS: Clinical and laboratory results did not differ between patients taking BPs with incident fractures and those without new fractures. However, BMSi was significantly lower (mean+/-SD) in those who fractured (73.76+/-6.49) than in no-fracture patients (81.64+/-6.26; p=0.001). Lumbar spine (LS) BMD was also lower in fractured patients (p=0.03). Adjusted models including age, body mass index, years on BP treatment, and LS-BMD confirmed an increase in fracture risk per BMSi standard deviation decrease: adjusted OR 23.5 [95% CI 2.16 to 255.66], p=0.01. ROC analyses showed an area under the curve of 0.82 (95% CI 0.68 to 0.95) for BMSi, higher than that for BMD at any location, which ranged from 0.64 (95% CI 0.47 to 0.82) for femoral neck (FN) BMD to 0.71 (95% CI 0.55 to 0.87) for LS-BMD. CONCLUSIONS: Patients who fracture while receiving BPs treatment have worse BMSi scores than BP-treated patients without fractures. The potential for BMSi to provide an additional osteoporosis treatment target should be explored. PMID- 28655604 TI - Melatonin synthesis in the human ciliary body triggered by TRPV4 activation: Involvement of AANAT phosphorylation. AB - Melatonin is a substance synthesized in the pineal gland as well as in other organs. This substance is involved in many ocular functions, giving its synthesis in numerous eye structures. Melatonin is synthesized from serotonin through two enzymes, the first limiting step into the synthesis of melatonin being aralkylamine N-acetyltransferase (AANAT). In this current study, AANAT phosphorylation after the activation of TRPV4 was studied using human non pigmented epithelial ciliary body cells. Firstly, it was necessary to determine the adequate time and dose of the TRPV4 agonist GSK1016790A to reach the maximal phosphorylation of AANAT. An increase of 72% was observed after 5 min incubation with 10 nM GSK (**p < 0.05, n = 6) with a concomitant rise in N-acetyl serotonin and melatonin synthesis. The involvement of a TRPV4 channel in melatonin synthesis was verified by antagonist and siRNA studies as a previous step to studying intracellular signalling. Studies performed on the second messengers involved in GSK induced AANAT phosphorylation were carried out by inhibiting several pathways. In conclusion, the activation of calmodulin and calmodulin dependent protein kinase II was confirmed, as shown by the cascade seen in AANAT phosphorylation (***p < 0.001, n = 4). This mechanism was also established by measuring N-acetyl serotonin and melatonin levels. In conclusion, the activation of a TRPV4 present in human ciliary body epithelial cells produced an increase in AANAT phosphorylation and a further melatonin increase by a mechanism in which Ca calmodulin and the calmodulin-dependent protein kinase II are involved. PMID- 28655605 TI - Gadolinium-enhanced 7.0 T magnetic resonance imaging assessment of the aqueous inflow in rat eyes in vivo. AB - The goal of this study was to calculate the anterior chamber volume and assess aqueous inflow in rat eyes in vivo, under anesthetic condition. Gadolinium contrast agent (Gd-DTPA, 234.5 mg/ml) was administered to Sprague-Dawley rat eyes via anterior chamber injection or instillation of 234.5 or 117.25 mg/ml Gd-DTPA in 0.2% azone as eye drops, and changes of Gd signal visualized by 7.0 T magnetic resonance imaging (MRI). The safety of local application of Gd-DTPA and azone were performed after MRI scanning. The anterior chamber injection of Gd-DTPA (234.5 mg/ml) group was used for anterior chamber volume and aqueous inflow calculating. Serial changes in Gd-DTPA relative concentration in the anterior chamber was determined based on the initial Gd signal gray values and the initial relative concentration of Gd-DTPA after anterior chamber Gd-DTPA injection. The mean aqueous inflow in rat eyes in vivo was assessed based on changes in Gd-DTPA relative concentration and the anterior chamber volume. Eye drops of Gd-DTPA (234.5 mg/ml) in 0.2% azone readily allowed safe assessment of the aqueous inflow by 7.0 T MRI. Under anesthetic condition in vivo, the mean anterior chamber volume (ACV) in rats was 8493.6 +/- 657.4 MUm3, no differences were observed in the aqueous inflow measured by topical instillation of 234.5 mg/ml Gd-DTPA in 0.2% azone (0.182 +/- 0.011 MUl/min) between that measured by anterior chamber injection (0.165 +/- 0.041 MUl/min, P > 0.05), Timolol reduced aqueous inflow to 0.124 +/- 0.020 MUl/min (P < 0.05). Our results indicated that Gd-enhanced 7.0 T MRI allows evaluation of the Gd signal variation and anterior chamber volume in rats in vivo. The aqueous inflow calculation via non-invasive local application of 234.5 mg/ml Gd-DTPA can be assessed by the variability of relative concentration of Gd-DTPA in anterior chamber and ACV in vivo, under anesthetic condition. PMID- 28655606 TI - The non-linear development of the right hemispheric specialization for human face perception. AB - The developmental origins of human adults' right hemispheric specialization for face perception remain unclear. On the one hand, infant studies have shown a right hemispheric advantage for face perception. On the other hand, it has been proposed that the adult right hemispheric lateralization for face perception slowly emerges during childhood due to reading acquisition, which increases left lateralized posterior responses to competing written material (e.g., visual letters and words). Since methodological approaches used in infant and children typically differ when their face capabilities are explored, resolving this issue has been difficult. Here we tested 5-year-old preschoolers varying in their level of visual letter knowledge with the same fast periodic visual stimulation (FPVS) paradigm leading to strongly right lateralized electrophysiological occipito temporal face-selective responses in 4- to 6-month-old infants (de Heering and Rossion, 2015). Children's face-selective response was quantitatively larger and differed in scalp topography from infants', but did not differ across hemispheres. There was a small positive correlation between preschoolers' letter knowledge and a non-normalized index of right hemispheric specialization for faces. These observations show that previous discrepant results in the literature reflect a genuine nonlinear development of the neural processes underlying face perception and are not merely due to methodological differences across age groups. We discuss several factors that could contribute to the adult right hemispheric lateralization for faces, such as myelination of the corpus callosum and reading acquisition. Our findings point to the value of FPVS coupled with electroencephalography to assess specialized face perception processes throughout development with the same methodology. PMID- 28655607 TI - Overexpression of the 18 kDa translocator protein (TSPO) in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects. AB - The 18 kDa translocator protein (TSPO) is a five transmembrane domain protein that plays a crucial role in neurosteroid (e.g., allopregnanolone) synthesis by promoting the transport of cholesterol to the inner mitochondrial membrane. This protein is predominantly expressed in steroid-synthesizing tissues, including the central and peripheral nervous system, affecting stress-related disorders such as anxiety and depression. Recent studies have focused on the hippocampal dentate gyrus, which is very important for involvement of anxiety and depression. However, the exact role that TSPO plays in the pathophysiology of anxiety and depression and the involvement of the hippocampal dentate gyrus in regulating these behavioural effects remain elusive. This study used the lentiviral vectors mediating TPSO overexpression to assess the effects of TPSO overexpression in the hippocampal dentate gyrus on anxiolytic and antidepressant-like behavioural effects in mice. The expression of TSPO and the concentration of allopregnanolone in hippocampus tissues (3 mm in diameter around the injection site on both sides) were measured by Western blot and ELISA, respectively. The results indicated that microinjection of the LV-TSPO resulted in a significant increase in TSPO expression and allopregnanolone concentration in the hippocampus. Moreover, TSPO overexpression of the mouse hippocampal dentate gyrus generated significant anxiolytic and antidepressant-like behavioural effects in a series of behavioural models. These effects were completely blocked by the TSPO antagonist PK11195 (3 mg/kg, intraperitoneally) and the 5alpha-reductase inhibitor finasteride (5 mg/kg,intraperitoneally). Meanwhile, the increased allopregnanolone was also reversed by PK11195 and finasteride. In addition, neither PK11195 nor finasteride had an effect on the expression of TSPO. Overall, our results are the first to suggest that the overexpression of TSPO in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects that are partially mediated by downstream allopregnanolone biosynthesis. Our results suggest that TSPO would be a potential anxiolytic and antidepressant therapeutic target. PMID- 28655610 TI - Neuropeptide S (NPS) is a neuropeptide with cellular actions in arousal and anxiety-related nuclei: Functional implications for effects of NPS on wakefulness and mood. AB - Neuropeptide S (NPS) is a peptide recently recognized to be present in the CNS, and believed to play a role in vigilance and mood control, as behavioral studies have shown it promotes arousal and has an anxiolytic effect. Although NPS precursor is found in very few neurons, NPS positive fibers are present throughout the brain stem. Given the behavioral actions of this peptide and the wide innervation pattern, we examined the cellular effects of NPS within two brain stem nuclei known to play a critical role in anxiety and arousal: the dorsal raphe (DR) and laterodorsal tegmentum (LDT). In mouse brain slices, NPS increased cytoplasmic levels of calcium in DR and LDT cells. Calcium rises were independent of action potential generation, reduced by low extracellular levels of calcium, attenuated by IP3 - and ryanodine (RyR)-dependent intracellular calcium store depletion, and eliminated by the receptor (NPSR) selective antagonist, SHA 68. NPS also exerted an effect on the membrane of DR and LDT cells inducing inward and outward currents, which were driven by an increase in conductance, and eliminated by SHA 68. Membrane actions of NPS were found to be dependent on store-mediated calcium as depletion of IP3 and RyR stores eliminated NPS-induced currents. Finally, NPS also had actions on synaptic events, suggesting facilitation of glutamatergic and GABAergic presynaptic transmission. When taken together, actions of NPS influenced the excitability of DR and LDT neurons, which could play a role in the anxiolytic and arousal-promoting effects of this peptide. PMID- 28655611 TI - miR-137 attenuates Abeta-induced neurotoxicity through inactivation of NF-kappaB pathway by targeting TNFAIP1 in Neuro2a cells. AB - BACKGROUND: Accumulation of beta-amyloid (Abeta) and neuroinflammation are implicated in the pathogenesis and development of Alzheimer's disease (AD). Neuron-enriched miR-137 was aberrantly downregulated and may be associated with the pathogenesis of AD. However, the detailed function of miR-137 in AD pathogenesis and the molecular mechanism have not been elucidated. METHODS: The expressions of miR-137 and tumor necrosis factor alpha (TNFalpha)-induced protein 1 (TNFAIP1) at mRNA and protein levels in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to different concentrations of Abeta25-35 were examined by qRT-PCR and western blot. Luciferase reporter assay was used to confirm the potential target of miR-137. MTT assay, flow cytometry analysis, caspase-3 activity assay, Enzyme-linked immunosorbent assay (ELISA), and western blot were used to detect cell viability, apoptosis, caspase-3 activity, Nuclear factor-kappa B (NF-kappaB) activity and level, respectively. RESULTS: Abeta25-35 downregulated miR-137 and upregulated TNFAIP1 in primary mouse cortical neurons and N2a cells. In addition, miR-137 was found to directly target TNFAIP1 and suppress its mRNA and protein levels. Moreover, miR-137 restoration and TNFAIP1 knockdown facilitate Abeta25-35-induced cell toxicity, apoptosis, caspase-3 activity, and activated NF-kappaB in N2a cells, which was partially abolished by TNFAIP1 overexpression. CONCLUSION: miR-137 attenuated Abeta-induced neurotoxicity through inactivation of NF-kappaB pathway by targeting TNFAIP1 in N2a cells, shedding light on the molecular mechanism of miR-137 underlying Abeta induced neurotoxicity. PMID- 28655609 TI - Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action. AB - Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety. PMID- 28655608 TI - Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease. AB - Cytochrome P450 46A1 (CYP46A1 or cholesterol 24-hydroxylase) controls cholesterol elimination from the brain and plays a role in higher order brain functions. Genetically enhanced CYP46A1 expression in mouse models of Alzheimer's disease mitigates the manifestations of this disease. We enhanced CYP46A1 activity pharmacologically by treating 5XFAD mice, a model of rapid amyloidogenesis, with a low dose of the anti-HIV medication efavirenz. Efavirenz was administered from 1 to 9 months of age, and mice were evaluated at specific time points. At one month of age, cholesterol homeostasis was already disturbed in the brain of 5XFAD mice. Nevertheless, efavirenz activated CYP46A1 and mouse cerebral cholesterol turnover during the first four months of administration. This treatment time also reduced amyloid burden and microglia activation in the cortex and subiculum of 5XFAD mice as well as protein levels of amyloid precursor protein and the expression of several genes involved in inflammatory response. However, mouse short-term memory and long-term spatial memory were impaired, whereas learning in the context-dependent fear test was improved. Additional four months of drug administration (a total of eight months of treatment) improved long-term spatial memory in the treated as compared to the untreated mice, further decreased amyloid-beta content in 5XFAD brain, and also decreased the mortality rate among male mice. We propose a mechanistic model unifying the observed efavirenz effects. We suggest that CYP46A1 activation by efavirenz could be a new anti Alzheimer's disease treatment and a tool to study and identify normal and pathological brain processes affected by cholesterol maintenance. PMID- 28655612 TI - Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer. AB - Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression. PMID- 28655613 TI - INT131 increases dendritic arborization and protects against Abeta toxicity by inducing mitochondrial changes in hippocampal neurons. AB - In previous studies, we have demonstrated the beneficial effects of classic PPARgamma agonists on neuroprotection against Abeta oligomer neurotoxicity in a double transgenic mouse model of Alzheimer' disease (AD). INT-131, a novel, non thiazolidinedione compound that belongs to a new family of drugs, selective PPARgamma modulators (SPPARMs), has provided an emerging opportunity for the treatment of type 2 diabetes mellitus and metabolic syndrome. However, its role in the central nervous system has not been studied. The aim of this study was to evaluate the putative neuroprotective role of INT131 in hippocampal neurons. We found that INT131 increased dendritic branching, promoted neuronal survival against Abeta amyloid, increased expression of PGC1-1alpha and modulated neuronal mitochondrial dynamics. Our results suggest that INT131, a drug that has been shown to be safe and effective in metabolic disorders, may constitute a new therapeutic alternative for AD. PMID- 28655614 TI - RNAi-mediated disruption of neuropeptide genes, nlp-3 and nlp-12, cause multiple behavioral defects in Meloidogyne incognita. AB - Owing to the current deficiencies in chemical control options and unavailability of novel management strategies, root-knot nematode (M. incognita) infections remain widespread with significant socio-economic impacts. Helminth nervous systems are peptide-rich and appear to be putative drug targets that could be exploited by antihelmintic chemotherapy. Herein, to characterize the novel peptidergic neurotransmitters, in silico mining of M. incognita genomic and transciptomic datasets revealed the presence of 16 neuropeptide-like protein (nlp) genes with structural hallmarks of neuropeptide preproproteins; among which 13 nlps were PCR-amplified and sequenced. Two key nlp genes (Mi-nlp-3 and Mi-nlp 12) were localized to the basal bulb and tail region of nematode body via in situ hybridization assay. Mi-nlp-3 and Mi-nlp-12 were greatly expressed (in qRT-PCR assay) in the pre-parasitic juveniles and adult females, suggesting the association of these genes in host recognition, development and reproduction of M. incognita. In vitro knockdown of Mi-nlp-3 and Mi-nlp-12 via RNAi demonstrated the significant reduction in attraction and penetration of M. incognita in tomato root in Pluronic gel medium. A pronounced perturbation in development and reproduction of NLP-silenced worms was also documented in adzuki beans in CYG growth pouches. The deleterious phenotypes obtained due to NLP knockdown suggests that transgenic plants engineered to express RNA constructs targeting nlp genes may emerge as an environmentally viable option to manage nematode problems in crop plants. PMID- 28655615 TI - lncRNA-Map2k4 sequesters miR-199a to promote FGF1 expression and spinal cord neuron growth. AB - Spinal cord injury (SCI) is a common critical illness in clinical practice. SCI prevention, treatment and rehabilitation have become important topics in today's medical profession. Studies have shown that long noncoding RNAs (lncRNAs) also play an important role in the pathology of SCI. The biology software analysis identified miR-199a binding sites in the lncRNA-Map2k4 and FGF1 sequences, which were confirmed by the subsequent dual luciferase reporter assay. When lncRNA Map2k4 expression was down-regulated by siRNA, miR-199a expression in neurons was up-regulated and FGF1 expression was down-regulated. In turn, miR-199a up regulation inhibited lncRNA-Map2k4 and FGF1 expression. But when lncRNA-Map2k4-m (a lncRNA-Map2k4 overexpression vector with mutated miR-199a binding sites) was co-transfected into neuronal cells with miR-199a mimics, lncRNA-Map2k4-m over expression did not block the inhibition of FGF1 expression by miR-199a. Moreover, lncRNA-Map2k4 and FGF1 promoted the proliferation and inhibited the apoptosis of neuronal cells, whereas miR-199a down-regulated the aforementioned functions of lncRNA-Map2k4 and FGF1; however, lncRNA-Map2k4-m could not block the inhibitory action of miR-199a on proliferation. Thus, lncRNA-Map2k4 regulates neuronal proliferation and apoptosis through a miR-199a/FGF1 pathway. This finding provides more evidence for the role of lncRNAs in SCI. PMID- 28655616 TI - Functional identification of a Lippia dulcis bornyl diphosphate synthase that contains a duplicated, inhibitory arginine-rich motif. AB - Lippia dulcis (Aztec sweet herb) contains the potent natural sweetener hernandulcin, a sesquiterpene ketone found in the leaves and flowers. Utilizing the leaves for agricultural application is challenging due to the presence of the bitter-tasting and toxic monoterpene, camphor. To unlock the commercial potential of L. dulcis leaves, the first step of camphor biosynthesis by a bornyl diphosphate synthase needs to be elucidated. Two putative monoterpene synthases (LdTPS3 and LdTPS9) were isolated from L. dulcis leaf cDNA. To elucidate their catalytic functions, E. coli-produced recombinant enzymes with truncations of their chloroplast transit peptides were assayed with geranyl diphosphate (GPP). In vitro enzyme assays showed that LdTPS3 encodes bornyl diphosphate synthase (thus named LdBPPS) while LdTPS9 encodes linalool synthase. Interestingly, the N terminus of LdBPPS possesses two arginine-rich (RRX8W) motifs, and enzyme assays showed that the presence of both RRX8W motifs completely inhibits the catalytic activity of LdBPPS. Only after the removal of the putative chloroplast transit peptide and the first RRX8W, LdBPPS could react with GPP to produce bornyl diphosphate. LdBPPS is distantly related to the known bornyl diphosphate synthase from sage in a phylogenetic analysis, indicating a converged evolution of camphor biosynthesis in sage and L. dulcis. The discovery of LdBPPS opens up the possibility of engineering L. dulcis to remove the undesirable product, camphor. PMID- 28655617 TI - The effects of berberine on a murine model of multiple sclerosis and the SPHK1/S1P signaling pathway. AB - Berberine (BBR) has shown neuroprotective properties. The present study aims to investigate the effects of BBR on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), and SphK1/S1P signaling, which plays a key role in MS. EAE was induced in mice, followed by treatment with BBR at 50, 100, or 300 mg/kg/d. Neurophysiological function was evaluated daily; inflammation, cell infiltration, and the severity of demyelination were also examined. The SphK1, SphK2, and S1P levels in the animals and primary astrocyte culture were measured. We found that treatment with BBR reduced the loss of neurophysiological function and the degree of demyelination. Moreover, BBR was associated with a decrease in SphK1 and S1P levels both in the animals and in culture. These results indicated that BBR suppresses demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway. The use of BBR as a treatment of MS warrant further exploration. PMID- 28655618 TI - Applications of Brewster angle microscopy from biological materials to biological systems. AB - Brewster angle microscopy (BAM) is a powerful technique that allows for real-time visualization of Langmuir monolayers. The lateral organization of these films can be investigated, including phase separation and the formation of domains, which may be of different sizes and shapes depending on the properties of the monolayer. Different molecules or small changes within a molecule such as the molecule's length or presence of a double bond can alter the monolayer's lateral organization that is usually undetected using surface pressure-area isotherms. The effect of such changes can be clearly observed using BAM in real-time, under full hydration, which is an experimental advantage in many cases. While previous BAM reviews focused more on selected compounds or compared the impact of structural variations on the lateral domain formation, this review provided a broader overview of BAM application using biological materials and systems including the visualization of amphiphilic molecules, proteins, drugs, extracts, DNA, and nanoparticles at the air-water interface. PMID- 28655619 TI - An update on minding the gap in cancer. AB - This article is a report of the "International Colloquium on Gap junctions: 50Years of Impact on Cancer" that was held 8-9 September 2016, at the Amphitheater "Pole Biologie Sante" of the University of Poitiers (Poitiers, France). The colloquium was organized by M Mesnil (Universite de Poitiers, Poitiers, France) and C Naus (University of British Columbia, Vancouver, Canada) to celebrate the 50th anniversary of the seminal work published in 1966 by Loewenstein and Kanno [Intercellular communication and the control of tissue growth: lack of communication between cancer cells, Nature, 116 (1966) 1248-1249] which initiated studies on the involvement of gap junctions in carcinogenesis. During the colloquium, 15 participants presented reviews or research updates in the field which are summarized below. PMID- 28655620 TI - 'My lips are sealed' - The impact of package resealability on the consumption of tempting foods. AB - Resealable packages are nowadays omnipresent on store shelves. While the main advantage of the resealability feature is its ability to reclose the package in order to extend the shelf life of the food product inside, the present research's aim is to assess whether this advantage also has implications for palatable, energy-dense food consumption. Two studies provide intentional as well as behavioral evidence for the claim that consumers are better able to self-regulate their consumption and thus eat less in one occasion when a palatable, energy dense food product is offered in a resealable (vs. unresealable) package. A third study investigates the effect of package resealability across multiple consumption occasions and reveals that the resealability feature limits the volume consumed on each occasion (conditional on consumption incidence) while it does not accelerate consumption frequency, resulting in a lower total consumed volume of palatable, energy-dense snacks over a six-day period. This research offers actionable insights for consumer welfare and public health care and aids manufacturers in delineating optimal food packaging strategies. PMID- 28655621 TI - Incidence and outcome of in-hospital cardiac arrest in Italy: a multicentre observational study in the Piedmont Region. AB - AIMS: to report the incidence, characteristics, and outcome of in-hospital cardiac arrest (IHCA) in a large Italian region. SETTING: all hospitals participating in the IHCA Registry Initiative of Piedmont. METHODS: observational cohort study in adult (>18year old) inpatients resuscitated from IHCA during three consecutive years (2012-2014). The main outcome measures were IHCA incidence and survival to hospital discharge. RESULTS: A total of1539 arrests in adult inpatients were recorded in the study period, yielding an overall incidence of 1.51 arrests/1000 admissions. The incidence was highest at day 1 after hospital admission and in the morning hours, with a peak at 9.00 a.m. Median age was 77 (interquartile range 68-83) years. The presenting rhythm was ventricular fibrillation/pulseless ventricular tachycardia in 291/1539 (18.9%) cases. A total of 549/1539 (35.7%) patients achieved recovery of spontaneous circulation (ROSC) and 228/1539(14.8%) survived hospital discharge, with 207 (90.8%) of the latter having good neurological outcome (Cerebral Performance Categories [CPC] 1 or 2).After adjustment for major confounders, a pre-arrest CPC=1, a cardiac cause of arrest, a shockable presenting rhythm, and a shorter duration of resuscitation were independently associated with a higher likelihood of survival to discharge. CONCLUSIONS: in this Italian registry the incidence of IHCA and its circadian distribution were comparable to those in the NCAA registry in the UK. Patients were older and had a lower ROSC rate than these observed in other large IHCA registries, but post-ROSC survival rate and factors affecting survival to discharge were similar. PMID- 28655623 TI - Dry drowning: A distinction without a difference. PMID- 28655622 TI - Increased cardiac arrest survival and bystander intervention in enclosed pedestrian walkway systems. AB - BACKGROUND: Cities worldwide have underground or above-ground enclosed walkway systems for pedestrian travel, representing unique environments for studying out of-hospital cardiac arrests (OHCAs). The characteristics and outcomes of OHCAs that occur in such systems are unknown. OBJECTIVE: To determine whether OHCAs occurring in enclosed pedestrian walkway systems have differing demographics, prehospital intervention, and survival outcomes compared to the encompassing city, by examining the PATH walkway system in Toronto. METHODS: We identified all atraumatic, public-location OHCAs in Toronto from April 2006 to March 2016. Exclusion criteria were obvious death, existing DNR, and EMS-witnessed OHCAs. OHCAs were classified into mutually exclusive location groups: Toronto, Downtown, and PATH-accessible. PATH-accessible OHCAs were those that occurred within the PATH system between the first basement and third floor. We analyzed demographic, prehospital intervention, and survival data using t-tests and chi-squared tests. RESULTS: We identified 2172 OHCAs: 1752 Toronto, 371 Downtown, and 49 PATH accessible. Compared to Toronto, a significantly higher proportion of PATH accessible OHCAs was bystander-witnessed (62.6% vs 83.7%, p=0.003), had bystander CPR (56.6% vs 73.5%, p=0.019), bystander AED use (11.0% vs 42.6%, p<0.001), shockable initial rhythm (45.5% vs 72.9%, p<0.001), and overall survival (18.5% vs 33.3%, p=0.009). Similar significant differences were observed when compared to Downtown. CONCLUSIONS: This study suggests that OHCAs in enclosed pedestrian walkway systems are uniquely different from other public settings. Bystander resuscitation efforts are significantly more frequent and survival rates are significantly higher. Urban planners in similar infrastructure systems worldwide should consider these findings when determining AED placement and public engagement strategies. PMID- 28655624 TI - Validity of the IQCODE-CA: An informant questionnaire on cognitive decline modified for a cardiac arrest population. AB - AIM: To examine the psychometric properties of a modified version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), for a cardiac arrest population (IQCODE-CA). METHODS: The IQCODE-CA, a 26-item observer reported questionnaire, was completed by informants, defined as relatives or close friends, of 268 out-of-hospital cardiac arrest (OHCA) survivors who participated in the Target Temperature Management trial in a scheduled follow-up 180+/-14days after OHCA. Survivors completed the Mini Mental State Examination (MMSE), the Rivermead Behavioural Memory Test (RBMT) and the Hospital Anxiety and Depression Scale (HADS). An exploratory factor analysis was performed. Associations between IQCODE-CA results and demographic variables along with other instruments were calculated. Area under the curve (AUC) ratios were evaluated to examine discrimination. RESULTS: The IQCODE-CA measured one factor, global cognitive decline, with high internal consistency (ordinal alpha=0.95). Age, gender or education did not influence the IQCODE-CA score. Associations with performance-based measures of global cognitive function as well as anxiety and depression ranged from small to moderate (rs=-0.29 to 0.38). AUC ratios ranged from fair to good (0.72-0.81). According to the MMSE and RBMT, the optimal cut off score to identify cognitive decline on the IQCODE-CA was 3.04. Using this value, 53% of the survivors were under the cut-off. CONCLUSIONS: The IQCODE-CA identified a large amount of survivors with possible cognitive problems, making it useful when screening for cognitive decline post-CA. Due to lower AUC ratios than desired, additional performance-based measures should be used to improve the overall screening methodology. PMID- 28655625 TI - Impact of city police layperson education and equipment with automatic external defibrillators on patient outcome after out of hospital cardiac arrest. AB - INTRODUCTION: Out of hospital cardiac arrest (OHCA) occurs frequently and the outcome is often dismal. Early defibrillation saves lives and brain function in OHCA. The Zurich city police (STAPO) forces were instructed and equipped to provide basic life support (BLS) and to use an AED in 2009. METHODS: Retrospective observational study comparing period 1 (P1) 2004-2009 before equipping and training of the STAPO and period 2 (P2) 2010-2015 after the implementation. Patients suffering from OHCA of cardiac or presumed cardiac origin in the city of Zurich undergoing CPR by EMS in P1 (n=709) and P2 (n=684) were included. Intervention periods and outcome were compared between the periods. Outcome variables were adjusted for patient age and gender, witnessed status, and defibrillation by the EMS, STAPO, layperson or no defibrillation. RESULTS: In P2, CPR was started by the STAPO in a median of 8 (IQR 6-9) minutes after the arrest and thus significantly earlier (median 3min) than by the EMS (p<0.001). STAPO performed the first defibrillation in a median of 9 (IQR 8-10) minutes and thus significantly earlier (median 6min) than the EMS (p<0.001). Outcome improved significantly in P2: proportion of patients with return of spontaneous circulation (ROSC, P2 35.8%, P1 24.0%, OR 1.8, 95% CI 1.4-2.2, p<0.001), hospital admission (P2 32.2%, P1 21.4%, OR 1.7, 95% CI 1.4-2.2, p<0.001) and survival to hospital discharge (P2 13.6%, P1 6.9%, OR 2.1 95% CI 1.5 3.0, p<0.001). If the patient was firstly defibrillated by the STAPO, ROSC (STAPO 74.4%, adj. OR 2.6, 95% CI 1.3-5.4, p=0.010) and hospital admission (STAPO 72.1%, adj. OR 2.8, 95% CI 1.4-5.6, p=0.005) was higher compared to patients firstly defibrillated by the EMS. Survival to hospital discharge (STAPO 30.2%, adj. OR 1.4, 95% CI 0.7-2.9, p=0.38) was unchanged. CONCLUSION: Dispatching BLS trained and AED equipped police forces results in earlier and more successful resuscitation of OHCA victims, leading to higher proportions of patients with ROSC, hospital admission and survival to hospital discharge. PMID- 28655626 TI - Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats. AB - Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague Dawley rats were subcutaneously injected twice per day (6h apart) with 5mg/kg CIT, 5mg/kg FLX, 15mg/kg BUP, or saline (SAL) from embryonic day (E) 6-21, and directly to the pups from postnatal day (P) 1-20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted. PMID- 28655627 TI - CpG methylation and the methyl CpG binding protein 2 (MeCP2) are required for restraining corticotropin releasing hormone (CRH) gene expression. AB - The hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in mounting a stress response and maintaining homeostasis. A dysregulated HPA axis and elevated levels of CRH are associated with a number of disorders. Although extensive research has been devoted to understanding molecular events associated with stimulated CRH gene, less is known about the mechanisms that restrain CRH expression. Using a cell culture system, we report here two molecular aspects of CRH gene regulation that are required for maintenance of basal level of CRH gene expression. These are a specific CpG methylation at a single CpG, and adequate levels of the methyl CpG binding protein 2 (MeCP2). The single site methylation allows the recruitment of MeCP2 to the CRH gene promoter region, and MeCP2 knockdown leads to increased expression of CRH gene. Taken together, the results indicate that site-specific methylation and MeCP2 are required for maintenance of basal levels of CRH gene expression. PMID- 28655628 TI - Tunnel positioning assessment after anterior cruciate ligament reconstruction at 12months: Comparison between 3D CT and 3D MRI. A pilot study. AB - BACKGROUND: Tunnel positioning assessment is a major issue after anterior cruciate ligament (ACL) reconstruction surgery. Historically, it used plain X-ray and, more recently, CT with 3D reconstruction. MRI is a reliable method of assessing ACL graft integrity and postoperative complications. To our knowledge, there have been no studies of efficacy in tunnel positioning assessment. The aim of this study was to assess the efficacy of 3D MRI in assessing femoral and tibial tunnel positioning after ACL reconstruction. The hypothesis was that 3D MRI sequences with reconstruction are as accurate as 3D CT for tunnel positioning assessment in ACL reconstruction. METHODS: Twenty-two patients who underwent an arthroscopic ACL reconstruction using hamstring graft were included in a prospective study. All patients were examined on 3D CT and 3D MRI at 12months post-surgery. Tunnel positioning was assessed on both imaging systems by a musculoskeletal radiologist and an orthopedic surgeon specialized in knee arthroscopy, both blind to all clinical data. RESULTS: No statistically significant difference was found between 3D CT and 3D MRI on coronal and sagittal reconstructions. For coronal assessment of tibial tunnel orifice, sagittal assessment of tibial tunnel orifice and sagittal assessment of femoral tunnel orifice, P-values ranged from 0.37 to 0.99, 0.051 to 0.64 and 0.19 to 0.59, respectively. For tibial and femoral tunnel angulation, P-values were respectively 0.52 and 0.29. CONCLUSION: 3D MRI is a reliable method to assess femoral and tibia tunnel positioning in ACL reconstruction, compared to 3D CT as gold standard. Indeed, in our opinion 3D MRI could in the future replace CT for ACL reconstruction assessment, concerning not only the meniscus and ligaments but also tunnel position. LEVEL OF EVIDENCE: Level 3; comparative prospective study. PMID- 28655629 TI - Intra- and inter-observer agreement in MRI assessment of rotator cuff healing using the Sugaya classification 10years after surgery. AB - BACKGROUND: The long-term outcomes of rotator cuff repair are unclear. Recurrent tears are common, although their reported frequency varies depending on the type and interpretation challenges of the imaging method used. The primary objective of this study was to assess the intra- and inter-observer reproducibility of the MRI assessment of rotator cuff repair using the Sugaya classification 10years after surgery. The secondary objective was to determine whether poor reproducibility, if found, could be improved by using a simplified yet clinically relevant classification. HYPOTHESIS: Our hypothesis was that reproducibility was limited but could be improved by simplifying the classification. MATERIAL AND METHOD: In a retrospective study, we assessed intra- and inter-observer agreement in interpreting 49 magnetic resonance imaging (MRI) scans performed 10years after rotator cuff repair. These 49 scans were taken at random among 609 cases that underwent re-evaluation, with imaging, for the 2015 SoFCOT symposium on 10-year and 20-year clinical and anatomical outcomes of rotator cuff repair for full thickness tears. Each of three observers read each of the 49 scans on two separate occasions. At each reading, they assessed the supra-spinatus tendon according to the Sugaya classification in five types. RESULTS: Intra-observer agreement for the Sugaya type was substantial (kappa=0.64) but inter-observer agreement was only fair (kappa=0.39). Agreement improved when the five Sugaya types were collapsed into two categories (1-2-3 and 4-5) (intra-observer kappa=0.74 and inter-observer kappa=0.68). CONCLUSION: Using the Sugaya classification to assess post-operative rotator cuff healing was associated with substantial intra-observer and fair inter-observer agreement. A simpler classification into two categories improved agreement while remaining clinically relevant. LEVEL OF EVIDENCE: II, prospective randomised low-power study. PMID- 28655630 TI - A novel anterior approach for the fixation of ulnar coronoid process fractures. AB - BACKGROUND: There is no universally accepted approach to the elbow for the fixation of coronoid process fractures. This study aims to introduce a novel anterior surgical approach for the fixation of the ulnar coronoid fracture, with minimal surgical dissection damage and excellent visualization for reduction and internal fixation. HYPOTHESIS: The anterior approach can facilitate satisfactory outcomes for coronoid process fractures. MATERIAL AND METHODS: From February 2010 to July 2014, 12 patients (8 males and 4 females; range 14-62years; mean age 31years) with a closed fracture of the coronoid process of the ulna were included in this study. According to Adams classification, we included 5 type II, 3 type III, 3 type IV AM, and 1 type IV AL. The fractures were treated operatively via an anterior approach between nerves and blood vessels. The anatomical reduction and fixation with cannulated screws or a mini plate was easily performed. One elbow showed significant joint instability, necessitating, another incision to repair the lateral collateral ligament, and a subsequent operation with a hinged external fixator was required. The remaining patients received a splint for 2 weeks followed by functional exercises. RESULTS: Mean follow-up was 21 months (13 36). Fracture union was achieved in each patient. The arc of elbow flexion and extension were (135+/-15) degrees , and forearm pronation/supination were restored to (165+/-15) degrees . When compared with the normal side, there was no significant difference in the functional outcome (P>0.05). According to Morrey' scale, the functional recovery of the injured arms was assessed as excellent in eleven patients and good in one. Mild heterotopic ossification was found in one case, which had not impaired the elbow function. No other complications were noted. CONCLUSIONS: The anterior approach has the benefits of simplicity, safety, minimal invasion, excellent exposure, and satisfactory prognosis for coronoid process fractures. LEVEL OF EVIDENCE: Prospective study, Level IV. PMID- 28655631 TI - Varieties of semantic cognition revealed through simultaneous decomposition of intrinsic brain connectivity and behaviour. AB - Contemporary theories assume that semantic cognition emerges from a neural architecture in which different component processes are combined to produce aspects of conceptual thought and behaviour. In addition to the state-level, momentary variation in brain connectivity, individuals may also differ in their propensity to generate particular configurations of such components, and these trait-level differences may relate to individual differences in semantic cognition. We tested this view by exploring how variation in intrinsic brain functional connectivity between semantic nodes in fMRI was related to performance on a battery of semantic tasks in 154 healthy participants. Through simultaneous decomposition of brain functional connectivity and semantic task performance, we identified distinct components of semantic cognition at rest. In a subsequent validation step, these data-driven components demonstrated explanatory power for neural responses in an fMRI-based semantic localiser task and variation in self generated thoughts during the resting-state scan. Our findings showed that good performance on harder semantic tasks was associated with relative segregation at rest between frontal brain regions implicated in controlled semantic retrieval and the default mode network. Poor performance on easier tasks was linked to greater coupling between the same frontal regions and the anterior temporal lobe; a pattern associated with deliberate, verbal thematic thoughts at rest. We also identified components that related to qualities of semantic cognition: relatively good performance on pictorial semantic tasks was associated with greater separation of angular gyrus from frontal control sites and greater integration with posterior cingulate and anterior temporal cortex. In contrast, good speech production was linked to the separation of angular gyrus, posterior cingulate and temporal lobe regions. Together these data show that quantitative and qualitative variation in semantic cognition across individuals emerges from variations in the interaction of nodes within distinct functional brain networks. PMID- 28655632 TI - Normative data of dopaminergic neurotransmission functions in substantia nigra measured with MRI and PET: Neuromelanin, dopamine synthesis, dopamine transporters, and dopamine D2 receptors. AB - The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D2 receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[beta 11C]DOPA, [18F]FE-PE2I and [11C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D2 receptor binding measured by PET in the substantia nigra. Although neuromelanin is synthesized from DOPA and dopamine in dopaminergic neurons, neuromelanin accumulation did not correlate with dopamine synthesis capacity in young healthy subjects. The role of dopamine transporters in the substantia nigra is considered to be the transport of dopamine into neurons, and therefore dopamine transporter binding might be related to neuromelanin accumulation; however, no significant correlation was observed between them. A positive correlation between dopamine D2 receptor binding and neuromelanin accumulation was observed, indicating a feedback mechanism by dopaminergic autoreceptors. Discrepancies in regional distribution between neuromelanin accumulation and dopamine synthesis capacity, dopamine transporter binding or dopamine D2 receptor binding were observed in the substantia nigra. PMID- 28655633 TI - Cross-validation failure: Small sample sizes lead to large error bars. AB - Predictive models ground many state-of-the-art developments in statistical brain image analysis: decoding, MVPA, searchlight, or extraction of biomarkers. The principled approach to establish their validity and usefulness is cross validation, testing prediction on unseen data. Here, I would like to raise awareness on error bars of cross-validation, which are often underestimated. Simple experiments show that sample sizes of many neuroimaging studies inherently lead to large error bars, eg+/-10% for 100 samples. The standard error across folds strongly underestimates them. These large error bars compromise the reliability of conclusions drawn with predictive models, such as biomarkers or methods developments where, unlike with cognitive neuroimaging MVPA approaches, more samples cannot be acquired by repeating the experiment across many subjects. Solutions to increase sample size must be investigated, tackling possible increases in heterogeneity of the data. PMID- 28655634 TI - COPASI and its applications in biotechnology. AB - COPASI is software used for the creation, modification, simulation and computational analysis of kinetic models in various fields. It is open-source, available for all major platforms and provides a user-friendly graphical user interface, but is also controllable via the command line and scripting languages. These are likely reasons for its wide acceptance. We begin this review with a short introduction describing the general approaches and techniques used in computational modeling in the biosciences. Next we introduce the COPASI package, and its capabilities, before looking at typical applications of COPASI in biotechnology. PMID- 28655635 TI - Mono-(2-ethylhexyl) phthalate induced ROS-dependent autophagic cell death in human vascular endothelial cells. AB - Mono-(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di-(2-ethylhexyl) phthalate (DEHP). MEHP has toxic effects on cardiovascular system, but the possible molecular mechanisms are not completely elucidated. In our study, 3 methyladenine (3-MA), an autophagosome formation inhibitor, protected the EA.hy926 cells against MEHP cytotoxicity, and rapamycin, an autophagosome formation stimulator, further decreased the cell viability in the MEHP-treated EA.hy926 cells. Thus, autophagy may play an important role in MEHP-induced toxicity. MEHP increased the autophagosome number in EA.hy926 cells detected under transmission electron microscope. Collapses of DeltaPsim and reactive oxygen species (ROS) level were increased in a dose-dependent manner under treatment with 0-200MUM MEHP for 24h. N-acetyl-l-cysteine (NAC), a ROS inhibitor, protected against MEHP-induced cytotoxicity and decreased the protein expression of LC3-II. These findings suggested that MEHP-induced autophagic cell death was ROS-dependent in EA.hy926 cells. Knockdown of Akt1 with Akt1 siRNA aggravated MEHP-induced cell death, and insulin, an Akt1 activator, alleviated MEHP-induced cell death. These results were consistent with the expression of LC3-II using western blot. The phospho-Akt1(Ser473) (p-Akt1) level was enhanced after pretreatment with NAC. In conclusion, it is possible that ROS elicited autophagy through Akt1 pathway in the MEHP-treated EA.hy926 cells. PMID- 28655636 TI - Diesel exhaust particulate associated chemicals attenuate expression of CXCL10 in human primary bronchial epithelial cells. AB - Air pollution affects a large proportion of the population particularly in urban areas, with diesel particulates recognised as particular causes for concern in respiratory conditions such as asthma. In this study we examined the response of human primary airway epithelial cells to diesel particulate chemical extracts (DE) and characterised gene expression alterations using RNA-SEQ. Using the antagonist CH223191, DE induced CYP1A1 and attenuation of CXCL10 among other genes were observed to be aryl hydrocarbon receptor dependent. Basal and toll like receptor dependent protein levels for CXCL10 were markedly reduced. Investigation of similar regulation in plasmacytoid dendritic GEN2.2 cells did not show DE dependent regulation of CXCL10. Instillation of DE into mice to recapitulate airway epithelial exposure to chemical extracts in an in vivo setting failed to demonstrate a reduction in CXCL10. There was however an increase in the Th2 type epithelial cell derived inflammatory mediators TSLP and SERPINB2. We also observed an increased macrophages and a decrease in the proportion of lymphocytes in bronchoalveolar lavage fluid. CXCL10 can play a role in allergic airway disease through recruitment of Th1 type CD4+ T-cells, which can act to counterbalance Th2 type allergic responses. Modulation of such chemokines within the airway epithelium may represent a mechanism through which pollutant material can modify respiratory conditions such as allergic asthma. PMID- 28655637 TI - Clinical and pathological factors related to brain relapse-free survival in breast cancer patients. PMID- 28655638 TI - High tumor budding count is associated with adverse clinicopathologic features and poor prognosis in breast carcinoma. AB - This study is to address the significance of tumor budding (TB) in breast carcinoma. Totally 244 estrogen receptor-positive (ER+)/HER2-negative (HER2-) and 131 triple-negative breast carcinoma (TNBC) diagnosed from 2004 to 2014 were analyzed. TB (cluster of up to 5 tumor cells at the invasive front) was evaluated using five 200* high-power fields (HPF) at the hotspot. The highest TB (H-TB) in 1 HPF and average TB (A-TB) in 5 HPFs were correlated with lymph node and distant metastasis, lymphovascular invasion (LVI), local recurrence, overall survival (OS), and disease-free survival (DFS). In ER+/HER2- cancer, H-TB and A-TB were significantly associated with distant metastasis. In TNBC, H-TB was associated with distant metastasis by univariate but not multivariate analysis; H-TB and A TB were associated with LVI and worse OS (all P < .05). TB is associated with poor prognosis in ER+/HER2- and TNBC cancer. Evaluation of H-TB may be sufficient in breast carcinoma. PMID- 28655639 TI - Inflammatory cell infiltrates in advanced metastatic uveal melanoma. AB - Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few and to date have demonstrated only marginal success. High densities of tumor-associated macrophages (TAMs) and infiltrating T lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole-tissue sections of liver mUM (n=35) were examined by immunohistochemistry. For TAMs, monoclonal antibodies against CD68 and CD163 were used. Macrophage density and morphology were scored using previous established systems. Density and spatial distribution of TILs were highlighted using antibodies against CD3 (pan-lymphocyte marker), CD4 (T-helper cells), and CD8 (T cytotoxic cells). CD68+ and CD163+ TAMs were seen within the tumor in all 35 specimens; their density was "moderate" in 50% of cases and "few" in 43%, and the majority showed an "indeterminate" phenotype. CD3+ TILs were noted both within mUMs and surrounding the tumor. Of these, CD8+ TILs were "few" in number within mUM but were predominantly seen peritumorally at the tumor/normal liver interface, whereas CD4+ TILs showed a high perivascular density within mUM. CD68+ and CD163+ TAMs of "indeterminate" morphology were observed in mUM, suggesting a tendency toward the protumorigenic M2 phenotype. CD4+ TILs were seen within the mUM, whereas CD8+ TILs tended to be peritumoral. The biological and functional roles of inflammatory cells in mUM require further investigation to determine if they represent potential targets for future therapies in mUM. PMID- 28655640 TI - Clinical and pathological factors related to brain relapse-free survival in breast cancer patients-reply. PMID- 28655641 TI - The emerging role of circular RNAs in transcriptome regulation. AB - Circular RNAs (circRNAs) are a recently discovered form of RNA that has been found to regulate mammalian transcription. CircRNAs are covalently closed, single stranded transcripts produced from precursor mRNA. While initially circRNAs were considered to be splicing artefacts, next-generation RNA sequencing of non polyadenylated transcriptomes has recently shown that the expression of circRNAs is widespread and over 20% of expressed genes in examined cells and tissues can produce these transcripts. Until now thousands of circRNAs have been discovered in organisms ranging from Drosophila melanogaster to Homo sapiens. Functional studies indicate that these transcripts regulate expression of protein-coding linear transcripts and thus comprise an important component of gene expression regulation. Here we provide a comprehensive overview on the biology of circRNAs, including the expression patterns and function. Moreover, we discuss current methodologies for the discovery and validation of circular transcripts. Finally, perspectives on the utilization of circRNA as molecular markers of complex diseases are presented. PMID- 28655642 TI - The use and abuse of Cre/Lox recombination to identify adult cardiomyocyte renewal rate and origin. AB - The adult mammalian heart, including the human, is unable to regenerate segmental losses after myocardial infarction. This evidence has been widely and repeatedly used up-to-today to suggest that the myocardium, contrary to most adult tissues, lacks an endogenous stem cell population or more specifically a bona-fide cardiomyocyte-generating progenitor cell of biological significance. In the last 15 years, however, the field has slowly evolved from the dogma that no new cardiomyocytes were produced from shortly after birth to the present consensus that new cardiomyocytes are formed throughout lifespan. This endogenous regenerative potential increases after various forms of injury. Nevertheless, the degree/significance and more importantly the origin of adult new cardiomyocytes remains strongly disputed. Evidence from independent laboratories has shown that the adult myocardium harbours bona-fide tissue-specific cardiac stem cells (CSCs). Their transplantation and in situ activation have demonstrated the CSCs regenerative potential and have been used to develop regeneration protocols which in pre-clinical tests have shown to be effective in the prevention and treatment of heart failure. Recent reports purportedly tracking the c-kit+CSC's fate using Cre/lox recombination in the mouse have challenged the existence and regenerative potential of the CSCs and have raised scepticism about their role in myocardial homeostasis and regeneration. The validity of these reports, however, is controversial because they failed to show that the experimental approach used is capable to both identify and tract the fate of the CSCs. Despite these serious shortcomings, in contraposition to the CSCs, these publications have proposed the proliferation of existing adult fully-matured cardiomyocytes as the relevant mechanism to explain cardiomyocyte renewal in the adult. This review critically ponders the available evidence showing that the adult mammalian heart possesses a definable myocyte-generating progenitor cell of biological significance. This endogenous regenerative potential is expected to provide the bases for novel approaches of myocardial repair in the near future. PMID- 28655643 TI - Activation of sirtuin 1 by catalpol-induced down-regulation of microRNA-132 attenuates endoplasmic reticulum stress in colitis. AB - Defective expression of NAD-dependent protein deacetylase sirtuin 1 (SIRT1) triggers endoplasmic reticulum (ER) stress and epithelial cell apoptosis in inflammatory bowel disease. MicroRNA-132 (miR-132) has been shown to regulate inflammatory processes through down-regulating SIRT1. Catalpol is a potential antioxidant and anti-apoptotic agent in inflammatory disease. This study aimed to investigate the signaling mechanisms underlying catalpol-induced SIRT1 activation and inhibition of ER stress in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. miR-132 expression was measured by quantitative real-time polymerase chain reaction and in situ hybridization, and the regulation of SIRT1 by miR-132 was examined by dual luciferase reporter assay. Protein expression related to ER stress and apoptosis was measured by western blotting. The ER stress marker proteins ATF6, CHOP, and caspase12, and acetylation of heat-shock factor-1 were increased in colitis and these increases were significantly reversed by catalpol, while the colitis-induced reduction in GRP78 was also reversed by catalpol. The inhibition of ER stress by catalpol was significantly inhibited by small interfering RNA targeting SIRT1 or miR-132. Moreover, other colitis symptoms including infiltration of inflammatory cells, cytokine profiles, oxidative responses, and epithelial cell apoptosis were also significantly decreased by catalpol. Mechanistically, the defective expression of SIRT1 in colitis was significantly counteracted by catalpol, while miR-132, which is a negative targeting regulator of SIRT1, was confirmed as the potential target of catalpol. These results support a link between ER stress and the miR-132/SIRT1/heat-shock factor-1 signaling pathway, and the modulation of this pathway by catalpol in colitis. PMID- 28655644 TI - Pregnenolone does not interfere with the effects of cannabinoids on synaptic transmission in the cerebellum and the nucleus accumbens. AB - The steroid hormone pregnenolone attenuates several in vivo behavioural and somatic effects of the phytocannabinoid Delta9-tetrahydrocannabinol, and it was suggested that pregnenolone can protect the brain from cannabis intoxication. The primary neuronal cannabinoid action behind most of the behavioural and somatic effects of cannabinoids is presynaptic inhibition of synaptic transmission. Therefore, the hypothesis of the present study was that pregnenolone attenuates the inhibition of synaptic transmission elicited by cannabinoids. Brain slices containing the cerebellum or the nucleus accumbens were prepared from brains of mice and rats. Spontaneous and electrically evoked GABAergic inhibitory postsynaptic currents (sIPSCs and eIPSCs) and evoked glutamatergic excitatory postsynaptic currents (eEPSCs) were recorded in superfused brain slices with patch-clamp electrophysiological techniques. Pregnenolone (10-7M) did not affect the spontaneous GABAergic synaptic input (sIPSCs) to Purkinje cells in mouse cerebellar slices. The synthetic mixed CB1/CB2 receptor agonists JWH-210 (5*10 6M) and JWH-018 (5*10-6M) inhibited the spontaneous GABAergic synaptic input (sIPSCs) to Purkinje cells. This inhibition was not affected by pregnenolone (10 7M). Tetrahydrodeoxycorticosterone (THDOC; 10-7M), an in vivo metabolite of pregnenolone, also did not affect the inhibition of the GABAergic synaptic transmission by JWH-018. The depolarization of the Purkinje cells induced suppression of the GABAergic input to Purkinje cells; pregnenolone (10-7M) did not affect this endocannabinoid-mediated form of synaptic suppression. In rat nucleus accumbens slices, glutamatergic and GABAergic synaptic input to medium spiny neurons was activated by electrical stimulation of axons. Delta9 Tetrahydrocannabinol (2*10-5M), which is a partial agonist of both CB1 and CB2 receptors, suppressed the glutamatergic and GABAergic synaptic transmission in the rat nucleus accumbens. These suppressive effects of Delta9 tetrahydrocannabinol were not changed by pregnenolone (10-7M). The suppression of the GABAergic synaptic transmission by Delta9-tetrahydrocannabinol in the rat nucleus accumbens was also not affected by THDOC (10-7M). The results indicate that pregnenolone, a neurosteroid, does not affect GABAergic synaptic transmission. The inhibition of GABAergic and glutamatergic synaptic transmission elicited by synthetic, endogenous and phyto-cannabinoids is also not changed by pregnenolone. Therefore, it is unlikely that interference with cannabinoid induced inhibition of synaptic transmission is the mechanism by which pregnenolone attenuates behavioural and somatic effects of Delta9 tetrahydrocannabinol in vivo. PMID- 28655645 TI - Optic flow-based collision-free strategies: From insects to robots. AB - Flying insects are able to fly smartly in an unpredictable environment. It has been found that flying insects have smart neurons inside their tiny brains that are sensitive to visual motion also called optic flow. Consequently, flying insects rely mainly on visual motion during their flight maneuvers such as: takeoff or landing, terrain following, tunnel crossing, lateral and frontal obstacle avoidance, and adjusting flight speed in a cluttered environment. Optic flow can be defined as the vector field of the apparent motion of objects, surfaces, and edges in a visual scene generated by the relative motion between an observer (an eye or a camera) and the scene. Translational optic flow is particularly interesting for short-range navigation because it depends on the ratio between (i) the relative linear speed of the visual scene with respect to the observer and (ii) the distance of the observer from obstacles in the surrounding environment without any direct measurement of either speed or distance. In flying insects, roll stabilization reflex and yaw saccades attenuate any rotation at the eye level in roll and yaw respectively (i.e. to cancel any rotational optic flow) in order to ensure pure translational optic flow between two successive saccades. Our survey focuses on feedback-loops which use the translational optic flow that insects employ for collision-free navigation. Optic flow is likely, over the next decade to be one of the most important visual cues that can explain flying insects' behaviors for short-range navigation maneuvers in complex tunnels. Conversely, the biorobotic approach can therefore help to develop innovative flight control systems for flying robots with the aim of mimicking flying insects' abilities and better understanding their flight. PMID- 28655646 TI - Vitamin D deficiency impairs testicular development and spermatogenesis in mice. AB - Vitamin D deficiency is prevalent especially in men. Nevertheless, whether vitamin D deficiency impairs male reproduction remains under debate. The aim of this study is to investigate whether vitamin D deficiency has an impact on testicular development and spermatogenesis in mice. In the control group and vitamin D deficient (VDD) diet group, dams and their pups were fed with standard chow diet and VDD diet, respectively. Interestingly, testicular weight and sperm quality are reduced, testicular germ cell proliferation is suppressed, and the percentage of mature seminiferous tubules is decreased in VDD diet-fed mice. Moreover, testicular testosterone (T) synthesis enzymes are down-regulated in VDD diet-fed mice. Correspondingly, serum and testicular T levels are reduced in VDD diet-fed mice. Importantly, fertility index is reduced and live fetuses are decreased when both males and females are fed with VDD diet. These results provide evidence that vitamin D deficiency impairs testicular development and spermatogenesis. PMID- 28655647 TI - Evaluation of the effects of alpha-cypermethrin on fetal rat testicular steroidogenesis. AB - Pregnant Sprague-Dawley rats were administered the insecticide alpha-cypermethrin at doses of 0.1, 1, 5, or 10mg/kg/day, or di-isobutyl phthalate (DIBP) at 250mg/kg/day, by gavage, from gestation day (GD) 13 to 19. Testicular testosterone production and the expression of several key genes related to cholesterol and androgen synthesis and transport were assessed in GD 19 male fetuses. Dams treated with 10mg/kg/day of alpha-cypermethrin showed clinical signs of neurotoxicity and reduced body weight gain. alpha-Cypermethrin had no significant effect on post-implantation loss, fetal weight, incidence of male fetuses per litter, or anogenital distance of the male fetuses. In the fetal testes, mRNA expressions of HMG-CoA synthase and reductase, SRB1, StAR, P450scc, 3betaHSD, P450 17A1, and 17betaHSD were not affected by exposure to alpha cypermethrin. Testosterone production by the fetal testis was significantly reduced at 5 and 10mg/kg/day of alpha-cypermethrin, although to a much smaller extent than in DIBP-exposed fetuses. PMID- 28655648 TI - Evolutionary transition from biological to social systems via generation of reflexive models of externality. AB - Evolutionary transition from biological to social systems corresponds to the emergence of the structure of subject that incorporates the internal image of the external world. This structure, established on the basis of referral of the subject (self) to its symbolic image, acquires a potential to rationally describe the external world through the semiotic structure of human language. It has been modelled in reflexive psychology using the algebra of simple relations (Lefebvre, V.A., J. Soc. Biol. Struct. 10, 129-175, 1987). The model introduces a substantial opposition of the two basic complementary types of reflexion defined as Western (W) and Eastern (E). These types generate opposite models of behavior and opposite organizations of societies. Development of human societies involves the interactions of W and E types not only between the societies but also within one society underlying its homeostasis and dynamics. Invention of new ideas and implementation of new technologies shift the probability pattern of reflexive choices, appearing as internal assessments of the individual agents within a society, and direct changes in the preference of reflexive types. The dynamics of societies and of interactions between societies is based on the interference of opposite reflexive structures and on the establishment of different patterns during such interference. At different times in the history of human civilization these changing patterns resulted in the formation and splitting of large empires, the development and spreading of new technologies, the consecutive periods of wellness and decline. PMID- 28655649 TI - Interregional electro-mechanical heterogeneity in the rabbit myocardium. AB - BACKGROUND: Increased electrical heterogeneity has been causatively linked to arrhythmic disorders, yet the knowledge about physiological heterogeneity remains incomplete. This study investigates regional electro-mechanical heterogeneities in rabbits, one of the key animal models for arrhythmic disorders. METHODS AND FINDINGS: 7 wild-type rabbits were examined by phase-contrast magnetic resonance imaging in vivo to assess cardiac wall movement velocities. Using a novel data processing algorithm regional contraction-like profiles were calculated. Contraction started earlier and was longer in left ventricular (LV) apex than base. Patch clamp recordings showed longer action potentials (AP) in LV apex compared to the base of LV, septum, and right ventricle. Western blots of cardiac ion channels and calcium handling proteins showed lower expression of Cav1.2, KvLQT1, Kv1.4, NCX and Phospholamban in LV apex vs. base. A single-cell in silico model integrating the quantitative regional differences in ion channels reproduced a longer contraction and longer AP in apex vs. base. CONCLUSIONS: Apico-basal electro-mechanical heterogeneity is physiologically present in the healthy rabbit heart. An apico-basal electro-mechanical gradient exists with longer APD and contraction duration in the apex and associated regionally heterogeneous expression of five key proteins. This pattern of apical mechanical dominance probably serves to increase pumping efficiency. PMID- 28655650 TI - Mechanical wounding promotes local and long distance response in the halophyte Cakile maritima through the involvement of the ROS and RNS metabolism. AB - Mechanical wounding in plants, which are capable of generating defense responses possibly associated with nitro-oxidative stress, can be caused by (a)biotic factors such as rain, wind, herbivores and insects. Sea rocket (Cakile maritima L.), a halophyte plant belonging to the mustard family Brassicaceae, is commonly found on sandy coasts throughout Europe. Using 7-day-old Cakile maritima L. seedlings, mechanical wounding was induced in hypocotyls by pinching with a striped-tip forceps; after 3 h, several biochemical parameters were analyzed in both the damaged and unwounded organs (green cotyledons and roots). We thus determined NO production, H2O2 content, lipid oxidation as well as protein nitration patterns; we also identified several antioxidant enzymes including catalase, superoxide dismutase (SOD) isozymes, peroxidases, ascorbate-glutathione cycle enzymes and NADP-dehydrogenases. All these parameters were differentially modulated in the damaged (hypocotyls) and unwounded organs, which clearly indicated an induction of CuZnSOD V in the three organs, an increase in protein nitration in green cotyledons and an induction of NADP-isocitrate dehydrogenase activity in roots. On the whole, our results indicate that the wounding of hypocotyls, which showed an active ROS metabolism and oxidative stress, causes long-distance signals that also trigger responses in unwounded tissues with a more active RNS metabolism. These data therefore confirm the existence of local and long-distance responses which counteract negative effects and provide appropriate responses, enabling the wounded seedlings to survive. PMID- 28655651 TI - Cichoric acid improved hyperglycaemia and restored muscle injury via activating antioxidant response in MLD-STZ-induced diabetic mice. AB - Cichoric acid (CA), extracted from edible plants and vegetables, is a potential natural nutraceutical, with antioxidant and hypoglycaemic biological functions. The objective of this study was to explore the potential underlying molecular mechanisms involved in normalizing diabetes-related changes in hyperglycaemia via pancreas apoptosis and muscle injury induced by multiple low-dose STZ (MLD-STZ) injection in response to dietary supplementation with CA. To induce the MLD-STZ diabetic mice, the C57BL/6J mice were intraperitoneally injected with STZ (50 mg/kg body weight) for consecutive five days. CA (60 mg/kg/d) was supplemented in drinking water for 4 weeks. Compared with control, CA inhibited pancreas apoptosis and adjusted islet function in diabetic mice, leading to an increase in insulin generation and secretion. Moreover, CA regulated mitochondrial biogenesis, glycogen synthesis, and inhibited inflammation via activating antioxidant responses, which contributes to the improvement in athletic ability and diabetic myopathy. In general, CA is a natural food-derived compound with the potential application for regulating glucose homeostasis and improving diabetes and its complications. PMID- 28655652 TI - (p-ClPhSe)2 stimulates carbohydrate metabolism and reverses the metabolic alterations induced by high fructose load in rats. AB - The modern life leads to excess consumption of food rich in fructose; however, the long-term changes in carbohydrate and lipid metabolism could lead to metabolic dysfunction in humans. The present study evaluated the in vitro insulin mimetic action of p-chloro-diphenyl diselenide (p-ClPhSe)2. The second aim of this study was to investigate if (p-ClPhSe)2 reverses metabolic dysfunction induced by fructose load in Wistar rats. The insulin-mimetic action of (p ClPhSe)2 at concentrations of 50 and 100 MUM was determined in slices of rat skeletal muscle. (p-ClPhSe)2 at a concentration of 50 MUM stimulated the glucose uptake by 40% in skeletal muscle. A dose-response curve revealed that (p-ClPhSe)2 at a dose of 25 mg/kg reduced (~20%) glycemia in rats treated with fructose (5 g/kg, i.g.). The administration of fructose impaired the liver homeostasis and (p ClPhSe)2 (25 mg/kg) protected against the increase (~25%) in the G-6-Pase and isocitrate dehydrogenase activities and reduced the triglyceride content (~25%) in the liver. (p-ClPhSe)2 regulated the liver homeostasis by stimulating hexokinase activity (~27%), regulating the TCA cycle activity (increased the ATP and citrate synthase activity (~15%)) and increasing the glycogen levels (~67%). In conclusion, (p-ClPhSe)2 stimulated carbohydrate metabolism and reversed metabolic dysfunction in rats fed with fructose. PMID- 28655653 TI - Antioxidant properties of 5-hydroxy-4-phenyl-butenolide via activation of Nrf2/ARE signaling pathway. AB - 5-Hydroxy-4-phenyl-butenolide (5H4PB) is a bioactive compound with antifungal and anti-obesity properties. Although it has recently been shown that 5H4PB activates peroxisome proliferator-activated receptor-gamma (PPARgamma), the effect of 5H4PB on intracellular signaling pathways has not been clarified. In this study, we found that 5H4PB activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which plays an important role in cellular defense against oxidative stress, and the subsequent upregulation of ARE-dependent cytoprotective genes, including the heme oxygenase 1, catalase, and superoxide dismutase genes, without exhibiting cytotoxicity. In addition, 5H4PB significantly attenuated intracellular ROS generation, glutathione oxidation, and DNA damage induced by hydrogen peroxide (H2O2) exposure in mouse fibroblast cells. Furthermore, we demonstrated that pretreatment with 5H4PB confers a significant cytoprotective effect against H2O2 induced cell death in mouse cultured fibroblasts and primary hepatocytes. Thus, our study demonstrated that 5H4PB enhanced cellular resistance to oxidative damage via activation of the Nrf2/ARE signaling pathway. PMID- 28655654 TI - Azo dyes in clothing textiles can be cleaved into a series of mutagenic aromatic amines which are not regulated yet. AB - Azo dyes represent the by far most important class of textile dyes. Their biotransformation by various skin bacteria may release aromatic amines (AAs) which might be dermally absorbed to a major extent. Certain AAs are well known to have genotoxic and/or carcinogenic properties. Correspondingly, azo dyes releasing one of the 22 known carcinogenic AAs are banned from clothing textiles in the European Union. In the present study, we investigated the mutagenicity of 397 non-regulated AAs potentially released from the 470 known textile azo dyes. We identified 36 mutagenic AAs via publicly available databases. After predicting their mutagenicity potential using the method by Bentzien, we accordingly allocated them into different priority groups. Ames tests on 18 AAs of high priority showed that 4 substances (22%) (CASRN 84-67-3, 615-47-4, 3282-99-3, 15791-87-4) are mutagenic in the strain TA98 and/or TA100 with and/or without rat S9 mix. Overall, combining the information from the Ames tests and the publicly available data, we identified 40 mutagenic AAs being potential cleavage products of approximately 180 different parent azo dyes comprising 38% of the azo dyes in our database. The outcome of this study indicates that mutagenic AAs in textile azo dyes are of much higher concern than previously expected, which entails implications on the product design and possibly on the regulation of azo dyes in the future. PMID- 28655655 TI - Relevance and reliability of experimental data in human health risk assessment of pesticides. AB - Evaluation of data relevance, reliability and contribution to uncertainty is crucial in regulatory health risk assessment if robust conclusions are to be drawn. Whether a specific study is used as key study, as additional information or not accepted depends in part on the criteria according to which its relevance and reliability are judged. In addition to GLP-compliant regulatory studies following OECD Test Guidelines, data from peer-reviewed scientific literature have to be evaluated in regulatory risk assessment of pesticide active substances. Publications should be taken into account if they are of acceptable relevance and reliability. Their contribution to the overall weight of evidence is influenced by factors including test organism, study design and statistical methods, as well as test item identification, documentation and reporting of results. Various reports make recommendations for improving the quality of risk assessments and different criteria catalogues have been published to support evaluation of data relevance and reliability. Their intention was to guide transparent decision making on the integration of the respective information into the regulatory process. This article describes an approach to assess the relevance and reliability of experimental data from guideline-compliant studies as well as from non-guideline studies published in the scientific literature in the specific context of uncertainty and risk assessment of pesticides. PMID- 28655656 TI - Lessons learned from read-across case studies for repeated-dose toxicity. AB - A series of case studies designed to further acceptance of read-across predictions, especially for chronic health-related endpoints, have been evaluated with regard to the knowledge and insight they provide. A common aim of these case studies was to examine sources of uncertainty associated with read-across. While uncertainty is related to the quality and quantity of the read across endpoint data, uncertainty also includes a variety of other factors, the foremost of which is uncertainty associated with the justification of similarity and quantity and quality of data for the source chemical(s). This investigation has demonstrated that the assessment of uncertainty associated with a similarity justification includes consideration of the information supporting the scientific arguments and the data associated with the chemical, toxicokinetic and toxicodynamic similarity. Similarity in chemistry is often not enough to justify fully a read across prediction, thus, for chronic health endpoints, toxicokinetic and/or toxicodynamic similarity is essential. Data from New Approach Methodology(ies) including high throughput screening, in vitro and in chemico assay and in silico tools, may provide critical information needed to strengthen the toxicodynamic similarity rationale. In addition, it was shown that toxicokinetic (i.e., ADME) similarity, especially metabolism, is often the driver of the overall uncertainty. PMID- 28655657 TI - Peptide-functionalized poly[oligo(ethylene glycol) methacrylate] brushes on dopamine-coated stainless steel for controlled cell adhesion. AB - : The modification of the surface of surgical implants with cell adhesion ligands has emerged as a promising approach to improve biomaterial-host interactions. However, these approaches are limited by the non-specific adsorption of biomolecules and uncontrolled presentation of desired bioactive ligands on implant surfaces. This leads to sub-optimal integration with host tissue and delayed healing. Here we present a strategy to grow non-fouling polymer brushes of oligo(ethylene glycol) methacrylate by atom transfer radical polymerization from dopamine-functionalized clinical grade 316 stainless steel. These brushes prevent non-specific adsorption of proteins and attachment of cells. Subsequently, the brushes can be modified with covalently tethered adhesive peptides that provide controlled cell adhesion. This approach may therefore have broad application to promote bone growth and improvements in osseointegration. STATEMENT OF SIGNIFICANCE: Stainless steel (SS) implants are widely used clinically for orthopaedic, spinal, dental and cardiovascular applications. However, non-specific adsorption of biomolecules onto implant surfaces results in sub-optimal integration with host tissue. To allow controlled cell-SS interactions, we have developed a strategy to grow non-fouling polymer brushes that prevent protein adsorption and cell adhesion and can be subsequently functionalized with adhesive peptides to direct cell adhesion and signaling. This approach has broad application to improve osseointegration onto stainless steel implants in bone repair. PMID- 28655658 TI - Multifunctional peptide-lipid nanocomplexes for efficient targeted delivery of DNA and siRNA into breast cancer cells. AB - : The development of carriers for the delivery of oligonucleotide therapeutics is essential for the successful translation of gene therapies to the clinic. In the present study, a delivery system, which combines the fusogenic lipid 1,2-dioleoyl sn-glycero-3-phosphoethanolamine (DOPE) with a well-defined synthetic multifunctional peptide, was produced and optimized for gene delivery, with the aim to develop an efficient gene delivery platform for breast cancer cells. For this purpose, a breast cancer-specific cell targeting peptide (CTP) was incorporated into our leading peptide-based gene delivery system (to generate DEN K(GALA)-TAT-K(STR)-CTP) to improve its cell-specific internalization, and investigated in combination with a formulation approach (DOPE/1,2-dioleoyl-3 trimethylammonium-propane (DOTAP)). DEN-K(GALA)-TAT-K(STR)-CTP alone efficiently complexed with DNA or siRNA, and promoted efficient cellular uptake, but low levels of gene expression. By adding the formulation approach, synergistic improvements in gene expression and silencing were observed compared to the peptide or formulation approaches alone. Of significance, this current system demonstrated more efficient gene knockdown when compared to the leading commercial siRNA delivery agent Lipofectamine(r) RNAiMAX. The utility of this system was demonstrated through the delivery of BCL2 (B-cell lymphoma 2) siRNA to MCF-7 cells, which led to near complete knockdown of the Bcl-2 protein, and inhibition of MCF-7 cell migration in a wound healing assay. The present peptide/lipid hybrid system is an excellent candidate for the delivery of DNA or siRNA into breast cancer cells. STATEMENT OF SIGNIFICANCE: The identification of safe and effective delivery systems for DNA and siRNA is of great importance. Herein, we developed a well-defined, multifunctional and cell-specific lipidic peptide DEN-K(GALA)-TAT-K(STR)-CTP as a breast cancer cell targeted gene delivery vector. When combined with a lipid component (DOTAP/DOPE), the peptide/lipid hybrid system demonstrated higher gene expression or knockdown levels compared to the peptide or lipid approach alone when used to deliver pDNA or siRNA respectively, indicating synergistic enhancement of gene delivery efficiency. Importantly, this delivery strategy achieved greater knockdown of the Bcl-2 protein when compared to the leading commercial siRNA delivery system Lipofectamine(r) RNAiMAX, suggesting its potential utility for the targeted treatment of Bcl-2 overexpressing breast cancers. PMID- 28655659 TI - Fungal chitosan and Lycium barbarum extract as anti-Listeria and quality preservatives in minced catfish. AB - Listeria monocytogenes is a foodborne bacterial pathogen that causes serious health risks. Chitosan (Ch) is a bioactive polymer that could be effectively applied for foodstuffs biopreservation. Lycium barbarum (Goji berry) is ethnopharmaceutical fruit that have diverse health protecting benefits. Chitosan was produced from A. niger and employed with L. barbarum extract (LBE) as blends for Listeria control and quality biopreservation of African catfish mince (Clarias gariepinus). Chitosan could utterly control L. monocytogenes survival in fish mince and its efficacy was strengthened with added LBE at 0.2 and 0.4%. Blending of fish mince with Ch could effectively reduce the progress of chemical spoilage parameters and this protective effect was greatly enhanced with increased addition of LBE. The sensorial assessment of treated minces indicated panelists preferences for the entire attributes of blended samples with Ch and LBE, particularly with storage prolongation. Scanning micrographs elucidated the antibacterial action of Ch against L. monocytogenes. Results recommended the application of fungal Ch/LBE composites as biopreservatives and anti-listerial agents, through their blending with catfish mince, to eliminate bacterial growth, enhance sensory and storage attributes of preserved fish. PMID- 28655660 TI - Novel oleyl amine-modified polymannuronic acid micelle loading tacrolimus for therapy of allergic conjunctivitis. AB - Marine polysaccharide-based nanomaterial attracted considerable attention due to its biocompatibility and biodegradability. Here, a novel polymannuronic acid derivative (PM-C18) was synthesized as nanocarrier modified with hydrophobic oleyl amine. Its structure was confirmed by Fourier-transformed infrared spectrometry and nuclear magnetic resonance. To investigate its function, we developed tacrolimus (FK506) loaded nanoparticle by self-assembling PM-C18 and studied its drug loading, cytotoxicity and mechanism of in vitro release. Furthermore, we established a mouse model of allergic conjunctivitis (AC) to evaluate the efficacy of FK506 loaded PM-C18. The results indicated that PM-C18 carrier can encapsule FK506 with high drug loading (18%) and average particle size of 110.34+/-1.6nm. The release mechanism was diffusion initially followed a lasting release induced by swelling and collapse of PM-C18. One-week treatment with FK506 loaded PM-C18 efficiently relieved the symptoms of AC, which indicated it could serve as a potential ophthalmic drug for patients with AC. Compared with FK506 ophthalmic suspension, FK506 loaded PM-C18 improved medication adherence. Most importantly, we developed a novel versatile nanomaterial of PM-C18 which could encapsule other active agents for more applications. PMID- 28655661 TI - Chitosan supramolecularly cross linked with trimesic acid - Facile synthesis, characterization and evaluation of adsorption potential for chromium(VI). AB - A facile synthesis of Chitosan Supramolecularly cross-linked with Trimesic Acid (CTMA) is reported in this work. The adsorption potential of CTMA for removal of hexavalent chromium was evaluated and the influence of pH, temperature, contact time and adsorbent dose on the adsorption process was investigated. The experimental results showed that CTMA could efficiently adsorb Cr6+ and partially reduce it to the less toxic Cr3+ state. The maximum adsorption capacity of CTMA for Cr6+ was found to be 129.53mg/g at pH 2.0. CTMA and chromium loaded CTMA were characterised by FT-IR, Raman, TGA-DSC, SEM-EDX, XRD, ESR and XPS spectroscopic techniques. Chitosan was observed to be cross- linked with TMA via ionic, hydrogen bonding and pi-pi supramolecular interactions while adsorption of chromium onto CTMA was by electrostatic forces and hydrogen bonding. From the observed results it was evident that CTMA was successfully applied for simultaneous removal of chromium, lead and iron from chrome plating effluent. PMID- 28655662 TI - Effects of carboxymethyl cellulose incorporated with garlic essential oil composite coatings for improving quality of strawberries. AB - The present study was aimed to determine the effects of carboxymethyl cellulose (CMC)/garlic essential oil (GEO) composite coatings in improving the quality of strawberries stored at 20 degrees C and 35-40% RH. To find the effects of CMC/GEO composite coatings, strawberries were coated with CMC, CMC+GEO (1%), CMC+GEO (2%), CMC+GEO (3%) and stored, while the uncoated strawberries were taken as control during storing. The effectiveness of CMC/GEO composite coatings was evaluated by measuring their weight loss, decay percentage, ascorbic acid, total phenols, anthocyanins, titratable acidity, total soluble solids and sensory evaluation. After 6days of storage, CMC+GEO (2%) composite coatings was found very effective in decreasing the senescence and maintaining the nutritional contents of strawberries. Results of this study confirm that CMC/GEO composite coatings can be used to improve the quality of strawberries. PMID- 28655663 TI - Resistive flow sensing of vital mitochondria with nanoelectrodes. AB - We report label-free detection of single mitochondria with high sensitivity using nanoelectrodes. Measurements of the conductance of carbon nanotube transistors show discrete changes of conductance as individual mitochondria flow over the nanoelectrodes in a microfluidic channel. Altering the bioenergetic state of the mitochondria by adding metabolites to the flow buffer induces changes in the mitochondrial membrane potential detected by the nanoelectrodes. During the time when mitochondria are transiently passing over the nanoelectrodes, this (nano) technology is sensitive to fluctuations of the mitochondrial membrane potential with a resolution of 10mV with temporal resolution of order milliseconds. Fluorescence based assays (in ideal, photon shot noise limited setups) are shown to be an order of magnitude less sensitive than this nano-electronic measurement technology. This opens a new window into the dynamics of an organelle critical to cellular function and fate. PMID- 28655664 TI - Protection of hydrophobic amino acids against moisture-induced deterioration in the aerosolization performance of highly hygroscopic spray-dried powders. AB - BACKGROUND: Inhalable particles containing amorphous form of drugs or excipients may absorb atmospheric moisture, causing powder aggregation and recrystallization, adversely affecting powder dispersion and lung deposition. The present study aims to explore hydrophobic amino acids for protection against moisture in spray-dried amorphous powders, using disodium cromoglycate (DSCG) as a model drug. MATERIALS AND METHODS: DSCG powders were produced by co-spray drying with isoleucine (Ile), valine (Val) and methionine (Met) in various concentrations (10, 20 and 40%w/w). Particle size distribution and morphology were measured by laser diffraction and scanning electron microscopy (SEM). Physiochemical properties of the powders were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and dynamic vapor sorption (DVS). Particle surface chemistry was analyzed by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro aerosolization performance was evaluated by a next generation impactor (NGI) after the powders were stored at 60% or 75% relative humidity (RH) for one month and three months. RESULTS AND DISCUSSION: Ile, Val and Met significantly reduced the deleterious effect of moisture on aerosol performance, depending on the amount of amino acids in the formulation. Formulations containing 10% or 20% of Ile, Val and Met showed notable deterioration in aerosol performance, with fine particle fraction (FPF) reduced by 6-15% after one-month storage at both 60% and 75% RH. However, 40% Ile was able to maintain the aerosol performance of DSCG stored at 75% RH for one month, while the FPF dropped by 7.5% after three months of storage. In contrast, 40% Val or Met were able to maintain the aerosol performance at 60% RH storage but not at 75% RH. At 40%w/w ratio, these formulations had particle surface coverage of 94.5% (molar percent) of Ile, 87.1% of Val and 84.6% of Met, respectively, which may explain their moisture protection effects. CONCLUSION: Ile, Val and Met showed promising moisture protection effect on aerosol performance. The results broaden the understanding on the use of hydrophobic amino acids as an excipient for long-term storage of inhalation powders formulations that are hygroscopic. PMID- 28655665 TI - Effect of amphiphilic graft co-polymer-carrier on physical stability of bosentan nanocomposite: Assessment of solubility, dissolution and bioavailability. AB - Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). But the solubility and bioavailability of this drug are poor, which has restricted the design and development of dosage forms for efficient and successful therapy. The present study was carried out to develop nanocomposites using an amphiphilic graft co-polymer (Soluplus(r)) as a carrier to enhance the solubility and bioavailability of bosentan. The graft co polymer-based nanocomposite formulation was prepared using the single-emulsion technique. The nanocomposite was characterised in terms of particle size analysis, solubility, percentage entrapment efficiency, drug-loading capacity, surface morphology, drug content, in vitro dissolution, stability and bioavailability. FT-IR study revealed that there was no interaction between the drug and Soluplus(r). DSC analysis of the nanocomposite formulation confirmed that the bosentan was completely encapsulated within a Soluplus(r). XRD analysis showed that the drug was converted to an amorphous form irreversibly. SEM images showed that the particles were of size 96-129MUm and had slightly smooth to rough textured surface. TEM analysis indicated that the diameters of the prepared bosentan nanocomposite after dispersion in distilled water were 13.69-96.78nm. Statistically significant increases in the solubility, dissolution and bioavailability of the drug were observed. It was confirmed that the use of a graft co-polymer carrier-based nanocomposite formulation is a good approach for efficient delivery of bosentan, the solubility and bioavailability being increased manifold. PMID- 28655666 TI - Wolbachia infection in Aedes aegypti mosquitoes alters blood meal excretion and delays oviposition without affecting trypsin activity. AB - Blood feeding in Aedes aegypti is essential for reproduction, but also permits the mosquito to act as a vector for key human pathogens such as the Zika and dengue viruses. Wolbachia pipientis is an endosymbiotic bacterium that can manipulate the biology of Aedes aegypti mosquitoes, making them less competent hosts for many pathogens. Yet while Wolbachia affects other aspects of host physiology, it is unclear whether it influences physiological processes associated with blood meal digestion. To that end, we examined the effects of wMel Wolbachia infection in Ae. aegypti, on survival post-blood feeding, blood meal excretion, rate of oviposition, expression levels of key genes involved in oogenesis, and activity levels of trypsin blood digestion enzymes. We observed that wMel infection altered the rate and duration of blood meal excretion, delayed the onset of oviposition and was associated with a greater number of eggs being laid later. wMel-infected Ae. aegypti also had lower levels of key yolk protein precursor genes necessary for oogenesis. However, all of these effects occurred without a change in trypsin activity. These results suggest that Wolbachia infection may disrupt normal metabolic processes associated with blood feeding and reproduction in Ae. aegypti. PMID- 28655667 TI - Ethics of health research partnerships in Global South : PhD students in learning. AB - In view of the worldwide epidemic processes that require and result in simultaneous research in several countries and in an increasingly more structured scientific community, especially in countries of Global South, it is essential to establish partnerships between researchers, policy-makers, local supervisors, and communities in both the North and the South. The objectives of this essay are to: 1) present the context and issues linked to research in the framework of a North South partnership; 2) describe the development of appropriate responses to improve consideration of ethical aspects; and 3) discuss the current role of young researchers in this era of multiple partnerships and share the observations and thoughts of PhD students in one research unit. PMID- 28655668 TI - Simulation training for emergency obstetric and neonatal care in Senegal preliminary results. AB - To describe a new training approach for emergency obstetric and neonatal care (EmONC) introduced in Senegal to strengthen the skills of healthcare providers. The approach was based on skills training according to the so-called "humanist" method and on "lifesaving skills". Simulated practice took place in the classroom through 13 clinical stations summarizing the clinical skills needed for EmONC. Evaluation took place in all phases, and the results were recorded in a database to document the progress of each learner. This approach was used to train 432 providers in 10 months and to document the increase in each participants' technical achievements. The combination of training with the "learning by doing" model ensured that providers learned and mastered all EmONC skills and reduced the missed learning opportunities observed in former EmONC training sessions. Assessing the impact of training on EmONC indicators and introducing this learning modality in basic training are the two major challenges we currently face. PMID- 28655669 TI - Health support for the Raid of the Seven Stones : in the footsteps of Navy physician Jules Crevaux in French Guiana. AB - In the summer of 2015, soldiers of the 3rd Foreign Infantry Regiment and civilian scientists mounted a joint expedition on foot to reconnoiter and better define the southern frontier of French Guiana with Brazil. Three doctor-nurse pairs worked in relay to provide medical support for this unprecedented 42-day, 320-km journey through a hostile and isolated environment, a mission whose success was made possible by large-scale logistic and technical prowess. The army health department, using knowledge gained from previous large-scale missions and expeditions and from its staff's local experience, provided its technical support for personnel selection, organization of the health logistics, and field support. This article describes the difficulties encountered from a medical perspective, the diseases encountered, and the final assessments of the personnel who completed this expedition. PMID- 28655670 TI - Cas de sparganose. PMID- 28655671 TI - Paludisme : artesunate et sulfadoxine-pyrimethamine versus artemether lumefantrine. PMID- 28655673 TI - Frequence de l'ascaridiose chez les enfants. PMID- 28655672 TI - Diffusion de Fasciola hepatica. PMID- 28655674 TI - Infection par Blastocystis. PMID- 28655675 TI - Emergence and spread of antibiotic resistance in West Africa : contributing factors and threat assessment. AB - The emergence and spread of antibiotic resistance present a major public health issue in both developed (DC) and less developed countries (LDC). Worldwide, its main cause is the uncontrolled and unjustified use of antibiotics. In countries with limited resources, such as West African nations, other features, more specifically socioeconomic and behavioral factors, contribute to exacerbate this problem. The objective of this review is to give an update of the common and specific factors involved in the amplification of antibiotic resistance phenomena in LCD, particularly in West African countries. In particular, some frequent societal behaviors (such as self-medication), inadequate healthcare infrastructure (insufficiently trained prescribers and inadequate diagnostic tools), and an uncontrolled drug sector (antibiotics sold over-the-counter, improperly stored, counterfeit, and/or expired) all strongly promote the emergence of antibiotic resistance. This risk is particularly worrisome for enterobacteriaceae producing extended spectrum beta-lactamases (10 to 100 % of colonizations and 30 to 50 % of infections). A similar trend has been observed for carbapenem resistance in enterobacteriaceae with rates ranging from 10 to 30 % and for methicillin resistance in Staphylococcus aureus, which now exceeds 30 %. These troubling observations call for effective health policies in these regions. These intervention strategies must be integrated and simultaneously target policy makers, prescribers, and users. PMID- 28655676 TI - Monitoring survey after intervention on the organization of a public service in senegal. AB - To better demonstrate the importance and usefulness of a scientific managerial approach in public health-care institutions to "team building" and institutional performance, this study aimed to evaluate the impact of interventions for organizational development of the Division of Reproductive Health (DRH) in Senegal. This cross-sectional assessment study, conducted in April-May 2014, focused on a sample of 25 DRH staff members and 4 key informants among partners/consultants after a review of the documentation relating to the process from design to implementation. Self-administered questionnaires and interviews provided the data. All respondents, including 19 women and 6 men, came from DRH offices. Staff unanimously noted the benefits of organizational development process, including improved understanding of DRH's vision, mission, and objectives, clarification of the roles and responsibilities of all staff members, improvement of the work environment, and the development of collective awareness, etc. Staff members noted the encouraging results. Nonetheless, the definitive establishment of an organizational culture remains to be shown. PMID- 28655677 TI - Private pharmacy staff in five main towns in Benin, Burkina Faso, and Mali: knowledge and practices concerning malaria care in 2014. AB - The Global Fund's involvement in the fight against malaria has led to significant improvements, but mostly through programs supporting public-sector health facilities and personnel. The authors report the results of the preliminary survey preceding their intervention with private pharmacies. A simple random sampling technique was used to select the sample of pharmacies in urban areas in Burkina Faso, Benin, and Mali. A pretested questionnaire was administered to the supervisor present in each pharmacy at the time of the survey. Data were collected by local students in the first quarter of 2014. In all, 94 pharmacies were surveyed, representing 17.6% of all the pharmacies in these 5 cities. Among the participants, 84% knew about the national malaria control program, and 77.7% about artemisinin-based combination therapy (ACT), while 38.8% knew the national protocols. Licensed pharmacists had a better knowledge of ACT than their assistants, and training improved knowledge of treatment for uncomplicated malaria episodes. These pharmacists and assistants would like to be more involved in the fight against malaria. They are ready to advise ACT when appropriate after rapid detection tests. It is necessary to find resources for subsidized inputs in the private sector to make these drugs and tests more accessible for all patients. PMID- 28655678 TI - Prevalence of extended-spectrum beta-lactamase phenotypes in enterobacteria isolated from blood cultures of patients at admission to the University Hospital of Bamako. AB - The aim of our study was to determine the frequency of extended-spectrum beta lactamase (ESBL) phenotypes among the enterobacteria present in blood cultures of patients at admission to two university hospitals of Bamako (Mali). During a period of three months, we isolated enterobacteria from blood cultures from patients upon admission to the Point G and Gabriel Toure University Hospitals. The ESBL-positive enterobacteria were initially identified by API 20E strips and VITEK(r)2 and then confirmed in France by MALDI-TOF mass spectrometry at the Bichat Hospital bacteriology laboratory. Antibiotic susceptibility was determined by the diffusion method as recommended by EUCAST. The species isolated were K. pneumoniae (14/40, 35.0 %), E. coli (11/40, 27.5 %), and E. cloacae (9/40, 22.5 %); 21/34 (61.8 %) had an ESBL phenotype, including 10/14 (71.4 %) K. pneumoniae, 8/11 (72.7 %) E. coli, and 3/9 (33 3 %), E. cloacae. The ESBL strains of K. pneumoniae, E. coli, and E. cloacae were associated, respectively, with resistance to the following antibiotics: gentamicin (10/10, 100 %; 6/8, 75%; 2/3, 67%), amikacin (2/10, 20 %; 0/8, 0%; 0/3, 0%), ofloxacin (8/10, 80. %; 7/8, 87%; 3/3, 100%), cotrimoxazole (10/10, 100 %; 6/8, 75%; 3/3, 100%). Almost two thirds (61.8%) of the enterobacteria isolated from blood cultures produced extended spectrum beta-lactamases. They retained regular sensitivity only to carbapenems and amikacin. PMID- 28655679 TI - Tetanus associated with road accidents in the infectious diseases department of Point G University Hospital, Bamako, Mali. AB - The aim of this study was to describe the epidemiological, clinical, and prognostic aspects of tetanus associated with road accidents and to make recommendations. This observational study collected retrospective clinical data over a 9-year period about adults admitted for trismus and/or generalized or localized paroxysm after a road accident. The study included 25 patients, accounting for 22.12 % of all tetanus cases. Men were massively overrepresented (sex-ratio M/F: 24/1). The median age was 34 +/- 8 years. In all, vaccination status was unknown for 4 patients and known to be negative for 21. Immunoprophylaxis was nonexistent in all cases. The generalized clinical form was dominant (96 %). Severity reached level III for 12 % of patients. The points of entry included open leg fractures (4 cases), head wounds (2), mucocutaneous wounds (14), and muscle contusions (5). The mean time to referral for tetanus was 8 +/- 7 days, and the median hospital stay 9.08 +/- 11 days. Patients were mostly residents of urban (56 %) and suburban areas (28 %) [P = 0.04]. Two cases were complicated by severe malaria. The mortality rate was 60 %, and 52 % of the deaths occurred within the first 72 hours after hospitalization. It is essential to promote serum therapy and tetanus immunization for patients after road accidents. Increasing the awareness of traditional healers of these treatments deserves consideration. PMID- 28655680 TI - Open wounds of the Achilles tendon in tropical settings: 36 cases at the Donka University Hospital in Guinea Conakry. AB - The aim of this study was to analyze the epidemiologic, etiologic, and therapeutic aspects of open wounds of the Achilles tendon managed in the Donka University Hospital. This 3-year prospective included all patients admitted for an Achilles tendon injury. Closed injuries, suppurating wounds, and those that occurred more than 24 hours before admission were excluded. Surgical treatment consisted in debridement and tendon repair, with plaster cast protection for 6 weeks. The study included 36 patients with a mean age of 23.4 years, 29 of whom were male. The primary cause was traffic accidents (n = 21), mainly due to motorcycle taxis (n = 18). The mean follow-up was 9 months. Infection (7 cases) and skin necrosis (5 cases) were the main postoperative complications. The functional result, evaluated by the McComis score, was excellent in 20 cases, good or satisfactory in 10, and poor in 6 cases. Open injuries of the Achilles tendon are common in Guinea-Conakry and mostly due to motorcycle taxis. Outcome of surgical treatment depends on the severity of the injury. Infection and skin necrosis are frequent complications, and their management is challenging in this setting. PMID- 28655681 TI - Depression and HIV: Epidemiological and clinical aspects at the Bamako University Hospital (Mali). AB - Depression plays an important role in clinical worsening, morbidity and mortality related to HIV/AIDS. To describe the epidemiological and clinical aspects of depressive disorders in people with HIV in Mali. This prospective study took place in the department of psychiatry and infectious diseases at the Bamako University Hospital from July 2004 through October, 2005 and included all HIV positive antiretroviral-naive patients with depression, diagnosed according to ICD-10 criteria. The study included 84 HIV-positive patients with a depressive disorder; our total population of HIV-positive patients was 316 during the study period, for a prevalence rate of 26.7 % in this population. The mean age of these depressed patients was 36.7 +/- 8.5 years (range: 20-57); 63.1% were women, 47.7% had not attended or at least not completed primary school; 66.6% were married, and 92.9% lived in urban areas. Sad mood, anxiety, and refusal to eat were reported by 27.7%, 10.9%, and 9.1%, respectively, as a reason for consultation. Depression was associated with an anxiety disorder in 33 (39.3%) and a delusional disorder in 14 (16.7%). Severe depression was associated with low BMI and at a CD4 count <200 cells/mm3. Depression was found at a high frequency in our study. Its detection, operational research about it, and improved management are recommended to improve the health of people living with HIV. PMID- 28655682 TI - Distal sensory polyneuropathy among HIV-infected patients at Parakou University Hospital, Benin, 2011. AB - Distal sensory polyneuropathy (DSP) is the most frequent neurological complication among HIV patients, and its risk increases with use of highly active antiretroviral therapy (HAART). We aimed to assess the prevalence of DSP and the factors associated with it among HIV-infected outpatients treated at Parakou University Hospital. This cross-sectional study took place from April 15 to July 15, 2011, and included 262 patients. All patients underwent a neurological examination by two neurologists with training and clinical experience in these examinations and in the Brief Peripheral Neuropathy Screening (BPNS), which was the primary tool used here. Data from nutritional status (body mass index: BMI), social and demographic information, HAART status, and CD4 count were recorded. The factors associated with DSP were studied with multivariate analysis, using a logistic regression model and a significance level of 0.05. The study included 60 men (22.9 %). Patients' ages ranged from 16 to 74 years and averaged 36.8+/-10 years. All patients but one patient were infected by HIV type 1 only; that one was coinfected by types 1 and 2. The mean BMI was 22.5+/-4.2 kg/m2. In all, 213 (81.3 %) received HAART, and the mean CD4 count was 355.0 cells/mm3+/-236.1. The prevalence of DSP was 42.4 %. The factors associated with it on univariate analysis were age, marital status, HAART status, duration of HIV infection, and duration of HAART. Only advanced age (OR 1.8, 95 % CI 1.1-5.3) and HAART use (OR 2.3, 95 % CI 1.5-4.9) were associated with DSP in the multivariate analysis. The main symptoms were paresthesia (numbness:75.7%; burning: 39.6%; pins and needles sensation 32.4 %) and pain (23.4 %). Vibration perception at the toes was missing or reduced for 84.4 %. According to the sensory symptoms grade, 93.7 % of patients were classified in Grades 2 or 3. This study showed that the prevalence of DSP is high and that it is associated with age and HAART. PMID- 28655683 TI - Integration of prevention of mother-to-child HIV transmission into maternal health services in Senegal. AB - The objective of this study was to assess the level of integration of prevention of mother-to-child HIV transmission (PMTCT) in facilities providing services for maternal, newborn, and child health (MNCH) and reproductive health (RH) in Senegal. The survey, conducted from August through November, 2014, comprised five parts : a literature review to assess the place of this integration in the health policies, standards, and protocols in effect in Senegal; an analysis by direct observation of attitudes and practices of 25 healthcare providers at 5 randomly selected obstetrics and gynecology departments representative of different levels of the health pyramid; a questionnaire evaluating knowledge and attitudes of 10 providers about the integration of PMTCT services into MNCH/RH facilities; interviews to collect the opinions of 70 clients, including 16 HIV-positive, about the quality of PMTCT services they received; and a questionnaire evaluating knowledge and opinions of 14 policy-makers/managers of health programs focusing on mothers and children about this integration. The literature review revealed several constraints impeding this integration : the policy documents, standards, and protocols of each of the programs involved do not clearly indicate the modalities of this integration; the programs are housed in two different divisions while the national Program against the Human Immunodeficiency Virus reports directly to the Prime Minister; program operations remains generally vertical; the resources for the different programs are not sufficiently shared; there is no integrated training module covering integrated management of pregnancy and delivery; and supervision for each of the different programs is organized separately.The observation of the providers supporting women during pregnancy, during childbirth, and in the postpartum period, showed an effort to integrate PMTCT into the MNCH/RH services delivered daily to clients. But this desire is hampered by many problems, including the inconsistent availability of HIV testing and antiretroviral drugs at program sites and the deficit in training and supervision for PMTCT. Clients interviewed after their contact with providers often complained about the lack of information received about PMTCT. They considered that effective integration of these services would provide them with better quality care while reducing their waiting time, costs, and trips to health facilities. The responses of policymakers and program managers interviewed mostly revealed gaps in their understanding and implementation of the integration. There is an effort to integrate MNCH/RH and PMTCT services at the healthcare facilities we visited. But our investigation revealed many shortcomings in both the screening and support of new or expectant HIV+ mothers. To improve this situation it is necessary to improve the skills and motivation of PMTCT providers, enhance the level of equipment, and empower local maternity wards. PMID- 28655684 TI - Profile of intestinal parasitosis among school-aged children in Kiliba (eastern DR Congo). AB - This study of feces sought to determine the prevalence of human intestinal parasites in the Kiliba area of the eastern DR Congo. Feces of 602 school children aged from 9 to 20 years were collected from April to June 2014 and examined. Direct analyses were supplemented with the Kato and Ritchie methods. The global prevalence of intestinal parasitosis in school-aged children in the Kiliba area was 91.4 % [95 % CI: 87.6-94.3%]. The frequency of helminthiasis was high at 73.8 % (95 % CI: 68.4-78.6%) and that of protozoa reached 32.9 % (95 % CI: 27.7-38.6%). Girls were infected more often than boys. The group aged 17-20 years had the highest infection rate (97.7 %), but no statistically significant difference was observed among the age groups studied. The most frequent parasite species were: Schistosoma mansoni (30.6 %), Strongyloides stercolaris (21.3 %), Entamoeba histolytica (17.6 %), Trichomonas intestinalis (14.6 %), Ankylostoma duodenale (13.6 %), Ascaris lumbricoides (12.6 %), Trichuris trichiura (9.0 %), Taenia saginata (6.6 %), and Giardia intestinalis (5.0 %). This investigation demonstrated the extreme frequency of these fecal infections. Preventive measures, including water distribution, sanitary installations, and hygiene education, should be implemented. PMID- 28655685 TI - Severe scorpion envenomation: pathophysiology and the role of inflammation in multiple organ failure. AB - Scorpion stings occur on every continent except Antarctica. The correlation between young age and severity of clinical manifestations after this envenomation is well-established. Several studies have emphasized the relevance of pro inflammatory mediators in the pathophysiological manifestations of human scorpion envenomation. Moreover, there is a significant association between pro inflammatory cytokine levels in the blood and the severity of scorpion envenomation. Release of these cytokines increases the severity of the visceral damage induced by the direct action of the venom and the activation of both the sympathetic and parasympathetic nervous systems. PMID- 28655688 TI - Balance and gait analysis of senior tumble-prone patients with cerebrovascular disease. AB - This study aims to observe the tumble status for senior patients with cerebrovascular disease, and to analyze the balance and gait condition in order to provide the basis for clinical prevention and nursing care. A total of 48 senior patients with cerebrovascular disease were investigated with the Tinetti balance and gait evaluation, and the relation between tumble occurrence and balance ability was interrogated. The total score of balance evaluation value and gait value for 89.1% of the senior patients with cerebrovascular disease was fewer than 19 points, which indicated a risk of tumble. The majority of patients could not complete the immediate standing balance well, turning stand balance, mild chest-pushed balance and eyes-closed standing balance. The occurrence of immediate standing balance and turning stand balance fewer than three times was less frequent than the occurrence of tumble for one time, which had significant difference (P<0.05). The senior patients with cerebrovascular disease and immediate standing balance and turning stand balance could easily tumble many times, which was crucial for the nursing staff to carry out preventive strategies. Detailed observations of balance and gait function for senior patients were described, which provided a promising basis for designing appropriate nursing measures. PMID- 28655686 TI - Inflammatory lumbar radiculalgia in Ouagadougou: posterior facet arthritis due to tuberculosis. AB - Posterior facet arthritis is rarely described. The authors report a case of arthritis of the posterior lumbar facet in a woman consulting for back pain associated with relative functional impairment. Modern imaging, in slices, enables better examination of the posterior arch and better diagnosis of pathologies. Tuberculosis is one of the conditions affecting the posterior lumbar facet, and its characteristics on MRI are well-defined. This case shows that tuberculosis is a not uncommon cause of posterior facet arthritis and should be considered even before the appearance of clinical and bacteriological signs to avoid catastrophic situations for the patient. PMID- 28655689 TI - Assessment of gait dynamics in rotenone-induced rat model of Parkinson's disease by footprint method. AB - Rotenone (organic pesticide and inhibitor of mitochondrial complex I) is used to generate an experimental model of Parkinson's disease (PD). In the present study, we investigated rotenone-induced locomotor deficits, gait dynamics and muscular weakness in rats. The study also determined dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels following rotenone administration. In the study, adult male rats were administered subcutaneously (s.c.) with rotenone (1.5 mg/kg/day) for 8 days. Motor activities were monitored by the Kondziela's inverted screen test, beam walking test and footprint test. Animals were decapitated after behavioral analysis and brains were dissected out for neurochemical estimation. Results showed that the levels of DA and DOPAC were significantly decreased, which further supported by significant impaired motor coordination in rotenone treated rats. In conclusion, the behavioral and neurochemical findings of our study further strengthen the previous report and emphasizes on short term administration of rotenone producing PD-like symptoms in rats. PMID- 28655690 TI - Metformin HCl has curative effect on rebuilding of ventricular diastolic functions in high-fat-diet fed rats. AB - Myocardial lipid accumulation due to diabetes and/or obesity plays a role in the progression of left ventricular diastolic dysfunction. Our aims were to exhibit the correlation between histopathologic stage of the liver and cardiac functions, and to evaluate the effects of metformin HCl and rosiglitazone on myocardial functions. Thirty-two male Sprague-Dawley rats were divided into four groups to exhibit the correlation between histopathologic stage of the liver and cardiac functions and to determine whether metformin HCl and rosiglitazone have effects on cardiac functions. For 20 weeks, one group was fed standard rat basic diet, whereas the other groups were on high-fat-diet. During the last 4 weeks, metformin HCl was given to the third group, rosiglitazone to the fourth group. Histological evaluation of rat livers yielded significantly higher steatosis grade in high-fat-diet group and different fibrosis stages among groups. Also, there was significant correlation between diastolic functions and steatosis grade/fibrosis stage of rat liver. Electrophysiological study of hearts via Langendorff technique showed better coronary perfusion pressures and diastolic functions in standard-diet and metformin HCl groups compared to other groups. Metformin HCl improves LV diastolic dysfunction and coronary perfusion pressures. PMID- 28655691 TI - Biosynthesis of (S)-naproxen starch ester by Carica papaya lipase in intermittent opening reaction mode. AB - Inorder to brought S-naproxen into small intestine, an optically pure (S) naproxen starch ester was produced by lipase through enantio-selective trans esterification of racemic naproxen methyl ester with pretreatment starch in solvent system. With carefully selection of the reaction medium (isooctane), lipase (Carica Papaya Lipase, CPL) and the reaction mode (intermittent opening), a high conversion rate (48.6%) and enantiomeric excess of product (99.6%) was obtained. The slow release macromolecular (S)-Naproxen had been synthesized to improve the efficacy of racemic naproxen and overcome its side effects. The enanitomeric ratio of CPL (E=52.5) was higher than CRL (E=22) and greatly influenced by the byproduct methyl alcohol. The intermittent opening reaction mode was the effective way to remove the inhibition of methyl alcohol and to improve the enantio-selectivity of CPL. S-naproxen starch was confirmed by HPLC and 1H NMR. This method may also apply to preparation the other optically pure 2 phenylpropionic acid derivatives. S-naproxen starch was a new optically pure derivatives possessing emulsifying and slow release properties would be widely applied to the food, pharmaceutical and biomedical industries. PMID- 28655692 TI - An interquartile relationship between polyherbal extract based lozenges linkus a phase IV comparative randomised control trial. AB - The aim of the study is to determine the efficacy of polyherbal linkus with the other pharmaceutical marketed syrup having Acefyllin Piperazine, Diphenhydramine group and Aminophylline Diphenhydramine group on the basis of interquartile ranges on children. It was open label multi centric randomize control trial. The study was conducted on different private schools of East and West Malir, Karachi Pakistan with the special approval from the school's honors .informed consent and assents were taking before the enrollment of the study subjects .The study enrolled participants were 147 who evaluate on cough. Participants were divided into 3 interventional group according to the treatment regimen .One group of participant received Linkus Syrup however the 2nd group received Acefyllin Piperazine and 3rd group received Aminophylline Diphenhydramine group. The frequency of the cough on linkus syrup was considered to be achieved on the basis of interquartile relationship and impact has been observed on child and parent sleep and found significant (p <0.01).Poly herbal Linkus Syrup has the significant impact on cough frequency and associated problem on children and parent's sleep with minimum side effects (p<0.01) however the pharmacological treatments are considered to be more unwanted effects on human subjects. PMID- 28655693 TI - In vitro comparative cytotoxic effect of Nimbolide: A limonoid from Azadirachta indica (Neem tree) on cancer cell lines and normal cell lines through MTT assay. AB - The present study was conducted to find the cytotoxicity in vitro of nimbolide, limonoids derivative of flowers and leaves from Azadirachta indica (neem tree) on the selected cell lines of cancer (Du-145, PC-3, A-549) and normal fibroblast cell lines (NIH3T3, CCD-18Co) using MTT assay. The cells were seeded in 96 multi well tissue plate using different concentrations of nimbolide for 24hrs and 48hrs. The percentage of viability of cell lines was calculated by optical density obtained by micro plate reader and cytotoxic effect in term of IC50 value was determined by using linear regression analysis. The percentages of viability of cells treated with different concentrations of nimbolide were significantly lower (P<0.05) than the untreated cancer cell lines while in normal cell lines no significant difference (P>0.05) between treated and the non-treated cells was observed. Nimbolide exerted time and dose dependent cytotoxic effect on the cancer lines and mild effect on the normal cell lines. It was further confirmed through PKH 26. Results of the present study suggested nimbolide as a potent chemotherapeutic and chemopreventive agent as it exerted a more cytotoxic effect on cancer cell lines as compared with the normal cell lines. Nimbolide may be a new hope as an anticancer drug in future. PMID- 28655694 TI - Total glucosides of Curculigo rhizome to perimenopausal period mice model. AB - To investigate the effects of total glucosides of Curculigo rhizome (TGC) to perimenopausal period (PMS) mice model. After removed the bilateral ovaries induced the PMS mice model, high, medium and low doses of TGC group were partly given TGC solution 400,200,100mg*kg-1, administered once a day, continuously 21 days. Compared with the model group (MG) mices, each dose of TGC group could significantly improve the activities of mice, increase thymus, uterus, spleen index(TI, UI, SI), the levels of testosterone(T), estradiol (E2), reduce the level of luteinizing hormone (LH), the high dose of TGC group(HD-C) group has the best effects. It prompted that TGC has the effect in treatment of PMS mice model, the HD-C group of TGC has the best effects. PMID- 28655695 TI - Influences of prophylactic implantation IABP and passive emergency placement IABP in clinical prognosis of high risk of coronary bypass patients. AB - This paper aims to study the influences of prophylactic placement of intra-aortic balloon pump (IABP) and passive emergency placement of IABP on the prognosis of patients with high risk of coronary bypass. In this study, 70 patients with high risk coronary artery bypass IABP admitted to our hospital from August 2012 to August 2015 were selected and retrospectively analyzed. These patients were divided into two groups based on the timing of IABP placement, namely prophylactic placement of IABP group (group A, n=35) and passive emergency placement of IABP group (group B, n=35). In group A, the IABP running time, postoperative ventilation time, the blood transfusion, postoperative drainage, the mortality, incidence of myocardial infarction, the positive inotropic drugs auxiliary time, Intensive Care Unit (ICU) monitoring time, length of stay were all significantly less than that of group B (P<0.05). However, there was no significant differences between the two groups in the number of bypass, the incidence of postoperative complications 20.00% (7/35), 17.14% (6/35) (P>0.05). For patients with high risk of coronary bypass, prophylactic implantation of IABP is more effective in improving clinical outcomes than passive emergency placement of IABP. PMID- 28655696 TI - Ulinastatin alleviated Lps-induced injury of cardiac micro vascular endothelial Cell via NF-kappaB pathway. AB - The aim of this study to investigate the effect of ulinastatin (UTI) on lipopolysaccharide (LPS) -induced injury of cardiac micro vascular endothelial cell, and explore potential mechanisms Primary cardiac micro vascular endothelial cells were harvested from neonatal Sprague Dawley rats. Cardiac micro vascular endothelial cells were prepared for further treatment after subculture. The experiment was designed into 4 groups: Control group, LPS (0.1U/ml) group, UTI (100U/ml) group and (UTI+LPS) group. MTT assay and scratch test were performed to assess cell viability of cardiac micro vascular endothelial cells. Flow cytometry was performed to examine apoptosis. Western blot was performed to examine expression of multiple proteins, including pAkt, Bcl-2, NF-kappaB, TNF-alpha and Caspase-3. Compared with control group, LPS treatment indeed increased protein expression of Caspase-3, and resulted in significant apoptosis of cardiac micro vascular endothelial cells. Compared with LPS group, UTI+LPS group had a higher level of cell viability, verified by MTT assay and scratch test. Moreover, expressions of pAkt, NF-kappaB and Bcl-2 were decreased after UTI treatment, suggesting UTI significantly alleviated LPS induced-apoptosis of cardiac micro vascular endothelial cell via Akt/NF-kappaB pathway. Ulinastatin could protect cardiovascular system by alleviating LPS-induced injury of cardiac micro vascular endothelial cell. The potential mechanism is Akt/NF-kappaB pathway. PMID- 28655697 TI - Banana fruit pulp and peel involved in antianxiety and antidepressant effects while invigorate memory performance in male mice: Possible role of potential antioxidants. AB - The present study was aimed to investigate the anti-stress and memory enhancing effects of banana (Musa sapientum L.) fruit pulp and peel extract in male mice. Locally bred albino Wistar mice were divided into control and 2 test groups (n=10). Control rats received drinking water while test groups were treated with banana fruit pulp (600 mg/kg; oral administration) and extract of banana peel (400mg/kg; oral administration). Behavioral activities of animals were monitored 14 days post administration of banana pulp and peel extract. Depression-like symptoms were measured by forced swimming test (FST). Anxiety like behavior was monitored using light-dark activity (LDA) test and plus maze activity (PMA) test and memory functions of rats were assessed by morris water maze (MWM) test. Following 2 weeks animals were decapitated and brain was removed for estimation of antioxidant enzymes such as catalase (CAT), super oxide dismutase (SOD) and reduced glutathione (GSH). In the present study both banana peel and pulp increased the time spent in light box and open arm, suggesting anxiolytic effects. A significant decrease in immobility time was observed in FST in both banana pulp and peel treated animals suggesting antidepressant like effects. Moreover, learning and memory assessed by MWM showed decrease in time to reach platform in both short term and long term memory test suggested increased memory function in both banana pulp and peel treated animals as compared to control animals. The activities of all antioxidant enzymes were significantly (p<0.05) greater in banana pulp and peel treated animals than control. It is concluded that both banana pulp and peel have anti-anxiety, antidepressant effect as well as strengthen the memory possibly via its antioxidant mechanism. Therefore, it is recommended that supplementation of banana could be taken a vital role in stress (anxiety and depression) relief and increased in memory function possibly by phyto-antioxidants. PMID- 28655698 TI - Traumatic brain injury research and expression of caveolin-1 and its relationship with disease prognosis. AB - The objective of this paper is to study the expression of caveolin-1 in the traumatic brain injury patients and its relationship with disease prognosis. Caveolin-1 was measured in 52 patients with ventricular hemorrhage within 8h, 24h, 48h, 72h and 1 week after onset by enzyme-linked immunosorbent assay (ELISA), to observe the changes of cerebrospinal fluid caveolin-1. The level of caveolin-1 in the brain of all patients was higher than that of the control group at 8 h, 24h, 48 h, 72h and 1 weeks after the onset (P<0.05) and the level of caveolin-1 in cerebrospinal fluid (CSF) of the severe group was higher than that of the light-medium group within 8h, 24h, 48 h and 72h after the onset (P<0.05). The level of caveolin-1 in CSF was significantly increased in patients with ventricular hemorrhage within 8h, 24h, 48h, 72h and 1 weeks after onset, and the expression of caveolin-1 in brain was related to the severity of craniocerebral injury. Therefore, the expression of caveolin-1 can be used as an indicator of the prognosis of traumatic brain injury disease. PMID- 28655699 TI - Evaluation of the antiproliferative and cytotoxic activities of marine invertebrates-derived fungi. AB - The present study focuses on the evaluation of the cytotoxicity and antiproliferative activities of the organic extracts of 70 fungal strains associated with twelve Red Sea marine invertebrates. The fungal strains were obtained 10 sponges, one tunicate and one soft coral. Three different media including Sabouraud dextrose agar, malt extract agar and Czapek-Dox agar were used for the purification of the fungal isolates. The purified fungal isolates were cultured in their corresponding media (Sabouraud dextrose broth, Malt extract broth and Czapek-Dox broth) on shaker for 14 days at 26 degrees C. After that, the cultures were lyophilized and the dried cultures were extracted with methanol. The methanolic extracts of these cultures were evaluated for their in vitro cytotoxicity and antiproliferative activities against three human cancer cell lines including breast adenocarcinoma (MCF-7), liver hepatocellular carcinoma (HepG2) and colorectal carcinoma (HCT-116). Nine extracts displayed potent and selective activity against MCF-7 with IC50 4.96-8.28MU g/mL without any significant effect on the other two cell lines. In addition, six extracts showed strong and selective activity against MCF-7 with IC50 11.37-15.53MU g/mL. On the other hand, most of the fungal extracts were inactive or weakly active against HepG2 and HCT-116. PMID- 28655700 TI - Phytochemical screening and assessment of analgesic, Anti-inflammatory and hematological properties of the fruit of Berberis baluchistanica. AB - Traditionally Berberis species have been used as anti-inflammatory, anti rheumatic, analgesic and anti-anemic drugs. This study was aimed to determine chemical constituents and to assess analgesic, anti-inflammatory and hematological effects of the crude extract of the berries of Berberis baluchistanica to verify these folkloric claims. Phytochemical screening, carried out by using different chemical reagents and techniques like Thin Layer Chromatography (TLC) and Fourier Transform infra-Red (FTIR) indicated presence of flavonoids, saponins, phytosterols and carbohydrates including reducing sugars. Analgesic and anti-inflammatory activities were assessed on mice by using acetic acid induced writhing method and formalin method. Potent anti-inflammatory and analgesic effects were observed during these experiments. The extract also showed anti anemic effect as it increased the levels of hemoglobin and red blood cells significantly. Increase in the platelet count was also noted. The extract of the berries was used at oral doses of 300 and 500 mg/kg during experiments. Anti inflammatory and analgesic activities were determined by comparing with the standard i.e. aspirin 300 mg/kg. Both doses produced significant anti inflammatory and analgesic activities at P<0.05. These activities were seemingly attributable to flavonoid and saponin contents of the drug. These results justify the folkloric claims that the drug could be used as good anti-inflammatory, antirehumatic, analgesic and anti-anemic drug. However, further chemical investigations on the drug are suggested for isolation and identification of compounds that could be safer and more effective than the currently available medicines in treating these disorders. PMID- 28655701 TI - Impact of oral supplementation of Glutamate and GABA on memory performance and neurochemical profile in hippocampus of rats. AB - Glutamate (GLU) and gamma-amino butyric acid (GABA) are essential amino acids (AA) for brain function serving as excitatory and inhibitory neurotransmitter respectively. Their tablets are available in market for improving gut function and muscle performance. Despite of having a major role during memory formation and processing, effects of these tablets on brain functioning like learning and memory have not been investigated. Therefore, present study is aimed to investigate the effects of orally supplemented GLU and GABA on learning and memory performance and further to monitor related effects of these orally supplemented GLU and GABA on brain levels of these AA. Three groups of rats were supplemented orally with drinking water (control group) or suspension of tablets of GABA and Glutamate, respectively for four weeks. Cognitive performance was determined using behavioral tests (Novel object recognition test, Morris water maze, Passive avoidance test) measuring recognition, spatial reference and aversive memory. Levels of GLU, GABA and acetylcholine (ACh) were estimated in rat hippocampus. Results showed that chronic oral administration of GLU and GABA tablets has a significant impact on brain function and can alter GLU and GABA content in rat hippocampus. Compared to GABA, GLU supplementation specifically enhances memory performance via increasing ACh. Thus, GLU can be suggested as a useful supplement for improving learning and memory performance and neurochemical status of brain and in future could be effective in the treatment of neurological disorders affecting learning and memory performance. PMID- 28655702 TI - Antioxidant and wound healing potential of saponins extracted from the leaves of Algerian Urtica dioica L. AB - The Nettle is a herbaceous and vivace plant of Asian origin. It is integrated in several areas especially alimentary, agricultural, industrial and medicinal. The aim of this work is to demonstrate through pharmacological tests a possible antioxidant and wound healing effect of crude saponins of the leaves of Urtica dioica L. The extraction method is based on the degree of solubility of saponins in organic solvents. The antioxidant activity of the leaves extracts was evaluated by the diphenyl-picryl-hydrazyl test (DPPH). The wound healing effect is interpreted on the basis of the healing time and the evaluation of the surface of wounds. It appears from this study that the Nettle is rich in saponins, either 4.08% to 30 g of plant powder. The results also showed significant antioxidant effect similar to that of ascorbic acid (p> 0.05) with an IC50 of 0.159mg/ml. As regards the healing power, treatment of rats with the product based on crude saponins is achieved after 15 days, either 100% of wound reduction. This value is much higher than that obtained by the reference product (Madecassol(r)) on the same duration of treatment with 93.73% of wound reduction. The achievement of pharmacological tests has thus shown that crude saponins extracted from the leaves of Urtica dioica L. can be integrated into the pharmaceutical field or even in cosmetic. PMID- 28655703 TI - In vitro antioxidant, hepatoprotective potential and chemical profiling of Syzygium aromaticum using HPLC and GC-MS. AB - The objective of the present study was to evaluate the in vitro antioxidant and hepatoprotective potential of Syzygium aromaticum (clove) against CCl4-induced hepatotoxicity using rat liver slice culture (LSC) model. Antioxidant activity in terms of DPPH radical scavenging activity and ferric reducing antioxidant power (FRAP) of different concentrations of S. aromaticum was in the range of 41.01 90.33% and 138.15-595.63 Fe (II) mg/mL, respectively. Plasmid pBR322 DNA protection activity was observed with all three concentrations of S. aromaticum against H2O2 induced oxidative damage, as no strand breaks were observed. Chemical profiling through HPLC confirmed the presence of six major phenolic acids and 13 volatile bioactive compounds were identified though GC-MS. Significant hepatoprotection (p<0.05) was observed in liver slice culture (LSC) as liver slices treated with various concentrations of S. aromaticum extract presented very low percentage cytotoxicity (7.35-16.16%) as compared to the CCl4 treated liver slices (75.58 %). The hepatoprotective potential of S. aromaticum may be due to the presence of bioactive components as confirmed by HPLC and GC MS. The results of present study support the use of S. aromaticum in the formation of potential hepatoprotective drugs against various liver diseases. PMID- 28655704 TI - The Living the Example Social Media Substance Use Prevention Program: A Pilot Evaluation. AB - BACKGROUND: Adolescent substance use rates in rural areas of the United States, such as upstate New York, have risen substantially in recent years, calling for new intervention approaches in response to this trend. The Mentor Foundation USA conducts the Living the Example (LTE) campaign to engage youth in prevention using an experiential approach. As part of LTE, youth create their own prevention messages following a training curriculum in techniques for effective messaging and then share them via social media. This paper reports on a pilot evaluation of the LTE program. OBJECTIVE: To conduct a pilot test of LTE in two rural high schools in upstate New York. We hypothesized that positive antidrug brand representations could be promoted using social media strategies to complement the Shattering the Myths (STM) in-person, event-based approach (hypothesis 1, H1), and that youth would respond positively and engage with prevention messages disseminated by their peers. We also hypothesized that exposure to the social media prevention messages would be associated with more positive substance use avoidance attitudes and beliefs, reductions in future use intentions, and decreased substance use at posttest (hypothesis 2, H2). METHODS: We adapted a previously published curriculum created by the authors that focuses on branding, messaging, and social media for prevention. The curriculum consisted of five, one hour sessions. It was delivered to participating youth in five sequential weeks after school at the two high schools in late October and early November 2016. We designed a pre- and posttest pilot implementation study to evaluate the effects of LTE on student uptake of the intervention and short-term substance use and related outcomes. Working at two high schools in upstate New York, we conducted a pilot feasibility evaluation of LTE with 9th-grade students (ie, freshmen) at these high schools. We administered a 125-item questionnaire online to capture data on media use; attitudes toward social media; next 30-day personal drug use intentions; personal reasons to use drugs; reasons participants believe their peers would use drugs; self-reported exposure to the LTE program; and receptivity to the LTE program, among those reporting exposure. We constructed multivariable logistic regression models to analyze the relationship between program receptivity and outcomes. First, in a cross-sectional logistic regression model, we regressed self-reported LTE message receipt on drug use intent and actions related to LTE messaging. Then, for analysis of participants with matched pre- and posttest responses, we used multilevel generalized estimating equation (GEE) techniques to model changes in behavior from baseline to follow-up. RESULTS: Youth reported increased intentions to use marijuana (odds ratio [OR] 2.134, P=.02) between pre- and posttest. However, youth who reported exposure and receptivity to LTE reported a significant decrease in intentions (OR 0.239, P=.008). We observed a similar pattern for sedatives/sleeping pills-an increase in intentions overall (OR 1.886, P=.07), but a decrease among youth who reported exposure and receptivity to LTE (OR 0.210, P=.02). We saw the same pattern for use of any drug-an increase in reported intentions overall (OR 2.141, P=.02), but a decrease among youth who reported exposure and receptivity to LTE (OR 0.111, P=.004). CONCLUSIONS: We observed some evidence of significant LTE program effects. Social media may be an effective strategy for peer-to-peer substance use prevention in the future. These findings point both to the potential of LTE and the social media diffusion model and to the need for more research on a larger scale with an expanded youth population in the future. PMID- 28655705 TI - Use of New Technologies in the Prevention of Suicide in Europe: An Exploratory Study. AB - BACKGROUND: New technologies are an integral component of today's society and can complement existing suicide prevention programs. Here, we analyzed the use of new technologies in the prevention of suicide in 8 different European countries. OBJECTIVE: The aim of this paper was to assess the opinions of professionals in incorporating such resources into the design of a suicide prevention program for the region of Zamora in Spain. This investigation, encompassed within the European project entitled European Regions Enforcing Actions against Suicide (EUREGENAS), includes 11 regions from 8 different countries and attempts to advance the field of suicide prevention in Europe. METHODS: Using a specifically designed questionnaire, we assessed the opinions of 3 different groups of stakeholders regarding the use, frequency of use, facilitators, content, and format of new technologies for the prevention of suicide. The stakeholders were comprised of policy and public management professionals, professionals working in the area of mental health, and professionals related to the social area and non governmental organizations (NGOs). A total of 416 participants were recruited in 11 regions from 8 different European countries. RESULTS: The utility of the new technologies was valued positively in all 8 countries, despite these resources being seldom used in those countries. In all the countries, the factors that contributed most to facilitating the use of new technologies were accessibility and free of charge. Regarding the format of new technologies, the most widely preferred formats for use as a tool for the prevention of suicide were websites and email. The availability of information about signs of alarm and risk factors was the most relevant content for the prevention of suicide through the use of new technologies. The presence of a reference mental health professional (MHP) was also considered to be a key aspect. The countries differed in the evaluations given to the different formats suggesting that the cultural characteristics of the country should be taken into account. CONCLUSIONS: New technologies are much appreciated resources; however they are not often underused in the field of suicide prevention. The results of this exploratory study show that new technologies are indeed useful resources and should be incorporated into suicide prevention programs. PMID- 28655706 TI - Knowledge of and willingness to try acupuncture for postoperative nausea and vomiting: an Australian survey of surgical patients. AB - INTRODUCTION: Level 1 evidence supports the use of acupuncture as a safe and effective treatment for postoperative nausea and vomiting (PONV). However, to date, very few hospitals in Western countries have incorporated this technique into their management strategies. OBJECTIVE: To conduct a survey to establish patients' knowledge and opinions of acupuncture as a treatment option for the management of PONV in a large Western teaching hospital that did not offer acupuncture. METHODS: Over a 4-week period, a self-completed, anonymous questionnaire survey was distributed to 171 consecutive patients attending the preadmission clinic pending surgery. RESULTS: Overall, 161 participants met the selection criteria and completed the survey (100%). The majority of them had a European background (88.8%) and were over 40 years old (87.6%). Seventy-eight participants (48%) had a history of nausea and vomiting and 39 (24%) had suffered from PONV. One hundred and four (65%) and 110 (68%) patients, respectively, stated that they would be willing to try acupuncture in hospital or at home following surgery to prevent or reduce PONV. Only 25 (15.5%) participants knew that acupuncture could be used to treat nausea and vomiting; however, 140 (87%) indicated that they would be willing to try the therapy after being informed of the potential benefit of acupuncture for PONV prevention/reduction. Those with previous experience of acupuncture were ~3.9 times more likely to be willing to use acupuncture for PONV than those without. CONCLUSION: Patients attending an Australian tertiary hospital showed an overwhelming interest in acupuncture to manage PONV. This provides strong support for the potential implementation of acupuncture in an acute hospital setting. PMID- 28655707 TI - David Oliver: What might the Queen's speech mean for hospital doctors? PMID- 28655708 TI - Characteristics and Outcomes of In-Hospital Palliative Care Consultation among Patients with Renal Disease Versus Other Serious Illnesses. AB - BACKGROUND AND OBJECTIVES: Despite significant morbidity and mortality associated with ESRD, these patients receive palliative care services much less often than patients with other serious illnesses, perhaps because they are perceived as having less need for such services. We compared characteristics and outcomes of hospitalized patients in the United States who had a palliative care consultation for renal disease versus other serious illnesses. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational study, we used data collected by the Palliative Care Quality Network, a national palliative care quality improvement collaborative. The 23-item Palliative Care Quality Network core dataset includes demographics, processes of care, and clinical outcomes of all hospitalized patients who received a palliative care consultation between December of 2012 and March of 2016. RESULTS: The cohort included 33,183 patients, of whom 1057 (3.2%) had renal disease as the primary reason for palliative care consultation. Mean age was 71.9 (SD=16.8) or 72.8 (SD=15.2) years old for those with renal disease or other illnesses, respectively. At the time of consultation, patients with renal disease or other illnesses had similarly low mean Palliative Performance Scale scores (36.0% versus 34.9%, respectively; P=0.08) and reported similar moderate to severe anxiety (14.9% versus 15.3%, respectively; P=0.90) and nausea (5.9% versus 5.9%, respectively; P>0.99). Symptoms improved similarly after consultation regardless of diagnosis (P>=0.50), except anxiety, which improved more often among those with renal disease (92.0% versus 66.0%, respectively; P=0.002). Although change in code status was similar among patients with renal disease versus other illnesses, from over 60% full code initially to 30% full code after palliative care consultation, fewer patients with renal disease were referred to hospice than those with other illnesses (30.7% versus 37.6%, respectively; P<0.001). CONCLUSIONS: Hospitalized patients with renal disease referred for palliative care consultation had similar palliative care needs, improved symptom management, and clarification of goals of care as those with other serious illnesses. PMID- 28655709 TI - National Differences in Trends for Heart Failure Hospitalizations by Sex and Race/Ethnicity. AB - BACKGROUND: National heart failure (HF) hospitalization rates have not been appropriately age standardized by sex or race/ethnicity. Reporting hospital utilization trends by subgroup is important for monitoring population health and developing interventions to eliminate disparities. METHODS AND RESULTS: The National Inpatient Sample (NIS) was used to estimate the crude and age standardized rates of HF hospitalization between 2002 and 2013 by sex and race/ethnicity. Direct standardization was used to age-standardize rates to the 2000 US standard population. Relative differences between subgroups were reported. The national age-adjusted HF hospitalization rate decreased 30.8% from 526.86 to 364.66 per 100 000 between 2002 and 2013. Although hospitalizations decreased for all subgroups, the ratio of the age-standardized rate for men compared with women increased from 20% greater to 39% (P trend=0.002) between 2002 and 2013. Black men had a rate that was 229% (P trend=0.141) and black women, 240% (P trend=0.725) with reference to whites in 2013 with no significant change between 2002 and 2013. Hispanic men had a rate that was 32% greater in 2002 and the difference narrowed to 4% (P trend=0.047) greater in 2013 relative to whites. For Hispanic women, the rate was 55% greater in 2002 and narrowed to 8% greater (P trend=0.004) in 2013 relative to whites. Asian/Pacific Islander men had a 27% lower rate in 2002 that improved to 43% (P trend=0.040) lower in 2013 relative to whites. For Asian/Pacific Islander women, the hospitalization rate was 24% lower in 2002 and improved to 43% (P trend=0.021) lower in 2013 relative to whites. CONCLUSIONS: National HF hospitalization rates have decreased steadily during the recent decade. Disparities in HF burden and hospital utilization by sex and race/ethnicity persist. Significant population health interventions are needed to reduce the HF hospitalization burden among blacks. An evaluation of factors explaining the improvements in the HF hospitalization rates among Hispanics and Asian/Pacific Islanders is needed. PMID- 28655710 TI - Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxaloacetate transaminase against stroke. AB - In the pathophysiologic setting of cerebral ischemia, excitotoxic levels of glutamate contribute to neuronal cell death. Our previous work demonstrated the ability of glutamate oxaloacetate transaminase (GOT) to metabolize neurotoxic glutamate in the stroke-affected brain. Here, we seek to identify small-molecule inducers of GOT expression to mitigate ischemic stroke injury. From a panel of phytoestrogen isoflavones, biochanin A (BCA) was identified as the most potent inducer of GOT gene expression in neural cells. BCA significantly increased GOT mRNA and protein expression at 24 h and protected against glutamate-induced cell death. Of note, this protection was lost when GOT was knocked down. To validate outcomes in vivo, C57BL/6 mice were intraperitoneally injected with BCA (5 and 10 mg/kg) for 4 wk and subjected to ischemic stroke. BCA levels were significantly increased in plasma and brain of mice. Immunohistochemistry demonstrated increased GOT protein expression in the brain. BCA attenuated stroke lesion volume as measured by 9.4T MRI and improved sensorimotor function-this protection was lost with GOT knockdown. BCA increased luciferase activity in cells that were transfected with the pERRE3tk-LUC plasmid, which demonstrated transactivation of GOT. This increase was lost when estrogen-related receptor response element sites were mutated. Taken together, BCA represents a natural phytoestrogen that mitigates stroke-induced injury by inducing GOT expression.-Khanna, S., Stewart, R., Gnyawali, S., Harris, H., Balch, M., Spieldenner, J., Sen, C. K., Rink, C. Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxaloacetate transaminase against stroke. PMID- 28655711 TI - Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis via sponging microRNA-150. AB - The function of most human long noncoding RNAs (lncRNAs) remains unclear. Our studies identified a highly up-regulated mammalian lncRNA, FOXD3-AS1, known as linc1623 in mice, in the setting of hyperoxia/reactive oxygen species (ROS) induced lung injury. We found that ROS induced a robust expression of FOXD3-AS1 in mouse lung tissue. Functionally, FOXD3-AS1 promoted oxidative stress-induced lung epithelial cell death. In human lung epithelial cells, the microRNA-150 (miR 150) was identified to interact with FOXD3-AS1; this finding was confirmed using the luciferase reporter assays. Consistently, mutation on the miR-150 pairing sequence in FOXD3-AS1 abolished the interactions between FOXD3-AS1 and miR-150. Additionally, miR-150 mimics suppressed the level of FOXD3-AS1. The antisense oligos of FOXD3-AS1 significantly augmented the intracellular level of miR-150, supporting the theory of sponging effects of FOXD3-AS1 on miR-150. We further investigated the cellular function of miR-150 in our lung injury models. MiR-150 conferred a cytoprotective role in lung epithelial cells after oxidative stress, whereas FOXD3-AS1 promoted cell death. Taken together, our studies indicated that FOXD3-AS1 serves as a sponge or as a competing endogenous noncoding RNA for miR 150, restricting its capability to promote cell growth and thereby exaggerating hyperoxia-induced lung epithelial cell death.-Zhang, D., Lee, H., Haspel, J. A., Jin, Y. Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis via sponging microRNA-150. PMID- 28655712 TI - BRAF-inhibitor Associated MEK Mutations Increase RAF-Dependent and -Independent Enzymatic Activity. AB - Alterations in MEK1/2 occur in cancers, both in the treatment-naive state and following targeted therapies, most notably BRAF and MEK inhibitors in BRAF-V600E mutant melanoma and colorectal cancer. Efforts were undertaken to understand the effects of these mutations, based upon protein structural location, and MEK1/2 activity. Two categories of MEK1/2 alterations were evaluated, those associated with either the allosteric pocket or helix-A. Clinically, MEK1/2 alterations of the allosteric pocket are rare and we demonstrate that they confer resistance to MEK inhibitors, while retaining sensitivity to BRAF inhibition. Most mutations described in patients fall within, or are associated with, helix-A. Mutations in this region reduce sensitivity to both BRAF and MEK inhibition and display elevated phospho-ERK1/2 levels, independent from increases in phospho-MEK1/2. Biochemical experiments with a representative helix-A variant, MEK1-Q56P, reveal both increased catalytic efficiency of the activated enzyme, and phosphorylation independent activity relative to wild-type MEK1. Consistent with these findings, MEK1/2 alterations in helix A retain sensitivity to downstream antagonism via pharmacologic inhibition of ERK1/2. This work highlights the importance of classifying mutations based on structural and phenotypic consequences, both in terms of pathway signaling output and response to pharmacologic inhibition.Implications: This study suggests that alternate modes of target inhibition, such as ERK inhibition, will be required to effectively treat tumors harboring these MEK1/2-resistant alleles. Mol Cancer Res; 15(10); 1431-44. (c)2017 AACR. PMID- 28655713 TI - Peers without fears? Barriers to effective communication among primary care physicians and oncologists about diagnostic delays in cancer. AB - OBJECTIVE: Relatively little attention has been devoted to the role of communication between physicians as a mechanism for individual and organisational learning about diagnostic delays. This study's objective was to elicit physicians' perceptions about and experiences with communication among physicians regarding diagnostic delays in cancer. DESIGN, SETTING, PARTICIPANTS: Qualitative analysis based on seven focus groups. Fifty-one physicians affiliated with three New York-based academic medical centres participated, with six to nine subjects per group. We used content analysis to identify commonalities among primary care physicians and specialists (ie, medical and surgical oncologists). PRIMARY OUTCOME MEASURE: Perceptions and experiences with physician-to-physician communication about delays in cancer diagnosis. RESULTS: Our analysis identified five major themes: openness to communication, benefits of communication, fears about giving and receiving feedback, infrastructure barriers to communication and overcoming barriers to communication. Subjects valued communication about cancer diagnostic delays, but they had many concerns and fears about providing and receiving feedback in practice. Subjects expressed reluctance to communicate if there was insufficient information to attribute responsibility, if it would have no direct benefit or if it would jeopardise their existing relationships. They supported sensitive approaches to conveying information, as they feared eliciting or being subject to feelings of incompetence or shame. Subjects also cited organisational barriers. They offered suggestions that might facilitate communication about delays. CONCLUSIONS: Addressing the barriers to communication among physicians about diagnostic delays is needed to promote a culture of learning across specialties and institutions. Supporting open and honest discussions about diagnostic delays may help build safer health systems. PMID- 28655714 TI - Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice. AB - Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation. PMID- 28655715 TI - Incretin secretion in humans is under the influence of cannabinoid receptors. AB - The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to evaluate GIP and GLP-1 responses during OGTT after administering placebo or nabilone (CBR agonist) in a randomized, double-blind, crossover fashion. Compared with the BLSA lean group, the BLSA obese group had significantly higher fasting and post-OGTT GIP levels, but similar fasting GLP-1 and significantly lower post-OGTT GLP-1 levels. In the nabilone vs. placebo study, when compared with placebo, nabilone resulted in significantly elevated post-dose fasting GIP levels and post-OGTT GIP levels, but no change in post-dose fasting GLP-1 levels together with significantly lower post-OGTT GLP-1 levels. Glucose levels were not different with both interventions. We conclude that elevated GIP levels in obesity are likely a consequence of increased endocannabinoid levels. CBRs exert tonic control over GIP secretion, which may have a homeostatic effect in suppressing GLP-1 secretion. This raises the possibility that gut hormones are influenced by endocannabinoids. PMID- 28655718 TI - Lipid remodeling and an altered membrane-associated proteome may drive the differential effects of EPA and DHA treatment on skeletal muscle glucose uptake and protein accretion. AB - In striated muscle, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on the metabolism of glucose and differential effects on the metabolism of protein. We have shown that, despite similar incorporation, treatment of C2C12 myotubes (CM) with EPA but not DHA improves glucose uptake and protein accretion. We hypothesized that these differential effects of EPA and DHA may be due to divergent shifts in lipidomic profiles leading to altered proteomic profiles. We therefore carried out an assessment of the impact of treating CM with EPA and DHA on lipidomic and proteomic profiles. Fatty acid methyl esters (FAME) analysis revealed that both EPA and DHA led to similar but substantials changes in fatty acid profiles with the exception of arachidonic acid, which was decreased only by DHA, and docosapentanoic acid (DPA), which was increased only by EPA treatment. Global lipidomic analysis showed that EPA and DHA induced large alterations in the cellular lipid profiles and in particular, the phospholipid classes. Subsequent targeted analysis confirmed that the most differentially regulated species were phosphatidylcholines and phosphatidylethanolamines containing long-chain fatty acids with five (EPA treatment) or six (DHA treatment) double bonds. As these are typically membrane-associated lipid species we hypothesized that these treatments differentially altered the membrane associated proteome. Stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics of the membrane fraction revealed significant divergence in the effects of EPA and DHA on the membrane-associated proteome. We conclude that the EPA-specific increase in polyunsaturated long-chain fatty acids in the phospholipid fraction is associated with an altered membrane-associated proteome and these may be critical events in the metabolic remodeling induced by EPA treatment. PMID- 28655716 TI - Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice. AB - Females are, in general, more insulin sensitive than males. To investigate whether this is a direct effect of sex-steroids (SS) in white adipose tissue (WAT), we developed a male mouse model overexpressing the aromatase enzyme, converting testosterone (T) to estradiol (E2), specifically in WAT (Ap2-arom mice). Adipose tissue E2 levels were increased while circulating SS levels were unaffected in male Ap2-arom mice. Importantly, male Ap2-arom mice were more insulin sensitive compared with WT mice and exhibited increased serum adiponectin levels and upregulated expression of Glut4 and Irs1 in WAT. The expression of markers of macrophages and immune cell infiltration was markedly decreased in WAT of male Ap2-arom mice. The adipogenesis was enhanced in male Ap2-arom mice, supported by elevated Pparg expression in WAT and enhanced differentiation of preadipocyte into mature adipocytes. In summary, increased adipose tissue aromatase activity reduces adipose tissue inflammation and improves insulin sensitivity in male mice. We propose that estrogen increases insulin sensitivity via a local effect in WAT on adiponectin expression, adipose tissue inflammation, and adipogenesis. PMID- 28655717 TI - Deletion of UCP1 enhances ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction. AB - Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin resistance (IR) despite no significant differences in BAT UCP1 content. UCP1 ablation increased HOMA-IR, AT-IR, and whitening of BAT in both sexes. Expression of UCP1 in thoracic aorta was greater in wild-type females compared with males. Importantly, deletion of UCP1 enhanced aortic vasomotor function in females only. UCP1 ablation did not promote oxidative stress in interscapular BAT. Furthermore, daily administration of the free radical scavenger tempol for 8 wk did not abrogate UCP1 deficiency-induced increases in adiposity, hyperinsulinemia, or liver steatosis. Collectively, we report that 1) in normal chow-fed mice housed at 25 degrees C, aortic UCP1 content was greater in females than males and its deletion improved ex vivo aortic vasomotor function in females only; 2) constitutive UCP1 content in BAT was similar between females and males and loss of UCP1 did not abolish sex differences in insulin sensitivity; and 3) the metabolic disruptions caused by UCP1 ablation did not appear to be contingent upon increased oxidative stress in mice under normal dietary conditions. PMID- 28655719 TI - Engineering a monomeric variant of macrophage colony-stimulating factor (M-CSF) that antagonizes the c-FMS receptor. AB - Enhanced activation of the signaling pathways that mediate the differentiation of mononuclear monocytes into osteoclasts is an underlying cause of several bone diseases and bone metastasis. In particular, dysregulation and overexpression of macrophage colony-stimulating factor (M-CSF) and its c-FMS tyrosine kinase receptor, proteins that are essential for osteoclast differentiation, are known to promote bone metastasis and osteoporosis, making both the ligand and its receptor attractive targets for therapeutic intervention. With this aim in mind, our starting point was the previously held concept that the potential of the M CSFC31S mutant as a therapeutic is derived from its inability to dimerize and hence to act as an agonist. The current study showed, however, that dimerization is not abolished in M-CSFC31S and that the protein retains agonistic activity toward osteoclasts. To design an M-CSF mutant with diminished dimerization capabilities, we solved the crystal structure of the M-CSFC31S dimer complex and used structure-based energy calculations to identify the residues responsible for its dimeric form. We then used that analysis to develop M-CSFC31S,M27R, a ligand based, high-affinity antagonist for c-FMS that retained its binding ability but prevented the ligand dimerization that leads to receptor dimerization and activation. The monomeric properties of M-CSFC31S,M27R were validated using dynamic light scattering and small-angle X-ray scattering analyses. It was shown that this mutant is a functional inhibitor of M-CSF-dependent c-FMS activation and osteoclast differentiation in vitro Our study, therefore, provided insights into the sequence-structure-function relationships of the M-CSF/c-FMS interaction and of ligand/receptor tyrosine kinase interactions in general. PMID- 28655720 TI - Are millennial GPs shunning full time working? PMID- 28655721 TI - Sixty seconds on ... snakebite. PMID- 28655724 TI - BMA annual meeting: BMA will work to ensure patients have timely access to wheelchairs. PMID- 28655722 TI - Patients may have been put at risk from L6m patient data mix-up, review says. PMID- 28655725 TI - Chemical chaperone 4-phenyl butyric acid (4-PBA) reduces hepatocellular lipid accumulation and lipotoxicity through induction of autophagy. AB - Defective autophagy has been linked to lipotoxicity in several cellular models. We aimed to investigate autophagy in lipid-stimulated hepatoma (Huh7) cells and tested whether 4-phenyl butyric acid (4-PBA), a chemical chaperone, has a beneficial role in hepatic fat accumulation and lipotoxicity. We report that long term (24 h) exposure of hepatocytes to palmitate block autophagic flux that leads to lipid accumulation and cell death. Western blotting analysis showed increased accumulation of SQSTM1/p62, and decreased expression of Beclin1 and Atg7 in palmitate-treated cells. Autophagy inhibition by 3-methyladenine (3-MA) in palmitate-treated cells neither increased SQSTMI/p62 accumulation nor cell death, thus suggesting complete blockade of autophagy by palmitate. 4-PBA reduced lipid accumulation and cell death that were associated with restoration of autophagy. siRNA-mediated knockdown of Atg7 and presence of autophagy inhibitors, 3-MA and chloroquine, resulted in the decrease in lipid-lowering effect of 4-PBA, suggesting that 4-PBA mediates its lipid-lowering effect via autophagy. Apoptotic parameters, including altered Bcl2:Bax ratio and PARP1 cleavage induced by palmitate, were improved by 4-PBA. Our results indicate that palmitate impairs autophagy and increases lipid accumulation in Huh7 cells, whereas 4-PBA plays a protective role in lipid accumulation and lipotoxicity through activation of autophagy. PMID- 28655727 TI - FDA Partners with ASCO's CancerLinQ. AB - A partnership between the FDA and the American Society of Clinical Oncology's CancerLinQ provides regulators with timely, real-world data on newly approved cancer therapies. The alliance may help investigators gain insights and assess the impact of drugs in patient populations that are not well represented in traditional clinical trials. PMID- 28655726 TI - High density lipoproteins and type 2 inflammatory biomarkers are negatively correlated in atopic asthmatics. AB - Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys(r) periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma. PMID- 28655728 TI - Opioid use during pregnancy: a population-based cohort study. AB - BACKGROUND: Opioid use has increased dramatically in North America. The safety of opioids in pregnancy is uncertain, but they are associated with several fetal abnormalities and contribute to rising rates of neonatal abstinence syndrome. We examined opioid use before and during pregnancy in a complete population-based cohort. METHODS: We examined opioid use in a cohort of all pregnant women in Manitoba, Canada, from 2001 to 2013. Opioid use was defined by prescriptions for opioids, converted to oral morphine equivalents (MEQ), during the 3 months before pregnancy and for each trimester. Given that the exposure per person may vary (because not all women complete all time periods), we determined a weighted number of pregnancies in each period. RESULTS: During the study period, 174 848 completed pregnancies were eligible for analysis (173 680 live births and 1168 stillbirths and intrauterine deaths), which represented a weighted value of 175 174 pregnancies. Among these pregnancies, 6.7% of the women filled opioid prescriptions in the 3 months before pregnancy. Use declined to 4.2% during the first trimester and further declined to 3.0% and 2.9% in the second and third trimesters, respectively. Over the study period, there was a modest increase in opioid use overall (from 7.3% to 7.7%). MEQ did not decline during pregnancy, and the mean MEQ increased significantly over the study period (from 284 mg to 1218 mg). Prescriptions for codeine were filled by 96.9% of the users, accounting for 66.2% of MEQ. INTERPRETATION: Although many of the women using opioids before pregnancy discontinued or reduced use of these drugs during pregnancy, the volume of opioids consumed by those who continued opioid use did not decline during pregnancy. The increasing dosage and increased use of higher-potency opioids by pregnant women highlights the need for continued evaluation of and education about the benefits and risks of this practice. PMID- 28655729 TI - Corneal collagen cross-linking in paediatric patients affected by keratoconus. AB - BACKGROUND/AIMS: To evaluate the effectiveness of corneal collagen cross-linking (CXL) in paediatric patients. METHODS: Fifty-two eyes of 43 paediatric patients with progressive keratoconus were enrolled in a prospective cohort study. Corneal CXL was performed using a conventional technique with instillation of 0.1% riboflavin solution containing dextran 20% for 30 min during the soaking phase and during the 30 min ultraviolet A irradiation (3 mW/cm2). Visual outcomes, topographic keratometry, maximum keratometry (K-max), refractive astigmatism, demarcation line and endothelial cell density were measured postoperatively. RESULTS: A significant decrease of K-max from 59.30+/-7.08 to 57.07+/-6.46 (p<0.001) was observed 2 years after treatment. Uncorrected visual acuity improved from 0.59+/-0.41 LogMAR (logarithm of the minimum angle resolution) to 0.46+/-0.33 LogMAR (p=0.06) 2 years after the procedure, while best spectacle corrected visual acuity improved from 0.17+/-0.11 LogMAR to 0.15+/-0.12 LogMAR (p=0.17). Twenty-five eyes had K-max values of 60 dioptres (D) or greater. In this subgroup, K-max significantly decreased from 64.94+/-4.99 D to 62.25+/-4.42 D at 2 years (p<0.001). The demarcation line of the CXL treatment had a mean value of 249+/-74 um and did not show a significant correlation with K-max flattening (Spearman r=0.019, p=0.899). Endothelial cell density remained stable 2 years after the procedure, changing from 2800+/-363 to 2736+/-659 cells/mm2 (p=0.90). CONCLUSION: CXL is an effective treatment for avoiding keratoconus progression in paediatric patients. The procedure is safe and successful in stabilising keratoconus in eyes with more advanced forms of the disease, characterised by topographic K-max values greater than 60 D. PMID- 28655730 TI - Costs of a community-based glaucoma detection programme: analysis of the Philadelphia Glaucoma Detection and Treatment Project. AB - BACKGROUND: Glaucoma is the foremost cause of irreversible blindness, and more than 50% of cases remain undiagnosed. Our objective was to report the costs of a glaucoma detection programme operationalised through Philadelphia community centres. METHODS: The analysis was performed using a healthcare system perspective in 2013 US dollars. Costs of examination and educational workshops were captured. Measures were total programme costs, cost/case of glaucoma detected and cost/case of any ocular disease detected (including glaucoma). Diagnoses are reported at the individual level (therefore representing a diagnosis made in one or both eyes). Staff time was captured during site visits to 15 of 43 sites and included time to deliver examinations and workshops, supervision, training and travel. Staff time was converted to costs by applying wage and fringe benefit costs from the US Bureau of Labor Statistics. Non-staff costs (equipment and mileage) were collected using study logs. Participants with previously diagnosed glaucoma were excluded. RESULTS: 1649 participants were examined. Mean total per-participant examination time was 56 min (SD 4). Mean total examination cost/participant was $139. The cost/case of glaucoma newly identified (open-angle glaucoma, angle-closure glaucoma, glaucoma suspect, or primary angle closure) was $420 and cost/case for any ocular disease identified was $273. CONCLUSION: Glaucoma examinations delivered through this programme provided significant health benefit to hard-to-reach communities. On a per-person basis, examinations were fairly low cost, though opportunities exist to improve efficiency. Findings serve as an important benchmark for planning future community-based glaucoma examination programmes. PMID- 28655731 TI - Ultra-low-dose intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case series. AB - BACKGROUND: Intravitreal bevacizumab (IVB) has emerged as an effective treatment modality for the management of retinopathy of prematurity (ROP) where the disease is severe and posterior. Despite evidence of systemic vascular endothelial growth factor suppression and concerns about how this might affect the developing neonate, the optimal dose is unknown to date. We report our experience of using ultra-low-dose (0.16 mg) IVB, one-quarter of the 'standard' dose that has widely been reported in the treatment of ROP. METHODS: A retrospective observational case series of consecutive infants who underwent ultra-low-dose IVB injection for the management of ROP at a regional neonatal intensive care unit in the North East of England, between November 2013 and August 2016. RESULTS: 29 eyes of 15 infants underwent IVB injection. We defined 'treatment success' as complete regression of retinopathy and vascularisation into (or laser ablation of) zone 3. Primary success (in response to IVB 0.16 mg alone) was observed in 23/29 eyes (79.3%). Secondary success (where additional treatment was required) was observed in 27/29 eyes (93.1%). One infant died of respiratory disease during follow-up. Retreatment occurred in 6/29 eyes (20.6%). Retreatments occurred at a mean of 9.8 weeks after initial IVB (range 6-15) and at a mean of 44 weeks postmenstrual age (range 40-50). CONCLUSION: 0.16 mg IVB is effective in the treatment of severe and posterior ROP, with no adverse ocular outcomes occurring in our series. PMID- 28655732 TI - Chemical Tools for Studying Lipid-Binding Class A G Protein-Coupled Receptors. AB - Cannabinoid, free fatty acid, lysophosphatidic acid, sphingosine 1-phosphate, prostanoid, leukotriene, bile acid, and platelet-activating factor receptor families are class A G protein-coupled receptors with endogenous lipid ligands. Pharmacological tools are crucial for studying these receptors and addressing the many unanswered questions surrounding expression of these receptors in normal and diseased tissues. An inherent challenge for developing tools for these lipid receptors is balancing the often lipophilic requirements of the receptor-binding pharmacophore with favorable physicochemical properties to optimize highly specific binding. In this study, we review the radioligands, fluorescent ligands, covalent ligands, and antibodies that have been used to study these lipid-binding receptors. For each tool type, the characteristics and design rationale along with in vitro and in vivo applications are detailed. PMID- 28655733 TI - Transcatheter Aortic Valve Implantation With or Without Percutaneous Coronary Artery Revascularization Strategy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Recent recommendations suggest that in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation and coexistent significant coronary artery disease, the latter should be treated before the index procedure; however, the evidence basis for such an approach remains limited. We performed a systematic review and meta-analysis to study the clinical outcomes of patients with coronary artery disease who did or did not undergo revascularization prior to transcatheter aortic valve implantation. METHODS AND RESULTS: We conducted a search of Medline and Embase to identify studies evaluating patients who underwent transcatheter aortic valve implantation with or without percutaneous coronary intervention. Random-effects meta-analyses with the inverse variance method were used to estimate the rate and risk of adverse outcomes. Nine studies involving 3858 participants were included in the meta analysis. Patients who underwent revascularization with percutaneous coronary intervention had a higher rate of major vascular complications (odd ratio [OR]: 1.86; 95% confidence interval [CI], 1.33-2.60; P=0.0003) and higher 30-day mortality (OR: 1.42; 95% CI, 1.08-1.87; P=0.01). There were no differences in effect estimates for 30-day cardiovascular mortality (OR: 1.03; 95% CI, 0.35 2.99), myocardial infarction (OR: 0.86; 95% CI, 0.14-5.28), acute kidney injury (OR: 0.89; 95% CI, 0.42-1.88), stroke (OR: 1.07; 95% CI, 0.38-2.97), or 1-year mortality (OR: 1.05; 95% CI, 0.71-1.56). The timing of percutaneous coronary intervention (same setting versus a priori) did not negatively influence outcomes. CONCLUSIONS: Our analysis suggests that revascularization before transcatheter aortic valve implantation confers no clinical advantage with respect to several patient-important clinical outcomes and may be associated with an increased risk of major vascular complications and 30-day mortality. In the absence of definitive evidence, careful evaluation of patients on an individual basis is of paramount importance to identify patients who might benefit from elective revascularization. PMID- 28655734 TI - Life's Simple 7 and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: The American Heart Association introduced the Life's Simple 7 (LS7) metrics to assess and promote cardiovascular health. We sought to examine the association between the LS7 metrics and incident heart failure (HF) in a multiethnic cohort. METHODS AND RESULTS: We analyzed data from 6506 participants of the Multi-Ethnic Study of Atherosclerosis free of cardiovascular disease at baseline. The LS7 metrics (smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose) were graded on a scale of 0 to 2, with 2 indicating "ideal" status, 1 "intermediate" status, and 0 "poor" status. Points were summed, thus the LS7 score ranged from 0 to 14. Cox proportional hazard ratios and incidence rates of HF per 1000 person-years were calculated. During a median follow-up of 12.2 years, 262 (4%) participants developed HF. Incidence of HF decreased as the number of ideal LS7 metrics increased; 5.9 per 1000 person-years for participants with 0 to 1 ideal metrics and 0.6 per 1000 person-years for those with 6 to 7 ideal metrics. Compared with inadequate scores (0-8 points), hazard ratios for HF were 0.57 (0.43-0.76) and 0.31 (0.19-0.49) for average (9-10 points) and optimal (11-14 points) scores, respectively. A similar pattern was observed when the results were stratified by 4 racial/ethnic groups: white, Chinese American, black, and Hispanic. CONCLUSIONS: A lower risk of HF with more favorable LS7 status regardless of race/ethnicity suggests that efforts to achieve ideal cardiovascular health may reduce the burden of HF, a major source of morbidity and mortality. PMID- 28655736 TI - Does Tail-Cuff Plethysmography Provide a Reliable Estimate of Central Blood Pressure in Mice? PMID- 28655735 TI - Tail-Cuff Technique and Its Influence on Central Blood Pressure in the Mouse. AB - BACKGROUND: Reliable measurement of blood pressure in conscious mice is essential in cardiovascular research. Telemetry, the "gold-standard" technique, is invasive and expensive and therefore tail-cuff, a noninvasive alternative, is widely used. However, tail-cuff requires handling and restraint during measurement, which may cause stress affecting blood pressure and undermining reliability of the results. METHODS AND RESULTS: C57Bl/6J mice were implanted with radio-telemetry probes to investigate the effects of the steps of the tail-cuff technique on central blood pressure, heart rate, and temperature. This included comparison of handling techniques, operator's sex, habituation, and influence of hypertension induced by angiotensin II. Direct comparison of measurements obtained by telemetry and tail cuff were made in the same mouse. The results revealed significant increases in central blood pressure, heart rate, and core body temperature from baseline following handling interventions without significant difference among the different handling technique, habituation, or sex of the investigator. Restraint induced the largest and sustained increase in cardiovascular parameters and temperature. The tail-cuff readings significantly underestimated those from simultaneous telemetry recordings; however, "nonsimultaneous" telemetry, obtained in undisturbed mice, were similar to tail-cuff readings obtained in undisturbed mice on the same day. CONCLUSIONS: This study reveals that the tail-cuff technique underestimates the core blood pressure changes that occur simultaneously during the restraint and measurement phases. However, the measurements between the 2 techniques are similar when tail-cuff readings are compared with telemetry readings in the nondisturbed mice. The differences between the simultaneous recordings by the 2 techniques should be recognized by researchers. PMID- 28655737 TI - Evaluation and Design of Genome-Wide CRISPR/SpCas9 Knockout Screens. AB - The adaptation of CRISPR/SpCas9 technology to mammalian cell lines is transforming the study of human functional genomics. Pooled libraries of CRISPR guide RNAs (gRNAs) targeting human protein-coding genes and encoded in viral vectors have been used to systematically create gene knockouts in a variety of human cancer and immortalized cell lines, in an effort to identify whether these knockouts cause cellular fitness defects. Previous work has shown that CRISPR screens are more sensitive and specific than pooled-library shRNA screens in similar assays, but currently there exists significant variability across CRISPR library designs and experimental protocols. In this study, we reanalyze 17 genome scale knockout screens in human cell lines from three research groups, using three different genome-scale gRNA libraries. Using the Bayesian Analysis of Gene Essentiality algorithm to identify essential genes, we refine and expand our previously defined set of human core essential genes from 360 to 684 genes. We use this expanded set of reference core essential genes, CEG2, plus empirical data from six CRISPR knockout screens to guide the design of a sequence-optimized gRNA library, the Toronto KnockOut version 3.0 (TKOv3) library. We then demonstrate the high effectiveness of the library relative to reference sets of essential and nonessential genes, as well as other screens using similar approaches. The optimized TKOv3 library, combined with the CEG2 reference set, provide an efficient, highly optimized platform for performing and assessing gene knockout screens in human cell lines. PMID- 28655738 TI - Two Variants in SLC24A5 Are Associated with "Tiger-Eye" Iris Pigmentation in Puerto Rican Paso Fino Horses. AB - A unique eye color, called tiger-eye, segregates in the Puerto Rican Paso Fino (PRPF) horse breed and is characterized by a bright yellow, amber, or orange iris. Pedigree analysis identified a simple autosomal recessive mode of inheritance for this trait. A genome-wide association study (GWAS) with 24 individuals identified a locus on ECA 1 reaching genome-wide significance (Pcorrected = 1.32 * 10-5). This ECA1 locus harbors the candidate gene, Solute Carrier Family 24 (Sodium/Potassium/Calcium Exchanger), Member 5 (SLC24A5), with known roles in pigmentation in humans, mice, and zebrafish. Humans with compound heterozygous mutations in SLC24A5 have oculocutaneous albinism (OCA) type 6 (OCA6), which is characterized by dilute skin, hair, and eye pigmentation, as well as ocular anomalies. Twenty tiger-eye horses were homozygous for a nonsynonymous mutation in exon 2 (p.Phe91Tyr) of SLC24A5 (called here Tiger-eye 1), which is predicted to be deleterious to protein function. Additionally, eight of the remaining 12 tiger-eye horses heterozygous for the p.Phe91Tyr variant were also heterozygous for a 628 bp deletion encompassing all of exon 7 of SLC24A5 (c.875-340_1081+82del), which we will call here the Tiger-eye 2 allele. None of the 122 brown-eyed horses were homozygous for either tiger-eye-associated allele or were compound heterozygotes. Further, neither variant was detected in 196 horses from four related breeds not known to have the tiger-eye phenotype. Here, we propose that two mutations in SLC24A5 affect iris pigmentation in tiger-eye PRPF horses. Further, unlike OCA6 in humans, the Tiger-eye 1 mutation in its homozygous state or as a compound heterozygote (Tiger-eye 1/Tiger-eye 2) does not appear to cause ocular anomalies or a change in coat color in the PRPF horse. PMID- 28655739 TI - Genome-Wide Associations for Water-Soluble Carbohydrate Concentration and Relative Maturity in Wheat Using SNP and DArT Marker Arrays. AB - Improving water-use efficiency by incorporating drought avoidance traits into new wheat varieties is an important objective for wheat breeding in water-limited environments. This study uses genome wide association studies (GWAS) to identify candidate loci for water-soluble carbohydrate accumulation-an important drought avoidance characteristic in wheat. Phenotypes from a multi-environment trial with experiments differing in water availability and separate single nucleotide polymorphism (SNP) and diversity arrays technology (DArT) marker sets were used to perform the analyses. Significant associations for water-soluble carbohydrate accumulation were identified on chromosomes 1A, 1B, 1D, 2D, and 4A. Notably, these loci did not collocate with the major loci identified for relative maturity. Loci on chromosome 1D collocated with markers previously associated with the high molecular weight glutenin Glu-D1 locus. Genetic * environmental interactions impacted the results strongly, with significant associations for carbohydrate accumulation identified only in the water-deficit experiments. The markers associated with carbohydrate accumulation may be useful for marker assisted selection of drought tolerance in wheat. PMID- 28655740 TI - Diabetes in a Large Dementia Cohort: Clinical Characteristics and Treatment From the Swedish Dementia Registry. AB - OBJECTIVE: We aimed to investigate the differences in clinical characteristics and pharmacological treatment associated with the presence of diabetes in a large cohort of patients with dementia. RESEARCH DESIGN AND METHODS: A cross-sectional registry-based study was conducted using data from the Swedish Dementia Registry (SveDem). Data on dementia diagnosis, dementia type, and demographic determinants were extracted from SveDem. Data from the Swedish Patient Register and Prescribed Drug Register were combined for the diagnosis of diabetes. Data on antidiabetic, dementia, cardiovascular, and psychotropic medications were extracted from the Swedish Prescribed Drug Register. Logistic regression was used to determine whether the variables were associated with diabetes after adjustment for confounders. In total, 29,630 patients were included in the study, and 4,881 (16.5%) of them received a diagnosis of diabetes. RESULTS: In the fully adjusted model, diabetes was associated with lower age at dementia diagnosis (odds ratio [OR] 0.97 [99% CI 0.97-0.98]), male sex (1.41 [1.27-1.55]), vascular dementia (1.17 [1.01-1.36]), and mixed dementia (1.21 [1.06-1.39]). Dementia with Lewy bodies (0.64 [0.44-0.94]), Parkinson disease dementia (0.46 [0.28-0.75]), and treatment with antidepressants (0.85 [0.77-0.95]) were less common among patients with diabetes. Patients with diabetes who had Alzheimer disease obtained significantly less treatment with cholinesterase inhibitors (0.78 [0.63-0.95]) and memantine (0.68 [0.54-0.85]). CONCLUSIONS: Patients with diabetes were younger at dementia diagnosis and obtained less dementia medication for Alzheimer disease, suggesting less optimal dementia treatment. Future research should evaluate survival and differences in metabolic profile in patients with diabetes and different dementia disorders. PMID- 28655742 TI - Respiratory Sensations in Dynamic Hyperinflation: Physiological and Clinical Applications. AB - Dynamic hyperinflation is a common cause of dyspnea and functional limitation in patients with emphysema. Dynamic hyperinflation occurs in individuals with air flow limitation when expiratory time is decreased during periods of relative tachypnea (such as during exercise or agitation, for example). In this setting, patients with emphysema develop lung hyperinflation, impairment of inspiratory respiratory muscles, and an increase in work of breathing. The associated decrease in inspiratory capacity results in the stimulation of several receptors, including chemoreceptors and pulmonary receptors, which signal the brain to increase tidal volume. The inability of the respiratory system to respond to signals of increased demand (eg, by enlarging tidal volume and increasing inspiratory flow) results in a dissociation between afferent and efferent signaling thereby intensifying breathing discomfort, or what clinicians term dyspnea. A thorough understanding of the physiology of dyspnea and pathophysiology of dynamic hyperinflation informs the interventions used to mitigate sensations of dyspnea and the physiologic effects of dynamic hyperinflation, respectively. Pharmacotherapy, pulmonary rehabilitation, breathing techniques, positive airway pressure, and lung volume reduction are well-studied interventions that target pathways to dyspnea in patients with dynamic hyperinflation. PMID- 28655741 TI - Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis. AB - In humans, gain-of-function (GOF) mutations in RHBDF2 cause the skin disease tylosis. We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG) secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation. Collectively, our data suggest that RHBDF2 plays a critical role in regulating EGFR signaling and its downstream events, including development of tylosis, by facilitating enhanced secretion of AREG. Thus, targeting AREG could have therapeutic benefit in the treatment of tylosis. PMID- 28655743 TI - Landing-related ankle injuries do not occur in plantarflexion as once thought: a systematic video analysis of ankle injuries in world-class volleyball. AB - BACKGROUND: Ankle injuries are prevalent in elite volleyball and suggested to result from player contact at the net. Traditionally, ankle sprains are thought to happen in a plantarflexed position, but case studies suggest plantarflexion may not be involved. AIM: Describe the injury situations and mechanisms of ankle injuries in world-class volleyball based on systematic video analysis of injuries reported through the Federation Internationale de Volleyball (FIVB) Injury Surveillance System. METHODS: Videos of 24 injuries from major FIVB tournaments were included for analysis (14 men, 10 women). Five analysts reviewed the videos to determine specific situations and mechanisms leading to injuries. RESULTS: The majority of injuries occurred during two volleyball situations, blocking (n=15) and attacking (n=6). Injuries to blockers were the result of landing on an opponent (n=11) or teammate (n=4). Attacking injuries most frequently occurred when a back-row player landed on a front-row teammate (n=4 of 6). When landing on an opponent under the net, the attacker landed into the opponent's court in 11 of 12 situations but without violating the centre line rule. Injuries mostly resulted from rapid inversion without any substantial plantarflexion. CONCLUSIONS: The majority of injuries occur while blocking, often landing on an opponent. The attacker is overwhelmingly to blame for injuries at the net secondary to crossing the centre line. Injuries while attacking often result from a back-row player landing on a front-row teammate. Landing-related injuries mostly result from rapid inversion with the absence of plantarflexion. PMID- 28655744 TI - Antimalarial Resistance Unlikely To Explain U.K. Artemether-Lumefantrine Failures. PMID- 28655745 TI - Reply to van der Pluijm et al., "Antimalarial Resistance Unlikely To Explain U.K. Artemether-Lumefantrine Failures". PMID- 28655747 TI - Mark Porter gives final speech to BMA annual meeting. PMID- 28655746 TI - Rethinking the right to work for refugee Syrian healthcare professionals: a call for innovation in global governance. PMID- 28655748 TI - Structural and functional analysis of the GABARAP interaction motif (GIM). AB - Through the canonical LC3 interaction motif (LIR), [W/F/Y]-X1-X2-[I/L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of 30 known core LIR motifs towards individual LC3s and GABARAPs. From these, we define a G ABARAP I nteraction M otif (GIM) sequence ([W/F]-[V/I]-X2-V) that the adaptor protein PLEKHM1 tightly conforms to. Using biophysical and structural approaches, we show that the PLEKHM1-LIR is indeed 11-fold more specific for GABARAP than LC3B. Selective mutation of the X1 and X2 positions either completely abolished the interaction with all LC3 and GABARAPs or increased PLEKHM1-GIM selectivity 20-fold towards LC3B. Finally, we show that conversion of p62/SQSTM1, FUNDC1 and FIP200 LIRs into our newly defined GIM, by introducing two valine residues, enhances their interaction with endogenous GABARAP over LC3B. The identification of a GABARAP-specific interaction motif will aid the identification and characterization of the expanding array of autophagy receptor and adaptor proteins and their in vivo functions. PMID- 28655749 TI - Polyprenols Are Synthesized by a Plastidial cis-Prenyltransferase and Influence Photosynthetic Performance. AB - Plants accumulate a family of hydrophobic polymers known as polyprenols, yet how they are synthesized, where they reside in the cell, and what role they serve is largely unknown. Using Arabidopsis thaliana as a model, we present evidence for the involvement of a plastidial cis-prenyltransferase (AtCPT7) in polyprenol synthesis. Gene inactivation and RNAi-mediated knockdown of AtCPT7 eliminated leaf polyprenols, while its overexpression increased their content. Complementation tests in the polyprenol-deficient yeast ?rer2 mutant and enzyme assays with recombinant AtCPT7 confirmed that the enzyme synthesizes polyprenols of ~55 carbons in length using geranylgeranyl diphosphate (GGPP) and isopentenyl diphosphate as substrates. Immunodetection and in vivo localization of AtCPT7 fluorescent protein fusions showed that AtCPT7 resides in the stroma of mesophyll chloroplasts. The enzymatic products of AtCPT7 accumulate in thylakoid membranes, and in their absence, thylakoids adopt an increasingly "fluid membrane" state. Chlorophyll fluorescence measurements from the leaves of polyprenol-deficient plants revealed impaired photosystem II operating efficiency, and their thylakoids exhibited a decreased rate of electron transport. These results establish that (1) plastidial AtCPT7 extends the length of GGPP to ~55 carbons, which then accumulate in thylakoid membranes; and (2) these polyprenols influence photosynthetic performance through their modulation of thylakoid membrane dynamics. PMID- 28655752 TI - Occipital Epilepsy, the Great Mimicker: Case Report and Review for the Pediatrician. PMID- 28655750 TI - AspWood: High-Spatial-Resolution Transcriptome Profiles Reveal Uncharacterized Modularity of Wood Formation in Populus tremula. AB - Trees represent the largest terrestrial carbon sink and a renewable source of ligno-cellulose. There is significant scope for yield and quality improvement in these largely undomesticated species, and efforts to engineer elite varieties will benefit from improved understanding of the transcriptional network underlying cambial growth and wood formation. We generated high-spatial resolution RNA sequencing data spanning the secondary phloem, vascular cambium, and wood-forming tissues of Populus tremula The transcriptome comprised 28,294 expressed, annotated genes, 78 novel protein-coding genes, and 567 putative long intergenic noncoding RNAs. Most paralogs originating from the Salicaceae whole genome duplication had diverged expression, with the exception of those highly expressed during secondary cell wall deposition. Coexpression network analyses revealed that regulation of the transcriptome underlying cambial growth and wood formation comprises numerous modules forming a continuum of active processes across the tissues. A comparative analysis revealed that a majority of these modules are conserved in Picea abies The high spatial resolution of our data enabled identification of novel roles for characterized genes involved in xylan and cellulose biosynthesis, regulators of xylem vessel and fiber differentiation and lignification. An associated web resource (AspWood, http://aspwood.popgenie.org) provides interactive tools for exploring the expression profiles and coexpression network. PMID- 28655753 TI - The thermodynamic basis of glucose-stimulated insulin release: a model of the core mechanism. AB - A model for glucose sensing by pancreatic beta-cells is developed and compared with the available experimental data. The model brings together mathematical representations for the activities of the glucose sensor, glucokinase, and oxidative phosphorylation. Glucokinase produces glucose 6-phosphate (G-6-P) in an irreversible reaction that determines glycolytic flux. The primary products of glycolysis are NADH and pyruvate. The NADH is reoxidized and the reducing equivalents transferred to oxidative phosphorylation by the glycerol phosphate shuttle, and some of the pyruvate is oxidized by pyruvate dehydrogenase and enters the citric acid cycle. These reactions are irreversible and result in a glucose concentration-dependent reduction of the intramitochondrial NAD pool. This increases the electrochemical energy coupled to ATP synthesis and thereby the cellular energy state ([ATP]/[ADP][Pi]). ATP and Pi are 10-100 times greater than ADP, so the increase in energy state is primarily through decrease in ADP The decrease in ADP is considered responsible for altering ion channel conductance and releasing insulin. Applied to the reported glucose concentration dependent release of insulin by perifused islet preparations (Doliba et al. 2012), the model predicts that the dependence of insulin release on ADP is strongly cooperative with a threshold of about 30 MUmol/L and a negative Hill coefficient near -5.5. The predicted cellular energy state, ADP, creatine phosphate/creatine ratio, and cytochrome c reduction, including their dependence on glucose concentration, are consistent with experimental data. The ability of the model to predict behavior consistent with experiment is an invaluable resource for understanding glucose sensing and planning experiments. PMID- 28655754 TI - The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer. AB - ERdj3/DNAJB11 is an endoplasmic reticulum (ER)-targeted HSP40 co-chaperone that performs multifaceted functions involved in coordinating ER and extracellular proteostasis. Here, we show that ERdj3 assembles into a native tetramer that is distinct from the dimeric structure observed for other HSP40 co-chaperones. An electron microscopy structural model of full-length ERdj3 shows that these tetramers are arranged as a dimer of dimers formed by distinct inter-subunit interactions involving ERdj3 domain II and domain III Targeted deletion of residues 175-190 within domain II renders ERdj3 a stable dimer that is folded and efficiently secreted from mammalian cells. This dimeric ERdj3 shows impaired substrate binding both in the ER and extracellular environments and reduced interactions with the ER HSP70 chaperone BiP. Furthermore, we show that overexpression of dimeric ERdj3 exacerbates ER stress-dependent reductions in the secretion of a destabilized, aggregation-prone protein and increases its accumulation as soluble oligomers in extracellular environments. These results reveal ERdj3 tetramerization as an important structural framework for ERdj3 functions involved in coordinating ER and extracellular proteostasis in the presence and absence of ER stress. PMID- 28655755 TI - Out-of-hospital cardiac arrests in the older population in Ireland. AB - INTRODUCTION: Age influences survival from an out-of-hospital cardiac arrest (OHCA) but it is unclear to what extent. Improved understanding of the impact of increasing age may be helpful in improving decision making on who should receive attempted resuscitation to optimise outcomes and minimise inappropriate end-of life management. Our aim is to describe the demographics, characteristics and outcomes following resuscitation attempts in OHCA patients aged 70 years and older in Ireland. METHODS: Data were extracted from the national OHCA Register. Patient and event characteristics were compared across three age categories (70 79; 80-89; >=90 years). Multivariable logistic regression was used to determine the predictors of the primary outcome (survival to hospital discharge). RESULTS: A total of 2281 patients aged 70 years and older were attended by emergency medical services and had resuscitation attempted between 2012 and 2014. Overall survival to hospital discharge was 2.9%. For those aged 70-79 years, 80-89 years, 90 years and older survival to hospital discharge in each age group was 4.0%, 1.8% and 1.4%, respectively. Older age (adjusted OR (AOR) 0.95 95% CI 0.90 to 0.99) and having an arrest in the subjects own home (AOR 0.14 95% CI 0.07 to 0.28) were independent predictor associated with reduced odds of survival to hospital discharge. An initial shockable rhythm (AOR 17.9. 95% CI 8.19 to 39.2) and having a bystander witnessed OHCA (AOR 3.98. 95% CI 1.38 to 11.50) were independent predictors associated with increased odds of survival to hospital discharge. CONCLUSION: In those aged 70 years and older, the rate of survival to hospital discharge declined with increasing age group. Younger age, an initial shockable rhythm and witnessed arrest were independent predictors of survival to hospital discharge. PMID- 28655757 TI - Actin turnover maintains actin filament homeostasis during cytokinetic ring contraction. AB - Cytokinesis in many eukaryotes involves a tension-generating actomyosin-based contractile ring. Many components of actomyosin rings turn over during contraction, although the significance of this turnover has remained enigmatic. Here, using Schizosaccharomyces japonicus, we investigate the role of turnover of actin and myosin II in its contraction. Actomyosin ring components self-organize into ~1-um-spaced clusters instead of undergoing full-ring contraction in the absence of continuous actin polymerization. This effect is reversed when actin filaments are stabilized. We tested the idea that the function of turnover is to ensure actin filament homeostasis in a synthetic system, in which we abolished turnover by fixing rings in cell ghosts with formaldehyde. We found that these rings contracted fully upon exogenous addition of a vertebrate myosin. We conclude that actin turnover is required to maintain actin filament homeostasis during ring contraction and that the requirement for turnover can be bypassed if homeostasis is achieved artificially. PMID- 28655758 TI - Ubiquitin-specific peptidase 7 (USP7)-mediated deubiquitination of the histone deacetylase SIRT7 regulates gluconeogenesis. AB - Sirtuin 7 (SIRT7), a member of the NAD+-dependent class III histone deacetylases, is involved in the regulation of various cellular processes and in resisting various stresses, such as hypoxia, low glucose levels, and DNA damage. Interestingly, SIRT7 is linked to the control of glycolysis, suggesting a role in glucose metabolism. Given the important roles of SIRT7, it is critical to clarify how SIRT7 activity is potentially regulated. It has been reported that some transcriptional and post-transcriptional regulatory mechanisms are involved. However, little is known how SIRT7 is regulated by the post-translational modifications. Here, we identified ubiquitin-specific peptidase 7 (USP7), a deubiquitinase, as a negative regulator of SIRT7. We showed that USP7 interacts with SIRT7 both in vitro and in vivo, and we further demonstrated that SIRT7 undergoes endogenous Lys-63-linked polyubiquitination, which is removed by USP7. Although the USP7-mediated deubiquitination of SIRT7 had no effect on its stability, the deubiquitination repressed its enzymatic activity. We also showed that USP7 coordinates with SIRT7 to regulate the expression of glucose-6 phosphatase catalytic subunit (G6PC), a gluconeogenic gene. USP7 depletion by RNA interference increased both G6PC expression and SIRT7 enzymatic activity. Moreover, SIRT7 targeted the G6PC promoter through the transcription factor ELK4 but not through forkhead box O1 (FoxO1). In summary, SIRT7 is a USP7 substrate and has a novel role as a regulator of gluconeogenesis. Our study may provide the basis for new clinical approaches to treat metabolic disorders related to glucose metabolism. PMID- 28655759 TI - RBM25 is a global splicing factor promoting inclusion of alternatively spliced exons and is itself regulated by lysine mono-methylation. AB - In eukaryotes, precursor mRNA (pre-mRNA) splicing removes non-coding intron sequences to produce mature mRNA. This removal is controlled in part by RNA binding proteins that regulate alternative splicing decisions through interactions with the splicing machinery. RNA binding motif protein 25 (RBM25) is a putative splicing factor strongly conserved across eukaryotic lineages. However, the role of RBM25 in global splicing regulation and its cellular functions are unknown. Here we show that RBM25 is required for the viability of multiple human cell lines, suggesting that it could play a key role in pre-mRNA splicing. Indeed, transcriptome-wide analysis of splicing events demonstrated that RBM25 regulates a large fraction of alternatively spliced exons throughout the human genome. Moreover, proteomic analysis indicated that RBM25 interacts with components of the early spliceosome and regulators of alternative splicing. Previously, we identified an RBM25 species that is mono-methylated at lysine 77 (RBM25K77me1), and here we used quantitative mass spectrometry to show that RBM25K77me1 is abundant in multiple human cell lines. We also identified a region of RBM25 spanning Lys-77 that binds with high affinity to serine- and arginine rich splicing factor 2 (SRSF2), a crucial protein in exon definition, but only when Lys-77 is unmethylated. Together, our findings uncover a pivotal role for RBM25 as an essential regulator of alternative splicing and reveal a new potential mechanism for regulation of pre-mRNA splicing by lysine methylation of a splicing factor. PMID- 28655760 TI - Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells. AB - The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays a key role in importing citrate from the circulation into liver cells. Recent evidence has revealed that SLC13A5 deletion protects mice from high-fat diet-induced hepatic steatosis and that mutation of the SLC13A5 orthologues in Drosophila melanogaster and Caenorhabditis elegans promotes longevity. However, despite the emerging importance of SLC13A5 in energy homeostasis, whether perturbation of SLC13A5 affects the metabolism and malignancy of hepatocellular carcinoma is unknown. Here, we sought to determine whether SLC13A5 regulates hepatic energy homeostasis and proliferation of hepatoma cells. RNAi-mediated silencing of SLC13A5 expression in two human hepatoma cell lines, HepG2 and Huh7, profoundly suppressed cell proliferation and colony formation, and induced cell cycle arrest accompanied by increased expression of cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin B1. Furthermore, such suppressive effects were also observed on the growth of HepG2 cell-derived xenografts expressing SLC13A5-shRNA in nude mice. Metabolically, knockdown of SLC13A5 in HepG2 and Huh7 cells was associated with a decrease in intracellular levels of citrate, the ratio of ATP/ADP, phospholipid content, and ATP citrate lyase expression. Moreover, both in vitro and in vivo assays demonstrated that SLC13A5 depletion promotes activation of the AMP activated protein kinase, which was accompanied by deactivation of oncogenic mechanistic target of rapamycin signaling. Together, our findings expand the role of SLC13A5 from facilitating hepatic energy homeostasis to influencing hepatoma cell proliferation and suggest a potential role of SLC13A5 in the progression of human hepatocellular carcinoma. PMID- 28655762 TI - The m6A methyltransferase Ime4 epitranscriptionally regulates triacylglycerol metabolism and vacuolar morphology in haploid yeast cells. AB - N6-Methyladenosine (m6A) is among the most common modifications in eukaryotic mRNA. The role of yeast m6A methyltransferase, Ime4, in meiosis and sporulation in diploid strains is very well studied, but its role in haploid strains has remained unknown. Here, with the help of an immunoblotting strategy and Ime4-GFP protein localization studies, we establish the physiological role of Ime4 in haploid cells. Our data showed that Ime4 epitranscriptionally regulates triacylglycerol metabolism and vacuolar morphology through the long-chain fatty acyl-CoA synthetase Faa1, independently of the RNA methylation complex (MIS complex). The MIS complex consists of the Ime4, Mum2, and Slz1 proteins. Our affinity enrichment strategy (methylated RNA immunoprecipitation assays) using m6A polyclonal antibodies coupled with mRNA isolation, quantitative real-time PCR, and standard PCR analyses confirmed the presence of m6A-modified FAA1 transcripts in haploid yeast cells. The term "epitranscriptional regulation" encompasses the RNA modification-mediated regulation of genes. Moreover, we demonstrate that the Aft2 transcription factor up-regulates FAA1 expression. Because the m6A methylation machinery is fundamentally conserved throughout eukaryotes, our findings will help advance the rapidly emerging field of RNA epitranscriptomics. The metabolic link identified here between m6A methylation and triacylglycerol metabolism via the Ime4 protein provides new insights into lipid metabolism and the pathophysiology of lipid-related metabolic disorders, such as obesity. Because the yeast vacuole is an analogue of the mammalian lysosome, our findings pave the way to better understand the role of m6A methylation in lysosome-related functions and diseases. PMID- 28655761 TI - The resolution of acute inflammation induced by cyclic AMP is dependent on annexin A1. AB - Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti inflammatory and pro-resolving effects. We have shown previously that the cAMP enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by using N-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drugs. PMID- 28655763 TI - Intramembrane attenuation of the TLR4-TLR6 dimer impairs receptor assembly and reduces microglia-mediated neurodegeneration. AB - Recently, a single study revealed a new complex composed of Toll-like receptor 4 (TLR4), TLR6, and CD36 induced by fibrillary Abeta peptides, the hallmark of Alzheimer's disease. Unlike TLRs located on the plasma membrane that dimerize on the membrane after ligand binding to their extracellular domain, the TLR4-TLR6 CD36 complex assembly has been suggested to be induced by intracellular signals from CD36, similar to integrin inside-out signaling. However, the assembly site of TLR4-TLR6-CD36 and the domains participating in Abeta-induced signaling is still unknown. By interfering with TLR4-TLR6 dimerization using a TLR4-derived peptide, we show that receptor assembly is abrogated within the plasma membrane. Furthermore, we reveal that the transmembrane domains of TLR4 and TLR6 have an essential role in receptor dimerization and activation. Inhibition of TLR4-TLR6 assembly was associated with reduced secretion of proinflammatory mediators from microglia cells, ultimately rescuing neurons from death. Our findings support TLR4-TLR6 dimerization induced by Abeta. Moreover, we shed new light on TLR4-TLR6 assembly and localization and show the potential of inhibiting TLR4-TLR6 dimerization as a treatment of Alzheimer's disease. PMID- 28655764 TI - Role of the E3 ubiquitin ligase RNF157 as a novel downstream effector linking PI3K and MAPK signaling pathways to the cell cycle. AB - The interconnected PI3K and MAPK signaling pathways are commonly perturbed in cancer. Dual inhibition of these pathways by the small-molecule PI3K inhibitor pictilisib (GDC-0941) and the MEK inhibitor cobimetinib (GDC-0973) suppresses cell proliferation and induces cell death better than either single agent in several preclinical models. Using mass spectrometry-based phosphoproteomics, we have identified the RING finger E3 ubiquitin ligase RNF157 as a target at the intersection of PI3K and MAPK signaling. We demonstrate that RNF157 phosphorylation downstream of the PI3K and MAPK pathways influences the ubiquitination and stability of RNF157 during the cell cycle in an anaphase promoting complex/cyclosome-CDH1-dependent manner. Deletion of these phosphorylation-targeted residues on RNF157 disrupts binding to CDH1 and protects RNF157 from ubiquitination and degradation. Expression of the cyclin-dependent kinase 2 (CDK2), itself a downstream target of PI3K/MAPK signaling, leads to increased phosphorylation of RNF157 on the same residues modulated by PI3K and MAPK signaling. Inhibition of PI3K and MEK in combination or of CDK2 by their respective small-molecule inhibitors reduces RNF157 phosphorylation at these residues and attenuates RNF157 interaction with CDH1 and its subsequent degradation. Knockdown of endogenous RNF157 in melanoma cells leads to late S phase and G2/M arrest and induces apoptosis, the latter further potentiated by concurrent PI3K/MEK inhibition, consistent with a role for RNF157 in the cell cycle. We propose that RNF157 serves as a novel node integrating oncogenic signaling pathways with the cell cycle machinery and promoting optimal cell cycle progression in transformed cells. PMID- 28655765 TI - Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel beta4 subunit explain its role in cell-cell adhesion. AB - Voltage-gated sodium channels (VGSCs) are transmembrane proteins required for the generation of action potentials in excitable cells and essential for propagating electrical impulses along nerve cells. VGSCs are complexes of a pore-forming alpha subunit and auxiliary beta subunits, designated as beta1/beta1B-beta4 (encoded by SCN1B-4B, respectively), which also function in cell-cell adhesion. We previously reported the structural basis for the trans homophilic interaction of the beta4 subunit, which contributes to its adhesive function. Here, using crystallographic and biochemical analyses, we show that the beta4 extracellular domains directly interact with each other in a parallel manner that involves an intermolecular disulfide bond between the unpaired Cys residues (Cys58) in the loop connecting strands B and C and intermolecular hydrophobic and hydrogen bonding interactions of the N-terminal segments (Ser30-Val35). Under reducing conditions, an N-terminally deleted beta4 mutant exhibited decreased cell adhesion compared with the wild type, indicating that the beta4 cis dimer contributes to the trans homophilic interaction of beta4 in cell-cell adhesion. Furthermore, this mutant exhibited increased association with the alpha subunit, indicating that the cis dimerization of beta4 affects alpha-beta4 complex formation. These observations provide the structural basis for the parallel dimer formation of beta4 in VGSCs and reveal its mechanism in cell-cell adhesion. PMID- 28655766 TI - A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1. AB - Bispecific antibodies combine two different antigen-binding sites in a single molecule, enabling more specific targeting, novel mechanisms of action, and higher clinical efficacies. Although they have the potential to outperform conventional monoclonal antibodies, many bispecific antibodies have issues regarding production, stability, and pharmacokinetic properties. Here, we describe a new approach for generating bispecific antibodies using a common light chain format and exploiting the stable architecture of human immunoglobulin G1 We used iterative experimental validation and computational modeling to identify multiple Fc variant pairs that drive efficient heterodimerization of the antibody heavy chains. Accelerated stability studies enabled selection of one Fc variant pair dubbed "DEKK" consisting of substitutions L351D and L368E in one heavy chain combined with L351K and T366K in the other. Solving the crystal structure of the DEKK Fc region at a resolution of 2.3 A enabled detailed analysis of the interactions inducing CH3 interface heterodimerization. Local shifts in the IgG backbone accommodate the introduction of lysine side chains that form stabilizing salt-bridge interactions with substituted and native residues in the opposite chain. Overall, the CH3 domain adapted to these shifts at the interface, yielding a stable Fc conformation very similar to that in wild-type IgG. Using the DEKK format, we generated the bispecific antibody MCLA-128, targeting human EGF receptors 2 and 3. MCLA-128 could be readily produced and purified at industrial scale with a standard mammalian cell culture platform and a routine purification protocol. Long-term accelerated stability assays confirmed that MCLA-128 is highly stable and has excellent biophysical characteristics. PMID- 28655767 TI - Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans. AB - Chemical RNA modifications are central features of epitranscriptomics, highlighted by the discovery of modified ribonucleosides in mRNA and exemplified by the critical roles of RNA modifications in normal physiology and disease. Despite a resurgent interest in these modifications, the biochemistry of 3 methylcytidine (m3C) formation in mammalian RNAs is still poorly understood. However, the recent discovery of trm141 as the second gene responsible for m3C presence in RNA in fission yeast raises the possibility that multiple enzymes are involved in m3C formation in mammals as well. Here, we report the discovery and characterization of three distinct m3C-contributing enzymes in mice and humans. We found that methyltransferase-like (METTL) 2 and 6 contribute m3C in specific tRNAs and that METTL8 only contributes m3C to mRNA. MS analysis revealed that there is an ~30-40% and ~10-15% reduction, respectively, in METTL2 and -6 null mutant cells, of m3C in total tRNA, and primer extension analysis located METTL2 modified m3C at position 32 of tRNAThr isoacceptors and tRNAArg(CCU) We also noted that METTL6 interacts with seryl-tRNA synthetase in an RNA-dependent manner, suggesting a role for METTL6 in modifying serine tRNA isoacceptors. METTL8, however, modified only mRNA, as determined by biochemical and genetic analyses in Mettl8 null-mutant mice and two human METTL8 mutant cell lines. Our findings provide the first evidence of the existence of m3C modification in mRNA, and the discovery of METTL8 as an mRNA m3C writer enzyme opens the door to future studies of other m3C epitranscriptomic reader and eraser functions. PMID- 28655768 TI - An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase Porcupine. AB - Wnt proteins are a family of secreted signaling proteins that play key roles in regulating cell proliferation in both embryonic and adult tissues. Production of active Wnt depends on attachment of palmitoleate, a monounsaturated fatty acid, to a conserved serine by the acyltransferase Porcupine (PORCN). Studies of PORCN activity relied on cell-based fatty acylation and signaling assays as no direct enzyme assay had yet been developed. Here, we present the first in vitro assay that accurately recapitulates PORCN-mediated fatty acylation of a Wnt substrate. The critical feature is the use of a double disulfide-bonded Wnt peptide that mimics the two-dimensional structure surrounding the Wnt acylation site. PORCN mediated Wnt acylation was abolished when the Wnt peptide was treated with DTT, and did not occur with a linear (non-disulfide-bonded) peptide, or when the double disulfide-bonded Wnt peptide contained Ala substituted for the Ser acylation site. We exploited this in vitro Wnt acylation assay to provide direct evidence that the small molecule LGK974, which is in clinical trials for managing Wnt-driven tumors, is a bona fide PORCN inhibitor whose IC50 for inhibition of Wnt fatty acylation in vitro closely matches that for inhibition of Wnt signaling. Side-by-side comparison of PORCN and Hedgehog acyltransferase (HHAT), two enzymes that attach 16-carbon fatty acids to secreted proteins, revealed that neither enzyme will accept the other's fatty acyl-CoA or peptide substrates. These findings illustrate the unique enzyme-substrate selectivity exhibited by members of the membrane-bound O-acyl transferase family. PMID- 28655769 TI - Isolation and structure-function characterization of a signaling-active rhodopsin G protein complex. AB - The visual photo-transduction cascade is a prototypical G protein-coupled receptor (GPCR) signaling system, in which light-activated rhodopsin (Rho*) is the GPCR catalyzing the exchange of GDP for GTP on the heterotrimeric G protein transducin (GT). This results in the dissociation of GT into its component alphaT GTP and beta1gamma1 subunit complex. Structural information for the Rho*-GT complex will be essential for understanding the molecular mechanism of visual photo-transduction. Moreover, it will shed light on how GPCRs selectively couple to and activate their G protein signaling partners. Here, we report on the preparation of a stable detergent-solubilized complex between Rho* and a heterotrimer (GT*) comprising a GalphaT/Galphai1 chimera (alphaT*) and beta1gamma1 The complex was formed on native rod outer segment membranes upon light activation, solubilized in lauryl maltose neopentyl glycol, and purified with a combination of affinity and size-exclusion chromatography. We found that the complex is fully functional and that the stoichiometry of Rho* to GalphaT* is 1:1. The molecular weight of the complex was calculated from small-angle X-ray scattering data and was in good agreement with a model consisting of one Rho* and one GT*. The complex was visualized by negative-stain electron microscopy, which revealed an architecture similar to that of the beta2-adrenergic receptor-GS complex, including a flexible alphaT* helical domain. The stability and high yield of the purified complex should allow for further efforts toward obtaining a high-resolution structure of this important signaling complex. PMID- 28655770 TI - Phosphorylation of p62 by AMP-activated protein kinase mediates autophagic cell death in adult hippocampal neural stem cells. AB - In the adult brain, programmed death of neural stem cells is considered to be critical for tissue homeostasis and cognitive function and is dysregulated in neurodegeneration. Previously, we have reported that adult rat hippocampal neural (HCN) stem cells undergo autophagic cell death (ACD) following insulin withdrawal. Because the apoptotic capability of the HCN cells was intact, our findings suggested activation of unique molecular mechanisms linking insulin withdrawal to ACD rather than apoptosis. Here, we report that phosphorylation of autophagy-associated protein p62 by AMP-activated protein kinase (AMPK) drives ACD and mitophagy in HCN cells. Pharmacological inhibition of AMPK or genetic ablation of the AMPK alpha2 subunit by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing suppressed ACD, whereas AMPK activation promoted ACD in insulin-deprived HCN cells. We found that following insulin withdrawal AMPK phosphorylated p62 at a novel site, Ser-293/Ser-294 (in rat and human p62, respectively). Phosphorylated p62 translocated to mitochondria and induced mitophagy and ACD. Interestingly, p62 phosphorylation at Ser-293 was not required for staurosporine-induced apoptosis in HCN cells. To the best of our knowledge, this is the first report on the direct phosphorylation of p62 by AMPK. Our data suggest that AMPK-mediated p62 phosphorylation is an ACD-specific signaling event and provide novel mechanistic insight into the molecular mechanisms in ACD. PMID- 28655771 TI - p115 RhoGEF activates the Rac1 GTPase signaling cascade in MCP1 chemokine-induced vascular smooth muscle cell migration and proliferation. AB - Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated RhoGEF in human aortic smooth muscle cells (HASMCs). Moreover, p115 RhoGEF inhibition suppressed MCP1-induced HASMC migration and proliferation. Consistent with these observations, balloon injury (BI) induced p115 RhoGEF tyrosine phosphorylation in rat common carotid arteries, and siRNA-mediated down regulation of its levels substantially attenuated BI-induced smooth muscle cell migration and proliferation, resulting in reduced neointima formation. Furthermore, depletion of p115 RhoGEF levels also abrogated MCP1- or BI-induced Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported previously, is involved in vascular wall remodeling. Our findings also show that protein kinase N1 (PKN1) downstream of Rac1-cyclin D1/CDK6 and upstream of CDK4 PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling axis is involved in the modulation of vascular wall remodeling. Of note, we also observed that CCR2-Gi/o-Fyn signaling mediates MCP1-induced p115 RhoGEF and Rac1 GTPase activation. These findings suggest that p115 RhoGEF is critical for MCP1 induced HASMC migration and proliferation in vitro and for injury-induced neointima formation in vivo by modulating Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4 PAK1 signaling. PMID- 28655772 TI - Post-translational modification of the membrane type 1 matrix metalloproteinase (MT1-MMP) cytoplasmic tail impacts ovarian cancer multicellular aggregate dynamics. AB - Membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) is a transmembrane collagenase highly expressed in metastatic ovarian cancer and correlates with poor survival. Accumulating evidence shows that the cytoplasmic tail of MT1-MMP is subjected to phosphorylation, and this post-translational modification regulates enzymatic activity at the cell surface. To investigate the potential role of MT1-MMP cytoplasmic residue Thr567 phosphorylation in regulation of metastasis-associated behaviors, ovarian cancer cells that express low endogenous levels of MT1-MMP were engineered to express wild-type MT1-MMP, a phosphomimetic mutant (T567E), or a phosphodeficient mutant (T567A). Results show that Thr567 modulation influences behavior of both individual cells and multicellular aggregates (MCAs). The acquisition of either wild-type or mutant MT1-MMP expression results in altered cohesion of epithelial sheets and the formation of more compact MCAs relative to parental cells. Cells expressing MT1-MMP-T567E phosphomimetic mutants exhibit enhanced cell migration. Furthermore, MCAs formed from MT1-MMP-T567E-expressing cells adhere avidly to both intact ex vivo peritoneal explants and three-dimensional collagen gels. Interaction of these MCAs with peritoneal mesothelium disrupts mesothelial integrity, exposing the submesothelial collagen matrix on which MT1-MMP-T567E MCAs rapidly disperse. Together, these findings suggest that post-translational regulation of the Thr567 in the MT1-MMP cytoplasmic tail may function as a regulatory mechanism to impact ovarian cancer metastatic success. PMID- 28655773 TI - Ectodysplasin A protein promotes corneal epithelial cell proliferation. AB - The EDA gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of Eda mutant Tabby mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in Tabby mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down regulated in Tabby mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, p-EGFR, and p-ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis. PMID- 28655774 TI - Stabilization of a nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator yields insight into disease-causing mutations. AB - Characterization of the second nucleotide-binding domain (NBD2) of the cystic fibrosis transmembrane conductance regulator (CFTR) has lagged behind research into the NBD1 domain, in part because NBD1 contains the F508del mutation, which is the dominant cause of cystic fibrosis. Research on NBD2 has also been hampered by the overall instability of the domain and the difficulty of producing reagents. Nonetheless, multiple disease-causing mutations reside in NBD2, and the domain is critical for CFTR function, because channel gating involves NBD1/NBD2 dimerization, and NBD2 contains the catalytically active ATPase site in CFTR. Recognizing the paucity of structural and biophysical data on NBD2, here we have defined a bioinformatics-based method for manually identifying stabilizing substitutions in NBD2, and we used an iterative process of screening single substitutions against thermal melting points to both produce minimally mutated stable constructs and individually characterize mutations. We present a range of stable constructs with minimal mutations to help inform further research on NBD2. We have used this stabilized background to study the effects of NBD2 mutations identified in cystic fibrosis (CF) patients, demonstrating that mutants such as N1303K and G1349D are characterized by lower stability, as shown previously for some NBD1 mutations, suggesting a potential role for NBD2 instability in the pathology of CF. PMID- 28655775 TI - The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. AB - Mammals incorporate a major proportion of absorbed iron as heme, which is catabolized by the heme oxygenase 1 (HO1)-NADPH-cytochrome P450 reductase (CPR) complex into biliverdin, carbon monoxide, and ferrous iron. Moreover, intestinal iron is incorporated as ferrous iron, which is transported via the iron importer, divalent metal transporter 1 (DMT1). Recently, we demonstrated that the iron chaperone poly(rC)-binding protein 2 (PCBP2) can directly receive ferrous iron from DMT1 or transfer iron to the iron exporter, ferroportin 1. To promote intracellular iron flux, an iron chaperone may be essential for receiving iron generated by heme catabolism, but this hypothesis is untested so far. Herein, we demonstrate that HO1 binds to PCBP2, but not to other PCBP family members, namely PCBP1, PCBP3, or PCBP4. Interestingly, HO1 formed a complex with either CPR or PCBP2, and it was demonstrated that PCBP2 competes with CPR for HO1 binding. Using PCBP2-deletion mutants, we demonstrated that the PCBP2 K homology 3 domain is important for the HO1/PCBP2 interaction. In heme-loaded cells, heme prompted HO1-CPR complex formation and decreased the HO1/PCBP2 interaction. Furthermore, in vitro reconstitution experiments with purified recombinant proteins indicated that HO1 could bind to PCBP2 in the presence of heme, whereas loading of PCBP2 with ferrous iron caused PCBP2 to lose its affinity for HO1. These results indicate that ferrous iron released from heme can be bound by PCBP2 and suggest a model for an integrated heme catabolism and iron transport metabolon. PMID- 28655776 TI - Protein Sam68 regulates the alternative splicing of survivin DEx3. AB - Messenger RNA alternative splicing (AS) regulates the expression of a variety of genes involved in both physiological and pathological processes. AS of the anti apoptotic and proliferation-associated survivin (BIRC5) gene generates six isoforms, which regulate key aspects of cancer initiation and progression. One of the isoforms is survivin DEx3, in which the exclusion of exon 3 generates a unique carboxyl terminus with specific anti-apoptotic functions. This isoform is highly expressed in advanced stages of breast and cervical tumors. Therefore, understanding the mechanisms that regulate survivin DEx3 mRNA AS is clearly important. To this end, we designed a minigene (M), and in combination with a series of deletions and site-directed mutations, we determined that the first 22 bp of exon 3 contain cis-acting elements that enhance the exclusion of exon 3 to generate the survivin DEx3 mRNA isoform. Furthermore, using pulldown assays, we discovered that Sam68 is a possible trans-acting factor that binds to this region and regulates exon 3 splicing. This result was corroborated using a cell line in which the Sam68 binding site in the survivin gene was mutated with the CRISPR/Cas system. This work provides the first clues regarding the regulation of survivin DEx3 mRNA splicing. PMID- 28655777 TI - Monogalactosyldiacylglycerol Facilitates Synthesis of Photoactive Protochlorophyllide in Etioplasts. AB - Cotyledon cells of dark-germinated angiosperms develop etioplasts that are plastids containing unique internal membranes called prolamellar bodies (PLBs). Protochlorophyllide (Pchlide), a precursor of chlorophyll, accumulates in PLBs and forms a ternary complex with NADPH and light-dependent NADPH:protochlorophyllide oxidoreductase (LPOR), which allows for the rapid formation of chlorophyll after illumination while avoiding photodamage. PLBs are 3D lattice structures formed by the lipid bilayer rich in monogalactosyldiacylglycerol (MGDG). Although MGDG was found to be required for the formation and function of the thylakoid membrane in chloroplasts in various plants, the roles of MGDG in PLB formation and etioplast development are largely unknown. To analyze the roles of MGDG in etioplast development, we suppressed MGD1 encoding the major isoform of MGDG synthase by using a dexamethasone inducible artificial microRNA in etiolated Arabidopsis (Arabidopsis thaliana) seedlings. Strong MGD1 suppression caused a 36% loss of MGDG in etiolated seedlings, together with a 41% decrease in total Pchlide content. The loss of MGDG perturbed etioplast membrane structures and impaired the formation of the photoactive Pchlide-LPOR-NADPH complex and its oligomerization, without affecting LPOR accumulation. The MGD1 suppression also impaired the formation of Pchlide from protoporphyrin IX via multiple enzymatic reactions in etioplast membranes, which suggests that MGDG is required for the membrane-associated processes in the Pchlide biosynthesis pathway. Suppressing MGD1 at several germination stages revealed that MGDG biosynthesis at an early germination stage is particularly important for Pchlide accumulation. MGDG biosynthesis may provide a lipid matrix for Pchlide biosynthesis and the formation of Pchlide-LPOR complexes as an initial step of etioplast development. PMID- 28655778 TI - Six-Rowed Spike3 (VRS3) Is a Histone Demethylase That Controls Lateral Spikelet Development in Barley. AB - The complex nature of crop genomes has long prohibited the efficient isolation of agronomically relevant genes. However, recent advances in next-generation sequencing technologies provide new ways to accelerate fine-mapping and gene isolation in crops. We used RNA sequencing of allelic six-rowed spike3 (vrs3) mutants with altered spikelet development for gene identification and functional analysis in barley (Hordeum vulgare). Variant calling in two allelic vrs3 mutants revealed that VRS3 encodes a putative histone Lys demethylase with a conserved zinc finger and Jumonji C and N domain. Sanger sequencing of this candidate gene in independent allelic vrs3 mutants revealed a series of mutations in conserved domains, thus confirming our candidate as the VRS3 gene and suggesting that the row type in barley is determined epigenetically. Global transcriptional profiling in developing shoot apical meristems of vrs3 suggested that VRS3 acts as a transcriptional activator of the row-type genes VRS1 (Hv.HOMEOBOX1) and INTERMEDIUM-C (INT-C; Hv.TEOSINTE BRANCHED1). Comparative transcriptome analysis of the row-type mutants vrs3, vrs4 (Hv.RAMOSA2), and int-c confirmed that all three genes act as transcriptional activators of VRS1 and quantitative variation in the expression levels of VRS1 in these mutants correlated with differences in the number of developed lateral spikelets. The identification of genes and pathways affecting seed number in small grain cereals will enable to further unravel the transcriptional networks controlling this important yield component. PMID- 28655779 TI - A new tool for rapid and reliable diagnosis of HLA loss relapses after HSCT. PMID- 28655780 TI - DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. AB - Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer-associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in DNMT3A or TET2 and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. TET2 mutations were more age dependent, associated with a modest neutropenic effect (9%, P = .012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in DNMT3A had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis. PMID- 28655781 TI - The hepatocyte-specific HNF4alpha/miR-122 pathway contributes to iron overload mediated hepatic inflammation. AB - Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe-/-) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4alpha expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy. PMID- 28655782 TI - ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK. AB - Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843-54. (c)2017 AACR. PMID- 28655783 TI - Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules. AB - The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. (c)2017 AACR. PMID- 28655784 TI - Inhibition of Megakaryocyte Differentiation by Antibody-Drug Conjugates (ADCs) is Mediated by Macropinocytosis: Implications for ADC-induced Thrombocytopenia. AB - Thrombocytopenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADC), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and trastuzumab emtansine (T DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MK) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers. Effects of AGS-16C3F, T-DM1, and control ADCs on maturing megakaryocytes were evaluated in an in vitro system in which human hematopoietic stem cells (HSC) were differentiated into MKs. AGS-16C3F, like T DM1, did not affect platelets directly, but inhibited MK differentiation by the activity of Cys-mcMMAF, its active metabolite. FcgammaRIIA did not appear to play an important role in ADC cytotoxicity to differentiating MKs. AGS-16C3F, cytotoxic to MKs, did not bind to FcgammaRIIA on MKs. Blocking the interaction of T-DM1 with FcgammaRIIA did not prevent the inhibition of MK differentiation and IgG1-mcMMAF was not as cytotoxic to MKs despite binding to FcgammaRIIA. Several lines of evidence suggest that internalization of AGS-16C3F into MKs is mediated by macropinocytosis. Macropinocytosis activity of differentiating HSCs correlated with cell sensitivity to AGS-16C3F. AGS-16C3F was colocalized with a macropinocytosis marker, dextran-Texas Red in differentiating MKs. Ethyl isopropyl amiloride (EIPA), a macropinocytosis inhibitor, blocked internalization of dextran-Texas Red and AGS-16C3F. These data support the notion that inhibition of MK differentiation via macropinocytosis-mediated internalization plays a role in ADC-induced thrombocytopenia. Mol Cancer Ther; 16(9); 1877-86. (c)2017 AACRSee related article by Zhao et al., p. 1866. PMID- 28655785 TI - A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia. AB - Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies, including cytarabine in acute myeloid leukemia (AML) and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine whether AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal. AZD1775 impaired homologous recombination in olaparib-treated cells, resulting in enhanced DNA damage accumulation and apoptosis induction. This combination enhanced disease control and increased survival in a murine AML model. Furthermore, we demonstrated that combined treatment with AZD1775 and olaparib reduces proliferation and colony formation and increases apoptosis in AML patient samples. In aggregate, these studies raise the possibility of rational combinations of targeted agents for leukemia in patients for whom conventional chemotherapeutics may not be effective or well tolerated. Mol Cancer Ther; 16(10); 2058-68. (c)2017 AACR. PMID- 28655786 TI - Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy. AB - Metronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynamic mathematical model that identifies in silico the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5-1 mg/kg gemcitabine as an optimal protocol to maximize antitumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation in vivo, while standard gemcitabine did not. Furthermore, metronomic gemcitabine yielded a 40%-50% decrease in tumor mass at the end of treatment as compared with control mice (P = 0.002; ANOVA on ranks with Dunn test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67%-72% reduction in tumor growth at study conclusion, P < 0.001; ANOVA on ranks with Dunn test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors in vivoCancer Res; 77(17); 4723-33. (c)2017 AACR. PMID- 28655787 TI - Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint. AB - Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here, we report that A3A is highly expressed in subsets of pediatric and adult acute myelogenous leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell-cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small-molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A expression in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy. Cancer Res; 77(17); 4579-88. (c)2017 AACR. PMID- 28655788 TI - PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer. AB - Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance in vitro and in vivo Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response. Cancer Res; 77(17); 4613-25. (c)2017 AACR. PMID- 28655789 TI - Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNgamma Signaling. AB - Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNgamma signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFNgamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. Cancer Res; 77(17); 4562-6. (c)2017 AACR. PMID- 28655790 TI - Targeting Vascular Endothelial-Cadherin in Tumor-Associated Blood Vessels Promotes T-cell-Mediated Immunotherapy. AB - T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell-specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8+ T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature. Cancer Res; 77(16); 4434-47. (c)2017 AACR. PMID- 28655791 TI - Nrf2 Mutagenic Activation Drives Hepatocarcinogenesis. AB - Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450 mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797-808. (c)2017 AACR. PMID- 28655792 TI - Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity. AB - Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. Cancer Res; 77(16); 4342-54. (c)2017 AACR. PMID- 28655793 TI - Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer. AB - Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy.Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS).Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61-5.16 vs. 4.90 months, 95% CI, 3.45-6.54, HR = 1.44; 80% CI, 1.09-1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5-18.9) and 12.1 months (95% CI, 9.3-not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671-8. (c)2017 AACR. PMID- 28655794 TI - Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials. AB - Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADCL," the mean of the lower ADC distribution. Pretreatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.Results: The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P = 0.4537). An ADCL threshold of 1.24 MUm2/ms produced the largest OS differences between patients (HR ~ 0.5), and patients with an ADCL > 1.24 MUm2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume.Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. (c)2017 AACR. PMID- 28655796 TI - Not Ready for Primetime: Challenges of Antenatal Ultrasound in Low- and Middle Income Country Settings. PMID- 28655795 TI - First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors. AB - Purpose: Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820.Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal.Results: Twenty-five patients received >=1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade >=3 treatment related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%).Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. Clin Cancer Res; 23(19); 5703-10. (c)2017 AACR. PMID- 28655797 TI - Long-Acting HIV Treatment and Prevention: Closer to the Threshold. PMID- 28655798 TI - The Importance of Mental Well-Being for Health Professionals During Complex Emergencies: It Is Time We Take It Seriously. PMID- 28655799 TI - Integrated Person-Centered Health Care for All Women During Pregnancy: Implementing World Health Organization Recommendations on Antenatal Care for a Positive Pregnancy Experience. PMID- 28655800 TI - Improving Adherence to Essential Birth Practices Using the WHO Safe Childbirth Checklist With Peer Coaching: Experience From 60 Public Health Facilities in Uttar Pradesh, India. AB - BACKGROUND: Adherence to evidence-based essential birth practices is critical for improving health outcomes for mothers and newborns. The WHO Safe Childbirth Checklist (SCC) incorporates these practices, which occur during 4 critical pause points: on admission, before pushing (or cesarean delivery), soon after birth, and before discharge. A peer-coaching strategy to support consistent use of the SCC may be an effective approach to increase birth attendants' adherence to these practices. METHODS: We assessed data from 60 public health facilities in Uttar Pradesh, India, that received an 8-month staggered coaching intervention from December 2014 to September 2016 as part of the BetterBirth Trial, which is studying effectiveness of an SCC-centered intervention on maternal and neonatal harm. Nurse coaches recorded birth attendants' adherence to 39 essential birth practices. Practice adherence was calculated for each intervention month. After 2 months of coaching, a subsample of 15 facilities was selected for independent observation when the coach was not present. We compared adherence to the 18 practices recorded by both coaches and independent observers. RESULTS: Coaches observed birth attendants' behavior during 5,971 deliveries. By the final month of the intervention, 35 of 39 essential birth practices had achieved >90% adherence in the presence of a coach, compared with only 7 of 39 practices during the first month. Key behaviors with the greatest improvement included explanation of danger signs, temperature measurement, assessment of fetal heart sounds, initiation of skin-to-skin contact, and breastfeeding. Without a coach present, birth attendants' average adherence to practices and checklist use was 24 percentage points lower than when a coach was present (range: -1% to 62%). CONCLUSION: Implementation of the WHO Safe Childbirth Checklist with coaching improved uptake of and adherence to essential birth practices. Coordination and communication among facility staff, as well as behaviors with an immediate, tangible benefit, showed the greatest improvement. Difficult-to-perform behaviors and those with delayed or theoretical benefits were less likely to be sustained without a coach present. Coaching may be an important component in implementing the Safe Childbirth Checklist at scale.Note: At the time of publication of this article, the results of evaluation of the impact of the BetterBirth intervention were pending publication in another journal. After the impact findings have been published, we will update this article on the effect of the intervention on birth practices with a reference to the impact findings. PMID- 28655801 TI - The BetterBirth Program: Pursuing Effective Adoption and Sustained Use of the WHO Safe Childbirth Checklist Through Coaching-Based Implementation in Uttar Pradesh, India. AB - Shifting childbirth into facilities has not improved health outcomes for mothers and newborns as significantly as hoped. Improving the quality and safety of care provided during facility-based childbirth requires helping providers to adhere to essential birth practices-evidence-based behaviors that reduce harm to and save lives of mothers and newborns. To achieve this goal, we developed the BetterBirth Program, which we tested in a matched-pair, cluster-randomized controlled trial in Uttar Pradesh, India. The goal of this intervention was to improve adoption and sustained use of the World Health Organization Safe Childbirth Checklist (SCC), an organized collection of 28 essential birth practices that are known to improve the quality of facility-based childbirth care. Here, we describe the BetterBirth Program in detail, including its 4 main features: implementation tools, an implementation strategy of coaching, an implementation pathway (Engage Launch-Support), and a sustainability plan. This coaching-based implementation of the SCC motivates and empowers care providers to identify, understand, and resolve the barriers they face in using the SCC with the resources already available. We describe important lessons learned from our experience with the BetterBirth Program as it was tested in the BetterBirth Trial. For example, the emphasis on relationship building and respect led to trust between coaches and birth attendants and helped influence change. In addition, the cloud-based data collection and feedback system proved a valuable asset in the coaching process. More research on coaching-based interventions is required to refine our understanding of what works best to improve quality and safety of care in various settings.Note: At the time of publication of this article, the results of evaluation of the impact of the BetterBirth Program were pending publication in another journal. After the impact findings have been published, we will update this article with a reference to the impact findings. PMID- 28655802 TI - Benefits and Limitations of Text Messages to Stimulate Higher Learning Among Community Providers: Participants' Views of an mHealth Intervention to Support Continuing Medical Education in Vietnam. AB - BACKGROUND: A randomized controlled trial was conducted in 2015 to evaluate a mobile continuing medical education (mCME) intervention that provided daily text messages to community-based physicians' assistants (CBPAs) in Thai Nguyen Province, Vietnam. Although the intervention failed to improve medical knowledge over a 6-month period, a companion qualitative study provided insights on the views and experiences of intervention participants. METHODS: We conducted focus group discussions (FGDs) and in-depth interviews (IDIs) among participants randomized to receive text messages containing either simple medical facts or quiz questions. Trained interviewers collected data immediately following the conclusion of the trial in December 2015. Using semi-structured question guides, respondents were queried on their views of the intervention, positive and negative, and perceived impacts of the intervention. During analysis, after learning that the intervention had failed to increase knowledge among participants, we also examined reasons for lack of improvement in medical knowledge. All analyses were performed in NVivo using a thematic approach. RESULTS: A total of 70 CBPAs engaged in one of 8 FGDs or an IDI. One-half were men; average age among all respondents was 40 years. Most (81%) practiced in rural settings and most (51%) focused on general medicine. The mean length of work experience was 3 years. All respondents made positive comments about the intervention; convenience, relevance, and quick feedback (quiz format) were praised. Downsides encompassed lack of depth of information, weak interaction, technology challenges, and challenging/irrelevant messages. Respondents described perceived impacts encompassing increased motivation, knowledge, collegial discussions, Internet use to search for more information, and clinical skills. Overall, they expressed a desire for the intervention to continue and recommended expansion to other medical professionals. Overreliance on the text messages, lack of effective self-study, and technical/language-based barriers may be potential explanations for intervention failure. CONCLUSION: As a form of mCME, daily text messages were well-received by community-level health care providers in Vietnam. This mCME approach appears very promising in low-resource environments or where traditional forms of CME are impractical. Future models might consider enhancements to foster linkages to relevant medical materials, improve interaction with medical experts, and tailor medical content to the daily activities of medical staff. PMID- 28655803 TI - Increasing Access to Family Planning Choices Through Public-Sector Social Franchising: The Experience of Marie Stopes International in Mali. AB - BACKGROUND: Mali has one of the world's lowest contraceptive use rates and a high rate of unmet need for family planning. In order to increase access to and choice of quality family planning services, Marie Stopes International (MSI) Mali introduced social franchising in public-sector community health centers (referred to as CSCOMs in Mali) in 3 regions under the MSI brand BlueStar. PROGRAM DESCRIPTION: Potential franchisees are generally identified from CSCOMs who have worked with MSI outreach teams; once accredited as franchisees, CSCOMs receive training, supervision, family planning consumables and commodities, and support for awareness raising and demand creation. To ensure availability and affordability of services, franchisees are committed to providing a wide range of contraceptive methods at low fixed prices. METHODS AND RESULTS: The performance of the BlueStar network from inception in March 2012 until December 2015 was examined using information from routine monitoring data, clinical quality audits, and client exit interviews. During this period, the network grew from 70 to 135 franchisees; an estimated 123,428 clients received voluntary family planning services, most commonly long-acting reversible methods of contraception. Franchisee efficiency and clinical quality of services increased over time, and client satisfaction with services remained high. One-quarter of clients in 2015 were under 20 years old, and three-quarters were adopters of family planning (that is, they had not been using a modern method during the 3 months prior to their visit). CONCLUSION: Applying a social franchising support package, originally developed for for-profit private-sector providers, to public-sector facilities in Mali has increased access, choice, and use of family planning in 3 regions of Mali. The experience of BlueStar Mali suggests that interventions that support quality supply of services, while simultaneously addressing demand-side barriers such as service pricing, can successfully create demand for a broad range of family planning services, even in settings with low contraceptive prevalence. PMID- 28655804 TI - Inequitable Access to Health Care by the Poor in Community-Based Health Insurance Programs: A Review of Studies From Low- and Middle-Income Countries. AB - BACKGROUND: Out-of-pocket payments for health care services lead to decreased use of health services and catastrophic health expenditures. To reduce out-of-pocket payments and improve access to health care services, some countries have introduced community-based health insurance (CBHI) schemes, especially for those in rural communities or who work in the informal sector. However, there has been little focus on equity in access to health care services in CBHI schemes. METHODS: We searched PubMed, Web of Science, African Journals OnLine, and Africa Wide Information for studies published in English between 2000 and August 2014 that examined the effect of socioeconomic status on willingness to join and pay for CBHI, actual enrollment, use of health care services, and drop-out from CBHI. Our search yielded 755 articles. After excluding duplicates and articles that did not meet our inclusion criteria (conducted in low- and middle-income countries and involved analysis based on socioeconomic status), 49 articles remained that were included in this review. Data were extracted by one author, and the second author reviewed the extracted data. Disagreements were mutually resolved between the 2 authors. The findings of the studies were analyzed to identify their similarities and differences and to identify any methodological differences that could account for contradictory findings. RESULTS: Generally, the rich were more willing to pay for CBHI than the poor and actual enrollment in CBHI was directly associated with socioeconomic status. Enrollment in CBHI was price-elastic-as premiums decreased, enrollment increased. There were mixed results on the effect of socioeconomic status on use of health care services among those enrolled in CBHI. We found a high drop-out rate from CBHI schemes that was not related to socioeconomic status, although the most common reason for dropping out of CBHI was lack of money to pay the premium. CONCLUSION: The effectiveness of CBHI schemes in achieving universal health coverage in low- and middle-income countries is questionable. A flexible payment plan where the poor can pay in installments, subsidized premiums for the poor, and removal of co-pays are measures that can increase enrollment and use of CBHI by the poor. PMID- 28655806 TI - Cost of Contraceptive Implant Removal Services Must Be Considered When Responding to the Growing Demand for Removals. PMID- 28655805 TI - Challenges of Implementing Antenatal Ultrasound Screening in a Rural Study Site: A Case Study From the Democratic Republic of the Congo. AB - Persistent global disparities in maternal and neonatal outcomes and the emergence of compact ultrasound technology as an increasingly viable technology for low resource settings provided the genesis of the First Look Ultrasound study. Initiated in 2014 in 5 low- and middle-income countries and completed in June 2016, the study's intervention included the training of health personnel to perform antenatal ultrasound screening and to refer women identified with high risk pregnancies to hospitals for appropriate care. This article examines the challenges that arose in implementing the study, with a particular focus on the site in Equateur Province of the Democratic Republic of the Congo (DRC) where the challenges were greatest and the efforts to meet these challenges most illuminating. During the study period, we determined that with resources and dedicated staff, it was possible to leverage the infrastructure and implement ultrasound at antenatal care across a variety of remote sites, including rural DRC. However, numerous technical and logistical challenges had to be addressed including security of the equipment, electricity requirements, and integration of the intervention into the health system. To address security concerns, in most of the countries field sonographers were hired and dispatched each day with the equipment to the health centers. At the end of each day, the equipment was locked in a secure, central location. To obtain the required power source, the DRC health centers installed solar panels bolted on adjacent poles since the thatch roofs of the centers prohibited secure roof-top installation. To realize the full value of the ultrasound intervention, women screened with high-risk pregnancies had to seek a higher level of care at the referral hospital for a definitive diagnosis and appropriate care. While the study did provide guidance on referral and systems management to health center and hospital administration, the extent to which this resulted in the necessary structural changes varied depending on the motivation of the stakeholders. In order for such an intervention to be scaled up and sustained as part of a health system's general services, it would require considerable effort, political will, and financial and human resources. Preliminary results from the study indicate that taking routine antenatal ultrasound screening to scale is not warranted. Lessons learned in implementing the study, however, can help inform future studies or programs that are considering use of ultrasound or other imaging technology for other applications in low-resource settings. PMID- 28655807 TI - Germline BRCA2 mutations detected in pediatric sequencing studies impact parents' evaluation and care. AB - There has been no indication to test for BRCA1/2 in children (with the rare exception of Fanconi anemia) as screening begins in adult years and there is a potential to induce anxiety related to adult-onset cancers. However, in the setting of pediatric cancer, with increasing utility and frequency of companion tumor-normal sequencing without regard for phenotype and with BRCA1/2 included in tumor profiling panels, germline mutations in BRCA1/2 and other DNA damage repair genes have been found. When mutations in these genes are revealed, there are implications for immediate family members. Here we present two children in whom BRCA2 mutations identified through tumor sequencing prompted parental genetic testing and medical action. These cases illustrate the potential importance of including a matched normal DNA sample when performing tumor profiling of pediatric cancer patients to ensure optimal care. PMID- 28655808 TI - Chronic myeloid leukemia: room for improvement? PMID- 28655809 TI - Minimal residual disease in mantle cell lymphoma: are we ready for a personalized treatment approach? PMID- 28655810 TI - Antithymocyte globulin and transplants for aplastic anemia. PMID- 28655811 TI - Rates of Spinal Cord Infarction After Repair of Aortic Aneurysm or Dissection. AB - BACKGROUND AND PURPOSE: The rate of spinal cord infarction (SCI) after surgical or endovascular repair of an aortic aneurysm or dissection is unclear. METHODS: Using administrative claims data, we identified adult patients discharged from nonfederal acute care hospitals in California, New York, and Florida who underwent surgical or endovascular repair of an aortic aneurysm or dissection between 2005 and 2013. Patients with SCI diagnosed before the aortic repair were excluded. Our primary outcome was an SCI during the index hospitalization for aortic repair. Descriptive statistics were used to estimate crude rates of SCI. Analyses were stratified by whether the aneurysm or dissection had ruptured and by type of repair (surgical versus endovascular). RESULTS: We identified 91 212 patients who had repair of an aortic aneurysm or dissection. SCI occurred in 235 cases (0.26%; 95% confidence interval [CI], 0.22%-0.29%). In patients with ruptured aneurysm or dissection, the rate of SCI was 0.74% (95% CI, 0.60%-0.88%) compared with 0.16% (95% CI, 0.13%-0.19%) with unruptured aneurysm. In secondary analyses, rates of SCI were similar after endovascular repair (0.91%; 95% CI, 0.62%-1.19%) compared with surgical repair (0.68%; 95% CI, 0.53%-0.83%; P=0.147) of ruptured aortic aneurysm or dissection; however, rates of SCI were higher after surgical repair (0.20%; 95% CI, 0.15%-0.25%) versus endovascular repair (0.11%; 95% CI, 0.08%-0.14%; P<0.001) of unruptured aneurysm. CONCLUSIONS: SCI occurs in ~1 in 130 patients undergoing aortic dissection or ruptured aortic aneurysm repair and in 1 in 600 patients undergoing unruptured aortic aneurysm repair. PMID- 28655812 TI - In-Patient Code Stroke: A Quality Improvement Strategy to Overcome Knowledge-to Action Gaps in Response Time. AB - BACKGROUND AND PURPOSE: Stroke is a relatively common and challenging condition in hospitalized patients. Previous studies have shown delays in recognition and assessment of inpatient strokes leading to poor outcomes. The goal of this quality improvement initiative was to evaluate an in-hospital code stroke algorithm and educational program aimed at reducing the response times for inpatient stroke. METHODS: An inpatient code stroke algorithm was developed, and an educational intervention was implemented over 5 months. Data were recorded and compared between the 36-month period before and the 15-month period after the intervention was implemented. Outcome measures included time from last seen normal to initial assessment and from last seen normal to brain imaging. RESULTS: During the study period, there were 218 inpatient strokes (131 before the intervention and 87 after the intervention). Inpatient strokes were more common on cardiovascular wards (45% of cases) and occurred mainly during the perioperative period (60% of cases). After implementation of an inpatient code stroke intervention and educational initiative, there were consistent reductions in all timed outcome measures (median time to initial assessment fell from 600 [109-1460] to 160 [35-630] minutes and time to computed tomographic scan fell from 925 [213-1965] to 348.5 [128-1587] minutes). CONCLUSIONS: Our study reveals the efficacy of an inpatient code stroke algorithm and educational intervention directed at nurses and allied health personnel to optimize the prompt management of inpatient strokes. Prompt assessment may lead to faster stroke interventions, which are associated with better outcomes. PMID- 28655813 TI - Neurovascular Unit Protection From Cerebral Ischemia-Reperfusion Injury by Radical-Containing Nanoparticles in Mice. AB - BACKGROUND AND PURPOSE: Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke. However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia-reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection. METHODS: C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radical-scavenging capacities were analyzed by an electron paramagnetic resonance-based method. RESULTS: RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O2- production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O2 improved by RNP treatment. CONCLUSIONS: An intra-arterial RNP injection after cerebral ischemia-reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection. PMID- 28655814 TI - Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation and Previous Stroke or Transient Ischemic Attack. AB - BACKGROUND AND PURPOSE: Limited real-world data exist comparing each non-vitamin K antagonist oral anticoagulant (NOAC) to warfarin in patients with nonvalvular atrial fibrillation who have had a previous ischemic stroke or transient ischemic attack. METHODS: Using MarketScan claims from January 2012 to June 2015, we identified adults newly initiated on oral anticoagulation, with >=2 diagnosis codes for nonvalvular atrial fibrillation, a history of previous ischemic stroke/transient ischemic attack, and >=180 days of continuous medical and prescription benefits before anticoagulation initiation. Three analyses were performed comparing 1:1 propensity score-matched cohorts of apixaban versus warfarin (n=2514), dabigatran versus warfarin (n=1962), and rivaroxaban versus warfarin (n=5208). Patients were followed until occurrence of a combined end point of ischemic stroke and intracranial hemorrhage (ICH) or major bleed, switch/discontinuation of index oral anticoagulation, insurance disenrollment, or end of follow-up. Mean follow-up was 0.5 to 0.6 years for all matched cohorts. RESULTS: Using Cox regression, neither apixaban nor dabigatran reduced the combined primary end point of ischemic stroke or ICH (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.33-1.48 and HR, 0.53; 95% CI, 0.26-1.07) and had nonsignificant effect on hazards of major bleeding (HR, 0.79; 95% CI, 0.38-1.64 and HR, 0.58; 95% CI, 0.26-1.27) versus warfarin. Rivaroxaban reduced the combined end point of ischemic stroke or ICH (HR, 0.45; 95% CI, 0.29-0.72) without an effect on major bleeding (HR, 1.07; 95% CI, 0.71-1.61). ICH occurred at rates of 0.16 to 0.61 events per 100 person-years in the 3 NOAC analyses, with no significant difference for any NOAC versus warfarin. CONCLUSIONS: Results from our study of the 3 NOACs versus warfarin in nonvalvular atrial fibrillation patients with a previous history of stroke/transient ischemic attack are relatively consistent with their respective phase III trials and previous stroke/transient ischemic attack subgroup analyses. All NOACs seemed no worse than warfarin in respect to ischemic stroke, ICH, or major bleeding risk. PMID- 28655815 TI - Geographic Variation in the Use of Oral Anticoagulation Therapy in Stroke Prevention in Atrial Fibrillation. AB - BACKGROUND AND PURPOSE: Underuse of oral anticoagulation in stroke prevention in atrial fibrillation is common; however, it remains unknown how it varies geographically. The objective of this study was to evaluate geographic variation in oral anticoagulation use and in the initiation of new oral anticoagulants (NOACs). METHODS: Using 2013 to 2014 claims data from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated NOACs (n=8659), warfarin (n=11 771) or no oral anticoagulation therapy (n=18 226) in 2013 to 2014. Each patient was assigned to 1 of the 306 Dartmouth hospital-referral regions based on his/her zip code. We constructed logistic regressions to calculate the mean adjusted probability of initiating oral anticoagulation and the mean adjusted probability of initiating an NOAC among patients on oral anticoagulation in each hospital-referral region, after adjustment for demographic, clinical, and provider characteristics and type of insurance. Finally, we computed the correlation between 2 probabilities. RESULTS: Higher in the Midwest (0.54) and Northeast (0.54) and lowest in the South (0.47), the mean adjusted probability of initiating oral anticoagulation was 0.51, ranging from 0.32 to 0.72. The mean adjusted probability of being prescribed an NOAC among those on oral anticoagulation was 0.42 and was highest in the South (0.50) and lowest in the Midwest (0.36) and Northeast (0.39). In areas with the lower use of oral anticoagulation, patients on any oral anticoagulation therapy had a higher likelihood of being prescribed an NOAC (correlation coefficient, -0.16; P=0.006). CONCLUSIONS: Large geographic variation exists in oral anticoagulation use in atrial fibrillation. The use of oral anticoagulation is lower in the South, where the rates of stroke are unusually high. In the future, it will be important to analyze whether the high rates of stroke in the South can be partially attributed to the underuse of oral anticoagulation in this region. PMID- 28655816 TI - Optimal Transport Destination for Ischemic Stroke Patients With Unknown Vessel Status: Use of Prehospital Triage Scores. AB - BACKGROUND AND PURPOSE: Patients with acute ischemic stroke (AIS) and large vessel occlusion may benefit from direct transportation to an endovascular capable comprehensive stroke center (mothership approach) as opposed to direct transportation to the nearest stroke unit without endovascular therapy (drip and ship approach). The optimal transport strategy for patients with AIS and unknown vessel status is uncertain. The rapid arterial occlusion evaluation scale (RACE, scores ranging from 0 to 9, with higher scores indicating higher stroke severity) correlates with the National Institutes of Health Stroke Scale and was developed to identify patients with large vessel occlusion in a prehospital setting. We evaluate how the RACE scale can help to inform prehospital triage decisions for AIS patients. METHODS: In a model-based approach, we estimate probabilities of good outcome (modified Rankin Scale score of <=2 at 3 months) as a function of severity of stroke symptoms and transport times for the mothership approach and the drip and ship approach. We use these probabilities to obtain optimal RACE cutoff scores for different transfer time settings and combinations of treatment options (time-based eligibility for secondary transfer under the drip and ship approach, time-based eligibility for thrombolysis at the comprehensive stroke center under the mothership approach). RESULTS: In our model, patients with AIS are more likely to benefit from direct transportation to the comprehensive stroke center if they have more severe strokes. Values of the optimal RACE cutoff scores range from 0 (mothership for all patients) to >9 (drip and ship for all patients). Shorter transfer times and longer door-to-needle and needle-to transfer (door out) times are associated with lower optimal RACE cutoff scores. CONCLUSIONS: Use of RACE cutoff scores that take into account transport times to triage AIS patients to the nearest appropriate hospital may lead to improved outcomes. Further studies should examine the feasibility of translation into clinical practice. PMID- 28655817 TI - Antibody against Microbial Neuraminidases Recognizes Human Sialidase 3 (NEU3): the Neuraminidase/Sialidase Superfamily Revisited. AB - Neuraminidases (NAs) are critical virulence factors for several microbial pathogens. With a highly conserved catalytic domain, a microbial NA "superfamily" has been proposed. We previously reported that murine polymorphonuclear leukocyte (PMN) sialidase activity was important in leukocyte trafficking to inflamed sites and that antibodies to Clostridium perfringens NA recognized a cell surface molecule(s), presumed to be a sialidase of eukaryotic origin on interleukin-8 stimulated human and murine PMNs. These antibodies also inhibited cell sialidase activity both in vitro and, in the latter instance, in vivo We therefore hypothesized that mammalian sialidases share structural homology and epitopes with microbial NAs. We now report that antibodies to one of the isoforms of C. perfringens NA, as well as anti-influenza virus NA serum, recognize human NEU3 but not NEU1 and that antibodies to C. perfringens NA inhibit NEU3 enzymatic activity. We conclude that the previously described microbial NA superfamily extends to human sialidases. Strategies designed to therapeutically inhibit microbial NA may need to consider potential compromising effects on human sialidases, particularly those expressed in cells of the immune system.IMPORTANCE We previously reported that sialidase activity of human neutrophils plays a critical role in the host inflammatory response. Since the catalytic domains of microbial neuraminidases are highly conserved, we hypothesized that antibodies against Clostridium perfringens neuraminidase might inhibit mammalian sialidase activity. Before the recognition of four mammalian sialidase (Neu) isoforms, we demonstrated that anti-C. perfringens neuraminidase antibodies inhibited human and murine sialidase activity in vivo and in vitro We now show that the antibodies to microbial neuraminidase (C. perfringens and influenza virus) recognize human NEU3, which is important for neural development and cell signaling. Since many microbes that infect mucosal surfaces express neuraminidase, it is possible that the use of sialidase inhibitors (e.g., zanamivir), might also compromise human sialidase activity critical to the human immune response. Alternatively, sialidase inhibitors may prove useful in the treatment of hyperinflammatory conditions. PMID- 28655818 TI - Novel Plasmid-Mediated Colistin Resistance Gene mcr-3 in Escherichia coli. AB - The mobile colistin resistance gene mcr-1 has attracted global attention, as it heralds the breach of polymyxins, one of the last-resort antibiotics for the treatment of severe clinical infections caused by multidrug-resistant Gram negative bacteria. To date, six slightly different variants of mcr-1, and a second mobile colistin resistance gene, mcr-2, have been reported or annotated in the GenBank database. Here, we characterized a third mobile colistin resistance gene, mcr-3 The gene coexisted with 18 additional resistance determinants in the 261-kb IncHI2-type plasmid pWJ1 from porcine Escherichia colimcr-3 showed 45.0% and 47.0% nucleotide sequence identity to mcr-1 and mcr-2, respectively, while the deduced amino acid sequence of MCR-3 showed 99.8 to 100% and 75.6 to 94.8% identity to phosphoethanolamine transferases found in other Enterobacteriaceae species and in 10 Aeromonas species, respectively. pWJ1 was mobilized to an E. coli recipient by conjugation and contained a plasmid backbone similar to those of other mcr-1-carrying plasmids, such as pHNSHP45-2 from the original mcr-1 harboring E. coli strain. Moreover, a truncated transposon element, TnAs2, which was characterized only in Aeromonas salmonicida, was located upstream of mcr-3 in pWJ1. This DeltaTnAs2-mcr-3 element was also identified in a shotgun genome sequence of a porcine E. coli isolate from Malaysia, a human Klebsiella pneumoniae isolate from Thailand, and a human Salmonella enterica serovar Typhimurium isolate from the United States. These results suggest the likelihood of a wide dissemination of the novel mobile colistin resistance gene mcr-3 among Enterobacteriaceae and aeromonads; the latter may act as a potential reservoir for mcr-3IMPORTANCE The emergence of the plasmid-mediated colistin resistance gene mcr-1 has attracted substantial attention worldwide. Here, we examined a colistin-resistant Escherichia coli isolate that was negative for both mcr-1 and mcr-2 and discovered a novel mobile colistin resistance gene, mcr-3 The amino acid sequence of MCR-3 aligned closely with phosphoethanolamine transferases from Enterobacteriaceae and Aeromonas species originating from both clinical infections and environmental samples collected in 12 countries on four continents. Due to the ubiquitous profile of aeromonads in the environment and the potential transfer of mcr-3 between Enterobacteriaceae and Aeromonas species, the wide spread of mcr-3 may be largely underestimated. As colistin has been and still is widely used in veterinary medicine and used at increasing frequencies in human medicine, the continuous monitoring of mobile colistin resistance determinants in colistin-resistant Gram-negative bacteria is imperative for understanding and tackling the dissemination of mcr genes in both the agricultural and health care sectors. PMID- 28655819 TI - Functional Role of Lanthanides in Enzymatic Activity and Transcriptional Regulation of Pyrroloquinoline Quinone-Dependent Alcohol Dehydrogenases in Pseudomonas putida KT2440. AB - The oxidation of alcohols and aldehydes is crucial for detoxification and efficient catabolism of various volatile organic compounds (VOCs). Thus, many Gram-negative bacteria have evolved periplasmic oxidation systems based on pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ-ADHs) that are often functionally redundant. Here we report the first description and characterization of a lanthanide-dependent PQQ-ADH (PedH) in a nonmethylotrophic bacterium based on the use of purified enzymes from the soil-dwelling model organism Pseudomonas putida KT2440. PedH (PP_2679) exhibits enzyme activity on a range of substrates similar to that of its Ca2+-dependent counterpart PedE (PP_2674), including linear and aromatic primary and secondary alcohols, as well as aldehydes, but only in the presence of lanthanide ions, including La3+, Ce3+, Pr3+, Sm3+, or Nd3+ Reporter assays revealed that PedH not only has a catalytic function but is also involved in the transcriptional regulation of pedE and pedH, most likely acting as a sensory module. Notably, the underlying regulatory network is responsive to as little as 1 to 10 nM lanthanum, a concentration assumed to be of ecological relevance. The present study further demonstrates that the PQQ-dependent oxidation system is crucial for efficient growth with a variety of volatile alcohols. From these results, we conclude that functional redundancy and inverse regulation of PedE and PedH represent an adaptive strategy of P. putida KT2440 to optimize growth with volatile alcohols in response to the availability of different lanthanides.IMPORTANCE Because of their low bioavailability, lanthanides have long been considered biologically inert. In recent years, however, the identification of lanthanides as a cofactor in methylotrophic bacteria has attracted tremendous interest among various biological fields. The present study reveals that one of the two PQQ-ADHs produced by the model organism P. putida KT2440 also utilizes lanthanides as a cofactor, thus expanding the scope of lanthanide-employing bacteria beyond the methylotrophs. Similar to the system described in methylotrophic bacteria, a complex regulatory network is involved in lanthanide-responsive switching between the two PQQ-ADHs encoded by P. putida KT2440. We further show that the functional production of at least one of the enzymes is crucial for efficient growth with several volatile alcohols. Overall, our study provides a novel understanding of the redundancy of PQQ-ADHs observed in many organisms and further highlights the importance of lanthanides for bacterial metabolism, particularly in soil environments. PMID- 28655820 TI - e-Biologics: Fabrication of Sustainable Electronics with "Green" Biological Materials. AB - The growing ubiquity of electronic devices is increasingly consuming substantial energy and rare resources for materials fabrication, as well as creating expansive volumes of toxic waste. This is not sustainable. Electronic biological materials (e-biologics) that are produced with microbes, or designed with microbial components as the guide for synthesis, are a potential green solution. Some e-biologics can be fabricated from renewable feedstocks with relatively low energy inputs, often while avoiding the harsh chemicals used for synthesizing more traditional electronic materials. Several are completely free of toxic components, can be readily recycled, and offer unique features not found in traditional electronic materials in terms of size, performance, and opportunities for diverse functionalization. An appropriate investment in the concerted multidisciplinary collaborative research required to identify and characterize e biologics and to engineer materials and devices based on e-biologics could be rewarded with a new "green age" of sustainable electronic materials and devices. PMID- 28655823 TI - Can an FDA-Approved Alzheimer's Drug Be Repurposed for Alleviating Neuronal Symptoms of Zika Virus? AB - Zika virus caught the world by surprise by its rapid spread and frightening disease outcomes. This major epidemic motivated many scientists to focus their attention on controlling this emerging pathogen. As many as 45 vaccine candidates are being developed, but progress in the antiviral arena has been slower. In a recent article (mBio 8:e00350-17, 2017, https://doi.org/10.1128/mBio.00350-17), Costa and colleagues showed that an FDA-approved drug used to treat Alzheimer's disease may moderate Zika virus-induced neuronal damage. This work is based on the premise that overstimulation of N-methyl-d-aspartate receptors (NMDARs) may drive neurodegeneration and that this may be responsible for neuronal cell death associated with Zika virus infection of the central nervous system (CNS). Thus, blockage of the NMDAR channel activity with FDA-approved memantine or other antagonists may reduce neurological complications associated with Zika virus infection. Repurposing a preapproved drug and targeting the host represent intriguing strategies and yet require more analysis prior to moving into clinical trials. PMID- 28655821 TI - A Novel Environmental Azole Resistance Mutation in Aspergillus fumigatus and a Possible Role of Sexual Reproduction in Its Emergence. AB - This study investigated the dynamics of Aspergillus fumigatus azole-resistant phenotypes in two compost heaps with contrasting azole exposures: azole free and azole exposed. After heat shock, to which sexual but not asexual spores are highly resistant, the azole-free compost yielded 98% (49/50) wild-type and 2% (1/50) azole-resistant isolates, whereas the azole-containing compost yielded 9% (4/45) wild-type and 91% (41/45) resistant isolates. From the latter compost, 80% (36/45) of the isolates contained the TR46/Y121F/T289A genotype, 2% (1/45) harbored the TR46/Y121F/M172I/T289A/G448S genotype, and 9% (4/45) had a novel pan triazole-resistant mutation (TR463/Y121F/M172I/T289A/G448S) with a triple 46-bp promoter repeat. Subsequent screening of a representative set of clinical A. fumigatus isolates showed that the novel TR463 mutant was already present in samples from three Dutch medical centers collected since 2012. Furthermore, a second new resistance mutation was found in this set that harbored four TR46 repeats. Importantly, in the laboratory, we recovered the TR463 mutation from a sexual cross between two TR46 isolates from the same azole-containing compost, possibly through unequal crossing over between the double tandem repeats (TRs) during meiosis. This possible role of sexual reproduction in the emergence of the mutation was further implicated by the high level of genetic diversity of STR genotypes in the azole-containing compost. Our study confirms that azole resistance mutations continue to emerge in the environment and indicates compost containing azole residues as a possible hot spot. Better insight into the biology of environmental resistance selection is needed to retain the azole class for use in food production and treatment of Aspergillus diseases.IMPORTANCE Composting of organic matter containing azole residues might be important for resistance development and subsequent spread of resistance mutations in Aspergillus fumigatus In this article, we show the dominance of azole-resistant A. fumigatus in azole-exposed compost and the discovery of a new resistance mutation with clinical relevance. Furthermore, our study indicates that current fungicide application is not sustainable as new resistance mutations continue to emerge, thereby threatening the use of triazoles in medicine. We provide evidence that the sexual part of the fungal life cycle may play a role in the emergence of resistance mutations because under laboratory conditions, we reconstructed the resistance mutation through sexual crossing of two azole-resistant A. fumigatus isolates derived from the same compost heap. Understanding the mechanisms of resistance selection in the environment is needed to design strategies against the accumulation of resistance mutations in order to retain the azole class for crop protection and treatment of Aspergillus diseases. PMID- 28655822 TI - Translation Initiation from Conserved Non-AUG Codons Provides Additional Layers of Regulation and Coding Capacity. AB - Neurospora crassa cpc-1 and Saccharomyces cerevisiae GCN4 are homologs specifying transcription activators that drive the transcriptional response to amino acid limitation. The cpc-1 mRNA contains two upstream open reading frames (uORFs) in its >700-nucleotide (nt) 5' leader, and its expression is controlled at the level of translation in response to amino acid starvation. We used N. crassa cell extracts and obtained data indicating that cpc-1 uORF1 and uORF2 are functionally analogous to GCN4 uORF1 and uORF4, respectively, in controlling translation. We also found that the 5' region upstream of the main coding sequence of the cpc-1 mRNA extends for more than 700 nucleotides without any in-frame stop codon. For 100 cpc-1 homologs from Pezizomycotina and from selected Basidiomycota, 5' conserved extensions of the CPC1 reading frame are also observed. Multiple non AUG near-cognate codons (NCCs) in the CPC1 reading frame upstream of uORF2, some deeply conserved, could potentially initiate translation. At least four NCCs initiated translation in vitroIn vivo data were consistent with initiation at NCCs to produce N-terminally extended N. crassa CPC1 isoforms. The pivotal role played by CPC1, combined with its translational regulation by uORFs and NCC utilization, underscores the emerging significance of noncanonical initiation events in controlling gene expression.IMPORTANCE There is a deepening and widening appreciation of the diverse roles of translation in controlling gene expression. A central fungal transcription factor, the best-studied example of which is Saccharomyces cerevisiae GCN4, is crucial for the response to amino acid limitation. Two upstream open reading frames (uORFs) in the GCN4 mRNA are critical for controlling GCN4 synthesis. We observed that two uORFs in the corresponding Neurospora crassa cpc-1 mRNA appear functionally analogous to the GCN4 uORFs. We also discovered that, surprisingly, unlike GCN4, the CPC1 coding sequence extends far upstream from the presumed AUG start codon with no other in frame AUG codons. Similar extensions were seen in homologs from many filamentous fungi. We observed that multiple non-AUG near-cognate codons (NCCs) in this extended reading frame, some conserved, initiated translation to produce longer forms of CPC1, underscoring the significance of noncanonical initiation in controlling gene expression. PMID- 28655827 TI - Science and Culture: Armed with a knack for patterns and symmetry, mathematical sculptors create compelling forms. PMID- 28655828 TI - Inner Workings: All eyes on Proxima Centauri b. PMID- 28655825 TI - A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in Toxoplasma gondii. AB - Apicomplexan parasites cause a variety of important infectious diseases, including malaria, toxoplasma encephalitis, and severe diarrhea due to Cryptosporidium Most apicomplexans depend on an organelle called the apicoplast which is derived from a red algal endosymbiont. The apicoplast is essential for the parasite as the compartment of fatty acid, heme, and isoprenoid biosynthesis. The majority of the approximate 500 apicoplast proteins are nucleus encoded and have to be imported across the four membranes that surround the apicoplast. Import across the second outermost membrane of the apicoplast, the periplastid membrane, depends on an apicoplast-specific endoplasmic reticulum-associated protein degradation (ERAD) complex and on enzymes of the associated ubiquitination cascade. However, identification of an apicoplast ubiquitin associated with this machinery has long been elusive. Here we identify a plastid ubiquitin-like protein (PUBL), an apicoplast protein that is derived from a ubiquitin ancestor but that has significantly changed in its primary sequence. PUBL is distinct from known ubiquitin-like proteins, and phylogenomic analyses suggest a clade specific to apicomplexans. We demonstrate that PUBL and the AAA ATPase CDC48AP both act to translocate apicoplast proteins across the periplastid membrane during protein import. Conditional null mutants and genetic complementation show that both proteins are critical for this process and for parasite survival. PUBL residues homologous to those that are required for ubiquitin conjugation onto target proteins are essential for this function, while those required for polyubiquitination and preprotein processing are dispensable. Our experiments provide a mechanistic understanding of the molecular machinery that drives protein import across the membranes of the apicoplast.IMPORTANCE Apicomplexan parasites are responsible for important human diseases. There are no effective vaccines for use in humans, and drug treatment faces multiple challenges, including emerging resistance, lack of efficacy across the lifecycle, and adverse drug effects. The apicoplast is a promising target for novel treatments: this chloroplast-like organelle is derived from an algal symbiont, is absent from the host, and is essential for parasite growth and pathogenesis. We use Toxoplasma gondii as a model to study the apicoplast due to its strong genetic tools and established functional assays. We identify a plastid ubiquitin like protein (PUBL) which is a novel ubiquitin-like protein and demonstrate its importance and that of the motor protein CDC48AP for apicoplast protein import. These findings broaden our understanding of the evolution and mechanistic workings of a unique parasite organelle and may lead to new opportunities for treatments against important human pathogens. PMID- 28655824 TI - Listeria Placental Infection. AB - The Gram-positive facultative intracellular bacterium Listeria monocytogenes is the causative agent of listeriosis, a severe food-borne infection. Pregnant women are at risk of contracting listeriosis, which can potentially lead to miscarriage, stillbirth, preterm birth, and congenital neonatal infections. While other systemic bacterial infections may result in adverse pregnancy outcomes at comparable frequencies, L. monocytogenes has particular notoriety because fetal complications largely occur in the absence of overt illness in the mother, delaying medical intervention. Here, we briefly review the pathophysiology and mechanisms of maternofetal listeriosis, discussed in light of a recent mBio report on Listeria transplacental infection in a nonhuman primate model. PMID- 28655830 TI - Correction for Luzader et al., "EutR Is a Direct Regulator of Genes That Contribute to Metabolism and Virulence in Enterohemorrhagic Escherichia coli O157:H7". PMID- 28655833 TI - BMA annual meeting: The BMA will lobby for the abolition of referral management systems. PMID- 28655832 TI - An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels. AB - RATIONALE: Postmitotic cells, such as cardiomyocytes, seem to be particularly susceptible to proteotoxic stimuli, and large, proteinaceous deposits are characteristic of the desmin-related cardiomyopathies and crystallin cardiomyopathic diseases. Increased activity of protein clearance pathways in the cardiomyocyte, such as proteasomal degradation and autophagy, has proven to be beneficial in maintaining cellular and cardiac function in the face of multiple proteotoxic insults, holding open the possibility of targeting these processes for the development of effective therapeutics. OBJECTIVE: Here, we undertake an unbiased, total genome screen for RNA transcripts and their protein products that affect aggregate accumulations in the cardiomyocytes. METHODS AND RESULTS: Primary mouse cardiomyocytes that accumulate aggregates as a result of a mutant CryAB (alphaB-crystallin) causative for human desmin-related cardiomyopathy were used for a total genome-wide screen to identify gene products that affected aggregate formation. We infected cardiomyocytes using a short hairpin RNA lentivirus library in which the mouse genome was represented. The screen identified multiple candidates in many cell signaling pathways that were able to mediate significant decreases in aggregate levels. CONCLUSIONS: Subsequent validation of one of these candidates, Jak1 (Janus kinase 1), a tyrosine kinase of the nonreceptor type, confirmed the usefulness of this approach in identifying previously unsuspected players in proteotoxic processes. PMID- 28655835 TI - Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk. AB - BACKGROUND: A decrease in sodium intake has been shown to lower blood pressure, but data from cohort studies on the association with cardiovascular and renal outcomes are inconsistent. In these studies, sodium intake was often estimated with a single baseline measurement, which may be inaccurate considering day-to day changes in sodium intake and sodium excretion. We compared the effects of single versus repetitive follow-up 24-hour urine samples on the relation between sodium intake and long-term cardiorenal outcomes. METHODS: We selected adult subjects with an estimated glomerular filtration rate >60 mL/min/1.73m2, an outpatient 24-hour urine sample between 1998 and 1999, and at least 1 collection during a 17-year follow-up. Sodium intake was estimated with a single baseline collection and the average of samples collected during a 1-, 5-, and 15-year follow-up. We used Cox regression analysis and the landmark approach to investigate the relation between sodium intake and cardiovascular (cardiovascular events or mortality) and renal (end-stage renal disease: dialysis, transplantation, and/or >60% estimated glomerular filtration rate decline, or mortality) outcomes. RESULTS: We included 574 subjects with 9776 twenty-four-hour urine samples. Average age was 47 years, and 46% were male. Median follow-up was 16.2 years. Average 24-hour sodium excretion, ranging from 3.8 to 3.9 g (165-170 mmol), was equal among all methods (P=0.88). However, relative to a single baseline measurement, 50% of the subjects had a >0.8-g (>34-mmol) difference in sodium intake with long-term estimations. As a result, 45%, 49%, and 50% of all subjects switched between tertiles of sodium intake when the 1-, 5-, or 15-year average was used, respectively. Consequently, hazard ratios for cardiorenal outcome changed up to 85% with the use of sodium intake estimations from short term (1-year) and long-term (5-year) follow-up instead of baseline estimations. CONCLUSIONS: Relative to a single baseline 24-hour sodium measurement, the use of subsequent 24-hour urine samples resulted in different estimations of an individual's sodium intake, whereas population averages remained similar. This finding had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcomes. PMID- 28655836 TI - Reply to Dong and Zhao: Plant stress via Raman spectroscopy. PMID- 28655837 TI - Limitations and challenges of using Raman spectroscopy to detect the abiotic plant stress response. PMID- 28655838 TI - Nonredox thiolation in tRNA occurring via sulfur activation by a [4Fe-4S] cluster. AB - Sulfur is present in several nucleosides within tRNAs. In particular, thiolation of the universally conserved methyl-uridine at position 54 stabilizes tRNAs from thermophilic bacteria and hyperthermophilic archaea and is required for growth at high temperature. The simple nonredox substitution of the C2-uridine carbonyl oxygen by sulfur is catalyzed by tRNA thiouridine synthetases called TtuA. Spectroscopic, enzymatic, and structural studies indicate that TtuA carries a catalytically essential [4Fe-4S] cluster and requires ATP for activity. A series of crystal structures shows that (i) the cluster is ligated by only three cysteines that are fully conserved, allowing the fourth unique iron to bind a small ligand, such as exogenous sulfide, and (ii) the ATP binding site, localized thanks to a protein-bound AMP molecule, a reaction product, is adjacent to the cluster. A mechanism for tRNA sulfuration is suggested, in which the unique iron of the catalytic cluster serves to bind exogenous sulfide, thus acting as a sulfur carrier. PMID- 28655839 TI - The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1. AB - The mechanisms that determine whether a neural progenitor cell (NPC) reenters the cell cycle or exits and differentiates are pivotal for generating cells in the correct numbers and diverse types, and thus dictate proper brain development. Combining gain-of-function and loss-of-function approaches in an embryonic stem cell-derived cortical differentiation model, we report that doublesex- and mab-3 related transcription factor a2 (Dmrta2, also known as Dmrt5) plays an important role in maintaining NPCs in the cell cycle. Temporally controlled expression of transgenic Dmrta2 in NPCs suppresses differentiation without affecting their neurogenic competence. In contrast, Dmrta2 knockout accelerates the cell cycle exit and differentiation into postmitotic neurons of NPCs derived from embryonic stem cells and in Emx1-cre conditional mutant mice. Dmrta2 function is linked to the regulation of Hes1 and other proneural genes, as demonstrated by genome-wide RNA-seq and direct binding of Dmrta2 to the Hes1 genomic locus. Moreover, transient Hes1 expression rescues precocious neurogenesis in Dmrta2 knockout NPCs. Our study thus establishes a link between Dmrta2 modulation of Hes1 expression and the maintenance of NPCs during cortical development. PMID- 28655840 TI - Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells. AB - Astrocytes regulate synaptic transmission through controlling neurotransmitter concentrations around synapses. Little is known, however, about their roles in neural circuit development. Here we report that Bergmann glia (BG), specialized cerebellar astrocytes that thoroughly enwrap Purkinje cells (PCs), are essential for synaptic organization in PCs through the action of the l-glutamate/l aspartate transporter (GLAST). In GLAST-knockout mice, dendritic innervation by the main ascending climbing fiber (CF) branch was significantly weakened, whereas the transverse branch, which is thin and nonsynaptogenic in control mice, was transformed into thick and synaptogenic branches. Both types of CF branches frequently produced aberrant wiring to proximal and distal dendrites, causing multiple CF-PC innervation. Our electrophysiological analysis revealed that slow and small CF-evoked excitatory postsynaptic currents (EPSCs) were recorded from almost all PCs in GLAST-knockout mice. These atypical CF-EPSCs were far more numerous and had significantly faster 10-90% rise time than those elicited by glutamate spillover under pharmacological blockade of glial glutamate transporters. Innervation by parallel fibers (PFs) was also affected. PF synapses were robustly increased in the entire dendritic trees, leading to impaired segregation of CF and PF territories. Furthermore, lamellate BG processes were retracted from PC dendrites and synapses, leading to the exposure of these neuronal elements to the extracellular milieus. These synaptic and glial phenotypes were reproduced in wild-type mice after functional blockade of glial glutamate transporters. These findings highlight that glutamate transporter function by GLAST on BG plays important roles in development and maintenance of proper synaptic wiring and wrapping in PCs. PMID- 28655841 TI - Poor caregiver mental health predicts mortality of patients with neurodegenerative disease. AB - Dementia and other neurodegenerative diseases cause profound declines in functioning; thus, many patients require caregivers for assistance with daily living. Patients differ greatly in how long they live after disease onset, with the nature and severity of the disease playing an important role. Caregiving can also be extremely stressful, and many caregivers experience declines in mental health. In this study, we investigated the role that caregiver mental health plays in patient mortality. In 176 patient-caregiver dyads, we found that worse caregiver mental health predicted greater patient mortality even when accounting for key risk factors in patients (i.e., diagnosis, age, sex, dementia severity, and patient mental health). These findings highlight the importance of caring for caregivers as well as patients when attempting to improve patients' lives. PMID- 28655842 TI - Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations. AB - Cell polarization and directional cell migration can display random, persistent, and oscillatory dynamic patterns. However, it is not clear whether these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent, and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all of these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechanochemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions. PMID- 28655844 TI - Demotivating incentives and motivation crowding out in charitable giving. AB - Research has shown that extrinsic incentives can crowd out intrinsic motivation in many contexts. Despite this, many nonprofits offer conditional thank-you gifts, such as mugs or tote bags, in exchange for donations. In collaboration with a nonprofit, this study implements a direct mail field experiment and demonstrates that thank-you gifts reduced donation rates in a fundraising campaign. Attention-based multiattribute choice models suggest that this is because prospective donors shift attention to the salient gift offer, causing them to underweight less salient intrinsic motives. Attention to the gift may also cause individuals to adopt a more cost-benefit mindset, further de emphasizing intrinsic motives. Consistent with these hypotheses, crowding out was driven by those who donated higher amounts in the previous year (i.e., those who likely had higher intrinsic motivation). In a complementary online experiment, thank-you gifts also reduced donation rates but only when the gift was visually salient. This corroborates the mediating role of attention in crowding out. Taken together, the laboratory and field results demonstrate that this fundraising technique can be demotivating in some contexts and that this may occur through an attention-based mechanism. PMID- 28655843 TI - Experimental evolution reveals an effective avenue to release catabolite repression via mutations in XylR. AB - Microbial production of fuels and chemicals from lignocellulosic biomass provides promising biorenewable alternatives to the conventional petroleum-based products. However, heterogeneous sugar composition of lignocellulosic biomass hinders efficient microbial conversion due to carbon catabolite repression. The most abundant sugar monomers in lignocellulosic biomass materials are glucose and xylose. Although industrial Escherichia coli strains efficiently use glucose, their ability to use xylose is often repressed in the presence of glucose. Here we independently evolved three E. coli strains from the same ancestor to achieve high efficiency for xylose fermentation. Each evolved strain has a point mutation in a transcriptional activator for xylose catabolic operons, either CRP or XylR, and these mutations are demonstrated to enhance xylose fermentation by allelic replacements. Identified XylR variants (R121C and P363S) have a higher affinity to their DNA binding sites, leading to a xylose catabolic activation independent of catabolite repression control. Upon introducing these amino acid substitutions into the E. coli D-lactate producer TG114, 94% of a glucose-xylose mixture (50 g?L-1 each) was used in mineral salt media that led to a 50% increase in product titer after 96 h of fermentation. The two amino acid substitutions in XylR enhance xylose utilization and release glucose-induced repression in different E. coli hosts, including wild type, suggesting its potential wide application in industrial E. coli biocatalysts. PMID- 28655845 TI - Force generation by groups of migrating bacteria. AB - From colony formation in bacteria to wound healing and embryonic development in multicellular organisms, groups of living cells must often move collectively. Although considerable study has probed the biophysical mechanisms of how eukaryotic cells generate forces during migration, little such study has been devoted to bacteria, in particular with regard to the question of how bacteria generate and coordinate forces during collective motion. This question is addressed here using traction force microscopy. We study two distinct motility mechanisms of Myxococcus xanthus, namely, twitching and gliding. For twitching, powered by type-IV pilus retraction, we find that individual cells exert local traction in small hotspots with forces on the order of 50 pN. Twitching bacterial groups also produce traction hotspots, but with forces around 100 pN that fluctuate rapidly on timescales of <1.5 min. Gliding, the second motility mechanism, is driven by lateral transport of substrate adhesions. When cells are isolated, gliding produces low average traction on the order of 1 Pa. However, traction is amplified approximately fivefold in groups. Advancing protrusions of gliding cells push, on average, in the direction of motion. Together, these results show that the forces generated during twitching and gliding have complementary characters, and both forces have higher values when cells are in groups. PMID- 28655847 TI - Structure-based control of complex networks with nonlinear dynamics. AB - What can we learn about controlling a system solely from its underlying network structure? Here we adapt a recently developed framework for control of networks governed by a broad class of nonlinear dynamics that includes the major dynamic models of biological, technological, and social processes. This feedback-based framework provides realizable node overrides that steer a system toward any of its natural long-term dynamic behaviors, regardless of the specific functional forms and system parameters. We use this framework on several real networks, identify the topological characteristics that underlie the predicted node overrides, and compare its predictions to those of structural controllability in control theory. Finally, we demonstrate this framework's applicability in dynamic models of gene regulatory networks and identify nodes whose override is necessary for control in the general case but not in specific model instances. PMID- 28655846 TI - Local thermal energy as a structural indicator in glasses. AB - Identifying heterogeneous structures in glasses-such as localized soft spots-and understanding structure-dynamics relations in these systems remain major scientific challenges. Here, we derive an exact expression for the local thermal energy of interacting particles (the mean local potential energy change caused by thermal fluctuations) in glassy systems by a systematic low-temperature expansion. We show that the local thermal energy can attain anomalously large values, inversely related to the degree of softness of localized structures in a glass, determined by a coupling between internal stresses-an intrinsic signature of glassy frustration-anharmonicity and low-frequency vibrational modes. These anomalously large values follow a fat-tailed distribution, with a universal exponent related to the recently observed universal [Formula: see text] density of states of quasilocalized low-frequency vibrational modes. When the spatial thermal energy field-a "softness field"-is considered, this power law tail manifests itself by highly localized spots, which are significantly softer than their surroundings. These soft spots are shown to be susceptible to plastic rearrangements under external driving forces, having predictive powers that surpass those of the normal modes-based approach. These results offer a general, system/model-independent, physical/observable-based approach to identify structural properties of quiescent glasses and relate them to glassy dynamics. PMID- 28655848 TI - Traces of surfactants can severely limit the drag reduction of superhydrophobic surfaces. AB - Superhydrophobic surfaces (SHSs) have the potential to achieve large drag reduction for internal and external flow applications. However, experiments have shown inconsistent results, with many studies reporting significantly reduced performance. Recently, it has been proposed that surfactants, ubiquitous in flow applications, could be responsible by creating adverse Marangoni stresses. However, testing this hypothesis is challenging. Careful experiments with purified water already show large interfacial stresses and, paradoxically, adding surfactants yields barely measurable drag increases. To test the surfactant hypothesis while controlling surfactant concentrations with precision higher than can be achieved experimentally, we perform simulations inclusive of surfactant kinetics. These reveal that surfactant-induced stresses are significant at extremely low concentrations, potentially yielding a no-slip boundary condition on the air-water interface (the "plastron") for surfactant concentrations below typical environmental values. These stresses decrease as the stream-wise distance between plastron stagnation points increases. We perform microchannel experiments with SHSs consisting of stream-wise parallel gratings, which confirm this numerical prediction, while showing near-plastron velocities significantly slower than standard surfactant-free predictions. In addition, we introduce an unsteady test of surfactant effects. When we rapidly remove the driving pressure following a loading phase, a backflow develops at the plastron, which can only be explained by surfactant gradients formed in the loading phase. This demonstrates the significance of surfactants in deteriorating drag reduction and thus the importance of including surfactant stresses in SHS models. Our time-dependent protocol can assess the impact of surfactants in SHS testing and guide future mitigating designs. PMID- 28655849 TI - Zero-field magnetic response functions in Landau levels. AB - We present a fresh perspective on the Landau level quantization rule; that is, by successively including zero-field magnetic response functions at zero temperature, such as zero-field magnetization and susceptibility, the Onsager's rule can be corrected order by order. Such a perspective is further reinterpreted as a quantization of the semiclassical electron density in solids. Our theory not only reproduces Onsager's rule at zeroth order and the Berry phase and magnetic moment correction at first order but also explains the nature of higher-order corrections in a universal way. In applications, those higher-order corrections are expected to curve the linear relation between the level index and the inverse of the magnetic field, as already observed in experiments. Our theory then provides a way to extract the correct value of Berry phase as well as the magnetic susceptibility at zero temperature from Landau level fan diagrams in experiments. Moreover, it can be used theoretically to calculate Landau levels up to second-order accuracy for realistic models. PMID- 28655834 TI - Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes). AB - BACKGROUND: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). METHODS: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. RESULTS: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. CONCLUSIONS: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720. PMID- 28655851 TI - BMA annual meeting: Social media abuse leads to new BMA code of conduct. PMID- 28655850 TI - System-wide organization of actin cytoskeleton determines organelle transport in hypocotyl plant cells. AB - The actin cytoskeleton is an essential intracellular filamentous structure that underpins cellular transport and cytoplasmic streaming in plant cells. However, the system-level properties of actin-based cellular trafficking remain tenuous, largely due to the inability to quantify key features of the actin cytoskeleton. Here, we developed an automated image-based, network-driven framework to accurately segment and quantify actin cytoskeletal structures and Golgi transport. We show that the actin cytoskeleton in both growing and elongated hypocotyl cells has structural properties facilitating efficient transport. Our findings suggest that the erratic movement of Golgi is a stable cellular phenomenon that might optimize distribution efficiency of cell material. Moreover, we demonstrate that Golgi transport in hypocotyl cells can be accurately predicted from the actin network topology alone. Thus, our framework provides quantitative evidence for system-wide coordination of cellular transport in plant cells and can be readily applied to investigate cytoskeletal organization and transport in other organisms. PMID- 28655852 TI - Role of ESAT-6 in renal injury by regulating microRNA-155 expression via TLR4/MyD88 signaling pathway in mice with Mycobacterium tuberculosis infection. AB - The study aims to investigate the underlying mechanism involved in the early secretory antigenic target-6 (ESAT-6) in renal injury through regulation of the expression of miR-155 through the oll-like receptor (TLR)-4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway in Mycobacterium tuberculosis (MTB)-infected mice. Sixty C57BL/6 mice with MTB-induced renal injury were randomly assigned into control, MTB, mimic, inhibitor, inhibitor + ESAT6, and inhibitor + ESAT6 + TAK242 groups. Body weight, the ratio of kidney weight to body weight (Kw/Bw), blood urea nitrogen (BUN), and serum creatinine (Scr) of mice were measured. Flow cytometry was used to detect renal activation in mice. Expressions of miR-155 and ESAT6 were detected by quantitative real-time PCR (qRT PCR), and Western blotting was used to examine the expressions of ESAT6, TLR4, and MyD88. Expressions of tumor necrosis factor-alpha (TNF-alpha), interleukin-17 (IL-17), and interferon-gamma (IFN-gamma) were measured by qRT-PCR and ELISA. Compared with the control group, the BUN and Scr levels as well as the expression levels of miR-155, TLR4, MyD88, TNF-alpha, IL-17, and IFN-gamma increased, while Kw/Bw decreased in the MTB and mimic groups. In comparison with the MTB group, the above indexes except Kw/Bw were elevated in the mimic group, but were reduced in the inhibitor group, while the Kw/Bw dropped in the mimic group but increased in the inhibitor group. Compared with the inhibitor group, the Kw/Bw decreased while the rest of the indexes increased in the inhibitor + ESAT6 group. ESAT6 may induce renal injury by promoting miR-155 expression through the TLR-4/MyD88 signaling pathway in MTB-infected mice. PMID- 28655853 TI - Rapamycin alleviates inflammation and muscle weakness, while altering the Treg/Th17 balance in a rat model of myasthenia gravis. AB - Myasthenia gravis (MG) is an autoimmune disease commonly treated with immunosuppressants. We evaluated the novel immunosuppressant, rapamycin (RAPA), in a rat model of experimental autoimmune MG (EAMG). Mortality rates in the RAPA (12%) were significantly down compared with the EAMG (88%) or cyclophosphamide (CTX) (68%) intervention groups. Muscular weakness decreased after both RAPA and CTX treatment. However, Lennon scores were lower (1.74 +/- 0.49, 3.39 +/- 0.21, and 3.81 +/- 0.22 in RAPA, CTX, and EAMG groups, respectively), and body weights (203.12 +/- 4.13 g, 179.23 +/- 2.13 g, and 180.13 +/- 5.13 g in RAPA, CTX, and EAMG groups, respectively) were significantly higher, only in the RAPA group. The proportion of regulatory T cells (Treg) significantly increased, while that of Th17 cells significantly decreased in the RAPA group compared with the EAMG group. In comparison, CTX intervention resulted in increased Th17 but significantly decreased Tregs. Hence, RAPA can be more effectively used in comparison with CTX to treat MG, with an efficacy higher than that of CTX. In addition, our results suggest RAPA's efficacy in alleviating symptoms of MG stems from its ability to correct the Treg/Th17 imbalance observed in MG. PMID- 28655855 TI - New connections: mTORC1 matures red blood cells. AB - Erythrocytes need mTORC1 for mitochondrial biogenesis and hemoglobin production. PMID- 28655856 TI - A nap a day keeps the pain away? AB - Getting more sleep or increasing caffeine intake during the day may relieve chronic pain better than typical pain-killers. PMID- 28655854 TI - The effect of sterol structure upon clathrin-mediated and clathrin-independent endocytosis. AB - Ordered lipid domains (rafts) in plasma membranes have been hypothesized to participate in endocytosis based on inhibition of endocytosis by removal or sequestration of cholesterol. To more carefully investigate the role of the sterol in endocytosis, we used a substitution strategy to replace cholesterol with sterols that show various raft-forming abilities and chemical structures. Both clathrin-mediated endocytosis of transferrin and clathrin-independent endocytosis of clustered placental alkaline phosphatase were measured. A subset of sterols reversibly inhibited both clathrin-dependent and clathrin-independent endocytosis. The ability of a sterol to support lipid raft formation was necessary for endocytosis. However, it was not sufficient, because a sterol lacking a 3beta-OH group did not support endocytosis even though it had the ability to support ordered domain formation. Double bonds in the sterol rings and an aliphatic tail structure identical to that of cholesterol were neither necessary nor sufficient to support endocytosis. This study shows that substitution using a large number of sterols can define the role of sterol structure in cellular functions. Hypotheses for how sterol structure can similarly alter clathrin-dependent and clathrin-independent endocytosis are discussed. PMID- 28655857 TI - Photoreception is not just for neurons. AB - Muscles in the mouse iris are intrinsically sensitive to light. PMID- 28655861 TI - In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D mediated activation of immature human NK cells. AB - Natural killer (NK) cells perform immunosurveillance of virally infected and transformed cells, and their activation depends on the balance between signaling by inhibitory and activating receptors. Cytokine receptor signaling can synergize with activating receptor signaling to induce NK cell activation. We investigated the interplay between the signaling pathways stimulated by the cytokine interleukin-2 (IL-2) and the activating receptor NKG2D in immature (CD56bright) and mature (CD56dim) subsets of human primary NK cells using mass cytometry experiments and in silico modeling. Our analysis revealed that IL-2 changed the abundances of several key proteins, including NKG2D and the phosphatase CD45. Furthermore, we found differences in correlations between protein abundances, which were associated with the maturation state of the NK cells. The mass cytometry measurements also revealed that the signaling kinetics of key protein abundances induced by NKG2D stimulation depended on the maturation state and the pretreatment condition of the NK cells. Our in silico model, which described the multidimensional data with coupled first-order reactions, predicted that the increase in CD45 abundance was a major enhancer of NKG2D-mediated activation in IL-2-treated CD56bright NK cells but not in IL-2-treated CD56dim NK cells. This dependence on CD45 was verified by measurement of CD107a mobilization to the NK cell surface (a marker of activation). Our mathematical framework can be used to glean mechanisms underlying synergistic signaling pathways in other activated immune cells. PMID- 28655863 TI - Evolution of biosynthetic diversity. AB - Since the emergence of the last common ancestor from which all extant life evolved, the metabolite repertoire of cells has increased and diversified. Not only has the metabolite cosmos expanded, but the ways in which the same metabolites are made have diversified. Enzymes catalyzing the same reaction have evolved independently from different protein folds; the same protein fold can produce enzymes recognizing different substrates, and enzymes performing different chemistries. Genes encoding useful enzymes can be transferred between organisms and even between the major domains of life. Organisms that live in metabolite-rich environments sometimes lose the pathways that produce those same metabolites. Fusion of different protein domains results in enzymes with novel properties. This review will consider the major evolutionary mechanisms that generate biosynthetic diversity: gene duplication (and gene loss), horizontal and endosymbiotic gene transfer, and gene fusion. It will also discuss mechanisms that lead to convergence as well as divergence. To illustrate these mechanisms, one of the original metabolisms present in the last universal common ancestor will be employed: polyamine metabolism, which is essential for the growth and cell proliferation of archaea and eukaryotes, and many bacteria. PMID- 28655864 TI - Early surgery for Hong Kong Chinese elderly patients with hip fracture reduces short-term and long-term mortality. AB - INTRODUCTION: Studies have shown that early surgery reduces hospital and 1-year mortality in elderly patients with hip fracture, but no major study has examined such relationship in Hong Kong. This study aimed to explore the relationship of early surgery and mortality in a Chinese elderly population with hip fracture. METHODS: This observational study included patients attending public hospitals in Hong Kong. All patients who underwent surgery for geriatric hip fracture in public hospitals from January 2000 to December 2011 were studied. Data were retrieved and collected from the Clinical Data Analysis and Reporting System of the Hospital Authority. Patients were divided into three groups according to timing of surgery: early (0-2 days after admission), delayed (3-4 days after admission), and late (>=5 days after admission) groups. Based on the date of death, we analysed 30-day and 1-year mortality, regardless of cause of death. Comparison of mortality rates was also made between the period before and after implementation of Key Performance Indicator formulated by the Hospital Authority. RESULTS: The overall 1-year mortality rate was 16.8%. The relative risks of 1 year mortality were 1.21 and 1.52 when the delayed and late groups were compared with the early group, respectively. The hazard ratios of long-term mortality were 1.16 (95% confidence interval, 1.13-1.20) and 1.37 (1.33-1.41), respectively for the same comparison. CONCLUSION: Prevalence of geriatric hip fracture will continue to rise and further increase the burden on our health care system. After implementation of Key Performance Indicator, most elderly patients with hip fracture underwent surgery within 2 days provided they were medically fit. Early surgery can reduce both short-term and long-term mortality. Setting up a fragility fracture registry would be beneficial for further studies. PMID- 28655862 TI - Differential abundance of CK1alpha provides selectivity for pharmacological CK1alpha activators to target WNT-dependent tumors. AB - Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1alpha (CK1alpha), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1alpha activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1alpha, was decreased in WNT driven tumors relative to normal gastrointestinal tissue, and knocking down CK1alpha increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1alpha abundance provides an enhanced therapeutic index for pharmacological CK1alpha activators to target WNT-driven tumors. PMID- 28655865 TI - Transcatheter aortic valve implantation: initial experience in Hong Kong. AB - INTRODUCTION: Aortic stenosis is one of the most common valvular heart diseases in the ageing population. Patients with symptomatic severe aortic stenosis are at high risk of sudden death. Surgical aortic-valve replacement is the gold standard of treatment but many patients do not receive surgery because of advanced age or co-morbidities. Recently, transcatheter aortic valve implantation has been developed as an option for these patients. This study aimed to assess efficacy and safety of this procedure in the Hong Kong Chinese population. METHODS: Data for baseline patient characteristics, procedure parameters, and clinical outcomes up to 1-year post-implantation in a regional hospital in Hong Kong were collected and analysed. RESULTS: A total of 56 patients with severe aortic stenosis underwent the procedure from December 2010 to September 2015. Their mean (+/- standard deviation) age was 81.9 +/- 4.8 years; 64.3% of them were male. Their mean logistic EuroSCORE was 22.6% +/- 13.4%. After implantation, the mean aortic valve area improved from 0.70 cm2 +/- 0.19 cm2 to 1.94 cm2 +/- 0.37 cm2. Of the patients, 92% were improved by at least one New York Heart Association functional class. Stroke and major vascular complications occurred in one (1.8%) and five (8.9%) patients, respectively. A permanent pacemaker was implanted in seven (12.5%) patients. Both hospital and 30-day mortalities were 1.8%. The 1-year all cause and cardiovascular mortality rates were 12.5% and 7.1%, respectively. CONCLUSIONS: Transcatheter aortic valve implantation has been developed as an alternative treatment for patients with symptomatic severe aortic stenosis who are deemed inoperable or high risk for surgery. Our results are very promising and comparable with those of major clinical trials. PMID- 28655868 TI - Double Peripheral Venous and Arterial Cannulation for Extracorporeal Membrane Oxygenation in Combined Septic and Cardiogenic Shock. AB - BACKGROUND The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle. CASE REPORT A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later. CONCLUSIONS In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option. PMID- 28655867 TI - Utility of Fluorescence In Situ Hybridization (FISH) to Sub-Classify Low-Grade Urothelial Carcinoma for Prognostication. AB - BACKGROUND Fluorescence in situ hybridization (FISH) is used widely to detect cancer levels, but its value in urothelial carcinoma remains unclear. The aim of this study was to use FISH to examine the urine specimens of low-grade urothelial carcinoma (UC) patients to determine the possibility of sub-classifying the prognosis of UC. MATERIAL AND METHODS We diagnosed 107 patients with low-grade UC using a UroVysion kit to detect chromosomes 3, 7, 17, and P16 in the urine. An average 46.6-month follow-up completed in January 2016 combined with the clinical follow-up data were evaluated with Spearman's correlation analysis to analyze the aberration of chromosomes in relation to the prognostication. Univariate and multivariate analysis using the Mantel-Cox log-rank test for overall, cancer specific, and disease-free survival were used to determine the prognostic significance of CSP7/CSP17 and CSP3/GLPp16. RESULTS In the 107 samples, 84 showed positive reaction in the FISH test. Furthermore, CSP7/CSP17 was found to be significantly related with age, tumor size, T stage, and tumor numbers, but not in CSP3/GLPp16. In addition, Kaplan-Meier analysis and Cox proportional hazards regression revealed a significant negative correlation between CSP7/CSP17 and survival, while CSP3/GLPp16 showed no significantly differences. CONCLUSIONS CSP7/CSP17 positivity on FISH test appears to play a critical role in low-grade UC and may be considered as a high-risk and prognosis factor. PMID- 28655869 TI - Analysis of the grape (Vitis vinifera L.) thaumatin-like protein (TLP) gene family and demonstration that TLP29 contributes to disease resistance. AB - Thaumatin-like protein (TLP) is present as a large family in plants, and individual members play different roles in various responses to biotic and abiotic stresses. Here we studied the role of 33 putative grape (Vitis vinifera L.) TLP genes (VvTLP) in grape disease resistance. Heat maps analysis compared the expression profiles of 33 genes in disease resistant and susceptible grape species infected with anthracnose (Elsinoe ampelina), powdery mildew (Erysiphe necator) or Botrytis cinerea. Among these 33 genes, the expression level of TLP29 increased following the three pathogens inoculations, and its homolog from the disease resistant Chinese wild grape V. quinquangularis cv. 'Shang-24', was focused for functional studies. Over-expression of TLP29 from grape 'Shang-24' (VqTLP29) in Arabidopsis thaliana enhanced its resistance to powdery mildew and the bacterium Pseudomonas syringae pv. tomato DC3000, but decreased resistance to B. cinerea. Moreover, the stomatal closure immunity response to pathogen associated molecular patterns was strengthened in the transgenic lines. A comparison of the expression profiles of various resistance-related genes after infection with different pathogens indicated that VqTLP29 may be involved in the salicylic acid and jasmonic acid/ethylene signaling pathways. PMID- 28655870 TI - Communicative knowledge pervasively influences sensorimotor computations. AB - Referential pointing is a characteristically human behavior, which involves moving a finger through space to direct an addressee towards a desired mental state. Planning this type of action requires an interface between sensorimotor and conceptual abilities. A simple interface could supplement spatially-guided motor routines with communicative-ostensive cues. For instance, a pointing finger held still for an extended period of time could aid the addressee's understanding, without altering the movement's trajectory. A more complex interface would entail communicative knowledge penetrating the sensorimotor system and directly affecting pointing trajectories. We compare these two possibilities using motion analyses of referential pointing during multi-agent interactions. We observed that communicators produced ostensive cues that were sensitive to the communicative context. Crucially, we also observed pervasive adaptations to the pointing trajectories: they were tailored to the communicative context and to partner-specific information. These findings indicate that human referential pointing is planned and controlled on the basis of partner-specific knowledge, over and above the tagging of motor routines with ostensive cues. PMID- 28655871 TI - Yeast surface display identifies a family of evasins from ticks with novel polyvalent CC chemokine-binding activities. AB - Chemokines function via G-protein coupled receptors in a robust network to recruit immune cells to sites of inflammation. Due to the complexity of this network, targeting single chemokines or receptors has not been successful in inflammatory disease. Dog tick saliva contains polyvalent CC-chemokine binding peptides termed evasins 1 and 4, that efficiently disrupt the chemokine network in models of inflammatory disease. Here we develop yeast surface display as a tool for functionally identifying evasins, and use it to identify 10 novel polyvalent CC-chemokine binding evasin-like peptides from salivary transcriptomes of eight tick species in Rhipicephalus and Amblyomma genera. These evasins have unique binding profiles compared to evasins 1 and 4, targeting CCL2 and CCL13 in addition to other CC-chemokines. Evasin binding leads to neutralisation of chemokine function including that of complex chemokine mixtures, suggesting therapeutic efficacy in inflammatory disease. We propose that yeast surface display is a powerful approach to mine potential therapeutics from inter-species protein interactions that have arisen during evolution of parasitism in ticks. PMID- 28655872 TI - Ca2+ ionophores are not suitable for inducing mPTP opening in murine isolated adult cardiac myocytes. AB - Opening of the mitochondrial permeability transition pore (mPTP) plays a major role in cell death during cardiac ischaemia-reperfusion. Adult isolated rodent cardiomyocytes are valuable cells to study the effect of drugs targeting mPTP. This study investigated whether the use of Ca2+ ionophores (A23187, ionomycin and ETH129) represent a reliable model to study inhibition of mPTP opening in cardiomyocytes. We monitored mPTP opening using the calcein/cobalt fluorescence technique in adult rat and wild type or cyclophilin D (CypD) knock-out mice cardiomyocytes. Cells were either treated with Ca2+ ionophores or subjected to hypoxia followed by reoxygenation. The ionophores induced mPTP-dependent swelling in isolated mitochondria. A23187, but not ionomycin, induced a decrease in calcein fluorescence. This loss could not be inhibited by CypD deletion and was explained by a direct interaction between A23187 and cobalt. ETH129 caused calcein loss, mitochondrial depolarization and cell death but CypD deletion did not alleviate these effects. In the hypoxia-reoxygenation model, CypD deletion delayed both mPTP opening and cell death occurring at the time of reoxygenation. Thus, Ca2+ ionophores are not suitable to induce CypD-dependent mPTP opening in adult murine cardiomyocytes. Hypoxia-reoxygenation conditions appear therefore as the most reliable model to investigate mPTP opening in these cells. PMID- 28655873 TI - Synergistic effect of human Bone Morphogenic Protein-2 and Mesenchymal Stromal Cells on chronic wounds through hypoxia-inducible factor-1 alpha induction. AB - Chronic skin ulcers and burns require advanced treatments. Mesenchymal Stromal Cells (MSCs) are effective in treating these pathologies. Bone Morphogenic Protein-2 (BMP-2) is known to enhance angiogenesis. We investigated whether recombinant human hBMP-2 potentiates the effect of MSCs on wound healing. Severe ulceration was induced in rats by irradiation and treated by co-infusion of MSCs with hBMP-2 into the ulcerated area which accelerated wound healing. Potentiation of the effect of MSCs by hBMP-2 on endothelial repair improved skin healing. HBMP 2 and MSCs synergistically, in a supra additive or enhanced manner, renewed tissue structures, resulting in normalization of the epidermis, hair follicles, sebaceous glands, collagen fibre density, and blood vessels. Co-localization of MSCs with CD31 + cells suggests recruitment of endothelial cells at the site of injection. HBMP-2 and MSCs enhanced angiogenesis and induced micro-vessel formation in the dermis where hair follicles were regenerated. HBMP-2 acts by causing hypoxia-inducible factor-1 alpha (HIF-1alpha) expression which impacts endothelial tube formation and skin repair. This effect is abolished by siRNA. These results propose that new strategies adding cytokines to MSCs should be evaluated for treating radiation-induced dermatitis, burns, and chronic ulcers in humans. PMID- 28655874 TI - Long-term cilostazol treatment reduces gliovascular damage and memory impairment in a mouse model of chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion is a major cause of age-related vascular cognitive impairment. A well-characterised mouse model has shown that hypoperfusion results in gliovascular and white matter damage and impaired spatial working memory. In this study, we assessed whether cilostazol, a phosphodiesterase III inhibitor, could protect against these changes. Adult, male C57Bl/6J mice were subjected to bilateral common carotid artery stenosis or a sham operation and fed normal or cilostazol diet for three months. Cilostazol treatment reduced the impairment in working memory and white matter function after hypoperfusion. Endothelial adhesion molecules and gliosis, increased after hypoperfusion, were ameliorated with cilostazol treatment. Interestingly, the improvement in working memory was closely correlated with reduced microglia and endothelial adhesion molecules. Further, the number of stroke lesions after hypoperfusion was reduced in the cilostazol-treated group. Altogether cilostazol showed potential to ameliorate the gliovascular damage and working memory impairments after hypoperfusion possibly via endothelial protection supporting its potential use in the treatment of vascular cognitive impairment. PMID- 28655875 TI - Proximal GATA-binding sites are essential for human HSD3B1 gene transcription in the placenta. AB - The enzyme 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) is involved in the synthesis of active steroid hormones. Two human 3beta-HSD isoforms are expressed in a tissue-specific pattern. HSD3B1 (type I) expression is essential to produce progesterone for pregnancy maintenance. To understand the mechanisms of human HSD3B1 activation in the placenta, 2.2 kb of 5'-flanking sequence and 5' deletions were fused to the luciferase reporter gene and transfected into human JEG-3 cells. The proximal -238/+337 sequence had the highest promoter activity. Two GATA elements were identified at -106/-99 and -52/-45. Mutations of either sites greatly reduced promoter activity in JEG-3 cells, demonstrating the importance of GATA sites. EMSA revealed the specific binding of GATA2 and GATA3 to the GATA sequences at -106/-99 and -52/-45. ChIP assays demonstrated the association of GATA2 but not GATA3 with the GATA-binding regions of the HSD3B1 promoter in JEG-3 cells. GATA2 knockdown significantly reduced HSD3B1 expression in JEG-3 cells; however, GATA3 knockdown increased HSD3B1 expression. Western blot analysis revealed high levels of GATA2 but not GATA3 in human placental tissues. This study identified GATA motifs as essential control elements for HSD3B1 transcription and GATA2 as a novel transcriptional regulator of HSD3B1 expression in the human placenta. PMID- 28655876 TI - Sensory systems: Tasting the water. PMID- 28655878 TI - NAFLD: Thermoneutral housing of mice improves modelling of NAFLD. PMID- 28655879 TI - Viral hepatitis: Charting HCV genotype 2/1 recombinant strains. PMID- 28655880 TI - Neurogastroenterology: The dynamic cycle of life in the enteric nervous system. PMID- 28655877 TI - Mammalian empathy: behavioural manifestations and neural basis. AB - Recent research on empathy in humans and other mammals seeks to dissociate emotional and cognitive empathy. These forms, however, remain interconnected in evolution, across species and at the level of neural mechanisms. New data have facilitated the development of empathy models such as the perception-action model (PAM) and mirror-neuron theories. According to the PAM, the emotional states of others are understood through personal, embodied representations that allow empathy and accuracy to increase based on the observer's past experiences. In this Review, we discuss the latest evidence from studies carried out across a wide range of species, including studies on yawn contagion, consolation, aid giving and contagious physiological affect, and we summarize neuroscientific data on representations related to another's state. PMID- 28655881 TI - Microglia: A protective population? PMID- 28655882 TI - Prefrontal-hippocampal interactions in episodic memory. AB - The roles of the hippocampus and prefrontal cortex (PFC) in memory processing - individually or in concert - are a major topic of interest in memory research. These brain areas have distinct and complementary roles in episodic memory, and their interactions are crucial for learning and remembering events. Considerable evidence indicates that the PFC and hippocampus become coupled via oscillatory synchrony that reflects bidirectional flow of information. Furthermore, newer studies have revealed specific mechanisms whereby neural representations in the PFC and hippocampus are mediated through direct connections or through intermediary regions. These findings suggest a model of how the hippocampus and PFC, along with their intermediaries, operate as a system that uses the current context of experience to retrieve relevant memories. PMID- 28655886 TI - Experimental Demonstration of Four-Dimensional Photonic Spatial Entanglement between Multi-core Optical Fibres. AB - Fibre transport of multi-dimensional photonic quantum states promises high information capacity per photon without space restriction. This work experimentally demonstrates transmission of spatial ququarts through multi-core optical fibres and measurement of the entanglement between two fibres with quantum state analyzers, each composed of a spatial light modulator and a single mode fibre. Quantum state tomography reconstructs the four-dimension entangled state that verifies the nonlocality through concurrences in two-dimensional subspaces, a lower bound of four-dimensional concurrence and a Bell-type CGLMP inequality. PMID- 28655885 TI - miR-15a/miR-16 down-regulates BMI1, impacting Ub-H2A mediated DNA repair and breast cancer cell sensitivity to doxorubicin. AB - The B-lymphoma Moloney murine leukemia virus insertion region-1 protein (BMI1) acts as an oncogene in various cancers, including breast cancer. Recent evidence suggests that BMI1 is rapidly recruited to sites of DNA double strand breaks where it facilitates histone H2A ubiquitination and DNA double strand break repair by homologous recombination. Here we show that miR-15a and miR-16 expression is decreased during the initial period after DNA damage where it would otherwise down-regulate BMI1, impairing DNA repair. Elevated miR-15a and miR-16 levels down-regulated BMI1 and other polycomb group proteins like RING1A, RING1B, EZH2 and also altered the expression of proteins associated with the BMI1 dependent ubiquitination pathway. Antagonizing the expression of miR-15a and miR 16, enhanced BMI1 protein levels and increased DNA repair. Further, overexpression of miR-15a and miR-16 sensitized breast cancer cells to DNA damage induced by the chemotherapeutic drug doxorubicin. Our results suggest that miR 15a and miR-16 mediate the down-regulation of BMI1, which impedes DNA repair while elevated levels can sensitize breast cancer cells to doxorubicin leading to apoptotic cell death. This data identifies a new target for manipulating DNA damage response that could impact the development of improved therapeutics for breast cancer. PMID- 28655883 TI - Taste buds: cells, signals and synapses. AB - The past decade has witnessed a consolidation and refinement of the extraordinary progress made in taste research. This Review describes recent advances in our understanding of taste receptors, taste buds, and the connections between taste buds and sensory afferent fibres. The article discusses new findings regarding the cellular mechanisms for detecting tastes, new data on the transmitters involved in taste processing and new studies that address longstanding arguments about taste coding. PMID- 28655884 TI - Intestinal lymphatic vasculature: structure, mechanisms and functions. AB - The mammalian intestine is richly supplied with lymphatic vasculature, which has functions ranging from maintenance of interstitial fluid balance to transport of antigens, antigen-presenting cells, dietary lipids and fat-soluble vitamins. In this Review, we provide in-depth information concerning the organization and structure of intestinal lymphatics, the current view of their developmental origins, as well as molecular mechanisms of intestinal lymphatic patterning and maintenance. We will also discuss physiological aspects of intestinal lymph flow regulation and the known and emerging roles of intestinal lymphatic vessels in human diseases, such as IBD, infection and cancer. PMID- 28655887 TI - Comparative proteome analysis between C . briggsae embryos and larvae reveals a role of chromatin modification proteins in embryonic cell division. AB - Caenorhabditis briggsae has emerged as a model for comparative biology against model organism C. elegans. Most of its cell fate specifications are completed during embryogenesis whereas its cell growth is achieved mainly in larval stages. The molecular mechanism underlying the drastic developmental changes is poorly understood. To gain insights into the molecular changes between the two stages, we compared the proteomes between the two stages using iTRAQ. We identified a total of 2,791 proteins in the C. briggsae embryos and larvae, 247 of which undergo up- or down-regulation between the two stages. The proteins that are upregulated in the larval stages are enriched in the Gene Ontology categories of energy production, protein translation, and cytoskeleton; whereas those upregulated in the embryonic stage are enriched in the categories of chromatin dynamics and posttranslational modification, suggesting a more active chromatin modification in the embryos than in the larva. Perturbation of a subset of chromatin modifiers followed by cell lineage analysis suggests their roles in controlling cell division pace. Taken together, we demonstrate a general molecular switch from chromatin modification to metabolism during the transition from C. briggsae embryonic to its larval stages using iTRAQ approach. The switch might be conserved across metazoans. PMID- 28655888 TI - Moving and unsinkable graphene sheets immobilized enzyme for microfluidic biocatalysis. AB - Enzymatic catalysis in microreactors has attracted growing scientific interest because of high specific surface enabling heat and mass transfer and easier control of reaction parameters in microreactors. However, two major challenges that limit their application are fast inactivation and the inability to the biocatalysts in microchannel reactors. A fluid and unsinkable immobilized enzyme were firstly applied in a microchannel reactor for biocatalysis in this study. Functionalized forms of graphene-immobilized naringinase flowing in microchannels have yielded excellent results for isoquercitrin production. A maximum yield of 92.24 +/- 3.26% was obtained after 20 min in a microchannel reactor. Ten cycles of enzymatic hydrolysis reaction were successively completed and an enzyme activity above 85.51 +/- 2.76% was maintained. The kinetic parameter V m/K m increased to 1.9-fold and reaction time was decreased to 1/3 compared with that in a batch reactor. These results indicated that the moving and unsinkable graphene sheets immobilized enzyme with a high persistent specificity and a mild catalytic characteristic enabled the repetitive use of enzyme and significant cost saving for the application of enzyme catalysis. Thus, the developed method has provided an efficient and simple approach for the productive and repeatable microfluidic biocatalysis. PMID- 28655889 TI - Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression. AB - We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression. PMID- 28655890 TI - High-throughput format for the phenotyping of fungi on solid substrates. AB - Filamentous fungi naturally grow on solid surfaces, yet most genetic and biochemical analyses are still performed in liquid cultures. Here, we report a multiplexing platform using high-throughput photometric continuous reading that allows parallel quantification of hyphal growth and reporter gene expression directly on solid medium, thereby mimicking natural environmental conditions. Using this system, we have quantified fungal growth and expression of secondary metabolite GFP-based reporter genes in saprophytic Aspergillus and phytopathogenic Fusarium species in response to different nutrients, stress conditions and epigenetic modifiers. With this method, we provide not only novel insights into the characteristic of fungal growth but also into the metabolic and time-dependent regulation of secondary metabolite gene expression. PMID- 28655891 TI - A Gelatin-sulfonated Silk Composite Scaffold based on 3D Printing Technology Enhances Skin Regeneration by Stimulating Epidermal Growth and Dermal Neovascularization. AB - One of the key problems hindering skin repair is the deficiency of dermal vascularization and difficulty of epidermis regeneration, which makes it challenging to fabricate scaffolds that can biologically fulfill the requirements for skin regeneration. To overcome this problem, three-dimensional printing was used to fabricate a gelatin-sulfonated silk composite scaffold that was incorporated with basic fibroblast growth factor 2 (FGF-2) through binding with a sulfonic acid group (SO3) (3DG-SF-SO3-FGF). The efficacy and mechanism by which the 3DG-SF-SO3-FGF scaffolds promote skin regeneration were investigated both within in vitro cell culture and in vivo with a full-thickness skin defect model. The histological results showed that the gelatin-sulfonated silk composite scaffolds promoted granulation, and that incorporation of FGF-2 significantly enhanced the regeneration of skin-like tissues after implantation in rat skin defects for 14 and 28 days. Further investigations demonstrated that 3DG-SF-SO3 FGF scaffolds might stimulate dermal vascularization. These findings thus suggest that incorporation of FGF-2 into the 3D printed scaffolds is a viable strategy for enhancing skin regeneration. PMID- 28655893 TI - Anderson localization in synthetic photonic lattices. AB - Synthetic photonic lattices provide unique capabilities to realize theoretical concepts emerging in different fields of wave physics via the utilization of powerful photonic technologies. Here we observe experimentally Anderson localization for optical pulses in time domain, using a photonic mesh lattice composed of coupled fiber loops. We introduce a random potential through programmed electro-optic pulse phase modulation, and identify the localization features associated with varying degree of disorder. Furthermore, we present a practical approach to control the band-gap width in photonic lattices by varying the coupling between the fiber loops, and reveal that the strongest degree of localization is limited and increases in lattices with wider band-gaps. Importantly, this opens a possibility to enhance or reduce the effect of disorder and associated localization of optical pulses. PMID- 28655892 TI - Disrupting ceramide-CD300f interaction prevents septic peritonitis by stimulating neutrophil recruitment. AB - Sepsis is a serious clinical problem. Negative regulation of innate immunity is associated with sepsis progression, but the underlying mechanisms remains unclear. Here we show that the receptor CD300f promotes disease progression in sepsis. CD300f -/- mice were protected from death after cecal ligation and puncture (CLP), a murine model of septic peritonitis. CD300f was highly expressed in mast cells and recruited neutrophils in the peritoneal cavity. Analysis of mice (e.g., mast cell-deficient mice) receiving transplants of wild-type or CD300f -/- mast cells or neutrophils indicated that CD300f deficiency did not influence intrinsic migratory abilities of neutrophils, but enhanced neutrophil chemoattractant production (from mast cells and neutrophils) in the peritoneal cavity of CLP-operated mice, leading to robust accumulation of neutrophils which efficiently eliminated Escherichia coli. Ceramide-CD300f interaction suppressed the release of neutrophil chemoattractants from Escherichia coli-stimulated mast cells and neutrophils. Administration of the reagents that disrupted the ceramide CD300f interaction prevented CLP-induced sepsis by stimulating neutrophil recruitment, whereas that of ceramide-containing vesicles aggravated sepsis. Extracellular concentrations of ceramides increased in the peritoneal cavity after CLP, suggesting a possible role of extracellular ceramides, CD300f ligands, in the negative-feedback suppression of innate immune responses. Thus, CD300f is an attractive target for the treatment of sepsis. PMID- 28655894 TI - Phonon engineering in proximity enhanced superconductor heterostructures. AB - In this research, we tailor the phonon density of states (DOS) in thin superconducting films to suppress quasiparticle losses. We examine a model system of a proximity-enhanced three-layered Al/Nb/Al heterostructure and show that the local quantized phonon spectrum of the ultrathin Al cladding layers in the heterostructure has a pronounced effect on the superconducting resonator's quality factors. Instead of a monotonic increase of quality factors with decreasing temperatures, we observe the quality factor reaches a maximum at 1.2 K in 5/50/5 nm Al/Nb/Al microstrip resonators, because of a quantized phonon ladder. The phonon DOS may be engineered to enhance the performance of quantum devices. PMID- 28655896 TI - On the Shortening of the Lead Time of Ocean Warm Water Volume to ENSO SST Since 2000. AB - The possible factors associated with the shortening of lead time between ocean warm water volume (WWV) variability along the equatorial Pacific and El Nino Southern Oscillation (ENSO) variability after 2000 are documented. It is shown that the shortening of lead time is due to frequency increases of both WWV and ENSO. During 1979-99 the dominant frequencies were 1.5-3.5 years for both the Nino3.4 and WWV indices. In contrast, during 2000-16, both indices had a relatively flatter spectrum and were closer to a white noise process with a relative maximum at 1.5-2.0 years for the Nino3.4 index and 0.8-1.3 years for the WWV index. The frequency change of ENSO and WWV were linked to a westward shift of the Bjerknes feedback region. The results here are consistent with previous argument that the westward shift of the air-sea coupling region will cause an increase of ENSO frequency, as the corresponding zonal advection feedback reduces the period and growth of coupled instability, thus favoring more frequent and weak El Nino events. PMID- 28655895 TI - Korean Variant Archive (KOVA): a reference database of genetic variations in the Korean population. AB - Despite efforts to interrogate human genome variation through large-scale databases, systematic preference toward populations of Caucasian descendants has resulted in unintended reduction of power in studying non-Caucasians. Here we report a compilation of coding variants from 1,055 healthy Korean individuals (KOVA; Korean Variant Archive). The samples were sequenced to a mean depth of 75x, yielding 101 singleton variants per individual. Population genetics analysis demonstrates that the Korean population is a distinct ethnic group comparable to other discrete ethnic groups in Africa and Europe, providing a rationale for such independent genomic datasets. Indeed, KOVA conferred 22.8% increased variant filtering power in addition to Exome Aggregation Consortium (ExAC) when used on Korean exomes. Functional assessment of nonsynonymous variant supported the presence of purifying selection in Koreans. Analysis of copy number variants detected 5.2 deletions and 10.3 amplifications per individual with an increased fraction of novel variants among smaller and rarer copy number variable segments. We also report a list of germline variants that are associated with increased tumor susceptibility. This catalog can function as a critical addition to the pre existing variant databases in pursuing genetic studies of Korean individuals. PMID- 28655897 TI - Automatic Thalamus Segmentation from Magnetic Resonance Images Using Multiple Atlases Level Set Framework (MALSF). AB - In this paper, we present an original multiple atlases level set framework (MALSF) for automatic, accurate and robust thalamus segmentation in magnetic resonance images (MRI). The contributions of the MALSF method are twofold. First, the main technical contribution is a novel label fusion strategy in the level set framework. Label fusion is achieved by seeking an optimal level set function that minimizes energy functional with three terms: label fusion term, image based term, and regularization term. This strategy integrates shape prior, image information and the regularity of the thalamus. Second, we use propagated labels from multiple registration methods with different parameters to take full advantage of the complementary information of different registration methods. Since different registration methods and different atlases can yield complementary information, multiple registration and multiple atlases can be incorporated into the level set framework to improve the segmentation performance. Experiments have shown that the MALSF method can improve the segmentation accuracy for the thalamus. Compared to ground truth segmentation, the mean Dice metrics of our method are 0.9239 and 0.9200 for left and right thalamus. PMID- 28655898 TI - The angular nature of road networks. AB - Road networks are characterised by several structural and geometrical properties. The topological structure determines partially the hierarchical arrangement of roads, but since these are networks that are spatially constrained, geometrical properties play a fundamental role in determining the network's behaviour, characterising the influence of each of the street segments on the system. In this work, we apply percolation theory to the UK's road network using the relative angle between street segments as the occupation probability. The appearance of the spanning cluster is marked by a phase transition, indicating that the system behaves in a critical way. Computing Shannon's entropy of the cluster sizes, different stages of the percolation process can be discerned, and these indicate that roads integrate to the giant cluster in a hierarchical manner. This is used to construct a hierarchical index that serves to classify roads in terms of their importance. The obtained classification is in very good correspondence with the official designations of roads. This methodology hence provides a framework to consistently extract the main skeleton of an urban system and to further classify each road in terms of its hierarchical importance within the system. PMID- 28655899 TI - Peptides derived from MARCKS block coagulation complex assembly on phosphatidylserine. AB - Blood coagulation involves activation of platelets and coagulation factors. At the interface of these two processes resides the lipid phosphatidylserine. Activated platelets expose phosphatidylserine on their outer membrane leaflet and activated clotting factors assemble into enzymatically active complexes on the exposed lipid, ultimately leading to the formation of fibrin. Here, we describe how small peptide and peptidomimetic probes derived from the lipid binding domain of the protein myristoylated alanine-rich C-kinase substrate (MARCKS) bind to phosphatidylserine exposed on activated platelets and thereby inhibit fibrin formation. The MARCKS peptides antagonize the binding of factor Xa to phosphatidylserine and inhibit the enzymatic activity of prothrombinase. In whole blood under flow, the MARCKS peptides colocalize with, and inhibit fibrin cross linking, of adherent platelets. In vivo, we find that the MARCKS peptides circulate to remote injuries and bind to activated platelets in the inner core of developing thrombi. PMID- 28655900 TI - Oxytocin administration suppresses hypothalamic activation in response to visual food cues. AB - The aim of this study was to use functional neuroimaging to investigate whether oxytocin modulates the neural response to visual food cues in brain regions involved in the control of food intake. Twenty-four normal weight volunteers received intranasal oxytocin (24 IU) or placebo in a double-blind, randomized crossover study. Measurements were made forty-five minutes after dosing. On two occasions, functional MRI (fMRI) scans were performed in the fasted state; the blood oxygen level-dependent (BOLD) response to images of high-calorie foods versus low-calorie foods was measured. Given its critical role in eating behaviour, the primary region of interest was the hypothalamus. Secondary analyses examined the parabrachial nuclei and other brain regions involved in food intake and food reward. Intranasal oxytocin administration suppressed hypothalamic activation to images of high-calorie compared to low-calorie food (P = 0.0125). There was also a trend towards suppression of activation in the parabrachial nucleus (P = 0.0683). No effects of intranasal oxytocin were seen in reward circuits or on ad libitum food intake. Further characterization of the effects of oxytocin on neural circuits in the hypothalamus is needed to establish the utility of targeting oxytocin signalling in obesity. PMID- 28655901 TI - Chronic Sleep Restriction Increases Negative Implicit Attitudes Toward Arab Muslims. AB - Chronic sleep restriction is a common experience; and while it has negative physiological effects, little is known about how it affects human behavior. To date, no study has investigated whether chronic sleep restriction can influence implicit attitudes (e.g., towards a race). Here, in a randomized, counterbalanced crossover design, we subjected participants to 3 weeks of chronic sleep restriction in the lab (i.e., 3 weekly cycles of 5 nights of 4 hours of sleep per night followed by 2 nights of 8 hours of sleep) and found evidence for an increased negative implicit bias towards Arab Muslims. No indicators of an implicit bias were found in these same individuals when they were rested (during a counterbalanced 3-week period of 8 hours time in bed per night). These findings suggest that chronic sleep restriction may "unmask" implicit racial or ethnic biases that are otherwise inhibited when in a rested state. Because chronic sleep restriction is prevalent among many occupations that routinely interact with ethnic minorities in potentially high-conflict situations (e.g., police officers), it is critical to consider the role that restricted sleep may play in exacerbating negative implicit attitudes and their potential for provoking unintentional and potentially harmful behavioral consequences. PMID- 28655902 TI - Inter-Model Warming Projection Spread: Inherited Traits from Control Climate Diversity. AB - Since Chaney's report, the range of global warming projections in response to a doubling of CO2-from 1.5 degrees C to 4.5 degrees C or greater -remains largely unscathed by the onslaught of new scientific insights. Conventional thinking regards inter-model differences in climate feedbacks as the sole cause of the warming projection spread (WPS). Our findings shed new light on this issue indicating that climate feedbacks inherit diversity from the model control climate, besides the models' intrinsic climate feedback diversity that is independent of the control climate state. Regulated by the control climate ice coverage, models with greater (lesser) ice coverage generally possess a colder (warmer) and drier (moister) climate, exhibit a stronger (weaker) ice-albedo feedback, and experience greater (weaker) warming. The water vapor feedback also inherits diversity from the control climate but in an opposite way: a colder (warmer) climate generally possesses a weaker (stronger) water vapor feedback, yielding a weaker (stronger) warming. These inherited traits influence the warming response in opposing manners, resulting in a weaker correlation between the WPS and control climate diversity. Our study indicates that a better understanding of the diversity amongst climate model mean states may help to narrow down the range of global warming projections. PMID- 28655903 TI - fMRI Repetition Suppression During Generalized Social Categorization. AB - Correctly identifying friends and foes is integral to successful group living. Here, we use repetition suppression to examine the neural circuitry underlying generalized group categorization-the process of categorizing in-group and out group members across multiple social categories. Participants assigned to an arbitrary team (i.e., Eagles or Rattlers) underwent fMRI while categorizing political and arbitrary in-group and out-group members. We found that frontoparietal control network exhibited repetition suppression in response to "identical in-group" (Democrat-Democrat or Eagles-Eagles) and "different in group" (Eagles-Democrat or Democrat-Eagles) trials relative to "out-group/in group trials" (Republican-Democrat or Rattler-Eagles). Specifically, the repetition suppression contrast map included bilateral superior parietal lobule, bilateral dorsolateral prefrontal cortex (DLPFC), and bilateral middle temporal gyrus. Participants who reported an increased tendency to join and value their social groups exhibited decreased repetition suppression in bilateral DLPFC. Comparison of our whole-brain repetition suppression map with an independently identified map of frontoparietal control network revealed 34.3% overlap. Social categorization requires recognizing both a target's group membership but also the target's orientation toward one's self. Fittingly, we find that generalized social categorization engages a network that acts as a functional bridge between dorsal attentional (exogenously-oriented) and default mode (internally-oriented) networks. PMID- 28655904 TI - Danhong injection reduces vascular remodeling and up-regulates the Kallikrein kinin system in spontaneously hypertensive rats. AB - Although Danhong injection (DHI) is one of the most prescribed cardiovascular medicines in China, its therapeutic indications and mechanisms remain partially defined. We now identify molecular targets of DHI in resistance vasculatures and demonstrate its role in vascular function and blood pressure (BP) regulation. BP was determined in DHI, Losartan, and placebo- treated Spontaneously Hypertensive Rats (SHR) by both noninvasive and invasive measurements. Vasorelaxation was examined both in conduit and resistance vasculature by ex vivo aortic rings. Microarray analysis was performed and gene expression changes were verified by RT qPCR and ELISA. Diastolic, systolic and mean BPs were significantly lower in DHI treated SHR than controls by both tail-cuff and invasive BP measurements. In ex vivo rings, aortic and mesenteric vessels from SHR treated with DHI exhibited significantly greater acetylcholine-mediated relaxation. Among the 282 genes that are differentially expressed in microarray analysis, DHI treatment up-regulated the expression of kallikrein and plasma kallikrein B genes. DHI also significantly increased serum kallikrein content in SHR. Treatment with DHI significantly increased the ratio of aortic lumen to outer diameter. Therefore, the reduction of vascular remodeling and the up-regulation of Kallikrein-kinin system contribute, at least in part, to the antihypertensive effect of DHI in SHR. PMID- 28655906 TI - Chromosome biology: Structuring interphase chromatin. PMID- 28655905 TI - Mechanisms of DNA-protein crosslink repair. AB - Covalent DNA-protein crosslinks (DPCs, also known as protein adducts) of topoisomerases and other proteins with DNA are highly toxic DNA lesions. Of note, chemical agents that induce DPCs include widely used classes of chemotherapeutics. Their bulkiness blocks virtually every chromatin-based process and makes them intractable for repair by canonical repair pathways. Distinct DPC repair pathways employ unique points of attack and are crucial for the maintenance of genome stability. Tyrosyl-DNA phosphodiesterases (TDPs) directly hydrolyse the covalent linkage between protein and DNA. The MRE11-RAD50-NBS1 (MRN) nuclease complex targets the DNA component of DPCs, excising the fragment affected by the lesion, whereas proteases of the spartan (SPRTN)/weak suppressor of SMT3 protein 1 (Wss1) family target the protein component. Loss of these pathways renders cells sensitive to DPC-inducing chemotherapeutics, and DPC repair pathways are thus attractive targets for combination cancer therapy. PMID- 28655907 TI - Cancer biology: Therapy-induced transcription is cryptically widespread. PMID- 28655908 TI - The effect of interface anisotropy on demagnetization progress in perpendicularly oriented hard/soft exchange-coupled multilayers. AB - The demagnetization progress of various hard/soft multilayers with perpendicular crystalline anisotropy has been studied by a micromagnetic model, incorporating the effect of the interface anisotropy, which is evident on the nucleation field when the soft layer thickness is small. Both microscopic and macroscopic hysteresis loops as well as angular distributions for the magnetizations in the thickness direction have been calculated, taking into account of realistic values of the interface anisotropy. The formula for the nucleation field has been derived analytically, where the nucleation field increases linearly with the interface anisotropy for a wide thickness region. While the nucleation field could change by more than 90% due to the influence of the interface anisotropy, the interface anisotropy has no effect on the pinning field or the coercivity, but it has some slight influence on the angular distributions. On the other hand, positive interface anisotropy enhances the remanence and the energy products, whereas negative interface anisotropy deteriorates both of them. Comparison with the experimental data justifies our calculation, indicating that negative interface anisotropy should be avoided in the experiment. PMID- 28655909 TI - PLK2 Plays an Essential Role in High D-Glucose-Induced Apoptosis, ROS Generation and Inflammation in Podocytes. AB - Diabetic kidney disease (DKD) is a serious complication of hyperglycemia. Currently, there is no effective therapeutic intervention for DKD. In this study, we sought to provide a set of gene profile in diabetic kidneys. We identified 338 genes altered in diabetes-induced DKD glomeruli, and PLK2 exhibited the most dramatic change. Gene set enrichment analysis (GSEA) indicated multiple signaling pathways are involved DKD pathogenesis. Here, we investigated whether PLK2 contributes to podocyte dysfunction, a characteristic change in the development of DKD. High D-glucose (HDG) significantly increased PLK2 expression in mouse podocytes. Suppressing PLK2 attenuated HDG-induced apoptosis and inflammatory responses both in vitro and in vivo. NAC, an antioxidant reagent, rescued HDG and PLK2 overexpression-induced kidney injuries. In summary, we demonstrated that silencing PLK2 attenuates HDG-induced podocyte apoptosis and inflammation, which may serve as a future therapeutic target in DKD. PMID- 28655910 TI - Magnetic field enhancement of organic photovoltaic cells performance. AB - Charge separation is a critical process for achieving high efficiencies in organic photovoltaic cells. The initial tightly bound excitonic electron-hole pair has to dissociate fast enough in order to avoid photocurrent generation and thus power conversion efficiency loss via geminate recombination. Such process takes place assisted by transitional states that lie between the initial exciton and the free charge state. Due to spin conservation rules these intermediate charge transfer states typically have singlet character. Here we propose a donor acceptor model for a generic organic photovoltaic cell in which the process of charge separation is modulated by a magnetic field which tunes the energy levels. The impact of a magnetic field is to intensify the generation of charge transfer states with triplet character via inter-system crossing. As the ground state of the system has singlet character, triplet states are recombination-protected, thus leading to a higher probability of successful charge separation. Using the open quantum systems formalism we demonstrate that the population of triplet charge transfer states grows in the presence of a magnetic field, and discuss the impact on carrier population and hence photocurrent, highlighting its potential as a tool for research on charge transfer kinetics in this complex systems. PMID- 28655911 TI - Versatility of nodal affiliation to communities. AB - Graph theoretical analysis of the community structure of networks attempts to identify the communities (or modules) to which each node affiliates. However, this is in most cases an ill-posed problem, as the affiliation of a node to a single community is often ambiguous. Previous solutions have attempted to identify all of the communities to which each node affiliates. Instead of taking this approach, we introduce versatility, V, as a novel metric of nodal affiliation: V ~ 0 means that a node is consistently assigned to a specific community; V >> 0 means it is inconsistently assigned to different communities. Versatility works in conjunction with existing community detection algorithms, and it satisfies many theoretically desirable properties in idealised networks designed to maximise ambiguity of modular decomposition. The local minima of global mean versatility identified the resolution parameters of a hierarchical community detection algorithm that least ambiguously decomposed the community structure of a social (karate club) network and the mouse brain connectome. Our results suggest that nodal versatility is useful in quantifying the inherent ambiguity of modular decomposition. PMID- 28655912 TI - Galactosylsphingamides: new alpha-GalCer analogues to probe the F'-pocket of CD1d. AB - Invariant Natural Killer T-cells (iNKT-cells) are an attractive target for immune response modulation, as upon CD1d-mediated stimulation with KRN7000, a synthetic alpha-galactosylceramide, they produce a vast amount of cytokines. Here we present a synthesis that allows swift modification of the phytosphingosine side chain by amidation of an advanced methyl ester precursor. The resulting KRN7000 derivatives, termed alpha-galactosylsphingamides, were evaluated for their capacity to stimulate iNKT-cells. While introduction of the amide-motif in the phytosphingosine chain is tolerated for CD1d binding and TCR recognition, the studied alpha-galactosylsphingamides showed compromised antigenic properties. PMID- 28655913 TI - Novel small peptides derived from VEGF125-136: potential drugs for radioactive diagnosis and therapy in A549 tumor-bearing nude mice. AB - Vascular endothelial growth factor receptor (VEGFR) is a critical factor in tumor angiogenesis and has been considered a potential target for receptor-mediated radionuclide imaging and therapy. In this study, we identified two peptides (QKRKRKKSRKKH and RKRKRKKSRYIVLS) derived from VEGF125-136 that displayed high binding affinities to VEGFR and strong inhibition of A549 cell growth. 99mTc- and 188Re-labeled peptides displayed high labeling efficiency and favorable stability in saline and human plasma. At the cellular level, the radiolabeled peptides could bind with A549 cells and be internalized via the VEGFR-1-mediated pathway. 99mTc/188Re-labeled peptide was significantly accumulated at xenograft tumors, as observed with single-photon emission computed tomography (SPECT) planar imaging. Moreover, 188Re-labeled peptides significantly inhibited tumor growth, prolonged the survival time of the tumor-bearing nude mice and resulted in much more necrotic regions and apoptotic cells in the A549 xenograft tumors. These results demonstrated that these two peptides as candidate drugs for radionuclide imaging and tumor therapy. PMID- 28655914 TI - IGF1R deficiency attenuates acute inflammatory response in a bleomycin-induced lung injury mouse model. AB - IGF1R (Insulin-like Growth Factor 1 Receptor) is a tyrosine kinase with pleiotropic cellular functions. IGF activity maintains human lung homeostasis and is implicated in pulmonary diseases such as cancer, ARDS, COPD, asthma and fibrosis. Here we report that lung transcriptome analysis in mice with a postnatally-induced Igf1r gene deletion showed differentially expressed genes with potentially protective roles related to epigenetics, redox and oxidative stress. After bleomycin-induced lung injury, IGF1R-deficient mice demonstrated improved survival within a week. Three days post injury, IGF1R-deficient lungs displayed changes in expression of IGF system-related genes and reduced vascular fragility and permeability. Mutant lungs presented reduced inflamed area, down regulation of pro-inflammatory markers and up-regulation of resolution indicators. Decreased inflammatory cell presence in BALF was reflected in diminished lung infiltration mainly affecting neutrophils, also corroborated by reduced neutrophil numbers in bone marrow, as well as reduced lymphocyte and alveolar macrophage counts. Additionally, increased SFTPC expression together with hindered HIF1A expression and augmented levels of Gpx8 indicate that IGF1R deficiency protects against alveolar damage. These findings identify IGF1R as an important player in murine acute lung inflammation, suggesting that targeting IGF1R may counteract the inflammatory component of many lung diseases. PMID- 28655915 TI - Multiple introns in a deep-sea Annelid (Decemunciger: Ampharetidae) mitochondrial genome. AB - Wood falls provide episodic fluxes of energy to the sea floor that are degraded by a species-rich benthic fauna. Part of this rich diversity includes annelid polychaetes but unfortunately, our understanding of such fauna is limited and their genetic variability and evolutionary origins remain poorly known. In this study, we sequenced complete mitochondrial genomes from three congeneric Decemunciger (Ampharetidae) individuals that had colonized multiple wood falls in the deep (~1600 m) NE Pacific Ocean. Mitochondrial gene order within Decemunciger was similar to the three other available Terebellomorpha genomes, consistent with the relatively conserved nature of mitochondrial genomes within annelids. Unexpectedly, we found introns within the cox1, nad1 and nad4 genes of all three genomes assembled. This is the greatest number of introns observed in annelid mtDNA genomes, and possibly in bilaterians. Interestingly, the introns were of variable sizes suggesting possible evolutionary differences in the age and origins of introns. The sequence of the introns within cox1 is similar to Group II introns previously identified, suggesting that introns in the mitochondrial genome of annelids may be more widespread then realized. Phylogenetically, Decemunciger appears to be a sister clade among current vent and seep deep-sea Ampharetinae. PMID- 28655916 TI - Effects of habitat constraints on soil microbial community function. AB - An underlying assumption of most soil carbon (C) dynamics models is that soil microbial communities are functionally similar; in other words, that microbial activity under given conditions is not dependent on the composition or diversity of the communities. Although a number of studies have indicated that microbial communities are not intrinsically functionally similar, most soil C dynamics models can adequately describe C dynamics without explicitly describing microbial functioning. Here, we provide a mechanistic basis for reconciling this apparent discrepancy. In a reciprocal transplant experiment, we show that the environmental context (soil and pore-network properties) of microbial communities can constrain the activity of functionally different communities to such an extent that their activities are indistinguishable. The data also suggest that when microbial activity is less constrained, the intrinsic functional differences among communities can be expressed. We conclude that soil C dynamics may depend on microbial community structure or diversity in environments where their activity is less constrained, such as the rhizosphere or the litter layer, but not in oligotrophic environments such as the mineral layers of soil. PMID- 28655917 TI - Dielectric Nanorod Scattering and its Influence on Material Interfaces. AB - This work elaborates on the high scattering which dielectric nanorods exhibit and how it can be exploited to control light propagation across material interfaces. A detailed overview of how dielectric nanorods interact with light through a combination of dipolar scattering and leaky modes is performed via outward power flux calculations. We establish and account for design parameters that best result in light magnification owing to resonant behavior of nanorods. Impact of material parameters on scattering and their dispersion have been calculated to establish that low loss dielectric oxides like ZnO when nanostructured show excellent antenna like resonances which can be used to control light coupling and propagation. Interfacial scattering calculations demonstrate the high forward directivity of nanorods for various dielectric interfaces. A systematic analysis for different configurations of single and periodic nanorods on air dielectric interface emphasizes the light coupling tendencies exhibited by nanorods to and from a dielectric. Spatial characteristics of the localized field enhancement of the nanorod array on an air dielectric interface show focusing attributes of the nanorod array. We give a detailed account to tailor and selectively increase light propagation across an interface with good spectral and spatial control. PMID- 28655918 TI - The role of SET/I2PP2A in canine mammary tumors. AB - Canine mammary tumor is the most common neoplasm in female dogs, and it has generated considerable attention as a translational model for human breast cancer. Ser/Thr protein phosphatase 2A (PP2A) plays a critical role as a tumor suppressor, and SET/I2PP2A, the endogenous inhibitory protein of PP2A, binds directly to PP2A and suppresses its phosphatase activity. Here, we investigated the role of SET in the tumorigenic growth in canine mammary tumor as well as in the sensitivity of tumors to existing therapeutics. Elevated protein levels of SET were observed in advanced-stage of canine mammary tumor tissues of dogs compared with paired normal tissues. Knockdown of SET expression in a canine mammary tumor cell line CIP-m led to increased PP2A activity and decreased cell proliferation, colony formation, and in vivo tumor growth. We observed suppression of mTOR, beta-catenin, and NFkappaB signaling by SET knockdown. The sensitivity of CIP-m cells to doxorubicin was decreased by SET knockdown, while SET knockdown in CIP-m cells did not affect sensitivity to 4-OH-tamoxifen, carboplatin, bortezomib, and X-ray radiation. These data suggest that SET plays important roles in the tumor progression of a subset of canine mammary tumor by suppressing PP2A activity and enhancing mTOR, beta-catenin, and NFkappaB signaling. PMID- 28655919 TI - Facile Fabrication of Nanofibrillated Chitin/Ag2O Heterostructured Aerogels with High Iodine Capture Efficiency. AB - Nanofibrillated chitin/Ag2O aerogels were fabricated for radioiodine removal. Chitin was first fabricated into nanofibers with abundant acetyl amino groups ( NHCOCH3) on the surface. Then, highly porous chitin nanofiber (ChNF) aerogels were obtained via freeze-drying. The ChNF aerogels exhibited a low bulk density of 2.19 mg/cm3 and a high specific surface area of 179.71 m2/g. Ag2O nanoparticles were evenly anchored on the surfaces of ChNF scaffolds via strong interactions with -NHCOCH3 groups, subsequently yielding Ag2O@ChNF heterostructured aerogels. The composites were used as efficient absorbents to remove radioiodine anions from water and capture a high amount of I2 vapor in the forms of AgI and iodine molecules. The adsorption capacity of the composite monoliths can reach up to 2.81 mmol/g of I- anions. The high adsorbability of the composite monolithic aerogel signifies its potential applications in radioactive waste disposal. PMID- 28655920 TI - Anisotropic Optical Response of Silver Nanorod Arrays: Surface Enhanced Raman Scattering Polarization and Angular Dependences Confronted with Ellipsometric Parameters. AB - Silver nanorod arrays prepared by oblique angle deposition (AgOADs) represent versatile, simple and inexpensive substrates for high sensitivity surface enhanced Raman scattering (SERS) applications. Their anisotropic nature suggests that their optical responses such as the SERS signal, the depolarization ratio, reflectivity and ellipsometric parameters critically depend on the states of polarization, nanorod angular arrangement and specific illumination-observation geometry. SERS polarization and angular dependences of AgOADs were measured using methylene blue (MB) molecule. Our study constitutes, to our knowledge, the most detailed investigation of such characteristics of plasmonic nanostructures to date. This is due to the 90 degrees -scattering geometry used in which two out of three Euler angles determining the nanorod spatial orientation and four polarization combinations can be varied simultaneously. We attributed the anisotropic optical response to anisotropic (pseudo)refractive index caused by different periodicity of our structures in different directions since the plasmonic properties were found rather isotropic. For the first time we demonstrate very good correspondence between SERS intensities and ellipsometric parameters for all measured configurations as compared on the basis of the surface selection rules. Obtained results enable quantitative analysis of MB Raman tensor elements, indicating that the molecules adsorb predominantly with the symmetry axis perpendicular to the surface. PMID- 28655921 TI - Novel insights into mitochondrial gene rearrangement in thrips (Insecta: Thysanoptera) from the grass thrips, Anaphothrips obscurus. AB - We sequenced the mitochondrial (mt) genome of the grass thrips, Anaphothrips obscurus, which is highly rearranged and differs from the four thrips species reported previously in the arrangement of both tRNA genes and a protein-coding gene, nad3, and in the copy number of the control region (CR). We reconstructed the phylogeny of the thrips with mt genome sequences, and used it as a framework to gain insights into mt genome evolution in thrips. It is evident that A. obscurus is less rearranged in mt genome organization than the other four known thrips. nad3 is in its ancestral location in A. obscurus but was translocated in other four thrips. Also, A. obscurus has one CR, which is ancestral to hexapods whereas other thrips have two or three CRs. All of the five thrips whose mt genomes have been sequenced to date are from the subfamily Thripinae, which represents about a quarter of the species richness in the order Thysanoptera. The high variation in mt genome organization observed in a subfamily challenges our knowledge about animal mt genomes. It remains to be investigated why mt genomes evolved so fast in the subfamily Thripinae and how mt genomes evolved in other lineages of thrips. PMID- 28655922 TI - Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds. AB - Brown adipocytes play an important role in human energy metabolism and prevention of obesity and diabetes. Induced pluripotent stem cells (iPSCs) represent a promising source for brown adipocytes; however, exogenous gene induction is generally required for iPSCs generation, which might cause undesired effects particularly in long-term treatment after transplantation. We have previously reported a cocktail of six small chemical compounds that enables a conversion of human fibroblasts into chemical compound-induced neuronal cells (CiNCs). Here, we report that modified combinations of the chemical compounds and rosiglitazone, a PPARgamma agonist, afforded direct conversion of human fibroblasts into brown adipocytes. The chemical compound-induced brown adipocytes (ciBAs) exhibit induction of human brown adipocyte-specific genes such as Ucp1, Ckmt1, Cited1 and other adipocyte-specific genes such as Fabp4, AdipoQ, and Ppargamma. Treatment with either isoproterenol or Forskolin further induced the expression of Ucp1, suggesting that beta adrenergic receptor signalling in ciBAs could be functional for induction of thermogenic genes. Moreover, oxygen consumption rates were elevated in ciBAs along with increase of cellular mitochondria. Our findings might provide an easily accessible approach for generating human brown adipocytes from fibroblasts and offer therapeutic potential for the management of obesity, diabetes, and related metabolic disorders. PMID- 28655923 TI - Quantitative Assessment of Hydrological Alteration Caused by Irrigation Projects in the Tarim River basin, China. AB - The Tarim River is the longest inland river at an arid area in China. Deterioration in its ecohydrological system has received much attention world widely. This study presents quantitative assessment of hydrological alterations in the hydrological regime of the Tarim River caused by reservoir irrigation and channel irrigation over a period of over a half century. The improved indicators of hydrologic alteration and range of variability approach were applied to the daily flow rates at the two representative hydrological stations. Our study shows that the annual extreme water conditions (1-, 3-, 7-day annual minimum and extreme low timing) have been altered, compared with the pre-impact period. The average flow rate in July, the 30-day annual maximum flow rates, the date for the maximum rate, the rise rate, and the fall rate show a significant decreasing trend. The improved overall degree of hydrological alteration for the two stations are approximately 68.7% and 61.8%, suggesting a high degree of alteration. This study greatly improved our understanding of impacts of irrigations on the ecohydrological characteristics in the Tarim River. PMID- 28655924 TI - Downregulated USP3 mRNA functions as a competitive endogenous RNA of SMAD4 by sponging miR-224 and promotes metastasis in colorectal cancer. AB - Increasing evidence shows that competitive endogenous RNAs (ceRNAs) can affect the expression of other transcripts by sequestering common microRNAs (miRNAs), and participate in tumourigenesis. As a potent tumour suppressor in colorectal cancer (CRC), SMAD4 is regulated by many miRNAs. However, the regulation of SMAD4 by ceRNAs has never been examined. In the present study, we found that USP3 modulated SMAD4 expression in a miRNA dependent, and protein-coding gene independent manner. USP3 and SMAD4 were directly targeted by miR-224, and overexpression of the USP3 3'UTR could inhibit metastasis caused by the loss of USP3. The correlation of USP3, SMAD4 and miR-224 expression was further verified in CRC specimens. Additionally, the loss of USP3 was associated with distal metastasis and a poor prognosis. Altogether, our study demonstrates USP3 as a bona fide SMAD4 ceRNA. The results from this study may provide new insights into the prevention and treatment of CRC. PMID- 28655925 TI - Natural history of t(11;14) multiple myeloma. AB - Translocation (11;14) on interphase fluorescent in situ hybridization in plasma cells is regarded as a standard risk prognostic marker in multiple myeloma based on studies conducted before introduction of current therapies. We identified 365 patients with t(11;14), and 730 matched controls:132 patients with non-(11;14) translocations and 598 patients with no chromosomal translocation. The median progression-free survival for the three groups were 23.0 (95% confidence interval (CI), 20.8-27.6), 19.0 (95% CI, 15.8-22.7) and 28.3 (95% CI, 25.7-30.6) months, respectively (P<0.01). The median overall survival (OS) for t(11;14), non-(11;14) translocation and no-translocation groups were 74.4 (95% CI, 64.8-89.3), 49.8 (95% CI, 40.0-60.6) and 103.6 (95% CI, 85.2-112.3) months, respectively (P<0.01). Excluding those with 17p abnormality, the median OS in the three groups were 81.7 (95% CI, 67.0-90.7), 58.2 (95% CI, 47.0-76.4) and 108.3 (95% CI, 92.4-140.1) months, respectively (P<0.01). The above relationship held true in patients with age <65 years, international staging system (ISS) I/II stage or those who received novel agent-based induction. Advanced age (hazard ratio (HR): 1.98), 17p abnormality (HR: 2.2) and ISS III stage (HR: 1.59) at diagnosis predicted reduced OS in patients with t(11;14). These results suggest that outcomes of t(11;14) MM are inferior to other standard risk patients. PMID- 28655926 TI - Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice. AB - We examined the effect of chronic high fat diet (HFD) on amyloid deposition and cognition of 12-months old APP23 mice, and correlated the phenotype to brain transcriptome and lipidome. HFD significantly increased amyloid plaques and worsened cognitive performance compared to mice on normal diet (ND). RNA-seq results revealed that in HFD mice there was an increased expression of genes related to immune response, such as Trem2 and Tyrobp. We found a significant increase of TREM2 immunoreactivity in the cortex in response to HFD, most pronounced in female mice that correlated to the amyloid pathology. Down regulated by HFD were genes related to neuron projections and synaptic transmission in agreement to the significantly deteriorated neurite morphology and cognition in these mice. To examine the effect of the diet on the brain lipidome, we performed Shotgun Lipidomics. While there was no difference in the total amounts of phospholipids of each class, we revealed that the levels of 24 lipid sub-species in the brain were significantly modulated by HFD. Network visualization of correlated lipids demonstrated overall imbalance with most prominent effect on cardiolipin molecular sub-species. This integrative approach demonstrates that HFD elicits a complex response at molecular, cellular and system levels in the CNS. PMID- 28655927 TI - Coordination of Bactericidal and Iron Regulatory Functions of Hepcidin in Innate Antimicrobial Immunity in a Zebrafish Model. AB - Hepcidin acts as both an antimicrobial peptide and a hormonal regulator of iron homeostasis; however, the biological significance of this dual-function in immune reactions remains elusive. In this study, we provide experimental evidence regarding the coordination of this dual-function in the innate antimicrobial immunity using a zebrafish model. The transcription of hepcidin gene was significantly upregulated in liver by Aeromonas hydrophila (A.h) DNA stimulation, which was accompanied by an increase of hepcidin protein and a decrease of iron concentration in serum. Thus, an enhanced bactericidal activity against A.h and Escherichia coli and inhibitory effects on A.h growth and OmpA expression were observed in A.h cells, the latter of which made the bacterium more susceptible to complement attack. The enhanced bacteriostatic activities in serum following the stimulation were dramatically impaired by neutralizing hepcidin or restoring iron to the samples. Immuno-protection assay showed that zebrafish administrated with A.h DNA or designed CpG-ODNs had a significantly enhanced defence against A.h and Vibrio alginolyticus infections, which was also eliminated by the neutralization of hepcidin. Results indicate that the induction of hepcidin leads to the decrease of iron in circulation, which eventually limits iron availability to invading microorganisms, thus contributing to host defence. PMID- 28655928 TI - Brain activity changes in a macaque model of oxaliplatin-induced neuropathic cold hypersensitivity. AB - The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 degrees C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity. PMID- 28655929 TI - Discovery of 2-hydroxyarbekacin, a new aminoglycoside antibiotic with reduced nephrotoxicity. PMID- 28655930 TI - A 2,4'-linked tetrahydroxanthone dimer with protein tyrosine phosphatase 1B inhibitory activity from the Okinawan freshwater Aspergillus sp. PMID- 28655931 TI - Genome-wide DNA methylation analysis of the porcine hypothalamus-pituitary-ovary axis. AB - Previous studies have suggested that DNA methylation in both CpG and CpH (where H = C, T or A) contexts plays a critical role in biological functions of different tissues. However, the genome-wide DNA methylation patterns of porcine hypothalamus-pituitary-ovary (HPO) tissues remain virtually unexplored. In this study, methylomes of HPO tissues were profiled to investigate their differences and similarities. We found that HPO methylomes displayed tissue-specific methylation patterns in both CpG and CpH contexts. At gene locations, the methylation and density of CpGs was negatively linked at transcription start sites but positively linked at transcription end sites. The densities of CpGs and CpHs at CpG island (CGI) locations were negatively correlated with their methylation. Moreover, the methylation interactions between CGIs and genes showed similar pattern in the CpG context but tissue-specific pattern in the CpH context. CpGs located in CGIs, upstream regions and exons were protected from methylation dynamics, whereas CGI shores, CGI shelves and intergenic regions were more likely to be targets of methylation changes. The methylation dynamics enriching in a tissue-specific manner appeared to maintain and establish the biological functions of HPO tissues. Our analyses provided valuable insights into the tissue-specific methylomes of porcine HPO tissues. PMID- 28655932 TI - Development and Validation of Non simultaneous Retinal Image Acquisition-Based Retinal Oximeter. AB - The purpose of this study was to develop and validate a tool for the measurement of retinal oxygen saturation using a conventional fundus camera-based nonsimultaneous imaging technique. Retinal oximetry setup comprising a conventional Zeiss FF450IR fundus camera, dual wavelength band-pass filters of wavelengths 570 and 600 nm were used. Image analysis was performed using MATLAB R2013b. All the study participants underwent comprehensive eye examination, fundus examination, complete hemogram analysis, and evaluation of systemic hemodynamics. Fundus images were captured by a nonsimultaneous retinal oximetry. A total of 45 subjects were included in the analysis. Median age of the subjects was 21 years ranging from 19 to 34 years. The median retinal arteriolar and venular oxygen saturation was 94.7% and 55.8%. Comparison of retinal oxygen saturation between three visits showed no statistically significant difference for both arteriolar (p = 0.33)and venular oxygen saturation (p = 0.79). Intraclass correlation coefficients for test-retest, short-term, and day-to-day repeatability were 0.84, 0.90, and 0.86 for arteriolar oxygen saturation and 0.92, 0.98, and 0.98 for retinal venular oxygen saturation. Oxygen saturation in retinal arteriolar and venular blood vessels can be measured by nonsimultaneous image acquisition technique using a conventional fundus camera with good repeatability. PMID- 28655933 TI - Fullerene-Containing Electrically Conducting Electron Beam Resist for Ultrahigh Integration of Nanometer Lateral-Scale Organic Electronic Devices. AB - An outstanding issue with organic devices is the difficulty of simultaneously controlling the lateral size and position of structures at submicron or nanometer scales. In this study, nanocomposite electron beam (EB) organic resists are proved to be excellent candidates for electrically conductive and/or memory component materials for submicron or nanometer lateral-scale organic electronic devices. The memory and the resist patterning characteristics are investigated for a positive electron beam resist of ZEP520a containing [6,6]-phenyl-C61 butyric acid methyl ester (PCBM). Regarding the memory characteristics, good programming and excellent retention characteristics are obtained for electrons. The carrier transfer and retention mechanisms are also investigated. Regarding the resist patterning characteristics, it is found that line patterns (square patterns) of ZEP520a containing PCBM can be made with widths (side lengths) of less than 200 nm by using an extremely simple process with only EB exposures and developments. The distribution of PCBM molecules or their aggregations is also clarified in ZEP520a containing PCBM. The results of this study open the door to the simple fabrication of highly integrated flexible memories and electrical wires as well as of single-electron or quantum devices, including quantum information devices and sensitive biosensors for multiplexed and simultaneous diagnoses. PMID- 28655934 TI - Oxidative stress induced by UVA photoactivation of the tryptophan UVB photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) inhibits nucleotide excision repair in human cells. AB - Potentially mutagenic DNA lesions induced by UVB (wavelengths 280-320 nm) are important risk factors for solar ultraviolet (UV) radiation-induced skin cancer. The carcinogenicity of the more abundant UVA (320-400 nm) is less well understood but is generally regarded to reflect its interaction with cellular chromophores that act as photosensitisers. The arylhydrocarbon receptor agonist 6 formylindolo[3,2-b] carbazole (FICZ), is a UVB photoproduct of tryptophan and a powerful UVA chromophore. Combined with UVA, FICZ generates reactive oxygen species (ROS) and induces oxidative DNA damage. Here we demonstrate that ROS generated by FICZ/UVA combinations also cause extensive protein damage in HaCaT human keratinocytes. We show that FICZ/UVA-induced oxidation significantly inhibits the removal of potentially mutagenic UVB-induced DNA photolesions by nucleotide excision repair (NER). DNA repair inhibition is due to FICZ/UVA induced oxidation damage to the NER proteome and DNA excision repair is impaired in extracts prepared from FICZ/UVA-treated cells. NER protects against skin cancer. As a likely UVB photoproduct of intracellular tryptophan, FICZ represents a de facto endogenous UVA photosensitiser in sun-exposed skin. FICZ formation may increase the risk of solar UV-induced skin cancer by promoting photochemical damage to the NER proteome and thereby preventing the removal of UVB-induced DNA lesions. PMID- 28655935 TI - Contribution of plasma membrane lipid domains to red blood cell (re)shaping. AB - Although lipid domains have been evidenced in several living cell plasma membranes, their roles remain largely unclear. We here investigated whether they could contribute to function-associated cell (re)shaping. To address this question, we used erythrocytes as cellular model since they (i) exhibit a specific biconcave shape, allowing for reversible deformation in blood circulation, which is lost by membrane vesiculation upon aging; and (ii) display at their outer plasma membrane leaflet two types of submicrometric domains differently enriched in cholesterol and sphingomyelin. We here reveal the specific association of cholesterol- and sphingomyelin-enriched domains with distinct curvature areas of the erythrocyte biconcave membrane. Upon erythrocyte deformation, cholesterol-enriched domains gathered in high curvature areas. In contrast, sphingomyelin-enriched domains increased in abundance upon calcium efflux during shape restoration. Upon erythrocyte storage at 4 degrees C (to mimick aging), lipid domains appeared as specific vesiculation sites. Altogether, our data indicate that lipid domains could contribute to erythrocyte function associated (re)shaping. PMID- 28655936 TI - A novel neutralizing monoclonal antibody targeting the N-terminal domain of the MERS-CoV spike protein. AB - This corrects the article DOI: 10.1038/emi.2017.18. PMID- 28655937 TI - [Evaluation of hazards caused by magnetic field emitted from magnetotherapy applicator to the users of bone conduction hearing prostheses]. AB - BACKGROUND: Low frequency magnetic field, inducing electrical field (Ein) inside conductive structures may directly affect the human body, e.g., by electrostimulation in the nervous system. In addition, the spatial distribution and level of Ein are disturbed in tissues neighbouring the medical implant. MATERIAL AND METHODS: Numerical models of magneto therapeutic applicator (emitting sinusoidal magnetic field of frequency 100 Hz) and the user of hearing implant (based on bone conduction: Bonebridge type - IS BB or BAHA (bone anchorde hearing aid) type - IS-BAHA) were worked out. Values of Ein were analyzed in the model of the implant user's head, e.g., physiotherapist, placed next to the applicator. RESULTS: It was demonstrated that the use of IS-BB or IS-BAHA makes electromagnetic hazards significantly higher (up to 4-fold) compared to the person without implant exposed to magnetic field heterogeneous in space. Hazards for IS-BAHA users are higher than those for IS-BB users. It was found that applying the principles of directive 2013/35/EU, at exposure to magnetic field below exposure limits the direct biophysical effects of exposure in hearing prosthesis users may exceed relevant limits. Whereas applying principles and limits set up by Polish labor law or the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines, the compliance with the exposure limits also ensures the compliance with relevant limits of electric field induced in the body of hearing implant user. CONCLUSIONS: It is necessary to assess individually electromagnetic hazard concerning hearing implant users bearing in mind significantly higher hazards to them compared to person without implant or differences between levels of hazards faced by users of implants of various structural or technological solutions. Med Pr 2017;68(4):469-477. PMID- 28655938 TI - Significance of High-frequency Electrical Brain Activity. AB - Electroencephalogram (EEG) data include broadband electrical brain activity ranging from infra-slow bands (< 0.1 Hz) to traditional frequency bands (e.g., the approx. 10 Hz alpha rhythm) to high-frequency bands of up to 500 Hz. High frequency oscillations (HFOs) including ripple and fast ripple oscillations (80 200 Hz and>200 / 250 Hz, respectively) are particularly of note due to their very close relationship to epileptogenicity, with the possibility that they could function as a surrogate biomarker of epileptogenicity. In contrast, physiological high-frequency activity plays an important role in higher brain functions, and the differentiation between pathological / epileptic and physiological HFOs is a critical issue, especially in epilepsy surgery. HFOs were initially recorded with intracranial electrodes in patients with intractable epilepsy as part of a long term invasive seizure monitoring study. However, fast oscillations (FOs) in the ripple and gamma bands (40-80 Hz) are now noninvasively detected by scalp EEG and magnetoencephalography, and thus the scope of studies on HFOs /FOs is rapidly expanding. PMID- 28655939 TI - Increased Anti-HSP60 and Anti-HSP70 Antibodies in Women with Unexplained Recurrent Pregnancy Loss. AB - Vascular dysfunction has been reported in women with recurrent pregnancy loss (RPL). We investigated the severity of vascular dysfunction in non-pregnant women with RPL and its correlation with anti-heat shock protein (HSP) antibodies that are known to induce arteriosclerosis. We measured the serum anti-HSP60 antibodies, anti-HSP70 antibodies, and anti-phospholipid antibodies (APA) in 68 women with RPL and 29 healthy controls. Among the women with RPL, 14 had a diagnosis of antiphospholipid syndrome (APS), and in the remaining 54, the causes for RPL were unexplained. Compared to the controls, the brachial-ankle pulse wave velocity (baPWV), carotid augmentation index (cAI), and uterine artery pulsatility index (PI) were all significantly higher in the women with both APS and unexplained RPL. Compared to the controls, the anti-HSP60 antibody levels were significantly higher in the APA-positive group of women with unexplained RPL, and the anti-HSP70 antibody levels were significantly higher in APS and APA positive group of women with unexplained RPL. However, the anti-HSP60 and anti HSP70 antibody levels did not correlate with the values of baPWV or cAI. Our results demonstrated anti-HSP60 and anti-HSP70 antibodies are increased in women with unexplained RPL. Further studies are needed to elucidate the roles of anti HSP antibodies and their pathophysiology in unexplained RPL. PMID- 28655940 TI - Evaluating the Effects of Air Pollution from a Plastic Recycling Facility on the Health of Nearby Residents. AB - We evaluated how exposure to airborne volatile organic compounds emitted from a plastic recycling facility affected nearby residents, in a cross-sectional study. Individuals>10 years old were randomly sampled from 50 households at five sites and given questionnaires to complete. We categorized the subjects by distance from the recycling facility and used this as a proxy measure for pollutant exposure. We sought to improve on a preceding study by generating new findings, improving methods for questionnaire distribution and collection, and refining site selection. We calculated the odds of residents living 500 or 900 m away from the facility reporting mucocutaneous and respiratory symptoms using a reference group of residents 2,800 m away. Self-reported nasal congestion (odds ratio=3.0, 95% confidence interval=1.02-8.8), eczema (5.1, 1.1-22.9), and sore throat (3.9, 1.1-14.1) were significantly higher among residents 500 m from the facility. Those 900 m away were also considerably more likely to report experiencing eczema (4.6, 1.4-14.9). Air pollution was found responsible for significantly increased reports of mucocutaneous and respiratory symptoms among nearby residents. Our findings confirm the effects of pollutants emitted from recycling facilities on residents' health and clarify that study design differences did not affect the results. PMID- 28655941 TI - The Immunological Impact of Chemotherapy on the Tumor Microenvironment of Oral Squamous Cell Carcinoma. AB - Anticancer drugs induce cell-cycle arrest and apoptosis not only in tumor cells, but also in immune cells. However, many preclinical and clinical findings show that some chemotherapeutic agents can improve the antitumor efficacy of immunotherapy. We immunohistochemically analyzed the degree of immune cell infiltration and the relevance of programmed cell death 1 ligand-1 (PD-L1) expression in surgically resected oral squamous cell carcinoma (OSCC) specimens from patients who had undergone pretreatment with certain chemotherapies and other patients without pretreatment. We divided the patients into the group of neoadjuvant chemotherapy (NAC) patients (n=8) and the nNAC (without NAC) patient group (n=10). We observed that NAC induced infiltrations of CD4, CD8 T cells and CD56 NK cells into the tumor microenvironment. Decreased numbers of Tregs and PD 1-positive cells were observed in the NAC group. No significant difference was observed in the degree of immune-cell infiltration between the patient groups except for CD56 NK cells in the stroma and PD-1 cells in cancer nests. Eighty percent of the nNAC specimens showed intermediate-to-strong PD-L1 protein expression, whereas 75% of the NAC specimens showed down-regulation of the PD-L1 protein, indicating the effectiveness of the chemotherapeutic treatment before surgery. PMID- 28655942 TI - Diagnostic Ureteroscopy for Cases Clinically Suspected of Carcinoma in Situ of the Upper Urinary Tract. AB - We elucidate the fate of cases clinically suspected of carcinoma in situ (Cis) of the upper tract with serial ureteroscopy. Of 143 patients who underwent ureteroscopy for suspected upper tract urothelial carcinoma (UTUC) between January 2008 and February 2016, 12 cases with consistently positive urine cytology and poorly detectable upper-tract malignancies by imaging were reviewed. In these 12 patients, 19 ureteroscopy procedures (25 renal units) were performed. Vesical random biopsy was performed before the 1st ureteroscopy to exclude malignancy of the bladder in all 12 cases. Median follow-up was 42 (13-67) months. Positive biopsy results at the 1st ureteroscopy were obtained in 3 (25%) patients and all were diagnosed wth Cis of the upper tract. Two (17%) of 9 patients who were negative or inconclusive at the 1st ureteroscopy were finally diagnosed as UTUC, but plural ureteroscopy procedures were needed for the diagnoses in both. Carcinoma of the bladder appeared in 5 (42%) patients during follow-up, despite the earlier ruling out of vesical malignancy. Four (33%) of those 5 patients never developed upper-tract urothelial carcinoma during follow up. Caution is required before undertaking radical surgery for cases clinically suspected of Cis of the upper tract. In our experience, only 42% of such patients developed UTUC; another 33% eventually developed carcinoma of the bladder without UTUC. PMID- 28655943 TI - Lesion Size on Ultrasonography Predicts Potential Invasion in Ductal Carcinoma in situ Preoperatively Diagnosed by Breast Needle Biopsy. AB - Ductal carcinoma in situ (DCIS) of the breast has no potential to metastasize, but over 20% of cases preoperatively diagnosed as DCIS are upstaged on final pathology. The rates of upstaging and the predictors for invasion on final pathology were evaluated. For 240 primary breast cancers, radiological findings on mammography, ultrasonography, and magnetic resonance imaging were investigated along with pathological and clinical information. Univariate and multivariate analyses were performed to identify predictors of potential invasion. Of the 240 breast cancers, 68 (28.3%) showed invasion on final pathology, and 5 (2.5%) had sentinel node metastasis. The multivariate analysis identified five independent predictors: non-mass lesions >2.4 cm on ultrasonography (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.02-7.95, p=0.047), comedo-type histology (OR 6.89, 95% CI 1.89-25.08, p<0.01), solid-type histology (OR 7.97, 95% CI 2.08-30.49, p<0.01), palpable mass (OR 2.63, 95% CI 1.05-6.64, p=0.04), and bloody nipple discharge (OR 4.61, 95% CI 1.20-17.66, p=0.02). These five predictors were associated with invasion on final pathology and may help select candidates for sentinel node biopsy. PMID- 28655944 TI - Importance of Second-look Endoscopy on an Empty Stomach for Finding Gastric Bezoars in Patients with Gastric Ulcers. AB - Most gastric bezoars can be treated with endoscopic fragmentation combined with or without cola dissolution, whereas laparotomy or laparoscopic surgery is generally inevitable for small intestinal bezoars because they cause small bowel obstruction. Therefore, early diagnosis and management of gastric bezoars are necessary to prevent bezoar-induced ileus. To investigate the incidence of overlooked gastric bezoars during the initial esophagogastroduodenoscopy, we retrospectively reviewed the cases of 27 patients diagnosed with gastrointestinal bezoars. The bezoars were diagnosed using esophagogastroduodenoscopy (n=25), abdominal ultrasonography (n=1), and barium follow-through examination (n=1). Bezoars were overlooked in 9/25 patients (36.0%) during the initial endoscopy examination because the bezoars were covered with debris in the stomach. Of the 9 patients, 8 had concomitant gastric ulcers, and the other patient had gastric lymphoma. Although a computed tomography (CT) scan was performed before the second-look endoscopy in 8 of the 9 patients, the bezoars were mistaken as food debris on CT findings and were overlooked in these patients. In conclusion, gastric bezoars may not be discovered during the initial esophagogastroduodenoscopy and CT scan. In cases with debris in the stomach, second-look endoscopy is essential to detect bezoars. PMID- 28655945 TI - A Case of Refractory Langerhans Cell Histiocytosis Complicated with Hemophagocytic Lymphohistiocytosis Rescued by Cord Blood Transplantation with Reduced-intensity Conditioning. AB - We diagnosed a female infant with Langerhans cell histiocytosis (LCH) who was refractory to conventional chemotherapy. She showed refractory inflammation that was complicated with hemophagocytic lymphohistiocytosis (HLH) during LCH chemotherapy; therefore, we changed the protocol to HLH2004 (dexamethasone, cyclosporine A and VP16). However, there were no signs of hematological recovery. We therefore performed cord blood transplantation with reduced-intensity conditioning, and she achieved complete remission for over 2 years. As salvage therapy for refractory LCH, hematopoietic stem cell transplantation may be a good therapeutic choice, especially when LCH is complicated with HLH. PMID- 28655946 TI - Autologous Internal Limiting Membrane Transplants Successfully Close a Large Parafoveal Retinal Hole. AB - Parafoveal retinal holes (PRHs) are one of the complications that can occur after internal limiting membrane (ILM) peeling during macular surgery. Here we describe a patient in whom an exceptionally large PRH (1,069-MUm dia.) was successfully closed by repeated autologous ILM transplantation. PMID- 28655947 TI - Reconstruction of Anterior Chest Wall with Polypropylene Mesh: Two Primary Sternal Chondrosarcoma Cases. AB - Primary sternal chondrosarcoma is a rare malignant tumor that is refractory to chemotherapy and radiation. Effective therapy is radical resection of the tumor. We present two patients with primary sternal chondrosarcoma who underwent a radical resection of the lower half of the sternum and bilateral ribs, followed by reconstruction with 2 sheets of polypropylene mesh layered orthogonally. The patients have maintained almost the same pulmonary function as preoperative values, with stability of the chest wall. Although there are various ways to reconstruct the anterior chest wall, reconstruction with polypropylene mesh layered orthogonally is an easy-to-use and sufficient method. PMID- 28655948 TI - Concealing research outcomes: Missing data, negative results and missed publications. PMID- 28655949 TI - Peri-operative blood management. AB - Anaemia and allogeneic blood transfusions in surgical patients are associated with poor outcomes. Patient blood management (PBM) has been developed as an evidence-based clinical tool, by which clinicians can optimise anaemia, manage peri-operative bleeding, avoid unnecessary blood transfusion and improve patient outcome. This article aims to highlight the recent updates regarding evidence based PBM in the perioperative period, following a thorough literature review involving original research articles, published guidelines and consensus documents discovered through an extensive PubMed and Medline search. PBM addresses three main pillars of the patient's journey through the pre-operative, intra-operative and post-operative periods. PBM encourages a restrictive approach to transfusion of blood products and promotes alternatives to blood transfusion to maximise clinical efficacy while minimising risks. Anaemia has been identified as an independent risk factor for poor outcomes. PBM highlights the importance of treating anaemia in the pre-operative period. Major elective surgery may be postponed until anaemia is corrected preoperatively. The intra-operative approach to PBM is a collaborative effort between the anaesthesia, surgery and transfusion laboratory teams. Use of tranexamic acid, meticulous haemostasis and cell salvage techniques play an important role during the intra-operative management of surgical and traumatic haemorrhage. Point-of-care coagulation tests with visco elastographic methods and haemoglobin measurement ensure that the transfusion prescription is tailored to a patient. In the post-operative period, PBM highlights the need for patients to be optimised before discharge from the hospital. Implementation of the PBM has been shown to have individual health as well as economic benefits. PMID- 28655950 TI - Comparison of ultrasound and anatomical landmark-guided technique for superior laryngeal nerve block to aid awake fibre-optic intubation: A prospective randomised clinical study. AB - BACKGROUND AND AIMS: Ultrasonography has emerged as a novel, portable, non invasive tool encouraging airway assessment and procedural interventions. This study assesses the feasibility of ultrasound for block of internal branch of superior laryngeal nerve (ibSLN) block during upper airway anaesthesia to aid awake fibre-optic intubation. METHODS: Forty American Society of Anesthesiologists' physical status I-II patients, aged 18-60 years, deemed to have a difficult airway (modified Mallampati class III-IV or inter-incisor distance <2.5 cm) and planned for awake fibre-optic intubation were randomised to either landmark group (L, n = 20) or ultrasound group (U, n = 20). All patients received nebulised 4% lignocaine (3 mL) and transtracheal injection 3 mL 2% lignocaine. Group L received landmark-guided bilateral ibSLN block with 1 mL 2% lignocaine. Group U received bilateral ibSLN block with 1 mL 2% lignocaine using a high-frequency ultrasound transducer to define the SLN space. The primary objective was assessment of quality of airway anaesthesia. Secondary objectives were time for intubation, haemodynamic parameters and patient perception of discomfort during procedure. RESULTS: The quality of anaesthesia was significantly better in Group U than in Group L (P < 0.001). The mean time for intubation was shorter in Group U (71.05 +/- 9.57 s) compared to Group L (109.05 +/- 30.09 s, P < 0.001). Heart rate, mean arterial pressure and patient perception of discomfort were significantly increased in Group L. CONCLUSION: Ultrasound for ibSLN block as a part of preparation for awake fibre-optic intubation improves quality of airway anaesthesia and patient tolerance. PMID- 28655951 TI - Comparative evaluation of Ambu AuraGainTM with ProSealTM laryngeal mask airway in patients undergoing laparoscopic cholecystectomy. AB - BACKGROUND AND AIMS: Second generation supraglottic airways are increasingly being used in surgical patients undergoing laparoscopic surgery. Preventing aspiration at higher airway pressures may be at the expense of a higher cuff pressure which can impair mucosal perfusion. We attempted to elucidate whether Ambu AuraGainTM (AAU) would provide a higher oropharyngeal leak pressure (OLP) with a lower mucosal pressure in comparison to ProSealTM laryngeal mask airway (PLMA). METHODS: This was a prospective randomised study involving sixty patients undergoing laparoscopic cholecystectomy under general anaesthesia, using either AAU (Group AAU [n = 30]) or PLMA (Group PLMA [n = 30]) for elective ventilation. Primary outcome measure was the OLP. Number of insertion attempts, ease of insertion, time required for placement and calculated pharyngeal mucosal pressure were the secondary outcome measures. Data were analysed using Student's t-test and Chi-square test. RESULTS: No significant difference in the OLP was noted in both groups. The ease of insertion and success rate at first attempt was similar between the groups. Time taken for insertion in Group AAU was longer than Group PLMA (13.57 +/- 1.94 vs. 11.60 +/- 2.22 s). The calculated pharyngeal mucosal pressures were lower with Group AAU than Group PLMA for all 3 sizes. The minimum cuff pressure and minimum cuff volume required to prevent leak were found similar in both groups. CONCLUSION: AAU provides adequate sealing pressures and effective ventilation with lower calculated pharyngeal mucosal pressure, compared to PLMA. PMID- 28655952 TI - A novel technique for insertion of ProSealTM laryngeal mask airway: Comparison of the stylet tool with the introducer tool in a prospective, randomised study. AB - BACKGROUND AND AIMS: The ProSealTM laryngeal mask airway (PLMA) has a soft cuff which tends to fold on itself during insertion, resulting in reduced first attempt success rate. We compared the standard introducer technique of PLMA insertion with a novel method to prevent folding of the cuff using a RuschTM Stylet. METHODS: This randomised superiority trial included 120 American Society of Anesthesiologists I-II patients between 18 and 80 years, undergoing elective surgeries under general anaesthesia using a PLMA for airway management. The PLMA was inserted using the standard introducer tool in sixty patients (Group IT), while in sixty other patients, a RuschTM Stylet was inserted through the drain tube up to its tip. (Group ST). The primary outcome was first-attempt success rate. Secondary outcomes included overall insertion success, number of attempts, total time to successful insertion, presence of air leaks, haemodynamic response to insertion and quality of fit assessed using Brimacombe's fibre-optic scoring. Continuous variables were compared using independent t-test or Mann-Whitney U test and categorical variables were analysed using Chi-square test or Fisher's exact test. RESULTS: First-attempt success rate of insertion was higher in Group ST compared to Group IT (95% vs. 82%, P = 0.04). Favourable grade of placement was better in Group ST (86.7% vs. 52.5%, P < 0.001). Overall insertion success rates and haemodynamic responses were comparable between the groups. CONCLUSIONS: PLMA insertion using the stylet tool has a higher first-attempt insertion success and superior placement compared to insertion using the conventional introducer tool. PMID- 28655953 TI - Effect of nitrous oxide on bispectral index values at equi-minimum alveolar concentrations of sevoflurane and desflurane. AB - BACKGROUND AND AIMS: Bispectral index (BIS) values may be anaesthetic agent specific, depending on their ability to suppress the electroencephalogram (EEG) signals. We carried out a prospective, randomised clinical trial to study the effect of nitrous oxide (N2O) on the BIS values at an equi-minimum alveolar concentration (MAC) of sevoflurane and desflurane. METHODS: Sixty adult patients undergoing spine surgery were randomised into two groups; Group S (sevoflurane; n = 30) and Group D (desflurane; n = 30) for the maintenance of anaesthesia in oxygen and air or oxygen and N2O mixture (FiO2-0.4) (Stage 1). BIS and fraction of inspired and end-tidal concentration of agents were noted at 1.0 MAC. In Stage 2, air or N2O was discontinued and the other carrier gas was introduced. At steady state of this carrier gas, values were again noted as in Stage 1. Statistical analysis was performed using two-way analysis of variance followed by Bonferroni correction, and Student's t-test for paired data. P<0.05 was considered statistically significant. RESULTS: With air-oxygen as the carrier gas, sevoflurane and desflurane resulted in comparable BIS values (P = 0.44). With addition of 60% N2O, there was a significant increase in BIS values at 1.0 MAC for both the agents. Furthermore, higher BIS values were observed with sevoflurane compared to desflurane (P = 0.01). CONCLUSION: Sevoflurane and desflurane at equi-MAC concentration exert similar effect on BIS values when used with air-oxygen. N2O results in higher BIS values; this effect is more pronounced in combination with sevoflurane. PMID- 28655954 TI - End-tidal capnography and upper airway ultrasonography in the rapid confirmation of endotracheal tube placement in patients requiring intubation for general anaesthesia. AB - BACKGROUND AND AIMS: Confirmation of correct endotracheal tube placement is essential immediately after intubation for general anaesthesia. In this study, we have compared upper airway ultrasonography (USG) with reference to capnography for rapid confirmation of endotracheal tube placement after general anaesthesia. METHODS: A prospective, single centre, observational study was conducted on 100 patients requiring tracheal intubation for general anaesthesia. Both capnography and upper airway USG were performed immediately after intubation to confirm the endotracheal tube (ETT) placement. Sensitivity, specificity, and positive and negative predictive values of upper airway USG were determined against capnography as the reference method. Agreement between the methods and time required to determine ETT placement by the two methods were assessed with kappa statistics and Student's t-test. RESULTS: Upper airway USG detected all five cases of oesophageal intubation, but could not detect five patients with correct tracheal intubation. Upper airway USG had a sensitivity of 96.84% (95% confidence interval [CI]: 94.25%-96.84%), specificity of 100% (95% CI: 50.6%-100%), positive predictive value of 100% (95% CI: 97.3%-100%) and negative predictive value of 62.5% (95% CI: 31.6%-62.5%). Kappa value was found to be 0.76, indicating a good agreement between upper airway USG and capnography for confirmation of ETT placement. Time taken for confirmation of ETT by capnography was 8.989 +/- 1.043 s vs. 12.0 +/- 1.318 s for upper airway USG (P < 0.001). CONCLUSION: Both capnography and upper airway USG may be used as primary procedures for the confirmation of ETT placement. PMID- 28655955 TI - Comparison of efficacy and cost-effectiveness of 0.55% ortho-phthalaldehyde and 2% glutaraldehyde for disinfection of laryngoscopes: A prospective pilot study. AB - BACKGROUND AND AIMS: The laryngoscope is a potential source of cross-infection as it involves contact with the mucous membrane, saliva and occasionally blood. This study compared efficacy and cost-effectiveness of two Centre for Disease Control approved agents for disinfection of laryngoscope blades. METHODS: One hundred and sixty patients requiring laryngoscopy and intubation for general anaesthesia were randomly allocated into two groups. After tracheal intubation, used laryngoscope blades were cleaned with tap water. The blades were then immersed in either 2% w/v glutaraldehyde for a contact time of 20 min or 0.55% w/v ortho-phthalaldehyde (OPA) for 10 min. The handles were wiped with 0.5% w/v chlorhexidine wipes. Samples were collected using sterile cotton swabs from the tip, flange and light bulb area of the laryngoscope blade and one from the handle. They were cultured aerobically on blood and McConkey agar. RESULTS: In 2% glutaraldehyde group, of 240 samples sent from the blades, 2 (0.8%) showed the growth of methicillin resistant coagulase-negative staphylococci (MRCONS) and Enterobacter. In OPA group, of 240 samples, 2 (0.8%) showed growth of MRCONS. Thus, 2% glutaraldehyde and 0.55% OPA were comparable in terms of efficacy of disinfection. Growth was seen on 4 out of 160 handles. CONCLUSIONS: We suggest OPA for high-level disinfection of laryngoscope blades as it is equally efficacious as compared to glutaraldehyde, with a shorter contact time and available as a ready to use formulation. PMID- 28655956 TI - Post-operative analgesic effect of dexmedetomidine administration in wound infiltration for abdominal hysterectomy: A randomised control study. AB - BACKGROUND AND AIMS: Local infiltration of the surgical wound is one of the important components of multimodal analgesia for post-operative pain relief. This study determines the post-operative analgesic effect of addition of dexmedetomidine to bupivacaine for local infiltration of the surgical wound. METHODS: Sixty women belonging to American Society of Anesthesiologists' Grade 1 or 2 posted for abdominal hysterectomy were randomly allocated to Group I (control group) where patients received wound infiltration with 30 mL 0.25% bupivacaine at the end of surgery, or Group II, where patients received wound infiltration with 1.0 MUg/kg dexmedetomidine diluted in 30 mL 0.25% bupivacaine. The primary objective of the study was to assess post-operative pain scores. Number of patients requiring rescue analgesia and total morphine consumption during 24 h after surgery were also recorded. Statistical significance for analgesic requirement was determined by one-way analysis of variance. RESULTS: Pain scores were lower at rest for 12 h and on cough for 6 h in Group II (<0.01). All patients in Group I required supplemental morphine compared to only 3 patients in Group II (P < 0.003). Post-operative analgesia requirement was significantly less in patients receiving dexmedetomidine in wound infiltration compared to patients receiving bupivacaine alone (P < 0.001). CONCLUSIONS: Wound infiltration of dexmedetomidine with bupivacaine provides superior pain relief compared to bupivacaine alone. PMID- 28655957 TI - Comparison of analgesic efficacy of caudal dexmedetomidine versus caudal tramadol with ropivacaine in paediatric infraumbilical surgeries: A prospective, randomised, double-blinded clinical study. AB - BACKGROUND AND AIMS: Caudal epidural analgesia is commonly practised regional block technique in children undergoing infraumbilical surgeries but has a short duration of action after single shot local anaesthetic injection. The aim of this study was to compare ropivacaine 0.25% with dexmedetomidine and tramadol in caudal anaesthesia in paediatric infraumbilical surgeries. METHODS: In a randomised, prospective, double-blinded study, sixty children (1-8 years) belonging to American Society of Anesthesiologists' physical status I or II scheduled for infraumbilical surgeries were included. They were randomly assigned into two groups: Group ropivacaine with tramadol (RT) (n = 30) received 0.25% ropivacaine 1 mL/kg with 2 mg/kg of tramadol, and Group ropivacaine with dexmedetomidine (RD) (n = 30) received 0.25% ropivacaine 1 mL/kg with dexmedetomidine 2 MUg/kg. The primary outcome variable was the duration of analgesia, and the secondary outcome variables included motor block, sedation score, time from caudal block to skin incision, emergence time and adverse effects. RESULTS: The mean duration of analgesia was 654.20 +/- 78.38 min in Group RT, while in Group RD, it was 780.29 +/- 71.21 min (P = 0.0001). The difference between the mean sedation score and mean emergence time between the two groups were statistically significant (P = 0.0001 and 0.0411, respectively). No significant difference was observed in the incidence of haemodynamic changes or side effects. CONCLUSION: Caudal dexmedetomidine with ropivacaine prolongs post-operative analgesia compared to caudal tramadol with ropivacaine. PMID- 28655958 TI - Spontaneous arterial catheter fracture and embolisation: Unpredicted complication. AB - Arterial cannulation is a common procedure in the care and management of critically ill patients. Blood pressure measurement, arterial blood sampling and cardiac output determinations are a few primary reasons for arterial cannulation. This invasive catheter placement also imposes certain risks and clinical management problems like bleeding, thrombosis and hematoma formation. Fracture and embolisation of arterial catheters placed in the femoral region is a rare and serious complication that may result in arterial occlusion and thrombosis. Percutaneous retrieval of the foreign body is frequently reported to be the technique of choice, leaving the surgical option to a small group. We report two consecutive cases of catheter fracture that was successfully retrieved by a combination of surgery and balloon tip retrieval device. PMID- 28655959 TI - Management of predicted difficult airway with conventional techniques in an infant with rhabdomyosarcoma of the upper lip. AB - In paediatric patients, airway management can be challenging due to unique anatomical and physiological variations. Hence, a thorough history, examination and pre-operative planning are essential in securing difficult airway in paediatrics. We report a case of a 7-month-old infant with rhabdomyosarcoma of the upper lip with anticipated difficult airway. The airway was managed with three different conventional techniques (modified nasal trumpet, supraglottic airway and direct laryngoscopy) for three different procedures in the same infant. The procedures were uneventful and recovery was good. This case report emphasises the use of conventional techniques in the management of difficult airway. PMID- 28655960 TI - Airway ultrasound to detect endotracheal tube cuff herniation. PMID- 28655961 TI - Use of Merocel(r) aids in prevention of nasal pressure ulcers following nasal intubation: Case series of 33 patients. PMID- 28655962 TI - The file drawer effect: A call for meticulous methodology and tolerance for non significant results. PMID- 28655963 TI - A novel approach to the anaesthetic management of a case of osteogenesis imperfecta. PMID- 28655964 TI - Anaesthetic consideration for robotic nipple sparing mastectomy. PMID- 28655965 TI - Sodium glucose co-transporter-2 inhibitor: Patient safety and clinical importance. PMID- 28655966 TI - Euglycemic diabetic ketoacidosis by sodium glucose co-transporter inhibitors: Real but preventable concern. PMID- 28655967 TI - Fluid resuscitation, laryngeal oedema and severe dengue. PMID- 28655968 TI - Can fluid resuscitation be a risk factor for laryngeal oedema in severe dengue? PMID- 28655969 TI - The Immunosignature of Mother/Fetus Couples in Gestational Diabetes Mellitus: Role of HLA-G 14 bp ins/del and PAPP-A A/C Polymorphisms in the Uterine Inflammatory Milieu. AB - We enrolled 151 healthy mother/newborn couples and 26 with gestational diabetes mellitus (GDM). HLA-G and PAPP-A plasma levels were measured by ELISA at first and second trimesters, at delivery, and in cord blood. HLA-G 14 bp ins/del and PAPP-A A/C polymorphisms were genotyped. HLA-G del/del and PAPP-A C/C genotypes were more frequent among GDM mothers than controls. We observed a genetic epistasis between the two polymorphisms: the HLA-G del/del and PAPP-A C/C combination was carried by 8% of GDM mothers and 1.3% of controls (OR = 9.5, 95% CI = 0.8-109, p = 0.07). GDM mothers showed increased sHLA-G levels compared to controls (p = 0.004), and those carrying the HLA-G del/del genotype produced more sHLA-G at the second trimester and at delivery (p = 0.014). A genetic pressure by fetal genotype on maternal sHLA-G production was observed in GDM mothers with heterozygous HLA-G del/ins newborns (p = 0.02). Babies born to GDM mothers showed higher sHLA-G concentrations compared to those born to healthy mothers, and those carrying HLA-G del/del showed the highest sHLA-G levels (p = 0.013). PAPP-A amounts significantly increased along pregnancy (p < 0.001), but the median levels at the first and second trimesters were significantly lower in GDM (p = 0.03). Our findings first suggest an involvement of HLA-G and PAPP-A gene-protein interaction in GDM and highlight a possible contribution of the fetus in balancing maternal inflammation. PMID- 28655970 TI - Association between the TACC3 rs798766 Polymorphism and Risk of Urinary Bladder Cancer: A Synthesis Based on Current Evidence. AB - BACKGROUND: A possible association between the TACC3 rs798766 polymorphism and urinary bladder cancer risk has been indicated in published literature. We performed this meta-analysis as a synthesis of all relevant data to summarize currently available evidence and to provide estimation with increased precision. METHODS: EMBASE, PubMed, Google Scholar, and Wanfang Data were searched. "rs798766" and "urinary bladder cancer" were used as the search terms. A total of 6 eligible studies were identified, in which 8194 cases and 50,165 controls were investigated. Meta-analysis was performed using extracted data. Subgroup analysis by ethnicity was also performed. Population attributable risk (PAR) was calculated. RESULTS: We found a significant association between rs798766[T] and increased risk of bladder cancer, allelic[T] OR = 1.27, 95%CI = 1.20-1.33. Subgroup analysis by ethnicity revealed similar results, allelic[T] OR = 1.24, 95%CI = 1.17-1.32 in Caucasian subjects and allelic[T] OR = 1.33, 95%CI = 1.21 1.46 in Asian subjects. PAR based on pooled allelic ORs and the frequency of the risk allele in control subjects was 4.63% in the overall population and 3.92% in Asians and 4.36% in Caucasians. CONCLUSION: rs798766 is associated with increased risk of bladder cancer, and no ethnic difference was found. PMID- 28655971 TI - Significant Improvement Selected Mediators of Inflammation in Phenotypes of Women with PCOS after Reduction and Low GI Diet. AB - Many researchers suggest an increased risk of atherosclerosis in women with polycystic ovary syndrome. In the available literature, there are no studies on the mediators of inflammation in women with PCOS, especially after dietary intervention. Eicosanoids (HETE and HODE) were compared between the biochemical phenotypes of women with PCOS (normal and high androgens) and after the 3-month reduction diet. Eicosanoid profiles (9(S)-HODE, 13(S)-HODE, 5(S)-HETE, 12(S) HETE, 15(S)-HETE, 5(S)-oxoETE, 16(R)-HETE, 16(S)-HETE and 5(S), 6(R)-lipoxin A4, 5(S), 6(R), 15(R)-lipoxin A4) were extracted from 0.5 ml of plasma using solid phase extraction RP-18 SPE columns. The HPLC separations were performed on a 1260 liquid chromatograph. No significant differences were found in the concentration of analysed eicosanoids in phenotypes of women with PCOS. These women, however, have significantly lower concentration of inflammatory mediators than potentially healthy women from the control group. Dietary intervention leads to a significant (p < 0.01) increase in the synthesis of proinflammatory mediators, reaching similar levels as in the control group. The development of inflammatory reaction in both phenotypes of women with PCOS is similar. The pathways for synthesis of proinflammatory mediators in women with PCOS are dormant, but can be stimulated through a reduction diet. Three-month period of lifestyle change may be too short to stimulate the pathways inhibiting inflammatory process. PMID- 28655972 TI - High Glucose Level Disturbs the Resveratrol-Evoked Curtailment of CX3CL1/CX3CR1 Signaling in Human Placental Circulation. AB - Hyperglycemia-induced hyperactivity of chemokine CX3CL1 (fractalkine) occurs in the human placenta. Anti-inflammatory/antioxidant activities of resveratrol (3,5,4'-trihydroxy-trans-stilbene) are related to the modulation of chemokine CX3CL1 and its receptor, CX3CR1, signaling pathways. We examined the influence of high glucose (25 mmol/L glucose; HG group; N = 36) on resveratrol-mediated effects on CX3CL1 and TNF-alpha production by the placental lobule, CX3CR1 expression and contents of CX3CR1, TNF-alpha receptor 1 (TNFR1), and NF-kappaB proteins in placental tissue. The placental lobules perfused under normoglycemic conditions formed the control NG group (N = 36). Resveratrol (50 and 100 MUM; subgroups B and C) administered into the perfusion fluid lowered the production of both CX3CL1 and TNF-alpha. The reductions in CX3CL1 levels were more evident in the NG group. CX3CR1 expression was significantly higher in the NG subgroups B and C compared to the HG subgroups B and C (385.2 and 426.5% versus 199.3 and 282.4%, resp.). An increase in CX3CR1 protein content in placental lysates was observed in the NG subgroups B and C. Also, resveratrol significantly decreased NF-kappaBp65 protein content only in the NG group, not affecting hyperglycemia elicited TNFR1 upregulation. In conclusion, euglycemia assures optimal effects of resveratrol pertaining to CX3CL1/CX3CR1 signaling in the placenta. Future studies on resveratrol are needed, especially those including maternal-fetal risk assessments. PMID- 28655973 TI - First-line therapies for Helicobacter pylori eradication: a critical reappraisal of updated guidelines. AB - Helicobacter pylori (H. pylori) treatment remains a challenge for the clinician, as no available therapy is able to cure the infection in all treated patients. In the last two decades, several antibiotic combinations have been proposed, including triple therapies, bismuth-free therapies (sequential, concomitant, hybrid regimens), and bismuth-based quadruple therapy. Some national and international guidelines on H. pylori management have recently been updated, recommending or discouraging the use of each of these therapeutic approaches, based mainly on the presumed pattern of primary antibiotic resistance in different geographic areas. We examined the recommendations on first-line therapies in the most recently updated guidelines worldwide, taking into account other data affecting the efficacy of a therapy regimen beyond the primary resistance pattern. Although several guidelines highlighted that the results achieved by an eradication therapy are population-specific and not directly transferable, it emerged that some therapy regimens are recommended or discouraged with no mention of the vital need for national data. PMID- 28655974 TI - Lymphocytic duodenitis or microscopic enteritis and gluten-related conditions: what needs to be explored? AB - Microscopic enteritis (ME) is characterized by abnormal infiltration of intraepithelial lymphocytes in intestinal mucosa. It was described as duodenal lymphocytosis or lymphocytic duodenitis until the dedicated Consensus Conference of 2015. ME represents a common feature of several gluten-mediated and non-gluten related diseases; therefore, it is an umbrella term embracing several conditions. The most frequent causes of ME are gluten-related disorders (celiac disease, non celiac gluten sensitivity, wheat allergy), Helicobacter pylori infection and drug related damages. Less frequently, ME may be secondary to inflammatory bowel disease, some autoimmune conditions, immunoglobulin deficiencies, blood malignancies, infections and irritable bowel syndrome. Therefore, the differential diagnosis of ME may be challenging. The diagnosis of ME needs to be driven by predominant symptoms and patient history. However, it is often difficult to achieve an immediate identification of the underlying condition, and a broad variety of diagnostic tests may be required. Ultimately, long-term surveillance is needed for a final diagnosis in many cases, since a hidden or quiescent condition may be disclosed after a period of latency. In any case, strict collaboration between the clinician and the pathologist is pivotal. The treatment of ME should be personalized, depending on the underlying disease. For gluten-related conditions (celiac disease, gluten sensitivity, wheat allergy, dermatitis herpetiformis), a gluten-free diet may be proposed. For other conditions, a targeted etiologic treatment is necessary. In conclusion, ME represents a novel entity that is attracting increasing interest. The growing epidemiologic trend confirms that it will become a common condition in clinical practice. PMID- 28655976 TI - Iron deficiency anemia in chronic liver disease: etiopathogenesis, diagnosis and treatment. AB - Chronic liver disease is accompanied by multiple hematological abnormalities. Iron deficiency anemia is a frequent complication of advanced liver disease. The etiology is multifactorial, mostly due to chronic hemorrhage into the gastrointestinal tract. The diagnosis of iron deficiency anemia is very challenging, as simple laboratory methods, including serum iron, ferritin, transferrin saturation (Tsat), and mean corpuscular volume are affected by the liver disease itself or the cause of the disease, resulting in difficulty in the interpretation of the results. Several new parameters, such as red blood cell ferritin, serum transferrin receptor test and index, and hepcidin, have been studied for their utility in indicating true iron deficiency in combination with chronic liver disease. Once iron deficiency anemia is diagnosed, it should be treated with oral or parenteral iron as well as portal pressure reducing drugs. Blood transfusion is reserved for symptomatic anemia despite iron supplementation. PMID- 28655975 TI - Stromal and immune cells in gut fibrosis: the myofibroblast and the scarface. AB - Post-inflammatory scarring is the end-result of excessive extracellular matrix (ECM) accumulation and tissue architectural destruction. It represents a failure to effectively remodel ECM and achieve proper reinstitution and healing during chronic relapsing inflammatory processes. Scarring may affect the functionality of any organ, and in the case of inflammatory bowel disease (IBD)-associated fibrosis leads to stricture formation and often surgery to remove the affected bowel. The activated myofibroblast is the final effector cell that overproduces ECM under the influence of various mediators generated by an intense interplay of classic and non-classic immune cells. This review focuses on how proinflammatory mediators from various sources produced in different stages of intestinal inflammation can form profibrotic pathways that eventually lead to tissue scarring through sustained activation of myofibroblasts. PMID- 28655977 TI - A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. AB - BACKGROUND: Increasing evidence has suggested that Helicobacter pylori (H. pylori) eradication might prevent the development of gastric cancer (GC). This systematic review and meta-analysis aimed to better explore the role of H. pylori eradication in preventing GC, with particular reference to patients with precancerous lesions at baseline histology. METHODS: Searches for human studies were performed through October 2016 and risk ratios (RRs), were obtained. Heterogeneity between studies was estimated using the Cochran Q test and I2 values, whereas the possibility of publication bias was estimated with funnel plots. Additionally, we performed subgroup and sensitivity analyses. RESULTS: In 26 studies suitable for meta-analysis (10 randomized controlled trials and 16 cohort studies) 52,363 subjects were included. The risk of GC among patients in whom H. pylori was successfully eradicated was significantly lower than that among controls: pooled RRs [95% CI] 0.56 [0.48-0.66], Z= -7.27, P=0.00001. This finding applied separately for randomized controlled trials (0.65 [0.51-0.84], Z= -3.33, P=0.0009) and for cohort studies (0.51 [0.42-0.62], Z= -6.63, P=0.00001). Concerning H. pylori eradication in patients with precancerous lesions, subgroup analyses showed that patients with non-atrophic or atrophic gastritis benefited from H. pylori eradication for the risk of GC development, whereas those with intestinal metaplasia or dysplasia did not. CONCLUSION: H. pylori eradication is associated with a significantly lower risk of GC; this finding has significant implications for the prevention of this cancer. The benefit is maximized when H. pylori eradication is applied at early stages of the infection. PMID- 28655978 TI - Early effect on intragastric pH of oral administration of rabeprazole with mosapride compared with rabeprazole alone. AB - BACKGROUND: An ideal medication for acid-related diseases would offer prompt stopping of blood flow as well as efficient symptom resolution. The aim of this study was to investigate the gastric acid suppression potency of a single oral dose of rabeprazole alone, compared with administration of rabeprazole plus mosapride. METHODS: Twelve male volunteers, Helicobacter pylori (H. pylori) negative, participated in this randomized, three-way crossover study. After a single oral administration of rabeprazole, rabeprazole with mosapride, or rabeprazole administered 1 h after mosapride, we monitored their intragastric pH constantly for 6 h. A 7-day washout period was allowed between each administration. RESULTS: The median 6-h intragastric pH after the administration of rabeprazole 1 h after mosapride was 4.41+/-1.22 (mean+/-s.d.), significantly higher than after rabeprazole alone 3.45+/-1.33, P=0.0376). There was no significant difference between the median 6-h pH after the administration of rabeprazole plus mosapride and that after rabeprazole alone (3.81+/-0.98 vs. 3.45+/-1.33, respectively; P=0.0927). CONCLUSION: An oral dose of rabeprazole administered 1 h after mosapride increased the intragastric pH more rapidly than rabeprazole alone, in healthy, male, H. pylori-negative volunteers. PMID- 28655979 TI - Diagnostic yield from colon biopsies in patients with inflammatory bowel disease and suspected cytomegalovirus infection: is it worth it? AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) are often immunosuppressed and are at risk for reactivation of latent cytomegalovirus (CMV) infection. We examined the diagnostic yield from colon biopsies in IBD patients with suspected CMV infection. METHODS: Patients above 18 years of age who underwent testing for CMV on colon biopsies between January 1st, 2012, and December 31st, 2015, were identified from a pathology data base. A positive CMV result was included only if testing included both hematoxylin/eosin staining and immunohistochemistry from two or more biopsy samples. RESULTS: One hundred twenty five patients met the inclusion criteria. Of these, 99 had a diagnosis of IBD: 30 with Crohn's disease, 63 with ulcerative colitis, and 6 with indeterminate colitis. As regards treatment, 21.2% of the patients had biologic therapy alone, 13.1% received immunomodulators, and 11.1% were treated with combined biologic and immunomodulator therapy within 3 months of the colon biopsy. In addition, 32.3% of the patients were on steroids. Of the 99 IBD patients, only 1 had biopsy proven CMV colitis. CONCLUSION: The yield from colon biopsies with hematoxylin/eosin staining and immunohistochemistry to test for CMV in IBD flare is very low. Further multicenter studies with large numbers of patients are needed to compare all testing modalities in the same cohort of patients. This may help identify which subgroup of IBD patients are likely to benefit from specific modalities of CMV testing, with potential cost-saving implications. PMID- 28655980 TI - Psychometry and Pescatori projective test in coloproctological patients. AB - BACKGROUND: Psychological assessment is not commonly performed nor easily accepted by coloproctological patients. Our aim was to evaluate the psychological component of coloproctological disorders using uncommon tools. METHODS: The 21 Item Depression Anxiety and Stress Scale and the Pescatori projective test were applied to coloproctological outpatients of the Gastroenterology Department of our hospital as well as to healthy volunteers. RESULTS: Seventy patients (median age 47 years, 22 male) divided in 4 groups (functional constipation, constipated irritable bowel syndrome, benign anorectal disease and perianal Crohn's disease) and 52 healthy volunteers (age 45 years, 18 male) completed the tests. Proctological patients showed higher scores of depression (P<0.001), anxiety (P<0.001), and stress (P<0.001) compared to healthy participants. Compared to the control group, patients with functional constipation, irritable bowel syndrome and perianal Crohn's disease maintained the highest scores in all subscales (P<0.05), while patients with benign anorectal disease only had higher anxiety and stress (P<0.001) scores. The patients' also showed lower scores in the Pescatori projective test (P=0.012). A weak association between the projective test and the depression subscale was found (P=0.05). CONCLUSION: Proctological patients had higher scores of depression, anxiety and stress and lower scores in the Pescatori projective test compared to healthy controls. PMID- 28655981 TI - Anal self-massage in the treatment of acute anal fissure: a randomized prospective study. AB - BACKGROUND: An anal fissure (AF) is a tear in the epithelial lining of the anal canal. This is a very common condition, but the choice of treatment is unclear. The use of anal dilators is effective, economic, and safe. The aim of the study was to compare the efficacy of two conservative treatments, the use of anal dilators or a finger for anal dilatation, in reducing anal pressure and resolving anal fissures. METHODS: Fifty patients with a clinical diagnosis of AF were randomly assigned to one of the treatments, self-massage of the anal sphincter (group A, 25 patients) or passive dilatation using dilators (group B, 25 patients). All patients were evaluated at baseline, at the end of treatment, and after 12 weeks and 6 months. Pain was measured using a visual analog scale. RESULTS: After the treatment, 60% of patients treated with dilators and 80% of patients treated with anal self-massage using a finger showed disappearance of their anal fissures. A comparison between signs and symptoms reported by the patients in the two groups showed a statistically significant reduction in anal pain (group A, P=0.0001; group B, P=0.0001) and bleeding after defecation (group A, P=0.001, group B, P=0.001). At 6 months after treatment, a significantly greater reduction in anal pain was observed in Group A compared to Group B (P=0.02). CONCLUSION: The use of anal self-massage with a finger appears to induce a better resolution of acute anal fissure than do anal dilators, and in a shorter time. PMID- 28655982 TI - Clinical impact of the immunochemical fecal occult blood test for colorectal cancer screening in Brazil. AB - BACKGROUND: Colorectal cancer (CRC) screening programs based on the fecal occult blood test (FOBT) reduce CRC mortality. We carried out an observational prospective study to determine the accuracy of immunochemical FOBTs for the detection of CRC in individuals at average risk for the disease. METHODS: This population-based study was performed between April 2015 and January 2016 in two gastroenterology referral centers in Southern Brazil. It included 1039 average risk volunteers aged 50-75 years who were symptom-free for colonic disease. Participants underwent OC-Light immunochemical fecal occult blood test (i-FOBT, EIKEN chemical Co., Tokyo, Japan) as well as screening colonoscopy. RESULTS: Nine hundred forty-eight (91.2%) of the 1039 participants completed and returned the i FOBT (95% confidence interval [CI] 89.4-92.9). Among the 73 participants with a positive i-FOBT who underwent colonoscopy, advanced CRC was detected in 9 (12.3%). Two (2.7%) early CRCs, 7 (9.5%) high-grade dysplasia adenomas and 25 (34.2%) low-grade dysplasia adenomas were also diagnosed. Among the 243 negative i-FOBT cases who underwent colonoscopy, one (0.4%) advanced CRC and 91 (37.6%) low-grade dysplasia adenomas were detected. The detection rate of CRC considering the whole screened population (n=1039) was 1.05% (11/1039). CONCLUSIONS: The i FOBT test in the CRC screening programs in Brazil showed a high compliance and high detection rates for cancers and high-risk adenomas. The i-FOBT test is feasible for CRC screening in an average-risk population. PMID- 28655983 TI - Experimental gastric endoscopic submucosal dissection: training in a porcine model. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) requires special skills and a long procedure time for a quality-controlled procedure. A universal training system remains to be established. Hands-on courses in animal models before advancing to the human colon appear to be essential, especially in Europe. The learning curve is a prerequisite in ESD, in order to improve technical outcomes and decrease the rate of procedural adverse events. METHODS: In the experimental research center of ELPEN Pharmaceuticals, 18 European endoscopists, inexperienced at ESD, performed gastric ESDs in porcine models. The course lasted two days and was conducted under the supervision of experts. RESULTS: A total of 72 of 76 ESDs were completed en bloc (94.7%). The procedural time and cutting speed differed significantly between the first and second day: 48+/-4.4 vs. 43+/-4.8 min (P=0.0045), and 1.38+/-0.20 vs. 1.63+/-0.23 cm2/min (P=0.0033), respectively. The complications were not significantly different between the two groups: five (13.88%) vs. four (11%) episodes of bleeding (P>0.05). The perforation rate was similar, at two episodes per day (5.55%). We documented an acceptable rate of en bloc resections and complications. CONCLUSION: ESD demands a new level of endoscopic skills in Europe. A formal sequential training program, using porcine models, may benefit countries with a low volume of cases. PMID- 28655984 TI - Bacterial load and cytokine profile in patients with cirrhosis following therapy with proton pump inhibitors: a prospective cohort study. AB - BACKGROUND: The aim of this study was to explore the presence of bacterial products and the cytokine profile in outpatients with cirrhosis before and after short-term (4-8 weeks) administration of proton pump inhibitors (PPIs). METHODS: Seventeen patients with cirrhosis-male/female: 12/5; age: median 59.2 years (49 65); etiology: HBV+/-HDV 23.5%, HCV 17.7%, alcohol 41.2%, other 17.6%; Child-Pugh score: median 7.5 (5-12); Model for End-stage Liver Disease: 10.5 (7-21); ascites (%): 3 (17.7)-attending the outpatient clinics were included. None had hepatocellular carcinoma. Indications for PPIs were: esophagitis (n=6, 35.3%), peptic ulcer (n=10, 58.6%) and other (n=1, 5.9%). Bacterial DNA in serum and the levels of endotoxin, lipopolysaccharide binding protein, transforming growth factor-beta, interleukin -1beta, -6, -8, -12, -10, tumor necrosis factor-alpha and nitric oxide were assessed at baseline (time 1) and at the end of treatment (time 2). The Wilcoxon signed rank test was used to evaluate significant differences in the parameters assayed before and after PPI administration. RESULTS: No patients developed infection during the study period. Bacterial DNA was not detected before or after treatment. No significant differences were observed between the concentrations of any indices between times 1 and 2 (P>0.05). Subgroup analysis according to Child-Pugh stage yielded similar results. CONCLUSION: Short-term administration of PPIs had no effect on bacterial DNA, bacterial products or cytokine concentrations in patients with liver cirrhosis. PMID- 28655985 TI - Circulating adipokines in children with nonalcoholic fatty liver disease: possible noninvasive diagnostic markers. AB - BACKGROUND: The growing obesity pandemic is the leading cause for increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in children. Histopathological evaluation of the liver remains the gold standard for NAFLD diagnosis, but it is an invasive procedure with a low but real risk of morbidity and mortality. The current study evaluated circulating chemerin and adiponectin as possible noninvasive diagnostic markers for NAFLD in obese non-diabetic children. METHODS: A prospective case-control study was conducted, which included 101 obese children with biopsy-proven NAFLD and 57 age- and sex-matched controls. The overall mean age of the children was 10.08+/-3.12 years. All underwent a full clinical assessment, routine laboratory investigation, and abdominal ultrasound. Homeostatic model assessment-insulin resistance was calculated and circulating chemerin and adiponectin were evaluated using ELISA. RESULTS: Elevated serum chemerin and decreased serum adiponectin were significantly associated with an increased likelihood of exhibiting NAFLD. Receiver operator characteristic curve analysis for differentiation of NAFLD patients from those in the control group demonstrated that chemerin, at a cutoff value of 186.7 ng/mL, yielded a sensitivity and specificity of 56.44% and 87.72% respectively (P<0.001), whereas adiponectin, at a cutoff value of 2.4 ug/mL, had a sensitivity and specificity of 74.26% and 3.51% respectively (P<0.001). Furthermore, body mass index, aspartate transaminase, alanine transaminase, triglycerides, and gamma-glutamyl transferase had significant positive correlations with chemerin and significant negative correlations with adiponectin (P<=0.001). CONCLUSION: Circulating chemerin and adiponectin could serve as simple noninvasive diagnostic markers for NAFLD in non diabetic obese children. PMID- 28655987 TI - Fully "Dual Knife J(r)" submucosal tunnel endoscopic resection (STER): a step up to bariatric surgery. PMID- 28655986 TI - A magnet-induced stomach ulcer causing abdominal pain. PMID- 28655988 TI - Submucosal pocket-assisted enucleation of gastric submucosal lesions. PMID- 28655989 TI - Strongyloides stercoralis infection: an "exotic" cause of chronic diarrhea. PMID- 28655990 TI - Clostridium septicum aortitis with synchronous ascending colon and rectal adenocarcinoma. AB - Clostridium septicum (C. septicum) aortitis is a rare condition frequently associated with colon adenocarcinoma and carries a poor prognosis. We report the case of a 66-year-old man who presented with abdominal pain, blood in the stool, fever and chills. Laboratory tests were significant for leukocytosis and microcytic anemia. Abdominal imaging revealed a right colon mass and aortitis. Colonoscopy confirmed the right colon mass and also discovered a rectal mass, both adenocarcinomas. Treatment consisted of antibiotics, aortic repair, right hemi-colectomy and later trans-anal excision of the rectal mass. Blood cultures and the aortic specimen grew C. septicum. The patient improved and was doing well in follow up. PMID- 28655991 TI - The impact of hepatitis C virus and human immunodeficiency virus coinfection on survival in patients with hepatocellular carcinoma. PMID- 28655992 TI - Authors' reply. PMID- 28655993 TI - Synovial Sarcoma of the Head and Neck: A Single Institution Review. AB - BACKGROUND: The prognosis and clinical characteristics of head and neck synovial sarcomas (HNSS) are unclear. Herein, we present an update using a cohort of patients treated at our institution. METHODS: We performed a retrospective chart review of 44 patients diagnosed with primary HNSS between March 1990 and June 2012. Overall survival (OS) and progression-free survival (PFS) curves were estimated and hazard ratios (HRs) were calculated. RESULTS: The entire cohort's median PFS was 4.6 years, and 20 of the 44 (45%) patients developed either local or distant recurrence. Tumor size >= 5 cm (p = 0.008, HR = 4.69; 95% CI = 1.34 16.38) and a primary presentation in the soft tissues of the neck (p = 0.04, HR = 2.41; 95% CI = 1.003-5.82) were associated with significantly worse PFS. The OS and PFS of patients who received definitive local therapy versus those who received additional adjuvant systemic therapy did not differ significantly. CONCLUSION: Despite the treatment challenges associated with HNSS, our cohort of patients had a better prognosis than one might expect in this unfavorable anatomical location. Our findings suggest that tumor size and site are predictive of PFS and that wide surgical excision is of vital importance, since traditional cytotoxic chemotherapy has limited efficacy at this site. PMID- 28655994 TI - Sleep Duration and Patterns in Chinese Older Adults: a Comprehensive Meta analysis. AB - This meta-analysis examined the mean sleep duration and patterns in Chinese older adult population. A literature search was systematically conducted covering major English (PubMed, Embase and PsycINFO) and Chinese (Chinese National Knowledge Infrastructure (CNKI), WanFang and SinoMed) databases. Data in studies with the mean and standard deviation of sleep duration and/or the proportion of short and long sleep durations in Chinese older adults were extracted and pooled using random-effects models. Subgroup analyses were conducted according to gender, region, area, survey time and sample size. A total of 36 studies with 150,616 subjects were included for analyses. The pooled mean sleep duration of 21 studies with available data was 6.82 hours/day (95% CI: 6.59-7.05 hours/day). The estimated proportions of sleep duration <5 hours/day, <6 hours/day, <7 hours/day were 18.8% (95% CI: 1.7%-35.9%), 26.7% (95% CI: 19.7%-33.7%) and 42.3% (95% CI: 34.8%-49.8%), respectively. The pooled proportions for long sleepers were 22.6% (95% CI: 13.9%-31.4%) (>8 hours/day) and 17.6% (95% CI: 12.4%-22.9%) (>9 hours/day). Given the adverse effects of unhealthy sleep patterns, health professionals should pay more attention to sleep patterns in this population in China. PMID- 28655995 TI - MicroRNA-142-3p and let-7g Negatively Regulates Augmented IL-6 Production in Neonatal Polymorphonuclear Leukocytes. AB - Neonatal PMN are qualitatively impaired in functions, yet they frequently reveal augmented inflammatory reactions during sepsis. Here, we hypothesized that PMN from newborns produce more IL-6 than those from adults under LPS stimulation, in which transcriptional or posttranscriptional regulation is involved in the altered expression. We found that neonatal PMN produced significantly higher IL-6 mRNA and protein than adult PMN. The higher IL-6 expression was not related to transcriptional but posttranscriptional regulation as the IL-6 expression was affected by the addition of cycloheximide but not actinomycin. To examine whether miRNA was involved in the IL-6 regulation of neonatal PMN, we surveyed differential displays of miRNAs that could potentially regulate IL-6 expression before and after LPS stimulation. Four miRNAs: hsa-miR-26a, hsa-miR-26b, hsa-miR 142-3p and hsa-let 7g decreased or increased after LPS treatment for 4 h. Further validation by qRT-PCR identified miR-26b, miR-142-3p and let-7g significantly changed in neonatal PMN after LPS stimulation. The functional verification by transfection of miR-142-3p and let-7g precursors into neonatal PMN significantly repressed the IL-6 mRNA and protein expression, suggesting that miR-142-3p and let-7g negatively regulate IL-6 expression in neonatal PMN. Modulation of miRNA expression may be used to regulate IL-6 production in newborns with altered inflammatory reactions. PMID- 28655996 TI - Eupafolin Exhibits Potent Anti-Angiogenic and Antitumor Activity in Hepatocellular Carcinoma. AB - Eupafolin is a flavonoid extracted from the common sage herb which has been used in China as traditional medicine. Previous studies had reported that eupafolin had antioxidative, anti-inflammatory and antitumor effects. However, the function and the mechanism of eupafolin to exert its antitumor activity, especially its effect on tumor angiogenesis, have not been elucidated. Herein, we showed that eupafolin significantly inhibited vascular endothelial growth factor (VEGF) induced cell proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Meanwhile, the new blood microvessels induced by VEGF in the matrigel plug were also substantially suppressed by eupafolin. The results of HCC xenograft experiments demonstrated eupafolin remarkably inhibited tumor growth and tumor angiogenesis in vivo, suggesting the antitumor activity exerted by eupafolin was closely correlated with its potency on tumor angiogenesis. Mechanism investigations revealed that eupafolin significantly blocked VEGF-induced activation of VEGFR2 in HUVEC cells as well as its downstream signaling pathway. In addition to the effect on endothelial cells, through inhibiting Akt activity in tumor cells, VEGF secretion in HepG2 was dramatically decreased after eupafolin treatment. Our study was the first to report the activity of eupafolin against tumor angiogenesis as well as the underlying mechanism by which eupafolin to exert its anti-angiogenic activity. PMID- 28655997 TI - Mechanism of ribosome translation through mRNA secondary structures. AB - A ribosome is a macromolecular machine that is responsible for translating the genetic codes in messenger RNA (mRNA) into polypeptide chains. It has been determined that besides translating through the single-stranded region, the ribosome can also translate through the duplex region of mRNA by unwinding the duplex. To understand the mechanism of ribosome translation through the duplex, several models have been proposed to study the dynamics of mRNA unwinding. Here, we present a comprehensive review of these models and also discuss other possible models. We evaluate each model and discuss the consistency and/or inconsistency between the theoretical results that are obtained based on each model and the available experimental data, thus determining which model is the most reasonable one to describe the mRNA unwinding mechanism and dynamics of the ribosome. Moreover, a framework for future studies in this subject is provided. PMID- 28655998 TI - Exosomes from Melatonin Treated Hepatocellularcarcinoma Cells Alter the Immunosupression Status through STAT3 Pathway in Macrophages. AB - Immunosuppression is a significant factor in the progression of tumor invasion and metastasis. Melatonin, a well-known hormone, has certain cytotoxic and immune regulatory effects to inhibit tumor function. Exosomes are small membrane vesicles released by many kinds of cells, which contain different macromolecules, such as mRNAs and microRNAs (miRNAs), and proteins that can mediate communications between cells. Tumor-derived exosomes may cause immunosuppression, however, it is unknown whether melatonin can attenuate an immunosuppressive status by altering the function of tumor-derived exosomes. In the present study, we evaluated the effects of hepatocellularcarcinoma-derived exosomes (Exo-con) and exosomes derived from hepatocellularcarcinoma cells treated with 0.1 mM melatonin (Exo-MT), on the expression of inflammatory factors and programmed death ligand 1(PD-L1) by co-culturing Exo-con and Exo-MT, respectively, with macrophages differentiated from THP-1 cells or RAW264.7 cells. Our in vitro results indicate that Exo-MT can downregulate the expression of PD-L1 on macrophages while Exo-con can upregulate the expression of PD-L1 through flow cytometry and immunofluorescence analysis. In addition, Exo-con upregulates the secretion of cytokines, such as IL-6, IL-10, IL-1beta, and TNF-alpha in macrophages. Accordingly, Exo-MT could attenuate the high expression of these inflammatory cytokines. Furthermore, in vivo experiments confirmed the results found in vitro. PD-L1 expression and cytokine secretion were lower in the Exo-MT group compared with those in the Exo-con group. Working to identify a specific mechanism, our research shows that Exo-MT decreases STAT3 activation compared to the Exo-con group. In summary, we found exosomes from melatonin treated hepatocellularcarcinoma cells alters the immunosupression status through STAT3 pathway in macrophages. Our study may provide a new avenue to investigate the mechanisms of melatonin in regulating an immunosuppressive status. PMID- 28655999 TI - Genome-wide Identification and Expression Analysis of Amino Acid Transporters in the Whitefly, Bemisia tabaci (Gennadius). AB - The whitefly (Bemisia tabaci) is a cosmopolitan and devastating pest of agricultural crops and ornamentals. B. tabaci causes extensive damage by feeding on phloem and by transmitting plant viruses. Like many other organisms, insects depend on amino acid transporters (AATs) to transport amino acids into and out of its cells. We present a genome-wide and transcriptome-wide investigation of the following two families of AATs in B. tabaci biotype B: amino acid/auxin permease (AAAP) and amino acid/polyamine/organocation (APC). A total of 14 putative APCs and 25 putative AAAPs were identified, and a 10-paralog B. tabaci-specific expansion of AAAPs was found by maximum likelihood phylogeny. Detailed gene structure information revealed that 9 members of the B. tabaci-specific AAAP family expansion closely situated on a same scaffold. Expression profiling of the B. tabaci B APC and AAAP genes as affected by stage and plant host showed diverse expression patterns. The analysis of evolutionary rates indicated that purifying selection can explain the B. tabaci-specific AAAP expansion. RNA interference (RNAi)-mediated suppression of two AAAP genes (BtAAAP15 and BtAAAP21) significantly increased the mortality of B. tabaci B adults. The results provide a foundation for future functional analysis of APC and AAAP genes in B. tabaci. PMID- 28656000 TI - Oncogenic Protein Kinase D3 Regulating Networks in Invasive Breast Cancer. AB - Protein Kinase D3 (PRKD3) functions as an important oncogenic driver in invasive breast cancer, which is the leading cause of women mortality. However, PRKD3 regulating network is largely unknown. In this study, we systematically explored PRKD3 regulating networks via investigating phosphoproteome, interactome and transcriptome to uncover the molecular mechanism of PRKD3 in invasive breast cancer. Using iTRAQ, 270 proteins were identified as PRKD3 regulated phosphoproteins from 4619 phosphosites matching 3666 phosphopeptides from 2016 phosphoproteins with p-value <0.005. Transcriptome analysis using affymetrix microarray identified 45 PRKD3 regulated genes, in which 20 genes were upregulated and 25 genes were downregulated with p-value <0.005 upon silencing PRKD3. Using Co-IP in combination of MS identification, 606 proteins were identified to be PRKD3 interacting proteins from 2659 peptides. Further network analysis of PRKD3 regulated phosphoproteins, interacting proteins and regulated genes, reveals 19 hub nodes, including ELAVL1, UBC and BRCA1. UBC was recognized as the most common hub node in PRKD3 regulating networks. The enriched pathway analysis reveals that PRKD3 regulates pathways contributing to multiple cancer related events, including cell cycle, migration and others. Enrichment of cell cycle and cell mobility related pathways across PRKD3 networks, explained the observations that depletion of oncogenic PRKD3 led to alternation of cell cycle and decrease of cell migration ability. Taken together, our current study provided valuable information on the roles as well as the molecular mechanisms of PRKD3 in invasive breast cancer. PMID- 28656001 TI - Two Olfactory Pathways to Detect Aldehydes on Locust Mouthpart. AB - Sensing chemical cues is crucial for insects through their olfactory systems to adapt the environments. The receptors employed in insect olfactory system belong to the Odorant Receptor (ORs) and Ionotropic Receptor (IRs) families. In general, ORs and IRs are present in distinct olfactory sensory neurons and function independently. Here, we present evidence that in locust, the abundant host plant odor Hexanal is detected by both IR- and OR-expressing neurons. Use of the palp opening response (POR) as a simple behavioral paradigm in conjunction with RNA interference (RNAi) revealed that these two pathways are both needed for the detection of Hexanal. Two-color fluorescence in situ hybridization showed that OR2 and odorant-binding protein 1 (obp1) were co-localized in palps sensilla basiconica. Obp2a and IR8a were co-localized as well, but associated with sensilla chaetica on the palps. Furthermore, both OR2- and obp1-knockdowns showed reduced POR responses to Hexanal and E-2-Hexenal, and the same was true for Hexanal with IR8a- and obp2a-knockdowns. Detection to E-2-Hexenal was independent of IR8a-mediated gene silencing. Besides, Hexanal and E-2-Hexenal evoked dose dependent responses in palp basiconica via extracellular recordings. Our results indicate that both OR and IR pathways are involved in the detection of one aldehyde. PMID- 28656002 TI - Angiomotin Family Members: Oncogenes or Tumor Suppressors? AB - Angiomotin (Amot) family contains three members: Amot (p80 and p130 isoforms), Amot-like protein 1 (Amotl1), and Amot-like protein 2 (Amotl2). Amot proteins play an important role in tube formation and migration of endothelial cells and the regulation of tight junctions, polarity, and epithelial-mesenchymal transition in epithelial cells. Moreover, these proteins regulate the proliferation and migration of cancer cells. In most cancers, Amot family members promote the proliferation and invasion of cancer cells, including breast cancer, osteosarcoma, colon cancer, prostate cancer, head and neck squamous cell carcinoma, cervical cancer, liver cancer, and renal cell cancer. However, in glioblastoma, ovarian cancer, and lung cancer, Amot inhibits the growth of cancer cells. In addition, there are controversies on the regulation of Yes-associated protein (YAP) by Amot. Amot promotes either the internalization of YAP into the nucleus or the retention of YAP in the cytoplasm of different cell types. Moreover, Amot regulates the AMPK, mTOR, Wnt, and MAPK signaling pathways. However, it is unclear whether Amot is an oncogene or a tumor suppressor gene in different cellular processes. This review focuses on the multifunctional roles of Amot in cancers. PMID- 28656003 TI - Dioscin Induces Gallbladder Cancer Apoptosis by Inhibiting ROS-Mediated PI3K/AKT Signalling. AB - Gallbladder cancer (GBC), highly aggressive form of cancer with an extremely poor prognosis, is the most common malignancy of the biliary tract. In this study, we investigated the effects of dioscin (DSN) on human GBC and the potential mechanisms underlying these effects. The results showed that DSN significantly inhibited GBC cell proliferation and migration. Moreover, DSN induced GBC cell apoptosis via mitochondrial dependent apoptotic signalling. Reactive oxygen species (ROS) and glutathione (GSH) levels were measured, and ROS scavengers completely inhibited DSN-induced apoptosis and migration, indicating that ROS play an essential role in GBC progression. Western blot analysis showed that AKT activity was significantly downregulated after DSN treatment, and that inhibition/ectopic expression of AKT enhanced/abolished DSN-induced apoptosis but not migration. Furthermore, we confirmed the relationship between ROS and the PI3K/AKT pathway and found that DSN induced apoptosis by regulating ROS-mediated PI3K/AKT signaling. Taken together, these findings indicate that DSN induces GBC apoptosis through inhibiting ROS-mediated PI3K/AKT signalling. PMID- 28656004 TI - Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1alpha. AB - Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1alpha were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1alpha occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1alpha-P gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1alpha downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer. PMID- 28656005 TI - Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer. AB - Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen super family, is a pleiotropic cytokine that impacts diverse cellular functions. Previous studies have shown that tumor cell-derived Fgl2 promotes tumorigenesis and metastasis in immune-deficient mice, and it also functions as an immune-suppressive modulator in glioblastoma multiform (GMB). This study aimed to evaluate whether and how tumor stroma-derived Fgl2 affects tumorigenesis and tumor progression. We established the syngeneic transplantable Lewis lung carcinoma (LLC) model in Fgl2 knock-out (Fgl2-KO) mice and we found that deficiency of host Fgl2 is associated with reduced growth of syngeneic LLC tumors. Furthermore, we confirmed that host Fgl2 deficiency significantly decreased the accumulation of myeloid-derived suppressor cells (MDSCs) through down-regulation of chemokine (C-X-C motif) ligand 12 (CXCL12) expression. More importantly, we demonstrated that Fgl2 induced an activated and pro-tumorigenic phenotype of cancer-associated fibroblasts (CAFs) which are the principal source of CXCL12 in the tumor microenvironment (TME). Our results present a novel role of stroma-derived Fgl2 in CAF activation and function, suggesting that Fgl2 is an effective therapeutic target for treating lung cancer. PMID- 28656006 TI - Clinical Characteristics of Influenza-Associated Pneumonia of Adults: Clinical Features and Factors Contributing to Severity and Mortality. AB - Background: Pneumonia is a major complication of influenza that contributes to mortality. Clinical characteristics and factors of influenza virus contributing to the severity and mortality of pneumonia have not been fully elucidated. Objective: The objective was to clarify clinical characteristics and factors contributing to the severity and mortality of influenza-associated pneumonia (flu p). Methods: We retrospectively analyzed patients with flu-p. Results: From December 1999 to March 2016, 210 patients with a median age of 69 (range, 17 to 92) years with flu-p based on positive rapid antigen tests, increased antibody titers of paired sera, or positive results of reverse transcription polymerase chain reaction were admitted to our institution. A multivariate analysis found that advanced age (>= 65 years), pneumonia subtypes (unclassified), diabetes mellitus, and acute kidney injury complicated with flu-p were independent factors associated with disease severity, whereas pneumonia subtypes (mixed viral and bacterial pneumonia and unclassified), healthcare-associated pneumonia, acute kidney injury complicated with flu-p, and severity on admission (severe) were independent factors associated with non-survival. Conclusion: The clinical characteristics of flu-p are varied, and the contribution of several factors to the severity and mortality of flu-p suggest their importance in either preventing flu-p or managing flu-p after it develops. PMID- 28656007 TI - Association of Plasmodium falciparum with Human Endothelial Cells in vitro. AB - Endothelial abnormalities play a critical role in the pathogenesis of malaria caused by the human pathogen, Plasmodium falciparum. In serious infections and especially in cerebral malaria, red blood cells infected with the parasite are sequestered in small venules in various organs, resulting in endothelial activation and vascular occlusion, which are believed to be largely responsible for the morbidity and mortality caused by this infection, especially in children. We demonstrate that after incubation with infected red blood cells (iRBCs), cultured human umbilical vein endothelial cells (HUVECs) contain parasite protein, genomic DNA, and RNA, as well as intracellular vacuoles with apparent parasite-derived material, but not engulfed or adherent iRBCs. The association of this material with the HUVECs is observed over 96 hours after removal of iRBCs. This phenomenon may occur in endothelial cells in vivo by the process of trogocytosis, in which transfer of material between cells depends on direct cell contact. This process may contribute to the endothelial activation and disruption involved in the pathogenesis of cerebral malaria. PMID- 28656008 TI - Segregation Lag in Polyploid Cells of the Pathogen Genus Borrelia: Implications for Antigenic Variation?. AB - Relapsing fever agents like Borrelia hermsii undergo multiphasic antigenic variation that is attributable to spontaneous DNA non-reciprocal transpositions at a particular locus in the genome. This genetic switch results in a new protein being expressed on the cell surface, allowing cells with that phenotype to escape prevailing immunity. But the switch occurs in only one of several genomes in these spirochetes, and a newly-switched gene is effectively "recessive" until homozygosity is achieved. The longer that descendants of the switched cell expressed both old and new proteins, the longer this lineage risks neutralization by antibody to the old protein. We investigated the implications for antigenic variation of the phenotypic lag that polyploidy would confer on cells. We first experimentally determined the average genome copy number in daughter cells after division during mouse infection with B. hermsii strain HS1. We then applied discrete deterministic and stochastic simulations to predict outcomes when genomes were equably segregated either linearly, i.e. according to their position in one-dimensional arrays, or randomly partitioned, as for a sphere. Linear segregation replication provided for a lag in achievement of homozygosity that was significantly shorter than could be achieved under the random segregation condition. For cells with 16 genomes, this would be a 4-generation lag. A model incorporating the immune response and evolved matrices of switch rates indicated a greater fitness for polyploid over monoploid bacteria in terms of duration of infection. PMID- 28656009 TI - Role of Microbial Agents in Pulmonary Fibrosis?. AB - Pulmonary fibrosis is a form of lung disease that develops due to aberrant wound healing following repeated alveoli injury in genetically susceptible individuals, resulting in chronic inflammation, excess deposition of the extracellular matrix components, mainly collagen, and scarring of lung tissue. In addition to irradiation, environmental agents such occupational inhalants, and chemotherapeutic agents, microbial agents also play a role in the etiology of the disease. While viruses have received the most attention, emerging evidence suggest that bacteria and fungi also play a part in the etiology of pulmonary fibrosis. Furthermore, successful use of antibiotics, antiviral and antifungal drugs in several studies to attenuate fibrosis progression is also an indication of microbial involvement in the pathogenesis of the disease and could be a promising therapeutic modality for treating pulmonary fibrosis initiated or exacerbated by infectious agents. PMID- 28656010 TI - Chromatin Regulation and the Histone Code in HIV Latency?. AB - The formation of a latent reservoir of Human Immunodeficiency Virus (HIV) infection hidden from immune clearance remains a significant obstacle to approaches to eradicate HIV infection. Towards an understanding of the mechanisms of HIV persistence, there is a growing body of work implicating epigenetic regulation of chromatin in establishment and maintenance of this latent reservoir. Here we discuss recent advances in the field of chromatin regulation, specifically in our understanding of the histone code, and how these discoveries relate to our current knowledge of the chromatin mechanisms linked to HIV transcriptional repression and the reversal of latency. We also examine mechanisms unexplored in the context of HIV latency and briefly discuss current therapies aimed at the induction of proviral expression within latently infected cells. We aim to emphasize that a greater understanding of the epigenetic mechanisms which govern HIV latency could lead to new therapeutic targets for latency reversal and clearance cure strategies. PMID- 28656012 TI - Pathobiology and Immunobiology of Acanthamoeba Keratitis: Insights from Animal Models?. AB - Acanthamoeba keratitis (AK) is a rare but sight-threatening disease caused by pathogenic species of Acanthamoeba. Despite its ubiquitous nature, the incidence of AK is relatively low compared to other forms of infectious keratitis. Although contact lens wear is a major risk factor, exposure to contaminated water and ocular trauma are also associated with AK. Once a patient develops AK the prognosis is very poor unless an aggressive treatment regimen is initiated early. Some of the intriguing features of AK are the lack of immunological memory, resistance of the dormant cyst form to treatment, differences between the pathogenic strains and soil isolates of Acanthamoeba and the unique role of the innate immune system in controlling this disease. Understanding the series of steps involved in the pathogenesis of the disease and the host immune response against Acanthamoeba antigens is crucial for developing effective therapeutic strategies targeting the disease. PMID- 28656011 TI - Mechanisms of Virologic Control and Clinical Characteristics of HIV+ Elite/Viremic Controllers. AB - Human immunodeficiency virus type 1 (HIV-1) disease is pandemic, with approximately 36 million infected individuals world-wide. For the vast majority of these individuals, untreated HIV eventually causes CD4+ T cell depletion and profound immunodeficiency, resulting in morbidity and mortality. But for a remarkable few (0.2 to 0.5 percent), termed elite controllers (ECs), viral loads (VLs) remain suppressed to undetectable levels (< 50 copies/ml) and peripheral CD4+ T cell counts remain high (200 to 1000/MUl), all in the absence of antiretroviral therapy (ART). Viremic controllers (VCs) are a similar but larger subset of HIV-1 infected individuals who have the ability to suppress their VLs to low levels. These patients have been intensively studied over the last 10 years in order to determine how they are able to naturally control HIV in the absence of medications, and a variety of mechanisms have been proposed. Defective HIV does not explain the clinical status of most ECs/VCs; rather these individuals appear to somehow control HIV infection, through immune or other unknown mechanisms. Over time, many ECs and VCs eventually lose the ability to control HIV, leading to CD4+ T cell depletion and immunologic dysfunction in the absence of ART. Elucidating novel mechanisms of HIV control in this group of patients will be an important step in understanding HIV infection. This will extend our knowledge of HIV-host interaction and may pave the way for the development of new therapeutic approaches and advance the cure agenda. PMID- 28656013 TI - Vancomycin Resistance in Staphylococcus aureus?. AB - The evolution of Staphylococcus aureus during the modern antibiotic era has been delineated by distinct strain emergence events, many of which include acquisition of antibiotic resistance. The relative high burden of methicillin-resistant S. aureus (MRSA) in healthcare and community settings is a major concern worldwide. Vancomycin, a glycopeptide antibiotic that inhibits cell wall biosynthesis, remains a drug of choice for treatment of severe MRSA infections. S. aureus strains exhibiting increased resistance to vancomycin, known as vancomycin intermediate-resistant S. aureus (VISA) (MIC = 4-8 ug/mL), were discovered in the 1990s. The molecular basis of resistance in VISA is polygenic and involves stepwise mutations in genes encoding molecules predominantly involved in cell envelope biosynthesis. S. aureus isolates with complete resistance to vancomycin (MIC >= 16 ug/mL) are termed vancomycin-resistant S. aureus (VRSA)-they were first reported in the U.S. in 2002. Resistance in VRSA is conferred by the vanA gene and operon, which is present on a plasmid. Although treatment of VRSA infections is challenging, the total number of human VRSA infections to date is limited (14 in the U.S.). By comparison, the burden of VISA is relatively high and the molecular mechanisms of resistance are less well-defined. VISA are associated with persistent infections, vancomycin treatment failure, and poor clinical outcomes. Here, we review in brief progress made toward understanding the acquisition of antibiotic resistance in S. aureus, with an emphasis on the molecular mechanisms underlying vancomycin resistance. PMID- 28656014 TI - The Role of Typhoid Toxin in Salmonella Typhi Virulence?. AB - Unlike many of the nontyphoidal Salmonella serovars such as S. Typhimurium that cause restricted gastroenteritis, Salmonella Typhi is unique in that it causes life-threatening typhoid fever in humans. Despite the vast difference in disease outcomes that S. Typhi and S. Typhimurium cause in humans, there are few genomic regions that are unique to S. Typhi. Of these regions, the most notable is the small locus encoding typhoid toxin, an AB toxin that has several distinct characteristics that contribute to S. Typhi's pathogenicity. As a result, typhoid toxin and its role in S. Typhi virulence have been studied in an effort to gain insight into potential treatment and prevention strategies. Given the rise of multidrug-resistant strains, research in this area has become increasingly important. This article discusses the current understanding of typhoid toxin and potential directions for future research endeavors in order to better understand the contribution of typhoid toxin to S. Typhi virulence. PMID- 28656015 TI - BiP: Master Regulator of the Unfolded Protein Response and Crucial Factor in Flavivirus Biology?. AB - Flaviviruses have an intimate relationship with their host cells, utilizing host proteins during replication. Much of viral genome replication and virion assembly occurs on and within the endoplasmic reticulum (ER). As a cellular protein folding hub, the ER provides an ideal environment for flaviviruses to replicate. Flaviviruses can interact with several ER processes, including the unfolded protein response (UPR), a cellular stress mechanism responsible for managing unfolded protein accumulation and ER stress. The UPR can alter the ER environment in several ways, including increasing ER volume and quantity of available chaperones, both of which can favor viral replication. BiP, a chaperone and master regulator of the UPR, has been demonstrated to play a key role in several flavivirus infections. Here we describe what is known in regard to BiP, its implicated role with flavivirus infection, and what remains to be discovered. PMID- 28656017 TI - Small RNAs of Borrelia burgdorferi: Characterizing Functional Regulators in a Sea of sRNAs?. AB - Borrelia (Borreliella) burgdorferi and closely related genospecies are the causative agents of Lyme disease, the most common tick-borne disease north of the equator. The bacterium, a member of the spirochete phylum, is acquired by a tick vector that feeds on an infected vertebrate host and is transmitted to another vertebrate during subsequent feeding by the next tick stage. The precise navigation of this enzootic cycle entails the regulation of genes required for these two host-specific phases as well as the transitions between them. Recently, an expansive swath of small RNAs has been identified in B. burgdorferi and likely many, if not most, are involved in regulating gene expression. Regardless, with only a few exceptions, the functions of these RNAs are completely unknown. However, several state-of-the-art approaches are available to identify the targets of these RNAs and provide insight into their role in the enzootic cycle and infection. PMID- 28656016 TI - The Transcription Factor EB Links Cellular Stress to the Immune Response??. AB - The transcription factor EB (TFEB) is the master transcriptional regulator of autophagy and lysosome biogenesis. Recent advances have led to a paradigm shift in our understanding of lysosomes from a housekeeping cellular waste bin to a dynamically regulated pathway that is efficiently turned up or down based on cellular needs. TFEB coordinates the cellular response to nutrient deprivation and other forms of cell stress through the lysosome system, and regulates a myriad of cellular processes associated with this system including endocytosis, phagocytosis, autophagy, and lysosomal exocytosis. Autophagy and the endolysosomal system are critical to both the innate and adaptive arms of the immune system, with functions in effector cell priming and direct pathogen clearance. Recent studies have linked TFEB to the regulation of the immune response through the endolysosmal pathway and by direct transcriptional activation of immune related genes. In this review, we discuss the current understanding of TFEB's function and the molecular mechanisms behind TFEB activation. Finally, we discuss recent advances linking TFEB to the immune response that positions lysosomal signaling as a potential target for immune modulation. PMID- 28656018 TI - Zika Virus and Sexual Transmission: A New Route of Transmission for Mosquito borne Flaviviruses?. AB - Beginning in 2015, concern over a new global epidemic has spread in the media, governmental agencies, legislative bodies and the public at large. This newly emerging threat has been reported to cause symptoms ranging from mild fever, rash, and body aches, to severe birth defects and acute onset paralysis. The causative agent of this disease, Zika virus, is closely related to two other important human pathogens, dengue and West Nile Virus (WNV), but has some distinguishing features that has raised alarms from the scientific community. Like its two close relatives, this virus is a member of the Flaviviridae family, a class of single stranded RNA viruses with a positive sense genome and is spread primarily via the bite of an infected mosquito. However, this virus has demonstrated another route of transmission that is particularly concerning for people outside of the regions where the main mosquito vector for this virus is present. Sexual transmission of Zika virus has been increasingly reported, from both infected males and females to their partner, which has resulted in the World Health Organization (WHO) and the Center for Disease Control (CDC) issuing warnings to those living in or travelling to areas of Zika transmission to practice abstinence and/or avoid unprotected sexual contact for up to six months after infection with this virus. This perspective will outline the evidence for sexual transmission and persistence of viral infection in semen and vaginal secretions as well as review the animal models for sexual transmission of Zika virus. PMID- 28656020 TI - Group A Streptococcal Bacteremia following Streptococcal Pharyngitis in an Older Patient with Diabetes: A Case Report???. AB - Group A streptococcus (GAS) is responsible for a wide range of both invasive and noninvasive infections. Severe invasive group A streptococcal infection is associated with morbidity and mortality and has been linked to chronic medical conditions with skin and soft tissues involvement, and intravenous drug use (IVDU). Invasive diseases are, however, rare and have been recognized to affect the extremes of age (younger than 10 years of age and older than 74). We report a case of Group A streptococcus bacteremia following pharyngitis in a 76-year-old diabetic male with no history of IVDU. This report's main goal is to illustrate that chronic illnesses such as diabetes and congestive heart failure might predispose elderly patients to invasive diseases such as Group A streptococcus bacteremia. PMID- 28656022 TI - Pancreatic Cancer. PMID- 28656019 TI - Characterization of Elite Suppressors Cell-Associated HIV-1 mRNA at Baseline and with T Cell Activation??. AB - Objective: Elite Controllers or Suppressors (ES) are patients who control HIV replication without antiretroviral therapy. In this study, we compared baseline and inducible HIV-1 mRNA levels in CD4+ T cells from ES and chronic progressors (CPs) receiving suppressive antiretroviral therapy. Methods: We quantified basal levels of cell associated HIV-1 mRNA in CD4+ T cells isolated from CPs and ES. Additionally, we measured the fold upregulation of intracellular HIV-mRNA after stimulation of CD4+ T cells with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and quantified the amount of HIV-mRNA levels released into culture supernatant. Results: ES have significantly less cell associated HIV-mRNA per 5x106 cells (p = 0.003); 8 of 10 CPs had quantifiable HIV-1 mRNA at baseline, whereas this was present in only 2 of 10 ES. Upon stimulation with PMA and ionomycin, 4 of 5 CPs and 7 of 9 ES showed increased cell associated HIV-mRNA. Interestingly, released HIV-1 mRNA could be detected in supernatants of CD4+ T cells stimulated with PMA/ionomycin from 5 of 8 ES. Conclusion: Our results demonstrate that while the baseline levels of cell associated HIV-1 mRNA are significantly lower in ES compared to CPs, stimulation of CD4+ T cells results in a comparable relative upregulation of viral transcription. PMID- 28656021 TI - From Skin Infections to Ebola: Practice, Policy, and Beyond: An Interview with Gregory Raczniak, MD, PhD?. PMID- 28656023 TI - GASTRO-HEP News. PMID- 28656025 TI - The Effect of Transjugular Intrahepatic Portosystemic Shunt on Platelet Counts in Patients With Liver Cirrhosis. AB - Thrombocytopenia is a well-known complication of liver cirrhosis. Although the pathogenesis of thrombocytopenia is not well understood, splenic congestion resulting from portal hypertension is considered the most significant underlying mechanism. Therapeutic measures that lower portal hypertension, such as transjugular intrahepatic portosystemic shunt (TIPS), are expected to improve thrombocytopenia associated with liver cirrhosis. At present, there are few studies on the effect of TIPS on platelet counts, and the results are conflicting. This article assesses the effect of TIPS on thrombocytopenia associated with liver cirrhosis. Methods: Seventy-four patients with liver cirrhosis who were referred for TIPS were included in this study. Platelet counts were measured on 3 different occasions over a 3-month period prior to and following placement of TIPS. Thrombocytopenia was defined as a platelet count of 150,000/mm3 or less. Moderate thrombocytopenia was defined as a platelet count of 100,000/mm3 or less. Severe thrombocytopenia was defined as a platelet count of 50,000/mm3 or less. A significant increase in platelet count was defined as a 20% or higher increase from pre-TIPS values. The portosystemic pressure gradient (PSPG) was measured before and after placement of TIPS. The patency of the shunt was checked using Doppler ultrasound 24 hours and 3 months after the procedure. Results: Thirty-four of the 74 patients (46%) who underwent TIPS showed a significant increase in platelet count, with an average increase of 22% (P<.0005). Twenty-five of 40 patients (62%) with moderate thrombocytopenia showed a significant increase in platelet count, with an average increase of 36% (P<.0005). Patients with severe thrombocytopenia showed the greatest response to TIPS; 8 of 11 patients (73%) had a significant increase in platelet count (average increase, 55%; P<.0005). No correlation was found between the response to TIPS and age, sex, etiology of liver disease, pre-TIPS PSPG, or the amount of decrease in PSPG. Conclusion: TIPS may improve thrombocytopenia associated with liver cirrhosis. Patients with severe thrombocytopenia are more likely to benefit from this procedure. No factors other than pre-TIPS platelet count were found to influence the response to TIPS. PMID- 28656024 TI - Current Status and Future Directions for Screening Patients at High Risk for Pancreatic Cancer. AB - It is well known that pancreatic ductal adenocarcinoma has a high mortality rate. Despite progress in understanding the biology and genetic basis of this disease, life expectancy has changed minimally in the last 50 years. This article highlights the importance of screening patients at high risk for developing pancreatic cancer and reviews current methods as well as methods in development for pancreatic cancer early detection and surveillance. PMID- 28656026 TI - HBV/HCV Coinfection and Possible Reactivation of HBV Following DAA Use. PMID- 28656027 TI - Combination Therapy for Inflammatory Bowel Disease. PMID- 28656028 TI - Clostridium difficile Infection and the Role of Adaptive Immunity in the Microbiome. PMID- 28656029 TI - Updates to the Rome Criteria for Irritable Bowel Syndrome. PMID- 28656030 TI - An Overview of Endoscopic Ultrasound-Guided Gastroenteric Anastomosis. PMID- 28656031 TI - Introduction to the special issue on high-resolution X-ray diffraction and imaging. AB - The latest virtual special issue of Journal of Applied Crystallography features some highlights of the 13th Biennial Conference on High-Resolution X-ray Diffraction and Imaging (XTOP 2016), held in Brno, Czech Republic, in September 2016. PMID- 28656032 TI - Threefold rotational symmetry in hexagonally shaped core-shell (In,Ga)As/GaAs nanowires revealed by coherent X-ray diffraction imaging. AB - Coherent X-ray diffraction imaging at symmetric hhh Bragg reflections was used to resolve the structure of GaAs/In0.15Ga0.85As/GaAs core-shell-shell nanowires grown on a silicon (111) substrate. Diffraction amplitudes in the vicinity of GaAs 111 and GaAs 333 reflections were used to reconstruct the lost phase information. It is demonstrated that the structure of the core-shell-shell nanowire can be identified by means of phase contrast. Interestingly, it is found that both scattered intensity in the (111) plane and the reconstructed scattering phase show an additional threefold symmetry superimposed with the shape function of the investigated hexagonal nanowires. In order to find the origin of this threefold symmetry, elasticity calculations were performed using the finite element method and subsequent kinematic diffraction simulations. These suggest that a non-hexagonal (In,Ga)As shell covering the hexagonal GaAs core might be responsible for the observation. PMID- 28656033 TI - Incorporation of interfacial roughness into recursion matrix formalism of dynamical X-ray diffraction in multilayers and superlattices. AB - Diffraction in multilayers in the presence of interfacial roughness is studied theoretically, the roughness being considered as a transition layer. Exact (within the framework of the two-beam dynamical diffraction theory) differential equations for field amplitudes in a crystalline structure with varying properties along its surface normal are obtained. An iterative scheme for approximate solution of the equations is developed. The presented approach to interfacial roughness is incorporated into the recursion matrix formalism in a way that obviates possible numerical problems. Fitting of the experimental rocking curve is performed in order to test the possibility of reconstructing the roughness value from a diffraction scan. The developed algorithm works substantially faster than the traditional approach to dealing with a transition layer (dividing it into a finite number of thin lamellae). Calculations by the proposed approach are only two to three times longer than calculations for corresponding structures with ideally sharp interfaces. PMID- 28656034 TI - X-ray dynamical diffraction in amino acid crystals: a step towards improving structural resolution of biological molecules via physical phase measurements. AB - In this work, experimental and data analysis procedures were developed and applied for studying amino acid crystals by means of X-ray phase measurements. The results clearly demonstrated the sensitivity of invariant triplet phases to electronic charge distribution in d-alanine crystals, providing useful information for molecular dynamics studies of intermolecular forces. The feasibility of using phase measurements to investigate radiation damage mechanisms is also discussed on experimental and theoretical grounds. PMID- 28656035 TI - Reconstruction of the near-field distribution in an X-ray waveguide array. AB - Iterative phase retrieval has been used to reconstruct the near-field distribution behind tailored X-ray waveguide arrays, by inversion of the measured far-field pattern recorded under fully coherent conditions. It is thereby shown that multi-waveguide interference can be exploited to control the near-field distribution behind the waveguide exit. This can, for example, serve to create a secondary quasi-focal spot outside the waveguide structure. For this proof of concept, an array of seven planar Ni/C waveguides are used, with precisely varied guiding layer thickness and cladding layer thickness, as fabricated by high precision magnetron sputtering systems. The controlled thickness variations in the range of 0.2 nm results in a desired phase shift of the different waveguide beams. Two kinds of samples, a one-dimensional waveguide array and periodic waveguide multilayers, were fabricated, each consisting of seven C layers as guiding layers and eight Ni layers as cladding layers. These are shown to yield distinctly different near-field patterns. PMID- 28656036 TI - Interface-sensitive imaging by an image reconstruction aided X-ray reflectivity technique. AB - Recently, the authors have succeeded in realizing X-ray reflectivity imaging of heterogeneous ultrathin films at specific wavevector transfers by applying a wide parallel beam and an area detector. By combining in-plane angle and grazing incidence angle scans, it is possible to reconstruct a series of interface sensitive X-ray reflectivity images at different grazing-incidence angles (proportional to wavevector transfers). The physical meaning of a reconstructed X ray reflectivity image at a specific wavevector transfer is the two-dimensional reflectivity distribution of the sample. In this manner, it is possible to retrieve the micro-X-ray reflectivity (where the pixel size is on the microscale) profiles at different local positions on the sample. PMID- 28656037 TI - Structure diagnostics of heterostructures and multi-layered systems by X-ray multiple diffraction. AB - This article presents the results of research on multi-layered heterostructures by a modified calculation technique of multiple X-ray diffraction. The Al x In1-x Sb heterostructure and a Zn(Mn)Se/GaAs(001) multi-layered system were used as models to specify conditions for cases of coincidental coplanar three-beam or coincidental noncoplanar four-beam X-ray diffraction. These conditions provide the means for a high-precision determination of lattice parameters and strain anisotropy in layers. PMID- 28656038 TI - X-ray topography of subsurface crystal layers. AB - New capabilities of the Berg-Barrett topographic method are demonstrated using a skew-asymmetric X-ray diffraction scheme for investigating structural changes near the surface of semiconductor materials. Specifying the X-ray extinction depth, the details of defects and strains are revealed with high resolution. Consequently, analysis of structural distortion of layers near the surface after various types of surface processing becomes more complete. PMID- 28656039 TI - An in situ USAXS-SAXS-WAXS study of precipitate size distribution evolution in a model Ni-based alloy. AB - Intermetallic gamma' precipitates typically strengthen nickel-based superalloys. The shape, size and spatial distribution of strengthening precipitates critically influence alloy strength, while their temporal evolution characteristics determine the high-temperature alloy stability. Combined ultra-small-, small- and wide-angle X-ray scattering (USAXS-SAXS-WAXS) analysis can be used to evaluate the temporal evolution of an alloy's precipitate size distribution (PSD) and phase structure during in situ heat treatment. Analysis of PSDs from USAXS-SAXS data employs either least-squares fitting of a preordained PSD model or a maximum entropy (MaxEnt) approach, the latter avoiding a priori definition of a functional form of the PSD. However, strong low-q scattering from grain boundaries and/or structure factor effects inhibit MaxEnt analysis of typical alloys. This work describes the extension of Bayesian-MaxEnt analysis methods to data exhibiting structure factor effects and low-q power law slopes and demonstrates their use in an in situ study of precipitate size evolution during heat treatment of a model Ni-Al-Si alloy. PMID- 28656040 TI - The origin of striation in the metastable beta phase of titanium alloys observed by transmission electron microscopy. AB - For the beta phase of Ti-5553-type metastable beta-Ti alloys, striations in transmission electron microscopy (TEM) bright- and dark-field images have been frequently observed but their origin has not been sufficiently investigated. In the present work, this phenomenon is studied in depth from the macroscopic scale by neutron diffraction to the atomic scale by high-resolution TEM. The results reveal that the beta phase contains homogeneously distributed modulated structures, intermediate between that of the beta phase (cubic) and that of the alpha phase or the omega phase (hexagonal), giving rise to the appearance of additional diffraction spots at 1/2, 1/3 and 2/3 beta diffraction positions. The intermediate structure between beta and alpha is formed by the atomic displacements on each second {110}beta plane in the [Formula: see text] direction, whereas that between beta and omega is formed by atomic displacements on each second and third {112}beta plane in the opposite [Formula: see text] direction. Because of these atomic displacements, the {110}beta and {112}beta planes become faulted, resulting in the streaking of beta diffraction spots and the formation of extinction fringes in TEM bright- and dark-field images, the commonly observed striations. The present work reveals the origin of the striations and the intrinsic correlation with the additional electron reflections of the beta phase. PMID- 28656041 TI - Instrumental resolution as a function of scattering angle and wavelength as exemplified for the POWGEN instrument. AB - The method of angular- and wavelength-dispersive (e.g. two-dimensional) Rietveld refinement is a new and emerging tool for the analysis of neutron diffraction data measured at time-of-flight instruments with large area detectors. Following the approach for one-dimensional refinements (using either scattering angle or time of flight), the first step at each beam time cycle is the calibration of the instrument including the determination of instrumental contributions to the peak shape variation to be expected for diffraction patterns measured by the users. The aim of this work is to provide the users with calibration files and - for the later Rietveld refinement of the measured data - with an instrumental resolution file (IRF). This article will elaborate on the necessary steps to generate such an IRF for the angular- and wavelength-dispersive case, exemplified for the POWGEN instrument. A dataset measured on a standard diamond sample is used to extract the profile function in the two-dimensional case. It is found that the variation of reflection width with 2theta and lambda can be expressed by the standard equation used for evaluating the instrumental resolution, which yields a substantially more fundamental approach to the parameterization of the instrumental contribution to the peak shape. Geometrical considerations of the POWGEN instrument and sample effects lead to values for Deltatheta, Deltat and DeltaL that yield a very good match to the extracted FWHM values. In a final step the refinement results are compared with the one-dimensional, i.e. diffraction focused, case. PMID- 28656042 TI - Single-shot full strain tensor determination with microbeam X-ray Laue diffraction and a two-dimensional energy-dispersive detector. AB - The full strain and stress tensor determination in a triaxially stressed single crystal using X-ray diffraction requires a series of lattice spacing measurements at different crystal orientations. This can be achieved using a tunable X-ray source. This article reports on a novel experimental procedure for single-shot full strain tensor determination using polychromatic synchrotron radiation with an energy range from 5 to 23 keV. Microbeam X-ray Laue diffraction patterns were collected from a copper micro-bending beam along the central axis (centroid of the cross section). Taking advantage of a two-dimensional energy-dispersive X-ray detector (pnCCD), the position and energy of the collected Laue spots were measured for multiple positions on the sample, allowing the measurement of variations in the local microstructure. At the same time, both the deviatoric and hydrostatic components of the elastic strain and stress tensors were calculated. PMID- 28656043 TI - Processing two-dimensional X-ray diffraction and small-angle scattering data in DAWN 2. AB - A software package for the calibration and processing of powder X-ray diffraction and small-angle X-ray scattering data is presented. It provides a multitude of data processing and visualization tools as well as a command-line scripting interface for on-the-fly processing and the incorporation of complex data treatment tasks. Customizable processing chains permit the execution of many data processing steps to convert a single image or a batch of raw two-dimensional data into meaningful data and one-dimensional diffractograms. The processed data files contain the full data provenance of each process applied to the data. The calibration routines can run automatically even for high energies and also for large detector tilt angles. Some of the functionalities are highlighted by specific use cases. PMID- 28656044 TI - Pictograms to Provide a Better Understanding of Gastroesophageal Reflux Symptoms in Chinese Subjects. AB - OBJECTIVE: To explore whether pictograms could help people understand reflux symptoms. METHODS: Gastroenterologists (n = 28), non-GI physicians (n = 30), healthy people without medical education (n = 34), patients with gastrointestinal reflux disease (GERD) (n = 45), and general people (n = 100) were included. Pictograms denoting classic reflux symptoms (sour regurgitation, heartburn, retrosternal pain, and regurgitation) were created by the joint efforts of an artist and a gastroenterologist. The subjects were asked to tell the meaning of each card within 30 s. RESULTS: Compared with the physicians, healthy people without medical education tended to make mistakes in the understanding of the terms of reflux symptoms. Among GERD patients, all the terms of reflux symptoms could be understood accurately. Compared with that of non-GI physicians, GI physician had a higher accuracy in the understanding of the term regurgitation (P < 0.05). Pictograms denoting reflux symptoms could be understood accurately in all four groups. A sample from the general population showed that the recognition of the pictogram was more accurate than the recognition of the terms. CONCLUSIONS: Pictograms could help ordinary people who do not have medical education to understand reflux symptoms more accurately in China. Compared with abstract terms, pictograms could be useful for epidemiological studies and diagnosis of GERD in the community. PMID- 28656045 TI - Difficult Laparoscopic Cholecystectomy and Trainees: Predictors and Results in an Academic Teaching Hospital. AB - Laparoscopic cholecystectomy (LC) is one of the first laparoscopic procedures performed by surgical trainees. This study aims to determine preoperative and/or intraoperative predictors of difficult LC and to compare complications of LC performed by trainees with that performed by trained surgeons. A cohort of 180 consecutive patients with cholelithiasis who underwent LC was analyzed. We used univariate and binary logistic regression analyses to predict factors associated with difficult LC. We compared the rate of complications of LCs performed by trainees and that performed by trained surgeons using Pearson's chi-square test. Patients with impacted stone in the neck of the gallbladder (GB) (OR, 5.0; 95% CI, 1.59-15.77), with adhesions in the Triangle of Calot (OR, 2.9; 95% CI, 1.27 6.83), or with GB rupture (OR, 3.4; 95% CI, 1.02-11.41) were more likely to experience difficult LC. There was no difference between trainees and trained surgeons in the rate of cystic artery injury (p = .144) or GB rupture (p = .097). However, operative time of LCs performed by trained surgeons was significantly shorter (median, 45 min; IQR, 30-70 min) compared with the surgical trainees' operative time (60 min; IQR, 50-90 min). Surgical trainees can perform difficult LC safely under supervision with no increase in complications albeit with mild increase in operative time. PMID- 28656046 TI - Association of Poor Differentiation or Positive Vertical Margin with Residual Disease in Patients with Subsequent Colectomy after Complete Macroscopic Endoscopic Resection of Early Colorectal Cancer. AB - In the presence of unfavorable pathologic results after endoscopic resection of colorectal cancer, colectomy is routinely performed. We determined the risk factors for residual diseases in patients with colectomy after complete macroscopic endoscopic resection of early colorectal cancer. We identified consecutive patients who underwent endoscopic resection of early colorectal cancer and subsequently underwent colectomy, from January 2011 to December 2014. Clinicopathologic risk factors related to the residual disease were analyzed. In total, 148 patients underwent endoscopic resection and subsequent colectomy. Residual disease on colectomy was noted in 16 (10.9%) patients. The rates of poorly differentiated/mucinous histology (p = 0.028) and of positive or unknown vertical resection margin (p = 0.047) were higher in patients with residual disease than in those without. In multivariate analysis, a poorly differentiated/mucinous histology and positive or unknown vertical resection margin were significantly associated with residual disease (odds ratio = 7.508 and 2.048, p = 0.015 and 0.049, resp.). After complete macroscopic endoscopic resection of early colorectal cancer, there is a greater need for additional colectomy in cases with a positive or unknown vertical resection margin or a poorly differentiated/mucinous histology, because of their higher risk of residual cancer and lymph node metastasis. PMID- 28656047 TI - Multicenter Phase 2 Study about the Safety of No Antimicrobial Prophylaxis Use in Low-Risk Patients Undergoing Laparoscopic Distal Gastrectomy for Gastric Carcinoma (KSWEET-01 Study). AB - BACKGROUND: Recent studies have shown a lower risk of surgical site infections (SSI) after laparoscopic distal gastrectomy compared to open surgery. This is a phase 2 study aiming to determine the incidence of SSI after laparoscopic distal gastrectomy without using antimicrobial prophylaxis (AMP). METHODS: cT1N0 gastric cancers that were subject to laparoscopic distal gastrectomy were enrolled. Based on the unacceptable SSI incidence of >=12.5% and the target SSI incidence of <=5%, 105 patients were enrolled with an alpha of 0.05 and a power of 80% (ClinicalTrials.gov, NCT02200315). RESULTS: In intention-to-treat analysis, patients did not reach the target SSI rate (12.4%, 95% confidence interval = 6.8%-19.8%). Of patients, 44 patients had a protocol violation, such as extended lymph node dissection (LND) or inappropriate nonpharmacological SSI prevention measures. Per-protocol analysis excluding these patients (n = 61) showed a SSI rate of 4.9%, which was within the target SSI range. Multivariate analysis revealed that extracorporeal anastomosis and extended LND were independent risk factors for SSI. CONCLUSIONS: This study failed to reach the target SSI rate without using AMP. However, per-protocol analysis suggests that no AMP might be feasible when limited LND and adequate SSI prevention measures were performed. PMID- 28656049 TI - Systemic Embolization from an Unusual Intracardiac Mass in the Left Ventricular Outflow Tract. AB - Endocarditis can affect any endocardial surface; in the vast majority of cases, the cardiac valves are involved. It is exceedingly rare to develop infective endocarditis on the endocardium of the left ventricular outflow tract due to the high velocity of blood that traverses this area. Herein, we present a rare case of left ventricular outflow tract endocarditis that likely occurred secondary to damage to the aortic valve leaflets (from healed prior aortic valve endocarditis) causing a high velocity aortic valve regurgitant jet that impinged upon the interventricular septum which damaged the endocardium and resulted in a fibrotic "jet lesion." This fibrous jet lesion served as a nidus for bacterial proliferation and vegetation formation. The high shear stress (due to high blood flow velocity through the left ventricular outflow tract) likely promoted the multiple embolic events observed in this case. Our patient was successfully treated with aortic valve replacement, vegetation resection, and antibiotics. PMID- 28656048 TI - Evaluation of Vitamin D Status in Rheumatoid Arthritis and Its Association with Disease Activity across 15 Countries: "The COMORA Study". AB - The aims of this study are to evaluate vitamin D status in 1413 RA patients of COMORA study from 15 countries and to analyze relationship between patients' RA characteristics and low levels of vitamin D. All demographic, clinical, and biological data and RA comorbidities were completed. The results showed that the average of vitamin D serum dosage was 27.3 ng/mL +/- 15.1 [0.1-151]. Status of vitamin D was insufficient in 54.6% and deficient in 8.5% of patients. 43% of RA patients were supplemented with vitamin D and absence of supplementation on vitamin D was related to higher prevalence of vitamin D deficiency (p < 0.001). Finally, our study shows that the status of low levels of vitamin D is common in RA in different countries and under different latitudes. Absence of supplementation on vitamin D was related to higher prevalence of vitamin D deficiency. Low levels of vitamin D were associated with patients characteristics (age, BMI, and educational level), RA (disease activity and corticosteroid dosage), and comorbidities (lung disease and osteoporosis therapy). This suggests the need for a particular therapeutic strategy to improve vitamin D status in RA patients. PMID- 28656050 TI - miR-142-3p Contributes to Early Cardiac Fate Decision of Embryonic Stem Cells. AB - MicroRNAs (miRNAs) play important roles in cell fate decisions. However, the miRNAs and their targets involved in the regulation of cardiac lineage specification are largely unexplored. Here, we report novel functions of miR-142 3p in the regulation of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). With a miRNA array screen, we identified a number of miRNAs significantly changed during mESC differentiation into the mesodermal and cardiac progenitor cells, and miR-142-3p was one among the markedly downregulated miRNAs. Ectopic expression and inhibition of miR-142-3p did not alter the characteristics of undifferentiated ESCs, whereas ectopic expression of miR-142-3p impaired cardiomyocyte formation. In addition, ectopic expression of miR-142-3p inhibited the expression of a cardiac mesodermal marker gene Mesp1 and downstream cardiac transcription factors Nkx2.5, Tbx5, and Mef2c but not the expression of three germ layer-specific genes. We further demonstrated that miR-142-3p targeted the 3'-untranslated region of Mef2c. These results reveal miR-142-3p as an important regulator of early cardiomyocyte differentiation. Our findings provide new knowledge for further understanding of roles and mechanisms of miRNAs as critical regulators of cardiomyocyte differentiation. PMID- 28656051 TI - Evaluating the Timeliness of Enteric Disease Surveillance in British Columbia, Canada, 2012-13. AB - Timely surveillance of enteric diseases is necessary to identify and control cases and outbreaks. Our objective was to evaluate the timeliness of enteric disease surveillance in British Columbia, Canada, compare these results to other settings, and recommend improvements. In 2012 and 2013, information was collected from case report forms and laboratory information systems on 2615 Salmonella, shigatoxin-producing E. coli, Shigella, and Listeria infections. Twelve date variables representing the surveillance process from onset of symptoms to case interview and final laboratory results were collected, and intervals were measured. The median time from onset of symptoms to reporting subtyping results to BC epidemiologists was 26-36 days and from onset of symptoms to case interview was 12-14 days. Our findings were comparable to the international literature except for a longer time (up to 29 day difference) to reporting of PFGE results to epidemiologists in BC. Such a delay may impact our ability to identify and solve outbreaks. Several process and system changes were implemented which should improve the timeliness of enteric disease surveillance. PMID- 28656052 TI - Effect of Huayu Tongluo Herbs on Reduction of Proteinuria via Inhibition of Wnt/beta-Catenin Signaling Pathway in Diabetic Rats. AB - The study investigated the expression of Wnt/beta-catenin pathway in diabetic rats and the intervention effect of Huayu Tongluo herbs (HTH). Ten rats were randomly selected as control group and the remaining rats were established as diabetic models. The diabetic rats were randomly divided into model group and HTH treatment group. The intervention was intragastric administration in all rats for 20 weeks. At the end of every 4 weeks, fasting blood glucose and 24 h urinary total protein quantitatively were measured. At the end of the 20th week, biochemical parameters and body weight were tested. The kidney tissues were observed under light microscope and transmission electron microscopy. We examined Wnt/beta-catenin signaling pathway key proteins and renal interstitial fibrosis related molecular markers expression. The results showed that HTH could reduce urinary protein excretion and relieve renal pathological damage. Wnt4, p-GSK3beta (S9), and beta-catenin expression were decreased in the signaling pathway, but GSK3beta level was not changed by HTH in diabetic rats. Furthermore, the expressions of TGF-beta1 and ILK were decreased, but the level of E-cadherin was increased in diabetic rats after treatment with HTH. This study demonstrated that HTH could inhibit the high expression of Wnt/beta-catenin pathway in kidney of diabetic rats. The effect might be one of the main ways to reduce urinary protein excretion. PMID- 28656053 TI - Ping-Chong-Jiang-Ni Formula Induces Apoptosis and Inhibits Proliferation of Human Ectopic Endometrial Stromal Cells in Endometriosis via the Activation of JNK Signaling Pathway. AB - Endometriosis is a common gynecological condition in childbearing age women and its therapy in modern medicine achieves usually temporary cure. Ping-Chong-Jiang Ni formula (PCJNF), a Chinese herbal medicine (CHM), was shown to be clinically effective on endometriosis. Meanwhile, c-Jun N-terminal kinase (JNK) signaling pathway was involved in the therapeutic process of CHM on endometriosis. Here, we explored the effect of PCJNF on the ectopic endometrial stromal cells (EESCs) from endometriosis and test whether JNK signaling was involved. After being treated with PCJNF-containing serum obtained from Sprague Dawley rat, cell proliferation, migration, invasion, and apoptosis were evaluated in EESCs, and the total and phosphorylated JNK, ERK, and p38 proteins were detected. Our results showed that PCJNF could suppress cell proliferation, migration, and invasion and induce apoptosis in EESCs. The suppressed proliferation and increased apoptosis were dependent on JNK activation. Additionally, PCJNF caused cell cycle arrest at G2/M phase and this effect was mediated by JNK signaling, while the decreased cell migration and invasion treated by PCJNF were independent of JNK signaling. In summary, our results provided the first evidence that PCJNF could suppress cell proliferation, migration, and invasion, while increasing apoptosis in EESCs, and the suppressed proliferation and enhanced apoptosis were mediated by JNK signaling. PMID- 28656054 TI - Neuroprotective Effect of the Ginsenoside Rg1 on Cerebral Ischemic Injury In Vivo and In Vitro Is Mediated by PPARgamma-Regulated Antioxidative and Anti Inflammatory Pathways. AB - The ginsenoside Rg1 exerts a neuroprotective effect during cerebral ischemia/reperfusion injury. Rg1 has been previously reported to improve PPARgamma expression and signaling, consequently enhancing its regulatory processes. Due to PPARgamma's role in the suppression of oxidative stress and inflammation, Rg1's PPARgamma-normalizing capacity may play a role in the observed neuroprotective action of Rg1 during ischemic brain injury. We utilized a middle cerebral artery ischemia/reperfusion injury model in rats in addition to an oxygen glucose deprivation model in cortical neurons to elucidate the mechanisms underlying the neuroprotective effects of Rg1. We found that Rg1 significantly increased PPARgamma expression and reduced multiple indicators of oxidative stress and inflammation. Ultimately, Rg1 treatment improved neurological function and diminished brain edema, indicating that Rg1 may exert its neuroprotective action on cerebral ischemia/reperfusion injury through the activation of PPARgamma signaling. In addition, the present findings suggested that Rg1 was a potent PPARgamma agonist in that it upregulated PPARgamma expression and was inhibited by GW9662, a selective PPARgamma antagonist. These findings expand our previous understanding of the molecular basis of the therapeutic action of Rg1 in cerebral ischemic injury, laying the ground work for expanded study and clinical optimization of the compound. PMID- 28656055 TI - Optimal Dose of Epidural Dexmedetomidine Added to Ropivacaine for Epidural Labor Analgesia: A Pilot Study. AB - BACKGROUND: Dexmedetomidine combined with local anesthetics can decrease the concentration of epidural ropivacaine. However, the optimal dose of epidural dexmedetomidine combined with ropivacaine for labor analgesia is still uncertain. This study investigated the effect of adding different dose of epidural dexmedetomidine to ropivacaine during epidural labor analgesia. METHODS: One hundred women were randomly assigned to one of the four groups (Groups A, B, C, and D received 0.25, 0.5, 0.75, and 1 MUg/ml of dexmedetomidine plus 0.1% ropivacaine, resp.). The onset of epidural anesthesia and stages of labor were studied, and pain was assessed using a visual analogue scale (VAS). Hemodynamic parameters and fetal heart rate were monitored. Apgar scores and umbilical artery pH were recorded. The side effects, if any, were recorded also. RESULTS: The addition of 0.25, 0.5, and 0.75 MUg/ml of dexmedetomidine to 0.1% ropivacaine provided safe and effective analgesia, but 1 MUg/ml of dexmedetomidine resulted in increasing incidence of motor block. The hemodynamic parameters were similar between groups (P > 0.05). Side effects in Group D were significantly higher than those in the other three groups (P < 0.05). CONCLUSIONS: When dexmedetomidine is combined with 0.1% ropivacaine, the optimal concentration of dexmedetomidine is 0.5 MUg/ml for epidural labor analgesia (this trial is registered with ChiCTR-OPC 16008548). PMID- 28656056 TI - Association between Nine Types of TCM Constitution and Five Chronic Diseases: A Correspondence Analysis Based on a Sample of 2,660 Participants. AB - OBJECTIVE: The purpose of this study was to explore the association of nine types of Traditional Chinese Medicine (TCM) constitution with the five chronic diseases: hypertension, hyperlipidemia, diabetes mellitus, heart disease, and obesity. METHODS: Chi-squared test was performed to investigate the distribution characteristics of TCM constitutions in the participants with the five chronic diseases in questionnaire. Correspondence analysis was used to explore the correlation between them. RESULTS: A total of 2,660 participants (1,400 males; 1,260 females) were included in this study. The mean age was 52.54 +/- 13.92. Of them, 600 were of gentleness type accounting for 22.56%. Proportions of gentleness type in the chronic diseases (16.00%~23.70%) were less than that in general population (32.14%). The gentleness type and yin-deficiency type were significantly correlated with hypertension and diabetes mellitus, qi-deficiency type was correlated with heart disease, phlegm-dampness type was associated with obesity, and dampness-heat type was correlated with hyperlipidemia. CONCLUSIONS: The correlations between TCM constitution types and the five chronic diseases were different. This may have a significant implication for TCM practice, and even the people with gentleness type should not be ignored in health management. PMID- 28656057 TI - Drug-Bearing Supramolecular Filament Hydrogels as Anti-Inflammatory Agents. AB - We report here on the covalent conversion of the anti-inflammatory agent ketoprofen into self-assembling prodrugs that enable the effective purification of ketoprofen enantiomers, the improved selectivity and potency of ketoprofen, as well as the formation of one-component drug-bearing supramolecular hydrogels. We found that the ketoprofen hydrogelator could exhibit much-enhanced selectivity for cyclooxygenase 2 (COX-2) over COX-1, reduce the concentration of inflammatory cytokines (IL-1 and TNFalpha), and induce apoptosis in fibroblast-like synoviocytes while maintaining biocompatibility with healthy chondrocytes. In addition, these anti-inflammatory agent-containing hydrogels demonstrated the ability to retain the therapeutic within a joint cavity after intra-articular injection, exhibiting a slow, steady release into the plasma. We believe that upon further optimization these drug-based injectable supramolecular hydrogels could provide the basis for a local treatment strategy for rheumatoid arthritis and similar conditions. PMID- 28656058 TI - Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice. AB - Melatonin (Mel) and its receptors (MT1 and MT2) have a well-documented efficacy in treating different pain conditions. However, the anti-nociceptive effects of Mel and Mel receptors in neuropathic pain (NP) are poorly understood. To elucidate this process, pain behaviors were measured in a dorsal root ganglia (DRG)-friendly sciatic nerve cuffing model. We detected up-regulation of MT2 expression in the DRGs of cuff-implanted mice and its activation by the agonist 8 M-PDOT (8MP). Also, Mel attenuated the mechanical and thermal allodynia induced by cuff implantation. Immunohistochemical analysis demonstrated the expression of MT2 in the DRG neurons, while MT1 was expressed in the satellite cells. In cultured primary neurons, microarray analysis and gene knockdown experiments demonstrated that MT2 activation by 8MP or Mel suppressed calcium signaling pathways via MAPK1, which were blocked by RAR-related orphan receptor alpha (RORalpha) activation with a high dose of Mel. Furthermore, expression of nitric oxide synthase 1 (NOS1) was down-regulated upon Mel treatment regardless of MT2 or RORalpha. Application of Mel or 8MP in cuff-implanted models inhibited the activation of peptidergic neurons and neuro-inflammation in the DRGs by down regulating c-fos, calcitonin gene-related peptide [CGRP], and tumor necrosis factor-1alpha [TNF-1alpha] and interleukin-1beta [IL-1beta]. Addition of the MT2 antagonist luzindole blocked the effects of 8MP but not those of Mel. In conclusion, only MT2 was expressed in the DRG neurons and up-regulated upon cuff implantation. The analgesic effects of Mel in cuff-implanted mice were closely associated with both MT2-dependent (MAPK-calcium channels) and MT2-independent (NOS1) pathways in the DRG. PMID- 28656059 TI - Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. AB - PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in the development of Parkinson's disease (PD). Although the neuroprotective role of parkin is well known, the mechanism of PARK2's function in neural stem differentiation has not yet been thoroughly studied. Co-expressions network analysis showed that synaptosomal-associated protein 25 (SNAP-25) and brain derived neurotrophic factor (BDNF) were positively correlated with parkin, but negatively correlated with p21 in human patient brain. We investigated a link between the ubiquitin E3 ligase parkin and proteasomal degradation of p21 for the control of neural stem cell differentiation. We found that the neurogenesis was lowered in PARK2 knockout (KO) mice compared with non-tg mice. Expression of the marker protein for neural cell differentiation such as class III beta tubulin (TUBBIII), glial fibrillary acidic protein (GFAP) and neurofilament, as well as SNAP25 and BDNF, was down regulated in PARK2 KO mice. Associated with the loss of differentiation function, p21 protein was highly accumulated in the neural stem cells of PARK2 KO mice. We discovered that p21 directly binds with parkin and is ubiquitinated by parkin which resulted in the loss of cell differentiation ability. Introduction of p21 shRNA in PARK2 KO mice significantly rescued the differentiation efficacy as well as SNAP25 and BDNF expression. c-Jun N-terminal kinase (JNK) pathway is implicated in neurogenesis and p21 degradation. We also defined the decreased p21 ubiquitination and differentiation ability were reversed after treatment with JNK inhibitor, SP600125 in PARK2 KO mice derived neural stem cells. Thus, the present study indicated that parkin knockout inhibits neural stem cell differentiation by JNK-dependent proteasomal degradation of p21. PMID- 28656060 TI - PET Tracer 18F-Fluciclovine Can Detect Histologically Proven Bone Metastatic Lesions: A Preclinical Study in Rat Osteolytic and Osteoblastic Bone Metastasis Models. AB - 18F-Fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid; anti-18F FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3H-2-deoxy-2-fluoro-D-glucose (3H-FDG), 3H-choline chloride (3H choline), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) by using triple tracer autoradiography in rat breast cancer osteolytic (on day 12 +/- 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 +/- 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14C-fluciclovine, 3H-FDG, and 3H-choline, but not 99mTc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99mTc-HMDP accumulated mostly in osteoblastic lesions. 14C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14C-fluciclovine and 3H-FDG existed, based on histological differences: low 14C-fluciclovine and high 3H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14C-fluciclovine was not clear, yet clearer than with 3H-FDG. Although half of the osteoblastic lesions with 14C fluciclovine accumulation showed negligible 3H-choline accumulation in comparison, they were histologically similar to lesions with marked 14C fluciclovine and 3H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and osteoblastic bone metastatic lesions. PMID- 28656061 TI - Metabolomics Identifies Metabolic Markers of Maturation in Human Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Cardiovascular disease is a leading cause of death worldwide. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) hold immense clinical potential and recent studies have enabled generation of virtually pure hPSC-CMs with high efficiency in chemically defined and xeno-free conditions. Despite these advances, hPSC-CMs exhibit an immature phenotype and are arrhythmogenic in vivo, necessitating development of strategies to mature these cells. hPSC-CMs undergo significant metabolic alterations during differentiation and maturation. A detailed analysis of the metabolic changes accompanying maturation of hPSC-CMs may prove useful in identifying new strategies to expedite hPSC-CM maturation and also may provide biomarkers for testing or validating hPSC-CM maturation. In this study we identified global metabolic changes which take place during long-term culture and maturation of hPSC-CMs derived from three different hPSC lines. We have identified several metabolic pathways, including phospholipid metabolism and pantothenate and Coenzyme A metabolism, which showed significant enrichment upon maturation in addition to fatty acid oxidation and metabolism. We also identified increases in glycerophosphocholine and the glycerophosphocholine:phosphocholine ratio as potential metabolic biomarkers of maturation. These biomarkers were also affected in a similar manner during murine heart development in vivo. These results support that hPSC-CM maturation is associated with extensive metabolic changes in metabolic network utilization and understanding the roles of these metabolic changes has the potential to develop novel approaches to monitor and expedite hPSC-CM maturation. PMID- 28656062 TI - c-Myc is Required for BRAFV600E-Induced Epigenetic Silencing by H3K27me3 in Tumorigenesis. AB - BRAFV600E mutation is frequently found in human cancers particularly thyroid cancer and melanoma, and is involved in the regulation of gene expression through activating MAPK/Erk signaling. Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing in tumorigenesis. However, molecular mechanism underlying the complex interplay between these two molecular events remains to be explored. In the present study, we conducted chromatin immunoprecipitation combined with next-generation sequencing (ChIP-Seq) and expression microarray analysis in NIH3T3 cells to explore the relationship between H3K27me3 and transcriptional regulation by BRAFV600E mutation. Our results showed that activated MAPK/Erk signaling by BRAFV600E mutation was a trigger of this epigenetic processing at many downstream target genes in cancer cell lines and BrafV600E-induced thyroid cancer of transgenetic mice. By integrating ChIP-Seq and gene expression microarray data, we identified 150 down-regulated loci with increased levels of H3K27me3 in BRAF mutant cells relative to BRAF wild-type cells. Our data also demonstrated that c Myc, a downstream key effector of BRAFV600E signaling, was required for BRAFV600E induced changes in H3K27me3 through regulating the components of the polycomb repressive complex 2 (PRC2) genes Ezh2, Suz12 and Jarid2 at both transcriptional levels via direct binding to their regulatory elements and post-transcriptional levels via repressing the miR-26a, miR-200b and miR-155. In addition, BRAFV600E also caused gene silencing through Erk1/2-induced RNA polymerase II (RNAPII) poising and chromatin architecture. Collectively, our data uncover a previously unknown epigenetic mechanism in the tumorigenesis of BRAFV600E-driven cancers. PMID- 28656063 TI - Suppression Of beta-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma. AB - Nuclear localization of beta-catenin is essential for the progression of various human cancers via transcriptional upregulation of downstream genes. The MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis has been reported to activate Wnt/beta-catenin signaling, and CGP57380, an inhibitor of MNK kinases, inhibits the proliferation of multiple cancers. In this study, we showed that beta-catenin signaling (including beta-catenin, cyclin D1, c-Myc, and MMP-7) and p-eIF4E expression were elevated in nasopharyngeal carcinoma (NPC) compared with non-cancerous nasopharyngeal epithelial tissues, and was associated with clinical characteristics of NPC patients. Lymph node metastasis, gender, aberrant beta catenin expression, and elevated levels of MMP-7 and cyclin D1 were independent prognostic factors. Significantly, expression of p-eIF4E was positively correlated with beta-catenin, and targeting the MNK-eIF4E axis with CGP57380 downregulated beta-catenin in the nucleus, which in turn decreased proliferation, cell cycle progression, migration, invasion, and metastasis of NPC in vitro and in vivo. CGP57380 also potentiated radiation-induced apoptosis in NPC. Moreover, CGP57380 upregulated beta-catenin in the cytoplasm thus blocking epithelial mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. Mechanistically, inhibition of beta-catenin nuclear translocation by CGP57380 was dependent on AKT activation. Notably, identification of the MNK/eIF4E/beta-catenin axis might provide a potential target for overcoming the poor prognosis mediated by beta-catenin in NPC. PMID- 28656065 TI - Clinching for sheet materials. AB - Latest developments in the clinching of sheet materials are reviewed in this article. Important issues are discussed, such as tool design, process parameters and joinability of some new lightweight sheet materials. Hybrid and modified clinching processes are introduced to a general reader. Several unaddressed issues in the clinching of sheet materials are identified. PMID- 28656066 TI - Endovascular Treatment of Renal Arteriovenous Fistula with N-Butyl Cyanoacrylate (NBCA). AB - BACKGROUND: Renal arteriovenous malformation (RAVM) is a rare disease. The causes of pathological connections between renal arteries may be congenital or iatrogenic - mainly as a consequence of a biopsy or due to renal carcinomas and postinflammatory changes. Computed tomography, ultrasound Doppler and angiography are the main diagnostic tools used for the detection of RAVMs. CASE REPORT: The aim of this study is to present a case of endovascular treatment of RAVM with a mixture of NBCA and lipiodol. A 29-year-old woman was suffering from drug resistant hypertension secondary to RAVM. The malformation was embolized using NBCA mixed with lipiodol. The postoperative course was uneventful. A follow-up angio-CT, performed 3 months and one year after the procedure, showed a complete occlusion of the RAVM. CONCLUSIONS: NBCA can be used alone to embolize RAVMs. Procedures involving a combination of NBCA and lipiodol are difficult and should be performed by experienced specialists. PMID- 28656064 TI - Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers. AB - Junctophilin (JPH) proteins stabilize junctional membrane complexes between plasma membrane and endoplasmic reticulum, also implicated in some human diseases. JPH3 mutations are linked to Huntington's disease-like 2 syndrome. Through epigenomic study of a colon cancer cell line pair (HCT116 and DKO), we identified JPH3 as a methylated novel tumor suppressor gene (TSG) candidate at 16q24. We further studied its epigenetic alterations and functions in digestive tumorigenesis. JPH3 expression at the RNA level was found to be frequently silenced or reduced in colorectal and gastric cancers due to its promoter CpG methylation, which is associated with tumor progression and poor survival of digestive cancer patients. Ectopic expression of JPH3 inhibited tumor cell growth in vitro and in vivo. JPH3 expression upregulated the cytosolic Ca2+ levels, and unfolded protein response gene expression upon endoplasmic reticulum stress. JPH3 also induced calpain activation and subsequent mitochondrial membrane depolarization and cell apoptosis. Thus, JPH3 was identified as a novel TSG methylated in colorectal and gastric tumors which promotes mitochondrial-mediated apoptosis, also as a potential metastasis and survival biomarker for digestive cancers. PMID- 28656067 TI - Stent-Assisted Coil Embolization of Posttraumatic Dissecting Carotid Aneurysm Causing Ophthalmoplegia. AB - BACKGROUND: Ophthalmoplegia secondary to a traumatic dissecting aneurysm in the cavernous segment of internal carotid artery (ICA) is a relatively rare entity. Anticoagulant or antiplatelet therapy is the preferred treatment option for carotid dissections. However, endovascular interventions are noninvasive and alternative methods to surgery, especially in cases of aneurysms that do not respond to medical therapy. CASE REPORT: We report of a 19-year-old man presenting with left-sided, total ophthalmoplegia after a traffic accident. Magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) revealed a dissection beginning at the cervical segment of internal carotid artery (ICA) together with a dissecting aneurysm in the cavernous segment. A stent was placed in the narrowed and dissected segment of ICA, and the dissecting aneurysm of the cavernous segment was successfully managed with a stent-assisted coil embolization. After the endovascular treatment of the aneurysm, a full recovery of cranial nerve function was achieved. CONCLUSIONS: Immediate diagnosis and appropriate therapy of dissecting aneurysms is necessary for good clinical outcomes in cases of ophthalmoplegia. PMID- 28656068 TI - Toxins in Brain! Magnetic Resonance (MR) Imaging of Toxic Leukoencephalopathy - A Pictorial Essay. AB - Toxic leukoencephalopathy results from damage to the white matter caused by various toxins. It manifests itself as white matter signal abnormalities with or without the presence of restricted diffusion. These changes are often reversible if the insulting agent is removed early, with the exception of posthypoxic leukoencephalopathy that can manifest itself 1-2 weeks after the initial insult. However, many other potential causes of white matter signal abnormalities can mimic the changes of toxic leukoencephalopathy. Thus, familiarity with the causes, clinical presentation and particularly imaging findings of toxic leukoencephalopathy is critical for early treatment and improved prognosis. The purpose of this pictorial essay is to familiarize the reader with the various causes of toxic leukoencephalopathy along with its differential diagnoses and mimics. PMID- 28656070 TI - Applied Theatre Facilitates Dialogue about Career Challenges for Scientists. AB - The design of programs in support of a strong, diverse, and inclusive scientific workforce and academe requires numerous difficult conversations about sensitive topics such as the challenges scientists can face in their professional development. Theatre can be an interactive and effective way to foster discussion around such subjects. This article examines the implementation and benefits of such interactive strategies in different contexts, including the benefits of getting early career academics and professionals talking about some of the situations that women and underrepresented minorities face in the workplace, while allowing more seasoned professionals and colleagues to join in the conversation. PMID- 28656069 TI - Define Your Goals Before You Design a CURE: A Call to Use Backward Design in Planning Course-Based Undergraduate Research Experiences. AB - We recommend using backward design to develop course-based undergraduate research experiences (CUREs). The defining hallmark of CUREs is that students in a formal lab course explore research questions with unknown answers that are broadly relevant outside the course. Because CUREs lead to novel research findings, they represent a unique course design challenge, as the dual nature of these courses requires course designers to consider two distinct, but complementary, sets of goals for the CURE: 1) scientific discovery milestones (i.e., research goals) and 2) student learning in cognitive, psychomotor, and affective domains (i.e., pedagogical goals). As more undergraduate laboratory courses are re-imagined as CUREs, how do we thoughtfully design these courses to effectively meet both sets of goals? In this Perspectives article, we explore this question and outline recommendations for using backward design in CURE development. PMID- 28656071 TI - Each to Their Own CURE: Faculty Who Teach Course-Based Undergraduate Research Experiences Report Why You Too Should Teach a CURE. AB - Course-based undergraduate research experiences (CUREs) meet national recommendations for integrating research experiences into life science curricula. As such, CUREs have grown in popularity and many research studies have focused on student outcomes from CUREs. Institutional change literature highlights that understanding faculty is also key to new pedagogies succeeding. To begin to understand faculty perspectives on CUREs, we conducted semi-structured interviews with 61 faculty who teach CUREs regarding why they teach CUREs, what the outcomes are, and how they would discuss a CURE with a colleague. Using grounded theory, participant responses were coded and categorized as tangible or intangible, related to both student and faculty-centered themes. We found that intangible themes were prevalent, and that there were significant differences in the emphasis on tangible themes for faculty who have developed their own independent CUREs when compared with faculty who implement pre-developed, national CUREs. We focus our results on the similarities and differences among the perspectives of faculty who teach these two different CURE types and explore trends among all participants. The results of this work highlight the need for considering a multi dimensional framework to understand, promote, and successfully implement CUREs. PMID- 28656073 TI - Neutrophil and Monocyte Bactericidal Responses to 10 Weeks of Low-Volume High Intensity Interval or Moderate-Intensity Continuous Training in Sedentary Adults. AB - Neutrophils and monocytes are key components of the innate immune system that undergo age-associated declines in function. This study compared the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on immune function in sedentary adults. Twenty-seven (43 +/- 11 years) healthy sedentary adults were randomized into ten weeks of either a HIIT (>90% maximum heart rate) or MICT (70% maximum heart rate) group training program. Aerobic capacity (VO2peak), neutrophil and monocyte bacterial phagocytosis and oxidative burst, cell surface receptor expression, and systemic inflammation were measured before and after the training. Total exercise time commitment was 57% less for HIIT compared to that for MICT while both significantly improved VO2peak similarly. Neutrophil phagocytosis and oxidative burst and monocyte phagocytosis and percentage of monocytes producing an oxidative burst were improved by training similarly in both groups. Expression of monocyte but not neutrophil CD16, TLR2, and TLR4 was reduced by training similarly in both groups. No differences in systemic inflammation were observed for training; however, leptin was reduced in the MICT group only. With similar immune-enhancing effects for HIIT compared to those for MICT at 50% of the time commitment, our results support HIIT as a time efficient exercise option to improve neutrophil and monocyte function. PMID- 28656072 TI - Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle. AB - Mitochondria are characterized by its pivotal roles in managing energy production, reactive oxygen species, and calcium, whose aging-related structural and functional deteriorations are observed in aging muscle. Although it is still unclear how aging alters mitochondrial quality and quantity in skeletal muscle, dysregulation of mitochondrial biogenesis and dynamic controls has been suggested as key players for that. In this paper, we summarize current understandings on how aging regulates muscle mitochondrial biogenesis, while focusing on transcriptional regulations including PGC-1alpha, AMPK, p53, mtDNA, and Tfam. Further, we review current findings on the muscle mitochondrial dynamic systems in aging muscle: fusion/fission, autophagy/mitophagy, and protein import. Next, we also discuss how endurance and resistance exercises impact on the mitochondrial quality controls in aging muscle, suggesting possible effective exercise strategies to improve/maintain mitochondrial health. PMID- 28656075 TI - Value of macrobiopsies and transanal endoscopic microsurgery in the histological work-up of rectal neoplasms: A retrospective study. AB - AIM: To evaluate a step up approach: Taking macrobiopsies and performing excision biopsies in patients with suspected rectal cancer in which biopsies taken though the flexible endoscope showed benign histology. METHODS: Patients with a rectal neoplasm who underwent flexible endoscopy and biopsies were included. In case of benign biopsies rigid rectoscopy and macrobiopsies were employed. If this failed to prove malignancy, transanal endoscopic microsurgery (TEM) was used in a final effort to establish a certain preoperative diagnosis. The preoperative results were compared with the findings after surgical excision and follow up to calculate the reliability of this algorithm. RESULTS: One hundred and thirty-two patients were included. One hundred and ten patients with a carcinoma and 22 with an adenoma. Seventy-five of 110 carcinomas were proven malignant after flexible endoscopy. With the addition of rigid endoscopy and taking of macrobiopsies, this number increased to 89. Performing TEM excision biopsies further enlarged the number of proven malignancies to 100. CONCLUSION: The step-up approach includes taking macrobiopsies through the rigid rectoscope and performing excision biopsies using transanal endoscopic microsurgery in addition to flexible endoscopy. This approach, reduced the number of missed preoperative malignant diagnoses from 32% to 9%. PMID- 28656076 TI - Effects of age on survival and morbidity in gastric cancer patients undergoing gastrectomy. AB - AIM: To evaluate clinicopathological features and surgical outcomes of gastric cancer in elderly and non-elderly patients after inverse probability of treatment weighting (IPTW) method using propensity score. METHODS: We enrolled a total of 448 patients with histologically confirmed primary gastric carcinoma who received gastrectomies. Of these, 115 patients were aged > 80 years old (Group A), and 333 patients were aged < 79 years old (Group B). We compared the surgical outcomes and survival of the two groups after IPTW. RESULTS: Postoperative complications, especially respiratory complications and hospital deaths, were significantly more common in Group A than in Group B (P < 0.05). Overall survival (OS) was significantly lower in Group A patients than in Group B patients. Among the subset of patients who had pathological Stage I disease, OS was significantly lower in Group A (P < 0.05) than Group B, whereas cause-specific survival was almost equal in the two groups. In multivariate analysis, pathological stage, histology, and extent of lymph node dissection were independent prognostic values for OS. CONCLUSION: When the gastrectomy was performed in gastric cancer patients, we should recognized high mortality and comorbidities in that of elderly. More extensive lymph node dissection might improve prognoses of elderly gastric cancer patients. PMID- 28656074 TI - Detecting circulating tumor material and digital pathology imaging during pancreatic cancer progression. AB - Pancreatic cancer (PC) is a leading cause of cancer-related death worldwide. Clinical symptoms typically present late when treatment options are limited and survival expectancy is very short. Metastatic mutations are heterogeneous and can accumulate up to twenty years before PC diagnosis. Given such genetic diversity, detecting and managing the complex states of disease progression may be limited to imaging modalities and markers present in circulation. Recent developments in digital pathology imaging show potential for early PC detection, making a differential diagnosis, and predicting treatment sensitivity leading to long-term survival in advanced stage patients. Despite large research efforts, the only serum marker currently approved for clinical use is CA 19-9. Utility of CA 19-9 has been shown to improve when it is used in combination with PC-specific markers. Efforts are being made to develop early-screening assays that can detect tumor-derived material, present in circulation, before metastasis takes a significant course. Detection of markers that identify circulating tumor cells and tumor-derived extracellular vesicles (EVs) in biofluid samples offers a promising non-invasive method for this purpose. Circulating tumor cells exhibit varying expression of epithelial and mesenchymal markers depending on the state of tumor differentiation. This offers a possibility for monitoring disease progression using minimally invasive procedures. EVs also offer the benefit of detecting molecular cargo of tumor origin and add the potential to detect circulating vesicle markers from tumors that lack invasive properties. This review integrates recent genetic insights of PC progression with developments in digital pathology and early detection of tumor-derived circulating material. PMID- 28656077 TI - Gastric plexiform fibromyxoma resected by endoscopic submucosal dissection after observation of chronological changes: A case report. AB - A 66-year-old man was diagnosed with a gastric submucosal tumor. Endoscopic ultrasound (EUS) revealed an iso/hypoechoic mass in the third layer. No malignant cells were detected in a histological examination. Yearly follow-up endoscopy and EUS showed the slow growth of the tumor. Endoscopic submucosal dissection (ESD) was performed and a glistening tumor was resected. The lesion showed a multinodular plexiform growth pattern consisting of spindle cells with an abundant fibromyxoid stroma that was rich in small vessels. The tumor was diagnosed as plexiform fibromyxoma (PF) by immunohistochemistry. Although difficulties are associated with reaching a diagnosis preoperatively, chronological changes on EUS may contribute to the diagnosis of PF. ESD may also be useful in the diagnosis and treatment of PF. PMID- 28656078 TI - Commentary: Comparison of activated charcoal and sodium polystyrene sulfonate resin efficiency on reduction of amitriptyline oral absorption in rat as treatments for overdose and toxicities. PMID- 28656079 TI - Construction, expression, purification and characterization of secretin domain of PilQ and triple PilA-related disulfide loop peptides fusion protein from Pseudomonas aeruginosa. AB - OBJECTIVES: Infection with Pseudomonas aeruginosa has been a long-standing obstacle for clinical therapy due to the complexity of the genetics and pathogenesis, as well for widespread resistance to antibiotics, thus attaching great importance to explore effective vaccines for prevention and treatment. This paper focuses on the introduction of novel Pseudomonas aeruginosa type IV pili (T4P)-based fusion protein containing the secretin domain of PilQ and tandem PilA related peptides. MATERIALS AND METHODS: We surveyed the expression of the PilQ380-705-PilA fusion protein in-frame with pET26b vector in which a rigid linker was used between two polypeptides and flexible linkers were inserted between the three tandem repeats and each pilA domains. The transformants were expressed in Escherichia coli BL21. The reactivity of specific antisera to the fusion protein was assessed by ELISA. The biological activities of this candidate vaccine were evaluated by western blotting, opsonophagocytosis, and twitching inhibition assays. RESULTS: The fusion protein was purified in high yield by osmotic shock method using HisTrap affinity column. The protein was confirmed by immunoblot analysis. The checkerboard titration showed that the optimal dilution of the antibody to react with antigen is 1:128. Results of opsonophagocytosis assay revealed that the antibodies elevated to the fusion protein promoted phagocytosis of the PAO1 and 6266E strains, so that the twitching immobilization test confirmed these results. CONCLUSION: Due to excellent killing activity mediated by opsonic antibodies and efficient immobilization of the strains, it seems that PilQ380-705-PilA fusion protein could be a reliable candidate vaccine against P. aeruginosa infection. PMID- 28656080 TI - One-step purification and characterization of alginate lyase from a clinical Pseudomonas aeruginosa with destructive activity on bacterial biofilm. AB - OBJECTIVES: Pseudomonas aeruginosa is a Gram-negative and aerobic rod bacterium that displays mucoid and non-mucoid phenotype. Mucoid strains secrete alginate, which is the main agent of biofilms in chronic P. aeruginosa infections, show high resistance to antibiotics; consequently, the biological disruption of mucoid P. aeruginosa biofilms is an attractive area of study for researchers. Alginate lyase gene (algl) is a member of alginate producing operon which by glycosidase activity produces primer for other enzymes in this cluster. Also this activity can destroy the extracellular alginate; therefore this enzyme participates in alginate production and destruction pathway. Alginate lyase causes detachment of a biofilm by reducing its adhesion to the surfaces, and increases phagocytosis and antibiotic susceptibility. In this study, alginate lyase was purified in just one step and its properties were investigated. MATERIALS AND METHODS: The purification was done by affinity chromatography, analysed by SDS-PAGE, and its effect on P. aeruginosa biofilms was surveyed by micro titer plate assay and SEM. The substrate specificity of the enzyme was determined by PCR. RESULTS: Alginate lyase from isolate 48 was purified in one step. It is more thermally resistant than alginate lyase from Pseudomonas aeruginosa PAO1 and poly M, poly G and poly MG alginate were the substrate of this enzyme. Moreover, it has an eradication effect on biofilms from P. aeruginosa 48 and PAO1. CONCLUSION: In this study an alginate lyase with many characteristics suitable in medicine such as thermal stability, effective on poly M alginate, and bacterial biofilm destructive was introduced and purified. PMID- 28656081 TI - Effect of rosiglitazone on amyloid precursor protein processing and Abeta clearance in streptozotocin-induced rat model of Alzheimer's disease. AB - OBJECTIVES: Increasing evidence suggests that Alzheimer's disease (AD) is associated with diabetes. Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist and anti-diabetic agent, may improve symptoms of AD. However, the underlying therapeutic potential of it has not been fully elucidated. MATERIALS AND METHODS: Rats were divided into four groups: control group, sham operated group, Streptozotocin (STZ) group, rosiglitazone (RGZ) group. Particularly, the STZ-induced rat model was established by intracerebroventricular injection (3 mg/kg) on the first and third day. The water maze behavioral test was performed to evaluate spatial reference learning and memory of the rats. Abeta1-40 and Abeta1-42 levels were measured by ELISA method. To determine APP-derived fragment, BACE1 and Abeta degrading enzymes levels, such as NEP and IDE, as well as Abeta transportation protein level, such as LRP1, RAGE, Abca1 and APOE, which were analyzed by Western blot. Immunohistochemistry was used to observe the change of Abeta1-40 and Abeta1-42 in hippocampus. RESULTS: Chronic treatment with RGZ could reduce the Abeta level and improved spatial memory performance in STZ-induced rat model. However, RGZ modified the expression of specific transport proteins monitoring Abeta clearance, such as ATP binding cassette transporter 1 (ABCA1), lipoprotein receptor-related protein 1 (LRP1), and the advanced glycation end product-specific receptor (RAGE) rather than change levels of Abeta degrading enzymes, such as IDE and NEP, nor affect APP processing. CONCLUSION: As a potential therapeutic strategy, rosiglitazone might exert anti-AD effect not by alteration of APP processing pathway and Abeta degradation directly, but through promotion of Abeta clearance indeed. PMID- 28656082 TI - MiR-570 inhibits cell proliferation and glucose metabolism by targeting IRS1 and IRS2 in human chronic myelogenous leukemia. AB - OBJECTIVES: Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder characterized by the accumulation of myeloid cells with a chromosomal translocation known as the Philadelphia chromosome. In this study, we investigated the roles of miR-570 in CML development. MATERIALS AND METHODS: Expression of miR-570 in CML samples and cell lines was determined by qRT-PCR. Glucose uptake and ATP concentration detection assays were used to analyze cell glucose metabolism. MTT and western blot assays were performed for cell proliferation and apoptosis, respectively. The targets of miR-570 were predicted by bioinformatics and confirmed using luciferase activity, qRT-PCR and western blot assays. RESULTS: The expression levels of miR-570 were significantly reduced in CML clinical samples and cells. Overexpression of miR-570 inhibited cell proliferation, promoted apoptosis, and suppressed glucose metabolism in CML cells. Insulin receptor substrates (IRS) 1 and IRS2 were identified as direct targets of miR-570. IRS1 or IRS2 were knocked down in K562 cells. Loss of IRS1/2 expression led to suppressed cell proliferation, elevated apoptosis, and decreased glucose metabolism in CML cells, which is consistent with their roles as miR-570 targets. CONCLUSION: MiR-570 directly targeted IRS1 and IRS2 in CML, suppressing cell proliferation and glucose metabolism. MiR-570 may provide a strategy for CML therapy. PMID- 28656083 TI - In vivo immunotherapy of lung cancer using cross-species reactive vascular endothelial growth factor nanobodies. AB - OBJECTIVES: Lung cancer is the main leading cause of cancer death worldwide. Angiogenesis is the main step in proliferation and spreading of tumor cells. Targeting vascular endothelial growth factor (VEGF) is an effective approach for inhibition of cancer angiogenesis. Nanobodies (NBs) are a novel class of antibodies derived from the camel. Unique characteristics of Nbs like their small size and good penetration to tumor tissues makes them promising tools in drug development. Development of NBs targeting both human and mouse VEGF is required for understanding their in vivo functions. Therefore, development of cross species reactive anti-VEGF Nbs for immunotherapy of lung cancer was the main aim of the current study. MATERIALS AND METHODS: Here we developed NBs from Camelus dromedarius library with high specificity and binding affinity to both human and mouse VEGF. In vitro and In vivo function of developed NB was evaluated on human endothelial cells and lung epithelial tumor cells (TC-1). RESULTS: A nanobody showed the highest affinity to human and mouse VEGF and potently inhibited VEGF in the ELISA experiment. Anti-VEGF NBs significantly inhibited in vitro human endothelial cell migration through blockade of VEGF (P=0.045). Anti-VEGF NBs also significantly inhibited in vivo TC-1 growth in a dose-dependent manner (P=0.001) and resulted in higher survival rate in the nanobody treated group. CONCLUSION: These findings demonstrate the potential of anti-VEGF NBs in tumor growth inhibition and are promising as novel cancer therapeutic candidate. PMID- 28656084 TI - Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin induced nephropathy via attenuation of oxidative stress. AB - OBJECTIVES: Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN). In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO) on the prevention of DN in streptozotocin induced-diabetic mice. MATERIALS AND METHODS: Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent), diabetic group and four treatment groups which received U. dioica, pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ) (200 mg/kg body wt, IP) diluted in citrate buffer (pH= 4.6). After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. RESULTS: Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO), protein carbonyl) in renal supernatant of diabetic mice was inhibited by U. dioica treatment. Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. CONCLUSION: Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN. PMID- 28656085 TI - Berberis vulgaris for cardiovascular disorders: a scoping literature review. AB - Cardiovascular disorders are the leading cause of mortality worldwide. Berberis vulgaris (B. vulgaris) is a commonly used plant in traditional medicine. In recent studies, B. vulgaris showed antiarrhythmic, antihypertensive, anticholinergic, and cardioprotective effects. We reviewed the literature to explore the possible prophylactic and therapeutic roles of B. vulgaris in cardiovascular medicine. A computer literature search was conducted to identify all relevant studies that have investigated the role of B. vulgaris in prevention or treatment of cardiovascular diseases. We also searched the citations of the retrieved articles. Using a systematic approach, we conducted a scoping review that included a total of 37 articles. Twelve studies examined the antihypertensive effects of B. vulgaris, seven studies investigated its antiarrhythmic effects, while its inotropic and cardioprotective effects were evaluated in four and eight studies, respectively. B. vulgaris showed a beneficial effect in reducing blood pressure, enhancing cardiac contractility, and protection from reperfusion injury. However, the mechanisms of these effects are still under investigation. Moreover, it could modify major risk factors for cardiovascular disorders, such as oxidative stress, hyperglycemia, and hyperlipidemia. Further studies are needed to translate these findings into effective cardiovascular medications. PMID- 28656086 TI - Berberine protects against metformin-associated lactic acidosis in induced diabetes mellitus. AB - OBJECTIVES: Causality of occurrence of metformin-associated lactic acidosis (MALA) is a clinical problem. Currently, there is no drug available to prevent MALA. The present study was conducted to evaluate the protective effect of Berberine (BBR) against MALA in induced diabetic rat model. MATERIALS AND METHODS: A sample of 75 healthy male Wistar rats was randomly selected according to inclusion and exclusion criteria. 75 male Wistar rats were randomly divided into a control and 4 experimental groups. Streptozotocin (STZ) in citrate buffer (pH 4.5) at a dose of 45 mg/kg was injected for induction of diabetes mellitus and rats achieving fasting blood glucose >250 mg/dl were included. Blood samples were collected 18 hr after the last dose of metformin and berberine. Ethical approval was taken before the study was conducted. Staistix 10.0 (USA) software was used for data analysis. RESULTS: Berberine decreased MALA. Metformin, metformin + BBR 50 mg/kg bwt, and metformin + BBR 100 mg/kg bwt showed serum lactate as 1.87+/-0.4 mmol/lL, 1.62 +/- 0.44 mmol/l and 1.47+/- 0.45 mmol/l, respectively (P=0.0001). Insulin resistance and liver enzymes were improved in BBR treated rats. CONCLUSION: The present study reports berberine protects against MALA in streptozocin-induced diabetes mellitus. PMID- 28656087 TI - Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine: a review. AB - Berberis vulgaris and berberine, its main component, traditionally have been used for treatment of various disorders. The pharmacological properties of them have been investigated using different in vivo and in vitro models. In spite of beneficial effects of B. vulgaris on different cell lines, there are documents have revealed negative impacts of it on animal and human. In this regards, the determination of its toxicity in a scientific view is necessary. In current report, we provide classified information about the toxicity of B. vulgaris and berberine in different conditions consist of acute, sub-acute, sub-chronic and chronic state. Besides, it discusses the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of B. vulgaris and berberine as well as developmental toxicity and clinical studies. Data from the present study indicate that their toxicity is depending on the route and duration of administration. According to present study, they could induce GI upset and ulceration, immunotoxicity, phototoxicity, neurotoxicity, cardiotoxicity and jaundice in a dose dependent manner. They should be used with caution in pregnancy, neonatal and G6PD deficiency. Besides, consideration should be taken in co-administration of berberine with drugs that are metabolized with CYP enzymes due their inhibitory effects on these enzymes. Furthermore, they evoke cytotoxicity on both normal and cancer cell line which is time and concentration dependent. PMID- 28656088 TI - Effects of berberine on the secretion of cytokines and expression of genes involved in cell cycle regulation in THP-1 monocytic cell line. AB - OBJECTIVES: Current acute myeloid leukemia (AML) therapeutic strategies have irreversible side-effects. Berberine (BBR) is an isoquinoline alkaloid, which has been known as an aryl hydrocarbon receptor (AhR) ligand. AhR is a cytoplasmic receptor, which is involved in the regulation of cellular and immune responses. Here, we investigated the expression profile of genes involved in the cell cycle and different cytokines upon BBR-mediated AhR activation on AML THP-1 cell line. MATERIALS AND METHODS: THP-1 cells and normal monocytes were treated with different concentrations of BBR (10 MUM, 25 MUM, 50 MUM, and 100 MUM) for 24 and 48 hr. The cell viability was measured by MTT assay. Real-time RT-PCR was conducted to evaluate the expression of AhR, cytochrome P450 1A1 (CYP1A1), interleukin 1 beta (IL1beta), p21, p27, cyclin-dependent kinase 2 (CDK2) and p53. Cellular expression of AhR was also assessed using immunofluorescence method. ELISA was used to determine the level of IL-10 and IL-12 cytokines. RESULTS: BBR inhibits the proliferation of THP-1 cells in a dose- and time-dependent manner with minimal toxicity on normal monocytes. Phorbol 12-myristate 13-acetate (PMA) treatment increased the cellular expression of AhR. The AhR target genes (CYP1A1, IL1beta) were overexpressed upon BBR treatment. BBR downregulated Cdk2 and upregulated p21, p27 and p53 genes in THP-1 cells. IL-10 was significantly increased upon BBR treatment, while IL-12 was not significantly changed in all combinations. CONCLUSION: BBR could be introduced as an effective chemotherapeutic agent against AML by giving rise to the expression of CDK inhibitors and anti-inflammatory cytokines and downregulation of CDK2. PMID- 28656089 TI - Berberis vulgaris and its constituent berberine as antidotes and protective agents against natural or chemical toxicities. AB - Berberis vulgaris L (B. vulgaris) and its main constituent berberine have been used in traditional medicine for a long time. This medicinal plant and berberine have many properties that have attracted the attention of researchers over the time. According to several studies, B. vulgaris and berberine exhibited anti inflammatory, antioxidant, anticonvulsant, antidepressant, anti-Alzheimer, anti cancer, anti-arrhythmic, antiviral, antibacterial and anti-diabetic effects in both in vitro and invivo experiments. In regard to many reports on protective effects of B. vulgaris and berberine on natural and chemical toxins, in the current review article, the inhibitory effects of these compounds against natural, industrial, environmental and chemical toxicities with focus on cellular mechanism have been categorized. It has been mentioned that berberine could ameliorate toxicity of chemical toxins in brain, heart, kidney, liver and lung in part through antioxidant, anti-inflammatory, anti-apoptotic, modulation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways. PMID- 28656090 TI - The effects of ethanol extract of Berberis vulgaris fruit on histopathological changes and biochemical markers of the liver damage in diabetic rats. AB - OBJECTIVES: Various studies have shown that the diabetes is associated with liver failure. The objective of this study was determining the effects of Berberis vulgaris fruit on histopathological and biochemical markers of liver in diabetic rats. MATERIALS AND METHODS: In this experimental study, 60 male Wistar rats weighing 200-250 g with free access to water and ad libitum were randomly divided to five twelve-membered groups including healthy control (group 1), diabetic control (group 2, this two groups received distilled water), treated diabetic positive control (group 3) using dose 150 mg/kg/day metformin, and two groups treated with doses 200 (group 4) and 600 (group 5) mg/kg/BW of B. vulgaris extracts via gavage feeding for 8 weeks. Diabetes mellitus was experimentally induced by one dose injection of alloxan 120 mg/kg. This pre-clinical study was performed on 120 mg/kg alloxan induced diabetic rats. RESULTS: The hepatic steatosis status, liver cholestasis and fibrosis were not changed in group 4 and 5. Glycogen deposition changed mildly and polymorphonuclear neutrophils infiltration changed moderately at group 5. Liver hepatitis changed mildly and severely at group 3 as well as group 5, respectively. Glucose, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and alkaline phosphatase were lower in high dose group compared to other groups. CONCLUSION: Results suggested that B. vulgaris extract can decrease liver damage by influencing hepatic histopathological and biochemical markers in diabetic rats. PMID- 28656091 TI - A review of the effects of Berberis vulgaris and its major component, berberine, in metabolic syndrome. AB - Metabolic syndrome (MetS), characterized by a cluster of metabolic abnormalities including hypertension, obesity, type 2 diabetes mellitus (T2DM) and dyslipidemia, is a well-known cardiovascular risk factor (CVRF). Cardiovascular disease (CVD) represents a massive healthcare burden worldwide. In recent years, with regard to the adverse effects of synthetic drugs, increasing attention has been paid by researchers to herbal medicines for a variety of disorders such as CVD. A large body of literature supports different pharmacological actions of Berberis vulgaris (B. vulgaris) and its active component, berberine (BBR), such as antidiabetic, antiobesity, hypotensive and hypolipidemic properties that could be interesting in the management of MetS associated with high CVD risk. Numerous preclinical in vitro and in vivo studies support all these effects. In this review, we evaluated the most related original articles to discover the role of B. vulgaris on various constituents of MetS and CVRF comprising dyslipidemia, obesity, high blood pressure and high blood glucose. This review suggests a potential role of B. vulgaris and BBR in the managing of MetS; nevertheless more investigations, especially reliable clinical trials, need to be accomplished to evaluate their effectiveness. PMID- 28656092 TI - Berberis vulgaris: specifications and traditional uses. AB - The medicinal plants from genus Berberis are particularly important in traditional medicine and the food basket of Iranians. Given various plants from genus Berberis and their economic, nutritional, and medicinal status in Iran, this study seeks to investigate the findings of recent studies on the phytochemical characteristics, specifications, and uses of Berberis vulgaris. In this review article, 350 articles were initially retrieved from reliable scientific databases using relevant search terms. Then, 230 articles were selected and 120 were excluded after a primary analysis. Finally, 98 articles related to the subject under study were meticulously examined and the required data were extracted and classified according to the research purposes. The findings were divided into eight separate sections: Introducing Berberidaceae family, different species of Berberis, pharmaceutical organs, B. vulgaris nutrition facts and minerals, the antioxidants and alkaloids compounds in fruit and other organs, action mechanisms of preventing and treating diseases, traditional uses of B. vulgaris, and its properties reported by recent studies. The results briefly indicate that B. vulgaris contains a large number of phytochemical materials including ascorbic acid, vitamin K, several triterpenoids, more than 10 phenolic compounds and more than 30 alkaloids. Therefore B. vulgaris may have anti-cancer, anti-inflammatory, antioxidant, antidiabetic, antibacterial, analgesic and anti-nociceptive and hepato-protective effects. Regarding the use of different organs of B. vulgaris in traditional medicine and their confirmed effects in the recent studies, it is possible to use different organs of B. vulgaris, especially fruit, to develop new drugs. PMID- 28656093 TI - Berberine attenuates convulsing behavior and extracellular glutamate and aspartate changes in 4-aminopyridine treated rats. AB - OBJECTIVES: K+ channel blocker 4-aminopyridine (4-AP) stimulates the release of glutamate from nerve terminals and induces seizures. Berberine as a potential herbal drug exerts several pharmacological actions on the central nervous system including anxiolytic, anticonvulsant, and neuroprotective properties. The present study aimed to investigate the effect of berberine on seizure onset and time course of the extracellular levels of excitatory amino acids (EAA), glutamate and aspartate, changes produced by 4-AP in rat hippocampus. MATERIALS AND METHODS: The rats were given either saline or berberine (50, 100 and 200 mg/kg, IP) 40 min before administration of 4-AP (15 mg/kg, IP) and the onset of seizure was recorded. A group of rats also received diazepam (DZP, 15 mg/kg, IP) 20 min prior to 4-AP administration. Hippocampal extracellular levels of EAA were also measured using microdialysis assay. Analysis of the dialysate samples was performed by reversed-phase high performance liquid chromatography (HPLC) with precolumn derivatization with o-phthaldialdehyde and fluorescence detection. RESULTS: Our findings suggest that berberine significantly delayed the seizure onset following 4-AP injection. There was a considerable increase in the extracellular glutamate and aspartate levels in 4-AP treated rats and 4-AP-evoked release of EAA was sharply reduced (about 4-5 fold especially at 20 min after 4 AP administration) in berberine treatment groups. CONCLUSION: The results of present study show that berberine attenuates 4-AP induced seizures by decreasing hippocampal aspartate and glutamate release in rats. PMID- 28656094 TI - Berberine protects against glutamate-induced oxidative stress and apoptosis in PC12 and N2a cells. AB - OBJECTIVES: Neurodegenerative diseases have been associated with glutamatergic dysfunction. Berberine, an isoquinoline alkaloid broadly present in different medicinal herbs, has been reported to have neuroprotective effect. In the present study, the effects of berberine against glutamate-induced oxidative damage and apoptosis were investigated. MATERIALS AND METHODS: The cultured PC12 and N2a cells were pretreated (2 hr) with varying concentrations of berberine (50-1000 uM), followed by exposure to glutamate (10 mM) for 24 hr. The cells viability, intracellular reactive oxygen species (ROS), lipid peroxidation, glutathione (GSH) content, superoxide dismutase (SOD) activity, DNA fragmentation and the expressions of pro-apoptotic (cleaved caspase-3 and bax) and anti-apoptotic (bcl 2) proteins were then measured. RESULTS: In both cell lines, pretreatment with berberine (especially at low concentrations) significantly decreased ROS generation, lipid peroxidation, and DNA fragmentation, while improving glutathione content and SOD activity in glutamate-injured cells. Moreover, berberine showed anti-apoptotic effects by reducing the glutamate-evoked caspase 3 and bax/bcl-2 overexpression. CONCLUSION: The results of present study suggest that berberine protects against glutamate-induced PC12 and N2a cells injury by decreasing oxidative stress and subsequently inhibiting apoptosis. This is relevant to berberine treatment in neurodegenerative disorders, such as dementia (Alzheimer's disease), seizures, and stroke. PMID- 28656095 TI - Controlling Lipids AIDS in the Prevention of Type 2 Diabetes, Hypertension, and Cardiovascular Diseases. AB - BACKGROUND: Abnormal lipid profiles are a characteristic feature of persons with chronic conditions in which the diabetic populations are recognized as the dominant group, regardless of gender and ethnicity worldwide. This study was conducted to identify and evaluate the abnormalities of serum lipid profiles in both nondiabetic and diabetic persons. METHODS: This study was a case-control investigation conducted between 2013 and 2015. The study enrolled 266 patients from the North Central and South West Regional Health Authorities of Trinidad. Of the 266 patients recruited, 126 were diabetic and 140 were nondiabetic. RESULTS: Our study observed that dyslipidemia was present among the nondiabetic populations as the nondiabetics had 55 women and 20 men with high cholesterol, 22 women and 14 men with high triglyceride (TG), 30 women and 25 men with low high density lipoprotein cholesterol (HDL-C), 42 women and 21 men with high low density level-cholesterol (LDL-C), 13 women and 8 men with high very low-density lipoprotein (VLDL), and also 30 women and 11 men with body mass index (BMI) over 30 kg/m2. We also observed that diabetic women had significantly lower TGs (P = 0.019) and higher HDL-C (P = 0.001) and LDL (P = 0.003) when compared with the diabetic men. In addition, the nondiabetic females also had higher HDL-C (P = 0.045) when compared to their male counterparts. Both diabetic and nondiabetic women exhibited significantly higher BMI of P = 0.000. A negative correlation was obtained among TGs and HDL (r = -0.356, n = 83, P = 0.001) and a positive correlation was observed among LDL and HDL (r = 0.230, n = 86, P = 0.035). CONCLUSIONS: This study observed the incidences in the abnormalities of serum lipid profiles in both nondiabetic and diabetic persons. It also presents the high occurrence of nondiabetic women with dyslipidemia as they presented with high cholesterol, high TG, low HDL-C, and high VLD-L with BMI over 30 kg/m2. PMID- 28656097 TI - A Comparative Study of the Effect of Nasal Intermittent Positive Pressure Ventilation and Nasal Continuous Positive Airway Pressure on the Regional Brain Tissue Oximetry in Premature Newborns Weighing <1500 g. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) provides the capability of monitoring oxygenation levels in cerebral microscopic vessels, enabling the operator to observe the spontaneous changes in the levels of hemoglobin concentration in tissue and interpret the resulting fluctuations. The current study tried to investigate whether brain's autoregulatory mechanisms in premature newborns have the potential to prevent the adverse effects caused by asynchronous changes of pressure in the rib cage. Therefore, NIRS method was applied to newborns that were alternatively shifted from nasal continuous positive airway pressure (nCPAP) to nasal intermittent positive pressure ventilation (NIPPV) and vice versa. METHODS: This study was done as a crossover randomized clinical trial on 30 very low-weight newborns under nCPAP, who had received surfactant as a result of respiratory distress syndrome diagnosis, from April 2015 to April 2016, in Isfahan Shahid Beheshti Educational Hospital. The newborns were 72 h old, experiencing continuous distending pressure (CDP) = 4-6 cmH2O with FiO2 = 30% 40%. The respiratory support would alternate from nCPAP to NIPPV and vice versa (with indicators of expiratory PAP (EPAP) = CDP and inspiratory PAP = EPAP + 4 cmH2O), and the cerebral regional oxygen saturation (CrSO2) was monitored using NIRS. RESULTS: The study results indicated that newborns significantly showed higher levels of CrSO2(84.93, P = 0.005) and oxygenation (94.63, P = 0.007) under nCPAP rather than NIPPV (82.43 and 93.43, respectively). The respiratory rate was also meaningfully slower when newborns were under nCPAP (P = 0.013). CONCLUSIONS: This study revealed that applying NIPPV may have an unfavorable effect on the premature newborn's brain tissue perfusion. However, more studies are needed to ensure solid outcomes. PMID- 28656096 TI - A Contemporary Review of the Relationship between Red Meat Consumption and Cardiovascular Risk. AB - Cardiovascular diseases burden is increasing due to aging populations and represents one of the major health issues worldwide. Dietary habits have been extensively studied in the cardiovascular field despite the difficulty in the quantification of the assumption of each single food and the observation that several foods affect cardiovascular risk with opposite effects. Moreover, some older findings have been reverted by more recent studies. Red meat has been widely studied in this context, and it has been suggested to increase cardiovascular risk primarily by causing dyslipidemia. Our aim is to review the relationship between red meat assumption and cardiovascular risk and to present novel findings regarding their link. PMID- 28656098 TI - Childbirth Rights for Pregnant Women: Success for Poland and Inspiration for Other Nations. PMID- 28656099 TI - Effects of Synbiotic Food Consumption on Serum Minerals, Liver Enzymes, and Blood Pressure in Patients with Type 2 Diabetes: A Double-blind Randomized Cross-over Controlled Clinical Trial. AB - BACKGROUND: This research was to examine the effects of synbiotic intake on minerals, liver enzymes, and blood pressure in patients with type 2 diabetes (T2D). METHODS: This randomized, cross-over clinical trial was performed among 62 diabetic patients. Persons were randomly assigned to intake either a synbiotic (n = 62) or a control food (n = 62) for 6 weeks. A 3-week washout period was applied following which persons were crossed over to the alternate intervention arm for an additional 6 weeks. The synbiotic was consisted of Lactobacillus sporogenes (1 * 107 CFU), 0.04 g inulin (HPX) as prebiotic. Persons were asked to consume the synbiotic and control foods 27 g a day. Blood pressure was measured, and blood samples were taken at baseline and after 6-week intervention to assess calcium, magnesium, iron, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin. RESULTS: The consumption of a synbiotic food, compared to the control food, resulted in a significant rise of calcium (0.66 vs. -0.14 mg/dL, P = 0.03) and iron (5.06 vs. -9.98 mg/dL, P = 0.03). The decrease of total bilirubin (0.08 vs. -0.04 mg/dL; P = 0.009) was also seen in the synbiotic group compared with the control group. CONCLUSIONS: Overall, synbiotic in T2D patients had beneficial effects on calcium, iron, and total bilirubin concentrations. PMID- 28656100 TI - Efficacy of Human Papillomavirus L1 Protein Vaccines (Cervarix and Gardasil) in Reducing the Risk of Cervical Intraepithelial Neoplasia: A Meta-analysis. AB - Human papillomavirus (HPV) can induce cervical intraepithelial neoplasia (CIN). Vaccination against HPV can play an important role in CIN prevention. This study aims to estimate the efficacy of L1 protein vaccines (Cervarix and Gardasil) in CIN 1, 2, 3 risk reduction using meta-analysis. Relevant articles were identified by two independent researchers searching international databanks. After application of inclusion/exclusion criteria and quality assessment, eligible articles were entered into the final meta-analysis. Inverse variance method and fixed effect model were used to combine the results of the primary studies. The heterogeneity between the results was assessed using Cochrane and I2 indices. Of 11,530 evidence identified during the primary search, three papers were found eligible for meta-analysis, including 7213 participants in the intervention groups and 7170 healthy controls. The efficacy (95% confidence interval) of HPV 6, 11, 16, 18 monovalent and quadrivalent vaccines against CIN 1, CIN 2, and CIN 3 were estimated as of 95% (88-98), 97% (85-99), and 95% (78-99), respectively. This study showed that L1 protein vaccines Cervarix and Gardasil are highly protective vaccines playing an effective role in the prevention of HPV 6, 11, 16, 18 which are responsible for CIN 1, CIN 2, and CIN 3. PMID- 28656102 TI - Treatment of Neovascular Age-Related Macular Degeneration with Anti-VEGF Agents: Predictive Factors of Long-Term Visual Outcomes. AB - PURPOSE: To evaluate the predictive factors of long-term visual outcomes in neovascular age-related macular degeneration (nAMD) treated with antivascular endothelial growth factor (anti-VEGF) agents. METHODS: Unicentric retrospective review of patients with nAMD treated with anti-VEGF agents. Visual outcomes, 12 and 60 months after diagnosis, were evaluated. In an attempt to identify predictive factors of visual outcomes, multiple variables (demographic and epidemiological characteristics, angiographic and tomographic features) were analyzed, at baseline and during follow-up. RESULTS: One hundred and seventeen patients were included. In multivariate analysis, baseline best-corrected visual acuity was associated with all visual endpoints at 12 and 60 months. Additionally, age, gender, number of injections, and development of subretinal fibrosis during follow-up were also significant predictors of visual outcomes at 60 months. CONCLUSIONS: Several factors can be useful in clinical practice as predictors of visual outcomes in response to anti-VEGF treatment of nAMD. PMID- 28656103 TI - The Effect of the Degree of Astigmatism on Optical Quality in Children. AB - PURPOSE: To investigate the effect of the degree of astigmatism on optical quality in children. The important objective evaluation parameters we focus on include the RMS of the high-order aberrations, MTF, and PSF. METHODS: The children, age ranging from 7 to 10 years old, underwent an optometry examination. Fifty-nine children who met the inclusion criteria were divided into three groups: A (1.0 D <= astigmatism < 2.0 D), B (2.0 D <= astigmatism < 3.0 D), and C (3.0 D <= astigmatism < 4.0 D). The OPD-SCAN-III aberrometer was used to measure PSF, MTF, and other optical parameters. Total higher-order aberrations, total coma aberrations, total spherical aberrations, and total trefoil aberrations corresponding to the RMS value, the AR value of MTF, and the SR value of PSF with a 4 mm pupil diameter were assessed. RESULTS: RMS-HO, RMS-T.Coma, RMS-T.Tre, and RMS-T.Sph in the three groups were significantly increased with increasing the degree of astigmatism, while there were no significant differences in RMS-T.Sph between the groups. The AR value and the SR value decreased with increasing degree of astigmatism, and there were significant differences in the AR value and the SR value. CONCLUSION: Astigmatism has a significant influence on the higher order aberrations, MTF, and PSF in the children. The effect of astigmatism value on the optical quality is mainly reflected in the change in these three parameters. PMID- 28656101 TI - A Brief View of the Surface Membrane Proteins from Trypanosoma cruzi. AB - Trypanosoma cruzi is the causal agent of Chagas' disease which affects millions of people around the world mostly in Central and South America. T. cruzi expresses a wide variety of proteins on its surface membrane which has an important role in the biology of these parasites. Surface molecules of the parasites are the result of the environment to which the parasites are exposed during their life cycle. Hence, T. cruzi displays several modifications when they move from one host to another. Due to the complexity of this parasite's cell surface, this review presents some membrane proteins organized as large families, as they are the most abundant and/or relevant throughout the T. cruzi membrane. PMID- 28656104 TI - Microinvasive Glaucoma Surgery. PMID- 28656105 TI - Incidence and Predictors of Pregnancy among Women on ART in Debre Markos Referral Hospital, Northwest Ethiopia: A Five-Year Retrospective Cohort Study. AB - Globally, death of women due to HIV/AIDS related causes during pregnancy or within 42 days after pregnancy was estimated to be 37,000. In Ethiopia, 42,900 pregnant women living with HIV gave birth in the year 2011. This study was aimed to assess incidence and predictors of pregnancy among women on ART in Debre Markos Referral Hospital, Northwest Ethiopia. A retrospective cohort study was conducted using data recorded from September 2011 to August 2015. Data was extracted from February to March, 2016, from 1,239 records and analyzed using SPSS version 16. A Kaplan-Meier survival analysis was used to estimate the probabilities of being pregnant. The Cox proportional hazards model was done and results were expressed using hazard ratios with 95% CI. A total of 1,239 women on ART were included in the study. The incidence of pregnancy was 49.2 per 1,000 person-years. Living in rural, being married, being widowed, being unemployed, and having <2 children at enrollment were found to be positively associated with being pregnant. The incidence of pregnancy among women on ART was found to be considerable. Provision of family planning and other reproductive health interventions have to be coupled with the ART service to address the problem. PMID- 28656107 TI - The Cooccurrence of Obesity, Osteoporosis, and Sarcopenia in the Ovariectomized Rat: A Study for Modeling Osteosarcopenic Obesity in Rodents. AB - BACKGROUND: Obesity, osteoporosis, and sarcopenia may individually occur due to age-related gradual alterations in body composition. This study investigates the cooccurrence of these age-related diseases in female animals with low levels of ovarian hormone in the absence of complex multifactorial process of chronological aging. METHODS: Thirty-six 5- and 10-month-old female rats were chosen to model pre- and postmenopausal women, respectively. Rats were divided into three treatment groups in each age category-sham, ovariectomized (ovx), and ovx + E2 (17beta-estradiol, 10 MUg/kg)-and were pair-fed. Volunteer wheel running activity, body composition, bone microstructure, serum C-telopeptides of type I collagen, bone specific alkaline phosphatase, E2, and gastrocnemius and soleus muscles were analyzed. RESULTS: The cooccurrence of osteoporosis, sarcopenia, and obesity was observed in the older ovx rats associated with a significant (p < 0.05) increased fat mass (30%), bone loss (9.6%), decreased normalized muscle mass-to-body-weight ratio (10.5%), and a significant decrease in physical activity (57%). The ratio of tibial bone mineral density to combined muscle mass was significantly decreased in both ovx age categories. CONCLUSION: Ovariectomized rat could be used as an experimental model to examine the effect of loss of ovarian hormones, while controlling for energy intake and expenditure, to conduct obesity and body composition translational research in females without the confounding effect of genetic background. PMID- 28656108 TI - Home Features and Assistive Technology for the Home-Bound Elderly in a Thai Suburban Community by Applying the International Classification of Functioning, Disability, and Health. AB - The ageing population is having an impact worldwide and has created a serious challenge in Thailand's healthcare systems, whereby healthcare practitioners play a major role in promoting independent interaction of their client's abilities, as well as environmental factors. The purpose of this study was to survey features of the home and assistive technology (AT) for the home-bound elderly in the community of Chiang Mai, Thailand. Home evaluation included features inside and outside the home, and AT was based on the International Classification of Functioning, Disability, and Health (ICF) concept. Methods included observation and an interview that were used by the researcher for evaluation. The study found that every home had at least one hazardous home feature such as inappropriate width of the door, high door threshold, tall stair steps, no bedside rail, and inappropriate height of the toilet pan. AT was found in houses as general products and technology for personal use in daily living and for personal indoor and outdoor mobility as well as transportation. Therefore, home features and AT can afford the home-bound elderly independent living within the community. Perspective AT according to the ICF concept could provide a common language for ageing in place benefits. PMID- 28656106 TI - Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs. AB - Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPARgamma, one of the subtypes of PPARs. Certain compounds under development have dual PPARalpha/gamma agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPARgamma agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPARgamma agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes. PMID- 28656109 TI - Stereopsis, Visuospatial Ability, and Virtual Reality in Anatomy Learning. AB - A new wave of virtual reality headsets has become available. A potential benefit for the study of human anatomy is the reintroduction of stereopsis and absolute size. We report a randomized controlled trial to assess the contribution of stereopsis to anatomy learning, for students of different visuospatial ability. Sixty-three participants engaged in a one-hour session including a study phase and posttest. One group studied 3D models of the anatomy of the deep neck in full stereoptic virtual reality; one group studied those structures in virtual reality without stereoptic depth. The control group experienced an unrelated virtual reality environment. A post hoc questionnaire explored cognitive load and problem solving strategies of the participants. We found no effect of condition on learning. Visuospatial ability however did impact correct answers at F(1) = 5.63 and p = .02. No evidence was found for an impact of cognitive load on performance. Possibly, participants were able to solve the posttest items based on visuospatial information contained in the test items themselves. Additionally, the virtual anatomy may have been complex enough to discourage memory based strategies. It is important to control the amount of visuospatial information present in test items. PMID- 28656110 TI - Erythrocyte Omega-3 Fatty Acid Content in Elite Athletes in Response to Omega-3 Supplementation: A Dose-Response Pilot Study. AB - INTRODUCTION: Supplementation of Omega-3 fatty acids (n-3FA) in athletes is related to the anti-inflammatory and/or antioxidant effect and consequently its action on all the processes of tissue restoration and adaptation to physical stress. OBJECTIVE: Evaluate the Omega-3 Index (O3Ix) response, in red blood cells, to supplemental EPA + DHA intake in the form of high purity and stable composition gums (G), in elite summer athletes. METHOD: Twenty-four summer sport athletes of both sexes, pertaining to the Olympic Training Center in Spain, were randomized to two groups (2G = 760 or 3G = 1140 mg of n-3 FA in Omegafort OKids, Ferrer Intl.) for 4 months. Five athletes and four training staff volunteers were control group. RESULTS: The O3Ix was lower than 8% in 93.1% of all the athletes. The supplementation worked in a dose-dependent manner: 144% for the 3G dose and 135% for the 2G, both p < 0.001, with a 3% significant decrease of Omega-6 FAs. No changes were observed for the control group. CONCLUSIONS: Supplementation with n-3FA increases the content of EPA DHA in the red blood cells at 4 months in a dose-dependent manner. Athletes with lower basal O3Ix were more prone to increment their levels. The study is registered with Protocol Registration and Results System (ClinicalTrials.gov) number NCT02610270. PMID- 28656111 TI - Readability Assessment of Online Patient Education Material on Congestive Heart Failure. AB - BACKGROUND: Online health information is being used more ubiquitously by the general population. However, this information typically favors only a small percentage of readers, which can result in suboptimal medical outcomes for patients. OBJECTIVE: The readability of online patient education materials regarding the topic of congestive heart failure was assessed through six readability assessment tools. METHODS: The search phrase "congestive heart failure" was employed into the search engine Google. Out of the first 100 websites, only 70 were included attending to compliance with selection and exclusion criteria. These were then assessed through six readability assessment tools. RESULTS: Only 5 out of 70 websites were within the limits of the recommended sixth-grade readability level. The mean readability scores were as follows: the Flesch-Kincaid Grade Level (9.79), Gunning-Fog Score (11.95), Coleman-Liau Index (15.17), Simple Measure of Gobbledygook (SMOG) index (11.39), and the Flesch Reading Ease (48.87). CONCLUSION: Most of the analyzed websites were found to be above the sixth-grade readability level recommendations. Efforts need to be made to better tailor online patient education materials to the general population. PMID- 28656112 TI - Nicotinamide Administration Improves Remyelination after Stroke. AB - AIMS: Stroke is a leading cause of morbidity and mortality. This study aimed to determine whether nicotinamide administration could improve remyelination after stroke and reveal the underlying mechanism. METHODS: Adult male C57BL/6J mice were intraperitoneally (i.p.) administered with nicotinamide (200 mg/kg, daily) or saline after stroke induced by photothrombotic occlusion of the middle cerebral artery. FK866 (3 mg/kg, daily, bis in die), an inhibitor of NAMPT, and ANA-12 (0.5 mg/kg, daily), an antagonist of tropomyosin-related kinase B (TrkB), were administered intraperitoneally 1 h before nicotinamide administration. Functional recovery, MRI, and histological assessment were performed after stroke at different time points. RESULTS: The nicotinamide-treated mice showed significantly lower infarct area 7 d after stroke induction and significantly higher fractional anisotropy (FA) in the ipsilesional internal capsule (IC) 14 d after stroke induction than the other groups. Higher levels of NAD+, BDNF, and remyelination markers were observed in the nicotinamide-treated group. FK866 administration reduced NAD+ and BDNF levels in the nicotinamide-treated group. ANA-12 administration impaired the recovery from stroke with no effect on NAD+ and BDNF levels. Furthermore, lesser functional deficits were observed in the nicotinamide-treated group than in the control group. CONCLUSIONS: Nicotinamide administration improves remyelination after stroke via the NAD+/BDNF/TrkB pathway. PMID- 28656113 TI - Cardiac Dysrhythmias and Neurological Dysregulation: Manifestations of Profound Hypomagnesemia. AB - Magnesium is the second most common intracellular cation and serves as an important metabolic cofactor to over 300 enzymatic reactions throughout the human body. Among its various roles, magnesium modulates calcium entry and release from sarcoplasmic reticulum and regulates ATP pumps in myocytes and neurons, thereby regulating cardiac and neuronal excitability. Therefore, deficiency of this essential mineral may result in serious cardiovascular and neurologic derangements. In this case, we present the clinical course of a 76-year-old woman who presented with marked cardiac and neurological signs and symptoms which developed as a result of severe hypomagnesemia. The patient promptly responded to magnesium replacement once the diagnosis was established. We herein discuss the clinical presentation, pathophysiology, diagnosis, and management of severe hypomagnesemia and emphasize the implications of magnesium deficiency in the cardiovascular and central nervous systems. Furthermore, this case highlights the importance of having high vigilance for hypomagnesemia in the appropriate clinical setting. PMID- 28656114 TI - A Mass of Pancreatic and Gastric Heterotopia Causing a Small Bowel Obstruction in a 61-Year-Old Male. AB - Heterotopic tissue is a congenital anomaly that has been previously reported. Gastric and pancreatic heterotopia are among the most studied ones. Herein, we describe a case of a combined pancreatic and gastric heterotopia that formed a mass and caused a small intestine obstruction in a 61-year-old male. We also did a brief literature review of cases with gastric and pancreatic heterotopia in adult patients. PMID- 28656115 TI - Two Cases of Rectal Xanthoma Presenting as Yellowish to Whitish Lesions during Colonoscopy. AB - Two cases of rectal xanthomas are described. One case is that of a 56-year-old Japanese man in whom multiple yellowish spots measuring approximately 3 to 5 mm were observed in the rectum during colonoscopy. The other case is that of a 78 year-old Japanese man in whom colonoscopy showed a whitish plaque of 4 mm in diameter in the rectum. Biopsy examinations performed on both patients revealed the deposition of xanthoma cells within the rectal mucosa. Within the gastrointestinal tract, xanthomas most frequently arise in the stomach, whereas the colorectum is rarely affected. Despite this infrequency, the two cases indicate that xanthomas should be recalled when yellowish to whitish lesions are observed in the colorectum. PMID- 28656116 TI - A Large Rice Body-Containing Cyst Mimicking Infection following Total Hip Arthroplasty: A Case Report. AB - INTRODUCTION: Soft tissue mass following total hip arthroplasty raises several differential diagnoses not limited to infection, hematoma, wear debris, malignancy, and bursitis. Rice body formation in the hip region is an uncommon process denoting a chronic inflammation. We report here the second case of its kind in the medical literature of a wide symptomatic rice-like body cyst complicating a total hip arthroplasty. CASE PRESENTATION: This is the case of an 82-year-old white female, presenting with a warm, red, and inflated groin five years after revision of right total hip arthroplasty. Surgical intervention reveals a large well circumscribed cyst containing well-organized rice-like bodies. This eventuality was never reported in differential diagnosis of hip periprosthetic soft tissue masses before. CONCLUSION: This case report helps widening the array of the differential diagnosis in patients presenting with a slow growing soft tissue mass following total hip arthroplasty, making rice-like bodies cyst a valid one to consider. PMID- 28656117 TI - Obsessive-Compulsive Disorder Associated with Posterior Cranial Fossa Meningioma. AB - We report here a patient in whom the effects of a cerebellum mass may have led to development of obsessive-compulsive disorder (OCD). A 33-year-old woman showed symptoms of OCD, including obsessive worry about infection from tainted blood and repetitive confirmation, which worsened during pregnancy. She had comprehension in regard to her illness and no evidence of cognitive dysfunction and did not meet other DSM-5 criteria such as depression. One month after giving childbirth, the symptoms worsened, while headache and dizziness also developed. The Yale Brown Obsessive-Compulsive Scale (Y-BOCS) score was 34. The patient was examined for a headache and a posterior cranial fossa meningioma was found. Following resection of the meningioma, the OCD symptoms were remarkably reduced (Y-BOCS score 10). There is only one previous report of pure OCD associated with a cerebellar mass and the present findings should help to elucidate the mechanism. PMID- 28656119 TI - Primary Signet-Ring Cell Carcinoma of the Urinary Bladder Successfully Managed with Radical Cystectomy in a Young Patient. AB - Primary signet-ring cell adenocarcinoma of bladder is a rare neoplasm, usually seen in middle age adults. We report the case of an 18-year-old man who presented with intermittent gross hematuria. Computed tomography imaging showed multifilling defects in the bladder. The patient underwent a transurethral resection of the bladder tumor. Histological findings were consistent with poorly differentiated mixed mucinous and signet-ring cell adenocarcinoma. We ruled out other possible origins of tumor by gastrointestinal endoscopy and colonoscopy. The patient was treated with radical cystectomy with prostate and seminal vesicle sparing technique and orthotopic diversion using "W" ileum pouch with pelvic lymphadenectomy to the bifurcation of the aorta was done. Six-month follow-up of patient showed normal conditions without metastatic spread or any recurrence. PMID- 28656118 TI - Pediatric Ovarian Growing Teratoma Syndrome. AB - Ovarian immature teratoma is a germ cell tumor that comprises less than 1% of ovarian cancers and is treated with surgical debulking and chemotherapy depending on stage. Growing teratoma syndrome (GTS) is the phenomenon of the growth of mature teratoma elements with normal tumor markers during or following chemotherapy for treatment of a malignant germ cell tumor. These tumors are associated with significant morbidity and mortality due to invasive and compressive growth as well as potential for malignant transformation. Current treatment modality is surgical resection. We discuss a 12-year-old female who presented following resection of a pure ovarian immature teratoma (grade 3, FIGO stage IIIC). Following chemotherapy and resection of a pelvic/liver recurrence demonstrating mature teratoma, she underwent molecular genetics based chemotherapeutic treatment. No standardized management protocol has been established for the treatment of GTS. The effect of chemotherapeutic agents for decreasing the volume of and prevention of expansion is unknown. We review in detail the history, diagnostic algorithm, and previous reported pediatric cases as well as treatment options for pediatric patients with GTS. PMID- 28656120 TI - The Circadian Rhythm of Copeptin, the C-Terminal Portion of Arginine Vasopressin. AB - BACKGROUND: Several studies have investigated copeptin as a prognostic marker of different acute diseases and as a diagnostic marker in disorders of water and salt homeostasis. However, no data of the normal circadian rhythm of copeptin in healthy subjects are available. AIM: To investigate the circadian rhythm of copeptin in healthy subjects under standardized conditions. METHODS: 19 healthy volunteers aged 18 to 53 years, male and female, were studied in a prospective observational study. In all 19 participants, blood samples for copeptin were taken in regular intervals of 30 minutes for 24 hours after a fasting period of minimum 8 hours. RESULTS: The mean values of copeptin showed a circadian rhythm, similar to that described for AVP release, with a trend towards higher levels (5.9 +/- 1 pmol/L) at night and early morning between 4 am and 6 am and lowest levels (2.3 +/- 0.2 pmol/L) in the late afternoon between 5 pm and 7 pm. This finding was only observed in individuals with initial higher copeptin levels, whereas in individuals with lower basal copeptin levels no circadian rhythm was observed. CONCLUSION: There is evidence for a circadian rhythm in copeptin release during 24 hours, however, of minor extent. These findings suggest that copeptin levels can be determined irrespectively of the time of the day. PMID- 28656121 TI - Quantitative and Qualitative Characterization of Gentiana rigescens Franch (Gentianaceae) on Different Parts and Cultivations Years by HPLC and FTIR Spectroscopy. AB - Gentiana rigescens Franch (Gentianaceae) is a famous medicinal plant for treatments of rheumatism, convulsion, and jaundice. Comprehensive investigation of different parts and cultivation years of this plant has not yet been conducted. This study presents the quantitative and qualitative characterization of iridoid glycosides from G. rigescens performed by HPLC and FTIR spectroscopy techniques. The accumulations of loganic acid, swertiamarin, gentiopicroside, and sweroside were determined. Results indicated that their content and distribution in different parts and cultivation years exhibit great variations. Gentiopicroside was identified as the most abundant compound among iridoid glycosides and its highest level was observed in the root of 2-year-old plant. With respect to qualitative variation of metabolic profile, the 1800-800 cm-1 band of FTIR spectra successfully discriminated different parts and cultivation years with the aid of PLS-DA. In addition, combined with PLSR, the feasibility of FTIR spectroscopy for determination of gentiopicroside was investigated by selecting characteristic wavelengths (1800-800 cm-1), which presented a good performance with a residual predictive deviation (RPD) of 3.646. Our results suggested that HPLC and FTIR techniques can complement each other and could be simultaneously applied for comparing and analyzing different parts and cultivation years of G. rigescens. PMID- 28656122 TI - UPLC-Tandem Mass Spectrometry Method for Simultaneous Determination of Fluoxetine, Risperidone, and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Pharmacokinetics Study in Rats. AB - Risperidone (RIS) is used as an antipsychotic drug alone or with other drugs, like fluoxetine (FLX). A simple method was developed and validated for the determination of both RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS), FLX, and olanzapine (OLA) as an internal standard in rat's plasma using UPLC MS/MS. FLX, RIS, 9-OH-RIS, and OLA were purified using acetonitrile as a protein precipitating agent. Separation was performed on an ACQUITYTM "UPLC BEHTM" C18 column (50 mm * 2.1 mm i.d., 1.7 MUm; Waters Corp., USA). The ranges of the calibration curves were 1.0-1000.0 ng/mL for FLX and 0.2-1000.0 ng/mL for RIS and 9-OH-RIS. Linearity, recovery, precision, and stability were within the acceptable range. This method is rapid, fast, and precise for the determination of RIS and FLX in plasma and is applicable in pharmacokinetic studies. PMID- 28656123 TI - Determination of Epimedin B in Rat Plasma and Tissue by LC-MS/MS: Application in Pharmacokinetic and Tissue Distribution Studies. AB - A simple, sensitive, and specific liquid chromatography tandem mass-spectrometric method was developed and validated for the determination of epimedin B in rat plasma and tissue samples. After being processed with a protein precipitation method, these samples were separated on an Agilent Eclipse XDB-C18 column with an isocratic mobile phase consisting of acetonitrile and 0.1% formic acid aqueous solution (32 : 68, v/v). The calibration curve of epimedin B was linear over the concentration range from 1 to 500 ng/mL in plasma and tissue homogenate. The method was then applied to pharmacokinetic and tissue distribution studies after a single oral administration of Herba Epimedii extract to SD rats. Results showed that epimedin B reached the plasma peak concentration at 0.4 h and the terminal elimination half-life was 1.6 h in rat plasma, and the plasma area under the curve from time zero to infinity (AUC0-infinity ) was 14.35 MUg/L.h. The concentration distribution of epimedin B in rat tissue was in the following order: liver > ovary > womb > lung > kidney > spleen > heart > brain, indicating that the compound could be widely distributed in rat, and the reproductive system may be the principal target of epimedin B for female rat. PMID- 28656124 TI - Surgeon Design Interface for Patient-Specific Concentric Tube Robots. AB - Concentric tube robots have potential for use in a wide variety of surgical procedures due to their small size, dexterity, and ability to move in highly curved paths. Unlike most existing clinical robots, the design of these robots can be developed and manufactured on a patient- and procedure-specific basis. The design of concentric tube robots typically requires significant computation and optimization, and it remains unclear how the surgeon should be involved. We propose to use a virtual reality-based design environment for surgeons to easily and intuitively visualize and design a set of concentric tube robots for a specific patient and procedure. In this paper, we describe a novel patient specific design process in the context of the virtual reality interface. We also show a resulting concentric tube robot design, created by a pediatric urologist to access a kidney stone in a pediatric patient. PMID- 28656126 TI - Hernia of Morgagni Presenting as Constipation in a 65-Year-Old Male. AB - Hernia of Morgagni is congenital defects in the diaphragm. They are mostly asymptomatic and present with vague symptoms when they do so. A high index of suspicion is required for timely diagnose of this condition. Here we present the case of a 65-year-old male patient presented to our institute with constipation for the past six months. Chest radiology raised the suspicion of a hernia which was further confirmed by contrast studies. Laparotomy was done and the hernia sac identified, colon and greater omentum reduced and defect repaired. He was discharged in stable condition and was doing well on follow-up. PMID- 28656125 TI - Delayed Endovascular Stenting for Severe Vertebral Artery Stenosis with Precarious Thrombosis. AB - A significant but less recognized cause of ischemic stroke and transient ischemic attack (TIA) is atherosclerosis of the vertebrobasilar system, which accounts for 20% of ischemic strokes. Pathology of the vertebrobasilar system can present significant challenges in determining the course of treatment. Due to the complexity of the vertebrobasilar system, there is slight disagreement about how to approach patients with atherosclerotic pathology of the posterior circulation. Two such approaches are either stenting of the vertebral or basilar artery or aggressive medical management. Here, we present the case of a 63-year-old male who presented with lightheadedness, diaphoresis, two episodes of loss of consciousness, and the abrupt onset of unilateral right-sided paresis. A computed tomography angiogram (CTA) of the head and neck demonstrated complex posterior circulation vertebrobasilar vascular stenosis and occlusions. There was an unstable clot located at the junction of the vertebral and basilar arteries requiring a carefully nuanced approach. The patient was started on dual antiplatelet therapy and heparin in an effort to resolve the clot. Repeat CTA after five days revealed resolution of the unstable clot; however, the distal intradural right vertebral artery remained occluded and the left vertebral artery remained stenosed. The patient was then treated with a balloon-mounted coronary stent to eliminate the stenosis, which ultimately restored normal posterior fossa flow dynamics. This case serves as a testament to the variability and complexity of vertebrobasilar arteriopathies as well as the benefit of experienced neurointerventionalists in the successful management of these cases. PMID- 28656127 TI - Postoperative Fractionated Stereotactic Radiosurgery to the Tumor Bed for Surgically Resected Brain Metastases. AB - Introduction Stereotactic radiosurgery (SRS) is increasingly used as an alternative to whole brain radiotherapy (WBRT) following surgical resection of brain metastases. We analyzed the outcomes of postoperative frameless fractionated stereotactic radiosurgery (fSRS) cases for surgically resected brain metastases at our institution. Materials and Methods We performed a retrospective review of 85 patients who underwent fSRS to 87 resection beds from 2006 - 2014 with a median follow-up of 6.4 months. Clinically relevant outcomes were assessed with analysis to determine predictors of these outcomes. Results The median target volume was 9.8 cm-3 (1.1 - 43.1 cm-3). The most frequently used fractionation scheme was 3,000 cGy in five fractions. The rates of local control (LC), distant brain failure (DBF), and overall survival (OS) at one-year were 87%, 52%, and 52%, respectively. Five patients (5.9%) experienced Grade >2 toxicity related to fSRS, including seizures (two), symptomatic radionecrosis (two), and potential treatment-related death (one). A multivariable analysis revealed that tumor volume (p < 0.001) and number of fractions (p < 0.001) were associated with LC, while recursive partitioning analysis (RPA) class (p < .0001), tumor volume (p = .0181), and the number of fractions (p = .0181) were associated with OS. Conclusions Postoperative fSRS for surgically resected brain metastases is well-tolerated and achieves durable LC. Further studies are needed to determine the optimal dose and fractionation for fSRS as well as to compare outcomes with WBRT. PMID- 28656128 TI - Atypical Presentation of Chronic Myelogenous Leukemia. AB - Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, t(9;22), which is a constitutively active tyrosine kinase that causes excessive proliferation and differentiation of myeloid cells in the bone marrow. Most patients are either asymptomatic or present with fatigue, abdominal fullness, and splenomegaly. This is a case in which a 72-year-old Caucasian male's initial presentation of CML was new-onset atrial fibrillation, chronic obstructive pulmonary disease (COPD) exacerbation, and pneumonia. The severity of his symptoms of atrial fibrillation and dyspnea complicated his stabilization, which delayed his diagnosis of CML and initiation of tyrosine kinase inhibitor for treatment. Unregulated proliferation of leukemic cells increases blood viscosity and results in aberrations in blood circulation that may result in atypical presenting symptoms in myeloproliferative disease. Thus, it is important to have a high clinical index of suspicion for CML in patients with leukocytosis and concurrent symptomatology that is unusual for leukemia. PMID- 28656129 TI - The Effects of Synbiotic "Bifidobacterium lactis B94 plus Inulin" Addition on Standard Triple Therapy of Helicobacter pylori Eradication in Children. AB - AIM: The aim of this study is to evaluate the effects of the synbiotic Bifidobacterium lactis B94 plus inulin addition to the standard triple therapy on Helicobacter pylori (H. pylori) infection eradication rates. METHODS: Children aged 6-16 years who had biopsy proven H. pylori infection were randomly classified into two groups. The first group received the standard triple therapy consisting of amoxicillin + clarithromycin + omeprazole. The second group was treated with the standard triple therapy and Bifidobacterium lactis B94 (5 * 109 CFU/dose) plus inulin (900 mg) for 14 days, concurrently. Eradication was determined by 14C-urea breath test 4-6 weeks after therapy discontinuation. RESULTS: From a total of 69 H. pylori infected children (F/M = 36/33; mean +/- SD = 11.2 +/- 3.0 years), eradication was achieved in 20/34 participants in the standard therapy group and 27/35 participants in the synbiotic group. The eradication rates were not significantly different between the standard therapy and the synbiotic groups [intent-to-treat, 58.8% and 77.1%, resp., p = 0.16; per protocol, 64.5% and 81.8%, resp., p = 0.19]. There was no difference between the groups in terms of symptom relief (p = 0.193). The reported side effects were ignorable. CONCLUSION: Considering the eradication rates, synbiotic addition to therapy showed no superiority over the standard triple therapy conducted alone. This trial is registered with NCT03165253. PMID- 28656130 TI - Tuberculosis control, and the where and why of artificial intelligence. AB - Countries aiming to reduce their tuberculosis (TB) burden by 2035 to the levels envisaged by the World Health Organization End TB Strategy need to innovate, with approaches such as digital health (electronic and mobile health) in support of patient care, surveillance, programme management, training and communication. Alongside the large-scale roll-out required for such interventions to make a significant impact, products must stay abreast of advancing technology over time. The integration of artificial intelligence into new software promises to make processes more effective and efficient, endowing them with a potential hitherto unimaginable. Users can benefit from artificial intelligence-enabled pattern recognition software for tasks ranging from reading radiographs to adverse event monitoring, sifting through vast datasets to personalise a patient's care plan or to customise training materials. Many experts forecast the imminent transformation of the delivery of healthcare services. We discuss how artificial intelligence and machine learning could revolutionise the management of TB. PMID- 28656132 TI - Cost-effectiveness of antibiotics for COPD management: observational analysis using CPRD data. AB - It is often difficult to determine the cause of chronic obstructive pulmonary disease (COPD) exacerbations, and antibiotics are frequently prescribed. This study conducted an observational cost-effectiveness analysis of prescribing antibiotics for exacerbations of COPD based on routinely collected data from patient electronic health records. A cohort of 45 375 patients aged 40 years or more who attended their general practice for a COPD exacerbation during 2000-2013 was identified from the Clinical Practice Research Datalink. Two groups were formed ("immediate antibiotics" or "no antibiotics") based on whether antibiotics were prescribed during the index general practice (GP) consultation, with data analysed according to subsequent healthcare resource use. A cost-effectiveness analysis was undertaken from the perspective of the UK National Health Service, using a time horizon of 4 weeks in the base case. The use of antibiotics for COPD exacerbations resulted in cost savings and an improvement in all outcomes analysed; i.e. GP visits, hospitalisations, community respiratory team referrals, all referrals, infections and subsequent antibiotics prescriptions were lower for the antibiotics group. Hence, the use of antibiotics was dominant over no antibiotics. The economic analysis suggests that use of antibiotics for COPD exacerbations is a cost-effective alternative to not prescribing antibiotics for patients who present to their GP, and remains cost-effective when longer time horizons of 3 months and 12 months are considered. It would be useful for a definitive trial to be undertaken in this area to determine the cost effectiveness of antibiotics for COPD exacerbations. PMID- 28656131 TI - Iatrogenic bleeding during flexible bronchoscopy: risk factors, prophylactic measures and management. AB - Significant iatrogenic bleeding during flexible bronchoscopy is fortunately rare and usually self-limiting. Life-threatening bleeding, however, can occur, especially after conventional or cryoprobe-assisted transbronchial biopsy. The aim of this review is to provide the practising pulmonologist with a concise overview of the incidence, severity and risk factors for bleeding, to provide sensible advice on prophylactic measures and to suggest a plan of action in the case of significant bleeding. Bronchoscopy units should have a standardised approach and plan of action in the case of life-threatening haemorrhage. Wedging the bronchoscope in the bleeding segment, turning the patient in an anti Trendelenburg position and onto the side in order for the bleeding lung to be in the dependent position, installing vasoconstrictors and using a tamponade balloon early are the recommended first-line strategies. Involving a resuscitation team should be considered early in the case of massive bleeding, desaturation and haemodynamic instability. PMID- 28656133 TI - The impact of blood glucose on community-acquired pneumonia: a retrospective cohort study. AB - Hyperglycaemia is common in patients with community-acquired pneumonia (CAP) and is a predictor of severe outcomes. Data are scarce regarding whether this association is affected by diabetes mellitus (DM) and also regarding its importance for severe outcomes in hospital. We determined the impact of blood glucose on severe outcomes of CAP in hospital. We studied 1318 adult CAP patients hospitalised at three Danish hospitals. The association between blood glucose and DM status and severe clinical outcome (admission to an intensive care unit (ICU) and/or in-hospital mortality) was assessed by logistic regression. Models were adjusted for CURB-65 score and comorbidities. 12% of patients had DM. In patients without DM an increase in admission blood glucose was associated with risk for ICU admittance (OR 1.25, 95% CI 1.13-1.39), but not significantly associated with in-hospital mortality (OR 1.10, 95% CI 0.99-1.23). In patients with DM an increase in admission blood glucose was not associated with ICU admittance (OR 1.05, 95% CI 1.00-1.12) or in-hospital mortality (OR 1.05, 95% CI 0.99-1.12). An increase in admission blood glucose (only in patients without DM) was associated with a higher risk for ICU admittance and a trend towards higher in-hospital mortality. DM was not associated with a more severe outcome of CAP. PMID- 28656134 TI - Corticosteroid-resistant inflammatory signalling in Pseudomonas-infected bronchial cells. AB - Decreasing the inflammatory response that leads to tissue damage during cystic fibrosis (CF) lung disease has been a long-standing goal of CF therapy. While corticosteroids are widely used anti-inflammatory drugs, their efficacy in CF lung disease remains debated. The complex interaction between the colonising bacteria and the host environment may impact corticosteroid responsiveness. In this study, sputum samples from adult CF patients were collected at baseline and during pulmonary exacerbation episodes. Lung function measurements and sputum microbiological analyses were performed. In parallel, the inflammatory response and corticosteroid sensitivity of airway epithelial cells to Pseudomonas-derived exoproducts was investigated. We report that adult CF patients colonised with mucoid Pseudomonas aeruginosa have higher levels of baseline inflammation, more frequent exacerbations and worse lung function compared with patients colonised with nonmucoid P. aeruginosa. Moreover, mucoid P. aeruginosa activates NF-kappaB via Toll-like receptor (TLR) 2, which acts in an additive manner to TLR5 to drive inflammation in airway epithelial cells. Furthermore, TLR2-mediated intracellular signalling is more resistant to the anti-inflammatory effects of corticosteroid when compared with other TLR signalling pathways. Overall, these results suggest that airway inflammation triggered by mucoid P. aeruginosa is less responsive to the anti-inflammatory action of corticosteroids. Whether this translates into a diminished response of CF patients to corticosteroid therapy should be examined in future clinical studies. PMID- 28656135 TI - No Significant Difference between Plasma miRNAs and Plasma-Derived Exosomal miRNAs from Healthy People. AB - BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that are involved in many biological regulation processes. Studies have reported that miRNAs are enriched in human plasma and plasma-derived exosome as novel diagnostic biomarkers. The aim of this study was to determine whether the miRNA expression levels are different between plasma and plasma-derived exosome. METHODS: We sequenced and quantified the miRNAs in plasma and exosome from healthy blood samples and validated three miRNAs in the two groups of lung cancer samples by qRT-PCR. RESULTS: The sequencing results showed that only several of miRNAs were differential, while the qRT-PCR further validated that most of them did not have the consistent differences. However, the levels of two upregulated miRNAs (miR 181b-5p and miR-21-5p) in lung cancer were significantly higher in exosomes than plasma. CONCLUSIONS: To the best of our knowledge, this study is the first to compare the expression levels of miRNAs between plasma and exosome in healthy blood samples. Our data suggested that the miRNA levels were similar in the two parts of the healthy people, whereas the two onco-miRNAs were significantly enriched in the exosome of lung cancer patients. PMID- 28656136 TI - Change of Renal Parenchymal Width in Patients with Unilateral Ureteral Stent: A Bicenter Retrospective Study. AB - PURPOSE: To determine whether kidney sizes were changed after ureteral stents were instilled, and if so, what parameters were significant. METHODS: Parenchymal width (PW) of 98 patients with unilateral ureteral stents was measured from the coronal view of CT scans for both stented and unstented contralateral kidney. The mean PW and % change of mean PW were calculated before stenting and at the time of last stent change. Estimated glomerular filtrate rate (eGFR) was recorded as well. RESULTS: The mean duration of ureteral stent indwelled was 15.6 +/- 10.2 (mean +/- SD) months. The change of mean PW of stented kidneys and unstented contralateral kidneys was -16.9 +/- 16.4 (mean +/- SD)% and 3.6 +/- 10.7%, respectively. eGFR before and at the time of the last stent change did not show significant difference (p = 0.294). Duration of ureteral stent indwelled was found to be inversely related to the % change of mean PW (Spearman's correlation coefficient = -0.291, p < 0.001). CONCLUSIONS: For unilateral ureteral obstruction, kidney size was decreased over time in spite of indwelling ureteral stent. This finding can be overlooked by clinicians due to compensatory growth of contralateral kidney and resultant normal eGFR. PMID- 28656137 TI - Experimental Germ Tube Induction in Candida albicans: An Evaluation of the Effect of Sodium Bicarbonate on Morphogenesis and Comparison with Pooled Human Serum. AB - OBJECTIVE: The potential of NaHCO3 versus human serum to induce germ tube formation in Candida albicans was investigated. SPECIMENS: A total of 100 isolates were obtained from oral swabs of patients presenting with thrush. Approval for the study was granted by the Joint Research Ethics Committee (JREC/23/08). METHOD: Confirmed C. albicans isolates by routine methods were tested for germ tube induction using 5 different concentrations of Tris-maleate buffered NaHCO3 and Tris-maleate buffer control. Standard control strains included were C. albicans (ATCC 10231) and C. krusei (ATCC 6258). Microculture was done in 20 MUL inoculums on microscope slides for 3 hours at 37 degrees C. The rate of germ tube formation at 10-minute intervals was determined on 100 isolates using the optimum 20 mM Tris-maleate buffered NaHCO3 concentration. Parallel germ tube formation using human serum was done in test tubes. RESULTS: The optimum concentration of NaHCO3 in Tris-maleate buffer for germ tube induction was 20 mM for 67% of isolates. Only 21% of isolates formed germ tubes in Tris-maleate buffer control. There was no significant difference in induction between human serum and Tris-maleate buffered NaHCO3. CONCLUSION: Tris-maleate buffered NaHCO3 induced germ tube formation in C. albicans isolates at rates similar to human serum. PMID- 28656138 TI - TDF Monotherapy Is Effective Regardless of Prior Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Patients in China. AB - BACKGROUND/AIMS: Many patients had to transfer to tenofovir disoproxil fumarate (TDF) if there is other nucleos(t)ide analogue (NA) resistance. We aimed to investigate antiviral effects of TDF monotherapy between NA-naive and NA experienced chronic hepatitis B (CHB) patients in China. METHODS: A total of 102 NA-naive and NA-experienced CHB patients with TDF monotherapy (300 mg/day) were retrospectively analyzed for useful parameters up to 72 weeks. RESULTS: There were 36 and 66 patients with matched HBV DNA baseline level in NA-naive and NA experienced group, respectively. There were no significant differences between NA naive and NA-experienced groups in HBV DNA levels (all P > 0.05) and HBV DNA undetectable rates (all P > 0.05) at all time points. At the end of follow-up, HBV DNA undetectable rates in NA-naive and NA-experienced group were 96.2% (25/26) and 91.8% (45/49), respectively (P = 0.476). Baseline HBV DNA level was the only independent predictor for HBV DNA negative time (P = 0.018). In addition, 27.8% (5/18) and 11.4% (4/35) achieved HBeAg seroconversion at the end of the follow-up, respectively (P = 0.133). CONCLUSIONS: TDF monotherapy was effective regardless of prior NA experienced. Baseline HBV DNA was a key predictive factor for HBV DNA negative time in TDF monotherapy. PMID- 28656139 TI - Access to N-Acetylated Chitohexaose with Well-Defined Degrees of Acetylation. AB - Chitohexaose has attracted wide interest due to its special bioactivities and these potential activities are significantly related to N-acetylation. Herein, six chitohexaose fractions with different degrees of acetylation were prepared by selective N-acetylation and ion-exchange chromatography and further analyzed by ESI/MS. It is revealed that all the six N-acetylated chitohexaoses were of single molecular weight, the molecular weights of which were exactly assigned to 1026.44 Da, 1068.44 Da, 1110.48 Da, 1152.48 Da, 1194.49 Da, and 1236.48 Da, respectively. These results suggested that the six prepared N-acetylated chitohexaoses were N acetylchitohexaose (D5A1), di-N-acetylchitohexaose (D4A2), tri-N acetylchitohexaose (D3A3), tetra-N-acetylchitohexaose (D2A4), penta-N acetylchitohexaose (D1A5), and hexa-N-acetylchitohexaose (A6), respectively, which are of great significance to screen their bioactivities and discover well defined chitooligosaccharide molecules as potential drugs. PMID- 28656140 TI - Insights into Living with Kidney Disease. PMID- 28656141 TI - Protein Supplementation to Augment the Effects of High Intensity Resistance Training in Untrained Middle-Aged Males: The Randomized Controlled PUSH Trial. AB - High intensity (resistance exercise) training (HIT) defined as a "single set resistance exercise to muscular failure" is an efficient exercise method that allows people with low time budgets to realize an adequate training stimulus. Although there is an ongoing discussion, recent meta-analysis suggests the significant superiority of multiple set (MST) methods for body composition and strength parameters. The aim of this study is to determine whether additional protein supplementation may increase the effect of a HIT-protocol on body composition and strength to an equal MST-level. One hundred and twenty untrained males 30-50 years old were randomly allocated to three groups: (a) HIT, (b) HIT and protein supplementation (HIT&P), and (c) waiting-control (CG) and (after cross-over) high volume/high-intensity-training (HVHIT). HIT was defined as "single set to failure protocol" while HVHIT consistently applied two equal sets. Protein supplementation provided an overall intake of 1.5-1.7 g/kg/d/body mass. Primary study endpoint was lean body mass (LBM). LBM significantly improved in all exercise groups (p <= 0.043); however only HIT&P and HVHIT differ significantly from control (p <= 0.002). HIT diverges significantly from HIT&P (p = 0.017) and nonsignificantly from HVHIT (p = 0.059), while no differences were observed for HIT&P versus HVHIT (p = 0.691). In conclusion, moderate to high protein supplementation significantly increases the effects of a HIT-protocol on LBM in middle-aged untrained males. PMID- 28656142 TI - Genetic and Epigenetic Regulation Networks: Governing from Cardiovascular Development to Remodeling. PMID- 28656143 TI - Efficacy and Safety of Cerebrolysin for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. AB - Cerebrolysin was reported to be effective in the neurological improvement of patients with acute ischemic stroke (AIS) in experimental models, while data from clinical trials were inconsistent. We performed a meta-analysis to explore the efficacy and safety of cerebrolysin for AIS. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials, which intervened within 72 hours after the stroke onset. We investigated the efficacy and safety outcomes, respectively. Risk ratios and mean differences were pooled with fixed-effects model or random-effects model. Seven studies were identified, involving 1779 patients with AIS. The summary results failed to demonstrate significant superiority of cerebrolysin in the assessment of efficacy outcomes of mRS and BI. Similarly, administration of cerebrolysin had neutral effects on safety outcomes compared with placebo, including mortality and SAE. However, the number of included studies was small, especially in the analysis of efficacy outcomes, which might cause publication bias and inaccurate between-studies variance in the meta-analysis. Conclusively, although it seemed to be safe, routine use of cerebrolysin to improve the long-term rehabilitation after stroke could not be supported by available evidence. PMID- 28656144 TI - Antibiotic Elution from Hip and Knee Acrylic Bone Cement Spacers: A Systematic Review. AB - Knowledge about the elution from antibiotic-loaded cement spacers is an indispensable premise for guarantee of clinical success. A systematic literature search was performed through PubMed. Search terms were "antibiotic elution" and "antibiotic release" in combination with "spacer," "hip spacer," and "knee spacer," respectively. A total of 11 studies could be identified. Seven studies reported on the release of antibiotics after spacer implantation, three studies at spacer removal, and one study on both time points. Seven studies reported on hip spacers, one study on knee spacers, and three studies on both. In eight studies, custom-made spacers have been implanted and in three prefabricated ones. In the majority of the studies, the cement has been loaded with an antibiotic combination, mostly consisting of aminoglycoside (either gentamicin or tobramycin) and vancomycin. Measured concentrations exceeded the minimal inhibitory concentration of the particular pathogen organisms in each case. However, large discrepancies were observed with regard to the height of the antibiotic concentration depending on the antibiotic combination and the antibiotic ratio used. Current literature data indicate a sufficient elution of antibiotics after spacer implantation and at spacer removal, respectively. Future studies are required to optimize the local antibiotic therapy at the site of spacer implantation. PMID- 28656145 TI - Reduction of Interhemispheric Functional Brain Connectivity in Early Blindness: A Resting-State fMRI Study. AB - OBJECTIVE: The purpose of this study was to investigate the resting-state interhemispheric functional connectivity in early blindness by using voxel mirrored homotopic connectivity (VMHC). MATERIALS AND METHODS: Sixteen early blind patients (EB group) and sixteen age- and gender-matched sighted control volunteers (SC group) were recruited in this study. We used VMHC to identify brain areas with significant differences in functional connectivity between different groups and used voxel-based morphometry (VBM) to calculate the individual gray matter volume (GMV). RESULTS: VMHC analysis showed a significantly lower connectivity in primary visual cortex, visual association cortex, and somatosensory association cortex in EB group compared to sighted controls. Additionally, VBM analysis revealed that GMV was reduced in the left lateral calcarine cortices in EB group compared to sighted controls, while it was increased in the left lateral middle occipital gyri. Statistical analysis showed the duration of blindness negatively correlated with VMHC in the bilateral middle frontal gyri, middle temporal gyri, and inferior temporal gyri. CONCLUSIONS: Our findings help elucidate the pathophysiological mechanisms of EB. The interhemispheric functional connectivity was impaired in EB patients. Additionally, the middle frontal gyri, middle temporal gyri, and inferior temporal gyri may be potential target regions for rehabilitation. PMID- 28656146 TI - Incidental and Underreported Pleural Plaques at Chest CT: Do Not Miss Them Asbestos Exposure Still Exists. AB - Pleural plaques (PPs) may be a risk factor for mortality from lung cancer in asbestos-exposed workers and are considered to be a marker of exposure. Diagnosing PPs is also important because asbestos-exposed patients should be offered a health surveillance that is mandatory in many countries. On the other hand PPs are useful for compensation purposes. In this study we aimed to evaluate the prevalence, as incidental findings, and the underreporting rate of PPs in chest CT scans (CTs) performed in a cohort of patients (1512) who underwent chest CT with a slice thickness no more than 1.25 mm. PPs were found in 76 out of 1482 patients (5.1%); in 13 out of 76 (17,1%) CTs were performed because of clinical suspicion of asbestos exposure and 5 of them (38%) were underreported by radiologist. In the remaining 63 cases (82.9%) there was no clinical suspicion of asbestos exposure at the time of CTs (incidental findings) and in 38 of these 63 patients (60.3%) PPs were underreported. Reaching a correct diagnosis of PPs requires a good knowledge of normal locoregional anatomy and rigorous technical approach in chest CT execution. However the job history of the patient should always be kept in mind. PMID- 28656147 TI - Impact of Different Levels of iPTH on All-Cause Mortality in Dialysis Patients with Secondary Hyperparathyroidism after Parathyroidectomy. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) usually required parathyroidectomy (PTX) when drugs treatment is invalid. Analysis was done on the impact of different intact parathyroid hormone (iPTH) after the PTX on all-cause mortality. METHODS: An open, retrospective, multicenter cohort design was conducted. The sample included 525 dialysis patients with SHPT who had undergone PTX. RESULTS: 404 patients conformed to the standard, with 36 (8.91%) deaths during the 11 years of follow-up. One week postoperatively, different levels of serum iPTH were divided into four groups: A: <=20 pg/mL; B: 21-150 pg/mL; C: 151 600 pg/mL; and D: >600 pg/mL. All-cause mortality in groups with different iPTH levels appeared as follows: A (8.29%), B (3.54%), C (10.91%), and D (29.03%). The all-cause mortality of B was the lowest, with D the highest. We used group A as reference (hazard ratio (HR) = 1) compared with the other groups, and HRs on groups B, C, and D appeared as 0.57, 1.43, and 3.45, respectively. CONCLUSION: The all-cause mortality was associated with different levels of iPTH after the PTX. We found that iPTH > 600 pg/mL appeared as a factor which increased the risk of all-cause mortality. When iPTH levels were positively and effectively reducing, the risk of all-cause mortality also decreased. The most appropriate level of postoperative iPTH seemed to be 21-150 pg/mL. PMID- 28656149 TI - Serum miR-200c and miR-371-5p as the Useful Diagnostic Biomarkers and Therapeutic Targets in Kawasaki Disease. AB - Kawasaki disease (KD) has complexly clinical features and laboratory parameters and there is no definitive biomarker for this disease and the therapy of KD also is complex and uncertain. In this study, 102 KD patients and 80 healthy controls were enrolled in this study and the serum microRNAs were detected by qRT-PCR. The results showed that, compared with KD patients with a good response to high-dose intravenous immunoglobulin (IVIG) therapy, serum miR-200c and miR-371-5p were significantly higher in KD patients with no response to IVIG therapy; compared with KD patients not needing plasma exchange, these two microRNAs were also significantly higher in KD patients needing plasma exchange. In addition, combination of serum miR-200c and miR-371-5p reflected obvious separation between KD patients and healthy controls or between KD patients with no response to IVIG therapy and KD patients with good response to IVIG therapy or KD patients needing plasma exchange and KD patients not needing plasma exchange. Finally, both serum miR-200c and miR-371-5p were also significantly lower in KD under different kinds of therapy. Therefore, serum miR-200c and miR-371-5p have ability as the useful diagnostic biomarkers and therapeutic targets in Kawasaki disease. PMID- 28656148 TI - Methods of MicroRNA Promoter Prediction and Transcription Factor Mediated Regulatory Network. AB - MicroRNAs (miRNAs) are short (~22 nucleotides) noncoding RNAs and disseminated throughout the genome, either in the intergenic regions or in the intronic sequences of protein-coding genes. MiRNAs have been proved to play important roles in regulating gene expression. Hence, understanding the transcriptional mechanism of miRNA genes is a very critical step to uncover the whole regulatory network. A number of miRNA promoter prediction models have been proposed in the past decade. This review summarized several most popular miRNA promoter prediction models which used genome sequence features, or other features, for example, histone markers, RNA Pol II binding sites, and nucleosome-free regions, achieved by high-throughput sequencing data. Some databases were described as resources for miRNA promoter information. We then performed comprehensive discussion on prediction and identification of transcription factor mediated microRNA regulatory networks. PMID- 28656150 TI - Microarray Analysis of Circular RNA Expression Profile Associated with 5 Fluorouracil-Based Chemoradiation Resistance in Colorectal Cancer Cells. AB - Preoperative 5-fluorouracil- (5-FU-) based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, the effect of 5 FU-based chemoradiotherapy on CRC is limited due to the development of chemoradiation resistance (CRR), and the molecular mechanisms underlying this resistance are yet to be investigated. Recently, circular RNAs (circRNAs), which can function as microRNA sponges, were found to be involved in the development of several cancers. In this study, we focused on clarifying the modulation of the expression profiles of circRNAs in CRR. Microarray analysis identified 71 circRNAs differentially expressed in chemoradiation-resistant CRC cells. Among them, 47 were upregulated and 24 were downregulated by more than twofold. Furthermore, expression modulation of five representative circRNAs was validated by quantitative reverse transcription PCR (qRT-PCR). Moreover, these modulated circRNAs were predicted to interact with 355 miRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer-related pathways, and the possible mechanism underlying CRR was discussed. This is the first report revealing the circRNA modulations in 5-FU chemoradiation-resistant CRC cells by microarray. The study provided a useful database for further understanding CRR and presents potential targets to overcome CRR in CRC. PMID- 28656151 TI - Effects of an Intensive Lifestyle Intervention to Treat Overweight/Obese Children and Adolescents. AB - OBJECTIVE: The purpose of the present study is to examine the effects of a multidisciplinary lifestyle intervention to treat overweight/obese children and adolescents. The main outcome was cardiometabolic risk based on the waist-to height ratio (WHTR) measurement. Secondary outcomes were (1) changes in body composition; (2) adherence to a Mediterranean diet; and (3) physical performance. METHOD: The study involved 74 overweight/obese children or adolescents. The intervention was multidisciplinary including nutrition, exercise, and psychological aspects based on a family-based approach; it was delivered for six months for children and three months for adolescents. Before and after the intervention, several anthropometric measures (height, body weight, body mass index or BMI, waist circumference, and body composition), cardiometabolic risk index (waist-to-height ratio or WHTR), and nutrition habits of the participants and their families were evaluated. In addition, a set of functional motor fitness tests was performed to evaluate physical performance measures. RESULTS: After the intervention both children and adolescents showed a significant reduction in body weight, BMI, waist circumference, fat mass, and WHTR index and an improvement of fat-free mass, adherence to the Mediterranean diet, and physical fitness performance. CONCLUSION: A family-based multidisciplinary approach is effective in the short term in ameliorating the health status, the nutrition habits, and physical performance in children and adolescents. PMID- 28656152 TI - The Effects of Lycopene and Insulin on Histological Changes and the Expression Level of Bcl-2 Family Genes in the Hippocampus of Streptozotocin-Induced Diabetic Rats. AB - The aim of this study was to evaluate the effects of antioxidants lycopene and insulin on histological changes and expression of Bcl-2 family genes in the hippocampus of streptozotocin-induced type 1 diabetic rats. Forty-eight Wistar rats were divided into six groups of control (C), control treated with lycopene (CL), diabetic (D), diabetic treated with insulin (DI), diabetic treated with lycopene (DL), and diabetic treated with insulin and lycopene (DIL). Diabetes was induced by an injection of streptozotocin (60 mg/kg, IP), lycopene (4 mg/kg/day) was given to the lycopene treated groups as gavages, and insulin (Sc, 1-2 U/kg/day) was injected to the groups treated with insulin. The number of hippocampus neurons undergoing cell death in group D had significant differences with groups C and DIL (p < 0.001). Furthermore, insulin and lycopene alone or together reduced the expression of Bax, but increased Bcl-2 and Bcl-xL levels in DI, DL, and DIL rats, especially when compared to group D (p < 0.001). The ratios of Bax/Bcl-2 and Bax/Bcl-xL in DI, DL, and DIL rats were also reduced (p < 0.001). Our results indicate that treatment with insulin and/or lycopene contribute to the prevention of cell death by reducing the expression of proapoptotic genes and increasing the expression of antiapoptotic genes in the hippocampus. PMID- 28656153 TI - The Relationship between Cardiovascular Autonomic Dysfunction and Ocular Abnormality in Chinese T2DM. AB - OBJECTIVE: This study aims to explore the relationship between autonomic nerve dysfunction-assessed by cardiovascular autonomic neuropathy risk score (CAN-RS) and ocular abnormality in Chinese type 2 diabetes mellitus (T2DM). METHOD: This is a cross-sectional study. A total of 335 subjects with T2DM were enrolled. The state of visual acuity, the lens, the vitreous, and the fundus were tested by professional ophthalmic instruments. The electrochemical skin conductance (ESC) of the hands and feet was measured by SUDOSCAN, from which a cardiovascular autonomic neuropathy risk score (CAN-RS) was calculated. Receiver operating characteristic (ROC) curves were drawn to evaluate the feasibility and accuracy of CAN-RS in diabetic oculopathy screening. RESULTS: Abnormalities of the lens, vitreous, and fundus accounted for 7.8%, 5.1%, and 9.9%, respectively, in this study. The means of hands and feet ESC were higher than 60 MUS, and CAN-RS was 33.1 +/- 14.8%. In logistic regression analysis, CAN-RS was positively associated with lens (OR = 1.055, P < 0.001) and vitreous (OR = 1.044, P < 0.01) abnormality. The area under ROC to detect lens and vitreous abnormality was 0.713 and 0.725, respectively. CONCLUSION: CAN-RS, a cardiac autonomic nerve dysfunction index calculated by SUDOSCAN, may be a promising index for lens and vitreous abnormality screening in T2DM patients. Further studies are needed to confirm the conclusion. PMID- 28656155 TI - Effects of Isx-9 and stress on adult hippocampal neurogenesis: Experimental considerations and future perspectives. AB - The development of synthetic small molecules capable of promoting neuronal fate in stem cells is a promising strategy to prevent the decline of hippocampal function caused by several neurological disorders. Within this context, isoxazole 9 (Isx-9) has been shown to strongly induce cell proliferation and neuronal differentiation in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), while also improving hippocampal function in healthy mice. We have recently demonstrated that Isx-9 is able to restore normal neurogenesis levels after procedural stress. Here, we further discuss these findings highlighting the importance of including a naive group in studies investigating the effects of either restraint stress or mild chronic unpredictable stress (CUS) on adult hippocampal neurogenesis. PMID- 28656154 TI - Antidiabetic Drugs in Alzheimer's Disease: Mechanisms of Action and Future Perspectives. AB - Diabetes mellitus (DM) and Alzheimer's disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD. PMID- 28656156 TI - The effects of aging on Amyloid-beta42-induced neurodegeneration and regeneration in adult zebrafish brain. AB - Alzheimer disease is the most prevalent neurodegenerative disease and is associated with aggregation of Amyloid-beta42 peptides. In mammals, Amyloid beta42 causes impaired neural stem/progenitor cell (NSPC) proliferation and neurogenesis, which exacerbate with aging. The molecular programs necessary to enhance NSPC proliferation and neurogenesis in our brains to mount successful regeneration are largely unknown. Therefore, to identify the molecular basis of effective brain regeneration, we previously established an Amyloid-beta42 model in adult zebrafish that displayed Alzheimer-like phenotypes reminiscent of humans. Interestingly, zebrafish exhibited enhanced NSPC proliferation and neurogenesis after microinjection of Amyloid-beta42 peptide. Here, we compare old and young fish to address the effects of aging on regenerative ability after Amyloid-beta42 deposition. We found that aging does not affect the rate of NSPC proliferation but reduces the neurogenic response and microglia/macrophage activation after microinjection of Amyloid-beta42 in zebrafish, suggesting an important link between aging, neuroinflammation, regenerative neurogenesis and neural stem cell plasticity. PMID- 28656158 TI - Adductor Canal Block for Knee Surgeries: An Emerging Analgesic Technique. PMID- 28656157 TI - Opportunities lost and gained: Changes in progenitor competence during nervous system development. AB - During development of the central nervous system, a small pool of stem cells and progenitors generate the vast neural diversity required for neural circuit formation and behavior. Neural stem and progenitor cells often generate different progeny in response to the same signaling cue (e.g. Notch or Hedgehog), including no response at all. How does stem cell competence to respond to signaling cues change over time? Recently, epigenetics particularly chromatin remodeling - has emerged as a powerful mechanism to control stem cell competence. Here we review recent Drosophila and vertebrate literature describing the effect of epigenetic changes on neural stem cell competence. PMID- 28656159 TI - The Prevalence of Unanticipated Hamate Hook Abnormalities in Computed Tomography Scans: A Retrospective Study. AB - BACKGROUND: It is possible that some hamate hook fractures are not diagnosed or treated, thereby affecting the study of their natural history. Study of the prevalence of incidental hamate hook fractures, nonunions, and other abnormalities on computed tomography (CT) ordered for another reason could document a subset of undiagnosed and untreated hamate hook fractures which might change our understanding about the natural history. METHODS: Reports of 2489 hand, wrist, and forearm CT scans for hamate hook abnormalities were searched. We excluded 19 patients with anticipated hamate fractures and 1 patient that had a hamate hook excision. Twenty-eight patients had an unanticipated hamate hook abnormality. RESULTS: There was a significant difference in the prevalence of incidental hamate hook abnormalities by sex but not by age. Among the 28 unexpected hamate hook abnormalities, there were 16 fractures of the base (12 acute, 1 nonunion, and 3 of uncertain age), 5 acute oblique fractures, and 7 tip abnormalities/ossicles. The patient with an incidental nonunion had a CT scan for wrist pain and was diagnosed with gout. All fractures involved a direct blow to the hand (distal radius or scaphoid fracture, or crush injury). The 7 patients with a hamate tip abnormality had a CT scan for a distal radius or metacarpal fracture, crush injury or wrist pain. Five acute fractures were treated operatively with excision and the other 23 fractures were treated nonoperatively. CONCLUSION: Hamate fractures can be diagnosed incidental to other hand and wrist problems on CT. PMID- 28656160 TI - An Assessment of Online Reviews of Hand Surgeons. AB - BACKGROUND: The purpose of this study is to evaluate the number of reviews and scores for active members of the American Society for Surgery of the Hand (ASSH) in popular physician rating websites (Healthgrades.com and Vitals.com). METHODS: A total of 433 ASSH active members were searched in two popular rating websites for a total of 866 web searches. Demographic data, overall and subcategory scores, number of reviews, and wait times were scored from each member's webpage. RESULTS: The average number of reviews per surgeon on Healthgrades.com and Vitals.com were 13.8 (range 1-108) and 9.4 (range 0-148), respectively. The average overall score for physicians was 8.1 out of 10 points. For both websites, the vast majority (80-90%) of active members of the ASSH had 20 or less reviews. Multivariate data analysis revealed no statistical differences in overall score by region (P=0.24) or gender (P=0.38). Increasing physician age negatively correlated with overall score (P=0.01). Wait time was not associated with a negative score (P=0.38). CONCLUSION: Active members of the ASSH received generally positive reviews. The average number of reviews for active members of the ASSH was exceedingly small, bringing into question the legitimacy and validity of these scores. This is especially important when taking into consideration the increasing popularity of these websites, and the reliance of patients on them to obtain physician information. The clinical implication of this study is that physicians have a vested interest in the legitimacy of the data provided by these websites and other physician rating outlets. PMID- 28656161 TI - A Comparison of Patients Absorption Doses with Bone Deformity Due to the EOS Imaging and Digital Radiology. AB - BACKGROUND: This study has aimed to measure the patient dose in entire spine radiography by EOS system in comparison with the digital radiography. METHODS: EOS stereo-radiography was used for frontal and lateral view spine imaging in 41 patients in a prospective analytical study. A calibrated dose area product (DAP) meter was used for calibration of the DAP in EOS system. The accuracy and precision of the system was confirmed according to the acceptance testing. The same procedure was used for 18 patients referred for lumbar spine digital radiology (overall 36 images). RESULTS: Although radiation fields in the EOS were almost twice of that in digital radiology, and the average peak tube voltage (kVp), current supply to the tube (mA), and the average size and age of the patients referred for EOS imaging were greater than digital radiology, however, the average DAP in EOS was 1/5 of that in digital radiology system. Also, the average dose in the EOS was about 1/20 of that in digital radiology. CONCLUSION: The patient dose in EOS imaging system was lower in comparison with digital radiology (1/20). PMID- 28656162 TI - Evaluation of Changes in the Tibiotalar joint after High Tibial Osteotomy. AB - BACKGROUND: There are limited studies regarding the effects of high tibial osteotomy (HTO) on other areas of lower extremity. In current study, we investigated the changes of tibiotalar joint following HTO. METHODS: A total of 39 patients with genu varum requiring HTO were enrolled in this before and after study. The genu varus, joint diversion (JDA), lateral distal tibial (LDTA) and lateral distal tibial-ground surface (LDT-GSA) angles were measured before the operation and compared with 6 months after the surgery. RESULTS: Twenty threeout of39 patients (59%) were females. The genu varus angle decreased significantly (13 degrees +/-1.7 degrees versus 0.6 degrees +/-1 degrees ). No significant changes were seen in JDA (P=0.45) and LDTA (P=0.071). LDT-GSA changed significantly (P=0.011) from 8.1 degrees +/-1 degrees in varus to -0.3 degrees +/-0.5 degrees in valgus. CONCLUSION: Although HTO did not change the JDA and LDTA, however, significant change in LDT-GSAindicates that HTO can significantly decrease the shearing forces exerted on the ankle joint. PMID- 28656163 TI - Responsiveness of Static and Dynamic Postural Balance Measures in Patients with Anterior Cruciate Ligament Reconstruction Following Physiotherapy Intervention. AB - BACKGROUND: The main goal of physiotherapy for patients with anterior cruciate ligament reconstruction (ACL-R) is to improve postural control and retain knee function. Therefore, clinicians need to use evaluative tools that assess postural changes during physiotherapy. To maximize the clinical utility of the results of these tools, the extracted measures should have appropriate psychometric properties of reliability, validity and responsiveness. No study has yet addressed responsiveness of postural measures in these patients. This study was designed to investigate the responsiveness and determine the minimal clinically important changes (MCIC) of static and dynamic postural measures in patients with (ACL-R) following physiotherapy. METHODS: Static and dynamic postural measures were evaluated at first occasion and again after four weeks physiotherapy. The static measures consisted of center of pressure (COP) parameters while dynamic measures included the stability indices. Correlation analysis and ROC curve were applied for assessing the responsiveness. RESULTS: The meanand SD velocity of COP had acceptable responsiveness in both conditions of standing on injured leg with open-eyes and on uninjured leg with closed-eyes, both with nocognitive task. For dynamic measures, stability indices in double-leg standing with closed-eyes with cognitive task condition attained acceptable responsiveness. MCICs for mean and SD velocity in anteroposterior and mediolateral directions were 0.28cm/s, 0.008cm/s, 0.02cm/s, respectively in standing on injured leg with open-eyes; and 0.14cm/s, 0.07cm/s, 0.06cm/s, respectively in uninjured leg with closed-eyes condition. Also, MCICs for anteroposterior, mediolateral and total stability indices were 0.51 degrees , 0.37 degrees , 0.34 degrees , respectively in DCT condition. CONCLUSION: Our findings provide evidence for selection of appropriate static and dynamic postural measures for assessment of changes in these patients. MCICs for these measures were determined, which provide practical information for clinicians to make decision on clinical significance of changes in patients' status. PMID- 28656164 TI - Ponseti Casting Method in Idiopathic Congenital Clubfoot and Its Correlation with Radiographic Features Abstract. AB - BACKGROUND: The aim of this study was to evaluate the idiopathic congenital clubfoot deformity treated by Ponseti method to determine the different factors such as radiological investigations that may have relations with the risk of failure and recurrence in mid-term follow-up of the patients. METHODS: Since 2006 to 2011, 226 feet from 149 patients with idiopathic congenital clubfoot were treated with weekly castings by Ponseti method. Anteroposterior and lateral foot radiographies were performed at the final follow-up visit and the data from clinical and radiological outcomes were analysed. RESULTS: In our patients, 191(84.9%) feet required percutaneous tenotomy. The successful correction rate was 92% indication no need for further surgical correction. No significant correlation was found between the remained deformity rate and the severity of the deformity and compliance of using the brace (P=0.108 and 0.207 respectively). The remained deformity rate had an inverse association with the beginning age of treatment (P=0.049). No significant correlation was found between the percutaneous tetonomy and passive dorsiflexion range (P=0.356). CONCLUSION: According to our results treatment with the Ponseti method resulted in poor or no correlation. The diagnosis of clubfoot is a clinical judgment; therefore, the outcome of the treatment must only be clinically evaluated. Although the Ponseti method can retrieve the normal shape of the foot, it fails to treat the bone deformities and eventually leads to remained radiologic deformity. Further studiesare suggested to define a different modification that can address the abnormal angles between the foot and ankle bones to minimize the risk of recurrence. PMID- 28656165 TI - Comparison of Double and Single Leg Weight-Bearing Radiography in Determining Knee Alignment. AB - BACKGROUND: Knee malalignment is an important modifiable cause of osteoarthritis (OA). Surgical therapeutic procedures depend on proper knee alignment assessment. The purpose of this study was to compare knee alignment parameters between double and single leg weight-bearing radiographs and to evaluate the reproducibility of inter- and intra-observer measurements. METHODS: One hundred eight patients (59 male and 49 female) with knee deformity visited at Kerman Knee Clinic were selected. Full limb anteroposterior (AP) Radiographs were taken for each participant in double and single leg weight-bearing positions. Hip-Knee-Ankle Angle (HKAA), Medial-Proximal-Tibial Angle (MPTA), Lateral-Distal-Femoral Angle (LDFA) and Joint-Line-Convergence Angle (JLCA) measured. Images stored on PC were examined by three observers to assess inter and intra observer reproducibility. Data analysis was done by SPSS software. RESULTS: The mean age of patients was 48.4 (+/-6.84) years, mean BMI was 26.55 (+/-1.94) Kg/m2. The mean HKAA and JLCA were significantly different between double and single leg weight-bearing radiographs. Intraclass correlation coefficient (ICC) test showed high (0.99) inter-reproducibility between three observers in all cases, except one (ICC=0.92). Intra-observer reproducibility indicated a strong correlation between the observer's measurements at different times (ICC > 0.99). CONCLUSION: HKAA and JLCA were affected by the patient's position. Observer and time interval had no effect on either of HKAA, MPTA, LDFA, and JLCA. Also the measurement of knee alignment parameters was not dependent on observer's experience. In conclusion single leg weight-bearing radiography is more representative of knee alignment and is inter and intra-observer reproducible. PMID- 28656166 TI - The Effect of Dynamic Hyperextension Brace on Osteoporosis and Hyperkyphosis Reduction in Postmenopausal Osteoporotic Women. AB - BACKGROUND: Osteoporosis and hyperkyphosis could impose a considerable financial and therapeutic burden on the affected society. Thus, new strategies to prevent or manage such complications are of significant importance. Here we evaluate the effect of 'Dynamic Hyperextension Brace' (DHB) on bone density, and hyperkyphosis correction. METHODS: Sixty postmenopausal women were randomly assigned to the case and control groups and followed for one year. DHB was applied in the case group according to the pre-designed protocol and the patients' clinical and paraclinical parameters, including bone mineral density (BMD), kyphosis angle, osteoporotic fracture, and serum alkaline phosphatase (ALP) were evaluated in two groups. RESULTS: Despite no significant difference in basic BMD and kyphosis between the case and control groups, BMD and kyphosis were significantly improved in the DHB treated group, at the end of the study (P=0.003 and P=0.001, respectively). Serum ALP level was significantly higher in cases compared to the controls (P=0.48). The vertebral fracture rate was also lower in the case group compared to the controls. CONCLUSION: The efficacy of bracing in osteoporosis and kyphosis management should be more emphasized. However, more detailed and controlled studies with more patients and a longer follow-up period is needed to adequately evaluate the long-term results of braces, including DHB. PMID- 28656167 TI - Epidemiological Profile of Extremity Fractures and Dislocations in Road Traffic Accidents in Kashan, Iran: a Glance at the Related Disabilities. AB - BACKGROUND: Apart from the mortality, road traffic injuries are associated with significant morbidities. This study has aimed to examine the pattern of traffic accident-related extremity fractures/dislocations and their related disabilities. METHODS: A retrospective hospital-based study was conducted to assess the characteristics of limb fractures/dislocations among road traffic accident victims registered in Trauma Research Center registry of Kashan University of Medical Sciences, Kashan, Iran, during 2012-2013. Age and sex distribution, cause of injury, and site of fractures/dislocations were recorded. Years lived with disability (YLD) was calculated as a scale to measure the disability. One-way ANOVA and chi-square tests were used for data analysis. RESULTS: From a total of 962 subjects, 812 (84.4%) were males (the male/female sex ratio: 5.4:1). The mean age of victims was 32.7+/-17.9. Leg (37%) and forearm (19%) fractures were the most frequent fractures. Shoulder dislocations were among the most affected joints accounting for 36.6% of the cases. The total calculated YLD was 135.6 (34.4 for temporal and 101.2 for lifelong disabilities, and totally 117.3 and 18.3 for males and females, respectively). The highest YLD was for motorcyclists (104) and while the most YLD was for 15-29 years (68.2). CONCLUSION: Young men motorcyclist accidents are a major problem in Kashan region. Generally, they have been accounted for the highest YLD due to fractures/dislocations, especially in lower extremity. Although the calculated YLD will be decreased with increasing age, the elder people also had the high rate of traffic-related limb injuries. PMID- 28656168 TI - Nail Psoriasis Triggered by the Reconstruction of Syndactyly. AB - Koebner phenomenon is observed in a number of inflammatory skin diseases. Psoriasis is one of the most common skin diseases associated with Koebner phenomenon. Nail psoriasis may be developed independently from inflammatory arthritis and skin psoriasis. This study reports on the reconstruction of third web of a 30-year-old woman, which performed on her right, due to congenital syndactyly. Four months postoperatively, she developed nail dystrophy, onycholysis and onychorrhexis of the middle, ring and little fingernails. The clinical and histopathology findings were compatible with diagnosis of isolated nail psoriasis. PMID- 28656169 TI - Chronic Recurrent Multifocal Osteomyelitis in a 9-year-old Boy. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is a rare aseptic, auto inflammatory bone disorder. CRMO presents with bone pain with or without fever. The diagnosis of CRMO is a diagnosis of exclusion and should be included in the differential diagnosis of chronic inflammatory bone lesions in children. Cultures of the bone are typically sterile, antibiotic therapy does not result in clinical improvement whereas anti-inflammatory drugs improve the condition. Furthermore, biopsy should be considered in chronic and relapsing bone pain and swelling unresponsive to treatment. Herein, we present a nine-year-old boy complaining of recurrent pain in his upper and lower extremities. On examination he had mild fever and cervical lymphadenopathy. He also had experienced bone pain and weight loss in the recent month. Based on biopsy and bone scan he was finally diagnosed with CRMO. Naproxen and Pamidronate was prescribed and he was getting better and returned to normal life and activity without need to corticosteroids. PMID- 28656170 TI - Anatomic Spring Ligament and Posterior Tibial Tendon Reconstruction: New Concept of Double Bundle PTT and a Novel Technique for Spring Ligament. AB - A new technique in spring ligament reconstruction using medial half of posterior tibial tendon is demonstrated as a means of supporting the arch. In addition a new concept of double bundle PTT reconstruction based on anatomical attachments of original PTT is presented with the goal of obtaining the full function of PTT. PMID- 28656171 TI - A Five-Year Review of Perforated Peptic Ulcer Disease in Irrua, Nigeria. AB - BACKGROUND: Peptic ulcer perforation is a common cause of emergency admission and surgery. This is the first study that documents the presentation and outcome of management in Irrua, Nigeria. PATIENTS AND METHOD: This is a prospective study of all patients operated on for perforated peptic ulcer between April 1, 2010, and March 31, 2015. A structured questionnaire containing patients' demographics, operation findings, and outcome was filled upon discharge or death. RESULTS: There were 104 patients. 81 males and 23 females (M : F = 3.5 : 1). The age range was between 17 years and 95 years. The mean age was 48.99 years +/- SD 16.1 years. The ratio of gastric to duodenal perforation was 1.88 : 1. Perforation was the first sign of peptic ulcer disease in 62 (59.6%). Pneumoperitoneum was detectable with plain radiographs in 95 (91%) patients. 72 (69.2%) had Graham's Omentopexy. Death rate was 17.3%. CONCLUSION: We note that gastric perforation is a far commoner disease in our environment. Perforation is often the first sign of peptic ulcer disease. We identify fasting amongst Christians as a risk factor for perforation. PMID- 28656172 TI - Sulfide Homeostasis and Nitroxyl Intersect via Formation of Reactive Sulfur Species in Staphylococcus aureus. AB - Staphylococcus aureus is a commensal human pathogen and a major cause of nosocomial infections. As gaseous signaling molecules, endogenous hydrogen sulfide (H2S) and nitric oxide (NO.) protect S. aureus from antibiotic stress synergistically, which we propose involves the intermediacy of nitroxyl (HNO). Here, we examine the effect of exogenous sulfide and HNO on the transcriptome and the formation of low-molecular-weight (LMW) thiol persulfides of bacillithiol, cysteine, and coenzyme A as representative of reactive sulfur species (RSS) in wild-type and DeltacstR strains of S. aureus. CstR is a per- and polysulfide sensor that controls the expression of a sulfide oxidation and detoxification system. As anticipated, exogenous sulfide induces the cst operon but also indirectly represses much of the CymR regulon which controls cysteine metabolism. A zinc limitation response is also observed, linking sulfide homeostasis to zinc bioavailability. Cellular RSS levels impact the expression of a number of virulence factors, including the exotoxins, particularly apparent in the DeltacstR strain. HNO, like sulfide, induces the cst operon as well as other genes regulated by exogenous sulfide, a finding that is traced to a direct reaction of CstR with HNO and to an endogenous perturbation in cellular RSS, possibly originating from disassembly of Fe-S clusters. More broadly, HNO induces a transcriptomic response to Fe overload, Cu toxicity, and reactive oxygen species and reactive nitrogen species and shares similarity with the sigB regulon. This work reveals an H2S/NO. interplay in S. aureus that impacts transition metal homeostasis and virulence gene expression. IMPORTANCE Hydrogen sulfide (H2S) is a toxic molecule and a recently described gasotransmitter in vertebrates whose function in bacteria is not well understood. In this work, we describe the transcriptomic response of the major human pathogen Staphylococcus aureus to quantified changes in levels of cellular organic reactive sulfur species, which are effector molecules involved in H2S signaling. We show that nitroxyl (HNO), a recently described signaling intermediate proposed to originate from the interplay of H2S and nitric oxide, also induces changes in cellular sulfur speciation and transition metal homeostasis, thus linking sulfide homeostasis to an adaptive response to antimicrobial reactive nitrogen species. PMID- 28656173 TI - Heparin Mimics Extracellular DNA in Binding to Cell Surface-Localized Proteins and Promoting Staphylococcus aureus Biofilm Formation. AB - Staphylococcus aureus is a leading cause of catheter-related bloodstream infections. Biofilms form on these implants and are held together by a matrix composed of proteins, polysaccharides, and extracellular DNA (eDNA). Heparin is a sulfated glycosaminoglycan that is routinely used in central venous catheters to prevent thrombosis, but it has been shown to stimulate S. aureus biofilm formation through an unknown mechanism. Data presented here reveal that heparin enhances biofilm capacity in many S. aureus and coagulase-negative staphylococcal strains, and it is incorporated into the USA300 methicillin-resistant S. aureus (MRSA) biofilm matrix. The S. aureus USA300 biofilms containing heparin are sensitive to proteinase K treatment, which suggests that proteins have an important structural role during heparin incorporation. Multiple heparin-binding proteins were identified by proteomics of the secreted and cell wall fractions. Proteins known to contribute to biofilm were identified, and some proteins were reported to have the ability to bind eDNA, such as the major autolysin (Atl) and the immunodominant surface protein B (IsaB). Mutants defective in IsaB showed a moderate decrease in biofilm capacity in the presence of heparin. Our findings suggested that heparin is substituting for eDNA during S. aureus biofilm development. To test this model, eDNA content was increased in biofilms through inactivation of nuclease activity, and the heparin enhancement effect was attenuated. Collectively, these data support the hypothesis that S. aureus can incorporate heparin into the matrix and enhance biofilm capacity by taking advantage of existing eDNA-binding proteins. IMPORTANCEStaphylococcus aureus and coagulase-negative staphylococci (CoNS) are the leading causes of catheter implant infections. Identifying the factors that stimulate catheter infection and the mechanism involved is important for preventing such infections. Heparin, the main component of catheter lock solutions, has been shown previously to stimulate S. aureus biofilm formation through an unknown pathway. This work identifies multiple heparin-binding proteins in S. aureus, and it reveals a potential mechanism through which heparin enhances biofilm capacity. Understanding the details of the heparin enhancement effect could guide future use of appropriate lock solutions for catheter implants. PMID- 28656174 TI - Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes. AB - Glioblastoma multiforme (GBM) is the most common brain tumor in adults. Human cytomegalovirus (HCMV) genomes are present in GBM tumors, yielding hope that antiviral treatments could prove therapeutic and improve the poor prognosis of GBM patients. We discovered that GBM cells infected in vitro with HCMV display properties of cancer stem cells. HCMV-infected GBM cells grow more slowly than mock-infected controls, demonstrate a higher capacity for self-renewal determined by a sphere formation assay, and display resistance to the chemotherapeutic drug temozolomide. Our data suggest that HCMV, while present in only a minority of the cells within a tumor, could contribute to the pathogenesis of GBMs by promoting or prolonging stem cell-like phenotypes, thereby perpetuating tumors in the face of chemotherapy. Importantly, we show that temozolomide sensitivity is restored by the antiviral drug ganciclovir, indicating a potential mechanism underlying the positive effects observed in GBM patients treated with antiviral therapy. IMPORTANCE A role for HCMV in GBMs remains controversial for several reasons. Some studies find HCMV in GBM tumors, while others do not. Few cells within a GBM may harbor HCMV, making it unclear how the virus could be contributing to the tumor phenotype without infecting every cell. Finally, HCMV does not overtly transform cells in vitro. However, tumors induced by other viruses can be treated with antiviral remedies, and initial results indicate that this may be true for anti-HCMV therapies and GBMs. With such a poor prognosis for GBM patients, any potential new intervention deserves exploration. Our work here describes an evidence-based model for how HCMV could contribute to GBM biology while infecting very few cells and without transforming them. It also illuminates why anti-HCMV treatments may be beneficial to GBM patients. Our observations provide blueprints for future in vitro studies examining how HCMV manipulates stem cell-specific pathways and future clinical studies of anti-HCMV measures as GBM therapeutics. PMID- 28656175 TI - Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. AB - The literature concerning gestational maternal influenza virus infection and risk of autism spectrum disorders (ASD) is inconclusive. To address this uncertainty, we obtained information from questionnaires and samples from the Autism Birth Cohort, a prospective birth cohort comprising mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaires, referrals, and linkages to the Norwegian National Patient Registry, we identified 338 mothers of children with ASD and 348 frequency-matched controls for whom plasma samples that had been collected midpregnancy and after delivery were available for influenza virus serology via luciferase immunoprecipitation and hemagglutinin inhibition assays for influenza virus strains circulating during the study period. Assay data were combined to define serological status and integrated with self-reports of influenza-like illness to estimate ASD risk. Neither influenza A nor influenza B virus infection was associated with increased ASD risk. Integration of reports of symptoms of influenza-like illness with serology revealed an increase in risk for seropositive women with symptoms, but this increase did not achieve statistical significance (a level of P < 0.05) in the comparison with seronegative women without symptoms (adjusted odds ratio, 1.93; 95% confidence interval, 0.95 to 3.89; P = 0.068). Although chance may explain our findings, the magnitude of the potential association may be of biological importance, and dismissing our findings could result in failure to detect a bona fide association (type II error). If the association is true, we posit that the risk is due to activation of the maternal immune system following infection rather than direct fetal infection. Data on levels of cytokines or other mediators of inflammation would allow us to test the validity of this hypothesis. IMPORTANCE The causes of most cases of autism spectrum disorders (ASD) are unknown. Some epidemiological studies suggest that maternal gestational influenza virus infection may increase the risk of ASD in offspring. Here, we describe an analysis of a large birth cohort with results based on questionnaires that prospectively addressed subjective reports of influenza-like illness and serological assays for objective determination of influenza virus infection. Although serologic evidence of gestational influenza virus infection alone was not associated with risk, positive serology and symptoms of influenza-like illness cannot yet be definitely ruled out as a risk factor. PMID- 28656176 TI - A Three-Dimensional Cell Culture System To Model RNA Virus Infections at the Blood-Brain Barrier. AB - The blood-brain barrier (BBB) comprises the foremost protective barrier in the brain and is composed in part of a layer of microvascular endothelial cells that line the capillaries surrounding the brain. Here, we describe a human three dimensional (3-D) cell-based model of the BBB microvascular endothelium that recapitulates properties of these cells in vivo, including physiologically relevant transcriptional profiles, the capacity to induce potent antimicrobial innate immune signaling, and the ability to resist infection by diverse RNA viruses, including members of the enterovirus (coxsackievirus B, echovirus 11, enterovirus 71, poliovirus) and flavivirus (dengue virus, Zika virus [ZIKV]) families. We show that disruption of apical tight junctions by proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) sensitizes 3-D-cultured BBB cells to ZIKV infection and that 3-D derived BBB cells can be used to model the transmigration of ZIKV-infected monocytes across the endothelial barrier to access underlying astrocytes. Taken together, our findings show that human BBB microvascular endothelial cells cultured in 3-D can be used to model the mechanisms by which RNA viruses access the central nervous system (CNS), which could be used for the development and screening of therapeutics to limit this event. IMPORTANCE Neurotropic viral infections are significant sources of global morbidity and mortality. The blood-brain barrier (BBB) is composed in part of a layer of microvascular endothelial cells and functions to restrict viral access to the brain. In vitro models that recapitulate many of the properties of the human BBB endothelium are lacking, particularly with respect to the unique cellular and immunological mechanisms by which these cells restrict viral infections of the brain. Here, we developed a three-dimensional cell culture model that recapitulates many of the morphological and functional properties of the BBB microvasculature and apply this model to the study of RNA virus infections. The model we describe can therefore be used to study a variety of aspects of BBB physiology, including the mechanisms by which viruses might access the CNS, and could be used for the development and screening of antiviral therapeutics to limit this important step in viral pathogenesis. PMID- 28656177 TI - Giardia Colonizes and Encysts in High-Density Foci in the Murine Small Intestine. AB - Giardia lamblia is a highly prevalent yet understudied protistan parasite causing significant diarrheal disease worldwide. Hosts ingest Giardia cysts from contaminated sources. In the gastrointestinal tract, cysts excyst to become motile trophozoites, colonizing and attaching to the gut epithelium. Trophozoites later differentiate into infectious cysts that are excreted and contaminate the environment. Due to the limited accessibility of the gut, the temporospatial dynamics of giardiasis in the host are largely inferred from laboratory culture and thus may not mirror Giardia physiology in the host. Here, we have developed bioluminescent imaging (BLI) to directly interrogate and quantify the in vivo temporospatial dynamics of Giardia infection, thereby providing an improved murine model to evaluate anti-Giardia drugs. Using BLI, we determined that parasites primarily colonize the proximal small intestine nonuniformly in high density foci. By imaging encystation-specific bioreporters, we show that encystation initiates shortly after inoculation and continues throughout the duration of infection. Encystation also initiates in high-density foci in the proximal small intestine, and high density contributes to the initiation of encystation in laboratory culture. We suggest that these high-density in vivo foci of colonizing and encysting Giardia likely result in localized disruption to the epithelium. This more accurate visualization of giardiasis redefines the dynamics of the in vivo Giardia life cycle, paving the way for future mechanistic studies of density-dependent parasitic processes in the host. IMPORTANCEGiardia is a single-celled parasite causing significant diarrheal disease in several hundred million people worldwide. Due to limited access to the site of infection in the gastrointestinal tract, our understanding of the dynamics of Giardia infections in the host has remained limited and largely inferred from laboratory culture. To better understand Giardia physiology and colonization in the host, we developed imaging methods to quantify Giardia expressing bioluminescent physiological reporters in two relevant animal models. We discovered that parasites primarily colonize and encyst in the proximal small intestine in discrete, high-density foci. We also show that high parasite density contributes to encystation initiation. PMID- 28656178 TI - Gene Knockout Shows That PML (TRIM19) Does Not Restrict the Early Stages of HIV-1 Infection in Human Cell Lines. AB - The PML (promyelocytic leukemia) protein is a member of the TRIM family, a large group of proteins that show high diversity in functions but possess a common tripartite motif giving the family its name. We and others recently reported that both murine PML (mPML) and human PML (hPML) strongly restrict the early stages of infection by HIV-1 and other lentiviruses when expressed in mouse embryonic fibroblasts (MEFs). This restriction activity was found to contribute to the type I interferon (IFN-I)-mediated inhibition of HIV-1 in MEFs. Additionally, PML caused transcriptional repression of the HIV-1 promoter in MEFs. In contrast, the modulation of the early stages of HIV-1 infection of human cells by PML has been investigated by RNA interference, with unclear results. In order to conclusively determine whether PML restricts HIV-1 or not in human cells, we used the clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9) system to knock out its gene in epithelial, lymphoid, and monocytic human cell lines. Infection challenges showed that PML knockout had no effect on the permissiveness of these cells to HIV-1 infection. IFN-I treatments inhibited HIV 1 equally whether PML was expressed or not. Overexpression of individual hPML isoforms, or of mPML, in a human T cell line did not restrict HIV-1. The presence of PML was not required for the restriction of nonhuman retroviruses by TRIM5alpha (another human TRIM protein), and TRIM5alpha was inhibited by arsenic trioxide through a PML-independent mechanism. We conclude that PML is not a restriction factor for HIV-1 in human cell lines representing diverse lineages. IMPORTANCE PML is involved in innate immune mechanisms against both DNA and RNA viruses. Although the mechanism by which PML inhibits highly divergent viruses is unclear, it was recently found that it can increase the transcription of interferon-stimulated genes (ISGs). However, whether human PML inhibits HIV-1 has been debated. Here we provide unambiguous, knockout-based evidence that PML does not restrict the early postentry stages of HIV-1 infection in a variety of human cell types and does not participate in the inhibition of HIV-1 by IFN-I. Although this study does not exclude the possibility of other mechanisms by which PML may interfere with HIV-1, we nonetheless demonstrate that PML does not generally act as an HIV-1 restriction factor in human cells and that its presence is not required for IFN-I to stimulate the expression of anti-HIV-1 genes. These results contribute to uncovering the landscape of HIV-1 inhibition by ISGs in human cells. PMID- 28656180 TI - Tuning interfacial complexation in aqueous two phase systems with polyelectrolytes and nanoparticles for compound all water emulsion bodies (AWE somes). AB - Interfacial complexation between two oppositely charged polymers in aqueous two phase systems (ATPSs) leads to the formation of mechanically robust microcapsules that can be stressed without losing their structural integrity. When a polyelectrolyte (PE) is replaced with a charged nanoparticle (NP), microcapsules with internal compartments can be generated within an encapsulated shell comprising NPs and PEs, named AWE-somes. These shells, made by interfacial complexation between PEs and NPs, are, however, very brittle and can lose their integrity under mechanical stress, potentially limiting their applications. Improved control over the properties and structure of microcapsules over a wide range is needed to enable their broad utilization. In this work, we show that interfacial complexation of a polycation with a mixture of a polyanion and a negatively charged NP in ATPS presents a simple yet versatile method of tuning the structure and properties of microcapsules. We show that internal structure, along with the mechanical robustness and stimuli-responsive properties of microcapsules, can be varied by changing the concentrations of polyanion and NP present in one of the two aqueous phases. Interfacial complexation of PE with mixtures of PE and NP provides a new strategy for controlling and imparting the properties and functionality of AWE-some interfacial membranes for applications in encapsulation and release of active agents and recapitulation of basic functions of living cells. PMID- 28656179 TI - Record-high thermal barrier of the relaxation of magnetization in the nitride clusterfullerene Dy2ScN@C80-Ih. AB - The Dy-Sc nitride clusterfullerene Dy2ScN@C80-Ih exhibits slow relaxation of magnetization up to 76 K. Above 60 K, thermally-activated relaxation proceeds via the fifth-excited Kramers doublet with the energy of 1735 +/- 21 K, which is the highest barrier ever reported for dinuclear lanthanide single molecule magnets. PMID- 28656181 TI - Understanding the effects of 3D porous architectures on promoting lithium or sodium intercalation in iodine/C cathodes synthesized via a biochemistry-enabled strategy. AB - Rechargeable sodium-iodine and lithium-iodine batteries have been demonstrated to be promising and scalable energy-storage devices, but their development has been seriously limited by challenges such as their inferior stability and the poor kinetics of iodine. Anchoring iodine to 3D porous carbon is an effective strategy to overcome these defects; however, both the external architecture and internal microstructure of the 3D porous carbon host can greatly affect the ion intercalation of iodine/C electrodes. To realize the full potential of iodine electrodes, a biochemistry-enabled route was developed to enable the controllable design of different 3D porous architectures, from hollow microspheres to 3D foam, for use in iodine/C cathodes. Two types of spores with spherical cells, i.e. Cibotium Barometz (C. Barometz) and Oetes Sinesis (O. Sinesis), are employed as bio-precursors. By carefully controlling the degree of damage on the bio precursors, different targeted carbon hosts were fabricated. Systematic studies were carried out to clarify the structural effects on modifying the ion intercalation capabilities of the iodine/C cathodes in lithium-iodine and sodium iodine batteries. Our results demonstrate the profound performance improvements of both 3D bio-foam and hollow sphere because their hierarchically porous structures can strongly immobilize iodine. Notably, the 3D bio-foam based iodine composites achieve faster ion kinetics and enhanced rate capability than their hollow sphere based counterparts. This was attributed to their higher micro/mesopore volume, larger surface area and improved packing density, which result in the highly efficient adsorption of iodine species. By virtue of the thinnest slices, the iodine/bio-foam derived from C. Barometz spores achieves the best high-rate long-term cycling capability, which retains 94% and 91% of their capacities in lithium-iodine and sodium-iodine batteries after 500 cycles, respectively. With the help of the biochemistry-assisted technique, our study provides a much-needed fundamental insight for the rational design of 3D porous iodine/C composites, which will promote a significant research direction for the practical application of lithium/sodium-iodine batteries. PMID- 28656182 TI - Simple solution-phase syntheses of tetrahalodiboranes(4) and their labile dimethylsulfide adducts. AB - Convenient solution-phase syntheses of tetrahalodiboranes(4) B2F4, B2Cl4 and B2I4 are presented herein from common precursor B2Br4. In addition, the dimethylsulfide adducts B2Cl4(SMe2)2 and B2Br4(SMe2)2 are conveniently prepared in one-step gram and multigram scale syntheses from the commercially-available starting material B2(NMe2)4. The results provide simple access to the full range of tetrahalodiboranes(4) for the exploration of their untapped synthetic potential. PMID- 28656183 TI - Nanorattles with tailored electric field enhancement. AB - Nanorattles are metallic core-shell particles with core and shell separated by a dielectric spacer. These nanorattles have been identified as a promising class of nanoparticles, due to their extraordinary high electric-field enhancement inside the cavity. Limiting factors are reproducibility and loss of axial symmetry owing to the movable metal core; movement of the core results in fluctuation of the nanocavity dimensions and commensurate variations in enhancement factor. We present a novel synthetic approach for the robust fixation of the central gold rod within a well-defined box, which results in an axisymmetric nanorattle. We determine the structure of the resulting axisymmetric nanorattles by advanced transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS). Optical absorption and scattering cross-sections obtained from UV-vis-NIR spectroscopy quantitatively agree with finite-difference time-domain (FDTD) simulations based on the structural model derived from SAXS. The predictions of high and homogenous field enhancement are evidenced by scanning TEM electron energy loss spectroscopy (STEM-EELS) measurement on single-particle level. Thus, comprehensive understanding of structural and optical properties is achieved for this class of nanoparticles, paving the way for photonic applications where a defined and robust unit cell is crucial. PMID- 28656184 TI - Intermediate selectivity in the oxidation of phenols using plasmonic Au/ZnO photocatalysts. AB - Tunable reaction selectivity on a single catalyst is a continual goal in chemical syntheses. Herein, we report an unexpected light-directed intermediate selectivity using well-known plasmonic photocatalysts. We observed distinct intermediate selectivity behaviors between using UV and visible light irradiations. Chemical computations and quenching experiments suggest that the radicals generated by the plasmonic excitation govern the light-directed selectivity. The broader impact of this work ranges from selective yield of desirable intermediates for subsequent syntheses without tedious separation procedures, to arousing interest in examining new opportunities for plasmonic photocatalysts. PMID- 28656189 TI - Niobate nanosheet membranes with enhanced stability for nanofiltration. AB - Niobate nanosheets are assembled into thin membranes by a vacuum filtration. The nanosheet membranes have a dense and stable structure in water via chemical cross linking and show higher permeance and salt rejection compared with graphene oxide membranes. A water pathway model based on the void structure is presented to explain the membrane performances. PMID- 28656190 TI - Oxidized and Si-doped graphene: emerging adsorbents for removal of dioxane. AB - Graphene-based materials have emerged as new potential adsorbents for the adsorption and removal of persistent pollutants, and they could play a key role in the remediation of 1,4-dioxane. In this framework, a quantum chemistry study was carried out to rationalize the sorption properties of oxidized graphene (GO) and Si-doped graphene (SiG) nanosheets for use in 1,4-dioxane removal, taking into account that these adsorbents are experimentally available. Dispersion corrected PBE-D3/SVP calculations show that GO and SiG adsorbs dioxane through non-covalent and covalent interactions, respectively, with adsorption energies of up to ~0.9 eV, which represents an important improvement with respect to the adsorption onto intrinsic graphene. The adsorption strength was also rationalized in terms of natural bond orbitals, atoms-in-molecules and energy decomposition analyses. In the case of GO, a high content of hydroxyl and carboxyl functional groups enhances the removal efficiency, and they are responsible for the high adsorption stability in aqueous environments and at room temperature (300 K). In addition, explicit/implicit solvent calculations and molecular dynamics trajectories show that the SiG-dioxane interaction is highly stable at 300 K, without pollutant diffusion; besides, the SiG-dioxane interaction is stabilized in the presence of H2O molecules. All the analyses suggest that GO and SiG should be considered as new remarkable candidates for sorption technologies related to the removal, control and remediation of 1,4-dioxane, where the sorption efficiency is sorted as SiG > GO ? G. PMID- 28656191 TI - Thermoplastic elastomer with advanced hydrophilization and bonding performances for rapid (30 s) and easy molding of microfluidic devices. AB - One of the most important areas of research on microfluidic technologies focuses on the identification and characterisation of novel materials with enhanced properties and versatility. Here we present a fast, easy and inexpensive microstructuration method for the fabrication of novel, flexible, transparent and biocompatible microfluidic devices. Using a simple hot press, we demonstrate the rapid (30 s) production of various microfluidic prototypes embossed in a commercially available soft thermoplastic elastomer (sTPE). This styrenic block copolymer (BCP) material is as flexible as PDMS and as thermoformable as classical thermoplastics. It exhibits high fidelity of replication using SU-8 and epoxy master molds in a highly convenient low-isobar (0.4 bar) and iso-thermal process. Microfluidic devices can then be easily sealed using either a simple hot plate or even a room-temperature assembly, allowing them to sustain liquid pressures of 2 and 0.6 bar, respectively. The excellent sorption and biocompatibility properties of the microchips were validated via a standard rhodamine dye assay as well as a sensitive yeast cell-based assay. The morphology and composition of the surface area after plasma treatment for hydrophilization purposes are stable and show constant and homogenous distribution of block nanodomains (~22 degrees after 4 days). These domains, which are evenly distributed on the nanoscale, therefore account for the uniform and convenient surface of a "microfluidic scale device". To our knowledge, this is the first thermoplastic elastomer material that can be used for fast and reliable fabrication and assembly of microdevices while maintaining a high and stable hydrophilicity. PMID- 28656192 TI - Nd3+-Sensitized multicolor upconversion luminescence from a sandwiched core/shell/shell nanostructure. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) have attracted interest for use in bioimaging, biosensing, and therapeutic applications. These motivations are empowered by multicolor upconversion luminescence (UCL) under single near infrared wavelength excitation at ~980 nm. However, this wavelength overlaps with the absorption peak of water that is dominant in the biological environment, eliciting a serious biological heating problem. This study reports tailored multicolor UCL from a Nd3+-sensitized sandwich-structure of core/shell/shell UCNPs of NaYbF4:0.5%Tm,1%Nd@ CaF2:30%Nd@CaF2:1%Nd,20%Yb,2%Er that can be excited at single wavelength of ~800 nm without producing any local heating. Incorporation of substantial Nd3+ sensitizers in the middle shell region allows efficient harvesting of excitation light, with the excitation then migrating bidirectionally across the core/shell interfaces to simultaneously activate blue emission from Tm in the core as well as green and red emission from Er in the outermost shell layer. By precise control of the content of lanthanide ions in each domain, a palette of multicolor UCL can be produced, ranging from blue to white. The described Nd3+-sensitized multicolor UCNPs hold promises for a variety of multiplexed biological applications, without complications from heating effects. PMID- 28656193 TI - A preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa. AB - AIM: Warfarin is a widely used anticoagulant for the prevention and treatment of thromboembolism. We conducted a retrospective review to determine the causes and management of warfarin toxicity of patients admitted to Tygerberg hospital between June 2014 and June 2015. RESULTS: We identified and evaluated 126 patients who met the inclusion criteria. The cause of warfarin toxicity was identified and addressed in only 14.3% (18/126) of patients. Where the cause was identified, 56% (10/18) was due to dosing errors and 17% (3/18) drug-drug interaction (DDI). However, 77% (97/126) of patients were retrospectively identified as receiving concomitant medicines known to interact with warfarin at the time of admission. Twenty-eight percent (35/126) of patients presented with major bleeding, which included seven cases of intracranial haemorrhage. Patients were admitted for a median of eight days at an average treatment cost of R10 578. CONCLUSION: We found that warfarin toxicity carries significant mortality and cost, but little attention is paid to the causes of toxicity. PMID- 28656194 TI - Excessive nNOS/NO/AMPK signaling activation mediated by the blockage of the CBS/H2S system contributes to oxygen-glucose deprivation-induced endoplasmic reticulum stress in PC12 cells. AB - Hypoxic-ischemia stress causes severe brain injury, leading to death and disability worldwide. Although it has been reported that endoplasmic reticulum (ER) stress is an essential step in the progression of hypoxia or ischemia induced brain injury, the underlying molecular mechanisms are and have not yet been fully elucidated. Accumulating evidence has indicated that both nitric oxide (NO) and hydrogen sulfide (H2S) play an important role in the development of cerebral ischemic injury. In the present study, we aimed to investigate the effect of the association between NO signaling and the cystathionine beta synthase (CBS)/H2S system on ER stress in a cell model of cerebral hypoxia ischemia injury. We found that oxygen-glucose deprivation (OGD) markedly increased the NO level and neuronal NO synthase (nNOS) activity. 3-Bromo-7 nitroindazole (3-Br-7-NI), a relatively selective nNOS inhibitor, abolished the OGD-induced inhibition of cell viability and the increased expression of ER stress-related proteins, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase-12 in PC12 cells, indicating the contribution of excessive nNOS/NO signaling to OGD-induced ER stress. Furthermore, we found that OGD increased the phosphorylated AMP-activated protein kinase (p-AMPK)/AMPK ratio, and the AMPK activator, 5-aminoimidazole-4 carboxamide-1-beta-D-ribofuranoside (AICAR), attenuated the effects on OGD induced ER stress, suggesting that OGD-induced NO overproduction results in AMPK activation in PC12 cells. We also found that OGD induced the downregulation of the CBS/H2S system, as indicated by the decreased H2S level in the culture supernatant and CBS activity in PC12 cells. In addition, we found that treatment with NaHS (a H2S donor) or S-adenosyl-L-methionine (SAM, a CBS agonist) mitigated OGD-induced ER stress, as well as the NO level, nNOS activity and AMPK phosphorylation in PC12 cells. On the whole, these results suggest that the inhibition of the CBS/H2S system, which facilitated excessive nNOS/NO/AMPK activation, contributes to OGD-induced ER stress. PMID- 28656195 TI - MicroRNA-322 attenuates aluminum maltolate-induced apoptosis in the human SH-SY5Y neuroblastoma cell line. AB - Aluminum-maltolate (Al-Malt) is a potent apoptosis inductor, which has been widely reported as an etiologic factor in Alzheimer's disease (AD). MicroRNA-322 (miR-322) is a vital regulator in various biological processes. The aim of the current study was to identify the role and possible underlying mechanism of miR 322 in Al-Malt-induced apoptosis. Eight concentrations of Al-Malt were prepared and used for treating the human neuroblastoma cell line, SH-SY5Y. Subsequent to treatment with Al-Malt for 3 days, cell viability, apoptosis and the expression levels of apoptosis-associated factors were measured. In addition, the mRNA expression level of miR-322 was monitored. Furthermore, cells were transfected with an miR-322 mimic and/or treated with Al-Malt, and cell viability, apoptosis and the expression levels of apoptosis-associated factors were measured again. Al Malt significantly inhibited cell viability, but promoted apoptosis. The apoptosis-associated factors, V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), Bcl-2-associated X protein, caspase-3 and cleaved caspase-3 were markedly upregulated by Al-Malt. The mRNA expression level of miR-322 was negatively regulated by Al-Malt. Furthermore, miR-322 attenuated the apoptosis induced by Al-Malt and recovered the expression changes of these four factors. Thus, miR-322 may attenuate Al-Malt-induced apoptosis by recovering the expression change of c-Myc. Furthermore, miR-322 may be involved in the pathogenesis of Al-Malt-associated AD. PMID- 28656196 TI - The ginsenoside metabolite compound K inhibits growth, migration and stemness of glioblastoma cells. AB - Glioblastoma (GBM) is the most aggressive and malignant form of primary brain cancer. Despite recent advances in cancer treatment, it remains a substantially incurable disease. Accordingly, more effective GBM therapeutic options are urgently required. In the present study, we investigated the anticancer effect of a ginsenoside metabolite, compound K (CK), against GBM cells. CK significantly inhibited not only growth, but also metastatic ability of U87MG and U373MG cells. CK arrested cell cycle progression at the G0/G1 phase with a decrease in the expression levels of cyclin D1 and cyclin D3 in both cell types. CK also induced apoptosis in GBM cells through nuclear condensation, an increase in ROS generation, mitochondrial membrane potential depolarization, and activation of caspase-3, caspase-9 and poly(ADP-ribose) polymerase (PARP). Furthermore, CK inhibited phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, contributing to the antiproliferative and apoptotic effects. Moreover, CK suppressed the self-renewal capacity as well as the invasiveness of U87MG and U373MG GBM stem-like cells (GSCs) by inducing a reduction in the expression of GSC markers, such as CD133, Nanog, Oct4 and Sox2. Taken together, our findings suggest that CK may potentially be useful for GBM treatment. PMID- 28656197 TI - Autophagy plays an important role in stemness mediation and the novel dual function of EIG121 in both autophagy and stemness regulation of endometrial carcinoma JEC cells. AB - Endometrial cancer (EC) is the third most common gynecologic malignancy in the world, and is considered a chemotherapy poor responding cancer. There are two underlying mechanisms on chemoresistance: the stemness of cancer stem cells (CSCs) and activation of pro-survival autophagy. It was found that autophagy is one of the main factors of cancer stem cell survival, multidrug resistance and maintenance of the homeostasis of cancer stem cells and normal cancer cells. However, the relationship between CSCs and autophagy of EC cells is still unknown. In this study, higher autophagy level was found in endometrial cancer stem cells (ECSCs) and stemness kept in line with autophagy in successive cultured JEC spheres. Autophagy inhibition decreased the properties of CSCs in JEC spheres and enhanced sensitivity of ECSCs to paclitaxel. Besides, it was found that EIG121 exerted dual functions in the regulation of autophagy and stemness not only in normal JEC cells but also JEC obtained CSCs. These findings could be useful for developing targeted therapies for endometrial carcinoma. PMID- 28656198 TI - miR-202 functions as a tumor suppressor in non-small cell lung cancer by targeting STAT3. AB - MicroRNAs (miRNAs) are a group of non-protein-coding, short single-stranded RNAs, which are considered as promising molecular markers and therapeutic targets in several cancers. The present study explored the expression patterns and functional roles of miR-202 in non-small cell lung cancer (NSCLC). The expression levels of miR-202 were determined in NSCLC tissues and cell lines using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The functional impact of miR-202 overexpression on NSCLC cell viability, migration and invasion were evaluated using Cell Counting Kit-8 reagent and Transwell migration and invasion assays, respectively. The molecular mechanism underlying the tumor suppressive roles of miR-202 on NSCLC was examined using bioinformatics analysis, luciferase reporter assay, RT-qPCR and western blot analysis. In addition, signal transducer and activator of transcription (STAT) 3 was overexpressed to investigate the impact on miR-202-mediated tumor suppression in NSCLC. The results indicated that miR-202 was downregulated in NSCLC tissues and cell lines, and was associated with tumor node metastasis stage and lymph node metastasis. Exogenous miR-202 expression reduced NSCLC cell viability, migration and invasion. Furthermore, STAT3 was identified as a direct target gene of miR-202 in NSCLC. STAT3 overexpression improved miR-202-impaired cell viability, migration and invasion. In conclusion, the present study revealed novel anticancer effects induced by miR-202 upregulation in NSCLC, and indicated that STAT3 may be a molecular target of miR-202. PMID- 28656199 TI - Wnt/beta-catenin signaling pathway activation reverses gemcitabine resistance by attenuating Beclin1-mediated autophagy in the MG63 human osteosarcoma cell line. AB - Anaberrant Wnt/beta-catenin signaling pathway is frequently implicated in tumorigenesis. However, whether the Wnt/beta-catenin pathway plays a role in resistance to antitumor chemotherapy drugs remains unknown. In the present study, the process of autophagy was assessed following overexpression of the autophagy associated gene Beclin 1 in gemcitabine-induced MG63 human osteosarcoma cells. Autophagy-associated gene expression was measured following activation or inhibition of the Wnt/beta-catenin pathway in gemcitabine-induced MG63 cells using reverse transcription-quantitative polymerase chain reaction. In addition, the percentage of MG63 cell apoptosis was measured by flow cytometry following Wnt/beta-catenin pathway activation or inhibition. The results demonstrated that Beclin 1 overexpression induced autophagy and reduced gemcitabine-induced apoptosis in MG63 human cell line. Furthermore, activation of the Wnt/beta catenin signaling pathway attenuated autophagy and enhanced gemcitabine-induced apoptosis. Additionally, the expression of Beclin 1 was reduced following Wnt/beta-catenin signaling pathway activation. The present study demonstrated that activation of the Wnt/beta-catenin signaling pathway may rescue chemotherapy drug resistance by downregulating the expression of Beclin 1. PMID- 28656200 TI - Cardioprotective effects and mechanism of Radix Salviae miltiorrhizae and Lignum Dalbergiae odoriferae on rat myocardial ischemia/reperfusion injury. AB - Radix Salviae miltiorrhizae (SM) and Lignum Dalbergiae odoriferae (DO) are traditional Chinese medicinal herbs used to treat ischemic heart disease and other cardiovascular diseases; however, to the best of our knowledge, there are currently few studies regarding their effects. The present study aimed to investigate the cardioprotective effects of SM and DO during myocardial ischemia/reperfusion (MI/R) injury in rats, and explore the molecular mechanisms that underlie their actions. In the present study, Sprague-Dawley rats were pretreated with SM, the aqueous extract of DO (DOA) and the volatile oil of DO (DOO), either as a monotherapy or in combination for 7 days. Subsequently, the rats were subjected to 30 min of ischemia followed by 180 min of reperfusion. Traditional pharmacodynamic evaluation and metabonomics based on gas chromatography/time-of-flight mass spectrometry were used to identify the therapeutic effects of these traditional Chinese medicines. The results revealed that SM, DOA and DOO monotherapies ameliorated cardiac function, and this effect was strengthened further when used in combined therapies. Among the combined treatments, SM + DOO exhibited the greatest potential (P<0.05) to improve electrocardiogram results and heart rate, reduce the heart weight index and myocardial infarct size, and decrease the levels of creatine kinase-MB and lactate dehydrogenase. In addition, metabonomics-based findings, including the principal component analysis and partial least squares discriminant analysis score plot of the metabolic state in rat serum, provided confirmation for the aforementioned results, verifying that SM + DOO exerted synergistic therapeutic efficacies to exhibit a greater effect on rats with MI/R injury when compared with the other pretreatment groups. Furthermore, the most effective duration of SM + DOO treatment was 30 min and the least effective duration was 180 min. Treatment with SM + DOO also significantly (P<0.01) reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells, tumor necrosis factor-alpha andinterleukin-6 expression, and malondialdehyde content, and increased the serum and tissue activity of superoxide dismutase. These results indicated that the combined effects of SM + DOO may be more effective compared with the single pretreatments against MI/R injury in rats. This effect may be achieved partly through anti-apoptotic, antioxidant and anti-inflammatory activities. Therefore, SM + DOO may be considered an effective and promising novel strategy for the prophylaxis and treatment of ischemic heart disease. PMID- 28656202 TI - Ameliorative efficacy of quercetin against cisplatin-induced mitochondrial dysfunction: Study on isolated rat liver mitochondria. AB - The present study aimed to investigate the hepatoprotective effects of the bioflavonoid quercetin (QR) on cisplatin (CP)-induced mitochondrial oxidative stress in the livers of rats, to elucidate the role of mitochondria in CP-induced hepatotoxicity, and its underlying mechanism. Isolated liver mitochondria were incubated with 100 ug/ml CP and/or 50 uM QR in vitro. CP treatment triggered a significant increase in membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, and a decrease in reduced glutathione (GSH) and non protein thiol (NP-SH) levels. In addition, CP caused a marked decline in the activities of enzymatic antioxidants and mitochondrial complexes (I, II, III and V) in liver mitochondria. QR pre-treatment significantly modulated the activities of enzymatic antioxidants and mitochondrial complex enzymes. Furthermore, QR reversed the alterations in LPO and PC levels, and GSH and NP-SH contents in liver mitochondria. The results of the present study suggested that QR supplementation may suppress CP-induced mitochondrial toxicity during chemotherapy, and provides a potential prophylactic and defensive candidate for anticancer agent-induced oxidative stress. PMID- 28656201 TI - Intratumoral and peritumoral expression of CD68 and CD206 in hepatocellular carcinoma and their prognostic value. AB - The aims of the present study were to determine whether the changes in density and location of CD68-positive and CD206-positive macrophages contribute to progression of hepatocellular carcinoma (HCC) and to evaluate prognostic values of these cells in post-surgical patients. A retrospective study involving 268 HCC patients was conducted. CD68-positive and CD206-positive macrophage infiltration in HCC tissues and adjacent tissues was examined by immunohistochemistry (IHC) and the relationship between the clinicopathological features and prognosis was analyzed. Receiver operating characteristics (ROC) curve was used to calculate diagnostic accuracy. There was an increase in CD68-positive and CD206-positive macrophage infiltration in adjacent tumor tissues compared with tumor tissues. ROC curve identified their optimal diagnostic cut-off values. The survival analysis showed that increased CD68 expression in adjacent tissues conferred superior overall survival (OS) and disease-free survival (DFS), while increase of CD206 in tumor yielded inferior OS and DFS. Cox regression analysis suggested both CD68-positive macrophages in adjacent area and intratumor CD206-positive macrophages as independent prognostic biomarkers for post-surgical HCC patients. Finally, a combination of CD68/CD206 and HBV-positive further improved prognostic stratification, especially in DFS. These results provide the first evidence for region- and subset-dependent involvement of CD68 and CD206 cells in HCC progression. A combination of CD68/CD206 density and HBV-positivity improves further predictive value for post-operative recurrence of HCC. Quantification of CD68/CD206 macrophages and their distribution can be exploited for better postsurgical management of HCC patients. These findings provide a basis for developing novel treatment strategies aimed at re-educating macrophages in tumor microenvironment. PMID- 28656203 TI - 1-Methyl-L-tryptophan promotes the apoptosis of hepatic stellate cells arrested by interferon-gamma by increasing the expression of IFN-gammaRbeta, IRF-1 and FAS. AB - Liver fibrosis, a precursor to cirrhosis, is the result of the deposition of extracellular matrix (ECM) proteins and is mediated primarily by activated hepatic stellate cells (HSCs). In this study, we investigated the anti-fibrotic effects of interferon (IFN)-gamma in activated HSCs in vitro and whether cell viability would be decreased by the inhibition of indoleamine 2,3-dioxygemase (IDO), which is responsible for cell cycle arrest. Following treatment with IFN gamma, cell signaling pathways and DNA content were analyzed to assess the inactivation of HSCs or the decrease in HSC proliferation. The IDO inhibitor, 1 methyl-L-tryptophan (1-MT), was used to determine whether IDO plays a key role in the regulation of activated HSCs, as IFN-gamma increases the expression of IDO. IFN-gamma significantly inhibited the growth of HSCs and downregulated the expression of alpha-smooth muscle actin (alpha-SMA) in the HSCs. IDO expression was markedly increased by IFN-gamma through signal transducer and activator of transcription 1 (STAT1) activation and resulted in the depletion of tryptophan. This depletion induced G1 cell cycle arrest. When the cells were released from IFN-gamma-mediated G1 cell cycle arrest by treatment with 1-MT, the apoptosis of the HSCs was markedly increased through the induction of IFN-gammaRbeta, interferon regulatory factor (IRF-1) and FAS. Our results thus suggest that the inhibition of IDO enhances the suppression of activated HSCs, and therefore co treatment with IFN-gamma and 1-MT may be applied to ameliorate liver fibrosis. PMID- 28656204 TI - Effects of bufalin on the mTOR/p70S6K pathway and apoptosis in esophageal squamous cell carcinoma in nude mice. AB - The aim of this study was to investigate the effects of bufalin on the mammalian target of rapamycin (mTOR/p70S6 kinase (p70S6K) signaling pathway and cell apoptosis in orthotopically transplanted tumors in nude mice. The mice were inoculated with human esophageal squamous cell carcinoma (ESCC) ECA109 cells in order to establish a model of orthotopicall transplanted ESCC tumors. The mice are administered low, medium and high doses of bufalin (0.5, 1.0 and 1.5 mg/kg) or rapamycin, or a combination of both. After the tumors were removed, the mRNA expression levels of mTOR, p70S6K, eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), cellular inhibitor of apoptosis protein 1 (cIAP1) and caspase-3 were detected by RT-PCR. In addition, we performed western blot analysis and immunohistochemical analysis to determine the protein expression of mTOR, p70S6K, 4EBP1, cIAP1, active caspase-3, Bcl-2 and Bad in the tumor tissue. The results revealed that bufalin exerted a significant anti-tumor effect in the nude mice with ESCC orthotopically transplanted tumors. This was shown by the decrease in the expression of mTOR, p70S6K and 4EBP1, which suggested that bufalin may possibly be used to inhibit tumor growth via the inhibition of the activation of p70S6K and 4EBP1. We also found that bufalin decreased the expression of cIAP1 and Bcl-2, and increased that of active caspase-3 and Bad, thus indicating that bufalin promoted apoptosis. Thus, our findings suggest that bufalin promotes tumor cell apoptosis, and this may be one of the important anti tumor mechanisms of action of bufalin. PMID- 28656205 TI - Role of PKA in the process of neonatal cardiomyocyte hypertrophy induced by urotensin II. AB - The model of urotensin II (UII)-induced cardiomyocyte hypertrophy has been widely used in studies on hypertrophy. However, the molecular mechanisms responsible for UII-induced cardiomyocyte hypertrophy have not yet been fully elucidated. It has been demonstrated that cardiomyocyte hypertrophy induced by UII is associated with changes in the intracellular Ca2+ concentration. In the present study, we investigated whether the cAMP-dependent protein kinase A (PKA)-mediated upregulation of the phosphorylation levels of phospholamban (PLN) at Ser16 contributes to UII-induced cardiomyocyte hypertrophy. After primary cultures of neonatal rat cardiomyocytes were exposed to UII for 48 h, cell size, protein/DNA contents and intracellular Ca2+ levels were detected. Western blot analysis was used to quantify the phosphorylated and total forms of PKA, PLN and the total amount of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)2a. UII increased the cell size, the protein/DNA ratio and the intracellular Ca2+ levels, consistent with the characteristics of hypertrophic response. In addition, exposure to UII upregulated the phosphorylation levels of PKA, and the expression levels of its downstream proteins, PLN and SERCA2a. However, treatment with PKA inhibitor (KT 5720) reversed all these effects of UII. On the whole, our results suggest that UII induces cardiomyocyte hypertrophy through the PKA-mediated upregulation of PLN phosphorylation at Ser16, which provides a new experimental foundation for the prevention and/or treatment of cardiac hypertrophy. PMID- 28656206 TI - Nicotinic acid impairs assembly of leading edge in glioma cells. AB - Malignant glioma is a clinically formidable disease. It commonly leads to death within 5 years after diagnosis. Physicians are often baffled since the inevitable diffuse invasion deteriorates clinical outcomes rapidly. Therefore, cancerous infiltration presents a foremost challenge to all therapeutic strategies on glioblastoma multiforme (GBM). Previously, we demonstrated that nicotinic acid (NA) possesses a brand new function by targeting F-actin stress fibers. By treating HEK293 or NIH3T3 cells with a certain concentration of NA, the F-actin stress fiber was significantly disassembled. This notable finding inspired us to explore NA further in cancer cell lines, such as GBM cells, since F-actin stress fibers are the critical foundation of cell migration, proliferation and numerous essential signaling pathways. Expectedly, we observed that optimized concentrations of NA, 3.5 mM and 7.0 mM, detached U251 from culturing petri dishes. Moreover, 7.0 mM of NA was capable of disrupting the leading-edge assembly. Additionally, we collected paraffin specimens from 85 GBM patients and evaluated the expression pattern of paxillin. Notably, we found that discernable paxillin signals were detected in 67 out of 85 samples. Given that leading edge is critical for cancer cell migration, we propose that NA treatment may be developed into a potential therapy for malignant glioma. PMID- 28656208 TI - Effect of nonylphenol on the regulation of cell growth in colorectal cancer cells. AB - Nonylphenol (NP) is a well-known endocrine-disrupting chemical (EDC), which can enhance the progression of cancer by functioning as an estrogen-like factor. In the present study, the effects of different concentrations of NP on COLO205 colorectal cancer (CRC) cells were examined. The results of flow cytometric analysis revealed that NP significantly decreased the proportion of cells in the G0/G1 phase in a dose-dependent manner, which was accompanied by a marginal increase in the proportions of cells in S and G2/M phases. NP did not induce apoptosis, whereas estradiol (E2) did induce apoptosis. To elucidate the mechanisms underlying the action of NP on COLO205 cells, the transcriptional levels of extracellular signal-regulated kinase (ERK)1, ERK2 and phosphoinositide 3-kinase (PI3K) were assessed using reverse transcription-quantitative polymerase chain reaction analysis. The expressions levels of ERK1, ERK2 and PI3K were increased by treatment with NP in a dose-dependent manner. On examining protein levels, the expression of PI3K p38 was increased by NP and E2, and the expression of ERK1/2 was increased by NP. The phosphorylation of the ERK protein was significantly increased by treatment with NP at a high concentration (10-4 M; P<0.01), but significantly decreased by E2 (P<0.01). Two key proteins in the transforming growth factor (TGF)beta pathway (c-Fos and SnoN) were selected for analysis using western blot analysis in the COLO205 cells treated with NP and E2. The expression levels of c-Fos and SnoN were significantly increased by treatment with E2 (10-7 M; P<0.01) and NP (10-7-10-4 M; P<0.01). Taken together, these results indicated that NP affected the development of CRC via the ERK signaling pathway and TGFbeta pathway. PMID- 28656207 TI - Expression of granulocyte colony-stimulating factor 3 receptor in the spinal dorsal horn following spinal nerve ligation-induced neuropathic pain. AB - In previous studies that have profiled gene expression in patients with complex regional pain syndrome (CRPS), the expression of granulocyte colony-stimulating factor 3 receptor (G-CSFR) was elevated, as were a number of pain-associated genes. The present study determined the expression of G-CSFR and the mechanisms by which it may affect hypersensitivity, focusing on the signal transducer and activator of transcription 3 (STAT3)/transient receptor potential cation channel subfamily V 1 (TRPV1) signaling pathway in particular, which is an important mediator of pain. Following L5 spinal nerve ligation (SNL) surgery, the protein and mRNA levels of G-CSFR increased in the ipsilateral spinal dorsal horn when compared with the sham and/or contralateral control. Double immunofluorescence further demonstrated that G-CSFR colocalized with TRPV1 and phosphorylated STAT in the neurons of the spinal dorsal horn. G-CSF treatment led to an increase in G CSFR and TRPV1 expression and phosphorylation of STAT3. These results indicate that G-CSF-induced G-CSFR expression may activate TRPV1 by promoting phosphorylation of STAT3. Collectively, the results suggest, for the first time, that the expression of G-CSFR in neurons following peripheral nerve injury may be involved in the induction and maintenance of neuropathic pain through the STAT3 and TRPV1 signaling pathway. PMID- 28656209 TI - Hydrogen sulfide reduced renal tissue fibrosis by regulating autophagy in diabetic rats. AB - The present study aimed to explore the effect of hydrogen sulfide (H2S) on renal tissue fibrosis and its mechanism in diabetic rats. Rats were randomly divided into four groups (n=13/group): Control group; induced diabetes mellitus group (STZ); induced diabetes mellitus treated with H2S group (STZ + H2S); normal rats treated with H2S group (H2S). The diabetic model was induced by intraperitoneal (i.p.) injections of 40 mg/kg body weight streptozotocin (STZ); the control group was treated with saline every day (i.p); NaHS (100 umol/kg i.p.) was administered to rats of STZ + H2S group and H2S group. After 8 weeks, rat body weight and 24 h proteinuria levels were determined in each group, renal pathological morphology was analyzed by Masson's trichrome staining, collagen IV content was detected by immunohistochemistry, and periodic acid-Schiff (PAS) staining was performed on renal glomerular and tubular basement membranes. The expression levels of matrix metalloproteinase 9 (MMP9), MMP7, tissue inhibitor of metalloproteinase 1 (TIMP1), superoxide dismutase (SOD), serine/threonine kinase AKT, transforming growth factor (TGF)-beta1, nuclear factor (NF)-kappaB and several autophagy related proteins were assessed by western blot analysis. Compared with the control group, renal tissue fibrosis was observed, collagen IV expression and the 24 h proteinuria quantity was markedly increased and the amount of PAS positive material in renal glomerular and tubular basement membranes was notably increased in STZ-treated rats. Furthermore, the expression levels of MMP9, MMP7, TIMP1, autophagy-associated proteins, AKT, TGF-beta1 and NF-kappaB protein were significantly increased, and SOD expression levels were significantly decreased in the STZ group compared with the control (P<0.05). In the H2S+STZ group, renal tissue fibrosis and the expression of collagen IV were improved, 24 h proteinuria was decreased, the amount of PAS positive material in renal glomerular and tubular basement membranes was decreased, the expression levels MMP9, MMP7, TIMP1, autophagy-associated proteins, AKT, TGF-beta1 and NF-kappaB protein were significantly decreased, and the expression levels of SOD were significantly increased compared with the STZ group (P<0.05). In conclusion, H2S may improve renal tissue fibrosis by inhibiting autophagy, upregulating SOD and downregulating AKT, TGF-beta1 and NF-kappaB. PMID- 28656210 TI - Pretreatment with bacterial components promotes DSS-injured colonic epithelial repair through the activation of STAT-3. AB - Bacterial protection and epithelial repair are important against inflammatory bowel disease (IBD). The present study was designed to examine the effects of different bacterial components on the repair of normal and dextran sodium sulfate (DSS)-treated colonic epithelial cells and the corresponding mechanisms. Human colonic epithelial cells (HT-29) were pretreated with various doses of LPS or CpG dsDNA for 24 h and then treated with or without DSS for another 24 h. The epithelial repair was assessed by video analyses following mechanical injury. The epithelial expression of cluster of differentiation (CD)40 was assayed using flow cytometeric analysis. The production of interleukin (IL)-6 and tumor necrosis factor (TNF) in the cell culture medium were measured using ELISA. The expression of p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)-3 were examined using western blot analysis and reverse transcription-quantitative polymerase chain reaction analysis. MAPK and STAT-3 inhibitors were also administrated to observe signaling-mediated repair. The results showed that pretreatment with lipopolysaccharide (LPS) or CpG-dsDNA promoted epithelial repair of the DSS-treated cells. The promoting effects were associated with the downregulation of CD40 molecules, inhibition of the p38 MAPK/TNFalpha pathway and activation of the STAT3/IL-6 pathway. The STAT3 inhibitor abrogated the protective effects of LPS and CpG-dsDNA on wound repair. These results demonstrated that LPS and CpG-dsDNA induced preadaptation to DSS injury. This preadaptation was accompanied by the activation of STAT-3. Thus, bacterial components may be used as a strategy for the therapeutic prevention of IBD. PMID- 28656211 TI - Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling. AB - Notch is an important pathway in that it regulates cell-to-cell signal transduction, which plays an essential role in skeletal remodeling. Bone morphogenetic protein (BMP)9 has been regarded as one of the most efficient BMPs by which to induce osteogenic differentiation in mesenchymal stem cells (MSCs). Understanding the interaction between Notch and BMP9 signaling is a critical issue for optimizing the application of MSCs and BMPs in bone tissue engineering. In the present study, we investigated the role of Notch signaling in the BMP9 induced osteogenic differentiation of MSCs. Our data demonstrated that Notch signaling obviously enhanced BMP9-induced osteogenic differentiation in MSCs in vitro and in vivo. Notch signaling augmented the activity of BMP9-induced BMP/Smad signaling and increased the gene expression of essential osteogenic factors induced by BMP9 in MSCs, such as runt-related transcription factor 2 (Runx2), type I collagen (Colla1) and inhibitor of differentiation (Id)1. We also found that Notch signaling promoted the expression of activin-like kinase 2 (ALK2) induced by BMP9, and the inhibitory effect of dnALK2 on BMP9-induced osteogenic differentiation was rescued by constitutive overexpression of Delta like 1 (DLL1). Notch signaling also exhibited an apparent effect on the proliferation of mouse embryo fibroblasts (MEFs) during BMP9-induced osteogenic differentiation. These results indicate that Notch plays a significant role in mediating BMP9-induced osteogenic differentiation in MSCs, which may be partly regulated by upregulation of the expression of ALK2. PMID- 28656212 TI - 18 beta-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration. AB - Accumulating evidence shows that 18 beta-glycyr-rhetinic acid (GRA) has antitumor activities in breast, ovarian cancer and leukemia, while its role in colorectal cancer remains unknown. In the present study, we investigated the effect of GRA in colorectal cancer cells LoVo, SW480 and SW620 and studied the underlying molecular mechanisms. Results showed that GRA had potent inhibitory effects on colorectal cancer cell proliferation in a dose- and time-dependent manner in vitro and in vivo. Growth inhibition was mediated by pro-apoptosis, as evident from Annexin V-FITC staining, the reduced expression of survivin and the induced expression of cleaved PARP. Furthermore, GRA treatment resulted in marked reduction of cell migration, invasion and wound healing capability, accompanying by the downregulated MMP expression. Moreover, GRA decreased the protein levels of p-PI3K, p-AKT, p-STAT3, p-JNK, p-p38 and p-NF-kappaB p65, of which the phosphorylation of PI3K and STAT3 decreased as early as 2 h after the GRA treatment. These results suggest that regulation of the apoptosis, invasion and migration of colorectal cancer cells by GRA might be through suppressing PI3K and STAT3 signaling pathways. the present study indicated that GRA could be a potential effective therapy for patients with colorectal cancer. PMID- 28656213 TI - BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells. AB - The nucleolus is a stress sensor associated with cell cycle progression and apoptosis. Studies have shown that nucleolar stress is positively correlated with apoptosis in breast, prostate and lung cancer cells. However, the role and function of nucleolar stress in ovarian cancer has not been reported. In this study, we found that the nucleolar stress inducer BMH-21 inhibited viability of SKOV3 ovarian cancer cells in a dose-dependent manner. Furthermore, BMH-21 induced the expression of nucleolar stress marker proteins (nucleolin, nucleophosmin and fibrillarin) and promoted the nuclear export of these proteins. BMH-21 also decreased MDM2 proto-oncogene expression and increased protein levels of the tumor suppressor p53 and p53 phosphorylated at serine 15 (p-p53-Ser15), which contributed to increased expression of the downstream apoptosis-related protein BCL2 associated X (BAX) and activation of caspase-3. Taken together, these data provide the first reported evidence that induction of p53-dependent nucleolar stress by BMH-21 induces apoptosis in ovarian cancer. Our data suggest that nucleolar stress might be a pathway suitable for targeting in ovarian cancer. PMID- 28656214 TI - HER2 regulates cancer stem-like cell phenotype in ALK translocated NSCLC. AB - We have previously shown that cancer stem-like cells (CSLCs) can mediate therapy resistance in ALK translocated lung cancers. HER2 has been linked to CSLCs in breast cancers and, therefore, we wanted to assess whether HER2 has a role in CSLCs in ALK translocated cancers. ALK translocated cell lines, H3122 and H2228, with variable sensitivity to ALK inhibition were used in the study. HER2 overexpression or knockdown was induced by retro- or lentiviral infections and cells were treated with pharmacological agents targeting HER2 and ALK signaling. Furthermore, tumorigenic properties of the cells were assessed in vitro using colony and sphere formation assays. In the ALK inhibitor sensitive H3122 cells, HER2 overexpression unaltered the primary response to ALK inhibition, but increased CSLC marker expression and enhanced colony and sphere formation and late AKT and ERK1/2 signaling recovery. In the ALK inhibitor semi-sensitive H2228 cells, HER2 knockdown reduced basal expression of CSLC markers, modestly increased sensitivity to ALK inhibition in colony and sphere formation assays, and reduced late AKT and ERK1/2 signaling recovery. In addition, HER2 induced cross activation of other ErbB-members of which HER3 followed most closely the CSLC marker expression and neuregulin-1, a HER3 ligand, or pan-ErbB inhibitor afatinib, were able to alter CSLC marker expression and colony formation. the present study suggests that HER2 has an important role in the regulation of the CSLC phenotype in ALK translocated lung cancers that is mainly orchestrated by HER2/HER3 heterodimers. PMID- 28656215 TI - Syringic acid inhibits apoptosis pathways via downregulation of p38MAPK and JNK signaling pathways in H9c2 cardiomyocytes following hypoxia/reoxygenation injury. AB - Syringic acid (SA), a naturally occur-ring O-methy-lated trihydroxybenzoic acid monomer extracted from Dendrobium nobile Lindl., has been demonstrated to attenuate renal ischemia-reperfusion (I/R) injury. However, the role of SA in myocardial I/R injury is unclear. The present study aimed to clarify the cardioprotective effect of SA in myocardial I/R injury in vitro and explore the potential molecular mechanisms. In the present study, it was revealed that pretreatment with SA increased the viability and inhibited oxidant stress in H9c2 cardiomyocytes that had suffered hypoxia/reoxygenation (H/R). SA also markedly downregulated B-cell lymphoma 2 (Bcl-2) expression and inhibited the expression of Bcl-2-like protein 4 (Bax) and cleaved caspase-3 in H9c2 cardiomyocytes induced by H/R. In addition, SA significantly alleviated H/R-induced the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N terminal kinase (JNK) in H9c2 cardiomyocytes. In conclusion, the present study demonstrated that SA inhibits the apoptosis of H9c2 cardiomyocytes following H/R injury via reduced activation of the p38MAPK and JNK signaling pathways. The results support the therapeutic usage of SA in the treatment of myocardial infarction. PMID- 28656216 TI - Hydrogen-containing saline alleviates pressure overload-induced interstitial fibrosis and cardiac dysfunction in rats. AB - Cardiac fibrosis induced by sustained pressure overload contributes to heart failure. Oxidative stress serves an important role in cardiac remodeling and heart failure independent of etiological factors. The application of hydrogen as an antioxidant is a novel concept in disease treatment, however no studies as present have investigated the effects of hydrogen on cardiac fibrosis. In the present study, the effects of hydrogen on pressure overload-induced cardiac fibrosis and heart failure were investigated in abdominal aortic-constricted rats. Masson's trichrome staining and echocardiography were used to evaluate the fibrotic area and cardiac function, respectively. Reactive oxygen species (ROS) content was detected by immunofluorescence. Malondialdehyde (MDA) concentration, the activity of superoxide dismutase (SOD) and hydroxyproline content were measured by spectrophotometry. Western blot analysis was used to detect the protein levels of transforming growth factor (TGF)-beta1, connective tissue growth factor (CTGF), NADPH oxidases (NOX)2, NOX4, p38 mitogen-activated protein kinase (MAPK) and Smad2/3. Reverse transcription-quantitative polymerase chain reaction was performed to detect the mRNA expression of collagen I (Col I) and fibronectin 1 (FN1). Hydrogen-containing saline (HCS) treatment was observed to improve interstitial fibrosis and cardiac function and to decrease the level of ROS, the oxidative-stress marker MDA and expression of NOXs, while increasing the activity of the anti-oxidant enzyme SOD. HCS treatment also decreased the phosphorylation of p38 MAPK and Smad2/3, and the expression of TGF-beta1 and CTGF, which were accompanied by reduced hydroxyproline content, Col I and FN1 mRNA levels. These results indicate that HCS treatment can improve cardiac function by reducing interstitial fibrosis in pressure-overloaded rats through its anti-oxidative properties and via suppression of TGF-beta1 signaling. PMID- 28656217 TI - Intra-arterially infused carbon dioxide-saturated solution for sensitizing the anticancer effect of cisplatin in a rabbit VX2 liver tumor model. AB - The present study aimed to evaluate the efficacy of an intra-arterially infused carbon dioxide (CO2)-saturated solution in sensitizing the anticancer effect of cisplatin in a rabbit VX2 liver tumor model. Forty VX2 liver tumor-bearing Japanese white rabbits were randomly divided into four groups and infused via the proper hepatic artery with a saline solution (control group), CO2-saturated solution (CO2 group), cisplatin solution (cisplatin group), or CO2-saturated solution and cisplatin solution (combined group). The tumor volume (TV) and the relative tumor volume (RTV), RTV = (TV on day 3 or 7)/(TV on day 0) x 100, were calculated using contrast-enhanced computed tomography. Hypoxia-inducible factor 1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX) staining were used to evaluate cellular hypoxia. Cleaved caspase-3 and cleaved caspase-9 were analyzed to assess tumor apoptosis. The mean RTV on days 3 and 7 were 202.6+/-23.7 and 429.2+/-94.8%, respectively, in the control group; 172.2+/-38.1 and 376.5+/-61.1% in the CO2 group; 156.1+/-15.1 and 269.6+/-45.2% in the cisplatin group; and 118.3+/-28.1 and 210.3+/-55.1% in the combined group. RTV was significantly lower in the CO2 group than in the control group (day 3; P<0.05), and in the combined group than in the cisplatin group (days 3 and 7; P<0.05). HIF-1alpha and CA IX suppression, and increased cleaved caspase-3 and cleaved caspase-9 expression, were detected in the CO2 and combined groups, compared with the other two groups. An intra-arterially infused CO2-saturated solution inhibits liver VX2 tumor growth and sensitizes the anticancer effect of cisplatin. PMID- 28656218 TI - Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL induced endothelial cell apoptosis. AB - The present study aimed to explore the direct toxicity of proprotein convertase subtilisin/kexin type 9 (PCSK9) to atherosclerosis (AS) and its association with apoptotic endothelial cells. Apolipoprotein E-/- mice were randomly divided into two groups, control and experimental. The control group was administered a normal diet and the experimental group was administered a high-fat diet. After 20 weeks, the aorta was isolated and dissected. Hematoxylin and eosin staining, and immunohistochemical analysis were performed. Human umbilical vein endothelial cells were incubated with varied concentrations of oxidized low-density lipoprotein (ox-LDL) for different times. The apoptotic rate was detected by flow cytometry. Western blotting and reverse transcription-quantitative polymerase chain reaction analysis were conducted to detect the expression of PCSK9, B-cell lymphoma 2 (Bcl-2), bcl-2-like protein 4 (Bax) and caspase-3. Short hairpin (sh) RNA-PCSK9 was transfected into endothelial cells using lentiviral transfection. The expression levels of PCSK9, Bax, Bcl-2, caspase-3 and the mitogen-activated protein kinase (MAPK) pathway proteins were detected. The high-fat group was successfully established as an AS model and PCSK9 was highly expressed in the AS plaque. Treatment with ox-LDL induced apoptosis and increased mRNA and protein levels of PCSK9. PCSK9 mRNA and proteins levels were downregulated by shRNA PCSK9. The deficiency of PCSK9 markedly inhibited the expression of pro-apoptotic proteins and promoted anti-apoptotic proteins. In addition, phosphorylation of p38 and c-Jun N-terminal kinases was altered by shRNA-PCSK9. Targeting of PCSK9 by shRNA-PCSK9 may repress endothelial cell apoptosis through MAPK signaling in AS, providing a novel direction for understanding the mechanism and treatment of AS. PMID- 28656219 TI - Induction of apoptosis by Galectin-9 in liver metastatic cancer cells: In vitro study. AB - Liver metastasis from gastrointestinal cancer defines a patient's prognosis. Despite medical developments, pancreatic cancer with liver metastasis confers a very poor prognosis. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been demonstrated to exert antitumor effects on various types of cancer cells by inducing apoptosis. However, the apoptotic pathway of Gal-9 in solid tumors is unclear. The aim of the present study was to evaluate the effects of Gal-9 on human liver metastasis from pancreatic cancer. Gal-9 suppressed cell proliferation in metastatic liver cancer cell lines derived from pancreatic cancer (KMP2, KMP7, and KMP8) and increased the levels of caspase-cleaved keratin 18 and fluorescein isothiocyanate (FITC)-conjugated Annexin V. Furthermore, expression of apoptosis-related molecules such as caspase-7, cleaved caspase-3, cleaved PARP, cytochrome c, Smac/Diablo and HtrA2/Omi was enhanced. However, Gal 9 did not affect expression of various cell cycle-related proteins. The microRNA (miRNA) expression profile was markedly altered by Gal-9, and various miRNAs might contribute to tumor growth suppression. Our data reveal that Gal-9 suppresses the growth of liver metastasis, possibly by inducing apoptosis through a mechanism involving mitochondria and changes in miRNA expression. Thus, Gal-9 might serve as a therapeutic agent for the treatment of liver metastasis from pancreatic cancer. PMID- 28656220 TI - JAK/STAT3 and Smad3 activities are required for the wound healing properties of Periplaneta americana extracts. AB - Periplaneta americana extracts (PAEs) play a crucial role in skin wound healing. However, their molecular effects and signaling pathways in regenerating tissues and cells are not clear. In this study, we refined the PAE from Periplaneta americana to investigate the mechanisms underlying skin wound healing. The human keratinocyte line HaCaT was selected and a mouse model of deep second-degree thermal burn was established for in vitro and in vivo studies, respectively. PAE treatment induced the proliferation and migration of HaCaT cells and wound healing in the burn model. Furthermore, the effects of PAE on wound healing were found to depend on the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway and Smad3 activities, according to western blot analysis and immunohistochemical (IHC) assays in vitro and in vivo. Pretreatment with a STAT3 inhibitor blocked the cell proliferation and migration induced by PAE. The results indicate the wound-healing function of PAE via enhanced JAK/STAT3 signaling and Smad3 activities. Our studies provide a theoretical basis underlying the role of PAE in cutaneous wound healing. PMID- 28656221 TI - Effect of transplantation of olfactory ensheathing cell conditioned medium induced bone marrow stromal cells on rats with spinal cord injury. AB - Spinal cord injury is a serious threat to human health and various techniques have been deployed to ameliorate or cure its effects. Stem cells transplantation is one of the promising methods. The primary aim of the present study was to investigate the effect of the transplantation of olfactory ensheathing cell (OEC) conditioned medium-induced bone marrow stromal cells (BMSCs) on spinal cord injury. Rat spinal cord compression injury animal models were generated, and the rats divided into the following three groups: Group A, (control) Dulbecco's modified Eagle's medium-treated group; group B, normal BMSC-treated group; group C, OEC conditioned medium-induced BMSC-treated group. The animals were sacrificed at 2, 4 and 8 weeks following transplantation for hematoxylin and eosin staining, and fluorescence staining of neurofilament protein, growth associated protein-43 and neuron-specific nuclear protein. The cavity area of the spinal cord injury was significantly reduced at 2 and 4 weeks following transplantation in group C, and a significant difference between the Basso, Beattie and Bresnahan score in group C and groups A and B was observed. Regenerated nerve fibers were observed in groups B and C; however, a greater number of regenerated nerve fibers were observed in group C. BMSCs induced by OEC conditioned medium survived in vivo, significantly reduced the cavity area of spinal cord injury, promoted nerve fiber regeneration following spinal cord injury and facilitated recovery of motor function. The present study demonstrated a novel method to repair spinal cord injury by using induced BMSCs, with satisfactory results. PMID- 28656222 TI - Activation of the Toll-like receptor 8 pathway increases the immunogenicity of mesenchymal stem cells from umbilical cord. AB - Mesenchymal stem cells (MSCs) are now widely used in clinical cell-based therapy due to their characteristics of low immunogenicity, multiple differentiation potency and the capability to modulate immune responses. However, accumulated research has indicated the absence of engrafted MSCs because of the increased immunogenicity of MSCs. Toll-like receptors (TLRs) are essential for the innate immune response and regulating the biological function of MSCs. The present study used human umbilical cord-derived MSCs (UCMSCs) and activated the TLR8 pathway of UCMSCs to study the role of TLR8 in mediating the immune status of UCMSCs. The results demonstrated that the activation of TLR8 increased both the proliferation of peripheral blood mononuclear cells (PBMCs) isolated from healthy human volunteers and the release of lactate dehydrogenase (LDH) in supernatant from the PBMC-UCMSCs co-culture system. Reverse transcription-quantitative polymerase chain reaction indicated that the TLR8 agonist increased the expression of many co-stimulatory molecules and pro-inflammatory genes, and flow cytometry indicated that activation of the TLR8 agonist increased co-stimulation protein levels but reduced specific surface markers, as confirmed by the part loss of stemness of UCMSCs. Finally, TLR8 increased osteocyte differentiation but had no effect on chondrocyte and adipocyte differentiation. The current study indicated the implication to TLR8 as regulators of the immunogenicity of UCMSCs. PMID- 28656224 TI - Chimeric antibody targeting SRPK-1 in the treatment of non-small cell lung cancer by inhibiting growth, migration and invasion. AB - Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in humans, and is characterized by rapid growth, migration, invasion and reoccurrence. Evidence has indicated that the protein and mRNA levels of serine arginine protein kinase-1 (SRPK-1) are upregulated in NSCLC tissues. However, the functions of SRPK1 and targeted therapy for SRPK1 in the progression and treatment of NSCLC remain to be fully elucidated. In the present study, the mRNA and protein expression levels of SRPK-1 in NSCLC cells and tissues were analyzed using reverse transcription-quantitative polymerase chain reaction analysis and SDS-PAGE, and the role of SRPK1 in the progression of NSCLC was investigated. In addition, a chimeric antibody target for SRPK-1 (ChanSRPK-1) was constructed, and the therapeutic effects of ChanSRPK-1 were investigated in H358-bearing mice. The curative effects of ChanSRPK-1 on the inhibition of growth, migration and invasion of NSCLC were also examined in vitro and in vivo. The results revealed that the mRNA and protein levels of SRPK-1 were upregulated in NSCLC cells and tumor tissues. Higher expression of SRPK1 promoted NSCLC cell growth, migration and invasion, whereas lower expression of SRPK-1 suppressed growth, migration and invasion of the NSCLC cells. Animal experiments demonstrated that ChanSRPK-1 inhibited the beta-catenin/T-cell factor complex. ChanSRPK-1 treatment also downregulated the phosphorylation levels of glycogen synthase kinase 3-beta and prolonged the survival of tumor-bearing mice. Taken together, SRPK-1 may offer potential as a therapeutic target oncogenic molecular in NSCLC, and ChanSRPK-1 may be a therapeutic agent with functions as a target and for oncolytic therapy in the treatment of NSCLC. PMID- 28656223 TI - Rapamycin inhibits CaCl2-induced thoracic aortic aneurysm formation in rats through mTOR-mediated suppression of proinflammatory mediators. AB - The aim of the present study was to investigate the effect of the mammalian target of rapamycin (mTOR) signaling pathway on thoracic aortic aneurysm (TAA) development. The study used a calcium chloride (CaCl2)-induced rat TAA model to explore the potential role of mTOR signaling pathway in the disease development. Adult male Sprague-Dawley rats underwent the periarterial exposure of thoracic aorta to either 0.5 M CaCl2 or normal saline, and a subgroup of CaCl2-treated rats received rapamycin 1 day prior to surgery. Without pre-administering rapamycin, significantly enhanced phosphorylation of mTOR and expression of proinflammatory cytokines [i.e., tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and interleukin (IL)-1beta] were observed in the CaCl2 treated aortic segments 2 days post-treatment compared with the NaCl-treated segments. At 2 weeks post-treatment, hematoxylin and eosin and Verhoeff-Van Gieson staining revealed aneurysmal alteration and disappearance of normal wavy elastic structures in the aortic segments exposed to CaCl2. In contrast, the CaCl2-induced TAA formation was inhibited by pre-administering rapamycin to CaCl2 treated rats, which demonstrated attenuated mTOR phosphorylation and downregulation of the proinflammatory mediators (i.e., TNF-alpha, IL-6, IL-1beta, matrix metallopeptidases 2 and 9) to the control level. Further in vitro cell culture experiments using aortic smooth muscle cell (SMC) suggested that the inhibition of the mTOR signaling pathway by rapamycin could promote the differentiation of SMCs, as reflected by the reduced expression of S100A4 and osteopontin. The present study indicated that the early enhanced mTOR signaling pathway in the TAA development and mTOR inhibitor rapamycin may inhibit CaCl2 induced TAA formation. PMID- 28656225 TI - Gossypol induces cell death by activating apoptosis and autophagy in HT-29 cells. AB - Gossypol is a polyphenolic, yellowish compound derived from cottonseed extract. The present study examined the effects of gossypol on the apoptosis and autophagy of HT-29 cells. A Cell Counting Kit-8 assay, Annexin V-FITC, JC-1 staining and western blotting were used to identify the viability of cells, stages of apoptosis and the expression levels of the signaling proteins. Gossypol promoted apoptosis and induced the loss of mitochondrial membrane potential. Further investigation of the apoptotic mechanism revealed that gossypol increased the ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 protein levels and upregulated the expression of caspase-3. Gossypol also enhanced the activity of microtubule-associated protein light chain 3 LC3-II and Beclin-1 and downregulated LC3-I, in a dose-dependent manner. Together, these finding suggested that gossypol may be a novel and potential antitumor agent. PMID- 28656227 TI - Associations of common IL-4 gene polymorphisms with cancer risk: A meta-analysis. AB - Cancer incidence is dramatically increasing worldwide, therefore improved prediction and therapeutic methods are needed. Single nucleotide polymorphisms in cytokine genes may contribute to carcinogenesis. Interleukin (IL)-4 gene polymorphisms have been intensively studied with regard to their associations with cancer. However, the results of these previous studies remain inconclusive. The present study, therefore, aimed to conduct a meta-analysis of previously published studies in order to clarify the association of IL-4 with cancer risk. Eligible published articles were searched in Medline, PubMed, Embase and China National Knowledge Infrastructure databases up to March 2016. Odds ratios and 95% confidence intervals were used to identify potential associations between IL-4 genetic polymorphisms and the risk of cancer. A meta-analysis was then performed on 10,873 patients and 14,328 controls for IL-4 rs2243250 polymorphism, 3,970 patients and 5,686 controls for IL-4 rs2070874 polymorphism, and 1,896 patients and 2,526 controls for IL-4 rs79071878 polymorphism. A significant association with cancer risk was observed for rs2243250 and rs79071878 polymorphisms. In the subgroup analysis by cancer type, rs2243250 polymorphism was demonstrated to be associated with an increased risk of gastric cancer and breast cancer, rs2070874 polymorphism was correlated with leukemia and oral carcinoma, and rs79071878 polymorphism was relevant to bladder carcinoma risk. In the subgroup analysis by ethnicity, IL-4 rs2243250 polymorphism was demonstrated to be associated with cancer risk in both Caucasian and Asian populations, rs2070874 was associated with cancer risk in Asian populations, while rs79071878 polymorphism was associated with cancer risk in Caucasian populations. In conclusion, the present results suggested that the IL-4 rs2243250 and rs79071878 polymorphisms were associated with cancer susceptibility. Further subgroup analyses revealed that the effects of IL-4 gene polymorphisms on cancer risk may vary by cancer type and by ethnicity. PMID- 28656226 TI - The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). AB - Protein phosphorylation is an impo-rtant cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation events, by means of kinases and phosph-atases. In particular, the protein kinases are responsible for cellular transduction signaling and their hyperactivity, malfunction or overexpression can be found in several diseases, mostly tumors. Therefore, it is evident that the use of kinase inhibitors can be valuable for the treatment of cancer. In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and pathological conditions. We also discuss the possibility of using kinase inhibitors in the treatment of tumors. PMID- 28656228 TI - Glioma cells enhance angiogenesis and inhibit endothelial cell apoptosis through the release of exosomes that contain long non-coding RNA CCAT2. AB - Angiogenesis is a key event in the progression of gliomas. Exosomes, as signaling extracellular organelles, modulate the tumor microenvironment and promote angiogenesis and tumor progression. We previously demonstrated that long intergenic non-coding RNA CCAT2 (linc-CCAT2) was overexpressed in glioma tissues and functioned to promote glioma progression. Therefore, this study aimed to explore an underlying mechanism of glioma cell-affected angiogenesis. First, qRT PCR was used to determine the expression level of linc-CCAT2 in 4 glioma cell lines and 293T cells, and the results revealed that the U87-MG cells exhibited the highest expression level. Subsequently, the pro-angiogenesis function of exosomes that were derived from negative control shRNA-treated U87-MG cells (ncU87-Exo) and linc-CCAT2 shRNA-treated U87-MG cells (shU87-Exo) was evaluated in vitro and in vivo. We found that ncU87-Exo, which was enriched in linc-CCAT2, could be taken up by HUVECs. ncU87-Exo improved the linc-CCAT2 expression level in HUVECs and more strongly promoted HUVEC migration, proliferation, tubular-like structure formation in vitro and arteriole formation in vivo as well as inhibited HUVEC apoptosis induced by hypoxia. Further mechanistic studies revealed that ncU87-Exo could upregulate VEGFA and TGFbeta expression in HUVECs as well as promote Bcl-2 expression and inhibit Bax and caspase-3 expression. Finally, gain /loss-of-function studies revealed that the overexpression of linc-CCAT2 in HUVECs activated VEGFA and TGFbeta, promoted angiogenesis, promoted Bcl-2 expression and inhibited Bax and caspase-3 expression, thus decreasing apoptosis. Downregulation of linc-CCAT2 revealed the opposite effect. Thus, our results revealed a new exosome-mediated mechanism by which glioma cells could promote angiogenesis through the transfer of linc-CCAT2 by exosomes to endothelial cells. Moreover, we suggest that exosomes and linc-CCAT2 are putative therapeutic targets in glioma. PMID- 28656229 TI - Co-expression of podoplanin and fibroblast growth factor 1 predicts poor prognosis in patients with lung squamous cell carcinoma. AB - Podoplanin and fibroblast growth factor (FGF) 1 have been detected more frequently in lung squamous cell carcinoma (SQCC) compared with lung adenocarcinoma. Furthermore, it has been previous demonstrated that FGF1 is located on the edge of tumor nests in certain lung SQCC sections, which resembles the characteristic expression pattern of podoplanin. Podoplanin and FGF1 have roles in lymphangiogenesis and angiogenesis. Based on their consistently specific expression in lung SQCC and similar localization patterns, the present study aimed to investigate whether the expression of podoplanin in tumor cells is correlated with FGF1 expression in lung SQCC and whether their co-expression has clinicopathological significance, particularly for lymphangiogenesis/angiogenesis. The correlation between podoplanin and FGF1 expression in tumor cells of 82 lung SQCC cases was investigated by immunohistochemical staining and the association between the co-expression of podoplanin and FGF1, and clinicopathological factors such as microvessel density (MVD), was examined in these samples. In addition, the prognostic value of co expression of podoplanin and FGF1 in tumor cells was determined, and the regulation of FGF1 expression and angiogenesis by podoplanin was examined in vitro in a human lung SQCC cell line. Immunohistochemical analysis demonstrated that there was a significant correlation between podoplanin and FGF1 expression in lung SQCC tumor cells (R=0.591; P<0.0001). Co-expression of podoplanin and FGF1 was significantly associated with larger primary tumor size, advanced TNM stage and higher intratumoral MVD. Survival analysis demonstrated that cases with podoplanin and FGF1 double-positive staining had a significantly lower survival rate compared with cases with double-negative staining. In vitro experiments revealed that podoplanin regulated FGF1 expression and affected tube formation of human umbilical vein endothelial cells. Combined, the results demonstrated that podoplanin was co-expressed with FGF1 in lung SQCC and this co-expression was correlated with poor prognosis. PMID- 28656230 TI - Vasohibin-1 inhibits angiogenesis and suppresses tumor growth in renal cell carcinoma. AB - Vasohibin-1 (VASH1) has recently been isolated as a novel inhibitor of angiogenesis. Several studies have demonstrated that VASH1 plays important roles in tumor angiogenesis but the role of this angiogenic inhibitor in renal cell carcinoma (RCC) has not been elucidated. We previously reported that VASH1 expression is reduced and is associated with clinicopathological features in RCC. In the present study, we investigated the biological effects of VASH1 in RCC by evaluating the effects of VASH1 on cell proliferation, cell cycle distribution, cell apoptosis and cell invasion in human umbilical vein endothelial cells (HUVECs) and 786-0 cells, and evaluating the effect of VASH1 on the growth of 786 0 cells in nude mice. A pReceiver-M61-VASH1 was transfected into HUVECs and 786-0 cells, and the expression level of VASH1 protein was examined by western blotting. Cell proliferation was detected by MTT assay, and cell cycle and apoptosis of HUVECs and 786-0 cells were analyzed by flow cytometry. The invasive ability of 786-0 cells was tested by Transwell assay. Finally, nude mouse models were established to evaluate the therapeutic effect of VASH1. The pReceiver-M61 VASH1 effectively induced the expression of VASH1 in HUVECs and 786-0 cells. VASH1 overexpression effectively inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase and promoted cell apoptosis of HUVECs and 786-0 cells. VASH1 overexpression effectively inhibited the subcutaneous growth of 786-0 tumors in vivo. Therefore, VASH1 is a potential molecular-targeted therapy for patients with RCC. PMID- 28656231 TI - Cytogenic and molecular studies of male infertility in cases of Y chromosome balanced reciprocal translocation. AB - Y-autosomal translocation has been previously reported in association with male infertility; however, the mechanisms of Y-autosomal translocation and non obstructive azoospermia or severe oligospermia remain unclear. G-banding and fluorescence in situ hybridization (FISH) were performed to analyze the translocation of chromosomes, and a single nucleotide polymorphism (SNP) genotyping assay was used to test mutations. The present study describes three new cases with a de novo balanced translocation t(Y;13), t(Y;9) and t(Y;6). To further explore the genotype-phenotype correlation, G-banding and FISH were performed and indicated the presence of a derivative chromosome. The SNP genotyping assay using a microarray revealed no abnormality, especially in the Y chromosome. Molecular deletion analysis demonstrated that no microdeletion was detected in the azoospermia factor region of the Y chromosome in the examined, infertile men. Based on these observations, the authors proposed the hypothesis that a position effect involving unknown spermatogenesis regulatory gene(s) serves a key role in male infertility. PMID- 28656232 TI - Transcription factor 7 like 2 promotes oligodendrocyte differentiation and remyelination. AB - Transcription factor 7 like 2 (TCF7L2, also termed TCF4), is a Wnt effector induced transiently in the oligodendroglial lineage. The current well accepted hypothesis is that TCF7L2 inhibits oligodendrocyte differentiation and remyelination through canonical Wnt/beta-catenin signaling. However, recent studies indicated that TCF7L2 activity is required during oligodendrocyte differentiation and remyelination. In order to clarify this, in situ hybridization, immunofluorescence and western blot analysis using in vivo TCF7L2 conditional knockout mice, were performed and it was found that TCF7L2 promotes oligodendrocyte differentiation during myelin formation and remyelination. Furthermore, it was established that TCF7L2 does not affect oligodendrocyte precursor cells during remyelination. These data are of important clinical significance to develop novel therapeutic targets to overcome multiple sclerosis and other demyelinating diseases. PMID- 28656233 TI - Resveratrol inhibits hypoxia-induced proliferation and migration of pulmonary artery vascular smooth muscle cells by inhibiting the phosphoinositide 3 kinase/protein kinase B signaling pathway. AB - Hypoxia is a risk factor for severe chronic obstructive pulmonary disease, which aggravates the disease and may cause mortality by inducing hypoxic pulmonary hypertension (HPH). Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) may mediate this effect. Resveratrol is a phenolic compound extracted from a plant and has been reported to alleviate HPH, although the underlying mechanisms remained to be elucidated. In cancer, resveratrol has been reported to abrogate the phosphoinositide 3-kinase/protein kinase B (AKT) signaling pathway, thereby inhibiting tumor development. Therefore, the present study aimed to investigate the role of resveratrol in preventing PASMCs from proliferating and migrating. Resveratrol was demonstrated to be inhibitory in a dose-dependent manner on hypoxia-induced cell proliferation and migration, and protein expression levels of phosphorylated AKT and AKT. Additionally, resveratrol was identified to act synergistically with LY-294002, a phosphorylation inhibitor of AKT, but antagonistically with insulin-like growth factor-1, an agonist of AKT phosphorylation. This suggested that resveratrol may reduce proliferation and migration by diminishing expression and phosphorylation of AKT, thereby preventing development of HPH. PMID- 28656234 TI - Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors. AB - Glioblastoma (GBM), the most frequent and aggressive malignant primary brain tumor, is characterized by a highly invasive growth. In our previous study we showed that overexpression of Carboxypeptidase E (CPE) mitigated glioma cell migration. In the present study we aimed at deciphering the regulatory mechanisms of the secreted form of CPE (sCPE). By transcriptome analysis and inhibition of signaling pathways involved in the regulation of cell growth and motility, we discovered that overexpression of sCPE was accompanied by differential regulation of mRNAs connected to the motility-associated networks, among others FAK, PAK, Cdc42, integrin, STAT3 as well as TGF-beta. Especially SLUG was downregulated in sCPE-overexpressing glioma cells, paralleled by reduced expression of matrix metalloproteinases (MMP) and, in consequence, by decreased cell migration. Expression of SLUG was regulated by ERK since inhibition of ERK reverted sCPE mediated SLUG downregulation and enhanced cell motility. In a mouse glioma model, overexpression of sCPE significantly prolonged survival. Our results implicate a novel role for sCPE that mainly affects the expression of motility-associated genes via several signal pathways. PMID- 28656235 TI - MicroRNA-661 promotes non-small cell lung cancer progression by directly targeting RUNX3. AB - Lung cancer is the primary cause of cancer-associated mortality in men and women worldwide. Increasing evidence indicates that abnormal microRNA (miRNA) expression contributes to the carcinogenesis and progression of multiple human cancers, including non-small cell lung cancer (NSCLC). Therefore, miRNAs exhibit the potential to act as biomarkers for the diagnosis, treatment and prognosis of human malignancies. miRNA-661 (miR-661) has previously been demonstrated to be important in the development of various human cancer types. However, the expression levels, functions and underlying mechanisms of miR-661 in NSCLC remain to be elucidated. The present study demonstrated that miR-661 was upregulated in NSCLC tissues and cell lines. In addition, miR-661 expression levels were significantly correlated with differentiation and tumor stage lymph node metastasis of NSCLC patients. Functional experiments demonstrated that miR-661 downregulation inhibited NSCLC cell proliferation and invasion in vitro. Furthermore, runt-related transcription factor 3 (RUNX3) was identified as a direct target of miR-661 in NSCLC. RUNX3 was expressed at a low level in NSCLC tissues and was negatively correlated with the miR-661 expression level. Further experiments revealed that RUNX3 knockdown significantly rescued the effects of miR-661 underexpression on NSCLC cell proliferation and invasion. In conclusion, the present findings indicated a role for miR-661 as an oncogene in NSCLC via direct targeting of RUNX3, thus suggesting that miR-661 may be used to develop novel therapies for NSCLC patients. PMID- 28656236 TI - Homeobox B9 facilitates hypertrophic scar formation via activating the mitogen activated protein kinase signaling pathway. AB - The functions and underlying mechanisms of homeobox B9 (HOXB9) in scar formation remain unclear; therefore, the present study aimed to investigate whether HOXB9 is highly expressed in hypertrophic scar formation. Immunohistochemistry was performed to examine the expression levels of laminin, fibronectin (FN), collagen type I (Col1) and HOXB9 in hypertrophic scar and healthy skin tissues, and in lentivirus-constructed HOXB9-overexpressed or -silenced fibroblasts (FBs). Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to evaluate the mRNA and protein expression levels of HOXB9, laminin, FN, Col1, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, p-c-Jun N-terminal kinase (JNK), p-ERK and p-p38. A gel contraction assay was used to evaluate the effect of HOXB9 on FB contraction. Co immunoprecipitation assays were performed to verify the reciprocal interactions between HOXB9 and ERK, JNK and p38. It was demonstrated that HOXB9, laminin, FN and Col1 were upregulated in hypertrophic scar tissues, and HOXB9 upregulated laminin, FN, Col1, p-ERK, p-JNK and p38, potentially by interacting directly with p38. Furthermore, FBs overexpressing HOXB9 exhibited enhanced contractile capacity. In conclusion, the present study demonstrated that HOXB9 may facilitate hypertrophic scar formation via activating the mitogen-activated protein kinase signaling pathway. PMID- 28656237 TI - Matrine increases the inhibitory effects of afatinib on H1975 cells via the IL 6/JAK1/STAT3 signaling pathway. AB - Resistance to epidermal growth factor receptor (EGFR) inhibitors is of primary concern in the treatment of non-small-cell lung cancer (NSCLC) with EGFR mutations. To investigate the effects of matrine on H1975 cells and to examine a novel, potential treatment option for NSCLC, the present study measured cell viability, apoptotic rate, interleukin 6 (IL-6) expression and activation of the janus kinase (JAK) 1/signal transducer and activator of transcription (STAT)3 signaling pathway in cells treated with or without matrine, in the presence or absence of afatinib. The results demonstrated that matrine treatment inhibited cell growth, decreased B-cell lymphoma 2 (Bcl-2) expression and induced apoptosis. Matrine treatment additionally decreased the mRNA and protein levels of IL-6 and inhibited activation of the JAK1/STAT3 signaling pathway in H1975 cells in a dose-dependent manner. H1975 cells treated with IL-6 small interfering RNA exhibited a decrease in Bcl-2 expression levels and cell viability. Treatment with a combination of matrine and afatinib demonstrated increased inhibitory effects on the growth rate of H1975 cells. The findings of the present study suggested that matrine treatment decreases IL-6 expression, inhibits activation of the JAK1/STAT3 signaling pathway, reduces the expression levels of Bcl-2 and inhibits cell growth. Furthermore, matrine treatment was demonstrated to increase the inhibitory effects of afatinib on H1975 cells with the T790M EGFR mutation. PMID- 28656238 TI - Protective effect of lutein on ARPE-19 cells upon H2O2-induced G2/M arrest. AB - Oxidative damage is a key factor for the pathogenesis of age-related macular degeneration (AMD), therefore, anti-oxidative stress is a valuable method for the prevention or treatment of AMD. The aim of the present study was to reveal the protective mechanism of lutein on retinal pigment epithelium (RPE) cells subjected to oxidative stress. Acute retinal pigment epithelial 19 (ARPE-19) cells were exposed to oxidative stress induced by H2O2 following lutein pretreatment. The activities of caspases, level of intracellular reactive oxygen species (ROS) and cell cycle were analyzed using flow cytometry. The expression levels of cell cycle regulatory proteins and inflammation-associated genes were detected using western blot and reverse transcription-polymerase chain reaction analyses, respectively. The data showed that oxidative stress reduced cell viability, and increased total apoptosis and ROS generation, however, lutein prevented cells from oxidative stress-induced damage. In addition, oxidative damage triggered G2/M phase arrest of the ARPE-19 cells, which was reversed by lutein in a concentration-dependent manner, through the activation of cyclin dependent kinase 1 and cell division cycle 25C, and degradation of cyclin B1. These results demonstrated that lutein may be an effective antioxidant, which can be applied in the prevention of AMD, or other age-related diseases associated with oxidative damage. PMID- 28656239 TI - Erythropoietin ameliorates PA-induced insulin resistance through the IRS/AKT/FOXO1 and GSK-3beta signaling pathway, and inhibits the inflammatory response in HepG2 cells. AB - Erythropoietin (EPO) contributes to insulin resistance in fat and muscle. In the present study, the role and mechanism of EPO in hepatic insulin resistance were investigated in HepG2 cells. Hepatic insulin resistance was induced by palmitic acid (PA) in the HepG2 cells, which were then treated with EPO (5 or 10 U/ml) or specific phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin or LY294002. EPO treatment significantly increased glycogen levels and reduced the protein expression of phosphoenolpyruvate carboxykinase in the PA-induced HepG2 cells. EPO also inhibited the serine phosphorylation of insulin receptor substrate (IRS) 1 (Ser307) and IRS-2 (Ser473), and increased the protein expression levels of PI3K, phosphorylated (p)-protein kinase B (AKT), p-forkhead box O1 (FOXO1) and p glycogen synthase kinase 3 (GSK-3) beta. In agreement with these result, the expression of p-FOXO1 (Ser256) and p-GSK-3beta (Ser9), downstream molecules of AKT, were enhanced by EPO treatment (P<0.05). The specific PI3K inhibitors, LY294002 and wortmannin, markedly inhibited the EPO-mediated increases in p-AKT (Ser473), p-FOXO1 (Ser256) and p-GSK-3beta (Ser9) in the PA-induced HepG2 cells (P<0.05). The gene expression levels of tumor necrosis factor-alpha, interleukin 1beta and monocyte chemoattractant protein-1, and the p-c-Jun N-terminal kinase (JNK)/total-JNK ratio were markedly suppressed by EPO treatment. These findings suggested that EPO treatment improved hepatic glucose metabolism, potentially through the IRS/AKT/FOXO1 and GSK-3beta signaling pathway, which may be associated with its inhibitory effect on the inflammation-associated response. PMID- 28656240 TI - Microarray analysis reveals differentially expressed lncRNAs in benign epithelial ovarian cysts and normal ovaries. AB - Recent studies suggest that long non-coding RNAs (lncRNAs) play crucial roles in many types of human malignant cancers. However, the function of lncRNAs in benign tumors remains poorly understood. In the present study, to explored the potential roles of lncRNAs in benign epithelial ovarian cysts (BEOCs) which commonly occur in young women and possess malignant potential, we described the expression profile of the lncRNAs between BEOC and normal ovarian tissues using lncRNA microarray techniques. The results showed that 1,325 transcripts of lncRNAs (1,014 upregulated and 311 downregulated) were differentially expressed in the BEOCs compared with the normal controls [absolute fold-change >=2, false discovery rate (FDR) <0.05]. We also conducted quantitative real-time PCR (qPCR) to confirm the microarray data. The results of qPCR revealed that the expression trend of 6 randomly selected lncRNAs was consistent with the microarray data. Furthermore, candidate lncRNAs were characterized by pathway analysis and Gene Ontology (GO). The present study is the first to demonstrate different expression profiles of lncRNAs between BEOCs and normal ovarian tissues. These lncRNAs may play a crucial role in the pathological process of BEOCs. PMID- 28656241 TI - Hydrogen sulfide protects against the development of experimental cerebral malaria in a C57BL/6 mouse model. AB - Hydrogen sulfide (H2S) has anti-inflammatory and neuroprotective properties, particularly during pathological processes. Experimental cerebral malaria (ECM), which is caused by vascular leakage into the brain, is characterized by inflammation, neurological deficits and cerebral hemorrhage. The present study investigated the correlation between ECM genesis and the levels of H2S. The results indicated that the levels of H2S derived from the brain decreased over time following ECM infection, and that the low H2S bioavailability was partially caused by decreased expression of the H2S generating enzyme, cystathionine-beta synthase. Administration of NaHS (an exogenous donor of H2S) provided protection against ECM. NaHS inhibited the destruction of the blood brain barrier and the secretion of proinflammatory biomarkers, including interluekin-18, matrix metalloproteinase-9 and serum cluster of differentiation 40 into the brain during ECM. In conclusion, these results suggested that low levels of H2S in brain contributed to the progression of ECM, and that H2S donor administration may represent a potential protective therapy against ECM. PMID- 28656242 TI - MicroRNA-21 promotes neurite outgrowth by regulating PDCD4 in a rat model of spinal cord injury. AB - Altered expression levels of microRNA-21 (miRNA-21) have been observed in a series of pathological processes, including cancer and central nervous system injury; however, the involvement of miRNA-21 in the molecular pathophysiology of spinal cord injury (SCI) has not been well documented. The present study examined the expression levels of miRNA-21 and its predicted target genes, programmed cell death 4 (PDCD4) and phosphatase and tensin homolog (PTEN), in rats using quantitative polymerase chain reaction and western blotting to further understand the role of miRNA-21 and the mechanisms underlying repair following SCI. The present study demonstrated that compared with uninjured spinal cords, miRNA-21 expression levels were significantly downregulated in injured spinal cords 4 and 8 h, and 1 day post-SCI, and were significantly upregulated after 3 and 7 days. Conversely, expression levels of PDCD4 and PTEN were significantly decreased at days 3 and 7 post-SCI compared with the control group. miRNA-21 overexpression in monolayer-cultured postnatal rat spinal cord neurons promoted neurite outgrowth and downregulated protein expression levels of PDCD4; however, PTEN protein expression levels were unaltered. To confirm that miRNA-21 directly targets PDCD4, a pRL-CMV luciferase reporter construct was used to detect miRNA-21 interactions with the PDCD4 3'-untranslated region. The results demonstrated that miRNA-21 decreased luciferase activity compared with a rat PDCD4 control reporter. The results of the present study suggested that increased miRNA-21 expression levels following SCI may promote the repair of injured spinal cords by inhibiting the expression of its target gene PDCD4. PMID- 28656243 TI - Increased PTPRA expression leads to poor prognosis through c-Src activation and G1 phase progression in squamous cell lung cancer. AB - PTPRA is reported to be involved in cancer development and progression through activating the Src family kinase (SFK) signaling pathways, however, the roles of PTPRA in the squamous cell lung cancer (SCC) development are unclear. The purpose of this study was to clarify the clinical relevance and biological roles of PTPRA in SCC. We found that PTPRA was upregulated in squamous cell lung cancer compared to matched normal tissues at the mRNA (N=20, P=0.004) and protein expression levels (N=75, P<0.001). Notably, high mRNA level of PTPRA was significantly correlated with poorer prognosis in 675 SCC patients from the Kaplan-Meier plotter database. With 75 cases, we found that PTPRA protein expression was significantly correlated with tumor size (P=0.002), lymph node metastasis (P=0.008), depth of tumor invasion (P<0.001) and clinical stage (P<0.001). The Kaplan-Meier plot suggested that high expression of PTPRA had poorer overall survival in SCC patients (P=0.009). Multivariate Cox regression analysis suggested that PTPRA expression was an independent prognostic factor in SCC patients. In the cellular models, PTPRA promotes SCC cell proliferation through modulating Src activation as well as cell cycle progression. In conclusion, higher PTPRA level was associated with worse prognosis of SCC patients and PTPRA could promote the cell cycle progression through stimulating the c-Src signaling pathways. PMID- 28656244 TI - A genome-wide analysis of the gene expression profiles and alternative splicing events during the hypoxia-regulated osteogenic differentiation of human cartilage endplate-derived stem cells. AB - It has been hypothesized that intervertebral disc degeneration is initiated by degeneration of the cartilage endplate (CEP), which is characterized by cartilage ossification. CEP-derived stem cells (CESCs), with the potential for chondro osteogenic differentiation, may be responsible for the balance between chondrification and ossification in the CEP. The CEP remains in an avascular and hypoxic microenvironment; the present study observed that hypoxia was able to markedly inhibit the osteogenic differentiation of CESCs. This tissue-specific CESC differentiation in response to a hypoxic microenvironment was physiologically important for the prevention of ossification in the CEP. In order to study the hypoxia-regulated mechanisms underlying osteogenic differentiation of CESCs, a Human Transcriptome Array 2.0 was used to detect differentially expressed genes (DEGs) and alternatively spliced genes (ASGs) during the osteogenic differentiation of CESCs under hypoxia, compared with those induced under normoxia. High-throughput analysis of DEGs and ASGs demonstrated that genes in the complement pathway were enriched, which may be a potential mechanism underlying hypoxia inhibition of CESCs osteogenesis. The results of the present study may provide a basis for future mechanistic studies regarding gene expression levels and alternative splicing events during the hypoxia-regulated inhibition of osteogenesis, which may be helpful in identifying targets for CEP degeneration therapy. PMID- 28656245 TI - Synergistic cytotoxic effects of arsenite and tetrandrine in human breast cancer cell line MCF-7. AB - To provide novel insight into the development of new therapeutic strategies to combat breast cancer using trivalent arsenic (AsIII)-based combination therapy, the cytotoxicity of a combination of AsIII and tetrandrine (Tetra), a Chinese plant-derived alkaloid, was investigated in the human breast cancer cell line MCF 7. Cytotoxicity was evaluated using cell viability, colony formation, wound healing, lactate dehydrogenase leakage and cell cycle assay. Alterations of genes associated with cell proliferation and death were analyzed using real-time PCR and western blotting. Intracellular arsenic accumulation (As[i]) was also determined. Tetra significantly enhanced the cytotoxicity of AsIII in MCF-7 cells in a synergistic manner. The combined treatment upregulated the expression level of FOXO3a, and subsequently resulted in a concomitant increase in the expression levels of p21, p27, and decrease of cycline D1, which occurred in parallel with G0/G1 phase arrest. Autophagy induction was also observed in the combination treatment. Importantly, combining AsIII with Tetra exhibited a synergistic inhibitory effect on the expression level of survivin. Furthermore, enhanced As[i] along with synergistic cytotoxicity was observed in MCF-7 cells treated with AsIII combined with Tetra or Ko134, an inhibitor of breast cancer resistance protein (BCRP), suggesting that Tetra or the BCRP inhibitor probably intervened in the occurrence of resistance to arsenic therapy by enhancing the As[i] via modulation of multidrug efflux transporters. These results may provide a rational molecular basis for the combination regimen of AsIII plus Tetra, facilitating the development of AsIII-based anticancer strategies and combination therapies for patients with solid tumors, especially breast cancer. PMID- 28656246 TI - Expression, purification and epitope analysis of Pla a 3 allergen from Platanus acerifolia pollen. AB - Platanus acerifolia (P. acerifolia) is an important cause of pollinosis in cities. The use of allergen extracts on patients with allergic diseases is the most commonly applied method to attempt to treat pollinosis. Pla a 3, a non specific lipid transfer protein, is a major allergen present in P. acerifolia pollen extracts. In the present study, the Pla a 3 gene was sub-cloned into a pSUMO-Mut vector using Stu I and Xho I sites and transformed into the Arctic ExpressTM (DE3) RP E. coli host strain. The purified Pla a 3 allergen was analyzed by western blotting and the results revealed that the Pla a 3 allergen has the ability to bind IgE in the P. acerifolia pollen of allergic patients' sera. Moreover, the authors predicted the potential B cell epitopes of the Pla a 3 allergen using the DNAStar Protean system, the Bioinformatics Predicted Antigenic Peptides system and the BepiPred 1.0 server. In addition, the T cell epitopes were predicted by the SYFPEITHI database and the NetMHCII-2.2 server. As a result, two B cell epitopes (35-45 and 81-86) and four potential T cell epitopes including 2-15, 45-50, 55-61 and 67-73 were predicted in the present study. The current results can be used to contribute to allergen immunotherapies and useful in peptide-based vaccine designs of pollen allergy. PMID- 28656248 TI - Nestin-positive microvessel density is an independent prognostic factor in breast cancer. AB - The process of angiogenesis based on new vessel formation within the tumour area plays a significant role in the progression of breast cancer. Nestin is an intermediate filament protein and participates in the cytoskeleton organization. Nestin expression in the endothelium of blood vessels is mainly limited to newly forming vessels, thus being a more specific marker of angiogenesis than the commonly used vascular antigens. The aim of this study was to determine the prognostic value of nestin-positive microvessel density (Nes+MVD) in breast cancer patients and to confirm that nestin expression is related to newly forming tumour vessels. In this study, 137 cases of ductal breast carcinoma and 19 cases of non-malignant breast tissue lesions (NBTLs) were examined. Immunohistochemical reactions were performed on paraffin sections using antibodies against nestin, CD34 and CD31 antigens. For each marker, the microvessel density (MVD) was determined. Nestin expression was also examined in human endothelial cell lines (HUVEC-SVT, HMEC-1 and HEPC-CB.1) representing a different level of endothelial cell maturity. HUVEC-SVT and HMEC-1 cells represent the endothelium of mature vessels, whereas HEPC-CB.1 cells represent the early endothelial progenitor cells (EPCs). We have demonstrated that high Nes+MVD may be associated with a more aggressive course of the disease and a poorer prognosis. We have also found a higher Nes+MVD in the cases with lymph node metastases, with higher histological grade, with advanced-stage disease and with the triple-negative (TN) breast cancer. In addition, nestin expression in vessels was associated with a shorter overall survival (OS) and earlier relapse, and in the case of OS nestin was an independent prognostic factor. Finally, we further confirmed that nestin expression in endothelial cells reflects a progenitor nature of newly forming vessels. PMID- 28656247 TI - Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4. AB - Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-beta (TGF-beta) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-beta. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis. PMID- 28656249 TI - Oxidative stress regulates mitogen-activated protein kinases and c-Jun activation involved in heat stress and lipopolysaccharide-induced intestinal epithelial cell apoptosis. AB - Heat stress and gut-derived endotoxinemia are common causes of multiple organ dysfunction syndrome in heat stroke patients. Evidence has demonstrated that cell apoptosis in the small intestine serves an important role in the pathogenesis of heatstroke, which leads to increased intestinal permeability to endotoxin or lipopolysaccharides (LPS) from the gut entering the circulation. However, little is known about the potential underlying mechanisms mediating heat stress combined with LPS-induced intestinal epithelial cell apoptosis. In the present study, LPS combined with heat stress induced production of reactive oxygen species (ROS), mitochondrial membrane potential disruption and cell apoptosis, which eventually led to increased intestinal permeability and reduced epithelial resistance in the IEC-6 cell line. Inductions in ROS, mitochondrial membrane potential disruption and cell apoptosis were detected by using an ROS assay kit, 5,5',6,6'-tetrachloro 1,1',3,3'tetraethylbenzimidazo carbocyanine iodide dye kit and annexin V fluorescein isothiocyanate apoptosis kit, respectively. The effect of ROS on mitogen activated protein kinases (MAPKs) and c-Jun activation was investigated using the antioxidant drug, butylated hydroxyanisole (BHA) by western blotting. The results of the present study demonstrated that ROS is essential to activate p38, extracellular signal-regulated kinase (ERK) and c-Jun, but not c-Jun N terminal kinase (JNK), in LPS combined with heat stress treated cells. Furthermore, ROS, and activation of p38, JNK and c-Jun, were revealed to serve pro-apoptosis roles which aggravated damage to epithelial barrier integrity, as assessed by flow cytometry using Annexin V-fluorescein isothiocyanate staining and pretreatment of cells with specific inhibitors of ROS, JNK, p38 and c-Jun (BHA, SP600125, SB203580 and c-Jun peptide, respectively). Transepithelial electrical resistance and horseradish peroxidase permeability were detected in cells treated with LPS combined with heat stress, which revealed that ERK serves an anti-apoptosis role, as determined by pretreatment of cells with PD98059, a specific inhibitor of ERK. In conclusion, these findings suggested a novel role of the ROS signaling pathway which involved activation of MAPKs and c-Jun, following LPS combined with heat stress-induced IEC-6 cell apoptosis and impairment of the epithelial barrier. These results may facilitate understanding of pathological conditions involving ROS, such as heat stroke. PMID- 28656250 TI - MicroRNA-605 functions as a tumor suppressor by targeting INPP4B in melanoma. AB - MicroRNAs (miRNAs) play crucial roles in the initiation and progression of various cancers, including melanoma. Recently, the genetic variants and deregulation of miR-605 have been reported to participate in carcinogenesis. However, the expression status of the miR-605 in melanoma tissues and its role in melanoma progression remain unknown. In this study, we found that miR-605 was significantly downregulated in melanoma cell lines and clinical specimens. Further function studies demonstrated that miR-605 suppressed melanoma cell growth both in vitro and in vivo. Moreover, INPP4B gene was identified as a target of miR-605 through bioinformatics analysis and luciferase reporter assays. Further analysis demonstrated that the inhibition of INPP4B mediated SGK3 activation was required for the suppressive role of miR-605 on melanomas cell growth. Collectively, our data suggest that miR-605 functions as a tumor suppressor by negatively regulating INPP4B mediated SGK3 activation in melanoma and may present a potential target for therapeutic intervention. PMID- 28656251 TI - Identification of a gene expression profile associated with the regulation of angiogenesis in endometrial cancer. AB - The publication of the human genome sequence provided direction in the search for novel diagnostic and therapeutic methods for the treatment of human diseases. The aim of the present study was to investigate the hypothesis that the expression profile of genes involved in the regulation of angiogenesis may be a marker in endometrial cancer that facilitates the diagnosis and prognosis of patients, as well as the identification of novel therapeutic targets. The current study included 36 patients with grade (G) 1 to 3 endometrial cancer, and a control group of patients consisting of females that qualified for the removal of the uterus. Out of these, 28 samples (control, 3; G1, 7; G2, 12; and G3, 6) were selected for microarray analysis. Molecular analysis of the endometrial samples involved the extraction of total RNA, purification of the obtained extracts and subsequent analysis of the gene expression profiles using an oligonucleotide microarray technique (GeneChip(r) Human Genome U133A plates). The results indicated that the mRNA expression profile of genes involved in the regulation of angiogenesis varies depending on the degree of histological differentiation of endometrial adenocarcinoma. Similar results were obtained from descriptive statistics characterizing the expression profile of 691 mRNAs associated with the regulation of angiogenesis in the groups of patients with endometrial adenocarcinoma. In addition, the results of the present study indicated that neuropilin2 (NRP2) may serve an important role in the activity of endothelial cells, and may affect vascular endothelial growth factor, and potentially plexins and integrins via regulation of their functions. An understanding of how these proteins interact remains to be determined; however, elucidating these interactions may provide an explanation for the mechanisms underlying angiogenesis. In conclusion, the results of the present study suggest that NRP2 may be a valuable target for investigation in future pharmacological studies involving angiogenesis in endometrial cancer. PMID- 28656252 TI - Unconjugated bilirubin ameliorates the inflammation and digestive protease increase in TNBS-induced colitis. AB - The authors previously demonstrated that unconjugated bilirubin (UCB) may inhibit the activities of various digestive proteases, including trypsin and chymotrypsin. The digestive proteases in the lower gut are important in the pathogenesis of inflammatory bowel diseases. The effects of UCB on the inflammation and levels of digestive proteases in feces of rats with colitis have not yet been revealed. The present study investigated the effect of UCB on the inflammatory status and levels of trypsin and chymotrypsin in the feces of rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis. The data indicated that treatment with TNBS resulted in a marked reduction in weight gain, which was significantly alleviated in UCB-treated rats. Furthermore, UCB treatment alleviated the inflammation induced by TNBS, detected via macroscopic damage and microscopic inflammation scores, and pro-inflammatory markers including myeloperoxidase (MPO), tumor necrosis factor (TNF)-alpha and interleukin (IL) 1beta. Furthermore, rats with colitis demonstrated significant increases in fecal trypsin and chymotrypsin levels, whereas UCB treatment significantly alleviated these increases. A significant positive correlation was additionally revealed among the pro-inflammatory markers (MPO, TNF-alpha and IL-1beta) and fecal digestive proteases (trypsin and chymotrypsin) in colitis. The results of the present study demonstrated that UCB ameliorated the inflammation and digestive protease increase in TNBS-induced colitis. PMID- 28656253 TI - Heat shock protein 90beta in the Vero cell membrane binds Japanese encephalitis virus. AB - The pathogenesis of Japanese encephalitis virus (JEV) is complex and unclearly defined, and in particular, the effects of the JEV receptor (JEVR) on diverse susceptible cells are elusive. In contrast to previous studies investigating JEVR in rodent or mosquito cells, in this study, we used primate Vero cells instead. We noted that few novel proteins co-immunoprecipitated with JEV, and discovered that one of these was heat shock protein 90beta (HSP90beta), which was probed by mass spectrometry with the highest score of 60.3 after questing the monkey and human protein databases. The specific HSP90beta-JEV binding was confirmed by western blot analysis under non-reducing conditions, and this was significantly inhibited by an anti-human HSP90beta monoclonal antibody in a dose-dependent manner, as shown by immunofluorescence assay and flow cytometry. In addition, the results of confocal laser scanning microscopic examination demonstrated that the HSP90beta-JEV binding occurred on the Vero cell surface. Finally, JEV progeny yields determined by plaque assay were also markedly decreased in siRNA-treated Vero cells, particularly at 24 and 36 h post-infection. Thus, our data indicate that HSP90beta is a binding receptor for JEV in Vero cells. PMID- 28656254 TI - MicroRNA-150 targets Rho-associated protein kinase 1 to inhibit cell proliferation, migration and invasion in papillary thyroid carcinoma. AB - Thyroid cancer is the most prevalent malignant tumor of the endocrine organs and accounts for one third of all head and neck tumors. Dysregulation of microRNAs is well-known to contribute to the development of various cancers, including papillary thyroid carcinoma (PTC), which accounts for 80-90% of all thyroid cancer cases. The present study aimed to investigate the expression, functional roles of microRNA-150 (miR-150) and its direct target gene in PTC. miR-150 expression in PTC tissues and cell lines was analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). After transfection with miR-150 mimics, cell proliferation, migration and invasion was analyzed by MTT and Transwell assays, respectively. Bioinformatics analysis was performed to investigate the potential target genes of miR-150, which were then confirmed by luciferase reporter assay, RT-qPCR and western blotting. Functional assays were also applied to investigate the effects of endogenous Rho-associated protein kinase 1 (ROCK1) in PTC. miR-150 was demonstrated to be significantly downregulated in PTC tissues and cell lines. In addition, reduced miR-150 expression was obviously correlated with TNM stage and lymph node metastasis in PTC patients. Restoration of miR-150 expression significantly inhibited PTC cell proliferation, migration and invasion in vitro. Furthermore, ROCK1 was identified as a direct target gene of miR-150. Therefore, ROCK1 knockdown may serve tumor suppressive functions in PTC, induced by miR-150 overexpression. In conclusion, miR-150 overexpression in PTC may inhibit growth and metastasis of PTC cells. miR 150/ROCK1-based targeted therapy may be a potential strategy for the treatment of PTC. PMID- 28656255 TI - Low expression of microRNA-320b correlates with tumorigenesis and unfavorable prognosis in glioma. AB - Accumulating evidence demonstrates that dysregulated microRNAs (miRNAs) play a critical role in tumorigenesis and progression of various cancers. miR-320b, a member of miR-320 family, was revealed downregulated in numerous human cancers, including nasopharyngeal carcinoma and colorectal cancer. However, the function of miR-320b in human glioma remained poorly defined. In this study, we report that miR-320b was lowly expressed in glioma tissues and cell lines in contrast with controls, being closely correlated with histological malignancy of glioma. Furthermore, patients with low expression of miR-320b were associated with poor prognostic outcomes. In vitro functional assays indicated that overexpression of miR-320b could markedly enhance cell apoptosis rate and suppress cell proliferation, migration and invasion. miR-320b mimic impaired cell cycle and metastasis through inhibiting the expression of G1/S transition key regulator Cyclin D1 as well as decreasing the expression level of MMP2 and MMP9. Additionally, upregulation of miR-320b could markedly promote apoptosis by increasing the level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggested that miR-320b might serve as a novel prognostic marker and potential therapeutic target for glioma. PMID- 28656256 TI - HS-1793, a resveratrol analogue, downregulates the expression of hypoxia-induced HIF-1 and VEGF and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model. AB - A synthetic analogue of resveratrol, 4-(6-hydroxy-2-naphtyl)-1,3-benzenediol (HS 1793), with improved photosensitivity and stability profiles, has been recently reported to exert anticancer activity on various cancer cells. However, the molecular mechanism of action and in vivo efficacy of HS-1793 in breast cancer cells have not been fully investigated. In the present study, we evaluated the effect of HS-1793 on hypoxia-inducible factor-1alpha (HIF-1alpha), which drives angiogenesis and the growth of solid tumors, in addition to the in vivo therapeutic effects of HS-1793 on breast cancer cells. HS-1793 was found to inhibit hypoxia (1.0% oxygen)-induced HIF-1alpha expression at the protein level, and its inhibitory effect was more potent than that of resveratrol in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, HS-1793 reduced the secretion and mRNA expression of vascular endothelial growth factor (VEGF), a key mediator of HIF-1-driven angiogenesis, without affecting cell viability. To evaluate the anticancer effects of HS-1793 in vivo, triple-negative MDA-MB-231 breast cancer xenografts were established in nude mice. HS-1793 significantly suppressed the growth of breast cancer tumor xenografts, without any apparent toxicity. Additionally, decreases in Ki-67, a proliferation index marker, and CD31, a biomarker of microvessel density, were observed in the tumor tissue. Expression of HIF-1 and VEGF was also downregulated in xenograft tumors treated with HS 1793. These in vivo results reinforce the improved anticancer activity of HS-1793 when compared with that of resveratrol. Overall, the present study suggests that the synthetic resveratrol analogue HS-1793 is a potent antitumor agent that inhibits tumor growth via the regulation of HIF-1, and demonstrates significant therapeutic potential for solid cancers. PMID- 28656257 TI - World Health Organization, radiofrequency radiation and health - a hard nut to crack (Review). AB - In May 2011 the International Agency for Research on Cancer (IARC) evaluated cancer risks from radiofrequency (RF) radiation. Human epidemiological studies gave evidence of increased risk for glioma and acoustic neuroma. RF radiation was classified as Group 2B, a possible human carcinogen. Further epidemiological, animal and mechanistic studies have strengthened the association. In spite of this, in most countries little or nothing has been done to reduce exposure and educate people on health hazards from RF radiation. On the contrary ambient levels have increased. In 2014 the WHO launched a draft of a Monograph on RF fields and health for public comments. It turned out that five of the six members of the Core Group in charge of the draft are affiliated with International Commission on Non-Ionizing Radiation Protection (ICNIRP), an industry loyal NGO, and thus have a serious conflict of interest. Just as by ICNIRP, evaluation of non-thermal biological effects from RF radiation are dismissed as scientific evidence of adverse health effects in the Monograph. This has provoked many comments sent to the WHO. However, at a meeting on March 3, 2017 at the WHO Geneva office it was stated that the WHO has no intention to change the Core Group. PMID- 28656258 TI - CIP2A, an oncoprotein, is associated with cell proliferation, invasion and migration in laryngeal carcinoma cells. AB - Laryngeal carcinoma is one of the most common malignant tumors in otorhinolaryngology. Moreover, experimental investigation showed that cancerous inhibitor of protein phosphatase 2A (CIP2A) expressed highly in various cancers. Therefore, we investigated whether CIP2A can regulate the proliferation, invasion and migration by RNA interference in Hep-2 cells and AMC-NH-8 cells and further affect the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Overexpression of CIP2A was evaluated in tumor tissue and laryngeal cancer cell lines (Hep-2 and AMC-NH-8 cells) by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot assay. In a follow-up experiment, we confirmed that CIP2A siRNA effectively suppressed the cell proliferation at 48 and 72 h, and arrested cell cycle at G0/G1 in Hep-2 cells and AMC-NH-8 cells. The invasion and migration of cell in siRNA CIP2A group were markedly inhibited. Moreover, the experimental results showed that the expression levels of invasion- and migration-related genes, including E-cadherin, metastasis associated gene 1 (MTA1) and matrix metalloproteinases-2/9 (MMP-2/9), were regulated by CIP2A siRNA. Phosphorylation levels of PI3K and AKT proteins were reduced by CIP2A siRNA. Importantly, it suggested signaling through PI3K/Akt as a critical mechanism by which CIP2A siRNA may suppress cell proliferation, invasion and migration in laryngeal carcinoma cells. PMID- 28656260 TI - Oncogenic miR-23a-5p is associated with cellular function in RCC. AB - In recent years, accumulating evidence has demonstrated that microRNAs (miRs, miRNAs) may serve an important role in the occurrence and development of tumors. miR-23a-5p has been confirmed as an oncogene in numerous diseases through gene chip analysis. However, as the most common type of renal tumor, the expression and function of miR-23a-5p in renal cell carcinoma (RCC) remains unclear. In the present study, reverse transcription-quantitative polymerase chain reaction (RT qPCR) analysis, and Cell Counting Kit-8 (CCK-8), wound scratch, Transwell, MTT and flow cytometry assays were performed to investigate the role of miR-23a-5p in RCC. The expression of miR-23a-5p in RCC tissue samples was significantly higher compared with that in normal tissue samples (P<0.01). Furthermore, the expression of miR-23a-5p in RCC cell lines (786O, ACHN and Caki-1) was significantly higher compared with that in the human embryo kidney 293T cell line, as determined using RT-qPCR (P<0.001). In addition, the results revealed that the upregulation of miR 23a-5p promoted the proliferation, migration and invasion of RCC cells, and inhibited RCC cell apoptosis. The downregulation of miR-23a-5p resulted in the reversal of the results described above. Additionally, it was observed that the downregulation of miR-23a-5p significantly promoted ACHN and 786O cell viability (P<0.001). The results of the present study suggest that miR-23a-5p is an oncogene in the occurrence and development of RCC and may be a novel therapeutic target for RCC. PMID- 28656259 TI - Anti-angiogenesis target therapy for advanced osteosarcoma (Review). AB - Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present, it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma, which, in a sense, have become a milestone as a second-line therapy for osteosarcoma. Although the recognization of muramyltripepetide phosphatidyl ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival. PMID- 28656261 TI - lncRNA XIST interacts with miR-140 to modulate lung cancer growth by targeting iASPP. AB - X-inactive specific transcript (XIST), one of the first found cancer-associated long non-coding RNAs (lncRNAs), is involved in the development and progression of many types of tumors. Aberrant expression of XIST has been observed in hepatocellular carcinoma, cervical, breast, ovarian and colorectal cancer. However, the exact effects and molecular mechanisms of XIST in lung cancer progression are still unknown to date. In the present study, we investigated the role of XIST in human lung cancer cell lines and clinical tumor samples in order to determine the function of this molecule. In our research, lncRNA-XIST was specifically upregulated in lung cancer cell lines and promoted lung cancer cell growth through targeting miR-140. Knockdown of XIST inhibited the proliferation and promoted cell apoptosis of human lung cancer cells and suppressed metastasis in vitro and in vivo. In addition, miR-140-dependent inhibitor of apoptosis stimulating protein of p53 (iASPP) regulation was required in XIST-induced lung cancer cell growth. These findings indicated that XIST may regulate the tumor growth and metastasis via miR-140-dependent iASPP regulation. Taken together, our data indicated that XIST may be an oncogenic lncRNA that promotes the proliferation and metastasis of lung cancer through the regulation of miR-140 and could be regarded as a therapeutic target in human lung cancer. PMID- 28656262 TI - Suppression of midkine gene promotes the antitumoral effect of cisplatin on human gastric cancer cell line AGS in vitro and in vivo via the modulation of Notch signaling pathway. AB - Midkine (MK) is reported to be associated with the clinical stages and distant metastases in gastric cancer, and to positively regulate the proliferation of human gastric cancer cells. However, the possible mechanisms of MK in the development of gastric cancer are still not fully clarified. In this study, the therapeutic effect of MK inhibition in gastric cancer in vivo and in vitro was investigated, by knock-down of MK expression with a small interfering RNA (siRNA). MK was expressed in gastric carcinoma tissues and cancer cells. The cytotoxic effect of cisplatin on AGS cells in vitro was attenuated by recombinant human MK, but was promoted by suppressing MK expression via downregulating the Notch signaling pathway-related proteins (Notch 1, Notch 2, Delta-like 1 and Jagged 1). Suppression of MK expression also promoted the inhibitory effect of cisplatin on AGS cells in vivo. In concusion, suppression of midkine gene promoted the antitumoral effect of cisplatin on human gastric cell line AGS in vitro and in vivo via Notch signaling pathway. PMID- 28656263 TI - Rho-kinase signaling pathway promotes the expression of PARP to accelerate cardiomyocyte apoptosis in ischemia/reperfusion. AB - It has been previously reported that Rho-kinase (ROCK) and poly ADP-ribose polymerase (PARP) serve critical roles in myocardial ischemia/reperfusion (I/R) injury. Studies have additionally demonstrated that the activation of ROCK and the expression of PARP are increased in I/R. However, the effect and mechanism of the two proteins remains to be fully elucidated in I/R. In addition, whether they can be influenced by each other is unclear. In the present study, it was demonstrated that ischemia followed by reperfusion resulted in a significant increase in ROCK and PARP. In addition, Y-27632 (ROCK inhibitor) and 3 aminobenzamide (3-AB; PARP inhibitor) pretreatment rescued myocardial infarction size and cardiomyocyte apoptosis. The inhibitory role of Y-27632 was observed to be superior to that of the 3-AB group. In addition, Y-27632 and 3-AB diminished extracellular signal-related kinase (ERK) phosphorylation and the production of tumor necrosis factor alpha and interleukin 6. Overall, the results of the present study suggested that the inhibition of ROCK leads to reduced myocardial infarction size and cardiomyocyte apoptosis via the PARP/ERK signaling pathway. PMID- 28656264 TI - miR612 is associated with esophageal squamous cell carcinoma development and metastasis, mediated through TP53. AB - MicroRNAs (miRNAs) serve an important role in the regulation of gene expression. In the present study, differential expressions of miRNAs were compared between esophageal squamous cell carcinoma (ESCC) tissues and normal esophageal tissues. In combination with miRNA target prediction databases, a significantly increased expression of miR-612 was discovered in ESCC. The relationship between miR-612 and TP53 gene expression and their roles in ESCC invasion and metastasis was further studied by reverse transcription-quantitative polymerase chain reaction and western blotting in EC109 cells and cancer tissues. The EC109 cell invasion and migration were significantly reduced after miR-612 expression was inhibited. The levels of wild type TP53 protein and mRNA were lower in ESCC tissues compared to the normal esophageal epithelium. In addition, the mRNA and protein expression levels were reported as downregulated further in tumors with metastasis than in tumors without. In conclusion, miR-612 is identified as associated with ESCC development and metastasis, likely through the regulation of TP53 expression, which could be a potential therapeutic target. PMID- 28656265 TI - Bioinformatic analysis reveals potential properties of human Claudin-6 regulation and functions. AB - Claudin-6 (CLDN6) is an integral component of the tight junction proteins in polarized epithelial and endothelial cells and plays a crucial role in maintaining cell integrity. Deregulation of CLDN6 expression and distribution in tumor tissues have been widely documented and correlated with cancer progression and metastasis. However, a complete mechanistic understanding of CLDN6 regulation and function remains to be studied. Herein, we show new potential properties of CLDN6 regulation and functions from bioinformatics analysis. Using numerous algorithms to characterize the CLDN6 gene promoter elements and the CLDN6 protein structure, physio-chemical and localization properties, and its evolutionary relationships. CLDN6 is regulated by a diverse set of transcription factors (SP1, SPR, AML-1a, CdxA, CRE-BP and CREB) and associated with the levels of methylation of CpG islands in promoters. The structural properties of CLDN6 indicate that it promotes cancer cell behavior via the ASK1-p38/JNK MAPK secretory signaling pathway. In conclusion, this information from bioinformatics analysis will help future attempts to better understand CLDN6 regulation and functions. PMID- 28656267 TI - Epoxyeicosatrienoic acid ameliorates cerebral ischemia-reperfusion injury by inhibiting inflammatory factors and pannexin-1. AB - Epoxyeicosatrienoic acid (EET) has wide applications due to the unique biological effects of anti-hyperlipidemia, inhibition of platelet aggregation, anti inflammation, anti-cancer, anti-lipid oxidation and the promotion of brain tissue development. The present study investigated whether EET ameliorates cerebral ischemia-reperfusion injury (CIRI) by inhibiting inflammatory factors and pannexin. Specific pathogen-free 7-week-old male Sprague-Dawley rats were randomly divided into three groups: Sham, CIRI and EET. Neurological deficit scores, cerebral infarct volume and cerebral edema were assessed in CIRI rats. Enzyme-linked immunosorbent assays were performed to detect tumor necrosis factor alpha, interleukin-6, nuclear factor-kappaB and inducible nitric oxide synthase (iNOS) levels, and western blot analysis was performed also used to assess cleaved caspase-3, phospholipase A2 (PLA2), cyclooxygenase-2 and prostaglandin E2 (PGE2) protein expression levels. EET ameliorated cerebral injury and CIRI induced cleaved caspase-3 protein expression levels in rats. EET additionally suppressed CIRI-induced inflammation reactions and iNOS protein expression in rats. Furthermore, the protein expression levels of PLA2, PGE2 and pannexin-1 in CIRI rats were inhibited by treatment with EET. These results indicated that EET reduces CIRI by inhibiting inflammation and levels of cleaved caspase-3, PLA2, PGE2 and pannexin-1. PMID- 28656266 TI - Peroxisome proliferator-activated receptor gamma agonist suppresses mast cell maturation and induces apoptosis. AB - Peroxisome proliferator-activated receptor gamma (PPAR gamma), is important in the immunoregulation of the allergic response. Mast cells are the most important inflammatory cells in immediate hypersensitivity and allergic diseases. However, there is limited information regarding the effects of PPAR gamma on mast cell maturation. In the present study, mouse bone marrow-derived mast cells (BMMCs) were cultured in interleukin (IL)-3 and stem cell factor (SCF), in the presence or absence of the PPAR gamma agonist, pioglitazone (PIO). The expression levels of the tyrosine kinase receptor CD117 and the high affinity IgE receptor FcepsilonRI alpha, were assessed by flow cytometry, cell viability was assessed by Alamar-Blue assay and histamine release was determined by measuring the activity of beta-hexosaminidase. IL-3 and SCF are required for the development of mast cells in vitro. PIO dose-dependently inhibited the expression of CD117 and FcepsilonRI alpha, and the maturation of BMMCs. Treatment with PIO additionally inhibited the formation of granules and reduced the expression of beta hexosaminidase. In addition, reverse transcription-polymerase chain reaction analysis revealed that BMMCs treated with PIO expressed a lower level of mast cell protease (MCP)-6 mRNA and PIO treatment enhanced the level of PPAR gamma mRNA. Furthermore, PIO induced mast cell progenitor apoptosis. PPAR gamma agonists may maintain mast cell homeostasis by inhibiting maturation of their precursors. The inhibitory effects of PPAR gamma agonists include suppression of the activation of mast cells and a decrease in mast cell function in the inflammatory response. Therefore, PPAR gamma agonists may serve as effective anti inflammatory reagents in the treatment of allergic reactions. PMID- 28656268 TI - Long non-coding RNA C5orf66-AS1 is downregulated in pituitary null cell adenomas and is associated with their invasiveness. AB - Pituitary null cell adenoma is a challenging clinical condition, and its pathogenesis remains to be elucidated. We performed this study to determine the roles of C5orf66-AS1, NORAD, and TINCR in the pathogenesis and invasion of pituitary null cell adenomas. Expression of the three long non-coding RNAs in pituitary null cell adenoma tissues of 11 patients and normal pituitary tissues from four donors was examined by performing quantitative reverse transcription polymerase chain reaction. We found that C5orf66-AS1 expression was lower in pituitary null cell adenoma tissues than in normal pituitary tissues. Moreover, C5orf66-AS1 expression level was significantly lower in invasive pituitary null cell adenomas than in non-invasive ones. After transfection of C5orf66-AS1 into pituitary adenoma cells, assessment of cell viability and invasion suggested that overexpressed C5orf66-AS1 inhibited cell viability and cell invasion. In silico algorithms predicted several cis- and trans-acting target genes of C5orf66-AS1, including PITX1 and SCGB3A1. In addition, expression of some of the predicted target genes was determined using microarray data of another cohort with pituitary null cell adenomas. It showed that some of these target genes were differentially expressed between pituitary null cell adenoma tissues and normal pituitary tissues as well as between invasive and non-invasive tumors. Co expression analysis in RNA sequencing data showed that PAQR7 was the most correlated gene of C5orf66-AS1 and that several predicted trans-acting target genes, including SCGB3A1, were highly correlated with C5orf66-AS1. NORAD and TINCR expression was not statistically significant in the complete cohort; however, a negative correlation was observed between NORAD expression and maximum tumor diameter in some subgroups. These results indicate that C5orf66-AS1 suppresses the development and invasion of pituitary null cell adenomas. However, our results do not provide enough statistical evidence to support the roles of NORAD and TINCR in the development and invasion of pituitary null cell adenomas. PMID- 28656270 TI - Degradation and removal of soybean allergen in Japanese soy sauce. AB - Soy sauce is a traditional fermented seasoning of Japan and is available throughout the world. The two main raw ingredients of soy sauce are soybean and wheat, both of which are established food allergens. The present study examined the degradation and removal of soybean allergens in soy sauce by immunoblotting with anti-soybean protein antibody from rabbit and sera from two children with soybean allergy. It was demonstrated that soybean allergens were gradually degraded during the fermentation process, but were not completely degraded in raw soy sauce. During the processes of heat-treatment and filtration, the soluble soybean allergens in raw soy sauce were denatured to insoluble allergens by heat treatment and subsequently completely removed from soy sauce by filtration. Therefore, to reduce the allergenicity of soy sauce, heat-treatment and filtration are very important processes in addition to the enzymatic degradation during the fermentation of soy sauce. PMID- 28656269 TI - High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling. AB - It has previously been demonstrated that glucose is important in the process of stem cell aging. However, the mechanisms of cell senescence induced by high glucose (HG) remain to be elucidated. The preliminary study indicated that D galactose induced mesenchymal stem cell (MSCs) aging. The present study demonstrated, following treatment with 11.0 or 22.0 mM HG for 14 days, that HG significantly promoted MSCs aging and the expression levels of phosphorylated (p )phosphatidylinositol 3-kinase/protein kinase B (Akt) and p-mammalian target of rapamycin signaling (mTOR) in the HG groups were increased compared with the control group. However, following Akt inhibition with 1.0 or 10.0 nM MK-2206, which is an Akt-specific small molecule inhibitor, the senescence-cell value in the HG group was significantly decreased compared with the control group. These results indicated that HG induced MSCs senescence and this effect was primarily mediated via the Akt/mTOR signaling pathway. PMID- 28656272 TI - Molecular mechanism and functional role of macrophage colony-stimulating factor in follicular granulosa cells. AB - Our previous demonstrated that macrophage colony-stimulating factor (M-CSF) stimulated the production of estradiol (E2) and progesterone (P) in luteinized granulosa cells (GCs), and that its secretion may be regulated by follicle stimulating hormone (FSH). The present study aimed to examine the effect of M-CSF alone or with Letrozole treatment on the function of non-luteinizing granulosa cells, using the COV434 cell line, and its interaction with FSH. Human luteinized granulosa cells (LGC) were isolated from the follicular fluid of superovulated infertile patients (average age, 30.8+/-2.1 years) undergoing an intracytoplasmic sperm injection. The LGC were cultured with various concentrations of recombinant human macrophage colony stimulating factor (rhM-CSF; 0, 10, 25, 50 or 100 ng/ml), rhM-CSF+Letrozole (10-6 mol/l), rhFSH (0, 10, 25, 50 or 100 IU/ml), or rhFSH+Letrozole (10-6 mol/l). E2 concentrations in the media were measured using ELISA. The expression levels of the FSH receptor and the M-CSF receptor were detected via reverse transcription-quantitative polymerase chain reaction. Following COV434 cell treatment with M-CSF, cell proliferation was quantified using the MTS assay and protein expression was detected by western blotting. It was demonstrated that M-CSF and FSH stimulated the production of E2. The production of FSH receptors was enhanced by rhM-CSF or rhM-CSF+Letrozole in vitro in a dose-dependent manner. It was observed that rhFSH promoted the expression of the M-CSF receptor, at a certain concentration. Proliferation of COV434 cells increased in a dose-dependent manner following treatment with RhM-CSF. Furthermore, M-CSF induced the phosphorylation of c-Jun N-terminal kinase (JNK) and p38; however, the level of E2 in the medium was not altered when the cells were pretreated with the JNK inhibitor SP600125 or the p38 inhibitor SB203580. The present study suggested that M-CSF may be important in regulating the response of GCs to gonadotropin and may have a promotive effect in the early phase of follicular development. The biological effects of M-CSF may partially be attributed to activation of the JNK and p38 signaling pathways. M-CSF may represent a novel follicular development regulator agent in the future. PMID- 28656271 TI - Role of transforming growth factor beta-1 in the pathogenesis of pelvic organ prolapse: A potential therapeutic target. AB - The present study aimed to reveal the metabolic alterations of the extracellular matrix (ECM) in uterosacral ligament (USL) with pelvic organ prolapse (POP) and to explore the role of transforming growth factor-beta1 (TGF-beta1) in pathogenesis of POP. For this purpse, 60 participants who underwent hysterectomy for benign indications were enrolled, 30 of which had symptomatic POP (grade II, III or IV) and composed the POP group, and the other 30 had asymptomatic POP (grade I or less) and served as the controls. Collagen fibers, elastin,matrix metalloproteinase (MMP)-2/9, tissue inhibitor of matrix metalloproteinases (TIMP) 2 and TGF-beta1 were examined by Masson's trichrome staining, immunohistochemistry and RT-qPCR using USL biopsies. In vitro, human USL fibroblasts (hUSLFs) were primary cultured, pre-treated with recombinant TGF beta1 (0, 5, or 10 ng/ml) and then subjected to cyclic mechanical stretching (CMS; 0 or 5,333 uepsilon strain). Changes in the expression levels of collagen type I/III, elastin, TIMP-2, MMP-2/9 and Smad were detected. Our results revealed that at the tissue level, the expression of collagen fibers, elastin, TIMP-2 and TGF-beta1 was significantly reduced in the POP group, while the activities of MMP 2/9 were significantly upregulated, compared with the control group. Statistical analysis indicated that the mRNA expression of TGF-beta1 inversely correlated with the severity of POP partially. Our in vitro experimental data demonstrated that a CMS of 5333 uepsilon strain promoted the degradation of ECM proteins, inhibited the synthesis of TIMP-2, and upregulated the proteolytic activities of MMP-2/9. Pre-treatment with TGF-beta1 attenuated the loss of ECM by stimulating the synthesis of TIMP-2 and inhibiting the activities of MMP-2/9 through the TGF beta1/Smad3 signaling pathway. On the whole, our data indicate that the reduced anabolism and increased catabolism of ECM proteins in USL are the pathological characteristics of POP. TGF-beta1 not only has a specific value in predicting the severity of POP, but should also be considered as a novel therapeutic target for POP. PMID- 28656273 TI - Network analysis of HBV- and HCV-induced hepatocellular carcinoma based on Random Forest and Monte Carlo cross-validation. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are two common risk factors for HCC. The majority of patients with HCC present at an advanced stage and are refractory to therapy. It is important to identify a method for efficient diagnosis at early stage. In the present study gene expression profile data, generated from microarray data, were pretreated according to the annotation files. The genes were mapped to pathways of Ingenuity Pathways Analysis. Dysregulated pathways and dysregulated pathway pairs were identified and constructed into individual networks, and a main network was constructed from individual networks with several edges. Random Forest (RF) classification was introduced to calculate the area under the curve (AUC) value of this network. Subsequently, 50 runs of Monte Carlo cross-validation were used to screen the optimal main network. The results indicated that a total of 4,929 genes were identified in the pathways and gene expression profile. By combining dysregulated pathways with Z<0.05 and dysregulated pathway pairs with Z<0.2, individual networks were constructed. The optimal main network with the highest AUC value was identified. In the HCV group, the network was identified with an AUC value of 0.98, including 41 pairs of pathways, and in the HBV group, the network was identified with an AUC value of 0.94, including eight pairs of pathways. In addition, four pairs were identified in both groups. In conclusion, the optimal networks of HCV and HBV groups were identified with the highest AUC values. The use of these networks is expected to assist in diagnosing patients effectively at an early stage. PMID- 28656274 TI - Proteomics of acute heart failure in a rat post-myocardial infarction model. AB - The aim of the present study was to identify the mechanisms underlying the development of post-myocardial infarction (post-MI) heart failure. The left anterior descending coronary artery of rats was occluded to mimic human ischemic heart disease. Linear Trap Quadropole OrbiTrap mass spectrometry was used to profile the expressions of energy metabolism-associated and calcium-binding proteins in the post-MI and control groups. Using the online Protein Analysis Through Evolutionary Relationships classification system, 78 differentially expressed proteins were identified, including 50 downregulated proteins and 28 upregulated proteins in post-MI group when compared with the control group. The differentially expressed proteins were closely associated with energy metabolism, contractile function, calcium handling, pathological hypertrophy and cardiac remodeling. These results were further validated using western blotting. At different postoperative time points (1st and 14th day following surgery) during the progression of advanced heart failure post-MI, dynamic alterations in differential protein expression were identified. The expression of the vitamin D protein was significantly upregulated on the 1st day post-MI however, was then downregulated with progression of the disease on the 14th day post-MI. These results identified various target proteins associated with the disease, which may be used as diagnostic markers. PMID- 28656275 TI - Histone deacetylase-2 is involved in stress-induced cognitive impairment via histone deacetylation and PI3K/AKT signaling pathway modification. AB - Exposure to chronic stress upregulates blood glucocorticoid levels and impairs cognition via diverse epigenetic mechanisms, such as histone deacetylation. Histone deacetylation can lead to transcriptional silencing of many proteins involved in cognition and may also cause learning and memory dysfunction. Histone deacetylase-2 (HDAC2) has been demonstrated to epigenetically block cognition via a reduction in the histone acetylation level; however, it is unknown whether HDAC2 is involved in the cognitive decline induced by chronic stress. To the best of authors' knowledge, this is the first study to demonstrate that the stress hormone corticosteroid upregulate HDAC2 protein levels in neuro-2a cells and cause cell injuries. HDAC2 knockdown resulted in a significant amelioration of the pathological changes in N2a cells via the upregulation of histone acetylation and modifications in the phosphoinositide 3-kinase/protein kinase B signaling pathway. In addition, the HDAC2 protein levels were upregulated in 12-month-old female C57BL/6J mice under chronic stress in vivo. Taken together, these findings suggested that HDAC2 may be an important negative regulator involved in chronic stress-induced cognitive impairment. PMID- 28656276 TI - Lentivirus-mediated RIG-I knockdown relieves cell proliferation inhibition, cell cycle arrest and apoptosis in ATRA-induced NB4 cells via the AKT-FOXO3A signaling pathway in vitro. AB - Retinoic acid inducible gene I (RIG-I) is upregulated during all-trans retinoic acid (ATRA)-induced terminal granulocytic differentiation of NB4 acute promyelocytic leukemia (APL) cells. However, the function and mechanism of RIG-I in NB4 cells remains to be fully elucidated. In the present study, lentivirus mediated RIG-I-knockdown was used to investigate the proliferation, cell cycle and apoptotic processes of ATRA-induced NB4 cells in vitro using an MTT assay and flow cytometry, respectively. The roles of RIG-I and the AKT-FOXO3A signaling pathway were investigated using western blot analysis. The results showed that the ATRA-induced expression of RIG-I was specifically and effectively knocked down at the mRNA and protein levels by lentivirus mediated RIG-I short hairpin RNA. In addition, silencing of RIG-I reduced the ATRA-induced inhibition of NB4 cell proliferation, cell cycle arrest and apoptosis. Further investigations indicated that with ATRA-induced expression of RIG-I, levels of phosphorylated (p)AKT-Thr308 and pForkhead Box (FOX) O3A-Thr32 were decreased, the expression levels of cell cycle arrest protein p27 and the apoptotic protein, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), directly transcribed by FOXO3A were increased. By contrast, following the knockdown of ATRA-induced expression of RIG-I, the levels of pAKT-Thr308 and pFOXO3A-Thr32 were increased, and the protein expression levels of p27 and TRAIL were decreased. Taken together, these results showed that the knockdown of RIG-I reduced the inhibition of cell proliferation, cell cycle arrest and apoptosis in the ATRA-induced NB4 cells via the AKT-FOXO3A signaling pathway. PMID- 28656277 TI - HNF1A-AS1 promotes growth and metastasis of esophageal squamous cell carcinoma by sponging miR-214 to upregulate the expression of SOX-4. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in the world, marked by dysphagia and weight loss, bringing great suffering to patients. HNF1A-AS1 (HAS1), a long non-coding RNA (lncRNA), has been identified prevalently involved in various human cancers. However, the exact effects and molecular mechanisms of HAS1 in ESCC progression are still elusive. In this study, upregulated expression of HAS1 was detected in ESCC tissues and four human ESCC cell lines (KYSE70, KYSE450, EC109 and EC970) compared with normal tissues and cell lines. Small interfering RNA (siRNA)-mediated knockdown of HAS1 largely suppressed cell proliferation and promoted cell apoptosis in KYSE70 and EC109 cells. The decreased expression of proliferation marker proteins and elevated level of apoptosis marker proteins further verified that HAS1-siRNA suppressed cell viability in ESCC cells. Besides, the silence of HAS1 strongly reduced the wound closing rate and the number of invasive cells compared with control group. HAS1-siRNA also restrained the expression of migration marker proteins matrix metalloproteinase-9 (MMP-9) and vascular endothelial cell growth factor (VEGF). In addition, miR-214 was predicted as a direct target of HAS1 by bioinformatics analysis. Downregulated expression of miR-214 was elevated in KYSE70 and EC109 cells transfected with HAS1-siRNA. Subsequently, elevated expression of miR-214 was suppressed by co-transfecting with miR-214 inhibitor in EC109 cells pretreated with HAS1-siRNA. The result of luciferase activity assay showed that luciferase activity was strongly weakened by the combination of LncR-HAS1 WT and miR-214 mimic. Moreover, the expression of SOX-4, a predicted target gene of miR 214, was suppressed by HAS1-siRNA and was increased by miR-214 inhibitor. HAS1 siRNA counteracted the effect of miR-214 inhibitor on cell viability and mobility in EC109 cells. Finally, the in vivo experiment revealed that HAS1-siRNA abated the role of miR-214 inhibitor in promoting tumor growth and metastasis. miR-214 also mediated the effect of HAS1 on upregulating the expression of SOX-4 in vivo. Taken together, our study indicated a HAS1-miR-214-SOX-4 pathway in regulating the growth and metastasis of ESCC, providing a promising target for ESCC therapy. PMID- 28656278 TI - Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor kappabeta ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion. PMID- 28656279 TI - Silencing of beta1 integrin regulates airway remodeling by regulating the transcription of SOCE-associated genes in asthmatic mice. AB - The incidence of asthma is increasing globally; however, current treatments are only able to cure a certain proportion of patients. There is an urgent need to develop novel therapies. beta1 integrin serves a role in the pathophysiology of asthma through the development of airway remodeling. The aim of the present study was to investigate silencing of the beta1 integrin gene in pre-clinical models of allergic asthma. BALB/c mice were sensitized with ovalbumin through intraperitoneal injection and repeated aerosolized ovalbumin. A short hairpin RNA of the beta1 integrin gene was designed and transfected into mouse models of asthma in vivo, in order to evaluate whether silencing of the beta1 integrin gene affects airway smooth muscle cell proliferation and inflammation by regulating the mRNA expression of store-operated Ca2+ entry (SOCE)-associated genes. Silencing the beta1 integrin gene may downregulate beta1 integrin mRNA while not statistically decreasing alpha-smooth muscle actin gene expression and airway smooth muscle thickness. beta1 integrin silencing was able to downregulate the transcription of SOCE-associated genes to normal levels, including calcium release-activated calcium modulator 1 and short transient receptor potential channel member 1, but not stromal interaction molecule 1, in asthma. Silencing of the beta1 integrin gene additionally maintained nuclear factor of activated T cells cytoplasmic 1 gene expression, and inflammatory cytokines interleukin-4 and interferon-gamma at normal levels. The results of the present study provide evidence to suggest that silencing of the beta1 integrin gene may be of therapeutic benefit for patients with asthma. PMID- 28656281 TI - MicroRNA-503 inhibits the proliferation and invasion of breast cancer cells via targeting insulin-like growth factor 1 receptor. AB - MicroRNAs (miRs), a class of non-coding RNAs that are 18-25 nucleotides in length, serve as key regulators in the development and progression of human cancers. Previously, miR-503 has been implicated in breast cancer. However, the underlying mechanism of miR-503 in regulating the proliferation and invasion of breast cancer cells remains largely unknown. In the present study, reverse transcription-quantitative polymerase chain reaction analysis indicated that the expression of miR-503 was significantly reduced in breast cancer tissues compared with their matched adjacent normal tissues. Furthermore, miR-503 expression levels were markedly reduced in T2-T4 stage breast cancer, compared with T1 stage. Insulin-like growth factor 1 receptor (IGF-1R) was further identified as a novel target of miR-503. Overexpression of miR-503 significantly suppressed the protein expression levels of IGF-1R. Furthermore, it inhibited the proliferation and invasion of human breast cancer MCF-7 cells, as assessed by MTT and Transwell assays, respectively. However, restoration of IGF-1R expression markedly ameliorated the suppressive effects of miR-503 overexpression on MCF-7 cell proliferation and invasion, indicating that miR-503 inhibits breast cancer cell proliferation and invasion at least partially via directly targeting IGF-1R. Furthermore, the mRNA and protein expression levels of IGF-1R were demonstrated to be significantly increased in breast cancer tissues compared with their matched adjacent normal tissues. In addition, IGF-1R mRNA expression levels were reversely correlated with miR-503 expression levels in breast tumors, suggesting that the upregulation of IGF-1R may be due to downregulation of miR-503 in breast cancer. In conclusion, the present study expanded the understanding of the regulatory mechanism of miR-503 in breast cancer, and implicates the miR-503/IGF 1R axis as a potential therapeutic target for breast cancer. PMID- 28656280 TI - Role of glycoprotein 78 and cidec in hepatic steatosis. AB - Hepatic glycoprotein (gp78), a membrane-anchored E3 ubiquitin ligase, has been reported to be involved in regulating lipid and energy metabolism in animals, and cell death-inducing DFFA-like effector c (cidec) has emerged as an important regulator of metabolism, which has been implicated in the process of fat differentiation. Nonalcoholic fatty liver disease is a metabolic disorder associated with hepatic steatosis. In the present study, to investigate the role of gp78 and cidec in hepatic steatosis, an in vitro cell culture model of hepatic steatosis was established, using the AML12 mouse hepatocyte cell line to assess the protein expression of gp78. The results of Oil Red O staining, phase contrast microscopy and triglyceride content detection experiments indicated that the overexpression of gp78 induced lipid accumulation, whereas gp78-knockdown led to a reduction in lipid accumulation in the AML12 cells. The increased expression of gp78 was associated with steatosis. The expression of cidec was consistent with gp78, and the colocalization of gp78 and cidec was observed on the surface of lipid droplets using immunofluorescence analysis. Furthermore, an interaction between gp78 and cidec was detected using coimmunoprecipitation analysis, and this interaction promoted lipid accumulation. Based on these data, it was hypothesized that gp78 is a regulator of hepatic steatosis, and that it may be a putative molecular mediator in metabolic diseases. PMID- 28656282 TI - AQP3 small interfering RNA and PLD2 small interfering RNA inhibit the proliferation and promote the apoptosis of squamous cell carcinoma. AB - Aquaporin 3 (AQP3) and phospholipase D2 (PLD2) are abnormally expressed and/or localized in squamous cell carcinoma (SCC). AQP3 transports glycerol to PLD2 for the synthesis of lipid second messenger, which can mediate the effect of the AQP3/PLD2 signaling module in the regulation of keratinocyte proliferation and differentiation. However, the role of the AQP3/PLD2 signaling module in the pathogenesis of SCC remains to be fully elucidated. In the present study, the expression levels of AQP3 and PLD2 in tissue samples were examined using immunohistochemistry, it was found that the expression levels of AQP3 and PLD2 in tissue samples of actinic keratosis (AK), Bowen's disease (BD) and SCC were significantly increased. AQP3 small interfering RNA (siRNA) and PLD2 siRNA were constructed and used for transfection into the human A431 SCC cell line, and their anticancer effect on SCC was examined. The mRNA expression and protein expression levels of AQP3 and PLD2 were significantly downregulated following siRNA transfection. AQP3 siRNA and PLD2 siRNA inhibited the proliferation and promoted the apoptosis of A431 cells. Taken together, the findings of the present study suggested that increased levels of AQP3 and PLD2 were correlated with tumor progression and development in SCC. AQP3 siRNA and PLD2 siRNA significantly downregulated the mRNA and protein levels of AQP3 and PLD2 in the A431 cells; inhibiting proliferation and promoting apoptosis in vitro. The concomitant effects of AQP3/PLD2 signaling by inhibiting the expression of siRNA may be important for the treatment of SCC in the future. PMID- 28656283 TI - Effects of moderate-intensity endurance exercise on angiotensin II and angiotensin II type I receptors in the rat heart. AB - The current study was aimed at examining the effects of moderate-intensity endurance exercise on the expression of angiotensin II (AngII) and AngII type 1 receptor (AT1R) in the rat heart. Male Sprague-Dawley rats were randomly divided into the control group (n=20) and moderate-intensity endurance exercise group (n=20). Cardiac hypertrophy was induced by treadmill endurance training for 8 weeks. The mRNA expression of AngII and AT1R were assessed by reverse transcription-quantitative polymerase chain reaction. The immune response positive area and optical density of AngII and AT1R was measured by immunohistochemistry. AngII was primarily expressed in the cytoplasm and membrane, however infrequently in coronary vascular wall smooth muscle cells. AT1R was primarily expressed in the coronary vessel wall smooth muscle, rarely in cardiac cells. The mRNA expression of cardiac AngII was significantly increased after the 8-week exercise period, while AT1R was significantly decreased. Immunohistochemistry indicated a significant increase in the AngII immune positive area and optical density after the 8-week exercise. The AT1R immune positive area and optical density was significantly reduced following the 8-week exercise. In conclusion, subsequent to 8-weeks endurance training, the AngII expression was increased and the AT1R expression was decreased. AT1R may expand the coronary artery, thereby increasing coronary blood flow and ensuring the energy supply of heart during exercise. The expression change in AngII does not reflect the character of cardiac hypertrophy. The exercise-induced change in the expression of AngII and AT1R may be a protective mechanism to avoid cardiac pathological hypertrophy. PMID- 28656284 TI - MicroRNA-31 inhibits tumor invasion and metastasis by targeting RhoA in human gastric cancer. AB - Previous studies have shown that microRNA-31 (miR-31) functions as a tumor suppressor in various types of cancer. In the present study we found that miR-31 was significantly downregulated in gastric cancer (GC) as determined by microRNA (miRNA) array screening analysis. Although aberrant expression of miR-31 has been found in different types of cancer, its pathophysiological effect and role in tumorigenesis still remain to be elucidated. In the present study, we detected miR-31 expression in both metastatic GC cell lines and tissues that are potentially highly metastatic by real-time polymerase chain reaction (PCR). Transwell and scratch healing assays were conducted to examine whether the ectopic expression of miR-31 could modify the invasion and migration abilities of GC cells in vitro. We found that miR-31 inhibited GC metastasis in a nude mouse xenograft model of GC. Luciferase reporter assays demonstrated that miR-31 could directly bind to the 3' untranslated region of RhoA and downregulate the expression of RhoA. Significant downregulation of miR-31 in 78 GC tissues and four GC cell lines was examined by real-time reverse transcription-PCR. Moreover, the decreased expression of miR-31 was demonstrated to be associated with lymph node metastasis, poor pT and pN stage, and invasion ability into lymphatic vessels as determined by the Mann-Whitney U test. We also found that miR-31 could inhibit cell invasion and migration abilities in vitro using the Transwell and scratch healing assays in BGC-823, SGC-7901, MGC-803 as well as AGS cells. Experiments in a nude mouse model revealed that miR-31 suppressed tumorigenicity in vivo. The luciferase activity assay and western blotting indicated that RhoA was the potential target of miR-31 in GC cells. Collectively, our results provide important evidence that the downregulation of miR-31 inhibited the invasion and migration abilities of GC cells through direct targeting of the tumor metastasis associated gene, RhoA. These findings suggest that miR-31 may be a promising therapeutic candidate in the treatment of GC metastasis. PMID- 28656285 TI - LKB1 promotes radioresistance in esophageal cancer cells exposed to radiation, by suppression of apoptosis and activation of autophagy via the AMPK pathway. AB - Liver kinase B (LKB) 1 acts as a tumor suppressor in a broad spectrum of human cancers, and is important in chemoradiotherapy treatment of various tumor types. However, the potential function of LKB1 in esophageal cancer radiotherapy remains to be elucidated. The aim of the present study was to investigate the role of LKB1 in radiosensitivity of esophageal cancer in vivo and in vitro, and to explore its molecular mechanism. Eca-109 cells transfected with LKB1 overexpression plasmid were xenografted into nude mice and subjected to irradiation and it was observed that the tumor volume was significantly increased in LKB1-overexpressed tumors compared with that of the control tumors. The in vitro study revealed that LKB1 overexpression led to the radioresistance of Eca 109 cells, as determined by MTT and colony formation assays. Furthermore, it was demonstrated that LKB1 overexpression inhibited apoptosis and activated autophagy of Eca-109 cells following radiation treatment, as determined by flow cytometry and western blot analyses. AMP-activated protein kinase (AMPK) inhibition attenuated LKB1-induced radioresistance of Eca-109 cells. To the best of our knowledge, the present study, for the first time, confirmed that LKB1 induces radioresistance of esophageal cancer cells to irradiation via suppression of apoptosis and activation of autophagy, and AMPK mediates this function of LKB1 in esophageal cancer radiotherapy. These findings suggest that LKB1 may act as a novel target in the future, to maximize the efficiency of esophageal cancer radiotherapy. PMID- 28656286 TI - MicroRNA-497 upregulation inhibits cell invasion and metastasis in T24 and BIU-87 bladder cancer cells. AB - Previous studies have reported the crucial role of microRNAs (miRNAs) in the biology and tumorigenesis of various types of cancer, including bladder cancer. The present study aimed to investigate the importance of miRNA (miR)-497 on the pathogenesis of bladder cancer. A total of 50 patients diagnosed with bladder cancer were enrolled in the current study. The expression levels of miR-497 in the cancerous and the adjacent noncancerous tissues were detected using reverse transcription-quantitative polymerase chain reaction. The association between miR 497 expression and various parameters, including age, tumor-node-metastasis (TNM) stage and pathological classification was determined. An miR-497-overexpressing vector was transfected into the T24 and BIU-87 bladder cancer cell lines in order to determine the effect of miR-497 expression on cell migration and invasion using Transwell assays. Additionally, the cell migration and invasion-associated protein expression levels were also analyzed using western blotting. The findings of the present study revealed that miR-497 was expressed at low levels in the cancer bladder tissue compared with the adjacent noncancerous tissue, and its expression was associated with the pathological classification, TNM stage and metastasis. Additionally, miR-497 overexpression significantly reduced the number of migrated and invasive T24 and BIU-87 cells. The mRNA and protein expression levels of E-cadherin were increased, whereas levels of vimentin and alpha-smooth muscle actin were reduced following miR-497 overexpression. The present study revealed that miR-497 overexpression may be a suppressor of the metastasis of bladder cancer, and may have an important role in the diagnosis of bladder cancer. PMID- 28656287 TI - Identification and characterization of miR-96, a potential biomarker of NSCLC, through bioinformatic analysis. AB - Lung cancer is the leading cause of cancer-related death worldwide. The poor prognosis is partly due to lack of efficient methods for early diagnosis. MicroRNAs play roles in almost all aspects of cancer biology, and can be secreted into the circulation and serve as molecular biomarkers for the early diagnosis of cancer. In the present study, we determined the expression of miR-96 and the function of its target genes in lung cancer through bioinformatic analysis. Four microRNA expression profiles of lung cancer were downloaded from Gene Expression Omnibus and the data were analyzed using SPSS 16.0 software. Compared to the control group, expression of miR-96 was significantly increased in non-small cell lung cancer (NSCLC) (GSE51855), lung adenocarcinoma (GSE48414), stage I adenocarcinoma tissues (GSE63805) and the plasma of lung cancer patients (GSE68951). miR-96 was also elevated in six different NSCLC cell lines. However, the expression level of miR-96 was not related to the age, gender, clinical stage and histological subtype of the NSCLC patients. GO analysis of 78 predicted target genes of miR-96 showed that 42 of the obtained GO terms are highly associated with specific cellular processes including response to stimulus, signaling pathway, cell division, cell communication, cell migration and calcium signaling. KEGG results indicated that the miR-96 targets are mainly involved in the GnRH signaling pathway, long-term potentiation and insulin signaling pathway. In conclusion, miR-96, functioning as an oncogene, may play an important role in the development and progression of lung cancer. miR-96 may have the potential to serve as a molecular biomarker for the early diagnosis of NSCLC. PMID- 28656288 TI - Vascular endothelial growth inhibitor 174 and its functional domains inhibit epithelial-mesenchymal transition in renal cell carcinoma cells in vitro. AB - The present study was carried out to investigate the effects of vascular endothelial growth inhibitor 174 (VEGI174) and its functional domains (V7 and V8) on epithelial-mesenchymal transition (EMT) in renal cell carcinoma (RCC) cells in vitro. The RCC cell lines A498 and 786-O were used in this study. Based on our preliminary study, we selected full-length VEGI174 and its functional domains (V7 and V8) as the target genes in this study. Plasmids containing VEGI174, V7 or V8 transgenes were constructed and transfected into A498 and 786-O cell lines. Cytological activity was tested during cell culture. Quantitative PCR and western blot analysis were performed to determine the expression levels of EMT markers (E cadherin, vimentin, beta-catenin and Slug). Overexpression of VEGI174, V7 or V8 did not have a significant influence on cell viability (P>0.05). The mRNA level of E-cadherin was significantly upregulated, while that of vimentin was downregulated in A498VEGIexp, A498V7exp, A498V8exp, 786-OVEGIexp, 786-OV7exp and 786-OV8exp cells compared with the cells containing the empty plasmid controls (P<0.05). The western blot results showed that changes in protein expression levels were consistent with the changes in mRNA expression. Both the mRNA and protein expression levels of beta-catenin and Slug were downregulated in the A498VEGIexp, A498V7exp, A498V8exp, 786-OVEGIexp, 786-OV7exp and 786-OV8exp cells. In conclusion, overexpression of VEGI174, V7 or V8 inhibited EMT in A498 and 786 O cells. Notably, V7 and V8 are two effective functional domains of VEGI174 that have the potential to be studied for peptide synthesis and the treatment of RCC. PMID- 28656289 TI - PRMT1 expression is elevated in head and neck cancer and inhibition of protein arginine methylation by adenosine dialdehyde or PRMT1 knockdown downregulates proliferation and migration of oral cancer cells. AB - Protein arginine methylation is a post-translational modification that has been implicated in signal transduction, gene transcription, DNA repair and RNA processing. Overexpression or deregulation of protein arginine methyltransferases (PRMTs) have been reported to be associated with various cancers but have not been studied in head and neck cancer (HNC). We investigated the involvement of the modification in HNC using oral cancer cell lines (SAS, OECM-1 and HSC-3) and an immortalized normal oral cells (S-G). The expression levels of the predominant PRMT1 were generally consistent with the levels of asymmetric dimethylarginine (ADMA), highest in SAS and OECM1, then S-G and low in HSC-3. Upon the treatment with an indirect methyltransferase inhibitor adenosine dialdehyde (AdOx), the ADMA levels in SAS and OECM1, but not that in S-G and HSC-3, decreased significantly. SAS and OECM with high ADMA levels grew faster than HSC-3 and S-G. The growth rate of the fast growing SAS and OECM, but not that of the other two cell lines, decreased significantly upon AdOx treatment. The migration activity of SAS and HSC-3, two cell lines with migration ability also decreased after the AdOx treatment. Immunohistochemical analyses of specimens from typical HNC patients showed strong PRMT1 expression in the tumor cells compared with neighboring normal cells. Knockdown of PRMT1 in SAS cells decreased the levels of PRMT1 and ADMA-containing proteins significantly. These cells showed decreased growth rate, reduced migration activity but increased expression of the epithelial marker E-cadherin. The present study thus provides fundamental background for evaluation of the PRMT1 gene as the therapeutic targets of HNC. PMID- 28656290 TI - miR-367 promotes tumor growth by inhibiting FBXW7 in NSCLC. AB - miR-367 is one of the most abundant miRNAs in human embryonic stem cells (hESCs) and is mainly involved in maintaining the pluripotency of stem cells. However, its role in cancer development remains poorly understood. In the present study, we explored the function and mechanism of the endogenous miR-367 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated that the level of miR-367 in NSCLC was significantly higher than that in adjacent normal tissues, and its upregulation was positively correlated with tumor size, tumor differentiation and tumor-node-metastasis (TNM) stage. miR-367 was an indicator of a poorer prognosis in NSCLC patients. Furthermore, overexpression of miR-367 significantly inhibited apoptosis and enhanced proliferation by promoting cell cycle transition from G1 to S phase. In contrast, knockdown of miR-367 markedly reversed the cellular events observed with miR-367 overexpression. Moreover, we identified that F-box and WD repeat domain-containing 7 (FBXW7) is a novel target of miR-367. It reverses the oncogenic effects of miR-367 by downregulating its substrates, c-Myc and c-Jun, in NSCLC cells. Finally, studies in vivo revealed that knockdown of miR-367 inhibited the growth of xenografts in the nude mice by increasing the expression of FBXW7. In summary, our findings indicate that miR 367 exerts tumor-promoting effect by negatively regulating FBXW7 in NSCLC, and it could become a potential therapeutic target for NSCLC intervention. PMID- 28656291 TI - USP7 is associated with greater disease activity in systemic lupus erythematosus via stabilization of the IFNalpha receptor. AB - An improved understanding of the mechanism of interferon (IFN)alpha activation in systemic lupus erythematosus (SLE) is likely to aid the identification of effective therapeutic targets. Increasing evidence has indicated that the activity of IFNalpha is mediated by the interplay of ubiquitylation/deubiquitylation enzyme regulators. The present study identified the deubiquitylation enzyme ubiquitin-specific-processing protease 7 (USP7) as a critical regulator of the human IFNalpha-2 receptor (IFNAR1) protein levels. A co immunoprecipitation assay was used to demonstrate that USP7 was physically associated with IFNAR1 in vivo. A glutathione S-transferase pull down assay revealed that USP7 interacted with IFNAR1 directly in vitro. Furthermore, USP7 may disassemble IFNAR1 dependent poly-ubiquitin chains and stabilize IFNAR1 in vivo. The activation effects of USP7 on the IFNalpha pathway were confirmed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Knockdown of USP7 expression consistently reduced the expression levels of signal transducer and activator of transcription (STAT)-1, STAT-2 and selected IFN-inducible genes, including IFN-induced protein with tetratricopeptide repeats 3, MX dynamin like GTPase 1 and 2'-5'-oligoadenylate synthetase 1. The present study demonstrated that USP7 was significantly overexpressed in 210 SLE patients compared with healthy controls. Furthermore, the association between USP7 levels, IFN scores, SLE disease activity index scores and anti-double stranded DNA were analyzed and, as expected, positive correlations were demonstrated, indicating that USP7 may be associated with SLE disease activity through the stabilization of IFNAR1. PMID- 28656292 TI - Novel mutations of FRMD7 in Chinese patients with congenital motor nystagmus. AB - The purpose of the current study was to identify novel mutations in the FRMD7 (FERM domain containing 7) gene and to characterize clinical features in Chinese patients with congenital motor nystagmus. For this purpose, 18 patients with congenital motor nystagmus were selected from the ocular genetic diseases bank of the Pediatric and Genetic Clinic of Zhongshan Ophthalmic Center (Guangdong, China). Direct sequencing was used to analyze the exons and adjacent introns of the FRMD7 gene. The heteroduplex-single strand conformation polypeptide method was used to analyze 96 unrelated normal controls and gene-screening positive patients. Slit lamp photography of the anterior segment, fundus photography, optical coherence tomography and electroretinogram were carried out to identify the clinical features of congenital motor nystagmus. The authors noted that in, 18 patients with congenital motor nystagmus, there were 7FRMD7 gene mutations (six new mutations). The screening rate was 38.89%, including c.41_43delAGA (p.13 15delK); c.473T>A (p.I158N); c.605T>A (p.I202N); c.580G>T (p.A194S); c.811T>A (p.C271S); c.1493insA (p.Y498X); c.57+1G>A (slice mutation). There were no such mutations in the 96 normal controls. These results enriched the gene mutation spectrum of FRMD7. The authors systematically investigated the clinical phenotype of congenital motor nystagmus in a Chinese population. The study provides further evidence for clinical diagnosis and differential diagnosis and genetic counseling. PMID- 28656293 TI - Anti-proliferation and anti-metastasis effect of barbaloin in non-small cell lung cancer via inactivating p38MAPK/Cdc25B/Hsp27 pathway. AB - Non-small cell lung carcinoma (NSCLC) is the most common lung cancer with high morbidity and mortality. The traditional treatment for NSCLC is particularly liable to relapse with many side-effects. Barbaloin is a natural compound with anticancer efficacy. The present study aimed to investigate the anticancer potential of barbaloin in NSCLC. The results displayed that barbaloin inhibited the viability of A549 cells by decreasing cell growth and the expression level of Ki-67 and proliferating cell nuclear antigen (PCNA), especially at high concentrations (50 and 100 uM). Besides, barbaloin increased the apoptosis rate of A549 cells and induced an accumulation of G2/M phase. Increased expression of apoptosis-related proteins (caspase-3, -8 and -9) and the changed levels of cell cycle checkpoint proteins (p27, p53 and cyclin A) further convinced of the anti viability effect of barbaloin in A549 cells. On the other hand, barbaloin significantly suppressed the invasion and migration of A549 cells, and restrained the expression of tumor metastasis-related proteins. We further explored the activation of pro-survival or pro-metastasis signaling pathways, including AKT, nuclear factor kappa B (NF-kappaB), mitogen-actived protein kinase (MAPK) and beta-catenin. The results revealed that barbaloin inactivated the p38MAPK/Cdc25B/Hsp27 pathway by inhibiting p38 nucleus translocation, while no significant influence was observed among other pathways. Finally, barbaloin restrained the growth and hepatic metastases of A549 cells in vivo. Taken together, our research indicated that barbaloin inhibited the proliferation and metastasis of NSCLC cells in vivo and in vitro. This may provide safer and more effective aspects for the treatment of NSCLC. PMID- 28656294 TI - Overexpression of A disintegrin and metalloprotease 10 promotes tumor proliferation, migration and poor prognosis in hypopharyngeal squamous cell carcinoma. AB - The aim of this study was to determine the effect of A disintegrin and metalloprotease 10 (ADAM10) protein expression on the progression, migration and prognosis of hypopharyngeal squamous cell carcinoma (HSCC). Immunohistochemistry and western blot analysis were performed to detect ADAM10 expression in human HSCC specimens. Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis and wound-healing assay were employed to investigate the effects of ADAM10 knockdown (ADAM10-RNAi) on major oncogenic properties of FaDu cells. We detected that ADAM10 was overexpressed in HSCC specimens and its expression level was associated with differentiation (p<0.001), tumor size (p=0.019), lymph node metastasis (p=0.001), clinical stage (p<0.001), proliferation marker Ki-67 expression (P=0.001) and overall survival (p<0.046). ADAM10-RNAi in FaDu cells resulted in the inhibition of proliferation and the decrease in migration. Moreover, mechanistic experiments revealed that ADAM10-RNAi resulted in an increase in E-cadherin and a decrease in N-cadherin and vimentin expression. Our study implies that high expression of ADAM10 promotes the proliferation and migration of HSCC. These findings may help to provide a method for treatment of HSCC. PMID- 28656295 TI - Inhibition of neuropeptide Y Y1 receptor induces osteoblast differentiation in MC3T3-E1 cells. AB - Neuropeptide Y (NPY) is a major neural signaling molecule. NPY is produced by peripheral tissues, such as osteoblasts, and binds to the corresponding Y1 receptor that belongs to the G-protein-coupled receptor family. Osteoblast specific Y1 receptor knockout mice exhibit high bone mass, indicating a role of the NPY-Y1 receptor axis in the regulation of bone homeostasis. In the bone microenvironment, peripheral nerve fibers and osteoblasts produce NPY. However, the effects of the Y1 receptor on osteoblasts remain unexplored. In the present study, an RNA interference approach was employed to target the Y1 receptor, in order to determine whether it may function to regulate the growth, differentiation and viability of osteoblasts. Knockdown of the Y1 receptor by small interfering RNA (siRNA) lead to induction of alkaline phosphatase (ALP) activity and mineralization in mouse MC3T3-E1 osteoblast cells. In addition, the mRNA expression levels of ALP, osteocalcin, collagen (I) alpha1, and bone sialoprotein were significantly increased following transfection of a Y1 receptor siRNA. Furthermore, the mRNA expression levels of Runx2 and osterix were significantly increased; however, no significant alterations in cell proliferation and caspase-3/7 activity were observed in Y1 receptor siRNA transfected cells when compared with non-targeting controls. The results demonstrate that Y1 receptor inhibition may increase osteoblastic differentiation, which indicates a role of the Y1 receptor in the regulation of osteoblastic differentiation. PMID- 28656297 TI - Klotho suppresses tumor progression via inhibiting IGF-1R signaling in T-cell lymphoma. AB - Klotho is a transmembrane protein and acts as an upstream modulator of insulin like growth factor-1 receptor (IGF-1R) signaling, which was indicated to be involved in the pathogenesis of solid cancer and hematological malignancies, including T-cell lymphoma. Although Klotho was recently identified as a tumor suppressor in several types of human malignancies, the potential role of Klotho in T-cell lymphoma has not been reported. In the present study, we investigated the expression level and the molecular events of Klotho in T-cell lymphoma. Significantly lower expression of Klotho was observed in T-cell lymphoma patient samples compared to normal lymph nodes. Functional analysis after Klotho overexpression revealed significantly inhibited tumor cell viability in T-cell lymphoma. Moreover, apoptosis of T-cell lymphoma cells were induced after transfected with Klotho-overexpressing vectors. Forced expression of Klotho resulted in decline of activation of IGF-1R signaling, accompanied by decreased phosphorylation of its downstream targets, including AKT and ERK1/2. These data indicated that Klotho acts as a tumor suppressor via inhibiting IGF-1R signaling, thus suppressing the viability and promoting apoptosis in T-cell lymphoma. Taken together, Klotho may serve as a potential target for the therapeutic intervention of T-cell lymphoma. PMID- 28656296 TI - The ACE2-Ang (1-7)-Mas receptor axis attenuates cardiac remodeling and fibrosis in post-myocardial infarction. AB - Myocardial remodeling serves an important role in the pathophysiology of coronary heart disease. The angiotensin-converting enzyme (ACE)2-angiotensin-(1-7) [Ang (1 7)]-Mas receptor (MasR) axis is a key regulator in myocardial remodeling and development of heart failure. To investigate how ACE2-Ang-(1-7)-MasR axis function on myocardial remodeling and cardiac fibrosis in post-myocardial infarction (MI), male Sprague-Dawley rats (weight, 200+/-20 g) were used to establish the model of myocardial infarction by ligating the left coronary artery. The present study suggests that telmisartan (Tel) and olmesartan (Olm) (5 mg/kg/d) can inhibit myocardial remodeling of post-myocardial infarction through the ACE2-Ang (1-7)-MasR pathway. Administration of Tel or Olm was demonstrated to significantly inhibit collagen deposition using Masson staining. In addition, telmisartan and olmesartan was indicated to antagonize angiotensin II (Ang II) and upregulate ACE2, MasR, Ang (1-7) expression in myocardial tissue using immunoassay and ELISA test, and the effect of Olm was more marked than that of Tel at the same dosage. Simultaneously, compared with the MI or Sham group, the mRNA and protein expression of ACE2, Ang II and MasR in myocardial tissue demonstrated a remarkable increase in the Olm group, when compared with the Tel group. Taken together, our data demonstrated that ACE2-Ang (1-7)-MasR axis may present a potential protective role in the development of myocardial remodeling and may provide a new target for drug development of cardiac fibrosis. In conclusion, Olm is superior to Tel in inhibiting myocardial local Ang II level reducing myocardial collagen deposition and improving myocardial remodeling by upregulating the expression of ACE2, Ang (1-7) and MasR. PMID- 28656298 TI - Interleukin-17 antagonist attenuates lung inflammation through inhibition of the ERK1/2 and NF-kappaB pathway in LPS-induced acute lung injury. AB - Interleukin (IL)-17 has been implicated in a variety of inflammatory lung diseases. However, little is known about the expression and biological role of IL 17 in acute lung injury (ALI). Therefore, the aim of the present study was to confirm whether the increase in IL-17 expression following ALI enhances expression of inflammatory cytokines/chemokines through activation of the extracellular signal-regulated kinase (ERK)1/2 and nuclear factor (NF)-kappaB signaling pathway in lipopolysaccharide (LPS)-induced acute lung injury; which, in turn, can be blocked by an IL-17 antagonist. The authors indicated that levels of IL-17 mRNA and protein were elevated in the bronchoalveolar lavage fluid (BALF) and lung tissues of ALI rats, and upregulation of IL-17 resulted in the enhanced severity of lung injury. Moreover, treatment with an IL-17 neutralizing antibody significantly inhibited the increases of parameters of ALI in rats, as evidenced by decreased histologic scores, BALF exudate volume, protein leakage and wet-to-dry weight ratio. In addition, management of IL-17 may markedly mitigate LPS-induced pulmonary inflammation, as reflected by the reduced levels of a multitude of proinflammatory cytokines in BALF. Of note, blockade of IL-17 effectively inhibited LPS-induced expression and activation of p-ERK1/2 and nuclear factor (NF)-kappaB p65 in lung tissues, and suppressed nuclear translocation of NF-kappaB p65. These results indicated that IL-17 serves an important role in LPS-induced ALI via stimulation of the ERK1/2 and NF-kappaB signaling pathway, and serves as a potential therapeutic target for treating LPS induced ALI. PMID- 28656299 TI - Utilization of E-cadherin by monocytes from tumour cells plays key roles in the progression of bone invasion by oral squamous cell carcinoma. AB - E-cadherin (E-cad) is recently reported to be expressed in early stages of osteoclastogenesis, and blocking E-cad with neutralizing antibodies decreases osteoclast differentiation. Since our previous research demonstrates the loss of E-cad protein in the bone invasion by oral squamous cell carcinoma (OSCC), we hypothesize that E-cad may be utilized by monocytes to fuse and differentiate into osteoclasts. Two research models are used in the present study to explore our hypothesis. On one hand, we use OSCC cells of SCC25 to establish an animal model of bone invasion by OSCC, and investigate whether E-cad protein disappears in vivo; on the other hand, we use the indirect co-culture model of SCC25 and RAW 264.7 cells, with the treatment of transforming growth factor-beta1 (TGF-beta1), and observe whether the decreased E-cad protein is 'hijacked' in vitro. Results showed the animal model of OSCC with bone invasion was successfully established. Immunohistochemistry (IHC) found similar changes of E-cad protein, which was weakly stained by tumour cells. By using 5 ng/ml of TGF-beta1, we confirmed the artificial epithelial-mesenchymal transition (EMT) of SCC25 cells, with changes of EMT marker expression and cell morphology. Real-time PCR showed E-cad mRNA decreased in SCC25 while increased in RAW 264.7 of the indirect cell co-culture model, and immunofluoresence (IF) observed the evident switch of E-cad staining from SCC25 to RAW 264.7. With the supplement of receptor activator of NF-kappaB ligand (RANKL), tartrate-resistant acid phosphatase (TRAP) and F-actin staining confirmed the increased number of osteoclasts. Taken together, our study found the switch of E-cad protein in the progression of bone invasion by OSCC. The loss of E-cad in tumour cells may be utilized by monocytes to differentiate into osteoclasts, thus further explaining the underlying mechanisms of bone invasion by OSCC, which may supply clues for future molecular biotherapies. PMID- 28656300 TI - Paecilomyces tenuipes extract prevents depression-like behaviors in chronic unpredictable mild stress-induced rat model via modulation of neurotransmitters. AB - The medicinal fungus Paecilomyces tenuipes exhibits a variety of pharmacological effects, including antidepressive effects. The chronic unpredictable mild stress (CUMS)-induced rat model has served an important role in studies involving antidepressants screening. The aim of the present study was to evaluate the antidepressant-like activity of P. tenuipes N45 aqueous extract (PTNE) in a CUMS induced rat model of behavioral despair depression. Following 4 weeks of PTNE treatment, behavioral tests were conducted to investigate the antidepressant-like activities, and the levels of neurotransmitters and hormones in blood and hypothalamus were measured. The results demonstrated that PTNE treatment significantly increased movement in the forced running test, whereas the immobility time was reduced in the hotplate test and the forced swim test in depression-model rats. PTNE treatment was able to normalize the levels of hormones and neurotransmitters in serum and hypothalamus of CUMS rats. The data demonstrated that PTNE treatment may be a potential pharmaceutical agent in treatment-resistant depression, and the effects of PTNE may be partly mediated through normalizing the levels of neurotransmitters. PMID- 28656301 TI - Involvement of exogenous 3-deoxyglucosone in beta-cell dysfunction induces impaired glucose regulation. AB - beta-cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1,2-dicarbonyl compounds, such as 3-deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair beta-cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre-diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing beta-cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose-stimulated insulin secretion in cultured pancreas islets and INS-1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin-PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ?Ins30-0/?G30-0. In 3DG-treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased beta-cell function. This idea was further supported by these results that non-cytotoxic 3DG concentration obviously decreased glucose stimulated insulin secretion in cultured pancreas islets and INS-1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS-1, PI3K-p85 and Akt in high glucose-induced INS-1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from beta-cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing beta-cell dysfunction, at least in part, through impairing IRS-1/PI3K/GLUT2 signaling. PMID- 28656302 TI - Inactivation of MSH3 by promoter methylation correlates with primary tumor stage in nasopharyngeal carcinoma. AB - The aim of this study was to investigate the inactivation of the MutS homolog human 3 (MSH3) gene by promoter methylation in nasopharyngeal carcinoma (NPC). Methylation-specific PCR, semi-quantitative reverse transcription PCR and immunohistochemical analysis were used to detect methylation and the mRNA and protein expression levels of MSH3 in 54 cases of NPC tissues and 16 cases of normal nasopharyngeal epithelial (NNE) tissues. The association between promoter methylation and mRNA expression, and the mRNA and protein expression of the gene and clinical factors was analyzed. The promoter methylation of MSH3 was detected in 50% (27/54) of the primary tumors, but not in the 16 NNE tissues. The mRNA and protein expression levels were significantly decreased in the 54 cases of human NPC as compared to the 16 NNE tissues (P<0.05). The MSH3-methylated cases exhibited significantly lower mRNA and protein expression levels than the unmethylated cases (P<0.05). The MSH3 mRNA and protein expression levels were significantly associated with the variable T stage (P<0.05); however, they did not correlate with the age and sex of the patients, or with the N stage, TNM classification or histopathological subtype (P>0.05). On the whole, MSH3 was frequently inactivated by promoter methylation and its mRNA and protein expression correlated with the primary tumor stage in NPC. PMID- 28656303 TI - Resveratrol reversed chronic restraint stress-induced impaired cognitive function in rats. AB - Chronic stress occurs in everyday life, and often results in memory impairments and depressive symptoms. Resveratrol is a natural polyphenol that possesses numerous biological properties, including potent antidepressant-like effects. The present study aimed to examine the effects of resveratrol treatment on chronic restraint stress (CRS)-induced cognitive impairment and to explore the underlying molecular mechanisms. Male Wistar rats were exposed to CRS for 21 days in order to induce depressive-like behavior. The results demonstrated that CRS (6 h/day, 21 days) was able to induce cognitive deficits in rats, as evidenced by Morris water maze and novel object recognition tests. In addition, CRS exposure significantly decreased the mRNA and protein expression levels of hippocampal brain-derived neurotrophic factor (BDNF) in the rats. Conversely, chronic treatment with resveratrol (80 mg/kg, i.p.; 21 days) significantly prevented the behavioral and biochemical alterations induced by CRS. The effects of resveratrol were nearly identical to those observed with fluoxetine treatment. In conclusion, the present study demonstrated that resveratrol may be a potential therapeutic agent for the treatment of chronic stress-induced cognitive impairments, and its underlying molecular mechanism may be associated with the increased levels of hippocampal BDNF. PMID- 28656304 TI - miR-138 inhibits gastric cancer growth by suppressing SOX4. AB - MicroRNA-138 (miR-138) has been reported to be downregulated and function as a tumor suppressor in several cancers. However, the role and molecular mechanisms of miR-138 in the progression of gastric cancer (GC) remain to be clarified. The aim of the present study was to determine the role of miR-138 in GC progression. In the present study we found that miR-138 expression was downregulated in GC tissues and cell lines. Statistical analysis demonstrated that low expression levels of miR-138 were associated with advanced tumor-node-metastasis (TNM) stage, and lymph node metastasis. Function assays demonstrated that overexpression of miR-138 impaired GC cell proliferation, colony formation, migration and invasion in vitro, as well as suppressed tumor growth in vivo. Through reporter gene, qRT-PCR and western blot assays, SRY-related high mobility group box 4 (SOX4), a master mediator in epithelial-mesenchymal transition (EMT), was confirmed to be a direct target of miR-138 in GC cells. Western blot assay revealed that miR-138 overexpression inhibited EMT procession in GC cells by upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers, N-cadherin and vimentin. Furthermore, the levels of miR-138 were inversely correlated with those of SOX4 expression in GC tissues. Overexpression of SOX4 rescued the inhibition effect in GC cells caused by miR-138. Collectively, these findings indicate that miR-138 may be a potential therapeutic target for GC. PMID- 28656305 TI - Cetuximab promotes SN38 sensitivity via suppression of heat shock protein 27 in colorectal cancer cells with wild-type RAS. AB - Combination treatment with cetuximab and CPT-11 produces beneficial and synergistic effects in wild-type RAS metastatic colorectal cancer (mCRC) patients. However, the mechanism underlying this synergism is not yet understood. We examined whether cetuximab had a synergistic effect with CPT-11 and its active metabolite, SN38, and examined the molecular mechanism of the synergism between cetuximab and SN38 in CRC cells with various mutational status. We hypothesized that cetuximab promotes sensitivity to SN38 via suppression of heat shock protein 27 (HSP27), a protein involved in multidrug resistance through blocking the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, which is associated with chemosensitivity. Four human CRC cell lines with different RAS and BRAF mutational status were used. Expression levels of HSP27 protein correlated with SN38 sensitivity in these cell lines (R=0.841, p=0.159). Exposure to cetuximab and various concentration of AG490, an inhibitor of JAK2, STAT3 and HSP27 protein levels, except in the KRAS G12V mutant line, SW620. A synergistic effect of cetuximab in combination with SN38 was observed in RAS and BRAF wild-type cells (here, Caco2), but not in the three other RAS- or BRAF-mutated cell lines. These results indicate that cetuximab may promote sensitivity to SN38 via suppression of HSP27 through blocking the JAK/STAT pathway in Caco2 cells. The mutational status of numerous downstream effectors, such as RAS and BRAF, is important in mono- or combination therapy with cetuximab. In conclusion, cetuximab may promote SN38 sensitivity via suppression of HSP27, through blocking the JAK/STAT signaling pathway, and shows synergistic effects when combined with SN38 in wild-type RAS CRC cells. PMID- 28656306 TI - 99Tc-MDP-induced human osteoblast proliferation, differentiation and expression of osteoprotegerin. AB - The aim of the present study was to examine the influence of technetium methylenediphosphonate (99Tc-MDP) on the proliferation and differentiation of human osteoblasts. Human iliac cancellous bone was isolated and cultured with either 99Tc-MDP, beta fibroblast growth factor (as a positive control) or medium only (as a negative control). Proliferation was assessed by direct cell counting, CCK-8 assay and bromodeoxyuridine staining. The cell cycle and rate of apoptosis was assessed by propidium iodide staining and flow cytometry. Alkaline phosphatase (ALP) activity was assessed by the p-nitrophenyl phosphate method and mineralized nodules were stained with Alizarin Red. Expression of osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2) was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and expression levels of osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) were assessed by RT-qPCR and ELISA. Isolated human osteoblasts stained positively for ALP and developed mineralized nodules. Treatment with 10-5-10-10 M 99Tc-MDP enhanced proliferation and 48 h incubation with 10-8 M 99Tc-MDP increased the proportion of cells in S-phase, decreased the proportion in G0/G1 phase, and increased the cell proliferation index. The rate of apoptosis also increased, but the increase was not significant. Cells incubated with 10-6-10-9 M 99Tc-MDP for 3-9 days exhibited increased ALP activity and mineralized nodule development. 10-8 M 99Tc-MDP increased BMP-2 and OPG expression levels and OPG secretion, but OCN mRNA expression levels and RANKL secretion were not significantly altered at 72 h. 99Tc-MDP treatment induced osteoblast proliferation and differentiation without affecting apoptosis. These findings provide proof of concept for the future use of 99Tc-MDP in the treatment of bone destructive diseases. PMID- 28656308 TI - Progress in mass spectrometry-based proteomic research of tumor hypoxia (Review). AB - A hypoxic microenvironment effects various signaling pathways in the human body, including those that are critical for normal physiology and those that support tumorigenesis or cancer progression. A hypoxic tumor microenvironment, in particular, modulates cell migration, invasion and resistance to radiotherapy and chemotherapy. Development of the mass spectrometry (MS) technique has allowed for expansion of proteomic study to a wide variety of fields, with the study of tumor hypoxia being among the latest to enjoy its benefits. In such studies, changes in the proteome of tumor tissue or cells induced by the hypoxic conditions are analyzed. A multitude of hypoxic regulatory proteins have already been identified, increasing our understanding of the mechanisms underlying tumor occurrence and development and representing candidate reference markers for tumor diagnosis and therapy. The present review provides the first summary of the collective studies on tumor microenvironment hypoxia that have been completed using MS-based proteomic techniques, providing a systematic discussion of the benefits and current challenges of the various applications. PMID- 28656307 TI - SIRT6 inhibits growth of gastric cancer by inhibiting JAK2/STAT3 pathway. AB - SIRT6, a member of NAD positivity-dependent class III deacetylase sirtuin family, played versatile roles in human cancers. However, the expression and biological function of SIRT6 in gastric cancer (GC) remain to be investigated. In this study, we found that SIRT6 expression level was decreased in gastric cancer tissues and cell lines. Decreased SIRT6 expression was associated with unfavorable clinical parameters including tumor differentiation, tumor size and TNM stage. Importantly, decreased level of SIRT6 was associated with decreased rate of overall survival (OS) and disease-free survival (DFS). Functionally, overexpression of SIRT6 in both BGC823 and SGC7901 cells inhibited cell viability and proliferation of GC cells. Furthermore, overexpression of SIRT6 in both BGC823 and SGC7901 cells prevented the cell cycle progress and increased cell apoptosis. In vivo experiments demonstrated that forced expression of SIRT6 in SGC-7901 cells inhibited the growth of SGC7901 cells in nude mice. Furthermore, the IHC staining for GC tissues showed that expression level of SIRT6 was decreased in GC tissues while the expression level of p-STAT3 was increased in GC tissues. GC tissues with high SIRT6 level showed significantly decreased level of p-STAT3. Mechanically, we demonstrated that SIRT6 blocked the activation of JAK2/STAT3 and inhibited the expression of cyclin D1 and Bcl2 which were downstream targets of JAK2/STAT3 pathway. Taken together, this study indicates that SIRT6 inhibits the growth of gastric cancer by inhibiting JAK2/STAT3 pathway. PMID- 28656309 TI - Nifedipine stimulates proliferation and migration of different breast cancer cells by distinct pathways. AB - Nifedipine is widely used to treat high blood pressure and angina. Were nifedipine able to promote the proliferation and migration of breast cancer, it would pose a significant threat for patients. Thus, it is important to determine the effects of nifedipine on breast cancer and the mechanism involved. The present study identified that nifedipine significantly promoted the proliferation and migration of breast cancer cells in vitro. The mechanism of nifedipine on different breast cancer cells was investigated and it was identified that the effects of nifedipine on MCF-7 cells were via the protein kinase B-endothelial constitutive nitric oxide synthase-nitric oxide axis, and on MDA-MB-231 cells via activation of the extracellular signal-regulated kinase pathway. These results identified the distinct pathways in the activation of cell proliferation and migration presented in different cell lines by nifedipine. The present study advises that nifedipine can promote breast cancer and should be avoided for women who suffer from breast cancer and hypertension. PMID- 28656310 TI - KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling. AB - Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor, which was confirmed as a tumor suppressor gene in colorectal cancers. KLF4 inhibits colorectal cancer cells proliferation through upregulating p21WAF1/Cip1 and downregulating cyclin D1. We firstly reported that N-Myc downstream regulated gene 2 (NDRG2) was a novel tumor suppressor gene in multiple cancers, such as glioma, breast cancer and colorectal cancer. Herein, we provide novel evidence that KLF4 can transcriptionally activate NDRG2 by binding with NDRG2 promoter. With MTT assay, EdU staining, colony formation assay and xenograft mouse model, we confirmed that KLF4 inhibited colorectal cancer cell proliferation and tumorigenesis dependent on NDRG2. Finally, with tissue array analysis, we found a positive correlation of combined detection of KLF4/NDRG2 co-expression with TNM grades and differentiation levels of colorectal cancer. Lower expression of KLF4 and NDRG2 in colorectal cancer patients was correlated with poor overall survival. Thus, KLF4 inhibited the proliferation of colorectal cancer cells dependent on NDRG2 signaling, which provides a novel strategy for therapy and early diagnosis of colorectal cancer. PMID- 28656311 TI - Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation. AB - The beneficial health properties of the Mediter-ranean diet are well recognized. The principle source of fat in Mediterranean diet is extra-virgin olive oil (EVOO). Oleocanthal (OC) is a naturally occurring minor phenolic compound isolated from EVOO, which has shown a potent anti-inflammatory activity, by means of its ability to inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2. A large body of evidence indicates that phenols exhibit anticancer activities. The aim of the present study was to evaluate the potential anticancer effects of OC in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) models. A panel of human HCC (HepG2, Huh7, Hep3B and PLC/PRF/5) and CRC (HT29, SW480) cell lines was used. Cells were treated with OC, and cell viability and apoptosis were evaluated. Compared with classical commercially available COX inhibitors (ibuprofen, indomethacin, nimesulide), OC was more effective in inducing cell growth inhibition in HCC and CRC cells. Moreover, OC inhibited colony formation and induced apoptosis, as confirmed by PARP cleavage, activation of caspases 3/7 and chromatin condensation. OC treatment in a dose dependent-manner induced expression of gammaH2AX, a marker of DNA damage, increased intracellular ROS production and caused mitochondrial depolarization. Moreover, the effects of OC were suppressed by the ROS scavenger N-acetyl-L-cysteine. Finally, OC was not toxic in primary normal human hepatocytes. In conclusion, OC treatment was found to exert a potent anticancer activity against HCC and CRC cells. Taken together, our findings provide preclinical support of the chemotherapeutic potential of EVOO against cancer. PMID- 28656312 TI - Nogo receptor knockdown and ciliary neurotrophic factor attenuate diabetic retinopathy in streptozotocin-induced diabetic rats. AB - Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM). We investigated whether Nogo receptor (NgR) knockdown and ciliary neurotrophic factor (CNTF) treatment, either alone or in combination, ameliorated diabetic retinopathy (DR) in diabetic rat model. STZ-induced diabetic rats were administrated for a total of 12 weeks with 3 uM siRNA (5 ul) once every 6 weeks and/or 1 ug CNTF weekly. The retinal tissues were excised. We measured cell number in ganglion cell layer (GCL) using H&E staining and cell apoptosis using TUNEL assay. Bax, Bcl-2, Caspase-3, F-actin, GAP-43, NgR, RhoA and Rock1 levels were then analyzed by Western blotting, Immunohistochemistry or Real-time PCR. We found that NgR siRNA or CNTF injection alone significantly increased cell count in GCL in diabetic rats, inhibited ganglion cell apoptosis, elevated Bcl-2, F actin and GAP-43, and decreased Bax, Caspase-3, NgR, RhoA and Rock1 levels. Combination treatment further prevented retinal ganglion cell loss, enhanced growth cone cytoskeleton and axonal regeneration, and suppressed NgR/RhoA/Rock1. Our results indicate that combination therapy has therapeutic potential for the treatment of DR. PMID- 28656314 TI - Suppression of gastric cancer by extract from the tuber of amorphophallus konjac via induction of apoptosis and autophagy. AB - The tuber of amorphophallus konjac (TuAK) is an antitumor herb used in traditional Chinese medicine. The present study investigated the inhibitory effect of TuAK against gastric cancer and the underlying mechanisms associated with two programmed cell death pathways, apoptosis and autophagy. TuAK was extracted by organic solvents including ethanol and ligarine. The extract of TuAK, shortened as TuAKe, significantly inhibited the growth of cultured gastric cancer cell lines SGC-7901 and AGS, with IC50 of 35-45 ug/ml. TuAKe could increase cell apoptosis and induce cell cycle arrest. For the apoptosis associated proteins, expressions of survivin and Bcl-2 were decreased by treatment of TuAKe, and the expression of Bax and caspase-9 was increased. Furthermore, TuAKe could promote autophagy, and the antitumor efficacy of TuAKe was significantly hampered by targeted suppression of autophagy, suggesting that autophagy contributed to TuAKe-induced cell death. Furthermore, patients with gastric cancer who received TuAK-based medicinal decoction achieved improved scores in assessment of life quality compared with those without TuAK treatment. This study demonstrated the antitumor activity of TuAKe against gastric cancer, and is the first report to show that the underlying mechanism is associated with induction of autophagy. Our data provided support of the clinical use of amorphophallus konjac-based medication in combination with classical chemotherapy to achieve optimized outcome for gastric cancer. PMID- 28656313 TI - Dopamine attenuates ethanol-induced neuroapoptosis in the developing rat retina via the cAMP/PKA pathway. AB - Apoptosis has been identified as the primary cause of fetal alcohol spectrum disorder (FASD), and the development of methods to prevent and treat FASD have been based on the mechanisms of alcohol-induced apoptosis. The present study aimed to explore the effects of dopamine on alcohol-induced neuronal apoptosis using whole-mount cultures of rat retinas (postnatal day 7). Retinas were initially incubated with ethanol (100, 200 or 500 mM), and in subsequent analyses retinas were co-incubated with ethanol (200 mM) and dopamine (10 uM). In addition, several antagonists and inhibitors were used, including a D1 dopamine receptor (D1R) antagonist (SCH23390; 10 uM), a D2R antagonist (raclopride; 40 uM), an adenosine A2A receptor (AA2AR) antagonist (SCH58261; 100 nM), an adenylyl cyclase (AC) inhibitor (SQ22536; 100 uM) and a PKA inhibitor (H-89; 1 uM). The results demonstrated that exposure increased neuroapoptosis in the retinal ganglion cell layer (GCL) in a dose-dependent manner. Dopamine treatment significantly attenuated ethanol-induced neuronal apoptosis. D1R, D2R and AA2AR antagonists partially inhibited the protective effects of dopamine against ethanol-induced apoptosis; similar results were observed with AC and PKA inhibitor treatments. In summary, the present study demonstrated that dopamine treatment may be able to attenuate alcohol-induced neuroapoptosis in the developing rat retina by activating D1R, D2R and AA2AR, and by upregulating cyclic AMP/protein kinase A signaling. PMID- 28656315 TI - Transcriptome profiling of cancer and normal tissues from cervical squamous cancer patients by deep sequencing. AB - Cervical cancer is the fourth leading cause of cancer mortality in women worldwide. High-risk human papillomavirus infection is a major cause of cervical cancer. A previous study revealed the role of different oncogenes and tumor suppressors in cervical cancer initiation and progression. However, the complicated genetic network regulating cervical cancer remains largely unknown. The present study reported transcriptome sequencing analysis of three cervical squamous cell cancer tissues and paired normal cervical tissues. Transcriptomic analysis revealed that 2,519 genes were differently expressed between cervical cancer tissues and their corresponding normal tissues. Among these, 236 differentially expressed genes (DEGs) were statistically significant, including many DEGs that were novel in cervical cancer, including gastrulation brain homeobox 2,5-hydroxytryptamine receptor 1D and endothelin 3. These 236 significant DEGs were highly enriched in 28 functional gene ontology categories. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis suggested involvement of these DEGs in multiple pathways. The present study provides a transcriptome landscape of cervical cancer in Chinese patients and an improved understanding of the genetic regulatory network in cervical cancer tumorigenesis. PMID- 28656316 TI - Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells. AB - Drug resistance in chemotherapy is a serious obstacle for the successful treatment of cancer. Drug resistance is caused by various factors, including the overexpression of P-glycoprotein (P-gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin-resistant breast cancer cells (MCF-7/ADR). In our experiments, apigenin significantly decreased cell growth and colony formation in MCF-7/ADR cells and parental MCF-7 cells. This growth inhibition was related to the accumulation of cells in the sub-G0/G1 apoptotic population and an increase in the number of apoptotic cells. Apigenin reduced the mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated proteins (MRPs) in MCF 7/ADR cells. Apigenin also downregulated the expression of P-gp. Apigenin reversed drug efflux from MCF-7/ADR cells, resulting in rhodamine 123 (Rho123) accumulation. Inhibition of drug resistance by apigenin is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Apigenin decreased STAT3 activation (p-STAT3) and its nuclear translocation and inhibited the secretion of VEGF and MMP-9, which are STAT3 target genes. A STAT3 inhibitor, JAK inhibitor I and an HIF-1alpha inhibitor decreased cell growth in MCF-7 and MCF-7/ADR cells. Taken together, these results demonstrate that apigenin can overcome drug resistance. PMID- 28656317 TI - [Imaging representation of peripheral veins]. AB - Several techniques are available for imaging of the venous system of the legs and pelvic region. In cases of suspected deep leg vein thrombosis B-mode compression ultrasound is applied. Its accuracy is sufficient to either confirm or exclude the diagnosis with certainty. For examination of the iliac veins, however, flow information has to be added by pulsed wave (PW) Doppler or color Doppler sonography. In cases of suspected arm vein thrombosis, ultrasound is also the method of choice. The more proximal or the central parts of the venous system, i. e. brachiocephalic veins or the superior and inferior vena cava can be visualized by cross-sectional imaging procedures. Computed tomography (CT) angiography accurately shows the vessel lumen and magnetic resonance imaging (MRI) provides more details of the surrounding soft tissue. The use of classical contrast medium phlebography is nowadays restricted to interventions on proximal or central parts of the venous system. In addition, venous imaging is required in the field of chronic venous insufficiency. For both differential diagnostics and choice of treatment options, e. g. for varicose veins, the mainstay is venous ultrasound. PMID- 28656318 TI - Efficiency of fragment specific fixation plates in the treatment of comminuted distal radial fractures. AB - PURPOSE: The purpose of this study was to assess the clinical, radiologic and functional outcome of treating comminuted intra-articular distal radius fractures with fragment specific fixation. METHODS: This was a retrospective chart review of 25 unstable intra-articular distal radius fractures (type C2 AO) that had fragment specific fixation done in the orthopaedic department of the Hamad General Hospital (level 1 trauma center) over three years (2010-2013), with a follow up of one year post-operatively. Pre-operative X-rays (wrist parameters) were compared to post-operative X-rays at different time points (i.e. 6 weeks, 3 months, 6 months, etc.). Range of motion and grip strength were recorded at different time points until the final follow up evaluation. All the data has been obtained from patients' charts (including outpatient and occupational therapy rehabilitation range of motion data) after final approval from the Hamad Corporation medical research center/Ethics committee. RESULTS: There were 25 patients ranging in age from 24 to 58 years with 13 patients above 35 years (52%) and 12 patients below 35 years (48%). There were 22 males (88%) and 3 females (12%) with different mechanisms of injury such as falling from height (average 2 metres), which was the most common with 13 patients (52%), and most were work related. Left wrist was more common than right wrist injuries and mostly in the non-dominant hand with 14 patients (56%). There was an obvious improvement between pre and post-operative wrist parameters at different time points, but P values were not significant; supination and pronation at six weeks of follow up showed significant values (p = 0.04 & 0.03, respectively). Grip strength improved about 76% compared to the normal side. CONCLUSIONS: Fragment specific fixation is a reasonable alternative for treating intra-articular distal radius fractures. At final follow up evaluations, results showed a better clinical, radiological and functional outcome. Stable fixation allowed starting active and passive motion of the wrist without compromising post-operative alignment. PMID- 28656319 TI - Erratum to: Impairment of pH gradient and membrane potential mediates redox dysfunction in the mitochondria of the post-ischemic heart. PMID- 28656321 TI - [Sports activities after osteotomies around the knee]. AB - In the current literature, the rate of return to sports following high tibial osteotomy is high. Patients are largely able to carry out the type of exercise done before the onset of symptoms and are satisfied with the clinical outcome. In general, however, a differentiated view of the sporting ability should be made, and the different requirements of the sport should be considered. A classification according to functional and biomechanical movement analysis seems to advisable. In addition, the recommendations of the treating physician seem to have a high impact on the postoperative level of the sports activities of the patients. A realistic assessment (by both the patient and the treating physician) that considers the sport, its requirements and the level of performance is necessary. PMID- 28656320 TI - Rho-kinase and the nitric oxide pathway modulate basilar arterial reactivity to acetylcholine and angiotensin II in streptozotocin-induced diabetic mice. AB - Diabetes mellitus comprises a heterogeneous group of metabolic disorders with underlying hyperglycemia and secondary cardiovascular complications. Growing evidence suggests that vascular dysfunction is among the most important causes of diabetic cardiovascular disease. Therefore, we determined whether streptozotocin (STZ)-induced diabetes in mice affects blood pressure and cerebral arterial responsiveness to angiotensin (Ang) II and acetylcholine (ACh), which are important modulators of cerebrovascular autoregulation. Diabetes was induced using a single intraperitoneal injection of STZ (50 mg/kg). Blood pressure was measured in conscious mice using the indirect tail-cuff method. Functional studies of the isolated arteries' response to vasoactive substances were performed using a micro-organ-bath system at 60 days after STZ injection. Systolic, diastolic, and mean blood pressures significantly increased at days 45 and 60 in the STZ-induced diabetic mice. In the isolated basilar arteries, ACh induced relaxation, which is dependent on nitric oxide (NO) production from endothelial cells, decreased. In contrast, Ang II-induced contraction, mediated via rho-kinase activation in the smooth muscle, increased in the diabetic mice. There was significantly greater relaxation in the precontracted isolated basilar arteries of diabetic mice that had been treated with Y27632, a rho-kinase inhibitor, than in the control mice arteries. Pretreatment with Nomega-nitro-L arginine (L-NAME), an NO synthase inhibitor, significantly enhanced Ang II induced contraction and Y27632-induced relaxation in the control basilar arteries but not in the STZ-induced diabetic mice arteries. These results suggest that decreased NO bioavailability and enhanced rho-kinase activity in basilar arteries contribute to altered reactivity to ACh and Ang II, respectively, in STZ-induced diabetic mice. PMID- 28656322 TI - The remedy within: will the microbiome fulfill its therapeutic promise? AB - The last decade of research has witnessed a tremendous upsurge in our understanding of the intestinal microbiome and its role in a large range of human diseases, which has incited hopes for a rapid clinical utilization of the new insights for the development of microbiome-based therapies. Nonetheless, only a single microbiome-targeted therapy has so far found its way into clinical routine: fecal microbiota transplantation for patients suffering from recurrent Clostridium difficile infections. Herein, we discuss the current hopes, advances, challenges, and obstacles for translating basic microbiome research into therapeutic applications for a larger number of diseases and provide an outline of how such clinical applications might emerge. PMID- 28656323 TI - Mediation of the effect of childhood socioeconomic position by educational attainment on adult chronic disease in Chile. AB - OBJECTIVES: We estimated the roles of childhood socioeconomic position (ChSEP) and education attainment on chronic diseases in Chilean adults, mediated through structural determinants and health behaviors, to identify potential pro-equity interventions. METHODS: We analyzed Chile's longitudinal Social Protection Surveys, a national sample of 14,788 adults with follow-up to 2009. Controlled direct effects (CDE) and natural effects (NDE and NIE) of ChSEP and education on number of chronic diseases were estimated with negative binomial models. RESULTS: CDE of low ChSEP with education fixed at 12 years showed a 12% increase with 4% indirect effects. CDEs at favorable levels of BMI, smoking, alcohol use, and physical activity were similar. CDE estimates for education adjusted for ChSEP were larger with negligible mediation. CDEs for women were generally larger. CONCLUSIONS: Low ChSEP exerts a primarily direct effect on later chronic disease, modestly mediated by education. Education attainment showed larger direct effects with minimal mediation by behaviors. Strengthening current-early child development and education policies, particularly gender aspects, may reduce social inequalities and key pathways for reducing chronic disease inequalities in Chile. PMID- 28656325 TI - Over-expression of GmSN1 enhances virus resistance in Arabidopsis and soybean. AB - KEY MESSAGE: GmSN1 enhances virus resistance in plants most likely by affecting the expression of signal transduction and immune response genes. Soybean mosaic virus (SMV) infection causes severe symptom and leads to massive yield loss in soybean (Glycine max). By comparative analyzing gene expression in the SMV resistant soybean cultivar Rsmv1 and the susceptible cultivar Ssmv1 at a transcriptome level, we found that a subgroup of Gibberellic Acid Stimulated Transcript (GAST) genes were down-regulated in SMV inoculated Ssmv1 plants, but not Rsmv1 plants. Sequence alignment and phylogenetic analysis indicated that one of the GAST genes, GmSN1, was closely related to Snakin-1, a well-characterized potato microbial disease resistance gene. When over-expressed in Arabidopsis and soybean, respectively, under the control of the 35S promoter, GmSN1 enhanced turnip mosaic virus resistance in the transgenic Arabidopsis plants, and SMV resistance in the transgenic soybean plants, respectively. Transcriptome analysis results showed that the up-regulated genes in the 35S:GmSN1 transgenic Arabidopsis plants were largely enriched in functional terms including "signal transduction" and "immune response". Real-time PCR assay indicated that the expression of GmAKT2, a potassium channel gene known to enhance SMV resistance when over-expressed in soybean, was elevated in the 35S:GmSN1 transgenic soybean plants. Taken together, our results suggest that GmSN1 enhances virus resistance in plants most likely by affecting the expression of signal transduction and immune response genes. PMID- 28656324 TI - GR1-like gene expression in Lycium chinense was regulated by cadmium-induced endogenous jasmonic acids accumulation. AB - KEY MESSAGE: The G1-like gene from the Lycium chinense was cloned and transferred into N. tabacum. Evidence showed that endogenous JA accumulation was crucial to LcGR gene expression in cadmium-stressed L. chinense. Glutathione reductase (GR) plays a vital role in glutathione-ascorbate metabolism and is a key enzyme in maintaining the redox state in plants. Jasmonic acids (JA) are important hormones regulating protective responses against bacteria and mechanic damage in plants. At present, the relationship between the endogenous JA accumulation, the glutathione (GSH) content and GR gene expression in plants under cadmium (Cd) stress has not been elucidated. This study primarily aims to explore their interconnected relations. First, we isolated the GR1-like gene from Lycium chinense (LcGR). Real-time PCR showed that gene LcGR and allene oxide cyclase (LcAOC) (a JA synthesis gene) expression in L. chinense plants was significantly enhanced by CdCl2 and reduced by CdCl2 cotreatment with 12,13-epoxy-octadecenoic acid (EOA), a JA synthesis inhibitor. Meanwhile, the JA content in plants strongly increased under Cd stress and decreased under Cd + EOA treatment, which was in accordance with expression pattern of LcAOC. The function of gene LcGR was confirmed in vitro with E. coli expression system. The subcellular localization in chloroplasts of LcGR gene was proved in Nicotiana tabacum leaves with transient transfection system of Agrobacterium tumefaciens. Furthermore, the overexpression of gene LcGR in the transgenic tabacum led to great Cd-tolerance and higher GSH accumulation. Overall, the results showed that the endogenous JA accumulation in Cd-stressed plants affects the GR expression which is crucial to the GSH accumulation and GSH-dependent tolerance to cadmium in LcGR transformants. PMID- 28656328 TI - Core curriculum illustration: blunt traumatic diaphragmatic hernia. AB - This is the 43rd installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.erad.org/page/CCIP_TOC . PMID- 28656327 TI - Detection of human T-cell lymphotropic virus type I-specific cytotoxic T-cells may predict treatment responses in adult T-cell leukemia/lymphoma patients. PMID- 28656326 TI - Advanced virtual monochromatic reconstruction of dual-energy unenhanced brain computed tomography in children: comparison of image quality against standard mono-energetic images and conventional polychromatic computed tomography. AB - BACKGROUND: Advanced virtual monochromatic reconstruction from dual-energy brain CT has not been evaluated in children. OBJECTIVE: To determine the most effective advanced virtual monochromatic imaging energy level for maximizing pediatric brain parenchymal image quality in dual-energy unenhanced brain CT and to compare this technique with conventional monochromatic reconstruction and polychromatic scanning. MATERIALS AND METHODS: Using both conventional (Mono) and advanced monochromatic reconstruction (Mono+) techniques, we retrospectively reconstructed 13 virtual monochromatic imaging energy levels from 40 keV to 100 keV in 5-keV increments from dual-source, dual-energy unenhanced brain CT scans obtained in 23 children. We analyzed gray and white matter noise ratios, signal-to-noise ratios and contrast-to-noise ratio, and posterior fossa artifact. We chose the optimal mono-energetic levels and compared them with conventional CT. RESULTS: For Mono+maximum optima were observed at 60 keV, and minimum posterior fossa artifact at 70 keV. For Mono, optima were at 65-70 keV, with minimum posterior fossa artifact at 75 keV. Mono+ was superior to Mono and to polychromatic CT for image quality measures. Subjective analysis rated Mono+superior to other image sets. CONCLUSION: Optimal virtual monochromatic imaging using Mono+ algorithm demonstrated better image quality for gray-white matter differentiation and reduction of the artifact in the posterior fossa. PMID- 28656330 TI - [Comparison of transperitoneal laparoscopic and open pyeloplasty in children]. PMID- 28656329 TI - Sacral fractures: classification and management. AB - Sacral fractures are a common component of pelvic fracture patterns and are an increasingly diagnosed injury both due to increased utilization of CT in trauma evaluation as well as an increasing rate of sacral fragility fractures as a result of an increase in general population age. Innovations in minimally invasive surgical techniques have also resulted in an increasing number of sacral fractures undergoing surgical management. It is vital that physicians practicing in an emergency setting are aware of the injury patterns and management of this increasingly injured and treated component of the bony pelvis. This article reviews the sacral anatomy as well as discusses the role of imaging and imaging appearance of sacral fractures. Sacral fracture patterns are described along with both historic and newer classification systems for sacral fractures and current management of sacral fracture. PMID- 28656331 TI - [Master trainer concept "structured specialist further education" : A joint project of the German Professional Associations of Internal Medicine, Surgeons and Orthopedic/Trauma Surgeons]. AB - BACKGROUND: The quality requirements in the practice of postgradual medical further education below the normal level of the further education regulations is a barely developed scientific field in Germany. A systematic use of internationally accepted scientific evidence barely exists. AIM: This research and development project was initiated in 2001 in order to be able to implement a practical but evidence-based model compatible with the existing structure of postgradual medical education. This project has been supported since 2013 by the Professional Associations of Internal Medicine (BDI), Surgeons (BDC) and Orthopedic and Trauma surgeons (BVOU). METHODS: The development phase of this complex intervention was based on three stages involving stakeholder interviews from relevant groups, the identification of a theoretical model for the construction and systematic literature reviews to identify the relevant evidence. RESULTS: The basic model for structured specialist further education developed included the creation and implementation of a simple core curriculum for every department, a tool for systematic feedback within the framework of the annual further education interviews and a simple clinical assessment to evaluate the actual clinical performance of physicians in further education. A pilot test of this model was carried out in 150 specialist departments in Germany and continually developed. DISCUSSION: The project shows that such a program can be systematically developed and pilot studies can be carried out. The central problems in implementation involve the traditional informal further education culture, which as a rule does not implement a systematic elicitation of the state of learning continuously distributed over the whole period of further education and the practical testing of competence development. PMID- 28656332 TI - [Unusual congenital iris finding]. PMID- 28656333 TI - Erratum to: The effect of a performance-based intra-procedural checklist on a simulated emergency laparoscopic task in novice surgeons. PMID- 28656334 TI - Impact of obesity on short- and long-term outcomes of laparoscopy assisted distal gastrectomy for gastric cancer. AB - BACKGROUND: Laparoscopy assisted distal gastrectomy (LADG) for gastric cancer has been rapidly adopted for the treatment of both early and advanced gastric cancers which need lymph node dissection, but remains difficult procedure, especially in patients with obesity. We evaluated the impact of obesity on short- and long-term outcomes of LADG for gastric cancer. METHODS: We retrospectively investigated 243 patients who underwent LADG for gastric cancer between January 2007 and December 2014. The patients were classified based on their body mass index (BMI) into the Obese (BMI >= 25) and Non-Obese (BMI < 25) Groups. Patient characteristics, clinicopathologic and operative findings, and short- and long-term outcomes were investigated and compared between the groups. RESULTS: The groups did not differ in age, sex, American Society of Anesthesiologists score, the presence of comorbidities, or pathologic stage. Operative time (265 +/- 46.6 vs. 244 +/- 55.6 min; P = 0.007) and estimated blood loss (113 +/- 101.4 vs. 66.5 +/- 95.2 ml; P = 0.007) were greater in the Obese Group. Fewer lymph nodes were retrieved in the Obese Group (38 +/- 23.7 vs. 47.5 +/- 24.3; P = 0.004). No differences were evident in postoperative complication rate (20% vs. 17%; P = 0.688) or the duration of postoperative hospital stay (9 +/- 8.5 vs. 9 +/- 5.1 days; P = 0.283) between the two groups. In the Obese Group, the 5-year overall survival rate was significantly lower than in the Non-Obese Group (67.6% vs. 90.3%; P = 0.036). Furthermore, 5-year disease-specific survival was significantly lower in the Obese Group than in the Non-Obese Group (72.7% vs. 94.9%; P = 0.015). CONCLUSIONS: LADG in patients with obesity could be performed as safe as in patients without obesity, with comparable postoperative results. But obesity may be a poor prognostic factor in gastric cancer. PMID- 28656335 TI - Gentamicin submucosal lavage during peroral endoscopic myotomy (POEM): a retrospective analysis. AB - BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) is an evolving therapeutic modality for achalasia. According to the original Inoue's technique, a submucosal lavage with gentamicin has been practiced due to the fear of infection. This single-tertiary center study was intended to assess the clinical significance of the topical antibiotic lavage during POEM. METHODS: A retrospective analysis of prospectively collected data was conducted. The outcomes of patients who received the gentamicin lavage (group A) during POEM were compared to those who did not (group B). The main outcome variables were infectious adverse events, post-POEM fever, and markers of systemic inflammatory response. One day before and after POEM, all patients received systemic antibiotic prophylaxis with ceftriaxone. RESULTS: Of 124 consecutive patients having undergone POEM, 60 patients received a lavage with 80 mg of gentamicin into the submucosal tunnel before starting the myotomy, while 64 patients did not. The overall treatment success at 3 months did not differ between the two groups (group A 94.7 vs. 97.5% group B). We did not experience any significant infectious adverse events in either group. CRP and WBC levels were lower in patients with lavage versus those without [CRP: median 52.7 (IQR 34.9) vs. 69.5 (54.1); p = 0.01; WBCs: median 10.9 (IQR 3.3) vs. 12.6 (3.9); p < 0.01]. Post-procedural fever was present in 10% of patients in either group. CONCLUSIONS: During POEM, the submucosal lavage with gentamicin prior to the myotomy does not play a role in the prevention of clinically significant infectious adverse events, although the systemic inflammatory response may be decreased. PMID- 28656336 TI - Multicenter evaluation of first-line endoscopic treatment with the OTSC in acute non-variceal upper gastrointestinal bleeding and comparison with the Rockall cohort: the FLETRock study. AB - INTRODUCTION: The over-the-scope clip (OTSC) overcomes limitations of standard clips and achieves a more efficient and reliable hemostasis in non-variceal upper gastrointestinal bleeding (NVUGIB). The study aims to evaluate mortality, rebleeding, and mortality after rebleeding of patients in whom the OTSC was used as the first-line endoscopic treatment (FLET) of NVUGIB. PATIENTS AND METHODS: In total, 118 patients (FLET cohort) with a median age of 73.5 years (range 29-93 years; mean (+/-SD) 71.39 +/- 12.39 years) were included. The distribution of patients with respect to risk category revealed a median Rockall score of 7 (range 3-10). For hypothesis testing, the FLET cohort was categorized into three risk groups taking into account the Rockall score: low risk [Rockall risk category (RRC <=3)], moderate risk (RRC 4-7), and high risk (RRC >=8). Event rates (mortality, rebleeding, and mortality after rebleeding) observed per risk group were compared to predicted event rates (Rockall cohort) using Fisher's Exact Test. RESULTS: Primary successful hemostasis (PSH) was achieved in 92.4% either by FLET alone or in combination with an additional hemostasis technique in 1.7% (SCS = secondary clinical success). In 7.5% of the FLET cohort PSH could not be achieved. Compared to RRC prediction, mortality after rebleeding was significantly reduced from 27.9 to 10.9% in the high-risk group (RRC >=8) treated with FLET (p < 0.011). Furthermore, the occurrence of rebleeding or continued bleeding was significantly lower in the moderate risk group (RRC 4-7) with 4.9% as well as in the high-risk group (RRC >=8) with 21.4% compared to the Rockall cohort 24.0 and 53.2%, respectively (p < 0.001). CONCLUSIONS: This study shows that OTSC is superior to standard care and FLET reduces significantly rebleeding and rebleeding-associated mortality in NVUGIB. For this reason, OTSC could be the treatment of choice as the first-line treatment as an alternative to standard hemostasis techniques in high-risk patients. PMID- 28656337 TI - Transanal Minimally Invasive Surgery (TAMIS): a clinical spotlight review. PMID- 28656338 TI - Risk factors for prolonged postoperative ileus after laparoscopic sphincter saving total mesorectal excision for rectal cancer: an analysis of 428 consecutive patients. AB - BACKGROUND: Prolonged postoperative ileus (PPOI) is a common complication after colorectal resection but data regarding PPOI risk factors after laparoscopic rectal cancer surgery is lacking. This study aimed to identify risk factors for PPOI after laparoscopic sphincter-saving total mesorectal excision (TME) for cancer. METHODS: All patients who underwent a laparoscopic sphincter-saving TME for cancer from 2005 to 2014 were identified from our prospective database. PPOI was defined as abdominal distension, nausea, and/or vomiting, requiring a nasogastric tube insertion, during the postoperative period. RESULTS: Among 428 consecutive patients, 65 patients (15%) presented with POI. In multivariate analysis, male gender (Odds Ratio (OR) 2.3 [1.1-4.5]; p = 0.026, age >70 years (OR: 2.0 [1.1-4.0]; p = 0.037)], conversion to open approach (OR 4.9 [1.5-15.4]; p = 0.007), and intra-abdominal surgical site infection (OR 3.8 [1.9-7.5]; p < 0.001) were identified as independent risk factor for PPOI. PPOI risk was 5% in patients without any risk factor but raised to 11, 28, and 54% in patients with 1, 2, or >=3 risk factors, respectively (p < 0.001). CONCLUSION: PPOI is observed in 15% of the patients after laparoscopic sphincter-saving surgery for rectal cancer. We identified four independent factors for PPOI in multivariate analysis: male, gender, age >70, conversion to open approach, and intra-abdominal surgical site infection, leading to the construction of a simple and pragmatic predictive score. This score might help the surgeon to assess patient at risk of PPOI. PMID- 28656339 TI - Short-term outcomes after laparoscopic versus open transhiatal resection of Siewert type II adenocarcinoma of the esophagogastric junction. AB - BACKGROUND: The potential advantages of laparoscopic surgery (LS) compared with open surgery (OS) for Siewert type II adenocarcinoma of the esophagogastric junction (AEG) have not been fully clarified. This study aimed to assess the feasibility and safety of the laparoscopic transhiatal approach for Siewert type II AEG, and compare the short-term outcomes of LS versus OS for Siewert type II AEG. METHODS: We retrospectively analyzed 87 consecutive patients with Siewert type II AEG who underwent curative surgery from January 2008 to November 2016. Surgery-related short-term variables were analyzed in LS versus OS. RESULTS: Forty-five patients underwent LS, and 42 underwent OS. Compared with OS, LS was associated with significantly less intraoperative blood loss (11 vs. 408 ml, p < 0.001) and extended operation time (256 vs. 226 min, p = 0.001). There was no significant difference between LS and OS in postoperative hospitalization duration (9 vs. 10 days, p = 0.193) or rate of surgical morbidity (>=grade 3) for complications such as anastomotic leakage (4.4 vs. 4.8%, p = 1.000), or pancreatic leakage (4.4 vs. 9.5%, p = 0.423), and there were no pulmonary associated complications in either group. There was no difference between groups in total number of harvested lymph nodes (24 vs. 29, p = 0.502), but the number of harvested mediastinum LNs was larger in LS (2 vs. 1, p = 0.002). There was no difference between groups in the length of the proximal margin (9 vs. 10 mm, p = 0.246), and the margins were negative in all cases in both groups. CONCLUSIONS: Laparoscopic transhiatal resection for Siewert type II AEG is technically challenging, but appears feasible and safe in technical or short-term oncological aspects when performed by an experienced surgical team. A large-scale prospective study is needed to evaluate long-term outcomes. PMID- 28656340 TI - Safety and efficacy of endoscopic submucosal dissection using IT knife nano with clip traction method for early esophageal squamous cell carcinoma. AB - BACKGROUND: Although endoscopic submucosal dissection (ESD) is an accepted and established treatment for early esophageal squamous cell carcinoma (EESCC), it is technically difficult, time consuming, and less safe than endoscopic mucosal resection. To perform ESD safely and more efficiently, we proposed a new technique of esophageal ESD using an IT knife nano with the clip traction method. This study aimed to evaluate the efficacy and safety of ESD using this new technique. METHODS: We retrospectively reviewed all consecutive cases of esophageal ESD performed using an IT knife nano with the clip traction method at our hospital between March 2013 and January 2017. Therapeutic efficacy and safety were also assessed. RESULTS: A total of 103 patients underwent esophageal ESD using the IT knife nano with the clip traction method. In all cases, we performed en bloc resection. Complete resection was achieved in 100 cases (97.1%). The median operating time was 40 (range 13-230) min. No cases of perforation or delayed bleeding occurred. Although two cases (2.0%) of mediastinal emphysema occurred without visible perforation at endoscopy, all were successfully managed conservatively. CONCLUSIONS: The new technique of esophageal ESD using the IT knife nano with the clip traction method appears to be feasible, effective, and safe for EESCC treatment. PMID- 28656341 TI - Educational implications for surgical telementoring: a current review with recommendations for future practice, policy, and research. AB - BACKGROUND: Surgical telementoring (ST) was introduced in the sixties, promoting videoconferencing to enhance surgical education across large distances. Widespread use of ST in the surgical community is lacking. Despite numerous surveys assessing ST, there remains a lack of high-level scientific evidence demonstrating its impact on mentorship and surgical education. Despite this, there is an ongoing paradigm shift involving remote presence technologies and their application to skill development and technique dissemination in the international surgical community. Factors facilitating this include improved access to ST technology, including ease of use and data transmission, and affordability. Several international research initiatives have commenced to strengthen the scientific foundation documenting the impact of ST in surgical education and performance. METHODS: International experts on ST were invited to the SAGES Project Six Summit in August 2015. Two experts in surgical education prepared relevant questions for discussion and organized the meeting (JP and HH). The questions were open-ended, and the discussion continued until no new item appeared. The transcripts of interviews were recorded by a secretary from SAGES. RESULTS: In this paper, we present a summary of the work performed by the SAGES Project 6 Education Working Group. We summarize the existing evidence regarding education in ST, identify and detail conceptual educational frameworks that may be used during ST, and present a structured framework for an educational curriculum in ST. CONCLUSIONS: The educational impact and optimal curricular organization of ST programs are largely unexplored. We outline the critical components of a structured ST curriculum, including prerequisites, teaching modalities, and key curricular components. We also detail research strategies critical to its continued evolution as an educational tool, including randomized controlled trials, establishment of a quality registry, qualitative research, learning analytics, and development of a standardized taxonomy. PMID- 28656343 TI - [Multimodal treatment of patients with bipolar disorder necessitates sufficient personnel resources]. PMID- 28656342 TI - Effect of intravitreal ranibizumab on the ocular circulation of the untreated fellow eye. AB - PURPOSE: To evaluate the effects of unilateral intravitreal ranibizumab (IVR) on the ocular circulation of the fellow eyes. METHODS: Fifteen eyes of 15 patients with macular edema (average age 69.6 +/- 11.8 years) were studied. Eleven eyes had diabetic macular edema (DME) and four eyes had macular edema associated with a branch retinal vein occlusion. Each eye received 0.5 mg of IVR. The blood circulation on the optic nerve head of the treated and untreated eyes were determined by laser speckle flowgraphy (LSFG, Softcare Co., Ltd) before, 1 day, and 1 week after the IVR. The mean blur rate (MBR) and the relative changes of the MBRs determined as dMBR(%) = 100-(MBR before/MB after) * 100) were evaluated. The central macular thickness (CMT) and the rate of reduction in the thickness (dCMT = 100-(CMT before/CMT after) * 100) were also evaluated. RESULTS: The mean dMBR was significantly higher in the treated eyes than the untreated eyes at 1 day (-16.4 +/- 17.0% vs 2.31 +/- 19.3%) and at 1 week (-12.0 +/- 14.6% vs 4.50 +/ 25.9%) after the IVR (P = 0.02, paired t tests). CONCLUSION: These findings indicate that if ranibizumab enters the systemic circulation, the concentration is not high enough to affect the ocular circulation of the fellow eyes. PMID- 28656344 TI - [The importance of neuronal networks for motor rehabilitation after a stroke]. AB - Every year in Europe 1.5 million patients suffer a new stroke. Despite the further developments in acute therapy with nationwide stroke units, thrombolysis, thrombectomy and post-acute neurorehabilitation, only a small proportion of patients recover to a satisfactory degree allowing them to return to their normal social and professional life. This makes stroke the main cause of long-term disability with a corresponding impact on patient lives, socioeconomics and the healthcare system. Thus, the concepts of neurorehabilitation have to be extended to enhance the effects of rehabilitative treatment strategies. To achieve this, an understanding of the prediction of the course of recovery, the mechanisms underlying functional recovery and factors influencing recovery have to be enhanced for the development towards patient-tailored precision medicine approaches. A central point towards this is the understanding of stroke as a disease, which not only influences the damaged area but also the associated network. This is crucial for the understanding of the stroke-induced deficits, for prediction of recovery and options for interventional treatment strategies, which can target different areas in this network (e.g. primary motor cortex and secondary motor regions) based on individual factors of the patient. The present article discusses the importance of network alterations for motor neurorehabilitation after a stroke and which novel options, concepts and consequences could arise from this for neurorehabilitation. PMID- 28656345 TI - Cobalt inhibits motility of axonal mitochondria and induces axonal degeneration in cultured dorsal root ganglion cells of rat. AB - Cobalt is a trace element that localizes in the human body as cobalamin, also known as vitamin B12. Excessive cobalt exposure induces a peripheral neuropathy, the mechanisms of which are yet to be elucidated. We investigated how cobalt may affect mitochondrial motility in primary cultures of rat dorsal root ganglion (DRG). We observed mitochondrial motility by time-lapse imaging after DsRed2 tagging via lentivirus, mitochondrial structure using transmission electron microscopy (TEM), and axonal swelling using immunocytochemical staining. The concentration of cobaltous ion (Co2+) required to significantly suppress mitochondrial motility is lower than that required to induce axonal swelling following a 24-h treatment. Exposure to relatively low concentrations of Co2+ for 48 h suppressed mitochondrial motility without leading to axonal swelling. TEM images indicated that Co2+ induces mitochondrial destruction. Our results show that destruction of the axonal mitochondria precedes the axonal degeneration induced by Co2+ exposure. PMID- 28656346 TI - Light regulation of nitrate reductase by catalytic subunits of protein phosphatase 2A. AB - MAIN CONCLUSION: PP2A catalytic subunit C2 is of special importance for light/dark regulation of nitrate reductase activity. The level of unmethylated PP2A catalytic subunits decreases in darkness. Protein phosphatase 2A (PP2A) dephosphorylates and activates nitrate reductase (NR) in photosynthetically active tissue when plants are transferred from darkness to light. In the present work, investigation of Arabidopsis thaliana PP2A mutant lines revealed that one of the five PP2A catalytic subunit genes, e.g., C2, was of special importance for NR activation. Impairment of NR activation was, especially pronounced in the c2c4 double mutant. Though weaker, NR activation was also impaired in the c2 single mutant, and c1c2 and c2c5 double mutants. On the other hand, NR activation in the c4c5 double mutant was as efficient as in WT. The c4 single mutant had low PP2A activity, whereas the c2 single mutant possessed WT levels of extractable PP2A activity. PP2A activity was low in both c2c4 and c4c5. Differences in extracted PP2A activity among mutants did not strictly correlate with differences in NR activation, but underpinned that C2 has a special function in NR activation in vivo. The terminal leucine in PP2A catalytic subunits is generally methylated to a high degree, but regulation and impact of methylation/demethylation is barely studied. In WT and PP2A mutants, the level of unmethylated PP2A catalytic subunits decreased during 45 min of darkness, but did not change much when light was switched on. In leucine carboxyl methyl transferase1 (LCMT1) knockout plants, which possess mainly unmethylated PP2A, NR was still activated, although not fully as efficient as in WT. PMID- 28656347 TI - Neural correlates of verbal memory in youth with heavy prenatal alcohol exposure. AB - Prenatal alcohol exposure can impact both brain development and neurobehavioral function, including verbal learning and recall, although the relation between verbal recall and brain structure in this population has not been examined fully. We aimed to determine the structural neural correlates of verbal learning and recall in youth with histories of heavy prenatal alcohol exposure using a region of interest (ROI) approach. As part of an ongoing multisite project, subjects (age 10-16 years) with prenatal alcohol exposure (AE, n = 81) and controls (CON, n = 81) were tested using the CVLT-C and measures of cortical volume, surface area, and thickness as well as hippocampal volume were derived from MRI. Group differences in brain and memory indices were tested with ANOVA. Multiple regression analyses tested whether brain ROIs significantly predicted memory performance. The AE group had lower scores than the CON group on all CVLT-C variables (ps <= .001) and volume and surface area (ps < .025), although results varied by ROI. No group differences in cortical thickness were found. The relations between cortical structure and memory performance differed between group among some ROIs, particularly those in the frontal cortex, generally with smaller surface area and/or thinner cortex predicting better performance in CON but worse performance in AE. Cortical surface area appears to be the most sensitive index to the effects of prenatal alcohol exposure, while cortical thickness appears to be the least sensitive. These findings also indicate that the neural correlates of verbal memory are altered in youth with heavy prenatal alcohol exposure compared to controls. PMID- 28656348 TI - PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker. AB - Pancreatic ductal adenocarcinoma (PDA) is a fatal and insidious malignant disease for which clinicians' tools are restricted by the current limits in knowledge of how tumor and stromal cells act during the disease. Among PDA hallmarks, neural remodeling (NR) and perineural invasion (PNI) drastically influence quality of life and patient survival. Indeed, NR and PNI are associated with neuropathic pain and metastasis, respectively, both of which impact clinicians' decisions and therapeutic options. The aim of this study was to determine the impact and clinical relevance of the peritumoral microenvironment, through pancreatitis associated protein (PAP/REG3A) expression, on PNI in pancreatic cancer. First, we demonstrated that, in PDA, PAP/REG3A is produced by inflamed acinar cells from the peritumoral microenvironment and then enhances the migratory and invasive abilities of cancer cells. More specifically, using perineural ex vivo assays we revealed that PAP/REG3A favors PNI through activation of the JAK/STAT signaling pathway in cancer cells. Finally, we analyzed the level of PAP/REG3A in blood from healthy donors or patients with PDA from three independent cohorts. Patients with high levels of PAP/REG3A had overall shorter survival as well as poor surgical outcomes with reduced disease-free survival. Our study provides a rationale for using the PAP/REG3A level as a biomarker to improve pancreatic cancer prognosis. It also suggests that therapeutic targeting of PAP/REG3A activity in PDA could limit tumor cell aggressiveness and PNI. PMID- 28656349 TI - Structural determinants of a conserved enantiomer-selective carvone binding pocket in the human odorant receptor OR1A1. AB - Chirality is a common phenomenon within odorants. Most pairs of enantiomers show only moderate differences in odor quality. One example for enantiomers that are easily discriminated by their odor quality is the carvones: humans significantly distinguish between the spearmint-like (R)-(-)-carvone and caraway-like (S)-(+) carvone enantiomers. Moreover, for the (R)-(-)-carvone, an anosmia is observed in about 8% of the population, suggesting enantioselective odorant receptors (ORs). With only about 15% de-orphaned human ORs, the lack of OR crystal structures, and few comprehensive studies combining in silico and experimental approaches to elucidate structure-function relations of ORs, knowledge on cognate odorant/OR interactions is still sparse. An adjusted homology modeling approach considering OR-specific proline-caused conformations, odorant docking studies, single nucleotide polymorphism (SNP) analysis, site-directed mutagenesis, and subsequent functional studies with recombinant ORs in a cell-based, real-time luminescence assay revealed 11 amino acid positions to constitute an enantioselective binding pocket necessary for a carvone function in human OR1A1 and murine Olfr43, respectively. Here, we identified enantioselective molecular determinants in both ORs that discriminate between minty and caraway odor. Comparison with orthologs from 36 mammalian species demonstrated a hominid-specific carvone binding pocket with about 100% conservation. Moreover, we identified loss-of-function SNPs associated with the carvone binding pocket of OR1A1. Given carvone enantiomer specific receptor activation patterns including OR1A1, our data suggest OR1A1 as a candidate receptor for constituting a carvone enantioselective phenotype, which may help to explain mechanisms underlying a (R)-(-)-carvone-specific anosmia in humans. PMID- 28656350 TI - Frequency of decompression illness among recent and extinct mammals and "reptiles": a review. AB - The frequency of decompression illness was high among the extinct marine "reptiles" and very low among the marine mammals. Signs of decompression illness are still found among turtles but whales and seals are unaffected. In humans, the risk of decompression illness is five times increased in individuals with Patent Foramen Ovale; this condition allows blood shunting from the venous circuit to the systemic circuit. This right-left shunt is characteristic of the "reptile" heart, and it is suggested that this could contribute to the high frequency of decompression illness in the extinct reptiles. PMID- 28656351 TI - Has the Quality of Aesthetic Surgery Research Improved over the Last 20 Years? PMID- 28656352 TI - Staying Out of Double-Bubble and Bottoming-Out Deformities in Dual-Plane Breast Augmentation: Anatomical and Clinical Study. AB - BACKGROUND: Double-bubble and bottoming-out deformities represent the second most common reason for revision surgery in breast augmentation. Etiopathogenesis of these complications is still unclear. The aim of this paper is to report our findings in breast cadaver dissections focusing on the inframammary fold (IMF) applied anatomy and to critically review our ten-year experience in breast augmentation. METHODS: A cadaveric study has been performed on four consecutive embalmed cadavers. A retrospective review of 207 consecutive women who underwent breast augmentation, using the submuscular dual-plane technique with a periareolar approach, between January 2003 and January 2013, was performed. RESULTS: According to our dissections, the IMF is a complex osseo-fascio cutaneous structure in which the superficial pectoralis fascia represents a key structure in breast augmentation surgery. Hence, a critical analysis of the IMF relationship with surrounding breast structures helps to understand the etiology of double-bubble and bottoming-out deformities and gives the anatomical basis to prevent them. In our early clinical experience, we experienced 3% of double bubble and 6% of bottoming-out deformities. Those complications were avoided later by dissection in the inferior pole according to the anatomical findings. CONCLUSIONS: Bottoming-out and double-bubble deformities can be avoided if an anatomical approach is used during pocket dissection at the level of the IMF, paying attention to avoid disrupting the superficial and deep attachments of the superficial pectoralis fascia at the IMF. A comprehensive understanding of IMF anatomy and the key surgical maneuvers to avoid these complications must be taken into account for each route of dissection. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28656353 TI - Effect of low tidal volume with PEEP on respiratory function in infants undergoing one-lung ventilation. AB - BACKGROUND: An increasing number of studies have shown that low tidal volume (TV) with positive end-expiratory pressure (PEEP) offers lung protection during one lung ventilation (OLV). Considering the unique physiological characteristics of infants, we aimed to determine the feasibility and effect of low TV with PEEP in infants undergoing OLV during thoracoscopy. PATIENTS AND METHODS: We randomized 60 infants to a conventional group (group I: TV, 8-10 ml/kg; RR, 23-45 bpm; PEEP, 0 cmH2O) or a low TV with PEEP group (group II: TV, 5-7 ml/kg; RR, 23-45 bpm; PEEP, 4-6 cmH2O). Arterial blood gas analyses were performed at four time points: 5 min of two-lung ventilation (TLV, T0), and 20 min, 40 min, and 60 min of OLV (T1, T2, T3); hemodynamic parameters (heart rate, mean blood pressure), temperature, as well as gas exchange (SpO2 and PETCO2) and ventilation parameters (FiO2, PEEP, Pmax) were recorded simultaneously. Lung compliance and shunt were also calculated. RESULT: No significant difference was found between both groups at T0. Compared with T0, PETCO2, Pmax, PaCO2, lactic acid, and intrapulmonary shunt volume (Qs/Qt) were increased while PaO2 and respiratory system compliance (Cdyx) were decreased noticeably in both groups at T1, T2, and T3. At T1, T2, and T3, Pmax and Qs/Qt were much lower while PETCO2, PaCO2, and Cdyx were higher in group II than in group I. There was no significant difference in lactic acid and PaO2 measurements between the two groups at T1, T2, and T3. CONCLUSION: Low TV with PEEP could be an effective intraoperative ventilation strategy for infants undergoing OLV during video-assisted thoracoscopic surgery and may reduce the risk of lung injury. However, this strategy, as well as the influence of intraoperative hypercapnia on infants, needs further investigation. PMID- 28656354 TI - Nonfatal and fatal intoxications with pure caffeine - report of three different cases. AB - Caffeine is not usually perceived as a drug by most people because it is found in many foods and drinks, including caffeinated energy drinks, as well as in over the counter analgesics and cold preparations. Recently in Poland it has become increasingly common to take pure caffeine, bought through online stores, as a psychoanaleptic. This creates a much higher risk of severe and even fatal poisoning in comparison with the risk associated with the abuse of food products and non-prescription medicines containing low doses of caffeine. This paper presents three different cases of poisoning that occurred when pure caffeine was taken as psychostimulant; in cases 1 and 2 poisoning was the result of a single overdose, while in the case 3 poisoning resulted from a cumulative overdose. In the case 1 there was a severe intoxication (persistent vomiting, hypotension, tremor), and the concentration of caffeine in the blood was found to be 80.16 MUg/mL. The patient was treated using hemodialysis, which caused a rapid decrease in blood levels of caffeine and relief of the clinical symptoms of poisoning. Cases 2 and 3 were fatal poisonings, and recorded levels of caffeine in post mortem blood samples were 140.64 MUg/mL and 613.0 MUg/mL. In case 2 the patient died 10 min after admission to hospital as a result of sudden cardiac arrest, which was preceded by an attack of convulsions, and in case 3 death occurred in home and was also sudden in nature. Taking pure caffeine as a stimulant is associated with a high risk of overdose and the development of serious and even fatal poisoning, and those using pure caffeine are generally completely unaware of these risks. In such cases, death is usually sudden due to functional mechanisms. PMID- 28656356 TI - Glomangiomatosis: a case report. AB - Glomangiomatosis is a benign vascular variant of a glomus tumor. The lesion represents only 5% of glomus tumors with unusual or atypical features and even fewer glomus tumors with typical features. The lesions are most commonly located in the distal extremities and are multiple, deep, extensive, and often pain producing. They develop from small arteriovenous anastamoses and are most often identified in young adults. The lesions may recur. We present a case of a 33-year old male who presented clinically with multiple slowly enlarging masses of the leg over a 5-year period, of which one caused significant pain. One of the lesions was reported to be present at birth. Imaging studies were performed and were suggestive of neurofibromatosis. Biopsies from multiple lesions led to an eventual diagnosis of multiple glomangiomatosis. PMID- 28656357 TI - Magnetic resonance imaging in evaluation of tunnel diameters prior to revision ACL reconstruction: a comparison to computed tomography. AB - OBJECTIVE: Revision ACL reconstruction is becoming more frequent because of a 10% rate of re-ruptures and insufficiencies. Currently, computed tomography (CT) represents the gold standard in detecting and measuring the tunnels of the initial ACL reconstruction. The purpose of this study was to compare measurement results of CT and thin-sliced MRI sequences, which were modified to a high soft tissue-bone contrast. MATERIALS AND METHODS: Prior to an ACL revision surgery, 16 consecutive patients had an MRI in addition to the standard CT scan. A dedicated 0.25-T Esaote G-Scan (Esaote Biomedica, Cologne, Germany) with a Turbo 3D T1 sequence was used for MRI. Tunnel diameters were measured at 11 defined points of interest. For the statistical evaluation, the Mann-Whitney U test for connected samples was used. Inter- and intraobserver reliability was additionally calculated. RESULTS: All measured diameters showed significant to highly significant correlations between both diagnostic tools (r = 0.7-0.98). In addition, there was no significant difference (p > 0.5) between the two techniques. Almost all diameters showed nearly perfect intraobserver reliability (ICC 0.8-0.97). Interobserver reliability showed an ICC of 0.91/0.92 for only one diameter in MRI and CT. CONCLUSION: Prior to ACL revision surgery, bone tunnel measurements can be done using a 3D T1-MRI sequence in low-field MRI. MRI measurements show the same accuracy as CT scans. Preoperative radiation exposure in mainly young patients could be reduced. Also the costs of an additional CT scan could be saved. PMID- 28656360 TI - Erratum to: Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. PMID- 28656361 TI - [Clinical Autopsies from the Perspective of a Hematologist/Oncologist]. PMID- 28656359 TI - Comparison of retroperitoneal and transperitoneal robotic partial nephrectomy for Pentafecta perioperative and renal functional outcomes. AB - BACKGROUND: We compared quality outcomes between transperitoneal (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN). METHODS: Two-center retrospective analysis of TRPN and RRPN from 10/2009 to 10/2015. Perioperative/renal function outcomes were analyzed. Primary endpoint was Pentafecta, a composite measure of quality [negative margin, no 30-day complication, ischemia time <=25 min, return of glomerular filtration rate (eGFR) to >90% from baseline at last follow-up, and no chronic kidney disease upstaging]. Multivariable analysis (MVA) for factors associated with lack of optimal outcome was performed. RESULTS: 404 patients (TRPN 263, RRPN 141) were analyzed. Comparing TRPN vs. RRPN, mean tumor size (3.1 vs. 2.9 cm, p = 0.122) and RENAL score (7.4 vs. 7.2, p = 0.503) were similar. Most TRPN were anterior (65.0%) and most RRPN posterior (65.3%, p < 0.001). Operative time (p = 0.001) was less for RRPN. No significant differences between TRPN vs. RRPN were noted for ischemia time (23.1 vs. 22.8 min, p = 0.313), blood loss (p = 0.772), positive margins (p = 0.590), complications (p = 0.537), length of stay (p = 0.296), DeltaeGFR (p = 0.246), eGFR recovery to >90% (55.9 vs. 57.4%, p = 0.833), and lack of CKD upstaging (84.0 vs. 87.2%, p = 0.464). Pentafecta rates were not significantly different (TRPN 33.9 vs. RRPN 43.3%, p = 0.526). MVA revealed increasing RENAL score (OR 1.5, p < 0.001) and decreasing baseline eGFR (OR 2.4, p = 0.017) as predictive for lack of Pentafecta. CONCLUSIONS: TRPN and RRPN have similar quality outcomes, though RRPN may offer modest benefit for operative time and have utility in posterior tumors. Association of increasing RENAL score and decreased baseline eGFR with lack of Pentafecta suggests dominant role of non modifiable factors. PMID- 28656362 TI - Limited capacity of working memory in unihemispheric random walks implies conceivable slow dispersal. AB - Phenomenologically inspired by dolphins' unihemispheric sleep, we introduce a minimal model for random walks with physiological memory. The physiological memory consists of long-term memory which includes unconscious implicit memory and conscious explicit memory, and working memory which serves as a multi component system for integrating, manipulating and managing short-term storage. The model assumes that the sleeping state allows retrievals of episodic objects merely from the episodic buffer where these memory objects are invoked corresponding to the ambient objects and are thus object-oriented, together with intermittent but increasing use of implicit memory in which decisions are unconsciously picked up from historical time series. The process of memory decay and forgetting is constructed in the episodic buffer. The walker's risk attitude, as a product of physiological heuristics according to the performance of objected oriented decisions, is imposed on implicit memory. The analytical results of unihemispheric random walks with the mixture of object-oriented and time-oriented memory, as well as the long-time behavior which tends to the use of implicit memory, are provided, indicating the common sense that a conservative risk attitude is inclinable to slow movement. PMID- 28656363 TI - Cytogenetic mapping of a major locus for resistance to Fusarium head blight and crown rot of wheat on Thinopyrum elongatum 7EL and its pyramiding with valuable genes from a Th. ponticum homoeologous arm onto bread wheat 7DL. AB - KEY MESSAGE: A major locus for resistance to different Fusarium diseases was mapped to the most distal end of Th. elongatum 7EL and pyramided with Th. ponticum beneficial genes onto wheat 7DL. Perennial Triticeae species of the Thinopyrum genus are among the richest sources of valuable genes/QTL for wheat improvement. One notable and yet unexploited attribute is the exceptionally effective resistance to a major wheat disease worldwide, Fusarium head blight, associated with the long arm of Thinopyrum elongatum chromosome 7E (7EL). We targeted the transfer of the temporarily designated Fhb-7EL locus into bread wheat, pyramiding it with a Th. ponticum 7el1L segment stably inserted into the 7DL arm of wheat line T4. Desirable genes/QTL mapped along the T4 7el1L segment determine resistance to wheat rusts (Lr19, Sr25) and enhancement of yield-related traits. Mapping of the Fhb-7EL QTL, prerequisite for successful pyramiding, was established here on the basis of a bioassay with Fusarium graminearum of different 7EL-7el1L bread wheat recombinant lines. These were obtained without resorting to any genetic pairing promotion, but relying on the close 7EL-7el1L homoeology, resulting in 20% pairing frequency between the two arms. Fhb-7EL resided in the telomeric portion and resistant recombinants could be isolated with useful combinations of more proximally located 7el1L genes/QTL. The transferred Fhb-7EL locus was shown to reduce disease severity and fungal biomass in grains of infected recombinants by over 95%. The same Fhb-7EL was, for the first time, proved to be effective also against F. culmorum and F. pseudograminearum, predominant agents of crown rot. Prebreeding lines possessing a suitable 7EL-7el1L gene/QTL assembly showed very promising yield performance in preliminary field tests. PMID- 28656365 TI - Bone mineral density in vocational and professional ballet dancers. AB - : According to existing literature, bone health in ballet dancers is controversial. We have verified that, compared to controls, young female and male vocational ballet dancers have lower bone mineral density (BMD) at both impact and non-impact sites, whereas female professional ballet dancers have lower BMD only at non-impact sites. INTRODUCTION: The aims of this study were to (a) assess bone mineral density (BMD) in vocational (VBD) and professional (PBD) ballet dancers and (b) investigate its association with body mass (BM), fat mass (FM), lean mass (LM), maturation and menarche. METHODS: The total of 152 VBD (13 +/- 2.3 years; 112 girls, 40 boys) and 96 controls (14 +/- 2.1 years; 56 girls, 40 boys) and 184 PBD (28 +/- 8.5 years; 129 females, 55 males) and 160 controls (27 +/- 9.5 years; 110 female, 50 males) were assessed at the lumbar spine (LS), femoral neck (FN), forearm and total body by dual-energy X-ray absorptiometry. Maturation and menarche were assessed via questionnaires. RESULTS: VBD revealed lower unadjusted BMD at all anatomical sites compared to controls (p < 0.001); following adjustments for Tanner stage and gynaecological age, female VBD showed similar BMD values at impact sites. However, no factors were found to explain the lower adjusted BMD values in VBD (female and male) at the forearm (non-impact site), nor for the lower adjusted BMD values in male VBD at the FN. Compared to controls, female PBD showed higher unadjusted and adjusted BMD for potential associated factors at the FN (impact site) (p < 0.001) and lower adjusted at the forearm (p < 0.001). Male PBD did not reveal lower BMD than controls at any site. CONCLUSIONS: Both females and males VBD have lower BMD at impact and non-impact sites compared to control, whereas this is only the case at non-impact site in female PBD. Maturation seems to explain the lower BMD at impact sites in female VBD. PMID- 28656364 TI - The critical role of macrophages in the pathogenesis of hidradenitis suppurativa. AB - INTRODUCTION: Hidradenitis suppurativa (HS) is a painful chronic inflammatory disease with a prevalence between 1 and 4% of general population. The pathogenesis of HS long eluded scientists, but growing evidence suggests that it is a consequence of inflammatory dysregulation. FINDINGS: Recent studies suggest that dysregulated immune response to skin flora and overexpression of inflammatory cytokines leads to chronic skin inflammation seen in HS. Macrophages are the most numerous inflammatory cells found in HS infiltrates and release numerous pro-inflammatory cytokines such as IL-23, and IL-1beta and TNF-alpha, exacerbating the inflammation and contributing to the pathogenesis of HS. Furthermore, in HS, there is dysregulated function of other immune players closely associated with macrophage function including: matrix metalloproteases (MMP) 2 and 9 overexpression, toll-like receptor upregulation, impaired Notch signalling, NLRP3 inflammasome upregulation, and dysregulated keratinocyte function. Lifestyle factors including obesity and smoking also contribute to macrophage dysfunction and correlate with HS incidence. CONCLUSIONS: The overexpression of pro-inflammatory cytokines and subsequent efficacy of anti cytokine biologic therapies highlights the importance of managing macrophage dysfunction. Future therapies should target key molecular drivers of macrophage dysfunction such as TLR2 and NLRP3 overexpression. PMID- 28656366 TI - Biographical background and origin of common eponymous terms in orthopedic surgery: anatomy and fractures in knee surgery. AB - An eponym is a person after whom an eponymous term is named. These eponymous terms are easy shorthand in communication between surgeons. Therefore, they are often used and hard to eradicate. We discuss eponymous terms that describe anatomical features and fracture types in the knee. With these terms, an overview of the historical background of the eponym and its current clinical implication is discussed. The eponymous terms discussed are Gerdy tubercle, Pellegrini-Stieda lesion, Segond fracture, Hoffa fracture and fat pad. The meaning of the eponymous term is clarified, the biography of the namegiver given and its contemporary clinical implication discussed. Since eponymous terms are used frequently in inter-collegial discussion and literature, the meaning should be clear for everyone, since otherwise it might give room for misunderstanding. PMID- 28656370 TI - Clinical Significance of Circumferential Aneurysmal Wall Enhancement in Symptomatic Patients with Unruptured Intracranial Aneurysms: a High-resolution MRI Study. AB - BACKGROUND AND PURPOSE: The estimates on the risk of rupture of intracranial aneurysms remain a controversial topic. Circumferential aneurysmal wall enhancement (CAWE) on vessel wall magnetic resonance imaging (MRI) has been described in unstable aneurysms. Sentinel headaches and third nerve palsy are possible symptoms prior to the rupture of intracranial aneurysms. In this study, we aimed to demonstrate that CAWE could be associated with these symptoms. METHODS: We performed a retrospective analysis of consecutive symptomatic or asymptomatic patients with unruptured intracranial aneurysms who were examined by high-resolution MRI from October 2014 to November 2016. Two experienced neurovascular radiologists read the images independently and determined whether there was CAWE of the unruptured intracranial aneurysms. Then, we compared variable factors between patients with and without symptoms through univariate comparison and multivariable logistic regression analyses. RESULTS: A total of 45 unruptured intracranial aneurysms were detected in 37 patients. The agreement between 2 experienced readers for CAWE was good (kappa = 0.82; 95% confidence interval 0.66-0.99). CAWE of unruptured intracranial aneurysm was more frequently observed in symptomatic than in asymptomatic patients (16/23, 69.6% versus 6/22, 27.3%, respectively, P < 0.05). The CAWE was the only independent factor associated with symptoms in the multivariable logistic regression analysis (odds ratio 5.17; 95% confidence interval 1.30-20.52; P = 0.02). CONCLUSIONS: Our study demonstrates that CAWE correlated with sentinel headaches and third nerve palsy caused by unruptured aneurysms, and this may be an additional clue to distinguish the cause of these symptoms. PMID- 28656371 TI - Cerebrospinal fluid monoamine metabolite profiles in bipolar disorder, ADHD, and controls. AB - Alterations in monoaminergic signaling are suggested as key aspects of the pathophysiology in bipolar disorder and ADHD, but it is not known if the monoamine metabolic profile differs between these disorders. One method to study monoaminergic systems in humans is to measure monoamine end-point metabolite concentrations in cerebrospinal fluid (CSF). Here, we analyzed CSF monoamine metabolite concentrations in 103 adults with bipolar disorder, 72 adults with ADHD, and 113 controls. Individuals with bipolar disorder had significantly higher homovanillic acid (HVA, 264 +/- 112 nmol/L, p < 0.001) and 5 hydroxyindoleacetic acid (5-HIAA, 116 +/- 42 nmol/L, p = 0.001) concentration, but lower 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG, 38 +/- 8 nmol/L, p < 0.001) concentrations than controls (HVA, 206 +/- 70 nmol/L; 5-HIAA, 98 +/- 31 nmol/L; and MHPG, 42 +/- 7 nmol/L). Higher HVA concentrations were associated with a history of psychosis in the bipolar disorder sample. Subjects with ADHD had higher HVA (240 +/- 94 nmol/L, p < 0.001) concentrations compared with controls. In addition, SSRI treatment was associated with lower 5-HIAA concentrations in both patient groups. A power analysis indicated that for within group comparisons, only large effects would be reliably detectable. Thus, there may be moderate-to-small effects caused by medication that were not detected due to the limited size of the sub-groups in these analyses. In conclusion, the present study suggests disorder-specific alterations of CSF monoamine metabolite concentrations in patients with bipolar disorder and ADHD compared with controls; these differences were independent of acute symptoms and medication effects. PMID- 28656374 TI - [Risk of heart failure in patients with Hodgkin lymphoma after radiation and anthracycline chemotherapy]. PMID- 28656372 TI - Increased gyrification and aberrant adult neurogenesis of the dentate gyrus in adult rats. AB - A remarkable example of maladaptive plasticity is the development of epilepsy after a brain insult or injury to a normal animal or human. A structure that is considered central to the development of this type of epilepsy is the dentate gyrus (DG), because it is normally a relatively inhibited structure and its quiescence is thought to reduce hippocampal seizure activity. This characteristic of the DG is also considered to be important for normal hippocampal-dependent cognitive functions. It has been suggested that the brain insults which cause epilepsy do so because they cause the DG to be more easily activated. One type of brain insult that is commonly used is induction of severe seizures (status epilepticus; SE) by systemic injection of a convulsant drug. Here we describe an alteration in the DG after this type of experimental SE that may contribute to chronic seizures that has not been described before: large folds or gyri that develop in the DG by 1 month after SE. Large gyri appeared to increase network excitability because epileptiform discharges recorded in hippocampal slices after SE were longer in duration when recorded inside gyri relative to locations outside gyri. Large gyri may also increase excitability because immature adult born neurons accumulated at the base of gyri with time after SE, and previous studies have suggested that abnormalities in adult-born DG neurons promote seizures after SE. In summary, large gyri after SE are a common finding in adult rats, show increased excitability, and are associated with the development of an abnormal spatial distribution of adult-born neurons. Together these alterations may contribute to chronic seizures and associated cognitive comorbidities after SE. PMID- 28656375 TI - Non-contact Raman spectroscopy for in-line monitoring of glucose and ethanol during yeast fermentations. AB - The monitoring of microbiological processes using Raman spectroscopy has gained in importance over the past few years. Commercial Raman spectroscopic equipment consists of a laser, spectrometer, and fiberoptic immersion probe in direct contact with the fermentation medium. To avoid possible sterilization problems and biofilm formation on the probe tip, a large-aperture Raman probe was developed. The design of the probe enables non-contact in-line measurements through glass vessels or inspection glasses of bioreactors and chemical reactors. The practical applicability of the probe was tested during yeast fermentations by monitoring the consumption of substrate glucose and the formation of ethanol as the product. Multiple linear regression models were applied to evaluate the Raman spectra. Reference values were determined by high-performance liquid chromatography. The relative errors of prediction for glucose and ethanol were 5 and 3%, respectively. The presented Raman probe allows simple adaption to a wide range of processes in the chemical, pharmaceutical, and biotechnological industries. PMID- 28656373 TI - Salvage radiotherapy for macroscopic local recurrences after radical prostatectomy : A national survey on patterns of practice. AB - INTRODUCTION: Although salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy provides better oncological outcomes when delivered early, in the absence of detectable disease many patients are treated for macroscopic locally recurrent tumors. Due to limited data from prospective studies, we hypothesized an important variability in the SRT management of these patients. Our aim was to investigate current practice patterns of SRT for local macroscopic recurrence after radical prostatectomy. MATERIAL AND METHODS: A total of 14 Swiss radiation oncology centers were asked to complete a survey on treatment specifications for macroscopic locally recurrent disease including information on pretherapeutic diagnostic procedures, dose prescription, radiation delivery techniques and androgen deprivation therapy (ADT). Treatment recommendations on ADT were analyzed using the objective consensus methodology. RESULTS: The majority of centers recommended pretreatment magnetic resonance imaging (MRI) of the pelvis and choline positron emission tomography (PET). The median prescribed dose to the prostate bed was 66 Gy (range 65-72 Gy) with a boost to the macroscopic lesion used by 79% of the centers with a median total dose of 72 Gy (range 70-80 Gy). Intensity-modulated rotational techniques were used by all centers and daily cone beam computed tomography (CT) was recommended by 43%. The use of concomitant ADT for any macroscopic recurrence was recommended by 43% of the centers while the remaining centers recommended it only for high-risk disease, which was not consistently defined. CONCLUSION: We observed a high variability of treatment paradigms when SRT is indicated for macroscopic local recurrences after prostatectomy. These data reflect the need for more standardized approaches and ultimately further research in this field. PMID- 28656376 TI - Acute disseminated encephalomyelitis in an elderly patient. PMID- 28656377 TI - Acute toxic leukoencephalopathy associated with a non-prescription weight loss supplement: a report of two cases. AB - Weight loss dietary supplements are used with some frequency by an increasingly overweight population. Some products are not adequately regulated and may pose potential health risks. We report two new cases of acute toxic leukoencephalopathy (ATL) due to the use of a supplement marketed as a thermogenic weight loss aid. ATL is a heterogeneous clinic-radiological entity that has been associated with various compounds, such as chemotherapeutic drugs and immunomodulators. It is characterized by an often reversible periventricular and infratentorial demyelination. The commercialization of non-regulated weight loss products continues to be a health risk in our population. PMID- 28656378 TI - Comparative transcriptomic analysis identifies evolutionarily conserved gene products in the vertebrate renal distal convoluted tubule. AB - Understanding the molecular basis of the complex regulatory networks controlling renal ion transports is of major physiological and clinical importance. In this study, we aimed to identify evolutionarily conserved critical players in the function of the renal distal convoluted tubule (DCT) by a comparative transcriptomic approach. We generated a transgenic zebrafish line with expression of the red fluorescent mCherry protein under the control of the zebrafish DCT specific promoter of the thiazide-sensitive NaCl cotransporter (NCC). The mCherry expression was then used to isolate from the zebrafish mesonephric kidneys the distal late (DL) segments, the equivalent of the mammalian DCT, for subsequent RNA-seq analysis. We next compared this zebrafish DL transcriptome to the previously established mouse DCT transcriptome and identified a subset of gene products significantly enriched in both the teleost DL and the mammalian DCT, including SLCs and nuclear transcription factors. Surprisingly, several of the previously described regulators of NCC (e.g., SPAK, KLHL3, ppp1r1a) in the mouse were not found enriched in the zebrafish DL. Nevertheless, the zebrafish DL expressed enriched levels of related homologues. Functional knockdown of one of these genes, ppp1r1b, reduced the phosphorylation of NCC in the zebrafish pronephros, similar to what was seen previously in knockout mice for its homologue, Ppp1r1a. The present work is the first report on global gene expression profiling in a specific nephron portion of the zebrafish kidney, an increasingly used model system for kidney research. Our study suggests that comparative analysis of gene expression between phylogenetically distant species may be an effective approach to identify novel regulators of renal function. PMID- 28656380 TI - Current knowledge on agarolytic enzymes and the industrial potential of agar derived sugars. AB - Agar is a major cell wall carbohydrate of red macroalgae (Rhodophyta). Sugars derived from agar, such as agarooligosaccharides (AOSs), neoagarooligosaccharides (NAOSs), neoagarobiose (NAB), and 3,6-anhydro-L-galactose (L-AHG), possess various physiological activities. These agar-derived sugars can be produced by hydrolysis using chemicals or agarolytic enzymes. Despite the industrial potential of agar-derived sugars, their application has been hampered mainly due to the absence of efficient processes for the liquefaction and saccharification of agar. In this review, we have focused on strategies for producing high value added sugars from agarose via chemical or enzymatic liquefaction and enzymatic saccharification. The liquefaction of agarose is a key step for preventing gelling and increasing the solubility of agarose in water by prehydrolyzing agarose into AOSs or NAOSs. For the industrial use of agar-derived sugars, AOS, NAOS, NAB, and L-AHG can be used as functional biomaterials owing to their physiological activities such as antiinflammation, skin whitening, and moisturizing. Recently, it was reported that AHG could be considered as a new anticariogenic sugar to replace xylitol. This review provides a comprehensive overview of processes for the hydrolysis of agar or agarose to produce high value added sugars and the industrial application of these sugars. PMID- 28656379 TI - Physiology and pathophysiology of the plasminogen system in the kidney. AB - The plasminogen system is important for fibrinolysis in addition to tissue remodeling and inflammation with significance for kidney disease. The system consists of the circulating zymogen plasminogen (Plg) and the tissue- and urokinase-type plasminogen activators, tPA and uPA, expressed in the glomeruli, endothelium and tubular epithelium, respectively, and the inhibitors alpha2 antiplasmin and plasminogen activator inhibitor-type1, PAI-1. Plasminogen is activated by surface receptors, some with renal expression: urokinase-type plasminogen activator receptor (uPAR), plasminogen receptor KT (Plg-RKT), and tPA, most evident in the endothelium. Plasmin may exert effects through protease activated receptors, PARs, expressed in the kidney. Deletion of plasminogen system component genes confers no major developmental or renal phenotypes in normal mice. In glomerular injury and renal interstitial fibrosis, deletion of various components, notably Plg, uPA, PAI, and uPAR is associated with protection suggesting a disease promoting effect of plasmin, in some cases exerted through PAR1 receptor activation. Plasminogen and uPA are aberrantly filtrated across the glomerular barrier in proteinuria, and plasminogen is activated in the tubular fluid. In the tubular fluid, plasmin may activate proteolytically the epithelial sodium channel (ENaC) and inhibit the apical calcium transporter transient receptor potential cation channel subfamily V member 5 (TRPV5), which could explain impaired sodium excretion and enhanced calcium excretion in proteinuria. Amiloride, a potassium-sparing diuretic, inhibits urokinase and plasmin activation in the tubular fluid and uPAR expression in vitro, which highlights new indications for an old drug. Protease inhibitors lowered blood pressure and antagonized fibrosis in salt-sensitive Dahl rats. Current knowledge indicates that the plasminogen system aggravates renal disease by direct and indirect hypertensive effects and is a promising target to antagonize disease progression. PMID- 28656382 TI - Model-based prediction of myelosuppression and recovery based on frequent neutrophil monitoring. AB - PURPOSE: To investigate whether a more frequent monitoring of the absolute neutrophil counts (ANC) during myelosuppressive chemotherapy, together with model based predictions, can improve therapy management, compared to the limited clinical monitoring typically applied today. METHODS: Daily ANC in chemotherapy treated cancer patients were simulated from a previously published population model describing docetaxel-induced myelosuppression. The simulated values were used to generate predictions of the individual ANC time-courses, given the myelosuppression model. The accuracy of the predicted ANC was evaluated under a range of conditions with reduced amount of ANC measurements. RESULTS: The predictions were most accurate when more data were available for generating the predictions and when making short forecasts. The inaccuracy of ANC predictions was highest around nadir, although a high sensitivity (>=90%) was demonstrated to forecast Grade 4 neutropenia before it occurred. The time for a patient to recover to baseline could be well forecasted 6 days (+/-1 day) before the typical value occurred on day 17. CONCLUSIONS: Daily monitoring of the ANC, together with model-based predictions, could improve anticancer drug treatment by identifying patients at risk for severe neutropenia and predicting when the next cycle could be initiated. PMID- 28656381 TI - Predicting Malignant and Paramalignant Pleural Effusions by Combining Clinical, Radiological and Pleural Fluid Analytical Parameters. AB - BACKGROUND: The usefulness of clinical, radiological and pleural fluid analytical parameters for diagnosing malignant and paramalignant pleural effusion is not clearly stated. Hence this study aimed to identify possible predictor variables of diagnosing malignancy in pleural effusion of unknown aetiology. METHODS: Clinical, radiological and pleural fluid analytical parameters were obtained from consecutive patients who had suffered pleural effusion of unknown aetiology. They were classified into three groups according to their final diagnosis: malignant, paramalignant and benign pleural effusion. The CHAID (Chi-square automatic interaction detector) methodology was used to estimate the implication of the clinical, radiological and analytical variables in daily practice through decision trees. RESULTS: Of 71 patients, malignant (n = 31), paramalignant (n = 15) and benign (n = 25), smoking habit, dyspnoea, weight loss, radiological characteristics (mass, node, adenopathies and pleural thickening) and pleural fluid analytical parameters (pH and glucose) distinguished malignant and paramalignant pleural effusions (all with a p < 0.05). Decision tree 1 classified 77.8% of malignant and paramalignant pleural effusions in step 2. Decision tree 2 classified 83.3% of malignant pleural effusions in step 2, 73.3% of paramalignant pleural effusions and 91.7% of benign ones. CONCLUSIONS: The data herein suggest that the identified predictor values applied to tree diagrams, which required no extraordinary measures, have a higher rate of correct identification of malignant, paramalignant and benign effusions when compared to techniques available today and proved most useful for usual clinical practice. Future studies are still needed to further improve the classification of patients. PMID- 28656383 TI - A phase II study of irinotecan and pegylated liposomal doxorubicin in platinum resistant recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study). AB - PURPOSE: We report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial. METHODS: PLD was administered intravenously at a dose of 30 mg/m2 on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m2 on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS). RESULTS: The response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of >=3 months, the response rate was 63.3%, and the median PFS was 7 months. CONCLUSIONS: The treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of >=3 months had a good response rate and PFS. This suggests that CPT 11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer. PMID- 28656384 TI - X-ray vs. CT in identifying significant C-spine injuries in the pediatric population. AB - PURPOSE: Evaluation of cervical spine injury (CSI) in children requires rapid, yet accurate assessment of damage. Given concerns of radiation exposure, expert consensus advises that computed tomography (CT) should be used sparingly. However, CT can provide superior image resolution and detection of pathology. Herein, we evaluate if X-ray offers equal diagnostic accuracy compared to CT imaging in identifying CSI in children. METHODS: We conducted a retrospective study between October 2000 and March 2012 of pediatric patients evaluated for cervical spine injury at a level 1 trauma center. All patients included in this study were imaged with cervical spine X-rays and CT at the time of injury. Demographic information, mechanism of injury, significant versus non-significant injury (as defined by the NEXUS criteria), radiographic findings, level of the injury, presence of spinal cord injury, treatment, clinical outcome, and length of follow-up were collected. Chi-squared (chi 2) and Fisher's exact tests were used as appropriate and means and standard deviations were reported. RESULTS: We identified 1296 patients who were screened for CSI. Of those, 164 patients were diagnosed with spinal cord/column injuries (CSI). Eighty-nine patients were excluded for only having a CT or X-ray imaging without the other modality. Thus, a total of 75 patients with CSI were included in the final cohort. Using the NEXUS definitions, 78% of patients had clinically significant injuries while 22% had non-significant injuries. There were no injuries detected on X-ray that were not also detected on CT. For all injuries, X-ray sensitivity was 50.7%. X-rays were more sensitive to significant injuries (62.3%) compared in non-significant injuries, which were missed on all X-rays (0%). Therefore, X-rays did not identify 24 significant cervical spine injuries (32%) as defined by NEXUS. CONCLUSIONS: CT is superior to X-rays in detecting both clinically significant and insignificant cervical spine injuries. These results were not dependent on patient age or location of the injury. We recommend CT imaging in the evaluation of suspected cervical spine injuries in children. LEVEL OF EVIDENCE: III. PMID- 28656385 TI - Health-related quality of life in non-paraplegic (ambulatory) children with myelomeningocele. AB - PURPOSE: Evaluation of the effects of ventriculoperitoenal shunt and incontinence presence on health-related quality of life of ambulatory myelomeningocele patients. METHODS: The study group included 35 myelomeningocele patients, between 5 and 18 years old (mean age = 9.6), who were neonatally operated. All patients were ambulatory. The Child Edition of the Child Health and Illness Profile (CHIP CE) used to evaluate the patient group. Seventeen patients were using clean intermittent catheterization and nine patients had ventriculoperitoneal shunt. RESULTS: The CHIP-CE has five domains, and in satisfaction, resilience and achievement domains, significant lower scores were obtained from our study group. In terms of clean intermittent catheterization use, we got significantly lower scores on satisfaction, resilience and achievement domains (p < 0.05). According to the presence of ventriculoperitoneal shunt, we found lower scores in satisfaction, resilience, risk avoidance and achievement domains but the differences were not significant (p > 0.05). No significant difference was spotted according to gender and age. CONCLUSIONS: Continence problems have important effects on life quality of myelomeningocele patients. Incontinency should always be considered as a major variable in health-related quality of life evaluations. PMID- 28656386 TI - Performance of microbial identification by MALDI-TOF MS and susceptibility testing by VITEK 2 from positive blood cultures after minimal incubation on solid media. AB - Bloodstream infections (BSIs) are a leading cause of patient morbidity and mortality. Rapid identification of organisms from BSIs is critical for initiating targeted antimicrobial therapy. Although many methods exist for rapid identification, they do not provide detailed or definitive susceptibility information. We assessed the utility of both the VITEK MS and Bruker Biotyper MALDI-TOF mass spectrometers to identify organisms from a positive blood culture bottle after only 4 h of growth on solid media compared to identification from overnight growth using the VITEK MS. Additionally, we determined whether this limited growth could yield accurate antimicrobial susceptibility testing (AST) results compared to overnight growth using the VITEK 2 AST system. Overall, identifications using the VITEK MS and Biotyper had agreements of 127/150 (84%) and 133/150 (88%), respectively. For rapid AST, the overall categorical agreement was 1010/1017 (99.3%), where Gram-negative bacteria had concordant results for 743/750 (99.1%) organism-drug combinations and Gram-positive bacteria had concordant results for 265/267 (99.3%). Gram-negative bacteria had 4, 2, and 1 minor, major, and very major discrepancies, respectively, while Gram-positive bacteria had no minor errors, one major, and one very major discrepancy. In conclusion, organisms grown for only 4 h on solid media were accurately identified by MALDI-TOF MS and have concordant phenotypic AST profiles. This method can also be implemented using common commercial instruments, providing a way to improve upon identification and gain detailed susceptibility information without significant additional laboratory costs. PMID- 28656387 TI - Spontaneous recovery of non-operated traumatic brachial plexus injury. AB - PURPOSE: We investigated the spontaneous recovery of non-operated traumatic brachial plexus injury (BPI). METHODS: A total of 25 cases of non-operated traumatic BPI were analysed by retrospective review of medical records; in all cases, consecutive electrodiagnostic studies (ES) were conducted from 1 to 4 months and 18 to 24 months post-trauma. Injury severity was assessed using a modified version of Dumitru and Wilbourn's scale (DWS) based on ES. Spontaneous recovery of brachial plexus components per subject was analysed using Wilcoxon's signed-rank test. A two-tailed Fisher's exact or Pearson's Chi-square test was used to examine the associations between initial injury severity (DWS grade 2 vs. 3, complete vs. incomplete), accompanying injury type (open vs. closed), main lesion location (supraclavicular vs. infraclavicular lesion), and spontaneous recovery. RESULTS: The most common cause of BPI was traffic accident (TA) (15 cases, 60%), and the most common type of TA-induced BPI was a motorcycle TA (5 cases), accounting for 20% of all injuries. The second most common type of injury was an occupational injury (6 cases, 24%). Thirty-eight (69%) of 55 injured brachial components in 25 cases had DWS grade 3 and 17 brachial components (31%) had grade 2. The DWS grade of brachial plexus components per subject significantly differed between the first and follow-up ES (p = 0.000). However, initial injury severity, accompanying injury type, and main lesion location were not statistically associated with spontaneous recovery (p > 0.05). CONCLUSIONS: Spontaneous recovery may be possible even in severe traumatic BPI. Multiple factors should be considered when predicting the clinical course of traumatic BPI. PMID- 28656388 TI - Indications and outcomes for tunneled central venous line placement via the axillary vein in children. AB - PURPOSE: To assess the indications, safety and outcomes of tunneled central venous catheters (CVCs) placed via a cutdown approach into the axillary vein in children, an approach not well described in this population. METHODS: A retrospective cohort study was performed on pediatric patients who received CVCs via open cannulation of the axillary vein or one of its tributaries between January 2006 and October 2016 at two hospitals. RESULTS: A total of 24 axillary CVCs were placed in 20 patients [10 male (42%); mean weight 7.0 kg (SD 2.9); mean age 10 months (SD 6)]. The most common indications for axillary vein access included neck or chest wall challenges (tracheostomies or chest wall wounds) (n = 18). The median duration of line placement was 140 days (IQR 146). The most common indications for removal were completion of therapy (n = 7, 39%) and infection (n = 5, 28%). There were no early complications. Long-term complications included infection (n = 5) or catheter malfunction (n = 3). CONCLUSIONS: Tunneled CVC placement via a cutdown approach into the axillary vein or its tributary can be an effective alternative approach to obtain long-term vascular access in children. Outcomes may be comparable to lines placed in traditional internal jugular and subclavian vein locations. PMID- 28656389 TI - Inoculation of cyprinid herpesvirus 3 (CyHV-3) on common carp brain cells influence of process parameters on virus yield. AB - Research of cyprinid herpesvirus 3 (CyHV-3) is focused on the infection mechanism and disease development in animals using genetic and immunological approaches to improve treatments and diagnostics. In contrast, only few tried to investigate the CyHV-3 replication behaviour in available cell cultures. Whereas, obtaining high virus yields by in vitro replication enables achieving of the mentioned above goals easier and more reliable. The following work presents an attempt to illuminate the KHV replication in common carp brain (CCB) cell cultures from the engineering point of view. The isolate KHV-TP30 was used testing the influence on process parameters, such as multiplicity of infection (MOI), time of infection (TOI) and time of harvest (TOH). Virus concentrations and infectivity at different time points of infection were examined using hydrolyzed probe qPCR (Gilad et al. 2004) and 50% tissue culture infectivity dose (TCID50). The data obtained show that while the amount of the virus DNA remains constant after reaching its maximum, the infectivity of the virus decreases. Thus, especially, TOH can be crucial for generating a high-quality virus stock. Applying optimized parameters improved the infectivity of the harvested virus and reached a robust titre as high as 1.9 * 108 TCID50/mL. To our knowledge, so far, there is no information in the peer-reviewed literature showing comparably high virus titres. Such virus yields not only facilitate conduction of further studies, including stability tests of the virus stock under various supplementation or disinfection trails, but also provide enough virus material to perform more detailed examinations of the infection mechanism. PMID- 28656390 TI - Association between habitual dietary and lifestyle behaviours and skin autofluorescence (SAF), a marker of tissue accumulation of advanced glycation endproducts (AGEs), in healthy adults. AB - PURPOSE: Advanced glycation endproducts (AGEs) are produced endogenously and also enter the body during the consumption of AGEs present in heat-processed food. It is unknown whether AGEs of dietary origin accumulate within the body of healthy individuals. AGEs can deposit within skin tissue long-term by crosslinking extracellular matrix proteins. The fluorescent nature of many AGEs enables their detection within the skin by non-invasively measuring skin autofluorescence (SAF). This study aimed to identify habitual dietary and lifestyle behaviours cross-sectionally associated with SAF in an adult population sample. METHODS: 251 Healthy adult volunteers completed validated food frequency and physical activity questionnaires. Waist circumference, BMI, blood pressure and blood glucose was also measured. SAF was measured using an AGE Reader. RESULTS: Significant positive correlations were found between SAF and chronological age (r = 0.63, P < 0.001), waist circumference (r = 0.28, P < 0.01), body weight (r = 0.24, P < 0.05), BMI (r = 0.23, P < 0.05) and consumption of meat and meat products (r = 0.22, P < 0.05). A negative correlation was found between SAF and cereal consumption (r = -0.21, P < 0.05). Cigarette smokers also had a significantly higher SAF than non-smokers (2.4 vs 2.0 U, P < 0.05). Regression analysis identified age, cigarette smoking, waist circumference and intake of meat products as significant predictors of SAF. The regression model explained 48% of the variation in SAF. CONCLUSIONS: Age, cigarette smoking, waist circumference and dietary consumption of meat/meat products were positively associated with SAF in this sample. Further research is required to determine whether frequent consumption of foods containing large quantities of dietary AGEs contribute to pathological disease processes in healthy individuals. PMID- 28656391 TI - Antioxidant activity of whole grain highland hull-less barley and its effect on liver protein expression profiles in rats fed with high-fat diets. AB - PURPOSE: Whole grain exhibits potential for regulating lipid levels, possibly because of its antioxidant activity. This study aims to investigate the antioxidant activity of whole grain highland hull-less barley (WHLB) and its effect on liver protein expression profiles in rats fed with high-fat diets. METHODS: Antioxidant activity of WHLB was investigated in vitro by analyzing phenolic and pentosan contents and oxygen radical absorbance capacity (ORAC). Proteins involved in lipid regulation were investigated in vivo by analyzing liver protein expression profiles in Sprague-Dawley rats fed with high-fat diet (HFD) with or without WHLB. RESULTS: WHLB possessed high total phenolic content (259.90 mg/100 g), total pentosan content (10.74 g/100 g), and ORAC values (418.05 +/- 5.65 MUmol/g). Rats fed with WHLB diet exhibited significantly (P < 0.05) lower liver lipid levels than those fed with the control HFD diet. Seven differentially expressed proteins were detected through liver proteome analysis and were found to be correlated with 11 pathways, including lipid metabolism, through annotation with Kyoto Encyclopedia of Genes and Genomes. Quantitative real-time polymerase chain reaction analysis showed that rats given with WHLB diet exhibited down-regulated expression of heat shock protein 60 (HSP60) and phosphatidylethanolamine binding protein 1 (PEBP1) and up-regulated expression of enoyl-coenzyme A hydratase (ECH) and peroxiredoxin 6 (PRDX6). CONCLUSIONS: HSP60, PEBP1, ECH, and PRDX6 may be involved in the lipid regulatory effect of WHLB. Moreover, the regulation of PRDX6 may be related to the antioxidant activity of WHLB. PMID- 28656392 TI - Performance improvement of ERP-based brain-computer interface via varied geometric patterns. AB - Recently, many studies have been focusing on optimizing the stimulus of an event related potential (ERP)-based brain-computer interface (BCI). However, little is known about the effectiveness when increasing the stimulus unpredictability. We investigated a new stimulus type of varied geometric pattern where both complexity and unpredictability of the stimulus are increased. The proposed and classical paradigms were compared in within-subject experiments with 16 healthy participants. Results showed that the BCI performance was significantly improved for the proposed paradigm, with an average online written symbol rate increasing by 138% comparing with that of the classical paradigm. Amplitudes of primary ERP components, such as N1, P2a, P2b, N2, were also found to be significantly enhanced with the proposed paradigm. In this paper, a novel ERP BCI paradigm with a new stimulus type of varied geometric pattern is proposed. By jointly increasing the complexity and unpredictability of the stimulus, the performance of an ERP BCI could be considerably improved. PMID- 28656394 TI - ? PMID- 28656395 TI - ? PMID- 28656396 TI - ? PMID- 28656397 TI - ? PMID- 28656398 TI - ? PMID- 28656393 TI - Emerging Roles of Sirtuins in Ischemic Stroke. AB - Ischemic stroke is one of the leading causes of death worldwide. It is characterized by a sudden disruption of blood flow to the brain causing cell death and damage, which will lead to neurological impairments. In the current state, only one drug is approved to be used in clinical setting and new therapies that confer ischemic neuroprotection are desperately needed. Several targets and pathways have been indicated to be neuroprotective in ischemic stroke, among which the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases has emerged as important modulators of several processes in the normal physiology and pathological conditions such as stroke. Recent studies have identified some members of the sirtuin family are able to ameliorate the devastating consequences of ischemic stroke by conferring neuroprotection by means of reducing neuronal cell death, oxidative stress, and neuroinflammation whereas some sirtuins are found to be detrimental in the pathophysiology of ischemic stroke. This review summarizes implications of sirtuins in ischemic stroke and the experimental evidences that demonstrate the potential of sirtuin modulators as neuroprotective therapy for ischemic stroke. PMID- 28656399 TI - ? PMID- 28656400 TI - ? PMID- 28656401 TI - ? PMID- 28656402 TI - ? PMID- 28656403 TI - [Measurement of liver stiffness using ultrasound]. PMID- 28656404 TI - [COPD, an update of current management recommendations]. PMID- 28656405 TI - [Lyme borreliosis after tick bite. When to consider the diagnosis Lyme borreliosis?] PMID- 28656406 TI - ? PMID- 28656407 TI - [Toxins in the garden. Activated charcoal as universal antidote]. PMID- 28656408 TI - [Poison in the garden: Poisonous plants relevant to clinical toxicology]. PMID- 28656409 TI - [Contact burns induced by phytophototoxic substances]. PMID- 28656410 TI - [Lawn mower injury in children - a lesson for life]. PMID- 28656411 TI - [Penetrating head injurys]. PMID- 28656412 TI - ? PMID- 28656413 TI - ? PMID- 28656414 TI - ? PMID- 28656415 TI - ? PMID- 28656416 TI - ? PMID- 28656417 TI - ? PMID- 28656418 TI - ? PMID- 28656419 TI - ? PMID- 28656420 TI - ? PMID- 28656421 TI - ? PMID- 28656422 TI - ? PMID- 28656423 TI - ? PMID- 28656424 TI - ? PMID- 28656425 TI - ? PMID- 28656426 TI - ? PMID- 28656427 TI - ? PMID- 28656428 TI - ? PMID- 28656429 TI - ? PMID- 28656430 TI - ? PMID- 28656431 TI - ? PMID- 28656432 TI - ? PMID- 28656433 TI - ? PMID- 28656434 TI - ? PMID- 28656435 TI - ? PMID- 28656436 TI - ? PMID- 28656437 TI - ? PMID- 28656439 TI - ? PMID- 28656438 TI - ? PMID- 28656440 TI - ? PMID- 28656441 TI - ? PMID- 28656443 TI - ? PMID- 28656442 TI - ? PMID- 28656444 TI - ? PMID- 28656446 TI - ? PMID- 28656447 TI - ? PMID- 28656449 TI - ? PMID- 28656448 TI - ? PMID- 28656450 TI - [Polyneuropathy - causes and treatment]. PMID- 28656451 TI - Individual-level exposure to disaster, neighborhood environmental characteristics, and their independent and combined associations with depressive symptoms in women. AB - PURPOSE: The severity of the stress response to experiencing disaster depends on individual exposure and background stress prior to the event. To date, there is limited research on the interaction between neighborhood environmental stress and experiencing an oil spill, and their effects on depression. The objective of the current study was to assess if the association between exposure to the Deepwater Horizon Oil Spill (DHOS) and depressive symptoms varied by neighborhood characteristics. METHODS: US Census data (2010) and longitudinal data collected in two waves (2012-2014 and 2014-2016) from female residents [N = 889 (Wave I), 737 (Wave II)] of an area highly affected by the DHOS were analyzed. Multilevel and individual-level negative binomial regressions were performed to estimate associations with depressive symptoms in both waves. An interaction term was included to estimate effect modification of the association between DHOS exposure and depressive symptoms by neighborhood characteristics. Generalized estimating equations were applied to the negative binomial regression testing longitudinal associations. RESULTS: Census tract-level neighborhood characteristics were not associated with depressive symptoms. Exposure to the DHOS and neighborhood physical disorder were associated with depressive symptoms cross-sectionally. There was no evidence of effect modification; however, physical/environmental exposure to the DHOS was associated with increased depressive symptoms only among women living in areas with physical disorder. Exposure to the DHOS remained associated with depressive symptoms over time. CONCLUSIONS: Findings support the enduring consequences of disaster exposure on depressive symptoms in women and identify potential targets for post-disaster intervention based on residential characteristics. PMID- 28656453 TI - Goal-concordant care in the ICU: a conceptual framework for future research. PMID- 28656452 TI - Homeless women with schizophrenia reported lower adherence to their medication than men: results from the French Housing First experience. AB - OBJECTIVE: The aim of this study was to investigate the factors associated with non-adherence to medication in a large multi-center sample of homeless schizophrenia (HSZ) patients. METHODS: This multi-center study was conducted in four French cities: Lille, Marseille, Paris, and Toulouse. In addition to the Medication Adherence Rating Scale (MARS), sociodemographic information, history of homelessness, illness severity using the Modified Colorado Symptom Index (MCSI) and the Multnomah Community Integration Scale (MCAS), and drug information were collected. RESULTS: In total, 218 HSZ patients (16.1% women, mean age 36.8 +/- 9.3 years) were included in this study. In the multivariate analysis, being a woman and having higher illness severity (MCSI score) and lower "acceptance of illness" (MCAS score) were significantly associated with lower MARS index scores. Compared to men, women had lower MARS dimension 1 ('medication adherence behavior') and dimension 3 ('negative side effects and attitudes toward psychotropic medication') scores. First-generation antipsychotic use was also associated with lower MARS dimension 3 scores. CONCLUSION: HSZ women reported lower adherence than men, mainly due to having more subjective negative side effects and worse attitudes toward psychotropic medication. Future longitudinal studies should confirm these findings and explore the applicability of specific pharmacological and non-pharmacological treatment strategies for HSZ women, including treatment dose adaptation and psychoeducation. Clinical trial number NCT01570712. PMID- 28656454 TI - Fat embolism syndrome. PMID- 28656455 TI - Malignancy Detection on Mammography Using Dual Deep Convolutional Neural Networks and Genetically Discovered False Color Input Enhancement. AB - Breast cancer is the most prevalent malignancy in the US and the third highest cause of cancer-related mortality worldwide. Regular mammography screening has been attributed with doubling the rate of early cancer detection over the past three decades, yet estimates of mammographic accuracy in the hands of experienced radiologists remain suboptimal with sensitivity ranging from 62 to 87% and specificity from 75 to 91%. Advances in machine learning (ML) in recent years have demonstrated capabilities of image analysis which often surpass those of human observers. Here we present two novel techniques to address inherent challenges in the application of ML to the domain of mammography. We describe the use of genetic search of image enhancement methods, leading us to the use of a novel form of false color enhancement through contrast limited adaptive histogram equalization (CLAHE), as a method to optimize mammographic feature representation. We also utilize dual deep convolutional neural networks at different scales, for classification of full mammogram images and derivative patches combined with a random forest gating network as a novel architectural solution capable of discerning malignancy with a specificity of 0.91 and a specificity of 0.80. To our knowledge, this represents the first automatic stand alone mammography malignancy detection algorithm with sensitivity and specificity performance similar to that of expert radiologists. PMID- 28656456 TI - Modifications of femoral component design in multi-radius total knee arthroplasty lead to higher lateral posterior femoro-tibial translation. AB - PURPOSE: As the aims of changes in total knee arthroplasty (TKA) designs are to reinstate more natural kinematics, the current study evaluated the in vivo kinematics in patients who underwent a cruciate retaining gradually changing femoral radius ("G-CURVE") against a cruciate retaining conventional changing femoral radius ("J-CURVE") geometry TKA design. The hypothesis of the study is that the G-CURVE design would allow a substantial increase in the femoral rollback compared to the J-CURVE design. METHODS: Retrospective study design. Thirty patients were included (G-CURVE, n = 20; J-CURVE, n = 10). Single-plane fluoroscopic analysis and marker-based motion capture gait analysis was performed to analyse dynamic tibiofemoral motion during weight-bearing and unloaded activities at 24 month after index surgery. RESULTS: The analysis of the medial and lateral points on the tibia plateau during the unloaded flexion-extension and the weight-bearing lunge activities revealed a significant difference in femoral rollback in G-CURVE TKA above 60 degrees (p = 0.001) and 30 degrees (p = 0.02) of knee flexion, respectively. Moreover, the lateral condyle of the G-CURVE showed a higher extent of femoral rollback while the lateral condyle of the J CURVE rolled forward. CONCLUSION: At 2 years post-operative, the G-CURVE TKA showed significant differences in femoro-tibial translation in comparison with the J-CURVE system, in vivo. The G-CURVE resulted in an increased lateral rollback and simultaneously in an elimination of the paradoxical medial roll forward present in the J-CURVE design. Moreover, knee kinematics analysis showed significant differences between unloaded and weight-bearing conditions revealing the impact of load and muscle force. The analysis conducted in this study contributes to further understand the principal movement characteristics in widely used older designs in comparison with recently developed concepts to get a better overview on their potential benefits on in vivo kinematics. LEVEL OF EVIDENCE: III. PMID- 28656457 TI - No superior treatment for primary osteochondral defects of the talus. AB - PURPOSE: The purpose of this systematic literature review is to detect the most effective treatment option for primary talar osteochondral defects in adults. METHODS: A literature search was performed to identify studies published from January 1996 to February 2017 using PubMed (MEDLINE), EMBASE, CDSR, DARE, and CENTRAL. Two authors separately and independently screened the search results and conducted the quality assessment using the Newcastle-Ottawa Scale. Subsequently, success rates per separate study were calculated. Studies methodologically eligible for a simplified pooling method were combined. RESULTS: Fifty-two studies with 1236 primary talar osteochondral defects were included of which forty-one studies were retrospective and eleven prospective. Two randomised controlled trials (RCTs) were identified. Heterogeneity concerning methodological nature was observed, and there was variety in reported success rates. A simplified pooling method performed for eleven retrospective case series including 317 ankles in the bone marrow stimulation group yielded a success rate of 82% [CI 78-86%]. For seven retrospective case series investigating an osteochondral autograft transfer system or an osteoperiosteal cylinder graft insertion with in total 78 included ankles the pooled success rate was calculated to be 77% [CI 66-85%]. CONCLUSIONS: For primary talar osteochondral defects, none of the treatment options showed any superiority over others. LEVEL OF EVIDENCE: IV. PMID- 28656458 TI - A genetic risk score is differentially associated with migraine with and without aura. AB - Although a number of migraine-associated single-nucleotide polymorphisms (SNP) with small effect size have been identified, little is known about the additive impact of these variants on migraine risk, frequency and severity. We investigated to what extent a genetic risk score (GRS) based on recently published, novel migraine-associated SNPs is associated with migraine prevalence, subtypes and severity in a large population-based sample. The sample comprised 446 subjects with migraine and 2511 controls from the CoLaus/PsyCoLaus study. Fifty-four SNPs earlier associated with migraine were selected. SNPs with a low impact on migraine prevalence in our sample were excluded using random forest. We combined the remaining 21 SNPs into a GRS and analyzed the association with migraine using logistic regression models. The GRS was significantly associated with migraine (OR = 1.56, p = 0.02) and migraine without aura (MWOA) (OR = 2.01, p = 0.003), but not with migraine with aura (MWA). The GRS was not associated with migraine frequency, intensity or interference with daily activities. We show that a GRS combining multiple genetic risk variants is associated with MWOA but not MWA, suggesting a different genetic susceptibility background underlying the two forms of migraine. PMID- 28656459 TI - Involvement of thermosensitive TRP channels in energy metabolism. AB - To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders. PMID- 28656460 TI - CT assessment-based direct surgical resection of part-solid nodules with solid component larger than 5 mm without preoperative biopsy: experience at a single tertiary hospital. AB - OBJECTIVES: To retrospectively evaluate the feasibility of CT assessment-based direct surgical resection of part-solid nodules (PSNs) with solid components > 5 mm without preoperative percutaneous transthoracic needle biopsies (PTNBs). METHODS: From January 2009-December 2014, 85 PSNs with solid components > 5 mm on CT were included. Preoperative PTNBs were performed for 41 PSNs (biopsy group) and CT assessment-based direct resections were performed for 44 PSNs (direct surgery group). Diagnostic accuracy and complication rates of the groups were compared. RESULTS: Pathological results of 83 PSNs excluding two indeterminate nodules included 76 adenocarcinomas (91.6%), two adenocarcinomas in situ (2.4%) and five benign lesions (6.0%). In the biopsy group, the overall sensitivity, specificity and accuracy for the diagnosis of adenocarcinoma were 78.9% (30/38), 100% (1/1) and 79.5% (31/39), respectively. Pneumothorax and haemoptysis occurred in 11 procedures (26.8%). In the direct surgery group, the respective values for the diagnosis of adenocarcinoma were 100% (38/38), 0% (0/6) and 86.4% (38/44), respectively. Seven pneumothoraces (15.9%); no haemoptysis occurred during localization procedures. There were no significant differences in diagnostic accuracy (P = 0.559) between the two groups. CONCLUSIONS: CT assessment-based direct resection can be reasonable for PSNs with solid part > 5 mm. KEY POINTS: * 91.6% of PSNs with solid component > 5 mm were adenocarcinomas. * PTNBs for PSNs with solid component > 5 mm had 79.5% accuracy. * CT-based resection for PSNs with solid component > 5 mm had 86.4% accuracy. * CT-based resection without biopsy can be a reasonable option in routine practice. PMID- 28656462 TI - A meta-analysis of use of Prostate Imaging Reporting and Data System Version 2 (PI-RADS V2) with multiparametric MR imaging for the detection of prostate cancer. AB - OBJECTIVES: This meta-analysis was undertaken to review the diagnostic accuracy of PI-RADS V2 for prostate cancer (PCa) detection with multiparametric MR (mp MR). METHODS: A comprehensive literature search of electronic databases was performed by two observers independently. Inclusion criteria were original research using the PI-RADS V2 system in reporting prostate MRI. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Data necessary to complete 2 * 2 contingency tables were obtained from the included studies. RESULTS: Thirteen studies (2,049 patients) were analysed. This is an initial meta-analysis of PI-RADs V2 and the overall diagnostic accuracy in diagnosing PCa was as follows: pooled sensitivity, 0.85 (0.78-0.91); pooled specificity, 0.71 (0.60-0.80); pooled positive likelihood ratio (LR+), 2.92 (2.09-4.09); pooled negative likelihood ratio (LR-), 0.21 (0.14-0.31); pooled diagnostic odds ratio (DOR), 14.08 (7.93-25.01), respectively. Positive predictive values ranged from 0.54 to 0.97 and negative predictive values ranged from 0.26 to 0.92. CONCLUSION: Currently available evidence indicates that PI-RADS V2 appears to have good diagnostic accuracy in patients with PCa lesions with high sensitivity and moderate specificity. However, no recommendation regarding the best threshold can be provided because of heterogeneity. KEY POINTS: * PI-RADS V2 shows good diagnostic accuracy for PCa detection. * Initially pooled specificity of PI-RADS v2 remains moderate. * PCa detection is increased by experienced radiologists. * There is currently a high heterogeneity in prostate diagnostics with MRI. PMID- 28656461 TI - Comparison of radial 4D Flow-MRI with perivascular ultrasound to quantify blood flow in the abdomen and introduction of a porcine model of pre-hepatic portal hypertension. AB - OBJECTIVES: Objectives of this study were to compare radial time-resolved phase contrast magnetic resonance imaging (4D Flow-MRI) with perivascular ultrasound (pvUS) and to explore a porcine model of acute pre-hepatic portal hypertension (PHTN). METHODS: Abdominal 4D Flow-MRI and pvUS in portal and splenic vein, hepatic and both renal arteries were performed in 13 pigs of approximately 60 kg. In six pigs, measurements were repeated after partial portal vein (PV) ligature. Inter- and intra-reader comparisons and statistical analysis including Bland Altman (BA) comparison, paired Student's t tests and linear regression were performed. RESULTS: PvUS and 4D Flow-MRI measurements agreed well; flow before partial PV ligature was 322 +/- 30 ml/min in pvUS and 297 +/- 27 ml/min in MRI (p = 0.294), and average BA difference was 25 ml/min [-322; 372]. Inter- and intra reader results differed very little, revealed excellent correlation (R 2 = 0.98 and 0.99, respectively) and resulted in BA differences of -5 ml/min [-161; 150] and -2 ml/min [-28; 25], respectively. After PV ligature, PV flow decreased from 356 +/- 50 to 298 +/- 61 ml/min (p = 0.02), and hepatic arterial flow increased from 277 +/- 36 to 331 +/- 65 ml/min (p = n.s.). CONCLUSION: The successful in vivo comparison of radial 4D Flow-MRI to perivascular ultrasound revealed good agreement of abdominal blood flow although with considerable spread of results. A model of pre-hepatic PHTN was successfully introduced and acute responses monitored. KEY POINTS: * Radial 4D Flow-MRI in the abdomen was successfully compared to perivascular ultrasound. * Inter- and intra-reader testing demonstrated excellent reproducibility of upper abdominal 4D Flow-MRI. * A porcine model of acute pre-hepatic portal hypertension was successfully introduced. * 4D Flow-MRI successfully monitored acute changes in a model of portal hypertension. PMID- 28656463 TI - Whole-body MRI quantitative biomarkers are associated significantly with treatment response in patients with newly diagnosed symptomatic multiple myeloma following bortezomib induction. AB - OBJECTIVES: To evaluate whole-body MRI (WB-MRI) parameters significantly associated with treatment response in multiple myeloma (MM). METHODS: Twenty-one MM patients underwent WB-MRI at diagnosis and after two cycles of chemotherapy. Scans acquired at 3.0 T included T2, diffusion-weighted-imaging (DWI) and mDixon pre- and post-contrast. Twenty focal lesions (FLs) matched on DWI and post contrast mDixon were selected for each time point. Estimated tumour volume (eTV), apparent diffusion coefficient (ADC), enhancement ratio (ER) and signal fat fraction (sFF) were derived. Clinical treatment response to chemotherapy was assessed using conventional criteria. Significance of temporal parameter change was assessed by the paired t test and receiver operating characteristics/area under the curve (AUC) analysis was performed. Parameter repeatability was assessed by interclass correlation (ICC) and Bland-Altman analysis of 10 healthy volunteers scanned at two time points. RESULTS: Fifteen of 21 patients responded to treatment. Of 254 FLs analysed, sFF (p < 0.0001) and ADC (p = 0.001) significantly increased in responders but not non-responders. eTV significantly decreased in 19/21 cases. Focal lesion sFF was the best discriminator of treatment response (AUC 1.0). Bone sFF repeatability was excellent (ICC 0.98) and better than bone ADC (ICC 0.47). CONCLUSION: WB-MRI derived focal lesion sFF shows promise as an imaging biomarker of treatment response in newly diagnosed MM. KEY POINTS: * Bone signal fat fraction using mDixon is a robust quantifiable parameter * Fat fraction and ADC significantly increase in myeloma lesions responding to treatment * Bone lesion fat fraction is the best discriminator of myeloma treatment response. PMID- 28656464 TI - Re-evaluation of a novel approach for quantitative myocardial oedema detection by analysing tissue inhomogeneity in acute myocarditis using T2-mapping. AB - OBJECTIVES: To re-evaluate a recently suggested approach of quantifying myocardial oedema and increased tissue inhomogeneity in myocarditis by T2 mapping. METHODS: Cardiac magnetic resonance data of 99 patients with myocarditis were retrospectively analysed. Thirthy healthy volunteers served as controls. T2 mapping data were acquired at 1.5 T using a gradient-spin-echo T2-mapping sequence. T2-maps were segmented according to the 16-segments AHA-model. Segmental T2-values, segmental pixel-standard deviation (SD) and the derived parameters maxT2, maxSD and madSD were analysed and compared to the established Lake Louise criteria (LLC). RESULTS: A re-estimation of logistic regression models revealed that all models containing an SD-parameter were superior to any model containing global myocardial T2. Using a combined cut-off of 1.8 ms for madSD + 68 ms for maxT2 resulted in a diagnostic sensitivity of 75% and specificity of 80% and showed a similar diagnostic performance compared to LLC in receiver-operating-curve analyses. Combining madSD, maxT2 and late gadolinium enhancement (LGE) in a model resulted in a superior diagnostic performance compared to LLC (sensitivity 93%, specificity 83%). CONCLUSIONS: The results show that the novel T2-mapping-derived parameters exhibit an additional diagnostic value over LGE with the inherent potential to overcome the current limitations of T2-mapping. KEY POINTS: * A novel quantitative approach to myocardial oedema imaging in myocarditis was re-evaluated. * The T2-mapping-derived parameters maxT2 and madSD were compared to traditional Lake-Louise criteria. * Using maxT2 and madSD with dedicated cut-offs performs similarly to Lake-Louise criteria. * Adding maxT2 and madSD to LGE results in further increased diagnostic performance. * This novel approach has the potential to overcome the limitations of T2-mapping. PMID- 28656465 TI - Strain analysis in CRT candidates using the novel segment length in cine (SLICE) post-processing technique on standard CMR cine images. AB - OBJECTIVES: Although myocardial strain analysis is a potential tool to improve patient selection for cardiac resynchronization therapy (CRT), there is currently no validated clinical approach to derive segmental strains. We evaluated the novel segment length in cine (SLICE) technique to derive segmental strains from standard cardiovascular MR (CMR) cine images in CRT candidates. METHODS: Twenty seven patients with left bundle branch block underwent CMR examination including cine imaging and myocardial tagging (CMR-TAG). SLICE was performed by measuring segment length between anatomical landmarks throughout all phases on short-axis cines. This measure of frame-to-frame segment length change was compared to CMR TAG circumferential strain measurements. Subsequently, conventional markers of CRT response were calculated. RESULTS: Segmental strains showed good to excellent agreement between SLICE and CMR-TAG (septum strain, intraclass correlation coefficient (ICC) 0.76; lateral wall strain, ICC 0.66). Conventional markers of CRT response also showed close agreement between both methods (ICC 0.61-0.78). Reproducibility of SLICE was excellent for intra-observer testing (all ICC >=0.76) and good for interobserver testing (all ICC >=0.61). CONCLUSIONS: The novel SLICE post-processing technique on standard CMR cine images offers both accurate and robust segmental strain measures compared to the 'gold standard' CMR TAG technique, and has the advantage of being widely available. KEY POINTS: * Myocardial strain analysis could potentially improve patient selection for CRT. * Currently a well validated clinical approach to derive segmental strains is lacking. * The novel SLICE technique derives segmental strains from standard CMR cine images. * SLICE-derived strain markers of CRT response showed close agreement with CMR-TAG. * Future studies will focus on the prognostic value of SLICE in CRT candidates. PMID- 28656466 TI - Quantitative analysis of scapholunate diastasis using stress speckle-tracking sonography: a proof-of-concept and feasibility study. AB - OBJECTIVE: To evaluate the feasibility and potential clinical applicability of speckle-tracking sonography for the dynamic evaluation of the scapholunate diastasis during stress manoeuvres. MATERIAL AND METHODS: Two readers used speckle tracking sonography to evaluate scapholunate diastasis during a clenching fist manoeuver in 30 normal wrists. Scapholunate peak strain, mean scapholunate diastasis and the diastasis variation coefficient were analysed. IRB exemption was granted for this study. Conventional and stress wrist radiographs of 26 patients with and without a scapholunate ligament tear were retrospectively analysed to ascertain the range of variation in scapholunate diastasis. RESULTS: Speckle-tracking parameters in normal wrists were similar between the two readers (p > 0.2061). The maximal scapholunate peak strain during stress was relatively low (<0.34-0.47 mm). The normal radiographic diastasis amplitude was similar to maximal strain peak values in normal volunteers (0.49 +/- 0.51 mm). The radiographic diastasis amplitude in cases of scapholunate ligament tears was 1.48 +/- 0.78 mm, which was higher than the 95% confidence interval of the scapholunate gap peak strain. CONCLUSION: Speckle-tracking sonography could represent an interesting alternative for stress evaluation of the scapholunate ligament in patients with scapholunate diastasis. KEY POINTS: * Speckle-tracking sonography can assess scapholunate diastasis under stress testing. * Scapholunate gap shows little variation under stress in healthy volunteers. * Scapholunate gap measurements are influenced by grip strength. * Sex and BMI have a significant influence on strain measurements. PMID- 28656467 TI - First Descents, an adventure program for young adults with cancer: who benefits? AB - BACKGROUND: Participation in camps, adventure programs, retreats, and other social events offers experiences that can promote self-efficacy and quality of life. PURPOSE: The purpose of the study was to examine whether participation in a 1-week outdoor adventure program resulted in improvements in psychological distress, self-efficacy, and/or social support for young adult cancer patients (AYAs) aged 18-40 years. The study examined the differential effect of participation for AYAs who indicated moderate to severe symptoms of psychological distress prior to their trip. METHODS: Standardized measures of distress, self efficacy, and social support were administered pre-trip, post-trip, and 1 month after program completion (follow-up). Univariate and multivariate models examined baseline scores for non-distressed participants compared to distressed participants, changes in outcomes from pre-trip to post-trip and follow-up for the entire sample, and the extent to which change rates for each outcome differed for distressed versus non-distressed participants. RESULTS: All participants demonstrated significant improvement in self-efficacy over time. Distressed participants reported a significantly greater decrease in distress symptoms and greater increase in self-efficacy and social support at post-trip and 1 month later when compared to non-distressed participants. CONCLUSIONS: Findings suggest that participation in an outdoor recreational activity designed specifically for AYAs with cancer contributes to significant reductions in distress and improvements in self-efficacy and social support, and particularly for AYAs reporting clinically significant distress symptoms prior to the initiation of their activity. PMID- 28656468 TI - The role of the built environment in a randomized controlled trial to increase physical activity among men with prostate cancer: the PROMOTE trial. AB - PURPOSE: The purpose of the study was to examine the association between the built environment and physical activity (PA) in prostate cancer survivors (PCS), as well as whether built environment factors (walkability, count of sports complexes) were effect modifiers of a PA intervention. METHODS: Our study included 165 PCS residing in Edmonton, Alberta, from the PROMOTE trial. The PROMOTE trial was a randomized controlled trial of a behaviour change intervention to increase PA and quality of life in PCS. In the PROMOTE trial, 423 PCS were randomly assigned to a standard physical activity recommendation, self administered implementation intention, or telephone-assisted implementation intention group. PA and quality of life outcomes were assessed at baseline, 1, and 3 months. To explore the role of the built environment, this study examined walkability and count of sport complexes. RESULTS: Linear regression analyses revealed that the self-administered intervention group had an increase in self reported PA minutes/week (beta = 133.4, 95% CI = -18.9 to 285.6); however, none of the built environment variables were found to be significantly associated with PA. The logistic regression showed that the self-administered intervention group had a significantly greater likelihood of meeting the PA guidelines (OR = 2.1, 95% CI = 0.9 to 4.9), though no built environment variables were associated with PA levels. CONCLUSIONS: Our findings suggest that the built environment was not associated with PA and was not an effect modifier in a PA behaviour change intervention for PCS. Further research is needed before clear conclusions can be generated ( ClinicalTrials.gov number NCT01410656). PMID- 28656469 TI - Optimizing VAP scars after childhood cancer treatment: a pilot study. AB - PURPOSE: Majority of pediatric cancer patients are treated with chemotherapy using Venous Access Ports (VAP). However, after surgical removal of the VAP prominent scars often remain and standard care is lacking. METHODS: Patients (N = 20) who were willing to participate were included prior to surgical removal of their VAP. All patients were off therapy at time of VAP removal. Patients had the option to either choose from Dermatix(r), meridian color therapy (MCT), or no additional treatment (NAT). Assessment of scars was done prior to and 3, 6, and 12 months after surgical VAP removal using Patient and Observer Scar Assessment Scales (POSAS) questionnaires. To identify whether Dermatix(r) or MCT is associated with better scar healing than without additional treatment, Mann Whitney U tests were used. RESULTS: After 12 months of follow-up, both patients and dermatologists noted VAP scars had healed better after MCT compared to those without treatment (P = 0.010 for both POSAS patient and POSAS observer). No significant differences were observed between VAP scars after Dermatix(r) use and those with no treatment. CONCLUSIONS: Scar healing after MCT significantly improved, whereas Dermatix(r) treatment showed no significant differences compared to NAT. To translate this to daily care, a larger prospective study is needed to validate these findings. PMID- 28656470 TI - Effectiveness of intervention with a perioperative multidisciplinary support team for radical esophagectomy. AB - PURPOSE: We aimed to evaluate the effectiveness of intervention by a perioperative multidisciplinary support team for radical esophagectomy for esophageal cancer. METHODS: We retrospectively reviewed 85 consecutive patients with esophageal cancer who underwent radical esophagectomy via right thoracotomy or thoracoscopic surgery with gastric tube reconstruction. Twenty-one patients were enrolled in the non-intervention group (group N) from May 2011 to September 2012, 31 patients in the perioperative rehabilitation group (group R) from October 2012 to April 2014, and 33 patients in the multidisciplinary support team group (group S) from May 2014 to September 2015. RESULTS: Morbidity rates were 38, 45.2, and 42.4% for groups N, R, and S, respectively. Although there were no significant differences in the incidence of pneumonia among the groups, the durations of fever and C-reactive protein positivity were shorter in group S. Moreover, postoperative oral intake commenced earlier [5.9 (5-8) days] and postoperative hospital stay was shorter [19.6 (13-29) days] for group S. CONCLUSIONS: The intervention by a perioperative multidisciplinary support team for radical esophagectomy was effective in preventing the progression and prolongation of pneumonia as well as earlier ambulation, oral feeding, and shortening of postoperative hospitalization. PMID- 28656471 TI - Mechanism of Lycium barbarum polysaccharides on primary cultured rat hippocampal neurons. AB - Lycium barbarum polysaccharides (LBP) have been reported to have a wide range of beneficial effects including neuroprotection, anti-aging and anticancer. However, the anti-inflammation mechanism of LBP on primary cultured rat hippocampal neurons injured by oxygen-glucose deprivation/reperfusion (OGD/RP) is incompletely understood. We investigate the neuroprotective effects of LBP on neonatal rat primary cultured hippocampal neurons injured by OGD/RP with different approaches: MTT assay was used to detect cell viability, lactate dehydrogenase leakage was used to detect neuronal damage, formation of reactive oxygen species was determined by using fluorescent probe DCFH-DA. Hoechst 33,342 staining and TUNEL staining were used to determine the cell apoptosis. JC-1 was used to evaluate loss of mitochondrial membrane potential (MMP). The fluorescence intensity of [Ca2+]i in hippocampal neurons was determined by laser scanning confocal microscopy. The expression of various apoptotic markers such as TLR4, IkappaB, IL-6 and NF-kappaB were investigated by RT-PCR and western blot analysis. Results from each approach demonstrated that LBP increased the cell abilities and decreased the cell morphologic impairment. Furthermore, LBP increased MMP but inhibited [Ca2+]i elevation and significantly suppressed overexpression of NF-kappaB, IL-6 TLR4 and increased IkappaB expression. PMID- 28656472 TI - Shared hemocyte- and intestine-dominant expression profiles of intelectin genes in ascidian Ciona intestinalis: insight into the evolution of the innate immune system in chordates. AB - Intelectin is a soluble lectin known as a pattern-recognition receptor for the innate immune system or as an intestinal lactoferrin receptor. Intelectin genes have been identified in a wide range of chordates and the shared expression pattern in their absorptive intestinal regions has been widely recognized. The chordate intelectins have a shared domain structure with a fibrinogen-related domain and an intelectin domain and an additional sequence has been reported only in ascidian Ciona intestinalis intelectins. However, little is known about the molecular features of the ascidian intelectins, including the distribution of the additional sequence in ascidians. Therefore, we focus on the ascidian species that are available for genome DNA sequence searches and survey intelectin genes with special reference to the additional sequence. We also assess the distribution of Ciona intelectin gene transcripts in transparent juveniles and adult specimens by means of in situ hybridization and reveal hemocyte-dominant expressions as well as stomach-exclusive expression. Comparative gene expression analysis with secretory digestive enzymes and absorption-related proteins in Ciona revealed that intelectin and secretory digestive enzymes were expressed in the same region of the stomach epithelium. Since the domain structure of intelectins and the hemocyte-dominant gene expression of intelectins seem relevant to ficolin, intelectin genes may have evolved from a ficolin-like ancestral gene with hemocytic expression in early chordate evolution. PMID- 28656473 TI - Kawasaki disease: what the paediatrician needs to know. PMID- 28656475 TI - Gravity and neuronal adaptation, in vitro and in vivo-from neuronal cells up to neuromuscular responses: a first model. AB - For decades it has been shown that acute changes in gravity have an effect on neuronal systems of human and animals on different levels, from the molecular level to the whole nervous system. The functional properties and gravity dependent adaptations of these system levels have been investigated with no or barely any interconnection. This review summarizes the gravity-dependent adaptation processes in human and animal organisms from the in vitro cellular level with its biophysical properties to the in vivo motor responses and underlying sensorimotor functions of human subjects. Subsequently, a first model for short-term adaptation of neuronal transmission is presented and discussed for the first time, which integrates the responses of the different levels of organization to changes in gravity. PMID- 28656476 TI - Coronary air embolism in a trauma patient. PMID- 28656474 TI - Dissecting Kawasaki disease: a state-of-the-art review. AB - : Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10 20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself. CONCLUSION: Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: * Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. * Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: * In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. * As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk. PMID- 28656477 TI - Right ventricular fistula post-TAVR: amenable to interventional closure treatment. PMID- 28656479 TI - [EMDR as a psychotherapeutic approach in the treatment of chronic pain : Is Eye Movement Desensitization and Reprocessing an effective therapy for patients with chronic pain who do not suffer from posttraumatic stress disorder?] AB - The efficacy of Eye Movement Desensitization and Reprocessing (EMDR) has been demonstrated for posttraumatic stress disorder. Despite promising research, it is still not clear if EMDR is a similarly effective treatment for chronic pain. Controlled trials are lacking and whether specific mechanisms underlie the effects remains unknown. The treatment of chronic pain aims at a reduction of subjective pain sensations. To achieve this goal without the usage of pain medications, i. e. through psychotherapy, is desirable for many reasons (e. g. reduction of treatment costs and side effects). Whether or not EMDR is an effective intervention for all chronic pain patients (or just a specific subgroup) constitutes an important question for psychological pain research. PMID- 28656478 TI - Autoantibodies against myelin sheath and S100beta are associated with cognitive dysfunction in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) has been associated with cognitive impairment and peripheral production of autoantibodies. Autoantibodies against central nervous system (CNS) proteins and S100 calcium-binding beta (S100beta) were found increased in diseases characterized by cognitive impairment like Alzheimer disease and Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). The aim of this study was to investigate the plasma levels of autoantibodies against myelin basic protein (anti-MBP), myelin oligodendrocyte glycoprotein (anti-MOG) and S100beta, and their relationships with cognitive performance in RA patients. Twenty patients with active rheumatoid arthritis and 19 age-, sex-, and schooling matched healthy controls were recruited. Multiple dimensions of cognitive function were evaluated by structured clinical questionnaires. Autoantibodies and S100beta levels were assessed by ELISAs. Patients had significantly higher levels of anti-MBP IgG (17.51 +/- 1.36 vs. 5.24 +/- 0.53 ng/mL), anti-MOG IgG (5.68 +/- 1.34 vs. 0.51 +/- 0.49 ng/mL), and S100beta protein (2.24 +/- 0.50 vs. 0.47 +/- 0.06) than controls (all p < 0.0001). After adjusting for potential confounders, RA group presented worse cognitive performance involving the working memory and executive functions such as inhibition, flexibility, and mental control in parallel to higher autoantibodies and S100beta levels than healthy controls (all p < 0.001). Levels of anti-MBP were negatively associated with delayed verbal recall (DVR; r = -0.42, p = 0.005), Stroop Color-Word (r = -0.48, p = 0.004), and N-Back Total scores (r = -0.59, p < 0.0001) and positively with Trail Making Test B (TMB, r = 0.53, p = 0.001). Negative correlation was found between levels of anti-MOG and DVR (r = -0.64, p < 0.0001), N-Back Total scores (r = -0.35, p = 0.03), Stroop Color-Word (r = -0.51, p = 0.001), and positively with TMB (r = 0.50, p = 0.003). S100beta levels were associated with DVR (r = -0.51, p = 0.002), TMB (r = 0.46, p = 0.008), Stroop Color-Word (r = -0.67, p < 0.0001), and N-Back Total (r = -0.52, p = 0.003). RA is associated with impaired cognitive performance associated with higher levels of CNS-related autoantibodies and S100beta levels. Given the importance of myelin integrity to cognition, our data indicate that these autoantibodies may be harmful to proper cognitive function. PMID- 28656480 TI - Drug-induced gingival overgrowth after renal transplantation. PMID- 28656481 TI - Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball. AB - PURPOSE OF REVIEW: The current definition of heart failure is mainly based on an inappropriate measure of cardiac function, i.e., left ventricular ejection fraction (LVEF). The initial sole entity, heart failure with reduced ejection fraction (HFrEF, LVEF <40%), was complemented by the addition of heart failure with preserved ejection fraction (HFpEF, LVEF >=50%) and most recently, heart failure with mid-range ejection fraction (HFmrEF, LVEF 40-49%). Initially, HFpEF was believed to be a purely left ventricular diastolic dysfunction. Pathophysiological concepts of HFpEF have changed considerably during the last years. In addition to intrinsic cardiac mechanisms, the heart failure pathogenesis is increasingly considered as driven by non-cardiac systemic processes including metabolic disorders, ischemic conditions, and pro inflammatory/pro-fibrotic or immunological alterations. Presentation and pathophysiology of HFpEF is heterogeneous, and its management remains a challenge since evidence of therapeutic benefits is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. RECENT FINDINGS: Several results from clinical and preclinical interventions targeting non-cardiac mechanisms or non-pharmacological interventions including new anti-diabetic or anti-inflammatory drugs, mitochondrial-targeted anti-oxidants, anti-fibrotic strategies, microRNases incl. antagomirs, cell therapeutic options, and high density lipoprotein-raising strategies are promising and under further investigation. This review addresses mechanisms and available data of current best clinical practice and novel approaches towards HFpEF. PMID- 28656483 TI - Great expectations: patient perspectives and anticipated utility of non diagnostic genomic-sequencing results. AB - The management of secondary findings is a challenge to health-care providers relaying clinical genomic-sequencing results to patients. Understanding patients' expectations from non-diagnostic genomic sequencing could help guide this management. This study interviewed 14 individuals enrolled in the eMERGE (Electronic Medical Records and Genomics) study. Participants in eMERGE consent to undergo non-diagnostic genomic sequencing, receive results, and have results returned to their physicians. The interviews assessed expectations and intended use of results. The majority of interviewees were male (64%) and 43% identified as non-Caucasian. A unique theme identified was that many participants expressed uncertainty about the type of diseases they expected to receive results on, what results they wanted to learn about, and how they intended to use results. Participant uncertainty highlights the complex nature of deciding to undergo genomic testing and a deficiency in genomic knowledge. These results could help improve how genomic sequencing and secondary findings are discussed with patients. PMID- 28656482 TI - Gestational Hypothyroxinemia Imprints a Switch in the Capacity of Astrocytes and Microglial Cells of the Offspring to React in Inflammation. AB - Hypothyroxinemia (Hpx) is a highly frequent condition characterized by low thyroxine (T4) and normal 3,3',5'-triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels in the blood. Gestational Hpx is closely related to cognitive impairment in the human offspring. In animal models gestational Hpx causes impairment at glutamatergic synapsis, spatial learning, and the susceptibility to suffer strong autoimmune diseases like experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying these phenotypes are unknown. On the other hand, it has been shown that astrocytes and microglia affect the outcome of EAE. In fact, the activation of astrocytes and microglia in the central nervous system (CNS) contributes to EAE progression. Thus, in this work, the reactivity of astrocytes and microglia from rats gestated in Hpx was evaluated aiming to understand whether these cells are targets of gestational Hpx. Interestingly, microglia derived from the offspring gestated in Hpx were less reactive compared to microglia derived from offspring gestated in euthyroidism. Instead, astrocytes derived from the offspring gestated in Hpx were significantly more reactive than the astrocytes from the offspring gestated in euthyroidism. This work contributes with novel information regarding the effects of gestational Hpx over astrocytes and microglia in the offspring. It suggests that astrocyte could react strongly to an inflammatory insult inducing neuronal death in the CNS. PMID- 28656484 TI - Effects of varying the 6-position oxidation state of hexopyranoses: a systematic comparative computational analysis of 48 monosaccharide stereoisomers. AB - Knowledge of multi-dimensional carbohydrate structure is essential when delineating structure-function relationships in the development of analytical techniques such as ion mobility-mass spectrometry and of carbohydrate-based therapeutics, as well as in rationally modifying the chemical and physical properties of drugs and materials based on sugars. Although monosaccharides are conventionally presumed to adopt the canonical 4C1 chair conformation, it is not well known how altering the substituent identity around the pyranose ring affects the favored conformational state. This work provides a comprehensive and systematic computational comparison of all eight aldohexose isomers in the gas phase with reduction and oxidation at the C-6 position using density functional theory (M05-2X/cc-pVTZ(-f)//B3LYP/6-31G**) to determine the conformational and anomeric preference for each sugar in the gas phase. All 6-deoxyhexose and aldohexose isomers favored the 4C1 chair conformation, while oxidation at C-6 showed a shift in equilibrium to favor the 1C4 chair for beta-alluronic acid, beta-guluronic acid, and beta-iduronic acid. The anomeric preference was found to be significantly affected by a remote change in oxidation state, with the alternate anomer favored for several isomers. These findings provide a fundamental platform to empirically test steric and electronic effects of pyranose substituents, with the goal of formulating straightforward rules that govern carbohydrate reactivity and drive quicker, more efficient syntheses. Graphical abstract A systematic comparative conformational analysis of all eight aldohexose isomers using DFT methods (M05-2X/cc-pVTZ(-f)) reveals changes in anomeric and ring conformational preference upon reduction or oxidation at the C 6 position for several sugars. PMID- 28656485 TI - Controlling Nutritional Status (CONUT) score is a prognostic marker for gastric cancer patients after curative resection. AB - BACKGROUND: Controlling Nutritional Status (CONUT), as calculated from serum albumin, total cholesterol concentration, and total lymphocyte count, was previously shown to be useful for nutritional assessment. The current study investigated the potential use of CONUT as a prognostic marker in gastric cancer patients after curative resection. METHODS: Preoperative CONUT was retrospectively calculated in 416 gastric cancer patients who underwent curative resection at Kumamoto University Hospital from 2005 to 2014. The patients were divided into two groups: CONUT-high (>=4) and CONUT-low (<=3), according to time dependent receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated. RESULTS: CONUT-high patients were significantly older (p < 0.001) and had a lower body mass index (p = 0.019), deeper invasion (p < 0.001), higher serum carcinoembryonic antigen (p = 0.037), and higher serum carbohydrate antigen 19-9 (p = 0.007) compared with CONUT-low patients. CONUT-high patients had significantly poorer overall survival (OS) compared with CONUT-low patients according to univariate and multivariate analyses (hazard ratio: 5.09, 95% confidence interval 3.12-8.30, p < 0.001). In time-dependent ROC analysis, CONUT had a higher area under the ROC curve (AUC) for the prediction of 5-year OS than the neutrophil lymphocyte ratio, the Modified Glasgow Prognostic Score, or pStage. When the time-dependent AUC curve was used to predict OS, CONUT tended to maintain its predictive accuracy for long-term survival at a significantly higher level for an extended period after surgery when compared with the other markers tested. CONCLUSIONS: CONUT is useful for not only estimating nutritional status but also for predicting long-term OS in gastric cancer patients after curative resection. PMID- 28656486 TI - Abamectin treatment affects glutamate decarboxylase expression and induces higher GABA levels in the citrus red mite, Panonychus citri. AB - The citrus red mite, Panonychus citri, is one of the most economically and globally destructive mite pests of citrus. Acaricide resistance has been a growing problem in controlling this pest. As the main inhibitory neurotransmitter in organisms, gamma-aminobutyric acid (GABA) is synthesized from the amino acid glutamate by the action of glutamate decarboxylases (GADs). In the present study, one novel GAD gene, PcGAD, was identified and characterized from P. citri. The opening reading frame of PcGAD contained 1548 nucleotides that encode 515 amino acids. The subsequent spatiotemporal expression pattern by RT-qPCR revealed that the expression levels of PcGAD were significantly higher in larvae than in adults. Challenging with various concentrations of abamectin resulted in the upregulation of PcGAD transcript levels. Furthermore, biochemical characterization indicated that changes in GAD activity coincided with its mRNA levels. High-performance liquid chromatography confirmed that the GABA contents of P. citri increased upon abamectin treatment. The application of abamectin induces PcGAD expression and activates GAD activity, thereby resulting in an increase in GABA content in P. citri, which contributes to the adaptability of the mite to abamectin challenge. PMID- 28656487 TI - Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. AB - Over half of patients diagnosed with B-cell acute lymphoblastic leukemia (ALL) develop relapsed or refractory disease. Traditional chemotherapy salvage is inadequate, and new therapies are needed. Chimeric antigen receptor (CAR) T cell therapy is a novel, immunologic approach where T cells are genetically engineered to express a CAR conferring specificity against a target cell surface antigen, most commonly the pan-B-cell marker CD19. After infusion, CAR T cells expand and persist, allowing ongoing tumor surveillance. Several anti-CD19 CAR T cell constructs have induced high response rates in heavily pre-treated populations, although durability of response varied. Severe toxicity (cytokine release syndrome and neurotoxicity) is the primary constraint to broad implementation of CAR T cell therapy. Here, we review the experience of CAR T cell therapy for ALL and ongoing efforts to modify existing technology to improve efficacy and decrease toxicity. As an anti-CD19 CAR T cell construct may be FDA approved soon, we focus on issues relevant to practicing clinicians. PMID- 28656488 TI - The role of monocyte subpopulations in vascular injury following partial and transient depletion. AB - The innate immunity system plays a critical role in vascular repair and restenosis development. Liposomes encapsulating bisphosphonates (LipBPs), but not free BPs, suppress neointima formation following vascular injury mediated in part by monocytes. The objective of this study was to elucidate the role of monocyte subpopulations on vascular healing following LipBP treatment. The potency- and dose-dependent treatment effect of clodronate (CLOD) and alendronate (ALN) liposomes on restenosis inhibition, total monocyte depletion, and monocytes subpopulation was studied. Rats subjected to carotid injury were treated by a single IV injection of LipBPs at the time of injury. Low- and high-dose LipALN treatment (3 and 10 mg/kg, respectively) resulted in a dose-dependent effect on restenosis development after 30 days. Both doses of LipALN resulted in a dose dependent inhibition of restenosis, but only high dose of LipALN depleted monocytes (-60.1 +/- 4.4%, 48 h post injury). Although LipCLOD treatment (at an equivalent potency to 3 mg/kg alendronate) significantly reduced monocyte levels (72.1 +/- 6%), no restenosis inhibition was observed. The major finding of this study is the correlation found between monocyte subclasses and restenosis inhibition. Non-classical monocyte (NCM) levels were found higher in LipALN treated rats, but lower in LipCLOD-treated rats, 24 h after injury and treatment. We suggest that the inhibition of circulating monocyte subpopulations is the predominant mechanism by which LipBPs prevent restenosis. The effect of LipBP treatment on the monocyte subpopulation correlates with the dose and potency of LipBPs. PMID- 28656489 TI - Detection of BRCA1 gross rearrangements by droplet digital PCR. AB - PURPOSE: Large genomic rearrangements (LGRs) constitute a significant share of pathogenic BRCA1 mutations. Multiplex ligation-dependent probe amplification (MLPA) is a leading method for LGR detection; however, it is entirely based on the use of commercial kits, includes relatively time-consuming hybridization step, and is not convenient for large-scale screening of recurrent LGRs. MATERIALS AND METHODS: We developed and validated the droplet digital PCR (ddPCR) assay, which covers the entire coding region of BRCA1 gene and is capable to precisely quantitate the copy number for each exon. RESULTS: 141 breast cancer (BC) patients, who demonstrated evident clinical features of hereditary BC but turned out to be negative for founder BRCA1/2 mutations, were subjected to the LGR analysis. Four patients with LGR were identified, with three cases of exon 8 deletion and one women carrying the deletion of exons 5-7. Excellent concordance with MLPA test was observed. Exon 8 copy number was tested in additional 720 BC and 184 ovarian cancer (OC) high-risk patients, and another four cases with the deletion were revealed; MLPA re-analysis demonstrated that exon 8 loss was a part of a larger genetic alteration in two cases, while the remaining two patients had isolated defect of exon 8. Long-range PCR and next generation sequencing of DNA samples carrying exon 8 deletion revealed two types of recurrent LGRs. CONCLUSION: Droplet digital PCR is a reliable tool for the detection of large genomic rearrangements. PMID- 28656490 TI - Different outcome in node-positive breast cancer patients found by axillary ultrasound or sentinel node procedure. AB - BACKGROUND: The Z0011 trial initiated a paradigm shift in the axillary treatment of breast cancer patients with a positive sentinel lymph node biopsy (SLNB), disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). We examined whether relevant differences exist between these patients to determine if the conclusions of the ACOSOG Z0011 trial are applicable to UGLNB positive patients. METHODS: Patients diagnosed with invasive breast cancer in the Netherlands between January 2008 and December 2014 were selected from the Netherlands Cancer Registry. RESULTS: A total of 11,820 cases were included: 9149 cases in the SLNB group and 2671 in the UGLNB group. Multivariate analyses showed that UGLNB-positive patients were older (p < 0.001), more likely to have a poorly differentiated tumor (p < 0.001), had a negative hormone receptor status (p < 0.001), and more often had extensive nodal involvement (p < 0.001). However, they were less likely to undergo adjuvant radiation (p = 0.004) or systemic therapy (p < 0.001). Even after adjusting for these factors, UGLNB-positive patients had a worse overall survival (HR = 1.38; 95% CI 1.23-1.56) than SLNB-positive patients. CONCLUSION: This nationwide retrospective study shows that young patients found positive by UGLNB have less favorable disease characteristics and a worse prognosis compared to patients with a positive SLNB. Selection by ultrasound plays an important role when axillary treatment strategies are considered. Hence, the conclusions of the Z0011 trial cannot unconditionally be applied to patients with a positive UGLNB. PMID- 28656491 TI - Methods of Model Reduction for Large-Scale Biological Systems: A Survey of Current Methods and Trends. AB - Complex models of biochemical reaction systems have become increasingly common in the systems biology literature. The complexity of such models can present a number of obstacles for their practical use, often making problems difficult to intuit or computationally intractable. Methods of model reduction can be employed to alleviate the issue of complexity by seeking to eliminate those portions of a reaction network that have little or no effect upon the outcomes of interest, hence yielding simplified systems that retain an accurate predictive capacity. This review paper seeks to provide a brief overview of a range of such methods and their application in the context of biochemical reaction network models. To achieve this, we provide a brief mathematical account of the main methods including timescale exploitation approaches, reduction via sensitivity analysis, optimisation methods, lumping, and singular value decomposition-based approaches. Methods are reviewed in the context of large-scale systems biology type models, and future areas of research are briefly discussed. PMID- 28656493 TI - CORR Insights(r): Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors? PMID- 28656492 TI - Treatment of chronic genotype-3 hepatitis C virus infection using direct-acting antiviral agents: An Indian experience. AB - BACKGROUND: Direct-acting antiviral drugs (DAAs) are favored for the treatment of hepatitis C virus (HCV) infection. However, the experience with the DAAs currently available in India in the treatment of genotype-3 HCV is limited. We therefore reviewed our experience with these drugs in treating patients with chronic genotype-3 HCV infection, including those with cirrhosis. METHODS: We prospectively followed adult patients with genotype-3 HCV infection who had received treatment regimens containing sofosbuvir with/without daclatasvir. Patients were categorized as chronic hepatitis C (CHC), compensated cirrhosis (CC), and decompensated cirrhosis (DC). They received either (i) sofosbuvir and ribavirin, with or without pegylated interferon (Peg-IFN) for 12 or 24 weeks, or (ii) sofosbuvir and daclatasvir, with or without ribavirin for 12 or 24 weeks. Response was assessed using HCV RNA testing after 2 or 4 weeks of treatment (rapid virological response [RVR]), at treatment completion (end-of-treatment response [ETR]) or 12 weeks after treatment completion (sustained virological response [SVR12]). RESULTS: Of the 160 patients (90% treatment-naive; CHC 49%, CC 32%, and DC 19%), 39 (24%) received Peg-IFN, sofosbuvir and ribavirin, 21 (13%) received sofosbuvir and ribavirin, and 100 (63%) received sofosbuvir and daclatasvir, with or without ribavirin. On intention-to-treat basis, RVR, ETR, and SVR12 in the entire cohort were 146/160 (91.3%), 151/160 (94.4%), and 147/160 (91.9%), respectively. Seven patients died (CC 2, DC 5) during treatment; four (2 CHC, 2 DC) patients discontinued treatment; and two patients with CC relapsed. CONCLUSIONS: Dual-DAA-based regimens were safe and highly effective in treating genotype-3 HCV infection in CHC and CC patients. PMID- 28656494 TI - CORR Insights(r): Pathologically Benign Lymph Nodes Can Mimic Malignancy on Imaging in Patients With Angiomatoid Fibrous Histiocytoma. PMID- 28656495 TI - CORR Insights(r): Can A Multivariate Model for Survival Estimation in Skeletal Metastases (PATHFx) Be Externally Validated Using Japanese Patients? PMID- 28656496 TI - Letter to Editor: Editorial: Appropriate Use? Guidelines on Arthroscopic Surgery for Degenerative Meniscus Tears Need Updating. PMID- 28656497 TI - The effect of biodegradation on gammacerane in crude oils. AB - Gammacerane is one of the major biomarkers widely used in depositional environment diagnosis, oil family classification, and oil-source correlation. It is generally accepted that gammacerane is more resistant to biodegradation than regular hopanes. However, whether it is biodegradable as well has not been reported in literatures. In order to investigate the effect of biodegradation on gammacerane in crude oils, 69 core samples from two biodegraded petroleum accumulations were geochemically characterized by quantitative GC-MS analysis. All samples are originated from lacustrine source rocks in China and have experienced at least level 8 degree of biodegradation on the scale of Peters and Moldowan (The biomarker guide: interpreting molecular fossils in petroleum and ancient sediments, Prentice Hall, Englewood Cliffs, 1993). Both case histories showed the concentration of gammacerane decrease with increasing severity of biodegradation, indicating the destruction of gammacerane by biodegradation. A whole series of 25-norhopanes paralleling the 17alpha,21beta-hopanes (up to C34), together with C28 18-alpha-25,30-bisnorneohopane, C29 25-nordiahopane and C29 25 norgammacerane, is found in the Liaohe sample suite but C33, C34 25-norhopane and 25-norgammacerane are almost undetectable in the Junggar case. The gammacerane in the Liaohe case study appear to be altered simultaneously with hopanes, although the rate of gammacerane alteration is slower. Its susceptibility to biodegradation is similar to 18alpha(H)-22,29,30-trisnorneohopane (Ts) and 17alpha(H)-22,29,30-trisnorhopane (Tm) but more vulnerable than 18alpha-30 norneohopane (C29 Ts), 15alpha-methyl-17alpha(H)-27-norhopane (C30 diahopane) and pregnanes. The gammacerane in the Junggar oils appear to be less biodegradable than the Liaohe case history. It was altered simultaneously with pregnanes and C29 Ts but faster than C30 diahopane. The present data suggest that biodegradation sequence is not universal since the relative rates of biodegradation of different compound classes depend upon specific environmental conditions. Like the case of hopane demethylation, the mechanism of gammacerane biodegradation is not straightforward. While the conversion of gammacerane to 25 norgammacerane is not quantitatively balanced in the Liaohe case history, no 25 norgammacerane has been formed from the degradation of gammacerane in the Junggar case history. The ratio of gammacerane to regular hopanes increases with biodegradation degree especially at extreme levels of degradation, gammacerane index is no longer valid for depositional environment assessment or oil-source correlation. PMID- 28656499 TI - Electrical properties of polyetherimide thin films: Non-parametric dielectric response analysis with distribution of relaxation times. AB - High temperature polymeric materials for electrical insulation and energy storage are needed for transformational power applications such as pulsed-power and hybrid electrical vehicles. One of the candidate materials has been polyetherimide, an amorphous thermoplastic with a glass transition over 200 degrees C. Here, the dielectric studies on the material are reported by taking into account the polarization and conduction processes in the polyetherimide. The dielectric data were analyzed with the distribution of relaxation times approach with Debye expression as the kernel in the inversion algorithm, the results then created the relaxation map for polyetherimide. The method satisfies the Kramers Kronig relationships, so the ohmic conductivity and permittivity at high frequencies could be estimated from the experimental data even if there exists significant measurement error. The data were compared to the published results on polyetherimide in the literature. The materials is a low loss polymer with negligible ohmic losses below 200 degrees C. The estimated fragility of the polyetherimide was high about 284 from the resolved relaxation map using the Vogel-Fulcher-Tammann-Hesse expression. Polyetherimide is a good dielectric for advanced energy storage and electrical insulation technologies up to 200 degrees C. PMID- 28656498 TI - Biphasic malignant tumours of the abdominal cavity. AB - Carcinosarcomas (CS) are uncommon, highly aggressive, biphasic tumours consisting of both sarcomatous and carcinomatous elements. They appear to originate from a common cell of origin, either via transformation from a single premature precursor or conversion of a mature epithelial cell through an epithelial mesenchymal transition. CS should be considered a unique cancer subtype with cells typically displaying diffuse mitotic activity and widespread atypical mitoses predisposing to early metastasis and a tendency to local recurrence following resection. This review addresses the pathophysiology of CS and discusses its presentation, natural history and management at a variety of sites within the abdominal cavity and retroperitoneum. PMID- 28656500 TI - Predictive Value of C-Reactive Protein for Complications Post-Laparoscopic Roux en-Y Gastric Bypass. PMID- 28656501 TI - Gastric Bypass and Synchronous Cholecystectomy: Not Only Numbers. PMID- 28656502 TI - Update on Treatment Options for Advanced Bile Duct Tumours: Radioembolisation for Advanced Cholangiocarcinoma. AB - Cholangiocarcinoma is a rare form of gastrointestinal cancer with a poor prognosis. Patients often present with biliary obstruction or non-specific abdominal pain, and a high proportion of patients have advanced disease at initial diagnosis. The goal of this review is to discuss treatment options for patients with advanced bile duct tumours focusing on radioembolisation (RE) and its impact on overall survival. RE provides a therapeutic option for patients with unresectable cholangiocarcinoma. However, although systemic chemotherapy has demonstrated a survival benefit in randomised controlled trials, there is limited supporting evidence for the use of RE in this setting. Studies are mostly limited to single-centre, small cohorts with variable outcome measures. Additionally, patients included in these studies received a variety of previous therapies including chemotherapy, surgery or alternative intra-arterial therapy; therefore, a true assessment of overall survival benefit is difficult. PMID- 28656504 TI - Can dehydrated human amnion/chorion membrane accelerate the return to potency after a nerve-sparing robotic-assisted radical prostatectomy? Propensity score matched analysis. AB - The objective of this study is to determine if the use of dehydrated human amnion/chorion membrane (dHACM) allograft wrapped around the NVB during a robotic assisted radical prostatectomy (RARP) accelerates the return to potency. 940 patients with preoperative SHIM >20 underwent RARP with some degree of bilateral NS. Of these, 235 patients underwent RARP, with bilateral placement of dHACM graft around the NVBs. They were matched in a 1:3 proportion with a similar group of patients (n = 705) who did not receive the allograft (control group or group 2). Minimum follow-up was 12 months. Postoperative outcomes were analyzed between propensity-matched dHACM graft (group 1) and non-graft groups (group 2). Kaplan Meier survival curves were compared across techniques using the log-rank test. There were no significant demographic differences between the two groups. Potency was defined as the ability to achieve and maintain satisfactory erections firm enough for sexual intercourse, with or without the use of PDE-5 inhibitors. The mean time to potency was significantly lower in group 1 (2.37 months) versus group 2 (3.94 months) (p < 0.0001). The potency recovery rates were superior for group 1 at all early time points measured except at 12 months. The time to potency was significantly shorter in the dHACM group with full NS, 2.19 +/- 1.84 versus 2.78 +/- 2.70 mo. in the non-dHACM with full NS (p = 0.029). In the dHACM group with partial NS, the mean time to potency was 3.05 +/- 2.32 versus 3.92 +/- 3.42 mo. in the non-dHACM with partial NS (p = 0.021). Patients who received the dHACM wrap around the NVB after RARP accelerates the return to potency when compared to a similar control group without the use of the allograft. We also demonstrated that this faster return to potency occurs regardless of the degree of the NS preservation. Younger patients (<55 years of age) had the highest overall advantage if they received the graft. Our results indicate that dHACM placement at the site of the prostatic NVB does not increase the risk of BCR after RARP, neither in the presence of PSM, extra-prostatic disease (>=pT3) nor high Gleason score (Gleason >=8). PMID- 28656503 TI - Electrophysiological and behavioral evidence reveals the effects of trait anxiety on contingent attentional capture. AB - Few studies have investigated the effects of anxiety on contingent attentional capture. The present study examined contingent attentional capture in trait anxiety by applying a rapid serial visual presentation (RSVP) paradigm during electroencephalographic recording. Overall, the behavioral and electrophysiological results showed a larger capture effect when a distractor was the same color as the target compared to when the distractor was not of the target color. Moreover, high-anxiety individuals showed a larger N2pc in the target colored distractor condition and nontarget colored distractor condition compared to the distractor-absent condition. In addition, the reaction time was slower when distractors were presented in the left visual field compared to when they were in the right visual field. This pattern was not seen in low-anxiety individuals. The findings may indicate that high-anxiety individuals allocate attention to the target less efficiently and have reduced suppression of distractors compared to low-anxiety individuals who could suppress attention to the distractors more efficiently. Future work could valuably investigate the consequences of such differences in terms of benefits and disruption associated with attentional capture differences in a range of anxious populations in different risk monitoring situations. PMID- 28656505 TI - Videoexoscopic real-time intraoperative navigation for spinal neurosurgery: a novel co-adaptation of two existing technology platforms, technical note. AB - Image-guided approaches to spinal instrumentation and interbody fusion have been widely popularized in the last decade [1-5]. Navigated pedicle screws are significantly less likely to breach [2, 3, 5, 6]. Navigation otherwise remains a point reference tool because the projection is off-axis to the surgeon's inline loupe or microscope view. The Synaptive robotic brightmatter drive videoexoscope monitor system represents a new paradigm for off-axis high-definition (HD) surgical visualization. It has many advantages over the traditional microscope and loupes, which have already been demonstrated in a cadaveric study [7]. An auxiliary, but powerful capability of this system is projection of a second, modifiable image in a split-screen configuration. We hypothesized that integration of both Medtronic and Synaptive platforms could permit the visualization of reconstructed navigation and surgical field images simultaneously. By utilizing navigated instruments, this configuration has the ability to support live image-guided surgery or real-time navigation (RTN). Medtronic O-arm/Stealth S7 navigation, MetRx, NavLock, and SureTrak spinal systems were implemented on a prone cadaveric specimen with a stream output to the Synaptive Display. Surgical visualization was provided using a Storz Image S1 platform and camera mounted to the Synaptive robotic brightmatter drive. We were able to successfully technically co-adapt both platforms. A minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) and an open pedicle subtraction osteotomy (PSO) were performed using a navigated high-speed drill under RTN. Disc Shaver and Trials under RTN were implemented on the MIS TLIF. The synergy of Synaptive HD videoexoscope robotic drive and Medtronic Stealth platforms allow for live image-guided surgery or real-time navigation (RTN). Off-axis projection also allows upright neutral cervical spine operative ergonomics for the surgeons and improved surgical team visualization and education compared to traditional means. This technique has the potential to augment existing minimally invasive and open approaches, but will require long-term outcome measurements for efficacy. PMID- 28656506 TI - Comparing naturally occurring glycosylated forms of proline rich antibacterial peptide, Drosocin. AB - Antimicrobial peptides (AMPs) are key players of innate immunity. Amongst various classes of AMPs, proline rich AMPs from insects enjoy special attention with few members of this class bearing O-glycosylation as post-translational modification. Drosocin, a 19 amino acid glycosylated AMP is a member of proline rich class, synthesized in the haemolymph of Drosophila melanogaster upon bacterial challenge. We report herein the chemical synthesis of drosocin carrying disaccharide (beta-Gal(1 -> 3)alpha-GalNAc) and comparison of its structural and functional properties with another naturally occurring monoglycosylated form of drosocin i.e. alpha-GalNAc-drosocin as well as with non-glycosylated drosocin. The disaccharide containing drosocin exhibited lower potency compared to monoglycosylated drosocin against all the tested Gram negative bacteria, suggesting the role of the distal sugar or increase in the sugar chain length on the activity. Circular dichroism studies failed to demonstrate the differential effect of sugars on the overall peptide conformation. Haemolytic and cytotoxic properties of drosocin were not altered due to an increase in the sugar chain length. In addition, we have also evaluated the effect of differentially glycosylated drosocins on two pro-inflammatory cytokines secreted by murine macrophages or LPS stimulated macrophages. All the drosocin forms tested, neither could stimulate the secretion of TNF-alpha and IL-6 nor could modulate LPS induced levels of TNF-alpha and IL-6 in murine macrophages. This study provides insights about naturally occurring two different glycosylated forms of drosocin. PMID- 28656507 TI - The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer. AB - The stem cell factor (SCF) is a cytokine that specifically binds the tyrosine kinase receptor c-KIT. The SCF/c-KIT interaction leads to receptor dimerization, activation of kinase activity and initiation of several signal transduction pathways that control cell proliferation, apoptosis, differentiation and migration in several tissues. The activity of SCF/c-KIT system is linked with the phosphatidylinositol 3-kinase (PI3-K), the Src, the Janus kinase/signal transducers and activators of transcription (JAK/STAT), the phospholipase-C (PLC gamma) and the mitogen-activated protein kinase (MAPK) pathways. Moreover, it has been reported that cancer cases display an overactivation of c-KIT due to the presence of gain-of-function mutations or receptor overexpression, which renders c-KIT a tempting target for cancer treatment. In the case of male cancers the most documented activated pathways are the PI3-K and Src, both enhancing abnormal cell proliferation. It is also known that the Src activity in prostate cancer cases depends on the presence of tr-KIT, the cytoplasmic truncated variant of c KIT that is specifically expressed in tumour tissues and, thus, a very interesting target for drug development. The present review provides an overview of the signalling pathways activated by SCF/c-KIT and discusses the potential application of c-KIT inhibitors for treatment of testicular and prostatic cancers. PMID- 28656508 TI - Risk of Mortality Associated with Anticholinergic Use in Elderly Nursing Home Residents with Depression. AB - BACKGROUND: Few studies have evaluated the association between anticholinergic use and mortality in elderly nursing home residents. OBJECTIVE: The aim of this study was to examine the risk of mortality associated with anticholinergic use among elderly nursing home residents with depression. METHODS: The study employed a population-based nested case-control design using 2007-2010 Minimum Data Set (MDS)-linked Medicare data from all states. The base cohort included Medicare beneficiaries aged >=65 years, diagnosed with depression as of 2007, and with any MDS assessment in 2007. Cases were identified as patients who died anytime between January 1, 2008 and December 31, 2010. For each case, four age- and sex matched controls were selected using incidence density sampling. Anticholinergic exposure was defined using the Anticholinergic Drug Scale (ADS). Prescription of clinically significant anticholinergic medications (ADS level 2/3) 60 days preceding the event date formed the primary exposure. Conditional logistic regression model stratified on matched case-control sets was performed to assess mortality risk, after controlling for other risk factors. RESULTS: The study sample included 44,948 cases who died and 179,792 matched controls. After adjusting for other risk factors, clinically significant anticholinergic use was associated with significant risk of death (odds ratio [OR] 1.31; 95% CI 1.28 1.34) compared with non-use. Level-specific analysis indicated high mortality risk with only markedly anticholinergic (ADS level 3) medication use (OR 1.46; 95% CI 1.42-1.51). CONCLUSIONS: Use of clinically significant anticholinergic medications was associated with a 31% increase in risk of mortality among elderly nursing home residents with depression. With increasing safety concerns, there is a significant need to optimize anticholinergic use in the vulnerable population. PMID- 28656509 TI - Older People's Preferences for Side Effects Associated with Antimuscarinic Treatments of Overactive Bladder: A Discrete-Choice Experiment. AB - INTRODUCTION: Understanding the importance older people attribute to the different side effects associated with oral antimuscarinic treatments for overactive bladder (OAB) could help inform prescribers, healthcare policy makers and the drug industry. OBJECTIVE: Our objective was to quantify the importance of the most prevalent cognitive and side effects of oral antimuscarinic treatments for OAB in older people. METHODS: We conducted a discrete-choice experiment (DCE) with the assistance of an interviewer with community-dwelling and hospitalized older people aged >65 years. The DCE involved two hypothetical drugs for imaginary OAB, with three levels of four side effects for each drug, and the International Consultation on Incontinence Questionnaire-Overactive Bladder and EuroQol 5-Dimensions (EQ-5D) questionnaire were also administered. Data were analysed using a conditional logit model. RESULTS: In total, 276 older people participated in the study. The median age was 75 years (interquartile range [IQR] 69-80), 63% were women and 21% had OAB syndrome. The most unwanted side effect in the choice of antimuscarinics for OAB was severe cognitive effects, followed by severe constipation, severe blurred vision, severe dry mouth, moderate cognitive effects and moderate constipation. Severe cognitive effects were at least 1.7 times as important as severe constipation. Exploratory subgroup analysis showed that none of the attributes was found to be significant in people who scored as anxious or depressed on the EQ-5D, and preferences about cognitive effects, constipation and blurred vision were equal in people with and without OAB. CONCLUSION: Older people attribute more importance to loss of cognitive function as a possible side effect of antimuscarinic treatment than to the three most prevalent possible side effects of this treatment. PMID- 28656510 TI - Alprostadil protects type 2 diabetes mellitus patients treated with metformin from contrast-induced nephropathy. AB - PURPOSE: Type 2 diabetes mellitus (T2DM) patients treated with metformin are predisposed to develop contrast-induced nephropathy (CIN) after received emergency contrast-enhanced computed tomography (CT) examination. We evaluated the protective effects of alprostadil on CIN in T2DM patients treated with metformin after contrast media (CM) administration. METHODS: In this single institution, single-blind, superiority trial, we randomly assigned 451 T2DM patients taking metformin and underwent emergency contrast-enhanced CT examination to either the alprostadil group (227 patients) receiving alprostadil or the control group (224 patients) without alprostadil. All subjects stopped taking metformin and drank 500 ml water within 12 h after CM exposure. In addition, patients in the alprostadil group were injected with alprostadil (10 MUg/day, for 3 days) plus 20 ml normal saline (alprostadil hydration) and the control group patients were daily injected with 20 ml normal saline as control for 3 days following CM administration. Serum creatinine (Scr) was measured before and <72 h after contrast-enhanced CT examination. CIN was defined as an increase in Scr >= 44.2 umol/l (0.5 mg/dL) or >25% over baseline within 3 days of contrast administration. RESULTS: There was a lower incidence of CIN in patients underwent alprostadil hydration than drinking water monohydration after CM administration, who with either normal renal function or chronic kidney disease (baseline eGFR < 60 ml.min-1.1.73 m-2). CONCLUSIONS: Alprostadil hydration was superior to drinking water monohydration regarding preventing CIN in T2DM patients treated with metformin after contrast-enhanced CT. PMID- 28656512 TI - Significance of perithyroidal lymph nodes in benign thyroid diseases. AB - PURPOSE: The incidences of perithyroidal lymph nodes (PTLNs) in benign thyroid diseases were investigated. METHODS: A total of 108 patients were divided into 36 with benign thyroid nodules, 33 with Hashimoto's thyroiditis, 14 with Graves' disease, 10 with hypothyroidism of undetermined etiology, nine with silent thyroiditis, and six with subacute thyroiditis. We assessed the relationships among PTLNs and these groups, thyroid volume, thyroid parenchyma echogenicity, and anti-thyroid-stimulating hormone receptor, anti-thyroglobulin, and anti thyroid peroxidase antibodies (TRAb, TgAb, and TPOAb). RESULTS: The PTLN-positive rates in Hashimoto's thyroiditis (69.7%), subacute thyroiditis (83.8%), silent thyroiditis (77.8%), and Graves' disease (35.7%) groups were significantly higher than those in benign thyroid nodules (5.6%) and hypothyroidism of unknown etiology (0%) groups. The PTLN-positive rates were significantly higher in cases with TgAb and/or TPOAb (P < 0.01) and in those with lower parenchyma echogenicity (P < 0.01). CONCLUSION: PTLNs were seen in inflammatory thyroid diseases, but were rarely detected in other thyroid diseases. These findings indicate that PTLNs are an indicator for differentiating inflammation of the thyroid. Lower echogenicity of the thyroid, known to correspond to inflammation, showed a correlation with the positive rate of PTLNs. PTLNs in cases of Graves' disease may be due to coexisting thyroiditis related to TgAb and/or TPOAb. PMID- 28656513 TI - Real-time ultrasound elastography of the Achilles tendon in patients with cerebral palsy: is there a correlation between strain ratio and biomechanical indicators? AB - PURPOSE: Our aim was to comparatively investigate the strain ratio and thickness of the Achilles tendon in children with cerebral palsy (CP), and to elucidate whether there is a correlation between biomechanical features of the Achilles tendon and strain ratio. METHODS: A total of 155 participants (72 CP patients and 83 healthy controls) who underwent real-time elastography of both Achilles tendons were studied. A linear transducer (4.8-11.0 MHz) was used to obtain the images. Correlation analysis between age, length, and thickness of the Achilles tendon, and strain ratio (SR) was performed by means of Pearson correlation and Spearman's rho tests. RESULTS: Comparison of results obtained from CP patients and controls showed that the length of the Achilles tendon was shorter (p < 0.001) and SR was higher (p < 0.001) in CP patients. In CP patients, there was a positive correlation between SR and age and between SR and the thickness and length of the Achilles tendon (p < 0.001 for all). Furthermore, the length of the tendon and age were positively associated (p < 0.001). ROC analysis revealed that the cut-off value for SR was 1.89. CONCLUSION: The results of the present study demonstrated that real-time elastography can constitute a simple, practical, and noninvasive method for evaluation of the elasticity of the Achilles tendon in children with CP. PMID- 28656514 TI - Is routine use of transanastomotic tube justified in the repair of esophageal atresia? AB - BACKGROUND: Transanastomotic feeding tube (TAFT) is commonly used for post operative enteral nutrition after esophageal atresia (EA)/tracheoesophageal fistula (TEF) repairs. The purpose of this study is to analyze the therapeutic implications of avoiding a TAFT and its impact on the outcomes post-operatively. METHODS: The medical data of 33 inpatients with EA/TEF type C repair from 2009 to 2014 were retrospectively reviewed. Patients were divided into two groups for comparison based on the usage of TAFT during the repair: TAFT- (without) and TAFT+ (with) groups, without randomization. Both groups were compared statistically for post-operative complications and outcomes. RESULTS: Eighteen neonates were males and 15 females, with an average birth weight of 2.43+/-0.43 kg and a mean gestational age of 36.15 weeks. Nineteen (57.5%) in the TAFT- group and 14 (42.4%) were in the TAFT+ group. The post-operative complications, need for dilatations, duration of total parenteral nutrition (TPN) and length of hospital stay were similar in both groups. The incidence of pneumonitis was significantly higher in the TAFT+ group. CONCLUSIONS: By avoiding a TAFT, there is no increase in complication rates nor does it entail a prolonged period of TPN. Besides, not using a TAFT may have the advantage of reducing incidence of aspiration and consequent pneumonitis. PMID- 28656511 TI - Hyperinsulinemic hypoglycemia: clinical, molecular and therapeutical novelties. AB - Hyperinsulinemic hypoglycemia (HI) is the most common cause of hypoglycemia in children. Impairment of cellular pathways involved in insulin secretion from pancreatic beta-cells, broadly classified as channelopathies and metabolopathies, have been discovered in the past two decades. The increasing use of NGS target panels, combined with clinical, biochemical and imaging findings allows differentiating the diagnostic management of children with focal forms, surgically curable, from those with diffuse forms, more conservatively treated with pharmacological and nutritional interventions. Specific approaches according to the subtype of HI have been established and novel therapies are currently under investigation. Despite diagnostic and therapeutic advances, HI remains an important cause of morbidity in children, still accounting for 26-44% of permanent intellectual disabilities, especially in neonatal-onset patients. Initial insult from recurrent hypoglycemia in early life greatly contributes to the poor outcomes. Therefore, patients need to be rapidly identified and treated aggressively, and require at follow-up a complex and regular monitoring, managed by a multidisciplinary HI team. This review gives an overview on the more recent diagnostic and therapeutic tools, on the novel drug and nutritional therapies, and on the long-term neurological outcomes. PMID- 28656515 TI - Computational predictions of the embolus-trapping performance of an IVC filter in patient-specific and idealized IVC geometries. AB - Embolus transport simulations are performed to investigate the dependence of inferior vena cava (IVC) filter embolus-trapping performance on IVC anatomy. Simulations are performed using a resolved two-way coupled computational fluid dynamics/six-degree-of-freedom approach. Three IVC geometries are studied: a straight-tube IVC, a patient-averaged IVC, and a patient-specific IVC reconstructed from medical imaging data. Additionally, two sizes of spherical emboli (3 and 5 mm in diameter) and two IVC orientations (supine and upright) are considered. The embolus-trapping efficiency of the IVC filter is quantified for each combination of IVC geometry, embolus size, and IVC orientation by performing 2560 individual simulations. The predicted embolus-trapping efficiencies of the IVC filter range from 10 to 100%, and IVC anatomy is found to have a significant influence on the efficiency results ([Formula: see text]). In the upright IVC orientation, greater secondary flow in the patient-specific IVC geometry decreases the filter embolus-trapping efficiency by 22-30 percentage points compared with the efficiencies predicted in the idealized straight-tube or patient-averaged IVCs. In a supine orientation, the embolus-trapping efficiency of the filter in the idealized IVCs decreases by 21-90 percentage points compared with the upright orientation. In contrast, the embolus-trapping efficiency is insensitive to IVC orientation in the patient-specific IVC. In summary, simulations predict that anatomical features of the IVC that are often neglected in the idealized models used for benchtop testing, such as iliac vein compression and anteroposterior curvature, generate secondary flow and mixing in the IVC and influence the embolus-trapping efficiency of IVC filters. Accordingly, inter subject variability studies and additional embolus transport investigations that consider patient-specific IVC anatomy are recommended for future work. PMID- 28656517 TI - Treatment of Hyperkalemia in Heart Failure. AB - PURPOSE OF REVIEW: The aim of this paper is to discuss strategies for prevention and management of hyperkalemia in patients with heart failure, including the role of novel therapies. RECENT FINDINGS: Renin-angiotensin-aldosterone system (RAAS) antagonists, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) decrease mortality and morbidity in heart failure but increase the risk of hyperkalemia, especially when used in combination. Prevention of hyperkalemia and its associated complications requires careful patient selection, counseling regarding dietary potassium intake, awareness of drug interactions, and regular laboratory surveillance. Recent data suggests that the risk of hyperkalemia may be further moderated through the use of combined angiotensin-neprilysin inhibitors, novel MRAs, and novel potassium binding agents. Clinicians should be mindful of the risk of hyperkalemia when prescribing RAAS inhibitors to patients with heart failure. In patients at highest risk, such as those with diabetes, the elderly, and advanced chronic kidney disease, more intensive laboratory surveillance of potassium and creatinine may be required. Novel therapies hold promise for reducing the risk of hyperkalemia and enhancing the tolerability of RAAS antagonists. PMID- 28656518 TI - Anatomy of the aortic root: implications for aortic root reconstruction. AB - Since the introduction of valve-preserving root replacement and aortic annuloplasty, precise understanding of the aortic root anatomy has emerged as a key to successful aortic valve-preservation surgery. Fundamentally, surgeons need to know the precise anatomical definition and structure of the aortic root, including its normal dimensions, know the anatomy of the coronary arteries, and understand the cardiac conduction system. Surgeons must be able to clearly distinguish normal and abnormal structures, and recognize the effects of aortic valve regurgitation or root expansion on dimensions and geometric relationships within the aortic root. Possessing a detailed understanding of the aortic root, surgeons can select appropriately sized grafts and achieve optimum annular fixation. This review covers the essentials of aortic root anatomy and provides tips for correct and safe performance of aortic valve-preservation surgery with a view toward durable late outcomes. PMID- 28656519 TI - Where Are We Headed with Neuromodulation for Overactive Bladder? AB - Overactive bladder (OAB) affects millions of people around the world and decreases quality of life for those affected. Over the past two decades, significant advances in treatment have transformed the lives of those with OAB. Sacral neuromodulation (SNM), posterior tibial nerve stimulation (PTNS), and dorsal genital nerve stimulation are the most effective contemporary treatment modalities. New techniques and bio-sensing schemes offer promise to advance therapy beyond what is currently available. Current neuromodulation techniques do not use real-time data from the body or input from the patient. Incorporating this is the goal of those pursuing a neuroprosthesis to enhance bladder function for these patients. Dorsal genital nerve, pudendal nerve, S3 afferent nerve roots, and S1 and S2 ganglia have all been used as targets for stimulation. Some of these have also been used as sources of afferent nerve information to detect significant bladder events and even to estimate the fullness of the bladder. As technology improves, an intelligent neuroprosthesis with the ability to sense significant bladder events may revolutionize treatment of OAB. PMID- 28656521 TI - Strategic interactions: Games of the Ju|'hoan. AB - Three strategic games played by the Ju|'hoan-a board, a card, and a gesture game complicate the rhetorics that suggest an evolutionary or psychological significance of play. They are mostly played by adults, although every individual adult does not necessarily engage in each game. The Ju|'hoan card and board game practices were transmitted through contact across large parts of Botswana and Namibia, while the gesture game n!ai has been known in other San communities. It suggests that the significance of strategic games is more likely found in its potential for social interaction (i.e., allowing to overcome cultural divides) than in evolution and psychology. Within the anthropological literature, strategy games were thought to be absent in egalitarian societies, such as that of the Ju|'hoan. Here, the roles of power, competition, and winning were thought to be disruptive and unwanted. A closer examination of the details behind the Ju|'hoan games shows that not only were strategy games adopted and adapted from neighboring societies but that the game of n!ai was developed by the Ju|'hoan into a competitive one. The evolutionary or psychological significance of play is informed by studies on individual play, children's play, and games with informal rules. When considering strategic games throughout history, it is their role of facilitator rather than the playing practice itself that makes games relevant across languages, cultural divides, and sociopolitical boundaries. PMID- 28656516 TI - Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure. AB - PURPOSE OF REVIEW: In highly prevalent cardiac diseases, new therapeutic approaches are needed. Since the first description of oxidative stress in heart failure, reactive oxygen species (ROS) have been considered as attractive drug targets. Though clinical trials evaluating antioxidant vitamins as ROS-scavenging agents yielded neutral results in patients at cardiovascular risk, the knowledge of ROS as pathophysiological factors has considerably advanced in the past few years and led to novel treatment approaches. Here, we review recent new insights and current strategies in targeting mitochondrial calcium handling and ROS in heart failure. RECENT FINDINGS: Mitochondria are an important ROS source, and more recently, drug development focused on targeting mitochondria (e.g. by SS-31 or MitoQ). Important advancement has also been made to decipher how the matching of energy supply and demand through calcium (Ca2+) handling impacts on mitochondrial ROS production and elimination. This opens novel opportunities to ameliorate mitochondrial dysfunction in heart failure by targeting cytosolic and mitochondrial ion transporters to improve this matching process. According to this approach, highly specific substances as the preclinical CGP-37157, as well as the clinically used ranolazine and empagliflozin, provide promising results on different levels of evidence. Furthermore, the understanding of redox signalling relays, resembled by catalyst-mediated protein oxidation, is about to change former paradigms of ROS signalling. Novel methods, as redox proteomics, allow to precisely analyse key regulatory thiol switches, which may induce adaptive or maladaptive signalling. Additionally, the generation of genetically encoded probes increased the spatial and temporal resolution of ROS imaging and opened a new methodological window to subtle, formerly obscured processes. These novel insights may broaden our understanding of why previous attempts to target oxidative stress have failed, and at the same time provide us with new targets for drug development. PMID- 28656520 TI - State of the Art for Treatment of Vesicovaginal Fistula. AB - BACKGROUND: Vesico-vaginal fistulae (VVF) remain the most prevalent genitourinary fistula detrimentally impacting quality of life. PURPOSE OF THE REVIEW: The purpose of this review is to examine relevant literature on management of VVF. RECENT FINDINGS: Obstructed labor is the leading cause of VVF in the developing world with most repairs performed via the transvaginal approach. Conversely, the predominate etiology in industrialized nations is iatrogenic injury with an increasing trend towards abdominal repair via a minimally invasive (laparoscopic and robotic) approach. No studies have compared transvaginal repair to minimally invasive transabdominal approaches. Further, an increasing number of authors have developed algorithms to determine optimum surgical approaches and risk factors for persistent incontinence. As surgeons become more facile with laparoscopic and robotic skills, there is a growing trend for minimally invasive surgical management of VVF in developed countries, perhaps widening the disparity gap between developing nations where transvaginal approaches predominate with good success. Further studies are needed to compare transvaginal to minimally invasive transabdominal approaches. PMID- 28656522 TI - Recent New Methodologies for Acetylenic Polymers with Advanced Functionalities. AB - Polymers synthesized from acetylenic monomers often possess electronically unsaturated fused rings and thus show versatile optoelectronic properties and advanced functionalities. To expand the family of acetylenic polymers, development of new catalyst systems and synthetic routes is critically important. We summarize herein recent research progress on development of new methodologies towards functional polymers using alkyne building blocks since 2014. The polymerizations are categorized by the number of monomer components, namely homopolymerizations, two-component polymerizations, and multicomponent polymerizations. The properties and applications of acetylenic polymers, such as aggregation-induced emission, fluorescent photopatterning, light refraction, chemosensing, mechanochromism, chain helicity, etc., are also discussed. PMID- 28656523 TI - Discovery of 5-methyl-2-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-4-(piperazin-1 yl)pyrimidine derivatives as novel GRP119 agonists for the treatment of diabetes and obesity. AB - A series of fused-pyrimidine derivatives were prepared and evaluated for their agonistic activities against human GPR119. Compound 9i showed high potent agonistic activity against HEK293T cells over-expressing human GPR119 and improved glucose tolerance in dose-dependent manner, as well as promoted insulin secretion. In a DIO mice model, 9i also ameliorated the obese-related symptoms by decreasing the body weights without markedly changing food intake, normalized some serum biomarkers, such as ALT, AST, ALP, GLU, CHOL, HDL, and LDL, and exerted therapeutic activity on fat deposition in liver tissue. We consider 9i to have utility as a GPR119 agonists for the treatment of type 2 diabetes mellitus and obese-related symptoms. PMID- 28656524 TI - Identification of potential trypanothione reductase inhibitors among commercially available beta-carboline derivatives using chemical space, lead-like and drug like filters, pharmacophore models and molecular docking. AB - American trypanosomiasis or Chagas disease caused by the protozoan Trypanosoma cruzi (T. cruzi) is an important endemic trypanosomiasis in Central and South America. This disease was considered to be a priority in the global plan to combat neglected tropical diseases, 2008-2015, which indicates that there is an urgent need to develop more effective drugs. The development of new chemotherapeutic agents against Chagas disease can be related to an important biochemical feature of T. cruzi: its redox defense system. This system is based on trypanothione ([Formula: see text],[Formula: see text] bis(glutathyonil)spermidine) and trypanothione reductase (TR), which are rather unique to trypanosomes and completely absent in mammalian cells. In this regard, tricyclic compounds have been studied extensively due to their ability to inhibit the T. cruzi TR. However, synthetic derivatives of natural products, such as [Formula: see text]-carboline derivatives ([Formula: see text]-CDs), as potential TR inhibitors, has received little attention. This study presents an analysis of the structural and physicochemical properties of commercially available [Formula: see text]-CDs in relation to compounds tested against T. cruzi in previously reported enzymatic assays and shows that [Formula: see text]-CDs cover chemical space that has not been considered for the design of TR inhibitors. Moreover, this study presents a ligand-based approach to discover potential TR inhibitors among commercially available [Formula: see text]-CDs, which could lead to the generation of promising [Formula: see text]-CD candidates. PMID- 28656525 TI - Hypomagnesemia: a Treatable Cause of Ataxia with Cerebellar Edema. PMID- 28656527 TI - Erratum to: Fisetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via TLR4-Mediated NF-kappaB Signaling Pathway in Rats. PMID- 28656526 TI - Action of three bioavailable antioxidants in orbital fibroblasts from patients with Graves' orbitopathy (GO): a new frontier for GO treatment? AB - OBJECTIVE: Oxidative stress is involved in the pathogenesis of Graves' orbitopathy (GO) and an antioxidant approach has been advocated for GO treatment. Here, we investigated the action of three antioxidants in orbital fibroblasts, namely, vitamin C, N-acetyl-L-cysteine, and melatonin. METHODS: Primary cultures of orbital fibroblasts from six GO patients and six control subjects were established. Cells were treated with H2O2 to induce oxidative stress. Cell vitality assays were performed to determine the non-cytotoxic dose of each antioxidant. The following assays were performed: glutathione disulfide (GSSG), as a measure of oxidative stress, cell proliferation, hyaluronic acid (HA), TNFalpha, IFNgamma, and IL1beta. RESULTS: H2O2 induced oxidative stress (augmented GSSG), increased cell proliferation as well as cytokine release, but did not affect HA release. All of the three antioxidant substances reduced H2O2 dependent oxidative stress. Vitamin C reduced proliferation in GO, but not in control fibroblasts. N-acetyl-L-cysteine reduced proliferation and IFNgamma in GO, and HA and IL1beta in both GO and control fibroblasts. Melatonin reduced IL1beta and HA in GO and control fibroblasts, and IFNgamma only in GO fibroblasts. CONCLUSIONS: Our study provides evidence in support of an antioxidant role of vitamin C, N-acetyl-L-cysteine and melatonin in orbital fibroblasts. Some of the effects of these compounds are exclusive to GO fibroblasts, whereas some other are observed also in control fibroblasts. Our observations provide a basis for a possible clinical use of these substances in patients with GO. PMID- 28656528 TI - Chitinase 3-Like-1-Deficient Splenocytes Deteriorated the Pathogenesis of Acute Graft-Versus-Host Disease via Regulating Differentiation of Tfh Cells. AB - Acute graft-versus-host disease (aGVHD) is an intractable complication in transplant patients, limiting the efficacy of this therapy. Chitinase 3-like-1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, plays a critical role in a variety of inflammatory diseases. Here, we investigated the in vitro and in vivo effects of CHI3L1 on the development of aGVHD. In this study, mixed lymphocyte reactions (MLR) in vitro showed that CHI3L1 deficiency in CD4+ T cell promoted the production of interferon (IFN) gamma and T follicular helper (Tfh)-related cytokines such as interleukin-6 (IL 6) and interleukin-21 (IL-21). Meanwhile, the inducible Tfh cell population increased remarkably in CHI3L1-KO CD4+ T cells' induction group, compared with WT group. Then, in the murine acute GVHD model, we found that CHI3L1 deficiency in donor splenocytes dramatically increased the severity of aGVHD through enhancing Tfh cell differentiation. Moreover, at mRNA and protein levels, we defined several molecules that may account for the enhanced ability of CHI3L1-KO splenocytes to migrate into target organs and produce IFN-gamma and Tfh-related cytokines and chemokines, such as IL-6, IL-21, and CXCL13. Expression of inducible co-stimulator (ICOS) and B cell lymphoma 6 (Bcl6) increased in the skin, the intestine, the lung, and the liver from CHI3L1-KO splenocyte-treated aGVHD mice. Therefore, these results strongly imply that CHI3L1 levels in donor cells may be related to the risk of aGVHD and targeting CHI3L1 represents a novel therapeutic strategy for controlling aGVHD progression. PMID- 28656529 TI - IL-22 Enhances TNF-alpha- and IL-1-Induced CXCL8 Responses by Intestinal Epithelial Cell Lines. AB - IL-22 is known to induce intestinal epithelial cells (IECs) to produce the chemokine CXCL8. However, IECs exist in a cytokine network during mucosal inflammation, such that IL-22 must act in concert with potent pro-inflammatory cytokines like TNF-alpha and IL-1. Our studies show that IL-22 alone increased CXCL8 secretion from HT-29 cells, but the levels were minimal compared to that of the cells treated with TNF-alpha or IL-1 only. More significantly, co-stimulation with IL-22 and TNF-alpha enhanced both CXCL8 secretion and mRNA levels well over that of TNF-alpha stimulation alone. A similar enhancing effect was seen with IL 22- and IL-1-stimulated CXCL8 secretion. The enhancing effect of IL-22 on TNF alpha-induced CXCL8 secretion was then determined to require the p38 MAPK, but not STAT1/3, PI3K, Akt, c-Jun N-terminal kinase, ERK, or IkappaBalpha. These experiments indicate that more significant effect of IL-22 on IECs responses may not be in inducing CXCL8 by itself, but in enhancing TNF-alpha- and IL-1-induced CXCL8 secretion to augment the contribution of IECs to local inflammatory responses. PMID- 28656530 TI - Deficiency of NALP3 Signaling Impairs Liver Regeneration After Partial Hepatectomy. AB - Inflammatory response is required to proceed the optimal liver regeneration after liver injury. Recent reports demonstrated that inflammasomes are involved in the innate immune response. Several NOD-Like receptors (NLRs) participated in the formation of the inflammasomes. NACHT, LRR, and PYD domain-containing protein 3 (NALP3) belongs to the NLR families and recognizes adenosine triphosphate (ATP), crystals, and reactive oxygen species. The present study examined the effect of inflammasomes on the process of liver regeneration using NALP3 knockout (KO) mice. The activation of inflammasomes in the liver was induced after 70% partial hepatectomy (PHx). The liver-to-body weight ratio was significantly decreased in NALP3-KO mice compared to that in WT mice after PHx. The number of Ki67-positive cells and the expression of Cyclin D1 and E1 after PHx were reduced in NALP3-KO mice compared to WT mice. The expression of pro-inflammatory cytokines (IL-1beta, TNF-alpha, and IL-6) were decreased in the remnant liver of NALP3-KO mice compared to WT mice. Flow cytometric analysis revealed that the expression of chemokines was decreased and the accumulation of CD11b-positive cells was suppressed in NALP3-KO mice after PHx. The treatment with ATP, which is a ligand to NALP3, increased the liver-to-body weight ratio in WT mice. These results indicate that NALP3 signaling is required for the induction of inflammatory response and the development of liver regeneration after PHx. PMID- 28656531 TI - ACL Injury Prevention: What Does Research Tell Us? AB - PURPOSE OF REVIEW: Mechanisms leading to anterior cruciate ligament (ACL) injury have been identified, yet re-injury or a secondary injury persists in the athletic population. The purpose of this review is to identify risk factors associated with ACL injury and investigate programs to prevent injury. RECENT FINDINGS: Faulty mechanics during dynamic movement that cause excessive valgus force at the knee increases the risk of ACL injury. Faulty mechanics may be a result of lateral displacement of the trunk, unequal limb loading, and lack of control to avoid the valgus knee position. Altered movements that place the ACL at risk are best identified in a fatigued state; however, could be recognized in a standard dynamic assessment. The faulty movement patterns are modifiable and should be addressed in an injury prevention program. Prevention programs include various modes of exercise such as plyometrics, neuromuscular training, and strength training. This review concludes that those programs which utilize neuromuscular training and strength training at a young age show the most promise in reducing ACL injuries. An ongoing thorough dynamic examination is necessary for all athletes while adjusting the intervention program in order to decrease the risk of ACL injury. PMID- 28656533 TI - Duration compression induced by visual and phonological repetition of Chinese characters. AB - Our prior experience heavily influences our subjective time. One of such phenomena is repetition compression, that is, repeated stimuli are perceived shorter than novel stimuli. However, most of the studies on repetition compression used identical stimuli, leaving the question whether similar repetition effects could take place in phonological and semantic level repetition. We used Chinese characters to manipulate different levels of repetition in a duration discrimination task. We replicated earlier findings that repetition of visual identical characters shortened the apparent duration and found the repetition compression was spatially independent. Phonological repetition also caused the duration compression though the effect was weaker than the visual repetition. However, we observed no duration compression during the semantic repetition. The results suggest that repetition compression is mediated by visual and phonological representation of a stimulus in an early stage in processing hierarchy. We explained our findings according to the framework of predictive coding. PMID- 28656532 TI - Current Controversies on Wernicke's Area and its Role in Language. AB - PURPOSE OF REVIEW: The aim of the study is to assess historical anatomical and functional definitions of Wernicke's area in light of modern lesion and neuroimaging data. RECENT FINDINGS: "Wernicke's area" has become an anatomical label usually applied to the left posterior superior temporal gyrus and adjacent supramarginal gyrus. Recent evidence shows that this region is not critical for speech perception or for word comprehension. Rather, it supports retrieval of phonological forms (mental representations of phoneme sequences), which are used for speech output and short-term memory tasks. Focal damage to this region produces phonemic paraphasia without impairing word comprehension, i.e., conduction aphasia. Neuroimaging studies in recent decades provide evidence for a widely distributed temporal, parietal, and frontal network supporting language comprehension, which does not include the anatomically defined Wernicke area. The term Wernicke's area, if used at all, should not be used to refer to a zone critical for speech comprehension. PMID- 28656534 TI - Relationship between subjective and actigraphy-measured sleep in 237 patients with metastatic colorectal cancer. AB - OBJECTIVE: Patients with cancers frequently experience sleep and circadian dysfunction. To date, only a few studies have used both a questionnaire and actigraphy for concomitant evaluation of sleep and circadian function in patients with cancer. We sought to evaluate objective sleep and circadian parameters in metastatic colon cancer (MCC) patients and their associations with symptoms and quality of life (QOL). METHODS: Patients reported subjective sleep problems on the EORTC QLQ-C30. Sleep and circadian parameters were calculated using a wrist actigraph that patients wore for 72 h. RESULTS: 237 Patients with MCC (mean age: 60.4 years; range: 20.7-77.6; Male/Female ratio: 1.66) participated in this cross sectional study. Subjective sleep problems were reported by 63.4% of patients (S+). No differences in any sleep parameters (sleep efficiency, sleep latency, total sleep time, total time in bed, wake after sleep onset, activity bathyphase) were observed between S+ and S- patients. However, S+ patients displayed a significantly worse circadian function than S- patients (96.4 vs 98.1%; p = 0.005). The presence of poor subjective sleep and objective circadian dysfunction negatively affected symptoms and QOL domains (p = 0.038). CONCLUSIONS: Subjective report of sleep problems was not associated with worse objectively measured sleep parameters in patients with MCC although it was associated with disrupted circadian rest-activity rhythm and poorer QOL. These findings coincide with prior research in cancer patients in that an inconsistent relationship exists between subjective and objective sleep measurements on some sleep domains. This study supports the value of coupled evaluation of self-reported and objective measures of sleep and circadian function in cancer patients. PMID- 28656537 TI - Triggering final follicular maturation: hCG, GnRH-agonist, or both, when and to whom? PMID- 28656536 TI - [The diagnostic disclosure of dementia: an ethnographic exploration]. AB - Giving adequate diagnostic information is considered to be fundamental in dementia care. An important question is how the diagnostic disclosure in dementia actually takes place. The aim of this explorative ethnographic study was therefore to provide insight into the disclosure practice of medical specialists. For this study, 22 interviews performed by seven medical specialists were analyzed.The results of this study show that the observed doctors are direct and explicit in disclosing the diagnosis. Actual (medical) information about the diagnosis and the performed investigations is provided. The main areas for improvement are involving the patient in the conversation, align your language to the lifeworld of the patient and his/her significant other(s), avoiding the use of medical jargon, discussing the consequences of the diagnosis for daily life, and explicitly recognizing the emotional and existential challenges associated with the disclosure. In providing further information, doctors could discuss emotional and existential support more specifically. PMID- 28656535 TI - Associations between health-related quality of life, cardiorespiratory fitness, muscle strength, physical activity and waist circumference in 10-year-old children: the ASK study. AB - PURPOSE: To examine the associations between cardiorespiratory fitness, muscle strength, physical activity and waist circumference with self-reported health related quality of life (HRQoL) in children. METHODS: We conducted a cross sectional analysis that included 1129 school children aged 10 years from 57 schools in Sogn and Fjordane County, Norway. The HRQoL outcome was assessed by the self-reported KIDSCREEN-27 questionnaire, which covers five life domains. Independent variables were cardiorespiratory fitness assessed by the Andersen intermittent field running test, handgrip strength measured by a hand dynamometer, explosive strength in the lower body using a standing broad jump test, physical activity (counts per minute) using an accelerometer and abdominal adiposity measured by waist circumference. Statistical analyses were performed using linear mixed-effect models including school site as a random effect. Age and sex were entered as covariates. RESULTS: Only cardiorespiratory fitness was positively associated with higher scores on all five KIDSCREEN-27 domains (P < 0.047 for all). Explosive strength in the lower body was positively associated with higher autonomy and parents scores (P = 0.018), while physical activity was positively associated with higher physical well-being scores (P = 0.008). CONCLUSIONS: Improving cardiorespiratory fitness might be especially useful for improving HRQoL in children. PMID- 28656538 TI - The dilemma of counseling patients about poor prognosis: live birth after IVF with autologous oocytes in a 43-year-old woman with FSH levels above 30 mIU/mL. AB - Providing reasonable expectations to patients with diminished ovarian reserve prior to attempting pregnancy through in vitro fertilization (IVF) is one of the most challenging aspects of fertility care. In some instances, advice from the clinician to pursue more effective treatment, such as donor oocytes, may not be acceptable to the patient. In this case report, a patient is presented who represents a poor prognosis candidate for IVF treatment. She was 43 years old with six prior failed IVF cycles and repetitive basal FSH values above 30 mIU/mL. Presented are the challenges in patient counseling and decision making. In her seventh IVF cycle, which she was strongly counseled against pursuing, the patient experienced the desired outcome of live birth. Increasing reports are emerging of live birth using autologous oocytes among women of advanced reproductive age. These instances, as well as the case of our patient, raise issues commonly encountered in patient counseling in poor prognosis patients. This discussion should include an emphasis on patient goals as well as an acknowledgement that no test for ovarian reserve has a 100% positive predictive value. PMID- 28656539 TI - Medical and elective fertility preservation: impact of removal of the experimental label from oocyte cryopreservation. AB - PURPOSE: The purpose of this study was to compare baseline characteristics and ovarian stimulation outcomes between patients presenting for medically indicated vs. elective fertility preservation consultation and to determine the impact of the 2013 ASRM guidelines on oocyte cryopreservation on the patient population presenting for fertility preservation consultation. METHODS: Retrospective cohort study conducted at an academic center. Study population included 332 patients presenting for medically indicated fertility preservation consultation and 210 patients presenting for elective consultation. RESULTS: Patients presenting for elective fertility preservation consultation were more likely to be of advanced age, non-Caucasian, highly educated, single, nulligravid, and meet criteria for diminished ovarian reserve (DOR). Additionally, patients presenting electively were more likely to have fertility insurance benefits. A higher percentage of patients with insurance benefits for oocyte cryopreservation proceeded to stimulation. There were no differences in stimulation parameters or number of retrieved oocytes between the groups when adjusted for age. Following release of the ASRM guidelines on oocyte cryopreservation, there was no difference in the percentage of patients in the medical group who proceeded with stimulation; however, a higher percentage of patients presenting electively underwent ovarian stimulation. CONCLUSION: Although the populations presenting for medical compared with elective fertility preservation differ at baseline, ovarian stimulation parameters and outcomes are similar when adjusted for age. Insurance benefits for fertility preservation are not comprehensive and impact the decision to proceed with stimulation in all patients. The publication of the ASRM guidelines on oocyte cryopreservation increased utilization of this technology among patients presenting electively; however, they remained at an advanced age and with decreased ovarian reserve parameters. PMID- 28656540 TI - Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase. AB - Human endogenous retrovirus W env (HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis (MS). These diseases are accompanied by immunological reactions in the central nervous system (CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter-nitric oxide (NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase (hiNOS) and enhanced the promoter activity of hiNOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases. PMID- 28656541 TI - Prevalence and Correlates of Smoking among Low-Income Adults Residing in New York City Public Housing Developments-2015. AB - To guide targeted cessation and prevention programming, this study assessed smoking prevalence and described sociodemographic, health, and healthcare use characteristics of adult smokers in public housing. Self-reported data were analyzed from a random sample of 1664 residents aged 35 and older in ten New York City public housing developments in East/Central Harlem. Smoking prevalence was 20.8%. Weighted log-binomial models identified to be having Medicaid, not having a personal doctor, and using health clinics for routine care were positively associated with smoking. Smokers without a personal doctor were less likely to receive provider quit advice. While most smokers in these public housing developments had health insurance, a personal doctor, and received provider cessation advice in the last year (72.4%), persistently high smoking rates suggest that such cessation advice may be insufficient. Efforts to eliminate differences in tobacco use should consider place-based smoking cessation interventions that extend cessation support beyond clinical settings. PMID- 28656542 TI - Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure: Results from the PROTECT Trial : Differential Response in Acute Heart Failure. AB - BACKGROUND: Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy. METHODS: We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model. Treatment response was survival from all-cause mortality through day 180. RESULTS: In the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82-1.28, p = 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum score model included TNF-R1alpha, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF R1alpha, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40-0.92, p = 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68-18.13, p = 0.005; treatment by score interaction p < 0.001). Internal validation estimated similar hazard ratio estimates (0 points: HR 5.56, 95% CI 5.27-7-5.87; 1 point: HR 1.31, 95% CI 1.25-1.33; 2 points: HR 0.75, 95% CI 0.74-0.76; 3 points: HR 1.13, 95% CI 1.11-1.15; 4 points, HR 0.61, 95% CI 0.61-0.62) compared to the original data. CONCLUSION: Biomarkers are superior to clinical characteristics to study treatment heterogeneity in acute heart failure. PMID- 28656543 TI - Ramucirumab for Treating Advanced Gastric Cancer or Gastro-Oesophageal Junction Adenocarcinoma Previously Treated with Chemotherapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ramucirumab (Cyramza(r), Eli Lilly and Company) to submit evidence of the clinical and cost effectiveness of the drug administered alone (monotherapy) or with paclitaxel (combination therapy) for treating adults with advanced gastric cancer or gastro-oesophageal junction (GC/GOJ) adenocarcinoma that were previously treated with chemotherapy, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. Clinical effectiveness evidence for ramucirumab monotherapy (RAM), compared with best supportive care (BSC), was based on data from the REGARD trial. Clinical effectiveness evidence for ramucirumab combination therapy (RAM + PAC), compared with paclitaxel monotherapy (PAC), was based on data from the RAINBOW trial. In addition, the company undertook a network meta-analysis (NMA) to compare RAM + PAC with BSC and docetaxel. Cost-effectiveness evidence of monotherapy and combination therapy relied on partitioned survival, cost-utility models. The base-case incremental cost-effectiveness ratio (ICER) of the company was L188,640 (vs BSC) per quality adjusted life-year (QALY) gained for monotherapy and L118,209 (vs BSC) per QALY gained for combination therapy. The ERG assessment indicated that the modelling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. The ERG provided a new base case, with ICERs (vs BSC) of L188,100 (monotherapy) per QALY gained and L129,400 (combination therapy) per QALY gained and conducted additional exploratory analyses. The NICE Appraisal Committee (AC), considered the company's decision problem was in line with the NICE scope, with the exception of the choice of comparators for the combination therapy model. The most plausible ICER for ramucirumab monotherapy compared with BSC was L188,100 per QALY gained. The Committee considered that the ERG's exploratory analysis in which RAM + PAC was compared with PAC by using the direct head-to-head data (including utilities) from the RAINBOW trial, provided the most plausible ICER (i.e. L408,200 per QALY gained) for ramucirumab combination therapy. The Committee concluded that end-of life considerations cannot be applied for either case, since neither failed to offer an extension to life of at least 3 months. The company did not submit a patient access scheme (PAS). After consideration of the evidence, the Committee concluded that ramucirumab alone or with paclitaxel could not be considered a cost-effective use of National Health Service resources for treating advanced GC/GOJ patients that were previously treated with chemotherapy, and therefore its use could not be recommended. We might wonder if a complete STA process is necessary for treatments without a PAS, which are, according to the company's submission, already associated with ICERs far above the currently accepted threshold in all (base-case, sensitivity and scenario) analyses. PMID- 28656544 TI - The relationship between diabetes, diabetes-related complications and productive activities among older Europeans. AB - AIMS: To assess the impact of diabetes and diabetes-related complications on two measures of productivity for people in the labour force and out of it, namely "being afraid health limits ability to work before retirement" and "volunteering". METHODS AND DATA: Logistic regressions were run to test the impact of diabetes and its complications on the probability of being afraid health limits work and being a formal volunteer. The longitudinal sample for the former outcome includes 53,631 observations, clustered in 34,393 individuals, aged 50-65 years old whereas the latter consists of 45,384 observations, grouped in 29,104 individuals aged 65 and above across twelve European countries taken from the Survey of Health, Ageing and Retirement in Europe, from 2006 to 2013. RESULTS: Diabetes increased the probability of being afraid health limited work by nearly 11% points, adjusted by clinical complications, and reduced the likelihood of being a formal volunteer by 2.7% points, additionally adjusted by mobility problems. We also found that both the probability of being afraid health limits work and the probability of being a formal volunteer increased during and after the crisis. Moreover, having diabetes had a larger effect on being afraid health limits work during the year 2010, possibly related to the financial crisis. CONCLUSIONS: Our findings show that diabetes significantly affects the perception of people regarding the effects of their condition on work, increasing the fear that health limits their ability to work, especially during the crisis year 2010, as well as the participation in volunteering work among retired people. PMID- 28656545 TI - Is it reasonable to use a lower DOAC dose in some patients with VTE? NO. AB - The international guidelines recommend the use of direct oral anticoagulants (DOACs) over vitamin K antagonists for anticoagulation long-term therapy in patients diagnosed with venous thromboembolism (VTE), and for stroke prevention in patients with non-valvular atrial fibrillation (AF). Efficacy and safety of DOACS have been extensively evaluated in large phase III trials. According to the product label, dose reductions of DOACs are recommended for patients with AF and renal impairment, low body weight and concomitant use of interfering medications. Except for Edoxaban, dose reductions of DOACs are not recommended in patients with VTE based on the same indications for AF patients. The aim of this article is to discuss the indication of a lower DOAC dose in some patients with VTE. Observational studies and randomized control trials (RCTs) show that patients with AF are usually older, more often have chronic diseases, and more often are treated with several concomitant medications, potentially increasing their haemorrhagic risk. Furthermore, many VTE patients need a shorter period of anticoagulation therapy than AF patients. In real-life studies, VTE patients treated with inappropriate DOAC doses present a higher rate of VTE recurrence, and the same risk of bleeding compared to those treated with the correct dose. In light of this evidence, the use of lower DOAC dose in patients with VTE does not appear reasonable and may be potentially dangerous. PMID- 28656546 TI - Epidemiology of acute kidney injury in patients with stroke: a retrospective analysis from the neurology ICU. AB - Acute kidney injury (AKI) is proven to be an independent risk factor for adverse clinical outcomes in patients with stroke, but data about the epidemiology of AKI in these patients are not well characterized. Therefore, we investigated the incidence, risk factors, and the impact of AKI on the clinical outcomes in a group of Chinese patients with stroke. We retrospectively recruited 647 stroke patients from the neurology ICU between 2012 and 2013. AKI was identified according to the 2012 KDIGO criteria. Baseline estimated glomerular filtration rate (eGFR) was calculated using modified Chronic Kidney Disease Epidemiology Collaboration equation for Chinese patients. National Institutes of Health Stroke Scale (NIHSS) score was assessed for the stroke severity. A total of 135 (20.9%) patients developed AKI. Patients with AKI stages from 1 to 3 were 84 (62.2%), 26 (19.3%), and 25 (18.5%), respectively. Logistic regression analysis showed that independent risk factors for AKI were higher NIHSS score (OR, 1.027; 95% CI 1.003 1.051), lower baseline eGFR (OR, 0.985; 95% CI 0.977-0.993), the presence of hypertension (OR, 1.592; 95% CI 1.003-2.529), and infectious complications (OR, 3.387; 95% CI 1.997-5.803) (P < 0.05 for all). AKI patients were also significantly associated with all-cause mortality in the neurology ICU [OR and 95% CI of AKI-stage 1, AKI-stage 2, and AKI-stage 3 were 4.961 (2.191-11.232), 19.722 (6.354-61.217), and 48.625 (17.616-134.222), respectively (P < 0.001 for all)]. AKI is common among patients with stroke and is associated with worse clinical outcomes after stroke. Prevention of AKI seems to be very important among these patients, because they are exposed to many risk factors for developing AKI. PMID- 28656547 TI - Severe Hyperhomocysteinemia Decreases Creatine Kinase Activity and Causes Memory Impairment: Neuroprotective Role of Creatine. AB - In the present study, we investigate the effect of severe hyperhomocysteinemia on biochemical (creatine kinase activity), behavioral (memory tests), and histological assessments (hippocampal volume). A possible neuroprotective role of creatine on hyperhomocysteinemia effects was also evaluated. Severe hyperhomocysteinemia was induced in neonate rats (starting at 6 days of age) by treatment with homocysteine (0.3-0.6 MUmol/g body weight) for 23 days. Creatine (50 mg/kg body weight) was administered concomitantly with homocysteine. Controls received saline in the same volumes. Twelve hours after the last injection, the rats were submitted to behavioral tests [(recognition task (NOR)] and inhibitory avoidance (IA)]. Following behavioral assessment, the animals were perfused and decapitated, the brain removed for subsequent morphological analysis of the hippocampus. Another group of animals was used to test creatine kinase activity in hippocampus. The results showed that rats treated with homocysteine decreased (44%) the exploration of the novel object in NOR. In the IA task, homocysteine treated animals presented decreased latencies to step down the platform in short- (32%) and long-term (18%) testings (3 h and 7 days, respectively), evidencing aversive memory impairment. Hippocampal volume was not altered by homocysteine administration. Hyperhomocysteinemia decreased (45%) creatine kinase activity, and creatine was able to prevent such effect probably by creatine kinase/phosphocreatine/creatine homeostasis, which serves as energy circuit within of the cell. This finding may be associated, at least in part, with memory improvement, suggesting that creatine might represent an effective adjuvant to protect against the effects of high homocysteine plasma levels. PMID- 28656548 TI - Treadmill Exercise Attenuates alpha-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease. AB - Accumulation of alpha-synuclein (alpha-Syn) is significantly correlated with the presence of progressive motor deficits, which is the main symptom of Parkinson's disease (PD). Although physical exercise reduces alpha-Syn levels, the molecular mechanisms by which physical exercise decreases alpha-Syn remain unclear. We hypothesized that treadmill exercise (TE) decreases alpha-Syn levels by improving mitochondrial function and promoting autophagy via the sirtuin-1 (SIRT1) signaling pathway in the chronic 1-methyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/P)-induced mouse model of PD. We found that TE reduces alpha-Syn levels, which subsequently ameliorates dopaminergic (DAergic) neuron loss and alpha-Syn-mediated apoptotic cell death. Most importantly, TE increases SIRT1 expression, which results in increased mitochondrial biogenesis and decreased oxidative stress by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). SIRT1 activation by TE also promotes autophagic clearance of alpha-Syn by inducing the activation of microtubule-associated protein 1 light chain 3 (LC3). Collectively, our results demonstrate that TE may reduce alpha-Syn levels by improving mitochondrial function and increasing autophagic flux, thereby ameliorating chronic MPTP/P-induced motor deficits in PD mice. PMID- 28656549 TI - Kanamycin Damages Early Postnatal, but Not Adult Spiral Ganglion Neurons. AB - Although aminoglycoside antibiotics such as kanamycin are widely used clinically to treat life-threatening bacterial infections, ototoxicity remains a significant dose-limiting side effect. The prevailing view is that the hair cells are the primary ototoxic target of aminoglycosides and that spiral ganglion neurons begin to degenerate weeks or months after the hair cells have died due to lack of neurotrophic support. To test the early developmental aspects of this issue, we compared kanamycin-induced hair cell and spiral ganglion pathology in rat postnatal day 3 cochlear organotypic cultures with adult whole cochlear explants. In both adult and postnatal day 3 cultures, hair cell damage began at the base of the cochleae and progressed toward the apex in a dose-dependent manner. In postnatal day 3 cultures, spiral ganglion neurons were rapidly destroyed by kanamycin prior to hair cell loss. In contrast, adult spiral ganglion neurons were resistant to kanamycin damage even at the highest concentration, consistent with in vivo models of delayed SGN degeneration. In postnatal day 3 cultures, kanamycin preferentially damaged type I spiral ganglion neurons, whereas type II neurons were resistant. Spiral ganglion degeneration of postnatal day 3 neurons was associated with upregulation of the superoxide radical and caspase-3-mediated cell death. These results show for the first time that kanamycin is toxic to postnatal day 3 spiral ganglion neurons, but not adult neurons. PMID- 28656550 TI - Efficient Production of gamma-GABA Using Recombinant E. coli Expressing Glutamate Decarboxylase (GAD) Derived from Eukaryote Saccharomyces cerevisiae. AB - gamma-Aminobutyric acid (gamma-GABA) is a non-proteinogenic amino acid, which acts as a major regulator in the central nervous system. Glutamate decarboxylase (namely GAD, EC 4.1.1.15) is known to be an ideal enzyme for gamma-GABA production using L-glutamic acid as substrate. In this study, we cloned and expressed GAD gene from eukaryote Saccharomyces cerevisiae (ScGAD) in E. coli BL21(DE3). This enzyme was further purified and its optimal reaction temperature and pH were 37 degrees C and pH 4.2, respectively. The cofactor of ScGAD was verified to be either pyridoxal 5'-phosphate (PLP) or pyridoxal hydrochloride. The optimal concentration of either cofactor was 50 mg/L. The optimal medium for E. coli-ScGAD cultivation and expression were 10 g/L lactose, 5 g/L glycerol, 20 g/L yeast extract, and 10 g/L sodium chloride, resulting in an activity of 55 U/mL medium, three times higher than that of using Luria-Bertani (LB) medium. The maximal concentration of gamma-GABA was 245 g/L whereas L-glutamic acid was near completely converted. These findings provided us a good example for bio production of gamma-GABA using recombinant E. coli expressing a GAD enzyme derived from eukaryote. PMID- 28656551 TI - Improvement of Lead Tolerance of Saccharomyces cerevisiae by Random Mutagenesis of Transcription Regulator SPT3. AB - Bioremediation of heavy metal pollution with biomaterials such as bacteria and fungi usually suffer from limitations because of microbial sensitivity to high concentration of heavy metals. Herein, we adopted a novel random mutagenesis technique called RAISE to manipulate the transcription regulator SPT3 of Saccharomyces cerevisiae to improve cell lead tolerance. The best strain Mutant VI was selected from the random mutagenesis libraries on account of the growth performance, with higher specific growth rate than the control strain (0.068 vs. 0.040 h-1) at lead concentration as high as 1.8 g/L. Combined with the transcriptome analysis of S. cerevisiae, expressing the SPT3 protein was performed to make better sense of the global regulatory effects of SPT3. The data analysis revealed that 57 of S. cerevisiae genes were induced and 113 genes were suppressed, ranging from those for trehalose synthesis, carbon metabolism, and nucleotide synthesis to lead resistance. Especially, the accumulation of intracellular trehalose in S. cerevisiae under certain conditions of stress is considered important to lead resistance. The above results represented that SPT3 was acted as global transcription regulator in the exponential phase of strain and accordingly improved heavy metal tolerance in the heterologous host S. cerevisiae. The present study provides a route to complex phenotypes that are not readily accessible by traditional methods. PMID- 28656552 TI - Single Cell Oil Production from Hydrolysates of Inulin by a Newly Isolated Yeast Papiliotrema laurentii AM113 for Biodiesel Making. AB - Microbial oils are among the most attractive alternative feedstocks for biodiesel production. In this study, a newly isolated yeast strain, AM113 of Papiliotrema laurentii, was identified as a potential lipid producer, which could accumulate a large amount of intracellular lipids from hydrolysates of inulin. P. laurentii AM113 was able to produce 54.6% (w/w) of intracellular oil in its cells and 18.2 g/l of dry cell mass in a fed-batch fermentation. The yields of lipid and biomass were 0.14 and 0.25 g per gram of consumed sugar, respectively. The lipid productivity was 0.092 g of oil per hour. Compositions of the fatty acids produced were C14:0 (0.9%), C16:0 (10.8%), C16:1 (9.7%), C18:0 (6.5%), C18:1 (60.3%), and C18:2 (11.8%). Biodiesel obtained from the extracted lipids could be burnt well. This study not only provides a promising candidate for single cell oil production, but will also probably facilitate more efficient biodiesel production. PMID- 28656553 TI - Molecular Identification of Cutaneous Alternariosis in a Renal Transplant Patient. AB - Cutaneous alternariosis is a rare condition, caused by an uncommon opportunistic pathogen. The most frequently affected individuals are immunosuppressed patients, e.g., organ transplant patients on immunosuppressive therapy. Clinical manifestations range from local skin lesions to disseminated disease. We present a case report of cutaneous alternariosis in a renal transplant recipient, confirmed by histological examination and molecular means. In addition, a review of the literature was performed. PMID- 28656555 TI - Search for key manifestations to predict inflammation on cardiac PET in suspected cardiac sarcoidosis population. PMID- 28656554 TI - Fluconazole Non-susceptible Cryptococcus neoformans, Relapsing/Refractory Cryptococcosis and Long-term Use of Liposomal Amphotericin B in an AIDS Patient. AB - The treatment of cryptococcosis is hampered by inefficacy or intolerance to the recommended antifungal agents. A patient diagnosed with AIDS had multiple relapses of cryptococcal infection, which became refractory to antifungal agents during the course of therapy. During the follow-up, the patient developed renal toxicity due to amphotericin B use and non-susceptibility of isolated Cryptococcus neoformans to fluconazole was detected. Thereafter, antifungal treatment was performed exclusively with liposomal amphotericin B, reaching a cumulative dose of 19,180 mg over 46 months. The final relapse of cryptococcosis occurred during the maintenance phase with liposomal formulation in a once-weekly dose. Measurement of the minimum serum concentrations of amphotericin B, determined sequentially before and after this relapse, suggested the importance of monitoring drug levels when the liposomal formulation is used for a long period. PMID- 28656556 TI - Dissipation of S-metolachlor in plant and soil and effect on enzymatic activities. AB - The present study aimed at evaluating the dissipation of S-metolachlor (S-MET) at three doses in maize growing on diverse physico-chemical properties of soil. The effect of herbicide on dehydrogenase (DHA) and acid phosphatase (ACP) activity was estimated. A modified QuEChERS method using LC-MS/MS has been developed. The limit of quantification (0.001 mg kg-1) and detection (0.0005 mg kg-1) were very low for soil and maize samples. The mean recoveries and RSDs for the six spiked levels (0.001-0.5 mg kg-1) were 91.3 and 5.8%. The biggest differences in concentration of S-MET in maize were observed between the 28th and 63rd days. The dissipation of S-MET in the alkaline soil was the slowest between the 2nd and 7th days, and in the acidic soil between the 5th and 11th days. DT50 of S-MET calculated according to the first-order kinetics model was 11.1-14.7 days (soil) and 9.6-13.9 days (maize). The enzymatic activity of soil was higher in the acidic environment. One observed the significant positive correlation of ACP with pH of soil and contents of potassium and magnesium and negative with contents of phosphorus and organic carbon. The results indicated that at harvest time, the residues of S-MET in maize were well below the safety limit for maize. The findings of this study will foster the research on main parameters influencing the dissipation in maize ecosystems. PMID- 28656557 TI - Distribution and assessment of heavy metal toxicity in sediment cores from Bizerte Lagoon, Tunisia. AB - To examine the state of pollution of Bizerte Lagoon which is exposed to intense anthropogenic pressure, two sediment cores were taken at two sites, one undergoes the dual effects of both marine waters arriving from the Mediterranean Sea through the Channel, and also of freshwater from the Tinja River; the other core is located at the center of the lagoon where water depth is maximal (12 m). Heavy metal concentrations in the two cores were assessed, with calculated enrichment factors and geo-accumulation indexes. Core sediments were also studied for chemical speciation and their monosulfide contents were measured. Results from enrichment factors and geo-accumulation indexes show an accumulation of Cd, Zn, Cr, and Pb, while chemical speciation revealed a risk only from Cd and Mn. Comparison of sequential extraction values with those of acid volatile sulfides revealed that non-toxic effects may be caused by any of the studied metals in the sediment. PMID- 28656558 TI - Organic carbon causes interference with nitrate and nitrite measurements by UV/Vis spectrometers: the importance of local calibration. AB - Compared with sporadic conventional water sampling, continuous water-quality monitoring with optical sensors has improved our understanding of freshwater dynamics. The basic principle in photometric measurements is the incident light at a given wavelength that is either reflected, scattered, or transmitted in the body of water. Here, we discuss the transmittance measurements. The amount of transmittance is inversely proportional to the concentration of the substance measured. However, the transmittance is subject to interference, because it can be affected by factors other than the substance targeted in the water. In this study, interference with the UV/Vis sensor nitrate plus nitrite measurements caused by organic carbon was evaluated. Total or dissolved organic carbon as well as nitrate plus nitrite concentrations were measured in various boreal waters with two UV/Vis sensors (5-mm and 35-mm pathlengths), using conventional laboratory analysis results as references. Organic carbon increased the sensor nitrate plus nitrite results, not only in waters with high organic carbon concentrations, but also at the lower concentrations (< 10 mg C L-1) typical of boreal stream, river, and lake waters. Our results demonstrated that local calibration with multiple linear regression, including both nitrate plus nitrite and dissolved organic carbon, can correct the error caused by organic carbon. However, high-frequency optical sensors continue to be excellent tools for environmental monitoring when they are properly calibrated for the local water matrix. PMID- 28656559 TI - Assessing indoor air quality of school environments: transplanted lichen Pseudovernia furfuracea as a new tool for biomonitoring and bioaccumulation. AB - The aim of this research is to evaluate the ability of transplanted lichen Pseudovernia (P). furfuracea to biomonitor and bioaccumulate in urban indoor environments. The elements As, Cd, Cr, Cu, Hg, Ni and Pb and 12 selected polycyclic aromatic hydrocarbons (PAHs) were used to assess P. furfuracea as a biomonitoring tool for the indoor air quality of school environments. To achieve this purpose, lichen samples were exposed for 2 months in the outdoor and indoor environments of five school settings located in urban and rural areas. The results demonstrated that transplanted lichen P. furfuracea is a suitable biomonitoring tool for metals and PAHs in indoor settings and can discriminate between different levels of air pollution related to urbanisation and indoor conditions, such as those characterised by school environments. A transplanted lichen biomonitoring strategy is cost-effective, "green", educational for attending children and less "invasive" than traditional air sampling methods. The feasibility of indoor monitoring by P. furfuracea is a relevant finding and could be a key tool to improve air quality monitoring programmes in school scenarios and thus focus on health prevention interventions for children, who are one of the most susceptible groups in the population. PMID- 28656560 TI - Barcelona Clinic Liver Cancer (BCLC) Staging: Does It Cover All Our Expectation. PMID- 28656561 TI - Neuroendocrine Tumors of the Esophagus: State of the Art in Diagnostic and Therapeutic Management. AB - INTRODUCTION: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms composed of cells containing dense-core neuroendocrine secretory granules in their cytoplasm. NETs of the esophagus are exceedingly uncommon, with a parallel absence of data published on clinical features, prognosis, and proposed treatment strategies. METHODS: As relevant classification is not well-established, knowledge acquired in NETs of lung and gastrointestinal sites usually guides esophageal NET management. Associated subtypes are divided based upon shared neuroendocrine features into small and large cell NET, typical and atypical carcinoid. RESULTS: Common presenting symptoms include dysphagia, abdominal discomfort, weight loss, melena, and on occasion, signs of carcinoid syndrome. Endoscopic findings describe a polypoid, nodular elevated lesion with an overlying surface depicted as mostly smooth and glistening. Disease metastasis is assessed using anatomical imaging, including computed tomography (CT), endoscopic ultrasonography (EUS), and positron emission tomography (PET)-CT. Prognosis is influenced by the extent of lymph node metastasis and potential lymphovascular invasion. Furthermore, proliferative activity, estimated using mitotic count or Ki-67 immunostaining, has been suggested as a significant prognostic parameter. CONCLUSION: Therapeutic approach depends on clinical staging. Nevertheless, currently, a specific treatment algorithm for esophageal NETs has not been elucidated. Endoscopic resection has been proposed in NETs less than 1 cm in size with absence of regional lymph node metastasis, while surgical excision combined with adjuvant chemotherapy remains the treatment of choice. PMID- 28656562 TI - Diagnosis and Treatment of Rosacea Fulminans: A Comprehensive Review. AB - Rosacea fulminans is a rare inflammatory condition of the central face marked by the abrupt onset of erythematous coalescing papules, pustules, nodules, and draining sinuses. Due to infrequent reporting in the literature, the pathophysiology, classification, and nomenclature of this condition remain controversial. This comprehensive review evaluated a total of 135 cases of rosacea fulminans for clinical and histopathologic features and reported treatment strategies. Patients were 91% female with an average age of onset of 31.3 years. Only 19% of cases reported duration of symptoms longer than 3 months, and reports of recurrence were uncommon. A majority of patients had history of rosacea or flushing, and common triggers included hormonal shifts, emotional stress, and medications. Extrafacial or systemic involvement was rare. Though oral and topical antibiotics were frequently utilized to treat rosacea fulminans, there was a clear shift in reported treatments for rosacea fulminans following the introduction of isotretinoin use in 1987, marked by increased reliance on isotretinoin in addition to topical and systemic corticosteroids. Newer treatments were associated with superior improvement compared with antibiotic monotherapy, most notably dramatically reduced rates of scarring, though reduced rates of disease recurrence were not evident. Several patterns revealed through this review reinforce the classification of rosacea fulminans as a severe yet distinct variant of rosacea and highlight key distinguishing clinical features and treatment options for optimal management. PMID- 28656564 TI - High prevalence of missed opportunities for secondary fracture prevention in a regional general hospital setting in Singapore. AB - : This study aims at assessing the gap in secondary fracture prevention at a regional general hospital setting in Singapore. Male patients have significantly lower rate of being investigated and treated for osteoporosis than their female counterparts. Vitamin D deficiency is prevalent in our population. PURPOSE: Secondary fracture prevention services are not routine in Singapore; we seek to assess the treatment gap that exists in the lack of diagnosis and treatment of osteoporosis in fragility fracture patients. METHODS: We performed a retrospective analysis of all admissions for fragility fractures between December 2013 and December 2014. Demographic data, rates of BMD performance, serum vitamin D investigation and calcium and vitamin D supplementation as well as antiresorptive initiation 1 year post admission were analysed. RESULTS: There were 125 fragility fractures in patients below 65 and 615 fractures in older patients. There was a slightly higher proportion of males in the younger population, whereas females predominated in the older population. Median vitamin D levels were low in both younger (19.1 MUg/L) and older (22.0 MUg/L) groups, but supplementation was lower in younger patients (4.8 versus 16.6%, p = 0.003). Rate of BMD performance was lower in younger patients (34.4 versus 64.6%, p < 0.01); there was a significant difference of BMD performance between male and female patients in the younger population (19.1 versus 52.8%, p < 0.01) which was not present in the older age group. Antiresportive initiation was significantly lower in the younger age group versus older (10.4 versus 31.5%, p < 0.01); male patients in the younger and older age groups had significantly lower antiresorptive initiation rate compared to the females. CONCLUSION: There is a significant treatment gap in diagnosis and treatment of osteoporosis in fragility fracture patients in a regional hospital setting in Singapore. Male osteoporosis remains inadequately investigated and treated in both age groups. PMID- 28656565 TI - Arrhythmia Vulnerability in Diabetic Cardiac Tissue is Species-Dependent: Effects of I KATP, Uncoupling, and Connexin Lateralization. AB - Amongst the complications of diabetes is arrhythmia, the risk of which depends on multiple factors. This study was designed to investigate several factors, including the effects of ATP-sensitive potassium current, lateralized connexins, and gap junction uncoupling. ATP-sensitive potassium channel (I KATP) opening is caused by ischemia, which can occur in diabetic or non-diabetic hearts. I KATP opening was simulated in this work to determine if the risk of ischemia-induced arrhythmias is affected by diabetes. Simulations were performed using healthy and diabetic models of rat and rabbit ventricle. Results showed that the diabetic rat model is less vulnerable to reentrant arrhythmia than the healthy rat model. The diabetic rabbit model was more vulnerable to reentrant arrhythmia than the healthy rabbit model. In both rabbit models, the vulnerability increased as the gap junctional coupling decreased. Opening of I KATP resulted in larger window of vulnerability. Conduction reserve was simulated based on 1D simulations for both rat and rabbit models. There was no difference between rat and rabbit conduction reserve. Our results showed that the simulation results are model-dependent, i.e., results from the rabbit model are similar to human clinical data, while the results from the rat model contradict human clinical observations, suggesting a significant species-dependence in arrhythmia vulnerability in the diabetic heart. PMID- 28656563 TI - Cutaneous Graft-Versus-Host Disease: Diagnosis and Treatment. AB - Graft-versus-host disease (GVHD) is an immunological reaction and a frequent complication following allogeneic hematopoietic stem cell transplantation. It is associated with high mortality rates and may have a significant negative impact on the patient's quality of life, particularly in the chronic-stage setting. Many different organs can be involved, which leads to a wide range of clinical manifestations. In this context, dermatologists play a key role by diagnosing and treating GVHD from the outset since cutaneous features are not just the most common but are also usually the presenting sign. Several skin-direct therapies are available and may be indicated as monotherapy or adjuvant treatment in order to allow faster tapering and withdrawal of systemic immunosuppression. Treatment of steroid-refractory patients remains a challenge and, to date, no consensus has been reached for one single agent in second-line therapy. This article aims to review skin involvement as well as provide and update discussion on therapeutic options for both acute and chronic cutaneous GVHD. PMID- 28656566 TI - In vitro comparison of two titanium dental implant surface treatments: 3MTMESPETM MDIs versus Ankylos(r). AB - BACKGROUND: An ideal implant should have a surface that is conducive to osseointegration. In vitro cell culture studies using disks made of same materials and surface as of implants may provide useful information on the events occurring at the implant-tissue interface. In the current study, we tested the hypothesis that there is no difference in the proliferation and differentiation capacities of osteoblastic cells when cultured on titanium disks mimicking the surface of 3MTMESPETM MDIs or standard (Ankylos(r)) implants. METHODS: Cells were grown on disks made of the same materials and with same surface texture as those of the original implants. Disks were sterilized and coated with 2% gelatin solution prior to the cell culture experiments. C2C12 pluripotent cells treated with 300 ng/ml bone morphogenetic protein 2 BMP-2 and a stably transfected C2C12 cell line expressing BMP2 were used as models for osteogenic cells. The Hoechst 33258-stained nuclei were counted to assay cell proliferation, while alkaline phosphatase (ALPL) immunostaining was performed to investigate osteogenic differentiation. MC3T3-E1 cells were cultured as model osteoblasts. The cells were differentiated and assayed for proliferation and metabolic activities by Hoechst 33258 staining and Alamar blue reduction assays, respectively. Additionally, cultures were stained by calcein to investigate their mineral deposition properties. RESULTS: Electron microscopy showed greater degree of roughness on the MDI surfaces. Nuclear counting showed significantly higher number of C2C12 cells on the MDI surface. Although immunostaining detected higher number of ALPL-positive cells, it was not significant when normalized by cell numbers. The number of MC3T3-E1 cells was also higher on the MDI surface, and accordingly, these cultures showed higher Alamar blue reduction. Finally, calcein staining revealed that the MC3T3-E1 cells grown on MDI surfaces deposited more minerals. CONCLUSIONS: Although both implant surfaces are conducive for osteoblastic cell attachment, proliferation, and extracellular matrix mineralization, cell proliferation is higher on MDI surfaces, which may in turn facilitate osseointegration via increased ECM mineralization. PMID- 28656567 TI - Varus-valgus instability in the anterior cruciate ligament-deficient knee: effect of posterior tibial load. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury is often accompanied with medial collateral ligament (MCL) injury. Assessment of varus-valgus (V-V) instability in the ACL-deficient knee is crucial for the management of the concomitant ACL-collateral ligaments injury. We evaluated the V-V laxity and investigated the effect of additional posterior tibial load on the laxity in the ACL-deficient knee. Our hypothesis was that the V-V laxity in the ACL-deficient knee was greater than that in the intact knee and attenuated by additional posterior tibial load. METHODS: Eight fresh-frozen porcine knees were used, and a 6 degrees -of-freedom (DOF) robotic system was utilized. A 5 Nm of V-V torque was applied to the intact knee, the ACL-deficient knee, and the ACL-deficient knee with 30 N of constant posterior tibial load, at 30 degrees and 60 degrees of flexion. Then, the 3D path in the intact knee was reproduced on the ACL-deficient knee. The total V-V angle under 5 Nm of V-V torque was assessed and compared among the three statuses. The in situ forces of the ACL under 5 Nm of varus and valgus torques, respectively, were also calculated. RESULTS: The total V-V angle in the ACL-deficient knee under 5 Nm of V-V torque was significantly greater than that in the intact knee, whereas the angle in the ACL-deficient knee with 30 N of posterior tibial load was significantly smaller than that in the ACL-deficient knee and approached that in the intact knee, at both 30 degrees and 60 degrees of flexion. The in situ force of the ACL was approximately 30 N at 30 degrees and 16 N at 60 degrees of flexion under 5 Nm of both varus and valgus torques. CONCLUSIONS: The V-V laxity in the isolated ACL-deficient knee was greater than that in the intact knee. The increased laxity was attenuated and approached that in the intact knee by adding posterior tibial load. Application of posterior tibial load is necessary for accurate assessment of V-V instability in the ACL deficient knee. Clinically, the V-V laxity in the combined ACL-MCL or ACL-LCL injured knee may be overestimated without posterior tibial load. PMID- 28656568 TI - Left atrial and left ventricular collapse secondary to pericardial effusion. PMID- 28656569 TI - Proximate composition and mineral contents in the body wall of two species of sea cucumber from Oman Sea. AB - The proximate composition and mineral contents of Stichopus horrens and Holothuria arenicola from Chabahar Bay were analyzed and investigated. During the present study, we aimed to demonstrate the nutritive value. The approximate percent composition of moisture, protein, fat, and ash were 92.8, 3.47, 0.4, and 3.33% in S. horrens and 93, 4.4, 0.6, and 2% in H. arenicola, respectively. Atomic absorption spectrophotometry of the ashes indicated the body wall of two species of sea cucumbers contained higher amounts of both macro minerals (92.5 mg/100 g Mg in S. horrens and 115 mg/100 g Mg in H. arenicola; 106.25 mg/100 g Ca in S. horrens and 83.25 mg/100 g Ca in H. arenicola) and trace elements (521.781 mg/100 g Fe in S. horrens; 60.354 mg/100 g Fe in H. arenicola, and 0.096 mg/100 g Zn in S. horrens; 0.04 mg/100 g Zn in H. arenicola). For both species, there were high content of protein and essential mineral. Also, they have low content of fat in the body wall of two species in the experiment. PMID- 28656570 TI - Simultaneous adsorption of Remazol brilliant blue and Disperse orange dyes on red mud and isotherms for the mixed dye system. AB - The paper presents the adsorption of Remazol brilliant blue (RBB) and Disperse orange 25 (DO25) dyes from aqueous solution of the mixture of dyes onto concentrated sulphuric acid-treated red mud (ATRM). First-order derivative spectrophotometric method was developed for the analysis of RBB and DO25 in mixed dye aqueous solution to overcome the limitations arising due to interference in the zero-order spectral method. The optimum conditions to maximize RBB adsorption favoured the adsorption of RBB, and those for DO25 favoured DO25 adsorption from the mixed dye aqueous solutions. Presence of a second dye always inhibited the adsorption of a target dye. The uptake and percentage adsorption of each of the dyes onto ATRM from the aqueous solution of the mixture of dyes decreased considerably with increasing concentrations of the other dye showing the antagonistic effect. Monocomponent Langmuir isotherm fitted the mixed dye adsorption equilibrium data better than the monocomponent Freundlich isotherm. However, monocomponent models are suitable for the fixed concentration of the other dye. Modified Langmuir isotherm model adequately predicted the multi component adsorption equilibrium data for RBB-DO25-ATRM adsorption system with a good accuracy and is more generic from the application point of view. PMID- 28656571 TI - Underlying mechanisms and effects of hydrated lime and selenium application on cadmium uptake by rice (Oryza sativa L.) seedlings. AB - A pot experiment was conducted to investigate the effects of selenium (Se) and hydrated lime (Lime), applied alone or simultaneously (Se+Lime), on growth and cadmium (Cd) uptake and translocation in rice seedlings grown in an acid soil with three levels of Cd (slight, mild, and moderate contamination). In the soil with 0.41 mg kg-1 Cd (slight Cd contamination), Se addition alone significantly decreased Cd accumulation in the root and shoot by 35.3 and 40.1%, respectively, but this tendency weakened when Cd level in the soil increased. However, Se+Lime treatment effectively reduced Cd accumulation in rice seedlings in the soil with higher Cd levels. The results also showed that Se application alone strongly increased Cd concentration in the iron plaque under slight Cd contamination, which was suggested as the main reason underlying the inhibition of Cd accumulation in rice seedlings. Se+Lime treatment also increased the ability of the iron plaques to restrict Cd uptake by rice seedlings across all Cd levels and dramatically decreased the available Cd concentration in the soil. These results suggest that Se application alone would be useful in the soil with low levels of Cd, and the effect would be enhanced when Se application is combined with hydrated lime at higher Cd levels. PMID- 28656572 TI - The use of ultrasound-assisted anaerobic compost tea washing to remove poly chlorinated dibenzo-p-dioxins (PCDDs), dibenzo-furans (PCDFs) from highly contaminated field soils. AB - The remediation of dioxin-contaminated soil of a specific coastal area previously employed for the manufacture of pentachlorophenol (PCP) in southern Taiwan's Tainan City has attracted much attention of researchers there. This work addresses the possibility of providing an effective and environmentally friendly option for removing PCDD/Fs from soil in that field. Soil screening/sieving was first conducted to assess particle distribution. Fine sand was observed to be the major component of the soil, accounting for more than 60% of the total mass. A combination of ultrasonification and mechanical double-blade agitation was used to facilitate the washing of the soil using the biosurfactant anaerobic compost tea. More than 85 and 95% of total removal efficiencies were achieved for moderately and highly contaminated soils after 6 and 10 washing cycles, respectively, under ambient temperature, a soil/liquid ratio 1:2.5, 700 rpm, and over a relatively short duration. These results were achieved through the collision and penetration effects of this combined treatment as well as PCDD/F partitioning between the particles and anaerobic compost tea. This study represents the first to report the use of anaerobic compost tea solvent to wash soil highly contaminated by dioxin. It was concluded that anaerobic compost tea, rich in non-toxic bio-surfactants (e.g., alcohols, humic acids), can be used to improve bioavailability and bioactivity of the soil making bio-attenuation and full remediation more efficient. PMID- 28656573 TI - Effect of tea saponin on phytoremediation of Cd and pyrene in contaminated soils by Lolium multiflorum. AB - Tea saponin (TS), a kind of green biosurfactant produced by plants, was added into the Cd-pyrene co-contaminated soils to evaluate its influence on phytoremediation of Cd and pyrene by Lolium multiflorum. The results showed that the accumulation of pyrene in L. multiflorum was significantly promoted by the TS. Compared with no TS treatments (PL and ML), the aboveground concentrations of pyrene in TS treatments (PLT and MLT) increased by 135 and 30%, respectively, and the underground concentrations of pyrene in TS treatments (PLT and MLT) increased by 40 and 25%. The concentrations of Cd in the aboveground and underground parts in single contaminated treatments were all significantly more than those in co contaminated treatments, while the situation of pyrene was quite the reverse. Besides, the addition of TS enhanced activities of dehydrogenase and polyphenol oxidase in soils and increased the biomass of L. multiflorum. The micromorphology of L. multiflorum was not affected by TS. The study suggests that the use of L. multiflorum with TS is an alternative technology for remediation of Cd-pyrene co contaminated soils. PMID- 28656574 TI - Impact of O3 or O3/H2O2 treatment via a membrane contacting system on the composition and characteristics of the natural organic matter of surface waters. AB - The present study aims to evaluate changes in the structure-composition of natural organic matter (NOM) that occur after the application of bubbleless ozonation or peroxone treatment of surface waters. The oxidation experiments (using 0.5-2 mg O3/mg DOC, or 2:1 O3:H2O2 molar ratio) were performed in a continuous mode, using a tubular ceramic membrane contactor. Fluorescence spectroscopy (emission-excitation matrix) and liquid chromatography-organic carbon detection (LC-OCD) were mainly used for the detailed DOC characterization. In brief, the application of single ozonation resulted to high reduction of humic like peak fluorescence intensities (50-85%) and also to the formation of two new peaks in the region of protein-like components. The co-addition of H2O2 did not present the anticipated increase in the reduction of fluorescence intensity; however, it resulted to the further oxidation of protein-like fluorophores. LC OCD measurements confirmed the decrease of average molecular weight of NOM during ozone treatment, due to the gradual degradation of biopolymers (14-23%) and humic substances (11-17%) towards building blocks and low molecular weight (LMW) neutrals. Advanced oxidation process (AOP) treatment by the mixture O3/H2O2 resulted in the simultaneous decrease of building blocks and LMW neutral concentrations. Conventional batch ozonation and AOP experiments were conducted using ozone-saturated solutions to investigate the effect of different contacting patterns. The results revealed that the different reaction pathways followed during bubbleless and conventional batch experiments may also influence the formation of NOM oxidation intermediates. PMID- 28656576 TI - Carbon-dioxide biofixation and phycoremediation of municipal wastewater using Chlorella vulgaris and Scenedesmus obliquus. AB - The pure cultures of microalgae Chlorella vulgaris ATCC 13482 and Scenedesmus obliquus FACHB 417 were grown in municipal wastewater in 7-L airlift bubble column photobioreactor supplied with 5% CO2/air (v/v). Batch experiments were conducted at 25 degrees C with 14-h light/10-h dark cycle for a period of 10 days. The CO2 capture efficiencies for both the microalgae were monitored in terms of their respective biomass productivities, carbon contents, and CO2 consumption rates. In the present study, the initial concentration of ammonia (43.7 mg L-1) was decreased to 2.9 and 3.7 mg L-1 by C. vulgaris and S. obliquus, respectively. And, the initial concentration of phosphate (18.5 mg L-1) was decreased to 1.1 and 1.6 mg L-1 by C. vulgaris and S. obliquus, respectively. CO2 biofixation rates by C. vulgaris and S. obliquus, cultivated in municipal wastewater, were calculated to be 140.91 and 129.82 mg L-1 day-1, respectively. The findings from the present study highlight the use of microalgae for wastewater treatment along with CO2 uptake and biomass utilization for pilot scale production of biodiesel, biogas, feed supplements for animals, etc., thus minimizing the production costs. PMID- 28656575 TI - Uptake of PAHs by cabbage root and leaf in vegetable plots near a large coking manufacturer and associations with PAHs in cabbage core. AB - Samples of ambient air (including gaseous and particulate phases), dust fall, surface soil, rhizosphere soil, core (edible part), outer leaf, and root of cabbage from eight vegetable plots near a large coking manufacturer were collected during the harvest period. Concentrations, compositions, and distributions of parent PAHs in different samples were determined. Our results indicated that most of the parent PAHs in air occurred in the gaseous phase, dominated by low molecular weight (LMW) species with two to three rings. Specific isomeric ratios and principal component analysis were employed to preliminarily identify the local sources of parent PAHs emitted. The main emission sources of parent PAHs could be apportioned as a mixture of coal combustion, coking production, and traffic tailing gas. PAH components with two to four rings were prevailing in dust fall, surface soil, and rhizosphere soil. Concentrations of PAHs in surface soil exhibited a significant positive correlation with topsoil TOC fractions. Compositional profiles in outer leaf and core of cabbage, dominated by LMW species, were similar to those in the local air. Overall, the order of parent PAH concentration in cabbage was outer leaf > root > core. Partial correlation analysis and multivariate linear stepwise regression revealed that PAH concentrations in cabbage core were closely associated with PAHs present both in root and in outer leaf, namely, affected by adsorption, then absorption, and translocation of PAHs from rhizosphere soil and ambient air, respectively. PMID- 28656577 TI - Ecological risk assessment of heavy metals and polycyclic aromatic hydrocarbons in sediments of rivers Niger and Benue confluence, Lokoja, Central Nigeria. AB - The concentrations of six heavy metals (HMs) and 16 US EPA priority polycyclic aromatic hydrocarbons (PAHs) in sediment samples of the confluence of rivers Niger and Benue were investigated. The ecological risk assessment of the contaminants was carried out. The results showed that the sediment samples were heavily polluted with iron and moderately polluted with Cd while other metals posed no pollution problem when compared with USEPA sediment quality guidelines. Only six out of the 16 priority PAHs were detected in the samples, and source apportionment of the PAHs indicated that they are of pyrogenic origin. The ?PAHs in the samples were lower than many of similar studies and were of no pollution risk. The ecological risk assessment result of the heavy metals showed that the sediments were of considerable risk due majorly to Cd levels. The HM concentration results statistically showed significant difference between seasons at probability value (P < .05). Data analysis by PCA classified the metals into three different components according to sources. The levels of HMS and PAHs detected in the sediments were correlated for source identification, and the correlation showed that the majority of the pollutants were mainly from anthropogenic sources. There is increasing level of anthropogenic activities at the vicinity of the confluence due to urbanization which may call for periodic monitoring of the sediment quality. PMID- 28656578 TI - Water-effect ratio of copper and its application on setting site-specific water quality criteria for protecting marine ecosystems of Hong Kong. AB - Generic water quality criteria (WQC) of a chemical are usually set based on results generated from toxicity tests which were conducted using standard laboratory water with well-controlled physiochemical properties. However, in natural aquatic environments, physiochemical characteristics, such as salinity, total suspended solid, total organic carbon and the co-existence of chemical contaminants, often vary spatially and temporally. These parameters can, in turn, alter the bioavailability of target chemicals and, thus, influence their toxicity to marine organisms. To account for site specificity, the US Environmental Protection Agency's water-effect ratio (WER = site water-LC50 / laboratory water LC50) procedure can be applied to derive site-specific WQC. Most past studies, however, were conducted for freshwater systems. Here, for the first time, the WER of copper (Cu) was determined for three marine water control zones (WCZs) in Hong Kong: Victoria Harbour, Deep Bay and Southern WCZs. Samples of water were collected from three locations within each WCZ, while acute toxicities to the marine diatom Skeletonema costatum, intertidal copepod Tigriopus japonicus and larvae of marine medaka Oryzias melastigma were determined in site or laboratory (artificial seawater) waters. Results of this study showed that conservative final WER relative coefficients for Cu ranged from 0.57 to 0.73 for the three WCZs, and water from some locations caused >30% mortality in the fish larvae in the controls (without Cu addition). These results suggested that current generic WQC for Cu are likely under-protective for marine organisms in the three areas, and it should be tightened by multiplying it with site-specific WER to offer better protection to marine biodiversity and integrity of the ecosystem. PMID- 28656579 TI - Distribution and human health risk assessment of PAHs in four fish species from a SW Atlantic estuary. AB - The aim of this study is to assess-for the first time-the concentration of the 16 polycyclic aromatic hydrocarbons (PAHs) in the muscle tissues of four fish species (Micropogonias furnieri, Cynoscion guatucupa, Ramnogaster arcuata, and Mustelus schmitti) from Bahia Blanca estuary, Argentina and to evaluate their sources, distribution, and the human health risks implicated. Considering the four species under study, mean total PAH concentrations showed the following decreasing accumulation trend: M. schmitti, R. arcuata, C. guatucupa, and M. furnieri. Low molecular weight PAHs, such as naphthalene and phenanthrene, were generally predominant, displaying properties of PAH mixtures generated from petrogenic pollution. Of the four fish species analyzed, M. furnieri was the only one that did not raise any human consumption warning. In the case of the other species, exceeding values were found above the safety human consumption guidelines. Nevertheless, the screening criteria for carcinogenic PAHs proposed by the USEPA indicated a good quality status for these fish species. PMID- 28656580 TI - Potential lung carcinogenicity induced by chronic exposure to PM2.5 in the rat. AB - Exposure to fine particulate matter (PM2.5) may increase lung cancer risk, but the underlying mechanisms are poorly understood. This study explored the potential carcinogenicity in rat lung induced by chronic exposure to PM2.5. Adult male rats (200-220 g) were treated with PM2.5 (10 mg/kg body weight) by tracheal perfusion once per week for 1 year; the rats were killed, and expression of tumor markers (carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), squamous cell carcinoma antigen (SCCA)), cancer-related genes, and pathological changes were detected. Chronic treatment with PM2.5 significantly increased SCCA and NSE expression in rat lung tissue and serum. Damaged lung tissue structure was observed by hematoxylin and eosin staining. Although no evidence of tumors was detected, the Wnt/beta-catenin signaling, epithelial-mesenchymal transition, vascular endothelial growth factor, and epidermal growth factor receptor pathways were all activated or overexpressed and likely involved in the potential carcinogenicity in the rat model. Additionally, abnormal expression of the proto oncogenes c-Myc and K-Ras and tumor suppressor p53 can be seen in lung tissue induced by PM2.5 exposure. Chronic exposure to PM2.5 has the potential to be carcinogenic in rat lung. PMID- 28656581 TI - Optimization of sampling strategy to determine pathogen removal efficacy of activated sludge treatment plant. AB - Large-scale wastewater schemes rely on multi-barrier approach for the production of safe and sustainable recycled water. In multi-barrier wastewater reclamation systems, conventional activated sludge process (ASP) often constitutes a major initial treatment step. The main aim of this research was to determine most appropriate sampling approach to establish pathogen removal efficacy of ASP. The results suggest that ASP is capable of reducing human adenovirus (HAdV) and polyomavirus (HPyV) by up to 3 log10. The virus removal data suggests that HAdV removal is comparable to somatic bacteriophage belonging to Microviridae family. Due to the high removal of Escherichia coli (>3 log10) and very poor correlation with the enteric virus, it is not recommended that E. coli be used as a surrogate for enteric virus removal. The results also demonstrated no statistically significant differences (t test, P > 0.05) in calculated log removal values (LRVs) for HAdV, HPyV, and Microviridae from samples collected on hydraulic retention time (HRT) or simultaneous paired samples collected for influent and effluent. This indicates that a more practical approach of simultaneous sampling for influent and effluent could be used to determine pathogen removal efficiency of ASP. The results also suggest that a minimum of 10, preferably 20 samples, are required to fully capture variability in the removal of virus. In order to cover for the potential seasonal prevalence of viruses such as norovirus and rotavirus, sampling should be spread across all seasons. PMID- 28656582 TI - An historical perspective of the discovery of titin filaments. AB - This review takes readers back to 1949, when two Australian scientists, Draper and Hodge, reported the first high-resolution electron microscopy images of striated muscle. In 1953, Jean Hanson and Hugh Huxley published phase-contrast microscopy and electron microscopy images that established the filamentous nature of the sarcomere, namely the myosin-containing thick filaments and actin containing thin filaments. They discussed a putative third filament system, possibly a thinner actin-containing S filament, that appeared to connect one Z disc to the next. The next year, two back-to-back papers appeared in Nature, the first by Andrew Huxley and Rolf. Niedergerke, the second by Hugh Huxley with Jean Hanson. Independently, they proposed the sliding of actin filaments and myosin filaments. These two filaments quickly became firmly established in the literature and, even today, they remain the basis for the sliding filament hypothesis. The putative third filament concept was dropped, mainly through the lack of evidence but also because it was difficult to accommodate in the hypothesis where two sets of filaments maintained their lengths constant while sliding produced sarcomere shortening. The view that actin and myosin comprise more than 80% of the myofibril proteins also made it difficult to accommodate a major new protein. In the following years, using selective extraction of myosin and actin, dos Remedios (PhD thesis, University of Sydney, 1965) revealed a residual filament system in the sarcomere, and, once again, a third filament system re-entered the literature. Filaments were reported crossing the gap between the ends of thick and thin filaments in highly stretched muscle fibres. These and other early studies necessarily focussed on light and electron microscopy, and set the scene for investigations into the chemical nature and biophysical functions of the third filament system for striated muscles. Further progress had to wait for the improvement and/or development of a number of techniques. For example, in 1970, Laemmli (Nature 227:680-685, 1970) published an often cited method for improving SDS polyacrylamide gel electrophoresis. The Lowry et al. (J Biol Chem 193:265-275, 1951) protein assay method developed in 1950 was both unstable and insensitive in comparison, but we had to wait until 1976 for the development of the Bradford method (1976). Atomic force microscopy was not known before 1986, but it eventually enabled the direct measurement of single molecules of titin. This extraordinarily large (>106 Da) elastic protein became known as connectin (Maruyama in J Biochem 80:405-407, 1976) and was subsequently named titin (Wang et al. in Proc Natl Acad Sci U S A 76:3698-3702, 1979). Prior to the discovery of titin/connectin, biophysicists found it difficult to understand how a single polypeptide chain could could stretch from the Z disc to the M line, a distance of more than 1 MUm. It was quite literally the 'elephant in the room'. In this review, we follow the trail of microscopy based reports that led to the emergence of what is now known and accepted as titin, an elastic third filamentous protein that is the focus of this Special Issue. PMID- 28656583 TI - Decellularization of Intact Lung Tissue Through Vasculature and Airways Using Negative and Positive Pressure. AB - Decellularization allows the production of extracellular matrix (ECM) scaffolds. Here we describe the use of combined positive pressure and negative pressure to drive decellularization reagents into the vasculature and airways, respectively, of structurally intact lungs in order to remove cells and cellular material leaving an intact ECM scaffold. PMID- 28656584 TI - Case-control study of risk factors for surgical site infection after three-column osteotomy for spine deformity. AB - AIM: To investigate risk factors for surgical site infection (SSI) after three column osteotomy (3CO) for spinal deformity. MATERIAL AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database (2012 2014) was reviewed. We included adult patients who underwent 3CO and compared pertinent cases (SSI) to controls (no SSI) in terms of preoperative and operative characteristics. Patients with clean/contaminated, contaminated, and dirty/infected wounds were excluded. A stepwise multivariate regression was used to identify independent predictors of SSI, with results presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: There were 293 patients who underwent 3CO for spinal deformity, out of whom 15 (5.1%) developed a SSI during the 30-day follow-up period. Of the 15 patients with SSI, 10 underwent reoperation (66.7%) within 30 days. Compared to controls, patients in the SSI group were more likely to be obese (p=0.030), have a higher ASA (American Society of Anesthesiologists physical status) class (p=0.051) and be more likely to undergo multilevel 3CO (p=0.013). After controlling for obesity, bleeding disorder, deformity type, ASA class, preoperative anemia, and multilevel procedures, Class II Obesity (OR 4.98; 95% CI, 1.24 - 19.94; p=0.023) and multilevel 3CO (OR 4.71; 95% CI, 1.30 - 16.94; p=0.018) were significant predictors of SSI occurrence. CONCLUSION: The findings in this study suggest that patients with Class II Obesity and patients who undergo multilevel osteotomy may be at a significantly increased risk of developing a SSI within 30 days after 3CO for spine deformity. PMID- 28656585 TI - A survey of the experiences of families with bereavement support services following a perinatal loss. AB - BACKGROUND: Although there are many studies that explore complicated grief, no studies have examined the impact of bereavement support services on the progression to complicated grief. The aims of our study were to describe the types of bereavement services utilised by families who have experienced a perinatal loss, and explore the impact of these services on the families' bereavement journey. METHODS: Women who experienced a perinatal loss were sent a survey consisting of the modified Perinatal Post Traumatic Stress Disorder (PTSD) questionnaire, items addressing use of bereavement services, and the Inventory of Complicated Grief. Respondents also provided free-text comments. RESULTS: Forty seven women were included in the study (34% response rate); 75% had a perinatal PTSD score which indicated the need for support from mental health services and 75% accessed services. Forty-three percent met the criteria for complicated grief. Women whose PTSD scores were in the highest quartile were most likely to access services; 45% of surveyed women used SIDS and Kids of the Australian Capital Territory (SKACT) accessing counselling (90%), support groups (50%), playgroups (15%) and the helpline (10%). Fifty-seven percent of women surveyed accessed non-SKACT services and predominantly used psychologists (66%) and general practitioners (30%). Requests were made for grief training of hospital staff, and for referral to bereavement services to be offered after hospital discharge. CONCLUSIONS: Following a perinatal loss, a high proportion of women had high PTSD scores and complicated grief despite utilising local bereavement services. Our findings support the continuation of current support services with modifications that may potentially improve recovery following a perinatal loss. PMID- 28656586 TI - PSA-NCAM expression in the teleost optic tectum is related to ecological niche and use of vision in finding food. AB - In this study, tangential migration and neuronal connectivity organization were analysed in the optic tectum of seven different teleosts through the expression of polysialylated neural cell adhesion molecule (PSA-NCAM) in response to ecological niche and use of vision. Reduced PSA-NCAM expression in rainbow trout Oncorhynchus mykiss optic tectum occurred in efferent layers, while in pike Esox lucius and zebrafish Danio rerio it occurred in afferent and efferent layers. Zander Sander lucioperca and European eel Anguilla anguilla had very low PSA-NCAM expression in all tectal layers except in the stratum marginale. Common carp Cyprinus carpio and wels catfish Silurus glanis had the same intensity of PSA NCAM expression in all tectal layers. The optic tectum of all studied fishes was also a site of tangential migration with sustained PSA-NCAM and c-series ganglioside expression. Anti-c-series ganglioside immunoreactivity was observed in all tectal layers of all analysed fishes, even in layers where PSA-NCAM expression was reduced. Since the optic tectum is indispensable for visually guided prey capture, stabilization of synaptic contact and decrease of neurogenesis and tangential migration in the visual map are an expected adjustment to ecological niche. The authors hypothesize that this stabilization would probably be achieved by down-regulation of PSA-NCAM rather than c-series of ganglioside. PMID- 28656587 TI - Allele-specific polymerase chain reaction for the detection of single nucleotide polymorphism in amlodipine-induced gingival enlargement. AB - WHAT IS KNOWN AND OBJECTIVE: Studies indicate that there is an increased serum concentration of amlodipine (a calcium channel blocker used to treat hypertension and angina) in patients having mutant multidrug resistance 1 (MDR1) gene. Hence, genetic factors may play a very significant role in amlodipine-induced complications including gingival enlargement. CASE DESCRIPTION: Three patients with amlodipine-induced gingival enlargement showed improvement following drug substitution of amlodipine with enalapril (an angiotensin-converting enzyme inhibitor) and non-invasive periodontal therapy. Using allele-specific polymerase chain reaction, single nucleotide polymorphism of MDR1 gene of heterozygous mutant type (CT genotype) was identified in all three cases. WHAT IS NEW AND CONCLUSION: Drug-induced complications can potentially be a result of genetic factors, in combination with various local and systemic factors. Identifying genetic polymorphisms early might help predict adverse reactions and determine prognosis. PMID- 28656588 TI - Allergic contact dermatitis caused by (meth)acrylates in long-lasting nail polish - are we facing a new epidemic in the beauty industry? AB - BACKGROUND: Allergic contact dermatitis (ACD) caused by (meth)acrylates has been described both in occupational and in non-occupational settings. OBJECTIVES: To evaluate the clinical patterns, the most frequent allergens and the prognosis in patients sensitized to (meth)acrylates in long-lasting nail polish. METHODS: The files of patients with ACD caused by (meth)acrylates in long-lasting nail polish diagnosed between January 2013 and June 2016 in four dermatology departments in Spain were reviewed. Patients were followed up by telephone interview. RESULTS: Overall, 2353 patients were patch tested. Forty-three (1.82%) were diagnosed with ACD caused by (meth)acrylates in long-lasting nail polish during that period; all were female, and all had hand dermatitis. Patients were mostly less than 40 years old (72.1%), non-atopic (95.4%) and had an occupational cause of their dermatitis (93%), which developed ~10.1 months after they had started to use this technique. The most frequent positive allergens were: 2-hydroxypropyl methacrylate, 2 hydroxyethyl methacrylate, and tetrahydrofurfuryl methacrylate. Eight of the 22 interviewed patients were able to improve their working technique and used 4H(r) protective material (fingerstalls/gloves). CONCLUSIONS: Long-lasting nail polishes have become widespread, and it is a matter of concern that we may be facing a new epidemic of ACD caused by these. Policies regulating their use are urgently needed. PMID- 28656589 TI - The prognostic value of a trend in modified SOFA score for patients with hematological malignancies in the intensive care unit. AB - BACKGROUND: Patients with hematological malignancies admitted to an intensive care unit (ICU) have a poor prognosis. The Sequential Organ Failure Assessment (SOFA) score is used to monitor patients on the ICU. Little is known about the value of this score in hematology patients. Therefore, the prognostic value of the SOFA score and a modified hematological SOFA score (SOFAhem) was studied. METHODS: Patients with hematological malignancies admitted to the ICU between 1999 and 2009 were analyzed in a retrospective cohort study. The SOFAhem score was defined as the original SOFA score omitting the coagulation and neurological parameters. RESULTS: In 149 admissions, ICU mortality was 52%. Mortality was significantly associated with higher SOFA and SOFAhem scores on admission, and trend in SOFAhem scores. An unchanged and increased SOFAhem score compared to decreasing SOFAhem scores was associated with a higher mortality rate (53% resp 67% resp 25%). CONCLUSIONS: Trends in SOFA or SOFAhem score are both suitable as prognostic parameter. The trend in SOFAhem score seems to be independently related to mortality in hematological patients admitted to the ICU, and because of the higher odds ratios and lower P-values compared to the SOFA score, it is probably stronger related to mortality than the classical score, but its prognostic value should be tested in a larger cohort. PMID- 28656590 TI - The advantages of live/real-time three-dimensional echocardiograhy in the assessment of left ventricular myxoma, which causes partial left ventricular outflow tract obstruction. AB - Myxomas are the most common cardiac primary tumors; however, left ventricular myxomas are extremely rare. We describe a young female patient with a giant left ventricular myxoma causing partial obstruction of the left ventricular outflow tract, who underwent successful surgical resection. Real-time three-dimensional echocardiography yielded incremental value to two-dimensional echocardiography by allowing better assess of the true size, extent, attachment, and morphology of the tumor. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:273-277, 2018. PMID- 28656591 TI - The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status. AB - BACKGROUND: The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. METHODS: Seventeen women with type 1 diabetes mellitus (T1DM) and nine age-matched healthy women with a median age of 22.6 years (range, 17.4, 23.8) were studied by 3T MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity (BMA). Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). RESULTS: Although women with T1DM had similar BMI and BMA to the controls, they had higher visceral and subcutaneous adiposity on MRI (P<.05) and total body FM by DXA (P=.03). Overall, in the whole cohort, a clear inverse association was evident between BMA and BMD at all sites (P<.05). These associations remained significant after adjusting for age, BMI, FM and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with BMA (r, .4, P=.03), and a negative association with total body BMD (r, .5, P=.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r, -.4, P=.04). CONCLUSION: Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured BMA and DXA-based assessment of BMD. Furthermore, an association between BMA and visceral adiposity supports the notion of a common origin of these two fat depots. PMID- 28656592 TI - Percentage arterial enhancement: An objective index for accurate identification of parathyroid adenoma/hyperplasia in primary hyperparathyroidism. AB - BACKGROUND: Radiation exposure to neck by four-dimensional computerized tomography (4DCT) is relatively high and limits its use as a first-line investigation in evaluation of primary hyperparathyroidism (PHPT). Radiation exposure can be reduced by restricting the number of CT phases. Our aim was to study the performance of 4DCT in cohort of surgery-naive PHPT patients, and to evaluate percentage enhancement as an objective radiological index to discriminate parathyroid lesions (adenoma/hyperplasia) from thyroid tissue and lymph nodes. MATERIALS AND METHOD: Retrospective study of 49 PHPT patients {(44 single-gland diseases (SGD) and five multiple-gland disease (MGD)} who underwent 4DCT (unenhanced, early arterial, early venous and delayed venous phase) pre operatively. Two radiologists who were blinded to surgical location of parathyroid lesions examined the scans. Attenuation values were recorded for parathyroid lesions (n=50), thyroid gland (n=50) and lymph nodes (n=12) in different phases. Percentage enhancement for different phases was calculated as "(HU in a specific enhanced phase-HU in unenhanced phase)/HU in unenhanced phase" *100. RESULTS: Inter-rater reliability between the two radiologists was 0.83 (Cohen's kappa). In SGD, sensitivity and PPV were 93.18% and 98.8% for lateralization, and 89.77% and 95.18% for quadrant localization, respectively. In MGD, 4DCT showed 50% sensitivity and 100% PPV. Percentage arterial enhancement showed highest area under curve (AUC=0.992) for differentiation of parathyroid lesions from thyroid tissue and lymph nodes. A cut-off value of 128.9% showed 95.8% sensitivity and 100% specificity for the identification of parathyroid lesions. CONCLUSIONS: We propose that percentage arterial enhancement can be used as an objective radiological index for accurate identification of parathyroid adenoma/hyperplasia. PMID- 28656594 TI - Review of Garcinia mangostana and its Xanthones in Metabolic Syndrome and Related Complications. AB - Metabolic syndrome is coexistence of abdominal obesity, hyperglycemia, hyperlipidemia and hypertension that causes cardiovascular diseases, diabetes and their complications, low quality and short lifespan. Garcinia mangostana and its xanthones such as alpha-mangostin have been shown desirable effects such as anti obesity, anti-hyperglycemic, anti-dyslipidemia, anti-diabetic and antiinflammatory effects in experimental studies. Various databases such as PubMed, Scopus and Web of Science with keywords of 'Garcinia mangostana', 'mangosteen', 'alpha-mangostin', 'metabolic syndrome', 'hypoglycemic', 'antihyperglicemic', 'antidiabetic', 'hypotensive', 'antihypertensive', 'atherosclerosis', 'arteriosclerosis' and 'hyperlipidemia' have been investigated in this search without publication time limitation. This study reviewed all pharmacological effects and molecular pathways of G. mangostana and its xanthones in the management of metabolic syndrome and its complications in in-vitro and in vivo studies. Based on these studies, mangosteen and its xanthones have good potential to design human studies for controlling and modification of metabolic syndrome and its related disorders such as obesity, disrupted lipid profile, diabetes and its complications. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28656593 TI - The Post-Deployment Mental Health (PDMH) study and repository: A multi-site study of US Afghanistan and Iraq era veterans. AB - The United States (US) Department of Veterans Affairs (VA) Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Post-Deployment Mental Health (PDMH) multi-site study examines post-deployment mental health in US military Afghanistan/Iraq-era veterans. The study includes the comprehensive behavioral health characterization of over 3600 study participants and the genetic, metabolomic, neurocognitive, and neuroimaging data for many of the participants. The study design also incorporates an infrastructure for a data repository to re-contact participants for follow-up studies. The overwhelming majority (94%) of participants consented to be re-contacted for future studies, and our recently completed feasibility study indicates that 73-83% of these participants could be reached successfully for enrollment into longitudinal follow-up investigations. Longitudinal concurrent cohort follow-up studies will be conducted (5-10+ years post-baseline) to examine predictors of illness chronicity, resilience, recovery, functional outcome, and other variables, and will include neuroimaging, genetic/epigenetic, serum biomarker, and neurocognitive studies, among others. To date, the PDMH study has generated more than 35 publications from the baseline data and the repository has been leveraged in over 20 publications from follow-up studies drawing from this cohort. Limitations that may affect data collection for a longitudinal follow-up study are also presented. PMID- 28656595 TI - Alloy-Based Anode Materials toward Advanced Sodium-Ion Batteries. AB - Sodium-ion batteries (SIBs) are considered as promising alternatives to lithium ion batteries owing to the abundant sodium resources. However, the limited energy density, moderate cycling life, and immature manufacture technology of SIBs are the major challenges hindering their practical application. Recently, numerous efforts are devoted to developing novel electrode materials with high specific capacities and long durability. In comparison with carbonaceous materials (e.g., hard carbon), partial Group IVA and VA elements, such as Sn, Sb, and P, possess high theoretical specific capacities for sodium storage based on the alloying reaction mechanism, demonstrating great potential for high-energy SIBs. In this review, the recent research progress of alloy-type anodes and their compounds for sodium storage is summarized. Specific efforts to enhance the electrochemical performance of the alloy-based anode materials are discussed, and the challenges and perspectives regarding these anode materials are proposed. PMID- 28656596 TI - If I do not have enough water, then how could I bring additional water for toilet cleaning?! Addressing water scarcity to promote hygienic use of shared toilets in Dhaka, Bangladesh. AB - OBJECTIVES: Provision of toilets is necessary but not sufficient to impact health as poor maintenance may impair toilet function and discourage their consistent use. Water in urban slums is both scarce and a prerequisite for toilet maintenance behaviours. We describe the development of behaviour change communications and selection of low-cost water storage hardware to facilitate adequate flushing among users of shared toilets. METHODS: We conducted nine focus group discussions and six ranking exercises with adult users of shared toilets (50 females, 35 males), then designed and implemented three pilot interventions to facilitate regular flushing and improve hygienic conditions of shared toilets. We conducted follow-up assessments 1 and 2 months post-pilot including nine in depth interviews and three focus group discussions with adult residents (23 females, 15 males) and three landlords in the pilot communities. RESULTS: Periodic water scarcity was common in the study communities. Residents felt embarrassed to carry water for flushing. Reserving water adjacent to the shared toilet enabled slum residents to flush regularly. Signs depicting rules for toilet use empowered residents and landlords to communicate these expectations for flushing to transient tenants. Residents in the pilot reported improvements in cleanliness and reduced odour inside toilet cubicles. CONCLUSIONS: Our pilot demonstrates the potential efficacy of low-cost water storage and behaviour change communications to improve maintenance of and user satisfaction with shared toilets in urban slum settings. PMID- 28656597 TI - Adherens junctions and desmosomes are damaged by Entamoeba histolytica: Participation of EhCPADH complex and EhCP112 protease. AB - Entamoeba histolytica trophozoites adhere to epithelium at the cell-cell contact and perturb tight junctions disturbing the transepithelial electrical resistance. Behind tight junctions are the adherens junctions (AJs) that reinforce them and the desmosomes (DSMs) that maintain the epithelium integrity. The damage produced to AJs and DMSs by this parasite is unknown. Here, we studied the effect of the trophozoites, the EhCPADH complex, and the EhCP112 recombinant enzyme (rEhCP112) on AJ and DSM proteins. We found that trophozoites degraded beta-cat, E-cad, Dsp l/ll, and Dsg-2 with the participation of EhCPADH and EhCP112. After contact of epithelial cells with trophozoites, immunofluorescence and transmission electron microscopy assays revealed EhCPADH and rEhCP112 at the intercellular space where they colocalised with beta-cat, E-cad, Dsp l/ll, and Dsg-2. Moreover, our results suggested that rEhCP112 could be internalised by caveolae and clathrin-coated vesicles. Immunoprecipitation assays showed the interaction of EhCPADH with beta cat and Dsp l/ll. Besides, in vivo assays demonstrated that rEhCP112 concentrates at the cellular borders of the mouse intestine degrading E-cad and Dsp I/II. Our research gives the first clues on the trophozoite attack to AJs and DSMs and point out the role of the EhCPADH and EhCP112 in the multifactorial event of trophozoites virulence. PMID- 28656598 TI - Sugar Blowing-Induced Porous Cobalt Phosphide/Nitrogen-Doped Carbon Nanostructures with Enhanced Electrochemical Oxidation Performance toward Water and Other Small Molecules. AB - Rational design of high active and robust nonprecious metal catalysts with excellent catalytic efficiency in oxygen evolution reaction (OER) is extremely vital for making the water splitting process more energy efficient and economical. Among these noble metal-free catalysts, transition-metal-based nanomaterials are considered as one of the most promising OER catalysts due to their relatively low-cost intrinsic activities, high abundance, and diversity in terms of structure and morphology. Herein, a facile sugar-blowing technique and low-temperature phosphorization are reported to generate 3D self-supported metal involved carbon nanostructures, which are termed as Co2 P@Co/nitrogen-doped carbon (Co2 P@Co/N-C). By capitalizing on the 3D porous nanostructures with high surface area, homogeneously dispersed active sites, the intimate interaction between active sites, and 3D N-doped carbon, the resultant Co2 P@Co/N-C exhibits satisfying OER performance superior to CoO@Co/N-C, delivering 10 mA cm-2 at overpotential of 0.32 V. It is worth noting that in contrast to the substantial current density loss of RuO2 , Co2 P@Co/N-C shows much enhanced catalytic activity during the stability test and a 1.8-fold increase in current density is observed after stability test. Furthermore, the obtained Co2 P@Co/N-C can also be served as an excellent nonprecious metal catalyst for methanol and glucose electrooxidation in alkaline media, further extending their potential applications. PMID- 28656599 TI - Sleep complaints are associated with frailty in Mexican older adults in a rural setting. AB - AIM: The aim of the present study was to examine the association between sleep complaints and frailty status in a cohort of older adults from rural Mexico, and determine if this association varies according to sex. METHODS: A cross-sectional study was carried out on a total of 591 community-dwelling adults aged >=70 years in rural settings of Mexico. Sleep complaints were based on self-reported sleep problems. Frailty status was assessed according to the Fried et al. proposal, as well as general health measurements taken from participants. Multivariate logistic regression was used to analyze the association between sleep complaints and frailty. RESULTS: Frail participants accounted for 10.7% of the study sample. After adjusting for potential confounders, sleep complaints were associated with increased odds of frailty in women (OR 3.24, 95% CI 1.34-7.84), but not in men (OR 0.76, 95% CI 0.23-2.51). CONCLUSIONS: In this cohort of rural Mexican older adults, sleep complaints were associated with frailty in older women. Because sleep quality is potentially remediable, future frailty prevention interventions should take sleep complaints into account. Geriatr Gerontol Int 2017; 17: 2573 2578. PMID- 28656600 TI - Evaluation of whole-blood conservation reagents for Hematoflow-based WBC differential count: Unsatisfactory results. PMID- 28656602 TI - Rapid response team calls to obstetric patients in a busy quaternary maternity hospital. AB - AIMS: There is limited published information regarding intensive care unit (ICU) led rapid response team (RRT) calls to obstetric patients. We examined the characteristics of RRT calls to obstetric patients at a tertiary teaching hospital. METHODS: Details of calls to pregnant and postpartum patients between October 2010 and June 2014 were obtained from the hospital RRT database. Each was retrospectively examined for data on patient demographics, call trigger, interventions and outcomes. Local obstetric-specific escalation practices (Code Pink/Green) for obstetrical concerns (not mandating maternal instability/involvement of the ICU team), were excluded. RESULTS: There were 106 RRT calls logged during 43 months, and 97 had data available for analysis. Women currently pregnant accounted for 33% of calls and postpartum women 67%, with nearly half of these occurring more than 24 h post-delivery. The most common reason (29% of calls) for calling the RRT was hypotension, followed by 'concern about patient' (21%) and decreased Glasgow Coma Score (GCS) (17%). An escalation in the environment of care occurred after 32% of calls, with approximately 11% of calls necessitating direct ICU admission. Twenty-three percent of all calls were to women who had an ICU admission during their hospital stay. Among the cohort who received an RRT call, there was one maternal and three neonatal deaths. CONCLUSION: At our institution generic RRT calls are called to both pregnant and postpartum women, and frequently result in an escalation in the care environment. Further study is required to understand better the specific needs of this important population. PMID- 28656601 TI - Silencing of AtRAP, a target gene of a bacteria-induced small RNA, triggers antibacterial defense responses through activation of LSU2 and down-regulation of GLK1. AB - Plants fine-tune their sophisticated immunity systems in response to pathogen infections. We previously showed that AtlsiRNA-1, a bacteria-induced plant endogenous small interfering RNA, silences the AtRAP gene, which encodes a putative RNA binding protein. In this study, we demonstrate that AtRAP functions as a negative regulator in plant immunity by characterizing molecular and biological responses of the knockout mutant and overexpression lines of AtRAP upon bacterial infection. AtRAP is localized in chloroplasts and physically interacts with Low Sulfur Upregulated 2 (LSU2), which positively regulates plant defense. Our results suggest that AtRAP negatively regulates defense responses by suppressing LSU2 through physical interaction. We also detected downregulation of the transcription factor GOLDEN2-LIKE 1 (GLK1) in atrap-1 using microarray analysis. The glk1 glk2 double mutant showed enhanced resistance to Pseudomonas syringae pv. tomato, which is consistent with a previous study showing enhanced resistance of a glk1 glk2 double mutant to Hyaloperonospora arabidopsidis. Taken together, our data suggest that silencing of AtRAP by AtlsiRNA-1 upon bacterial infection triggers defense responses through regulation of LSU2 and GLK1. PMID- 28656604 TI - Consistency in quality correction factors for ionization chamber dosimetry in scanned proton beam therapy. AB - PURPOSE: The IAEA TRS-398 code of practice details the reference conditions for reference dosimetry of proton beams using ionization chambers and the required beam quality correction factors (kQ ). Pencil beam scanning (PBS) systems cannot approximate reference conditions using a single spot. However, dose distributions requested in TRS-398 can be reproduced with PBS using a combination of spots. This study aims to demonstrate, using Monte Carlo (MC) simulations, that kQ factors computed/measured for broad beams can be used with scanned beams for similar reference dose distributions with no additional significant uncertainty. METHODS: We consider the Alfonso formalism13 usually employed for nonstandard photon beams. To approach reference conditions similar as IAEA TRS-398 and the associated dose distributions, PBS must combine many pencil beams with range or energy modulation and shaping techniques that differ from those used in passive systems (broad beams). In order to evaluate the impact of these differences on kQ factors, ionization chamber responses are computed with MC (Geant4 9.6) in three different proton beams, with their corresponding quality factors (Q), producing a 10 * 10 cm2 field with a flat dose distribution for (a) a dedicated scanned pencil beam (Qpbs ), (b) a hypothetical proton source (Qhyp ), and (c) a double scattering beam (Qds ). The tested ionization chamber cavities are a 2 * 2 * 0.2 mm3 air cavity, a Roos-type ionization chamber, and a Farmer-type ionization chamber. RESULTS AND DISCUSSION: Ranges of Qpbs , Qhyp , and Qds are consistent within 0.4 mm. Flatnesses of dose distributions are better than 0.5%. Calculated kQpbs,Qhypfpbs,fref is 0.999 +/- 0.002 for the air cavity and the Farmer-type ionization chamber and 1.001 +/- 0.002 for the Roos-type ionization chamber. The quality correction factors kQpbs,Qdsfpbs,fref is 0.999 +/- 0.002 for the Farmer type and Roos-type ionization chambers and 1.001 +/- 0.001 for the Roos-type ionization chamber. CONCLUSION: The Alfonso formalism was applied to scanned proton beams. In our MC simulations, neither the difference in the beam profiles (scanned beam vs hypothetical beam) nor the different incident beam energies influenced significantly the beam correction factors. This suggests that ionization chamber quality correction factors in scanned or broad proton beams are indistinguishable within the calculation uncertainties provided dose distributions achieved by both modalities are similar and compliant with the TRS 398 reference conditions. PMID- 28656603 TI - A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). AB - BACKGROUND: Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome-wide evaluation of inherited risks and possible mechanisms of etiology in BPH. METHODS: We performed a three stage, genome-wide association study (GWAS) of men from three independent populations, the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, the CLUE II cohort, and a Finnish hospital-based population. DNA samples were genotyped using the Illumina HumanOmniExpress BeadChip in REDUCE and CLUE II, and using the Sequenom iPLEX system for the confirmation stage in the Finnish population. A logistic regression model was used to evaluate the association between each SNP and BPH/LUTS. RESULTS: Fourteen SNPs reached P < 5.0 * 10-4 in the meta-analysis of the two GWASs (CLUE II and REDUCE). A total of 773 SNPs were chosen for the confirmation step in the Finish cohort. Only one SNP (rs17144046) located ~489 kb downstream of GATA3 remained significant after correction for multiple testing (P < 6.5 * 10-5 ). This SNP marginally reached the GWAS significance level after performing a meta-analysis of the three stages (P-meta = 8.89 * 10-7 ). Expression quantitative trait loci (eQTL) analyses showed that the risk allele (G) of rs17144046 was significantly associated with increased expression of GATA3 (P = 0.017). Reported studies indicated a close correlation between GATA3 and BPH pathogenesis and progression. CONCLUSIONS: Rs17144046 located near GATA3 was significantly associated with BPH/LUTS in three independent populations, but did not reach a stringent GWAS significance level. Genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS. Further research in this area is needed. PMID- 28656605 TI - Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial. AB - OBJECTIVE: To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). DESIGN: Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). PATIENTS: Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once daily Norditropin(r) SimpleXx(r) (0.03 mg/kg; n=2 each) for 7 days. MEASUREMENTS: Pharmacokinetic and pharmacodynamic profiles were assessed. RESULTS: Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. CONCLUSIONS: Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified. PMID- 28656606 TI - Preventive Effects of Ginseng Total Saponins on Chronic Corticosterone-Induced Impairment in Astrocyte Structural Plasticity and Hippocampal Atrophy. AB - To further explore the underlying antidepressant mechanism of ginseng total saponins (GTS), this study observed the effects on hippocampal astrocyte structural plasticity and hippocampal volume in the corticosterone-induced mouse depression model. Corticosterone (20 mg/kg/day) was administered subcutaneously for 5 weeks, and GTS (12.5, 25, and 50 mg/kg/day; namely GTSL, GTSM, and GTSH) or fluoxetine (10 mg/kg/day) were given intragastrically during the last 3 weeks. On day 33 and day 34, depression-like behavior was observed via a forced swimming test and a tail suspension test, respectively. At 6 h after the last dose of corticosterone (day 35), all mice were sacrificed followed by serum corticosterone assays, stereological analysis of hippocampal glial fibrillary acidic protein-positive (GFAP+ ) astroctyes and hippocampal volume, and hippocampal glycogen tests. Results showed that all doses of GTS ameliorated depression-like behavior and the decrease in hippocampal glycogen without normalizing hypercortisolism. Moreover, GTSH and GTSM reversed the corticosterone induced reduction in the total number of hippocampal GFAP+ astrocytes and hippocampal volume. Additionally, GTSH alleviated the diminished protrusion length and somal volume of GFAP+ astrocytes induced by corticosterone. These findings imply that the effects of GTS on corticosterone-induced depression-like behavior may be mediated partly through the protection to hippocampal astrocyte structural plasticity. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28656607 TI - Prospective, randomized, controlled study of the efficacy of transcatheter arterial chemoembolization with miriplatin for hepatocellular carcinoma. AB - AIM: Transcatheter arterial chemoembolization (TACE) has been recognized as a treatment option for patients with intermediate hepatocellular carcinoma (HCC). This randomized, controlled study compared the local control efficacy of TACE with miriplatin (platinum monohydrate) or with epirubicin. METHODS: The study group consisted of 200 Japanese patients with unresectable HCC treated at the Kitasato University East Hospital (Sagamihara, Japan) between July 2010 and June 2013. The primary end-point of the study was time to tumor progression (TTP). RESULTS: We analyzed 198 patients (99 in the miriplatin group and 99 in the epirubicin group) treated with TACE. The median TTP in the epirubicin group was 5.9 months (95% confidence interval [CI], 4.8-7.0) and 7.6 months (95% CI, 5.8 9.4) in the miriplatin group. There was a significant difference between the two groups (P = 0.021; risk ratio, 1.488; 95% CI: 1.061-2.086). In the epirubicin group, 53 patients (53%) had complete response, 24 patients (24%) had partial response, 12 patients (12%) had stable disease, and 10 patients (10%) had progressive disease. In the miriplatin group, 38 patients (38%) had complete response, 41 patients (41%) had partial response, 2 patients (2%) had stable disease, and 18 patients (18%) had progressive disease. There was no significant difference in the response rate (P = 0.862). Overall incidences of adverse events and adverse drug reactions did not differ significantly between the two groups. CONCLUSION: Miriplatin proved more effective than epirubicin in TACE for unresectable HCC. The trial described in this work has been registered under the trial number: UMIN000004790. PMID- 28656608 TI - Flexible Ionic-Electronic Hybrid Oxide Synaptic TFTs with Programmable Dynamic Plasticity for Brain-Inspired Neuromorphic Computing. AB - Emulation of biological synapses is necessary for future brain-inspired neuromorphic computational systems that could look beyond the standard von Neuman architecture. Here, artificial synapses based on ionic-electronic hybrid oxide based transistors on rigid and flexible substrates are demonstrated. The flexible transistors reported here depict a high field-effect mobility of ~9 cm2 V-1 s-1 with good mechanical performance. Comprehensive learning abilities/synaptic rules like paired-pulse facilitation, excitatory and inhibitory postsynaptic currents, spike-time-dependent plasticity, consolidation, superlinear amplification, and dynamic logic are successfully established depicting concurrent processing and memory functionalities with spatiotemporal correlation. The results present a fully solution processable approach to fabricate artificial synapses for next generation transparent neural circuits. PMID- 28656609 TI - The ecological consequences of environmentally induced phenotypic changes. AB - Population dynamics and species persistence are often mediated by species traits. Yet many important traits, like body size, can be set by resource availability and predation risk. Environmentally induced changes in resource levels or predation risk may thus have downstream ecological consequences. Here, we assess whether quantity and type of resources affect the phenotype, the population dynamics, and the susceptibility to predation of a mixotrophic protist through experiments and a model. We show that cell shape, but not size, changes with resource levels and type, and is linked to carrying capacity, thus affecting population dynamics. Also, these changes lead to differential susceptibility to predation, with direct consequences for predator-prey dynamics. We describe important links between environmental changes, traits, population dynamics and ecological interactions, that underscore the need to further understand how trait mediated interactions may respond to environmental shifts in resource levels in an increasingly changing world. PMID- 28656610 TI - Rheumatoid nodule on cytology. PMID- 28656612 TI - Preventing Episodic Migraine With Caloric Vestibular Stimulation: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. BACKGROUND: Migraine causes significant disability in ~12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. METHODS: In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNMTM device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance. RESULTS: Per-protocol, active-arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3 months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.9 +/- 0.6 from a baseline burden of 7.7 +/- 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1 +/- 0.6 from a baseline burden = 6.9 +/- 0.7 migraine days) and represented a therapeutic gain of -2.8 migraine days, CI = -0.9 to -4.7, P = .012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. CONCLUSION: The TNMTM device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine. PMID- 28656611 TI - Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury. AB - Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as 'endothelial progenitor' that may mediate vascular repair such as pro-angiogenic cells and endothelial colony-forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre clinical studies. PMID- 28656613 TI - The Effects of Briefly Interrupting Marital Conflict. AB - This study examined couples' (N = 94) behavior resulting from two proximal change interventions. One was a spousal "compliments intervention" to increase positivity, and the other was a "criticize intervention" to increase negativity. Participants were randomly assigned to one of the two intervention conditions or a control group. There was no main effect in affect from the pretest conflict discussion to the posttest conflict discussion between the interventions or control group. However, a manipulation check on how couples acted during either intervention produced a significant interaction effect. Pretest affect during conflict and marital satisfaction significantly predicted couples' construal of the intervention. Professionals may need to monitor how couples use specific interventions and direct the processes how the intervention is construed by the couple. PMID- 28656614 TI - Automatic renal segmentation for MR urography using 3D-GrabCut and random forests. AB - PURPOSE: To introduce and evaluate a fully automated renal segmentation technique for glomerular filtration rate (GFR) assessment in children. METHODS: An image segmentation method based on iterative graph cuts (GrabCut) was modified to work on time-resolved 3D dynamic contrast-enhanced MRI data sets. A random forest classifier was trained to further segment the renal tissue into cortex, medulla, and the collecting system. The algorithm was tested on 26 subjects and the segmentation results were compared to the manually drawn segmentation maps using the F1-score metric. A two-compartment model was used to estimate the GFR of each subject using both automatically and manually generated segmentation maps. RESULTS: Segmentation maps generated automatically showed high similarity to the manually drawn maps for the whole-kidney (F1 = 0.93) and renal cortex (F1 = 0.86). GFR estimations using whole-kidney segmentation maps from the automatic method were highly correlated (Spearman's rho = 0.99) to the GFR values obtained from manual maps. The mean GFR estimation error of the automatic method was 2.98 +/- 0.66% with an average segmentation time of 45 s per patient. CONCLUSION: The automatic segmentation method performs as well as the manual segmentation for GFR estimation and reduces the segmentation time from several hours to 45 s. Magn Reson Med 79:1696-1707, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28656615 TI - A pilot study of a novel smartphone application for the estimation of sleep onset. AB - The aim of the study was to investigate the accuracy of Sleep On Cue: a novel iPhone application that uses behavioural responses to auditory stimuli to estimate sleep onset. Twelve young adults underwent polysomnography recording while simultaneously using Sleep On Cue. Participants completed as many sleep onset trials as possible within a 2-h period following their normal bedtime. On each trial, participants were awoken by the app following behavioural sleep onset. Then, after a short break of wakefulness, commenced the next trial. There was a high degree of correspondence between polysomnography-determined sleep onset and Sleep On Cue behavioural sleep onset, r = 0.79, P < 0.001. On average, Sleep On Cue overestimated sleep-onset latency by 3.17 min (SD = 3.04). When polysomnography sleep onset was defined as the beginning of N2 sleep, the discrepancy was reduced considerably (M = 0.81, SD = 1.96). The discrepancy between polysomnography and Sleep On Cue varied between individuals, which was potentially due to variations in auditory stimulus intensity. Further research is required to determine whether modifications to the stimulus intensity and behavioural response could improve the accuracy of the app. Nonetheless, Sleep On Cue is a viable option for estimating sleep onset and may be used to administer Intensive Sleep Retraining or facilitate power naps in the home environment. PMID- 28656616 TI - Embedding assessment in a simulation skills training program for medical and midwifery students: A pre- and post-intervention evaluation. AB - BACKGROUND: Simulation-based programs are increasingly being used to teach obstetrics and gynaecology examinations, but it is difficult to establish student learning acquired through them. Assessment may test student learning but its role in learning itself is rarely recognised. We undertook this study to assess medical and midwifery student learning through a simulation program using a pre test and post-test design and also to evaluate use of assessment as a method of learning. METHODS: The interprofessional simulation education program consisted of a brief pre-reading document, a lecture, a video demonstration and a hands-on workshop. Over a 24-month period, 405 medical and 104 midwifery students participated in the study and were assessed before and after the program. Numerical data were analysed using paired t-test and one-way analysis of variance. Students' perceptions of the role of assessment in learning were qualitatively analysed. RESULTS: The post-test scores were significantly higher than the pre-test (P < 0.001) with improvements in scores in both medical and midwifery groups. Students described the benefit of assessment on learning in preparation of the assessment, reinforcement of learning occurring during assessment and reflection on performance cementing previous learning as a post assessment effect. CONCLUSION: Both medical and midwifery students demonstrated a significant improvement in their test scores and for most students the examination process itself was a positive learning experience. PMID- 28656617 TI - Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. PMID- 28656618 TI - Sulfur-Doped Graphene Oxide Quantum Dots as Photocatalysts for Hydrogen Generation in the Aqueous Phase. AB - Sulfur-doped graphene oxide quantum dots (S-GOQDs) were synthesized and investigated for efficient photocatalytic hydrogen generation application. The UV/Vis, FTIR, and photoluminescence spectra of the synthesized S-GOQDs exhibit three absorption bands at 333, 395, and 524 nm, characteristic of C=S and C-S stretching vibration signals at 1075 and 690 cm-1 , and two excitation-wavelength independent emission signals with maxima at 451 and 520 nm, respectively, confirming the successful doping of S atom into the GOQDs. Electronic structural analysis suggested that the S-GOQDs exhibit conduction band minimum (CBM) and valence band maximum (VBM) levels suitable for water splitting. Under direct sunlight irradiation, an initial rate of 18 166 MUmol h-1 g-1 in pure water and 30 519 MUmol h-1 g-1 in 80 % ethanol aqueous solution were obtained. Therefore, metal-free and inexpensive S-GOQDs hold great potential in the development of sustainable and environmentally friendly photocatalysts for efficient hydrogen generation from water splitting. PMID- 28656619 TI - An unusual cause of chest pain: An isolated huge cardiac hydatid cyst. AB - Hydatid disease is a human parasitic infection caused by the larval stage of Echinococcus granulosus. The most common locations for hydatid cysts are the liver and lungs. Cardiac involvement is rare, and isolated cardiac hydatid cysts are even more unusual. We report the case a 48-year-old female patient with an isolated huge cardiac hydatid cyst involving both the left ventricular free wall and the pericardium, and presenting with atypical chest pain. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:262-264, 2018. PMID- 28656620 TI - Autonomous cortisol secretion in adrenal incidentalomas and increased visceral fat accumulation during follow-up. AB - OBJECTIVE: Autonomous cortisol secretion of adrenal incidentalomas (AIs) is associated with poor cardiovascular outcome. Because centripetal obesity is a cardiovascular risk factor, we aimed to investigate whether autonomous cortisol secretion is associated with increased visceral fat accumulation. DESIGN: Retrospective cohort study. PATIENTS: Patients with AIs who attended for follow up between January 2014 and December 2016 were evaluated. Autonomous cortisol secretion was diagnosed when 1 mg overnight dexamethasone (post-DST) cortisol was >50 nmol/L at baseline and follow-up. Follow-up duration was 34 (12-105) months. Thirty patients with nonfunctioning AIs and 44 patients with autonomous cortisol secretion were included. Adrenalectomy was performed in five patients. Six patients with Cushing's syndrome were also recruited. MEASUREMENTS: Hormonal evaluation and assessment of total (T), visceral (V) and subcutaneous (S) fat area by computed tomography and calculation of V:S and V:T ratios at baseline and follow-up. RESULTS: V, V:S and V:T increased (P<.001 for each comparison, Wilcoxon signed rank test for repeated measures) in patients with autonomous cortisol secretion while did not change significantly in patients with nonfunctioning adenomas. Linear regression models including post-DST cortisol, gender, concomitant treatments and follow-up duration showed that both baseline and follow-up DST significantly predicted Delta(V:S) and Delta(V:T) (P<.01 for all models). CONCLUSIONS: In patients with AIs, a post-DST cortisol >50 nmol/L at both baseline and follow-up, was associated with a significant increase in visceral fat after a follow-up duration of ~3 years. This may be of importance to explain the link between autonomous cortisol secretion and poor cardiovascular outcome. PMID- 28656621 TI - Fabrication of Redox-Responsive Degradable Capsule Particles by a Shell-Selective Photoinduced Cross-Linking Approach from Spherical Polymer Particles. AB - In this study, a fabrication route towards functional capsule particles was successfully developed by means of a self-templating shell-selective cross linking strategy that enables us to prepare shell-cross-linked hollow polymer particles directly from homogeneous spherical polymer particles. To prepare redox responsive degradable capsule particles, a newly designed monomer bearing a photoinduced post-cross-linking group (cinnamoyl group) and a redox-environment responsive cleavable group (disulfide group), N-cinnamoyl-N' methyacryloylcystamine (MCC), was synthesized. Redox-responsive degradable capsule particles were successfully prepared from homogeneous spherical poly(MCC) based particles by a self-templating shell-selective photoinduced cross-linking approach. Moreover, the cargo loading capability of the shell-cross-linked hollow particles was confirmed through a solvent exchange procedure using dyes, polymer precursors and anticancer reagents. Furthermore, redox-responsive degradability of the capsule polymer particles was also confirmed by adding a reducing agent for cleavage of the disulfide linkage. We hope that the efficient fabrication route of functional capsule particles directly from spherical polymer particles opens efficient routes for the fabrication of a wide range of capsule particles; in particular, this technique is robust, productive, and facile because neither additional sacrificial template particles nor toxic solvents are required. PMID- 28656623 TI - Dosing considerations in the use of the direct oral anticoagulants in the antiphospholipid syndrome. AB - WHAT IS KNOWN AND OBJECTIVES: At least four prospective trials have been initiated investigating the direct oral anticoagulants in the antiphospholipid syndrome. Preliminary reports have supported their use in patients with a history of venous thrombosis and a target INR of 2-3, but there have also been reports of failure of these agents in the antiphospholipid syndrome. The objective is to present a case report that illustrates there may be important dosing issues when considering the use of these agents in patients with the antiphospholipid syndrome. CASE SUMMARY: A 50-year-old woman with the antiphospholipid syndrome, manifesting clinically with recurrent pyoderma gangrenosum-like leg ulcers, was treated with apixaban, resulting in improved ulcer healing. For insurance purposes, she was switched to rivaroxaban with worsening of the ulcers which again improved when apixaban was resumed. WHAT IS NEW AND CONCLUSION: Despite a similar half-life, pharmacokinetics and pharmacodynamics, the manufacturer recommended maintenance dosing of apixaban is twice daily and rivaroxaban once daily. We believe this difference in recommended dose accounts for the differential clinical response noted in the present case report and that twice daily dosing and a larger daily dose of these agents may be more efficacious in potent hypercoagulable disorders, such as the antiphospholipid syndrome. PMID- 28656624 TI - To what extent can ecosystem services motivate protecting biodiversity? AB - Society increasingly focuses on managing nature for the services it provides people rather than for the existence of particular species. How much biodiversity protection would result from this modified focus? Although biodiversity contributes to ecosystem services, the details of which species are critical, and whether they will go functionally extinct in the future, are fraught with uncertainty. Explicitly considering this uncertainty, we develop an analytical framework to determine how much biodiversity protection would arise solely from optimising net value from an ecosystem service. Using stochastic dynamic programming, we find that protecting a threshold number of species is optimal, and uncertainty surrounding how biodiversity produces services makes it optimal to protect more species than are presumed critical. We define conditions under which the economically optimal protection strategy is to protect all species, no species, and cases in between. We show how the optimal number of species to protect depends upon different relationships between species and services, including considering multiple services. Our analysis provides simple criteria to evaluate when managing for particular ecosystem services could warrant protecting all species, given uncertainty. Evaluating this criterion with empirical estimates from different ecosystems suggests that optimising some services will be more likely to protect most species than others. PMID- 28656622 TI - A population level atlas of Mus musculus craniofacial skeleton and automated image-based shape analysis. AB - Laboratory mice are staples for evo/devo and genetics studies. Inbred strains provide a uniform genetic background to manipulate and understand gene environment interactions, while their crosses have been instrumental in studies of genetic architecture, integration and modularity, and mapping of complex biological traits. Recently, there have been multiple large-scale studies of laboratory mice to further our understanding of the developmental basis, evolution, and genetic control of shape variation in the craniofacial skeleton (i.e. skull and mandible). These experiments typically use micro-computed tomography (micro-CT) to capture the craniofacial phenotype in 3D and rely on manually annotated anatomical landmarks to conduct statistical shape analysis. Although the common choice for imaging modality and phenotyping provides the potential for collaborative research for even larger studies with more statistical power, the investigator (or lab-specific) nature of the data collection hampers these efforts. Investigators are rightly concerned that subtle differences in how anatomical landmarks were recorded will create systematic bias between studies that will eventually influence scientific findings. Even if researchers are willing to repeat landmark annotation on a combined dataset, different lab practices and software choices may create obstacles for standardization beyond the underlying imaging data. Here, we propose a freely available analysis system that could assist in the standardization of micro-CT studies in the mouse. Our proposal uses best practices developed in biomedical imaging and takes advantage of existing open-source software and imaging formats. Our first contribution is the creation of a synthetic template for the adult mouse craniofacial skeleton from 25 inbred strains and five F1 crosses that are widely used in biological research. The template contains a fully segmented cranium, left and right hemi-mandibles, endocranial space, and the first few cervical vertebrae. We have been using this template in our lab to segment and isolate cranial structures in an automated fashion from a mixed population of mice, including craniofacial mutants, aged 4-12.5 weeks. As a secondary contribution, we demonstrate an application of nearly automated shape analysis, using symmetric diffeomorphic image registration. This approach, which we call diGPA, closely approximates the popular generalized Procrustes analysis (GPA) but negates the collection of anatomical landmarks. We achieve our goals by using the open-source advanced normalization tools (ANT) image quantification library, as well as its associated R library (ANTsR) for statistical image analysis. Finally, we make a plea to investigators to commit to using open imaging standards and software in their labs to the extent possible to increase the potential for data exchange and improve the reproducibility of findings. Future work will incorporate more anatomical detail (such as individual cranial bones, turbinals, dentition, middle ear ossicles) and more diversity into the template. PMID- 28656625 TI - The applications of PCA in QSAR studies: A case study on CCR5 antagonists. AB - Principal component analysis (PCA), as a well-known multivariate data analysis and data reduction technique, is an important and useful algebraic tool in drug design and discovery. PCA, in a typical quantitative structure-activity relationship (QSAR) study, analyzes an original data matrix in which molecules are described by several intercorrelated quantitative dependent variables (molecular descriptors). Although extensively applied, there is disparity in the literature with respect to the applications of PCA in the QSAR studies. This study investigates the different applications of PCA in QSAR studies using a dataset including CCR5 inhibitors. The different types of preprocessing are used to compare the PCA performances. The use of PC plots in the exploratory investigation of matrix of descriptors is described. This work is also proved PCA analysis to be a powerful technique for exploring complex datasets in QSAR studies for identification of outliers. This study shows that PCA is able to easily apply to the pool of calculated structural descriptors and also the extracted information can be used to help decide upon an appropriate harder model for further analysis. PMID- 28656626 TI - Physical interaction between the strawberry allergen Fra a 1 and an associated partner FaAP: Interaction of Fra a 1 proteins and FaAP. AB - The strawberry fruit allergens Fra a 1.01E, Fra a 1.02 and Fra a 1.03 belong to the group of pathogenesis-related 10 (PR-10) proteins and are homologs of the major birch pollen Bet v 1 and apple allergen Mal d 1. Bet v 1 related proteins are the most extensively studied allergens but their physiological function in planta remains elusive. Since Mal d 1-Associated Protein has been previously identified as interaction partner of Mal d 1 we studied the binding of the orthologous Fra a 1-Associated Protein (FaAP) to Fra a 1.01E/1.02/1.03. As the C terminal sequence of FaAP showed strong auto-activation activity in yeast 2 hybrid analysis a novel time resolved DNA-switching system was successfully applied. Fra a 1.01E, Fra a 1.02, and Fra a 1.03 bind to FaAP with KD of 4.5 +/- 1.1, 15 +/- 3, and 11 +/- 2 nM, respectively. Fra a 1.01E forms a dimer, whereas Fra a 1.02 and Fra a 1.03 bind as monomer. The results imply that PR-10 proteins might be integrated into a protein-interaction network and FaAP binding appears to be essential for the physiological function of the Fra a 1 proteins. PMID- 28656628 TI - Nanofence Stabilized Platinum Nanoparticles Catalyst via Facet-Selective Atomic Layer Deposition. AB - A facet-selective atomic layer deposition method is developed to fabricate oxide nanofence structure to stabilize Pt nanoparticles. CeOx is selectively deposited on Pt nanoparticles' (111) facets and naturally exposes Pt (100) facets. The facet selectivity is realized through different binding energies of Ce precursor fragments chemisorbed on Pt (111) and Pt (100), which is supported by in situ mass gain experiment and corroborated by density functional theory simulations. Such nanofence structure not only has exposed Pt active facets for carbon monoxide oxidation but also forms ceria-metal interfaces that are beneficial for activity enhancement. The composite catalysts show excellent sintering resistance up to 700 degrees C calcination. CeOx anchors Pt nanoparticles with a strong metal oxide interaction, and nanofence structure around Pt nanoparticles provides physical blocking that suppresses particles migration. The study reveals that forming oxide nanofence structure to encapsulate precious metal nanoparticles is an effective way to simultaneously enhance catalytic activity and thermal stability. PMID- 28656627 TI - CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. AB - The central amygdala (CeA) is involved in the processing of anxiety and stress and plays a role in ethanol consumption. Chronic ethanol recruits stress systems in the CeA, leading to aversive withdrawal symptoms. Although primarily GABAergic, CeA contains glutamatergic afferents, and we have reported inhibitory effects of ethanol on locally evoked glutamatergic responses in CeA of Wistar and Marchigian Sardinian alcohol-preferring (msP) rats. Notably, msP rats display enhanced anxiety, stress and alcohol drinking, simulating the alcohol-dependent phenotype. Endocannabinoids are also involved in regulation of stress, and we previously demonstrated that cannabinoid receptor type 1 (CB1 ) activation decreases CeA GABAergic signaling and blocks ethanol enhancement of GABAergic signaling. Here, we sought to investigate the effects of CB1 activation (WIN 55,212-2; Win) and antagonism (AM251) with and without acute ethanol on glutamatergic synapses in CeA of female and male Wistar and msP rats. Using intracellular sharp pipette electrophysiology, we examined the effects of CB1 compounds on locally evoked excitatory postsynaptic potentials (EPSPs) in CeA and compared effects between strains, gender and estrous cycle. Acute ethanol decreased EPSP amplitudes in Wistars, and in male but not female msPs. Win decreased EPSP amplitudes in msPs, and in male but not female Wistars. Combined application of Win and ethanol resulted in strain-specific effects in female rats. We found no tonic CB1 signaling at glutamatergic synapses in CeA of any groups, and no interaction with ethanol. Collectively, these observations demonstrate sex-strain-specific differences in ethanol and endocannabinoid effects on CeA glutamatergic signaling. PMID- 28656629 TI - P53-induced miR-30e-5p inhibits colorectal cancer invasion and metastasis by targeting ITGA6 and ITGB1. AB - The tumor suppressor P53 is a critical regulator of normal cellular homeostasis whose function is either distorted or lost in several cancer types including colorectal cancer (CRC). A small group of microRNAs have come to be recognized as essential mediators of P53 function. In a genome-wide systematic approach, we explored miRNAs that are substantially altered by P53 loss and found miR-30e to be the most significantly deregulated miRNA in P53-knockout human CRC cells. We identified miR-30e-5p to be a novel direct transcriptional target of P53 with gain and loss of function experiments revealing miR-30e-5p to be a significant regulator of tumor cell migration, invasion and in vivo metastasis mediated in part by integrins alpha-6 and beta-1 as novel targets. MiR-30e-5p also significantly reduced tumor cell proliferation by causing G1/S cell cycle arrest, which was achieved by inducing P21 and P27 expression. Finally, we found miR-30e 5p to be lost in resected CRC tumors as compared to normal colon tissues. Taken together, miR-30e-5p is a novel effector of P53-induced suppression of migration, invasion and metastasis. PMID- 28656631 TI - Effect of myelin water exchange on DTI-derived parameters in diffusion MRI: Elucidation of TE dependence. AB - PURPOSE: Water exchange exists between different neuronal compartments of brain tissue but is often ignored in most diffusion models. The goal of the current study was to demonstrate the dependence of diffusion measurements on echo time (TE) in the human brain and to investigate the underlying effects of myelin water exchange. METHODS: Five healthy subjects were examined with single-shot pulsed gradient spin-echo echo-planar imaging with fixed duration (delta) and separation (Delta) of diffusion gradient pulses and a set of varying TEs. The effects of water exchange and intrinsic T2 difference in cellular environments were investigated with Monte Carlo simulations. RESULTS: Both in vivo measurements and simulations showed that fractional anisotropy (FA) and axial diffusivity (AD) had positive correlations with TE, while radial diffusivity (RD) showed a negative correlation, which is consistent with a previous study. The simulation results further indicated the sensitivity of TE dependence to the change of g-ratio. CONCLUSION: The exchange between myelin and intra/extra-axonal water pools often plays a non-negligible role in the observed TE dependence of diffusion parameters, which may accompany or alter the effect of intrinsic T2 in causing such dependence. The TE dependence may potentially serve as a biomarker for demyelination processes (e.g., in multiple sclerosis and Alzheimer's disease). Magn Reson Med 79:1650-1660, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28656630 TI - Deleting the first disulphide bond in an arenicin derivative enhances its expression in Pichia pastoris. AB - : The marine antimicrobial peptide NZ17074, a variant of arenicin-3 from Arenicola marina that has broad antimicrobial activity and high bioavailability, can be designed to treat bacterial and fungal diseases. To reduce the toxicity of NZ17074, N6 was designed by replacing a cysteine in positions 3 and 20 with alanine, fused to the C-terminus of the small ubiquitin-like modifier tag (SUMO), and expressed in yeast. SUMO-N6 yielded as much as 921 mg l-1 at 72 h after induction in a fermentor and increased 1.8-fold over SUMO-NZ17074. After cleavage with 30% formic acid and purification by a Sephadex G-25 column, 9.7 mg of the recombinant peptide N6 (rN6) was obtained from one-litre fermentation broth, increasing 1.4-fold over NZ17074. Compared to NZ17074, rN6 displayed almost identical antimicrobial activity with a minimal inhibitory concentration of 0.5, 0.25-0.5, 4, 0.25-16 and 16 MUg ml-1 against Escherichia, Salmonella, Pseudomonas, Staphylococcus and Streptococcus strains. Our results indicate that the first disulphide bond, Cys3-Cys20, in NZ17074 is not necessary for antimicrobial activity and that its deletion might reduce toxicity to host cells. These findings may help design new antimicrobial peptides harbouring fewer disulphide bridges and may have more potent activity. SIGNIFICANCE AND IMPACT OF THE STUDY: Disulphide bond formation is an important step in the protein expression and can also influence protein secretion. A deletion of the first disulphide bond in NZ17074 increased the secreted level of target protein, and its antimicrobial activity was almost unaffected by the deletion of the first disulphide bond. The first disulphide bond in NZ17074 is favourable for correctly forming another disulphide bond during expression but not necessary for its activity. This may help design and produce a novel class of antimicrobial peptides harbouring fewer disulphide bridges to save the cost. PMID- 28656632 TI - Serum brain-derived neurotrophic factor (BDNF) in sleep-disordered patients: relation to sleep stage N3 and rapid eye movement (REM) sleep across diagnostic entities. AB - Experimental and clinical evidence suggests an association between neuroplasticity, brain-derived neurotrophic factor and sleep. We aimed at testing the hypotheses that brain-derived neurotrophic factor is associated with specific aspects of sleep architecture or sleep stages in patients with sleep disorders. We included 35 patients with primary insomnia, 31 patients with restless legs syndrome, 17 patients with idiopathic hypersomnia, 10 patients with narcolepsy and 37 healthy controls. Morning serum brain-derived neurotrophic factor concentrations were measured in patients and controls. In patients, blood sampling was followed by polysomnographic sleep investigation. Low brain-derived neurotrophic factor levels were associated with a low percentage of sleep stage N3 and rapid eye movement sleep across diagnostic entities. However, there was no difference in brain-derived neurotrophic factor levels between diagnostic groups. Our data indicate that serum levels of brain-derived neurotrophic factor, independent of a specific sleep disorder, are related to the proportion of sleep stage N3 and REM sleep. This preliminary observation is in accordance with the assumption that sleep stage N3 is involved in the regulation of neuroplasticity. PMID- 28656633 TI - The roles of B vitamins in phytoplankton nutrition: new perspectives and prospects. AB - Contents 62 I. 62 II. 63 III. 63 IV. 66 V. 66 VI. 67 67 References 67 SUMMARY: B vitamins play essential roles in central metabolism. These organic water-soluble molecules act as, or as part of, coenzymes within the cell. Unlike land plants, many eukaryotic algae are auxotrophic for certain B vitamins. Recent progress in algal genetic resources and environmental chemistry have promoted a renewal of interest in the role of vitamins in governing phytoplankton dynamics, and illuminated amazing versatility in phytoplankton vitamin metabolism. Accumulating evidence demonstrates metabolic complexity in the production and bioavailability of different vitamin forms, coupled with specialized acquisition strategies to salvage and remodel vitamin precursors. Here, I describe recent advances and discuss how they redefine our view of the way in which vitamins are cycled in aquatic ecosystems and their importance in structuring phytoplankton communities. PMID- 28656634 TI - Satellite Data and Machine Learning for Weather Risk Management and Food Security. AB - The increase in frequency and severity of extreme weather events poses challenges for the agricultural sector in developing economies and for food security globally. In this article, we demonstrate how machine learning can be used to mine satellite data and identify pixel-level optimal weather indices that can be used to inform the design of risk transfers and the quantification of the benefits of resilient production technology adoption. We implement the model to study maize production in Mozambique, and show how the approach can be used to produce countrywide risk profiles resulting from the aggregation of local, heterogeneous exposures to rainfall precipitation and excess temperature. We then develop a framework to quantify the economic gains from technology adoption by using insurance costs as the relevant metric, where insurance is broadly understood as the transfer of weather-driven crop losses to a dedicated facility. We consider the case of irrigation in detail, estimating a reduction in insurance costs of at least 30%, which is robust to different configurations of the model. The approach offers a robust framework to understand the costs versus benefits of investment in irrigation infrastructure, but could clearly be used to explore in detail the benefits of more advanced input packages, allowing, for example, for different crop varieties, sowing dates, or fertilizers. PMID- 28656635 TI - Clinical trials in acute heart failure: beginning of the end or end of the beginning? PMID- 28656636 TI - Soft but Powerful Artificial Muscles Based on 3D Graphene-CNT-Ni Heteronanostructures. AB - Bioinspired soft ionic actuators, which exhibit large strain and high durability under low input voltages, are regarded as prospective candidates for future soft electronics. However, due to the intrinsic drawback of weak blocking force, the feasible applications of soft ionic actuators are limited until now. An electroactive artificial muscle electro-chemomechanically reinforced with 3D graphene-carbon nanotube-nickel heteronanostructures (G-CNT-Ni) to improve blocking force and bending deformation of the ionic actuators is demonstrated. The G-CNT-Ni heteronanostructure, which provides an electrically conductive 3D network and sufficient contact area with mobile ions in the polymer electrolyte, is embedded as a nanofiller in both ionic polymer and conductive electrodes of the ionic actuators. An ionic exchangeable composite membrane consisting of Nafion, G-CNT-Ni and ionic liquid (IL) shows improved tensile modulus and strength of up to 166% and 98%, respectively, and increased ionic conductivity of 0.254 S m-1 . The ionic actuator exhibits enhanced actuation performances including three times larger bending deformation, 2.37 times higher blocking force, and 4 h durability. The electroactive artificial muscle electro chemomechanically reinforced with 3D G-CNT-Ni heteronanostructures offers improvements over current soft ionic actuator technologies and can advance the practical engineering applications. PMID- 28656637 TI - Intraoperative sonographic guidance for intracavitary brachytherapy of cervical cancer. AB - BACKGROUND: To describe the role and benefits of intraoperative sonographic (US) guidance in intracavitary brachytherapy of cervical cancer. METHODS: The data of 142 patients who received tandem-based intracavitary brachytherapy for cervical cancer between January 2010 and June 2015 were retrospectively reviewed. US guidance was carried out for tandem selection and appropriate application. The complications and applicator conformity were assessed with planning CT. RESULTS: Intracavitary brachytherapy was performed under US guidance for 412 insertions in 113 consecutive patients with cervical cancer. Before we started to use US guidance, applications were done in 29 patients: uterine perforation occurred in two patients (6.9%), the tandem length was short in two patients (6.9%), the tandem length was long in four patients (13.8%), and tandem was in myometrium in three patients (10.3%). We then decided to use US guidance routinely. With US guidance, only 1 of 113 patients had uterine perforation (0.9%), tandem length was short in only one patient (0.9%), and tandem was in myometrium in one patient (0.9%). CONCLUSIONS: Real-time US provided safe and effective guidance for intracavitary brachytherapy of cervical cancer resulting in decreased rates of perforations and misplacement of applicators. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:8-13, 2018. PMID- 28656638 TI - New York State Breast Density Mandate: Follow-up Data With Screening Sonography. AB - OBJECTIVES: To evaluate the impact on breast cancer detection from screening breast sonography performed in women with mammographically dense breasts. METHODS: This study used a retrospective chart review. Data collected included total number of screening mammograms, total number of dense breast screening sonograms, total number of procedures performed, biopsy results, and demographic data. Data were obtained from January 1, 2013, through August 31, 2015. During this period, there were a total of 195,982 screening mammographic examinations performed at our facility. Of these, 83,234 patients (42.5%) were informed that their breast tissue was heterogeneously dense or extremely dense. We specifically reviewed cases to identify those with findings on sonography only. The positive predictive value, biopsy rate, and cancer detection rate were determined. RESULTS: During the study period, 5434 screening sonographic examinations were performed in 4898 women with heterogeneously dense or extremely dense breasts. Most (95.7%) of the sonographic examinations resulted in an American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) category 1 or 2 designation. A total of 101 lesions were given a BI-RADS 3 designation; 134 suspicious findings were given a BI-RADS 4 or 5 designation; and 100 of these were seen on sonography only, all of which underwent tissue sampling, resulting in the diagnosis of 18 malignancies; all were invasive. In evaluating screening sonographic findings, we found a positive predictive value of 18.0%, with an overall biopsy rate of 2.0% and a cancer detection rate of 3.3 per 1000. CONCLUSIONS: The results of our continued evaluation of our screening sonography program confirm that screening breast sonography in women with dense breast tissue can detect otherwise occult malignancy, with a low biopsy rate. PMID- 28656639 TI - Comparison of immunomagnetic separation beads for detection of six non-O157 Shiga toxin-producing Escherichia coli serogroups in different matrices. AB - : Immunomagnetic separation used with culture based methods has been a useful technique in the detection of pathogens. However, previous studies have not answered many of the necessary questions for real world applications. The objective of this study was to assess the efficacy of different immunomagnetic separation (IMS) bead types in recovery of the correct serogroup from a mixture of big six non-O157 Shiga toxin-producing Escherichia coli strains. To determine the impact of different matrices on recovery, samples of sterile phosphate buffered saline (PBS), sterile and non-sterile cattle faeces, ground beef and lettuce were inoculated with 10 CFU per ml mixture of isolates representing the six serogroups. After a 6 h incubation at 37 degrees C, samples were mixed with IMS beads from three different commercial sources and plated on eosin methylene blue agar (EMB). Three suspect E. coli colonies were selected from each EMB plate and multiplex polymerase chain reaction was used to determine the serogroup. The rate of correct identification varied with the serogroup, IMS bead manufacturer and matrix. Overall, recovery of the correct serogroup became less likely with increase in matrix complexity, with enrichments containing lettuce having the greatest number of bead types with significantly lower likelihood of correct recovery compared to recovery in PBS. SIGNIFICANCE AND IMPACT OF THE STUDY: The need to accurately and efficiently detect Shiga toxin-producing Escherichia coli (STEC) O26, O45, O103, O111, O121 and O145, which have caused outbreaks on numerous occasions, is a major public health and food safety concern in the United States. Detecting these STEC serogroups can be challenging because methods to detect non-O157 serogroups have not been refined as compared to those for O157. Immunomagnetic separation (IMS) has the potential to isolate STEC from a mixture in complex matrices. Our results highlight the need for optimization of IMS-based detection of STEC to effectively recover the targeted serogroup from a variety of sample matrices. PMID- 28656640 TI - Recent advances in endoscopic ultrasound-guided biliary drainage. AB - Endoscopic ultrasound-guided biliary drainage (EUS-BD) is increasingly used as an alternative in patients with biliary obstruction who fail standard endoscopic retrograde cholangiopancreatography (ERCP). The two major endoscopic approach routes for EUS-BD are the transgastric intrahepatic and the transduodenal extrahepatic approaches. Biliary drainage can be achieved by three different methods, transluminal biliary stenting, transpapillary rendezvous technique, and antegrade biliary stenting. Choice of approach route and drainage method depends on individual anatomy, underlying disease, and location of the biliary stricture. Recent meta-analyses have revealed that cumulative technical success and adverse event rates were 90-94% and 16-23%, respectively. Development of new dedicated devices for EUS-BD would help refine the technical aspects and minimize the possibility of complications, making it a more promising procedure. PMID- 28656641 TI - Putative gravisensors among microtubule associated proteins. AB - Despite of long period of investigation (over 100 years), still a lot of questions remain unclear about molecular mechanisms of plant graviperception. This requires designing new experiments and new approaches to be applied in gravitational biology. Investigation of plant cell reactions under clinorotation (plant disorientation in respect to gravity vector) is of significant importance to such type of research. Clinorotation is known to cause changes of cell polarity and exert mechanical stress in plant cells. Microtubular cytoskeleton is highly dynamic structure and it responds to both of these stresses. Due to turgor pressure and cell elongation, endogenous mechanical forces influence microtubule orientation in order to coordinate cell growth. Rearrangements of microtubules are regulated by numerous associated proteins which functional activity is not fully clear. In this review, we discuss how MT associated proteins regulate cortical MT arrays under mechanical stress and consider how these proteins may act as plant cell gravisensors. Investigation of microtubule associated proteins under clinorotation might shed the light on molecular mechanism of plant cytoskeleton arrangement and its involvement in initial reactions of cell graviperception. PMID- 28656642 TI - Influence of cervical, thoracic and lumbar spines, and shoulder girdle range of motion on swallowing function of dependent older adults. AB - AIM: The present study examined the cervical, thoracic and lumbar spines, and shoulder girdle range of motion (ROM) of dependent older adults to clarify the influence of these variables on swallowing function, in order to evaluate the efficiency of ROM training to maintain older adults' swallowing function. METHODS: A total of 37 (mean age 86.8 +/- 6.2 years; 11 men; 26 women) dependent older adults were included in the study. The level of swallowing function was assessed using the Functional Oral Intake Scale. The following ROM were measured three times to calculate the mean: the cervical spine (flexion, extension, rotation and lateral bending); thoracic and lumbar spines (flexion, extension, rotation and lateral bending); and shoulder girdle (flexion, extension, elevation and depression). In order to compare ROM, the participants showing Functional Oral Intake Scale scores of 7 were classified as dysphagia (-), and those showing scores <7 were included in the dysphagia (+) subgroups. RESULTS: The dysphagia (+) group showed significantly limited cervical spine (flexion, extension and lateral bending), thoracic and lumbar spines (flexion, extension, rotation and lateral bending), and shoulder girdle (flexion, elevation, and depression) ROM. CONCLUSIONS: Although strict relationships were not clarified, the results of the present study suggested the influence of some joint ROM on swallowing function. This suggests the feasibility of preventing dysphagia among dependent older adults by maintaining and enhancing the elasticity and extensibility of their muscles through cervical, thoracic and lumbar spines, and shoulder girdle ROM training. Geriatr Gerontol Int 2017; 17: 2565-2572. PMID- 28656643 TI - Risk factors for medication-related osteonecrosis of the jaws: A systematic review. AB - The purpose of this study was to identify the patient populations at risk of medication-related osteonecrosis of the jaw (MRONJ) and determine which medical and dental comorbidities are significant risk factors for this disease. An electronic search of Embase, MEDLINE, Cochrane Central Register of Controlled Trials, WHO International Clinical Trials Registry Platform and ProQuest Dissertations and Theses Global was conducted to identify all human studies that reported risk factors for MRONJ. Only a qualitative analysis was performed due to significant heterogeneity in the collected data. The search strategy identified 2872 records, of which 219 studies were eligible for inclusion. A total of 4106 patients with MRONJ were identified, 39 different systemic diseases were implicated, and 14 medical and 11 dental risk factors were reported, although no statistical analysis of the significance of each of these factors was possible. The clinical reach of MRONJ may be wider than anticipated, and more data on the significance of each potential risk factor are needed to guide the identification and management of at-risk patients. PMID- 28656645 TI - Regulation of Nuclear Receptor Interacting Protein 1 (NRIP1) Gene Expression in Response to Weight Loss and Exercise in Humans. AB - OBJECTIVE: Nuclear receptor interacting protein 1 (NRIP1) is an important energy regulator, but few studies have addressed its role in humans. This study investigated adipose tissue and skeletal muscle NRIP1 gene expression and serum levels in response to weight loss and exercise in humans. METHODS: NRIP1 expression was measured by microarray and serum NRIP1 by ELISA and Western blotting. Skeletal muscle transcriptomes were analyzed from Gene Expression Omnibus databases. Network-based proximity analysis was performed on the proximity of NRIP1 interacting genes in the human interactome. RESULTS: In patients with obesity, adipose tissue NRIP1 mRNA expression increased during weight loss and weight maintenance and showed strong associations with metabolic markers and anthropometric parameters. Serum NRIP1 protein levels also increased after weight loss. In skeletal muscle, imposed rest increased NRIP1 expression by 80%, and strength training increased expression by ~25% compared to baseline. Following rest, NRIP1 expression became sensitive to insulin stimulation. After re-training, NRIP1 expression decreased. Interactome analysis showed significant proximity of NRIP1 interacting partners to the obesity network/module. CONCLUSIONS: NRIP1 gene expression and serum levels are strongly associated with metabolic states such as obesity, weight loss, different types of exercise, and peripheral tissue insulin resistance, potentially as a mediator of sedentary effects. PMID- 28656644 TI - Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats. AB - The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse-3 (GSK-3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK-3 by lateral ventricular infusion of wortmannin (WT) and GF-109203X (GFX), the inhibitors of phosphoinositol-3 kinase (PI3-K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor-kappaB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK-3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK-3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients. PMID- 28656646 TI - Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia. AB - BACKGROUND: No studies have been performed comparing intravenous (IV) iron with transfused red blood cells (RBCs) for treating anemia during infection. In a previous report, transfused older RBCs increased free iron release and mortality in infected animals when compared to fresher cells. We hypothesized that treating anemia during infection with transfused fresh RBCs, with minimal free iron release, would prove superior to IV iron therapy. STUDY DESIGN AND METHODS: Purpose-bred beagles (n = 42) with experimental Staphylococcus aureus pneumonia rendered anemic were randomized to be transfused RBCs stored for 7 days or one of two IV iron preparations (7 mg/kg), iron sucrose, a widely used preparation, or ferumoxytol, a newer formulation that blunts circulating iron levels. RESULTS: Both irons increased the alveolar-arterial oxygen gradient at 24 to 48 hours (p = 0.02-0.001), worsened shock at 16 hours (p = 0.02-0.003, respectively), and reduced survival (transfusion 56%; iron sucrose 8%, p = 0.01; ferumoxytol 9%, p = 0.04). Compared to fresh RBC transfusion, plasma iron measured by non-transferrin bound iron levels increased with iron sucrose at 7, 10, 13, 16, 24, and 48 hours (p = 0.04 to p < 0.0001) and ferumoxytol at 7, 24, and 48 hours (p = 0.04 to p = 0.004). No significant differences in cardiac filling pressures or performance, hemoglobin (Hb), or cell-free Hb were observed. CONCLUSIONS: During canine experimental bacterial pneumonia, treatment of mild anemia with IV iron significantly increased free iron levels, shock, lung injury, and mortality compared to transfusion of fresh RBCs. This was true for iron preparations that do or do not blunt circulating free iron level elevations. These findings suggest that treatment of anemia with IV iron during infection should be undertaken with caution. PMID- 28656647 TI - Epigenetic silencing of ASPP1 confers 5-FU resistance in clear cell renal cell carcinoma by preventing p53 activation. AB - Inactivation of p53 has been shown to correlate with drug resistance in tumors. However, in clear cell renal cell carcinoma (ccRCC), p53 is rarely mutated, yet the tumors remain highly insensitive to the conventional chemotherapeutic drugs. The underlying mechanisms responsible for the non-genetic p53 inactivation remain obscure. Here, we report, for the first time, that Apoptosis Stimulating of P53 Protein 1 (ASPP1) was remarkably downregulated at both mRNA (about 3.9-fold) and protein (about 4.9-fold) levels in ccRCC human specimens in comparison with the paired normal controls. In addition, lower ASPP1 was closely related to the higher grade of tumors and shorter life expectancy of ccRCC patients, both with p < 0.001. We also find that CpG island hypermethylation at promoter region contributed to the suppression of ASPP1 expression in ccRCC that contained relatively low levels of ASPP1. Further functional studies demonstrated that forced expression ASPP1 not only significantly inhibited the growth rate of ccRCC, but also promoted sensitivity of ccRCC to the conventional chemotherapeutic drug 5-fluorouracil (5-FU)-induced apoptosis. Moreover, ASPP1 expression was accompanied with the apoptosis-prone alterations of p53 targets expression and p53 target PIG3 luciferase reporter activation. In contrast, ASPP1 knockdown promoted cell growth and prevent 5-FU-induced p53 activation and apoptosis. In conclusion, our results suggest that ASPP1 silencing is one of dominate mechanisms in inhibiting wild type p53 in ccRCC. ASPP1, therefore, may be potentially used as a promising biomarker for prognosis and therapeutic intervention in ccRCC. PMID- 28656648 TI - Prenatal incision of ureterocele causing bladder outlet obstruction: a multicenter case series. AB - We reviewed data from a cohort of fetuses with ureterocele diagnosed and operated prenatally in four fetal therapy centers. Inclusion criteria were (1) ureterocele confirmed on detailed fetal ultrasound examination, (2) absence of additional fetal malformations, and (3) fetal intervention to decompress the ureterocele with local institutional review boards' approval. Data on sonographic follow-up, obstetrical, neonatal outcome, and postnatal evaluation were collected. Ten cases of prenatally treated ureterocele are described. Six cases benefited from a fetoscopy for laser incision and decompression, two cases had an ultrasound guided puncture before resorting to a fetoscopy with laser incision, one case had a balloon catheterization under ultrasound guidance, and one case had an ultrasound-guided opening of the ureterocele with a laser fiber passed through a 20-gauge needle. Mean gestational age at diagnosis was 21.6 GW. Two cases underwent termination of pregnancy. The remaining eight cases recovered normal amniotic fluid volume and delivered a liveborn child at a mean gestational age of 38.6 GW with normal creatinine levels during the first week of life. Prenatal incision provided complete treatment of severely obstructive ureteroceles in 80% of the cases and allowed improvement of urinary electrolytes, renal size and echogenicity, bladder filling in all survivors, and recollection of normal amniotic fluid volume, in case of oligoanhydramnios. (c) 2017 John Wiley & Sons, Ltd. PMID- 28656649 TI - Multi-gradient-echo myelin water fraction imaging: Comparison to the multi-echo spin-echo technique. AB - PURPOSE: Myelin water fraction (MWF) mapping based on multi-gradient recalled echo (MGRE) imaging has been proposed as an alternative to the conventional multi echo-spin-echo (MESE) approach. In this work, we performed a comparative study of MESE and MGRE-derived MWFs in the same subject group. METHODS: MESE and MGRE data were acquired in 12 healthy volunteers at 3T. T2* decay curves were corrected for the effects of field inhomogeneities and multicomponent analysis of T2 and T2* signals was performed using non-negative least-squares fitting. RESULTS: When comparing MGRE and MESE-MWFs across volunteers, no significant differences were observed between average values in WM, deep GM (dGM), and cortical GM (cGM) that were (14 +/- 3%), (6 +/- 2%), and (8 +/- 2%) for MGRE, and (13 +/- 2%), (6 +/- 1%), and (7 +/- 1%), respectively, for MESE. The MGRE and MESE-MWFs showed a strong correlation (r2 = 0.84) and Bland-Altman analysis revealed a small positive bias of (0.8 +/- 1.6%) (absolute difference) for the MGRE-MWF. CONCLUSION: Overall, we observed excellent agreement between the two techniques. The small positive bias of the MGRE-MWF is thought to be a consequence of its potentially reduced sensitivity to water exchange effects, compared to the MESE MWF. This work suggests that with careful correction for the effects of field inhomogeneities, MGRE-MWF imaging is a promising alternative to the MESE approach. Magn Reson Med 79:1439-1446, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28656650 TI - Effects of signal artefacts on electroencephalography spectral power during sleep: quantifying the effectiveness of automated artefact-rejection algorithms. AB - Electroencephalography (EEG) recordings during sleep are often contaminated by muscle and ocular artefacts, which can affect the results of spectral power analyses significantly. However, the extent to which these artefacts affect EEG spectral power across different sleep states has not been quantified explicitly. Consequently, the effectiveness of automated artefact-rejection algorithms in minimizing these effects has not been characterized fully. To address these issues, we analysed standard 10-channel EEG recordings from 20 subjects during one night of sleep. We compared their spectral power when the recordings were contaminated by artefacts and after we removed them by visual inspection or by using automated artefact-rejection algorithms. During both rapid eye movement (REM) and non-REM (NREM) sleep, muscle artefacts contaminated no more than 5% of the EEG data across all channels. However, they corrupted delta, beta and gamma power levels substantially by up to 126, 171 and 938%, respectively, relative to the power level computed from artefact-free data. Although ocular artefacts were infrequent during NREM sleep, they affected up to 16% of the frontal and temporal EEG channels during REM sleep, primarily corrupting delta power by up to 33%. For both REM and NREM sleep, the automated artefact-rejection algorithms matched power levels to within ~10% of the artefact-free power level for each EEG channel and frequency band. In summary, although muscle and ocular artefacts affect only a small fraction of EEG data, they affect EEG spectral power significantly. This suggests the importance of using artefact-rejection algorithms before analysing EEG data. PMID- 28656651 TI - Convection-Diffusion Layer in an "Open Space" for Local Surface Treatment and Microfabrication using a Four-Aperture Microchemical Pen. AB - A four-aperture microchemical pen was used to produce a stable convection diffusion layer in an "open space" for microreactions and microfabrication. The process represents a new method for microreactions and microfabrication in a convection-diffusion layer. To prove the concept of a convection-diffusion layer in an "open space", bovine serum albumin was labeled with 4-fluoro-7-nitro-2,1,3 benzoxadiazole to confirm that the small convection-diffusion layer was effective for local surface treatment. To demonstrate the potential for microfabrication, silver patterns were fabricated on a glass surface with a convection-diffusion layer by using the silver-mirror reaction. The widths of each silver pattern could be easily controlled from 10 to 60 MUm. Patterned silver lines with uniform widths or gradient widths were prepared. This is the first proof of concept study of a convection-diffusion layer in an "open space" used in local surface treatment and microfabrication on a surface. The microchemical pen represents a potential method for the region-selective microtreatment of tissues, cells, and other biological interfaces. PMID- 28656652 TI - Impressive tissue regeneration of severe oral mucositis post stem cell transplantation using cord blood platelet gel. AB - BACKGROUND: Platelet gel from cord blood (CBPG) is a recently developed blood component for topical use. We report a case of life-threatening mucositis after high-dose chemotherapy with fotemustine and cytarabine that was successfully treated with CBPG. CASE REPORT: A patient with non-Hodgkin lymphoma who was undergoing autologous hematopoietic stem cell transplantation developed severe oral and esophageal mucositis with severe bacterial sepsis and cytomegalovirus infection, causing prolonged neutropenia. CBPG was topically administered daily to the oral cavity. The CBPG was partially reabsorbed and partially swallowed. RESULTS: After 8 consecutive days of administration, the patient's oral mucosa markedly improved, showing restitutio ad integrum, and the patient's clinical status progressively improved. No side effects were seen after CBPG application. CONCLUSION: This case supports the need to conduct controlled studies comparing the efficacy of autologous and allogeneic platelet gel from adult and umbilical cord blood for the topical treatment of severe oral mucositis occurring after high-dose chemotherapy. PMID- 28656653 TI - Flood Risk Management: Exploring the Impacts of the Community Rating System Program on Poverty and Income Inequality. AB - Flooding remains a major problem for the United States, causing numerous deaths and damaging countless properties. To reduce the impact of flooding on communities, the U.S. government established the Community Rating System (CRS) in 1990 to reduce flood damages by incentivizing communities to engage in flood risk management initiatives that surpass those required by the National Flood Insurance Program. In return, communities enjoy discounted flood insurance premiums. Despite the fact that the CRS raises concerns about the potential for unevenly distributed impacts across different income groups, no study has examined the equity implications of the CRS. This study thus investigates the possibility of unintended consequences of the CRS by answering the question: What is the effect of the CRS on poverty and income inequality? Understanding the impacts of the CRS on poverty and income inequality is useful in fully assessing the unintended consequences of the CRS. The study estimates four fixed-effects regression models using a panel data set of neighborhood-level observations from 1970 to 2010. The results indicate that median incomes are lower in CRS communities, but rise in floodplains. Also, the CRS attracts poor residents, but relocates them away from floodplains. Additionally, the CRS attracts top earners, including in floodplains. Finally, the CRS encourages income inequality, but discourages income inequality in floodplains. A better understanding of these unintended consequences of the CRS on poverty and income inequality can help to improve the design and performance of the CRS and, ultimately, increase community resilience to flood disasters. PMID- 28656654 TI - Sheep pox in Tunisia: Current status and perspectives. AB - Sheep pox, a well-known endemic capripox infection, has significant impacts on small ruminant populations in Tunisia. It is responsible for high economic losses throughout North Africa due to its enzootic nature and to the active animal transhumance existing in some governorates in Tunisia. The aim of this review was to analyse data gathered on annual vaccination campaigns designed to control its spread by reducing the level of endemicity and to describe diagnostic and management tools adapted to the Tunisian situation. Seasonal, temporal and spatial distributions of sheep pox outbreaks, as well as related clinical features, were found. It was concluded from this review that establishing strong herd immunization through individual animal immunization, creating adequate infrastructure, increasing awareness among breeders, setting up a field-based surveillance network and improving routine diagnostic methods need to be the major components of a programme to eradicate the disease. It was also felt that cost-benefit analyses of the surveillance and control strategies used would help in controlling its persistence. PMID- 28656655 TI - Clinical utility of a passive immune basophil activation test for the analysis of allergic transfusion reactions. AB - BACKGROUND: In previous studies, we demonstrated that the basophil activation test, which is performed using patient blood and the supernatants from transfused blood components, was able to elucidate not only the causative relationship between allergic transfusion reactions and the transfusion but also the mechanisms behind allergic transfusion reactions. However, for a large number of allergic transfusion reactions, patients are in a state of myelosuppression, and the basophil activation test cannot be performed for these patients because there are insufficient numbers of peripheral blood basophils. STUDY DESIGN AND METHODS: To overcome this obstacle, we developed a passive immune basophil activation test, in which patient plasma and residually transfused blood are used as the patient's sources of immunoglobulin E and allergen, respectively, whereas healthy volunteer basophils serve as the responder cell source. The passive immune basophil activation test was performed for two patients who had severe allergic transfusion reactions, using supernatants of the residual platelet concentrates and the patients' own immunoglobulin E. RESULTS: There were no differences in either surface immunoglobulin E or activation in response to allergens between untreated basophils and so-called quasi-basophils, in which immunoglobulin E was replaced by a third party's immunoglobulin E. In these patients, the supernatants of the residual platelet concentrates exclusively activated basophils in response to quasi-basophils onto which the patients' immunoglobulin E, but not a third party's immunoglobulin E, was bound. CONCLUSION: The passive immune basophil activation test may help clarify the causal relationship between allergic transfusion reactions and transfused blood, even when patients experience myelosuppression. PMID- 28656657 TI - Early Activation of MAPK and Apoptosis in Nutritive Embryos of Calyptraeid Gastropods. AB - Investigation of alternative phenotypes, different morphologies produced by a single genome, has contributed novel insights into development and evolution. Yet, the mechanisms underlying developmental switch points between alternative phenotypes remain poorly understood. The calyptraeid snails Crepidula navicella and Calyptraea lichen produce two phenotypes: viable and nutritive embryos, where nutritive embryos arrest their development after gastrulation and are ingested by their viable siblings as a form of intracapsular nutrition. Here, we investigate the activity of mitogen-activated protein kinase (MAPK, ERK1/2) and apoptosis during early cleavage. MAPK and apoptosis, found in a previous transcriptomic study, are known to be involved in organization of other spiralian embryos and nutritive embryo development, respectively. In the model Crepidula fornicata, MAPK activation begins at the 16-cell stage. In contrast, we discovered in C. navicella and C. lichen that many embryos begin MAPK activation at the one-cell stage. A subset of embryos shows a similar pattern of MAPK activation to C. fornicata at later stages. In all stages where MAPK is detected, the activation pattern is highly variable, frequently occurring in all quadrants or in multiple tiers of cells. We also detected apoptosis in cleaving embryos, while C. fornicata and Crepidula lessoni, which do not produce nutritive embryos, show no signs of apoptosis during cleavage. Our results show that MAPK and apoptosis are expressed during early development in species with nutritive embryos, and raises the possibility that these processes may play a role and even interact with one another in producing the nutritive embryo phenotype. PMID- 28656656 TI - The dawn of automated insulin delivery: A new clinical framework to conceptualize insulin administration. PMID- 28656658 TI - PL10 DEAD-Box Protein is Expressed during Germ Cell Differentiation in the Reptile Podarcis sicula (Family Lacertidae). AB - Among genes involved in the regulation of germ cell differentiation, those of DDX4/Vasa and the Ded1/DDX3 subfamilies encode for DEAD-box ATP-dependent RNA helicases, proteins involved in many mechanisms related to RNA processing. For the first time in reptiles, using specific antibodies at confocal microscopy, we analysed the localization pattern of a Ded1/DDX3 subfamily member in testis and ovary of Podarcis sicula (Ps-PL10) during the reproductive cycle. In testis, Ps PL10 is expressed in the cytoplasm of spermatocytes and it is not detected in spermatogonia. Differently from Ps-VASA, in round spermatids, Ps-PL10 is not segregated in the chromatoid body but it accumulates in the cytoplasm of residual bodies, and mature spermatozoa are unstained. These observations suggest that in males, Ps-PL10 (1) is involved in spermatogenesis and (2) is then eliminated with residual bodies. In the ovary, Ps-PL10 is present with granules in the cytoplasm of early meiotic cells of the germinal bed (GB), while it is not present in oogonia and somatic cells of the GB stroma. In follicular cells of ovarian follicles, Ps-PL10 expression starts after their fusion with the oocyte. Numerous Ps-PL10 spots are visible in pyriform (nurse-like) cells concomitantly with the protein accumulation in the cytoplasm of differentiating oocyte. In pyriform cells, Ps-PL10 spots are present in the cytoplasm and nuclei, as observed for Ps VASA, and in the nucleoli, suggesting for Ps-PL10 a role in rRNA processing and in the transport of molecules from the nucleus to cytoplasm and from nurse cells to the oocyte. PMID- 28656659 TI - Multidisciplinary biopsychosocial rehabilitation for subacute low back pain. AB - BACKGROUND: Low back pain (LBP) is associated with enormous personal and societal burdens, especially when it reaches the chronic stage of the disorder (pain for a duration of more than three months). Indeed, individuals who reach the chronic stage tend to show a more persistent course, and they account for the majority of social and economic costs. As a result, there is increasing emphasis on the importance of intervening at the early stages of LBP.According to the biopsychosocial model, LBP is a condition best understood with reference to an interaction of physical, psychological, and social influences. This has led to the development of multidisciplinary biopsychosocial rehabilitation (MBR) programs that target factors from the different domains, administered by healthcare professionals from different backgrounds.This review is an update of a Cochrane Review on MBR for subacute LBP, which was published in 2003. It is part of a series of reviews on MBR for musculoskeletal pain published by the Cochrane Back and Neck Group and the Cochrane Musculoskeletal Group. OBJECTIVES: To examine the effectiveness of MBR for subacute LBP (pain for a duration of six to 12 weeks) among adults, with a focus on pain, back-specific disability, and work status. SEARCH METHODS: We searched for relevant trials in any language by a computer-aided search of CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO and two trials registers. Our search is current to 13 July 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults with subacute LBP. We included studies that investigated a MBR program compared to any type of control intervention. We defined MBR as an intervention that included a physical component (e.g. pharmacological, physical therapy) in combination with either a psychological, social, or occupational component (or any combination of these). We also required involvement of healthcare professionals from at least two different clinical backgrounds with appropriate training to deliver the component for which they were responsible. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. In particular, the data extraction and 'risk of bias' assessment were conducted by two people, independently. We used the Cochrane tool to assess risk of bias and the GRADE approach to assess the overall quality of the evidence for each outcome. MAIN RESULTS: We included a total of nine RCTs (981 participants) in this review. Five studies were conducted in Europe and four in North America. Sample sizes ranged from 33 to 351. The mean age across trials ranged between 32.0 and 43.7 years.All included studies were judged as having high risk of performance bias and high risk of detection bias due to lack of blinding, and four of the nine studies suffered from at least one additional source of possible bias.In MBR compared to usual care for subacute LBP, individuals receiving MBR had less pain (four studies with 336 participants; SMD -0.46, 95% CI -0.70 to -0.21, moderate-quality of evidence due to risk of bias) and less disability (three studies with 240 participants; SMD -0.44, 95% CI -0.87 to -0.01, low-quality of evidence due to risk of bias and inconsistency), as well as increased likelihood of return-to work (three studies with 170 participants; OR 3.19, 95% CI 1.46 to 6.98, very low quality of evidence due to serious risk of bias and imprecision) and fewer sick leave days (two studies with 210 participants; SMD -0.38 95% CI -0.66 to -0.10, low-quality of evidence due to risk of bias and imprecision) at 12-month follow up. The effect sizes for pain and disability were low in terms of clinical meaningfulness, whereas effects for work-related outcomes were in the moderate range.However, when comparing MBR to other treatments (i.e. brief intervention with features from a light mobilization program and a graded activity program, functional restoration, brief clinical intervention including education and advice on exercise, and psychological counselling), we found no differences between the groups in terms of pain (two studies with 336 participants; SMD 0.14, 95% CI -0.36 to 0.07, low-quality evidence due to imprecision and risk of bias), functional disability (two studies with 345 participants; SMD -0.03, 95% CI -0.24 to 0.18, low-quality evidence due to imprecision and risk of bias), and time away from work (two studies with 158 participants; SMD -0.25 95% CI -0.98 to 0.47, very low-quality evidence due to serious imprecision, inconsistency and risk of bias). Return-to-work was not reported in any of the studies.Although we looked for adverse events in both comparisons, none of the included studies reported this outcome. AUTHORS' CONCLUSIONS: On average, people with subacute LBP who receive MBR will do better than if they receive usual care, but it is not clear whether they do better than people who receive some other type of treatment. However, the available research provides mainly low to very low quality evidence, thus additional high-quality trials are needed before we can describe the value of MBP for clinical practice. PMID- 28656660 TI - Replacement of Biphenyl by Bipyridine Enabling Powerful Hole Transport Materials for Efficient Perovskite Solar Cells. AB - Here, 2,2'- and 3,3'-bipyridine are introduced for the first time as the core structure to get two new hole transport materials (HTMs), namely F22 and F33. The electron-withdrawing nature of bipyridine lowers the HOMO level of the new compounds and enhances the open-circuit voltage of perovskite solar cells. Especially for F33, the better planarity leads to better conjugation in the whole molecule and the molecular interaction is enhanced. Hole-mobility tests, steady state photoluminescence (PL) spectra as well as time-resolved PL decay results demonstrate that the new HTMs exhibit good hole extraction and hole-transporting property. Impressive power conversion efficiencies of 17.71 and 18.48 % are achieved in conventional planar perovskite (CH3 NH3 PbI3-x Clx ) solar cells containing F22 and F33 as HTMs, respectively. As far as we know, this is the first report on bypiridine-based HTMs with leading efficiencies, and the design motif in this work opens a new way for devising HTMs in the future. PMID- 28656661 TI - Sonographic localization of a retained urethral foreign body in an elderly patient. AB - A retained urethral foreign body is an uncommon presentation in the Emergency Department. The diagnosis and treatment of retained urethral foreign bodies are determined by their size, location, shape, and mobility and often require specialty consultation and operative intervention. In this case of a 74-year-old man with a self-inserted, retained urethral foreign body, we present the utility of a bedside ultrasound to detect the depth, size, and distance from the meatus of the object to guide the approach to extraction of the object at the bedside in the Emergency Department. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:296-298, 2018. PMID- 28656662 TI - Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men. AB - CONTEXT: Male ageing is associated with lower circulating testosterone (T) and increased incidence of cardiovascular disease (CVD). Whether physical activity (PA) interacts with hormones to modify CVD risk is unclear. OBJECTIVE: We assessed whether PA and sex hormone concentrations were independently associated with measures of CVD risk. PARTICIPANTS: A total of 1649 men. METHODS: Leisure, home, work and total PA were ascertained. At baseline, serum T, dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Men were stratified into high PA+high hormone (H/H); low PA+high hormone (L/H); high PA+low hormone (H/L); and low PA+low hormone (L/L). RESULTS: Mean age was 49.8 years at outset with 415 CVD events and 127 CVD deaths occurring during 20-year follow-up. Men with higher PA and higher T or DHT had lower odds of metabolic syndrome (eg leisure H/H vs L/L odds ratio [OR] 0.17 P<.001 for T, 0.26 P<.001 for DHT). Men with higher PA and E2 had lower risk of metabolic syndrome (eg leisure PA H/H vs L/L OR 0.51, P=.001). Men with higher leisure, work or total PA and higher DHT had the lowest risk of CVD death (eg leisure H/H hazard ratio [HR] 0.55 vs L/L, P=.033). Men with lower leisure, home or work PA and higher E2 were at greater risk of CVD death (eg leisure L/H HR 1.60 vs L/L, P=.039). CONCLUSIONS: Considering T, DHT and E2 in the context of PA better informs consideration of cardiovascular risk. A 2*2 factorial RCT assessing PA and androgens would illuminate the scope for preventing CVD in men. PMID- 28656665 TI - Testing for HTLV 1 and HTLV 2 among blood donors in Western Saudi Arabia: prevalence and cost considerations. AB - BACKGROUND: Screening all blood donors for human T-cell lymphotropic viruses 1 and 2 (HTLV 1 and HTLV 2) is mandatory in Saudi Arabia. The aim of this study is to evaluate the results and costs associated with the current testing policy for HTLV 1 and HTLV 2 in blood donors at King Abdulaziz University Hospital (KAUH), Jeddah. STUDY DESIGNS AND METHODS: Donor-testing results from Blood Transfusion Services at KAUH were reviewed over a 10-year period, from January 2006 through December 2015. All donors were screened using chemiluminescent microparticle immunoassay. Reactive samples were then tested by Western blot for confirmation. Costs associated with testing were calculated. RESULTS: Data of 107 419 donations in the study period were reviewed. Saudi nationals constituted 51 168 donors (47.6%). Of 107 419 blood donors tested for HTLV 1 and HTLV 2 antibody, and 95 (0.088%) donors were reactive to screening tests. None of the samples found to be reactive to screening tests was positive by Western blot. The average cost of testing was US$ 171 870 per year. CONCLUSION: No donors were confirmed to have HTLV 1 and HTLV 2 in this cohort exceeding 100 000 donors. We propose changes to the policy mandating universal testing by replacing it with universal leukodepletion coupled with targeted screening to donors coming from endemic area or donors at risk. Such changes are expected to lead to a reduction of testing cost without affecting safety. PMID- 28656664 TI - Poor adherence to chronic obstructive pulmonary disease medications in primary care: Role of age, disease burden and polypharmacy. AB - AIM: The aim of the present study was to assess the occurrence and determinants of poor adherence to pharmacological treatment in a cohort of primary care patients with chronic obstructive pulmonary disease (COPD), paying special attention to the role of age, comorbidity and polypharmacy. METHODS: We identified a cohort of COPD patients using the primary care Italian Health Search - IMS Longitudinal Patient Database. We assessed 1-year adherence to COPD maintenance pharmacotherapy (encompassing inhaled corticosteroids, long-acting beta agonists and long-acting anticholinergics). Poor adherence was defined as <80% of proportion of days covered by pharmacological treatment over a 1-year period. RESULTS: Of 22 505 patients (mean age 67.3 +/- 13.2; 41.3% women) entering the study, 17 486 (77.7%) were poorly adherent. According to multivariate analysis, poor adherence is less likely in older adults (OR 0.51, 95% CI 0.40-0.66), in non-smokers (OR 0.77, 95% CI 0.69-0.86) and in those with a history of alcohol abuse (OR 0.74, 95% CI 0.58-0.94). Higher comorbidity (OR 1.43, 95% CI 1.13-1.80) was positively associated with poor adherence. Polypharmacy was associated with poor adherence only in patients aged >=65 years (OR 1.34, 95% CI 1.13-1.59). Finally, COPD severity was associated with a reduced likelihood of poor adherence (OR 0.20, 95% CI 0.07-0.61 for stage IV). CONCLUSIONS: The present findings show that poor medication adherence is common in patients with COPD receiving long-term treatment. The interaction between age and polypharmacy, and the role of comorbidity suggest a pivotal role of biological age as a steering determinant of poor adherence. Geriatr Gerontol Int 2017; 17: 2500-2506. PMID- 28656663 TI - In Situ Capture of Bacterial Toxins for Antivirulence Vaccination. AB - Antivirulence vaccination is a promising strategy for addressing bacterial infection that focuses on removing the harmful toxins produced by bacteria. However, a major challenge for creating vaccines against biological toxins is that the vaccine potency is often limited by lack of antigenic breadth, as most formulations have focused on single antigens, while most bacteria secrete a plethora of toxins. Here, a facile approach for generating multiantigenic nanotoxoids for use as vaccines against pathogenic bacteria by leveraging the natural affinity of virulence factors for cellular membranes is reported. Specifically, multiple virulent toxins from bacterial protein secretions are concurrently and naturally entrapped using a membrane-coated nanosponge construct. The resulting multivalent nanotoxoids are capable of delivering virulence factors together, are safe both in vitro and in vivo, and can elicit functional immunity capable of combating live bacterial infections in a mouse model. Despite containing the same bacterial antigens, the reported nanotoxoid formulation consistently outperforms a denatured protein preparation in all of the metrics studied, which underscores the utility of biomimetic nanoparticle based neutralization and delivery. Overall this strategy helps to address major hurdles in the design of antivirulence vaccines, enabling increased antigenic breadth while maintaining safety. PMID- 28656667 TI - Tight control of sulfur assimilation: an adaptive mechanism for a plant from a severely phosphorus-impoverished habitat. AB - Hakea prostrata (Proteaceae) has evolved in extremely phosphorus (P)-impoverished habitats. Unlike species that evolved in P-richer environments, it tightly controls its nitrogen (N) acquisition, matching its low protein concentration, and thus limiting its P requirement for ribosomal RNA (rRNA). Protein is a major sink for sulfur (S), but the link between low protein concentrations and S metabolism in H. prostrata is unknown, although this is pivotal for understanding this species' supreme adaptation to P-impoverished soils. Plants were grown at different sulfate supplies for 5 wk and used for nutrient and metabolite analyses. Total S content in H. prostrata was unchanged with increasing S supply, in sharp contrast with species that typically evolved in environments where P is not a major limiting nutrient. Unlike H. prostrata, other plants typically store excess available sulfate in vacuoles. Like other species, S-starved H. prostrata accumulated arginine, lysine and O-acetylserine, indicating S deficiency. Hakea prostrata tightly controls its S acquisition to match its low protein concentration and low demand for rRNA, and thus P, the largest organic P pool in leaves. We conclude that the tight control of S acquisition, like that of N, helps H. prostrata to survive in P-impoverished environments. PMID- 28656666 TI - Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study. AB - Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU) induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in the P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1770 patients were included in the analysis of SU efficacy, assessed as the combined outcome of the HbA1c reduction and the prescribed SU daily dose. Sixty nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia (OR, 2.81; 95% CI, 1.30-6.09; P = .009) and better response to SU treatment (beta, -0.218; SE, 0.074; P = .003) only in patients carrying the POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment. PMID- 28656668 TI - Coloured overlays and precision-tinted lenses: poor repeatability in a sample of adults and children diagnosed with visual stress AB - PURPOSE: Visual stress consists of perceived distortions or discomfort while reading. It is claimed that these symptoms are alleviated by viewing through coloured lenses or overlays, with a specific colour required for each individual. This has been explained on the basis of altered visual cortex excitation as affected by the spectral content of the viewing light. If symptoms are indeed alleviated by a particular colour that has an impact on the individual's visual system, we would expect that selection of the most beneficial colour would be repeatable. The aim of this study was to determine whether this is the case. METHODS: Twenty-one participants (mean age 26 years (range 8-55 years); 12 female, nine male) with visual stress and no other uncorrected ocular or visual anomaly were recruited. Each participant selected the colour most beneficial in alleviating their symptoms from a standard set of 10 coloured overlays, and underwent intuitive colorimetry in which the most beneficial of a wide range of chromatic illuminance settings was selected. Without prescribing an overlay at the first appointment, this process was repeated on a second occasion at a mean of 25 days later. RESULTS: About half of the participants (n = 10) chose the same (n = 7) or similar (with one common colour in both choices; n = 3) coloured overlay on the two occasions, while 11 participants chose a completely different overlay colour. Across all participants, the colorimetry setting shifted by, on average, 9.6 just noticeable differences, indicating that the colours were perceptually very different. CONCLUSION: These findings suggest that people with visual stress are unlikely to find exactly the same colour to be optimal on different occasions, and raise questions about the need for precise colour specification in tinted lenses for visual stress. PMID- 28656669 TI - Optical coherence tomography predicts 4-year incident diabetic neuropathy. AB - PURPOSE: To examine the capability of optical coherence tomography-derived retinal thickness measures in detecting 4-year incident diabetic peripheral neuropathy (DPN). METHODS: 145 eyes of 145 participants with diabetes but no DPN at baseline were examined for incident DPN. HbA1c levels, nephropathy, neuropathy (DPN), cardiovascular measures, and various retinal thickness measures were examined at baseline and after 4 years. Incidence of DPN was defined as newly developed DPN at follow-up. Baseline factors were assessed by univariate and a step-wise multiple logistic regression, and the predictors were examined for diagnostic capabilities. RESULTS: Of the 145 participants without DPN at baseline, 51 had developed DPN when examined after 4 years (35% incidence). Of the ophthalmic variables, the mean (S.D.) of the overall thickness in the parafovea at baseline was 315 (18) MUm in the no DPN group and 306 (18) MUm in the 'incidence' group, and the differences were significant, p = 0.005. The superior hemisphere parafovea (mean (S.D.): 318 (17) MUm vs 310 (20) MUm, p = 0.02) and inferior hemisphere parafovea (313 (19) MUm vs 302 (18) MUm, p = 0.002) were different in the incident DPN group compared with the no DPN group. When adjusted for age, retinal thickness in the parafovea (AUC = 0.65, p = 0.003, 86% sensitivity and 44% specificity at 321 MUm criterion), and body mass index or BMI (AUC = 0.65, p = 0.003, 49% sensitivity and 83% specificity at 29.3 kg m-2 criterion) at baseline were significant predictors for 4-year incident DPN. CONCLUSIONS: A lower retinal thickness at the parafovea and a higher BMI can predict 4-year incident neuropathy in patients with diabetes, with acceptable diagnostic accuracies. This OCT-derived measure may serve as a potential ophthalmic marker in the screening of patients at risk of developing DPN. PMID- 28656670 TI - The corneal nerve density in the sub-basal plexus decreases with increasing myopia: a pilot study. AB - PURPOSE: Myopia can cause many changes in the health of the eye. As it becomes more prevalent worldwide, more patients seek correction in the form of glasses, contact lenses and refractive surgery. In this study we explore the impact that high myopia has on central corneal nerve density by comparing sub basal nerve plexus density measured by confocal microscopy in a variety of refractive errors. METHODS: Seventy healthy adult subjects between the ages of 21-50 years participated in this study. The study took place in two phases with no overlapping subjects (n = 30 phase 1 and n = 40 phase 2). In both phases an autorefraction, keratometry reading, corneal thickness measure and confocal corneal scan of the sub basal nerve plexus were performed for both eyes. There were 11 hyperopes (+0.50 to +3.50DS), six emmetropes (-0.25 to +0.50DS), 30 low myopes (-5.50 to -0.50DS), and 23 high myopes (-5.50DS and above). In the second phase of the study additional tests were performed including an axial length, additional corneal scans, and a questionnaire that asked about age of first refractive correction and contact lens wear. Corneal nerves were imaged over the central cornea with a Nidek CS4 confocal microscope (460 * 345 MUm field). Nerves were evaluated using the NeuronJ program for density calculation. One eye was selected for inclusion based on image quality and higher refractive error (more myopic or hyperopic). RESULTS: As myopia increased, nerve density decreased (t1 = 3.86, p < 0.001). We also note a decrease in data scatter above -7 D. The relationship between axial length values and nerve density was also significant and the slope was not as robust as refractive error (t1 = 2.4, p < 0.04). As expected there was a significant difference between the four groups in axial length (F3 = 19.9, p < 0.001) and age of first refractive correction of the myopic groups (14.9 vs 11.5 years; t46 = 2.99 p < 0.01). There was no difference in keratometry readings or corneal thickness between the groups (F3 = 0.6, p = 0.66 and F3 = 1.2, p = 0.33 respectively). CONCLUSION: Corneal nerve density in the sub-basal plexus decreased with increasing myopia. This could have implications for corneal surgery and contact lens wear in this patient population. PMID- 28656671 TI - Effect of simulated refractive error on adult visual acuity for paediatric tests. AB - PURPOSE: Although vanishing optotype preferential-looking tasks are commonly used to measure visual acuity (VA), the relative sensitivity of these tests to refractive error is not well understood. To address this issue, we determined the effect of spherical and astigmatic simulated refractive errors on adult VA measures obtained using vanishing optotypes, picture optotypes and Sloan letters. METHODS: VA was determined uniocularly for adults under conditions of spherical (0.0-3.0 DS; n = 23) and astigmatic (0.0-3.0 DC at 90 degrees and 180 degrees ; n = 20) defocus using the Cardiff Acuity Test (vanishing optotypes), crowded linear Lea Symbols (picture-optotype recognition task) and the Early Treatment of Diabetic Retinopathy Study (ETDRS) letter chart. RESULTS: The Cardiff Acuity Test over-estimated VA compared with the Lea Symbols and ETDRS charts in both focused and defocused conditions. The mean difference between the Cardiff Acuity Test and the ETDRS chart was 0.31 logMAR (95% limits of agreement (LOA) 0.10-0.52 logMAR) in focused conditions and 0.64 logMAR (95% LOA 0.25-1.05 logMAR) with 3D of spherical defocus. Defocus degraded VA on all charts, however there was a significant chart-by-defocus interaction whereby the Cardiff Acuity Test was more resistant to the effects of both spherical (P < 0.0001) and cylindrical (P < 0.001) optical defocus than the recognition acuity tasks at all defocus levels. CONCLUSION: Although the Cardiff Acuity Test provides an easy method for VA measurement in infants and toddlers, there is a considerable overestimation of VA compared with recognition acuity tasks particularly in the presence of defocus. A simple correction factor (of for example three lines overestimate) cannot be applied to Cardiff acuity measures as there is increasing over-estimation of VA with increasing defocus. Infants with significant refractive error may fall within normal visual acuity ranges for the Cardiff Acuity Test. PMID- 28656672 TI - Drilling into the functional significance of stereopsis: the impact of stereoscopic information on surgical performance. AB - PURPOSE: One suggested advantage of human binocular vision is the facilitation of sophisticated motor control behaviours via stereopsis - but little empirical evidence exists to support this suggestion. We examined the functional significance of stereopsis by exploring whether stereopsis is used to perform a highly skilled real-world motor task essential for the occupational practice of dentistry. METHODS: We used a high fidelity virtual reality simulator to study how dentists' performance is affected by the removal of horizontal retinal image disparities under direct and indirect (mirror) observation. Thirteen qualified dentists performed a total of four different dental tasks under non-stereoscopic and stereoscopic vision conditions, with two levels of task complexity (direct and indirect observation) using a virtual reality dental simulator. RESULTS: Depth related errors were significantly higher under non-stereoscopic viewing but lateral errors did not differ between conditions. Indirect observation led to participants drilling less of the target area compared to direct viewing, but this did not interact with the stereopsis manipulation. CONCLUSIONS: The data confirm that dental practitioners use stereopsis and its presence results in improved dental performance. It remains to be determined whether individuals with stereo-deficits can compensate adequately. Nevertheless, these findings suggest an important role for stereopsis within at least one occupation and justify the design of simulators with 3D displays. PMID- 28656673 TI - Fourier analysis algorithm for the posterior corneal keratometric data: clinical usefulness in keratoconus. AB - PURPOSE: To develop an algorithm for the Fourier analysis of posterior corneal videokeratographic data and to evaluate the derived parameters in the diagnosis of Subclinical Keratoconus (SKC) and Keratoconus (KC). METHODS: This was a cross sectional, observational study that took place in the Eye Institute of Thrace, Democritus University, Greece. Eighty eyes formed the KC group, 55 eyes formed the SKC group while 50 normal eyes populated the control group. A self-developed algorithm in visual basic for Microsoft Excel performed a Fourier series harmonic analysis for the posterior corneal sagittal curvature data. The algorithm decomposed the obtained curvatures into a spherical component, regular astigmatism, asymmetry and higher order irregularities for averaged central 4 mm and for each individual ring separately (1, 2, 3 and 4 mm). The obtained values were evaluated for their diagnostic capacity using receiver operating curves (ROC). Logistic regression was attempted for the identification of a combined diagnostic model. RESULTS: Significant differences were detected in regular astigmatism, asymmetry and higher order irregularities among groups. For the SKC group, the parameters with high diagnostic ability (AUC > 90%) were the higher order irregularities, the asymmetry and the regular astigmatism, mainly in the corneal periphery. Higher predictive accuracy was identified using diagnostic models that combined the asymmetry, regular astigmatism and higher order irregularities in averaged 3and 4 mm area (AUC: 98.4%, Sensitivity: 91.7% and Specificity:100%). CONCLUSIONS: Fourier decomposition of posterior Keratometric data provides parameters with high accuracy in differentiating SKC from normal corneas and should be included in the prompt diagnosis of KC. PMID- 28656674 TI - Saccades and fixations in children with delayed reading skills. AB - PURPOSE: Previous studies have reported that eye movements differ between good/average and poor readers. However, these studies have been limited to investigating eye movements during reading related tasks, and thus, the differences found could arise from deficits in higher cognitive processes involved in reading rather than oculomotor performance. The purpose of the study is to determine the extent to which eye movements in children with delayed reading skills are different to those obtained from children with good/average reading skills in non-reading related tasks. METHODS: After a screening optometric assessment, eye movement recordings were obtained from 120 children without delayed reading skills and 43 children with delayed reading skills (4 to 11 years) using a Tobii TX300 eye tracker. Cartoon characters were presented horizontally from -20 degrees to +20 degrees in steps of 5 degrees to study saccades. An animated stimulus in the centre of the screen was presented for 8 seconds to study fixation stability. Saccadic main sequences, and the number and amplitude of the saccades during fixation were obtained for each participant. Children with delayed reading skills (n = 43) were unmasked after data collection was completed. Medians and quartiles were calculated for each eye movement parameter for children without (n = 120) and with (n = 43) delayed reading skills. RESULTS: Independent t-tests with Bonferroni correction showed no significant differences in any of the saccadic main sequence parameters (Slope, Intercept, A, n and Q ratio) between children without and with delayed reading (p > 0.01). Similarly, no significant differences were found in the number of saccades and their amplitude during the fixation task between the two groups (p > 0.05). Further, none of the gross optometric parameters assessed (visual acuity, refractive error, ocular alignment, convergence, stereopsis and accommodation accuracy) were found to be associated with delayed reading skills (p > 0.05). CONCLUSIONS: Eye movements in children with delayed reading skills are quantitatively similar to those found in children without delayed reading skills. These findings suggest that, in these children, delayed reading skills are not associated with eye movements and further question interventions targeted at improving eye movement control. PMID- 28656675 TI - Attenuation of short wavelengths alters sleep and the ipRGC pupil response. AB - PURPOSE: Exposure to increasing amounts of artificial light during the night may contribute to the high prevalence of reported sleep dysfunction. Release of the sleep hormone melatonin is mediated by the intrinsically photosensitive retinal ganglion cells (ipRGCs). This study sought to investigate whether melatonin level and sleep quality can be modulated by decreasing night-time input to the ipRGCs. METHODS: Subjects (ages 17-42, n = 21) wore short wavelength-blocking glasses prior to bedtime for 2 weeks. The ipRGC-mediated post illumination pupil response was measured before and after the experimental period. Stimulation was presented with a ganzfeld stimulator, including one-second and five-seconds of long and short wavelength light, and the pupil was imaged with an infrared camera. Pupil diameter was measured before, during and for 60 s following stimulation, and the six-second and 30 s post illumination pupil response and area under the curve following light offset were determined. Subjects wore an actigraph device for objective measurements of activity, light exposure, and sleep. Saliva samples were collected to assess melatonin content. The Pittsburgh Sleep Quality Index (PSQI) was administered to assess subjective sleep quality. RESULTS: Subjects wore the blue-blocking glasses 3:57 +/- 1:03 h each night. After the experimental period, the pupil showed a slower redilation phase, resulting in a significantly increased 30 s post illumination pupil response to one-second short wavelength light, and decreased area under the curve for one and five-second short wavelength light, when measured at the same time of day as baseline. Night time melatonin increased from 16.1 +/- 7.5 pg mL-1 to 25.5 +/- 10.7 pg mL-1 (P < 0.01). Objectively measured sleep duration increased 24 min, from 408.7 +/- 44.9 to 431.5 +/- 42.9 min (P < 0.001). Mean PSQI score improved from 5.6 +/- 2.9 to 3.0 +/- 2.2. CONCLUSIONS: The use of short wavelength-blocking glasses at night increased subjectively measured sleep quality and objectively measured melatonin levels and sleep duration, presumably as a result of decreased night-time stimulation of ipRGCs. Alterations in the ipRGC-driven pupil response suggest a shift in circadian phase. Results suggest that minimising short wavelength light following sunset may help in regulating sleep patterns. PMID- 28656676 TI - TMSCF3 as a Convenient Source of CF2 =CF2 for Pentafluoroethylation, (Aryloxy)tetrafluoroethylation, and Tetrafluoroethylation. AB - A new method for the on-site preparation of tetrafluoroethylene (TFE) and a procedure for its efficient use in pentafluoroethylation by fluoride addition were developed by using a simple two-chamber system. The on-site preparation of TFE was accomplished by dimerization of difluorocarbene derived from (trifluoromethyl)trimethylsilane (TMSCF3 ) under mild conditions. Other fluoroalkylation reactions, such as (aryloxy)tetrafluoroethylation and tetrafluoroethylation processes, were also achieved using a similar approach. This work not only demonstrates a convenient and safe approach for the generation and use of TFE in academic laboratories, but also provides a new strategy for pentafluoroethylation. PMID- 28656677 TI - Author's response to letter to the editor on: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. PMID- 28656678 TI - Mother-Adolescent Dialogues and Adolescents' Behavior Problems in a Multicultural Sample: The Mediating Role of Representations. AB - This study examined whether the link between higher maternal sensitive guidance of emotional dialogues and fewer adolescent behavior problems is mediated by adolescents' more coherent representations of their mothers. The study also explored the consistency of this model across families from varied cultural backgrounds. Participants were 143 Jewish-Israeli mother-adolescent dyads from three cultural groups: immigrants from the Former Soviet Union, immigrants from Western countries, and native-born Israelis. Maternal sensitive guidance was observed during mother-adolescent dialogues about emotional experiences. Adolescents' representations were assessed via their narratives regarding their mother and their relationship. Examiners reported adolescents' behavior problems. Results indicated that across cultural groups adolescents' more coherent representations partially mediated the association between higher maternal sensitive guidance and fewer adolescent behavior problems. PMID- 28656679 TI - Sculptors, Architects, and Painters Conceive of Depicted Spaces Differently. AB - Sculptors, architects, and painters are three professional groups that require a comprehensive understanding of how to manipulate spatial structures. While it has been speculated that they may differ in the way they conceive of space due to the different professional demands, this has not been empirically tested. To achieve this, we asked architects, painters, sculptors, and a control group questions about spatially complex pictures. Verbalizations elicited were examined using cognitive discourse analysis. We found significant differences between each group. Only painters shifted consistently between 2D and 3D concepts, architects were concerned with paths and spatial physical boundedness, and sculptors produced responses that fell between architects and painters. All three differed from controls, whose verbalizations were generally less elaborate and detailed. Thus, for the case of sculptors, architects, and painters, profession appears to relate to a different spatial conceptualization manifested through a systematically contrasting way of talking about space. PMID- 28656680 TI - Evaluation of the "assessment for continuous treatment with hepatic arterial infusion chemotherapy" scoring system in patients with advanced hepatocellular carcinoma. AB - AIM: Sorafenib is the recommended standard of care for advanced hepatocellular carcinoma (HCC) patients. However, hepatic arterial infusion chemotherapy (HAIC) is a treatment option in Asia. We recently developed the assessment for continuous treatment with HAIC (ACTH) score to guide decision-making for continuous HAIC treatment. The purpose of this study was to validate the utility of the ACTH score in a dedicated cohort. METHODS: One hundred and thirty-one patients with advanced HCC were enrolled in this study (90 in the training group and 41 in the validation group). The point score (range, 0-3) was calculated as follows: Child-Pugh score before HAIC (A = 0, B = 1), alpha-fetoprotein (AFP) response (yes = 0, no = 1), and des-gamma-carboxy prothrombin (DCP) response (yes = 0, no = 1). The AFP and DCP responses were assessed 2 weeks after HAIC induction; a positive response was defined as a reduction of >=20% from the baseline. RESULTS: The DCP response in the validation group was significantly associated with treatment response, and the median survival time (MST) was longer in patients with an ACTH score <=1 (15.9 months) than in those with a score >=2 (7.0 months; P = 0.002). Survival in all patients showed significant stratification according to the ACTH score; the MSTs associated with scores of 0, 1, 2, and 3 points were 21.7, 14.4, 9.5, and 3.8 months, respectively. CONCLUSION: The ACTH score can aid in the therapeutic assessment and continued treatment planning of HCC patients receiving HAIC. PMID- 28656681 TI - In Situ Derived Co?B Nanoarray: A High-Efficiency and Durable 3D Bifunctional Electrocatalyst for Overall Alkaline Water Splitting. AB - The development of efficient bifunctional catalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is of extreme importance for future renewable energy systems. This Communication reports the recent finding that room-temperature treatment of CoO nanowire array on Ti mesh by NaBH4 in alkaline media leads to in situ development of Co?B nanoparticles on nanowire surface. The resulting self-supported Co?B@CoO nanoarray behaves as a 3D bifunctional electrocatalyst with high activity and durability for both HER (<17% current density degradation after 20 h electrolysis) and OER (<14% current density degradation after 20 h electrolysis) with the need of the overpotentials of 102 and 290 mV to drive 50 mA cm-2 in 1.0 m KOH, respectively. Moreover, its two-electrode alkaline water electrolyzer also shows remarkably high durability and only demands a cell voltage of 1.67 V to deliver 50 mA cm-2 water-splitting current with a current density retention of 81% after 20 h electrolysis. This work provides a promising methodology for the designing and fabricating of metal boride based nanoarray as a high-active water-splitting catalyst electrode for applications. PMID- 28656682 TI - Mechanisms of PTHrP-induced inhibition of smooth muscle contractility in the guinea pig gastric antrum. AB - BACKGROUND: Parathyroid hormone-related protein (PTHrP) that causes hypercalcemia of malignancy appears to function as an endogenous smooth muscle relaxant. For example, PTHrP released upon bladder wall distension relaxes detrusor smooth muscle to accommodate urine. Here, we explored mechanisms underlying PTHrP induced suppression of the smooth muscle contractility in the gastric antrum that also undergoes a passive distension. METHODS: Effects of PTHrP on phasic contractions and electrical slow waves in the antral smooth muscle of the guinea pig stomach were studied using isometric tension and intracellular microelectrode recordings, respectively. Fluorescent immunohistochemistry was also carried out to identify the distribution of PTH/PTHrP receptors. KEY RESULTS: Parathyroid hormone-related protein (1-100 nM) reduced the amplitude of phasic contractions and the basal tension. Nomega -nitro-l-arginine (L-NA, 100 MUM), a nitric oxide (NO) synthase inhibitor, or 1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 10 uM), a guanylate cyclase inhibitor, diminished the PTHrP (10 nM)-induced reduction in the amplitude of phasic contractions. SQ22536 (300 MUM), an adenylate cyclase inhibitor, attenuated the PTHrP-induced reduction in basal tension. The combination of ODQ (10 MUM) and SQ22536 (300 MUM) inhibited the PTHrP-induced reductions in both phasic contractions and basal tension. PTHrP (100 nM) had no inhibitory effect on the electrical slow waves in the antral smooth muscle. PTH/PTHrP receptors were expressed in cell bodies of PGP9.5 positive neurons in the myenteric plexus. CONCLUSIONS & INFERENCES: Parathyroid hormone-related protein exerts its inhibitory actions on the antral smooth muscle via both nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and cyclic adenosine monophosphate (AMP) pathways. Thus, PTHrP may act as an endogenous relaxant of the gastric antrum employing the two complementary signaling pathways to ensure the adaptive relaxation of stomach. PMID- 28656683 TI - Associations of endocrine stress-related gene polymorphisms with risk of autism spectrum disorders: Evidence from an integrated meta-analysis. AB - : Autism spectrum disorders (ASD) are related to serotonin transporter (5-HTT) and catechol-O-methyl transferase (COMT) as two most monoaminergic polymorphic variations. However, multiple studies assessing rs4680 and 5-HTTLPR variants in ASD have reported inconsistent results. Therefore, we conducted an integrated meta-analysis to combine case-control and transmission/disequilibrium test (TDT) studies to determine whether COMT and 5-HTT are associated with ASD. We searched multiple electronic databases (PubMed, EmBase and Web of Science) to identify studies assessing the rs4680 and 5-HTTLPR variants in ASD from Jan 1997 to Dec 2016. Then allelic data from case-control and TDT studies were analyzed by the Catmap package in the R software. A total of 5 studies were eligible for the meta analysis of rs4680, including 3 case-control, 1 TDT and 1 TDT & case-control studies. Meanwhile, 22 studies of 5-HTTLPR were available, including 16 TDT, 4 case-control and 2 TDT & case-control studies. The current meta-analysis included 814 ASD cases, 741 controls and 311 families related to rs4680; 749 ASD cases, 1,118 controls and 1,861 families relevant to 5-HTTLPR were also evaluated. For rs4680, the pooled OR was 1.18 (95% CI = 0.87-1.59, P = 0.29, Pheterogeneity < 0.00001). There was no significant association of rs4680 with risk of ASD between the two subgroups. For 5-HTTLPR, the pooled OR was 1.05 (95% CI = 0.92-1.20, P = 0.4652, Pheterogeneity < 0.00001). Meanwhile, we found no significant risk in individual case-control or TDT studies. The above findings indicated that neither COMT rs4680 nor 5-HTT 5-HTTLPR polymorphism significantly affects ASD risk. Autism Res 2017, 10: 1722-1736. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Our results showed no evidence of significant association of either COMT rs4680 or 5-HTT 5-HTTLPR variants with ASD, showing that these two genes may not be major susceptible genetic factors in ASD occurrence, and may have a reciprocal action with each other in combination with environmental factors. These findings further provide evidence that a single gene variant may not dictate autism occurrence, but possibly contributes to a specific phenotype or subtype of ASD. PMID- 28656684 TI - The effect of World Blood Donor Day on digital information seeking and donor recruitment. AB - BACKGROUND: The purpose of World Blood Donor Day (WBDD) is to raise awareness for the importance of blood donation. The aim of this study was to quantify the impact of WBDD on digital information seeking and donor recruitment. STUDY DESIGN AND METHODS: Google Trends data were used to quantify seeking behavior on "blood donation" and "blood donor." Differences in relative search volume (RSV) between the 3 weeks surrounding WBDD and the rest of the year were calculated. Second, mean differences in RSV were compared to assess the additional effect of hosting using translated search terms. Third, we compared the period around WBDD with the control period regarding page views of the Sanquin website and Facebook likes and number of newly registered donors in 2016. RESULTS: The mean RSV for "blood donation" in the period of interest was 78.6, compared to 72.1 in the control period (difference, 6.5; 95% confidence interval [95% CI], 1.2-11.8). For "blood donor" this was 78.9 compared to 65.9 (difference, 12.9; 95% CI, 8.1-17.8). We found no additional effect of hosting. In the period of interest, the website of Sanquin was visited 6862 times a day and 4293 times in the control period (difference, 2569; 95% CI, 1687-3451). In June 2016, 54.6% (95% CI, 53.0-56.2) more new donors were registered compared to the control period. CONCLUSION: An international campaign like WBDD raises the awareness of blood donation and is effective in convincing people to register as blood donors. PMID- 28656685 TI - Impacts of lung and tumor volumes on lung dosimetry for nonsmall cell lung cancer. AB - The purpose of this study was to determine the impacts of lung and tumor volumes on normal lung dosimetry in three-dimensional conformal radiotherapy (3DCRT), step-and-shoot intensity-modulated radiotherapy (ssIMRT), and single full-arc volumetric-modulated arc therapy (VMAT) in treatment of nonsmall cell lung cancers (NSCLC). All plans were designed to deliver a total dose of 66 Gy in 33 fractions to PTV for the 32 NSCLC patients with various total (bilateral) lung volumes, planning target volumes (PTVs), and PTV locations. The ratio of the lung volume (total lung volume excluding the PTV volume) to the PTV volume (LTR) was evaluated to represent the impacts in three steps. (a) The least squares method was used to fit mean lung doses (MLDs) to PTVs or LTRs with power-law function in the population cohort (N = 32). (b) The population cohort was divided into three groups by LTRs based on first step and then by PTVs, respectively. The MLDs were compared among the three techniques in each LTR group (LG) and each PTV group (PG). (c) The power-law correlation was tested by using the adaptive radiation therapy (ART) planning data of individual patients in the individual cohort (N = 4). Different curves of power-law function with high R2 values were observed between averaged LTRs and averaged MLDs for 3DCRT, ssIMRT, and VMAT, respectively. In the individual cohort, high R2 values of fitting curves were also observed in individual patients in ART, although the trend was highly patient-specific. There was a more obvious correlation between LTR and MLD than that between PTV and MLD. PMID- 28656686 TI - Estimation of genetic risk function with covariates in the presence of missing genotypes. AB - In genetic epidemiological studies, family history data are collected on relatives of study participants and used to estimate the age-specific risk of disease for individuals who carry a causal mutation. However, a family member's genotype data may not be collected because of the high cost of in-person interview to obtain blood sample or death of a relative. Previously, efficient nonparametric genotype-specific risk estimation in censored mixture data has been proposed without considering covariates. With multiple predictive risk factors available, risk estimation requires a multivariate model to account for additional covariates that may affect disease risk simultaneously. Therefore, it is important to consider the role of covariates in genotype-specific distribution estimation using family history data. We propose an estimation method that permits more precise risk prediction by controlling for individual characteristics and incorporating interaction effects with missing genotypes in relatives, and thus, gene-gene interactions and gene-environment interactions can be handled within the framework of a single model. We examine performance of the proposed methods by simulations and apply them to estimate the age-specific cumulative risk of Parkinson's disease (PD) in carriers of the LRRK2 G2019S mutation using first-degree relatives who are at genetic risk for PD. The utility of estimated carrier risk is demonstrated through designing a future clinical trial under various assumptions. Such sample size estimation is seen in the Huntington's disease literature using the length of abnormal expansion of a CAG repeat in the HTT gene but is less common in the PD literature. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28656687 TI - Mitochondrial respiratory chain complex enzyme activities of limbic structures and psychiatric diagnosis in temporal lobe epilepsy patients: Preliminary results. PMID- 28656688 TI - Endoscopic treatment of pancreatic duct stones under direct vision: Revolution or resignation? Systematic review. AB - BACKGROUND AND AIM: The main treatment aim in chronic pancreatitis (CP) is symptom control and especially pain relief. Management of stone-predominant CP is challenging and requires a multidisciplinary approach. Extracorporeal shock wave lithotripsy (ESWL) has emerged as the cornerstone of non-surgical treatment as a result of disappointing results of available endoscopic treatment options during the last decades. With new developments in the field of direct peroral pancreatoscopy (POP) and intracorporeal lithotripsy, direct intraluminal treatment of main pancreatic duct (MPD) stones returns to the spotlight. METHODS: Herein, we reviewed the current data on direct pancreatoscopic treatment of MPD stones with a focus on efficiency and safety of available technologies, endoscopes and lithotripsy devices. A systematic Medline search for relevant studies was done. RESULTS: Ten relevant publications meeting the inclusion criteria were identified (two prospective series, six retrospective trials, two case reports, n = 87 patients). Successful ductal clearance for POP-guided treatment was reported as between 43% and 100% compared to ESWL with 59% to 80%. Adverse event rate for POP-guided therapy was reported as 0-13.5%. One study showed a noticeable higher adverse event rate of 43%. In this trial, POP was carried out after ESWL. There is no reported mortality following POP treatment. CONCLUSION: Available results are promising in terms of ductal clearance and pain relief compared to standard endoscopic techniques and ESWL as the current gold standard for lithotripsy. Interpretation of this data is limited by the small number of cases for POP and the lack of prospective randomized controlled trials. PMID- 28656689 TI - Multiple reaction monitoring (MRM)-profiling for biomarker discovery applied to human polycystic ovarian syndrome. AB - RATIONALE: We describe multiple reaction monitoring (MRM)-profiling, which provides accelerated discovery of discriminating molecular features, and its application to human polycystic ovary syndrome (PCOS) diagnosis. The discovery phase of the MRM-profiling seeks molecular features based on some prior knowledge of the chemical functional groups likely to be present in the sample. It does this through use of a limited number of pre-chosen and chemically specific neutral loss and/or precursor ion MS/MS scans. The output of the discovery phase is a set of precursor/product transitions. In the screening phase these MRM transitions are used to interrogate multiple samples (hence the name MRM profiling). METHODS: MRM-profiling was applied to follicular fluid samples of 22 controls and 29 clinically diagnosed PCOS patients. Representative samples were delivered by flow injection to a triple quadrupole mass spectrometer set to perform a number of pre-chosen and chemically specific neutral loss and/or precursor ion MS/MS scans. The output of this discovery phase was a set of 1012 precursor/product transitions. In the screening phase each individual sample was interrogated for these MRM transitions. Principal component analysis (PCA) and receiver operating characteristic (ROC) curves were used for statistical analysis. RESULTS: To evaluate the method's performance, half the samples were used to build a classification model (testing set) and half were blinded (validation set). Twenty transitions were used for the classification of the blind samples, most of them (N = 19) showed lower abundances in the PCOS group and corresponded to phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Agreement of 73% with clinical diagnosis was found when classifying the 26 blind samples. CONCLUSIONS: MRM-profiling is a supervised method characterized by its simplicity, speed and the absence of chromatographic separation. It can be used to rapidly isolate discriminating molecules in healthy/disease conditions by tailored screening of signals associated with hundreds of molecules in complex samples. PMID- 28656690 TI - Neighborhood perception and self-rated health among Mexican American older adults. AB - AIM: The aim of the present study was to assess the relationship between neighborhood perception and poor self-rated health among older Mexican Americans, adjusting for important background characteristics, such as neighborhood ethnic composition and other health conditions. METHODS: Drawing on the 2004-2005 Hispanic Established Populations for the Epidemiologic Study of the Elderly data (n = 1780), the present study used logistic regression to examine the effects of neighborhood perception on poor self-rated health of older Mexican Americans. RESULTS: The results show that participants with a greater positive perception of their neighborhood were less likely to report poor self-rated health, controlling for both socioeconomic status and health status covariates. CONCLUSIONS: The findings suggest that positive neighborhood perception serves as an important protective factor in overall health. Geriatr Gerontol Int 2017; 17: 2559-2564. PMID- 28656692 TI - The negative secondary test for bacterial contamination: reducing the risk of septic transfusion reactions from platelets. PMID- 28656693 TI - Meta-analysis of randomized and quasi-randomized clinical trials of topical antibiotics after primary closure for the prevention of surgical-site infection. AB - BACKGROUND: Surgical-site infections (SSIs) increase patient morbidity and costs. The aim was to identify and synthesize all RCTs evaluating the effect of topical antibiotics on SSI in wounds healing by primary intention. METHODS: The search included Ovid MEDLINE, Ovid Embase, the Cochrane Wounds Specialized Register, Central Register of Controlled Trials and EBSCO CINAHL from inception to May 2016. There was no restriction of language, date or setting. Two authors independently selected studies, extracted data and assessed risk of bias. When sufficient numbers of comparable trials were available, data were pooled in meta analysis. RESULTS: Fourteen RCTs with 6466 participants met the inclusion criteria. Pooling of eight trials (5427 participants) showed that topical antibiotics probably reduced the risk of SSI compared with no topical antibiotic (risk ratio (RR) 0.61, 95 per cent c.i. 0.42 to 0.87; moderate-quality evidence), equating to 20 fewer SSIs per 1000 patients treated. Pooling of three trials (3012 participants) for risk of allergic contact dermatitis found no clear difference between antibiotics and no antibiotic (RR 3.94, 0.46 to 34.00; very low-quality evidence). Pooling of five trials (1299 participants) indicated that topical antibiotics probably reduce the risk of SSI compared with topical antiseptics (RR 0.49, 0.30 to 0.80; moderate-quality evidence); 43 fewer SSIs per 1000 patients treated. Pooling of two trials (541 participants) showed no clear difference in the risk of allergic contact dermatitis with antibiotics or antiseptic agents (RR 0.97, 0.52 to 1.82; very low-quality evidence). CONCLUSION: Topical antibiotics probably prevent SSI compared with no topical antibiotic or antiseptic. No conclusion can be drawn regarding whether they cause allergic contact dermatitis. PMID- 28656691 TI - Listeria monocytogenes cytosolic metabolism promotes replication, survival, and evasion of innate immunity. AB - Listeria monocytogenes, the causative agent of listeriosis, is an intracellular pathogen that is exquisitely evolved to survive and replicate in the cytosol of eukaryotic cells. Eukaryotic cells typically restrict bacteria from colonising the cytosol, likely through a combination of cell autonomous defences, nutritional immunity, and innate immune responses including induction of programmed cell death. This suggests that L. monocytogenes and other professional cytosolic pathogens possess unique metabolic adaptations, not only to support replication but also to facilitate resistance to host-derived stresses/defences and avoidance of innate immune activation. In this review, we outline our current understanding of L. monocytogenes metabolism in the host cytosol and highlight major metabolic processes which promote intracellular replication and survival. PMID- 28656694 TI - Probabilistic forecasting in infectious disease epidemiology: the 13th Armitage lecture. AB - Routine surveillance of notifiable infectious diseases gives rise to daily or weekly counts of reported cases stratified by region and age group. From a public health perspective, forecasts of infectious disease spread are of central importance. We argue that such forecasts need to properly incorporate the attached uncertainty, so they should be probabilistic in nature. However, forecasts also need to take into account temporal dependencies inherent to communicable diseases, spatial dynamics through human travel and social contact patterns between age groups. We describe a multivariate time series model for weekly surveillance counts on norovirus gastroenteritis from the 12 city districts of Berlin, in six age groups, from week 2011/27 to week 2015/26. The following year (2015/27 to 2016/26) is used to assess the quality of the predictions. Probabilistic forecasts of the total number of cases can be derived through Monte Carlo simulation, but first and second moments are also available analytically. Final size forecasts as well as multivariate forecasts of the total number of cases by age group, by district and by week are compared across different models of varying complexity. This leads to a more general discussion of issues regarding modelling, prediction and evaluation of public health surveillance data. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28656695 TI - Preparation and evaluation of cefquinome-loaded gelatin microspheres and the pharmacokinetics in pigs. AB - Cefquinome (CEF) is widely used for veterinary clinical applications because of its broad spectrum and high efficiency. However, frequent administrations are required due to its short elimination half-life. In this study, cefquinome sulfate gelatin microspheres (CEF-GMS) were prepared as a sustained-release formulation using emulsion chemical cross-linking technique. Physical properties, stability, sustained-release property in vitro, and pharmacokinetics in pigs were assessed. The morphology of CEF-GMS showed a good sphericity with porous structure on the surface, and the mean diameter was 8.80 +/- 0.78 MUm, with 90.60 +/- 3.98% of the total in the range of 5-20 MUm. There were no significant changes of all estimated indexes in the stability tests. In vitro drug release study showed that the release of CEF from CEF-GMS was much slower than that from crude CEF in a release medium. Pharmacokinetic characteristics were evaluated following intramuscular administration of CEF-GMS or Cefquinome sulfate injection (CEF-Inj) in pigs at a dosage of 4 mg CEF/kg body weight. The plasma drug concentration-time data of CEF-GMS and CEF-Inj were both best fitted by two compartment models with first-order absorption, and the elimination half-life of CEF-GMS was almost 10 times that of CEF-Inj. Overall, CEF-GMS might be used as a sustained-release formulation of CEF for veterinary clinical applications. PMID- 28656698 TI - Lower muscle tissue is associated with higher pulse wave velocity: A systematic review and meta-analysis of observational study data. AB - Muscle loss and arterial stiffness share common risk factors and are commonly seen in the elderly. We aimed to synthesise the existing literature on studies that have examined this association. We searched electronic databases for studies reporting correlations or associations between a measure of muscle tissue and a measure of arterial stiffness. Meta-analysis was conducted using Fisher's Z transformed r-correlation (rZ ) values. Pooled weighted rZ and 95% confidence intervals were calculated in an inverse-variance, random-effects model. Heterogeneity was assessed by the inconsistency index (I2 ). Study quality was assessed on a checklist using items from validated quality appraisal guidelines. 1195 records identified, 21 satisfied our inclusion criteria totalling 8558 participants with mean age 52+/-4 years (range 23-74). Most studies reported an inverse relationship between muscle tissue and arterial stiffness. Eight studies had data eligible for meta-analysis. Muscle tissue was inversely associated with pulse wave velocity in healthy individuals [rZ =-.15 (95% CI -0.24, -0.07); P=.0006; I2 =85%; n=3577] and in any population [rZ =-.18 (-0.26, -0.10); P<.0001; I2 =81%; n=3930]. In a leave-one-out sensitivity analysis, the results remained unchanged. Lower muscle tissue was associated with arterial stiffness. Studies were limited by cross-sectional design. Cardiovascular risk monitoring may be strengthened by screening for low muscle mass and maintaining muscle mass may be a primary prevention strategy. PMID- 28656696 TI - Predictive factors of long-term outcomes of surgery for mesial temporal lobe epilepsy associated with hippocampal sclerosis. AB - OBJECTIVE: The reasons for failure of surgical treatment for mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) remain unclear. This retrospective study analyzed seizure, cognitive, and psychiatric outcomes, searching for factors associated with seizure relapse or cognitive and psychiatric deterioration after MTLE-HS surgery. METHODS: Seizure, cognitive, and psychiatric outcomes were reviewed after 389 surgeries performed between 1990 and 2015 on patients aged 15-67 years at a tertiary center. Three surgical approaches were used: anterior temporal lobectomy (ATL; n = 209), transcortical selective amygdalohippocampectomy (SAH; n = 144), and transsylvian SAH (n = 36). RESULTS: With an average follow-up of 8.7 years (range = 1.0-25.2), seizure outcome was classified as Engel I in 83.7% and Engel Ia in 57.1% of patients. The histological classification of HS was type 1 for 75.3% of patients, type 2 for 18.7%, and type 3 for 1.2%. Two factors were significantly associated with seizure recurrence: past history of status epilepticus and preoperative intracranial electroencephalographic recording. In contrast, neither HS type, the presence of a dual pathology, nor surgical approach was associated with seizure outcome. Risk of cognitive impairment was 3.12 (95% confidence interval = 1.27 7.70), greater in patients after ATL than in patients after transcortical SAH. A presurgical psychiatric history and postoperative cognitive impairment were associated with poor psychiatric outcome. SIGNIFICANCE: The SAH and ATL approaches have similar beneficial effects on seizure control, whereas transcortical SAH tends to minimize cognitive deterioration after surgery. Variation in postsurgical outcome with the class of HS should be investigated further. PMID- 28656697 TI - Hypoxia-ischemia is not an antecedent of most preterm brain damage: the illusion of validity. AB - : Brain injury in preterm newborn infants is often attributed to hypoxia-ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that - despite all the work done in human fetal neuropathology and developmental models in animals - the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally-based title we think appropriate is 'encephalopathy of prematurity'. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors. WHAT THIS PAPER ADDS: Fetal hypoxemia is rarely documented in brain injury studies. Animal studies fail to consider human-animal fetal anatomical differences. Putative treatments from animal models have not found clinical use. Observational studies constitute the only approach to etiological understanding. No convincing evidence yet that hypoxemia injures preterm brain. Encephalopathy of prematurity is preferable to hypoxia-ischemia as a term for this disorder. Encephalopathy of prematurity is preferable to hypoxia-ischemia as a term for this disorder. PMID- 28656699 TI - Social inequality in youth violence: The role of heavy episodic drinking. AB - INTRODUCTION AND AIMS: Alcohol use is an important risk factor for violence, and violent behaviour is more prevalent in lower socioeconomic status (SES) groups. The aim of this study was to examine whether the SES difference in youth violence can be explained by differential exposure to-and/or differential vulnerability to heavy episodic drinking (HED). In the latter case, effect modification by impulsivity could be assumed. DESIGN AND METHODS: We analysed cross-sectional data from a school survey of 15- to 17-year-olds in Norway (n = 9853). We employed two measures of low-SES group. Associations between SES, HED and violence were estimated by Poisson regressions, applying a residual centring procedure to test effect modification. RESULTS: Violent behaviour frequency, HED frequency and impulsivity scores were all elevated in the low-SES group. The SES difference in violent behaviour was significantly reduced when adjusting for HED. The stronger association between HED and violence in the low, compared with the medium-SES/high-SES group, was modified when accounting for impulsivity. Sensitivity analyses suggested robust findings. DISCUSSION AND CONCLUSIONS: The findings lend support to both the differential exposure hypothesis and to the differential vulnerability hypothesis as well as the hypothesis of an enhancing effect of impulsivity on the HED-violence association. The SES difference in youth violence can be accounted for by: (i) an elevated prevalence of HED in low SES groups; and (ii) a stronger than average link between HED and violence in low SES groups due to their higher than average impulsivity score. [Norstrom T, Rossow I, Pape H. Social inequality in youth violence: The role of heavy episodic drinking. Drug Alcohol Rev 2017;00:000-000]. PMID- 28656700 TI - Chromosomal abnormalities of high-grade mucinous tubular and spindle cell carcinoma of the kidney. AB - AIMS: Mucinous tubular and spindle cell carcinoma (MTSC) of the kidney is a distinct entity characterized by bland tightly packed elongated tubules and spindle cells with low nucleolar grade in a basophilic mucinous stroma. Several case studies have reported MTSC with high-grade features and have brought into question whether they represented MTSC or a variant of papillary renal cell carcinoma. METHODS AND RESULTS: We searched our pathology database and identified seven cases: six MTSC with high International Society of Urological Pathology (ISUP) nucleolar grade and one MTSC with overall low nucleolar grade but extensive necrosis. DNA samples were extracted from paraffin blocks and analysed using a single nucleotide polymorphism (SNP) array platform. Six of seven patients were female, aged between 46 and 82 years. Tumour sizes ranged from 3 to 7.5 cm. One case showed involvement of renal sinus fat and a second case showed involvement of the perinephric fat. All cases shared common chromosomal abnormalities observed with the more typical MTSC, with monosomy of chromosomes 1, 4, 6, 8, 9, 13, 14, 15 and 22. Trisomy of chromosomes 7, 17 and loss of Y chromosome were not observed in any of the cases. None of the patients showed evidence of recurrence or metastasis. DISCUSSION: The molecular analysis performed in this study supports that MTSC of the kidney can have high nucleolar grade or extensive necrosis, and that they are not papillary renal cell carcinoma. We support modifying the definition of MTSC to include those with higher nucleolar grade. PMID- 28656701 TI - Salinomycin overcomes acquired tamoxifen resistance through AIB1 and inhibits cancer cell invasion in endocrine resistant breast cancer. AB - Salinomycin is a monocarboxylic polyether ionophore isolated from Streptomyces albus. It has been widely used as an antibiotic in veterinary medicine in poultry. A recent study demonstrated that salinomycin selectively inhibits human breast cancer stem cells; one possible mechanism of tamoxifen resistance. Our results show that salinomycin is effective in inhibiting MCF-7/LCC2 and MCF 7/LCC9 cell lines which are well-established endocrine resistant cells and has a synergistic effect in combination with tamoxifen using MTT proliferation assay. The inhibitory effect of salinomycin on the reduction of critical ER co activator; amplified breast 1 (AIB1) mRNA and protein expression is overcoming tamoxifen resistance. Moreover, salinomycin significantly inhibits cell invasion in Matrigel invasion assay. The effect was mediated at least in part by the decrease of matrix metalopeptidase 9 (MMP-9) which is one critical enzyme facilitated in the cell invasion process. In conclusion, salinomycin should be developed as a novel agent used alone or in combination for endocrine-resistant breast cancer. PMID- 28656702 TI - Analysis of falls that caused serious events in hospitalized patients. AB - AIM: Falls are common adverse events for hospitalized elderly patients that can cause fracture, which decreases activities of daily living, and other injuries that can be fatal. The purpose of the present study was to investigate serious events due to fall, and to consider measures for fall prevention. METHODS: Incidents of fall were obtained from a database of 163 558 inpatients at Nagoya University Hospital, Nagoya, Aichi, Japan, from April 2012 to March 2016. The risk of fall was evaluated using a fall assessment score sheet at admission and during hospitalization, based on which patients were divided into risk grades 1, 2 and 3. A fall that led to fracture or a life-threatening injury was defined as a serious event. RESULTS: Fall occurred in 3099 patients for 4 years (1.89%). Most patients that fell (45%) were in the highest (grade 3) risk category. Serious events associated with fall occurred in 36 of the 3099 patients (1.2%), and the overall incidence of serious events was 0.22%. These events included fracture in 24 patients, intracranial injury in 10 patients and others in two patients. Finally, one patient died. Serious events occurred significantly more frequently after falls in patients wearing slippers compared with other footwear (P < 0.01). The incidences of serious events and fall were significantly higher in patients with a higher risk of fall (P < 0.05). CONCLUSIONS: The present results support the validity of our risk assessment scale for fall, but it should be recognized that fall can also occur in a patient with a low predicted risk of fall. Geriatr Gerontol Int 2017; 17: 2403-2406. PMID- 28656703 TI - Examination of competing diagnostic models of functional gastrointestinal disorders related to pain in children. AB - BACKGROUND: There have been no empirical validations of the Rome III or Rome IV criteria in children. The aim of the current study was to examine whether symptoms naturally occur in a pattern consistent with Rome III and/or Rome IV pediatric criteria for functional dyspepsia (FD) and irritable bowel syndrome (IBS). METHODS: We conducted a retrospective cohort study of 250 children, ages 8 17 years, presenting to an abdominal pain clinic with pain of at least 8 weeks duration. We evaluated patterns of gastrointestinal (GI) and non-gastrointestinal (non-GI) symptoms which had been collected in a standardized fashion as part of routine clinical care. Confirmatory factor analyses were used to compare pre existing models of symptoms clusters, namely Rome III and Rome IV criteria for IBS and FD in children and adolescents. Factor intercorrelations also were examined to determine whether IBS symptoms and non-GI somatic complaints correlate uniquely with FD symptom clusters. KEY RESULTS: Both models demonstrated good fit with observed data [3-factor: chi2 (101, n=250)110.75, P<.05, TLI=.99, CFI=.99; 4-factor: chi2 (98, n=250)117.54, P<.05, TLI=.96, CFI=.97]. Fit indices and intercorrelations favored the more parsimonious 3 factor solution (3-factor: AIC=4654.91, BIC=4778.17; 4-factor: AIC=4757.16, BIC=4890.97) consistent with pediatric Rome III criteria that conceptualizes FD as a single diagnostic category. FD demonstrated significant overlap with IBS (.42), while non-GI-specific symptoms correlated significantly with FD (.64), but not IBS (.14) symptoms. CONCLUSIONS & INFERENCES: GI symptoms in children presenting for initial evaluation of chronic functional abdominal pain occur in a pattern consistent with Rome III and IV pediatric criteria. Rome III offers a more parsimonious model. The presence of FD symptoms is strongly, and uniquely, associated with non-GI symptoms. PMID- 28656704 TI - Validation of US cerebral palsy growth charts using a UK cohort. AB - AIM: Growth charts for cerebral palsy (CP) have been constructed using data for 24 920 Californian patients, covering ages 2 to 20 years, with separate charts for the five severity levels of the Gross Motor Function Classification System (GMFCS). Our aim was to test how the data for British children with CP fit these charts, compared with conventional local charts. METHOD: US CP growth reference was reanalysed using the lambda-mu-sigma (LMS) method to allow calculation of standard deviation z-scores. Growth data for 195 children with CP in Glasgow, UK, were retrieved and converted to z-scores using the CP reference as well as the combined World Health Organization and UK 1990 growth reference (UK-WHO). RESULTS: Compared to the UK-WHO reference, measurements diverged progressively with increasing severity, with mean height for GMFCS level V being close to the second UK-WHO centile. Compared with the CP reference, mean height and weight z scores were between the 50th and 75th centiles for all severity levels, while body mass index was just below the 50th centile. INTERPRETATION: British children with severe CP seem relatively very small when their growth data are plotted on non-CP charts, but their data for weight and body mass index fit well to US CP charts and reasonably well for height. The LMS look-up tables will make it possible to calculate z-scores and produce charts in local formats. PMID- 28656705 TI - Chemical agents transported by xylem mass flow propagate variation potentials. AB - Long-distance signalling is important for coordinating plant responses to the environment. Variation potentials (VPs) are a type of long-distance electrical signal that are generated in plants in response to wounding or flaming. Unlike self-propagating action potentials, VPs can be measured beyond regions of dead or chemically treated tissue that block signal generation, suggesting a different mode of propagation. Two alternative propagation mechanisms have been proposed: movement of a chemical agent and a pressure wave through the vasculature. Variants of these two signalling mechanisms have been suggested. Here, we use simple models of the underlying physical processes to evaluate and compare these predictions against independent data. Our models suggest that chemical diffusion and pressure waves are unlikely to capture existing data with parameters that are known from other sources. The previously discarded hypothesis of mass flow in the xylem transporting a chemical agent, however, is able to reproduce experimental propagation speeds for VPs. We therefore suggest that chemical agents transported by mass flow within the xylem are more likely than a pressure wave or chemical diffusion as a VP propagation mechanism. Understanding this mode of long-distance signalling within plants is important for unravelling how plants coordinate physiological responses via cell-to-cell communication. PMID- 28656708 TI - Letter to the Editor, Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. PMID- 28656706 TI - On the structure and mechanism of two-pore channels. AB - In eukaryotes, two-pore channels (TPC1-3) comprise a family of ion channels that regulate the conductance of Na+ and Ca2+ ions across cellular membranes. TPC1-3 form endolysosomal channels, but TPC3 can also function in the plasma membrane. TPC1/3 are voltage-gated channels, but TPC2 opens in response to binding endolysosome-specific lipid phosphatidylinositol-3,5-diphosphate (PI(3,5)P2 ). Filoviruses, such as Ebola, exploit TPC-mediated ion release as a means of escape from the endolysosome during infection. Antagonists that block TPC1/2 channel conductance abrogate filoviral infections. TPC1/2 form complexes with the mechanistic target of rapamycin complex 1 (mTORC1) at the endolysosomal surface that couple cellular metabolic state and cytosolic nutrient concentrations to the control of membrane potential and pH. We determined the X-ray structure of TPC1 from Arabidopsis thaliana (AtTPC1) to 2.87A resolution-one of the two first reports of a TPC channel structure. Here, we summarize these findings and the implications that the structure may have for understanding endolysosomal control mechanisms and their role in human health. PMID- 28656707 TI - Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. AB - AIMS: To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: PubMed, Embase and ClinicalTrials.gov sites were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate outcomes. RESULTS: In the analysis of 25 randomized trials, which involved 14 619 patients, SGLT-2is were associated with a significantly stronger reduction in haemoglobin A1c (HbA1c) (WMD 0.13%, 95% credible interval [CI], 0.04%-0.22%, P = .005) and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI, 0.58-1.01 mmol/L, P < .00001) than were DPP-4is. However, no significant difference between the 2 drug categories was found in the risk of hypoglycaemic events (RR, 0.99; 95% CI, 0.78-1.26, P = .92). SGLT-2is plus Met was associated with a more significant decrease in FPG (WMD 0.71 mmol/L, 95% CI, 0.43-1.00 mmol/L, P < .00001) than was DPP-4is plus Met. However, no differences were found in the reduction of HbA1c (WMD 0.11%, 95% CI, 0.03%-0.25%, P = .12) or the risk of hypoglycaemic events (RR, 1.02; 95% CI, 0.80 1.31, P = .86). CONCLUSIONS: This review revealed that, compared to DPP-4is, SGLT 2is significantly reduced HbA1c, FPG and body weight without increasing the risk of hypoglycaemia in diabetes treatment. PMID- 28656709 TI - Zingiberis Siccatum Rhizoma, the active component of the Kampo formula Daikenchuto, induces anti-inflammatory actions through alpha7 nicotinic acetylcholine receptor activation. AB - BACKGROUND: We previously reported that Daikenchuto (DKT), a gastrointestinal prokinetic Japanese herbal (Kampo) medicine used for the treatment of postoperative ileus (POI), has characteristic potent anti-inflammatory activity. This effect may be partly mediated by the activation of alpha7 nicotinic acetylcholine receptor (nAChR). In this study, we identified the specific herbs in DKT that induce anti-inflammatory action. METHODS: The herbal components of DKT were individually administered orally to each mouse four times before and after intestinal manipulation (IM) was carried out on the distal ileum. The anti inflammatory activity of each crude drug was subsequently evaluated using immunohistochemical analyses of relevant molecules. KEY RESULTS: Treatment with Zingiberis Siccatum Rhizoma (ZSR) but not the other components inhibited the infiltration of cluster of differentiation 68 (CD68)-positive macrophages as effectively as DKT treatment. Selective alpha7nAChR antagonists, such as methyllycaconitine citrate, or transient receptor potential ankyrin 1 (TRPA1) antagonists, such as HC-030031, significantly inhibited the amelioration of macrophage infiltration by ZSR. The inhibition of macrophage infiltration by ZSR was abolished in both alpha7nAChR and 5-hydroxytryptamine 4 receptor (5-HT4 R) knockout mice. CONCLUSIONS & INFERENCES: Daikenchuto-induced anti-inflammatory activity, which was mediated by inhibiting macrophage infiltration in POI, is dependent on the effects of ZSR. Zingiberis Siccatum Rhizoma activates TRPA1 channels possibly in enterochromaffin (EC) cells to release 5-HT, which stimulates 5-HT4 R in the myenteric plexus neurons to release ACh, which in turn activates alpha7nAChR on macrophages to inhibit inflammation in POI. PMID- 28656710 TI - Effect of liquid properties on swallowing and ventilation coordination in rats. AB - BACKGROUND: One aspect of rehabilitation in swallowing disorders is to change liquid properties. The objective of our study was to test how liquid properties could improve oropharyngeal dysphagia and swallowing and ventilation coordination in an animal model. METHODS: Forty-two healthy male rats were distributed in six groups, including a control group. Rats were deprived of water for 24 h and then each group was administered liquid with different properties: tap water, sugar water, sparkling water, salt water, cold water, and acidic water. Rats were studied without and with oropharyngeal dysphagia achieved by unilateral section of the hypoglossal nerve. Swallowing and ventilation were analyzed by barometric plethysmograph. KEY RESULTS: In healthy rats, swallowing occurred during expiratory time for all liquid properties. Most deglutitions were during expiratory time for all liquid properties (88+/-12%) and were not modified. There was an increase in VT/TI during swallowing with sparkling water and cold water (P<.05). In the operated groups, rats had significantly fewer swallows with tap water (P<.05) and significantly more swallows with sparkling water (P<.001), sugar water (P<.001) and cold water (P<.001) during expiratory time. The mean inspiratory volume (VT/TI) increased with sparkling water (P<.05). CONCLUSION AND INFERENCES: Sparkling water seemed to improve swallowing and ventilation coordination in an animal model, to be confirmed in a study including patients with oropharyngeal dysphagia. PMID- 28656711 TI - Left atrial compression with acute heart failure caused by esophageal bolus. AB - We report a case of left atrial extrinsic compression caused by an esophageal food bolus in a patient presenting with acute heart failure. Transthoracic echocardiography along with contrast-enhanced CT showed evidence of esophageal dilation producing left atrial compression. Esophageal endoscopy and fragmentation of the bolus, allowing the accumulated food to descend into the stomach, produced a rapid improvement of hemodynamic and clinical status. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:259-261, 2018. PMID- 28656712 TI - Uterine tumour resembling ovarian sex cord tumour: first report of a large series with follow-up. AB - AIMS: Uterine tumour resembling ovarian sex cord tumour (UTROSCT) is an uncommon mesenchymal neoplasm of uncertain histogenesis. While it is considered a neoplasm of uncertain but low malignant potential, there is limited evidence for this as there are no large studies with follow-up. We aimed to determine the clinical behaviour of this uncommon neoplasm and investigate clinicopathological parameters which predict behaviour. METHODS AND RESULTS: From a series of 34 cases of UTROSCT, mainly from consultation practice, we obtained follow-up information which was obtained by contacting referring pathologists and clinicians. The follow-up periods ranged from 6 to 135 months (mean 39 months). Eight of 34 patients (23.5%) developed extrauterine metastasis to a variety of sites, including pelvic and abdominal peritoneum, ovary, lymph nodes, bone, liver and lung, and three patients (8.8%) died of tumour. Those neoplasms which exhibited malignant behaviour occurred on average in older patients, and were larger and more likely to exhibit necrosis, lymphovascular invasion, cervical involvement, significant nuclear atypia and significant mitotic activity. However, only the presence of necrosis and significant mitotic activity was statistically significant. CONCLUSIONS: While our figure of 23.5% of cases exhibiting malignant behaviour may reflect some bias related to consultation practice our results show that, not uncommonly, these neoplasms have an aggressive clinical course with extrauterine metastasis. Given the overlap in pathological parameters between clinically benign and malignant neoplasms, UTROSCTs are all best regarded as potentially malignant. PMID- 28656713 TI - Lateral ridge augmentation with two different ratios of deproteinized bovine bone and autogenous bone: A 2-year follow-up of a randomized and controlled trial. AB - BACKGROUND: The optimal ratio of deproteinized bovine bone (DPBB) and autogenous bone (AB) for lateral augmentation is presently unknown. PURPOSE: To evaluate implant treatment outcome and radiological graft changes after lateral ridge augmentation with 2 different mixtures of DPBB and AB, 2 years after functional loading. MATERIALS AND METHODS: Thirteen patients were included in a split mouth, randomized, controlled trial. Four partially edentulous and 10 totally edentulous jaws with an alveolar ridge width of <4 mm were augmented with a graft mixture of 90:10 (DPBB:AB) on one side and 60:40 (DPBB:AB) on the contra lateral side. Graft width changes were measured on CBCT scans at different time points. Implant survival and success rates were calculated. Resonance frequency analysis and marginal bone measurements were performed after 2 years of loading. RESULTS: The survival rate was 94.4% for implants installed in the 90:10 and 100% for implants installed in the 60:40. There were no statistically significant differences in survival rate or success rate between the mixtures. The width was 5.7 mm and 6.2 mm, respectively for the 2 groups without any significant difference between the groups after 2 years of loading. There was a significant difference in graft reduction between the groups, 54.4% (90:10) and 37.5% (60:40), respectively. There were no statistically significant differences in implant stability or marginal bone levels at any time points. CONCLUSIONS: The 2 treatment modalities may be successfully used for lateral ridge augmentation and presented good clinical results after 2 years of loading. However, long-term RCTs are required before final conclusions can be provided on this specific topic. PMID- 28656714 TI - Is there an optimum number needed to retrieve to justify inclusion of a database in a systematic review search? AB - OBJECTIVE: To determine whether calculation of a 'Number Needed to Retrieve' (NNTR) is possible and desirable as a means of evaluating the utility of a database for systematic review. METHODS: To determine an overall NNTR, eight systematic reviews were tracked to determine how many abstracts were retrieved compared to the number of articles meeting the inclusion criteria. An NNTR was calculated for each database searched to measure the utility of including it in systematic review searches. RESULTS: Across eight systematic reviews, 17 378 abstracts were reviewed. Of these, 122 met the inclusion criteria for their reviews resulting in an overall NNTR of 142. Individual reviews had an NNTR range of 28-310. Three databases delivered unique results (medline, cinahl and globalhealth). The majority of the included studies appeared in multiple databases. Only five articles were found in a single database. CONCLUSIONS: This research offers a proof of concept of 'NNTR'. While the eight review NNTRs varied widely, all were consistent with the range initially reported by Booth. Included articles consistently appeared in multiple databases, suggesting that duplicate abstracts should be screened first as these are likely to include highly relevant, high-quality results. PMID- 28656715 TI - Modified Lung Ultrasonographic Technique for Evaluation of Idiopathic Pulmonary Fibrosis: Lateral Decubitus Position. AB - OBJECTIVES: To compare lung ultrasonography (US) in the sitting or supine positions and the lateral decubitus position, with regard to the feasibility, duration, patient convenience, and assessment of B-lines, in patients with idiopathic pulmonary fibrosis. METHODS: Twenty consecutive patients with idiopathic pulmonary fibrosis were prospectively enrolled. Lung US included scanning of 56 intercostal spaces. Each patient was examined twice by 2 protocols. During protocol 1, patients were examined in the supine and sitting positions for the anterior and dorsal chest, respectively. During protocol 2, patients were examined in the left lateral decubitus position for the evaluation of the right hemithorax and the reverse. Total, anterior, and posterior US scores resulted from the sum of B-lines at the whole, anterior, and posterior chest, respectively. High-resolution computed tomography (CT) was considered the reference standard. The duration of each protocol was recorded. Patients were questioned about which protocol they preferred. RESULTS: There was no difference regarding feasibility between the protocols. A significant correlation was found between total US scores for both protocols and high-resolution CT findings (P < .0001), with protocol 2 showing a slightly higher correlation. A positive correlation was found between the protocols regarding total, anterior, and posterior US scores (P < .0001). The mean duration of protocol 2 was less than that of protocol 1 (P < .005). Nineteen patients (95%) reported a preference for protocol 2. CONCLUSIONS: Lung US in the lateral decubitus position seems to be faster and more convenient. There appears to be no difference regarding feasibility and the number of B-lines, whereas it shows slightly higher correlation with high-resolution CT, compared with the sitting or supine positions in patients with idiopathic pulmonary fibrosis. PMID- 28656716 TI - The effects of chronic smoking on total cerebral blood volume measured by carotid and vertebral artery doppler ultrasonography. AB - PURPOSE: To evaluate the effects of chronic cigarette smoking on total cerebral blood flow in healthy adults by Doppler ultrasonography (US). METHODS: We evaluated 50 smoker (median age 29) and 50 nonsmoker (median age 28) healthy, 20- to 40-year-old subjects without any cardiovascular and cerebrovascular disease. Peak systolic maximal blood flow velocity (PSV), end-diastolic maximal blood flow velocity (EDV), time-averaged mean blood flow velocity (TAMV), resistance index (RI), and pulsatility index (PI) were measured in the left and right carotid and vertebral arteries, and total cerebral blood flow volume was calculated. RESULTS: There was no significant difference of smoking rate between genders. Blood pressure and PSV values were similar in both groups. EDV values of internal carotid artery (ICA) and vertebral artery (VA) were lower and RI and PI values were higher in smokers. TAMV, total ICA (-10.8%) and VA (-6%) flow volume, and tCBF (-9.2%) were lower in smokers. CONCLUSIONS: Doppler US is an effective tool to detect tCBF volume decrease in chronic cigarette smokers. Although minimal, this decrease, as demonstrated here in asymptomatic, healthy people, might be critical in patients with subclinical cerebral arterial insufficiency. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:561-565, 2017. PMID- 28656717 TI - Filling the gaps in the genomic catalogue of melanoma subtypes. PMID- 28656718 TI - Targeting the beta-clamp in Helicobacter pylori with FDA-approved drugs reveals micromolar inhibition by diflunisal. AB - The beta-clamp is the processivity-promoting factor for most of the enzymes in prokaryotic DNA replication; hence, it is a crucial drug target. In the present study, we investigated the beta-clamp from Helicobacter pylori, aiming to seek potential drug molecules against this gastric-cancer-causing bacterium. An in silico screening of Food and Drug Administration (FDA) approved drugs against the H. pylori beta-clamp, followed by its in vitro inhibition using a surface competition approach, yielded the drug diflunisal as a positive initial hit. Diflunisal inhibits the growth of H. pylori in the micromolar range. We determined the structure of diflunisal in complex with the beta-clamp to show that the drug binds at subsite I, which is a protein-protein interaction site. Successful identification of FDA-approved molecules against H. pylori may lead to better and faster drug development. PMID- 28656719 TI - Importance of Distending Stomach With Fluid for Ultrasound Detection of Focal Lesion in the Elongated Left Lobe of the Liver. AB - OBJECTIVES: The purpose of this study was to evaluate distending the stomach with water for ultrasound detection of focal lesions in the elongated left lobe of the liver. METHODS: A total of 13,277 patients undergoing liver ultrasound were evaluated for the presence of an elongated left lobe of the liver and a focal lesion. Patients with an elongated left lobe of the liver had their stomach distended with oral water for further evaluation of a focal lesion. A portion of the patients had computed tomography (CT) examinations, which were compared with the ultrasound studies. RESULTS: A total of 643 patients were found with elongated left lobe of the liver by ultrasound; of them, 451 underwent CT, 259 out of the 451 patients meeting the inclusion criteria underwent second ultrasound and final analysis, and 16 of these 259 patients had focal lesion in the elongated left lobe of the liver on CT study. The sonographic visualization of the liver and spleen at the same scan view before and after distending the stomach were 7% (7 of 100) and 100% (100 of 100), respectively (P < .001). The sonographic detection of the lesions before and after distending the stomach were zero and 87.5%, respectively (P < .001). CONCLUSIONS: Distending the stomach with water can greatly increase ultrasound detection of focal lesions in the elongated left lobe of the liver. PMID- 28656720 TI - Down-regulation of fibronectin and the correlated expression of neuroligin in hirschsprung disease. AB - AIM: The goal of this study was to investigate the expression of fibronectin (FN) and the correlated abundance of neuroligins (NLs) in the enteric nervous system (ENS) and to find a novel diagnostic marker in the serum of Hirschsprung disease (HSCR) patients. METHODS: The expression levels of FN, neuroligin-1 and neuroligin-2 were detected in 114 children with or without HSCR. The expression and localization of the NLs and FN were assessed morphologically by immunohistochemical staining. Western blot analysis and real-time fluorescence quantitative PCR (qPCR) were performed to examine the correlated expression of the NLs and FN in aganglionic, transitional, and normal ganglionic colon tissues. An enzyme-linked immunosorbent assay (ELISA) was performed to evaluate and compare serum FN levels between HSCR and non-HSCRand between long-type HSCR and short-type HSCR. RESULTS: These studies showed that both neuroligin-1 and neuroligin-2 were expressed at low levels in aganglionic segments and at intermediate levels in transitional segments compared to their high level of expression in normal tissue. In contrast, FN expression was negatively correlated, with expression in these three samples transitioning from highest to lowest. The serum FN level was higher in HSCR than in non-HSCR, but no significant difference between short-type HSCR and long-type HSCR was observed. CONCLUSION: FN affects the expression of both neuroligin-1 and neuroligin-2 in HSCR, which may lead to the hypoplasia of ganglion cells in the ENS. This correlation may play a key role in the pathogenesis, diagnosis, or classification of HSCR. PMID- 28656721 TI - Nanoporous Atomically Thin Graphene Membranes for Desalting and Dialysis Applications. AB - Dialysis is a ubiquitous separation process in biochemical processing and biological research. State-of-the-art dialysis membranes comprise a relatively thick polymer layer with tortuous pores, and suffer from low rates of diffusion leading to extremely long process times (often several days) and poor selectivity, especially in the 0-1000 Da molecular weight cut-off range. Here, the fabrication of large-area (cm2 ) nanoporous atomically thin membranes (NATMs) is reported, by transferring graphene synthesized using scalable chemical vapor deposition (CVD) to polycarbonate track-etched supports. After sealing defects introduced during transfer/handling by interfacial polymerization, a facile oxygen-plasma etch is used to create size-selective pores (<=1 nm) in the CVD graphene. Size-selective separation and desalting of small model molecules (~200 1355 Da) and proteins (~14 000 Da) are demonstrated, with ~1-2 orders of magnitude increase in permeance compared to state-of-the-art commercial membranes. Rapid diffusion and size-selectivity in NATMs offers transformative opportunities in purification of drugs, removal of residual reactants, biochemical analytics, medical diagnostics, therapeutics, and nano-bio separations. PMID- 28656722 TI - Formation of spheroids by dental pulp cells in the presence of hypoxia and hypoxia mimetic agents. AB - AIM: To evaluate the impact of hypoxia and hypoxia mimetic agents (HMA) on the formation and activity of spheroids by dental pulp cells (DPC). METHODOLOGY: DPC on agarose-coated plates were treated with hypoxia and the HMA dimethyloxallyl glycine (DMOG), desferrioxamine (DFO) and L-mimosine (L-MIM). Images of spheroids were taken directly after seeding and at 6 h and 24 h. Spheroid sizes were quantified by area measurement with ImageJ software. Viability was assessed with Live-Dead staining, MTT and resazurin-based toxicity assay. Production of VEGF, IL-8 and SDF-1 was evaluated using immunoassays. Data were analysed using Kruskal Wallis test and post hoc Mann-Whitney U-test. RESULTS: DPC formed spheroids in the presence of hypoxia, HMA and combined treatment with hypoxia and HMA. No pronounced difference in spheroid size was found in the groups treated with hypoxia, DMOG, DFO, L-MIM and the combination of hypoxia and the HMA relative to their normoxic controls (P > 0.05). Spheroids appeared vital in Live-Dead and MTT staining and the resazurin-based toxicity assay. Evaluation of protein production with immunoassays revealed significantly enhanced levels of VEGF and IL-8 (P < 0.05), but there was no significant effect on SDF-1 production (P > 0.05). Treatment with a combination of hypoxia and HMA did not further boost VEGF and IL 8 production (P > 0.05). CONCLUSIONS: Pre-conditioning with hypoxia and HMA increased the pro-angiogenic capacity of spheroids whilst not interfering with their formation. Pre-clinical studies will reveal whether pre-conditioning of spheroids with hypoxia and HMA can effectively improve the efficiency of cell transplantation approaches for regenerative endodontics. PMID- 28656723 TI - Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: A randomized controlled, clinical trial. AB - BACKGROUND: Stem cell therapy with bone marrow-derived mesenchymal stem cells is a promising tissue engineering strategy to promote regeneration of craniofacial bone. PURPOSE: To determine whether cell therapy with ex vivo expanded stem cell populations would be safe and efficacious in the regeneration of large alveolar defects in patients with a history of cleft palate or craniofacial trauma. MATERIALS AND METHODS: Eighteen patients (10 patients with traumatic injury and 8 patients with cleft palate) presenting with missing teeth associated with horizontal alveolar bone deficiencies were included in this randomized controlled clinical trial. Patients were randomized to receive either conventional autogenous block grafts or stem cell therapy. After a healing period of 4 months the treated sites were re-entered and the bone width re-assessed prior to implant placement. Implant stability was evaluated through torque testing of the implant upon insertion and at 6 months postloading. RESULTS: The mean gain in bone width was 1.5 +/- 1.5 mm in the stem cell therapy group and 3.3 +/- 1.4 mm in the control group. Overall, bone gain was higher in trauma patients as compared to patients with cleft palate, for both the control and the stem cell therapy groups. Most postoperative complications were wound dehiscences and incision line openings. Implants were placed successfully in 5 out of 10 patients in the stem cell therapy group and in all 8 patients in the control group. One implant from the control/cleft palate group failed before loading, while the rest of the implants were loaded successfully and remained stable at 6 months. The patients who did not receive implants were re-treated with autogenous block bone graft. CONCLUSION: The ability of stem cells to treat large alveolar defects is safe, yet, their ability to completely reconstitute large alveolar defects is limited. This approach requires further optimization to meet the outcomes seen using current methods to treat large defects, particularly those resultant of cleft palate. PMID- 28656724 TI - MiR-148a promotes myocardial differentiation of human bone mesenchymal stromal cells via DNA methyltransferase 1 (DNMT1). AB - MicroRNAs have potential to modulate the differentiation of stem cells. In previous study, we found that miR-148a was up-regulated in myocardial differentiation of human bone mesenchymal stromal cells (hBMSCs) induced by 5' azacytidine. However, the role of miR-148a in regulating this process still remains unclear. In this study, we investigated the function and molecular mechanism of miR-148a in myocardial differentiation of hBMSCs. We found that miR 148a was significantly increased while DNA methyltransferase 1 (DNMT1) was significantly decreased in myocardial differentiation of hBMSCs. Then, the dual luciferase reporter assays method indicated that DNMT1 was the direct target of miR-148a. In addition, we showed that up-regulation of miR-148a could enhance myocardial differentiation of hBMSCs, while down-regulation of miR-148a could inhibit myocardial differentiation process. Moreover, knockdown of DNMT1 could block the role of miR-148a in promoting myocardial differentiation of hBMSCs. Finally, MiR-148a acted on methylation level of GATA-4 and knockdown of DNMT1 could block this function. Therefore, our results indicate that miR-148a plays a vital role in regulating myocardial differentiation of hBMSCs by targeting DNMT1. PMID- 28656725 TI - American Diabetes Association 77th Scientific Sessions. AB - Payal H. Marathe, Abigail E. Dove, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Marathe, Dove, and Close review the latest developments relevant to researchers and clinicians. PMID- 28656726 TI - Correlation distance dependence of the resonance frequency of intermolecular zero quantum coherences and its implication for MR thermometry. AB - PURPOSE: Because the resonance frequency of water-fat intermolecular zero-quantum coherences (iZQCs) reflects the water-fat frequency separation at the microscopic scale, these frequencies have been proposed and used as a mean to obtain more accurate temperature information. The purpose of this work was to investigate the dependence of the water-fat iZQC resonance frequency on sample microstructure and on the specific choice of the correlation distance. METHODS: The effect of water fat susceptibility gradients on the water-methylene iZQC resonance frequency was first computed and then measured for different water-fat emulsions and for a mixture of porcine muscle and fat. Similar measurements were also performed for mixed heteronuclear spin systems. RESULTS: A strong dependence of the iZQC resonance frequency on the sample microstructure and on the specific choice of the correlation distance was found for spin systems like water and fat that do not mix, but not for spin systems that mix at the molecular level. CONCLUSIONS: Because water and fat spins do not mix at the molecular level, the water-fat iZQC resonance frequency and its temperature coefficient are not only affected by sample microstructure but also by the specific choice of the correlation distance. Magn Reson Med 79:1429-1438, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28656727 TI - The Eastern European experience on occupational skin diseases. Make underreporting an issue? AB - BACKGROUND: While legislation in most of the Eastern European countries is nowadays widely harmonized with the legal safety and health provisions of Western countries, there is still a sustained resistance to the notification of occupational skin diseases (OSD). OBJECTIVE: The aim of the study was to identify the main barriers in notification and recognition of OSD in 22 Eastern European countries. METHODS: An online survey was administered to key persons in the field of occupational safety and health in 22 Eastern European countries. Multiple variables of the notification system were studied, including clinical, organizational and educational issues. RESULTS: The main causes of underreporting OSD are ineffective enforcement of occupational safety and health legislation, contractual relationship employer-employee, long duration of the notifying process, restrictions of the notification systems in terms of who is entitled to notify an OSD, ineffective regulations in regards to the pre-employment and periodical medical examination, ineffective compensation schemes, restraints and hesitations, mainly from the doctors, inappropriate mentalities - fear of losing the jobs, fining of the employers by the authorities, stigmatization of the workers with OSD, additional costs for employers, stakeholders' lack of interest in notifying, lack of guidelines and protocols and lack of preventive programmes. CONCLUSIONS: The most valuable method for a proper recognition of OSD is to increase the awareness of physicians involved in the management of OSD (occupational physicians, GPs, dermatologists), as well as employers and workers. There is an urgent need to improve national legislation, to develop and promote adequate preventive programmes, emphasizing ethical, legal, economical and psychological aspects in order to achieve an increased recognition and a real reporting of OSD, and to enforce an international action plan for Eastern Europe in order to improve the notification of OSD. PMID- 28656728 TI - Minimum standards on prevention, diagnosis and treatment of occupational and work related skin diseases in Europe - position paper of the COST Action StanDerm (TD 1206). AB - BACKGROUND: Skin diseases constitute up to 40% of all notified occupational diseases in most European countries, predominantly comprising contact dermatitis, contact urticaria, and skin cancer. While insufficient prevention of work-related skin diseases (WRSD) is a top-priority problem in Europe, common standards for prevention of these conditions are lacking. OBJECTIVE: To develop common European standards on prevention and management of WRSD and occupational skin diseases (OSD). METHOD: Consensus amongst experts within occupational dermatology was achieved with regard to the definition of minimum evidence-based standards on prevention and management of WRSD/OSD. RESULTS: By definition, WRSDs/OSDs are (partially or fully) caused by occupational exposure. The definition of OSD sensu stricto additionally includes diverging national legal requirements, with an impact on registration, prevention, management, and compensation. With the implementation of the classification of WRSD/OSD in the International Classification of Diseases (ICD) 11th Revision in future, a valid surveillance and comparability across countries will be possible. Currently, WRDS and OSD are still under-reported. Depending on legislation and regulations, huge differences exist in notification procedures in Europe, although notification is crucial to prevent chronic and relapsing disease. Facilities for early diagnosis, essential for individual patient management, should be based on existing guidelines and include a multidisciplinary approach. Patch testing is essential if contact dermatitis persists or relapses. Workplace exposure assessment of WRSD/OSD requires full labelling of product ingredients on material safety data sheets helping to identify allergens, irritants and skin carcinogens. Comparable standards in primary, secondary and tertiary prevention must be established in Europe to reduce the burden of WRSD/OSD in Europe. CONCLUSION: The adoption of common European standards on prevention of WRSD/OSD will contribute to reduce the incidence of OSD and their socio-economic burden. PMID- 28656729 TI - Instructions for use of the OSD notification forms. PMID- 28656730 TI - Occupational skin diseases - Development and Implementation of European Standards on Prevention of Occupational Skin Diseases. PMID- 28656732 TI - Niche conservatism and the invasive potential of the wild boar. AB - Niche conservatism, i.e. the retention of a species' fundamental niche through evolutionary time, is cornerstone for biological invasion assessments. The fact that species tend to maintain their original climate niche allows predictive maps of invasion risk to anticipate potential invadable areas. Unravelling the mechanisms driving niche shifts can shed light on the management of invasive species. Here, we assessed niche shifts in one of the world's worst invasive species: the wild boar Sus scrofa. We also predicted potential invadable areas based on an ensemble of three ecological niche modelling methods, and evaluated the performance of models calibrated with native vs. pooled (native plus invaded) species records. By disentangling the drivers of change on the exotic wild boar population's niches, we found strong evidence for niche conservatism during biological invasion. Ecological niche models calibrated with both native and pooled range records predicted convergent areas. Also, observed niche shifts are mostly explained by niche unfilling, i.e. there are unoccupied areas in the exotic range where climate is analogous to the native range. Niche unfilling is expected as result of recent colonization and ongoing dispersal, and was potentially stronger for the Neotropics, where a recent wave of introductions for pig-farming and game-hunting has led to high wild boar population growth rates. The invasive potential of wild boar in the Neotropics is probably higher than in other regions, which has profound management implications if we are to prevent their invasion into species-rich areas, such as Amazonia, coupled with expansion of African swine fever and possibly great economic losses. Although the originally Eurasian-wide distribution suggests a pre-adaptation to a wide array of climates, the wild boar world-wide invasion does not exhibit evidence of niche evolution. The invasive potential of the wild boar therefore probably lies on the reproductive, dietary and morphological characteristics of this species, coupled with behavioural thermoregulation. PMID- 28656731 TI - Occupational skin diseases: actual state analysis of patient management pathways in 28 European countries. AB - BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe. OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment and rehabilitation in different European countries. METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu). RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks (synonyms: insurance against work accidents and occupational injuries; statutory social accident insurance)]. Legal standards for the assessment of occupationally triggered diseases with a genetic background differ between different countries, however, in most European member states recognition as OSD is possible. In one-third of the countries UV light induced tumours can be recognized as OSD under specific conditions. CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness of this fact and further efforts for standardization are necessary. PMID- 28656733 TI - Obesity and the prevalence of nocturia in Japanese elderly patients with type 2 diabetes mellitus: The Dogo study. AB - AIM: Nocturia is common among patients with type 2 diabetes mellitus, but limited evidence regarding the association between body mass index (BMI) and nocturia exists among such patients. The aim of the present study, therefore, was to evaluate the association between BMI and nocturia among Japanese patients with type 2 diabetes mellitus. METHODS: Study participants were 809 Japanese patients with type 2 diabetes mellitus. Study participants were considered to have nocturia if they answered "two or more" to the question: "How many times do you typically wake up to urinate from sleeping at night until waking in the morning?" We used the following two outcomes: (i) moderate nocturia was defined as >=2 voids per night; and (ii) severe nocturia was defined as >=3 voids per night. Participants were categorized into four groups according to their BMI: (i) BMI <18.5; (ii) 18.5 <= BMI < 25; (iii) 25 <= BMI < 30; and (iv) BMI >=30. Multiple logistical regression analysis for nocturia in relation to BMI was used, with the category of 18.5 <= BMI < 25 as the reference. RESULTS: Obesity (BMI >=30) was independently positively associated with severe nocturia among elderly patients (age >=65 years) with type 2 diabetes mellitus, but not among young and middle aged patients: the adjusted OR was 2.96 (95% CI 1.10-7.83). BMI was not associated with moderate nocturia in all patients. CONCLUSIONS: In Japanese elderly patients with type 2 diabetes mellitus, obesity was independently positively associated with severe nocturia. Geriatr Gerontol Int 2017; 17: 2460 2465. PMID- 28656734 TI - Simvastatin induced actin cytoskeleton disassembly in normal and transformed fibroblasts without affecting lipid raft integrity. AB - Statins are the most commonly prescribed agents used to modulate cholesterol levels in course of hypercholesterolemia treatment because of their relative tolerability and LDL-C lowering effect. Recently, there are emerging interests in the perspectives of statin drugs as anticancer agents based on preclinical evidence of their antiproliferative, proapoptotic, and anti-invasive properties. Functional impact of statin application on transformed cells still remains obscure that requires systematic study on adequate cellular models to provide correct comparison with their non-transformed counterparts. Cholesterol is the major lipid component of mammalian cells and it plays a crucial role in organization, lateral heterogeneity, and dynamics of plasma membrane as well as in membrane-cytoskeleton interrelations. To date, it is uncertain whether cellular effects of statins involve lipid-dependent alteration of plasma membrane. Here, the effects of simvastatin on lipid rafts, F-actin network and cellular viability were determined in comparative experiments on transformed fibroblasts and their non-transformed counterpart. GM1 lipid raft marker staining indicated no change of lipid raft integrity after short- or long-term simvastatin treatments. In the same time, simvastatin induced cytoskeleton rearrangement including partial F-actin disruption in cholesterol- and lipid raft-independent manner. Simvastatin dose-dependently affected viability of BALB/3T3 and 3T3B-SV40 cell lines: transformed fibroblasts were noticeably more sensitive to simvastatin comparing to non-transformed cells. PMID- 28656735 TI - An analysis of genetic association in opioid dependence susceptibility. AB - WHAT IS KNOWN: Drug addiction is a novelty-seeking personality trait that is associated with the candidate genes OPRD1 (opioid delta receptors), OPRK1 (opioid kappa receptors) and PDYN (prodynorphin). However, associations between single nucleotide polymorphisms (SNPs) rs1042114 (80G>T) of the OPRD1 gene, rs702764 (843 A>G) of the OPRK1 gene, and rs910080 (3' UTR _743T>C), rs1997794 (5' UTR 381A>G) and rs1022563 (3' UTR) of the PDYN gene and novelty seeking remain controversial as reported results have not been reproducible. OBJECTIVE: The goal of this study was to determine the frequencies of SNPs rs1042114, rs702764, rs1997794, rs1022563 and rs910080 in the Malaysian population and to study their association with opioid dependence in Malaysian Malays. METHODS: A total of 459 Malay male with opioid dependence and 543 healthy male (controls) subjects were included in this study. SNPs were genotyped using the TaqMan SNP genotyping assay. Statistical analysis was performed using Golden Helix SVS software suite to identify the distribution of allele and genotype frequencies, and SNP-SNP interactions were also analysed in this study. RESULTS AND DISCUSSION: SNP rs1042114 in the OPRD1 gene is strongly associated with opiate addiction (P=.0001). In individuals homozygous for this risk allele, the likelihood of opiate addiction is increased by a factor 1.62 (95% confidence interval (CI) 1.412-1.875). Polymorphic alleles at SNP rs702764 of OPRK1 were not associated with opioid dependence. A significant association between opioid dependence and SNP rs910080 of PDYN (P=.0217) was detected, but there was no association for SNPs rs199774 and rs1022563. A significant interaction was also identified between homozygous wild-type genotype TT of rs702764 with the risk genotypes TG/GG of rs1042114 (odds ratio (OR)=2.111 (95% CI 1.227-3.631), P=.0069) and with the risk genotypes GA/AA of rs910080 (OR=1.415 (95% CI 1.04-1.912), P=.0239). WHAT IS NEW AND CONCLUSION: The results indicate that SNPs rs1042114 and rs910080 contribute to vulnerability to opioid dependence in the Malaysian Malay population. These results will help us to understand the effect of the SNPs and the SNP-SNP interaction on opioid dependence and may assist in efforts to screen vulnerable individuals and match them with individually tailored prevention and treatment strategies. PMID- 28656736 TI - Hepatitis C virus infection and risk of multiple myeloma: Evidence from a meta analysis based on 17 case-control studies. AB - Hepatitis C virus (HCV) infection is a leading cause of chronic liver damage and is associated with other diseases. Some studies reported that patients with HCV have a significantly increased risk of multiple myeloma while others do not report an association. We aimed to clarify the association between HCV and multiple myeloma and analyse the factors that affect the controversial conclusions through a meta-analysis. We conducted a systematic literature search of HCV and myeloma in the databases of PubMed/MEDLINE, Cochrane Library, EMBASE, Wanfang and China National Knowledge Infrastructure (CNKI) from inception to September 2016. Outcomes were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). A positive correlation between HCV infection and risk of developing multiple myeloma was revealed (OR=2.67, 95% CI=1.35-5.26, P=.005) based on meta-analysis of 17 case-control observational studies. When the data were stratified by source of control, significant associations were observed in hospital-based studies, but not population-based studies. Further subgroup analyses showed increased risk of multiple myeloma in HCV patients when studies were conducted in high HCV prevalent countries, but not in low or moderate HCV prevalent countries. In addition, similar positive association was detected in studies performed in the East Asia and in intermediate-quality studies. In summary, the association of HCV infection with increased risk of multiple myeloma depended on several factors, including study design, quality and environmental HCV prevalence. Further large-scale, well-designed studies are needed to validate the role of HCV in the aetiology of multiple myeloma. PMID- 28656737 TI - Fear of falling and gait parameters in older adults with and without fall history. AB - AIM: Fear of falling (FOF) is associated with spatial and temporal gait parameters in older adults. FOF is prevalent among older adults, both those with and without fall history. It is still unclear whether the relationships between FOF and gait parameters are affected by fall history. The aim of the present study was to compare gait parameters by the presence of FOF and fall history. METHODS: A total of 3575 older adults (mean age 71.7 years, 49.7% female) met the inclusion criteria for the present study. We assessed the presence of fall history and FOF by face-to-face interview, and gait parameters (gait speed, stride length, step rate, double support time and variation of stride length) at a comfortable speed using a computerized electronic walkway. RESULTS: Prevalences of fall history and FOF were as follows: non-fallers without FOF 52.6% (n = 1881); fallers without FOF 6.3% (n = 227); non-fallers with FOF 34.4% (n = 1229); and fallers with FOF 6.7% (n = 238). Analysis of covariance showed significant differences among the four groups in all gait variables even after adjusting for age, sex and number of medications used. It should be noted that non-fallers with FOF showed significantly slower gait speed, shorter stride length and longer double support time than did non-fallers without FOF (P < 0.001). CONCLUSIONS: The present results suggest that spatial and temporal gait parameters are influenced by FOF, even in the absence of fall history. The assessment of FOF might be helpful for better understanding of age-related changes in gait control. Geriatr Gerontol Int 2017; 17: 2455-2459. PMID- 28656738 TI - Mid-term outcomes of consecutive 998 cases of coronary atherectomy in contemporary clinical practice. AB - OBJECTIVES: To compare clinical and safety endpoints with use of rotational (RA) and orbital (OA) atherectomy in a large patient population with moderate to severely calcified lesions undergoing percutaneous coronary intervention (PCI). BACKGROUND: Coronary artery calcification (CAC) has been recognized as a risk factor for adverse outcomes with coronary artery disease (CAD). Though atheroablative techniques, RA and OA have been used extensively, comparison of their clinical and safety endpoints is lacking. Comparison of these two modalities formed the basis of our study. METHODS AND RESULTS: Of 12 001 patients who underwent PCI at our institution between January 2013-December 2015, we studied 998 consecutive patients with severe calcification treated with atheroablation. We assessed clinical outcomes including death, myocardial infarction (MI) and target lesion revascularization (TLR) at 30 days and 6 months in addition to post-procedural complications. Device perforation occurred more frequently with use of OA at high burr speed versus RA (1.9%, n = 3 vs. 0.2%, n = 2, P = 0.03). Rates of composite adverse events were similar between groups at 6 months (18.55 vs. 11.46%; P = 0.11) CONCLUSION: In this retrospective, single center study, we observed no significant differences in 6-month rates of adverse events associated with use of OA vs. RA in patients with moderate to severe calcification undergoing PCI. Larger, prospective studies are needed to confirm our findings. PMID- 28656739 TI - Estimation of the shielding ability of a tungsten functional paper for diagnostic x-rays and gamma rays. AB - Tungsten functional paper (TFP) is a novel paper-based radiation-shielding material. We measured the shielding ability of TFP against x-rays and gamma rays. The TFP was supplied in 0.3-mm-thick sheets that contained 80% tungsten powder and 20% cellulose (C6 H10 O5 ) by mass. In dose measurements for x-rays (60, 80, 100, and 120 kVp), we measured doses after through 1, 2, 3, 5, 10, and 12 TFP sheets, as well as 0.3 and 0.5 mm of lead. In lead equivalence measurements, we measured doses after through 2 and 10 TFP sheets for x-rays (100 and 150 kVp), and 0, 7, 10, 20, and 30 TFP sheets for gamma rays from cesium-137 source (662 keV). And then, the lead equivalent thicknesses of TFP were determined by comparison with doses after through standard lead plates (purity >99.9%). Additionally, we evaluated uniformity of the transmitted dose by TFP with a computed radiography image plate for 50 kVp x-rays. A single TFP sheet was found to have a shielding ability of 65%, 53%, 48%, and 46% for x-rays (60, 80, 100, and 120 kVp), respectively. The lead equivalent thicknesses of two TFP sheets were 0.10 +/- 0.02, 0.09 +/- 0.02 mmPb, and of ten TFP sheets were 0.48 +/- 0.02 and 0.51 +/- 0.02 mmPb for 100 and 150 kVp x-rays, respectively. The lead equivalent thicknesses of 7, 10, 20, and 30 sheets of TFP for gamma rays from cesium-137 source were estimated as 0.28, 0.43, 0.91, and 1.50 mmPb with an error of +/- 0.01 mm. One TFP sheet had nonuniformity, however, seven TFP sheets provided complete shielding for 50 kVp x-rays. TFP has adequate radiation shielding ability for x-rays and gamma rays within the energy range used in diagnostic imaging field. PMID- 28656740 TI - Tailoring reablement: A grounded theory study of establishing reablement in a community setting in Norway. AB - Reablement is an interprofessional, home-based rehabilitation service that aims to enable senior residents to cope with everyday life and to prevent functional impairments. Systematic accounts of what practitioners actually do when establishing reablement are lacking. This study aims to generate a grounded theory of practitioners' patterns of action when establishing reablement. The study is located in Norway, and grounded theory is the methodological approach. Data were collected from January 2014 to August 2016 through participant observations, focus group interviews and individual interviews. Informants are municipal healthcare employees in different organisational areas associated with the process of establishing reablement services (managers of conventional home care and representatives from the administration and service-provider offices). Altogether, 17 individuals are interviewed. The empirical data are analysed several times using open, selective and theoretical coding. The grounded theory, "tailoring reablement," includes three phases-replicating, adapting and establishing-and the strategies of collaborating, developing knowledge, habituating and filtering. The theory of tailoring reablement also includes the impact of the contextual factors. The study seeks to bridge the gap between research and practice. The theory of tailoring reablement emerges from an inductive approach and theorises participants' actions. The theory focuses on the phases from innovation to implementation. Establishing a new service model in a complex welfare setting requires a wide range of actors and agencies. Tailoring reablement also requires flexibility and professional autonomy. It is important to create terms and conditions for this within a stringent health and care service. The insights of this study have implications for practice development of reablement and can fit other public sector fields. PMID- 28656741 TI - Tuning 2D Light Upconversion Emission by Modulating Phonon Relaxation. AB - The photonic upconversion in rare earth atoms is widely used to convert "invisible" near infrared photons to "visible" photons with continuous wave light. By using a patterned substrate, upconversion become a route for creating new information-incorporating security codes. The amount of information in the cipher increases in proportion to the number of emission colors as well as the pattern structure. Subsequently, changing the chemical composition of upconversion phosphors on 2 D substrates is required to manufacture information rich upconversion cryptography. In this study, we exploited temperature controlled thermal reaction on upconversion films deposited on a quartz substrate to prepare security information codes. Multiple color emission was generated from upconversion films as the result of inserting high-frequency molecular oscillators into the film structures. Fourier-transform infrared (FTIR) and time resolved study corroborated the mechanism of spectral variation of upconversion films. PMID- 28656743 TI - Sandwiched Thin-Film Anode of Chemically Bonded Black Phosphorus/Graphene Hybrid for Lithium-Ion Battery. AB - A facile vacuum filtration method is applied for the first time to construct sandwich-structure anode. Two layers of graphene stacks sandwich a composite of black phosphorus (BP), which not only protect BP from quickly degenerating but also serve as current collector instead of copper foil. The BP composite, reduced graphene oxide coated on BP via chemical bonding, is simply synthesized by solvothermal reaction at 140 degrees C. The sandwiched film anode used for lithium-ion battery exhibits reversible capacities of 1401 mAh g-1 during the 200th cycle at current density of 100 mA g-1 indicating superior cycle performance. Besides, this facile vacuum filtration method may also be available for other anode material with well dispersion in N-methyl pyrrolidone (NMP). PMID- 28656742 TI - Long-term subregion-specific encoding of enhanced ethanol intake by D1DR medium spiny neurons of the nucleus accumbens. AB - The nucleus accumbens (NAc) is a critical component of the mesocorticolimbic system and is involved in mediating the motivational and reinforcing aspects of ethanol consumption. Chronic intermittent ethanol (CIE) exposure is a reliable model to induce ethanol dependence and increase volitional ethanol consumption in mice. Following a CIE-induced escalation of ethanol consumption, NMDAR (N-methyl D-aspartate receptor)-dependent long-term depression in D1 dopamine receptor expressing medium spiny neurons of the NAc shell was markedly altered with no changes in plasticity in D1 dopamine receptor medium spiny neurons from the NAc core. This disruption of plasticity persisted for up to 2 weeks after cessation of ethanol access. To determine if changes in AMPA receptor (AMPAR) composition contribute to this ethanol-induced neuroadaptation, we monitored the rectification of AMPAR excitatory postsynaptic currents (EPSCs). We observed a marked decrease in the rectification index in the NAc shell, suggesting the presence of GluA2-lacking AMPARs. There was no change in the amplitude of spontaneous EPSCs (sEPSCs), but there was a transient increase in sEPSC frequency in the NAc shell. Using the paired pulse ratio, we detected a similar transient increase in the probability of neurotransmitter release. With no change in sEPSC amplitude, the change in the rectification index suggests that GluA2-containing AMPARs are removed and replaced with GluA2-lacking AMPARs in the NAc shell. This CIE-induced alteration in AMPAR subunit composition may contribute to the loss of NMDAR-dependent long-term depression in the NAc shell and therefore may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model. PMID- 28656744 TI - Accuracy of food photographs for quantifying food servings in a lunch meal setting among Danish children and adults. AB - BACKGROUND: Visual aids, such as food photographs, are widely used in estimating food quantities in dietary surveys. The present study aimed to assess how accurately Danish adults and children can estimate food portion sizes using 37 series of photographs illustrating four to six different portion sizes under real life conditions; determine whether adults were more accurate than children; and estimate the error caused by using portion size photographs to estimate weights of foods consumed in macronutrient calculation. METHODS: Six hundred and twenty two adults and 109 children were recruited in three workplace canteens and in two schools, respectively, to estimate their lunchtime portions based on photographs. Participants were instructed to keep the foods separated on their plate when taking lunch. Participants thereafter estimated their own portions by looking at the relevant series of photographs. The actual food portions were then weighed. RESULTS: The proportion of correct estimations was 42% overall (range 19-77%). The mean difference (%) between estimated and actual weight was 17% (range 1 111%). Small portion size photographs were more often used correctly compared to larger portion photographs. Children had as many correct estimations as adults, although they overestimated portions more. Participants using fractions of (or more than) one photograph to estimate the portion of a food had significantly larger errors. When calculating the macronutrient content of a weekly menu using the estimated portion sizes, protein had the largest error (29%). CONCLUSIONS: When used in a real-life situation, the portion size photographs validated in the present study showed a certain inaccuracy compared to the actual weights. PMID- 28656745 TI - Anxiety affects disability and quality of life in patients with painful diabetic neuropathy. AB - BACKGROUND: Painful diabetic neuropathy (PDN) is known to negatively affect psychosocial functioning as expressed by enhanced levels of anxiety and depression. The aim of this study was to specify diabetes and pain-related fears. METHODS: This questionnaire-based cross-sectional study included 154 patients with PDN (mean age 65.7 +/- 6.6 years). Correlation analyses corrected for age, gender, pain intensity, pain duration and insulin treatment were performed to assess the associations of fear of hypoglycaemia (Hypoglycaemia Fear Survey, HFS), kinesiophobia (Tampa Scale of Kinesiophobia, TSK), fear of pain (Pain Anxiety Symptom Scale, PASS-20), fear of falling (Falls Efficacy Scale-I, FES-I), fear of fatigue (Tampa Scale of Fatigue, TSF) and fear of negative evaluation (Brief Fear of Negative Evaluation Scale, BFNE), with quality of life (QoL) (Norfolk Quality of Life Questionnaire, Diabetic Neuropathy Version, QOL-DN) and disability (Pain Disability Index, PDI), respectively. RESULTS: In univariate analyses, all fears were independently associated with QOL-DN and PDI (p < 0.001 for all variables). Linear regression models including all fears and confounders, showed that pain intensity, pain duration and FES-I were significantly associated with QOL-DN (R2 = 0.603). Pain intensity, male gender and FES-I were significantly associated with PDI (R2 = 0.526). CONCLUSIONS: After controlling for confounders, levels of pain intensity, duration of pain and fear of falling were negatively associated with QoL in patients with PDN. Pain intensity, male gender and fear of falling were positively associated with disability. Specifying fears enables us to identify potential targets for behavioural interventions that aim to improve psychosocial well-being in patients with PDN. SIGNIFICANCE: This study shows that patients with PDN suffer from various fears, which should enable us to design a treatment strategy that directly targets these fears, hereby improving physical and psychosocial well-being in these patients. PMID- 28656746 TI - Therapeutic inertia in patients treated with two or more antidiabetics in primary care: Factors predicting intensification of treatment. AB - AIMS: To determine the patterns and predictors of treatment intensification in patients with type 2 diabetes on >=2 non-insulin antidiabetic drugs (NIADs) and inadequate glycaemic control in primary care in Catalonia, Spain. MATERIAL AND METHODS: This was a retrospective analysis using electronic medical records from patients with HbA1c >= 7% and a first prescription for a new NIAD or insulin recorded from January 2010 to December 2014. Therapeutic inertia was defined as no intensification if HbA1c was >=8% at baseline or during follow-up. Time to first intensification was evaluated by time-to-event analysis, and factors predicting intensification through a competing-risk regression model. RESULTS: Among 23 678 patients with HbA1c >= 7%, 26.2% were censored without treatment intensification after a median follow up of 4.2 years. Among the 12 730 patients in the subgroup with HbA1c >= 8% at baseline or during follow-up, therapeutic inertia was present in 18.1% of cases. In the overall cohort, mean HbA1c at initiation of insulin and NIAD were 9.4% +/- 1.5% and 8.7% +/- 1.3%, respectively. Median time to first intensification was 17.1 months in patients with HbA1c 8.0% to 9.9%, and 10.1 months in those with HbA1c > 10%. Variables strongly associated with intensification were HbA1c values 8.0% to 9.9% (subhazard ratio [SHR], 1.7; 95% CI, 1.65-1.78) and >10% (SHR, 2.5; 95% CI, 2.37 2.68); diabetes duration >=20 years (SHR, 1.25; 95% CI, 1.11-1.41) and, to a lesser extent, female gender, presence of comorbidities, chronic kidney disease and microvascular complications. CONCLUSIONS: Intensification was not undertaken in 1 in 5 patients. Both HbA1c thresholds and time until therapy intensification exceeded current recommendations. PMID- 28656747 TI - Metastatic endophthalmitis and thyroid abscess complicating Klebsiella pneumoniae liver abscess. AB - The thyroid is resistant to infection due to its anatomical and physiological characteristics. We present a rare case of invasive liver abscess with metastatic thyroid abscess and endogenous endophthalmitis in a previously healthy 55-year old female patient without diabetes or other medical illness. This report raises an important question of the virulence of Klebsiella pneumoniae as an increasingly common causative agent of liver abscess. PMID- 28656749 TI - Bioinspired Synthesis of Photocatalytic Nanocomposite Membranes Based on Synergy of Au-TiO2 and Polydopamine for Degradation of Tetracycline under Visible Light. AB - A bioinspired photocatalytic nanocomposite membrane was successfully prepared via polydopamine (pDA)-coated poly(vinylidene fluoride) (PVDF) membrane, as a secondary platform for vacuum-filtrated Au-TiO2 nanocomposites, with enhanced photocatalytic activity. The degradation efficiency of Au-TiO2/pDA/PVDF membranes reached 92% when exposed to visible light for 120 min, and the degradation efficiency of Au-TiO2/pDA/PVDF membranes increased by 26% compared to that of Au TiO2 powder and increased by 51% compared to that of TiO2/pDA/PVDF nanocomposite membranes. The degradation efficiency remained about 90% after five cycle experiments, and the Au-TiO2/pDA/PVDF nanocomposite membranes showed good stability, regeneration performance, and easy recycling. The pDA coating not only served as a bioadhesion interface to improve the bonding force between the catalyst and the membrane substrate but also acted as a photosensitizer to broaden the wavelength response range of TiO2, and the structure of Au TiO2/pDA/PVDF also improves the transfer rate of photogenerated electrons; the surface plasmon resonance effect of Au also played a positive role in improving the activity of the catalyst. Therefore, we believe that this study opens up a new strategy in preparing the bioinspired photocatalytic nanocomposite membrane for potential wastewater purification, catalysis, and as a membrane separation field. PMID- 28656748 TI - Adenosine Monophosphate Binding Stabilizes the KTN Domain of the Shewanella denitrificans Kef Potassium Efflux System. AB - Ligand binding is one of the most fundamental properties of proteins. Ligand functions fall into three basic types: substrates, regulatory molecules, and cofactors essential to protein stability, reactivity, or enzyme-substrate complex formation. The regulation of potassium ion movement in bacteria is predominantly under the control of regulatory ligands that gate the relevant channels and transporters, which possess subunits or domains that contain Rossmann folds (RFs). Here we demonstrate that adenosine monophosphate (AMP) is bound to both RFs of the dimeric bacterial Kef potassium efflux system (Kef), where it plays a structural role. We conclude that AMP binds with high affinity, ensuring that the site is fully occupied at all times in the cell. Loss of the ability to bind AMP, we demonstrate, causes protein, and likely dimer, instability and consequent loss of function. Kef system function is regulated via the reversible binding of comparatively low-affinity glutathione-based ligands at the interface between the dimer subunits. We propose this interfacial binding site is itself stabilized, at least in part, by AMP binding. PMID- 28656750 TI - Ultrafast SET-LRP with Peptoid Cytostatic Drugs as Monofunctional and Bifunctional Initiators. AB - To continue expanding the use of Single Electron Transfer-Living Radical Polymerization (SET-LRP) in applications at the interface between macromolecular science, biomacromolecules, biology and medicine, it is essential to develop novel initiators that do not compromise the structural stability of synthesized polymers in biological environments. Here, we report that stable 2-bromopropionyl peptoid-type initiators such as 1,4-bis(2-bromopropionyl)piperazine and 4-(2 bromopropionyl)morpholine are an alternative that meets the standards reached by the well-known secondary and tertiary alpha-haloester-type initiators in terms of excellent control over molecular weight evolution and distribution as well as polymer chain ends. SET-LRP methodologies in organic, aqueous, and biphasic organic-aqueous media were evaluated for this purpose. PMID- 28656751 TI - Gadolinium-Labeled Biodegradable Dendron-Hyaluronic Acid Hybrid and Its Subsequent Application as a Safe and Efficient Magnetic Resonance Imaging Contrast Agent. AB - Novel magnetic resonance imaging (MRI) contrast agents with high sensitivity and good biocompatibility are required for the diagnosis of cancer. Herein, we prepared and characterized the gadolinium [Gd(III)]-labeled peptide dendron hyaluronic acid (HA) conjugate-based hybrid (dendronized-HA-DOTA-Gd) by combining the advantages of HA and the peptide dendron. The dendronized-HA-DOTA-Gd hybrid with 3.8% Gd(III) as weight percentage showed a negative zeta potential (-35 mV). The in vitro degradation results indicated that the dendronized-HA-DOTA-Gd hybrid degraded into products with low molecular weights in the presence of hyaluronidase. The dendronized-HA-DOTA-Gd hybrid showed a 3-fold increase in longitudinal relaxivity and much higher in vivo signal enhancement in 4T1 breast tumors of mice compared with clinical Magnevist (Gd-DTPA). The dendronized-HA DOTA-Gd hybrid had a higher accumulation in tumors than Gd-DTPA; it was 2-3-fold after administration. Meanwhile, the polymeric hybrid resulted in low Gd(III) residue in the body compared with that of Gd-DTPA. The systematic biosafety evaluations, including blood compatibility and toxicity assessments, suggested that the dendronized-HA-DOTA-Gd hybrid exhibited good biocompatibility. Thus, the gadolinium-labeled and dendronized HA hybrid shows promise as a safe and efficient macromolecular MRI contrast agent based on high sensitivity, low residue content in the body, and good biosafety. PMID- 28656753 TI - pi-Expanded Dipyrrolonaphthyridinediones with Large Two-Photon Absorption Cross Section Values. AB - A synthetic entry to novel dyes based on the dipyrrolonaphthyridinedione core was developed via the Heck reaction. These weakly fluorescent compounds bearing double bond linkages between the core and the peripheral units absorbed strongly in the far-red/NIR region and possessed large values of two-photon absorption (TPA) cross-sections (up to 5180 GM). Additionally, analogous dyes bearing triple bond linkages were also efficient TPA materials with relatively large two-photon absorption cross-sections (up to 2840 GM) as well as two-photon brightness (up to 1450 GM). The centrosymmetric nature of both of these families of dyes is responsible for the location of the maxima of two-photon absorption being at much higher energy than the ones corresponding to the double wavelength of the lowest energy one-photon absorption. Theoretical calculations clarified that the enhancement of the TPA by the peripheral substitutions arose through different mechanisms depending on either the electron-donating or electron-withdrawing ability of a given substituent to the ambipolar core. The change in the electron distribution of HOMO and HOMO-1 by the push-pull effect was found to govern the strength of the lowest-energy TPA-allowed transition. Importantly, compounds from both series possessed a beneficial ratio of sigma2/MW (1.6-9.8 GM/g). PMID- 28656752 TI - Airborne PCBs and OH-PCBs Inside and Outside Urban and Rural U.S. Schools. AB - PCBs appear in school air because many school buildings were built when PCBs were still intentionally added to building materials and because PCBs are also present through inadvertent production in modern pigment. This is of concern because children are especially vulnerable to the toxic effects of PCBs. Here we report indoor and outdoor air concentrations of PCBs and OH-PCBs from two rural schools and four urban schools, the latter near a PCB-contaminated waterway of Lake Michigan in the United States. Samples (n = 108) were collected as in/out pairs using polyurethane foam passive air samplers (PUF-PAS) from January 2012 to November 2015. Samples were analyzed using GC/MS-MS for all 209 PCBs and 72 OH PCBs. Concentrations inside schools were 1-2 orders of magnitude higher than outdoors and ranged from 0.5 to 194 ng/m3 (PCBs) and from 4 to 665 pg/m3 (OH PCBs). Congener profiles were similar within each sampling location across season but different between schools and indicated the sources as Aroclors from building materials and individual PCBs associated with modern pigment. This study is the first cohort-specific analysis to show that some children's PCB inhalation exposure may be equal to or higher than their exposure through diet. PMID- 28656754 TI - Soybean P34 Probable Thiol Protease Probably Has Proteolytic Activity on Oleosins. AB - P34 probable thiol protease (P34) and Gly m Bd 30K (30K) show high relationship with the protease of 24 kDa oleosin of soybean oil bodies. In this study, 9 day germinated soybean was used to separate bioprocessed P34 (P32) from bioprocessed 30K (28K). Interestingly, P32 existed as dimer, whereas 28K existed as monomer; a P32-rich sample had proteolytic activity and high cleavage site specificity (Lys Thr of 24 kDa oleosin), whereas a 28K-rich sample showed low proteolytic activity; the P32-rich sample contained one thiol protease. After mixing with purified oil bodies, all P32 dimers were dissociated and bound to 24 kDa oleosins to form P32-24 kDa oleosin complexes. By incubation, 24 kDa oleosin was preferentially hydrolyzed, and two hydrolyzed products (HPs; 17 and 7 kDa) were confirmed. After most of 24 kDa oleosin was hydrolyzed, some P32 existed as dimer, and the other as P32-17 kDa HP. It was suggested that P32 was the protease. PMID- 28656755 TI - Microfluidic Separation of Lymphoblasts for the Isolation of Acute Lymphoblastic Leukemia Using the Human Transferrin Receptor as a Capture Target. AB - Acute lymphocytic leukemia (ALL) is the most prevalent pediatric cancer, and the peripheral blood lymphoblast percentage is an important index for ALL diagnosis and prognosis. We describe a microfluidic device that isolates and enumerates peripheral blood lymphoblasts using affinity separations. The innovative use of a nonspecific ligand allows a widespread "net" for cancer cells, without a priori knowledge of the cancer type. Using lymphoblasts spiked into blood, we simulated leukemia cases with lymphoblast concentrations ranging from 1 to 30% of total leukocytes. Lymphoblasts were isolated using monoclonal antibodies for the Human Transferring Receptor (CD71). Anti-CD71 antibodies were found to be more effective for capturing lymphoblasts than commonly used, ALL-specific antibodies for CD7 and CD10. CCRF-CEM lymphoblasts were isolated in the chip with 82-97% purity, with lower concentrations tested (7%) still showing >80% purity for cell capture. Patient-derived ALL cell lines COG-LL-332 and COG-LL-317 were isolated in the chip with 80%-97% and 57% -92% of purity, respectively, with the initial spike concentrations as low as 1%. The ability to capture ALL lymphoblasts present in blood at low concentrations provides a novel approach for characterization of ALL cells, including patients with low leukemic burdens during and after therapy. PMID- 28656756 TI - Bioinspired Transparent Laminated Composite Film for Flexible Green Optoelectronics. AB - Herein, we report a new version of a bioinspired chitin nanofiber (ChNF) transparent laminated composite film (HCLaminate) made of siloxane hybrid materials (hybrimers) reinforced with ChNFs, which mimics the nanofiber-matrix structure of hierarchical biocomposites. Our HCLaminate is produced via vacuum bag compressing and subsequent UV-curing of the matrix resin-impregnated ChNF transparent paper (ChNF paper). It is worthwhile to note that this new type of ChNF-based transparent substrate film retains the strengths of the original ChNF paper and compensates for ChNF paper's drawbacks as a flexible transparent substrate. As a result, compared with high-performance synthetic plastic films, such as poly(ethylene terephthalate), poly(ether sulfone), poly(ethylene naphthalate), and polyimide, our HCLaminate is characterized to exhibit extremely smooth surface topography, outstanding optical clarity, high elastic modulus, high dimensional stability, etc. To prove our HCLaminate as a substrate film, we use it to fabricate flexible perovskite solar cells and a touch-screen panel. As far as we know, this work is the first to demonstrate flexible optoelectronics, such as flexible perovskite solar cells and a touch-screen panel, actually fabricated on a composite film made of ChNF. Given its desirable macroscopic properties, we envision our HCLaminate being utilized as a transparent substrate film for flexible green optoelectronics. PMID- 28656758 TI - Copper-Catalyzed Cyanation of N-Tosylhydrazones with Thiocyanate Salt as the "CN" Source. AB - A novel protocol for the synthesis of alpha-aryl nitriles has been successfully achieved via a copper-catalyzed cyanation of N-tosylhydrazones employing thiocyanate as the source of cyanide. The features of this method include a convenient operation, readily available substrates, low-toxicity thiocyanate salts, and a broad substrate scope. PMID- 28656757 TI - Challenges in the Greener Production of Formates/Formic Acid, Methanol, and DME by Heterogeneously Catalyzed CO2 Hydrogenation Processes. AB - The recent advances in the development of heterogeneous catalysts and processes for the direct hydrogenation of CO2 to formate/formic acid, methanol, and dimethyl ether are thoroughly reviewed, with special emphasis on thermodynamics and catalyst design considerations. After introducing the main motivation for the development of such processes, we first summarize the most important aspects of CO2 capture and green routes to produce H2. Once the scene in terms of feedstocks is introduced, we carefully summarize the state of the art in the development of heterogeneous catalysts for these important hydrogenation reactions. Finally, in an attempt to give an order of magnitude regarding CO2 valorization, we critically assess economical aspects of the production of methanol and DME and outline future research and development directions. PMID- 28656759 TI - Single-Atomic Ruthenium Catalytic Sites on Nitrogen-Doped Graphene for Oxygen Reduction Reaction in Acidic Medium. AB - The cathodic oxygen reduction reaction (ORR) is essential in the electrochemical energy conversion of fuel cells. Here, through the NH3 atmosphere annealing of a graphene oxide (GO) precursor containing trace amounts of Ru, we have synthesized atomically dispersed Ru on nitrogen-doped graphene that performs as an electrocatalyst for the ORR in acidic medium. The Ru/nitrogen-doped GO catalyst exhibits excellent four-electron ORR activity, offering onset and half-wave potentials of 0.89 and 0.75 V, respectively, vs a reversible hydrogen electrode (RHE) in 0.1 M HClO4, together with better durability and tolerance toward methanol and carbon monoxide poisoning than seen in commercial Pt/C catalysts. X ray adsorption fine structure analysis and aberration-corrected high-angle annular dark-field scanning transmission electron microscopy are performed and indicate that the chemical structure of Ru is predominantly composed of isolated Ru atoms coordinated with nitrogen atoms on the graphene substrate. Furthermore, a density function theory study of the ORR mechanism suggests that a Ru-oxo-N4 structure appears to be responsible for the ORR catalytic activity in the acidic medium. These findings provide a route for the design of efficient ORR single atom catalysts. PMID- 28656760 TI - CuInS2/ZnS Quantum Dots Conjugating Gd(III) Chelates for Near-Infrared Fluorescence and Magnetic Resonance Bimodal Imaging. AB - A bimodal contrast nanoagent was developed by chelating gadolinium ions to 2 [bis[2-[carboxymethyl-[2-oxo-2-(2-sulfanylethyl amino)ethyl]amino]ethyl]amino]acetic acid (DTDTPA)-modified CuInS2/ZnS quantum dots (QDs). The longitudinal relaxivity (r1) of the resulted QDs@DTDTPA-Gd nanoparticles (NPs) was calculated to be 9.91 mM-1 s-1, which was 2.5 times as high as that of clinically approved Gd-DTPA (3.9 mM-1 s-1). In addition, the in vivo imaging experiments showed that QDs@DTDTPA-Gd NPs could enhance both near infrared fluorescence and T1-weighted magnetic resonance (MR) imaging of tumor tissue through passive targeting accumulation. Moreover, the high colloidal and fluorescence stabilities and good biocompatibility indicate that QDs@DTDTPA-Gd NPs have a great potential for use as an efficient nanoagent to integrate the extremely high sensitivity of fluorescence imaging to the high resolution of MR imaging. Integration of bimodal detectability in the same agent of QDs@DTDTPA-Gd NPs can avoid extra stress on the blood clearance mechanisms as the administration of multiple dose of agents. PMID- 28656761 TI - Orthogonal Solution-Processable Electron Transport Layers Based on Phenylpyridine Side-Chain Polystyrenes. AB - This article reports the synthesis and characterization of a series of polystyrenes containing phenylpyridine moieties as side chains. Methanol solubility of these polymers is induced if the relative pyridine content of the overall aromatic units of the side chains is larger than 0.5. This allows for orthogonal processing of multilayered organic light emitting diode (OLED) stacks fabricated from solutions. The polymers show high thermal stability due to their glass-transition temperatures ranging from 136 up to 247 degrees C. High triplet energies of up to 2.8 eV are obtained by combination of the side-chain aromatic rings in the meta position. The use of the methanol soluble side-chain polymers as an electron transport layer (ETL) is demonstrated in an orthogonally processed three-layer green-emitting OLED stack. When depositing the ETL from methanol, redissolution of the underlying emission layer does not occur. PMID- 28656762 TI - Radical Difluororomethylation of Thiols with Difluoromethylphosphonium Triflate under Photoredox Catalysis. AB - A convenient, visible light-induced radical difluoromethylation of aryl-, heteroaryl-, and alkylthiols with difluoromethyltriphenylphosphonium triflate was developed to afford various difluoromethyl thioethers in moderate to excellent yields. The key reaction features include the use of a readily available CF2H radical source, mild reaction conditions, and excellent chemoselective thiol difluoromethylation. PMID- 28656763 TI - Glucosylation of Smoke-Derived Volatiles in Grapevine (Vitis vinifera) is Catalyzed by a Promiscuous Resveratrol/Guaiacol Glucosyltransferase. AB - Vinification of grapes (Vitis vinifera) exposed to forest fire smoke can yield unpalatable wine due to the presence of taint compounds from smoke and the release of smoke derived volatiles from their respective glycosides during the fermentation process or in-mouth during consumption. To identify glycosyltransferases (GTs) involved in the formation of glycosidically bound smoke-derived volatiles we performed gene expression analysis of candidate GTs in different grapevine tissues. Second, substrates derived from bushfire smoke or naturally occurring in grapes were screened with the candidate recombinant GTs. A resveratrol GT (UGT72B27) gene, highly expressed in grapevine leaves and berries was identified to be responsible for the production of the phenolic glucosides. UGT72B27 converted the stilbene trans-resveratrol mainly to the 3-O-glucoside. Kinetic analyses yielded specificity constants (kcat/KM) of 114, 17, 9, 8, and 2 mM-1 s-1 for guaiacol, trans-resveratrol, syringol, methylsyringol, and methylguaiacol, respectively. This knowledge will help to design strategies for managing the risk of producing smoke-affected wines. PMID- 28656764 TI - The K-Region in Pyrenes as a Key Position to Activate Aggregation-Induced Emission: Effects of Introducing Highly Twisted N,N-Dimethylamines. AB - A new design strategy to activate aggregation-induced emission (AIE) in pyrene chromophores is reported. In a previous report, we demonstrated that highly twisted N,N-dialkylamines of anthracene and naphthalene induce drastic AIE when these donors are introduced at appropriate positions to stabilize the S1/S0 minimum energy conical intersection (MECI). In the present study, this design strategy was applied to pyrene: the introduction of N,N-dimethylamine substituents at the 4,5-positions of pyrene, the so-called K-region, are likely to stabilize MECIs. To examine this hypothesis, four novel pyrene derivatives, which contain highly twisted N,N-dimethylamino groups at the 4- (4-Py), 4,5- (4,5 Py), 1- (1-Py), or 1,6-positions (1,6-Py) were tested. The nonradiative transitions of 4,5-Py are highly efficient (knr = 57.1 * 107 s-1), so that its fluorescence quantum yield in acetonitrile decreases to Phifl = 0.04. The solid state fluorescence of 4,5-Py is efficient (Phifl = 0.49). In contrast, 1,6-Py features strong fluorescence (Phifl = 0.48) with a slow nonradiative transition (knr = 11.0 * 107 s-1) that is subject to severe quenching (Phifl = 0.03) in the solid state. These results underline that the chemistry of the pyrene K-region is intriguing, both from a photophysical perspective and with respect to materials science. PMID- 28656765 TI - Fluorination of an Alumina Surface: Modeling Aluminum-Fluorine Reaction Mechanisms. AB - Density functional theory (DFT) calculations were performed to examine exothermic surface chemistry between alumina and four fluorinated, fragmented molecules representing species from decomposing fluoropolymers: F-, HF, CH3F, and CF4. The analysis has strong implications for the reactivity of aluminum (Al) particles passivated by an alumina shell. It was hypothesized that the alumina surface structure could be transformed due to hydrogen bonding effects from the environment that promote surface reactions with fluorinated species. In this study, the alumina surface was analyzed using model clusters as isolated systems embedded in a polar environment (i.e., acetone). The conductor-like screening model (COSMO) was used to mimic environmental effects on the alumina surface. Four defect models for specific active -OH sites were investigated including two terminal hydroxyl groups and two hydroxyl bridge groups. Reactions involving terminal bonds produce more energy than bridge bonds. Also, surface exothermic reactions between terminal -OH bonds and fluorinated species produce energy in decreasing order with the following reactant species: CF4 > HF > CH3F. Additionally, experiments were performed on aluminum powders using thermal equilibrium analysis techniques that complement the calculations. Consistently, the experimental results show a linear relationship between surface exothermic reactions and the main fluorination reaction for Al powders. These results connect molecular level reaction kinetics to macroscopic measurements of surface energy and show that optimizing energy available in surface reactions linearly correlates to maximizing energy in the main reaction. PMID- 28656766 TI - Photoredox Catalysis: Construction of Polyheterocycles via Alkoxycarbonylation/Addition/Cyclization Sequence. AB - A novel visible-light-induced cascade reaction for the preparation of ester functionalized polyheterocycles was developed under metal-free conditions, which was initiated by an intermolecular radical addition to a carbon-carbon double bond of N-arylacrylamide derivatives using alkyl carbazate as the ester source followed by cyano-mediated cyclization. The desired phenanthridine derivative products were isolated in moderate to high yields with broad substrate scope. PMID- 28656767 TI - Visible-Light-Mediated Addition of Phenacyl Bromides onto Cyclopropenes. AB - Visible-light-promoted addition of alpha-bromoacetophenones onto the cyclopropene pi-system in the presence of the fac-Ir(ppy)3 catalyst was shown to afford the corresponding 1(4H)-naphthalenones. The syn-carboarylation of the cyclopropene is followed by a cyclopropane ring opening under the basic conditions, allowing the formation of two C-C bonds and the generation of 1(4H)-naphthalenones bearing an all-carbon benzylic quaternary stereocenter. PMID- 28656768 TI - Phosphine-Catalyzed Asymmetric (3 + 2) Annulations of delta-Acetoxy Allenoates with beta-Carbonyl Amides: Enantioselective Synthesis of Spirocyclic beta-Keto gamma-Lactams. AB - While the phosphine catalysis is a powerful tool for the construction of N heterocycles, the phosphine-catalyzed annulations toward lactam motif are still extremely scarce. Here, we report the asymmetric (3 + 2) annulations of delta acetoxy allenoates with beta-carbonyl amides by using the (R)-SITCP catalyst. The deltaC and gammaC of allenoate respectively engage in annulation with the alphaC and N of the amide, forging a gamma-lactam with good to excellent stereoselectivity. PMID- 28656769 TI - Room-Temperature Processing of TiOx Electron Transporting Layer for Perovskite Solar Cells. AB - In order to realize high-throughput roll-to-roll manufacturing of flexible perovskite solar cells, low-temperature processing of all device components must be realized. However, the most commonly used electron transporting layer in high performance perovskite solar cells is based on TiO2 thin films processed at high temperature (>450 degrees C). Here, we demonstrate room temperature solution processing of the TiOx layer that performs as well as the high temperature TiO2 layer in perovskite solar cells, as evidenced by a champion solar cell efficiency of 16.3%. Using optical spectroscopy, electrical measurements, and X-ray diffraction, we show that the room-temperature processed TiOx is amorphous with organic residues, and yet its optical and electrical properties are on par with the high-temperature TiO2. Flexible perovskite solar cells that employ a room temperature TiOx layer with a power conversion efficiency of 14.3% are demonstrated. PMID- 28656770 TI - Mimicking Peroxidase Activities with Prussian Blue Nanoparticles and Their Cyanometalate Structural Analogues. AB - Nanoparticles composed of Prussian Blue, PB, and the cyanometalate structural analogues, CuFe, FeCoFe, and FeCo, are examined as inorganic clusters that mimic the functions of peroxidases. PB acts as a superior catalyst for the oxidation of dopamine to aminochrome by H2O2. The oxidation of dopamine by H2O2 in the presence of PB is 6-fold faster than in the presence of CuFe. The cluster FeCo does not catalyze the oxidation of dopamine to aminochrome. The most efficient catalyst for the generation of chemiluminescence by the oxidation of luminol by H2O2 is, however, FeCo, and PB lacks any catalytic activity toward the generation of chemiluminescence. The order of catalyzed chemiluminescence generation is FeCo ? CuFe > FeCoFe. The clusters PB, CuFe, FeCoFe, and FeCo mimic the functions of NADH peroxidase. The catalyzed oxidation of NADH by H2O2 to form NAD+ follows the order PB ? CuFe ~ FeCoFe, FeCo. The efficient generation of chemiluminescence by the FeCo-catalyzed oxidation of luminol by H2O2 is used to develop a glucose sensor. The aerobic oxidation of glucose in the presence of glucose oxidase, GOx, yields gluconic acid and H2O2. The chemiluminescence intensities formed by the GOx-generated H2O2 relate to the concentration of glucose, thus providing a quantitative readout signal for the concentrations of glucose. PMID- 28656771 TI - Antagonistic Enzymes in a Biocatalytic pH Feedback System Program Autonomous DNA Hydrogel Life Cycles. AB - Enzymes regulate complex functions and active behavior in natural systems and have shown increasing prospect for developing self-regulating soft matter systems. Striving for advanced autonomous hydrogel materials with fully programmable, self-regulated life cycles, we combine two enzymes with an antagonistic pH-modulating effect in a feedback-controlled biocatalytic reaction network (BRN) and couple it to pH-responsive DNA hydrogels to realize hydrogel systems with distinct preprogrammable lag times and lifetimes in closed systems. The BRN enables precise and orthogonal internal temporal control of the "ON" and "OFF" switching times of the temporary gel state by modulation of programmable, nonlinear pH changes. The time scales are tunable by variation of the enzyme concentrations and additional buffer substances. The resulting material system operates in full autonomy after injection of the chemical fuels driving the BRN. The concept may open new applications inherent to DNA hydrogels, for instance, autonomous shape memory behavior for soft robotics. We further foresee general applicability to achieve autonomous life cycles in other pH switchable systems. PMID- 28656772 TI - Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition of 2-Azaallyl Anions to Epoxides. AB - We report the direct preparation of 1,3-amino alcohols that contain up to three contiguous stereogenic centers by the umpolung coupling of imines and epoxides. Nucleophilic 2-azaallyl anions, generated from imines, are stereoselectively added to epoxides to furnish 1,3-amino alcohols after hydrolysis of the product imine. Transformations afford amino alcohols with >98% site selectivity with respect to both reaction partners and in up to >98% yield and >20:1 dr. PMID- 28656773 TI - Biofortification with Iron and Zinc Improves Nutritional and Nutraceutical Properties of Common Wheat Flour and Bread. AB - The effect of field foliar Fe and Zn biofortification on concentration and potential bioavailability of Fe and Zn and health-promoting compounds was studied in wholemeal flour of two common wheat varieties (old vs modern). Moreover, the effect of milling and bread making was studied. Biofortification increased the concentration of Zn (+78%) and its bioavailability (+48%) in the flour of the old variety, whereas it was ineffective in increasing Fe concentration in both varieties. However, the old variety showed higher concentration (+41%) and bioavailability (+26%) of Fe than the modern one. As regard milling, wholemeal flour had higher Fe, Zn concentration and health-promoting compounds compared to white flour. Bread making slightly change Fe and Zn concentration but greatly increased their bioavailability (77 and 70%, respectively). All these results are of great support for developing a production chain of enriched functional bread having a protective role against chronic cardio-vascular diseases. PMID- 28656774 TI - Emulating Bilingual Synaptic Response Using a Junction-Based Artificial Synaptic Device. AB - Excitatory and inhibitory postsynaptic potentials are the two fundamental categories of synaptic responses underlying the diverse functionalities of the mammalian nervous system. Recent advances in neuroscience have revealed the co release of both glutamate and GABA neurotransmitters from a single axon terminal in neurons at the ventral tegmental area that can result in the reconfiguration of the postsynaptic potentials between excitatory and inhibitory effects. The ability to mimic such features of the biological synapses in semiconductor devices, which is lacking in the conventional field effect transistor-type and memristor-type artificial synaptic devices, can enhance the functionalities and versatility of neuromorphic electronic systems in performing tasks such as image recognition, learning, and cognition. Here, we demonstrate an artificial synaptic device concept, an ambipolar junction synaptic devices, which utilizes the tunable electronic properties of the heterojunction between two layered semiconductor materials black phosphorus and tin selenide to mimic the different states of the synaptic connection and, hence, realize the dynamic reconfigurability between excitatory and inhibitory postsynaptic effects. The resulting device relies only on the electrical biases at either the presynaptic or the postsynaptic terminal to facilitate such dynamic reconfigurability. It is distinctively different from the conventional heterosynaptic device in terms of both its operational characteristics and biological equivalence. Key properties of the synapses such as potentiation and depression and spike-timing-dependent plasticity are mimicked in the device for both the excitatory and inhibitory response modes. The device offers reconfiguration properties with the potential to enable useful functionalities in hardware-based artificial neural network. PMID- 28656775 TI - Advocacy Coalition for Safer Sex in the Adult Film Industry: The Case of Los Angeles County's Measure B. AB - BACKGROUND: Performers in the adult film industry are routinely exposed to bloodborne pathogens. In 2012, public health advocates in Los Angeles County convinced voters to pass a ballot initiative-Measure B-to mandate condom use on adult film sets. This article presents a case study of the advocacy coalition's strategies used to achieve greater workplace safety using the advocacy coalition framework. METHOD: The authors were given access to all memoranda, market research, and campaign tools used to promote Measure B. To reconstruct adult film industry counterefforts, the authors reviewed trade publications, social media, and blog posts. RESULTS: When legislative efforts failed, advocates engaged in a step-by-step strategy built around voters to achieve passage of a ballot initiative mandating condom use for all adult films produced in Los Angeles County. Although the industry immediately filed a lawsuit after passage of Measure B, its constitutionality has been upheld. CONCLUSIONS: Measure B passed because public health advocates were able to assemble scientific evidence, build public support, counter false claims, and maintain consistent messages throughout the campaign. The adult film industry lacked social capital, cohesion, and nimbleness. To bolster regulatory efforts, appealing to voters to favor safe workplaces may be an effective advocacy strategy for other industries. PMID- 28656776 TI - Is it beneficial to add electromyostimulation to conventional exercise training in heart failure? PMID- 28656777 TI - Commentary on McGorry PD (2017), Back to the future: Schizophrenia in retrospect and prospect. PMID- 28656778 TI - Common atrial flutter catheter ablation without discontinuing oral anticoagulation. AB - AIM: To determine if performing catheter ablation under oral anticoagulation is associated with a higher risk of thromboembolic or bleeding complications. METHODS: Patients with common atrial flutter that underwent catheter ablation of the cavo-tricuspid isthmus were consecutively included in the study. All patients were taking oral anticoagulants at least 3 weeks before the ablation. RESULTS: A total of 102 patients (mean age 67.9 +/- 10.3 years; 83.3% male) were included. Among them 80.6% patients were taking acenocoumarol, 10.7% dabigatran, 7.8% rivaroxaban and 0.9% apixaban. After the procedure, no new pericardial effusion or major complications were detected. In the study 7.8% of patients had mild hematoma in the puncture site. CONCLUSION: Performing common atrial flutter catheter ablation under oral anticoagulation is associated with low risk of complications. PMID- 28656779 TI - Primary Cutaneous Histoplasma capsulatum Infection in a Patient Treated With Fingolimod: A Case Report. AB - Fingolimod is an immune-modulating drug used in the treatment of multiple sclerosis. Histoplasma capsulatum is a dimorphic fungus that can infect humans. Infection with the pathogen typically affects the lungs, but it is usually asymptomatic and self-limited. However, immunocompromised patients infected with the pathogen can present atypically, including the development of primary cutaneous lesions. We describe an interesting clinical case of a cutaneous H capsulatum infection in a patient treated with fingolimod. PMID- 28656780 TI - Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation. AB - INTRODUCTION: Brimonidine tartrate and brinzolamide eye drops are often used as third and fourth line treatment options to reduce intraocular pressure (IOP) in the management of glaucoma and ocular hypertension. Better tolerated, more effective topical agents requiring once daily instillation including prostaglandin analogues and beta-blockers usually are preferred as initial therapy, unless there are contraindications. Brimonidine and brinzolamide are often required owing to progressive glaucoma or intolerances to or ineffectiveness of front-line agents. Areas covered: We review the safety of formulations containing brimonidine tartrate and/or brinzolamide. Safety considerations for these agents in higher risk populations are highlighted. Expert opinion: Each class of ocular hypotensive eye drop has a unique set of possible side effects. Brimonidine might have neuro-protective capabilities and offer reasonable IOP control, but its use is limited by a relatively high rate of ocular allergy, hyperemia and discomfort. Brinzolamide is generally well tolerated, but often lacks efficacy. The introduction of brimonidine/brinzolamide fixed combination suspension improves adherence (by simplifying the medical regimen) and reduces preservative load on the ocular surface. New drug delivery systems incorporating brimonidine and brinzolamide are in development and promise to improve the safety profiles of both drugs. PMID- 28656781 TI - Endoglin-based biological therapy in the treatment of angiogenesis-dependent pathologies. AB - INTRODUCTION: Alterations in the process of angiogenesis, either by excess or by defect, are present in different common pathologies. For this reason, great efforts are being made toward the development of pro- and anti-angiogenic therapies. Since endoglin levels are enhanced in tissues undergoing angiogenesis, and changes in its expression lead to alterations in vessel formation, endoglin has become an ideal target for these types of therapies. Areas covered: In this review, the role of endoglin in angiogenesis is summarized. In addition, the authors review pro- and anti-angiogenic therapies that are currently being used and new approaches that target endoglin. The article includes therapies that are both in preclinical and clinical development. Expert opinion: Endoglin is a very good target for anti-angiogenic therapy, as demonstrated by the positive results obtained with anti-endoglin antibodies. However, although endoglin in pro angiogenic therapies has been successful in vitro, its use has not yet reached clinical settings. Moreover, the authors believe that establishing the exact role of endoglin in angiogenesis is essential and that this should be the next step in this field in the coming years. PMID- 28656782 TI - Impact of Generalized Joint Laxity on Plantar Loading Patterns in Young Females. AB - BACKGROUND: Generalized joint laxity is often associated with gait deviations. The aim of this study was to investigate the static and dynamic loading pattern of the foot with increasing joint mobility and to discuss the potential impact of this condition on the plantar loading patterns. METHODS: Seventy female participants between ages of 18 and 30 were included in this cross-sectional survey. The Beighton-Horan Joint Mobility Index scores were assessed and participants divided into 3 categories: no hypermobility (NH) group, scores 0 to 2; moderate hypermobility (MH) group, scores 3 to 4; distinct hypermobility (DH) group, scores 5 to 9. Pedobarographic analysis was performed both in static and walking conditions. Dynamic foot loading examined in 10 anatomic zones. Contact areas of forefoot, midfoot, and rearfoot were recorded. RESULTS: In the dynamic pedobarographic analysis, individuals with distinct joint hypermobility displayed higher peak pressure and maximum force values under the hallux, compared with other groups ( P < .05). The maximum force value of the second metatarsal was higher in the DH group than in the MH group ( P < .05). CONCLUSION: Our study results suggest that plantar loading pattern differs with increasing degrees of the hypermobility score. CLINICAL RELEVANCE: Differences in plantar loading parameters in people with severe joint mobility scores may be useful in interpreting the foot pathologies of these individuals. PMID- 28656783 TI - Oxidative stress and antioxidant biomarker responses after a moderate-intensity soccer training session. AB - The present study investigated the effects of a moderate-intensity soccer training session on the production of reactive oxygen species (ROS) and the antioxidant capacity in athletes along with the biomarkers creatine kinase and transaminases for lesions in muscle and liver cells. Twenty-two male soccer players participated in this study. Blood samples were collected 5 min before and after a moderate-intensity game simulation. The results showed a decrease in the concentration of reduced glutathione (GSH) from an elevation in the production of ROS that maintained the redox homeostasis. Although the session promoted an elevated energy demand, observed by an increase in lactate and glucose levels, damage to muscle and/or liver cells was only suggested by a significant elevation in the levels of alanine transaminase (ALT). Of the two biomarkers analysed, the results suggest that measurements of the ALT levels could be adopted as a method to monitor recovery in athletes. PMID- 28656786 TI - Improving the management of obsessive-compulsive disorder by considering the autoimmune diathesis. PMID- 28656785 TI - Relationship between treatment of erectile dysfunction and future risk of cardiovascular disease: A nationwide cohort study. AB - Aims Erectile dysfunction is associated with increased risk of cardiovascular disease; however, little is known about patients seeking treatment for erectile dysfunction. This study investigated the risk of cardiovascular disease for patients receiving medication for erectile dysfunction. Methods and results This nationwide cohort study included 71,710 men aged 40-80 years receiving their first erectile dysfunction medication from 2000 to 2012. Their adjusted risk of cardiovascular events in time intervals after the first erectile dysfunction medication was compared to the general male population using multivariate Poisson regression models and was expressed as a risk ratio (RR). The risk for overall cardiovascular disease was decreased in the first 3 years: the RR in the first year was 0.92 (95% confidence interval [CI] 0.87-0.97, p = 0.003; incidence: 23.68 per 1000 patient-years), and after 1-3 years the RR was 0.94 (95% CI 0.90 0.97, p = 0.002; incidence: 24.92 per 1000 patient-years). After 3 years, there was no significant difference. The risk of myocardial infarction was decreased in all time intervals: the RR in the first year was 0.60 (95% CI 0.50-0.73, p < 0.001; incidence: 1.82 per 1000 patient-years), after 1-3 years the RR was 0.72 (95% CI 0.63-0.82, p < 0.001; incidence: 2.16 per 1000 patient-years) and after 3 years the RR was 0.80 (95% CI 0.73-0.88, p < 0.001; incidence: 2.25 per 1000 patient-years). The risk of heart failure was decreased in the first 3 years. Conclusion Receiving medication for erectile dysfunction was associated with a decreased risk of myocardial infarction and cardiovascular diseases for the first 3 years. PMID- 28656784 TI - The spectrum of mitral valve pathologies: relevance for surgical and structural interventions. AB - INTRODUCTION: The mitral valve apparatus, both functionally and morphologically is composed of a constellation of individual structures, including the annulus, anterior and posterior leaflets, chordae tendineae, and papillary muscles. Most also include the left ventricular wall and the left atrium which are essential for the valve to function normally. Areas covered: The commonest conditions responsible for mitral valve dysfunction in the Western World are degenerative and functional mitral regurgitation, which are discussed in detail. Treatment strategies in patients at high surgical risk are rapidly evolving, as more options for transcatheter mitral valve repair and replacement become available. Expert commentary: Although surgery remains the gold standard, many elderly patients with severe comorbidities need intervention as surgery may no longer be an option. Today, transcatheter mitral valve therapies are in their infancy but with advances in technology they will likely become tomorrow's therapy. The heart team plays an important role, discussing and addressing individualized strategies for each patient. However, a thorough knowledge and the understanding of mitral valve anatomy, pathology, and clinical assessment is mandatory in order to choose the best treatment possible. PMID- 28656787 TI - Quality assessment of chicken eggshell cuticle by infrared spectroscopy and staining techniques: a comparative study. AB - 1. The cuticle is a very thin organic layer that coats the eggshell surface and plugs the eggshell pores preventing bacterial penetration. It also reduces eggshell permeability which is important to maintain internal quality of the egg. Thus, the eggshell cuticle quality is crucial to ensure the food safety and quality of eggs. 2. A new methodology to assess eggshell cuticle quality, based on attenuated total reflection-Fourier transform infrared spectroscopy (ATR FTIR), is compared with a more traditional method based on cuticle staining techniques. 3. Both techniques are useful to determine the amount of cuticle; however, the ATR-FTIR technique is independent of egg colour, more sensitive and provides complete information about the cuticle and its composition. Additionally, it provides information about eggshell permeability. 4. The methodology for cuticle quality assessment described in this work can be very useful for genetic selection programmes aimed to improve the safety and quality of eggs. PMID- 28656788 TI - Harms and benefits of the haemoglobin glycation index (HGI). PMID- 28656789 TI - Suicide Prevention in Correctional Settings: Current Standards and Recommendations for Research, Prevention, and Training. AB - Inmates remain a vulnerable group at elevated risk for suicide, especially in light of stresses associated with incarceration. Despite the elevated risk for inmates, suicide prevention practices in corrections remain tenuous at best. The present article reviews literature on risk and protective factors for suicide among inmates as well as current recommended best practices. It then provides directions for suicide prevention provision, training, and research in correctional settings. These include adaptations for security staff of current empirically supported models of suicide risk training and intervention. PMID- 28656790 TI - The Dot Counting Test adds up: Validation and response pattern analysis in a mixed clinical veteran sample. AB - OBJECTIVE: This study cross-validated the Dot Counting Test (DCT) as a performance validity test (PVT) among a mixed clinical veteran sample. Completion time and error patterns also were examined by validity group and cognitive impairment status. METHOD: This cross-sectional study included 77 veterans who completed the DCT during clinical evaluation. Seventy-four percent (N = 57) were classified as valid and 26% as noncredible (N = 20) via the Word Memory Test (WMT) and Test of Memory Malingering (TOMM). Among valid participants, 47% (N = 27) were cognitively impaired, and 53% (N = 30) were unimpaired. RESULTS: DCT performance was not significantly associated with age, education, or bilingualism. Seventy-five percent of the overall sample committed at least one error across the 12 stimulus cards; however, valid participants had a 27% higher rate of 0 errors, while noncredible participants had a 35% higher rate of >=4 errors. Overall, noncredible individuals had significantly longer completion times, more errors, and higher E-scores. Conversely, those with cognitive impairment had longer completion times, but comparable errors to their unimpaired counterparts. Finally, DCT E-scores significantly predicted group membership with 83.1% classification accuracy and an area under the curve of .87 for identifying invalid performance. The optimal cut-score of 15 was associated with 70% sensitivity and 88% specificity. CONCLUSION: The DCT demonstrated good classification accuracy and sensitivity/specificity for identifying noncredible performance in this mixed clinical veteran sample, suggesting utility as a non memory-based PVT with this population. Moreover, cognitive impairment significantly contributed to slower completion times, but not reduced accuracy. PMID- 28656791 TI - Impact of laparoscopy on the biological behavior and gene expression of endometrial adenocarcinoma cells. AB - The current study investigated the effect of laparoscopy on the biological behavior and gene expression of endometrial adenocarcinoma cells. Totally, 40 patients with stage I endometrial adenocarcinoma and 20 patients with benign uterine diseases were enrolled in this study. For patients with endometrial adenocarcinoma, laparoscopy was performed in 20 cases and laparotomy was carried out in the other 20 cases. Total laparoscopic hysterectomy was performed in patients with benign diseases. Cell apoptotic rate and the gene expression of N myc, Fas, metastasis-associated protein 1 (MTA1), and nm23-H1 were determined in the normal and cancerous endometrial tissues both preoperatively and postoperatively. For endometrial adenocarcinoma cells, laparoscopy, instead of laparotomy, promoted the apoptosis of endometrial adenocarcinoma cells, down regulated the expression of apoptosis suppressor gene N-myc and metastasis promoting gene MTA1, up-regulated the expression of apoptosis-promoting gene Fas and metastasis suppressor gene nm23-H1. However, laparoscopy did not affect the apoptotic rate and gene expression in normal endometrial cells. Laparoscopy may be used as a safe and effective intervention for endometrial cancer. PMID- 28656792 TI - Recent advances in targeted advanced lung cancer therapy in the elderly. AB - INTRODUCTION: With increasing life expectancy over the last several decades, the incidence of lung cancer is increasing in the elderly population too. In clinical practice about 50% of lung cancers were diagnosed in patients older than 65 years and about 30-40% of lung cancer patients are 70 years old or more. Treatment of elderly patients with non-small-cell lung cancer (NSCLC) represents a challenge in clinical practice, because these patients are not eligible for aggressive therapies for the age-related reduction of functional reserve of many organs and comorbidities. Areas covered: The activity and safety of small molecules for the treatment of NSCLC harbouring EGFR mutations or ALK rearrangement are reviewed and discussed here, using evidence from clinical trials. Expert commentary: Age alone should not dictate treatment-related decisions for elderly patients with advanced NSCLC. Some evidence has shown that the only relevant factor for survival outcome in the elderly is performance status and organ functions both with chemotherapy and targeted therapy too. Considering the toxicity profile of tyrosine kinase inhibitors, these small molecules are particularly attractive to treat elderly patients, who could experience potentially more toxicity from chemotherapy. Studies specifically addressed to evaluate the activity of targeted therapy are still more limited. PMID- 28656794 TI - Nonparametric combination tests for comparing two survival curves with informative and non-informative censoring. AB - This paper looks at permutation methods used to deal with hypothesis testing within the survival analysis framework. In the literature, several attempts have been made to deal with the comparison of survival curves and, depending on the survival and hazard functions of two groups, they can be more or less efficient in detecting differences. Furthermore, in some situations, censoring can be informative in that it depends on treatment effect. Our proposal is based on the nonparametric combination approach and has proven to be very effective under different configurations of survival and hazard functions. It allows the practitioner to test jointly on primary and censoring events and, by using multiple testing methods, to assess the significance of the treatment effect separately on the survival and the censoring process. PMID- 28656793 TI - Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations. AB - INTRODUCTION: Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs. PMID- 28656795 TI - Likelihood inference for COM-Poisson cure rate model with interval-censored data and Weibull lifetimes. AB - In this paper, we consider a competing cause scenario and assume the number of competing causes to follow a Conway-Maxwell Poisson distribution which can capture both over and under dispersion that is usually encountered in discrete data. Assuming the population of interest having a component cure and the form of the data to be interval censored, as opposed to the usually considered right censored data, the main contribution is in developing the steps of the expectation maximization algorithm for the determination of the maximum likelihood estimates of the model parameters of the flexible Conway-Maxwell Poisson cure rate model with Weibull lifetimes. An extensive Monte Carlo simulation study is carried out to demonstrate the performance of the proposed estimation method. Model discrimination within the Conway-Maxwell Poisson distribution is addressed using the likelihood ratio test and information-based criteria to select a suitable competing cause distribution that provides the best fit to the data. A simulation study is also carried out to demonstrate the loss in efficiency when selecting an improper competing cause distribution which justifies the use of a flexible family of distributions for the number of competing causes. Finally, the proposed methodology and the flexibility of the Conway-Maxwell Poisson distribution are illustrated with two known data sets from the literature: smoking cessation data and breast cosmesis data. PMID- 28656796 TI - Bayesian cure rate models induced by frailty in survival analysis. AB - Frailty models provide a convenient way of modeling unobserved dependence and heterogeneity in survival data which, if not accounted for duly, would result incorrect inference. Gamma frailty models are commonly used for this purpose, but alternative continuous distributions are possible as well. However, with cure rate being present in survival data, these continuous distributions may not be appropriate since individuals with long-term survival times encompass zero frailty. So, we propose here a flexible probability distribution induced by a discrete frailty, and then present some special discrete probability distributions. We specifically focus on a special hyper-Poisson distribution and then develop the corresponding Bayesian simulation, influence diagnostics and an application to real dataset by means of intensive Markov chain Monte Carlo algorithm. These illustrate the usefulness of the proposed model as well as the inferential results developed here. PMID- 28656797 TI - Low dose radiation effects on the brain - from mechanisms and behavioral outcomes to mitigation strategies. AB - Based on the most recent estimates by the Canadian Cancer Society, 2 in 5 Canadians will develop cancer in their lifetimes. More than half of all cancer patients receive some type of radiation therapy, and all patients undergo radiation-based diagnostics. While radiation is one of the most important diagnostic and treatments modalities, high-dose cranial radiation therapy causes numerous central nervous system side-effects, including declines in cognitive function, memory, and attention. While the mechanisms of these effects have been studies, they still need to be further elucidated. On the other hand, the effects of low dose radiation as well as indirect radiation bystander effects on the brain remain elusive. We pioneered analysis of the molecular and cellular effects of low dose direct, bystander and scatter radiation on the brain. Using a rat model, we showed that low dose radiation exposures cause molecular and cellular changes in the brain and impacts animal behavior. Here we reflect upon our recent findings and current state of knowledge in the field, and suggest novel radiation effect biomarkers and means of prevention. We propose strategies and interventions to prevent and mitigate radiation effects on the brain. PMID- 28656798 TI - Limited role and benefit of ivabradine in the treatment of angina and heart failure with reduced ejection fraction. AB - Ivabradine is an original drug that has been approved in two indications (systolic heart failure and angina). The aim of this short review is to draw the attention of clinician prescribers to the evidence base of ivabradine. Three large randomized trials testing ivabradine versus placebo have been performed. The BEAUTIFUL and SIGNIFY trials were in fact negative in the treatment of angina while the SHIFT trial found a marginal benefit of ivabradine over placebo in the treatment of heart failure. These important results are put into perspective in order to improve the assessment of risk-cost/benefit balances when ivabradine is considered. Ideally, a further clinical trial investigating the use of ivabradine in heart failure should be carried out with optimal treatment of the patient population in order to identify the subgroup of patients who respond to ivabradine. PMID- 28656799 TI - p53R2 is oncogenic in human cervical cancer. PMID- 28656800 TI - Position paper on management of iron deficiency in adult cancer patients. AB - INTRODUCTION: Disorders of iron metabolism are commonly seen in onco hematological clinical practice. Iron-deficiency anemia and cancer-associated anemia are usually treated with supportive therapies. Optimal management of these conditions are discussed in this perspective paper. Areas covered: A position paper discussing a number of hot topics on anemia in cancer patients is presented. The main areas covered by experts in the field are: definitions, prevalence and consequences of anemia and iron deficiency, incidence of anemia resulting from targeted therapies, importance of anemia diagnosis and monitoring, evaluation of iron status before and during treatment, role of transfusions and erythropoiesis-stimulating agents, management of iron deficiency with or without anemia, parenteral iron supplementation, role of new oral iron formulations, safety and cost issues regarding different iron compounds and administration routes. Expert commentary: Despite the availability of newer therapeutic options for its management, anemia still represents a major complication of treatment in cancer patients (surgery, chemotherapy, radiotherapy, targeted therapies), aggravating physical impairment, and negatively affecting general outcome. The view expressed by the panelists, attendees of the 4th Mediterranean Course on Iron Anemia, summarizes what they consider optimal clinical practice for screening, diagnosis, treatment and monitoring of iron deficiency and anemia in cancer patients. PMID- 28656801 TI - The vulnerability of self-reported disability measures to malingering: a simulated ADHD study. AB - OBJECTIVE: Making diagnostic and accommodation decisions for potential Attention Deficit/Hyperactivity Disorder (ADHD) in adults is difficult, as the assessor often relies more on self-reported symptoms and functional disability than in childhood evaluations. Malingering of ADHD occurs frequently in the educational setting and for a variety of reasons, including the potential benefits of access to stimulant medications and academic accommodations. METHOD: The present study utilized a simulation design to examine the potential for malingering of self reported functional disability on the World Health Organization Disability Schedule 2.0 (WHODAS). Participants were 167 students from two Midwestern universities. Thirty-six self-reported a previous diagnosis of ADHD, and the remaining 131 students were randomly assigned to one of three conditions: best effort, malingering for the purpose of receiving stimulant medication, or malingering for the purpose of receiving extra time accommodations. RESULTS: Individuals in both malingering groups reported higher levels of disability on all domains of the WHODAS compared to healthy controls and individuals with ADHD. There were no significant differences between malingering groups. CONCLUSIONS: Results suggest the WHODAS is susceptible to non-credible responses and should not be relied upon solely as a measure of disability in the context of ADHD evaluations. PMID- 28656802 TI - Pyruvate kinase M2 interacts with mammalian sterile 20-like kinase 1 and inhibits tamoxifen-induced apoptosis in human breast cancer cells. AB - Tamoxifen has been reported to be associated with antagonism of estrogen-mediated cell growth signaling and activation of estrogen receptor-independent apoptosis events. It has been demonstrated that mammalian sterile 20-like kinase 1 is a direct target of Caspases to amplify the apoptotic signaling pathway. Here, we presented that breast cancer MCF-7 and SKBR3 cells under treatment with 4 hydroxytamoxifen displayed decreased level of pyruvate kinase M2. Western blot results also showed that 4-hydroxytamoxifen induced the activity of pro-apoptotic protein Caspase-3 in MCF-7 and SKBR3 cells, as evidenced by the cleavage of mammalian sterile 20-like kinase 1 substrate in a dose-dependent manner. Co immunoprecipitation and immunofluorescence experiments were performed to clarify the relationship between pyruvate kinase M2 and mammalian sterile 20-like kinase 1. The results indicated that mammalian sterile 20-like kinase 1 was associated with pyruvate kinase M2 in cultured mammalian cells, and the interaction between mammalian sterile 20-like kinase 1 and pyruvate kinase M2 was decreased in response to 4-hydroxytamoxifen treatment. In addition, knockdown of pyruvate kinase M2 upregulated the level of cleaved Caspase-3 and subsequently facilitated the nuclear translocation of mammalian sterile 20-like kinase 1. Our data further supplemented the extensive functions of pyruvate kinase M2 in mediating breast cancer cell viability by substantially abating the mammalian sterile 20-like kinase 1-mediated apoptosis. In summary, our results identified that mammalian sterile 20-like kinase 1 is a novel downstream target of pyruvate kinase M2, and knockdown of pyruvate kinase M2 contributes apoptosis via promoting nuclear translocation of mammalian sterile 20-like kinase 1 by enhancing Caspase-3 dependent cleavage. PMID- 28656804 TI - Olopatadine hydrochloride ophthalmic solution for the treatment of allergic conjunctivitis. AB - INTRODUCTION: Olopatadine hydrochloride is an antihistamine and mast cell stabilizer available as oral, intranasal and ocular preparations. Most of the practical applications of olopatadine therapy focus on the treatment of allergic rhinoconjunctivitis via intranasal and ocular routes. Areas covered: This article was created from a comprehensive literature search with information taken from meta-analyses, systematic reviews, and clinical trials of children and adults. The articles that have been selected, evaluate the use of intranasal and ocular antihistamines and their role in allergic rhinoconjunctivitis. Expert opinion: Olopatadine is significantly more effective than placebos in relieving the symptoms of allergic rhinoconjunctivitis. It can function both as a viable alternative or addition to first line therapies such as intranasal steroids and oral antihistamines. PMID- 28656803 TI - Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression. AB - OBJECTIVES: Current evidence supports participation of neurotrophic and inflammatory factors in the pathogenesis of major depressive disorder (MDD). Some studies reported an association between the Val66Met polymorphism (rs6265) of brain-derived neurotrophic factor (BDNF) gene with MDD and peripheral BDNF levels. However, no previous studies have examined the association of this polymorphism with inflammation. The present study assessed the association of the Val66Met polymorphism with serum levels of BDNF and inflammatory markers among depressed outpatients. METHODS: All participants (n = 73) met DSM-IV criteria for a unipolar depressive episode. The serum levels of BDNF and inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, TNF-alpha and IFN-gamma) were compared between individuals presenting with at least one Met allele (Met-carriers) and those homozygous for the Val allele. RESULTS: In our sample (84.9% female, mean age 52.4 +/- 10.3 years), 24.7% (n = 18) were Met-carriers. After Bonferroni correction, the Met allele was significantly associated with higher BDNF and lower TNF-alpha. These associations persisted after adjusting for potential confounders. CONCLUSIONS: The pattern of low BDNF and high inflammation in MDD may be influenced by the Val66Met polymorphism. The association of a polymorphism in the BDNF gene with inflammatory markers in addition to BDNF levels suggests an interaction between these systems. PMID- 28656805 TI - Verbal working memory-related functional connectivity alterations in boys with attention-deficit/hyperactivity disorder and the effects of methylphenidate. AB - OBJECTIVE: Few studies have investigated verbal working memory-related functional connectivity patterns in participants with attention-deficit/hyperactivity disorder (ADHD). Thus, we aimed to compare working memory-related functional connectivity patterns in healthy children and those with ADHD, and study effects of methylphenidate (MPH). METHOD: Twenty-two boys with ADHD were scanned twice, under either MPH (single dose, 10 mg) or placebo, in a randomised, cross-over, counterbalanced placebo-controlled design. Thirty healthy boys were scanned once. We used fMRI during a numerical n-back task to examine functional connectivity patterns in case-control and MPH-placebo comparisons, using independent component analysis. RESULTS: There was no significant difference in behavioural performance between children with ADHD, treated with MPH or placebo, and healthy controls. Compared with controls, participants with ADHD under placebo showed increased functional connectivity within fronto-parietal and auditory networks, and decreased functional connectivity within the executive control network. MPH normalized the altered functional connectivity pattern and significantly enhanced functional connectivity within the executive control network, though in non overlapping areas. CONCLUSION: Our study contributes to the identification of the neural substrates of working memory. Single dose of MPH normalized the altered brain functional connectivity network, but had no enhancing effect on (non impaired) behavioural performance. PMID- 28656806 TI - Baseline Characteristics of Dependent Youth Who Have Been Commercially Sexually Exploited: Findings From a Specialized Treatment Program. AB - Commercial sexual exploitation of children has emerged as a critical issue within child welfare, but little is currently known about this population or effective treatment approaches to address their unique needs. Children in foster care and runaways are reported to be vulnerable to exploitation because they frequently have unmet needs for family relationships, and they have had inadequate supervision and histories of trauma of which traffickers take advantage. The current article presents data on the demographic characteristics, trauma history, mental and behavioral health needs, physical health needs, and strengths collected on a sample of 87 commercially sexually exploited youth. These youth were served in a specialized treatment program in Miami-Dade County, Florida, for exploited youth involved with the child welfare system. Findings revealed that the youth in this study have high rates of previous sexual abuse (86% of the youth) and other traumatic experiences prior to their exploitation. Youth also exhibited considerable mental and behavioral health needs. Given that few programs emphasize the unique needs of children who have been sexually exploited, recommendations are offered for providing a continuum of specialized housing and treatment services to meet the needs of sexually exploited youth, based on the authors' experiences working with this population. PMID- 28656808 TI - Plan one, do one, see one: learning about appraisal during GP training. PMID- 28656807 TI - The Influence of Noise Reduction on Speech Intelligibility, Response Times to Speech, and Perceived Listening Effort in Normal-Hearing Listeners. AB - Single-microphone noise reduction leads to subjective benefit, but not to objective improvements in speech intelligibility. We investigated whether response times (RTs) provide an objective measure of the benefit of noise reduction and whether the effect of noise reduction is reflected in rated listening effort. Twelve normal-hearing participants listened to digit triplets that were either unprocessed or processed with one of two noise-reduction algorithms: an ideal binary mask (IBM) and a more realistic minimum mean square error estimator (MMSE). For each of these three processing conditions, we measured (a) speech intelligibility, (b) RTs on two different tasks (identification of the last digit and arithmetic summation of the first and last digit), and (c) subjective listening effort ratings. All measurements were performed at four signal-to-noise ratios (SNRs): -5, 0, +5, and +infinity dB. Speech intelligibility was high (>97% correct) for all conditions. A significant decrease in response time, relative to the unprocessed condition, was found for both IBM and MMSE for the arithmetic but not the identification task. Listening effort ratings were significantly lower for IBM than for MMSE and unprocessed speech in noise. We conclude that RT for an arithmetic task can provide an objective measure of the benefit of noise reduction. For young normal-hearing listeners, both ideal and realistic noise reduction can reduce RTs at SNRs where speech intelligibility is close to 100%. Ideal noise reduction can also reduce perceived listening effort. PMID- 28656809 TI - A Systematic Review of Predictors of Reintervention After EVAR: Guidance for Risk Stratified Surveillance. AB - BACKGROUND: Current surveillance protocols after endovascular aneurysm repair (EVAR) are ineffective and costly. Stratifying surveillance by individual risk of reintervention requires an understanding of the factors involved in developing post-EVAR complications. This systematic review assessed risk factors for reintervention after EVAR and proposals for stratified surveillance. METHODS: A systematic search according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed using EMBASE and MEDLINE databases to identify studies reporting on risk factors predicting reintervention after EVAR and proposals for stratified surveillance. RESULTS: Twenty-nine studies reporting on 39 898 patients met the primary inclusion criteria for reporting predictors of reintervention or aortic complications with or without suggestions for stratified surveillance. Five secondary studies described external validation of risk scores for reintervention or aortic complications. There was great heterogeneity in reporting risk factors identified at the pre EVAR, intraoperative, and post-EVAR stages of treatment, although large preoperative abdominal aortic aneurysm diameter was the most commonly observed risk factor for reintervention after EVAR. CONCLUSION: Existing data on predictors of post-EVAR complications are generally of poor quality and largely derived from retrospective studies. Few studies describing suggestions for stratified surveillance have been subjected to external validation. There is a need to refine risk prediction for EVAR failure and to conduct prospective comparative studies of personalized surveillance with standard practice. PMID- 28656810 TI - Exercise Facilitates Smoking Cessation Indirectly via Intention to Quit Smoking: Prospective Cohort Study Among a National Sample of Young Smokers. AB - INTRODUCTION: We evaluated the specific association between exercise and smoking cessation via smoking-mediated intentions to quit smoking among a national sample of young daily smokers in the United States. DESIGN: Prospective cohort study over a 2-year period, with daily smokers assessed across all 50 states in the United States. SETTING: Data from the 2003 to 2005 National Youth Smoking Cessation Survey were used. PARTICIPANTS: A total of 1175 young adult smokers aged between 18 and 24 years. MEASURES: Baseline exercise and intent to quit smoking were assessed via validated survey measures. Smoking status at the 2-year follow-up period was assessed via survey assessment. RESULTS: After adjustments, meeting exercise guidelines at baseline was associated with an increased baseline intent to quit smoking among this national sample of daily smokers (OR = 1.49; 95% confidence interval [CI]: 1.07-2.07; P = .01). After adjustments, those with a baseline intent to quit smoking had a 71% increased odds ratio (OR) of being a nonsmoker at the 2-year follow-up (OR = 1.71; 95% CI: 1.20-2.44; P = .003). Baseline exercise was not associated with 2-year follow-up smoking status (OR = 0.87; 95% CI: 0.60-1.28; P = .50). CONCLUSION: In this nationally representative sample of young daily smokers, there was a positive association between exercise participation and intention to quit smoking. Baseline intent to quit smoking was independently associated with nonsmoking status at a 2-year follow-up. Thus, this indirect link between exercise and smoking status may be partially explained by the influence of exercise engagement on smoking-specific intentions. PMID- 28656811 TI - Nudging Resisters Toward Change: Self-Persuasion Interventions for Reducing Attitude Certainty. AB - PURPOSE: To identify effective self-persuasion protocols that could easily be adapted to face-to-face clinical sessions or health-related computer applications as a first step in breaking patient resistance. DESIGN: Two self-persuasion interventions were tested against 2 controls in a between-subject randomized control experiment. SETTING: GuidedTrack-a web-based platform for social science experiments. PARTICIPANTS: Six hundred seventeen adult participants recruited via Mechanical Turk. INTERVENTION: The experimental interventions prompted participants for self-referenced pro- and counterattitudinal arguments to elicit attitude-related thought (ART) and subsequent doubt about the attitude. The hypothesis was that the self-persuasion interventions would elicit larger and more frequent attitude certainty decreases than the controls. In the experimental groups, we also predicted a correlation between the amount of ART and attitude certainty decreases. MEASURES: Changes in attitude certainty were measured by participants' pre- and post-ratio scale ratings; ART was measured by the number of words participants used to respond to the interventions. ANALYSIS: Analysis of variance (ANOVA), chi2, and correlation. RESULTS: A goodness-of-fit chi2 showed that the number of participants who decreased their attitude certainty was not equally distributed between the combined experimental groups (n = 104) and the combined control groups (n = 39), chi2(1, n = 143) = 28.64, P < .001. Within each intervention, goodness-of-fit chi2 with a Bonferroni correction ( P = .01 or .05/4) indicated there were significantly more "decreasers" than "increasers" in intervention 1, chi2(1, n = 86) = 6.16, P = .01, but not intervention 2, chi2(1, n = 84) = 2.02, P = .16, the nonsense control, chi2(1, n = 42) = .22, P = .64), or the distraction control, chi2(1, n = 34) = .02, P = .89. A 1-way ANOVA revealed a significant main effect for intervention on mean certainty change ( F3,613 = 4.62, P = .003). Five post hoc comparisons using Tukey's honest significant difference (HSD) test indicated that the mean decrease in attitude certainty resulting from intervention 1 (M = -3.29) was significantly larger than the mean decrease in attitude certainty resulting from the nonsense control (M = 0.62, t = -2.72, P = .03), the distraction control (M = 0.11, t = 3.48, P = .003), but not intervention 2 (M = -0.87, t = -2.54, P = .06). Attitude-related thought was significantly correlated with attitude certainty change in intervention 1, r(158) = -.17, t = -4.28, P = .02, but not intervention 2, r(161) = -.002, t = -.03, P = .98. CONCLUSION: The implication for clinical practitioners and designers of health applications is that it may be worthwhile to let patients elaborate on their personal reasons for initially forming an unhealthy attitude to increase doubt about the strongly held attitude. PMID- 28656812 TI - Effects of bilirubin photoisomers on the measurement of direct bilirubin by the bilirubin oxidase method. AB - Background We occasionally encounter increases in direct bilirubin value on reanalysis of the surplus serum collected in the past from a neonate with indirect hyperbilirubinemia. But the details of this phenomenon are unclear. We evaluated the change of direct bilirubin and the relation of bilirubin photoisomer of the serum exposed to room light. Methods Surplus serum samples from neonates with indirect hyperbilirubinemia were exposed to room light for 24 h. The bilirubin fraction assay of samples was performed by the bilirubin oxidase method (Nescauto and Aqua-auto Kainos reagent) and high-performance liquid chromatography. Results Direct bilirubin increased significantly from 0.61 to 2.36 mg/dL. The respective ratios of bilirubin photoisomers before and after exposure were as follows: cyclobilirubin (0.007 to 0.29) and (EZ)-bilirubin (0.018 to 0.041) increased significantly, (ZZ)-bilirubin decreased 0.84 to 0.55 significantly. The difference of the cyclobilirubin concentration was most closely associated with those of the direct bilirubin concentration. Conclusion Direct bilirubin value was increased after exposure to the room light, and increase in direct bilirubin was significantly correlated by cyclobilirubin increase in the serum samples from neonates with indirect hyperbilirubinemia. PMID- 28656813 TI - Bone turnover marker determinants in young women: results from the Safe-D study. AB - Background Bone turnover markers (BTMs) may provide insight into bone health in young women, but have been little studied in this demographic. We aimed to explore the association between body composition, hormonal contraception, bone mineral density and biochemical parameters and BTMs in young women. Methods Participants were community-dwelling females aged 16-25 years, living in Victoria, Australia. Carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX) and total procollagen type 1 N-propeptide (P1NP) were analysed on the Roche Elecsys automated analyzer. A total of 305 were evaluated, after excluding participants with medical conditions or medications (except hormonal contraceptives), which may affect bone metabolism. Results Median (Q1, Q3) BTM values were 540 (410, 690) ng/L for CTX and 61.7 (46.2, 83.7) ug/L for P1NP. Serum CTX and P1NP were inversely associated with chronological age ( P < 0.001), transferrin ( P < 0.020) and serum dehydroepiandrosterone sulphate concentration ( P < 0.001). BTM values were up to 22% lower in combined oral contraceptive (COC) pill users ( P < 0.001). Serum CTX was inversely associated with per cent body fat ( P = 0.009) and tibial cortical volumetric bone mineral density (vBMD; P = 0.003). Serum P1NP concentrations were 23 ug/L higher in participants who reported using an osteopath in the previous year ( P = 0.007). Conclusions These data suggest that BTMs are influenced by age, COC use, body composition, iron status and hormonal profiles. Higher CTX values were associated with lower tibial cortical vBMD. Examining BTMs in relation to interventions aimed at improving bone health in young women is warranted. PMID- 28656814 TI - Standardization of steroid tests and implications for the endocrine community. PMID- 28656815 TI - Newborn screening for sickle cell disorders using tandem mass spectrometry: three years' experience of using a protocol to detect only the disease states. AB - Background Tandem mass spectrometry (MS/MS) has recently become an alternative method for the newborn screening of sickle cell disorders (SCD), as it is able to detect haemoglobin (Hb) peptides following digestion of bloodspots with trypsin. Using the SpOtOn Diagnostics Reagent Kit, we previously developed a screening protocol to detect only the disease states of SCD, using action values based on the ratio between the variant Hb peptide to wild-type peptide abundances for the HbS, C, DPunjab, OArab, E and Lepore peptides. Methods Action values using the ratios between the wild type HbA (betaT1-3) peptides and the foetal Hb (gammaT2) peptide were developed to identify bloodspot samples from premature and transfused infants. An evaluation was undertaken to assess the transferability of the action values onto an additional MS/MS instrument. We report here our experience using this MS/MS protocol. Results During a three-year period, we screened 100,456 babies and identified 10 SCD cases (1 HbS/HPFH, 5 HbS/S and 4 HbS/C) and a case of HbE/beta-thalassaemia that was identified as a by-product. The Hb variant to wild-type peptide ratio action values were transferable to a second MS/MS instrument. Our protocol prevented the identification of an estimated 810 carrier infants. Gestational age-related action values for HbA to HbF peptide ratios were required to minimize the number of samples referred for second-line testing to exclude beta-thalassaemia. Conclusion MS/MS is a robust alternative screening technology for SCD; in addition, it also optimizes the use of equipment and expertise that currently exist in newborn screening laboratories. PMID- 28656816 TI - Quantitative measurement of a candidate serum biomarker peptide derived from alpha2-HS-glycoprotein, and a preliminary trial of multidimensional peptide analysis in females with pregnancy-induced hypertension. AB - Purpose We previously attempted to develop quantitative enzyme-linked immunosorbent assay (ELISA) systems for the PDA039/044/071 peptides, potential serum disease biomarkers (DBMs) of pregnancy-induced hypertension (PIH), primarily identified by a peptidomic approach (BLOTCHIP(r)-mass spectrometry (MS)). However, our methodology did not extend to PDA071 (cysteinyl alpha2-HS glycoprotein341-367), due to difficulty to produce a specific antibody against the peptide. The aim of the present study was to establish an alternative PDA071 quantitation system using liquid chromatography-multiple reaction monitoring (LC MRM)/MS, to explore the potential utility of PDA071 as a DBM for PIH. Methods We tested heat/acid denaturation methods in efforts to purify serum PDA071 and developed an LC-MRM/MS method allowing for specific quantitation thereof. We measured serum PDA071 concentrations, and these results were validated including by three-dimensional (3D) plotting against PDA039 (kininogen-1439-456)/044 (kininogen-1438-456) concentrations, followed by discriminant analysis. Results PDA071 was successfully extracted from serum using a heat denaturation method. Optimum conditions for quantitation via LC-MRM/MS were developed; the assayed serum PDA071 correlated well with the BLOTCHIP(r) assay values. Although the PDA071 alone did not significantly differ between patients and controls, 3D plotting of PDA039/044/071 peptide concentrations and construction of a Jackknife classification matrix were satisfactory in terms of PIH diagnostic precision. Conclusions Combination analysis using both PDA071 and PDA039/044 concentrations allowed PIH diagnostic accuracy to be attained, and our method will be valuable in future pathophysiological studies of hypertensive disorders of pregnancy. PMID- 28656817 TI - High sensitivity troponin T and I reflect left atrial function being assessed by cardiac magnetic resonance imaging. AB - Background Left atrial function (LAF) plays an interactive role between pulmonary and systemic circulation. Cardiac biomarkers, such as amino-terminal pro-brain natriuretic peptide (NT-proBNP) and troponins, might reflect cardiac function. This study aims to evaluate the association between high sensitivity troponins (hsTn) and left atrial function in patients undergoing cardiac magnetic resonance imaging (cMRI). Methods Patients undergoing cardiac magnetic resonance imaging (cMRI) were enrolled prospectively. Patients with right ventricular dysfunction (<50%) were excluded. Blood samples for measurements of hsTn and NT-proBNP were collected at the time of cMRI. Results Eighty-four patients were included. Median LVEF was 59% (IQR 51-64%). HsTn correlated inversely with LAF within multivariable linear regression models (hsTnI: Beta -0.46; T -4.44; P = 0.0001; hsTnT: Beta -0.29; T -3.06; P = 0.003). High sensitivity troponins increased significantly according to decreasing stages of impaired LAF ( P = 0.0001). High sensitivity troponins discriminated patients with impaired LAF < 55% (hsTnT: AUC = 0.80; P = 0.0001; hsTnI: AUC = 0.74; P = 0.0001) and <45% (hsTnT: AUC = 0.75; P = 0.0001; hsTnI: AUC = 0.73; P = 0.001) and were still significantly associated in multivariable logistic regression models (LAF < 55%: hsTnT: OR = 21.78; P = 0.0001; hsTnI: OR = 5.96; P = 0.009; LAF < 45%: hsTnT: OR = 10.27; P = 0.0001; hsTnI: OR = 12.56; P = 0.001). Conclusions This study demonstrates that hsTn are able to reflect LAF being assessed by cardiac magnetic resonance imaging. PMID- 28656818 TI - Foetal haemoglobin concentration at postmenstrual age is unaffected by gestational age at birth. AB - Background Our aim was to determine whether the postnatal age or postmenstrual age is a more appropriate criterion for evaluating foetal haemoglobin concentrations. Methods Blood samples ( n = 1095) were obtained from 394 infants and were divided into two groups based on gestational age at birth: <37 weeks ( n = 491) and >=37 weeks ( n = 604). (1) Foetal haemoglobin concentrations divided by one month at age after birth were compared between the groups. (2) Foetal haemoglobin concentrations divided into <=9 months from last menstruation and one month thereafter were compared between the groups. Results In samples from infants >=37 weeks' gestational age at birth, the median foetal haemoglobin concentrations were 69.5%, 21.4% and 3.6% at 0-1 month, 2-3 months and >=5 months after birth, respectively. The median foetal haemoglobin concentrations in infants <37 weeks' gestational age at birth were 75.5%, 62.7% and 5.1% at 0-1 month, 2-3 months and >=5 months after birth, respectively. The median foetal haemoglobin concentrations in infants <37 weeks' gestational age at birth were significantly higher than that in infants >=37 weeks' gestational age at birth at all postnatal age points. (2) There was no significant difference between the groups at all age points after nine months of postmenstrual age: 72.5 and 75.3% at 9-10 months, 25.1 and 26.6% at 11-12 months and 5.5 and 4.6% at >13 months after last menstruation in infants >=37 and <37 weeks' gestational age at birth, respectively. Conclusions Evaluation of foetal haemoglobin concentrations at postmenstrual age is unaffected by gestational age at birth. PMID- 28656819 TI - Urinary albumin: a risk marker under-requested in primary care in Spain. AB - Background To study the inter-practice regional variation in the request of urinary albumin by general practitioners and compare to guideline recommendations. Methods A cross-sectional study enrolled laboratories from different Spanish autonomous communities. Laboratories were invited to report the number of urinary albumin requested by general practitioners during 2012 and 2014. Urinary albumin requested per 1000 inhabitants and the index of variability (90th centile/10th centile) was calculated, and compared between autonomous communities and time periods. To investigate potential inappropriate requesting in the management of diabetes and arterial hypertension, the actual number of requests was compared to the theoretical, based on prevalence and guideline recommendations. Results Urinary albumin requested per 1000 inhabitants was similar for years 2012 and 2014 (78.2 (60.1) to 85.4 (55.4); P = 0.235), as was the variability index (4.6 for both). There were significant differences between autonomous communities, with the indicator ranging from 46.0 (33.1) to 125.8 (64.3) ( P < 0.05). The theoretical cut-off ratios of urinary albumin per 1000 inhabitants to manage patients with diabetes and arterial hypertension were, respectively, 78 and 159; no laboratory reached both values. Conclusions Requesting of urinary albumin showed a significant regional variability in primary care in Spain, and was insufficient to correctly monitor patients with diabetes and arterial hypertension. PMID- 28656820 TI - Best Practices for Nutrition Care of Pregnant Women in Prison. AB - Approximately 3% to 4% of women are pregnant upon their admission to prison. Pregnant inmates present unique challenges for correctional health providers, including meeting the nutritional needs for healthy pregnancy outcomes. The authors outline six recommendations for nutrition care for pregnant inmates, including (1) test for pregnancy; (2) prescribe prenatal vitamins; (3) follow nutrition recommendations outlined by the Academy of Nutrition and Dietetics; (4) provide additional food, monitor over time, and allow for modifications to meet pregnancy needs; (5) ensure regular access to water; and (6) provide inmates with resources and education on healthy diet. The degree to which correctional facilities address the nutritional needs of pregnant women may have short- and long-term consequences for the health of women and their offspring. PMID- 28656822 TI - Excessive internet use causes blood pressure rise and anxiety. AB - Some people who use the internet a lot experience significant physiological changes such as increased heart rate and blood pressure when they stop, according to research. PMID- 28656821 TI - Increased Coccidioidomycosis Among Inmates at a California Prison: Initial Investigation in 2005 to 2006. AB - Since 2005, coccidioidomycosis has increased among inmates at a California prison. Our initial investigation found an incidence of 3,323 cases/100,000 persons. Black race, age >=41 years, and residence on Yard C were significantly associated with coccidioidomycosis ( p < .05). Inmates at this prison have continued to be at risk for coccidioidomycosis. PMID- 28656823 TI - Expressive writing may help wounds to heal faster. AB - People who wrote emotionally about past stressful events two weeks before having a biopsy saw their wound heal faster than people who wrote about factual day-to day activities, a study has found. PMID- 28656824 TI - Fifty-seven years and counting.... AB - Sally Jorden is a Macmillan breast care nurse at Southend General Hospital in Essex. After completing her nurse training in 1960, she worked as a midwife, health visitor, staff nurse, night sister and ward sister. Now aged 74, she has been a nurse for 57 years, and set up the first breast care nurse service for Macmillan at Basildon hospital in 1994. PMID- 28656825 TI - Spread the word about research. AB - A senior research nurse working in rheumatology is helping to change the way researchers communicate with patients and staff. Helen Hanson ran a two-year study, funded by the charity Arthritis Research UK, which looked at how to expand awareness of and recruitment to research. As part of the project she introduced a package of interventions targeting staff at her trust, including short talks, clinic room posters and regular feedback sessions in departmental meetings, each tailored to their specific audience. PMID- 28656826 TI - Summer of protest is our best chance to scrap the cap. AB - Momentum has been building and now is the time for nurses and other NHS staff to seize the moment.The government is weak and there is popular support for an end to the 1% public sector pay cap, so the RCN's summer of protest on the issue has every chance of success. PMID- 28656828 TI - Inspiring nurse advised me to set my anxieties aside to help my daughter. AB - Helen Laverty is the epitome of excellent nursing, possessing that rare and magical combination of warmth, integrity, experience and professionalism - mixed with a sprinkle of fairy dust. PMID- 28656827 TI - Spotting the signs of domestic slavery. AB - Essential facts Health professionals, including district and community nurses and health visitors, are being encouraged to look out for signs of domestic slavery during home visits. PMID- 28656829 TI - Use of dexmedetomidine infusion as a sedative drug for patients in the intensive care unit. AB - The administration of sedatives may present several challenges for critical care nurses. Evidence-based practice requires critical care nurses to remain up to date with developments in sedation management and ensure safe and effective use of sedative agents in their practice. Dexmedetomidine is a sedative drug that has been increasingly used in the intensive care setting in recent years. This article provides an overview of the pharmacological properties of dexmedetomidine and discusses nurses' responsibilities in caring for patients receiving dexmedetomidine infusion. PMID- 28656830 TI - Moving from city to country can be a shock. AB - In November 2016 I moved from Cardiff to West Wales after securing a job as team leader of a nascent mental health liaison service in Hywel Dda University Health Board. PMID- 28656831 TI - Recognition. AB - Nurses and nursing students gathered for a night of celebration at the annual Cavell Nurses' Trust (CNT) Awards in London on 22 June. PMID- 28656832 TI - NHS reviews fire safety procedures at its buildings. AB - The NHS has confirmed it is reviewing fire safety procedures in the wake of the Grenfell Tower tragedy in London, amid concerns about the safety of hospital buildings. PMID- 28656834 TI - Extra insulin after meals may curb cardiovascular disease in diabetes. AB - People with type 1 diabetes may be protected from cardiovascular disease by an additional injection of insulin three hours after eating, according to research. PMID- 28656835 TI - Causes of major birth defects still largely unknown. AB - The causes of major birth defects remain largely unknown, say researchers, who were able to establish a definite cause in only one in every five infants they studied. PMID- 28656836 TI - Swearing can ease social hurt as well as physical pain. AB - Swearing not only eases physical pain but also helps ease hurt feelings, a psychology lecturer has claimed. PMID- 28656838 TI - Chronic heart failure: part 1. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article outlined the physiology of the heart, the pathophysiology, signs and symptoms of chronic heart failure, and how the condition is diagnosed. PMID- 28656839 TI - Transforming the care of patients with heart failure. AB - A nurse-led service run by the heart failure team at the Northern General Hospital in Sheffield is breaking new ground. PMID- 28656840 TI - Team praised for terror response. AB - The senior sister in charge of the unit where five patients were treated following the terror attack in Finsbury Park, London, has paid tribute to her team. PMID- 28656842 TI - May's initial offer to EU citizens in the UK welcomed as 'a step in the right direction'. AB - Health organisations have given a cautious welcome to prime minister Theresa May's initial proposals on the right of European Union (EU) citizens to remain in the UK after Brexit. PMID- 28656841 TI - Cigbreak Free: Game to Quit Smoking. AB - Created by a games developer, this is described as the UK's first smoking cessation app in the form of an interactive game. PMID- 28656843 TI - Processing tragedy: the aftermath of Grenfell Tower. AB - Palliative care nurse Simone Williams was woken by sirens on the night of the fire at nearby Grenfell Tower and rushed out to see what was happening. She helped look after those who had escaped from the burning building and knocked on doors appealing for blankets for them. PMID- 28656844 TI - New toolkit for recording the public health impact of care. AB - A toolkit has been created by Public Health England (PHE) and the Royal Society for Public Health (RSPH) to help nurses, midwives and others record the impact of their work on public health. PMID- 28656848 TI - Whistleblowers urged to share their experiences with National Guardian. AB - Nurses who feel they have been treated badly after raising concerns about care have been urged to put their case forward for review as part of an NHS initiative. PMID- 28656847 TI - The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer Blackburn Elizabeth and Epel Elissa The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer 417pp L14.99 Orion Books 9780297609230 0297609238 [Formula: see text]. AB - Elizabeth Blackburn received a Nobel prize for discovering the molecular nature of telomeres (the ends of our chromosomes that serve as protective caps) and telomerase (the enzyme that maintains telomeres). PMID- 28656849 TI - Healthcare Professionalism: Improving Practice through Reflections on Workplace Dilemmas Monrouxe Lynn V and Rees Charlotte E Healthcare Professionalism: Improving Practice through Reflections on Workplace Dilemmas 272pp L34.99 Wiley Blackwell 9781119044444 1119044448 [Formula: see text]. AB - This book may be appear to be a 'stiff read', given its topic and the density of the text. However, I was pleasantly surprised and waded through it with ease. PMID- 28656850 TI - Suffolk trust to test Dutch community care model. AB - A Suffolk trust is set to trial a nurse-led community care model that has enjoyed great success in the Netherlands. PMID- 28656851 TI - Consistent sepsis care. AB - 'My goal as a nurse is to ensure that every child attending our department is given the best care possible. We should treat the families as if they were our own, and I knew we were not good enough at dealing with sepsis.' PMID- 28656852 TI - How we eat dictates our overall well-being. AB - Few things give more pleasure than wining and dining with old friends, but I was glad not to be chef on this occasion as each of us is on a set diet. Sorry, I mean 'eating plan' - dieting is so 20th century. PMID- 28656853 TI - RCN 'summer of protest' begins. AB - Nurses across the UK are taking part in the first wave of protests as part of an RCN-led initiative to campaign against the 1% public sector pay cap. PMID- 28656854 TI - Readers' panel - Do fees deter mature students from applying for courses? AB - Our experts consider a hot topic of the day. PMID- 28656855 TI - Top nursing universities fall short in new ratings. AB - Several universities with leading nursing schools have failed to score highly under new teaching assessments. PMID- 28656856 TI - Student life - Handling negative feedback. AB - It is worth spending time reflecting on the expectations you set for yourself. Hopefully, your aim is to be the best nurse you can be, but there is a reason that your course is the length it is; the skills and aptitude needed to become a proficient nurse take time to master. PMID- 28656858 TI - Prioritise the safety of people with dementia who go missing. AB - A scheme that helps find people with dementia who go missing from care homes, using personal dossiers and, in some cases, tracking devices, is being extended to those living in the community. PMID- 28656859 TI - Coping with the stress of a major incident. AB - When you are involved in any kind of traumatic event, at work or in your personal life, you may initially go into auto pilot and think of everyone else but yourself. However, once the shock and adrenaline wear off, you are likely to experience a wide range of thoughts and emotions. PMID- 28656860 TI - Fair blame, not no blame. AB - All nurses have a professional responsibility to report medication errors, and patients must be made aware of any incident involving them. I have been involved in investigating medication errors, and emotions often run high for the patients and staff involved, but you should never try to hide an error. Not only is this dangerous for patients, it can have serious consequences for your career, as you may be reported to the Nursing and Midwifery Council and face a disciplinary panel. PMID- 28656861 TI - Scrap the cap or we will ballot RCN members on strike action. AB - This summer the RCN will be protesting across the country to continue our fight for better pay for nurses. PMID- 28656862 TI - Understanding the link between obesity and diabetes. AB - The incidence of type 2 diabetes is rising alongside increasing rates of obesity, in part because of people's lifestyle behaviours, such as an unhealthy diet and a lack of physical activity. The pathophysiological changes caused by central obesity can lead to metabolic syndrome and type 2 diabetes, both of which increase the risk of developing cardiovascular disease. Managing obesity has been identified as the optimum strategy for preventing the development of type 2 diabetes and cardiovascular complications. This article discusses the role of healthcare professionals in educating patients and the public about the causes and effects of obesity and diabetes, and outlines the evidence-based strategies that can enable healthcare professionals to reduce patients' risk of developing these conditions. The article examines some of the strategies that healthcare professionals can implement to minimise the risk of further complications for patients who have been diagnosed with type 2 diabetes. PMID- 28656863 TI - Don't meddle with mentors. AB - The NMC is looking at replacing mentors with supervisors and assessors (Readers' Panel, 21 June). I'm sure someone puts nursing issues in a hat and randomly picks one out per week. PMID- 28656864 TI - Making personal experience count. AB - My first placement in my first year of training was on an adult psychiatric ward. Prior to this, my only care experience had been as an inpatient in mental health settings. PMID- 28656865 TI - Letter. AB - The RCN wants pets allowed in hospitals, but we just need to watch - with the way our governments are watering down the skill mix we might soon have golden retrievers doing drug rounds. PMID- 28656867 TI - Autism spectrum network. AB - I was unable to attend this year's RCN congress, but as a nurse with Asperger's syndrome I followed the congress autism resolution debate with interest ('More research for autism,' say nurses across disciplines, online news, 16 May). PMID- 28656868 TI - How to free patients from the tobacco trap. AB - Saturday 1 July is an important landmark for public health in England as we celebrate the tenth anniversary of smoke-free legislation that stubbed out smoking in enclosed public spaces. PMID- 28656869 TI - Pets would be such an asset. AB - The RCN wants patients' pets allowed in hospitals (online news, 21 June). PMID- 28656870 TI - Pay caps not confined to NHS. AB - I am fully behind the call to remove the pay cap on NHS pay for the reasons outlined by the RCN and other unions (RCN head is lead signatory on scrap the cap letter to PM, online news, 16 June). PMID- 28656871 TI - Is minimally invasive surgery superior to open surgery for treatment of lumbar spinal stenosis? A systematic review. AB - PURPOSE: The purpose of this study is to review the updated evidence comparing outcomes between minimally invasive surgery (MIS) and conventional open surgery (COS) for lumbar spinal stenosis (LSS). METHODS: All randomized controlled trials (RCTs) published from January 2005 to August 2016 were identified through PubMed and MEDLINE databases. Only RCTs including patients with LSS and with direct comparison between COS and MIS were selected for analysis. The intra- and post operative effects of different MIS and COS on patients with LSS were evaluated for any differences. RESULTS: We reviewed 10 RCTs comparing the effect of MIS and COS for LSS. Most trials showed that MIS rendered a shorter duration of hospital stay, lower reoperation rate, visual analogue scale (VAS), 36-Item Form Health Survey (SF-36) score, creatinine phosphokinase-skeletal muscle (CPK-MM) levels and a higher Japanese Orthopaedic Association (JOA) score. However, the intergroup differences were not statistically significant for all comparisons and were only present for selected mild cases of spinal stenosis. CONCLUSIONS: This systematic review suggests that MIS reduces operating time, duration of hospital stay and CPK-MM levels. However, the evidence for these parameters is weak. Moreover, there is no conclusive evidence that MIS reduces reoperation or has better improvement in pain and outcome scores like VAS, SF-36 and JOA scores. The evidence is limited due to poor standardization of MIS definition, methodology and details of surgeon experience. MIS techniques should not be studied as a group, as each procedure is vastly different from each other. PMID- 28656872 TI - Prospective study of surgical fixation of radial head fractures using cannulated headless compression screws for simple and complex radial head fractures. AB - INTRODUCTION: Fixing the two-part Mason II radial head fracture using screws is becoming a popular practice. However, the screw fixation efficacy for three-part Mason III and IV fractures is controversial. The purpose of this study is to determine the effectiveness of using a uniform technique of headless compression screw fixation in simple, isolated Mason II and complex three-part Mason III and IV radial head fractures in terms of functional outcome, treatment efficiency and assessment of complications with the procedure. METHODS: A prospective evaluation were performed on 31 adult patients with closed, non-pathological Mason II, III and IV radial head fractures sustained due to trauma and who underwent fixation using either two or three cannulated headless compression screws of 2.0 to 2.5 mm, and all patients were followed up for 2 years after the injury. They were divided into simple Mason II fracture group and complex three-part Mason III-IV fracture group. Operation time, time to discharge and radiological union were used as parameters for assessment of clinical outcome, while Mayo Elbow Performance Score, range of motion and complications were used to assess the functional outcomes. RESULTS: Twelve cases of two-part simple fracture group and 18 cases of complex fracture group were identified. The mean age of 39 years is comparable between the two groups. Both groups had comparable days to union, mean hospital stay and operation time. In the simple fracture group, the mean Mayo Elbow Score was 97 (80-100), which is better than the complex fracture group score of 89 (75-100), p = 0.035. Both groups had no statistical difference in complication rates. All fractures united in our series. The mean range of motion for the simple fracture group was significant, with 133 degrees +/- 17.0 degrees for flexion-extension arc, 85 degrees +/- 5 degrees in pronation and supination as compared to the complex fracture group with 120 degrees +/- 20 degrees flexion-extension arc, 69 degrees +/- 10 degrees in pronation and 70 degrees +/- 8 degrees in supination, p = 0.068. CONCLUSION: Overall clinical and functional outcomes of this technique are satisfactory in both simple and complex fracture groups, with simple Mason II fracture group doing better than the complex three-part Mason III and IV fractures in terms of Mayo Elbow Score and range of motion. Screw fixation has the advantage of less periosteal stripping and less impingement compared to other fixation methods and also allows for flexible fixation in constrained areas. Headless compression screw fixation can be considered as a method of fracture fixation for both simple and complex three-part radial head fractures. PMID- 28656873 TI - Health-related quality of life with long-term retention of the PROSthesis of Antibiotic Loaded Acrylic Cement system following infection resolution in low demand patients. AB - BACKGROUND: The study purpose was to (1) evaluate health-related quality of life (HRQL) with the PROSthesis of Antibiotic Loaded Acrylic Cement (PROSTALAC) in situ for infected total hip arthroplasty (THA), (2) determine infection resolution, and (3) compare subjects who underwent second stage surgery with those who retained the PROSTALAC on a longer term basis. METHODS: Demographics, physical demand level, and comorbidities were recorded prospectively in 29 subjects followed to at least 24 months after initial PROSTALAC insertion. HRQL was evaluated using the Western Ontario McMaster Osteoarthritis Index (WOMAC) and RAND 36-Item Health Survey. Infection resolution was determined using a pre specified clinical definition. RESULTS: Twenty-five of 29 (86%) subjects' infections resolved. Three subjects died, of whom two had resolved infections. For survivors, 22/26 (85%) completed HRQL evaluations. After PROSTALAC insertion, pain and function improved within 3-6 months and was retained at 24 months. Of those followed to 24 months, 7/22 (32%) subjects underwent second stage surgery. They were higher physical demand subjects ( p = 0.03) than those not undergoing second stage surgery. We found no difference in WOMAC scores at 24 months between those who underwent second stage surgery and those who retained the PROSTALAC ( p > 0.32). DISCUSSION: The PROSTALAC system for THA appears to allow acceptable HRQL while in situ for at least 2 years in low physical demand patients. Subjects with higher physical demand levels are more likely to undergo second stage surgery. CONCLUSION: Further evaluation is required to determine whether longer term PROSTALAC retention may be appropriate for specific patient groups. PMID- 28656874 TI - Cementless femoral components in bicondylar hybrid knee arthroplasty in patients with rheumatoid arthritis: A 10-year survivorship analysis. AB - BACKGROUND: Total knee arthroplasty (TKA) has been established as a successful surgical treatment in the late stages of rheumatoid joint destruction. The purpose of this study was to review the clinical outcome and survivorship in rheumatoid arthritis (RA) patients undergoing TKA in hybrid technique with a cementless fixation of the femoral component. METHODS: We analysed retrospectively 66 RA patients who underwent 72 TKAs (P.F.C. Sigma(r)). Mean follow-up time was 124 +/- 41 months. To evaluate postoperative clinical outcome, knee injury and osteoarthritis outcome score (KOOS) and Oxford knee score (OKS) were assessed. Kaplan-Meier analysis was used to calculate survivorship. The primary outcome was revision for any reason. RESULTS: Thirty-four patients (36 knees) died and two patients (2 knees) were lost to follow-up. Three patients (four knees) did not agree to participate. Twenty-seven patients (30 knees) were available for assessing clinical scores. The average scores were 85 +/- 14 for KOOS and 34 +/- 10 for OKS. In three patients (three knees), revision was necessary, including restricted range of motion ( n = 1), instability ( n = 1), and infection ( n = 1). There were no cases of loosening in this cohort study. The survival rates were 100% at 5 years, 97.1% at 10 years (95% CI 89.0-99.2%) and 95.6% at 15 years (95% CI 86.9-98.5%). CONCLUSIONS: This study confirms that excellent clinical results and a good 10-year survivorship can be obtained with hybrid fixation technique in TKA in the unique population of RA patients. PMID- 28656875 TI - Remote monitoring of heart failure: benefits for therapeutic decision making. AB - INTRODUCTION: Chronic heart failure is a cardiovascular disorder with high prevalence and incidence worldwide. The course of heart failure is characterized by periods of stability and instability. Decompensation of heart failure is associated with frequent and prolonged hospitalizations and it worsens the prognosis for the disease and increases cardiovascular mortality among affected patients. It is therefore important to monitor these patients carefully to reveal changes in their condition. Remote monitoring has been designed to facilitate an early detection of adverse events and to minimize regular follow-up visits for heart failure patients. Several new devices have been developed and introduced to the daily practice of cardiology departments worldwide. Areas covered: Currently, special tools and techniques are available to perform remote monitoring. Concurrently there are a number of modern cardiac implantable electronic devices that incorporate a remote monitoring function. All the techniques that have a remote monitoring function are discussed in this paper in detail. All the major studies on this subject have been selected for review of the recent data on remote monitoring of HF patients and demonstrate the role of remote monitoring in the therapeutic decision making for heart failure patients. Expert commentary: Remote monitoring represents a novel intensified follow-up strategy of heart failure management. Overall, theoretically, remote monitoring may play a crucial role in the early detection of heart failure progression and may improve the outcome of patients. PMID- 28656876 TI - Co-dependency between KRAS addiction and ARHGEF2 promotes an adaptive escape from MAPK pathway inhibition. AB - Oncogenic KRAS engages multiple effector pathways including the MAPK cascade to promote proliferation and survival of pancreatic cancer cells. KRAS-transformed cancer cells exhibit oncogene addiction to sustained activity of RAS for maintenance of malignant phenotypes. Previously, we have shown an essential role for the RHO guanine exchange factor ARHGEF2 for growth and survival of RAS transformed pancreatic tumors. Here, we have determined that pancreatic cancer cells demonstrating KRAS addiction are significantly dependent on expression of ARHGEF2. Furthermore, enforced expression of ARHGEF2 desensitizes cells to pharmacological MEK inhibition and initiates a positive feedback loop which activates ERK phosphorylation and the downstream ARHGEF2 promoter. Therefore, targeting ARHGEF2 expression may increase the efficacy of MAPK inhibitors for treatment of RAS-dependent pancreatic cancers. PMID- 28656877 TI - "The Action Level"(r). PMID- 28656878 TI - Proteasome beta-4 subunit contributes to the development of melanoma and is regulated by miR-148b. AB - The proteasome beta-4 subunit is required for the assembly of 20S proteasome complex, forming a pivotal component for the ubiquitin-proteasome system. Emerging evidence indicates that proteasome beta-4 subunit may be involved in underlying progression and mechanisms of malignancies. However, the role of proteasome beta-4 subunit in melanoma is currently unknown. Here, we reported that proteasome beta-4 subunit was markedly upregulated in human melanoma tissues and cells, compared with normal skin samples. High proteasome beta-4 subunit levels were significantly associated with poor overall survival in patients with melanoma. Proteasome beta-4 subunit knockdown strongly decreased melanoma cell growth in vitro and in vivo. We further identified miR-148b as a negative regulator of proteasome beta-4 subunit. Enforced expression of miR-148b resulted in vitro growth inhibition of melanoma cells, whereas this inhibition was further abolished by enforced expression of proteasome beta-4 subunit. Our findings, for the first time, indicated that the miR-148b/proteasome beta-4 subunit axis contributed to the development of melanoma, revealing novel therapeutic targets for the treatment of melanoma. PMID- 28656880 TI - Downregulation of beta-catenin blocks fibrosis via Wnt2 signaling in human keloid fibroblasts. AB - Keloid is a disorder of fibroproliferative diseases that occurs in wounds, characterized by an exaggerated response to injury. The key factor responsible for the disease process has not been identified. This study sought to elucidate the role of beta-catenin in the regulation of keloid phenotypes and signaling. Expression of beta-catenin in keloid and normal non-keloid samples was measured by real-time polymerase chain reaction. Knockdown of beta-catenin was achieved by delivering small interfering RNA to target beta-catenin. Cell proliferation, cell cycle progression, and apoptosis of keloid cells were measured by functional assays in vitro. The proteins related to keloid fibrosis were measured by Western blotting. beta-catenin expression was significantly upregulated in keloid tissue samples compared with the normal non-keloid age-adjusted skin sample counterparts. Functionally, targeting beta-catenin with lipofection-delivered small interfering RNA oligonucleotide inhibited the proliferation and cell cycle arrest in G0/G1 phase and increased apoptosis of fibroblast cells, accompanied by downregulation of Wnt2 and cyclin D1 as well as the phosphorylation level of glycogen synthase kinase 3 beta in the keloid fibrosis. Our study supports a crucial role of beta-catenin in the regulation of fibroproliferation and extracellular matrix deposition. Targeting beta-catenin using small interfering RNA oligonucleotide may be a promising approach for preventing excessive fibroproliferative development after wound healing and may lead to the development of novel strategies for restoring keloid diseases. PMID- 28656879 TI - Long non-coding RNA PVT1 serves as a competing endogenous RNA for miR-186-5p to promote the tumorigenesis and metastasis of hepatocellular carcinoma. AB - Hepatocellular carcinoma is third leading cause of cancer-related death globally. Long non-coding RNA plasmacytoma variant translocation 1 has been reported to be dysregulated and plays a crucial role in various cancers. In this study, we investigated the interactions between plasmacytoma variant translocation 1 and miR-186-5p in the progression of hepatocellular carcinoma and explored the functional significance of plasmacytoma variant translocation 1. It was determined that plasmacytoma variant translocation 1 was significantly higher, while miR-186-5p was statistically lower in the hepatocellular carcinoma tissues than that in the adjacent normal tissues. Using gain-of-function and loss-of function methods, our results revealed that plasmacytoma variant translocation 1 affected hepatocellular carcinoma cells proliferation, invasion, and migration. It was found that there was direct interaction between miR-186-5p and the binding site of plasmacytoma variant translocation 1 by performing dual-luciferase assay and RNA immunoprecipitation assay. Furthermore, it was identified that plasmacytoma variant translocation 1 regulated the expression of the miR-186-5p target gene, yes-associated protein 1. Taken together, plasmacytoma variant translocation 1 served as an endogenous sponge for miR-186-5p to reduce its inhibiting effect on yes-associated protein 1 and thus promoted the tumorigenesis of hepatocellular carcinoma. PMID- 28656881 TI - Low expression of hsa_circ_0006633 in human gastric cancer and its clinical significances. AB - Circular RNAs are new type of endogenous RNAs, which play an important role in the regulation of gene expression and indicate a great capacity in clinical diagnosis and treatments of diseases. However, the role of circular RNAs in gastric cancer remains unknown. In this study, we chose hsa_circ_0006633 as the target circular RNA and measured its levels in human gastric cancer tissues, plasma, and gastric cell lines by real-time quantitative reverse transcription polymerase chain reaction. Hsa_circ_0006633 levels at multiple stages of gastric tumorigenesis were then explored, and its relationships with clinicopathological features were analyzed as well. We found that the expression levels of hsa_circ_0006633 in four gastric cancer cell lines, HGC-27, SGC-7901, MGC-803, and AGS, were downregulated than those in normal gastric mucosal epithelial cell line GES-1. Then, we further detected that it was downregulated in 79.2% (76/96) gastric cancer tissues compared with the adjacent non-tumorous tissues. The lower expression of hsa_circ_0006633 was associated with cancer distal metastasis ( p = 0.037) and tissue carcinoembryonic antigen level ( p = 0.041). In addition, hsa_circ_0006633 expression was significantly decreased in gastritis and dysplasia tissues comparing with the healthy control. Moreover, plasma hsa_circ_0006633 levels were significantly increased in gastric cancer compared with healthy control. Our data imply that hsa_circ_0006633 may play an important role in gastric carcinogenesis and is also a potential biomarker for screening gastric cancer. PMID- 28656882 TI - siRNA-mediated silencing of bFGF gene inhibits the proliferation, migration, and invasion of human pituitary adenoma cells. AB - Human pituitary adenoma is one of the most common intracranial tumors with an incidence as high as 16.7%. Recent evidence has hinted a relationship between growth factors of pituitary or hypothalamic origin and proliferation of human pituitary adenoma cells. This study explores the effects of small interfering RNA mediated silencing of basic fibroblast growth factor gene on the proliferation, migration, and invasion of human pituitary adenoma cells. Human pituitary adenoma tissues were collected to obtain human pituitary adenoma cells. The basic fibroblast growth factor silencing interference plasmid was constructed, and the human pituitary adenoma cells were transfected and assigned as basic fibroblast growth factor-small interfering RNA, negative control-small interfering RNA, and blank groups. The quantitative real-time polymerase chain reaction and Western blotting were carried out to detect the expression of basic fibroblast growth factor, pituitary tumor transforming gene, vascular endothelial growth factor, cluster of differentiation 147, and matrix metalloproteinase 9. Cell Counting Kit 8 assay was conducted to observe cell proliferation at 0, 24, 48, and 72 h. Flow cytometry was used to determine cell cycle. Transwell and scratch test were applied to detect the invasion and migration of pituitary adenoma cells. Protein kinase C activity was detected. In comparison with the blank group, the basic fibroblast growth factor-small interfering RNA group showed reduced messenger RNA and protein expression of basic fibroblast growth factor, reduced cell viability at 24, 48, and 72 h, increased cells in G0/G1 stage, declined cells in S and G2/M stages, decreased number of cell migration, shortened migrating distance, reduced protein kinase C activity, and decreased expression of pituitary tumor transforming gene, vascular endothelial growth factor, cluster of differentiation 147, and matrix metalloproteinase 9. However, the negative control-small interfering RNA group had no evident differences in basic fibroblast growth factor expression, cell viability, cell cycle, number of cell migration, migrating distance, protein kinase C activity, and expression of pituitary tumor transforming gene, vascular endothelial growth factor, cluster of differentiation 147, and matrix metalloproteinase 9 compared with the blank group. The study provides evidence that small interfering RNA-mediated silencing of basic fibroblast growth factor gene inhibits the proliferation, migration, and invasion of human pituitary adenoma cells. PMID- 28656883 TI - MiR-136 inhibits gastric cancer-specific peritoneal metastasis by targeting HOXC10. AB - Functions of microRNAs have been characterized in the embryologic, physiologic, and oncogenic processes, but the role of microRNAs in mediating tumor-specific organ metastasis was addressed only recently and still absent in gastric cancer peritoneal metastasis. Here, we used the microarray analysis to define the gastric cancer peritoneal metastasis-related microRNAs from highly peritoneal metastatic derivatives (GC-9811P cells) and the parental GC-9811 human gastric cancer cells. MiR-136 was found to be decreased in all peritoneal metastatic sublines when compared with that in the parental line. We further confirmed that miR-136 expression is frequently downregulated in gastric cancer peritoneal metastasis cells and tissues and its low expression is significantly associated with more peritoneal metastasis and worse prognosis. Moreover, restoring the expression of miR-136 could inhibit gastric cancer peritoneal metastasis in vitro and in vivo. Subsequent investigation characterized HOXC10 as a direct target of miR-136. In addition, knockdown of HOXC10 reduced GC-9811P cell migration and invasion, similar to the phenotype observed with miR-136 restoration in these cells, indicating that HOXC10 functions as a metastasis promoter in gastric cancer peritoneal metastasis. Upregulation of HOXC10 in parental GC-9811 cells resulted in a dramatic reduction of in vitro migration, invasion, and in vivo peritoneal metastasis. Furthermore, our results showed that ectopic expression of HOXC10 could reverse inhibition of metastasis by overexpressed miR-136 in GC 9811P cells. Our findings provide new insights into the role of miR-136 in the gastric cancer-specific peritoneal metastasis and implicate the potential application of miR-136 in gastric cancer peritoneal metastasis therapy. PMID- 28656884 TI - A Network Model of Hand Hygiene: How Good Is Good Enough to Stop the Spread of MRSA? AB - BACKGROUND Simulation models have been used to investigate the impact of hand hygiene on methicillin-resistant Staphylococcus aureus (MRSA) transmission within the healthcare setting, but they have been limited by their ability to accurately model complex patient-provider interactions. METHODS Using a network-based modeling approach, we created a simulated neonatal intensive care unit (NICU) representing the potential for per-hour infant-infant MRSA transmission via the healthcare worker resulting in subsequent colonization. The starting prevalence of MRSA colonized infants varied from 2% to 8%. Hand hygiene ranged from 0% (none) to 100% (theoretical maximum), with an expected effectiveness of 88% inferred from literature. RESULTS Based on empiric care provided within a 1-hour period, the mean number of infant-infant MRSA transmissible opportunities per hour was 1.3. Compared to no hand hygiene and averaged across all initial colonization states, colonization was reduced by approximately 29%, 51%, 67%, 80%, and 86% for the respective levels of hygiene: 24%, 48%, 68%, 88%, and 100%. Preterm infants had a 61% increase in MRSA colonization, and mechanically ventilated infants had a 27% increase. CONCLUSIONS Even under optimal hygiene conditions, horizontal transmission of MRSA is possible. Additional prevention paradigms should focus on the most acute patients because they are at greatest risk. Infect Control Hosp Epidemiol 2017;38:945-952. PMID- 28656885 TI - Social Cognition Abilities in Patients With Different Multiple Sclerosis Subtypes. AB - OBJECTIVES: Multiple sclerosis (MS) can be associated with impaired social cognition. However, social cognition skills have never been explored in the different subtypes of MS. The first aim of this study was to examine whether MS subtypes differ on the course of social cognition. The second aim was to explore the relationship between social cognition performances and executive abilities and mood variables. METHODS: Sixty-two patients with MS and 33 healthy matched controls performed experimental tasks assessing facial emotion recognition, theory of mind (ToM), and cognitive functioning, in particular executive functions. RESULTS: Patients differed from controls on both measures of social cognition. On the ToM measures, patients with progressive MS scored significantly lower than healthy participants. Patients with primary progressive MS performed worse than both healthy participants and patients with relapsing-remitting MS on the recognition of fearful facial expressions, while patients with secondary progressive MS performed worse on the recognition of facial expressions of sadness. Patients' social cognition difficulties were correlated with processing speed, working memory, and verbal fluency. CONCLUSIONS: These preliminary results suggested that there may be qualitative differences in social cognition difficulties among the phenotypes. Furthermore, these impairments were related to executive functions, but unrelated to patients' disability or level of depression. These data highlight the need for research to determine the real impact of these deficits on interpersonal relationships among patients and to confirm these disorders in a larger population with progressive forms of MS. (JINS, 2017, 23, 653-664). PMID- 28656889 TI - Untangling the web of opioid addictions in the USA. PMID- 28656887 TI - Corrupted adipose tissue endogenous myelopoiesis initiates diet-induced metabolic disease. AB - Activation and increased numbers of inflammatory macrophages, in adipose tissue (AT) are deleterious in metabolic diseases. Up to now, AT macrophages (ATM) accumulation was considered to be due to blood infiltration or local proliferation, although the presence of resident hematopoietic stem/progenitor cells (Lin-/Sca+/c-Kit+; LSK phenotype) in the AT (AT-LSK) has been reported. By using transplantation of sorted AT-LSK and gain and loss of function studies we show that some of the inflammatory ATM inducing metabolic disease, originate from resident AT-LSK. Transplantation of AT-LSK sorted from high fat diet-fed (HFD) mice is sufficient to induce ATM accumulation, and to transfer metabolic disease in control mice. Conversely, the transplantation of control AT-LSK improves both AT-inflammation and glucose homeostasis in HFD mice. Our results clearly demonstrate that resident AT-LSK are one of the key point of metabolic disease, and could thus constitute a new promising therapeutic target to fight against metabolic disease. PMID- 28656890 TI - Holding Europe to a count. PMID- 28656888 TI - The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms. AB - Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1 (TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase. XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines and mice. XIAP/TRIP-Br1-mediated degradation of ACs forms part of a negative-feedback loop that controls the homeostasis of cAMP signaling in mice. Our findings reveal a previously unrecognized mechanism for degrading multiple AC isoforms and modulating the homeostasis of cAMP signaling. PMID- 28656891 TI - Asylum seekers: Australia's shame. PMID- 28656892 TI - Clinical trials during epidemics. PMID- 28656893 TI - Offline: A unique opportunity for WHO. PMID- 28656894 TI - Recognition matters: only one in ten awards given to women. PMID- 28656895 TI - WHO R&D Blueprint: a global coordination mechanism for R&D preparedness. PMID- 28656896 TI - Palestinian surgical training: local faculty, local delivery. PMID- 28656897 TI - Tuberculosis in India: health policy alone is not enough. PMID- 28656899 TI - Department of Error. PMID- 28656898 TI - Tuberculosis in India: health policy alone is not enough. PMID- 28656900 TI - Validation of the Spanish Version of the Food Allergy Quality of Life Questionnaire-Parent Form (S-FAQLQ-PF). AB - BACKGROUND: Food allergy is an emerging health problem. Several questionnaires can be used to establish health-related quality of life (HRQOL) in food allergy patients. Current questionnaires should be translated in such a way that they take account of the culture of the country in which they are to be used. Objective: To translate and perform a cross-sectional validation of the Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF). METHODS: The parents of 54 children diagnosed with food allergy were recruited to assess the Spanish version of the FAQLQ-PF (S-FQLQ-PF). RESULTS: The S-FQLQ-PF was translated into Spanish according to WHO guidelines (including a forward-backward translation). The statistical analysis showed that feasibility, reliability, and internal consistency were very good for the global S-FAQLQ-PF score and for the different domains. Assessment of construct validity indicated that S-FAQLQ-PF has reduced capacity for measurement of HRQOL in younger children. Cross-sectional validation of the S-FAQLQ-PF demonstrated that HRQOL of a Spanish pediatric population was affected by patient age, severity of symptoms, and number of reactions. HRQOL was not affected by sex, food implicated, number of foods implicated, ingestion of the implicated food, or presence of anaphylaxis. CONCLUSIONS: Translation into Spanish and cultural validation of the FAQLQ-PF demonstrated the influence of factors, such as patient age, severity of symptoms, and number of reactions on the HRQOL of a pediatric Spanish population. PMID- 28656901 TI - Material characterisation of nanowires with intrinsic stress. AB - When fabricating nanowires (NWs) in a doubly-clamped beam configuration it is possible for a residual axial stress to be generated. Here, we show that material characterisation of metal and semiconductor NWs subjected to residual axial stress can be problematic. Benchmark measurements of the Young's modulus of NWs are performed by sectioning a doubly-clamped NW into two cantilevered wires, eliminating residual axial stress. Use of models for doubly-clamped beams that incorporate the effects of residual stress are found to lead to ambiguity in the extracted Young's modulus as a function of displacement fit range, even for NWs with no residual stress. This is due to coupling of bending and axial stress effects at small displacements, and the limited displacement range of force curves prior to fracture or plastic deformation. This study highlights the importance of fabricating metal and semiconductor NWs that exhibit little or no residual axial stress for materials characterisation. PMID- 28656902 TI - Ligand-free attachment of plasmonic Au nanoparticles on ZnO nanowire to make a high-performance broadband photodetector using a laser-based method. AB - We report a new strategy for ligand-free attachment of plasmonic Au nanoparticles on the surface of a ZnO nanowire to make high-performance broadband photodetectors using a pulsed laser ablation technique in a liquid medium. The photoresponse of the ZnO-based photodetector is enhanced and the photodetection limit is broadened from UV to visible, which can be controlled by varying the concentration of Au nanoparticles attached to the ZnO surface. This Au nanoparticle concentration can be tuned by varying the number of laser pulses used in the ablation process. We found that the responsivity of the detector is 10 mA W-1 for [Formula: see text] and increases to as much as 0.4 A W-1 for lambda <= 400 nm for the maximum Au concentration. The enhanced responsivity was found to be linked to increased absorption over a broad spectral range arising from direct and indirect plasmonic processes due to Au nanoparticle attachment, and the enhanced absorption also leads to a large increment in photocurrent generation. We also found that the attachment of Au nanoparticles makes the relaxation of the photocurrent (persistence) considerably faster in both the UV and visible regions of the spectrum and that the persistence directly depends on the concentration of Au nanoparticles attached to the ZnO nanowire. This single step pulsed laser ablation-based nanoparticle attachment process can be further used to make other plasmonic nanoparticle-decorated nanowire devices. PMID- 28656903 TI - Association of extended nitric oxide parameters with bronchial hyperresponsiveness and bronchodilator response in children with asthma. AB - Theoretical non-linear modeling of exhaled nitric oxide has revealed extended flow-independent parameters that could explain where or how nitric oxide is produced in the lung and transferred to the airway gas stream. We aimed to evaluate the associations of bronchial hyperresponsiveness and bronchodilator response with extended flow-independent nitric oxide parameters. Nitric oxide (30, 50, 100, 200 ml s-1) was measured in 432 children with asthma on the same day with either a methacholine challenge test (n = 156) or spirometry with bronchodilator (n = 276; 96 previously diagnosed with asthma and treated with inhaled corticosteroid, 37 with acute exacerbation treated with systemic corticosteroid). We additionally included 107 healthy controls for evaluation of the suitability of the non-linear model of exhaled nitric oxide. In asthmatic children, the response-dose ratio of the methacholine challenge test was correlated positively with bronchial nitric oxide (JawNO) and airway tissue nitric oxide (CawNO) (r = 0.367 and r = 0.299, respectively; both p < 0.001), while the change in forced expiratory volume in 1 s, representing bronchodilator response, was associated positively with only JawNO (r = 0. 216, p < 0.001). On multiple regression, JawNO, CawNO, and the diffusing capacity of NO (DawNO) were significantly associated with the response-dose ratio. JawNO was significantly associated with change in forced expiratory volume in children with stable asthma but not those with acute exacerbation. Our findings suggest that bronchial hyperresponsiveness is associated with CawNO while factors other than airway tissue inflammation could affect bronchodilator response in children with mild asthma. Systemic corticosteroid use during asthma exacerbation could affect the association of bronchodilator response with extended nitric oxide parameters. PMID- 28656904 TI - Mapping quorum sensing onto neural networks to understand collective decision making in heterogeneous microbial communities. AB - Microbial communities frequently communicate via quorum sensing (QS), where cells produce, secrete, and respond to a threshold level of an autoinducer (AI) molecule, thereby modulating gene expression. However, the biology of QS remains incompletely understood in heterogeneous communities, where variant bacterial strains possess distinct QS systems that produce chemically unique AIs. AI molecules bind to 'cognate' receptors, but also to 'non-cognate' receptors found in other strains, resulting in inter-strain crosstalk. Understanding these interactions is a prerequisite for deciphering the consequences of crosstalk in real ecosystems, where multiple AIs are regularly present in the same environment. As a step towards this goal, we map crosstalk in a heterogeneous community of variant QS strains onto an artificial neural network model. This formulation allows us to systematically analyze how crosstalk regulates the community's capacity for flexible decision making, as quantified by the Boltzmann entropy of all QS gene expression states of the system. In a mean-field limit of complete cross-inhibition between variant strains, the model is exactly solvable, allowing for an analytical formula for the number of variants that maximize capacity as a function of signal kinetics and activation parameters. An analysis of previous experimental results on the Staphylococcus aureus two-component Agr system indicates that the observed combination of variant numbers, gene expression rates and threshold concentrations lies near this critical regime of parameter space where capacity peaks. The results are suggestive of a potential evolutionary driving force for diversification in certain QS systems. PMID- 28656905 TI - Probing cooperative force generation in collective cancer invasion. AB - Collective cellular dynamics in the three-dimensional extracellular matrix (ECM) plays a crucial role in many physiological processes such as cancer invasion. Both chemical and mechanical signaling support cell-cell communications on a variety of length scales, leading to collective migratory behaviors. Here we conduct experiments using 3D in vitro tumor models and develop a phenomenological model in order to probe the cooperativity of force generation in the collective invasion of breast cancer cells. In our model, cell-cell communication is characterized by a single parameter that quantifies the correlation length of cellular migration cycles. We devise a stochastic reconstruction method to generate realizations of cell colonies with specific contraction phase correlation functions and correlation length a. We find that as a increases, the characteristic size of regions containing cells with similar contraction phases grows. For small a values, the large fluctuations in individual cell contraction phases smooth out the temporal fluctuations in the time-dependent deformation field in the ECM. For large a values, the periodicity of an individual cell contraction cycle is clearly manifested in the temporal variation of the overall deformation field in the ECM. Through quantitative comparisons of the simulated and experimentally measured deformation fields, we find that the correlation length for collective force generation in the breast cancer diskoid in geometrically micropatterned ECM (DIGME) system is [Formula: see text], which is roughly twice the linear size of a single cell. One possible mechanism for this intermediate cell correlation length is the fiber-mediated stress propagation in the 3D ECM network in the DIGME system. PMID- 28656906 TI - Polydopamine-functionalized nanographene oxide: a versatile nanocarrier for chemotherapy and photothermal therapy. AB - For releasing both drug and heat to selected sites, a combination of chemotherapy and photothermal therapy in one system is a more effective way to destroy cancer cells than monotherapy. Graphene oxide (GO) with high drug-loading efficiency and near-infrared (NIR) absorbance has great potential in drug delivery and photothermal therapy, but it is difficult to load drugs with high solubility. Herein, we develop a versatile drug delivery nanoplatform based on GO for integrated chemotherapy and photothermal therapy by a facile method of simultaneous reduction and surface functionalization of GO with poly(dopamine) (PDA). Due to the excellent adhesion of PDA, both low and high solubility drugs can be encapsulated in the PDA-functionalized GO nanocomposite (rGO-PDA). The fabricated nanocomposite exhibits good biocompatibility, excellent photothermal performance, high drug loading capacity, an outstanding sustained release property, and efficient endocytosis. Moreover, NIR laser irradiation facilitates the release of loaded drugs from rGO-PDA. These features make the rGO-PDA nanocomposite achieve excellent in vivo synergistic antitumor therapeutic efficacy. PMID- 28656907 TI - Measuring individual carbon nanotubes and single graphene sheets using atomic force microscope infrared spectroscopy. PMID- 28656908 TI - Scanning probe microscopy induced surface modifications of the topological insulator Bi2Te3 in different environments. AB - We investigated the topological insulator (TI) Bi2Te3 in four different environments (ambient, ultra-high vacuum (UHV), nitrogen gas and organic solvent environment) using scanning probe microscopy (SPM) techniques. Upon prolonged exposure to ambient conditions and organic solvent environments the cleaved surface of the pristine Bi2Te3 is observed to be strongly modified during SPM measurements, while imaging of freshly cleaved Bi2Te3 in UHV and nitrogen gas shows considerably less changes of the Bi2Te3 surface. We conclude that the reduced surface stability upon exposure to ambient conditions is triggered by adsorption of molecular species from ambient, including H2O, CO2, etc which is verified by Auger electron spectroscopy. Our findings of the drastic impact of exposure to ambient on the Bi2Te3 surface are crucial for further in-depth studies of the intrinsic properties of the TI Bi2Te3 and for potential applications that include room temperature TI based devices operated under ambient conditions. PMID- 28656909 TI - Trichorrhexis nodosa due to repetitive trivial trauma. PMID- 28656910 TI - Effectiveness and safety of levocetirizine 10 mg versus a combination of levocetirizine 5 mg and montelukast 10 mg in chronic urticaria resistant to levocetirizine 5 mg: A double-blind, randomized, controlled trial. AB - BACKGROUND: Chronic urticaria is a vexing problem for patients and treating physicians alike. The EAACI/GA[2]LEN/EDF/WAO guidelines advocate an increased antihistamine dosage up to four times the standard, before adding leukotriene receptor antagonists. Patients are frequently intolerant of these higher dosages. We conducted this study to determine whether the addition of leukotriene receptor antagonists to the standard antihistamine dose was comparable to higher dosages of antihistamines alone, in terms of efficacy, safety and quality of life changes. We compared levocetirizine 10 mg (double dose of standard) versus a combination of levocetirizine 5 mg and montelukast 10 mg in cases of chronic urticaria not responding to single daily dose of 5 mg levocetirizine. METHODS: A single-center, double-blind, randomized, active-controlled, parallel group phase IV trial (CTRI/2014/12/005261) was conducted on 120 patients of chronic urticaria of either sex not responding to 5 mg levocetirizine. Patients were randomized into receiving either levocetirizine 10 mg or levocetirizine 5 mg + montelukast 10 mg for 4 weeks. Primary outcome measures were Urticaria Activity Score (UAS) and Urticaria Total Severity Score (TSS). Routine hematological and biochemical tests and treatment-emergent adverse events were monitored for safety. RESULTS: Fifty-two patients on levocetirizine 10 mg group and 51 patients on levocetirizine 5 mg + montelukast 10 mg group were analyzed. UAS and TSS reduced significantly in both treatment groups and reduction of score were comparable in between the groups (P = 0.628, P = 0.824, respectively). Among adverse effects, sedation was noted significantly more (P = 0.013) in levocetirizine 10 mg group. Quality of life was significantly improved in levocetirizine 5 mg + montelukast 10 mg group (P = 0.031). LIMITATIONS: The limitation of the study was that the follow-up period was 4 weeks. CONCLUSION: EAACI/GA[2]LEN/EDF/WAO guidelines need to be more flexible in allowing usage of montelukast before escalation of anti histamine dosage. PMID- 28656911 TI - Serum macrophage migration inhibitory factor levels in leprosy patients with erythema nodosum leprosum. AB - Background: Erythema nodosum leprosum is an immune-mediated complication of leprosy which causes significant morbidity. Biomarkers in the pathogenesis of erythema nodosum leprosum are not yet fully determined. Aim: To determine macrophage migration inhibitory factor levels in the sera of leprosy patients with erythema nodosum leprosum and to correlate the same with clinical parameters. Methods: This cross-sectional study included 37 consecutive leprosy patients with active erythema nodosum leprosum and 31 age- and sex-matched controls. Detailed clinical history and examination findings were recorded including the severity and frequency of erythema nodosum leprosum. Slit skin smears and histopathologic examination were done in all patients at baseline. Serum macrophage migration inhibitory factor levels were determined using an enzyme-linked immunosorbent assay. Results: Most of our patients were males (78.4%) and suffering from lepromatous leprosy (27, 73%) with a mean initial bacillary index of 3.38 +/- 1.36. Recurrent and chronic patterns of erythema nodosum leprosum were seen in 15 (40.5%) and 6 (16.3%) patients, respectively. Most (86.5%) of our patients presented with moderate to severe erythema nodosum leprosum. The mean serum macrophage migration inhibitory factor level was 21.86 +/- 18.7 ng/ml among patients while it was 11.78 +/- 8.4 ng/ml in the control group (P < 0.01). There were no statistically significant correlations of macrophage migration inhibitory factor levels with erythema nodosum leprosum frequency or severity. Limitation: Serum macrophage migration inhibitory factor levels in leprosy patients with no erythema nodosum leprosum and in patients with other inflammatory and autoimmune conditions were not assessed. Hence, this study falls short of providing the predictive value and specificity of higher macrophage migration inhibitory factor concentrations in serum as a biomarker of erythema nodosum leprosum. Conclusion: Macrophage migration inhibitory factor levels are elevated in erythema nodosum leprosum patients as compared to controls. A larger sample size and macrophage migration inhibitory factor gene polymorphism analysis will be needed to elucidate the role of this pro inflammatory cytokine in erythema nodosum leprosum. PMID- 28656912 TI - Capecitabine-induced acral and mucosal hyperpigmentation. PMID- 28656913 TI - Retrospective study on the characteristics and treatment of late-onset vitiligo. AB - BACKGROUND: Late-onset vitiligo, defined as being aged 50 years and above at the point of clinical onset, remains poorly characterized till now. AIM: This study aims to describe the clinical characteristics and treatment response of patients with late-onset vitiligo. METHODS: We retrospectively reviewed the case records of all patients diagnosed with late-onset vitiligo, from January 1, 2010 to December 31, 2014. Information obtained included patient demographics, characteristics of vitiligo and treatment responses. RESULTS: Of the 3128 patients diagnosed with vitiligo over the 5-year period, 461 (14.7%) had late onset disease. The study had more females (n = 260, 56.4%) than males, with an average onset age of 59.4 +/- 7.4 years. Majority of patients were Chinese (n = 308, 66.8%) and 45 (9.8%) patients had an associated autoimmune disease. Focal vitiligo, defined as the localized presence of depigmented patches, was most common (n = 209, 45.3%). Treatment response was evaluated in 359 patients, of which 216 received monotherapy (topical creams: n = 210, 97.2%; phototherapy: n = 6, 2.8%) and 143 received both modalities. Fifty six (15.6%) patients received oral steroids. Patients who were treated with both topical creams and phototherapy yielded better clinical responses compared to those on monotherapy (P < 0.001) with 56.6% (n = 81) of them achieving good epidermal repigmentation, defined as >50% return of pigmentation compared to baseline (vs. n = 66, 30.6% in the monotherapy group). The choice of phototherapy (targeted, narrowband ultraviolet B or psoralen + ultraviolet A) did not significantly affect clinical response (P = 0.774). LIMITATIONS: This study is limited by its retrospective nature, the nonstandardized documentation resulting in the inability to determine disease progression and associated metabolic comorbidities and also by the gradual loss to follow-up of patients. CONCLUSION: Late-onset vitiligo is not uncommon and tends to be of the focal vitiligo subtype. Nonsegmented vitiligo is more prevalent than segmental vitiligo. Combination therapy with topical medications and phototherapy is superior to monotherapy. PMID- 28656914 TI - Syringocystadenocarcinoma papilliferum with coexisting trichoblastoma: A case report with review of literature. AB - We present a unique case of syringocystadenoma with malignant transformation into syringocystadenocarcinoma papilliferum and coexisting trichoblastoma arising de novo in a scalp swelling of long duration in a 78-year-old woman. Syringocystadenocarcinoma papilliferum was described by the World Health Organization as an extremely rare malignant adnexal tumor of apocrine origin with varied histology with some cases reported in literature. PMID- 28656915 TI - Clinical and serological characteristics of nail psoriasis in Indian patients: A cross-sectional study. AB - BACKGROUND: Nail involvement in psoriasis is common with a lifetime incidence of 80-90%. It may reflect severity of cutaneous involvement and predict joint disease. Yet it remains, poorly studied and evaluated especially in Indian psoriatic patients. AIM: The present study was undertaken to evaluate clinical and serological profile of nail involvement in psoriasis and to assess quality of life impairment associated with nail involvement in Indian patients. METHODS: Consecutive patients with nail psoriasis were assessed for severity of cutaneous disease (psoriasis area severity index score) and nail disease (nail psoriasis severity index score). The impairment in quality of life attributable to nail disease was scored with nail psoriasis quality of life 10 score. All patients were also assessed for joint disease and tested for inflammatory and serological markers as erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor and anti-cyclic citrullinated peptide antibodies. RESULTS: In our cohort of 38 patients with nail psoriasis, 9 had concomitant psoriatic arthritis. The mean psoriasis area severity index was 14.4 +/- 9.6 (range = 0.4-34). The most commonly recorded psoriatic nail changes were pitting (97.4%), onycholysis (94.7%) and subungual hyperkeratosis (89.5%). The mean nail psoriasis severity index score was 83.2 +/- 40.1 (range = 5-156) and mean nail psoriasis quality of life 10 was 1.1 +/- 0.4. Erythrocyte sedimentation rate and C-reactive protein were raised in 22/38 (57.9%) and 15/38 (39.5%) patients, respectively; rheumatoid factor was positive in 5/38 (13.2%) and anti-cyclic citrullinated peptide antibody was raised in 4/38 (10.5%) patients. LIMITATIONS: Small sample size and lack of a control group. CONCLUSIONS: In Indian patients with nail psoriasis, severity of nail involvement was found to be poorly correlated with the extent of cutaneous disease. In addition the impact of nail disease on patient's quality of life was found to be minimal. This suggests the need for a quality of life questionnaire suited to the Indian population. Serological markers were raised overall in the study patients and more so in the patients with concomitant arthritis. PMID- 28656916 TI - A correlation of symptomatology with lung function in patients with allergic rhinosinusitis. AB - BACKGROUND: Allergic rhinosinusitis is clinically defined as a symptomatic disorder of the nose induced by an IgE-mediated inflammation following allergen exposure to the membrane lining of the nose. It constitutes a global health problem. Both allergic rhinosinusitis and bronchial asthma are systemic inflammatory conditions that often coexist. OBJECTIVE: The objectives of the study are to assess the pattern of allergic rhinosinusitis and to correlate nasal symptom score with lung volumes of patients with allergic rhinosinusitis. METHODS: This is a prospective study of all the adult patients with clinically diagnosed allergic rhinosinusitis at the study center. Patients' biodata, symptoms, and signs were obtained using a specially designed form. The symptoms were scored using nasal symptom scoring protocol and the lung volumes determined using spirometry. The data were collated and analyzed using SPSS Version 15 statistical software. RESULTS: There were 300 patients and another 300 nonallergic individuals as control. The most common presenting symptom was nasal congestion (98%), whereas the most common sign was engorged turbinates (91%). The most common trigger of allergic symptoms was dust (72.3%). Spirometric test results were below 90% on average in both sexes and significantly (P < 0.05) below those of the participants in the control group. A large number of patients with abnormal spirometry results have total nasal symptom scores of above 5 (n = 119), whereas few (n = 7) had symptom scores of 5 and below. There was a statistically significant correlation between high total nasal symptom score and abnormal spirometry (chi2 = 72, P = 0.0001). CONCLUSION: There is a significant correlation between nasal symptom score and reduced lung volumes in patients with allergic rhinosinusitis even in the absence of asthma. PMID- 28656917 TI - To compare aneuploidy rates between ICSI and IVF Cases. AB - INTRODUCTION: Intracytoplasmic sperm injection (ICSI) currently helps many couples with male infertility. However, ICSI procedure may cause asynchronous sperm decondensation. This could introduce a risk for aneuploidy. The ICSI technique also could cause damage to the second meiotic spindle during injection and cause significantly abnormal pairing of chromosomes when compared with In vitro fertilization (IVF). In this study, we have examined whether ICSI has a higher incidence of aneuploidy when compared with IVF. MATERIAL AND METHODS: A retrospective study was conducted on 36 individuals. Common numbers of chromosome abnormalities were detected using fluorescent in-situ hybridization (FISH). Seven probes were used to detect chromosome X, Y, 13, 16, 18, 21, and 22. Chi-square test was used for statistical analysis and presented as odd ratios with confidence intervals. RESULTS: The age range was 26 through 44 (mean age 35.5) for IVF and 25 through 46 (mean age 35.8) for ICSI. From the 36 egg retrievals, 57 embryos were obtained from nine individuals using IVF and 183 embryos were obtained from 27 individuals using ICSI. For the IVF group, 37 of the 57 examined embryos were abnormal (65%), whereas 128 of 183 examined embryos were abnormal for the ICSI group (69.9%). Among the 57 embryos from the IVF cases, the number of absolute abnormal chromosomes were as follows: X&Y chromosomes: 4 (12.9%), chromosome 13: 9 (29%), chromosome 16: 7 (22.5%), chromosome 18: 6 (19.3%), chromosome 21: 8 (25.8%), chromosome 22: 10 (32.2%). For the ICSI embryos: X and Y chromosomes: 18 (14%), chromosome 13: 34 (26.5%), chromosome 16: 23 (18%), chromosome 18: 23 (18%), chromosome 21: 26 (20.3%), chromosome 22: 31 (24.2%). The odds ratios for the difference between IVF and ICSI for each chromosome were as follows: X&Y chromosomes: 1.53 (0.598-3.916), chromosome 13: 0.969 (0.443 2.122), chromosome 16: 0.709 (0.307-1.639), chromosome 18: 1.650 (0.650-4.188), chromosome 21: 0.777 (0.350-1.724), chromosome 22: 0.647 (0.311-1.348). Overall no significant difference between two insemination procedures was seen 0.948 (0.678-1.324). CONCLUSIONS: As a result; ICSI does not create a significantly higher aneuploidy number when compared with IVF as examined by FISH analysis of seven chromosome pairs. PMID- 28656918 TI - Study of kissing molars in Turkish population sample. AB - BACKGROUND: "Kissing" or "rosetting" of molars are extremely rare phenomenon with limited cases in the dental literature. It was first described in 1973, refers to contacting occlusal surfaces of the impacted mandibular second and third molars. The aim of the present study was to report the incidence of kissing molars (KMs), classification, incorporated pathologies, and its management in a group of Turkish population. MATERIALS AND METHODS: The panoramic radiographs of the patients who referred to Gaziantep University Faculty of Dentistry between January 2012 and November 2014 for surgical treatment retrospectively were evaluated. The cases of KM were determined and evaluated with respect to its type, combined pathology, and treatment. RESULTS: Of the 6570 radiographs included in the study, 4 were seen to present as KM illustrating 0.060% of the sample. Three cases were Class II (0.045%), and only one case was encountered as Class III (0.015%). The mean age at the time that the KM teeth were identified was 34 years with a range from 29 to 40 years. Three of the patients were male, one of the patients was female, and all cases were seen unilaterally. One of the KMs was associated with dentigerous cyst formation. CONCLUSION: KM is a very rare clinical condition and few treatment options described. Early detection is essential to preclude complications and to provide more successful treatment. In this study, we evaluated the cases of KM and review of the literature also presented. PMID- 28656919 TI - Psychosocial dysfunction among adolescents who abuse substances in secondary schools in Abakaliki, Nigeria. AB - BACKGROUND: Substance abuse has been associated with psychosocial dysfunction from previous reports; however, the prevalence and pattern of such morbidity is unknown in our environment. AIMS: The aim of the study was to determine the prevalence and pattern of psychosocial dysfunction among adolescents who abuse substance. METHODS: A case-control study was carried out among adolescents selected from five secondary schools in Abakaliki. A multistage sampling procedure was used to select the students and the World Health Organization student drug use questionnaire was used to screen respondents for substance abuse. Substance abusers and matched controls (non substance abusers) were assessed for psychosocial dysfunction using the 35-item Pediatric Symptom Checklist (PSC). Socioeconomic classification was done using the parental educational attainment and occupation. RESULTS: Two hundred and four students were abusers of one or more substances. The mean PSC score for substance abusers was 21.96 +/- 10.77 whereas that for controls was 16.07 +/- 8.69 (t = -6.74, P = 0.000). Eighty-nine individuals (43.7%) and 28 controls (13.9%) had PSC scores in the morbidity range of >= 28 for psychosocial dysfunction. This was statistically significant (chi2 = 13.57, P = 0.001). Prevalence of dysfunction was significantly associated with age group, gender, and socioeconomic class in both participants and controls. The prevalence of dysfunction was significantly higher in multiple abusers than the single abusers. CONCLUSION: The prevalence of psychosocial dysfunction is higher in adolescents abusing substance than in controls. Psychosocial dysfunction was however not related to age, gender, or social classes in the study population but was related to the abuse of multiple substances. PMID- 28656920 TI - The prevalence of metabolic syndrome and its components among overweight and obese Nigerian adolescents and young adults. AB - BACKGROUND: The incidence of metabolic syndrome (MetS), is rapidly increasing in developing countries. However, the epidemiology of MetS is not well reported in the pediatric and young adult population. We determined the prevalence of MetS and its components among overweight and obese Nigerian adolescents and young adults presenting for university admission. MATERIALS AND METHODS: A cross sectional study of overweight and obese adolescents and young adults was performed. Blood pressure readings were taken while participants were seated. Anthropometric measures of waist circumference, weight and height were also taken using standard protocols and the body mass index was computed thereafter. Venous blood for fasting plasma glucose, triglycerides and high density lipoprotein cholesterol was collected and assayed using standard laboratory methods. Metabolic syndrome was defined by the International Diabetes Federation criteria. Statistical significance was set at 0.05. RESULTS: 91 individuals (18 males) aged 18.1 +/- 4.85 years were studied. 13 (14.3%) of them had MetS and 11 (84.6%) of these were adolescents. Abdominal obesity was prevalent in 89 (97.8%) participants, hypertension was prevalent in 39 (42.9%) participants and hyperglycaemia was prevalent in 5 (5.5%) participants. Hypertriglyceridaemia was least prevalent in one (1.1%) participant who did not have MetS. All the participants who had hyperglycaemia (5.5%) had MetS. CONCLUSIONS: There is a high prevalence of MetS in obese and overweight Nigerian adolescents and young adults with the clustering of two components in half of the population. These findings have profound implications hence there is an urgent need to institute primary and secondary interventions in this population. PMID- 28656921 TI - A comparative study of ketamine gargle and lidocaine jelly application for the prevention of postoperative throat pain following general anaesthesia with endotracheal intubation. AB - BACKGROUND: Postoperative throat pain is an established complication of general anaesthesia with endotracheal intubation. We thus sought to determine the incidence of postoperative throat pain and the efficacy of lidocaine jelly and ketamine gargle in the prevention of postoperative throat pain. MATERIALS AND METHOD: One hundred and fifty ASA I or II, male: female ratio of 1:2 patients, aged18 -64 year, scheduled for elective general surgery requiring general anaesthesia with endotracheal intubation were randomly recruited into two groups, ketamine (K group) and lidocaine (L group). Group K received ketamine gargle (40 mg in 30 ml normal saline) for 30 sec, five minutes before induction of anaesthesia, while Group L received 2% lidocaine jelly applied to the ETT cuff and 30 ml normal saline was gargled for 30 sec, five minutes before induction of anaesthesia. RESULTS: Postoperative throat pain was defined as pain present with swallowing and it was assessed using verbal rating scale. Time from extubation to onset of postoperative throat pain was significantly longer for patients in K group compared to the lidocaine group, P<0.01. Group L patients recorded a higher occurrence of moderate to severe pain (44.1% vs. 23.5%) as against group K with 58.3% no pain and 36.5% mild pain, P< 0.01. The overall incidence of postoperative throat pain for the study was 55.4%. CONCLUSION: The study demonstrated that ketamine gargle has more protection against moderate to severe postoperative pain as compared to topical lidocaine jelly. Patients undergoing surgery under general anaesthesia with endotracheal intubation will benefit from ketamine gargle five minutes before induction of anaesthesia as prophylaxis against postoperative throat pain. PMID- 28656922 TI - Quantitative evaluation of the enamel caries which were treated with casein phosphopeptide-amorphous calcium fluoride phosphate. AB - OBJECTIVES: The aim of this in vivo study was to quantitatively evaluate the remineralization of the enamel caries on smooth and occlusal surfaces using DIAGNOdent, after daily application of casein phosphopeptide-amorphous calcium fluoride phosphate (CPP-ACFP). MATERIALS AND METHODS: Thirty volunteers, aged 18 30 years, with white spot lesions on the smooth and occlusal surfaces of the teeth were included in the study. These white spot lesions were visually examined and the degree of demineralization was quantitatively evaluated using DIAGNOdent. Volunteers with lesions scored as enamel caries on smooth surfaces (n = 109) and on occlusal surfaces (n = 176) were randomly divided into control and study groups. Both groups were instructed regarding oral hygiene and were asked to brush their teeth with the same tooth paste and tooth brush. In the study group, CPP-ACFP was applied daily for 4 min on the existing enamel caries lesions. After 4 weeks, the mineralization changes in enamel caries on the smooth and occlusal surfaces were assessed by DIAGNOdent. Recorded data were statistically analyzed by Wilcoxon signed-rank test and Mann-Whitney U-test. RESULTS: Comparison of DIAGNOdent values evaluated before and after the application of CPP-ACFP showed that the remineralization of enamel caries lesions on smooth and occlusal surfaces occurred in the study group (both, P < 0.001). The control group showed no quantitative changes at the end of 4 weeks (P > 0.05). At the end of the study period, the DIAGNOdent values differed significantly between the control and study groups (P < 0.001). CONCLUSIONS: Daily local application of CPP-ACFP for 4 min for 4 weeks results in significant remineralization of the initial caries lesions. CLINICAL RELEVANCE: CPP-ACFP can be used in the treatment of white spot lesions. PMID- 28656923 TI - Assessment of gross malnutrition among primary school children using body mass index as an assessment tool in abakaliki metropolis of Ebonyi State, South-East Nigeria. AB - BACKGROUND: Obesity and overweight are emerging major health problems in developing countries in the background of undernutrition. These have been linked to a substantial increase in mortality and morbidity. OBJECTIVES: This cross sectional survey was aimed at determining the prevalence of underweight, overweight, and obesity using body mass index (BMI) in primary school pupils in Abakaliki metropolis of Ebonyi State, south-east Nigeria. METHOD: Eight hundred and four participants aged 6-12 years, from four public and four private primary schools had their weights and heights measured using standard methods. BMI value was calculated for each subject and compared with BMI for age and sex from World Health Organisation (WHO 2007) reference standard. Socioeconomic status was determined using method proposed by Oyedeji. RESULTS: Out of 804 subjects, 426 (53.0%) were from public schools, whereas 378 (47%) were from private schools (P <= 0.01). Four hundred and fifteen (51.6%) were males and 389 (48.4%) were female (P = 0.88). The prevalence of underweight, overweight, and obesity using BMI were 4.5% and 1.2%, 0% in public schools and 1.1%, 5.0%, and 3.0% in private schools, (P < 0.001). The socioeconomic class significantly affected the prevalence of underweight, overweight, and obesity as more subjects with overweight and obesity belonged to upper social class, whereas more underweight subjects belonged to lower social class. CONCLUSION: Overweight and obesity are emerging in a background of undernutrition, showing ''double burden'' of nutritional disorder. PMID- 28656924 TI - Comparison of intracoronal bleaching methods on teeth discolored by different antibiotic pastes. AB - AIM: To compare the bleaching efficacy of sodium perborate with different activation methods on crowns discolored by two different antibiotic pastes. MATERIALS AND METHODS: Eighty-five extracted human incisors were prepared to size #30 using ProTaper rotary instruments. After chemomechanical preparation and irrigation procedures, the specimens received triple antibiotic paste (TAP, n = 40), minocycline paste (MP, n = 40), or calcium hydroxide (n = 5, control group) and coronally sealed with temporary filling material. Spectrophotometric readings were obtained on day 0-week 4. Data were analyzed with the Mann-Whitney U-test and Wilcoxon sign test (P < 0.05). Sodium perborate was then inserted into the pulp chambers of discolored teeth (four subgroups, n = 10) and activated by heat or ultrasonically using two different frequencies and times. Spectrophotometric readings were obtained on days 3-7. Data were analyzed by the Mann-Whitney U-test and Kruskal-Wallis test (P > 0.05). RESULTS: Both groups showed statistically significant coronal discoloration at each time interval (P < 0.01), but their final shades did not significantly differ between the groups (P > 0.05). Although the MP subgroups exhibited more bleaching than the TAP subgroups on days 3 and 7, the difference was not significant (P > 0.05). The bleaching results for the sodium perborate activation techniques did not significantly differ among groups (P > 0.05). CONCLUSIONS: Both antibiotic pastes induced crown discoloration that was reversible using all sodium perborate bleaching techniques. PMID- 28656925 TI - Family planning practices of rural community dwellers in cross River State, Nigeria. AB - BACKGROUND: Nigeria is the most populous nation in Africa and the seventh most populous in the world. Despite a high fertility rate of 5.5 per woman and a high population growth rate of 3.2%, Nigeria's contraceptive prevalence is 15%, which is one of the lowest in the world. The objective of this study was to determine the knowledge of family planning and family planning preferences and practices of rural community women in Cross River State of Nigeria. MATERIALS AND METHODS: This was a cross-sectional study involving 291 rural women. Convenience sampling method was used. The women were assembled in a hall and a semi-structured questionnaire was administered to every consenting woman until the sample size was attained. Data obtained from the study were analyzed using the Statistical Package for the Social Sciences version 20 and presented in tables as frequencies and percentages as well as figures. Association between categorical variables was explored using chi-square test. Binary logistic regression was also performed to determine predictors of use of at least one family planning method at some point in time. RESULTS: Fifty (17.2%) respondents were using at least one family planning method. One hundred and ninety-eight (68.3%) respondents had used at least one family planning method at some point in time. Reasons given for not using any family planning method included "Family planning is against my religious beliefs" (56%); "it is against our culture" (43.8%); "I need more children" (64.9%); "my partner would not agree" (35.3%); "family planning does not work" (42.9%); "it reduces sexual enjoyment" (76%); and "it promotes unfaithfulness/infidelity" (59%). Binary logistic regression conducted to predict the use of at least one family planning method at some point in time using some independent variables showed that who makes the decision regarding family planning use was the strongest predictor of family planning use (OR = 0.567; 95% CI = 0.391-0.821). This suggests that family planning uptake is more likely when couples make a joint decision. CONCLUSION: The proportion of respondents who were currently using at least one family planning method was low. The findings of this study suggest that family planning uptake would increase if couples make joint decisions in this regard. PMID- 28656926 TI - Structural echocardiographic abnormalities seen in HIV/AIDS patients are independent of cd4 count. AB - INTRODUCTION: The human immunodeficiency virus (HIV) infection remains one of the most daunting public health challenges today. Cardiac involvement in HIV/acquired immune deficiency syndrome (AIDS) is frequent and has been recognized on autopsy since the emergence of the pandemic. The objective of the study was to assess the pattern of structural echocardiographic (echo) findings in HIV/AIDS patients and compare this to the echo findings in apparently healthy HIV-negative controls. MATERIALS AND METHODS: One hundred and fifty HIV-positive patients were recruited consecutively from the HIV patients attending the University of Ilorin Teaching Hospital, Ilorin, North Central, Nigeria. One hundred and fifty age- and sex matched controls were also recruited from the surrounding community. All the individuals had clinical examination, electrocardiography (ECG) and echocardiography (echo) done. RESULTS: ECG abnormalities were seen in 55.3% of the HIV-positive patients compared with 2.7% of controls (P < 0.001). The overall prevalence of echo abnormalities among the patients was 54%, against 15.3% (P < 0.001) of the controls. All the structural dimensions of the cardiac chambers were significantly greater than the cardiac chamber dimensions in the controls except for left atrial dimension (LAD). When the patients were considered in two groups of those with CD4 count less than 200 cells/mm3 than those with CD4 count more than 200 cells/mm3, the structural chamber dimensions were similar between both groups. CONCLUSIONS: Echo is an important tool for detecting cardiac abnormalities in HIV/AIDS patients. There is a high prevalence of echo abnormalities among HIV patients seen in our centre. The HIV infection was associated with increased structural dimensions of cardiac chambers compared with HIV-negative controls. This however did not seem to be related to disease severity as the chamber dimensions were similar between those with CD4 count below and above 200 cells/mm3. PMID- 28656927 TI - Evaluation of the frequency and characteristics of hypercementosis in the turkish population with cone-beam computed tomography. AB - AIMS: The aim of this study was to evaluate the frequency and characteristics of hypercementosis in the Turkish population using cone-beam computed tomography (CBCT). SETTINGS AND DESIGN: A retrospective study was performed using CBCT (I CAT Vision TM Imaging Science International) in 1263 patients admitted to the Faculty of Dentistry at the University of Dicle (Diyarbakir, Turkey) between January 2013 and January 2015. SUBJECTS AND METHODS: A total of 1152 patient and 29,606 teeth were evaluated with CBCT. The age, gender, location (left vs. right side, maxillary vs. mandibular teeth, incisors, premolars, and molars), and missing teeth were recorded for all patients. STATISTICAL ANALYSIS USED: The Pearson Chi-squared test was used to determine the potential differences. RESULTS: Hypercementosis was observed with a frequency of 2.4%. Of these, 18 of 28 (64.3%) had only 1 tooth with hypercementosis and 10 (35.7%) had more than 1 tooth. It was identified in 42 of the 29,606 teeth examined (0.14%). The lesion was found in 2.47% (n = 14) of females and 2.38% (n = 14) of males. The lesion was detected in 28 molars and 14 premolars, but hypercementosis was not detected in incisors. Of the 42 teeth, 12 (28.6%) maxillary and 30 (71.4%) mandibular teeth were associated with hypercementosis. Of the 28 cases, 20 (59.0%) were unilateral and 8 (41.0%) were bilateral. Of the 20 unilateral cases, 12 (69.6%) were on the right and 8 (30.4%) were on the left side. CONCLUSIONS: In our study, the prevalence of hypercementosis has been found 2.4% in the Turkish population. Besides, the lesion has been found more in the mandible than the maxilla, in the molars than the premolars and in the unilateral distribution than the bilateral distribution. PMID- 28656928 TI - Dynamic and morphologic evaluation of erectile dysfunction on penile doppler sonography and contrast cavernosography. AB - BACKGROUND: Penile erection is a complex phenomenon that involves coordinated interaction of the psychologic, hormonal, nervous, arterial, venous, and sinusoidal systems. Erectile dysfunction (ED) is the persistent inability to attain or maintain penile erection sufficient for sexual intercourse. This study aims to determine the real-time morphologic vascular abnormalities in men with ED using penile Doppler sonography in Kano, Nigeria. MATERIALS AND METHODS: Twenty one patients who were referred from urology clinics on account of suspected vasculogenic ED were reviewed. The cavernorsal arteries were examined with 7.5 MHz linear transducer in gray scale and duplex Doppler modes before and after intracavernosal injection of 60 mg papevarine. Serial peak systolic velocity (PSV), end diastolic velocity (EDV), and diameter measurements were performed at 5-min intervals for 30 min. RESULTS: The mean age of the patients was 43.14 +/- 9.84 years. Out of the 21 patients examined, 5 showed normal findings while 10 had evidence of venous leakage. Five patients had arterial insufficiency; out of which 3 patients showed calcifications of the tunica albuginea, suggesting Peyronie's disease. Interestingly, 1 patient showed combining features of arterial insufficiency and of venous leakage. Those with arterial insufficiency were relatively older than other patients. They also had compounding medical conditions of diabetes and hypertension. CONCLUSION: Vascular etiologies are important contributors of ED in our setting. Papavarine-induced Doppler sonography and cavernosography shows promise in accurate assessment and overall care of these patients. PMID- 28656929 TI - Effect of Erbium:yttrium aluminum garnet laser on bond strength of a total-etch adhesive system to caries-affected dentin on gingival wall. AB - PURPOSE: To assess the effect of the erbium:yttrium aluminum garnet (Er:YAG) laser on bond strength of a total-etch adhesive system to the caries-affected dentin on the gingival wall. MATERIALS AND METHODS: Ten human molars with proximal carious lesions were randomly divided into two groups. In the first group, the carious dentin was removed with a bur, whereas in the second group it was removed with the Er:YAG laser. Carious lesions were excavated with one of these two techniques until laser fluorescence values decreased to 15 in the center of the lesions. The teeth were then restored with a total-etch adhesive system (Adper Single Bond 2) and composite resin (Filtek Z250). Five teeth from each group were sectioned to obtain 1 mm2 stick-shaped microtensile specimens from each tooth. Twenty-five specimens were obtained for each group with using this technique. The data were analyzed in independent-samples t-test (alpha = 0.05). For each removal technique, one sample was analyzed using scanning electron microscopy. RESULTS: No statistically significant differences were found between the bond strength of the Er:YAG laser and the bur-treated groups (P > 0.05). CONCLUSION: The Er:YAG laser treatment did not negatively affect the bonding performance of the total-etch adhesive system to caries-affected dentin on the gingival wall. PMID- 28656930 TI - A prospective cohort study on the clinical utility of second trimester mean arterial blood pressure in the prediction of late-onset preeclampsia among Nigerian women. AB - BACKGROUND: Early detection of preeclampsia will help reduce the morbidities and mortalities associated with the disorder. Late-onset preeclampsia was the predominant presentation in this cohort. The search for biomarkers for predicting preeclampsia is still ongoing. Mean arterial blood pressure (MABP), which has the advantage of presenting a single cutoff value compared with the use of systolic and diastolic blood pressure measurements, merits evaluation. AIM: The study aims to evaluate the clinical utility of second trimester MABP in the prediction of preeclampsia. METHODS: This was a prospective cohort study of 155 normotensive, nonproteinuric pregnant women without prior history of gestational hypertension. The women were booked patients attending the antenatal clinic at the Lagos University Teaching Hospital and were all in their second trimesters of pregnancy. The outcome measures were systolic blood pressure, diastolic blood pressure, and MABP. The end point of the study was the development of preeclampsia. The diagnosis of preeclampsia was made by the attending obstetrician. The data were analyzed using the IBM SPSS statistical software. Statistical significance was set at P < 0.05. RESULTS: One hundred and fifty-five pregnant women participated in the study. Eleven (7.1%) of the women developed preeclampsia after 34 weeks gestation and 144 (92.9%) had normal pregnancy. The mean gestational age at the time of assessment was 18.88 +/- 3.15 weeks with a range of 14 weeks to 27 completed weeks. There was a statistically significant increase in the systolic blood pressure, diastolic blood pressure, and MABP values in the group of women who later developed preeclampsia, P = 0.005, 0.001, and <0.001, respectively. At a false-positive rate of 10%, MABP value of 88.33 mmHg predicted preeclampsia with a specificity of 90% and a sensitivity of 45.5%, P <0.05. The area under the receiver-operative characteristics curve (AUC) was 0.732 (95% confidence interval, 0.544-0.919, P = 0.011). The negative predictive value (NPV) was 88.88% and the positive predictive value (PPV) was 45.45%, P < 0.05. At an MABP cutoff of 88.33 mmHg, preeclampsia was predicted with a relative risk of 4.44 and a positive likelihood ratio of 6.46, P < 0.05. CONCLUSIONS: With an AUC of 0.732, MABP performed moderately (considering that excellent performance has an AUC of 1.0) in the prediction of late-onset preeclampsia in Nigerian women. Its high NPV suggests a strong ability to rule out preeclampsia and help to appropriate management. PMID- 28656931 TI - Community-Acquired acute kidney injury in critically Ill children as seen in the emergency unit of a tertiary hospital in Enugu, Southeast Nigeria. AB - BACKGROUND: Acute kidney injury (AKI) has been shown to be common in critically ill patients with associated very poor outcome. There is paucity of data regarding its epidemiology, particularly in developing countries. This study aims to assess the presence of AKI among critically ill children to determine its prevalence, outcome, and outcome determinants in children suffering from AKI. PATIENTS AND METHODS: This is a cross-sectional observational study of critically ill children admitted to the children emergency unit of University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu. Critically ill children suffering from AKI were identified and classified using the pediatric RIFLE criteria. RESULT: A total of 300 children were studied. One hundred and eighty (60%) were males. The prevalence of AKI in the study population was 56%. Factors associated with AKI included age <5 years (OR = 3.618; 95% CI = 2.100-6.235; P < 0.001), inability to drink (OR = 2.866; 95% CI = 1.723-4.766; P < 0.001), tachycardia (OR = 2.111; 95% CI = 1.071-4.163; P = 0.031), unconsciousness (OR = 3.128, 95% CI = 1.303-7.511; P = 0.011), and hypotension (OR = 2.619; 95% CI = 1.008-6.804; P = 0.048). The odds of death increased with increasing severity of AKI among those who had pRIFLE-F, who were 24 times more likely to die than those with no AKI (OR = 24.38; 95% CI = 5.702-104.194; P = 0.001). CONCLUSION: The prevalence of AKI in the study population was unacceptably high. The risk factors to its occurrence can be determined from epidemiologic and clinical data, and therefore, clinicians attending to critically ill patients should identify those with AKI for early intervention to reduce the expected poor outcomes associated with its occurrence. PMID- 28656932 TI - Patterns of gestational weight gain and its association with birthweight in Nigeria. AB - BACKGROUND: Despite the increasing global importance of gestational weight gain (GWG) and its impact on birthweight, little is known about the patterns of GWG in African populations. OBJECTIVES: To determine the pattern of GWG and its association with birthweight in Nigeria. METHODS: It was a longitudinal study of 200 pregnant women receiving antenatal care at two tertiary hospitals in Enugu, south eastern Nigeria. The women were consecutively recruited at <14 weeks gestation and their body mass indexes recorded upon recruitment. Thereafter, weight measurements were taken at each visit until 38-39 weeks. RESULTS: Mean total GWG was 10.7 +/- 3.4 kg, while mean birthweight was 3.3 +/- 0.6 kg. GWG in second trimester had positive correlation with birthweight (r = 0.164, P = 0.02). Obese women gained above the recommended limits by the "institute of medicine" while underweight women gained below the limits. Excessive total GWG was associated with higher risk of macrosomia [8/21 (38.1%) vs. 7/179; RR: 9.74; 95% CI: 3.9-24.2; P < 0.001] while inadequate total GWG was associated with higher risk of low birth weight [7/72 (9.7%) vs. 3/128 (2.3%; RR: 4.15; 95% CI: 1.1 15.4; P = 0.03]. Maternal age of <35 years, high social class, nulliparity, and regular antenatal care were associated with normal GWG while maternal age <35 years and regular antenatal care were associated with normal birthweight (P < 0.05). CONCLUSIONS: Women should be counseled on the factors that influence GWG and birthweight. Interventions to assist women achieve appropriate GWG may need to include components related to improved dietary intake for the underweight and increased physical activity for the obese. PMID- 28656933 TI - Efficacy of manual and mechanical instrumentation techniques for removal of overextended root canal filling material. AB - OBJECTIVE: To compare the efficacy of manual and mechanical instrumentation techniques, including ProTaper Universal retreatment system, Mtwo retreatment system, Reciproc system, and Hedstrom files, regarding removal of overextended root canal filling material. MATERIALS AND METHODS: Eighty extracted human mandibular premolar teeth were prepared at the apical foramen level using Revo-S rotary files and subsequently obturated. The root canal filling material was deliberately extruded from the apex. Samples were transferred to glass vials that simulated the periapical area. Eighty samples of overfilled teeth were randomly assigned to four equal groups (n = 20) for removal of the root filling material with ProTaper Universal retreatment files (Group 1), Mtwo retreatment files (Group 2), Reciproc system (Group 3), and hand files (Group 4). Removal of the root canal filling material and additional preparation were performed by individual instruments from each different system up to a #40 size. The external apical surface of the teeth and the surrounding glass vials were checked using a dental operation microscope with *12.5 magnification. Samples were divided into two groups based on whether removal of the overextended root canal filling material was successful or not. The Fisher's exact test was used to detect any significant difference between the groups (alpha = 0.05). RESULTS: The success rate for removal of overextended gutta-percha was greater for the Mtwo (30%) and hand files (30%) compared with the ProTaper (20%) and Reciproc (10%). However, no significant statistical differences existed among the experimental groups (P > 0.05). CONCLUSIONS: This study demonstrated that all tested systems had similar efficacy in removing overextended root canal filling material. PMID- 28656934 TI - Insulin sensitivity and mortality risk estimation in patients with type 2 diabetes mellitus. AB - BACKGROUND: There is at present the dearth of information on the possible contribution of insulin resistance to scores obtained from mortality risk estimation in patients with type 2 diabetes mellitus (T2DM). AIM: This study determined the mortality risk scores in patients with T2DM and its relationship with insulin resistance. METHODS: Fasting plasma glucose, total cholesterol, high density lipoprotein cholesterol (HDL), triglycerides, serum and urinary creatinine, glycated hemoglobin (HbA1c), serum insulin, and urinary albumin were determined in 111 T2DM patients. Thereafter, low-density lipoprotein cholesterol (LDL), quantitative insulin sensitivity check index (QUICKI), urinary albumin-to creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR) were calculated using the standard formula. Mortality risk was estimated using the validated Gargano mortality risk calculator with scores <=0.67, 0.68-0.79, and >=0.80 considered as low, intermediate, and high risks, respectively. RESULTS: Of the total patients, 5 (4.5%), 28 (25.2%), and 78 (70.3%) patients had high, intermediate, and low mortality risk, respectively. There was no difference in the median QUICKI values when the three groups were compared. However, there was a significant elevation in the median eGFR in patients with high mortality risk compared with patients with low and intermediate mortality risks. Also, the median mortality risk score of patients with low insulin sensitivity (QUICKI <=0.3) was similar to that obtained in patients with normal insulin sensitivity (QUICKI >=0.31). No significant correlation was found between QUICKI and mortality risk scores. CONCLUSION: Insulin sensitivity status does not have a direct effect on scores obtained from the Gargano mortality risk prediction model. PMID- 28656935 TI - Hamartomatous polyp of the tonsil: A case report. AB - Hamartomatous polyps of the tonsil are rare. They have been described using various terms such as a lymphangiomatous polyp, lymphangiectatic fibrous polyp, lipomatous polyp, or pedunculated tonsil; hence, the actual incidence is difficult to be quantified. Polyp of the palatine tonsils is an unusual benign lesion of the head and neck. It is a rare polypoidal mass that generally arises from a pedicle attached to the tonsil and projecting into the oropharynx. Polypoid lesions of the head and neck are likewise rare, and such tumors arising from the palatine tonsils are sparse. Tonsillar polyp is an uncommon hamartomatous lesion that generally arises from the tonsillar surface. It has rarely been reported in the medical literature. We present a case of hamartomatous polyp of the palatine tonsil in a 17-year-old male patient. PMID- 28656937 TI - Erratum: Prevalence of depression among health workers in Enugu, South East Nigeria. AB - [This corrects the article DOI: 10.4103/1119-3077.151726.]. PMID- 28656936 TI - Blastic plasmacytoid dendritic cell leukemia in a black malian. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematologic malignancy, that most commonly manifests as cutaneous lesions. A 19-year-old Malian female was admitted to the Unit of Medicine of Hopital du Mali with anemia, fever, weakness, and weight loss. On physical examination she was wasted, pale, febrile (37.4 degrees C), and had inguinal and axillary lymphadenopathies. The complete blood count found pancytopenia with Hemoglobin level of 4.8 g/dL, Leucocytes count of 1900/MUL (neutrophil: 300/MUL), and platelets count of 56 000/MUL. The ultrasonographic examination found hepatomegaly and splenomegaly. The bone marrow biopsy and flow cytometer analysis were in keeping with a diagnosis of BPDCN. The patient, unfortunately, was lost four months later after her hospital admission due to late diagnosis by septicemia. The early diagnosis and availability of specific drugs for acute leukemia could improve the clinical outcome of patients with BPDCN in Mali. PMID- 28656938 TI - Suitability of Root and Rhizome Anatomy for Taxonomic Classification and Reconstruction of Phylogenetic Relationships in the Tribes Cardueae and Cichorieae (Asteraceae). AB - The value of root and rhizome anatomy for the taxonomic characterisation of 59 species classified into 34 genera and 12 subtribes from the Asteraceae tribes Cardueae and Cichorieae was assessed. In addition, the evolutionary history of anatomical characters was reconstructed using a nuclear ribosomal DNA sequence based phylogeny of the Cichorieae. Taxa were selected with a focus on pharmaceutically relevant species. A binary decision tree was constructed and discriminant function analyses were performed to extract taxonomically relevant anatomical characters and to infer the separability of infratribal taxa, respectively. The binary decision tree distinguished 33 species and two subspecies, but only five of the genera (sampled for at least two species) by a unique combination of hierarchically arranged characters. Accessions were discriminated-except for one sample worthy of discussion-according to their subtribal affiliation in the discriminant function analyses (DFA). However, constantly expressed subtribe-specific characters were almost missing and even in combination, did not discriminate the subtribes. Most anatomical characters showed at least some degree of homoplasious evolution limiting their suitability as phylogenetically informative characters. PMID- 28656939 TI - Chitosan-Montmorillonite Polymer Composites: Formulation and Evaluation of Sustained Release Tablets of Aceclofenac. AB - The present study reports the preparation and evaluation of polymer composites of chitosan and montmorillonite. The prepared polymer composites were evaluated for various powder properties and characterized by FTIR-ATR (Fourier Transform Infrared Spectroscopy- Attenuated Total Reflectance), XRD (X Ray Diffraction), and SEM (Scaning Electron Microscopy) techniques. Heckel and Kawakita equations indicated good compression characteristics of the composites. The polymer composites were employed in formulating sustained release tablets of aceclofenac. The formation of intercalated lamellar structures due to the entrapment of clay particles in the polymeric matrix network was found to be responsible for the drug release retardant behavior of the composites. The in vitro drug release data were fitted to various models like zero-order, first-order, Higuchi, Korsmeyer Peppas, and Hixon and Crowell for studying the mechanism of drug release from the formulation. The value of release exponent (n) was found to range between 0.59 and 0.82, indicating non-Fickian (anomalous) drug release behavior. Swelling induced diffusion of the drug through the polymer matrix and polymer matrix chain relaxation appeared to play a role in the release of the drug from the polymer composites. PMID- 28656940 TI - Orphan Drug Pricing: An Original Exponential Model Relating Price to the Number of Patients. AB - In managing drug prices at the national level, orphan drugs represent a special case because the price of these agents is higher than that determined according to value-based principles. A common practice is to set the orphan drug price in an inverse relationship with the number of patients, so that the price increases as the number of patients decreases. Determination of prices in this context generally has a purely empirical nature, but a theoretical basis would be needed. The present paper describes an original exponential model that manages the relationship between price and number of patients for orphan drugs. Three real examples are analysed in detail (eculizumab, bosentan, and a data set of 17 orphan drugs published in 2010). These analyses have been aimed at identifying some objective criteria to rationally inform this relationship between prices and patients and at converting these criteria into explicit quantitative rules. PMID- 28656941 TI - Effect of Aromatic Substitution of Curcumin Nanoformulations on Their Stability. AB - Curcumin, a poorly water-soluble bioactive compound, was successfully loaded into three different aromatic contents of hydroxypropylmethacrylamide (HPMA)-based polymeric micelles in order to develop water-soluble curcumin nanoformulations (Cur-Nano). The stability study of Cur-Nano was done by keeping the formulations at 4, 30, and 40 degrees C for 90 days. The physical appearance, curcumin remaining, and particle size of Cur-Nano were examined by visual inspection, high performance liquid chromatography, and dynamic light scattering, respectively. After the storage period, the Cur-Nano composed of 100% aromatic-substituted polymer exhibited the highest stability of curcumin (80% of curcumin remaining) with a similar particle size as measured on the first day (50-60 nm) in all storage conditions. Curcumin in Cur-Nano composed of 25% and 0% aromatic substituted polymer was significantly less stable accordingly. The results suggested that aromatic substitution to HPMA-based polymeric micelles can significantly enhance the stability of the loaded curcumin, considerably due to the pi-pi stacking interactions between the aromatic groups of curcumin and the polymer. It is concluded that curcumin-loaded polymeric micelles with high substituted aromatic content can be promising candidates with good storage stability for further clinical evaluations. PMID- 28656942 TI - Formulation, Characterisation, and in Vitro Skin Diffusion of Nanostructured Lipid Carriers for Deoxyarbutin Compared to a Nanoemulsion and Conventional Cream. AB - The long-term use of topical hydroquinone as an anti-hyperpigmentation treatment has well-known, unwanted effects. Deoxyarbutin (4-[(tetrahydro-2H-pyran-2 yl)oxy]phenol) is a relatively new tyrosinase inhibitor, with stronger inhibitory potency than hydroquinone, that exhibited decreased cytotoxicity against melanocytes and other cells. This study developed novel nanostructured lipid carriers (NLCs) for improved topical delivery of deoxyarbutin (dArb), leading to improved depigmenting efficacy. dArb is a hydrophobic substance, but it easily degrades in aqueous medium and is thermolabile. Screening and optimisation of the solid lipid, liquid lipid, surfactant, co-surfactant and production methods were performed to choose the optimum particle size and stability for NLCs. One percent dArb NLCs were obtained from a combination of cetyl palmitate (CP) and caprylic/capric tryglicerides (Myr) in 12% total lipids using poloxamer 188 (P 188) and polyethylene glycol (PEG) 400 as a surfactant and co-surfactant, respectively, with a particle diameter of approximately 500 nm and a polydispersity index (PI) <0.4. These NLCs were produced using the simple method of high-shear homogenisation (10,000 rpm, 5 minutes) and ultrasonication (3.5 min). The compatibility between the substances in the formula was evaluated using Fourier Transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The morphology of the NLCs was observed using transmission electron microscopy (TEM). In vitro penetration of dArb NLCs was evaluated and compared to the nanoemulsion (NE) and conventional emulsion (CR) delivery methods across Spangler's membrane (SS). Delivery improvement was clearly observed, and after 8 h of application, dArb gel-NLCs showed the highest dArb penetration, followed by liquid NLCs, NE, and CR. PMID- 28656945 TI - [Forensic medical expertise in the cases of neglect of the exigencies of the juveniles]. AB - The objective of the present study was the development of the method and the criteria to be used for forensic medical diagnostics of the constituent elements of neglect of the exigencies (abandonment) of the juveniles. The work was focused on the consideration of the performance of expert examination of one of the most widespread forms of the child abuse, such as neglect of the exigencies of the juveniles. We undertook the analysis of the causes underlying the emergence of the difficulties that tend to hamper the conduction of expert examination of the cases of neglect of the exigencies of the juveniles with special reference to the judicial qualification of such wrongdoings. The physical development, neuro psychic health status, and general morbidity of the children whose legitimate representatives are charged with neglect of their requirements in accordance with article 156 of the Criminal Code of the Russian Federation have been considered for the first time. The analysis revealed the factors responsible for the negative effects on the juvenile health status associated with the criminal failure of the aforementioned legitimate representatives to act for the sake of the children's health and guidance as envisaged by law. PMID- 28656946 TI - [The possibilities for determining the shooting distance by means of inductively coupled plasma optical emission spectrometry]. AB - The objective of the present study was to evaluate the possibilities for determining the shooting distance for the MR-79-9 Makarych non-lethal pistol (diameter 9 mm, rubber bullet, shot energy 50 J) by means of inductively coupled plasma optical emission spectrometry. The experiments were carried under the conditions of a ballistic shooting range making the shots from a distance of 0 to 120 cm. The 15*15 cm pieces of muslin fabric and biomaterials (leather) were used as the targets. The morphological signs of the damages inflicted to the targets were evaluated either with the unassisted eye, a criminalistical magnifying glass or the SMT-4 binocular stereoscopic microscope (Germany). The shot products, the area and boundaries of their dispersion were determined in reflected IR and filtered UV rays. Inductively coupled plasma optical emission spectrometry was applied for the qualitative and quantitative analysis of various shot products from the entry hole zone with the contamination (wipedown) bands and contusion collars being 0.2-0.5 cm (group 1) and 2-3 cm (group 2) in width, with special reference to the identification of Ba, Cu, Cr, Fe, K, Ni, Pb, Sb, Sn and Zn. The results of the study give evidence that the detection of Ba, Pb, and Sb among the products of a shot fired from the MR-79-9 Makarych non-lethal pistol is of especially high informative value for determining the shooting distance whereas the detection of Cr, K, Sn and Ni is of a minimum value for this purpose. PMID- 28656947 TI - [The significance of the results of crash-tests with the use of the models of the pedestrians' lower extremities for the prevention of the traffic road accidents]. AB - The disabling injuries inflicted during road traffic accidents (RTA) create a serious challenge for the public health services and are at the same time a major socio-economic problem in the majority of the countries throughout the world. The injuries to the lower extremities of the pedestrians make up the largest fraction of the total number of the non-lethal RTA injuries. Most of them are responsible for the considerable deterioration of the quality of life for the participants in the accidents during the subsequent period. The objective of the present study was to summarize the currently available results of experimental testing of the biomechanical models of the pedestrians' lower extremities in the framework of the program for the prevention of the road traffic accidents as proposed by the World Health Organization (WHO, 2004). The European Enhanced Safety Vehicle Committee (EEVC) has developed a series of crash-tests with the use of the models of the pedestrians' lower extremities simulating the vehicle bumper-pedestrian impact. The models are intended for the assessment of the risk of the tibia fractures and the injuries to the knee joint ligaments. The experts of EEVC proposed the biomechanical criteria for the acceleration of the knee and talocrural parts of the lower limbs as well as for the shear displacement of the knee and knee-bending angle. The engineering solution of this problem is based on numerous innovation proposals being implemented in the machine-building industry with the purpose of reducing the stiffness of structural elements of the bumper and other front components of a modern vehicle designed to protect the pedestrians from severe injuries that can be inflicted in the road traffic accidents. The activities of the public health authorities (in the first place, bureaus of forensic medical expertise and analogous facilities) have a direct bearing on the solution of the problem of control of road traffic injuries because they are possessed of comprehensive and reliable objective information about all forms of the damage to health associated with vehicle-pedestrian collisions and their victims' condition. It is concluded that making use of the experience and professional knowledge of forensic medical experts and automotive specialists could considerably contribute to the enhancement of safety of all the participants in the vehicular traffic. PMID- 28656948 TI - [The changes in the temperature of a corpse in the course of its decomposition (an experimental study)]. AB - The objective of the present work was to study dynamics of the temperature of a corpse of an experimental animal (a pig) between the moment of death till complete skeletization, The porcine corpse weighing approximately 100 kg was placed in the bilberry spruce forest in the southern part of the Karelian Republic. Variations in the temperature of the corpse were measured with the use of the EClrerk-USB-2Pt logger (an autonomous register of temperature) along with those of the environmental (the air and the soil) temperature during 86 days in the period from June till September. It was shown that the temperature of the corpse first decreased but began to increase thereafter due to the enhancement of the biological activity of microorganisms. It is concluded that putrefactive decomposition of the corpse does not always suggest the necessity to discontinue the measurement of its temperature. The forensic medical examination of a corrupted corpse should take into consideration the possibility of an increase of its temperature in the course of time because it may be a source of a mistake when estimating prescription of death coming. The problem of postmortem rise in the temperature of a corpse undergoing putrefactive decomposition needs a thorough theoretical interpretation with a view to promoting the practical application of the proposed method with due regard for the difference in the environmental conditions in various climatographical regions of the Russian Federation. PMID- 28656949 TI - [The peculiar features of the morphological manifestations of the damage to the liver associated with the death cap mushroom poisoning]. AB - This article is focused on the peculiar features of the morphological manifestations of massive hepatic necrosis associated with the death cap mushroom (Amanita phalloides) poisoning in comparison with similar cases of intoxication. It has been shown that the poisoning is associated with cell proliferation in the peri-portal regions of the liver and induction of the mechanisms of apoptosis responsible for the death of hepatocytes. PMID- 28656950 TI - [The determination of pyrovaleron in the urine by gas chromatography in the combination with the method of extractive chilling-out and centrifugation]. AB - The express-method for the determination of pyrovaleron in the urine based on the combination with the method of extractive freezing-out and centrifugation of the samples as the preliminary stage of the preparation of a biological object for the analysis. The identification and quantitative determination of the substance of interest were performed using gas chromatography with nitrogen-selective detection. The preparation of the samples was carried out as a single-step procedure no longer than 30 min in duration. The limit of alpha-pyrovaleron detection in the urine was estimated at 1 mcg/ml. Its concentration after extraction from the urine increased by a factor of more than nine. PMID- 28656951 TI - [The peculiar features of the sidewise collision involving a pedestrian and an automobile moving in the reverse gear along an arc of a circle]. AB - This article was designed to report the results of the analysis of the consequences of a real case of the sidewise collision and run-over involving a pedestrian and an automobile moving in the reverse gear along an arc of a circle. Special attention was given to the mechanism behind the collision, its peculiar features, and characteristic damages inflicted to the pedestrian's body and clothes. PMID- 28656952 TI - [The clinical and expert evaluation of the unfavourable consequences of the provision of the dental implantation treatment]. AB - The clinical and expert evaluation of the unfavourable consequences of the provision of the inadequate dental implantation treatment has demonstrated the ever increasing number of justified complaints and civilian lawsuits instituted annually in connection with the infringements of health associated with the poor quality of the medical care provided to the patients. The authors present the results of commission forensic medical expertise performed on account of the civilian lawsuits instituted by a 74 year-old patient K. against a private stomatological polyclinic. It was shown that the medical personnel of the polyclinic disregarded the objective contraindications for the surgical treatment of the patient on the day of her application for the medical assistance. It is concluded that the advanced age of the patient and well apparent atrophy of the alveolar part of the lower jaw required preliminary substantiation of the necessity of the surgical intervention. However, the diagnostic and treatment errors in the form of incomprehensive examination and the application of the inadequate implantation technique resulted in postoperative complications including severe disturbances of the masticatory function and painful sensations. The commission forensic medical expertise reported in the present article has failed to reveal any objective factors that might have been responsible for the above diagnostic and treatment errors and established the immediate cause-and effect relationship between them and the resultant unfavourable consequences of the treatment. The opinion of the commission was recognized to be well substantiated by the court and provided a basis for the judicial judgement in favour of patient K. PMID- 28656953 TI - [The infarction or the traumatic rupture of the spleen?] AB - The clinical observation reported in the present article is of special interest for the forensic medical experts taking into consideration the rare occurrence of infarction of the spleen in the medical legal practice. More comprehensive detailed information about such cases is needed for their thorough in-depth investigation and systematization of the differential diagnostic signs and clinical manifestations of the injury (rupture of the spleen) and pathology of the organ (infarction) for the purpose of the more reliable differentiation between these conditions, creation of the relevant diagnostic database, formulation of more conclusive recommendations, and their better substantiation. PMID- 28656954 TI - [The forensic medical assessment of the causes and conditions of the formation of the chilling injury]. AB - The authors present the data of the literature publications and theoretical considerations concerning the causes and conditions behind the formation of the chilling injury. It is demonstrated that the chilling injury develops as a consequence of a disturbance in the relationship between the hypothermic protection of the organism and the cooling potential of its environment. The thermal balance of the human organism depends not only on the natural mechanisms of physical and chemical thermoregulation but also on the character of artificial thermoregulation including the man-made means of cold protection. The critical evaluation of all the available data on chilling injuries to the human body gave evidence that the causes and conditions of their development can be highly multivarious which does not however exclude the possibility of their systematization. PMID- 28656955 TI - [MRI diagnostics of bone marrow oedema and its significance for the forensic medical evaluation of the injuries to bones and articulations]. AB - The objective of the present study was the analysis of the publications in the literature dealing with radiological methods employed for the diagnostics of injuries to and diseases of the bones and articulations as well as the role of bone marrow oedema in the development of these conditions in the specific context of the problems facing forensic medical expertise. The main results of the domestic and foreign authors concerning MRI-based investigations into the nature of injuries and other pathological changes in bones and articulations during different periods after their development are discussed with the major emphasis placed on diagnostics of bone marrow oedema. Magnetic resonance visualization of this diagnostic feature and the related manifestations of the above conditions in many cases provides an indisputable evidence of the damage whereas the discovery of its distribution to and localization in the bone structures makes it possible to elucidate the sources of this condition, such as a blow, torsional stress, stretching, etc., and its underlying mechanisms. The character and the mode of distribution of the signal from a bone marrow oedema under various conditions of visualization allow to carry out differential diagnostics of the damage prescription period of up to 1.5 months. PMID- 28656956 TI - [The coroner's autopsies in the Great Britain: the problems related to the quality of the studies, standardization, auditing, financial support and the approaches to their solution]. AB - The objective of the present study was to analyze the experience of the coroners and pathologists in the Great Britain based on the results of the coroner's autopsies and recommendations of the experts involved in the activities carried out in the framework of the National Confidential Enquiry into Patient Outcome and Death program (NCEPOD). The recommendations are designed to reform the country's medical examiner system, improve the equipment of the mortuary facilities, and optimize funding for the autopsy studies. The authors consider in the chronological order the following issues of the coroners and pathologists' activities: organization of their work and its procedural aspects, ordering coroner's autopsies, preparation for their performance, analysis of the relevant documentation (autopsy reports) and medical case histories (discharge summaries). Also discussed are the recommendations of the NCEPOD experts for the improvement of the said studies with the detailed analysis of the causes underlying the aforementioned problems and concise comments of the authors. PMID- 28656957 TI - [The contribution of E.O. Mukhin to the development of forensic medicine in Russia during the first half of the XIXth century (on the occasion of his 250th birthday anniversary)]. AB - Efrem Osipovich Mukhin, actual state councilor, was a known surgeon, anatomist, physiologist, toxicologist, and hygienist. He is honoured as one of the founders of the Russian school of forensic medical expertise and traumatology. During 22 years, E.O. Mukhin headed the Department of Anatomy, Physiology and Forensic Medicine at the Moscow Imperial University where he taught forensic medicine, anatomy, physiology, toxicology, and medical police. He was the first Russian scientist to develop the fundamentals of reflexology and most comprehensively present the problem of integration of the organism and its environment. E.O. Mukhin is considered to be the initiator of anatomo-physiological research in medicine. PMID- 28656958 TI - Virus-host relationships of marine single-celled eukaryotes resolved from metatranscriptomics. AB - Establishing virus-host relationships has historically relied on culture dependent approaches. Here we report on the use of marine metatranscriptomics to probe virus-host relationships. Statistical co-occurrence analyses of dsDNA, ssRNA and dsRNA viral markers of polyadenylation-selected RNA sequences from microbial communities dominated by Aureococcus anophagefferens (Quantuck Bay, NY), and diatoms (Narragansett Bay, RI) show active infections by diverse giant viruses (NCLDVs) associated with algal and nonalgal hosts. Ongoing infections of A. anophagefferens by a known Mimiviridae (AaV) occur during bloom peak and decline. Bloom decline is also accompanied by increased activity of viruses other than AaV, including (+) ssRNA viruses. In Narragansett Bay, increased temporal resolution reveals active NCLDVs with both 'boom-and-bust' and 'steady-state infection'-like ecologies that include known as well as novel virus-host interactions. Our approach offers a method for screening active viral infections and develops links between viruses and their potential hosts in situ. Our observations further demonstrate that previously unknown virus-host relationships in marine systems are abundant. PMID- 28656959 TI - Do we need to distinguish exosomes from microvesicles in hematological malignancies? PMID- 28656960 TI - Ensemble-averaged Rabi oscillations in a ferromagnetic CoFeB film. AB - Rabi oscillations describe the process whereby electromagnetic radiation interacts coherently with spin states in a non-equilibrium interaction. To date, Rabi oscillations have not been studied in one of the most common spin ensembles in nature: spins in ferromagnets. Here, using a combination of femtosecond laser pulses and microwave excitations, we report the classical analogue of Rabi oscillations in ensemble-averaged spins of a ferromagnet. The microwave stimuli are shown to extend the coherence-time resulting in resonant spin amplification. The results we present in a dense magnetic system are qualitatively similar to those reported previously in semiconductors which have five orders of magnitude fewer spins and which require resonant optical excitations to spin-polarize the ensemble. Our study is a step towards connecting concepts used in quantum processing with spin-transport effects in ferromagnets. For example, coherent control may become possible without the complications of driving an electromagnetic field but rather by using spin-polarized currents. PMID- 28656961 TI - Neutral and charged inter-valley biexcitons in monolayer MoSe2. AB - In atomically thin transition metal dichalcogenides (TMDs), reduced dielectric screening of the Coulomb interaction leads to strongly correlated many-body states, including excitons and trions, that dominate the optical properties. Higher-order states, such as bound biexcitons, are possible but are difficult to identify unambiguously using linear optical spectroscopy methods. Here, we implement polarization-resolved two-dimensional coherent spectroscopy (2DCS) to unravel the complex optical response of monolayer MoSe2 and identify multiple higher-order correlated states. Decisive signatures of neutral and charged inter valley biexcitons appear in cross-polarized two-dimensional spectra as distinct resonances with respective ~20 and ~5 meV binding energies-similar to recent calculations using variational and Monte Carlo methods. A theoretical model considering the valley-dependent optical selection rules reveals the quantum pathways that give rise to these states. Inter-valley biexcitons identified here, comprising of neutral and charged excitons from different valleys, offer new opportunities for developing ultrathin biexciton lasers and polarization entangled photon sources. PMID- 28656963 TI - Critical mingling and universal correlations in model binary active liquids. AB - Ensembles of driven or motile bodies moving along opposite directions are generically reported to self-organize into strongly anisotropic lanes. Here, building on a minimal model of self-propelled bodies targeting opposite directions, we first evidence a critical phase transition between a mingled state and a phase-separated lane state specific to active particles. We then demonstrate that the mingled state displays algebraic structural correlations also found in driven binary mixtures. Finally, constructing a hydrodynamic theory, we single out the physical mechanisms responsible for these universal long-range correlations typical of ensembles of oppositely moving bodies. PMID- 28656962 TI - Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein. AB - Germline mutations in the Folliculin (FLCN) tumour suppressor gene result in fibrofolliculomas, lung cysts and renal cancers, but the precise mechanisms of tumour suppression by FLCN remain elusive. Here we identify Rab7A, a small GTPase important for endocytic trafficking, as a novel FLCN interacting protein and demonstrate that FLCN acts as a Rab7A GTPase-activating protein. FLCN-/- cells display slower trafficking of epidermal growth factor receptors (EGFR) from early to late endosomes and enhanced activation of EGFR signalling upon ligand stimulation. Reintroduction of wild-type FLCN, but not tumour-associated FLCN mutants, suppresses EGFR signalling in a Rab7A-dependent manner. EGFR signalling is elevated in FLCN-/- tumours and the EGFR inhibitor afatinib suppresses the growth of human FLCN-/- cells as tumour xenografts. The functional interaction between FLCN and Rab7A appears conserved across species. Our work highlights a mechanism explaining, at least in part, the tumour suppressor function of FLCN. PMID- 28656965 TI - Exsolution trends and co-segregation aspects of self-grown catalyst nanoparticles in perovskites. AB - In perovskites, exsolution of transition metals has been proposed as a smart catalyst design for energy applications. Although there exist transition metals with superior catalytic activity, they are limited by their ability to exsolve under a reducing environment. When a doping element is present in the perovskite, it is often observed that the surface segregation of the doping element is changed by oxygen vacancies. However, the mechanism of co-segregation of doping element with oxygen vacancies is still an open question. Here we report trends in the exsolution of transition metal (Mn, Co, Ni and Fe) on the PrBaMn2O5+delta layered perovskite oxide related to the co-segregation energy. Transmission electron microscopic observations show that easily reducible cations (Mn, Co and Ni) are exsolved from the perovskite depending on the transition metal-perovskite reducibility. In addition, using density functional calculations we reveal that co-segregation of B-site dopant and oxygen vacancies plays a central role in the exsolution. PMID- 28656964 TI - IL-33 promotes gastrointestinal allergy in a TSLP-independent manner. AB - Atopic dermatitis (AD) often precedes asthma and food allergy, indicating that epicutaneous sensitization to allergens may be important in the induction of allergic responses at other barrier surfaces. Thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 are two cytokines that may drive type 2 responses in the skin; both are potential targets in the treatment of allergic diseases. We tested the functional role of IL-33 and the interplay between IL-33 and TSLP in mouse models of atopic march and gastrointestinal (GI) allergy. IL-33-driven allergic disease occurred in a TSLP-independent manner. In contrast, mice lacking IL-33 signaling were protected from onset of allergic diarrhea in TSLP-driven disease. Epithelial-derived IL-33 was important in this model, as specific loss of IL-33 expression in the epithelium attenuated cutaneous inflammation. Notably, the development of diarrhea following sensitization with TLSP plus antigen was ameliorated even when IL-33 was blocked after sensitization. Thus, IL-33 has an important role during early cutaneous inflammation and during challenge. These data reveal critical roles for IL-33 in the "atopic march" that leads from AD to GI allergy. PMID- 28656966 TI - E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. AB - Optimal regulation of the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is essential for controlling bacterial infections and inflammatory disorders. Chronic NOD2 stimulation induces non-responsiveness to restimulation, termed NOD2-induced tolerance. Although the levels of the NOD2 adaptor, RIP2, are reported to regulate both acute and chronic NOD2 signalling, how RIP2 levels are modulated is unclear. Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation. A fraction of RIP2 localizes to the endoplasmic reticulum (ER), where it interacts with ZNRF4 under either 55 unstimulated and muramyl dipeptide-stimulated conditions. Znrf4 knockdown monocytes have sustained nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB) activation, and Znrf4 knockdown mice have reduced NOD2-induced tolerance and more effective control of Listeria monocytogenes infection. Our results thus demonstrate E3-ubiquitin ligase ZNRF4 mediated RIP2 degradation as a negative regulatory mechanism of NOD2-induced NF kappaB, cytokine and anti-bacterial responses in vitro and in vivo, and identify a ZNRF4-RIP2 axis of fine-tuning NOD2 signalling to promote protective host immunity. PMID- 28656967 TI - Low appendicular muscle mass is associated with mortality in peritoneal dialysis patients: a single-center cohort study. AB - BACKGROUND/OBJECTIVES: There are few studies of the association between low appendicular muscle mass (LAM) and clinical outcomes in peritoneal dialysis (PD) patients. We aimed to determine the clinical association between LAM and clinical outcomes in PD patients. SUBJECT/METHODS: We reviewed all PD patients who underwent PD between January 2001 and April 2014. Each patient's appendicular lean mass was estimated using dual-energy X-ray absorptiometry. The appendicular muscle mass index (AMI) was calculated using total appendicular lean mass (kg) over body mass index (kg/m2). The cut-off AMI value for LAM was <0.789 for men and <0.512 for women. RESULTS: The number of patients in the Non-LAM and LAM groups was 328 and 303, respectively. The median follow-up durations in the Non LAM and LAM groups were 47 and 49 months, respectively. The numbers of deaths in the Non-LAM and LAM groups were 96 (29.3%) and 160 (52.8%), respectively. In a comparison with the Non-LAM group, the hazard ratio in the LAM group was 1.74 (95% confidence interval (CI), 1.35-2.24) in univariate and 1.71 (95% CI, 1.28 2.26) in multivariate Cox regression analysis. In addition, the hazard ratio for a 0.1 increase in baseline AMI was 0.89 (95% CI, 0.84-0.95) in univariate analysis and 0.84 (95% CI, 0.76-0.91) in multivariate analysis. Analyses using the 1-year AMI showed trends similar to those for the initial AMI. CONCLUSIONS: Our study showed the association of LAM with mortality in the incident PD patients. PMID- 28656968 TI - Nutrient intake and contribution of home enteral nutrition to meeting nutritional requirements after oesophagectomy and total gastrectomy. AB - BACKGROUND/OBJECTIVES: This study evaluated nutrition after oesophago-gastric resection and the influence of home jejunostomy feeding in the six months after surgery. SUBJECTS/METHODS: Data on nutritional intake and physiologic measures were collected as part of a randomised trial with measurements taken before and up to six months after surgery. RESULTS: A total of 41 participants (32 oesophagectomy, 9 total gastrectomy) received home jejunostomy feeding (n=18) or usual care without feeding (n=23). At hospital discharge, oral intakes were adequate for energy and protein in 9% and 6%, respectively. By three and six months, these values had increased to 61% and 55%, 94% and 77% respectively. Six participants (26%) who received usual care required rescue feeding. Six weeks after hospital discharge, energy intakes were met in those who received jejunal feeding because of the contribution of enteral nutrition. Jejunal feeding did not affect oral intake, being similar in both groups (fed: 77% estimated need, usual care: 79%). At three months, inadequate micronutrient intakes were seen in over one third. Compared to baseline values, six weeks after surgery, weight loss exceeding 5% was seen in 5/18 (28%) who received feeding, 14/17 (82%) who received usual care and 5/6 (83%) of those who required rescue feeding, P=0.002. Weight loss averaged 4.1% (fed), 10.4% (usual care) and 9.2% (rescue fed), P=0.004. These trends persisted out to six months. CONCLUSIONS: Supplementary jejunostomy feeding made an important contribution to meeting nutrition after oesophago-gastric resection. Importantly, oral nutritional intake was not compromised dispelling the assertion that jejunal feeding deincentivises patients from eating. PMID- 28656969 TI - Breastfeeding trends in healthy infants since 1990-results of the DONALD study. AB - Exclusive breastfeeding is recommended for infants during the first 6 months of life. The aim of this analysis was to examine time trends in breastfeeding between 1990 and 2013 in Germany using data from the DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) Study. Although partial breastfeeding was observed to constantly increase over time in both 3-month and 6-month-old infants, fully breastfeeding rates did not further increase in 3-month-old infants since 2002, and even showed a tendency to decrease in 6-month-old infants. In conclusion, this finding emphasises the need for improvements in breastfeeding promotion in Germany, which currently seems to be ineffective in case of continuation of full breastfeeding until the age of 6 months. PMID- 28656970 TI - Association studies of genetic scores of serum vitamin B12 and folate levels with symptoms of depression and anxiety in two danish population studies. AB - BACKGROUND/OBJECTIVES: Observational studies have suggested low serum levels of vitamin B12 or folate to be risk factors of depression and anxiety. However, these results may be biased by confounding and reverse causation. Mendelian randomization studies are not subject to these limitations. The aim was to examine the association of genetic scores of vitamin B12 and folate-associated alleles with depression and anxiety. SUBJECTS/METHODS: The study included 4126 participants from two Danish population-based studies. Serum vitamin B12 and folate were measured. Weighed allele scores were calculated as the sum of weights (genetic effect sizes) for 12 and two variants increasing circulating levels of vitamin B12 and folate, respectively. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety. RESULTS: An increased weighed allele score for serum vitamin B12 was associated with decreased odds of a SCL-90-R score above the 90th percentile (OR 0.540 (95%CI 0.302-0.967)) in Health2006 but not in Inter99, in the pooled analysis (OR 0.817 (95%CI 0.331-2.018)) or with other outcomes. The weighed allele score for serum folate was not associated with any of the measured outcome variables: SCL-90-R scores of depression (pooled OR 0.603 (95%CI 0.101 3.602)), anxiety (pooled OR 0.619 (95%CI 0.110-3.495)), combined score or history of doctor-diagnosed depression or anxiety. CONCLUSION: Our results do not provide evidence for a causal effect of circulating folate or vitamin B12 on the risk of depression or anxiety. However, we cannot rule out small to moderate effects, and thus large scale studies are needed. PMID- 28656971 TI - Dietary patterns, cost and compliance with low-protein diet of phenylketonuria and other inherited metabolic diseases. AB - BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) and several other inherited metabolic diseases (IMD) require a lifelong low-protein diet (LPD), otherwise they lead to many health complications. LPDs, however, carry a significant economic burden for patients and their families. The objective of this study was to explore the costs of low-protein foods (LPFs) necessary for LPD as well as dietary patterns and compliance towards an LPD. SUBJECTS/METHODS: A detailed questionnaire was created in cooperation with National Association of PKU and other IMD (NSPKU), and consequently sent to all NSPKU members treated with an LPD (n=303). A total of 184 respondents from the Czech Republic were included in the study (174 had PKU, 10 had other IMD). RESULTS: The average daily consumption of LPF was equal to 411.7 g (PKU) and 345.6 g (other IMD), which corresponds to energy value of 5558 kJ and 4438 kJ, respectively, per patient per day. Patients mostly consumed low-protein flour (~30% of energy intake), pasta (~18%), basic pastry (~15%) and sweets (~10%). The average monthly costs of LPDs were equal to [euro ]130 (PKU) and [euro ]129 (other IMD) per patient per month. The compliance with LPD was decreasing with increasing age (P<0.0001). CONCLUSIONS: This is the largest study examining costs and dietary patterns of LPDs in patients with PKU and the first study of this kind in other IMD patients requiring an LPD. The study clearly showed that an LPD carries a very high economic burden for families, which may lead to less LPD compliance and potential severe health consequences. PMID- 28656972 TI - Analytical shortcomings and other considerations related to the identification of biomarkers of dairy fat intake. PMID- 28656973 TI - Body composition assessment of Crohn's outpatients and comparison with gender- and age-specific multiple matched control pairs. AB - BACKGROUND/OBJECTIVES: Routine clinical care for Crohn's disease (CD) outpatients does not cover the assessment of body composition (BC); although this disease (because of inflammation, surgeries, lack of physical activity and appetite) may have a severe impact on lean body mass. The main aims of this prospective research were to assess the nutritional status of the patients and to compare their data with apparently healthy gender- and age-specific matched control pairs. SUBJECTS/METHODS: Overall, 136 CD patients and 1752 apparently healthy people were involved in the study. All participants were measured by the same bioelectrical impedance analyser. RESULTS: Using body mass index (BMI) and fat free mass index (FFMI) as the markers of nutritional status, we found low BMI for 21% of the patients and low FFMI for 30% of them. Low BMI values were not gender specific, but substantially more females had low FFMI values. Low BMI was diagnosed in the patients' vs the control group for 21 vs 4% for men and 21 vs 2% for women; whereas low FFMI was diagnosed for 25 vs 5% for men and 36 vs 14% for women. Significant differences were found between patients' and control groups (median BMI: 22.0 vs 25.1 kg/m2, P<0.0001; FFMI: 17.3 vs 18.4 kg/m2, P=0.0044). CONCLUSIONS: This study confirmed the higher prevalence of low FFMI than that of low BMI among the subjects. We recommend implementing the assessment of BC into routine clinical care to diagnose low FFMI and to start intervention in time. PMID- 28656974 TI - Leisure time sedentary behavior, physical activity and frequency of protein consumption on lower extremity strength and lean mass. AB - BACKGROUND/OBJECTIVES: The purpose of this study was to evaluate the independent and combined associations of moderate-to-vigorous physical activity (MVPA), leisure time sedentary behavior and daily protein consumption on lower extremity muscular strength and lean mass. SUBJECTS/METHODS: Data from the 1999-2002 NHANES were utilized (N=1080 adults 50-85 y). Leg lean mass was estimated from dual energy x-ray absorptiometry scans. Knee extensor strength was assessed objectively using the Kin Com MP dynamometer. MVPA and leisure time sedentary behavior were assessed via questionnaire, with the number of meals per day of ?30 g of protein per meal assessed via a 'multiple pass' 24-h dietary interview. RESULTS: Meeting MVPA guidelines (beta=16.3, P=0.02) and consuming at least two meals per day of ?30 g of protein per meal (beta=28.8, P=0.02) were independently associated with greater lower extremity strength, whereas sedentary behavior was not (beta=11.6, P=0.23). Finally, there was no evidence of a three-way interaction of these behaviors on lower extremity strength (beta=-8.7; P=0.70) or lower extremity lean mass (beta=144.5; P=0.75). CONCLUSIONS: Although MVPA and frequency of protein consumption of ?30 g of protein per meal were independently associated with lower extremity lean mass and strength, the results of the present study do not provide evidence to suggest that there is a three-way interplay between MVPA, sedentary behavior and frequency of protein consumption ?30 g of protein per meal on lower extremity lean mass and strength. PMID- 28656975 TI - Light controlled 3D micromotors powered by bacteria. AB - Self-propelled bacteria can be integrated into synthetic micromachines and act as biological propellers. So far, proposed designs suffer from low reproducibility, large noise levels or lack of tunability. Here we demonstrate that fast, reliable and tunable bio-hybrid micromotors can be obtained by the self-assembly of synthetic structures with genetically engineered biological propellers. The synthetic components consist of 3D interconnected structures having a rotating unit that can capture individual bacteria into an array of microchambers so that cells contribute maximally to the applied torque. Bacterial cells are smooth swimmers expressing a light-driven proton pump that allows to optically control their swimming speed. Using a spatial light modulator, we can address individual motors with tunable light intensities allowing the dynamic control of their rotational speeds. Applying a real-time feedback control loop, we can also command a set of micromotors to rotate in unison with a prescribed angular speed. PMID- 28656976 TI - Pituitary Adenylate Cyclase-Activating Peptide in the Bed Nucleus of the Stria Terminalis Mediates Stress-Induced Reinstatement of Cocaine Seeking in Rats. AB - Stressors often contribute to difficulties in maintaining behavior change following a period of abstinence, and may play a significant role in drug relapse. The activation of pituitary adenylate cyclase-activating peptide (PACAP) systems in the bed nucleus of the stria terminalis (BNST) mediates many consequences of chronic stressor exposure. Here we ask whether PACAP is also involved in producing reinstatement in a model of stress-induced relapse to drug taking. Rats self-administered cocaine for 1 h daily over 10 days that was followed by 20 days of extinction training in which lever pressing no longer produced cocaine. In experiment 1, quantitative PCR (qPCR) was performed at several stages to determine transcript levels of PACAP and corresponding receptors. Reinstatement of cocaine seeking was then tested after footshock exposure in different groups of rats that were pretreated with vehicle solution, a PAC1 receptor antagonist (experiment 2), or a PACAP agonist (experiment 3) without footshock. In experiment 1, cocaine self-administration increased BNST PACAP transcript levels similar to what we have previously reported with chronic stress. In experiment 2, intra-BNST infusions of the PAC1/VPAC2 antagonist, PACAP 6-38, prevented footshock-induced reinstatement of extinguished cocaine seeking. In experiment 3, intra-BNST PACAP infusion reinstated previously extinguished cocaine-seeking behavior in the absence of footshock. Cocaine self-administration elevated BNST PACAP, and BNST PACAP receptor activation was necessary and sufficient for stress-induced reinstatement of cocaine seeking. These data suggest that BNST PACAP systems may be viable targets for relapse prevention. PMID- 28656978 TI - Aptazyme-embedded guide RNAs enable ligand-responsive genome editing and transcriptional activation. AB - Programmable sequence-specific genome editing agents such as CRISPR-Cas9 have greatly advanced our ability to manipulate the human genome. Although canonical forms of genome-editing agents and programmable transcriptional regulators are constitutively active, precise temporal and spatial control over genome editing and transcriptional regulation activities would enable the more selective and potentially safer use of these powerful technologies. Here, by incorporating ligand-responsive self-cleaving catalytic RNAs (aptazymes) into guide RNAs, we developed a set of aptazyme-embedded guide RNAs that enable small molecule controlled nuclease-mediated genome editing and small molecule-controlled base editing, as well as small molecule-dependent transcriptional activation in mammalian cells. PMID- 28656977 TI - Polyaromatic molecular peanuts. AB - Mimicking biological structures such as fruits and seeds using molecules and molecular assemblies is a great synthetic challenge. Here we report peanut-shaped nanostructures comprising two fullerene molecules fully surrounded by a dumbbell like polyaromatic shell. The shell derives from a molecular double capsule composed of four W-shaped polyaromatic ligands and three metal ions. Mixing the double capsule with various fullerenes (that is, C60, C70 and Sc3N@C80) gives rise to the artificial peanuts with lengths of ~3 nm in quantitative yields through the release of the single metal ion. The rational use of both metal ligand coordination bonds and aromatic-aromatic pi-stacking interactions as orthogonal chemical glue is essential for the facile preparation of the multicomponent, biomimetic nanoarchitectures. PMID- 28656982 TI - Data models to GO-FAIR. PMID- 28656979 TI - MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. AB - Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including cardiovascular and Alzheimer's disease. Here we show that microtubule-affinity regulating kinase 4 (MARK4) binds to NLRP3 and drives it to the microtubule organizing centre, enabling the formation of one large inflammasome speck complex within a single cell. MARK4 knockdown or knockout, or disruption of MARK4-NLRP3 interaction, impairs NLRP3 spatial arrangement and limits inflammasome activation. Our results demonstrate how an evolutionarily conserved protein involved in the regulation of microtubule dynamics orchestrates NLRP3 inflammasome activation by controlling its transport to optimal activation sites, and identify a targetable function for MARK4 in the control of innate immunity. PMID- 28656981 TI - Promoting transcription over long distances. AB - Promoters and enhancers have long been regarded as distinct elements, a notion that has been challenged more recently. Two new studies now identify promoters that function as long-range enhancers in vivo to regulate the transcription of distal genes. PMID- 28656980 TI - Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception. AB - Adult neural stem cells reside in a specialized niche in the subventricular zone (SVZ). Throughout life they give rise to adult-born neurons in the olfactory bulb (OB), thus contributing to neural plasticity and pattern discrimination. Here, we show that the neurovascular protein EGFL7 is secreted by endothelial cells and neural stem cells (NSCs) of the SVZ to shape the vascular stem-cell niche. Loss of EGFL7 causes an accumulation of activated NSCs, which display enhanced activity and re-entry into the cell cycle. EGFL7 pushes activated NSCs towards quiescence and neuronal progeny towards differentiation. This is achieved by promoting Dll4-induced Notch signalling at the blood vessel-stem cell interface. Fewer inhibitory neurons form in the OB of EGFL7-knockout mice, which increases the absolute signal conducted from the mitral cell layer of the OB but decreases neuronal network synchronicity. Consequently, EGFL7-knockout mice display severe physiological defects in olfactory behaviour and perception. PMID- 28656984 TI - Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses. AB - A study in this issue demonstrates that epigenome-modifying drugs used in cancer chemotherapy induce transcription from thousands of previously unannotated transcription start sites, most of which are derived from ancient endogenous retroviruses (ERVs). This work, coupled with previous related findings, suggests that induction of ERVs, rather than direct effects on specific genes, may have a central role in the cellular responses to such agents and, in turn, their therapeutic efficacy. PMID- 28656983 TI - Transposase-driven rearrangements in human tumors. AB - A new study shows that aberrant DNA transposase activity promotes structural alterations that are clonally selected to drive tumor development. This discovery uncovers novel mechanisms of tumor-suppressor gene inactivation and highlights a new approach to cancer gene identification. PMID- 28656985 TI - [The psychological profile of pilots of passenger planes: Analysis of temperamental traits, aggression and risk]. AB - BACKGROUND: Over the years it has been assumed, that the greater the number of pilot flight hours, the better the development of problem-solving skills among pilots. Research suggests, however, that the problem is more complex than that. Not only one's experience is of importance - temperament, aggression and risk may also affect the decision-making process under stressful conditions. MATERIAL AND METHODS: We examined 97 male pilots of passenger planes, who had flew ATRs, Boeings, Airbuses, Embraers, and Saabs. The comparative group was made up of 127 graduates of technical studies (not connected with aviation). In our study, we used the following methods: the PTS (Pavlovian Temperament Survey) Temperament Questionnaire by Strelau, the Aggression Questionnaire by Buss and Perry, and the Stimulating-Instrumental Risk Inventory (SIRI) by Zaleskiewicz. RESULTS: Following the analyses we could categorize the pilots into 3 distinct groups: group 1 - strong type of nervous system with a tendency to avoid risk; group 2 - strong type of nervous system with a tendency to take risks; group 3 - the relatively weakest type of nervous system with a tendency toward aggressive behavior. CONCLUSIONS: Members of each group were analyzed to assess how they function in a task situation, i.e., whilst piloting a passenger plane. The study showed that individuals with high need for stimulation may - consciously or not - seek situations of excessive or unnecessary risks, and this is done in order to reach the right level of stimulation. A constellation of the following variables: temperament, risk, and aggression could be - we argue - useful in psychological examinations, and should be taken into account in training procedures for pilots. Med Pr 2017;68(5):639-651. PMID- 28656986 TI - Mycophenolate mofetil as a possible therapeutic option for idiopathic membranoproliferative glomerulonephritis. PMID- 28656987 TI - Collapsing glomerulopathy presenting as the initial manifestation of systemic lupus erythematosus. PMID- 28656988 TI - The administration of cinacalcet hydrochloride just before a haemodialysis session suppresses the transient rise in intact parathyroid hormone induced by a low-calcium dialysate: when should cinacalcet hydrochloride be administered? PMID- 28656989 TI - Cystinuria-transitory recovery: is it possible? PMID- 28656990 TI - Vertebral fractures in patients on dialysis: a clinically relevant problem with insufficient investigation. PMID- 28656991 TI - Particular cutaneous lesions and chronic renal failure. PMID- 28656992 TI - High prevalence of Chlamydophila pneumoniae infection in patients with myeloperoxidase antineutrophil cytoplasmic autoantibody (MPO-ANCA)-associated glomerulonephritis. PMID- 28656993 TI - Disseminated cutaneous papillomas in Schimke immuno-osseous dysplasia. PMID- 28656994 TI - Kidney transplantation from a brain-dead heart transplant candidate treated with biventricular assist device: 12-month follow-up. PMID- 28656995 TI - Interleukin-6 receptor inhibition with tocilizumab in various renal involvements associated with multicentric Castleman's disease: a report of three cases. AB - Multicentric Castleman's disease (MCD) is an inflammatory lymphoproliferative disorder characterized by polyclonal hypergammopathy and dysregulated overproduction of interleukin-6 (IL-6). A variety of renal involvements infrequently arise in patients with MCD. However, there is no established treatment for MCD and its associated renal involvements. We present the effects of an anti-IL-6 receptor monoclonal antibody, tocilizumab, on three patients with MCD associated with various renal manifestations. In all three patients, tocilizumab treatment was very effective in reducing proteinuria and stabilizing renal function, as well as improving other clinical symptoms. These findings indicate the pathological significance of IL-6 in renal involvements associated with MCD, and the potential use of tocilizumab in its treatment. PMID- 28656997 TI - Chest pain and pseudoclubbing in a haemodialysis patient. PMID- 28656996 TI - The impact of end-stage kidney disease (ESKD) on close persons: a literature review. PMID- 28656998 TI - 2,8-Dihydroxyadeninuria-induced progressive renal failure. PMID- 28656999 TI - Evaluation of depression, quality of life and malnutrition-inflammation scores in haemodialysis patients: a cross-sectional analysis. PMID- 28657000 TI - How much is red blood cell fragmentation increased by the use of closed luer lock access devices on catheter hubs? PMID- 28657001 TI - Secondary syphilis after renal transplantation. PMID- 28657003 TI - End-stage renal disease after bariatric surgery. PMID- 28657004 TI - Note from the Editorial Office. PMID- 28657005 TI - Invasive maxillary sinus mass in a renal transplant patient. PMID- 28657002 TI - The prevention of acute kidney injury: an in-depth narrative review Part 1: volume resuscitation and avoidance of drug- and nephrotoxin-induced AKI. AB - This narrative clinical review in two parts discusses the prevention of clinical acute kidney injury (AKI). The first part focuses on general prevention measures, including identification of individuals at high risk for AKI, and on the role of volume expansion and fluid therapy. The latter discusses the timing, the goals, the selection of the fluids and the haemodynamic management of the patient receiving parenteral fluids for the prevention of AKI. In addition, this part summarizes the interaction of intensivist-nephrologist in the ICU with attention to tight glycaemia control and the use of low doses of corticoids in the septic shock patients. Finally, the avoidance of drug- and nephrotoxin-induced AKI is discussed. The second part of this review will summarize the possible pharmacological interventions in the patient at risk. PMID- 28657006 TI - Lanthanum carbonate possibly responsible for acute liver failure in a patient with Child-Pugh stage A liver cirrhosis. AB - The majority of patients with end-stage renal disease have hyperphosphataemia, which is associated with significant morbidity and mortality. Lanthanum carbonate has been introduced as a new treatment modality to lower serum phosphorus. But there has been ongoing concern about lanthanum accumulation in tissues, especially in liver. We describe the case of a woman with pre-existing liver disease, who presented with acute liver failure after introduction of lanthanum carbonate to her treatment. The condition was fully reversible after stopping lanthanum carbonate. PMID- 28657007 TI - Calciphylaxis associated with chronic kidney disease and low bone turnover: management with recombinant human PTH-(1-34). PMID- 28657008 TI - Fatal acute hepatorenal failure during antimalarial-based combination treatment. PMID- 28657009 TI - Nocturnal hypoxia is associated with elevated C-reactive protein in dialysis patients. PMID- 28657011 TI - High mortality after pelvis and lower limb fractures in ESRD. PMID- 28657010 TI - Unilateral pleural effusion associated with ipsilateral arm and breast oedema: a rare complication of brachiocephalic and SVC stenosis in association with an arteriovenous fistula. PMID- 28657012 TI - Renal impairment resulting from hypothyroidism. PMID- 28657013 TI - Rare oxygen, a rare way to diagnose Conn's syndrome. AB - Background. Symptoms of mountain sickness are due to hypoxia of the brain. The pathogenesis is complex, but acid-base disturbances certainly play a role. When arterial oxygen levels drop, hyperventilation is induced, resulting in a respiratory alkalosis. However, this alkalosis inhibits the hyperventilation necessary for maintaining oxygen pressure. We present a case of a patient with symptoms of mountain sickness at relatively low altitudes, who appeared to have Conn's syndrome (primary hyperaldosteronism). Case. A 61-year-old male with hypokalaemic hypertension presented with symptoms of mountain sickness at relatively low altitudes. Hyperaldosteronism was suspected and laboratory results showed a non-suppressible aldosterone concentration and a mild metabolic alkalosis. A CT scan of the abdomen revealed an adenoma in the left adrenal gland. Treatment of aldosterone blockade by eplerone normalized blood pressure and the symptoms of mountain sickness at low altitudes disappeared completely. Discussion. We suggest that in our patient with hyperaldosteronism, the pre existing metabolic alkalosis inhibited the central respiratory centre after relatively mild hyperventilation. Therefore, mountain sickness in our patient could occur at a relatively low altitude. PMID- 28657014 TI - Contrast-enhanced ultrasonography with microbubbles for successful screening of kidney tumours. PMID- 28657015 TI - Pyrexia of unknown origin in a haemodialysis patient. PMID- 28657017 TI - Sweet and sour-a patient with life-threatening metabolic acidosis and acute renal failure. PMID- 28657016 TI - Renal failure associated with colonoscopy-what is the link? PMID- 28657018 TI - Occlusion of the fistula in a dialysis patient-is it always a common reason? PMID- 28657019 TI - Tubulointerstitial nephritis and uveitis (TINU) syndrome: epidemiology, diagnosis and management. PMID- 28657020 TI - Mechanical haemolysis related to the use of tandem dialyzers. PMID- 28657021 TI - Implementation of high-throughput screening for Fabry disease in Toronto dialysis patients. PMID- 28657022 TI - Acute renal failure and haemorrhagic syndrome secondary to toxin of caterpillars (Lonomia obliqua). PMID- 28657023 TI - Complete remission of IgA nephropathy after bone marrow transplantation for acute myeloid leukaemia. AB - IgA nephropathy is the most common primary glomerulonephritis, but the pathogenesis of IgA nephropathy is still unclear. A 32-year-old woman was found to have IgA nephropathy and acute myeloid leukaemia. She was treated with allogenic bone marrow transplantation (BMT). After BMT, immunoflourescent staining of IgA and proteinuria disappeared. These findings suggest bone marrow cells are involved in the pathogenesis of IgA nephropathy. We herein report a case of complete remission of IgA nephropathy after BMT for acute myeloid leukaemia. PMID- 28657025 TI - Ecthyma gangrenosum in a cirrhotic haemodialysis patient. PMID- 28657026 TI - A rare cause of flank pain. PMID- 28657024 TI - Advances in the cardiovascular assessment of patients with chronic kidney disease. AB - Cardiovascular mortality is grossly elevated in patients with chronic kidney disease (CKD), and is associated with a wide variety of structural and functional abnormalities. These issues have driven additional attempts to further characterise these abnormalities to elucidate the pathophysiology involved, assess individual risk and/or target and monitor therapies specifically directed at the cardiovascular (CV) system. This review aims to assess the techniques that are currently available for the study of the CV system. This includes conventional assessments of the whole CV system from heart to peripheral microcirculation (although not deal with VC assessment), as well as the key functional consequences relating to stress induced cardiovascular reserve, perfusion and vasoregulation. In addition this review will introduce a variety of techniques aiming to expand the envelope of conventional measurements. PMID- 28657027 TI - Antibody-negative Goodpasture's disease. PMID- 28657028 TI - Long-term results of a calcineurin inhibitor-free immunosuppression based on Thymoglobulin(r) and mycophenolate mofetil in elderly kidney transplant recipients. PMID- 28657029 TI - Successful treatment for thrombotic thrombocytopenic purpura complicated with myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated vasculitis. AB - Thrombotic thrombocytopenic purpura (TTP) complicated with myeloperoxidase anti neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis is rare and generally has a serious prognosis. We report a case wherein TTP was successfully treated with repeated plasma exchange (PE) and MPO-ANCA-associated vasculitis with corticosteroids. The renal function consequently improved such that haemodialysis could be discontinued and the patient was discharged without any significant complications. PMID- 28657030 TI - Pseudo-anion gap acidosis. PMID- 28657031 TI - Marked improvement in renal function after rectal cancer resection in a case of anti-neutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis. PMID- 28657032 TI - The difficult distinction between haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. PMID- 28657033 TI - Rituximab for plasma exchange-dependent recurrent focal segmental glomerulosclerosis after renal transplantation. PMID- 28657034 TI - Lactate-buffered dialysis in cardiogenic shock associated with severe combined lactic acidosis. AB - The level of lactate that would serve as cut-off for contraindication of lactate buffer is so far unclear. An acute exogenous load of lactate does not affect the basal endogenous lactate production and metabolism. It is also well metabolized in patients suffering from acute renal failure and severe sepsis with a compromised haemodynamic status. We report a case of extreme lactic acidosis in a patient admitted with a combination of cardiogenic shock, uraemia and suspected accumulation of biguanide. The patient was successfully treated with lactate buffered dialysis due to the accidental absence of the bicarbonate-buffered fluids. PMID- 28657035 TI - The May-Hegglin anomaly in a kidney transplant recipient. PMID- 28657036 TI - The rare event of exercise-induced dissection of the renal artery: successful long-term treatment by localized lysis. PMID- 28657037 TI - Combination of bortezomib-based chemotherapy and extracorporeal free light chain removal for treating cast nephropathy in multiple myeloma. AB - Besides amyloidosis and light chain deposition disease, the most common histological type of renal lesion is cast nephropathy in 30% of patients with multiple myeloma [2]. In contrast to amyloidosis, cast nephropathy is believed to be potentially reversible when circulating light chains are rapidly reduced. We report on three patients with multiple myeloma and cast nephropathy treated with a bortezomib-based chemotherapy in addition to a newly developed high-cutoff polyflux(r) haemofilter. Reduction in serum free light chain levels was achieved within 10-12 days, with all three patients improving their renal function. PMID- 28657038 TI - Renal ultrasound in acute kidney injury: long-term findings. PMID- 28657039 TI - A rare retroperitoneal schwannoma in a patient with neurofibromatosis Type 2. AB - Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour-prone disorder, characterized by the development of multiple schwannomas, meningiomas and ependymomas. Its prevalence is around 1:60 000. Vestibular schwannoma (VS) is the hallmark of NF2. Retroperitoneal schwannomas are expected to occur in only 3% of cases. We present the case of a large retroperitoneal schwannoma in a patient with NF2. A well-circumscribed heterogenic mass (9.5 * 4 * 4 cm) behind and under the left kidney and extending into the left retroperitoneal space was revealed during a lumbar and retroperitoneal space magnetic resonance imaging (MRI). Brain, orbits, cervical, thoracic and lumbar MRI revealed bilateral VS, multiple meningiomas as well as multiple schwannomas and ependymomas in the cervical, thoracic and lumbar spine. The retroperitoneal mass represents a schwannoma probably derived from an intercostal nerve. The patient underwent neurosurgical excision of the VS, and 3 months later, the patient's condition remained stable. PMID- 28657041 TI - Superior vena cava syndrome caused by haemodialysis catheter. PMID- 28657040 TI - Chronic kidney disease and end-stage renal disease-a review produced to contribute to the report 'the status of health in the European union: towards a healthier Europe'. AB - The Report on the Status of Health in the European Union (EUGLOREH) is a project aimed at describing health problems in member states of the European Community. This project is an effort of more than 170 European experts and the collaboration of the health authorities or institutions from all EU Member States, major intergovernmental, International and European Organizations and Agencies. In this report, for the first time special emphasis is given to chronic diseases. Chronic kidney disease (CKD) is increasingly recognized as a major public health problem. However, with some notable exceptions, until now this disease has received scarce attention both at European level and at member states level. In 2007, the ERA EDTA Registry was invited to contribute to EUGLOREH. The Registry made a major effort to gather published and unpublished information on the epidemiology of CKD and ESRD and to provide a comprehensive overview on CKD and ESRD in European countries. The review was completed in early 2008 and included into the final EUGLOREH published in the WEB as of 20 March 2009. PMID- 28657042 TI - Urinary stones resembling uric acid stones. PMID- 28657043 TI - An immunocompromised dialysis patient with skin and bone lesions. PMID- 28657044 TI - Interstitial cystitis: an enigmatic disorder of unclear aetiology. PMID- 28657045 TI - Tophaceous gout in a renal allograft recipient. PMID- 28657046 TI - Simvastatin-induced myoglobinuric acute kidney injury following ciclosporin treatment for alopecia universalis. AB - Alopecia areata can affect the entire scalp (alopecia totalis) or cause loss of all body hair (alopecia universalis). Ciclosporin (CsA) has been suggested for its treatment, with controversial results. Concomitant use of statins and CsA may increase the risk of rhabdomyolysis due to drug-drug interactions. Here we report the case of a 45-year-old woman treated with CsA for alopecia universalis, who presented a severe myoglobinuric acute kidney injury following the concomitant use of simvastatin. Upon admission to our unit, she was oligo-anuric. Her serum creatinine level was 13.8 mg/dl. CsA and simvastatin therapy were stopped, and haemodialysis treatment was started (eight daily dialysis sessions) until sufficient kidney function was regained. After 1 month, her serum creatinine level was 3.5 mg/dl; after 2 months and onwards (follow-up of 4 months), her serum creatinine level was 1.4 mg/dl and creatinine clearance was 43.2 ml/min. In conclusion, physicians should be aware of the potential risks of the combined use of CsA and statins. Patients should be advised to report any muscle symptoms when they are on statins and CsA. The laboratory follow-up should include the monitoring of serum creatinine and muscle enzyme levels, blood CsA levels and liver function tests. PMID- 28657047 TI - Renal dysfunction manifesting in subclinical hypothyroidism-a possible role for thyroxine. AB - Renal dysfunction, both acute and chronic, is a recognized association of overt hypothyroidism. We describe a patient who developed renal dysfunction at the stage of subclinical hypothyroidism. We emphasize that renal dysfunction is a reflection of tissue hypothyroidism, dissociated with the severity of biochemical hypothyroidism and can manifest in patients with subclinical hypothyroidism. This report also makes a case for thyroxine therapy if an alternative cause of renal dysfunction is not found in a patient with subclinical hypothyroidism. PMID- 28657048 TI - Treatment of severe dialysis reactions with the AN69-ST membrane: biocompatibility does matter. AB - Dialysis reactions with biocompatible membranes are rare, and complement activation has been suggested to be a culprit. We report here a case of an incident haemodialysis patient with asthma disease who experienced severe adverse reactions late into dialysis session, with different synthetic membranes (FX 80, Fresenius; Polyflux 17L, Gambro; FX 10, Fresenius; BLS 512, Bellco-Sorin). After replacing the dialyser by the surface-treated AN69 membrane (Nephral ST 500, Hospal), the dialysis sessions became uneventful. The case reinforces the need for biocompatible dialysers with high permeability and adsorptive capacity in susceptible patients experiencing severe dialysis reactions with synthetic membranes. PMID- 28657050 TI - Who ever said size doesn't matter? The association between journal title length and impact factor. PMID- 28657049 TI - Spontaneous perinephric haemorrhage and acute renal failure in pregnancy due to cocaine intoxication. AB - Cocaine abuse may contribute to the diverse forms of renal injury. We report a case of a pregnant woman who developed a large subcapsular renal haematoma after cocaine intoxication at 18-week gestation. She stabilized on conservative management and presented again at 29-week gestation with pre-eclampsia, acute renal failure and fetal demise. She required caesarean section delivery and intensive antihypertensive therapy to control severe pre-eclampsia associated with cocaine intoxication. This case is unique in that it is the first report of cocaine intoxication in pregnancy complicated by subcapsular haemorrhage. We discuss the possible mechanisms for the occurrence of this complication. PMID- 28657051 TI - Actinomyces peritonitis: removal of the peritoneal catheter unnecessary for resolution. PMID- 28657052 TI - A case of cetuximab-related tumour lysis syndrome in metastatic rectal carcinoma. AB - A 60-year-old man was diagnosed with a moderately differentiated adenocarcinoma in November 2006. The computed tomography (CT), magnetic resonance imaging (MRI) and whole-body positron emission tomography-CT (PET-CT) scan showed the presence of multiple liver metastases which were confined to its right lobe. He had the first session of a combined therapy with cetuximab and 5-fluorouracil (5-FU) in March 2009; however, soon afterwards, he presented with the symptoms, signs and biochemistry suggestive of tumour lysis syndrome. Our unusual case highlights that tumour lysis syndrome can also develop in 'low risk' category tumours, and that clinicians should be vigilant in identifying at-risk patients. PMID- 28657053 TI - Cinacalcet is effective in the treatment of hyperparathyroidism secondary to malignant transformation of autotransplanted parathyroid tissue. A case report. AB - Calcimimetics are effective in lowering serum parathyroid hormone (PTH) levels in hyperparathyroidism (HPT). However, they failed to reduce PTH levels in the long term in the setting of primary malignant HPT. A haemodialysis patient suffering from severe longstanding secondary HPT underwent total parathyroidectomy with autotransplantation of parathyroid tissue in her left arm. In the following years, she developed a severe HPT sustained by cancerous transformation of the parathyroid transplanted tissue and resistant both to pharmacological and repeated surgical treatments. The calcimimetic 'cinacalcet' was able to effectively reduce serum PTH levels over a 3-year follow-up and to induce disappearance of the neoplastic lesion on radionuclide imaging. Biochemical control of HPT was associated with a remarkable improvement in cardiac function. PMID- 28657054 TI - Reply. PMID- 28657055 TI - Chylous ascites. PMID- 28657056 TI - Severe left ventricular systolic dysfunction in a patient with a typical haemolytic-uraemic syndrome treated with rituximab-coincidence or cause? AB - A 26-year-old female with haemolytic-uraemic syndrome (HUS) refractory to daily plasma exchange was successfully treated with rituximab. Subsequent testing confirmed the presence of mutations in genes encoding complement factor I and CD46. On Day 32 she developed pulmonary oedema, and echocardiography demonstrated severe left ventricular systolic dysfunction. There was no evidence of recent myocardial infarction. Cardiac involvement has been reported, not only in thrombotic thrombocytopaenic purpura (TTP) but also with rituximab therapy. However, it is unclear if atypical HUS is also associated with cardiac disease. We recommend echocardiography in all patients with TTP-HUS and in any patients commencing treatment with rituximab. PMID- 28657057 TI - Treatment of paediatric vancomycin intoxication: a case report and review of the literature. PMID- 28657059 TI - Acute renal failure, severe sodium and potassium imbalance and sudden tetraplegia. PMID- 28657058 TI - Educating end-stage renal disease patients on dialysis modality selection. PMID- 28657060 TI - Association of bladder adenocarcinoma and BK virus infection in a pancreatico renal transplant recipient. AB - Viral infection has been related to post-transplantation tumour development, particularly Epstein-Barr virus, human papillomavirus, hepatitis B and C viruses, and herpes virus 8. Recently, BK virus (BKV) has emerged as an important cause of tumour formation in solid organ transplant recipients. BKV oncogenic potential relates to the ability to inactivate the functions of tumour suppression proteins p53 and pRB family, and induction of chromosomal aberrations. We report a case of urinary bladder adenocarcinoma in a pancreatico-renal transplant recipient which was diagnosed 2 years after BKV infection. Immunohistochemical staining for SV-40 was positive in neoplastic cells but negative in non-neoplastic cells. PMID- 28657061 TI - Bacterial infections following adjuvanted H1N1 vaccination in three renal transplant recipients. PMID- 28657062 TI - Two cases of nephrogenic systemic fibrosis after exposure to the macrocyclic compound gadobutrol. AB - Nephrogenic systemic fibrosis (NSF) is a disease with progressive fibrosis. We describe two cases of NSF after exposure to a macrocyclic gadolinium-based contrast agent (GBCA) gadobutrol, which has been considered as a low-risk agent compared to linear GBCAs. The first case had chronic kidney disease (CKD) Stage 3 and was exposed to 17.5 ml of gadobutrol. The second case has been exposed twice to GBCA: 10 ml of gadodiamide (in 2001) and 15 ml of gadobutrol (in 2008). Before the second exposure, he had CKD Stage 5 and was in haemodialysis. Both patients have been diagnosed with NSF. Our cases suggest that cyclic GBCAs can also cause NSF. PMID- 28657064 TI - Renal resistance index-think of more than just the kidney. PMID- 28657063 TI - Central venous catheter-related right atrial thrombus in two kidney transplantation recipients. AB - Right atrial thrombus formation is a known mechanical complication of central venous catheter insertion, with an incidence of between 1.9% and 42%. There is an increased risk of thromboembolism following renal transplantation. However, a right atrial thrombosis is rarely reported in renal transplant recipients. Here, we report two cases of renal transplant recipients in whom a right atrial thrombus developed after kidney transplantation. One of them required surgery, whereas the other patient recovered after being given an anticoagulant therapy with warfarin. PMID- 28657065 TI - IgG4-related disease should be considered in cases of hypocomplementemic immune complex tubulointerstitial nephritis. PMID- 28657066 TI - Fabry disease in donor kidneys with 3- and 12-year follow-up after transplantation. AB - Enzyme replacement therapy (ERT) has been introduced for Fabry disease and has been reported to clear some renal cell types of accumulated glycolipids and to reduce the accumulation in other cell types. We describe two patients without Fabry disease who were transplanted with kidney allografts from a male donor with Fabry disease. Biopsies were taken at transplantation and after 3 years in the first case and after 12 years in the second case. Even though these Fabry kidney allografts for many years had been exposed to normal levels of circulating alpha galactosidase A (alpha-gal-A), the amount of accumulated lysosomal deposits in the podocytes remained unchanged. Additionally, small deposits were also found in tubular cells and glomerular endothelial cells as long as 12 years after transplantation. PMID- 28657068 TI - A case of being 'double unlucky'. PMID- 28657067 TI - A haemodialysis patient with back pain: brown tumour as a cause of spinal cord compression under cinacalcet therapy. AB - A 43-year-old haemodialysis patient was admitted to hospital because of paroxysmal pain in the upper abdominal region radiating to the back. Laboratory tests showed severe hyperparathyroidism [intact parathyroid hormone (iPTH) 69 pmol/L; reference range: 1.3-6.8 pmol/L], hypercalcaemia (2.79 mmol/L), hyperphosphataemia (1.6 mmol/L) and elevated serum total alkaline phosphatase (200 U/L). After developing a disturbed sensation and paraesthesia in both feet, epidural compression of the spinal cord was suspected. Magnetic resonance imaging showed a tumour that severely compressed the myelum of the thoracic spine. Histological investigation revealed a brown tumour or osteoclastoma, an erosive bony lesion caused by increased osteoclastic activity and peritrabecular fibrosis. A brown tumour is a benign tumour that is a rare complication of severe renal hyperparathyroidism. The brown tumour developed despite a 1-year treatment of the patient with cinacalcet, which, however, did not result in a major decrease in serum iPTH concentration (from 110 to 69 pmol/L: 37% reduction). Urgent decompressive neurosurgery and subtotal parathyroidectomy resulted in a complete recovery. PMID- 28657069 TI - Chronic urate nephropathy with a disproportionated elevation in serum uric acid. PMID- 28657070 TI - Use of RNA-Protein Complexes for Genome Editing in Non-albicans Candida Species. AB - Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 genome modification systems have greatly facilitated the genetic analysis of fungal pathogens. In CRISPR-Cas9 genome editing methods designed for use in Candida albicans, DNAs that encode the necessary components are expressed in the target cells. Unfortunately, expression constructs that work efficiently in C. albicans are not necessarily expressed well in other pathogenic species within the genus Candida or the related genus Clavispora. To circumvent the need for species specific expression constructs, we implemented an expression-free CRISPR genome editing system and demonstrated its successful use in three different non albicans Candida species: Candida (Clavispora) lusitaniae, Candida glabrata, and Candida auris. In CRISPR-Cas9-mediated genome editing methods, a targeted double stranded DNA break can be repaired by homologous recombination to a template designed by the investigator. In this protocol, the DNA cleavage is induced upon transformation of purified Cas9 protein in complex with gene-specific and scaffold RNAs, referred to as RNA-protein complexes (RNPs). In all three species, the use of RNPs increased both the number of transformants and the percentage of transformants in which the target gene was successfully replaced with a selectable marker. We constructed mutants defective in known or putative catalase genes in C. lusitaniae, C. glabrata, and C. auris and demonstrated that, in all three species, mutants were more susceptible to hydrogen peroxide than the parental strain. This method, which circumvents the need for expression of CRISPR Cas9 components, may be broadly useful in the study of diverse Candida species and emergent pathogens for which there are limited genetic tools. IMPORTANCE Existing CRISPR-Cas9 genome modification systems for use in Candida albicans, which rely on constructs to endogenously express the Cas9 protein and guide RNA, do not work efficiently in other Candida species due to inefficient promoter activity. Here, we present an expression-free method that uses RNA-protein complexes and demonstrate its use in three Candida species known for their drug resistance profiles. We propose that this system will aid the genetic analysis of fungi that lack established genetic systems. PMID- 28657071 TI - Hepatitis C virus core antigen test in virological monitoring of patients on long term dialysis. PMID- 28657072 TI - Development of a CRISPR-Cas9 System for Efficient Genome Editing of Candida lusitaniae. AB - Candida lusitaniae is a member of the Candida clade that includes a diverse group of fungal species relevant to both human health and biotechnology. This species exhibits a full sexual cycle to undergo interconversion between haploid and diploid forms. C. lusitaniae is also an emerging opportunistic pathogen that can cause serious bloodstream infections in the clinic and yet has often proven to be refractory to facile genetic manipulations. In this work, we develop a clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (Cas9) system to enable genome editing of C. lusitaniae. We demonstrate that expression of CRISPR-Cas9 components under species-specific promoters is necessary for efficient gene targeting and can be successfully applied to multiple genes in both haploid and diploid isolates. Gene deletion efficiencies with CRISPR-Cas9 were further enhanced in C. lusitaniae strains lacking the established nonhomologous end joining (NHEJ) factors Ku70 and DNA ligase 4. These results indicate that NHEJ plays an important role in directing the repair of DNA double-strand breaks (DSBs) in C. lusitaniae and that removal of this pathway increases integration of gene deletion templates by homologous recombination. The described approaches significantly enhance the ability to perform genetic studies in, and promote understanding of, this emerging human pathogen and model sexual species. IMPORTANCE The ability to perform efficient genome editing is a key development for detailed mechanistic studies of a species. Candida lusitaniae is an important member of the Candida clade and is relevant both as an emerging human pathogen and as a model for understanding mechanisms of sexual reproduction. We highlight the development of a CRISPR-Cas9 system for efficient genome manipulation in C. lusitaniae and demonstrate the importance of species specific promoters for expression of CRISPR components. We also demonstrate that the NHEJ pathway contributes to non-template-mediated repair of DNA DSBs and that removal of this pathway enhances efficiencies of gene targeting by CRISPR-Cas9. These results therefore establish important genetic tools for further exploration of C. lusitaniae biology. PMID- 28657073 TI - MRI-guided tumor chemo-photodynamic therapy with Gd/Pt bifunctionalized porphyrin. AB - Porphyrin derivatives have been widely applied in MR imaging and photodynamic cancer therapy. We here report a novel Gd/Pt bifunctionalized porphyrin derivative (Gd/Pt-P1) for MRI-guided chemo-photodynamic cancer therapy. Gd/Pt-P1 was prepared from tetra(4-pyridyl) porphyrin (P1) via step by step coordination to cisplatin and gadolinium (Gd(iii)). Gd/Pt-P1 showed a particularly high synergetic chemo-photodynamic antitumor effect in vivo with a tumor inhibition rate (TIR) of 96.6% and excellent MR imaging performance. PMID- 28657074 TI - Chemically individual armoured bioreporter bacteria used for the in vivo sensing of ultra-trace toxic metal ions. AB - A chemically engineered armour is developed for simultaneously improving bioreporter bacterial vitality and shielding infectivity. The armour can help bacteria to resist various insults and even immune phagocytosis. Meanwhile, the bacterial infectivity has proven to be greatly shielded as well. Most importantly, the original bacterial biosensing activity is well preserved, which is competent for sensing trace arsenic in water, serum, and even in vivo. PMID- 28657075 TI - Bioinspired onion epithelium-like structure promotes the maturation of cardiomyocytes derived from human pluripotent stem cells. AB - Organized cardiomyocyte alignment is critical to maintain the mechanical properties of the heart. In this study, we present a new and simple strategy to fabricate a biomimetic microchip designed with an onion epithelium-like structure and investigate the guided behavior of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) on the substrate. The hiPSC-CMs were observed to be confined by the three dimensional surficial features morphologically, analogous to the in vivo microenvironment, and exhibited an organized anisotropic alignment on the onion epithelium-like structure with good beating function. The calcium imaging of hiPSC-CMs demonstrated a more mature Ca2+ spark pattern as well. Furthermore, the expression of sarcomere genes (TNNI3, MYH6 and MYH7), potassium channel genes (KCNE1 and KCNH2), and calcium channel genes (RYR2) was significantly up-regulated on the substrate with an onion epithelium-like structure instead of the surface without the structure, indicating a more matured status of cardiomyocytes induced by this structure. It appears that the biomimetic micropatterned structure, analogous to in vivo cellular organization, is an important factor that might promote the maturation of hiPSC-CMs, providing new biological insights to guide hiPSC-CM maturation by biophysical factors. The established approach may offer an effective in vitro model for investigating cardiomyocyte differentiation, maturation and tissue engineering applications. PMID- 28657076 TI - Exploring the structure and photodissociation mechanism of the electronic states of iodocarbene, CHI: a theoretical contribution. AB - We present herein a high-level ab initio study on the mono-iodine substituted carbene, CHI, using internally contracted multireference configuration interaction (icMRCI-F12) with Davidson correction which employs wave functions that explicitly depend on the electron-electron distance. The spin-orbit coupling (SOC) effect was included in our calculations. A total of 20 spin-free states with vertical transition energy up to 7.4 eV, as well as 50 spin-coupled states generated from the spin-free states via the SOC were studied. The results show significant influence of the SOC on the bond angles and the harmonic vibrational frequencies of the bending mode of the ground state (X1A') and the lowest triplet state (a3A''). Potential energy curves along the bond angle and the bond lengths of the electronic excited states of CHI were investigated. Based on our calculations, photodissociation dynamics in the ultraviolet region was disscussed for the first time, which would pave the way to further experimental investigations of CHI. PMID- 28657077 TI - Resistive switching mechanism of GeTe-Sb2Te3 interfacial phase change memory and topological properties of embedded two-dimensional states. AB - A theoretical study of an interfacial phase change memory made of a GeTe-Sb2Te3 superlattice with W electrodes is presented to identify the high and low resistance states and the switching mechanism. The ferro structure of the GeTe layer block in the Te-Ge-Te-Ge sequence can be in the low resistance state only if the SET/RESET mode consists of a two step dynamical process, corresponding to a vertical flip of the Ge layer with respect to the Te layer, followed by lateral motion driven by thermal relaxation. The importance of spin-orbit coupling at the GeTe/Sb2Te3 interface to the "bias polarity-dependent" SET/RESET operation is shown, and an analysis of the two-dimensional states confined at the GeTe/Sb2Te3 interface inside the resistive switching layer is presented. Our results allow us to propose a phase diagram for the transition from a topologically nontrivial to a trivial gap state of these two-dimensional compounds. PMID- 28657078 TI - A novel artificial synapse with dual modes using bilayer graphene as the bottom electrode. AB - Resistive Random Access Memory (RRAM) shows great potential to be used as an artificial synapse for neuromorphic applications. The resistance can be gradually reduced during reset, which can enable enough states to mimic the "forgetting" process. However, the abrupt set (Mode I) cannot generate enough states to mimic the "learning" process, which results in depression-only behavior. In this work, we introduce another mode (Mode II) in an Al/AlOx/graphene 'RRAM' stack by using oxygen vacancies as trapping centers and bottom electrode bilayer graphene as the channel material. In this way, since the pulse can gradually create the oxygen vacancies, post-synaptic current (PSC) can be gradually potentiated or depressed. By introducing Mode II, we can realize 166 potentiation states, which is higher than the previously reported conventional RRAM with insufficient potentiation states due to the abrupt set. Moreover, Mode II can help realize an inhibitory synapse. By combining modes I and II, we can realize both excitatory and inhibitory synapses in a single device. This work shows great potential to enable neuromorphic computations with greater learning and reconfigurability. PMID- 28657079 TI - Combining random walk and regression models to understand solvation in multi component solvent systems. AB - Polysaccharides, such as cellulose, are often processed by dissolution in solvent mixtures, e.g. an ionic liquid (IL) combined with a dipolar aprotic co-solvent (CS) that the polymer does not dissolve in. A multi-walker, discrete-time, discrete-space 1-dimensional random walk can be applied to model solvation of a polymer in a multi-component solvent mixture. The number of IL pairs in a solvent mixture and the number of solvent shells formable, x, is associated with n, the model time-step, and N, the number of random walkers. The mean number of distinct sites visited is proportional to the amount of polymer soluble in a solution. By also fitting a polynomial regression model to the data, we can associate the random walk terms with chemical interactions between components and probe where the system deviates from a 1-D random walk. The 'frustration' between solvents shells is given as ln x in the random walk model and as a negative IL:IL interaction term in the regression model. This frustration appears in regime II of the random walk model (high volume fractions of IL) where walkers interfere with each other, and the system tends to its limiting behaviour. In the low concentration regime, (regime I) the solvent shells do not interact, and the system depends only on IL and CS terms. In both models (and both regimes), the system is almost entirely controlled by the volume available to solvation shells, and thus is a counting/space-filling problem, where the molar volume of the CS is important. Small deviations are observed when there is an IL-CS interaction. The use of two models, built on separate approaches, confirm these findings, demonstrating that this is a real effect and offering a route to identifying such systems. Specifically, the majority of CSs - such as dimethylformide - follow the random walk model, whilst 1-methylimidazole, dimethyl sulfoxide, 1,3-dimethyl-2 imidazolidinone and tetramethylurea offer a CS-mediated improvement and propylene carbonate results in a CS-mediated hindrance. It is shown here that systems, which are very complex at a molecular level, may, nonetheless, be effectively modelled as a simple random walk in phase-space. The 1-D random walk model allows prediction of the ability of solvent mixtures to dissolve cellulose based on only two dissolution measurements (one in neat IL) and molar volume. PMID- 28657080 TI - Synergistic effect in the heterostructure of ZnCo2O4 and hydrogenated zinc oxide nanorods for high capacitive response. AB - Herein, a novel heterostructure was fabricated by combining electrochemically and optically active materials to achieve a high capacitive response of 896 F g-1 at 5 A g-1. A network of ZnCo2O4 nanorods (NRs) was directly grown on a three dimensional matrix of H : ZnO NRs (ZnCo2O4/H : ZnO NRs) that offered synergistic advantages by providing an optimum ion/charge transportation path, large electrochemically active surface area, and stable capacitive response during the electrolytic process. Furthermore, the fabricated solid-state asymmetric supercapacitor ZnCo2O4/H : ZnO NRs//activated carbon induced a large potential window of 1.5 V that offered excellent energy and power densities. In addition, optically active ZnCo2O4/H : ZnO NRs were also used for the conversion of optical energy over a broad wavelength range; thus, the as-fabricated asymmetric solid state supercapacitor could easily provide the required power for the operation of a photodetector. Therefore, the unique heterostructure of ZnCo2O4/H : ZnO NRs not only presents excellent capacitive response but also demonstrates great potential for energy conversion. PMID- 28657081 TI - A comparative study on the N-heterocyclic carbene adducts of Ih-C60, D5h-C70 and Sc3N@Ih-C80. AB - We found that the standard B3LYP and dispersion-corrected B3LYP-D3 methods predicted completely opposite energy order for the Lewis acid-base adducts formed by Ih-C60 or D5h-C70 with normal C2-bound (nNHC) and abnormal C5-bound (aNHC) N heterocyclic carbenes. By using the validated B3LYP-D3 method and taking the solvent effects into account, the exclusive formations of the nNHC-C60/70 (Li et al. J. Am. Chem. Soc., 2011, 133, 12410-12413) and aNHC-Sc3N@Ih-C80 complexes (Chen et al. Chem. Sci., 2016, 7, 2331-2334) in two recent experiments were suggested to be thermodynamically and kinetically controlled, respectively. In contrast to the reported reactions of endohedral metallofullerenes, aNHC-Sc3N@Ih C80 hardly isomerizes to the low-energy normal adducts under heat treatment probably due to the substantial energy barrier and excess NHC reagent used in the experiment. Furthermore, the highly regioselective addition of aNHC to the triple hexagon-junction carbon atom of Sc3N@Ih-C80 was rationalized by using the frontier molecular orbital theory. PMID- 28657082 TI - A nondestructive approach to study resistive switching mechanism in metal oxide based on defect photoluminescence mapping. AB - The mechanism of resistive switching in metal oxides is a widely studied topic with interest in both fundamental physics and the practical need to improve device characteristics for memory based applications. Various experimental approaches were employed to reveal the different aspects of resistive switching; however, there is still a debate on the switching mechanism due to the lack of nondestructive microscopic characterization tools to monitor the oxygen vacancies. In this study, a novel approach using photoluminescence (PL) mapping was developed to study switching dynamics in metal oxides. By monitoring the emission properties with a confocal PL system, information regarding the switching mechanism can be obtained. The nondestructive nature of this approach allowed us to make comparisons between different switching conditions and endurance cycles. SrTiO3 based switching devices were used in the study. The distribution of oxygen vacancies can be positioned by mapping the integrated intensity of oxygen vacancy emission on a transparent top electrode, and both interface switching and filament switching can be distinguished. Moreover, the endurance study revealed a sudden rise in the emission intensity correlated with the device failure, which indicates an abrupt increase in the localized density of oxygen vacancies that results in an irreversible set process for the conductive filament. PMID- 28657085 TI - Molecular simulation of CH4/CO2/H2O competitive adsorption on low rank coal vitrinite. AB - The competitive adsorptions of CH4/CO2/H2O on coal vitrinite (DV-8, C214H180O24N2) were computed based on density function theory (DFT) and grand canonical Monte Carlo (GCMC). The adsorption process reaches the saturation state after adsorbing 17 CH4s, 22 CO2s, and 35 H2Os per C214H180O24N2 respectively. The optimal configurations of CH4-vitrinite, CO2-vitrinite, and H2O-vitrinite respectively manifest as aromatic1/T2/rT3 (1 adsorption location, 2 adsorption sites and T here represents sites above the carbon atom and the heteroatom, 3 adsorption orientation and rT here means the orientations of three hydrogen atoms pointing to vitrinite), aromatic/T/v (v represents the orientations perpendicular to the plane of vitrinite), and aromatic/rV/T (rV represents an oxygen atom pointing to the vitrinite surface). The GCMC results show that high temperature is not conducive to the vitrinite's adsorption of adsorbates and the adsorption capacity order is H2O > CO2 > CH4 (263-363 K) in the one-component, binary, and ternary adsorbate systems. The optimal configurations of vitrinite are similar to graphite/graphene, while DeltaE is significantly lower than graphite/graphene. Simulation data are in good agreement with the experimental results. PMID- 28657083 TI - Experimental evidence of an electronic transition in CeP under pressure using Ce L3 XAS. AB - Cerium phosphide undergoes a unit-cell volume discontinuity without any structural phase transitions upon application of a high pressure of ~10 GPa. This phenomenon is attributed to a change in the electronic charge distribution of the cerium in CeP, but to date no direct experimental verification for this hypothesis has been presented. Here, we report a Ce L3-edge X-ray absorption spectroscopy study under pressure, which provides direct compelling evidence of an electronic transition associated with the above-mentioned isostructural volume discontinuity. The present results should be relevant to the understanding of the phenomenon of pressure induced isostructural transitions involving unit-cell volume collapse. PMID- 28657087 TI - Halides tuning the subcellular-targeting in two-photon emissive complexes via different uptake mechanisms. AB - We reported a simple and universal strategy by tuning halides (Cl, Br and I) in terpyridine-Zn(ii) complexes to achieve different subcellular organelle targeting (nucleolus, nucleus and intracellular membrane systems, respectively) via different cellular uptake mechanisms, resulting from halide triggering different polymorphs of these complexes. PMID- 28657088 TI - Hierarchical self-assembly of photoluminescent CdS nanoparticles into a bile acid derived organogel: morphological and photophysical properties. AB - We have described a strategy towards integrating photoluminescent semiconductor nanoparticles into a bio-surfactant derived organogel. A facially amphiphilic bile thiol was used for capping CdS nanoparticles (NPs) which were embedded in a bile acid derived new organogelator in order to furnish a soft hybrid material. The presence of CdS NPs in a well-ordered 1D array on the organogel network was confirmed using microscopic techniques. Photophysical studies of the gel-NP hybrid revealed resolved excitation and emission characteristics. Time resolved spectroscopic studies showed that the average lifetime value of the CdS NPs increased in the gel state compared to the sol phase. A kinetic model was utilized to obtain quantitative information about the different decay pathways of the photoexcited NPs in the sol and gel states. PMID- 28657089 TI - Enhanced electro-active phase in a luminescent P(VDF-HFP)/Zn2+ flexible composite film for piezoelectric based energy harvesting applications and self-powered UV light detection. AB - We have prepared a flexible polymer composite film containing poly(vinylidene fluoride-co-hexafluoropropylene) (P(VDF-HFP)) and Zn2+ for the fabrication of a multifunctional piezoelectric based nanogenerator (MFNG), where a traditional electrical poling treatment was avoided. The desirable amount of Zn2+ yields more than 99% of electro-active phases in the P(VDF-HFP) matrix that co-operates to enhance the dielectric properties of the composite film via hydrogen bonding interactions. In situ thermal Fourier transform infrared (FT-IR) spectroscopy affirms the improved thermal stability of the electro-active beta-phase and the beta->gamma phase transition temperature in the Zn2+ doped composite film. It also shows UV absorption and intense blue light emission confirmed by a CIE 1931 chart that gives it applicability as a flexible optical sensor. The MFNG behaves as an efficient mechanical energy harvester that delivers an open-circuit voltage ~6 V and an output power of 2.4 MUW and successfully enables the charging of a capacitor by simple repetitive finger touch and release motions (a pressure amplitude of ~14 kPa). The UV light sensing ability of the MFNG is confirmed under the continuous application and removal of applied stress, which is very promising for designing versatile self-powered optoelectronic smart sensors. Our approach is very simple and cost effective for the construction of a new class of flexible multifunctional energy harvesters that have wonderful applications in the areas of piezo-photonics, wireless detection and flexible self-powered opto electronics. PMID- 28657090 TI - Expanding light utilization to the near-infrared region for hybrid bio photoelectrochemical cells. AB - The insatiable energy demand asks for the maximum conversion of green renewable sources. Herein, we propose the first NIR-assisted glucose/air bio photoelectrochemical (BPEC) cell comprising a rare earth up-conversion microcrystal (UCMC)-based polyterthiophene (pTTh) cathode. Upon irradiation with a 980 nm laser, UCMCs emit robust luminescence in the visible range, which can efficiently excite pTTh, catalyzing the reduction of oxygen and generating photocurrent. Coupling with a glucose oxidation bioanode, this assembled BPEC cell exhibits a maximal output power density of 40.6 MUW cm-2 and an open circuit voltage of 0.53 V. This success is an essential conceptual steppingstone towards the comprehensive utilization of whole sunlight and offers alternative solutions for multiple energy conversions. PMID- 28657091 TI - Depleted upconversion luminescence in NaYF4:Yb3+,Tm3+ nanoparticles via simultaneous two-wavelength excitation. AB - We report optical depletion of upconversion luminescence (UCL) in NaYF4:Yb3+,Tm3+ nanoparticles excited simultaneously by 980 nm and 1550 nm lasers. The UCL intensity is greatly depleted, while the downshifted emission at 1210 nm is obviously enhanced. The disturbances of 1550 nm photons on energy transfer between Yb3+ and Tm3+, cross relaxation (CR), the thermal effect and the stimulated emission depletion (STED) process are qualitatively evaluated. Our investigations verify that the unexpected depletion phenomena are governed by the STED process. The power densities of the 980 nm and 1550 nm lasers are both less than 100 W cm-2, which will greatly reduce the thermal effect and damage and extend the applications of such nanomaterials. These results provide keen insights into controlling emission colors in optical processes, and offer potential applications in multicolor displays and STED nanoscopy. PMID- 28657092 TI - Spontaneous polarization switching and piezoelectric enhancement of PVDF through strong hydrogen bonds induced by layered double hydroxides. AB - The spontaneous dipole alignment of PVDF has been achieved in the formation process of a film through strong hydrogen bonds between PVDF and layered double hydroxides (LDHs), and the as-prepared composite film exhibits excellent energy conversion and storage ability. PMID- 28657093 TI - Investigation of the shock-induced chemical reaction (SICR) in Ni + Al nanoparticle mixtures. AB - Molecular dynamics (MD) simulations are used to investigate the shock-compression response of Ni + Al spherical nanoparticles arranged in a NaCl-like structure. The deformation and reaction characteristics are studied from the particle level to the atomic scale at various piston velocities. Shock-induced chemical reactions (SICRs) occur during non-equilibrium processes, accompanied by a sharp rise in temperature and rapid mixing of atoms. The preferentially deformed Al particles form a high-speed mass flow relative to the Ni at the shock front, which impinges on the Ni particles, and mixing of Ni and Al atoms occurs immediately at the interface. The particle velocity dispersion (PVD) that appears at the shock front has important implications for the initiation of shock-induced chemical reactions. We show that dislocations are mainly generated at the beginning of particle deformation or at the shock front, and do not directly affect the occurrence of SICRs. The intimate contact of the molten Al and the amorphous Ni is found to be critical to the subsequent reactions for the extensive mixing of Ni and Al. We conclude that the mechanisms of SICRs involve mechanochemical processes near the shock front and subsequent interdiffusion processes. PMID- 28657094 TI - Universal self-assembly of one-component three-dimensional dodecagonal quasicrystals. AB - Using molecular dynamics simulations, we study computational self-assembly of one component three-dimensional dodecagonal (12-fold) quasicrystals in systems with two-length-scale potentials. Existing criteria for three-dimensional quasicrystal formation are quite complicated and rather inconvenient for particle simulations. So to localize numerically the quasicrystal phase, one should usually simulate over a wide range of system parameters. We show how to universally localize the parameter values at which dodecagonal quasicrystal order may appear for a given particle system. For that purpose, we use a criterion recently proposed for predicting decagonal quasicrystal formation in one-component two-length-scale systems. The criterion is based on two dimensionless effective parameters describing the fluid structure which are extracted from the radial distribution function. The proposed method allows reduction of the time spent for searching the parameters favoring a certain solid structure for a given system. We show that the method works well for dodecagonal quasicrystals; this result is verified on four systems with different potentials: the Dzugutov potential, the oscillating potential which mimics metal interactions, the repulsive shoulder potential describing effective interactions for the core/shell model of colloids and the embedded-atom model potential for aluminum. Our results suggest that the mechanism of dodecagonal quasicrystal formation is universal for both metallic and soft-matter systems and it is based on competition between interparticle scales. PMID- 28657096 TI - Enhancing TMR and spin-filtration by using out-of-plane graphene insulating barrier in MTJs. AB - First principles investigations are performed to understand the spin-polarized transport in Magnetic Tunnel Junctions (MTJs) consisting of an out-of-plane graphene sheet as a barrier in between two CrO2 Half-Metallic-Ferromagnetic (HMF) electrodes. Upon comparison of the results with the results of in-plane graphene based MTJs reported in the past, it is observed that out-of-plane structures offer a high TMR of ~100% and the transport phenomenon is tunneling since there are no transmission states near the Fermi level. However, in in-plane structures, the transport phenomenon cannot be tunneling since there are a significant number of transmission states near the Fermi level, although a high Magneto Resistance (MR) of ~90% is observed. Both the TMR and Spin Injection Efficiency eta (Spin Filtration) are higher in out-of-plane structures in comparison to in-plane structures, which is due to the graphene sheet acting as a perfect barrier in out of-plane structures, which results in negligible spin down current (I?) in both the Parallel Configuration (PC) and Antiparallel Configuration (APC). PMID- 28657097 TI - A PbI2-xClx seed layer for obtaining efficient planar-heterojunction perovskite solar cells via an interdiffusion process. AB - Despite the previous reports on the fabrication of CH3NH3PbI3-xClx films via sequential deposition, the positioning and formation of PbI2 in MAPbI3-xClx perovskite films made from the seed layer containing PbI2 and PbCl2 in different ratios have not yet been addressed. In this study, the PbI2 content in a perovskite absorber layer is controlled by changing the PbCl2 ratio in a PbI2 xClx seed layer. The addition of PbCl2 in the seed layer facilitates PbI2 generation and affects the morphology of the perovskite film. By integrating a perovskite absorber via the PbI2-xClx seed-layer into a solar cell, we investigated the effects of the correlation between the chlorine and PbI2 contents on the device performance through intensity-modulated photocurrent spectroscopy and intensity-modulated photovoltage spectroscopy. Elemental depth profiling analyses confirm that not only was the formed PbI2 preferentially located near the metal-oxide layer, but residual chlorine was adsorbed at the TiO2 layer. Our findings demonstrate that the geometric features of the formed PbI2 affected the perovskite solar cells according to the chlorine content, likely because of the elemental gradient induced by annealing. The PbI2-xClx derived planar-heterojunction perovskite solar cells exhibited maximum power conversion efficiencies of 17.56% at reverse scan and 17.21% at forward scan, suppressed current density-voltage hysteresis, and good performance distributions. PMID- 28657098 TI - Adsorption on graphene: flat to edge to end transitions of phenyl hydroquinone. AB - The adsorption of phenyl hydroquinone (PHQ) on graphene surfaces at the liquid solid interface is investigated revealing a flat orientation and two different vertically adsorbed states of PHQ on graphene nanoplatelets (GNPs), namely edgewise or endwise adsorption. The transition between these states is driven by increasing concentrations of PHQ in solution leading to increased absolute coverages on the graphene surface. At low adsorbate concentrations (<=21 mM), the adsorption process is also shown to be Langmuirian with an adsorption constant of (9.5 +/- 0.2) mM-1. Independent measurements are conducted using a single particle electrochemical technique to confirm the surface coverage of PHQ on GNPs at low concentrations, showing excellent agreement with the UV-Vis studies. PMID- 28657099 TI - Exploiting the dual role of ethynylbenziodoxolones in gold-catalyzed C(sp)-C(sp) cross-coupling reactions. AB - Reported herein is the gold-catalyzed alkynylation of terminal alkynes using ethynylbenziodoxolones (EBXs), where EBXs serve a dual role as oxidants as well as alkyne transfer agents to access unsymmetrical 1,3-diynes. Hence, the catalytic system requires no external oxidants and is compatible with a broad range of substrates, including those with polar functional groups such as NH, OH and B(OH)2. PMID- 28657100 TI - Nanocrystalline SnS2 coated onto reduced graphene oxide: demonstrating the feasibility of a non-graphitic anode with sulfide chemistry for potassium-ion batteries. AB - An anode material incorporating a sulfide is reported. SnS2 nanoparticles anchored onto reduced graphene oxide are produced via a chemical route and demonstrate an impressive capacity of 350 mA h g-1, exceeding the capacity of graphite. These results open the door for a new class of high capacity anode materials (based on sulfide chemistry) for potassium-ion batteries. PMID- 28657101 TI - Cross-linking of COOH-containing polymers using Ag(i)-catalyzed oxidative decarboxylation in aqueous solution. AB - Cross-linking that defines the three-dimensional networks in hydrogels has a significant impact on their physiochemical properties. The cross-linking of hydrophilic polymers via post-polymerization reactions is an ideal way to manufacture hydrogels with high reproducibility and without monomer residuals. We herein report the use of Ag(i)-catalyzed oxidative decarboxylation to cross-link poly(acrylic acid) (PAA) and a family of COOH-containing hydrophilic polymers. Our method is based on the radical-mediated elimination reaction to remove COOH group(s) and generate alkyl radical(s) simultaneously, in the presence of AgNO3 and persulfates. The further intermolecular radical coupling is demonstrated to be very effective in inducing cross-linking and gelation of COOH-containing hydrophilic polymers. The cross-linking reaction can be readily achieved by simply mixing a small amount of AgNO3 (as low as 0.03 wt%) and persulfates with polymers at room temperature in air. Rheological measurements show that the gelation occurs in 20-30 min. The applications of oxidative decarboxylation in the preparation of hydrogels of COOH-containing hydrophilic copolymers and their interpenetrating polymer network (IPN) hydrogels are further validated. Finally, the residual Ag(i) ions in hydrogels are discussed in terms of how Ag(i) ions further change the mechanical and optical properties of hydrogels by photoreduction of Ag(i) to Ag nanoparticles. We expect that this Ag(i)-catalyzed oxidative decarboxylation chemistry can not only serve as a facile and general strategy to produce hydrogels through post-polymerization, but also enrich the toolbox of cross-linking chemistries of COOH-containing polymers in all forms (e.g. films, colloids and dispersions). PMID- 28657102 TI - Fragmentation of pure and hydrated clusters of 5Br-uracil by low energy carbon ions: observation of hydrated fragments. AB - The fragmentation of the isolated 5-bromouracil (5BrU) molecule and pure and nano hydrated 5BrU clusters induced by low energy 12C4+ ions has been studied. A comparison indicates that the environment, on the one hand, protects the system against the complete break-up into small fragments, but, on the other hand, triggers 'new' pathways for fragmentation, for example the loss of the OH group. The most striking result is the observation of several series of hydrated fragments in the hydrated cluster case, with water molecules bound to hydrophilic sites of 5BrU. This highlights the strong interaction between 5BrU and water molecules and the blocking of specific fragmentation pathways, such as the loss of the BrC2H group for example. PMID- 28657104 TI - An investigation of Na-related defects in Cu2ZnSnSe4. AB - Using hybrid density functional theory, here, we have investigated the electronic, defect and migration properties of Na-related defects in the earth abundant solar cell absorber material Cu2ZnSnSe4 (CZTSe). We find that among all the Na-related defects, NaZn acts the same way as VCu and CuZn; it is an acceptor and contributes to the p-type conductivity. NaSn is a deep level defect, but it is energetically unfavorable and can be suppressed by the growth conditions. Besides, through migration energy analysis, we prove that Na can easily move in CZTSe through interstitial Na and Cu vacancy mediated mechanisms. PMID- 28657105 TI - Influence of HMW tail chains on the structural evolution of HDPE induced by second melt penetration. AB - It is widely accepted that the role of the high molecular weight (HMW) component is cooperative in shear-induced crystallization, owing to entanglements among long chains. However, this paper demonstrates that the HMW component has a novel effect on structural evolution during the process of multi-melt multi-injection molding (M3IM), organized as follows. First, the appropriate HDPE system with an incremental concentration of HMW tails was established. Second, the crystalline morphologies and orientation behaviors of the M3IM samples were characterized using a combination of scanning electron microscopy (SEM) and two-dimensional small angle X-ray scattering (2D-SAXS), and these suggested that the amount of shish-kebabs was not monotonically promoted with an increasing content of HMW tails but tended to reduce at a certain value. Third, in order to explain this phenomenon, the special temperature and shear profiles of M3IM were depicted subsequently, and finally the mechanism of hierarchical structure formation with the influence of various amounts of HMW tail chains was discussed, based on the classical rheological viewpoint. PMID- 28657106 TI - Aqueous self-assembly of hydrophobic macromolecules with adjustable rigidity of the backbone. AB - P(FpC3P) (Fp: CpFe(CO)2; C3P: propyl diphenyl phosphine) has a helical backbone, resulting from piano stool metal coordination geometry, which is rigid with intramolecular aromatic interaction of the phenyl groups. The macromolecule is hydrophobic, but the polarized CO groups can interact with water for aqueous self assembly. The stiffness of P(FpC3P), which is adjustable by temperature, is an important factor influencing the morphologies of kinetically trapped assemblies. P(FpC3P)7 self-assembles in DMSO/water (10/90 by volume) into lamellae at 25 degrees C, vesicles at 40 degrees C and irregular aggregates at higher temperatures (60 and 70 degrees C). The colloidal stability decreases in the order of lamellae, vesicles and irregular aggregates. Dissipative particle dynamics (DPD) simulation reveals the same temperature-dependent self-assembled morphologies with an interior of hydrophobic aromatic groups covered with the metal coordination units. The rigid backbone at 25 degrees C accounts for the formation of the layered morphology, while the reduced rigidity of the same P(FpC3P)7 at 40 degrees C curves up the lamellae into vesicles. At a higher temperature (60 or 70 degrees C), P(FpC3P)7 behaves as a random coil without obvious amphiphilic segregation, resulting in irregular aggregates. The stiffness is, therefore, a crucial factor for the aqueous assembly of macromolecules without obvious amphiphilic segregation, which is reminiscent of the solution behavior observed for many hydrophobic biological macromolecules such as proteins. PMID- 28657107 TI - Optical surgical instrument tracking system based on the principle of stereo vision. AB - Optical tracking systems are widely adopted in surgical navigation. An optical tracking system is designed based on the principle of stereo vision with high precision and low cost. This system uses optical infrared LEDs that are installed on the surgical instrument as markers and a near-infrared filter is added in front of the Bumblebee2 stereo camera lens to eliminate the interference of ambient light. The algorithm based on the region growing method is designed and used for the marker's pixel coordinates' extraction. In this algorithm, the singular points are eliminated and the gray centroid method is applied to solve the pixel coordinate of the marker's center. Then, the marker's matching algorithm is adopted and three-dimensional coordinates' reconstruction is applied to derive the coordinates of the surgical instrument tip in the world coordinate system. In the simulation, the stability, accuracy, rotation tests, and the tracking angle and area range were carried out for a typical surgical instrument and the miniature surgical instrument. The simulation results show that the proposed optical tracking system has high accuracy and stability. It can meet the requirements of surgical navigation. PMID- 28657108 TI - Stress-strain relationship and seismic performance of cast-in-situ phosphogypsum. AB - BACKGROUND: Phosphogypsum is a waste by-product during the production of phosphoric acid. It not only occupies landfill, but also pollutes the environment, which becomes an important factor restricting the sustainable development of the phosphate fertilizer industry. Research into cast-in-situ phosphogypsum will greatly promote the comprehensive utilization of stored phosphogypsum. The aim of this study was to clarify the mechanical properties of phosphogypsum. METHODS: Stress-strain relationships of cast-in-situ phosphogypsum were investigated through axial compressive experiments, and seismic performance of cast-in-situ phosphogypsum walls and aerated-concrete masonry walls were simulated based on the experimental results and using finite element analysis. RESULTS: The results showed that the stress-strain relationship fitted into a polynomial equation. Moreover, the displacement ductility index and the energy dissipation index of cast-in-situ phosphogypsum wall were 6.587 and 3.425, respectively. CONCLUSIONS: The stress-strain relationship for earthquake resistant performance of cast-in-situ phosphogypsum walls is better than that of aerated-concrete masonry walls. The curve of stress-strain relationship and the evaluation of earthquake-resistant performance provide theoretical support for the application of cast-in-situ phosphogypsum in building walls. PMID- 28657110 TI - Early impact of the Japanese immunization program implemented before the HPV vaccination crisis. PMID- 28657109 TI - Long-term follow-up after bariatric surgery in a national cohort. AB - BACKGROUND: Lifelong medical follow-up is mandatory after bariatric surgery. The aim of this study was to assess the 5-year follow-up after bariatric surgery in a nationwide cohort of patients. METHODS: All adult obese patients who had undergone primary bariatric surgery in 2009 in France were included. Data were extracted from the French national health insurance database. Medical follow-up (medical visits, micronutrient supplementation and blood tests) during the first 5 years after bariatric surgery was assessed, and compared with national and international guidelines. RESULTS: Some 16 620 patients were included in the study. The percentage of patients with at least one reimbursement for micronutrient supplements decreased between the first and fifth years for iron (from 27.7 to 24.5 per cent; P < 0.001) and calcium (from 14.4 to 7.7 per cent; P < 0.001), but increased for vitamin D (from 33.1 to 34.7 per cent; P < 0.001). The percentage of patients with one or more visits to a surgeon decreased between the first and fifth years, from 87.1 to 29.6 per cent (P < 0.001); similar decreases were observed for visits to a nutritionist/endocrinologist (from 22.8 to 12.4 per cent; P < 0.001) or general practitioner (from 92.6 to 83.4 per cent; P < 0.001). The mean number of visits to a general practitioner was 7.0 and 6.1 in the first and the fifth years respectively. In multivariable analyses, male sex, younger age, absence of type 2 diabetes and poor 1-year follow-up were predictors of poor 5-year follow-up. CONCLUSION: Despite clear national and international guidelines, long-term follow-up after bariatric surgery is poor, especially for young men with poor early follow-up. PMID- 28657111 TI - Changing Me, Changing Us: Relationship Quality and Collective Efficacy as Major Outcomes in Systemic Couple Therapy. AB - We examine the sensitivity to change in the Evaluation of Social Systems (EVOS) scale, which assesses relationship quality and collective efficacy. In Study 1 we conducted a waitlist-control, short-term couple therapy RCT study (N = 43 couples) with five systemic therapy sessions treating communication and partnership problems; our intent was to provide high external validity. Construct validity of EVOS was assessed by comparison with additionally applied scales (Family Scales; Outcome Questionnaire, OQ-45.2). In Study 2, N = 332 individuals completed an experiment with high internal validity in order to verify sensitivity to change in three different social contexts. Results from Study 1 revealed a significant increase in relationship quality in the treatment group directly after treatment, as compared to the control group. Sensitivity to change was slightly better for EVOS than for other measures. While this positive change could not be fully sustained between posttreatment and a 4-week follow-up, EVOS score did not fall below baseline and pretreatment levels, supporting moderate-to large sensitivity to change. Study 2 supported high sensitivity to change in EVOS for couple relations, family relations, and work-team relationships. Therefore, EVOS can be used as an outcome measure to monitor the process of systemic interventions focusing on relationship quality and collective efficacy. Due to its sensitivity to change, EVOS can provide evidence for treatment success with regard to relationship aspects. PMID- 28657112 TI - Design and validation of a CT-guided robotic system for lung cancer brachytherapy. AB - PURPOSE: Currently, lung brachytherapy in clinical setting is a complex procedure. Operation accuracy depends on accurate positioning of the template; however, it is difficult to guarantee the positioning accuracy manually. Application of robotic-assisted systems can simplify the procedure and improve the manual positioning accuracy. Therefore, a novel CT-guided robotic system was developed to assist the lung cancer brachytherapy. METHODS: A four degree-of freedom (DOF) robot, controlled by a lung brachytherapy treatment planning system (TPS) software, was designed and manufactured to assist the template positioning. Target position of the template can be obtained from the treatment plan, thus the robot is driven to the target position automatically. The robotic system was validated in both the laboratory and the CT environment. In laboratory environment, a 3D laser tracker and an inertial measurement unit (IMU) were used to measure the mechanical accuracy in air, which includes positioning accuracy and position repeatability. Working reliability was also validated in this procedure by observing the response reliability and calculating the position repeatability. Imaging artifacts and accuracy of the robot registration were validated in the CT environment by using an artificial phantom with fiducial markers. CT images were obtained and used to test the image artifact and calculate the registration accuracy. Phantom experiments were conducted to test the accuracy of needle insertion by using a transparent hydrogel phantom with a high imitation artificial phantom. Also, the efficiency was validated in this procedure by comparing time costs in manual positioning with robotic positioning under the same experimental conditions. RESULTS: The robotic system achieved the positioning accuracy of 0.28 +/- 0.25 mm and the position repeatability of 0.09 +/- 0.11 mm. Experimental results showed that the robot was CT-compatible and responded reliably to the control commands. The mean registration accuracy of the robotic system was 0.49 +/- 0.29 mm. Phantom experiments indicated that the accuracy of needle insertion was 1.5 +/- 1.7 mm at a depth ranging from 30 to 80 mm. The time used to adjust the template to the target position was 12 min on average by robotic system automatically. An average of 30 min was saved compared with the manual positioning procedure in phantom experiments. CONCLUSIONS: This paper describes the design and experimental validation of a novel CT-guided robotic system for lung cancer brachytherapy. The robotic system was validated in a number of aspects which prove that it was capable of locating the template with clinically acceptable accuracy in the CT environment. All experimental results indicated that the system is reliable and ready to be applied to further studies on animals. PMID- 28657113 TI - High burden of coronary atherosclerosis in patients with cirrhosis. AB - BACKGROUND: Population studies report increased cardiovascular mortality in patients with cirrhosis. Coronary artery disease may be a trait of end-stage liver disease, but whether it is frequent or extensive in cirrhosis in general is unknown. Thus, we aimed to assess the prevalence and extent of coronary artery disease in unselected cirrhosis patients. MATERIALS AND METHODS: Using coronary computed tomography angiography, we investigated 52 patients from all Child-Pugh classes and aetiologies of cirrhosis without known cardiac disease for presence and severity of coronary artery disease in a cross-sectional design. Persons referred with new-onset chest pain served as controls. RESULTS: The prevalence of coronary artery disease was not significantly different between cirrhosis patients and controls (77% vs. 65%, P=0.19). However, cirrhosis patients had a markedly higher coronary artery calcification (Agatston) score than controls (120 [interquartile range, 0-345] vs. 5 [interquartile range, 0-86] HU, P=0.001). Likewise, patients with cirrhosis had a higher prevalence of extensive (>=5 coronary segments involved; 45% vs. 18%, P=0.01) and multivessel coronary disease (>=2 vessels involved; 75% vs. 53%, P=0.02). Furthermore, the total plaque volume whether noncalcified or calcified was higher in cirrhosis (117 [interquartile range, 0-310] vs. 36 [interquartile range, 0-148] mm3 , P=0.02). CONCLUSION: Coronary artery disease is equally prevalent in patients with cirrhosis and subjects with new-onset chest pain, but cirrhosis patients have more extensive and severe disease including several coronary high-risk features associated with myocardial ischaemia and a poor clinical outcome. The potential of preventive measures for coronary artery disease in cirrhosis needs attention. PMID- 28657114 TI - Development of a flattening filter free multiple source model for use as an independent, Monte Carlo, dose calculation, quality assurance tool for clinical trials. AB - PURPOSE: The Imaging and Radiation Oncology Core-Houston (IROC-H) Quality Assurance Center (formerly the Radiological Physics Center) has reported varying levels of compliance from their anthropomorphic phantom auditing program. IROC-H studies have suggested that one source of disagreement between institution submitted calculated doses and measurement is the accuracy of the institution's treatment planning system dose calculations and heterogeneity corrections used. In order to audit this step of the radiation therapy treatment process, an independent dose calculation tool is needed. METHODS: Monte Carlo multiple source models for Varian flattening filter free (FFF) 6 MV and FFF 10 MV therapeutic x ray beams were commissioned based on central axis depth dose data from a 10 * 10 cm2 field size and dose profiles for a 40 * 40 cm2 field size. The models were validated against open-field measurements in a water tank for field sizes ranging from 3 * 3 cm2 to 40 * 40 cm2 . The models were then benchmarked against IROC-H's anthropomorphic head and neck phantom and lung phantom measurements. RESULTS: Validation results, assessed with a +/-2%/2 mm gamma criterion, showed average agreement of 99.9% and 99.0% for central axis depth dose data for FFF 6 MV and FFF 10 MV models, respectively. Dose profile agreement using the same evaluation technique averaged 97.8% and 97.9% for the respective models. Phantom benchmarking comparisons were evaluated with a +/-3%/2 mm gamma criterion, and agreement averaged 90.1% and 90.8% for the respective models. CONCLUSIONS: Multiple source models for Varian FFF 6 MV and FFF 10 MV beams have been developed, validated, and benchmarked for inclusion in an independent dose calculation quality assurance tool for use in clinical trial audits. PMID- 28657115 TI - Monosynaptic retrograde tracing of neurons expressing the G-protein coupled receptor Gpr151 in the mouse brain. AB - GPR151 is a G-protein coupled receptor for which the endogenous ligand remains unknown. In the nervous system of vertebrates, its expression is enriched in specific diencephalic structures, where the highest levels are observed in the habenular area. The habenula has been implicated in a range of different functions including behavioral flexibility, decision making, inhibitory control, and pain processing, which makes it a promising target for treating psychiatric and neurological disease. This study aimed to further characterize neurons expressing the Gpr151 gene, by tracing the afferent connectivity of this diencephalic cell population. Using pseudotyped rabies virus in a transgenic Gpr151-Cre mouse line, monosynaptic afferents of habenular and thalamic Gpr151 expressing neuronal populations could be visualized. The habenular and thalamic Gpr151 systems displayed both shared and distinct connectivity patterns. The habenular neurons primarily received input from basal forebrain structures, the bed nucleus of stria terminalis, the lateral preoptic area, the entopeduncular nucleus, and the lateral hypothalamic area. The Gpr151-expressing neurons in the paraventricular nucleus of the thalamus was primarily contacted by medial hypothalamic areas as well as the zona incerta and projected to specific forebrain areas such as the prelimbic cortex and the accumbens nucleus. Gpr151 mRNA was also detected at low levels in the lateral posterior thalamic nucleus which received input from areas associated with visual processing, including the superior colliculus, zona incerta, and the visual and retrosplenial cortices. Knowledge about the connectivity of Gpr151-expressing neurons will facilitate the interpretation of future functional studies of this receptor. PMID- 28657116 TI - Short-term atrazine exposure at breeding has no impact on Blanchard's cricket frog (Acris blanchardi) reproductive success. AB - Studies of endocrine-disrupting contaminants have focused on early-life exposures, but later exposures could impact fitness. We exposed adult frogs (Acris blanchardi) at reproduction to ecologically relevant atrazine concentrations (0, 1, or 10 ug/L) in outdoor arenas. We measured likelihood of breeding and number of resulting tadpoles. Atrazine impacted neither the probability of breeding nor the number of tadpoles produced, suggesting anuran reproductive success may not be impacted by short-term exposure to low concentrations. Environ Toxicol Chem 2017;36:3284-3288. (c) 2017 SETAC. PMID- 28657117 TI - Low-grade intraductal carcinoma of the prostate: an idea whose time has not yet come. PMID- 28657118 TI - Clinicopathological findings in female-to-male gender-affirming breast surgery. AB - AIMS: Gender dysphoria is a diagnosis whereby an individual identifies as the opposite gender. The management of patients seeking female-to-male (FTM) transition includes hormonal therapy and surgical intervention, including mastectomy. The aim of this study was to characterize the immunohistological findings in resection specimens from FTM patients. METHODS AND RESULTS: We reviewed 68 cases (67 patients, one with re-excision) of FTM breast tissue resection by collecting clinical data, reviewing breast imaging and pathology reports (gross fibrous density, specimen weight, and number of cassettes submitted), and reviewing pathology slides [number of tissue pieces submitted, number of terminal duct lobule units (TDLUs), and the presence of histological findings]. Significant histological findings were present in 51 of 68 (75.0%) cases, including one case (1.5%) of flat epithelial atypia. Fibrocystic changes were the most common finding (27/68, 39.7%), followed by gynaecomastoid change, fibrotic stage, (22/68, 32.4%), and fibroadenomatoid change (11/68, 16.2%). Fibrocystic change was associated with increased numbers of TDLUs, and gynaecomastoid change was associated with lower body mass index and decreased numbers of TDLUs. Gynaecomastoid change showed a moderate proportion of luminal epithelial cells with strong-intensity immunohistochemical staining for oestrogen receptor, progesterone receptor, and androgen receptor, and a three-layered epithelium demonstrated by the use of cytokeratin 5/6 immunohistochemistry. CONCLUSIONS: We identified gynaecomastoid change at a significantly higher rate than previously reported in female patients. We support the continued gross and histological evaluation of FTM specimens in light of the identification of atypia in one case. PMID- 28657119 TI - Ultralong Phosphorescence of Water-Soluble Organic Nanoparticles for In Vivo Afterglow Imaging. AB - Afterglow or persistent luminescence eliminates the need for light excitation and thus circumvents the issue of autofluorescence, holding promise for molecular imaging. However, current persistent luminescence agents are rare and limited to inorganic nanoparticles. This study reports the design principle, synthesis, and proof-of-concept application of organic semiconducting nanoparticles (OSNs) with ultralong phosphorescence for in vivo afterglow imaging. The design principle leverages the formation of aggregates through a top-down nanoparticle formulation to greatly stabilize the triplet excited states of a phosphorescent molecule. This prolongs the particle luminesce to the timescale that can be detected by the commercial whole-animal imaging system after removal of external light source. Such ultralong phosphorescent of OSNs is inert to oxygen and can be repeatedly activated, permitting imaging of lymph nodes in living mice with a high signal-to noise ratio. This study not only introduces the first category of water-soluble ultralong phosphorescence organic nanoparticles but also reveals a universal design principle to prolong the lifetime of phosphorescent molecules to the level that can be effective for molecular imaging. PMID- 28657120 TI - Genetic diversity and antifungal susceptibility of Fusarium isolates in onychomycosis. AB - Fusarium species have emerged as an important human pathogen in skin disease, onychomycosis, keratitis and invasive disease. Onychomycosis caused by Fusarium spp. The infection has been increasingly described in the immunocompetent and immunosuppressed hosts. Considering onychomycosis is a difficult to treat infection, and little is known about the genetic variability and susceptibility pattern of Fusarium spp., further studies are necessary to understand the pathogenesis and better to define the appropriate antifungal treatment for this infection. Accordingly, the objective of this study was to describe the in vitro susceptibility to different antifungal agents and the genetic diversity of 35 Fusarium isolated from patients with onychomycosis. Fusarium spp. were isolated predominantly from female Caucasians, and the most frequent anatomical location was the nail of the hallux. Results revealed that 25 (71.4%) of isolates belonged to the Fusarium solani species complex, followed by 10 (28.5%) isolates from the Fusarium oxysporum species complex. Noteworthy, the authors report the first case of Neocosmospora rubicola isolated from a patient with onychomycosis. Amphotericin B was the most effective antifungal agent against the majority of isolates (60%, MIC <=4 MUg/mL), followed by voriconazole (34.2%, MIC <=4 MUg/mL). In general, Fusarium species presented MIC values >64 MUg/mL for fluconazole, itraconazole and terbinafine. Accurate pathogen identification, characterisation and susceptibility testing provide a better understanding of pathogenesis of Fusarium in onychomycosis. PMID- 28657122 TI - Agreement and diagnostic accuracy of vision screening in children by teachers, community eye-health workers and vision technicians. AB - BACKGROUND: To compare the agreement and diagnostic accuracy of vision screening conducted by trained community eye-health workers (CEHWs) and teachers with reference to vision technicians in Movva Mandal (sub-district) in Krishna District in the Indian state of Andhra Pradesh. METHODS: As part of a large epidemiological study on visual impairment in children, vision screening was conducted in all the schools in a sub-district. The children were screened using a screening card with 6/12 tumbling E optotypes by trained CEHWs, teachers and a vision technician. Teachers were included if they had screened at least 100 children and had at least five children identified with visual impairment. RESULTS: Of a total 6,197 children from 75 schools, 4,929 children were screened by all three categories of examiners (one vision technician, five CEHWs and 79 teachers). The overall agreement between the vision technician and CEHWs was 0.84 (95 per cent CI: 0.79-0.9) with a range of 0.77-0.9. Overall sensitivity of CEHWs to detect visual impairment was 83.3 per cent (95 per cent CI: 73.6-90.6) with a range of 71.4-87.1 per cent. Overall agreement of the five teachers with the vision technician was 0.81 (95 per cent CI: 0.74-0.88) with a range of 0.32-0.92. The overall sensitivity of teachers to detect vision problem was 72.3 per cent (95 per cent CI: 61.4-81.6) with a range from 20 per cent to 85.7 per cent and specificity was near 100 per cent. CONCLUSION: There was no significant difference in the agreement and diagnostic accuracy of CEHWs and teachers compared to those of the vision technician. There was a large variability among teachers, which needs to be considered in school vision screening programs. PMID- 28657121 TI - Differential UBE2C and HOXA1 expression in melanocytic nevi and melanoma. AB - BACKGROUND: Recent molecular advances suggest that Spitz nevi and other spitzoid neoplasms are biologically distinct from melanoma and conventional nevi. The ubiquitin ligase UBE2C and the homeobox transcription factor HOXA1 are candidate oncogenes in melanoma. METHODS: Using RNA expression analysis and immunohistochemistry, we evaluated these biomarkers in Spitz nevi (n = 20), melanoma (n = 20), and by immunohistochemistry in conventional nevi (n = 20). RESULTS: RNA analysis with branched DNA multiplex assay identified upregulation of UBE2C in melanomas vs Spitz nevi (P = .003), whereas HOXA1 was downregulated in melanoma (P < .0001). Immunohistochemical analysis confirmed increased nuclear expression of UBE2C in melanoma (mean = 18% of cells; range 3%-44%) when compared with Spitz nevi (mean = 9%; range 2%-28%; P = .001) and conventional nevi (mean = 1.5%; range 0-9%; P < .0001). Strong UBE2C staining was identified in cells undergoing mitosis. UBE2C RNA and protein detection correlated with mitotic rate (P < .0001). On the other hand, HOXA1 nuclear staining was low in melanoma (mean = 69%; range 5%-100%) when compared with Spitz nevi (mean = 94%; range 66%-100%; P = .0024) and conventional nevi (mean = 94%; range 83%-99%; P = .009). CONCLUSIONS: UBE2C and HOXA1 RNA and protein are differentially expressed in conventional and Spitz nevi and melanoma. PMID- 28657123 TI - The role of skeletal muscle contractile duration throughout the whole day: reducing sedentary time and promoting universal physical activity in all people. AB - A shared goal of many researchers has been to discover how to improve health and prevent disease, through safely replacing a large amount of daily sedentary time with physical activity in everyone, regardless of age and current health status. This involves contrasting how different muscle contractile activity patterns regulate the underlying molecular and physiological responses impacting health related processes. It also requires an equal attention to behavioural feasibility studies in extremely unfit and sedentary people. A sound scientific principle is that the body is constantly sensing and responding to changes in skeletal muscle metabolism induced by contractile activity. Because of that, the rapid time course of health-related responses to physical inactivity/activity patterns are caused in large part directly because of the variable amounts of muscle inactivity/activity throughout the day. However, traditional modes and doses of exercise fall far short of replacing most of the sedentary time in the modern lifestyle, because both the weekly frequency and the weekly duration of exercise time are an order of magnitude less than those for people sitting inactive. This can explain why high amounts of sedentary time produce distinct metabolic and cardiovascular responses through inactivity physiology that are not sufficiently prevented by low doses of exercise. For these reasons, we hypothesize that maintaining a high metabolic rate over the majority of the day, through safe and sustainable types of muscular activity, will be the optimal way to create a healthy active lifestyle over the whole lifespan. PMID- 28657124 TI - LARGE-PD: Examining the genetics of Parkinson's disease in Latin America. PMID- 28657125 TI - Excess Electron Transfer through DNA Duplexes Comprising a Metal-Mediated Base Pair. AB - Excess electron transfer through one set of DNA duplexes comprising either one or two metal-mediated thymine-HgII -thymine base pairs was studied. Towards this end, the metal-mediated base pair(s) were introduced between an artificial nucleoside bearing a N,N,N',N'-tetramethyl-1,5-diaminonaphthalene derivative (dN, acting as a photoinducible electron donor) and 5-bromo-2'-deoxyuridine (dB, acting as an electron acceptor). Upon one-electron reduction, dB loses a bromide ion. The amount of unreacted dB remaining after irradiation-determined by LC/ICP MS-was used to evaluate the charge-transfer efficiency across the metal-mediated base pair(s). Reference measurements with canonical adenine:thymine base pairs prove the applicability of this approach for the detection of charge transfer in DNA. The data indicate that, for the set of DNA duplexes under investigation, excess electron transfer across a thymine-HgII -thymine base pair proceeds with low efficiency, comparable to the transfer across a thymine:thymine mispair. Two contiguous thymine-HgII -thymine base pairs effectively shut down excess electron transfer. PMID- 28657126 TI - A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss. AB - Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor mutation p.T144_E145insPFQ has been described as one of the causes for LCCS1 whereas LAAHD is caused by a heterocompound FinMajor mutation together with p.R569H, p.V617M or p.I684T missense mutation. None of these heterocompound missense mutations have previously been reported as homozygous states. Here we present the clinical features of 2 siblings with a homozygous p.I684T mutation in GLE1. The patients suffered from similar, but milder symptoms than in LCCS1 and LAAHD, surviving up to 6 months before they died due to a progressive disease course including respiratory failure. Arthrogryposis, lack of spontaneous movements, and epilepsy were notable in both cases and lack of anterior horn cells was identified in autopsy samples. Our studies on patient-derived fibroblasts show that the homozygous p.I684T impairs the nuclear localization of GLE1 further confirming the pathogenic role of this mutation. PMID- 28657127 TI - Thermal buffering capacity of the germination phenotype across the environmental envelope of the Cactaceae. AB - Recruitment from seeds is among the most vulnerable stage for plants as global temperatures change. While germination is the means by which the vast majority of the world's flora regenerate naturally, a framework for accurately predicting which species are at greatest risk of germination failure during environmental perturbation is lacking. Taking a physiological approach, we assess how one family, the Cactaceae, may respond to global temperature change based on the thermal buffering capacity of the germination phenotype. We selected 55 cactus species from the Americas, all geo-referenced seed collections, reflecting the broad environmental envelope of the family across 70 degrees of latitude and 3700 m of altitude. We then generated empirical data of the thermal germination response from which we estimated the minimum (Tb ), optimum (To ) and ceiling (Tc ) temperature for germination and the thermal time (theta50 ) for each species based on the linearity of germination rate with temperature. Species with the highest Tb and lowest Tc germinated fastest, and the interspecific sensitivity of the germination rate to temperature, as assessed through theta50 , varied tenfold. A left-skewed asymmetry in the germination rate with temperature was relatively common but the unimodal pattern typical of crop species failed for nearly half of the species due to insensitivity to temperature change at To . For 32 fully characterized species, seed thermal parameters correlated strongly with the mean temperature of the wettest quarter of the seed collection sites. By projecting the mean temperature of the wettest quarter under two climate change scenarios, we predict under the least conservative scenario (+3.7 degrees C) that 25% of cactus species will have reduced germination performance, whilst the remainder will have an efficiency gain, by the end of the 21st century. PMID- 28657128 TI - Sea-ice loss boosts visual search: fish foraging and changing pelagic interactions in polar oceans. AB - Light is a central driver of biological processes and systems. Receding sea ice changes the lightscape of high-latitude oceans and more light will penetrate into the sea. This affects bottom-up control through primary productivity and top-down control through vision-based foraging. We model effects of sea-ice shading on visual search to develop a mechanistic understanding of how climate-driven sea ice retreat affects predator-prey interactions. We adapt a prey encounter model for ice-covered waters, where prey-detection performance of planktivorous fish depends on the light cycle. We use hindcast sea-ice concentrations (past 35 years) and compare with a future no-ice scenario to project visual range along two south-north transects with different sea-ice distributions and seasonality, one through the Bering Sea and one through the Barents Sea. The transect approach captures the transition from sub-Arctic to Arctic ecosystems and allows for comparison of latitudinal differences between longitudes. We find that past sea ice retreat has increased visual search at a rate of 2.7% to 4.2% per decade from the long-term mean; and for high latitudes, we predict a 16-fold increase in clearance rate. Top-down control is therefore predicted to intensify. Ecological and evolutionary consequences for polar marine communities and energy flows would follow, possibly also as tipping points and regime shifts. We expect species distributions to track the receding ice-edge, and in particular expect species with large migratory capacity to make foraging forays into high-latitude oceans. However, the extreme seasonality in photoperiod of high-latitude oceans may counteract such shifts and rather act as a zoogeographical filter limiting poleward range expansion. The provided mechanistic insights are relevant for pelagic ecosystems globally, including lakes where shifted distributions are seldom possible but where predator-prey consequences would be much related. As part of the discussion on photoperiodic implications for high-latitude range shifts, we provide a short review of studies linking physical drivers to latitudinal extent. PMID- 28657130 TI - A compact and facile microfluidic droplet creation device using a piezoelectric diaphragm micropump for droplet digital PCR platforms. AB - We have exploited a compact and facile microfluidic droplet creation device consisting of a poly(dimethylsiloxane) microfluidic chip possessing T-junction channel geometry, two inlet reservoirs, and one outlet reservoir, and a piezoelectric (PZT) diaphragm micropump with controller. Air was evacuated from the outlet reservoir using the PZT pump, reducing the pressure inside. The reduced pressure within the outlet reservoir pulled oil and aqueous solution preloaded in the inlet reservoirs into the microchannels, which then merged at the T-junction, successfully forming water-in-oil emulsion droplets at a rate of ~1000 per second with minimal sample loss. We confirmed that the onset of droplet formation occurred immediately after turning on the pump (<1 s). Over repeated runs, droplet formation was highly reproducible, with droplet size purity (polydispersity, <4%) comparable to that achieved using other microfluidic droplet preparation techniques. We also demonstrated single-molecule PCR amplification in the created droplets, suggesting that the device could be used for effective droplet digital PCR platforms in most laboratories without requiring great expense, space, or time for acquiring technical skills. PMID- 28657129 TI - Acetyl-CoA production from pyruvate is not necessary for preservation of myelin. AB - Oligodendrocytes and Schwann cells not only form myelin in the central and peripheral nervous system, but also provide metabolic and trophic support to the axons they ensheathe. Acetyl-CoA is potentially a key molecule in Schwann cells and oligodendrocytes because it is at the crossroads of cellular lipid biosynthesis and energy generation. The main route for acetyl-CoA production is the oxidation of pyruvate by the pyruvate dehydrogenase complex (PDC). PDC deficiency in humans results in neurodegeneration and developmental impairments in both white and gray matter structures. To address the importance of PDC in myelinating glia, we deleted Pdha1 gene specifically in oligodendrocytes and Schwann cells. Surprisingly, sciatic and optic nerve morphology and the motor performance of Pdha1f/Y; CnpCre/+ mice are undistinguishable from those of controls at 1 month of age. In addition, myelin is stably maintained for at least 10 months. However, Pdha1f/Y; CnpCre/+ mice showed reduced fiber density and signs of axonal degeneration in both sciatic and optic nerves from 6 months of age. In contrast, 10 month-old mice bearing a floxed Pdha1 gene with either P0 Cre (expressed only by Schwann cells) or NG2-CreER (expressed in oligodendrocyte precursor cells) do not show any sign of axonal pathology or alterations in myelin structure or thickness. This indicates that the axonopathy is specific to the Pdha1f/Y; CnpCre/+ mice. Taken together, these results suggest that acetyl CoA derived from pyruvate is not necessary for myelin maintenance and, thus, myelin-forming cells are not likely to contribute to the pathophysiology of PDC deficiency. PMID- 28657131 TI - A 37-year-old Menkes disease patient-Residual ATP7A activity and early copper administration as key factors in beneficial treatment. AB - Menkes disease (MD) is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving MD patient (37 years) receiving early-onset and long-term copper treatment. He has few neurological symptoms without connective tissue disturbances; and a missense ATP7A variant, p.(Pro852Leu), which results in impaired protein trafficking while the copper transport function is spared. These findings suggest that some cuproenzymes maintain their function when sufficient copper is provided to the cells; and underline the importance of early initiated copper treatment, efficiency of which is likely to be dependent on the mutant ATP7A function. PMID- 28657132 TI - Two New Sesquiterpene Alcohols Isolated from Senecio hadiensis Forssk. Grown in Saudi Arabia. AB - Phytochemical investigation on the aerial parts of Senecio hadiensis Forssk. led to the isolation of two new sesquiterpenoids, presilphiperfolan 2alpha,5alpha,8alpha-triol (1) and presilphiperfolan-2alpha,5alpha,8alpha,10alpha tetraol (2) featuring the rare presilphiperfolane-type frameworks. The structures of 1 and 2 were elucidated on the basis of extensive spectroscopic (1D- and 2D NMR, HR-ESI-MS) methods and by comparison with the literature data. The isolates 1 and 2 were evaluated in-vitro for antiinflammatory, cytotoxic, and peroxisome proliferator activated receptor alpha and gamma (PPARalpha and PPARgamma) agonistic activities. PMID- 28657133 TI - Assessment of efficacy of two chlorhexidine mouthrinses on oral hygiene and gingival health in adolescents wearing two types of orthodontic brackets. AB - OBJECTIVE: To investigate the efficacy of two formulations of chlorhexidine 0.2% (CHX) mouthrinses in terms of oral hygiene and gingival health status in adolescents with fixed orthodontic appliances wearing two different types of brackets during 18 weeks. STUDY POPULATION AND METHODOLOGY: Eighty subjects were randomly divided into two equal groups according to brackets type: (i) metal stainless steel, (ii) ceramic. Four weeks after the placement of the fixed orthodontic appliances the subjects from each group were randomly allocated into two equal subgroups and were provided with two different mouthrinses for 14 days: (i) alcohol-free CHX, (ii) CHX with antidiscoloration system (CHX-ADS). Assessment was carried out according to gingival index (GI) and oral hygiene index-simplified (OHI-S) performed prior to the placement of the appliance (t1 ), 6 weeks (t2 ), and 18 weeks (t3 ) after the placement. To analyse the data, two way mixed model MANOVA. Pearson correlations, one-way ANOVA and Independent Samples t test were conducted. RESULTS: Statistically significant decrease in GI and OHI-S indices after 6 weeks and then increase after 18 weeks for all groups was found. Both GI and OHI-S values were lower in subjects wearing ceramic brackets, with statistically significant difference for GI after the usage of the mouthrinse for 14 days, at t2 (P<.05). CONCLUSION: The results revealed that the ceramic brackets as well as usage of CHX-ADS resulted in improved gingival status. PMID- 28657134 TI - Phototherapy for treating foot ulcers in people with diabetes. AB - BACKGROUND: Foot ulcers are a disabling complication of diabetes that affect 15% to 25% of people with diabetes at some time in their lives. Phototherapy is a relatively new, non-invasive, and pain-free treatment method, which promotes the ulcer repair process through multiple mechanisms such as increased cell growth and vascular activity. Phototherapy may be used as an alternative approach for the treatment of foot ulcers in people with diabetes, but the evidence for its effect compared with placebo or other treatments has not yet been established. OBJECTIVES: To assess the effects of phototherapy for the treatment of foot ulcers in people with diabetes. SEARCH METHODS: We searched the Cochrane Wounds Specialised Register (11 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 10), Ovid MEDLINE (11 October 2016), Ovid MEDLINE (In-Process & Other Non-Indexed Citations) (11 October 2016), Ovid Embase (11 October 2016), EBSCO CINAHL Plus (11 October 2016), and China National Knowledge Infrastructure (24 June 2017). We also searched clinical trials registries for ongoing and unpublished studies on 24 June 2017, and screened reference lists to identify additional studies. We used no restrictions with respect to language, date of publication, or study setting. SELECTION CRITERIA: Randomised controlled trials or cluster randomised controlled trials that 1) compared phototherapy with sham phototherapy, no phototherapy, or other physical therapy modalities, 2) compared different forms of phototherapy, or 3) compared phototherapy of different output power, wavelength, power density, or dose range, in adults with diabetes and an open foot ulcer of any severity, in any setting. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and 'Risk of bias' assessment. We combined the study outcomes when appropriate. MAIN RESULTS: Eight trials with 316 participants met the inclusion criteria. Most of the included studies were single centre studies that were carried out in clinics or hospitals with a sample size ranging from 14 to 84. We generally considered the included studies to be at unclear or high risk of bias, as they had one domain at high risk of bias, or three or more domains at unclear risk of bias.We did not identify any studies that reported valid data for time to complete wound healing. Meta-analysis of four studies including 116 participants indicated that participants receiving phototherapy may experience a greater proportion of wounds completely healed during follow-up compared with those receiving no phototherapy/placebo (64.5% for the phototherapy group versus 37.0% for the no phototherapy/placebo group; risk ratio 1.57, 95% confidence interval 1.08 to 2.28; low-quality evidence, downgraded for study limitations and imprecision). Two studies mentioned adverse events in the results; one study with 16 participants suggested that there were no device-related adverse events, and the other study with 14 participants suggested that there was no clear difference between phototherapy and placebo group.Four studies reported change in ulcer size, but primarily due to high heterogeneity, they were not combined. Results from individual trials (including 16 participants to 84 participants) generally suggested that after two to four weeks of treatment phototherapy may result in a greater reduction in ulcer size but the quality of the evidence was low due to unclear risk of bias in the original trial and small sample size. We based the analyses for quality of life and amputations on only one study each (28 participants and 23 participants respectively); both outcomes showed no clear difference between the phototherapy group and the no phototherapy/placebo group. AUTHORS' CONCLUSIONS: This systematic review of randomised trials suggested that phototherapy, when compared to no phototherapy/placebo, may increase the proportion of wounds completely healed during follow-up and may reduce wound size in people with diabetes, but there was no evidence that phototherapy improves quality of life. Due to the small sample size and methodological flaws in the original trials, the quality of the evidence was low, which reduces our confidence in these results. Large, well designed randomised controlled trials are needed to confirm whether phototherapy could be an effective option for the treatment of foot ulcers in people with diabetes. PMID- 28657135 TI - DNA-methylation-mediated repression of miR-766-3p promotes cell proliferation via targeting SF2 expression in renal cell carcinoma. AB - Aberrant expression of microRNA (miRNA) emerges as an important role in a wide range of human malignances, and further identification as well as validation of the change of these endogenous non-protein-coding transcripts is warranted. Here, we identify a novel epigenetic regulation of miR-766-3p and investigate its biological function as well as clinical significance in renal cell carcinoma (RCC). Bisulfate analysis elucidates that the promoter of miR-766-3p is highly methylated in RCC tissues compared to non-tumorous tissues. Notably, the downregulation of miR-766-3p is obviously associated with clinical stage and worse prognosis in RCC patients. Upregulated miR-766-3p attenuates cell-cycle progression via targeting SF2 expression and additional SF2/P-AKT/P-ERK signaling pathway. Moreover, high level of SF2, as a novel oncoprotein in RCC, was significantly associated with poor survival in a large cohort of RCC specimens. Taken together, our study presents a road map for the prediction and validation of miR-766-3p/SF2 axis and thus imparts a therapeutic way for further RCC progression. PMID- 28657136 TI - Reprogramming mouse embryo fibroblasts to functional islets without genetic manipulation. AB - The constant quest for generation of large number of islets aimed us to explore the differentiation potential of mouse embryo fibroblast cells. Mouse embryo fibroblast cells isolated from 12- to 14-day-old pregnant mice were characterized for their surface markers and tri-lineage differentiation potential. They were subjected to serum-free media containing a cocktail of islet differentiating reagents and analyzed for the expression of pancreatic lineage transcripts. The islet-like cell aggregates (ICAs) was confirmed for their pancreatic properties via immunofluorecence for C-peptide, glucagon, and somatostain. They were positive for CD markers-Sca1, CD44, CD73, and CD90 and negative for hematopoietic markers-CD34 and CD45 at both transcription and translational levels. The transcriptional analysis of the ICAs at different day points exhibited up regulation of islet markers (Insulin, PDX1, HNF3, Glucagon, and Somatostatin) and down-regulation of MSC-markers (Vimentin and Nestin). They positively stained for dithizone, C-peptide, insulin, glucagon, and somatostatin indicating intact insulin producing machinery. In vitro glucose stimulation assay revealed three fold increase in insulin secretion as compared to basal glucose with insulin content being the same in both the conditions. The preliminary in vivo data on ICA transplantation showed reversal of diabetes in streptozotocin induced diabetic mice. Our results demonstrate for the first time that mouse embryo fibroblast cells contain a population of MSC-like cells which could differentiate into insulin producing cell aggregates. Hence, our study could be extrapolated for isolation of MSC-like cells from human, medically terminated pregnancies to generate ICAs for treating type 1 diabetic patients. PMID- 28657137 TI - A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency. AB - Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi system autosomal recessive disorders, where SCID might represent the main feature. PMID- 28657138 TI - Mixed-species aggregations in arthropods. AB - This review offers the first synthesis of the research on mixed-species groupings of arthropods and highlights the behavioral and evolutionary questions raised by such behavior. Mixed-species groups are commonly found in mammals and birds. Such groups are also observed in a large range of arthropod taxa independent of their level of sociality. Several examples are presented to highlight the mechanisms underlying such groupings, particularly the evidence for phylogenetic proximity between members that promotes cross-species recognition. The advantages offered by such aggregates are described and discussed. These advantages can be attributed to the increase in group size and could be identical to those of nonmixed groupings, but competition-cooperation dynamics might also be involved, and such effects may differ between homo- and heterospecific groups. We discuss three extreme cases of interspecific recognition that are likely involved in mixed-species groups as vectors for cross-species aggregation: tolerance behavior between two social species, one-way mechanism in which one species is attractive to others and two-way mechanism of mutual attraction. As shown in this review, the study of mixed-species groups offers biologists an interesting way to explore the frontiers of cooperation-competition, including the process of sympatric speciation. PMID- 28657139 TI - Complications Following the Insertion of Two Synthetic Mid-urethral Slings and Subsequent Removal. AB - OBJECTIVE: To determine outcomes after removal of two synthetic mid-urethral slings (MUS) at a tertiary care center. METHODS: Following IRB approval, a retrospective chart review of non-neurogenic, symptomatic women requiring re operation after >=2 MUS was performed. Data reviewed by a third party included: demographics, prior anti-incontinence surgery, complications, pelvic/urinary symptoms, subsequent investigations, surgical repair and outcomes (including UDI 6/IIQ-7 questionnaires) at a minimum 6 months follow-up. Cure was defined as being continent, no dyspareunia, and no additional surgical therapy. RESULTS: Between 2007 and 2014, 21 women met the inclusion criteria. Mean age was 57 years (range: 40-82) and mean follow-up was 30.2 months (range: 6-78). The majority of patients presented with one or more symptoms of voiding dysfunction (95%), urinary incontinence (86%), irritative voiding symptoms (62%), dyspareunia (57%), recurrent urinary tract infections (UTIs) (29%), vaginal extrusion (20%) and erosion involving the urinary tract (5%). Patients had a mean of 2 prior anti incontinence procedures (range 2-3). Over two-thirds had a combination of retropubic and transobturator MUS. Mean number of pre-operative investigations was 3.5 (1-6) including voiding cystourethrogram, cystoscopy and urodynamics. Two patients had complete remission, 14 partial remission, and five failed. Mean postoperative total UDI-6 and IIQ-7 scores at last clinic visit were 10 (range: 0 16/SD 4.1) and 11 (range: 0-28/SD 10.3), respectively. CONCLUSION: The management of women with suboptimal outcomes following two synthetic MUS from transvaginal excision results in modest symptomatic improvement but low permanent complete remission and frequent need for additional therapies. PMID- 28657140 TI - Evaluation of microextraction by packed sorbent, liquid-liquid microextraction and derivatization pretreatment of diet-derived phenolic acids in plasma by gas chromatography with triple quadrupole mass spectrometry. AB - Miniaturized sample pretreatments for the analysis of phenolic metabolites in plasma, involving protein precipitation, enzymatic deconjugation, extraction procedures, and different derivatization reactions were systematically evaluated. The analyses were conducted by gas chromatography with mass spectrometry for the evaluation of 40 diet-derived phenolic compounds. Enzyme purification was necessary for the phenolic deconjugation before extraction. Trimethylsilanization reagent and two different tetrabutylammonium salts for derivatization reactions were compared. The optimum reaction conditions were 50 MUL of trimethylsilanization reagent at 90 degrees C for 30 min, while tetrabutylammonium salts were associated with loss of sensitivity due to rapid activation of the inert gas chromatograph liner. Phenolic acids extractions from plasma were optimized. Optimal microextraction by packed sorbent performance was achieved using an octadecylsilyl packed bed and better recoveries for less polar compounds, such as methoxylated derivatives, were observed. Despite the low recovery for many analytes, repeatability using an automated extraction procedure in the gas chromatograph inlet was 2.5%. Instead, using liquid-liquid microextraction, better recoveries (80-110%) for all analytes were observed at the expense of repeatability (3.8-18.4%). The phenolic compounds in gerbil plasma samples, collected before and 4 h after the administration of a calafate extract, were analyzed with the optimized methodology. PMID- 28657141 TI - Neural correlates of atomoxetine improving inhibitory control and visual processing in Drug-naive adults with attention-deficit/hyperactivity disorder. AB - Atomoxetine improves inhibitory control and visual processing in healthy volunteers and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about the neural correlates of these two functions after chronic treatment with atomoxetine. This study aimed to use the counting Stroop task with functional magnetic resonance imaging (fMRI) and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to investigate the changes related to inhibitory control and visual processing in adults with ADHD. This study is an 8-week, placebo-controlled, double-blind, randomized clinical trial of atomoxetine in 24 drug-naive adults with ADHD. We investigated the changes of treatment with atomoxetine compared to placebo-treated counterparts using the counting Stroop fMRI and two CANTAB tests: rapid visual information processing (RVP) for inhibitory control and delayed matching to sample (DMS) for visual processing. Atomoxetine decreased activations in the right inferior frontal gyrus and anterior cingulate cortex, which were correlated with the improvement in inhibitory control assessed by the RVP. Also, atomoxetine increased activation in the left precuneus, which was correlated with the improvement in the mean latency of correct responses assessed by the DMS. Moreover, anterior cingulate activation in the pre-treatment was able to predict the improvements of clinical symptoms. Treatment with atomoxetine may improve inhibitory control to suppress interference and may enhance the visual processing to process numbers. In addition, the anterior cingulate cortex might play an important role as a biological marker for the treatment effectiveness of atomoxetine. Hum Brain Mapp 38:4850-4864, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28657142 TI - Comparative analysis of main bio-active components in the herb pair Danshen Honghua and its single herbs by ultra-high performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. AB - A sensitive, reliable, and powerful ultra-high performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry method was developed for simultaneous quantification of the 15 main bio-active components including phenolic acids and flavonoids within 13 min for the first time. The proposed method was first reported and validated by good linearity (r2 > 0.9975), limit of detection (1.12-7.01 ng/mL), limit of quantification (3.73-23.37 ng/mL), intra and inter-day precisions (RSD <= 1.92%, RSD <= 2.45%), stability (RSD <= 5.63%), repeatability (RSD <= 4.34%), recovery (96.84-102.12%), and matrix effects (0.92 1.02). The established analytical methodology was successfully applied to comparative analysis of main bio-active components in the herb pair Danshen Honghua and its single herbs. Compared to the single herb, the content of most flavonoid glycosides was remarkably increased in their herb pair, and main phenolic acids were decreased, conversely. The content changes of the main components in the herb pair supported the synergistic effects on promoting blood circulation and removing blood stasis. The results provide a scientific basis and reference for the quality control of Danshen-Honghua herb pair and the drug interactions based on variation of bio-active components in herb pairs. PMID- 28657143 TI - Emergence of drug resistance-associated variants and changes in serum lipid profiles in sofosbuvir plus ledipasvir-treated chronic hepatitis C patients. AB - Combination of sofosbuvir plus ledipasvir therapy has been expected to enhance sustained virological response (SVR) rates in hepatitis C virus (HCV) genotype 1 chronic infected patients. We analyzed the emergence of drug resistance associated variants (RAVs) in treatment failure and changes in lipid profiles in sofosbuvir/ledipasvir-treated patients. A total of 176 patients with chronic HCV genotype 1 infection without decompensated liver cirrhosis were treated with sofosbuvir/ledipasvir for 12 weeks. NS5A and NS5B RAVs were determined by either Invader assay or direct sequencing. Serum lipid-related markers were measured at the start of treatment and at week 4 in patients who received sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir therapies. SVR was achieved in 94.9% (167 out of 176) of patients. SVR12 rate was 97.1% for patietns with low frequncy (<25%) of baseline NS5A RAVs, but 82.8% for patients with high frequency (>75%) of NS5A RAVs. In multivariate regression analysis, higher albumin (odds ratio [OR] = 0.020 for presence; P = 0.007), and NS5A-L31/Y93 RAVs with a population frequency <75% (OR = 29.860 for presence; P = 0.023) were identified as significant independent predictors for SVR12. NS5A-Y93H substitutions were detected in all nine treatment failures at HCV relapse, and three out of six patients with NS5A inhibitor-naive patients achieved additional NS5A RAVs. Serum low-density lipoprotein cholesterol and apolipoprotein B levels were significantly elevated at week 4 in sofosbuvir/ledipasvir-treated patients. These elevations were greater than in ombitasvir/paritaprevir/ritonavir-treated patients. In conclusion, NS5A multi-RAVs are likely to develop in patients who fail to respond to sofosbuvir/ledipasvir therapy. Inhibition of HCV replication with sofosbuvir might affect lipid metabolism. PMID- 28657144 TI - Ptn functions downstream of C/EBPbeta to mediate the effects of cAMP on uterine stromal cell differentiation through targeting Hand2 in response to progesterone. AB - Ptn is a pleiotropic growth factor involving in the regulation of cellular proliferation and differentiation, but its biological function in uterine decidualization remains unknown. Here, we showed that Ptn was highly expressed in the decidual cells, and could induce the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1 which were two well-established differentiation markers for decidualization, suggesting an important role of Ptn in decidualization. In the uterine stromal cells, progesterone stimulated the expression of Ptn accompanied with an accumulation of intracellular cAMP level. Silencing of Ptn impeded the induction of progesterone and cAMP on the differentiation of uterine stromal cells. Administration of PKA inhibitor H89 resulted in a blockage of progesterone on Ptn expression. Further analysis evidenced that regulation of progesterone and cAMP on Ptn was mediated by C/EBPbeta. During in vitro decidualization, knockdown of Ptn could weaken the up regulation of Prl8a2 and Prl3c1 elicited by C/EBPbeta overexpression, while constitutive activation of Ptn reversed the repressive effects of C/EBPbeta siRNA on the expression of Prl8a2 and Prl3c1. Meanwhile, Ptn might mediate the regulation of C/EBPbeta on Hand2 which was a downstream target of Ptn in the differentiation of uterine stromal cells. Attenuation of Ptn or C/EBPbeta by specific siRNA blocked the stimulation of Hand2 by progesterone and cAMP. Collectively, Ptn may play a vital role in the progesterone-induced decidualization pathway. PMID- 28657145 TI - Macrophage Migration Inhibitory Factor (MIF) Gene Promotor Polymorphism Is Associated with Increased Fibrosis in Biliary Atresia Patients, but Not with Disease Susceptibility. AB - Two polymorphisms, rs755622 and rs5844572, in the promoter region of the macrophage migration inhibitory factor (MIF) gene influence the basal and/or induced transcriptional activity and have been linked to several inflammatory and autoimmune diseases. The aim of this study was to investigate the association between these two polymorphisms and disease susceptibility in patients with biliary atresia (BA). Allele frequencies of rs755622 and rs5844572 were assessed in 60 Egyptian infants with a confirmed diagnosis of BA. DNA was extracted from archival material. For the rs755622, samples were tested using Taqman real-time PCR, and for the rs5844572, samples were tested using fluorescence-based genotyping. The allele frequency in the general population was assessed in 141 healthy adults from the same geographical location. No statistical differences were observed in the allele frequencies of either rs755622 or rs5844572 between BA patients and controls. The homozygous and heterozygous short repeats (5/5, or 5/X) of rs5844572 were observed more frequently (16/28, 57.1%) in BA patients with mild to moderate fibrosis compared with those with marked fibrosis (10/32, 31.3%). The difference was statistically significant (P = 0.032). In conclusion, we observed no association between MIF rs755622 and rs5844572 polymorphisms and susceptibility to BA; however, the rs5844572 could be linked to the rate of progression of the disease and extent of fibrosis. PMID- 28657146 TI - An examination of advanced practice nurses' job satisfaction internationally. AB - AIM: To examine the level of job satisfaction of nurse practitioners/advanced practice nurses in developing and developed countries. BACKGROUND: The nurse practitioner/advanced practice nurse has the advanced, complex skills and experience to play an important role in providing equitable health care across all nations. INTRODUCTION: Key factors that contribute to health disparities include lack of access to global health human resources, the right skill mix of healthcare providers and the satisfaction and retention of quality workers. METHODS: The study utilized a descriptive analysis and cross-sectional survey methodology with quantitative and qualitative sections of 1419 job satisfaction survey respondents from an online survey. RESULTS: Age, number of hours worked in a week and length of time that nurse practitioners/advanced practice nurses worked in their current jobs were statistically significant in job satisfaction. A key barrier was the lack of respect from supervisors and physicians. DISCUSSION: It was clear from the number of comments in the qualitative section of the survey that having a wide scope of practice is rewarding and challenging to the nurse practitioner and advanced practice nurse. CONCLUSION AND IMPLICATIONS FOR HEALTH POLICY: The challenges to transform healthcare gaps of access into a better distribution of health care in all countries would constitute a systematic change in policy including providing education and training for doctors and nurses that will match the skills needed in the workplace; emphasizing the right skill mix for the healthcare team; supporting advanced practice nurses in the workplace; and utilizing all healthcare providers to the fullest extent of their abilities. PMID- 28657147 TI - LncRNA-PVT1 promotes pancreatic cancer cells proliferation and migration through acting as a molecular sponge to regulate miR-448. AB - The identification and characterization of long non-coding RNAs (lncRNAs) in diverse biological process has currently developed rapidly. LncRNA-PVT1, located adjacent to the MYC locus on chromosomal region 8q24, has been reported to be associated with many biological processes. However, the function and mechanism of PVT1 in pancreatic carcinoma (PC) is poorly understood. In this present study, we first measured the level of PVT1 in the PC cell lines and tissues by quantitative real-time PCR (qRT-PCR), and then employed loss-of-function and gain-of-function approaches to explore the association between PVT1 expression levels and PC cell proliferation/migration ability. Furthermore, bioinformatics analysis was utilized to show that PVT1 contains binding site for miR-448 and an inverse correlation between PVT1 and miR-448 was obtained in PC specimens. Additionally, dual luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) and applied biotin-avidin pulldown system were applied to further confirm that PVT1 directly bind with microRNA binding site harboring in the PVT1 sequence. Then, SERBP1 was identified as a target of miR-448 according to the gene expression array analysis of PC clinical samples. Together, we revealed that PVT1 functions as an endogenous "sponge" by competing for miR-448 binding to regulate the miRNA target SERBP1 and, therefore, promotes the proliferation and migration of PC cells. PMID- 28657149 TI - Incidence, procedural management, and clinical outcomes of coronary in-stent restenosis: Insights from the National VA CART Program. AB - BACKROUND: In-stent restenosis (ISR) remains a common clinical problem associated with significant morbidity. We sought to evaluate the temporal trends in incidence and procedural management of coronary restenosis as well as evaluate the association between different treatment modalities and clinical outcomes. METHODS: We identified all patients treated for coronary ISR within the Veterans Affairs Healthcare System from October 1, 2006 to September 30, 2014. The temporal trends in incidence as well as intraprocedural management were assessed. Among patients treated for single vessel restenosis, a propensity matched cohort was created for those treated with drug-eluting stents (DES) or other treatment modalities. Target vessel revascularization (TVR) and mortality were compared between the two subpopulations. RESULTS: From 2006 to 2014, 65,443 patients underwent percutaneous coronary intervention and 6,872 patients (10.5%) with 8,921 lesions were treated for ISR. The proportion of patients undergoing revascularization for restenosis increased 0.28% per year (P = 0.055). Among a propensity-matched cohort of 6,231, the rates of TVR (subdistribution HR: 0.623, 95% CI: 0.511-0.760) and mortality (HR: 0.730, 95% CI: 0.641-0.830) were significantly lower among patients treated with a DES compared with other treatments. After adjustment for known risk factors, treatment with DES continued to be associated with a reduction in mortality rate (Adjusted HR: 0.802, 95% CI: 0.704-0.913). CONCLUSIONS: There is a trend toward an increasing proportion of coronary interventions for ISR in a national cohort of Veterans and treatment with a DES is associated with the lowest rate of TVR and overall mortality. PMID- 28657148 TI - Association between mitochondrial DNA content and baseline serum levels of HBsAg in chronic hepatitis B infection. AB - Recent studies have demonstrated a potential link between mitochondrial DNA (mtDNA) content and cirrhosis or hepatocellular carcinoma (HCC). However, there are few studies evaluating mtDNA content as a noninvasive marker of chronic hepatitis B infection (CHB). In this study, we conducted a case-control study to determine mtDNA content in peripheral blood leukocyte (PBL) samples from 76 CHB cases naive to antivirus therapy and 96 healthy controls, and then evaluated the association between mtDNA content and baseline serum concentration of HBV markers. Consequently, CHB cases had significantly higher mtDNA content than healthy controls (1052.85 vs 618.98, P < 0.001). Pearson's correlation analysis revealed that mtDNA content was negatively correlated with the baseline levels of hepatitis B surface antigen (HBsAg) (r = -0.291, P = 0.011) in CHB patients. In a trend analysis, a statistically significant association was detected between lower mtDNA content and increasing levels of HBsAg (P = 0.015). In conclusion, our study provides the first epidemiological evidence that mtDNA content of CHB cases naive to antivirus therapy is significantly higher than healthy controls and the levels of mtDNA content is negatively associated with HBsAg. mtDNA content may serve as a potential noninvasive biomarker of CHB which may need more researches to validate. PMID- 28657151 TI - Joint genotype- and ancestry-based genome-wide association studies in admixed populations. AB - In genome-wide association studies (GWAS) genetic loci that influence complex traits are localized by inspecting associations between genotypes of genetic markers and the values of the trait of interest. On the other hand, admixture mapping, which is performed in case of populations consisting of a recent mix of two ancestral groups, relies on the ancestry information at each locus (locus specific ancestry). Recently it has been proposed to jointly model genotype and locus-specific ancestry within the framework of single marker tests. Here, we extend this approach for population-based GWAS in the direction of multimarker models. A modified version of the Bayesian information criterion is developed for building a multilocus model that accounts for the differential correlation structure due to linkage disequilibrium (LD) and admixture LD. Simulation studies and a real data example illustrate the advantages of this new approach compared to single-marker analysis or modern model selection strategies based on separately analyzing genotype and ancestry data, as well as to single-marker analysis combining genotypic and ancestry information. Depending on the signal strength, our procedure automatically chooses whether genotypic or locus-specific ancestry markers are added to the model. This results in a good compromise between the power to detect causal mutations and the precision of their localization. The proposed method has been implemented in R and is available at http://www.math.uni.wroc.pl/~mbogdan/admixtures/. PMID- 28657150 TI - Improving power for rare-variant tests by integrating external controls. AB - Due to the drop in sequencing cost, the number of sequenced genomes is increasing rapidly. To improve power of rare-variant tests, these sequenced samples could be used as external control samples in addition to control samples from the study itself. However, when using external controls, possible batch effects due to the use of different sequencing platforms or genotype calling pipelines can dramatically increase type I error rates. To address this, we propose novel summary statistics based single and gene- or region-based rare-variant tests that allow the integration of external controls while controlling for type I error. Our approach is based on the insight that batch effects on a given variant can be assessed by comparing odds ratio estimates using internal controls only vs. using combined control samples of internal and external controls. From simulation experiments and the analysis of data from age-related macular degeneration and type 2 diabetes studies, we demonstrate that our method can substantially improve power while controlling for type I error rate. PMID- 28657152 TI - An Efficient, "Burn in" Free Organic Solar Cell Employing a Nonfullerene Electron Acceptor. AB - A comparison of the efficiency, stability, and photophysics of organic solar cells employing poly[(5,6-difluoro-2,1,3-benzothiadiazol-4,7-diyl)-alt-(3,3'" di(2-octyldodecyl)-2,2';5',2";5",2'"-quaterthiophen-5,5'"-diyl)] (PffBT4T-2OD) as a donor polymer blended with either the nonfullerene acceptor EH-IDTBR or the fullerene derivative, [6,6]-phenyl C71 butyric acid methyl ester (PC71 BM) as electron acceptors is reported. Inverted PffBT4T-2OD:EH-IDTBR blend solar cell fabricated without any processing additive achieves power conversion efficiencies (PCEs) of 9.5 +/- 0.2%. The devices exhibit a high open circuit voltage of 1.08 +/- 0.01 V, attributed to the high lowest unoccupied molecular orbital (LUMO) level of EH-IDTBR. Photoluminescence quenching and transient absorption data are employed to elucidate the ultrafast kinetics and efficiencies of charge separation in both blends, with PffBT4T-2OD exciton diffusion kinetics within polymer domains, and geminate recombination losses following exciton separation being identified as key factors determining the efficiency of photocurrent generation. Remarkably, while encapsulated PffBT4T-2OD:PC71 BM solar cells show significant efficiency loss under simulated solar irradiation ("burn in" degradation) due to the trap-assisted recombination through increased photoinduced trap states, PffBT4T-2OD:EH-IDTBR solar cell shows negligible burn in efficiency loss. Furthermore, PffBT4T-2OD:EH-IDTBR solar cells are found to be substantially more stable under 85 degrees C thermal stress than PffBT4T 2OD:PC71 BM devices. PMID- 28657153 TI - Diagnostic reliability of Architect anti-HCV assay: Experience of a tertiary care hospital in India. AB - BACKGROUND & AIMS: Anti-HCV assays are prone to false positive results. Thus, accurate detection of HCV infection is critical for the timely therapeutic management. This study ascertained the reliability of Architect anti-HCV assay (Abbott) and to estimate the agreement of this assay with Ortho HCV 3.0 ELISA Test System with Enhanced SAVe (Ortho), HCV Tri-dot (Tri-dot) and HCV-PCR in a tertiary care setting. METHODS: A total of 78 788 consecutive sera were routinely screened for anti-HCV antibodies using Architect. All repeatedly reactive anti HCV sera (n=1000) and anti-HCV negative sera (n=300) were tested in Ortho and in Tri-dot assays. Representative proportions of sera (n=500) with various signal-to cut-off (S/Co) ratio were also compared with HCV-PCR. RESULTS: When Architect was compared with Ortho, Tri-dot, and HCV-PCR, the level of agreement as assessed by kappa were .26, .16, and .27 respectively. Using Latent class analysis (LCA), we found that sensitivity and specificity were 100% and 36.1% for Architect, 93.8% and 100% for Ortho and 63.8% and 100% for Tri-dot respectively. The median S/CO ratio of Architect and Ortho anti-HCV assays were significantly different between HCV-PCR positive and negative results (P<.0001). Furthermore, Architect S/CO ratio of >8 showed higher accuracy indices in both anti-HCV assays. CONCLUSIONS: Architect can be used as a screening assay because of its high sensitivity, high throughput, and short turnaround time. However, S/Co ratios of >=1 to <8 in Architect necessitates HCV PCR to identify current infection and or EIA to distinguish true positivity from false biological positivity. PMID- 28657154 TI - Tissue-engineered tendon constructs for rotator cuff repair in sheep. AB - Current rotator cuff repair commonly involves the use of single or double row suture techniques, and despite successful outcomes, failure rates continue to range from 20 to 95%. Failure to regenerate native biomechanical properties at the enthesis is thought to contribute to failure rates. Thus, the need for technologies that improve structural healing of the enthesis after rotator cuff repair is imperative. To address this issue, our lab has previously demonstrated enthesis regeneration using a tissue-engineered graft approach in a sheep anterior cruciate ligament (ACL) repair model. We hypothesized that our tissue engineered graft designed for ACL repair also will be effective in rotator cuff repair. The goal of this study was to test the efficacy of our Engineered Tissue Graft for Rotator Cuff (ETG-RC) in a rotator cuff tear model in sheep and compare this novel graft technology to the commonly used double row suture repair technique. Following a 6-month recovery, the grafted and contralateral shoulders were removed, imaged using X-ray, and tested biomechanically. Additionally, the infraspinatus muscle, myotendinous junction, enthesis, and humeral head were preserved for histological analysis of muscle, tendon, and enthesis structure. Our results showed that our ETC-RCs reached 31% of the native tendon tangent modulus, which was a modest, non-significant, 11% increase over that of the suture-only repairs. However, the histological analysis showed the regeneration of a native-like enthesis in the ETG-RC-repaired animals. This advanced structural healing may improve over longer times and may diminish recurrence rates of rotator cuff tears and lead to better clinical outcomes. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:289-299, 2018. PMID- 28657155 TI - Unexpected Importance of Aromatic-Aliphatic and Aliphatic Side Chain-Backbone Interactions in the Stability of Amyloids. AB - The role of aromatic and nonaromatic amino acids in amyloid formation has been elucidated by calculating interaction energies between beta-sheets in amyloid model systems using density functional theory (B3LYP-D3/6-31G*). The model systems were based on experimental crystal structures of two types of amyloids: (1) with aromatic amino acids, and (2) without aromatic amino acids. Data show that these two types of amyloids have similar interaction energies, supporting experimental findings that aromatic amino acids are not essential for amyloid formation. However, different factors contribute to the stability of these two types of amyloids. In the former, the presence of aromatic amino acids significantly contributes to the strength of interactions between side chains; interactions between aromatic and aliphatic side chains are the strongest, followed by aromatic-aromatic interactions, while aliphatic-aliphatic interactions are the weakest. In the latter, that is, the amyloids without aromatic residues, stability is provided by interactions of aliphatic side chains with the backbone and, in some cases, by hydrogen bonds. PMID- 28657156 TI - Multiple molecular dynamics simulations of human LOX-1 and Trp150Ala mutant reveal the structural determinants causing the full deactivation of the receptor. AB - Multiple classical molecular dynamics simulations have been applied to the human LOX-1 receptor to clarify the role of the Trp150Ala mutation in the loss of binding activity. Results indicate that the substitution of this crucial residue, located at the dimer interface, markedly disrupts the wild-type receptor dynamics. The mutation causes an irreversible rearrangement of the subunits interaction pattern that in the wild-type protein allows the maintaining of a specific symmetrical motion of the monomers. The subunits dislocation determines a loss of linearity of the arginines residues composing the basic spine and a consequent alteration of the long-range electrostatic attraction of the substrate. Moreover, the anomalous subunits arrangement observed in the mutated receptor also affects the integrity of the hydrophobic tunnel, actively involved in the short-range hydrophobic recognition of the substrate. The combined effect of these structural rearrangements generates the impairing of the receptor function. PMID- 28657157 TI - CyberKnife with integrated CT-on-rails: System description and first clinical application for pancreas SBRT. AB - PURPOSE: This article reports on the integration of a sliding-gantry CT-on-rails with a robotic linear accelerator. METHODS: The system consists of a SOMATOM Definition AS CT scanner (Siemens Healthcare, Forchheim, Germany) and a CyberKnife M6 FIM (Accuray, Inc., Sunnyvale, CA, USA). Additional movement programs were implemented in the robotic treatment table (RoboCouch, Accuray Inc.) to move between CT and treatment position. Acceptance testing was performed on the CT scanner according to AAPM83 guidelines, as well as safety tests for collision avoidance and electromagnetic (EM) compatibility. For the first clinical application of the system, daily dose was evaluated in five pancreas SBRT patients. A second envisioned use is the optimal alignment of the treatment beams to soft-tissue targets without the use of implanted fiducials. To this end, an offset vector feature has been implemented, which shifts the treatment center according to the daily position of the tumor relative to the spine (established by a CT scan). This offset can be applied by either moving the treatment couch (physical couch shift) or by moving the CyberKnife robot (virtual couch shift). An End-to-End (E2E) test was specifically designed to evaluate the accuracy of this feature using the Xsight Lung Tracking Phantom (Computerized Imaging Reference Systems, Inc., Norfolk, VA, USA). The position of the tumor with respect to the spine was varied by moving the insert inside the phantom and a CT scan was made for each position. The treatment plan was subsequently delivered to the phantom employing spine tracking. The test was repeated four times for a physical couch shift and four times for a virtual couch shift. RESULTS: All acceptance, safety and EM compatibility testing was successful. For the first pancreas SBRT patients treated using daily CT imaging, the volume of stomach, duodenum, or small bowel receiving >35 Gy was found to increase or remain constant during treatment; however, the clinical constraint of 5 cc was not violated. For the offset vector E2E test, the reference accuracy (without any tumor shift) was (0.74, -0.61, -0.33) mm in the inferior, left, and anterior direction respectively. The difference in deviation with respect to the reference was (-0.1 +/- 0.15, 0.01 +/- 0.16, -0.17 +/- 0.25) mm, when applying a physical couch shift. With a virtual couch shift, the deviations were (0.02 +/- 0.15, 0.06 +/- 0.23, -0.4 +/- 0.31) mm. CONCLUSIONS: The first combination of a CyberKnife treatment unit with a sliding-gantry CT scanner is operational in our department enabling future developments toward image-guided online-adaptive SBRT supported by diagnostic-quality CT imaging. PMID- 28657158 TI - Application of a dispersive solid-phase extraction method using an amino-based silica-coated nanomagnetic sorbent for the trace quantification of chlorophenoxyacetic acids in water samples. AB - Herein, an amino-based silica-coated nanomagnetic sorbent was applied for the effective extraction of two chlorophenoxyacetic acids (2-methyl-4 chlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid) from various water samples. The sorbent was successfully synthesized and subsequently characterized by scanning electron microscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. The analytes were extracted by the sorbent mainly through ionic interactions. Once the extraction of analytes was completed, they were desorbed from the sorbent and detected by high-performance liquid chromatography with ultraviolet detection. A number of factors affecting the extraction and desorption of the analytes were investigated in detail and the optimum conditions were established. Under the optimum conditions, the calibration curves were linear over the concentration range of 1-250, and based on a signal-to-noise ratio of 3, the method detection limits were determined to be 0.5 MUg/L for both analytes. Additionally, a preconcentration factor of 314 was achieved for the analytes. The average relative recoveries obtained from the fortified water samples varied in the range of 91-108% with relative standard deviations of 2.9 8.3%. Finally, the method was determined to be robust and effective for environmental water analysis. PMID- 28657160 TI - Ketamine as an adjuvant to opioids for cancer pain. AB - BACKGROUND: This is an update of a review first published in 2003 and updated in 2012.Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects. OBJECTIVES: To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults. SEARCH METHODS: For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017. SELECTION CRITERIA: The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre-existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient-reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update.Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The second study with 10 participants examined the addition of intravenous ketamine bolus in two different doses to ongoing morphine therapy, compared with placebo. Both of these studies reported reduction in pain intensity and reduction in morphine requirements when ketamine was added to opioid for refractory cancer pain. The new study identified by the updated search had a parallel group design and 185 participants. This placebo-controlled study examined rapid titration of subcutaneous ketamine to high dose (500 mg) in participants who were using different opioids. There were no differences between groups for patient-reported pain intensity.Pooling of the data from the three included trials was not appropriate because of clinical heterogeneity.The study examining intrathecal drug administration reported no adverse events related to ketamine. In the study using intravenous bolus administration, ketamine caused hallucinations in four of 10 participants. In the rapid dose escalation/high-dose subcutaneous ketamine study, there was almost twice the incidence of adverse events in the ketamine group, compared to the placebo group, with the most common adverse events being needle site irritation and cognitive disturbance. Two serious adverse events (bradyarrhythmia and cardiac arrest) thought to be related to ketamine were also reported in this trial.For all three studies there was an unclear risk of bias overall. Using GRADE, we judged the quality of the evidence to be very low due to study limitations and imprecision due to the small number of participants in all comparisons. AUTHORS' CONCLUSIONS: Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain. The evidence was of very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is high. Rapid dose escalation of ketamine to high dose (500 mg) does not appear to have clinical benefit and may be associated with serious adverse events. More randomised controlled trials (RCTs) examining specific low-dose ketamine clinical regimens in current use are needed. PMID- 28657161 TI - Unambiguous regiochemical assignment of sulfoquinovosyl mono- and diacylglycerols in parsley and spinach leaves by liquid chromatography/electrospray ionization sequential mass spectrometry assisted by regioselective enzymatic hydrolysis. AB - RATIONALE: Sulfoquinovosylmonoglycerides (SQMG) and sulfoquinovosyldiglycerides (SQDG) in the lipid extracts of parsley (Petroselinum crispum) and spinach (Spinacia oleracea) leaves were investigated. The aim of this work was to assess and establish the chemical characterization of fatty acyl chains in sulfolipids (SQMG and SQDG) and their regiochemistry. METHODS: A key component of this approach is a combination of hydrolysis reactions catalyzed by Lecitase(r) Ultra, which is a sn1 -regioselective hydrolase enzyme, and reversed-phase liquid chromatography with electrospray ionization and sequential mass spectrometry (RPLC/ESI-MS) by collision-induced dissociation (CID)-MSn (n = 2, 3). RESULTS: The occurrence of SQMG bearing 16:0 or 18:3 acyl chains was established for the first time. A regiochemistry-dependent fragmentation pattern of SQMG was attained whereby the sulfoquinovosyl anion ([C6 H11 O8 S]- at m/z 243.0) provides a diagnostic product ion. Regioselective enzymatic treatment also provided a posteriori confirmation of a widely accepted fragmentation rule for SQDG. The sulfoquinovosyl anion was found to play a role also in the fragmentation pattern of SQDG, whose regiochemical assignment could be ultimately confirmed by MS3 experiments. CONCLUSIONS: The predominant sulfolipid in leaf extracts of raw parsley (Petroselinum crispum) and spinach (Spinacia oleracea) was identified as SQDG 18:3/16:0, along with SQMG 18:3/0:0 and SQMG 16:0/0:0. The present CID-MS based method can be considered a successful approach to validate the regiochemical characterization of sulfolipids paving the way for their unambiguous characterization. PMID- 28657159 TI - Mapping the order and pattern of brain structural MRI changes using change-point analysis in premanifest Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that progressively affects motor, cognitive, and emotional functions. Structural MRI studies have demonstrated brain atrophy beginning many years prior to clinical onset ("premanifest" period), but the order and pattern of brain structural changes have not been fully characterized. In this study, we investigated brain regional volumes and diffusion tensor imaging (DTI) measurements in premanifest HD, and we aim to determine (1) the extent of MRI changes in a large number of structures across the brain by atlas-based analysis, and (2) the initiation points of structural MRI changes in these brain regions. We adopted a novel multivariate linear regression model to detect the inflection points at which the MRI changes begin (namely, "change-points"), with respect to the CAG-age product (CAP, an indicator of extent of exposure to the effects of CAG repeat expansion). We used approximately 300 T1-weighted and DTI data from premanifest HD and control subjects in the PREDICT-HD study, with atlas-based whole brain segmentation and change-point analysis. The results indicated a distinct topology of structural MRI changes: the change-points of the volumetric measurements suggested a central-to-peripheral pattern of atrophy from the striatum to the deep white matter; and the change points of DTI measurements indicated the earliest changes in mean diffusivity in the deep white matter and posterior white matter. While interpretation needs to be cautious given the cross sectional nature of the data, these findings suggest a spatial and temporal pattern of spread of structural changes within the HD brain. Hum Brain Mapp 38:5035-5050, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28657163 TI - Surface-Casting Synthesis of Mesoporous Zirconia with a CMK-5-Like Structure and High Surface Area. AB - About 15 years ago, the Ryoo group described the synthesis of CMK-5, a material consisting of a hexagonal arrangement of carbon nanotubes. Extension of the surface casting synthesis to oxide compositions, however, was not possible so far, in spite of many attempts. Here it is demonstrated, that crystalline mesoporous hollow zirconia materials with very high surface areas up to 400 m2 g 1 , and in selected cases in the form of CMK-5-like, are indeed accessible via such a surface casting process. The key for the successful synthesis is an increased interaction between the silica hard template surface and the zirconia precursor species by using silanol group-rich mesoporous silica as a hard template. The surface areas of the obtained zirconias exceed those of conventionally hard-templated ones by a factor of two to three. The surface casting process seems to be applicable also to other oxide materials. PMID- 28657162 TI - CodeMapper: semiautomatic coding of case definitions. A contribution from the ADVANCE project. AB - BACKGROUND: Assessment of drug and vaccine effects by combining information from different healthcare databases in the European Union requires extensive efforts in the harmonization of codes as different vocabularies are being used across countries. In this paper, we present a web application called CodeMapper, which assists in the mapping of case definitions to codes from different vocabularies, while keeping a transparent record of the complete mapping process. METHODS: CodeMapper builds upon coding vocabularies contained in the Metathesaurus of the Unified Medical Language System. The mapping approach consists of three phases. First, medical concepts are automatically identified in a free-text case definition. Second, the user revises the set of medical concepts by adding or removing concepts, or expanding them to related concepts that are more general or more specific. Finally, the selected concepts are projected to codes from the targeted coding vocabularies. We evaluated the application by comparing codes that were automatically generated from case definitions by applying CodeMapper's concept identification and successive concept expansion, with reference codes that were manually created in a previous epidemiological study. RESULTS: Automated concept identification alone had a sensitivity of 0.246 and positive predictive value (PPV) of 0.420 for reproducing the reference codes. Three successive steps of concept expansion increased sensitivity to 0.953 and PPV to 0.616. CONCLUSIONS: Automatic concept identification in the case definition alone was insufficient to reproduce the reference codes, but CodeMapper's operations for concept expansion provide an effective, efficient, and transparent way for reproducing the reference codes. PMID- 28657164 TI - Monitoring, imperfect detection, and risk optimization of a Tasmanian devil insurance population. AB - Most species are imperfectly detected during biological surveys, which creates uncertainty around their abundance or presence at a given location. Decision makers managing threatened or pest species are regularly faced with this uncertainty. Wildlife diseases can drive species to extinction; thus, managing species with disease is an important part of conservation. Devil facial tumor disease (DFTD) is one such disease that led to the listing of the Tasmanian devil (Sarcophilus harrisii) as endangered. Managers aim to maintain devils in the wild by establishing disease-free insurance populations at isolated sites. Often a resident DFTD-affected population must first be removed. In a successful collaboration between decision scientists and wildlife managers, we used an accessible population model to inform monitoring decisions and facilitate the establishment of an insurance population of devils on Forestier Peninsula. We used a Bayesian catch-effort model to estimate population size of a diseased population from removal and camera trap data. We also analyzed the costs and benefits of declaring the area disease-free prior to reintroduction and establishment of a healthy insurance population. After the monitoring session in May-June 2015, the probability that all devils had been successfully removed was close to 1, even when we accounted for a possible introduction of a devil to the site. Given this high probability and the baseline cost of declaring population absence prematurely, we found it was not cost-effective to carry out any additional monitoring before introducing the insurance population. Considering these results within the broader context of Tasmanian devil management, managers ultimately decided to implement an additional monitoring session before the introduction. This was a conservative decision that accounted for uncertainty in model estimates and for the broader nonmonetary costs of mistakenly declaring the area disease-free. PMID- 28657166 TI - NMR, HS-SPME-GC/MS, and HPLC/MSn Analyses of Phytoconstituents and Aroma Profile of Rosmarinus eriocalyx. AB - In this work, a comprehensive study on the chemical constituents of the aerial parts of Rosmarinus eriocalyx (Lamiaceae), an aromatic shrub traditionally consumed as a food and herbal remedy in Algeria, is presented. The aroma profile was analysed by headspace solid phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC/MS), whereas the crude extract constituents were analyzed by 1 H-NMR and by high performance liquid chromatography coupled with mass spectrometry (HPLC/MSn ). Thirty-nine volatile compounds, most of them being monoterpenes, have been identified, with camphor, camphene, and alpha pinene as the most abundant constituents. 1 H-NMR analysis revealed the presence of phenolic compounds and betulinic acid while HPLC/MSn allowed the identification of glycosilated and aglyconic flavonoids as well as phenylpropanoid derivatives. Some of these constituents, namely as betulinic acid, rosmanol, and cirsimaritin were reported for the first time in R. eriocalyx. PMID- 28657165 TI - Serum N-glycome alterations in breast cancer during multimodal treatment and follow-up. AB - Using our recently developed high-throughput automated platform, N-glycans from all serum glycoproteins from patients with breast cancer were analysed at diagnosis, after neoadjuvant chemotherapy, surgery, radiotherapy and up to 3 years after surgery. Surprisingly, alterations in the serum N-glycome after chemotherapy were pro-inflammatory with an increase in glycan structures associated with cancer. Surgery, on the other hand, induced anti-inflammatory changes in the serum N-glycome, towards a noncancerous phenotype. At the time of first follow-up, glycosylation in patients with affected lymph nodes changed towards a malignant phenotype. C-reactive protein showed a different pattern, increasing after first line of neoadjuvant chemotherapy, then decreasing throughout treatment until 1 year after surgery. This may reflect a switch from acute to chronic inflammation, where chronic inflammation is reflected in the serum after the acute phase response subsides. In conclusion, we here present the first time-course serum N-glycome profiling of patients with breast cancer during and after treatment. We identify significant glycosylation changes with chemotherapy, surgery and follow-up, reflecting the host response to therapy and tumour removal. PMID- 28657167 TI - Ladder-type Heteroarenes: Up to 15 Rings with Five Imide Groups. AB - A series of novel imide-functionalized ladder-type heteroarenes with well-defined structure and controllable conjugation lengths were synthesized and characterized. The synthetic route shows remarkable efficacy for constructing the electron-deficient ladder backbones. pi-Conjugation extension leads to narrowed band gaps with enhanced electron affinities. The ladder arenes are incorporated into organic thin-film transistors, and show encouraging electron mobilities of 0.013-0.045 cm2 V-1 s-1 . The heteroarenes reported here provide a remarkable platform for fundamental physicochemical studies and materials innovation in organic electronics. PMID- 28657168 TI - Differences in body composition and physical function related to pure sarcopenia and sarcopenic obesity: A study of community-dwelling older adults in Japan. AB - AIM: We compared skeletal muscle mass and physical function between older adults with sarcopenia and those with sarcopenic obesity. METHODS: Body composition and physical and cognitive function were measured for 1283 community-dwelling older adults. Participants responded to questionnaires about pain and exercise. The pure sarcopenia group (PS) included individuals with sarcopenia only. The sarcopenic obesity group (SO) included individuals with both sarcopenia and obesity. Groups were compared after adjusting for sex, age and height through propensity score matching. RESULTS: The PS and SO included 129 and 105 individuals, respectively. Comorbidities were more frequent in the SO (P < 0.001). The SO had higher upper limb muscle mass (P < 0.001), and had lower ratios of lower limb muscle mass to upper limb muscle mass (P < 0.001) and of lower limb muscle mass to weight (P < 0.001). The SO also had poorer grip power (P = 0.007), gait times (usual pace, P = 0.001; maximum speed, P = 0.001), Timed Up and Go test (P < 0.001), and time standing on one foot (P = 0.005) than the PS. The SO had a higher frequency of gonalgia (P = 0.013). After adjusting for covariates, comorbidities, upper limb muscle mass, lower limb muscle mass to upper limb muscle mass ratio, lower limb muscle mass to weight ratio, gait time, Timed Up and Go test, time standing on one foot, and gonalgia differed significantly between the PS and SO. CONCLUSIONS: Sarcopenic obesity decreases the ratio of lower limb muscle mass to weight by increasing weight. It affects physical function in older Japanese adults with low weight. Decreased relative lower limb muscle mass is an important function-limiting factor in sarcopenic obesity. Geriatr Gerontol Int 2017; 17: 2602-2609. PMID- 28657169 TI - Pilot study of the Mini Nutritional Assessment on predicting outcomes in older adults with type 2 diabetes. AB - AIM: To date, few studies have focused on the nutritional status of elderly hospitalized patients with diabetes. Our aims were to explore the prevalence of malnutrition among elderly diabetes patients admitted to the hospital, and to explore the relationships between malnutrition and geriatric syndromes, diabetic complications, and clinical outcomes. METHODS: A prospective, observational study including diabetes patients aged >=65 years was carried out in a central hospital in Western China. Nutritional status was assessed using the Mini Nutritional Assessment incorporated into a comprehensive geriatric assessment. Follow up was carried out for <=2.8 years. RESULTS: Of 302 participants, the prevalence of malnutrition, risk of malnutrition, and normal nutrition was 18.5%, 33.1% and 48.3%, respectively. In multivariate analysis, incontinence (odds ratio [OR] 3.17, 95% confidence interval [CI] 1.08-9.36), diabetic microvascular complications (OR 2.22, 95% CI 1.06-4.61) and activities of daily living (ADL) dependence (OR 11.6, 95% CI 5.10-26.5) were independently associated with malnutrition. Malnourished patients had longer hospital stays (P = 0.003) and higher mortality rates (P < 0.001) than patients either at risk of malnutrition or with a normal nutritional status. Multivariate analysis also showed that malnutrition was independently associated with an increased risk of death (OR 2.86, 95% CI 1.30-6.28). CONCLUSIONS: The present study showed a high prevalence of malnutrition among elderly diabetes patients hospitalized for geriatric care. Considering the negative impact of malnutrition on hospital stay and mortality, adequate nutritional care should be emphasized for each elderly patient with diabetes, regardless of body mass index. Geriatr Gerontol Int 2017; 17: 2485 2492. PMID- 28657170 TI - The past decade in bench research into pulmonary infectious diseases: What do clinicians need to know? AB - Respiratory infections are primarily treated with antibiotics, drugs that are mostly inexpensive and have been widely available since the 1940s and 1950s. Nevertheless, despite antibiotics, the burden of disease in pneumonia, bronchiectasis, cystic fibrosis, COPD and rare respiratory infections remains exceptionally high. There is an urgent need for translational studies to develop new treatments or new biomarkers to improve outcomes in these conditions. The 'translational gaps' between bench science and clinical practice are particularly challenging in respiratory infections. This is partly due to the poor representativeness of animal models of infection to human disease, and a long term lack of investment into pulmonary infection research. The revolution in genomics and other omics technologies, however, is beginning to unlock clinically important information about the host response to infection, the behaviour of bacterial communities and the development of new antibiotics. It is not possible to review the extensive progress made in the last decade into the pathophysiology of the different respiratory infections and so here, we focus on major technologies that are now changing respiratory infection research, specifically bacterial whole-genome sequencing, the microbiota, personalized medicine with omics technologies, new antibiotic development and host inflammatory cell biology. PMID- 28657171 TI - Is it safe to use lamotrigine during pregnancy? A prospective comparative observational study. AB - BACKGROUND: Lamotrigine is a second-generation antiepileptic drug, also used as a mood stabilizer. Published data on its use in human pregnancy are largely derived from pregnancy registries. Pregnancy experience in most studies has been reassuring. However, data from the North American Antiepileptic Drug Pregnancy Registry suggested an increased risk for oral clefts. The primary objective of the study was to evaluate the rate of major anomalies after lamotrigine exposure during pregnancy compared with pregnancies of women counseled for nonteratogenic exposure (NTE). METHODS: Callers who contacted the Israeli Teratology Information Service regarding lamotrigine treatment or NTE during pregnancy between 1997 and 2008 were prospectively followed-up. RESULTS: The rate of major congenital anomalies was similar between 218 lamotrigine exposed pregnancies (208 in the first trimester) and 865 NTE-pregnancies. There was no case of oral cleft in the lamotrigine-exposed group. The median lamotrigine dose in the beginning of pregnancy was 200 mg/d. The dose was increased during pregnancy in 29%. The majority of women in the cohort (82%) were treated for neurologic indications, while 18% for psychiatric disorders. Monotherapy was taken by 72%. CONCLUSION: The data available, thus far, on lamotrigine monotherpy-exposed pregnancies are encouraging. However, further studies are needed to determine with greater certainty the overall risk for major anomalies, as well as the specific risk for oral clefts. Based on the current and previously published data, lamotrigine, seems a reasonable alternative for pregnant women when clinically indicated. Birth Defects Research 109:1196-1203, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28657173 TI - Among nurses, how does education level impact professional values? A systematic review. AB - BACKGROUND: Professional nursing values have been acknowledged globally as the foundation of daily nursing care practice. Understanding how nurses identify, comprehend and apply their professional nursing values is an important step towards improving nursing practice and patient care quality. Research has demonstrated that nurses' professional values are cultivated during prelicensure academic education. AIM: The aim of this systematic review was to determine how level of education affects professional nursing values of clinical practising nurses. METHODS: A systematic search of quantitative research published through December 2015 was performed in the following five electronic databases: CINAHL, Cochrane Library, MEDLINE, Web of Science and Religion and Philosophy Collection. The search was not limited to country of origin. The studies were assessed for methodological quality using established criteria. RESULTS: Of 1501 articles identified through the literature search, only seven studies met the inclusion criteria with the majority being of good to high quality. Most of the studies found registered nurses pursuing a bachelor of science in nursing or higher had a greater awareness and application of professional values than nurses with lower levels of academic or non-academic education. Nurses with higher education also embraced professional values as fundamental for quality nursing care practice. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Health and academic institutions should support nurses through quality continuing and higher education that reinforces professional values, thus improving the quality of patient care. CONCLUSIONS: The level of nurses' education appears to play an important role in developing both an awareness and an integration of professional values into practice. More research is needed to discover methods that may be used to promote nurses' professional values among nurses already practising clinically. PMID- 28657172 TI - ASIC1A in neurons is critical for fear-related behaviors. AB - Acid-sensing ion channels (ASICs) have been implicated in fear-, addiction- and depression-related behaviors in mice. While these effects have been attributed to ASIC1A in neurons, it has been reported that ASICs may also function in nonneuronal cells. To determine if ASIC1A in neurons is indeed required, we generated neuron-specific knockout (KO) mice with floxed Asic1a alleles disrupted by Cre recombinase driven by the neuron-specific synapsin I promoter (SynAsic1a KO mice). We confirmed that Cre expression occurred in neurons, but not all neurons, and not in nonneuronal cells including astrocytes. Consequent loss of ASIC1A in some but not all neurons was verified by western blotting, immunohistochemistry and electrophysiology. We found ASIC1A was disrupted in fear circuit neurons, and SynAsic1a KO mice exhibited prominent deficits in multiple fear-related behaviors including Pavlovian fear conditioning to cue and context, predator odor-evoked freezing and freezing responses to carbon dioxide inhalation. In contrast, in the nucleus accumbens ASIC1A expression was relatively normal in SynAsic1a KO mice, and consistent with this observation, cocaine conditioned place preference (CPP) was normal. Interestingly, depression related behavior in the forced swim test, which has been previously linked to ASIC1A in the amygdala, was also normal. Together, these data suggest neurons are an important site of ASIC1A action in fear-related behaviors, whereas other behaviors likely depend on ASIC1A in other neurons or cell types not targeted in SynAsic1a KO mice. These findings highlight the need for further work to discern the roles of ASICs in specific cell types and brain sites. PMID- 28657174 TI - Effect of the Leaf Essential Oil from Cinnamosma madagascariensis Danguy on Pentylenetetrazol-induced Seizure in Rats. AB - In the Malagasy traditional practices, the smoke from burning leaves of Cinnamosma madagascariensis Danguy is inhaled to treat brain disorders such as dementia, epilepsy, and headache. In the present work, we have evaluated the in vivo anticonvulsant effects of the essential oil from leaves of C. madagascariensis (CMEO). CMEO was isolated by steam distillation. The anticonvulsant activity of CMEO (0.4 and 0.8 ml/kg bw) administered subcutaneously was evaluated on pentylenetetrazol (PTZ)-induced seizures in Wistar rats; diazepam was used as positive control. Linalool, limonene, and myrcene were the major CMEO constituents. At the dose of 0.8 ml/kg, CMEO completely arrested the PTZ-induced convulsions with moderate sedative effects. The traditional anticonvulsant use of C. madagascariensis was confirmed allowing us to candidate molecules from CMEO as potential drugs to treat convulsions associated with strong agitation. PMID- 28657175 TI - Socioeconomic and demographic disparities in breast cancer stage at presentation and survival: A Swiss population-based study. AB - We explored socioeconomic and demographic disparities in breast cancer (BC) stage at presentation and survival in a Swiss population-based sample of female BC patients linked to the census-based Swiss National Cohort. Tumor stage was classified according to Surveillance, Epidemiology and End Results Program summary stage (in situ/localized/regional/distant). We used highest education level attained to estimate SEP (low/middle/high). Further demographic characteristics of interest were age at presentation (30-49/50-69/70-84 years), living in a canton with organized screening (yes/no), urbanity of residence (urban/peri-urban/rural), civil status (single/married/widowed/divorced) and nationality (Swiss/non-Swiss). We used ordered logistic regression models to analyze factors associated with BC stage at presentation and competing risk regression models for factors associated with survival. Odds of later-stage BC were significantly increased for low SEP women (odds ratio 1.19, 95%CI 1.06-1.34) compared to women of high SEP. Further, women living in a canton without organized screening program, women diagnosed outside the targeted screening age and single/widowed/divorced women were more often diagnosed at later stages. Women of low SEP experienced an increased risk of dying from BC (sub-hazard ratio 1.22, 95%CI 1.05-1.43) compared to women of high SEP. Notably, these survival inequalities could not be explained by socioeconomic differences in stage at presentation and/or other sociodemographic factors. It is concerning that these social gradients have been observed in a country with universal health insurance coverage, high health expenditures and one of the highest life expectancies in the world. PMID- 28657177 TI - Diagnostic clusters associated with an early onset schizophrenia diagnosis among children and adolescents. PMID- 28657176 TI - An improved PCR-CTPP assay for the detection of ADH1B Arg48His polymorphism. AB - BACKGROUND: ADH1B Arg48His polymorphism is associated with the development of alcohol-related diseases. In this study, we aimed to explore an improved polymerase chain reaction with confronting two-pair primers (PCR-CTPP) assay for the detection of ADH1B Arg48His polymorphism. METHODS: A mismatch was introduced at the 3' end of each of the two allele-specific to increase the specificity of the reaction. But beyond that, a new mismatch at-3 positions of outer primers was designed to decrease the efficiency of the aforementioned primers and depresses the amplification of an internal nonspecific DNA control. A total of 180 samples from healthy volunteers Han Chinese were tested to evaluate this new assay. RESULTS: The protocol of PCR-CTPP was successful for genotyping of ADH1B Arg48His. The results from the improved PCR-CTPP assay were confirmed by Sanger sequencing, and correct genotyping rates were 100%.The genotype frequencies were 49.44% (89 cases) for His/His, 46.67% (84 cases) for Arg/His, and 3.89% (seven cases) for Arg/Arg respectively. CONCLUSIONS: This improved PCR-CTPP assay is simple, rapid, cost-effective, and reliable, specific for the detection of ADH1B Arg48His polymorphism in most clinical diagnostic laboratories. PMID- 28657178 TI - 1-cyclohexyl-x-methoxybenzene derivatives, novel psychoactive substances seized on the internet market. Synthesis and in vivo pharmacological studies in mice. AB - INTRODUCTION: Among novel psychoactive substances notified to EMCDDA and Europol were 1-cyclohexyl-x-methoxybenzene stereoisomers (ortho, meta, and para). These substances share some structural characteristics with phencyclidine and tramadol. Nowadays, no information on the pharmacological and toxicological effects evoked by 1-cyclohexyl-x-methoxybenzene are reported. The aim of this study was to investigate the effect evoked by each one stereoisomer on visual stimulation, body temperature, acute thermal pain, and motor activity in mice. METHODS: Mice were evaluated in behavioral tests carried out in a consecutive manner according to the following time scheme: observation of visual placing response, measures of core body temperature, determination of acute thermal pain, and stimulated motor activity. RESULTS: All three stereoisomers dose-dependent inhibit visual placing response (rank order: meta > ortho > para), induce hyperthermia at lower and hypothermia at higher doses (meta > ortho > para) and cause analgesia to thermal stimuli (para > meta = ortho), while they do not alter motor activity. CONCLUSIONS: For the first time, this study demonstrates that systemic administration of 1-cyclohexyl-x-methoxybenzene compounds markedly inhibit visual response, promote analgesia, and induce core temperature alterations in mice. This data, although obtained in animal model, suggest their possible hazard for human health (i.e., hyperthermia and sensorimotor alterations). In particular, these novel psychoactive substances may have a negative impact in many daily activities, greatly increasing the risk factors for workplace accidents and traffic injuries. PMID- 28657179 TI - Novel psychoactive substances: Shedding new lights on the ever-changing drug scenario and the associated health risks. PMID- 28657180 TI - 4,4'-Dimethylaminorex ("4,4'-DMAR"; "Serotoni") misuse: A Web-based study. AB - BACKGROUND: 4,4'-DMAR (4,4'-dimethylaminorex; "Serotoni") is a potent stimulant drug that has recently been associated with a number of fatalities in Europe. Over the last few years, online communities have emerged as important resources for disseminating levels of technical knowledge on novel psychoactive substances. OBJECTIVE: Analysing the information provided by the fora communities on 4,4' DMAR use, additionally critical reviewing the available evidence-based literature on this topic. METHODS: Different website drug fora were identified. A critical review of the existing evidence-based literature was undertaken. Individuation and analysis of qualitative data from the identified website fora were performed. RESULTS: The combined search results identified six website fora from which a range of qualitative data on recurring themes was collected. These themes included routes of administration and doses; desired effects; adverse effects; comparison with other drugs; association with other drugs; medications self administered to reverse 4,4'-DMAR action; overall impression; and provision of harm-reduction advice. CONCLUSIONS: Although being characterized by a number of methodological limitations, the social networks' Web monitoring approach (netnography) may be helpful to better understand some of the clinical and psychopharmacological issues pertaining to a range of novel psychoactive substances, including 4,4'-DMAR, for which only extremely little, if any, scientific knowledge is available. PMID- 28657181 TI - Effectiveness of agomelatine on anhedonia in depressed patients: An outpatient, open-label, real-world study. PMID- 28657182 TI - Retraction: 'Effect of blonanserin on cognitive function in antipsychotic-naive first-episode schizophrenia'. AB - : The above article from Human Psychopharmacology, first published on 25 January 2012 in Wiley OnlineLibrary (onlinelibrary.wiley.com), and in Volume 90, pp. 90 100, has been retracted by agreement between the authors, the journal Editor in Chief, David Baldwin, and John Wiley & Sons Ltd. The retraction has been agreed following an investigation by the St Marianna University Ethics Committee which determined that the paper was not as originally designed and approved. REFERENCES: Tenjin, T., Miyamoto, S., Miyake, N., Ogino, S., Kitajima, R., Ojima, K., ... Yamaguchi, N. (2012). Effect of blonanserin on cognitive function in antipsychotic-naive first-episode schizophrenia. Hum. Psychopharmacol Clin Exp, 27, 90-100. https://doi.org/10.1002/hup.1276. PMID- 28657184 TI - The use of supplements and performance and image enhancing drugs in fitness settings: A exploratory cross-sectional investigation in the United Kingdom. AB - OBJECTIVE: The strive for perfection is prevalent in the fitness industry. This study aimed to explore the use of products to enhance performance alongside exposure to exercise addiction, appearance anxiety and self-esteem in fitness settings. METHODS: An online survey was prepared and piloted before wider dissemination in fitness clubs via snowballing and selected mailing lists. A list of commonly used products, including Performance and Image Enhancing Drugs (PIEDs) was provided. Exercise addiction (Exercise Addiction Inventory; EAI), anxiety levels (Appearance Anxiety Inventory; AAI) and their self-esteem (Rosenberg's Self-Esteem Scale; RSE) were also measured. RESULTS: 377 questionnaires were completed. A significant number of participants declared the use products either to lose weight (16%) or to reach their fitness goals (41%). The Internet played a major role in both the supply of information and the provision of the enhancement products (33.7%) and side effects were reported (10.5%). Only a limited number of participants sought a medical opinion about taking products (5.1%). EAI scores were high (m=20.02 +/- 4.1), AAI (m=15.98 +/- 4.8) showed an intermediate level of anxiety, while self-esteem was low (RSE m=12.59 +/- 2.2). CONCLUSION: This pilot study identified the emergence of a new drug trend in fitness settings and showed a potential relationship to exercise addiction, anxiety disorders and low self-esteem. The Internet played a crucial role in disseminating often untested products, including PIEDs without medical supervision and unwanted side-effects were reported. More studies in the field are required in order to safeguard public health and inform policy making. PMID- 28657183 TI - A matter of life and death: substance-caused and substance-related fatalities in Ibiza in 2015. AB - OBJECTIVES AND METHODS: In the framework of the EU-funded project "EU-Madness," we collected and analysed all the reports of fatalities directly or indirectly related to substances of abuse registered in Ibiza from January to September 2015, in order to analyse the characteristics of the sample, the identified substances, and the nature of deaths associated with their consumption. RESULTS: A significant increase of substance-caused deaths with respect to the previous 4 years has been highlighted. Most of the subjects were young males, more than half were not Spanish. Males prevailed also amongst the victims of traffic accidents and suicides. The most commonly involved substances included MDMA, alcohol, cocaine, THC, opiates and prescription drugs. CONCLUSIONS: Although the use of NPS is rapidly increasing in Europe, according to the results from our sample, alcohol and well-known stimulants (MDMA and cocaine) are still the substances of abuse mainly involved in the cases of substance-caused and substance-related fatalities. The significant increase of fatalities in Ibiza in the last 5 years is an issue that must be taken into account and should be better investigated, as other theories besides NPS-increased diffusion should be proposed, and therefore, targeted prevention strategies should be designed. PMID- 28657185 TI - Patterns of use and toxicity of new para-halogenated substituted cathinones: 4 CMC (clephedrone), 4-CEC (4-chloroethcatinone) and 4-BMC (brephedrone). AB - OBJECTIVE: This paper aims to present results of the analysis of clephedrone (4 CMC), 4-chloroethcathinone (4-CEC), and brephedrone (4-BMC) on recreational drug markets and a systematic review of all the available information concerning these substances. MATERIAL AND METHODS: Samples collected by the drug checking service of the Spanish harm reduction NGO-Energy Control were analyzed and systematic research was conducted. Between June 2014 and October 2016, 1,471 samples with at least one NPS were analyzed, 397 of which contained cathinones. RESULTS: Clephedrone was found in 29 samples, brephedrone in 8, and both were present in 2 samples. 4-Chloroethcathinone was detected in 5 samples. Eleven out of the 47 purchased samples (23.4%) were tested to contain the substance the user expected. Samples received were mainly sold as 3-MMC, MDMA, ketamine, and other cathinones. No literature on the effects or toxicity of these substances was found; the only information available was on internet fora. On many posts, users exhibit concerns about potential toxicity and side effects of using these substances. CONCLUSION: Since the emergence of these substances could prove to be the next step to the cat-and-mouse game existing between drug producers and legislation, further clinical and epidemiological research should be carried out in order to build evidence to support policy for public health issues. PMID- 28657186 TI - Novel psychoactive substances (NPS) use in severe mental illness (SMI) patients: Potential changes in the phenomenology of psychiatric diseases. AB - OBJECTIVE: Literature is quite poor about the clinical effects of novel psychoactive substances (NPS) and the long-term consequences of NPS use in psychiatric patients. Consequently, it is of the greatest interest to examine which effects NPS can exert in patients with previous severe mental illness (SMI), such as psychotic patients. The aim of this work was a comprehensive review about NPS use in patients with SMI. METHODS: We searched Medline or PubMed for relevant English-language citations and reviews describing relationships between NPS use and mental disorders, as well as for the main groups of substances and associated psychiatric manifestations. All studies reporting single case or case series of patients were selected. RESULTS: The NPS use in patients with SMI is probably underestimated. The one existing systematic review considers only 14 studies, 12 of which are case reports. Most clinical results report acute symptom exacerbation of preexisting psychosis. Paranoid, mood, and aggression symptoms occur more frequently. CONCLUSIONS: NPS use could modify clinical features of SMI, but these conclusions cannot be generalizable. More evidence is needed to establish the causal and effective connection between NPS use and course of illness, type of psychiatric symptoms, and outcome of treatment in terms of adherence or response. PMID- 28657187 TI - An insight into the deep web; why it matters for addiction psychiatry? AB - OBJECTIVE: Nowadays, the web is rapidly spreading, playing a significant role in the marketing or sale or distribution of "quasi" legal drugs, hence facilitating continuous changes in drug scenarios. The easily renewable and anarchic online drug-market is gradually transforming indeed the drug market itself, from a "street" to a "virtual" one, with customers being able to shop with a relative anonymity in a 24-hr marketplace. The hidden "deep web" is facilitating this phenomenon. The paper aims at providing an overview to mental health's and addiction's professionals on current knowledge about prodrug activities on the deep web. METHODS: A nonparticipant netnographic qualitative study of a list of prodrug websites (blogs, fora, and drug marketplaces) located into the surface web was here carried out. A systematic Internet search was conducted on Duckduckgo(r) and Google(r) whilst including the following keywords: "drugs" or "legal highs" or "Novel Psychoactive Substances" or "NPS" combined with the word deep web. RESULTS: Four themes (e.g., "How to access into the deepweb"; "Darknet and the online drug trading sites"; "Grams-search engine for the deep web"; and "Cryptocurrencies") and 14 categories were here generated and properly discussed. CONCLUSIONS: This paper represents a complete or systematical guideline about the deep web, specifically focusing on practical information on online drug marketplaces, useful for addiction's professionals. PMID- 28657188 TI - From concept(ion) to life after death/the grave: The 'natural' history and life cycle(s) of novel psychoactive substances (NPS). AB - A range of information needs should be met in order to better understand and predict the longevity/existence of novel psychoactive substances (NPS). This conceptual paper argues that one way of assessing how long a molecule may be around is to document how the life cycles or natural histories of 'traditional' drugs and NPS evolve. The earliest indication of the possible appearance of a new substance might be evidenced on the DeepWeb. However, this means they are less visible, in line with the clandestine nature of drug use and supply. Therefore, monitoring discussion groups/fora needs the development of new methods compared to those used in the Surface Net. Issues needing consideration in establishing NPS life cycles are outlined here, together with the probable outcomes that could result. The approach advocated means that it should be easier to identify which NPS are likely to come up or are emerging in real time, and, therefore, pre empt/prevent their supply. PMID- 28657189 TI - Utility of Web search query data in testing theoretical assumptions about mephedrone. AB - OBJECTIVE: With growing access to the Internet, people who use drugs and traffickers started to obtain information about novel psychoactive substances (NPS) via online platforms. This paper aims to analyze whether a decreasing Web interest in formerly banned substances-cocaine, heroin, and MDMA-and the legislative status of mephedrone predict Web interest about this NPS. METHODS: Google Trends was used to measure changes of Web interest on cocaine, heroin, MDMA, and mephedrone. Google search results for mephedrone within the same time frame were analyzed and categorized. RESULTS: Web interest about classic drugs found to be more persistent. Regarding geographical distribution, location of Web searches for heroin and cocaine was less centralized. Illicit status of mephedrone was a negative predictor of its Web search query rates. The connection between mephedrone-related Web search rates and legislative status of this substance was significantly mediated by ecstasy-related Web search queries, the number of documentaries, and forum/blog entries about mephedrone. CONCLUSIONS: The results might provide support for the hypothesis that mephedrone's popularity was highly correlated with its legal status as well as it functioned as a potential substitute for MDMA. Google Trends was found to be a useful tool for testing theoretical assumptions about NPS. PMID- 28657190 TI - Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications. AB - OBJECTIVE: "Krokodil" is the street name for an impure homemade drug mixture used as a cheap substitute for heroin, containing desomorphine as the main opioid. Abscesses, gangrene, thrombophlebitis, limb ulceration and amputations, jaw osteonecrosis, skin discoloration, ulcers, skin infections, and bleeding are some of the typical reported signs in humans. This study aimed to understand the toxicity of krokodil using Wistar male rats as experimental model. METHODS: Animals were divided into seven groups and exposed subcutaneously to NaCl 0.9% (control), krokodil mixture free of psychotropic substances (blank krokodil), pharmaceutical grade desomorphine 1 mg/kg, and four different concentrations of krokodil (containing 0.125, 0.25, 0.5, and 1 mg/kg of desomorphine) synthesized accordingly to a "domestic" protocol followed by people who inject krokodil (PWIK). Daily injections for five consecutive days were performed, and animals were sacrificed 24 hr after the last administration. Biochemical and histological analysis were carried out. RESULTS: It was shown that the continuous use of krokodil may cause injury at the injection area, with formation of necrotic zones. The biochemical results evidenced alterations on cardiac and renal biomarkers of toxicity, namely, creatine kinase, creatine kinase-MB, and uric acid. Significant alteration in levels of reduced and oxidized glutathione on kidney and heart suggested that oxidative stress may be involved in krokodil mediated toxicity. Cardiac congestion was the most relevant finding of continuous krokodil administration. CONCLUSIONS: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil. PMID- 28657192 TI - Effects of age and pathology on shear wave speed of the human rotator cuff. AB - Rotator cuff tears are common and often repaired surgically, but post-operative repair tissue healing, and shoulder function can be unpredictable. Tear chronicity is believed to influence clinical outcomes, but conventional clinical approaches for assessing tear chronicity are subjective. Shear wave elastography (SWE) is a promising technique for assessing soft tissue via estimates of shear wave speed (SWS), but this technique has not been used extensively on the rotator cuff. Specifically, the effects of age and pathology on rotator cuff SWS are not well known. The objectives of this study were to assess the association between SWS and age in healthy, asymptomatic subjects, and to compare measures of SWS between patients with a rotator cuff tear and healthy, asymptomatic subjects. SWE images of the supraspinatus muscle and intramuscular tendon were acquired from 19 asymptomatic subjects and 11 patients with a rotator cuff tear. Images were acquired with the supraspinatus under passive and active (i.e., minimal activation) conditions. Mean SWS was positively associated with age in the supraspinatus muscle and tendon under passive and active conditions (p <= 0.049). Compared to asymptomatic subjects, patients had a lower mean SWS in their muscle and tendon under active conditions (p <= 0.024), but no differences were detected under passive conditions (p >= 0.783). These findings identify the influences of age and pathology on SWS in the rotator cuff. These preliminary findings are an important step toward evaluating the clinical utility of SWE for assessing rotator cuff pathology. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:282-288, 2018. PMID- 28657193 TI - Establishment of in vitro model of corneal scar pathophysiology. AB - Corneal scarring is the major source of permanent blindness worldwide. The complex pathophysiology of corneal scarring is not comprehensibly understood as it involves the interaction of a constellation of pro-fibrotic cytokines influencing several signaling pathways involved in corneal scar development. In the present study, an attempt has been made to generate a relatively simple in vitro corneal scar model using primary corneal keratocytes by exogenously providing an optimized dose of combination of cytokines (TGF-beta1, IL-6, and IL 8) involved in scar formation in situ. Data obtained from gene and protein expression analysis depicted enhanced ECM production with discrete expression of myofibroblast specific markers. The protein-protein interactions associated these proteins to various pathways involved in wound healing, cellular migration, and cytoskeletal remodeling justifying high relevance to in vivo scar formation. Hence the developed model can be used to acquire understanding about corneal scar pathophysiology and thus might be useful for designing the treatment modalities and efficacies for controlling scar formation. PMID- 28657191 TI - Intended and unintended use of cathinone mixtures. AB - INTRODUCTION: Cathinones are one of the most popular categories of new psychoactive substances (NPS) consumed. Cathinones have different pharmacological activities and receptor selectivity for monoamine transporters based on their chemical structures. They are incorporated into NPS mixtures and used with other NPS or 'traditional' drugs. Cathinone use represents significant health risks to individuals and is a public health burden. METHODS: Evidence of poly-NPS use with cathinones, seizure information, and literature analyses results on NPS mixtures was systematically gathered from online database sources, including Google Scholar, Scopus, Bluelight, and Drugs-Forum. RESULTS AND DISCUSSION: Results highlight the prevalence of NPS with low purity, incorporation of cathinones into NPS mixtures since 2008, and multiple members of the cathinone family being present in individual UK-seized samples. Cathinones were identified as adulterants in NPS marketed as being pure NPS, drugs of abuse, branded products, herbal blends, and products labelled "not for human consumption." Toxicity resulting from cathinone mixtures is unpredictable because key attributes remain largely unknown. Symptoms of intoxication include neuro-psychological, psychiatric, and metabolic symptoms. Proposed treatment includes holistic approaches involving psychosocial, psychiatric and pharmacological interventions. CONCLUSION: Raising awareness of NPS, education, and training of health care professionals are paramount in reducing harms related to cathinone use. PMID- 28657194 TI - Accommodating missingness in environmental measurements in gene-environment interaction analysis. AB - For the prognosis of complex diseases, beyond the main effects of genetic (G) and environmental (E) factors, gene-environment (G-E) interactions also play an important role. Many approaches have been developed for detecting important G-E interactions, most of which assume that measurements are complete. In practical data analysis, missingness in E measurements is not uncommon, and failing to properly accommodate such missingness leads to biased estimation and false marker identification. In this study, we conduct G-E interaction analysis with prognosis data under an accelerated failure time (AFT) model. To accommodate missingness in E measurements, we adopt a nonparametric kernel-based data augmentation approach. With a well-designed weighting scheme, a nice "byproduct" is that the proposed approach enjoys a certain robustness property. A penalization approach, which respects the "main effects, interactions" hierarchy, is adopted for selection (of important interactions and main effects) and regularized estimation. The proposed approach has sound interpretations and a solid statistical basis. It outperforms multiple alternatives in simulation. The analysis of TCGA data on lung cancer and melanoma leads to interesting findings and models with superior prediction. PMID- 28657195 TI - David Cockburn OAM MScOptom DSc (Honoris Causa) FACO 25 August 1923-26 September 2016: A tribute to David Cockburn, a consummate clinician and educator. PMID- 28657196 TI - Volume 100: a major milestone and still travelling. PMID- 28657197 TI - Mechanism and Origins of the Chemo- and Regioselectivities in Nickel-Catalyzed Intermolecular Cycloadditions of Benzocyclobutenones with 1,3-Dienes. AB - The nickel-catalyzed intermolecular cycloadditions of benzocyclobutenones with 1,3-dienes developed by Martin and co-workers are featured with the exclusive proximal C-C bond cleavage and a high chemoselectivity of the [4+4] over the [4+2] cycloaddition. In this report, the detailed reaction mechanism and the origins of the selectivities were investigated by means of density functional theory calculations. The results show that the reaction is initiated by a C-C oxidative addition of the benzocyclobutenone to form the five-membered nickelacycles. A subsequent exo 1,4-insertion/C-C reductive elimination and an endo 1,4-insertion/C-C reductive elimination lead to the [4+4] and [4+2] cycloaddition products, respectively. The 1,4-insertion of the 1,3-diene into the Ni-C bond was calculated to be the rate- and selectivity-determining step of the reaction. The calculations reproduced quite well the experimentally observed exclusive proximal C-C bond cleavage and the high chemoselectivity of the [4+4] over the [4+2] cycloaddition. In particular, it was found that the steric repulsion between the phosphine ligand and the alpha-substituent of the benzocyclobutenone has a dramatic impact on the 1,4-insertion, which enables the experimentally observed selectivities. PMID- 28657198 TI - Family Science Talk in Museums: Predicting Children's Engagement From Variations in Talk and Activity. AB - Children's developing reasoning skills are better understood within the context of their social and cultural lives. As part of a research-museum partnership, this article reports a study exploring science-relevant conversations of 82 families, with children between 3 and 11 years, while visiting a children's museum exhibit about mammoth bones, and in a focused one-on-one exploration of a "mystery object." Parents' use of a variety of types of science talk predicted children's conceptual engagement in the exhibit, but interestingly, different types of parent talk predicted children's engagement depending on the order of the two activities. The findings illustrate the importance of studying children's thinking in real-world contexts and inform creation of effective real-world science experiences for children and families. PMID- 28657199 TI - InterPrEP: internet-based pre-exposure prophylaxis with generic tenofovir disoproxil fumarate/emtrictabine in London - analysis of pharmacokinetics, safety and outcomes. AB - OBJECTIVES: The National Health Service in England (NHS England) does not provide pre-exposure prophylaxis (PrEP) against HIV, forcing people to purchase generic versions on the internet. However, there are concerns about the authenticity of medicines purchased online. We established an innovative service offering plasma tenofovir (TFV) and emcitrabine (FTC) therapeutic drug monitoring for people buying generic PrEP online, to ensure that drug concentrations in vivo were consistent with those of propriety brands and previously published data. METHODS: TFV/FTC concentrations were measured by ultra-performance liquid chromatography ultraviolet detection. Evaluation of renal function and testing for HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) were also carried out, at baseline and every 3-6 months, with risk reduction advice. RESULTS: A total of 293 individuals presented having purchased PrEP on the internet: 85% were white, 84% were taking daily PrEP, and 16% were event-driven. Most were on generic TFV disoproxil fumarate (TDF)/FTC from Cipla Ltd. Median (range) TFV and FTC plasma concentrations were 104 (21-597) ng/mL and 140 (17-1876) ng/mL, respectively. All concentrations were above our established plasma TFV and FTC targets, based on previously published data. Renal function was normal in all evaluable individuals and no new cases of HIV, HBV or HCV infection were seen. CONCLUSIONS: In a population at high risk of HIV acquisition, who cannot yet access PrEP on the NHS, concentrations of TFV and FTC in generic formulations purchased over the internet were similar to (or slightly higher than) those measured in phase I studies with the original formulation from Gilead (TruvadaTM), which has demonstrated high levels of protection against HIV infection in previous PrEP clinical trials. PMID- 28657200 TI - Molecular Mechanism of Swing Effect in Zeolitic Imidazolate Framework ZIF-8: Continuous Deformation upon Adsorption. AB - Zeolitic imidazolate framework ZIF-8 displays flexibility of its structure by rotation of its imidazolate linker. This "swing effect" has been widely described in the literature, both experimentally and theoretically, as a bistable system where the linker oscillates between two structures: "open window" and "closed window". By using quantum chemistry calculations and first-principles molecular dynamics simulations, it is shown that the deformation upon adsorption is in fact continuous upon pore loading, with thermodynamics of packing effects being the reason behind stepped adsorption isotherms experimentally observed. Finally, we study a variant of ZIF-8 with a different linker, highlighting the influence of the linker and the balance of microscopic interactions on the framework's flexibility. PMID- 28657201 TI - Comparison of low- and ultralow-dose computed tomography protocols for quantitative lung and airway assessment. AB - PURPOSE: Quantitative computed tomography (CT) measures are increasingly being developed and used to characterize lung disease. With recent advances in CT technologies, we sought to evaluate the quantitative accuracy of lung imaging at low- and ultralow-radiation doses with the use of iterative reconstruction (IR), tube current modulation (TCM), and spectral shaping. METHODS: We investigated the effect of five independent CT protocols reconstructed with IR on quantitative airway measures and global lung measures using an in vivo large animal model as a human subject surrogate. A control protocol was chosen (NIH-SPIROMICS + TCM) and five independent protocols investigating TCM, low- and ultralow-radiation dose, and spectral shaping. For all scans, quantitative global parenchymal measurements (mean, median and standard deviation of the parenchymal HU, along with measures of emphysema) and global airway measurements (number of segmented airways and pi10) were generated. In addition, selected individual airway measurements (minor and major inner diameter, wall thickness, inner and outer area, inner and outer perimeter, wall area fraction, and inner equivalent circle diameter) were evaluated. Comparisons were made between control and target protocols using difference and repeatability measures. RESULTS: Estimated CT volume dose index (CTDIvol) across all protocols ranged from 7.32 mGy to 0.32 mGy. Low- and ultralow-dose protocols required more manual editing and resolved fewer airway branches; yet, comparable pi10 whole lung measures were observed across all protocols. Similar trends in acquired parenchymal and airway measurements were observed across all protocols, with increased measurement differences using the ultralow-dose protocols. However, for small airways (1.9 +/- 0.2 mm) and medium airways (5.7 +/- 0.4 mm), the measurement differences across all protocols were comparable to the control protocol repeatability across breath holds. Diameters, wall thickness, wall area fraction, and equivalent diameter had smaller measurement differences than area and perimeter measurements. CONCLUSIONS: In conclusion, the use of IR with low- and ultralow-dose CT protocols with CT volume dose indices down to 0.32 mGy maintains selected quantitative parenchymal and airway measurements relevant to pulmonary disease characterization. PMID- 28657203 TI - Photoaligned Nanorod Enhancement Films with Polarized Emission for Liquid-Crystal Display Applications. AB - Semiconductor nanorods (NR) emit polarized light, which is expected to bring manifold benefits, in terms of brightness and color enhancement, for modern liquid-crystal displays (LCD). In this regard, photoaligned nanorod enhancement films (NREF) for color and polarization conversion for LCD backlights are introduced here. The photoinduced anchoring forces, by the photoalignment layer, stimulate well-ordered self-assembly of NR in the thin polymer films. Green and red emitting NR with a quantum yield of ~80% are aligned unidirectionally and in plane, showing a polarization ratio of >7:1 and a degree of polarization of >0.81. The photoalignment technique facilitates the fabrication of mixed and multiple stacked NREF for LCDs, which improves the color gamut and polarization efficiency, and is thus expected to increase the optical efficiency of conventional LCDs by ~60%. PMID- 28657202 TI - Assessing Pharmacodynamic Interactions in Mice Using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models. AB - The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log10 colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log10 CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development. PMID- 28657204 TI - Self-Assembled Dendritic Pt Nanostructure with High-Index Facets as Highly Active and Durable Electrocatalyst for Oxygen Reduction. AB - The durability issues of Pt catalyst should be resolved for the commercialization of proton exchange membrane fuel cells. Nanocrystal structures with high-index facets have been recently explored to solve the critical durability problem of fuel cell catalysts as Pt catalysts with high-index facets can preserve the ordered surfaces without change of the original structures. However, it is very difficult to develop effective and practical synthetic methods for Pt-based nanostructures with high-index facets. The current study describes a simple one pot synthesis of self-assembled dendritic Pt nanostructures with electrochemically active and stable high-index facets. Pt nanodendrites exhibited 2 times higher ORR activity and superior durability (only 3.0 % activity loss after 10 000 potential cycles) than a commercial Pt/C. The enhanced catalytic performance was elucidated by the formation of well-organized dendritic structures with plenty of reactive interfaces among 5 nm-sized Pt particles and the coexistence of low- and high-index facets on the particles. PMID- 28657205 TI - MicroRNAs in retinoblastoma: Potential diagnostic and therapeutic biomarkers. AB - Retinoblastoma (Rb) is known as one of important childhood malignancies which due to inactivation of the RB gene (tumor suppressor gene in various patients). The early detection of Rb could provide better treatment for Rb patients. Imaging techniques (e.g., MRI and CT) are known as one of effective diagnosis approaches for detection of patients with Rb. It has been shown that utilization of imaging techniques is associated with some limitations. Hence, identification of new diagnosis approaches might provide a better treatment for Rb patients. Identification of new biomarkers could contribute to better understanding of pathogenesis events involved in Rb and provide new insights into design better treatment approaches for these patients. Among the various biomarkers, microRNAs (miRNAs) have emerged as attractive tools for Rb detection. miRNAs are one classes of small non-coding RNAs which could anticipate in a variety of biological process via targeting sequence of cellular and molecular pathways. Deregulations of these molecules are associated with cancerous condition. Multiple lines of evidence indicated that deregulation of various miRNAs involved in various stages of Rb. Here, we summarized a variety of tissue-specific and circulating miRNAs involved in Rb pathogenesis which could be used as diagnostic, prognostic, and therapeutic biomarkers in Rb patients. PMID- 28657206 TI - Projections of climate-driven changes in tuna vertical habitat based on species specific differences in blood oxygen affinity. AB - Oxygen concentrations are hypothesized to decrease in many areas of the ocean as a result of anthropogenically driven climate change, resulting in habitat compression for pelagic animals. The oxygen partial pressure, pO2 , at which blood is 50% saturated (P50 ) is a measure of blood oxygen affinity and a gauge of the tolerance of animals for low ambient oxygen. Tuna species display a wide range of blood oxygen affinities (i.e., P50 values) and therefore may be differentially impacted by habitat compression as they make extensive vertical movements to forage on subdaily time scales. To project the effects of end-of-the century climate change on tuna habitat, we calculate tuna P50 depths (i.e., the vertical position in the water column at which ambient pO2 is equal to species specific blood P50 values) from 21st century Earth System Model (ESM) projections included in the fifth phase of the Climate Model Intercomparison Project (CMIP5). Overall, we project P50 depths to shoal, indicating likely habitat compression for tuna species due to climate change. Tunas that will be most impacted by shoaling are Pacific and southern bluefin tunas-habitat compression is projected for the entire geographic range of Pacific bluefin tuna and for the spawning region of southern bluefin tuna. Vertical shifts in P50 depths will potentially influence resource partitioning among Pacific bluefin, bigeye, yellowfin, and skipjack tunas in the northern subtropical and eastern tropical Pacific Ocean, the Arabian Sea, and the Bay of Bengal. By establishing linkages between tuna physiology and environmental conditions, we provide a mechanistic basis to project the effects of anthropogenic climate change on tuna habitats. PMID- 28657207 TI - Screening of Polish Fir Honeydew Honey Using GC/MS, HPLC-DAD, and Physical Chemical Parameters: Benzene Derivatives and Terpenes as Chemical Markers. AB - GC/MS of headspace solid phase micro extraction (HS-SPME) and solvent extractives along with targeted HPLC-DAD of Polish fir (Abies alba Mill.) honeydew honey (FHH), were used to determine the chemical profiles and potential markers of botanical origin. Additionally, typical physical-chemical parameters were also assigned. The values determined for FHH were: conductivity (1.2 mS/cm), water content (16.7 g/100 g), pH (4.5), and CIE chromaticity coordinates (L* = 48.4, a* = 20.6, b* = 69.7, C* = 72.9, and h degrees = 73.5). FHH contained moderate-high total phenolic content (533.2 mg GAE/kg) and antioxidant activity (1.1 mmol TEAC/kg) and (3.2 mmol Fe2+ /kg) in DPPH and FRAP assays. The chemical profiles were dominated by source plant-originated benzene derivatives: 3,4 dihydroxybenzoic acid (up to 8.7 mg/kg, HPLC/honey solution), methyl syringate (up to 14.5%, GC/solvent extracts) or benzaldehyde (up to 43.7%, GC/headspace). Other markers were terpenes including norisoprenoid (4-hydroxy-3,5,6-trimethyl-4 (3-oxobut-1-enyl)cyclohex-2-en-1-one, up to 20.3%, GC/solvent extracts) and monoterpenes, mainly linalool derivatives (up to 49%, GC/headspace) as well as borneol (up to 5.9%, GC/headspace). The application of various techniques allowed comprehensive characterisation of FHH. 4-Hydroxy-3,5,6-trimethyl-4-(3-oxobut-1 enyl)cyclohex-2-en-1-one, coniferyl alcohol, borneol, and benzaldehyde were first time proposed for FHH screening. Protocatechuic acid may be a potential marker of FFH regardless of the geographical origin. PMID- 28657208 TI - Silibinin stimluates apoptosis by inducing generation of ROS and ER stress in human choriocarcinoma cells. AB - Silibinin is a flavonolignan extracted from seeds of milk thistles. Traditionally, it has been used as a therapeutic agent for liver disorders, and now it is well-known for its anti-cancer effects. However, studies on anti-cancer effects of silibinin on choriocarcinoma are very limited. Therefore, we performed proliferation and apoptosis assays to determine effects of silibinin on the viability of human choriocarcinoma (JAR and JEG3) cells. Our results showed that silibinin significantly inhibited proliferation and induced apoptosis in both JAR and JEG3 cells, and significantly increased reactive oxygen species (ROS) and lipid peroxidation. Moreover, silibinin disrupted mitochondrial function by inducing permeabilization of mitochondrial membrane potential and calcium ion efflux in JAR and JEG3 cells. Furthermore, silibinin-induced apoptosis in choriocarcinoma cells via AKT, mitogen-activated protein kinases (MAPK) and unfolded protein response (UPR) signal transduction. Collectively, our results suggest that silibinin is a novel therapeutic agent or dietary supplement for management of human placental choriocarcinomas. PMID- 28657209 TI - Robotic radical cystectomy - revision and resection: An evolution in operative technique and platforms. PMID- 28657210 TI - The growing number of cancer survivors in western countries: How can our health systems best meet their needs? PMID- 28657211 TI - Quality of life after bone sarcoma surgery around the knee: A long-term follow-up study. AB - It remains unclear if quality of life (QoL) improvements could be expected in young patients after malignant bone tumour surgery after 2 years. To assess the course of QoL over time during a long-term follow-up, malignant bone tumour survivors of a previous short-term study were included. Assessments were done at least 5 years after surgery. QoL was measured with Short-form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and Bone tumour (Bt)-DUX. QoL throughout the follow-up was analysed by linear mixed model analysis. From the original cohort of 44 patients; 20 patients were included for this study, 10 males; mean age at surgery 15.1 years and mean follow-up 7.2 years. Twenty-one patients of the initial cohort (47%) deceased. Fifteen patients (75%) underwent limb-salvage and five (25%) ablative surgery. QoL improved significantly during follow-up at Physical Component Summary Scale scale of the SF-36 and TAAQOL and all subscales of the Bt-DUX (p < .01). No significant differences were found between current evaluations and previous evaluations at 2 years after surgery (p = .41-.98). Significant advantages after limb-salvage were seen at the PCS scale of the SF-36 (MD 13.7, p = .05) and the cosmetic scale of the Bt-DUX (MD 17.7, p = .04). PMID- 28657213 TI - Lateral Organization of Host Heterogeneous Raft-like Membranes Altered by the Myristoyl Modification of Tyrosine Kinase c-Src. AB - Membrane-bound c-Src non-receptor tyrosine kinase, unlike other acyl-modified lipid-anchored proteins, anchors to the membrane by a myristoyl chain along with a polybasic residue stretch, which is shorter in chain length than its host membrane. The packing defect arising from this mismatched chain length of the host and the lipid anchor significantly affects the lateral organization of heterogeneous membranes. We reveal the mixing of phase domains and formation of novel nanoscale-clusters upon membrane binding of the Myr-Src (2-9) peptide. Fluorescence cross correlation spectroscopy was used to explore the nature of these clusters. We show that Myr-Src (2-9) is able to oligomerize, and the peptide clusters are embedded in a lipid platform generated by lipid sorting. Further, using confocal fluorescence microscopy and FRET assays we show that localized charge enrichment and membrane curvature are able to shift the partition coefficient towards the more ordered lipid phase. PMID- 28657212 TI - Radiation therapy utilisation in patients with bone metastases secondary to prostate cancer: A multicenter study. PMID- 28657214 TI - Detection of Reactive Oxygen Species in Anion Exchange Membrane Fuel Cells using In Situ Fluorescence Spectroscopy. AB - The objectives of this study were: 1) to confirm superoxide anion radical (O2.- ) formation, and 2) to monitor in real time the rate of O2.- generation in an operating anion exchange membrane (AEM) fuel cell using in situ fluorescence spectroscopy. 1,3-Diphenlisobenzofuran (DPBF) was used as the fluorescent molecular probe owing to its selectivity and sensitivity toward O2.- in alkaline media. The activation energy for the in situ generation of O2.- during AEM fuel cell operation was estimated to be 18.3 kJ mol-1 . The rate of in situ generation of O2.- correlated well with the experimentally measured loss in AEM ion-exchange capacity and ionic conductivity attributable to oxidative degradation. PMID- 28657215 TI - Surface Engineering of ITO Substrates to Improve the Memory Performance of an Asymmetric Conjugated Molecule with a Side Chain. AB - Organic multilevel random resistive access memory (RRAM) devices with an electrode/organic layer/electrode sandwich-like structure suffer from poor reproducibility, such as low effective ternary device yields and a wide threshold voltage distribution, and improvements through organic material renovation are rather limited. In contrast, engineering of the electrode surfaces rather than molecule design has been demonstrated to boost the performance of organic electronics effectively. Herein, we introduce surface engineering into organic multilevel RRAMs to enhance their ternary memory performance. A new asymmetric conjugated molecule composed of phenothiazine and malononitrile with a side chain (PTZ-PTZO-CN) was fabricated in an indium tin oxide (ITO)/PTZ-PTZO-CN/Al sandwich like memory device. Modification of the ITO substrate with a phosphonic acid (PA) prior to device fabrication increased the ternary device yield (the ratio of effective ternary device) and narrowed the threshold voltage distribution. The crystallinity analysis revealed that PTZ-PTZO-CN grown on untreated ITO crystallized into two phases. After the surface engineering of ITO, this crystalline ambiguity was eliminated and a sole crystal phase was obtained that was the same as in the powder state. The unified crystal structure and improved grain mosaicity resulted in a lower threshold voltage and, therefore, a higher ternary device yield. Our result demonstrated that PA modification also improved the memory performance of an asymmetric conjugated molecule with a side chain. PMID- 28657217 TI - Role of active and passive smoking in high-risk human papillomavirus infection and cervical intraepithelial neoplasia grade 2 or worse. AB - OBJECTIVE: We performed a pooled analysis to examine cigarette smoking and household passive smoke exposure in relation to the risk of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia grade 2+ (CIN2+). METHODS: Data were pooled from 12 cross-sectional studies for cervical cancer screenings from 10 provinces of China in 1999-2007. A total of 16,422 women were analyzed, along with 2,392 high-risk-HPV (hr-HPV) positive women and 381 CIN2+ cases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models controlling for sexual and non-sexual confounding factors. RESULTS: There was an excess risk between active smoking and hr-HPV infection and CIN2+. Adjusted OR for ever smokers vs. never smokers was 1.45 (95% CI=1.10-1.91), for hr-HPV infection and 1.89 (95% CI=1.03-3.44), for CIN2+. Passive smoking had a slightly increased risk on the hr-HPV infection with adjusted OR 1.11 (1.00-1.24), but no statistical association was observed between passive smoke exposure and CIN2+. Compared with the neither active nor passive smokers, both active and passive smokers had a 1.57-fold (95% CI=1.14-2.15) increased risk of HPV infection and a 1.99-fold (95% CI=1.02-3.88) risk of CIN2+. CONCLUSION: Our large multi-center cross-sectional study found active smoking could increase the risk of overall hr-HPV infection and CIN2+ adjusted by passive smoking and other factors. Passive smoking mildly increased the risk of HPV infection but not the CIN2+. An interaction existed between passive tobacco exposure and active smoking for hr-HPV infection and the CIN2+. PMID- 28657218 TI - Clinical validation of the PCR-reverse dot blot human papillomavirus genotyping test in cervical lesions from Chinese women in the Fujian province: a hospital based population study. AB - OBJECTIVE: To determine the clinical significance of the polymerase chain reaction (PCR)-reverse dot blot (RDB) human papillomavirus (HPV) genotyping assay in cervical cancer screening. METHODS: A total of 10,442 women attending the Fujian Provincial Maternity and Children's Health Hospital were evaluated using the liquid-based cytology (thinprep cytologic test [TCT]) and the PCR-RDB HPV test. Women with HPV infection and/or abnormal cytology were referred for colposcopy and biopsy. For HPV DNA sequencing, 120 specimens were randomly selected. Pathological diagnosis was used as the gold standard. RESULTS: Using the PCR-RDB HPV test, overall HPV prevalence was 20.57% (2,148/10,442) and that of high-risk (HR)-HPV infection was 18.68% (1,951/10,442). There was 99.2% concordance between HPV PCR-RDB testing and sequencing. In this studied population, the most common HR-HPV types were HPV-16, -52, -58, -18, -53, -33, and -51, rank from high to low. HPV-16, -18, -58, -59, and -33 were the top 5 prevalent genotypes in cervical cancer but HPV-16, -18, -59, -45, and -33 were the top 5 highest risk factors for cancer (odds ratio [OR]=34.964, 7.278, 6.728, 6.101, and 3.658; all p<0.05, respectively). Among 10,442 cases, 1,278 had abnormal cytology results, of which, the HR-HPV positivity rate was 83.02% (1,061/1,278). To screen for cervical cancer by PCR-RDB HPV testing, when using CIN2+, CIN3+, and cancer as observed endpoints, the sensitivity was 90.43%, 92.61%, and 94.78% and the negative predictive value (NPV) was 99.06%, 99.42%, and 99.78%, respectively. PCR-RDB HPV and TCT co-testing achieved the highest sensitivity and NPV. CONCLUSION: For cervical cancer screening, the PCR-RDB HPV test can provide a reliable and sensitive clinical reference. PMID- 28657219 TI - Traditional herbal medicine, Rikkunshito, for chemotherapy-induced nausea and vomiting. PMID- 28657216 TI - Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02). AB - OBJECTIVE: Rikkunshito, an herbal medicine, is widely prescribed in Japan for the treatment of anorexia and functional dyspepsia, and has been reported to recover reductions in food intake caused by cisplatin. We investigated whether rikkunshito could improve chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients treated with cisplatin. METHODS: Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m2 day 1) and paclitaxel (135 mg/m2 day 0) as first-line chemotherapy were randomly assigned to the rikkunshito group receiving oral administration on days 0-13 with standard antiemetics, or the control group receiving antiemetics only. The primary endpoint was the rate of complete control (CC: no emesis, no rescue medication, and no significant nausea) in the overall phase (0-120 hours). Two-tailed p<0.20 was considered significant in the planned analysis. RESULTS: The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group (57.9% vs. 35.3%, p=0.175), as were the secondary endpoints: the CC rate in the delayed phase (24-120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed phases (63.2% vs. 35.3%, p=0.095; 84.2% vs. 52.9%, p=0.042; 84.2% vs. 52.9%, p=0.042, respectively), and time to treatment failure (p=0.059). Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6. CONCLUSION: Rikkunshito provided additive effect for the prevention of CINV and anorexia. PMID- 28657220 TI - Prognostic models for locally advanced cervical cancer: external validation of the published models. AB - OBJECTIVE: To externally validate the prognostic models for predicting the time dependent outcome in patients with locally advanced cervical cancer (LACC) who were treated with concurrent chemoradiotherapy in an independent cohort. METHODS: A historical cohort of 297 women with LACC who were treated with radical concurrent chemoradiotherapy from 1999 to 2014 at the 12 de Octubre University Hospital (H12O), Madrid, Spain. The external validity of prognostic models was quantified regarding discrimination, calibration, measures of overall performance, and decision curve analyses. RESULTS: The review identified 8 studies containing 13 prognostic models. Different (International Federation of Gynecology and Obstetrics [FIGO] stages, parametrium involvement, hydronephrosis, location of positive nodes, and race) but related cohorts with validation cohort (5-year overall survival [OS]=70%; 5-year disease-free survival [DFS]=64%; average age of 50; and over 79% squamous cell) were evaluated. The following models exhibited good external validity in terms of discrimination and calibration but limited clinical utility: the OS model at 3 year from Kidd et al.'s study (area under the receiver operating characteristic curve [AUROC]=0.69; threshold of clinical utility [TCU] between 36% and 50%), the models of DFS at 1 year from Kidd et al.'s study (AUROC=0.64; TCU between 24% and 32%) and 2 years from Rose et al.'s study (AUROC=0.70; TCU between 19% and 58%) and the distant recurrence model at 5 years from Kang et al.'s study (AUROC=0.67; TCU between 12% and 36%). CONCLUSION: The external validation revealed the statistical and clinical usefulness of 4 prognostic models published in the literature. PMID- 28657221 TI - Implications of para-aortic lymph node metastasis in patients with endometrial cancer without pelvic lymph node metastasis. AB - OBJECTIVE: The aim of this study was to confirm the incidence and implications of a lymphatic spread pattern involving para-aortic lymph node (PAN) metastasis in the absence of pelvic lymph node (PLN) metastasis in patients with endometrial cancer. METHODS: We carried out a retrospective chart review of 380 patients with endometrial cancer treated by surgery including PLN dissection and PAN dissection at Hokkaido Cancer Center between 2003 and 2016. We determined the probability of PAN metastasis in patients without PLN metastasis and investigated survival outcomes of PLN-PAN+ patients. RESULTS: The median numbers of PLN and PAN removed at surgery were 41 (range: 11-107) and 16 (range: 1-65), respectively. Sixty-four patients (16.8%) had lymph node metastasis, including 39 (10.3%) with PAN metastasis. The most frequent lymphatic spread pattern was PLN+PAN+ (7.9%), followed by PLN+PAN- (6.6%), and PLN-PAN+ (2.4%). The probability of PAN metastasis in patients without PLN metastasis was 2.8% (9/325). The 5-year overall survival rates were 96.5% in PLN-PAN-, 77.6% in PLN+PAN-, 63.4% in PLN+PAN+, and 53.6% in PLN-PAN+ patients. CONCLUSION: The likelihood of PAN metastasis in endometrial cancer patients without PLN metastasis is not negligible, and the prognosis of PLN-PAN+ is likely to be poor. The implications of a PLN-PAN+ lymphatic spread pattern should thus be taken into consideration when determining patient management strategies. PMID- 28657223 TI - Unenhanced region on magnetic resonance imaging represents tumor progression in uterine carcinosarcoma. AB - OBJECTIVE: Carcinosarcoma of the uterine corpus has a poor prognosis. Although pathological necrosis is a prognostic factor of endometrial cancer, the clinicopathological influences of an unenhanced region observed on magnetic resonance imaging (MRI) are inconclusive. The aim of our study was to determine the clinicobiological impact of the presence of an unenhanced region on MRI, which can represent necrosis, in uterine carcinosarcoma. METHODS: The clinicopathological factors of 29 patients diagnosed with uterine carcinosarcoma were assessed retrospectively. The percentage of the tumor that was unenhanced on MRI was determined. The clinicopathological factors related to the unenhanced regions were evaluated. The prognostic significance was assessed using the Kaplan Meier method and Cox regression model. RESULTS: Although the presence of pathological necrosis was not a poor prognostic factor (p=0.704), unenhanced regions on MRI correlated with poor prognosis when the unenhanced regions in the tumor accounted for more than 10% of the total tumor (p=0.019). The percentage of unenhanced regions was positively correlated with stage (p=0.028; r=0.4691) and related to tumor size (p=0.086; r=0.3749). The Cox regression analysis indicated that the presence of lymph node (LN) metastasis and more than 10% of the tumor being unenhanced on MRI were prognostic factors of overall survival in the univariate analyses (p=0.018 and p=0.047, respectively). CONCLUSION: The unenhanced region on MRI, which represents pathological necrosis, reflects tumor progression, and semi-quantification of the region is useful to predict the prognosis in patients with uterine carcinosarcoma. PMID- 28657222 TI - Young Israeli women with epithelial ovarian cancer: prevalence of BRCA mutations and clinical correlates. AB - OBJECTIVE: The current study investigates disease patterns and outcomes in young Israeli epithelial ovarian cancer (EOC) patients and their association with BRCA mutation status. METHODS: Consecutive EOC patients diagnosed at or below 50 years in a single institution between 1995-2011 were identified. All patients are referred for genetic counseling and testing for the predominant Jewish BRCA mutations: BRCA1-185delAG, BRCA1-5382insC, and BRCA2-6174delT. A comparison between BRCA mutation carriers and non-carriers was undertaken across demographic, pathologic, and clinical features; recurrence and survival were compared using the Kaplan-Meier method and associations with the variables of interest were analyzed using the Cox proportional hazards method. RESULTS: One hundred eighty-six patients diagnosed with EOC at 50 years or younger were included, with a total follow-up of 1,088 person years. Mean age at diagnosis was 44+/-5 years. Of 113 patients with documented BRCA testing, 49.6% carried a germline BRCA mutation, compared with 29% in the general Israeli EOC population (p=0.001). BRCA mutation carriers had a higher rate of serous tumors (75% vs. 64%, p=0.040) and higher CA125 levels at diagnosis (median, 401 vs. 157, p=0.001) than non-carriers. No significant association between BRCA mutations and recurrence (hazard ratio [HR]=1.03; p=0.940) or survival (HR=1.40; p=0.390) was found. CONCLUSION: BRCA mutations are encountered in almost 50% of young Israeli ovarian cancer patients; they are associated with serous tumors and high CA125 levels at diagnosis, but are not independently associated with recurrence or survival in this patient population. PMID- 28657224 TI - Nationwide cervical cancer screening in Korea: data from the National Health Insurance Service Cancer Screening Program and National Cancer Screening Program, 2009-2014. AB - OBJECTIVE: The rates of participation in the Korean nationwide cervical cancer screening program and the rates of abnormal test results were determined. METHODS: The database of the National Health Insurance Service (NHIS) was used during the study period (2009-2014). RESULTS: The participation rate increased from 41.10% in 2009 to 51.52% in 2014 (annual percentage change, 4.126%; 95% confidence interval [CI]=2.253-6.034). During the study period, women >=70 years of age had the lowest rate of participation (range, 21.7%-31.9%) and those 30-39 years of age the second-lowest (27.7%-44.9%). The participation rates of National Health Insurance beneficiaries (range, 48.6%-52.5%) were higher than those of Medical Aid Program (MAP) recipients (29.6%-33.2%). The rates of abnormal results were 0.65% in 2009 and 0.52% in 2014, with a decreasing tendency in all age groups except the youngest (30-39 years). Every year the abnormal result rates tended to decrease with age, from the age groups of 30-39 years to 60-69 years but increased in women >=70 years of age. The ratio of patients with atypical squamous cells of undetermined significance compared with those with squamous intraepithelial lesions increased from 2.71 in 2009 to 4.91 in 2014. CONCLUSION: Differences related to age and occurring over time were found in the rates of participation and abnormal results. Further efforts are needed to encourage participation in cervical cancer screening, especially for MAP recipients, elderly women and women 30-39 years of age. Quality control measures for cervical cancer screening programs should be enforced consistently. PMID- 28657225 TI - Programmed death-1 pathway blockade produces a synergistic antitumor effect: combined application in ovarian cancer. AB - Programmed death-1 (PD-1) and its ligand are part of the immune checkpoint pathway that down-regulates effector T cells in immune response, thereby causing immune suppression. The PD-1/programmed death-ligand 1 (PD-L1) pathway can be blocked by antibodies to reverse tumor-mediated immunosuppression. However, advanced cancers such as stage III-IV ovarian cancer (OC) and certain types such as ID8 OC (a clone of C57BL/6 mouse OC) may hijack the PD-1/PD-L1 pathway to escape immune attack. When combined with chemotherapy, radiotherapy, targeted therapy, immunotherapy, or other agents, these PD-1/PD-L1 pathway blockages can produce a synergistic antitumor response in OC. Combined immunotherapy significantly prolongs overall survival by changing the tumor microenvironment through processes such as increasing the number of CD4+ or CD8+ T cells or cytokines in mice with OC and decreasing the number of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). OC patients treated with combined immunotherapy received better prognoses than those treated with monotherapy. This review reflects the move toward novel therapy combinations for OC and discusses these promising immunotherapeutic approaches, which are more cost-effective and effective than other approaches. PMID- 28657228 TI - Use of a cognitive computing system for treatment of cervical cancer. PMID- 28657227 TI - Prospective comparison of hybrid capture 2 and SPF10-LiPA for carcinogenic human papillomavirus detection and risk prediction of cervical cancer: a population based cohort study in China. AB - OBJECTIVE: To investigate the extent of the cross-reactivity of hybrid capture 2 (HC2) assay and evaluate the potential effect of cross-reactivity on the long term risk for cervical cancer and precancers. METHODS: Based on the Shanxi Province Cervical Cancer Screening Study-I (SPOCCS-I) cohort from 2005 to 2014 in Shanxi, China, SPF10-line probe assay (LiPA) was performed in all 598 HC2 positive and 300 random-selected HC2 negative cervical specimens. Ten-year cumulative incidence rate (CIR) of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) of these two tests was evaluated using Kaplan-Meier methods. Possible human papillomavirus (HPV) types to be cross-reacted by HC2 were also analyzed. RESULTS: The overall agreement between HC2 and SPF10-LiPA for detecting carcinogenic HPV was 73.27%. The highest 10-year cumulative risk of CIN2+ was observed in both HC2 positive and LiPA-carcinogenic HPV positive women (25.70%; 95% confidence interval [CI]=23.55%-27.91%), followed by HC2 positive but LiPA non-carcinogenic HPV positive women (9.97%; 95% CI=8.57%-11.50%), HC2 negative but LiPA-carcinogenic HPV positive (2.56%; 95% CI=2.44%-2.70%) and HC2 positive but LiPA-HPV negative (1.85%; 95% CI=1.78%-1.92%) women. The proportion of cross reactivity of HC2 with untargeted carcinogenic types was 8.9%, most of which were attributable to HPV26, 73, 82, 69, 71, 53, 11, 43, and 54. CONCLUSION: The noticeable high risk of CIN2+ in women infected with cross-reacted non carcinogenic HPV and low risk in those with miss-to-detective carcinogenic HPV supported an overall good clinical performance of HC2 for a general cervical cancer screening. PMID- 28657226 TI - Factors associated with survival after relapse in patients with low-risk endometrial cancer treated with surgery alone. AB - OBJECTIVE: To determine factors influencing overall survival following recurrence (OSFR) in women with low-risk endometrial cancer (EC) treated with surgery alone. METHODS: A multicenter, retrospective department database review was performed to identify patients with recurrent "low-risk EC" (patients having less than 50% myometrial invasion [MMI] with grade 1 or 2 endometrioid EC) at 10 gynecologic oncology centers in Turkey. Demographic, clinicopathological, and survival data were collected. RESULTS: We identified 67 patients who developed recurrence of their EC after initially being diagnosed and treated for low-risk EC. For the entire study cohort, the median time to recurrence (TTR) was 23 months (95% confidence interval [CI]=11.5-34.5; standard error [SE]=5.8) and the median OSFR was 59 months (95% CI=12.7-105.2; SE=23.5). We observed 32 (47.8%) isolated vaginal recurrences, 6 (9%) nodal failures, 19 (28.4%) peritoneal failures, and 10 (14.9%) hematogenous disseminations. Overall, 45 relapses (67.2%) were loco regional whereas 22 (32.8%) were extrapelvic. According to the Gynecologic Oncology Group (GOG) Trial-99, 7 (10.4%) out of 67 women with recurrent low-risk EC were qualified as high-intermediate risk (HIR). The 5-year OSFR rate was significantly higher for patients with TTR >=36 months compared to those with TTR <36 months (74.3% compared to 33%, p=0.001). On multivariate analysis for OSFR, TTR <36 months (hazard ratio [HR]=8.46; 95% CI=1.65-43.36; p=0.010) and presence of HIR criteria (HR=4.62; 95% CI=1.69-12.58; p=0.003) were significant predictors. CONCLUSION: Low-risk EC patients recurring earlier than 36 months and those carrying HIR criteria seem more likely to succumb to their tumors after recurrence. PMID- 28657229 TI - Early ovarian cancer surgery with indocyanine-green-guided targeted compartmental lymphadenectomy (TCL, pelvic part). AB - OBJECTIVE: Para-aortic indocyanine-green (ICG)-guided targeted compartmental lymphadenectomy is feasible in early ovarian cancer; systematic pelvic and para aortic lymphadenectomy could potentially be avoided if thoroughly investigated sentinel nodes could predict whether residual nodes will be involved or free of disease. In contrast to advanced ovarian cancer, where the therapeutic potential of lymphadenectomy will soon be clarified by the results of the Arbeitsgemeinschaft Gynakologische Onkologie lymphadenectomy in ovarian neoplasms (AGO LION) trial, systematic lymphadenectomy seems to be mandatory for diagnostic and also therapeutic purposes in early ovarian cancer. Sentinel node biopsy or resection of the regional lymphatic network may reduce morbidity compared to systematic lymphadenectomy as shown already for other entities. Apart from the ovarian mesonephric pathway, a second Mullerian uterine pathway exists for lymphatic drainage of the ovary. Lymphatic valves apparently do not exist at this level of the utero-ovarian network since injection of radioactivity into the ovarian ligaments also labelled pelvic nodes. METHODS: We applied ICG using 4*0.5 mL of a 1.66 mg/mL ICG solution for transcervical injection into the fundal and midcorporal myometrium at each side [10] instead of injection into the infundibulopelvic ligament, since the utero-ovarian drainage was intact. RESULTS: In this case a 1.8 cm cancer of the right ovary was removed in continuity with its draining lymphatic vessels and at least the first 2 sentinel nodes in each channel "en bloc" as shown in this video for the pelvic part, consistent with the loco-regional ontogenetic approach. CONCLUSION: This could potentially avoid most of systematic lymphadenectomies in early ovarian cancer. PMID- 28657232 TI - Serum Prolactin and Cardiac Remodeling in Subjects with Prediabetes. PMID- 28657231 TI - Does a robotic surgery approach offer optimal ergonomics to gynecologic surgeons?: a comprehensive ergonomics survey study in gynecologic robotic surgery. AB - OBJECTIVE: To better understand the ergonomics associated with robotic surgery including physical discomfort and symptoms, factors influencing symptom reporting, and robotic surgery systems components recommended to be improved. METHODS: The anonymous survey included 20 questions regarding demographics, systems, ergonomics, and physical symptoms and was completed by experienced robotic surgeons online through American Association of Gynecologic Laparoscopists (AAGL) and Society of Robotic Surgery (SRS). RESULTS: There were 289 (260 gynecology, 22 gynecology-oncology, and 7 urogynecology) gynecologic surgeon respondents regularly practicing robotic surgery. Statistical data analysis was performed using the t-test, chi2 test, and logistic regression. One hundred fifty-six surgeons (54.0%) reported experiencing physical symptoms or discomfort. Participants with higher robotic case volume reported significantly lower physical symptom report rates (p<0.05). Gynecologists who felt highly confident about managing ergonomic settings not only acknowledged that the adjustments were helpful for better ergonomics but also reported a lower physical symptom rate (p<0.05). In minimizing their symptoms, surgeons changed ergonomic settings (32.7%), took a break (33.3%) or simply ignored the problem (34%). Fingers and neck were the most common body parts with symptoms. Eye symptom complaints were significantly decreased with the Si robot (p<0.05). The most common robotic system components to be improved for better ergonomics were microphone/speaker, pedal design, and finger clutch. CONCLUSION: More than half of participants reported physical symptoms which were found to be primarily associated with confidence in managing ergonomic settings and familiarity with the system depending on the volume of robotic cases. Optimal guidelines and education on managing ergonomic settings should be implemented to maximize the ergonomic benefits of robotic surgery. PMID- 28657230 TI - Malignant transformation of ovarian mature cystic teratoma into squamous cell carcinoma: a Taiwanese Gynecologic Oncology Group (TGOG) study. AB - OBJECTIVE: The malignant transformation (MT) of ovarian mature cystic teratoma (MCT) to squamous cell carcinoma (SCC) is very rare. This study analyzed cases from multiple medical centers in Taiwan to investigate the clinicopathologic characteristics, treatment, and prognostic factors of this disease and reviewed related literature. METHODS: Pathological reports of 16,001 patients with primary ovarian cancer who were treated at Taiwan medical centers from 1990 to 2011 were reviewed. In total, 52 patients with MT of MCT to SCC were identified. RESULTS: Among all ovarian MCTs, the incidence of MT to SCC is 0.2%. The median age of patients was 52 years (range, 29-89 years), and the mean tumor size was 10.5 cm (range, 1-40 cm). We analyzed the patients in our study and those in the literature and determined that early identification and complete surgical resection of the tumor are essential for long-term survival. In addition, adjuvant chemotherapy or concurrent chemoradiotherapy can be used to treat this malignancy. Old age, large tumor size (>=15.0 cm), and solid components in MCTs are suitable indicators predicting the risk of MT of MCT to SCC. CONCLUSION: Similar to general epithelial ovarian cancers, the early detection of MT of MCT to SCC is critical to long-term survival. Therefore, older patients with a large tumor or those with a tumor containing a solid component in a clinically diagnosed MCT should be evaluated to exclude potential MT to SCC. PMID- 28657233 TI - Knowledge, Attitude, and Practice of Iranian Internists Regarding Diabetes: A Cross Sectional Study. AB - BACKGROUND: A number of studies investigated the general practitioners' and family physicians' knowledge, attitude, and practice (KAP) on diabetes. However, studies on internists' KAP on diabetes management are limited. This study aimed to investigate the Iranian internists' KAP on diabetes mellitus and its management. METHODS: A cross-sectional study was conducted on a random sample of internists who participated in the 26th annual congress of internists in Tehran, Iran. The level of KAP and affecting factor was evaluated by a validated instrument. RESULTS: One-hundred internists with the mean age of 41.98+/-9.26 years were evaluated. Totally, the physicians possessed 66.29%+/-19.5%, 50.44%+/ 19.39%, and 64.5%+/-15.3% of the scores in KAP, respectively. The time since graduation in general medicine had significant negative correlation with their knowledge and practice, that was along with the subjects' age (P<0.05). The KAP level had not significant difference between subjects participated in a continuing medical education (CME) program during the last year compared to subjects did not participated (P>0.05). Attitude, and practice scores were significantly higher in physicians who were working at diabetes clinic (P<0.05), and attitude was more in physicians working at teaching hospitals compared to those who were not working (57.82 vs. 47.72, P=0.020). CONCLUSION: According to our results, subjects' age and time since graduation in general medicine and specialty were inversely correlated by knowledge and practice. So internists with older age seems to be in priority for educational programs. And holding CME programs in current forms seems to be not suitable to increase the KAP regarding diabetes. PMID- 28657234 TI - Impact of Gender on the Association between Low Serum Prolactin and Left Ventricular Mass in Subjects with Prediabetes. AB - BACKGROUND: Low circulating prolactin hormone was associated with increased risk for type 2 diabetes mellitus. An inverse association of serum prolactin with cardiac remodeling was also previously suggested. Thus, the first question arises whether low serum prolactin is associated with adverse cardiac remodeling in subjects with prediabetes and if so what the impact of gender is? Second, could serum prolactin be considered a predictor of cardiac morbidity in those subjects? This study was conducted to assess prolactin level variations in relation to echocardiographic indices of cardiac remodeling among adult men and women with prediabetes. METHODS: This cross sectional study enrolled 80 subjects with prediabetic; 40 men and 40 women. Anthropometric measurements, plasma glucose, lipid profile, homeostasis model assessment of insulin resistance, white blood cells count, prolactin and echocardiography were assessed. RESULTS: Prolactin was significantly lower in men than in women with prediabetes. Left ventricular mass (LVM) was significantly higher in men than in women with prediabetes. The proportion of left ventricular hypertrophy (LVH) in men with prediabetes was 45% compared with 22.5% in women (P=0.03). We also found inverse independent associations of serum prolactin with LVM and LVH in men, but not in women. CONCLUSION: In prediabetes, physiologically low serum prolactin is an independent predictor of increased LVM and LVH in adult men, but not in women. Prolactin may be a potential diagnostic biomarker for cardiac remodeling in adult men with prediabetes. PMID- 28657235 TI - Satisfaction Survey on Information Technology-Based Glucose Monitoring System Targeting Diabetes Mellitus in Private Local Clinics in Korea. AB - BACKGROUND: Private local clinics in Korea have little experience with information technology (IT)-based glucose monitoring (ITGM). Our aim is to examine user satisfaction and the possibility of using ITGM service practically. METHODS: Patients sent their blood glucose levels to physicians in local clinics. The physicians reviewed the blood glucose values online and provided personal consultations through text messaging or phone calls. Thereafter, a satisfaction survey on the ITGM service, the modified Morisky scale, and patient assessment of chronic illness care were administered. RESULTS: One hundred and seventy patients from seven private local clinics used the ITGM. Overall satisfaction, including that about the ITGM service, the device, and its usefulness, was rated higher than "mostly satisfied" (score 4.2+/-0.8 out of 5.0) and even higher among the elderly. Satisfaction was positively associated with age, especially in those older than 60 years. The main reason for intent for future use of the service was the time/place flexibility. Highly motivated patients tended to answer positively regarding information satisfaction (P=0.0377). CONCLUSION: Our study is the first to investigate ITGM satisfaction in private local clinics. The feasibility of users utilizing ITGM should be clarified, and future clinical research on the service's clinical effects and cost-benefit analysis is needed. PMID- 28657236 TI - Letter: Regulating Hypothalamus Gene Expression in Food Intake: Dietary Composition or Calorie Density? (Diabetes Metab J 2017;41:121-7). PMID- 28657237 TI - Response: Regulating Hypothalamus Gene Expression in Food Intake: Dietary Composition or Calorie Density? (Diabetes Metab J 2017;41:121-7). PMID- 28657238 TI - Burnout In Doctors. PMID- 28657239 TI - The Ketogenic Diet: A Solution to Ireland's Obesity Epidemic? PMID- 28657240 TI - Satisfaction rates with the current Special Type Consultation (STC) reimbursement scheme among General Practitioners - A Mixed Methods Study. AB - The Special Type Consultation (STC) scheme is a fee-for-service reimbursement scheme for General Practitioners (GPs) in Ireland. Introduced in 1989, the scheme includes specified patient services involving the application of a learned skill, e.g. suturing. This study aims to establish the extent to which GPs believe this scheme is appropriate for current General Practice. This is an embedded mixed methods study combining quantitative data on GPs working experience of and qualitative data on GPs attitudes towards the scheme. Data were collected by means of an anonymous postal questionnaire. The response rate was 60.4% (n=159.) Twenty-nine percent (n=46) disagreed and 65% (n=104) strongly disagreed that the current list of special items is satisfactory. Two overriding themes were identified: economics and advancement of the STC process. This study demonstrates an overwhelming consensus among GPs that the current STC scheme is outdated and in urgent need of revision to reflect modern General Practice. PMID- 28657241 TI - Out of sight, out of mind? A national survey of paediatricians in Ireland regarding Fetal Alcohol Spectrum Disorders. AB - Fetal Alcohol Spectrum Disorders (FASDs) are one of the major causes of preventable developmental delay. There is no register of children with FASDs in Ireland. Up to 81% of Irish women report drinking alcohol during the periconceptual period or pregnancy. We aimed to evaluate self-reported knowledge and practice of doctors working in paediatrics in Ireland with regards to FASDs and alcohol consumption during pregnancy. We circulated a survey to all paediatric doctors in Ireland, either enrolled in specialist training or registered as trainers. Fifty-six respondents (31.3%) were unaware of the existence of FASDs. Sixty-two (34.6%) believed most patients with FASDs have dysmorphic features. Seventy-three respondents (40.8%) routinely ask about maternal alcohol consumption during pregnancy in the context of developmental delay. Thirty-one respondents (17.3%) stated that mild alcohol intake in the third trimester of pregnancy is safe. Our survey suggests prenatal alcohol exposure may not be routinely considered in the evaluation of children with developmental delay by paediatric doctors in Ireland. PMID- 28657242 TI - An Irish Experience in Establishing and Evaluating an Intern Led Teaching Programme. AB - Near-Peer Teaching is a relatively new and expanding area of medical education. The benefit to medical students has been demonstrated in numerous contexts around the world. Our aim was to establish a structured Intern-Led Teaching (ILT) programme in the context of an Irish Intern Training Network affiliated to an Irish Medical School. We then sought to evaluate the success of this programme. Seventy interns were enrolled in the ILT programme and completed a Train the Trainer course involving teaching methods and skills of effective feedback. Following this, the intern tutors delivered several one-hour teaching sessions in small groups to final year medical students on a weekly basis. At the end of each teaching block, a feedback questionnaire was distributed to participating students to evaluate their experiences of this new teaching modality. Tutorial topics were varied. They included clinical examination, history taking, prescribing, and emergencies. Eighty-one percent of students found the intern-led tutorials to be beneficial compared to tutorials run by more senior doctors. Additionally, students felt that with intern led tutorials they could ask questions they otherwise would not. There was a more comfortable environment, and information taught was considered more relevant. A significant number of students felt less nervous about the final medical examinations after the intern-led tutorials. The establishment of a structured intern-led teaching programme was well received by final year medical students. This project shows that interns are a valuable teaching resource in the medical school and should be included in medical schools' curricula. PMID- 28657243 TI - Nurse Triage in an Irish Out-of-hours General Practice Co-Operative. AB - Specially trained triage nurses play a crucial role in the operation of out-of hours GP co-operatives. This study aimed to establish the proportion of all patient contacts with the out-of-hours GP co-operative based in the Mid-West of Ireland (Shannondoc), which were managed by triage nurses. A retrospective, descriptive analysis was conducted on the database of contacts to the Shannondoc urgent, out-of-hours primary care co-operative. Of the 110,039 contacts to the service in 2013, 19,147 (17.4%) were classified as being managed by nurses and 14.2% were managed by nurse telephone triage alone. Twenty-four percent of the 19,147 calls managed by nurses involved children under six years. Triage nurses play an important role in administering safe medical advice over the phone. This has implications for the training of triage nurses and the future planning of urgent out-of-hours primary care services. PMID- 28657244 TI - Emergency Aeromedical Services in Ireland: A Single-Centre Study in 2014. AB - This retrospective analysis includes patients requiring Emergency Aeromedical Services (EAS) in 2014. The aim of this paper is to evaluate the HEMS service in a single centre and to accurately assess whether certain internationally validated criteria can predict admission rates better than the currently used criteria. Using the American College of Surgeons (ACS) trauma-related dispatch criteria, each case was retrospectively evaluated. Results showed the mean total criteria met were 2.73 (?=0.88) and 1.45 (?=0.82) in admitted and discharged patients respectively. The total criteria met had a significant predictive value on admission rates (p<0.05). Increased admission rates were shown in patients with a high Mechanism of Injury (MOI) (p<0.05). False positive rates of HEMS transfer were higher when applying the current criteria compared to the ACS criteria. ACS total criteria can predict admission in HEMS patients with a higher specificity than currently used guidelines. PMID- 28657245 TI - Difficulties in the Diagnosis and Management of Paediatric Posterior Circulation Stroke. AB - We present two children with posterior circulation stroke (PCS) highlighting the wide spectrum of presentation, the need for complete radiological assessment, and the relatively high recurrence risk. PMID- 28657246 TI - Aggressive Recurrence of Oral Squamous Cell Carcinoma in a patient with Fanconi's Anaemia (FA). AB - Fanconi's Anaemia is a rare autosomal recessive disease for which the incidence of head and neck cancer can be increased 700-fold1. We report a case of a 31-year old Caucasian male with FA who initially presented in July 2007 with oral squamous cell carcinoma for which he received radical surgery and radiotherapy. He was disease-free until August 2015 when he presented with an extremely aggressive recurrence. PMID- 28657248 TI - Dilated cardiomyopathy secondary to vitamin D deficiency and hypocalcaemia in the Irish paediatric population: A case report. AB - We identified three infants with dilated cardiomyopathy (DCM) secondary to severe vitamin D deficieny and hypocalcaemia. All infants were exclusively breast fed, from dark skinned ethnic backgrounds, born and living in Ireland. None of these pregnant mothers or infants received the recommended vitamin D supplementation. Each infant presented in heart failure and required inotropic support as well as calcium and vitamin D replacement. Cardiac function subsequently improved. This highlights the public health issue that many high risk pregnant mothers and infants are not receiving the recommended vitamin D supplementation. PMID- 28657247 TI - Giant desmoid tumour of the thorax following latissimus dorsi and implant breast reconstruction: case report and review of the literature. AB - The case of a giant thoracic desmoid tumour in a 44-year-old woman, who presented two years following a breast reconstruction with a latissimus dorsi (LD) flap and implant, is reported. Clinical findings included a rapidly growing, painless mass. Computed tomography (CT) suggested skin and intercostal soft tissue invasion. The tumour was resected en bloc with the LD muscle, implant capsule and underlying rib segments. The resultant thoracic and abdominal wall defects were reconstructed with Dualmesh(r) and polypropylene meshes respectively. There was no evidence of recurrence at thirty-six months follow-up. PMID- 28657249 TI - Multidisciplinary emergent removal of a metal penoscrotal constriction device. AB - Strangulation of the genital organs is a rare presentation to the emergency department which requires urgent intervention to avoid long term complications. Penoscrotal constriction devices are either used for autoerotic stimulus or to increase sexual performance by maintaining an erection for a longer period. We report a case of a man who presented with penile strangulation following the application of a titanium penoscrotal constriction ring during sexual intercourse seven hours previously. The Fire Brigade department attended with an electric operated angle grinder to facilitate removal of the ring as standard medical equipment (orthopaedic saws, bolt and bone cutters) were insufficient. Fully functional recovery was achieved. PMID- 28657250 TI - Hearing Voices: Lessons from the History of Psychiatry in Ireland. AB - The history of psychiatry is a history of therapeutic enthusiasm, with all of the triumph and tragedy, hubris and humility that such enthusiasm brings. During the 1800s and early 1900s, Ireland-s public asylums were routinely overcrowded, unhygienic and, quite commonly, fatal. The asylums became all-too-convenient options for a society with an apparently insatiable hunger for institutions, incarceration and control. The emergence of clinical professionals, both medical and nursing, was inevitably a factor in this complex mix, but the effects of any search for professional prestige were dwarfed by asylum doctors' clear outrage at what the asylum system became. There were powerful, non-medical, vested interests in keeping large asylums open. Irish society consistently failed to generate solutions to real human suffering (mental illness, disability, disease, poverty, ill fortune) other than the extraordinary network of institutions that characterised so much of Irish history: orphanages, industrial schools, reformatories, workhouses, laundries, borstals, prisons and asylums. As a result, Ireland's remarkable asylum system was primarily a social creation rather than a medical one. Notwithstanding this complex history, Ireland's mental health services have been transformed over the past five decades, although real challenges remain, especially in relation to the homeless mentally ill, the mentally ill in prison, and providing meaningful support to families. PMID- 28657252 TI - Implementation of a Clinical Handover Diary at a Rehabilitation Hospital. PMID- 28657251 TI - The Words of a Veteran Trainee. PMID- 28657253 TI - A Clinical Presentation of Tuberculoid Leprosy in a Rural GP Setting. PMID- 28657254 TI - The Causation of Cerebral Palsy is Evolving. PMID- 28657255 TI - Managing Epilepsy in Pregnancy. PMID- 28657256 TI - Chronic Disease Management - The Patient's Perspective. AB - A paucity of data exists on Irish patients' perspective of chronic disease management. This study explores patients' views on what is the most appropriate setting for their chronic disease management, the advantages and disadvantages of these settings, and where they get information on their condition. Semi structured qualitative interviews were carried out with 24 patients. Three main themes emerged: Current Care Model, Health Literacy and Treatment Burden. Patients believe that the GP-patient relationship plays a pivotal role in the provision of chronic disease management. Health literacy and psychosocial burden were found to impact significantly on the lives of patients with chronic disease(s). PMID- 28657257 TI - Communication skills in Obstetrics: what can we learn from bereaved parents? AB - Communicating bad news in obstetrics is challenging. This study explores the impact of how bad news was communicated to parents following a diagnosis of stillbirth. Qualitative in-depth interviews were conducted with 12 mothers and 5 fathers, bereaved following stillbirth at a tertiary maternity hospital where the perinatal mortality rate is 5.2/1000. Data were analysed using Interpretative Phenomenological Analysis. How the diagnosis of stillbirth was communicated had a profound and lasting impact on parents. Dominant superordinate themes were Language used, Sensitivity and Diversionary techniques. Parents recalled in detail where and how bad news was broken and language used. Diversionary techniques created a sense of mistrust especially when parents felt information was being withheld. Bereaved parents valued privacy at the time of diagnosis of stillbirth.This study highlights the importance of language, sensitivity and environment where clinicians can learn from the experiences of bereaved parents who value open, sensitive and honest communication. The results of this study highlight the importance of patient-focused communication training for clinicians. PMID- 28657258 TI - Parental Decisions regarding pre-hospital therapy and costing of the Emergency Department Visit. AB - Paediatric patients represent a large percentage of Emergency Department (ED) visits and there is often a perception that the acuity of these presentations is low. The decision-making process that results in parents attending the ED is poorly understood. We designed a cross-sectional cohort study to explore the reasons for attendance, the treatment initiated at home and to assess parental perception of the economic cost of attendance. Data was collected on 200 patients using a survey administered to parents in ED with a follow-up phone call 4-6 weeks later. Our results suggest that attendances are often prompted by parental anxiety rather than clinical deterioration and that prior ED usage is common among those presenting for assessment. Many parents had attempted community therapy with 128/200 patients (64%) having been referred by a healthcare professional and medical therapy at home having been employed by 114/200 (57%) parents before attendance. Parental knowledge of the safety of over-the-counter medications was variable the economic cost of an ED visit was poorly understood by participants. The results of our study suggest that parental desire for control over worrisome symptoms drives much of their management strategy prior to hospital attendance. Strategies in the ED may need to focus more on managing parental expectations than on managing the illness itself and management strategies employed should focus not only on medical therapy of the child's illness but on educating and empowering the parent. PMID- 28657259 TI - Infants of hypothyroid mothers- are postnatal Thyroid Function Tests necessary? A Retrospective Study in a Regional Hospital. AB - Congenital hypothyroidism is a preventable cause of intellectual disability. The aim of this study was to establish whether adding an additional thyroid function check between days of life 10-14 in infants born to mothers with known hypothyroidism identified any additional cases of congenital hypothyroidism requiring treatment that were not detected by the national newborn bloodspot screening programme. Babies who had Thyroid Function Tests (TFTs) measured at 10 14 days of age were identified using the Paediatric Ward attenders log from the years 2012-2014. Data were collected on patients' TFTs and their mothers' Anti Thyroid Peroxidase (Anti-TPO) antibody levels. Of the 121 patients included, none were found to have a significantly raised TSH requiring treatment. 40 infants had repeat TFTs performed. None of the 121 infants had a significantly raised TSH, which required treatment with thyroxine. Congenital hypothyroidism is already being screened for as part of the National Newborn Screening Programme. The findings of our study have led us to recommend stopping current practice of routinely checking TFTs on day 10-14 of life in infants of hypothyroid mothers. PMID- 28657260 TI - Utilising magnetic resonance imaging as the gold-standard in management of suspected scaphoid fractures in the emergency department setting. AB - Scaphoid fractures are the most common carpal bone fracture. Up to 40% of scaphoid fractures can be missed at initial presentation and investigation. Follow-up plain film radiograph has overall poor sensitivity and reliability. MRI has been shown to have an almost 100% sensitivity and specificity and so is the gold standard in scaphoid fracture diagnosis. Additionally, early specialist involvement is recommended. We proposed that following a designated pathway, there would be no significant increase in MRI requests. Following implementation of a pathway for the management of suspected scaphoid fractures in St James's Hospital in 2012 re-auditing demonstrated that management changed to either MRI directly after initial x-ray (16/145, 11%), MRI after second x-ray (9/28, 32%) or orthopaedic follow-up (19/28, 68%). The number of MRIs requested was consistent with our predictors of demand. Thus, our new protocol maximises diagnostics, cost effectiveness and quality of patient care. PMID- 28657261 TI - Rare case of non-tuberculous mycobacterium: a diagnostic dilemma. AB - Non-Tuberculous Mycobacterial (NTM) infections occur in HIV-negative patients with or without underlying lung disease. It is generally felt that these organisms are acquired from the environment. Unlike tuberculosis, there are no convincing data demonstrating human-to-human OR animal-to-human transmission of NTM. We report a case of NTM infection in a 38 year old patient with underlying emphysematous lung disease. The case highlights the diagnostic dilemma which occurs when persistent sputum Acid- Fast Bacilli (AFB) smears are positive, but Nucleic acid amplification test is negative. To aid the diagnosis and rule out Pulmonary Tuberculosis as the other differential diagnosis, we applied American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guidelines & recommendations1. The decision to treat was taken on basis of CT findings, clinical, microbiologic criteria and expert consultation with Microbiology department at Waterford. PMID- 28657262 TI - Seasonal Influenza Vaccine Uptake in a Respiratory Outpatients Clinic. AB - Influenza is an acute viral respiratory illness that continues to cause significant morbidity and mortality in Ireland. Despite well-established national and international guidelines1 and increased public awareness campaigns, vaccine uptake rates are well below target worldwide2. We performed an audit of influenza vaccine uptake at a Respiratory outpatient clinic in a tertiary referral centre. 54% (n=41) of patients received the annual vaccine, well below the target of 75% set by the European Centre for Disease Prevention and Control (ECDC). PMID- 28657263 TI - Ghana health services and the Irish health system - bridging the gap. PMID- 28657265 TI - E-Cigarette: Why do we forget to document in the medical notes? PMID- 28657264 TI - The role of transcatheter arterial embolisation in the management of epistaxis. PMID- 28657266 TI - Pulmonary Recurrence of Urachal Carcinoma. PMID- 28657267 TI - Use of HIPE coding for spinal cord injury. PMID- 28657268 TI - The Implications of Delayed Access to MRI Imaging: A 3-month Historical Prospective Study. PMID- 28657270 TI - Doctors and the Effects of the Complaints Process. PMID- 28657269 TI - Increasing Compliance Rates with a Hip Fracture Analgesia Protocol in a Trauma and Orthopaedic Centre. PMID- 28657271 TI - Hospital-in-the-Home - essential to an integrated model of paediatric care. PMID- 28657272 TI - Trends in fractures and fatalities of farmyard injuries in Ireland: a 10 year analysis. AB - The farming and agricultural sector remains one of Ireland's primary industries. Fatality rates remain higher than the European average. The aim of this study was to analyze the national trend in hospital in-patient admissions for farmyard related fractures and related fatalities in Ireland from 2005 to 2014. Relevant socioeconomic trends were used for comparison. There were 2,064 farm-related fractures and 187 fatalities recorded over the same period. Despite a decrease in incidence of farmyard fractures over 2005-2014, fatality rates have increased indicating the alarming continued occupational hazards and severity of sustained injuries. PMID- 28657273 TI - Predictors of live birth after vasectomy reversal in a specialist fertility centre. AB - In a retrospective review of 106 consecutive vasectomy reversals (May 2002-April 2015) in our institution, patients were stratified according to post vasectomy obstructive interval (PVOI); less than 5 years, 5-10 years, 10-15 years and >15 years. Positive semen analysis and live birth rates were analysed. Logistic regression tested potential predictors for these outcomes. Overall patency rate (positive semen analysis) was 75% and live birth rate was 41%. Shorter PVOI was a significant predictor for positive semen analysis (p=0.028). Male smoking or male age at reversal had no significant correlation (p=0.99 and 0.95 respectively). For a live birth, PVOI and female age (threshold: 36 years) at reversal were significant predictors (p=0.007 and p=0.043 respectively). Outcomes compared favourably with international series yielding satisfactory pregnancy rates, particularly with a short obstructive interval and in females <36 years of age. PMID- 28657274 TI - Pilot evaluation of an online weight management programme. AB - This intervention examined the efficacy of a six-week online weight loss programme. Students and staff of a third level institution (n=183) were recruited to the programme which provided individualised dietary advice for weight loss. Eighty-five participants (mean age 29.7 years, mean BMI 28.9kg/m2, 33% male) met the minimum inclusion criterion of logging on to the study website at least twice. All participants who completed the full six-week programme lost weight (n=31), with significant reductions in mean weight (2.8kg), BMI (0.9kg/m2) and waist circumference (4.1cm) observed between the start and end of the programme (all P<0.001). Among "completers", males lost more weight than females (4.2kg vs. 1.9kg, P=0.004). One in four completers lost >5% of their bodyweight, with reductions in biscuit and alcohol consumption being most predictive of weight loss. These findings suggest that individualised online dietary advice is effective in achieving short-term weight loss, especially in males. PMID- 28657275 TI - Improving time to surgery for hip fracture patients. Impact of the introduction of an emergency theatre. AB - Hip fractures are a major cause of morbidity and mortality1. Surgery performed on the day of or after admission is associated with improved outcome2,3. An audit cycle was performed examining time to surgery for hip fracture patients. Our initial audit identified lack of theatre space as one factor delaying surgery. A dedicated daytime emergency theatre was subsequently opened and a re-audit was performed to assess its impact on time to surgery. Following the opening of the theatre, the proportion of patients with a delay to hip fracture surgery greater than 36 hours was reduced from 49% to 26% with lack of theatre space accounting for 23% (3 of 13) of delayed cases versus 28.6% (9 of 32) previously. 44% of hip fracture surgeries were performed in the emergency theatre during daytime hours, whilst in-hospital mortality rose from 4.6% to 6%. We conclude that access to an emergency theatre during daytime hours reduced inappropriate delays to hip fracture surgery. PMID- 28657276 TI - Venous Thromboembolism - Risk Assessment Tool and Thromboprophylaxis Policy: A National Survey. AB - Venous Thromboembolic (VTE) events in hospitalised patients are associated with significant mortality and morbidity and a major economic burden on the health service. It is well established in the literature that active implementation of a mandatory risk assessment tool and thromboprophylaxis policy reduces the incidence of hospital associated thrombosis (HAT). This study examines the utilization of a VTE risk assessment tool and thromboprophylaxis (TP) policy in Irish hospitals that manage acute admissions. A national survey was distributed to forty acute hospitals throughout Ireland. The response rate was 78% (31/40). The results showed that only 26% (n=8/31) of acute hospitals in Ireland have a local implemented TP policy. Six (75%) of these eight had a risk assessment tool in conjunction with the TP policy. All respondents who did not report to have a TP policy and risk assessment tool agreed that they should implement VTE prevention policy at their hospital. Based on the data from this survey and evidence from the effectiveness of the VTE prevention programme introduced in the United Kingdom, there is a need for a national risk assessment and thromboprophylaxis policy in Ireland. This change in practice would have the potential to prevent or reduce the morbidity and mortality associated with hospital acquired thrombosis. PMID- 28657277 TI - Shiitake Flagellate Dermatitis: the First Case Reported in Ireland. AB - Shiitake (Lentinula edodes) is the second most commonly consumed mushroom worldwide. The first case of shiitake mushroom flagellate dermatitis was described in Japan in 1977 and it is now being reported in the western world. We describe the first reported case in Ireland. PMID- 28657278 TI - Interarterial Left Circumflex: The Forgotten Coronary Artery Anomaly. AB - Anomalous coronary artery origin is a rare, but important cause of cardiac ischemia, particularly in younger patients. These anomalies of origin can be divided into two groups, benign or malignant, based on their propensity to cause ischemia or sudden death. Symptomatic, or malignant coronary artery anomalies are usually described with respect to anomalous origins of the right coronary artery or left main coronary artery. We present a unique case of a previously unreported entity, an anomalous left circumflex coronary artery causing ischemia. PMID- 28657279 TI - Knowledge of HIV PEP Among Healthcare Workers in Ireland, 2016: Room for Improvement. AB - Post-exposure prophylaxis (PEP) is an important aspect of HIV prevention following potential exposure. We conducted a survey to assess knowledge of HIV PEP, and awareness of HIV PEP resources, among key healthcare professionals, using an anonymous online questionnaire. Twelve (18%) of 68 respondents answered five or more of six knowledge questions correctly; 49 (72%) cited the Emergency Management of Injuries (EMI) toolkit as a resource. Although most respondents were aware of the EMI Toolkit for HIV PEP, the low number of respondents correctly answering knowledge questions suggests a need for training to avoid potential suboptimal HIV PEP use. PMID- 28657280 TI - George Boole and Childhood Mortality in the Cork Union Workhouse. PMID- 28657281 TI - Does My Baby Have Congenital Zika Virus Infection? PMID- 28657282 TI - Consider Beta-blocker withdrawal when using the Aldosterone Renin Ratio for case detection of Primary Aldosteronism. PMID- 28657283 TI - A Statistical Methodology to determine factors affecting Patient Experience Time Targets in the Emergency Department. PMID- 28657285 TI - Pilomatrixoma or a "hair line fracture". PMID- 28657284 TI - Hump in The Road: An Unusual Opacity on Admission Chest X-Ray. PMID- 28657286 TI - Personality and Total Health Through Life Project Eye Substudy: Methodology and Baseline Retinal Features. AB - PURPOSE: To describe the methodology and present the retinal grading findings of an older sample of australians with well-defined indices of neurocognitive function in the Personality and total Health (PATH) through life project. DESIGN: A cross-sectional study. METHODS: Three hundred twenty-six individuals from the PatH through life project were invited to participate. Participants completed a general questionnaire and 2-field, 45-degree nonmydriatic color digital retinal photography. Photographs were graded for retinal pathology according to established protocols. RESULTS: Two hundred fifty-four (77.9%) subjects, aged 72 to 78 years, agreed to participate in the eye substudy. gradable images of at least 1 eye were acquired in 211 of 254 subjects (83.1%). retinal photographic screening identified 1 or more signs of pathology in 130 of the 174 subjects (74.7%) with gradable images of both eyes. a total of 45 participants (17.7%) had self-reported diabetes and diabetic retinopathy was observed in 22 (48.9%) of these participants. CONCLUSIONS: This well-defined sample of older australians provides a unique opportunity to interrogate associations between retinal findings, including retinal vascular geometric parameters, and indices of neurocognitive function. PMID- 28657287 TI - Highly Conductive Solid-State Hybrid Electrolytes Operating at Subzero Temperatures. AB - We report a unique, highly conductive, dendrite-inhibited, solid-state polymer electrolyte platform that demonstrates excellent battery performance at subzero temperatures. A design based on functionalized inorganic nanoparticles with interconnected mesopores that contain surface nitrile groups is the key to this development. Solid-state hybrid polymer electrolytes based on succinonitrile (SN) electrolytes and porous nanoparticles were fabricated via a simple UV-curing process. SN electrolytes were effectively confined within the mesopores. This stimulated favorable interactions with lithium ions, reduced leakage of SN electrolytes over time, and improved mechanical strength of membranes. Inhibition of lithium dendrite growth and improved electrochemical stability up to 5.2 V were also demonstrated. The hybrid electrolytes exhibited high ionic conductivities of 2 * 10-3 S cm-1 at room temperature and >10-4 S cm-1 at subzero temperatures, leading to stable and improved battery performance at subzero temperatures. Li cells made with lithium titanate anodes exhibited stable discharge capacities of 151 mAh g-1 at temperatures below -10 degrees C. This corresponds to 92% of the capacity achieved at room temperature (164 mAh g-1). Our work represents a significant advance in solid-state polymer electrolyte technology and far exceeds the performance available with conventional polymeric battery separators. PMID- 28657289 TI - Reinforced Superhydrophobic Coating on Silicone Rubber for Longstanding Anti Icing Performance in Severe Conditions. AB - We present a simple method for fabricating the superhydrophobic coatings on composite silicone rubber used for electrical outdoor applications. The coating is characterized by contact angles as high as 170 degrees and is mechanically durable in contact with the aqueous phase. We discuss the impact of mechanical durability of the surface texture on the anti-icing performance of the coating on the basis of the experimental data on freezing delay of sessile aqueous droplets. A set of complementary data obtained in laboratory and outdoor experiments on freezing delay time, variation of wettability and practical work of adhesion for supercooled aqueous sessile droplets, impacting behavior of droplets at low negative temperatures, as well as the results of snow and ice accumulation in outdoor experiments indicate the very prospective icephobic properties of the developed coating. PMID- 28657288 TI - Structural Engineering for High Sensitivity, Ultrathin Pressure Sensors Based on Wrinkled Graphene and Anodic Aluminum Oxide Membrane. AB - Nature-motivated pressure sensors have been greatly important components integrated into flexible electronics and applied in artificial intelligence. Here, we report a high sensitivity, ultrathin, and transparent pressure sensor based on wrinkled graphene prepared by a facile liquid-phase shrink method. Two pieces of wrinkled graphene are face to face assembled into a pressure sensor, in which a porous anodic aluminum oxide (AAO) membrane with the thickness of only 200 nm was used to insulate the two layers of graphene. The pressure sensor exhibits ultrahigh operating sensitivity (6.92 kPa-1), resulting from the insulation in its inactive state and conduction under compression. Formation of current pathways is attributed to the contact of graphene wrinkles through the pores of AAO membrane. In addition, the pressure sensor is also an on/off and energy saving device, due to the complete isolation between the two graphene layers when the sensor is not subjected to any pressure. We believe that our high performance pressure sensor is an ideal candidate for integration in flexible electronics, but also paves the way for other 2D materials to be involved in the fabrication of pressure sensors. PMID- 28657290 TI - Relaxation-Induced Memory Effect of LiFePO4 Electrodes in Li-Ion Batteries. AB - In Li-ion batteries, memory effect has been found in several commercial two-phase materials as a voltage bump and a step in the (dis)charging plateau, which delays the two-phase transition and influences the estimation of the state of charge. Although memory effect has been first discovered in olivine LiFePO4, the origination and dependence are still not clear and are critical for regulating the memory effect of LiFePO4. Herein, LiFePO4 has been synthesized by a home built spray drying instrument, of which the memory effect has been investigated in Li-ion batteries. For as-synthesized LiFePO4, the memory effect is significantly dependent on the relaxation time after phase transition. Besides, the voltage bump of memory effect is actually a delayed voltage overshooting that is overlaid at the edge of stepped (dis)charging plateau. Furthermore, we studied the kinetics of LiFePO4 electrode with electrochemical impedance spectroscopy (EIS), which shows that the memory effect is related to the electrochemical kinetics. Thereby, the underlying mechanism has been revealed in memory effect, which would guide us to optimize two-phase electrode materials and improve Li-ion battery management systems. PMID- 28657291 TI - Surface PEG Grafting Density Determines Magnetic Relaxation Properties of Gd Loaded Porous Nanoparticles for MR Imaging Applications. AB - Surface PEGylation of nanoparticles designed for biomedical applications is a common and straightforward way to stabilize the materials for in vivo administration and to increase their circulation time. This strategy becomes less trivial when MRI active porous nanomaterials are concerned as their function relies on water/proton-exchange between the pores and bulk water. Here we present a comprehensive study on the effects of PEGylation on the relaxometric properties of nanozeolite LTL (dimensions of 20 * 40 nm) ion-exchanged with paramagnetic GdIII ions. We evidence that as long as the surface grafting density of the PEG chains does not exceed the "mushroom" regime (conjugation of up to 6.2 wt % of PEG), Gd-LTL retains a remarkable longitudinal relaxivity (38 s-1 mM-1 at 7 T and 25 degrees C) as well as the pH-dependence of the longitudinal and transverse relaxation times. At higher PEG content, the more compact PEG layer (brush regime) limits proton/water diffusion and exchange between the interior of LTL and the bulk, with detrimental consequences on relaxivity. Furthermore, PEGylation of Gd-LTL dramatically decreases the leakage of toxic GdIII ions in biological media and in the presence of competing anions, which together with minimal cytotoxicity renders these materials promising probes for MRI applications. PMID- 28657292 TI - Plasma-Functionalized Polytetrafluoroethylene Nanoparticles for Improved Wear in Lubricated Contact. AB - Plasma-functionalized polytetrafluoroethylene (PTFE) nanoparticles were employed to evaluate their utility in improving the lubrication property of a group III mineral oil with a significantly low amount of zinc dialkyl dithiophosphate (ZDDP). The particles were coated with two consecutive films; the initial coating contained silica to enhance amorphous glassy tribofilm formation, followed by a methacrylate film to protect the silica coating and enhance dispersibility in the oil. The functionalized nanoparticles were evaluated for their tribological performance using a high-frequency reciprocating rig, in a cylinder-on-flat configuration. The oil formulations containing ZDDP (350 ppm phosphorus level) and the functionalized nanoparticles resulted in dramatic reductions in the friction coefficient and overall wear compared to the samples containing nonfunctionalized PTFE nanoparticles, ZDDP (350 ppm P), and samples devoid of nanoparticles but containing ZDDP with a 700 ppm P treat rate. XPS and XANES spectroscopy were employed to characterize the tribological films formed on the test samples. The samples with functionalized particles and ZDDP clearly exhibited tribofilms with Si- and F-doped polyphosphates of Zn coupled with the presence of ZnS at the metal-tribofilm interface. On the other hand, oils without the functionalized nanoparticles have oxides of Fe and to a lesser extent short chain phosphates of Zn. The overall results suggest that the synergism between plasma-coated PTFE nanoparticles and ZDDP contributed to the development of protective tribofilms even at reduced amount of phosphorus in the oil. This new method of employing nanoparticles to deliver novel antifriction and antiwear chemistries at the tribological interfaces stands out as a promising approach to further reduce P levels in oils without compromising friction and wear performance. PMID- 28657293 TI - High-Crystallinity Covalent Organic Framework with Dual Fluorescence Emissions and Its Ratiometric Sensing Application. AB - High crystallinity of covalent organic frameworks (COFs) with dual fluorescence emissions has not been reported so far. Here, we show the rational design and preparation of high-crystallinity COF TzDa via the synergetic interaction of docking sites and hydrogen bonds: 4,4',4"-(1,3,5-Triazine-2,4,6-triyl)trianiline (Tz) with the docking site and 2,5-dihydroxyterephthalaldehyde (Da) with the OH group are employed to synthesize the imine-linked two-dimensional high crystallinity layered structure TzDa. The prepared mesoporous TzDa (ca. 36 A) exhibits high thermal and chemical stability. The intramolecular charge transfer (ICT) and excited-state intramolecular proton transfer (ESIPT) effects bring TzDa two main fluorescence emissions around 500 and 590 nm. Water molecules can interfere with the ICT and ESIPT effects, allowing the development of a ratiometric fluorescent sensor for water in organic solvents. The proposed sensor shows high sensitivity to trace water in conventional organic solvents. The high stability of TzDa allows its recyclable uses for trace water detection. This work not only offers a platform for the construction of high-crystallinity COFs, but also provides a rational design of COFs with dual fluorescence emissions for ratiometric sensing applications. PMID- 28657294 TI - Engineering the Aromaticity of Cationic Helical Polypeptides toward "Self Activated" DNA/siRNA Delivery. AB - The development of potent yet nontoxic membrane-penetrating materials is in high demand for effective intracellular gene delivery. We have recently developed alpha-helical polypeptides which afford potent membrane activities to facilitate intracellular DNA delivery via both endocytosis and the nonendocytic "pore formation" mechanism. Endocytosis will cause endosomal entrapment of the DNA cargo, while excessive "pore formation" would cause appreciable cytotoxicity. Additionally, helical polypeptides with stiff, rodlike structure suffer from low siRNA binding affinity. To address such critical issues, we herein incorporated various aromatic domains (benzyl, naphthyl, biphenyl, anthryl, and pyrenyl) into the side-chain terminals of guanidine-rich, helical polypeptides, wherein the flat-rigid shape, pi-electronic structures of aromatic motifs "self-activated" the membrane-penetrating capabilities of polypeptides to promote intracellular gene delivery. Benzyl (Bn)- and naphthyl (Naph)-modified polypeptides demonstrated the highest DNA uptake level that outperformed the unmodified polypeptide, P2, by ~4 fold. More importantly, compared with P2, Bn- and Naph modified polypeptides allowed more DNA cargos to be internalized via the nonendocytic pathway, which significantly bypassed the endosomal entrapment and accordingly enhanced the transfection efficiency by up to 42 fold, outperforming PEI 25k as the commercial reagent by 3-4 orders of magnitude. The aromatic modification also improved the siRNA condensation capability of polypeptides, achieving notably enhanced gene-silencing efficiency against tumor necrosis factor-alpha to treat acute hepatic inflammation. Furthermore, we revealed that aromaticity-augmented membrane activity was accompanied by comparable or even significantly reduced "pore formation" capability, thus leading to diminished cytotoxicity at high concentrations. This study therefore provides a promising approach to manipulate the membrane activities and penetration mechanisms of polycations, which overcomes the multiple critical barriers preventing effective and safe gene delivery. PMID- 28657295 TI - Rhenium(I) Tricarbonyl Complexes with (2-Hydroxyphenyl)diphenylphosphine as PO Bidentate Ligand. AB - In the present work, we investigated potential means to obtain neutral tricarbonyl mixed-ligand fac-[M(CO)3L1L2] complexes (M = Re, 99mTc) containing the (2-hydroxyphenyl)diphenylphosphine (POH) bidentate ligand (L1H) and a series of monodentate ligands (L2). First, fac-[Re(CO)3(PO)(H2O)], 1, was synthesized by reaction of POH and [Et4N]2[Re(CO)3Br3] in equimolar amounts in MeOH at room temperature. Interestingly, with excess of POH this reaction afforded fac [Re(CO)3(PO)(POH)], 2, with POH operating both as a bidentate and as a monodentate ligand. Owing to the presence of the labile aqua ligand, which can be readily replaced by various monodentate ligands, 1 was further used as a precursor to generate a small library of the desired fac-[M(CO)3L1L2] complexes. Specifically, by reaction of triphenylphosphine (PPh3), imidazole (im), pyridine (py), cyclohexyl isocyanide (cisc), and tert-butyl isocyanide (tbi), the following products were readily obtained in excellent yields (92%-95%): fac [Re(CO)3(PO)(PPh3)], 3, fac-[Re(CO)3(PO)(im)], 4, fac-[Re(CO)3(PO)(py)], 5, fac [Re(CO)3(PO)(cisc)], 6, and fac-[Re(CO)3(PO)(tbi)], 7. All compounds were fully characterized by elemental analysis, IR and NMR spectroscopies, and electrospray ionization(+) mass spectrometry. Their solid-state structure was elucidated by X ray crystallography. Of considerable interest is the fact that the corresponding 2'-7' were easily accessible at the 99mTc-tracer level in quantitative yields after reaction of POH and the respective monodentate ligand L2 with fac [99mTc(CO)3(H2O)3]+ in aqueous MeOH, as verified by comparative chromatographic methods adopting dual photo- and radiometric detection modes. The high stability displayed by all 99mTc complexes during histidine and cysteine challenge assays underscored the suitability of the fac-[M(CO)3(PO)L2] system for radiopharmaceutical development purposes. PMID- 28657296 TI - A Yellow-Emitting Homoleptic Iridium(III) Complex Constructed from a Multifunctional Spiro Ligand for Highly Efficient Phosphorescent Organic Light Emitting Diodes. AB - To suppress concentration quenching and to improve charge-carrier injection/transport in the emission layer (EML) of phosphorescent organic light emitting diodes (PhOLEDs), a facial homoleptic iridium(III) complex emitter with amorphous characteristics was designed and prepared in one step from a multifunctional spiro ligand containing spiro[fluorene-9,9'-xanthene] (SFX) unit. Single-crystal X-ray analysis of the resulting fac-Ir(SFXpy)3 complex revealed an enlarged Ir...Ir distance and negligible intermolecular pi-pi interactions between the spiro ligands. The emitter exhibits yellow emission and almost equal energy levels compared to the commercial phosphor iridium(III) bis(4 phenylthieno[3,2-c]pyridinato-N,C2')acetylacetonate (PO-01). Dry-processed devices using a common host, 4,4'-bis(N-carbazolyl)-1,1'-biphenyl, and the fac Ir(SFXpy)3 emitter at a doping concentration of 15 wt % exhibited a peak performance of 46.2 cd A-1, 36.3 lm W-1, and 12.1% for the current efficiency (CE), power efficiency (PE), and external quantum efficiency (EQE), respectively. Compared to control devices using PO-01 as the dopant, the fac-Ir(SFXpy)3-based devices remained superior in the doping range between 8 and 15 wt %. The current densities went up with increasing doping concentration at the same driving voltage, while the roll-offs remain relatively low even at high doping levels. The superior performance of the new emitter-based devices was ascribed to key roles of the spiro ligand for suppressing aggregation and assisting charge carrier injection/transport. Benefiting from the amorphous stability of the emitter, the wet-processed device also exhibited respectful CE, PE, and EQE of 32.2 cd A-1, 22.1 lm W-1, and 11.3%, respectively, while the EQE roll-off was as low as 1.7% at the luminance of 1000 cd m-2. The three-dimensional geometry and binary-conjugation features render SFX the ideal multifunctional module for suppressing concentration quenching, facilitating charge-carrier injection/transport, and improving the amorphous stability of iridium(III)-based phosphorescent emitters. PMID- 28657297 TI - Synthesis and the Optical and Electrochemical Properties of Indium(III) Bis(arylimino)acenaphthene Complexes. AB - Aryl bis(imino)acenaphthenes (Ar-BIANs) are well-established rigid and sterically bulky diimine ligands, which are redox-noninnocent and versatile pi-acceptors due to their low-lying pi* orbitals and are frequently used to bind transition metals. However, the coordination chemistry of Ar-BIAN ligands to main group elements is not as well-developed as that of their transition metal counterparts. In particular, there are no comprehensive studies describing the spectroscopic and electrochemical properties of main group Ar-BIAN complexes. Herein, we report the synthesis and full characterization of a series of new indium(III) Ar-BIAN complexes, bearing 2,6-dialkyl (1b and 2b), 4-nitro (3b), and 4-dimethylamino (4b) groups at the aryl-diimine part of the ligand. Their optical and electrochemical properties have been revealed by UV-vis spectroscopy and cyclic voltammetry, respectively. Additionally, DFT calculations were performed to gain insights into the nature of the properties displayed. PMID- 28657298 TI - Aspergillus niger Prolyl Endoprotease for Hydrogen-Deuterium Exchange Mass Spectrometry and Protein Structural Studies. AB - To monitor the structural integrity of therapeutic proteins, hydrogen-deuterium exchange mass spectrometry (HDX-MS) is increasingly utilized in the pharmaceutical industry. The successful outcome of HDX-MS analyses depends on the sample preparation conditions, which involve the rapid digestion of proteins at 0 degrees C and pH 2.5. Very few proteases are able to withstand such harsh conditions, with pepsin being the best-known exception, even though its activity is also strongly reduced at 0 degrees C. Here, we evaluate the usage of a prolyl endopeptidase from Aspergillus niger (An-PEP) for HDX-MS. What makes this protease very attractive is that it cleaves preferentially the hardest to digest amino acid, proline. To our surprise, and in contrast to previous reports, An-PEP activity was found optimal around pH 2.5 and could be further enhanced by urea up to 40%. Under typical HDX-MS conditions and using small amounts of enzyme, An-PEP generated an equivalent number of peptides as pepsin, as exemplified by using the two model systems tetrameric human hemoglobin (Hb) and human IgG4. Interestingly, because An-PEP peptides are shorter than pepsin-generated peptides, higher sequence resolution could be achieved, especially for Pro-containing protein regions in the alpha subunit of Hb, revealing new protected Hb regions that were not observed with pepsin. Due to its Pro-preference and resistance to low pH, we conclude that An-PEP is an archetype enzyme for HDX-MS, highly complementary to pepsin, and especially promising for structural studies on Pro-rich proteins or proteins containing Pro-rich binding domains involved in cellular signaling. PMID- 28657299 TI - Prussian Blue Analogues for the Separation of Hydrocarbons in Humid Conditions. AB - The relative affinity of a series of Prussian Blue analogues presenting various chemical compositions for the adsorption of different gases, such as water vapor and hydrocarbons, was studied. The ability of Co[CoIII(CN)6]0.66.5.2H2O for the separation of hydrocarbons in a humid atmosphere was demonstrated. PMID- 28657300 TI - Reversible and Topotactic Solvent Removal in a Magnetic Ni(NCS)2 Coordination Polymer. AB - Reaction of Ni(NCS)2 with 4-(Boc-amino)pyridine in acetonitrile leads to the formation of a new coordination polymer with the composition Ni(NCS)2(4-(Boc amino)pyridine)2.MeCN (1-MeCN). In the crystal structure the Ni(II) cations are linked by the anionic ligands into chains that are further connected into layers by intermolecular N-H...O hydrogen bonding. These layers are stacked and channels are formed, in which acetonitrile molecules are located. Solvent removal leads to the ansolvate 1, which shows microporosity as proven by sorption measurements. Single crystal X-ray investigations reveal that the solvent removal leads to a change in symmetry from primitive to C-centered, which is reversible and which proceeds via a topotactic reaction leaving the network intact. The magnetic properties of 1-MeCN and 1 are governed by the ferromagnetic exchange between spins of Ni(II) forming chains. The susceptibility and specific heat for such a quantum Heisenberg chain of S = 1 spins with zero-field splitting are calculated using the DMRG method and compared with the experimental results. PMID- 28657301 TI - Magnetically Frustrated Quaternary Chalcogenides with Interpenetrating Diamond Lattices. AB - A series of quaternary sulfides of the composition Na3MGaS4 (M = Mn (1), Fe (2), and Co (3)) have been synthesized in sealed quartz ampules. In these compounds, divalent transition metal and Ga occupy the same crystallographic site in the Ga S network, forming a supertetrahedral, T2 (adamantane) unit, through the corner sharing of four M/GaS4 tetrahedra. The corner sulfur atoms of the T2 clusters are further connected to similar T2 units to form an open continuous three dimensional (3D) anionic framework of composition {[Ga2M2S8]n}6-. The framework resembles a zinc blende structure type if each T2 cluster is considered as a single tetrahedron and two such frameworks are intertwined to generate channels wherein reside the extra-framework Na+ ions. Placement of transition metals (Mn or Fe or Co) in the corner of a perfect supertetrahedron, adamantane building unit, generates an ideal lattice for geometrical magnetic frustration, which, on dilution with nonmagnetic metal (Ga), creates an ideal case for random frustration. Preliminary magnetic measurements indicate high negative values of the Weiss constant (-200 to -400 K) and the absence of any magnetic ordering, reinforcing the presence of magnetic frustration in all of these compounds. PMID- 28657302 TI - PtPb/PtNi Intermetallic Core/Atomic Layer Shell Octahedra for Efficient Oxygen Reduction Electrocatalysis. AB - Although explosive studies on pursuing high-performance Pt-based nanomaterials for fuel cell reactions have been carried out, the combined controls of surface composition, exposed facet, and interior structure of the catalyst remains a formidable challenge. We demonstrate herein a facile chemical approach to realize a new class of intermetallic Pt-Pb-Ni octahedra for the first time. Those nanostructures with unique intermetallic core, active surface composition, and the exposed facet enhance oxygen reduction electrocatalysis with the optimized PtPb1.12Ni0.14 octahedra exhibiting superior specific and mass activities (5.16 mA/cm2 and 1.92 A/mgPt) for oxygen reduction reaction (ORR) that are ~20 and ~11 times higher than the commercial Pt/C, respectively. Moreover, the PtPb1.12Ni0.14 octahedra can endure at least 15 000 cycles with negligible activity decay, showing a new class of Pt-based electrocatalysts with enhanced performance for fuel cells and beyond. PMID- 28657304 TI - Sensitive and Label-Free Fluorescent Detection of Transcription Factors Based on DNA-Ag Nanoclusters Molecular Beacons and Exonuclease III-Assisted Signal Amplification. AB - Transcription factors (TFs) regulate gene expression by binding to regulatory regions, and their dysregulation is involved in numerous diseases. Thus, they are therapeutic targets and potential diagnostic markers. However, widely used methods for TFs detection are either cumbersome or costly. Herein, we first applied DNA-Ag nanoclusters molecular beacons (AgMBs) in TFs analysis and designed an assay based on the switchable fluorescence of AgMBs. In the absence of TFs, a single-stranded DNA functioned as a reporter is released from a double stranded DNA probe (referred as dsTFs probe) under exonuclease III (Exo III) digestion. Then, the reporter triggers downstream Exo III-assisted signal amplification by continuously consuming the guanine-rich enhancer sequences in AgMBs, resulting in significant fluorescent decrease eventually. Conversely, the presence of TFs protects the dsTFs probe from digestion and blocks the downstream reaction to keep a highly fluorescent state. To testify this rationale, we utilized nuclear factor-kappa B p50 (NF-kappaB p50) as a model TFs. Owing to the amplification strategy, this method exhibited high sensitivity toward NF-kappaB p50 with a limit of detection of 10 pM, and a broad linear range from 30 pM to 1.5 nM. Furthermore, this method could detect multiple TFs in human colon cancer DLD-1 cells and reflect the variation in their cellular levels after stimulation. Finally, by conducting an inhibition assay we revealed the potential of this method for screening TFs-targeted drugs and calculating the IC50 of corresponding inhibitors. PMID- 28657303 TI - Cooperative RNA Folding under Cellular Conditions Arises From Both Tertiary Structure Stabilization and Secondary Structure Destabilization. AB - RNA folding has been studied extensively in vitro, typically under dilute solution conditions and abiologically high salt concentrations of 1 M Na+ or 10 mM Mg2+. The cellular environment is very different, with 20-40% crowding and only 10-40 mM Na+, 140 mM K+, and 0.5-2.0 mM Mg2+. As such, RNA structures and functions can be radically altered under cellular conditions. We previously reported that tRNAphe secondary and tertiary structures unfold together in a cooperative two-state fashion under crowded in vivo-like ionic conditions, but in a noncooperative multistate fashion under dilute in vitro ionic conditions unless in nonphysiologically high concentrations of Mg2+. The mechanistic basis behind these effects remains unclear, however. To address the mechanism that drives RNA folding cooperativity, we probe effects of cellular conditions on structures and stabilities of individual secondary structure fragments comprising the full length RNA. We elucidate effects of a diverse set of crowders on tRNA secondary structural fragments and full-length tRNA at three levels: at the nucleotide level by temperature-dependent in-line probing, at the tertiary structure level by small-angle X-ray scattering, and at the global level by thermal denaturation. We conclude that cooperative RNA folding is induced by two overlapping mechanisms: increased stability and compaction of tertiary structure through effects of Mg2+, and decreased stability of certain secondary structure elements through the effects of molecular crowders. These findings reveal that despite having very different chemical makeups RNA and protein can both have weak secondary structures in vivo leading to cooperative folding. PMID- 28657305 TI - Solid Phase Speciation and Solubility of Vanadium in Highly Weathered Soils. AB - Vanadium (V) is increasingly recognized both as a medical trace element with essential biological functions and as a potentially toxic environmental pollutant, yet the current knowledge on V speciation in soils is limited. Here, we investigated the chemical speciation and extractability of V in highly weathered tropical soils, which are often rich in V compared to soils of temperate climatic regions. Vanadium K-edge X-ray absorption near edge structure (XANES) spectra of soil samples, along with a range of reference compounds differing in V-oxidation state and coordination chemistry, revealed the predominance of V4+/5+ in a primarily octahedral or tetrahedral coordination. The soil spectra were best fitted with linear combinations of reference spectra of V4+ in the structure of kaolinite, V5+ adsorbed to kaolinite, and other V5+ sorbed solids. Vanadate adsorbed to goethite, ferrihydrite, gibbsite, and/or Fe(III)-natural organic matter complexes and V4+ in the structure of goethite may be present, but cannot unequivocally be distinguished from each other by XANES spectroscopy. Sequential and single chemical extractions provided complementary information on the solubility of V under various conditions. The most labile V fractions, interpreted as weakly and strongly adsorbed V5+, are the most relevant to V mobility and bioavailability in the environment, and accounted for only ~2% of total soil V. Our results demonstrate that kaolinite and Fe oxides can effectively sequester V in highly weathered soils by mechanisms of adsorption and structural incorporation and are relevant to other Fe-oxide-rich environments under acidic and oxic conditions. PMID- 28657306 TI - Subnanometer-Sized Copper Clusters: A Critical Re-evaluation of the Synthesis and Characterization of Cu8(MPP)4 (HMPP = 2-Mercapto-5-n-propylpyrimidine). AB - We report a critical re-evaluation of the synthesis and characterization of Cu8(MPP)4. This product was reportedly formed by the reaction of Cu(NO3)2 with 2 mercapto-5-n-propylpyrimidine (HMPP) and NaBH4, in ethanol, in the presence of [N(C8H17)4][Br]. In our hands, we found no experimental evidence to support the existence of Cu8(MPP)4 in the reaction mixture. Instead, we demonstrate that the material isolated from this reaction is a complex mixture containing [N(C8H17)4]+, Br-, NO3-, and 2-mercapto-5-n-propyl-1,6-dihydropyrimidine (H2MPP*), along with the Cu(I) coordination polymer, [Cu(MPP)]n. To support our conclusions, we have independently synthesized H2MPP* and [Cu(MPP)]n, as well as the related Cu(I) coordination complexes, [Cu(HMPP*)]n and [Cu2(MPP*)]n. All new materials were characterized by NMR spectroscopy and mass spectrometry, while H2MPP*, [Cu(HMPP*)]n (n = 4), and [Cu(MPP)]n (n = 6) were also characterized by X ray crystallography. PMID- 28657307 TI - Chemical Synthesis and Luminescence Applications of Colloidal Semiconductor Quantum Dots. AB - We describe the close connection between novel chemical synthesis and optimized light emission by colloidal semiconductor quantum dots (qdots). We describe how new insights and systematic improvement in synthesis and characterization have led to highly luminescent qdots that are now used in three-color liquid-crystal displays in large televisions. We outline synthetic and structural issues that require further work to enable additional applications in solar concentrators, solid-state lighting, single-photon devices, optical computing, and in vivo infrared medical imaging. Chemical synthesis is the most creative and critical aspect of colloidal qdots. PMID- 28657308 TI - Reversible Changes in the Structural Features of Photosynthetic Light-Harvesting Complex 2 by Removal and Reconstitution of B800 Bacteriochlorophyll a Pigments. AB - Light-harvesting complex 2 (LH2) is an integral membrane protein in purple photosynthetic bacteria. This protein possesses two types of bacteriochlorophyll (BChl) a, termed B800 and B850, which exhibit lowest-energy absorption bands (Qy bands) around 800 and 850 nm. These BChl a pigments in the LH2 protein play crucial roles not only in photosynthetic functions but also in folding and maintaining its protein structure. We report herein the reversible structural changes in the LH2 protein derived from a purple photosynthetic bacterium, Rhodoblastus acidophilus, induced by the removal of B800 BChl a (denoted as B800 free LH2) and the reconstitution of exogenous BChl a. Atomic force microscopy observation clearly visualized the nonameric ring structure of the B800-free LH2 with almost the same diameter as the native LH2. Size exclusion chromatography measurements indicated a considerable decrease in the size of the protein induced by the removal of B800 BChl a. The protein size was almost recovered by the insertion of BChl a pigments into the B800 binding sites. The decrease in the LH2 size would mainly originate from the shrinkage of the B800 binding sites perpendicular to the macrocycle of B800 BChl a without deformation of the circular arrangement. The reversible changes in the LH2 structure induced by the removal and reconstitution of B800 BChl a will be helpful for understanding the structural principle and the folding mechanism of photosynthetic pigment-protein complexes. PMID- 28657309 TI - Synthesis and Superconductivity of a Strontium Digermanide SrGe2-delta with ThSi2 Structure. AB - We have succeeded in crystallizing a new strontium digermanide (SrGe2-delta) with the ThSi2-type structure (tetragonal SrGe2), which is theoretically predicted to compete with the EuGe2-type one (trigonal SrGe2) under pressure. The tetragonal SrGe2 appeared as a metastable phase in samples at approximately 900 degrees C under a pressure of 2 GPa. X-ray diffraction studies show that the tetragonal SrGe2 is formed by the reaction between trigonal SrGe2 and excess Sr. The composition of the tetragonal SrGe2 was analyzed to be SrGe1.66(4). Lattice parameters for the tetragonal SrGe2 are determined to be a = 4.559(4) A and c = 14.42(1) A. The tetragonal SrGe2 shows metallic resistivity behavior and exhibits superconductivity with a critical temperature (Tc) of 7.3 K, which is the highest among compounds with the ThSi2-type structure. Superconducting properties of the tetragonal SrGe2, such as the upper critical field, and the effect of pressure on Tc, are presented and superconductivity is discussed on the basis of electronic band structure calculations. PMID- 28657310 TI - A Coarse-Grained Force Field Parameterized for MgCl2 and CaCl2 Aqueous Solutions. AB - Calcium and magnesium ions play important roles in many physicochemical processes. To facilitate the investigation of phenomena related to these ions that occur over large length and time scales, a coarse-grained force field (CGFF) is developed for MgCl2 and CaCl2 aqueous solutions. The ions are modeled by CG beads with characteristics of hydration shells. To accurately describe the nonideal behavior of the solutions, osmotic coefficients in a wide range of concentrations were used as guidance for parametrization. The osmotic coefficients were obtained from the chemical potential increments of water calculated using the Bennett acceptance ratio (BAR) method. The result CGFF accurately reproduces experimental osmotic coefficients, densities, surface tensions, and cation-anion separations of calcium chloride and magnesium chloride solutions at molalities up to 3.0 mol/kg. As a preliminary application, the force field is applied to simulate aggregations of sodium dodecyl sulfate (SDS) in calcium chloride solution, and the simulation results are consistent with experimental observations. PMID- 28657311 TI - Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I. AB - The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 MUM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 MUM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling. PMID- 28657312 TI - Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein. AB - Cystic fibrosis (CF) is a lethal, genetic disease found in particular in humans of European origin which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The search for CF therapies acting by modulating the impaired function of mutant CFTR will be greatly advanced by high resolution structures of CFTR in different states. To date, two medium resolution electron microscopy (EM) structures of CFTR are available (one of a distant zebrafish (Danio rerio) CFTR ortholog and one of human CFTR). The two models are nearly identical to one another, and both correspond to the inward-facing, nucleotide binding domains (NBDs) separated, closed state of the channel. In addition, lower resolution structural data are available for human CFTR in an alternative conformation which likely features associated NBDs and thus geometrically resembles the conducting state of the channel. Multiple homology models of human CFTR in multiple states have been developed over the years, yet their correspondence to the existing structural information is unexplored. In this work we use molecular dynamics flexible fitting (MDFF) simulations to refine two previously described CFTR models based on the available cryo-EM map of the human protein. This map was recorded in the absence of ATP and consequently represents closed-state CFTR yet its features likely correspond to an NBD associated conformation of the protein. Accordingly, the resulting models feature dimerized NBDs yet with no membrane traversing pore. Moreover, the open probability of the new models as deduced from the MDFF trajectories is significantly lower than that deduced from control MD trajectories initiated from the starting models. We propose that the new models correspond to a CFTR conformation which to date was largely unexplored yet is one that is relevant to the gating cycle of the protein. In particular this conformation may participate in rapid channel opening and closing through small allosteric movements controlled by nucleotide binding and dissociation events. Analyzing the resulting trajectories (and not only the final models as is usually the case), we demonstrate that the refined models have good stereochemical properties and are also in favorable agreement with multiple experimental data. Moreover, despite different starting points, the final models share many common features. Finally, we propose that the combination of high resolution cryo-EM maps, which are currently emerging from multiple laboratories, and MDFF simulations will be of value for the development of yet more reliable CFTR models as well as for the identification of binding sites for CFTR modulators. PMID- 28657313 TI - Novel Methods for Prioritizing "Close-In" Analogs from Structure-Activity Relationship Matrices. AB - Here we describe the development of novel methods for compound evaluation and prioritization based on the structure-activity relationship matrix (SARM) framework. The SARM data structure allows automatic and exhaustive extraction of SAR patterns from data sets and their organization into a chemically intuitive scaffold/functional-group format. While SARMs have been used in the retrospective analysis of SAR discontinuity and identifying underexplored regions of chemistry space, there have been only a few attempts to apply SARMs prospectively in the prioritization of "close-in" analogs. In this work, three new ways of prioritizing virtual compounds based on SARMs are described: (1) matrix pattern based prioritization, (2) similarity weighted, matrix pattern-based prioritization, and (3) analysis of variance based prioritization (ANV). All of these methods yielded high predictive power for six benchmark data sets (prediction accuracy R2 range from 0.63 to 0.82), yielding confidence in their application to new design ideas. In particular, the ANV method outperformed the previously reported SARM based method for five out of the six data sets tested. The impact of various SARM parameters were investigated and the reasons why SARM based compound prioritization methods provide higher predictive power are discussed. PMID- 28657314 TI - Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization. AB - Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL 2 and shares with it the IL-2 beta and gamma receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rbeta chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity. PMID- 28657315 TI - Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide. AB - Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity. PMID- 28657316 TI - Total Synthesis of Pestalotioprolide G and Putative Structure of Pestalotioprolide H. AB - A concise and convergent route for the stereoselective total synthesis of cytotoxic macrolides pestalotioprolides G and H has been developed for the first time. Intramolecular Heck coupling has been chosen to cyclize the 14-membered macrocycle. This synthetic study strongly suggests that the proposed structure of pestalotioprolide H may need to be corrected as the spectroscopic data on the synthesized molecule deviate from the values reported for the isolated natural product. PMID- 28657318 TI - Correction to "Structure-Dynamics Relation in Physically-Plausible Multi Chromophore Systems". PMID- 28657317 TI - On the Origin of Covalent Bonding in Heavy Actinides. AB - Recent reports have suggested the late actinides participate in more covalent interactions than the earlier actinides, yet the origin of this shift in chemistry is not understood. This report considers the chemistry of actinide dipicolinate complexes to identify why covalent interactions become more prominent for heavy actinides. A modest increase in measured actinide:dipicolinate stability constants is coincident with a significant increase in An 5f energy degeneracy with the dipicolinate molecular orbitals for Bk and Cf relative to Am and Cm. While the interactions in the actinide dipicolinate complex are largely ionic, the decrease in 5f orbital energy across the series manifests in orbital-mixing and, hence, covalency driven by energy degeneracy. This observation suggests the origin of covalency in heavy actinide interactions stems from the degeneracy of 5f orbitals with ligand molecular orbitals rather than spatial orbital overlap. These findings suggest that the limiting radial extension of the 5f orbitals later in the actinide series could make the heavy actinides ideal elements to probe and tune effects of energy degeneracy driven covalency. PMID- 28657319 TI - Gradient Coating of Polydopamine via CDR. AB - Surfaces with gradient properties are of central importance for a number of chemical and biological processes. Here, we report rapid generation of a polydopamine (PDA) gradient on hydrophobic surfaces by a simple, low cost, and general technology, cyclic draining-replenishing (CDR). Due to the unique surface chemistry of PDA, it enables continuous and precise control of surface wettability and subsequent deposition of organic and inorganic compounds. Using kanamycin as a model compound, we show that the gradient PDA membrane potentially can be used to prepare minimum inhibitory concentration (MIC) test strips for quantifying resistance of antimicrobial agents from microorganisms. Because CDR is experimentally simple, scalable, fast, and does not require specialized reagents or instruments, we envision this platform can be easily adopted to create a variety of functional surfaces. PMID- 28657321 TI - Determination of Redox Sensitivity in Structurally Similar Biological Redox Sensors. AB - Redox stimuli govern a variety of biological processes. The relative sensitivity of redox sensors plays an important role in providing a calibrated response to environmental stimuli and cellular homeostasis. This cellular machinery plays a crucial role in the human pathogen Mycobacterium tuberculosis as it encounters diverse microenvironments in the host. The redox sensory mechanism in M. tuberculosis is governed by two component and one-component systems, alongside a class of transcription factors called the extra cytoplasmic function (ECF) sigma factors. ECF sigma factors that govern the cellular response to redox stimuli are negatively regulated by forming a complex with proteins called zinc associated anti-sigma factors (ZAS). ZAS proteins release their cognate sigma factor in response to oxidative stress. The relative sensitivity of the ZAS sensors to redox processes dictate the concentration of free ECF sigma factors in the cell. However, factors governing the redox threshold of these sensors remain unclear. We describe here, the molecular characterization of three sigma factor/ZAS pairs sigmaL/RslA, sigmaE/RseA, and sigmaH/RshA-using a combination of biophysical and electrochemical techniques. This study reveals, conclusively, the differences in redox sensitivity in these proteins despite apparent structural similarity and rationalizes the hierarchy in the activation of the cognate ECF sigma factors. Put together, the study provides a basis for examining sequence and conformational features that modulate redox sensitivity within the confines of a conserved structural scaffold. The findings provide the guiding principles for the design of intracellular redox sensors with tailored sensitivity and predictable redox thresholds, providing a much needed biochemical tool for understanding host-pathogen interaction. PMID- 28657320 TI - Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells. AB - To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and amide analogs. All compounds were high affinity estrogen receptor alpha (ERalpha) ligands but displayed a range of efficacies and potencies as antiproliferative and ERalpha-downregulating agents. There were large differences in activity between compounds having minor structural changes, but antiproliferative and ERalpha-downregulating efficacies generally paralleled one another. Some compounds with side chain polar groups had particularly high affinities. The secondary carboxamides had the best cellular activities, and the 3 hydroxypropylamide was as efficacious as fulvestrant in suppressing cell proliferation and gene expression. This study has produced structurally novel antiestrogens based on a simple adamantyl core structure with acrylate side chains optimized for cellular antagonist activity. PMID- 28657322 TI - Copper-Catalyzed Direct Acyloxylation of C(sp2)-H Bonds in Aromatic Amides. AB - Copper-catalyzed ortho-acyloxylation of the sp2 C-H bond of aryl amides with carboxylic acids is reported. Benzoic acids, cinnamic acids, and aliphatic acids can be involved, and the desired products were obtained in moderate to good yields. This procedure is compatible with a wide range of functional groups and heteroarenes without the use of any ligands or additives. This method provides an operationally simple approach for the synthesis of benzoate and cinnamate. PMID- 28657323 TI - Doubly Resonant Nanoantennas on Diamond for Spatial Addressing of Spin States. AB - The negatively charged nitrogen-vacancy (NV) color center in diamond is an important atom-like system for emergent quantum technologies and sensing at room temperature. The light emission rates and collection efficiency are key issues toward realizing NV-based quantum devices. In that aspect, we propose and experimentally demonstrate a selective and spatially localized method for enhancing the light-matter interaction of shallow NV centers in bulk diamonds. This was achieved by polarized doubly resonant plasmonic antennas, tuned to the NV phonon sideband transition peak in the red and the narrowband near infrared (NIR) singlet transition. We obtained a photoluminescence (PL) enhancement factor of about 10 from NV centers within the hot spot of the antenna area (excluding the extraction efficiency enhancement) and similar emission lifetime reduction. The functionality of the double resonance antenna is controlled by the impinging light polarization. PMID- 28657324 TI - Copper-Catalyzed Regio- and Stereoselective Iodocyanation and Dicyanation of Alkynes with Cyanogen Iodide. AB - anti-Selective iodocyanation and dicyanation of various internal alkynes has been developed by means of a simple copper catalyst system. The selectivity of the products was switched by tuning the reaction conditions. Mechanistic studies have revealed all of the stepwise pathways including diiodide formation, selective monocyanation, and second cyanation processes. PMID- 28657325 TI - Rashba Effect in a Single Colloidal CsPbBr3 Perovskite Nanocrystal Detected by Magneto-Optical Measurements. AB - This study depicts the influence of the Rashba effect on the band-edge exciton processes in all-inorganic CsPbBr3 perovskite single colloidal nanocrystal (NC). The study is based on magneto-optical measurements carried out at cryogenic temperatures under various magnetic field strengths in which discrete excitonic transitions were detected by linearly and circularly polarized measurements. Interestingly, the experiments show a nonlinear energy splitting between polarized transitions versus magnetic field strength, indicating a crossover between a Rashba effect (at the lowest fields) to a Zeeman effect at fields above 4 T. We postulate that the Rashba effect emanates from a lattice distortion induced by the Cs+ motion degree of freedom or due to a surface effect in nanoscale NCs. The unusual magneto-optical properties shown here underscore the importance of the Rashba effect in the implementation of such perovskite materials in various optical and spin-based devices. PMID- 28657326 TI - Rh(II)-Catalyzed Chemoselective Oxidative Amination and Cyclization Cascade of 1 (Arylethynyl)cycloalkyl)methyl Sulfamates. AB - A Rh(II)-catalyzed chemoselective oxidative amination and cyclization cascade of 1-(arylethynyl)cycloalkyl)methyl sulfamates has been presented. For a cyclopropyl or cyclobutyl moiety containing alkynyl sulfamates, the reactions underwent a metallonitrene-initiated alkyne oxidation along with cyclopropyl ring expansion or alkoxyl moiety migration to give cyclobutane-fused or methylenecyclobutane containing heterocycles. In the case of a cyclopentyl or cyclohexyl moiety containing sulfamate, the reaction underwent a direct C-H bond insertion event to afford the corresponding nitrogen-containing heterocyclic product. PMID- 28657327 TI - Polydopamine Coating To Stabilize a Free-Standing Lipid Bilayer for Channel Sensing. AB - An appropriate method to study the function of membrane channels is to insert them into free-standing lipid bilayers and to record the ion conductance across the membrane. The insulating property of a free-standing lipid bilayer versus the single-channel conductivity provides sufficient sensitivity to detect minor changes in the pathway of ions along the channel. A potential application is to use membrane channels as label-free sensors for molecules, with DNA sequencing as its most prominent application. However, the inherent instability of free standing bilayers limits broader use as a biosensor. Here we report on a possible stabilization of free-standing lipid bilayers using polydopamine deposition from dopamine-containing solutions in the presence of an oxidant. This stabilization treatment can be initiated after protein reconstitution and is compatible with most reconstitution protocols. PMID- 28657328 TI - (3 + 2)-Annulation of p-Quinamine and Aryne: A Strategy To Construct the Multisubstituted Hydrocarbazoles. AB - A strategy for the synthesis of multisubstituted hydrocarbazoles has been developed through (3 + 2)-annulation of p-quinamines and arynes. In this way, new analogs of hydrocarbazoles with quaternary carbon center can be synthesized in satisfactory yield under mild conditions. Furthermore, this (3 + 2)-annulation can be easily scaled-up, and the products can be modified through simple transformation. PMID- 28657329 TI - Direct Synthesis of beta-Aminoenals through Reaction of 1,2,3-Triazine with Secondary Amines. AB - Simple and direct nucleophilic addition of secondary amines, including imidazole, to 1,2,3-triazine under mild reaction conditions (THF, 25-65 degrees C, 12-48 h), requiring no additives, cleanly provides beta-aminoenals 4 in good yields (21 examples, 31-79%). The reaction proceeds by amine nucleophilic addition to C4 of the 1,2,3-triazine, in situ loss of N2, and subsequent imine hydrolysis to provide 4. PMID- 28657330 TI - Multiple T-DNA Delivery to Plants Using Novel Mini Binary Vectors with Compatible Replication Origins. AB - Improved plants are necessary to meet human needs. Agrobacterium-mediated transformation is the most common method used to rewire plant capabilities. For plant gene delivery, DNA constructs are assembled into binary T-DNA vectors that rely on broad host range origins for bacterial replication. Here we present pLX vectors, a set of mini binary T-DNA plasmids suitable for Type IIS restriction endonuclease- and overlap-based assembly methods. pLX vectors include replicons from compatible broad host range plasmids. Simultaneous usage of pBBR1- and RK2 based pLX vectors in a two-plasmid/one-Agrobacterium strain strategy allowed multigene delivery to plants. Adoption of pLX vectors will facilitate routine plant transformations and targeted mutagenesis, as well as complex part and circuit characterization. PMID- 28657331 TI - Anti-Cryptococcus Phenalenones and Cyclic Tetrapeptides from Auxarthron pseudauxarthron. AB - Auxarthrones A-E (1-5), five new phenalenones, and two new naturally occurring cyclic tetrapeptides, auxarthrides A (7) and B (8), were obtained from three different solvent extracts of cultures of the coprophilous fungus Auxarthron pseudauxarthron. Auxarthrones C (3) and E (5) possess an unusual 7a,8 dihydrocyclopenta[a]phenalene-7,9-dione ring system that has not been previously observed in natural products. Formation of 1-5 was found to be dependent on the solvent used for culture extraction. The structures of these new compounds were elucidated primarily by analysis of NMR and MS data. Auxarthrone A (1) was obtained as a mixture of chromatographically inseparable racemic diastereomers (1a and 1b) that cocrystallized, enabling confirmation of their structures by X ray crystallography. The absolute configurations of 7 and 8 were assigned by analysis of their acid hydrolysates using Marfey's method. Compound 1 displayed moderate antifungal activity against Cryptococcus neoformans and Candida albicans, but did not affect human cancer cell lines. PMID- 28657333 TI - 60 Minutes for health: examining the feasibility and acceptability of a low resource behavioral intervention designed to promote retention in HIV care. AB - Sustained retention in HIV medical care is a key health behavior for the long term health of people living with HIV (PLWH). Approximately 60% of PLWH in the U.S. are poorly retained in HIV care, yet to date, the few available evidence based retention-promoting interventions are resource and time intensive to implement. The current study describes the feasibility and acceptability of a theory-based retention-promoting intervention designed to meet the needs of a busy clinical care setting. 60 Minutes for Health reflects a low-resource single session intervention, implemented by a health educator, to PLWH who have had a recent gap in care (>=6-months) in the past 18-months. Intervention content was informed by a situated application of the Information Motivation Behavioral Skills Model and delivered using a Motivational Interviewing-based format. The intervention uses a workbook to guide a series of activities that: (1) Identify and reduce misinformation guiding HIV care attendance. (2) Enhance motivation to maintain care via personal health goals. (3) Build skills for coping with emotional distress related to living with HIV. (4) Increase self-efficacy for navigating the logistics of maintaining care amidst competing priorities. A small feasibility pilot of this intervention protocol was conducted to assess its potential to improve retention in care and to obtain estimates for a larger-scale efficacy trial. Participants were randomized to the 60-minute intervention session (n = 8), or a theory-based time-and-attention control session focused on diet and nutrition (n = 8). Medical records were abstracted to evaluate changes in participants' retention in care status at 12- and 24-months post-intervention. Findings suggest the intervention is both feasible and acceptable to implement with poorly retained PLWH in a clinic setting. Post-intervention a larger proportion of intervention participants were retained in care (12-months: 87.5%, 24-months: 62.5%), compared control participants (12-months: 50.0%, 24-months: 25.0%). Future work should aim to evaluate a larger-scale efficacy trial. PMID- 28657334 TI - Large-Scale Network Analysis of Whole-Brain Resting-State Functional Connectivity in Spinal Cord Injury: A Comparative Study. AB - Network analysis based on graph theory depicts the brain as a complex network that allows inspection of overall brain connectivity pattern and calculation of quantifiable network metrics. To date, large-scale network analysis has not been applied to resting-state functional networks in complete spinal cord injury (SCI) patients. To characterize modular reorganization of whole brain into constituent nodes and compare network metrics between SCI and control subjects, fifteen subjects with chronic complete cervical SCI and 15 neurologically intact controls were scanned. The data were preprocessed followed by parcellation of the brain into 116 regions of interest (ROI). Correlation analysis was performed between every ROI pair to construct connectivity matrices and ROIs were categorized into distinct modules. Subsequently, local efficiency (LE) and global efficiency (GE) network metrics were calculated at incremental cost thresholds. The application of a modularity algorithm organized the whole-brain resting-state functional network of the SCI and the control subjects into nine and seven modules, respectively. The individual modules differed across groups in terms of the number and the composition of constituent nodes. LE demonstrated statistically significant decrease at multiple cost levels in SCI subjects. GE did not differ significantly between the two groups. The demonstration of modular architecture in both groups highlights the applicability of large-scale network analysis in studying complex brain networks. Comparing modules across groups revealed differences in number and membership of constituent nodes, indicating modular reorganization due to neural plasticity. PMID- 28657335 TI - Immunometabolic Regulation of Vascular Redox State: The Role of Adipose Tissue. AB - SIGNIFICANCE: Vascular oxidative stress plays a crucial role in atherogenesis and cardiovascular disease (CVD). Recent evidence suggests that vascular redox state is under the control of complex pathophysiological mechanisms, ranging from inflammation to obesity and insulin resistance (IR). Recent Advances: Adipose tissue (AT) is now recognized as a dynamic endocrine and paracrine organ that secretes several bioactive molecules, called adipokines. AT has recently been shown to regulate vascular redox state in both an endocrine and a paracrine manner through the secretion of adipokines, therefore providing a mechanistic link for the association between obesity, IR, inflammation, and vascular disease. Importantly, AT behaves as a sensor of cardiovascular oxidative stress, modifying its secretory profile in response to cardiovascular oxidative injury. CRITICAL ISSUES: The present article presents an up-to-date review of the association between AT and vascular oxidative stress. We focus on the effects of individual adipokines on modulating reactive oxygen species production and scavenging in the vascular wall. In addition, we highlight how inflammation, obesity, and IR alter the biology and secretome of AT leading to a more pro-oxidant phenotype with a particular focus on the local regulatory mechanisms of perivascular AT driven by vascular oxidation. FUTURE DIRECTIONS: The complex and dynamic biology of AT, as well as its importance in the regulation of vascular redox state, provides numerous opportunities for the development of novel, targeted treatments in the management of CVD. Therapeutic modulation of AT biology could improve vascular redox state affecting vascular disease pathogenesis. Antioxid. Redox Signal. 29, 313-336. PMID- 28657336 TI - Predictors of pre-hospital delay in Hong Kong Chinese patients with acute myocardial infarction. AB - BACKGROUND: The pre-hospital delay to seek care remains the most significant barrier for effective management of acute myocardial infarction. Many of the previous studies mainly took place in Western countries. Few data are available about the care-seeking behavior of Hong Kong Chinese. AIM: The purpose of this study was to identify the predictors of pre-hospital delay in care seeking among Hong Kong Chinese patients with acute myocardial infarction. METHODS: Adult Chinese patients ( n=301) with a confirmed diagnosis of acute myocardial infarction were recruited from the cardiac units of three regional hospitals in Hong Kong. Various socio-demographic, clinical, symptom presentation characteristics and patient perceptual factors were considered as potential predictors. Multivariate analysis was conducted to identify the independent predictors with pre-hospital delay in care-seeking among acute myocardial infarction patients. RESULTS: Perceived barriers to care seeking constituted the most significant predictor for longer pre-hospital delay in acute myocardial infarction patients. Female gender was also significant in predicting longer delay, whereas a greater extent of symptom congruence and a greater extent of typical symptom presentation were significantly associated with a shorter delay. The final model accounted for 49.6% of the variance in pre-hospital delay as a whole. CONCLUSION: The most prominent predictors of pre-hospital delay are modifiable in nature, including the perceived barriers to care seeking and symptom congruence. Other sociodemographic and clinical factors also influence patients' decision. Although these are non-modifiable, our findings provide important insight for educating high-risk individuals. PMID- 28657332 TI - Role of Hypohalous Acids in Basement Membrane Homeostasis. AB - SIGNIFICANCE: Basement membranes (BMs) are sheet-like structures of specialized extracellular matrix that underlie nearly all tissue cell layers including epithelial, endothelial, and muscle cells. BMs not only provide structural support but are also critical for the development, maintenance, and repair of organs. Animal heme peroxidases generate highly reactive hypohalous acids extracellularly and, therefore, target BMs for oxidative modification. Given the importance of BMs in tissue structure and function, hypohalous acid-mediated oxidative modifications of BM proteins represent a key mechanism in normal development and pathogenesis of disease. Recent Advances: Peroxidasin (PXDN), a BM-associated animal heme peroxidase, generates hypobromous acid (HOBr) to form sulfilimine cross-links within the collagen IV network of BM. These cross-links stabilize BM and are critical for animal tissue development. These findings highlight a paradoxical anabolic role for HOBr, which typically damages protein structure leading to dysfunction. CRITICAL ISSUES: The molecular mechanism whereby PXDN uses HOBr as a reactive intermediate to cross-link collagen IV, yet avoid collateral damage to nearby BM proteins, remains unclear. FUTURE DIRECTIONS: The exact identification and functional impact of specific hypohalous acid-mediated modifications of BM proteins need to be addressed to connect these modifications to tissue development and pathogenesis of disease. As seen with the sulfilimine cross-link of collagen IV, hypohalous acid oxidative events may be beneficial in select situations rather than uniformly deleterious. Antioxid. Redox Signal. 27, 839-854. PMID- 28657337 TI - Mitochondrial and Reactive Oxygen Species Signaling Coordinate Stem Cell Fate Decisions and Life Long Maintenance. AB - SIGNIFICANCE: Recent discoveries in mitochondrial biology have transformed and further solidified the importance of mitochondria in development, aging, and disease. Within the realm of regenerative and stem cell research, these recent advances have brought forth new concepts that revolutionize our understanding of metabolic and redox states in the establishment of cellular identity and fate decisions. Recent Advances: Mitochondrial metabolism, morphology, and cellular redox states are dynamic characteristics that undergo shifts during stem cell differentiation. Although it was once thought that this was solely because of changing metabolic needs of differentiating cells, it is now clear that these events are driving forces in the regulation of stem cell identity and fate decisions. CRITICAL ISSUES: Although recent discoveries have placed mitochondrial function and physiological reactive oxygen species (ROS) at the forefront for the regulation of stem cell self-renewal, how this may impact tissue homeostasis and regenerative capacity is poorly understood. In addition, the role of mitochondria and ROS on the maintenance of a stem cell population in many degenerative diseases and during aging is not clear, despite the fact that mitochondrial dysfunction and elevated ROS levels are commonly observed in these conditions. FUTURE DIRECTIONS: Given the newly established role for mitochondria and ROS in stem cell self-renewal capacity, special attention should now be directed in understanding how this would impact the development and progression of aging and diseases, whereby mitochondrial and ROS defects are a prominent factor. PMID- 28657339 TI - Corrigendum. PMID- 28657338 TI - Reply: The Choice of Indicators for Obstructive Sleep Apnea Treatment Outcome Evaluation: A Matter of Time-Dependent Response? PMID- 28657341 TI - Corrigendum. PMID- 28657340 TI - ICRP Publication 134: Occupational Intakes of Radionuclides: Part 2. AB - Abstract -: The 2007 Recommendations of the International Commission on Radiological Protection (ICRP, 2007) introduced changes that affect the calculation of effective dose, and implied a revision of the dose coefficients for internal exposure, published previously in the Publication 30 series (ICRP, 1979, 1980, 1981, 1988b) and Publication 68 (ICRP, 1994b). In addition, new data are available that support an update of the radionuclide-specific information given in Publications 54 and 78 (ICRP, 1988a, 1997b) for the design of monitoring programmes and retrospective assessment of occupational internal doses. Provision of new biokinetic models, dose coefficients, monitoring methods, and bioassay data was performed by Committee 2, Task Group 21 on Internal Dosimetry, and Task Group 4 on Dose Calculations. A new series, the Occupational Intakes of Radionuclides (OIR) series, will replace the Publication 30 series and Publications 54, 68, and 78. Part 1 of the OIR series has been issued (ICRP, 2015), and describes the assessment of internal occupational exposure to radionuclides, biokinetic and dosimetric models, methods of individual and workplace monitoring, and general aspects of retrospective dose assessment. The following publications in the OIR series (Parts 2-5) will provide data on individual elements and their radioisotopes, including information on chemical forms encountered in the workplace; a list of principal radioisotopes and their physical half-lives and decay modes; the parameter values of the reference biokinetic model; and data on monitoring techniques for the radioisotopes encountered most commonly in workplaces. Reviews of data on inhalation, ingestion, and systemic biokinetics are also provided for most of the elements. Dosimetric data provided in the printed publications of the OIR series include tables of committed effective dose per intake (Sv per Bq intake) for inhalation and ingestion, tables of committed effective dose per content (Sv per Bq measurement) for inhalation, and graphs of retention and excretion data per Bq intake for inhalation. These data are provided for all absorption types and for the most common isotope(s) of each element. The electronic annex that accompanies the OIR series of reports contains a comprehensive set of committed effective and equivalent dose coefficients, committed effective dose per content functions, and reference bioassay functions. Data are provided for inhalation, ingestion, and direct input to blood. The present publication provides the above data for the following elements: hydrogen (H), carbon (C), phosphorus (P), sulphur (S), calcium (Ca), iron (Fe), cobalt (Co), zinc (Zn), strontium (Sr), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), and technetium (Tc). PMID- 28657342 TI - Macrovascular function indices for the prediction of diabetic retinopathy development in patients with type 2 diabetes. PMID- 28657343 TI - Diagnostic reliability of mandibular second molar maturation in the identification of the mandibular growth peak: A longitudinal study. AB - OBJECTIVE: To investigate the diagnostic reliability of mandibular second molar maturation in assessing the mandibular growth peak using a longitudinal design. MATERIALS AND METHODS: From the files of the Burlington and Oregon growth studies, 40 subjects (20 from each collection, 20 males and 20 females) with at least seven annual lateral cephalograms taken from 9 to 16 years were included. Mandibular second molar maturation was assessed according to Demirjian et al., and mandibular growth was defined as annual increments of Co-Gn distance. A full diagnostic reliability analysis (including positive likelihood ratio) was performed to establish the diagnostic reliability of dental stages E, F, and (pooled) GH in identifying the imminent mandibular growth peak. RESULTS: None of the dental maturation stages reliably identified the mandibular growth peak with greatest overall mean accuracy and positive likelihood ratio of 0.77 (stage F) and 2.7 (stage E), respectively. CONCLUSIONS: Use of the mandibular second molar maturation is not recommended for planning treatment requiring identification of the mandibular growth peak. PMID- 28657344 TI - Value of Frequency Domain Resting-State Functional Magnetic Resonance Imaging Metrics Amplitude of Low-Frequency Fluctuation and Fractional Amplitude of Low Frequency Fluctuation in the Assessment of Brain Tumor-Induced Neurovascular Uncoupling. AB - The aim of this study was to explore whether the phenomenon of brain tumor related neurovascular uncoupling (NVU) in resting-state blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) (rsfMRI) may also affect the resting-state fMRI (rsfMRI) frequency domain metrics the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF). Twelve de novo brain tumor patients, who underwent clinical fMRI examinations, including task based fMRI (tbfMRI) and rsfMRI, were included in this Institutional Review Board approved study. Each patient displayed decreased/absent tbfMRI activation in the primary ipsilesional (IL) sensorimotor cortex in the absence of a corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for the motor tasks were obtained from general linear model analysis (reflecting motor activation vs. rest). Seed-based correlation analysis (SCA) maps of sensorimotor network, ALFF, and fALFF were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and IL hemispheres were parcellated using an automated anatomical labeling template for each patient. Region of interest (ROI) analysis was performed on four maps: tbfMRI, SCA, ALFF, and fALFF. Voxel values in the CL and IL ROIs of each map were divided by the corresponding global mean of ALFF and fALFF in the cortical brain tissue. Group analysis revealed significantly decreased IL ALFF (p = 0.02) and fALFF (p = 0.03) metrics compared with CL ROIs, consistent with similar findings of significantly decreased IL BOLD signal for tbfMRI (p = 0.0005) and SCA maps (p = 0.0004). The frequency domain metrics ALFF and fALFF may be markers of lesion-induced NVU in rsfMRI similar to previously reported alterations in tbfMRI activation and SCA derived resting-state functional connectivity maps. PMID- 28657345 TI - VEGF-C-mediated cardiac lymphangiogenesis in high salt intake accelerated progression of left ventricular remodeling in spontaneously hypertensive rats. AB - High salt (HS) diet can accelerate the progress of hypertensive left ventricular (LV) remodeling. But the detailed mechanism remains poorly understood. We hypothesized HS intake could impact cardiac lymphangiogenesis through tonicity responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway which might play an important role in HS intake accelerated LV remodeling. Eight-week-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to 0.5% NaCl (Low salt, LS) and 8% NaCl (high salt, HS) diets for 12 weeks. LV remodeling was determined by echocardiography. LV invasive hemodynamic analysis and morphologic staining (cardiomyocyte hypertrophy, collagen deposition, TonEBP expression, macrophage infiltration and lymphatic density) were performed at the time of sacrifice. The blood pressure of SHR-HS group was significantly increased compared to SHR-LS and WKY groups. Meanwhile, The LV chamber size was markedly enlargement, LV function apparently compromised accompanied with a severe macrophage infiltration, and fibrosis in the perivascular and interstitium of LV compared with SHR-LS group. Furthermore, the expression levels of VEGF-C, TonEBP, and lymphatic markers in SHR-HS group were significantly increased parallel with apparent lymphangiogenesis compared with SHR-LS group. Our work indicates that TonEBP/VEGF C signaling pathway was up-regulated in HS intake accelerated hypertensive LV remodeling process that may be valuable for further investigation. PMID- 28657346 TI - Retaining Traditional Dietary Practices among Greek Immigrants to Australia: The Role of Ethnic Identity. AB - This article explores why some Greek immigrants to Australia continue to adhere to a traditional Mediterranean diet whereas others have adopted eating behaviors characteristic of a less healthy "Australian" diet. Twelve qualitative interviews were conducted and comparisons made between individuals consuming more (n = 6) and less traditional diets (n = 6). The level of adherence to the diet was previously assessed by a diet score in a separate quantitative study (MEDIS Australia) from which the subset of 12 participants for the present study was recruited. Analysis revealed that maintenance of a strong ethnic identity offers a pathway through which individuals retain dietary practices of their homeland. PMID- 28657347 TI - It's Your Place: Development and Evaluation of an Evidence-Based Bystander Intervention Campaign. AB - Preventing sexual assault on college campuses is a national priority. Bystander intervention offers a promising approach to change social norms and prevent sexual misconduct. This study presents the implementation and evaluation of a theory-based campaign to promote active bystander intervention. The theory of planned behavior (TPB) served as a conceptual framework throughout campaign development and evaluation. Formative research published elsewhere was used to develop campaign strategies, communication channels, and messages, including "It is your place to prevent sexual assault: You're not ruining a good time." The It's Your Place multi-media campaign fosters a culture of bystander intervention through peer-to-peer facilitation and training, as well as traditional and new media platforms. A cross-sectional post-test only web-based survey was designed to evaluate the campaign and test the TPB's ability to accurately predict intention to intervene. Survey data were collected from 1,505 currently enrolled students. The TPB model predicted intention to intervene. There was a significant effect of campaign exposure on attitude, subjective norms, and perceived behavioral intention. This theory-based communication campaign offers implications for promoting active bystander intervention and reducing sexual assault. PMID- 28657348 TI - Comparing the economic burden of ischemic stroke patients with and without atrial fibrillation: a retrospective study in Beijing, China. AB - BACKGROUND: Little is known about the economic burden for ischemic stroke (IS) patients with atrial fibrillation (AF) in China. AIM: We aimed to compare the economic burden of treatment-related costs in IS patients with AF vs. without AF in China. METHODS: This retrospective analysis used economic burden data from the Beijing urban health insurance database. Using a random sampling method, 10% of the patients diagnosed with IS from 1 January through 31 December 2012 were enrolled. First hospitalization was considered as the index event and hospital utilization after the index event was followed up until September 2013. Overall healthcare cost during the study period was analyzed. RESULTS: In 4061 patients with IS (mean +/- SD age, 68.45 +/- 13.95 years; AF: 992; without AF: 3069), the AF group had a higher percentage of patients with co-morbidities at baseline. Compared with the non-AF group, the AF group had significantly greater hospitalization at the index event (p < .001). Overall inpatient cost per patient during the observational period (Renminbi (RMB) 141,875.9 +/- 121,071.8 vs. RMB 53,834.03 +/- 63,535.72, in 2012 terms), total healthcare cost per patient (RMB 163,550.4 +/- 131,103.5 vs. RMB 64,735.41 +/- 67,584.95), total healthcare cost covered by health insurance, and annualized total healthcare cost per patient were higher in the AF group than in the non-AF group (p < .001). Treatment costs were significantly associated with old age, male gender, AF, and frequency of outpatient visits and hospitalization. CONCLUSIONS: AF increased the use of healthcare resources, treatment cost, and economic burden in patients with IS. Therefore, prevention of cardio-embolic events in patients with AF by anticoagulants may decrease the economic burden in patients with IS. PMID- 28657349 TI - A new triterpene ester and other chemical constituents from the aerial parts of Anodendron paniculatum and their cytotoxic activity. AB - The aim of the research was to study the active constituents of Anodendron paniculatum Roxb. (Apocynaceae). A new triterpene ester, named anopaniester (1), and cycloartenol (2), ursolic acid (3), esculenic acid (4), bis-(2-ethylhexyl) phthalate (5), desmosterol (6), stigmasterol (7), vaniline (8), and (E)-phytol (9), were isolated from the aerial parts of A. paniculatum. Compounds 3 and 6 showed the significant inhibitory effect (IC50 values ranging from 30.89 +/- 3.60 to 44.37 +/- 5.40 MUg/ml) against tested human cancer cell lines LU-1 and MKN-7. The compounds 1-4, and 6 were isolated from this genus Anodendron for the first time. PMID- 28657350 TI - Bispectral index as a predictor of unsalvageable traumatic brain injury. AB - PRIMARY OBJECTIVE: We aimed to assess the utility of bispectral index (BIS) monitoring to diagnose brain death (BD) in patients with severe traumatic brain injury (TBI). RESEARCH DESIGN AND METHODS: A prospective observational study was conducted for patients with severe TBI between 2012 and 2014. MAIN OUTCOMES AND RESULTS: This study included 62 patients with a mean age of 32.5 +/- 10.5 years. Nine patients had BD on admission with a sustainable BIS value of 0. Fifty-three patients were not initially diagnosed with BD with BIS values of 2-56. Forty-four patients deteriorated to BD, and their respective BIS values progressively decreased to 0. Nine patients with mean BIS of 39.2 +/- 9.0 recovered and were transferred to a specialized high dependency unit. BIS values showed positive correlation with the Glasgow Coma Score (GCS) on admission (r = 0.43, p = 0.001). Survivors had higher BIS values than those who were initially declared BD or those who died during the hospitalization course (p = 0.001). CONCLUSION: BIS values have a significant correlation with initial GCS and can assist in the early detection of BD in patients with severe acute TBI. Further larger studies are needed to support our findings. PMID- 28657351 TI - World health organization disability assessment schedule 2.0 as an objective assessment tool for predicting return to work after a stroke. AB - PURPOSE: To analyze whether World Health Organization Disability Assessment Schedule 2.0 can be used as an objective assessment tool for predicting the return-to-work status of working-age patients with stroke. METHOD: We obtained the data on 2963 patients disabled by stroke (age <60 years) from the Taiwan Data Bank of Persons with Disability for the July 2012-January 2014 period. Of these patients, 119 could return to work, whereas 2844 could not. Demographic data and World Health Organization Disability Assessment Schedule 2.0 standardized scores of patients with stroke who could return to work and those who could not (return to work and nonreturn-to-work groups, respectively) were analyzed and compared using the chi-squared and independent Student's t-tests. Receiver operating characteristic curve analysis was performed to investigate the prediction accuracy for the return-to-work status, and the optimal cutoff point was determined using the Youden index. Binary logistic regression was employed to determine the predictors of the return-to-work status of patients with stroke. RESULTS: The World Health Organization Disability Assessment Schedule 2.0 scores in all domains were lower in the return-to-work group than in the nonreturn-to work group. The receiver operating characteristic curve showed moderate accuracy for all domain-specific scores [area under the curve, 0.6-0.8] and good accuracy for the summary scores of World Health Organization Disability Assessment Schedule 2.0 (area under the curve, >0.8). Binary logistic regression revealed that younger age, less severe stroke and standardized World Health Organization Disability Assessment Schedule 2.0 summary scores below the cutoff points were predictors of the return to work status of working-age patients disabled by stroke. CONCLUSIONS: World Health Organization Disability Assessment Schedule 2.0 can be used as an objective assessment tool for predicting the return-to-work status of working-age patients disabled by stroke. This tool can aid in establishing rehabilitation strategies and goal-setting processes for the return to-work of patients with stroke. Implications for rehabilitation World Health Organization Disability Assessment Schedule 2.0 summary scores can predict the return-to-work status of working-age patients with stroke. Younger age and less severe stroke are associated with the return-to-work status of patients with stroke. Lower disability scores of the World Health Organization Disability Assessment Schedule 2.0 items result in a favorable return-to-work status and help in establishing effective rehabilitation strategies for facilitating the return-to-work of young patients with stroke. PMID- 28657352 TI - Wrong-way driving crashes: A multiple correspondence approach to identify contributing factors. AB - OBJECTIVE: Wrong-way driving (WWD) crashes result in 1.34 fatalities per fatal crash, whereas for other non-WWD fatal crashes this number drops to 1.10. As such, further in-depth investigation of WWD crashes is necessary. The objective of this study is 2-fold: to identify the characteristics that best describe WWD crashes and to verify the factors associated with WWD occurrence. METHODS: We collected and analyzed 15 years of crash data from the states of Illinois and Alabama. The final data set includes 398 WWD crashes. The rarity of WWD events and the consequently small sample size of the crash database significantly influence the application of conventional log-linear models in analyzing the data, because they use maximum-likelihood estimation. To overcome this issue, in this study, we employ multiple correspondence analysis (MCA) to define the structure of the crash data set and identify the significant contributing factors to WWD crashes on freeways. RESULTS: The results of the present study specify various factors that characterize and influence the probability of WWD crashes and can thus lead to the development of several safety countermeasures and recommendations. According to the obtained results, factors such as driver age, driver condition, roadway surface conditions, and lighting conditions were among the most significant contributors to WWD crashes. CONCLUSIONS: Despite many other methods that identify only the contributing factors, this method can identify possible associations between various contributing factors. This is an inherent advantage of the MCA method, which can provide a major opportunity for state departments of transportation (DOTs) to select safety countermeasures that are associated with multiple safety benefits. PMID- 28657353 TI - Probing consciousness in a sensory-disconnected paralyzed patient. AB - BACKGROUND: Diagnosis of consciousness can be very challenging in some clinical situations such as severe sensory-motor impairments. CASE STUDY: We report the case study of a patient who presented a total "locked-in syndrome" associated with and a multi-sensory deafferentation (visual, auditory and tactile modalities) following a protuberantial infarction. RESULT: In spite of this severe and extreme disconnection from the external world, we could detect reliable evidence of consciousness using a multivariate analysis of his high density resting state electroencephalogram. This EEG-based diagnosis was eventually confirmed by the clinical evolution of the patient. CONCLUSION: This approach illustrates the potential importance of functional brain-imaging data to improve diagnosis of consciousness and of cognitive abilities in critical situations in which the behavioral channel is compromised such as deafferented locked-in syndrome. PMID- 28657354 TI - Update on afatinib-based combination regimens for the treatment of EGFR mutation positive non-small-cell lung cancer. PMID- 28657355 TI - A single error is one too many: Examining alternative cutoffs on Trial 2 of the TOMM. AB - OBJECTIVE: This study investigated the potential of alternative, more liberal cutoffs on Trial 2 of the Test of Memory Malingering (TOMM) to improve classification accuracy relative to the standard cutoffs (<=44). METHOD: The sample consisted of 152 patients (49.3% male) with psychiatric conditions (PSY) and traumatic brain injury (TBI) referred for neuropsychological assessment in a medico-legal setting (MAge = 44.4, MEducation = 11.9 years). Classification accuracy for various TOMM Trial 2 cutoffs was computed against three criterion measures. RESULTS: Patients with TBI failed TOMM Trial 2 cutoffs at higher rates than patients with PSY. Trial 2 <=49 achieved acceptable combinations of sensitivity (0.38-0.67) and specificity (0.89-0.96) in all but one comparison group. Trial 2 <=48 improved specificity (0.94-0.98) with minimal loss in sensitivity. The standard cutoff (<=44) disproportionally traded sensitivity (0.15-0.50) for specificity (0.96-1.00). CONCLUSIONS: One error on TOMM Trial 2 constitutes sufficient evidence to question the credibility of a response set. However, the confidence in classifying a score as invalid continues to increase with each additional error. Even at the most liberal conceivable cutoff (<=49), the TOMM detected only about half of the patients who failed other criterion measures. Therefore, it should never be used in isolation to determine performance validity. PMID- 28657356 TI - What Is the Story with Narratives? How Using Narratives in Journalism Changes Health Behavior. AB - Health journalists frequently use narratives to bring news stories to life, with little understanding about how this influences the health behavior of readers. This study was designed to examine the effect of a New York Times health news article about a person who developed a life-threatening illness after using ibuprofen on readers' future use of ibuprofen. We recruited an Internet sample (N = 405) to participate in a longitudinal study examining ibuprofen use before, immediately following, and two weeks after reading the story. Ibuprofen use two weeks after reading the heath news article was significantly lower than baseline use. Furthermore, intentions to use ibuprofen were also significantly reduced suggesting that the observed behavior change may persist beyond the two-week period studied. Health journalists should be cautious in their use of stories about health outcomes, particularly when those stories deviate from data about objective risks. PMID- 28657357 TI - ECG markers associated with ischemic stroke at young age - a case-control study. AB - INTRODUCTION: Certain electrocardiographic (ECG) abnormalities are associated with ischemic stroke (IS), especially cardioembolic subtype. Besides atrial fibrillation, markers of left ventricular hypertrophy (LVH) or atrial pathology also reflect elevated risk. We studied the association of ECG markers with IS in young adults. METHODS: We performed a case-control study including 567 consecutive IS patients aged 15-49 years (inclusion period: 1994-2007) and one or two age- and sex-matched control subjects enrolled during 1978-1980 (n = 1033), and investigated also the stroke aetiologic subgroups. We studied ECGs of all participants for markers of atrial abnormality, i.e. P-terminal force (PTF) on lead V1, interatrial blocks (IAB; P-wave duration >=110 ms), and LVH. Conditional logistic regression analyses were used. RESULTS: IAB (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.16-2.13) and PTF combined with LVH (HR: 6.83, 95% CI: 1.65-28.31), were independently associated with IS. LVH, abnormal P-wave (HR: 6.87, 95% CI: 1.97-135.29), PTF, IAB, and combinations of these P-wave abnormalities with LVH - were associated with cardioembolic subtype. Abnormal P wave and IAB were associated with cryptogenic stroke subtype. In unadjusted analysis, LVH was associated with small-vessel disease subtype. CONCLUSION: P wave abnormalities on ECG were associated with cardioembolic but also with a cryptogenic subtype of IS. Key messages ECG patterns associated with atrial pathology are markers of increased risk of ischemic stroke in young adults. The ECG markers reflecting atrial pathology were seen in patients with cardioembolic and cryptogenic subtypes of ischemic stroke. PMID- 28657359 TI - Social communication assessment during post-traumatic amnesia and the post-acute period after traumatic brain injury. AB - BACKGROUND: Social communication impairment is a persisting and debilitating consequence of traumatic brain injury (TBI). However, there has been little empirical speech-language pathology (SLP) study focusing on the early stage of recovery after TBI, including during post-traumatic amnesia (PTA). This research reports on social communication presentation and recovery during late PTA and the post-acute period, assessed with standardized measures. METHOD: Using mixed methods case study research, four participants with severe TBI were assessed with social communication assessment measures over the later stages of PTA and/or at PTA emergence, and at follow-up three months later. Assessment tools included the Measure of Cognitive Linguistic Abilities Family Questionnaire, the La Trobe Communication Questionnaire and The Profile of Pragmatic Impairment in Communication and included patient and friend/family perspectives. RESULTS: It was possible to identify a profile of social communication disorder on SLP measures for participants during PTA that persisted at follow-up, but with decreased severity. Self and friend/family member ratings of social communication indicated an increased awareness of social difficulty at three months after PTA emergence. CONCLUSION: Findings provided information about presentation and course of recovery of social communication ability for participants in the early stage of rehabilitation after TBI. These findings have implications for timing and methods of SLP assessment during PTA. PMID- 28657358 TI - Adeno-Associated Virus (AAV) gene therapy for cystic fibrosis: current barriers and recent developments. AB - INTRODUCTION: Since the cystic fibrosis (CF) gene was discovered in 1989, researchers have worked to develop a gene therapy. One of the most promising and enduring vectors is the AAV, which has been shown to be safe. In particular, several clinical trials have been conducted with AAV serotype 2. All of them detected viral genomes, but identification of mRNA transduction was not consistent; clinical outcomes in Phase II studies were also inconsistent. The lack of a positive outcome has been attributed to a less-than-efficient viral infection by AAV2, a weak transgene promoter and the host immune response to the vector. Areas covered: Herein, the authors focus on AAV gene therapy for CF, evaluating past experience with this approach and identifying ways forward, based on the progress that has already been made in identifying and overcoming the limitations of AAV gene therapy. Expert opinion: Such progress makes it clear that this is an opportune time to push forward toward the development of a gene therapy for CF. Drugs to treat the basic defect in CF represent a remarkable advance but cannot treat a significant cohort of patients with rare mutations. Thus, there is a critical need to develop a gene therapy for those individuals. PMID- 28657360 TI - A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer. AB - BACKGROUND: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. SCOPE: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC). The last search was on 10 June 2017. FINDINGS: CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development - palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment. CONCLUSION: CDK4/6 inhibition is a new and promising target for patients with hormone-receptor positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy. PMID- 28657361 TI - Sleep Deprivation and Chronic Health Conditions Among Sexual Minority Adults. AB - OBJECTIVES: To examine associations between sleep duration and health outcomes among distinct groups of sexual minority adults. METHODS: Using data from the 2014 Behavioral Risk Factor Surveillance System, we compared sleep duration (very short: <= 5 hr; short: 6 hr; normal: 7-8 hr; and long: >= 9 hr per day) between cisgender straight adults and distinct groups of sexual minorities. We further examined associations between sleep duration and 10 chronic health conditions among sexual minorities. RESULTS: Of 146,893 respondents, 142,507 (96.2%) were cisgender straight, and 4,386 (3.8%) were lesbian, gay, bisexual, transgender (LGBT). Overall, 17.3% of LGBT respondents reported very short sleep per day, compared with 12.2% for cisgender straight respondents (p < 0.0001). Among LGBT populations, the prevalence of very short sleep varied significantly among distinct groups, ranging from 13.2% among transgender female to male adults to 35.5% among transgender gender nonconforming adults. Very short sleep was further associated with increased odds of having stroke (aOR = 4.1, 95% CI [2.2-7.6]), heart attack (aOR = 3.0, CI [1.6-5.8]), coronary heart disease (aOR = 3.1, 95% CI [1.5-6.2]), asthma (aOR = 1.7, 95% CI [1.1-2.4]), chronic obstructive pulmonary disease (aOR = 2.5, CI [1.5-4.0]), arthritis (aOR = 2.1, CI [1.4-3.0]), and cancer (aOR = 1.8, 95% CI [1.0-3.2]) among sexual minorities. Disparities in the prevalence of stroke, heart attack, coronary health disease, COPD, diabetes, obesity, arthritis, and cancer were found among LGBT populations. CONCLUSIONS: Sexual minorities have a higher prevalence of sleep deprivation as compared with their straight counterparts. Sleep deprivation varies by sexual identity and gender. Very short sleep duration is associated with some chronic health conditions among LGBT populations. Promotion of sleep health education and routine medical assessment of sleep disorders are critically needed for sexual minority adults. PMID- 28657363 TI - Assessment of motor cortex excitability and inhibition during a cognitive task in individuals with concussion. AB - PRIMARY OBJECTIVE: To examine the function of the motor cortex during executive function tasks in individuals with concussion, relative to healthy controls. METHODS AND PROCEDURES: Transcranial magnetic stimulation (TMS) was used to assess motor cortex excitability and inhibition acutely, within 72 hours, and over two months, post-concussion in 23 participants, nine individuals with concussion and 14 controls. Participants performed a cognitive task during TMS to determine the impact of cognitive task on the motor cortex. MAIN OUTCOMES AND RESULTS: Resting motor threshold (p = 0.02) and motor-evoked potential (MEPRest) amplitude (p = 0.03) were different between groups, both suggesting greater corticospinal excitability in individuals with concussion. Cortical silent period (CSP) duration was greater at 72 hours (p = 0.03), one month (p = 0.003) and two months (p = 0.05) in individuals with concussion, suggesting increased intracortical inhibition. The performance of a cognitive task caused an increase in MEPRest (p = 0.006) and CSP (p = 0.04), compared to baseline in both groups, but no interaction of condition by group (p >= 0.91) for either measure. CONCLUSION: Simultaneously performing a cognitive task during motor cortex assessments increased corticospinal excitability and intracortical inhibition; however, the increase was not different between groups. PMID- 28657362 TI - ERPs While Judging Meaningfulness of Sentences With and Without Homonym or Morpheme Spelling Foils: Comparing 4th to 9th Graders With and Without Spelling Disabilities. AB - Thirteen students with and twelve students without spelling disabilities judged whether sentences (1/3 all correct spellings, 1/3 with homonym foil, 1/3 with morpheme foil) were meaningful while event-related potentials (ERPs) were measured with EGI Geodesic EEG System 300 (128-channel hydro-cell nets). For N400, Rapid Automatic Switching (RAS) correlated with comprehending sentences with homonym foils in control group but with morpheme foils in SLD group. For P600, dictated spelling correlated with comprehending sentences with morpheme foils in the control group but solving anagrams with homonym foils in the SLD group. Educational significance and neuropsychological significance of these contrasting results are discussed. PMID- 28657364 TI - Documentation of person-centred health plans for patients with acute coronary syndrome. AB - BACKGROUND: Personalised care planning is argued for but there is a need to know more about what the plans actually contain. AIM: To describe the content of person-centred health, plans documented at three healthcare levels for patients with acute coronary syndrome. DESIGN: Patients with acute coronary syndrome aged under 75 years and admitted to two coronary care units at a university hospital were enrolled in the study. This retrospective descriptive study documented 89 person-centred health plans at three healthcare levels: hospital, outpatient and primary care. In total, 267 health plans were reviewed and a quantitative content analysis conducted. The health plans included commonly formulated goals, patients' own resources and support needed. RESULTS: The health plan goals were divided into three categories: lifestyle changes, illness management and relational activities. The most frequently reported goal for better health was increased physical activity, followed by social life/leisure activities and return to paid professional work. In order to reach the goals, patients identified three ways: own resources, family and social support and healthcare system, in total three categories. The most frequently reported own capability was self-motivation. Spouses and children were important sources of family and social support. The most frequently reported healthcare support was cardiac rehabilitation. CONCLUSION: In traditional care and treatment plans devised by health professionals, patient goals often comprise behavioural changes. When patients identify their own goals and resources with the help of professionals, they include maintaining social relations and being able to return to important activities such as work. PMID- 28657365 TI - Acute hypobaric hypoxia augments ROCK2 protein level and activity. AB - AIM: Rho kinase activation plays an important role in hypoxic pulmonary vasoconstriction and increased vascular resistance. The present study investigated changes in the level and activity of rho kinase isoform 2 (ROCK2) under acute hypobaric hypoxia exposure. For this, Wistar rats were taken as the model organism. MATERIALS AND METHODS: Fifteen male Wistar rats (4-6 week old, 250 grams) were normalized with the surrounding environment by providing a 12/12 hour day and night acclimatization cycle. The rats were divided into 3 groups: (a) control group (no exposure, n = 5), (b) Group 1 (12 hour hypobaric-hypoxia exposure, n = 5) and (c) Group 2 (12 hour hypobaric hypoxia and 12 hour normobaric normoxia exposure, n = 5). A change in behavior of the animals was noted before sacrifice. Blood was collected from the beating heart of the anesthetized animal. Lungs were dissected out and used to estimate the levels and activity of ROCK2 in different groups using commercially available kits. Lung histology was evaluated by immunohistochemistry. ROCK2 gene expression was studied in the blood and lungs using quantitative PCR. RESULTS AND CONCLUSIONS: Control and Group 2 animals had an active movement while the Group 1 animals were sluggish before the sacrifice. Formation of a large perivascular edema cuff and collagen deposition in lungs of Group 1 and a reduction in Group 2 was observed. The protein levels and activities of ROCK2 were increased in Group 1 (p < 0.05) and became normal in Group 2 which was akin to control group animals. ROCK2 expression in PBMCs was increased in Group 1 (10.7 fold, p = 0.005) and was decreased in Group 2 (5.5 fold, p = 0.02). The outcomes establish that acute hypobaric hypoxia augments ROCK2 protein level and activity. PMID- 28657366 TI - Psychiatric disorders, acne and systemic retinoids: comparison of risks. AB - BACKGROUND: The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids. MATERIALS AND METHODS: Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest. RESULTS: Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin. CONCLUSION: Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations. PMID- 28657367 TI - The self-recovery of facial skin barrier and erythema after nanochip treatment. AB - OBJECTIVE: To determine the degree of acute skin damage and the time required for the recovery of facial skin barrier function after the skin was treated with micro-needles and nanochips of various tip lengths. METHODS: For this split face comparative study, a total of 16 subjects were enrolled and randomly divided into 2 groups. In the first group, one of the facial side of each subject was treated with 0.25-mm long nanotips for a total of 6 times while the other facial side was treated with 0.25-mm traditional micro-needles with a straight blade for a total of 6 times. In the second group, one of the facial side was treated with 0.5-mm nanotips for a total of 6 times while the other facial side was treated with 0.5 mm traditional micro-needles with a straight blade for a total of 6 times. Evaluations for trans-epidermal water loss (TEWL), skin hydration and erythema were carried out at baseline, 0, 4, 8, 24, 48 and 72 hours after the treatment. RESULTS: There was no significant difference in TEWL, skin hydration and erythema between the two facial sides of the subjects in the Group one who were treated with 0.25 mm nanochips and traditional micro-needles. However, in the subjects of the Group two, the mean TEWL of the facial side treated with 0.5 mm nanochips was relatively lower than that of the 0.5 mm traditional micro-needles treated facial side at 0, 4, 8 and 24 hours after the treatment. Mean erythema of the facial side treated with 0.5-mm nanochips micro-needles was also relatively lower than that of the 0.5-mm traditional micro-needles treated facial side at 8 hours after the treatment. Rapid recovery of skin barrier function was observed within 4-8 hours after treatment with various lengths of nanochips while it took at least 48 72 hours for recovery of skin barrier function after treatment with various lengths of traditional micro-needles as measured by TEWL. CONCLUSION: The skin disruption caused by nanotips treatment recovers quicker than the traditional microneedle treatment at equal lengths. PMID- 28657369 TI - Naphthoquinone amino acid derivatives, synthesis and biological activity as proteasome inhibitors. AB - The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the beta1 and beta5 subunits of the proteasome with IC50 values in the sub-um range. PMID- 28657370 TI - Brachial plexus injury after microwave-based treatment for axillary hyperhidrosis and osmidrosis. AB - Axillary hyperhidrosis combined with osmidrosis is a common problem, especially in Asian communities, that patients find annoying. Even though several surgical techniques have been reported to treat hyperhidrosis/osmidrosis permanently, patients would prefer a non-surgical approach. A microwave-based device was invented during this decade, and it has proven to be a safe and efficient way to treat axillary hyperhidrosis/osmidrosis without major complications. Mild complications reported are vacuum-associated marks, oedema, tenderness and temporary altered skin sensation. We herein report a rare case of brachial plexus injury with sensory and motor dysfunction that occurred after microwave-based treatment. The patient did not fully recover after 6 months of rehabilitation. Our case suggests that a lower initial energy level should be used for thin patients with less fat tissue on the underarm areas, regardless of the patient's sex. PMID- 28657371 TI - HMGB1 is a promising therapeutic target for acute liver failure. AB - INTRODUCTION: Although acute liver failure (ALF) is a rare disease, it continues to have high mortality and morbidity rates due to its many causes. High mobility group box 1 (HMGB1), originally reported as a ubiquitous non-histone chromosomal protein, is a multi-functional protein with varying functions depending on its location, such as in the nucleus, cytoplasm and extracellular space. The role of extracellular HMGB1 as an inflammatory mediator has been well studied, and the elevation of serum HMGB1 has been reported in several diseases that are closely associated with ALF. Areas covered: In this review, we focus on the relationship between causes of acute liver failure, such as viral infection, drug-induced liver injury, ischemia/reperfusion injury, and acute-on-chronic liver failure, and the role of HMGB1. Furthermore, we also consolidate and summarize the current reports of HMGB1-targeting therapies in hepatic injury models. Expert commentary: HMGB1 could be a novel therapeutic candidate for ALF, and the clinical testing of HMGB1-targeting therapies for ALF patients is expected. PMID- 28657372 TI - Phthalocyanine induced phototherapy coupled with Doxorubicin; a promising novel treatment for breast cancer. AB - INTRODUCTION: Globally, breast cancer is the most common life-threatening malignant disease among women. Adjuvant chemotherapeutic treatment of anthracycline-based chemotherapy (e.g., doxorubicin) has been shown to be more advantageous over non-anthracycline-based therapies, yet possess the tenacity of developing resistance and potential side effects which have limited its use in the clinical setting. These reasons necessitate combining doxorubicin with emerging photodynamic treatment regimens. Areas covered: In this review, the authors have concisely explained doxorubicin chemotherapy and the photobiological processes of phthalocyanine triggered photodynamic therapy (PDT). A literature search was conducted and reports demonstrating the use of doxorubicin and photodynamic therapy as a treatment modality for breast cancer were identified. More emphasis was made on studies demonstrating the efficacy and improved anticancer effect of combining chemotherapy with photodynamic therapy. However, it was concluded that for this combination therapy, still in it's infancy, it could be relevant when integrated into standard treatment. Expert Commentary: To these effects, comprehensive models based on experimental evaluations are needed for rational design of anthracycline-based chemotherapy and PDT to be integrated into the clinical setting. PMID- 28657373 TI - Extended infusion of beta-lactam antibiotics: optimizing therapy in critically ill patients in the era of antimicrobial resistance. AB - INTRODUCTION: Beta-lactams are at the cornerstone of therapy in critical care settings, but their clinical efficacy is challenged by the rise in bacterial resistance. Infections with multi-drug resistant organisms are frequent in intensive care units, posing significant therapeutic challenges. The problem is compounded by a dearth in the development of new antibiotics. In addition, critically-ill patients have unique physiologic characteristics that alter the drugs pharmacokinetics and pharmacodynamics. Areas covered: The prolonged infusion of antibiotics (extended infusion [EI] and continuous infusion [CI]) has been the focus of research in the last decade. As beta-lactams have time dependent killing characteristics that are altered in critically-ill patients, prolonged infusion is an attractive approach to maximize their drug delivery and efficacy. Several studies have compared traditional dosing to EI/CI of beta lactams with regard to clinical efficacy. Clinical data are primarily composed of retrospective studies and some randomized controlled trials. Several reports show promising results. Expert commentary: Reviewing the currently available evidence, we conclude that EI/CI is probably beneficial in the treatment of critically-ill patients in whom an organism has been identified, particularly those with respiratory infections. Further studies are needed to evaluate the efficacy of EI/CI in the management of infections with resistant organisms. PMID- 28657374 TI - Factors influencing father's antenatal and perinatal involvement in maternal health care. AB - BACKGROUND: Maternal health care refers to the better outcome of labor and reduced maternal mortality. Antenatal care utilization is an important determinant for improved maternal health care. In this study, we examine how father's involvement influences antenatal and perinatal care utilization by mothers. METHODS: A community-based cross-sectional study was performed in the Pakistan Institute of Medical Sciences for three months. Systematic random sampling method was used for obtaining the desired sample. Safe Motherhood Questionnaire (Woman) developed by Johns Hopkins Program for International Education in Gynecology and Obstetrics (JHPIEGO) was adapted and utilized to gather the required data. Sample size for the study was calculated as 303 by the WHO calculator keeping confidence level at 95% and with an associated prevalence of 73%. The data were entered into SPSS version 21 (Chicago, IL). Frequencies and percentages were calculated for qualitative variables. Mean and standard deviation was calculated for quantitative variables. RESULTS: This study revealed that the father's attitude toward antenatal care was found to be significantly (p < .05) associated with a higher education and greater income level. While father's favorable attitude toward childbirth was found to be significantly (p < .05) associated with higher education and lower age (18-29 years). Frequency of fathers who disagreed to the statement "It is not necessary for a husband/partner to accompany his wife to antenatal care visits" was 204 (67.1%), whereas those who disagreed with the statement "It is not necessary for a husband/partner to accompany his wife when she is giving birth" were 255 (83.8%). While frequency of fathers who disagreed with the statement "Giving birth is mostly a woman's matter; Husbands/partners have little to contribute" was 267 (87.9%). CONCLUSIONS: Our study found a positive association between father's involvement in maternal health and factors such as paternal education level, age, income level and father's attitude. Fathers' antenatal involvement was associated with paternal age and income level, while their perinatal involvement was associated with paternal age and education level. Our study on father's attitude toward presence at time of birth showed 83.8% compliance. Similarly, there was 67.1% compliance for presence during antenatal checkups. PMID- 28657375 TI - Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta analysis. AB - This meta-analysis provides an updated and comprehensive estimate of the effects of obesity on metabolic disorders in adolescent polycystic ovary syndrome (PCOS). Relevant articles consistent with the search terms published up to 31 January 2014 were retrieved from PubMed, EMBASE, PsycINFO and CENTRAL. Thirteen articles (16 independent studies) conformed to the inclusion criteria. The evaluated outcomes were the metabolic parameters of obese adolescents with PCOS (case group) relative to normal-weight adolescents with PCOS, or obese adolescents without PCOS. Compared with normal-weight adolescents with PCOS, the case group had significantly lower sex hormone-binding globulin and high-density lipoprotein cholesterol, and significantly higher triglycerides, leptin, fasting insulin, low density lipoprotein cholesterol and free testosterone levels. Relative to obese adolescents without PCOS, the case group had significantly higher fasting insulin, low-density lipoprotein cholesterol, free testosterone levels and 2-h glucose during the oral glucose tolerance test. These results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Impact statement What is already known about this subject: Obesity and PCOS share many of the same metabolic disorders, for example, hyperandrogenism and hyperinsulinemia with subsequent insulin resistance. Knowledge regarding metabolic features in obese adolescents with PCOS is limited, and there is concern whether obesity and PCOS are related. What do the results of this study add: Relative to PCOS adolescents of normal weight, obese adolescents with PCOS (the case group) had significantly lower SHBG and HDL-C, and significantly higher triglycerides, leptin, fasting insulin, LDL-C and free testosterone levels. The results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. What are the implications of these findings for clinical practice and/or further research: Obesity, metabolic disorders and PCOS in adolescents are associated. Obesity exacerbates metabolic disorders in adolescent PCOS. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Therapeutic intervention combined with lifestyle modification may provide better treatment for adolescent PCOS. The aetiologies of PCOS combined with obesity in adolescents require further investigation. PMID- 28657376 TI - Glycolic acid peel in disseminated facial verrucae. AB - Facial warts are a common cause of cosmetic concern and also affect the self esteem of the affected patients. These are benign skin papillomas caused by human papillomavirus infections. Warts affecting the face are mainly due to HPV-3 and HPV-10. Destructive and caustic agents used for the treatment can produce scarring at these site, hence should be used with care. Earlier, glycolic acid alone as well as in combination with salicylic acid in gel base formulation have been used to treat facial recalcitrant wart with good results. We used glycolic acid peel in aqueous base with dramatic improvement. PMID- 28657377 TI - Predictors and outcomes of delayed plastic biliary stent removal following endoscopic retrograde cholangiopancreatography. AB - OBJECTIVE: Plastic biliary stents are commonly placed during endoscopic retrograde cholangiopancreatography (ERCP) and should be removed or replaced within 3 months to reduce the risk of stent obstruction. The aim of the study was to identify predictors and outcomes of patients who had delayed plastic biliary stent removal following ERCP. MATERIALS AND METHODS: Consecutive patients who received ERCP with plastic biliary stent placement at Loma Linda University Medical Center (10/2004-6/2013) were identified. Delayed removal was defined as presence of stent >3 months after index ERCP. Multivariable regression analysis to identify baseline characteristics associated with delayed removal was performed. Clinical outcomes of stent obstruction (e.g., cholangitis, hospitalization, intensive care) were also collected for those with delayed removal. RESULTS: Among 374 patients undergoing ERCP with plastic biliary stent, 71 (19%) had delayed stent removal. Patients who had anesthesia assistance (AOR = 3.8, 95%CI 1.2-11.4), non-English primary language (AOR = 3.0, 95%CI 1.5-6.2), and outpatient ERCP (AOR = 2.0, 95%CI 1.1-3.4) had increased while choledocholithiasis (AOR = 0.5, 95%CI 0.3-0.99) had lower odds of delayed stent removal. Among those with delayed removal, 13 (18%) were hospitalized for stent obstruction (5 (7%) had cholangitis, 8 (11%) were hospitalized for more than a week, and 3 (4%) required intensive care). CONCLUSIONS: Almost one-fifth of patients who underwent ERCP with plastic biliary stent placement had delayed removal with nearly one-fifth of these patients requiring hospitalization for stent obstruction. Targeting patients at risk by improving communication and ease of scheduling an ERCP may reduce preventable adverse events associated with delayed biliary stent removal. PMID- 28657378 TI - A split-face, investigator-blinded comparative study on the efficacy and safety of Q-switched Nd:YAG laser plus microneedling with vitamin C versus Q-switched Nd:YAG laser for the treatment of recalcitrant melasma. AB - BACKGROUND: High recurrence has previously been reported in the treatment of melasma with low-fluence 1,064-nm Q-switched neodymium-doped yttrium aluminium garnet (QS-Nd:YAG) laser. On the other hand, the efficacy and safety of the QS Nd:YAG laser plus microneedling with vitamin C have not been evaluated in patients with mixed-type melasma. MATERIAL AND METHODS: Sixteen patients with recalcitrant dermal- or mixed-type melasma were included in the study. One side of patients' face was treated with QS-Nd:YAG laser plus microneedling with vitamin C (Group A) and the other side with QS-Nd:YAG laser alone (Group B) for four sessions at four-week intervals. Melasma Area Severity Index (MASI) scores and clinician's evaluation of clinical response were assessed monthly. RESULTS: Group A had a significantly lower mean MASI score and better treatment response than Group B according to clinician's evaluation. According to MASI scores, in Group B, two patients had a good response while 12 were unresponsive to treatment. Good or very good improvement was reported by 10 patients in Group A and three patients in Group B. Adverse effects and recurrence rates were similar in Groups A and B (31.3 and 43.8%, respectively). DISCUSSION: QS-Nd:YAG increases the blood circulation in the dermis, thereby enhancing the mechanical effect of microneedling to promote the penetration of vitamin C. CONCLUSION: Vitamin C application with microneedling immediately after treatment with QS-Nd:YAG laser is a promising adjunctive method for the treatment of recalcitrant melasma. PMID- 28657379 TI - A new imaging technique for assessment of the effectiveness of long pulse Nd:YAG 532 nm laser in treatment of facial port wine stain. AB - BACKGROUND: PWS is a vascular malformation presented at birth and associated with a psychological problem to the patients. Many types of laser systems were used to solve this problem. AIM OF THE STUDY: To assess the efficacy of long-pulsed Nd:YAG 532-nm laser in the treatment of port wine stain both clinically and by imaging technique. PATIENTS AND METHODS: This is an interventional therapeutic clinical study for the treatment of facial port-twine stain with long-pulsed, 532 nm, Nd:YAG laser. The treatment sessions were done every 4 weeks for 12 sessions and follow-up after 3 months of the last session. The assessment of the response was done before and at the end of follow-up period, both objectively (percent of improvement, photo comparison by using PSNR) and subjectively (patient satisfaction). RESULTS: Sixteen patients completed all sessions of the treatment. The improvement score for the PWS were failure = 0%, mild = 6.25%, moderate = 12.5%, good = 31.25%, and excellent = 50%. The values of PSNR for all the patients have been recorded and were fewer than 25 which means that the response for the treated lesions was very good. CONCLUSION: The long-pulsed Nd:YAG laser 532 nm is an effective and safe method of treatment of facial PWSs without significant residue. The PSNR was a new, simple, cheap and noninvasive method for assessment of the response of PWSs to laser therapy. PMID- 28657380 TI - Non-specific abdominal pain remains as the most common reason for acute abdomen: 26-year retrospective audit in one emergency unit. AB - OBJECTIVE: Distribution of diagnoses causing acute abdominal pain (AAP) may change because of population aging, increased obesity, advanced diagnostic imaging and changes in nutritional habits. Our aim was to evaluate the diagnoses causing AAP during a 26-year period. MATERIALS AND METHODS: This was a retrospective cross-sectional cohort study in one emergency department (ED) covering population about 250,000. All patients admitted to the ED in 1986, 2003 and 2012 were evaluated from hospital electronic database. Demographic data, utilization of diagnostic tests, surgical treatment and discharge diagnosis were analyzed. Statistical data of population aging, obesity and alcohol consumption during 1980-2012 were obtained from national registers. RESULTS: The AAP patients represented 10-20% of our total ED census. The most common causes of AAP were nonspecific abdominal pain (NSAP, 31-37%), acute appendicitis (11-23%), biliary disease (9-11%), bowel obstruction (5-7%), acute pancreatitis (4-8%) and acute diverticulitis (1-7%). The percentage of NSAP remained highest throughout the study period. Decrease in the number of acute appendicitis (from 23 to 11%; p < .0001), increase in acute diverticulitis (from 1 to 5%; p <= .0001) and acute pancreatitis (from 4 to 7%; p = .0273) was observed over time. The utilization of diagnostic imaging increased significantly (CT from 2 to 37% and US from 4 to 38%, p < .0001). Hospital mortality was very low (1-2%). CONCLUSIONS: NSAP is still the main differential diagnostic problem in the ED. Except acute appendicitis, distribution of specific diagnoses causing AAP remained rather stable through 26-year audit. PMID- 28657381 TI - Safety profile of biological therapies for treating rheumatoid arthritis. AB - INTRODUCTION: Biological agents such as tumor necrosis factor inhibitors (TNFi), abatacept, rituximab and tocilizumab have proven efficacy in RA. However, these agents are also associated with adverse events so further data is essential to detect them at the earliest stage possible. Areas covered: Herein, the authors review the safety profile of biological therapy, including TNFi and non-TNF agents including abatacept (ABA), rituximab (RTX) and tocilizumab (TCZ). The authors analyze both published articles and congress communications including clinical trials, meta-analyses, observational studies, data from registries and spontaneous clinical reports. The authors classify studies according to the most common and relevant adverse events associated with biological agents. Expert opinion: Biological therapies have a reasonable safety profile and, globally, the benefits far outweigh the possible risk of adverse events. Currently, the risk of serious infections is low and no increased risk in solid malignancies or cardiovascular events have been found after a long clinical experience with these therapies. However, there are still potential risks as well as concerns of immunogenicity induced by TNFi. More studies are required to understand these risks, design safer drugs, and implement pharmacogenomics into the clinic. This will lead to a more personalized medicine in the future. PMID- 28657382 TI - A pilot study evaluating the prescribing of ceftriaxone in hospitals in Ghana: findings and implications. AB - BACKGROUND AND OBJECTIVES: Widespread empiric use of antibiotics exists especially in developing countries. This is a concern since inappropriate use of antibiotics, including their extended inappropriate use, will increase resistance rates. Consequently, there is a need to evaluate antibiotic utilisation across healthcare sectors to improve future use. This includes ceftriaxone, widely used among hospitals including those in Ghana. METHODS: A cross-sectional study to evaluate the appropriateness of ceftriaxone prescribing in a leading hospital in Ghana. Ceftriaxone prescribing in patient-record cards was assessed using a modified WHO drug-utilization evaluation criteria as well as referencing the national standard treatment guidelines in Ghana and the ceftriaxone package insert. RESULTS: A total of 251 patients were assessed. Ceftriaxone was most commonly prescribed for comorbid malaria with bacterial infections, urinary tract infections, sepsis and gastroenteritis. The appropriateness of the indication was 86% (n = 218). The doses most prescribed were 1g (41%) and 2g (39%). Stat dose and once-daily dosage regimen constituted 51.4% and 84.5%, respectively. The most common duration of treatment was 1 (51.4%) and 2 days (35.1%). The overall appropriateness of prescribing was 93% against a pre-set threshold of 97%. CONCLUSION: The appropriateness of ceftriaxone prescribing was high in this leading hospital in Ghana; however, there is room for improvement with targeted education initiatives, with further research planned. PMID- 28657383 TI - Retrospective evaluation of pregnancy outcomes and clinical implications of 34 Han Chinese women with unicornuate uterus who received IVF-ET or ICSI-ET treatment. AB - This retrospective study aimed to evaluate pregnancy outcome and newborn health condition for a specific group of infertile patients with unicornuate uterus. A total of 34 patients were confirmed to have unicornuate uterus. These patients received 47 cycles of in vitro fertilisation-embryo transfer (IVF-ET) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET), achieved 21 clinical pregnancies with a clinical pregnancy rate of 60.61%. Full-term delivery rate was 76.47%. Eleven patients gave birth to single neonates, while six patients gave birth to twins. Foetal growth restriction was detected in three foetuses in twins. Obstetric complications were reported in three patients with single foetus (27.27%, 3/11), and four out of six patients with twin pregnancies (66.67%, 4/6). This study demonstrated that Han Chinese women with unicornuate uterus have a good chance to conceive and deliver healthy neonates despite increased risk of complications. Impact statement What is already known on this subject: Unicornuate uterus is a rare form of malformation affecting about 1% of infertile patients. Patients with unicornuate uterus have a lower chance of conceiving. It has been reported that assisted reproduction such as in vitro fertilisation embryo transfer (IVF-ET) was less likely to be successful in patients with unicornuate uterus. What do the results of this study add: Retrospective study of 34 cases of Han Chinese women with unicornuate uterus offered a new perspective. Half of these 34 patients conceived and delivered 23 neonates (11 singletons and 6 pairs of twins). Complications were more frequent but manageable. What are the implications of these findings for clinical practice and/or further research: Our data will serve as a valuable tool for counselling infertile patients with unicornuate uterus with regard to their expected pregnancy outcomes. PMID- 28657385 TI - The complex interplay of sex steroids manifested by endocrine treatment of prostate cancer. PMID- 28657386 TI - Dilatation of the prostate - then and now. PMID- 28657384 TI - Cutaneous metastasis from vulvar squamous cell carcinoma: a rare occurrence that should not be forgotten. AB - Vulvar cancer accounts for 5% of the female genital tract cancers. Cutaneous metastases from vulvar cancer are extremely rare and for this reason, it can be difficult to reach a diagnosis with a consequent delay in the treatment. A systematic literature review of articles on this subject was conducted through a MEDLINE-based search for articles published in English or French. To date, 16 cases (including ours unpublished) of cutaneous metastasis from vulvar cancer have been reported. Cutaneous metastasis can occur from any stage of vulvar cancer, even after a short period. Different treatments have been described but none of them seems to be more effective. In all reported cases the prognosis was very poor. Every time a vulvar cancer survivor shows a suspicious cutaneous lesion, this should be biopsied to exclude skin relapse. Impact statement Cutaneous metastases from vulvar cancer are extremely rare and due to its rarity, a standard treatment has not been established yet. Cutaneous metastasis can occur from any stage of vulvar cancer, even after a short period. In all the reported cases, the prognosis was very poor. Every time a vulvar cancer survivor shows a suspect cutaneous lesion, this should be biopsied to exclude skin relapse. PMID- 28657387 TI - Studies on Varicocele and Subfertility - an Ongoing Debate. PMID- 28657388 TI - Incidental detection of renal cell carcinoma. PMID- 28657389 TI - Use of diagnostic biopsies in kidney tumors. PMID- 28657390 TI - Drugs and risk of cancer. PMID- 28657392 TI - Half a decade of fluorescence in the bladder. PMID- 28657393 TI - Contemporary and past challenges of prostate cancer diagnostics. PMID- 28657394 TI - Epidemiology a Major Focus of a New National Academies Report. PMID- 28657395 TI - Do causal concentration-response functions exist? A critical review of associational and causal relations between fine particulate matter and mortality. AB - Concentration-response (C-R) functions relating concentrations of pollutants in ambient air to mortality risks or other adverse health effects provide the basis for many public health risk assessments, benefits estimates for clean air regulations, and recommendations for revisions to existing air quality standards. The assumption that C-R functions relating levels of exposure and levels of response estimated from historical data usefully predict how future changes in concentrations would change risks has seldom been carefully tested. This paper critically reviews literature on C-R functions for fine particulate matter (PM2.5) and mortality risks. We find that most of them describe historical associations rather than valid causal models for predicting effects of interventions that change concentrations. The few papers that explicitly attempt to model causality rely on unverified modeling assumptions, casting doubt on their predictions about effects of interventions. A large literature on modern causal inference algorithms for observational data has been little used in C-R modeling. Applying these methods to publicly available data from Boston and the South Coast Air Quality Management District around Los Angeles shows that C-R functions estimated for one do not hold for the other. Changes in month-specific PM2.5 concentrations from one year to the next do not help to predict corresponding changes in average elderly mortality rates in either location. Thus, the assumption that estimated C-R relations predict effects of pollution reducing interventions may not be true. Better causal modeling methods are needed to better predict how reducing air pollution would affect public health. PMID- 28657397 TI - Histological outcomes in conventional cervical cytology for invasive carcinoma: not always cancer. AB - The value of cytology for the detection of invasive cancer remains unknown. We performed a retrospective cohort study with 884 patients diagnosed of premalignant lesions and invasive carcinoma in cytology. 382 (43.2%) of them had cytological results of high-grade squamous intraepithelial lesions (HSIL), 244 (27.6%) showed low-grade squamous intraepithelial lesions (LSIL), 120 (13.6%) patients had atypical squamous cells of undetermined significance (ASC-US), 67 (7.6%) patients with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), 38 (4.3%) had invasive carcinoma and 33 (3.7%) patients presented with atypical glandular cells (ACG). From 38 patients with cytological results of invasive carcinoma, 24 had confirmatory histological results (63.2%). The other 14 had 4 benign lesions and 10 HSIL. The predictive positive value (PPV) was 63.2%. Cytology results of carcinoma do not confer a definitive diagnosis of invasive lesion, but it is strongly an indication of, at least, a precancerous lesion. PMID- 28657398 TI - The Choice of Indicators for Obstructive Sleep Apnea Treatment Outcome Evaluation: A Matter of Time-Dependent Response? PMID- 28657396 TI - Preoperative methylprednisolone does not reduce loss of knee-extension strength after total knee arthroplastyA randomized, double-blind, placebo-controlled trial of 61 patients. AB - Background and purpose - Patients undergoing total knee arthroplasty (TKA) face challenges related to postoperative reduction in knee-extension strength. We evaluated whether inhibition of the inflammatory response by a single preoperative dose of methylprednisolone (MP) reduces the pronounced loss of knee extension strength at discharge after fast-track TKA. Patients and methods - 70 patients undergoing elective unilateral TKA were randomized (1:1) to preoperative intravenous (IV) MP 125 mg (group MP) or isotonic saline IV (group C). All procedures were performed under spinal anesthesia without tourniquet, and with a standardized multimodal analgesic regime. The primary outcome was change in knee extension strength from baseline to 48 hours postoperatively. Secondary outcomes were knee joint circumference, functional performance using the Timed Up and Go (TUG) test, pain during the aforementioned tests, rescue analgesic requirements, and plasma C-reactive protein (CRP) changes. Results - 61 patients completed the follow-up. The loss in quadriceps muscle strength was similar between groups; group MP 1.04 (0.22-1.91) Nm/kg (-89%) vs. group C 1.02 (0.22-1.57) Nm/kg (-88%). Also between-group differences were similar for knee circumference, TUG test, and pain scores. MP reduced the inflammatory response (CRP) at 24 hours postoperatively; group MP 33 (IQR 21-50) mg/L vs. group C 72 (IQR 58-92) mg/L (p < 0.001), and 48 hours postoperatively; group MP 83 (IQR 56-125) mg/L vs. group C 192 (IQR 147-265) mg/L (p < 0.001), respectively. Interpretation - Preoperative systemic administration of MP 125 mg did not reduce the pronounced loss of knee extension strength or other functional outcomes at discharge after fast-track TKA despite a reduced systemic inflammatory response. PMID- 28657399 TI - Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. AB - Among persons with type 2 diabetes (t2d), the development of glucose intolerance involves dysfunction in several organs and tissues, including the muscle, liver, pancreas, kidney, gastrointestinal tract, adipose tissue, and brain. individuals with t2d typically have a number of comorbidities, including hypertension, hyperlipidemia, and being overweight or obese, and are, consequently, at high cardiovascular risk. guidelines recommend a comprehensive care strategy that includes treatment of diabetes-related complications and comorbidities beyond those related to hyperglycemia. use of glucose-lowering therapies with complementary activities that address multiple facets of the disease may improve long-term outcomes for patients with t2d. two recent drug classes developed for use in t2d, glucagon-like peptide-1 receptor agonists (glp-1ras) and sodium glucose cotransporter 2 (sglt2) inhibitors, have been shown in clinical trials to have beneficial effects on glycemic control, body weight, cardiovascular risk factors, and (for liraglutide, semaglutide, and empagliflozin) cardiovascular outcomes, while having an acceptable safety profile. between them, these drug classes directly or indirectly affect many of the organs and tissues involved in the pathogenesis of t2d, and their beneficial effects on glycemic- and cardiovascular-related parameters are likely to be complementary and potentially additive. in the largest clinical trial of a glp-1ra and an sglt2 inhibitor in combination (duration-8), patients with t2d (n = 685) who received exenatide plus dapagliflozin added to their treatment regimen for 28 weeks had significantly greater reductions from baseline in glycated hemoglobin, body weight, and systolic blood pressure compared with patients who received either drug as monotherapy. this review summarizes the complementary aspects of these drug classes and presents the available data among patients receiving dual therapy with a glp-1ra and an sglt2 inhibitor. PMID- 28657400 TI - A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with 'standard of care' medicinal and procedures not requiring regulatory approval for use. AB - PURPOSE: Terrorist attacks, with their intent to maximize psychological and economic damage as well as inflicting sickness and death on given targeted populations, are an ever-growing worldwide concern in government and public sectors as they become more frequent, violent, and sensational. If given the chance, it is likely that terrorists will use radiological or nuclear weapons. To thwart these sinister efforts, both physical and medical countermeasures against these weapons are currently being researched and developed so that they can be utilized by the first responders, military, and medical providers alike. This is the third article of a three-part series in which we have reviewed additional radiation countermeasures that are currently under early preclinical phases of development using largely animal models and have listed and discussed clinical support measures, including agents used for radiation-induced emesis, as well as countermeasures not requiring Food and Drug Administration approval. CONCLUSIONS: Despite the significant progress that has been made in this area during the last several years, additional effort is needed in order to push promising new agents, currently under development, through the regulatory pipeline. This pipeline for new promising drugs appears to be unreasonably slow and cumbersome; possible reasons for this inefficiency are briefly discussed. Significant and continued effort needs to be afforded to this research and development area, as to date, there is no approved radioprotector that can be administered prior to high dose radiation exposure. This represents a very significant, unmet medical need and a significant security issue. A large number of agents with potential to interact with different biological targets are under development. In the next few years, several additional radiation countermeasures will likely receive Food and Drug Administration approval, increasing treatment options for victims exposed to unwanted ionizing irradiation. PMID- 28657401 TI - A case of foetal intra-abdominal umbilical vein varix with adjacent extra abdominal vein constriction. PMID- 28657402 TI - In vitro evaluation of the inhibition and induction potential of olaparib, a potent poly(ADP-ribose) polymerase inhibitor, on cytochrome P450. AB - 1. In vitro studies were conducted to evaluate potential inhibitory and inductive effects of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, on cytochrome P450 (CYP) enzymes. Inhibitory effects were determined in human liver microsomes (HLM); inductive effects were evaluated in cultured human hepatocytes. 2. Olaparib did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2D6 or CYP2E1 and caused slight inhibition of CYP2C9, CYP2C19 and CYP3A4/5 in HLM up to a concentration of 100 MUM. However, olaparib (17-500 MUM) inhibited CYP3A4/5 with an IC50 of 119 MUM. In time-dependent CYP inhibition assays, olaparib (10 MUM) had no effect against CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 and a minor effect against CYP3A4/5. In a further study, olaparib (2-200 MUM) functioned as a time-dependent inhibitor of CYP3A4/5 (KI, 72.2 MUM and Kinact, 0.0675 min-1). Assessment of the CYP induction potential of olaparib (0.061-44 MUM) showed minor concentration-related increases in CYP1A2 and more marked increases in CYP2B6 and CYP3A4 mRNA, compared with positive control activity; however, no significant change in CYP3A4/5 enzyme activity was observed. 3. Clinically significant drug-drug interactions due to olaparib inhibition or induction of hepatic or intestinal CYP3A4/5 cannot be excluded. It is recommended that olaparib is given with caution with narrow therapeutic range or sensitive CYP3A substrates, and that prescribers are aware that olaparib may reduce exposure to substrates of CYP2B6. PMID- 28657403 TI - Practitioner Training for Use of Evidence-Based Practice in Occupational Therapy. AB - The purpose of this integrative review was to examine the evidence-based practice (EBP) training literature for occupational therapy practitioners in order to describe the relationships between EBP use in practice and practitioner training for EBP. A systematic search of literature related to EBP training in occupational therapy was followed by a research evaluation, review of case examples, and qualitative content analysis. Findings suggest that comprehensive, contextually-relevant, and collaborative training approaches are necessary for practitioners to address implementation of EBP. Research investigating the mechanisms of practitioner training and ways to measure the relationships between training, changes in how practitioners use evidence-based practices, and client outcomes and other quality indicators is recommended. PMID- 28657404 TI - New perspective to develop memantine orally disintegrating tablet formulations: SeDeM expert system. AB - Nowadays pharmaceutical industries and regulatory authorities suggest new approaches such as Quality by Design principles to reduce experiments of formulation studies, improve product quality, save cost and time. SeDeM Expert System is a predictive approach for the preformulation studies and it provides information about suitability of API for direct compression by evaluating 12 parameters. The system also allows selecting appropriate excipients by determining same parameters to improve compressibility of API. The objective of this study was to develop direct compressed memantine orally disintegrating tablets using SeDeM Expert System. Memantine was found to have poor flow and compressibility properties. Three different direct compressibility and super disintegrating agents (Ludiflash(r), Ludipress(r) and Parteck(r)) were used to improve compressibility of memantine and according to SeDeM diagrams, Parteck(r) was selected for final formulation. Memantine direct compressed tablets showed proper friability, hardness and thickness. The disintegration time of the tables were found below 15 s which was suitable for ODTs. It was found that SeDeM Expert System was easy to use and application of this method provided to develop memantine direct compressed ODT formulation was successful. PMID- 28657405 TI - Systemic antibiotic prophylaxis prior to gastrointestinal surgery - is oral administration of doxycycline and metronidazole adequate? AB - BACKGROUND: Antibiotic prophylaxis is recommended prior to a wide range of gastrointestinal operations to reduce the rate of surgical site infections (SSIs). Traditional intravenous (IV) drugs are costly and their preparation strains nursing resources at the wards. While oral administration may attenuate these limitations, its use remains limited. We aimed to assess whether a dual oral antibiotic prophylaxis regimen provides adequate serum concentrations throughout the surgical procedure. METHODS: We measured serum concentrations of doxycycline and metronidazole following single oral doses of 400 mg doxycycline and 1200 mg metronidazole at first incision and repeated at wound closure in a cohort of patients undergoing elective gastrointestinal surgery. Both drugs were dispensed at least two hours before skin incision. Serum concentrations were compared to minimum inhibitory concentrations (MIC) and epidemiological cut-off values (ECOFFs) for relevant pathogens. RESULTS: Mean serum concentrations of doxycycline at first incision and at wound closure were 5.75 mg/L and 4.66 mg/L and of metronidazole 18.88 mg/L and 15.56 mg/L, respectively. Metronidazole concentrations were above ECOFF (2 mg/L) for relevant anaerobic species in 103/104 of patients in both samples. Doxycycline serum concentrations were above the ECOFF for common Enterobacteriaceae species (4 mg/L) in both samples in 58/104 patients (55.8%). CONCLUSIONS: A single dose of orally administered metronidazole provides adequate concentrations throughout surgery in a heterogeneous cohort of patients. Uncertainty persists regarding the adequacy of doxycycline concentrations, as the optimal serum level of doxycycline in a prophylactic setting has not been established. PMID- 28657406 TI - A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. AB - PURPOSE: The threat of a radiological/nuclear event is a critical concern for all government agencies involved in national security and public health preparedness. Countermeasures that are safe, easily administered, and effective at diminishing or eliminating adverse health effects to individuals and the overall public health impact of radiation exposure are urgently needed. Radiation countermeasures included in this three-part series have been classified under various subheadings based specifically on their developmental stages for United States Food and Drug Administration (FDA) approval. We have included FDA-approved agents for acute radiation syndrome (ARS) in part I. This is part II in which we have reviewed FDA-approved agents for limited indications, internalized radionuclides, emesis, late effects, radiomitigators available in the strategic national stockpile (SNS), agents with FDA investigational new drug (IND) status, and those with NHP efficacy data without FDA IND. Agents discussed in part III are those agents that have been peer reviewed, published, and have demonstrated significant survival benefits in animal models of ARS. Agents investigated in in vitro models only or studied in animal models without peer-reviewed publications have not been included. CONCLUSIONS: The dearth of FDA-approved radiation countermeasures has prompted intensified research for a new generation of radiation countermeasures. A number of promising radiation countermeasures are currently moving forward with continued support and effort by both governmental agencies and by publicly and privately held pharmaceutical companies. There is a limited number of countermeasures which are progressing well following the Animal Rule and may get approved in the near future, thus serving to close the gap of this critically important, unmet radiobiomedical need. PMID- 28657407 TI - Comorbidity does not predict long-term mortality after total hip arthroplasty. AB - Background and purpose - In-hospital death following total hip arthroplasty (THA) is related to comorbidity. The long-term effect of comorbidity on all-cause mortality is, however, unknown for this group of patients and it was investigated in this study. Patients and methods - We used data from the Swedish Hip Arthroplasty Register, linked to the National Patient Register from the National Board of Health and Welfare, for patients operated on with THA in 1999-2012. We identified 120,836 THAs that could be included in the study. We evaluated the predictive power of the Charlson and Elixhauser comorbidity indices on mortality, using concordance indices calculated after 5, 8, and 14 years after THA. Results All comorbidity indices performed poorly as predictors, in fact worse than a base model with age and sex only. Elixhauser was, however, the least bad choice and it predicted mortality with concordance indices 0.59, 0.58, and 0.56 for 5, 8, and 14 years after THA. Interpretation - Comorbidity indices are poor predictors of long-term mortality after THA. PMID- 28657408 TI - Shared Care of Childhood Cancer Survivors: A Telemedicine Feasibility Study. AB - PURPOSE: With an increasing number of childhood cancer survivors (CCSs), determining the best model of survivorship transition care is becoming a growing priority. Shared care between pediatric oncology and adult primary care is often necessary, making survivorship a time of transition, but effective standard models are lacking. We sought to provide a more integrated approach to transition using telemedicine. METHODS: Recruited primary care provider/CCS dyads were instructed to log-in to a password-protected virtual meeting room using telemedicine equipment at the time or a regularly scheduled office visit. Dyads were joined by a pediatric survivorship clinic team member who conducted the telemedicine portion of the transition visit, which consisted of the review of an individualized treatment summary and care plan. Postquestionnaires were developed to evaluate key points such as fund of knowledge, satisfaction with the visit, and effectiveness of this electronic tool. RESULTS: There were 19 transition visits conducted, 13 of which used the telemedicine equipment as planned. Those that did not use the equipment were primarily unable to due to technical difficulties. Postquestionnaires were overall positive, confirming increased knowledge, comfort and abilities, and patient satisfaction in survivorship care. Negative comments were primarily related to equipment difficulties. CONCLUSIONS: A gap still remains in helping CCSs transition from oncology to primary care and this pilot study offered insights into how we might better bridge that gap through the use of telemedicine. Further research is needed to refine the transition process for CCSs, including evaluation and testing models for standard of care. PMID- 28657409 TI - Serum 25-hydroxyvitamin D and Age-Related Cataract. AB - PURPOSE: Cataract and insufficient vitamin D intake are both increasing worldwide concerns, yet little is known about the relationship between serum 25 hydroxyvitamin D (25(OH)D) levels and age-related cataract. We performed this study to determine the association between serum 25(OH)D levels and age-related cataract in adults. METHODS: Study participants comprised 16,086 adults aged 40 years or older who had never been diagnosed with or undergone surgery for cataract using Korean National Health and Nutrition Examination Survey data from 2008 to 2012. Participants were assessed to have cataract when diagnosed with cortical, nuclear, anterior subcapsular, posterior subcapsular, or mixed cataract. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the magnitude and significance of the association between serum 25(OH)D levels and cataract in multivariable logistic regression models. RESULTS: The OR for nuclear cataract with the highest quintile of serum 25(OH)D levels was 0.86 (95% CI 0.75-0.99) compared to the lowest quintile. A linear trend across quintiles was significant. Natural log-transformed serum 25(OH)D levels were also significantly associated with nuclear cataract (OR 0.84, 95% CI 0.75-0.95). The opulation-attributable fraction of nuclear cataract due to serum 25(OH)D insufficiency (<30 ng/mL) was 8.8% (p = 0.048). CONCLUSIONS: Serum 25(OH)D levels were inversely associated with the risk of nuclear cataract. Prospective studies investigating the effects of serum 25(OH)D levels on the development of nuclear cataract are needed to confirm our findings. PMID- 28657410 TI - The relationship between fragmented QRS and non-dipper status in hypertensive patients without left ventricular hypertrophy. AB - BACKGROUND: Fragmented QRS (fQRS) has been shown to be associated with poor outcome in various cardiovascular diseases. Non-dipper hypertension is also associated with increased cardiovascular mortality. The aim of our study is to investigate the relationship between fQRS and non-dipper status in hypertensive patients without left ventricular hypertrophy (LVH). METHODS: This study included 106 hypertensive patients without LVH. Patients were divided into two groups: dipper hypertension and non-dipper hypertension. The presence of fQRS was analyzed from surface electrocardiography. RESULTS: Frequency of fQRS (56% vs. 19.6%, p < 0.001) and mean number of leads with fQRS (1.9 +/- 1.7 vs. 0.6 +/- 1.0, p < 0.001) were significantly higher in patients with non-dipper hypertension compared to dipper hypertension. In addition, the number of leads with fQRS was positively correlated with systolic (r = 0.334, p < 0.001) and diastolic (r = 0.280, p = 0.004) blood pressures (BP). By a multivariate regression analysis, fQRS (OR: 5.207, 95% CI: 2.195-12.353, p < 0.001) was found to be independent predictor of non-dipper status. CONCLUSION: fQRS is independent predictor of non-dipper status in hypertensive patients without LVH. Also, the higher number of leads with fQRS is associated with higher sleep systolic and diastolic BPs. PMID- 28657412 TI - Relationship between proton affinities and structures of proton-bound dimers. AB - This work presents a structural approach for determination of proton affinities of molecules. In proton-bound dimer [X...H...M]+, M and X compete with each other to capture the proton. The correlation between proton affinities of a series of molecules, M, and X...H bond length was studied while X was a common molecule in the all proton-bound dimers. Linear relationships were observed between proton affinities of a series of alcohols, ethers, aldehydes, ketones and amines and X...H bond length, where H2O and HF were used as X. The method was employed for the measurement of proton affinities of (HF)1-10 clusters using NH3 and H2O as common molecules, [NH3...H...(HF)n]+ and [H2O...H...(HF)n]+. A linear correlation was observed for the PAs of (HF)n clusters versus N...H bond length. PMID- 28657411 TI - Recommendations of the Fertility Preservation Working Group in Oncological, Hematological and Other Patients Treated With Gonadotoxic Therapies "ONCOFERTILITY" (GROF) of the Polish Society of Oncological Gynecology. PMID- 28657413 TI - Dynamic measurement of newly formed carbonyl compounds in vapors from electronic cigarettes. AB - Recently, the formation of carbonyl compound within e-cigarettes usage has been reported. The aim of this study was to develop a new analytical method for the direct analysis of carbonyl compounds in vaporized liquids. Two different types of e-cigarettes and different puff's duration have been evaluated, using a modified smoking machine for vapor generation. An isotopic dilution approach, based on deuterated internal standard addition to the e-liquid before filling the e-cigarette tank, has been developed. Carbonyl compounds have been sampled in vapors using a direct, simple, solid-phase microextraction technique with on fiber derivatization. Related oximes have been analyzed by gas chromatography/mass spectrometry technique. Results confirmed that new carbonyl compounds are formed during the vaping process, and that formation depends both from the heating device and from puffing topography. PMID- 28657414 TI - Using aromatic polyamines with high proton affinity as "proton sponge" dopants for electrospray ionisation mass spectrometry. AB - Proton sponges are polyamines with high proton affinity that enable gentle deprotonation of even mildly acidic compounds. In this study, the concept of proton sponges as signal enhancing dopants for electrospray ionisation is presented for the first time. 1,8-Bis(dimethylamino)naphthalene (DMAN) and 1,8 bis(tetramethylguanidino)naphthalene (TMGN) were chosen as dopants, using methanol and acetonitrile/methanol as solvents. Individual standard compounds, compound mixtures and a diesel fuel as a complex sample matrix were investigated. Both proton sponges enhanced signal intensities in electrospray ionisation negative mode, but TMGN decomposed rapidly in methanolic solution. Significantly higher signals were only achieved using the acetonitrile/methanol mixture. On average a more than 10-fold higher signal intensity was measured with 10-3 mol l 1 DMAN concentration. A stronger signal increase of alcohol functionalities was observed compared to acid functionalities. All compound classes which were detected in the diesel fuel (CH- and CHOx-class) received roughly 100-fold higher signal intensities when using DMAN as a dopant. Furthermore, the number of detected compounds as well as the double bond equivalent of the detected compounds increased. The compound class distribution shifted when adding DMAN and the formerly dominant CHO2-, CHO3-, and CHO4- classes received similar relative intensities as formerly less accessible classes. The findings depict DMAN as a promising additive for electrospray ionisation negative analysis of at least mildly acidic compounds, even within complex sample material. PMID- 28657415 TI - The investigation of the bio-oil produced by hydrothermal liquefaction of Spirulina platensis using ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry. AB - We report the investigation of the hydrothermal liquefaction products of the Spirulina platensis microalgae by using the Fourier transform ion cyclotron resonance mass spectrometry. The hydrothermal liquefaction produced two fractions: one with boiling temperature below 300C and the dense residue that remained in the reactor. It was observed that N2 and N classes of compounds that dominate in the positive ESI Fourier transform ion cyclotron resonance spectra for both fractions, and that the light fraction is considerably more saturated then the heavy one. The performed hydrogen/deuterium exchange reaction indicated the presence of the onium compounds in the bio-oil. PMID- 28657416 TI - MALDI-TOF mass spectrometry provides high accuracy in identification of Salmonella at species level but is limited to type or subtype Salmonella serovars. AB - Salmonella can cause global foodborne illnesses in humans and many animals. The current diagnostic gold standard used for detecting Salmonella infection is microbiological culture followed by serological confirmation tests. However, these methods are complicated and time-consuming. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis offers some advantages in rapid identification, for example, simple and fast sample preparation, fast and automated measurement, and robust and reliable identification up to genus and species levels, possibly even to the strain level. In this study, we established a reference database for species identification using whole-cell MALDI-TOF MS; the database consisted of 12 obtained main spectra of the Salmonella culture collection strains belonged to seven serotypes. Eighty two clinical isolates of Salmonella were identified using established database, and partial 16S rDNA gene sequencing and serological method were used as comparison. We found that MALDI-TOF mass spectrometry provided high accuracy in identification of Salmonella at species level but was limited to type or subtype Salmonella serovars. We also tried to find serovar-specific biomarkers and failed. Our study demonstrated that (a) MALDI-TOF MS was suitable for identification of Salmonella at species level with high accuracy and (b) that MALDI-TOF MS method presented in this study was not useful for serovar assignment of Salmonella currently, because of its low matching with serological method and (c) MALDI-TOF MS method presented in this study was not suitable to subtype S. typhimurium because of its low discriminatory ability. PMID- 28657417 TI - Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. AB - BACKGROUND: Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events. CONCLUSIONS: Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013-003778-29 ; Current Controlled Trials number, ISRCTN13633058 .). PMID- 28657419 TI - Hepatoprotective, Hypoglycemic, and Hypolipidemic Effect of Chokeberry Pomace on Polish Merino Lambs. AB - To properly understand the biological effect of polyphenol compounds, it should not be assumed that they are generally bioavailable and are reaching tissues as expected. It is important to fully understand how polyphenol compounds are absorbed, metabolized, and finally eliminated from the organism. Most polyphenol compounds occur in the forms that cannot be absorbed in their primary form. Sheep make compounds bioavailable due to their unique digestive system properties. Despite this, several species of ruminants likely to serve as an experimental model were considered. However, due to the high costs for cattle and low popularity in the region of goats, sheep were selected as the experimental model. In the study, 24 Polish Merino lambs were randomly divided into a control and two experimental groups. The experimental groups were administered diets with the addition of 150 or 300 g of chokeberry pomace per each kg of complete feed mixture. Phenolics present in the chokeberry pomace were found to modulate biochemical blood parameters, resulting in hypoglycemic and hypolipidemic effects. Finally, the increase in total phenolics in the serum and liver of lambs induced a health-promoting effect on liver metabolic profile parameters. PMID- 28657418 TI - Chemically-defined camelid antibody bioconjugate for the magnetic resonance imaging of Alzheimer's disease. AB - Today, molecular imaging of neurodegenerative diseases is mainly based on small molecule probes. Alternatively, antibodies are versatile tools that may be developed as new imaging agents. Indeed, they can be readily obtained to specifically target any antigen of interest and their scaffold can be functionalized. One of the critical issues involved in translating antibody-based probes to the clinic is the design and synthesis of perfectly-defined conjugates. Camelid single-domain antibody-fragments (VHHs) are very small and stable antibodies that are able to diffuse in tissues and potentially cross the blood brain barrier (BBB). Here, we selected a VHH (R3VQ) specifically targeting one of the main lesions of Alzheimer's disease (AD), namely the amyloid-beta (Abeta) deposits. It was used as a scaffold for the design of imaging probes for magnetic resonance imaging (MRI) and labeled with the contrastophore gadolinium using either a random or site-specific approach. In contrast to the random strategy, the site-specific conjugation to a single reduced cysteine in the C-terminal part of the R3VQ generates a well-defined bioconjugate in a high yield process. This new imaging probe is able to cross the BBB and label Abeta deposits after intravenous injection. Also, it displays improved r1 and r2 relaxivities, up to 30 times higher than a widely used clinical contrast agent, and it allows MRI detection of amyloid deposits in post mortem brain tissue of a mouse model of AD. The ability to produce chemically-defined VHH conjugates that cross the BBB opens the way for future development of tailored imaging probes targeting intracerebral antigens. PMID- 28657420 TI - Driver and front passenger injury in frontal crashes: Update on the effect of unbelted rear occupants. AB - PURPOSE: This is a study of the influence of an unbelted rear occupant on the risk of severe injury to the front seat occupant ahead of them in frontal crashes. It provides an update to earlier studies. METHODS: 1997-2015 NASS-CDS data were used to investigate the risk for severe injury (Maximum Abbreviated Injury Score [MAIS] 4+F) to belted drivers and front passengers in frontal crashes by the presence of a belted or unbelted passenger seated directly behind them or without a rear passenger. Frontal crashes were identified with GAD1 = F without rollover (rollover <= 0). Front and rear outboard occupants were included without ejection (ejection = 0). Injury severity was defined by MAIS and fatality (F) by TREATMNT = 1 or INJSEV = 4. Weighted data were determined. The risk for MAIS 4+F was determined using the number of occupants with known injury status MAIS 0+F. Standard errors were determined. RESULTS: The risk for severe injury was 0.803 +/- 0.263% for the driver with an unbelted left rear occupant and 0.100 +/- 0.039% with a belted left rear occupant. The driver's risk was thus 8.01 times greater with an unbelted rear occupant than with a belted occupant (P <.001). With an unbelted right rear occupant behind the front passenger, the risk for severe injury was 0.277 +/- 0.091% for the front passenger. The corresponding risk was 0.165 +/- 0.075% when the right rear occupant was belted. The front passenger's risk was 1.68 times greater with an unbelted rear occupant behind them than a belted occupant (P <.001). The driver's risk for MAIS 4+F was highest when their seat was deformed forward. The risk was 9.94 times greater with an unbelted rear occupant than with a belted rear occupant when the driver's seat deformed forward. It was 13.4 +/- 12.2% with an unbelted occupant behind them and 1.35 +/- 0.95% with a belted occupant behind them. CONCLUSIONS: Consistent with prior literature, seat belt use by a rear occupant significantly lowered the risk for severe injury to belted occupants seated in front of them. The reduction was greater for drivers than for front passengers. It was 87.5% for the driver and 40.6% for the front passenger. These results emphasize the need for belt reminders in all seating positions. PMID- 28657422 TI - Vision Profile and Ocular Characteristics of Special Olympics Athletes: Report from India. AB - PURPOSE: Previous reports, albeit isolated, of vision and ocular screening of athletes with intellectual disability participating in the Special Olympics, UK, indicated high rates of refractive error and ocular morbidity; however, there have been no reports of similar sports events for this population from India. This study set out to evaluate the vision profile and ocular characteristics of athletes with intellectual disability attending the Special Olympics Lions Club International Opening Eyes (SOLCIOE) event in 2012 in India. METHODS: A cross sectional study was conducted, where a protocol-based ophthalmological assessment was performed by trained optometrists at a tertiary eye care center. RESULTS: Overall, 172 athletes (mean age 18.6 years, 70% male) with intellectual disability participated, and 138 (80%) were able to cooperate for complete or nearly complete vision and ocular assessment. A total of 56 (32%) had never had a previous vision or ocular health status examination. A total of 46 (32%) presented with low vision (World Health Organization definition <6/18 to 3/60 in the better eye), 21% needed a first or updated spectacle prescription, and 28% had significant ocular pathology as the cause of visual loss. CONCLUSIONS: The proportions of refractive errors and ocular disorders in athletes with intellectual disability attending the SOLCIOE program in South India are similar to those reported for able-bodied school-aged children in urban and rural India. Like that of their able-bodied peers, the visual needs of children with intellectual disability are also not adequately being met. PMID- 28657421 TI - Chemo brain: From discerning mechanisms to lifting the brain fog-An aging connection. AB - Mounting evidence indicates that cancer treatments cause numerous deleterious effects, including central nervous system (CNS) toxicity. Chemotherapy-caused CNS side effects encompass changes in cognitive function, memory, and attention, to name a few. Although chemotherapy treatment-induced side effects occur in 16-75% of all patients, the mechanisms of these effects are not well understood. We have recently proposed a new epigenetic theory of chemo brain and, in a pioneer study, determined that cytotoxic chemotherapy agents induce oxidative DNA damage and affect molecular and epigenetic processes in the brain, and may be associated with brain aging processes. In this paper, we discuss the implications of chemo brain epigenetic effects and future perspectives, as well as outline potential links with brain aging and future translational research opportunities. PMID- 28657423 TI - In vitro metabolism of alectinib, a novel potent ALK inhibitor, in human: contribution of CYP3A enzymes. AB - 1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated. 2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b. 3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major. 4. In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug drug interactions. PMID- 28657424 TI - Heroin-piracetam mixture: Suggested mechanisms of action and risks of misinterpretation for drug users. AB - Piracetam is a positive allosteric modulator of the alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid receptor that has been frequently used in the treatment of cognitive disorders. Press and internet reports indicate that the use of piracetam, as a heroin adulterant, has spread rapidly in some countries, especially in Asia and Europe. Its use, as adulterant, is believed to produce more profound desirable effects, while decreasing hangover. Recent surveys demonstrated that piracetam protects neurons from heroin-induced apoptosis. The protective role of this adulterating substance may be related to restoration of beta-endorphin levels and to its neuroprotective effects. The aim of this paper is to review the relevant literature and suggest the main hypothetical mechanisms that justify its use as a heroin adulterant, try to understand if its use could help people who want to come off heroin by reducing withdrawal symptoms and, finally, give useful information that permit us to understand why drug trafficking organisations started to use piracetam as heroin adulterant. PMID- 28657425 TI - The Regulatory Network Controlling Ethanol-Induced Expression of Alcohol Dehydrogenase in the Endophyte Azoarcus sp. Strain BH72. AB - The habitat of the nitrogen-fixing endophyte Azoarcus sp. strain BH72 is grass roots grown under waterlogged conditions that produce, under these conditions, ethanol. Strain BH72 is well equipped to metabolize ethanol, with eight alcohol dehydrogenases (ADHs), of which ExaA2 and ExaA3 are the most relevant ones. exaA2 and exaA3 cluster and are surrounded by genes encoding two-component regulatory systems (TCSs) termed ExaS-ExaR and ElmS-GacA. Functional genomic analyses revealed that i) expression of the corresponding genes was induced by ethanol, ii) the genes were also expressed in the rhizoplane or even inside of rice roots, iii) both TCSs were indispensable for growth on ethanol, and iv) they were important for competitiveness during rice root colonization. Both TCSs form a hierarchically organized ethanol-responsive signal transduction cascade with ExaS ExaR as the highest level, essential for effective expression of the ethanol oxidation system based on ExaA2. Transcript and expression levels of exaA3 increased in tcs deletion mutants, suggesting no direct influence of both TCSs on its ethanol-induced expression. In conclusion, this underscores the importance of ethanol for the endophytic lifestyle of Azoarcus sp. strain BH72 and indicates a tight regulation of the ethanol oxidation system during root colonization. PMID- 28657426 TI - Oncogenic Ect2 signaling regulates rRNA synthesis in NSCLC. AB - The Rho GTPase family members Rac1, Cdc42 and RhoA play key contributory roles in the transformed phenotype of human cancers. Epithelial Cell Transforming Sequence 2 (Ect2), a guanine nucleotide exchange factor (GEF) for these Rho GTPases, has also been implicated in a variety of human cancers. We have shown that Ect2 is frequently overexpressed in both major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC), which together make up approximately 70% of all lung cancer diagnoses. Furthermore, we have found that Ect2 is required for multiple aspects of the transformed phenotype of NSCLC cells including transformed growth and invasion in vitro and tumorigenesis in vivo. More recently, we showed that a major mechanism by which Ect2 drives KRAS-mediated LADC transformation is by regulating rRNA (rRNA) synthesis. However, it remains unclear whether Ect2 plays a similar role in ribosome biogenesis in LSCC. Here we demonstrate that Ect2 expression correlates positively with expression of ribosome biogenesis genes and with pre ribosomal 45S RNA abundance in primary LSCC tumors. Furthermore, we demonstrate that Ect2 functionally regulates rRNA synthesis in LSCC cells. Based on these data, we propose that inhibition of Ect2-mediated nucleolar signaling holds promise as a potential therapeutic strategy for improved treatment of both LADC and LSCC. PMID- 28657428 TI - Abnormal functional connectivity of thalamic sub-regions contributes to fatigue in multiple sclerosis. AB - OBJECTIVE: To investigate sub-regional thalamic resting-state (RS) functional connectivity (FC) abnormalities in multiple sclerosis (MS) and their correlation with fatigue and its subcomponents (physical, cognitive, and psychosocial). METHODS: From 122 MS patients and 94 healthy controls, 5 thalamic sub-regions (frontal, motor, postcentral, occipital, temporal) were parcellated based on their cortico-thalamic structural connectivity and used for a seed-based RS FC analysis. Abnormalities of thalamic RS FC in MS patients and their correlation with Modified Fatigue Impact Scale (MFIS) were assessed. RESULTS: Compared to controls and non-fatigued MS ( n = 86), fatigued MS patients ( n = 36) showed thalamic RS FC abnormalities with middle frontal gyrus, sensorimotor network, precuneus, insula, and cerebellum, which correlated with global MFIS. Higher thalamic RS FC with precuneus and lower RS FC with posterior cerebellum correlated with cognitive MFIS. Higher thalamic RS FC with sensorimotor network in frontal-, motor-, and temporal thalamic sub-regions correlated with physical and psychosocial MFIS. Reduced thalamic RS FC with right insula in motor-, postcentral-, and occipital thalamic sub-regions correlated with psychosocial fatigue. CONCLUSION: Regional thalamic RS FC abnormalities with different cortical regions, including the frontal lobe, sensorimotor network, precuneus, insular cortices, and cerebellum contribute to fatigue in MS. Abnormal RS FC of selected thalamo-cortical connections explains different components of fatigue. PMID- 28657427 TI - Expression of Metabolic Syndrome in Women with Severe Obesity. AB - BACKGROUND: The prevalence of metabolic syndrome (MetS) generally rises with increasing adiposity, but tends to plateau at the highest levels of body mass index (BMI) with some individuals, even with severe obesity, expressing few or no components of MetS. We examined factors associated with the expression of MetS in severely obese women participating in a large observational study. METHODS: Anthropometrics, including Heath equation-adjusted bioimpedance-determined fat free mass (FFM) and fat mass (FM), lipids and related laboratory measurements, resting energy expenditure (REE), and respiratory quotient (RQ), were studied in 949 women with severe obesity. RESULTS: Even though the mean BMI was 45.7 kg/m2 and all participants met MetS criteria for increased waist circumference, 30% of subjects did not have MetS. Unadjusted FM (P = 0.0011), FFM (P < 0.0001), and REE (P < 0.0001) were greater in the women with MetS. Surprisingly, in multivariate logistic regression FFM was positively associated with MetS (P = 0.0002), while FM was not (P = 0.89). Moreover, FFM, not FM, was significantly associated with all five components of MetS except for triglyceride levels. REE and RQ were higher in those with MetS, and REE was strongly associated with multiple components of MetS. CONCLUSIONS: In women with severe obesity, higher FFM and REE were paradoxically associated with increased rather than decreased risk of MetS, while FFM-adjusted FM was unrelated to MetS. PMID- 28657429 TI - Safety profile of snake antivenom (use) in Hong Kong - a review of 191 cases from 2008 to 2015. AB - INTRODUCTION: The mainstay of treatment for significant envenoming from snakebites is antivenom. However, there is insufficient data regarding the safety of antivenom used in Hong Kong. We describe the incidence of hypersensitivity reactions from antivenom use and review the frequency and reasons for intensive care unit (ICU) admission. METHODS: The Hong Kong Poisons Information Centre database was reviewed. All patients given snake antivenom between 2008 and 2015 were included. Patient demographics, species of snake involved, details of antivenom used, treatment location, use of pre-treatment, reasons for ICU admission (where applicable) and details of early and late antivenom reactions were extracted. RESULTS: There were 191 patients who received snake antivenom. Most (93%) were treated with either the green pit viper antivenom from Thailand or the Agkistrodon halys antivenom from China. The incidences of early hypersensitivity reactions to green pit viper antivenom and Agkistrodon Halys antivenom were 4.7% and 1.4%, respectively. Most patients (69%) were managed in the ED observation ward or general ward. There were 59 patients managed in ICU, most (90%) of whom were admitted for close monitoring during antivenom administration. There were no cases of significant morbidity from antivenom administration. Eight patients (5.6%) had features suggestive of mild serum sickness. CONCLUSIONS: The incidence of immediate hypersensitivity reaction to antivenom commonly used in Hong Kong is low. Majority of patients were managed safely in the emergency department observation ward or general ward. Serum sickness appears to be uncommon and possible cases presented with mild features. PMID- 28657430 TI - Tumescent anesthesia for reducing pain, swelling, and ecchymosis during polycaprolactone filler injections in the face. AB - PCL filler can be injected in two major ways to control pain. One such method involves mixing 0.3cc of PCL filler with lidocaine, and the other is the method introduced in this report, which involves pre-injection with a tumescent solution. It is hard to reduce pain effectively with pre-mixing PCL filler with lidocaine because there may be not enough time to act lidocaine solution effect immediately for pain control. The pre-mixing method changes the properties of the original filler, especially the property of the CMC portion. Therefore, in my simple and novel technique, tumescent solution is injected, followed by PCL filler which preserves the original CMC property. This is done after sedation of the tissue by the tumescent solution and dissection of soft tissue to create a space for the ensuing PCL injection. After pre-injection with tumescent solution, histological analysis indicated that the tissue did not become irritated in response to the foreign body material (PCL filler) or the mechanical trauma caused by the needle. That is the key mechanism of the tumescent injection method for reducing tissue reaction and that may reduce pain and swelling during and after PCL filler injections. PMID- 28657431 TI - CSF and clinical data are useful in differentiating CNS inflammatory demyelinating disease from CNS lymphoma. AB - BACKGROUND: It is often difficult to diagnose central nervous system (CNS) inflammatory demyelinating diseases (IDDs) because they are similar to CNS lymphoma and glioma. OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) analysis can differentiate CNS IDDs from CNS lymphoma and glioma. METHODS: We measured CSF cell counts; concentrations of proteins, glucose, interleukin (IL) 6, IL-10, soluble IL-2 receptor (sIL-2R), and myelin basic protein; and IgG index in patients with multiple sclerosis (MS, n = 64), neuromyelitis optica spectrum disorder (NMOSD, n = 35), tumefactive demyelinating lesion (TDL, n = 17), CNS lymphoma ( n = 12), or glioma ( n = 10). We detected diagnostic markers using logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: Median CSF IL-10 and sIL-2R levels were higher in CNS lymphoma patients than in MS, NMOSD, or TDL patients. Logistic regression revealed that CSF sIL-2R levels predicted CNS lymphoma. In the ROC analysis of CSF sIL-2R levels, the area under the curve was 0.867, and the sensitivity and specificity were 83.3% and 90.0%, respectively. CONCLUSION: CSF sIL-2R levels can be used to differentiate CNS lymphoma from CNS IDDs. Further studies may identify other applications of CSF as a diagnostic biomarker. PMID- 28657432 TI - Accelerated Changes in Cortical Thickness Measurements with Age in Military Service Members with Traumatic Brain Injury. AB - Finding objective and quantifiable imaging markers of mild traumatic brain injury (TBI) has proven challenging, especially in the military population. Changes in cortical thickness after injury have been reported in animals and in humans, but it is unclear how these alterations manifest in the chronic phase, and it is difficult to characterize accurately with imaging. We used cortical thickness measures derived from Advanced Normalization Tools (ANTs) to predict a continuous demographic variable: age. We trained four different regression models (linear regression, support vector regression, Gaussian process regression, and random forests) to predict age from healthy control brains from publicly available datasets (n = 762). We then used these models to predict brain age in military Service Members with TBI (n = 92) and military Service Members without TBI (n = 34). Our results show that all four models overpredicted age in Service Members with TBI, and the predicted age difference was significantly greater compared with military controls. These data extend previous civilian findings and show that cortical thickness measures may reveal an association of accelerated changes over time with military TBI. PMID- 28657433 TI - Editorial. PMID- 28657434 TI - Quick elucidation of cyclodepsipeptide sequence from sacoglossan Elysia grandifolia using electrospray ionisation-tandem mass spectrometry. AB - Butanol fraction of sacoglossan Elysia grandifolia was investigated for identifying peptides using electrospray ionisation-tandem mass spectrometry (ESI MS/MS). Without prior isolation, the structural determination is achieved on the basis of mass fragmentation pattern and comparison with the previously established data. The ESI-MS of the fraction in the positive ion mode gave clusters of singly and doubly charged molecular ion peaks. The ESI-MS spectrum showed peaks for the presence of the peptides kahalalides F, G, R and S reported earlier. In addition, it also showed molecular ion peaks at m/z 1557.8 [M+H]+ and doubly charged ions at m/z 779.4 [M+2H]2+, 790.4 [M+Na]2+ and 796.4 [M+K]2+. The MS/MS at m/z 779.4 [M+2H]+2 at collision energy 40 V obtained series of b and y fragment ions. The MS/MS spectrum showed identical fragment ion y6 at m/z 643 which revealed that cyclic part is identical with kahalalide F, R and S. Careful examination of the fragment ions b1 to b7 with their corresponding y fragment ions y12 to y6, respectively and by comparison of MS/MS pattern of kahalalide S, established that proline can be replaced by tyrosine amino acid residue. The mass difference between b4 ( m/z 511) and b5 ( m/z 674) is equal to 163 which is equivalent to mass residue of tyrosine. Their y fragment ions also quickly helped in fixing the puzzle. This resulted in the identification of the peptide sequence cyclo-[Val-(5-MeHex-Val-Thr-Val-Val-Tyr-Lys-Ile)Thr-Ile-Val-Phe-Dhb)] for the new cyclodepsipeptide, kahalalide Z3. Thus, ESI-MS/MS has set a trend in quick identification of new marine molecules. PMID- 28657435 TI - Enhanced detection of amino acids in hydrophilic interaction chromatography electrospray tandem mass spectrometry with carboxylic acids as mobile phase additives. AB - Liquid chromatography coupled with mass spectrometry technique has been widely used in the analysis of biological targets such as amino acids, peptides, and proteins. In this work, eight common single carboxylic acids or diacids, which contain different pKa have been investigated as the additives to the analysis of amino acids. As the results, carboxylic acid additive can improve the signal intensity of acidity amino acids such as Asp and Glu and the chromatographic separation of basic amino acids such as Arg, His, and Lys. In particular, the diacids have better performance than single acids. The proposed mechanism is that the diacid has hydrogen bond interaction with amino acids to reduce their polarity/amphiprotic characteristics. Besides, oxalic acid has been found having better enhancement than phthalic acid by overall consideration. Therefore, we successfully quantified the 15 amino acids in Sepia bulk pharmaceutical chemical by using oxalic acid as the additive. PMID- 28657436 TI - Unexpected hydrated ions in the detection of sodium adduct coumarins using electrospray tandem mass spectrometry. AB - A series of coumarins were analyzed using electrospray ionization quadrupole time of-flight tandem mass spectrometry in the positive-ion mode. Unexpected hydrated ions ([M + H2O + Na]+) was observed upon collision-induced dissociation of the sodiated ions ([M + Na]+) of eight coumarins. Several factors which affected relative abundance of [M + H2O + Na]+ ions such as collision energy, concentration and solvent were investigated. None of them have effect on the relative abundance of [M + H2O + Na]+. However, the peak of hydrated ions was not detected in the further collision-induced dissociation of protonated ions of coumarins. Apigenin and Quercetin sharing similar benzopyrone structural unit with coumarins are selected for tandem mass spectrometry analysis. There were no hydrated ions in their tandem mass spectrometry spectra of the precursor [M + Na]+ ions. Thus, both coumarins and sodium were necessary for the formation of [M + H2O + Na]+. Together with the result that hydrated ions are not formed by hydrolysis reactions, a six-membered ring structure which involves with the formation of [M + H2O + Na]+ was presented. And D-labeling experiment indicates that the H2O molecule did not come from solvent. PMID- 28657437 TI - Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies. AB - Spinal cord as a connection between brain and peripheral nervous system is an essential material for studying neural transmission, especially in pain-related research. This study was the first to investigate pain-related neuropeptide distribution in rat spinal cord using a matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry (MALDI TOF MS) approach. The imaging workflow was evaluated and showed that MALDI TOF MS provides efficient resolution and robustness for neuropeptide imaging in rat spinal cord tissue. The imaging result showed that in naive rat spinal cord the molecular distribution of haeme, phosphatidylcholine, substance P and thymosin beta 4 were well in line with histological features. Three groups of pain-related neuropeptides, which are cleaved from prodynorphin, proenkephalin and protachykinin-1 proteins were detected. All these neuropeptides were found predominantly localized in the dorsal spinal cord and each group had unique distribution pattern. This study set the stage for future MALDI TOF MS application to elucidate signalling mechanism of pain-related diseases in small animal models. PMID- 28657438 TI - 4D phase-space acceptance of the quadrupole mass filter. AB - Simulations of the four-dimensional (4D) phase-space acceptance volume of a quadrupole mass filter (QMF) are discussed. The 4D acceptance is considered since the ion trajectories in the X and Y phase planes are dependent via the initial RF phase at ion entry into QMF. The QMF parameters are set up for resolution equal to the ion mass number M. For a wide range of ion masses, the acceptance is characterized by relatively large aperture with about 5% transmission, primarily defined by phase dependent ellipses. Contrary to expectations, the small-aperture central spot with 75% transmission accepts a very small portion, namely less than 1% of the passed through particles. PMID- 28657439 TI - Elucidating proton-mediated conformational changes in an acid-sensing ion channel 1a through molecular dynamics simulation. PMID- 28657441 TI - Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs. AB - A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.3 MUg/mL, respectively. A molecular docking study was also conducted to evaluate the stability of the active compounds, and compound with ethyl substitution at second position of indolizine nucleus showed the highest free binding energy of DeltaG -24.11 (kcal/mol), a low clash score of 3.04, and high lipo score of -13.33. Indolizine analog with ethyl substitution at second position demonstrated Molecular Mechanics/Generalized Born Surface Area (-23.85 kcal/mol). Two molecular dynamics studies were computed (100 ps and 50 ns) to calculate the relationship between the potential and kinetic energies of the active anti-TB compound with time and temperature. The discovery of this lead may have a positive impact on anti-TB drug discovery. PMID- 28657443 TI - Giant pulmonary artery aneurysm associating right pulmonary artery thrombi in a patient with idiopathic pulmonary arterial hypertension. PMID- 28657440 TI - Abeta seeds and prions: How close the fit? AB - The prion paradigm is increasingly invoked to explain the molecular pathogenesis of neurodegenerative diseases involving the misfolding and aggregation of proteins other than the prion protein (PrP). Extensive evidence from in vitro and in vivo studies indicates that misfolded and aggregated Abeta peptide, which is the probable molecular trigger for Alzheimer's disease, manifests all of the key characteristics of canonical mammalian prions. These features include a beta sheet rich architecture, tendency to polymerize into amyloid, templated corruption of like protein molecules, ability to form structurally and functionally variant strains, systematic spread by neuronal transport, and resistance to inactivation by heat and formaldehyde. In addition to Abeta, a growing body of research supports the view that the prion-like molecular transformation of specific proteins drives the onset and course of a remarkable variety of clinicopathologically diverse diseases. As such, the expanded prion paradigm could conceptually unify fundamental and translational investigations of these disorders. PMID- 28657444 TI - Bridging the gap for lipid lowering therapy: plaque regression, coronary computed tomographic angiography, and imaging-guided personalized medicine. AB - INTRODUCTION: Lipid-lowering therapy effectively decreases cardiovascular risk on a population level, but it remains difficult to identify an individual patient's personal risk reduction while following guideline directed medical therapy, leading to overtreatment in some patients and cardiovascular events in others. Recent improvements in cardiac CT technology provide the ability to directly assess an individual's atherosclerotic disease burden, which has the potential to personalize risk assessment for lipid-lowering therapy. Areas covered: We review the current unmet need in identifying patients at elevated residual risk despite guideline directed medical therapy, the evidence behind plaque regression as a potential marker of therapeutic response, and highlight state-of-the-art advances in coronary computed tomographic angiography (CCTA) for measurement of quantitative and qualitative changes in coronary atherosclerosis over time. Literature search was performed using PubMed and Google Scholar for literature relevant to statin therapy and residual risk, coronary plaque regression measurement, and CCTA assessment of quantitative and qualitative change in coronary atherosclerosis. Expert commentary: We discuss the potential ability of CCTA to guide lipid-lowering therapy as a bridge between population and personalized medicine in the future, as well as the potential barriers to its use. PMID- 28657445 TI - Editorial. PMID- 28657446 TI - Observed adducts on positive mode direct analysis in real time mass spectrometry Proton/ammonium adduct selectivities of 600-sample in-house chemical library. AB - In this study, direct analysis in real time adduct selectivities of a 558 in house high-resolution mass spectrometry sample library was evaluated. The protonated molecular ion ([M + H]+) was detected in 462 samples. The ammonium adduct ion ([M + NH4]+) was also detected in 262 samples. [M + H]+ and [M + NH4]+ molecular ions were observed simultaneously in 166 samples. These adduct selectivities were related to the elemental compositions of the sample compounds. [M + NH4]+ selectivity correlated with the number of oxygen atom(s), whereas [M + H]+ selectivity correlated with the number of nitrogen atom(s) in the elemental compositions. For compounds including a nitrogen atom and an oxygen atom [M + H]+ was detected; [M + NH4]+ was detected for compounds including an oxygen atom only. Density functional theory calculations were performed for selected library samples and model compounds. Energy differences were observed between compounds detected as [M + H]+ and [M + NH4]+, and between compounds including a nitrogen atom and an oxygen atom in their elemental compositions. The results suggested that the presence of oxygen atoms stabilizes [M + NH4]+, but not every oxygen atom has enough energy for detection of [M + NH4]+. It was concluded that the nitrogen atom(s) and oxygen atom(s) in the elemental compositions play important roles in the adduct formation in direct analysis in real time mass spectrometry. PMID- 28657447 TI - Investigation of collision-induced dissociation products and structures of gas phase [ M.GlyGlyHis-H]+ ( M = Fe, Ni, Cu, and Zn) complexes. AB - Collision-induced dissociation is carried out for electrosprayed [Fe.GlyGlyHis H]+, [Ni.GlyGlyHis-H]+, [Cu.GlyGlyHis-H]+, and [Zn.GlyGlyHis-H]+ complexes. [Fe.GlyGlyHis-H]+, [Ni.GlyGlyHis-H]+, and [Zn.GlyGlyHis-H]+ yield metal-bound peptide sequence ions and dehydrated ions as primary products, whereas [Cu.GlyGlyHis-H]+ generates a more extensive series of metal-bound sequence ions and a product arising from the unusual loss of a formaldehyde moiety; dehydration is significantly suppressed for this complex. Density functional theory calculations show that the copper ion-deprotonated peptide binding energy is substantially higher than those in other complexes, suggesting that there is a correlation between ion-ligand binding energy and their fragmentation behavior. PMID- 28657448 TI - Nudged elastic band method and density functional theory calculation for finding a local minimum energy pathway of p-benzoquinone and phenol fragmentation in mass spectrometry. AB - Analysis of the fragmentation pathways of molecules in mass spectrometry gives a fundamental insight into gas-phase ion chemistry. However, the conventional intrinsic reaction coordinates method requires knowledge of the transition states of ion structures in the fragmentation pathways. Herein, we use the nudged elastic band method, using only the initial and final state ion structures in the fragmentation pathways, and report the advantages and limitations of the method. We found a minimum energy path of p-benzoquinone ion fragmentation with two saddle points and one intermediate structure. The primary energy barrier, which corresponded to the cleavage of the C-C bond adjacent to the CO group, was calculated to be 1.50 eV. An additional energy barrier, which corresponded to the cleavage of the CO group, was calculated to be 0.68 eV. We also found an energy barrier of 3.00 eV, which was the rate determining step of the keto-enol tautomerization in CO elimination from the molecular ion of phenol. The nudged elastic band method allowed the determination of a minimum energy path using only the initial and final state ion structures in the fragmentation pathways, and it provided faster than the conventional intrinsic reaction coordinates method. In addition, this method was found to be effective in the analysis of the charge structures of the molecules during the fragmentation in mass spectrometry. PMID- 28657449 TI - Chemical and biological comparison of different sections of Uncaria rhynchophylla (Gou-Teng). AB - Uncaria rhynchophylla (Gou-Teng in Chinese) is officially documented in Chinese pharmacopoeia as one of the authentic sources for the crude drug of Gou-Teng which has long been used for mental and cardiovascular diseases. Indole alkaloids are the characteristic constituents responsible for the desired hypotensive effect; however, the psychiatric active constituents of Gou-Teng are still unclear. According to traditional Chinese medicine theory, only the hook-bearing stems of U. rhynchophylla are used as the crude materials for Gou-Teng, while its leaves and fruits are scarcely used. The present study aimed to compare the metabolic fingerprints of different parts (hooks, stems, leaves and fruits) of U. rhynchophylla by LC-DAD-MS/MS analysis and further evaluate their psychiatric activities on HEK293 cell line in vitro. A total of 38 constituents including 26 alkaloids, six flavonoids, two triterpenoids, two chlorogenic acid analogs and two other compounds were characterized. The different parts of U. rhynchophylla can be well differentiated from their chemical profiles. Leaves displayed the most potent activity on both MT1 and MT2 receptors, with agonistic rates of 39.7% and 97.6%. For 5-HT1A and 5-HT2C receptors, hooks showed the strongest activity with agonistic rates of 92.6% and 83.1%, respectively. This investigation provided valuable information for understanding the chemical divergence between different parts of U. rhynchophylla, and their substantial bases for psychiatric purposes. PMID- 28657450 TI - Comprehensive chemical comparison of fuel composition and aerosol particles emitted from a ship diesel engine by gas chromatography atmospheric pressure chemical ionisation ultra-high resolution mass spectrometry with improved data processing routines. AB - The analysis of petrochemical materials and particulate matter originating from combustion sources remains a challenging task for instrumental analytical techniques. A detailed chemical characterisation is essential for addressing health and environmental effects. Sophisticated instrumentation, such as mass spectrometry coupled with chromatographic separation, is capable of a comprehensive characterisation, but needs advanced data processing methods. In this study, we present an improved data processing routine for the mass chromatogram obtained from gas chromatography hyphenated to atmospheric pressure chemical ionisation and ultra high resolution mass spectrometry. The focus of the investigation was the primary combustion aerosol samples, i.e. particulate matter extracts, as well as the corresponding fossil fuels fed to the engine. We demonstrate that utilisation of the entire transient and chromatographic information results in advantages including minimisation of ionisation artefacts and a reliable peak assignment. A comprehensive comparison of the aerosol and the feed fuel was performed by applying intensity weighted average values, compound class distribution and principle component analysis. Certain differences between the aerosol generated with the two feed fuels, diesel fuel and heavy fuel oil, as well as between the aerosol and the feed were revealed. For the aerosol from heavy fuel oil, oxidised species from the CHN and CHS class precursors of the feed were predominant, whereas the CHOx class is predominant in the combustion aerosol from light fuel oil. Furthermore, the complexity of the aerosol increases significantly compared to the feed and incorporating a higher chemical space. Coupling of atmospheric pressure chemical ionisation to gas chromatography was found to be a useful additional approach for characterisation of a combustion aerosol, especially with an automated utilisation of the information from the ultra-high resolution mass spectrometer and the chromatographic separation. PMID- 28657451 TI - Cost-effectiveness of dedicated dietitians for hyperphosphatemia management among hemodialysis patients in Lebanon: results from the Nutrition Education for Management of Osteodystrophy trial. AB - AIM: To assess the cost-effectiveness of nutrition education by dedicated dietitians (DD) for hyperphosphatemia management among hemodialysis patients. MATERIALS AND METHODS: This was a trial-based economic evaluation in 12 Lebanese hospital-based units. In total, 545 prevalent patients were cluster randomized to DD, trained hospital dietitian (THD), and existing practice (EP) groups. During Phase I (6 months), DD (n = 116) received intensive education by DD trained on renal nutrition, THD (n = 299) received care from trained hospital dietitians, and EP (n = 130) received usual care from untrained hospital dietitians. Patients were followed-up during Phase II (6 months). RESULTS: At baseline, EP had the lowest weekly hemodialysis time, and DD had the highest serum phosphorus and malnutrition-inflammation score. The additional costs of the intervention were low compared with the societal costs (DD: $76.7, $21,007.7; EP: $4.6, $18,675.4; THD: $17.4, $20,078.6, respectively). Between Phases I and II, DD showed the greatest decline in services use and societal costs (DD: -$2,364.0; EP: $1,727.7; THD: -$1,105.7). At endline, DD experienced the highest decrease in adjusted serum phosphorus (DD: -0.32; EP: +0.16; THD: +0.04 mg/dL), no difference in quality-adjusted life-years (QALY), and the highest societal costs. DD had a cost-effectiveness ratio of $7,853.6 per 1 mg decrease in phosphorus, compared with EP; and was dominated by THD. Regarding QALY, DD was dominated by EP and THD. The results were sensitive to changes in key parameters. LIMITATIONS: The analysis depended on numerous assumptions. Interpreting the results is limited by the significant baseline differences in key parameters, suggestive of higher baseline societal costs in DD. CONCLUSIONS: DD yielded the greatest effectiveness and decrease in societal costs, but did not affect QALY. Regarding serum phosphorus, DD was likely to be cost-effective compared with EP, but had a low cost-effectiveness probability compared with THD. Regarding QALY, DD was not likely to be cost-effective. Assessing the long-term cost-effectiveness of DD, on similar groups, is recommended. PMID- 28657452 TI - Tuning of the surface biological behavior of poly(L-lactide)-based composites by the incorporation of polyelectrolyte complexes for bone regeneration. AB - Poly(L-lactide)(PLLA)-based composites have been widely used for tissue regeneration. Novel polyelectrolyte complexes (PECs) consisted of carboxymethyl starch sodium (CMS) and chitosan oligosaccharide (COS) was fabricated and evaluated. The results suggested that the CMS/COS-PECs (CC-PECs) distinguished from the original polymers alone, presenting an amorphous structure. Then, the CC PECs/PLLA composites were prepared by varying the relative amount of CC-PECs in the PLLA-matrix, demonstrated by means of the surface morphology, hydrophilicity, water uptake, in vitro degradability and primary cell responses. The results suggested that the CC-PECs physically attached on the PLLA surface enhanced the formation of the surface seepage network, which could target modification of the surface biological behavior of the materials. The phenomena had been evidenced by the performed tests in respect to hydrophilicity, water uptake and degradation in PBS, which also may provide effective support for cell adhesion and proliferation. Further, the CC-PECs/PLLA surfaces clearly promoted the adhesion and proliferation of MC3T3-E1 cells compared with PLLA materials, indicating excellent cytocompatibility. This study suggested that the CC-PECs/PLLA-50 composite with excellent biological behavior could be a promising candidate for bone repair. PMID- 28657453 TI - Tetralogy of Fallot with fifth aortic arch. PMID- 28657454 TI - Causality on longitudinal data: Stable specification search in constrained structural equation modeling. AB - A typical problem in causal modeling is the instability of model structure learning, i.e., small changes in finite data can result in completely different optimal models. The present work introduces a novel causal modeling algorithm for longitudinal data, that is robust for finite samples based on recent advances in stability selection using subsampling and selection algorithms. Our approach uses exploratory search but allows incorporation of prior knowledge, e.g., the absence of a particular causal relationship between two specific variables. We represent causal relationships using structural equation models. Models are scored along two objectives: the model fit and the model complexity. Since both objectives are often conflicting, we apply a multi-objective evolutionary algorithm to search for Pareto optimal models. To handle the instability of small finite data samples, we repeatedly subsample the data and select those substructures (from the optimal models) that are both stable and parsimonious. These substructures can be visualized through a causal graph. Our more exploratory approach achieves at least comparable performance as, but often a significant improvement over state-of-the-art alternative approaches on a simulated data set with a known ground truth. We also present the results of our method on three real-world longitudinal data sets on chronic fatigue syndrome, Alzheimer disease, and chronic kidney disease. The findings obtained with our approach are generally in line with results from more hypothesis-driven analyses in earlier studies and suggest some novel relationships that deserve further research. PMID- 28657455 TI - A joint overdispersed marginalized random-effects model for analyzing two or more longitudinal ordinal responses. AB - Disease severity is a latent concept which should be observed using a measurement tool; it can be useful in assessing disease status both cross-sectionally and longitudinally. Medsger scale is a valid instrument for assessing the systemic sclerosis severity in which the items are categorized from 0 (normal) to 4 (endstage) for each organ system. We simultaneously analyzed two of the Medsger scale items, namely, general system and skin system as two correlated ordinal responses using an overdispersed marginalized random-effects model for longitudinal ordinal data exhibiting an overdispersion pattern. In general, a random-effects approach is implemented to account for the correlation between these two stochastic processes and to make simultaneous inference; our model also accounts for temporal correlations amongst observations taken on the same subject. Another important aspect of our model is its capacity to handle data overdispersion in order to make reliable inference. Last but not least, it is proved that certain parameters in our joint model have marginal interpretations. We investigate the statistical properties of our estimators through extensive simulation study. Finally, the methodology is applied to a data of systemic sclerosis patients. PMID- 28657456 TI - Challenging diagnosis of prosthetic infective endocarditis and para-aortic conduit abscess - the role of multimodality approach. PMID- 28657457 TI - The spectrum of spontaneous coronary artery dissection: illustrated review of the literature. AB - Spontaneous coronary artery dissection or SCAD is a rare and challenging disease that is increasingly diagnosed. It is characterized by a non-traumatic, non iatrogenic separation of the coronary artery wall and occurs predominantly in young and middle-aged women without traditional cardiovascular risk factors. SCAD is often associated with predisposing conditions such as the peripartum period, systemic inflammatory disease and heritable connective tissue disease. More recently, independent investigators have demonstrated an important association with fibromuscular dysplasia. Extreme emotional or physical stress as well as intense hormonal therapy or drug abuse have been pointed out as precipitating factors. The diagnosis of SCAD can be challenging and starts with clinical suspicion. Advanced imaging techniques such as intravascular ultrasound and optical coherence tomography are useful for the differentiation from atherosclerotic disease and are increasingly used for this indication. The proposed treatment in the acute setting is based on findings from single-centre retrospective series: in stable patients with a TIMI-flow >=2 a conservative management is proposed because of the high risk of procedural failure and complications as well as a high probability of spontaneous healing. Long-term treatment is comparable to that in non-SCAD acute coronary syndromes (ACS) but dual antiplatelet therapy should only be started in case of stenting and should be kept as short as possible in patients with vascular Ehlers-Danlos syndrome. Prognosis seems to be better compared to non-SCAD ACS but there is a reasonable risk of recurrence. In this review, we discuss the current knowledge of SCAD and provide a clinical pathway for the diagnosis, management and work-up of SCAD patients. PMID- 28657462 TI - The reception of Gall's organology in early-nineteenth-century Vilnius. AB - Much has been written about the development and reception of Franz Joseph Gall's (1758-1828) ideas in Western Europe. There has been little coverage, however, of how his Schadellehre or organology was received in Eastern Europe. With this in mind, we examined the transmission and acceptance/rejection of Gall's doctrine in Vilnius (now Lithuania). We shall focus on what two prominent professors at Vilnius University felt about organology. The first of these men was Andrew Sniadecki (1768-1838), who published an article on Gall's system in the journal Dziennik Wilenski in 1805. The second is his contemporary, Joseph Frank (1771 1842), who wrote about the doctrine in his memoirs and published an article on phrenology in the journal Bibliotheca Italiana in 1839. Both Frank and Sniadecki had previously worked in Vienna's hospitals, where they became acquainted with Gall and his system, but they formed different opinions. Sniadecki explained the doctrine not only to students and doctors but also to the general public in Vilnius, believing the new science had merit. Frank, in contrast, attempted to prove the futility of cranioscopy. Briefer mention will be made of the assessments of Johann Peter Frank (1745-1821) and Ludwig Heinrich Bojanus (1776 1827), two other physicians who overlapped Gall in Vienna and went to Vilnius afterward. Additionally, we shall bring up how a rich collection of human skulls was used for teaching purposes at Vilnius University, and how students were encouraged to mark the organs on crania using Gall's system. Though organology in Vilnius, as in many other places, was always controversial, it was taught at the university, accepted by many medical professionals, and discussed by an inquisitive public. PMID- 28657464 TI - Body mass index and mortality after acute coronary syndromes: a systematic review and meta-analysis. AB - OBJECTIVE: The association between body mass index (BMI) and mortality after acute coronary syndromes (ACS) is controversial. The objective of this analysis is to summarize the available evidence of this association and perform meta analysis using adjusted estimates. METHODS AND RESULTS: Systematic review from MEDLINE and EMBASE through May 2015 was performed. Studies were considered eligible if they described the association between BMI and all-cause mortality after ACS, and those reporting adjusted estimates were included in the meta analysis. We included 35 articles with 316,455 participants, with overall poor to moderate quality. No study reported that overweight, type-I or type-II obesity was related to an increased risk of mortality compared to normal weight. Pooled adjusted estimates from 18 studies (137,975 participants) showed lower adjusted mortality both overweight (RR: 0.83; 95% CI: 0.75-0.91; p < .001; I2 51%) and obese (RR: 0.79; 95% CI: 0.71-0.88; p < .001; I2 33%) categories when compared to normal weight. Heterogeneity was not explained in pre-specified subgroups analysis. CONCLUSIONS: Increased BMI was associated with increased adjusted survival after ACS when compared to normal BMI. Unexplained heterogeneity and suboptimal quality of studies limit the strength of the results. This seemingly paradoxical finding needs to be confirmed with further research. PMID- 28657463 TI - Transplantation of Human Dental Pulp-Derived Stem Cells or Differentiated Neuronal Cells from Human Dental Pulp-Derived Stem Cells Identically Enhances Regeneration of the Injured Peripheral Nerve. AB - Human dental mesenchymal stem cells isolated from the dental follicle, pulp, and root apical papilla of extracted wisdom teeth have been known to exhibit successful and potent neurogenic differentiation capacity. In particular, human dental pulp-derived stem cells (hDPSCs) stand out as the most prominent source for in vitro neuronal differentiation. In this study, to evaluate the in vivo peripheral nerve regeneration potential of hDPSCs and differentiated neuronal cells from DPSCs (DF-DPSCs), a total of 1 * 106 hDPSCs or DF-hDPSCs labeled with PKH26 tracking dye and supplemented with fibrin glue scaffold and collagen tubulization were transplanted into the sciatic nerve resection (5-mm gap) of rat models. At 12 weeks after cell transplantation, both hDPSC and DF-hDPSC groups showed notably increased behavioral activities and higher muscle contraction forces compared with those in the non-cell transplanted control group. In immunohistochemical analysis of regenerated nerve specimens, specific markers for angiogenesis, axonal fiber, and myelin sheath increased in both the cell transplantation groups. Pretransplanted labeled PKH26 were also distinctly detected in the regenerated nerve tissues, indicating that transplanted cells were well-preserved and differentiated into nerve cells. Furthermore, no difference was observed in the nerve regeneration potential between the hDPSC and DF-hDPSC transplanted groups. These results demonstrate that dental pulp tissue is an excellent stem cell source for nerve regeneration, and in vivo transplantation of the undifferentiated hDPSCs could exhibit sufficient and excellent peripheral nerve regeneration potential. PMID- 28657465 TI - WHY LEOPARDS NEVER CHANGE THEIR SPOTS: A REPLY TO MOSS, TYLER, AND JENNINGS. AB - Laws, Evans, Hodges, and McCarthy (1995) documented a selective impairment for associative knowledge about living things in the post-encephalitic patient SE. By contrast, Moss, Tyler, and Jennings (1997) recently described a selective loss of visual knowledge for living things in the same patient. The apparent contradiction in these papers highlights novel and critical methodological issues in the study of category-specific disorders. A main contention of this paper is that Moss et al.'s data do not meet sufficient conditions for demonstrating a category-specific naming deficit for living things. One implication of this is that their experiments may suffer from a confounding variable that encourages an underestimation of SE's visual knowledge. Finally, it is argued that Moss et al.'s theoretical interpretation of SE's deficit receives no empirical support. PMID- 28657466 TI - AGE-RELATED DEFICITS IN MOTOR LEARNING AND DIFFERENCES IN FEEDBACK PROCESSING DURING THE PRODUCTION OF A BIMANUAL COORDINATION PATTERN. AB - Learning and transfer of a new bimanual coordination pattern were investigated in a group of adolescents and elderly subjects. The pattern consisted of continuous horizontal flexionextension movements with a 90 phase offset between the upper limbs. All subjects practised the task under augmented feedback conditions, involving a real-time orthogonal display of both limb movements. Three different transfer test conditions were administered at regular intervals during practice, i.e. blindfolded, with normal vision, and with augmented visual feedback. Findings showed that the performance levels of the elderly group were lower than the group of adolescents and their rate of improvement was also smaller. The observed learning deficits in the elderly are hypothesised to be a consequence of a decreased capability to overcome the preferred coordination modes, as required for developing new coordination modes. This reduced capability to suppress prepotent response tendencies may reflect an age-related decrease in the efficiency of inhibitory processes in the central nervous system and may be associated with changes in frontal lobe functioning. PMID- 28657467 TI - MEMORY FOR GENERALITIES: ACCESS TO HIGHER-LEVEL CATEGORICAL RELATIONSHIPS IN AMNESIA. AB - This paper presents results from four studies in which the distinction between exemplar and higher-level categorical knowledge was investigated in amnesic patients and non-memory impaired controls. After studying a series of face occupation associations it was found that patients could only discriminate faces at a level of knowledge that was higher in a specified occupational hierarchy than the one studied. This effect was illustrated most clearly in Experiment 1, where patients discriminated the faces of educators from those of tradespeople accurately, but were unable to discriminate between the types of educator and types of tradespeople that they had originally studied. This differentiation in performance between exemplar and more general level knowledge in amnesia is referred to as preserved memory for generality. A similar tendency to discriminate faces at the higher occupational level was observed in Experiment 2, where the study context was changed to include subtypes of teacher and lecturer. For one patient there was some evidence of improvement in ability to discriminate at a level of categorisation that was not accessible in the first experiment (i.e. at the level of teacher/lecturer). In Experiment 3 we investigated the contribution of direct and indirect testing to results of the previous studies. It was found that indirect testing facilitated access to higher-level knowledge. Results of a final study indicated that non-memory-impaired controls also produced superior memory for generalities under suboptimal learning conditions. However, unlike patients, controls performed equally well on direct and indirect tests of higher-level knowledge. These results are discussed with reference to theories of amnesia and to explanations of the phenomenon in dementia. PMID- 28657468 TI - Cooked Chickpea Consumption Inhibits Colon Carcinogenesis in Mice Induced with Azoxymethane and Dextran Sulfate Sodium. AB - SCOPE: The objective of the study was to evaluate the effect of daily consumption of cooked chickpea (2% and 10%) in ICR male mice in which colon cancer was induced with azoxymethane and dextran sulfate sodium. METHODS AND RESULTS: The effect of consumption of 2% or 10% cooked chickpeas on carcinogenesis-induced colon azoxymethane (AOM)/dextran sulfate sodium (DSS) in ICR mice was determined. Protein oxidation and lipids were determined by colorimetric methods and oxidation of DNA through the identification of adducts 8-hydroxy-2' desoxiguanosine and proliferation markers (proliferating cell nuclear antigen [PCNA], Ki-67, and beta-catenin), and inflammation (cyclooxygenase [COX]-2 and inducible nitric oxide synthase [iNOS]) were identified by immunohistochemistry reactions. The results showed the protective effect of daily consumption of rich cooked chickpeas in the carcinogenesis process, decreasing lipid, protein, and DNA oxidation and decreasing the expression of inflammatory enzymes (COX-2 and iNOS) as well as beta-catenin, one of the most important oncogenic proteins in colon cancer. Animals that were fed with the 10% chickpea diet showed an inhibition in cellular proliferation (Ki-67 and PCNA expression). CONCLUSIONS: The addition of cooked chickpea seed (2% and 10%) to the daily diet is proposed as a chemopreventive agent against colon cancer. PMID- 28657469 TI - Perceptions of the influence of computer-mediated communication on the health and well-being of early adolescents. AB - Recent technological advances have provided many youth with daily, almost continuous cell-phone and Internet connectivity through portable devices. Young people's experiences with computer-mediated communication (CMC) and their views about how this form of communication affects their health have not been fully explored in the scientific literature. A purposeful maximum variation sample of young people (aged 11-15 years) across Ontario was identified, using key informants for recruitment. The young people participated in seven focus groups (involving a total of 40 adolescents), and discussed various aspects of health including the health impacts of CMC. Inductive content analysis of the focus group transcripts revealed two overarching concepts: first, that the relationship between health and the potential impacts of CMC is multidimensional; and secondly, that there exists a duality of both positive and negative potential influences of CMC on health. Within this framework, four themes were identified involving CMC and: (1) physical activity, (2) negative mental and emotional disturbance, (3) mindfulness, and (4) relationships. With this knowledge, targeted strategies for healthy technology use that draw on the perspectives of young people can be developed, and can then be implemented by parents, teachers, and youth themselves. PMID- 28657470 TI - Point-of-Care Adipose-Derived Stromal Vascular Fraction Cell Isolation and Expanded Polytetrafluoroethylene Graft Sodding. AB - Adipose-derived stromal vascular fraction (SVF) cell populations are being evaluated for numerous clinical applications. The current study evaluated a point of-care technology, the Tissue Genesis "TGI 1000" Cell Isolation SystemTM, to perform an automated isolation of adipose-derived SVF cells to be used in the fabrication of a tissue-engineered vascular graft in the operating room. A total of seven patients were enrolled in this study and received femoral to tibial expanded polytetrafluoroethylene bypass grafts to treat peripheral arterial disease. Lipoaspiration of fat was performed on five patients, and the fat sample was processed immediately in the automated system in the operating room. The mean processing time, from the point of fat delivery into the instrument to removal of the SVF-containing syringe, was 70 min. The SVF cell population was evaluated for cell yield, cell viability, endotoxin levels, and microbial contamination. Samples of the SVF preparation were further subjected to microbiologic evaluation both microscopically before implantation of the graft and through a microbiologic screening using aerobic and anaerobic culture conditions. Mean cell yield was 1E5 cells per cc of fat, and endotoxin levels were below the FDA recognized standards. All SVF preparations were released for graft preparation, and the intimal surface of 90-cm-long grafts was pressure sodded with cells at a concentration of 2E5 cells/cm2. The sodded grafts (n = 5) and control grafts (n = 2) were immediately implanted and graft patency assessed for 1 year. One year patency was 60% for sodded grafts and 50% for control grafts. Automated preparation of autologous adipose-derived SVF cells for immediate use to create cellular linings on vascular grafts is feasible and safe. PMID- 28657472 TI - Evaluating the effects of exercise on cognitive function in hypertensive and diabetic patients using the mental test and training system. AB - OBJECTIVES: Systemic arterial hypertension (SAH) and diabetes mellitus (DM) are important risk factors for developing cognitive impairment. General life-style changes including physical training are known to reduce elevated blood pressure and sugar levels, as well as improve mental health. The objective of this study was to evaluate whether supervised physical exercise enhances the cognitive status of patients with chronic diseases. METHODS: Volunteers with SAH, DM or SAH + DM participated in either aerobic or resistance training during a period of 12 weeks. Several domains of cognitive functions were evaluated using the mental test and training system before and after the 3 months. RESULTS: Participants with either of these chronic diseases demonstrated significantly improved attention and concentration, but not reaction time, following the supervised exercise. CONCLUSIONS: Structured physical training promotes several aspects of cognitive functions in diabetic and hypertensive patients. PMID- 28657474 TI - 'You have to bow right here': heteronormative scripts and intimate partner violence in women's same-sex relationships. AB - Intimate partner violence is increasingly recognised as occurring not only between heterosexual partners but also in same-sex relationships. Heterogendered relationship norms have been identified as intersecting with other social inequalities to create and sustain power differentials between partners - and fuel violence - yet remain largely unexplored in relation to women's same-sex relationships. Building on existing feminist research we explore the use of gendered scripts in South African lesbian and bisexual women's accounts of relationship norms and practices. We apply a feminist poststructuralist lens to focus-group discussion data to investigate how such scripts are drawn on to either uphold or challenge violent and coercive relationship practices. The findings illustrate the salience of heterogendered norms and demonstrate how violent practices become possible in contexts of deepening socioeconomic impoverishment - such as in post-apartheid South Africa - where race, space, gender and sexuality are tied to attempts at reclaiming respectable personhood. Efforts to dismantle inequitable gendered power relations and attendant violent practices require both macro-interventions aimed at shifting structural constraints on lesbian and bisexual women's agency, as well as micro-processes aimed at scripting equal power relations between partners as desirable. PMID- 28657473 TI - Vonoprazan fumarate for the management of acid-related diseases. AB - INTRODUCTION: Proton pump inhibitors (PPIs) display a number of limitations and unmet clinical needs that have prompted the development of novel drugs to improve the outcomes of acid-related diseases, including the eradication of H. pylori. In this context, a new synthesized potassium-competitive acid blocker (P-CAB), vonoprazan, showed higher suppression of gastric acid secretion. Areas covered: This review discusses the current knowledge regarding the efficacy of vonoprazan in the treatment of acid-related diseases, with a particular focus on its use in Helicobacter pylori eradication. Expert opinion: Vonoprazan showed some advantages over PPIs in terms of the pharmacokinetic and pharmacodynamic profile: fast onset of action without requiring acid activation and specific administration timing, more potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability. Recent evidence suggests that vonoprazan can be preferred to PPIs as maintenance therapy for reflux esophagitis and eradication of Helicobacter pylori owing to its stronger antisecretory effect. Moreover, vonoprazan displays favorable safety and tolerability profiles, even though long-term studies on the effects of vonoprazan are required. PMID- 28657475 TI - Predicting Time Spent in Treatment in a Sample of Danish Survivors of Child Sexual Abuse. AB - The aim of this study was to identify significant predictors of length of time spent in treatment. In a convenience sample of 439 Danish survivors of child sexual abuse, predictors of time spent in treatment were examined. Assessments were conducted on a 6-month basis over a period of 18 months. A multinomial logistic regression analysis revealed that the experience of neglect in childhood and having experienced rape at any life stage were associated with less time in treatment. Higher educational attainment and being male were associated with staying in treatment for longer periods of time. These factors may be important for identifying those at risk of terminating treatment prematurely. It is hoped that a better understanding of the factors that predict time spent in treatment will help to improve treatment outcomes for individuals who are at risk of dropping out of treatment at an early stage. PMID- 28657476 TI - Comparison of Peptide- and Lipid-Based Delivery of miR-34a-5p Mimic into PPC-1 Cells. AB - The microRNA (miRNA) microRNA-34a (miR-34a) regulates a number of genes involved in cell cycle control and is therefore considered to have a high therapeutic potential. MiR-34a expression is often downregulated in cancer cells and its restoration has been shown to exert a tumor-suppressive effect. However, effective and safe delivery of synthetic miRNA analogs into cancer cells remains a challenge. The aim of this study was to evaluate cell-penetrating peptide PepFect (PF)14 as a carrier for delivery of miR-34a-5p into human primary prostate carcinoma-1 (PPC-1) cells. Using microarray expression analysis, we identified a total of 3,283 (1,744 upregulated and 1,539 downregulated) differentially expressed genes in PF14:miR-34a-5p-transfected cells. In comparison, miR-34a-5p delivery with the commercially available lipid-based reagent siPORT-NeoFX (siPORT) had less robust effects on differential expression and affected fewer genes significantly (90 upregulated and 91 downregulated genes). Functional annotation revealed significant enrichment for downregulated genes in processes and pathways associated with the cell cycle and proliferation regulation in PF14:miR-34a-5p-transfected cells. Five genes (ARHGAP1, AXL, CDC25A, FOSL1, and PDGFRA) were identified and validated as relevant quantitative real-time polymerase chain reaction-based markers of miR-34a-5p transfection efficiency. Our experiments revealed novel potential miR-34a-5p targets and demonstrate that PF14 is a reliable transfection reagent for miRNA mimics characterized by high efficiency and low toxicity relative to lipid-based reagents. PMID- 28657477 TI - Re: "Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum" by Alexander et al. (Thyroid 2017;27:315-389). PMID- 28657478 TI - Promoting beliefs in the inalienability of human rights by attributing uniquely human emotions through multiple categorization. AB - The combination of multiple categorization (i.e., the use of multiple criteria to define others) and human identity-the superordinate group of human beings-has recently been highlighted as a method to reduce implicit (i.e., attribution of secondary emotions) and explicit (i.e., attribution of human rights) dehumanization toward Blacks. In two studies aimed to replicate such evidence the mediating role of secondary emotions in explaining the impact of multiple and human categorization in reducing dehumanization was assessed. The role of implicit cognition, such as attribution of secondary emotions in leading people to attribute human rights to minorities, is discussed. PMID- 28657479 TI - First Israeli National Iodine Survey Demonstrates Iodine Deficiency Among School Aged Children and Pregnant Women. AB - BACKGROUND: National data on iodine status in Israel are lacking. Reliance on iodine-depleted desalinated water, the absence of a salt iodization program, and reports of increased use of thyroid medication in Israel suggest that the population's iodine intake is likely inadequate. The aims of this study were therefore to determine the iodine status of Israeli school-age children (SAC) and pregnant women (PW) in a nationally representative sample obtained by a novel approach of using pre-discard urinalysis samples collected from a centralized national laboratory. METHODS: Spot urine samples from 1023 SAC and 1074 PW, representing all regions and major sectors in Israel, were collected during 2016 at the Maccabi Healthcare Services central laboratory. Urinary iodine concentration (UIC) was measured, and the results were analyzed by trimester, sex, region, and sector. RESULTS: SAC were iodine deficient, with a median (interquartile range [IQR]) UIC of 83 MUg/L (52-127 MUg/L); 62% of SAC UICs were below the World Health Organization adequacy range for SAC (100-199 MUg/L). PW were also iodine deficient, with a median (IQR) UIC of 61 MUg/L (36-97 MUg/L); 85% of PW UICs were below the adequacy range for PW (150-249 MUg/L). For both SAC and PW, the median UIC was below the World Health Organization's adequacy range across all sectors, sexes, and districts. Among SAC, the median (IQR) UIC was lower among females (75 MUg/L; 48-119 MUg/L) than males (92 MUg/L; 59-133 MUg/L; p < 0.05). Median UIC values of PW correlated significantly with the median UIC for SAC by sub-district (R2 = 0.3, p < 0.05). CONCLUSIONS: Urine sampling via a centralized national laboratory was efficient and cost-saving. Iodine deficiency in Israeli SAC and PW is a serious public-health concern. A national program of salt iodization and iodine supplementation of PW should be urgently considered. PMID- 28657480 TI - Brain activity, regional gray matter loss, and decision-making in multiple sclerosis. AB - BACKGROUND: Decision-making (DM) abilities deteriorate with multiple sclerosis (MS) disease progression which impairs everyday life and is thus clinically important. OBJECTIVE: To investigate the underlying neurocognitive processes and their relation to regional gray matter (GM) loss induced by MS. METHODS: We used a functional magnetic resonance imaging (fMRI) Iowa Gambling Task to measure DM related brain activity in 36 MS patients and 21 healthy controls (HC). From this activity, we determined neural parameters of two cognitive stages, a deliberation ("choice") period preceding a choice and a post-choice ("feedback") stage reporting decision outcomes. These measures were related to DM separately in intact and damaged GM areas as determined by a voxel-based morphometry analysis. RESULTS: Severely affected patients (with high lesion burden) showed worse DM learning than HC ( t = -1.75, p = 0.045), moderately affected (low lesion burden) did not. Activity in the choice stage in intact insular ( t = 4.60, pFamily-Wise Error [FWE] corrected = 0.034), anterior cingulate ( t = 4.50, pFWE = 0.044), and dorsolateral prefrontal areas ( t = 4.43, pFWE = 0.049) and in insular areas with GM loss ( t = 3.78, pFWE = 0.011) was positively linked to DM performance across patients with severe tissue damage and HC. Furthermore, activity in intact orbitofrontal areas was positively linked to DM-learning during the feedback stage across these participants ( t = 4.49, pFWE = 0.032). During none of the stages, moderately affected patients showed higher activity than HC, which might have indicated preserved DM due to compensatory activity. CONCLUSION: We identified dysregulated activity linked to impairment in specific cognitive stages of reward-related DM. The link of brain activity and impaired DM in areas with MS-induced GM loss suggests that this deficit might be tightly coupled to MS neuropathology. PMID- 28657481 TI - Effectiveness of a Radiographic Anatomy Software Application for Enhancing Learning of Veterinary Radiographic Anatomy. AB - The goal of this study was to determine the effectiveness of an interactive radiology software application that we developed to enhance learning of normal canine radiographic anatomy. All first-year veterinary medical students were eligible to participate in this subject pre-test-post-test experimental design. When presented with the software application, all students had completed two terms of gross anatomy in which the complete anatomy of the dog had been taught using a combination of lectures and laboratory dissections, including radiographic examples. The software application was divided into four body regions: front limb, hind limb, skull/spine, and thorax/abdomen, each with a learning mode and a quiz mode. Quizzes were composed of 15 questions drawn pseudo randomly without repeat from all structures within a region (median 206 structures). Students were initially given the software application with only the quiz mode activated. After completing four quizzes, one for each body region, students were given access to the software application with both learning mode and quiz mode activated. Students were instructed to spend 30 minutes using the learning mode to study the radiographic anatomy of each region and to retake each quiz. Quiz scores after using the learning mode were significantly higher for each body region (p<.001), with a large effect size for all four regions (Cohen's d=0.83-1.56). These results suggest that this radiographic anatomy software application is an effective tool for students to use to learn normal radiographic anatomy. PMID- 28657482 TI - Beyond Competence: Why We Should Talk About Employability in Veterinary Education. AB - The purpose of this article is to explore employability as a complement to competency in defining the overarching objectives of veterinary education. Although the working usage of the term competency has evolved and stretched in recent years, and contemporary competence frameworks have expanded to better reflect the range of capabilities required of a veterinary professional, the potential remains for the dominance of competency-led discourse to obscure the aim of producing not only competent but also successful and satisfied veterinarians. Expanding the educational mission to include employability may provide this broader focus, by stretching the end point, scope, and scale of veterinary education into the crucial transition-to-practice period, and beyond. In this article we review available evidence from multiple stakeholder perspectives and argue that employability expands the focus beyond servicing the needs of the public to better integrate and balance the needs of all the stakeholders in veterinary education, including the graduates themselves. By refocusing the goal of veterinary education to include the richer end point of success, turning the attention to employability could enhance current attribute frameworks and result in veterinarians who not only better meet the needs of those they serve but are also better prepared to experience fulfilling and satisfying careers. Finally, we suggest one educational approach may be to conceptualize competency, professionalism, and employability as overlapping dimensions of the successful veterinary professional. PMID- 28657483 TI - Student-Initiated Feedback Using Clinical Encounter Cards during Clinical Rotations in Veterinary Medicine: A Feasibility Study. AB - Despite its critical role for successful student learning, providing adequate teacher feedback is still a major issue during clinical education. In human medical education, the implementation of clinical encounter cards (CECs) has led to more frequent, timely, and structured teacher feedback. The present study aimed to introduce student-initiated CECs in a veterinary medical setting (clinical rotations). A total of 24 students were randomly assigned to a control group (standard rotations) and an intervention group where they had to ask for teacher feedback using CECs. The feasibility of implementing CECs was evaluated by examining the content of the completed CECs and by using anonymous student and teacher questionnaires. In addition, acceptance of the intervention and changes in feedback behavior were examined from both the teachers' and students' perspectives. Overall, it was shown that using CECs is not only feasible in a veterinary clinical setting but also conducive to more frequent and constructive teacher feedback. However, some teachers postponed completing the CECs due to time pressure, leading to less direct and timely feedback. Moreover, students felt more comfortable asking for feedback from less experienced, younger teachers, and teachers' quantitative ratings and open commentaries seemed to be affected by leniency bias. Finally, a focus group including teachers and students discussed these results in light of their practical experiences. This led to a streamlining of the implementation process and optimizations to facilitate future large-scale implementation. The study has implications for veterinary educators wishing to improve feedback in their institution. PMID- 28657484 TI - Teaching Veterinary Anesthesia: A Survey-Based Evaluation of Two High-Fidelity Models and Live-Animal Experience for Undergraduate Veterinary Students. AB - In veterinary medical education, reduction, replacement, and refinement (the three Rs) must be considered. Three clinical skills in anesthesia were identified as challenging to students: endotracheal intubation, intravenous catheterization, and drug dose calculations. The aims of this project were to evaluate students' perception of their level of confidence in performing these three clinical skills in veterinary anesthesia, to document the extent of students' previous experience in performing these three tasks, and to describe students' emotional states during this training. Veterinary students completed a series of four surveys over the period of their pre-clinical training to evaluate the usefulness of high fidelity models for skill acquisition in endotracheal intubation and intravenous catheterization. In addition, practice and ongoing assessment in drug dose calculations were performed. The curriculum during this period of training progressed from lectures and non-animal training, to anesthesia of pigs undergoing surgery from which they did not recover, and finally to anesthesia of dogs and cats in a neutering clinic. The level of confidence for each of the three clinical skills increased over the study period. For each skill, the number of students with no confidence decreased to zero and the proportion of students with higher levels of confidence increased. The high-fidelity models for endotracheal intubation and intravenous catheterization used to complement the live-animal teaching were considered a useful adjunct to the teaching of clinical skills in veterinary anesthesia. With practice, students became more confident performing drug dose calculations. PMID- 28657485 TI - Factors Associated with Veterinary Clinical Faculty Attrition. AB - Faculty attrition and recruitment for veterinary clinical faculty positions have been reported as significant problems in veterinary medical education. To investigate the factors that may be important in veterinary clinical faculty retention, the perceptions and views of veterinary clinical academic faculty were determined using a web-distributed electronic survey. Responses were dichotomized by whether the respondent had or had not left an academic position and were analyzed for their association with faculty attrition. A total of 1,226 responses were recorded, and results demonstrated that factors other than compensation were associated with veterinary clinical faculty attrition, including departmental culture, work-life balance, and recognition and support of clinical medicine by the administration. Forty-four percent of respondents who had held a faculty appointment reported leaving academia either voluntarily or for non-voluntary reasons such as failure to achieve tenure, retirement, or having their position closed. Attention to correcting deficiencies in workplace culture and professional rewards could be a beneficial means by which to decrease the faculty attrition rates currently observed in clinical academic veterinary medicine. PMID- 28657486 TI - Phylogenetic structure and ancestry of Korean clawed salamander, Onychodactylus koreanus (Caudata: Hynobiidae). AB - Onychodactylus koreanus, a hynobiid salamander species endemic to the Korean Peninsula, can be regarded as a strict ecological specialist, probably vulnerable to anthropogenic environmental modifications and climate change. We used mitochondrial cytochrome b gene to analyze the genetic diversity and phylogenetic structure of O. koreanus from 19 populations collected in an attempt to cover its major distribution within South Korea. A total of 76 haplotypes of O. koreanus obtained in our analyses could be subdivided into three phylogenetic clades, KR, NE and SE. Clade KR haplotypes occur in most of the regions throughout the Korean Peninsula with four distinct subclades (KR I-IV). Clade NE and SE haplotypes were only observed in two populations YY and YS, respectively. Haplotype sharing was scarce even among populations in geographical proximity, and most of the populations were represented by a single clade or subclade, indicating the low level of gene flow among populations. O. koreanus likely originated from the historical southward dispersal of its ancestral lineages following divergence from Chinese O. zhaoermii that was recovered as the sister of O. koreanus in our phylogenetic analysis. Our results have critical implications for the taxonomic status of O. koreanus and its long-term management plan. PMID- 28657487 TI - Delayed Spinal Cord-Brachial Plexus Reconnection after C7 Ventral Root Avulsion: The Effect of Reinnervating Motoneurons Rescued by Riluzole Treatment. AB - Ventral root avulsion induces dramatic loss of the affected spinal cord motoneurons. The neuroprotective effect of riluzole has been previously proven on the injured motoneurons: the vast majority of them can be rescued even when they have no possibility to regenerate their axons. In this study the number of injured motoneurons rescued by riluzole treatment and their capacity to reinnervate the denervated forelimb muscles was investigated. Surgical reconnection with a peripheral nerve graft between the affected spinal cord segment and the C7 spinal nerve was established immediately or with 1- and 3-week delay after avulsion. Avulsion and immediate reconnection of the motoneuron pool to the spinal nerve resulted in moderate reinnervation of the spinal nerve (281 +/- 23 standard error of mean [SEM] retrogradely labeled motoneurons), whereas treatment of the injured motoneurons with riluzole yielded considerably higher numbers of reinnervating motoneurons (548 +/- 18 SEM). Reconnection of the motor pool with the C7 spinal nerve with 1-week delay allowed fewer motor axons to reinnervate their targets in control and riluzole-treated animals (159 +/- 21 vs. 395 +/- 16 SEM). A clinically relevant 3-week delay in reconnection further reduced the number of reinnervating motoneurons (76 +/- 22 SEM), but riluzole pre treatment still enabled a significant number of rescued motoneurons (396 +/- 17 SEM) to regenerate their axons into the C7 spinal nerve. These results show that those injured adult motoneurons that are rescued by riluzole treatment started immediately after the avulsion injury are able to reinnervate their targets even if they are provided with a conduit several weeks after the primary injury. This finding suggests that partial rescue of injured motoneurons with riluzole in patients who suffered a brachial plexus avulsion injury may provide an available pool of surviving motoneurons for late reconnection/reimplantation surgeries. PMID- 28657489 TI - Effect of platelet-rich plasma on rat Achilles tendon healing is related to microbiota. PMID- 28657488 TI - The risks associated with the use of lamotrigine during pregnancy. AB - OBJECTIVE: This paper reviewed the relevant literature on the effects of lamotrigine on pregnancy outcomes to provide useful information regarding lamotrigine use in pregnant women with bipolar disorder. METHODS: A systematic search of electronic databases and other original sources was conducted that examined the effects of lamotrigine on pregnancy outcomes. RESULTS: It is not clear that foetuses of lamotrigine-exposed pregnant women are at higher risk of malformation or neurodevelopmental delay. When treating pregnant women with bipolar disorder, the risks associated with lamotrigine use have to be balanced with the risks of uncontrolled maternal symptoms. The information obtained from our review of psychotropic medications will assist clinicians in managing pregnant women with bipolar disorder. CONCLUSIONS: Although lamotrigine has emerged as the safest mood stabiliser for use during pregnancy based on the clinical evidence thus far, further studies are needed to inform the best clinical practice when treating bipolar disorder in pregnant women. PMID- 28657490 TI - Uncertainty of measurement in andrology: UK best practice guideline from the Association of Biomedical Andrologists. AB - Uncertainty of measurement has become a paramount factor to consider in pathology. In the UK, consideration of uncertainty of measurement is mandatory for medical laboratories who apply to be accredited against ISO15189:2012 via the United Kingdom Accreditation Service. This guideline intends to help those working within diagnostic andrology to better understand the concept of uncertainty, and how it can be applied to semen analysis and post-vasectomy semen analysis. The various areas where uncertainty may exist are identified, and guidance is provided to minimise this uncertainty. This guidance is produced by the Association of Biomedical Andrologists alongside experts in the field of andrology, in order to aid laboratory scientists in understanding and undertaking important tasks that will improve quality of their service. PMID- 28657491 TI - Novel Noninvasive Method of Cerebrovascular Blood Volume Assessment Using Brain Bioimpedance. AB - Cerebrovascular autoregulation (CAR) is the ability of vessels to modulate their tone in response to changes in pressure. As an auto-protective mechanism, CAR is critical in preventing secondary brain injury post-trauma. Monitoring of changes in cerebral blood volume might be valuable in evaluating CAR and response to various therapies. In this study, we utilized an ocular-brain bioimpedance interface to assess real time changes in cerebral blood volume in response to a number of physiological challenges. We hypothesize that changes in brain bioimpedance (dz) would track changes in cerebral blood volume. Anesthetized animals were instrumented for monitoring of intracranial pressure (ICP), mean arterial blood pressure, cerebral perfusion pressure (CPP) and cerebral blood flow (CBF). Bioimpedance was monitored continuously through electrocardiographic electrodes placed over the eyelids. Interventions such as hyperventilation, vasopressor administration, creation of an epidural hematoma, and systemic hemorrhage were used to manipulate levels of ICP, CPP, and CBF. The dz correlated with changes in ICP, CPP, and CBF (r = -0.72 to -0.88, p < 0.0001). The receiver operating characteristic for dz at different thresholds of CPP and CBF showed high impedance performance with area under the curve between 0.80-1.00 (p < 0.003) and sensitivity and specificity varying between 83%-100% and 70%-100%, respectively. Our preliminary tests show that brain bioimpedance as measured through the ocular-brain interface tracks changes in CPP and CBF with high precision and may prove to be valuable in the future in assessing changes in cerebral blood volume and CAR. PMID- 28657492 TI - Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: a randomized, double-blind clinical trial. AB - BACKGROUND: Marfan syndrome (MFS) is a multisystemic hereditary connective tissue disease. Aortic root aneurysms and dissections are the most common and life threatening cardiovascular disorders affecting these patients. Other cardiac manifestations include mitral valve prolapse, ventricular dysfunction and arrhythmias. Medical treatment of cardiovascular features is ultimately aimed at slowing down aortic root growth rate and preventing dissection. Losartan has been proposed as a new therapeutic tool for this purpose. To which extent losartan affects cardiac function has not been studied previously. METHODS: We designed a prospective, double-blind, randomized placebo-controlled trial to evaluate the effect of losartan added to beta-blocker therapy on aortic growth and ventricular function in patients with MFS. Secondary outcomes were aortic dissection, prophylactic aortic surgery and death. RESULTS: Twenty-two patients were enrolled in the trial. There was a mild and similar increase in the aortic root during the 3 years of follow-up in both groups (median 1 mm, IQR [-1-1.5] and 1 mm, IQR [ 0.25-1] in the losartan and placebo group, respectively, p = 1). Diastolic and systolic ventricular function was normal at baseline in both groups and remained stable during the study. One patient in the placebo group presented a subclavian artery dissection during follow-up. CONCLUSION: Losartan on top of beta-blocker therapy has no additional effect on aortic growth or on cardiac function in patients with MFS. Our results are underpowered but are in line with the result from other groups. In order to have a better insight on whether a group of patients could benefit more from losartan therapy, the outcome of an on-going meta-analysis should be awaited. PMID- 28657493 TI - Three-dimensional graphene oxide-coated polyurethane foams beneficial to myogenesis. AB - The development of three dimensional (3D) scaffolds for promoting and stimulating cell growth is one of the greatest concerns in biomedical and tissue engineering. In the present study, novel biomimetic 3D scaffolds composed of polyurethane (PU) foam and graphene oxide (GO) nanosheets were designed, and their potential as 3D scaffolds for skeletal tissue regeneration was explored. The GO-coated PU foams (GO-PU foams) were characterized by scanning electron microscopy and Raman spectroscopy. It was revealed that the 3D GO-PU foams consisted of an interconnected foam-like network structure with an approximate 300 MUm pore size, and the GO was uniformly distributed in the PU foams. On the other hand, the myogenic stimulatory effects of GO on skeletal myoblasts were also investigated. Moreover, the cellular behaviors of the skeletal myoblasts within the 3D GO-PU foams were evaluated by immunofluorescence analysis. Our findings showed that GO can significantly promote spontaneous myogenic differentiation without any myogenic factors, and the 3D GO-PU foams can provide a suitable 3D microenvironment for cell growth. Furthermore, the 3D GO-PU foams stimulated spontaneous myogenic differentiation via the myogenic stimulatory effects of GO. Therefore, this study suggests that the 3D GO-PU foams are beneficial to myogenesis, and can be used as biomimetic 3D scaffolds for skeletal tissue engineering. PMID- 28657494 TI - Interaction of renal failure and dyslipidaemia in the development of calcific aortic valve disease in rats. AB - OBJECTIVE: Calcific aortic valve disease (CAVD) is currently the most common heart valve disease worldwide and is known to be an active process. Both renal failure and dyslipidaemia are considered to be promoting factors for the development of valvular calcifications. The aim of this study is to prospectively evaluate the respective contribution and interaction of renal failure and dyslipidaemia on CAVD in a rat model, using echocardiography and compared with histology. METHODS AND RESULTS: Sixty-eight male Wistar rats were prospectively divided in eight groups, each fed a different diet to induce renal failure alone and combined with hyperlipidaemia or hypercholesterolemia. CAVD was detected and quantified by calibrated integrated backscatter of ultrasound (cIB) and compared with the histological calcium score. The study follow-up was 20 weeks. At the end of the study, the cIB value and the calcium score of the aortic valve were significantly increased in the group with isolated renal failure but not with dyslipidaemia. The combination of renal failure with high cholesterol or high-fat diet did not significantly increase calcifications further. CONCLUSIONS: Renal failure alone does induce aortic valve calcifications in a rat model of CAVD, whereas dyslipidaemia alone does not. The combination of renal failure with dyslipidaemia does not increase calcification further. These findings suggest that a combination of atherosclerotic and calcifying factors is not required to induce aortic valve calcifications in this model. PMID- 28657495 TI - In Silico Structural Studies and Molecular Docking Analysis of Delta6-desaturase in HUFA Biosynthetic Pathway. AB - Fish are an important source of highly unsaturated fatty acids (HUFA) such as eicosapentaenoic acid EPA (20:5 n-3) and docosahexaenoic acid DHA (22:6 n-3) and play a significant role in human nutrition. The fatty acyl delta6-desaturase (Delta6 desaturase) is a rate-limiting enzyme in the biosynthetic pathway of highly unsaturated fatty acids (HUFA) that converts polyunsaturated fatty acids (PUFA) such as linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids into HUFA. In this study, fatty acyl Delta6 desaturase was identified from pangasius (Pangasianodon hypophthalmus) and further analyzed for sequenced-based characterization and 3D structural conformation. Sequenced-based analysis revealed some important secondary information such as physicochemical property. e.g., isoelectric point, extinction coefficient, aliphatic index, and grand average hydropathy, among others, and also post-translational modification sites were identified. An evolutionary-conserved stretch of amino acid residue and a functionally significant conserved structural ancestor, N-terminal cytochrome b5 and membrane FADS-like superfamily, were identified. Protein association analysis showed a high confidence score with acyl-CoA synthetase, elovl5, elovl2, and phospholipase A2. Herein, we report, for the first time, a 3D native structure of Delta6 desaturase protein by homology modeling approach; molecular docking analysis was performed with linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids, which are the two key substrates in the HUFA biosynthetic pathway. This work provides insight into the structural and functional characterization of Delta6 desaturase, which is involved in HUFA biosynthesis as a rate-limiting enzyme. PMID- 28657497 TI - Hesperidin attenuates inflammation and oxidative damage in pleural exudates and liver of rat model of pleurisy. AB - OBJECTIVES: This study investigated the potential anti-inflammatory effect of hesperidin against carrageenan induced pleurisy in rat model. METHODS: Twenty four adult female Wistar rats (350 - 450g) were grouped as follows: Group I: rats were administered saline solution only (Normal control group); Group II: rats were administered saline solution (NaCl 0.9%) orally and injected with carrageenan (Inflammation control group); Group III: rats were administered hesperidin only (Hesperidin group); Group IV: rats were administered hesperidin orally and intrapleurally injected with 2% carrageenan (Inflammation treated with hesperidin group). The exudate volume, total leukocyte count, reactive oxygen species (ROS), myeloperoxidase (MPO),delta-aminolevulinate dehydratase (delta-ALA D), catalase (CAT), superoxide dismutase (SOD), activities as well as non-protein thiol group (NPSH) and thiobarbituric acid reactive substances (TBARS) levels were determined. RESULTS: Pretreatment with hesperidin at a dose of 80 mg/kg orally per day for 21 days, minimized the increase in pleural exudate volume and leucocyte count and modulated the activities of MPO, SOD and CAT, as well as the levels of ROS, NPSH and TBARS in carrageenan-induced rats. CONCLUSION: Our results suggest that hesperidin can elicit its anti-inflammatory action by blocking exudate and leukocyte influx into pleural cavity, inhibiting MPO activity and preventing oxidative damage. PMID- 28657499 TI - Education and hypertension: impact on global cardiovascular risk. AB - BACKGROUND: Improving cardiovascular risk prediction continues to be a major challenge and effective prevention of cardiovascular disease. Accordingly, several studies have recently reported on the role of cardiovascular risk education. This study was designed to evaluate the impact of education on global cardiovascular risk in hypertensive patients. SUBJECTS AND METHODS: The study population consisted of 223 consecutive hypertensive outpatients. Their educational status was categorized according to the number of years of formal education as follows: (1) low education (less than 10 years) and (2) medium-high education (10-15 years). RESULTS: In both groups, cardiometabolic comorbidities, global cardiovascular risk and echocardiographic measurements were analysed. Less educated hypertensive subjects were characterized by a significantly higher prevalence of patients with metabolic syndrome (MetS) (p < .01), greater global cardiovascular risk (p < .001), and a higher consumption of antihypertensive drugs (p < .01) rather than medium-high educated hypertensive subjects. In the same subjects, a significant increase in microalbuminuria (MA) (p < .01) and a significant decrease in E/A (p < .001) ratio was found. Univariate analysis indicated that global cardiovascular risk correlated directly with waist-hip ratio, mean blood pressure, MA, left ventricular mass index, MetS and inversely with education (r = -0.45; p < .001). Education was independently (p < .001) associated with global CV risk. CONCLUSIONS: Our data suggest that education may be considered the best predictor of global cardiovascular risk in hypertensives and thus has to be evaluated in the strategies of hypertension and cardiovascular risk management. PMID- 28657498 TI - Synthesis and Characterization of a Rosmarinic Acid Derivative that Targets Mitochondria and Protects against Radiation-Induced Damage In Vitro. AB - Mitochondrial dysfunction plays an important role in gamma-radiation-induced mediating oxidative stress. Scavenging radiation-induced reactive oxygen species (ROS) can help mitochondria to maintain their physiological function. Rosmarinic acid is a polyphenol antioxidant that can scavenge radiation-induced ROS, but the structure prevents it from accumulating in mitochondria. In this study, we designed and synthesized a novel rosmarinic acid derivative (Mito-RA) that could use the mitochondrial membrane potential to enter the organelle and scavenge ROS. The DCFH-DA assay revealed that Mito-RA was more effective than rosmarinic acid at scavenging ROS. DNA double-strand breaks, chromosomal aberration, micronucleus and comet assays demonstrated the ability of Mito-RA to protect against radiation induced oxidative stress in vitro. These findings demonstrate the potential of Mito-RA as an antioxidant, which can penetrate mitochondria, scavenge ROS and protect cells against radiation-induced oxidative damage. PMID- 28657500 TI - "A Very Steep Climb": Therapists' Perspectives on Barriers to Disclosure of Child Sexual Abuse Experiences for Men. AB - Recent studies indicate that men experience unique barriers to disclosure of child sexual abuse. Blind spots held by mental health providers and social service agencies may inadvertently help produce and sustain these barriers. However, therapists who specialize in treating this population may also hold important insights into the barriers clients face. Because delayed and nondisclosure of child sexual abuse have been associated with negative mental health outcomes for adult survivors, understanding these barriers is critical to improve clinical practice and facilitate help-seeking. Using conventional content analysis, this study examined the perceptions of nine therapists who specialize in the treatment of men who were sexually abused in childhood, many of whom are considered pioneers in the field. Analyses identified nine types of barriers, which were organized into three categories: intrapersonal experience (difficult feelings, lack of language, and self-engagement), social milieu (internalized social stigma, negative responses, social loss or judgment, and masculine identity dissonance), and health care environment (structural barriers, relational challenges with therapists, and unhelpful therapeutic strategies). Implications for future research, clinical training, and clinical practice are discussed. PMID- 28657501 TI - Profiles of law enforcement agency body armor policies-A latent class analysis of the LEMAS 2013 data. AB - The life-saving benefits of body armor have been well-documented, and law enforcement agency (LEA) body armor wear requirements have been cited by police officers as one of the most important reasons for them to wear body armor. However, research on LEAs' policies and practices regarding body armor is scarce. This study examined whether there are different agency-level profiles of various body armor-related policies, and related these body armor policy profiles to agency characteristics, size, location, etc. U.S. LEAs fell into four distinct profiles based on their body armor policies. Close to half of the LEAs had comprehensive coverage of body armor policies in all aspects. However, nearly one in five LEAs had very weak body armor policies in all aspects. The rest of the LEAs split into two groups, each with different strengths and weaknesses on selection, training, fitting, wearing, and inspection policies. Sheriff's offices and smaller LEAs were found to have weaker policies. In contrast, LEAs with a community policing emphasis and those with body armor grants were found to have stronger body armor polices, especially when it comes to mandatory wearing polices. Findings from the study provide a portrait of the current state of LEA body armor policies, and provide guidance for improving LEAs' body armor policies and practices. PMID- 28657502 TI - Brugada-like coved-type electrocardiogram pattern induced by apical right ventricular pacemaker stimulation. PMID- 28657503 TI - Sequence-dependent rotation axis changes in tennis. AB - The purpose of this study was to evaluate the role of rotation axes during a tennis serve. A motion capture system was used to evaluate the contribution of the potential axes of rotation (minimum inertia axis, shoulder-centre of mass axis and the shoulder-elbow axis) during the four discrete tennis serve phases (loading, cocking, acceleration and follow through). Ten ranked athletes (International Tennis Number 1-3) repeatedly performed a flat service aiming at a target on the other side of the net. The four serve phases are distinct and thus, each movement phase seems to be organised around specific rotation axes. The results showed that the limbs' rotational axis does not necessarily coincide with the minimum inertia axis across the cocking phase of the tennis serve. Even though individual serving strategies were exposed, all participants showed an effect due to the cocking phase and changed the rotation axis during the task. Taken together, the results showed that despite inter-individual differences, nine out of 10 participants changed the rotation axis towards the minimum inertia and/or the mass axis in an endeavour to maximise external rotation of the shoulder to optimally prepare for the acceleration phase. PMID- 28657505 TI - UNLEARNING JOHN MAJOR: THE USE OF ERRORLESS LEARNING IN THE REACQUISITION OF PROPER NAMES FOLLOWING HERPES SIMPLEX ENCEPHALITIS. AB - In this study we examined the value of errorless learning as a means of restoring memory for proper names in an individual who had becomedysnomic following herpes simplex encephalitis. In Experiment 1 the errorless learning technique was used to teach the subject (PM) the names of eightpoliticians thathe had forgotten. In evaluating thetechnique, we also examined whether there was any generalisation to the naming of untrained politicians' names that he had also forgotten and whether the technique had any effect on politicians' names he was able to produce at the outset of training. Training was successful in that PM reached criterion on naming the trained faces but there was no recovery of untrained names. Moreover, we also observed inhibition of politicians' name he was able to produce at the outset of the study. Experiment 2 used a similar procedure to teach PM the names of personal friends that he could not remember. However, the technique was modified so as to include a "refresh" trial at the end of each training session for those friends' names he was already able to produce. Errorless learning again facilitated the reacquisition of names but there was no inhibition of names available at the outset. These data illustrate that errorless learning can be used as a means of restoring lost vocabulary but demonstrate how retrieval inhibition is an important element in evaluating overall effectiveness. In addition, the data are discussed in relation to recent theories of memory restoration. PMID- 28657506 TI - PERSEVERATION AND ACTIVATION IN APHASIC SPEECH PRODUCTION. AB - This paper presents a single-case study of the speech production performance of an aphasic subject, CJ. CJ's productions included a large number of perseverations. Perseverated responses comprised real words, nonwords, and subword segments and the majority of them were unrelated to the target items (either by sound or meaning). An analysis of the determinants of perseverate responding revealed that the frequency of the target name was an important factor. Moreover, there appeared to be both a semantic and a phonological basis for perseveration. These results are used to evaluate a recent account of perseveration. PMID- 28657504 TI - Prevalence and Characterization of Thyroid Hemiagenesis in Japan: The Fukushima Health Management Survey. AB - BACKGROUND: Thyroid hemiagenesis is a rare congenital variant characterized by the lack of development of one thyroid lobe with no clinical manifestations. METHODS: This study was performed to determine the prevalence and characteristics of thyroid hemiagenesis in a normal Japanese population. This cross-sectional study was performed from October 9, 2011, to April 30, 2015. In total, 299,908 children and young adults in the Fukushima Health Management Survey were examined to determine the presence of thyroid agenesis or hemiagenesis. Thyroid width, thickness, and length were measured in 292,452 of these subjects. RESULTS: Thyroid agenesis was diagnosed in 13 subjects, and hemiagenesis was detected in 67 subjects (0.02%; 22.3/100,000 individuals). Although there was no significant sex-related difference (p = 0.067), the female:male ratio was 1.67:1.00. Females were significantly dominant in right hemiagenesis, while there was no difference in left hemiagenesis between males and females. The thyroid volumes at the 2.5th and 97.5th percentiles for age and body surface area were determined for each sex. Multivariate regression analysis showed that a large hemithyroid volume was independently associated with the presence of contralateral hemiagenesis (p < 0.001). CONCLUSION: The prevalence of thyroid hemiagenesis in the present study is in agreement with that reported in other countries. The prevalence of right hemiagenesis was higher in females, and the larger contralateral lobe in patients with rather than without hemiagenesis may have been caused by a compensatory feedback mechanism to prevent hypothyroidism. In addition, the prevalence of hemiagenesis, especially right hemiagenesis, may be affected by sex-related factors similar to those in patients with an ectopic thyroid gland. PMID- 28657507 TI - WORD MEANING BLINDNESS REVISITED. AB - Lambon Ralph, Sage, and Ellis (1996) described a patient, JO, who had impaired understanding of written words in the presence of normal comprehension of objects and spoken words.She was able to recognise letters and could differentiate written words from nonwords in lexical decision tasks. JO's ability to read aloud all types of words and nonwords was also intact. Although JO's understanding with silent reading was compromised, her comprehension was dramatically improved when she was permitted to read words aloud. Lambon Ralph et al. interpreted this disorder as due to a partial disconnection of the visual input lexicon from the semantic system and labelled the disorder "word meaning blindness". JO's word meaning blindness resulted from a progressive illness that provided us with an opportunity to investigate the pattern of deterioration in this apparently rare form of dyslexia. Over a period of one year we tested her on three occasions with a battery of neuropsychological tasks designed to assess her comprehension across modalities and her ability to read aloud various words, including words with exceptional spelling-to-sound correspondences. The main finding of this longitudinal assessment was a further reduction in her understanding of written words read silently with a preservation of spoken word comprehension. Throughout the period there was little or no change in JO's ability to read aloud words and nonwords, including exception words. The implications of this pattern for theories that emphasise the role of semantics in reading aloud are discussed. PMID- 28657508 TI - LEXICALISATION IN SPEECH PRODUCTION: EVIDENCE FROM FORM RELATED WORD SUBSTITUTIONS IN APHASIA. AB - One of the major empirical sources of theories of speech production are speech errors in normal speakers. Speech errors occurring during lexicalisation of a concept to be expressed can result in whole-word substitutions that are target related in form and/ or meaning or can appear as nonword productions (neologism). Similar error phenomena have been reported for aphasic patients. The present study describes the aphasic, HZ, who produced mainly form-related word substitutions and neologisms in several single-word processing tasks (picture naming, repetition, and reading aloud). In picture naming, meaning-related substitutions also occurred as well as substitutions that were related both in meaning and form (mixed errors). Three hypotheses of the origin of formal errors were tested: the full interactive activation hypothesis postulating meaning-form interactions, the lexical (form) retrieval hypothesis, and the post-lexical phonological encoding hypothesis. HZ's performance on repetition and reading aloud (tests showed no mixed errors and no effects of imageability and of target frequency on formal errors) failed to support the predictions of the first two hypotheses. However, the phonological encoding hypotheses (enriched by a comprehensionbased editor) could also not account for the data (e.g. for some task-specific asymmetries in the error pattern). Instead, an attempt is made to account for formal and mixed errors by construing word form encoding as an interactively organised component within a two-stage model of lexicalisation. Formal errors are traced back to interactions between lexical forms and sublexical phonological information during the second stage of lexicalisation. Mixed errors occur when lexical forms of the target's semantic competitors are involved in word form encoding. PMID- 28657510 TI - Results of Screening in Familial Non-Medullary Thyroid Cancer. AB - BACKGROUND: Although a family history of thyroid cancer is one of the main risk factors for thyroid cancer, the benefit of screening individuals with a family history of thyroid cancer is not known. METHODS: A prospective cohort study was performed with yearly screening using neck ultrasound and fine-needle aspiration biopsy of thyroid nodule(s) >0.5 cm in at-risk individuals whose relatives were diagnosed with familial non-medullary thyroid cancer (FNMTC). The eligibility criteria were the presence of thyroid cancer in two or more first-degree relatives and being older than seven years of age. Twenty-five kindred were enrolled in the study (12 families with two members affected, and 13 with three or more members affected at enrollment). RESULTS: Thyroid cancer was detected by screening in 4.6% (2/43) of at-risk individuals from families with two members affected, and in 22.7% (15/66) of at-risk members from families with three or more patients affected (p = 0.01). FNMTC detected by screening was characterized by a smaller tumor size (0.7 +/- 0.5 cm vs. 1.5 +/- 1.1 cm; p = 0.006), a lower rate of central neck lymph node metastases (17.6% vs. 51.1%; p = 0.02), less extensive surgery (hemithyroidectomy 23.5% vs. 0%; p = 0.002), and a lower rate of radioactive iodine therapy (23.5% vs. 79%; p < 0.001) compared to those affected at enrollment. CONCLUSIONS: Screening of at-risk family members resulted in earlier detection of low-risk FNMTC and was associated with a less aggressive initial treatment. Screening with thyroid ultrasound should be considered in kindred with three or more family members affected by FNMTC. Since active screening might be associated with the risk of overtreatment, it should be implemented with caution, specifically in elderly individuals. PMID- 28657512 TI - Heat shock proteins and the Na+/H+ exchanger. PMID- 28657511 TI - Validation of American Thyroid Association Ultrasound Risk Assessment of Thyroid Nodules Selected for Ultrasound Fine-Needle Aspiration. AB - OBJECTIVE: The aim of this study was to validate the American Thyroid Association (ATA) sonographic risk assessment of thyroid nodules. METHODS: The ATA sonographic risk assessment was prospectively applied to 206 thyroid nodules selected for ultrasound-guided fine-needle aspiration (US-FNA), and analyzed with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), as well as surgical pathology for the subset undergoing surgical excision. RESULTS: The analysis included 206 thyroid nodules averaging 2.4 cm (range 1-7 cm; standard error of the mean 0.07). Using the ATA US pattern risk assessment, nodules were classified as high (4%), intermediate (31%), low (38%), and very low (26%) risk of malignancy. Nodule size was inversely correlated with sonographic risk assessment, as lower risk nodules were larger on average (p < 0.0001). Malignancy rates determined by cytology/surgical pathology were high 100%, intermediate 11%, low 8%, and very low 2%, which were closely aligned with ATA malignancy risk estimates (high 70-90%, intermediate 10-20%, low 5-10%, and very low 3%). ATA US pattern risk assessment also appropriately predicted the proportion of nodules classified as malignant or suspicious for malignancy through TBSRTC classification-high (77%), intermediate (6%), low (1%), and very low 0%-as well as benign TBSRTC classification-high (0%), intermediate (47%), low (61%), and very low (70%) (p < 0.0001). Malignancy rates of surgically excised, cytologically indeterminate nodules followed ATA sonographic risk stratification (high 100%, intermediate 21%, low 17%, and very low 12%; p = 0.003). CONCLUSION: This prospective study supports the new ATA sonographic pattern risk assessment for selection of thyroid nodules for US-FNA based upon TBSRTC and surgical pathology results. In the setting of indeterminate cytopathology, nodules categorized as atypia of undetermined significance/follicular lesion of undetermined significance with ATA high-risk sonographic patterns have a high likelihood of being malignant. PMID- 28657513 TI - Editorial. PMID- 28657514 TI - NOTE: DOES THE GRAPHEMIC BUFFER PLAY A ROLE IN READING? AB - In this paper, we investigate the reading performance of a patient previously reported as having an impairment at the level of the graphemic buffer (Kay & Hanley, 1994). Despite his spelling problems, this patient is good at reading familiar words, at reading nonwords, and at written lexical decision. This pattern of performance is discussed with respect to Caramazza, Capasso, and Miceli's (1996) recent claim that damage to the graphemic buffer leads to a problem in reading that will be obvious especially when the patient is asked to read nonwords. PMID- 28657515 TI - AGNOSIA WITHOUT PROSOPAGNOSIA OR ALEXIA: EVIDENCE FOR STORED VISUAL MEMORIES SPECIFIC TO OBJECTS. AB - A single-case study is presented of a patient w ith a modality-specific problem in visual object recognition, w hich can be linked to impaired stored descriptions for objects. Performance was poor on tasks requiring naming, semantic decisions, and object decisions to seen objects. Performance on semantic decisions w ith w ords, however, was relatively good, demonstrating that the problem was not due solely to a general semantic impairment. Moreover, in contrast to the impairments in visual object recognition, both face recognition and on-line visual word recognition w ere within normal limits. The data indicate that im pairments of object recognition can be distinguished from impairments of face and visual w ord recognition, even when the problem can be localised within the structural description system for objects. We discuss the im plications of the results for understanding the relations between object, face, and word identification. PMID- 28657516 TI - SPATIO-MOTOR REPRESENTATIONS IN REACHING: EVIDENCE FOR SUBTYPES OF OPTIC ATAXIA. AB - Optic ataxia, a disorder of visually guided reaching, has been attributed to a failure in the transmission of visuospatial information to motor systems. This account fails to explain why many patients w ith optic ataxia misreach only when targets are presented in non-foveal vision, but not w hen targets are view ed directly. We present data from two patients with unusually severe optic ataxia that suggest an alternative account of this relatively com mon pattern of misreaching. DP is utterly unable to reach to targets unless he gazes directly at them. We provide evidence that he is unable to program reaches in appropriate shoulder and hand-centred spatio-motor coordinates, but instead reaches using oculocentric coding. The gaze (and visual attention) of AM is frequently "captured" by his own hand, and his attentional allocation is influenced by the location at which he performs a hand movement. This suggests that he programs eye movements within hand-centred spatial coordinate frames. Taken together, these data suggest that residual reaching in optic ataxia may be enabled by linkage of the systems coding the spatio-m otor actions of the eye and hand. PMID- 28657517 TI - The allocation of valenced concepts onto 3D space. AB - The valence-space metaphor research area investigates the metaphorical mapping of valenced concepts onto space. Research findings from this area indicate that positive, neutral, and negative concepts are associated with upward, midward, and downward locations, respectively, in the vertical plane. The same research area has also indicated that such concepts seem to have no preferential location on the horizontal plane. The approach-avoidance effect consists in decreasing the distance between positive stimuli and the body (i.e. approach) and increasing the distance between negative stimuli and the body (i.e. avoid). Thus, the valence space metaphor accounts for the mapping of valenced concepts onto the vertical and horizontal planes, and the approach-avoidance effect accounts for the mapping of valenced concepts onto the "depth" plane. By using a cube conceived for the study of allocation of valenced concepts onto 3D space, we show in three studies that positive concepts are placed in upward locations and near the participants' body, negative concepts are placed in downward locations and far from the participants' body, and neutral concepts are placed in between these concepts in both planes. PMID- 28657518 TI - SEVEN QUESTIONS ABOUT PURE ALEXIA (LETTER-BY-LETTER READING). AB - I discuss ways in which the subsequent papers offer answers to some basic questions about pure alexia (letter-by-letter reading). Is the disorder a homogeneous one? Is the relevant impairment specific to the reading system or is it a more general visual impairment? What is the nature and the locus of the letter-by-letter reader's impairment, within some functional model of reading? What causes the patients to read letter-by-letter? What contribution does the right hemisphere make? Why is letter-by-letter reading accuracy affected by imageability (concreteness)? Why do some letter-by-letter readers show covert processing and others not? PMID- 28657519 TI - IMPLICIT VS. LETTER-BY-LETTER READING IN PURE ALEXIA: A TALE OF TWO SYSTEMS. AB - Recent studies of pure alexia present a contradictory picture. Despite evidence of impaired letter identification in letter-by-letter readers, some patients are able to carry out lexical decision and other tasks under conditions of rapid presentation, although they are seldom able to identify these stim uli explicitly. We review evidence for both facets of pure alexic performance and offer an accountof this pattern in terms ofright-and left-hemisphere reading mechanisms. Specifically, we suggest that the right hemisphere supports performance in covert reading tasks, and that letter-by-letter reading is the product of the left hemisphere, operating on information transmitted from the right. PMID- 28657520 TI - EXTENT AND LIMITS OF COVERT LEXICAL ACTIVATION IN LETTER-BY-LETTER READING. AB - The occurrence of implicit reading in brain-damaged patients with letter-by letter dyslexia suggests a process of covert lexical activation, whereby lexical access occurs on the basis of parallel letter encoding. The extent and limitations of this process w ere studied by examining masked orthographic and phonological w ord priming as well as orthographic neighbourhood size effects in letter-by-letter reader IH. In Exp. 1, masked repetition priming occurred with primes displayed in a case-alternate format that were show n for 100 m sec (a duration that does not reliably support overt word identification in IH). Under sim ilar exposure conditions, however, prim es that are homophones to the target failed to affect performance, in contrast to neurologically intact observers (Exp. 2). Exp. 3 showed that IH's naming latencies are reduced for words with m any (vs. few) orthographic neighbours. This result suggests that overt word recognition in the patient is not strictly mediated by sequential letter recognition, but rather that it is conjointly affected by covert lexical activation. Relative to neurologically intact subjects, however, the pattern of the neighbourhood size effect shown by IH as a function of word frequency is abnormal and suggests that lexical activation based on the parallel processing of letters is w eakened in the patient compared to normal readers. Overall, results from IH point to a w eak form of activation of abstract orthographic lexical representations on the basis of parallel letter encoding, but no significant degree of phonological access. This account is discussed in relation to other similar proposals seeking an explanation of letter-by-letter dyslexia and of the covert lexical activation phenomena that accompany the disorder. PMID- 28657521 TI - PERCEPTUA.ND LEXICA.ACTORS IN A CAS.F LETTER-BY-LETTER READING. AB - We report the case of a letter-by-letter reader (MJ) who showed normal processing of single letters and who could normally access the orthographic input lexicon when presented with letter names for aural recognition, or when allow ed enough tim e to process a visually presented letter string. However, MJ showed severe difficulties in simultaneously processing multiple letters and other simple visual stimuli. Furthermore, she does not have normal access to lexical orthographic representations and their meanings when stimuli are presented for too brief a time to allow for serial processing of the letter string. We found no evidence of (partial) lexical or semantic access without corresponding recognition of the letters in a word: No signs of implicit reading were observed w hen the input stimuli were controlled for the relevant visual features; "implicit reading" was only obtained under conditions that allowed sophisticated guessing. This pattern of results is interpreted as indicating that LBL reading (at least in MJ) results from damage to prelexical processing mechanisms. In MJ's case, the deficit reflects the degraded transfer of information from a normal visual processing system in the right hemisphere to a normal language processing system in the left hemisphere. PMID- 28657522 TI - PURE ALEXIA AND THE VIEWING POSITION EFFECT IN PRINTED WORDS. AB - In the present article, we investigated the reading ability of CP, a pure alexic patient, using an experimental paradigm that is known to elicit the viewing position effect in norm al readers. The viewing position effect consists of a systematic variation of word recognition performance as a function of fixation location w ithin a word: Word recognition is best when the eyes fixate slightly left from the word centre and decreases when the eyes deviate from this optimal viewing position. A mathematical model (Nazir, O'Regan, & Jacobs, 1991), which provides a good description and quantification of the prototypical shape of the viewing position effect, served to interpret CP's reading performance. The results show ed that, like normal readers, CP was able to process all letters of a w ord in one fixation. However, in contrast to normal readers, reading performance was optimal when CP w as fixating the right half of the word. This somewhat abnormal pattern of performance was due to (1) poor perceptual processing in the right visual field, and (2) poor processing of letters situated towards the end of the word, independent of visual field presentation. A similar pattern of perform ance w as obtained with normal readers under experimental conditions in which lexical know ledge was of restricted use. We suggest that CP's reading impairment stems from a dysfunction in the coupling between incoming visual information and stored lexical information. This dysfunction is thought to uncover a prelexical level of word processing, where letter information is weighted differently as a function of letter position in a word-centred space. PMID- 28657523 TI - VARIETIES OF PURE ALEXIA: THE CASE OF FAILURE TO ACCESS GRAPHEMIC REPRESENTATIONS. AB - We document the case of a patient (GV) w ho, following a left posterior brain lesion, showed a selective and severe deficit in naming visual objects and in reading letters, words, and numerals. Three sets of findings are critical for the interpretation of the patient's alexia. First, despite intact visual processing abilities and preserved ability to recognise the shape and orientation of letters, GV could not determ ine whether a pair of letters had the same name. Second, she should not access the orthographic structure and meaning of visually presented words, although she could access meaning from orally spelled words and she could access orthographic structure from m eaning in w ritten words. Third, GV could access partial semantic information from pictures and Arabic num erals. Based on this pattern of results, we conclude that the form of alexia manifested by our patient results from failure to access the graphemic representations of letters and w ords from normally processed visual input. The findings further suggest that access to letter forms and grapheme representations are sequentially ordered stages of processing in word recognition. The results also suggest that graphemic processing may be a distinct property of the left hemisphere. PMID- 28657524 TI - A LITERATURE REVIEW AND NEW DATA SUPPORTING AN INTERACTIVE ACCOUNT OF LETTER-BY LETTER READING. AB - We present a theoretical account of letter-by-letter reading (LBL) that reconciles discrepant findings associated with this form of acquired dyslexia. We claim that LBL reading is caused by a deficit that affects the normal activation of the orthographic representation of the stimulus. In spite of this lower-level deficit, the degraded orthographic information may be processed further, and lexical, semantic, and higher-order orthographic information may still influence the reading patterns ofthese patients.In supportof our position, w e present a review of 57 published cases of LBL reading in w hich w e demonstrate that a peripheral deficit was evident in almost all of the patients and that, simultaneously, strong effects oflexical/ semantic variables were observed on reading performance. We then go on to report findings from an empirical analysis of seven LBL readers in whom w e document the joint effects of lexical variables (word frequency and im ageability) and word length on naming latency. We argue that the reading perform ance of these patients reflects the residual functioning of the same interactive system that supported normal reading premorbidly. PMID- 28657525 TI - [Is Aging Sonication in Children Morally Ethical?] PMID- 28657526 TI - Useful of Tokyo guidelines in the diagnosis of acute cholecystitis. Anatomopathologie correlationship. AB - BACKGROUND: In the year 2007 a group of experts come together to discuss criteria for acute cholecystitis and to establish therapeutic guidelines and states of gravity in this disease. OBJECTIVES: we correlated the criteria of the Tokyo Guidelines 2007 with the anatomopathology study of the surgical specimen. SETTING: Service of Urgencies of the National Clinic Hospital in Cordoba, Argentine. METHODS: We studied 324 patients (120 male and 204 female) older than 15 years and without limits of age with the criteria of acute cholecystitis a cord to the Tokyo guidelines 2007. 202 patients had a preoperative diagnosis of chronic cholecystitis and 89 of acute cholecystitis, all received cholecystectomy and studied the operative specimen in the anatomopathology department. Anatomopathology criteria for acute cholecystitis were the presence of polimorpho nuclear cells (PMN), for acute exacerbation of chronic cholecystitis the presence of PMN and monomorpho nuclear cells (MN), and for chronic cholecystitis the presence of MN with or without fibrosis. RESULTS: This work showed 82,14% of sensitivity for the diagnostic criteria of Tokyo guidelines, 74,03% of specificity, and positive predictive value of 46%. With the Bayes Theorem the predictive value in Cordoba city was 18,49%. CONCLUSION: There is an important difference in the specificity and positive predictive value between our work and the Tokyo guidelines for acute cholecystitis. There is an important group of patients in our work with acute exacerbation of chronic cholecystitis that is not classified in the diagnostic criteria for acute cholecystitis of Tokyo guidelines. PMID- 28657527 TI - [Behavior of predictive variables of exacerbations of the COPD in the neumological hospital of Cuba.] AB - The use of predictive variables of exacerbations of the COPD is not a practice generalized in our environment, for what we cannot characterize the exacerbating patient neither to design strategies for its integral handling. There was carried out a prospective descriptive study to correlate in patient with diagnosis of COPD from the Neumologic Hospital of Cuba, with the objective of determining the association between clinical, functional variables and imagenological and the exacerbations frequency a year. The population was constituted for patients with clinical diagnosis of COPD and the sample for those patients with confirmed diagnosis that they completed the inclusion approaches. The correlation among the variables was carried out by means of the Coefficient of Correlation of Pearson with an interval of Trust of 95% and the test t student with a significance level (p) smaller than 0.05. 81.82% of the very serious patients are exacerbating with emphysema. 75% of the patients with index of the lung artery / aorta have more than two exacerbations a year. 84.61% of the patient exacerbating presented degree four of the dyspnea. The half pressure of the lung artery next to the VEF1 constituted the best exacerbations predictors in the group of studied patients. PMID- 28657528 TI - IL-6, MMP 3 and prognosis in previously healthy sepsis patients. AB - Sepsis and septic shock are clinical conditions with high mortality despite advances in technology and are the leading cause of death in intensive care. Clinical manifestations and morbidity may be attributable to a disproportionate increase in proinflammatory cytokines. The aim of this study was to evaluate the ability to predict mortality from interleukin 6 [IL-6] and matrix metalloproteinase 3 [MMP-3]. This single-center, observational, prospective study included 48 adult patients admitted to the Hospital Nacional de Clinicas in Cordoba, Argentina, with sepsis or septic shock. Serum levels of IL-6 and MMP-3 were measured at the time of diagnosis and 72 hours later. At time of admission, MMP-3 was 13.77 mg/ml in patients who died and 10.55 mg/ml in patients who survived up to 28 days after hospitalization [p = 0.012], while IL-6 did not differ between the groups. The change in IL-6 over 72 hours was increased in nonsurvivors by 21.11 +/- 11.81 pg/ml and decreased in survivors by 40.87 +/- 14.94 pg/ml [p = 0.007]. No difference in the change of MMP-3 over 72 hours was observed between survivors and nonsurvivors. This study shows that MMP-3 at admission and the change in IL-6 over the first 72 hours of hospitalization could provide prognostic information in septic patients. Further studies are needed to define the utility of these cytokines as a measure of sepsis severity and as predictors of mortality. PMID- 28657529 TI - Comparison of the efficacy and tolerability of chondroitin plus glucosamine and D 002 (beeswax alcohols) in subjects with osteoarthritis symptoms. AB - BACKGROUND/AIMS: Osteoarthritis (OA), the commonest joint disorder, is a leading cause of disability. Symptomatic slow-acting drugs for OA (SYSADOA), particularly glucosamine plus chondroitin sulphate (GS/CS), are effective for symptom relief, protect joint cartilage and delay OA progression, with a good safety profile. D 002, a mixture of beeswax alcohols that inhibits both cyclooxygenase and 5 lipoxygenase activities, has been effective in experimental and clinical OA studies, showing also a chondroprotective effect. OBJECTIVES: To compare the effects of D-002 and GS/SC administered for 12 weeks on OA symptoms. METHODS: Participants were randomized to GS/CS (375/300 mg) or 50 mg D-002 once daily for 12 weeks. Symptoms were assessed by the Western Ontario and McMaster Individual Osteoarthritis Index (WOMAC) and the Visual Analogy Scale (VAS) scores. The primary outcome was the reduction of the total WOMAC score. Secondary outcomes included WOMAC pain, stiffness and function scores, VAS score and rescue medication consumption. RESULTS: Of 60 randomized patients, 59 completed the study. D-002 and GS/SC reduced significantly total WOMAC score (72.1% and 78.5%, respectively), and pain, joint stiffness and physical function scores versus baseline. VAS scores decreased significantly with D-002 (76.6%) and GS/SC (76.8%). The reductions, significant from the second week, were enhanced over the trial. Rescue medications were consumed by 3/30 D-002 and 4/30 GS/SC patients. No differences between groups were found. Treatments were well tolerated. CONCLUSIONS: D-002 (50 mg/day) administered for 12 weeks was safe and comparable to GS/SC for alleviating OA symptoms (pain, stiffness, and functional limitation) (RPCEC00000180). PMID- 28657530 TI - [Analysis of tissue bioavailability of total polyphenols by Folin Ciocalteu and Fast Blue BB techniques in organs of BALB/C/c mice]. AB - : Biomedical potential of polyphenols lies in their ability to modulate redox balance and the mechanisms involved in the development of chronic noncommunicable diseases. OBJECTIVE: The aim of this study was to determine the concentration of total polyphenols in different murine organs by assaying analytical techniques of Folin Ciocalteu (FC) and Fast Blue BB (FBBB). METHOD: Balb/c female mice (n>=3) received for 15 days 100 mg/kg/d of extract of Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQB) or Ilex paraguariensis (IP) and control group (treated with water without extract). Polyphenolic concentrations were measured in telencephalon, diencephalon, midbrain, brainstem, cerebellum, spleen, thymus and cardiopulmonary tissue by FC and FBBB methods. Results were compared by ANOVA followed by Tukey test (p<0.05). RESULTS: FBBB method reported higher detections than FC (4.5 fold in telencephalon, 8.4 in midbrain, 5 in brainstem, 7.2 in spleen, 68.5 in thymus and 4 in cardiopulmonary tissue). Regarding the treatments, the group that received AQB showed to have increased polyphenolic bioavailability in brainstem (p<0.02). With FBBB, a decrease on thymic polyphenol content after treatment with IP was detected (p<0.005). In cerebellum of the groups treated with IP and telencephalon of the control group showed significant differences when these were analyzed with FC (p<0.05, p<0.0035 respectively). CONCLUSIONS: FBBB method showed higher estimations of polyphenolic bioavailability than FC, and this could be related to higher specificity of the technique to react with phenolic compounds. PMID- 28657531 TI - [Analysis of nasal cytology in children and adolescents with rhinitis]. AB - BACKGROUND: Nasal cytology in a easy-to apply method to differentiate rhinitis phenotypes from a physiopathogenic and diagnostic perspective. There are controversies about the relationship between clinical severity of rhinitis and inflammatory patterns expressed in the nasal cytology. OBJECTIVES: To study the characteristic of the eosinophil and neutrophil patterns in the nasal scraping for Allergic Rhinitis (AR) and Non Allergic Rhinitis (NAR) and its relationship with the clinical grades of rhinitis established by the Allergic Rhinitis and its Impact on Asthama Guideline (ARIA) Methods: In a observational, cross-sectional study we included patients aged 5 to 18 years presenting symptoms of either allergic (AR) or non- allergic rinitis (NAR) without asthma. Cytology was performed by analyzing nasal scraping obtained from the mucosal surface of the inferior turbinate and samples were stained using thr hematoxylin and eosin stain procedure. Inflammatory patterns between AR and NAR and between clinical grades of rhinitis classified by ARIA guide were compared. RESULTS: A total of 231 patients were included. Patients with AR exhibited higher percentage of eosinophils in nasal cytology than those with NAR (p = 0.0012) but no differences were observed in neutrophil count (p = 0.4011). No differences in the percentage of eosinophils and neutrophils between different grades of AR (p = 0.7342 and p = 0.0797 respectively) and NAR (p = 0.1010 and p = 0.1422 respectively) were observed. CONCLUSION: Eosinophil count in the nasal cytology was useful to differentiate rhinitis with a positive allergen skin test from rhinitis with negative skin test, but as neutrophils count, does not help to distinguish clinical grades of AR and NAR as classified by ARIA. PMID- 28657532 TI - [Human Bocavirus 1: role in the acute respiratory infection and epidemiology in Cordoba, Argentina]. AB - Human bocavirus 1 (HBoV1) is an agent of acute respiratory infection frequent in children. It can cause pneumonia in infants, in the absence of epidemiological risk factors and comorbidities. Well-controlled studies of clinical cases and case series are still useful for the characterization of the clinicoepideiological features of the infection, while research dives on the molecular biology of the virus and the virus-cell relationship allowing to unveil tha natural history of the infection. This article reviews the state of the art and future perspectives on this new human parvovirus and its etiological role in the respiratory pathology. PMID- 28657533 TI - [The ametropias: updated review for non-ophthalmologists physicians]. AB - Refractive errors are caused by a decoupling of the power of convergence of the eye lens, the cornea and lens, which make the rays reaching the eye to focus and generate an image, and the retina, which is the biological photosensitive screen where the image will be transformed into a nerve impulse. These defects include myopia, hyperopia and astigmatism. Presbyopia can also be considered a refractive defect, but of special features, since only affects near vision in patients older than 40 years. By altering the quality of the focused image on the most sensitive area of the retina (the macula), they decrease visual acuity. For their management several options exist, from the use of glasses and contact lenses to surgical correction (refractive surgery). The incidence of certain refractive errors (myopia specifically) has increased in recent decades, some environmental factors related to it have been identified. Some medical management measures have shown a positive effect in controlling its onset and progression. PMID- 28657534 TI - [Mutations in the BCR-ABL1 gene in a peruvian patient with acute lymphoblastic leukemia resistant to therapy]. AB - CONTEXT: The fusion gene BCR-ABL1 is present in at least the fourth part of B cell acute lymphoblastic leukemia adult cases. Patients with this fusion gene are candidates to tyrosine kinase inhibitors treatment, and the response to this therapy can be measure by quantification of BCR-ABL1 transcripts. Some patients relapse because the presence of mutations in the tyrosine kinase domain of BCR ABL1. CASE REPORT: This is a report of a patient with BCR-ABL1 who initially achieved molecular response with imatinib therapy, relapsing after fifteen months. The treatment was changed to dasatinib, but the patient doesn't achieve molecular response. Retrospectively, we analyzed the tyrosine kinase domain of BCR-ABL1 and we found three mutations (E459K, E255K and V299L). CONCLUSIONS: We conclude that gain of mutations during treatment with TKIs has strong impact in the progress of disease, being relevant the detection of BCR-ABL1 mutations in relapsed patients or in case of BCR-ABL1 persistence. PMID- 28657535 TI - [Neurogenic heterotopic ossification]. PMID- 28657536 TI - [Is the scientific name important in medical journals?: Experience in a Colombian university Is the scientific name important in medical journals?] AB - . PMID- 28657537 TI - Psychometric properties of the Internalized Stigma of Mental Illness scale adapted for people who use psychoactive substances. AB - BACKGROUND: People who consume psychoactive substances may experience situations of social stigma on the part of the society in general, and also situations of internalized-stigma derived from their own consumption of substances. The Internalized Stigma of Mental Illness (ISMI) scale has been shown to be valid and reliable to evaluate the internalized-stigma in people with severe mental disorders, but in Argentina there is no a Spanish version of this scale for use with people who use psychoactive substances. The objective of this work was to evaluate the psychometric properties of the Spanish version of the Internalized Stigma of Mental Illness instrument adapted for people who use psychoactive substances. METHOD: The work was carried out on a sample of 200 patients older than 18 years under treatment of rehabilitation by consumption of psychoactive substances in a public institution of the city of Cordoba (Argentina) between the years 2014 and 2016. The instrument used was the Internalized Stigma of Mental Illness (ISMI) previously adapted for use in these groups of patients. It was determined the reliability of the scale through Cronbach's coefficients alpha and factorial structure was analyzed through an exploratory factor analysis. RESULTS: The obtained coefficients showed a high reliability, while in the factorial structure emerged the 4 theoretical dimensions described by Ritsher, namely: social isolation, perceived discrimination, alienation and stereotyping. CONCLUSION: It is concluded that the scale adapted for people who use psychoactive substances is reliable and with an adequate factorial structure. PMID- 28657538 TI - Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring. AB - BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive. OBJECTIVES: The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring. METHODS: Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to 0.5 MUg/kg BW/d (BPA0.5; n=21) or 50 MUg/kg BW/d (BPA50; n=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (n=26). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring. RESULTS: Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels (0.81±0.10 mmol/L compared with 0.57±0.03 mmol/L, females BPA50 p=0.04; 0.81±0.05 mmol/L compared with 0.61±0.04 mmol/L, males BPA0.5 p=0.005) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls (68.2±4.4 number of adipocytes/HPF compared with 55.9±1.5 number of adipocytes/HPF; p=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2±4.4 number of adipocytes/high power field (HPF) compared with 55.3±2.9 number of adipocytes/HPF; p=0.04). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals (69.9±5.1 number of adipocytes/HPF compared with 54.0±3.4 number of adipocytes/HPF; p=0.03). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex. CONCLUSIONS: Developmental exposure to 0.5 MUg/kg BW/d of BPA, which is 8-10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of 4 MUg/kg BW/d and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at 0.5 MUg/kg BW/d were compared with the offspring of unexposed controls. https://doi.org/10.1289/EHP505. PMID- 28657539 TI - Analysis of Temporal Variability in the Short-term Effects of Ambient Air Pollutants on Nonaccidental Mortality in Rome, Italy (1998-2014). AB - OBJECTIVES: The association between short-term air pollution exposure and daily mortality has been widely investigated, but little is known about the temporal variability of the effect estimates. We examined the temporal relationship between exposure to particulate matter (PM) (PM10, PM2.5) and gases (NO2, SO2, and CO) with mortality in a large metropolitan area over the last 17 y. METHODS: Our analysis included 359,447 nonaccidental deaths among >=35-y-old individuals in Rome, Italy, over the study period 1998-2014. We related daily concentrations to mortality counts with a time-series Poisson regression analysis adjusted for long-term trends, meteorology, and population dynamics. RESULTS: Annual average concentrations decreased over the study period for all pollutants (e.g., from 42.9 to 26.6 MUg/m3 for PM10). Each pollutant was positively associated with mortality, with estimated percentage increases over the entire study period ranging from 0.19% (95% CI: 0.13, 0.26) for a 1-Mg/m3 increase in CO (0-1 d lag) to 3.03% (95% CI: 2.44, 3.63) for a 10-MUg/m3 increase in NO2 (0-5 d lag). We did not observe clear temporal patterns in year- or period-specific effect estimates for any pollutant. For example, we estimated that a 10-MUg/m3 increase in PM10 was associated with 1.16% (95% CI: 0.53, 1.79), 0.99% (95% CI: 0.23, 1.77), and 1.87% (95% CI: 1.00, 2.74) increases in mortality for the periods 2001-2005, 2006 2010, and 2011-2014, respectively, and corresponding estimates for a 10-MUg/m3 increase in NO2 were 4.20% (95% CI: 3.15, 5.25), 1.78% (95% CI: 0.73, 2.85), and 3.32% (95% CI: 2.03, 4.63). CONCLUSIONS: Mean concentrations of air pollutants have decreased over the last two decades in Rome, but effect estimates for a fixed increment in each exposure were generally consistent. These findings suggest that there has been little or no change in the overall toxicity of the air pollution mixture over time. https://doi.org/10.1289/EHP19. PMID- 28657540 TI - Identification of an 88-microRNA signature in whole blood for diagnosis of hepatocellular carcinoma and other chronic liver diseases. AB - Hepatocellular carcinoma (HCC) is a common cancer with very poor survival due to lack of reliable biomarker for early diagnosis. In this study, we investigated microRNA (miRNA) profile of whole blood with a custom microarray containing probes for 1849 miRNA species in a total 213 successive subjects who were divided into a discovery set and a validation set. An 88-miRNA signature was established to diagnose health controls (HC), chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC with 100% accuracy in the discovery set using Fisher discriminant analysis. This diagnostic signature was confirmed in the validation set with accuracy rates of 100%, 95.2%, 93.7% and 98.4% for HC, CHB, LC and HCC patients, respectively. Compared with AFP, the only available non-invasive and routinely used biomarker for diagnosis of HCC, the 88-miRNA signature has much higher accuracy (99.5% vs 76.5%), sensitivity (100% vs 63.8%), and specificity (99.2% vs 84.2%). More importantly, the signature detects small HCCs (<3cm) with 100% (17/17) accuracy while AFP has only 64.7% (11/17). In conclusion, we have identified a powerful and sensitive blood 88-miRNA signature for diagnosing early HCC and other chronic liver diseases (CHB and LC) with a high accuracy. PMID- 28657541 TI - CircRNA_100269 is downregulated in gastric cancer and suppresses tumor cell growth by targeting miR-630. AB - Although CircRNA_100269 is a biomarker used to predict cancer recurrence, its expression and function in gastric cancer (GC) remain unknown. In this study, the expression of circRNA_100269 and its potential downstream miRNA targets were investigated. The molecular function and regulatory mechanism of circRNA_100269 in GC cell lines were also elucidated. The expression levels of circRNA_100269 and its linear isomer LPHN2 mRNA were found to be downregulated (p<0.01) in GC tissues. The target miRNA was predicted to be miR-630, whose expression was upregulated (p<0.01) and found to be negatively correlated with that of circRNA_100269 (r = -0.688) in GC tissues. Moreover, direct interaction of circRNA_100269 and miR-630 was confirmed through dual-luciferase assays. Overexpressing the circRNA_100269 plasmid inhibited cell proliferation (p<0.05). Furthermore, transfection of miR-630 mimics into cell lines overexpressing circRNA_100269 blocked the function of circRNA_100269 (p<0.05). Thus, circRNA_100269 level was downregulated in GC and correlated negatively with that of miR-630. Taken together, our results suggest that circRNA_100269 and miR-630 comprise a novel pathway that regulates proliferation of GC cells. PMID- 28657542 TI - Tumor suppressors revival in CLL. PMID- 28657543 TI - Melatonin prevents postovulatory oocyte aging and promotes subsequent embryonic development in the pig. AB - Oxidative stress is known as a major contributing factor involved in oocyte aging, which negatively affects oocyte quality and development after fertilization. Melatonin is an effective free radical scavenger and its metabolites AFMK and AMK are powerful detoxifiers that eliminate free radicals. In this study, we used porcine oocytes to test the hypothesis that melatonin could scavenge free radicals produced during oocyte aging, thereby maintaining oocyte quality. We compared reactive oxygen species levels, apoptosis levels, mitochondrial membrane potential ratios, total glutathione contents and expression levels in fresh, aged and melatonin-treated aged porcine oocytes and observed the percentage of blastocyst formation following parthenogenetic activation. We found that melatonin could effectively maintain the morphology of oocytes observed in control oocytes, alleviate oxidative stress, markedly decrease early apoptosis levels, retard the decline of mitochondrial membrane potential and significantly promote subsequent embryonic development in oocytes aged for 24 hr in vitro. These results strongly suggest that melatonin can prevent postovulatory oocyte aging and promote subsequent embryonic development in the pig, which might find practical applications to control oocyte aging in other mammalian species including humans to maintain the quality of human oocytes when performing clinical assisted reproductive technology. PMID- 28657545 TI - BET-inhibitors as sensitizers for BH3-mimetics. PMID- 28657546 TI - Sensitive detection of dopamine via leucodopaminechrome on polyacrylic acid coated ceria nanorods. AB - The major hurdle in detection of dopamine (DA) by electro-analysis is the presence of physiological interferents with a similar oxidation potential of DA. The conventional method is to enlarge the difference of their oxidation potentials. Here, we report an unconventional method to detect DA via leucodopaminechrome on CeO2 nanorods. Leucodopaminechrome is produced from the cyclization of dopamine-quinone, a product of two-electron oxidation of DA. Thus, its concentration is proportional to the DA concentration. Determining DA is demonstrated by measuring the reduction current of leucodopaminechrome on CeO2 nanorods. CeO2 nanorods demonstrate high electrocatalytic activity for reduction of leucodopaminechrome with a low potential at -0.27 V. The low detection potential of leucodopaminechrome can avoid the interference from ascorbic acid (AA) and uric acid (UA). Therefore, detecting DA via leucodopaminechrome is an effective method to avoid interference from AA and UA, and the suggested biosensor also displays good reproducibility and stability. PMID- 28657544 TI - Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. AB - The current study was conducted to investigate the effect of sodium fluoride (NaF) on the oxidative stress and apoptosis as well as their relationship in the mouse liver by using methods of flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, biochemistry and experimental pathology. 240 four-week-old ICR mice were randomly divided into 4 groups and exposed to different concentration of NaF (0 mg/kg, 12 mg/kg, 24 mg/kg and 48 mg/kg) for a period of 42 days. The results showed that NaF caused oxidative stress and apoptosis. NaF-caused oxidative stress was accompanied by increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreasing mRNA expression levels and activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-PX) and glutathione-s-transferase (GST). NaF induced apoptosis via tumor necrosis factor recpter-1 (TNF-R1) signaling pathway, which was characterized by significantly increasing mRNA and protein expression levels of TNF-R1, Fas associated death domain (FADD), TNFR associated death domain (TRADD), cysteine aspartate specific protease-8 (caspase 8) and cysteine aspartate specific protease-3 (caspase-3) in dose- and time dependent manner. Oxidative stress is involved in the process of apoptotic occurrence, and can be triggered by promoting ROS production and reducing antioxidant function. NaF-caused oxidative stress and apoptosis finally impaired hepatic function, which was strongly supported by the histopathological lesions and increased serum alanine amino transferase (ALT), aspartic acid transferase (AST), alkaline phosphatase (AKP) activities and TBIL contents. PMID- 28657547 TI - Frontier molecular orbitals of a single molecule adsorbed on thin insulating films supported by a metal substrate: electron and hole attachment energies. AB - We present calculations of vertical electron and hole attachment energies to the frontier orbitals of a pentacene molecule absorbed on multi-layer sodium chloride films supported by a copper substrate using a simplified density functional theory (DFT) method. The adsorbate and the film are treated fully within DFT, whereas the metal is treated implicitly by a perfect conductor model. We find that the computed energy gap between the highest and lowest unoccupied molecular orbitals-HOMO and LUMO -from the vertical attachment energies increases with the thickness of the insulating film, in agreement with experiments. This increase of the gap can be rationalised in a simple dielectric model with parameters determined from DFT calculations and is found to be dominated by the image interaction with the metal. We find, however, that this simplified model overestimates the downward shift of the energy gap in the limit of an infinitely thick film. PMID- 28657548 TI - Pressure induced effects on the chemical and magnetic structure of spinel MnV2O4. AB - The influence of external pressure (P ? 5 GPa) on both the structural and magnetic ordering in MnV2O4 has been investigated using neutron diffraction technique. The volume and the V-V distance decrease with pressure while the c/a ratio increases, suggesting a lowering of the distortion with pressure. Under ambient conditions this compound exhibits a structural transition (T S) from tetragonal to cubic at ~53 K and a magnetic transition (T N ) at ~56 K. It is found that with an increase in pressure to 5 GPa, T N increases (from 56 K to 80 K), dT N /dP > 0, while T S decreases (from 53 K to 37 K). The non collinear magnetic structure in the tetragonal phase at 5 GPa and 10 K remains the same as at ambient pressure. However, the Mn and V sublattice, now exhibits distinct transition temperatures, [Formula: see text] ~ 80 K, and [Formula: see text] ~ 60 K. The transition to the cubic phase at T S is accompanied by a collinear alignment of the Mn and V spins and a reduction in the Mn moment. The region in which the structure remains in the cubic phase with collinear magnetic structure increases with pressure from ~3 K at ambient pressure to ~43 K at 5 GPa pressure. PMID- 28657549 TI - An effective intracellular delivery system of monoclonal antibody for treatment of tumors: erythrocyte membrane-coated self-associated antibody nanoparticles. AB - Antibody-based drugs have attracted much attention for their targeting ability, high efficacy and low toxicity. But it is difficult for those intrabodies, a kind of antibody whose targets are intracellular biomarkers, to become effective drugs due to the lack of intracellular delivery strategy and their short circulation time in blood. Human telomerase reverse transcriptase (hTERT), an important biomarker for tumors, is expressed only in cytoplasm instead of on cell membrane. In this study, the anti-hTERT blocking monoclonal antibody (mAb), as the model intrabody, was used to prepare nanoparticles (NPs), followed by the encapsulation of erythrocyte membrane (EM), to obtain the EM-coated anti-hTERT mAb NPs delivery system. The final NPs showed a z-average hydrodynamic diameter of about 197.3 nm. The in vitro cellular uptake by HeLa cells confirmed that compared with free anti hTERT mAb, the EM-coated anti-hTERT mAb NPs exhibited a significantly increased uptake by tumor cells. Besides, the pharmacokinetic study confirmed that the EM encapsulation can remarkably prolong the circulation time and increase the area under curve (AUC) of NPs in blood. The EM-coated anti-hTERT mAb NPs exhibited a remarkably decreased uptake by macrophages than uncoated NPs, which may be responsible for the prolonged circulation time and increased AUC. Furthermore, the frozen section of tumor tissue was performed and proved that the EM-coated anti-hTERT mAb NPs can be more effectively accumulated in tumor tissues than the free mAb and uncoated NPs. In summary, this study indicated that EM-coated anti hTERT mAb NPs are an effective delivery system for the long circulation and intracellular delivery of an intrabody, and make it possible for the intracellular biomarkers to become the potential targets of drugs. PMID- 28657550 TI - Pre-treatment patient-specific stopping power by combining list-mode proton radiography and x-ray CT. AB - The relative stopping power (RSP) uncertainty is the largest contributor to the range uncertainty in proton therapy. The purpose of this work was to develop a systematic method that yields accurate and patient-specific RSPs by combining (1) pre-treatment x-ray CT and (2) daily proton radiography of the patient. The method was formulated as a penalized least squares optimization problem (argmin([Formula: see text])). The parameter A represents the cumulative path length crossed by the proton in each material, separated by thresholding on the HU. The material RSPs (water equivalent thickness/physical thickness) are denoted by x. The parameter b is the list-mode proton radiography produced using Geant4 simulations. The problem was solved using a non-negative linear-solver with [Formula: see text]. A was computed by superposing proton trajectories calculated with a cubic or linear spline approach to the CT. The material's RSP assigned in Geant4 were used for reference while the clinical HU-RSP calibration curve was used for comparison. The Gammex RMI-467 phantom was first investigated. The standard deviation between the estimated material RSP and the calculated RSP is 0.45%. The robustness of the techniques was then assessed as a function of the number of projections and initial proton energy. Optimization with two initial projections yields precise RSP (?1.0%) for 330 MeV protons. 250 MeV protons have shown higher uncertainty (?2.0%) due to the loss of precision in the path estimate. Anthropomorphic phantoms of the head, pelvis, and lung were subsequently evaluated. Accurate RSP has been obtained for the head ([Formula: see text]), the lung ([Formula: see text]) and the pelvis ([Formula: see text]). The range precision has been optimized using the calibration curves obtained with the algorithm, yielding a mean [Formula: see text] difference to the reference of 0.11 +/-0.09%, 0.28 +/- 0.34% and [Formula: see text] in the same order. The solution's accuracy is limited by the assumed HU/RSP bijection, neglecting inherent degeneracy. The proposed formulation of the problem with prior knowledge x-ray CT demonstrates potential to increase the accuracy of present RSP estimates. PMID- 28657551 TI - Groupwise registration of MR brain images with tumors. AB - A novel groupwise image registration framework is developed for registering MR brain images with tumors. Our method iteratively estimates a normal-appearance counterpart for each tumor image to be registered and constructs a directed graph (digraph) of normal-appearance images to guide the groupwise image registration. Particularly, our method maps each tumor image to its normal appearance counterpart by identifying and inpainting brain tumor regions with intensity information estimated using a low-rank plus sparse matrix decomposition based image representation technique. The estimated normal-appearance images are groupwisely registered to a group center image guided by a digraph of images so that the total length of 'image registration paths' to be the minimum, and then the original tumor images are warped to the group center image using the resulting deformation fields. We have evaluated our method based on both simulated and real MR brain tumor images. The registration results were evaluated with overlap measures of corresponding brain regions and average entropy of image intensity information, and Wilcoxon signed rank tests were adopted to compare different methods with respect to their regional overlap measures. Compared with a groupwise image registration method that is applied to normal-appearance images estimated using the traditional low-rank plus sparse matrix decomposition based image inpainting, our method achieved higher image registration accuracy with statistical significance (p = 7.02 * 10-9). PMID- 28657552 TI - The neural correlates of the metacognitive function of other perspective: a multiple regression analysis study. AB - Perspective taking is defined as the social cognitive function of imagining the world or imagining oneself from another's viewpoint. Previously, we reported that behavioral activation increased the dorsal medial prefrontal cortex (dmPFC) activation during other perspective self-referential processing for positive words in subthreshold depression, but did not report whether metacognitive function was related to the dmPFC activation. Therefore, we sought to test the relationship between the dmPFC activation during other perspective self referential processing for positive words and an individual's metacognitive evaluation of other perspective. Thirty-four healthy individuals underwent functional MRI scans during a referential task with two viewpoints (self/other) and two emotional valences (positive/negative). Neural activation during other perspective self-referential processing for positive words was correlated with the metacognitive function of participants measured by the Interpersonal Reactivity Index (IRI). We found a positive correlation between the score in perspective taking of the IRI and activation in the dmPFC during other perspective self-referential processing for positive words. The present findings showed that self-report questionnaires assessing participants' metacognitive evaluation of other perspective were correlated with dmPFC activation during positive metacognition of other perspective task. However, we did not conduct a behavioral activation intervention in the present study. The present students were healthy. The IRI is a subjective measure of multidimensional trait empathy. It is necessary to develop an objective measurement for the metacognitive function of other perspective in the near future. PMID- 28657553 TI - The Almost Right Word: The Move From Medical to Health Humanities. AB - Since the emergence of the field in the 1970s, several trends have begun to challenge the original assumptions, claims, and practices of what became known as the medical humanities. In this article, the authors make the case for the health humanities as a more encompassing label because it captures recent theoretical and pedagogical developments in higher education such as the shift from rigid disciplinary boundaries to multi- and interdisciplinary inquiry, which has transformed humanities curricula in health professions. Calling the area of study health humanities also underscores the crucial distinction between medicine and health. Following a brief history of the field and the rationales that brought humanities disciplines to medical education in the first place-the "why" of the medical humanities-the authors turn to the "why" of the health humanities, using disability studies to illuminate those methodologies and materials that represent the distinction between the two. In addition, the authors make note of how humanities inquiry has now expanded across the landscape of other health professions curricula; how there is both awareness and evidence that medicine is only a minor determinant of health in human populations alongside social and cultural factors; and finally, how the current movement in health professions education is towards interdisciplinary and interprofessional learning experiences for students. PMID- 28657554 TI - Meeting ACGME Standards Under a Unified Accreditation System: Challenges for Osteopathic Graduate Medical Education Programs. AB - In 2014, the American Osteopathic Association (AOA) and the American Association of Colleges of Osteopathic Medicine signed a memorandum of understanding (MOU) with the Accreditation Council for Graduate Medical Education (ACGME) to create a unified accreditation system for graduate medical education (GME) under the ACGME. The AOA will cease to accredit GME programs on June 30, 2020. By then, AOA accredited programs need to apply for and achieve ACGME initial accreditation. The terms of the MOU also made it advantageous for some formerly nonteaching hospitals to establish AOA programs, chiefly in primary care, as a step toward future ACGME accreditation.In transitioning AOA programs to the ACGME system, hospitals with osteopathic GME can expect to encounter challenges related to major differences between AOA and ACGME standards. The minimum numbers of residents for ACGME programs in most specialties are greater than those for AOA programs, which will require hospitals that may already be at their federal caps to add additional residency positions. ACGME standards are also more faculty- and staff-intensive and require additional infrastructure, necessitating additional financial investments. In addition, greater curricular specificity in ACGME standards will generate new educational and financial challenges.To address these challenges, hospitals may need to reallocate resources and positions among their current AOA programs, reducing the number of programs (and specialties) they sponsor. It is expected that a number of established and new AOA programs will choose not to pursue ACGME accreditation or will fail to qualify for ACGME initial accreditation. PMID- 28657555 TI - "It Feels Like a Lot of Extra Work": Resident Attitudes About Quality Improvement and Implications for an Effective Learning Health Care System. AB - PURPOSE: The learning health care system promotes development and application of evidence generated within the health care system to enhance the quality of patient care. The purpose of this study was to understand resident attitudes about quality improvement (QI) in Accreditation Council for Graduate Medical Education-approved programs. METHOD: Four focus groups were conducted with 45 residents at the University of Utah School of Medicine during September and October 2014. Residents discussed the perceived value of QI and their experiences with QI. Qualitative analysis was conducted iteratively, resulting in a set of constructs that were then consolidated into overarching themes. RESULTS: Five themes emerged from the qualitative analysis. Four of these represented QI participation barriers: challenges with understanding the vision of QI, confusion about basic aspects of QI, a sense that resident contributions to QI are not valued/valuable to the QI process, and challenges with prioritizing responsibilities relating to QI compared with other responsibilities. One theme represented a facilitator of successful QI: factors that make QI work successfully (e.g., clear goals and a sense of being on the "same page"). CONCLUSIONS: If resident attitudes about QI do not improve, the culture of the learning health care system is threatened. An important step in enhancing the perceived value of QI is resolving the perceived tension between providing excellent patient care and satisfying other goals. Involving residents more effectively in QI may result in improved attitudes and promote development of a better-functioning learning health care system. PMID- 28657556 TI - Unmatched U.S. Allopathic Seniors in the 2015 Main Residency Match: A Study of Applicant Behavior, Interview Selection, and Match Outcome. AB - PURPOSE: The application and interview behaviors of unmatched U.S. allopathic medical school senior students (U.S. seniors) participating in the 2015 National Resident Matching Program (NRMP) Main Residency Match were studied in conjunction with their United States Medical Licensing Examination (USMLE) Step 1 scores and ranking preferences to understand their effects on Match outcome. METHOD: USMLE Step 1 score and preferred specialty information were reviewed for U.S. seniors who responded to the 2015 NRMP Applicant Survey. Unmatched U.S. seniors were categorized as "strong," "solid," "marginal," or "weak" based on the perceived competitiveness of their Step 1 scores compared with U.S. seniors who matched in the same preferred specialty. The numbers of applications sent, interviews obtained, and programs ranked also were examined by Match outcome. RESULTS: Strong unmatched U.S. seniors submitted significantly more applications to achieve and attend approximately the same number of interviews as strong matched U.S. seniors. Strong unmatched seniors ranked fewer programs than their matched counterparts. As a group, unmatched U.S. seniors were less likely than their matched counterparts to rank a mix of competitive and less competitive programs and more likely to rank programs based on their perceived likelihood of matching. A small number of unmatched U.S. seniors would have matched if they had ranked programs that ranked them. CONCLUSIONS: U.S. seniors' Match outcomes may be affected by applicant characteristics that negatively influence their selection for interviews, and their difficulties may be exacerbated by disadvantageous ranking behaviors. PMID- 28657557 TI - Enhancing Student Empathetic Engagement, History-Taking, and Communication Skills During Electronic Medical Record Use in Patient Care. AB - PURPOSE: To examine whether an intervention on proper use of electronic medical records (EMRs) in patient care could help improve medical students' empathic engagement, and to test the hypothesis that the training would reduce communication hurdles in clinical encounters. METHOD: Seventy third-year medical students from the Sidney Kimmel Medical College at Thomas Jefferson University were randomly divided into intervention and control groups during their six-week pediatric clerkship in 2012-2013. The intervention group received a one-hour training session on EMR-specific communication skills, including discussion of EMR use, the SALTED mnemonic and technique (Set-up, Ask, Listen, Type, Exceptions, Documentation), and role-plays. Both groups completed the Jefferson Scale of Empathy (JSE) at the clerkship's start and end. At clerkship's end, faculty and standardized patients (SPs) rated students' empathic engagement in SP encounters, using the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE), and their history-taking and communication skills. RESULTS: Faculty mean ratings on the JSPPPE, history-taking skills, and communication skills were significantly higher for the intervention group than the control group. SP mean ratings on history-taking skills were significantly higher for the intervention group than the control group. Both groups' JSE mean scores increased pretest to posttest, but the changes were not significant. The intervention group's posttest JSE mean score was higher than the control group's, but the difference was not significant. CONCLUSIONS: The findings suggest that a simple intervention providing specialized training in EMR-specific communication can improve medical students' empathic engagement in patient care, history-taking skills, and communication skills. PMID- 28657558 TI - Knee arthroplasty. AB - /. PMID- 28657559 TI - Evolution of TKA design. AB - The use of Total Knee Arthroplasty (TKA) in treatment of chronic degenerative pathologies of the knee boasts of an experience of 50 years. During this period the collaboration between surgeons and engineers produced many developments in the design of the prosthesis. Today this procedure is safe and established even if in continuous development. The progress in technologies and the use of new materials let researches try again old-fashioned techniques from the past in order to be improved. This enthusiasm for those discovers is not always going hand to hand with scientific validation: many open questions remains Every different concept of the design tries to answer to special needs as the reach of the highest ROM, the reduction of pain and debris, articular geometry, the type of fixation, the modularity of augments and stems, the types of constraints, knee kinematic and of course costs. PMID- 28657560 TI - Understanding the human knee and its relationship to total knee replacement. AB - The knee is the intermediate joint of the lower limb and it allows the movement between the femur, tibia and patella. Under normal conditions there is a normal distribution of the load forces on these three articular components in both the static load and during ambulation. The understanding of anatomy and knee biomechanics is important for the gait analysis, the diagnosis of joint diseases and the design and development of prosthetic implants. In the last decades comprehension of knee physiology and kinematics has led to the introduction of a wide range of enhanced prosthetic implant designs for a variety of indications. There are a number of types of total knee arthroplasty implant designs, which are intended to offer the surgeon options for individual patients. The various choices imply that each specific problem has a corresponding implant that provides a reliable solution. However, until the current date, it has not been possible to produce a prosthetic design fully restoring the complex kinematics of the normal knee joint. PMID- 28657561 TI - Total knee replacement: intraoperative and postoperative kinematic assessment. AB - BACKGROUND AND AIM: The main goals of the total knee arthroplasty (TKA) is to reduce the perceived pain and restore knee mobility and function in case of osteoarthritic knees joints. Literature shows how the three major causes of TKA failures are related to wear, loosening and instability and this is due to a problem of imbalance and malalignment. Intraoperative and postoperative kinematics analysis could be of benefit for improving surgery outcome. The aim of the present paper is to give an overview of the two set-up with the highest accuracy for intraoperative and postoperative TKA kinematics evaluation, currently in use at Istituto Ortopedico Rizzoli. Introperative and Postoperative Evaluation: For intraoperative evaluation it has been presented a navigation system with a specifically developed software, while for the postoperative it has been presented the roentgen stereophotogrammetric analysis (RSA). The navigation system consists in a laptop connected with an optoelectronic localizer (Polaris, Northern Digital Inc, Canada). Two reference arrays with passive optical markers and a marked probe are used to localize the knee joint in the 3D space and track the joint kinematics. The RSA is a radiographic technique used in orthopaedic field for measuring micromotion at bone/prosthesis interface or for joint kinematics evaluation. The RSA uses two X-ray sources synchronized with two digital flat-panels. CONCLUSIONS: The present paper shows that using the navigation system allows the surgeon to easily perform kinematic and alignment evaluation during TKA surgery while the RSA allows a quantitative evaluation of the joint kinematics during the recovery time. PMID- 28657562 TI - Patient specific instrumentation in total knee arthroplasty. AB - BACKGROUND AND AIM OF THE WORK: The international literature and analysis of the prosthetic registers highlight a significant relationship between the alignment of the components and the survival of prosthetic implants of the knee. The patient specific instrumentation (PSI) technology exploits the data obtained with the MRN for the production of cutting blocks (CB) useful to a TKA. Revisiting the recent international literature, comparing the results of the conventional method and PSI, numerous studies confirm a statistically significant difference of inliers (+/- 3 degrees) for HKA. The purpose of this retrospective study was to investigate whether these statistically significant difference is also present in our group. METHODS: Postoperative radiographic measures of alignment based on a mechanical limb axis (hip-knee-ankle angle, HKA) of 180 degrees were sought. A range of 180 degrees +/- 3 degrees varus/valgus was defined as optimal for mechanical axis. RESULTS: The percentage of knees that had a HKA within +/-3 degrees of the desired value was 92.2. CONCLUSION: the CB did accurately produce the desired HKA. The PS system is an effective and reproducible, whose organizational effort is fully justified. PMID- 28657563 TI - Medial vs lateral unicompartmental knee arthrroplasty: clinical results. AB - Unicompartmental Knee Arthroplasty (UKA) is a common procedure for the management of isolated osteoarthritis. UKA is considered less invasive compared to total knee arthroplasty, associated with less operative time, blood loss and faster recovery. Isolated lateral osteoarthritis is a relatively uncommon clinical problem, with an incidence about ten times lower than the medial compartment. In fact, lateral UKA are about 5-10% of the total amount of the UKAs. In addition, it's historically considered more challenging and with poorer results. The aim of this paper was to compare current indications, modes of failure, survivorship and clinical results of medial and lateral UKA by a narrative review of the latest literature. PMID- 28657564 TI - Computer assisted total knee arthroplasty: a real navigation to better results? AB - BACKGROUND AND AIM OF THE WORK: Computer assisted surgery in knee replacement is still in discussion, but majority of papers affirm an increase of the accuracy in alignment. Aim of our study is to evaluate the accuracy of mechanical axis, the posterior tibial slope and the femoral component rotation with navigation, x-ray and CT data. METHODS: We have analysed 145 patients who underwent total knee arthroplasty between January 2012 and December 2014. We have checked each patient at 6, 12 and 24 months of follow-up. During each visit, we did a clinical evaluation checking the ROM and a clinical score (KOOS). At 2 years, we did a CT evaluation and a plain x-ray evaluation. RESULTS: 125 patients have completed the follow-up. Mean follow-up time was 2,6 years. Both ROM and KOOS values increased during follow-up. About the mechanical axis, both x-ray and CT data showed a mean deviation <2 degrees from the target. About posterior tibial slope and femoral component rotation, CT data showed a mean deviation of <3 degrees from the target. Mean difference between navigation and CT data was <1 degrees . CONCLUSIONS: According to literature data, our data confirm that computer assisted surgery in knee replacement have a good accuracy of coronal alignment, rotational alignment and posterior tibial slope. PMID- 28657565 TI - Robotic-arm assisted partial knee arthroplasty: a single centre experience. AB - BACKGROUND AND AIM OF THE WORK: UKA has proven to be an effective surgical procedure, but its survivorship is still negatively affected by inaccuracy in component component positioning, implant and limb alignment. Robotic surgery has been introduced in order to minimize such technical errors. The aim of the present paper was to evaluate clinical and surgical outcomes after a 3 years' experience of robotic assisted UKA with the Mako Robotic Arm. METHODS: Seventy three patients undergoing UKA with robotic instrumentation (65 medial UKAs, 8 lateral UKAs) and with a clinical follow-up of 3 -37 months were included in the present study. A complete clinical evaluation with KOOS, FJS-12 and SF-12 was administered to all patients pre and post operatively. Post-operative HKA angle and surgical time were also recorded. RESULTS: Mean post-operative KOOS score was 81.32 (SD 17.19), while the mean FJS-12 score was 75.51 (SD 30.12) and the mean SF-12 Physical Score 42.25 (SD 9.97). 91% to 88% of post-operative results were considered satisfactory. Only 1 UKA failure was reported (1.3%) caused by peri prosthetic infection. In medial UKAs mean postoperative HKA angle in extension was 3.9 degrees varus (SD 2.5 degrees ), with no case of overcorrection; in lateral UKAs mean postoperative HKA angle in extension was 1.9 degrees valgus (SD 1.9 degrees ) with 1 case (13%) of overcorrection. Mean skin to skin surgical time decreased from 83.2 minutes (SD 13.0) to 70.0 minutes (SD 10.9) along the learning curve. CONCLUSIONS: Robotic UKA has provided an improvement both in clinical and technical results, determining satisfactory clinical outcomes and a low risk of post-operative complications. PMID- 28657566 TI - The painful knee after total knee arthroplasty: evaluation and management. AB - Total knee arthroplasty (TKA) is the treatment of choice for end-stage osteoarthritis of the knee. The aging of population and the need to maintain high quality of life have increased the demand for TKA. Although considered a successful procedure, 15-30% of patients presenting persistent pain. The management of these patients requires a clinical, laboratory and radiological assessment in order to address the underlying aetiology. There are several causes of pain, divided in joint and non-joint related, which should be diagnosed and treated promptly. Patients with unexplained pain should be treated conservatively since a plausible reason has been identified. PMID- 28657567 TI - Bone scan in painful knee arthroplasty: obsolete or actual examination? AB - : ptic loosening, instability and infection are the major causes of TKA failure. For many years, nuclear medicine (NM) imaging was helpful to frame a painful total joint arthroplasty. The differentiation of septic from aseptic prosthetic loosening is critical. The latest AAOS guidelines to detect periprosthetic joint infection (PJI) restrict the role of NM scintigraphy. On the other hand, several studies suggest that NM imaging plays an important role in the evaluation of patients with painful prosthesis, but its specificity in differentiating aseptic loosening from infection is low. Moreover, scintigraphic exams showed different diagnostic accuracy in TKA compared to total hip arthroplasty (THA). PURPOSE: To assess and discuss current knowledges about the diagnostic value of the various scans in TKA failure alone. METHODS: We perform a pubmed/medline search to identify all papers published in the literature matching the following key words: "total knee arthroplasty", "bone", "scintigraphy", "imaging", "three-phase", "triple-phase", "99mTc-HDP", "99mTc-MDP", "99mTc-hydroxymethane diphosphonate", and "99m Tc-methylenediphosphonate", "leukocyte scanning", "labeled leukocyte scintigraphy", "antigranulocyte", "nuclear medicine", "septic loosening", "aseptic loosening" and "infection". RESULTS: Three phases bone scintigraphy results an early diagnostic screening test or part of the preoperative tests for painful TKA and when PJI is suspected. Instead, leukocyte/bone marrow scintigraphy is superior to other scintigraphic tools in diagnosis of TKA infections. Granulocyte scintigraphy, seems to be an excellent choice when the diagnosis is unclear. Moreover, nuclear diagnostic tests showed different diagnostic accuracy between TKA and THA. CONCLUSIONS: Although nuclear diagnostic tests for THA failure are superior in diagnostic accuracy compared to TKA, NM scintigraphy is still an effective tool in the identification of chronic, low grade PJI. To date, scintigraphic exams have an higher levels of sensitivity, specificity and accuracy. Currently, leukocyte/bone marrow scintigraphy is considered the gold standard for this aim. Nevertheless, further studies are needed to assess and improve the accuracy of the scintigraphic exams in order to discriminate the causes of failure for painful TKA. PMID- 28657568 TI - Metal hypersensitivity after knee arthroplasty: fact or fiction? AB - BACKGROUND AND AIM OF THE WORK: Hypersensitivity to metals in the general population has an incidence of about 15%, and in rising also for the higher number of joint replacements in the last decades. Total Knee Arthroplasty (TKA) represents the most performed orthopaedic procedure during last years, and it seems to be particularly associated with sensitization after surgery. On the other hand, there is a rising amount of patients with painful but well implanted and functioning TKAs: in certain cases, after the exclusion of the most frequent causes of failure, a condition of hypersensitivity may be found, and a revision with anallergic implants is mandatory. The present study is a review of the potential problems related to hypersensitivity in TKA, its possible diagnostic procedures, and the surgical options to date available. METHODS: Medical history, patch testing, and other specific laboratory assays are useful to assess a status of metals hypersensitivity before surgery in subjects undergoing a knee replacement, or even after TKA in patients complaining pain in otherwise well implanted and aligned prostheses. However, few groups worlwide deal with such condition, and all proposed diagnostic protocols may be considered still today conjectural. On the other hand, these represent the most updated knowledge of this condition, and may be useful for both the patient and the orthopaedic surgeon. Once assessed a possible or ascertained allergy to metals, several options are available for primary andr revision knee surgery, in order to avoid the risk of hypersensitivity. RESULTS: A review of the recent publications on this topic and an overview of the related aspects has been made to understand a condition to date considered negligible. CONCLUSIONS: Hypersensitivity to metals has not to be nowadays considered a "fiction", but rather a possible preoperative risk or a postoperative cause of failure of TKA. Crucial is the information of patients and the medical history, associated in suspect cases to laboratory testings. Today in the market several knee implants are available and safe for allergic patients undergoing TKA. PMID- 28657569 TI - Acute periprosthetic knee infection: is there still a role for DAIR? AB - BACKGROUND AND AIM OF THE WORK: Periprosthetic knee infection is a rare complication associated with prosthetic failure; incidence change from 0,4-2% of primary total knee replacement and 5.6% in revisions. Indications for debridment, antibiotics and implant retention (DAIR) are early acute infections or acute delayed infection. Aim of the work is to check if this technique is still a successful in early infections. METHODS: We have analyzed recent literature data on DAIR and all DAIR procedures in our clinic in the last 10 years, the mean time between onset of symptoms and surgery, the mean antibiotic therapy duration and results we have obtained. We evaluate the diagnostic process and different treatments in early knee periprosthetic infections, especially the DAIR approach. RESULTS: If correct indications are followed, DAIR has a success rate in 31-100% of the cases; if it is applied in late chronic infection the success rate is 28 62%. In our experience DAIR has an 80% success rate: in 20 patients treated with DAIR we had 4 failures. CONCLUSIONS: DAIR can be considered a successful treatment, but it depends from individual patient factors, from the microorganisms involved, from the duration of antibiotic therapy and from correct choice in timing and in execution of DAIR by the orthopedic surgeon. PMID- 28657570 TI - Two-stage revision after total knee arthroplasty. AB - BACKGROUND AND AIM OF THE WORK: Periprosthetic knee infection is a complication associated with prosthetic failure; incidence change from 0,4-2% of primary total knee replacement and 5,6% in revisions; incidence is increasing over the years. Two-stage revision is the technique used in chronic infection. Aim of the work is to check success rate in our data. Methods. We analyzed retrospectively data of patients who undergone two stage revision surgery between 01/01/2010 to 31/12/2015. We made a clinical and radiological control after 1, 3, 6, 12, 24 months and we evaluate the outcome in December 2016. Results. Between 2010 and 2015 we treated 45 patients with two-stage revision. Mean follow-up was 3,4 years. Success rate is 89,9%. We had failure in 5 patients: everyone had knee surgery before first knee arthroplasty and Charlson Comorbidity Score was greater then 4 in 4 cases. Conclusions. Two stage revision can be considered a successful treatment in chronic periprosthetic knee infection. It has an optimal success rate, but it has some disadvantages as joint stiffness and pain in the interval between stages. This is a technique with two major surgery procedure with associated morbidity, discomfort, cost and prolonged stay in hospital. PMID- 28657571 TI - Management of metaphyseal bone loss in revision knee arthroplasty. AB - BACKGROUND AND AIM OF THE WORK: Revision total knee arthroplasty (TKA) is usually made more complex by the presence of bone defects, which may be caused by periprosthethic infection, polyethylene wear, implant loosening or fractures. The main aim of the present work is to review the available literature to understand the current options to manage with the bone loss during knee revisions. METHODS: Available English literature for bone defects in revision TKAs has been evaluated looking at treatment options and their results in terms of clinical and radiological outcomes and failure rates. RESULTS: Anderson Orthopaedic Research Institute (AORI) classification is the most frequently used because it helps in the choice of the most suitable treatment. Several options are available in the management of metaphyseal bone loss in revision knee arthroplasty. For small and contained defects (AORI type 1) cement with or without screws and auto- or allograft morcellized bone are available. In uncontained but mild defects (AORI type 2A) metal augments should be use while large and uncontained defects (AORI type 2B and 3) are best addressed with structural allograft or metal filling devices (cones and sleeves). Stemmed components, either cemented or cementless, are recommended to reduce the strain at the interface implant-host. CONCLUSIONS: The treatment of bone defects in revision TKAs has evolved during the last years providing different options with good results at a short/medium term follow up. With the increasing revision burden, further scientific evidence is requested to identify the best approach for each patient. Long-term clinical outcome as well as implant survival after revision TKA are still sub-optimal and depend upon many factors including cause for revision, surgical approach, type of implants used and various patient factors. PMID- 28657572 TI - Varus-valgus constrained implants in total knee arthroplasty: indications and technique. AB - Total knee arthroplasty is a successful operation that significantly improves patient's quality of life. However, studies demonstrated as only 82% to 89% of patients are satisfied with their surgery, being the other disappointed with regard to their expectations. Two to 5.7% of total knee arthroplasties (TKAs) require revision within 5 years. Both complex primary cases and revision TKA often necessitate for a higher degree of constrain than cruciate retaining or postero-stabilized implant design. In the 1970s varus-valgus constrained (VVC) or semi-constrained implants have been developed by Insall and associates from the PS design, which provide varus-valgus stability preserving a fair amount of host bone. VVC TKAs allows for a small amount of movement in the coronal, antero posterior and axial planes. In this paper, the authors give an overview of the indications, outcomes and technique for varus-valgus constrained implants, both in the setting of primary and revision knee arthroplasty. PMID- 28657573 TI - Periprosthetic knee fractures. A review of epidemiology, risk factors, diagnosis, management and outcome. AB - BACKGROUND AND AIM OF THE WORK: Periprosthetic knee fractures incidence is gradually raising due to aging of population and increasing of total knee arthroplasties. Management of this complication represents a challenge for the orthopaedic surgeon. Aim of the present study is to critically review the recent literature about epidemiology, risk factors, diagnosis, management and outcome of periprosthetic knee fractures. METHODS: A systematic search of Embase, Medline and Pubmed was performed by two reviewers who selected the eligible papers favoring studies published in the last ten years. Epidemiology, risk factors, diagnostic features, clinical management and outcome of different techniques were all reviewed. RESULTS: 52 studies including reviews, meta-analysis, clinical and biomechanical studies were selected. CONCLUSIONS: Correct clinical management requires adequate diagnosis and evaluation of risk factors. Conservative treatment is rarely indicated. Locking plate fixation, intramedullary nailing and revision arthroplasty are all valuable treatment methods. Surgical technique should be chosen considering age and functional demand, comorbidities, fracture morphology and location, bone quality and stability of the implant. Given the correct indication all surgical treatment can lead to satisfactory clinical and radiographic results despite a relevant complication rate. PMID- 28657574 TI - Megaprosthesis of the knee in tumor and revision surgery. AB - The introduction of multidisciplinary approach with chemo and radiotherapy, the advances in surgical and the improvements of diagnostic techniques allowed limb salvage surgery in most cases of bone sarcomas instead of amputation. Modular megaprostheses are the most common method of reconstruction after segmental resection of the long bones in the extremities for their availability, immediate fixation, early weight bearing, good function. Despite the advances in materials and implant designs, these systems have an high incidence of complications. Aim of this study was to report the experience on mega-prostheses implanted around the knee in tumor and revision surgery to analyze: the most frequent used current systems, the problems of stems fixation, extensor mechanism reconstructions in proximal tibia resections and the preservation of growth of the lower extremity in children. PMID- 28657575 TI - Perioperative pain management in fast-track knee arthroplasty. AB - /. PMID- 28657576 TI - Nortriterpenoids from the Fruiting Bodies of the Mushroom Ganoderma resinaceum. AB - Ganoderma resinaceum is usually used as ethnomedicine for immune-regulation, hyperglycemia, and liver disease. To date, only a few chemical constituents have been reported from G. resinaceum. In this study, fifteen nortriterpenoids including six new nortriterpenoids (1-6) and nine known analogs (7-15), were separated and purified from the fruiting bodies of G. resinaceum. New compounds were identified as lucidone I (1), lucidone J (2), lucidone K (3), lucidone I (4), ganosineniol B (5), and ganosineniol C (6), based on analysis of extensive spectroscopic data (high resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), infrared (IR), and ultraviolet (UV)). The known compounds were assigned as lucidone A (7), lucidone B (8), lucidone H (9), lucidone E (10), lucidone F (11), lucidone D (12), lucidone C (13), ganoderense F (14), and ganosineniol A (15), by comparing their spectroscopic data with those reported in the literature. Compounds 3, 4, and 7-13 were examined for alpha-glucosidase inhibitory activity and display no significant activity, but the finding may support that the side chain of ganoderma triterpenoids played an important role in alpha-glucosidase inhibitory activity. PMID- 28657577 TI - SLAE-CPS: Smart Lean Automation Engine Enabled by Cyber-Physical Systems Technologies. AB - In the context of Industry 4.0, the demand for the mass production of highly customized products will lead to complex products and an increasing demand for production system flexibility. Simply implementing lean production-based human centered production or high automation to improve system flexibility is insufficient. Currently, lean automation (Jidoka) that utilizes cyber-physical systems (CPS) is considered a cost-efficient and effective approach for improving system flexibility under shrinking global economic conditions. Therefore, a smart lean automation engine enabled by CPS technologies (SLAE-CPS), which is based on an analysis of Jidoka functions and the smart capacity of CPS technologies, is proposed in this study to provide an integrated and standardized approach to design and implement a CPS-based smart Jidoka system. A set of comprehensive architecture and standardized key technologies should be presented to achieve the above-mentioned goal. Therefore, a distributed architecture that joins service oriented architecture, agent, function block (FB), cloud, and Internet of things is proposed to support the flexible configuration, deployment, and performance of SLAE-CPS. Then, several standardized key techniques are proposed under this architecture. The first one is for converting heterogeneous physical data into uniform services for subsequent abnormality analysis and detection. The second one is a set of Jidoka scene rules, which is abstracted based on the analysis of the operator, machine, material, quality, and other factors in different time dimensions. These Jidoka rules can support executive FBs in performing different Jidoka functions. Finally, supported by the integrated and standardized approach of our proposed engine, a case study is conducted to verify the current research results. The proposed SLAE-CPS can serve as an important reference value for combining the benefits of innovative technology and proper methodology. PMID- 28657578 TI - Antioxidants Mediate Both Iron Homeostasis and Oxidative Stress. AB - Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions. PMID- 28657579 TI - Self-Sterilizing Sputtered Films for Applications in Hospital Facilities. AB - This review addresses the preparation of antibacterial 2D textile and thin polymer films and 3D surfaces like catheters for applications in hospital and health care facilities. The sputtering of films applying different levels of energy led to the deposition of metal/oxide/composite/films showing differentiated antibacterial kinetics and surface microstructure. The optimization of the film composition in regards to the antibacterial active component was carried out in each case to attain the fastest antibacterial kinetics, since this is essential when designing films avoiding biofilm formation (under light and in the dark). The antimicrobial performance of these sputtered films on Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) were tested. A protecting effect of TiO2 was found for the release of Cu by the TiO2-Cu films compared to films sputtered by Cu only. The Cu-released during bacterial inactivation by TiO2-Cu was observed to be much lower compared to the films sputtered only by Cu. The FeOx-TiO2-PE films induced E. coli inactivation under solar or under visible light with a similar inactivation kinetics, confirming the predominant role of FeOx in these composite films. By up-to-date surface science techniques were used to characterize the surface properties of the sputtered films. A mechanism of bacteria inactivation is suggested for each particular film consistent with the experimental results found and compared with the literature. PMID- 28657582 TI - Biocompatibility of HbV: Liposome-Encapsulated Hemoglobin Molecules-Liposome Effects on Immune Function. AB - Hemoglobin vesicles (HbVs) are oxygen carriers consisting of Hb molecules and liposome in which human hemoglobin (Hb) molecules are encapsulated. Investigations of HbV biocompatibility have shown that HbVs have no significant effect on either the quality or quantity of blood components such as RBC, WBC, platelets, complements, or coagulation factors, reflecting its excellent biocompatibility. However, their effects on the immune system remain to be evaluated. HbVs might affect the function of macrophages because they accumulate in the reticuloendothelial system. Results show that splenic T cell proliferation is suppressed after injection of not only HbV but also empty liposome into rat, and show that macrophages that internalized liposomal particles are responsible for the suppression. However, the effect is transient. Antibody production is entirely unaffected. Further investigation revealed that those macrophages were similar to myeloid-derived suppressor cells (MDSCs) in terms of morphology, cell surface markers, and the immune-suppression mechanism. Considering that MDSCs appear in various pathological conditions, the appearance of MDSC-like cells might reflect the physiological immune system response against the substantial burden of liposomal microparticles. Therefore, despite the possible induction of immunosuppressive cells, HbVs are an acceptable and promising candidate for use as a blood substitute in a clinical setting. PMID- 28657581 TI - Bacillus amyloliquefaciens SAY09 Increases Cadmium Resistance in Plants by Activation of Auxin-Mediated Signaling Pathways. AB - Without physical contact with plants, certain plant growth-promoting rhizobacteria (PGPR) can release volatile organic compounds (VOCs) to regulate nutrient acquisition and induce systemic immunity in plants. However, whether the PGPR-emitted VOCs can induce cadmium (Cd) tolerance of plants and the underlying mechanisms remain elusive. In this study, we probed the effects of Bacillus amyloliquefaciens (strain SAY09)-emitted VOCs on the growth of Arabidopsis plants under Cd stress. SAY09 exposure alleviates Cd toxicity in plants with increased auxin biosynthesis. RNA-Seq analyses revealed that SAY09 exposure provoked iron (Fe) uptake- and cell wall-associated pathways in the Cd-treated plants. However, SAY09 exposure failed to increase Cd resistance of plants after treatment with 1 naphthylphthalamic acid (NPA) or 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO). Under Cd stress, SAY09 exposure markedly promoted Fe absorption in plants with the increased hemicellulose 1 (HC1) content and Cd deposition in root cell wall, whereas these effects were almost abrogated by treatment with NPA or c-PTIO. Moreover, exogenous NPA remarkably repressed the accumulation of nitric oxide (NO) in the SAY09-exposed roots under Cd stress. Taken together, the findings indicated that NO acted as downstream signals of SAY09-induced auxin to regulate Fe acquisition and augment Cd fixation in roots, thereby ameliorating Cd toxicity. PMID- 28657580 TI - Phytochemicals Targeting Estrogen Receptors: Beneficial Rather Than Adverse Effects? AB - In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERalpha and ERbeta. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors. PMID- 28657583 TI - Epidermal Growth Factor Receptor Signaling Enhances the Proinflammatory Effects of Staphylococcus aureus Gamma-Toxin on the Mucosa. AB - Staphylococcus aureus (S. aureus) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of S. aureus, and are commonly expressed in clinical isolates recovered from menstrual Toxic Shock Syndrome (mTSS) patients. This study set out to investigate the cytotoxic and proinflammatory effects of gamma toxins on vaginal epithelial surfaces. We found that both HlgAB and HlgCB were cytotoxic to cultured human vaginal epithelial cells (HVECs) and induced cytokine production at sub-cytotoxic doses. Cytokine production induced by gamma-toxin treatment of HVECs was found to involve epidermal growth factor receptor (EGFR) signaling and mediated by shedding of EGFR ligands from the cell surface. The gamma-toxin subunits displayed differential binding to HVECs (HlgA 93%, HlgB 97% and HlgC 28%) with both components (HlgAB or HlgCB) required for maximum detectable binding and significant stimulation of cytokine production. In studies using full thickness ex vivo porcine vaginal mucosa, HlgAB or HlgCB stimulated a dose-dependent cytokine response, which was reduced significantly by inhibition of EGFR signaling. The effects of gamma-toxins on porcine vaginal tissue and cultured HVECs were validated using ex vivo human ectocervical tissue. Collectively, these studies have identified the EGFR-signaling pathway as a key component in gamma-toxin-induced proinflammatory changes at epithelial surfaces and highlight a potential therapeutic target to diminish toxigenic effects of S. aureus infections. PMID- 28657584 TI - Tuning Selectivity of Fluorescent Carbon Nanotube-Based Neurotransmitter Sensors. AB - Detection of neurotransmitters is an analytical challenge and essential to understand neuronal networks in the brain and associated diseases. However, most methods do not provide sufficient spatial, temporal, or chemical resolution. Near infrared (NIR) fluorescent single-walled carbon nanotubes (SWCNTs) have been used as building blocks for sensors/probes that detect catecholamine neurotransmitters, including dopamine. This approach provides a high spatial and temporal resolution, but it is not understood if these sensors are able to distinguish dopamine from similar catecholamine neurotransmitters, such as epinephrine or norepinephrine. In this work, the organic phase (DNA sequence) around SWCNTs was varied to create sensors with different selectivity and sensitivity for catecholamine neurotransmitters. Most DNA-functionalized SWCNTs responded to catecholamine neurotransmitters, but both dissociation constants (Kd) and limits of detection were highly dependent on functionalization (sequence). Kd values span a range of 2.3 nM (SWCNT-(GC)15 + norepinephrine) to 9.4 MUM (SWCNT-(AT)15 + dopamine) and limits of detection are mostly in the single-digit nM regime. Additionally, sensors of different SWCNT chirality show different fluorescence increases. Moreover, certain sensors (e.g., SWCNT-(GT)10) distinguish between different catecholamines, such as dopamine and norepinephrine at low concentrations (50 nM). These results show that SWCNTs functionalized with certain DNA sequences are able to discriminate between catecholamine neurotransmitters or to detect them in the presence of interfering substances of similar structure. Such sensors will be useful to measure and study neurotransmitter signaling in complex biological settings. PMID- 28657586 TI - Nanoporous Gold Nanocomposites as a Versatile Platform for Plasmonic Engineering and Sensing. AB - Plasmonic metal nanostructures have shown great potential in sensing applications. Among various materials and structures, monolithic nanoporous gold disks (NPGD) have several unique features such as three-dimensional (3D) porous network, large surface area, tunable plasmonic resonance, high-density hot-spots, and excellent architectural integrity and environmental stability. They exhibit a great potential in surface-enhanced spectroscopy, photothermal conversion, and plasmonic sensing. In this work, interactions between smaller colloidal gold nanoparticles (AuNP) and individual NPGDs are studied. Specifically, colloidal gold nanoparticles with different sizes are loaded onto NPGD substrates to form NPG hybrid nanocomposites with tunable plasmonic resonance peaks in the near infrared spectral range. Newly formed plasmonic hot-spots due to the coupling between individual nanoparticles and NPG disk have been identified in the nanocomposites, which have been experimentally studied using extinction and surface-enhanced Raman scattering. Numerical modeling and simulations have been employed to further unravel various coupling scenarios between AuNP and NPGDs. PMID- 28657588 TI - Physical Layer Secret-Key Generation Scheme for Transportation Security Sensor Network. AB - Wireless Sensor Networks (WSNs) are widely used in different disciplines, including transportation systems, agriculture field environment monitoring, healthcare systems, and industrial monitoring. The security challenge of the wireless communication link between sensor nodes is critical in WSNs. In this paper, we propose a new physical layer secret-key generation scheme for transportation security sensor network. The scheme is based on the cooperation of all the sensor nodes, thus avoiding the key distribution process, which increases the security of the system. Different passive and active attack models are analyzed in this paper. We also prove that when the cooperative node number is large enough, even when the eavesdropper is equipped with multiple antennas, the secret-key is still secure. Numerical results are performed to show the efficiency of the proposed scheme. PMID- 28657587 TI - Towards Mobile Gait Analysis: Concurrent Validity and Test-Retest Reliability of an Inertial Measurement System for the Assessment of Spatio-Temporal Gait Parameters. AB - The purpose of this study was to assess the concurrent validity and test-retest reliability of a sensor-based gait analysis system. Eleven healthy subjects and four Parkinson's disease (PD) patients were asked to complete gait tasks whilst wearing two inertial measurement units at their feet. The extracted spatio temporal parameters of 1166 strides were compared to those extracted from a reference camera-based motion capture system concerning concurrent validity. Test retest reliability was assessed for five healthy subjects at three different days in a two week period. The two systems were highly correlated for all gait parameters ( r > 0.93 ). The bias for stride time was 0 +/- 16 ms and for stride length was 1.4 +/- 6.7 cm. No systematic range dependent errors were observed and no significant changes existed between healthy subjects and PD patients. Test retest reliability was excellent for all parameters (intraclass correlation (ICC) > 0.81) except for gait velocity (ICC > 0.55). The sensor-based system was able to accurately capture spatio-temporal gait parameters as compared to the reference camera-based system for normal and impaired gait. The system's high retest reliability renders the use in recurrent clinical measurements and in long term applications feasible. PMID- 28657585 TI - Issues of Acute Kidney Injury Staging and Management in Sepsis and Critical Illness: A Narrative Review. AB - Acute kidney injury (AKI) has a high incidence on intensive care units around the world and is a major complication in critically ill patients suffering from sepsis or septic shock. The short- and long-term complications are thereby devastating and impair the quality of life. Especially in terms of AKI staging, the determination of kidney function and the timing of dialytic AKI management outside of life-threatening indications are ongoing matters of debate. Despite several studies, a major problem remains in distinguishing between beneficial and unnecessary "early" or even harmful renal replacement therapy (RRT). The latter might prolong disease course and renal recovery. AKI scores, however, provide an insufficient outcome-predicting ability and the related estimation of kidney function via serum creatinine or blood urea nitrogen (BUN)/urea is not reliable in AKI and critical illness. Kidney independent alterations of creatinine- and BUN/urea-levels further complicate the situation. This review critically assesses the current AKI staging, issues and pitfalls of the determination of kidney function and RRT timing, as well as the potential harm reflected by unnecessary RRT. A better understanding is mandatory to improve future study designs and avoid unnecessary RRT for higher patient safety and lower health care costs. PMID- 28657589 TI - Surgical Outreach for Children by International Humanitarian Organizations: A Review. AB - Low- and middle-income countries carry a disproportionate share of the global burden of pediatric surgical disease and have limited local healthcare infrastructure and human resources to address this burden. Humanitarian efforts that have improved or provided access to necessary basic or emergency surgery for children in these settings have included humanitarian assistance and disaster relief, short-term surgical missions, and long-term projects such as building pediatric specialty hospitals and provider networks. Each of these efforts may also include educational initiatives designed to increase local capacity. This article will provide an overview of pediatric humanitarian surgical outreach including reference to available evidence-based analyses of these platforms and make recommendations for surgical outreach initiatives for children. PMID- 28657590 TI - Gestational Alcohol Exposure Altered DNA Methylation Status in the Developing Fetus. AB - Ethanol is well known as a teratogenic factor that is capable of inducing a wide range of developmental abnormalities if the developing fetus is exposed to it. Duration and dose are the critical parameters of exposure that affect teratogenic variation to the developing fetus. It is suggested that ethanol interferes with epigenetic processes especially DNA methylation. We aimed to organize all of the available information on the alteration of DNA methylation by ethanol in utero. Thus, we have summarized all published information regarding alcohol-mediated alterations in DNA methylation during gestation. We tried to arrange information in a way that anyone can easily find the alcohol exposure time, doses, sampling time, and major changes in genomic level. Manuscript texts will also represent the correlation between ethanol metabolites and subsequent changes in methylome patterns. We hope that this review will help future researchers to further examine the issues associated with ethanol exposure. PMID- 28657592 TI - Sino-Nasal 5 Questionnaire is Associated with Poor Asthma Control in Children with Asthma. AB - Up to 80% of asthmatic children may experience upper airway symptoms which are often perceived as coming from the lower airways. Currently, there are no validated questionnaires to assess upper airway contribution to pediatric asthma symptoms. The Sino-Nasal 5 (SN-5) questionnaire was previously validated for identifying radiographic confirmed sinus disease in children. In this study, we hypothesize that significant SN-5 scores (>=3.5) are associated with abnormal National Asthma Education and Prevention Program (NAEPP) based asthma impairment and control in asthmatic children. Retrospective data collected on children with asthma referred for pulmonary evaluation included age, gender, ethnicity, NAEPP asthma severity, asthma control (Test for Respiratory and Asthma Control in Kids (TRACK) < 5 years, Asthma Control Test (ACT) 5 years) and pulmonary function testing. Associations between SN-5 scores and asthma impairment and control were identified. Seventy-six children were evaluated; 38% were female with a mean age of 6.9 years. Significant SN-5 scores were associated with decreased control of daytime symptoms (odds ratio (OR): 0.16 (95% confidence interval (CI): 0.06 0.44)), night time awakenings (0.09 (0.03-0.29)), activity interference (0.2 (0.06-0.68)), NAEPP defined asthma control (0.32 (0.12-0.85)) and poor asthma control based on TRACK (p < 0.001) and ACT (p < 0.001). This suggests upper airways may play a larger role in perceived lower airway symptoms, and SN-5 may be beneficial in assessing the contribution of upper airway conditions on asthma control. PMID- 28657591 TI - Assessing Autophagy in Mouse Models and Patients with Systemic Autoimmune Diseases. AB - Autophagy is a tightly regulated mechanism that allows cells to renew themselves through the lysosomal degradation of proteins, which are misfolded or produced in excess, and of damaged organelles. In the context of immunity, recent research has specially attempted to clarify its roles in infection, inflammation and autoimmunity. Autophagy has emerged as a spotlight in several molecular pathways and trafficking events that participate to innate and adaptive immunity. Deregulation of autophagy has been associated to several autoimmune diseases, in particular to systemic lupus erythematosus. Nowadays, however, experimental data on the implication of autophagy in animal models of autoimmunity or patients remain limited. In our investigations, we use Murphy Roths Large (MRL)/lymphoproliferation (lpr) lupus-prone mice as a mouse model for lupus and secondary Sjogren's syndrome, and, herein, we describe methods applied routinely to analyze different autophagic pathways in different lymphoid organs and tissues (spleen, lymph nodes, salivary glands). We also depict some techniques used to analyze autophagy in lupus patient's blood samples. These methods can be adapted to the analysis of autophagy in other mouse models of autoinflammatory diseases. The understanding of autophagy implication in autoimmune diseases could prove to be very useful for developing novel immunomodulatory strategies. Our attention should be focused on the fact that autophagy processes are interconnected and that distinct pathways can be independently hyper-activated or downregulated in distinct organs and tissues of the same individual. PMID- 28657593 TI - Spectroscopic Investigation of the Interaction of the Anticancer Drug Mitoxantrone with Sodium Taurodeoxycholate (NaTDC) and Sodium Taurocholate (NaTC) Bile Salts. AB - The focus of the present work was to investigate the interaction of the anticancer drug mitoxantrone with two bile salts, sodium taurodeoxycholate (NaTDC) and sodium taurocholate (NaTC). Ultraviolet-visible (UV-Vis) absorption and electron paramagnetic resonance (EPR) spectroscopy were used to quantify the interaction and to obtain information on the location of mitoxantrone in bile salt micelles. The presence of submicellar concentrations of both bile salts induces mitoxantrone aggregation and the extent of drug aggregation in NaTDC is higher than in NaTC. For micellar bile salts concentrations, mitoxantrone monomers are entrapped in the micellar core. Binding constants, micelle/water partition coefficients and the corresponding thermodynamic parameters for binding and partitioning processes were estimated using the changes in monomer absorbance in the presence of bile salts. Binding interaction of mitoxantrone is stronger for NaTDC than NaTC micelles, whereas partitioning efficiency is higher for NaTC micelles for all investigated temperatures. Thermodynamic parameters indicate that both binding and partitioning processes are spontaneous and entropy controlled. The spectral behavior and thermodynamic parameters indicate distinct types of mitoxantrone interaction with NaTDC and NaTC micelles supported by the differences in nature and structure of bile salts micelles. PMID- 28657595 TI - Review of Portable and Low-Cost Sensors for the Ambient Air Monitoring of Benzene and Other Volatile Organic Compounds. AB - This article presents a literature review of sensors for the monitoring of benzene in ambient air and other volatile organic compounds. Combined with information provided by stakeholders, manufacturers and literature, the review considers commercially available sensors, including PID-based sensors, semiconductor (resistive gas sensors) and portable on-line measuring devices as for example sensor arrays. The bibliographic collection includes the following topics: sensor description, field of application at fixed sites, indoor and ambient air monitoring, range of concentration levels and limit of detection in air, model descriptions of the phenomena involved in the sensor detection process, gaseous interference selectivity of sensors in complex VOC matrix, validation data in lab experiments and under field conditions. PMID- 28657594 TI - The Cytological Events and Molecular Control of Life Cycle Development of Trypanosoma brucei in the Mammalian Bloodstream. AB - African trypanosomes cause devastating disease in sub-Saharan Africa in humans and livestock. The parasite lives extracellularly within the bloodstream of mammalian hosts and is transmitted by blood-feeding tsetse flies. In the blood, trypanosomes exhibit two developmental forms: the slender form and the stumpy form. The slender form proliferates in the bloodstream, establishes the parasite numbers and avoids host immunity through antigenic variation. The stumpy form, in contrast, is non-proliferative and is adapted for transmission. Here, we overview the features of slender and stumpy form parasites in terms of their cytological and molecular characteristics and discuss how these contribute to their distinct biological functions. Thereafter, we describe the technical developments that have enabled recent discoveries that uncover how the slender to stumpy transition is enacted in molecular terms. Finally, we highlight new understanding of how control of the balance between slender and stumpy form parasites interfaces with other components of the infection dynamic of trypanosomes in their mammalian hosts. This interplay between the host environment and the parasite's developmental biology may expose new vulnerabilities to therapeutic attack or reveal where drug control may be thwarted by the biological complexity of the parasite's lifestyle. PMID- 28657596 TI - Antibacterial Activity and Toxicity of Analogs of Scorpion Venom IsCT Peptides. AB - Seven analogs of the natural, alpha-helix peptides IsCT1 and IsCT2-found in the venom of scorpion Opithancatus Madagascariensis-have been synthesized and tested to compare their antibacterial and hemolytic activity against natural peptides. In general, results show that increasing hydrophobicity by substituting positions 5 and 9 of the sequences with alanine, valine, and leucine, enhances antibacterial activity. However, this also increases hemolytic activity. The analog with an increased net positive charge from +1 to +3 produces moderate bacterial growth inhibition but also has high hemolytic activity. On the other hand, the analog with a negative net charge (-1) has low antibacterial properties but also no cytotoxicity under the tested conditions, a similar result was found for five of the seven studied analogs. PMID- 28657597 TI - Benefits of Argan Oil on Human Health-May 4-6 2017, Errachidia, Morocco. AB - n/a. PMID- 28657598 TI - Secretion of IFN-gamma Associated with Galectin-9 Production by Pleural Fluid Cells from a Patient with Extrapulmonary Tuberculosis. AB - In this study, we investigated the role of a matricellular protein galectin-9 (Gal-9) in pleural effusion related to tuberculosis (TB). Plasma and pleural fluid of a patient with extrapulmonary TB were analyzed for cytokine content by ELISA and Luminex. Peripheral blood mononuclear cells (PBMCs) and pleural fluid cells (PFCs) were examined for interferon-gamma (IFN-gamma) secretion by the enzyme-linked immunospot (ELISPOT) assay or IFN-gamma ELISA, for apoptosis and necrosis by Cell Death Detection ELISA, and also underwent cell sorting. The results indicate that compared to plasma, pleural fluid had increased levels of IFN-gamma (1.6 vs. 55.5 pg/mL), IL-10, IL-12p40, vascular endothelial growth factor (VEGF), and Gal-9 (3.0 vs. 936.0 pg/mL), respectively. PFCs culture supernatant exhibited higher concentration of Gal-9 compared to PBMCs in culture, consistent with enriched Gal-9 staining in the granuloma that is in closer vicinity to PFCs compared to PBMCs. PFCS displayed higher IFN-gamma secretion after stimulation with TB antigens ESAT-6/CFP-10. Furthermore, in PFCs, Gal-9 alone could stimulate IFN-gamma synthesis in culture or ELISPOT, which was inhibited by a Gal-9 antagonist lactose, and which may promote apoptosis and necrosis. These findings suggest that Gal-9 could modulate immune responses and participate in immunopathology of pleural effusion during TB. PMID- 28657599 TI - Controllable Charge Transfer in Ag-TiO2 Composite Structure for SERS Application. AB - The nanocaps array of TiO2/Ag bilayer with different Ag thicknesses and co sputtering TiO2-Ag monolayer with different TiO2 contents were fabricated on a two-dimensional colloidal array substrate for the investigation of Surface enhanced Raman scattering (SERS) properties. For the TiO2/Ag bilayer, when the Ag thickness increased, SERS intensity decreased. Meanwhile, a significant enhancement was observed when the sublayer Ag was 10 nm compared to the pure Ag monolayer, which was ascribed to the metal-semiconductor synergistic effect that electromagnetic mechanism (EM) provided by roughness surface and charge-transfer (CT) enhancement mechanism from TiO2-Ag composite components. In comparison to the TiO2/Ag bilayer, the co-sputtered TiO2-Ag monolayer decreased the aggregation of Ag particles and led to the formation of small Ag particles, which showed that TiO2 could effectively inhibit the aggregation and growth of Ag nanoparticles. PMID- 28657600 TI - The Association between the Mediterranean Dietary Pattern and Cognitive Health: A Systematic Review. AB - The ageing population is accompanied by increased rates of cognitive decline and dementia. Not only does cognitive decline have a profound impact on an individual's health and quality of life, but also on that of their caregivers. The Mediterranean diet (MD) has been known to aid in reducing the risk of cardiovascular diseases, cancer and diabetes. It has been recently linked to better cognitive function in the elderly population. The purpose of this review was to compile evidence based data that examined the effect of adherence to the MD on cognitive function and the risk of developing dementia or Alzheimer's disease. This review followed PRISMA guidelines and was conducted using four databases and resulted in 31 articles of interest. Cross-sectional studies and cohort studies in the non-Mediterranean region showed mixed results. However, cohort studies in the Mediterranean region and randomized controlled trials showed more cohesive outcomes of the beneficial effect of the MD on cognitive function. Although more standardized and in-depth studies are needed to strengthen the existing body of evidence, results from this review indicate that the Mediterranean diet could play a major role in cognitive health and risk of Alzheimer's disease and dementia. PMID- 28657601 TI - The Diuretic Action of Weak and Strong Alcoholic Beverages in Elderly Men: A Randomized Diet-Controlled Crossover Trial. AB - With ageing, there is a greater risk of dehydration. This study investigated the diuretic effect of alcoholic beverages varying in alcohol concentration in elderly men. Three alcoholic beverages (beer (AB), wine (AW), and spirits (S)) and their non-alcoholic counterparts (non-alcoholic beer (NAB), non-alcoholic wine (NAW), and water (W)) were tested in a diet-controlled randomized crossover trial. For the alcoholic beverages, alcohol intake equaled a moderate amount of 30 g. An equal volume of beverage was given for the non-alcoholic counterpart. After consumption, the urine output was collected every hour for 4 h and the total 24 h urine output was measured. AW and S resulted in a higher cumulative urine output compared to NAW and W during the first 4 h (effect size: 0.25 mL p < 0.003, effect size: 0.18 mL, p < 0.001, respectively), but not after the 24h urine collection (p > 0.40, p > 0.10). AB and NAB did not differ at any time point (effect size: -0.02 mL p > 0.70). For urine osmolality, and the sodium and potassium concentration, the findings were in line. In conclusion, only moderate amounts of stronger alcoholic beverages, such as wine and spirits, resulted in a short and small diuretic effect in elderly men. PMID- 28657602 TI - Colorization-Based RGB-White Color Interpolation using Color Filter Array with Randomly Sampled Pattern. AB - Recently, several RGB-White (RGBW) color filter arrays (CFAs) have been proposed, which have extra white (W) pixels in the filter array that are highly sensitive. Due to the high sensitivity, the W pixels have better SNR (Signal to Noise Ratio) characteristics than other color pixels in the filter array, especially, in low light conditions. However, most of the RGBW CFAs are designed so that the acquired RGBW pattern image can be converted into the conventional Bayer pattern image, which is then again converted into the final color image by using conventional demosaicing methods, i.e., color interpolation techniques. In this paper, we propose a new RGBW color filter array based on a totally different color interpolation technique, the colorization algorithm. The colorization algorithm was initially proposed for colorizing a gray image into a color image using a small number of color seeds. Here, we adopt this algorithm as a color interpolation technique, so that the RGBW color filter array can be designed with a very large number of W pixels to make the most of the highly sensitive characteristics of the W channel. The resulting RGBW color filter array has a pattern with a large proportion of W pixels, while the small-numbered RGB pixels are randomly distributed over the array. The colorization algorithm makes it possible to reconstruct the colors from such a small number of RGB values. Due to the large proportion of W pixels, the reconstructed color image has a high SNR value, especially higher than those of conventional CFAs in low light condition. Experimental results show that many important information which are not perceived in color images reconstructed with conventional CFAs are perceived in the images reconstructed with the proposed method. PMID- 28657603 TI - Effects on Rotational Dynamics of Azo and Hydrazodicarboxamide-Based Rotaxanes. AB - The synthesis of novel hydrogen-bonded [2]rotaxanes having two pyridine rings in the macrocycle and azo- and hydrazodicarboxamide-based templates decorated with four cyclohexyl groups is described. The different affinity of the binding sites for the benzylic amide macrocycle and the formation of programmed non-covalent interactions between the interlocked components have an important effect on the dynamic behavior of these compounds. Having this in mind, the chemical interconversion between the azo and hydrazo forms of the [2]rotaxane was investigated to provide a chemically-driven interlocked system enable to switch its circumrotation rate as a function of the oxidation level of the binding site. Different structural modifications were carried out to further functionalize the nitrogen of the pyridine rings, including oxidation, alkylation or protonation reactions, affording interlocked azo-derivatives whose rotation dynamics were also analyzed. PMID- 28657604 TI - Fruit Fiber Consumption Specifically Improves Liver Health Status in Obese Subjects under Energy Restriction. AB - The prevalence of non-alcoholic-fatty-liver-disease (NAFLD) is associated with obesity, diabetes, and metabolic syndrome (MS). This study aimed to evaluate the influence of two energy-restricted diets on non-invasive markers and scores of liver damage in obese individuals with features of MS after six months of follow up and to assess the role of fiber content in metabolic outcomes. Seventy obese individuals from the RESMENA (Reduction of Metabolic Syndrome in Navarra) study were evaluated at baseline and after six months of energy-restricted nutritional intervention (American Heart Association (AHA) and RESMENA dietary groups). Dietary records, anthropometrical data, body composition by dual energy X-ray absorptiometry (DXA), and routine laboratory measurements were analyzed by standardized methods. Regarding liver status, cytokeratin-18 fragments and several non-invasive scores of fatty liver were also assessed. The RESMENA strategy was a good and complementary alternative to AHA for the treatment of obesity-related comorbidities. Participants with higher insoluble fiber consumption (>=7.5 g/day) showed improvements in fatty liver index (FLI), hepatic steatosis index (HIS), and NAFLD liver fat score (NAFLD_LFS), while gamma glutamyl transferase (GGT) and transaminases evidenced significant improvements as a result of fruit fiber consumption (>=8.8 g/day). Remarkably, a regression model evidenced a relationship between liver status and fiber from fruits. These results support the design of dietary patterns based on the consumption of insoluble fiber and fiber from fruits in the context of energy restriction for the management of obese patients suffering fatty liver disease. PMID- 28657605 TI - Pharmacological Modulation of Radiation Damage. Does It Exist a Chance for Other Substances than Hematopoietic Growth Factors and Cytokines? AB - In recent times, cytokines and hematopoietic growth factors have been at the center of attention for many researchers trying to establish pharmacological therapeutic procedures for the treatment of radiation accident victims. Two granulocyte colony-stimulating factor-based radiation countermeasures have been approved for the treatment of the hematopoietic acute radiation syndrome. However, at the same time, many different substances with varying effects have been tested in animal studies as potential radioprotectors and mitigators of radiation damage. A wide spectrum of these substances has been studied, comprising various immunomodulators, prostaglandins, inhibitors of prostaglandin synthesis, agonists of adenosine cell receptors, herbal extracts, flavonoids, vitamins, and others. These agents are often effective, relatively non-toxic, and cheap. This review summarizes the results of animal experiments, which show the potential for some of these untraditional or new radiation countermeasures to become a part of therapeutic procedures applicable in patients with the acute radiation syndrome. The authors consider beta-glucan, 5-AED (5-androstenediol), meloxicam, gamma-tocotrienol, genistein, IB-MECA (N6-(3-iodobezyl)adenosine-5'-N methyluronamide), Ex-RAD (4-carboxystyryl-4-chlorobenzylsulfone), and entolimod the most promising agents, with regards to their contingent use in clinical practice. PMID- 28657606 TI - Fabrication and Cytotoxicity of Gemcitabine-Functionalized Magnetite Nanoparticles. AB - Nanotechnology has been successfully used for the fabrication of targeted anti cancer drug carriers. This study aimed to obtain Fe3O4 nanoparticles functionalized with Gemcitabine to improve the cytotoxic effects of the chemotherapeutic substance on cancer cells. The (un) functionalized magnetite nanoparticles were synthesized using a modified co-precipitation method. The nanoconjugate characterization was performed by XRD, SEM, SAED and HRTEM; the functionalizing of magnetite with anti-tumor substances has been highlighted through TGA. The interaction with biologic media has been studied by means of stability and agglomeration tendency (using DLS and Zeta Potential); also, the release kinetics of the drug in culture media was evaluated. Cytotoxicity of free Gemcitabine and the obtained nanoconjugate were evaluated on human BT 474 breast ductal carcinoma, HepG2 hepatocellular carcinoma and MG 63 osteosarcoma cells by MTS. In parallel, cellular morphology of these cells were examined through fluorescence microscopy and SEM. The localization of the nanoparticles related to the cells was studied using SEM, EDX and TEM. Hemolysis assay showed no damage of erythrocytes. Additionally, an in vivo biodistribution study was made for tracking where Fe3O4@Gemcitabine traveled in the body of mice. Our results showed that the transport of the drug improves the cytotoxic effects in comparison with the one produced by free Gemcitabine for the BT474 and HepG2 cells. The in vivo biodistribution test proved nanoparticle accumulation in the vital organs, with the exception of spleen, where black-brown deposits have been found. These results indicate that our Gemcitabine-functionalized nanoparticles are a promising targeted system for applications in cancer therapy. PMID- 28657608 TI - The Impact of a Nickel-Copper Smelter on Concentrations of Toxic Elements in Local Wild Food from the Norwegian, Finnish, and Russian Border Regions. AB - Toxic elements emitted from the Pechenganickel complex on the Kola Peninsula have caused concern about potential effects on local wild food in the border regions between Norway, Finland and Russia. The aim of this study was to assess Ni, Cu, Co, As, Pb, Cd, and Hg concentrations in local wild foods from these border regions. During 2013-2014, we collected samples of different berry, mushroom, fish, and game species from sites at varying distances from the Ni-Cu smelter in all three border regions. Our results indicate that the Ni-Cu smelter is the main source of Ni, Co, and As in local wild foods, whereas the sources of Pb and Cd are more complex. We observed no consistent trends for Cu, one of the main toxic elements emitted by the Ni-Cu smelter; nor did we find any trend for Hg in wild food. Concentrations of all investigated toxic elements were highest in mushrooms, except for Hg, which was highest in fish. EU maximum levels of Pb, Cd, and Hg were exceeded in some samples, but most had levels considered safe for human consumption. No international thresholds exist for the other elements under study. PMID- 28657609 TI - Active Multimodal Sensor System for Target Recognition and Tracking. AB - High accuracy target recognition and tracking systems using a single sensor or a passive multisensor set are susceptible to external interferences and exhibit environmental dependencies. These difficulties stem mainly from limitations to the available imaging frequency bands, and a general lack of coherent diversity of the available target-related data. This paper proposes an active multimodal sensor system for target recognition and tracking, consisting of a visible, an infrared, and a hyperspectral sensor. The system makes full use of its multisensor information collection abilities; furthermore, it can actively control different sensors to collect additional data, according to the needs of the real-time target recognition and tracking processes. This level of integration between hardware collection control and data processing is experimentally shown to effectively improve the accuracy and robustness of the target recognition and tracking system. PMID- 28657607 TI - Gut Microbiota as a Target for Preventive and Therapeutic Intervention against Food Allergy. AB - The gut microbiota plays a pivotal role in immune system development and function. Modification in the gut microbiota composition (dysbiosis) early in life is a critical factor affecting the development of food allergy. Many environmental factors including caesarean delivery, lack of breast milk, drugs, antiseptic agents, and a low-fiber/high-fat diet can induce gut microbiota dysbiosis, and have been associated with the occurrence of food allergy. New technologies and experimental tools have provided information regarding the importance of select bacteria on immune tolerance mechanisms. Short-chain fatty acids are crucial metabolic products of gut microbiota responsible for many protective effects against food allergy. These compounds are involved in epigenetic regulation of the immune system. These evidences provide a foundation for developing innovative strategies to prevent and treat food allergy. Here, we present an overview on the potential role of gut microbiota as the target of intervention against food allergy. PMID- 28657610 TI - The Clinical and Economic Impact of Inaccurate EGFR Mutation Tests in the Treatment of Metastatic Non-Small Cell Lung Cancer. AB - Advances in personalized medicine are supported by companion diagnostic molecular tests. Testing accuracy is critical for selecting patients for optimal therapy and reducing treatment-related toxicity. We assessed the clinical and economic impact of inaccurate test results between laboratory developed tests (LDTs) and a US Food and Drug Administration (FDA)-approved test for detection of epidermal growth factor receptor (EGFR) mutations. Using a hypothetical US cohort of newly diagnosed metastatic non-small cell lung cancer (NSCLC) patients and EURTAC (erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer) clinical trial data, we developed a decision analytic model to estimate the probability of misclassification with LDTs compared to a FDA-approved test. We estimated the clinical and economic impact of inaccurate test results by quantifying progression-free and quality-adjusted progression-free life years (PFLYs, QAPFLYs) lost, and costs due to incorrect treatment. The base-case analysis estimated 2.3% (n = 1422) of 60,502 newly diagnosed metastatic NSCLC patients would be misclassified with LDTs compared to 1% (n = 577) with a FDA approved test. An average of 477 and 194 PFLYs were lost among the misclassified patients tested with LDTs compared to the FDA-approved test, respectively. Aggregate treatment costs for patients tested with LDTs were approximately $7.3 million more than with the FDA-approved test, due to higher drug and adverse event costs among patients incorrectly treated with targeted therapy or chemotherapy, respectively. Invalid tests contributed to greater probability of patient misclassification and incorrect therapy. In conclusion, risks associated with inaccurate EGFR mutation tests pose marked clinical and economic consequences to society. Utilization of molecular diagnostic tests with demonstrated accuracy could help to maximize the potential of personalized medicine. PMID- 28657611 TI - CSPG4: A Target for Selective Delivery of Human Cytolytic Fusion Proteins and TRAIL. AB - Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane glycoprotein overexpressed on malignant cells in several cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Expression may serve as a prognostic marker for survival and risk of relapse in treatment-resistant malignancies including melanoma, triple negative breast cancer, rhabdomyosarcoma and acute lymphoblastic leukemia. This tumor-associated overexpression of CSPG4 points towards a highly promising therapeutic target for antibody-guided cancer therapy. Monoclonal alphaCSPG4 antibodies have been shown to inhibit cancer progression by blocking ligand access to the CSPG4 extracellular binding sites. Moreover, CSPG4-directed antibody conjugates have been shown to be selectively internalized by CSPG4 expressing cancer cells via endocytosis. CSPG4-directed immunotherapy may be approached in several ways, including: (1) antibody-based fusion proteins for the selective delivery of a pro-apoptotic factors such as tumor necrosis factor related apoptosis-inducing ligand to agonistic death receptors 4 and 5 on the cell surface; and (2) CSPG4-specific immunotoxins which bind selectively to diseased cells expressing CSPG4, are internalized by them and induce arrest of biosynthesis, closely followed by initiation of apoptotic signaling. Here we review various methods of exploiting tumor-associated CSPG4 expression to improve targeted cancer therapy. PMID- 28657612 TI - Margarines and Fast-Food French Fries: Low Content of trans Fatty Acids. AB - The lipid fraction of margarines and fast food French fries, two types of foods traditionally high in trans fatty acids (TFA), is assessed. TFA data reported worldwide during the last 20 years have been gathered and show that some countries still report high TFA amounts in these products. The content of TFA was analysed in margarines (two store and four premium brands) and French-fries from fast-food restaurants (five chains). All samples were collected in Pamplona (Navarra, Spain). The margarines showed mean values of 0.68% and 0.43% (g TFA/100 g fat) for the store and premium brands, respectively. The French fries' values ranged from 0.49% to 0.89%. All samples were lower than the 2% set by some European countries as the maximum legal content of TFA in fats, and contained less than 0.5 g/serving, so they could also be considered "trans free products". This work confirmed that the presence of TFA is not significant in the two analysed products and contributes updated food composition tables, key tools for epidemiological and nutrition studies. PMID- 28657614 TI - Genetic analysis of a hybrid sterility gene that causes both pollen and embryo sac sterility in hybrids between Oryza sativa L. and Oryza longistaminata. AB - Oryza longistaminata originates from African wild rice and contains valuable traits conferring tolerance to biotic and abiotic stress. However, interspecific crosses between O. longistaminata and Oryza sativa cultivars are hindered by reproductive barriers. To dissect the mechanism of interspecific hybrid sterility, we developed a near-isogenic line (NIL) using indica variety RD23 as the recipient parent and O. longistaminata as the donor parent. Both pollen and embryo sac semi-sterility were observed in F1 hybrids between RD23 and NIL. Cytological analysis demonstrated that pollen abortion in F1 hybrids occurred at the early bi-nucleate stage due to a failure of the first mitosis in microspores. Partial embryo sacs in the F1 hybrids were defective during the functional megaspore formation stage. Most notably, nearly half of the male or female gametes were aborted in heterozygotes S40iS40l, regardless of their genotypes. Thus, S40 was indicated as a one-locus sporophytic sterility gene controlling both male and female fertility in hybrids between RD23 and O. longistaminata. A population of 16 802 plants derived from the hybrid RD23/NIL-S40 was developed to fine-map S40. Finally, the S40 locus was delimited to an 80-kb region on the short arm of chromosome 1 in terms with reference sequences of cv. 93-11. Eight open reading frames (ORFs) were localized in this region. On the basis of gene expression and genomic sequence analysis, ORF5 and ORF8 were identified as candidate genes for the S40 locus. These results are helpful in cloning the S40 gene and marker-assisted transferring of the corresponding neutral allele in rice breeding programs. PMID- 28657615 TI - Carbon dots for tracking and promoting the osteogenic differentiation of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) hold great potential for tissue engineering and regeneration medicine. However, for clinical use, MSCs may be detrimental due to their uncertain fate during the transplantation. It is therefore highly desirable to develop biocompatible nanomaterials to integrate cell fate regulation with monitoring for MSC-based therapy. Herein, we employ recently developed citric acid-based carbon dots (CDs) and their derivatives (Et-IPCA) for labeling and tracking of rat bone marrow mesenchymal stem cells (rBMSCs). We further investigate their biocompatibility and effects on the osteogenic differentiation of rBMSCs. These highly fluorescent probes provide labeling of rBMSCs by internalization without affecting cell viability or inducing apoptosis when the concentration is lower than 50 MUg mL-1. Importantly, the presence of the CDs and Et-IPCA facilitates high-efficiency osteogenic differentiation of rBMSCs by promoting osteogenic transcription and enhancing matrix mineralization. Compared to Et-IPCA, CDs considerably provide long-term tracking and promote the differentiation of rBMSCs toward osteoblasts through the ROS-mediated MAPK pathway. Taken together, our results consistently demonstrate that carbon dots are capable of both tracking and enhancing the osteogenic differentiation of MSCs. This study sheds new light on the potential of carbon dots as a bifunctional tool in the thriving field of MSC-based therapy. PMID- 28657616 TI - Efficient conversion of N6-threonylcarbamoyladenosine (t6A) into a tRNA native hydantoin cyclic form (ct6A) performed at nucleoside and oligoribonucleotide levels. AB - A t6A nucleoside was efficiently and stereospecifically transformed into a hydantoin cyclic form of N6-l-threonylcarbamoyladenosine (ct6A) by the use of polymer bounded carbodiimide (EDC-P) and HOBt. The procedure was successfully applied for a post-synthetic conversion of t6A-containing RNA 17-mers (of the sequences of anticodon stem and loop (ASL) fragments of S. pombe tRNAi and E. coli tRNALys) into the products bearing the ct6A unit. PMID- 28657619 TI - Zeolitic imidazole framework coated Au nanorods for enhanced photothermal therapy and stability. AB - Metal-Organic Frameworks (MOFs) were exploited to coat Au nanorods (AuNRs) as a hyperthermia agent for enhanced plasmonic photothermal therapy. The utilization of a MOF shell reduces the cytotoxicity of AuNRs and enhances the photothermal transduction efficiency of AuNRs, resulting in the improved phototoxicity of MOF coated AuNRs compared with the unmodified AuNRs. PMID- 28657613 TI - Nuts and Dried Fruits: An Update of Their Beneficial Effects on Type 2 Diabetes. AB - Nuts and dried fruit are essential foods in the Mediterranean diet. Their frequent consumption has been associated with the prevention and/or the management of such metabolic conditions as type 2 diabetes (T2D), metabolic syndrome and cardiovascular diseases. Several previous reviews of epidemiological studies and clinical trials have evaluated the associations of nuts and/or dried fruit with various metabolic disorders. However, no reviews have focused on the mechanisms underlying the role of nuts and/or dried fruit in insulin resistance and T2D. This review aims to report nut and dried-fruit nutritional interventions in animals and humans, and to focus on mechanisms that could play a significant role in the prevention and treatment of insulin resistance and T2D. PMID- 28657620 TI - Impact of the composition of the bacterial population and additional carbon source on the pathway and kinetics of degradation of endosulfan isomers. AB - Abiotic and bacterial degradation is presented for the two isomers alpha- and beta- of the organochlorine pesticide endosulfan, denoted as ES-1 and ES-2, respectively. Biodegradation studies were conducted with two indigenous species Pseudomonas putida (P. putida) and Rhodococcus sp. Both ES isomers rapidly hydrolyzed in water at pH >= 7 but the hydrolysis was inhibited in the presence of biomass. The pesticide partitioned onto the biomass making it unavailable for abiotic hydrolytic reaction. Spontaneous temperature dependent abiotic conversion of ES-2 to ES-1 was reported in the presence of dual air-water phases but was not observed in the abiotic aqueous phase. Biodegradation experiments with pure isomers showed a small amount of interconversion (~5%) in either direction and ruled out any preferential interconversion of the ES-2 isomer to ES-1 or vice versa. Both the species were shown to degrade ES-2 at a higher rate compared to ES-1 which may lead to enrichment of ES-1 in agricultural fields in short-term following application of the pesticide. P. putida degraded both the ES isomers through oxidative and hydrolytic pathways while the Rhodococcus sp. used only the hydrolytic pathway. Since ES-S (product of the oxidative pathway) is orders of magnitude more toxic than the parent isomers, the short term toxicity of a field following the application of the pesticide may increase if the composition of the indigenous bacterial population is such that the oxidative pathway is preferred over the hydrolytic one. The presence of an additional carbon source increased the rates of degradation of both the isomers but the enhancement was greater for the degradation rate of ES-2 than ES-1. PMID- 28657621 TI - Ultrafast dynamics in the DNA building blocks thymidine and thymine initiated by ionizing radiation. AB - Understanding how energetic charged particles damage DNA is crucial for improving radiotherapy techniques such as hadron therapy and for the development of new radiosensitizer drugs. In the present study, the damage caused by energetic particles was simulated by measuring the action of extreme ultraviolet (XUV) attosecond pulses on the DNA building blocks thymine and thymidine. This allowed the ultrafast processes triggered by direct ionization to be probed with an optical pulse with a time resolution of a few femtoseconds. By measuring the yields of fragment ions as a function of the delay between the XUV pulse and the probe pulse, a number of transient processes typically lasting 100 femtoseconds or less were observed. These were particularly strong in thymidine which consists of the thymine base attached to a deoxyribose sugar. This dynamics was interpreted as excited states of the cation, formed by the XUV pulse, rapidly decaying via non-adiabatic coupling between electronic states. This provides the first experimental insight into the mechanisms which immediately proceed from the action of ionizing radiation on DNA and provides a basis on which further theoretical and experimental studies can be conducted. PMID- 28657622 TI - From ethylzinc guanidinate to [Zn10O4]-supertetrahedron. AB - The controlled hydrolysis of an ethylzinc guanidinate complex affording an alkylzinc cluster containing a [Zn10O4]12+ supertetrahedron core stabilized by the guanidinate ligands is described. Accompanying investigations on the reactivity of this unprecedented cluster toward alcohols resulted in the formation of a mononuclear zinc alkoxide supported by the guanidinate ligands. PMID- 28657623 TI - The ability of a zinc pyrrolidine complex to catalyze the synthesis of cyclic carbonates from carbon dioxide and epoxides: a mechanistic theoretical investigation. AB - The reaction mechanism for the synthesis of cyclic carbonates from carbon dioxide and epoxides catalyzed by a zinc pyrrolidine complex has been elucidated using the density functional level of theory. The obtained potential energy surface shows that the recently proposed zinc complex is able to efficiently and selectively catalyze the formation of cyclic carbonate using carbon dioxide. In the proposed mechanism, the reaction occurs in two steps: in the first step, the epoxide cycle is activated by iodide nucleophile, whereas in the second step, carbon dioxide is inserted into the oxy-anion species to form the cyclic carbonate. The rate determining step is the epoxide opening process, which requires 31.6 kcal mol-1. The entire reaction results to be exergonic by 11.8 kcal mol-1. Comparison with the uncatalyzed process reveals that the presence of the co-catalyst and catalyst contribute not only to lower the activation energy but also to determine the regioselectivity. PMID- 28657624 TI - Advances in the preparation of highly selective nanocatalysts for the semi hydrogenation of alkynes using colloidal approaches. AB - In the last decade, the semi-hydrogenation of alkynes has experienced significant advances in terms of fine control of alkene selectivity and prevention of the over-hydrogenation reaction. Such advances have been possible to a large extent through the progress in colloidal methods for the preparation of metallic nanoparticles. The present review describes the contributions in the field of the selective hydrogenation of alkynes involving the utilization of colloidal methodologies. These approaches permit the fine modulation of several parameters affecting the catalytic performance of the active phase such as the particle size, the bulk and the surface structure and composition. For the transformation of liquid substrates, the nature of the stabilizers, the reducing agents and the metal precursors employed for the synthesis of the catalysts can be tuned to enhance the alkene selectivity. In contrast, in catalytic transformations of gaseous substrates, the presence of adsorbed species at the metal surface usually gives detrimental results while the interplay between the support and the active phase appears to be a more convincing alternative for catalyst tuning. PMID- 28657625 TI - How roughness affects the depletion mechanism. AB - We develop a simple model, in the spirit of the Asakura-Oosawa theory, able to describe the effects of surface roughness on the depletion potential. The resulting explicit expressions are easily computed, without free parameters, for a wide range of physically interesting conditions. Comparison with recent numerical simulations [M. Kamp et al., Langmuir, 2016, 32, 1233] shows an encouraging agreement and allows predicting the onset of colloidal aggregation in dilute suspensions of rough particles. Furthermore, the model proves to be suitable to investigate the role of the geometry of the roughness. PMID- 28657627 TI - How do hydrophobic nucleobases differ from natural DNA nucleobases? Comparison of structural features and duplex properties from QM calculations and MD simulations. AB - Computational (DFT and MD simulation) methods are employed to systematically characterize the structural and energetic properties of five hydrophobic nucleobases (FEMO, MMO2, NaM, 5SICS and TPT3) that constitute four unnatural base pairs (FEMO:5SICS, MMO2:5SICS, NaM:5SICS and TPT3:NaM). These hydrophobic bases have been recently shown to be replicated when present between natural bases in DNA duplexes, with the highest replication fidelity and efficiency occuring for the TPT3:NaM pair. Our QM calculations suggest that the preferred (anti) glycosidic orientations of nucleosides containing hydrophobic bases are similar to the natural DNA nucleosides despite differences in their chemical structures. However, due to the inability to form interbase hydrogen bonds, hydrophobic base pairs intrinsically prefer nonplanar, distorted geometries, many of which are stabilized through pi-pi stacking interactions. Furthermore, the intrinsic stacking potential between a hydrophobic and a natural base is similar to that between two natural bases, indicating that the strength of stacking interactions in DNA duplexes containing hydrophobic bases is likely comparable to natural DNA. However, in contrast to the isolated base-pair geometries, our MD simulations suggest that the hydrophobic base pairs adopt variable geometries within DNA, which range from stacked (5SICS:FEMO) to nearly planar (5SICS:NaM and SICS:MMO2) to planar (TPT3:NaM). As a result, the duplex structural features at the site of modification depend on the identity of the hydrophobic base pair, where the TPT3:NaM pair causes the least structural changes compared to natural DNA. Overall, the structural insight obtained from our calculations on DNA containing hydrophobic base pairs explains the experimentally-observed higher fidelity and efficiency during replication of TPT3:NaM compared to other hydrophobic nucleobase pairs. By providing valuable structural information that explains the intrinsic and duplex properties of this class of unnatural nucleobases, the present work may aid the future design of improved hydrophobic analogues. PMID- 28657628 TI - Tracking the dissolution of calcite single crystals in acid waters: a simple method for measuring fast surface kinetics. AB - Although the dissolution kinetics of calcite in acid waters has been studied for more than a century, the process is not fully understood, and for particles and microcrystals the process is often assumed to be diffusion-controlled. Herein, the dissolution kinetics of calcite single microcrystals in aqueous solution (pH ca. 3) has been investigated for the first time by a combination of real-time optical microscopy coupled with numerical simulations. The small size and well defined geometry of rhombohedral calcite single crystals enables the measurement of the dissolution rates of the individual crystal faces exposed to the solvent and an assessment of the relative importance of corners and edges compared to the {104} faces. Data are used to parameterise finite element method (FEM) models for the quantitative analysis of dissolution kinetics. The simulations provide an accurate determination of the near-interface concentration of solution species during dissolution, as well as concentration gradients. The intrinsic first-order dissolution rate constant for the attack of protons on the exposed {104} faces, ksurf = (6.4 +/- 2.8) * 10-4 m s-1, is in good agreement with previous microscopic and macroscopic measurements, corroborating the method. This study is a further demonstration of the power of simple in situ optical microscopy for quantitative interfacial (dissolution/growth) kinetic measurements, using a configuration of practical relevance for processes as diverse as the remediation of acid water and scale removal. PMID- 28657629 TI - Fluorescent sensing and selective adsorption properties of metal-organic frameworks with mixed tricarboxylate and 1H-imidazol-4-yl-containing ligands. AB - Herein, two metal-organic frameworks (MOFs), [Co4(MU3-OH)2(L)(BTB)2(H2O)3].5.6H2O (1) and [Cd3(L)2(BTB)2(MU2-H2O)].7.4H2O (2), based on 1,3-di(1H-imidazol-4 yl)benzene (L) and 1,3,5-tri(4-carboxyphenyl)benzene (H3BTB), respectively, have been achieved. Compound 1 is a porous three-dimensional (3D) framework with butterfly-like tetranuclear clusters as 7-connected nodes, and compund 2 is a 3D net with a different topology. Remarkably, compounds 1 and 2 exhibit selective adsorption of CO2 over N2 and methyl orange (MO) dye molecules. Magnetic measurements reveal that there are antiferromagnetic interactions within the tetranuclear cluster in 1. Furthermore, 2 was well-dispersed in different solvents, and their luminescent properties were investigated, and the results indicated that 2 could be considered as a potential luminescent probe for the detection of ketone molecules. PMID- 28657632 TI - Interfacial adsorption of pH-responsive polymers and nanoparticles. AB - Using dissipative particle dynamics (DPD), we model the interfacial adsorption of pH-responsive polyelectrolytes and polyelectrolyte-grafted nanoparticles (PNPs) at a planar water-oil interface. The electrostatic interactions in the presence of the dielectric discontinuity across the interface are modeled by exploiting the Groot method, which uses an iterative method to solve the Poisson equation on a uniform grid with distributed charge. We reveal the effects of the pH and salinity of the aqueous solution and the length of the polyelectrolyte on the adsorption behavior of weak polyelectrolytes. The adsorption kinetics is monitored via the trajectory of the center of mass of the polyelectrolyte in the direction normal to the interface. The residence time at the interface and the pair correlation function between the polyelectrolyte and the oil are measured to quantitatively characterize the adsorption. Similar to the weak polyelectrolytes, the influences of pH, salinity and grafted chain length on the adsorption of an individual PNP are explored. Our results show that by grafting polyelectrolytes, the interfacial behavior of the nanoparticles can be tuned by changing the pH and salinity of the solution, which is dictated by the contact angle, the pair correlation function between the particles and the oil, the desorption energy, and the particle morphology at the interface. We also observe that the electrostatic-driven variations in the interfacial activity and morphology of the PNPs are not sensitive to the length of the grafted polyelectrolytes. PMID- 28657626 TI - From ice-binding proteins to bio-inspired antifreeze materials. AB - Ice-binding proteins (IBP) facilitate survival under extreme conditions in diverse life forms. IBPs in polar fishes block further growth of internalized environmental ice and inhibit ice recrystallization of accumulated internal crystals. Algae use IBPs to structure ice, while ice adhesion is critical for the Antarctic bacterium Marinomonas primoryensis. Successful translation of this natural cryoprotective ability into man-made materials holds great promise but is still in its infancy. This review covers recent advances in the field of ice binding proteins and their synthetic analogues, highlighting fundamental insights into IBP functioning as a foundation for the knowledge-based development of cheap, bio-inspired mimics through scalable production routes. Recent advances in the utilisation of IBPs and their analogues to e.g. improve cryopreservation, ice templating strategies, gas hydrate inhibition and other technologies are presented. PMID- 28657633 TI - Energy landscapes and dynamics of glycine on Cu(110). AB - Amino acids adsorbed on single-crystal metal surfaces have emerged as prototypical systems for exploring the properties that govern the development of long-range chirality in self-assembled monolayers (SAM) and supramolecular 2D networks. In this study, we characterise the self-assembly mechanism for glycine on the Cu(110) surface. This process occurs on a time scale that is too fast for most atomically resolved microscopic techniques, so the mechanism we propose here provides new insight for an important unexplored surface phenomenon. PMID- 28657634 TI - Multiscale modeling of a rectifying bipolar nanopore: explicit-water versus implicit-water simulations. AB - In a multiscale modeling approach, we present computer simulation results for a rectifying bipolar nanopore at two modeling levels. In an all-atom model, we use explicit water to simulate ion transport directly with the molecular dynamics technique. In a reduced model, we use implicit water and apply the Local Equilibrium Monte Carlo method together with the Nernst-Planck transport equation. This hybrid method makes the fast calculation of ion transport possible at the price of lost details. We show that the implicit-water model is an appropriate representation of the explicit-water model when we look at the system at the device (i.e., input vs. output) level. The two models produce qualitatively similar behavior of the electrical current for different voltages and model parameters. Looking at the details of concentration and potential profiles, we find profound differences between the two models. These differences, however, do not influence the basic behavior of the model as a device because they do not influence the z-dependence of the concentration profiles which are the main determinants of current. These results then address an old paradox: how do reduced models, whose assumptions should break down in a nanoscale device, predict experimental data? Our simulations show that reduced models can still capture the overall device physics correctly, even though they get some important aspects of the molecular-scale physics quite wrong; reduced models work because they include the physics that is necessary from the point of view of device function. Therefore, reduced models can suffice for general device understanding and device design, but more detailed models might be needed for molecular level understanding. PMID- 28657635 TI - Selective production of mono-aromatics from lignocellulose over Pd/C catalyst: the influence of acid co-catalysts. AB - The 'lignin-first' approach has recently gained attention as an alternative whole biomass pretreatment technology with improved yield and selectivity of aromatics compared with traditional upgrading processes using technical lignins. Metal triflates are effective co-catalysts that considerably speed up the removal of lignin fragments from the whole biomass. As their cost is too high in a scaled-up process, we explored here the use of HCl, H2SO4, H3PO4 and CH3COOH as alternative acid co-catalysts for the tandem reductive fractionation process. HCl and H2SO4 were found to show superior catalytic performance over H3PO4 and CH3COOH in model compound studies that simulate lignin-carbohydrate linkages (phenyl glycoside, glyceryl trioleate) and lignin intralinkages (guaiacylglycerol-beta-guaiacyl ether). HCl is a promising alternative to the metal triflates as a co-catalyst in the reductive fraction of woody biomass. Al(OTf)3 and HCl, respectively, afforded 46 wt% and 44 wt% lignin monomers from oak wood sawdust in tandem catalytic systems with Pd/C at 180 degrees C in 2 h. The retention of cellulose in the solid residue was similar. PMID- 28657636 TI - Bioelectrochemical conversion of CO2 to chemicals: CO2 as a next generation feedstock for electricity-driven bioproduction in batch and continuous modes. AB - The recent concept of microbial electrosynthesis (MES) has evolved as an electricity-driven production technology for chemicals from low-value carbon dioxide (CO2) using micro-organisms as biocatalysts. MES from CO2 comprises bioelectrochemical reduction of CO2 to multi-carbon organic compounds using the reducing equivalents produced at the electrically-polarized cathode. The use of CO2 as a feedstock for chemicals is gaining much attention, since CO2 is abundantly available and its use is independent of the food supply chain. MES based on CO2 reduction produces acetate as a primary product. In order to elucidate the performance of the bioelectrochemical CO2 reduction process using different operation modes (batch vs. continuous), an investigation was carried out using a MES system with a flow-through biocathode supplied with 20 : 80 (v/v) or 80 : 20 (v/v) CO2 : N2 gas. The highest acetate production rate of 149 mg L-1 d-1 was observed with a 3.1 V applied cell-voltage under batch mode. While running in continuous mode, high acetate production was achieved with a maximum rate of 100 mg L-1 d-1. In the continuous mode, the acetate production was not sustained over long-term operation, likely due to insufficient microbial biocatalyst retention within the biocathode compartment (i.e. suspended micro organisms were washed out of the system). Restarting batch mode operations resulted in a renewed production of acetate. This showed an apparent domination of suspended biocatalysts over the attached (biofilm forming) biocatalysts. Long term CO2 reduction at the biocathode resulted in the accumulation of acetate, and more reduced compounds like ethanol and butyrate were also formed. Improvements in the production rate and different biomass retention strategies (e.g. selecting for biofilm forming micro-organisms) should be investigated to enable continuous biochemical production from CO2 using MES. Certainly, other process optimizations will be required to establish MES as an innovative sustainable technology for manufacturing biochemicals from CO2 as a next generation feedstock. PMID- 28657638 TI - Who Watches the Watchers. Working Towards Safety for EHR Knowledge Resources. AB - The rise in the use of electronic health records (EHRs) and associated resources over the last decade is leading to the end of the paper medical record and all the risks associated with the use of a paper chart. However, there has not been a concomitant creation of a systematic oversight body that is specifically charged with ensuring the public's safety through the use of EHR knowledge resource tools or EHRs themselves. We recommend the formation a Health Information Technology Safety Center. Such a center could collect error reports, review EHRs and the knowledge resources incorporated within them, and investigate particularly challenging EHR-related safety issues at participating health care delivery organizations. Safety issues could be identified, corrected, and the solutions widely disseminated. PMID- 28657637 TI - Domain Modeling and Application Development of an Archetype- and XML-based EHRS. Practical Experiences and Lessons Learnt. AB - BACKGROUND: Access to patient data within the hospital or between hospitals is still problematic since a variety of information systems is in use applying different vendor specific terminologies and underlying knowledge models. Beyond, the development of electronic health record systems (EHRSs) is time and resource consuming. Thus, there is a substantial need for a development strategy of standardized EHRSs. We are applying a reuse-oriented process model and demonstrate its feasibility and realization on a practical medical use case, which is an EHRS holding all relevant data arising in the context of treatment of tumors of the sella region. In this paper, we describe the development process and our practical experiences. METHODS: Requirements towards the development of the EHRS were collected by interviews with a neurosurgeon and patient data analysis. For modelling of patient data, we selected openEHR as standard and exploited the software tools provided by the openEHR foundation. The patient information model forms the core of the development process, which comprises the EHR generation and the implementation of an EHRS architecture. Moreover, a reuse oriented process model from the business domain was adapted to the development of the EHRS. RESULTS: The reuse-oriented process model is a model for a suitable abstraction of both, modeling and development of an EHR centralized EHRS. The information modeling process resulted in 18 archetypes that were aggregated in a template and built the boilerplate of the model driven development. The EHRs and the EHRS were developed by openEHR and W3C standards, tightly supported by well established XML techniques. The GUI of the final EHRS integrates and visualizes information from various examinations, medical reports, findings and laboratory test results. CONCLUSION: We conclude that the development of a standardized overarching EHR and an EHRS is feasible using openEHR and W3C standards, enabling a high degree of semantic interoperability. The standardized representation visualizes data and can in this way support the decision process of clinicians. PMID- 28657639 TI - Analytical strategies to determine whether job strain is an important risk factor for occurrence of low-back pain. PMID- 28657640 TI - Cognitive behavioural therapy for reducing fatigue in post-polio syndrome and in facioscapulohumeral dystrophy: A comparison. AB - BACKGROUND: Cognitive behavioural therapy does not reduce fatigue in post-polio syndrome, but is effective in facioscapulohumeral dystrophy. This difference in efficacy might be explained by a different role of cognitions in these conditions. OBJECTIVE: To compare fatigue-related cognitions between patients with post-polio syndrome and facio-scapulohumeral dystrophy. SUBJECTS: Patients with post-polio syndrome (n = 21) and facioscapulohumeral dystrophy (n = 24) allocated to a cognitive behavioural therapy intervention in 2 identical trials. METHODS: Assessed cognitions included: sense of control over fatigue; catastrophizing; acceptance; focusing on fatigue; and perceived social support. Group differences in cognitions (independent t-tests or Mann-Whitney U tests) and group differences in the association of cognitions with fatigue (linear regression models) were studied. RESULTS: No differences in cognitions were found between the 2 groups (p > 0.18). Furthermore, there were no cognition-by-group interaction effects, except for "perceived social support", for which a different association with fatigue was found between the 2 groups (p = 0.01). However, univariate models revealed no associations per group. CONCLUSION: Fatigue-related cognitions in severely fatigued patients with post-polio syndrome are not clearly different from that in facioscapulohumeral dystrophy. Thus, the lack of efficacy of cognitive behavioural therapy in post-polio syndrome cannot be attributed to unique cognitive characteristics of this population. PMID- 28657641 TI - Life satisfaction in spouses of stroke survivors and control subjects: A 7-year follow-up of participants in the Sahlgrenska Academy study on ischaemic stroke. AB - OBJECTIVE: To investigate life satisfaction in spouses of middle-aged stroke survivors from the long-term perspective and to identify factors that explain their life satisfaction. DESIGN: Cross-sectional, case-control study. SUBJECTS: Cohabitant spouses of survivors of ischaemic stroke aged < 70 years at stroke onset (n = 248) and spouses of controls (n = 246). METHODS: Assessments were made 7 years after inclusion to the study. Spouses' life satisfaction was assessed with the Fugl-Meyer's Life Satisfaction Check-List (LiSAT 11). Stroke-related factors were examined with the National Institutes of Health stroke scale, Mini Mental State Examination, Barthel Index and modified Rankin Scale. RESULTS: Spouses of stroke survivors had significantly lower satisfaction with general life, leisure, sexual life, partner relationship, family life, and poorer somatic and psychological health than spouses of controls. Caregiving spouses had significantly lower scores on all life domains except vocation and own activities of daily living than non-caregiving spouses. Spouses' satisfaction on different life domains was explained mainly by their age, sex, support given to the partner, and the survivor's level of global disability, to which both physical and cognitive impairments contributed. CONCLUSION: Seven years after stroke, spouses of stroke survivors reported lower life satisfaction compared with spouses of controls. Life satisfaction in stroke survivors' spouses was associated with spouses' age, sex, giving support, and the stroke survivors' level of global disability. PMID- 28657642 TI - Are job strain and sleep disturbances prognostic factors for low-back pain?A cohort study of a general population of working age in Sweden. AB - The aim of this study was to determine whether job strain, i.e. a combination of job demands and decision latitude (job control), and sleep disturbances among persons with occasional low-back pain are prognostic factors for developing troublesome low-back pain; and to determine whether sleep disturbances modify the potential association between job strain and troublesome low-back pain. A population-based cohort from the Stockholm Public Health Cohort surveys in 2006 and 2010 (= 25,167) included individuals with occasional low-back pain at baseline 2006 (= 6,413). Through logistic regression analyses, potential prognostic effects of job strain and sleep disturbances were studied. Stratified analyses were performed to assess modification of sleep disturbances on the potential association between job strain and troublesome low-back pain. Those exposed to job strain; active job (odds ratio (OR) 1.3, 95% confidence interval (95% CI) 1.1-1.6), or high strain (OR 1.5, 95% CI 0.9-2.4) and those exposed to severe sleep disturbances (OR 3.0, 95% CI 2.3-4.0), but not those exposed to passive jobs (OR 1.1, 95% CI 0.9-1.4) had higher odds of developing troublesome low-back pain. Sleep disturbances did not modify the association between job strain and troublesome low-back pain. These findings indicate that active job, high job strain and sleep disturbances are prognostic factors for troublesome low back pain. The odds of developing troublesome low-back pain due to job strain were not modified by sleep disturbance. PMID- 28657643 TI - Principles of Assessment of Rehabilitation Services in Health Systems: Learning from experiences. AB - OBJECTIVE: Strengthening of health-related rehabilitation services must start from the needs of persons with health conditions experiencing disability and should be implemented within health systems. The implementation of rehabilitation services in health systems should be planned and realized according to the World Health Organization's 6 constituents of health systems (i.e. health service delivery; health workforce; health information systems; essential medicines; financing; and leadership and governance). The development of recommendations based on situation analysis and best-available data is crucial. METHODS: In order to facilitate such data collection at a national level, a checklist and a related questionnaire (Rehabilitation Service Assessment Tool (RSAT)) were developed and implemented. The following steps were followed to develop a checklist for implementation of rehabilitation services: a literature search, drafting, checking and testing the list, and development of the RSAT. RESULTS: The RSAT comprises 8 sections derived from 5 main domains of the most important areas of information (i.e. country profile; health system; disability and rehabilitation; national policies, laws, and responsibilities; and relevant non-governmental stakeholders). CONCLUSION: The implementation of RSAT in different missions has shown that the principles are working well and that RSAT is feasible and helpful. Further field testing is important and the development of an internationally agreed tool should be promoted. PMID- 28657644 TI - Communication in children and adolescents after acquired brain injury: An exploratory study. AB - OBJECTIVE: The usability of the Communicative Effectiveness Index (CETI) in adolescents with acquired brain injury was investigated and compared with linguistic, cognitive and brain injury data. DESIGN: A prospective, longitudinal, between-group design. SUBJECTS: Thirty participants were divided into 2 subgroups: CETI+ and CETI- groups. METHODS: Parental CETI ratings of daily communication were compared with linguistic data and IQ test results. Lesion site and aetiology were also studied. RESULTS: The CETI+ group (n = 16) had a mean score greater than 75 out of 100, while the mean score of the CETI- group (n = 14) was below 75. Complex daily communication was impaired in both groups, but the CETI- group scored significantly lower on verbal IQ and grammar comprehension tests and had more naming difficulties. A majority of subjects in the CETI- group had a left hemisphere injury. Traumatic vs non-traumatic acquired brain injury did not differentiate the results. Conclusion: Specific complex CETI items provided unique information that is not easily measured by linguistics and cognitive tests for use with the acquired brain injury group. Parental evaluations of communication skills were well reflected in language and verbal IQ test results. Left hemisphere injury was associated with poorer communication outcome. PMID- 28657645 TI - Post-traumatic changes in energy expenditure and body composition in patients with acute spinal cord injury. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To investigate the changes in resting energy expenditure and body composition over time in a cohort of patients with spinal cord injury during acute treatment, rehabilitation, and 2 years after the end of rehabilitation. METHODS: Adult patients admitted for acute treatment and rehabilitation after traumatic spinal cord injury were recruited. Measurements of resting energy expenditure and body composition were scheduled at 2, 6, 10 and 14 weeks after spinal cord injury, at the end of rehabilitation, and 2 years later. RESULTS: Patients' mean age was 38.8 years (standard deviation 14.0). Resting energy expenditure began to decrease up to the 10-week measurement (p = 0.02) and further decreased after the 130-week measurement (p< 0.001). Body weight was already decreased after the 6-week measurement (p< 0.01) and increased after the end of rehabilitation (p = 0.009). Percentage body fat mass showed similar changes. CONCLUSION: After an initial decrease in resting energy expenditure, body weight and percentage of body fat, these values levelled off during the rehabilitation period. After the end of the rehabilitation period, body weight and body fat mass increased again to the baseline levels, whereas resting energy expenditure decreased further. These results suggest that rehabilitation programmes should focus on adapting to these foreseeable changes. PMID- 28657646 TI - Wendan decoction (Traditional Chinese medicine) for schizophrenia. AB - BACKGROUND: Wendan decoction (WDD) is one of the classical Chinese herb formulas used for psychotic symptoms. It is thought to be safe, accessible and inexpensive. OBJECTIVES: To investigate the effects of WDD for treatment of people with schizophrenia or schizophrenia-like illness compared with placebo, antipsychotic drugs and other interventions for outcomes of clinical importance. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (February 2016), which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, China biomedical databases group (SinoMed, CNKI, VIP, Wanfang) and clinical trials registries. There are no language, date, document type, or publication status limitations for inclusion of records in the register. We also inspected references of identified studies and contacted relevant authors for additional information. SELECTION CRITERIA: Randomised controlled trials with useable data comparing WDD with antipsychotics, placebo or other interventions for people with schizophrenia. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratios (RR) and 95% confidence intervals (CIs), on an intention-to-treat basis. For continuous data, we estimated mean differences (MD) between groups and their 95% CIs. We employed a random-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included 15 randomised trials (1437 participants) of WDD for schizophrenia. There was a high risk of performance bias within the trials but overall, risk for selection, attrition and reporting bias was low or unclear.Data showed WDD improved the short-term global state of participants compared with placebo or no treatment (1 RCT n = 72, RR 0.53, 95% CI 0.39 to 0.73, low-quality evidence).When WDD was compared with antipsychotic drugs, such as chlorpromazine or risperidone, no difference in short-term global state of participants was observed (2 RCTs n = 140, RR 1.18 95% CI 0.98 to 1.43, moderate-quality evidence) and mental state (total endpoint Positive and Negative Syndrome Scale (PANSS): 2 RCTs, n = 140, MD 0.84, 95% CI -4.17 to 5.84, low-quality evidence). However, WDD was associated with fewer people experiencing extrapyramidal effects (EPS) compared with other treatments (2 RCTs 0/70 versus 47/70, n = 140, RR 0.02, 95% CI 0.00 to 0.15, moderate-quality evidence).WDD is often used as an add-on intervention alongside antipsychotics. When WDD + antipsychotic was compared to antipsychotic alone, the combination group had better global state (short-term results, 6 RCTs, n = 684, RR 0.60, 95% CI 0.50 to 0.72, moderate-quality evidence) and mental state (short-term total endpoint PANSS: 5 RCTs, n = 580, MD 11.64, 95% CI -13.33 to - 9.94, low-quality evidence), fewer people with EPS (2 RCTs n = 308, RR 0.46, 95% CI 0.30 to 0.70, moderate-quality evidence) and reduction of the mean use of risperidone (1 RCT n = 107, MD -0.70, 95% CI -0.87 to -0.53, low-quality evidence). But, there was no effect on weight gain (1 RCT n = 108, RR 0.50, 95% CI 0.20 to 1.24, low-quality evidence).When WDD + low-dose antipsychotic was compared with normal-dose antipsychotic alone, the combination again showed benefits for short-term global state (7 RCTs n = 522, RR 0.69, 95% CI 0.51 to 0.93, moderate-quality evidence), mental state (total endpoint PANSS: 4 RCTs n = 250, MD -9.53, 95% CI -17.82 to -1.24, low-quality evidence), and fewer participants with EPS (3 RCTS n = 280, RR 0.29, 95% CI 0.16 to 0.51, moderate-quality evidence).Across all comparisons, we found no data on outcomes directly reporting quality of life, hospital service use and economics. AUTHORS' CONCLUSIONS: Limited evidence suggests that WDD may have some positive short-term antipsychotic global effects compared to placebo or no treatment. However when WDD was compared with other antipsychotics there was no effect on global or mental state, but WDD was associated with fewer adverse effects. When WDD was combined with an antipsychotic, positive effects were found for global and mental state and the combination caused fewer adverse effects. The available evidence is not high quality. Better designed large studies are needed to fully and fairly test the effects of WDD for people with schizophrenia. PMID- 28657648 TI - Perceptual flexibility is coupled with reduced executive inhibition in students of the visual arts. AB - Artists often report that seeing familiar stimuli in novel and interesting ways plays a role in visual art creation. However, the attentional mechanisms which underpin this ability have yet to be fully investigated. More specifically, it is unclear whether the ability to reinterpret visual stimuli in novel and interesting ways is facilitated by endogenously generated switches of attention, and whether it is linked in turn to executive functions such as inhibition and response switching. To address this issue, the current study explored ambiguous figure reversal and executive function in a sample of undergraduate students studying arts and non-art subjects (N = 141). Art students showed more frequent perceptual reversals in an ambiguous figure task, both when viewing the stimulus passively and when eliciting perceptual reversals voluntarily, but showed no difference from non-art students when asked to actively maintain specific percepts. In addition, art students were worse than non-art students at inhibiting distracting flankers in an executive inhibition task. The findings suggest that art students can elicit endogenous shifts of attention more easily than non-art students but that this faculty is not directly associated with enhanced executive function. It is proposed that the signature of artistic skill may be increased perceptual flexibility accompanied by reduced cognitive inhibition; however, future research will be necessary to determine which particular subskills in the visual arts are linked to aspects of perception and executive function. PMID- 28657647 TI - Influences of PON1 on airway inflammation and remodeling in bronchial asthma. AB - This study aims to explore the influences of Paraoxonase-1 (PON1) involved in airway inflammation and remodeling in asthma. Mice were divided into control, asthma, asthma + PON1 and asthma + NC groups, and asthma models were established via aerosol inhalation of ovalbumin (OVA). HE, Masson, and PAS stains were used to observe airway inflammation and remodeling, Giemsa staining to assess inflammatory cells in bronchoalveolar lavage fluid (BALF), qRT-PCR and Western blot to detect PON1 expression, lipid peroxidation and glutathione assays to quantify malondialdehyde (MDA) activity and glutathione peroxidase (GSH) levels, ELISA to determine inflammatory cytokines and immunoglobulin, and colorimetry to detect PON1 activities. Additionally, mice lung macrophages and fibroblasts were transfected with PON1 plasmid in vitro; ELISA and qRT-PCR were performed to understand the effects of PON1 on inflammatory cytokines secreted by lung macrophages, MTT assay for lung fibroblasts proliferation and qRT-PCR and Western blot for the expressions of PON1, COL1A1, and fibronectin. After overexpression of PON1, the asthma mice had decreased inflammatory cell infiltration, fibrosis degree, and airway wall thickness; inflammatory cells and inflammatory cytokines in BALF were also reduced, expressions of OVA-IgE and IgG1, and MDA activity were decreased, but the expressions of OVA-IgG2a and INF-gamma and GSH levels were increased. Besides, PON1 significantly inhibited microphage expression of LPS induced inflammatory cytokines, lung fibroblast proliferation, and COL1A1 and fibronectin expression. Thus, PON1 could relieve airway inflammation and airway remodeling in asthmatic mice and inhibit the secretion of LPS-induced macrophage inflammatory cytokines and the proliferation of lung fibroblasts. PMID- 28657649 TI - Application of pretreatment methods on agricultural products prior to frying: a review. AB - Frying is one of the methods of processing foods, which imparts flavour, taste, colour and crispness in the fried foods. In spite of an increase in the demand for fried foods by consumers all over the world, the danger posed by consuming too much fat is still a challenge. Many researchers have put forward many ideas on how to reduce the oil uptake and improve the nutritional and organoleptic qualities of foods during frying. Several pretreatment techniques applied to food materials prior to frying have been investigated by researchers in a bid to reduce the oil uptake and improve the quality parameters of fried foods. Therefore, this review focuses on the various pretreatment methods and the recent novel methods like ultrasound, infrared, superheated steam drying, microwave technique and pulsed electric field applied to foods prior to frying and its effects on the qualities of fried foods. (c) 2017 Society of Chemical Industry. PMID- 28657650 TI - A review on symptoms, treatments protocols, and proteomic profile in sulfur mustard-exposed victims. AB - Sulfur mustard (SM) as an alkylating and vesicating agent was used for 100 years as a chemical weapon. SM as bi-functional mustard can attacks and alkylates lots of biomolecules. Different cellular mechanism and molecular pathways are responsible for damages to body tissues. Such as DNA damages, oxidative stress, Apoptosis, and inflammation. Sulfur mustard penetrated body organs and induces long term eye, skin, lung, gastrointestinal, urogenital damages and can cause carcinogenic and mutagenic consequences. Currently there is no definitive treatment protocol for SM exposed patients. The goal of treatment is relieving the symptoms with fast healing rate and retrieval of damaged tissues to normal function and appearance in short period of time. Evaluation of proteomics profile in SM-exposed victims has been performed in animal model and human patients. These studies revealed that different protein were involved in the patients with SM damages to skin and lungs. Apolipoprotein A1, type I cytokeratins K14, K16 and K17, S100 calcium-binding protein A8, alpha1 haptoglobin isoforms, Amyloid A1, albumin, haptoglobin, and keratin isoforms, immunoglobulin kappa chain are defined expressed proteins in the damaged tissues. PMID- 28657651 TI - Diet and cancer prevention: Dietary compounds, dietary MicroRNAs, and dietary exosomes. AB - Cancer is one of main health public problems worldwide. Several factors are involved in beginning and development of cancer. Genetic and internal/external environmental factors can be as important agents that effect on emerging and development of several cancers. Diet and nutrition may be as one of important factors in prevention or treatment of various cancers. A large number studies indicated that suitable dietary patterns may help to cancer prevention or could inhibit development of tumor in cancer patients. Moreover, a large numbers studies indicated that a variety of dietary compounds such as curcumin, green tea, folat, selenium, and soy isoflavones show a wide range anti-cancer properties. It has been showed that these compounds via targeting a sequence of cellular and molecular pathways could be used as suitable options for cancer chemoprevention and cancer therapy. Recently, dietary microRNAs and exosomes have been emerged as attractive players in cancer prevention and cancer therapy. These molecules could change behavior of cancer cells via targeting various cellular and molecular pathways involved in cancer pathogenesis. Hence, the utilization of dietary compounds which are associated with powerful molecules such as microRNAs and exosomes and put them in dietary patterns could contribute to prevention or treatment of various cancers. Here, we summarized various studies that assessed effect of dietary patterns on cancer prevention shortly. Moreover, we highlighted the utilization of dietary compounds, dietary microRNAs, and dietary exosomes and their cellular and molecular pathways in cancer chemoprevention. PMID- 28657652 TI - Life histories and conservation of long-lived reptiles, an illustration with the American crocodile (Crocodylus acutus). AB - Successful species conservation is dependent on adequate estimates of population dynamics, but age-specific demographics are generally lacking for many long-lived iteroparous species such as large reptiles. Accurate demographic information allows estimation of population growth rate, as well as projection of future population sizes and quantitative analyses of fitness trade-offs involved in the evolution of life-history strategies. Here, a long-term capture-recapture study was conducted from 1978 to 2014 on the American crocodile (Crocodylus acutus) in southern Florida. Over the study period, 7,427 hatchlings were marked and 380 individuals were recaptured for as many as 25 years. We estimated survival to be strongly age dependent with hatchlings having the lowest survival rates (16%) but increasing to nearly 90% at adulthood based on mark-recapture models. More than 5% of the female population were predicted to be reproductive by age 8 years; the age-specific proportion of reproductive females steadily increased until age 18 when more than 95% of females were predicted to be reproductive. Population growth rate, estimated from a Leslie-Lefkovitch stage-class model, showed a positive annual growth rate of 4% over the study period. Using a prospective sensitivity analysis, we revealed that the adult stage, as expected, was the most critical stage for population growth rate; however, the survival of younger crocodiles before they became reproductive also had a surprisingly high elasticity. We found that variation in age-specific fecundity has very limited impact on population growth rate in American crocodiles. We used a comparative approach to show that the original life-history strategy of American crocodiles is actually shared by other large, long-lived reptiles: while adult survival rates always have a large impact on population growth, this decreases with declining increasing growth rates, in favour of a higher elasticity of the juvenile stage. Crocodiles, as a long-lived and highly fecund species, deviate from the usual association of life histories of "slow" species. Current management practices are focused on nests and hatchling survival; however, protection efforts that extend to juvenile crocodiles would be most effective for conservation of the species, especially in an ever-developing landscape. PMID- 28657653 TI - Intrinsic Photoprotective Mechanisms in Chlorophylls. AB - Photosynthetic energy conversion competes with the formation of chlorophyll triplet states and the generation of reactive oxygen species. These may, especially under high light stress, damage the photosynthetic apparatus. Many sophisticated photoprotective mechanisms have evolved to secure a harmless flow of excitation energy through the photosynthetic complexes. Time-resolved laser induced optoacoustic spectroscopy was used to compare the properties of the T1 states of pheophytin a and its metallocomplexes. The lowest quantum yield of the T1 state is always observed in the Mg complex, which also shows the least efficient energy transfer to O2 . Axial coordination to the central Mg further lowers the yield of both T1 and singlet oxygen. These results reveal the existence of intrinsic photoprotective mechanisms in chlorophylls, embedded in their molecular design, which substantially suppress the formation of triplet states and the efficiency of energy transfer to O2 , each by 20-25 %. Such intrinsic photoprotective effects must have created a large evolutionary advantage for the Mg complexes during their evolution as the principal photoactive cofactors of photosynthetic proteins. PMID- 28657655 TI - The effect of nail characteristics on surface bacterial counts of surgical personnel before and after scrubbing. AB - OBJECTIVE: To determine the influence of nail characteristics on bacterial counts on the fingers of surgery personnel. STUDY DESIGN: Randomized nonblinded controlled crossover study design. SAMPLE POPULATION: Veterinary students, small animal surgery technicians, small animal surgery interns/residents, and small animal surgery faculty in a veterinary teaching hospital (n = 21). METHODS: Subjects were randomized into one of 2 groups; group 1 wore nail polish (P) for 1 week and group 2 (control) had nonpolished (NP) fingernails. Each subject changed groups the following week. Fingernail lengths were measured each day and fingernail samples were collected before and after presurgical scrub and after surgery. Total bacterial counts (TBC) and suspected staphylococci were counted on blood agar media and mannitol salt agar. The association between bacterial counts and nail biting, position of the volunteer, duration of the surgery, whether the nail polish was chipped, duration of nail polish application, type of surgery, and handedness was tested. Log-transformed CFU counts were compared with a Student's t test and presence or absence of bacteria were compared using Fisher's exact test. RESULTS: TBC, quantities of staphylococci, other gram-positive organisms, and gram-negative bacilli did not differ between P and NP personnel. The only variable associated with higher bacterial counts consisted of nail lengths greater than 2 mm. CONCLUSION: Nail polish did not influence bacterial counts and types of isolates, but nail length is a risk factor for increased bacterial counts. Based on our results, we recommend that nail length be kept under 2 mm. PMID- 28657654 TI - Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease. AB - Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer's disease (AD); however, detailed molecular characterization of this important protein post translational modification at the proteome level has been highly challenging, owing to its low stoichiometry and labile nature. Herein, we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in postmortem human brain tissues with and without AD by the use of isobaric tandem mass tag labelling, chemoenzymatic photocleavage enrichment, and liquid chromatography coupled to mass spectrometry. A total of 1850 O-GlcNAc peptides covering 1094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty-one O-GlcNAc peptides covering 81 proteins were altered in AD brains as compared with controls (q < 0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins, and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic AD. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28657657 TI - Why is digital pathology in cytopathology lagging behind surgical pathology? PMID- 28657656 TI - Functional interrelationship between TFII-I and E2F transcription factors at specific cell cycle gene loci. AB - Transcription factor TFII-I is a multifunctional protein implicated in the regulation of cell cycle and stress-response genes. Previous studies have shown that a subset of TFII-I associated genomic sites contained DNA-binding motifs for E2F family transcription factors. We analyzed the co-association of TFII-I and E2Fs in more detail using bioinformatics, chromatin immunoprecipitation, and co immunoprecipitation experiments. The data show that TFII-I interacts with E2F transcription factors. Furthermore, TFII-I, E2F4, and E2F6 interact with DNA regulatory elements of several genes implicated in the regulation of the cell cycle, including DNMT1, HDAC1, CDKN1C, and CDC27. Inhibition of TFII-I expression led to a decrease in gene expression and in the association of E2F4 and E2F6 with these gene loci in human erythroleukemia K562 cells. Finally, TFII-I deficiency reduced the proliferation of K562 cells and increased the sensitivity toward doxorubicin toxicity. The results uncover novel interactions between TFII-I and E2Fs and suggest that TFII-I mediates E2F function at specific cell cycle genes. PMID- 28657658 TI - Successful design and delivery of a professional poster. AB - BACKGROUND AND PURPOSE: Poster presentations are increasingly popular for dissemination of scientific and clinical knowledge at professional meetings; however, this professional skill is generally absent from advanced practice registered nurse (APRN) curricula and acquisition of the skill must occur in other arenas. The purpose of this article is to promote professional development by educating APRNs, students, and faculty on the essentials of poster development and presentation. METHODS: To aid in poster presentation skill development, types of posters, advantages and disadvantages, content and design, and tips to enhance these presentations are discussed. What is known on these topics is summarized and emphasis on professional appearance and conduct is highlighted. CONCLUSIONS: Content and layout, use of color, imagery, and positive and negative space are crucial design elements. Poster presentation essentials include being prepared, professional appearance, and professional behavior. IMPLICATIONS FOR PRACTICE: Designing and presenting a professional poster is an essential skill for all APRNs as the ability to communicate knowledge is central to the role. PMID- 28657659 TI - Current status of cadaver sources in Turkey and a wake-up call for Turkish anatomists. AB - Persisting difficulties in body procurement in Turkey led to the acquisition of donated, unclaimed, autopsied, and imported bodies regulated under current legislature. Yet, no study had investigated the extent of the on-going cadaver problem. This study was aimed to outline cadaver sources in anatomy departments and their effectiveness by means of an online survey. Additionally, official websites of each department were investigated regarding any information on body donation. Unclaimed cadavers (84.8%) were the major source for anatomy departments, followed by donated (50%) and imported cadavers (39.1%). Foundation based medical faculties were more likely to import cadavers (P = 0.008). There was a moderate increase (rs = 0.567; P = 0.018) in donation registrations to our department after 2000. The departments in cities with significantly higher City Based Gross Domestic Product measures (US$9,900 vs. US$16,772, P = 0.041), frequencies for mid- or high-school graduates (30.4% vs. 31.3%, P = 0.041), and frequencies for under- or post-graduates (13.1% vs. 15.8%, P = 0.24) had managed to use donated cadavers. Anatomy departments' major reasons for using unclaimed cadavers were education (45.9%), unclaimed cadavers being the only source (24.3%), and receiving inadequate donations (21.6%). Nine out of seventy-four departments (12.2%) provided information regarding body donation on their websites. Body procurement remains as a serious problem in Turkey and it is apparent that current legislature does not provide a sufficient cadaver inflow. Similarly, anatomy departments' effectiveness in public awareness of body donation and support in the National Body Donation Campaign seems questionable. Anat Sci Educ 11: 155-165. (c) 2017 American Association of Anatomists. PMID- 28657660 TI - FOXC1 haploinsufficiency due to 6p25 deletion in a patient with rapidly progressing aortic valve disease. AB - 6p25 deletion is a rare but well-known entity. The main clinical features include an abnormal facial appearance, developmental delay, and ocular anomalies. Cardiac anomalies are frequently seen but remain poorly delineated. We describe a 4-year old girl with 6p25.3 deletion, which includes the FOXC1 gene, typical dysmorphic features associated with developmental delay and oculo-motor anomalies. Aortic valve dysplasia was diagnosed early in life. The cardiac lesion progressed very rapidly between the age of 3 and 4 years requiring aortic valve replacement. Genomic analysis of blood and excised valve tissue showed down-regulation of FOXC1 but also FOXC2 expression in the diseased aortic valve. This allows us to speculate on the potential role of FOXC1 in aortic valve anomalies. PMID- 28657661 TI - Topotactic Synthesis of Porous Cobalt Ferrite Platelets from a Layered Double Hydroxide Precursor and Their Application in Oxidation Catalysis. AB - Monocrystalline, yet porous mosaic platelets of cobalt ferrite, CoFe2 O4 , can be synthesized from a layered double hydroxide (LDH) precursor by thermal decomposition. Using an equimolar mixture of Fe2+ , Co2+ , and Fe3+ during co precipitation, a mixture of LDH, (FeII CoII )2/3 FeIII1/3 (OH)2 (CO3 )1/6 ?m H2 O, and the target spinel CoFe2 O4 can be obtained in the precursor. During calcination, the remaining FeII fraction of the LDH is oxidized to FeIII leading to an overall Co2+ :Fe3+ ratio of 1:2 as required for spinel crystallization. This pre-adjustment of the spinel composition in the LDH precursor suggests a topotactic crystallization of cobalt ferrite and yields phase pure spinel in unusual anisotropic platelet morphology. The preferred topotactic relationship in most particles is [111]Spinel ?[001]LDH . Due to the anion decomposition, holes are formed throughout the quasi monocrystalline platelets. This synthesis approach can be used for different ferrites and the unique microstructure leads to unusual chemical properties as shown by the application of the ex-LDH cobalt ferrite as catalyst in the selective oxidation of 2-propanol. Compared to commercial cobalt ferrite, which mainly catalyzes the oxidative dehydrogenation to acetone, the main reaction over the novel ex-LDH cobalt is dehydration to propene. Moreover, the oxygen evolution reaction (OER) activity of the ex-LDH catalyst was markedly higher compared to the commercial material. PMID- 28657662 TI - From Well-Defined Alkylzinc Phosphinates to Quantum-Sized ZnO Nanocrystals. AB - Despite various applications of alkylzinc carboxylates in chemistry and materials science, the corresponding organozinc derivatives of organophosphorus compounds still represent an insufficiently explored area. To fill this gap, we report on the synthesis of alkylzinc phosphinates and their use as efficient precursors of phosphinate-coated ZnO nanocrystals in the quantum size regime. Examples of a series of alkylzinc phosphinates with the general formula [RZn(O2 PR'2 )] (R=tBu or Et) have been prepared through equimolar reactions between ZnR2 and a selected phosphinic acid, namely dimethylphosphinic acid (dmpha-H), methylphenylphosphinic acid (mppha-H), diphenylphosphinic acid (dppha-H), or bis(4 methoxyphenyl)phosphinic acid (dmppha-H). The reactivities of alkylzinc phosphinate complexes toward H2 O and O2 have also been investigated, which resulted in the isolation of two oxo-zinc phosphinate clusters, that is, [Zn4 (MU4 -O)(dppha)6 ] and [Zn4 (MU4 -O)(dmppha)6 ], as well as the unique alkoxy(oxo)zinc cluster [Zn4 (MU4 -O)(MU2 -OtBu)(dppha)5 ]. Analysis of the crystal structures has revealed that organozinc complexes incorporating phosphinate ligands exhibit a unique capacity for shape-driven self-assembly to produce extended networks, including noncovalent quasi-porous materials. Finally, monodispersed and quantum-sized ZnO NCs coated with phosphinate ligands have been prepared using a non-external-surfactant-assisted wet-chemical organometallic approach based on well-defined [RZn(O2 PR'2 )]-type compounds. The resulting brightly luminescent ZnO NCs exhibit average core sizes and hydrodynamic diameters in the ranges 2-4.5 nm and 5-8 nm, respectively. The size of the inorganic core is slightly affected by the character of the incorporated phosphinate ligand, being smallest for ZnO NCs coated by asymmetrically substituted mppha ligands. Regardless of whether or not various phosphinate coating ligands could be controllably applied on the ZnO NC surface, no significant differences were found in the luminescence profiles of the analyzed nanosystems. PMID- 28657663 TI - Next generation deep sequencing corrects diagnostic pitfalls of traditional molecular approach in a patient with prenatal onset of Pompe disease. AB - Pompe disease is a rare inherited metabolic disorder of glycogen metabolism caused by mutations in the GAA gene, encoding the acid alpha-1,4 glucosidase. Successful diagnosis of Pompe disease is achieved by clinical and biochemical evaluation followed by confirmation with DNA testing. Here, we report a male infant with a prenatal onset of cardiac symptoms and enzyme testing consistent with Pompe disease, but DNA testing by Sanger sequencing revealed no pathogenic variants. Due to the strong indication from clinical, enzymatic, and histological studies (despite the absence of molecular confirmation by traditional Sanger sequencing), enzyme replacement therapy (ERT) for Pompe disease was initiated. Reanalysis of the patient's DNA sample using next generation sequencing (NGS) of a panel of target genes causing glycogen storage disorders demonstrated compound heterozygosity for a point mutation and an exonic deletion in the GAA gene. This case illustrates the value of astute clinical judgement in patient management as well as the power of target capture deep NGS in the simultaneous detection of both a point mutation and a heterozygous exonic deletion by correcting pitfalls of the traditional PCR based sequencing, namely; allele dropout and the inability to detect exonic deletions. PMID- 28657665 TI - Obacunone causes sustained expression of MKP-1 thus inactivating p38 MAPK to suppress pro-inflammatory mediators through intracellular MIF. AB - Obacunone (OBA) is a highly oxygenated triterpenoid with various pharmacological activities. In this study, we explored its anti-inflammatory effect and underlying mechanisms in LPS-activated macrophages. Our data showed that OBA potently decreased pro-inflammatory mediators (eg, NO, IL-6, IL-1beta, and MCP-1) at the transcriptional and translational levels without cytotoxicity. A mechanism study showed that OBA significantly suppressed p38-mediated AP-1 signaling by stabilizing the mRNA of mitogen-activated protein kinase phosphatase 1 (MKP-1), thus prolonging the expression time of the MKP-1 protein. Next, we used computational target-fishing technology to predict the possible target of OBA. Only one potential target, macrophage migration inhibitory factor (MIF), was presented. Experimentally, the interaction between OBA and MIF was also confirmed. By using an anti-mouse MIF antibody, extracellular MIF (exMIF) was neutralized. Our results showed that autocrine MIF had slight influence on the pro-inflammatory mediator production. Correspondingly, the anti-inflammatory activity of OBA was also not affected. Accordingly, we knocked down the MIF gene in RAW 264.7 cells and obtained stable MIF deficient cells MIF(-), in which the effects of OBA on p38 phosphorylation, AP-1 activation, and pro-inflammatory mediator production in response to LPS nearly disappeared. In contrast to MIF(+) cells, the MKP-1 protein expression time of the MIF(-) cells was markedly prolonged. We conclude that OBA exerts its anti-inflammatory effect by targeting intracellular MIF (inMIF) inhibition to regulate the MKP-1/p38/AP-1 pathway. Our findings also provide a chain of evidence that the inhibition of inMIF, rather than exMIF, may become a novel target for inflammation. PMID- 28657664 TI - Conditional abrogation of transforming growth factor-beta receptor 1 in PTEN inactivated endometrium promotes endometrial cancer progression in mice. AB - Although a putative role for transforming growth factor-beta (TGFB) signalling in the pathogenesis of human endometrial cancer has long been proposed, the precise function of TGFB signalling in the development and progression of endometrial cancer remains elusive. Depletion of phosphatase and tensin homologue (PTEN) in the mouse uterus causes endometrial cancer. To identify the potential role of TGFB signalling in endometrial cancer, we simultaneously deleted TGFB receptor 1 (Tgfbr1) and Pten in the mouse uterus by using Cre-recombinase driven by the progesterone receptor (termed Ptend/d ;Tgfbr1d/d ). We found that Ptend/d ;Tgfbr1d/d mice developed severe endometrial lesions that progressed more rapidly than those resulting from conditional deletion of Pten alone, suggesting that TGFB signalling synergizes with PTEN to suppress endometrial cancer progression. Remarkably, Ptend/d ;Tgfbr1d/d mice developed distant pulmonary metastases, leading to a significantly reduced lifespan. The development of metastasis and accelerated tumour progression in Ptend/d ;Tgfbr1d/d mice are associated with increased production of proinflammatory chemokines, enhanced cancer cell motility, as shown by myometrial invasion and disruption, and an altered tumour microenvironment characterized by recruitment of tumour-associated macrophages. Thus, conditional deletion of Tgfbr1 in PTEN-inactivated endometrium leads to a disease that recapitulates invasive and lethal human endometrial cancer. This mouse model may be valuable for preclinical testing of new cancer therapies, particularly those targeting metastasis, one of the hallmarks of cancer and a major cause of death in endometrial cancer patients. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28657666 TI - Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of beta2-microglobulin: A molecular dynamics simulation study. AB - Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic beta2-microglobulin (beta2m) protein around skeletal joints and bones. The recent studies highlighted a critical role of the DE loop region for beta2m stability and amyloid aggregation propensity. Despite significant efforts, the molecular mechanism of enhanced aggregation due to D59P mutation in the DE loop region remain elusive. In the present study, explicit solvent molecular dynamics (MD) simulations were performed to examine the key changes in the structural and dynamic properties of wild type (wt) beta2m upon D59P mutation. MD simulations reveal a decrease in the average number of hydrogen bonds in the loop regions on D59P mutation that enhances conformational flexibility, which lead to higher aggregation propensity of D59P as compare to wt beta2m. The principal component analysis (PCA) highlight that D59P covers a larger region of phase space and display a higher trace value than wt beta2m, which suggest an overall enhancement in the conformational flexibility. D59P display two minimum energy basins in the free energy landscape (FEL) that are associated with thermodynamically less stable conformational states as compare to single minimum energy basin in wt beta2m. The present study provides theoretical insights into the molecular mechanism behind the higher aggregation propensity of D59P as compare to wt beta2m. PMID- 28657667 TI - Germline genetic variants in men with prostate cancer and one or more additional cancers. AB - BACKGROUND: Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of the disease. The aim of the current study was to describe the prevalence of pathogenic germline variants in cancer-predisposing genes in men with prostate cancer and at least 1 additional primary cancer. METHODS: Using a multigene panel, the authors sequenced germline DNA from 102 men with prostate cancer and at least 1 additional primary cancer who also met >=1 of the following criteria: 1) age <=55 years at the time of diagnosis of the first malignancy; 2) rare tumor type or atypical presentation of a common tumor; and/or 3) >=3 primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine whether the patient met established criteria for testing for a hereditary cancer syndrome. RESULTS: Sequencing identified approximately 3500 variants. Nine protein-truncating deleterious mutations were found across 6 genes, including BRCA2, ataxia telangiectasia mutated (ATM), mutL homolog 1 (MLH1), BRCA1 interacting protein C terminal helicase 1 (BRIP1), partner and localizer of BRCA2 (PALB2), and fibroblast growth factor receptor 3 (FGFR3). Likely pathogenic missense variants were identified in checkpoint kinase 2 (CHEK2) and homeobox protein Hox-B13 (HOXB13). In total, 11 of 102 patients (10.8%) were found to have pathogenic or likely pathogenic mutations in cancer-predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. CONCLUSIONS: Men with prostate cancer and at least 1 additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer predisposing gene that may impact cancer prognosis and treatment, but the majority do not meet current criteria for clinical genetic testing. Cancer 2017;123:3925-32. (c) 2017 American Cancer Society. PMID- 28657668 TI - Long noncoding RNA BDNF-AS inversely regulated BDNF and modulated high-glucose induced apoptosis in human retinal pigment epithelial cells. AB - In this study, we characterized the functional role of long noncoding RNA (lncRNA), brain derived neurotrophic factor anti-sense (BDNF-AS) in regulating D glucose-induced (DGI) apoptosis in human retinal pigment epithelial (RPE) cells. Human RPE cell line, ARPE-19 cells were cultured in vitro and treated with various concentrations of D-glucose for 24 h. A TUNEL assay was applied with immunohistochemical and quantitative approaches to assess the apoptotic effect of D-glucose. Under the condition of 50 mM D-glucose, qPCR was used to assess gene expression of BDNF and BDNF-AS in ARPE-19 cells. Using siRNA transfection, BDNF AS was endogenously knocked down in ARPE-19 cells. The effects of BDNF-AS downregulation on DGI apoptosis and BDNF expression were assessed by TUNEL assay, qPCR, and Western blot, respectively. Furthermore, in BDNF-AS-downregulated ARPE 19 cells, secondary siRNA transfection was conducted to knock down endogenous BDNF expression. Its effect on BDNF-AS-associated apoptotic regulation was further evaluated. High concentrations of D-glucose induced significant apoptosis in ARPE-19 cells in vitro. With treatment of 50 mM D-glucose, BDNF was markedly downregulated whereas BDNF-AS upregulated in ARPE-19 cells. SiRNA-mediated BDNF AS downregulation ameliorated DGI apoptosis and upregulated BDNF in ARPE-19 cells. In addition, inhibiting BDNF reversed the protective effect of BDNF-AS downregulation on DGI apoptosis. Our results suggest that BDNF-AS, through inverse regulation of BDNF, might play a critical role in the process of DGI apoptosis in diabetic retinopathy. PMID- 28657669 TI - Does the use of arteriovenous loops increase complications rates in posttraumatic microsurgical lower extremity reconstruction?-A matched-pair analysis. AB - INTRODUCTION: The use of arteriovenous (AV) loops in microsurgical lower extremity reconstruction is a controversial topic. The objective of the present study was to assess the impact of AV loops on complication rates following microsurgical reconstruction of posttraumatic lower extremity defects. PATIENTS AND METHODS: Patients who underwent free flap coverage of posttraumatic defects in combination with an AV loop (Group 1) were identified and matched for age, body mass index (BMI), tobacco use, defect location, and flap type with patients who underwent reconstruction without vein grafts (Group 2). Outcomes of interest included complication rate and flap loss rate. RESULTS: Groups 1 and 2 consisted of 10 patients each with a mean age of 51 years (range, 21-79 years) and 47.3 years (range, 22-69 years), respectively (P = 0.596). No differences were noted regarding flap loss (P = 1.0), intraoperative (P = 0.474) or postoperative complication rate [surgical site infection (P = 1.0), bleeding (P = 1.0), delayed wound healing (P = 0.23), dehiscence (P = 0.58), and osseous non-union (P = 1.0)]. Only one flap loss was noted in Group 1. The only differences were increased operative time (P = 0.03) and increased length of stay (P = 0.009) in Group 1. CONCLUSION: Our results suggest that utilization of vein grafts with creation of AV loops followed by single-stage division and free flap transfer for reconstruction of posttraumatic lower extremity defects achieve reconstructive outcomes similar to those obtained in patients in whom no vein grafts are necessary. PMID- 28657670 TI - Mapping the recognition domains of pneumococcal fibronectin-binding proteins PavA and PavB demonstrates a common pattern of molecular interactions with fibronectin type III repeats. AB - Colonization of mucosal respiratory surfaces is a prerequisite for the human pathobiont Streptococcus pneumoniae (the pneumococcus) to cause severe invasive infections. The arsenal of pneumococcal adhesins interacts with a multitude of extracellular matrix proteins. A paradigm for pneumococci is their interaction with the adhesive glycoprotein fibronectin, which facilitates bacterial adherence to host cells. Here, we deciphered the molecular interaction between fibronectin and pneumococcal fibronectin-binding proteins (FnBPs) PavA and PavB respectively. We show in adherence and binding studies that the pneumococcal interaction with fibronectin is a non-human specific trait. PavA and PavB target at least 13 out of 15 type III fibronectin domains as demonstrated in ligand overlay assays, surface plasmon resonance studies and SPOT peptide arrays. Strikingly, both pneumococcal FnBPs recognize similar peptides in targeted type III repeats. Structural comparisons revealed that the targeted type III repeat epitopes cluster on the inner strands of both beta-sheets forming the fibronectin domains. Importantly, synthetic peptides of FnIII1 , FnIII5 or FnIII15 bind directly to FnBPs PavA and PavB respectively. In conclusion, our study suggests a common pattern of molecular interactions between pneumococcal FnBPs and fibronectin. The specific epitopes recognized in this study can potentially be tested as antimicrobial targets in further scientific endeavours. PMID- 28657671 TI - Effects of astragalus polysaccharide on apoptosis of myocardial microvascular endothelial cells in rats undergoing hypoxia/reoxygenation by mediation of the PI3K/Akt/eNOS signaling pathway. AB - The study explores the effect of astragalus polysaccharide (APS) mediating P13K/Akt/eNOS signaling pathway on apoptosis of myocardial microvascular endothelial cells (MMECs) in hypoxia/reoxygenation (H/R). MMECs were classified into blank, H/R, H/R + 25 mg/L APS, H/R + 50 mg/L APS, H/R + 100 mg/L APS, H/R + LY, and HR + 100 mg/L APS + LY groups. Cell viability was detected using MTT assay and apoptotic cell morphological changes by Hoechst staining. NO content, cell cycle and apoptosis, PI3K/Akt/eNOS signaling pathway proteins were detected using nitrate reductase assay, flow cytometry and Western blotting. An increased cell survival rate, NO content and expression of PI3K/Akt/eNOS signaling pathway associated proteins, and a decreased apoptosis rate was observed in the H/R + 50 mg/L APS and H/R + 100 mg/L APS groups compared with the H/R and H/R + 25 mg/L APS groups. Compared with the H/R + 50 mg/L APS group, the apoptosis rate decreased, whereas the cell survival rate, NO content and expression of PI3K/Akt/eNOS signaling pathway associated proteins increased in the H/R + 100 mg/L APS group. The H/R + LY and HR + 100 mg/L APS + LY groups followed opposite trends. In comparison to the HR + 100 mg/L APS group, the apoptosis rate in the H/R + LY and HR + 100 mg/L APS + LY groups increased, and the cell survival rate, NO content and expression of PI3K/Akt/eNOS signaling pathway associated proteins decreased. Collectively, APS improves the damage caused by H/P by mediating PI3K/Akt/eNOS signaling pathway. PMID- 28657672 TI - Genetic variants in 3'-UTRs of MTHFR in the pregnancies complicated with preeclampsia and bioinformatics analysis. AB - Preeclampsia (PE) as a pregnancy-specific disorder is the major cause of mortality and morbidity of mothers and fetuses. This study attempts to investigate the possible association between the 2572C>A (rs4846049) and 4869C>G (rs1537514) polymorphisms in the 3'- untranslated region of MTHFR gene and the risk of PE. A total of 198 patients diagnosed with PE and 171 unrelated, age matched healthy pregnant women, were recruited for this case-control study. The MTHFR 2572C>A and 4869C>G genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The CG genotype of MTHFR 4869C>G was associated with decreased risk of PE, and this genotype was found to be a protective factor for PE susceptibility. There was no significant difference in the genotypes of MTHFR 2572C>A polymorphism between PE patients and control group. The frequency of combined AC/CG genotypes of MTHFR 2572C>A and 4869C>G polymorphisms were less frequent in PE patients and were associated with a lower risk of PE. The C-G and A-G haplotypes of MTHFR 2572C>A and 4869C>G polymorphisms were significantly lower in PE patients. In conclusion, the CG genotype of MTHFR 4869C>G polymorphism was associated with a lower risk of PE. No association was found between MTHFR 2572C>A polymorphism and PE. PMID- 28657673 TI - European guidelines for workplace drug testing in oral fluid. AB - These guidelines for Legally Defensible Workplace Drug Testing have been prepared and updated by the European Workplace Drug Testing Society (EWDTS). The European Guidelines are designed to establish best practice procedures whilst allowing individual countries to operate within the requirements of national customs and legislation. The EWDTS recommends that all European laboratories that undertake legally defensible workplace drug testing should use these guidelines as a template for accreditation. These guidelines are relevant to laboratory-based testing only. These guidelines follow current best practices and are constantly under review. PMID- 28657674 TI - A Convergent Synthesis of Functionalized Alkenyl Halides through Cobalt(III) Catalyzed Three-Component C-H Bond Addition. AB - A CoIII -catalyzed three-component coupling of C(sp2 )-H bonds, alkynes, and halogenating agents to give alkenyl halides is reported. This transformation proceeds with high regio- and diastereoselectivity, and is effective for a broad range of aryl and alkyl terminal alkynes. Diverse C-H bond partners also exhibit good reactivity for a range of heteroaryl and aryl systems as well as synthetically useful secondary and tertiary amide, urea, and pyrazole directing groups. This multicomponent transformation is also compatible with allenes in place of alkynes to furnish tetrasubstituted alkenyl halides, showcasing the first halo-arylation of allenes. PMID- 28657675 TI - Reply to Why is digital pathology in cytopathology lagging behind surgical pathology? PMID- 28657676 TI - Rate disparity of near-field versus far-field ICD electrograms: A clue to the diagnosis of dissimilar ventricular rhythms. PMID- 28657678 TI - Kinetics of CO2 Hydrogenation to Hydrocarbons over Iron-Silica Catalysts. AB - The conversion of CO2 to hydrocarbons is increasingly seen as a potential alternative source of fuel and chemicals, while at the same time contributing to addressing global warming effects. An understanding of kinetics and mass transfer limitations is vital to both optimise catalyst performance and to scale up the whole process. In this work we report on a systematic investigation of the influence of the different process parameters, including pore size, catalyst support particle diameter, reaction temperature, pressure and reactant flow rate on conversion and selectivity of iron nanoparticle -silica catalysts. The results provided on activation energy and mass transfer limitations represent the basis to fully design a reactor system for the effective catalytic conversion of CO2 to hydrocarbons. PMID- 28657677 TI - Effects of Pimozide Derivatives on pSTAT5 in K562 Cells. AB - STAT5 is a transcription factor, a member of the STAT family of signaling proteins. STAT5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), in which this protein is found constitutively activated as a consequence of BCR-ABL expression. The neuroleptic drug pimozide was recently reported to act as an inhibitor of STAT5 phosphorylation and is capable of inducing apoptosis in CML cells in vitro. Our research group has synthesized simple derivatives of pimozide with cytotoxic activity and that are able to decrease the levels of phosphorylated STAT5. In this work we continued the search for novel STAT5 inhibitors, synthesizing compounds in which the benzoimidazolinone ring of pimozide is either maintained or modified, in order to obtain further structure-activity relationship information for this class of STAT5 inhibitors. Two compounds of the series showed potent cytotoxic activity against BCR-ABL-positive and pSTAT5-overexpressing K562 cells and were able to markedly decrease the levels of phosphorylated STAT5. PMID- 28657679 TI - CO2 -Sourced alpha-Alkylidene Cyclic Carbonates: A Step Forward in the Quest for Functional Regioregular Poly(urethane)s and Poly(carbonate)s. AB - Described is a robust platform for the synthesis of a large diversity of novel functional CO2 -sourced polymers by exploiting the regiocontrolled ring-opening of alpha-alkylidene carbonates by various nucleophiles. The reactivity of alpha alkylidene carbonates is dictated by the exocyclic olefinic group. The polyaddition of CO2 -sourced bis(alpha-alkylidene carbonate)s (bis-alphaCCs) with primary and secondary diamines provides novel regioregular functional poly(urethane)s. The reactivity of bis-alphaCCs is also exploited for producing new poly(beta-oxo-carbonate)s by organocatalyzed polyaddition with a diol. This synthesis platform provides new functional variants of world-class leading polymer families (polyurethanes, polycarbonates) and valorizes CO2 as a chemical feedstock. PMID- 28657680 TI - Lysophosphatidic acid-triggered pathways promote the acquisition of trophoblast endovascular phenotype in vitro. AB - Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Defects in this mechanism correlate with severe obstetric complications as implantation failure and preeclampsia. Lysophosphatidic acid (LPA) participates in embryo implantation and contributes to vascular physiology in different biological systems. However, the role of LPA on trophoblast endovascular transformation has not been studied. Due to difficulties in studying human pregnancy in vivo, we adopted a pharmacological approach in vitro to investigate LPA action in various aspects of trophoblast endovascular response, such as the formation of endothelial capillary-like structures, migration, and proliferation. The HTR-8/SVneo cell line established from human first trimester cytotrophoblast was used to model the acquisition of the endovascular phenotype by the invading trophoblast. LPA increased HTR-8/SVneo tube formation, migration (wound healing assay and phalloidin staining) and proliferation (MTT assay). LPA G protein-coupled receptors, LPA1 and LPA3 , were expressed in HTR-8/SVneo. By using selective antagonists, we showed that enhanced tubulogenesis was mediated by LPA3 . In addition, cyclooxygenase-2 and inducible nitric oxide synthase pathways participated in LPA-stimulated tubulogenesis. Inducible nitric oxide synthase was activated downstream cyclooxygenase-2. Furthermore, prostaglandin E2 and a nitric oxide donor (SNAP) increased trophoblast tube formation in a concentration-dependent manner. Finally, we observed that cyclooxygenase-2 and inducible nitric oxide synthase were localized in the nucleus, and LPA did not modify their cellular distribution. Our results show that LPA-triggered regulatory pathways promote trophoblast endovascular response in vitro, suggesting a new role for LPA during spiral artery remodeling at the maternal fetal interface. PMID- 28657682 TI - Vinyl (Thio)Ethers versus Enamines: A DFT Insight into Their Divergent Reactivities toward Nitroalkenes. AB - Despite their apparent similarities, vinyl (thio)ethers and enamines display divergent reactivities toward nitroalkenes. Whereas [4+2] cycloadduct derivatives are generally obtained in the first case, a variety of adducts are observed in the second, and depend on the substrates and reaction conditions. Herein, a rationalization of this versatility is proposed through a theoretical study, in which the interactions between these electron-rich alkenes and nitroethylene are compared in conjugate addition, [4+2] and [2+2] cycloadditions, and ene reaction processes. The conjugate zwitterionic adduct is shown to play a key role. With vinyl (thio)ethers, its formation is disfavored, whereas, for enamines, it appears as a stabilized intermediate, leading to the thermodynamically favored formal ene adduct. This adduct is, however, kinetically disfavored, which opens up the way to control the selectivity of the whole process. PMID- 28657681 TI - Negative regulation of filamentous growth in Candida albicans by Dig1p. AB - Transcriptional regulation involves both positive and negative regulatory elements. The Dig1 negative regulators are part of a fungal-specific module that includes a transcription factor (a Ste12 family member) and a Dig1 family member. In Saccharomyces cerevisiae, the post-genome-duplication Dig1/Dig2 proteins regulate MAP kinase controlled signalling pathways involved in mating and filamentous growth. We have identified the single Dig1 orthologue in the fungal pathogen Candida albicans. Genetic studies and transcriptional profiling experiments show that this single protein is implicated in the regulation of MAP kinase-controlled processes involved in mating, filamentous growth and biofilm formation, and also influences cAMP-regulated processes. This suggests that the multiple cellular roles of the Dig1 protein are ancestral and predate the sub functionalization apparent in S. cerevisiae after the genome duplication. Intriguingly, even though loss of Dig1 function in C. albicans enhances filamentous growth and biofilm formation, colonization of the murine gastrointestinal tract is reduced in the mutant. The complexity of the processes influenced by Dig1 in C. albicans, and the observation that Dig1 is one of the few regulatory proteins that were retained in the duplicated state after the whole genome duplication event in yeast, emphasizes the important role of these negative regulators in fungal transcriptional control. PMID- 28657684 TI - karmoisin and cardinal ortholog genes participate in the ommochrome synthesis of Nilaparvata lugens (Hemiptera: Delphacidae). AB - Ommochrome is the major source for eye coloration of all insect species so far examined. Phenoxazinone synthetase (PHS) has always been regarded as the terminal step enzyme for ommochrome formation, which is encoded by cardinal or karmoisin genes. Our previous study indicated that the karmoisin ortholog gene (Nl karmoisin) product in the brown planthopper (BPH) was a monocarboxylate transporter, while not a PHS. Here, based on full-length complementary DNA, the cardinal ortholog gene in BPH (Nl-cardinal) product was predicted to be a haem peroxidase rather than a PHS. We suggest for the first time that neither karmoisin nor cardinal encodes the PHS, but whether PHS participates in BPH eye pigmentation needs further research. Nymphal RNA interference (RNAi) experiments showed that knockdown Nl-cardinal transcript led the BPH ocelli and compound eye to color change from brown to red, while knockdown Nl-karmoisin only made the ocelli present the red phenotype. Notably, not only the Nl-cardinal transcript, dscd injection (Nl-cardinal targeting double-stranded DNA (dsRNA)) also significantly reduced the Nl-karmoisin transcript by 33.7%, while dska (Nl karmoisin targeting dsRNA) injection did not significantly change the Nl-cardinal transcript. Considering the above RNAi and quantitative real-time polymerase chain reaction results, we propose that Nl-cardinal plays a more important role in ommochrome synthesis than Nl-karmoisin, and it may be an upstream gene of Nl karmoisin. The present study suggested that both karmoisin and cardinal ortholog genes play a role in ommochrome synthesis in a hemimetabolous insect. PMID- 28657683 TI - Association between social functioning and prefrontal cortex function during a verbal fluency task in schizophrenia: A near-infrared spectroscopic study. AB - AIM: Impaired social functioning is a common characteristic of patients with schizophrenia. Social functioning requires the complex operation of various executive functions. Deficits in the prefrontal cortex (PFC) have been implicated in executive dysfunction. Here we aimed to clarify the relation between subjectively and objectively assessed social functioning, and their associations with PFC function in patients with schizophrenia. METHODS: Twenty-three patients and 22 age- and sex-matched healthy controls (HC) were assessed. In the schizophrenia group, self- and caregiver-rated social functioning were measured using the Specific Level of Functioning Assessment (SLOF). The hemodynamic responses elicited by a verbal fluency task (VFT) in three regions of interest in the frontotemporal area were measured using multi-channel near-infrared spectroscopy (NIRS). We also investigated psychiatric symptoms, neurocognition, and cognitive insight to assess possible confounding factors. RESULTS: Significant positive correlations were found between self- and caregiver-rated SLOF composite scores and three subdomain scores. Self- and caregiver-rated SLOF composite scores were significantly associated with dorsolateral PFC and frontopolar cortex (DLPFC/FPC) activation during the VFT. Psychiatric symptoms, global functioning, neurocognition, and cognitive insight were not associated with NIRS signals. General psychopathology was associated with NIRS signals in the ventrolateral PFC and the anterior temporal cortex. DLPFC and FPC activity may be associated with social functioning in patients with schizophrenia. CONCLUSION: Our results suggest that the two distinct assessments of social functioning were significantly correlated. Moreover, DLPFC and FPC function was strongly associated with social functioning and the ability to carry out daily life in patients with schizophrenia. PMID- 28657686 TI - Environmental toxicology and chemistry in Latin America: Introduction. PMID- 28657685 TI - Proton in a Confined Space: Structural Studies of H+ ?Crypt-111 Iodide and Some Halogen-Bonded Derivatives. AB - Experimental observations and modeling data are reported on the solid-state structural features of crypt- 111?HI (1) and the three-component co-crystals that 1 forms with alpha,omega-diiodoperfluoroalkanes 2 a-d. X-ray analyses indicate that, in all five systems and at low temperature, the caged proton is covalently bonded to a single nitrogen atom and is involved in a network of intramolecular hydrogen bonds. In contrast, room-temperature, solid-state 15 N NMR spectroscopy suggests magnetic equivalency of the two N atoms of crypt-111 in both 1 and co crystals of 1 with diiodoperfluoroalkanes. Computational modelling confirms that the acidic hydrogen inside the cavity preferentially sits along the internitrogen axis and is covalently bonded to one nitrogen. The computed energy barriers suggest that the hopping of the encapsulated proton between the two N atoms of the cage can occur in the halogen-bonded co-crystals of 1?2, but it is hardly possible in the pure H+ ?crypt-111 iodide 1. These different pictures of the proton position and dynamics obtained by using different techniques and conditions confirm the unique characteristics of the confined space within the cavity of crypr-111 and the distinctive features of processes occurring therein. PMID- 28657687 TI - Fostering integrity in scientific research and publishing. PMID- 28657688 TI - ET&C Best Paper of 2016. PMID- 28657689 TI - Neoadjuvant chemotherapy with MRI monitoring for breast cancer. AB - BACKGROUND: Neoadjuvant chemotherapy (NACT) is increasingly being offered to patients with breast cancer. No survival benefit has been demonstrated for NACT, but it may serve to reduce tumour size and improve prognosis through the attainment of a pathological complete response (pCR). The role and mode of MRI monitoring during NACT remain unclear. METHODS: Patients managed with NACT at a UK centre over 7 years were studied using a prospectively maintained database, which also included details of MRI. Clinicopathological and radiological predictors of NACT response were analysed in a univariable setting and survival analysis was undertaken using the Kaplan-Meier method. RESULTS: A total of 278 patients underwent surgery following NACT, of whom 200 (71.9 per cent) had residual invasive disease and 78 (28.1 per cent) achieved a pCR. Attaining a pCR improved survival significantly compared with that of patients with residual invasive disease (mean 77.1 versus 66.0 months; P = 0.004) and resulted in significantly fewer recurrences (6.0 versus 24.3 per cent; P = 0.001). The pCR rate varied significantly among molecular subgroups of breast cancer (P < 0.001): luminal A, 6 per cent; luminal B/human epidermal growth factor 2 receptor (Her2) negative, 21 per cent; luminal B/Her2-positive, 35 per cent, Her2-positive/non luminal, 72 per cent; and triple-negative breast cancer (TNBC), 32 per cent. High grade disease (G3) correlated with an increased rate of pCR. A radiological response seen on the mid-treatment MRI was predictive of pCR (sensitivity 77.6 per cent, but specificity only 53.3 per cent), as was complete radiological response at final MRI (specificity 97.6 per cent, but sensitivity only 32.2 per cent). CONCLUSION: NACT allows identification of patient subgroups within TNBC and Her2-positive cohorts with a good prognosis. MRI can be used to identify patients who are responding to treatment. PMID- 28657690 TI - A DNA-Based Encryption Method Based on Two Biological Axioms of DNA Chip and Polymerase Chain Reaction (PCR) Amplification Techniques. AB - Researchers have gained a deeper understanding of DNA-based encryption and its effectiveness in enhancing information security in recent years. However, there are many theoretical and technical issues about DNA-based encryption that need to be addressed before it can be effectively used in the field of security. Currently, the most popular DNA-based encryption schemes are based on traditional cryptography and the integration of existing DNA technology. These schemes are not completely based on DNA computing and biotechnology. Herein, as inspired by nature, encryption based on DNA has been developed, which is, in turn, based on two fundamental biological axioms about DNA sequencing: 1) DNA sequencing is difficult under the conditions of not knowing the correct sequencing primers and probes, and 2) without knowing the correct probe, it is difficult to decipher precisely and sequence the information of unknown and mixed DNA/peptide nucleic acid (PNA) probes, which only differ in nucleotide sequence, arranged on DNA chips (microarrays). In essence, when creating DNA-based encryption by means of biological technologies, such as DNA chips and polymerase chain reaction (PCR) amplification, the encryption method discussed herein cannot be decrypted, unless the DNA/PNA probe or PCR amplification is known. The biological analysis, mathematical analysis, and simulation results demonstrate the feasibility of the method, which provides much stronger security and reliability than that of traditional encryption methods. PMID- 28657691 TI - Pseudoshikonin I enhances osteoblast differentiation by stimulating Runx2 and Osterix. AB - Pseudoshikonin I (PSI), a novel biomaterial isolated from Lithospermi radix, has been recognized as an herbal medicine for the treatment of infectious and inflammatory diseases. Bone remodeling maintains a balance through bone resorption (osteoclastogenesis) and bone formation (osteoblastogenesis). Bone formation is generally attributed to osteoblasts. However, the effects of PSI on the bone are not well known. In this study, we found that the ethanol extracts of PSI induced osteoblast differentiation by increasing the expression of bone morphogenic protein 4 (BMP 4). PSI positively regulates the transcriptional expression and osteogenic activity of osteoblast-specific transcription factors such as Runx2 and Osterix. To identify the signaling pathways that mediate PSI induced osteoblastogenesis, we examined the effects of serine-threonine kinase inhibitors that are known regulators of Osterix and Runx2. PSI-induced upregulation of Osterix and Runx2 was suppressed by treatment with AKT and PKA inhibitors. These results suggest that PSI enhances osteoblast differentiation by stimulating Osterix and Runx2 via the AKT and PKA signaling pathways. Thus, the activation of Runx2 and Osterix is modulated by PSI, thereby demonstrating its potential as a treatment target for bone disease. PMID- 28657693 TI - Ultrathin Two-Dimensional Nanostructured Materials for Highly Efficient Water Oxidation. AB - Water oxidation, also known as the oxygen evolution reaction (OER), is a crucial process in energy conversion and storage, especially in water electrolysis. The critical challenge of the electrochemical water splitting technology is to explore alternative precious-metal-free catalysts for the promotion of the kinetically sluggish OER. Recently, emerging two-dimensional (2D) ultrathin materials with abundant accessible active sites and improved electrical conductivity provide an ideal platform for the synthesis of promising OER catalysts. This Review focuses on the most recent advances in ultrathin 2D nanostructured materials for enhanced electrochemical activity of the OER. The design, synthesis and performance of such ultrathin 2D nanomaterials-based OER catalysts and their property-structure relationships are discussed, providing valuable insights to the exploration of novel OER catalysts with high efficiency and low overpotential. The potential research directions are also proposed in the research field. PMID- 28657692 TI - Systemic bevacizumab for recurrent respiratory papillomatosis: A national survey. AB - OBJECTIVES/HYPOTHESIS: Aggressive laryngeal, tracheal, and pulmonary papilloma is an extremely challenging clinical problem without proven treatment options. A recent German report documented promising results with systemic bevacizumab. The objective of this study is to report the initial experience of this novel treatment in the United States for recurrent respiratory papillomatosis (RRP). STUDY DESIGN: Cases series. METHODS: Electronic survey of the RRP Task Force of the American Society of Pediatric Otolaryngology, American Broncho Esophagological Association, and physicians known to the authors to have used systemic bevacizumab for RRP. RESULTS: Eleven completed surveys were obtained. In three cases, systemic bevacizumab was considered clinically but not administered. Eight patients were treated with systemic bevacizumab, all for aggressive papillomatosis uncontrolled by surgical and adjuvant therapy, including seven of eight with pulmonary disease. Treatment dosing ranged from 5 to 10 mg/kg every 2 to 4 weeks, with all patients responding (7/8 partial response, 1/8 complete response). In four patients who had postbevacizumab chest imaging, three demonstrated improvement of disease and one stabilization. Treatment interval could be lengthened in seven patients and clinical response maintained. One patient with long-standing pulmonary disease (>10 years) was diagnosed with malignant transformation while on treatment, and bevacizumab was discontinued in lieu of other chemotherapeutic agents. All other patients continue on systemic bevacizumab with minimal complications (hemoptysis n = 1, proteinuria n = 1). CONCLUSIONS: Systemic bevacizumab appears to have significant promise in the most treatment-resistant and aggressive forms of papillomatosis with a low complication profile. These results suggest bevacizumab should be studied in a formal clinical trial for RRP. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2225-2229, 2017. PMID- 28657694 TI - The Aspergillus nidulans Velvet-interacting protein, VipA, is involved in light stimulated heme biosynthesis. AB - Filamentous fungi are able to differentiate morphologically and adapt the metabolism to internal and external cues. One major regulator is the so-called velvet protein, VeA, best studied in Aspergillus nidulans. The protein interacts with several other proteins to regulate light sensing, the balance between asexual and sexual development, penicillin biosynthesis or mycotoxin production. Here, we characterized a novel VeA-interacting protein, VipA. The 334 amino acid long protein comprises a FAR1-like DNA-binding domain, known from plant transcription factors like FHY3 (Far-red elongated hypocotyl 3). VipA interacted not only with VeA, but also with the WC orthologue LreA in the nuclei and with the phytochrome FphA in the cytoplasm. Conidia and cleistothecia formation was similarly affected in a vipA-deletion strain as in an fphA mutant. However, the effect was less pronounced, suggesting a modulating and not an essential role in light sensing. In addition, VipA modulated heme biosynthesis in response to light through association with the hemB promoter, the gene encoding 5-aminolevulinic acid dehydratase. After illumination of A. nidulans mycelia with white light the intracellular heme concentration increased by 30% in comparison to a vipA deletion mutant. Hence, VipA couples heme biosynthesis to the illumination conditions. PMID- 28657695 TI - Rare PDCD11 variations are not associated with risk of schizophrenia in Japan. AB - AIM: Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three-stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia. METHODS: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls. RESULTS: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His). CONCLUSION: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population. PMID- 28657696 TI - Evaluation of high-fidelity simulation as a training tool in transoral robotic surgery. AB - OBJECTIVES/HYPOTHESIS: To develop and evaluate a high-fidelity training simulator for transoral robotic posterior hemiglossectomy. STUDY DESIGN: Prospective observational study. METHODS: We constructed a transoral robotic surgery (TORS) simulator using porcine tongue in a modified airway mannequin. Twenty-nine surgeons performed transoral robotic posterior hemiglossectomy on the simulator. The 20 resident subjects completed six trials each, and the five fellows and four attending surgeons completed two trials each. In addition to instrument vibrations, surgical video was recorded for each trial and was blindly rated using the Global Evaluative Assessment of Robotic Skill (GEARS), a validated instrument for assessing robotic surgical skill. RESULTS: Attending surgeons were faster (P = .004) and demonstrated greater technical skill than fellows or residents (P < .001). Resident completion time generally decreased over the study, becoming significantly faster by the fifth trial (P = .02). A similar trend was seen in resident GEARS scores, which generally increased and were significantly improved by the fourth trial (P = .008). Instrument vibrations were not significantly different between subject groups. Finally, subjects highly rated the realism and training value of the TORS simulator (mean 4.4 and 4.7 out of 5, respectively). CONCLUSIONS: The reported findings support using the described simulator as a training tool for TORS. Residents significantly improved in speed and technical skill over the course of six trials but did not achieve the performance levels of attending surgeons. These results demonstrate that high fidelity simulation is a valuable tool for training novice surgeons in transoral robotic surgery. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2790-2795, 2017. PMID- 28657697 TI - Vascular risk factors in older patients with depression: outcome of electroconvulsive therapy versus medication. AB - OBJECTIVE: Research suggests that in depression, vascular burden predicts a lower efficacy for medication (MED) and a more favourable outcome for electroconvulsive therapy (ECT). Therefore, we investigated the influence of the following vascular risk factors (VRF): hypercholesterolemia, hypertension, smoking, diabetes mellitus, cardiovascular disease, and cerebral vascular accident/transient ischemic attack, on remission from major depression after ECT versus MED. METHODS: The study sample consisted of 81 inpatients with a DSM-IV unipolar major depression diagnosis (mean age 72.2 years, SD = 7.6, mean Montgomery-Asberg Depression Rating Scale score 32.9, SD = 6.2) participating in a randomized controlled trial comparing nortriptyline versus venlafaxine and 43 inpatients (mean age 73.7 years, SD = 7.5, mean Montgomery-Asberg Depression Rating Scale score 30.6, SD = 7.1) from an randomized controlled trial comparing brief pulse versus ultrabrief pulse ECT. The presence of VRF was established from the medical records. The remission rate of patients with VRF was compared with those of patients without VRF. RESULTS: The remission rate was 58% (19/33) in the ECT group with >=1 VRF and 32% (23/73) in the MED group with >=1 VRF (chi2 = 6.456, p = 0.011). Comparing patients with no VRF versus >=1 VRF, the remission rate decreased from 80 to 58% (chi2 = 1.652, p = 0.276) in ECT patients and from 38 to 32% (chi2 = 0.119, p = 0.707) in MED patients. Applying different cut-offs for the number of VRFs yielded the same trends. Logistic regression revealed no interaction between VRF and treatment condition. CONCLUSION: The superior efficacy of ECT over pharmacotherapy in major depression in older age was independent of the presence of VRF. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28657698 TI - Mental and Physical Health Conditions in US Combat Veterans: Results From the National Health and Resilience in Veterans Study. AB - Objective: To identify sociodemographic and military characteristics of combat exposed and non-combat-exposed veterans in the United States and to compare rates of mental and physical health conditions in these populations. Methods: Data were analyzed from the National Health and Resilience in Veterans Study (NHRVS), a contemporary, nationally representative survey of 1,480 US veterans conducted September-October 2013. Poststratification weights were applied to analyses to permit generalizability of results to the US veteran population. Outcomes measured included lifetime and current psychiatric disorders and physical health conditions. Results: A total 38% of US veterans reported being exposed to combat. Compared to noncombat veterans, combat veterans were younger, had greater household income, and served a greater number of years in the military; were more likely to be male, to have served in the Marine Corps, and to use the Veterans Affairs Healthcare System as their main source of health care; and reported a greater number of lifetime potentially traumatic events. After adjustment for these sociodemographic and military differences, combat veterans were more than 3 times as likely as noncombat veterans to screen positive for lifetime posttraumatic stress disorder (PTSD) and more than twice as likely for current PTSD and had 82% greater odds of screening positive for current generalized anxiety disorder. After additionally controlling for lifetime diagnoses of PTSD and depression, alcohol or drug use disorder, and nicotine dependence, combat veterans had 68% greater odds of having attempted suicide and 85% and 38% greater odds of being diagnosed with a stroke and chronic pain, respectively. Younger combat veterans were more likely than older combat veterans to screen positive for lifetime (30.6% vs 10.1%) and current PTSD (19.2% vs 4.9%) and suicidal ideation (18.6% vs 6.9%) and to have been diagnosed with migraine headaches (12.8% vs 2.1%), while older combat veterans were more likely than younger combat veterans to report having been diagnosed with heart disease (19.2% vs 2.6%) and heart attack (13.9% vs 2.5%). Conclusions: Compared to noncombat veterans in the United States, combat veterans have elevated rates of PTSD, suicide attempt, stroke, and chronic pain independent of other sociodemographic, military, and mental health factors. Younger combat veterans have elevated rates of PTSD, suicidal ideation, and migraine headaches, while older combat veterans have elevated rates of heart disease and heart attack. These results characterize the population-based burden of mental and physical health conditions in combat veterans. They further underscore the importance of age- and condition-sensitive screening, monitoring, and treatment efforts in this population. PMID- 28657699 TI - Randomized Controlled Trial to Explore the Effect of Experimental Low Abrasivity Dentifrices on Enamel Gloss and Smoothness, and the Build-up of Extrinsic Tooth Stain. AB - OBJECTIVES: To evaluate and compare examiner-assessed changes in enamel gloss, extrinsic dental stain, and surface smoothness following one, two, four, and eight weeks of twice-daily use of an experimental low abrasivity desensitizing dentifrice (relative dentin abrasivity [RDA] ~40) containing 5% sodium tripolyphosphate (STP) chemical cleaning agent and 1% aluminum trioxide abrasive. This was compared with an ultra-low abrasivity dentifrice (5% STP only; RDA ~13), a moderate abrasivity fluoride dentifrice (RDA ~80), and a higher abrasivity marketed whitening dentifrice (RDA ~142). METHODS: This was a single-center, examiner-blind, randomized, controlled, parallel group study in healthy adults stratified by gloss score and age. Following a washout period with a conventional silica abrasive dentifrice, subjects received a dental scale and polish and were randomized to treatment. Subjects brushed their teeth for two minutes, twice daily, with their assigned dentifrice. Enamel gloss was assessed visually by comparing the facial surfaces of the maxillary incisors to the Sturzenberger gloss standards. Extrinsic dental stain was measured on the 12 anterior teeth (facial and lingual) using the Macpherson modification of the Lobene Stain Index (MLSI). Tooth smoothness was assessed using scanning electron microscope (SEM) analysis of a silicone impression of the central incisors. RESULTS: Of 120 screened subjects, 95 were randomized to the study. Subjects using the low abrasivity aluminum trioxide/STP dentifrice demonstrated statistically significant (p < 0.05) and increasing improvements in surface gloss over baseline at all time points, with a significant treatment effect compared to all other study dentifrices from Week 2 (p < 0.05). With respect to dental stain, the low abrasivity dentifrice group had the lowest stain score at each post-treatment time point and demonstrated statistically significantly less stain compared to all study dentifrices at Weeks 2 (p < 0.05) and 8 (p < 0.01). For tooth smoothness, at Week 8, statistically significant increases in surface smoothness were observed for most treatment groups compared to baseline (p < 0.05), except for the moderate abrasivity dentifrice. CONCLUSIONS: This study shows the benefit of a low abrasivity dentifrice containing STP and aluminum trioxide in reducing stain build-up and increasing tooth gloss compared to a non-alumina ultra-low abrasivity STP-containing dentifrice, and moderate and high abrasivity dentifrices, over an eight-week period. PMID- 28657700 TI - A Randomized Clinical Study to Evaluate the Efficacy of an Experimental 3.75% (w/w) Potassium Chloride Dentifrice for the Relief of Dentin Hypersensitivity. AB - OBJECTIVES: To evaluate the clinical efficacy of an experimental "Test" dentifrice containing 3.75% (w/w) potassium chloride (KCl) in reducing dentin hypersensitivity (DH) compared with that of a standard fluoride "Reference" dentifrice after eight weeks' twice-daily brushing. METHODS: This was a randomized, controlled, examiner-blind, stratified, parallel-group, single-center study in healthy subjects with selfreported and clinically diagnosed DH. After an initial lead-in period, subjects were randomized to either the Test (n = 67) or the Reference dentifrice (n = 66) and instructed to brush twice daily for the next eight weeks. DH was assessed at baseline and following two, four, and eight weeks of dentifrice use by response to an evaporative air stimulus (as evaluated by Schiff sensitivity score and 100 mm visual analog scale [VAS]) and by response to a tactile stimulus (tactile threshold). RESULTS: Both dentifrices were associated with statistically significant reductions in DH from baseline after two, four, and eight weeks' use, as determined by all efficacy measures (all p < 0.0001). The reduction in Schiff sensitivity score was significantly greater in the Test dentifrice group compared with the Reference dentifrice group at all time points (p < 0.0001). There was a statistically significantly greater increase in tactile threshold in the Reference dentifrice group compared with the Test dentifrice group after eight weeks (p < 0.05); however, reductions in DH as determined by VAS were not significantly different between the treatment groups at any time point. Both dentifrices were generally well tolerated. CONCLUSIONS: Throughout eight weeks of use, the experimental 3.75% (w/w) KCl dentifrice was more effective than the Reference fluoride dentifrice in reducing DH, as determined by the primary endpoint of Schiff sensitivity score. Secondary assessment measures of change in DH (VAS score and tactile threshold) were not consistent with this finding. PMID- 28657701 TI - Clinical Effects of Stabilized Stannous Fluoride Dentifrice in Reducing Plaque Microbial Virulence I: Microbiological and Receptor Cell Findings. AB - OBJECTIVES: Lipopolysaccharides (LPSs) and lipoteichoic acids (LTAs), or bacterial endotoxins, bind with Toll-like receptors (TLRs) that are expressed on host cells of the periodontium, thereby contributing to the periodontal pathogenicity of oral bacteria. Stannous fluoride (SnF2), an antibacterial fluoride that treats and controls gingivitis, has been shown to react with lipophilic domains/anionic charges in LPS and LTA. The effects of bacterial species and dental plaque on toll receptors can be studied using genetically engineered cell lines containing linked toll receptors on their surfaces. This randomized, examiner-blinded study examined the clinical effects of stabilized SnF2 dentifrice intervention on gingivitis and dental plaque virulence in populations exhibiting high and low levels of clinical gingivitis. METHODS: Recruited populations were evaluated for gingival inflammation (MGI) and gingival bleeding (GBI) at baseline and assigned into two cohorts of 20 each, those with high (GBI > 20 sites) and low (GBI < 3 sites) levels of observed bleeding/gingivitis. Participants were sampled at baseline for both supra- and subgingival dental plaque at both healthy (no bleeding, PD = 2 mm), as well as clinically diseased sites (bleeding, PD = 3-4 mm), and then provided with an intervention hygiene product including a stabilized SnF2 dentifrice and a new soft bristle manual toothbrush. Following two and four weeks of assigned dentifrice use, participants returned for a re-evaluation of gingival inflammation and bleeding and repeat samplings of dental plaque. Plaque samples were analyzed by anaerobic culturing of gram negative anaerobes (GNA), as well as by incubation of subgingival sampled plaques with TLR4 transfected HEK293 cells, where gene expression was assessed by measurement of a SEAP alkaline phosphatase reporter as a marker of toll receptor activation. RESULTS: Clinical assessments showed statistically significant reductions in MGI (24-26%) and GBI (42-53%) gingivitis in both diseased and healthy cohorts following four weeks of dentifrice intervention. For all clinical examinations, MGI and bleeding sites were statistically significantly different (lower) in the low bleeding versus the higher bleeding cohort. Supragingival and subgingival GNAs were significantly reduced (p < 0.05) in both high and low disease cohorts at bleeding and healthy sites following four weeks of stabilized SnF2 dentifrice use. TLR activation from subgingival sampled plaque was reduced following four weeks of stabilized SnF2 dentifrice use in both high and low disease cohorts and in both healthy, as well as diseased sites. CONCLUSIONS: Collectively, these results support the potential for stabilized SnF2 dentifrice to provide clinical gingivitis benefits via mechanisms beyond control of plaque mass, potentially directly decreasing the pathogenicity of plaque biofilms by blocking reactivity of LPS and LTA ligands with tissue receptors associated with inflammation. Importantly, benefits could be seen in both diseased sites, as well as sites not yet exhibiting symptoms of inflammation, supporting the activity of SnF2 not just in treating diseased sites, but in preventing disease development. These learnings may influence treatment planning for patients susceptible to gingivitis. PMID- 28657702 TI - In Situ Study to Confirm the Anticaries Potential of a Sodium Monofluorophosphate Dentifrice Containing Calcium Sodium Phosphosilicate. AB - OBJECTIVES: A randomized, investigator-blind, five-treatment, crossover, non inferiority study was conducted to investigate the effect of the addition of calcium sodium phosphosilicate (CSPS), an agent known to relieve dentin hypersensitivity, to a sodium monofluorophosphate (SMFP)-containing dentifrice on the enamel remineralization potential of fluoride (F), as assessed by percentage surface microhardness recovery (%SMHR) and enamel fluoride uptake (EFU) using a standard in situ caries model. METHODS: Seventy-seven subjects wearing bilateral mandibular partial dentures holding partially demineralized bovine enamel specimens 24 hours/day brushed their teeth with their assigned randomized dentifrice containing either 1500 or 0 ppm F with 5% CSPS or 1500, 500, or 0 ppm F with 0% CSPS twice daily for 21 days. The success criterion was to observe a difference in % SMHR between dentifrices containing 1500 ppm F of six units or less in the upper bound of the two-sided 95% confidence interval (CI). RESULTS: Following 21 days of treatment, the upper bound CI of the %SMHR difference between the dentifrices containing 1500 ppm F was 1.66, thus within the non inferiority limit. No statistically significant differences for %SMHR (p = 0.2601) and EFU (p = 0.2984) were noted between these two dentifrices. CONCLUSIONS: The present in situ caries study provides evidence demonstrating that the addition of the calcium-containing compound CSPS to a 1500 ppm F dentifrice does not interfere with the ability of fluoride to remineralize surface-softened enamel; i.e., CSPS neither impairs nor improves the potential cariostatic value of SMFP dentifrice. PMID- 28657703 TI - A Randomized Clinical Trial to Measure Mouth Moisturization and Dry Mouth Relief in Dry Mouth Subjects Using Dry Mouth Products. AB - OBJECTIVES: This study examined ratings of two subjective aspects (moisturization and dry mouth relief) that may be changed following the use of dry mouth relief products (an oral gel, an oral rinse, or a mouth spray), in comparison to water over a period of four hours following a single supervised use on two separate occasions. METHODS: This was a single-center, two site, randomized, examiner blind, four treatment arm, stratified (by dry mouth screening score at baseline), parallel group study in healthy subjects with a self-reported feeling of dry mouth. Prior to product use, subjects rated their current subjective perception of moisturization and dry mouth on an 11-point scale. Subjects then rated the two questions immediately after product use and 30, 60, 90, 120, and 240 minutes later. At the 240-minute time point, subjects also rated global efficacy questions regarding "overall" and "long-lasting" moisturization and dry mouth relief, and overall product opinion. Subjects then used their assigned products at home for three days and the procedures were repeated on Day 4. RESULTS: In total, 300 subjects were randomized to treatment. Compared with water, all test products showed statistically significantly greater improvements over baseline on both Day 1 and Day 4 at most time points, on the area under the curve from baseline for the moisturization and dryness questions, and after 240 minutes for the global efficacy and overall opinion assessments (all p < 0.05). There was a statistically significant difference between the pre-dosing assessments on Day 1 versus Day 4 (p < 0.001) for both efficacy questions. Products were generally well-tolerated. CONCLUSIONS: Three different types of dry mouth relief products were shown to provide significant relief of dry mouth and increased feelings of moisturization compared to water using subjective questionnaires. PMID- 28657704 TI - Assembly and Stacking of Flow-through Enzymatic Bioelectrodes for High Power Glucose Fuel Cells. AB - Bioelectrocatalytic carbon nanotube based pellets comprising redox enzymes were directly integrated in a newly conceived flow-through fuel cell. Porous electrodes and a separating cellulose membrane were housed in a glucose/oxygen biofuel cell design with inlets and outlets allowing the flow of electrolyte through the entire fuel cell. Different flow setups were tested and the optimized single cell setup, exploiting only 5 mmol L-1 glucose, showed an open circuit voltage (OCV) of 0.663 V and provided 1.03 +/- 0.05 mW at 0.34 V. Furthermore, different charge/discharge cycles at 500 Omega and 3 kOmega were applied to optimize long-term stability leading to 3.6 J (1 mW h) of produced electrical energy after 48 h. Under continuous discharge at 6 kOmega, about 0.7 mW h could be produced after a 24 h period. The biofuel cell design further allows a convenient assembly of several glucose biofuel cells in reduced volumes and their connection in parallel or in series. The configuration of two biofuel cells connected in series showed an OCV of 1.35 V and provided 1.82 +/- 0.09 mW at 0.675 V, and when connected in parallel, showed an OCV of 0.669 V and provided 1.75 +/- 0.09 mW at 0.381 V. The presented design is conceived to stack an unlimited amount of biofuel cells to reach the necessary voltage and power for portable electronic devices without the need for step-up converters or energy managing systems. PMID- 28657705 TI - New Insight of Li-Doped Cu2ZnSn(S,Se)4 Thin Films: Li-Induced Na Diffusion from Soda Lime Glass by a Cation-Exchange Reaction. AB - In our recent report (ACS Appl. Mater. Interfaces 2016, 8, 5308), Li+ ions had been successfully incorporated into the lattice of the selenized Cu2ZnSn(S,Se)4 thin film on a quartz substrate by substituting equivalent Cu+ ions, and Li+ ions was also found to have the little effect on the crystal growth and defect passivation. To further improve the cell performance of Li-doped CZTSSe devices, we conducted the same experiments on the sodium-rich soda-lime glass (SLG) substrate in this study, instead of sodium-free quartz substrate. Surprisingly, only trace amounts of Li (Li/Cu molar ratio ~1 * 10-4) were detected in the final CZTSSe thin films; meanwhile, a large amount of sodium was present on the surface and at the grain boundaries of the selenized thin films. A Li/Na exchange mechanism is used to explain this phenomenon. Only on the sodium-free substrate can Li+ ions enter the CZTSSe host lattice, and doping Li+ ions on the SLG substrate are nearly identical to doping Na+ ions. PMID- 28657706 TI - Crystalline Microporous Organosilicates with Reversed Functionalities of Organic and Inorganic Components for Room-Temperature Gas Sensing. AB - A deepened investigation on an innovative organic-inorganic hybrid material, referred to as ECS-14 (where ECS = Eni carbon silicates), revealed the possibility to use them as gas sensors. Indeed, among ECS phases, the crystalline state and the hexagonal microplateletlike morphology characteristic of ECS-14 seemed favorable properties to obtain continuous and uniform films. ECS-14 phase was used as functional material in screen-printable compositions and was thus deposited by drop coating for morphological, structural, thermal, and electrical characterizations. Possible operation at room temperature was investigated as technological progress, offering intrinsic safety in sensors working in harsh or industrial environments and avoiding high power consumption of most common sensors based on metal oxide semiconductors. Electrical characterization of the sensors based on ECS-14 versus concentrations of gaseous analytes gave significant results at room temperature in the presence of humidity, thereby demonstrating fundamental properties for a good quality sensor (speed, reversibility, and selectivity) that make them competitive with respect to systems currently in use. Remarkably, we observed functionality reversal of the organic and inorganic components; that is, in contrast to other hybrids, for ECS 14 the functional site has been ascribed to the inorganic phase while the organic component provided structural stability to the material. The sensing mechanism for humidity was also investigated. PMID- 28657709 TI - Theranostic Prodrug Vesicles for Imaging Guided Codelivery of Camptothecin and siRNA in Synergetic Cancer Therapy. AB - The construction of prodrugs has been a popular strategy to overcome the limitations of chemotherapeutic drugs. However, complicated synthesis procedures and laborious purification steps make the fabrication of amphiphilic prodrugs rather difficult. By harnessing the concept of host-guest interaction, we designed and prepared a supra-amphiphile consisting of a dendritic cyclodextrin host and an adamantane/naphthalimide-modified camptothecin guest through glutathione-responsive disulfide linkage. This host-guest complex could self assemble in aqueous solution to give nanosized vesicles. When the disulfide bond in adamantane/naphthalimide-modified camptothecin was cleaved by glutathione, the fluorescence of the freed adamantane/naphthalimide unit showed a significant red shift with enhanced intensity. Such glutathione-responsive fluorescence change allows for intracellular imaging and simultaneous monitoring of drug release in real time. On account of abundant positively charged amine groups on the supramolecular vesicle surface, siRNA (siPlK1) could be efficiently loaded on the vesicle. The gel retardation and fluorescence experiments proved that the siPlK1 was successfully bonded to the supramolecular vesicle. The vesicle with dendritic cyclodextrin ring exhibited negligible cytotoxicity even at high concentrations, avoiding the shortcoming of cytotoxicity from commonly used gene vectors. In vitro studies demonstrated that the loaded siRNA was transported into cancer cells to improve cancer therapeutic efficacy. Thus, we developed a prodrug-based supramolecular amphiphile via the host-guest interaction with better therapeutic performance than free camptothecin. The assembled system was utilized as a drug/gene vector to achieve combinational gene therapy and chemotherapy with a synergistic effect, providing an alternative strategy to deliver both prodrug and therapeutic gene. PMID- 28657708 TI - Combined Proteomic-Molecular Epidemiology Approach to Identify Precision Targets in Brain Cancer. AB - Primary brain tumors are predominantly malignant gliomas. Grade IV astrocytomas (glioblastomas, GBM) are among the most deadly of all tumors; most patients will succumb to their disease within 2 years of diagnosis despite standard of care. The grim outlook for brain tumor patients indicates that novel precision therapeutic targets must be identified. Our hypothesis is that the cancer proteomes of glioma tumors may contain protein variants that are linked to the aggressive pathology of the disease. To this end, we devised a novel workflow that combined variant proteomics with molecular epidemiological mining of public cancer data sets to identify 10 previously unrecognized variants linked to the risk of death in low grade glioma or GBM. We hypothesize that a subset of the protein variants may be successfully developed in the future as novel targets for malignant gliomas. PMID- 28657707 TI - Identification of Biologically Active Pyrimido[5,4-b]indoles That Prolong NF kappaB Activation without Intrinsic Activity. AB - Most vaccine adjuvants directly stimulate and activate antigen presenting cells but do not sustain immunostimulation of these cells. A high throughput screening (HTS) strategy was designed to identify compounds that would sustain NF-kappaB activation by a stimulus from the Toll-like receptor (TLR)4 ligand, lipopolysaccharide (LPS). Several pilot studies optimized the parameters and conditions for a cell based NF-kappaB reporter assay in human monocytic THP-1 cells. The final assay evaluated prolongation of LPS induced NF-kappaB activation at 12 h. The dynamic range of the assay was confirmed in a pilot screen of 14 631 compounds and subsequently in a main extensive screen with 166 304 compounds. Hit compounds were identified using an enrichment strategy based on unsupervised chemoinformatic clustering, and also by a naive "Top X" approach. A total of 2011 compounds were then rescreened for levels of coactivation with LPS at 5 h and 12 h, which provided kinetic profiles. Of the 407 confirmed hits, compounds that showed correlation of the kinetic profiles with the structural similarities led to identification of four chemotypes: pyrimido[5,4-b]indoles, 4H-chromene-3 carbonitriles, benzo[d][1,3]dioxol-2-ylureas, and tetrahydrothieno[2,3 c]pyridines, which were segregated by 5 h and 12 h kinetic characteristics. Unlike the TLR4 agonistic pyrimidoindoles identified in previous studies, the revealed pyrimidoindoles in the present work did not intrinsically stimulate TLR4 nor induce NF-kappaB but rather prolonged NF-kappaB signaling induced by LPS. A 42-member combinatorial library was synthesized which led to identification of potent N3-alkyl substituted pyrimidoindoles that were not only active in vitro but also enhanced antibody responses in vivo when used as a coadjuvant. The novel HTS strategy led to identification of compounds that are intrinsically quiescent but functionally prolong stimulation by a TLR4 ligand and thereby potentiate vaccine efficacy. PMID- 28657710 TI - Graphene-Based Functional Architectures: Sheets Regulation and Macrostructure Construction toward Actuators and Power Generators. AB - Graphene, with large delocalized pi electron cloud on a two-dimensional (2D) atom thin plane, possesses excellent carrier mobility, large surface area, high light transparency, high mechanical strength, and superior flexibility. However, the lack of intrinsic band gap, poor dispersibility, and weak reactivity of graphene hinder its application scope. Heteroatom-doping regulation and surface modification of graphene can effectively reconstruct the sp2 bonded carbon atoms and tailor the surface chemistry and interfacial interaction, while microstructure mediation on graphene can induce the special chemical and physical properties because of the quantum confinement, edge effect, and unusual mass transport process. Based on these regulations on graphene, series of methods and techniques are developed to couple the promising characters of graphene into the macroscopic architectures for potential and practical applications. In this Account, we present our effort on graphene regulation from chemical modification to microstructure control, from the morphology-designed macroassemblies to their applications in functional systems excluding the energy-storage devices. We first introduce the chemically regulative graphene with incorporated heteroatoms into the honeycomb lattice, which could open the intrinsic band gap and provide many active sites. Then the surface modification of graphene with functional components will improve dispersibility, prevent aggregation, and introduce new functions. On the other hand, microstructure mediation on graphene sheets (e.g., 0D quantum dots, 1D nanoribbons, and 2D nanomeshes) is demonstrated to induce special chemical and physical properties. Benefiting from the effective regulation on graphene sheets, diverse methods including dimension-confined strategy, filtration assembly, and hydrothermal treatment have been developed to assemble individual graphene sheets to macroscopic graphene fibers, films, and frameworks. These rationally regulated graphene sheets and well-constructed assemblies present promising applications in energy-conversion materials and device systems focusing on actuators that can convert different energy forms (e.g., electric, chemical, photonic, thermal, etc.) to mechanical actuation and electrical generators that can directly transform environmental energy to electric power. These results reveal that graphene sheets with surface chemistry and microstructure regulations as well as their rationally designed assemblies provide a promising and abundant platform for development of diverse functional devices. We hope that this Account will promote further efforts toward fundamental research on graphene regulation and the wide applications of advanced designed assemblies in new types of energy-conversion materials/devices and beyond. PMID- 28657711 TI - Self-Assembled DNA/Peptide-Based Nanoparticle Exhibiting Synergistic Enzymatic Activity. AB - Designing enzyme-mimicking active sites in artificial systems is key to achieving catalytic efficiencies rivaling those of natural enzymes and can provide valuable insight in the understanding of the natural evolution of enzymes. Here, we report the design of a catalytic hemin-containing nanoparticle with self-assembled guanine-rich nucleic acid/histidine-rich peptide components that mimics the active site and peroxidative activity of hemoproteins. The chemical complementarities between the folded nucleic acid and peptide enable the spatial arrangement of essential elements in the active site and effective activation of hemin. As a result, remarkable synergistic effects of nucleic acid and peptide on the catalytic performances were observed. The turnover number of peroxide reached the order of that of natural peroxidase, and the catalytic efficiency is comparable to that of myoglobin. These results have implications in the precise design of supramolecular enzyme mimetics, particularly those with hierarchical active sites. The assemblies we describe here may also resemble an intermediate in the evolution of contemporary enzymes from the catalytic RNA of primitive cells. PMID- 28657713 TI - Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption. AB - Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ). Pt MPQ promotes the displacement of two telomeric proteins (TRF2 and TRF1) from telomeres, as well as the formation of telomere damage and telomere sister losses, whereas the control compound MPQ does not. This suggests that the platinum moiety potentiates the targeting of the G-quadruplex ligand to telomeres, opening a new perspective for telomere biology and anticancer therapy. Interestingly, the chemotherapy drug cisplatin, which has no specific affinity for G-quadruplex structures, partially induces the TRF2 delocalization from telomeres but produces less telomeric DNA damage, suggesting that this TRF2 displacement could be independent of G-quadruplex recognition. PMID- 28657714 TI - Probing Nuclear Spin Effects on Electronic Spin Coherence via EPR Measurements of Vanadium(IV) Complexes. AB - Quantum information processing (QIP) has the potential to transform numerous fields from cryptography, to finance, to the simulation of quantum systems. A promising implementation of QIP employs unpaired electronic spins as qubits, the fundamental units of information. Though molecular electronic spins offer many advantages, including chemical tunability and facile addressability, the development of design principles for the synthesis of complexes that exhibit long qubit superposition lifetimes (also known as coherence times, or T2) remains a challenge. As nuclear spins in the local qubit environment are a primary cause of shortened superposition lifetimes, we recently conducted a study which employed a modular spin-free ligand scaffold to place a spin-laden propyl moiety at a series of fixed distances from an S = 1/2 vanadium(IV) ion in a series of vanadyl complexes. We found that, within a radius of 4.0(4)-6.6(6) A from the metal center, nuclei did not contribute to decoherence. To assess the generality of this important design principle and test its efficacy in a different coordination geometry, we synthesized and investigated three vanadium tris(dithiolene) complexes with the same ligand set employed in our previous study: K2[V(C5H6S4)3] (1), K2[V(C7H6S6)3] (2), and K2[V(C9H6S8)3] (3). We specifically interrogated solutions of these complexes in DMF-d7/toluene-d8 with pulsed electron paramagnetic resonance spectroscopy and electron nuclear double resonance spectroscopy and found that the distance dependence present in the previously synthesized vanadyl complexes holds true in this series. We further examined the coherence properties of the series in a different solvent, MeCN-d3/toluene-d8, and found that an additional property, the charge density of the complex, also affects decoherence across the series. These results highlight a previously unknown design principle for augmenting T2 and open new pathways for the rational synthesis of complexes with long coherence times. PMID- 28657712 TI - A Ruthenium(II) Complex as a Luminescent Probe for DNA Mismatches and Abasic Sites. AB - [Ru(bpy)2(BNIQ)]2+ (BNIQ = Benzo[c][1,7]naphthyridine-1-isoquinoline), which incorporates the sterically expansive BNIQ ligand, is a highly selective luminescent probe for DNA mismatches and abasic sites, possessing a 500-fold higher binding affinity toward these destabilized regions relative to well matched base pairs. As a result of this higher binding affinity, the complex exhibits an enhanced steady-state emission in the presence of DNA duplexes containing a single base mismatch or abasic site compared to fully well-matched DNA. Luminescence quenching experiments with Cu(phen)22+ and [Fe(CN)6]3- implicate binding of the complex to a mismatch from the minor groove via metalloinsertion. The emission response of the complex to different single base mismatches, binding preferentially to the more destabilized mismatches, is also consistent with binding by metalloinsertion. This work shows that high selectivity toward destabilized regions in duplex DNA can be achieved through the rational design of a complex with a sterically expansive aromatic ligand. PMID- 28657715 TI - Aldehyde Approach to Hydrophobic Modification of Chitosan Aerogels. AB - Biobased nanofiber aerogels are ones of the attractive emerging materials in the fields of biochemistry and materials chemistry, but their poor humidity stability due to high hydrophilicity has limited their practical uses. In this paper, a new series of hydrophobic nanofibrous aerogels made from regenerated chitosan and alkyl aldehydes were prepared via a simple one-pot reaction followed by supercritical drying. Hexanal-modified chitosan aerogel shows excellent hydrophobicity with a water contact angle of ~136 degrees , a low density of 0.04 0.07 g cm-3, and structurally homogeneous three-dimensional nanofiber network at the nanoscale. Systematic investigations using various alkyl aldehydes revealed that pentanal-modified aerogel has similar high hydrophobicity and low density compared to the hexanal-modified material, while heptanal- and octanal-modified aerogels show drastic shrinkage during gelation. The aldehyde modification also suppresses permeation of water droplets into aerogel monoliths as well as reducing shrinkage under high humidity conditions. PMID- 28657716 TI - Bactericidal Specificity and Resistance Profile of Poly(Quaternary Ammonium) Polymers and Protein-Poly(Quaternary Ammonium) Conjugates. AB - Antibacterial polymers are potentially powerful biocides that can destroy bacteria on contact. Debate in the literature has surrounded the mechanism of action of polymeric biocides and the propensity for bacteria to develop resistance to them. There has been particular interest in whether surfaces with covalently coupled polymeric biocides have the same mechanism of action and resistance profile as similar soluble polymeric biocides. We designed and synthesized a series of poly(quaternary ammonium) polymers, with tailorable molecular structures and architectures, to engineer their antibacterial specificity and their ability to delay the development of bacterial resistance. These linear poly(quaternary ammonium) homopolymers and block copolymers, generated using atom transfer radical polymerization, had structure-dependent antibacterial specificity toward Gram positive and negative bacterial species. When single block copolymers contained two polymer segments of differing antibacterial specificity, the polymer combined the specificities of its two components. Nanoparticulate human serum albumin-poly(quaternary ammonium) conjugates of these same polymers, synthesized via "grafting from" atom transfer radical polymerization, were strongly biocidal and also exhibited a marked decrease in the rate of bacterial resistance development relative to linear polymers. These protein-biocide conjugates mimicked the behavior of surface presented polycationic biocides rather than their nonproteinaceous counterparts. PMID- 28657717 TI - Hydrogenation of CO2 at Room Temperature and Low Pressure with a Cobalt Tetraphosphine Catalyst. AB - Large-scale implementation of carbon neutral energy sources such as solar and wind will require the development of energy storage mechanisms. The hydrogenation of CO2 into formic acid or methanol could function as a means to store energy in a chemical bond. The catalyst reported here operates under low pressure, at room temperature, and in the presence of a base much milder (7 pKa units lower) than the previously reported CO2 hydrogenation catalyst, Co(dmpe)2H. The Co(I) tetraphosphine complex, [Co(L3)(CH3CN)]BF4, where L3 = 1,5-diphenyl-3,7 bis(diphenylphosphino)propyl-1,5-diaza-3,7-diphosphacyclooctane (0.31 mM), catalyzes CO2 hydrogenation with an initial turnover frequency of 150(20) h-1 at 25 degrees C, 1.7 atm of a 1:1 mixture of H2 and CO2, and 0.6 M 2-tert-butyl 1,1,3,3-tetramethylguanidine. PMID- 28657718 TI - CAGE: Chromatin Analogous Gene Expression. AB - Self-assembled nucleic acids perform biological, chemical, and mechanical work at the nanoscale. DNA-based molecular machines have been designed here to perform work by reacting with cancer-specific miRNA mimics and then regulating gene expression in vitro by tuning RNA polymerase activity. Because RNA production is topologically restrained, the machines demonstrate chromatin analogous gene expression (CAGE). With modular and tunable design features, CAGE has potential for molecular biology, synthetic biology, and personalized medicine applications. PMID- 28657719 TI - Nanoscale Analysis Reveals the Maturation of Neurodegeneration-Associated Protein Aggregates: Grown in mRNA Granules then Released by Stress Granule Proteins. AB - TDP-43 and FUS are two mRNA-binding proteins associated with neurodegenerative diseases that form cytoplasmic inclusions with prion-like properties in affected neurons. Documenting the early stages of the formation of TDP-43 or FUS protein aggregates and the role of mRNA stress granules that are considered as critical intermediates for protein aggregation is therefore of interest to understand disease propagation. Here, we developed a single molecule approach via atomic force microscopy (AFM), which provides structural information out of reach by fluorescence microscopy. In addition, the aggregation process can be probed in the test tube without separating the interacting partners, which would affect the thermodynamic equilibrium. The results demonstrate that isolated mRNA molecules serve as crucibles to promote TDP-43 and FUS multimerization. Their subsequent merging results in the formation of mRNA granules containing TDP-43 and FUS aggregates. Interestingly, TDP-43 or FUS protein aggregates can be released from mRNA granules by either YB-1 or G3BP1, two stress granule proteins that compete for the binding to mRNA with TDP-43 and FUS. Altogether, the results indicate that age-related successive assembly/disassembly of stress granules in neurons, regulated by mRNA-binding proteins such as YB-1 and G3BP1, could be a source of protein aggregation. PMID- 28657720 TI - Disassembly of Dipeptide Single Crystals Can Transform the Lipid Membrane into a Network. AB - Coupling between cytoskeleton and membranes is critical to cell movement as well as organelle formation. Here, we demonstrate that self-assembled single crystals of a dipeptide, diphenylalanine (FF), can interact with liposomes to form cytoskeleton-like structures. Under a physiological condition, disassembly of FF crystals deforms and translocates supported lipid membrane. The system exhibits similar dynamic characteristics to the endoplasmic reticulum (ER) network in cells. This bottom-up system thus indicates that external matter can participate in the deformation of liposomes, and disassembly of the nanostructures enables a system with distinct dynamic behaviors. PMID- 28657721 TI - Response to Comment on "Robust Fit of Toxicokinetic-Toxicodynamic Models Using Prior Knowledge Contained in the Design of Survival Toxicity Tests". PMID- 28657723 TI - High Tolerance to Iron Contamination in Lead Halide Perovskite Solar Cells. AB - The relationship between charge-carrier lifetime and the tolerance of lead halide perovskite (LHP) solar cells to intrinsic point defects has drawn much attention by helping to explain rapid improvements in device efficiencies. However, little is known about how charge-carrier lifetime and solar cell performance in LHPs are affected by extrinsic defects (i.e., impurities), including those that are common in manufacturing environments and known to introduce deep levels in other semiconductors. Here, we evaluate the tolerance of LHP solar cells to iron introduced via intentional contamination of the feedstock and examine the root causes of the resulting efficiency losses. We find that comparable efficiency losses occur in LHPs at feedstock iron concentrations approximately 100 times higher than those in p-type silicon devices. Photoluminescence measurements correlate iron concentration with nonradiative recombination, which we attribute to the presence of deep-level iron interstitials, as calculated from first principles, as well as iron-rich particles detected by synchrotron-based X-ray fluorescence microscopy. At moderate contamination levels, we witness prominent recovery of device efficiencies to near-baseline values after biasing at 1.4 V for 60 s in the dark. We theorize that this temporary effect arises from improved charge-carrier collection enhanced by electric fields strengthened from ion migration toward interfaces. Our results demonstrate that extrinsic defect tolerance contributes to high efficiencies in LHP solar cells, which inspires further investigation into potential large-scale manufacturing cost savings as well as the degree of overlap between intrinsic and extrinsic defect tolerance in LHPs and "perovskite-inspired" lead-free stable alternatives. PMID- 28657722 TI - Hydrolyzable Poly[Poly(Ethylene Glycol) Methyl Ether Acrylate]-Colistin Prodrugs through Copper-Mediated Photoinduced Living Radical Polymerization. AB - Through the recently developed copper-mediated photoinduced living radical polymerization (CP-LRP), a novel and well-defined polymeric prodrug of the antimicrobial lipopeptide colistin has been developed. A colistin initiator (Boc5 col-Br2) was synthesized through the modification of colistin on both of its threonine residues using a cleavable initiator linker, 2-(2-bromo-2 methylpropanoyloxy) acetic acid (BMPAA), and used for the polymerization of acrylates via CP-LRP. Polymerization proceeds from both sites of the colistin initiator, and through the polymerization of poly(ethylene glycol) methyl ether acrylate (PEGA480), three water-soluble polymer-colistin conjugates (col-PPEGA, having degrees of polymerization of 5, 10, and 20) were achieved with high yield (conversion of >=93%) and narrow dispersities (D < 1.3) in 2-4 h. Little or no effect on the structure and activity of the colistin was observed during the synthesis, and most of the active colistin can be recovered from the conjugates in vitro within 2 days. Furthermore, in vitro biological analyses including disk diffusion, broth microdilution, and time-kill studies suggested that all of the conjugates have the ability to inhibit the growth of multidrug-resistant (MDR) Gram-negative bacteria, of which col-PPEGA DP5 and DP10 showed similar or better antibacterial performance compared to the clinically relevant colistin prodrug CMS, indicating their potential as an alternative antimicrobial therapy. Moreover, considering the control over the polymerization, the CP-LRP technique has the potential to provide an alternative platform for the development of polymer bioconjugates. PMID- 28657725 TI - Evaluation of Phi6 Persistence and Suitability as an Enveloped Virus Surrogate. AB - Recent outbreaks involving enveloped viruses, such as Ebola virus, have raised questions regarding the persistence of enveloped viruses in the water environment. Efforts have been made to find enveloped virus surrogates due to challenges investigating viruses that require biosafety-level 3 or 4 handling. In this study, the enveloped bacteriophage Phi6 was evaluated as a surrogate for enveloped waterborne viruses. The persistence of Phi6 was tested in aqueous conditions chosen based on previously published viral persistence studies. Our results demonstrated that the predicted T90 (time for 90% inactivation) of Phi6 under the 12 evaluated conditions varied from 24 min to 117 days depending on temperature, biological activity, and aqueous media composition. Phi6 persistence was then compared with persistence values from other enveloped viruses reported in the literature. The apparent suitability of Phi6 as an enveloped virus surrogate was dependent on the temperature and composition of the media tested. Of evaluated viruses, 33%, including all conditions considered, had T90 values greater than the 95% confidence interval for Phi6. Ultimately, these results highlight the variability of enveloped virus persistence in the environment and the value of working with the virus of interest for environmental persistence studies. PMID- 28657724 TI - Engineering of Bacteriophage T4 Genome Using CRISPR-Cas9. AB - Bacteriophages likely constitute the largest biomass on Earth. However, very few phage genomes have been well-characterized, the tailed phage T4 genome being one of them. Even in T4, much of the genome remained uncharacterized. The classical genetic strategies are tedious, compounded by genome modifications such as cytosine hydroxylmethylation and glucosylation which makes T4 DNA resistant to most restriction endonucleases. Here, using the type-II CRISPR-Cas9 system, we report the editing of both modified (ghm-Cytosine) and unmodified (Cytosine) T4 genomes. The modified genome, however, is less susceptible to Cas9 nuclease attack when compared to the unmodified genome. The efficiency of restriction of modified phage infection varied greatly in a spacer-dependent manner, which explains some of the previous contradictory results. We developed a genome editing strategy by codelivering into E. coli a CRISPR-Cas9 plasmid and a donor plasmid containing the desired mutation(s). Single and multiple point mutations, insertions and deletions were introduced into both modified and unmodified genomes. As short as 50-bp homologous flanking arms were sufficient to generate recombinants that can be selected under the pressure of CRISPR-Cas9 nuclease. A 294-bp deletion in RNA ligase gene rnlB produced viable plaques, demonstrating the usefulness of this editing strategy to determine the essentiality of a given gene. These results provide the first demonstration of phage T4 genome editing that might be extended to other phage genomes in nature to create useful recombinants for phage therapy applications. PMID- 28657726 TI - Prediction of the Iron-Based Polynuclear Magnetic Superhalogens with Pseudohalogen CN as Ligands. AB - To explore stable polynuclear magnetic superhalogens, we perform an unbiased structure search for polynuclear iron-based systems based on pseudohalogen ligand CN using the CALYPSO method in conjunction with density functional theory. The superhalogen properties, magnetic properties, and thermodynamic stabilities of neutral and anionic Fe2(CN)5 and Fe3(CN)7 clusters are investigated. The results show that both of the clusters have superhalogen properties due to their electron affinities (EAs) and that vertical detachment energies (VDEs) are significantly larger than those of the chlorine element and their ligand CN. The distribution of the extra electron analysis indicates that the extra electron is aggregated mainly into pseudohalogen ligand CN units in Fe2(CN)5- and Fe3(CN)7- cluster. These features contribute significantly to their high EA and VDE. Besides superhalogen properties, these two anionic clusters carry a large magnetic moment just like the Fe2F5- cluster. Additionally, the thermodynamic stabilities are also discussed by calculating the energy required to fragment the cluster into various smaller stable clusters. It is found that Fe(CN)2 is the most favorable fragmentation product for anionic Fe2(CN)5- and Fe3(CN)7- clusters, and both of the anions are less stable against ejection of Fe atoms than Fe(CN)n-x. PMID- 28657727 TI - Comment on "Robust Fit of Toxicokinetic-Toxicodynamic Models Using Prior Knowledge Contained in the Design of Survival Toxicity Tests". PMID- 28657728 TI - Flexible Quasi-Two-Dimensional CoFe2O4 Epitaxial Thin Films for Continuous Strain Tuning of Magnetic Properties. AB - Epitaxial thin films of CoFe2O4 (CFO) have successfully been transferred from a SrTiO3 substrate onto a flexible polyimide substrate. By bending the flexible polyimide, different levels of uniaxial strain are continuously introduced into the CFO epitaxial thin films. Unlike traditional epitaxial strain induced by substrates, the strain from bending will not suffer from critical thickness limitation, crystalline quality variation, and substrate clamping, and more importantly, it provides a more intrinsic and reliable way to study strain controlled behaviors in functional oxide systems. It is found that both the saturation magnetization and coercivity of the transferred films can be changed over the bending status and show a high accord with the movement of the curvature bending radius of the polyimide substrate. This reveals that the mechanical strain plays a critical role in tuning the magnetic properties of CFO thin films parallel and perpendicular to the film plane direction. PMID- 28657729 TI - A Generic HPLC Method for Absolute Quantification of Oxidation in Monoclonal Antibodies and Fc-Fusion Proteins Using UV and MS Detection. AB - Oxidation of biopharmaceuticals may affect their bioactivity, serum half-life, and (bio)chemical stability. The Fc domain of IgG monoclonal antibodies (mAbs) contains two methionine residues which are susceptible to oxidation. Here, we present a middle-down approach employing the cysteine protease IdeS under reducing conditions to obtain three mAb subunits of approximately 25 kDa: Fc/2, Fd', and LC. These subunits were separated by ion-pair reversed-phase high performance liquid chromatography (IP-RP-HPLC) and detected by UV spectroscopy as well as Orbitrap mass spectrometry (MS), as well as MS upon all-ion fragmentation (AIF-MS). We evaluated the feasibility of three strategies for absolute quantification of oxidation in the Fc region of hydrogen peroxide-stressed Rituximab, using a single, commercially available software platform both for data acquisition and evaluation: UV spectroscopy, full-scan MS, and monitoring of product ions obtained by AIF-MS. UV spectroscopy showed the lowest limits of quantification (LOQ) (0.96 ng MUL-1) and featured the lowest relative process standard deviation (Vx0%) of 7.2% compared to MS and AIF-MS with LOQs of 1.24 4.32 ng MUL-1 and relative process standard deviations of 9.0-14%, respectively. Our approach is generic in that it allows monitoring and quantification of oxidation in the Fc regions of fully human and humanized IgG1 mAbs as well as of Fc-fusion proteins. This is exemplified by limits of detection of 1.2%, 1.0%, and 1.2% of oxidation in drug products containing the biopharmaceuticals Rituximab, Adalimumab, and Etanercept, respectively. The presented method is an attractive alternative to conventional time-intensive peptide mapping which is prone to artificial oxidation due to extensive sample preparation. PMID- 28657730 TI - Land Use Regression Models for Alkylbenzenes in a Middle Eastern Megacity: Tehran Study of Exposure Prediction for Environmental Health Research (Tehran SEPEHR). AB - Land use regression (LUR) has not been applied thus far to ambient alkylbenzenes in highly polluted megacities. We advanced LUR models for benzene, toluene, ethylbenzene, p-xylene, m-xylene, o-xylene (BTEX), and total BTEX using measurement based estimates of annual means at 179 sites in Tehran megacity, Iran. Overall, 520 predictors were evaluated, such as The Weather Research and Forecasting Model meteorology predictions, emission inventory, and several new others. The final models with R2 values ranging from 0.64 for p-xylene to 0.70 for benzene were mainly driven by traffic-related variables but the proximity to sewage treatment plants was present in all models indicating a major local source of alkylbenzenes not used in any previous study. We further found that large buffers are needed to explain annual mean concentrations of alkylbenzenes in complex situations of a megacity. About 83% of Tehran's surface had benzene concentrations above air quality standard of 5 MUg/m3 set by European Union and Iranian Government. Toluene was the predominant alkylbenzene, and the most polluted area was the city center. Our analyses on differences between wealthier and poorer areas also showed somewhat higher concentrations for the latter. This is the largest LUR study to predict all BTEX species in a megacity. PMID- 28657731 TI - Structural Effects of Single Mutations in a Filamentous Viral Capsid Across Multiple Length Scales. AB - Filamentous bacteriophage (phage) are single-stranded DNA viruses that infect bacteria. Single-site mutants of fd phage have been studied by magic-angle spinning nuclear magnetic resonance and by small-angle X-ray scattering. Detailed analysis has been performed that provides insight into structural variations on three length scales. The results, analyzed in conjunction with existing literature data, suggest that a single charge mutation on the capsid surface affects direct interviral interactions but not the structure of individual particles or the macroscale organization. On the other hand, a single hydrophobic mutation located at the hydrophobic interface that stabilizes capsid assembly alters the atomic structure of the phage, mainly affecting intersubunit interactions, affects its macroscale organization, that is, the pitch of the cholesteric liquid crystal formed by the particles, but skips the nanoscale hence does not affect direct interparticle interactions. An X-ray scattering under osmotic pressure assay provides the effective linear charge density of the phage and we obtain values of 0.6 A-1 and 0.4 A-1 for fd and M13 phage, respectively. These values agree with a simple consideration of a single cylinder with protein and DNA charges spread according to the most recent atomic-resolution models of the phage. PMID- 28657732 TI - An Iminosemiquinone-Coordinated Oxidovanadium(V) Complex: A Combined Experimental and Computational Study. AB - Ligand H4Sar(AP/AP) contained two terminal amidophenolate units that were connected by a disulfane bridge. The ligand reacted with VOSO4.5H2O in the presence of Et3N under air and provided a mononuclear octahedral oxidovanadium complex (1). X-ray crystal structure analysis of complex 1 revealed that the oxidation state of the V ion was V and the VO3+ unit was coordinated to an iminosemiquinone radical anion. An isotopic signal at g = 1.998 in the X-band electron paramagnetic resonance (EPR) spectrum and the solution magnetic moment MUeff = 1.98 MUB at 298 K also supported the composition. The formation of complex 1 preceded through the initial generation of a diamagnetic VO2+ iminoisemiquinone species, as established by time-dependent UV-vis-near-IR (NIR), X-band EPR, and density functional theory studies. The UV-vis-NIR spectrum of complex 1 consisted of four ligand-to-metal charge-transfer transitions in the visible region, while an intervalence ligand-to-ligand charge transfer appeared at 1162 nm. The cyclic voltammogram of the complex showed four oxidation waves and one reduction wave. Spectroelectrochemical studies at fixed potentials revealed that the oxidation and reduction processes were ligand-based. PMID- 28657733 TI - Constrained-Orbital Density Functional Theory. Computational Method and Applications to Surface Chemical Processes. AB - We present a method for performing density-functional theory (DFT) calculations in which one or more Kohn-Sham orbitals are constrained to be localized on individual atoms. This constrained-orbital DFT (CO-DFT) approach can be used to tackle two prevalent shortcomings of DFT: the lack of transparency with regard to the governing electronic structure in large (planewave based) DFT calculations and the limitations of semilocal DFT in describing systems with localized electrons or a large degree of static correlation. CO-DFT helps to address the first of these issues by decomposing complex orbital transformations occurring during elementary chemical processes into simpler and more intuitive transformations. The second issue is addressed by using the CO-DFT method to generate configuration states for multiconfiguration Kohn-Sham calculations. We demonstrate both of these applications for elementary reaction steps involved in the oxygen evolution reaction. PMID- 28657735 TI - NMR Methods for Identification of False Positives in Biochemical Screens. AB - Over the past few decades, NMR spectroscopy has become an established tool in drug discovery. This communication will highlight the potential of NMR spectroscopy as a method for identification of problematic compounds and as a valuable aid toward revealing some mechanisms of promiscuous behavior. NMR methods for detecting false positives will be analyzed on the basis of their performance, strengths, limitations, and potential pitfalls. Additionally, this communication aims to provide an insight into the limitations of NMR-based methodologies applied to ligand screening in the context of false-positive hits. PMID- 28657734 TI - Anthocyanins from Black Chokeberry (Aroniamelanocarpa Elliot) Delayed Aging Related Degenerative Changes of Brain. AB - Aging is the greatest risk factor for most neurodegenerative diseases, which is associated with decreasing cognitive function and significantly affecting life quality in the elderly. Computational analysis suggested that 4 anthocyanins from chokeberry fruit increased Klotho (aging-suppressor) structural stability, so we hypothesized that chokeberry anthocyanins could antiaging. To explore the effects of anthocyanins treatment on brain aging, mice treated with 15 or 30 mg/kg anthocyanins by gavage and injected D-galactose accelerated aging per day. After 8 weeks, cognitive and noncognitive components of behavior were determined. Our studies showed that anthocyanins blocked age-associated cognitive decline and response capacity in senescence accelerated mice. Furthermore, mice treated with anthocyanins-supplemented showed better balance of redox systems (SOD, GSH-PX, and MDA) in all age tests. Three major monoamines were norepinephrine, dopamine, and 5-hydroxytryptamine, and their levels were significantly increased; the levels of inflammatory cytokines (COX2, TGF-beta1, and IL-1) transcription and DNA damage were decreased significantly in brains of anthocyanins treated mice compared to aged models. The DNA damage signaling pathway was also regulated with anthocyanins. Our results suggested that anthocyanins was a potential approach for maintaining thinking and memory in aging mice, possibly by regulating the balance of redox system and reducing inflammation accumulation, and the most important factor was inhibiting DNA damage. PMID- 28657736 TI - Kinetics from Replica Exchange Molecular Dynamics Simulations. AB - Transitions between metastable states govern many fundamental processes in physics, chemistry and biology, from nucleation events in phase transitions to the folding of proteins. The free energy surfaces underlying these processes can be obtained from simulations using enhanced sampling methods. However, their altered dynamics makes kinetic and mechanistic information difficult or impossible to extract. Here, we show that, with replica exchange molecular dynamics (REMD), one can not only sample equilibrium properties but also extract kinetic information. For systems that strictly obey first-order kinetics, the procedure to extract rates is rigorous. For actual molecular systems whose long time dynamics are captured by kinetic rate models, accurate rate coefficients can be determined from the statistics of the transitions between the metastable states at each replica temperature. We demonstrate the practical applicability of the procedure by constructing master equation (Markov state) models of peptide and RNA folding from REMD simulations. PMID- 28657737 TI - Structure-Pungency Relationships and TRP Channel Activation of Drimane Sesquiterpenes in Tasmanian Pepper (Tasmannia lanceolata). AB - Sensory-guided fractionation of extracts of Tasmanian pepper berries revealed 20 drimane sesquiterpens, among which polygodial, warburganal, and 1beta-acetoxy-9 deoxy-isomuzigadial exhibited the lowest pungency threshold concentrations on the tongue surface (0.6-2.8 nmol/cm2) and elicited a dose-dependent calcium influx into mTRPA1 expressing CHO cells with the lowest EC50 values (4.5 +/- 1.0 to 16.7 +/- 7.5 MUmol/L) and a good correlation to oral pungency thresholds (R2 = 0.986, linear regression). Calcium imaging assays demonstrated these chemosensates to induce a calcium influx into cultured trigeminal neurons prepared from wildtype (TRPA1+/+) mice, whereas no calcium influx was observed in neurons from TRPA1 knockout mice (TRPA1-/-), thus confirming the alpha,beta-unsaturated 1,4 dialdehyde structure to be the required structural motif for a low oral puncency thresholds and activation of the Transient Receptor Potential Channel A1 (TRPA1). Time-resolved NMR experiments confirmed the pungency mediating mechanism for electrophilic drimane sesquiterpene dialdehydes to be different from that found for other electrophilic pungent agents like isothiocyanates, which have been shown to undergo a covalent binding with cysteine residues in TRPA1. Instead, the high-impact chemosensates polygodial, warburganal, and 1beta-acetoxy-9-deoxy isomuzigadial showed immediate reactivity with the epsilon-amino group of lysine side chains to give pyrrole-type conjugates, thus showing evidence for TRPA1 activation by covalent lysine modification. PMID- 28657739 TI - Pyro-Borates, Spiro-Borates, and Boroxinates of BINOL-Assembly, Structures, and Reactivity. AB - VANOL and VAPOL ligands are known to react with three equivalents of B(OPh)3 to form a catalytic species that contains a boroxinate core with three boron atoms, and these have proven to be effective catalysts for a number of reactions. However, it was not known whether the closely related BINOL ligand will likewise form a boroxinate species. It had simply been observed that mixtures of BINOL and B(OPh)3 were very poor catalysts compared to the same mixtures with VANOL or VAPOL. Borate esters of BINOL have been investigated as chiral catalysts, and these include meso-borates, spiro-borates, and diborabicyclo-borate esters. Borate esters are often in equilibrium, and their structures can be determined by stoichiometry and/or thermodynamics, especially in the presence of a base. The present study examines the structures of borate esters of BINOL that are produced with different stoichiometric combinations of BINOL with B(OPh)3 in the presence and absence of a base. Depending on conditions, pyro-borates, spiro-borates, and boroxinate species can be generated and their effectiveness in a catalytic asymmetric aziridination was evaluated. The finding is that BINOL borate species are not necessarily inferior catalysts to those of VANOL and VAPOL but that, under the conditions, BINOL forms two different catalytic species (a boroxinate and a spiro-borate) that give opposite asymmetric inductions. However, many BINOL derivatives with substitutents in the 3- and 3'-positions gave only the boroxinate species and the 3,3'-Ph2BINOL ligand gave a boroxinate catalyst that gives excellent inductions in the aziridination reaction. BINOL derivatives with larger groups in the 3,3'-position will not form either spiro-borates or boroxinate species and thus are not effective catalysts at all. PMID- 28657738 TI - Genetic Code Expansion in Zebrafish Embryos and Its Application to Optical Control of Cell Signaling. AB - Site-specific incorporation of unnatural amino acids into proteins provides a powerful tool to study protein function. Here we report genetic code expansion in zebrafish embryos and its application to the optogenetic control of cell signaling. We genetically encoded four unnatural amino acids with a diverse set of functional groups, which included a photocaged lysine that was applied to the light-activation of luciferase and kinase activity. This approach enables versatile manipulation of protein function in live zebrafish embryos, a transparent and commonly used model organism to study embryonic development. PMID- 28657740 TI - Miscibility and Thermodynamics of Mixing of Different Models of Formamide and Water in Computer Simulation. AB - The thermodynamic changes that occur upon mixing five models of formamide and three models of water, including the miscibility of these model combinations itself, is studied by performing Monte Carlo computer simulations using an appropriately chosen thermodynamic cycle and the method of thermodynamic integration. The results show that the mixing of these two components is close to the ideal mixing, as both the energy and entropy of mixing turn out to be rather close to the ideal term in the entire composition range. Concerning the energy of mixing, the OPLS/AA_mod model of formamide behaves in a qualitatively different way than the other models considered. Thus, this model results in negative, while the other ones in positive energy of mixing values in combination with all three water models considered. Experimental data supports this latter behavior. Although the Helmholtz free energy of mixing always turns out to be negative in the entire composition range, the majority of the model combinations tested either show limited miscibility, or, at least, approach the miscibility limit very closely in certain compositions. Concerning both the miscibility and the energy of mixing of these model combinations, we recommend the use of the combination of the CHARMM formamide and TIP4P water models in simulations of water-formamide mixtures. PMID- 28657741 TI - Active Sites in Supported Single-Site Catalysts: An NMR Perspective. AB - Development of well-defined heterogeneous catalysts requires detailed structural characterization of active sites, an essential step toward establishing structure activity relationships and promoting rational designs of catalysts. Solid-state NMR has emerged as a powerful approach to provide key molecular-level information about active-site structures and dynamics in heterogeneous catalysis. Here, we describe how one can apply solid-state NMR, ranging from 1D chemical shift assignments (and additional parameters, CQ and eta, for quadrupolar nuclei, I > 1/2) to 2D correlations, to analysis of chemical shift anisotropy, providing unprecedented structural information about a broad range of materials. We also describe how modern hyperpolarization techniques like dynamic nuclear polarization can be used to improve the sensitivity of NMR, and make various challenging 1D/2D NMR experiments feasible, thus paving the way to determine the structures of surface sites. PMID- 28657743 TI - Visible-Light-Driven Carboxylation of Aryl Halides by the Combined Use of Palladium and Photoredox Catalysts. AB - A highly useful, visible-light-driven carboxylation of aryl bromides and chlorides with CO2 was realized using a combination of Pd(OAc)2 as a carboxylation catalyst and Ir(ppy)2(dtbpy)(PF6) as a photoredox catalyst. This carboxylation reaction proceeded in high yields under 1 atm of CO2 with a variety of functionalized aryl bromides and chlorides without the necessity of using stoichiometric metallic reductants. PMID- 28657742 TI - MicroRNA268 Overexpression Affects Rice Seedling Growth under Cadmium Stress. AB - MicroRNAs (miRNAs) are 21-24-nucleotide-long RNAs that function as ubiquitous post-transcriptional regulators of gene expression in plants and animals. Increasing evidence points to the important role of miRNAs in plant responses to abiotic and biotic stresses. Cadmium (Cd) is a nonessential heavy metal highly toxic to plants. Although many genes encoding metal transporters have been characterized, the mechanisms for the regulation of the expression of the heavy metal transporter genes are largely unknown. In this study, we found that the expression of miR268 in rice was significantly induced under Cd stress. By contrast, expression of natural resistance-associated macrophage protein 3 (NRAMP3), a target gene of miR268, was dramatically decreased by Cd treatment. Overexpression of miR268 inhibited rice seedling growth under Cd stress. The transgenic miR268-overexpressing plant leaves contained increased levels of hydrogen peroxide and malondialdehyde, and their seedlings accumulated increased levels of Cd when compared to those in wild-type plants. These results indicate that miR268 acts as a negative regulator of rice's tolerance to Cd stress. Thus, miRNA-guided regulation of gene expression plays an important role in plant responses to heavy-metal stress. PMID- 28657745 TI - Recent Advances in Structure-Based Drug Design Targeting Class A G Protein Coupled Receptors Utilizing Crystal Structures and Computational Simulations. AB - G protein-coupled receptors (GPCRs) represent the largest and most physiologically important integral membrane protein family, and these receptors respond to a wide variety of physiological and environmental stimuli. GPCRs are among the most critical therapeutic targets for numerous human diseases, and approximately one-third of the currently marketed drugs target this receptor family. The recent breakthroughs in GPCR structural biology have significantly contributed to our understanding of GPCR function, ligand binding, and pharmacological action as well as to the design of new drugs. This perspective highlights the latest advances in GPCR structures with a focus on the receptor ligand interactions of each receptor family in class A nonrhodopsin GPCRs as well as the structural features for their activation, biased signaling, and allosteric mechanisms. The current state-of-the-art methodologies of structure-based drug design (SBDD) approaches in the GPCR research field are also discussed. PMID- 28657744 TI - Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications. AB - A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with beta arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no beta-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5 HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine induced hyperactivity model, compound (+)-19 showed significant antipsychotic drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity. PMID- 28657746 TI - Perspectives on Mussel-Inspired Wet Adhesion. AB - Nature employs sophisticated control of a structure's properties at multiple length scales to achieve its wet adhesion. However, the translation of such structures has very often been missing in biomimetic adhesives; in turn, their performance is significantly limited as compared to that of biological adhesion, e.g., from mussels. In this Perspective, we overview the major breakthroughs in this field, highlighting the recent advances that demonstrate that holistic multiscale translation is essential to biomimetic design. We argue that the multiscale coordination of numerous key elements in the natural adhesive system is essential to replicate the strong, instant, and durable wet adhesion of the marine sessile organism. PMID- 28657747 TI - Understanding How Prolyl-4-hydroxylase Structure Steers a Ferryl Oxidant toward Scission of a Strong C-H Bond. AB - Prolyl-4-hydroxylase (P4H) is a non-heme iron hydroxylase that regio- and stereospecifically hydroxylates proline residues in a peptide chain into R-4 hydroxyproline, which is essential for collagen cross-linking purposes in the human body. Surprisingly, in P4H, a strong aliphatic C-H bond is activated, while thermodynamically much weaker aliphatic C-H groups, that is, at the C3 and C5 positions, are untouched. Little is known on the origins of the high regio- and stereoselectivity of P4H and many non-heme and heme enzymes in general, and insight into this matter may be relevant to Biotechnology as well as Drug Development. The active site of the protein contains two aromatic residues (Tyr140 and Trp243) that we expected to be crucial for guiding the regioselectivity of the reaction. We performed a detailed quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) study on wild type and mutant structures. The work shows that Trp243 is involved in key protein loop-loop interactions that affect the shape and size of the substrate binding pocket and its mutation has major long-range effects. By contrast, the Tyr140 residue is shown to guide the regio- and stereoselectivity by holding the substrate and ferryl oxidant in a specific orientation through hydrogen bonding and pi-stacking interactions. Compelling evidence is found that the Tyr140 residue is involved in expelling the product from the binding pocket after the reaction is complete. It is shown that mutations where the hydrogen bonding network that involves the Tyr140 and Trp243 residues is disrupted lead to major changes in folding of the protein and the size and shape of the substrate binding pocket. Specifically, the Trp243 residue positions the amino acid side chains of Arg161 and Glu127 in specific orientations with substrate. As such, the P4H enzyme is a carefully designed protein with a subtle and rigid secondary structure that enables the binding of substrate, guides the regioselectivity, and expels product efficiently. PMID- 28657748 TI - Epitaxial Growth and Band Structure of Te Film on Graphene. AB - Tellurium (Te) films with monolayer and few-layer thickness are obtained by molecular beam epitaxy on a graphene/6H-SiC(0001) substrate and investigated by in situ scanning tunneling microscopy and spectroscopy (STM/STS). We reveal that the Te films are composed of parallel-arranged helical Te chains flat-lying on the graphene surface, exposing the (1 * 1) facet of (1010) of the bulk crystal. The band gap of Te films increases monotonically with decreasing thickness, reaching the near-infrared band for the monolayer Te. An explicit band bending at the edge between the monolayer Te and graphene substrate is visualized. With the thickness controlled in the atomic scale, Te films show potential applications of electronics and optoelectronics. PMID- 28657749 TI - Biocompatible Polyelectrolyte Complex Nanoparticles from Lactoferrin and Pectin as Potential Vehicles for Antioxidative Curcumin. AB - Polyelectrolyte complex nanoparticles (PEC NPs) were fabricated via electrostatic interactions between positively charged heat-denatured lactoferrin (LF) particles and negatively charged pectin. The obtained PEC NPs were then utilized as curcumin carriers. PEC NPs were prepared by mixing 1.0 mg/mL solutions of heat denatured LF and pectin at a mass ratio of 1:1 (w/w) in the absence of NaCl at pH 4.50. PEC NPs that were prepared under optimized conditions were spherical in shape with a particle size of ~208 nm and zeta potential of ~-32 mV. Hydrophobic curcumin was successfully encapsulated into LF/pectin PEC NPs with high encapsulation efficiency (~85.3%) and loading content (~13.4%). The in vitro controlled release and prominent antioxidant activities of curcumin from LF/pectin PEC NPs were observed. The present work provides a facile and fast method to synthesize nanoscale food-grade delivery systems for the improved water solubility, controlled release, and antioxidant activity of hydrophobic curcumin. PMID- 28657750 TI - Coalescence of Nanoclusters Analyzed by Well-Tempered Metadynamics. Comparison with Straightforward Molecular Dynamics. AB - The coalescence process of two nanoparticles to yield a core-shell structure is analyzed by a well-tempered metadynamics procedure. This methodology has been shown to be useful in understanding the present phenomenon in terms of two collective variables: the distance between the center of mass of the coalescing particles and the gyration radius of the resulting core element. The free-energy contour plots clearly show that the coalescence process involves the deformation of the core material, which is manifested in the residence of the system in regions with a larger gyration radius. Results from molecular dynamics for the same system were found helpful to reach the definition of this second collective variable. The advantages and limitations of the latter approach are discussed. PMID- 28657751 TI - Quantifying van der Waals Interactions in Layered Transition Metal Dichalcogenides from Pressure-Enhanced Valence Band Splitting. AB - van der Waals (vdW) forces, despite being relatively weak, hold the layers together in transition metal dichalcogenides (TMDs) and play a key role in their band structure evolution, hence profoundly affecting their physical properties. In this work, we experimentally probe the vdW interactions in MoS2 and other TMDs by measuring the valence band maximum (VBM) splitting (Delta) at K point as a function of pressure in a diamond anvil cell. As high pressure increases interlayer wave function coupling, the VBM splitting is enhanced in 2H-stacked MoS2 multilayers but, due to its specific geometry, not in 3R-stacked multilayers, hence allowing the interlayer contribution to be separated out of the total VBM splitting, as well as predicting a negative pressure (2.4 GPa) where the interlayer contribution vanishes. This negative pressure represents the threshold vdW interaction beyond which neighboring layers are electronically decoupled. This approach is compared to first-principles calculations and found to be widely applicable to other group-VI TMDs. PMID- 28657752 TI - Ultralow Self-Doping in Two-dimensional Hybrid Perovskite Single Crystals. AB - Unintentional self-doping in semiconductors through shallow defects is detrimental to optoelectronic device performance. It adversely affects junction properties and it introduces electronic noise. This is especially acute for solution-processed semiconductors, including hybrid perovskites, which are usually high in defects due to rapid crystallization. Here, we uncover extremely low self-doping concentrations in single crystals of the two-dimensional perovskites (C6H5C2H4NH3)2PbI4.(CH3NH3PbI3)n-1 (n = 1, 2, and 3), over three orders of magnitude lower than those of typical three-dimensional hybrid perovskites, by analyzing their conductivity behavior. We propose that crystallization of hybrid perovskites containing large organic cations suppresses defect formation and thus favors a low self-doping level. To exemplify the benefits of this effect, we demonstrate extraordinarily high light-detectivity (1013 Jones) in (C6H5C2H4NH3)2PbI4.(CH3NH3PbI3)n-1 photoconductors due to the reduced electronic noise, which makes them particularly attractive for the detection of weak light signals. Furthermore, the low self-doping concentration reduces the equilibrium charge carrier concentration in (C6H5C2H4NH3)2PbI4.(CH3NH3PbI3)n-1, advantageous in the design of p-i-n heterojunction solar cells by optimizing band alignment and promoting carrier depletion in the intrinsic perovskite layer, thereby enhancing charge extraction. PMID- 28657753 TI - Complete Ag4M2(DMSA)4 (M = Ni, Pd, Pt, DMSA = Dimercaptosuccinic Acid) Cluster Series: Optical Properties, Stability, and Structural Characterization. AB - The cluster series Ag4M2(DMSA)4 (M = Ni, Pd, Pt) has been synthesized and the optical spectra and stability have been examined as a function of the metal, M. We have also obtained the structure of Ag4Ni2(DMSA)4 using X-ray crystallography, confirming the previously calculated structure. In the optical spectrum, there is a significant blue shift as the substituted metal M progresses down the periodic table. Theoretical calculations suggest that the blue shift is due to the lowering in energy of the d orbitals of the transition metal, M; however the expected metal-metal excitations are optically weak, and the spectra are dominated by metal-ligand excitations. The Ag4Pd2(DMSA)4 species has exceptionally high stability relative to the previously reported Ni and Pt analogues. PMID- 28657754 TI - Understanding and Modeling the Liquid Uptake in Porous Compacted Powder Preparations. AB - Porous solid materials commonly undergo coating processes during their manufacture, where liquids are put in contact with solids for different purposes. The study of liquid penetration in porous substrates is a process of high relevance in activities in several industries. In particular, powder detergents are subject to coating with surfactants that will boost their performance, although this may affect the flowability and even cause caking of the particulate material, which can be detrimental to consumer acceptance. Here we present a methodology to make compacted preparations of powders relevant to detergent making and evaluate the internal structure of such porous substrates by means of X-ray microcomputed tomography. Liquid penetration in the preparation and the total mass uptake of fluid were monitored by a gravimetric technique based on a modified Wilhelmy plate method consisting of consecutive cycles. Taking into account the geometry of the system, two models were proposed to describe the liquid uptake based on the process being driven by mass (model 1) or pressure (model 2) gradients. A comparison between both from statistical and physical points of view led to the conclusion that the latter was more appropriate for describing the process and retrieving values of the permeability of the solid between 0.03 * 10-12 and 0.95 * 10-12 m2. Finally, with the parameters retrieved from model 2, the force balance observed throughout the experiment was simulated satisfactorily. PMID- 28657756 TI - Seeds and Potentials Mediated Synthesis of High-Index Faceted Gold Nanocrystals with Enhanced Electrocatalytic Activities. AB - Because high-index facets (HIFs) possess high surface energy, the metal nanoparticles enclosed with HIFs are eliminated during their growth in a conventional shape-controlled synthesis due to the thermodynamics that drives the particles minimizing their total surface energy. This study develops a double step potential method to prepare an unprecedentedly stellated Au nanocrystals (NCs) bounded by high-index {711} and {331} facets in deep eutectic solvent (DES) medium. The formation of Au NCs bounded by HIFs was systematically studied. It has demonstrated that the shapes of Au NCs are strongly dependent on the size of seeds and the growth potentials as well as the urea adsorbates in the DES. By adjusting the size of seeds and the growth potentials, the stellated Au NCs can be transformed into concave hexoctahedra (HOH) with high-index {421} facets and concave trisoctahedra (TOH) with high-index {991} facets. The electrocatalytic activities of the as-prepared Au NCs are evaluated by glucose oxidation. Thanks to HIFs having high density of atomic steps and kinks, the stellated, TOH, and HOH Au NCs exhibit higher electrocatalytic activity than that of the polycrystalline Au electrode, demonstrating that the steps and kinks serve as the active sites and play an important role in glucose electro-oxidation. PMID- 28657755 TI - Simultaneous Enhancement of Photoluminescence, MRI Relaxivity, and CT Contrast by Tuning the Interfacial Layer of Lanthanide Heteroepitaxial Nanoparticles. AB - Nanoparticle (NP) based exogenous contrast agents assist biomedical imaging by enhancing the target visibility against the background. However, it is challenging to design a single type of contrast agents that are simultaneously suitable for various imaging modalities. The simple integration of different components into a single NP contrast agent does not guarantee the optimized properties of each individual components. Herein, we describe lanthanide-based core-shell-shell (CSS) NPs as triple-modal contrast agents that have concurrently enhanced performance compared to their individual components in photoluminescence (PL) imaging, magnetic resonance imaging (MRI), and computed tomography (CT). The key to simultaneous enhancement of PL intensity, MRI r1 relaxivity, and X-ray attenuation capability in CT is tuning the interfacial layer in the CSS NP architecture. By increasing the thickness of the interfacial layer, we show that (i) PL intensity is enhanced from completely quenched/dark state to brightly emissive state of both upconversion and downshifting luminescence at different excitation wavelengths (980 and 808 nm), (ii) MRI r1 relaxivity is enhanced by 5 fold from 11.4 to 52.9 mM-1 s-1 (per Gd3+) at clinically relevant field strength 1.5 T, and (iii) the CT Hounsfield Unit gain is 70% higher than the conventional iodine-based agents at the same mass concentration. Our results demonstrate that judiciously designed contrast agents for multimodal imaging can achieve simultaneously enhanced performance compared to their individual stand-alone structures and highlight that multimodality can be achieved without compromising on individual modality performance. PMID- 28657757 TI - How Cubic Can Ice Be? AB - Using an X-ray laser, we investigated the crystal structure of ice formed by homogeneous ice nucleation in deeply supercooled water nanodrops (r ~ 10 nm) at ~225 K. The nanodrops were formed by condensation of vapor in a supersonic nozzle, and the ice was probed within 100 MUs of freezing using femtosecond wide angle X-ray scattering at the Linac Coherent Light Source free-electron X-ray laser. The X-ray diffraction spectra indicate that this ice has a metastable, predominantly cubic structure; the shape of the first ice diffraction peak suggests stacking-disordered ice with a cubicity value, chi, in the range of 0.78 +/- 0.05. The cubicity value determined here is higher than those determined in experiments with micron-sized drops but comparable to those found in molecular dynamics simulations. The high cubicity is most likely caused by the extremely low freezing temperatures and by the rapid freezing, which occurs on a ~1 MUs time scale in single nanodroplets. PMID- 28657758 TI - Valley Phase and Voltage Control of Coherent Manipulation in Si Quantum Dots. AB - With any roughness at the interface of an indirect-bandgap semiconducting dot, the phase of the valley-orbit coupling can take on a random value. This random value, in double quantum dots, causes a large change in the exchange splitting. We demonstrate a simple analytical method to calculate the phase, and thus the exchange splitting and singlet-triplet qubit frequency, for an arbitrary interface. We then show that, with lateral control of the position of a quantum dot using a gate voltage, the valley-orbit phase can be controlled over a wide range, so that variations in the exchange splitting can be controlled for individual devices. Finally, we suggest experiments to measure the valley phase and the concomitant gate voltage control. PMID- 28657759 TI - Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding? AB - Halogens are present in a significant number of drugs, contributing favorably to ligand-protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand-protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C-X...HBD orientations. Notably, the orientation dependence of the halogen-HBD (X-HBD) interactions is minimal over greater than 100 degrees with favorable interaction energies ranging from -2 to -14 kcal/mol. This contrasts halogen bonds in that X-HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand-protein binding and, therefore, should be actively considered during rational ligand design. PMID- 28657760 TI - Effect of Monovalent Ion Parameters on Molecular Dynamics Simulations of G Quadruplexes. AB - G-quadruplexes (GQs) are key noncanonical DNA and RNA architectures stabilized by desolvated monovalent cations present in their central channels. We analyze extended atomistic molecular dynamics simulations (~580 MUs in total) of GQs with 11 monovalent cation parametrizations, assessing GQ overall structural stability, dynamics of internal cations, and distortions of the G-tetrad geometries. Majority of simulations were executed with the SPC/E water model; however, test simulations with TIP3P and OPC water models are also reported. The identity and parametrization of ions strongly affect behavior of a tetramolecular d[GGG]4 GQ, which is unstable with several ion parametrizations. The remaining studied RNA and DNA GQs are structurally stable, though the G-tetrad geometries are always deformed by bifurcated H-bonding in a parametrization-specific manner. Thus, basic 10-MUs-scale simulations of fully folded GQs can be safely done with a number of cation parametrizations. However, there are parametrization-specific differences and basic force-field errors affecting the quantitative description of ion-tetrad interactions, which may significantly affect studies of the ion binding processes and description of the GQ folding landscape. Our d[GGG]4 simulations indirectly suggest that such studies will also be sensitive to the water models. During exchanges with bulk water, the Na+ ions move inside the GQs in a concerted manner, while larger relocations of the K+ ions are typically separated. We suggest that the Joung-Cheatham SPC/E K+ parameters represent a safe choice in simulation studies of GQs, though variation of ion parameters can be used for specific simulation goals. PMID- 28657761 TI - Grignard Reagents on a Tab: Direct Magnesium Insertion under Flow Conditions. AB - An on-demand preparation of organomagnesium reagents is presented using a new flow protocol. The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Required amounts of solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups. PMID- 28657762 TI - Hematologic complications in a patient with Glycine soja polyagglutination following fresh frozen plasma transfusion. AB - CONCLUSIONS: Polyagglutination is a rare and underdiagnosed condition, characterized by agglutination of red blood cells(RBCs) with almost all ABO compatible adult sera. Polyagglutination can occur when a cryptantigen is exposed on RBCs via microbial enzyme activity. Becausenearly all adults naturally produce antibodies against cryptantigens, transfusion of plasma can cause unexpected hemolysis and hematologic complications, such as thrombocytopenia and disseminated intravascular coagulation, in patients whose cryptantigens are exposed. We report a case of Glycine soja polyagglutination occurring in a 60 year-old African-American man with disseminated methicillin-resistant Staphylococcus aureus (MRSA) infection. Prior to transfusion, the patient developed severe anemia of unknown etiology. Following transfusion of 3 units of fresh frozen plasma (FFP), his RBC count could not be determined for 24 days because of RBC agglutination in his blood sample. In addition, the FFP transfusion correlated with the rapid development of severe, transfusionrefractory thrombocytopenia and anemia. The perplexed clinical team consulted the blood bank. A direct antiglobulin test demonstrated 1+ mixed-field reactivity with both monoclonal anti-IgG and anti-C3d. Lectin panel testing showed reactivity with only Glycine soja, confirming the condition. Subsequently, plasma components were avoided, and RBC and platelet (PLT) components were washed prior to transfusion. After a 44-day hospitalization involving the transfusion of 22 units of RBCs and 13 units of PLTs, the patient was discharged to a long-term care facility. The patient's confounding hematologic complications can best be explained by polyagglutination, which developed secondary to the severe MRSA infection. The FFP transfusion likely passively transferred antibodies that bound to the patient's RBC cryptantigens, leading to RBC agglutination and anemia. The development of severe thrombocytopenia may be related to cryptantigen exposure on the patient's PLTs. Although difficult to identify, polyagglutination needs to be recognized to appropriately manage hemotherapy. The purpose of this case study is to report hematologic complications following FFP transfusion in a patient with Glycine soja polyagglutination, a rarely described condition. PMID- 28657763 TI - The Vel blood group system: a review. AB - CONCLUSIONS: The blood group antigen Vel has been one of immunohematology's greatest enigmas: the variation in antigen strength from one individual to another, the property of anti-Vel to readily hemolyze Vel+ red blood cells (RBCs), and the difficulty to screen for sufficient numbers of Vel- blood donors had made Vel a tough nut to crack. In 2013, a small, previously unknown protein called small integral membrane protein 1 (SMIM1) was identified on the RBC by three independent research groups using different approaches, and all three groups demonstrated that Vel- RBCs lacked SMIM1. This discovery correlated with homozygosity for deletion c.64_60del in SMIM1 and meant that for the first time there was a universal method to screen for Vel- blood donors. This finding was not the whole answer, however, and an explanation behind the variability in antigen strength was later shown to be due to polymorphism in SMIM1 intron 2, a region that is responsible for gene transcription. Clinically, anti-Vel is important and has caused severe transfusion reactions, although hemolytic disease of the fetus and newborn caused by anti-Vel is uncommon. However, while screening for Vel- blood donors has become easier, the function of SMIM1 is still unknown, and despite its well-conserved sequence across the animal kingdom, the enigma continues. PMID- 28657764 TI - Two cases of the variant RHD*DAU5 allele associated with maternal alloanti-D. AB - CONCLUSIONS: Rh is a complex blood group system with diverse genotypes that may encode weak and partial D variants. Standard serologic analysis may identify clinically significant D variants as D+; nevertheless, individuals with these D variants should be managed as D- patients to prevent antibody formation to absent D epitopes. Variant identification is necessary during pregnancy to allow for timely and appropriate Rh immune globulin (RhIG) prophylaxis for hemolytic disease of the fetus and newborn (HDFN) as D alloimmunization can occur with some D variants. Here, we describe two cases of the RHD*DAU5 allele associated with maternal alloanti-D in patients of African ancestry. Two obstetric patients were initially serologically classified as D+ with negative antibody detection tests on routine prenatal testing. Repeat testing at delivery identified anti-D in both patients with no history of RhIG administration or transfusion. DNA sequencing revealed that both patients possessed the RHD*DAU5 allele. Cord blood testing on both infants revealed positive direct antiglobulin test (DAT) results with anti-D eluted from the red blood cells (RBCs) of one of the infants. Despite the positive DAT, neither infant experienced anemia or hyperbilirubinemia. We document two cases of pregnant women whose RBCs expressed a partial D variant and were classified as D+ on the basis of standard serologic testing, resulting in subsequent failure to provide RhIG prophylaxis. Both cases were associated with alloanti-D formation but without significant HDFN. To our knowledge, these are the first reported cases of maternal alloanti-D associated with the RHD*DAU5 partial D variant. PMID- 28657765 TI - The FORS awakens: review of a blood group system reborn. AB - CONCLUSIONS: The presence of the FORS1 antigen on red blood cells was discovered relatively recently, and in 2012, the International Society of Blood Transfusion (ISBT) acknowledged FORS as blood group system number 031. This rare antigen is carried by a glycosphingolipid and formed by elongation of the P antigen. Most people have naturally occurring anti-FORS1 in their plasma. The clinical significance of these antibodies is unknown in the transfusion setting, but they can hemolyze FORS1+ erythrocytes in the presence of complement in vitro. First believed to be part of the ABO system, it was later shown that the gene encoding the glycosyltransferase giving rise to FORS1 expression is GBGT1. This gene had previously been deemed nonfunctional in humans, but a mutation, so far only detected in FORS1+ individuals, restores the enzymatic activity. Tissue distribution of the antigen in FORS1+ individuals has not been studied in detail, although the gene is expressed in several cell types. The antigen itself is known to be a receptor for various pathogens and toxins and has been detected in different forms of cancer, but the implications thereof are not fully understood. PMID- 28657766 TI - A suspected delayed hemolytic transfusion reaction mediated by anti-Joa. AB - CONCLUSIONS: A 32-year-old African-American woman with a history of sickle cell disease presented for surgical evaluation of left total hip arthroplasty due to avascular necrosis of the femoral head. In anticipation of a complex orthopedic procedure, pre-surgical blood work was ordered. The patient's Fenwal blood sample typed as group O, D+. Although the patient had a history of anti-Fya, the antibody identification was inconclusive, so the workup was sent to a reference laboratory. The patient was last transfused with red blood cells (RBCs) 2 years earlier, but had no history of transfusion reactions. Due to surgery, the patient's hemoglobin (Hb) decreased from 10.2 g/dL (preoperative) to 8.6 g/dL (postoperative). One unit of weakly crossmatch-incompatible Fy(a-), C-, E-, K-, and sickle cell hemoglobin S (HbS)-negative RBCs was transfused without incident, and the patient was discharged. Several days later, the reference lab reported two new specificities, anti-Joa and anti-Jkb. Fortunately, the transfused RBC unit was Jk(b-). Therefore, the crossmatch incompatibility was attributed to anti Joa, which targets a high-prevalence antigen found in 100 percent of most populations. Two weeks after discharge, the patient returned in sickle vaso occlusive pain crisis. The patient was clinically stable, but her Hb was 6.7 g/dL. One unit of Fy(a-), Jk(b-), C-, E-, K-, HbS- RBCs, which was weakly crossmatch-incompatible, was transfused. The following day, her Hb was unchanged, lactic acid dehydrogenase increased from 951 to 2464 U/L, potassium increased from 3.7 to 4.6 mEq/L, creatinine increased from 0.60 to 0.98 mg/dL, and the patient developed a 38.4 degrees C fever. These findings are consistent with a delayed hemolytic transfusion reaction (DHTR), mediated by anti-Joa, occurring 2 weeks after the first RBC transfusion. Further care could not be provided because the patient left the hospital against medical advice. The purpose of this case study is to report findings consistent with a DHTR attributed to anti-Joa, an antibody with relatively unknown clinical significance. PMID- 28657768 TI - Bloody Brilliant: A History of Blood Groups and Blood Groupers. AB - CONCLUSIONS: What a joy and privilege to read and reread this unique and extraordinarily informative history for this review! Pierce and Reid have authored a 633-page, 28-chapter tome, containing 796 illustrations, including photographs of individual contributors to the field of blood group serology, as well as group photographs of landmark meetings and conferences held during the past 100 years. The Index lists the names of 1046 individuals who are acknowledged as contributors to the history of blood group serology, many of whom are the subject of cameo biographies. PMID- 28657767 TI - Recognizing and resolving ABO discrepancies. AB - CONCLUSIONS: Patient samples are routinely typed for ABO prior to transfusion. Determining the ABO group requires both red blood cell (RBC) antigen typing for A and B (forward type) and testing for anti-A and anti-B in the plasma (reverse type). An ABO discrepancy exists when the result of an ABO RBC typing, or forward type, does not agree with the result of the plasma typing, or reverse type. This brief review examines several causes of ABO discrepancies encountered in the clinical transfusion service. Options for resolving these discrepancies are presented, including a discussion of which discrepancies should be resolved using molecular testing. Finally, case studies illustrate transfusion options in patients with ABO discrepancies. Discrepancies can also be encountered when ABO typing is performed on samples from blood or tissue donors, although those discrepancies will not be discussed in this review. PMID- 28657770 TI - Oversampling in Health Surveys: Why, When, and How? PMID- 28657769 TI - Monurelle Biogel(r) vaginal gel in the treatment of vaginal dryness in postmenopausal women. AB - OBJECTIVES: To evaluate efficacy, tolerability and safety of Monurelle Biogel(r) vaginal gel for treatment of vaginal dryness. METHODS: Multicenter, national, randomized, controlled vs. no-treatment, open-label study. Ninety-five postmenopausal women were randomized (48 to Monurelle Biogel(r) and 47 to no treatment). Primary endpoint was the change of Verbal Rating Scale (VRS) total score of vaginal atrophy (VA) symptoms after 8-week treatment. The main secondary endpoints were VRS single-item score, Vaginal Health Index (VHI) score, Maturation Index (MI), Female Sexual Function Index (FSFI), and Female Sexual Distress Scale-Revised (FSDS-R). RESULTS: The VRS total score was statistically significant in favor of the treatment group on day 28 (p = 0.001) but not on day 56 (p = 0.064). By excluding women who were not sexually active, the total VRS scores reached the criteria for clinical success in 27/43 subjects (62.8%) in the control arm and in 38/46 subjects (82.6%) in the treatment arm (p = 0.035) on day 56. The VHI score significantly changed in the active arm (4.71 +/- 4.85 vs. 0.28 +/- 1.71) (p < 0.001) on day 56. Even the MI significantly improved, with an increase in the percentage of superficial cells (p = 0.01). The improvements in both VHI and MI were still present at the follow-up visit after the discontinuation of the treatment (day 84). Sexual function and distress showed a statistical significant difference on day 56. CONCLUSIONS: Monurelle Biogel(r) vaginal gel applied twice daily for 8 weeks is effective in relieving vaginal dryness and other VA symptoms. Such a clinical meaningful effect persists at least 4 weeks and is supported by an improvement in the vaginal environment. Trial Registration clinicaltrials.gov Identifier: NCT02994342. PMID- 28657771 TI - Dermatopathology and Social Media: A Survey of 131 Medical Professionals From 29 Countries. AB - CONTEXT: - Use of social media in the medical profession is an increasingly prevalent and sometimes controversial practice. Many doctors believe social media is the future and embrace it as an educational and collaborative tool. Others maintain reservations concerning issues such as patient confidentiality, and legal and ethical risks. OBJECTIVE: - To explore the utility of social media as an educational and collaborative tool in dermatopathology. DESIGN: - We constructed 2 identical surveys containing questions pertaining to the responders' demographics and opinions regarding the use of social media for dermatopathology. The surveys were available on Twitter and Facebook for a period of 10 days. RESULTS: - The survey was completed by 131 medical professionals from 29 different countries: the majority (81%, 106 of 131) were 25 to 45 years of age. Most replied that they access Facebook or Twitter several times a day (68%, 89 of 131) for both professional and social purposes (77%, 101 of 131). The majority agreed that social media provides useful and relevant information, but stated limitations they would like addressed. CONCLUSIONS: - Social media is a powerful tool with the ability to instantaneously share dermatopathology with medical professionals across the world. This study reveals the opinions and characteristics of the population of medical professionals currently using social media for education and collaboration in dermatopathology. PMID- 28657772 TI - Comparison of Clinical Diagnoses and Autopsy Findings: Six-Year Retrospective Study. AB - CONTEXT: - The frequency of autopsies has declined in most developed countries beginning in the latter half of the 20th century. During this time period the technology of medicine made significant advances; however, it is important to regularly reevaluate the role of the autopsy to confirm suspected diagnoses and identify unsuspected findings. OBJECTIVE: - To determine what portion of autopsies reveal clinically meaningful unexpected findings. DESIGN: - Reports that included clinical histories of autopsies performed at Jackson Memorial Hospital during the 6 years between 2009 and 2014 were reviewed by 2 pathologists. Each case was classified using the Goldman Classification. RESULTS: - In the given time period, 923 autopsies were performed; 512 patients (55.5%) were adults. A total of 334 cases were subject to review after excluding those with a short (<1 day) hospital stay, restriction to a single organ or body cavity, and cases referred from other facilities. A total of 33 of 334 cases (9.9%) were identified as class I discrepancy, where the autopsy revealed a discrepant diagnosis with a potential impact on survival or treatment. Critical findings, such as untreated infection (15 of 33 cases; 45.5%), pulmonary embolism (8 of 33 cases; 24.2%), and undiagnosed malignancy (6 of 33 cases; 18.2%), were found in these cases. Major significant findings that had not been clinically detected, whether clinically manageable or not (class I and II), were found in 65 of 334 cases (19.5%). CONCLUSION: - Despite intensive modern clinical investigations, autopsies continue to reveal major antemortem diagnostic errors in a significant number of cases. PMID- 28657775 TI - Why I Am Opposed to the Elimination of the Sexual Orientation Question by the Administration for Community Living. PMID- 28657773 TI - Patterns of referral in high school concussion management programs: A pilot study of consultants from different disciplines. AB - School-based concussion management programs cover thousands of young athletes, yet there is little in the way of research to assess program processes or outcomes. This study examined the referral patterns of consultants working with ten high school concussion management programs. In addition to the number of referrals made to specialists, other potential outcome variables were explored. The sample included over 5,000 athlete-seasons and 298 concussions managed directly by certified athletic trainers. All programs used computerized neuropsychological testing (both baseline and post injury). Two groups were compared: five programs used a clinical neuropsychologist (NP) as the testing consultant and five used nonneuropsychologists (non-NP) with advanced clinical degrees as the testing consultant. There was no significant difference in concussion incidence rates between groups. Referrals to outside specialists were significantly higher for the non-NP group: X2(1) = 16.474, p < .0001. Further, concussions in the non-NP group took longer to recover overall (Mann-Whitney U, p = .013) and had significantly more cases taking longer than 2 weeks to complete their testing protocol: X2(1) = 9.672, p = .003. The findings of this pilot study support the idea that neuropsychologists are best suited for the role of testing consultant to high school concussion management programs. PMID- 28657776 TI - Correlates of Mono- and Dual-Victims of Cybergrooming and Cyberbullying: Evidence from Four Countries. AB - Today's adolescents grow up using information and communication technologies as an integral part of their everyday life. This affords them with extensive opportunities, but also exposes them to online risks, such as cybergrooming and cyberbullying victimization. The aims of this study were to investigate correlates of cybergrooming and cyberbullying victimization and examine whether victims of both cybergrooming and cyberbullying (dual-cybervictims) show higher involvement in compulsive Internet use (CIU) and troubled offline behavior (TOB) compared to victims of either cybergrooming or cyberbullying (mono-cybervictims). The sample consisted of 2,042 Dutch, German, Thai, and U.S. adolescents (age = 11 17 years; M = 14.2; SD = 1.4). About every ninth adolescent (10.9 percent) reported either mono- or dual-cybervictimization. Second, both CIU and TOB were associated with all three types of cybervictimization, and finally, both CIU and TOB were more strongly linked to dual-cybervictimization than to both forms of mono-cybervictimization. These findings contribute to a better understanding of the associations between different forms of cybervictimization and psychological health and behavior problems among adolescents. PMID- 28657774 TI - Integrative Structural Brain Network Analysis in Diffusion Tensor Imaging. AB - In diffusion tensor imaging, structural connectivity between brain regions is often measured by the number of white matter fiber tracts connecting them. Other features such as the length of tracts or fractional anisotropy (FA) are also used in measuring the strength of connectivity. In this study, we investigated the effects of incorporating the number of tracts, the tract length, and FA values into the connectivity model. Using various node-degree-based graph theory features, the three connectivity models are compared. The methods are applied in characterizing structural networks between normal controls and maltreated children, who experienced maltreatment while living in postinstitutional settings before being adopted by families in the United States. PMID- 28657779 TI - Challenges and Solutions to Collecting Sexual Orientation and Gender Identity Data. PMID- 28657777 TI - Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality. AB - Epithelial injury has been proposed to be the initiating factor in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have shown previously that heparan sulfate 6-O-endosulfatase (Sulf) 2 is overexpressed in the hyperplastic type II alveolar epithelial cells (AECs) in the IPF lungs. By removing 6-O-sulfates from specific heparan sulfate intrachain sites, Sulf2 modulates the functions of many growth factors and cytokines. In this study, we hypothesized that Sulf2 plays a regulatory role in alveolar epithelial injury and repair, using the murine bleomycin model. Consistent with our findings in human IPF lungs, bleomycin treatment in mice resulted in up-regulation of Sulf2 mRNA in whole-lung extracts and overexpression of Sulf2 protein in type II AECs on lung tissue sections. Sulf2 protein was detectable in bronchoalveolar lavage fluid at baseline, and its level was significantly increased after bleomycin exposure. To study the role of Sulf2 in alveolar injury and repair in vivo, we generated a doxycycline-inducible epithelial-specific Sulf2 conditional knockout (Sulf2 CKO) mouse line. After bleomycin exposure, Sulf2 CKO mice exhibited enhanced neutrophil infiltration in the lung, with elevated levels of total protein, lactate dehydrogenase, and cytokines (granulocyte colony-stimulating factor and interferon-gamma-inducible protein 10) in bronchoalveolar lavage fluid compared with wild-type littermates. We further showed that both the p53-p21 DNA damage response and the transforming growth factor-beta1 signaling pathway were up regulated in Sulf2 CKO mice compared with wild-type. Finally, Sulf2 CKO mice suffered increased mortality after bleomycin exposure. In conclusion, Sulf2 expression in type II AECs plays a protective role in epithelial injury, inflammation and mortality. PMID- 28657778 TI - Successful Return to Sport After Arthroscopic Shoulder Stabilization Versus Nonoperative Management in Contact Athletes With Anterior Shoulder Instability: A Prospective Multicenter Study. AB - BACKGROUND: The debate continues regarding the optimal treatment of intercollegiate contact athletes with in-season anterior shoulder instability. PURPOSE: To examine return to sport and recurrent instability in the season after the index in-season anterior instability event. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Forty-five contact intercollegiate athletes treated nonoperatively or with arthroscopic stabilization were prospectively followed in a multicenter observational study to evaluate return to play (RTP) and recurrent instability in the season after an initial in-season anterior glenohumeral instability event. Baseline data collection included sport played, previous instability events, direction of instability, type of instability (subluxation or dislocation), and treatment method (nonoperative management or arthroscopic stabilization). All nonoperatively treated athletes underwent a standardized accelerated rehabilitation program without shoulder immobilization. Surgical stabilization was performed arthroscopically in all cases, and successful RTP was evaluated during the next competitive season after complete rehabilitation. RESULTS: Thirty-nine of 45 intercollegiate contact athletes had remaining National Collegiate Athletic Association eligibility and were followed through the subsequent competitive season after the index instability event. Of the 10 athletes electing nonoperative treatment, 4 (40%) successfully returned to play without recurrence during the subsequent season. Of the 29 athletes treated surgically, 26 (90%) were able to successfully return to play without recurrence the following season (recurrence: n = 1; inadequate function: n = 2). Athletes who underwent surgical reconstruction before the next season were 5.8 times (95% CI, 1.77-18.97; P = .004) more likely to complete the subsequent season without recurrent instability. Of the 29 athletes electing surgical stabilization, there was no difference (risk ratio, 0.95; 95% CI, 0.10-9.24; P > .99) in RTP between the 9 stabilized after a single instability event (90% RTP rate) and the 20 stabilized after multiple in-season recurrent instability events (89% RTP rate). CONCLUSION: Collegiate contact and collision athletes with in-season anterior shoulder instability are significantly more likely to successfully return to sport without subsequent instability events the next season if they undergo surgical repair in the off-season. PMID- 28657780 TI - LGBT Data Collection Amid Social and Demographic Shifts of the US LGBT Community. PMID- 28657781 TI - AJPH Dossier on the Erasure of the Sexual Orientation Question From the National Survey of Older Americans Act Participants. PMID- 28657782 TI - Recording Sexual Orientation in the UK: Pooling Data for Statistical Power. PMID- 28657783 TI - Big Five Personality Traits of Cybercrime Victims. AB - The prevalence of cybercrime has increased rapidly over the last decades and has become part of the everyday life of citizens. It is, therefore, of great importance to gain more knowledge on the factors related to an increased or decreased likelihood of becoming a cybercrime victim. The current study adds to the existing body of knowledge using a large representative sample of Dutch individuals (N = 3,648) to study the relationship between cybercrime victimization and the key traits from the Big Five model of personality (i.e., extraversion, agreeableness, conscientiousness, emotional stability, and openness to experience). First, multinomial logistic regression analyses were used to examine the associations between the personality traits and three victim groups, that is, cybercrime victims versus nonvictims, traditional crime victims versus nonvictims, and cybercrime victims versus traditional crime victims. Next, logistic regression analyses were performed to predict victimization of cyber dependent crimes (i.e., hacking and virus infection) and cyber-enabled crimes (i.e., online intimidation, online consumer fraud, and theft from bank account). The analyses show that personality traits are not specifically associated with cybercrime victimization, but rather with victimization in general. Only those with higher scores on emotional stability were less likely to become a victim of cybercrime than traditional crime. Furthermore, the results indicate that there are little differences between personality traits related to victimization of cyber-enabled and cyber-dependent crimes. Only individuals with higher scores on openness to experience have higher odds of becoming a victim of cyber-enabled crimes. PMID- 28657784 TI - Effect of Emphysema Extent on Serial Lung Function in Patients with Idiopathic Pulmonary Fibrosis. AB - RATIONALE: Patients with idiopathic pulmonary fibrosis and emphysema may have artificially preserved lung volumes. OBJECTIVES: In this post hoc analysis, we investigated the relationship between baseline emphysema and fibrosis extents, as well as pulmonary function changes, over 48 weeks. METHODS: Data were pooled from two phase III, randomized, double-blind, placebo-controlled trials of IFN-gamma 1b in idiopathic pulmonary fibrosis (GIPF-001 [NCT00047645] and GIPF-007 [NCT00075998]). Patients with Week 48 data, baseline high-resolution computed tomographic images, and FEV1/FVC ratios less than 0.8 or greater than 0.9 (<0.7 or >0.9 in GIPF-007), as well as randomly selected patients with ratios of 0.8 0.9 and 0.7-0.8, were included. Changes from baseline in pulmonary function at Week 48 were analyzed by emphysema extent. The relationship between emphysema and fibrosis extents and change in pulmonary function was assessed using multivariate linear regression. MEASUREMENTS AND MAIN RESULTS: Emphysema was identified in 38% of patients. A negative correlation was observed between fibrosis and emphysema extents (r = -0.232; P < 0.001). In quartile analysis, patients with the greatest emphysema extent (28 to 65%) showed the smallest FVC decline, with a difference of 3.32% at Week 48 versus patients with no emphysema (P = 0.047). In multivariate analyses, emphysema extent greater than or equal to 15% was associated with significantly reduced FVC decline over 48 weeks versus no emphysema or emphysema less than 15%. No such association was observed for diffusing capacity of the lung for carbon monoxide or composite physiologic index. CONCLUSIONS: FVC measurements may not be appropriate for monitoring disease progression in patients with idiopathic pulmonary fibrosis and emphysema extent greater than or equal to 15%. PMID- 28657785 TI - Cyber-Dependent Crime Victimization: The Same Risk for Everyone? AB - The Internet has simplified daily life activities. However, besides its comfortability, the Internet also presents the risk of victimization by several kinds of crimes. The present article addresses the question of which factors influence cyber-dependent crime and how they vary between three kinds of cyber dependent offences: malware infection, ransomware infection, and misuse of personal data. According to the Routine Activity Approach, it is assumed that crime is determined by a motivated offender, the behavior of the Internet user, and the existence of prevention factors. Our analyses were based on a random sample of 26,665 Internet users in two federal states in Germany, aged 16 years and older; 16.6 percent of the respondents had experienced at least one form of cyber-dependent victimization during the year 2014. The results indicate that individual and household factors, as well as online and prevention behavior, influence the risk of cyber-dependent victimization. Furthermore, the effects differ between the three types of offences. In conclusion, the risk of being victimized by cyber-dependent crime is not the same for anyone, but depends on multivariate factors according to the idea of Routine Activity Approach. However, in view of the fact that crime-related factors also matter, studying different cybercrime offences separately seems to be an appropriate research approach. PMID- 28657786 TI - Data Move Us Closer to Full Equality by Speaking for Those Who Cannot: Advocating for LGBT Older Adults. PMID- 28657787 TI - Erasing LGBT People From Federal Data Collection: A Need for Vigilance. PMID- 28657790 TI - Magnitude and Spatial Distribution of Impact Intensity Under the Foot Relates to Initial Foot Contact Pattern. AB - In running, foot contact patterns (rear-, mid-, or forefoot contact) influence impact intensity and initial ankle and foot kinematics. The aim of the study was to compare impact intensity and its spatial distribution under the foot between different foot contact patterns. Forty-nine subjects ran at 3.2 m.s-1 over a level runway while ground reaction forces (GRF) and shoe-surface pressures were recorded and foot contact pattern was determined. A 4-zone footmask (forefoot, midfoot, medial and lateral rearfoot) assessed the spatial distribution of the vertical GRF under the foot. We calculated peak vertical instantaneous loading rate of the GRF (VILR) per foot zone as the impact intensity measure. Midfoot contact patterns were shown to have the lowest, and atypical rearfoot contact patterns the highest impact intensities, respectively. The greatest local impact intensity was mainly situated under the rear- and midfoot for the typical rearfoot contact patterns, under the midfoot for the atypical rearfoot contact patterns, and under the mid- and forefoot for the midfoot contact patterns. These findings indicate that different foot contact patterns could benefit from cushioning in different shoe zones. PMID- 28657791 TI - Selective Changes in the Mechanical Capacities of Lower-Body Muscles After Cycle Ergometer Sprint Training Against Heavy and Light Resistances. AB - PURPOSE: To explore the feasibility of the linear force-velocity (F-V) modeling approach to detect selective changes of F-V parameters (ie, maximum force [F0], maximum velocity [V0], F-V slope [a], and maximum power [P0]) after a sprint training program. METHODS: Twenty-seven men were randomly assigned to a heavy load group (HLG), light-load group (LLG), or control group (CG). The training sessions (6 wk * 2 sessions/wk) comprised performing 8 maximal-effort sprints against either heavy (HLG) or light (LLG) resistances in leg cycle-ergometer exercise. Pre- and posttest consisted of the same task performed against 4 different resistances that enabled the determination of the F-V parameters through the application of the multiple-point method (4 resistances used for the F-V modeling) and the recently proposed 2-point method (only the 2 most distinctive resistances used). RESULTS: Both the multiple-point and the 2-point methods revealed high reliability (all coefficients of variation <5% and intraclass correlation coefficients >.80) while also being able to detect the group-specific training-related changes. Large increments of F0, a, and P0 were observed in HLG compared with LLG and CG (effect size [ES] = 1.29-2.02). Moderate increments of V0 were observed in LLG compared with HLG and CG (ES = 0.87-1.15). CONCLUSIONS: Short-term sprint training on a leg cycle ergometer induces specific changes in F-V parameters that can be accurately monitored by applying just 2 distinctive resistances during routine testing. PMID- 28657792 TI - Do You Love Me? Psychological Characteristics of Romance Scam Victims. AB - The online dating romance scam is an Advance Fee Fraud, typically conducted by international criminal groups via online dating sites and social networking sites. This type of mass-marketing fraud (MMF) is the most frequently reported type of MMF in most Western countries. This study examined the psychological characteristics of romance scam victims by comparing romance scam victims with those who had never been scammed by MMFs. Romance scam victims tend to be middle aged, well-educated women. Moreover, they tend to be more impulsive (scoring high on urgency and sensation seeking), less kind, more trustworthy, and have an addictive disposition. It is argued here that these findings might be useful for those developing prevention programs and awareness campaigns. PMID- 28657794 TI - Corrigendum. PMID- 28657793 TI - Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin. AB - RATIONALE: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. OBJECTIVES: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses. METHODS: The migratory accuracy of blood neutrophils from young (aged <35 yr) and old (aged >60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. MEASUREMENTS AND MAIN RESULTS: In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly. CONCLUSIONS: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011 002082-38). PMID- 28657795 TI - p38 MAPK Inhibition Improves Heart Function in Pressure-Loaded Right Ventricular Hypertrophy. AB - Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-beta-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-beta-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-beta-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms. PMID- 28657796 TI - A Systematic Review of the Literature Addressing Veterinary Care for Underserved Communities. AB - Currently, there is a care gap in veterinary medicine affecting low-income and underserved communities, resulting in decreased nonhuman-animal health and welfare. The use of low-price and community veterinary clinics in underserved populations is a strategy to improve companion-animal health through preventative care, spay/neuter, and other low-price care programs and services. Little research has documented the structure and effectiveness of such initiatives. This systematic review aimed to assess current published research pertaining to accessible health care, community-based veterinary medicine, and the use of community medicine in teaching programs. The review was an in-depth literature search identifying 51 publications relevant to the importance, benefits, drawbacks, and use of low-price and community clinics in underserved communities. These articles identified commonly discussed barriers to care that may prevent underserved clientele from seeking veterinary care. Five barriers were identified including the cost of veterinary care, accessibility of care, problems with or lack of veterinarian-client communication, culture/language, and lack of client education. The review also identified a need for additional research regarding evidence of effectiveness and efficiency in community medicine initiatives. PMID- 28657797 TI - Role of Emergency Medical Dispatch in Responding to Acute Stroke: Expanding Beyond High Priority Dispatch? PMID- 28657798 TI - Up-Dating: Ratings of Perceived Dating Success Are Better Online than Offline. AB - The primary aims of this study were to test whether perceived dating success would differ between offline and online zero-acquaintance dating contexts and to investigate the role that self-esteem might play in these evaluations. Participants were presented with the same photos of targets in either an offline or online dating scenario and rated their chances of dating success along with their perceptions of how attractive they thought the target would consider them. Higher self-esteem individuals believed they would be rated as more attractive. There was an overall perception that, irrespective of self-esteem level, meeting online would lead to better chances of dating success. These findings are considered in relation to an increased ability to more precisely manage impressions and develop an image of the self which would be evaluated more positively online. PMID- 28657799 TI - Is There an Optimal Ischemic-Preconditioning Dose to Improve Cycling Performance? AB - INTRODUCTION: Ischemic preconditioning (IPC) may enhance endurance performance. No previous study has directly compared distinct IPC protocols for optimal benefit. PURPOSE: To determine whether a specific IPC protocol (ie, number of cycles, amount of muscle tissue, and local vs remote occlusion) elicits greater performance outcomes. METHODS: Twelve cyclists performed 5 different IPC protocols 30 min before a blinded 375-kJ cycling time trial (TT) in a laboratory. Responses to traditional IPC (4 * 5-min legs) were compared with those to 8 * 5 min legs and sham (dose cycles), 4 * 5-min unilateral legs (dose tissue), and 4 * 5-min arms (remote). Rating of perceived exertion and blood lactate were recorded at each 25% TT completion. Power (W), heart rate (beats/min), and oxygen uptake ([Formula: see text]) (mL . kg-1 . min-1) were measured continuously throughout TTs. Magnitude-based-inference statistics were employed to compare variable differences to the minimal practically important difference. RESULTS: Traditional IPC was associated with a 17-s (0, 34) faster TT time than sham. Applying more dose cycles (8 * 5 min) had no impact on performance. Traditional IPC was associated with likely trivial higher blood lactate and possibly beneficial lower [Formula: see text] responses vs sham. Unilateral IPC was associated with 18-s ( 11, 48) slower performance than bilateral (dose tissue). TT times after remote and local IPC were not different (0 [-16, 16] s). CONCLUSION: The traditional 4 * 5-min (local or remote) IPC stimulus resulted in the fastest TT time compared with sham; there was no benefit of applying a greater number of cycles or employing unilateral IPC. PMID- 28657800 TI - Effects of Emergency Medical Services Agency Ownership Status on Patient Transport. AB - OBJECTIVES: Medical insurers have clearly defined which ambulance services will be reimbursed and which will not. Thus, ambulance agencies that provide emergency 9-1-1 services must be highly cognizant of their organization's revenue needs. This presents a distinction between publicly funded and privately funded organizations. This study seeks to identify any differences in the transport decision among agency ownership types. METHODS: This retrospective study captured all 9-1-1 ambulance requests in the state of Virginia for the years 2009 through 2013. Each request was answered by either a publicly funded ambulance service or a privately funded ambulance service. The outcome variable of interest was patient disposition and the key explanatory variable was organizational ownership type. Multivariate logistic regression was utilized for data analysis. RESULTS: Of the 4.6 million 9-1-1 requests, approximately 30% were attended to by a private ambulance service. After controlling for potential confounders, ownership type was found to have a statistically significant effect on the transport decision. Private for-profit ambulance services were 4.5 times more likely to transport a patient than were their publicly funded counterparts (OR: 4.56, 95% CI: 4.47-4.65). Private non-profit organizations were twice as likely to engage in patient transport (OR: 2.12, 95% CI: 2.09-2.14). Private for-profit ambulance organizations were also found to be less likely to allow for patient refusal (OR: 0.54, 95% CI: 0.53-0.55) or to medically treat on-scene without subsequent transport (OR: 0.48, 95% CI: 0.45-0.50). CONCLUSIONS: Given the reimbursement practices of medical insurers, private ambulance services are incentivized towards patient transport. Operational revenue for these services is not generated through public budgeting processes but through user fees. Thus, private agencies are more reliant on billable services than are their publicly funded counterparts. PMID- 28657801 TI - Beneficial Effects of Adjuvant Melatonin in Minimizing Oral Mucositis Complications in Head and Neck Cancer Patients Receiving Concurrent Chemoradiation. AB - OBJECTIVES: Oral mucositis is a major cause of pain and delayed cancer treatment leading to poor survival in head and neck cancer patients receiving concurrent chemoradiation. The study evaluated the effect of adjuvant melatonin on minimizing oral mucositis complications to reduce these treatment delays and interruptions. DESIGN: A randomized, double-blind, double dummy, placebo controlled clinical trial. SETTING: Ubon Ratchathani Cancer Hospital, Thailand. PARTICIPANTS: Thirty-nine head and neck cancer patients receiving concurrent chemoradiation (5 days/week of radiation plus chemotherapy three or six cycles). METHODS: Patients were randomized to receive 20 mg melatonin gargle (or matched placebo) before each irradiation, and 20 mg melatonin capsules (or matched placebo) taken nightly during 7 weeks of concurrent chemoradiation. Endpoints were oral mucositis events (incidence and time to grade 3 mucositis or grade 2 xerostomia), pain medication consumption and quality of life (QOL). RESULTS: Melatonin group reported lower incidence of grade 3 oral mucositis (42% vs. 55%) and grade 2 xerostomia (20% vs. 21%); no statistical significance was detected. Melatonin regimen delayed onset of grade 3 mucositis (median 34 days vs. 50 days; p = 0.0318), allowing median time of 16 more patient visits before its onset and fewer interrupted treatments due to oral mucositis were reported (n = 1 vs. n = 5). There was no difference of grade 2 xerostomia (median 32 days vs. 50 days; p = 0.624). Morphine consumption was also reduced (median 57 mg vs. 0 mg; p = 0.0342), while QOL was comparable during the study period. CONCLUSION: Adjuvant melatonin delayed the onset of oral mucositis, which enables uninterrupted cancer treatment and reduced the amount of morphine used for pain treatment. PMID- 28657802 TI - Exiting the Emergency Medical Services Profession and Characteristics Associated with Intent to Return to Practice. AB - OBJECTIVE: Inadequate staffing of agencies, increasing attrition rates, and frequent turnover of personnel make employee retention an ongoing concern for Emergency Medical Services (EMS). Faced with increasing demand for EMS, understanding the causes underlying turnover is critical. The objectives of this study were to describe the proportion of individuals that left EMS, likelihood of returning to the profession, and key factors contributing to the decision to leave EMS. METHODS: This was a cross-sectional study of nationally-certified EMS professionals who left EMS. Respondents to a census survey who reported not practicing EMS were directed to a subsection of items regarding their choice to leave EMS. Demographic and employment characteristics, likelihood of returning to EMS, and factors influencing the decision to leave EMS were assessed. Descriptive and comparative statistics (Chi-square and nonparametric test of trend [p-trend]) and univariable odds ratios were calculated. RESULTS: The overall response rate for the full survey was 10% (n = 32,114). A total of 1247 (4%) respondents reported leaving the profession and completed the exit survey. The majority (72%) reported that they will likely return to EMS. A stepwise decrease in the reported likelihood of returning was seen with increasing years of EMS experience (e.g., 2 or less years of experience: 83%; 16 or more years: 52%; p-trend < 0.001) and months away from EMS (e.g., 0-2 months: 89%; more than 12 months: 57%; p-trend < 0.001). The most common factors reported to influence the decision to leave EMS included desire for better pay/benefits (65%), decision to pursue further education (60%), dissatisfaction with organization's management (54.7%), and desire for career change (54.1%). CONCLUSION: This cross-sectional study found an attrition rate of approximately 4% among nationally certified EMS professionals; however, the majority reported that they intended to return to the EMS profession. Intention to return to EMS decreased as years of experience and months away from the profession increased. Important factors in the decision to leave EMS included a desire for better pay and benefits and the decision to pursue further education. Targeting the factors identified as important in this study should be a priority for key stakeholders in improving recruitment and retention of EMS professionals. PMID- 28657803 TI - Effects of Aerobic, Strength or Combined Exercise on Perceived Appetite and Appetite-Related Hormones in Inactive Middle-Aged Men. AB - Aerobic exercise (AE) and strength exercise (SE) are reported to induce discrete and specific appetite-related responses; however, the effect of combining AE and SE (i.e., combined exercise; CE) remains relatively unknown. Twelve inactive overweight men (age: 48 +/- 5 y; BMI: 29.9 +/- 1.9 kg?m2) completed four conditions in a random order: 1) nonexercise control (CON) (50 min seated rest); 2) AE (50 min cycling; 75% VO2peak); 3) SE (10 * 8 leg extensions; 75% 1RM); and 4) CE (50% SE + 50% AE). Perceived appetite, and appetiterelated peptides and metabolites were assessed before and up to 2 h postcondition (0P, 30P, 60P, 90P, 120P). Perceived appetite did not differ between trials (p < .05). Acylated ghrelin was lower at 0P in AE compared with CON (p = .039), while pancreatic polypeptide (PP) was elevated following AE compared with CON and CE. Glucose dependent insulinotropic peptide (GIPtotal) was greater following all exercise conditions compared with CON, as was glucagon, although concentrations were generally highest in AE (p < .05). Glucose was acutely increased with SE and AE (p < .05), while insulin and C-peptide were higher after SE compared with all other conditions (p < .05). In inactive, middle-aged men AE, SE and CE each have their own distinct effects on circulating appetite-related peptides and metabolites. Despite these differential exercise-induced hormone responses, exercise mode appears to have little effect on perceived appetite compared with a resting control in this population. PMID- 28657804 TI - Physiological Profile of an Uphill Time Trial in Elite Cyclists. AB - CONTEXT: While a number of studies have researched road-cycling performance, few have attempted to investigate the physiological response in field conditions. PURPOSE: To describe the physiological and performance profile of an uphill time trial (TT) frequently used in cycling competitions. METHODS: Fourteen elite road cyclists (mean +/- SD age 25 +/- 6 y, height 174 +/- 4.2 cm, body mass 64.4 +/- 6.1 kg, fat mass 7.48% +/- 2.82%) performed a graded exercise test to exhaustion to determine maximal parameters. They then completed a field-based uphill TT in a 9.2-km first-category mountain pass with a 7.1% slope. Oxygen uptake (VO2), power output, heart rate (HR), lactate concentration, and perceived-exertion variables were measured throughout the field-based test. RESULTS: During the uphill TT, mean power output and velocity were 302 +/- 7 W (4.2 +/- 0.1 W/kg) and 18.7 +/- 1.6 km/h, respectively. Mean VO2 and HR were 61.6 +/- 2.0 mL . kg-1 . min-1 and 178 +/- 2 beats/min, respectively. Values were significantly affected by the 1st, 2nd, 6th, and final kilometers (P < .05). Lactate concentration and perceived exertion were 10.87 +/- 1.12 mmol/L and 19.1 +/- 0.1, respectively, at the end of the test, being significantly different from baseline measures. CONCLUSION: The studied uphill TT is performed at 90% of maximum HR and VO2 and 70% of maximum power output. To the authors' knowledge, this is the first study assessing cardiorespiratory parameters combined with measures of performance, perceived exertion, and biochemical variables during a field-based uphill TT in elite cyclists. PMID- 28657805 TI - Daily Distribution of Macronutrient Intakes of Professional Soccer Players From the English Premier League. AB - The daily distribution of macronutrient intake can modulate aspects of training adaptations, performance and recovery. We therefore assessed the daily distribution of macronutrient intake (as assessed using food diaries supported by the remote food photographic method and 24-hr recalls) of professional soccer players (n = 6) of the English Premier League during a 7-day period consisting of two match days and five training days. On match days, average carbohydrate (CHO) content of the prematch (<1.5 g.kg-1 body mass) and postmatch (1 g.kg-1 body mass) meals (in recovery from an evening kick-off) were similar (p > .05) though such intakes were lower than contemporary guidelines considered optimal for prematch CHO intake and postmatch recovery. On training days, we observed a skewed and hierarchical approach (p < .05 for all comparisons) to protein feeding such that dinner (0.8 g.kg-1)>lunch (0.6 g.kg-1)>breakfast (0.3 g.kg-1)>evening snacks (0.1 g.kg-1). We conclude players may benefit from consuming greater amounts of CHO in both the prematch and postmatch meals so as to increase CHO availability and maximize rates of muscle glycogen resynthesis, respectively. Furthermore, attention should also be given to ensuring even daily distribution of protein intake so as to potentially promote components of training adaptation. PMID- 28657806 TI - Profiling Single-Leg Balance by Leg Preference and Position in Rugby Union Athletes. AB - Our aims were to assess single-leg balance in rugby union athletes and compare the stability indices between legs and between positions. Thirty athletes, forwards and backs (n = 15/15), performed single-leg balance measured at two difficulty levels (Level 8: more stable and Level 2: less stable) using the Biodex Balance SD System. The backs' nonpreferred leg had worse scores in medial lateral and overall indices (effect size = 1.05 and 0.63) compared with the preferred leg on Level 8 stability. Backs had better scores in all indices in the preferred (effect size = -1.20 to -1.82) and nonpreferred (effect size = -0.66 to -1.36) legs compared with the forwards at both stability difficulties. Asymmetry between the two legs is also present between forwards and backs when examined on an individual basis. This study illuminates the importance of single-leg balance screening among rugby athletes to detect individuals with asymmetries in balance that may increase the risk of lower-extremity injury. PMID- 28657807 TI - Variability, Predictability, and Race Factors Affecting Performance in Elite Biathlon. AB - PURPOSE: To investigate variability, predictability, and smallest worthwhile performance enhancement in elite biathlon sprint events. In addition, the effects of race factors on performance were assessed. METHODS: Data from 2005 to 2015 including >10,000 and >1000 observations for each sex for all athletes and annual top-10 athletes, respectively, were included. Generalized linear mixed models were constructed based on total race time, skiing time, shooting time, and proportions of targets hit. Within-athlete race-to-race variability was expressed as coefficient of variation of performance times and standard deviation (SD) in proportion units (%) of targets hit. The models were adjusted for random and fixed effects of subject identity, season, event identity, and race factors. RESULTS: The within-athlete variability was independent of sex and performance standard of athletes: 2.5-3.2% for total race time, 1.5-1.8% for skiing time, and 11-15% for shooting times. The SD of the proportion of hits was ~10% in both shootings combined (meaning +/-1 hit in 10 shots). The predictability in total race time was very high to extremely high for all athletes (ICC .78-.84) but trivial for top-10 athletes (ICC .05). Race times during World Championships and Olympics were ~2-3% faster than in World Cups. Moreover, race time increased by ~2% per 1000 m of altitude, by ~5% per 1% of gradient, by 1-2% per 1 m/s of wind speed, and by ~2-4% on soft vs hard tracks. CONCLUSIONS: Researchers and practitioners should focus on strategies that improve biathletes' performance by at least 0.8-0.9%, corresponding to the smallest worthwhile enhancement (0.3 * within-athlete variability). PMID- 28657808 TI - Chronologic Trends in Studies on Fluoride Mechanisms of Action. AB - Fluoride has been widely used for the prevention of dental caries since the mid 20th century. The aim of this study was to investigate the chronologic trends in studies on fluoride mechanisms of action against dental caries during the years 1950 to 2015. To this aim, queries such as "fluoride," "fluoride and demineralization," "fluoride and remineralization," "fluoride and (plaque or biofilms)," and "fluoride and (bacteria or microbials)" were submitted to PubMed to collect research article information, including titles, abstracts, publication dates, author affiliations, and publication journals. The article information that PubMed produced was then collected by an automatic web crawler and examined through informetrics and linguistic analyses. We found that the number of articles concerned with fluoride mechanisms of action against dental caries was 6,903 and gradually increased over time during the years 1950 to 2015. They were published by 1,136 journals-most notably, Caries Research and Journal of Dental Research. Of the articles published, those related to bacteria/microbials had a higher percentage (44%) than those dealing with plaque/biofilms, demineralization, and remineralization. With regard to the geographic distribution of authors, Europe and North America accounted for 65% of the articles during the years 1987 to 2015, although the number of authors in Asia sharply increased in recent years. Among the fluoride compounds, NaF was mentioned more frequently than SnF2, Na2PO3F, amine fluoride, and acidulated phosphate fluoride during the years 1986 to 2015. Water fluoridation received the most attention among the various fluoride application methods (toothpastes, mouthwashes, fluoride varnishes, and fluoride gels) during the same period. These results, obtained from employing informetrics and linguistic analyses, suggest that in studies on fluoride mechanisms of action, 1) the unbalanced geographic distribution of articles and 2) the heavy concentration of articles on particular fluoride compounds and application methods should be overcome in future research. PMID- 28657809 TI - Medical Oversight, Educational Core Content, and Proposed Scopes of Practice of Wilderness EMS Providers: A Joint Project Developed by Wilderness EMS Educators, Medical Directors, and Regulators Using a Delphi Approach. AB - INTRODUCTION: A disparity exists between the skills needed to manage patients in wilderness EMS environments and the scopes of practice that are traditionally approved by state EMS regulators. In response, the National Association of EMS Physicians Wilderness EMS Committee led a project to define the educational core content supporting scopes of practice of wilderness EMS providers and the conditions when wilderness EMS providers should be required to have medical oversight. METHODS: Using a Delphi process, a group of experts in wilderness EMS, representing educators, medical directors, and regulators, developed model educational core content. This core content is a foundation for wilderness EMS provider scopes of practice and builds on both the National EMS Education Standards and the National EMS Scope of Practice Model. These experts also identified the conditions when oversight is needed for wilderness EMS providers. RESULTS: By consensus, this group of experts identified the educational core content for four unique levels of wilderness EMS providers: Wilderness Emergency Medical Responder (WEMR), Wilderness Emergency Medical Technician (WEMT), Wilderness Advanced Emergency Medical Technician (WAEMT), and Wilderness Paramedic (WParamedic). These levels include specialized skills and techniques pertinent to the operational environment. The skills and techniques increase in complexity with more advanced certification levels, and address the unique circumstances of providing care to patients in the wilderness environment. Furthermore, this group identified that providers having a defined duty to act should be functioning with medical oversight. CONCLUSION: This group of experts defined the educational core content supporting the specific scopes of practice that each certification level of wilderness EMS provider should have when providing patient care in the wilderness setting. Wilderness EMS providers are, indeed, providing health care and should thus function within defined scopes of practice and with physician medical director oversight. PMID- 28657810 TI - Improvement of Balance Stability in Older Individuals by On-Water Training. AB - In the present investigation we evaluated the effect of stand-up paddle practice on upright postural control in older individuals. Participants were assigned to a group practicing stand-up paddle on seawater or to a walking control group. Balance stability was evaluated in the tandem Romberg and tiptoes postures, comparing the conditions of eyes open versus closed. Results showed that stand-up paddle practice led to reduced anteroposterior and mediolateral amplitudes of body sway in both visual conditions, while walking led to no effect on balance. These results suggest that the challenge of keeping body balance on an unstable board during on-water stand-up paddle practice is transferred to postural tasks performed on a stable support surface, with generalization to sensory and biomechanical conditions different from those experienced during the training. Our results suggest that on-water balance training could be considered as a potential procedure to improve balance control in older adults. PMID- 28657812 TI - Improvement of Oxygen-Uptake Kinetics and Cycling Performance With Combined Prior Exercise and Fast Start. AB - PURPOSE: To investigate whether oxygen-uptake ([Formula: see text]) kinetics and simulated 4-km cycling performance are synergistically improved by prior "priming" exercise and an all-out starting strategy. METHODS: Nine men completed 4 target work trials (114 +/- 17 kJ) to assess [Formula: see text] kinetics and cycling performance in a repeated-measures, crossover experimental design. Trials were initiated with either a 12-s all-out start or a self-selected start and preceded by prior severe-intensity (70%Delta) priming exercise or no priming exercise. RESULTS: The [Formula: see text] mean response time (MRT) was lower (indicative of faster [Formula: see text] kinetics) in the all-out primed condition (20 +/- 6 s) than in the all-out unprimed (23 +/- 6 s), self-paced unprimed (42 +/- 13 s), and self-paced-primed (42 +/- 11 s) trials (P < .05), with the [Formula: see text] MRT also lower in the all-out unprimed than the self paced unprimed and self-paced primed trials (P < .05). Trial-completion time was shorter (performance was enhanced) in the all-out primed trial (402 +/- 14 s) than in the all-out unprimed (408 +/- 14 s), self-paced unprimed (411 +/- 16 s), and self-paced primed (411 +/- 19 s) trials (P < .05), with no differences between the latter 3 trials. CONCLUSIONS: The findings from this study suggest that combining severe-intensity priming exercise with a short-duration all-out starting strategy can expedite the adjustment of [Formula: see text] and lower completion time during a cycling performance trial to a greater extent than either intervention administered independently. These results might have implications for optimizing performance in short-duration high-intensity competitive events such as a 4-km cycling time trial. PMID- 28657811 TI - Description of the case mix experienced by chiropractic students during a clinical internship. AB - OBJECTIVE: The primary objective of this study was to describe the case mix experienced by chiropractic students during their clinical internship at the Canadian Memorial Chiropractic College. Secondary objectives were to characterize teaching clinic patient populations, assess the similarity to previously published data for practicing chiropractors, and describe the treatment plans being recommended by interns. METHODS: A prospective, observational study was conducted using a convenience sample of 24 chiropractic interns. Data were collected by interns using a standardized form that was completed for each new patient and each new complaint examined during the 1-year internship. Standardized forms included data regarding patient demographics, complaint characteristics, and treatment recommendations. RESULTS: Data were included for 23 of 24 participating interns, who described 828 patients and a total of 948 unique complaint presentations. Overall, 60% of patients were female, 86% were 18 to 64 years old, and 23% were naive to chiropractic care. Of all presenting complaints, 93% were pain-based, 67% were chronic, 65% included spinal complaints, and 7% presented with red flags; individual interns' experiences were variable and are described. On average, treatment recommendations called for 9.4 visits and often included multimodal treatment approaches, most commonly soft tissue therapies (91%), home-based active care (84%), and spine manipulation (70%). CONCLUSIONS: The findings of this study suggest that patients presenting to CMCC teaching clinics are similar to those reported previously to attend private chiropractic clinics. While all participating interns encountered multiple complex clinical cases, very few had experience with pediatric populations. This study adds to the few that detail the characteristics of patients attending chiropractic teaching clinics; to our knowledge it is the first to describe average case loads of chiropractic interns. PMID- 28657813 TI - Social Isolation, Physical Capacity, and Physical Activity in Older Community Dwelling Adults Post-Hospitalization. AB - This paper investigated the potential relationships between physical capacity and physical activity (recreational and household) with social isolation amongst older adults. Data for hospitalized Victorians (n = 311) were analyzed in univariable, multivariable and latent growth curve analyses over six months. Measures included items from the Friendship Scale, Lubben Social Network Scale (LSNS-6), Australian Survey of Disability, Ageing and Carers Household (SDAC), and Phone-FITT. Over six months, improvements in physical capacity were related to reduced social isolation (-0.65, CI = -1.21, -0.09). Increased total (0.02, CI = 0.004, 0.04) and household-based physical activity (0.03, CI = 0.001, 0.06) were related to contact with more relatives. Higher baseline household-based physical activity was related to contact with fewer relatives (-0.01, CI = -0.02, -0.001). Along with physical capacity and activity, household-based physical activity appears to be strongly related to social isolation. Further research is required to determine the direction of relationships, to provide evidence for effective interventions. PMID- 28657815 TI - Adaption to Stroke: A Nonlinear Thinking Approach in Occupational Therapy. AB - This paper explores the role of perturbance and attractor, two key nonlinear features described by the Neuro-occupation model in shaping human behavior. A convenience sample of eleven Iranian participants who had both strokes and demonstrated high resilience were recruited for this study. To explore the process of how participants fell under the influence of the perturbance and attractor, the content analysis with pre-determined categories using deductive reasoning was used. The findings suggest that perturbance and attractor exerted considerable influences on adaptation to stroke and assist in the understanding of the Neuro-occupation model. PMID- 28657814 TI - Impact of Recurrence and Salvage Surgery on Survival After Multidisciplinary Treatment of Rectal Cancer. AB - Purpose After preoperative chemoradiotherapy followed by total mesorectal excision for locally advanced rectal cancer, patients who experience local or systemic relapse of disease may be eligible for curative salvage surgery, but the benefit of this surgery has not been fully investigated. The purpose of this study was to characterize recurrence patterns and investigate the impact of salvage surgery on survival in patients with rectal cancer after receiving multidisciplinary treatment. Patients and Methods Patients with locally advanced (cT3-4 or cN+) rectal cancer who were treated with preoperative chemoradiotherapy followed by total mesorectal excision at our institution during 1993 to 2008 were identified. We examined patterns of recurrence location, time to recurrence, treatment factors, and survival. Results A total of 735 patients were included. Tumors were mostly midrectal to lower rectal cancer, with a median distance from the anal verge of 5.0 cm. The most common recurrence site was the lung followed by the liver. Median time to recurrence was shorter in liver-only recurrence (11.2 months) than in lung-only recurrence (18.2 months) or locoregional-only recurrence (24.7 months; P = .001). Salvage surgery was performed in 57% of patients with single-site recurrence and was associated with longer survival after recurrence in patients with lung-only and liver-only recurrence ( P < .001) but not in those with locoregional-only recurrence ( P = .353). Conclusion We found a predilection for lung recurrence in patients with rectal cancer after multidisciplinary treatment. Salvage surgery was associated with prolonged survival in patients with lung-only and liver-only recurrence, but not in those with locoregional recurrence, which demonstrates a need for careful consideration of the indications for resection. PMID- 28657816 TI - Retrospective Evaluation of Risk Factors for Pediatric Secondary Transport. AB - OBJECTIVE: Emergency medical services (EMS) typically transports patients to the nearest emergency department (ED). After initial presentation, children who require specialized care must undergo secondary transport, exposing them to additional risks and delaying definitive treatment. EMS direct transport protocols exist for major trauma and certain adult medical conditions, however the same cannot be said for pediatric medical conditions or injuries that do not meet trauma center criteria ('minor trauma'). To explore the utility of such future protocols, we sought to first describe the pediatric secondary transport population and examine prehospital risk factors for secondary transport. METHODS: Pediatric secondary transport patients aged 0-18 years were identified. Patients meeting state EMS trauma protocol criteria or who were clinically unstable were excluded. Data were abstracted by chart review of EMS, community hospital ED, and specialty hospital records. Patients were compared to control patients with similar conditions who did not require secondary transport. RESULTS: This study identified 211 medical or minor trauma pediatric secondary transport patients between 2013 and 2014. The three most prevalent conditions were seizure (n = 52), isolated orthopedic injury (n = 49), and asthma/respiratory distress (n = 27). Increased odds of secondary transport for seizure patients were associated with administration of supplemental oxygen, glucose measurement, and online medical direction; for isolated orthopedic injuries, online medical direction; and for asthma/respiratory distress, administration of supplemental oxygen, and online medical direction. Decreased odds of secondary transport for seizure patients were associated with a higher GCS; for isolated orthopedic injuries, increased age and oxygen saturation; and for asthma/respiratory distress, administration of albuterol only. CONCLUSIONS: Children with seizures, isolated orthopedic injuries, and asthma/respiratory distress comprised the majority of the medical or minor trauma pediatric secondary transport population. Each of those conditions had specific risk factors for secondary transport. This study's results provide information to guide future prospective studies and the development of direct transport protocols for those populations. PMID- 28657817 TI - ? PMID- 28657818 TI - Examining Impulse-Variability Theory and the Speed-Accuracy Trade-Off in Children's Overarm Throwing Performance. AB - This study examined variability in throwing speed and spatial error to test the prediction of an inverted-U function (i.e., impulse-variability [IV] theory) and the speed-accuracy trade-off. Forty-five 9- to 11-year-old children were instructed to throw at a specified percentage of maximum speed (45%, 65%, 85%, and 100%) and hit the wall target. Results indicated no statistically significant differences in variable error across the target conditions (p = .72), failing to support the inverted-U hypothesis. Spatial accuracy results indicated no statistically significant differences with mean radial error (p = .18), centroid radial error (p = .13), and bivariate variable error (p = .08) also failing to support the speed-accuracy trade-off in overarm throwing. As neither throwing performance variability nor accuracy changed across percentages of maximum speed in this sample of children as well as in a previous adult sample, current policy and practices of practitioners may need to be reevaluated. PMID- 28657819 TI - CARES: A Community-wide Collaboration Identifies Super-utilizers and Reduces Their 9-1-1 Call, Emergency Department, and Hospital Visit Rates. AB - BACKGROUND: A subset of individuals who inefficiently and frequently use emergency department (ED) services are called "super-utilizers." Our healthcare system is fragmented and complex, making it difficult for providers to identify super-utilizers and address their wide range of health issues. OBJECTIVE: The objective of our study was to evaluate a novel community-wide collaboration program called CARES (Community Assistance Referral and Education Services) designed to identify super-utilizers through local partnering organizations. CARES assists patients in developing their personal health and wellness goals, and navigates them away from 9-1-1 calls, emergency room visits, and hospital admissions, and toward more appropriate resources over 90 days. METHODS: This was a retrospective observational analysis of the CARES program. Data were collected from March 2013 to December 2015. The study population included: enrolled adults with non-compliance of medication or treatment; behavioral health problems; multiple 9-1-1 responses in a short period of time; three or more ED visits within six months; patients with multiple hospital admissions. Adults who were outside of the study period or had missing outcome information were excluded. The primary outcomes of this study were the median rate of 9-1-1 calls/month/person, ED and hospital visits/month/person. Wilcoxon rank-sum tests were used to compare changes between pre- vs. post-enrollment for each subject. RESULTS: A total of 441 subjects were included in this study. The majority of patients (64%) were female, 64% were white, and the median (IQR) age was 48 (35-62) years old. A total of 51% were on Medicaid and 69% identified behavioral health issues as their barriers to optimal health care. Between pre- and post-enrollment periods, the median (IQR) monthly rate of 9-1-1 calls, ED visits, and hospital admissions significantly decreased by 0.26 (-0.06, 0.90), 0.25 (-0.08, 0.71), and 0.18 (0.04, 0.53) (p < 0.001 for all). CONCLUSIONS: When health systems in a geographic area share data, they are better able to recognize patterns of overuse, and address them properly. This study demonstrated that a collaborative 90-day intervention identifying super-utilizers reduced the monthly rate of 9-1-1 calls, ED visits, and hospital admissions. PMID- 28657820 TI - Are Providers Prepared to Engage Younger Women in Shared Decision-Making for Mammography? AB - BACKGROUND: The U.S. Preventive Services Task Force recommends providers engage women aged 40-49 years in shared decision-making (SDM) for mammography. This requires mammography knowledge, adequate time to discuss screening, and self confidence in doing so. Yet, to date, no studies have assessed provider readiness to engage younger women in SDM. METHODS: An online survey of primary care providers was conducted in Cleveland in 2015. It inquired about knowledge of screening benefits and harms, including the impact of screening on mortality, risk of additional imaging, biopsy, overtreatment following screening, and likelihood of a true-positive result. Key knowledge was defined as accurate estimation of the impact of screening on mortality and risk of overtreatment. Respondents reported time typically spent with patients discussing mammography, self-assessed competence in engaging patients in screening discussions, and perspectives on SDM for mammography. RESULTS: Of 612 providers invited, 220 completed the survey (response rate: 36%). Knowledge of harms was low: 90% and 82% underestimated the risk of additional imaging or breast biopsy, respectively. Sixty-two percent correctly estimated screening's impact on mortality. The majority (83%) believed in SDM for mammography, yet, most (77%) spent less than 5 minutes with patients discussing screening. Of those who believed in SDM, only 10% had key mammography knowledge and also felt highly competent at engaging women in screening discussions. CONCLUSIONS: Most providers in our sample were inadequately equipped to engage women in SDM for mammography. Broad-based efforts are needed to increase the capacity of providers to engage younger women in decision-making. PMID- 28657821 TI - A Scientific Approach to Improve Physiological Capacity of an Elite Cyclist. AB - Previous studies in endurance athletes have indicated that block periodization (BP) can be a good alternative to the more traditional organization of training despite the fact that the total volume and intensity of the training are similar. However, these studies usually last only 4-12 wk. The aim of the present single case study was to investigate the consequences of 58 wk with systematic BP of low intensity training (LIT), moderate-intensity training (MIT), and high-intensity interval training (HIT) including incorporation of heavy strength training. It is important that a maintenance stimulus on the nonprioritized training modalities was added in the different training blocks. Performance-related variables were tested regularly during the intervention. The studied cyclist started with a maximal oxygen uptake (VO2max) of 73.8 mL . kg-1 . min-1, peak aerobic power (Wmax) of 6.14 W/kg, and a power output at 3 mmol/L blood lactate concentration (Power3la-) of 3.6 W/kg. Total training volume during the 58-wk intervention was 678 h, of which 452 h were LIT (67%), 124 h were MIT (18%), 69 h were HIT (10%), and 34 h were heavy strength training (5%). The weekly training volume had a large range depending on the focus of the training block. After the intervention the cyclist's VO2max was 87 mL . kg-1 . min-1, Wmax was 7.35 W/kg, and Power3la- was 4.9 W/kg. This single case indicates that the present training program can be a good alternative to the more traditional organization of long-term training of endurance athletes. However, a general recommendation cannot be given based on this single-case study. PMID- 28657822 TI - Health-Related Quality of Life and Physiological Outcomes of Peroral Endoscopic Myotomy for Achalasia. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) has gained acceptance as a treatment for achalasia. The aim of this study was to assess symptomatic, quality of life (QoL), and physiological outcomes of POEM using standardized methods. MATERIALS AND METHODS: Patients who were planned to undergo POEM were evaluated pre- and postoperatively with timed barium esophagogram (TBE), high-resolution manometry (HRM), the achalasia symptom questionnaire (ASQ) (best score 10, worst score 31), and the short form (SF)-36 (best score 100, worst score 0). Nine patients completed postoperative HRM, TBE, and 48 hours esophageal pH monitoring. A P-value of <.05 was considered statistically significant. RESULTS: A total of 34 of 37 patients completed the POEM procedure. There was improvement in the ASQ scores and in QoL. HRM integrated relaxation pressures (IRPs) improved from 31.4 +/- 10.8 mmHg preoperatively to 12.3 +/- 6.7 mmHg postoperatively, and lower esophageal sphincter pressure (LESP) improved from 49.1 +/- 16.9 mmHg preoperatively to 23.1 +/- 9.4 mmHg postoperatively. Of the 7 patients who were evaluated with 48-hour pH monitoring postoperatively, 5 patients (71%) demonstrated pathological reflux with an average Demeester score of 23.1 +/- 19.1. There was a negative linear correlation between LESP change and Demeester scores (r = -0.7, P = .03). CONCLUSION: The POEM procedure significantly improves achalasia-related symptoms and improves social functioning. Physiologically, there is reduction in both IRP and LESP. Postoperative pathological reflux is correlated with LESP reduction. PMID- 28657824 TI - From Olancho to Bedside. PMID- 28657825 TI - Effectiveness of Tai Chi on Cardiac Autonomic Function and Symptomatology in Women With Fibromyalgia: A Randomized Controlled Trial. AB - The present study examined the effects of a 12-week Tai Chi (TC) training regimen on heart rate variability (HRV), symptomatology, muscle fitness and body composition in women with fibromyalgia. Participants were randomly assigned to either a TC training group (n = 18) or a control group (n = 19). HRV, symptomatology, muscle fitness and body composition were measured before and after 12 weeks. There were significant decreases (p < 0.05) in sympathovagal balance (LnLF/LnHF), sympathetic tone (LnLF, nLF), pain, and fatigue, and significant increases (p < 0.05) in parasympathetic tone (LnHF, nHF), strength and flexibility following TC compared with no changes after control. The changes in LnLF and LnLF/LnHF were correlated with changes in pain. There were no significant changes in HR, sleep quality and body composition after TC or control. TC may be an effective therapeutic intervention for improving sympathovagal balance, pain, fatigue, strength and flexibility in women with fibromyalgia. PMID- 28657823 TI - Recovery Housing: Evolving Models to Address Resident Needs. AB - Recovery housing is a service delivery modality that simultaneously addresses the social support and housing needs of those in recovery from substance use disorders. This article describes a group of recovery homes in Texas (N = 10) representing a lesser-studied type of recovery housing, one which explicitly bridges treatment and peer support by providing a variety of recovery support services. All residents meet with a recovery coach, undergo regular drug screening, and have access to intensive outpatient treatment-a program that was developed specifically to support the needs of residents in the homes. Unlike the Oxford HouseTM model and California sober living houses, which are primarily financed through resident fees, these homes are supported through a mix of resident fees as well as private and public insurance. While adhering to some aspects of the social model of recovery, none of these homes would meet criteria to be considered a true social model program, largely because residents have a limited role in the governance of the homes. Residences like the ones in this study are not well-represented in the literature and more research is needed. PMID- 28657826 TI - Seeing suicidology in a new light. PMID- 28657827 TI - Comparison of Transperitoneal and Retroperitoneal Laparoscopic Nephrectomy for Nonfunctional Tuberculous Kidneys: A Single-Center Experience. AB - OBJECTIVES: To compare the effectiveness and safety between retroperitoneal laparoscopic nephrectomy (RLN) and transperitoneal laparoscopic nephrectomy (TLN) for nonfunctional tuberculous kidneys (NTK). METHODS: From March 2013 to February 2016, 24 patients with NTK underwent laparoscopic nephrectomy in our department. Eleven patients underwent RLN, and 13 underwent TLN. The demographics and perioperative outcomes were compared retrospectively. RESULTS: Characteristics, including gender, age, body mass index, and location, were similar in these two groups. All operations were successfully completed in the RLN group, while 1 case in the TLN group was converted to open surgery due to severe adhesions and excessive bleeding (1 of 13 patients). Time to oral intake after surgery in the TLN and RLN group was 43.85 +/- 6.01 hours and 27.45 +/- 6.83 hours (P < .05). No notable differences were found between two groups in terms of estimated blood loss, operative time, days of drain removal, and postoperative hospital stay. No local or disseminated recurrence was identified during the follow-up period. CONCLUSION: Taking the same safety and effectiveness into consideration, TLN can be an alternative choice for experienced surgeons to deal with NTK. Also, further studies with a larger sample size should be performed to confirm this finding. PMID- 28657828 TI - Corrigendum. PMID- 28657830 TI - Glove-Finger Extraction Technique in Uniportal Video-Assisted Thoracoscopic Surgery. AB - BACKGROUND: Uniportal video-assisted thoracoscopic surgery (VATS) is increasingly being performed worldwide. During the operation, specimen extraction from a small incision less than or equal to 2 cm can be challenging without the use of a commercial specimen retrieval device. There have been no reports regarding the use of the glove-finger technique in uniportal VATS. The aim of this study was to assess the feasibility of the alternative specimen retrieval method by glove finger technique. METHODS: We retrospectively investigated 50 patients with peripheral lung lesions who underwent uniportal VATS wedge resection with a 2-cm incision at Kaohsiung Medical University Hospital between August 2015 and December 2016. The cut end of the glove-finger was used to extract the specimen. RESULTS: Fifty-five wedge-resected specimens were extracted successfully by glove finger technique. There was no conversion to two-port nor three-port VATS. After intraoperative frozen section analysis for all specimens, 24 were revealed to have primary lung cancer and subsequently underwent completion lobectomy or segmentectomy; the other 31 showed 10 pulmonary metastases, 9 pulmonary benign lesions, and 12 pulmonary infectious lesions. All specimens were resected with free margins and the mean diameter of the lesions was 1.64 +/- 0.59 cm (range: 0.2-2.6 cm) by pathological examination. No intraoperative complication related to the technique was observed. CONCLUSIONS: This is the first study to reveal the efficacy and benefits of the glove-finger extraction technique in uniportal VATS. In our preliminary experience, this method can decrease costs without compromising the quality and safety of patient care. PMID- 28657829 TI - CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. AB - BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.). PMID- 28657831 TI - Case Report: Life Saving Application of Commercial Tourniquet in Pediatric Extremity Hemorrhage. AB - Hemorrhage is the leading preventable cause of death in civilian and military trauma. Recent data from the ongoing conflicts in Iraq and Afghanistan suggest that early and aggressive tourniquet utilization is a safe and effective way to dramatically reduce mortality from extremity hemorrhage. As a result, prehospital tourniquet use is now endorsed by a majority of professional emergency medicine, emergency medical service and trauma professional societies. However, there currently exists scant evidence supporting the efficacy of commercially available tourniquets in controlling extremity hemorrhage in pediatric trauma patients. PMID- 28657832 TI - Voices that want to be heard: Using bereaved Danish students suggestions to update school bereavement response plans. AB - This study explored how Danish students experienced returning to school following parental bereavement. Eighteen focus group interviews were conducted with 39 participants aged 9 to 17. All participants had experienced the loss of a primary caregiver. Data collection was divided into two phases. In Phase I, 22 participants from four grief groups were interviewed 4 times over the course of a year. During Phase II, confirmatory focus groups were undertaken with the 17 participants. This article explores the findings related to ideas and suggestions made by the students about how the Danish school response could be improved to better meet their needs. The presentation of data is divided into seven themes, which are: Desired school response; Desired support from teachers; Desired boundaries between students and teachers; Desired collaboration; Desired support from peers; Desired rules and structure, and; Desires related to gifts and rituals. Study findings indicate that most students want to be included and have a say when the school plans how to respond to their loss. Students further highlight a need for teacher support when having to reconnect with the class; a need for set rules in relation to leaving the class when feeling sad, and; a need for schools to see the loss as a life-changing event, and grief as something that does not simply disappear after a few months. The article concludes by discussing the ways in which the recommendations provided by the participants can be incorporated into a modern revision of Danish school bereavement response plans. PMID- 28657834 TI - Special Issue: Selected Papers of the Inaugural DahShu Data Science Symposium: Computational Precision Health (CPH 2017). PMID- 28657833 TI - Serum interleukin-6 and survivin levels predict clinical response to etanercept treatment in patients with established rheumatoid arthritis. AB - OBJECTIVES: To investigate the correlation of nine potential biomarkers with clinical response to etanercept (ETN) therapy in establish rheumatoid arthritis (RA) patients. METHODS: Seventy-three patients with established RA were enrolled in the prospective cohort study. Sixty-nine of 73 cases were included into final analysis for response after 24-week ETN therapy. Serum expression of nine studied proteins was measured by enzyme-linked immunosorbent assay (ELISA). Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-17A, IL 21, IL-34, RANKL, survivin, and COMP were selected as candidate biomarkers. RESULTS: Serum IL-6 level was increased in responders than in nonresponders at baseline, p = .034; to the contrary, serum survivin level was decreased in responders, p = .009. Receiver operating characteristic (ROC) curve illuminated the combination of IL-6 and survivin expressions could predict clinical response with a high AUC 0.875, 95% CI: 0.771-0.976. Furthermore, we found the combination of IL-6 high expression and survivin low expression increased the responding possibility to nearly 20-fold (OR 19.687, 95% CI: 4.087-94.839, p < .001) compared to IL-6 low or survivin high expression by univariate analysis. However, only survivin low expression (p = .002) and CRP (p = .014) high expression were independent predictive factors for achieving clinical response, while IL-6 lack independent predictive value (p = .267). CONCLUSIONS: Comprehensive measurement of IL-6 and survivin in serum could be served as a convincing biomarker for clinical response in ETN-treated patients with established RA. PMID- 28657835 TI - Identifying Cell Subpopulations and Their Genetic Drivers from Single-Cell RNA Seq Data Using a Biclustering Approach. AB - Single-cell RNA-Seq (scRNA-Seq) has attracted much attention recently because it allows unprecedented resolution into cellular activity; the technology, therefore, has been widely applied in studying cell heterogeneity such as the heterogeneity among embryonic cells at varied developmental stages or cells of different cancer types or subtypes. A pertinent question in such analyses is to identify cell subpopulations as well as their associated genetic drivers. Consequently, a multitude of approaches have been developed for clustering or biclustering analysis of scRNA-Seq data. In this article, we present a fast and simple iterative biclustering approach called "BiSNN-Walk" based on the existing SNN-Cliq algorithm. One of BiSNN-Walk's differentiating features is that it returns a ranked list of clusters, which may serve as an indicator of a cluster's reliability. Another important feature is that BiSNN-Walk ranks genes in a gene cluster according to their level of affiliation to the associated cell cluster, making the result more biologically interpretable. We also introduce an entropy based measure for choosing a highly clusterable similarity matrix as our starting point among a wide selection to facilitate the efficient operation of our algorithm. We applied BiSNN-Walk to three large scRNA-Seq studies, where we demonstrated that BiSNN-Walk was able to retain and sometimes improve the cell clustering ability of SNN-Cliq. We were able to obtain biologically sensible gene clusters in terms of GO term enrichment. In addition, we saw that there was significant overlap in top characteristic genes for clusters corresponding to similar cell states, further demonstrating the fidelity of our gene clusters. PMID- 28657836 TI - Short- and long-term reliability of leg extensor power measurement in middle-aged and older adults. AB - Muscular power is important for maintaining physical functioning with aging. Proper quantification of the reliability of muscular power tests is crucial to inform monitoring of individuals and sample size planning for interventional studies. This study evaluated short- and long-term reliability of leg extensor power measurement in 72 adults (age 62.7 +/- 8.6 years). Participants completed four repeat trials on the Nottingham leg extensor power rig, with a further trial twelve weeks later. Mean change, typical error, and intraclass correlation coefficients (ICC) were calculated. For short-term reliability, mean change in power output was trivial after two trials (1.2-4.8%). Typical errors were small following four trials in the dominant leg of males (10.9-5.8%), three in the non dominant leg of males (9.9-6.2%) and the dominant leg of females (10.0-9.6%) and two in the non-dominant leg in females (8.3%). Intraclass correlation coefficients (ICCs) were very high (0.88-0.96). For long-term reliability, mean change remained trivial (1.0-2.5%), typical errors remained small (5.8-8.6%), and ICCs very high (0.94-0.96). The leg extensor power rig is a reliable method for assessing lower body muscular power, both short- and long-term, with only minimal habituation effects. PMID- 28657837 TI - McKittrick Wheelock Syndrome Treated by Transanal Minimally Invasive Surgery: A Single-Center Experience and Review of the Literature. AB - INTRODUCTION: McKittrick Wheelock Syndrome (MKWS) is a rare syndrome characterized by secretory diarrhea, dehydration, prerenal acute kidney injury, and severe electrolyte abnormalities caused by a large hypersecretory villous adenoma located in the rectum or rectosigmoid junction. Transabdominal (laparoscopic) procedures are the most described procedures in the treatment of MKWS. We report an alternative surgical approach, transanal minimally invasive surgery (TAMIS), to solve this syndrome. MATERIALS AND METHODS: All patients who underwent transanal endoscopic microsurgery or TAMIS were included in a prospectively collected database in our center. Between 1996 and 2015, 3 patients were found to have MKWS and treated by TAMIS. Demographics, characteristics of the adenoma, surgery-related data, and outcome were analyzed. RESULTS: The first patient had a villous adenoma 0-12 cm from the anal verge. After TAMIS, she complained of a stenosis that was successfully treated by dilatation. The second patient had an impressive bulky tumor in the rectum. An endoscopic mucosal resection was attempted twice, but incompletely. Pathology analysis showed villous adenoma with high-grade dysplasia and intramucosal carcinoma. One year after TAMIS, a recurrence was detected and treated by an abdominal-perineal resection. A TAMIS was performed in the third patient because of a giant villous circular adenoma, but because of high mucus and fluid production, no proper overview could be obtained. Together with opening of the peritoneum, this prompted us to convert to a laparoscopic Hartmann procedure. Besides this technical difficulty, the patient recovered uneventful. CONCLUSIONS: MKWS is a rare syndrome and missed diagnosis could result in life-threatening situations. Different endoscopic and surgical treatments are described to solve this syndrome. TAMIS should be considered as a rectum-preserving surgical treatment option for such extensive adenomas. PMID- 28657838 TI - Reducing Calorie Intake May Not Help You Lose Body Weight. AB - As the widespread availability of highly calorific food has resulted in a high incidence of obesity, attempts to decrease body weight have concentrated on trying to reduce energy intake. It is suggested that this is not the best approach. Although consuming more calories than expended is part of the initial problem, it does not follow that reducing intake, unless consciously counting calories, is the best solution. Mechanisms smooth out the large day-to-day differences in energy consumption, decreasing the importance of the size of a meal. In the short term a reduction in energy intake is counteracted by mechanisms that reduce metabolic rate and increase calorie intake, ensuring the regaining of lost weight. For example, even a year after dieting, hormonal mechanisms that stimulate appetite are raised. Over a million calories are consumed a year yet weight changes to only a small extent; there must be mechanisms that balance energy intake and expenditure. As obesity reflects only a small malfunctioning of these mechanisms, there is a need to understand the control of energy balance and how to prevent the regaining of weight after it has been lost. By itself, decreasing calorie intake will have a limited short-term influence. PMID- 28657839 TI - Intratrunk Coordination During High-Effort Treadmill Running in Individuals With Spinal Fusion for Adolescent Idiopathic Scoliosis. AB - The purpose of the study was to determine if the intratrunk coordination of axial rotation exhibited by individuals with spinal fusion for adolescent idiopathic scoliosis (SF-AIS) during running varies from healthy individuals and how the coordination differs among adjacent trunk-segment pairs. Axial rotations of trunk segments (upper, middle, lower trunk) and pelvis were collected for 11 SF-AIS participants and 11 matched controls during running. Cross-correlation determined the phase lag between the adjacent segment motions. The coupling angle was generated using the vector coding method and classified into 1 of the 4 major, modified coordination patterns: in-phase, anti-phase, superior, and inferior phase. Two-way, mixed-model ANCOVA was employed to test phase lag, cross correlation r, and time spent in each major coordination pattern. A significantly lower phase lag for SF-AIS was observed compared with controls. Qualitatively, there was a tendency that SF-AIS participants spent less time in anti-phase for middle-lower trunk and lower trunk-pelvis coordinations compared to controls. Phase lag and anti-phase time was significantly increased from cephalic to caudal segment pairs, regardless of group. In conclusion, SF-AIS participants and controls displayed similar patterns of intra-trunk coordination; however, the spinal fusion hindered decoupling of intra-trunk motions particularly between the lower trunk-pelvic motion. PMID- 28657840 TI - Therapeutic warfarin use and the extrahepatic functions of vitamin K-dependent proteins. AB - The impact of warfarin therapy on the functions of extrahepatic vitamin K dependent proteins (VKDP) is less clearly understood and less widely recognised in clinical practice than that on the hepatic counterparts (clotting factors II, VII, IX and X). Warfarin inhibits osteocalcin, an abundant extrahepatic VKDP involved in the mineralisation and maturation of bone and thus, primarily by this mechanism, may have an adverse effect on bone health. Whilst some studies do link warfarin use to an increase in osteoporosis and fracture risk others have not. Warfarin also inhibits the extrahepatic VKDP matrix gla protein (MGP) which acts to prevent ectopic calcification of the vasculature. Studies have consistently found a correlation between warfarin use and vascular calcification with inhibition of MGP believed to be the main cause. Inhibition of MGP also appears to explain warfarin's well established teratogenic effect. Further adverse effects may also arise from warfarin's inhibition of other known extrahepatic VKDPs. The available evidence is intriguing, and suggests that the impact of warfarin on the extrahepatic functions of vitamin K-dependent proteins warrants further careful consideration. PMID- 28657841 TI - Association between dementia and vascular disease-associated polymorphisms in a Tunisian population. AB - PURPOSE: Dementia is a multifactorial idiopathic pathology caused by clinical, eDementia is a multifactorial idiopathic pathology caused by clinical, environmental and genetic factors. Hence, its etiology is still unknown. We aimed to evaluate the association between five genetic risk factors for vascular diseases and dementia individually and when gathered in haplotypes. MATERIALS AND METHOD: We enrolled 200 dementia patients and 300 controls. All subjects were genotyped for vascular diseaseassociated polymorphisms in the genes coding for Apolipoprotein-E (ApoE), angiotensin converting enzyme (ACE) and Paraoxonase-1 (PON1). RESULTS: The association between dementia risk and all the studied polymorphisms except of PON1-Q192R was found to be significant. Carrying the ApoE e4 allele seems to increase dementia risk by 4.32 fold (p = 0.001). The risk associated with ACE I and PON1-L55M T alleles were lower (2.58 and 2.11 fold, p < 0.001 and p = 0.015, respectively). When combined in haplotypes, these polymorphisms showed a cumulative and synergetic effect. GTICC haplotype appears to be associated with 9-fold dementia risk (p < 0.001), whereas AADTT seems to reduce dementia risk by 80% (p = 0.003). CONCLUSION: Our results suggest that, ApoE epsilon4, ACE I and PON1-L55M T alleles are associated with dementia risk whether these polymorphisms were studied separately or gathered in haplotypes. Still, the contribution of each gene to the pathophysiological development of dementia must be more investigated. PMID- 28657842 TI - JOURNAL CLUB: Can Coronal STIR Be Used as Screening for Acute Nontraumatic Hip Pain in Children? AB - OBJECTIVE: The objective of this study is to evaluate whether coronal STIR MRI can be used as a screening test for nontraumatic acute hip pain in children. MATERIALS AND METHODS: From 2008 to 2012, we identified all patients younger than 18 years at our tertiary care facility who underwent pelvic MRI including coronal STIR for the following indications: acute hip pain, limping, or refusal to bear weight. Patients with a history of trauma were excluded. Each MR image was independently reviewed by four radiologists who were blinded to the clinical outcome. After first reviewing the coronal STIR images only, they then reviewed the full MRI studies in a random order different from that used for review of the coronal STIR images. The sensitivity and specificity of STIR-only images in identifying the presence of abnormality and specific diagnoses were calculated, with the full MRI study considered as the reference standard. Kappa values were calculated for STIR-only and full MRI studies. RESULTS: A total of 127 patients (67 female patients and 60 male patients; median age, 9 years; range, 5 months to 17 years) were identified. The most common abnormalities (calculated as the mean of frequency values noted by four readers) were hip effusion (52%; range, 46 58%), osteomyelitis (42%; range, 29-48%), and myositis (32%; range, 20-40%). For the detection of any abnormality, STIR-only images had a mean sensitivity of 95% and a mean specificity of 67%. For approximately one-third of STIR-only studies with true-positive results, additional abnormalities were found on full MRI studies. CONCLUSION: Coronal STIR imaging of the pelvis has high sensitivity (95%) in the detection of abnormalities associated with acute nontraumatic hip pain in children, but it often misses additional abnormalities. PMID- 28657843 TI - Interreader Agreement of Prostate Imaging Reporting and Data System Version 2 Using an In-Bore MRI-Guided Prostate Biopsy Cohort: A Single Institution's Initial Experience. AB - OBJECTIVE: The purpose of this study is to determine the interobserver agreement of the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) for diagnosing prostate cancer using in-bore MRI-guided prostate biopsy as the reference standard. MATERIALS AND METHODS: Fifty-nine patients underwent in-bore MRI-guided prostate biopsy between January 21, 2010, and August 21, 2013, and underwent diagnostic multiparametric MRI 6 months or less before biopsy. A single index lesion per patient was selected after retrospective review of MR images. Three fellowship-trained abdominal radiologists (with 1-11 years' experience) blinded to clinical information interpreted all studies according to PI-RADSv2. Interobserver agreement was assessed using Cohen kappa statistics. RESULTS: Thirty-eight lesions were in the peripheral zone and 21 were in the transition zone. Cancer was diagnosed in 26 patients (44%). Overall PI-RADS scores were higher for all biopsy-positive lesions (mean +/- SD, 3.9 +/- 1.1) than for biopsy negative lesions (3.1 +/- 1.0; p < 0.0001) and for clinically significant lesions (4.2 +/- 1.0) than for clinically insignificant lesions (3.1 +/- 1.0; p < 0.0001). Overall suspicion score interobserver agreement was moderate (kappa = 0.45). There was moderate interobserver agreement among overall PI-RADS scores in the peripheral zone (kappa = 0.46) and fair agreement in the transition zone (kappa = 0.36). CONCLUSION: PI-RADSv2 scores were higher in the biopsy-positive group. PI-RADSv2 showed moderate interobserver agreement among abdominal radiologists with no prior experience using the scoring system. PMID- 28657844 TI - Doppler Parameters of the Hepatic Artery as Predictors of Graft Status in Pediatric Liver Transplantation. AB - OBJECTIVE: The purpose of this article is to determine whether hepatic artery (HA) Doppler parameters can be used to predict pediatric liver graft status in the immediate postoperative (< 10 days) period and in the first year after transplant. MATERIALS AND METHODS: A retrospective review of the liver transplant database was performed to review operative, clinical, laboratory, histopathologic, and ultrasound findings at three time points after surgery: 3 days, 3 months, and 1 year. The association between HA velocity and resistive index (RI) with graft status was assessed. RESULTS: Of 120 children (54 girls and 66 boys; mean age, 3 years 2 months) enrolled, 70 had satisfactory graft status at the 1-year follow-up examination. HA velocity of 50-200 cm/s at 3 days was associated with normal graft status during the immediate postoperative period (p = 0.003), at 3 months (p = 0.0653), and at the 1-year follow-up examination (p = 0.0268). Vascular and biliary complications in the immediate postoperative period were more frequent at an HA velocity of 201-300 cm/s (p = 0.0024). There was a significant association between RI at 3 days and graft status in the immediate postoperative period (p = 0.0308), with an RI less than 0.5 associated with vascular complications (p = 0.0116). CONCLUSION: An RI less than 0.5 is associated with vascular complications. An HA velocity of 50-200 cm/s and an RI of 0.5-0.8 are associated with normal graft status in children within the first year after transplant. Values outside this range, or in this range along with a constellation of other ultrasound findings and clinical status, support the initiation of additional more-specific investigations that may help in early treatment to prevent complications. PMID- 28657845 TI - The Role of Percutaneous Image-Guided Thermal Ablation for the Treatment of Pulmonary Malignancies. AB - OBJECTIVE: Image-guided thermal ablation is a minimally invasive treatment option for patients with primary and secondary pulmonary malignancies. Modalities include radiofrequency ablation, microwave ablation, and cryoablation. CONCLUSION: Although no large randomized studies exist comparing ablation to surgery or radiotherapy, numerous studies have reported safety and efficacy for the treatment of both primary and metastatic disease in select patients. Future studies will refine patient selection, procedural technique, and assessment for local recurrence and will evaluate long-term survival. PMID- 28657846 TI - Immune Checkpoint Inhibitors in Lung Cancer: Imaging Considerations. AB - OBJECTIVE: The purpose of this article is to review the mechanisms of action of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC), highlight imaging manifestations of common adverse events, and discuss new criteria for using imaging to assess unique treatment response patterns. CONCLUSION: Immune checkpoint inhibitor therapy is a breakthrough in cancer treatment that has shown unprecedented success when used for a variety of malignancies. In recent phase 3 clinical trials for NSCLC, monoclonal antibodies that target the programmed death-1 (PD-1) receptor and its ligand PD-L1 (i.e., the PD-1/PD-L1 axis) were associated with better overall survival in head-to-head comparisons with conventional cytotoxic chemotherapy. On the strength of the results of these trials, the PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of advanced NSCLC. Because of their unique mechanisms of action, these agents differ from conventional cytotoxic chemotherapy in both patterns of treatment response and treatment related adverse events. Given the rapidly expanding clinical use of immune checkpoint inhibitors and the central role of radiology in the care of patients with lung cancer, it is important for radiologists to be familiar with these agents and their unique imaging findings. PMID- 28657847 TI - Incidence of Inadvertent Dural Puncture During CT Fluoroscopy-Guided Interlaminar Epidural Corticosteroid Injections in the Cervical Spine: An Analysis of 974 Cases. AB - OBJECTIVE: The objective of this study is to determine the rate of inadvertent dural puncture during CT fluoroscopy-guided cervical interlaminar epidural corticosteroid injection. In addition, in a subanalysis, we aim to assess the rate of inadvertent dural puncture superior to C5-C6 occurring during interlaminar epidural corticosteroid injection using CT fluoroscopy guidance because such injections are not performed using conventional fluoroscopy. MATERIALS AND METHODS: Images obtained from consecutive CT fluoroscopy-guided cervical interlaminar epidural corticosteroid injections conducted from November 2009 to November 2015 were reviewed. The following information was recorded: the presence of inadvertent dural puncture, the level of the cervical interlaminar space, approach laterality (left or right), anteroposterior spinal canal diameter, and the presence of a trainee. Two-tailed Fisher exact tests were used for assessment of categoric variables, and t tests were used for continuous variables. RESULTS: A total of 974 cervical interlaminar epidural corticosteroid injections were identified in 728 patients. Inadvertent dural punctures were identified in association with 1.4% (14/974) of these injections; all punctures were recognized during the procedure. Needle placements were performed at every cervical level (C1-C2 through C7-T1). The highest rate of dural puncture (2.8%) occurred at C5-C6. No dural punctures occurred superior to C5-C6 (16.6% of cases). The complication rate was 0.4%. Only greater anteroposterior spinal canal diameter was associated with increased dural puncture rates (p = 0.049). CONCLUSION: CT fluoroscopy-guided cervical interlaminar epidural corticosteroid injections were performed at all levels throughout the cervical spine. A very low complication rate and a minimal rate of inadvertent dural puncture were noted, similar to previously reported rates for conventional fluoroscopy-guided injections limited to the lower cervical spine only. PMID- 28657848 TI - Plasma Glucose Level Is Predictive of Serum Ammonia Level After Retrograde Occlusion of Portosystemic Shunts. AB - OBJECTIVE: The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis. MATERIALS AND METHODS: Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO. RESULTS: Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75 g oral glucose tolerance test results. CONCLUSION: Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control of blood ammonia levels by BRTO alone may be difficult in patients with glucose intolerance. PMID- 28657849 TI - The Impact of Patient Demographics on the Selection of Breast Imaging Centers. AB - OBJECTIVE: Studies show that health care tailored to patient preferences results in significant improvements in physician performance, patient satisfaction, and health outcomes. Limited information in the literature exists on the factors driving patient preferences for establishing care at specific breast imaging centers. In this study, we identified factors that drive cohort preferences in the selection of a breast imaging center. MATERIALS AND METHODS: An 18-question survey was deployed in a large metropolitan area to gather information on patient demographics and preferences for breast imaging center location and radiologist training level. Cluster analysis and the K-means method were used to classify patients into groups on the basis of their answers about preference. Clusters were tested for significant differences by location, reason for visit, age, education, marital status, ethnicity, insurance, history of cancer, and income. RESULTS: A total of 1682 survey responses (18% of total patient visits) were obtained. Four distinct cohorts (comprising 876 patients) based on patient care preferences were identified: convenience optimizers (n = 109, 12.4%), ambivalent patients (n = 237, 27.1%), medical center seekers (n = 324, 37.0%), and expertise seekers (n = 206, 23.5%). Each cohort showed distinct preferences for imaging center location and radiologist training. Cohorts were differentiated on the basis of patient education level, ethnicity, and patient cancer history. Across the cohorts, there were no significant differences in age, marital status, insurance, income, and other demographic factors. CONCLUSION: Patient preferences for breast imaging care and location vary and are correlated with specific demographic characteristics. An understanding of these population characteristics can shape organizational strategies for improving patient-centered care and outcomes. PMID- 28657850 TI - Comparison of Visual Assessment of Breast Density in BI-RADS 4th and 5th Editions With Automated Volumetric Measurement. AB - OBJECTIVE: The purpose of this study was to compare visual assessments of mammographic breast density by radiologists using BI-RADS 4th and 5th editions in correlation with automated volumetric breast density measurements. MATERIALS AND METHODS: A total of 337 consecutive full-field digital mammographic examinations with standard views were retrospectively assessed by two radiologists for mammographic breast density according to BI-RADS 4th and 5th editions. Fully automated measurement of the volume of fibroglandular tissue and total breast and percentage breast density was performed with a commercially available software program. Interobserver and intraobserver agreement was assessed with kappa statistics. The distributions of breast density categories for both editions of BI-RADS were compared and correlated with volumetric data. RESULTS: Interobserver agreement on breast density category was moderate to substantial (kappa = 0.58 0.63) with use of BI-RADS 4th edition and substantial (kappa = 0.63-0.66) with use of the 5th edition but without significant difference between the two editions. For intraobserver agreement between the two editions, the distributions of density category were significantly different (p < 0.0001), the proportions of dense breast increased, and the proportion of fatty breast decreased with use of the 5th edition compared with the 4th edition (p < 0.0001). All volumetric breast density data, including percentage breast density, were significantly different among density categories (p < 0.0001) and had significant correlation with visual assessment for both editions of BI-RADS (p < 0.01). CONCLUSION: Assessment using BI-RADS 5th edition revealed a higher proportion of dense breast than assessment using BI-RADS 4th edition. Nevertheless, automated volumetric density assessment had good correlation with visual assessment for both editions of BI-RADS. PMID- 28657851 TI - Curative Resection of Single Primary Hepatic Malignancy: Liver Imaging Reporting and Data System Category LR-M Portends a Worse Prognosis. AB - OBJECTIVE: The purpose of this study was to examine the associations between preoperative Liver Imaging Reporting and Data System (LI-RADS) categories and prognosis after curative resection of single hepatic malignancies in patients with chronic liver disease. MATERIALS AND METHODS: Between January 2008 and December 2010, 225 patients with chronic liver disease underwent resection of single hepatic malignant tumors (218 hepatocellular carcinomas, three cholangiocarcinomas, four biphenotypic carcinomas) after undergoing gadoxetic acid-enhanced MRI. Two radiologists retrospectively categorized the tumors into LI-RADS categories. Differences in disease-free survival duration between categories were analyzed by the Kaplan-Meier method with the log-rank test. RESULTS: Reviewer 1 categorized two (0.9%) patients as having LR-3, 53 (23.6%) LR 4, 159 (70.7%) LR-5, and 11 (4.9%) LR-M lesions. The corresponding numbers for reviewer 2 were six (2.7%) LR-3, 30 (13.3%) LR-4, 178 (79.1%) LR-5, and 11 (4.9%) LR-M. The 2-year cumulative recurrence or death rates were 15.1% for lesions categorized LR-3 or LR-4 by reviewer 1, 31.7% for LR-5, and 60% for LR-M. For lesions categorized by reviewer 2 the corresponding rates were 20.6% for LR-3 or LR-4, 29% for LR-5, and 54.5% for LR-M. Disease-free survival was significantly worse among patients with lesions categorized as LR-M than for lesions categorized as LR-3 or LR-4 or as LR-5 (p < 0.01 for both reviewers). Disease free survival did not significantly differ between patients with LR-3 or LR-4 and those with LR-5 lesions (reviewer 1, p = 0.301; reviewer 2, p = 0.291). CONCLUSION: Patients with tumors preoperatively categorized as LR-M may have a worse prognosis than those with tumors categorized LR-3, LR-4, or LR-5 after curative resection of single hepatic malignancy. PMID- 28657852 TI - Iterative Assessment of Statistically-Oriented and Standard Algorithms for Determining Muscle Onset with Intramuscular Electromyography. AB - The onset of muscle activity, as measured by electromyography (EMG), is a commonly applied metric in biomechanics. Intramuscular EMG is often used to examine deep musculature and there are currently no studies examining the effectiveness of algorithms for intramuscular EMG onset. The present study examines standard surface EMG onset algorithms (linear envelope, Teager-Kaiser Energy Operator, and sample entropy) and novel algorithms (time series mean variance analysis, sequential/batch processing with parametric and nonparametric methods, and Bayesian changepoint analysis). Thirteen male and 5 female subjects had intramuscular EMG collected during isolated biceps brachii and vastus lateralis contractions, resulting in 103 trials. EMG onset was visually determined twice by 3 blinded reviewers. Since the reliability of visual onset was high (ICC(1,1): 0.92), the mean of the 6 visual assessments was contrasted with the algorithmic approaches. Poorly performing algorithms were stepwise eliminated via (1) root mean square error analysis, (2) algorithm failure to identify onset/premature onset, (3) linear regression analysis, and (4) Bland Altman plots. The top performing algorithms were all based on Bayesian changepoint analysis of rectified EMG and were statistically indistinguishable from visual analysis. Bayesian changepoint analysis has the potential to produce more reliable, accurate, and objective intramuscular EMG onset results than standard methodologies. PMID- 28657853 TI - Racing an Opponent: Alteration of Pacing, Performance, and Muscle-Force Decline but Not Rating of Perceived Exertion. AB - PURPOSE: Performing against a virtual opponent has been shown to invite a change in pacing and improve time-trial (TT) performance. This study explored how this performance improvement is established by assessing changes in pacing, neuromuscular function, and perceived exertion. METHODS: After a peak-power output test and a familiarization TT, 12 trained cyclists completed two 4-km TTs in randomized order on a Velotron cycle ergometer. TT conditions were riding alone (NO) and riding against a virtual opponent (OP). Knee-extensor performance was quantified before and directly after the TT using maximal voluntary contraction force (MVC), voluntary activation (VA), and potentiated doublet twitch force (PT). Differences between the experimental conditions were examined using repeated-measures ANOVAs. Linear-regression analyses were conducted to associate changes in pacing to changes in MVC, VA, and PT. RESULTS: OP was completed faster than NO (mean power output OP 289.6 +/- 56.1 vs NO 272.2 +/- 61.6 W; P = .020), mainly due to a faster initial pace. This was accompanied by a greater decline in MVC (MVC pre vs post -17.5% +/- 12.4% vs -11.4% +/- 10.9%, P = .032) and PT (PT pre vs post -23.1% +/- 14.0% vs -16.2% +/-11.4%, P = .041) after OP than after NO. No difference between conditions was found for VA (VA pre vs post -4.9% +/- 6.7% vs -3.4% +/- 5.0%, P = .274). Rating of perceived exertion did not differ between OP and NO. CONCLUSION: The improved performance when racing against a virtual opponent was associated with a greater decline in voluntary and evoked muscle force than riding alone, without a change in perceived exertion, highlighting the importance of human-environment interactions in addition to one's internal state for pacing regulation and performance. PMID- 28657854 TI - Differences Between Relative and Absolute Speed and Metabolic Thresholds in Rugby League. AB - PURPOSE: To compare relative and absolute speed and metabolic thresholds for quantifying match output in elite rugby league. METHODS: Twenty-six professional players competing in the National Rugby League were monitored with global positioning systems (GPS) across a rugby-league season. Absolute speed (moderate intensity running [MIRTh > 3.6 m/s] and high-intensity running [HIRTh > 5.2 m/s]) and metabolic (>20 W/kg) thresholds were compared with individualized ventilatory (first [VT1IFT] and second [VT2IFT]) thresholds estimated from the 30-15 Intermittent Fitness Test (30-15IFT), as well as the metabolic threshold associated with VT2IFT (HPmetVT2), to examine difference in match-play demands. RESULTS: VT2IFT mean values represent 146%, 138%, 167%, and 144% increases in the HIR dose across adjustables, edge forwards, middle forwards, and outside backs, respectively. Distance covered above VT2IFT was almost certainly greater (ES range = 0.79-1.03) than absolute thresholds across all positions. Trivial to small differences were observed between VT1IFT and MIRTh, while small to moderate differences were reported between HPmetVT2 and HPmetTh. CONCLUSIONS: These results reveal that the speed at which players begin to run at higher intensities depends on individual capacities and attributes. As such, using absolute HIR speed thresholds underestimates the physical HIR load. Moreover, absolute MIR and high metabolic thresholds may over- or underestimate the work undertaken above these thresholds depending on the respective fitness of the individual. Therefore, using relative thresholds enables better prescription and monitoring of external training loads based on measured individual physical capacities. PMID- 28657855 TI - Errors Associated With Utilizing Prescribed Scapular Kinematics to Estimate Unconstrained, Natural Upper Extremity Motion in Musculoskeletal Modeling. AB - Musculoskeletal modeling is capable of estimating physiological parameters that cannot be directly measured, however, the validity of the results must be assessed. Several models utilize a scapular rhythm to prescribe kinematics, yet it is unknown how well they replicate natural scapular motion. This study evaluated kinematic errors associated with a model that employs a scapular rhythm using 2 shoulder movements: abduction and forward reach. Two versions of the model were tested: the original MoBL ARMS model that utilizes a scapular rhythm, and a modified MoBL ARMS model that permits unconstrained scapular motion. Model estimates were compared against scapulothoracic kinematics directly measured from motion capture. Three-dimensional scapulothoracic resultant angle errors associated with the rhythm model were greater than 10 degrees for abduction (mean: 16.4 degrees , max: 22.4 degrees ) and forward reach (mean: 11.1 degrees , max: 16.5 degrees ). Errors generally increased with humerothoracic elevation with all subjects reporting greater than 10 degrees differences at elevations greater than 45 degrees . Errors associated with the unconstrained model were less than 10 degrees . Consequently, use of the original MoBL ARMS model is cautioned for applications requiring precise scapulothoracic kinematics. These findings can help determine which research questions are suitable for investigation with these models and assist in contextualizing model results. PMID- 28657857 TI - GENETIC CHARACTERIZATION OF CANINE PARVOVIRUS IN SYMPATRIC FREE-RANGING WILD CARNIVORES IN PORTUGAL. AB - Since its emergence in the 1970s, canine parvovirus (CPV) has been reported in domestic and nondomestic carnivores worldwide with severe implications on their health and survival. Here, we aim to better understand CPV circulation in multihost-pathogens systems by characterizing CPV DNA or viruses in 227 free ranging wild carnivores of 12 species from Portugal. Collected samples during 1995-2011 were analyzed by PCR and sequence analysis. The canine parvovirus DNA was detected in 4 (2%) animals of two species, namely in wolves (Canis lupus; 3/63, 5%, 95% confidence interval=1.6-3.15) and in a stone marten (Martes foina; 1/36, 3%, 95% confidence interval=0.5-14.2). Viruses in two wolves had VP2 residue 426 as aspartic acid (so-called CPV-2b) and the third had VP2 residue 426 as asparagine (CPV-2a), while the virus in the stone marten uniquely had VP2 residue 426 as glutamic acid (CPV-2c). The comparative analysis of the full length VP2 gene of our isolates showed other nonsynonymous mutations. The phylogenetic analysis demonstrated that the sequences from wolves clustered together, showing a close relationship with European domestic dogs (Canis lupus familiaris) and wolf strains while the viral sequence from the stone marten grouped with other viruses contained the glutamic acid VP2 426 along with raccoon (Procyon lotor), bobcat (Lynx rufus), and domestic dog strains. This study confirmed that wild carnivores in Portugal are infected by CPV variants, strongly suggesting viral transmission between the wild and domestic populations and suggesting a need for a better understanding of the epidemiology of the disease and its management in wild populations. PMID- 28657858 TI - SCREENING FOR BOVINE TUBERCULOSIS IN AFRICAN BUFFALO (SYNCERUS CAFFER) IN NGORONGORO CONSERVATION AREA, NORTHERN TANZANIA: IMPLICATIONS FOR PUBLIC HEALTH. AB - In the Ngorongoro Conservation Area (NCA), Tanzania, where wildlife and livestock interaction is intense, greater potential for intra- and interspecies disease transmission is expected. We assessed the prevalence of bovine tuberculosis in African buffalo (Syncerus caffer) residing on the valley floor of the crater in the NCA. Apparently healthy animals were randomly selected from herds in nine sites of the Ngorongoro Crater. Syncerus caffer buffalo herds were located using very high-frequency radio-aided rangers positioned in various observation points around the crater in the NCA. A total of 102 African buffalo from 16 herds were immobilized from the ground using a cocktail of 4-10 mg etorphine hydrochloride (M99) and 60-150 mg azaperone tartrate. The M99 was reversed using 10-25 mg diprenorphine hydrochloride depending on age of animals. An interferon gamma assay was performed on harvested plasma samples using sandwich enzyme linked immunosorbent assay. Of the 102 animals sampled, two (2%) African buffalo tested positive for bovine tuberculosis. These results corroborate those of the skin test done recently in cattle in the NCA. The presence of bovine tuberculosis in livestock and wildlife suggested the possibility of cross-species transmission of the disease, indicating the need for appropriate intervention measures. PMID- 28657859 TI - The First 10 Years (2006-15) of Epizootic Hemorrhagic Disease Virus Serotype 6 in the USA. AB - Epizootic hemorrhagic disease virus (EHDV) is a Culicoides biting midge transmitted orbivirus (family Reoviridae) of wild and domestic ruminants and is an important pathogen of white-tailed deer (Odocoileus virginianus). Historically, only two serotypes, EHDV-1 and EHDV-2, have been known to be endemic in the US. However, in 2006, an exotic serotype (EHDV-6) was first detected in the US by a long-term passive surveillance system for EHDV and bluetongue viruses. Here we report EHDV-6 detections made through these passive surveillance efforts by the Southeastern Cooperative Wildlife Disease Study (University of Georgia, Athens, Georgia, USA) and the National Veterinary Services Laboratories (US Department of Agriculture, Ames, Iowa, USA) over a 10 yr period (2006-15). The results demonstrated that EHDV-6 was detected from ruminants every year since 2006 and was widespread in the central and eastern US, providing evidence that EHDV-6 is likely now established in the US. PMID- 28657860 TI - PREVALENCE OF BABESIA SPP., EHRLICHIA SPP., AND TICK INFESTATIONS IN OKLAHOMA BLACK BEARS (URSUS AMERICANUS). AB - American black bears (Ursus americanus) are commonly infested with ticks throughout their range, but there are few surveys for tick-borne disease agents in bears. To characterize tick infestations and determine the prevalence of current infection with Babesia spp. and past or current infection with Ehrlichia spp. in newly re-established populations of black bears in east central and southeastern Oklahoma, US, we identified adult (n=1,048) and immature (n=107) ticks recovered from bears (n=62). We evaluated serum and whole blood samples from a subset (n=49) for antibodies reactive to, and characteristic DNA fragments of, Ehrlichia spp., as well as characteristic DNA fragments of Babesia spp. Amblyomma americanum, the most common tick identified, was found on a majority (56/62; 90%) of bears and accounted for 697/1,048 (66.5%) of all ticks recovered. Other ticks included Dermacentor variabilis (338/1,048; 32.3%) from 36 bears, Amblyomma maculatum (9/1,048; 0.9%) from three bears, and Ixodes scapularis (4/1,048; 0.4%) from three bears. Antibodies reactive to Ehrlichia spp. were detected in every bear tested (49/49; 100%); maximum inverse titers to Ehrlichia chaffeensis ranged from 64-4,096 (geometric mean titer 1,525). However, PCR failed to identify active infection with E. chaffeensis, Ehrlichia ewingii, or an Ehrlichia ruminantium-like agent. Infection with Babesia spp. was detected by PCR in 3/49 (6%) bears. Together these data confirm that tick infestations and infection with tick-borne disease agents are common in bears in the southern US. The significance of these infestations and infections to the health of bears, if any, and the identity of the Ehrlichia spp. responsible for the antibody reactivity seen, warrant further evaluation. PMID- 28657862 TI - A poly(glycerol sebacate) based photo/thermo dual curable biodegradable and biocompatible polymer for biomedical applications. AB - Due to its biomimetic mechanical properties to soft tissues, excellent biocompatibility and biodegradability, poly (glycerol sebacate) (PGS) has emerged as a representative bioelastomer and been widely used in biomedical engineering. However, the typical curing of PGS needs high temperature (>120 degrees C), high vacuum (>1 Torr), and long duration (>12 h), which limit its further applications. Accordingly, we designed, synthesized and characterized a photo/thermo dual curable polymer based on PGS. Treatment of PGS with 2 isocyanatoethyl methacrylate without additional reagents readily produced a methacrylated PGS (PGS-IM). Photo-curing of PGS-IM for 10 min at room temperature using salt leaching method efficiently produced porous scaffolds with a thickness up to 1 mm. PGS-IM was adapt to thermo-curing as well. The combination of photo and thermo curing provided a further way to modulate the properties of resultant porous scaffolds. Interestingly, photo-cured scaffolds exhibited hierarchical porous structures carrying extensive micropores with a diameter from several to hundreds micrometers. All the scaffolds showed good elasticity and biodegradability. In addition, PGS-IM exhibited good compatibility with L929 fibroblast cells. We expect this new PGS based biomaterial will have a wide range of biomedical applications. PMID- 28657861 TI - Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy. PMID- 28657863 TI - Carbohydrate intake and training efficacy - a randomized cross-over study. AB - Carbohydrate (CHO) availability during endurance exercise seems to attenuate exercise-induced perturbations of cellular homeostasis and might consequently diminish the stimulus for training adaptation. Therefore, a negative effect of CHO intake on endurance training efficacy seems plausible. This study aimed to test the influence of carbohydrate intake on the efficacy of an endurance training program on previously untrained healthy adults. A randomized cross-over trial (8-week wash-out period) was conducted in 23 men and women with two 8-week training periods (with vs. without intake of 50g glucose before each training bout). Training intervention consisted of 4x45 min running/walking sessions/week at 70% of heart rate reserve. Exhaustive, ramp-shaped exercise tests with gas exchange measurements were conducted before and after each training period. Outcome measures were maximum oxygen uptake (VO2max) and ventilatory anaerobic threshold (VT). VO2max and VT increased after training regardless of CHO intake (VO2max: Non-CHO 2.6 +/- 3.0 ml*min-1*kg-1 p = 0.004; CHO 1.4 +/- 2.5 ml*min-1*kg 1 p = 0.049; VT: Non-CHO 4.2 +/- 4.2 ml*min-1*kg-1 p < 0.001; CHO 3.0 +/- 4.2 ml*min-1*kg-1 p = 0.003). The 95% confidence interval (CI) for the difference between conditions was between +0.1 and +2.1 ml*min-1*kg-1 for VO2max and between -1.2 and +3.1 for VT. It is concluded that carbohydrate intake could potentially impair the efficacy of an endurance training program. PMID- 28657864 TI - Two-Year Outcome after Endovascular Treatment for Stroke. PMID- 28657865 TI - Noninvasive Brain Stimulation for Depression - The Devil Is in the Dosing. PMID- 28657866 TI - Case 20-2017 - A 48-Year-Old Man with Weight Loss, Confusion, Skin Lesions, and Pancytopenia. PMID- 28657867 TI - Machine Learning and Prediction in Medicine - Beyond the Peak of Inflated Expectations. PMID- 28657868 TI - Regulatory Review of New Therapeutic Agents. PMID- 28657869 TI - Decision Aids and Elective Joint Replacement - How Knowledge Affects Utilization. PMID- 28657872 TI - Desmoid Tumors and Celecoxib with Sorafenib. PMID- 28657871 TI - Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression. AB - BACKGROUND: We compared transcranial direct-current stimulation (tDCS) with a selective serotonin-reuptake inhibitor for the treatment of depression. METHODS: In a single-center, double-blind, noninferiority trial involving adults with unipolar depression, we randomly assigned patients to receive tDCS plus oral placebo, sham tDCS plus escitalopram, or sham tDCS plus oral placebo. The tDCS was administered in 30-minute, 2-mA prefrontal stimulation sessions for 15 consecutive weekdays, followed by 7 weekly treatments. Escitalopram was given at a dose of 10 mg per day for 3 weeks and 20 mg per day thereafter. The primary outcome measure was the change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score (range, 0 to 52, with higher scores indicating more depression). Noninferiority of tDCS versus escitalopram was defined by a lower boundary of the confidence interval for the difference in the decreased score that was at least 50% of the difference in the scores with placebo versus escitalopram. RESULTS: A total of 245 patients underwent randomization, with 91 being assigned to escitalopram, 94 to tDCS, and 60 to placebo. In the intention-to-treat analysis, the mean (+/-SD) decrease in the score from baseline was 11.3+/-6.5 points in the escitalopram group, 9.0+/-7.1 points in the tDCS group, and 5.8+/-7.9 points in the placebo group. The lower boundary of the confidence interval for the difference in the decrease for tDCS versus escitalopram (difference, -2.3 points; 95% confidence interval [CI], -4.3 to -0.4; P=0.69) was lower than the noninferiority margin of -2.75 (50% of placebo minus escitalopram), so noninferiority could not be claimed. Escitalopram and tDCS were both superior to placebo (difference vs. placebo, 5.5 points [95% CI, 3.1 to 7.8; P<0.001] and 3.2 points [95% CI, 0.7 to 5.5; P=0.01], respectively). Patients receiving tDCS had higher rates of skin redness, tinnitus, and nervousness than did those in the other two groups, and new-onset mania developed in 2 patients in the tDCS group. Patients receiving escitalopram had more frequent sleepiness and obstipation than did those in the other two groups. CONCLUSIONS: In a single-center trial, tDCS for the treatment of depression did not show noninferiority to escitalopram over a 10-week period and was associated with more adverse events. (Funded by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and others; ELECT-TDCS ClinicalTrials.gov number, NCT01894815 .). PMID- 28657870 TI - A Placebo-Controlled Trial of Antibiotics for Smaller Skin Abscesses. AB - BACKGROUND: Uncomplicated skin abscesses are common, yet the appropriate management of the condition in the era of community-associated methicillin resistant Staphylococcus aureus (MRSA) is unclear. METHODS: We conducted a multicenter, prospective, double-blind trial involving outpatient adults and children. Patients were stratified according to the presence of a surgically drainable abscess, abscess size, the number of sites of skin infection, and the presence of nonpurulent cellulitis. Participants with a skin abscess 5 cm or smaller in diameter were enrolled. After abscess incision and drainage, participants were randomly assigned to receive clindamycin, trimethoprim sulfamethoxazole (TMP-SMX), or placebo for 10 days. The primary outcome was clinical cure 7 to 10 days after the end of treatment. RESULTS: We enrolled 786 participants: 505 (64.2%) were adults and 281 (35.8%) were children. A total of 448 (57.0%) of the participants were male. S. aureus was isolated from 527 participants (67.0%), and MRSA was isolated from 388 (49.4%). Ten days after therapy in the intention-to-treat population, the cure rate among participants in the clindamycin group was similar to that in the TMP-SMX group (221 of 266 participants [83.1%] and 215 of 263 participants [81.7%], respectively; P=0.73), and the cure rate in each active-treatment group was higher than that in the placebo group (177 of 257 participants [68.9%], P<0.001 for both comparisons). The results in the population of patients who could be evaluated were similar. This beneficial effect was restricted to participants with S. aureus infection. Among the participants who were initially cured, new infections at 1 month of follow-up were less common in the clindamycin group (15 of 221, 6.8%) than in the TMP-SMX group (29 of 215 [13.5%], P=0.03) or the placebo group (22 of 177 [12.4%], P=0.06). Adverse events were more frequent with clindamycin (58 of 265 [21.9%]) than with TMP-SMX (29 of 261 [11.1%]) or placebo (32 of 255 [12.5%]); all adverse events resolved without sequelae. One participant who received TMP SMX had a hypersensitivity reaction. CONCLUSIONS: As compared with incision and drainage alone, clindamycin or TMP-SMX in conjunction with incision and drainage improves short-term outcomes in patients who have a simple abscess. This benefit must be weighed against the known side-effect profile of these antimicrobials. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00730028 .). PMID- 28657873 TI - Subclinical Hypothyroidism. PMID- 28657875 TI - Irritable Bowel Syndrome. PMID- 28657876 TI - Air Pollution Still Kills. PMID- 28657877 TI - Eye Injury from a Firecracker. PMID- 28657878 TI - Air Pollution and Mortality in the Medicare Population. AB - BACKGROUND: Studies have shown that long-term exposure to air pollution increases mortality. However, evidence is limited for air-pollution levels below the most recent National Ambient Air Quality Standards. Previous studies involved predominantly urban populations and did not have the statistical power to estimate the health effects in underrepresented groups. METHODS: We constructed an open cohort of all Medicare beneficiaries (60,925,443 persons) in the continental United States from the years 2000 through 2012, with 460,310,521 person-years of follow-up. Annual averages of fine particulate matter (particles with a mass median aerodynamic diameter of less than 2.5 MUm [PM2.5]) and ozone were estimated according to the ZIP Code of residence for each enrollee with the use of previously validated prediction models. We estimated the risk of death associated with exposure to increases of 10 MUg per cubic meter for PM2.5 and 10 parts per billion (ppb) for ozone using a two-pollutant Cox proportional-hazards model that controlled for demographic characteristics, Medicaid eligibility, and area-level covariates. RESULTS: Increases of 10 MUg per cubic meter in PM2.5 and of 10 ppb in ozone were associated with increases in all-cause mortality of 7.3% (95% confidence interval [CI], 7.1 to 7.5) and 1.1% (95% CI, 1.0 to 1.2), respectively. When the analysis was restricted to person-years with exposure to PM2.5 of less than 12 MUg per cubic meter and ozone of less than 50 ppb, the same increases in PM2.5 and ozone were associated with increases in the risk of death of 13.6% (95% CI, 13.1 to 14.1) and 1.0% (95% CI, 0.9 to 1.1), respectively. For PM2.5, the risk of death among men, blacks, and people with Medicaid eligibility was higher than that in the rest of the population. CONCLUSIONS: In the entire Medicare population, there was significant evidence of adverse effects related to exposure to PM2.5 and ozone at concentrations below current national standards. This effect was most pronounced among self-identified racial minorities and people with low income. (Supported by the Health Effects Institute and others.). PMID- 28657879 TI - Achenbach's Syndrome. PMID- 28657880 TI - Home Modifications among Community-Dwelling Older Adults: A Closer Look at Race and Ethnicity. AB - This study investigated racial and ethnic differences in home modification use. Data from the 2011 National Health and Aging Trends Study were used (n=6,764). Compared with non-Hispanic Whites, Hispanics were less likely to have a grab bar (odds ratio (OR) = 0.6), bath seat (OR = 0.8), or raised toilet (OR = 0.6). Non Hispanic Blacks were less likely to have a grab bar (OR = 0.7) or bath seat (OR = 0.7) than non-Hispanic Whites, but more likely to have a raised toilet (OR = 1.3). English proficiency largely explained ethnic differences, while health status partially accounted for racial disparities. PMID- 28657881 TI - First, Do No Harm: Referring Primary Care Patients with Depression to an Internet Support Group. AB - BACKGROUND: Internet Support Groups (ISGs) offer people easy access to information regarding depression as well as support from others who are either currently suffering from depression or have previously suffered from depression. The safety and efficacy of ISGs for people with depression have not been thoroughly studied. INTRODUCTION: The safety and helpfulness of a depression ISG were assessed by analyzing pre- and postintervention depressive symptoms, other psychological outcomes, and participant ratings of helpfulness. MATERIALS AND METHODS: Participants were recruited through self-referral from six primary care offices. Participants were given access to a depression ISG and participated in an ISG for 6 weeks. RESULTS: Thirty-four (n = 34) participants enrolled in the study (mean age = 32.53, standard deviation [SD] = 16.10). Depressive symptoms approached significance for decreasing over time and self-efficacy increased over time. No self-harm occurred over the course of the study, but two participants developed self-harm ideation. Ratings of ISG helpfulness were mixed. DISCUSSION: Primary care patients participating in depression ISGs reported few adverse experiences directly related to the ISG. Depressive symptoms and self-efficacy have beneficial findings while ratings of helpfulness were mixed. CONCLUSIONS: Primary care patients can benefit from the use of an ISG. This could be particularly pertinent to people in rural settings where mental health resources are not as available. An ISG offers a low-cost and easily accessible resource for primary care patients with depression. PMID- 28657882 TI - Does optimism weaken the negative effects of being lonely on suicide risk? AB - The present study investigated loneliness and optimism as predictors of suicide risk, specifically, depressive symptoms and suicidal ideation, in 457 Hungarian college students. Beyond the expected role of loneliness in suicide risk, being optimistic buffered the positive association between loneliness and suicide. The findings implicate the importance of fostering optimism for potentially lowering suicide risk among lonely college students. PMID- 28657883 TI - Clostridium difficile Toxin Biology. AB - Clostridium difficile is the cause of antibiotics-associated diarrhea and pseudomembranous colitis. The pathogen produces three protein toxins: C. difficile toxins A (TcdA) and B (TcdB), and C. difficile transferase toxin (CDT). The single-chain toxins TcdA and TcdB are the main virulence factors. They bind to cell membrane receptors and are internalized. The N-terminal glucosyltransferase and autoprotease domains of the toxins translocate from low pH endosomes into the cytosol. After activation by inositol hexakisphosphate (InsP6), the autoprotease cleaves and releases the glucosyltransferase domain into the cytosol, where GTP-binding proteins of the Rho/Ras family are mono-O glucosylated and, thereby, inactivated. Inactivation of Rho proteins disturbs the organization of the cytoskeleton and affects multiple Rho-dependent cellular processes, including loss of epithelial barrier functions, induction of apoptosis, and inflammation. CDT, the third C. difficile toxin, is a binary actin ADP-ribosylating toxin that causes depolymerization of actin, thereby inducing formation of the microtubule-based protrusions. Recent progress in understanding of the toxins' actions include insights into the toxin structures, their interaction with host cells, and functional consequences of their actions. PMID- 28657884 TI - Evolutionary Origins of Two-Barrel RNA Polymerases and Site-Specific Transcription Initiation. AB - Evolution-related multisubunit RNA polymerases (RNAPs) carry out RNA synthesis in all domains life. Although their catalytic cores and fundamental mechanisms of transcription elongation are conserved, the initiation stage of the transcription cycle differs substantially in bacteria, archaea, and eukaryotes in terms of the requirements for accessory factors and details of the molecular mechanisms. This review focuses on recent insights into the evolution of the transcription apparatus with regard to (a) the surprisingly pervasive double-Psi beta-barrel active-site configuration among different nucleic acid polymerase families, (b) the origin and phylogenetic distribution of TBP, TFB, and TFE transcription factors, and PMID- 28657886 TI - The Critical Roles of Polysaccharides in Gut Microbial Ecology and Physiology. AB - The human intestine harbors a dense microbial ecosystem (microbiota) that is different between individuals, dynamic over time, and critical for aspects of health and disease. Dietary polysaccharides directly shape the microbiota because of a gap in human digestive physiology, which is equipped to assimilate only proteins, lipids, simple sugars, and starch, leaving nonstarch polysaccharides as major nutrients reaching the microbiota. A mutualistic role of gut microbes is to digest dietary complex carbohydrates, liberating host-absorbable energy via fermentation products. Emerging data indicate that polysaccharides play extensive roles in host-gut microbiota symbiosis beyond dietary polysaccharide digestion, including microbial interactions with endogenous host glycans and the importance of microbial polysaccharides. In this review, we consider multiple mechanisms through which polysaccharides mediate aspects of host-microbe symbiosis in the gut, including some affecting health. As host and microbial metabolic pathways are intimately connected with diet, we highlight the potential to manipulate this system for health. PMID- 28657887 TI - Lessons from the Environmental Antibiotic Resistome. AB - Antibiotic resistance is a global public health issue of growing proportions. All antibiotics are susceptible to resistance. The evidence is now clear that the environment is the single largest source and reservoir of resistance. Soil, aquatic, atmospheric, animal-associated, and built ecosystems are home to microbes that harbor antibiotic resistance elements and the means to mobilize them. The diversity and abundance of resistance in the environment is consistent with the ancient origins of antibiotics and a variety of studies support a long natural history of associated resistance. The implications are clear: Understanding the evolution of resistance in the environment, its diversity, and mechanisms is essential to the management of our existing and future antibiotic resources. PMID- 28657888 TI - The RNAi Universe in Fungi: A Varied Landscape of Small RNAs and Biological Functions. AB - RNA interference (RNAi) is a conserved eukaryotic mechanism that uses small RNA molecules to suppress gene expression through sequence-specific messenger RNA degradation, translational repression, or transcriptional inhibition. In filamentous fungi, the protective function of RNAi in the maintenance of genome integrity is well known. However, knowledge of the regulatory role of RNAi in fungi has had to wait until the recent identification of different endogenous small RNA classes, which are generated by distinct RNAi pathways. In addition, RNAi research on new fungal models has uncovered the role of small RNAs and RNAi pathways in the regulation of diverse biological functions. In this review, we give an up-to-date overview of the different classes of small RNAs and RNAi pathways in fungi and their roles in the defense of genome integrity and regulation of fungal physiology and development, as well as in the interaction of fungi with biotic and abiotic environments. PMID- 28657889 TI - Evolution of Mating in the Saccharomycotina. AB - The fungal phylum Ascomycota comprises three subphyla: Saccharomycotina, Pezizomycotina, and Taphrinomycotina. In many Saccharomycotina species, cell identity is determined by genes at the MAT (mating-type) locus; mating occurs between MATa and MATalpha cells. Some species can switch between MATa and MATalpha mating types. Switching in the Saccharomycotina originated in the common ancestor of the Saccharomycetaceae, Pichiaceae, and Metschnikowiaceae families, as a flip/flop mechanism that inverted a section of chromosome. Switching was subsequently lost in the Metschnikowiaceae, including Candida albicans, but became more complex in the Saccharomycetaceae when the mechanism changed from inversion to copy-and-paste between HML/HMR and MAT. Based on their phylogenetic closeness and the similarity of their MTL (mating-type like) loci, some Metschnikowia species may provide useful models for the sexual cycles of Candida species. Conservation of synteny demonstrates that, despite changes in its gene content, a single orthologous locus (MAT/MTL) has controlled cell type throughout ascomycete evolution. PMID- 28657885 TI - Evolutionary Genomics of Defense Systems in Archaea and Bacteria. AB - Evolution of bacteria and archaea involves an incessant arms race against an enormous diversity of genetic parasites. Accordingly, a substantial fraction of the genes in most bacteria and archaea are dedicated to antiparasite defense. The functions of these defense systems follow several distinct strategies, including innate immunity; adaptive immunity; and dormancy induction, or programmed cell death. Recent comparative genomic studies taking advantage of the expanding database of microbial genomes and metagenomes, combined with direct experiments, resulted in the discovery of several previously unknown defense systems, including innate immunity centered on Argonaute proteins, bacteriophage exclusion, and new types of CRISPR-Cas systems of adaptive immunity. Some general principles of function and evolution of defense systems are starting to crystallize, in particular, extensive gain and loss of defense genes during the evolution of prokaryotes; formation of genomic defense islands; evolutionary connections between mobile genetic elements and defense, whereby genes of mobile elements are repeatedly recruited for defense functions; the partially selfish and addictive behavior of the defense systems; and coupling between immunity and dormancy induction/programmed cell death. PMID- 28657890 TI - Pulmonary hyalinosis in captive sugar gliders ( Petaurus breviceps). AB - Pulmonary hyalinosis is an idiopathic, typically incidental lesion of old dogs, characterized by multifocal aggregates of epithelioid and multinucleate macrophages that surround periodic acid-Schiff (PAS)-positive hyaline material in airways. Lung lesions resembling pulmonary hyalinosis were observed in 6 captive adult sugar gliders ( Petaurus breviceps; 5 females and 1 male) in a retrospective review of 18 autopsied animals. Clinical signs for 3 of the sugar gliders included lethargy, tachypnea, and dyspnea. At autopsy, 5 of 6 animals had comorbid lesions that were the primary cause of death. Gross pulmonary lesions were characterized by mildly firm, discolored, vaguely nodular areas of parenchyma. Histologic examination of the lung revealed granulomatous inflammation with intracellular and extracellular amphophilic hyaline bodies within alveoli and airways. Hyaline bodies were positive for PAS and oil red O staining, blue via crystal violet staining, and displayed birefringence under polarized light, similar to findings in dogs with pulmonary hyalinosis. PMID- 28657891 TI - Associations of Prenatal Urinary Bisphenol A Concentrations with Child Behaviors and Cognitive Abilities. AB - BACKGROUND: Prenatal bisphenol A (BPA) exposure has been associated with adverse neurodevelopment in epidemiological studies. However, prior studies had limited statistical power to examine sex-specific effects, and few examined child cognition. OBJECTIVES: We estimated the association between prenatal BPA exposure and child neurobehavior at 3 y of age in a prospective cohort of 812 mothers and their children. METHODS: We measured BPA concentration in urine samples collected at ~12 wk gestation among women enrolled in a 10-city Canadian cohort study. At approximately 3 y of age, we assessed children's cognitive abilities with the Wechsler Primary and Preschool Scale of IntelligenceTM-III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF P). Parents reported children's behavior using the Behavior Assessment System for Children-2 (BASC-2) and the Social Responsiveness ScaleTM-2 (SRS-2). We estimated covariate-adjusted differences in neurobehavioral outcomes with a doubling in BPA concentration and sex-specific associations. RESULTS: BPA was not associated with WPPSI-III scores; child sex did not modify these associations. The association between BPA and BRIEF-P scores was modified by child sex (BPA*sex p values<=0.03). For example, a doubling of BPA concentration was associated with 1 point (95% CI: 0.3, 1.7) poorer working memory in boys and 0.5-point (95% CI: 1.1, 0.1) better scores in girls. BPA was not associated with most BASC-2 scales; however, it was associated with more internalizing and somatizing behaviors in boys, but not in girls (BPA*sex p&-values<=0.08). A doubling of BPA concentration was associated with poorer SRS-2 scores [beta=0.3 ( 95% CI: 0, 0.7)]; this association was not modified by sex. CONCLUSION: Prenatal urinary BPA concentration was associated with some aspects of child behavior in this cohort, and some associations were stronger among boys. https://doi.org/10.1289/EHP984. PMID- 28657893 TI - Up in the Air: Does Ground-Level Ozone Trigger Kawasaki Disease? PMID- 28657892 TI - Plasma Perfluoroalkyl and Polyfluoroalkyl Substances Concentration and Menstrual Cycle Characteristics in Preconception Women. AB - BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent synthetic chemicals that are widely used in industrial applications and often detectable in humans. In rats, PFASs can interfere with the estrous cycle. In humans, menstruation has been viewed as a proxy of female fecundity, and periodic menstruation plays a critical role in endometrial sloughing in the absence of pregnancy and in preparing for embryo implantation. OBJECTIVES: We investigated the association between PFAS exposure and menstrual cycle characteristics in women who plan to become pregnant. METHODS: Plasma level of 10 PFASs was measured in 950 women who were attempting to become pregnant and recruited in two preconception care clinics in Shanghai, China, from August 2013 to April 2015. Information on menstrual cycle characteristics was collected by questionnaires. Associations between PFAS levels and menstrual cycle regularity, length, and bleeding volume were examined using multiple logistic regression models. RESULTS: Pre-pregnant women with higher levels of log-transformed perfluorooctanate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonate (PFHxS) had increased odds of self-reported history of irregular menstrual cycle [PFOA-adjusted odds ratio (OR)=1.52 (95% CI: 1.08, 2.15); PFOS OR=1.29 (95% CI: 0.98, 1.70); PFNA OR=1.50 (95% CI: 1.03, 2.07); PFHxS OR=1.80 (95% CI: 1.17, 2.77)] and long menstrual cycle [PFOA OR=1.50 (95% CI: 1.06, 2.10); PFOS OR=1.34 (95% CI: 1.02, 1.75); PFNA OR=1.49 (95% CI: 1.05, 2.11); PFHxS OR=1.73 (95% CI: 1.13, 2.65)]. Log-transformed PFOA, PFOS, PFNA. and PFHxS levels were negatively associated with self-reported history of menorrhagia [PFOA OR=0.37 (95% CI: 0.21, 0.65); PFOS OR=0.57 (95% CI: 0.37, 0.90); PFNA OR=0.47 (95% CI: 0.26, 0.86); PFHxS OR=0.14 (95% CI: 0.06, 0.36)]. CONCLUSIONS: Certain PFASs are associated with abnormal menstruation in humans. https://doi.org/10.1289/EHP1203. PMID- 28657895 TI - Clinician Panel Recommendations for Use of Negative Pressure Wound Therapy with Instillation. AB - Addition of an instilled topical wound solution to negative pressure wound therapy (NPWT) is designed to facilitate regular wound cleansing to help improve outcomes of some complex wounds, but the addition of instillation to NPWT adds a level of complexity to the wound care process. The paucity of knowledge and experience with instillation may affect optimal use of this treatment modality. In an effort to address this knowledge gap, a 2-day panel meeting of nurses (N = 11) with experience using negative pressure wound therapy with instillation and dwell time (NPWTi-d) was convened to discuss their usage recommendations for managing wounds with this treatment modality in the acute care setting. Panelists reviewed available evidence and presented recommendations for managing wounds treated with NPWTi-d. Panelists agreed NPWTi-d is primarily suited to prepare surgical or nonsurgical wounds for delayed primary closure and preparing/protecting periwound skin improves maintenance of a tight seal. Educating a team of nurses on basic NPWTi-d troubleshooting, providing a short checklist of tasks to perform every shift, and organizing needed supplies and resources may help continuity of care and prevent problems. Panelists also emphasized the im- portance of wound assessment and documentation and recommend educating the patient, family members, and other members of the patient-care team. Research to compare the safety, ef cacy, and effectiveness of NPWTi-d and other irrigation techniques on patient outcomes and research to validate these recommendations is needed. PMID- 28657894 TI - Humoral Immunity in Arsenic-Exposed Children in Rural Bangladesh: Total Immunoglobulins and Vaccine-Specific Antibodies. AB - BACKGROUND: Early-life arsenic exposure has been associated with reduced cell mediated immunity, but little is known about its effects on humoral immunity. OBJECTIVE: We evaluated whether prenatal and childhood arsenic exposure was associated with humoral immune function in school-aged children. METHODS: Children born in a prospective mother-child cohort in rural Bangladesh were immunized with measles, mumps, and rubella (MMR) vaccines at 9 years of age (n=525). Arsenic exposure was assessed in urine (U-As), from mothers during pregnancy and their children at 4.5 and 9 years of age. Total IgG (tIgG), tIgE, tIgA, and MMR-specific IgG concentrations were measured in plasma using immunoassays. RESULTS: Arsenic exposure was positively associated with child tIgG and tIgE, but not tIgA. The association with tIgG was mainly apparent in boys (p for interaction=0.055), in whom each doubling of maternal U-As was related to an increase in tIgG by 28 mg/dL. The associations of U-As at 9 years with tIgG and tIgE were evident in underweight children (p for interaction <0.032). Childhood arsenic exposure tended to impair mumps-specific vaccine response, although the evaluation was complicated by high preimmunization titers. Postimmunization mumps specific IgG titers tended to decrease with increasing U-As at 4.5 and 9 years of age [regression coefficient (beta)=-0.16; 95% confidence interval (CI): -0.33, 0.01; p=0.064 and beta=-0.12; 95% CI: -0.27, -0.029; p=0.113, respectively) in 25% children with the lowest preexisting mumps-specific IgG titers. CONCLUSIONS: Arsenic exposure increased tIgG and tIgE in plasma, and tended to decrease mumps specific IgG in children at 9 years of age. https://doi.org/10.1289/EHP318. PMID- 28657896 TI - The Effect of a Patient Education Intervention on Knowledge and Venous Ulcer Recurrence: Results of a Prospective Intervention and Retrospective Analysis. AB - Patient education may help reduce the recurrence of venous ulcers. To examine the effectiveness of a home-based patient education program on disease and self-care knowledge and ulcer recurrence rates, a prospective study and retrospective analysis of patient outcomes was conducted among 3 groups of patients. Group A (n = 28) had received the education intervention and assessments as part of an earlier study and were recruited to participate in a 36-week follow-up.Group B patients (n = 22) participated in the prospective component of this study and were assessed after 2, 9, and 36 weeks. Data from control group patients (group C, n = 45) were abstracted following a retrospective chart review. Group A and B participants had a healing venous ulcer for at least 5 weeks before the education intervention. Group C patients had been treated for 41 weeks, had a positive wound healing trajectory until week 5, and did not receive additional education. Demographic data for each group were abstracted from the patients' charts. The educational intervention consisted of a 45-minute, one-on-one presentation in the patient's home that included visual aids, a brochure, and a handout addressing important aspects of care and activity. Pre- and post-intervention knowledge was assessed using the Checklist for Patient Learning, which includes 2 subscales to measure knowledge of disease process (6 items, range 0-6) and knowledge of self care activities to prevent recurrence (7 items, range 0-7), with higher scores indicating more knowledge. Wound healing and recurrence, as observed by the patient's wound care provider and reported by the patient, was noted as Yes or No. Descriptive statistics and unpaired t-tests were used to analyze the data. In all 3 groups, >50% of patients were female and 65 to 74 years of age. In group A and B, knowledge scores at the 36-week assessment were higher than those at baseline (4.13 +/- 0.437 and 10.7 +/- 0.421, respectively, for group A and 4.22 +/- 0.231 and 10.9 +/- 0.871, respectively, for group B). The 36-week scores did not differ significantly between groups A and B (P = .687). Recurrence rates were lower in group A and B (50% and 45%, respectively) than in the control group (69%). The results of this study confirm patient education improves disease and self-care knowledge scores and may reduce venous ulcer recurrence rates. Studies including larger patient cohorts and longer follow-up times are warranted. PMID- 28657897 TI - A Retrospective Review of Adverse Events Related to Diabetic Foot Ulcers. AB - The risk of adverse events (AEs) such as infection and amputation related to diabetic foot ulcers (DFUs) has been studied, but less is known about rate of other AEs such as falls. As part of a quality improvement project, AEs in veterans with diabetes mellitus (DM) with and without a DFU were examined. Demographic data including ICD-9 codes, AEs, and comorbidities for all patients with a diagnosis of DM and/or DFU treated between 2009 and 2014 at the James A. Haley Veterans' Hospital, Tampa, FL, were reviewed retrospectively utilizing the Corporate Data Warehouse (CDW) database. Identifiable protected health information data using patient scrambled social security numbers were collected from the CDW to allow the longitudinal data to be linked at the unique patient level. Descriptive statistics (eg, mean, standard deviation) were determined for demographics, AE, and comorbidities. Adjusted models of AE association with DM and DFU were analyzed using regression modeling via a statistical analysis system. The models were adjusted for age, race, gender, marital status, and comorbidities. Data extracted included individuals diagnosed with diabetes with a DFU (n = 3238, average age 66.0 +/- 10.6 years) and diabetes without DFU (n= 41 324, average age 64.4 +/- 11.5 years). Participants were mostly Caucasian in both the DFU and non-DFU cohorts (2655 [82.0%] and 32 269 [78.1%], respectively) and male (3129 [96.6%] and 39 580 [95.8%], respectively). The most common comorbidities in this population were peripheral vascular disease (PVD, 39.5%) and peripheral neuropathy (PN, 23.2%). PVD was more common in veterans with (39.5%) than without a DFU (9.2%). Compared to individuals with DM, those with DM and DFU were significantly more likely to experience an infection (OR = 9.43; 95% CI 8.54-10.4), undergo an amputation (OR = 7.40; 95% CI 6.16-8.89), or experience a fracture (OR = 3.65; 95% CI 2.59-5.15) or fall (OR = 2.26; 95% CI 1.96-2.60) (P <.01 for all variables). Although the increased risk of infection and amputation among persons with DFUs has been documented, less is known about the rate of falls and fractures. The current findings will serve as baseline data for future implementation trials to reduce DFU-associated AEs, and clinicians may want to consider expanding DFU patient education efforts to include fall risk. PMID- 28657898 TI - Negative Pressure Wound Therapy for a Complicated Abdominal Laparotomy in Neonatal Necrotizing Enterocolitis: A Case Report. AB - Necrotizing enterocolitis (NEC) is the most common surgical emergency in neonatal intensive care units, and patients who require surgery have high mortality and morbidity rates. The utility of negative pressure in the management of adults with complicated abdominal wounds has been documented, but there are few reports describing the use of negative pressure wound therapy (NPWT) in children or following neonatal surgery. The case of a 6 day old, 5-weeks premature neonate with NEC is presented. An exploratory midline laparotomy was performed on day 3 of life owing to rectal bleeding and abdominal distension that did not respond to gastric decompression, bowel rest, and intravenous antibiotics. Ten (10) cm of necrosis in the distal ileum were noted and resected; in addition, an ileostomy was performed, and a Penrose drain was left in the surgical site. On postoperative day 5, the laparotomy dehisced. Continuous NPWT (50 mm Hg) was initiated and changed owing to patient tolerance to intermittent therapy (5 minutes on, 30 seconds off) at 80 mm Hg. By postoperative day 11, granulation tissue formation was complete. No surgical procedures were required for the complete closure of the abdominal wall, and no adverse reactions were noted. The baby was discharged from the hospital on postop day 15. In this patient, the use of negative pressure was found to be safe and facilitated management of a complicated abdominal wound in the presence of a stoma and the formation of healthy granulation tissue. Additional research is needed to help clinicians provide optimal, evidence-based care for dehisced wounds in this vulnerable population. PMID- 28657899 TI - A Descriptive, Cross-sectional Survey of Turkish Nurses' Knowledge of Pressure Ulcer Risk, Prevention, and Staging. AB - Nurses' knowledge of pressure ulcer (PU) prevention and management is an important first step in the provision of optimal care. To evaluate PU prevention/risk, staging, and wound description knowledge, a descriptive, cross sectional survey was conducted among nurses working in an acute care Turkish hospital. The survey instrument was a modified and translated version of the Pieper Pressure Ulcer Knowledge Test (PUKT), and its validity and reliability were established. Nurses completed a Personal Characteristics Form, including sociodemographic information and exposure to educational presentations and information about and experience with PUs, followed by the 49-item modified PUKT which includes 33 prevention/risk items, 9 staging items, and 7 wound description items. All items are true/false questions with an I don't know option (scoring: minimum 0, maximum 49). Correct answers received 1 point and incorrect/unknown answers received 0 points. The paper-pencil questionnaires were distributed by 2 researchers to all nurses in the participating hospital and completed by those willing to be included. Responses were analyzed using descriptive statistics. Pearson's correlation test was used to examine the relationship between quantitative variables, and mean scores were compared using the Mann-Whitney U and Kruskal-Wallis tests. Among the 308 participating nurses (mean age 29.5 +/- 8.1 [range 19-56] years) most were women (257, 83.4%) with 7.3 +/- 7.8 (range 1 36) years of experience. The mean knowledge score for the entire sample was 29.7 +/- 6.7 (range 8-42). The overall percentage of correct answers was 60.6% to 61.8% for PU prevention/risk assessment, 60% for wound description, and 56.6% for PU staging. Knowledge scores were significantly (P <.05) higher for participants who attended at least 1 lecture/conference/course on PUs in the last year, read articles/books about PUs, cared for patients with PUs, or believed their patients were at risk for PU development. Most participants (180, 58.4%) scored 60% or more correct; 8 (2.6%) correctly answered 80% or more of the items. The lowest number of correct answers was for the item, "Bunny boots and gel pads relieve pressure on the heels" (22, 7.1%). The results of this study suggest education and experience caring for patients who are at risk for or have a PU affect nurses' knowledge. This study, and additional research examining nurse knowledge, will help the development of much-needed education programs. PMID- 28657900 TI - Brain ageing changes proteoglycan sulfation, rendering perineuronal nets more inhibitory. AB - Chondroitin sulfate (CS) proteoglycans in perineuronal nets (PNNs) from the central nervous system (CNS) are involved in the control of plasticity and memory. Removing PNNs reactivates plasticity and restores memory in models of Alzheimer's disease and ageing. Their actions depend on the glycosaminoglycan (GAG) chains of CS proteoglycans, which are mainly sulfated in the 4 (C4S) or 6 (C6S) positions. While C4S is inhibitory, C6S is more permissive to axon growth, regeneration and plasticity. C6S decreases during critical period closure. We asked whether there is a late change in CS-GAG sulfation associated with memory loss in aged rats. Immunohistochemistry revealed a progressive increase in C4S and decrease in C6S from 3 to 18 months. GAGs extracted from brain PNNs showed a large reduction in C6S at 12 and 18 months, increasing the C4S/C6S ratio. There was no significant change in mRNA levels of the chondroitin sulfotransferases. PNN GAGs were more inhibitory to axon growth than those from the diffuse extracellular matrix. The 18-month PNN GAGs were more inhibitory than 3-month PNN GAGs. We suggest that the change in PNN GAG sulfation in aged brains renders the PNNs more inhibitory, which lead to a decrease in plasticity and adversely affect memory. PMID- 28657901 TI - Increased intraepithelial CD3+ T-lymphocytes and high PD-L1 expression on tumor cells are associated with a favorable prognosis in esophageal squamous cell carcinoma and allow prognostic immunogenic subgrouping. AB - Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis and additional therapeutic strategies must be implemented to optimize ESCC treatment. Meanwhile, the important biologic role and potential prognostic and therapeutic implications of a tumors immunologic microenvironment (IM) have been recognized in various cancers.In order to investigate the contexture and the prognostic relevance of the IM in ESCC, we immunohistochemically evaluated the extent of overall/intraepithelial TILs (CD3+/CD8+) and of PD-1 / PD-L1 expression in a cohort of 125 therapy-naive ESCCs, additionally assessing PD-L1 copy number status via fluorescence in-situ hybridization.High intraepithelial CD3+ TILs (CD3ihigh) and high PD-L1 expression on tumor cells (PD-L1high) were each significantly associated with improved overall- (OS) (CD3+: p = 0.019; PD-L1: p = 0.028), disease specific- (DSS) (CD3+: p = 0.05; PD-L1: p = 0.006) and disease free survival (DFS) (CD3+: p = 0.009; PD L1: p < 0.001). CD3ihigh- and PD-L1high cases were significantly associated with one another (p < 0.001). Subgrouping of ESCC revealed decreased OS (p = 0.031), DSS (p = 0.012) and DFS (p < 0.001) for CD3ilow/PD-L1low cancers.Our data not only associate CD3ihigh- and PD-L1high ESCC with a beneficial outcome, but also demonstrate PD-L1high- and CD3ihigh status to be closely intertwined. Furthermore, our study demarcates a prognostically unfavorable, "non immunoreactive" CD3ilow / PD-L1low ESCC-subgroup, potentially forming the basis for an immune-based stratification of ESCC. PMID- 28657903 TI - Light-induced photoisomerization of a diarylethene molecular switch on solid surfaces. AB - Diarylethenes are molecular switches, the state of which can efficiently be controlled by illumination with ultraviolet or visible light. To use the change in the molecular properties when switching between the two states for a specific function, direct contact with solid surfaces is advantageous as it provides immobilization. Here we present a study of a diarylethene derivate (T-DAE, 1,2 bis(5-methyl-2-phenylthiazol-4-yl)cyclopent-1-ene) in direct contact with highly ordered graphite as well as with semimetallic Bi(1 1 1) surfaces by x-ray photoelectron spectroscopy, x-ray absorption spectroscopy and simulated spectra based on density functional theory. On both surfaces, the molecule can be switched from its open to its closed form by 325-475 nm broadband or ultraviolet illumination. On the other hand, back isomerization to the ring-open T-DAE was not possible. PMID- 28657902 TI - Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands. AB - Klotho (KL) is described as an anti-aging gene because mutation of Kl gene leads to multiple pre-mature aging phenotypes and shortens lifespan in mice. Growing evidence suggests that an increase in KL expression may be beneficial for age related diseases such as arteriosclerosis and diabetes. It remains largely unknown, however, how Kl expression could be induced. Here we discovered novel molecular mechanism for induction of Kl expression with a small molecule 'Compound H', N-(2-chlorophenyl)-1H-indole-3-caboxamide. Compound H was originally identified through a high-throughput screening of small molecules for identifying Kl inducers. However, how Compound H induces Kl expression has never been investigated. We found that Compound H increased Kl expression via demethylation in CpG islands of the Kl gene. The demethylation was accomplished by activating demethylases rather than inhibiting methylases. Due to demethylation, Compound H enhanced binding of transcription factors, Pax4 and Kid3, to the promoter of the Kl gene. Pax4 and Kid3 regulated Kl promoter activity positively and negatively, respectively. Thus, our results show that demethylation is an important molecular mechanism that mediates Compound H induced Kl expression. Further investigation is warranted to determine whether Compound H demethylates the Kl gene in vivo and whether it can serve as a therapeutic agent for repressing or delaying the onset of age-related diseases. PMID- 28657904 TI - Systems analysis of carbon nanotubes: opportunities and challenges for space applications. AB - Recent availability of carbon nanotubes (CNTs) in quantities and formats amenable to producing macroscale components invites consideration of these materials in space applications where their attractive properties can enable the realization of bold concepts for affordable space exploration. The challenge is to identify relevant systems and quantify the benefits at the systems level. Before significant investment or adoption of CNTs for large aerospace systems can be justified, there must be a plausible path to attain the perceived systems level benefits. This challenging step requires a close collaboration among experts on CNTs and aerospace system communities. This paper provides an overview of a few relevant potential CNTs applications for space systems and the gap that must be overcome for deployment of CNTs. It also provides a simple engineering-level systems analysis approach to quantify the benefits of using CNTs over state of the art material solutions. PMID- 28657905 TI - Methods of minimising doses incurred by external exposure while moving in radiation hazardous areas. AB - Radiation doses received by workers during their movement within areas contaminated as a result of events and activities, leading to emergency or existing exposure situations, may provide a substantial contribution to total external exposure during remediation work. This paper describes an approach to minimise worker external exposure in these circumstances, based on graph theory. The paper describes several tasks, including: searching for a route with the lowest dose, searching for an optimal bypass with a given set of control points and searching for the optimal road network coverage. Classical graph theory algorithms have been used (Dijkstra's algorithm, Chinese postman problem and travelling salesman problem). Algorithms for solving the above mentioned problems have been developed and were included in the information-analytical system for radiation safety. This software has been applied for optimisation of protection during remediation work at the Andreeva Bay site of temporary storage for spent fuel and radioactive waste in the Kola Peninsula, both in the context of existing exposure situations and improving the preparedness for emergency exposure situations. PMID- 28657907 TI - A Forensic Epidemiological Study of Homicide in Isfahan Province and Review of the Literature. AB - The epidemic of deaths by homicide affects every society around the world and represents a major public health crisis. Detailed information on the characteristics of homicides victims from Islamic countries is limited. This article presents forensic epidemiological data on homicides in Isfahan, Iran, during 2013-2015. Isfahan has a population of more than 5 million and 69,387 deaths with 246 homicides between 2013 and 2015. Most victims were male (73%), between the ages of 15 to 29 years (39.5%), married (54%), and employed (54%). The relationship between the actor and the victims showed that 12% were married, 15% friends, 25% strangers, and 47% others or unknown. The most frequent method of homicides was by stabbing (45%), followed by firearms (23%), strangulation (14%), and blunt force trauma (7%). The top 3 methods among males were stabbing, firearms, and strangulation, whereas among females, it was stabbing, strangulation, and by other methods. There was no significant effect on homicide rates by month, weekday, or temperature. Investigators examining deaths in Muslin countries must understand and adjust for the culture, norms, and religious ideology. PMID- 28657908 TI - Idiopathic Megacolon: Report of 2 Deaths With Review of the Literature. AB - Abnormal dilation of the colon and rectum can develop from a range of disease processes. When encountered at autopsy, its contribution to death requires assessment and a thorough investigation of its origins. Elimination of known causes elicits a diagnosis of idiopathic megacolon. This entity is uncommonly encountered and presents with similar gross anatomic findings as Hirschsprung disease. Although death is infrequent, it most commonly results from disruption of the bowel wall and subsequent peritonitis. The authors report 2 rare deaths from idiopathic megacolon with retained integrity of the bowel wall. The first was a 9-year-old girl who was administered a laxative and subsequently died the following day. She expressed difficulty passing stool since birth with a marked decline at the age of 7 years. The second case was a 16-year-old adolescent girl with recent diarrhea who collapsed after showering. She, too, had a long history of chronic constipation. Years before death, her rectum and sigmoid colon were found to be dilated on x-ray for an unrelated event, but follow-up was never pursued. Cases such as these require a thorough review of the medical history and exclusion of established conditions, such as infectious, inflammatory, metabolic, and neurogenic origins. PMID- 28657909 TI - Life-Threatening and Suspicious Lesions Caused by Mechanical Cardiopulmonary Resuscitation. AB - Chest compression devices for mechanical cardiopulmonary resuscitation (CPR) have become more common. Here, we report the case of a young woman who attempted resuscitated with LUCASTM2 after she was found unconscious at home. At autopsy, we found extensive intramuscular hemorrhages in posterior neck, between the scapulae, and in the lumbar region. Investigation of internal organs showed injuries to the lung, spleen, and kidney. The extension of the injuries gave rise to suspicion of homicide by smothering, which police investigation subsequently did not support. The pattern of injury could be attributed to automatic compression decompression CPR with LUCASTM2.The injuries may have been lethal had the patient survived. For the forensic pathologists, it is important to remain updated on developments in treatment techniques to avoid pitfalls when interpreting injury.Larger studies, prospective or retrospective, may be able to qualify the possible risks of automatic compression decompression CPR even further. PMID- 28657906 TI - Radiogenomics and radiotherapy response modeling. AB - Advances in patient-specific information and biotechnology have contributed to a new era of computational medicine. Radiogenomics has emerged as a new field that investigates the role of genetics in treatment response to radiation therapy. Radiation oncology is currently attempting to embrace these recent advances and add to its rich history by maintaining its prominent role as a quantitative leader in oncologic response modeling. Here, we provide an overview of radiogenomics starting with genotyping, data aggregation, and application of different modeling approaches based on modifying traditional radiobiological methods or application of advanced machine learning techniques. We highlight the current status and potential for this new field to reshape the landscape of outcome modeling in radiotherapy and drive future advances in computational oncology. PMID- 28657910 TI - A palladium(II)-saccharinate complex of terpyridine exerts higher anticancer potency and less toxicity than cisplatin in a mouse allograft model. AB - The main aim of this study is to assess the safety and antitumor efficacy of a palladium(II) (Pd)-saccharinate complex with terpyridine. To characterize the Pd(II) complex in vitro, its cytotoxicity was evaluated using a water-soluble tetrazolium salt cell viability assay and the mechanism of cell death was assessed by DNA fragmentation/condensation and live cell imaging analyses. The antitumor efficacy and safety of the Pd(II) complex in-vivo were examined by analyzing reduction in tumor size, changes in body and organ weight, histopathological analysis of liver, kidney, and tumor sections, and biochemical analysis of serum in C57BL/6 mice. Our results showed that the Pd(II) complex was more cytotoxic to cancer cells than noncancer cell lines and caused cell death through apoptotic pathways. The treatment of the Pd(II) complex in tumor-bearing mice effectively reduced the tumor size at half the dose used for cisplatin. The Pd(II) complex appeared to exert less liver damage than the cisplatin-based complex on changes in the hepatic enzymes levels in the serum. Hence, the complex appears to be a potential chemotherapeutic drug with high antitumor efficacy and fewer hepatotoxic complications, providing an avenue for further studies. PMID- 28657911 TI - Efficacy of Whole-Body Vibration Board Training on Strength in Athletes After Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Study. AB - OBJECTIVE: To evaluate whether an 8-week whole-body vibration training program may improve recovery of knee flexion/extension muscular strength in athletes after arthroscopic anterior cruciate ligament (ACL) reconstruction. DESIGN: Randomized controlled trial. SETTING: Single outpatient rehabilitation center. PARTICIPANTS: Thirty-eight female volleyball/basketball players (aged between 20 and 30), randomized into 2 treatment groups. INTERVENTIONS: During a standardized six-month rehabilitation program, from week 13 to week 20 after surgery, the whole-body vibration group (n = 19) and the control group (n = 19) performed additional static knee flexor/extensor exercises on a vibration platform. For the whole-body vibration group, the vibration platform was set to 2.5 mm of amplitude and 26 Hz of frequency. The control group followed the same whole-body vibration board training with no vibrations. MAIN OUTCOME MEASURES: All patients were evaluated using an isokinetic strength test with a Biodex dynamometer at the beginning and at the end of the additional treatment protocol. The parameters tested were the peak torque and the maximum power of knee flexor and extensor muscles performing strength and endurance tests. RESULTS: No vibration-related side effects were observed. Improvements were noticed in both groups, but increase in knee muscle isokinetic strength values was statistically significant in the whole-body vibration group when compared with the control group (differences in extension: peak torque 11.316/10.263 N.m and maximum power 13.684/11.211 W; flexion: peak torque 9.632/11.105 N.m and maximum power 10.158/9.474 W; P < 0.001). CONCLUSIONS: When combined with a standardized rehabilitation program, whole-body vibration may increase muscular strength and be an effective additional treatment option in the rehabilitation of athletes after ACL arthroscopic reconstruction. PMID- 28657912 TI - From Heartbreak to Left Bundle Branch Block: A Case of Amitriptyline Overdose. PMID- 28657913 TI - Strong Correlation Between Concentrations of Antiretrovirals in Home-Collected and Study-Collected Hair Samples: Implications for Adherence Monitoring. PMID- 28657914 TI - Enhancing Communication to Improve Patient Safety and to Increase Patient Satisfaction. AB - With the continuous rise of sentinel and adverse events due to ineffective communication, it is time for health care organizations to start implementing a focus on enhancing effective communication in which will, in turn, improve patient safety and experience, boosting the bottom line. This article identifies and discusses different communication protocols that can be used to enhance the consistency of more efficient and effective communication within a health care organization to overall improve patient care and patient satisfaction. The rising importance of patient satisfaction and Hospital Consumer Assessment of Healthcare Providers and Systems scores required by the Centers for Medicare and Medicaid Services are causing a shift in how hospitals evaluate and manage their health care organizations today. Following the situation-background-assessment recommendation and acknowledge-introduce-duration-explain-thank protocols, as well as proper and effective training and educational programs, enhances more effective communication in health care organizations which improves patient safety and increases patient satisfaction. PMID- 28657915 TI - Teleradiology in Southeast Iran: Evaluating the Views of Senior Executives and Radiologists. AB - Teleradiology is considered as one of the important forms of telemedicine. Positive views of the users and providers of these services play an important role in its successful implementations. The aim of this study was to investigate the views of radiologists used in the radiology departments of teaching hospitals in the Zahedan University of Medical Sciences through teleradiology, as well as evaluate the executive possibility of teleradiology in these hospitals by the views of chief executive officer and comparison between these two views. The current cross-sectional research was performed in 2014 at Zahedan teaching hospitals. The views of 13 chief executive officers on the possibility of the execution of teleradiology and 26 radiologists on the teleradiology process were evaluated by means of two valid and reliable questionnaires. The results of the research revealed that most of the radiologists had knowledge of and positive opinions about teleradiology. Conversely, the view by chief executive officers was that implementation of these processes was not possible in the studied hospitals. Dealing with some issues including data security, controlling or restricting access to clinical information of patients during the process of teleradiology, the possibility of legal protection for the participating radiologists, constitution of executive teams in the organization along with the financial supports, and, subsequently, invitation of the supports from the chief executive officers as the main sponsors of teleradiology implementation in the teaching hospitals are all guidelines for improvement of the successful implementation of teleradiology. PMID- 28657916 TI - Evaluation of Huddles: A Multisite Study. AB - Regular, interdisciplinary group meetings, "huddles," may be useful in improving communication among disciplines, resolving problems, and sharing information. Daily use of huddles may contribute to the development of a highly reliable health care organization. The purpose of this study was to describe safety huddles in relation to (1) problem type, (2) timeliness of resolution, (3) attendance of representatives from each discipline, (4) amount of information sharing, and (5) attendees' satisfaction with the process. Overall, results demonstrated that the primary function of huddles was the exchange of information that posed or had the potential to pose safety risks to patients. Across seven hospitals, the range of information sharing during huddles was 61.0% to 95.6%. Regarding satisfaction with the huddle process, staff reported that huddles were useful in improving awareness of safety concerns and also improved communication between disciplines. Huddles provide a structured format in which staff can positively impact safety concerns, form a greater sense of medical community, increase sharing of information between disciplines, quickly resolve discipline based problems, and increase awareness of safety concerns. Given the results of this study, it is recommended that health care administrators and managers develop a huddle process. PMID- 28657918 TI - Authors' Response to a Letter to the Editor on Radial Extracorporeal Shockwave in the Management of Lateral Epicondylitis. PMID- 28657917 TI - Patient Registry of Spasticity Care World: Data Analysis Based on Physician Experience. AB - OBJECTIVE: The aim of the study was to report physician experience-based "real world" treatment patterns with botulinum toxin type A in patients with stroke and traumatic brain injury. DESIGN: A prospective, multicenter, international observational registry design was used. RESULTS: Six hundred twenty-seven participants with stroke and 132 participants with traumatic brain injury were assessed and treated by 17 more experienced physicians and 12 less experienced physicians. Due to the limited usage of abobotulinumtoxinA Dysport and incobotulinumtoxinA Xeomin, data were reported on onabotulinumtoxinA BOTOX only. Based on physician experience, onabotulinumtoxinA doses were statistically different with larger mean doses injected by more experienced physicians in the upper limb (59.9 [39.0], P = 0.001) and in the lower limb (101.8 [69.2], P < 0.001). Treated deformities significantly differed for both upper limb and lower limb (P < 0.001). More experienced physicians showed a larger mean change in Ashworth Scale scores from baseline for the equinovarus/equinus foot and stiff knee (P = 0.001 and 0.03). Less experienced physicians showed a larger mean change in Ashworth Scale scores from baseline for the adducted thigh (P = 0.05). Less experienced physicians had statistically significant larger change in hand pain scores for clenched fist deformity treatment at follow-up compared with more experienced physicians (P = 0.01). Physician experience demonstrated a significant difference on patients reported satisfaction toward their secondary goal with higher scores for more experienced physician (P = 0.04). CONCLUSIONS: This international registry provides clinical nuances of treatment based on physician clinical experience in a robust sample size. PMID- 28657919 TI - Asynchronous slipped capital femoral epiphysis in a patient with a seizure disorder: case report and review of the literature. AB - Debate remains about the appropriate treatment of the asymptomatic side following treatment of a unilateral slipped capital femoral epiphysis (SCFE). A 12-year-old boy with a seizure disorder presented with an unstable SCFE on the left hip following a seizure. He underwent percutaneous pinning of the left only. At 8 months postoperatively, he returned with an unstable slip of the right hip, again following a seizure. No literature discussing the treatment of patients with risk of SCFE and seizure disorders was identified. Further study may identify an increased incidence of contralateral slip following an initial slip in this population. If a greater risk exists, contralateral prophylactic fixation at time of index surgery may be indicated. PMID- 28657920 TI - Functional outcome of displaced intercondylar fractures of the humerus in children and adolescents. AB - The main aim of this study was to retrospectively evaluate the clinical, functional, and radiographic outcome of displaced intercondylar fractures of the humerus in children and adolescents, and evaluate upper-extremity function with the short version of the Disabilities of the Arm, Shoulder and Hand outcome questionnaire (Quick DASH), the hypothesis being that intercondylar fractures have poorer functional outcome than do other upper-limb fractures. The mean age at the time of injury was 11.9+/-2.5 years (range: 7.5-15.8 years). The male female ratio was 3.5 : 1. Using the Toniolo & Wilkins classification, 13 (72%) fractures were classified as type II and five (28%) as type III. The overall complication rate was 50%. The mean Quick DASH score was 9+/-11 (range: 0-31.8). Displaced intercondylar fractures of the humerus, although uncommon in skeletally immature patients, are characterized by poorer clinical and functional outcome compared with other pediatric humerus and elbow fractures. Minimally displaced fractures with articular surface displacement of less than 2 mm can be safely managed with closed reduction and percutaneous fixation, but any greater intra articular displacement requires open reduction and internal fixation, which means a higher complication rate and poorer functional outcome should be expected, especially in patients older than 10 years. PMID- 28657923 TI - Long-term Outcomes of Infliximab Use for Pediatric Crohn Disease: A Canadian Multicenter Clinical Practice Experience. AB - BACKGROUND: Data on long-term real-world outcomes of infliximab in pediatric Crohn disease are limited. AIM: The aim of the study was to evaluate infliximab optimization and durability in children with Crohn disease. METHODS: We performed a retrospective review of children with Crohn disease who started infliximab from January 2008 to December 2012 in 4 Canadian tertiary care centers. A priori factors associated with optimization and discontinuation from loss of response were evaluated using logistic regression and Cox proportional hazards model, respectively. RESULTS: One hundred eighty children (54.4% boys) started infliximab; all completed induction. Median age at infliximab start was 14.3 years (Q1, Q3: 12.8, 15.9 years) and median time from diagnosis to infliximab start was 1.5 years (Q1, Q3: 0.6, 3.5 years). At last follow-up, 87.1% were maintained on infliximab (median duration follow-up 85.9 weeks [Q1, Q3: 43.8, 138.8 weeks]). Infliximab optimization occurred in 57.3% (dose escalation 15.2%, interval shortening 3.9%, both 38.2%), primarily due to loss of response. Younger age at diagnosis (<10 years old) and nonstricturing, nonpenetrating behavior were associated with optimization (odds ratio 6.5, 95% confidence interval [CI] 2.0 21.1 and odds ratio 2.1, 95% CI 1.0-4.2, respectively). The 1- and 2-year durability of infliximab (percentage in follow-up who were continuing on infliximab) were 95.5% (95% CI 90.4-98.3) and 91.0% (95% CI 82.4-96.3), respectively. Annual discontinuation due to loss of response occurred at 3.2% per year (95% CI 1.1-5.2). CONCLUSIONS: Children with Crohn disease maintain a durable response to infliximab. Optimization occurs frequently and allows for continued use. Younger age at diagnosis and nonstricturing, nonpenetrating behavior are associated with increased need for infliximab optimization. PMID- 28657921 TI - Comment on ) Exploring the Relationship Between Working Memory, Compressor Speed, and Background Noise Characteristics, Ear Hear 37, 137-143. PMID- 28657925 TI - New Kids in the Neighborhood: Biosimilars. PMID- 28657924 TI - Health Status and Anthropometric Changes in Resettled Refugee Children. AB - BACKGROUND: Recently the United States has experienced an increase in refugees. Pediatric refugees are at risk for health and nutrition problems. Literature on longitudinal change in nutritional status of resettled pediatric refugees is scant. OBJECTIVE: The present study reports the health and nutritional status of pediatric refugees and tracks changes in nutritional status. METHODS: Data were extracted retrospectively from the records of a community health center in Buffalo, NY. Two cohorts of refugees (0-18 years) were selected. Cohort A was followed during 5 years and consisted of 225 subjects whose initial visit occurred between January 1, 2007 and December 31, 2009. The 199 subjects in cohort B had an initial visit between January 1, 2013 and December 31, 2013 and were followed for 1 year. Cohort B was chosen because vitamin levels were available only for this group. Descriptive and anthropometric data, infectious disease status, and initial vitamin and hemoglobin levels were recorded. Height for-age (HFA) z scores and body mass index (BMI) z scores were computed. Longitudinal changes were analyzed. RESULTS: The cohorts A and B differed in country of origin and infectious disease burden. On arrival, both cohorts exhibited HFA z scores reflecting short stature. BMI z scores were normal. HFA and BMI z scores increased during 5 years and 1 year for cohorts A and B, respectively. Anemia, vitamin D deficiency, and lead toxicity were identified. CONCLUSIONS: Resettled pediatric refugees were short. Some were stunted. Catch-up growth, however, occurred. There were increases in HFA and BMI z scores. Vitamin D deficiency, anemia, and lead toxicity were documented. PMID- 28657926 TI - Improving cancer care in metastatic kidney and prostate cancer: steps in the right direction. PMID- 28657928 TI - Insights into Pediatric Ventricular Assist Device Selection, Adverse Events, and Outcomes-A Favorable Evolution. PMID- 28657927 TI - Comparison of 4 Methods for Dynamization of Locking Plates: Differences in the Amount and Type of Fracture Motion. AB - BACKGROUND: Decreasing the stiffness of locked plating constructs can promote natural fracture healing by controlled dynamization of the fracture. This biomechanical study compared the effect of 4 different stiffness reduction methods on interfragmentary motion by measuring axial motion and shear motion at the fracture site. METHODS: Distal femur locking plates were applied to bridge a metadiaphyseal fracture in femur surrogates. A locked construct with a short bridge span served as the nondynamized control group (LOCKED). Four different methods for stiffness reduction were evaluated: replacing diaphyseal locking screws with nonlocked screws (NONLOCKED); bridge dynamization (BRIDGE) with 2 empty screw holes proximal to the fracture; screw dynamization with far cortical locking (FCL) screws; and plate dynamization with active locking plates (ACTIVE). Construct stiffness, axial motion, and shear motion at the fracture site were measured to characterize each dynamization methods. RESULTS: Compared with LOCKED control constructs, NONLOCKED constructs had a similar stiffness (P = 0.08), axial motion (P = 0.07), and shear motion (P = 0.97). BRIDGE constructs reduced stiffness by 45% compared with LOCKED constructs (P < 0.001), but interfragmentary motion was dominated by shear. Compared with LOCKED constructs, FCL and ACTIVE constructs reduced stiffness by 62% (P < 0.001) and 75% (P < 0.001), respectively, and significantly increased axial motion, but not shear motion. CONCLUSIONS: In a surrogate model of a distal femur fracture, replacing locked with nonlocked diaphyseal screws does not significantly decrease construct stiffness and does not enhance interfragmentary motion. A longer bridge span primarily increases shear motion, not axial motion. The use of FCL screws or active plating delivers axial dynamization without introducing shear motion. PMID- 28657930 TI - Vasoinhibin Serum Levels Are Required to Demonstrate Their Role in Peripartum Cardiomyopathy Etiopathology. PMID- 28657929 TI - Exercise Performance During the First Two Years After Left Ventricular Assist Device Implantation. AB - Exercise performance of patients with left ventricular assist devices (LVADs) improves after postimplant cardiac rehabilitation (CR). Few studies assess the effectiveness of a CR and its long-term effect of exercise performance. For this purpose, we retrospectively analyzed data from LVAD patients, who underwent a stationary CR twice after pump implantation. Data from exercise training and cardiopulmonary exercise tests (CPETs) were analyzed. Fifteen patients (age: 57 +/- 10 years, male 87%) were admitted to the rehabilitation clinic twice 39 +/- 18 and 547 +/- 197 days after LVAD implantation. An improvement from the beginning to the end of the second CR was observed in bicycle ergometer training (14.0 +/- 8.8 vs. 35.7 +/- 14.7 W; p < 0.001), in muscular strength (e.g., leg press: 41 +/- 10 vs. 53 +/- 14 kg; p < 0.001), and in 6 minute walk distance (421 +/- 126 m vs. 480 +/- 133 m; p = 0.040). Between the first and the second CR, improvement in all the training modules was observed as well as an increase in CPETs peak workload (56 +/- 24 vs. 83 +/- 26 W; p < 0.001) but not in peak oxygen consumption (12.3 +/- 3.2 vs. 12.2 +/- 4.0 ml/min/kg; p = 0.906). Thus, over long implant periods, patients showed improvement of their exercise performance in the submaximal load range, but no change in the aerobic capacity was observed. PMID- 28657931 TI - From Research Lab to Clinical Routine of MCS. PMID- 28657932 TI - The Influence of External Load on Quadriceps Muscle and Tendon Dynamics during Jumping. AB - : Tendons possess both viscous (rate-dependent) and elastic (rate-independent) properties that determine tendon function. During high-speed movements external loading increases both the magnitude (FT) and rate (RFDT) of tendon loading. PURPOSE: The influence of external loading on muscle and tendon dynamics during maximal vertical jumping was explored. METHODS: Ten resistance-trained men performed parallel-depth, countermovement vertical jumps with and without additional load (0%, 30%, 60%, and 90% of maximum squat lift strength), while joint kinetics and kinematics, quadriceps tendon length (LT) and patellar tendon FT and RFDT were estimated using integrated ultrasound, motion analysis and force platform data and muscle tendon modelling. RESULTS: Estimated FT and RFDT, but not peak LT, increased with external loading. Temporal comparisons between 0% and 90% loads revealed that FT was greater with 90% loading throughout the majority of the movement (11%-81% and 87%-95% movement duration). However, RFDT was greater with 90% load only during the early movement initiation phase (8%-15% movement duration) but was greater in the 0% load condition later in the eccentric phase (27%-38% movement duration). LT was longer during the early movement (12%-23% movement duration) but shorter in the late eccentric and early concentric phases (48%-55% movement duration) with 90% load. DISCUSSION: External loading positively influenced peak FT and RFDT but tendon strain appeared unaffected, suggesting no additive effect of external loading on patellar tendon lengthening during human jumping. Temporal analysis revealed that external loading resulted in a large initial RFDT that may have caused dynamic stiffening of the tendon and attenuated tendon strain throughout the movement. These results suggest that external loading influences tendon lengthening in both a load- and movement-dependent manner. PMID- 28657933 TI - Impact of HSCT Conditioning and Glucocorticoid Dose on Exercise Adherence and Response. AB - PURPOSE: Evidence from randomized controlled trials (RCT) that exercise interventions have beneficial effects in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is growing. However, intensive chemotherapy conditioning and glucocorticoid (GC) treatment is always part of an allo-HSCT and possibly affect exercise adherence and training response. Therefore, we aimed to examine whether various conditioning protocols or different doses of GC treatment affect exercise adherence and/or training response during the inpatient period. METHODS: We analyzed inpatient data from intervention groups of two large RCT in allo-HSCT patients (n = 113). The intervention incorporated partly supervised endurance and resistance exercise three to five times per week. According to the potentially interfering factors, the patients were divided into groups depending on intensity of conditioning (myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), and nonmyeloablative conditioning (NMC)) and cumulative dose of GC treatment (GC low <=9 mg.kg prednisone or GC high >9 mg.kg prednisone) and were compared. RESULTS: Median exercise adherence (target value, five sessions weekly) during the inpatient period was 64% in MAC, 54% in RIC, and 63% in NMC. The proportion of prematurely terminated training sessions ranged from 11% to 15%. Tiredness was the most frequent cause of exercise termination in all groups. Exercise adherence, duration (min.wk) and type of training was significantly associated with GC dose. With regard to training response, results suggest that GC-low patients tend to respond better in knee extensor muscle strength. CONCLUSIONS: Exercise adherence during inpatient period is significantly affected by dose of GC treatment but not by condition regimen. However, given the reasonable adherence rates also in the GC-high group, data support the feasibility and importance of exercising for all allo-HSCT patients during the inpatient period. PMID- 28657934 TI - Multitarget botanical pharmacotherapy in major depression: a toxic brain hypothesis. AB - A significant number of patients with major depression do not respond optimally to current antidepressant drugs. As depression is likely to be a heterogeneous disorder, it is possible that existing neurotransmitter-based antidepressant drugs do not fully address other pathologies that may exist in certain cases. Biological pathologies related to depression that have been proposed and studied extensively include inflammation and immunology, hypercortisolemia, oxidative stress, and impaired angiogenesis. Such pathologies may induce neurodegeneration, which in turn causes cognitive impairment, a symptom increasingly being recognized in depression. A neurotoxic brain hypothesis unifying all these factors may explain the heterogeneity of depression as well as cognitive decline and antidepressant drug resistance in some patients. Compared with neurotransmitter-based antidepressant drugs, many botanical compounds in traditional medicine used for the treatment of depression and its related symptoms have been discovered to be anti-inflammatory, immunoregulatory, anti infection, antioxidative, and proangiogenic. Some botanical compounds also exert actions on neurotransmission. This multitarget nature of botanical medicine may act through the amelioration of the neurotoxic brain environment in some patients resistant to neurotransmitter-based antidepressant drugs. A multitarget multidimensional approach may be a reasonable solution for patients resistant to neurotransmitter-based antidepressant drugs. PMID- 28657936 TI - Trend of blood pressure in hypertensive and normotensive volunteers during Ramadan fasting. AB - INTRODUCTION: It is believed that Ramadan fasting regulates blood pressure, heart rate, and other cardiovascular risk factors. This study aimed to investigate the effect of Ramadan fasting on ambulatory blood pressure in hypertensive patients. PATIENTS AND METHODS: This prospective, observational study was carried out in two groups: one group included hypertensive patients treated with two antihypertensive agents (n=6) and the other group included healthy individuals (n=12). We performed 24-h blood pressure monitoring at four time points: before Ramadan, during the first and last 10 days of Ramadan, and 1 month after Ramadan. All hypertensive patients followed their twice-daily treatment regimen. Mean 24-h blood pressure (as well as mean blood pressure values during awake and sleep periods), body weight, and waist circumference were measured in the two groups. RESULTS: There were no significant differences in the trends of systolic and diastolic blood pressure between the hypertensive and nonhypertensive groups during Ramadan and 1 month after it. However, the trends of variations in heart rate and body weight were not significantly different in the two groups (P<0.001 and P=0.016, respectively). There was a significant increase in heart rate during the first period of Ramadan in hypertensive patients (P=0.018), whereas it improved during the post-Ramadan period in comparison with the second period of measurements (P=0.019). Furthermore, there was a significant decline in heart rate during the post-Ramadan measurement compared with that before Ramadan in the nonhypertensive group (P=0.008).In addition, there was a significant weight gain in the third period in comparison with the previous period in the hypertensive group (73.1+/-11 vs. 72.2+/-12; P=0.011). CONCLUSION: This finding indicates that Ramadan fasting might be nonthreatening for patients with essential hypertension if the treatment regimen is complied with. PMID- 28657938 TI - Anatomical Resections Improve Disease-free Survival in Patients With KRAS-mutated Colorectal Liver Metastases. AB - OBJECTIVE: To investigate the potential clinical advantage of anatomical resection versus nonanatomical resection for colorectal liver metastases, according to KRAS mutational status. BACKGROUND: KRAS-mutated colorectal liver metastases (CRLM) are known to be more aggressive than KRAS wild-type tumors. Although nonanatomical liver resections have been demonstrated as a viable approach for CRLM patients with similar oncologic outcomes to anatomical resections, this may not be the case for the subset of KRAS-mutated CRLM. METHODS: 389 patients who underwent hepatic resection of CRLM with known KRAS mutational status were identified. Survival estimates were calculated using the Kaplan-Meier method, and multivariable analysis was conducted using the Cox proportional hazards regression model. RESULTS: In this study, 165 patients (42.4%) underwent nonanatomical resections and 140 (36.0%) presented with KRAS mutated CRLM. Median disease-free survival (DFS) in the entire cohort was 21.3 months, whereas 1-, 3-, and 5-year DFS was 67.3%, 34.9%, and 31.5% respectively. Although there was no difference in DFS between anatomical and nonanatomical resections in patients with KRAS wild-type tumors (P = 0.142), a significant difference in favor of anatomical resection was observed in patients with a KRAS mutation (10.5 vs. 33.8 months; P < 0.001). Five-year DFS was only 14.4% in the nonanatomically resected group, versus 46.4% in the anatomically resected group. This observation persisted in multivariable analysis (hazard ratio: 0.45; 95% confidence interval: 0.27-0.74; P = 0.002), when corrected for number of tumors, bilobar disease, and intraoperative ablations. CONCLUSIONS: Nonanatomical tissue sparing hepatectomies are associated with worse DFS in patients with KRAS-mutated tumors. Because of the aggressive nature of KRAS-mutated CRLM, more extensive anatomical hepatectomies may be warranted. PMID- 28657937 TI - Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLO COMET Randomized Controlled Trial. AB - OBJECTIVE: To perform the first randomized controlled trial to compare laparoscopic and open liver resection. SUMMARY BACKGROUND DATA: Laparoscopic liver resection is increasingly used for the surgical treatment of liver tumors. However, high-level evidence to conclude that laparoscopic liver resection is superior to open liver resection is lacking. METHODS: Explanatory, assessor blinded, single center, randomized superiority trial recruiting patients from Oslo University Hospital, Oslo, Norway from February 2012 to January 2016. A total of 280 patients with resectable liver metastases from colorectal cancer were randomly assigned to undergo laparoscopic (n = 133) or open (n = 147) parenchyma-sparing liver resection. The primary outcome was postoperative complications within 30 days (Accordion grade 2 or higher). Secondary outcomes included cost-effectiveness, postoperative hospital stay, blood loss, operation time, and resection margins. RESULTS: The postoperative complication rate was 19% in the laparoscopic-surgery group and 31% in the open-surgery group (12 percentage points difference [95% confidence interval 1.67-21.8; P = 0.021]). The postoperative hospital stay was shorter for laparoscopic surgery (53 vs 96 hours, P < 0.001), whereas there were no differences in blood loss, operation time, and resection margins. Mortality at 90 days did not differ significantly from the laparoscopic group (0 patients) to the open group (1 patient). In a 4-month perspective, the costs were equal, whereas patients in the laparoscopic-surgery group gained 0.011 quality-adjusted life years compared to patients in the open surgery group (P = 0.001). CONCLUSIONS: In patients undergoing parenchyma-sparing liver resection for colorectal metastases, laparoscopic surgery was associated with significantly less postoperative complications compared to open surgery. Laparoscopic resection was cost-effective compared to open resection with a 67% probability. The rate of free resection margins was the same in both groups. Our results support the continued implementation of laparoscopic liver resection. PMID- 28657939 TI - Should Patients With Cystic Lesions of the Pancreas Undergo Long-term Radiographic Surveillance?: Results of 3024 Patients Evaluated at a Single Institution. AB - OBJECTIVE: In 2015, the American Gastroenterological Association recommended the discontinuation of radiographic surveillance after 5 years for patients with stable pancreatic cysts. The current study evaluated the yield of continued surveillance of pancreatic cysts up to and after 5 years of follow up. METHODS: A prospectively maintained registry of patients evaluated for pancreatic cysts was queried (1995-2016). Patients who initially underwent radiographic surveillance were divided into those with <5 years and >=5 years of follow up. Analyses for the presence of cyst growth (>5 mm increase in diameter), cross-over to resection, and development of carcinoma were performed. RESULTS: A total of 3024 patients were identified, with 2472 (82%) undergoing initial surveillance. The >=5 year group (n = 596) experienced a greater frequency of cyst growth (44% vs. 20%; P < 0.0001), a lower rate of cross-over to resection (8% vs 11%; P = 0.02), and a similar frequency of progression to carcinoma (2% vs 3%; P = 0.07) compared with the <5 year group (n = 1876). Within the >=5 year group, 412 patients (69%) had demonstrated radiographic stability at the 5-year time point. This subgroup, when compared with the <5 year group, experienced similar rates of cyst growth (19% vs. 20%; P= 0.95) and lower rates of cross-over to resection (5% vs 11%; P< 0.0001) and development of carcinoma (1% vs 3%; P= 0.008). The observed rate of developing cancer in the group that was stable at the 5-year time point was 31.3 per 100,000 per year, whereas the expected national age-adjusted incidence rate for this same group was 7.04 per 100,000 per year. CONCLUSION: Cyst size stability at the 5-year time point did not preclude future growth, cross-over to resection, or carcinoma development. Patients who were stable at 5 years had a nearly 3-fold higher risk of developing cancer compared with the general population and should continue long-term surveillance. PMID- 28657940 TI - The Fifth Vital Sign: Postoperative Pain Predicts 30-day Readmissions and Subsequent Emergency Department Visits. AB - OBJECTIVE: We hypothesized that inpatient postoperative pain trajectories are associated with 30-day inpatient readmission and emergency department (ED) visits. BACKGROUND: Surgical readmissions have few known modifiable predictors. Pain experienced by patients may reflect surgical complications and/or inadequate or difficult symptom management. METHODS: National Veterans Affairs Surgical Quality Improvement data on inpatient general, vascular, and orthopedic surgery from 2008 to 2014 were merged with laboratory, vital sign, health care utilization, and postoperative complications data. Six distinct postoperative inpatient patient-reported pain trajectories were identified: (1) persistently low, (2) mild, (3) moderate or (4) high trajectories, and (5) mild-to-low or (6) moderate-to-low trajectories based on postoperative pain scores. Regression models estimated the association between pain trajectories and postdischarge utilization while controlling for important patient and clinical variables. RESULTS: Our sample included 211,231 surgeries-45.4% orthopedics, 37.0% general, and 17.6% vascular. Overall, the 30-day unplanned readmission rate was 10.8%, and 30-day ED utilization rate was 14.2%. Patients in the high pain trajectories had the highest rates of postdischarge readmissions and ED visits (14.4% and 16.3%, respectively, P < 0.001). In multivariable models, compared with the persistently low pain trajectory, there was a dose-dependent increase in postdischarge ED visits and readmission for pain-related diagnoses, but not postdischarge complications (chi trend P < 0.001). CONCLUSIONS: Postoperative pain trajectories identify populations at risk for 30-day readmissions and ED visits, and do not seem to be mediated by postdischarge complications. Addressing pain control expectations before discharge may help reduce surgical readmissions in high pain categories. PMID- 28657942 TI - Perception of Safety of Surgical Practice Among Operating Room Personnel From Survey Data Is Associated With All-cause 30-day Postoperative Death Rate in South Carolina. AB - OBJECTIVE: To evaluate whether the perception of safety of surgical practice among operating room (OR) personnel is associated with hospital-level 30-day postoperative death. BACKGROUND: The relationship between improvements in the safety of surgical practice and benefits to postoperative outcomes has not been demonstrated empirically. METHODS: As part of the Safe Surgery 2015: South Carolina initiative, a baseline survey measuring the perception of safety of surgical practice among OR personnel was completed. We evaluated the relationship between hospital-level mean item survey scores and rates of all-cause 30-day postoperative death using binomial regression. Models were controlled for multiple patient, hospital, and procedure covariates using supervised principal components regression. RESULTS: The overall survey response rate was 38.1% (1793/4707) among 31 hospitals. For every 1 point increase in the hospital-level mean score for respect [adjusted relative risk (aRR) 0.78, 95% CI 0.65-0.93, P = 0.0059], clinical leadership (aRR 0.86, 95% CI 0.74-0.9932, P = 0.0401), and assertiveness (aRR 0.71, 95% CI 0.54-0.93, P = 0.01) among all survey respondents, there were associated decreases in the hospital-level 30-day postoperative death rate after inpatient surgery ranging from 14% to 29%. Higher hospital-level mean scores for the statement, "I would feel safe being treated here as a patient," were associated with significantly lower hospital-level 30 day postoperative death rates (aRR 0.83, 95% CI 0.70-0.97, P = 0.02). Although most findings seen among all OR personnel were seen among nurses, they were often absent among surgeons. CONCLUSIONS: Perception of OR safety of surgical practice was associated with hospital-level 30-day postoperative death rates. PMID- 28657941 TI - Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: Long-term Follow-up From ACOSOG Z1071 (Alliance). AB - BACKGROUND: Women with node-positive breast cancer are at high risk for recurrence. We evaluate the impact of approximated tumor subtype and response to chemotherapy on long-term outcomes in a node-positive cohort receiving neoadjuvant chemotherapy. METHODS: ACOSOG Z1071 enrolled cT0-4N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009 to 2011. Factors impacting breast cancer-specific survival (BCSS) and overall survival (OS) were analyzed. RESULTS: Median follow-up of 701 eligible patients was 4.1 years (0.4 6.5). Ninety patients (12.8%) died from breast cancer. Approximated subtype and chemotherapy response were significantly associated with BCSS and OS (P < 0.0001). BCSS and OS were highest in patients who achieved pathologic complete response (pCR) (P < 0.0001 and P < 0.0001, respectively).Five-year BCSS was highest in human epidermal growth factor receptor 2 (HER2)-positive disease [95.8%; 95% confidence interval (CI): 87.7-98.6], followed by hormone receptor positive/HER2-negative (80.4%; 95% CI: 73.2-85.9) and lowest in triple-negative (TNBC) (74.8%; 95% CI: 66.6-81.2; P < 0.0001). Similar patterns were seen in OS.In TNBC (n = 174), 5-year BCSS was higher in patients with pCR versus residual disease (89.8%; 95% CI: 78.8-95.3 vs 65.8%; 95% CI: 54.5-74.9; P = 0.0013). In hormone receptor-positive/HER2-negative (n = 318) disease, BCSS was 100% in patients with pCR and 78.3% (95% CI: 70.4-84.3) in those with residual disease (P = 0.018). In HER2-positive disease (n = 204) there was no difference between pCR and residual disease (96.0%; 95% CI: 83.6-99.1 vs 95.8%; 95% CI: 81.4-99.1; P = 0.77). CONCLUSIONS: In node-positive breast cancer patients treated with neoadjuvant chemotherapy, BCSS and OS were associated with approximated subtype and chemotherapy response and were lowest in TNBC patients with residual disease. Five-year BCSS was > 95% in HER2-positive disease independent of chemotherapy response. PMID- 28657943 TI - Rebranding "The Lab Years" as "Professional Development" in Order to Redefine the Modern Surgeon Scientist. PMID- 28657944 TI - Health-related Quality of Life and Functional Outcomes in 5-year Survivors After Pancreaticoduodenectomy. AB - OBJECTIVE: Our aim was to assess quality of life (QOL) and functionality in a large cohort of patients >=5-years after pancreaticoduodenectomy (PD). BACKGROUND: Long-term QOL outcomes after PD for benign or malignant disease are largely undocumented. METHODS: We administered the EORTC QLQ-C30 questionnaire to patients who underwent PD for neoplasms from 1998 to 2011 and compared their scores with an age- and sex-matched normal population. Clinical relevance (CR) of differences was scored as small (5-10), moderate (10-20), or large (>20) based on validated interpretation of clinically important differences. RESULTS: Of 305 PD survivors, 245 (80.3%) responded, of whom 157 (64.1%) underwent PD for nonmalignant lesions. Median follow-up was 9.1 years (range 5.1 -21.2 yrs). New onset diabetes developed in 10.6%; 50.4% reported taking pancreatic enzymes; 54.6% reported needing antacids. Compared with the age- and sex-adjusted controls, PD survivors demonstrated higher global QOL (78.7 vs 69.7, CR small, P < 0.001), physical (86.7 vs 77.9, CR small, P < 0.001) and role-functioning scores (86.3 vs 74.1, CR medium, P < 0.001). Using linear regression and adjusting for socioeconomic variables, there were no differences in QOL or functional scores in the benign versus malignant subgroups. Older age at operation was associated with worse physical-functioning (-0.4/yr, P = 0.008). Taking pancrelipase (-6.8, P = 0.035) or antacids (-6.3, P = 0.044) were both associated with lower social-functioning scores. CONCLUSIONS: Patients who had a PD demonstrated better global QOL, physical- and role-functioning scores at 5 years when compared with age- and sex-matched controls. Approximately half of the patients required pancreatic enzyme replacement, while only 11% developed new onset diabetes. PMID- 28657945 TI - Expanding the Margins: High Volume Utilization of Marginal Liver Grafts Among >2000 Liver Transplants at a Single Institution. AB - OBJECTIVE: Marginal livers (ML) have been used to expand the donor pool. National utilization of MLs is variable, and in some centers, they are never used. We examined the outcomes of MLs in the largest single center series of MLs used to date and compared outcomes to standard (SL) and living donor (LD) livers. METHODS: Analysis of a prospectively maintained database of all liver transplants performed at our institution from 1998 to 2016. ML grafts were defined as livers from donors >70, livers discarded regionally and shared nationally, livers with cold ischemic time >12 hours, livers from hepatitis C virus positive donors, livers from donation after cardiac death donors, livers with >30% steatosis, and livers split between 2 recipients. RESULTS: A total of 2050 liver transplant recipients were studied, of these 960 (46.8%) received ML grafts. ML recipients were more likely to have lower MELDs and have hepatocellular carcinoma. Most MLs used were from organs turned down regionally and shared nationally (69%) or donors >70 (22%). Survival of patients receiving MLs did not significantly differ from patients receiving SL grafts (P = 0.08). ML and SL recipients had worse survival than LDs (P < 0.01). Despite nearly half of our recipients receiving MLs, overall survival was significantly better than national survival over the same time period (P = 0.04). Waitlist mortality was significantly lower in our series compared with national results (19% vs 24.0%, P < 0.0001). CONCLUSIONS: Outcomes of recipients of ML grafts are comparable to SL transplants. Despite liberal use of these grafts, we have been able to successfully reduce waitlist mortality while exceeding national post-transplant survival metrics. PMID- 28657946 TI - Reconstruction/Repair of Iatrogenic Biliary Injuries: Is the Robot Offering a New Option? Short Clinical Report. AB - OBJECTIVE: The aim of this study is to analyze perioperative outcomes of robotic reconstruction of iatrogenic biliary injuries and describe the surgical technique in detail. BACKGROUND: Iatrogenic bile duct injuries (BDIs) continue to be a major concern in open and laparoscopic cholecystectomy. In the past decade, robotic surgery has been applied to many different procedures showing technical advantages, especially in microsurgical fields. Few cases of robotic BDI reconstructions have been described in the literature so far. This is the first clinical series of consecutive patients undergoing robotic BDI reconstructions. METHODS: This study is a single-surgeon retrospective review of a prospectively maintained database including 14 patients who underwent robot-assisted biliary reconstruction due to iatrogenic BDIs. RESULTS: In all, 14 patients underwent robot-assisted BDI reconstructions. The mean operative time, blood loss, and length of hospitalization were 280.6 min (SD = 132.0), 135.0 mL (SD = 169.7), and 8.4 days (SD = 6.7), respectively. The conversion rate to open surgery was 0%. Long-term follow-up was available in 85.7% (12 out of 14 patients) with a mean follow-up of 36.1 months (SD = 28.1). The >30-day complication rate was 14.3% (n = 2). These 2 patients presented with recurrent episodes of cholangitis due to hepatico-jejunostomy mild stenosis, which were successfully treated with transhepatic percutaneous biliary drainage and multiple dilatations. CONCLUSIONS: Robot-assisted BDI reconstruction is feasible, safe, and may represent an interesting option in expert hands. It maintains all the benefits of minimally invasive surgery and seems to have technical advantages in fine dissection and microsuturing in the liver hilum (magnified microsuturing). In this series, 14 patients with major BDIs were repaired with the robotic approach, with conversion and reoperation rates of 0%. Long-term outcome evaluation requires a longer follow up and larger series, but the initial results are promising. PMID- 28657947 TI - Modern Surgeons: Still Masters of Their Trade or Just Operators of Medical Equipment? PMID- 28657948 TI - Impact of the Hospital Readmission Reduction Program on Surgical Readmissions Among Medicare Beneficiaries. AB - OBJECTIVE: To understand the impact of the Hospital Readmission Reduction Program on both future targeted and nontargeted surgical procedures. BACKGROUND: The Hospital Readmission Reduction Program, established under the Affordable Care Act in March of 2010, placed financial penalties on hospitals with higher than expected rates of readmission beginning in 2012 for targeted medical conditions. Multiple studies have suggested a "spill-over" effect into other conditions, but the extent of that effect for specific surgical procedures is unknown. METHODS: A retrospective review 5,122,240 Medicare beneficiaries who underwent future targeted procedures (total hip replacement, total knee replacements) or nontargeted procedures (colectomy, lung resection, abdominal aortic aneurysm repair, coronary artery bypass graft, aortic valve replacement, mitral valve repair) using an interrupted time series model to assess the rates of readmission before the Hospital Readmission Reduction Program was announced (2008-2010), whereas the program was being implemented (2010-2012) and after penalties were initiated (2012-2014). We also explored if the change in readmission rates were correlated with changes in index length of stay, use of observation status, or discharge to a skilled nursing facility. RESULTS: From 2008 to 2014 rates of readmission declined for both target conditions (6.8%-4.8%; slope change -0.07 to -0.10, P < 0.001) and nontarget conditions (17.1%-13.4%; slope change -0.04 to 0.11, P < 0.001). The rate of reduction was most prominent after announcement of the program between 2010 and 2012 for both targeted and nontargeted conditions. During the same time period, mean hospital length of stay decreased; nontargeted conditions (10.4-8.4 days) and targeted conditions (3.6-2.8 days). There was no correlation between hospital reduction in readmissions and use of observation only admissions (Pearson correlation coefficient = 0.01) or discharge to a skilled nursing facility (Pearson correlation coefficient = 0.05). CONCLUSIONS: Trends in readmissions after inpatient surgery are consistent with hospitals responding to financial incentives announced in the Hospital Readmission Reduction Program. There appears to be both an anticipatory effect (future targeted procedures reducing readmission before payments implemented) and a spillover effect (nontargeted procedures also reducing readmissions). PMID- 28657949 TI - Laparoscopic Surgery for Adhesive Small Bowel Obstruction Is Associated With a Higher Risk of Bowel Injury: A Population-based Analysis of 8584 Patients. AB - OBJECTIVE: We set out to compare the incidence of bowel repair and/or resection in a large cohort of patients with adhesive small bowel obstruction (SBO) managed operatively. BACKGROUND: Laparoscopic lysis of adhesions for adhesive SBO (aSBO) is becoming more common, yet might increase the risk of bowel injury given the distended and/or potentially compromised small bowel. METHODS: We used administrative discharge data derived from a large geographic region, identifying patients who underwent surgery for their first episode of aSBO during 2005 to 2014. Procedure codes were used to determine the exposure: either an open approach or a laparoscopic approach (including procedures converted to open). The primary outcome was incidence of bowel intervention, defined as intraoperative enterotomy, suture repair of intestine, or bowel resection. We estimated the odds of bowel intervention after adjusting for patient and clinical factors. RESULTS: A total of 8584 patients underwent operation for aSBO. Patients undergoing laparoscopic procedures were younger with fewer comorbid conditions. The rate of laparoscopic approaches increased more than 3-fold during the study period (4.3% 14.3%, P < 0.0001). The incidence of bowel intervention was 53.5% versus 43.4% in laparoscopic versus open procedures (P < 0.0001). After adjustment for potential confounders, the odds of bowel intervention among patients treated laparoscopically versus open was 1.6 (95% confidence interval: 1.4-1.9). CONCLUSIONS: Laparoscopic procedures for aSBO are associated with a greater likelihood of intervention for bowel injury and/or repair. This increase might be due to challenges inherent with laparoscopic approaches in patients with distended small bowel. Surgeons should approach laparoscopic lysis of adhesions with a higher level of awareness and use strategies to mitigate this risk. PMID- 28657950 TI - National Trends in Readmission Following Inpatient Surgery in the Hospital Readmissions Reduction Program Era. AB - OBJECTIVE: The aim of this study was to investigate whether the Hospital Readmissions Reduction Program, a national program that introduced financial penalties for high readmission rates for certain medical conditions, had a "spillover" effect on surgical conditions. SUMMARY BACKGROUND DATA: During the past decade, there have been multiple national efforts to improve surgical care. Readmission rates are a key metric for assessing surgical quality. Whether surgical readmission rates have declined, and whether the Hospital Readmissions Reduction Program has had an influence is unclear. METHODS: Using national Medicare data, we identified patients undergoing a range of procedures during the past decade. We examined whether certain procedures that would be targeted by the HRRP had a differential change in readmissions compared to other procedures. We used an interrupted time-series model to examine readmission trends in three time periods: pre-ACA, HRRP implementation, and HRRP penalty. RESULTS: Between 2005 and 2014, 17,423,106 patients underwent the procedures of interest; risk-adjusted rates of readmission across the 8 procedures declined from 12.2% to 8.6%. Pre-ACA rates of readmission were decreasing [-0.060% per quarter (-0.072%, -0.048%), P < 0.001]. During the HRRP implementation period, the rate of decline of readmissions increased [-0.129% (-0.142%, -0.116%), P < 0.001] and continued declining at a similar rate during the penalty period [-0.118% (-0.131%, 0.105%), P < 0.001]. Largest declines in surgical readmissions were seen among the nontargeted procedures. The hospitals with the greatest reductions in medical readmissions also had the greatest drop in surgical readmissions. CONCLUSIONS: Surgical readmission rates have fallen during the past decade and rates of decline have increased during the HRRP period. PMID- 28657951 TI - Firearm Deaths in America: Can We Learn From 462,000 Lives Lost? AB - OBJECTIVE: We sought to determine whether state firearm legislation correlated with firearm-related fatality rates (FFR) during a 15-year period. BACKGROUND: The politicized and controversial topic of firearm legislation has been grossly understudied when the relative impact of American firearm violence is considered. Scientific evidence regarding gun legislation effectiveness remains scant. METHODS: Demographic and intent data (1999-2013) were collected from the Centers for Disease Control and Prevention's Web-Based Injury Statistics Query and Reporting System database and compared by state firearm legislation rankings with respect to FFR. State scorecards were obtained from firearm-restrictive (Brady Campaign/Law Center against Gun Violence [BC/LC]) and less-restrictive (National Rifle Association) groups. FFR were compared between restrictive and least restrictive states during 3 periods (1999-2003, 2004-2008, 2009-2013). RESULTS: During 1999 to 2013, 462,043 Americans were killed by firearms. Overall FFR did not change during the 3 periods (10.89 +/- 3.99/100,000; 10.71 +/- 3.93/100,000; 11.14 +/- 3.91/100,000; P = 0.87). Within each period, least-restrictive states had greater unintentional, pediatric, and adult suicide, White and overall FFR than restrictive states (all P < 0.05). Conversely, no correlation was seen, during any of the 3 time periods, with either homicide or Black FFR-population subsets accounting for 41.7% of firearm deaths. CONCLUSIONS: Restrictive firearm legislation is associated with decreased pediatric, unintentional, suicide, and overall FFR, but homicide and Black FFR appear unaffected. Future funding and research should be directed at both identifying the most effective aspects of firearm legislation and creating legislation that equally protects every segment of the American population. PMID- 28657952 TI - Diagnosis of Superior Semicircular Canal Dehiscence in the Presence of Concomitant Otosclerosis. AB - OBJECTIVE: To review three patients with concurrent otosclerosis and superior canal dehiscence identified before operative intervention and provide a practical diagnostic approach to this clinical scenario. STUDY DESIGN: Retrospective patient series. SETTING: Tertiary/quaternary referral center. PATIENTS: Individuals with confirmed diagnoses of concurrent otosclerosis and superior semicircular canal dehiscence syndrome. INTERVENTIONS: Detailed history and physical examinations were performed on these patients, as well as detailed audiovestibular testing and computed tomography imaging. MAIN OUTCOME MEASURES: Establishing a clear diagnosis of concurrent otosclerosis and superior semicircular canal dehiscence syndrome using a thorough diagnostic approach. RESULTS: Three patients presented with conductive hearing loss and normal tympanic membranes. When history and physical examination yielded suspicious third window symptoms/signs, more detailed audiovestibular testing and computed tomography scan imaging were performed. All three patients were ultimately identified to have concurrent otosclerosis and superior canal dehiscence. Conservative management was the option of choice for two of these patients (trial of a hearing aid) and surgical intervention was performed to treat the otosclerosis in the remaining patient. PMID- 28657953 TI - The Influence of Intraoperative Testing on Surgical Decision-making During Cochlear Implantation. AB - OBJECTIVE: To review our use of intraoperative testing during cochlear implantation (CI) and determine its impact on surgical decision-making. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: A total of 197 children and adults who underwent a total of 266 primary and/or revision CI by a single surgeon from 2010 to 2015. INTERVENTION: Intraoperative electrophysiologic monitoring including evoked compound action potentials and electrical impedances. MAIN OUTCOME MEASURES: Whether surgical management was changed based on intraoperative testing. RESULTS: In only 2 of 266 patients (0.8%), the back-up device was used due to findings on intraoperative testing. In three patients (1.1%), X-ray was performed intraoperatively to confirm intracochlear electrode placement, which was found to be normal in all patients. CONCLUSION: Our data suggest that with respect to CI in children and adults in straightforward cases (e.g., normal anatomy, nondifficult insertion, etc.), routine intraoperative evoked compound action potentials, impedances, and imaging rarely influence surgical decision-making in our clinic and may have limited usefulness in these patients. The implications of this are discussed and a review of the literature is presented. PMID- 28657955 TI - The Hannover Coupler: Controlled Static Prestress in Round Window Stimulation With the Floating Mass Transducer. AB - INTRODUCTION: Stimulation of the cochlear round window (RW) with the floating mass transducer (FMT) still suffers from large variation in clinical outcomes. Beside the geometric mismatch between RW and FMT diameter that is a known limiting factor in achieving optimal coupling between actuator and RW membrane, the applied static force between FMT and RW is usually undefined. In this study, the feasibility and efficacy of a specially designed FMT coupler permitting application of static preloads to the RW membrane to optimize FMT-RW coupling was investigated. METHODS: Experiments were performed in fresh human cadaveric temporal bones. The "Hannover Coupler" FMT-prosthesis has a spherical tip (d=0.5 mm) at the front end and a spring at the prosthesis back that enables the application of static preloads and mobility of the FMT at the same time. Stapes footplate (SFP) displacements in response to acoustic stimulation of the tympanic membrane and to RW stimulation by the FMT were measured by a Laser-Doppler vibrometer. RESULTS: Average SFP displacement responses of ASTM standard F2504-05 compliant temporal bones to RW stimulation by the "Hannover Coupler" were dependent on the applied force (~0-100 mN) and increased by up to 25 dB at frequencies >= 1 kHz. When averaged at speech relevant frequencies (0.5, 1, 2, 4 kHz) SFP displacements showed a global maximum at RW preloads of ~4 mN. CONCLUSION: The coupling between FMT and RW membrane was improved by the application of static RW preloads as indicated by increased SFP amplitudes to RW stimulation. PMID- 28657954 TI - Outcomes and Time to Emergence of Auditory Skills After Cochlear Implantation of Children With Charge Syndrome. AB - OBJECTIVE: Review perioperative complications, benefits, and the timeframe over which auditory skills develop in children with CHARGE syndrome who receive a cochlear implant (CI). STUDY DESIGN: IRB-approved retrospective chart review of children with CHARGE syndrome who had at least 12 months of cochlear implant use. SETTING: Tertiary care children's hospital. PATIENTS: Twelve children, seven males and five females. Mean age implant = 3.5 years (1.7-8.2 yr); mean duration follow-up = 4.7 years (1.5-10.1 yr). INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: Auditory skills categorized into four levels, temporal bone imaging findings, perioperative complications, time to emergence of speech perception, expressive communication mode. RESULTS: All children imaged with magnetic resonance imaging had cochlear nerve deficiency in at least one ear. Speech awareness threshold improved with the CI compared with aided preoperative in 83% of children, with means of 51.7 dB SAT preoperative and 27.1 dB with the CI (p <= 0.002). Overall, four children improved to auditory Level 2 (improved detection), three obtained Level 3 (closed-set speech perception), and three had open-set speech perception with their CIs (Level 4) that was first evident at 3.5, 3.3, and 0.8 years postimplant testing. Two children had minimal or limited improvement. One child with hypoplasia of the cochlear nerve obtained open-set levels. CONCLUSION: Auditory skills may develop slowly in children with CHARGE syndrome who receive a CI but most can achieve at least improved detection. In our series, half acquired some speech perception ability. Cochlear nerve deficiency is frequent, but should not be a contraindication to implantation. PMID- 28657956 TI - Long-axis Ultrasonic Images of the Pediatric Larynx and Trachea with a Cuffed Endotracheal Tube. PMID- 28657957 TI - A Prospective Study of Age-dependent Changes in Propofol-induced Electroencephalogram Oscillations in Children. AB - BACKGROUND: In adults, frontal electroencephalogram patterns observed during propofol-induced unconsciousness consist of slow oscillations (0.1 to 1 Hz) and coherent alpha oscillations (8 to 13 Hz). Given that the nervous system undergoes significant changes during development, anesthesia-induced electroencephalogram oscillations in children may differ from those observed in adults. Therefore, we investigated age-related changes in frontal electroencephalogram power spectra and coherence during propofol-induced unconsciousness. METHODS: We analyzed electroencephalogram data recorded during propofol-induced unconsciousness in patients between 0 and 21 yr of age (n = 97), using multitaper spectral and coherence methods. We characterized power and coherence as a function of age using multiple linear regression analysis and within four age groups: 4 months to 1 yr old (n = 4), greater than 1 to 7 yr old (n = 16), greater than 7 to 14 yr old (n = 30), and greater than 14 to 21 yr old (n = 47). RESULTS: Total electroencephalogram power (0.1 to 40 Hz) peaked at approximately 8 yr old and subsequently declined with increasing age. For patients greater than 1 yr old, the propofol-induced electroencephalogram structure was qualitatively similar regardless of age, featuring slow and coherent alpha oscillations. For patients under 1 yr of age, frontal alpha oscillations were not coherent. CONCLUSIONS: Neurodevelopmental processes that occur throughout childhood, including thalamocortical development, may underlie age-dependent changes in electroencephalogram power and coherence during anesthesia. These age-dependent anesthesia-induced electroencephalogram oscillations suggest a more principled approach to monitoring brain states in pediatric patients. PMID- 28657958 TI - Measuring Perioperative Mortality: The Key to Improvement. PMID- 28657960 TI - Characterization of Risk-Taking in Adults With Bipolar Spectrum Disorders. AB - Individuals with bipolar spectrum disorders experience higher morbidity and mortality rates relative to the general population because of increased commission of dangerous behaviors. Despite this impact, little is known about the overall rates of risk-taking behaviors in patients currently being treated for such illness. This study examined the frequency of a variety of risk-taking behaviors in 100 adults with bipolar spectrum disorders in an active outpatient psychiatric treatment. It was found that 70% of individuals assessed reported at least one risk-taking behavior over the preceding 7 days. Implications for assessment and intervention are discussed. PMID- 28657961 TI - Suicidality and Survivability in Schizophrenia. PMID- 28657959 TI - Monitoring Anesthesia Care Delivery and Perioperative Mortality in Kenya Utilizing a Provider-driven Novel Data Collection Tool. AB - BACKGROUND: Perioperative mortality rate is regarded as a credible quality and safety indicator of perioperative care, but its documentation in low- and middle income countries is poor. We developed and tested an electronic, provider report driven method in an East African country. METHODS: We deployed a data collection tool in a Kenyan tertiary referral hospital that collects case-specific perioperative data, with asynchronous automatic transmission to central servers. Cases not captured by the tool (nonobserved) were collected manually for the last two quarters of the data collection period. We created logistic regression models to analyze the impact of procedure type on mortality. RESULTS: Between January 2014 and September 2015, 8,419 cases out of 11,875 were captured. Quarterly data capture rates ranged from 423 (26%) to 1,663 (93%) in the last quarter. There were 93 deaths (1.53%) reported at 7 days. Compared with four deaths (0.53%) in cesarean delivery, general surgery (n = 42 [3.65%]; odds ratio = 15.80 [95% CI, 5.20 to 48.10]; P < 0.001), neurosurgery (n = 19 [2.41%]; odds ratio = 14.08 [95% CI, 4.12 to 48.10]; P < 0.001), and emergency surgery (n = 25 [3.63%]; odds ratio = 4.40 [95% CI, 2.46 to 7.86]; P < 0.001) carried higher risks of mortality. The nonobserved group did not differ from electronically captured cases in 7-day mortality (n = 1 [0.23%] vs. n = 16 [0.58%]; odds ratio =3.95 [95% CI, 0.41 to 38.20]; P = 0.24). CONCLUSIONS: We created a simple solution for high-volume, prospective electronic collection of perioperative data in a lower- to middle income setting. We successfully used the tool to collect a large repository of cases from a single center in Kenya and observed mortality rate differences between surgery types. PMID- 28657963 TI - Maternal HIV infection is an important health determinant in non-HIV-infected infants. AB - OBJECTIVE: To assess morbidity and mortality in HIV-exposed uninfected (HEU) children to help guiding appropriate clinical care and effective preventive interventions. DESIGN: This is a longitudinal study comparing two cohorts of children; one born to HIV-infected women and the other born to HIV-uninfected women. METHODS: We have analyzed prospectively obtained information on nutritional status, morbidity and mortality from 966 HEU and 909 HIV-unexposed infants followed up until their first 18 months of life at a referral health facility in southern Mozambique. Determinants for adverse health outcomes in HEU children were also assessed using multivariate logistic regression. RESULTS: Increased incidence of hospital admissions (P = 0.0015), shorter survival in the first 18 months of life (P = 0.0510) and moderate and severe malnutrition (P = 0.0006 and 0.0014, respectively) were observed among HEU children compared with HIV-unexposed children. Incidence of outpatient attendance in HEU children was associated with being men, older age and the mother being on antiretroviral treatment. Among HEU children, those who were never breastfed, or who were weaned or were partially breastfed, had an increased incidence of hospital admissions compared with children who were exclusively breastfed. CONCLUSION: Maternal HIV infection has important health consequences in non-HIV-infected children. As the prevalence of HIV-infected pregnant women is maintained and the proportion of HIV infected children declines because of the scale-up of antiretroviral treatment during pregnancy and breastfeeding, more focus should be given to the health needs of HEU children to ensure that the post-2015 sustainable development goals are met. PMID- 28657962 TI - A common anti-cytomegalovirus drug, ganciclovir, inhibits HIV-1 replication in human tissues ex vivo. AB - BACKGROUND: Cytomegalovirus (CMV) is a common HIV-1 copathogen. Since CMV infection is an important contributor to immune activation, the driving force of HIV disease, an anti-CMV strategy might be beneficial to HIV-infected patients. Shin et al. (J Acquir Immune Defic Syndr 2014; 65:251-258) reported that anti-CMV therapy with valganciclovir in coinfected individuals results in a decrease of HIV viral load that is not accompanied by a decrease of immune activation. This suggests an alternative mechanism for HIV inhibition other than suppression of CMV-mediated inflammation. METHOD: We evaluated the anti-HIV activity of ganciclovir (GCV), the active form of valganciclovir, on HIV replication in human tissues ex vivo. RESULTS: We show that GCV has a direct suppressive activity on HIV replication in human tissues ex vivo, including laboratory strains, drug resistant and primate HIV-1 isolates. We deciphered the mechanism of this inhibition and showed that GCV-TP is incorporated in the nascent DNA chain and acts as a delayed chain terminator. CONCLUSION: Our results suggest that anti-CMV strategy using valganciclovir in HIV-1-infected individuals may reduce HIV-1 viral load not only indirectly by decreasing CMV-mediated immune activation but also directly by inhibiting HIV-1 reverse transcriptase. PMID- 28657964 TI - MSM starting preexposure prophylaxis are at risk of hepatitis C virus infection. AB - OBJECTIVES AND DESIGN: Hepatitis C virus (HCV) has been recognized as an emerging sexually transmitted infection (STI) among HIV-positive MSM. However, HIV negative MSM at high risk for HIV might also be at increased risk for HCV. We studied the HCV prevalence in HIV-negative MSM who start preexposure prophylaxis (PrEP) in Amsterdam. Phylogenetic analysis was used to compare HCV strains obtained from HIV-negative and HIV-positive MSM. METHODS: At enrolment in the Amsterdam PrEP demonstration project, HIV-negative MSM were tested for the presence of HCV antibodies and HCV RNA. If positive for HCV RNA, an HCV NS5B gene fragment (709 bp) was sequenced and compared with HCV isolates from HIV-positive MSM (n = 223) and risk groups other than MSM (n = 153), using phylogenetic analysis. RESULTS: Of 375 HIV-negative MSM enrolled in Amsterdam PrEP, 18 (4.8%, 95% confidence interval 2.9-7.5%) of participants were anti-HCV and/or HCV RNA positive at enrolment; 15 of 18 (83%) had detectable HCV RNA. HCV genotyping showed genotype 1a (73%), 4d (20%), and 2b (7%). All HCV-positive MSM starting PrEP were part of MSM-specific HCV clusters containing MSM with and without HIV. CONCLUSION: HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported. All HIV-negative HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status. Hence, routine HCV testing should be offered to MSM at high risk for HIV, especially for those enrolling in PrEP programs. PMID- 28657965 TI - Fatty liver disease in HIV: common, underappreciated, and understudied. PMID- 28657966 TI - Dolutegravir-induced paresthesias. PMID- 28657967 TI - Publication trends during the HIV pandemic: contributions by country. PMID- 28657968 TI - Urine tenofovir and emtricitabine concentrations provide biomarker for exposure to HIV preexposure prophylaxis. PMID- 28657969 TI - Varicella-related Primary Health-care Visits, Hospitalizations and Mortality in Norway, 2008-2014. AB - BACKGROUND: Norway does not currently implement universal varicella vaccination in childhood. We aimed to characterize health care burden of varicella in Norway in the prevaccine era. METHODS: We linked individual patient data from different national registries to examine varicella vaccinations and varicella-coded primary care consultations, hospitalizations, outpatient hospital visits, deaths and viral infections of central nervous system in the whole population of Norway during 2008-2014. We estimated health care contact rates and described the epidemiology of medically attended varicella infection. RESULTS: Each year approximately 14,600 varicella-related contacts occurred within primary health care and hospital sector in Norway. The annual contact rate was 221 cases per 100,000 population in primary health care and 7.3 cases per 100,000 in hospital care. Both in primary and hospital care, the highest incidences were observed among children 1 year of age: 2,654 and 78.1 cases per 100,000, respectively. The annual varicella mortality was estimated at 0.06 deaths per 100,000 and in hospital case-fatality rate at 0.3%. Very few (0.2-0.5%) patients were vaccinated against varicella. Among hospitalized varicella patients, 22% had predisposing conditions, 9% had severe-to-very severe comorbidities and 5.5% were immunocompromised. Varicella-related complications were reported in 29.3% of hospitalized patients. Varicella zoster virus was the third most frequent virus found among 16% of patients with confirmed viral infections of central nervous system. CONCLUSIONS: Varicella causes a considerable health care burden in Norway, especially among children. To inform the policy decision on the use of varicella vaccination, a health economic assessment of vaccination and mathematical modeling of vaccination impact are needed. PMID- 28657971 TI - Laryngeal mask airway as a rescue device for failed endotracheal intubation during scene-to-hospital air transport of combat casualties. AB - BACKGROUND: Advanced airway management of combat casualties during scene-to hospital air transport is challenging. Because of the short transport time, flight physicians of the Israeli military airborne combat evacuation unit are approved for the use of a laryngeal mask airway (LMA) in the event of failed endotracheal intubation (ETI). The aim of this study was to assess the effectiveness of LMA use during scene-to-hospital transport of combat casualties in Israel. PATIENTS AND METHODS: A retrospective cohort analysis of all combat casualties treated with ETI during scene-to-hospital transport over a 3-year period was carried out. Successful LMA insertion was defined as satisfactory placement of the device on the basis of adequate chest expansion with bag-mask ventilation. RESULTS: The median flight time from scene to hospital was 13 min [interquartile range (IQR): 9-15 min]. Sixty-five casualties underwent ETI attempts, 47 successful and 18 failed. All 18 casualties who had failed ETI underwent LMA insertion as a rescue treatment. Six casualties suffered from traumatic brain injury, six had firearm injuries, two had blast injuries, and two had inhalational injuries. LMA insertion was successful in 16/18 (88.9%) casualties, 14 survived to hospital discharge, whereas two were declared dead upon hospital arrival. Two cases of LMA insertion were unsuccessful, but patients survived to hospital discharge. Among the 16 successful cases, the median oxygen saturation on scene-pickup before LMA insertion and on hospital-handover with LMA in place were 90% (IQR: 84-96%) and 98% (IQR: 96-99%), respectively (P<0.0001, the 95% confidence interval for difference between medians was 4-11). CONCLUSION: The findings of this study suggest that in the event of failed ETI, combat casualties can be treated effectively with LMA during a short scene-to-hospital transport time. PMID- 28657970 TI - Trends in Otitis Media Incidence After Conjugate Pneumococcal Vaccination: A National Observational Study. AB - BACKGROUND: Pneumococcal conjugate vaccine (PCV) was introduced in 2000. The first 7-valent vaccine (PCV7) was followed by a 13-valent vaccine (PCV13) with the same conjugate, and a 10-valent vaccine (PCV10), conjugated to protein D from Haemophilus influenzae. The vaccines offer some protection against pneumococcal acute otitis media (AOM), and, with PCV10, possibly also some protection against H. influenzae AOM. PCV7 was introduced in Sweden in 2009, but from 2010, Swedish counties were free to use either PCV13 or PCV10. The purpose of this study was to investigate the incidence of AOM-related diagnoses and surgical procedures before and after the introduction of PCV in Sweden, but also to compare the areas using PCV13 and PCV10. METHODS: Data showing the number of AOM diagnoses, ventilation tube insertions, myringotomies, acute mastoiditis cases and mastoidectomies between 2005 and 2014 were extracted from the National Board of Health and Welfare database. Yearly national incidences were calculated, and areas using PCV13 and PCV10 were compared. RESULTS: AOM incidence decreased, both in outpatients (39%) and hospital admissions (42%). Ventilation tube insertions decreased by 18%, and myringotomies by 15%. The decline in outpatient AOM and ventilation tube insertions was more pronounced in areas that used PCV10, but geographical differences were large also before vaccine introduction. CONCLUSION: Otitis media-related diagnoses have decreased in Sweden since the introduction of PCV. Though some decreases were more pronounced in areas where PCV10 were used, figures should be interpreted with great caution, because considerable geographical differences were obvious also before vaccine introduction. PMID- 28657973 TI - Guidelines under fire again! PMID- 28657974 TI - Carotid artery plaque and arterial stiffness: about conflicts between ultrasound and tonometry and between local and global. PMID- 28657972 TI - Expertise: no longer a sine qua non for guideline authors? AB - : Several sets of guidelines have been published recently and more are in the works. The very recent American College of Physicians/American Academy of Family Practitioners guidelines were put together by a set of authors and consultants without any expertise in the topic under discussion, that is, hypertension. Although we are not maintaining that all guidelines should be written exclusively by experts, complete lack of expertise among guideline authors is not acceptable. PMID- 28657975 TI - Retinal microvascular diameters: normative data and their use in clinical hypertension. PMID- 28657976 TI - How should we treat patients with primary aldosteronism to prevent new-onset diabetes mellitus? PMID- 28657977 TI - 'Oscillometric': a type of device, not a type of measurement. Oh when will they ever learn? PMID- 28657978 TI - Reply. PMID- 28657979 TI - Is there an increased heme oxygenase-1 behind the antioxidant effects of green tea on blood pressure and sympathoexcitation reduction? PMID- 28657980 TI - Reply. PMID- 28657981 TI - Lateralization of renal blood flow and renin secretion in fibromuscular dysplasia. PMID- 28657982 TI - Reply. PMID- 28657983 TI - Antihypertensive medication use and breast cancer risk. PMID- 28657984 TI - Reply. PMID- 28657985 TI - An Exemplary Review. PMID- 28657986 TI - The Truth Behind Transvaginal Mesh Litigation: Devices, Timelines, and Provider Characteristics. AB - OBJECTIVES: Following Food and Drug Administration communications about the safety of transvaginal prolapse, more than 73,000 patients with complications from treatment of pelvic organ prolapse (POP) or stress urinary incontinence (SUI) have filed product liability claims. This research analyzes the transvaginal mesh claims filed in the United States to identify key characteristics that may inform clinical decision-making. METHODS: We evaluated a 1% random sample from the Bloomberg Law Database: 2000 to 2014 and associated legal documents. Outcomes and measures used included annual rate of claim, mesh type, time interval between surgery and claim, defendants, and surgeon training. RESULTS: The search returned 76,865 results, and 2979 were excluded, leaving 73,915 claims. Of 739 claims (1%), 63.3% involved slings for SUI, 13.3% mesh for POP, and 165 (23.2%) involved both. The mesh named most often in claims was retropubic slings at 30.3% and transobturator slings at 27.1%. The number of cases filed increased significantly from 730 in 2011 to 11,798 in 2012, which then almost tripled in 2013 to 34,017. The interval from surgery to claim filing ranged from 4.8 to 5.3 years. Only 12% of implanting surgeons were or became board certified in Female Pelvic Medicine and Reconstructive Surgery. Only 4 cases named providers as codefendants. CONCLUSIONS: Most legal claims involved slings for SUI and began after the 2011 Food and Drug Administration communication about mesh for POP. The rise in lawsuits does not reflect the acceptably low complication rates for slings for SUI reported in the literature. PMID- 28657987 TI - Polypropylene Mesh Predicts Mesh/Suture Exposure After Sacrocolpopexy Independent of Known Risk Factors: A Retrospective Case-Control Study. AB - OBJECTIVE(S): The aim of this study was to determine if ultralightweight polypropylene mesh reduced the risk of mesh/suture exposure after sacrocolpopexy compared with heavier-weighted polypropylene. METHODS: Bivariate and multivariate analyses were used to interpret data from 133 cases and 261 control subjects to evaluate independent predictors of mesh/suture exposure after sacrocolpopexy from 2003 to 2013. RESULTS: Multivariate logistic regression revealed that prior surgery for incontinence (odds ratio [OR], 2.87; 95% confidence interval [CI], 1.19-6.96), porcine acellular cross-linked collagen matrix with medium-weight polypropylene mesh (OR, 4.95; 95% CI, 1.70-14.42), other polypropylene mesh (OR, 6.73; 95% CI, 1.12-40.63), nonabsorbable braided suture for vaginal mesh attachment (OR, 4.52; 95% CI, 1.53-15.37), and immediate perioperative complications (OR, 3.64; 95% CI, 1.53-13.37) were independent risk factors for mesh/suture exposure. After multivariate analysis, ultralightweight polypropylene mesh was no longer associated with decreased rates of mesh/suture exposure after controlling for known risk factors identified during bivariate analysis (P = 0.423). CONCLUSIONS: Both mesh choice and suture selection remained independent predictors of mesh/suture exposure, with heavier meshes increasing and monofilament suture decreasing rates of mesh/suture exposure. Based on this study, surgeons may consider use of delayed-absorbable, monofilament suture over nonabsorbable braided suture for attachment of vaginal mesh to reduce the risk of mesh/suture exposure when using mesh. PMID- 28657989 TI - Can the Learning Curve of Laparoscopic Sacrocolpopexy Be Reduced by a Structured Training Program? AB - OBJECTIVE: The aim of this study was to establish whether the learning curve for laparoscopic sacral colpopexy (LSC) could be significantly reduced in a structured learning program. METHODS: We conducted a prospective study aimed at mapping the learning curve of LSC in the setting of a structured learning program for a urogynecology fellow at the Royal Brisbane and Women's Hospital.The fellow was laparoscopic suturing and dissection naive at the commencement of her fellow position and was required to assist in 20 LSCs, video-edit 2 procedures, and undertake laparoscopic suturing and knot tying training on a laparoscopic trainer for 2 h/wk during the trial period.After the completion of this structured learning program, the fellow began performing LSC as the primary surgeon.Symptomatic assessment of pelvic organ prolapse and pelvic floor dysfunction was undertaken preoperatively and 12 months postoperatively using the Australian Pelvic Floor Questionnaire.Objective success at 12 months was defined as less than stage 2 prolapse in any compartment. Subjective success was defined as no prolapse on Q 28 to 31 on the Australian Pelvic Floor Questionnaire, and patient-determined success was defined as "much" or "very much better" on the Patient Global Impression of Improvement at 12 months. RESULTS: Five consecutive LSC in 90 minutes or less without intraoperative or postoperative complications was achieved by case 18. Overall objective success at 12 months was 91%, and subjective and patient-determined success was 95%. CONCLUSION: Previous studies on LSC that report a similar learning curve have recorded much longer operating times. We believe that the shorter operating time, without compromise to outcomes and complication rates, is a result of the structured learning program. PMID- 28657988 TI - Vaginal Uterosacral Ligament Suspension: A Retrospective Cohort of Absorbable and Permanent Suture Groups. AB - OBJECTIVE: The aim of this study was to compare anatomic results after vaginal uterosacral ligament suspension with absorbable versus permanent suture. METHODS: We performed a retrospective cohort study of women who underwent vaginal uterosacral ligament suspension, from 2006 to 2015. We compared 2 groups: (1) absorbable suspension suture and (2) permanent suspension suture (even if accompanied by absorbable suture). Our primary outcome was composite anatomic failure defined as (1) recurrent prolapse in any compartment past the hymen or (2) retreatment for prolapse. Continuous variables were analyzed using the Student t test or Mann-Whitney U test, and categorical variables were analyzed using chi or Fisher exact test. Multivariable logistic regression analysis was performed to control for confounders. P < 0.05 was considered significant. RESULTS: Of the 242 patients with medium-term follow-up (3 months to 2 years after surgery), 188 underwent vaginal uterosacral ligament suspension with only absorbable suture, and 54 underwent suspension with permanent suture. Compared with the absorbable suture cohort, the permanent suture cohort was more likely to have had advanced preoperative prolapse (P = 0.01), less likely to have had a prior hysterectomy (P = 0.01), and less likely to have undergone a concomitant posterior colporrhaphy/perineoplasty (P < 0.01). Overall, there were no differences in composite anatomic failure between the absorbable and permanent suture groups (17.0% vs 20.4%, P = 0.41). In multivariable logistic regression analyses, when controlling for covariates, there remained no difference in composite anatomic failure between permanent and absorbable suture groups. CONCLUSIONS: Completion of vaginal uterosacral ligament suspension using only absorbable suture affords similar anatomic outcomes in the medium term as compared with suspension with additional permanent suture. PMID- 28657990 TI - Urinary Incontinence in Pregnant Young Women and Adolescents: An Unrecognized At Risk Group. AB - OBJECTIVES: The aims of this study were to determine the prevalence of urinary incontinence (UI) in pregnant young women and adolescents, characterize UI subtype, and identify characteristics associated with UI. METHODS: This was a cross-sectional study of pregnant females aged 25 years or below, presenting for routine obstetrical care at a New York City community hospital. Subjects were stratified into 2 groups: adolescents (age, <=19 years) and young adults (age, >19 years). Demographic and obstetric data were collected. The 3 Incontinence Questions questionnaire was used to screen and evaluate UI symptoms. RESULTS: A total of 98 young females with a mean age of 20.3 +/- 2.6 years were enrolled. Most participants were nulliparous (64%). Of parous women, route of previous obstetric delivery was primarily vaginal (83%). Mean gestational age at recruitment was 34.5 +/- 7.5 weeks. The prevalence of UI was 52%. Urinary incontinence was associated with the following conditions: strenuous activity, 73%; urinary urgency, 67%; and absence of either, 20%. However, the most predominant UI subtype was with strenuous activity (63%). There was no statistical difference detected in demographic characteristics (such as age, parity, mode of delivery, race, education, and trimester of pregnancy) between continent and incontinent pregnant females (P > 0.18). No differences were appreciated between pregnant adolescents and young adult females with UI (P > 0.18). CONCLUSIONS: Urinary incontinence was present in 52% of pregnant females aged 25 years or below. By age group, approximately 50% of both adolescents and young adults reported UI during pregnancy. Continent and incontinent patients did not seem to differ demographically. Our study highlights the extent of UI in this segment of the population. This data may support the need for services targeting UI prevention and early intervention in this newly identified at-risk group. PMID- 28657991 TI - Age and Dyssynergia Subtypes Associated With Normal Sphincter Pressures in Women With Fecal Incontinence. AB - OBJECTIVES: Fecal incontinence (FI) is frequently associated with low sphincter pressures, sensory abnormalities, and advanced age. Twenty-three percent of patients with FI and 22% of healthy patients demonstrate dyssynergic defecation (DD) on high-resolution anorectal manometry. Overflow incontinence occurs in some DD patients with normal resting and squeeze anal sphincter pressures. Our aim was to identify factors associated with normal sphincter pressures in women with FI. METHODS: We reviewed medical records of 134 women with FI. Patients with normal resting and squeeze anal pressures were compared with those with abnormal pressures using Wilcoxon rank sum test and Fisher exact. Multivariable logistic regression was performed to identify factors associated with normal resting and squeeze anal pressures. RESULTS: Among 134 women, abnormal resting and/or squeeze pressures were identified in 113 and normal pressures were identified in 21. Women with normal sphincter pressures were younger (mean age 52.7 +/- 10.8 years vs 59.0 +/- 14.0 years, P = 0.036), more often had abnormal defecation indices (100% vs 83.2%, P = 0.043) and higher rectal defecation pressures (30.8 +/- 18.8 mm Hg vs 50.8 +/- 22.6 mm Hg, P < 0.001). There was an overall association between DD subtype and normal and abnormal sphincter pressure groups (P = 0.021). Dyssynergia subtypes I or III (odds ratio, 7.2; 95% confidence interval, 1.8 28.8) and age younger than 67 years (odds ratio, 8.5; 95% confidence interval, 1.5-48.6) were associated with greater odds of having normal sphincter pressures. CONCLUSIONS: Female FI patients with normal anal sphincter pressures are younger, have higher rectal defecation pressures, and more often have type I or type III DD. PMID- 28657992 TI - Ready or Not? Obstetrics and Gynecology Resident Preparedness for Female Pelvic Medicine and Reconstructive Surgery Training. AB - OBJECTIVE: The aim of this study was to assess the perception of female pelvic medicine and reconstructive surgery (FPMRS) program directors (PDs) and obstetrics and gynecology (OG) FMPRS fellows regarding the adequacy of OG residency as preparation for FPMRS fellowship. METHODS: Electronic invitations to complete a modified version of a validated survey were extended to FPMRS PDs and their second- and third-year OG FPMRS fellows who had just completed their first or second year of FPMRS fellowship, respectively. The survey consisted of 5 domains; qualitative questions and recommendations for improvement were elicited. RESULTS: Program directors (33%, 16/48) and second-year (64%, 29/45) and third year (53%, 26/49) fellows completed the surveys. While incoming fellows were deemed professional, serious surgical skill competency issues were identified: (1) PDs felt they could not leave their incoming fellow to operate independently on a major case for 30 minutes while in the next room compared with fellow responses (PDs: 33.3% vs second-year fellows: 67.9%; P = 0.03); (2) no PDs felt their fellows could suture laparoscopically; and (3) there was group consensus that incoming fellows were not proficient at cystoscopy (PDs: 40.0%, second-year fellows: 39.3%, third-year fellows: 32.0%; P = 0.82). Mostly, fellows could clinically evaluate and manage patients. Program directors thought their fellows had better understanding of statistics than fellows believed of themselves (P = 0.05). Increasing FPMRS exposure during residency was favored as the method to better prepare OG residents for fellowship. CONCLUSIONS: Quantitative and emerging qualitative outcomes highlight that fellows are professional and are largely able to evaluate and care for patients but that achieving independence, surgical skills, and scholarship requires further training. PMID- 28657993 TI - Outcomes and Characteristics of Patients Undergoing Surgical Management for Mesh Related Complications. AB - OBJECTIVE: The aims of this study were to describe the characteristics of women presenting with mesh-related complications and evaluate postoperative quality of life, sexual functioning, and patient-perceived outcomes. METHODS: This institutional review board-approved study included a retrospective chart review and a cross-sectional follow-up with validated questionnaires. Demographics and medical histories were collected from charts of women treated for mesh-related complaints between 2010 and 2014. Subjects completed follow-up validated questionnaires regarding health, sexual functioning, postoperative symptom improvement/severity, satisfaction, and regret with the decision to pursue treatment. RESULTS: Ninety-three charts were analyzed. Mean subject age was 55 years, median body mass index was 28.7 kg/m, and median time from mesh placement to presentation was 2.7 years. Forty-nine had midurethral sling mesh only, 30 had prolapse-related mesh, and 14 had both. Forty-two subjects (48.9%) had mesh exposures, 19 involving prolapse-related mesh (52.4% transvaginal and 47.4% sacrocolpopexy). Surgical revisions were most often for exposure and pain. Seventy-five women were reached for follow-up; 71 agreed to participate, 53 (75%) returned the questionnaires. Thirty had sling revision, 22 had prolapse mesh revision, and 1 had both. Questionnaire results revealed no changes in health or sexual function after treatment. Postoperatively, subjects reported symptom improvement, low symptom severity, as well as high satisfaction and low regret with the decision to pursue surgical intervention. CONCLUSIONS: Women with mesh complications presented 2 years after initial placement, most often complaining of exposure or pain/dyspareunia. Although no changes in health or sexual functioning were noted postoperatively, participants reported symptom improvement after revision and satisfaction with the decision to pursue treatment. PMID- 28657994 TI - Pudendal Neuromodulation as a Treatment for Persistent Genital Arousal Disorder-A Case Series. AB - BACKGROUND: Persistent genital arousal disorder (PGAD) is a rare life-altering condition characterized by unwanted, uncomfortable genital sensations or spontaneous orgasms without physical or emotional stimulation. Its etiology remains unclear, and a variety of treatments have been attempted with incomplete resolution. We propose that chronic pudendal neuromodulation (CPN) may be a useful treatment for PGAD symptoms. METHODS: A retrospective chart review was performed for women older than 18 years with a diagnosis of PGAD that had staged neuromodulation with placement of a tined lead at the pudendal nerve. Demographic, operative, and postoperative data were collected. A survey was then sent to these women to assess additional demographic data, preoperative and postoperative symptoms, and patient satisfaction. Descriptive statistics were performed. RESULTS: Six women underwent CPN for PGAD. Mean age was 52 (SD, 9) years. Five (83%) of 6 were still implanted at time of survey, at a mean of 38 months after implantation; 1 device was removed for nonuse. Four of 6 completed surveys and were still using their device. Three of 4 had met their treatment goals and were satisfied with CPN; 3 of 4 felt CPN was the most useful treatment modality they had used overall. Chronic pudendal neuromodulation also improved chronic pelvic pain (4/4), bowel function (3/4), and bladder function (3/4). CONCLUSIONS: Chronic pudendal neuromodulation can be an effective treatment for decreasing frequency of PGAD symptoms and providing symptom relief. PMID- 28657995 TI - One and the Same? Nocturnal Enuresis and Overactive Bladder in the Female Veteran Population: Evaluation of a Large National Database. AB - OBJECTIVES: The aims of this study were to describe relationships between women given a diagnosis of nocturnal enuresis (NE) and controls without any urinary complaints and to compare women with NE with those with overactive bladder (OAB). We hypothesized that NE has unique associations with demographics and medical and psychosocial diagnoses. METHODS: This is a secondary analysis of a database that included all female veterans who established care with a primary care provider from 1997 to 2015. International Classification of Diseases, Ninth Revision, codes identified women with a diagnosis of NE or OAB. Patient characteristics, medical diagnoses, and psychosocial factors previously described as relating to NE and/or OAB were compared between the 2 distinct comparative groups, with significance set at P < 0.05. Stepwise logistic regression was used to assess all significant findings. RESULTS: A total of 596,815 women were identified; controls totaled 570,049, the group with OAB totaled 26,446 (4.4%), and the group with NE totaled 301 (0.05%).Multivariable analysis compared the group with NE with controls; all measured psychosocial characteristics remained significantly associated with an NE diagnosis (all Ps < 0.05), as well as obstructive sleep apnea history, stroke, self-identification as "minority," smoking, hypertension, and a body mass index higher than those of the general control population (all Ps < 0.05).When the populations with NE and OAB were compared, a diagnosis of posttraumatic stress disorder, an overdose history, depression, military sexual trauma, increasing body mass index, and younger age remained significantly associated with NE (all Ps < 0.05). CONCLUSIONS: The association of NE with psychosocial characteristics and psychiatric illnesses persisted irrespective of the comparison population. Practitioners should investigate the diagnosis of NE in those female veterans with psychosocial issues. PMID- 28657996 TI - Effect of Cystocele Repair on Cervix Location in Women With Uterus In Situ. AB - INTRODUCTION AND HYPOTHESIS: Our objective was to test the hypothesis that cystocele repair, in the absence of hysterectomy or apical suspension, results in higher cervix location in some women. METHODS: We performed a retrospective chart review of women with a uterus in situ who underwent native tissue anterior repair without hysterectomy/apical suspension from 2008 to 2014. Demographics, medical history, and preoperative and 6-week postoperative Pelvic Organ Prolapse Quantification System measurements were abstracted. Cervix location was defined by the clinic Pelvic Organ Prolapse Quantification System point C value. Women with higher (more negative) postoperative point C values were compared with those with a lower (more positive)/unchanged point C. RESULTS: Of the 33 women included, mean age was 59.8 +/- 11.3 years. Median preoperative point C was -6.0 (interquartile range [IQR]: -6.75, -5.0) and point Ba was +2.0 (IQR: +0.5, +3.0). Point C was higher postoperatively in 21 (64%) of 33 women. Overall, point C was 1 cm higher post- versus preoperatively (-7.0 [IQR: -8.0, -6.0] vs -6.0 [IQR: 6.75, -5.0], P < 0.001) and point Ba was 4 cm higher (-2 [IQR: -3.0, -2.0] vs 2.0 [IQR: 0.5, 3.0], P < 0.001). Compared with women with lower/unchanged postoperative point C, those with higher point C were older (53.9 +/- 12.3 vs 63.1 +/- 9.4, P = 0.02) with lower parity (3.0 [IQR: 2.0, 3.0] vs 2.0 [IQR: 2.0, 3.0], P = 0.028). CONCLUSIONS: The test of our hypothesis shows that in certain women with cystocele, anterior repair alone may be associated with higher cervix location 6 weeks postoperatively. PMID- 28657997 TI - Women's Perception of Their Vulvar Appearance in a Predominantly Low-Income, Minority Population. AB - OBJECTIVES: The aim of this study was to investigate the effect of certain predictors, such as age and media exposure, on a woman's perception of her vulva anatomy. METHODS: We recruited 346 female visitors from a county teaching hospital to complete questionnaires that determine the following: demographics, satisfaction with their vulvar appearance, whether they consider their vulvar anatomy to be normal, exposure to media (namely having had Internet access or learned about genitalia from the Internet or any type of pornography), and consideration of cosmetic vulvar surgery for themselves. The participants were divided into 2 age groups; group I (45 years or older) and group II (18-44 years). Personal satisfaction, self-perceived normality, and one's consideration of cosmetic vulvar surgery were then compared between the 2 groups. RESULTS: A large percentage of women considered their vulva to be "normal," 93.1% of group I versus 96.0% of group II (P = 0.24). For group I, 87.5% were satisfied with their vulva versus 91.5% of group II (P = 0.24). The participants with media exposure report self-perceived normal-appearing vulvas at higher rates than those not exposed to media (96.7% vs 90.8%, respectively; P = 0.03). Of those who were satisfied with their vulvar appearance, 92.3% were exposed to media, whereas 84.5% were not exposed (P = 0.03). However, of the participants who reported consideration of vulvar surgery, 74.4% of them had exposure to media, whereas 25.6% had no media exposure (P = 0.034). CONCLUSIONS: Age does not play a significant role in determining a woman's acceptance of the appearance of her vulvar anatomy. However, media exposure was a significant determinant for self perception, satisfaction, and desire for cosmetic vulvar surgery. PMID- 28657998 TI - Long-Term Outcomes After Ventral Rectopexy With Sacrocolpo- or Hysteropexy for the Treatment of Concurrent Rectal and Pelvic Organ Prolapse. AB - OBJECTIVE: The primary objective is to describe the long-term anatomic and subjective outcomes in women undergoing ventral rectopexy with sacrocolpo- or hysteropexy. The secondary objective is to describe the perioperative adverse events. METHODS: This is a retrospective cohort of women who underwent ventral rectopexy with either concurrent sacrocolpo- or hysteropexy at a tertiary care center between 2009 and 2015. A composite outcome for recurrent pelvic organ prolapse and rectal prolapse was defined as subjective failure (vaginal or rectal prolapse symptoms), objective failure (prolapse to or beyond the hymen or full thickness rectal prolapse), or any retreatment for prolapse. Patient's Global Impression of Change was recorded at baseline and at all follow-up visits. Perioperative adverse events were defined a priori and collected up to 6 weeks after surgery. RESULT: A total of 59 patients underwent a ventral rectopexy, either a sacrocolpopexy (48/59, 81.3%) or sacrohysteropexy (11/59, 18.6%). The median follow-up after surgery for all patients was 17 months (range, 1-76) with a composite success rate for both pelvic organ prolapse and rectal prolapse (estimated by Kaplan-Meier method) of 57.4%. Forty (91%) of 44 patients reported a Patient's Global Impression of Change score of 6 or 7, indicating significant improvement after surgery. Of the patients, 15 (25.4%) experienced a perioperative adverse event. Use of biologic graft was associated with a higher rate of adverse event (40.0% [95% confidence interval, 24.6-57.5] vs 10.3% [95% confidence interval, 3.6-26.3]; P < 0.01). CONCLUSIONS: Ventral rectopexy with sacrocolpo- or hysteropexy is associated with significant improvement in anatomic and subjective outcomes. One in 4 women experienced a perioperative adverse event. PMID- 28657999 TI - Radiographic Misdiagnoses After Periurethral Bulking Agents. AB - OBJECTIVES: Injectable urethral bulking agents are commonly used to manage stress urinary incontinence. Urologic or other symptoms may prompt pelvic imaging at a later date, when bulking agents may be visualized and incorrectly interpreted. Our goal was to evaluate the incidence of misdiagnosis and which pathologies were the most common misinterpretations and their frequency. METHODS: All records were reviewed for patients who underwent periurethral injection for stress urinary incontinence for pelvic imaging after treatment from 2005 to 2015. Radiological reports were reviewed for any description potentially related to injection therapy, and descriptive statistics performed. RESULTS: A total of 528 patients underwent injection of a urethral bulking agent. Of these, 79 patients (15%) had a total of 111 additional abdominal or pelvic imaging studies performed with abnormal periurethral findings mentioned. Thirty-nine (35%) of 111 studies were correctly interpreted as urethral bulking agents, and in 72 (65%) of 111 studies, the urethral bulking agents were not correctly identified. The most common misdiagnoses were bladder calcification (26; 23%), urethral diverticulum with stone (12; 11%), periurethral calcification (9; 8%), unknown pelvic density (8; 7%), and mass suspicious for malignancy (6; 5%). CONCLUSIONS: Urethral bulking agents commonly were not mentioned on subsequent imaging but, when commented on, were misinterpreted 65% of the time including worrisome pathologies (diverticulum with stone, unknown mass, and malignancy), requiring subsequent evaluation and potentially procedural/surgical management. It is critical for the ordering clinician to inform the radiologist of this history and for radiologists to consider bulking agents in the differential diagnosis of radiographic findings in this location. PMID- 28658000 TI - The Effect of Resident Involvement in Pelvic Prolapse Surgery: A Retrospective Study From a Nationwide Inpatient Sample. AB - OBJECTIVE: The primary aim of this study was to assess the effect of resident involvement on perioperative complication rates in pelvic organ prolapse surgery using the National Surgical Quality Improvement database. METHODS: All pelvic organ prolapse operations from 2006 to 2012 were identified and dichotomized by resident participation. Preoperative characteristics and 30-day perioperative outcomes were compared using chi and Student t test. To control for nonrandomization of cases, propensity scores representing the probability of resident involvement as a function of a case's comorbidities were calculated. They were then divided into quartiles, and because of equal probabilities for the first and second quartiles, 3 groups were created (Q1/2, Q3, and Q4), followed by substratification and analysis. As a control, complications of transurethral resection of prostate and nephrectomy were dichotomized by resident involvement. RESULTS: We identified 2637 cases. Resident involvement was associated with increased postoperative urinary tract infections, perioperative complications, and procedure length. After stratification by propensity scoring, the following unique findings occurred in each group: in the first group, resident involvement was associated with increased rates of readmission, pulmonary embolism, and sepsis; in the second and third groups, resident involvement was associated with increased rates of superficial surgical site infection. Resident involvement in nephrectomy observed increased perioperative complications and procedural length. In prostate resection, increased procedure lengths and decreased postoperative length of stay were observed. CONCLUSIONS: Resident involvement in pelvic organ prolapse surgery was associated with an increased risk of adverse outcomes. A similar effect was seen with nephrectomy but not with a more simple endoscopic urologic procedure. PMID- 28658001 TI - Trends and Clinical Practice Patterns of Sacral Neuromodulation for Overactive Bladder. AB - OBJECTIVES: The aim of this study was to investigate surgical practice patterns of American urologists treating refractory overactive bladder (OAB) over the past decade. Refractory OAB remains a management challenge to urologists. When multiple medical therapies have failed, treatment options may include sacral neuromodulation (SNM) or surgery such as augmentation cystoplasty (AC). METHODS: Data on SNM and AC performed between 2003 and 2012 by certifying and recertifying urologists were obtained in the form of annualized case logs from the American Board of Urology (ABU). Associations between surgeon characteristics (type of certification, annual volume, practice type, and location) and these procedures were evaluated. RESULTS: Over the past decade, 756 of 6355 urologists certified with the ABU performed SNM or AC for the treatment of refractory OAB. Forty-five (6%) of these surgeons completed fellowships in female urology and 71 surgeons (9%) completed another type of fellowship program. Surgeons recertifying with ABU performed 76% of all SNM procedures. Although SNM and AC have increased from 64 to 2086 between 2003 and 2012, however, this is mainly driven by the increase of SNM from 48 to 2068 cases. Rates of AC have remained stable with 14 to 38 cases reported annually. However, they have declined relative to the total, from 25% in 2003 to less than 1% in 2012. CONCLUSIONS: Sacral neuromodulation has increased dramatically over the past decade in surgeons certified with the ABU. This is in contrast to AC, which while remaining stable in number of procedures. PMID- 28658002 TI - Obesity and Perioperative Complications in Pelvic Reconstructive Surgery in 2013: Analysis of the National Inpatient Sample. AB - OBJECTIVES: The primary aim of this study was to determine the impact of obesity on national rates of perioperative complications in women undergoing pelvic reconstructive surgery in 2013 in the United States. METHODS: Women who underwent pelvic reconstructive surgery were identified in the 2013 National Inpatient Sample using International Classification of Diseases, Ninth Revision procedure codes. Demographic data and comorbidities including obesity (body mass index >=30 kg/m) were abstracted. Perioperative complications and mortalities that occurred during the same admission were abstracted from the data set using International Classification of Diseases, Ninth Revision diagnosis codes. The complication rates were compared between obese and nonobese subjects. Univariate analysis was performed to determine factors associated with the primary outcome. Significant factors were included in the regression model to determine the adjusted odds ratio for perioperative complications in obese women. RESULTS: A total of 16,639 women underwent pelvic reconstructive surgery in the 2013 National Inpatient Sample data set and were included in the analysis. Approximately 10% of the study cohort was obese. The overall perioperative complication rate during the surgical admission was 25%. On multivariate analysis, obesity was found to increase the odds of perioperative complications by approximately 40% after controlling for age, race, income, concomitant hysterectomy, and medical comorbidities (adjusted odds ratio, 1.40; 95% confidence interval, 1.24-1.58; P < 0.0001). CONCLUSIONS: Obesity is an independent risk factor for perioperative complications in women who undergo pelvic reconstructive surgery. This information can be used for preoperative counseling and risk stratification. PMID- 28658003 TI - Anatomical Outcome and Patient Satisfaction After Laparoscopic Uterosacral Ligament Hysteropexy for Anterior and Apical Prolapse. AB - OBJECTIVES: The aim of this study was to determine anatomical and clinical cure, as well as patient satisfaction in uterine-preserving laparoscopic uterosacral ligament suspension (LUSLS) in women with anterior and apical prolapse. METHODS: This was a retrospective cohort study including all women who underwent LUSLS for anterior and apical prolapse between January 2012 and December 2015 at a tertiary care university hospital. All women had LUSLS hysteropexy and anterior colporrhaphy. Pre- and postoperative pelvic organ prolapse quantification (POP-Q) measurements were taken. Prolapse symptoms were queried via standardized history. Patient satisfaction was measured by the Patient Global Impression of Improvement (PGI-I). RESULTS: Fifty-three women underwent the procedure during the study period. Follow-up data were available for 48 women. The mean preoperative POP-Q Ba point was 2.7 +/- 1.6 and C point was -0.8 +/- 2.8. At a mean follow-up of 17.5 +/- 16.0 months with a median of 12 months (range, 1-54 months), there was a significant improvement of POP-Q points Ba, C, and Bp (P < 0.001 for all comparisons). Anatomical cure, defined as no prolapse of any POP-Q point at or below 1 cm above the hymen (-1), was 85.4%. Clinical cure, defined as a composite outcome of no prolapse outside the hymen, C point above total vaginal length/2, no prolapse symptoms, and no need for further treatment, was 95.8%. At a mean of 22.2 +/- 12.4 months postoperatively, patient satisfaction was high, with 95.5% stating their condition was very much better (PGI-I-A) or much better (PGI-I-B). CONCLUSION: Laparoscopic uterosacral ligament suspension is a valid uterine preserving option for women with anterior and apical prolapse, with high anatomical and clinical cure rates and patient satisfaction. PMID- 28658004 TI - Is the Collapsibility Index of the Inferior Vena Cava an Accurate Predictor for the Early Detection of Intravascular Volume Change? AB - The ultrasonographic evaluation of inferior vena cava (IVC) parameters, particularly the collapsibility index (CI), has been widely used in the assessment of the fluid responsiveness of critically ill patients, but the results are conflicting. In this study, we aimed to investigate the early change in CI after increased intravascular volume (IVV) induced by passive leg raising (PLR). A total of 145 healthy volunteers over 18 years old were enrolled between September and December in 2015. Before and 2 min after PLR, the maximum and minimum IVC diameters (maxIVC and minIVC) were measured by color Doppler ultrasonography, and the difference in CI (DeltaCI) was calculated. The heart rate (HR) and noninvasive mean arterial pressure (MAP) were also monitored. We found that there was a significant increase in the mean maxIVC and minIVC values and a reduction in CI. Nevertheless, no significant differences in HR or MAP were observed before or 2 min after PLR. The baseline CI had no relationship with individual characteristics and a multiple linear regression analysis of the DeltaCI and individual characteristics showed that age, baseline CI, and BMI were independent variables for DeltaCI. In conclusion, IVC-CI measured by ultrasound is useful for the detection of early IVV change induced by 2 min PLR. However, its ability to detect the increased IVV value is influenced by age, BMI, and baseline CI. Moreover, only 50.3% of the subjects had an IVC-CI reduction of more than 10%, making IVC-CI of little value for clinical applications, due to its poor sensitivity. PMID- 28658005 TI - Polysaccharides from Bupleurum Induce Immune Reversal in Late Sepsis. AB - BACKGROUND: Bupleurum chinense, a well-known Traditional Chinese Medicine, has been used for thousands of years in China. In this study, we would suggest that Bupleurum polysaccharides (BPS) could improve the prognosis of sepsis through its impact on redistribution of BMCs, which triggers immune reversal in late sepsis. METHODS: BALB/c mice were divided into five groups: sham burn group, burn plus P aeruginosa group, burn plus P aeruginosa with BPS (40 mg/kg, 100 mg/kg, and 250 mg/kg) treatment group, and they were sacrificed at post-burn day (PBD) 0, 3, 5, and 7. BMCs, liver cells, and dendritic cells (DCs) were harvested. Flow cytometry was used to determine the change of phenotypes of DCs and isolate these cells. Cytometric beads array was utilized to analyze the level of inflammatory factors. Cell therapy of BMCs, liver cells, and DCs was administrated to explore the protective role of regional organ immunity. RESULTS: BPS could decrease the lethality of burn sepsis in a dose-dependent fashion and increase both the percentage of CD11cCD45RB DCs in bone marrow (BM) and liver and the number of BMCs and liver cells significantly. Cell therapy of BMCs, liver cells, and CD11cCD45RB DCs at PBD7 could protect septic mice from sepsis. CONCLUSION: BPS has shown its potential in promoting the prognosis of post-burn sepsis through its effect on immune redistribution of BMCs, especially via differentiation of CD11cCD45RB DC cells in BM and nonimmune organs to induce immune reversal in late sepsis. PMID- 28658008 TI - Intravenous Midazolam as a Diagnostic Test for Catatonia. PMID- 28658009 TI - Is Maintenance Electroconvulsive Therapy Always an Elective Procedure?: Weighing Medical Versus Psychiatric Risk. AB - Because of the severe nature of psychiatric illness, electroconvulsive therapy (ECT) is not always an "elective procedure." The pre-ECT medical evaluation, although important, should not be an impediment to timely ECT. We argue that an arbitrary regulation requiring new assessments every 30 days may be unduly burdensome and unnecessary. The small medical risk of treatment should be weighed against the potential psychiatric risk (including suicide) of delayed treatment. PMID- 28658006 TI - Whole Blood Redox Potential Correlates With Progressive Accumulation of Oxygen Debt and Acts as A Marker of Resuscitation in A Swine Hemorrhagic Shock Model. AB - INTRODUCTION: Oxidation-reduction reactions involve electron exchanges that require optimal balance for proper cell function. This balance is measured via redox potential and reflects oxidative stress. Despite the critical role of oxidative stress in critical illness and injury, little is known regarding redox potential. We hypothesize redox potential measurements will correlate with accumulation of O2 debt produced by hemorrhage over time. METHODS: Ten swine were studied using a polytrauma hemorrhagic shock model. Whole blood and plasma redox potential measures were obtained at defined stages of O2 debt (20 mL/kg, 40 mL/kg, 60 mL/kg, 80 mL/kg), and through resuscitation. Redox potential was determined by measuring open circuit potential using novel gold nanoporous electrodes with Ag/AgCl reference. RESULTS: Whole blood redox potential showed negative change as O2 debt accumulated, exhibiting positive response during resuscitation, and correlated with O2 debt across all animals (P < 0.001). Redox potential changes throughout O2 debt accrual were significant compared with baseline (P<=0.05), and at end resuscitation compared with O2 debt 60 mL/kg (P = 0.05) and 80 mL/kg (P = 0.02). Whole blood redox potential measures also correlated with oxygen extraction ratio, ScvO2, and lactic acid, appearing very sensitive to acute changes. Plasma redox potential showed no correlation with O2 debt. CONCLUSIONS: Whole blood redox potential demonstrates significant correlation to O2 debt at all stages in this model. These results set the stage for further study of redox potential as a direct measure of oxidative stress and potential clinical tool. Given redox potential plasma performance, these measures should be made in whole blood versus plasma. PMID- 28658010 TI - Refractory Catatonia Due to N-methyl-D-Aspartate Receptor Encephalitis Responsive to Electroconvulsive Therapy: The Clinical Use of the Clock Drawing Test. PMID- 28658011 TI - The Clinical Alliance and Research in Electroconvulsive Therapy Network: An Australian Initiative for Improving Service Delivery of Electroconvulsive Therapy. AB - OBJECTIVE: There is currently substantial heterogeneity in electroconvulsive therapy (ECT) treatment methods between clinical settings. Understanding how this variation in clinical practice is related to treatment outcomes is essential for optimizing service delivery. The Clinical Alliance and Research in ECT Network is a clinical and research framework with the aims of improving clinical practice, enabling auditing and benchmarking, and facilitating the collection of naturalistic clinical data. METHODS: The network framework and clinical and treatment variables collected and rationale for the use of particular outcome measures are described. Survey results detailing the use of ECT across initial participating clinical centers were examined. RESULTS: The data are reported from 18 of 22 participating centers, the majority based in Australia. Melancholic unipolar depression was the most common clinical indication (78%). Right unilateral (44%) and bifrontal (39%) were the most commonly used electrode placements. Eighty one percent of the centers used individual seizure titration for initial dosing. CONCLUSIONS: There was substantial heterogeneity in the use of ECT between participating centers, indicating that the Network is representative of modern ECT practice. The Clinical Alliance and Research in ECT Network may therefore offer the opportunity to improve service delivery and facilitate the investigation of unresolved research questions pertaining to modern ECT practice. PMID- 28658012 TI - Use of Electroconvulsive Therapy in Dementia-Related Agitation: A Case Series. AB - OBJECTIVES: This naturalistic prospective observation study examines the efficacy of electroconvulsive therapy (ECT) in treating dementia-related agitation. METHODS: Patients with dementia-related agitation who received ECT were compared with patients with the same condition who did not receive ECT using Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI)-nursing home version, and Clinical Global Impression Scale (CGI). Outcomes were compared between ECT-treated and non-ECT-treated patients. RESULTS: A total of 9 patients were included in the study. Six received ECT, and 3 did not. Patients in the ECT and non-ECT-treated groups had comparable baseline scores (CMAI, P = 0.880; NPI, P = 0.814; and CGI, P = 0.445). The CMAI, NPI, and CGI scores were lower on final assessment in both groups with no statistically significant difference (CMAI, P = 0.771; NPI, P = 0.243; and CGI, P = 0.519). CONCLUSIONS: Electroconvulsive therapy should be considered as a treatment option in the management of severe treatment refractory dementia-related agitation. PMID- 28658013 TI - Hippocampal Gray Volumes Increase in Treatment-Resistant Depression Responding to Vagus Nerve Stimulation. AB - BACKGROUND: Changes in hippocampal gray matter volumes are proposed to be involved in pathogenesis, course, and treatment response of major depressive disorder. Converging evidence suggests that reduced neurogenesis may occur in treatment-resistant depression (TRD). Vagus nerve stimulation (VNS) is a well defined, long-term brain stimulation treatment for TRD. However, its in vivo positive effect on hippocampal modulation as mechanism of action has never been investigated before in clinical studies. In this study, we intended to explore hippocampal volumetric changes and clinical antidepressant responses in patients with TRD after 6 and 12 months of treatment with VNS. METHODS: The TRD outpatients were evaluated for VNS implantation. Right and left hippocampal volumes in 6 TRD patients, who met the criteria for VNS treatment, were measured at baseline before the implantation and after 6 and 12 months. The patients were assessed using Beck Depression Inventory and Hamilton Depression Rating Scale at baseline and at follow-up visits. RESULTS: There was a statistically significant and progressive increase in right and left hippocampal volumes during the follow up (P < 0.05). Furthermore, patients showed a significant improvement on Hamilton Depression Rating Scale and Beck Depression Inventory scores (P < 0.05). CONCLUSIONS: Our data suggest a VNS modulatory effect on hippocampal plasticity as measured by hippocampal gray volume increase in TRD patients. These preliminary findings indicate the fundamental role of hippocampal remodeling as a marker of response to VNS in TRD. PMID- 28658014 TI - Penetrating injuries to the duodenum: An analysis of 879 patients from the National Trauma Data Bank, 2010 to 2014. AB - BACKGROUND: Despite wide belief that the duodenal Organ Injury Scale has been validated, this has not been reported in the published literature. Based on clinical experience, we hypothesize that the American Association for Surgery of Trauma Organ Injury Scale (AAST-OIS) for duodenal injuries can independently predict mortality. Our objectives were threefold: (1) describe the national profile of penetrating duodenal injuries, (2) identify predictors of morbidity and mortality, and (3) validate the duodenum AAST-OIS as a statistically significant predictor of mortality. METHODS: Using the Abbreviated Injury Scale 2005 and International Classification of Diseases-9th Rev.-Clinical Modification (ICD-9-CM) E-codes, we identified 879 penetrating duodenal trauma patients from the National Trauma Data Bank between 2010 and 2014. We controlled patient-level covariates of age, biological sex, systolic blood pressure (SBP), Glasgow Coma Scale (GCS) score, pulse, Injury Severity Score (ISS), and Organ Injury Scale (OIS) grade. We estimated multivariable generalized linear mixed models to account for the nesting of patients within trauma centers. RESULTS: Our results indicated an overall mortality rate of 14.4%. Approximately 10% of patients died within 24 hours of admission, of whom 76% died in the first 6 hours. Patients averaged approximately five associated injuries, 45% of which involved the liver and colon. Statistically significant independent predictors of mortality were firearm mechanism, SBP, GCS, pulse, ISS, and AAST-OIS grade. Specifically, odds of death were decreased with 10 mm Hg higher admission SBP (13% decreased odds), one point higher GCS (14.4%), 10-beat lower pulse (8.2%), and 10-point lower ISS (51.0%). CONCLUSION: This study is the first to report the national profile of penetrating duodenal injuries. Using the National Trauma Data Bank, we identified patterns of injury, predictors of outcome, and validated the AAST-OIS for duodenal injuries as a statistically significant predictor of morbidity and mortality. LEVEL OF EVIDENCE: Epidemiologic/Prognostic, level IV. PMID- 28658015 TI - A Framework for Integrating Implicit Bias Recognition Into Health Professions Education. AB - Existing literature on implicit bias is fragmented and comes from a variety of fields like cognitive psychology, business ethics, and higher education, but implicit-bias-informed educational approaches have been underexplored in health professions education and are difficult to evaluate using existing tools. Despite increasing attention to implicit bias recognition and management in health professions education, many programs struggle to meaningfully integrate these topics into curricula. The authors propose a six-point actionable framework for integrating implicit bias recognition and management into health professions education that draws on the work of previous researchers and includes practical tools to guide curriculum developers. The six key features of this framework are creating a safe and nonthreatening learning context, increasing knowledge about the science of implicit bias, emphasizing how implicit bias influences behaviors and patient outcomes, increasing self-awareness of existing implicit biases, improving conscious efforts to overcome implicit bias, and enhancing awareness of how implicit bias influences others. Important considerations for designing implicit-bias-informed curricula-such as individual and contextual variables, as well as formal and informal cultural influences-are discussed. The authors also outline assessment and evaluation approaches that consider outcomes at individual, organizational, community, and societal levels. The proposed framework may facilitate future research and exploration regarding the use of implicit bias in health professions education. PMID- 28658016 TI - Leadership Development Programs at Academic Health Centers: Results of a National Survey. AB - PURPOSE: To identify the prevalence and characteristics of faculty leadership development programs (LDPs) offered by North American academic health centers (AHCs) and to uncover gaps in leadership training. METHOD: Faculty development/affairs deans of the 161 Association of American Medical Colleges member schools were surveyed in 2015 on their approach to faculty leadership training. For AHCs delivering their own training, the survey included questions about LDP participants, objectives, curriculum, delivery, resources, and evaluation. The literature on leadership and leadership development was used to develop a taxonomy of leadership competencies, which formed the basis of the survey questions related to program content. Survey results were analyzed with descriptive statistics and chi-square analysis for categorical data. RESULTS: Of the 94 respondents (response rate 58%), 93 provided some form of leadership training and 61 provided a formal internal faculty LDP. Content was variable and rarely based on a specific leadership competency model. Although programs described innovative approaches to learning, lectures and case discussions were the predominant approaches. Evaluation beyond participant satisfaction was uncommon. CONCLUSIONS: Faculty LDPs were common, with some programs describing elements informed by the leadership literature. However, nationally programs can improve by basing content on a leadership competency model, incorporating multiple approaches to teaching, and implementing more rigorous program evaluation. PMID- 28658017 TI - Rethinking the Match: A Proposal for Modern Matchmaking. AB - Since the 1950s, the National Resident Matching Program, or "the Match," has governed the placement of medical students into residencies. The Match was created to protect students in an era when residency positions outnumbered applicants and hospitals pressured students early in their academic careers to commit to a residency position. Now, however, applicants outnumber positions, applicants are applying to increasing numbers of programs, and the costs of the Match for applicants and programs are high. Meanwhile, medical education is evolving toward a competency-based approach, a U.S. physician shortage is predicted, and some researchers describe a "July effect"-worse clinical outcomes correlated with the mass entry of new residents.Against this background, the authors argue for adopting a more modern, free-market approach to residency matchmaking that might better suit the needs of applicants, programs, and the public. They propose allowing students who have been identified by their medical schools as having achieved graduation-level competency to apply to residency programs at any point during the year. Residency programs would set their own application timetables and extend offers in an ongoing fashion. Students, counseled by their schools, would accept or decline offers as desired. The authors argue this approach would better support competency-based education while allowing applicants and programs more choice regarding how they engage and adapt within the selection process. The approach's staggered start times for new residents might attenuate the July effect and improve outcomes for patients. Medical students might also enter and thereby complete residency earlier, increasing the physician workforce. PMID- 28658018 TI - Team Investment and Longitudinal Relationships: An Innovative Global Health Education Model. AB - PROBLEM: Increasing student interest in global health has resulted in medical schools offering more global health opportunities. However, concerns have been raised, particularly about one-time, short-term experiences, including lack of follow-through for students and perpetuation of unintentional messages of global health heroism, neocolonialism, and disregard for existing systems and communities of care. Medical schools must develop global health programs that address these issues. APPROACH: The Global Health Scholars Program (GHSP) was created in 2008-2009 at Penn State College of Medicine. This four-year program is based on values of team investment and longitudinal relationships and uses the service-learning framework of preparation, service, and reflection. Teams of approximately five students, with faculty oversight, participate in two separate monthlong trips abroad to the same host community in years 1 and 4, and in campus and Web-based activities in years 2 and 3. OUTCOMES: As of December 2016, 191 students have been accepted into the GHSP. Since inception, applications have grown by 475% and program sites have expanded from one to seven sites on four continents. The response from students has been positive, but logistical challenges persist in sustaining team investment and maintaining longitudinal relationships between student teams and host communities. NEXT STEPS: Formal methods of assessment should be used to compare the GHSP model with more traditional approaches to global health education. Other medical schools with similar aims can adapt the GHSP model to expand their global health programming. PMID- 28658019 TI - History and Outcomes of 50 Years of Physician-Scientist Training in Medical Scientist Training Programs. AB - Physician-scientists are needed to continue the great pace of recent biomedical research and translate scientific findings to clinical applications. MD-PhD programs represent one approach to train physician-scientists. MD-PhD training started in the 1950s and expanded greatly with the Medical Scientist Training Program (MSTP), launched in 1964 by the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health. MD-PhD training has been influenced by substantial changes in medical education, science, and clinical fields since its inception. In 2014, NIGMS held a 50th Anniversary MSTP Symposium highlighting the program and assessing its outcomes. In 2016, there were over 90 active MD-PhD programs in the United States, of which 45 were MSTP supported, with a total of 988 trainee slots. Over 10,000 students have received MSTP support since 1964. The authors present data for the demographic characteristics and outcomes for 9,683 MSTP trainees from 1975-2014. The integration of MD and PhD training has allowed trainees to develop a rigorous foundation in research in concert with clinical training. MSTP graduates have had relative success in obtaining research grants and have become prominent leaders in many biomedical research fields. Many challenges remain, however, including the need to maintain rigorous scientific components in evolving medical curricula, to enhance research oriented residency and fellowship opportunities in a widening scope of fields targeted by MSTP graduates, to achieve greater racial diversity and gender balance in the physician-scientist workforce, and to sustain subsequent research activities of physician-scientists. PMID- 28658021 TI - A Free-Market Approach to the Match: A Proposal Whose Time Has Not Yet Come. AB - The authors respond to a proposal in this issue of Academic Medicine by Ray, Bishop, and Dow, who recommend adopting a free-market approach to the Match in which applicants and programs negotiate directly with each other to find and fill residency positions year-round. This Invited Commentary examines and responds to the reasons Ray and colleagues give for changing the Match and explores their proposal's implications and likelihood of success.The authors question Ray and colleagues' argument that assumptions underlying the National Resident Matching Program algorithm have been violated. The authors suggest there is insufficient evidence for the "July effect" and that the possibility for improvement in physician supply due to the year-round entry of graduates into the workforce ultimately faces the rate-limiting step of caps on residency positions allocated to programs. Most important, competency-based medical education, on which the free-market proposal depends, is not yet sufficiently developed.Nonetheless, the imbalanced ratio of applicants to positions in the Match is contributing to a rise in the numbers of student applications and program interviews. Although the proposed free-market approach might, as Ray and colleagues envision, curtail applications as well as reduce time and financial resources currently expended on the process, it would require significant changes on the part of applicants, residency programs, medical schools, and other stakeholders.Because the proposed free-market approach could reduce some negative effects of the imbalance of applicants and positions, it merits ongoing discussion along with other more immediate practical solutions to issues with the Match. PMID- 28658020 TI - Socially Accountable Medical Education: An Innovative Approach at Florida International University Herbert Wertheim College of Medicine. AB - PROBLEM: Despite medical advances, health disparities persist, resulting in medicine's renewed emphasis on the social determinants of health and calls for reform in medical education. APPROACH: The Green Family Foundation Neighborhood Health Education Learning Program (NeighborhoodHELP) at Herbert Wertheim College of Medicine provides a platform for the school's community-focused mission. NeighborhoodHELP emphasizes social accountability and interprofessional education while providing evidence-based, patient- and household-centered care. NeighborhoodHELP is a required, longitudinal service-learning outreach program in which each medical student is assigned a household in a medically underserved community. Students, teamed with learners from other professional schools, provide social and clinical services to their household for three years. Here the authors describe the program's engagement approach, logistics, and educational goals and structure. OUTCOMES: During the first six years of NeighborhoodHELP (September 2010-August 2016), 1,470 interprofessional students conducted 7,452 visits to 848 households with, collectively, 2,252 members. From August 2012, when mobile health centers were added to the program, through August 2016, students saw a total of 1,021 household members through 7,207 mobile health center visits. Throughout this time, households received a variety of free health and social services (e.g., legal aid, tutoring). Compared with peers from other schools, graduating medical students reported more experience with clinical interprofessional education and health disparities. Surveyed residency program directors rated graduates highly for their cultural sensitivity, teamwork, and accountability. NEXT STEPS: Faculty and administrators are focusing on social accountability curriculum integration, systems for assessing and tracking relevant educational and household outcomes, and policy analysis. PMID- 28658022 TI - Educational Technologies for Physician Continuous Professional Development: A National Survey. AB - PURPOSE: To determine the past experiences with, current use of, and anticipated use of online learning and simulation-based education among practicing U.S. physicians, and how findings vary by age. METHOD: The authors surveyed 4,648 randomly sampled board-certified U.S. physicians, September 2015 to April 2016, using Internet-based and paper questionnaires. Survey items (some optional) addressed past and current technology usage, perceived technology effectiveness, and anticipated future use of specific technology innovations. RESULTS: Of 988 respondents, 444 completed optional items. Of these, 429/442 (97.1%) had used online learning and 372/442 (84.2%) had used simulation-based education in the past five years. Desire for more online learning was modest (mean [standard deviation], 4.6 [1.5]; 1 = strongly disagree, 7 = strongly agree), as was desire for more simulation-based education (4.2 [1.7]). Both online learning and simulation-based education were perceived as effective (5.2 [1.4]; 5.0 [1.4]). Physicians believed they possess adequate skills for online learning (5.8 [1.2]) and that point-of-care learning is vital to effective patient care (5.3 [1.3]). Only 39.0% used objective performance data to guide their learning choices, although 64.6% agreed that such information would be useful. The highest-rated innovations included a central repository for listing educational opportunities and tracking continuing education credits, an app to award credit for answering patient-focused questions, 5-minute and 20-minute clinical updates, and an e mailed "question of the week." Responses to most survey items were similar across age groups. CONCLUSIONS: Practicing physicians generally seem receptive and prepared to use a variety of educational technologies, regardless of age. PMID- 28658023 TI - Preadmission Use of Calcium Channel Blocking Agents Is Associated With Improved Outcomes in Patients With Sepsis: A Population-Based Propensity Score-Matched Cohort Study. AB - OBJECTIVES: Use of calcium channel blockers has been found to improve sepsis outcomes in animal studies and one clinical study. This study determines whether the use of calcium channel blockers is associated with a decreased risk of mortality in patients with sepsis. DESIGN: Population-based matched cohort study. SETTING: National Health Insurance Research Database of Taiwan. PATIENTS: Hospitalized severe sepsis patients identified from National Health Insurance Research Database by International Classification of Diseases, Ninth Revision, Clinical Modification codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The association between calcium channel blocker use and sepsis outcome was determined by multivariate-adjusted Cox proportional hazard models and propensity score analysis. To examine the influence of healthy user bias, beta-blocker was used as an active comparator. Our study identified 51,078 patients with sepsis, of which, 19,742 received calcium channel blocker treatments prior to the admission. Use of calcium channel blocker was associated with a reduced 30-day mortality after propensity score adjustment (hazard ratio, 0.94; 95% CI, 0.89 0.99), and the beneficial effect could extend to 90-day mortality (hazard ratio, 0.95; 95% CI, 0.89-1.00). In contrast, use of beta-blocker was not associated with an improved 30-day (hazard ratio, 1.06; 95% CI, 0.97-1.15) or 90-day mortality (hazard ratio, 1.00; 95% CI, 0.90-1.11). On subgroup analysis, calcium channel blockers tend to be more beneficial to patients with male gender, between 40 and 79 years old, with a low comorbidity burden, and to patients with cardiovascular diseases, diabetes, or renal diseases. CONCLUSIONS: In this national cohort study, preadmission calcium channel blocker therapy before sepsis development was associated with a 6% reduction in mortality when compared with patients who have never received calcium channel blockers. PMID- 28658024 TI - The Impact of Mortality on Total Costs Within the ICU. AB - OBJECTIVES: The high cost of critical care has engendered research into identifying influential factors. However, existing studies have not considered patient vital status at ICU discharge. This study sought to determine the effect of mortality upon the total cost of an ICU stay. DESIGN: Retrospective cohort study. SETTING: Twenty-six ICUs at 13 hospitals in the United States. PATIENTS: 58,344 admissions from January 1, 2012, to June 30, 2016, obtained from a commercial ICU database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median observed cost of a unit stay was $9,619 (mean = $16,353). A multivariable regression model was developed on the log of total costs for a unit stay, using severity of illness, unit admitting diagnosis, mortality in the unit, daily unit occupancy (occupying a bed at midnight), and length of mechanical ventilation. This model had an r of 0.67 and a median difference between observed and expected costs of $437. The first few days of care and the first day receiving mechanical ventilation had the largest effect on total costs. Patients dying before unit discharge had 12.4% greater costs than survivors (p < 0.01; 99% CI = 9.3-15.5%) after multivariable adjustment. This effect was most pronounced for patients with an extended ICU stay who were receiving mechanical ventilation. CONCLUSIONS: While the largest drivers of ICU costs at the patient level are day 1 room occupancy and day 1 mechanical ventilation, mortality before unit discharge is associated with substantially higher costs. The increase was most evident for patients with an extended ICU stay who were receiving mechanical ventilation. Studies evaluating costs among ICUs need to take mortality into account. PMID- 28658025 TI - Determinants of Receiving Palliative Care and Ventilator Withdrawal Among Patients With Prolonged Mechanical Ventilation. AB - OBJECTIVES: Increasing numbers of patients with prolonged mechanical ventilation generates a tremendous strain on healthcare systems. Patients with prolonged mechanical ventilation suffer from long-term poor quality of life. However, no study has ever explored the willingness to receive palliative care or terminal withdrawal and the factors influencing willingness. DESIGN: Cross-sectional study. SETTING: Five different hospitals of Taipei City Hospital system. PATIENTS: Adult patients with ventilatory support for more than 60 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified the family members of 145 consecutive patients with prolonged mechanical ventilation in five hospitals of Taipei City Hospital system and enrolled family members for 106 patients (73.1%). We collected information from patient families' regarding concepts (knowledge, attitude, and experiences) of palliative care, caregiver burden, family function, patient quality of life, and physician-family communications. From the medical record, we obtained duration of hospitalization, consciousness level, disease severity, medical cost, and the presence of do-not resuscitate orders. The vast majority of family members agreed with the concept of palliative care (90.4%) with 17.3% of the family members agreeing to ventilator withdrawal currently and 67.5% terminally in anticipation of death. Approximately half of the family members regretted having chosen prolonged mechanical ventilation (56.7%). Reduced patient quality of life and increased family understanding of palliative care significantly associated with increased caregiver willingness to endorse palliative care and withdraw life-sustaining agents in anticipation of death. Longer duration of ventilator usage and hospitalization was associated with increased feelings of regret about choosing prolonged mechanical ventilation. CONCLUSIONS: During prolonged mechanical ventilation, physicians should thoroughly discuss its benefits and burdens. Families should be given the opportunity to discuss the circumstances under which they might request the implementation of palliative care or withdrawal of mechanical ventilation in order to avoid prolonging the dying process. PMID- 28658026 TI - Faster Blood Flow Rate Does Not Improve Circuit Life in Continuous Renal Replacement Therapy: A Randomized Controlled Trial. AB - OBJECTIVES: To determine whether blood flow rate influences circuit life in continuous renal replacement therapy. DESIGN: Prospective randomized controlled trial. SETTING: Single center tertiary level ICU. PATIENTS: Critically ill adults requiring continuous renal replacement therapy. INTERVENTIONS: Patients were randomized to receive one of two blood flow rates: 150 or 250 mL/min. MEASUREMENTS AND MAIN RESULTS: The primary outcome was circuit life measured in hours. Circuit and patient data were collected until each circuit clotted or was ceased electively for nonclotting reasons. Data for clotted circuits are presented as median (interquartile range) and compared using the Mann-Whitney U test. Survival probability for clotted circuits was compared using log-rank test. Circuit clotting data were analyzed for repeated events using hazards ratio. One hundred patients were randomized with 96 completing the study (150 mL/min, n = 49; 250 mL/min, n = 47) using 462 circuits (245 run at 150 mL/min and 217 run at 250 mL/min). Median circuit life for first circuit (clotted) was similar for both groups (150 mL/min: 9.1 hr [5.5-26 hr] vs 10 hr [4.2-17 hr]; p = 0.37). Continuous renal replacement therapy using blood flow rate set at 250 mL/min was not more likely to cause clotting compared with 150 mL/min (hazards ratio, 1.00 [0.60-1.69]; p = 0.68). Gender, body mass index, weight, vascular access type, length, site, and mode of continuous renal replacement therapy or international normalized ratio had no effect on clotting risk. Continuous renal replacement therapy without anticoagulation was more likely to cause clotting compared with use of heparin strategies (hazards ratio, 1.62; p = 0.003). Longer activated partial thromboplastin time (hazards ratio, 0.98; p = 0.002) and decreased platelet count (hazards ratio, 1.19; p = 0.03) were associated with a reduced likelihood of circuit clotting. CONCLUSIONS: There was no difference in circuit life whether using blood flow rates of 250 or 150 mL/min during continuous renal replacement therapy. PMID- 28658028 TI - The double jeopardy of percutaneous coronary interventions in patients with previous stroke. PMID- 28658027 TI - Transcranial Doppler Microemboli Monitoring for Stroke Risk Stratification in Blunt Cerebrovascular Injury. AB - OBJECTIVES: To assess whether microemboli burden, assessed noninvasively by bedside transcranial Doppler ultrasonography, correlates with risk of subsequent stroke greater than 24 hours after hospital arrival among patients with blunt cerebrovascular injury. The greater than 24-hour time frame provides a window for transcranial Doppler examinations and therapeutic interventions to prevent stroke. DESIGN: Retrospective cohort study. SETTING: Level I trauma center. PATIENTS: One thousand one hundred forty-six blunt cerebrovascular injury patients over 10 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 1,146 blunt cerebrovascular injury patients; 54 (4.7%) experienced stroke detected greater than 24 hours after arrival. Among those with isolated internal carotid artery injuries, five of nine with delayed stroke had positive transcranial Dopplers (at least one microembolus detected with transcranial Dopplers) before stroke, compared with 46 of 248 without (risk ratio, 5.05; 95% CI, 1.41-18.13). Stroke risk increased with the number of microemboli (adjusted risk ratio, 1.03/microembolus/hr; 95% CI, 1.01-1.05) and with persistently positive transcranial Dopplers over multiple days (risk ratio, 16.0; 95% CI, 2.00 127.93). Among patients who sustained an internal carotid artery injury with or without additional vessel injuries, positive transcranial Dopplers predicted stroke after adjusting for ipsilateral and contralateral internal carotid artery injury grade (adjusted risk ratio, 2.91; 95% CI, 1.42-5.97). No patients with isolated vertebral artery injuries had positive transcranial Dopplers before stroke, and positive transcranial Dopplers were not associated with delayed stroke among patients who sustained a vertebral artery injury with or without additional vessel injuries (risk ratio, 0.90; 95% CI, 0.21-3.83). CONCLUSIONS: Microemboli burden is associated with higher risk of stroke due to internal carotid artery injuries, but monitoring was not useful for vertebral artery injuries. PMID- 28658030 TI - Fatigue and physical fitness of mildly disabled persons with multiple sclerosis: a cross-sectional study. AB - Fatigue is frequent and disabling in persons with multiple sclerosis (pwMS) with mild neurological disability. These patients also have impaired physical fitness. Whether mildly disabled pwMS are deconditioned, and this deconditioning is linked to fatigue, remains unknown. Our aim is to determine the physical fitness of mildly disabled patients with multiple sclerosis and study its relationship with perceived fatigue and to link perceived fatigue with other parameters. Twenty patients (14 women; mean age: 45.5 years) with mild disability (Expanded Disability Status Scale 0-4) underwent a 2-min walking test, Timed Up-and-Go test, aerobic capacity testing, and isometric knee extension testing to assess strength and neuromuscular fatigability. They completed questionnaires assessing perceived fatigue, psychological status, and physical activity. Correlation coefficients and multivariate regression were used to analyze the relationships among variables. Seventeen (85%) patients reported a high level of fatigue. Thirteen (65%) patients had subnormal aerobic capacity. Fatigue was weakly to moderately associated with aerobic capacity, mobility, walking capacity, depression, and neuromuscular fatigability. An association of disease duration, aerobic capacity, and the neuromuscular fatigability index explained 65.1% of fatigue. A high proportion of pwMS with mild neurological disability are fatigued and deconditioned. Perceived fatigue is linked to aerobic capacity, neuromuscular fatigability, depression, mobility, and walking capacity. Focusing on these parameters could help in the management of fatigue. PMID- 28658031 TI - Performance Indicators in Spine Surgery. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To elucidate how performance indicators are currently used in spine surgery. SUMMARY OF BACKGROUND DATA: The Patient Protection and Affordable Care Act has given significant traction to the idea that healthcare must provide value to the patient through the introduction of hospital value-based purchasing. The key to implementing this new paradigm is to measure this value notably through performance indicators. METHODS: MEDLINE, CINAHL Plus, EMBASE, and Google Scholar were searched for studies reporting the use of performance indicators specific to spine surgery. We followed the Prisma-P methodology for a systematic review for entries from January 1980 to July 2016. All full text articles were then reviewed to identify any measure of performance published within the article. This measure was then examined as per the three criteria of established standard, exclusion/risk adjustment, and benchmarking to determine if it constituted a performance indicator. RESULTS: The initial search yielded 85 results among which two relevant studies were identified. The extended search gave a total of 865 citations across databases among which 15 new articles were identified. The grey literature search provided five additional reports which in turn led to six additional articles. A total of 27 full text articles and reports were retrieved and reviewed. We were unable to identify performance indicators. The articles presenting a measure of performance were organized based on how many criteria they lacked. We further examined the next steps to be taken to craft the first performance indicator in spine surgery. CONCLUSION: The science of performance measurement applied to spine surgery is still in its infancy. Current outcome metrics used in clinical settings require refinement to become performance indicators. Current registry work is providing the necessary foundation, but requires benchmarking to truly measure performance. LEVEL OF EVIDENCE: 1. PMID- 28658032 TI - Assessment of the Change in Alignment of Fixed Segment After Adult Spinal Deformity Surgery. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To determine the prevalence of loss in fixed segment alignment after surgical correction of adult spinal deformity (ASD) and identify associated risk factors. SUMMARY OF BACKGROUND DATA: Altered fixed segment alignment influences global spinal alignment; however, associated risk factors have not been determined. METHODS: Data of 63 patients with ASD (55 females; mean age, 68.0 yrs), who underwent corrective fusion from the lower thoracic spine to the pelvis and completed the 2-year follow up, were retrospectively analyzed. Change in alignment early postoperatively and at 2 years postoperatively was evaluated using the fixed segmental angle (FSA) and fixed vertebral angle (FVA). The predictive value of the following parameters was evaluated: age, sex, body mass index (BMI), high grade osteotomy, rod material, screw loosening, spinopelvic parameters [T1 pelvic angle (TPA), sagittal vertical axis (SVA), pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis (TK), and proximal junctional kyphosis (PJA), and Oswestry Disability Index (ODI) scores]. RESULTS: Change of 2.4 degrees in FSA and -3.1 degrees in FVA were identified 2 years postoperatively, with higher intrarater and interrater reliability for FSA. Based on minimal detectable change in FSA, patients were classified into two groups: (+) loss (DeltaFSA >3 degrees ) and (-) loss (DeltaFSA <=3 degrees ). Correction loss occurred in 17 patients; these patients had a greater BMI, higher rate of high-grade osteotomies, commercially pure titanium (CP) rods implanted, screw loosening, higher preoperative and postoperative TPA, and higher TPA, SVA, and PT after 2 years, than patients without correction loss. CONCLUSION: The loss of sagittal fixed segment alignment was relatively high at 27%. Greater BMI, high grade osteotomies, CP rod use, and sagittal malalignment were associated with correction loss after ASD surgery. LEVEL OF EVIDENCE: 4. PMID- 28658033 TI - Laminoplasty Does not Lead to Worsening Axial Neck Pain in the Properly Selected Patient With Cervical Myelopathy: A Comparison With Laminectomy and Fusion. AB - STUDY DESIGN: Retrospective cohort study of prospectively collected data. OBJECTIVE: To determine if laminoplasty (LP) is associated with worsening axial neck pain in patients with multilevel cervical myelopathy, and to compare neck pain, clinical outcomes, and radiographic measures in a group undergoing laminectomy and fusion (LF). SUMMARY OF BACKGROUND DATA: Postoperative new or worsening axial neck pain is commonly cited as a major disadvantage of laminoplasty. However, there remains a paucity of corroborative data from large series. METHODS: Following institutional review board approval, we reviewed the medical records, radiographs, and prospective clinical outcomes database of 85 patients undergoing LP and 52 patients undergoing LF for cervical myelopathy with minimum 1-year radiographic follow-up and average clinical follow-up of 18.5 months. LP was performed in those with neutral to lordotic C2-7 alignment and who did not complain of diffuse axial pain. Otherwise, LF was performed. Clinical outcomes included visual analogue score (VAS)-neck pain, VAS-total pain, neck disability index (NDI), short form 36, modified Japanese Orthopaedic Association (mJOA), and several radiographic parameters. RESULTS: VAS-neck did not worsen in LP (-0.2, P = 0.54) and did improve in LF (-2.0, P = 0.0013). VAS-total improved significantly in both groups (LF -1.04 +/- 0.52, P = 0.05; LP -1.4 +/- 0.51, P = 0.008). NDI improved in both groups, but was significant in only LP (LP decreased 6.79 +/- 2.25, P = 0.0032; LF decreased 4.01 +/- 3.05, P = 0.19). mJOA scores improved significantly in both groups (LP improved 2.89 +/- 0.27, P < 0.0001; LF improved 2.45 +/- 0.33, P < 0.0001). There was a small loss of cervical lordosis in both groups that was significant in LP (LP 2.92 degrees loss, P = 0.0181; LF 1.25 degrees loss, P = 0.53). CONCLUSION: In a carefully selected group of myelopathic patients without significant diffuse axial pain preoperatively and appropriate sagittal alignment, laminoplasty did not lead to worsening axial neck pain, and it was associated with significant improvements in other clinical and myelopathy outcomes. Although laminoplasty is not indicated in every myelopathic patient, this study exemplifies its efficacy as a non-fusion operation in the appropriately selected patient and assuages concerns regarding worsening axial neck pain in such patients following surgery. LEVEL OF EVIDENCE: 3. PMID- 28658034 TI - Do Occupational Risks for Low Back Pain Differ From Risks for Specific Lumbar Disc Diseases?: Results of the German Lumbar Spine Study (EPILIFT). AB - STUDY DESIGN: A multicenter, population based, case-control study. OBJECTIVE: The aim of the present analysis is to clarify potential differences in the "occupational risk profiles" of structural lumbar disc diseases on the one hand, and low back pain (LBP) on the other hand. SUMMARY OF BACKGROUND DATA: Physical workplace factors seem to play an important etiological role. METHODS: We recruited 901 patients with structural lumbar disc diseases (disc herniation or severe disc space narrowing) and 233 control subjects with "low-back-pain." Both groups were compared with 422 "low-back pain free" control subjects. Case history, pain data, neurological deficits, and movement restrictions were documented. LBP was recorded by the Nordic questionnaire on musculoskeletal symptoms. All magnetic resonance imaging, computed tomography, and X-rays were inspected by an independent study radiologist. The calculation of cumulative physical workload was based on a computer-assisted interview and a biomechanical analysis by 3-D-dynamic simulation tool. Occupational exposures were documented for the whole working life. RESULTS: We found a positive dose-response relationship between cumulative lumbar load and LBP among men, but not among women. Physical occupational risks for structural lumbar disc diseases [odds ratio (OR) 3.7; 95% confidence interval (95% CI) 2.3-6.0] are higher than for LBP (OR 1.9; 95% CI 1.0-3.5). CONCLUSION: Our finding points to potentially different etiological pathways in the heterogeneous disease group of LBP. Results suggest that not all of the structural disc damage arising from physical workload leads to LBP. LEVEL OF EVIDENCE: 4. PMID- 28658035 TI - Unplanned Reoperations in Magnetically Controlled Growing Rod Surgery for Early Onset Scoliosis With a Minimum of Two-Year Follow-Up. AB - STUDY DESIGN: A retrospective review of prospectively collected clinical and radiologic data of patients with magnetically controlled growing rods (MCGRs) from a multi-centered study with a minimum of 2-year follow-up. OBJECTIVE: The aim of this study was to describe the incidence and causes of unplanned reoperations and to report the outcomes of patients treated with MCGR for early onset scoliosis (EOS). SUMMARY OF BACKGROUND DATA: Published clinical studies have demonstrated that MCGR is safe and effective for curvature control of EOS, and can avoid repeated surgeries for distractions. However, there have been no reports on the unplanned reoperations and complications of MCGR for EOS with a large series of patients. METHODS: Between 2009 and 2012, 30 patients with EOS underwent MCGR implantation in six institutions. A retrospective review of prospectively collected clinical and radiologic data with a minimum of 2-year follow-up was conducted. Demographic data, radiologic measurements, unplanned reoperations, and other complications were noted. Risk factors for unplanned reoperations were analyzed. RESULTS: Patients underwent MCGR implantation at the mean age of 7.2 years. The mean follow-up period was 37 months. Fourteen patients (46.7%) underwent an unplanned reoperation within the follow-up period, with a mean time to reoperation of 23 months after initial surgery (range, 5-48 months). Causes of unplanned reoperation were failure of rod distractions, proximal foundation failure, rod breakage, and infection. More frequent distractions (between 1 week and 2 months) were associated with a higher rate of reoperation than distraction frequencies between 3 and 6 months (71% vs. 25%). CONCLUSION: This is the largest series with the longest follow-up to date that examines the need for additional unplanned surgery after the initial procedure. It highlights that MCGR surgery can be associated with unplanned reoperations, and more frequent distractions may be a risk factor. Long-term comparative studies with traditional growing rod are required to evaluate the effectiveness of this implant. LEVEL OF EVIDENCE: 4. PMID- 28658036 TI - Short Limited Fusion Versus Long Fusion With Deformity Correction for Spinal Stenosis With Balanced De Novo Degenerative Lumbar Scoliosis: A Meta-analysis of Direct Comparative Studies. AB - STUDY DESIGN: A systematic review and meta-analysis. OBJECTIVE: The aim of this study was to identify advantages and disadvantages of long versus short fusion for patients with Spinal stenosis with Balanced de novo degenerative lumbar Scoliosis without substantial Sagittal imbalance (SBSS), and to determine whether short fusions and long fusions have different curve progression after surgeries and differences in operative characteristics. SUMMARY OF BACKGROUND DATA: Patients with SBSS usually undergo short limited fusion or long fusion with curve correction. There is debate regarding whether short fusion is insufficient for SBSS for prevention scoliosis progression. METHODS: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was performed to find studies assessing the comparison of surgical techniques for SBSS. We included all direct comparative studies comparing short and long fusion and extracted data about scoliosis progression, changes in the Oswestry Disability Index (ODI), perioperative outcomes, and complication rates. A meta-analysis was performed to calculate weighted mean differences (WMDs) and 95% confidence intervals (CIs). RESULTS: We included data from six studies involving 362 patients (short fusion, 202 patients; long fusion, 160 patients). Both the short fusion and the long fusion groups showed decreased Cobb angle (short, 22.38 degrees -11.69 degrees ; long, 30.74 degrees -12.77 degrees ) and C7 plumb at the final follow-up. The long fusion group showed a substantial decrease in Cobb angle (WMD, 8.94; 95% CI, 2.55-15.33) and in C7 plumb (WMD, 5.90; 95% CI, -0.39-12.18), compared to the short fusion group. At final follow-up, ODI had decreased similarly in both groups (WMD, 1.70; 95% CI, -13.04-9.65). The short fusion group showed advantages including decreased blood loss (mean difference, 739.9 mL) and shorter operative time (mean difference, 68.0 minutes) compared to the long fusion group. CONCLUSION: Short fusion may be a reasonable option for patients with SBSS and at low risk for curve progression. LEVEL OF EVIDENCE: 1. PMID- 28658037 TI - Investigation of the Effect of Diabetes on Radiculopathy Induced by Nucleus Pulposus Application to the DRG in a Spontaneously Diabetic Rat Model. AB - STUDY DESIGN: A controlled, interventional animal study. OBJECTIVE: The aim of this study was to evaluate the effect of diabetes mellitus (DM) on radiculopathy due to lumbar disc herniation (LDH), by investigating pain-related behavior and the expression of tumor necrosis factor-alpha (TNF-alpha) and growth-associated protein 43 (GAP43) in type 2 diabetic rats following application of nucleus pulposus (NP) to the dorsal root ganglion (DRG). SUMMARY OF BACKGROUND DATA: Previous clinical studies suggested negative effects of DM on radiculopathy due to LDH, and that inflammation and nerve regeneration could interact with DM and radiculopathy. METHODS: We applied autologous NP to the left L5 DRG of adult male Wistar rats and Goto-Kakizaki rats. Behavioral testing measured the mechanical withdrawal threshold of rats. We immunohistochemically evaluated the localization of ionized calcium-binding adapter molecule-1 (Iba-1), receptor of advanced glycation end products (RAGE), and TNF-alpha in DRGs. TNF-alpha and GAP43 expression levels in DRG were determined by quantitative real-time PCR and western blotting. RESULTS: The mechanical withdrawal threshold significantly declined in the non-DM NP group compared with the non-DM sham group for 28 days, whereas the decline in threshold extended to 35 days in the DM NP group compared with the DM sham group. RAGE and TNF-alpha expression in DRGs was colocalized in Iba-1 positive cells. The non-DM NP rats had higher TNF-alpha protein expression levels versus the non-DM sham rats on day 7, and the DM NP group had higher levels versus the DM sham group on days 7 and 14. The non-DM NP group had higher GAP43 mRNA expression than the non-DM sham group for 28 days, while the DM NP group had a higher level than the DM sham group for 35 days. CONCLUSION: DM prolongs the pain-related behavior caused by NP. The prolonged inflammation and nerve regeneration could elucidate the pathogenesis of continuous pain of radiculopathy initiated by LDH. LEVEL OF EVIDENCE: N /A. PMID- 28658038 TI - Immediate versus Delayed Surgical Treatment of Lumbar Disc Herniation for Acute Motor Deficits: The Impact of Surgical Timing on Functional Outcome. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of the study was to assess the impact of time to surgery in patients with MDs on their functional outcome. The current single-center study presents results of emergency surgery for LDH in a group of patients with acute paresis in a "real-world" setting. SUMMARY OF BACKROUND DATA: Motor deficits (MDs) are a frequent symptom of lumbar disc herniation (LDH). While surgery within 48 hours has been recommended for cauda-equina syndrome, the best timing of surgery for acute MDs continues to be debated. The effect of early surgery has been proposed but remains to be unproven. METHODS: 330 patients with acute paresis due to LDH acutely referred to our department and surgically treated using microsurgical discectomy from 01/2013 12/2015 were included. Based on the duration of MD and surgical timing, all patients were classified into two categories: Group I included all patients with a paresis <48 h and Group II >48 h. Patient demographics, LDH/clinical/treatment characteristics, and outcomes were collected prospectively.Severity of paresis (MRC 0-4), surgery-related complications, functional recovery of motor/sensory deficits, sciatica, retreatment/recurrence rates, and overall neurological outcome were analyzed. RESULTS: Group I showed significantly faster recovery of moderate/severe paresis (MRC 0-3) at discharge, and 6-weeks/3-months follow-up (P<=0.001), while there were no significant differences in recovery for mild paresis (MRC 4). Sensory deficits also recovered substantially faster in Group I at 6-weeks (P = 0.003) and 3-months follow-up (P = 0.045). BMI, preoperative MRC grade and duration of MDs were identified as significant predictors for recovery of paresis at all follow-ups with substantial impact on patient reported outcomes including sciatica and/or dermatomal sensory deficits. CONCLUSIONS: Given the superior rates of neurological recovery of acute moderate/severe MDs, immediate surgery should be the primary option. Yet, a prospective randomized clinical trial is needed to confirm the superiority of emergency surgery. LEVEL OF EVIDENCE: 3. PMID- 28658039 TI - Radiographic Analysis of Psoas Morphology and its Association With Neurovascular Structures at L4-5 With Reference to Lateral Approaches. AB - STUDY DESIGN: Retrospective imaging review. OBJECTIVE: Utilize magnetic resonance imaging (MRI) to expand the anatomical description of psoas morphology and its association with neurovascular structures at L4-5. SUMMARY OF BACKGROUND DATA: Anatomical psoas muscle variants may present a greater risk of neurovascular injury at the L4-5 level during lateral transpsoas approaches. METHODS: Axial L4 5 sections of consecutive patients who obtained lumbar MRIs were analyzed. Teardrop psoas morphology was assessed qualitatively. MRI described psoas morphology and proximity of neurovascular structures, whereas plain radiographs were evaluated for lumbosacral transitional vertebrae (LSTV). Teardrop morphology was tested for associations with radiographic measurements using t tests and chi analysis. RESULTS: Fifty teardrop and 476 nonteardrop psoas muscles were identified. Teardrop morphology was associated with greater longitudinal length (53.1 vs. 49.3 mm, P = 0.012), and shorter transverse length (34.9 vs. 44.8 mm, P < 0.001) compared with nonteardrop. Teardrop morphology was associated with anterior and lateral migration of the psoas with greater distance between the anterior borders of the psoas and disc (13.5 vs. 6.3 mm, P < 0.001), and greater distance between the medial border of the psoas to the lateral disc border (1.6 vs. 0.5 mm, P < 0.001). Teardrop morphology was associated with a higher incidence of the lumbar plexus migrating anteriorly adjacent to the middle-third of the disc (43.4% vs. 17.6%, P < 0.001) and the iliac vasculature being more laterally and posteriorly located, adjacent to the anterior-third of the disc (43.4% vs. 30.0%, P = 0.047). Teardrop morphology was not associated with presence of LSTV (3.8% vs. 7.6%, P = 0.306). CONCLUSION: The current study provides detailed metrics of teardrop psoas muscles and surrounding structures. The study confirms that the presence of teardrop anatomy on L4-5 axial imaging is associated with anterior migration of the lumbar plexus and posterolateral migration of the iliac vasculature which may increase the risk of neurovascular injury during direct and oblique-lateral lumbar spine procedures. LEVEL OF EVIDENCE: 3. PMID- 28658040 TI - Minimal Clinically Important Difference in Quality of Life for Patients With Low Back Pain. AB - STUDY DESIGN: Multicenter, prospective, cohort study. OBJECTIVE: To estimate the Minimal Clinically Important Difference (MCID) for the physical (PCS) and mental (MCS) component summaries of Short Form SF-12 (SF-12), in patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: Quality of life is one of the core domains recommended to be assessed in patients with LBP. SF-12 is the most widely used instrument for this purpose, but its MCID was unknown. METHODS: A total of 458 patients with subacute and chronic LBP were consecutively recruited across 21 practices. LBP, referred pain, disability, PCS, and MCS were assessed upon recruitment and 12 months later. Self-reported health status change between baseline and 12 month-assessment, was used as the external criterion. The MCID for SF-12 was estimated following four anchor-based methods; minimal detectable change (MDC); average change (AC); change difference (CD); and receiver operating characteristic curve (ROC), for which the area under the curve (AUC) was calculated. The effect on MCID values of pain duration and baseline scores was assessed. RESULTS: Values for PCS were: MDC: 0.56, AC: 2.71, CD: 3.29, and ROC: 1.14. Values for MCS were: MDC: 3.77, AC: 3.54, CD: 1.13, and ROC: 4.23. AUC values were <0.7; MCID values were smaller among chronic patients and those with better baseline quality of life. CONCLUSION: Different methods for MCID calculation lead to different results. In patients with subacute and chronic LBP, improvements >3.77 in MCS and >3.29 in PCS, can be considered clinically relevant. MCID is smaller in patients with longer pain duration and better baseline quality of life. LEVEL OF EVIDENCE: 2. PMID- 28658041 TI - Utility of Intraoperative Monitoring in the Resection of Spinal Cord Tumors: An Analysis by Tumor Location and Anatomical Region. AB - STUDY DESIGN: Retrospective review of institutional data. OBJECTIVE: The aim of this study was to assess the utility of somatosensory-evoked potentials (SSEP) and transcranial electric motor-evoked potentials (MEP) in the resection of spine tumors and evaluate the ability of both single and multi-modal monitoring to predict postoperative neurological deficits. SUMMARY OF BACKGROUND DATA: Although the utility of intraoperative monitoring (IOM) is well established in scoliosis and degenerative surgery, studies in spine tumor patients have been limited. METHODS: A series of consecutive patients who underwent resection with the use of IOM at a single institution between August 2009 and March 2013 was identified. Demographic, clinical, and neuromonitoring data were collected preoperatively, during surgery, at the moment of discharge, and at a 6-month follow-up visit. Three cohorts were established based on the anatomical location of the tumor: intramedullary, intradural extramedullary, and extradural. Additional groupings were formed based on spinal region. Patients with significant changes in SSEPs or MEPs during surgery were identified and the rate of neurological deficits was assessed. RESULTS: A total of 52 patients were analyzed. A change in SSEPs or MEPs was detected in 11 (21.2%) cases whereas 14 patients (26.9%) developed permanent postoperative deficits. SSEPs predicted deficits in the resection of intramedullary tumors (P = 0.015) (area under cover, AUC = 0.83), and intradural extramedullary tumors (P = 0.048; AUC = 0.70). MEP monitoring did not predict postoperative deficits in the resection of intramedullary (P = 0.21; AUC = 0.69) or intradural extramedullary tumors (P = 0.31; AUC = 0.63). Neither SSEPs nor MEPs predicted deficits for extradural tumors. CONCLUSION: The efficacy of IOM in spine tumor resection is dependent on tumor location relative to the spinal cord and dura. The accuracy of SSEPs and their ability to predict postoperative deficits was greatest for intramedullary lesions. For this series, MEP and multi modal monitoring did not confer a benefit in predicting permanent neurological deficits. LEVEL OF EVIDENCE: 4. PMID- 28658042 TI - Coagulation Profile as a Risk Factor for 30-day Morbidity Following Cervical Laminectomy and Fusion. AB - STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: The aim of this study was to determine the ability of abnormal coagulation profile to predict adverse events following posterior cervical laminectomy and fusion (PCLF). SUMMARY OF BACKGROUND DATA: PCLF is an increasingly common procedure used to treat a variety of traumatic and degenerative spinal conditions. Abnormal coagulation profile is associated with postoperative adverse events, including blood transfusion. There is a paucity of literature that specifically addresses the relationship between coagulation profile and complications following PCLF. METHODS: ACS-NSQIP was utilized to identify patients undergoing PCLF between 2006 and 2013. A total of 3546 patients met inclusion criteria. Multivariate analysis was utilized to identify associations between abnormal coagulation profile and postoperative complications. RESULTS: Membership in the low-platelet cohort was an independent risk factor for myocardial infarction (Odds Ratio (OR) = 5.4 [1.0, 29.1], P = 0.049) and bleeding transfusion (OR = 2.0 [1.2, 3.4], P = 0.011). Membership in the high international normalized ratio group was an independent risk factor for pneumonia (OR = 6.3 [2.5, 16.1], P < 0.001), ventilation >48 hours (OR = 6.5 [2.3, 18.4], P < 0.001), organ space surgical site infection (OR = 11.1 [2.1, 57.3], P = 0.004), urinary tract infection (OR = 3.0 [1.2, 8.0], P = 0.024), bleeding transfusion (OR = 6.0 [3.4, 10.7], P < 0.001), sepsis (OR = 5.1 [1.6, 16.4], P = 0.006), and septic shock (OR = 6.8 [1.7, 27.4], P = 0.007). Membership in the bleeding disorders cohort was an independent predictor of unplanned intubation (OR = 3.2 [1.1, 9.5], P = 0.041), pneumonia (OR = 2.9 [1.2, 7.2], P = 0.023), ventilation >48 hours (OR = 4.8 [1.9, 12.4], P = 0.001), cerebrovascular accident/stroke with neurological deficit (OR = 24.8 [2.9, 210.6], P = 0.003), bleeding transfusion (OR = 2.1 [1.1, 4.1], P = 0.032), reoperation (OR = 3.6 [1.4, 9.3], P = 0.008), and sepsis (OR = 3.4 [1.1, 10.4], P = 0.031). CONCLUSION: This is the first large study to document abnormal coagulation profile as an independent predictor of outcomes following PCLF. Abnormal coagulation profile represents a predictor of complications that can be medically mitigated, and is therefore a valuable parameter to assess preoperatively. Coagulation profile should continue to play a role in targeting patients for risk stratification, preoperative optimization, and quality improvement initiatives. LEVEL OF EVIDENCE: 3. PMID- 28658043 TI - Impact of Cervical Spine Deformity on Preoperative Disease Severity and Postoperative Outcomes Following Fusion Surgery for Degenerative Cervical Myelopathy: Sub-analysis of AOSpine North America and International Studies. AB - STUDY DESIGN: Sub-analysis of the prospective AOSpine CSM North America and International studies. OBJECTIVE: The aim of this study was to investigate the impact of cervical spine deformity on pre- and postoperative outcomes in fusion surgeries for degenerative cervical myelopathy. SUMMARY OF BACKGROUND DATA: The associations between cervical alignment and patient outcomes have been reported but are not well established in a myelopathy cohort. The impact of deformity correction in this population also needs to be elucidated. METHODS: A total of 757 patients were enrolled in two prospective international multicenter AOSpine studies. Among those who underwent anterior or posterior fusion surgeries, pre- and 1-year postoperative upright neutral lateral radiographs of cervical spine were investigated to measure C2-7 Cobb angle and C2-7 sagittal vertical axis (SVA). Patient outcome measures included the modified Japanese Orthopedic Association score for myelopathy severity, Neck Disability Index (NDI), and Short form 36 (SF-36). These scores were compared between patients with and without cervical deformity, which was defined as C2-7 Cobb >10 degrees kyphosis and/or SVA >40 mm. RESULTS: A total of 178 patients were included with complete pre- and postoperative radiographs. SVA significantly increased postoperatively (27.4 vs. 30.7 mm, P = 0.004). All outcome measurement showed significant improvements above minimal clinically important differences. 23.6% of the patients had cervical deformity preoperatively; preoperative deformity was associated with worse preoperative NDI scores (45.7 vs. 38.9, P = 0.04). Postoperatively, those with deformity exhibited significantly lower SF-36 physical component scores (37.2 vs. 41.4, P = 0.048). However, when focusing on the preoperatively deformed cohort, we did not find any significant differences in the postoperative outcome scores between those with and without residual deformity. CONCLUSION: There was a significant association between cervical deformity and both preoperative disease severity and postoperative outcomes; however, no impact of deformity correction was shown. LEVEL OF EVIDENCE: 2. PMID- 28658044 TI - The Modified Low Back Pain Disability Questionnaire: Reliability, Validity, and Responsiveness of a Dutch Language Version. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: The goal of this study is to translate the English version of the Modified Low Back Pain Disability Questionnaire (MDQ) into a Dutch version and investigate its clinimetric properties for patients with nonspecific chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Fritz et al (2001) developed a modified version of the Oswestry Disability Questionnaire (ODI) to assess functional status and named it the MDQ. In this version, a question regarding employment and homemaking ability was substituted for the question related to sex life. Good clinimetric properties for the MDQ were identified but up until now it is not clear whether the clinimetric properties of the MDQ would change if it was translated into a Dutch version. METHODS: Translation of the MDQ into Dutch was done in 4 steps. Test-retest reliability was investigated using the intraclass correlation coefficient (ICC) model. Validity was calculated using Pearson correlations and a 2-way analysis of variance for repeated measures. Finally, responsiveness was calculated with the area under the curve (AUC), minimal detectable change (MDC), and the standardized response mean (SRM). RESULTS: A total of 80 completed questionnaires were collected in 3 different hospitals and a total of 43 patients finished a 9 weeks intervention period, completing the retest. Test-retest reliability was excellent with an ICC of 0.89 (95% confidence interval [CI], 0.74-0.95). To confirm the convergent validity, the MDQ answered all predefined hypothesises (r = -0.65 0.69/P = 0.01-0.00) and good results for construct validity were found (P = 0.02). The MDQ had an AUC of 0.64 (95% confidence interval [CI], 0.47-0.81), an MDC of 8.80 points, and a SRM of 0.65. CONCLUSION: The Dutch version of the MDQ shows good clinimetric properties and is shown to be usable in the assessment of the functional status of Dutch-speaking patients with nonspecific CLBP. LEVEL OF EVIDENCE: 3. PMID- 28658045 TI - Pedicle Screw Loosening After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis in Upper and Lower Instrumented Vertebrae Having Major Perforation. AB - STUDY DESIGN: A retrospective chart review. OBJECTIVE: The aim of this study was to investigate the incidence and characteristics of screw loosening in surgically treated adolescent idiopathic scoliosis (AIS) patients. SUMMARY OF BACKGROUND DATA: Pedicle screws are widely used in posterior spinal fusion for AIS, although postoperative loosening can occur. However, few reports exist on screw loosening after pedicle screw fixation in young scoliosis patients and the etiology of loosening is not well known. METHODS: One hundred twenty AIS patients (9 males, 111 females; mean age: 15.0 years) who had received pedicle screw fixation were retrospectively reviewed. All patients underwent routine computed tomography (CT) reconstruction scans at 6 months postoperatively to assess screw position, bony fusion, and the presence of screw loosening. The perforation status of each pedicle screw was assigned a grade of 0 to 3 using Rao classification. RESULTS: Forty-three of 1624 (2.6%) screws showed evidence of loosening on CT. Screw loosening rates according to vertebral insertion level were upper instrumented vertebra (UIV): 9.6%; lower instrumented vertebra (LIV): 5.4%; one vertebra below the UIV: 1.8%; one vertebra above the LIV: 0.5%; two vertebrae below the UIV: 1.2%; and three vertebrae below the UIV: 0.9%. Screw loosening rates based on screw perforation grade were Grade 0: 1.4%; Grade 1: 3.1%; Grade 2: 15.5%; and Grade 3: 15.2%. Multivariate analysis revealed a distance from the UIV or LIV of one vertebra as well as the presence of major perforation to be independent factors affecting screw loosening. The odds ratios (ORs) of UIV/LIV insertion and major perforation were 73.4 and 17.2, respectively. When major perforations occurred in the UIV or LIV, the OR for loosening approached 1262. CONCLUSION: Pedicle screw loosening after posterior spinal fusion in AIS patients tend to occur in the UIV or LIV. Major screw perforation is also significantly associated with screw loosening. The risk of loosening becomes compounded when major perforations are present in the UIV or LIV. LEVEL OF EVIDENCE: 4. PMID- 28658046 TI - Induction of Endogenous Neural Stem Cells By Extracorporeal Shock Waves After Spinal Cord Injury. AB - STUDY DESIGN: Animal experimental study OBJECTIVES.: The purpose of this study is to investigate the effects of extracorporeal shock waves (ESWs) on endogenous neural stem cells (NSCs) proliferation after spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Exogenous stem cell transplantation for SCI still has many limitations to be addressed such as ideal cell sources, timing of transplantation, and fate of the transplanted cells. Moreover, the efficacy is another issue owing to a peculiar pathologic condition in the chronic phase of SCI. METHODS: Contusive SCI was made using 24 Sprague-Dawley rats, and ESWs were applied at post-injury 4 weeks in rats. Proliferation and differentiation of endogenous NSCs (DCX, Sox-2) and axonal sprouting (GAP-43 and MAP-2) were observed at 6 weeks after application of ESWs. Differentiation of the activated neural stem cells was also investigated by coexpression of neuronal/glial cell markers (GFAP, Neu N, and CC-1). Immunofluorescence staining and western blotting were performed for quantitative analysis, and these results were compared with those in the control group. For clinical assessment, the BBB locomotor rating scale was performed. RESULTS: More proliferation of endogenous neural stem cells was noted in the experimental groups, and these activated cells were mainly founded in the ependymal layer of the central canal and the injured posterior horn. Differentiation into neuronal and glial cells was also noted in a limited number of cells. With respect to axonal regeneration, GAP-43 and MAP-2 expressions in the experimental groups were also significantly higher than those in the control group. During 6 weeks' clinical observation following ESWs application, functional improvement of the hindlimb was observed without clinical deterioration by trials. CONCLUSION: Collectively, these findings indicate that ESWs on the chronic phase of SCI induce activation of endogenous NSCs and consequent functional improvement. LEVEL OF EVIDENCE: N/A. PMID- 28658047 TI - A magnetoencephalography investigation of coherence source imaging in panic disorder. AB - Limbic and frontal structures are largely implicated in panic disorder (PD). Decreased coherence imaging values, as determined by magnetoencephalography (MEG), are suggestive of decreased or inefficient communication among these structures. We have previously demonstrated that coherence source imaging (CSI) values could be similar or higher in some PD patients. The purpose of the current investigation was to replicate these finding in a larger sample. Nine strictly diagnosed PD patients and nine age-matched and sex-matched healthy controls were examined. The CSI-MEG values of 26 frontotemporal regions (FTRs) and 28 extra frontotemporal regions (ex-FTR; Brodmann areas) were determined for each participant. MEG scans were acquired using a 151-channel whole-head biomagnetometer system. Despite the relatively small sample size, CSI values were significantly lower in a number of FTRs in PD patients. In none of the ex-FTRs (i.e. posterior regions) were there differences between panic and control groups. The above data add to the complexity of understanding the nature of the pathophysiology of PD. Our finding of decreased focal coherence imaging values may reflect decreased excitability in these areas. The preliminary finding could be interpreted as an inhibitory process guarding against the spread of activity in closer hyperexcitable areas as seen in epilepsy. The current data provide evidence for dysfunctional communication within the frontotemporal structures. The findings have implications for the understanding of the neural circuitry underlying PD. PMID- 28658048 TI - Increased activation of the hippocampus during a Chinese character subvocalization task in adults with cleft lip and palate palatoplasty and speech therapy. AB - This study aimed to explore brain activation in patients with cleft lip and palate (CLP) using a Chinese character subvocalization task, in which the stimuli were selected from a clinical articulation evaluation test. CLP is a congenital disability. Individuals with CLP usually have articulation disorder caused by abnormal lip and palate structure. Previous studies showed that primary somatosensory and motor areas had a significant difference in activation in patients with CLP. However, whether brain activation was restored to a normal level after palatoplasty and speech rehabilitation is not clear. Two groups, adults after palatoplasty with speech training and age-matched and sex-matched controls, participated in this study. Brain activation during Chinese character subvocalization task and behavioral data were recorded using functional MRI. Patients with CLP responded to the target significantly more slowly compared with the controls, whereas no significant difference in accuracy was found between the groups. Brain activation had similar patterns between groups. Broca's area, Wernicke's area, motor areas, somatosensory areas, and insula in both hemispheres, and the dorsolateral prefrontal cortex and the ventrolateral prefrontal cortex in the right hemisphere were activated in both groups, with no statistically significant difference. Furthermore, the two-sample t-test showed that the hippocampus in the left hemisphere was activated significantly in patients with CLP compared with the controls. The results suggested that the hippocampus might be involved in the language-related neural circuit in patients with CLP and play a role of pronunciation retrieval to help patients with CLP to complete the pronunciation effectively. PMID- 28658049 TI - High emotion-control value reduces error-detection impairment following emotion suppression: an event-related potential study. AB - The present study investigated whether individuals characterized by different emotion-control values (ECV) differed in their cognitive effort after being required to suppress emotions. Emotions of sadness were induced using a video clip and individuals were instructed to suppress their emotional expression. Behavioral measures of an event-related potentials related to Stroop task performance following suppression were obtained. Results show that whereas suppression led to attenuated error or conflict monitoring in low-ECV participants, as indicated by significantly lower error-related negativity amplitudes compared with ECV-matched controls, participants high in ECV did not differ from the controls. Emotion suppression in high-ECV individuals seems to come at a much lower cost and to be more effective in lowering both arousal and sadness than in low-ECV individuals. PMID- 28658050 TI - Effects of Src kinase inhibition on expression of pro-caspase-2 after brain hypoxia in a piglet animal model. AB - Caspase-2 has features of both initiator and effector caspases. Previously, we have shown that brain hypoxia-induced production of caspases 1, 3, 8, and 9 is Src kinase mediated, a nonreceptor intracellular family of kinases. The present study tests the hypothesis that hypoxia results in increased expression of caspase-2 and this effect is mediated by Src kinase. Two to three days old newborn piglets were subjected to normoxia, hypoxia (Hx, FiO2 7%), and Src kinase inhibition (using PP2, 1 mg/kg, intravenous), followed by 30 min of acute hypoxia (Hx+PP2). ATP and phosphocreatine were determined biochemically to verify energy molecule depletion in the hypoxic groups. The cytosolic brain function was isolated and a western blot analysis was carried out using an antibody specific for the caspase-2. The immune-complex band density was expressed as OD/mm. Caspase-2 expression was increased two-fold in the Hx group. After Src kinase inhibition followed by hypoxia, caspase-2 expression was similar to normoxia levels. We conclude that hypoxia results in increased expression of caspase-2 protein in the cytosolic fraction of the cerebral cortex of the newborn piglets. This increase is mediated by Src kinase. PMID- 28658051 TI - The relationship between cognitive style and event-related potentials during auditory and somatosensory Go/No-go paradigms. AB - Cognitive style including field dependence/independence (FDI) is an important factor affecting individual personalities. The present study aimed to clarify the relationship between cognitive styles and the characteristics of cognitive processing using event-related potentials. We used the Embedded-Figures Test to assess the cognitive styles [field dependence (FD), field independence (FI)] of the individuals, and individuals performed auditory and somatosensory Go/No-go paradigms. Participants were divided into two groups (FD and FI) on the basis of EFT scores. Reaction times during auditory Go/No-go paradigms were significantly earlier in the FI group than in the FD group, and response variabilities and omission errors were significantly smaller in the FI group than in the FD group. Go-P300 and No-go-P300 amplitudes were significantly larger in the FI group than in the FD group, suggesting that the FI group exhibited greater neural activity for response executive and inhibitory processing. No significant differences were observed in the amplitudes or latencies of auditory N100 and somatosensory N140 components between the FI and FD groups, suggesting that auditory-related and somatosensory-related neural activities were not related to FDI cognitive styles. Our results showed that FDI cognitive styles were related to neural activity for response executive and inhibitory processing. PMID- 28658052 TI - Assessment of nodal involvement in non-small-cell lung cancer with 18F-FDG PET/CT: mediastinal blood pool cut-off has the highest sensitivity and tumour SUVmax/2 has the highest specificity. AB - OBJECTIVES: Lymph node involvement in non-small-cell lung cancer (NSCLC) is a major factor in determining management and prognosis. We aimed to evaluate the accuracy of fluorine-18-fluorodeoxyglucose-PET/computed tomography (CT) for the assessment of nodal involvement in patients with NSCLC. PATIENTS AND METHODS: In this retrospective study, we included 61 patients with suspected or confirmed resectable NSCLC over a 2-year period from April 2013 to April 2015. 221 nodes with pathological staging from surgery or endobronchial ultrasound-guided transbronchial needle aspiration were assessed using a nodal station-based analysis with original clinical reports and three different cut-offs: mediastinal blood pool (MBP), liver background and tumour standardized uptake value maximal (SUVmax)/2. RESULTS: Using nodal station-based analysis for activity more than tumour SUVmax/2, the sensitivity was 45%, the specificity was 89% and the negative predictive value (NPV) was 87%. For activity more than MBP, the sensitivity was 93%, the specificity was 72% and NPV was 98%. For activity more than liver background, the sensitivity was 83%, the specificity was 84% and NPV was 96%. Using a nodal staging-based analysis for accuracy at detecting N2/3 disease, for activity more than tumour SUVmax/2, the sensitivity was 59%, the specificity was 85% and NPV was 80%. For activity more than MBP, the sensitivity was 95%, the specificity was 61% and NPV was 96%. For activity more than liver background, the sensitivity was 86%, the specificity was 81% and NPV was 92%. Receiver-operating characteristic analysis showed the optimal nodal SUVmax to be more than 6.4 with a sensitivity of 45% and a specificity of 95%, with an area under the curve of 0.85. CONCLUSION: Activity more than MBP was the most sensitive cut-off with the highest sensitivity and NPV. Activity more than primary tumour SUVmax/2 was the most specific cut-off. Nodal SUVmax more than 6.4 has a high specificity of 95%. PMID- 28658053 TI - Radiosynthesis and in-vivo evaluation of [125I]IBT: a single-photon emission computed tomography radiotracer for alpha7-nicotinic acetylcholine receptor imaging. AB - AIM: The aim of this study was to develop several novel alpha7-nicotinic acetylcholine receptor (nAChR) radioligands for the early diagnosis and treatment of Alzheimer's disease. PATIENTS AND METHODS: The study reported six compounds and studied the in-vitro receptor binding affinity, and selected the I-labeled IBT with good characteristics as a novel radioligand suitable for studying alpha7 nAChRs. After verifying the stability of the radiotracer [I]IBT, the biodistribution in vivo and regional brain biodistribution studies were carried out in mice. Blocking studies with methyllycaconitine citrate and nicotine were carried out under control and blocking conditions, and the metabolic stability was assessed in vivo in the plasma, brain, and liver. RESULTS AND CONCLUSION: The results of our study suggested that [I]IBT had affinity for alpha7-nAChRs. The in vivo evaluation in mice of [I]IBT showed a high brain/blood ratio and excellent metabolic stability. The regional brain distribution studies and the blocking studies showed that it had favorable selectivity and specificity and was a potential alpha7-nAChRs radioligand. PMID- 28658054 TI - Retrospective Imaging and Characterization of Nuclear Material. AB - Modern techniques for detection of covert nuclear material requires some combination of real time measurement and/or sampling of the material. More common is real time measurement of the ionizing emission caused by radioactive decay or through the materials measured in response to external interrogation radiation. One can expose the suspect material with various radiation types, including high energy photons such as x rays or with larger particles such as neutrons and muons, to obtain images or measure nuclear reactions induced in the material. Stand-off detection using imaging modalities similar to those in the medical field can be accomplished, or simple collimated detectors can be used to localize radioactive materials. In all such cases, the common feature is that some or all of the nuclear materials have to be present for the measurement, which makes sense; as one might ask, "How you can measure something that is not there?" The current work and results show how to do exactly that: characterize nuclear materials after they have been removed from an area leaving no chemical trace. This new approach is demonstrated to be fully capable of providing both previous source spatial distribution and emission energy grouping. The technique uses magnetic resonance for organic insulators and/or luminescence techniques on ubiquitous refractory materials similar in theory to the way the nuclear industry carries out worker personnel dosimetry. Spatial information is obtained by acquiring gridded samples for dosimetric measurements, while energy information comes through dose depth profile results that are functions of the incident radiation energies. PMID- 28658055 TI - Appropriate Use of Effective Dose in Radiation Protection and Risk Assessment. AB - Effective dose was introduced by the ICRP for the single, over-arching purpose of setting limits for radiation protection. Effective dose is a derived quantity or mathematical construct and not a physical, measurable quantity. The formula for calculating effective dose to a reference model incorporates terms to account for all radiation types, organ and tissue radiosensitivities, population groups, and multiple biological endpoints. The properties and appropriate applications of effective dose are not well understood by many within and outside the health physics profession; no other quantity in radiation protection has been more confusing or misunderstood. According to ICRP Publication 103, effective dose is to be used for "prospective dose assessment for planning and optimization in radiological protection, and retrospective demonstration of compliance for regulatory purposes." In practice, effective dose has been applied incorrectly to predict cancer risk among exposed persons. The concept of effective dose applies generally to reference models only and not to individual subjects. While conceived to represent a measure of cancer risk or heritable detrimental effects, effective dose is not predictive of future cancer risk. The formula for calculating effective dose incorporates committee-selected weighting factors for radiation quality and organ sensitivity; however, the organ weighting factors are averaged across all ages and both genders and thus do not apply to any specific individual or radiosensitive subpopulations such as children and young women. Further, it is not appropriate to apply effective dose to individual medical patients because patient-specific parameters may vary substantially from the assumptions used in generalized models. Also, effective dose is not applicable to therapeutic uses of radiation, as its mathematical underpinnings pertain only to observed late (stochastic) effects of radiation exposure and do not account for short-term adverse tissue reactions. The weighting factors incorporate substantial uncertainties, and linearity of the dose-response function at low dose is uncertain and highly disputed. Since effective dose is not predictive of future cancer incidence, it follows that effective dose should never be used to estimate future cancer risk from specific sources of radiation exposure. Instead, individual assessments of potential detriment should only be based on organ or tissue radiation absorbed dose, together with best scientific understanding of the corresponding dose-response relationships. PMID- 28658056 TI - KDEP: A Resource for Calculating Particle Deposition in the Respiratory Tract. AB - This paper presents KDEP, an open-source implementation of the ICRP lung deposition model developed by the authors. KDEP, which is freely available to the public, can be used to calculate lung deposition values under a variety of different conditions using the ICRP methodology. The paper describes how KDEP implements this model and discusses some key points of the implementation. The published lung deposition values for intakes by workers were reproduced, and new deposition values were calculated for intakes by members of the public. KDEP can be obtained for free at github.com or by emailing the authors directly. PMID- 28658057 TI - Plasma Retention and Systemic Kinetics of 90Sr Intramuscularly Injected in Female Nonhuman Primates. AB - Thirteen female Rhesus macaques were intramuscularly injected with Sr(NO3)2 diluted in sodium citrate solution. The biokinetic data from these animals were compared against the predictions of the NCRP 156 wound models combined with the ICRP systemic models. It was observed that the activities measured in plasma of these nonhuman primates (NHPs) were consistently lower than those predicted by the default human biokinetic models. The urinary excretion from the NHPs at times immediately after injection was much greater than that in humans. The fecal excretion rates were found to be in relatively better agreement with humans. Similarly, the activities retained in the skeleton of the NHPs were lower than those in humans. These differences were attributed to the higher calcium diet of the NHPs (0.03 to 0.12 g d kg body weight) compared to that of humans. These observations were consistent with the early animal and human studies that showed the effect of calcium on strontium metabolism, specifically urinary excretion. Strontium is preferentially filtered at a much higher rate in kidneys than calcium because it is less completely bound to protein than is calcium. These differences, along with large inter-animal variability, should be considered when estimating the behavior of strontium in humans from the metabolic data in animals or vice versa. PMID- 28658058 TI - Influence of a Commercial Lead Apron on Patient Skin Dose Delivered During Oral and Maxillofacial Examinations under Cone Beam Computed Tomography (CBCT). AB - The purpose of this paper is to investigate the impact of a commercial lead apron on patient skin dose delivered during maxillofacial CBCT in five critical regions by means of solid-state-dosimetry. Five anatomical regions (thyroid gland, left and right breast, gonads, back of the phantom torso) in an adult female anthropomorphic phantom were selected for dose measurement by means of the highly sensitive solid-state dosimeter QUART didoSVM. Ten repeated single exposures were assessed for each patient body region for a total of five commercial CBCT devices with and without a lead apron present. Shielded and non-shielded exposures were compared under the paired Wilcoxon test, with absolute and relative differences computed. Reproducibility was expressed as the coefficient of variation (CV) between the 10 repeated assessments. The highest doses observed at skin level were found at the thyroid (mean shielded +/- SD: 450.5 +/- 346.7 MUGy; non shielded: 339.2 +/- 348.8 MUGy, p = 0.4922). Shielding resulted in a highly significant (p < 0.001) 93% dose reduction in skin dose in the female breast region with a mean non-shielded dose of approximately 35 MUGy. Dose reduction was also significantly lower for the back-region (mean: -65%, p < 0.0001) as well as for the gonad-region (mean: -98%, p < 0.0001) in the shielded situation. Reproducibility was inversely correlated to skin dose (Rspearman = -0.748, p < 0.0001) with a mean CV of 10.45% (SD: 24.53 %). Skin dose in the thyroid region of the simulated patient was relatively high and not influenced by the lead apron, which did not shield this region. Dose reduction by means of a commercial lead apron was significant in all other regions, particularly in the region of the female breast. PMID- 28658059 TI - Imaging of Gamma-ray Scatter from a Polymethyl-methacrylate Phantom Using a Compton Imaging Spectrometer. AB - Commercially available gamma-ray imaging spectrometers have been introduced recently and are currently undergoing investigations for various applications in nuclear power plants, environmental management, and medical environments. A Compton imaging gamma-ray spectrometer uses an array of detectors or a single position-sensitive crystal to create planar images of radionuclide distributions. The typical software included with these devices creates images of specific radionuclides using only the counts under their known gamma emission photopeaks. This approach prevents the direct imaging of scattered radiation, which is of interest for many radiation protection applications. In this paper, a technique for imaging radiation scatter or portions of the scatter spectrum is implemented. This involves the creation of a virtual radionuclide in software with peaks placed throughout the backscatter continuum of interest and then imaging that virtual radionuclide in the post-processing software. This technique is used to image the Compton scatter successfully from a polymethyl-methacrylate (PMMA) phantom placed in a Cs irradiator beam. Measured scatter energies were found to be within 15% of the expected values, sufficient to predict scatter behavior and individually measure separate sources of scatter at different angles. PMID- 28658060 TI - Photon-Fluence-Weighted let for Radiation Fields Subjected to Epidemiological Studies. AB - In order to estimate the uncertainty of the radiation risk associated with the photon energy in epidemiological studies, photon-fluence-weighted LET values were quantified for photon radiation fields with the target organs and irradiation conditions taken into consideration. The photon fluences giving a unit absorbed dose to the target organ were estimated by using photon energy spectra together with the dose conversion coefficients given in ICRP Publication 116 for the target organs of the colon, bone marrow, stomach, lung, skin and breast with three irradiation geometries. As a result, it was demonstrated that the weighted LET values did not show a clear difference among the photon radiation fields subjected to epidemiological studies, regardless of the target organ and the irradiation geometry. PMID- 28658061 TI - ICNIRP Statement on Diagnostic Devices Using Non-Ionizing Radiation: Existing Regulations and Potential Health Risks. PMID- 28658062 TI - Reply to Kromhout et al. PMID- 28658063 TI - Contextual Information for the Potential Enhancement of Annual Radiation Protection Program Review Reports. AB - Organizations possessing sources of ionizing radiation are required to develop, document, and implement a "radiation protection program" that is commensurate with the scope and extent of permitted activities and sufficient to ensure compliance with basic radiation safety regulations. The radiation protection program must also be reviewed at least annually, assessing program content and implementation. A convenience sample assessment of web-accessible and voluntarily submitted radiation protection program annual review reports revealed that while the reports consistently documented compliance with necessary regulatory elements, very few included any critical contextual information describing how important the ability to possess radiation sources was to the central mission of the organization. Information regarding how much radioactive material was currently possessed as compared to license limits was also missing. Summarized here are suggested contextual elements that can be considered for possible inclusion in annual radiation protection program reviews to enhance stakeholder understanding and appreciation of the importance of the ability to possess radiation sources and the importance of maintaining compliance with associated regulatory requirements. PMID- 28658067 TI - Seasonal Allergic Rhinitis: A focused systematic review and practice parameter update. AB - PURPOSE OF REVIEW: The review compares and contrasts seven major United States and international allergic rhinitis guidelines from 2008 to 2017. RECENT FINDINGS: Despite many treatment options for allergic rhinitis, patients often report lack of therapeutic control and a reduced quality of life. Guidelines intended to improve allergic rhinitis care have been evolving into evidence based, systematic reviews, with less reliance on consensus of expert opinion characteristic of more traditional guidelines. The first Grading of Recommendations Assessment, Development, and Evaluation-based guideline developed in the United States for seasonal allergic rhinitis was first published in 2017. SUMMARY: When critically analyzing the allergic rhinitis guidelines that use the rigorous Grading of Recommendations Assessment, Development, and Evaluation methodology, different groups of expert authors, using the same reference articles, will, at times, reach different conclusions regarding the quality of the evidence and the strength of the recommendation. Factors potentially contributing to these divergent determinations include: lack of objective primary outcome measures in allergic rhinitis, poorly defined Minimal Clinically Important Difference, failure to include all interested parties in guideline development, for example, patients, and subjectivity inherent in the expert panel. PMID- 28658069 TI - Components of Fatigue: Mind and Body. AB - Carriker, CR. Components of fatigue: mind and body. J Strength Cond Res 31(11): 3170-3176, 2017-Maximal intensity exercise requires significant energy demand. Subsequently, prolonged high-intensity effort eventually initiates volitional cessation of the event; often preceeded by a sensation of fatigue. Those examining the basis of fatigue tend to advocate either a peripheral or central model to explain such volitional failure. Practitioners and athletes who understand the tenants of fatigue can tailor their exercise regimens to target areas of potential physical or mental limitation. This review examines the rationale surrounding 2 separate models which postulate the origination of fatigue. Although the peripheral model suggests that fatigue occurs at the muscles, others have suggested a teloanticipatory cognitive component which plays a dominant role. Those familiar with both models may better integrate practice based evidence into evidence-based practice. The highly individual nature of human performance further highlights the compulsion to comprehend the spectrum of fatigue, such that the identification of insufficiencies should mandate the development of a training purview for peak human performance. PMID- 28658068 TI - Depression and insomnia among individuals with celiac disease or on a gluten-free diet in the USA: results from a national survey. AB - BACKGROUND: There is uncertainty regarding the prevalence of psychiatric illnesses in patients with celiac disease (CD) and people who avoid gluten (PWAG) without a diagnosis of CD. PARTICIPANTS AND METHODS: We obtained data from 22 274 participants from the 2009-2014 National Health and Nutrition Examination Survey to compare the prevalence of depression, insomnia, quality-of-life variables, and psychotropic medication use in CD participants and PWAGs to controls. We used multivariable logistic regression to assess for independent associations between CD/PWAG status and the outcomes of these variables. RESULTS: Depression was present in 8.2% of controls compared with 3.9% of participants with CD (P=0.18) and 2.9% of PWAGs (P=0.002). After adjustment for age, sex, race, income, and access to healthcare, PWAGs maintained lower odds of depression compared with controls (odds ratio=0.25; 95% confidence interval: 0.12-0.51; P=0.0001). The prevalence estimates of sleep difficulty among controls (27.3%) compared to participants with CD or PWAGs were 37.7% (P=0.15) and 34.1% (P=0.11). Those with diagnosed CD had increased odds of sleep difficulty (odds ratio=2.41; 95% confidence interval 1.04-5.60), but this was no longer significant after multivariable adjustment (P=0.17). CONCLUSION: Among a nationally representative US sample, participants with CD overall showed no increased odds of depression or sleep difficulty. PWAGs showed lower odds of depression compared with controls. Future research should investigate the relationship between a diagnosis of CD and the development of psychiatric conditions. PMID- 28658070 TI - A Simple Model to Identify Risk of Sarcopenia and Physical Disability in HIV Infected Patients. AB - Farinatti, P, Paes, L, Harris, EA, Lopes, GO, and Borges, JP. A simple model to identify risk of sarcopenia and physical disability in HIV-infected patients. J Strength Cond Res 31(9): 2542-2551, 2017-Early detection of sarcopenia might help preventing muscle loss and disability in HIV-infected patients. This study proposed a model for estimating appendicular skeletal muscle mass (ASM) to calculate indices to identify "sarcopenia" (SA) and "risk for disability due to sarcopenia" (RSA) in patients with HIV. An equation to estimate ASM was developed in 56 patients (47.2 +/- 6.9 years), with a cross-validation sample of 24 patients (48.1 +/- 6.6 years). The model validity was determined by calculating, in both samples: (a) Concordance between actual vs. estimated ASM; (b) Correlations between actual/estimated ASM vs. peak torque (PT) and total work (TW) during isokinetic knee extension/flexion; (c) Agreement of patients classified with SA and RSA. The predictive equation was ASM (kg) = 7.77 (sex; F = 0/M = 1) + 0.26 (arm circumference; cm) + 0.38 (thigh circumference; cm) + 0.03 (Body Mass Index; kg.m) - 8.94 (R = 0.74; Radj = 0.72; SEE = 3.13 kg). Agreement between actual vs. estimated ASM was confirmed in validation (t = 0.081/p = 0.94; R = 0.86/p < 0.0001) and cross-validation (t = 0.12/p = 0.92; R = 0.87/p < 0.0001) samples. Regression characteristics in cross-validation sample (Radj = 0.80; SEE = 3.65) and PRESS (RPRESS = 0.69; SEEPRESS = 3.35) were compatible with the original model. Percent agreements for the classification of SA and RSA from indices calculated using actual and estimated ASM were of 87.5% and 77.2% (gamma correlations 0.72-1.0; p < 0.04) in validation, and 95.8% and 75.0% (gamma correlations 0.98-0.97; p < 0.001) in cross-validation sample, respectively. Correlations between actual/estimated ASM vs. PT (range 0.50-0.73, p <= 0.05) and TW (range 0.59-0.74, p <= 0.05) were similar in both samples. In conclusion, our model correctly estimated ASM to determine indices for identifying SA and RSA in HIV-infected patients. PMID- 28658071 TI - A Review Of Field-Based Assessments Of Neuromuscular Control And Their Utility In Male Youth Soccer Players. AB - Lower extremity injuries in male youth soccer are common and equate to a substantial time-loss from training and competitions during the course of a season. Extended periods of absence will impact player involvement in skill and physical development activities, as well as participation in competitive match play. Neuromuscular risk factors for lower extremity injury in male youth soccer players can be categorized into quadriceps dominance; leg dominance; ligament dominance; trunk dominance and reduced dynamic stability. Valid screening methods to identify risk factors that are practically viable are needed for youth athletes who may be at a greater risk of injury in soccer. While field-based tests of neuromuscular control provide a reliable option for the assessment of injury risk in adults and females, less data are available in male youth soccer players and further research is required to examine their ability to predict injury risk. This article provides a review of the current literature pertaining to field-based screening tests and critically appraises their suitability for use with male youth soccer players. Currently the only method that has been validated in male youth soccer players is the landing error scoring system. Asymmetrical anterior reach measured during the Y-Balance test may also be considered due to its strong predictive ability in male youth basketball players; however, further research is required to fully support its use with soccer players. PMID- 28658072 TI - The NFL Combine 40-Yard Dash: How Important is Maximum Velocity? AB - This investigation analyzed the sprint velocity profiles for athletes who completed the 40-yard (36.6m) dash at the 2016 NFL Combine. The purpose was to evaluate the relationship between maximum velocity and sprint performance, and to compare acceleration patterns for fast and slow athletes. Using freely available online sources, data were collected for body mass and sprint performance (36.6m time with split intervals at 9.1 and 18.3m). For each athlete, split times were utilized to generate modeled curves of distance vs. time, velocity vs. time, and velocity vs. distance using a mono-exponential equation. Model parameters were used to quantify acceleration patterns as the ratio of maximum velocity to maximum acceleration (vmax / amax, or tau). Linear regression was used to evaluate the relationship between maximum velocity and sprint performance for the entire sample. Additionally, athletes were categorized into fast and slow groups based on maximum velocity, with independent t-tests and effect size statistics used to evaluate between-group differences in sprint performance and acceleration patterns. Results indicated that maximum velocity was strongly correlated with sprint performance across 9.1m, 18.3m, and 36.6m (r of 0.72, 0.83, and 0.94, respectively). However, both fast and slow groups accelerated in a similar pattern relative to maximum velocity (tau = 0.768 +/- 0.068s for the fast group and tau = 0.773 +/- 0.070s for the slow group). We conclude that maximum velocity is of critical importance to 36.6m time, and inclusion of more maximum velocity training may be warranted for athletes preparing for the NFL Combine. PMID- 28658073 TI - Monitoring Changes In Power, Speed, Agility And Endurance In Elite Cricketers During The Off-Season. AB - The purpose of this study was to monitor changes in power, speed, agility and endurance in elite cricketers during the 20-week off-season period. Fourteen elite male cricketers (age 26.2 +/- 5.3years; height 180.8 +/- 8.5cm; mass 83.5 +/- 6.7kg) conducted a physical testing battery in week 1 and week 18 of the off season period. The testing included a yoyo intermittent recovery test (yoyo IRT), bilateral and unilateral countermovement jumps (CMJ), squat jump (SJ), broad jump (BJ), drop jump (to calculate reactive strength index - [RSI]), pro agility and 5, 10, 20m sprint tests. Results showed significant improvements (p < 0.05) in all fitness tests except for the pro-agility test (p = 0.076), with effect sizes ranging from 0.26-2.8 across the test battery. The results of this study show the off-season in cricket allows adequate time for significant improvements of physical qualities needed for the demanding in-season schedule of the sport and provide normative values for an elite cricket population. PMID- 28658074 TI - Effect of Physical and Psychosocial Interventions on Hormone and Performance Outcomes in Professional Rugby Union Players: A Systematic Review. AB - Strahorn, J, Serpell, BG, McKune, A, and Pumpa, KL. Effect of physical and psychosocial interventions on hormone and performance outcomes in professional rugby union players: a systematic review. J Strength Cond Res 31(11): 3158-3169, 2017-This systematic review investigates the acute effects of physical or psychosocial interventions on testosterone and cortisol responses in elite male rugby union players, and the subsequent association with physical performance areas (e.g., strength, power, sprint performance) or key performance indicators (e.g., coach-identified skills). Medline (via EBSCO), SPORTDiscus, Web of Science, InformIT, ProQuest, Cochrane, and Scopus were searched for relevant articles. Nine articles met the inclusion criteria, with 6 articles examining the effect of speed, strength or power training, and the remaining 3 psychosocial interventions. Quality assessment of the articles as determined by their PEDro score was either 6 or 7 out of 11. This review found that both physical and psychosocial interventions can alter testosterone and cortisol, and physical performance areas important for rugby union are affected by these changes. The limited literature in the field supports the notion that physical interventions of short duration and high intensity, and psychosocial interventions that create a positive environment may elicit a hormonal response that is associated with favorable performance outcomes. Studies that reported psychosocial interventions suggest that testosterone and cortisol may be altered in elite rugby players without metabolic stress, something of great interest to elite athletes and coaches who are looking to elicit a performance advantage without increasing athlete load. Overall, this review identified that when the testosterone responses to an intervention are notably greater than that of cortisol, favorable outcomes are likely. Further research is required to improve our understanding on how to best manipulate training to induce these favorable changes. PMID- 28658075 TI - Evaluation Of The Official Match External Load In Soccer Players With Cerebral Palsy. AB - The aims of this study were to analyze the official match external loads (i.e. total distance [TD], distance covered at different speeds, accelerations, decelerations, player load [PL], peak metabolic power [PMP] and changes of direction [CODs]) of football players with cerebral palsy (CP), and to determine the external loads according to playing time (i.e. < 20 min, 20-40 min and > 40 min). The external load of thirty-one international football players with CP (23.0 +/- 6.6 years; 69.1 +/- 9.0 kg; 174.8 +/- 7.3 cm) was analyzed during a World Championship Qualification Tournament (n = 8 matches, 58 individual observations). Results showed that the football players with CP, covered less distance at high intensity running and sprinting, performing a smaller number of moderate and high intensity accelerations and decelerations, had a lower PL and made fewer CODs in official matches compared to conventional football players as reported in other studies. The number of minutes played by the players (i.e. < 20 min, 20-40 min and > 40 min) could significantly influence the players' match external load (ES = 0.3-5.5, small to extremely large). The impairments presented by football players with CP affect players' match external loads, especially in short-term high-intensity neuromuscular actions. PMID- 28658076 TI - Recovery time profiling after short-, middle- and long-distance swimming performance. AB - We investigated cardiac autonomic responses and hemodynamic parameters on recovery time following short-, middle- and long-swimming performance. Ten male regional-level swimmers were tested to estimate time and frequency domains of arterial baroreflex sensitivity and heart rate variability after 100-, 200-, and 400-m of front crawl. We found a BRS reduction for 90 min after a maximal 100- and 200-m front crawl event, meanwhile the reflex was restored back to the baseline value about 70 min after 400-m. The vagally mediated HF power of R-R intervals was significantly reduced for 30 min after 400-m, and more than 90 min after 100- and 200-m, with a concomitant increase of sympathetic modulation. After 400-m athletes have reduced their stroke volume for 50 min, which remained at the baseline level following 100- and 200-m. HR was restored back after 90 min in all conditions, whereas TPR was significantly reduced for 50 min after 200- and 400-m, with a persistent reduction after 100-m. Time course of autonomic recovery after 3 different swimming performances is influenced by exercise intensity and duration, showing a rapid recovery after 400-m, an intermediate recovery after 200-m, and a significantly delayed recovery after a more strictly anaerobic performance like 100-m of front crawl. These results could encourage coaches to consider that athlete might be affected by the specific recovery time of the previous exercise performed, suggesting that the management of the exercise intensity, and appropriate monitoring of cardiac autonomic parameters might be helpful to know the physical condition of each athlete. PMID- 28658077 TI - Pitch size and Game Surface in Different Small-Sided Games. Global Indicators, Activity Profile and Acceleration of Female Soccer Players. AB - The aim of this research was to evaluate the influence of game surface and pitch size on the movement profile in female soccer players during Small-Sided-Games (SSGs) of 4 v 4. 16 women played three different 4-a-side (400 m, 600 m and 800 m) on three surfaces (ground [GR], artificial turf [AT] and natural grass [NG]). Time-motion variables were assessed through GPS devices (Spi Pro X, GPSports, Australia). GR had the worst outputs on most variables. NG achieved higher results than AT in terms of total distance [SSG 400 (+37.000 m; p=0.006); SSG 600 (+59.989 m; p<0.001); SSG 800 (+42.284 m; p=0.001)]. On the other hand, the smaller SSG (400) had the lowest values on most variables. However, while the middle SSG (600) presented higher output than the bigger one (800) for Body Load [NG (+7.745 a.u.; p<0.001); AT (+8.207 a.u.; p<0.001); GR (+5.879 a.u.; p<0.001)], it had lower results for High Intensity Distance [NG (-13.15 m; p=0.025); AT (-13.59 m; p=0.026)]. Despite women's performance being higher on AT than GR, the NG surface still showed the highest outcomes in the most intense SSG. Moreover, although the performance increase in bigger pitches, if the size is too large the outputs could be reduced. PMID- 28658078 TI - Comparison of incremental intermittent and time trial testing in age-group swimmers. AB - The aim of this study was to compare physiological and biomechanical characteristics between an incremental intermittent test and a time trial protocol in age-group swimmers. 11 national level age-group swimmers (6 male and 5 female) performed a 7 x 200-m incremental intermittent protocol (until exhaustion; 30 s rest) and a 400-m test (T400) in front crawl on separate days. Cardiorespiratory variables were measured continuously using a telemetric portable gas analyzer. Swimming speed, stroke rate, stroke length and stroke index were assessed by video analysis. Physiological (oxygen uptake, heart rate and lactate concentrations) and biomechanical variables between 7 200-m step (in which the minimal swimming speed that elicits maximal oxygen uptake - vV[Combining Dot Above]O2max was identified) and T400 (time trial/fixed distance) were compared with a paired student's t-test, Pearson's product-moment correlation, Passing-Block regression and Bland-Altman plot analyses. There were high level of agreement and high correlations (r-values ~ 0.90; p < 0.05) for all physiological variables between the 7 200-m step and T400. Similarly, there were high level of agreements and high correlations (r-values ~ 0.90; p <= 0.05) for all biomechanical variables, and only trivial bias in swimming speed (0.03 m.s; 2%). Primary physiological and biomechanical responses between incremental intermittent and representative time trial protocols were similar, but best practice dictates protocols should not be used interchangeably to minimize errors in prescribing swimming training speeds. The T400 is a valid, useful and easier to administer test for aerobic power assessment in age-group swimmers. PMID- 28658079 TI - Validity and Usability of a New System for Measuring and Monitoring Variations in Vertical Jump Performance. AB - Loturco, I, Pereira, LA, Kobal, R, Kitamura, K, Cal Abad, CC, Marques, G, Guerriero, A, Moraes, JE, and Nakamura, FY. Validity and usability of a new system for measuring and monitoring variations in vertical jump performance. J Strength Cond Res 31(9): 2579-2585, 2017-Vertical jump (VJ) height is one of the most sensitive measures to quantify training-related fatigue and athletic performance in elite athletes. Currently, however, there is no equipment designed to graphically deliver the daily performance changes in VJ compared with the smallest worthwhile change (SWC), which is considered essential in "progressive statistics" to judge meaningful performance fluctuations. The aims of the study were to analyze the criterion validity of a new contact mat (i.e., Elite Jump), alongside testing its usability to detect meaningful changes in VJ of elite team sport athletes. A total of 31 athletes participated in the criterion validity part of the study, whereas 17 rugby players participated in the VJ sensitivity part. When compared with the force plate, the contact mat produced squat jump (SJ) and countermovement jump (CMJ) values with very high intraclass correlation coefficients (0.998 and 0.997, respectively) and very low biases (-0.11 and -0.08 cm, respectively), as assessed by the Bland-Altman plot. In addition, during a training microcycle, rugby players presented identical meaningful changes in performance in both SJ and CMJ when comparing the Elite Jump and Hopkins' spreadsheet outputs. Therefore, the contact mat is valid and the proprietary software can properly execute the SWC calculations, providing coaches and researchers with accurate information concerning variations in the physical performance of elite athletes. PMID- 28658080 TI - Blood pressure response during resistance training of different work to rest ratio. AB - : Changes in the work to rest ratio (W:R) of resistance training protocols (RTP) (i.e. decreasing work and/or increasing rest) reduce the marked elevation in blood pressure (BP) that occurs during RTP execution. However, whether changes in RTP protocol structure without changing W:R can change BP responses to RTP is unknown. To investigate the effect of different structures of rest intervals and number of repetitions per set on BP response among RTP equated and nonequated for W:R, 20 normotensive participants (25+/-4 years) performed four different RTP of the leg extension exercise with the same work but different W:R structures. Two protocols followed the recommendations for cardiovascular disorders: I) HIGHW:R 3x15:44s - 3x15:44s (setxreps:rest between sets), which has high W:R (45reps:88s) and II) LOWW:R-3x15:88s - 3x15:88s, which has low W:R (45reps:176s). The other two protocols were W:R-equated to LOWW:R (45reps:176s): III) LOWW:R-9x5:22s and IV) LOWW:R-45x1:4s. Systolic BP (DeltaSBP) and diastolic BP (DeltaDBP) were assessed by finger photoplethysmography. There were significant main effects for DeltaSBP following RTP (p<0.05): HIGHW:R-3x15:44s = LOWW:R-3x15:88s > LOWW:R 45x1:4s > LOWW:R-9x5:22s (+87+/-5 and +84+/-5 vs. +61+/-4 vs. 57+/-4 mmHg). For DeltaDBP, there was a significant interaction between RTP and moment (p<0.05). Thus, HIGHW:R-3x15:44 > LOWW:R-3x15:88s > LOWW:R-45x1:4s > LOWW:R-9x5:22s (+53+/ 5 vs. +49+/-5 vs. +44+/-4 vs. +38+/-3 mmHg). HIGHW: R-3x15:44s produced the highest increase in DeltaDBP and LOWW:R-9x5:22s produced the lowest increase in DeltaSBP and DeltaDBP. Our findings may help the development of RT protocols that may mitigate pressure peaks without changing important exercise variables (i.e. volume or duration). PMID- 28658081 TI - Positional Anthropometric and Performance Profile of Elite Gaelic Football Players. AB - Shovlin, A, Roe, M, Malone, S, and Collins, K. Positional anthropometric and performance profile of elite gaelic football players. J Strength Cond Res 32(8): 2356-2362, 2018-The aim of the current investigation was to evaluate the variation in the anthropometric and performance characteristics of elite Gaelic football players with respect to position. One hundred forty-eight elite Gaelic footballers underwent anthropometric (height, body mass, sum of 7 skinfolds, and % adipose tissue) and performance (counter movement jump [CMJ] height, CMJ peak power, CMJ relative peak power, squat jump [SJ] height, SJ peak power, SJ relative peak power, 5-, 10-, and 20-m sprint times, and Yo-Yo Intermittent Recovery Test Level 2 [Yo-YoIRT2]) during "the early in-season" phase. Data were split into 5 positional groups (full back, half back, midfield, half forward, and full forward). Higher adipose tissue percentage estimate was observed in full forwards when compared with the half backs (p = 0.001), midfielders (p = 0.035), and half forwards (p = 0.021). Full forwards had significantly greater SJ (p = 0.036) and CMJ (p = 0.013) when compared with the midfielders with no other positional differences observed. No significant variation in sprint times was observed across the positions. When Yo-YoIRT2 was considered, full forwards and full backs completed significantly lower distances compared with the middle 3 positional lines of half backs, midfielders, and half forwards (p = 0.00). The current study is the first to provide normative data for anthropometric and performance values of elite Gaelic football players which in turn can be used by coaches to generate appropriate training regimes to maximize position-specific preparation for competitive match-play. PMID- 28658082 TI - Acute Responses to the 7-Minute Workout. AB - Riegler, M, Stotz, G, Fitzgerald, K, Munoz, CK, Lewis, J, Ring, S, and Astorino, TA. Acute responses to the 7-minute workout. J Strength Cond Res 31(9): 2572 2578, 2017-A popular smartphone application called the 7-Minute Workout (7Min) claims to be scientifically proven to promote weight loss and improve cardiovascular function. The application has 10 million downloads and has been reviewed by 350,000 users. However, changes in metabolic and perceptual variables in response to 7Min are unknown. Our study compared acute responses between 7Min and a time-matched session of cycling-based high-intensity interval exercise (HIIE). Fourteen active men and women (age and V[Combining Dot Above]O2max = 25.4 +/- 8.3 years and 40.5 +/- 6.4 ml.kg.min) initially underwent V[Combining Dot Above]O2max testing. During 2 subsequent sessions separated by >=48 hours, they completed 7Min or HIIE. During exercise, oxygen uptake (V[Combining Dot Above]O2), heart rate (HR), blood lactate concentration (BLa), and rating of perceived exertion were measured. Peak V[Combining Dot Above]O2 was higher (p < 0.001) in HIIE vs. 7Min, and HIIE yielded greater (p < 0.001) mean V[Combining Dot Above]O2 (1.83 +/- 0.41 L.min vs. 1.44 +/- 0.32 L.min) and HR (159.0 +/- 10.7 b.min vs. 140.7 +/- 18.3 b.min, p < 0.001) vs. 7Min. Blood lactate concentration increased (p < 0.001) during exercise but was similar between bouts (p = 0.07). Rating of perceived exertion was higher (p = 0.008) in response to HIIE vs. 7Min. Although 7Min yields lower peak V[Combining Dot Above]O2 and HR than HIIE, it is characterized by bursts approaching 90 %HRmax and causes significant BLa accumulation, representing vigorous exercise. Nevertheless, 7Min is on the low end of the intensity spectrum, which questions whether it represents true HIIE and will confer similar benefits if performed long term. PMID- 28658083 TI - Relationship between percentages of heart rate reserve and oxygen uptake reserve during cycling and running: a validation study. AB - The present study investigated the relationship between percentages of heart rate reserve (%HRR) and oxygen uptake reserve (%VO2R) during a cardiopulmonary exercise test (CPET) and discrete bouts of isocaloric cycling and treadmill running. Thirty men visited the laboratory three times for anthropometrical and resting VO2 assessments, and perform cycling and running CPETs. Ten men visited the laboratory twice more to investigate the validity of the %HRR-%VO2R relationships during isocaloric bouts of cycling and running at 75% VO2R with energy expenditures of 400 kcals. The %HRR was significantly higher than the %VO2R during both CPETs at all exercise intensities (P < 0.001). During isocaloric exercise bouts, mean %HRR-%VO2R differences of 6.5% and 7.0% were observed for cycling and running, respectively (P = 0.007 to P < 0.001). The %HRR and %VO2R increased over time (P < 0.001), the rate of which was influenced by exercise modality (P < 0.001). On average, heart rate was 5 (P = 0.007) and 8 (P < 0.001) beats.min higher than predicted from the second energy expenditure quartile for cycling and running, respectively; however, observed VO2 was lower than predicted during all quartiles for cycling, and the first quartile for running. Consequently, time to achieve the target energy expenditure was greater than predicted (P < 0.01). In conclusion, the %HRR-%VO2R relationship observed during CPET data did not accurately transpose to prolonged isocaloric bouts of cycling and running. Additionally, power outputs and speeds defined by the ACSM equations for cycling and running, respectively, overestimated VO2 and energy expenditure. PMID- 28658084 TI - Addition of Glute-Ham-Gastroc Raise to a Resistance Training Program: Effect on Jump Propulsion and Landing. AB - Chiu LZF, Yaremko A, and vonGaza GL. Addition of glute-ham-gastroc raise to a resistance training program: effect on jump propulsion and landing. J Strength Cond Res 31(9): 2562-2571, 2017-Exercises such as squats and cleans are commonly used in resistance training programs to enhance athletic performance. However, these exercises may not effectively train the gastrocnemius, an important muscle for energy generation and absorption. The purpose of this research was to examine the effects of adding glute-ham-gastroc raise exercise to target the gastrocnemius to a traditional resistance training program involving squats and cleans. Vertical jump height, weight-bearing ankle dorsiflexion, and jump propulsion and landing mechanics were examined before and after an 8-week training intervention in female youth volleyball players. Approach (with: [INCREMENT] = 2.6 +/- 1.7 cm; 90% confidence interval [CI] [1.8-3.6 cm] vs. without: [INCREMENT] = 1.8 +/- 1.9 cm; 90% CI [0.8-2.8 cm]) and standing (with: [INCREMENT] = 2.7 +/- 1.7 cm; 90% CI [1.7-3.6 cm] vs. without: [INCREMENT] = 1.6 +/- 1.5 cm; 90% CI [0.8-2.4 cm]) vertical jump height increased more in the group performing glute-ham-gastroc raise. Weight-bearing ankle dorsiflexion increased when glute-ham-gastroc raise was included (left: [INCREMENT] = 4.1 +/- 4.1 degrees ; 90% CI [1.9-6.4 degrees ] and right: [INCREMENT] = 4.1 +/- 3.9 degrees ; 90% CI [1.9-6.2 degrees ]) but did not appear to change with resistance training only (left: [INCREMENT] = 1.4 +/- 4.5 degrees ; 90% CI [-1.0 to 3.9 degrees ] and right: [INCREMENT] = 2.5 +/- 4.4 degrees ; [-0.3 to 4.5 degrees ]). No discernible differences were observed for changes in jump propulsion and landing mechanics between groups. Glute-ham-gastroc raise may have a beneficial effect with young athletes when added to squat- and clean-based resistance training programs. PMID- 28658085 TI - Mixed martial arts induces significant fatigue and muscle damage up to 24 hours post-combat. AB - This study investigates the physiological/physical responses to a simulated mixed martial arts (MMA) competition over 24 hr. Twelve fighters performed a simulated MMA competition, consisting of three 5-min MMA matches. Physiological/physical data were assessed before (Trest), directly after round 1 (Trd1), round 2 (Trd2) and round 3 (Trd3), and then 30-min (Trecovery30min) and/or 24-hr (Trecovery24h) post-competition. Heart rate (HR), rating of perceived exertion (RPE) and blood lactate concentration ([La]) were assessed at Trest, Trd1, Trd2 and Trd3. Biological data were collected at Trest, Trd3, Trecovery30min and Trecovery24h. Physical tests were performed at Trest, Trecovery30min and Trecovery24h. HR, RPE and [La] were high during competition. Leukocytes, hemoglobin, total protein and glycemia were increased at Trd3 compared with all other time points (p<0.05). Cortisol was increased at Trd3 compared with Trest and Trecovery24h (p<0.05). Testosterone was higher at Trd3 and Trecovery30min than Trest (p<0.001). Higher values of uric acid were noted during recovery periods (p<0.001). Lactate dehydrogenase was lower at Trest compared with Trd3, Trecovery30min and Trecovery24h (p<0.05). Countermovement jump was higher at Trest than Trecovery30min (p=0.020). Consequently, MMA is a high-intensity intermittent combat sport that induces significant fatigue and muscle damage, both of which are still present 24-hr post-competition. PMID- 28658086 TI - Muscle Strength Is Protective Against Osteoporosis in an Ethnically Diverse Sample of Adults. AB - McGrath, RP, Kraemer, WJ, Vincent, BM, Hall, OT, and Peterson, MD. Muscle strength is protective against osteoporosis in an ethnically diverse sample of adults. J Strength Cond Res 31(9): 2586-2589, 2017-The odds of developing osteoporosis may be affected by modifiable and nonmodifiable factors such as muscle strength and ethnicity. This study sought to (a) determine whether increased muscle strength was associated with decreased odds of osteoporosis and (b) identify whether the odds of osteoporosis differed by ethnicity. Data from the 2013 to 2014 National Health and Nutrition Examination Survey were analyzed. Muscle strength was measured with a hand-held dynamometer, and dual-energy x-ray absorptiometry was used to assess femoral neck bone mineral density. A T-score of <=2.5 was used to define osteoporosis. Separate covariate-adjusted logistic regression models were performed on each sex to determine the association between muscle strength and osteoporosis. Odds ratios (ORs) were also generated to identify if the association between muscle strength and osteoporosis differed by ethnicity using non-Hispanic blacks as the reference group. There were 2,861 participants included. Muscle strength was shown to be protective against osteoporosis for men (OR: 0.94; 95% confidence interval [CI]: 0.94-0.94) and women (OR: 0.90; CI: 0.90-0.90). Although ORs varied across ethnicities, non Hispanic Asian men (OR: 6.62; CI: 6.51-6.72) and women (OR: 6.42; CI: 6.37-6.48) were at highest odds of osteoporosis. Increased muscle strength reduced the odds of osteoporosis among both men and women in a nationally representative, ethnically diverse sample of adults. Non-Hispanic Asians had the highest odds of developing osteoporosis. Irrespective of sex or ethnicity, increased muscle strength may help protect against the odds of developing osteoporosis. PMID- 28658087 TI - Physical Fitness Characteristics of High vs. Low Performers on an Occupationally Specific Physical Agility Test for Patrol Officers. AB - Law enforcement agencies frequently use physical ability tests (PATs) as a method of evaluating occupational performance. These tests are designed to replicate essential occupational tasks frequently performed by officers in the field. The purpose of this study was to determine whether significant relationships exist between the selected physical fitness tests and PAT performance and to determine which of these tests best differentiates between high and low PAT performers. Full-time highway patrol officers (n = 495) submitted self-reported anthropometric data (mean age = 39.6 + 7.7 years) along with fitness assessments taken from their organization's yearly fitness tests. All subjects completed a series of field-based fitness tests, as well as an occupationally specific PAT. Results of the study indicated that the selected tests accounted for almost 69% of the total variance on PAT performance. Overall, the 20-m meter multistage fitness test, 1-minute sit-up performance, and vertical jump height best predicted PAT performance. Furthermore, it was revealed that high performers were significantly more fit in all measures of dynamic fitness when compared with lower performers. No significant differences were discovered in static strength between groups. Strength and conditioning specialists should focus on developing aerobic capacity, trunk muscular endurance, and whole-body anaerobic power to improve PAT and occupational performance. PMID- 28658088 TI - Laboratory and Match Physiological Data From an Elite Male Collegiate Soccer Athlete. AB - This study compared physiological data from an elite collegiate soccer player to those of his teammates over 2 seasons. The player of special interest (player A) was the winner of the MAC Hermann Trophy and was therefore considered the top player in National Collegiate Athletic Association (NCAA) division I soccer for each of the 2 seasons in which data were collected. Maximal oxygen consumption (V[Combining Dot Above]O2max) was measured during preseasons and heart rate (HR) was recorded during competitive matches. Polar Training Loads (PTL) were calculated using the Polar Team2 Pro (Polar USA) system based on time spent in HR zones. Player A had a lower V[Combining Dot Above]O2max than the team average in 2012 (56 vs. 61.5 +/- 4.3 ml.kg.min) and a similar value in 2013 (54 vs. 56.9 +/- 5.1 ml.kg.min). During matches, player A showed consistent significant differences from the team in percentage of time spent at 70-79% maximal heart rate (HRmax) (12.8 +/- 5.5% vs. 10.1 +/- 4.0%), 80-89% HRmax (54.3 +/- 11.5% vs. 29.3 +/- 6.8%), and 90-100% HRmax (23.1 +/- 10.6% vs. 45.4 +/- 8.5%). This led to a consistently lower PTL per minute accumulated by player A compared with his teammates (3.6 +/- 0.4 vs. 4.4 +/- 0.3), which may be beneficial over a season and may be related to his success. Thus, the ability to regulate moments of maximal exertion is useful in reducing training load and may be a characteristic of elite players, although whether our findings relate to differences in the playing style, position, or aerobic capacity of player A are unknown. PMID- 28658089 TI - No association of GRIK4 polymorphisms with schizophrenia in the Chinese Han population. PMID- 28658090 TI - Patient Needs, Required Level of Care, and Reasons Delaying Hospital Discharge for Nonacute Patients Occupying Acute Hospital Beds. AB - This study aims to determine the proportion of nonacute patients occupying acute care beds and to describe their needs, the appropriate level of alternative care, and reasons preventing discharge. Data from 952 patients hospitalized in an acute care unit for 30 days were obtained from their medical charts and by consulting with the medical team at two tertiary teaching hospitals. Among them, 333 (35%) were determined nonacute on day 30 of hospitalization. According to the Appropriateness Evaluation Protocol (AEP), 55% had no medical, nursing, or patient needs. Among nonacute patients with AEP needs, 88% were related to nursing/life-support services and 12% related to patient condition factors. Regarding alternative level of care, 186 (56%) were waiting for out-of-hospital resources, of which 36% were waiting for palliative care, 33% for long-term care, 18% for rehabilitation, and 12% for home care. For the remaining 147 (44%) nonacute patients, the alternative resources remained undetermined although acute care was no longer required. Main reasons preventing discharge included unavailability of alternative resources, ongoing assessment to determine appropriate resources, ongoing process with community care, and family/patient education/counseling. Available subacute facilities and community-based care would liberate acute care beds and facilitate their appropriate use. PMID- 28658091 TI - Assessing Estimates of Patient Safety Derived From Coded Data. AB - The Agency for Healthcare Research and Quality (AHRQ) developed Patient Safety Indicators (PSI) with the goal of detecting and preventing adverse events using administrative data. Use of PSIs to measure safety and quality of care raises questions since they rely heavily on coded data. The goal of this paper is to review literature on AHRQ PSIs, specifically their accuracy in detecting adverse events, and how recent coding changes affect the accuracy of these estimates. The Healthcare Utilization Project (HCUP) National Inpatient Sample (NIS) contains data on more than seven million hospital stays yearly. Trending these estimates over time indicate there has been a decrease in rates for the majority of PSIs, with Accidental Puncture or Laceration, Central Venous Catheter Blood Stream Infections, Iatrogenic Pneumothorax, and Deaths from complications decreasing significantly each year from 2008-2012. Birth Trauma, Retained Foreign Bodies, Post-op Sepsis and Post-Op Respiratory Failure PSIs show no improvement from 2008 2012. A literature review on accuracy of PSIs and the affect of the Present on Admission (POA) indicator on PSI estimates reveals mixed results. PSIs serve as a useful tool in identifying problem areas in quality of care but should be used cautiously in determining hospital performance. PMID- 28658092 TI - Healthcare Affiliation Networks: A Unique Quality Partnership to Aid in Making Communities Healthier. AB - As the healthcare environment continues to evolve, many community hospitals of all sizes are finding it difficult to thrive and grow in the headwinds of increasing regulatory requirements, decreased reimbursements amidst healthcare reform efforts, increased requirements for efficiency, demands for improvement in the patient experience, and increasing penalties for lagging performance in patient safety and quality metrics. A unique partnership, involving an organization built upon expertise in operating community hospitals and an academic center with expertise in patient safety, quality, innovation, and care delivery, has provided a successful solution for a growing number of challenged community facilities. The purpose of this article is to demonstrate how using standardized patient safety, quality improvement processes, and high-reliability strategies in community hospitals has been supported and enhanced through the development of a healthcare affiliation network with an academic medical center. By developing this type of quality affiliation, hospitals across a broad spectrum of sizes and locations can achieve significant improvement in safety culture while demonstrating measureable advances in quality and safety and supporting their mission of "making communities healthier, together." PMID- 28658093 TI - Inflammatory myofibroblastic tumor of the lumbar spinal canal: A Case Report With Literature Review. AB - RATIONALE: Inflammatory myofibroblastic tumor (IMT) is a rare type of mesenchymal tumor. IMT can arise in multiple anatomic locations. IMT of the lumbar spinal canal is exceptionally rare. PATIENT CONCERNS: Here, we report the case of a 56 year-old male patient with an IMT who was in good health until 1 year prior to admission, when he began experiencing pain in both lower extremities and the lower back. INTERVENTIONS: A space-occupying lesion in the lumbar canal was identified by magnetic resonance imaging and then surgically resected. DIAGNOSES: Histopathological analysis of the lesion revealed a composition of mucous edema, inflammatory cells, collagenous fibers, and spindle cells that were diffuse and positive for smooth muscle actin and CD68; focal positive for vimentin and desmin; and negative for CD34 (marker of vascular endothelial cells), CD21, CD23, CD35, S-100, Epstein-Barr virus infection, Ki-67, and anaplastic lymphoma kinase. Thus, the diagnosis was an IMT of the lumbar canal. OUTCOMES: In the spinal canal, IMT should be considered in the evaluation of tumors although it is a very rare diagnosis. It is a benign lesion, but it has potential for invasion and recurrence. LESSONS: There are no characteristic imaging features of these tumors, but they can be addressed by complete surgical excision. Patients with these lesions should undergo frequent long-term follow-up to detect and address recurrence. PMID- 28658094 TI - Multimorbidity and polypharmacy in diabetic patients with NAFLD: Implications for disease severity and management. AB - An observational study describing the number and type of chronic conditions and medications taken by diabetic patients with NAFLD and identifying characteristics that may impact liver disease severity or clinical management.Adults with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) and increased risk of developing advanced liver disease. Appropriate management should consider the characteristics of the diabetic NAFLD population, as comorbid conditions and medications may increase the complexity of treatment strategies.Diabetic patients with NAFLD at risk of clinically significant liver disease (as assessed by the FIB-4 or NAFLD fibrosis scores) were recruited consecutively from the Endocrine clinic or primary care. Medical conditions, medication history, anthropometric measurements, and laboratory tests were obtained during assessment. NAFLD severity was classified by transient elastography and liver ultrasound into "no advanced disease" (LSM < 8.2 kPa) or "clinically significant liver disease" (LSM >= 8.2 kPa).The most common coexistent chronic conditions were metabolic syndrome (94%), self-reported "depression" (44%), ischaemic heart disease (32%), and obstructive sleep apnoea (32%). Polypharmacy or hyperpolypharmacy was present in 59% and 31% of patients respectively. Elevated LSM (>= 8.2 kPa) suggesting significant liver disease was present in 37% of this at-risk cohort. Increasing obesity and abdominal girth were both independently associated with likelihood of having significant liver disease.There is a high burden of multimorbidity and polypharmacy in diabetic NAFLD patients, highlighting the importance of multidisciplinary management to address their complex health care needs and ensure optimal medical treatment. PMID- 28658095 TI - A clinical review on megalencephaly: A large brain as a possible sign of cerebral impairment. AB - Megalencephaly and macrocephaly present with a head circumference measurement 2 standard deviations above the age-related mean. However, even if pathologic events resulting in both megalencephaly and macrocephaly may coexist, a distinction between these two entities is appropriate, as they represent clinical expression of different disorders with a different approach in clinical work-up, overall prognosis, and treatment. Megalencephaly defines an increased growth of cerebral structures related to dysfunctional anomalies during the various steps of brain development in the neuronal proliferation and/or migration phases or as a consequence of postnatal abnormal events. The disorders associated with megalencephaly are classically defined into 3 groups: idiopathic or benign, metabolic, and anatomic. In this article, we seek to underline the clinical aspect of megalencephaly, emphasizing the main disorders that manifest with this anomaly in an attempt to properly categorize these disorders within the megalencephaly group. PMID- 28658096 TI - Is pregabalin effective and safe in total knee arthroplasty? A PRISMA-compliant meta-analysis of randomized-controlled trials. AB - BACKGROUND: Pain management after total knee arthroplasty (TKA) varies and has been investigated for years. Pregabalin as an anticonvulsant agent that selectively affects the nociceptive process has been used for pain relief after operation. This meta-analysis was conducted to examine the evidence of pregabalin in TKA. METHODS: Systematic searches of all related literatures were conducted using the following databases: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Only randomized-controlled trials (RCTs) for TKA were included. The postoperative narcotic requirements, visual analog scale scores, knee flexion range, and relative risk of incidence rate of adverse effects in the pregabalin group versus placebo group were extracted throughout the study. RESULTS: Seven placebo-controlled RCTs met the inclusion criteria. The use of pregabalin significantly decrease the postoperative total morphine consumption (P < .05) and increase the passive knee flexion range (P < .05). Compared with the control group, the incidence of some side effects (nausea, vomiting, pruritus, and constipation) was less in the pregabalin group (P < .05). CONCLUSIONS: The administration of pregabalin is not only efficacious in the reduction of narcotic requirements and incidence of some adverse effect, but also workable for the improvement of passive knee flexion range after TKA. PMID- 28658097 TI - A thermal dysregulation problem after breast cancer surgery; what could be? AB - RATIONALE: Chronic fatigue syndrome (CFS) is a complicated disorder characterized by severe fatigue that is not relieved with rest and associated with physical symptoms such as sleep problems, headache, muscle pain, or joint pain. PATIENT CONCERNS: Forty-one year old patient complained from feeling cold after breast cancer surgery. DIAGNOSES: The diagnoses of fibromyalgia, depression, neurological, psychiatric, and vascular disorders were excluded by appropriate clinical and laboratory investigations. She was diagnosed as CFS. INTERVENTIONS: The patient was treated successfully via aerobic exercise therapy that scheduled for 30 min at least 3 days per week. OUTCOMES: At 6-month follow-up, her complaints were almost resolved and the patient regained her physical health and mental attitude. LESSONS: A thermal dysregulation should be taken into consideration as one of the symptoms of CFS. PMID- 28658098 TI - Renal incidental findings on computed tomography: Frequency and distribution in a large non selected cohort. AB - Renal incidental findings (IFs) are common. However, previous reports investigated renal IFs were limited to patient selection. The purpose of this study was to estimate the prevalence and distribution of all renal IFs on computed tomography (CT) in a large patient collective.All patients, who underwent CT investigations of the abdominal region at our institution in the time period between January 2006 and February 2014 were included in this study. Inclusion criteria were as follows: no previous history of renal diseases and well image quality. Patients with known kidney disorders were excluded from the study. Overall, 7365 patients meet the inclusion criteria were identified. There were 2924 (39.7%) women and 4441 men (60.3%) with a mean age of 59.8 +/- 16.7 years. All CTs were retrospectively analyzed in consensus by 2 radiologists. Collected data were evaluated by means of descriptive statistics.Overall, 2756 patients (37.42% of all included patients) showed 3425 different renal IFs (1.24 findings per patient). Of all renal IFs, 123 (3.6%) findings were clinically relevant, 259 (7.6%) were categorized as possibly clinically relevant, and 3043 (88.8%) were clinically non relevant.Different renal IFs can be detected on CT. The present study provides a real prevalence and proportion of them in daily clinical routine. Kidneys should be thoroughly evaluated because of the fact that incidental renal findings occur frequently. PMID- 28658099 TI - Menopausal status and the risk of lung cancer in women: A PRISMA-compliant meta analysis. AB - BACKGROUND: Quantification of the association between menopausal status and risk of lung cancer is inconsistent. We carried out a meta-analysis of available studies to examine this issue. METHODS: Relevant articles were identified by searching PudMed and Embase databases. Reference lists from selected papers were also reviewed. A random-effect model was used to calculate summary odds ratios (OR) and relative risk (RR) with 95% confidence interval (CI). Publication bias was estimated using Egger regression asymmetry test. RESULTS: Eight eligible studies, including 5 case-control studies and 3 cohort studies, provided data for meta-analysis. Postmenopausal women had a statistically significant increased risk of lung cancer in all included studies (RR = 1.44, 95% CI: 1.12-1.85) and cohort studies (RR = 1.39, 95% CI: 1.05-1.86), but not in case-control studies (OR = 1.46, 95% CI: 0.95-2.24). CONCLUSIONS: Overall, there was evidence that postmenopause is related to increased lung cancer risk. However, studies have produced slightly heterogeneous results (I = 38.40%). To obtain a better indication of relationship, well-designed large prospective studies are required. PMID- 28658100 TI - Echocardiography and Electrocardiography Variables Correlate With the New York Heart Association classification: An Observational Study of Ischemic Cardiomyopathy Patients. AB - The aim of our study was to determine whether combinations of ultrasound echocardiography (UCG) and electrocardiography (EKG) parameters correlated with the functional status of ischemic cardiomyopathy (ICM) patients according to the New York Heart Association (NYHA) classification system.We assessed 536 elderly Chinese ICM patients according to the NYHA criteria, which included 196 patients with type 2 diabetes mellitus (T2DM). All of the patients underwent UCG. Transmural dispersion of ventricular repolarization was examined using EKG. Cumulative odds logistic regression was performed to evaluate associations between NYHA class and the demographic, clinical, UCG, and EKG variables based on the odds ratio (OR) and 95% confidence interval (CI). A Pearson analysis was also performed to examine correlations between the NYHA classification and the UCG and EKG variables.Based on the NYHA assessment, 140, 147, 138, and 111 patients were identified as class I, II, III and IV, respectively. A comparison of UCG and EKG variables based on T2DM status showed that CO and Tp-e differed significantly between all NYHA classes (P < .05 for all), with values of each increasing with increasing NYHA class regardless of T2DM status. Multivariate logistic regression analysis showed that the disease course (OR: 1.30; 95% CI: 1.20-1.40), heart rate (OR: 1.16; 95% CI: 1.12-1.21), T wave peak to endpoint (Tp-e; OR: 1.22; 95% CI: 1.18-1.27), dispersion of the QT interval (OR: 0.98; 95% CI: 0.95-1.22), left ventricular fractional shortening (OR: 0.82; 95% CI: 0.78-0.87), cardiac output (CO; OR: 5.58; 95% CI: 3.08-10.13) were significantly associated with the NYHA class (P < .0001 for all). A Pearson correlation analysis showed that Tp-e (r = 0.75982, P < .0001), CO (r = 0.56072, P < .0001), and stroke volume (r = 0.14839, P = .0006) significantly correlated with the NYHA class.An index consisting of Tp-e and CO will be useful for corroborating the results of the NYHA assessment of ICM patients. PMID- 28658101 TI - Propensity score matched analysis comparing the clinical outcome of Klebsiella pneumoniae and Escherichia coli causing community-onset monomicrobial bacteremia. AB - Bacteremia is a life-threatening condition that is associated with substantial healthcare costs. Escherichia coli and Klebsiella pneumoniae are the leading causes of community-onset gram-negative bacteremia. However, a comprehensive comparison between these pathogens involved in bacteremia episodes has yet to be reported.In this retrospective cohort study, adults with community-onset monomicrobial bacteremia caused by E coli or K pneumoniae were recruited in the emergency department of a medical center during a 6-year period, and the clinical variables were collected retrospectively from medical records. The complicated abscess occurrence was determined through imaging studies, according to the opinion of an infectious disease consultant. According to the independent predictors of 28-day mortality identified through multivariate regression analyses, patients in the E coli group were propensity score matched (PSM) in a 1:1 ratio to those in the K pneumoniae group.A total of 274 and 823 adults with K pneumoniae and E coli bacteremia were included in the present study. The K pneumoniae group had more patients with fatal comorbidities (McCabe classification), critical illness (Pitt bacteremia score >= 4) at bacteremia onset, and initial syndrome (e.g., severe sepsis and septic shock) as well as a higher crude mortality rate than did the E coli group. After appropriate matching, no significant differences were observed in the critical illness at bacteremia onset, initial syndrome, major comorbidities, and comorbidity severity of the 2 groups (E coli, n = 242; K pneumoniae, n = 242). Furthermore, despite similar 14- and 28-day crude mortality rates between the 2 PSM groups, more frequent abscess occurrences and a longer length of hospitalization were observed in the K pneumoniae group than in the E coli group.Conclusively, numerous clinical features at initial presentations varied between the E coli and K pneumoniae groups. Despite conducting a PSM analysis to control the differences in the baseline characteristics, a longer length of hospitalization and more frequent abscess occurrences were observed in the K pneumoniae group than in the E coli group. PMID- 28658102 TI - Predictive risk factors associated with synchronous multiple early gastric cancer. AB - The aim of this study was to elucidate the predictive risk factors of synchronous multiple early gastric cancer regardless of the treatment modality.Patients who underwent early gastric cancer treatment between July 2005 and June 2015 were retrospectively reviewed. In total, 1529 patients who were treated for early gastric cancer were included. We analyzed the patient's data to find predictive factors of synchronous multiple early gastric cancer compared to solitary early gastric cancer. Further analysis was performed to verify the difference between endoscopic and surgical treatment groups.Among the 1529 patients, synchronous multiple early gastric cancer was diagnosed in 68 (4.4%) patients. Significant differences in sex (P = .004), gross appearance (P = .038), depth of invasion (P = .007), and lymphovascular invasion (P = .039) were found between patients with solitary early gastric cancer and synchronous multiple early gastric cancer by univariate analysis. In multivariate analysis, male sex (odds ratio, 2.475; P = .011) and submucosal invasion (odds ratio, 1.850; P = .033) were independent predictive risk factors of synchronous multiple early gastric cancer. In addition, in multivariate analysis, significant differences in age, tumor size, longitudinal location, depth of invasion, and histology were found between patients groups depending on the mode of treatment.Male sex and submucosal invasion were predictive risk factors of synchronous multiple early gastric cancer. Patients with these factors should undergo more meticulous endoscopic surveillance. PMID- 28658103 TI - Application of anterior debridement and reconstruction with anatomical screw plate fixation for lumbosacral tuberculosis: A 2-year-plus follow-up. AB - This study aimed to determine the efficacy and safety of anterior debridement and reconstruction with anatomical screw-plate fixation in patients with lumbosacral junction tuberculosis (TB).A total of 48 patients (30 males and 18 females) diagnosed with lumbosacral junction TB were included in this study. All patients underwent surgery in our institution from January 2008 to July 2014, using anterior debridement and reconstruction with anatomical screw-plate. Outcome data were evaluated before and after surgery and included lumbosacral angle, Frankel classification, bone fusion, and visual analog scale (VAS) scores.All patients were then followed up for an average of 49.4 months (range, 24-96 months). The mean lumbosacral angle improved from 8.36 degrees +/- 5.92 degrees pre operation to 22.38 degrees +/- 4.52 degrees post-operation and 21.13 degrees +/- 3.73 degrees during the final follow-up (both P < .05). Solid vertebral fusion was achieved in all patients after 7.6 months on average (range, 6-12 months). No severe complications appeared during operation and post-operation. Neurological performance and VAS scores were significantly improved compared with pre-operation (P < .05).Following standard anti-TB chemotherapy, anterior debridement and reconstruction with anatomical screw-plate fixation may be a feasible and effective therapeutical option for lumbosacral junction TB. This procedure can result in satisfactory bone fusion and deformity correction, and effectively restore lumbosacral junction stability. PMID- 28658104 TI - Thrombotic complications and tip position of transjugular chronic dialysis catheter scheduled into superior vena cava: Findings on HR-MRCP and HR-T2WI. AB - BACKGROUND: Catheter-related thrombotic complications(TCs) can occur during the long term use of a chronic dialysis catheter (CDC), including fibrin sheath (FS), mural thrombosis (MT), venous thrombosis (VT), and intraluminal clots (IC), which has not been reported with MRI. The aim of our study was to evaluate the determination of catheter tip position (TP) and resolution of TCs in patients with transjugular CDC scheduled into the superior vena cava using high resolution magnetic resonance cholangiopancreatography (HR-MRCP) and T2-weighted imaging (HR T2WI). METHODS: The study protocol was approved by the local Research Ethics Committee. Informed consent was obtained from all patients. In total, 41 consecutively enrolled transjugular CDC patients with suspected catheter dysfunction were scanned with HRMRCP and HR-T2WI. The distance from the top to the tip of the catheter and the presence and nature of catheter TCs were assessed by 2 experienced radiologists. Chest x-ray was taken within 1 to 2 days and CDC was withdrawn within 3 to 10 days from those patients with TCs identified by HR MRI. RESULTS: A total of 38 subjects successfully underwent HR-MRI, including 13 normal and 25 with TCs (fibrin sheath [FS]: n = 21, mural thrombosis [MT]: n = 7, venous thrombosis [VT]: n = 3, intraluminal clots [IC]: n = 4). There was no significant difference between HR-MRCP and chest x-ray in catheter TP determination (P = .124). Normal catheter appeared as "double eyes" on HR-T2WI and "double tracks" on HR-MRCP. TCs appeared as follows: FS displayed as a "thin ring" (<1mm) around the catheter, MT as patchy hyperintensity and VT as a "thick ring" (>5mm) on HR-T2WI. Unilateral IC appeared as a "single eye" on HR-T2WI and a "single track" on HR-MRCP (n = 3). Bilateral IC appeared as neither "eye" nor "track" (n = 1). Catheter withdrawal confirmed FS (n = 16), MT (n = 6), VT (n = 1), and IC (n = 4). CONCLUSION: HR-MRCP and HR-T2WI are promising methods for visualizing TP and TCs in CDC patients, and are helpful in adjusting the treatment plan and avoiding the risk of pulmonary embolism. PMID- 28658105 TI - Association between formaldehyde exposure and miscarriage in Chinese women. AB - The aim of this study was to assess whether higher plasma formaldehyde concentration existed in women diagnosed with miscarriage and whether it contributed to higher risk of miscarriage in Chinese women.A case-control study was conducted in 118 women with a diagnosed miscarriage at the first trimester and 191 healthy women who delivered at term. Plasma levels of formaldehyde were measured by gas chromatography in conjunction with mass spectrometry after derivatization of the formaldehyde to the pentafluorophenylhydrazone and characteristics of the subjects including age, education level, occupation, family income, home decoration status, and exposure to second-hand smoke were recorded. Logistic regression analyses were performed to investigate the relationship between miscarriage and levels of formaldehyde.Women with miscarriage were comparable to controls in terms of age, education level, occupation, family income, and home decoration status. They were, however, more likely to be exposed to second-hand smoke. Plasma levels of formaldehyde were significantly higher in women with miscarriage (0.0944 +/- 0.0105 vs. 0.0239 +/- 0.0032 MUg/mL, P < .001). Multivariate logistic regression showed that higher level of formaldehyde (odds ratio [OR]: 8.06, 95% confidence interval [CI]: 4.96 13.09) and exposure to second-hand smoke (OR: 3.60, 95% CI: 1.58-8.20) were independently and significantly associated with higher risk of miscarriage.Plasma levels of formaldehyde were significantly higher in women who were diagnosed with miscarriage than those who delivered at term and higher levels of formaldehyde was an independent risk factor for miscarriage, with higher levels being associated with higher risk of miscarriage. PMID- 28658106 TI - Drones at the service for training on mass casualty incident: A simulation study. AB - Mass casualty incidents (MCI) are characterized by a large number of victims with respect to the resources available. In this study, we aimed to analyze the changes produced in the self-perception of students who were able to visualize aerial views of a simulation of a MCI. A simulation study, mixed method, was performed to compare the results from an ad hoc questionnaire. The 35 students from the Emergency Nursing Master from the UCAM completed a questionnaire before and after watching an MCI video with 40 victims in which they had participated. The main variable measured was the change in self-perception (CSP). The CSP occurred in 80% (28/35) of the students (P = .001). Students improved their individual (P = .001) and group (P = .006) scores. They also described that their personal performance had better results than the group performance (P = .047). The main conclusion of this study is that drones could lead to CSP and appraisal of the MCI simulation participants. PMID- 28658107 TI - Pre-sarcopenia is associated with renal hyperfiltration independent of obesity or insulin resistance: Nationwide Surveys (KNHANES 2008-2011). AB - Renal hyperfiltration is closely linked to cardiometabolic disorders, and it may increase the mortality risk of the general population. Despite the well established association between cardiometabolic diseases and sarcopenia, the relationship between renal hyperfiltration and sarcopenia has not yet been assessed.This population-based, cross-sectional study used a nationally representative sample of 13,800 adults from the 2008 to 2011 Korea National Health and Nutrition Examination Survey. Renal hyperfiltration was defined as the age- and sex-specific glomerular filtration rate above the 90th percentile in subjects with normal kidney function (>60 mL/min/1.73 m). Appendicular skeletal muscle (ASM), measured by dual-energy x-ray absorptiometry, was used to assess pre-sarcopenia, which the international consensus defines as both ASM per se and ASM that was adjusted for the body mass index and the height.A total of 1402 (10.2%) participants were classified as having renal hyperfiltration. The prevalence of pre-sarcopenia ranged from 11.6% to 33.0%, by definition. Individuals with pre-sarcopenia had higher risks of renal hyperfiltration compared to those without pre-sarcopenia (10.9% vs 17.4%, P < .001; odds ratio [OR] = 1.71, 95% confidential interval [CI] = 1.48-1.99, P < .001). Multiple logistic regression analyses also demonstrated this independent association between pre-sarcopenia and renal hyperfiltration, following adjustment for confounding factors such as insulin resistance and obesity (OR = 1.84, 95% CI = 1.57-2.15, P < .001).In the general population of healthy individuals, pre sarcopenia might be associated with renal hyperfiltration independent of obesity or insulin resistance. PMID- 28658108 TI - Effectiveness and safety of valsartan/amlodipine in hypertensive patients with stroke: China Status II subanalysis. AB - High blood pressure (BP) is a major risk factor associated with stroke in China. This is a subanalysis of patients from the China Status II study, aimed to evaluate the effectiveness and safety of valsartan/amlodipine (Val/Aml) single pill combination (SPC) in hypertensive patients with different stroke subtypes (hemorrhagic, ischemic, or mixed).China Status II was a multicenter, postmarketing, prospective observational study in hypertensive patients uncontrolled on monotherapy. The study was an 8-week open-label treatment period with 2 4-week follow-ups. Change in BP from baseline to weeks 4 and 8, BP control rate, and response rate at weeks 4 and 8, and safety of 8-week treatment with Val/Aml (80/5 mg) were assessed.A total of 565 hypertensive patients with different types of stroke were analyzed in this China Status II substudy. Significant mean sitting systolic/diastolic BP (MSSBP/MSDBP) reductions from baseline to week 8 were observed across all stroke subtypes (P < .0001). At week 8, percentages of patients achieving MSSBP response (>=20 mm Hg reduction from baseline) were 76.3%, 74.4%, and 85.7%, MSDBP response (>=10 mm Hg reduction from baseline) were 67.8%, 65.9%, and 64.3%, and BP control (<140/90 mm Hg) were 74.6%, 80.5%, and 92.9%, in the hemorrhagic, ischemic, and mixed stroke subgroups, respectively. Adverse events (AEs) and serious AEs were reported in 5 patients (1%) and 1 patient (0.2%), respectively, in the ischemic stroke subgroup, while no AEs were reported in hemorrhagic and mixed stroke subgroups.Val/Aml SPC was effective in hypertensive patients with different stroke subtypes and was well tolerated. PMID- 28658109 TI - Exchange of supraglottic airways for endotracheal tube using the Eschmann Introducer during simulated child resuscitation: A randomized study comparing 4 devices. AB - BACKGROUND: The aim of this study was to examine the application of the Eschmann tracheal tube introducer (ETTI) with 4 types of supraglottic airway devices (SADs) using a child-manikin. METHODS: A total of 79 paramedics were asked to exchange the 4 SADs for an endotracheal tube with the ETTI in 3 different scenarios using a randomized crossover study format: normal airway without chest compression; normal airway with uninterrupted chest compression; and difficult airway with uninterrupted chest compression. The primary outcome was time to SAD exchange, with the secondary outcome measuring the success of SAD exchange. Each attempt was assessed by a trained assistant. RESULTS: The mean exchange times for LMA, Cobra PLA, Air-Q, and SALT were as follows: 21, 23, 21, and 18, respectively for Scenario A; 23, 27, 22.5, and 21 for Scenario B; and 23, 28, 23, and 23 for Scenario C. The percent efficacy of SADs exchange with LMA, Cobra PLA, Air-Q and SALT were 98.7%, 94.9%, 100%, and 100% for scenario A; 98.7%, 88.6%, 98.7%, and 97.5% for scenario B; and 93.7%, 87.3%, 94.9%, and 93.7% for scenario C. CONCLUSIONS: In this model of pediatric resuscitation, the SAD exchange using an ETTI has (LMA, Cobra PLA, Air-Q and SALT) proved to be effective in paramedics with no previous experience. Furthermore, experimental findings indicated that SAD exchange can be achieved without interrupting chest compression. PMID- 28658111 TI - Occurrence of and factors influencing elderly homebound in Chinese urban community: A cross-sectional study. AB - Studies on the occurrence of homebound and the factors influencing it are available. However, the study of community homebound in China is still in its preliminary stage. No previous studies about this issue are available. This study aims to assess the occurrence of and factors influencing homebound elderly in Chinese communities and to provide a basis for effective intervention and prevention of homebound elderly people.One sample community from three provinces was randomly selected. Investigations were performed on the selected communities and 2180 elderly people were chosen as the research subjects. Unified survey scales were used. Home visit and face-to-face interviews were performed to ensure that no single qualified survey respondent was missed.The rate of morbidity in homebound elderly Chinese community was found to be 15.49% and it gradually increased with age, and also with a lower education or poorer Activities of Daily Living (ADL). Single factor analysis showed that general situation, living habits, physical condition, mental condition, society, social support, and other factors affected the occurrence of community homebound elderly. Women were more likely to be homebound than men (P < .05). Having a spouse or high income reduced the rate of morbidity in the homebound elderly (P < .05). Multifactor regression analysis revealed that poor ADL, depression, hearing impairment, being old, no exercise, and low social support are the main influencing factors.Appropriate measures should be taken based on the specific influencing factor to prevent the occurrence of homebound. PMID- 28658110 TI - The clinical outcome correlations between radiation dose and pretreatment metabolic tumor volume for radiotherapy in head and neck cancer: A retrospective analysis. AB - This study was to investigate the clinical outcomes between radiation dose and pretreatment metabolic tumor volume (MTV) in patients with head and neck cancer treated with definitive chemoradiotherapy.Thirty-four patients received pretreatment F-fluorodeoxyglucose (F-FDG) positron emission tomography-computed tomography (PET/CT) were recruited for this study. The CT-based volume (gross tumor volume of the primary [GTVp]) and 4 types of MTVs were measured on the basis of either a maximal standardized uptake value (SUVmax) of 2.5 (MTV2.5), 3.0 (MTV3.0), or a fixed threshold of 40% (MTV40%), 50% (MTV50%). F-FDG PET-CT images before treatment, and data including response to treatment, local recurrence, death due to the cancer, disease-free survival (DFS) and primary relapse-free survival (PRFS), were collected for analysis.The Wilcoxon rank test showed that all values determined by the different delineation techniques were significantly different from the GTVp (P < .05). Tumor volume and the homogeneity of target dose of MTV2.5, MTV3.0, MTV40%, and MTV50% were significantly different between the 2 groups of patients through treatment outcomes (P < .05).The survival curves for DFS and PRFS demonstrated that the homogeneity of the target dose in MTVs was a good indicator. The homogeneity of target dose in the tumor is a potential indicator of DSF and PRFS in patients with head and neck cancer who underwent radiotherapy. PMID- 28658112 TI - Propofol decreases etomidate-related myoclonus in gastroscopy. AB - OBJECTIVE: Myoclonus, a common complication during intravenous induction with etomidate, is bothersome to both anesthesiologists and patients. This study explored the preventive effect of pretreatment with propofol on etomidate-related myoclonus. METHODS: This was a prospective, double-blind, clinical, randomized controlled study. Totally, 363 patients who were scheduled for a short-duration, painless gastrointestinal endoscopy were divided into 5 groups. Four groups received 0 mg/kg (E group), 0.25 mg/kg (LPE group), 0.50 mg/kg (MPE group), or 0.75 mg/kg (HPE group) propofol pretreatment before etomidate anesthesia. Another group only received 1 to 2 mg/kg of propofol (P group) as anesthesia. The incidence and severity of myoclonus, patient circulation and respiratory status, and intraoperative and postoperative complications were recorded. RESULTS: The incidence of myoclonus in the LPE group (26.8%), MPE group (16.4%), HPE group (14.9%), and P group (0) was lower than the E group (48.6%, P < .05). The incidence of grade 1, 2, and 3 of myoclonus in the LPE group, MPE group, HPE group, and P group was significantly lower than the E group, and that in the P group was lower than the LPE group (P < .05). The incidence of hypoxemia in the P group was higher than the E group, and the incidence of adverse events in the HPE group and P group was lower than the E group (P < .05). DISCUSSION: Pretreatment with propofol was feasible for preventing etomidate-related myoclonus. Furthermore, as propofol dosage increased, its effect on reducing the incidence and severity of myoclonic movements induced by etomidate increased. PMID- 28658114 TI - Correlation between polymorphism of vitamin D receptor TaqI and susceptibility to colorectal cancer: A meta-analysis. AB - The meta-analysis aimed to investigate the correlation between the polymorphism of the vitamin D receptor (VDR) TaqI and susceptibility of colorectal cancer.Studies were extracted from the electronic databases of PubMed and Embase. The balance of heredity was estimated by the Hardy-Weinberg equilibrium test, and heterogeneity was assessed by Cochran Q statistics and I test. Four assessed models, namely additive (t vs T), dominant (Tt + tt vs TT), recessive (tt vs Tt + TT), and codominant (Tt vs TT and tt vs TT), were used to evaluate the correlations and the effective results were measured as odds ratio (OR) with 95% confidence interval (CI).A total of 14 studies, including 4632 patients and 5086 controls, were enrolled in this meta-analysis. With no significant heterogeneities observed among the 4 models, the fixed-effect model was used to examine the pooled effect value. There were no significant differences among t vs T (OR = 1.01; 95% CI, 0.94-1.09; P = .70), Tt + tt vs TT (OR = 1.05; 95% CI, 0.96 1.15; P = .32), tt vs Tt + TT (OR = 1.01; 95% CI, 0.87-1.17; P = .92), Tt vs TT (OR = 1.03; 95% CI, 0.93-1.13; P = .62), and tt vs TT (OR = 1.00; 95% CI, 0.85 1.17; P = .98) with respect to increasing CRC frequency.No evidence showed that TaqI polymorphisms were significantly associated with susceptibility to CRC. PMID- 28658113 TI - The changing epidemiology of tuberculosis in a Spanish tertiary hospital (1995 2013). AB - Important epidemiological changes and improvement of new diagnostic approaches, mainly molecular tools, might have impacted the management and outcome of tuberculosis (TB) in the last years in industrialized countries. In order to describe the epidemiological trends, and changes in clinical, diagnostic, and therapeutic aspects in patients with TB, an observational study was performed in a tertiary hospital in Western Europe (Madrid, Spain).All adult patients (>16 years) with a diagnosis of TB in the period 1995 to 2013 were included in the study.TB was diagnosed in 1284 patients, including 304 (24%) foreign-born and 298 (23.2%) human immunodeficiency virus (HIV)-infected patients. The proportion of foreign-born patients increased significantly, from 7.4% (1995) to 40.3% (2013), P < .001, while the proportion of patients with HIV infection decreased (from 41% to 15%, P < .001). Extrapulmonary locations of TB increased (from 23.9% to 37.1%, P < .001), although the miliary forms were less frequent (from 16% to 5.6%, P < .001). Pulmonary involvement remained constant during the period of study (from 50% to 46%, P = .18). The yield of microbiological diagnostic methods in different clinical specimens has remained very similar. Only molecular techniques have improved the diagnosis in respiratory, urinary, and peritoneal samples. The global cure rate was 64.8% and mortality rate was 9.1% (6.5% directly attributable to TB). Mortality has decreased significantly during the years of study (from 11% to 2%, P < .001).There has been a significant decline in the number of patients with TB. Changes in HIV coinfection and immigration have conditioned other epidemiological and clinical aspects of the disease, including the clinical presentation, treatment response, and mortality. Only the use of molecular tests has provided an improvement in the diagnosis of pulmonary and extrapulmonary TB. PMID- 28658115 TI - Decreased CD8+CD28+/CD8+CD28- T cell ratio can sensitively predict poor outcome for patients with complicated Crohn disease. AB - Crohn disease (CD) with complications such as penetrating, stricturing, and perianal disease is called complicated CD. The aim of this study is to test the efficiency with which the CD8CD28/CD8CD28 cell balance can predict a subsequent active stage in patients with newly diagnosed complicated CD.Seventeen patients with complicated CD and 48 CD patients with no complications were enrolled. Blood CD8 T cells were tested from all of the 65 newly diagnosed CD patients upon enrollment. The potential risk factors were compared between the 2 groups. A 30 week follow-up was performed, and the efficiency of the CD8 cell balance at predicting active CD was analyzed using receiver-operating characteristic curves. The cumulative remission lasting rates (CRLRs) were analyzed using the Kaplan Meier method.Compared with the control CD group, patients with complicated CD were predominantly male and younger in age; they also had lower body mass indices (BMIs), higher Crohn disease activity indices (CDAIs), higher immunosuppressant and steroid prescription rates, and significantly higher surgical rates. The CD8CD28/CD8CD28 balance was associated with BMI, CDAI, steroids, and surgery. The CD8CD28/CD8CD28 ratios were significantly lower at week 0 and on the 6th, 22nd, and 30th week during follow-up with a shorter lasting time of remission for the complicated CD patients. The CD8CD28/CD8CD28 ratio could accurately predict the active stage for the patients with complicated CD, and the highest sensitivity (89.2%) and specificity (85.3%) were found when the ratio was 1.03. Treatment with steroids and surgery, along with a significantly lower CD8CD28/CD8CD28 ratio and lower CRLRs, was closely related to a worse outcome for the patients with complicated CD.Patients requiring steroids and surgery experience more severe disease activity and thus a disequilibrated immunological balance, which could be the main reason for a decreased CD8CD28/CD8CD28 ratio. This ratio can sensitively predict the active stage for patients with complicated CD, and more care should be taken when this ratio is <1.03. PMID- 28658116 TI - An interesting implantable cardioverter defibrillator treatment for lethal ventricular arrhythmias caused by coronary artery spasm: A case report. AB - RATIONALE: Coronary artery spasm (CAS) could cause serious lethal ventricular arrhythmias. While implantable cardioverter defibrillators (ICDs) have been recommend for secondary prevention of sudden cardiac death related to lethal ventricular arrhythmias. However, in resuscitated sudden cardiac death caused by CAS, the effect of ICD is still not well clear. PATIENT CONCERNS: A 60-year-old male presented with 2 episodes of syncope. Coronary angiography showed normal coronary arteries. Twenty-four hour Holter electrocardiograms revealed that there were repeatedly transient marked ST segment elevation in the all leads except avR lead, junctional rhythm, and subsequently nonsustained ventricular tachycardia. DIAGNOSES: Ischemic-induced lethal ventricular arrhythmias caused by CAS. INTERVENTIONS: Both calcium channel blocker (diltiazem, 180 mg twice daily) and nitrate (isosorbide dinitrate 40 mg twice daily) were initially administrated, and ICD was subsequently implanted as a secondary prevention. OUTCOMES: In the early stage of CAS, ICD therapy terminated the lethal ventricular arrhythmias. Conversely, after the administration of epinephrine, ICD therapy, even combined with external defibrillation, failed in resuscitating sudden cardiac death. LESSONS: For the sudden cardiac death related to lethal ventricular arrhythmias caused by CAS, ICD therapy is an efficient secondary prevention base on administrating coronary vasodilators. Furthermore, administration of epinephrine should be avoided during cardiorespiratory resuscitation of sudden cardiac death caused by CAS. PMID- 28658118 TI - Cross-cultural adaption and validation of the Persian version of the SWAL-QOL. AB - The aim of this study was to translate and cross-culturally adapt the swallowing quality-of-life questionnaire (SWAL-QOL) to Persian language and to determine validity and reliability of the Persian version of the swallow quality-of-life questionnaire (PSWAL-QOL) in the patients with oropharyngeal dysphagia.The cross sectional survey was designed to translate and cross-culturally adapt SWAL-QOL to Persian language following steps recommended in guideline. A total of 142 patients with dysphagia (mean age = 56.7 +/- 12.22 years) were selected by non probability consecutive sampling method to evaluate construct validity and internal consistency. Thirty patients with dysphagia were completed the PSWAL-QOL 2 weeks later for test-retest reliability.The PSWAL-QOL was favorably accepted with no missing items. The floor effect was ranged 0% to 21% and ceiling effect was ranged 0% to 16%. The construct validity was established via exploratory factor analysis. Internal consistency was confirmed with Cronbach alpha >0.7 for all scales except eating duration (alpha = 0.68). The test-retest reliability was excellent with intraclass correlation coefficient (ICC) >=0.75 for all scales.The SWAL-QOL was cross-culturally adapted to Persian and demonstrated to be a valid and reliable self-report questionnaire to measure the impact of dysphagia on the quality-of-life in the Persian patients with oropharyngeal dysphagia. PMID- 28658117 TI - Predictors of upper trapezius pain with myofascial trigger points in food service workers: The STROBE study. AB - Shoulder pain occurs commonly in food service workers (FSWs) who repetitively perform motions of the upper limbs. Myofascial trigger points (MTrPs) on the upper trapezius (UT) are among the most common musculoskeletal shoulder pain syndromes. This study determined the psychological, posture, mobility, and strength factors associated with pain severity in FSWs with UT pain due to MTrPs.In this cross-sectional study, we measured 17 variables in 163 FSWs with UT pain due to MTrPs: a visual analog scale (VAS) pain score, age, sex, Borg rating of perceived exertion (BRPE) scale, beck depression inventory, forward head posture angle, rounded shoulder angle (RSA), shoulder slope angle, scapular downward rotation ratio, cervical lateral-bending side difference angle, cervical rotation side difference angle, glenohumeral internal rotation angle, shoulder horizontal adduction angle, serratus anterior (SA) strength, lower trapezius (LT) strength, bicep strength, and glenohumeral external rotator strength, in 163 FSWs with UT pain due to MTrPs.The model for factors influencing UT pain with MTrPs included SA strength, age, BRPE, LT strength, and RSA as predictor variables that accounted for 68.7% of the variance in VAS (P < .001) in multiple regression models with a stepwise selection procedure. The following were independent variables influencing the VAS in the order of standardized coefficients: SA strength (beta = -0.380), age (beta = 0.287), BRPE (beta = 0.239), LT strength (beta = -0.195), and RSA (beta = 0.125).SA strength, age, BRPE, LT strength, and RSA variables should be considered when evaluating and intervening in UT pain with MTrPs in FSWs. PMID- 28658119 TI - Is neuromuscular blocker needed in children undergoing inguinal herniorrhaphy?: A prospective, randomized, and controlled trial. AB - BACKGROUND: Intraoperative neuromuscular blocker is widely used, but is known to be associated with postoperative residual paralysis, which is known to be associated with increased risk of pulmonary complications. Hence, its use should be individualized and restricted to procedures where it is mandatory. We examined whether not using a neuromuscular blocker affects the surgical conditions in children undergoing inguinal herniorrhaphy. METHODS: Anesthesia was induced and maintained with sevoflurane in 60% nitrous oxide, and the airway was maintained using an I-gel. In total, 66 children aged 1 to 6 years were randomized to receive rocuronium (rocuronium group, n = 33) or saline (control group, n = 33); 61 children of them finished the study. A single surgeon who performed the operation rated the surgical condition of each patient on a 4-point scale (1 = poor, 2 = acceptable, 3 = good, and 4 = excellent). Intraoperative patient movement, recovery time, emergence agitation, and postoperative pain scores were evaluated. RESULTS: One patient in control group and no patient in rocuronium group showed intraoperative movement. When noninferiority test was done for intraoperative patient movement, with the noninferiority margin of 20%, the difference of absolute risk was 3.3% (95% confidence interval -8.0% to 16.7%) and saline group was noninferior to rocuronium group. All of the patients showed good to excellent surgical conditions, and no difference was found between the 2 groups. The recovery time was shorter in the control group than in the rocuronium group (4.5 +/- 1.8 vs 5.6 +/- 2.2 minutes, respectively; P = .028). CONCLUSION: In children aged 1 to 6 years undergoing inguinal herniorhaphy under sevoflurane anesthesia using an I-gel, not using neuromuscular blocker showed similar intraoperative condition and shortened recovery time compared with using neuromouscular blocker. PMID- 28658120 TI - The effect of platelet-rich plasma on reducing blood loss after total knee arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: Efficacy and safety of platelet-rich plasma (PRP) compared with control for preventing postoperative bleeding after total knee arthroplasty (TKA) is controversial. We performed a meta-analysis of randomized controlled trials (RCTs) to determine whether PRP might reduce blood loss and improve function following TKA. METHODS: PubMed, Medline, Embase, Web of Science, and the Cochrane Library were searched to identify RCTs comparing PRP with control for patients undergoing unilateral TKA. The mean difference (MD) of total blood loss, hemoglobin (Hb) level, Hb drop, drain volume, range of motion (ROM), Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores, length of hospital stay (LOS), and odds ratios of transfusion rate and postoperative complications in the PRP and control groups were pooled throughout the study. Relevant data were meta analyzed using RevMan v5.3. RESULTS: Six RCTs involving 529 patients were included (208 PRP vs. 321 controls). The application of PRP in TKA had a significantly less calculated total blood loss (MD = -98.11; 95% confidence interval [CI]: -153.63 to -42.59, P = .0005) and lower Hb drop (MD = -0.34; 95% CI: -0.59 to -0.09, P = .008) than the control in the early postoperative period while decreasing the LOS (MD = -2.12; 95% CI: -3.47 to -0.76, P = .002). No significant differences were seen in drain volume, Hb level, transfusion rate, ROM, WOMAC scores, and complications between the 2 groups (P > .05). CONCLUSIONS: Our meta-analysis suggests that PRP appears to be effective in reducing postoperative blood loss and lowering Hb drop without increasing the risks of postoperative complications after TKA. However, owing to the variation of included studies, no firm conclusions can be drawn. PMID- 28658122 TI - Surgical outcome and etiologic heterogeneity of infants with biliary atresia who received Kasai operation less than 60 days after birth: A retrospective study. AB - This study aimed to analyze the impact of etiologic heterogeneity and operation age on prognosis of infants with biliary atresia (BA) who received Kasai operation prior to 60 days of age.From 2004 to 2010, 158 infants received Kasai operation before turning 60 days old. According to Davenport 2012 classifications, 4 groups of BA were defined: cystic BA, syndrome BA, and associated malformation, cytomegalovirus (CMV)-associated BA, and isolated BA. Native (autologous) liver survival rates and incidence of cholangitis 2 years after operation, as well as jaundice clearance rates 3 months after operation, were recorded.Although infants who received the operation between 51 and 60 days of age had a better jaundice clearance 3 months after operation and lower incidence of cholangitis as compared with those under 40 or between 41 and 50 days of age, there was no significant difference in survival rates. Among types of BA, infants with cystic BA had the best prognosis. In the syndrome BA and associated malformations group, as well as CMV-associated group, infants who received the operation early (<40 days of age) had a worse outcome as compared with those who received the operation between 41 and 50 days or 51 and 60 days of age.Both clinical etiologic heterogeneity and operation age may influence BA prognosis. PMID- 28658121 TI - PIVKA-II is a useful tool for diagnostic characterization of ultrasound-detected liver nodules in cirrhotic patients. AB - Protein induced by vitamin K absence-II (PIVKA-II) is a potential screening marker for hepatocellular carcinoma (HCC). Limited data are available about its utility in discriminating neoplastic from regenerative nodules at ultrasonography (US) evaluation in cirrhotic patients. Aim of this study was to investigate the diagnostic utility of PIVKA-II in cases showing liver nodules of uncertain diagnosis at US.Ninety cirrhotics with US evidence of liver nodule(s) were enrolled. All patients underwent blood sampling within 1 week of US and were thereafter followed up. HCC was confirmed in 40/90 cases, and in all cases it was in a very early/early stage. All sera were tested for PIVKA-II and alpha fetoprotein (AFP) at the end of follow-up. PIVKA-II at a cut off of 60 mAU/mL was significantly associated with HCC at both univariate and multivariate analysis (P = .016 and P = .032, respectively). AFP at a cut off of 6.5 ng/mL was not associated with HCC at univariate analysis (P = .246). ROC curves showed that PIVKA-II had 60% sensitivity, 88% specificity, 80% positive predictive value (PPV), and 73% negative predictive value (NPV), whereas AFP had 67% sensitivity, 68% specificity, 63% PPV, and 72% NPV. AUROC curves showed that the combination of both biomarkers increased the diagnostic accuracy for HCC (AUC 0.76; sensitivity 70%, specificity 94%, PPV 91%, and NPV 79%).In conclusion, PIVKA-II is a useful tool for the diagnostic definition of US-detected liver nodules in cirrhotic patients, and it provides high diagnostic accuracy for HCC when combined with AFP. PMID- 28658123 TI - Sarcoidosis mimicking metastatic progression of pancreatic neuroendocrine tumor: A case report. AB - RATIONALE: Pancreatic neuroendocrine tumors (PNETs) account for less than 5% of all pancreatic tumors. PNETs develop from pancreatic endocrine islet cells and have a variable range of malignant potential. These neoplasms tend to have a slower growth rate than exocrine tumors and may remain undetectable for years. Achieving a correct diagnosis and staging is of key importance for the optimal management of the disease and requires experience with the disease, an accurate clinical status evaluation and a critical interpretation of the radiological findings derived from morphological and functional imaging techniques as well as an integrated multidisciplinary approach. The possibility that some clinical data and radiological findings encountered during the diagnostic and staging procedures may not be related to PNETs but to concomitant clinical conditions should always be taken into consideration. This is mandatory as an incorrect stadiation may lead to patients' mis-management. PATIENT CONCERNS: We report the case of a 34-year-old female, with a past medical history of idiopathic acute pancreatitis, presenting with a severe upper abdominal pain, steady and radiating to the back. DIAGNOSES: Initial investigations incidentally detected a nonfunctioning pancreatic neuroendocrine tumor (NF-PNET) of intermediate grade G2. Subsequent investigations aimed at determining a correct tumor staging showed a negative indium-111- OctreoScan but an increased 18F-labeled fluorodesossiglucose (18F-FDG) uptake in multiple bilateral nodules in the lungs and in 1 nodular lesion located in the right gluteal subcutaneous tissue. An early tumor progression of a G2 NF-PNET that had to be treated with chemotherapy was suspected. INTERVENTIONS: The histological examination of the gluteal subcutaneous nodule showed noncaseating granulomas, disproving the initial clinical suspect and allowing the diagnosis of active sarcoidosis in the G2 NF PNET patient. LESSONS: A misdiagnosis and a consequent therapeutic mismanagement were avoided with the support of an integrated multidisciplinary team. PMID- 28658124 TI - Diagnosis and management of head and neck cancers in a high-incidence area in France: A population-based study. AB - Head and neck cancers have a very poor prognosis and are common in France. They are subject to various recommendations for early detection and management, but there is no detailed data in the French general population to fuel the public health debate on it.A high-resolution population-based study about cancer management was conducted, using cancers registries in the north-west of France, on 1729 tumors diagnosed between 2008 and 2010.The tumors were diagnosed late (70.3% stage III-IV), mainly after the onset of symptoms (93.2%). After adjustment, advanced stages were more frequent in patients with hypopharyngeal [adjusted odds ratio (ORa): 4.68; 95% confidence interval [CI] 3.11-7.05] and oropharyngeal tumors (ORa: 2.84; 95% CI 2.02-3.99) compared with oral cavity ones. They were also more frequent in patients with moderate (ORa 1.68; 95% CI 1.12-2.52) or severe comorbidities (ORa 1.86; 95% CI: 1.23-2.80). A multidisciplinary meeting (MM) had taken place in 96.9% of cases. The assessment included a panendoscopy in 80.3% of cases, a cervical computerized tomography (CT) scan in 89.3% and a chest CT scan in 87.3%. The vast majority of patients (90.7%) had received treatment, with surgery in 48.7% of cases and/or radiotherapy in 76.9%.Despite the recommendations for early detection, diagnoses are often made late, even for tumors that can be detected by a direct visual and tactile examination of the oral cavity. However, the major risk of advanced stage concerns deep tumors and the most weakened subjects. Otherwise, diagnostic assessment is broadly consistent with the recommendations, and multidisciplinary treatment decisions are widespread. PMID- 28658125 TI - Anterior cervical distraction and screw elevating-pulling reduction for traumatic cervical spine fractures and dislocations: A retrospective analysis of 86 cases. AB - Treatment of cervical fracture and dislocation by improving the anterior cervical technique.Anterior cervical approach has been extensively used in treating cervical spine fractures and dislocations. However, when this approach is used in the treatment of locked facet joints, an unsatisfactory intraoperative reduction and prying reduction increases the risk of secondary spinal cord injury. Thus, herein, the cervical anterior approach was improved. With distractor and screw elevation therapy during surgery, the restoration rate is increased, and secondary injury to the spinal cord is avoided.To discuss the feasibility of the surgical method of treating traumatic cervical spine fractures and dislocations and the clinical application.This retrospective study included the duration of patients' hospitalization from January 2005 to June 2015. The potential risks of surgery (including death and other surgical complications) were explained clearly, and written consents were obtained from all patients before surgery.The study was conducted on 86 patients (54 males and 32 females, average age of 40.1 +/- 5.6 years) with traumatic cervical spine fractures and dislocations, who underwent one-stage anterior approach treatment. The effective methods were evaluated by postoperative follow-up.The healing of the surgical incision was monitored in 86 patients. The follow-up duration was 18 to 36 (average 26.4 +/- 7.1) months. The patients achieved bones grafted fusion and restored spine stability in 3 to 9 (average 6) months after the surgery. Statistically, significant improvement was observed by Frankel score, visual analog scale score, Japanese Orthopedic Association score, and correction rate of the cervical spine dislocation pre- and postoperative (P < .01).The modified anterior cervical approach is simple with a low risk but a good effect in reduction. In addition, it can reduce the risk of iatrogenic secondary spinal cord injury and maintain optimal cervical spine stability as observed during follow-ups. Therefore, it is suitable for clinical promotion and application. PMID- 28658126 TI - Antihypertensive treatments for spontaneous intracerebral hemorrhage in patients with cerebrovascular stenosis: A randomized clinical trial (ATICHST). AB - INTRODUCTION: Antihypertensive treatment is associated with clinical outcomes in patients with spontaneous intracerebral hemorrhage (sICH). ADAPT showed that intensive blood pressure lowering (<140 mm Hg) does not reduce peri-hematoma regional cerebral blood flow (rCBF) in patients with sICH. However, the stenosis of main cerebral arteries that has a high presence in patients with sICH is well known related to the brain ischemia. The effect of intensive BP lowering for sICH in patients with cerebrovascular stenosis is still unknown. AIM: The aim of this study was to determine the safety and effectiveness of intensive BP lowering for sICH in patients with cerebrovascular stenosis. METHODS AND ANALYSIS: A pilot trial has been conducted to calculate the sample size and 80 patients of sICH with cerebrovascular stenosis will be involved. The target of systolic blood pressure (SBP) will be maintained at from 120 to 140 mm Hg or from 140 to 180 mm Hg for 7 days. Cerebral ischemia will be assessed at 24 hours after onset by computed tomography (CT) perfusion imaging and the follow-up will be conducted at 30-day and 90-day. The primary outcome is the reduction of peri-hematoma rCBF. The other cerebral perfusion indexes and the rate of ischemic stroke are regarded as other primary outcomes. The secondary outcomes include clinical outcome at 30 days and 90 days, complications, and hospital stays. DISCUSSION: The ATICHST trial has been signed as a parallel, prospective, randomized, assessor-blinded clinical trial to determine the effects of intensive BP lowering on sICH in patients with cerebrovascular stenosis, the results of which will contribute to guide the management of blood pressure in sICH. CONCLUSION: The protocol will determine the safety and effectiveness of intensive BP lowering for sICH with cerebrovascular stenosis. PMID- 28658127 TI - Effects of atorvastatin on chronic subdural hematoma: A systematic review. AB - BACKGROUND: The high recurrent rate of chronic subdural hematoma (CSDH) has consistently confused the neurosurgeons, and the role of atorvastatin in the management of CSDH has remained unclear over past decade, and atorvastatin seems to be a safe and cost-effective treatment to CSDH. Therefore, it is necessary to conduct a systematic review to discuss the effect of atorvastatin in CSDH. METHOD: We searched the PubMed, EMBASE, Cochrane Library, and the China Biology Medicine disc, up to March 2017, for published studies on the effects of atorvastatin in the management of CSDH, and reviewers performed a brief qualitative descriptive analysis of atorvastatin's efficacy in the management of CSDH. RESULTS: Three eligible studies were included in this systematic review. Results indicated that atorvastatin accelerated hematoma absorption, decreased recurrence risk, and surgical requirement. CONCLUSION: Limited evidence suggests that oral atorvastatin may be beneficial in the management of CSDH. Further high quality studies focused on dosage, duration, hematoma size are needed to further elucidate the role of atorvastatin in the management of CSDH. PMID- 28658128 TI - Association of WDR36 polymorphisms with primary open angle glaucoma: A systematic review and meta-analysis. AB - BACKGROUND: The association of the WDR36 gene with glaucoma has been controversial in the literature. We therefore conducted a systematic review and meta-analysis to assess the association of all reported common polymorphisms in WDR36 with primary open angle glaucoma (POAG) and its subtypes: high tension glaucoma (HTG) and normal tension glaucoma (NTG). METHODS: Publications in PUBMED and EMBASE databases up to March 9, 2016 were searched for case-control association studies of WDR36 with POAG, HTG, and/or NTG. Reported studies giving adequate genotype and/or allele information were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of individual polymorphisms were estimated using the allelic model. RESULTS: Our literature search yielded 122 records, among which 5 studies were eligible for meta-analysis, involving a total of 1352 POAG patients and 894 controls. Five WDR36 polymorphisms were meta analyzed, rs11241095, rs10038177, rs17553936, rs13186912, and rs13153937. However, none of them was significantly associated with POAG, HTG, or NTG. The most-investigated polymorphisms, rs11241095 and rs10038177, had a pooled-OR of 1.09 (95% CI: 0.94-1.28, P = .25, I = 0) and 0.99 (95% CI: 0.71-1.39, P = .97, I = 77%), respectively, for POAG. CONCLUSION: The existing data in the literature do not support a significant role of WDR36 in the genetic susceptibility of POAG or its subtypes. Further replication studies in specific populations are warranted. PMID- 28658129 TI - Cancer incidence and mortality in Hebei province, 2013. AB - To estimate the numbers of new cancer cases and deaths in Hebei province in 2013 and to investigate the real cancer burden in Hebei province to develop strategies for cancer prevention and control.Data on new cancer cases and deaths in 2013 were collected from 31 population-based cancer registries of Hebei province. All data were checked and evaluated based on data quality criteria from the "Chinese Guideline for Cancer Registration" and "Cancer Incidence in Five Continents Volume IX" by the International Agency for Research on Cancer/International Association of Cancer Registration (IARC/IACR). Qualified data from 21 registries were used for analysis after evaluation. Data analysis was stratified by areas (urban/rural), gender, age group, and cancer type. New cancer cases and deaths in Hebei province were estimated using age-specific rates and the corresponding provincial population. The 10 most common cancers in different groups and the cumulative rates were calculated. The Chinese population census in 2000 and the population of Segi were used for age-standardized incidence/mortality rates.The covered populations included 11, 185,626 people (5,709,393 in males and 5,476,233 in females) from 21 qualified cancer registries, accounting for 15.25% of Hebei provincial population. The major indicators of quality control, that is, the percentage of cases morphologically verified (MV%), percentage of cancer cases identified with a death certificate only (DCO%), and the mortality to incidence rate ratio (M/I), were 75.56%, 3.23%, and 0.65, respectively. In 2013, it was estimated that there were approximately 164,100 newly diagnosed cancer cases and 105,200 cancer deaths in Hebei province. The incidence rate of cancer was 225.36/100,000 (248.03/100,000 in males, 201.73/100,000 in females), and the age standardized incidence rates by Chinese standard population (ASIRC) and the world standard population (ASIRW) were 182.81/100,000 and 181.36/100,000, respectively. The cancer incidence and ASIRC were 225.49/100,000 and 173.84/100,000 in urban areas and 225.27/100,000 and 189.31/100,000 in rural areas, respectively. The cancer mortality rate was 145.46/100,000 (177.85/100,000 in males and 111.70/100,000 in females). Age-standardized mortality rates by Chinese standard population (ASMRC) and world standard population (ASMRW) were 119.09/100,000 and 118.73/100,000, respectively. The cancer mortality rate in rural areas (152.64/100,000) was higher than that in urban areas (135.71/100,000). The most common cancers were lung cancer, stomach cancer, esophageal cancer, liver cancer, breast cancer, and colorectal cancer. Lung cancer, stomach cancer, liver cancer, esophageal cancer, and colorectal cancer were the major causes of cancer death in Hebei province.The coverage of cancer registration population has rapidly increased and may reveal the cancer burden in Hebei province more comprehensively. The cancer burden in Hebei province is heavy, and prevention and control measures should be enhanced. PMID- 28658130 TI - Acupuncture for asthma: Protocol for a systematic review. AB - BACKGROUND: Asthma is a common chronic disease in both adults and children. Inhaled corticosteroids (ICS) and beta2-agonists are the major medications treating asthma with many side effects. Acupuncture has been used in many diseases including asthma. We aim to assess the efficacy and safety of acupuncture for asthma. METHODS: The following electronical databases will be searched from inception to January 1, 2017: Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), SinoMed, the China National Knowledge Infrastructure Database (CNKI), the Chinese Scientific Journal Database (VIP database), and the Wanfang database. We will also search reference lists of identified studies, potential gray literatures, relevant conference abstracts, and registers of clinical trials. Two reviewers will independently undertake study selection, data extraction, and quality assessment. Data will be synthesized by either the fixed-effects or random-effects model according to a heterogeneity test. Changes in lung function will be assessed as the primary outcome. The level of control, medication usage, quality of life, exacerbations, symptoms, adverse events will be evaluated as the secondary outcomes. The RevMan V.5.3.5 will be employed for meta-analysis. Continuous outcomes will be presented as mean difference or standard mean difference, while dichotomous data will be expressed as relative risk. RESULTS: This study will provide a high-quality synthesis of current evidence of acupuncture for asthma from several aspects including lung function, the level of control, medication usage, quality of life, exacerbations, symptoms and adverse events. CONCLUSION: The conclusion of our study will provide updated evidence to judge whether acupuncture is an effective intervention for children with asthma. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42017054562. PMID- 28658131 TI - Polymyalgia rheumatica and giant cell arteritis-three challenges-consequences of the vasculitis process, osteoporosis, and malignancy: A prospective cohort study protocol. AB - INTRODUCTION: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are common inflammatory conditions. The diagnosis of PMR/GCA poses many challenges since there are no specific diagnostic tests. Recent literature emphasizes the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to assess global disease activity in inflammatory diseases. 18F-FDG PET/CT may lead to the diagnosis at an earlier stage than conventional imaging and may also assess response to therapy. With respect to the management of PMR/GCA, there are 3 significant areas of concern as follows: vasculitis process/vascular stiffness, malignancy, and osteoporosis. METHODS AND ANALYSIS: All patients with suspected PMR/GCR referred to the Rheumatology section of Medicine Department at Svendborg Hospital, Denmark. The 4 separate studies in the current protocol focus on: the association of clinical picture of PMR/GCA with PET findings; the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy; the prevalence of newly diagnosed malignancies in patients with PMR/GCA, or PMR-like syndrome, with the focus on diagnostic accuracy of 18F-FDG PET/CT scan compared with conventional workup (ie, chest X-ray/abdominal ultrasound); and the impact of disease process, and also steroid treatment on bone mineral density, body composition, and vasculitis/vascular stiffness in PMR/GCA patients. ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethics Committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). Results of the study will be disseminated via publications in peer-reviewed journals, and presentation at national and international conferences. PMID- 28658132 TI - Emergency 1-stage anterior approach for cervical spine infection complicated by epidural abscess. AB - It was a retrospective analysis.The aim of the study was to explore the safety and reliability of emergency 1-stage radical debridement and reconstruction using titanium mesh filled with autologous bone for patients with cervical spine infection complicated by epidural abscess.At present, cervical spine infection complicated by epidural abscess is known as a severe spine disease. Recently, case report of this disease is showing quite an increasing tendency, particularly in economically undeveloped areas and countries. Regarding the treatment of this disease, 1-stage radical debridement and reconstruction has been widely adopted; however, emergency 1-stage anterior approach surgery without medication is considered as a relatively taboo, since it is generally acknowledged that such operation would possibly cause unexpected infection. Nevertheless, regular elective surgery may require longer time for preparation. In addition, long hour compression and stimulation of the abscess may leave the patients with irreversible spinal neural impairment. However, our department has finished 14 cases of cervical spine infection complicated with epidural abscess without 1 single case of postoperative infection.A retrospective study was conducted on 14 patients (9 males and 5 females; average age 57.4 years) who were diagnosed with cervical spine infection complicated by epidural abscess from January 2005 to December 2014. All the patients were admitted to hospital with varying degrees of neurological function losses, and then underwent 1-stage anterior focal debridement and reconstruction using titanium mesh within 24 hours after admission. They received postoperative standard antibiotic chemotherapy for 10 to 12 weeks. They were followed up for 18 to 36 months, an average of 27.4 months. X ray, computed tomography (CT), and MRI (magnetic resonance imaging (MRI) were used to determine the fusion state and vertebral stability. American Spinal Injury Association (ASIA) international standards for neurological classification were adopted, white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were evaluated to infection activity, and Japanese Orthopaedic Association (JOA) and visual analog scale (VAS) criteria were used to judge clinical efficacy.All the 14 patients had no postoperative spread of infection. No recurrence of infection was found during the last follow-up. ASIA grade, VAS score, and JOA score were significantly improved (P < .05) after the operation. WBC, ESR, and CRP became normal after the operation (P < .05). Postoperative follow-up imaging results showed no significant loss of cervical curvature, collapse of the grafted bone or implant displacement but good spinal canal volume.Emergency 1-stage radical debridement and reconstruction using titanium mesh filled with autologous bone, combined with antibiotic chemotherapy, is a safe and effective surgical therapy for cervical infection complicated by epidural abscess. PMID- 28658133 TI - Expression of geminin, p16, and Ki67 in cervical intraepithelial neoplasm and normal tissues. AB - Geminin is a protein involved in cell cycle progression. We aimed to evaluate the diagnostic value of geminin expression in cervical intraepithelial neoplasm (CIN).The expression of geminin, p16, and Ki67 was examined in 95 samples, including CIN1 (n = 45), CIN2/3 (n = 40), and normal cervical tissues (n = 10) by immunohistochemistry. The correlation between geminin or p16 expression and human papillomavirus (HPV) status was also evaluated.Geminin expression was negative in all normal tissues and expressed in 13.3% of CIN1 and 90.0% of CIN2/3. P16 expression was demonstrated in 24.4% of CIN1 and 87.5% of CIN2/3. The corresponding Ki67 expression was 35.6% and 95.0%. The specificity of geminin for differentiating between CIN1 and CIN2/3 was 86.7%, while for p16 and Ki67 the corresponding values were 75.6% and 64.4%. The sensitivity of geminin, p16, and Ki67 was 90.0%, 87.5%, and 95.0%, respectively. The positive predictive value (PPV) and accuracy of geminin were higher than p16 and Ki67. In addition, geminin expression showed a weak correlation with HPV status, but there was no association between p16 expression and HPV status.These results suggested that geminin had a high degree of sensitivity and specificity in determining CIN2/3. In addition to p16 and Ki67, geminin might be used as a new biomarker to distinguish between CIN1 and CIN2/3. PMID- 28658134 TI - Treprostinil for persistent pulmonary hypertension of the newborn, with early onset sepsis in preterm infant: 2 Case reports. AB - RATIONALE: Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth with persisting increased pulmonary vascular resistance that is associated with high mortality rates especially in preterm infants. PATIENT CONCERNS: We reported 2 cases of PPHN in preterm infants with respiratory distress syndrome and early onset sepsis refractory to therapy with vasopressors, inotropes, and inhaled nitric oxide (iNO), in whom treatment with treprostinil was successful. DIAGNOSES: Infants showed a difference of more than 10% between pre- and postductal saturation of peripheral oxygen by pulse oximetry. Echocardiogram showed flattened ventricular septum, right to left shunting through the patent ductus arteriosus, and tricuspid regurgitation velocity above 2.9 m/s. INTERVENTIONS: The patients received treprostinil through central venous line because iNO therapy was not effective. OUTCOMES: Within 6 to 12 hours after treatment with treprostinil, the patients showed dramatic clinical improvement, and no systemic side effects were observed, including intraventricular hemorrhage (>=grade II). LESSONS: IV treprostinil might be given to preterm infants with severe PPHN, who did not respond to conservative therapies, including iNO. PMID- 28658135 TI - Experiences with cytoreduction surgery plus hyperthermic intraperitoneal chemotherapy in Taiwan. AB - Our hospital was the first institution to offer cytoreduction surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in Taiwan. Therefore, we report our experience and outcomes among patients who underwent HIPEC.Since 2002, 164 eligible patients underwent HIPEC, and we excluded cases of laparoscopic or prophylactic HIPEC. The cases were categorized according to whether they were treated before 2012 (Period 1: 80 cases) or after 2012 (Period 2: 84 cases).The rates of surgical morbidity were 46.3% during Period 1 and 20.2% during Period 2 (P < .01), and the rates of severe complications were 25% during Period 1 and 9.5% during Period 2 (P < .01). The 5-year overall survival rate was 35.8%, with rates of 13.4% for gastric cancer, 27.3% for colon cancer, 70.0% for appendiceal cancer, and 52.4% for ovarian cancer (median follow-up: 34 months). The survival rate was 42.1% when we achieved a cytoreduction score of 0/1, compared with 21.1% in the group with a cytoreduction score of 2/3 (P < .01). Severe complications were associated with a 5-year survival rate of 23.4%, compared with 37.9% among cases without severe complications (P = .01). Complete cytoreduction was achieved in 78.6% of the patients if they underwent their first surgery at our hospital.We have become an experienced hospital for CRS plus HIPEC. Although our complication rate for CRS plus HIPEC was high, it was within the acceptable range. Long-term survival was achieved in a few cases. PMID- 28658136 TI - Penile metastases from primary lung cancer: Case report and literature review. AB - BACKGROUND: Metastasis to the penis from primary lung cancer is quite rare. To improve the understanding, we present a case diagnosed as penile metastasis from primary lung cancer and review the literature. METHODS: One case report and retrospectively analysis penile cancer patient secondary from primary lung cancer. RESULTS: The patient complained of perineal pain and burning on urination for about 2 months. On physical examination, painful nodular masses at the base of left side of the corpora cavernosa were found. 18F-fluorodeoxyglucose positron emission tomography/CT (PET/CT) scan showed that maximum standardized uptake value (SUVmax) in left side corpora cavernosa and right hilar increased to 12.0 and 13.5 respectively. On flexible bronchoscopy checking, stenosis of the opening of apical segmental and posterior segmental bronchi of right upper lobe was found. The lateral segmental bronchi of left lower lobe was obstructed by a neoplasm. The pathological result was primary pulmonary adenosquamous carcinoma (ASC). Two months later, total penectomy was performed. The pathological result was penile ASC derived from pulmonary. On reviewing the literature, there are 39 cases reported. The patient we present is the 40 one. The average age at diagnosis was (60.5 +/- 10.7) years old. The most common symptom was mass, followed by priapism, pain. The overall survival time was (4.5 +/- 3.9) months. CONCLUSIONS: The penis may be a site of metastasis from lung cancer, especially for old patient. Metastasis to the penis usually indicates that the primary lung cancer is at an advanced stage and the prognosis is very poor. PMID- 28658137 TI - Cardiovascular disease in immune-mediated inflammatory diseases: A cross sectional analysis of 6 cohorts. AB - To analyze in several immune-mediated inflammatory diseases (IMIDs) the influence of demographic and clinical-related variables on the prevalence of cardiovascular disease (CVD), and compare their standardized prevalences.Cross-sectional study, including consecutive patients diagnosed with rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn disease, or ulcerative colitis, from rheumatology, gastroenterology, and dermatology tertiary care outpatient clinics located throughout Spain, between 2007 and 2010. Our main outcome was defined as previous diagnosis of angina, myocardial infarction, peripheral vascular disease, and/or stroke. Bivariate and multivariate logistic and mixed-effects logistic regression models were performed for each condition and the overall cohort, respectively. Standardized prevalences (in subjects per 100 patients, with 95% confidence intervals) were calculated using marginal analysis.We included 9951 patients. For each IMID, traditional cardiovascular risk factors had a different contribution to CVD. Overall, older age, longer disease duration, presence of traditional cardiovascular risk factors, and male sex were independently associated with a higher CVD prevalence. After adjusting for demographic and traditional cardiovascular risk factors, systemic lupus erythematosus exhibited the highest CVD standardized prevalence, followed by rheumatoid arthritis, psoriasis, Crohn disease, psoriatic arthritis, and ulcerative colitis (4.5 [95% confidence interval (CI): 2.2, 6.8], 1.3 [95% CI: 0.8, 1.8], 0.9 [95% CI: 0.5, 1.2], 0.8 [95% CI: 0.2, 1.3], 0.6 [95% CI: 0.2, 1.0], and 0.5 [95% CI: 0.1, 0.8], respectively).Systemic lupus erythematosus, rheumatoid arthritis, and psoriasis are associated with higher prevalence of CVD compared with other IMIDs. Specific prevention programs should be established in subjects affected with these conditions to prevent CVD. PMID- 28658138 TI - A novel technique for the treatment of stages III to IV hemorrhoids: Homemade anal cushion suspension clamp combined with harmonic scalpel. AB - To compare the efficacy of homemade anal cushion suspension clamp combined with harmonic scalpel (ACS) and Milligan-Morgan hemorrhoidectomy combined with electric knife (MMH) in the treatment of stages III to IV hemorrhoids. We conducted a retrospective study of 99 patients with stages III to IV hemorrhoids hospitalized from January to December in 2013. Among them, 51 patients were treated with ACS, while 48 patients received MMH. Data from clinical recording and follow-up included operative time, intraoperative blood loss, hospitalization information, postoperative pain, and postoperative complications. Operative time, intraoperative blood loss and hospitalization time in ACS group were significantly less than those in MMH group (P < .05). Compared with MMH group, ACS group had a lower postoperative static pain score from days 1 to 14 (P < .01). The patients in ACS group exhibited less postoperative defecation pain scores from days 3 to 20 than those of MMH group (P < .05). The incidence of postoperative anal edema and delayed wound healing in ACS group was lower than that in MMH group (P < .05). Compared with MMH, our novel technique ACS was more effective and had fewer postoperative complications in the treatment of stages III to IV hemorrhoids. PMID- 28658139 TI - Computer-designed surgical guide template compared with free-hand operation for mesiodens extraction in premaxilla using "trapdoor" method. AB - The aim of this study was to introduce a novel method of mesiodens extraction using a vascularized pedicled bone flap by piezosurgery and to compare the differences between a computer-aided design surgical guide template and free-hand operation.A total of 8 patients with mesiodens, 4 with a surgical guide (group I), and 4 without it (group II) were included in the study. The surgical design was to construct a trapdoor pedicle on the superior mucoperiosteal attachment with application of piezosurgery. The bone lid was repositioned after mesiodens extraction. Group I patients underwent surgeries based on the preoperative planning with surgical guide templates, while group II patients underwent free hand operation. The outcome variables were success rate, intraoperative time, anterior nasal spine (ANS) position, changes of nasolabial angle (NLA), and major complications. Data from the 2 groups were compared by SPSS 17.0, using Wilcoxon test.The operative time was significantly shorter in group I patients. All the mesiodentes were extracted successfully and no obvious differences of preoperative and postoperative ANS position and NLA value were found in both groups. The patients were all recovered uneventfully.Surgical guide templates can enhance clinical accuracy and reduce operative time by facilitating accurate osteotomies. PMID- 28658140 TI - Is there differential responsiveness to a future cigarette price increase depending on adolescents' source of cigarette access? AB - We examined whether the responsiveness to an increase in cigarettes price differed by adolescents' cigarette acquisition source. We analyzed data on 6134 youth smokers (grades 7-12) from a cross-sectional survey in Korea with national representativeness. The respondents were classified into one of the following according to their source of cigarette acquisition: commercial-source group, social-source group, and others. Multiple logistic regressions were performed to estimate the effects of an increase in cigarette price on the intention to quit smoking on the basis of the cigarette acquisition source. Of the 6134 youth smokers, 36.0% acquired cigarettes from social sources, compared to the 49.6% who purchased cigarettes directly from commercial sources. In response to a future cigarette price increase, regardless of an individual's smoking level, there was no statistically significant difference in the odds ratio for the intention to stop smoking in association with cigarette acquisition sources. The social-source group had nonsignificant, but consistently positive, odds ratios (1.07-1.30) as compared to that of the commercial-source group. Our findings indicate that the cigarette acquisition source does not affect the responsiveness to an increase in cigarette price. Therefore, a cigarette price policy is a comprehensive strategy to reduce smoking among youth smokers, regardless of their source. PMID- 28658141 TI - Pharmacogenetic and case-control study on potassium channel related gene variants and genetic generalized epilepsy. AB - Potassium channels are the targets of antiepileptic drugs (AEDs), which play important roles in the etiology of epilepsy. KCNA1 and KCNA2 encode mammalian Kv1.1 and Kv1.2 channels, which are essential roles in the initiation and shaping of action potentials. KCNV2 encodes Kv8.2, which is a regional overlap with Kv2 subunits as functional heterotetramers. In our study, we aim to investigate whether variants of KCNA1, KCNA2, and KCNV2 genes influence susceptibility to genetic generalized epilepsies (GGEs) and the efficacy of AEDs. Seven hundred sixty-seven subjects (284 healthy controls, 279 drug-responsive, and 204 drug resistant GGE patients) were enrolled in our study. Eight variants of KCNA1, KCNA2, and KCNV2 were assessed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. Results showed that there were no statistically significant correlations between the 8 variants of KCNA1, KCNA2, and KCNV2 and the risk/drug resistance of GGEs. In conclusion, our study suggests that KCNA1, KCNA2, and KCNV2 variants may not be involved in the risk/drug resistance of GGEs. Further multicenter, multiethnic, and large sample size pharmacogenetic and case-control studies are warranted to confirm our negative results. PMID- 28658142 TI - Use of neuromuscular blockers and neostigmine for general anesthesia and its association with neuraxial blockade: A retrospective study. AB - This research aimed to assess the use of neuromuscular blockers (NMB) and its reversal, associated or not with neuraxial blockade, after general anesthesia.This retrospective study analyzed 1295 patients that underwent surgery with general anesthesia at Prof. Dr. Jose Aristodemo Pinotti Hospital in 2013. The study included patients aged >1 year, with complete, readable medical charts and anesthetic records.Rocuronium (ROC) was the most used NMB (96.7%), with an initial dose of 0.60 (0.52-0.74) mg/kg and total dose of 0.38 (0.27-0.53) mg/kg/h. In 24.3% of the cases, neuraxial blockade was associated with a significantly longer anesthesia (P < .001) than in cases without neuraxial block, regardless of technique (total intravenous (TIV) vs intravenous and inhalational (IV+IN)). In 71.9% of the cases, a single dose of NMB was used. Patients under TIV general anesthesia associated with neuraxial blockade had a lower total dose of ROC (mg/kg/h) in comparison with TIV GA alone (0.30 (0.23-0.39) and 0.42 (0.30 0.56) mg/kg/h, respectively, P < .001). The same was observed for patients under IV+IN GA (0.32 (0.23-0.41) and 0.43 (0.31-0.56) mg/kg/h, respectively, P < .001). The duration of anesthesia was longer according to increasing number of additional NMB doses (P < .001). Dose of neostigmine was 2.00 (2.00-2.00) mg or 29.41 (25.31-33.89) MUg/kg. The interval between neostigmine and extubation was >30 minutes in 10.9% of cases.The most widely used NMB was ROC. Neuroaxial blockade (spinal or epidural) was significantly associated with reduced total dose of ROC (mg/kg/h) during general anesthesia, even in the absence of neuromuscular monitoring and regardless of general anesthetic technique chosen. In most cases, neostigmine was used to reverse neuromuscular block. The prolonged interval between neostigmine and extubation (>30 minutes) was neither associated with total doses of ROC or neostigmine, nor with the time of NMB administration. This study corroborates the important role of quantitative neuromuscular monitors and demonstrates that neuraxial blockade is associated with reduced total ROC dose. Further studies are needed to evaluate the possible role of neuraxial blockade in reducing the incidence of postoperative residual curarization. PMID- 28658143 TI - Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, and anti-CTLA-4 antibody ipilimumab are being in clinic trials to treat melanoma. Here, we performed a meta-analysis to evaluate the efficacy and toxicity of them against advanced melanoma. METHODS: Eleven reports from 6 randomized control trials on treating metastatic melanoma, which were divided into 3 subgroups, nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, were included and the meta-analysis was performed for each subgroup. The outcome measures were objective response rates (ORR), median progression free survival (PFS), 1-year overall survival rates (OS), and toxicity estimated by grade 3 to 4 adverse events. RESULTS: For nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, the pooled risk ratios (RR) of the ORR were 3.43 (95% CI: 2.57-4.58), 2.51 (95% CI: 2.03-3.09), and 3.28 (95% CI: 2.58-4.17), respectively. The pooled HR of PFS were 0.42 (95% CI: 0.36-0.49), 0.58 (95% CI: 0.50-0.66), and 0.41 (95% CI: 0.30-0.52), respectively. The pooled RR of 1-year OS was 1.37 (95% CI: 1.08-1.74) and 1.54 (95% CI: 0.90-2.63) for nivolumab versus ipilimumab and nivolumab-plus-ipilimumab versus ipilimumab. These results suggested that anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy had ORR and PFS benefit compared with the control group. Anti-PD-1 treatment increased 1-year OS for patients compared with ipililumab treatment. But there is no significantly difference on 1-year OS between the nivolumab-plus ipilimumab treatment and the ipilimumab treatment group. The toxicity analysis showed that there is less risk of adverse events in the anti-PD-1 treatment group compared with the chemotherapy and ipilimumab group. Combining nivolumab with ipilimumab increased the risk for high-grade adverse events compared with ipilimumab alone but the adverse events were generally manageable. CONCLUSIONS: Anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy improved ORR and prolonged PFS of patients with advanced melanoma and the adverse events are generally manageable. The therapy is indeed a promising approach for treatment of advanced melanoma. PMID- 28658144 TI - Comparison of the efficacy and safety of 3 treatments for patients with osteoporotic vertebral compression fractures: A network meta-analysis. AB - BACKGROUND: Osteoporotic vertebral compression fractures (OVCFs) constitute an age-related health problem that affects approximately 200 million people worldwide. Currently, various treatments are performed with the goal of reducing pain, stabilizing the vertebrate, and restoring mobility. In this study, we aimed to assess the efficacy and safety of vertebroplasty (VP), kyphoplasty (KP), and conservative treatment (CT) for the treatment of OVCFs. METHODS: We performed a network meta-analysis. PubMed and Embase databases were searched to identify randomized controlled trials (RCTs) that contained at least one of the following outcomes: visual analog scale (VAS), Roland-Morris Disability Questionnaire (RDQ), European Quality of Life-5 Dimensions (EQ-5D), and new fractures. Odds ratios with 95% confidence intervals (CIs) were used to calculate the risk of new fractures, and mean differences (MDs) with 95% CIs were utilized to express RDQ, EQ-5D, and VAS outcomes. RESULTS: Sixteen RCTs with 2046 participants were included in this meta-analysis. Compared with CT, patients treated with VP had improved pain relief, daily function, and quality of life; however, no significant differences were found between VP and KP for these 3 outcomes. All treatment options were associated with comparable risk of new fractures. When the rank probability was assessed to distinguish subtle differences between the treatments, VP was the most effective treatment for pain relief, followed by KP and CT; conversely, KP was the most effective in improving daily function and quality of life and decreasing the incidence of new fractures, followed by VP and CT. CONCLUSION: VP might be the best option when pain relief is the principle aim of therapy, but KP was associated with the lowest risk of new fractures and might offer better outcomes in terms of daily function and quality of life. PMID- 28658145 TI - Central hypothyroidism in a pediatric case of primary acute monoblastic leukemia with central nervous system infiltration: A case report. AB - RATIONALE: Central nervous system (CNS) leukemia is a frequent diagnosis in pediatric acute myeloblastic leukemia (AML) and includes neural symptoms. However, CNS leukemia is rarely associated with central hypsothyroidism. PATIENT CONCERNS AND DIAGNOSES: A 2-year-old female with AML with MLL rearrangement presented with CNS infiltration. Laboratory tests suggested the presence of central hypothyroidism (thyroid-stimulating hormone [TSH]: 0.48 mIU/ml, normal range 0.7-6.4 mIU/ml; serum free thyroxine [FT4]: 0.62 ng/dl, normal range 0.8 2.2 ng/dl; free triiodothyronine: 1.57 pg/ml, normal range 2.7-5.6 pg/ml). Magnetic resonance imaging detected no lesions in the hypothalamus, pituitary, or thyroid. INTERVENTIONS AND OUTCOMES: Levothyroxine (2.5 mg/kg/day) was administered together with chemotherapy and intrathecal injection of methotrexate, cytarabine, and hydrocortisone into the cerebrospinal fluid. The FT4 concentration increased after levothyroxine treatment, but later decreased after relapse of CNS leukemia. The TSH concentrations remained low. After remission of CNS leukemia, the TSH and FT4 concentrations quickly recovered to their normal ranges. LESSONS: We believe that the CNS leukemia directly affected TSH and thyroid hormone secretion in our patient. PMID- 28658146 TI - Diplopia in a patient with Hashimoto's thyroiditis: A case report and literature review. AB - BACKGROUND: A case report of Hashimoto's thyroiditis-associated ophthalmopathy that masqueraded as double elevator palsy in 1 eye. CASE PRESENTATION: A 54-year old woman presented to our strabismus clinic with diplopia for 1 year. She was diagnosed with double elevator palsy in the left eye. The forced duction test yielded positive findings for the inferior rectus of the left eye; hence, computed tomography of the orbit and thyroid-associated blood tests were performed; surprisingly, the thyroid function test results were consistent with hypothyroidism and the antibody results such as antithyroglobulin and antithyroid peroxidase were markedly elevated, and the patient was diagnosed with Hashimoto's thyroiditis and treated with corticosteroids. Unfortunately, her diplopia was not relieved with medical management. Subsequently, a 9-mm left inferior rectus recession was performed. CONCLUSION: Clinicians should be aware of the atypical signs of Hashimoto's thyroiditis for its proper diagnosis and management. PMID- 28658147 TI - Paradoxical embolism: A report of 2 cases. AB - RATIONALE: Paradoxical embolism (PDE) refers to direct passage of venous thrombi into the arterial circulation through an arteriovenous shunt. PATIENT CONCERNS: Case 1 presented with initial symptoms of shock and cerebral infarction. Case 2 developed middle cerebral artery occlusion during angiography. DIAGNOSES: 2 cases were diagnosed as PDE. INTERVENTIONS: They received thrombolytic therapy and anticoagulant therapy. OUTCOMES: The patients had recovery. LESSONS: This report highlights the myriad clinical manifestations of PDE and underlines the importance of meticulous history taking and physical examination for early diagnosis. PMID- 28658148 TI - Graft-versus-host-disease after kidney transplantation: A case report and literature review. AB - INTRODUCTION: Acute graft-versus-host-disease (GVHD) in kidney recipients is extremely rare. Knowledge about its clinical manifestations, diagnosis, treatment, and prognosis is limited and needs to be increased. CLINICAL FINDINGS: One male kidney transplant recipient developed diarrhea and suffered kidney function damage. Primarily diagnosed with acute rejection, he was given methylprednisolone (MP) bolus treatment. Meanwhile, intravenous immunoglobulin (IVIG) and decreased immunosuppressive agents were applied for the corresponding infection. During the treatment, skin rashes occurred over his whole body. Biopsies were then taken. The pathology of the kidney graft showed no rejection, while the skin pathology revealed typical GVHD. Furthermore, fluorescence in situ hybridization proved the presence of donor-derived cells in the skin lesions, and infiltrating cytotoxic T cells and NK cells were identified in the rash. OUTCOME: Based on the clinical presentations, pathological findings, and chimerism detection, GVHD after kidney transplantation was confirmed as the final diagnosis. The recipient responded well to treatment. His kidney function recovered, and the skin lesions were completely resolved. He has been followed for 1 year without any further episodes. CONCLUSION: GVHD after kidney transplantation has its own characteristics. In the presence of a highly immunocompromised state, diarrhea and rashes, a diagnosis of GVHD needs to be considered. Kidney function impairment may be involved. Pathological changes and detection of chimerism and immunocyte infiltration are required for diagnosis. MP bolus, IVIG, and decreased immunosuppression could be beneficial to the clinical outcome. Kidney recipients have a prognosis superior to recipients of organs bearing large numbers of lymphocytes. PMID- 28658149 TI - A rare case report: enlarged iliopsoas cystic solid mass associated with femoral head necrosis induced by heavy alcohol consumption. AB - RATIONALE: This article presents an unusual case of a large iliopsoas cystic solid mass associated with femoral head necrosis in a patient with heavy alcohol consumption for years. PATIENT CONCERNS: The patient reported pain and limitation of movement at the right hip for 4 months. A soft tissue mass can be palpated deep in the groin several days after the onset of pain. DIAGNOSES: The laboratory assessments indicated an inflammatory response of the patient. Imaging was performed on the femoral head and iliopsoas cyst. The pathological feature of the mass was evaluated through biopsy examination. It was found that iliopsoas cystic solid mass is secondary to the femoral head necrosis induced by heavy alcohol consumption. INTERVENTIONS: The patient underwent elective total hip arthroplasty. The bursa was excised and the anterior hip capsule closure was performed. OUTCOMES: After the surgery, imaging results showed a well-positioned prosthesis. At 1-year follow-up, the prosthesis was still well-positioned and no signs of recurrence of iliopsoas bursa were found. LESSONS: We suggested the performance of elective total hip arthroplasty, bursa excision, and closure of the anterior hip capsule in patients with femoral necrosis and iliopsoas bursitis presented simultaneously. PMID- 28658150 TI - Remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma impact on prognosis: A systematic review and meta-analysis. AB - BACKGROUND: The aim of this study was to evaluate the outcomes of patients with pathologic T0 esophageal carcinoma after neoadjuvant therapy and surgery. METHODS: We searched PubMed, Embase, Cochrane Library, and Medline databases from inception up to November 12, 2016. The meta-analysis was performed to compare odds ratios (OR) for overall survival (OS), disease-free survival (DFS), local control (LC), and distant control (DC). RESULTS: Eight published studies of 837 patients were included in the meta-analysis. Data showed that the ypT0N1 group was associated with worse outcomes compared with the ypT0N0 group. The pooled OR and 95% confidence interval (CI) for 3-year and 5-year OS were 3.08 [2.07, 4.57] and 4.27 [2.76, 6.59], respectively. Whereas, the pooled OR and 95% CI for 3-year and 5-year DFS were 3.90 [2.08, 7.34] and 5.17 [1.93, 13.87], respectively. The pooled OR and 95% CI for LR and DR were 4.52 [1.72, 11.91] and 2.65 [1.38, 5.09], respectively. CONCLUSIONS: Remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma portend poor survival, and it is an important prognostic factor. PMID- 28658151 TI - Establishment of a risk scoring system for predicting locoregional recurrence in T1 to T2 node-negative breast cancer patients treated with mastectomy: Implications for postoperative radiotherapy. AB - To establish a risk scoring system for predicting locoregional recurrence (LRR) and explore the potential value of radiotherapy in T1 to T2 node-negative breast cancer patients treated with mastectomy. From January 2001 to February 2008, a total of 353 node-negative T1 to T2 breast cancer cases treated with mastectomy without adjuvant radiotherapy were retrospectively analyzed. Preliminary screening of the prognostic factors was accomplished by Kaplan-Meier univariate analysis, and survival curves between different groups were compared by log-rank test. Risk factors were determined using Cox proportional hazards model. A categorical risk scoring system was generated according to the Cox model, weighing the relative importance of each risk variable. Median follow-up was 115.7 months (range, 1.2-238.4 months). The overall 5-year locoregional recurrence-free survival (LRFS) was 89.8% (95% confidence interval [CI] = 86.7% 92.9%). Chest wall (53.8%) was found to be the most common site of LRR, followed by supraclavicular nodes (48.7%). Age <=40 years, primary tumor size >=4.5 cm and number of nodes resected <=10 were found to be independent factors for poor prognosis of LRR. Two risk stratifications based on the scoring system were subsequently obtained. The 5-year LRFS was 91.6% (95% CI = 88.5%-94.7%) with low risk (score <2) and 75.7% (95% CI = 61.8%-89.6%) with high risk (score >=2), respectively (chi = 7.544, P = .006). In addition, significant differences in overall survival (P = .045) and disease-free survival (P = .019) were presented between them. Patients with T1-2N0M0 breast cancer achieved favorable prognosis in general. Those with risk factors, including age <=40 years, primary tumor size >=4.5 cm and number of nodes resected <=10, were at higher risk of LRR. The established scoring system could help to distinguish the subgroups that might potentially benefit from postoperative radiotherapy. PMID- 28658152 TI - The clinical features of epithelioid hemangioendothelioma in a Han Chinese population: A retrospective analysis. AB - Epithelioid hemangioendothelioma (EHE) is a rare indolent vascular tumor which occurs at liver, lung, bone, and so on. However, the etiology of EHE is evasive.These patients were enrolled at the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to December 2015. Retrospective analysis is done by demographic data of clinical manifestations, laboratory parameters, CT imaging, histological, and immunohistochemical features in 9 cases in Shaanxi.Of the patients, 8 were females (88.9%) and 1 were males (11.1%). The age ranged from 34 to 71 years (mean 49 years; median 49 years). Anatomical sites of primary lesions were as follows: liver (n = 6, 66.7%), upper extremities (n = 1, 11.1%), sublingual gland (n = 1, 11.1%), and spine (n = 1, 11.1%). Metastatic disease was diagnosed in 5 cases (55.6%) with occurrence in lung (n = 4, 44.4%), bone (n = 2, 22.2%), upper extremities (n = 1, 11.1%), pleura (n = 1, 11.1%), and spleen (n = 1, 11.1%). Tumor size ranged from 0.5 to 6.8 cm (mean 3 cm). The most tumors were composed of highly cellular areas with small and prominent nucleoli in vesicular nuclei, and ERG (100%) was the most frequently positive in these cases, followed by CD31 (88.9%) and CD34 (77.8%) via histology and immunohistochemistry techniques.EHE is a very rare in Shaanxi. It is significant to find its clinical, radiological, and pathological characters, helping for EHE early diagnosis and treatment, reducing misdiagnosis and improving life quality. PMID- 28658153 TI - Bmi-1 overexpression as an efficient prognostic marker in patients with nonsmall cell lung cancer. AB - BACKGROUND: The prognostic effect of B-cell-specific Moloney leukemia virus insertion site 1 (Bmi-1) in patients with nonsmall cell lung cancer (NSCLC) remains controversial. We thus performed a meta-analysis to reveal the correlation between Bmi-1 with clinical features and overall survival (OS) in NSCLC. METHODS: Relevant studies were searched through PubMed, Embase, and Web of Science. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) as well as odds ratios (ORs) and 95% CIs were calculated by using STATA version 12.0. RESULTS: Fourteen studies consisting of 1323 patients were included for quantitative analysis. The results showed that Bmi-1 was significantly associated with tumor size (n = 7, OR = 1.79, 95% CI = 1.19-2.71, P = .005, fixed effect), poor differentiation (OR = 1.61, 95% CI = 1.11-2.33, P = .011, fixed effect), and distant metastasis (n = 4, OR = 4.69, 95% CI = 1.52-14.41, P = .007, fixed effect). In addition, high Bmi-1 expression also predicted poor OS (HR = 1.62, 95% CI = 1.14-2.3, P < .001). There was no significant publication bias for any of the analyses. CONCLUSION: In conclusion, Bmi-1 overexpression was correlated with tumor size, poor differentiation, distant metastasis, and worse OS in NSCLC. Therefore, Bmi-1 could be recommended as an efficient prognostic marker for NSCLC. PMID- 28658155 TI - Long-term follow-up of elite controllers: Higher risk of complications with HCV coinfection, no association with HIV disease progression. AB - To estimate the effect of hepatitis C virus (HCV) coinfection on the development of complications and progression of human immunodeficiency virus (HIV) disease among HIV-infected elite controllers.Single-center retrospective cohort. Kaplan Meier methods, prevalence ratios, and Cox proportional-hazards models were used.In all, 55 HIV-infected elite controllers were included in this study. Among them, 45% were HIV/HCV coinfected and 55% were HIV mono-infected. Median follow up time for the cohort was 11 years. Twenty-five patients experienced a complication and 16 lost elite controller status during the study period. HCV coinfected patients were 4.78 times (95% confidence interval 1.50-15.28) more likely to develop complications compared with HIV mono-infected patients. There was no association between HCV coinfection status and loss of elite control (hazard ratio 0.75, 95% confidence interval 0.27-2.06).Hepatitis C virus coinfection was significantly associated with the risk of complications even after controlling for sex, injecting drug use, and older age. HCV coinfected patients had higher levels of cellular activation while also having similar levels of lipopolysaccharide and soluble CD14. HCV coinfection was not associated with loss of elite controller status. Taken together, this suggests that HCV coinfection does not directly affect HIV replication dynamics or natural history, but that it may act synergistically with HIV to produce a greater number of associated complications. Continued follow-up will be needed to determine whether HCV cure through the use of direct-acting antivirals among HIV/HCV coinfected elite controllers will make the risk for complications among these patients similar to their HIV mono-infected counterparts. PMID- 28658154 TI - 16S sequencing and functional analysis of the fecal microbiome during treatment of newly diagnosed pediatric inflammatory bowel disease. AB - The human microbiome is of considerable interest to pediatric inflammatory bowel disease (PIBD) researchers with 1 potential mechanism for disease development being aberrant immune handling of the intestinal bacteria. This study analyses the fecal microbiome through treatment in newly diagnosed PIBD patients and compares to cohabiting siblings where possible. Patients were recruited on clinical suspicion of PIBD before diagnosis. Treatment-naive fecal samples were collected, with further samples at 2 and 6 weeks into treatment. Samples underwent 16S ribosomal ribonucleic acid (RNA) gene sequencing and short-chain fatty acids (SCFAs) analysis, results were analyzed using quantitative-insights into-microbial-ecology. Six PIBD patients were included in the cohort: 4 Crohn disease (CD), 1 ulcerative colitis (UC), 1 inflammatory bowel disease (IBD) unclassified, and median age 12.6 (range 10-15.1 years); 3 patients had an unaffected healthy sibling recruited. Microbial diversity (observed species/Chao1/Shannon diversity) was reduced in treatment-naive patients compared to siblings and patients in remission. Principal coordinate analysis using Bray Curtis dissimilarity and UniFrac revealed microbial shifts in CD over the treatment course. In treatment-naive PIBD, there was reduction in functional ability for amino acid metabolism and carbohydrate handling compared to controls (P = .038) and patients in remission (P = .027). Metabolic function returned to normal after remission was achieved. SCFA revealed consistent detection of lactate in treatment-naive samples. This study adds in-depth 16S rRNA sequencing analysis on a small longitudinal cohort to the literature and includes sibling controls and patients with UC/IBD unclassified. It highlights the initial dysbiosis, reduced diversity, altered functional potential, and subsequent shifts in bacteria from diagnosis over time to remission. PMID- 28658156 TI - Comprehensive geriatric care reduces acute perioperative delirium in elderly patients with hip fractures: A meta-analysis. AB - BACKGROUND: The aim of the current meta-analysis was to assess the treatment effect of comprehensive geriatric care in reducing acute perioperative delirium in older patients with hip fractures, compared with the effect of a routine orthopedic treatment protocol. METHODS: We conducted a search of multiple databases to identify randomized controlled trials (RCTs) and quasi-RCTs comparing comprehensive geriatric care and routine orthopedic treatment regarding the following outcomes: incidence of delirium, assessment of cognitive status, and duration of delirium. Odds ratios (ORs) and mean differences (MDs) were pooled using either a fixed-effects or a random-effects model, depending on the heterogeneity of the trials included in the analysis. RESULTS: Six RCTs and 1 quasi-RCT provided data from 1840 patients. These data revealed that comprehensive geriatric care may reduce the incidence of perioperative delirium (OR = 0.71; 95% confidence interval [CI], 0.57-0.89; P = .003) and that it was associated with higher cognitive status during hospitalization or at 1 month postoperatively (MD = 1.03; 95% CI, 0.93-1.13; P <= .00001). There was no significant difference in duration of perioperative delirium between the 2 treatment groups (MD = -2.48; 95% CI, -7.36 to 2.40; P = .32). CONCLUSION: Based on the quality of evidence provided, comprehensive geriatric care may reduce the incidence of perioperative delirium. To obtain evidence regarding the merits of comprehensive geriatric care in reducing severity of delirium and shortening the duration of delirium, there is a need for multicenter RCTs with high methodological quality. PMID- 28658157 TI - Efficacy of tranexamic acid plus drain-clamping to reduce blood loss in total knee arthroplasty: A meta-analysis. AB - BACKGROUND: Perioperative blood loss is still an unsolved problem in total knee arthroplasty (TKA). The efficacy of the preoperative use of tranexamic acid (TXA) plus drain-clamping to reduce blood loss in TKA has been debated. This meta analysis aimed to illustrate the efficacy of TXA plus drain-clamping to reduce blood loss in patients who underwent a TKA. METHODS: In February 2017, a systematic computer-based search was conducted in PubMed, EMBASE, Web of Science, the Cochrane Database of Systematic Reviews, and Google Scholar. Data from patients prepared for TKA in studies that compared TXA plus drain-clamping versus TXA alone, drain-clamping alone, or controls were retrieved. The primary endpoint was the need for transfusion. The secondary outcomes were total blood loss, blood loss in drainage, the decrease in hemoglobin, and the occurrence of deep venous thrombosis. After testing for publication bias and heterogeneity between studies, data were aggregated for random-effects models when necessary. RESULTS: Ultimately, 5 clinical studies with 618 patients (TXA plus drain-clamping group = 249, control group = 130, TXA-alone group = 60, and drain-clamping group = 179) were included. TXA plus drain-clamping could decrease the need for transfusion, total blood loss, blood loss in drainage, and the decrease in hemoglobin than could the control group, the TXA-alone group, and the drain-clamping group (P < .05). There was no significant difference between the occurrence of deep venous thrombosis between the included groups (P > .05). CONCLUSIONS: TXA plus drain clamping can achieve the maximum effects of hemostasis in patients prepared for primary TKA. Because the number and the quality of the included studies were limited, more high-quality randomized controlled trials are needed to identify the optimal dose of TXA and the clamping hours in patients prepared for TKA. PMID- 28658158 TI - Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report. AB - RATIONALE: The carbamoyl phosphate synthetase I deficiency (CPS1D) was rare and hard to diagnose due to its atypical symptoms. Brain magnetic resonance imaging (MRI) was typically unavailable in other reports because most patients died before diagnosis was confirmed. Furthermore, it was found a new mutation that had not been described previously. PATIENT CONCERNS: This is a case of neonatal-onset CPS1D with nonspecific clinical manifestations and deteriorating rapidly. Poor feeding, low activity, and tachypnoea were observed, with rapid progression on day 2 after birth. Severe systematic infection was considered first. However, blood culture and cerebrospinal fluid examination were negative. Symptoms were relief temporarily. Then seizure and tachypnoea reappeared as intravenous amino acids were provided. Further examination indicated severe hyperammonemia (serum ammonia level >500mmol/L). Brain MRI showed diffused white matter lesions. DIAGNOSES: Genetic analysis revealed 2 heterozygous mutations in the CPS1 gene: c.2407C>G (p.803, R>G) in exon 20 and C.323G>A (p.108, G>E) in exon 4. The diagnosis of CSP1D was confirmed. INTERVENTIONS: Fasting, the withdrawal of amino acids and plans to treat hyperammonemia were immediately implemented. OUTCOMES: The parents decided to discontinue medical care. LESSONS: Many CPS1D patients died before the diagnoses are confirmed due to its sudden onset, rapid deterioration, atypical symptoms, and low morbidity. Once hyperammonemia is confirmed, blood and urea amino acid analysis in combination with genetic examinations should be performed as early as possible, this approach would help establish diagnoses at an early stage and thus contribute to reducing mortality and improving prognosis. PMID- 28658159 TI - Outcomes of primary gastric transposition for long-gap esophageal atresia in neonates. AB - BACKGROUND: Gastric transposition is a relatively novel method of esophageal replacement. The purpose of this retrospective study was to assess the outcomes of long-gap esophageal atresia (LGEA) treated with esophageal replacement using primary gastric transposition in neonates. METHODS: Between March 2008 and May 2015, 14 newborns with LGEA were treated in our hospital. They were all found to have gaps of over 3 cm at the time of the surgery and were diagnosed with LGEA. Primary gastric transposition was performed. They also underwent a gastric drainage procedure by pyloromyotomy. The nasogastric tube was removed if no anastomotic fistula was present and oral feeding was initiated. After initial recovery and discharge, the patients were evaluated with outpatient follow-ups or telephone follow-ups from 1 month after the surgery. RESULTS: The mean age of the neonates at the time of the surgery was 32 hours (range, 4-96 h). The mean birth weight was 2550 g (range, 2100-3500 g). There were 2 deaths in this series of patients due to respiratory failure or withdrawal of treatment by the parents, with a mortality rate of 14.3%. Seven of the neonates developed unilateral or bilateral severe pneumonia. Early anastomotic leak occurred in 3 cases and anastomotic strictures occurred in 4 cases. These 4 neonates were able to eat a fairly normal diet after esophageal balloon dilation. Gastroesophageal reflux occurred in 7 of 12 cases. Feeding multiple small meals and postural support for positioning and feeding were instructed for these 7 cases. Subsequently, the symptoms alleviated and they had no additional surgical therapy. None of the neonates had delayed gastric emptying or gastric retention. CONCLUSION: Primary gastric transposition may be a rewarding reconstructive option in the treatment of LGEA. PMID- 28658160 TI - The effect of intra-articular stimulation by pulsed radiofrequency on chronic sacroiliac joint pain refractory to intra-articular corticosteroid injection: A retrospective study. AB - We investigated the degree of pain reduction following intra-articular (IA) pulsed radiofrequency (PRF) stimulation of the sacroiliac joint (SIJ) in patients with chronic SIJ pain that had not responded to IA corticosteroid injection. Twenty patients were recruited. Clinical outcomes after applying PRF stimulation of the SIJ were evaluated by a numeric rating scale (NRS) and a 7-point Likert scale. The NRS scores significantly changed over time. The NRS scores at 1, 2, and 3 months after PRF were significantly lower than those before PRF. However, 4 of the 20 patients (20%) reported successful pain relief (pain relief of >= 50%) and were satisfied with the PRF stimulation at 3 months after treatment. IA PRF stimulation of the SIJ was not successful in most patients (80% of all patients). Based on our results, we cannot recommend this procedure to patients with chronic SIJ pain that was unresponsive to IA SIJ corticosteroid injection. Further studies on the effective mode of PRF stimulation and appropriate patient group, and studies on pain conditions that are most responsive to PRF are needed in the future. PMID- 28658161 TI - Old age and hydrocephalus are associated with poor prognosis in patients with tuberculous meningitis: A retrospective study in a Chinese adult population. AB - Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis with a very poor prognosis. We aimed at assessing risk factors related to the prognosis of patients with TBM.Forty-five inpatients with TBM in our institution from January 2013 to December 2015 were enrolled retrospectively. The good or poor prognosis in the patients was defined, based on Glasgow Outcome Scale System at discharge. Patients with a GOS score less than 5 were defined as "poor prognosis." Univariate and multivariate logistic regression analyses were performed to assess the predictors for TBM outcome.Among 45 TBM patients, 35 (77.8%) and 10 (22.2%) were in good, poor prognoses, respectively. Old age, disturbance of consciousness, moderate to severe electroencephalogram abnormality, hydrocephalus, remarkable increase of protein (>= 236 mg/dL) and white blood cell counts (>= 243 /MUL) in cerebral spinal fluid were associated with poor prognosis. Multivariate analysis indicated that old age (odds ratio (OR) = 18.395, P = .036) and hydrocephalus (OR = 32.995, P = .049) were independent factors for a poor outcome of TBM.In conclusion, old age and hydrocephalus are the predictors for poor prognosis of TBM. Patients with these risk factors should be treated promptly with a special care paid to improve their outcomes. PMID- 28658162 TI - A multidisciplinary team approach for nutritional interventions conducted by specialist nurses in patients with advanced colorectal cancer undergoing chemotherapy: A clinical trial. AB - BACKGROUND & AIMS: Nutritional interventions for malnutrition in cancer patients can be helpful. However, concise intervention recommendations remain controversial. Thus, the aim of this study was to report on a nutrition intervention conducted by a multidisciplinary team of specialist nurses and to explore the effect of nutritional intervention on cancer patients. METHODS: This prospective clinical trial study enrolled 110 colorectal cancer patients undergoing chemotherapy. The patients were evaluated upon admission using the 2002 Nutritional Risk Screening system (NRS-2002). The patients were randomly divided into intervention and control groups including 55 patients each. Patients in the control group were administered a normal diet, while those in the intervention group received individual recipes developed by a team of professional nurses, clinical doctors, dietitian, family caregivers, and the patients themselves. Patient weight and serum albumin and prealbumin levels were compared between the 2 groups at different time points. RESULTS: There was a significant difference in patient weight and serum albumin and prealbumin levels before and after nutrition intervention in the intervention group (P < .05). In the control group, weight did not change during ordinary diet guidance. Serum albumin level was slightly improved after 12 cycles of chemotherapy, similar to the prealbumin results. There were statistically significant differences in serum albumin and prealbumin levels between the intervention and control groups after nutrition intervention (P < .05). However, there was no statistically significant difference in weight between the groups after nutrition intervention (P > .05). CONCLUSION: A multidisciplinary team approach for nutrition intervention conducted by specialist nurses improved prealbumin levels in colorectal cancer patients undergoing chemotherapy, with no weight change. PMID- 28658163 TI - Effects of preconditioning of electro-acupuncture on postoperative cognitive dysfunction in elderly: A prospective, randomized, controlled trial. AB - Electro-acupuncture is a burgeoning treatment using the needle inserting into the body acupoints and the low-frequency pulse current being electrified by an electric acupuncture machine. This study was designed to evaluate the effects of preconditioning of electro-acupuncture on postoperative cognitive dysfunction in elderly.Ninety patients scheduled spine surgery were randomly assigned into 2 groups using a random number table: control group (group C) and electro acupuncture group (group EA). In group EA, electro-acupuncture was applied on Baihui, Dazhui, and Zusanli acupoints 30 minutes before anesthesia. At 0 minute before treatment of electro-acupuncture, 1 hour after skin incision and surgery completed (T1-3), blood samples were taken for detection of interleukin (IL)-6, IL-10, and S100beta by enzyme-linked immunosorbent assay. The total dose of remifentanil and propofol during surgery were recorded. Mini-Mental State Examination was applied to evaluate the cognitive function of patients at 1 day before surgery and 7th and 30th day after surgery.The results showed that compared with group C, score of MMSE increased after surgery, the serum concentration of IL-6, IL-10, and S100beta decreased at 1 hour after skin incision, and surgery completed in group EA. Moreover, the total dose of remifentanil and propofol reduced during surgery in group EA.The present study suggests that preconditioning of electro-acupuncture could improve the postoperative cognitive function, and the reduction of inflammatory reaction and brain injury may be involved in the mechanism. PMID- 28658164 TI - The analgesic efficacy of oxycodone hydrochloride versus fentanyl during outpatient artificial abortion operation: A randomized trial. AB - BACKGROUND: Problems like body movement, respiratory depression, and complained of pain are still common phenomenon in outpatient artificial abortion general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid and has a good therapeutic effect on visceral pain. We hypothesize that oxycodone hydrochloride would be superior to fentanyl in outpatient artificial abortion surgery. METHODS: In this clinical trial 149 American Society of Anesthesiologists (ASA) I or II female outpatients scheduled for elective artificial abortion surgeries under general anesthesia were randomly divided into 3 groups: oxycodone hydrochloride 0.06 mg/kg group (group A), oxycodone hydrochloride 0.08 mg/kg group (group B), and control group fentanyl 2 ug/kg (group C). The primary outcome was level body movement and respiratory depression during the surgery, the second outcome included the visual analogue scale (VAS) score 30 minutes after waking. RESULTS: A total of 120 participants completed the study, n = 40 in each group. There was no significant difference in patients' age, body mass index (BMI), preoperative heart rate, mean arterial blood pressure, consumption dose of propofol, intraoperative body movement type and times, and duration of surgery among the 3 groups (P > .05). Comparing the incidence of intraoperative respiratory depression and SPO2 < 90% among the 3 groups, group C's was significantly higher than those of groups A and B, and the difference was statistically significant (P < .05). Group A had no difference compared with group B. In VAS score 30minutes after waking, group C was the highest, followed by group A, with group B as the lowest. The difference among the 3 groups was statistically significant (P < .05), but a difference delta less than 1 on the VAS scale is not clinically significant. CONCLUSION: The analgesic effect of oxycodone hydrochloride at 0.06 mg/kg applied to painless artificial abortion surgery is not superior than that of fentanyl, but the incidence of intraoperative respiratory depression and hypoxemia is significantly lower than fentanyl. PMID- 28658165 TI - Changes in skeletal muscle mass after endoscopic treatment in patients with esophageal varices. AB - To the best of our knowledge, no available data with regard to changes in skeletal muscle mass for liver cirrhosis (LC) patients with esophageal varices (EVs) undergoing endoscopic therapy as a primary prophylaxis could exist. As endoscopic therapies, such as endoscopic injection sclerotherapy or endoscopic band ligation for EVs, accompany invasive procedure and patients with EVs receiving endoscopic therapies mostly rest in bed during hospitalization, clarifying these issues are clinically of importance. The purposes of this study were therefore to examine changes in skeletal muscle mass for LC patients with EVs undergoing endoscopic therapy as a primary prophylaxis and to identify pretreatment predictors which are associated with the amelioration in skeletal muscle mass. This is a subgroup analysis in our previous randomized controlled trial. A total of 51 LC patients with EVs were analyzed. Skeletal muscle mass was assessed using bioimpedance analysis (BIA). Skeletal muscle index (SMI) was defined as sum of skeletal muscle mass in body trunk and upper and lower extremities divided by height squared (cm/m) using data for BIA. We compared the changes in SMI at baseline and SMI at Day 50 after endoscopic treatment for EVs. Our study cohort included 33 males and 18 females with median (range) age of 62 (29-81) years. There were 31 patients with Child-Pugh A and 20 with Child-Pugh B. The median SMI for the entire cohort at baseline was 8.96 cm/m (range, 5.87-13.11 cm/m), while the median SMI for the entire cohort at Day 50 was 8.83 cm/m (range, 5.59-12.29 cm/m) (P = .9995). In baseline characteristics, prealbumin (P = .0477), branched-chain amino acid to tyrosine ratio (BTR) (P = .0056), and retinol-binding protein (P = .0296) in the increased SMI group (n = 15) were significantly higher than those in the nonincreased SMI group (n = 36). Multivariate analysis for the above 3 significant factors showed that only BTR was a significant prognostic pretreatment factor linked to the presence of increased SMI (P = .0235). In conclusion, pretreatment BTR level can be helpful for predicting increased SMI after endoscopic therapy as a primary prophylaxis for LC patients with EVs. PMID- 28658166 TI - A cross-sectional study on the associations of insulin resistance with sex hormone, abnormal lipid metabolism in T2DM and IGT patients. AB - Type 2 diabetes mellitus (T2DM) is a long-term metabolic disorder. It is characterized by hyperglycemia, insulin resistance (IR), and relative impairment in insulin secretion. IR plays a major role in the pathogenesis of T2DM. Many previous studies have investigated the relationship between estrogen, androgen, and obesity, but few focused on the relationship between sex hormones, abnormal lipid metabolism, and IR. The goal for the present study was to identify the association of IR with sex hormone, abnormal lipid metabolism in type 2 diabetes, and impaired glucose tolerance (IGT) patients.In total 13,400 participants were analyzed based on the results of the glucose tolerance test. Using a cross sectional study, we showed the relationship between IR and the level of sex hormones among 3 different glucose tolerance states: normal control people, IGT, and T2DM patients. We also analyzed the relationship between IR and abnormal lipid metabolism.Significantly, luteinizing, progesterone, estradiol, prolactin, and follicle-stimulating hormone levels decreased in T2DM and IGT patients compared with those in normal control people. The association between IR and lipid metabolism disorders in T2DM and IGT patients was also observed.Our clinical findings may offer new insights into understanding the mechanism of metabolic disorders and in new therapeutic methods for the treatment of the prevalence of type 2 diabetes. PMID- 28658167 TI - Loss of nighttime blood pressure dipping as a risk factor for coronary artery calcification in nondialysis chronic kidney disease. AB - Diurnal variations in blood pressure (BP) loss are closely associated with target organ damage and cardiovascular events. The quantity of coronary artery calcification (CAC) correlates with the atherosclerotic plaque burden, and an increased quantity indicates a substantially increased risk of cardiovascular events. This study investigated the nighttime diurnal variation in BP loss associated with CAC in patients with chronic kidney disease (CKD).Of the 1958 participants, we enrolled 722 participants with CKD without a history of acute coronary syndrome or symptomatic coronary artery disease. CAC was measured with computed tomography. BP was measured using 24-hour ambulatory BP monitoring. Central BP was measured using a SphygmoCor waveform analysis system.Participants with CAC had significantly higher 24-hour systolic, daytime systolic, and nighttime systolic ambulatory BP and central systolic BP. The percentage of participants with dipping loss was significantly higher among those with CAC. Multivariate logistic regression analysis indicated that dipping loss and dipping ratio were independently associated with CAC after adjusting for traditional and nontraditional cardiovascular risk factors and other BP parameters, including measurements of office-measured BP and central BP. The dipping status improved risk prediction for CAC after considering traditional risk factors and office measured BP, using the net reclassification improvement and integrated discrimination improvement.Nighttime loss of diurnal variation in BP is an independent risk factor for CAC in CKD patients. PMID- 28658168 TI - Efficacy and safety of autologous hematopoietic stem cell therapy for refractory Crohn's disease: A systematic review and meta-analysis. AB - BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) has been proposed for patients with refractory Crohn's disease (CD), but it is associated with mortality and adverse events; the balance between risks and benefits becomes significantly important in the therapy. The aim of the study was to assess the efficacy and safety of autologous HSCT therapy for refractory CD. METHODS: We conducted a comprehensive search of PubMed, Embase, the Cochrane library, and Web of Science from inception to February 2017. The pooled estimate rates for efficacy and safety of refractory CD was performed by meta-analysis and reported according to the standard Cochrane guidelines and the PRISMA statement. RESULTS: Four prospective uncontrolled cohort studies, 4 prospective case series, and 1 randomized controlled trial (RCT) were included. Autologous HSCT had a high rate of clinical and endoscopic remission in refractory CD [79.4%, 95% confidence interval (95% CI): 0.550-0.924; 81.9%, 95% CI: 0.603-0.931, respectively]. In the case of safety, it had a relatively high incidence rate of transplant-related mortality (6.4%, 95% CI: 0.028-0.140). A significant association was observed between autologous HSCT and the incidence of febrile neutropenia (83.2%, 95% CI: 0.632-0.934). About 18.5% (95% CI: 0.061-0.442) of patients with refractory CD reached clinical remission at mobilization phase. Besides, 82.1% (95% CI: 0.692 0.903) and 54.1% (95% CI: 0.261-0.797) patients with refractory CD could achieve immunosuppressive-free and steroid-free remission for at least 12 months after the therapy. CONCLUSION: Autologous HSCT could be a complicated treatment with relatively high mortality and significantly high efficacy for refractory CD, which should be used with caution. However, more RCTs of larger samples using refined and standardized protocols and longer period of follow-up time are needed to further assess the outcomes of autologous HSCT therapy. PMID- 28658169 TI - Imaging features for diffuse-type tenosynovial giant cell tumor of the temporomandibular joint: A case report. AB - RATIONALE: The tenosynovial giant cell tumor (TGCT) is a benign but locally aggressive tumor that arises from the synovial membrane of joints, tendon sheaths, and bursae. Although any joint can be affected, involvement of the temporomandibular joint (TMJ) was reported very rarely, and there is no relevant report on F-FDG PET/computerized tomography (CT). PATIENT CONCERNS AND DIAGNOSES: We present here a rare case of diffuse-type of TGCT (D-TGCT) arising from the right TMJ in a 74-year-old woman. The patient was discovered a mass of the right temporal fossa during a head CT scan. However, she did not receive any treatment and was discharged from the hospital. She visited our institution again after 4 years with worsening headache and swelling of the right preauricular area. An enhanced CT demonstrated a 6.0 * 3.4 * 5.0 cm mass of mixed density involving the right TMJ, with evident enhancement and extensive erosion of adjacent bones. Magnetic resonance imaging (MRI) showed hypointensity in the solid part of the mass but high signal intensity in the cystic part or necrosis on T2-weighted images (T2WI). In F-FDG PET/CT images, the solid portion of the mass had increased FDG uptake with a SUVmax of 19.8. It was then diagnosed as D-TGCT by postoperative pathology. LESSONS: The case report shows the imaging features of the TGCT, including CT, MRI, and F-FDG PET/CT, especially the typical hypointensity on T2WI. Careful preoperative examination and complete resection are the factors that lead to the optimal treatment of the TGCT. PMID- 28658170 TI - Prognostic factors for patients with World Health Organization grade III meningiomas treated at a single center. AB - We analyzed the characteristics of patients with World Health Organization (WHO) grade III meningioma to identify factors that may predict tumor recurrence and overall survival (OS).We retrospectively reviewed the patients diagnosed with WHO grade III meningioma who were surgically treated at our institute between 2008 and 2016. Survival outcome was assessed by Kaplan-Meier analysis. Cox regression analyses were performed to identify the prognostic factors associated with tumor recurrence and OS.Forty-two patients were included. The mean follow-up time was 23.2 months (range 2-75 months). At the end of analysis, 30 patients were found with tumor recurrence. The 1-year, 3-year, and 5-year recurrence-free survival (RFS) were 51.6%, 33.9%, and 12.0%, respectively. At final follow-up, 23 patients were deceased, the 1-year, 3-year, and 5-year OS were 66.2%, 39.7%, and 35.8%, respectively. Twenty-eight newly diagnosed patients were included, and the 1 year, 3-year, and 5-year RFS were 63.5%, 44.3%, and 19.4%, respectively, and the 1-year, 3-year, and 5-year OS were 74.6%, 52.5%, and 46.7%, respectively. Extent of resection was the only factor associated with tumor recurrence and OS.WHO grade III meningioma is rare, and difficult to manage with a high rate of recurrence and poor OS. Extent of resection is an independent prognostic factor related to tumor recurrence and OS. We could not confirm the usefulness of Ki-67. We suggest that more aggressive treatment, such as safety maximizing cytoreduction by surgery, would improve treatment outcomes. PMID- 28658171 TI - Gonadal germ cell tumors in children: A retrospective review of a 10-year single center experience. AB - BACKGROUND: The true incidence of gonadal germ cell tumors (GCTs) in children is unknown. Few studies have been published concerning about pediatric gonadal GCTs. The aim of this study is to review and analyze clinical data on the diagnosis and management of gonadal GCTs in children. METHODS: Between 2005 and 2015, 127 pediatric patients (<14 years old) with gonadal GCTs admitted to our institute were reviewed. Clinical features, imaging and laboratory studies, surgical approaches, as well as pathological diagnoses were recorded. RESULTS: The series comprised 53 males with testicular GCTs and 74 females with ovarian GCTs. Their median age was 5.8 years old. Palpable mass was the main clinical manifestation of testicular GCTs, while abdominal pain and abdominal distention were the most frequent presenting symptoms of ovarian GCTs. Both computed tomography and magnetic resonance imaging showed a high diagnostic yield. AFP levels were elevated in most malignant GCTs, markedly elevated in yolk sac tumors. All patients were treated surgically. Mature teratoma was the most common type of benign GCTs, while yolk sac tumor was the most common type of malignant GCTs. CONCLUSION: Gonadal GCTs in children have various of pathological types, as well as clinical manifestations. Imaging and laboratory data could be useful for differentiation of malignant from benign tumors. Final diagnosis depends on pathology. Surgical excision of the gonadal GCTs is the prior option. PMID- 28658172 TI - Effect of an electric blanket plus a forced-air warming system for children with postoperative hypothermia: A randomized controlled trial. AB - BACKGROUND: Postoperative hypothermia in children in postanesthesia care unit (PACU) is a well-known serious complication as it increases the risk of blood loss, wound infections, and cardiac arrhythmias. We conducted this prospective randomized controlled trial to evaluate the effect of an electric blanket plus a forced-air warming system on rewarming in children with postoperative hypothermia. METHODS: We recruited 346 children (aged < 3 years) who were admitted to a PACU after surgery and diagnosed with hypothermia between March and August 2016. They were randomly divided into 3 groups: group C (n = 108, rewarmed with only a regular blanket), group E (n = 123, rewarmed with a regular blanket plus an electric blanket), and group EF (n = 115, rewarmed with an electric blanket plus a forced-air warming system). From the beginning of rewarming, the rectal temperature was recorded every 5 minutes for the first half hour, then every 10 minutes up to when the patient left the PACU. The primary outcome was the rewarming time of children (from the beginning of rewarming to recovery of normothermia). The rewarming rate, increase in temperature (compared with the beginning of rewarming), hemodynamics, recovery time, and incidences of adverse effects were recorded. RESULTS: There were no significant differences among the 3 groups in terms of the baseline clinical characteristics, use of narcotic drugs, intraoperative temperature, and hemodynamics (P > .05). Compared with the children in groups C and E, both the heart rate and mean arterial pressure of those in group EF were significantly increased after 10 minutes of arriving at the PACU (P < .05). Children in the EF group had the shortest rewarming time (35.61 +/- 16.45 minutes, P < .001) and highest rewarming efficiency (0.028 +/- 0.001 degrees C/min, P < .001), while there was no evidence of a difference in increased rectal temperature among the 3 groups. Children in the EF group had lower incidences of arrhythmia, shivering, nausea, and vomiting (P < .05). CONCLUSION: The combination of an electric blanket and a forced-air warming system was shown to be an effective rewarming method for children with postoperative hypothermia. PMID- 28658173 TI - Human otoacariasis caused by Amblyomma testudinarium: Diagnosis and management: Case report. AB - RATIONALE: Tick infestation of the external auditory canal (EAC) constitutes <1% of all patients presenting with ear complaints. Consequently, parameters for the diagnosis and management of ticks in the EAC have not been established. PATIENT CONCERNS: We report 2 cases of EAC infestation by Amblyomma testudinarium in 2 female patients, aged 12- and 72 years old. DIAGNOSES INTERVENTIONS AND OUTCOMES: In both patients, otoscopic examination revealed engorged ticks attached to the ear canal. The 12-year-old girl had a narrow EAC, necessitating slight dislodging of the tick to determine if its mouth parts were embedded in the EAC skin. The tick's mouth parts were confirmed to be free, enabling complete removal of the tick. The 72-year-old woman had a wide EAC, enabling tick removal using Hartman's forceps because the tick's mouth parts were confirmed to be free of the skin. Prophylactic tetracycline (200 mg/day) was administered to each patient for 7 days; neither showed any signs of fever or rash. LESSONS: This report describes 2 patients with A testudinarium infestation of the EAC, and proposes a simple, noninvasive protocol for determining if the tick is anchored to the ear canal. PMID- 28658174 TI - Electric bicycle-related injuries presenting to a provincial hospital in China: A retrospective study. AB - The use of electric bicycles (EBs) in China is growing. In the present study, we aimed to characterize the pattern and outcomes of EB-related injuries presenting to a major general hospital in China.This was a retrospective review of EB related injuries presenting to Zhejiang Provincial People's Hospital from 2008 to 2011. Cases were identified from medical records according to diagnosis codes. Data captured included demographics, injury characteristics, and outcomes.A total of 3156 cases were reviewed in the present study. There were 1460 cases of traffic accidents, of which 482 cases were EB-related (32.7%). In addition, most of EB-related cases (44.6%) belonged to the 41- to 60-year-old age group. Median injury severity score was 10. Moreover, 34.9% underwent surgery and 24.7% were admitted to intensive care unit. The median hospitalization cost was 14,269 USD. Fracture (56.5%) was the most frequently diagnosed injury type, and head was the most commonly injured body region (31.1%).EB-related injuries have become a major health concern, making up a sizeable proportion of injuries presenting to the emergency department. Therefore, it is necessary to establish injury prevention and strategies for EB road safety. Implementation of policy such as compulsory helmet use, as well as popularization of EB road safety education should be considered to improve the current situation of EB-related injuries in China. PMID- 28658175 TI - Association between periodontal disease and non-communicable diseases: A 12-year longitudinal health-examinee cohort study in South Korea. AB - The National Health Insurance Service-Health Examinee Cohort during 2002 to 2013 was used to investigate the associations between periodontal disease (PD) and the following non-communicable diseases (NCDs): hypertension, diabetes mellitus, osteoporosis, cerebral infarction, angina pectoris, myocardial infarction, and obesity.Univariate and multivariate logistic regression analyses adjusting for potential confounders during the follow-up period-including age, sex, household income, insurance status, residence area, health status, and comorbidities-were used to estimated odds ratios (ORs) with 95% confidence intervals (CIs) in order to assess the associations between PD and NCDs.We enrolled 200,026 patients with PD and 154,824 subjects with a healthy oral status. Statistically, significant associations were found between PD and the investigated NCDs except for cerebral and myocardial infarction after adjusting for sociodemographic and comorbidity factors (P < .05). In particular, obesity (OR = 1.30, 95% CI = 1.04-1.63, P = .022), osteoporosis (OR = 1.22, 95% CI = 1.18-1.27, P < .001), and angina pectoris (OR = 1.22, 95% CI = 1.17-1.27, P < .001) were significantly and positively associated with PD.This longitudinal cohort study has provided evidence that patients with PD are at increased risk of NCDs. Further studies are required to confirm the reliability of this association and elucidate the role of the inflammatory pathway in periodontitis pathogenesis as a triggering and mediating mechanism. PMID- 28658176 TI - Circulating fibrocytes are involved in inflammation and leukocyte trafficking in neonates with necrotizing enterocolitis. AB - Fibrocytes, ahematopoietic stem cell source of fibroblasts/myofibroblasts, were previously implicated to infiltrate into the intestinal and enhance inflammation.The aims of the present study were to elucidate the role of fibrocytes in necrotizing enterocolitis (NEC) pathogenesis and to explore the mechanisms by which fibrocytes contributed to the inflammatory responses.We investigated circulating and intestinal local fibrocytes from 32 patients with NEC, 8 patients with noninflammatory conditions of the gastrointestinal tract and 12 normal subjects.Significantly higher numbers of circulating fibrocytes were found in the peripheral blood from NEC patients than the controls (P < .01). Numerous fibrocytes were found infiltrating the NEC intestinal mucous membranes. The percentage of fibrocytes to total leukocytes in the NEC inflammatory lesions was significantly increased compared with the percentage in the noninflammatory gastrointestinal tract. The fibrocyte attractant chemokine C-X-C motif chemokine ligand 12 (CXCL12) was significantly increased in the plasma and was detectable in 80% of the peritoneal lavage fluid from NEC patients but not the controls. Furthermore, chemokine expression was increased in fibrocytes infiltrating and trafficking to leukocyte sites. In culture, lipopolysaccharide (LPS) induced a significant increase in the expression of the Toll-like receptor (TLR4) signal, with the upregulation of p38 in both the isolated fibrocytes and macrophages. Similarly, interleukin (IL)-1beta induced increased the upregulation of the IL-6, tumor necrosis factor (TNF)-alpha, and intercellular cell adhesion molecule-1 mRNAs but downregulated ColI in fibrocytes isolated from NEC patients compared with the controls.These findings indicate that circulating fibrocytes are increased in NEC patients and may be recruited to the inflammatory intestinal track, most likely through the CXCR4/CXCL12 axis. These cells may contribute to intestinal inflammation through TLR4 signaling by producing the TNF-alpha and IL 6 cytokines. PMID- 28658177 TI - Short-term microcurrent electrical neuromuscular stimulation to improve muscle function in the elderly: A randomized, double-blinded, sham-controlled clinical trial. AB - BACKGROUND: Microcurrent electrical neuromuscular stimulation (MENS) has been suggested to improve muscle function and restore damaged muscle. However, current evidence is insufficient to determine the effectiveness of this therapy in age dependent muscle weakness. Therefore, a prospective, randomized, double-blinded, sham-controlled clinical trial was designed to evaluate the effects of short-term MENS on muscle function in the elderly. METHODS: A total of 38 healthy elderly participants aged 65 years and above were enrolled and randomly divided into 2 stimulation groups: real or sham MENS group. Real or sham MENS were applied to the 8 anatomical points of the dominant arm and leg during the course of 40 minutes. We performed muscle function tests at baseline and after the intervention: the handgrip strength tests (HGS, kg), the root mean square values (RMS, MUV), and the single leg heel-rise tests (HRT) to determine changes in the strength, activity, and endurance of the elderly muscle, respectively. RESULTS: In the real MENS group, the mean values of the HGS and the number of plantar flexions were significantly increased, but the RMS value of the electromyography signal was significantly decreased after the real intervention (P < .05). However, the sham MENS group showed a significant decrease in the number of plantar flexions and the total time for HRT after the sham stimulation (P < .05). The mean difference in the RMS value was significantly lower, but the number of plantar flexions and the total time for HRT was significantly higher in the real MENS group than in the sham MENS group (P < .05). CONCLUSION: The findings suggest that short-term application of MENS may play a partial role in enhancing physical activities of the elderly, as it can improve some muscle function. PMID- 28658179 TI - Ablative Fractional Laser Resurfacing With Laser-Assisted Delivery of 5 Fluorouracil for the Treatment of Cicatricial Ectropion and Periocular Scarring. AB - PURPOSE: Cicatricial ectropion and periocular scarring can cause significant functional and cosmetic deficits. Surgical treatments can be associated with recicatrization, donor site morbidity, and textural and pigmentary abnormalities. This case series reports on efficacy and safety of a novel nonsurgical approach to treating cicatricial ectropion using ablative fractional laser resurfacing and laser-assisted delivery of 5-fluorouracil. METHODS: A retrospective review was conducted of all patients at a single institution who received >=3 rounds of ablative fractional laser resurfacing with laser-assisted delivery of 5 fluorouracil. Six patients with cicatricial ectropion and periocular scarring secondary to reconstructive surgery, traumatic lacerations, and facial burns were included. Aesthetic and functional improvement were evaluated via fluorescein staining, tear breakup time, external photography, questionnaires gauging dry eye symptoms, and scar appearance. RESULTS: All patients showed functional improvement based on fluorescein staining (mean improvement 6.0 +/- 1.4; p = 0.0007) and other indicators of dry eye. All 4 patients with lagophthalmos improved and 2 showed complete resolution. All patients demonstrated significant cosmetic improvement based on a validated scar assessment questionnaire (mean improvement 37.5 +/- 18.9; p = 0.004), and 5 of 6 patients reported improved satisfaction with scar appearance (mean improvement 19.3 +/- 12.8; p = 0.014). There were no adverse effects reported. CONCLUSIONS: Ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil appears to be a safe and effective modality for treating the functional and aesthetic abnormalities associated with periocular scarring, yielding results that are difficult to attain through surgery alone. Optimal management of cicatricial ectropion and periocular scarring often requires multimodality treatment, and ablative fractional laser resurfacing with laser-assisted delivery of 5-fluorouracil may be considered as part of a comprehensive approach to managing periocular scars. PMID- 28658178 TI - Liver cirrhosis: a risk factor for gallstone disease in chronic hepatitis C patients in China. AB - We investigated the possible link between liver cirrhosis and gallstone risk in chronic hepatitis C (CHC) patients in China.To analyze the association between liver cirrhosis and gallstone development, we compared outcomes of 133 Chinese CHC patients with gallstones and an age-, sex-, and hepatitis C virus RNA level matched control group of 431 CHC patients without gallstones.We found that liver cirrhosis was more prevalent in gallstone patients (40.6%) than in the control group (24.4%). Logistic regression analyses adjusting for demographic features and other gallstone risk factors revealed that liver cirrhosis increased the risk of gallstone development 2-fold (adjusted odds ratio [AOR]: 2.122; 95% confidence interval [CI]: 1.408-3.198). Moreover, multivariate analyses comparing the risk of gallstone development in liver cirrhosis patients with decompensated or compensated liver cirrhosis yielded an estimated AOR (95% CI) of 2.869 (1.277 6.450) in patients with decompensated liver cirrhosis. Gallstone risk also increased significantly with older age (>60 years) (AOR: 2.019; 95% CI: 1.017 4.009).Liver cirrhosis significantly correlates with increased risk of gallstone development in CHC patients in China. Decompensated liver cirrhosis and older age further heighten this risk in patients diagnosed with hepatitis C-related cirrhosis. PMID- 28658180 TI - Morphometric Analysis of the Orbital Process of the Palatine Bone and its Relationship to Endoscopic Orbital Apex Surgery. AB - BACKGROUND: Endoscopic approaches to the orbit improve the ability to directly access apical lesions while minimizing manipulation of normal structures. Inferomedial orbital access is limited by the orbital process of the palatine bone (OPPB) which prevents dissection and retraction in the inferolateral vector. OBJECTIVE: The objective of this study was to examine the morphometric characteristics of the OPPB and quantify the benefit of complete resection to surgical access. METHODS: Morphometric osteologic measurements of the OPPB were performed in 59 human skulls. A radius subtended by the OPPB was calculated to generate a hemispheric dissection corridor achievable by complete resection of the OPPB. Cadaveric and live surgical dissections were then performed on 15 orbits to develop discreet endoscopic surgical landmarks which could be used to both identify the OPPB and verify complete resection. RESULTS: The mean(+/- SD) radius of the OPPB was 0.47 +/- 0.28 cm. Complete OPPB resection provided an additional 0.36 +/- 0.42 cm of surgical exposure within the inferomedial apex. Relative to the Caucasian (n = 27) skulls, the radii in the Asian (n = 27) and African (n = 5) skulls were significantly smaller (p < 0.001 and p = 0.02, respectively). CONCLUSION: The OPPB significantly limits surgical access to the inferomedial orbital apex during endoscopic approaches. Complete surgical resection of the OPPB improves surgical exposure facilitating retraction of the inferior rectus muscle and circumferential dissection of lesions within this space. Knowledge of the morphology and clinical relevance of this structure provides an opportunity to improve surgical exposure for relevant pathologic assessment and optimize endoscopic surgical outcomes. PMID- 28658181 TI - A Prospective, Randomized Comparison of Lower Eyelid Retraction Repair With Autologous Auricular Cartilage, Bovine Acellular Dermal Matrix (Surgimend), and Porcine Acellular Dermal Matrix (Enduragen) Spacer Grafts. AB - PURPOSE: To compare outcomes of lower eyelid retraction repair with 3 types of spacer grafts: autologous auricular cartilage, bovine acellular dermal matrix (Surgimend, Integra, Plainsboro, NJ), porcine acellular dermal matrix (Enduragen, Stryker, Kalamazoo, MI). METHODS: A prospective, randomized clinical trial was conducted in patients undergoing lower eyelid retraction repair with spacer graft. Subjects received autologous auricular cartilage, bovine acellular dermal matrix, or porcine acellular dermal matrix between June 2015 and July 2016. Patient demographics, margin to reflex distance 2, conjunctival injection, eyelid swelling, tearing, discomfort, itching, and complications were recorded preoperatively and at postoperative week 1, month 1, month 3, and month 6. RESULTS: Of the 49 randomized lower eyelids (39 patients), 42 eyelids (32 patients) completed the study. The preoperative margin to reflex distance 2, conjunctival injection, eyelid swelling, tearing, discomfort, and itching showed no statistical difference. Postoperative week 1 swelling was statistically significantly higher in auricular cartilage, followed by bovine acellular dermal matrix, then porcine acellular dermal matrix (p = 0.04). The mean postoperative month 6 margin to reflex distance 2 trended toward a better outcome from auricular cartilage over bovine acellular dermal matrix (p = 0.029), but after p was adjusted for multiple pairwise comparisons, this was no longer statistically significant (p = 0.088). All other postoperative 6-month measurements showed no statistical difference. CONCLUSIONS: Among patients randomized to 3 types of spacer grafts for lower eyelid retraction repair, outcomes were not statistically significant different when the 3 groups were compared. PMID- 28658182 TI - Using Kotter's Change Framework to Implement and Sustain Multiple Complementary ICU Initiatives. AB - This article describes the planning, implementation, and outcomes of 2 complementary quality initiatives, bedside handoff and nurse-initiated interdisciplinary bedside rounds, in a 24-bed medical/surgical intensive care unit. Systematic approaches such as Kotter's change model and unit-based champions were used to redesign care processes and standardize daily communication and workflows. Active partnership with the patient and the family during these changes promoted a strong intensive care unit culture of patient- and family-centered care. PMID- 28658183 TI - Chasing Zero: Increasing Infection Control Compliance on an Inpatient Cystic Fibrosis Unit. AB - Patients with cystic fibrosis have increased risk of pulmonary infections, and reducing spread of microorganisms is critical. To improve hospital-staff adherence to infection control guidelines, we implemented brightly colored Safe Zone floor decals, staff compliance contracts, and an infection control in service video. Audits of staff adherence conducted pre and postintervention demonstrated an increased and sustainable improvement among each group (P < .05). These effective measures may be implemented to improve infection control compliance elsewhere. PMID- 28658184 TI - Improving Compliance in Obtaining Daily Weights in a Large Academic Children's Hospital. AB - Noncompliance in obtaining daily weights leads to delays in establishing treatment and discharge plans in pediatric populations. An inpatient gastrointestinal and endocrine nursing unit aimed to increase compliance of obtaining daily weights from baseline of 38% to 80%. The time daily weights were obtained was changed from 8 AM to an interval of time 4 PM to 6 PM. The compliance rate increased to 96% and has been sustained at an average of 94% over 24 months. This report describes a low-risk intervention that took minimal effort to implement but yielded high results to exceed the goal. PMID- 28658185 TI - Using Local Data to Improve Care and Collaborative Practice: Insights From a Qualitative Study. AB - A qualitative study was undertaken to explore the experiences and perceptions of project leaders, clinicians, managers, and mentors associated with the implementation of a strategy aimed at enhancing clinicians' ability to use data to guide quality improvement projects. Our study findings elucidated the value and benefits including (1) using data to understand local context and move forward and (2) improving care and engaging in collaborative professional practice. PMID- 28658186 TI - Impact of The Daily Plan on Length of Stay and Readmission. AB - The Veterans Health Administration implemented The Daily Plan (TDP) to improve patient safety. We compared length of stay and readmission between intervention and control units. Length of stay decreased for both groups. Readmission rates increased for controls (21.3%-25.0%, P = .02) and barely changed for TDP units (21.7%-22.5%, P = .37). Although there were no efficiency improvements, TDP's ultimate goal was safety. Not all patient safety actions improve efficiency; nonetheless, their value continues. PMID- 28658187 TI - Impact of No-Interruption Intervention on Safety and Efficiency. PMID- 28658188 TI - Noise Reduction in Progressive Care Units. AB - Uncontrolled noise in the hospital setting can have a negative physiological and psychological impact on patients and nurses. To reduce unit noise levels and create a quiet patient and nurse experience, an evidence-based practice project was conducted in 4 progressive care units in a community hospital. The Quiet Time Bundle implementation improved patient satisfaction and patient and nurse perceptions of noise even though the decrease in noise levels may not be discernible. PMID- 28658189 TI - Impact of a Restraint Management Bundle on Restraint Use in an Intensive Care Unit. AB - Restraint use has been linked to longer lengths of stay and other undesirable outcomes. This evidence-based project explored the impact of a restraint management bundle on restraint use, quality, and safety outcomes. Results indicated that the proportion of intensive care unit patients restrained decreased significantly (24.3% vs 20.9%) following program implementation. Project results suggest that the restraint management bundle may provide a framework for guiding the process to reduce restraint use, minimize harm, and improve patient safety. PMID- 28658190 TI - Factors Associated With Barcode Medication Administration Technology That Contribute to Patient Safety: An Integrative Review. AB - In an effort to prevent medication errors, barcode medication administration technology has been implemented in many health care organizations. An integrative review was conducted to understand the effect of barcode medication administration technology on medication errors, and characteristics of use demonstrated by nurses contribute to medication safety. Addressing poor system use may support improved patient safety through the reduction of medication administration errors. PMID- 28658191 TI - Predictors of Second Medical Emergency Team Activation Within 24 Hours of Index Event. AB - This study explored the trajectory of patients who remained on a general unit after medical emergency team activation. Of those who had a second activation within 24 hours, 80% occurred within 12 hours of the baseline activation. Chest pain and recent intensive care unit discharge were associated with having a second activation. There were statistically, not clinically, significant associations between mean vital signs and second activations; however, the patterns of change may be clinically useful. PMID- 28658192 TI - Article Summaries for July-August 2017 Psychosomatic Medicine, Volume 79, Issue 6. PMID- 28658193 TI - Genetic and Environmental Influences on Sleep, Pain, and Depression Symptoms in a Community Sample of Twins. AB - OBJECTIVE: We used quantitative genetic methods to evaluate whether sleep quality, pain, and depression symptoms share a common genetic diathesis, to estimate the genetic and environmental sources of covariance among these symptoms, and to test for possible causal relationships. METHODS: A community sample of 400 twins from the University of Washington Twin Registry completed standardized self-report questionnaires. We used biometric modeling to assess genetic and environmental contribution to the association between sleep quality measured by the Pittsburgh Sleep Quality Index, pain measured by the Brief Pain Inventory, and depression symptoms measured by the Brief Symptom Inventory. Trivariate Cholesky structural equation models were used to decompose correlations among the phenotypes. RESULTS: Heritability was estimated at 37% (95% confidence interval = 20%-51%) for sleep quality, 25% (9%-41%) for pain, and 39% (22%-53%) for depression. Nonshared environmental influences accounted for the remaining variance. The genetic correlation between sleep quality and pain had an rg value of .69 (95% confidence interval [CI] = 0.33-0.97), rg value of .56 (95% CI = 0.55-0.98) between pain and depression, and rg value of .61 (95% CI = 0.44-0.88) between depression and sleep quality. Nonshared environmental overlap was present between pain and sleep quality as well as depression and sleep quality. CONCLUSIONS: The link between sleep quality, pain, and depression was primarily explained by shared genetic influences. The genetic factors influencing sleep quality and pain were highly correlated even when accounting for depression. Findings support the hypothesis of a genetic link between depression and pain as well as potential causality for the association of sleep quality with pain and depression. PMID- 28658195 TI - Noncompletion of Nighttime Ambulatory Blood Pressure Monitoring: Potential for Selection Bias in Analyses of Nondipping. PMID- 28658194 TI - Posttraumatic Stress Disorder, Orientation to Pain, and Pain Perception in Ex Prisoners of War Who Underwent Torture. AB - OBJECTIVE: Studies suggest that torture survivors often experience long-term chronic pain and increased pain perception. However, it is unclear whether the actual experience of torture or rather the subsequent posttraumatic stress disorder (PTSD) explains these pain problems. Furthermore, although catastrophic and fearful orientations to pain have been suggested to play a significant role in the association between trauma and pain, the underlying mechanisms remain unclear. This study examined whether chronic pain and pain perception among torture survivors are associated with torture experience or PTSD and whether catastrophic and fearful orientations mediate or moderate these associations. METHODS: Fifty-nine ex-prisoners of war who underwent torture and 44 matched veterans participated in this study. Pain perception was evaluated by assessing pain threshold and reactivity to experimental suprathreshold noxious stimuli. Participants completed self-administered questionnaires assessing PTSD, chronic pain, pain catastrophizing, and fear of pain. RESULTS: Although chronic pain was associated with PTSD (0.44 < beta < 0.49, p < .002), increased pain perception was correlated with torture (0.33 < beta < 0.65, p < .05). Pain catastrophizing was found to mediate the association between PTSD and chronic pain (beta = 0.18 and 0.19, respectively; p < .05). Fear of pain moderated the association between torture and pain perception (beta = 0.41 and 0.42, respectively; p < .017). CONCLUSIONS: The findings suggest that chronic pain is contingent upon the psychological toll of torture, that is, PTSD. This study also indicates that PTSD exacerbates catastrophic orientation, which in turn may amplify chronic pain. Reactivity to experimental noxious stimuli was related to previous experiences of torture, which enhances perceived pain intensity when interacting with a fearful pain orientation. These findings highlight the significance of orientation to bodily experiences after trauma. PMID- 28658196 TI - Late-Term Gestation Is Associated With Improved Survival in Neonates With Congenital Heart Disease Following Postoperative Extracorporeal Life Support. AB - OBJECTIVE: Several population-based studies have shown that gestational age 39-40 weeks at birth is associated with superior outcomes in various pediatric settings. A high proportion of births for neonates with congenital heart disease occur before 39 weeks. We aimed to assess the influence of late-term gestation (39-40 wk) on survival in neonates requiring extracorporeal life support following surgery for congenital heart disease. DESIGN: Retrospective cohort study. SETTING: The Royal Children's Hospital, Melbourne, Australia. PATIENTS: Neonates requiring extracorporeal life support after cardiac surgery for congenital heart disease. MEASUREMENTS AND MAIN RESULTS: From 2005 to 2014, 110 neonates (10.5% of neonates undergoing cardiac surgery) required extracorporeal life support after cardiac surgery. Indications were failure to separate from cardiopulmonary bypass in 40 (36%), extracorporeal cardiopulmonary resuscitation in 48 (44%), progressive low cardiac output in 15 (14%), and other reasons in seven (6%). Extracorporeal life support duration was 94 hours (interquartile range, 53-135), and 54 (49%) underwent single ventricle repair. Gestation at birth (n [%]) was as follows: less than 37 weeks, 19 (17%); 37-38 weeks, 38 (35%); 39-40 weeks, 50 (45%); 41 weeks or more, 3 (3%). By multivariable analysis (controlling for age, era of extracorporeal life support 2005-2009 vs 2010-2014, single ventricle status and acute renal failure), gestational age of 39-40 weeks was associated with the lowest odds for intensive care mortality: using less than 37 weeks as referent, the adjusted odds ratio (95% CI) for 37-38 weeks was 0.41 (0.12-1.33); for 39-40 weeks, 0.27 (0.08-0.84); and for 41 weeks or more, 1.06 (0.07-14.7). Similar association was also seen in a subcohort of study neonates (n = 66) who were commenced on extracorporeal life support after admission to intensive care: using less than 37 weeks as referent, the adjusted odds ratio (95% CI) for 37-38 weeks was 0.52 (0.10-2.80) and for 39-40 weeks, 0.15 (0.03 0.81). CONCLUSIONS: In this cohort of neonates requiring extracorporeal life support following cardiac surgery, 39-40 weeks of gestation at birth is associated with the best survival. The additional maturity gained by reaching a gestation of at least 39 weeks is likely to confer a survival advantage in this high-risk cohort. PMID- 28658197 TI - Hydrocortisone Therapy in Catecholamine-Resistant Pediatric Septic Shock: A Pragmatic Analysis of Clinician Practice and Association With Outcomes. AB - OBJECTIVES: The 2012 Surviving Sepsis Campaign pediatric guidelines recommend stress dose hydrocortisone in children experiencing catecholamine-dependent septic shock with suspected or proven absolute adrenal insufficiency. We evaluated whether stress dose hydrocortisone therapy in children with catecholamine dependent septic shock correlated with random serum total cortisol levels and was associated with improved outcomes. DESIGN: Retrospective cohort study. SETTING: Non-cardiac PICU. PATIENTS: Critically ill children (1 mo to 18 yr) admitted between January 1, 2013, and December 31, 2013, with catecholamine dependent septic shock who had random serum total cortisol levels measured prior to potential stress dose hydrocortisone therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was dichotomized to random serum total cortisol less than 18 mcg/dL and greater than or equal to 18 mcg/dL. Associations of stress dose hydrocortisone with outcomes: PICU mortality, PICU and hospital length of stay, ventilator-free days, and vasopressor-free days were examined. Seventy children with catecholamine-dependent septic shock and measured random serum total cortisol levels were eligible (16% PICU mortality). Although 43% (30/70) had random serum total cortisol less than 18 MUg/dL, 60% (42/70) received stress dose hydrocortisone. Children with random serum total cortisol less than 18 MUg/dL had lower severity of illness and lower Vasopressor Inotrope Scores than those with random serum total cortisol greater than or equal to 18 MUg/dL (all p < 0.05). Children with stress dose hydrocortisone had higher severity of illness and PICU mortality than those without stress dose hydrocortisone (all p < 0.05). Mean random serum total cortisol levels were similar in children with and without stress dose hydrocortisone (21.1 vs 18.7 MUg/dL; p = 0.69). In children with random serum total cortisol less than 18 MUg/dL, stress dose hydrocortisone was associated with greater PICU and hospital length of stay and fewer ventilator free days (all p < 0.05). In children with random serum total cortisol greater than 18 MUg/dL, stress dose hydrocortisone was associated with greater PICU mortality and fewer ventilator-free days and vasopressor-free days (all p < 0.05). CONCLUSIONS: Stress dose hydrocortisone therapy in children with catecholamine-dependent septic shock correlated more with severity of illness than random serum total cortisol levels and was associated with worse outcomes, irrespective of random serum total cortisol levels. PMID- 28658198 TI - Professional Responsibility, Consensus, and Conflict: A Survey of Physician Decisions for the Chronically Critically Ill in Neonatal and Pediatric Intensive Care Units. AB - OBJECTIVE: To describe neonatologist and pediatric intensivist attitudes and practices relevant to high-stakes decisions for children with chronic critical illness, with particular attention to physician perception of professional duty to seek treatment team consensus and to disclose team conflict. DESIGN: Self administered online survey. SETTING: U.S. neonatal ICUs and PICUs. SUBJECTS: Neonatologists and pediatric intensivists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We received 652 responses (333 neonatologists, denominator unknown; 319 of 1,290 pediatric intensivists). When asked about guiding a decision for tracheostomy in a chronically critically ill infant, only 41.7% of physicians indicated professional responsibility to seek a consensus decision, but 73.3% reported, in practice, that they would seek consensus and make a consensus-based recommendation; the second most common practice (15.5%) was to defer to families without making recommendations. When presented with conflict among the treatment team, 63% of physicians indicated a responsibility to be transparent about the decision-making process and reported matching practices. Neonatologists more frequently reported a responsibility to give decision making fully over to families; intensivists were more likely to seek out consensus among the treatment team. CONCLUSIONS: ICU physicians do not agree about their responsibilities when approaching difficult decisions for chronically critically ill children. Although most physicians feel a professional responsibility to provide personal recommendations or defer to families, most physicians report offering consensus recommendations. Nearly all physicians embrace a sense of responsibility to disclose disagreement to families. More research is needed to understand physician responsibilities for making recommendations in the care of chronically critically ill children. PMID- 28658199 TI - Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation. AB - BACKGROUND: Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. METHODS: Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens, and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. RESULTS: One thousand four hundred eleven recipients were included (54.4% AA) with 39 521 concentrations used to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs versus non-AAs (39.9 +/- 19.8 % vs 34.8 +/- 15.8% P < 0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (adjusted hazard ratio, 1.20, 1.13-1.28; P < 0.001) and the risk of graft loss by 30% (adjusted hazard ratio, 1.30, 1.23-1.37; P < 0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. CONCLUSIONS: These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients. PMID- 28658200 TI - Critical Ischemia Times and the Effect of Novel Preservation Solutions HTK-N and TiProtec on Tissues of a Vascularized Tissue Isograft. AB - BACKGROUND: We herein investigate critical ischemia times and the effect of novel preservation solutions such as new histidine-tryptophan-ketoglutarate (HTK-N) and TiProtec on the individual tissues of a rat limb isograft. METHODS: Orthotopic hind-limb transplantations were performed in male Lewis rats after 2 hours, 6 hours, or 10 hours of cold ischemia (CI). Limbs were flushed and stored in HTK-N, TiProtec, HTK, or saline solution. Muscle, nerve, vessel, skin, and bone samples were procured on day 10 for histology, immunohistochemistry, confocal and electron microscopy, and quantitative real-time polymerase chain reaction analysis. RESULTS: Histomorphology of the muscle showed a mainly perivascular inflammatory infiltrate, fibrotic degeneration, and neovascularization after 6 hours and 10 hours of CI. However, centrally aligned nuclei observed in muscle fibers suggest for muscle regeneration in these samples. In addition to Wallerian degeneration, nerve injury was significantly aggravated (P = 0.032) after prolonged CI. Proinflammatory and regulatory cytokines were most significantly upregulated after 2-hour CI. Our data suggest no superiority of novel perfusates HTK-N and TiProtec in terms of tissue preservation, compared with HTK and saline. CONCLUSIONS: Limiting CI time for less than 6 hours is the most significant factor to reduce tissue damage in vascularized tissue transplantation. Signs of muscle regeneration give rise that ischemic muscle damage in limb transplantation might be reversible to a certain extent. PMID- 28658201 TI - Targeted Next-Generation Sequencing in Brazilian Children With Nephrotic Syndrome Submitted to Renal Transplant. AB - BACKGROUND: The aims of this study were to identify the genetic mutations profile in Brazilian children with nephrotic syndrome (NS) and to determine a genotype phenotype correlation in this disease. METHODS: Next-generation sequencing and mutation analysis were performed on 24 genes related to NS in a cross-sectional study involving 95 children who underwent kidney transplantation due to NS, excluding congenital cases. RESULTS: A total of 149 variants were identified in 22 of 24 sequenced genes. The mutations were classified as pathogenic, likely pathogenic, likely benign and benign per the chance of causing the disease. NPHS2 was the most common mutated gene. We identified 8 (8.4%) patients with hereditary NS and 5 (5%) patients with probably genetically caused NS. COL4A3-5 variants were found as well, but it is not clear whether they should be considered isolated FSGS or simply a misdiagnosed type of the Alport spectrum. Considering the clinical results, hereditary NS patients presented a tendency to early disease onset when compared with the other groups (P = 0.06) and time to end stage renal disease (ESRD) was longer in this group (P = 0.03). No patients from hereditary NS group had NS recurrence after transplantation. CONCLUSIONS: This is the first study in children with steroid-resistant NS who underwent kidney transplantation using next-generation sequencing. Considering our results, we believe this study has shed some light to the uncertainties of genotype-phenotype correlation in NS, where several genes cooperate to produce or even to modify the course of the disease. PMID- 28658202 TI - Pharmacokinetics and Clinical Outcomes of Generic Tacrolimus (Hexal) Versus Branded Tacrolimus in De Novo Kidney Transplant Patients: A Multicenter, Randomized Trial. AB - BACKGROUND: Scrupulous comparison of the pharmacokinetic and clinical characteristics of generic tacrolimus formulations versus the reference drug (Prograf) is essential. The pharmacokinetics of the Tacrolimus Hexal (TacHexal) formulation is similar to Prograf in stable renal transplant patients, but data in de novo patients are lacking. METHODS: De novo kidney transplant patients were randomized to generic tacrolimus (TacHexal) or Prograf in a 6-month open-label study. RESULTS: The primary end point, the dose-normalized area under the curve0 12h at month 1 posttransplant, was similar with TacHexal or Prograf; back transformed geometric means of adjusted log-transformed values (analysis of variance) were 18.99 ng.h.L (TacHexal) and 20.48 ng.h.L (Prograf) (ratio, 1.08; 90% confidence interval, 0.84-1.38; P = 0.605). The dose-normalized peak concentration geometric means at month 1 was also comparable between treatments (ratio, 1.16; 90% confidence interval, 0.88-1.54; P = 0.377). There were no relevant differences in other pharmacokinetic parameters at month 1 or in area under the curve0-4h and trough concentration when measured at months 3 and 6. The adjusted change in mean estimated glomerular filtration rate from baseline to month 6 (Nankivell) was noninferior for TacHexal versus Prograf using observed values (47.7 vs 38.6 mL/min per 1.73 m, P < 0.001) and was superior based on observed values (P = 0.044) but not using last observation-carried forward method. Rates of biopsy-proven acute rejection (5.7% vs 7.9%), adverse events, and serious adverse events were similar with TacHexal or Prograf. CONCLUSION: Tacrolimus pharmacokinetics is similar with TacHexal and Prograf early after kidney transplantation. Efficacy and safety in this limited data set were comparable, with at least equivalent graft function under TacHexal. PMID- 28658203 TI - Biosensors: Enhancing the Natural Ability to Sense and Their Dependence on Bioinformatics. AB - Single cells, as part of their evolution, acquired the ability to sense their internal and external environment, move to or away from a particular environment, the latter depending on the appropriate integration of the sensory input with motor ability. Clearly, the ability to sense stimuli must be a rapid process and one that has been selected upon for survival over long periods of time in concert with environmental challenges. Interestingly, various differing sensory inputs have their own receptors to respond to a specific stimulus. PMID- 28658204 TI - Tracing the origins of relapse in acute myeloid leukaemia to stem cells. AB - In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse. PMID- 28658206 TI - Corrigendum: Mineral supply for sustainable development requires resource governance. AB - This corrects the article DOI: 10.1038/nature21359. PMID- 28658207 TI - Climate change drives expansion of Antarctic ice-free habitat. AB - Antarctic terrestrial biodiversity occurs almost exclusively in ice-free areas that cover less than 1% of the continent. Climate change will alter the extent and configuration of ice-free areas, yet the distribution and severity of these effects remain unclear. Here we quantify the impact of twenty-first century climate change on ice-free areas under two Intergovernmental Panel on Climate Change (IPCC) climate forcing scenarios using temperature-index melt modelling. Under the strongest forcing scenario, ice-free areas could expand by over 17,000 km2 by the end of the century, close to a 25% increase. Most of this expansion will occur in the Antarctic Peninsula, where a threefold increase in ice-free area could drastically change the availability and connectivity of biodiversity habitat. Isolated ice-free areas will coalesce, and while the effects on biodiversity are uncertain, we hypothesize that they could eventually lead to increasing regional-scale biotic homogenization, the extinction of less competitive species and the spread of invasive species. PMID- 28658205 TI - mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. AB - Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program. PMID- 28658210 TI - Cancer genomics: Less is more in the hunt for driver mutations. PMID- 28658208 TI - Recurrent and functional regulatory mutations in breast cancer. AB - Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients. PMID- 28658213 TI - Maximum human lifespan may increase to 125 years. PMID- 28658209 TI - Fine-mapping inflammatory bowel disease loci to single-variant resolution. AB - Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms. PMID- 28658211 TI - Electron cryo-microscopy structure of the mechanotransduction channel NOMPC. AB - Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells. How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the bacterial MscL channel and certain eukaryotic potassium channels. The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviours such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans, Drosophila and zebrafish. NOMPC is the founding member of the TRPN subfamily, and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton. Thus, a goal of studying NOMPC is to reveal the underlying mechanism of force-induced gating, which could serve as a paradigm of the tether model. NOMPC fulfils all the criteria that apply to mechanotransduction channels and has 29 ankyrin repeats, the largest number among TRP channels. A key question is how the long ankyrin repeat domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of Drosophila NOMPC determined by single-particle electron cryo-microscopy. Structural analysis suggests that the ankyrin repeat domain of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel. The NOMPC architecture underscores the basis of translating mechanical force into an electrical signal within a cell. PMID- 28658214 TI - Contesting the evidence for limited human lifespan. PMID- 28658212 TI - RNase III nucleases from diverse kingdoms serve as antiviral effectors. AB - In contrast to the DNA-based viruses in prokaryotes, the emergence of eukaryotes provided the necessary compartmentalization and membranous environment for RNA viruses to flourish, creating the need for an RNA-targeting antiviral system. Present day eukaryotes employ at least two main defence strategies that emerged as a result of this viral shift, namely antiviral RNA interference and the interferon system. Here we demonstrate that Drosha and related RNase III ribonucleases from all three domains of life also elicit a unique RNA-targeting antiviral activity. Systemic evolution of ligands by exponential enrichment of this class of proteins illustrates the recognition of unbranched RNA stem loops. Biochemical analyses reveal that, in this context, Drosha functions as an antiviral clamp, conferring steric hindrance on the RNA-dependent RNA polymerases of diverse positive-stranded RNA viruses. We present evidence for cytoplasmic translocation of RNase III nucleases in response to virus in diverse eukaryotes including plants, arthropods, fish, and mammals. These data implicate RNase III recognition of viral RNA as an antiviral defence that is independent of, and possibly predates, other known eukaryotic antiviral systems. PMID- 28658215 TI - Dong et al. reply. PMID- 28658216 TI - Metastasis: Lymphatic detours for cancer. PMID- 28658217 TI - Taxonomy: naming algae, fungi, plants. PMID- 28658218 TI - Taxonomy: swallow the costly medicine. PMID- 28658219 TI - Dong et al. reply. PMID- 28658222 TI - Corrigendum: Dermatologist-level classification of skin cancer with deep neural networks. AB - This corrects the article DOI: 10.1038/nature21056. PMID- 28658224 TI - Optical physics: A larger quantum alphabet. PMID- 28658220 TI - Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine. AB - Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress. Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear. Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches. Injectable lymphatic tracers have been developed, but their limited diffusion precludes whole-body imaging at visceral sites. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer. Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis. PMID- 28658225 TI - Making waves in a photoactive polymer film. AB - Oscillating materials that adapt their shapes in response to external stimuli are of interest for emerging applications in medicine and robotics. For example, liquid-crystal networks can be programmed to undergo stimulus-induced deformations in various geometries, including in response to light. Azobenzene molecules are often incorporated into liquid-crystal polymer films to make them photoresponsive; however, in most cases only the bending responses of these films have been studied, and relaxation after photo-isomerization is rather slow. Modifying the core or adding substituents to the azobenzene moiety can lead to marked changes in photophysical and photochemical properties, providing an opportunity to circumvent the use of a complex set-up that involves multiple light sources, lenses or mirrors. Here, by incorporating azobenzene derivatives with fast cis-to-trans thermal relaxation into liquid-crystal networks, we generate photoactive polymer films that exhibit continuous, directional, macroscopic mechanical waves under constant light illumination, with a feedback loop that is driven by self-shadowing. We explain the mechanism of wave generation using a theoretical model and numerical simulations, which show good qualitative agreement with our experiments. We also demonstrate the potential application of our photoactive films in light-driven locomotion and self-cleaning surfaces, and anticipate further applications in fields such as photomechanical energy harvesting and miniaturized transport. PMID- 28658226 TI - Physical chemistry: The fingerprints of reaction mechanisms. PMID- 28658227 TI - Taxonomy: the IUBS responds. PMID- 28658228 TI - On-chip generation of high-dimensional entangled quantum states and their coherent control. AB - Optical quantum states based on entangled photons are essential for solving questions in fundamental physics and are at the heart of quantum information science. Specifically, the realization of high-dimensional states (D-level quantum systems, that is, qudits, with D > 2) and their control are necessary for fundamental investigations of quantum mechanics, for increasing the sensitivity of quantum imaging schemes, for improving the robustness and key rate of quantum communication protocols, for enabling a richer variety of quantum simulations, and for achieving more efficient and error-tolerant quantum computation. Integrated photonics has recently become a leading platform for the compact, cost efficient, and stable generation and processing of non-classical optical states. However, so far, integrated entangled quantum sources have been limited to qubits (D = 2). Here we demonstrate on-chip generation of entangled qudit states, where the photons are created in a coherent superposition of multiple high-purity frequency modes. In particular, we confirm the realization of a quantum system with at least one hundred dimensions, formed by two entangled qudits with D = 10. Furthermore, using state-of-the-art, yet off-the-shelf telecommunications components, we introduce a coherent manipulation platform with which to control frequency-entangled states, capable of performing deterministic high-dimensional gate operations. We validate this platform by measuring Bell inequality violations and performing quantum state tomography. Our work enables the generation and processing of high-dimensional quantum states in a single spatial mode. PMID- 28658229 TI - The architecture of structured DNA. PMID- 28658230 TI - Many possible maximum lifespan trajectories. PMID- 28658231 TI - Dong et al. reply. PMID- 28658232 TI - Developing countries: Growing threat of urban waste dumps. PMID- 28658233 TI - Dong et al. reply. PMID- 28658234 TI - Corrigendum: CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. AB - This corrects the article DOI: 10.1038/nature21710. PMID- 28658235 TI - Is there evidence for a limit to human lifespan? PMID- 28658236 TI - Bibliometrics: An obituary for the impact factor. PMID- 28658237 TI - Clean energy: 'Flammable ice' - extract with caution. PMID- 28658239 TI - Questionable evidence for a limit to human lifespan. PMID- 28658240 TI - Dong et al. reply. PMID- 28658242 TI - Taxonomy: retain scientific autonomy. PMID- 28658241 TI - Materials science: A light-fuelled wave machine. PMID- 28658243 TI - Taxonomy: use the red list as a registry. PMID- 28658246 TI - Taxonomy: avoid extra bureaucracy. PMID- 28658247 TI - Optimal structure of metaplasticity for adaptive learning. AB - Learning from reward feedback in a changing environment requires a high degree of adaptability, yet the precise estimation of reward information demands slow updates. In the framework of estimating reward probability, here we investigated how this tradeoff between adaptability and precision can be mitigated via metaplasticity, i.e. synaptic changes that do not always alter synaptic efficacy. Using the mean-field and Monte Carlo simulations we identified 'superior' metaplastic models that can substantially overcome the adaptability-precision tradeoff. These models can achieve both adaptability and precision by forming two separate sets of meta-states: reservoirs and buffers. Synapses in reservoir meta states do not change their efficacy upon reward feedback, whereas those in buffer meta-states can change their efficacy. Rapid changes in efficacy are limited to synapses occupying buffers, creating a bottleneck that reduces noise without significantly decreasing adaptability. In contrast, more-populated reservoirs can generate a strong signal without manifesting any observable plasticity. By comparing the behavior of our model and a few competing models during a dynamic probability estimation task, we found that superior metaplastic models perform close to optimally for a wider range of model parameters. Finally, we found that metaplastic models are robust to changes in model parameters and that metaplastic transitions are crucial for adaptive learning since replacing them with graded plastic transitions (transitions that change synaptic efficacy) reduces the ability to overcome the adaptability-precision tradeoff. Overall, our results suggest that ubiquitous unreliability of synaptic changes evinces metaplasticity that can provide a robust mechanism for mitigating the tradeoff between adaptability and precision and thus adaptive learning. PMID- 28658248 TI - A systematic approach to estimate the distribution and total abundance of British mammals. AB - Robust policy decisions regarding the protection and management of terrestrial mammals require knowledge of where species are and in what numbers. The last comprehensive review, presenting absolute estimates at a national scale, was published nearly 20 years ago and was largely based on expert opinion. We investigated and propose a systematic data driven approach combing publically available occurrence data with published density estimates to predict species distribution maps and derive total abundance figures for all terrestrial mammals inhabiting Britain. Our findings suggest that the methodology has potential; generally producing plausible predictions consistent with existing information. However, inconsistencies in the availability and recording of data impact the certainty of this output limiting its current application for policy. Restrictions on access and use of occurrence data at a local level produces "data deserts" for which models cannot compensate. This leads to gaps in spatial distribution of species and consequently underestimates abundance. For many species the limited number of geo-referenced densities hampered the extrapolation from habitat suitability to absolute abundance. Even for well-studied species, further density estimates are required. Many density estimates used were pre-1995 and therefore the derived abundance should not be considered a current estimate. To maximise a systematic approach in the future we make the following recommendations: To mitigate the attitudes of a minority of local data providers occurrence records must be submitted to national surveys such as the Mammal Society's Mammal Tracker.Studies are required to estimate density for common species and in areas of low or no abundance.To ensure such studies can be collated and used efficiently we propose a standardised approach reporting density estimates based on the 1km resolution British National Grid, or habitat representative of the 1km square, with digital maps to accompany publications. PMID- 28658250 TI - Estimating the prevalence of food risk increasing behaviours in UK kitchens. AB - Foodborne disease poses a serious threat to public health. In the UK, half a million cases are linked to known pathogens and more than half of all outbreaks are associated with catering establishments. The UK Food Standards Agency (FSA) has initiated the UK Food Hygiene Rating Scheme in which commercial food establishments are inspected and scored with the results made public. In this study we investigate the prevalence of food risk increasing behaviours among chefs, catering students and the public. Given the incentive for respondents to misreport when asked about illegal or illicit behaviours we employed a Randomised Response Technique designed to elicit more accurate prevalence rates of such behaviours. We found 14% of the public not always hand-washing immediately after handling raw meat, poultry or fish; 32% of chefs and catering students had worked within 48 hours of suffering from diarrhoea or vomiting. 22% of the public admitted having served meat "on the turn" and 33% of chefs and catering students admitted working in kitchens where such meat was served; 12% of the public and 16% of chefs and catering students admitted having served chicken at a barbeque when not totally sure it was fully cooked. Chefs in fine-dining establishment were less likely to wash their hands after handling meat and fish and those who worked in award winning restaurants were more likely to have returned to work within 48 hours of suffering from diarrhoea and vomiting. We found no correlation between the price of a meal in an establishment, nor its Food Hygiene Rating Score, and the likelihood of any of the food malpractices occurring. PMID- 28658249 TI - Similar white matter changes in schizophrenia and bipolar disorder: A tract-based spatial statistics study. AB - Several strands of evidence reported a significant overlapping, in terms of clinical symptoms, epidemiology and treatment response, between the two major psychotic disorders-Schizophrenia (SCZ) and Bipolar Disorder (BD). Nevertheless, the shared neurobiological correlates of these two disorders are far from conclusive. This study aims toward a better understanding of possible common microstructural brain alterations in SCZ and BD. Magnetic Resonance Diffusion data of 33 patients with BD, 19 with SCZ and 35 healthy controls were acquired. Diffusion indexes were calculated, then analyzed using Tract-Based Spatial Statistics (TBSS). We tested correlations with clinical and psychological variables. In both patient groups mean diffusion (MD), volume ratio (VR) and radial diffusivity (RD) showed a significant increase, while fractional anisotropy (FA) and mode (MO) decreased compared to the healthy group. Changes in diffusion were located, for both diseases, in the fronto-temporal and callosal networks. Finally, no significant differences were identified between patient groups, and a significant correlations between length of disease and FA and VR within the corpus callosum, corona radiata and thalamic radiation were observed in bipolar disorder. To our knowledge, this is the first study applying TBSS on all the DTI indexes at the same time in both patient groups showing that they share similar impairments in microstructural connectivity, with particular regards to fronto-temporal and callosal communication, which are likely to worsen over time. Such features may represent neural common underpinnings characterizing major psychoses and confirm the central role of white matter pathology in schizophrenia and bipolar disorder. PMID- 28658251 TI - HIV disease progression among women following seroconversion during a tenofovir based HIV prevention trial. AB - BACKGROUND: Little is known regarding HIV disease outcomes among individuals who become infected with HIV while receiving antiretroviral medications for prevention. We compared HIV disease parameters among women who seroconverted while receiving tenofovir-containing oral or vaginal pre-exposure prophylaxis (PrEP) to placebo. METHODS: Participants with HIV seroconversion in a randomized placebo-controlled trial of oral tenofovir, oral tenofovir/emtricitabine, and vaginal tenofovir gel (MTN-003) were followed in a longitudinal cohort study (MTN 015). The effect of oral and vaginal tenofovir-containing PrEP on HIV disease progression was compared to placebo using linear mixed effects and Cox proportional hazard models, as appropriate. Additional analyses were performed to compare the outcomes among participants with detectable tenofovir or emtricitabine in plasma at the first quarterly visit in MTN-003. RESULTS: A total of 224 participants were included in the analysis; 93% from South Africa and 94% clade C virus. No differences in HIV RNA at steady state or the trajectory over 12 months were observed for each active arm compared to placebo; tenofovir gel recipients had higher CD4+ T cell counts (722 vs 596 cells/mm3; p = 0.02) at 90 days after estimated HIV seroconversion and higher average rates of change over 12 months compared to placebo (-181 vs -92 cells/mm3 per year; p = 0.08). With a median follow-up of 31 months, no significant differences were observed for time to CD4+ T cell count <=350 cells/mm3, or the composite endpoint of CD4+ T cells <=350 cells/mm3, initiation of antiretroviral therapy or death for each active arm compared to placebo. Additionally, there were no significant differences in the HIV RNA or CD4+ T cell counts at baseline, the change to month 12, or any disease progression outcomes among participants with oral drug detected and no oral drug detected compared to placebo. CONCLUSIONS: No clinically significant differences in HIV seroconversion outcomes were observed among women randomized to tenofovir-containing oral or vaginal PrEP regimens, however low overall adherence limits the generalizability of these findings. PMID- 28658252 TI - Integration of individual and social information for decision-making in groups of different sizes. AB - When making judgments in a group, individuals often revise their initial beliefs about the best judgment to make given what others believe. Despite the ubiquity of this phenomenon, we know little about how the brain updates beliefs when integrating personal judgments (individual information) with those of others (social information). Here, we investigated the neurocomputational mechanisms of how we adapt our judgments to those made by groups of different sizes, in the context of jury decisions for a criminal. By testing different theoretical models, we showed that a social Bayesian inference model captured changes in judgments better than 2 other models. Our results showed that participants updated their beliefs by appropriately weighting individual and social sources of information according to their respective credibility. When investigating 2 fundamental computations of Bayesian inference, belief updates and credibility estimates of social information, we found that the dorsal anterior cingulate cortex (dACC) computed the level of belief updates, while the bilateral frontopolar cortex (FPC) was more engaged in individuals who assigned a greater credibility to the judgments of a larger group. Moreover, increased functional connectivity between these 2 brain regions reflected a greater influence of group size on the relative credibility of social information. These results provide a mechanistic understanding of the computational roles of the FPC-dACC network in steering judgment adaptation to a group's opinion. Taken together, these findings provide a computational account of how the human brain integrates individual and social information for decision-making in groups. PMID- 28658253 TI - Return of warm conditions in the southeastern Bering Sea: Phytoplankton - Fish. AB - In 2014, the Bering Sea shifted back to warmer ocean temperatures (+2 oC above average), bringing concern for the potential for a new warm stanza and broad biological and ecological cascading effects. In 2015 and 2016 dedicated surveys were executed to study the progression of ocean heating and ecosystem response. We describe ecosystem response to multiple, consecutive years of ocean warming and offer perspective on the broader impacts. Ecosystem changes observed include reduced spring phytoplankton biomass over the southeast Bering Sea shelf relative to the north, lower abundances of large-bodied crustacean zooplankton taxa, and degraded feeding and body condition of age-0 walleye pollock. This suggests poor ecosystem conditions for young pollock production and the risk of significant decline in the number of pollock available to the pollock fishery in 2-3 years. However, we also noted that high quality prey, large copepods and euphausiids, and lower temperatures in the north may have provided a refuge from poor conditions over the southern shelf, potentially buffering the impact of a sequential-year warm stanza on the Bering Sea pollock population. We offer the hypothesis that juvenile (age-0, age-1) pollock may buffer deleterious warm stanza effects by either utilizing high productivity waters associated with the strong, northerly Cold Pool, as a refuge from the warm, low production areas of the southern shelf, or by exploiting alternative prey over the southern shelf. We show that in 2015, the ocean waters influenced by spring sea ice (the Cold Pool) supported robust phytoplankton biomass (spring) comprised of centric diatom chains, a crustacean copepod community comprised of large-bodied taxa (spring, summer), and a large aggregation of midwater fishes, potentially young pollock. In this manner, the Cold Pool may have acted as a trophic refuge in that year. The few age-0 pollock occurring over the southeast shelf consumed high numbers of euphausiids which may have provided a high quality alternate prey. In 2016 a retracted Cold Pool precluded significant refuging in the north, though pollock foraging on available euphausiids over the southern shelf may have mitigated the effect of warm waters and reduced large availability of large copepods. This work presents the hypothesis that, in the short term, juvenile pollock can mitigate the drastic impacts of sustained warming. This short-term buffering, combined with recent observations (2017) of renewed sea ice presence over southeast Bering Sea shelf and a potential return to average or at least cooler ecosystem conditions, suggests that recent warm year stanza (2014-2016) effects to the pollock population and fishery may be mitigated. PMID- 28658254 TI - Inhaled nitric oxide prevents NSAID-induced renal impairment in pseudo normovolaemic piglets. AB - OBJECTIVE: Inhaled nitric oxide (iNO) is commonly used as a treatment of pulmonary hypertension. Its action is purported to be specific to the lung, but extrapulmonary effects have been reported. The objective of this study was to evaluate if iNO could compensate the renal impairment induced by ketoprofen, a conventional non-steroidal anti-inflammatory drug (NSAID), during general anaesthesia. METHODS: Under pseudo-normovolaemic condition, thirty piglets were randomly assigned into 5 equal groups and equipped for renal and systemic parameters measurements. A first experiment was carried out to validate methods and reproduce the renal effects of iNO (40 ppm) in comparison with a placebo (100% oxygen). In a second experiment, iNO was inhaled for 120 minutes right after NSAID treatment (ketoprofen 2 mg*kg-1 IV, and 40 ppm iNO; group KiNO) and its effects were compared to ketoprofen alone (2 mg*kg-1 IV; group K) and placebo (saline; group C). RESULTS: In this model, iNO increased significantly renal blood flow measured by ultrasonic (RBFUL: +53.2+/-17.2%; p = 0.008) and by PAH clearance (RBFPAH:+78.6+/-37.6%; p = 0.004) methods, glomerular filtration rate (GFR: +72.6+/-32.5%; p = 0.006) and urinary output (UO: +47.4+/-24.2%; p = 0.01). In the second experiment, no significant temporal variation was noted for renal parameters in groups KiNO and C, whereas a significant and constant decrease was observed in the group K for RBFUL (max -19.0+/-7.1%), GFR (max -26.6+/-10.4%) and UO (max -30.3+/-10.5%). CLINICAL SIGNIFICANCE: Our experiments show that iNO, released from its transport forms after its inhalation, can improve renal safety of NSAIDs. This result is promising regarding the use of NSAIDs in critical conditions, but needs to receive clinical confirmation. PMID- 28658255 TI - Parallel body shape divergence in the Neotropical fish genus Rhoadsia (Teleostei: Characidae) along elevational gradients of the western slopes of the Ecuadorian Andes. AB - Neotropical mountain streams are important contributors of biological diversity. Two species of the characid genus Rhoadsia differing for an ecologically important morphological trait, body depth, have been described from mountain streams of the western slopes of the Andes in Ecuador. Rhoadsia altipinna is a deeper-bodied species reported from low elevations in southwestern Ecuador and northern Peru, and Rhoadsia minor is a more streamlined species that was described from high elevations (>1200 m) in the Esmeraldas drainage in northwestern Ecuador. Little is known about these species and their validity as distinct species has been questioned. In this study, we examine how their body shape varies along replicated elevational gradients in different drainages of western Ecuador using geometric morphometrics and the fineness ratio. We also use sequences of the mitochondrial cytochrome oxidase c I gene and the second intron of the S7 nuclear gene to examine whether genetic data are consistent with the existence of two species. We found that body depth varies continuously among populations within drainages as a function of elevation, and that body shape overlaps among drainages, such that low elevation populations of R. minor in the Esmeraldas drainage have similar body depths to higher elevation R. altipinna in southern drainages. Although a common general trend of declining body depth with elevation is clear, the pattern and magnitude of body shape divergence differed among drainages. Sequencing of mitochondrial and nuclear genes failed to meet strict criteria for the recognition of two species (e.g., reciprocal monophyly and deep genetic structure). However, there was a large component of genetic variation for the COI gene that segregated among drainages, indicating significant genetic divergence associated with geographic isolation. Continued research on Rhoadsia in western Ecuador may yield significant insight into adaptation and speciation in Neotropical mountain streams. PMID- 28658256 TI - A noncoding RNA containing a SINE-B1 motif associates with meiotic metaphase chromatin and has an indispensable function during spermatogenesis. AB - A search for early response genes that are activated following germ cell induction from mouse embryonic stem cells in vitro led us to the isolation of a long noncoding RNA that contains a SINE (short interspersed element)-B1F motif that was named R53. In situ hybridization and northern blot analyses revealed that the R53 subfragment RNA bears a B1F motif, is processed from the primary transcript, is expressed in adult testis and is predominantly localized in meiotic metaphase chromatin during spermatogenesis. Recent studies of chromosome associated RNAs have explored novel functions of noncoding RNAs. Specifically, chromosome-bound noncoding RNAs function not only as structural components of chromosome but also as scaffolds that recruit epigenetic modulators for transcriptional regulation, and they are dynamically rearranged during the cell cycle. However, few studies have explored meiotic chromatin; thus, R53 RNA appears to be the first long noncoding RNA to be tightly associated with the metaphase chromatin during spermatogenesis. Furthermore, R53 knockdown using a lentivirus-mediated RNAi injected into mouse testis and organ culture of the fragments revealed a remarkable reduction in postmeiotic cells and irregular up regulation of several postmeiotic genes, which suggests the possibility that the SINE-B1-derived noncoding RNA R53 plays an indispensable role in the transcriptional regulation of key spermatogenesis genes. PMID- 28658257 TI - Mothers' education and ANC visit improved exclusive breastfeeding in Dabat Health and Demographic Surveillance System Site, northwest Ethiopia. AB - INTRODUCTION: Despite its proven benefit in reducing child mortality and morbidity, the coverage of exclusive breastfeeding (EBF) remains sub-optimal. In Ethiopia, about 52% of infants under six months of age were exclusively breastfed, implying the need for further identification of the barriers to optimal EBF practice. Therefore, this study aimed to investigate EBF and its determinants in the predominantly rural northwest Ethiopia. METHODS: The study was conducted at the Dabat Health and Demographic Surveillance System (HDSS) site, which is located in Dabat District, northwest Ethiopia. A total of 5,227 mothers with children under five years of age were included for analysis. Multivariable binary logistic regression analysis was employed to identify factors associated with EBF. The Adjusted Odds Ratio (AOR) with a 95% Confidence Interval (CI) was estimated to show the strength of association. A P-value of <0.05 was used to declare statistical significance. RESULTS: About 54.5% [95% CI: 51.9, 57.1] of the mothers practiced EBF. Mothers' education [AOR = 2.10; 95% CI: 1.63, 2.71], age (20-35 years) [AOR = 1.39; CI: 1.07, 1.80], urban residence [AOR = 1.28; 95% CI: 1.07, 1.54], at least one ANC visit [AOR = 1.41; 95% CI: 1.23,1.61], initiation of breastfeeding within one hour of birth [AOR = 1.32; 95% CI: 1.15,1.50], richer household [AOR = 1.34; 95% CI: 1.07, 1.65], and withholding prelacteal feeds [AOR = 1.34; 95% CI: 1.17, 1.53] were found important determinants of EBF. CONCLUSION: In this study area, the prevalence of EBF is lower than the national as well as the global recommendation for universal coverage of EBF. Therefore, strengthening the implementation of Infant and Young Child Feeding strategy (IYCF) and maternal health care utilization are essential for stepping up EBF coverage. Moreover, attention should be given to uneducated, rural resident, and adolescent mothers. PMID- 28658258 TI - Genome-scale analysis of the genes that contribute to Burkholderia pseudomallei biofilm formation identifies a crucial exopolysaccharide biosynthesis gene cluster. AB - Burkholderia pseudomallei, the causative agent of melioidosis, is an important public health threat due to limited therapeutic options for treatment. Efforts to improve therapeutics for B. pseudomallei infections are dependent on the need to understand the role of B. pseudomallei biofilm formation and its contribution to antibiotic tolerance and persistence as these are bacterial traits that prevent effective therapy. In order to reveal the genes that regulate and/or contribute to B. pseudomallei 1026b biofilm formation, we screened a sequence defined two allele transposon library and identified 118 transposon insertion mutants that were deficient in biofilm formation. These mutants include transposon insertions in genes predicted to encode flagella, fimbriae, transcriptional regulators, polysaccharides, and hypothetical proteins. Polysaccharides are key constituents of biofilms and B. pseudomallei has the capacity to produce a diversity of polysaccharides, thus there is a critical need to link these biosynthetic genes with the polysaccharides they produce to better understand their biological role during infection. An allelic exchange deletion mutant of the entire B. pseudomallei biofilm-associated exopolysaccharide biosynthetic cluster was decreased in biofilm formation and produced a smooth colony morphology suggestive of the loss of exopolysaccharide production. Conversely, deletion of the previously defined capsule I polysaccharide biosynthesis gene cluster increased biofilm formation. Bioinformatics analyses combined with immunoblot analysis and glycosyl composition studies of the partially purified exopolysaccharide indicate that the biofilm-associated exopolysaccharide is neither cepacian nor the previously described acidic exopolysaccharide. The biofilm-associated exopolysaccharide described here is also specific to the B. pseudomallei complex of bacteria. Since this novel exopolysaccharide biosynthesis cluster is retained in B. mallei, it is predicted to have a role in colonization and infection of the host. These findings will facilitate further advances in understanding the pathogenesis of B. pseudomallei and improve diagnostics and therapeutic treatment strategies. PMID- 28658259 TI - Neutrophil derived LTB4 induces macrophage aggregation in response to encapsulated Streptococcus iniae infection. AB - Immune cells sense and react to a multitude of factors including both host and microbe-derived signals. Understanding how cells translate these cues into particular cellular behaviors is a complex yet critical area of study. We have previously shown that both neutrophils and macrophages are important for controlling the fish pathogen Streptococcus iniae. Here, we report both host and bacterial determinants leading to the formation of organized macrophage aggregates as part of the host inflammatory response in a subset of infected larvae. Streptococcal capsule was a required signal for aggregate formation. Macrophage aggregation coincided with NFkappaB activity, and the formation of these aggregates is mediated by leukotriene B4 (LTB4) produced by neutrophils. Depletion, inhibition, or genetic deletion of leukotriene A4 hydrolase (Lta4h), which catalyzes the last step in LTB4 synthesis, resulted in the absence of macrophage aggregation. Larvae with impaired neutrophil function also had impaired macrophage aggregation; however, aggregate formation was partially rescued with the addition of exogenous LTB4. Neutrophil-specific expression of lta4h was sufficient to rescue macrophage aggregation in Lta4h-deficient larvae and increased host survival following infection. In summary, our findings highlight a novel innate immune response to infection in which specific bacterial products drive neutrophils that modulate macrophage behavior through eicosanoid signaling. PMID- 28658260 TI - Spatiotemporal variability and environmental factors of harmful algal blooms (HABs) over western Lake Erie. AB - Over the past decades, numerous studies have been carried out in understanding causes of Harmful Algal Blooms (HABs) and their dynamics, yielding great knowledge in this field. Lake Erie, the fourth-largest lake of the five Great Lake, is among those highly vulnerable to the impacts of HABs and has received substantial attention from the public, water management sectors, and academic field. Building upon previous work, this study aims to characterize spatiotemporal variability of Chlorophyll a (Chl-a), which is an important indicator of HABs, and to explore relative importance of environmental factors associated with HABs in the west Lake Erie. Ten years of biweekly Chl-a information over western Lake Erie were derived from MERIS data at the pixel scale. Based on the MERIS-derived information high concentrations of Chl-a were observed in the south near shore area in spring and fall and in the west corner area of western Lake Erie in all three seasons except winter. Wavelet analysis suggested that the 0.5- and 1-year periods were dominant modes for the Chl-a series. The Multivariate Adaptive Regression Splines (MARS) analysis was performed to explore factors associated with the dynamics of Chl-a. The results suggested that overall both phenological (e.g. wind) and ecological (e.g. nutrient levels) factors exhibited significant correlations with the remotely sensed imagery based observations of Chl-a despite spatial and temporal variations. The important phenological and ecological factors include solar radiation and wind speed in spring, water temperature, solar radiation, and total Kjeldahl nitrogen concentration in summer, wind speed in fall, and water temperature and streamflow in winter. Both consistency and differences of findings of the study with others in the region may suggest strengths and limitations of the remotely sensed imagery-based analysis, offering valuable information for future work. PMID- 28658261 TI - Sequential sampling of visual objects during sustained attention. AB - In a crowded visual scene, attention must be distributed efficiently and flexibly over time and space to accommodate different contexts. It is well established that selective attention enhances the corresponding neural responses, presumably implying that attention would persistently dwell on the task-relevant item. Meanwhile, recent studies, mostly in divided attentional contexts, suggest that attention does not remain stationary but samples objects alternately over time, suggesting a rhythmic view of attention. However, it remains unknown whether the dynamic mechanism essentially mediates attentional processes at a general level. Importantly, there is also a complete lack of direct neural evidence reflecting whether and how the brain rhythmically samples multiple visual objects during stimulus processing. To address these issues, in this study, we employed electroencephalography (EEG) and a temporal response function (TRF) approach, which can dissociate responses that exclusively represent a single object from the overall neuronal activity, to examine the spatiotemporal characteristics of attention in various attentional contexts. First, attention, which is characterized by inhibitory alpha-band (approximately 10 Hz) activity in TRFs, switches between attended and unattended objects every approximately 200 ms, suggesting a sequential sampling even when attention is required to mostly stay on the attended object. Second, the attentional spatiotemporal pattern is modulated by the task context, such that alpha-mediated switching becomes increasingly prominent as the task requires a more uniform distribution of attention. Finally, the switching pattern correlates with attentional behavioral performance. Our work provides direct neural evidence supporting a generally central role of temporal organization mechanism in attention, such that multiple objects are sequentially sorted according to their priority in attentional contexts. The results suggest that selective attention, in addition to the classically posited attentional "focus," involves a dynamic mechanism for monitoring all objects outside of the focus. Our findings also suggest that attention implements a space (object)-to-time transformation by acting as a series of concatenating attentional chunks that operate on 1 object at a time. PMID- 28658262 TI - Mycobacteria induce TPL-2 mediated IL-10 in IL-4-generated alternatively activated macrophages. AB - IL-4 drives expansion of Th2 cells that cause generation of alternatively activated macrophages (AAMs). Filarial infections are established early in life, induce increased IL-4 production are co-endemic with tuberculosis (TB). We sought to understand, therefore, how mycobacteria are handled in the context of IL-4 induced AAM. Comparing IL-4 generated in vitro monocyte derived human AAMs to LPS and IFN-gamma generated classically macrophages (CAMs), both infected with mycobacteria (BCG), we demonstrated increased early BCG uptake and increased IL 10 production in AAMs compared to CAMs. We further demonstrated that increased IL 10 production is mediated by upregulation of tumor progression locus 2 (TPL-2), an upstream activator of extracellular signal related kinases (ERKs) in AAMs but not in CAMs, both at the transcript as well as the protein level. Pharmacologic inhibition of TPL-2 significantly diminished IL-10 production only in BCG infected AAMs. Finally, we validated our findings in an in vivo C57Bl/6 model of filarial infection, where an exaggerated Th2 induced lung-specific alternative activation led to TPL-2 and IL-10 upregulation on subsequent TB infection. These data show that in response to mycobacterial infection, IL-4 generated AAMs in chronic filarial infections have impaired immune responses to TB infection by increasing IL-10 production in a TPL-2 mediated manner. PMID- 28658263 TI - Identification of benzazole compounds that induce HIV-1 transcription. AB - Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed "shock and kill". This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents. PMID- 28658265 TI - Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody. AB - Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL. PMID- 28658264 TI - Preterm infants have significantly longer telomeres than their term born counterparts. AB - There are well-established morbidities associated with preterm birth including respiratory, neurocognitive and developmental disorders. However several others have recently emerged that characterise an 'aged' phenotype in the preterm infant by term-equivalent age. These include hypertension, insulin resistance and altered body fat distribution. Evidence shows that these morbidities persist into adult life, posing a significant public health concern. In this study, we measured relative telomere length in leukocytes as an indicator of biological ageing in 25 preterm infants at term equivalent age. Comparing our measurements with those from 22 preterm infants sampled at birth and from 31 term-born infants, we tested the hypothesis that by term equivalent age, preterm infants have significantly shorter telomeres (thus suggesting that they are prematurely aged). Our results demonstrate that relative telomere length is highly variable in newborn infants and is significantly negatively correlated with gestational age and birth weight in preterm infants. Further, longitudinal assessment in preterm infants who had telomere length measurements available at both birth and term age (n = 5) suggests that telomere attrition rate is negatively correlated with increasing gestational age. Contrary to our initial hypothesis however, relative telomere length was significantly shortest in the term born control group compared to both preterm groups and longest in the preterm at birth group. In addition, telomere lengths were not significantly different between preterm infants sampled at birth and those sampled at term equivalent age. These results indicate that other, as yet undetermined, factors may influence telomere length in the preterm born infant and raise the intriguing hypothesis that as preterm gestation declines, telomere attrition rate increases. PMID- 28658266 TI - Post-exercise hypotension and heart rate variability response after water- and land-ergometry exercise in hypertensive patients. AB - BACKGROUND: systemic arterial hypertension is the most prevalent cardiovascular disease; physical activity for hypertensive patients is related to several beneficial cardiovascular adaptations. This paper evaluated the effect of water- and land-ergometry exercise sessions on post-exercise hypotension (PEH) of healthy normotensive subjects versus treated or untreated hypertensive patients. METHODS: Forty-five older women composed three experimental groups: normotensive (N, n = 10), treated hypertensive (TH, n = 15) and untreated hypertensive (UH, n = 20). The physical exercise acute session protocol was performed at 75% of maximum oxygen consumption (VO2max) for 45 minutes; systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure were evaluated at rest, peak and at 15, 30, 45, 60, 75 and 90 minutes after exercise cessation. Additionally, the heart rate variability (HRV) was analyzed by R-R intervals in the frequency domain for the assessment of cardiac autonomic function. RESULTS: In both exercise modalities, equivalent increases in SBP were observed from rest to peak exercise for all groups, and during recovery, significant PEH was noted. At 90 minutes after the exercise session, the prevalence of hypotension was significantly higher in water than in the land-based protocol. Moreover, more pronounced reductions in SBP and DBP were observed in the UH patients compared to TH and N subjects. Finally, exercise in the water was more effective in restoring HRV during recovery, with greater effects in the untreated hypertensive group. CONCLUSION: Our data demonstrated that water-ergometry exercise was able to induce expressive PEH and improve cardiac autonomic modulation in older normotensive, hypertensive treated or hypertensive untreated subjects when compared to conventional land-ergometry. PMID- 28658267 TI - Impact of a hybrid TGfU-Sport Education unit on student motivation in physical education. AB - The Teaching Games for Understanding (TGfU) and Sport Education (SE) pedagogical models share several objectives and pedagogical processes. Despite this seemingly uncanny relationship, few studies have examined the efficacy of a hybrid TGfU/SE pedagogical model, particularly how a teacher's utilization of such a model impacts on student motivation. The purpose of the current study was to investigate the effect a hybrid TGfU/SE unit, in comparison to direct instruction, on students' perceptions of various aspects of their motivation to engage in physical education (autonomous motivation, basic psychological needs, enjoyment and intention to be physically active). A crossover design was utilized, using the technique of counterbalancing. One group experienced a hybrid SE/TGfU unit first, followed by a unit of direct instruction. A second group experienced the units in the opposite order. Participants were 55 students. The intervention was conducted over a total of 16 lessons. The hybrid unit was designed according to the characteristics of SE by using seasons, roles, persistent teams, etc. Learning tasks set by the teacher during individual lessons, however, were designed according to the pedagogical principles of TGfU. Student motivation data was generated using validated questionnaires. Results showed that regardless of the order of intervention, the two groups showed significant improvements in autonomy, competence and enjoyment when they were taught using the hybrid model. Instead, in the variables autonomous motivation, relatedness and intention to be physically active there were no significant improvements in one group. These results demonstrate that it is possible to design varied learning situations in which affiliation, leadership and trust are fostered, while tasks are adapted to the characteristics of the students. All this can cause greater autonomous motivation, and consequently, perceived competence in the student, a positive image of the sport to practice, and therefore greater enjoyment and to be physically active. PMID- 28658268 TI - WetA bridges cellular and chemical development in Aspergillus flavus. AB - Bridging cellular reproduction and survival is essential for all life forms. Aspergillus fungi primarily reproduce by forming asexual spores called conidia, whose formation and maturation is governed by the central genetic regulatory circuit BrlA->AbaA->WetA. Here, we report that WetA is a multi-functional regulator that couples spore differentiation and survival, and governs proper chemical development in Aspergillus flavus. The deletion of wetA results in the formation of conidia with defective cell walls and no intra-cellular trehalose, leading to reduced stress tolerance, a rapid loss of viability, and disintegration of spores. WetA is also required for normal vegetative growth, hyphal branching, and production of aflatoxins. Targeted and genome-wide expression analyses reveal that WetA exerts feedback control of brlA and that 5,700 genes show altered mRNA levels in the mutant conidia. Functional category analyses of differentially expressed genes in DeltawetA RNA-seq data indicate that WetA contributes to spore integrity and maturity by properly regulating the metabolic pathways of trehalose, chitin, alpha-(1,3)-glucan, beta-(1,3)-glucan, melanin, hydrophobins, and secondary metabolism more generally. Moreover, 160 genes predicted to encode transcription factors are differentially expressed by the absence of wetA, suggesting that WetA may play a global regulatory role in conidial development. Collectively, we present a comprehensive model for developmental control that bridges spore differentiation and survival in A. flavus. PMID- 28658269 TI - Leptospira diversity in animals and humans in Tahiti, French Polynesia. AB - BACKGROUND: Leptospirosis is a highly endemic bacterial zoonosis in French Polynesia (FP). Nevertheless, data on the epidemiology of leptospirosis in FP are scarce. We conducted molecular studies on Leptospira isolated from humans and the potential main animal reservoirs in order to identify the most likely sources for human infection. METHODOLOGY/PRINCIPAL FINDINGS: Wild rats (n = 113), farm pigs (n = 181) and domestic dogs (n = 4) were screened for Leptospira infection in Tahiti, the most populated island in FP. Positive samples were genotyped and compared to Leptospira isolated from human cases throughout FP (n = 51), using secY, 16S and LipL32 sequencing, and MLST analysis. Leptospira DNA was detected in 20.4% of rats and 26.5% of pigs. We identified two Leptospira species and three sequence types (STs) in animals and humans: Leptospira interrogans ST140 in pigs only and L. interrogans ST17 and Leptospira borgpetersenii ST149 in humans and rats. Overall, L. interrogans was the dominant species and grouped into four clades: one clade including a human case only, two clades including human cases and dogs, and one clade including human cases and rats. All except one pig sample showed a unique L. interrogans (secY) genotype distinct from those isolated from humans, rats and dogs. Moreover, LipL32 sequencing allowed the detection of an additional Leptospira genotype in pigs, clearly distinct from the previous ones. CONCLUSIONS/SIGNIFICANCE: Our data confirm rats as a major potential source for human leptospirosis in FP. By contrast to what was expected, farm pigs did not seem to be a major reservoir for the Leptospira genotypes identified in human patients. Thus, further investigations will be required to determine their significance in leptospirosis transmission in FP. PMID- 28658270 TI - Ethanol production improvement driven by genome-scale metabolic modeling and sensitivity analysis in Scheffersomyces stipitis. AB - The yeast Scheffersomyces stipitis naturally produces ethanol from xylose, however reaching high ethanol yields is strongly dependent on aeration conditions. It has been reported that changes in the availability of NAD(H/+) cofactors can improve fermentation in some microorganisms. In this work genome scale metabolic modeling and phenotypic phase plane analysis were used to characterize metabolic response on a range of uptake rates. Sensitivity analysis was used to assess the effect of ARC on ethanol production indicating that modifying ARC by inhibiting the respiratory chain ethanol production can be improved. It was shown experimentally in batch culture using Rotenone as an inhibitor of the mitochondrial NADH dehydrogenase complex I (CINADH), increasing ethanol yield by 18%. Furthermore, trajectories for uptakes rates, specific productivity and specific growth rate were determined by modeling the batch culture, to calculate ARC associated to the addition of CINADH inhibitor. Results showed that the increment in ethanol production via respiratory inhibition is due to excess in ARC, which generates an increase in ethanol production. Thus ethanol production improvement could be predicted by a change in ARC. PMID- 28658271 TI - Regulatory T cell frequencies and phenotypes following anti-viral vaccination. AB - Regulatory T cells (Treg) function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays investigated, but the impact of vaccination on Treg homeostasis is still largely unknown. This may be a relevant safety aspect, since loss of tolerance through reduced Treg may trigger autoimmunity. In exploratory clinical trials, healthy adults were vaccinated with an influenza subunit vaccine plus or minus the adjuvant MF59(r), an adjuvanted hepatitis B subunit vaccine or a live attenuated yellow fever vaccine. Frequencies and phenotypes of resting (rTreg) and activated (aTreg) subpopulations of circulating CD4+ Treg were determined and compared to placebo immunization. Vaccination with influenza vaccines did not result in significant changes in Treg frequencies and phenotypes. Vaccination with the hepatitis B vaccine led to slightly increased frequencies of both rTreg and aTreg subpopulations and a decrease in expression of functionality marker CD39 on aTreg. The live attenuated vaccine resulted in a decrease in rTreg frequency, and an increase in expression of activation marker CD25 on both subpopulations, possibly indicating a conversion from resting to migratory aTreg due to vaccine virus replication. To study the more local effects of vaccination on Treg in lymphoid organs, we immunized mice and analyzed the CD4+ Treg frequency and phenotype in draining lymph nodes and spleen. Vaccination resulted in a transient local decrease in Treg frequency in lymph nodes, followed by a systemic Treg increase in the spleen. Taken together, we showed that vaccination with vaccines with an already established safe profile have only minimal impact on frequencies and characteristics of Treg over time. These findings may serve as a bench-mark of inter-individual variation of Treg frequencies and phenotypes following vaccination. PMID- 28658272 TI - Sensing of minute airflow motions near walls using pappus-type nature-inspired sensors. AB - This work describes the development and use of pappus-like structures as sensitive sensors to detect minute air-flow motions. We made such sensors from pappi taken from nature-grown seed, whose filiform hairs' length-scale is suitable for the study of large-scale turbulent convection flows. The stem with the pappus on top is fixated on an elastic membrane on the wall and tilts under wind-load proportional to the velocity magnitude in direction of the wind, similar as the biological sensory hairs found in spiders, however herein the sensory hair has multiple filiform protrusions at the tip. As the sensor response is proportional to the drag on the tip and a low mass ensures a larger bandwidth, lightweight pappus structures similar as those found in nature with documented large drag are useful to improve the response of artificial sensors. The pappus of a Dandelion represents such a structure which has evolved to maximize wind driven dispersion, therefore it is used herein as the head of our sensor. Because of its multiple hairs arranged radially around the stem it generates uniform drag for all wind directions. While still being permeable to the flow, the hundreds of individual hairs on the tip of the sensor head maximize the drag and minimize influence of pressure gradients or shear-induced lift forces on the sensor response as they occur in non-permeable protrusions. In addition, the flow disturbance by the sensor itself is limited. The optical recording of the head motion allows continuously remote-distance monitoring of the flow fluctuations in direction and magnitude. Application is shown for the measurement of a reference flow under isothermal conditions to detect the early occurrence of instabilities. PMID- 28658274 TI - Long term monitoring of jaguars in the Cockscomb Basin Wildlife Sanctuary, Belize; Implications for camera trap studies of carnivores. AB - In this study, we estimate life history parameters and abundance for a protected jaguar population using camera-trap data from a 14-year monitoring program (2002 2015) in Belize, Central America. We investigated the dynamics of this jaguar population using 3,075 detection events of 105 individual adult jaguars. Using robust design open population models, we estimated apparent survival and temporary emigration and investigated individual heterogeneity in detection rates across years. Survival probability was high and constant among the years for both sexes (phi = 0.78), and the maximum (conservative) age recorded was 14 years. Temporary emigration rate for the population was random, but constant through time at 0.20 per year. Detection probability varied between sexes, and among years and individuals. Heterogeneity in detection took the form of a dichotomy for males: those with consistently high detection rates, and those with low, sporadic detection rates, suggesting a relatively stable population of 'residents' consistently present and a fluctuating layer of 'transients'. Female detection was always low and sporadic. On average, twice as many males than females were detected per survey, and individual detection rates were significantly higher for males. We attribute sex-based differences in detection to biases resulting from social variation in trail-walking behaviour. The number of individual females detected increased when the survey period was extended from 3 months to a full year. Due to the low detection rates of females and the variable 'transient' male subpopulation, annual abundance estimates based on 3 month surveys had low precision. To estimate survival and monitor population changes in elusive, wide-ranging, low-density species, we recommend repeated surveys over multiple years; and suggest that continuous monitoring over multiple years yields even further insight into population dynamics of elusive predator populations. PMID- 28658273 TI - A structural variant in the 5'-flanking region of the TWIST2 gene affects melanocyte development in belted cattle. AB - Belted cattle have a circular belt of unpigmented hair and skin around their midsection. The belt is inherited as a monogenic autosomal dominant trait. We mapped the causative variant to a 37 kb segment on bovine chromosome 3. Whole genome sequence data of 2 belted and 130 control cattle yielded only one private genetic variant in the critical interval in the two belted animals. The belt associated variant was a copy number variant (CNV) involving the quadruplication of a 6 kb non-coding sequence located approximately 16 kb upstream of the TWIST2 gene. Increased copy numbers at this CNV were strongly associated with the belt phenotype in a cohort of 333 cases and 1322 controls. We hypothesized that the CNV causes aberrant expression of TWIST2 during neural crest development, which might negatively affect melanoblasts. Functional studies showed that ectopic expression of bovine TWIST2 in neural crest in transgenic zebrafish led to a decrease in melanocyte numbers. Our results thus implicate an unsuspected involvement of TWIST2 in regulating pigmentation and reveal a non-coding CNV underlying a captivating Mendelian character. PMID- 28658276 TI - Correction: Sequence variability of the respiratory syncytial virus (RSV) fusion gene among contemporary and historical genotypes of RSV/A and RSV/B. AB - [This corrects the article DOI: 10.1371/journal.pone.0175792.]. PMID- 28658275 TI - bioA mutant of Mycobacterium tuberculosis shows severe growth defect and imparts protection against tuberculosis in guinea pigs. AB - Owing to the devastation caused by tuberculosis along with the unsatisfactory performance of the Bacillus Calmette-Guerin (BCG) vaccine, a more efficient vaccine than BCG is required for the global control of tuberculosis. A number of studies have demonstrated an essential role of biotin biosynthesis in the growth and survival of several microorganisms, including mycobacteria, through deletion of the genes involved in de novo biotin biosynthesis. In this study, we demonstrate that a bioA mutant of Mycobacterium tuberculosis (MtbDeltabioA) is highly attenuated in the guinea pig model of tuberculosis when administered aerogenically as well as intradermally. Immunization with MtbDeltabioA conferred significant protection in guinea pigs against an aerosol challenge with virulent M. tuberculosis, when compared with the unvaccinated animals. Booster immunization with MtbDeltabioA offered no advantage over a single immunization. These experiments demonstrate the vaccinogenic potential of the attenuated M. tuberculosis bioA mutant against tuberculosis. PMID- 28658277 TI - Chlorantraniliprole as a candidate pesticide used in combination with the attracticides for lepidopteran moths. AB - Methomyl is currently used as a toxicant for the attracticide BioAttract in cotton and vegetables in China. However, methomyl is highly toxic to non-target organisms and a more environmental friendly acceptable alternative is required. Larvae of three lepidopteran insects Helicoverpa armigera, Agrotis ipsilon and Spodoptera litura are important pests of these crops in China. In the present study, the toxicity of 23 commonly used insecticides were tested on H. armigera, then tested the susceptibility of A. ipsilon and S. litura moths to the insecticides which were the most toxic to H. armigera, and the acute toxicity of the most efficacious insecticides were further investigated under laboratory conditions. Chlorantraniliprole, emamectin benzoate, spinetoram, spinosad and methomyl exhibited high levels of toxicity to H. armigera moths with a mortality of 86.67%, 91.11%, 73.33%, 57.78% and 80.00%, respectively, during 24 h period at the concentration of 1 mg a.i. L-1. Among these five insecticides, A. ipsilon and S. litura moths were more sensitive to chlorantraniliprole, emamectin benzoate and methomyl. The lethal time (LT50) values of chlorantraniliprole and methomyl were shorter than emamectin benzoate for all three lepidopteran moth species at 1000 mg a.i. L-1 compared to concentrations of 500, 100 and 1 mg a.i L-1. Chlorantraniliprole was found to have similar levels of toxicity and lethal time on the three lepidopteran moths tested to the standard methomyl, and therefore, can be used as an alternative insecticide to methomyl in the attracticide for controlling these pest species. PMID- 28658278 TI - Antimicrobial use surveillance in broiler chicken flocks in Canada, 2013-2015. AB - There is a paucity of data on the reason for and the quantity of antimicrobials used in broiler chickens in Canada. To address this, the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) implemented surveillance of antimicrobial use (AMU) and antimicrobial resistance (AMR) in broiler chicken flocks in 2013. Shortly after this (2014), the poultry industry banned the preventive use of ceftiofur in broiler chickens. The objectives of this analysis were to describe antimicrobial use (AMU) in Canadian broiler chickens between 2013 and 2015 (n = 378 flocks), compare these results to other animal species in Canada, to highlight the utility of farm surveillance data to evaluate the impact of a policy change, and to explore how different antimicrobial use metrics might affect data interpretation and communication. The surveillance data indicated that the poultry industry policy resulted in lower antimicrobial use and resistance, and they successfully captured information on when, where, why, and how much antimicrobials were being used. The majority of antimicrobials were administered via the feed (95%). The relative frequency of antimicrobial classes used in broiler chickens differed from those used in swine or in food animal production in general. Coccidiostats were the most frequently used antimicrobial classes (53% of total kg). Excluding coccidiostats, the top three most frequently used antimicrobial classes were bacitracin (53% of flocks), virginiamycin (25%) and avilamycin (21%), mainly used for the prevention of necrotic enteritis. Depending on the AMU metric utilized, the relative rankings of the top antimicrobials changed; hence the choice of the AMU metric is an important consideration for any AMU reporting. When using milligrams/Population Correction Unit (mg/PCU) the top three antimicrobial classes used were bacitracins (76 mg/PCU), trimethoprim-sulfonamides (24 mg/PCU), and penicillins (15 mg/PCU), whereas when using a number of Defined Daily Doses in animals using Canadian standards /1,000 chicken-days at risk (nDDDvetCA/1,000 CD) the ranking was bacitracins (223 nDDDvetCA/1,000 CD), streptogramins (118 nDDDvetCA/1,000 CD), and trimethoprim-sulfonamides (87 nDDDvetCA/1,000 CD). The median animal treatment days in feed for one cycle (ATD/cycle) during the three-year study were 34 ATD/cycle; this was equal to the mean age of the flocks at pre-harvest sampling day (days at risk), indicating that the studied flocks except those that were raised without antibiotics and organic, were fed with medicated rations throughout the observation period. Overall, more than half (59%) of antimicrobials used in broiler chickens were in classes not used in human medicine, such as ionophores and chemical coccidiostats aimed to prevent coccidiosis. Compared to grower-finisher pigs and in production animal species (national sales data), the mg/PCU of antimicrobials used in broiler chickens was relatively lower. The findings of this paper highlighted the importance of farm level AMU surveillance in measuring the impact of interventions to reduce antimicrobials in poultry. PMID- 28658279 TI - Genetic basis of calcifying cystic odontogenic tumors. AB - Calcifying cystic odontogenic tumors (CCOTs) are benign cystic tumors that form abnormally keratinized ghost cells. Mutations in CTNNB1, which encodes beta catenin, have been implicated in the development of these tumors, but a causal relationship has not been definitively established. Thus, mutational hot spots in 50 cancer genes were examined by targeted next-generation sequencing in 11 samples of CCOT. Mutations in CTNNB1, but not in other genes, were observed in 10 of 11 cases. These mutations constitutively activate beta-catenin signaling by abolishing the phosphorylation sites Asp32, Ser33, or Ser37, and are similar to those reported in pilomatrixoma and adamantinomatous craniopharyngioma. In contrast, BRAF or NRAS mutations were observed in 12 and two control samples of ameloblastoma, respectively. In HEK293 cells, overexpression of mutated CTNNB1 also upregulated hair keratin, a marker of ghost cells. Furthermore, ghost cells were present in two cases of ameloblastoma with BRAF and CTNNB1 mutations, indicating that ghost cells form due to mutations in CTNNB1. The data suggest that mutations in CTNNB1 are the major driver mutations of CCOT, and that CCOT is the genetic analog of pilomatrixoma and adamantinomatous craniopharyngioma in odontogenic tissue. PMID- 28658280 TI - Reversible perturbations of gene regulation after genome editing in Drosophila cells. AB - The prokaryotic phage defense CRISPR/cas-system has developed into a versatile toolbox for genome engineering and genetic studies in many organisms. While many efforts were spent on analyzing the consequences of off-target effects, only few studies addressed side-effects that occur due to the targeted manipulation of the genome. Here, we show that the CRISPR/cas9-mediated integration of an epitope tag in combination with a selection cassette can trigger an siRNA-mediated, epigenetic genome surveillance pathway in Drosophila melanogaster cells. After homology-directed insertion of the sequence coding for the epitope tag and the selection marker, a moderate level of siRNAs covering the inserted sequence and extending into the targeted locus was detected. This response affected protein levels less than two-fold and it persisted even after single cell cloning. However, removal of the selection cassette abolished the siRNA generation, demonstrating that this response is reversible. Consistently, marker-free genome engineering did not trigger the same surveillance mechanism. These two observations indicate that the selection cassette we employed induces an aberrant transcriptional arrangement and ultimately sets off the siRNA production. There have been prior concerns about undesirable effects induced by selection markers, but fortunately we were able to show that at least one of the epigenetic changes reverts as the marker gene is excised. Although the effects observed were rather weak (less than twofold de-repression upon ago2 or dcr-2 knock-down), we recommend that when selection markers are used during genome editing, a strategy for their subsequent removal should always be included. PMID- 28658281 TI - Next-generation sequencing of the human TRPV1 gene and the regulating co-players LTB4R and LTB4R2 based on a custom AmpliSeqTM panel. AB - BACKGROUND: Transient receptor potential cation channel subfamily V member 1 (TRPV1) are sensitive to heat, capsaicin, pungent chemicals and other noxious stimuli. They play important roles in the pain pathway where in concert with proinflammatory factors such as leukotrienes they mediate sensitization and hyperalgesia. TRPV1 is the target of several novel analgesics drugs under development and therefore, TRPV1 genetic variants might represent promising candidates for pharmacogenetic modulators of drug effects. METHODS: A next generation sequencing (NGS) panel was created for the human TRPV1 gene and in addition, for the leukotriene receptors BLT1 and BLT2 recently described to modulate TRPV1 mediated sensitisation processes rendering the coding genes LTB4R and LTB4R2 important co-players in pharmacogenetic approaches involving TRPV1. The NGS workflow was based on a custom AmpliSeqTM panel and designed for sequencing of human genes on an Ion PGMTM Sequencer. A cohort of 80 healthy subjects of Western European descent was screened to evaluate and validate the detection of exomic sequences of the coding genes with 25 base pair exon padding. RESULTS: The amplicons covered approximately 97% of the target sequence. A median of 2.81 x 106 reads per run was obtained. This identified approximately 140 chromosome loci where nucleotides deviated from the reference sequence GRCh37 hg19 comprising the three genes TRPV1, LTB4R and LTB4R2. Correspondence between NGS and Sanger derived nucleotide sequences was 100%. CONCLUSIONS: Results suggested that the NGS approach based on AmpliSeqTM libraries and Ion Personal Genome Machine (PGM) sequencing is a highly efficient mutation detection method. It is suitable for large-scale sequencing of TRPV1 and functionally related genes. The method adds a large amount of genetic information as a basis for complete analysis of TRPV1 ion channel genetics and its functional consequences. PMID- 28658282 TI - Population structure of elephant foot yams (Amorphophallus paeoniifolius (Dennst.) Nicolson) in Asia. AB - The corms and leaves of elephant foot yams (Amorphophallus paeoniifolius (Dennst.) Nicolson) are important foods in the local diet in many Asian regions. The crop has high productivity and wide agroecological adaptation and exhibits suitability for the agroforestry system. Although the plant is assumed to reproduce via panmixia, a comprehensive study on the genetic background across regions to enhance wider consumer palatability is still lacking. Here, ten informative microsatellites were analyzed in 29 populations across regions in India, Indonesia and Thailand to understand the genetic diversity, population structure and distribution to improve breeding and conservation programs. The genetic diversity was high among and within regions. Some populations exhibited excess heterozygosity and bottlenecking. Pairwise FST indicated very high genetic differentiation across regions (FST = 0.274), and the Asian population was unlikely to be panmictic. Phylogenetic tree construction grouped the populations according to country of origin with the exception of the Medan population from Indonesia. The current gene flow was apparent within the regions but was restricted among the regions. The present study revealed that Indonesia and Thailand populations could be alternative centers of the gene pool, together with India. Consequently, regional action should be incorporated in genetic conservation and breeding efforts to develop new varieties with global acceptance. PMID- 28658283 TI - Heritability of hoarding symptoms across adolescence and young adulthood: A longitudinal twin study. AB - BACKGROUND: Twin studies of hoarding symptoms indicate low to moderate heritability during adolescence and considerably higher heritability in older samples, suggesting dynamic developmental etiological effects. The aim of the current study was to estimate the relative contribution of additive genetic and environmental effects to hoarding symptoms during adolescence and young adulthood and to estimate the sources of stability and change of hoarding symptoms during adolescence. METHODS: Univariate model-fitting was conducted in three cohorts of twins aged 15 (n = 7,905), 18 (n = 2,495) and 20-28 (n = 6,218). Longitudinal analyses were conducted in a subsample of twins for which data on hoarding symptoms was available at both age 15 and 18 (n = 1,701). RESULTS: Heritability estimates for hoarding symptoms at ages 15, 18 and 20-28 were 41% (95% confidence interval [CI]: 36-45%), 31% (95% CI: 22-39%) and 29% (95% CI: 24-34%) respectively. Quantitative sex-differences emerged in twins aged 15 at which point the heritability in boys was 33% (95% CI: 22-41%) and 17% (95% CI: 0-36%) in girls. Shared environmental effects played a negligible role across all samples with the exception of girls aged 15 where they accounted for a significant proportion of the variance (22%; 95% CI 6-36%). The longitudinal bivariate analyses revealed a significant phenotypic correlation of hoarding symptoms between ages 15 and 18 (0.40; 95% CI: 0.36-0.44) and a strong but imperfect genetic correlation (0.75; 95% CI: 0.57-0.94). The bivariate heritability was estimated to 65% (95% CI: 50-79%). CONCLUSIONS: Hoarding symptoms are heritable from adolescence throughout young adulthood, although heritability appears to slightly decrease over time. Shared environmental effects contribute to hoarding symptoms only in girls at age 15. The stability of hoarding symptoms between ages 15 and 18 is largely explained by genetic factors, while non-shared environmental factors primarily have a time-specific effect. The findings indicate that dynamic developmental etiological effects may be operating across the life span. PMID- 28658284 TI - Fasting plasma glucose and serum uric acid levels in a general Chinese population with normal glucose tolerance: A U-shaped curve. AB - OBJECTIVE: Although several epidemiological studies assessed the relationship between fasting plasma glucose (FPG) and serum uric acid (SUA) levels, the results were inconsistent. A cross-sectional study was conducted to investigate this relationship in Chinese individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: A total of 5,726 women and 5,457 men with normal glucose tolerance were enrolled in the study. All subjects underwent a 75-g oral glucose tolerance test. Generalized additive models and two-piecewise linear regression models were applied to assess the relationship. RESULTS: A U-shaped relationship between FPG and SUA was observed. After adjusting for potential confounders, the inflection points of FPG levels in the curves were 4.6 mmol/L in women and 4.7 mmol/L in men respectively. SUA levels decreased with increasing fasting plasma glucose concentrations before the inflection points (regression coefficient [beta] = -36.4, P < 0.001 for women; beta = -33.5, P < 0.001 for men), then SUA levels increased (beta = 17.8, P < 0.001 for women; beta = 13.9, P < 0.001 for men). Additionally, serum insulin levels were positively associated with FPG and SUA (P < 0.05). CONCLUSIONS: A U-shaped relationship between FPG and SUA levels existed in Chinese individuals with normal glucose tolerance. The association is partly mediated through serum insulin levels. PMID- 28658285 TI - Shared acoustic codes underlie emotional communication in music and speech Evidence from deep transfer learning. AB - Music and speech exhibit striking similarities in the communication of emotions in the acoustic domain, in such a way that the communication of specific emotions is achieved, at least to a certain extent, by means of shared acoustic patterns. From an Affective Sciences points of view, determining the degree of overlap between both domains is fundamental to understand the shared mechanisms underlying such phenomenon. From a Machine learning perspective, the overlap between acoustic codes for emotional expression in music and speech opens new possibilities to enlarge the amount of data available to develop music and speech emotion recognition systems. In this article, we investigate time-continuous predictions of emotion (Arousal and Valence) in music and speech, and the Transfer Learning between these domains. We establish a comparative framework including intra- (i.e., models trained and tested on the same modality, either music or speech) and cross-domain experiments (i.e., models trained in one modality and tested on the other). In the cross-domain context, we evaluated two strategies-the direct transfer between domains, and the contribution of Transfer Learning techniques (feature-representation-transfer based on Denoising Auto Encoders) for reducing the gap in the feature space distributions. Our results demonstrate an excellent cross-domain generalisation performance with and without feature representation transfer in both directions. In the case of music, cross domain approaches outperformed intra-domain models for Valence estimation, whereas for Speech intra-domain models achieve the best performance. This is the first demonstration of shared acoustic codes for emotional expression in music and speech in the time-continuous domain. PMID- 28658287 TI - An experimental test of host's life history traits modulation in response to cuckoo parasitism risk. AB - Hosts can counteract parasites through defences based on resistance and/or tolerance. The mechanistic basis of tolerance, which involve defensive mechanisms minimizing parasite damage after a successful parasitic attack, remains poorly explored in the study of cuckoo-host interactions. Here, we experimentally explore the possibility that the risk of great spotted cuckoo Clamator glandarius parasitism may induce tolerance defences in magpie Pica pica hosts through plasticity in life-history traits. We predict that magpies exposed to auditory cues indicating high parasitism risk will more likely exhibit resistance and/or modify their life-history traits to minimize parasitism costs (i.e. tolerance) compared to magpies under low parasitism risk. We found that manipulating the perceived parasitism risk did not affect host resistance (i.e. rejection of parasitic eggs) nor host life-history traits. Unexpectedly, host's egg volume increased over the season in nests exposed to auditory cues of control non harmful hoopoes Upupa epops. Our results do not provide support for inducible defences (either based on resistance or tolerance) in response to risk of parasitism in magpie hosts. Even so, we encourage studying plastic expression of breeding strategies in response to risk of cuckoo parasitism to achieve a better understanding of the mechanistic basis of tolerance defences. PMID- 28658286 TI - MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. AB - The "super-relaxed state" (SRX) of myosin represents a 'reserve' of motors in the heart. Myosin heads in the SRX are bound to the thick filament and have a very low ATPase rate. Changes in the SRX are likely to modulate cardiac contractility. We previously demonstrated that the SRX is significantly reduced in mouse cardiomyocytes lacking cardiac myosin binding protein-C (cMyBP-C). Here, we report the effect of mutations in the cMyBP-C gene (MYBPC3) using samples from human patients with hypertrophic cardiomyopathy (HCM). Left ventricular (LV) samples from 11 HCM patients were obtained following myectomy surgery to relieve LV outflow tract obstruction. HCM samples were genotyped as either MYBPC3 mutation positive (MYBPC3mut) or negative (HCMsmn) and were compared to eight non failing donor hearts. Compared to donors, only MYBPC3mut samples display a significantly diminished SRX, characterised by a decrease in both the number of myosin heads in the SRX and the lifetime of ATP turnover. These changes were not observed in HCMsmn samples. There was a positive correlation (p < 0.01) between the expression of cMyBP-C and the proportion of myosin heads in the SRX state, suggesting cMyBP-C modulates and maintains the SRX. Phosphorylation of the myosin regulatory light chain in MYBPC3mut samples was significantly decreased compared to the other groups, suggesting a potential mechanism to compensate for the diminished SRX. We conclude that by altering both contractility and sarcomeric energy requirements, a reduced SRX may be an important disease mechanism in patients with MYBPC3 mutations. PMID- 28658288 TI - A conceptual framework for quality assessment and management of biodiversity data. AB - The increasing availability of digitized biodiversity data worldwide, provided by an increasing number of institutions and researchers, and the growing use of those data for a variety of purposes have raised concerns related to the "fitness for use" of such data and the impact of data quality (DQ) on the outcomes of analyses, reports, and decisions. A consistent approach to assess and manage data quality is currently critical for biodiversity data users. However, achieving this goal has been particularly challenging because of idiosyncrasies inherent in the concept of quality. DQ assessment and management cannot be performed if we have not clearly established the quality needs from a data user's standpoint. This paper defines a formal conceptual framework to support the biodiversity informatics community allowing for the description of the meaning of "fitness for use" from a data user's perspective in a common and standardized manner. This proposed framework defines nine concepts organized into three classes: DQ Needs, DQ Solutions and DQ Report. The framework is intended to formalize human thinking into well-defined components to make it possible to share and reuse concepts of DQ needs, solutions and reports in a common way among user communities. With this framework, we establish a common ground for the collaborative development of solutions for DQ assessment and management based on data fitness for use principles. To validate the framework, we present a proof of concept based on a case study at the Museum of Comparative Zoology of Harvard University. In future work, we will use the framework to engage the biodiversity informatics community to formalize and share DQ profiles related to DQ needs across the community. PMID- 28658289 TI - Risk of serous retinal detachment in patients with end-stage renal disease on dialysis. AB - The aim of this retrospective, nationwide, matched cohort study was to investigate the association of serous retinal detachment with having end-stage renal disease (ESRD) while on dialysis. The cohort study included 94,024 patients with ESRD on dialysis registered between January 2000 to December 2009 in the Taiwan National Health Insurance Research Database. An age- and sex-matched control group comprised 94,024 patients selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. Twenty-seven ESRD patients and 11 controls developed serous retinal detachment (P < 0.001) during follow-up, demonstrating a significantly increased risk of serous retinal detachment in patients with ESRD on dialysis compared with controls (incidence rate ratio = 3.39, 95% confidence interval [CI] = 1.68-6.83). After adjustment for potential confounders, patients were 3.86 times more likely to develop serous retinal detachment than the full cohort (adjusted HR = 3.86, 95% CI = 1.15-12.96). In conclusion, patients with ESRD on dialysis demonstrate an increased risk of serous retinal detachment. Interdisciplinary collaboration between nephrologists and ophthalmologists is important to deal with serous retinal detachment in patients with ESRD on dialysis and prevent impairments of visual acuity. PMID- 28658290 TI - Firewood, smoke and respiratory diseases in developing countries-The neglected role of outdoor cooking. AB - Smoke from cooking in the kitchen is one of the world's leading causes of premature child death, claiming the lives of 500,000 children under five annually. This study analyses the role of outdoor cooking and the prevalence of respiratory diseases among children under five years by means of probit regressions using information from 41 surveys conducted in 30 developing countries from Asia, Africa and Latin America. I find that outdoor cooking reduces respiratory diseases among young children aged 0-4 by around 9 percent, an effect that reaches 13 percent among children aged 0-1. The results suggest that simple behavioral interventions, such as promoting outdoor cooking, can have a substantial impact on health hazards. PMID- 28658291 TI - Importance of neonatal immunoglobulin transfer for hippocampal development and behaviour in the newborn pig. AB - Neurological disorders are among the main clinical problems affecting preterm children and often result in the development of communication and learning disabilities later in life. Several factors are of importance for brain development, however the role of immunoglobulins (passive immunity transfer) has not yet been investigated. Piglets are born agammaglobulinemic, as a result of the lack of transfer of maternal immunoglobulins in utero, thus, they serve as an ideal model to mimic the condition of immunoglobulin deficiency in preterm infants. Thirty six, unsuckled newborn piglets were fed an infant formula or colostrum and supplemented orally or intravenously with either species-specific or foreign immunoglobulin and then compared to both newborn and sow-reared piglets. Two days after the piglets were born behavioural tests (novel recognition and olfactory discrimination of conspecifics scent) were performed, after which the piglets were sacrificed and blood, cerebrospinal fluid and hippocampi samples were collected for analyses. Both parameters of neuronal plasticity (neuronal maturation and synapse-associated proteins) and behavioural test parameters appeared to be improved by the appearance of species-specific porcine immunoglulin in the circulation and cerebrospinal fluid of the piglets. In conclusion, we postulate possible positive clinical effects following intravenous infusion of human immunoglobulin in terms of neuronal plasticity and cognitive function in preterm infants born with low blood immunoglobulin levels. PMID- 28658292 TI - The relationship between motor competence and health-related fitness in children and adolescents. AB - BACKGROUND AND AIMS: In the last twenty years, there has been increasing evidence that Motor Competence (MC) is vital for developing an active and healthy lifestyle. This study analyses the associations between motor competence and its components, with health-related fitness (HRF). METHODS: A random sample of 546 children (278 males, mean = 10.77 years) divided into four age groups (7-8; 9-10; 11-12; 13-14 years old) was evaluated. A quantitative MC instrument (evaluating stability, locomotor and manipulative skills), a maximal multistage 20-m shuttle run test and the handgrip test, height and BMI were used in the analyses. Pearson correlations and standard regression modelling were performed to explore the associations between variables. RESULTS: Moderate to strong significant correlations (0.49 < r < 0.73) were found between MC and HRF, for both sexes, and correlation values were stable across the age groups. The MC model explained 74% of the HRF variance, with the locomotor component being the highest predictor for the entire sample (beta = .302; p < .001). Gender-related differences were found when boys and girls were analysed at each age group. Locomotor MC for girls was the most consistent significant predictor of HRF across all age groups (0.47 < beta < 0.65; all p<=.001). For boys, significant predictors were locomotor and manipulative MC (0.21 < beta < 0.49; all p < .05) in the two younger age groups (7-8 and 9-10 years) and stability (0.50 < beta < 0.54; all p<=.001) for the older two age groups (11-12 and 13-14 years). CONCLUSION: These results support the idea that: (1) the relationship between overall MC and HRF is strong and stable across childhood and early adolescence; (2) when accounting for the different MC components, boys and girls show different relationship patterns with HFR across age. PMID- 28658293 TI - Green design of a paper test card for urinary iodine analysis. AB - When young children do not receive adequate amounts of the micronutrient iodine in their diet, their growth and cognitive development can be impaired. Nearly every country in the world has programs in place to track iodine intake and provide supplemental iodine if needed, usually in the form of fortified salt. The iodine nutrition status of a population can be tracked by monitoring iodine levels in urine samples to see if the median value falls in the range of 100-300 micrograms of iodine per liter of urine (MUg I/L), which indicates adequate or more than adequate iodine nutrition. Many low and middle-income countries (LMIC) do not have a laboratory capable of carrying out this challenging assay, so samples must be sent out for assay in external labs, which is expensive and time consuming. In most LMIC, population iodine surveys are carried out every 5-10 years, which limits the utility of the data for program monitoring and evaluation. To solve this problem, we developed a field-friendly paper test card that uses the Sandell-Kolthoff reaction to measure urinary iodine levels. A blind internal validation study showed that 93% of samples (n = 60) of iodide in an artificial urine matrix were categorized correctly by visual analysis as deficient, adequate, or excessive for levels set forth by the World Health Organization. Quantitative measurements based on computer image analysis had an error of 40 +/- 20 MUg I/L (n = 35 for samples in the calibration range) and these results categorized 88% of the samples (n = 60) correctly. We employed lifecycle analysis principles to address the known toxicity of arsenic, which is an obligatory reagent in the Sandell-Kolthoff reaction. Disposal of the cards in a landfill (their most likely destination after use) could let arsenic leach into groundwater; toxicity characteristic leaching procedure (TCLP) tests showed that the level of arsenic leached from the cards was 28.78 ppm, which is above the United States Environmental Protection Agency's limit of 5 parts per million for solid waste. We integrated a remediation module into the card. This module contains oxone, to oxidize As(III) to As(V) oxyacids, and the iron oxide goethite. TCLP testing showed that the leachable amount of arsenic was reduced by at least 97.6%-from 28.8 ppm to lower than 0.7 +/- 0.7 ppm (n = 20). This upstream intervention rendered the test card suitable for landfilling while retaining its functionality to perform a critical public health evaluation. PMID- 28658294 TI - Dynamic properties of successful smiles. AB - Facial expression of emotion is a foundational aspect of social interaction and nonverbal communication. In this study, we use a computer-animated 3D facial tool to investigate how dynamic properties of a smile are perceived. We created smile animations where we systematically manipulated the smile's angle, extent, dental show, and dynamic symmetry. Then we asked a diverse sample of 802 participants to rate the smiles in terms of their effectiveness, genuineness, pleasantness, and perceived emotional intent. We define a "successful smile" as one that is rated effective, genuine, and pleasant in the colloquial sense of these words. We found that a successful smile can be expressed via a variety of different spatiotemporal trajectories, involving an intricate balance of mouth angle, smile extent, and dental show combined with dynamic symmetry. These findings have broad applications in a variety of areas, such as facial reanimation surgery, rehabilitation, computer graphics, and psychology. PMID- 28658295 TI - Coral reef fish predator maintains olfactory acuity in degraded coral habitats. AB - Coral reefs around the world are rapidly degrading due to a range of environmental stressors. Habitat degradation modifies the sensory landscape within which predator-prey interactions occur, with implications for olfactory mediated behaviours. Predator naive settlement-stage damselfish rely on conspecific damage-released odours (i.e., alarm odours) to inform risk assessments. Yet, species such as the Ambon damselfish, Pomacentrus amboinensis, become unable to respond appropriately to these cues when living in dead-degraded coral habitats, leading to increased mortality through loss of vigilance. Reef fish predators also rely on odours from damaged prey to locate, assess prey quality and engage in prey-stealing, but it is unknown whether their responses are also modified by the change to dead-degraded coral habitats. Implications for prey clearly depend on how their predatory counterparts are affected, therefore the present study tested whether olfactory-mediated foraging responses in the dusky dottyback, Pseudochromis fuscus, a common predator of P. amboinensis, were similarly affected by coral degradation. A y-maze was used to measure the ability of Ps. fuscus to detect and move towards odours, against different background water sources. Ps. fuscus were exposed to damage-released odours from juvenile P. amboinensis, or a control cue of seawater, against a background of seawater treated with either healthy or dead-degraded hard coral. Predators exhibited an increased time allocation to the chambers of y-mazes injected with damage released odours, with comparable levels of response in both healthy and dead degraded coral treated waters. In control treatments, where damage-released odours were replaced with a control seawater cue, fish showed no increased preference for either chamber of the y-maze. Our results suggest that olfactory mediated foraging behaviours may persist in Ps. fuscus within dead-degraded coral habitats. Ps. fuscus may consequently gain a sensory advantage over P. amboinensis, potentially altering the outcome of predator-prey interactions. PMID- 28658296 TI - Ultrastructural analysis of salivary glands in a phytophagous stink bug revealed the presence of unexpected muscles. AB - The exceptional abilities of stink bugs (Hemiptera: Pentatomidae) to colonize a diverse group of plants have been attributed to the feeding behaviors and the functions of the salivary complex of these insects. Here, we describe the ultrastructure of the salivary glands of the Neotropical brown stink bug, Euschistus heros, which is a major component of the pentatomid pest complex on soybeans, Glycine max, in the neotropics. Our results revealed a salivary gland complex consisting of two lobes (i.e., anterior and posterior), with a constriction between them (i.e., the hilum), in which the salivary and accessory gland ducts are inserted. The principal gland epithelium has a single layer of cells lining an enlarged lumen filled with saliva, and these cells are cuboidal, rich in rough endoplasmic reticulum and secretory vesicles, with well-developed nuclei, all of which are typical features of protein-secreting cells. We report, for the first time in insects, the presence of a layer of muscle cells surrounding the columnar hilum epithelium. The accessory salivary gland cells are cuboidal with nuclei containing condensed chromatin and cytoplasm rich in vacuoles and rough endoplasmic reticulum, indicating the potential involvement of these glands in water transport/secretion. The lumen content of each lobe of the principal gland suggests that the lobes produce different compounds. Thus, our results suggest that the E. heros salivary complex might have unconventional mechanisms to mix/release saliva, which might help explain the polyphagous abilities of these insects. PMID- 28658298 TI - Bayesian Lasso and multinomial logistic regression on GPU. AB - We describe an efficient Bayesian parallel GPU implementation of two classic statistical models-the Lasso and multinomial logistic regression. We focus on parallelizing the key components: matrix multiplication, matrix inversion, and sampling from the full conditionals. Our GPU implementations of Bayesian Lasso and multinomial logistic regression achieve 100-fold speedups on mid-level and high-end GPUs. Substantial speedups of 25 fold can also be achieved on older and lower end GPUs. Samplers are implemented in OpenCL and can be used on any type of GPU and other types of computational units, thereby being convenient and advantageous in practice compared to related work. PMID- 28658297 TI - Abnormal dendritic maturation of developing cortical neurons exposed to corticotropin releasing hormone (CRH): Insights into effects of prenatal adversity? AB - Corticotropin releasing hormone (CRH) produced by the hypothalamus initiates the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the body's stress response. CRH levels typically are undetectable in human plasma, but during pregnancy the primate placenta synthesizes and releases large amounts of CRH into both maternal and fetal circulations. Notably, placental CRH synthesis increases in response to maternal stress signals. There is evidence that human fetal exposure to high concentrations of placental CRH is associated with behavioral consequences during infancy and into childhood, however the direct effects on of the peptide on the human brain are unknown. In this study, we used a rodent model to test the plausibility that CRH has direct effects on the developing cortex. Because chronic exposure to CRH reduces dendritic branching in hippocampal neurons, we tested the hypothesis that exposure to CRH would provoke impoverishment of dendritic trees in cortical neurons. This might be reflected in humans as cortical thinning. We grew developing cortical neurons in primary cultures in the presence of graded concentrations of CRH. We then employed Sholl analyses to measure dendritic branching and total dendritic length of treated cells. A seven-day exposure to increasing levels of CRH led to a significant, dose-dependent impoverishment of the branching of pyramidal-like cortical neurons. These results are consistent with the hypothesis that, rather than merely being a marker of prenatal stress, CRH directly decreases dendritic branching. Because dendrites comprise a large portion of cortical volume these findings might underlie reduced cortical thickness and could contribute to the behavioral consequences observed in children exposed to high levels of CRH in utero. PMID- 28658299 TI - Prenatal exposure to testosterone (2D:4D) and social hierarchy together predict voice behavior in bankers. AB - Prohibitive voice behaviors are employees' expressions of concern about practices, incidents, or behaviors that may potentially harm the organization. In this study, we examined a potential biological correlate of prohibitive voice: prenatal exposure to testosterone. In a sample of bankers, we used 2D:4D (i.e., the ratio of the length of the index finger to the length of the ring finger) as a marker for prenatal exposure to testosterone (lower 2D:4D suggests higher prenatal exposure to testosterone). We used a self-report scale to measure prohibitive voice. For low-ranked employees, lower 2D:4D was related to using less voice. No such relation was found for high-ranked employees. Conclusions should be drawn with caution, because the findings only applied to voice regarding the organization as a whole (and not to voice regarding the own team), and because of methodological limitations. However, the findings are consistent with the ideas that (a) people low in 2D:4D tend to strive to attain and maintain social status and that (b) remaining silent about perceived problems in the organization is-at least for low-ranked employees-a means to achieve this goal. PMID- 28658300 TI - The association between levels of alcohol consumption and mental health problems and academic performance among young university students. AB - PURPOSE: Mental health problems and harmful alcohol consumption have been found to be high among young university students compared to the general population in Australia. This research aimed to investigate the association between levels of drinking and mental health problems and academic performance among university students aged 18 to 24 years. METHODS: This study used a quantitative cross sectional design using data that were collected in 2014 as part of the Youth Alcohol Project (YAP). Participants were randomly drawn from a cross sectional sample of 6000 undergraduate students. Included in the study were only students who were within the age of 18-24, undergraduate, and internally enrolled at the main campus. A total of 2518 undergraduate students aged 18 to 24 years who were enrolled internally at Curtin University Bentley campus were randomly recruited. Data were collected through an online survey. Students were invited to participate in the study through their student email address. The email invitations coincided with the release of semester results to increase the likelihood of students accessing their emails. A further 628 students were randomly recruited through face to face intercept survey during the campus market days. Data were collected by trained research assistants. Validated instruments were used to collected data on levels of alcohol consumption, mental health, and academic performance. RESULTS: A considerable proportion of participants (44%) reported consuming alcohol at hazardous or harmful levels. Multiple logistic regression analysis showed that students who were consuming alcohol at hazardous levels were 1.2 times more likely to report psychological distress than those with lower levels of alcohol consumption (aOR 1.2, 95% CI: 1.1-1.5). In addition, being late for class (aOR 1.7, 95% CI:1.1-2.4), missing classes (aOR = 2.6, 95% CI: 1.9-2.6), inability to concentrate in class (aOR = 2.6, 95% CI: 1.9-3.4), and inability to complete assignments (aOR = 3.5, 95% CI 2.0-6.0) independently predicted for moderate or hazardous alcohol consumption. CONCLUSION: The study shows that a considerable proportion of undergraduate students at university consume alcohol at hazardous or harmful levels. In addition, high levels of alcohol consumption are associated with poor academic performance and mental health outcomes among students. The results of the study warrant multi-strategy interventions that focus on policy, organisational, educational, environmental and economic strategies that will help to reduce alcohol related harms among university students. PMID- 28658301 TI - The effect of anti-rheumatic medications for coronary artery diseases risk in patients with rheumatoid arthritis might be changed over time: A nationwide population-based cohort study. AB - OBJECTIVES: To determine whether anti-rheumatic drug usage is associated with risk of coronary artery diseases (CAD) in incident Rheumatoid Arthritis (RA) patients. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database. The study cohort comprised 6260 patients who were newly diagnosed with RA between 2001-2010. The study endpoint was occurrence of CAD according to the ICD-9-CM codes. We used the WHO Defined Daily Dose (DDD) as a tool to assess the drugs exposure. The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) of disease after controlling for demographic and other co-morbidities. When the proportionality assumption is violated, a spline curve of the Scaled Schoenfeld residuals is fitted to demonstrate the estimated effect on CAD over time for drug usage. RESULTS: Among RA patients, use of celecoxib, and etoricoxib was associated with significantly decreased incidence of CAD. The adjusted HR(95% CI) of CAD for low-dose celecoxib (DDD?1) and high-dose user were 0.47(0.34, 0.65) and 0.37(0.24, 0.58) during the 4 year follow-up time; however, it became 0.98(0.70, 1.37) and1.29(0.85, 1.95). Adjusted HR(95% CI) of CAD for etoricoxib users remained 0.47(0.26, 0.84). CONCLUSIONS: This study revealed association of decreased CAD risk in RA patients taking 2 different kinds of COX-2i in comparison with nonusers. The effect might be changed over time, after about 4 years. PMID- 28658302 TI - One ligand, two regulators and three binding sites: How KDPG controls primary carbon metabolism in Pseudomonas. AB - Effective regulation of primary carbon metabolism is critically important for bacteria to successfully adapt to different environments. We have identified an uncharacterised transcriptional regulator; RccR, that controls this process in response to carbon source availability. Disruption of rccR in the plant associated microbe Pseudomonas fluorescens inhibits growth in defined media, and compromises its ability to colonise the wheat rhizosphere. Structurally, RccR is almost identical to the Entner-Doudoroff (ED) pathway regulator HexR, and both proteins are controlled by the same ED-intermediate; 2-keto-3-deoxy-6 phosphogluconate (KDPG). Despite these similarities, HexR and RccR control entirely different aspects of primary metabolism, with RccR regulating pyruvate metabolism (aceEF), the glyoxylate shunt (aceA, glcB, pntAA) and gluconeogenesis (pckA, gap). RccR displays complex and unusual regulatory behaviour; switching repression between the pyruvate metabolism and glyoxylate shunt/gluconeogenesis loci depending on the available carbon source. This regulatory complexity is enabled by two distinct pseudo-palindromic binding sites, differing only in the length of their linker regions, with KDPG binding increasing affinity for the 28 bp aceA binding site but decreasing affinity for the 15 bp aceE site. Thus, RccR is able to simultaneously suppress and activate gene expression in response to carbon source availability. Together, the RccR and HexR regulators enable the rapid coordination of multiple aspects of primary carbon metabolism, in response to levels of a single key intermediate. PMID- 28658303 TI - Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation. AB - Chronic inflammation is a well-known precursor for cancer development and proliferation. We have recently demonstrated that high salt (NaCl) synergizes with sub-effective interleukin (IL)-17 to induce breast cancer cell proliferation. However, the exact molecular mechanisms mediating this effect are unclear. In our current study, we adopted a phosphoproteomic-based approach to identify salt modulated kinase-proteome specific molecular targets. The phosphoprotemics based binary comparison between heavy labelled MCF-7 cells treated with high salt (Delta0.05 M NaCl) and light labelled MCF-7 cells cultured under basal conditions demonstrated an enhanced phosphorylation of Serine-493 of SIK3 protein. The mRNA transcript and protein expression analysis of SIK3 in MCF 7 cells demonstrated a synergistic enhancement following co-treatment with high salt and sub-effective IL-17 (0.1 ng/mL), as compared to either treatments alone. A similar increase in SIK3 expression was observed in other breast cancer cell lines, MDA-MB-231, BT20, and AU565, while non-malignant breast epithelial cell line, MCF10A, did not induce SIK3 expression under similar conditions. Biochemical studies revealed mTORC2 acted as upstream mediator of SIK3 phosphorylation. Importantly, cell cycle analysis by flow cytometry demonstrated SIK3 induced G0/G1-phase release mediated cell proliferation, while SIK3 silencing abolished this effect. Also, SIK3 induced pro-inflammatory arginine metabolism, as evidenced by upregulation of the enzymes iNOS and ASS-1, along with downregulation of anti-inflammatory enzymes, arginase-1 and ornithine decarboxylase. Furthermore, gelatin zymography analysis has demonstrated that SIK3 induced expression of tumor metastatic CXCR4 through MMP-9 activation. Taken together, our data suggests a critical role of SIK3 in mediating three important hallmarks of cancer namely, cell proliferation, inflammation and metastasis. These studies provide a mechanistic basis for the future utilization of SIK3 as a key drug discovery target to improve breast cancer therapy. PMID- 28658304 TI - Validating alpha-particle emission from 211At-labeled antibodies in single cells for cancer radioimmunotherapy using CR-39 plastic nuclear track detectors. AB - Recently, 211At has received increasing attention as a potential radionuclide for cancer radioimmunotherapy. It is a alpha-particle emitter, which is extremely effective against malignant cells. We demonstrate a method to verify the efficiency of 211At-labeled trastuzumab antibodies (211At-trastuzumab) against HER2 antigens, which has not been determined for radioimmunotherapy. A CR-39 plastic nuclear detector is used for measuring the position and the linear energy transfer (LET) of individual 211At alpha- particle tracks. The tracks and 211At trastuzumab-binding cells were co-visualized by using the geometric information recorded on the CR-39. HER2-positive human gastric cancer cells (NCI-N87), labelled with 211At-trastuzumab, were dropped on the centre of the CR-39 plate. Microscope images of the cells and the corresponding alpha-tracks acquired by position matching were obtained. In addition, 3.5 cm * 3.5 cm macroscopic images of the whole plate were acquired. The distribution of number of alpha-particles emitted from single cells suggests that 80% of the 211At-trastuzumab-binding cells emitted alpha-particles. It also indicates that the alpha-particles may strike the cells several times along their path. The track-averaged LET of the alpha-particles is evaluated to be 131 keV/MUm. These results will enable quantitative evaluation of delivered doses to target cells, and will be useful for the in vitro assessment of 211At-based radioimmunotherapeutic agents. PMID- 28658305 TI - Predicting human protein subcellular localization by heterogeneous and comprehensive approaches. AB - Drug development and investigation of protein function both require an understanding of protein subcellular localization. We developed a system, REALoc, that can predict the subcellular localization of singleplex and multiplex proteins in humans. This system, based on comprehensive strategy, consists of two heterogeneous systematic frameworks that integrate one-to-one and many-to-many machine learning methods and use sequence-based features, including amino acid composition, surface accessibility, weighted sign aa index, and sequence similarity profile, as well as gene ontology function-based features. REALoc can be used to predict localization to six subcellular compartments (cell membrane, cytoplasm, endoplasmic reticulum/Golgi, mitochondrion, nucleus, and extracellular). REALoc yielded a 75.3% absolute true success rate during five fold cross-validation and a 57.1% absolute true success rate in an independent database test, which was >10% higher than six other prediction systems. Lastly, we analyzed the effects of Vote and GANN models on singleplex and multiplex localization prediction efficacy. REALoc is freely available at http://predictor.nchu.edu.tw/REALoc. PMID- 28658306 TI - Contrasting bacterial communities in two indigenous Chionochloa (Poaceae) grassland soils in New Zealand. AB - The cultivation of grasslands can modify both bacterial community structure and impact on nutrient cycling as well as the productivity and diversity of plant communities. In this study, two pristine New Zealand grassland sites dominated by indigenous tall tussocks (Chionochloa pallens or C. teretifolia) were examined to investigate the extent and predictability of variation of the bacterial community. The contribution of free-living bacteria to biological nitrogen fixation is predicted to be ecologically significant in these soils; therefore, the diazotrophic community was also examined. The C. teretifolia site had N-poor and poorly-drained peaty soils, and the C. pallens had N-rich and well-drained fertile soils. These soils also differ in the proportion of organic carbon (C), Olsen phosphorus (P) and soil pH. The nutrient-rich soils showed increased relative abundances of some copiotrophic bacterial taxa (including members of the Proteobacteria, Bacteroidetes and Firmicutes phyla). Other copiotrophs, Actinobacteria and the oliogotrophic Acidobacteria showed increased relative abundance in nutrient-poor soils. Greater diversity based on 16S rRNA gene sequences and the Tax4Fun prediction of enhanced spore formation associated with nutrient-rich soils could indicate increased resilience of the bacterial community. The two sites had distinct diazotrophic communities with higher diversity in C. teretifolia soils that had less available nitrate and ammonium, potentially indicating increased resilience of the diazotroph community at this site. The C. teretifolia soils had more 16S rRNA gene and nifH copies per g soil than the nutrient rich site. However, the proportion of the bacterial community that was diazotrophic was similar in the two soils. We suggest that edaphic and vegetation factors are contributing to major differences in the composition and diversity of total bacterial and diazotrophic communities at these sites. We predict the differences in the communities at the two sites will result in different responses to environmental change. PMID- 28658307 TI - The reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland. AB - The aim of this study was to explore the reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland. The study took the form of semi-structured interviews. Forty-one pharmaceutical companies and pharmaceutical wholesalers were invited to participate in the study. The pharmaceutical companies were the member organizations of Pharma Industry Finland (PIF) (N = 30) and the Finnish Generic Pharmaceutical Association (FGPA) (N = 7). One company which is a central player in the pharmaceutical market in Finland but does not belong to PIF or FGPA was also invited. The pharmaceutical wholesalers were those with a nationwide distribution network (N = 3). A total of 30 interviews were conducted between March and June 2016. The data were subjected to qualitative thematic analysis. The most common reasons behind medicine shortages in Finland were the small size of the pharmaceutical market (29/30), sudden or fluctuating demand (28/30), small stock sizes (25/30), long delivery time (23/30) and a long or complex production chain (23/30). The reasons for the medicine shortages were supply-related more often than demand-related. However, the reasons were often complex and there was more than one reason behind a shortage. Supply-related reasons behind shortages commonly interfaced with the country-specific characteristics of Finland, whereas demand-related reasons were commonly associated with the predictability and attractiveness of the market. Some reasons, such as raw material shortages, were considered global and thus had similar effects on other countries. PMID- 28658308 TI - Unprotected left main revascularization: Percutaneous coronary intervention versus coronary artery bypass. An updated systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: The optimal treatment of unprotected left main (UPLM) with either PCI or CABG remains uncertain. AIM: The purpose of this study was to determine the comparative safety and efficacy of PCI versus CABG in patients with UPLM disease. METHODS: Search of BioMedCentral, CENTRAL, mRCT, PubMed, major cardiological congresses proceedings and references cross-check (updated November 2016). Outcomes were the rate of MACE [all cause death, MI, stroke], the rates of the individual components of MACE and the rate of target vessel revascularisation (TVR). RESULTS: We identified 6 Randomised Controlled Trials totalling 4717 patients allocated to PCI or CABG. At 1 year follow up, PCI and CABG were substantially equivalent with respect to the rates of MACE [PCI 8.5% vs CABG 8.9%, OR 1.02,(0.76-1.36), p = 0.9], death [PCI 5.4% vs CABG 6.6%, OR 0.81,(0.63 1.03),p = 0.08] and MI [PCI 3.4% vs CABG 4.3%, OR 0.80(0.59-1.07), p = 0.14]. Notably, PCI was associated with a significantly lower rate of stroke [PCI 0.6% vs CABG 1.8%, OR 0.36,(0.17-0.79), p = 0.01] and with a significantly higher rate of TVR [PCI 8.7% vs CABG 4.5%, OR 2.00(1.46-2.75), p<0.01]. At a median follow up of 5years, the rates of MACE were similar between the two strategies: PCI 14.6% vs CABG 13.8%, OR 1.02(0.76-1.38), p = 0.89. Likewise, the rates of death [PCI 8% and CABG 7.7%, OR 1(0.77-1.31), P = 0.9], MI [PCI 6.1% vs CABG 5%, OR 1.41(0.85 2.34), P = 0.19, I2 59%], and stroke [PCI 2% vs CABG 2.2%, OR 0.85(0.42-1.81), p = 0.65,] were similar while PCI was associated with a significantly higher rate of TVR [14.5% vs CABG 8.9%, OR 1.73(1.41-2.13), p<0.01]. CONCLUSION: In patients with UPLM disease, PCI and CABG are associated with similar rates of MACE and mortality at 1 year as well as after 5 years. Differences can be detected for individual end points at both short and long term FU. PMID- 28658309 TI - Microstructural integrity of white matter tracts amongst older fallers: A DTI study. AB - OBJECTIVES: This study assesses the whole brain microstructural integrity of white matter tracts (WMT) among older individuals with a history of falls compared to non-fallers. METHODS: 85 participants (43 fallers, 42 non-fallers) were evaluated with conventional MRI and diffusion tensor imaging (DTI) sequences of the brain. DTI metrics were obtained from selected WMT using tract-based spatial statistics (TBSS) method. This was followed by binary logistic regression to investigate the clinical variables that could act as confounding elements on the outcomes. The TBSS analysis was then repeated, but this time including all significant predictor variables from the regression analysis as TBSS covariates. RESULTS: The mean diffusivity (MD) and axial diffusivity (AD) and to a lesser extent radial diffusivity (RD) values of the projection fibers and commissural bundles were significantly different in fallers (p < 0.05) compared to non fallers. However, the final logistic regression model obtained showed that only functional reach, white matter lesion volume, hypertension and orthostatic hypotension demonstrated statistical significant differences between fallers and non-fallers. No significant differences were found in the DTI metrics when taking into account age and the four variables as covariates in the repeated analysis. CONCLUSION: This DTI study of 85 subjects, do not support DTI metrics as a singular factor that contributes independently to the fall outcomes. Other clinical and imaging factors have to be taken into account. PMID- 28658310 TI - The prognostic value of abnormally expressed lncRNAs in colorectal cancer: A meta analysis. AB - BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer type and the third leading cause of cancer-related deaths worldwide, it is urgently needed to discover a new marker for the progress of CRC. Many long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in CRC, and may be feasible as effective biomarkers and prognostic factors. The aim of this study was to identify the prognostic value of various lncRNAs in CRC. METHODS: Pubmed, Web of Science, Embase and Cochrane Library were searched for potentially related studies. A total of 34 eligible studies including 30 on overall survival (OS), 7 on disease-free survival (DFS), 1 on relapse-free survival (RFS), 2 on disease specific survival (DSS) and 29 on clinicopathological features were qualified from the databases. RESULTS: The results showed that the expression levels of lncRNAs were significantly associated with poor OS (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.68-2.57, P<0.001, I2 = 70%), DFS (HR = 1.79, 95% CI = 1.54-2.08, P<0.001, I2 = 6%) and DSS (HR = 0.11, 95% CI = 0.02-0.54, P = 0.007, I2 = 14%). Subgroup analysis further showed that lncRNA transcription level was significantly associated with tumor differentiation (odds ratio (OR) = 0.51, 95% CI = 0.34-0.77, P = 0.001), lymph node metastasis (OR = 1.63, 95% CI = 1.23-2.17, P = 0.0007), distant metastasis (OR = 2.06, 95% CI = 1.29-3.30, P = 0.002), TNM stage (OR = 0.44, 95% CI = 0.32-0.62, P<0.001), tumor invasion depth (OR = 0.48, 95% CI = 0.39-0.60, P<0.001). CONCLUSIONS: The meta-analysis demonstrated that abnormal lncRNA transcription level may serve as a promising indicator for prognostic of patients with CRC. PMID- 28658311 TI - Evolutionary divergence of the vertebrate TNFAIP8 gene family: Applying the spotted gar orthology bridge to understand ohnolog loss in teleosts. AB - Comparative functional genomic studies require the proper identification of gene orthologs to properly exploit animal biomedical research models. To identify gene orthologs, comprehensive, conserved gene synteny analyses are necessary to unwind gene histories that are convoluted by two rounds of early vertebrate genome duplication, and in the case of the teleosts, a third round, the teleost genome duplication (TGD). Recently, the genome of the spotted gar, a holostean outgroup to the teleosts that did not undergo this third genome duplication, was sequenced and applied as an orthology bridge to facilitate the identification of teleost orthologs to human genes and to enhance the power of teleosts as biomedical models. In this study, we apply the spotted gar orthology bridge to help describe the gene history of the vertebrate TNFAIP8 family. Members of the TNFAIP8 gene family have been linked to regulation of immune function and homeostasis and the development of multiple cancer types. Through a conserved gene synteny analysis, we identified zebrafish orthologs to human TNFAIP8L1 and TNFAIP8L3 genes and two co-orthologs to human TNFAIP8L2, but failed to identify an ortholog to human TNFAIP8. Through the application of the orthology bridge, we determined that teleost orthologs to human TNFAIP8 genes were likely lost in a genome inversion event after their divergence from their common ancestor with spotted gar. These findings demonstrate the value of this enhanced approach to gene history analysis and support the development of teleost models to study complex questions related to an array of biomedical issues, including immunity and cancer. PMID- 28658312 TI - Red rot resistant transgenic sugarcane developed through expression of beta-1,3 glucanase gene. AB - Sugarcane (Saccharum spp.) is a commercially important crop, vulnerable to fungal disease red rot caused by Colletotrichum falcatum Went. The pathogen attacks sucrose accumulating parenchyma cells of cane stalk leading to severe losses in cane yield and sugar recovery. We report development of red rot resistant transgenic sugarcane through expression of beta-1,3-glucanase gene from Trichoderma spp. The transgene integration and its expression were confirmed by quantitative reverse transcription-PCR in first clonal generation raised from T0 plants revealing up to 4.4-fold higher expression, in comparison to non transgenic sugarcane. Bioassay of transgenic plants with two virulent C. falcatum pathotypes, Cf 08 and Cf 09 causing red rot disease demonstrated that some plants were resistant to Cf 08 and moderately resistant to Cf 09. The electron micrographs of sucrose storing stalk parenchyma cells from these plants displayed characteristic sucrose-filled cells inhibiting Cf 08 hyphae and lysis of Cf 09 hyphae; in contrast, the cells of susceptible plants were sucrose depleted and prone to both the pathotypes. The transgene expression was up-regulated (up to 2.0-fold in leaves and 5.0-fold in roots) after infection, as compared to before infection in resistant plants. The transgene was successfully transmitted to second clonal generation raised from resistant transgenic plants. beta-1,3 glucanase protein structural model revealed that active sites Glutamate 628 and Aspartate 569 of the catalytic domain acted as proton donor and nucleophile having role in cleaving beta-1,3-glycosidic bonds and pathogen hyphal lysis. PMID- 28658313 TI - A novel in vivo model of puncture-induced iris neovascularization. AB - PURPOSE: To assess iris neovascularization by uveal puncture of the mouse eye and determine the role of angiogenic factors during iris neovascularization. METHODS: Uveal punctures were performed on BalbC mouse eyes to induce iris angiogenesis. VEGF-blockage was used as an anti-angiogenic treatment, while normoxia- and hypoxia-conditioned media from retinal pigment epithelium (RPE) cells was used as an angiogenic-inducer in this model. Iris vasculature was determined in vivo by noninvasive methods. Iris blood vessels were stained for platelet endothelial cell adhesion molecule-1 and vascular sprouts were counted as markers of angiogenesis. Expression of angiogenic and inflammatory factors in the puncture induced model were determined by qPCR and western blot. RESULTS: Punctures led to increased neovascularization and sprouting of the iris. qPCR and protein analysis showed an increase of angiogenic factors, particularly in the plasminogen activating receptor and inflammatory systems. VEGF-blockage partly reduced iris neovascularization, and treatment with hypoxia-conditioned RPE medium led to a statistically significant increase in iris neovascularization. CONCLUSIONS: This study presents the first evidence of a puncture-induced iris angiogenesis model in the mouse. In a broader context, this novel in vivo model of neovascularization has the potential for noninvasive evaluation of angiogenesis modulating substances. PMID- 28658314 TI - Early evidence (late 2nd millennium BCE) of plant-based dyeing of textiles from Timna, Israel. AB - In this article, we focus on the analysis of dyed textile fragments uncovered at an early Iron Age (11th-10th centuries BCE) copper smelting site during new excavations in the Timna Valley conducted by the Central Timna Valley (CTV) Project, as well as those found by the Arabah Expedition at the Hathor Temple (Site 200), dated to the Late Bronze/early Iron Ages (13th-11th centuries BCE). Analysis by HPLC-DAD identified two organic dyestuffs, Rubia tinctorum L. and indigotin, from a plant source (probably Isatis tinctoria L.). They are among the earliest plants known in the dyeing craft and cultivated primarily for this purpose. This study provides the earliest evidence of textiles dyed utilizing a chemical dyeing process based on an industrial dyeing plant from the Levant. Moreover, our results shed new light on the society operating the copper mines at the time, suggesting the existence of an elite that was interested in these high quality textiles and invested efforts in procuring them by long-distance trade. PMID- 28658315 TI - Choroidal change in acute anterior uveitis associated with human leukocyte antigen-B27. AB - PURPOSE: To evaluate choroidal changes in eyes with acute anterior uveitis associated with human leukocyte antigen (HLA)-B27. METHODS: In 44 patients with first-onset, unilateral, acute-onset (<1 week) anterior uveitis for which diagnostic work-ups revealed positivity only for HLA-B27, wide-field three dimensional volumetric raster scan using swept-source optical coherence tomography was performed for both eyes. Choroidal thickness was measured by automated segmentation and thickness mapping and compared between eyes with uveitis and the fellow eyes at baseline. Choroidal thickness was compared before and after topical and/or systemic corticosteroid therapy. Relative choroidal thickening was defined as the choroidal thickness of the uveitic eye minus that of the corresponding eye and correlated with the degree of intraocular inflammation. RESULTS: Compared to the fellow eyes, eyes with acute anterior uveitis showed significant choroidal thickening on the subfoveal and parafoveal areas at baseline (all P <0.05). En face choroidal imaging showed dilation of large choroidal vessels on the macula. Relative choroidal thickening significantly correlated with the degree of anterior chamber inflammation at baseline (correlation coefficient = 0.341, P = 0.023). After treating inflammation, the choroid on the macula thinned significantly (from 262.1 +/- 66.5 to 239.5 +/- 61.0 MUm in the subfoveal choroid, P<0.001). CONCLUSIONS: Eyes with HLA-B27-associated anterior uveitis showed significant choroidal thickening at acute phase that subsequently decreased after treatment, indicating subclinical choroidal inflammation in the eyes. Choroidal thickness might indicate disease activity in acute anterior uveitis associated with HLA-B27. PMID- 28658316 TI - Morphological and genetic diversity of camu-camu [Myrciaria dubia (Kunth) McVaugh] in the Peruvian Amazon. AB - Camu-camu [Myrciaria dubia (Kunth) McVaugh] is currently an important and promising fruit species grown in the Peruvian Amazon, as well as in Brazil, Colombia, and Bolivia. The species is valued for its high content of fruit-based vitamin C. Large plantations have been established only in the last two decades, and a substantial part of the production is still obtained by collecting fruits from the wild. Domestication of the species is at an early stage; most farmers cultivate the plants without any breeding, or only through a simple mass selection process. The main objective of the study was to characterize morphological and genetic variation within and among cultivated and natural populations of camu-camu in the Peruvian Amazon. In total, we sampled 13 populations: ten wild in the Iquitos region, and three cultivated in the Pucallpa region in the Peruvian Amazon. To assess the genetic diversity using seven microsatellite loci, we analyzed samples from ten individual trees per each population (n = 126). Morphological data was collected from five trees from each population (n = 65). The analysis did not reveal statistically significant differences for most of the morphological descriptors. For wild and cultivated populations, the observed heterozygosity was 0.347 and 0.404 (expected 0.516 and 0.506), and the fixation index was 0.328 and 0.200, respectively. Wild populations could be divided into two groups according to the UPGMA and STRUCTURE analysis. In cultivated populations, their approximate origin was determined. Our findings indicate a high genetic diversity among the populations, but also a high degree of inbreeding within the populations. This can be explained by either the isolation of these populations from each other or the low number of individuals in some populations. This high level of genetic diversity can be explored for the selection of superior individuals for further breeding. PMID- 28658317 TI - Climatic anomaly affects the immune competence of California sea lions. AB - The past decades have been characterized by a growing number of climatic anomalies. As these anomalies tend to occur suddenly and unexpectedly, it is often difficult to procure empirical evidence of their effects on natural populations. We analysed how the recent sea surface temperature (SST) anomaly in the northeastern Pacific Ocean affects body condition, nutritional status, and immune competence of California sea lion pups. We found that pup body condition and blood glucose levels of the pups were lower during high SST events, although other biomarkers of malnutrition remained unchanged, suggesting that pups were experiencing early stages of starvation. Glucose-dependent immune responses were affected by the SST anomaly; specifically, pups born during high SST events had lower serum concentrations of IgG and IgA, and were unable to respond to an immune challenge. This means that not only were pups that were born during the SST anomaly less able to synthesize protective antibodies; they were also limited in their ability to respond rapidly to nonspecific immune challenges. Our study provides empirical evidence that atypical climatic conditions can limit energetic reserves and compromise physiological responses that are essential for the survival of a marine top predator. PMID- 28658318 TI - WEclMon - A simple and robust camera-based system to monitor Drosophila eclosion under optogenetic manipulation and natural conditions. AB - Eclosion in flies and other insects is a circadian-gated behaviour under control of a central and a peripheral clock. It is not influenced by the motivational state of an animal, and thus presents an ideal paradigm to study the relation and signalling pathways between central and peripheral clocks, and downstream peptidergic regulatory systems. Little is known, however, about eclosion rhythmicity under natural conditions, and research into this direction is hampered by the physically closed design of current eclosion monitoring systems. We describe a novel open eclosion monitoring system (WEclMon) that allows the puparia to come into direct contact with light, temperature and humidity. We demonstrate that the system can be used both in the laboratory and outdoors, and shows a performance similar to commercial closed funnel-type monitors. Data analysis is semi-automated based on a macro toolset for the open imaging software Fiji. Due to its open design, the WEclMon is also well suited for optogenetic experiments. A small screen to identify putative neuroendocrine signals mediating time from the central clock to initiate eclosion showed that optogenetic activation of ETH-, EH and myosuppressin neurons can induce precocious eclosion. Genetic ablation of myosuppressin-expressing neurons did, however, not affect eclosion rhythmicity. PMID- 28658319 TI - Hypomorphic A20 expression confers susceptibility to psoriasis. AB - Psoriasis is a common inflammatory skin disease that affects approximately 1% of the population worldwide. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene polymorphisms have been strongly associated with psoriasis susceptibility. In this study, we investigate how TNFAIP3, also known as A20, may regulate psoriasis susceptibility. We found that haplo-insufficient A20+/- mice develop severe toll-like receptor (TLR)-induced skin inflammation compared to wild type mice owing to amplified production of interleukin (IL)-17 and IL-23. Examination of TNFAIP3 mRNA expression in skin biopsies from patients with psoriasis revealed reduced expression in both involved and uninvolved skin. Our results demonstrate the clinical importance of reduced dermal expression of A20 in psoriasis and suggest that A20 restriction of the IL-23/17 axis protects against psoriasis. PMID- 28658320 TI - A U-Pb zircon age constraint on the oldest-recorded air-breathing land animal. AB - The oldest-known air-breathing land animal is the millipede Pneumodesmus newmani, found in the Cowie Harbour Fish Bed at Stonehaven, Scotland. Here we report the youngest, most concordant 238U-206Pb zircon age from ash below the fish bed of 413.7+/-4.4 Ma (+/-2sigma), whereas the youngest age from a tuffaceous sandstone above the fish bed is statistically indistinguishable at 414.3+/-7.1 Ma. The Cowie Harbour Fish Bed thus appears to be lowermost Devonian (Lochkovian), contrary to the previously accepted mid-Silurian age based on palynomorphs from adjacent exposures. This has implications for the evolutionary timetable of land colonization, as the Cowie ages overlap late Lochkovian zircon ages reported elsewhere for andesite below the nearby (~50 mi) Rhynie Chert, which has more advanced terrestrial biota. The results postdate the possible late Silurian Ludford Lane locality in Shropshire, England. Pneumodesmus newmani is thus not the earliest air-breathing land animal, unless the Ludford Lane locality is younger than presently assigned. PMID- 28658321 TI - Effect of the p53-tristetraprolin-stathmin-1 pathway on trophoblasts at maternal fetal interface. AB - PROBLEM: To reveal the effect of p53-tristetraprolin-stathmin-1 signaling on trophoblasts and recurrent spontaneous abortion (RSA). METHOD OF STUDY: Stathmin 1 (STMN1), p53, and tristetraprolin (TTP) expression in paraffin-embedded villus tissue was determined using immunohistochemistry. HTR-8/SVneo cells were treated with doxorubicin to activate p53; STMN1 and TTP levels were detected by quantitative reverse transcription-PCR and western blotting. Western blotting and immunofluorescence were used to investigate STMN1 expression after TTP overexpression or knockdown in HTR-8 cells. RESULTS: STMN1 was downregulated and p53 was upregulated in the villus tissue from patients with RSA. Doxorubicin decreased STMN1 expression but enhanced TTP expression in HTR-8 cells. In vitro, TTP overexpression inhibited STMN1 production; TTP knockdown promoted it. TTP downregulated STMN1 expression in trophoblasts by directly binding its 3' untranslated region. CONCLUSIONS: TTP modulates trophoblast function and interacts with STMN1 and p53, and is related to pregnancy outcomes. PMID- 28658322 TI - Prevalence of ESBL-producing Pseudomonas aeruginosa isolates in Warsaw, Poland, detected by various phenotypic and genotypic methods. AB - Knowledge of the prevalence of ESBL enzymes among P. aeruginosa strains compared to the Enterobacteraiceae family is limited. The phenotypic tests recommended by EUCAST for the detection of ESBL-producing Enterobacteriaceae are not always suited for P. aeruginosa strains. This is mainly due to the presence of other families of ESBLs in P. aeruginosa isolates more often than in Enterobacteriaceae, production of natural AmpC cephalosporinase and its overexpression, and co-production of metallo-beta-lactamases. The aim of this study was to determine the occurrence of ESBLs in P. aeruginosa isolated from patients from hospitals in Warsaw, to evaluate the ESBL production of these isolates using currently available phenotypic tests, their modifications, multiplex PCR and molecular typing of ESBL-positive isolates by PFGE. Clinical isolates of P. aeruginosa were collected in 2000-2014 from four Warsaw hospitals. Based on the data obtained in this study, we suggest using three DDST methods with inhibitors, such as clavulanic acid, sulbactam and imipenem, to detect ESBL producing P. aeruginosa strains. Depending on the appearance of the plates, we suggest a reduction in the distance between discs with antibiotics to 15 mm and the addition of boronic acid at 0.4 mg per disc. The analysed isolates carried genes encoding ESBL from the families VEB (69 isolates with VEB-9), GES (6 with GES-1, 1 GES-5, 5 GES-13 and 2 with GES-15), OXA-2 (12 with OXA-15, 1 OXA-141, 1 OXA-210, 1 OXA-543 and 1 with OXA-544) and OXA-10 (5 isolates with OXA-74 and one with OXA-142). The most important result of this study was the discovery of three new genes, blaGES-15, blaOXA-141 and blaOXA-142; their nucleotide sequences have been submitted to the NCBI GenBank. It is also very important to note that this is the first report on the epidemiological problem of VEB-9-producing bacterial strains, not only in Poland but also worldwide. PMID- 28658323 TI - Using c-kit to genetically target cerebellar molecular layer interneurons in adult mice. AB - The cerebellar system helps modulate and fine-tune motor action. Purkinje cells (PCs) provide the sole output of the cerebellar cortex, therefore, any cerebellar involvement in motor activity must be driven by changes in PC firing rates. Several different cell types influence PC activity including excitatory input from parallel fibers and inhibition from molecular layer interneurons (MLIs). Similar to PCs, MLI activity is driven by parallel fibers, therefore, MLIs provide feed-forward inhibition onto PCs. To aid in the experimental assessment of how molecular layer inhibition contributes to cerebellar function and motor behavior, we characterized a new knock-in mouse line with Cre recombinase expression under control of endogenous c-kit transcriptional machinery. Using these engineered c-Kit mice, we were able to obtain high levels of conditional MLI transduction in adult mice using Cre-dependent viral vectors without any PC or granule cell labeling. We then used the mouse line to target MLIs for activity perturbation in vitro using opto- and chemogenetics. PMID- 28658324 TI - Expanding the geography of evapotranspiration: An improved method to quantify land-to-air water fluxes in tropical and subtropical regions. AB - The development of new reference evapotranspiration (ETo) methods hold significant promise for improving our quantitative understanding of climatic impacts on water loss from the land to the atmosphere. To address the challenge of estimating ETo in tropical and subtropical regions where direct measurements are scarce we tested a new method based on geographical patterns of extraterrestrial radiation (Ra) and atmospheric water potential (Psiair). Our approach consisted of generating daily estimates of ETo across several climate zones in Brazil-as a model system-which we compared with standard EToPM (Penman Monteith) estimates. In contrast with EToPM, the simplified method (EToMJS) relies solely on Psiair calculated from widely available air temperature (oC) and relative humidity (%) data, which combined with Ra data resulted in reliable estimates of equivalent evaporation (Ee) and ETo. We used regression analyses of Psiair vs EToPM and Ee vs EToPM to calibrate the EToMJS(Psiair) and EToMJS estimates from 2004 to 2014 and between seasons and climatic zone. Finally, we evaluated the performance of the new method based on the coefficient of determination (R2) and correlation (R), index of agreement "d", mean absolute error (MAE) and mean reason (MR). This evaluation confirmed the suitability of the EToMJS method for application in tropical and subtropical regions, where the climatic information needed for the standard EToPM calculation is absent. PMID- 28658326 TI - Otolith shape variability and associated body growth differences in giant grenadier, Albatrossia pectoralis. AB - Fish stocks can be defined by differences in their distribution, life history, and genetics. Managing fish based on stock structure is integral to successful management of a species because fishing may affect stocks disproportionately. Genetic and environmental differences can affect the shape and growth of otoliths and these differences may be indicative of stock structure. To investigate the potential for speciation or stock structure in giant grenadier, Albatrossia pectoralis, we quantified the shape of female giant grenadier otoliths and compared body growth rates for fish with three otolith shapes; shape types were classified visually by an experienced giant grenadier age reader, and were not defined by known distribution or life history differences. We found extreme variation in otolith shape among individuals; however, the shapes were a gradation and not clearly defined into three groups. The two more extreme shapes, visually defined as "hatchet" and "comb", were discernable based on principal component analyses of elliptical Fourier descriptors, and the "mixed" shape overlapped both of the extreme shapes. Fish with hatchet-shaped otoliths grew faster than fish with comb-shaped otoliths. A genetic test (cytochrome c oxidase 1 used by the Fish Barcode of Life Initiative) showed almost no variability among samples, indicating that the samples were all from one species. The lack of young specimens makes it difficult to link otolith shape and growth difference to life history. In addition, shape could not be correlated with adult movement patterns because giant grenadiers experience 100% mortality after capture and, therefore, cannot be tagged and released. Despite these limitations, the link between body growth and otolith shape indicates measurable differences that deserve more study. PMID- 28658325 TI - Comparison of efficacy of treatments for early syphilis: A systematic review and network meta-analysis of randomized controlled trials and observational studies. AB - BACKGROUND: Parenteral penicillin is the first-line regimen for treating syphilis, but unsuitable for some patients due to penicillin allergy and lacking health resources. Unfortunately, the efficacy of penicillin alternatives remains poorly understood. This study aimed to assess the efficacy of ceftriaxone and doxycycline/tetracycline in treating early syphilis relative to that of penicillin, and thereby to determine which antibiotic is a better replacement for penicillin. METHOD: By searching literature from PubMed, Cochrane Central Register of Controlled Trials, Embase, the Web of Science, and ClinicalTrials.gov and systematically screening relevant studies, eligible randomized controlled trials (RCTs) and observational studies on treatments with penicillin, doxycycline/tetracycline, and ceftriaxone for early syphilis were identified and combined in this systematic review. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were utilized to compare their serological response and treatment failure rates. At 12-month follow up, serological response rates were compared by a direct meta-analysis and network meta-analysis (NMA), while treatment failure rates were compared with a direct meta-analysis. RESULT: Three RCTs and seven cohort studies were included in this research. The results of NMA demonstrated that no significant differences existed in serological response rate at 12-month follow-up between any two of the three treatments (doxycycline/tetracycline vs. penicillin RR = 1.01, 95%CI 0.89-1.14; ceftriaxone vs. penicillin RR = 1.00, 95%CI 0.89-1.13; ceftriaxone vs. doxycycline/tetracycline RR = 0.99, 95%CI 0.96-1.03), which was consistent with the outcomes of the direct meta-analysis. In addition, the direct meta-analysis indicated that, at 12-month follow-up, penicillin and ceftriaxone treatment groups had similar treatment failure rates (RR = 0.92, 95%CI 0.12-6.93), while treatment failure rate was significantly lower among penicillin recipients than among doxycycline/tetracycline recipients (RR = 0.58, 95%CI 0.38-0.89). CONCLUSION: Ceftriaxone is as effective as penicillin in treating early syphilis with regard to serological response and treatment failure rate. Compared with doxycycline/tetracycline, ceftriaxone appears to be a better choice as the substitution of penicillin. PMID- 28658327 TI - Pancreatic cancer screening. PMID- 28658328 TI - Inguinodynia in patients submitted to conventional inguinal hernioplasty. AB - Objective: to evaluate the incidence of chronic pain and its impact on the quality of life of patients submitted to inguinal hernioplasty using the Lichtenstein technique. Methods:: this was a descriptive, cross-sectional study of patients operated under spinal anesthesia from February 2013 to February 2015 and who had already completed six postoperative months. We questioned patients about the presence of chronic inguinal pain and, if confirmed, invited them to a consultation in which we assessed the pain and its impact on quality of life. Results:: out of 158 patients submitted to the procedure, we identified 7.6% as having inguinodynia. Of these, there was an impact on the quality of life in 25%. Conclusion:: the incidence of inguinodynia after hernioplasty with repercussion in quality of life was similar to the one of found in the world literature. Objetivo: : avaliar a incidencia de dor cronica e o seu impacto na qualidade de vida de pacientes submetidos a hernioplastia inguinal pela tecnica de Lichtenstein. Metodos: : trata-se de estudo transversal descritivo, de pacientes operados de hernia inguinal pela tecnica de Lichtenstein sob anestesia raquidiana, no periodo de fevereiro de 2013 a fevereiro de 2015, e que ja haviam completado seis meses de pos-operatorio. Os pacientes foram questionados sobre a presenca de dor inguinal cronica e, caso confirmada, convidados a uma consulta na qual foi feita analise da qualidade da dor e seu impacto na qualidade de vida. Resultados: : do total de 158 pacientes submetidos ao procedimento, 7,6% foram identificados como portadores de inguinodinia. Destes, houve impacto na qualidade de vida em 25%. Conclusao: : observou-se incidencia de inguinodinia pos hernioplastia com repercussao na qualidade de vida semelhante a literatura mundial. PMID- 28658329 TI - Impact of non-adherent Ibuprofen foam dressing in the lives of patients with venous ulcers. AB - Objective :: to evaluate pain in patients with lower limb venous ulcer who used non-adherent Ibuprofen foam dressing (IFD). Methods :: we conducted a prospective study of patients with lower limb venous ulcers treated from April 2013 to August 2014. We used the Numerical Scale and McGill Pain Questionnaire, performing the assessments at the moment of inclusion of the patient in the study and every eight days thereafter, totaling five consultations. We divided the patients into two groups: 40 in the Study Group (SG), who were treated with IFD, and 40 in the Control Group (CG), treated with primary dressing, according to tissue type and exudate. Results :: at the first consultation, patients from both groups reported intense pain. On the fifth day, SG patients reported no pain and the majority of CG reported moderate pain. Regarding the McGill Pain Questionnaire, most patients of both groups reported sensations related to sensory, affective, evaluative and miscellaneous descriptors at the beginning of data collection; after the second assessment, there was slight improvement among the patients in the SG. After the third consultation, they no longer reported the mentioned descriptors. CG patients displayed all the sensations of these descriptors until the fifth visit. Conclusion :: non-adherent Ibuprofen foam dressing is effective in reducing the pain of patients with venous ulcers. Objetivo:: avaliar a dor em pacientes portadores de ulcera venosa de membros inferiores que utilizaram curativo de espuma nao aderente com Ibuprofeno (CEI). Metodos:: estudo prospectivo de pacientes portadores de ulceras venosas de membros inferiores tratados no periodo de abril de 2013 a agosto de 2014. Foram utilizados os questionarios Escala Numerica e Questionario de Dor de McGille, as avaliacoes eram feitas no momento da inclusao do paciente no estudo e a cada oito dias, totalizando cinco consultas. Os pacientes foram divididos em dois grupos: 40 no Grupo Estudo (GE), que foram tratados com CEI, e 40 no Grupo Controle (GC), tratados com curativo primario, conforme o tipo de tecido e exsudato. Resultados:: na primeira consulta os pacientes de ambos os grupos relataram dor intensa. No quinto dia os pacientes do GE relataram ausencia de dor e a maioria do GC relatou dor moderada. Com relacao ao Questionario de Dor de McGill, a maioria dos pacientes de ambos os grupos, no inicio da coleta de dados, relataram sensacoes relacionadas aos descritores sensorial, afetivo, avaliativo e miscelanea, sendo que entre os pacientes do GE houve discreta melhora apos a segunda consulta. Apos a terceira consulta ja nao referiram os descritores citados. Os pacientes do GC manifestaram todas as sensacoes desses descritores ate quinta a consulta. Conclusao:: o curativo de espuma nao aderente com Ibuprofeno e eficaz na reducao da dor de pacientes portadores de ulceras venosas. PMID- 28658330 TI - Transaxillary single-port subtotal parathyroidectomy: feasibility study in cadavers. AB - Objective: to test the minimally invasive technique of single-port transaxillary subtotal parathyroidectomy in non-formalized cadavers to evaluate its viability and reproduction. Method: we performed ten subtotal parathyroidectomies through a transaxillary TriPort access in cadavers. The technique consisted of access through the axillary fossa, creating a subcutaneous tunnel to the anterior cervical region, for handling of the thyroid gland and dissection and resection of the parathyroid glands. Results: all surgeries were successful. The mean time of surgery was 65 minutes (57-79 min), with uncomplicated identification of all anatomical structures. There was no need for complementary incisions in the cervical region. Conclusion: the transaxillary single-port subtotal parathyroidectomy technique was feasible and reproducible, suggesting an alternative for minimally invasive cervical surgery. PMID- 28658331 TI - Evaluation of Telomerase (hTert), Ki67 and p16ink4a expressions in low and high grade cervical intraepithelial lesions. AB - Objective:: to study the association between the histological grading of cervical intraepithelial neoplasia (CIN I, CIN II and CIN III) and the immunohistochemical expression for p16ink4a, hTert and Ki67, as well as to evaluate the relationship of these markers with the risk of recurrence after surgical treatment. Methods:: we studied a historical cohort of 94 women with intraepithelial lesions CIN I (low grade), CIN II and CIN III (high grades) submitted to conization or electrosurgical excision of the transformation zone. We evaluated all surgical specimens for immunohistochemical expression of p16ink4a, hTert and Ki67. Results:: the mean age was 38.2 years; p16ink4a was absent in most CIN I cases. In patients with CIN II or I/II (association of low and high-grade lesions), we observed p16ink4a <=10%. In patients with CIN III, we found a higher expression frequency of p16ink4a >50%. In CIN I, the majority had Ki67<=10% and low frequency of Ki67>50%. In the CIN III category, there were fewer patients with Ki67<=10%, and Ki67 was absent in most patients of CIN II and III groups. There was no association between hTert expression and histologic grade. There were no statistically significant differences between the expression of the markers in patients with and without recurrence. Conclusion:: there was a statistically significant association of p16ink4a and Ki67 with histological grade. The markers' expression, as for disease recurrence, was not statistically significant in the period evaluated. Objetivo:: estudar a associacao entre a graduacao histologica das neoplasias intraepiteliais cervicais (NIC I, NIC II e NIC III) e a expressao imuno-histoquimica para p16ink4a, hTert e Ki67, assim como, avaliar a relacao destes marcadores com o risco de recorrencia apos tratamento cirurgico. Metodos:: estudo de coorte historica de 94 mulheres portadoras de lesoes intraepiteliais NIC I (baixo grau), NIC II e NIC III (altos graus), submetidas a conizacao ou a excisao eletrocirurgica da zona de transformacao. Todas as pecas cirurgicas foram avaliadas quanto a expressao imuno-histoquimica para p16ink4a, hTert e Ki67. Resultados:: a media de idade das pacientes foi 38,2 anos. Nas pacientes NIC I, a p16ink4a estava ausente na maioria dos casos; nas pacientes NIC II ou I/II (associacao de lesoes de baixo e alto graus), observou-se frequencia de p16ink4a<=10%. Nas pacientes NIC III, observou-se maior frequencia de expressao de p16ink4a>50%. Na categoria NIC I, a maioria apresentava Ki67<=10% e baixa frequencia de Ki67>50%. Na categoria NIC III houve menor numero de pacientes com Ki67<=10%, sendo que a maior parte das pacientes tinha Ki67 ausente nos grupos NIC II e III. Nao houve associacao entre a expressao do marcador imuno histoquimico hTert e a graduacao histologica. Nao houve diferencas estatisticamente significativas entre as expressoes dos marcadores em pacientes com e sem recorrencia. Conclusao:: houve associacao estatisticamente significativa apenas de p16ink4a e Ki67 com a graduacao histologica. A expressao dos marcadores em relacao a recorrencia da doenca nao foi estatisticamente significativa no periodo avaliado. PMID- 28658332 TI - Does the Attention Deficit Hyperactivity Disorder interfere with bariatric surgery results? AB - Objective:: to analyze possible negative effects of Attention Deficit Hyperactivity Disorder (ADHD) on the success of bariatric surgery. Methods:: we evaluated forty patients undergoing bariatric surgery and with regular post operative follow-up of at least one year. To all, we applied the questionnaire advocated in the fourth edition of the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association for ADHD, as well as analyzed their postoperative data. Results:: fifteen (38%) patients presented a positive questionnaire for ADHD. Patients with ADHD presented higher BMI than patients without the disorder (45.8 vs. 40.9 kg/m2, p=0.017), and the difference remained in all postoperative stages. There was no statistically significant difference in surgery success (33.3% x 66.7%, p=0.505) or in BMI reduction (30.71% x 31.88%, p=0.671) one year after the procedure. Conclusion:: ADHD patients have a higher BMI. However, the presence of ADHD does not influence the success of bariatric surgery and the reduction of BMI. Objetivos:: analisar possiveis efeitos negativos do Transtorno do Deficit de Atencao e Hiperatividade (TDAH) no sucesso da cirurgia bariatrica. Metodos: : foram avaliados 40 pacientes submetidos a cirurgia bariatrica e com acompanhamento pos-operatorio regular minimo de um ano. Todos foram submetidos ao questionario preconizado na quarta edicao do Diagnostic and Statistical Manual (DSM-IV) da Associacao Americana de Psiquiatria para TDAH e analisados os dados pos operatorios. Resultados: : quinze (38%) pacientes apresentaram questionario positivo para TDAH. Os pacientes com TDAH apresentaram IMC maior do que os pacientes sem o transtorno (45,8x40,9 Kg/m2; p=0,017), mantendo-se a diferenca em todas as etapas do pos-operatorio. Nao foi encontrada diferenca estatisticamente significativa no sucesso da cirurgia (33,3% x 66,7%; p=0,505), e na reducao do IMC (30,71% x 31,88%; p=0,671) apos um ano do procedimento. Conclusao: : pacientes com TDAH apresentam maior IMC, entretanto, a presenca do TDAH nao apresenta influencia no sucesso da cirurgia bariatrica e na reducao do IMC. PMID- 28658333 TI - Bacterial genus is a risk factor for major amputation in patients with diabetic foot. AB - Objective: : to evaluate whether bacterial genus is a risk factor for major amputation in patients with diabetic foot and infected ulcer. Methods: : we conducted a case-control, observational study of 189 patients with infected ulcers in diabetic feet admitted to the Vascular Surgery Service of the Risoleta Tolentino Neves Hospital, from January 2007 to December 2012. The bacteriological evaluation was performed in deep tissue cultures from the lesions and amputation was considered major when performed above the foot'smiddle tarsus. Results: : the patients'mean age was 61.9+/-12.7 years; 122 (64.6%) were men. The cultures were positive in 86.8%, being monomicrobial in 72% of the cases. In patients with major amputation, Acinetobacter spp. (24.4%), Morganella spp. (24.4%), Proteus spp. (23.1%) and Enterococcus spp. (19.2%) were the most frequent types of bacteria. The most commonly isolated species were Acinetobacter baumannii, Morganella morganii, Pseudomonas aeruginosa and Proteus mirabilis. As predictors of major amputation, we identified the isolation of the generaAcinetobacter spp. and Klebsiella spp., serum creatinine >=1.3mg/dl and hemoglobin <11g/dl. Conclusion: : the bacterial genera Acinetobacter spp. and Klebsiella spp. identified in infected ulcers of patients with diabetic foot were associated with a higher incidence of major amputation. Objetivo:: avaliar se genero bacteriano e fator de risco para amputacao maior em pacientes com pe diabetico e ulcera infectada. Metodo:: estudo observacional do tipo caso-controle de 189 pacientes com ulcera infectada em pe diabetico admitidos pelo Servico de Cirurgia Vascular do Hospital Risoleta Tolentino Neves, no periodo de janeiro de 2007 a dezembro de 2012. A avaliacao bacteriologica foi realizada em cultura de tecido profundo das lesoes e a amputacao foi considerada como maior quando realizada acima do medio tarso do pe. Resultados:: a media de idade dos pacientes foi 61,9+/-12,7 anos e 122 (64,6%) eram homens. As culturas foram positivas em 86,8%, sendo monomicrobianas em 72% dos casos. Nos pacientes com amputacao maior, os generos de bacterias mais frequentes foram Acinetobacter spp. (24,4%), Morganella spp. (24,4%), Proteus spp. (23,1%) e Enterococcus spp. (19,2%) e as especies mais isoladas foram Acinetobacter baumannii, Morganella morganii, Pseudomonas aeruginosa e Proteus mirabilis. Identificou-se como fatores preditivos para amputacao maior o isolamento dos generos Acinetobacter spp. e Klebsiella spp.,e niveis sericos de creatinina >=1,3mg/dl e de hemoglobina <11g/dl. Conclusao:: os generos bacterianos Acinetobacter spp. e Klebsiella spp. identificados nas ulceras infectadas dos pacientes com pe diabetico associaram-se a maior incidencia de amputacao maior. PMID- 28658334 TI - Customized acrylic implants for reconstruction of extensive skull defects: an exception approach for selected patients. AB - Objective: : to present our experience in the surgical treatment of extensive skullcap defects with customized acrylic implants. Methods: : we conducted a retrospective analysis of patients with extensive skull defects undergoing acrylic cranioplasties between 2004 and 2013. We carefully selected all patients and classified surgical results based on three scales (craniofacial esthetics, improvement of facial symmetry and need for additional surgery). Results: : fifteen patients underwent cranioplasty with intraoperative acrylic implants, whether manually customized (46.67%) or made with prototyped three-dimensional biomodels (53.33%). There were two (13.33%) complications (one infection with implant withdrawal and one seroma). We considered the craniofacial aesthetics excellent (50%), the degree of improvement of craniofacial symmetry satisfactory (57.14%), and the overall mean of surgical results according to the need for new surgeries was 1.5+/-0.52. Conclusion: : cranioplasties of patients with extensive skullcap defects should obey careful and predetermined criteria, both for selection and for the acrylic implant customization method. Objetivo: : apresentar nossa experiencia no tratamento cirurgico dos defeitos extensos da calota craniana com implantes de acrilico customizados. Metodos:: analise retrospectiva de pacientes com defeitos extensos da calota craniana submetidos a cranioplastias com acrilico entre 2004 e 2013. Todos os pacientes foram criteriosamente selecionados e os resultados cirurgicos foram classificados com base em tres escalas (estetica craniofacial, melhora da simetria facial e necessidade de cirurgia adicional). Resultados:: Quinze pacientes foram submetidos a cranioplastia com implantes de acrilico customizados manualmente no intraoperatorio (46,67%) e confeccionados com base em biomodelos tridimensionais prototipados (53,33%). Mesmo respeitando criterios de selecao, houve duas (13,33%) complicacoes (infeccao com retirada do implante e seroma). A estetica craniofacial foi considerada excelente (50%), o grau de melhora da simetria craniofacial foi considerado satisfatorio (57,14%) e a media global dos resultados cirurgicos de acordo com a necessidade de novas cirurgias foi 1,5+/ 0,52. Conclusao:: as cranioplastias dos pacientes com defeitos da calota craniana extensos devem ser criteriosamente indicadas, obedecendo a criterios pre determinados de selecao dos pacientes, bem como, do metodo de customizacao do implante de acrilico. PMID- 28658335 TI - Invasive ductal carcinoma: relationship between pathological characteristics and the presence of axillary metastasis in 220 cases. AB - Objective:: to analyze the relation of anatomopathological features and axillary involvement in cases of invasive ductal carcinoma. Methods: : this is a cross sectional study of 220 breast cancer patients submitted to radical mastectomy or quadrantectomy with axilar emptying, from the Mastology Service of the Assis Chateaubriand Maternity School, Ceara, Brazil. We submitted the tumors to histological processing and determined the histological (HG), tubular (TG) and nuclear (NG) grades, and the mitotic index (MI) by the classification of Scarff Bloom-Richadson, verified the presence of angiolymphatic invasion (AI) and measured the largest tumor diameter (TD). We then correlated these variables with the presence of axillary metastases. Results:: the mean patients'age was 56.81 years +/- 13.28. Tumor size ranged from 0.13 to 22 cm, with an average of 2.23cm +/- 2.79. HG3, TG3 and NG3 prevailed, respectively 107 (48.6%), 160 (72.7%) and 107 (48.6%). Mitotic indexes 1, 2 and 3 presented a homogeneous distribution, respectively 82 (37.2%), 68 (31%) and 70 (31.8%). We observed no relation between the HG, TG and NG with the occurrence of axillary metastases (p=0.07, p=0.22 and p=0.21, respectively). Mitotic indices 2 and 3 were related with the occurrence of axillary metastases (p=0.03). Tumors larger than 2cm and cases that presented angiolymphatic invasion had a higher index of axillary metastases (p=0.0003 and p<0.0001). Conclusion:: elevated mitotic indexes, tumors with a diameter greater than 2cm and the presence of angiolymphatic invasion were individuallyassociatedwith the occurrence of axillary metastases. Objetivo:: analisar a relacao das caracteristicas anatomopatologicas com o comprometimento axilar em casos de carcinoma ductal invasor. Metodos:: estudo transversal de 220 pacientes com cancer de mama, submetidas a mastectomia radical ou quadrantectomia com esvaziamento axilar, oriundos do Servico de Mastologia da Maternidade Escola Assis Chateaubriand, Ceara, Brasil. Os tumores foram submetidos a processamento histologico e, em seguida, foram determinados os graus histologico (GH), tubular (GT), nuclear (GN), indice mitotico (IM) pela classificacao de Scarff-Bloom Richadson, verificada a presenca de invasao angiolinfatica (IA) e mensurado o maior diametro do tumor (DT). Tais variaveis foram correlacionadas com a presenca de metastases axilares. Resultados:: a media de idade das pacientes foi 56,81 anos +/- 13,28. O tamanho do tumor variou de 0,13 a 22 cm, com media de 2,23cm +/ 2,79. Os GH3, GT3 e GN3 prevaleceram: n=107 (48,6%), n=160 (72,7%) e n=107 (48,6%), respectivamente. Os indices mitoticos 1, 2 e 3 apresentaram distribuicao homogenea: n=82 (37,2%), n=68 (31%) e n=70 (31,8%), respectivamente. Nao foi evidenciada relacao do GH, GT e GN com a ocorrencia de metastases axilares (p=0,07; p=0,22 e p=0,21). Indices mitoticos 2 e 3 apresentaram relacao com a o ocorrencia de metastases axilares (p=0,03). Tumores maiores do que 2cm e casos com invasao angiolinfatica apresentaram maior indice de metastases axilares (p=0,0003 e p<0,0001). Conclusao:: indices mitoticos elevados, tumores com diametro maior do que 2cm e presenca de invasao angiolinfatica apresentaram isoladamente relacao com a ocorrencia de metastases axilares. PMID- 28658336 TI - Analysis of obese patients' medical conditions in the pre and postoperative periods of bariatric surgery. AB - Objective: to compare the clinical conditions of obese patients in the pre and postoperative period of bariatric surgery. Methods: we carried out a descriptive, retrospective, quantitative study by consulting the charts of 134 patients who underwent bariatric surgery in the period from 2009 to 2014. We collected the data between September and November 2015. We performed a descriptive statistical analysis and comparative analysis of anthropometric, metabolic, biochemical and clinical variables, considering six months before and after surgery. Results: the majority of the patients were female (91.8%), with a higher prevalence (35%) in the age group 18-29 years old, complete high-school education (65.6%) and grade III obesity (60.4%). Six months after surgery, weight and lipid profile reduction were significant in both genders, but the impact on biochemical, anthropometric, metabolic and clinical parameters was significant only in female subjects, with a reduction in morbidities associated with obesity, such as arterial hypertension, diabetes mellitus, dyslipidemia and metabolic syndrome and in the use of drugs to control them. Conclusion: bariatric surgery was effective in weight loss, with improvements in anthropometric, metabolic and biochemical parameters and in the reduction of morbidities associated with obesity. PMID- 28658337 TI - Immediate reconstruction with autologous fat grafting: influence in breast cancerregional recurrence. AB - Objective: to evaluate local and systemic recurrence of breast cancer in patients submitted to autologous fat grafting in the immediate reconstruction after conservative surgery for breast cancer. Methods: this is a historical cohort study comparing 167 patients submitted to conservative surgery without reconstruction (conservative surgery group) with 27 patients submitted to conservative treatment with immediate graft reconstruction, following the Coleman's technique (lipofilling group). All patients had invasive carcinoma and were operated by a single surgeon from 2004 to 2011. The postoperative follow-up time was 36 months. Results: the overall incidence of local recurrence was 2.4%. No patient in the lipofilling group had local recurrence during the study period. For systemic recurrence, the rates obtained were 3.7% (one patient) for the fat grafting group and 1.8% (three patients) for the conservative surgery group without reconstruction. Conclusion: there was no significant difference for local or systemic recurrence in the groups studied. Immediate autologous fat grafting appears to be a safe procedure. PMID- 28658338 TI - Profile of skin cancer in Pomeranian communities of the State of Espirito Santo. AB - Objectives: to evaluate the profile of skin cancer in Pomeranian communities of the State of Espirito Santo, composed of descendants of European immigrants, regarding gender and age at diagnosis, lesion size and histological type. Method: we studied histopathological reports of 3,781 patients operated between 2000 and 2010, with resection of 4,881 lesions. We assessed histological type, lesion size, age and gender of the patients at diagnosis and their correlations in the 11-year period. Results: the histopathological examination revealed basal cell carcinoma in 3,159 patients (83.5%), squamous cell carcinoma in 415 (11%), melanoma in 64 (1.7%), and 143 patients (3.8%) had combined lesions of basal cell carcinoma and squamous cell carcinoma. As to size, 47.1% measured between 5.1 and 10mm. The age group of 61 to 70 years was the one that sustained the largest number of surgical interventions (24.3%). There was a predominance of the female gender (2,027, 53.6%) in relation to the male (1,754, 46.4%). Conclusion: basal cell carcinoma was the most frequent histological type. The prevalences of squamous cell carcinoma and melanoma were below the national estimate of the National Cancer Institute. The diagnosis of tumors occurred at more advanced ages (above 60 years) and there was an increase in the incidence and size of skin tumors in the male population. PMID- 28658339 TI - Tracheobronchial injuries in chest trauma: a 17-year experience. AB - Objective: to discuss the clinical and therapeutic aspects of tracheobronchial lesions in victims of thoracic trauma. Methods: we analyzed the medical records of patients with tracheobronchial lesions treated at the Sao Paulo Holy Home from April 1991 to June 2008. We established patients' severity through physiological (RTS) and anatomical trauma indices (ISS, PTTI). We used TRISS (Trauma Revised Injury Severity Score) to evaluate the probability of survival. Results: nine patients had tracheobronchial lesions, all males, aged between 17 and 38 years. The mean values of the trauma indices were: RTS - 6.8; ISS - 38; PTTI - 20.0; and TRISS - 0.78. Regarding the clinical picture, six patients displayed only emphysema of the thoracic wall or the mediastinum and three presented with hemodynamic or respiratory instability. The time interval from patient admission to diagnosis ranged from one hour to three days. Cervicotomy was performed in two patients and thoracotomy, in seven (77.7%), being bilateral in one case. Length of hospitalization ranged from nine to 60 days, mean of 21. Complications appeared in four patients (44%) and mortality was nil. Conclusion: tracheobronchial tree trauma is rare, it can evolve with few symptoms, which makes immediate diagnosis difficult, and presents a high rate of complications, although with low mortality. PMID- 28658340 TI - Surgery in Brazilian Health Care: funding and physician distribution. AB - Objective: to analyze demographic Brazilian medical data from the national public healthcare system (SUS), which provides free universal health coverage for the entire population, and discuss the problems revealed, with particular focus on surgical care. Methods: data was obtained from public healthcare databases including the Medical Demography, the Brazilian Federal Council of Medicine, the Brazilian Institute of Geography and Statistics, and the National Database of Healthcare Establishments. Density and distribution of the medical workforce and healthcare facilities were calculated, and the geographic regions were analyzed using the public private inequality index. Results: Brazil has an average of two physicians for every 1,000 inhabitants, who are unequally distributed throughout the country. There are 22,276 board certified general surgeons in Brazil (11.49 for every 100,000 people). The country currently has 257 medical schools, with 25,159 vacancies for medical students each year, with only around 13,500 vacancies for residency. The public private inequality index is 3.90 for the country, and ranges from 1.63 in the Rio de Janeiro up to 12.06 in Bahia. Conclusions: A significant part of the local population still faces many difficulties in accessing surgical care, particularly in the north and northeast of the country, where there are fewer hospitals and surgeons. Physicians and surgeons are particularly scarce in the public health system nationwide, and better incentives are needed to ensure an equal public and private workforce. PMID- 28658341 TI - Incidence of colorectal cancer in young patients. AB - Sporadic colorectal cancer (CRC) is traditionally diagnosed after de sixth decade of life, although a small percentage of cases are diagnosed in patients under 40 years of age, and incidence is increasing. There exists a great volume of controversy regarding clinical outcome of young patients diagnosed with colorectal cancer (CRC) when compared to elder counterparts. Our aims were to evaluate the rate of CRC in young patients, to review the pertaining literature and to discuss outcomes and clinical prognosis. A retrospective review involving patients with CRC was undertaken, focusing on age at diagnosis. The information extracted from this literature review showed a trend towards a decreased incidence in older people with an opposite effect among adolescents and young adults. Moreover, biological aggressiveness in young adults diagnosed with CRC has not been fully recognized, although it is usually diagnosed later and in association with adverse histological features. Besides that, these features don't affect outcome. These apparent increase in CRC incidence among young patients during the last decades raises the need for a greater suspicious when evaluating common symptoms in this group. Thus, educational programs should widespread information for both population and physicians to improve prevention and early diagnosis results. RESUMO O cancer colorretal (CCR) esporadico e tradicionalmente diagnosticado apos a sexta decada de vida, embora uma pequena porcentagem de casos seja diagnosticada em doentes abaixo dos 40 anos de idade, e a incidencia esta aumentando. Existe uma grande controversia a respeito da evolucao clinica de doentes jovens portadores de CCR em comparacao aos mais idosos. Os objetivos deste estudo foram avaliar a prevalencia de CCR em doentes jovens, rever a literatura pertinente e discutir suas caracteristicas mais importantes nesta faixa etaria. Para tanto realizou-se revisao da literatura envolvendo doentes com CCR com foco na idade ao diagnostico. A informacao extraida da revisao de literatura demonstrou uma tendencia de reducao da incidencia em pessoas mais idosas com efeito oposto em adolescentes e adultos jovens. Sua agressividade biologica ainda nao foi claramente reconhecida, embora seja usualmente diagnosticado mais tardiamente e em associacao com caracteristicas histologicas adversas. Apesar disso, estas caracteristicas nao afetam a evolucao. Este aparente aumento na incidencia de CCR entre pacientes jovens durante as ultimas decadas levanta a necessidade de uma maior suspeita diagnostica na avaliacao de sintomas comuns neste grupo. Assim, programas educacionais devem disseminar informacao tanto para populacao como para medicos a fim de melhorar a prevencao e o diagnostico precoce. PMID- 28658342 TI - Robotic Transversus Abdominis Release (TAR): is it possible to offer minimally invasive surgery for abdominal wall complex defects? AB - We describe the preliminary national experience and the early results of the use of robotic surgery to perform the posterior separation of abdominal wall components by the Transversus Abdominis Release (TAR) technique for the correction of complex defects of the abdominal wall. We performed the procedures between 04/2/2015 and 06/15/2015 and the follow-up time was up to six months, with a minimum of two months. The mean surgical time was five hours and 40 minutes. Two patients required laparoscopic re-intervention, since one developed hernia by peritoneal migration of the mesh and one had mesh extrusion. The procedure proved to be technically feasible, with a still long surgical time. Considering the potential advantages of robotic surgery and those related to TAR and the results obtained when these two techniques are associated, we conclude that they seem to be a good option for the correction of complex abdominal wall defects. PMID- 28658343 TI - Overweight in youth and sleep quality: is there a link? AB - OBJECTIVE: Overweight seems to be related to a higher prevalence of sleep disturbances. Decreased sleep duration and altered sleep quality are risk factors for obesity. Our aim was to compare the sleep pattern of overweight children with that of a matched control group and assess the relationship between sleep quality and obesity. MATERIALS AND METHODS: Retrospective cohort study comparing 41 overweight children with a normal-weight control group, both submitted to polysomnography. The samples were matched for age, sex, and apnea-hypopnea index. Body mass index (BMI) z-scores were calculated using World Health Organization (WHO) growth charts. Insulin resistance in the study group was determined using the homeostatic model assessment for insulin resistance (HOMA-IR). Sleep patterns were compared. The statistical analysis was performed using SPSS(r) version 21. RESULTS: The mean age (+/- standard deviation) of the population was 10 +/- 3.4 years (min. 5 years; max. 17 years). Fifty-six percent of the participants in both groups were girls. N3% was lower in the study group (18.95 +/- 6.18%) compared with the control group (21.61 +/- 7.39%; t (40) = 2.156, p = 0.037). We found a correlation in the study group between HOMA-IR and N3% (Rs = -0.434, p = 0.008). CONCLUSION: The present study suggests a link between overweight/obesity and altered sleep quality due to compromised non-rapid eye movement sleep, an indirect marker of sleep quality. There was also a link between slow-wave sleep duration and insulin resistance. We must find a strategy to provide adequate slow wave sleep duration to reduce the obesity epidemic at young ages. Further research is needed. PMID- 28658344 TI - Substernal goiter and laryngopharyngeal reflux. AB - OBJECTIVE: This study aims to compare the prevalence of laryngopharyngeal reflux signs between two groups of patients undergoing thyroidectomy for voluminous goiter: substernal goiters and voluminous cervical goiter without thoracic extension. SUBJECTS AND METHODS: A retrospective case-control study was performed with data retrieved of the charts of the patients submitted to thyroidectomies occurred at a tertiary care center (Head and Neck Surgery Department, University of Sao Paulo Medical School) between 2010 and 2014. The selected thyroidectomies were allocated in two groups for study: patients with substernal goiters and patients with voluminous cervical goiter without thoracic extension. Cervical goiters were selected by ultrasonography mensuration. Clinical criterion was used to define substernal goiter. RESULTS: The average thyroid volume in patients with substernal goiter was significantly greater than the average volume in patients with only cervical goiter (p < 0.001). The prevalence of signs of reflux laryngitis at laryngoscopy was significantly greater in substernal goiter patients (p = 0.036). Moreover, substernal goiter was considered as the unique independent variable for high reflux laryngitis signs at laryngoscopy (OR = 2.75; CI95%: 1.05-7.20; p = 0.039) when compared to only cervical goiter patients. CONCLUSION: This study shows a significant association between substernal goiters and signs of laryngopharyngeal reflux at preoperative laryngoscopy. Therefore, when compared with voluminous cervical goiters, the substernal goiters increase the chance of reflux laryngitis signs in patients. PMID- 28658345 TI - Medullary thyroid carcinoma - Adverse events during systemic treatment: risk benefit ratio. AB - Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring. PMID- 28658346 TI - Effects of energetic restriction diet on butyrylcholinesterase in obese women from southern Brazil - A longitudinal study. AB - OBJECTIVE: Butyrylcholinesterase (BChE) activity has been associated with obesity, lipid concentrations, and CHE2 locus phenotypes. This, the aim of this study was to evaluate the effects of an energetic restriction diet intervention on anthropometrical and biochemical variables and on absolute and relative BChE activity in CHE2 C5+ and CHE2 C5- individuals. SUBJECTS AND METHODS: One hundred eleven premenopausal obese women from Southern Brazil participated in an energetic restriction diet intervention (deficit of 2500 kJ/day) for 8 weeks. Their anthropometric and biochemical parameters were evaluated before and after the intervention. Plasma BChE activity was measured, and BChE bands in plasma and CHE2 locus phenotypes were detected by electrophoresis. RESULTS: The dietetic intervention decreased anthropometric and biochemical parameters as well as absolute BChE activity and relative activity of the G4 band. The CHE2 C5+ phenotype presented a different effect when compared with the CHE2 C5- phenotype. The CHE2 C5+ phenotype showed an effect in absolute BChE activity and in the relative activity of the G4 form, maintaining higher BChE activity regardless of the metabolic changes. CONCLUSION: In our study, 8 weeks was not sufficient time to lower the body mass index to normal, but it was enough to significantly reduce the absolute BChE activity, which became similar to the levels in nonobese individuals. CHE2 C5+ individuals were resistant to the decrease in BChE activity compared to CHE2 C5- individuals. This shows that the diet did not affect the CHE2 and G4 fraction complex and that the products of the CHE2 locus in association with BChE have a role in energy metabolism, maintaining high levels of enzymatic activity even after dietary intervention. PMID- 28658347 TI - Circulating omentin-1 might be associated with metabolic health status in different phenotypes of body size. AB - OBJECTIVE: Adipokines are mediators of body composition and are involved in obesity complications. This study aimed to assess the association of circulating omentin-1, vaspin, and RBP-4 with body composition indices and metabolic health status (MHS) in different phenotypes of body size. SUBJECTS AND METHODS: A total of 350 subjects were included in the current cross-sectional study. Body composition was measured using a body composition analyzer, and serum concentrations of omentin-1, vaspin, and RBP-4 were assessed by ELISA kits. RESULTS: Circulating omentin-1 was significantly (OR = 1.81, 95% CI: 1.00-1.91, P = 0.01) and marginally (OR = 1.63, 95%CI: 1.00-1.75, P = 0.06) associated with MHS in the overweight and obese subjects, respectively. But no association was seen between omentin-1 and MHS in normal-weight subjects. Serum levels of vaspin and RBP-4 were not correlated with MHS. Furthermore, a significant positive correlation was observed between circulating omentin-1 and body mass index (BMI) as well as fat percentage (P = 0.02) in the MHS group. Serum vaspin concentrations were not related to body composition components in both groups. In addition, in the MHS group, circulating RBP-4 was positively correlated with fat percentage and fat mass (FM) (p < 0.0001) and was negatively correlated with fat free mass (FFM) and total body water (TBW) (p < 0.0001). In contrast, in the metabolically unhealthy group, RBP-4 was negatively correlated with fat percentage, FM, and BMI (p < 0.0001) and was positively correlated with FFM and TBW (p < 0.0001). CONCLUSIONS: This study showed that circulating levels of omentin-1 are useful predictors of metabolic health status in overweight and obese people. PMID- 28658348 TI - New insights into the effects of irisin levels in HIV-infected subjects: correlation with adiposity, fat-free mass, and strength parameters. AB - OBJECTIVE: Patients infected with the human immunodeficiency virus (HIV) have an increased risk of metabolic disorders and alterations on irisin levels. Therefore, the purpose of the current investigation was to quantify the circulating irisin concentration in HIV-infected subjects under highly active antiretroviral therapy and to determine possible correlations between irisin levels with fat mass, fat-free mass, body mass index (BMI), and muscle strength. SUBJECTS AND METHODS: Cross-sectional study of 10 men (36.7 +/- 11.3 years) and 10 women (42.5 +/- 10.3 years) infected with HIV, recruited from the Specialized Service Center in the State Center of Reference for High and Medium Complexity. Blood samples were collected to determine plasma irisin levels, glucose, HDL, total cholesterol, triglycerides, and LDL. Body composition (fat mass, fat-free mass) and anthropometrics (body mass index; BMI) were measured by bioelectrical impedance. Muscle strength was assessed using a mechanic hand dynamometer and one maximum repetition tests. RESULTS: Irisin levels correlated positively with fat mass (r = 0.67; p = 0.001) and BMI (r = 0.48; p = 0.036). In contrast, there was an inverse correlation between irisin levels and fat-free mass (r = -0.41; p = 0.008) and five strength parameters: right hand grip (r = -0.46; p = 0.044); left hand grip (r = -0.50; p = 0.027), relative hand grip (r = -0.79; p = 0.001), bench press (r = -0.58; p = 0.009), leg press (r = -0.40; p = 0.085), and biceps curl (r = -0.059; p = 0.009). CONCLUSION: Irisin levels correlated positively with body fat and negatively with fat-free mass and strength parameters in HIV infected patients. Female patients infected with HIV receiving highly active antiretroviral therapy have higher levels of irisin compared with men in a similar circumstance. PMID- 28658349 TI - Endothelial dysfunction in children with type 1 diabetes mellitus. AB - OBJECTIVE: The purpose of this study was to verify the presence of endothelial dysfunction and initial structural atherosclerotic changes in children with Type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: The study population comprised 31 diabetic children aged 6 to 12 years, divided into two subgroups according to the duration of the T1DM diagnosis: subgroup 1, with less than 5 years elapsed since diagnosis, and subgroup 2, with more than 5 years elapsed since diagnosis. The control group comprised 58 age-matched healthy children. Ultrasonographic techniques were used to measure the flow-mediated dilatation (FMD) of the brachial artery and the intima-media thickness (IMT) of the carotid arteries. RESULTS: Children with T1DM with longer disease duration showed significantly decreased mean values of FMD compared with those in the control group. No significant differences between the groups were found in relation to IMT. The FMD percentage presented a moderate negative correlation with glycated hemoglobin (HbA1c) and fasting glucose levels. CONCLUSION: Our findings suggest that endothelial dysfunction may be already present in children with 5 years or more elapsed since diagnosis, even in the absence of atherosclerotic structural changes. The decreased vasodilation response correlated with hyperglycemia. PMID- 28658350 TI - Multifocal oral melanoacanthoma associated with Addison's disease and hyperthyroidism: a case report. AB - Oral melanoacanthoma is a mucocutaneous, pigmented, rare, benign, and probably reactive lesion. This paper reports for the first time in the literature a case of multifocal oral melanoacanthoma in a patient diagnosed with Addison's disease and concomitant Graves' disease with hyperthyroidism. The patient presented with oral pigmented lesions, which were hypothesized to be mucosal pigmentation associated with Addison's disease. Due to their unusual clinical pattern, these oral lesions were biopsied and diagnosed as oral melanoacanthoma on histopathology and immunohistochemistry for HMB-45. At the moment of this report, the patient was being treated for her systemic conditions, but the lesions had not regressed. Reactive hyperpigmentation of the skin and mucous membranes may be found in Addison's disease and hyperthyroidism. This case reinforces the hypothesis of a reactive nature for oral melanoacanthoma and highlights the need for investigation of endocrine disorders in patients with multifocal oral melanoacanthoma. PMID- 28658351 TI - Why do some orthodontic treatments last so long while others do not? PMID- 28658352 TI - Premaxilla: an independent bone that can base therapeutics for middle third growth! AB - Premaxilla, in its early descriptions, had the participation of Goethe. In our face, in a certain period of growth and development processes, premaxilla is an independent and, then, a semi-independent bone to finally be totally integrated to the maxilla. Formation of the premaxilla acts as a stabilization element inside the facial skeleton comparable to the cornerstone of a Roman arch and is closely related to the development of human face and its abnormal growth with characteristic malformations. Until when the premaxillary-maxillary suture remains open and offers opportunities to orthopedically influence facial growth to exert influence over facial esthetics and function? Contact with preliminary results in 1183 skulls from anatomic museums at USP, Unicamp and Unifesp led us to question therapeutic perspectives and its clinical applicability. PMID- 28658353 TI - An interview with. PMID- 28658354 TI - Retention period after treatment of posterior crossbite with maxillary expansion: a systematic review. AB - OBJECTIVE:: The aim of this systematic review was to evaluate the duration of the retention period in growing patients undergoing maxillary expansion and its relation with posterior crossbite stability. METHODS: : Search strategies were executed for electronic databases Cochrane Library, Web of Science, PubMed and Scopus, which were completed on January 15, 2016. The inclusion criteria included randomized, prospective or retrospective controlled trials in growing subjects with posterior crossbite; treated with maxillary expanders; retention phase after expansion; post-retention phase of at least 6 months. The exclusion criteria were anterior crossbite, craniofacial anomalies, surgery or another orthodontic intervention; case reports; author's opinions articles, thesis, literature reviews and systematic reviews. The risk of bias of selected articles was assessed with Cochrane risk of bias tool for RCTs and Downs and Black checklist for non-RCTs. RESULTS: : A total of 156 titles/abstracts was retrieved, 44 full texts were examined, and 6 articles were selected and assessed for their methodological quality. The retention period after maxillary expansion ranged between 4 weeks and 16 months. Fixed (acrylic plate, Haas, Hyrax and quad-helix) or removable (Hawley and Hawley expander) appliances were used for retention. CONCLUSIONS: : Six months of retention with either fixed or removable appliances seem to be enough to avoid relapse or to guarantee minimal changes in a short term follow-up. PMID- 28658355 TI - Discoloration and force degradation of orthodontic elastomeric ligatures. AB - OBJECTIVE:: The aim of the present study was to evaluate color changes and force degradation of orthodontic elastomeric ligatures in different stretching patterns during a 8-weeks period. METHODS: : Two elastomers with the minimum and two with the maximum color changing, and gray elastomers of two brands (American Orthodontics and Ortho Technology) were selected according to an opinion poll with clinicians and color changes after 4 weeks of intraoral use were evaluated. These elastomers were mounted on special jigs fabricated using a CAD-CAM technique, underwent different stretching patterns and the force was measured in 0, 24 hours, 2, 4 and 8 weeks. During in vivo part of the study, force levels of elastomers were measured after 4 weeks on a material testing machine. Data were analyzed with four-way ANOVA and Tukey post hoc tests. RESULTS: : All the elastomers showed color changing but the degree of color stability was significantly different. The mean force degradation was higher in 1-mm stretch groups. After 8 weeks, the average residual force of elastomers was 1.45 +/- 0.18 N and the maximum force decay was seen in the elastomers that exhibited the maximum initial force. CONCLUSION: : There is significant relationship between the stretching pattern and the amount of residual force of elastomers. Elastomers with higher initial forces exhibited higher percentages of force loss after 8 weeks. It seems that there is a relationship between initial color and color changing of elastomers. PMID- 28658356 TI - Does the CO2 laser reduce bond strength in different types of ceramic brackets? AB - OBJECTIVE:: The aim of this study was to assess in vitro the influence of the CO2 laser and of the type of ceramic bracket on the shear bond strength (SBS) to enamel. METHODS: : A total of 60 enamel test surfaces were obtained from bovine incisors and randomly assigned to two groups, according to the ceramic bracket used: Allure (A); Transcend (T). Each group was divided into 2 subgroups (n = 15): L, laser (10W, 3s); C, no laser, or control. Twenty-four hours after the bonding protocol using Transbond XT, SBS was tested at a crosshead speed of 0.5 mm/min in a universal testing machine. After debonding, the Adhesive Remnant Index (ARI) was evaluated at 10 x magnification and compared among the groups. Data were analyzed by one-way ANOVA, Tukey's, Mann-Whitney's and Kruskal-Wallis tests (alpha = 0.05). RESULTS: : Mean SBS in MPa were: AL = 0.88 +/- 0.84; AC = 12.22 +/- 3.45; TL = 12.10 +/- 5.11; TC = 17.71 +/- 6.16. ARI analysis showed that 73% of the specimens presented the entire adhesive remaining on the tooth surfaces (score 3). TC group presented significantly higher SBS than the other groups. The lased specimens showed significantly lower bond strength than the non lased groups for both tested brackets. CONCLUSION: : CO2 laser irradiation decreased SBS values of the polycrystalline ceramic brackets, mainly Allure. PMID- 28658357 TI - Evaluation of the rapid and slow maxillary expansion using cone-beam computed tomography: a randomized clinical trial. AB - OBJECTIVE:: The aim of this randomized clinical trial was to evaluate the dental, dentoalveolar, and skeletal changes occurring right after the rapid maxillary expansion (RME) and slow maxillary expansion (SME) treatment using Haas-type expander. METHODS: : All subjects performed cone-beam computed tomography (CBCT) before installation of expanders (T1) and right after screw stabilization (T2). Patients who did not follow the research parameters were excluded. The final sample resulted in 21 patients in RME group (mean age of 8.43 years) and 16 patients in SME group (mean age of 8.70 years). Based on the skewness and kurtosis statistics, the variables were judged to be normally distributed and paired t-test and student t-test were performed at significance level of 5%. RESULTS: : Intermolar angle changed significantly due to treatment and RME showed greater buccal tipping than SME. RME showed significant changes in other four measurements due to treatment: maxilla moved forward and mandible showed backward rotation and, at transversal level both skeletal and dentoalveolar showed significant changes due to maxillary expansion. SME showed significant dentoalveolar changes due to maxillary expansion. CONCLUSIONS: : Only intermolar angle showed significant difference between the two modalities of maxillary expansion with greater buccal tipping for RME. Also, RME produced skeletal maxillary expansion and SME did not. Both maxillary expansion modalities were efficient to promote transversal gain at dentoalveolar level. Sagittal and vertical measurements did not show differences between groups, but RME promoted a forward movement of the maxilla and backward rotation of the mandible. PMID- 28658358 TI - Six-month bracket failure rate with a flowable composite: A split-mouth randomized controlled trial. AB - INTRODUCTION:: The use of flowable composites as an orthodontic bonding adhesive merits great attention because of their adequate bond strength, ease of clinical handling and reduced number of steps in bonding. OBJECTIVE: : The aim of this Randomized Controlled Trial was to comparatively evaluate over a 6-month period the bond failure rate of a flowable composite (Heliosit Orthodontic, Ivoclar Vivadent AG, Schaan) and a conventional orthodontic bonding adhesive (Transbond XT, 3M Unitek). METHODS: : 53 consecutive patients (23 males and 30 females) who fulfilled the inclusion and exclusion criteria were included in the study. A total of 891 brackets were analyzed, where 444 brackets were bonded using Heliosit Orthodontic and 447 brackets were bonded using Transbond XT. The survival rates of brackets were estimated with the Kaplan-Meier analysis. Bracket survival distributions for bonding adhesives, tooth location and dental arch were compared with the log-rank test. RESULTS: : The failure rates of the Transbond XT and the Heliosit Orthodontic groups were 8.1% and 6% respectively. No significant differences in the survival rates were observed between them (p= 0.242). There was no statistically significant difference in the bond failure rates when the clinical performance of the maxillary versus the mandibular arches and the anterior versus the posterior segments were compared. CONCLUSIONS: : Both systems had clinically acceptable bond failure rates and are adequate for orthodontic bonding needs. PMID- 28658359 TI - The influence of sagittal position of the mandible in facial attractiveness and social perception. AB - OBJECTIVE:: This study aims at comparing the perception of orthodontists, maxillofacial surgeons, visual artists and laypersons when evaluating the influence of sagittal position of the mandible - in lateral view - in facial attractiveness; at a job hiring; and in the perception of socioeconomic profile. METHODS: : A black male, a white male, a black female and a white female with harmonic faces served as models to obtain a facial profile photograph. Each photograph was digitally manipulated to obtain seven facial profiles: an ideal, three simulating mandibular advancement and three simulating mandibular retrusion, producing 28 photographs. These photographs were evaluated through a questionnaire by orthodontists, maxillofacial surgeons, visual artists and laypersons. RESULTS: : The anteroposterior positioning of the mandible exerted strong influence on the level of facial attractiveness, but few significant differences between the different groups of evaluators were observed (p < 0.05). CONCLUSIONS: : The profiles pointed as the most attractive were also pointed as more favorable to be hired to a job position and pointed also as having the best socioeconomic condition. PMID- 28658360 TI - Subjective facial analysis and its correlation with dental relationships. AB - INTRODUCTION:: Subjective facial analysis is a diagnostic method that provides morphological analysis of the face. Thus, the aim of the present study was to compare the facial and dental diagnoses and investigate their relationship. METHODS: : This sample consisted of 151 children (7 to 13 years old), without previous orthodontic treatment, analyzed by an orthodontist. Standardized extraoral and intraoral photographs were taken for the subjective facial classification according to Facial Pattern classification and occlusal analyses. It has been researched the occurrence of different Facial Patterns, the relationship between Facial Pattern classification in frontal and profile views, the relationship between Facial Patterns and Angle classification, and between anterior open bite and Long Face Pattern. RESULTS: : Facial Pattern I was verified in 64.24% of the children, Pattern II in 21.29%, Pattern III in 6.62%, Long Face Pattern in 5.96% and Short Face Pattern in 1.99%. A substantial strength of agreement of approximately 84% between frontal and profile classification of Facial Pattern was observed (Kappa = 0.69). Agreement between the Angle classification and the Facial Pattern was seen in approximately 63% of the cases (Kappa = 0.27). Long Face Pattern did not present more open bite prevalence. CONCLUSION: : Facial Patterns I and II were the most prevalent in children and the less prevalent was the Short Face Pattern. A significant concordance was observed between profile and frontal subjective facial analysis. There was slight concordance between the Facial Pattern and the sagittal dental relationships. The anterior open bite (AOB) was not significantly prevalent in any Facial Pattern. PMID- 28658361 TI - Do different vertical positions of maxillary central incisors influence smile esthetics perception? AB - INTRODUCTION:: The purpose of this study was to determine the perception of smile esthetics among orthodontists and layperson, with respect to different maxillary central incisors vertical positions in full-face and close-up smile analyses. METHODS: : Frontal photographs of the smiles of two adult women were used. Images were altered to create a symmetrical image with the gingival margin levels of the maxillary canines matching the central incisors and a 1.0-mm central-to-lateral incisal step. Later, the images were altered in order to create six different central incisor vertical positions in 0.5-mm increments. The images were randomly assembled in an album, which was given to 114 judges, 57 orthodontists and 57 laypersons, who were asked to evaluate the attractiveness of the images using the visual analog scale. The data collected were statistically analyzed by means of 1 way analysis of variance with the Tukey post-hoc test and the Student t test. RESULTS: : The highest rated smiles showed two notable characteristics: a) the central incisor gingival margins matched or were 0.5 mm below the line of the canine gingival margins and; b) the central-to-lateral incisal step was 1.0 to 1.5 mm. The worst smiles showed two notable characteristics: a) the central incisor gingival margins were 1.0 mm above or 1.5 mm below the canine gingival margins and; b) no step between the centrals and laterals or a 2.5-mm step. CONCLUSION: : The vertical position of the maxillary central incisors significantly affected the perception of the smile esthetics, whereas slightly extruded central incisors were more esthetically preferred than intruded. PMID- 28658362 TI - Agenesis of mandibular second premolar in patient with dental bimaxillary protrusion. AB - The present study reports the treatment carried out in a patient with mandibular second premolar agenesis associated with early loss of a deciduous second molar, deep overbite, severe overjet and dentoalveolar bimaxillary protrusion, which led to lip incompetence and a convex facial profile. The main objectives of this treatment were: to eliminate the spaces in mandibular arch, correct overbite, as well as eliminate bimaxillary protrusion and lip incompetence, thus leading to a balanced profile. The case was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO) as part of the requirements to obtain the title of BBO diplomate. PMID- 28658363 TI - Early vertical correction of the deep curve of Spee. AB - Even though few technological advancements have occurred in Orthodontics recently, the search for more efficient treatments continues. This paper analyses how to accelerate and improve one of the most arduous phases of orthodontic treatment, i.e., correction of the curve of Spee. The leveling of a deep curve of Spee can happen simultaneously with the alignment phase through a method called Early Vertical Correction (EVC). This technique uses two cantilevers affixed to the initial flexible archwire. This paper describes the force system produced by EVC and how to control its side effects. The EVC can reduce treatment time in malocclusions with deep curves of Spee, by combining two phases of the therapy, which clinicians ordinarily pursue sequentially. PMID- 28658364 TI - Prevalence and factors associated with human brucellosis in livestock professionals. AB - OBJECTIVE: The objective of this study is to estimate the seroprevalence of human brucellosis in livestock professionals and analyze the factors associated with brucellosis focusing on sociodemographic variables and the variables of knowledge and practices related to the characteristics of the activities carried out in livestock. METHODS: This is a cross-sectional seroepidemiological study with a population of 131 workers of butchers, slaughter rooms, and slaughterhouse and 192 breeders sampled randomly in Namibe province, Angola. The data were obtained from the collection of blood and use of questionnaires. The laboratory tests used were rose bengal and slow agglutination. The questionnaire allowed us to collect sociodemographic information and, specifically on brucellosis, it incorporated questions about knowledge, attitudes, and behaviors of livestock professionals. In addition to the descriptive statistical approach, we used the Chi-square test of independence, Fisher's test, and logistic regression models, using a significance level of 10%. RESULTS: The general weighted prevalence of brucellosis was 15.6% (95%CI 13.61-17.50), being it 5.3% in workers and 16.7% (95%CI 11.39-21.93) in breeders. The statistical significance was observed between human seroprevalence and category (worker and breeder) (p < 0.001) and education level (p = 0.032), start of activity (p = 0079), and service location (p = 0.055). In a multivariate context, the positive factor associated with brucellosis in professionals was the professional category (OR = 3.54; 95%CI 1.57 8.30, related to breeders in relation to workers). CONCLUSIONS: Human brucellosis in livestock professionals is prevalent in Namibe province (15.6%), where the professional category was the most important factor. The seroprevalence levels detected are high when compared with those found in similar studies. OBJECTIVO: Estimar a seroprevalencia da brucelose humana em profissionais da pecuaria e analisar os factores associados a brucelose com foco em variaveis sociodemograficas, de conhecimento e praticas relativas as caracteristicas das actividades desenvolvidas na pecuaria. METODOS: Estudo transversal seroepidemiologico em populacao de 131 trabalhadores de talhos, salas de abate e matadouro e 192 criadores amostrados aleatoriamente na provincia do Namibe, Angola. Os dados foram obtidos por meio de colheita de sangue e aplicacao de questionario. Os testes laboratoriais utilizados foram o Rosa de Bengala e a aglutinacao lenta em tubos. O questionario permitiu recolher informacao sociodemografica e, especificamente sobre a brucelose, incorporou questoes sobre conhecimento, atitudes e comportamentos dos profissionais da pecuaria. Alem da abordagem estatistica descritiva, foram utilizados os testes de Independencia do Qui-quadrado, Fisher e modelos de regressao logistica, utilizando um nivel de significancia de 10%. RESULTADOS: A prevalencia geral ponderada da brucelose foi de 15.6% (IC95% 13.61-17.50), sendo 5.3% em trabalhadores e 16.7% (IC95% 11.39 21.93) em criadores. A significancia estatistica foi observada entre a seroprevalencia humana e a categoria (trabalhador e criador) (p < 0.001) e o nivel de instrucao (p = 0.032), inicio de actividade (p = 0.079) e local de servico (p = 0.055). Em um contexto multivariado, o factor positivamente associado a brucelose em profissionais foi a categoria profissional (OR = 3.54; IC95% 1.57-8.30, relativo aos criadores em relacao a trabalhadores). CONCLUSOES: A brucelose humana em profissionais da pecuaria e prevalente na provincia do Namibe (15.6%), onde a categoria profissional foi o factor mais relevante. Os niveis de seroprevalencia detectados sao elevados se comparados com outros encontrados em estudos semelhantes. PMID- 28658365 TI - Factors associated with access to physical rehabilitation for victims of traffic accidents. AB - OBJECTIVE: Evaluate the level of access to physical rehabilitation for survivors of traffic accidents and the associated factors. METHODS: A cross-sectional study performed in Natal, Northeastern Brazil, through a telephone survey of 155 victims of traffic accidents admitted to an emergency hospital between January and August of 2013, with a diagnosis of fracture, traumatic brain injury or amputation. Participants were identified in the database of the reference hospital for care of traffic accident victims. We calculated point estimates and confidence interval (95%CI) for the frequency of subjects who had access, in addition to multivariate analysis (logistic regression) between access (dependent variable) and sociodemographic, clinical, and assistance variables. RESULTS: Among the 155 respondents, the majority were adolescents and adults between 15-29 years of age (47.7%), men (82.6%), education up to high school (92.3%), income of up to two minimum wages (78.0%) and bikers (75.5%). Although 85.8% of traffic accident survivors reported the need for physical rehabilitation, there was little access (51.6%; 95%CI 43.7-59.4) and a delay to start the physical rehabilitation (average = 67 days). We classified factors associated with access to physical rehabilitation as: (i) unmodifiable individuals in the short term - family income greater than two minimum wages (OR = 3.7), informal worker (OR = 0.11) or unemployed (OR = 0.15) and possession of a private health care plan (OR = 0.07); and (ii) assistance modifiable by service management - written referral for physical rehabilitation (OR = 27.5) and perceived need of physical rehabilitation (OR = 10). CONCLUSIONS: This study found a low and slow access to physical rehabilitation for individuals potentially in need. The associated factors were the organizational processes of health care (health information and referral) and social determinants (income, occupation and private health care plan). OBJETIVO: Avaliar o nivel de acesso a reabilitacao fisica para sobreviventes de acidentes de transito e seus fatores associados. METODOS: Estudo transversal realizado em Natal, Nordeste do Brasil, com inquerito telefonico a 155 vitimas de acidentes de transito atendidos no hospital de emergencia, entre janeiro e agosto de 2013, com diagnostico de fratura, traumatismo cranioencefalico ou amputacao. Os participantes foram identificados no banco de dados do hospital referencia para atendimentos de acidentes de transito. Calculou se a estimativa pontual e o intervalo de confianca (IC95%) da porcentagem de acesso e tempo para acesso, alem de analise multivariada (regressao logistica) entre o acesso (variavel dependente) e as variaveis sociodemograficas, clinicas e assistenciais. RESULTADOS: Entre os 155 entrevistados, predominaram jovens e adultos de 15-29 anos (47,7%), sexo masculino (82,6%), escolaridade ate o ensino medio (92,3%), renda de ate dois salarios minimos (78,0%) e motociclistas (75,5%). Embora 85,8% dos sobreviventes de acidentes de transito tivessem relatado a necessidade de reabilitacao fisica, houve baixo acesso geral (51,6%; IC95% 43,7-59,4) e demora para inicio da reabilitacao fisica (media = 67 dias). Os fatores associados ao acesso a reabilitacao fisica classificaram-se em: (i) individuais nao modificaveis em curto prazo - renda familiar maior que dois salarios minimos (OR = 3,7), ser trabalhador informal (OR = 0,11) ou desempregado (OR = 0,15) e ter plano privado de saude (OR = 0,07); e (ii) assistenciais modificaveis pela gestao do servico - encaminhamento escrito para reabilitacao fisica (OR = 27,5) e necessidade percebida de reabilitacao fisica (OR = 10). CONCLUSOES: Este estudo encontrou um baixo e demorado acesso a reabilitacao fisica para individuos potencialmente necessitados. Os fatores associados foram os processos organizativos dos cuidados em saude (encaminhamento e informacao em saude) e os determinantes sociais (renda, ocupacao e plano privado de saude). PMID- 28658366 TI - Fuzzy model to estimate the number of hospitalizations for asthma and pneumonia under the effects of air pollution. AB - OBJECTIVE: Predict the number of hospitalizations for asthma and pneumonia associated with exposure to air pollutants in the city of Sao Jose dos Campos, Sao Paulo State. METHODS: This is a computational model using fuzzy logic based on Mamdani's inference method. For the fuzzification of the input variables of particulate matter, ozone, sulfur dioxide and apparent temperature, we considered two relevancy functions for each variable with the linguistic approach: good and bad. For the output variable number of hospitalizations for asthma and pneumonia, we considered five relevancy functions: very low, low, medium, high and very high. DATASUS was our source for the number of hospitalizations in the year 2007 and the result provided by the model was correlated with the actual data of hospitalization with lag from zero to two days. The accuracy of the model was estimated by the ROC curve for each pollutant and in those lags. RESULTS: In the year of 2007, 1,710 hospitalizations by pneumonia and asthma were recorded in Sao Jose dos Campos, State of Sao Paulo, with a daily average of 4.9 hospitalizations (SD = 2.9). The model output data showed positive and significant correlation (r = 0.38) with the actual data; the accuracies evaluated for the model were higher for sulfur dioxide in lag 0 and 2 and for particulate matter in lag 1. CONCLUSIONS: Fuzzy modeling proved accurate for the pollutant exposure effects and hospitalization for pneumonia and asthma approach. OBJETIVO: Prever o numero de internacoes por asma e pneumonia associadas a exposicao a poluentes do ar no municipio em Sao Jose dos Campos, estado de Sao Paulo. METODOS: Trata-se de um modelo computacional que utiliza a logica fuzzy baseado na tecnica de inferencia de Mamdani. Para a fuzzificacao das variaveis de entrada material particulado, ozonio, dioxido de enxofre e temperatura aparente foram consideradas duas funcoes de pertinencia para cada variavel com abordagem linguisticas: bom e ruim. Para a variavel de saida numero internacoes por asma e pneumonia, foram consideradas cinco funcoes de pertinencias: muito baixo, baixo, medio, alto e muito alto. O numero de internacoes no ano de 2007 foi obtido do Datasus e o resultado fornecido pelo modelo foi correlacionado com os dados reais de internacao com defasagem (lag) de zero a dois dias. A acuracia do modelo foi estimada pela curva ROC para cada poluente e nestas defasagens. RESULTADOS: No ano de 2007 foram registradas 1.710 internacoes por pneumonia e asma em Sao Jose dos Campos, SP, com media diaria de 4,9 internacoes (dp = 2,9). Os dados de saida do modelo mostraram correlacao positiva e significativa (r = 0,38) com os dados reais; as acuracias avaliadas para o modelo foram maiores para o dioxido de enxofre nos lag 0 e 2 e para o material particulado no lag 1. CONCLUSOES: Modelagem fuzzy se mostrou acurada para a abordagem de efeitos da exposicao aos poluentes e internacao por pneumonia e asma. PMID- 28658367 TI - Potentially inappropriate medications among older adults in Pelotas, Southern Brazil. AB - OBJECTIVE: To assess the use of potentially inappropriate medications among older adults. METHODS: This is a population-based cross-sectional study with 1,451 older individuals aged 60 years or more in the city of Pelotas, State of Rio Grande do Sul, Brazil, in 2014. We have investigated the use of medications in the last 15 days. Using the Beers criteria (2012), we have verified the use of potentially inappropriate medications and their relationship with socioeconomic and demographic variables, polypharmacy, self-medication, and burden of disease. RESULTS: Among the 5,700 medications used, 5,651 could be assessed as to being inappropriate. Of these, 937 were potentially inappropriate for the older adults according to the 2012 Beers criteria (16.6%). Approximately 42.4% of the older adults studied used at least one medication considered as potentially inappropriate. The group of medications for the nervous system accounted for 48.9% of the total of the potentially inappropriate medications. In the adjusted analysis, the variables female, advanced age, white race, low educational level, polypharmacy, self-medication, and burden of disease were associated with the use of potentially inappropriate medications. CONCLUSIONS: It is important to known the possible consequences of the use of medication among older adults. Special attention should be given to the older adults who use polypharmacy. Specific lists should be created with more appropriate medications for the older population in the National Essential Medicine List. OBJETIVO: Avaliar o uso de medicamentos potencialmente inadequados entre idosos. METODOS: Estudo transversal de base populacional com 1.451 idosos com 60 anos ou mais em Pelotas, RS, em 2014. Investigou-se o uso de medicamentos nos ultimos 15 dias. Utilizando os criterios de Beers (2012), verificou-se a potencial inadequacao dos medicamentos e sua relacao com variaveis socioeconomicas e demograficas, polifarmacia, automedicacao e carga de doenca. RESULTADOS: Dentre os 5.700 medicamentos utilizados, 5.651 puderam ser avaliados quanto a inadequacao. Destes, 937 eram potencialmente inadequados para idosos segundo os criterios de Beers de 2012 (16,6%). Cerca de 42,4% dos idosos usaram no minimo um medicamento considerado potencialmente inapropriado. O grupo de medicamentos para o sistema nervoso correspondeu a 48,9% do total de medicamentos potencialmente inadequados. Na analise ajustada, as variaveis sexo feminino, idade avancada, cor da pele branca, baixa escolaridade, polifarmacia, automedicacao e carga de doenca mostraram-se associadas ao uso de medicamentos potencialmente inadequados. CONCLUSOES: E importante que sejam bem conhecidas as possiveis consequencias do uso de medicamentos entre idosos. Atencao especial deve ser dada aos idosos que fazem uso de polifarmacia. E necessario existir listas especificas com medicamentos mais adequados para uso em idosos na Relacao Nacional de Medicamentos Essenciais. PMID- 28658368 TI - Burden of disease and health situation analysis: results of the Global Burden of Disease (GBD) Brazil network. PMID- 28658369 TI - [Global Burden of Disease 2015 study: summary of methods used]. PMID- 28658371 TI - Quality of mortality statistics' information: garbage codes as causesof death in Belo Horizonte, 2011-2013. AB - Objective:: To assess the quality of mortality information by analyzing the frequency of garbage codes (GC) registered as underlying cause-of-death in Belo Horizonte, Minas Gerais, Brazil. Methods:: Data of deaths of residents from 2011 to 2013 were selected. GC causes were classified as proposed by the Global Burden of Disease Study (GBD) 2015. They were grouped into GCs from ICD-10 Chapter XVIII and GCs excluding codes of Chapter XVIII. Proportions of GC were calculated by sex, age, and place of occurrence. Results:: In Belo Horizonte, 30.5% of the total of 44,123 deaths were GC. Higher proportion of these codes was observed in children (1 to 4 years) and in people aged over 60 years. The following leading GCs observed were: other ill-defined and unspecified causes of death (code R99), unspecified pneumonia (J18.9), unspecified stroke (hemorrhagic or ischemic) (I64), and unspecified septicemia (A41.9). The proportions of GC were 28.7% and 36.9% in deaths that occurred in hospitals and at home, respectively. An important difference occurred in the GC group from Chapter XVIII of ICD-10: 1.7% occurred in hospitals and 16.9% at home. Conclusion:: The high proportions of GC in mortality statistics in Belo Horizonte demonstrated its importance for assessing the quality of information on causes of death. PMID- 28658370 TI - Completeness of death-count coverage and adult mortality (45q15) for Brazilian states from 1980 to 2010. AB - Objective:: Assess the completeness of the DataSUS SIM death-count registry, by sex and Brazilian state, and estimate the probability of adult mortality (45q15), by sex and state, from 1980 to 2010. Methods:: The study was based on mortality data obtained in the DataSUS Mortality Information System, from 1980 to 2010, and on population data from the 1980, 1991, 2000, and 2010 demographic censuses. The quality assessment of the registry data was conducted using traditional demographic and death distribution methods, and death probabilities were calculated using life-table concepts. Results:: The results show a considerable improvement in the completeness of the death-count coverage in Brazil since 1980. In the southeast and south, we observed the complete coverage of the adult mortality registry, which did not occur in the previous decade. In the northeast and north, there were still places with a low coverage from 2000 to 2010, although there was a clear improvement in the quality of data. For all Brazilian states, there was a decline in the probability of adult mortality; we observed, however, that the death probability for males is much higher than that for females throughout the whole analysis period. Conclusion:: The observed improvements seem to be related to investments in the public health care system and administrative procedures to improve the recording of vital events. PMID- 28658372 TI - Leading causes of child mortality in Brazil, in 1990 and 2015: estimates from the Global Burden of Disease study. AB - Objective:: To analyze under-5 mortality rates and leading causes in Brazil and states in 1990 and 2015, using the Global Burden of Disease Study (GBD) 2015 estimates. Methods:: The main sources of data for all-causes under-5 mortality and live births estimates were the mortality information system, surveys, and censuses. Proportions and rates per 1,000 live births (LB) were calculated for total deaths and leading causes. Results:: Estimates of under-5 deaths in Brazil were 191,505 in 1990, and 51,226 in 2015, 90% of which were infant deaths. The rates per 1,000 LB showed a reduction of 67.6% from 1990 to 2015, achieving the proposed target established by the Millennium Development Goals (MDGs). The reduction generally was more than 60% in states, with a faster reduction in the poorest Northeast region. The ratio of the highest and lowest rates in the states decreased from 4.9 in 1990 to 2.3 in 2015, indicating a reduction in socioeconomic regional disparities. Although prematurity showed a 72% reduction, it still remains as the leading cause of death (COD), followed by diarrheal diseases in 1990, and congenital anomalies, birth asphyxia and septicemia neonatal in 2015. Conclusion:: Under-5 mortality has decreased over the past 25 years, with reduction of regional disparities. However, pregnancy and childbirth related causes remain as major causes of death, together with congenital anomalies. Intersectoral and specific public health policies must be continued to improve living conditions and health care in order to achieve further reduction of under-5 mortality rates in Brazil. PMID- 28658373 TI - Mortality due to cirrhosis, liver cancer, and disorders attributed to alcohol use: Global Burden of Disease in Brazil, 1990 and 2015. AB - Introduction:: Alcohol use is one of the main preventable risk factors affecting mortality and premature disability. Objective:: To describe the estimates of mortality and years of life lost as a result of premature death (YLL) due to cirrhosis, liver cancer, and disorders attributed to alcohol use in Brazil and its federated units in 1990 and 2015. Methods:: Descriptive study using data from the Global Burden of Disease Study (2015) and the Mortality Information System (SIM). Statistical models were used to obtain corrected mortality estimates for selected causes. Rates were standardized by age. Results:: In 1990, 16,226 deaths were estimated for the three conditions (17.0/100 thousand inhabitants), while in 2015 there were 28,337 deaths (15.7/100 thousand inhabitants). There was a reduction in mortality (per 100 thousand) due to cirrhosis (from 11.4 to 9.5), stability in mortality rates related to liver cancer (1.5 and 1.9), and stability in mortality rates caused by alcohol use disorders (4.1 and 4.3). Mortality rates were 5.1 times higher among men, and the five states with the highest mortality rates and YLL were from the Northeast Region: Sergipe, Ceara, Pernambuco, Paraiba, and Alagoas. Mortality and YLL rates for the three conditions studied increased in the ranking of causes of death in both sexes, with the exception of cirrhosis in the female population. Conclusion:: The three conditions studied are responsible for a significant burden of premature mortality in Brazil, especially among men and residents of the northeast region. These results reinforce the urgent need for public policies that address harmful alcohol consumption in Brazil. PMID- 28658374 TI - Mortality and disability from tobacco-related diseases in Brazil, 1990 to 2015. AB - Introduction:: The global tobacco epidemic has taken pandemic proportions, with about 1.3 billion users and 6 million annual deaths. This study aimed to analyze the trends in mortality from chronic obstructive pulmonary disease (COPD) and lung, lips, oral cavity, pharynx, and esophagus cancer in Brazil between 1990 and 2015. Methods:: The study was made possible through a partnership between the Metrics and Health Assessment Institute (IHME), University of Washington, Ministry of Health and the GBD Brazil technical group, using estimates from the Global Disease Charge 2015 study. Results:: The mortality rates due to COPD fell; in 1990, it was 64.5/100,000 inhabitants and in 2015, 44.5, a decrease of 31%. For the various types of cancer related to smoking, the decrease was in a lower proportion than for COPD. For lung cancer, rates were 18.7/100,000 inhabitants in 1990 to 18.3 in 2015. For women, there is an upward curve for lung cancer from 1990 to 2015, with an increase of 20.7%. Discussion:: The study points to smoking as a risk factor for premature mortality and disability due to COPD and cancer. The significant reduction in tobacco prevalence in recent decades could explain reductions in tobacco-related disease trends. The higher mortality from lung cancer in women may express the delayed increase in smoking in this gender. Conclusion:: Nationwide actions taken in the last decades have had a great effect on reducing mortality from tobacco-related diseases, but there are still major challenges, especially when it comes to women and young people. PMID- 28658375 TI - The burden of diabetes and hyperglycemia in Brazil and its states: findings from the Global Burden of Disease Study 2015. AB - Introduction and objective:: The global burden of disease (GBD) 2015 project, extends GBD analyses to include Brazilian federative units separately. We take advantage of GBD methodological advances to describe the current burden of diabetes and hyperglycemia in Brazil. Methods:: Using standard GBD 2015 methods, we analyzed the burden of diabetes, chronic kidney disease due to diabetes and high fasting plasma glucose in Brazil and its states. Results:: The age standardized rate of disability-adjusted life years (DALYs) which was lost to high fasting plasma glucose, a category which encompasses burdens of diabetes and of lesser hyperglycemia, were 2448.85 (95% UI 2165.96-2778.69) /100000 for males, and 1863.90 (95% UI 1648.18-2123.47) /100000 for females in 2015. This rate was more than twice as great in states with highest burden, these being overwhelmingly in the northeast and north, compared with those with lowest rates. The rate of crude DALYs for high fasting plasma glucose, increased by 35% since 1990, while DALYs due to all non-communicable diseases increased only by 12.7%, and DALYs from all causes declined by 20.5%. Discussion:: The worldwide pandemic of diabetes and hyperglycemia now causes a major and growing disease burden in Brazil, especially in states with greater poverty and a lesser educational level. Conclusion:: Diabetes and chronic kidney disease due to diabetes, as well as high fasting plasma glucose in general, currently constitute a major and growing public health problem in Brazil. Actions to date for their prevention and control have been slow considering the magnitude of this burden. PMID- 28658376 TI - Magnitude and variation of the burden of cancer mortality in Brazil and Federation Units, 1990 and 2015. AB - Objective:: To analyze the mortality rates from malignant neoplasia in Brazil and Federal Units (FU) in the years 1990 and 2015, according to sex and main types of cancer. Methods:: Using estimates of global disease burden for Brazil made by the GBD 2015 study, age-adjusted cancer mortality rates and respective 95% uncertainty intervals were calculated for Brazil and FU in 1990 and 2015, as well as their percentage variation in the period. The main causes of cancer mortality by sex were analyzed, considering the five highest rates in the country and for each state. Results:: The cancer mortality rate for male and female population remained stable between the two years in the country. The same behavior pattern was observed in almost all the FU, and the majority of states in the northeast region and half of the north region showed a non-significant increase in mortality rates. Regarding the types of cancer, there was a drop in mortality rates for stomach cancers in both sexes (women: -38.9%, men: -37.3%), cervical cancer in women (-33.9%), and lung and esophagus cancer in men (-12.0% and 14.1%, respectively); in contrast, there was an increase in lung cancers in women (+20.7%) and colon and rectum cancers in men (+29.5%). Conclusion:: Differences in the behavior of major cancers, with a decrease mainly in the more developed regions and an increase in the less developed regions of the country, seem to reflect the socioeconomic inequalities as well as difficulties in access to health services by the Brazilian population. PMID- 28658377 TI - Variations and particularities in cardiovascular disease mortality in Brazil and Brazilian states in 1990 and 2015: estimates from the Global Burden of Disease. AB - Objective:: To analyze variations and particularities in mortality due to cardiovascular disease (CVD) in Brazil and in Brazilian states, in 1990 and 2015. Methods:: We used data compiled from the Global Burden of Disease (GBD) 2015, obtained from the database of the Mortality Information System (SIM) of the Brazilian Ministry of Health. Correction of the sub-registry of deaths and reclassification of the garbage codes were performed using specific algorithms. The cardiovascular causes were subdivided into 10 specific causes. Age standardized CVD mortality rates - in 1990 and 2015 - were analyzed according to sex and Brazilian state. Results:: Age-standardized CVD mortality rate decreased from 429.5 (1990) to 256.0 (2015) per 100,000 inhabitants (40.4%). The proportional decrease was similar in both sexes, but death rates in males were substantially higher. The reduction of age-standardized mortality rate was more significant for rheumatic heart disease (44.5%), ischemic cardiopathy (43.9%), and cerebrovascular disease (46.0%). The decline in mortality was markedly different across states, being more pronounced in those of the southeastern and southern regions and the Federal District, and more modest in most states in the north and northeast regions. Conclusion:: Age-standardized CVD mortality has declined in Brazil in recent decades, but in a heterogeneous way across states and for different specific causes. Considering the burden magnitude and the Brazilian population aging, policies to prevent and manage CVD should continue to be prioritized. PMID- 28658378 TI - Cerebrovascular disease in Brazil from 1990 to 2015: Global Burden of Disease 2015. AB - Objective:: To verify the time trends of mortality rates, years of lost life (YLL), and years lived with disability (YLD) caused by cerebrovascular disease in Brazil between 1990 and 2015. Methods:: The estimates from the Global Burden of Diseases 2015 were used to analyze the magnitude and trends of mortality rates and disability-adjusted life years (DALY) for cerebrovascular disease (ICD-10: I 60-69) in the 27 units of the Federation between 1990 and 2015. The states were analyzed by the social development index (SDI), based on average income per person, educational attainment at 15 years- old and total fertility rate. Results:: Despite the increase in the absolute number of deaths due to cerebrovascular disease, the proportion of deaths below 70 years of age has been halved between 1990 and 2015. The acceleration of the reduction was higher among women; and increased from 1990 to 2005, when compared to the period from 2005 to 2015. The risk of death has been halved across the country, but states in the lower SDI tertile had less significant reductions (-1.23 and -1.84% a year) compared to the middle tertile (-1.94 and - 2.22%) and the upper tertile (-2.85 and -2.82%) for men and women, respectively. The years lived with disability also presented a reduction among states, but less expressively. Conclusion:: Despite the reduction of age-adjusted mortality rates throughout the country, cerebrovascular disease still presents a high disease burden, especially in states with lower socioeconomic development. PMID- 28658379 TI - Mortality and years of life lost by interpersonal violence and self-harm: in Brazil and Brazilian states: analysis of the estimates of the Global Burden of Disease Study, 1990 and 2015. AB - Objective:: To analyze mortality and years of life lost due to death or disability (disability-adjusted life years - DALYs) for interpersonal violence and self-harm, comparing 1990 and 2015, in Brazil and Federated Units, using estimates produced by the Global Burden of Disease 2015 (GBD 2015). Methods:: Secondary data analysis of estimates from the GBD 2015, producing standardized death rates and years of life lost due to death or disability. The main source of death data was the Mortality Information System, submitted to correction of underreporting of deaths and redistribution of garbage codes. Results:: From 1990 to 2015, homicide mortality rates were stable, with a percentage variation of 0.9%, from 28.3/100 thousand inhabitants (95% UI 26.9-32.1) in 1990 to 27.8/100,000 (95% UI 24.3-29.8) in 2015. Homicide rates were higher in Alagoas and Pernambuco, and there was a reduction in Sao Paulo (-40.9%). Suicide rates decreased by 19%, from 8.1/100,000 (95% UI 7.5-8.6) in 1990 to 6.6/100,000 (95% UI 6.1-7,9) in 2015. Higher rates were found in Rio Grande do Sul. In the ranking of external causes for years of life lost due to death or disability (DALYs), firearm aggression predominated, followed by transportation accidents; self inflicted injuries were in sixth place. Conclusions:: The study shows the importance of external causes among young people and men as a cause of premature death and disabilities, which is a priority problem in the country. The Global Burden of Disease study may support public policies for violence prevention. PMID- 28658380 TI - Road traffic accidents: Global Burden of Disease study, Brazil and federated units, 1990 and 2015. AB - Objective:: To describe the global burden of disease due to road traffic accidents in Brazil and federated units in 1990 and 2015. Methods:: This is an analysis of secondary data from the 2015 Global Burden of Disease study estimates. The following estimates were used: standardized mortality rates and years of life lost by death or disability, potential years of life lost due to premature death, and years of unhealthy living conditions. The Mortality Information System was the main source of death data. Underreporting and redistribution of ill-defined causes and nonspecific codes were corrected. Results:: Around 52,326 deaths due to road traffic accidents were estimated in Brazil in 2015. From 1990 to 2015, mortality rates decreased from 36.9 to 24.8/100 thousand people, a reduction of 32.8%. Tocantins and Piaui have the highest mortality risks among the federated units (FU), with 41.7/100 and 33.1/100 thousand people, respectively. They both present the highest rates of potential years of life lost due to premature deaths. Conclusion:: Road traffic accidents are a public health problem. Using death- or disability-adjusted life years in studies of these causes is important because there are still no sources to know the magnitude of sequelae, as well as the weight of early deaths. Since its data are updated every year, the Global Burden of Disease study may provide evidence to formulate traffic security and health attention policies, which are guided to the needs of the federated units and of different groups of traffic users. PMID- 28658381 TI - Burden of disease by lower respiratory tract infections in Brazil, 1990 to 2015: estimates of the Global Burden of Disease 2015 study. AB - Introduction:: Lower respiratory tract infections (LRTIs) present significant incidence and mortality in the world. This article presents the impact of LRTIs in the burden of disease, according to the metrics used in the Global Burden of Disease study (GBD 2015) for Brazil in 1990 and 2015. Methods:: Analysis of estimates from the GBD 2015: years of life lost due to premature death (YLLs), years lived with disability (YLDs), years of life lost due to death or disability (DALYs = YLLs + YLDs). Results:: LRTIs were the third cause of mortality in Brazil in 1990 and 2015, with 63.5 and 47.0 deaths/100,000 people, respectively. Although the number of deaths increased 26.8%, there was a reduction of 25.5% in mortality rates standardized by age, with emphasis on children under 5 years of age. The disability indicators, as measured by the DALYs, demonstrate a progressive reduction of the disease burden by LRTIs. Discussion:: Despite the reduction in mortality rates in the period, LRTIs were an important cause of disability and still the third cause of death in Brazil in 2015. The increase in the number of deaths occurred due to the increase in population and its aging. The reduction in mortality rates accompanied the improvement of socioeconomic conditions, broader access to health care, national availability of antibiotics, and vaccination policies adopted in the country. Conclusion:: Despite the current socioeconomic difficulties, there has been a progressive reduction of the LRTIs load effect in Brazil, mostly in mortality and disability, and among children under 5 years of age. PMID- 28658382 TI - HIV/AIDS Mortality in Brazil, 2000-2015: Are there reasons for concern? AB - Introduction and objective:: Mortality studies are essential for the monitoring of the HIV/AIDS epidemic. Quality and completeness of data from the mortality information system (SIM) require complementary approaches. Methods:: Two sources of data were used to assess mortality trends due to HIV/AIDS in Brazil from 2000 and 2014/15: a) data from the SIM published by the Department of STDs, AIDS, and viral hepatitis, and b) Global Burden of Disease 2015 (GBD 2015) studies. Descriptive analyses were carried out and trends in relative reduction of age adjusted mortality rates per 100,000 inhabitants were compared according to the two methods. Results:: Overall, the magnitude of the mortality rates estimated by the GBD method, for Brazil and its Federative Units (FU), was greater than those obtained from the SIM. The relative reduction was higher for SIM data and there were shifts in the ranking according to the FUs. Between 2000 and 2014/15 there was an increase in the mortality rates for most of the FUs (78 and 88% according to the SIM and GBD, respectively). Conclusion:: Data regarding mortality due to HIV/AIDS in Brazil should be of concern, regardless of the method used. Differences in magnitude, relative reductions, and ranking can be attributed to methodological differences, but the GBD is broader, with a higher capacity to capture incorrectly classified data and causes of death not registered or not coded as being due to HIV/AIDS. Alternative and complementary data sources can provide important information for HIV/AIDS public policies in Brazil. PMID- 28658383 TI - The Burden of disease attributable to mental and substance use disorders in Brazil: Global Burden of Disease Study, 1990 and 2015. AB - Introduction:: Mental and substance use disorders (MD) are highly prevalent and have a high social and economic cost. Objective:: To describe the burden of disease attributable to mental and substance use disorders in Brazil and Federated Units in 1990 and 2015. Methods:: Descriptive study of the burden of mental and substance use disorders, using age-standardized estimates from the Global Burden of Disease Study 2015: years of life lost due to premature mortality (YLL); years lived with disability (YLD); and disability-adjusted life year (DALY=YLL+YLD). Results:: In Brazil, despite low mortality rates, there has been a high burden for mental and substance use disorders since 1990, with high YLD. In 2015, these disorders accounted for 9.5% of all DALY, ranking in the third and first position in DALY and YLD, respectively, with an emphasis on depressive and anxiety disorders. Drug use disorders had their highest increase in DALY rates between 1990 and 2015 (37.1%). The highest proportion of DALY occurred in adulthood and in females. There were no substantial differences in burden of mental and substance use disorders among Federated Units. Conclusion:: Despite a low mortality rate, mental and substance use disorders are highly disabling, which indicates the need for preventive and protective actions, especially in primary health care. The generalization of estimates in all the Federated Units obtained from studies conducted mostly in the south and southeast regions probably does not reflect the reality of Brazil, indicating the need for studies in all regions of the country. PMID- 28658384 TI - Increase in the burden of dengue in Brazil and federated units, 2000 and 2015: analysis of the Global Burden of Disease Study 2015. AB - Objective:: To describe the main metrics on dengue generated by Global Burden of Disease (GBD) Study 2015, for Brazil and its 27 federated units, in the years 2000 and 2015. Methods:: The metrics described were: incidence and mortality rates by dengue, standardized by age, years of life lost (YLL), years lived with disability (YLD), and disability-adjusted life years (DALY) (in absolute frequency and age-standardized rates). The estimated metrics were presented with uncertainty intervals (UI 95%) for the years 2000 and 2015, accompanied by the relative percentages of changes. Results:: The number of cases increased 232.7% and the number of deaths increased 639.0% between 2000 and 2015 in the country. The incidence rate varied 184.3% and the mortality rate was low, but with an increase of 500.0% in the period evaluated. The YLL, YLD, and DALY rates increased 420.0, 187.2, and 266.1%, respectively. In 2015, DALY was similar among women and men (21.9/100,000). The DALY increased more than double in all the Brazilian federated units. Conclusion:: The marked increase in dengue over the years is associated with the introduction and/or circulation of one or more serotypes of the transmitter virus and an increasing proportion of patients affected by the severe form of the disease. Despite the low mortality rate of the disease in comparison between the years of study, the disease contributes to the loss of healthy years of life in Brazil as it affects a large number of people, from all age groups, causing some degree of disability during the infection and deaths, especially, in children. PMID- 28658385 TI - Risk factors related to the global burden of disease in Brazil and its Federated Units, 2015. AB - Objective:: To analyze the global burden of disease related to disability adjusted life years (DALYs) attributed to selected risk factors in Brazil and its 27 Federated Units. Methods:: Databases from the Global Burden of Disease study in Brazil and its Federated Units were used, estimating the summary exposure value (SEV) for selected environmental, behavioral, and metabolic risk factors (RFs), and their combinations. The DALYs were used as the main metric. The ranking of major RFs between 1990 and 2015 was compiled, comparing data by sex and states. Results:: The analyzed RFs account for 38.8% of the loss of DALYs in the country. Dietary risks was the main cause of DALYs in 2015. In men, dietary risks contributed to 12.2% of DALYs and in women, to 11.1%. Other RFs were high systolic blood pressure, high body mass index, smoking, high fasting plasma glucose and, among men, alcohol and drug use. The main RFs were metabolic and behavioral. In most states, dietary risks was the main RF, followed by high blood pressure. Conclusion:: Dietary risks leads the RF ranking for Brazil and its Federated Units. Men are more exposed to behavioral risk factors, and women are more exposed to metabolic ones. PMID- 28658386 TI - Phylogeny of the genus Stephomyia Tavares, 1916 (Diptera: Cecidomyiidae). AB - Stephomyia Tavares, 1916 comprises seven species, all Neotropical: S. clavata (Tavares, 1920); S. epeugeniae Gagne, 1994; S. espiralis Maia, 1993; S. mina Maia, 1993; S. rotundifoliorum Maia, 1993; S. tetralobae Maia, 1993; and S. eugeniae (Felt, 1913). In the present study, a cladistic analysis based upon adult, pupa, larva and gall morphological characters as well as host plant data is carried out in order to discuss the monophyly of the genus and the relationships among the known species. The Stephomyia monophyly was supported by eight synapomorphies: five homoplastic characters and three non-homoplastic characters. Analyzes showed S. clavata with great instability within the genus, probably due to lack of larva, pupa and female data, so S. clavata was deactivated in analyze. The topology found was (S. mina ((S. eugeniae + S. epeugeniae) (S. tetralobae (S. rotundifoliorum + S. espiralis)))). PMID- 28658387 TI - First record of Craspedacusta sowerbii Lankester, 1880 (Hydrozoa, Limnomedusae) in a natural freshwater lagoon of Uruguay, with notes on polyp stage in captivity. AB - The freshwater cnidarian Craspedacusta sowerbii Lankester 1880, has invaded lakes and ponds as well as artificial water bodies throughout the world. The first record in Uruguay corresponding to the jellyfish was made in 1961 in two artificial fountains, with no mention of the polyp form. Although local reports of other related polyp species have been made, information on the benthic form of C. sowerbii is lacking. Here we report the finding of live frustules, solitary individuals, medusae and colonies from a natural lagoon in August 2010, allowing us to observe the morphology and behavior of the polyp stage in captivity. In addition, molecular identification and remarks on the potencial path of introduction are presented. This is the first record in Uruguay of both polyp and medusa stages of C. sowerbii in a natural water body, Del Medio Lagoon (Dpto. de Florida), Uruguay. PMID- 28658388 TI - Aquatic macrophyte mats as dispersers of one invasive plant species. PMID- 28658389 TI - Cry protein in the predatory mite Neoseiulus californicus and spider mite Tetranychus urticae prey fed with transgenic maize. PMID- 28658390 TI - Foliar phenolic compounds of ten wild species of Verbenacea as antioxidants and specific chemomarkers. AB - The family Verbenaceae hosts important species used in traditional medicine of many countries. The taxonomic controversies concerning the specific delimitation of several of its species make it difficult to guarantee the botanical origin of herbal preparations based on species of this family. To contribute to the development of both specific chemomarkers and a quality control tool to authenticate the botanical origin of herbal preparations of Verbenacea species, we determined the foliar HPLC-DAD phenolic profiles and the antioxidant properties of 10 wild species of this family occurring in Mexico. The contents of phenols and flavonoids varied significantly among species. Priva mexicana showed the highest levels of total phenolics (53.4 mg g-1 dry tissue) and Verbena carolina had the highest levels of flavonoids (17.89 mg g-1 dry tissue). Relevant antioxidant properties revealed by antiradical and reducing power were found for the analyzed species. These properties varied significantly in a species dependent manner. The phenolic compounds accumulated were flavones and phenolic acids. Flavones were the only type of flavonoids found. The results of a cluster analysis showed that the compounds were accumulated in species-specific profiles. The phenolic profiles are proposed as valuable chemomarkers that can become a useful tool for the quality control concerning the botanical origin of herbal medicinal preparations based on the species analyzed. In addition, phenolic profiles could contribute importantly to solve the taxonomic controversies concerning species delimitation in the family Verbenaceae. PMID- 28658391 TI - Escherichia coli is not a suitable fecal indicator to assess water fecal contamination by otters. AB - The detection of pathogenic microorganisms in aquatic environments is extremely relevant in terms of public health. As these laboratorial methodologies are usually difficult, expensive and time-consuming, they are frequently replaced by the assessment of fecal indicator bacteria, such as Escherichia coli. This study aimed to assess the presence of E. coli in fecal samples from Neotropical otters, to evaluate its potential as fecal indicator to be applied to the determination of water microbiological quality in areas where otters' populations are high. Twenty-six otter fecal samples, collected in Alto Paranapanema river basin, Sao Paulo State, Brazil, were analyzed for the presence of E. coli, using conventional bacteriological methods. Only 8 scat samples (30%) were E. coli positive, indicating that this microorganism is not a suitable fecal indicator to assess water fecal contamination by Neotropical otters, and should not be used to infer the presence of otter related pathogens in waters. PMID- 28658392 TI - Maize plants produce direct resistance elicited by Tetranychus urticae Koch (Acari: Tetranychidae). AB - Plants can be attacked by a wide variety of herbivores. Thus, developing protective mechanisms for resistance against these agents is an advantage for survival and reproduction. Over the course of evolution, many resistance mechanisms against herbivory have been developed by the plants. Induced direct and indirect resistance mechanisms can manifest in plants after herbivore attack. The two-spotted spider mite Tetranychus urticae is not a pest of maize crops (Zea mays), despite being reported infesting plants that may have resistances against this herbivore. We tested the hypothesis that maize plants would be able to induce direct resistance against T. urticae after, evaluating the effect of T. urticae infestation in maize plants on the development and reproduction of conspecifics. We tested induced direct resistance performing infestation and measuring biological parameters upon a second infestation. Maize plants, 40 days after sowing, were divided into two groups: 30 not infested by T. urticae (clean plants clean) and, 30 infested by the spider mite. Infestation of maize plants by T. urticae reduced the conspecific female adult survival. However, no change in the survival of immature or reproduction was observed. These results suggest the induction of induced direct resistances in maize by T. urticae. This is first report of direct resistance induction in Z. mays by the two-spotted spider mite T. urticae. PMID- 28658393 TI - Quality of life of workers who underwent work adjustments and adaptations in a public state university. AB - Objective: Assess the quality of life of workers who underwent work adjustments and adaptations in a public state university. Methods: This was a cross-sectional study carried out with 92 employees from a public state university. Data were collected from November 2012 to May 2013 using a population characterization questionnaire and the Medical Outcome Study 36-item Short Form, and then underwent a univariate and bivariate analysis through the Mann-Whitney test. Results: The two domains that obtained the best scores were social function and emotional performance, whereas the ones with the worst scores were physical performance and body pain. Most workers did not note changes in their health status in the last year. Conclusions: The quality of life scores, in general, were not high, especially in physical aspects. Therefore, measures need to be implemented to evaluate the effectiveness of work adjustments and adaptations, in order to improve occupational health. PMID- 28658394 TI - The influence of capitalism on the production of knowledge in nursing. AB - Objective: To understand the capitalist influence over the production of nursing knowledge according to Brazilian and Portuguese researchers. Method: Descriptive, exploratory, and qualitative research, with 17 research nurses selected using the snowball technique. Data were collected from October 2011 to November 2012 in Brazil and Portugal, by means of semi-structured interviews. We analysed the content of the interviews and produced inferences based in the theoretical assumptions of Gaston Bachelard and the notion of an epistemological obstacle. Results: The results were organised into three categories: Blocks to creativity/innovation and the practice of repetition; Overestimation of the quantitative; and Resistance to rupture. Conclusion: It is necessary to create new ways of assessing scientific literature from a qualitative perspective that allows room for creativity, professional development, and critical and reflective thinking. Solidarity is perceived as an alternative to overcoming the problems caused by the capitalist way of producing knowledge. PMID- 28658395 TI - Nurses' knowledge of blood transfusion in neonate. AB - Objective: To analyze nurses' knowledge of blood transfusion in neonates in a neonatal intensive unit care. Methods: A descriptive and exploratory qualitative study conducted in two hospitals in the city of Belo Horizonte, Minas Gerais. The participants were 15 nurses who performed their activities in the neonatal intensive unit care, from August to December 2014. Data was subjected to thematic content analysis. Results: The category created was divided into the following sub-categories, namely: nurses' care during blood transfusion: care during blood transfusion monitoring; a different perception of nurses regarding responses to blood transfusion and notification: the essence of care. Conclusion: The identification of nurses' knowledge of blood transfusion, it is possible to promote their capacity for quality and safety of care related to the transfusion process in newborns. PMID- 28658396 TI - Teaching in higher education in nursing and identity construction: entry, career and permanence. AB - Objective: To identify and analyze the relation between biographical and relational processes in constituting the professional identity of the nursing course faculty in higher education institutions in the state of Goias, Brazil. Method: This study is a qualitative research, data were collected in 2014, attended by 11 teachers from four nursing courses. A semi-structured interview was used. Data analysis was guided by the thematic content analysis modality and discussions used the theoretical-philosophical framework of Dubar. Results: Three thematic categories were identified: The entry into higher education teaching in nursing; The identity construction process of teaching in nursing and; Identity, career and permanence in the teaching profession. Final considerations: The constitution of the teaching professional identity required a complex negotiation between the biographic and relational aspects, highlighting the search for professional faculty development mechanisms. PMID- 28658397 TI - Perception of nursing and medical professionals on patient safety in neonatal intensive care units. AB - Objective: To describe patient safety in the perception of nursing and medical professionals of neonatal intensive care units. Method: Exploratory and descriptive study with a qualitative approach, using the instrument Hospital Survey on Patient Safety Culture for data collection. Twenty-eight nursing and medical professionals of three neonatal intensive care units in the city of Florianopolis, state of Santa Catarina, participated in the study, from 2013 to 2015. Content thematic analysis was used for data analysis. Results: The following categories emerged: perception and strategies for patient safety; risk factors that interfere with patient safety; challenges in the communication of errors associated with health care. Conclusions: Patient safety in the perception of professionals reflected the importance of safe care and the identification of risk factors in work conditions, predisposing to errors. Communication of risk situations, development of safety culture, and qualification are of utmost importance. PMID- 28658398 TI - Activities developed by the committees of prevention of infant and fetal deaths: integrative review. AB - Objective: To systematize knowledge on the activities developed by the committees involved in the prevention of infant and fetal deaths. Method: Integrated literature review conducted in November 2015 at PubMed, CINAHL, Scopus, LILACS, BDEnf and SciELO databases using keywords and descriptors of infant mortality, infant death, infant deaths, fetal death, fetal deaths, fetal mortality, neonatal mortality, professional committee, committee, committees, advisory committees. The 34 selected studies were organized and analyzed using Microsoft Excel(r). Results: International, national, regional, state and local committees analyze the deaths and conduct activities aimed to qualify maternal and childcare and feed the health information systems. Conclusion: The committees for the prevention of infant and fetal mortality collect, produce, analyze and disseminate information related to these deaths in order to reduce infant and fetal mortality rates. PMID- 28658399 TI - Unveiling the mysteries of hereditary prion diseases in Brazil. PMID- 28658400 TI - High phenotypic variability in Gerstmann-Straussler-Scheinker disease. AB - Gerstmann-Straussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity. PMID- 28658401 TI - Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a family report from South Brazil. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early onset, neurodegenerative disorder caused by mutations in SACS, firstly reported in Quebec, Canada. The disorder is typically characterized by childhood onset ataxia, spasticity, neuropathy and retinal hypermyelination. The clinical picture of patients born outside Quebec, however, is often atypical. In the present article, the authors describe clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil. We present a review on the neuroimaging, ophthalmologic and neurophysiologic clues for ARSACS diagnosis. The early-onset, slowly progressive, spastic-ataxia phenotype of reported patients was similar to ARSACS patients from Quebec. The SACS sequencing revealed the novel homozygous c.5150_5151insA frameshift mutation confirming the ARSACS diagnosis. ARSACS is a frequent cause of early onset ataxia/spastic-ataxia worldwide, with unknown frequency in Brazil. PMID- 28658402 TI - Is there a relationship between narcolepsy, multiple sclerosis and HLA DQB1*06:02? AB - We studied multiple sclerosis (MS) patients with the HLA-DQB1*06:02 allele and compared them with MS patients who did not carry the HLA-DQB1*06:02 allele. We analyzed clinical and neurophysiological criteria for narcolepsy in six MS patients with HLA-DQB1*06:02, compared with 12 MS patients who were HLA DQB1*06:02 non-carriers. Only two patients with HLA-DQB1*06:02 allele scored higher than 10 on the Epworth Sleepiness Scale. Polysomnography recording parameters and the multiple sleep latency test showed an absence of narcolepsy in the study group. Our study suggested no significant correlation between narcolepsy, MS and HLA-DQB1*06:02. The HLA-DQB1*06:02 allele alone was not sufficient to cause MS patients to develop narcolepsy. PMID- 28658403 TI - Dementia and legal determination of capacity. AB - Objective: To assess the legal capacity and guardianship proceedings in patients diagnosed with dementia. Methods: Ninety-seven patients diagnosed with dementia and seen at a tertiary hospital were evaluated. Results: Of these 97 patients, 60 (62%) were female. The mean age of the patients was 77.9 years; average schooling was 5.5 years. The main diagnosis was Alzheimer's disease (73%): 16 patients were at a mild stage, eight at a moderate stage and 73 at an advanced stage of dementia. Only 28 patients had been legally declared incapable. Conclusion: The large numbers of patients at an advanced stage of dementia, and the relatively few patients legally declared incapable show that legal issues in dementia are problematic. PMID- 28658404 TI - Key performance indicators for stroke from the Ministry of Health of Brazil: benchmarking and indicator parameters. AB - Methods: All 16 KPIs were analyzed, including the percentage of patients admitted to the stroke unit, venous thromboembolism prophylaxis in the first 48 hours after admission, pneumonia and hospital mortality due to stroke, and hospital discharge on antithrombotic therapy in patients without cardioembolic mechanism. Results: Both centers admitted over 80% of the patients in their stroke unit. The incidence of venous thromboembolism prophylaxis was > 85%, that of in-hospital pneumonia was < 13%, the hospital mortality for stroke was < 15%, and the hospital discharge on antithrombotic therapy was > 70%. Conclusion: Our results suggest using the parameters of all of the 16 KPIs required by the Ministry of Health of Brazil, and the present results for the two stroke units for future benchmarking. PMID- 28658405 TI - Potential role of a cognitive rehabilitation program following left temporal lobe epilepsy surgery. AB - Objectives: To assess the effects of a memory rehabilitation program in patients with left temporal lobe epilepsy following surgery. Methods: Twenty-four patients agreed to participate and 18 completed the study; nine received memory rehabilitation while nine had no input and were designated as controls. Verbal learning efficiency, naming abilities, memory subjective ratings, ecological activity measures and a language fMRI paradigm were used as outcome measures. Results: Improved verbal learning and naming test performance, increase in memory strategy use and improved self-perception were observed following the rehabilitation. Changes in fMRI activation patterns were seen in the rehabilitation group over the long term. Conclusion: The findings support the potential role of a cognitive rehabilitation program following left temporal lobe surgery. PMID- 28658406 TI - Malignant peripheral nerve sheath tumor with and without neurofibromatosis type 1. AB - Objective: In this study, we review the institution's experience in treating malignant peripheral nerve sheath tumors (MPNSTs). A secondary aim was to compare outcomes between MPNSTs with and without neurofibromatosis type 1 (NF1). Methods: Ninety-two patients with MPNSTs, over a period of 20 years, were reviewed. A retrospective chart review was performed. The median age was 43.5 years (range, 3 84 years) and 55.4% were female; 41 patients (44.6%) had NF1-associated tumors. Results: Mean tumor sizes were 15.8 +/- 8.2 cm and 10.8 +/- 6.3 cm for patients with and without NF1, respectively. Combined two- and five-year overall survival was 48.5% and 29%. Multivariate analysis confirmed the association of tumor size greater than 10 cm (hazard ratio (HR) 2.99; 95% confidence interval (CI) 1.14 7.85; p = 0.0258) and presence of NF1 (HR 3.41; 95%CI 1.88-6.19; p < 0.001) with a decreased overall survival. Conclusion: Tumor size and NF1 status were the most important predictors of overall survival in our population. PMID- 28658407 TI - Revisiting head circumference of Brazilian newborns in public and private maternity hospitals. AB - Objective: To revisit the head circumference (HC) of newborns in public and private maternity hospitals; to correlate our findings with the gestational age, gender, and type of delivery; and build and validate graphs and curves. Methods: This was a prospective study performed on healthy newborns. Differences in HC were analyzed as a function of gestational age, gender, the healthcare system and the type of delivery. Smoothed percentile curves were created using the least mean squares method. Results: Of the included newborns, 697 were born in private maternity hospitals and 2,150 were born in public maternity hospitals. In all, 839 were born by vaginal delivery, and 1,311 were born by cesarean delivery. At 37 to 42 weeks of gestation, male newborns had a larger HC than females. Infants born in private maternity and those born by cesarean delivery had a larger HC. Conclusion: An important result of the present study is that our analyses allowed us to generate curves and statistically-validated graphs that can be used in clinical neonatal practice. PMID- 28658408 TI - Discordant clinical outcomes of congenital Zika virus infection in twin pregnancies. AB - Congenital Zika syndrome is an emergent cause of a congenital infectious disorder, resulting in severe damage to the central nervous system and microcephaly. Despite advances in understanding the pathophysiology of the disease, we still do not know all the mechanisms enrolled in the vertical transmission of the virus. As has already been reported in other types of congenital infectious disorders in dizygotic twin pregnancies, it is possible that the virus affects only one of the fetuses. In this article, we report on two cases of twin pregnancies exposed to the Zika virus, but with only one of the fetuses affected with microcephaly and brain damage. This indicates the urgent need for more studies regarding the pathophysiology of viral infection and the mechanisms involved in the natural protection against the virus. PMID- 28658409 TI - Traumatic spinal cord injury: current concepts and treatment update. AB - Spinal cord injury (SCI) affects 1.3 million North Americans, with more than half occurring after trauma. In Brazil, few studies have evaluated the epidemiology of SCI with an estimated incidence of 16 to 26 per million per year. The final extent of the spinal cord damage results from primary and secondary mechanisms that start at the moment of the injury and go on for days, and even weeks, after the event. There is convincing evidence that hypotension contributes to secondary injury after acute SCI. Surgical decompression aims at relieving mechanical pressure on the microvascular circulation, therefore reducing hypoxia and ischemia. The role of methylprednisolone as a therapeutic option is still a matter of debate, however most guidelines do not recommend its regular use. Neuroprotective therapies aiming to reduce further injury have been studied and many others are underway. Neuroregenerative therapies are being extensively investigated, with cell based therapy being very promising. PMID- 28658410 TI - Benign multiple sclerosis: aspects of cognition and neuroimaging. AB - The existence of a benign multiple sclerosis (BMS) form is a controversial subject. Recent studies of these patients reveal different levels of cognitive impairment, despite the apparent preservation of motor function. The objective of this study was to review and analyze a number of publications that discuss the general aspects of this disease form, such as the definition criteria, prevalence, and clinical and neuroimaging markers. A systematic review of published data on BMS up to October 2015 was performed. Thirty-one published articles were analyzed. The estimated frequency of BMS varied between 6% and 73%. Cognitive impairment was recognized as affecting 17% to 47% of the subjects and presented significant correlation with neuroimaging, such as brain atrophy, increased lesion volume in T2 magnetic resonance assay, and regional grey matter atrophy. The current criteria overestimated the frequency of BMS and, for that reason, this highlights the importance of validating the diagnostic methods practiced. PMID- 28658411 TI - Charcot's irony and sarcasm. AB - Jean-Martin Charcot is considered the father of modern neurology and was the first neurologist to hold a professorship of international stature devoted to the study of the diseases of the nervous system. His biographers paint an image of an austere presence, reserved manner, shyness, economy of gestures and an impenetrable, impassive face. However, a wry and sarcastic side of Charcot can be demonstrated in several situations, and these examples help to clarify the intricacies of his personality and work style. PMID- 28658412 TI - Epilepsia partialis continua induces transient brain edema. PMID- 28658413 TI - Optochiasmatic cavernous malformation: a rare cause of acute vision loss. PMID- 28658414 TI - Herd-level spatial cluster analysis of bovine cysticercosis in the state of Paraiba, northeastern Brazil. AB - The aim of this survey was to identify spatial clustering of bovine cysticercosis positive herds in the state of Paraiba. The state was divided into three sampling groups: sampling stratum 1 (Sertao mesoregion), sampling stratum 2 (Borborema mesoregion) and sampling stratum 3 (Zona da Mata and Agreste mesoregions), and 2382 cows aging >= 24 months from 474 farms were sampled. Serological diagnoses of bovine cysticercosis were initially done by means of indirect ELISA, and positive serum samples were confirmed by a immunoblot test. Herds were deemed positive for cysticercosis if they presented at least one positive animal in herds of up to 29 females, and two positive animals in herds with more than 29 females. The spatial clustering was assessed using the Cuzick-Edwards k-nearest neighbor method and spatial scan statistics. A significant clustering of positive herds was detected in the southern part of the Borborema mesoregion. Given that serological tests for bovine cysticercosis are not widely available, and also that replacement and maintenance of herds through animal purchases is common in the region, it can be concluded that prevention measures should be applied at herd level. PMID- 28658415 TI - Ehrlichia canis and Rickettsia spp. in dogs from urban areas in Paraiba state, northeastern Brazil. AB - The aims of our study was to identify Ehrlichia canis and antibodies against Rickettsia spp. belonging to the spotted fever group (SFG) in dogs sampled from Paraiba state, northeastern Brazil. Blood and serum samples collected by convenience from dogs in urban areas of five municipalities were analyzed by real time PCR for the detection of E. canis DNA and by immunofluorescence assay test (IFAT) for the identification of antibodies against Rickettsia rickettsii, R. felis, R. parkeri, R. amblyommii and R. rhipicephali antigens. E. canis DNA was detected in 8.9% (64/719) of the blood samples, whereas 5.63% (43/763) of the serum samples were positive for at least one of the Rickettsia antigens tested by IFAT. This study showed for the first time the occurrence of E. canis and suggested the circulation of SFG Rickettsia in dogs in the study region of Paraiba state, northeastern Brazil. PMID- 28658416 TI - First report of scuticociliatosis caused by Uronema sp. in ornamental reef fish imported into Brazil. AB - Scuticociliatosis, which is caused by an opportunistic ciliate protozoan, is responsible for significant economic losses in marine ornamental fish. This study reports the occurrence of Uronema sp., which was found to be parasitizing three species of marine reef fish imported into Brazil and maintained in quarantine: Vanderbilt's Chromis (Chromis vanderbilti), blue-green damselfish (Chromis viridis), and sea goldie (Pseudanthias squamipinnis). During the quarantine period, some fish presented with behavioral disorders and hemorrhages and ulcerative lesions on the body surface. Histopathological analysis showed hemorrhages, inflammation comprising mononuclear and granular cells in the skeletal muscle, and necrosis of the skin and the secondary lamellae of the gills, and parasites were also observed in the renal capsule. The absence of transboundary measures available to prevent the occurrence of ornamental fish diseases is also discussed. PMID- 28658417 TI - Evaluation of recombinant Cryptosporidium hominis GP60 protein and anti-GP60 chicken polyclonal IgY for research and diagnostic purposes. AB - In this study, a method for expressing Cryptosporidium hominis GP60 glycoprotein in Escherichia coli for production of polyclonal anti-GP60 IgY in chickens was developed aiming future studies concerning the diagnosis, prevention and treatment of cryptosporidiosis. The full-length nucleotide sequence of the C. hominis gp60 gene was codon-optimized for expression in E. coli and was synthesized in pET28-a vector. Subcloning was performed on several different strains of BL21 E. coli. Temperature, time and inducer IPTG concentration assays were also performed and analyzed using SDS-PAGE. The optimal conditions were observed at a temperature of 37 degrees C, with overnight incubation and 1 mM of IPTG. Purification was performed by means of affinity chromatography using the AKTA Pure chromatography system and the Hi-TrapTM HP column (GE Healthcare). The recombinant protein GP60 (rGP60) thus generated was used to immunize laying hens owing the production of polyclonal IgY. Western blot and indirect immunofluorescence showed that the polyclonal antibody was capable of binding to rGP60 and to Cryptosporidium parvum sporozoites, respectively. The rGP60 and the IgY anti-rGP60 generated in this study may be used as templates for research and for the development of diagnostic methods for cryptosporidiosis. PMID- 28658419 TI - EDITORS' NOTE. PMID- 28658418 TI - Risk factors associated with Toxoplasma gondii infection in free-range chickens in the semiarid region of Brazil. AB - This study aimed to investigate the frequency of anti-Toxoplasma gondii antibodies in serum from 629 chickens on 39 family farms in seven municipalities in the semiarid region, Pernambuco, Brazil, and to identify risk factors associated with T. gondii infection. The risk factors were studied in 421 samples from 29 farms. Anti-T. gondii antibodies were investigated by indirect fluorescent antibody test with a 1:16 cutoff. The frequency of positive chickens was 27.9% (176/629) and 94.8% of the farms studied had chickens infected by T. gondii. Multivariate analysis showed variables significantly associated with anti T. gondii antibodies in serum: slaughter of animals on the farm, reproductive disorders in sheep, consumption of fetal adnexa and placentas by chickens, presence of sheep in the property and birth of sheep the property. The results suggest that there is a complex relationship between general management practices for different animal species raised on the same farm and the prevalence of T. gondii infection in chickens. In addition, the results draw attention to the risk of human infection by T. gondii via consumption of infected chicken meat, because the farming conditions and the low human development indices observed in the region studied result in inappropriate meat preparation practices. PMID- 28658420 TI - The cholera epidemic as condenser of meanings: urban cultures, clinical narratives, and hygiene policies in Rosario, Argentina, 1886-1887. AB - This article investigates how the 1886-1887 cholera epidemic in Rosario, Argentina led to discrimination among city spaces associated with foci, the production of certain socio-moral images about the sectors most affected, and the development of emergency clinical practices. Based on analysis of the signifiers used to define areas of segregation, I seek to show how working-class living conditions were one of the most pressing problems of urban expansion, to identify tensions between the application of hygiene measures and the evacuation or eviction of working-class sectors and to examine the role of displacement in the definition of suburban spaces. PMID- 28658421 TI - "Fight the poisoners of the people!" The beginnings of food regulation in Sao Paulo and Rio de Janeiro, 1889-1930. AB - For urban Brazil, the First World War triggered a dramatic food crisis that brought with it a massive increase in falsified goods and led to an uproar among the general public. Critics targeted the health authorities, who were evidently unable to suppress these frauds. This text spans the First Republic period and shows that since its proclamation the issue of regulating the food trade was part of health policies, but implementation was repeatedly delayed because of other priorities. This situation only changed with the health reforms of the early 1920s, which allows us to identify the First World War food crisis as a decisive point for the Brazilian state to take responsibility in this area. PMID- 28658422 TI - [Rural internship in the Amazon region: historical aspects, current context and main challenges]. PMID- 28658423 TI - [From environmental ethics to environmental bioethics: antecedents, trajectories, and perspectives]. AB - The relationship between humans and the environment became an ethical problem in the twentieth century, when accelerated economic and scientific development was accompanied by profound alterations in global ecological systems. In response, environmental ethics called for limits in the dichotomous relationship between man and nature. In 1970, Van Potter proposed bioethics as the interdisciplinary study of "human survival." Subsequently, the discipline focused on clinical and hospital conflicts. Environmental bioethics is analyzed in this article as a theoretical perspective that has historically drawn on Van Potter's approach to bioethics, marked by the interpersonal, socioeconomic, and political dimensions of environmental ethical dilemmas. PMID- 28658424 TI - East German medical aid to Nicaragua: the politics of solidarity between biomedicine and primary health care. AB - Between 1979 and 1989 the government of the German Democratic Republic provided health assistance to Sandinista Nicaragua. After initial relief aid, the Sandinista embrace of a primary health care-based health system made East German health support difficult. The non-convertible currency, the repressive quality of the East German leadership, and the lack of experience with primary health care processes all limited its potential to provide support. After 1985, when implementation of this system stalled, East German health assistance was revitalized with the donation of the Hospital Carlos Marx. Providing medical services to three hundred thousand people, it combined elements of a strictly East German institution, using German personnel and equipment, with some integration into local systems. PMID- 28658425 TI - [Spanish Flu in Sorocaba and the case of the Santa Rosalia factory, 1918: local history contributions to the study of epidemics in Brazil]. AB - An investigation is presented of the tensions that emerged during the Spanish flu epidemic in the city of Sorocaba, Brazil, between October and December 1918. It draws on previously unused primary sources, namely the narratives contained in the local press, taking the Santa Rosalia factory as a case study, particularly its owner's refusal to maintain the work stoppage at the height of the epidemic, even when requested to by the municipal authority. This research contributes to the study of epidemics in Brazil's inland municipalities, emphasizing how local history can contribute to investigations of the history of disease in the country. PMID- 28658426 TI - [Reciprocal material agency: an ecology for studies of science]. AB - In the historiography of the sciences there are consolidated dichotomies that can hinder better research. Fissures include mental-material, subject-object and nature-society, and the bitter conflict between relativism and realism that draws on these dichotomies and can block research. The aim of this article is to tackle these disputes, to unravel them and to move on. The proposed solution is to give consideration to the agency of material things alongside the actions of human subjects. One obstacle is presented by Latour who simulates this result by means of hylozoistic rhetoric. Here, an alternative to Latour is presented, containing no elements of animism, which gives evidence of the concrete way in which the material agency of objects participates in the doing of science, alongside humans. PMID- 28658427 TI - [History of ideas, history of social sciences, and the sociology of knowledge]. AB - This article seeks to determine the mutual influence between the sociology of knowledge and the history of ideas within the history of the social sciences. In addition, it intends to outline a preliminary research program for the area in question which integrates relevant contributions from the social sciences and history to contribute to the dialog between parallel research programs for connected development in the history of science and the history of the social sciences, as well as to pursue a sociology of knowledge which is attentive to the political and economic framework of epistemic practices on which it focuses, without reducing these practices to extrinsic discourses or to the subjective intentions of the causal agents. PMID- 28658428 TI - [Deforestation in the state of Mato Grosso in the book Journey around Brazil 1875 1878, by the doctor Joao Severiano da Fonseca]. AB - This presents reflections on scientific production issued by the Commission for the Demarcation of the Empire's Border Limits with Bolivia, with a focus on the environmental destruction of Mato Grosso state, as reported in Joao Severiano da Fonseca's book, Journey around Brazil 1875-1878. Fonseca reported severe deforestation on the banks of the river Paraguay and advocated for protectionist measures from the state government. He set out a vision for Mato Grosso's development that involved better use of the state's natural resources, raw materials exports, and regional industrialization support. The methodology created an interface between environmental history and history of the sciences. PMID- 28658429 TI - [When paradigms change in public health: what changes in history?] AB - This conceptual essay investigates the idea of paradigmatic rupture and its implications in historical interpretations of public/collective health, where the dimensions of politics and science intermingle. The polysemic and pre-conceptual nature of "paradigm" is clarified, taking account of the conceptual implications, while reaffirming their semantic usefulness. Essential and cumulative ruptures are discussed and applied to the confrontation of the epistemic rupture brought about by district health centers and the goals of the public health reform movement. The difficulty of the collective health paradigm in maintaining its discursive independence is presented, such that the global spread of the discursive matrix of health centers by the Rockefeller Foundation still constitutes the most recent holistic paradigmatic rupture in Brazilian public health. PMID- 28658430 TI - Evidences of the circulation of natural philosophical knowledge about Brazil in a 1763 manuscript by Antonio Nunes Ribeiro Sanches. AB - Antonio Nunes Ribeiro Sanches was a Portuguese physician and the author of several works about education and science in Portugal and its Empire. Many of these texts circulated and were made public through letters written by him and sent to other intellectuals. This article sheds light on an unpublished manuscript written by Sanches in 1763, in which he argued for the recognition of Brazilian natural resources and their exploitation for trade and medicine. PMID- 28658431 TI - Influence of the prone position on a stretcher for pregnant women on maternal and fetal hemodynamic parameters and comfort in pregnancy. AB - OBJECTIVES:: To analyze the influence of lying in prone position on a specially designed stretcher on the maternal-fetal hemodynamic parameters and comfort of pregnant women. METHODS:: A randomized, controlled trial with 33 pregnant women divided into 2 groups: pregnant group sequence 1 and pregnant group sequence 2. The order of positions used in sequence 1 was Fowler's position, prone position, supine position, left lateral, Fowler's position 2, supine position 2, prone position 2 and left lateral 2. The order of positions used in sequence 2 was Fowler's position, prone position, left lateral, supine position, Fowler's position 2, left lateral 2, prone position 2 and supine position 2. Each woman remained in each position for 6 minutes. For the statistical analyses, we used Wilcoxon's test for 2 paired samples when comparing the prone position with the other positions. The variables are presented in graphs showing the means and 95% confidence intervals. Trial Registration: Clinical Trial No. ISRCTN41359519. RESULTS:: All the parameters were within the standards of normality. There were no differences between positions in terms of maternal heart rate, diastolic blood pressure, oxygen saturation and fetal heart rate. However, there were significant decreases in respiratory rate and systolic blood pressure in prone position 2 compared with left lateral 2. There was an increase in oxygen saturation in prone position compared with Fowler's position and supine position 2 in both sequences. All the women reported feeling comfortable in the prone position. CONCLUSIONS:: The prone position was considered safe and comfortable and could be advantageous for improving oxygen saturation and reducing the systolic blood pressure and respiratory rate. PMID- 28658432 TI - Predictors of micro-costing components in liver transplantation. AB - OBJECTIVES:: Although liver transplantation procedures are common and highly expensive, their cost structure is still poorly understood. This study aimed to develop models of micro-costs among patients undergoing liver transplantation procedures while comparing the role of individual clinical predictors using tree regression models. METHODS:: We prospectively collected micro-cost data from patients undergoing liver transplantation in a tertiary academic center. Data collection was conducted using an Intranet registry integrated into the institution's database for the storing of financial and clinical data for transplantation cases. RESULTS:: A total of 278 patients were included and accounted for 300 procedures. When evaluating specific costs for the operating room, intensive care unit and ward, we found that in all of the sectors but the ward, human resources were responsible for the highest costs. High cost supplies were important drivers for the operating room, whereas drugs were among the top four drivers for all sectors. When evaluating the predictors of total cost, a MELD score greater than 30 was the most important predictor of high cost, followed by a Donor Risk Index greater than 1.8. CONCLUSION:: By focusing on the highest cost drivers and predictors, hospitals can initiate programs to reduce cost while maintaining high quality care standards. PMID- 28658433 TI - Comparison of Electrocardiographic Criteria for Identifying Left Ventricular Hypertrophy in Athletes from Different Sports Modalities. AB - OBJECTIVES:: In athletes, isolated electrocardiogram high voltage criteria are widely used to evaluate left ventricular hypertrophy, but positive findings are thought to represent normal electrocardiogram alterations. However, which electrocardiogram criterion can best detect left ventricular hypertrophy in athletes of various sport modalities remains unknown. METHODS:: Five electrocardiogram criteria used to detect left ventricular hypertrophy were tested in 180 male athletes grouped according to their sport modality: 67% low static and high-dynamic components and 33% high-static and high-dynamic components of exercise. The following echocardiogram parameters are the gold standard for diagnosing left ventricular hypertrophy: left ventricular mass index >=134 g.m-2, relative wall thickness >=0.42 mm, left ventricular diastolic diameter index >=32 mm.m-2, septum wall thickness >=13 mm, and posterior wall thickness >=13 mm. Results for the various criteria were compared using the kappa coefficient. Significance was established at p<0.05. RESULTS:: Fifty athletes (28%) presented with left ventricular hypertrophy according to electrocardiogram findings, with the following sensitivities and specificities, respectively: 38 53% and 79-83% (Perugia), 22-40% and 89-91% (Cornell), 24-29% and 90% (Romhilt Estes), 68-87% and 20-23% (Sokolow-Lyon), and 0% and 99% (Gubner). The Perugia and Cornell criteria had higher negative predictive values for the low-static and high-dynamic subgroup. Kappa coefficients were higher for Romhilt-Estes, Cornell and Perugia criteria than for Sokolow-Lyon and Gubner criteria. CONCLUSION:: All five evaluated criteria are inadequate for detecting left ventricular hypertrophy, but the Perugia, Cornell and Romhilt-Estes criteria are useful for excluding its presence. The Perugia and Cornell criteria were more effective at excluding left ventricular hypertrophy in athletes involved in a sport modality with low-static and high-dynamic component predominance. PMID- 28658434 TI - Language assessment of children with severe liver disease in a public service in Brazil. AB - OBJECTIVE:: The aim of this research was to compare language development (expressive and receptive skills) in children awaiting liver transplantation with that of children who have already undergone the surgical procedure. METHODS:: An observational, descriptive, cross-sectional study was conducted with 76 children divided into groups, as follows: 31 children who were candidates for liver transplantation (Group 1; G1), 45 children who had already undergone liver transplantation (Group 2; G2), and a control group (CG) of 60 healthy, normally developing children. Health status information was gathered, and the Test of Early Language Development (TELD)-3 was used to assess language skills. Family household monthly income data were also gathered using a specific questionnaire. RESULTS:: G1 had poorer language performance compared with G2 and the CG. G2 had lower language performance when compared with the CG. However, when considering the TELD-3 standard scores, G2 had scores within normal limits. The regression analysis indicated age as a risk factor for language deficits in Group 1 and family income as a risk factor for language deficits in G2. CONCLUSIONS:: The results suggested that children with chronic liver disease have delays in language development. Transplanted children have linguistic performance within normal limits, but their scores tended to be lower than the CG. PMID- 28658435 TI - Sonographic Findings of the Bifid Median Nerve and Persistent Median Artery in Carpal Tunnel: A Preliminary Study in Chinese Individuals. AB - OBJECTIVE:: The aim of this study was to investigate the prevalence of anatomic variations of the bifid median nerve, persistent median artery and persistent median vein in Chinese individuals and their relationship with carpal tunnel syndrome. METHODS:: One hundred and sixty median nerves were examined using ultrasonography and colour Doppler ultrasonography. The location, shape, and size of the bifid median nerve, persistent median artery and persistent median vein were recorded. The cross-sectional area of the bifid median nerve (two trunks) was measured at the level of the pisiform. RESULTS:: Among the 160 wrists examined, a bifid median nerve was observed in 15 (9.4%) wrists, and a persistent median artery was observed in 12 (7.5%) wrists. These two variations either coexisted or were observed independently, and the probability of coexistence (6.3%) was higher than the probability of existing independently (bifid median nerve only 3.1%, persistent median artery only 1.3%). The cross-sectional area of the radial trunk was greater than (13 in 15, 86.7%) the cross-sectional area of the ulnaris trunk. Persistent median vein was observed in 9 wrists (5.6%). CONCLUSIONS:: The persistent median artery and bifid median nerve tend to coexist, and the persistent median vein sometimes runs parallel to the persistent median artery. Their positional relationship in carpal tunnel is uncertain, and thus, preoperative ultrasound is necessary. These three variations do not present any additional risk for the development of carpal tunnel syndrome. PMID- 28658436 TI - Combined aerobic and resistance training: are there additional benefits for older hypertensive adults? AB - OBJECTIVES:: The objective of this study was to compare the effects of a combination of aerobic and resistance training to those of isolated aerobic training on blood pressure, body composition, and insulin sensitivity in hypertensive older adults. METHOD:: Forty-four patients were randomly assigned to the aerobic group, resistance and aerobic group, and control group. Before and after 10 weeks, the following data were obtained: 24-hour ambulatory blood pressure data, abdominal circumference, waist circumference, body mass index, lean mass, fat mass, and insulin sensitivity. The study was conducted with 3 training sessions per week. RESULTS:: Comparison revealed significant reductions in the body mass index, abdominal and waist circumferences, and ambulatory blood pressure (24-hour, wakefulness and sleep systolic/diastolic blood pressures) in both the aerobic group and the resistance and aerobic (combined) group. The fat mass only changed in the combined group. There was no difference in the insulin sensitivity in any group. CONCLUSIONS:: The combined treatment and aerobic treatment alone were equally effective in reducing the blood pressure, body mass index, and abdominal and waist circumferences, although the addition of the resistance component also helped reduce the fat mass. PMID- 28658437 TI - Indications and visual outcomes of intrastromal corneal ring segment implantation in a large patient series. AB - OBJECTIVES:: To describe the indications for and visual outcomes of intrastromal corneal ring segment implantation. METHODS:: A large retrospective case-series chart-review study was conducted using Sorocaba Ophthalmological Hospital medical records. This study included 1222 eyes (1196 patients) that were surgically treated between November 2009 and December 2012. The following preoperative data were collected: age, gender, type of medical care and funding source, surgical technique, best-corrected visual acuity, manifest sphere and cylinder refractive error, maximum and minimum central keratometry, and pachymetry measurements of the cornea at the thinnest point and at the ring channel. The postoperative best corrected visual acuity and patient satisfaction were also determined. The cases were classified into six groups: four keratoconus groups (severe, advanced, moderate and mild), a pellucid marginal degeneration group and a post-graft irregular astigmatism group. This study was approved by the Brazilian Registry of Clinical Trials (UTN number 1111-1182-6181, TRIAL RBR-6S72RF). RESULTS:: The age (mean+/-standard deviation) of the patients was 31.0+/-10.0 years. The most prevalent pathology was keratoconus (1147 eyes, 93.8%). A correlation was found between ectasia severity and medical assistance (p<0.001), and the most serious cases was treated by the Brazilian public health system. No complications were found in a total of 1155 surgeries, and after surgery, 959 patients were satisfied. Among the 164 dissatisfied patients, the majority failed to show improved best-corrected visual acuity. CONCLUSION:: Patients in the public health system underwent surgical intervention for keratoconus later than those with private sources of funding. In the vast majority of operated cases, the patients reported improvements in vision. PMID- 28658438 TI - Effectiveness and safety of first-generation protease inhibitors in real-world patients with hepatitis C virus genotype 1 infection in Brazil: a multicenter study. AB - OBJECTIVE:: To evaluate the effectiveness and safety of first-generation protease inhibitors for the treatment of genotype 1 hepatitis C virus-infected patients at Brazilian reference centers. METHODS:: This multicenter cross-sectional study included hepatitis C virus genotype 1 monoinfected patients treated with Peg interferon, ribavirin, and either boceprevir (n=158) or telaprevir (n=557) between July 2013 and April 2014 at 15 reference centers in Brazil. Demographic, clinical, virological, and adverse events data were collected during treatment and follow-up. RESULTS:: Of the 715 patients, 59% had cirrhosis and 67.1% were treatment-experienced. Based on intention-to-treat analysis, the overall sustained viral response was 56.6%, with similar effectiveness in both groups (51.9% for boceprevir and 58% for telaprevir, p=0.190). Serious adverse events occurred in 44.2% of patients, and six deaths (0.8%) were recorded. Cirrhotic patients had lower sustained viral response rates than non-cirrhotic patients (46.9% vs. 70.6%, p<0.001) and a higher incidence of serious adverse events (50.7% vs. 34.8%, p<0.001). Multivariate analysis revealed that sustained viral response was associated with the absence of cirrhosis, viral recurrence after previous treatment, pretreatment platelet count greater than 100,000/mm3, and achievement of a rapid viral response. Female gender, age>65 years, diagnosis of cirrhosis, and abnormal hemoglobin levels/platelet counts prior to treatment were associated with serious adverse events. CONCLUSION:: Although serious adverse events rates were higher in this infected population, sustained viral response rates were similar to those reported for other patient cohorts. PMID- 28658439 TI - Perioperative management of drugs commonly used in patients with rheumatic diseases: a review. AB - Rheumatic diseases are very prevalent, affecting about 7 million people in North America; they affect the musculoskeletal system, often with systemic involvement and potential for serious consequences and limitation on quality of life. Clinical treatment is usually long-term and includes drugs that are considered either simple or complex and are occasionally unknown to many health professionals who do not know how to manage these patients in emergency units and surgical wards. Thus, it is important for clinicians, surgeons and anesthesiologists who are involved with rheumatic patients undergoing surgery to know the basic principles of therapy and perioperative management. This study aims to do a review of the perioperative management of the most commonly used drugs in rheumatologic patients. Manuscripts used in this review were identified by surveying MEDLINE, LILACS, EMBASE, and COCHRANE databases and included studies containing i) the perioperative management of commonly used drugs in patients with rheumatic diseases: and ii) rheumatic diseases. They are didactically discussed according to the mechanism of action and pharmacokinetics; and perioperative management. In total, 259 articles related to the topic were identified. Every medical professional should be aware of the types of drugs that are appropriate for continuous use and should know the various effects of these drugs before indicating surgery or assisting a rheumatic patient postoperatively. This information could prevent possible complications that could affect a wide range of patients. PMID- 28658440 TI - New evidences on the regulation of SF-1 expression by POD1/TCF21 in adrenocortical tumor cells. AB - OBJECTIVES:: Transcription Factor 21 represses steroidogenic factor 1, a nuclear receptor required for gonadal development, sex determination and the regulation of adrenogonadal steroidogenesis. The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors. METHODS:: We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA. In addition, using overexpression of Transcription Factor 21 in human adrenocortical carcinoma cells, we analyzed the protein expression of steroidogenic factor 1 using Western blotting. RESULTS:: Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells. Additionally, Transcription Factor 21 overexpression inhibited the protein expression of steroidogenic factor 1 by 0.41-fold and 0.64-fold in two different adult adrenocortical carcinoma cell cultures, H295R and T36, respectively. CONCLUSIONS:: Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors. PMID- 28658441 TI - Indirect self-destructiveness in individuals with schizophrenia. AB - OBJECTIVE: To explore the indirect self-destructiveness syndrome in patients with schizophrenia. METHODS: Two hundred individuals with paranoid schizophrenia (117 men and 83 women, mean age 37.15 years), all in remission, were examined using the Polish version of the Chronic Self-Destructiveness Scale. Two hundred well matched healthy individuals served as a control group. RESULTS: The intensity of indirect self-destructiveness was greater in the schizophrenia group than in controls. The intensity of each manifestation was as follows (in decreasing order): helplessness and passiveness in the face of difficulties (A5), personal and social neglects (A3), lack of planfulness (A4), poor health maintenance (A2), transgression and risk (A1). CONCLUSION: Patients with schizophrenia displayed more behaviors that were indirectly self-destructive than healthy controls; they scored better than healthy controls only on caring for their own health. The patients showed the lowest intensity of behaviors connected with the active form of indirect self-destructiveness, and the highest intensity of behaviors connected with the passive form. These findings may enable delivery of more effective forms of pharmacological and psychosocial help to patients with schizophrenia. PMID- 28658443 TI - Introduction. PMID- 28658444 TI - Towards a tobacco-free Americas: the importance of measuring progress. PMID- 28658442 TI - Mood disorder, anxiety, and suicide risk among subjects with alcohol abuse and/or dependence: a population-based study. AB - OBJECTIVE: To evaluate the prevalence of alcohol abuse and/or dependence in a population-based sample of young adults and assess the prevalence of comorbid mood disorders, anxiety, and suicide risk in this population. METHODS: This cross sectional, population-based study enrolled 1,953 young adults aged 18-35 years. The CAGE questionnaire was used to screen for alcohol abuse and/or dependence, with CAGE scores >= 2 considered positive. Psychiatric disorders were investigated through the structured Mini International Neuropsychiatric Interview (MINI). RESULTS: Alcohol abuse and/or dependence was identified in 187 (9.60%) individuals (5.10% among women and 15.20% among men). Alcohol abuse and/or dependence were more prevalent among men than women, as well as among those who used tobacco, illicit drugs or presented with anxiety disorder, mood disorder, and suicide risk. CONCLUSION: These findings suggest that alcohol abuse and/or dependence are consistently associated with a higher prevalence of psychiatric comorbidities, could be considered important predictors of other psychiatric disorders, and deserve greater public heath attention, pointing to the need for alcohol abuse prevention programs. PMID- 28658445 TI - Global challenges in tobacco control. PMID- 28658446 TI - Protocol to eliminate illicit trade in tobacco products: the dawn of a new era. PMID- 28658447 TI - Measuring progress in tobacco prevention and control: the role of surveillance. PMID- 28658448 TI - Monitoring Caribbean tobacco use: baseline adolescent smoking prevalence and regional disparities. AB - Objective:: To provide baseline information on tobacco use among adolescents in the Caribbean for the period before country-level implementation of the Framework Convention on Tobacco Control (WHO-FCTC). Materials and methods:: Using Global Youth Tobacco Surveys (GYTS) between 2000 and 2008, we report baseline prevalence, 5-year change, and disparities in tobacco use (ever smoked, currently smoke) among adolescents. Results:: The Caribbean prevalence of ever-smoked fell from 33.3 to 29.0% with nine of 14 countries reporting a 5-year decrease, and the prevalence of current smokers fell from 12.1 to 11.7% with eight of 14 countries reporting a 5-year decrease. Between-country disparities in the prevalence of ever smoked decreased, while between-country disparities in currently smoked saw little change. Conclusions:: This regional summary of tobacco use provides baseline estimates of adolescent smoking, and cross-country smoking disparities for the period before MPOWER implementation. Subsequent GYTS survey rounds can be used to monitor program success. PMID- 28658449 TI - Linking Global Youth Tobacco Survey (GYTS) data to tobacco control policy in Suriname. AB - Objective:: To use evidence from the Global Youth Tobacco Survey (GYTS) to inform tobacco-control policy in Suriname. Materials and methods:: The GYTS was conducted in 2000, 2004 and 2009 among secondary school students (13 to 15 years) in a two-stage cluster sample design. Results:: 2744 students, age 13 to 15, participated. From 2000 to 2009, results showed an increased prevalence of "current use of cigarettes" and "other tobacco products" in females (31 and 98%). Additionally, students reported high exposure to second-hand smoking at home (56.6 to 46.6%) and in public places (67.8 to 53.3%). Less than half of all respondents were taught about the dangers of smoking in school. Conclusion:: National smoking prevalence coincides with regional trends. The results of the GYTS provided the evidence-base towards developing comprehensive tobacco control legislation. Tobacco legislation was passed in 2013. Future GYTS will monitor legislation implementation and progress made in achieving WHO Framework Convention on Tobacco Control (FCTC) goals. PMID- 28658450 TI - [Smoking tobacco in Costa Rica: susceptibility, consumption and dependence]. AB - Objective:: To identify factors associated with susceptibility, tobacco use and addiction in young people from 13 to 15 years of age, to determine conditions of risk and identify possible correlates to the development of public policies on smoking in Costa Rica. Materials and methods:: Information available from the four rounds of the Global Youth Tobacco Survey (GYTS) Costa Rica was used. It was based on a sample size of 11 540 youngsters from public and private schools. Indicators of interest and logistic regression models for smoking, susceptibility and addiction were estimated. Results:: The prevalence of current consumption shows a significant decrease over the 14 years of the study (17.3% in 1999 and 5.0% in 2013) and, to a lesser intensity, in the index of smoking susceptibility (19.3% in 1999 and 12.4% in 2013). The proportion of young people with addiction has shown a significant increase in the same period. Conclusions:: The conditions that explained the significant reduction in smoking prevalence and less susceptibility must be maintained and deepened to achieve full compliance of the MPower measures. PMID- 28658451 TI - [Impact of tobacco control policy on teenager population in Uruguay]. AB - Objective:: To analyze the evolution of the prevalence of tobacco use, comparing data obtained from the Global Youth Tobacco Survey in 2007 and 2014 editions. Materials and methods:: Data from the World Youth Tobacco Survey 2007 and 2014 were compared. Tobacco control measures implemented in the period under review were also analyzed. Results:: Data shows a decrease in 30-day cigarette consumption in population aged 13 to 15 years: from 20.2% in 2007 to 8.2% in 2014. No significant differences were found between the sexes. Susceptibility to become a smoker in the next year decreased from 25.8% in 2007 to 16.6% in 2014. Conclusions:: The implementation, almost simultaneously, of measures included in WHO Framework Convention for Tobacco Control, is an effective strategy to achieve the objectives of reducing the prevalence of tobacco use. PMID- 28658452 TI - Smoking behavior among third year dental students in Latin American countries: prevalence, perceptions, and risk factors. AB - Objective:: To examine the association between tobacco-related risk factors and smoking among third-year dental students in Latin American countries. Materials and methods:: Logistic regression models were used to analyze Global Health Professions Student Survey (GHPSS) data. Results:: Of 5 605 respondents, 33% smoked and 45% had been exposed to secondhand smoke during the previous month, 34% smoked in school buildings during the past year, and 85% had never received formal training in smoking cessation. Smoking was significantly associated with male sex; Bolivian, Chilean, or Mexican nationality; exposure to secondhand smoke; lacking self-perception of being a "role model" for patients; and not believing that health professionals who smoke are less likely to advise patients to quit smoking. Conclusions:: All dental schools should encourage tobacco-free policies and offer cessation services. Cessation training must be incorporated into dental curricula to include dental professionals in the battle against the tobacco epidemic. PMID- 28658453 TI - [Quitting smoking and willingness to pay for cessation in Panama]. AB - Objective:: To characterize the desire for cessation and willingness to pay for abandonment therapy. Materials and methods:: The data source is the Global Adult Tobacco Survey (GATS). Cessation and willingness to pay were characterized by sociodemographic (SD) and socioeconomic (SE) variables. Logistic regressions were performed to estimate associations. Results:: A greater desire for cessation was observed in variables: women, education, non-governmental and inactive employees, rural areas, occasional smokers and middle income, and greater willingness to pay, in: education, over 60 years old, non-governmental, self-employed, urban area, occasional smokers and low median income. Conclusions:: There is a high relation between the desire for abandonment, and willingness to pay with SD and SE variables. Cessation therapies can be applied in work centers, and require a change of focus in the intervention. PMID- 28658454 TI - [Smoking among adolescents: quantitative and qualitative analysis of psychosocial factors associated with the decision to smoke among Mexican students]. AB - Objective:: To analyze psychosocial factors associated with the decision to smoke in students 13 to 15 years in Mexico City. Materials and methods:: Logistic regression models of Youth Tobacco Survey (n=945) and four Focus Groups (GF) in two secondary schools, conducted in 2011-2012, were used. Results:: Factors associated with smoking: a) believe that it is safe (OR=2.4, CI95% 1.28-4.7), GF: ability to control over consumption and long-term damage; b) to have at least one smoking parent (OR=1.6, CI95% 1.1-2.3), GF: influence to start/maintain consumption; c) to have friends who smoke (OR=5.0, CI95% 1.9-13.6), GF: influence to experimentation/repeat, schools without rules on prohibition and have access to cigarettes (OR=2.1, CI95% 0.9-4.1). Protective factors: a) believe that it is harmful (OR=0.3, CI95% 0.14-0.65), GF: rejection of cohabitation with smokers; b) communication with family (OR=0.5, CI95% 0.36-0.91), GF: appeal to self-care; c) consider is young for smoking (OR=0.2, CI95% 0.12-0.43), GF: knowledge about damage and risk perception. Conclusion:: It is necessary to strengthen positive psychosocial skills and strengthen compliance with youth protection legislation. PMID- 28658455 TI - [Seduction and aversion: susceptibility and disincentive factors among 13 to 15 years old Bolivian teenagers]. AB - Objective:: To analyze tobacco consumption susceptibility and disincentive factors among non-smoker teenagers in Bolivia. Materials and methods:: A secondary data analysis of the Global Youth Tobacco Survey was conducted. A multivariate logistic regression was developed to estimate the relation between the susceptibility to smoke and social factors, smoking behaviour, and tobacco control policies. Results:: Susceptibility increases by: close smoker friends (OR=1.74); comfort perception when smoking on social events (OR=1.86); observing smokers in public places (OR=1.54); teenager's cigarettes promotion (OR=4.05); exposure to tobacco advertising (OR=2.08); and male teenagers (OR=2.00). Tobacco disincentives are parental information about smoking (OR=0.38) and health warning labels (OR=0.63). Conclusion:: Bolivia requires, at minimum, to implement the other basic measures of the Framework Convention on Tobacco Control. PMID- 28658456 TI - [Tobacco advertisement exposure and tobacco consumption among youths in South America]. AB - Objective: : To assesses the statistical association between exposure to tobacco marketing and tobacco consumption among adolescents in South America, by using data from the Global Youth Tobacco Survey. Materials and methods:: Using data from the Global Youth Tobacco Survey (GYTS), the exposure to tobacco marketing at the school level was studied from advertising in TV, radio, massive public events and street advertisement. Tobacco behaviour was considered. The total pooled sample used was 134 073 youths from Argentina, Bolivia, Chile, Peru, Brazil, Uruguay, Suriname, Colombia, Guyana, Ecuador, Paraguay and Venezuela. Results:: The exposure to tobacco marketing is positively and significantly associated to the probability of youths experimenting with tobacco (at least once in their lifetime). For regular smokers, exposure to tobacco marketing is positively and significantly associated to smoking intensity. Conclusions:: These results call for the implementation of strong restrictions on tobacco advertisement of various types in South American countries. PMID- 28658457 TI - [Socioeconomic factors associated with the illegal purchase of tobacco products in Panama]. AB - Objective:: To characterize the illegal purchase of tobacco products in Panama and the ssocation with sociodemographic and socioeconomic variables. Materials and methods:: Study population derived from the Global Adult Tobacco Survey (GATS) conducted in 2013. The association of sociodemographic and socioeconomic variables with illegal purchase of tobacco products was estimated by means of logistic regression models. Results:: Men, age group 15 to 39, no formal education, non-governmental, inactive employees,current smoking, lowest quintile of income and living in rural areas were factors associated with the illegal purchase of tobacco products. Conclusions.: Sociodemographic and socioeconomic factors play an important role in the illegal purchase of tobacco products. These results suggest the importance of surveillance over illicit trade and of the effective implementation of the current laws. PMID- 28658458 TI - [Exposure to point-of-sale tobacco displays in Argentina: evidence from the 2013 National Risk Factor Survey]. AB - Objective:: To describe the population that reports to have visited tobacco points of sale (POS) in Argentina and their perception of tobacco advertising. Materials and methods:: We used data from the 2013 National Risk Factor Survey. Results:: We included 31 167 respondents (96% of the total) who attended a store that sells cigarettes in the previous 30 days. Overall, 54.1% (67.3% of current smokers, 55.1% of former smokers and 49% of non smokers) referred having seen tobacco advertising at the POS. Males (OR=1.2) and current smokers (OR=1.9 vs. non smokers) were more likely to report having seen tobacco advertising at the POS. Those who were exposed to second hand smoke in bars and restaurants (OR=1.2) were also more likely to have seen advertising. We found that younger people (age 18 - 24) were more likely to be exposed (OR=2.8 vs older than 65). Among smokers, those who referred to have seen the advertising were more likely to have tried to quit smoking during the previous year. Conclusions:: It is important to regulate advertising at the POS to limit exposure, particularly among young people. PMID- 28658459 TI - Advertising of tobacco products at point of sale: who are more exposed in Brazil? AB - Objective:: To describe the adult population perception of cigarette advertising at point of sale, according their tobacco-use status and socio-demographic characteristics such as sex, age, race/color, region, household location and schooling. Materials and methods:: A multivariable analysis was carried out using data from the Global Adult Tobacco Survey in 2008 and the National Health Survey in 2013. Results:: Both surveys showed that among nonsmokers: women, young adults and those who had over 10 years of schooling had more frequently noticed advertising of cigarettes at point of sale. It was also observed that among the population with fewer years of schooling these proportions increased significantly. Conclusion:: A measure that completely bans tobacco advertising would be more effective to protect the vulnerable groups from tobacco consumption. PMID- 28658460 TI - [Ten years of the WHO Framework Convention on Tobacco Control: progress in the Americas]. AB - The objective of this article is to analyze the progress made in the Americas in the implementation of the World Health Organization Framework Convention on Tobacco Control (FCTC) after its tenth anniversary of entry into force. At the time of the analysis, 30 of the 35 countries of the Americas are Parties to the FCTC. While progress has been made in implementing the measures contained in the FCTC, the level of implementation has not been homogeneous either across mandates or across countries. Forty percent of Parties to the Convention in the Americas are yet to implement any of the measures at their highest level of implementation according to the WHO classification. It is crucial that the countries of the Americas continue to progress towards the full implementation of the FCTC progressively. In these efforts, it is important to take into account that FCTC measures such as those related to smoke-free environments and adoption of effective health warnings are basic public health measures, which are almost entirely within the competence of health authorities and therefore susceptible to be implemented in a prompt fashion in all countries of the region. PMID- 28658461 TI - Modern Electroconvulsive Therapy: Vastly Improved yet Greatly Underused. PMID- 28658463 TI - Pathologic Outcomes of Laparoscopic vs Open Mesorectal Excision for Rectal Cancer. PMID- 28658464 TI - Association of Procedures and Patient Factors With 30-Day Readmission Rates After Pediatric Surgery. PMID- 28658462 TI - Isotretinoin and Timing of Procedural Interventions: A Systematic Review With Consensus Recommendations. AB - Importance: The notion that systemic isotretinoin taken within 6 to 12 months of cutaneous surgery contributes to abnormal scarring or delayed wound healing is widely taught and practiced; however, it is based on 3 small case series from the mid-1980s. Objective: To evaluate the body of literature to provide evidence based recommendations regarding the safety of procedural interventions performed either concurrently with, or immediately following the cessation of systemic isotretinoin therapy. Evidence Review: A panel of national experts in pediatric dermatology, procedural/cosmetic dermatology, plastic surgery, scars, wound healing, acne, and isotretinoin was convened. A systematic PubMed review of English-language articles published from 1982 to 2017 was performed using the following search terms: isotretinoin, 13-cis-retinoic acid, Accutane, retinoids, acitretin, surgery, surgical, laser, ablative laser, nonablative laser, laser hair removal, chemical peel, dermabrasion, wound healing, safety, scarring, hypertrophic scar, and keloid. Evidence was graded, and expert consensus was obtained. Findings: Thirty-two relevant publications reported 1485 procedures. There was insufficient evidence to support delaying manual dermabrasion, superficial chemical peels, cutaneous surgery, laser hair removal, and fractional ablative and nonablative laser procedures for patients currently receiving or having recently completed isotretinoin therapy. Based on the available literature, mechanical dermabrasion and fully ablative laser are not recommended in the setting of systemic isotretinoin treatment. Conclusions and Relevance: Physicians and patients may have an evidence-based discussion regarding the known risk of cutaneous surgical procedures in the setting of systemic isotretinoin therapy. For some patients and some conditions, an informed decision may lead to earlier and potentially more effective interventions. PMID- 28658465 TI - Treating Perioperative Complications: Should Everyone Be This Expensive? PMID- 28658466 TI - Fat Grafting-More Than Just the Hype. PMID- 28658467 TI - Assessing Depression Among New Fathers-Reply. PMID- 28658468 TI - Human Papillomavirus Vaccination and Keratinocyte Carcinomas-Reply. PMID- 28658469 TI - Assessing Depression Among New Fathers. PMID- 28658470 TI - Correlation Among Cancer Incidence and Mortality Rates and Internet Searches in the United States. AB - Importance: Population-level disease metrics are critical to guide the distribution of resources and implementation of public health initiatives. Internet search data reflect population interest in health topics and may be an alternative metric of disease characteristics when traditional sources are lacking, such as in basal and squamous cell carcinomas, which are not included in national cancer registries. However, these data are not yet well validated or understood. Objective: To evaluate whether state-specific normalized internet search volume correlates with incidence and mortality rates of common cancers in the United States, including melanoma. Design, Setting, and Participants: This was a cross-sectional analysis of Google search volume index data and US cancer incidences and mortalities of 8 of the most incident cancers in the United States in 2009 to 2013, at the state level, per the National Program of Cancer Registries. Participants were people performing Google searches and patients diagnosed as having cancers reported to cancer registries. Main Outcomes and Measures: Correlation between Google search volumes, normalized to total Google search volume, and National Program of Cancer Registries recorded cancer incidence and mortality rates. Results: By state, relative Google search volume statistically significantly correlated with cancer incidence rates in 5 of 8 commonly diagnosed cancers in the United States (colon cancer: R = 0.61; P < .001; lung cancer: R = 0.73; P < .001; lymphoma: R = 0.51; P < .001; melanoma: R = 0.36; P = .01; and thyroid cancer: R = 0.30; P = .03). For 4 of those 5 cancers (colon cancer: R = 0.61; P < .001; lung cancer: R = 0.62; P < .001; lymphoma: R = 0.38; P = .006; and melanoma: R = 0.31; P = .03), relative Google search volume also correlated with mortality rates. Conclusions and Relevance: Population-level internet search behavior may be a valuable real-time tool to estimate cancer incidence and mortality rates, especially for cancers not included in national registries, such as basal and squamous cell carcinomas. PMID- 28658471 TI - Association Between Medication Use and Performance on Higher Education Entrance Tests in Individuals With Attention-Deficit/Hyperactivity Disorder. AB - Importance: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for academic problems. Pharmacologic treatment is effective in reducing the core symptoms of ADHD, but it is unclear whether it helps to improve academic outcomes. Objective: To investigate the association between the use of ADHD medication and performance on higher education entrance tests in individuals with ADHD. Design, Setting, and Participants: This cohort study observed 61 640 individuals with a diagnosis of ADHD from January 1, 2006, to December 31, 2013. Records of their pharmacologic treatment were extracted from Swedish national registers along with data from the Swedish Scholastic Aptitude Test. Using a within-patient design, test scores when patients were taking medication for ADHD were compared with scores when they were not taking such medication. Data analysis was performed from November 24, 2015, to November 4, 2016. Exposures: Periods with and without ADHD medication use. Main Outcomes and Measures: Scores from the higher education entrance examination (score range, 1-200 points). Results: Among 930 individuals (493 males and 437 females; mean [SD] age, 22.2 [3.2] years) who had taken multiple entrance tests (n = 2524) and used ADHD medications intermittently, the test scores were a mean of 4.80 points higher (95% CI, 2.26-7.34; P < .001) during periods they were taking medication vs nonmedicated periods, after adjusting for age and practice effects. Similar associations between ADHD medication use and test scores were detected in sensitivity analyses. Conclusions and Relevance: Individuals with ADHD had higher scores on the higher education entrance tests during periods they were taking ADHD medication vs nonmedicated periods. These findings suggest that ADHD medications may help ameliorate educationally relevant outcomes in individuals with ADHD. PMID- 28658473 TI - Disseminated Whitish Papules and Scars on a Patient With Bowel Perforation. PMID- 28658472 TI - Association of Fat Grafting With Patient-Reported Outcomes in Postmastectomy Breast Reconstruction. AB - Importance: Fat grafting has proven to be a useful adjunct to breast reconstruction for the treatment of contour irregularities and volume deficits, but the proposed US Food and Drug Administration regulations may severely limit the ability of plastic surgeons to continue its use in this clinical context. Objective: To determine whether fat grafting is associated with patient-reported outcomes (PROs) in patients undergoing breast reconstruction. Design, Setting, and Participants: A longitudinal, multicenter, prospective cohort study was conducted between February 1, 2012, and July 31, 2016, at the 11 sites associated with the Mastectomy Reconstruction Outcomes Consortium Study. Eligible patients included women 18 years or older presenting for breast reconstruction after mastectomy with 2 years or more of follow-up. All primary procedure types (implant based and flap based) were eligible. Patients were excluded if they had not completed breast mound reconstruction by 1 year after starting reconstruction. Interventions: Fat grafting as an adjunct to breast mound reconstruction. Main Outcomes and Measures: Primary end points were patient reported outcome measures as assessed by the validated BREAST-Q survey, with higher scores on a 0- to 100-point scale indicating better health-related quality of life. Survey subscales included breast satisfaction, as well as psychosocial, physical, and sexual well-being. Patient-reported outcomes were compared between those who received and did not receive fat grafting. Results: A total of 2048 women were included (mean [SD] age, 49.4 [10] years), with 165 (8.1%) undergoing fat grafting between years 1 and 2. One year postoperatively, patients who later underwent fat grafting reported significantly lower breast satisfaction (adjusted mean difference [AMD], -4.74; 95% CI, -8.21 to -1.28; P = .008), psychosocial well-being (AMD, -3.87; 95% CI, -7.33 to -0.40; P = .03), and sexual well-being (AMD, -5.59; 95% CI, -9.70 to -1.47; P = .008), compared with those who did not receive subsequent fat grafting. Following the procedure, the fat-grafted cohort reported similar breast satisfaction (AMD, -0.68; 95% CI, -4.42 to 3.06; P = .72), psychosocial well-being (AMD, -0.59; 95% CI, -3.92 to 2.74; P = .73), and sexual well-being (AMD, -2.94; 95% CI, -7.01 to 1.12; P = .15) 2 years postoperatively. Conclusions and Relevance: Fat grafting may improve breast satisfaction, psychosocial well-being, and sexual well-being in patients undergoing breast reconstruction. PMID- 28658475 TI - Major Bleeding in Patients With Diabetes and Atrial Fibrillation Treated With New Oral Anticoagulants. PMID- 28658476 TI - Efficacy of Stimulants Beyond Treatment of Core Symptoms of Attention Deficit/Hyperactivity Disorder. PMID- 28658474 TI - The Evolving Story of Overlapping Surgery. PMID- 28658477 TI - Machine Learning of the Progression of Intermediate Age-Related Macular Degeneration Based on OCT Imaging. AB - Purpose: To develop a data-driven interpretable predictive model of incoming drusen regression as a sign of disease activity and identify optical coherence tomography (OCT) biomarkers associated with its risk in intermediate age-related macular degeneration (AMD). Methods: Patients with AMD were observed every 3 months, using Spectralis OCT imaging, for a minimum duration of 12 months and up to a period of 60 months. Segmentation of drusen and the overlying layers was obtained using a graph-theoretic method, and the hyperreflective foci were segmented using a voxel classification method. Automated image analysis steps were then applied to identify and characterize individual drusen at baseline, and their development was monitored at every follow-up visit. Finally, a machine learning method based on a sparse Cox proportional hazard regression was developed to estimate a risk score and predict the incoming regression of individual drusen. Results: The predictive model was trained and evaluated on a longitudinal dataset of 61 eyes from 38 patients using cross-validation. The mean follow-up time was 37.8 +/- 13.8 months. A total of 944 drusen were identified at baseline, out of which 249 (26%) regressed during follow-up. The prediction performance was evaluated as area under the curve (AUC) for different time periods. Prediction within the first 2 years achieved an AUC of 0.75. Conclusions: The predictive model proposed in this study represents a promising step toward image-guided prediction of AMD progression. Machine learning is expected to accelerate and contribute to the development of new therapeutics that delay the progression of AMD. PMID- 28658479 TI - Pathologic Outcomes of Laparoscopic vs Open Mesorectal Excision for Rectal Cancer. PMID- 28658480 TI - Use of Instrumental Variables Methods in Examining Psychiatric Readmissions. PMID- 28658478 TI - Long-term Safety and Efficacy of New-Generation Drug-Eluting Stents in Women With Acute Myocardial Infarction: From the Women in Innovation and Drug-Eluting Stents (WIN-DES) Collaboration. AB - Importance: Women with acute myocardial infarction (MI) undergoing mechanical reperfusion remain at increased risk of adverse cardiac events and mortality compared with their male counterparts. Whether the benefits of new-generation drug-eluting stents (DES) are preserved in women with acute MI remains unclear. Objective: To investigate the long-term safety and efficacy of new-generation DES vs early-generation DES in women with acute MI. Design, Setting, and Participants: Collaborative, international, individual patient-level data of women enrolled in 26 randomized clinical trials of DES were analyzed between July and December 2016. Only women presenting with an acute coronary syndrome were included. Study population was categorized according to presentation with unstable angina (UA) vs acute MI. Acute MI included non-ST-segment elevation MI (NSTEMI) or ST-segment elevation MI (STEMI). Interventions: Randomization to early- (sirolimus- or paclitaxel-eluting stents) vs new-generation (everolimus-, zotarolimus-, or biolimus-eluting stents) DES. Main Outcomes and Measures: Composite of death, MI or target lesion revascularization, and definite or probable stent thrombosis at 3-year follow-up. Results: Overall, the mean age of participants was 66.8 years. Of 11 577 women included in the pooled data set, 4373 (37.8%) had an acute coronary syndrome as clinical presentation. Of these 4373 women, 2176 (49.8%) presented with an acute MI. In women with acute MI, new generation DES were associated with lower risk of death, MI or target lesion revascularization (14.9% vs 18.4%; absolute risk difference, -3.5%; number needed to treat [NNT], 29; adjusted hazard ratio, 0.78; 95% CI, 0.61-0.99), and definite or probable stent thrombosis (1.4% vs 4.0%; absolute risk difference, -2.6%; NNT, 46; adjusted hazard ratio, 0.36; 95% CI, 0.19-0.69) without evidence of interaction for both end points compared with women without acute MI (P for interaction = .59 and P for interaction = .31, respectively). A graded absolute benefit with use of new-generation DES was observed in the transition from UA, to NSTEMI, and to STEMI (for death, MI, or target lesion revascularization: UA, 0.5% [NNT, 222]; NSTEMI, -3.1% [NNT, 33]; STEMI, -4.0% [NNT, 25] and for definite or probable ST: UA, -0.4% [NNT, 278]; NSTEMI, -2.2% [NNT, 46]; STEMI, -4.0% [NNT, 25]). Conclusions and Relevance: New-generation DES are associated with consistent and durable benefits over 3 years in women presenting with acute MI. The magnitude of these benefits appeared to be greater per increase in severity of acute coronary syndrome. PMID- 28658481 TI - Pathologic Outcomes of Laparoscopic vs Open Mesorectal Excision For Rectal Cancer Reply. PMID- 28658483 TI - Human Papillomavirus Vaccination and Keratinocyte Carcinomas. PMID- 28658482 TI - Association of Expanded Medicaid Coverage With Hospital Length of Stay After Injury. AB - Importance: The expansion of Medicaid eligibility under the Affordable Care Act is a state-level decision that affects how patients with traumatic injury (trauma patients) interact with locoregional health care systems. Washington, DC; Maryland; and Virginia represent 3 unique payer systems with liberal, moderate, and no Medicaid expansion, respectively, under the Affordable Care Act. Characterizing the association of Medicaid expansion with hospitalization after injury is vital in the disposition planning for these patients. Objective: To determine the association between expanded Medicaid eligibility under the Affordable Care Act and duration of hospitalization after injury. Design, Setting, and Participants: This retrospective cohort study included patients admitted from Virginia, Maryland, and Washington, DC, to a single level I trauma center. Data were collected from January 1, 2013, through March 6, 2016, in Virginia and Washington, DC, and from May 1, 2013, through March 6, 2016, in Maryland. All patients with Medicare or Medicaid coverage and all uninsured patients were included. Patients with private insurance, patients with severe head or pelvic injuries, and those who died during hospitalization were excluded. Main Outcomes and Measures: Hospital length of stay (LOS) and whether its association with patient insurance status varied by state of residence. Results: A total of 2314 patients (1541 men [66.6%] and 773 women [33.4%]; mean [SD] age, 52.9 [22.8] years) were enrolled in the study. The uninsured rate in the Washington, DC, cohort (190 of 1699 [11.2%]) was significantly lower compared with rates in the Virginia (141 of 296 [47.6%]) or the Maryland (106 of 319 [33.2%]) cohort (P < .001). On multivariate regression controlling for injury severity and demographic variables, the difference in LOS for Medicaid vs non Medicaid recipients varied significantly by state. For Medicaid recipients, mean LOS in Washington, DC, was significantly shorter (2.57 days; 95% CI, 2.36-2.79 days) than in Maryland (3.51 days; 95% CI, 2.81-4.38 days; P = .02) or Virginia (3.9 days; 95% CI, 2.79-5.45 days; P = .05). Conclusions and Relevance: Expanded Medicaid eligibility is associated with shorter hospital LOS in mildly injured Medicaid recipients. PMID- 28658484 TI - Polysyllable Speech Accuracy and Predictors of Later Literacy Development in Preschool Children With Speech Sound Disorders. AB - Purpose: The aim of this study was to determine if polysyllable accuracy in preschoolers with speech sound disorders (SSD) was related to known predictors of later literacy development: phonological processing, receptive vocabulary, and print knowledge. Polysyllables-words of three or more syllables-are important to consider because unlike monosyllables, polysyllables have been associated with phonological processing and literacy difficulties in school-aged children. They therefore have the potential to help identify preschoolers most at risk of future literacy difficulties. Method: Participants were 93 preschool children with SSD from the Sound Start Study. Participants completed the Polysyllable Preschool Test (Baker, 2013) as well as phonological processing, receptive vocabulary, and print knowledge tasks. Results: Cluster analysis was completed, and 2 clusters were identified: low polysyllable accuracy and moderate polysyllable accuracy. The clusters were significantly different based on 2 measures of phonological awareness and measures of receptive vocabulary, rapid naming, and digit span. The clusters were not significantly different on sound matching accuracy or letter, sound, or print concept knowledge. Conclusions: The participants' poor performance on print knowledge tasks suggested that as a group, they were at risk of literacy difficulties but that there was a cluster of participants at greater risk-those with both low polysyllable accuracy and poor phonological processing. PMID- 28658486 TI - Misspelling of Coauthor Surname. PMID- 28658485 TI - Association of Hospital Costs With Complications Following Total Gastrectomy for Gastric Adenocarcinoma. AB - Importance: Postoperative complications are associated with increased hospital costs following major surgery, but the mechanism by which they increase cost and the categories of care that drive this increase are poorly described. Objective: To describe the association of postoperative complications with hospital costs following total gastrectomy for gastric adenocarcinoma. Design, Setting, and Participants: This retrospective analysis of a prospectively collected gastric cancer surgery database at a single National Cancer Institute-designated comprehensive cancer center included all patients undergoing curative-intent total gastrectomy for gastric adenocarcinoma between January 2009 and December 2012 and was conducted in 2015 and 2016. Main Outcomes and Measures: Ninety-day normalized postoperative costs. Hospital accounting system costs were normalized to reflect Medicare reimbursement levels using the ratio of hospital costs to Medicare reimbursement and categorized into major cost categories. Differences between costs in Medicare proportional dollars (MP $) can be interpreted as the amount that would be reimbursed to an average hospital by Medicare if it paid differentially based on types and extent of postoperative complications. Results: In total, 120 patients underwent curative-intent total gastrectomy for stage I through III gastric adenocarcinoma between 2009 and 2012. Of these, 79 patients (65.8%) were men, and the median (interquartile range) age was 64 (52-70) years. The 51 patients (42.5%) who underwent an uncomplicated total gastrectomy had a mean (SD) normalized cost of MP $12 330 (MP $2500), predominantly owing to the cost of surgical care (mean [SD] cost, MP $6830 [MP $1600]). The 34 patients (28.3%) who had a major complication had a mean (SD) normalized cost of MP $37 700 (MP $28 090). Surgical care was more expensive in these patients (mean [SD] cost, MP $8970 [MP $2750]) but was a smaller contributor to total cost (24%) owing to increased costs from room and board (mean [SD] cost, MP $11 940 [MP $8820]), consultations (mean [SD] cost, MP $3530 [MP $2410]), and intensive care unit care (mean [SD] cost, MP $7770 [MP $14 310]). Conclusions and Relevance: Major complications were associated with tripled normalized costs following curative-intent total gastrectomy. Most of the excess costs were related to the treatment of complications. Interventions that decrease the number or severity of postoperative complications could result in substantial cost savings. PMID- 28658487 TI - Can a Diet That Mimics Fasting Turn Back the Clock? PMID- 28658488 TI - Major Bleeding in Patients With Diabetes and Atrial Fibrillation Treated With New Oral Anticoagulants-Reply. PMID- 28658489 TI - Association of Electroconvulsive Therapy With Psychiatric Readmissions in US Hospitals. AB - Importance: Although electroconvulsive therapy (ECT) is considered the most efficacious treatment available for individuals with severe affective disorders, ECT's availability is limited and declining, suggesting that information about the population-level effects of ECT is needed. Objective: To examine whether inpatient treatment with ECT is associated with a reduction in 30-day psychiatric readmission risk in a large, multistate sample of inpatients with severe affective disorders. Design, Setting, and Participants: A quasi-experimental instrumental variables probit model of the association correlation of ECT administration with patient risk of 30-day readmission was estimated using observational, longitudinal data on hospital inpatient discharges from US general hospitals in 9 states. From a population-based sample of 490 252 psychiatric inpatients, a sample was drawn that consisted of 162 691 individuals with a principal diagnosis of major depressive disorder (MDD), bipolar disorder, or schizoaffective disorder. The key instrumental variable used in the analysis was ECT prevalence in the prior calendar year at the treating hospital. To examine whether ECT's association with readmissions was heterogeneous across population subgroups, analyses included interactions of ECT with age group, sex, race/ethnicity, and diagnosis group. The study was conducted from August 27, 2015, to March 7, 2017. Main Outcome and Measures: Readmission within 30 days of being discharged. Results: Overall, 2486 of the 162 691 inpatients (1.5%) underwent ECT during their index admission. Compared with other inpatients, those who received ECT were older (mean [SD], 56.8 [16.5] vs 45.9 [16.5] years; P < .001) and more likely to be female (65.0% vs 54.2%; P < .001) and white non Hispanic (85.3% vs 62.1%; P < .001), have MDD diagnoses (63.8% vs 32.0%; P < .001) rather than bipolar disorder (29.0% vs 40.0%; P < .001) or schizoaffective disorder (7.1% vs 28.0%; P < .001), have a comorbid medical condition (31.3% vs 26.6%; P < .001), have private (39.4% vs 21.7%; P < .001) or Medicare (49.2% vs 39.4%; P < .001) insurance coverage, and be located in urban small hospitals (31.2% vs 22.3%; P < .001) or nonurban hospitals (9.0% vs 7.6%; P = .02). Administration of ECT was associated with a reduced 30-day readmission risk among psychiatric inpatients with severe affective disorders from an estimated 12.3% among individuals not administered ECT to 6.6% among individuals administered ECT (risk ratio [RR], 0.54; 95% CI, 0.28-0.81). Significantly larger associations with ECT on readmission risk were found for men compared with women (RR, 0.44; 95% CI, 0.20-0.69 vs 0.58; 95% CI, 0.30-0.88) and for individuals with bipolar disorder (RR, 0.42; 95% CI, 0.17-0.69) and schizoaffective disorder (RR, 0.44; 95% CI, 0.11-0.79) compared with those who had MDD (RR, 0.53; 95% CI, 0.26-0.81). Conclusions and Relevance: Electroconvulsive therapy may be associated with reduced short-term psychiatric inpatient readmissions among psychiatric inpatients with severe affective disorders. This potential population health effect may be overlooked in US hospitals' current decision making regarding the availability of ECT. PMID- 28658490 TI - Indications for Surgical Management of Hyperparathyroidism: A Review. AB - Importance: Primary hyperparathyroidism (pHPT) is a common clinical entity, with approximately 100 000 new cases diagnosed each year in the United States. Most patients with pHPT have a relatively mild form of the disease and present with few if any overt signs or symptoms. This has led to a dilemma regarding which patients should be considered for parathyroid surgery. In this article, we review the established literature on the indications for surgery in asymptomatic pHPT and discuss the most recent consensus conference guidelines. Observations: The reviewed literature suggests that there were improved outcomes among patients with asymptomatic pHPT who underwent curative surgery. Conclusions and Relevance: Most patients with pHPT should be considered for parathyroidectomy. More randomized clinical trials are needed to strongly support a surgical recommendation for all asymptomatic patients with pHPT. PMID- 28658492 TI - The Elephant Returns! Being Sick Around the World. PMID- 28658493 TI - Addressing Questions About Registered Nurses in Primary Care. PMID- 28658491 TI - Health Status Benefits of Transcatheter vs Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis at Intermediate Surgical Risk: Results From the PARTNER 2 Randomized Clinical Trial. AB - Importance: In patients with severe aortic stenosis (AS) at intermediate surgical risk, treatment with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) results in similar 2-year survival. The effect of TAVR vs SAVR on health status in patients at intermediate surgical risk is unknown. Objective: To compare health-related quality of life among intermediate risk patients with severe AS treated with either TAVR or SAVR. Design, Setting, and Participants: Between December 2011 and November 2013, 2032 intermediate-risk patients with severe AS were randomized to TAVR with the Sapien XT valve or SAVR in the Placement of Aortic Transcatheter Valve 2 Trial and were followed up for 2 years. Data analysis was conducted between March 1, 2016, to April 30, 2017. Main Outcomes and Measures: Health status was assessed at baseline, 1 month, 1 year, and 2 years using the Kansas City Cardiomyopathy Questionnaire (KCCQ) (23 items covering physical function, social function, symptoms, self-efficacy and knowledge, and quality of life on a 0- to 100-point scale; higher scores indicate better quality of life), Medical Outcomes Study Short Form-36 (36 items covering 8 dimensions of health status as well as physical and mental summary scores; higher scores represent better health status), and EuroQOL-5D (assesses 5 dimensions of general health on a 3-level scale, with utility scores ranging from 0 [death] to 1 [ideal health]). Analysis of covariance was used to examine changes in health status over time, adjusting for baseline status. Results: Of the 2032 randomized patients, baseline health status was available for 1833 individuals (950 TAVR, 883 SAVR) who formed the primary analytic cohort. A total of 1006 (54.9%) of the population were men; mean (SD) age was 81.4 (6.8) years. Over 2 years, both TAVR and SAVR were associated with significant improvements in both disease specific (16-22 points on the KCCQ-OS scale) and generic health status (3.9-5.1 points on the SF-36 physical summary scale). At 1 month, TAVR was associated with better health status than SAVR, but this difference was restricted to patients treated via transfemoral access (mean difference in the KCCQ overall summary [KCCQ-OS] score, 14.1 points; 95% CI, 11.7 to 16.4; P < .01) and was not seen in patients treated via transthoracic access (mean difference in KCCQ-OS, 3.5 points; 95% CI, -1.4 to 8.4; P < .01 for interaction). There were no significant differences between TAVR and SAVR in any health status measures at 1 or 2 years. Conclusions and Relevance: Among intermediate-risk patients with severe AS, health status improved significantly with both TAVR and SAVR through 2 years of follow up. Early health status improvement was greater with TAVR, but only among patients treated via transfemoral access. Longer term follow-up is needed to assess the durability of quality-of-life improvement with TAVR vs SAVR in this population. Trial Registration: clinicaltrials.gov Identifier: NCT01314313. PMID- 28658494 TI - Registered Nurses in Primary Care: One School's Experience. PMID- 28658495 TI - Recommendations for Promoting Quality and Safety in Health Care Systems. AB - Are you a nurse leader or professional development practitioner in a health care facility? This article provides recommendations to promote quality and safety education with a focus on systems thinking awareness among direct care nurses. A key point is error prevention, which requires a shared effort among all nurses. J Contin Educ Nurs. 2017;48(7):295-297. PMID- 28658497 TI - Collaborative Testing. AB - Collaborative testing is an assessment or evaluation strategy in which two or more learners, during discussion and negotiation, determine the correct answer to a test question. This strategy promotes collaboration, team skills, and clinical decision making. Implementation involves developing questions that require clinical judgment, determining groups, and allocating adequate time for collaboration. J Contin Nurs Educ. 2017;48(7):302-303. PMID- 28658496 TI - Psychodynamics of Onboarding New Graduate Nurses. AB - The new graduate RNs' first job lands them squarely in the middle of extraordinary workplace complexity and extreme psychological stress. Met with a whole host of daily challenges, the organization's understanding of the new graduate's psychodynamic coping strategies can make a difference in the sucess of the onboarding program. J Contin Educ Nurs. 2017;48(7):299-301. PMID- 28658498 TI - Evaluating Evidence-Based Practice Knowledge and Beliefs Through the e-Learning EBP Academy. AB - BACKGROUND: This research examined evidence-based practice (EBP) knowledge and beliefs before and after a 3-month e-learning program was implemented to build EBP capacity at a large children's hospital. METHOD: Ten clinicians completed the development, implementation, and evaluation of the e-learning education, comprising phase one. Revision and participation by 41 clinicians followed in phase two. Participants in both phases completed the EBP Beliefs and Implementation Scales preintervention, postintervention, and 6 months after postintervention. RESULTS: EBP beliefs and implementation increased immediately and 6 months after postintervention, with statistically significant increases in both phases. Participants in both phases applied knowledge by completing mentor supported EBP projects. CONCLUSION: Although EBP beliefs and implementation scores increased and e-learning provided flexibility for clinician participation, challenges arose, resulting in lower-than-expected completion. Subsequent revisions resulted in hybrid education, integrating classroom and e-learning with project mentoring. This funded e-learning research contributes knowledge to the growing specialty of professional development. J Contin Educ Nurs. 2017;48(7):304 311. PMID- 28658499 TI - Learning to Use Motivational Interviewing Effectively: Modules. AB - Motivational interviewing (MI) is used by a variety of professionals to help clients to develop motivation for lifestyle changes and has been shown to be an effective way to induce health-promoting activities. Education of health professionals in MI communication techniques can be done many ways, including attending a seminar and completing online classes. In a review of the literature, support was found for a variety of methods. Miller and Moyers described eight steps to MI education that were used to formulate two modules for nurses and exercise physiologists in a cardiac rehabilitation department, as described in this article. The strategies used in the current article included PowerPoint presentations with audio linkage, participant practice with MI techniques via response to prompts, and self-evaluation of performance. J Contin Educ Nurs. 2017;48(7):312-319. PMID- 28658500 TI - Transitioning Communication Education to an Interactive Online Module Format. AB - BACKGROUND: The Changing Talk intervention improves nursing home staff communication by reducing elderspeak. To facilitate dissemination, interactive online modules were created, maintaining the original content. This article reports on the process of transitioning and the results of pilot testing the modules. METHOD: Interactive online modules were developed, pilot tested, and the evaluated in comparison to outcomes from the classroom format training. RESULTS: Online participants (N = 9) demonstrated pre to posttest knowledge gain (scores improved from M = 82.4% to M = 91.2%). Rating of a staff-resident interaction showed improved recognition of elderspeak and person-centered communication after training. Online and original participants reported similar intentions to use learned skills and rated the program highly. CONCLUSION: Evidence-based interventions can be translated from traditional classroom to online format maintaining effects on increasing staff knowledge and intentions to use learned skills in practice. However, the modules should be tested in a larger and more representative sample. J Contin Educ Nurs. 2017;48(7):320-328. PMID- 28658501 TI - Palliative and End-of-Life Care Education Needs of Nurses Across Inpatient Care Settings. AB - BACKGROUND: Educating nurses about palliative and end-of-life (EOL) care is a high priority in health care settings. The purpose of this study was to assess nurses' perceived competency regarding the provision of palliative and EOL care to hospitalized patients. METHOD: This study surveyed nurses from 25 pediatric and adult acute and intensive care units (ICU; N = 583) Quantitative data analysis was descriptive and correlational. Qualitative data analysis identified themes of participant concerns. RESULTS: Data analysis revealed that perceived competency in palliative and EOL care is significantly higher in the ICU nurses (p <.0001). Mean scores were significantly higher when nurses had more than 10 years of experience (p <.0001). Open-ended responses indicated concerns regarding improved communication behaviors, decision making, and facilitation of continuity of care. CONCLUSION: The results provide guidance for development of palliative and EOL care nursing education programs tailored to address specific unit needs according to staff characteristics, patient population focus of care, and acuity level of care. J Contin Educ Nurs. 2017;48(7):329-336. PMID- 28658502 TI - Immediate moxifloxacin hypersensitivity: Is there more than currently meets the eye? AB - Immediate drug hypersensitivity reactions (IDHR) to moxifloxacin constitute a pathomechanistic conundrum and a diagnostic challenge. Our objective was to study whether simultaneous phenotyping and quantification of histamine release might add to our knowledge about the basophil activation properties of moxifloxacin and constitute a reliable diagnostic aid. Fifteen patients with an IDHR to moxifloxacin and nine moxifloxacin challenged controls were selected. All had a basophil activation test (BAT) with moxifloxacin. Flow cytometric analysis of basophil responses implied labeling for CD63, CD203c, and intracellular histamine. Unlike tolerant challenged controls, basophilic upregulation of CD203c in response to moxifloxacin was observed in seven of 15 patients. Only two of these seven patients demonstrated appearance of CD63 and release of histamine. In the remainder eight patients, no basophil responses were demonstrable. In conclusion, immediate hypersensitivity to moxifloxacin might involve mechanisms difficult to capture by traditional CD63-/CD203c-based BAT. Deciphering the complexity of quinolone IDHR seems mandatory. PMID- 28658503 TI - Delayed-type hypersensitivity reactions induced by proton pump inhibitors: A clinical and in vitro T-cell reactivity study. AB - BACKGROUND: Proton pump inhibitors (PPIs) have been known to induce type I hypersensitivity reactions. However, severe delayed-type hypersensitivity reactions (DHR) induced by PPI, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI related DHR, followed up their tolerability to alternative anti-ulcer agents, and investigated the T-cell reactivity to PPI in PPI-related DHR patients. METHODS: We retrospectively analyzed patients with PPI-related DHR from multiple medical centers in Taiwan during the study period January 2003 to April 2016. We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross-hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. Drug lymphocyte activation test (LAT) was conducted by measuring granulysin and interferon-gamma to confirm the causalities. RESULTS: There were 69 cases of PPI related DHR, including SJS/TEN (n=27) and DRESS (n=10). The LAT by measuring granulysin showed a sensitivity of 59.3% and specificity of 96.4%. Esomeprazole was the most commonly involved in PPI-related DHR (51%). Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross-hypersensitivity reactions, whereas three patients developed cross hypersensitivity reactions to alternative structurally similar PPI. The cross reactivity to structurally similar PPI was also observed in LAT assay. CONCLUSIONS: PPIs have the potential to induce life-threatening DHR. In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered. PMID- 28658504 TI - FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-beta signalling in fibroblasts. AB - Renal fibrosis is the common final manifestation of chronic kidney diseases and usually results in end-stage renal failure. In this study, we evaluated the effect of fingolimod (FTY720), an analogue of sphingosine 1-phosphate (S1P), as a treatment for the unilateral ureteral obstruction (UUO)-induced renal fibrosis animal model. We treated mice with FTY720 at a dosage of 1 mg/kg/day by intragastric administration from day 1 until day 7. The control group received the same amount of saline. FTY720 reduced significantly the urine albumin/creatinine ratio (UACR) in treated UUO mice. FTY720 treatment also caused a significant decrease in interstitial expansion and collagen deposition in the kidney, accompanied by reduced mononuclear cell recruitment and inflammatory cytokine expression. In addition, the expression levels of the endothelial cell adhesion molecules P-selectin and vascular cell adhesion protein 1 (VCAM-1) were suppressed in the ligated kidney by FTY720 administration, suggesting reduced renal endothelial cell activation. Furthermore, in renal interstitial fibroblast normal rat kidney (NRK)-49F cells, FTY720 significantly affected transforming growth factor (TGF)-beta-induced alpha-smooth muscle actin (SMA) expression and collagen synthesis by inhibiting both the Mothers against decapentaplegic homologue (Smad)2/3 and phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K/AKT/GSK3beta) signalling pathways. S1P1 knock-down by siRNA reversed this effect significantly in our fibroblast cell culture model. Therefore, FTY720 attenuates renal fibrosis via two different mechanisms: first, FTY720 suppresses the synthesis of extracellular matrix in interstitial fibroblasts by interfering with TGF-beta signalling; and secondly, FTY720 affects endothelial cell activation and chemokine expression, thereby reducing immune cell recruitment into the kidney. PMID- 28658505 TI - Fast kVp-switching dual energy contrast-enhanced thorax and cardiac CT: A phantom study on the accuracy of iodine concentration and effective atomic number measurement. AB - PURPOSE: To assess the effect of vessel diameter and exposure parameters on the estimation accuracy of concentration and effective atomic number (Zeff ) of iodine (I) in contrast-enhanced thorax and cardiac dual-energy CT using a modern fast kVp-switching CT scanner. METHODS: A standard semi-anthropomorphic cardiac CT phantom devised to simulate the human chest at three different body habitus i.e., medium-sized, large-sized, and obese, was scanned using a fast kVp switching Revolution-GSI GE CT scanner. Five cylindrical, 10 mm diameter, vials were filled with solutions prepared by diluting I contrast at five concentrations (2.5, 5, 10, 15, and 20 mg I/ml). To simulate small vessels, pipette tips with a diameter ranging from 5 mm to 0.5 mm were employed. The vials and pipette tips were accommodated within the semi-anthropomorphic phantom. CT acquisitions were performed in the fast kVp-switching dual-energy mode at six different CTDIw values. Acquisitions were also performed at 80, 100, 120, and 140 kVp. Images were acquired at 64 * 0.625 mm beam collimation and reconstructed at 2.5 mm using all available reconstruction filter kernels. Virtual monochromatic spectral (VMS) images, iodine concentration (IMeas ), and Zeff maps were reconstructed. Hounsfield unit as a function of energy (HUkeV ) in VMS and single-kVp (HUkVp ), IMeas and Zeff were measured at each CTDIw . The effect of vessel diameter on IMeas and Zeff was investigated. Measured HUkeV and Zeff were compared to theoretically estimated values and IMeas were compared to nominal (INom ) values. RESULTS: In 10 mm diameter vessels, HUkeV values were accurate to 18% for the medium-sized, 22% for the large-sized and 39% for the obese phantoms. IMeas was underestimated by up to 10% for the medium-sized, 26% for the large-sized and 33% for the obese phantom. IMeas error decreased with increasing CTDIw from +/-0.799 mg/ml at 8.61 mGy to +/-0.082 mg/ml at 32.01 mGy. The percentage difference between measured and theoretically estimated Zeff ranged from -3.9% to -14.5%. In pipette tip vessels, IMeas was found to depend on the kernel employed. At the standard kernel, IMeas , for INom = 20 mg/ml, was reduced with vessel diameter from 19.25 +/- 0.39 mg/ml, at 10 mm, to 2.52 +/- 0.31 mg/ml, at 1 mm. Linear regression between IMeas and INom resulted in IMeas /INom factors of 0.925 for 5 mm, 0.815 for 4 mm, 0.651 for 3 mm, 0.377 for 2 mm, and 0.129 for 1 mm vessel diameter. Measured Zeff values were underestimated when vessel diameter was decreased from 5 mm to 1 mm by 27% for the 20 mg I/ml and 21% for the 2.5 mg I/ml. CONCLUSIONS: HUkeV , IMeas , and Zeff depend on several parameters such as body size, vessel size, exposure parameters, and reconstruction kernel. The limiting spatial resolution of the CT system results in considerable underestimation of HUkVp , IMeas , and Zeff in vessels smaller than 5 mm diameter. The underestimation of I uptake may be experimentally corrected, if the diameter of the investigated vessel is measured and the correction factors produced in this study are employed. PMID- 28658506 TI - MATERNAL PERCEPTIONS OF PARENTING FOLLOWING AN EVIDENCE-BASED PARENTING PROGRAM: A QUALITATIVE STUDY OF LEGACY FOR CHILDRENTM. AB - This article presents the findings of a qualitative study of maternal perceptions of parenting following participation in Legacy for ChildrenTM (Legacy), an evidence-based parenting program for low-income mothers of young children and infants. To further examine previous findings and better understand participant experiences, we analyzed semistructured focus-group discussions with predominantly Hispanic and Black, non-Hispanic Legacy mothers at two sites (n = 166) using thematic analysis and grounded theory techniques. The qualitative study presented here investigated how mothers view their parenting following participation in Legacy, allowing participants to describe their experience with the program in their own words, thus capturing an "insider" perspective. Mothers at both sites communicated knowledge and use of positive parenting practices targeted by the goals of Legacy; some site-specific differences emerged related to these parenting practices. These findings align with the interpretation of quantitative results from the randomized controlled trials and further demonstrate the significance of the Legacy program in promoting positive parenting for mothers living in poverty. This study emphasizes the importance of understanding real-world context regarding program efficacy and the benefit of using qualitative research to understand participant experiences. PMID- 28658507 TI - Antibiotics for neonates born through meconium-stained amniotic fluid. AB - BACKGROUND: Approximately 1 in 10 pregnancies is affected by meconium passage at delivery, which can result in meconium aspiration syndrome (MAS). MAS can cause respiratory complications and, very rarely, death. Antibiotics have been prescribed for neonates exposed to meconium in amniotic fluid, with the intention of preventing infection due to potential bacterial contaminants. OBJECTIVES: We conducted this review to assess the efficacy and safety of antibiotics for:1. prevention of infection, morbidity, and mortality among infants born through meconium-stained amniotic fluid (MSAF) who are asymptomatic at birth; and2. prevention of infection, morbidity, and mortality among infants born through MSAF who have signs and symptoms compatible with meconium aspiration syndrome (MAS). SEARCH METHODS: We performed a literature search using the following databases: MEDLINE (1966 to July 2016); Embase (1980 to July 2016); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to July 2016); and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 7) in the Cochrane Library. We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared antibiotics administered via any route versus placebo or no treatment for prevention of infection among neonates exposed to MSAF, or who developed MAS. We excluded cohort, case control, and any other non-randomised studies and applied no language restrictions. We included studies of term and preterm infants, and we included studies examining use of any antibacterial antibiotics. We included studies that reported on any outcomes of interest. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of included trials by reviewing information provided in study reports and obtained by personal communication with study authors. We extracted data on relevant outcomes, estimated effect size, and reported values as risk ratios (RRs), risk differences (RDs), and mean differences (MDs), as appropriate. We conducted subgroup analyses for treatment of MAS and for prophylaxis (asymptomatic neonates exposed to meconium). MAIN RESULTS: Four randomised controlled studies including a total of 695 participants were eligible for inclusion. Three studies evaluated neonates with MAS, and one study assessed asymptomatic neonates exposed to meconium in amniotic fluid. These studies exhibited varying degrees of methodological rigour: Two studies were at low risk of bias, and two were at unclear risk. We graded evidence derived from these studies as low quality. We downgraded overall evidence owing to the large number of participants lost to follow-up in one trial, the small sample sizes of all trials, and unclear methodological details provided for two trials.The primary outcome was risk of early- and late-onset neonatal sepsis. Antibiotics did not decrease the risk of sepsis in neonates with a diagnosis of MAS (RR 1.54, 95% confidence interval (CI) 0.27 to 8.96; RD 0.00, 95% CI -0.02 to 0.03; 445 participants, three studies; I2 = 0%) nor in asymptomatic neonates exposed to meconium in amniotic fluid (RR 0.76, 95% CI 0.25 to 2.34; RD -0.01, 95% CI -0.07 to 0.04; 250 participants, one study; I2 = 0%). Results show no significant differences in mortality or duration of stay in hospital between groups given antibiotics and control groups of symptomatic and asymptomatic neonates. One study in asymptomatic neonates reported a significant reduction in duration of mechanical ventilation for the control group compared with the antibiotic group (MD 0.26, 95% CI 0.15 to 0.37; 250 participants, one study; I2 = 0%). AUTHORS' CONCLUSIONS: Upon review of available evidence, we found no differences in infection rates following antibiotic treatment among neonates born through meconium-stained fluid and those with meconium aspiration syndrome. The overall quality of evidence is low owing to the small number of included studies. Well controlled studies of adequate power are needed. PMID- 28658509 TI - Relationship between Achilles tendon length and running performance in well trained male endurance runners. AB - This study aimed to determine the relationship between Achilles tendon (AT) length and running performance, including running economy, in well-trained endurance runners. We also examined the reasonable portion of the AT related to running performance among AT lengths measured in three different portions. The AT lengths at three portions and cross-sectional area (CSA) of 30 endurance runners were measured using magnetic resonance imaging. Each AT length was calculated as the distance from the calcaneal tuberosity to the muscle-tendon junction of the soleus, gastrocnemius medialis (GMAT ), and gastrocnemius lateralis, respectively. These AT lengths were normalized with shank length. The AT CSA was calculated as the average of 10, 20, and 30 mm above the distal insertion of the AT and normalized with body mass. Running economy was evaluated by measuring energy cost during three 4-minutes submaximal treadmill running trials at 14, 16, and 18 km/h, respectively. Among three AT lengths, only a GMAT correlated significantly with personal best 5000-m race time (r=-.376, P=.046). Furthermore, GMAT correlated significantly with energy cost during submaximal treadmill running trials at 14 km/h and 18 km/h (r=-.446 and -.429, respectively, P<.05 for both), and a trend toward such significance was observed at 16 km/h (r=-.360, P=.050). In contrast, there was no correlation between AT CSA and running performance. These findings suggest that longer AT, especially GMAT , may be advantageous to achieve superior running performance, with better running economy, in endurance runners. PMID- 28658508 TI - Selectivity of C-H versus C-F Bond Oxygenation by Homo- and Heterometallic Fe4 , Fe3 Mn, and Mn4 Clusters. AB - A series of tetranuclear [LM3 (HFArPz)3 OM'][OTf]2 (M, M'=Fe or Mn) clusters that displays 3-(2-fluorophenyl)pyrazolate (HFArPz) as bridging ligand is reported. With these complexes, manganese was demonstrated to facilitate C(sp2 )-F bond oxygenation via a putative terminal metal-oxo species. Moreover, the presence of both ortho C(sp2 )-H and C(sp2 )-F bonds in proximity of the apical metal center provided an opportunity to investigate the selectivity of intramolecular C(sp2 ) X bond oxygenation (X=H or F) in these isostructural compounds. With iron as the apical metal center, (M'=Fe) C(sp2 )-F bond oxygenation occur almost exclusively, whereas with manganese (M'=Mn), the opposite reactivity is preferred. PMID- 28658510 TI - Room-Temperature Columnar Nematic and Soft Crystalline Columnar Assemblies of a New Series of Perylene-Centred Disc Tetramers. AB - Three new oligomeric perylene (PE) tetraester derivatives, consisting of a PE based core with four pentaalkynylbenzene units attached through flexible alkyl spacers, are reported. These derivatives were investigated for their mesomorphic properties and thermal, photophysical, and electrochemical behaviour. Small- (SAXS) and wide-angle X-ray scattering (WAXS) studies were performed to deduce the exact nature of the phases. To resolve overlapping reflections and facilitate their indexing, grazing-incidence SAXS/WAXS experiments were carried out on oriented thin films on indium tin oxide (ITO)-coated glass substrate. The corresponding electron density maps were derived from the intensities observed in the diffraction pattern. Whereas compounds with shorter alkyl spacers (n=6 and 8) were found to self-organise into soft crystalline columnar assemblies, those with longer spacers (n=10) exhibited a liquid-crystalline columnar nematic mesophase. This is in contrast to previous reports that describe highly symmetric 2D hexagonal and rectangular columnar structures of PE-based mesogens. The morphology of self-assembly was found to transform from soft crystal columnar to nematic columnar phase through simple variation in the number of alkyl spacers. All compounds exhibited excellent fluorescence emission properties with a very good quantum yield and large band gap. Apart from high solubility and good quantum yield, these compounds can serve as standards to measure quantum yields of unknown samples. These compounds also display green luminescence and may find applications for various optoelectronic devices. PMID- 28658511 TI - Occult hepatitis B virus infection in immunized children born to carrier mothers. AB - BACKGROUND: The prevalence of occult hepatitis B virus (HBV) infection (OBI) in children due to mother-to-child transmission (MTCT) despite immunoprophylaxis remains controversial and is still unknown in Japan. The aim of this study was to determine the OBI prevalence in such children in Japan and identify the genomic mutations that might be associated with the pathogenesis of OBI in children. METHODS: The data on 158 children born to HBV carrier mothers and who received complete passive-active immunoprophylaxis after birth in 2002-2014 were reviewed. HBV markers were detected using commercial enzyme-linked immunosorbent assay kits. HBV-DNA was detected using real-time and nested polymerase chain reaction. Complete genomic sequences were determined. RESULTS: Among the 158 children studied, three had HBV MTCT: two had OBI, and one had resolved HBV infection (RBI). The prevalence of OBI and RBI was estimated to be 1.3% and 0.6%, respectively. The HBV genomes of the two OBI children were wild type and 100% identical to those of their mothers. Of these two children, one received repeated hepatitis B immunoglobulin (HBIG) and developed overt HBV infection. Her HBV genome had a G145R mutation in the S gene that might have been induced by HBIG treatment. The RBI child was persistently positive for antibody to HBV core antigen (10-12 signal/cut-off ratio; S/CO). CONCLUSIONS: A low prevalence of OBI was observed in children who received immunoprophylaxis for preventing MTCT in Japan. The development of overt HBV infection in infants with OBI indicates the necessity of close and long-term monitoring. PMID- 28658512 TI - Early clearance vs persistence of de novo donor-specific antibodies following lung transplantation. AB - BACKGROUND: The natural history of de novo donor-specific antibodies (dnDSA) after lung transplantation is not well-described. We sought to determine the incidence and risk factors associated with dnDSA and compare outcomes between recipients with transient (or isolated) vs persistent dnDSA after transplantation. METHODS: A single-center review of all lung transplants from 1/2009-7/2013. DSAs were tested eight times in the first year and every 4 months thereafter. Outcomes examined included acute rejection and graft failure. RESULTS: Median follow-up was 18 months (range: 1-61 months), and 24.6% of 333 first-time lung-only transplant recipients developed a dnDSA. Ethnicity, HLA-DQ mismatches, post-transplantation platelet transfusion and Lung Allocation Score >60 were associated with dnDSA (P<.05). Overall graft survival was worse for dnDSA-positive vs negative recipients (P=.025). Of 323 recipients with 1-year follow-up, 72 (22.2%) developed dnDSA, and in 25 (34.7%), the dnDSA was transient and cleared. Recipients with transient dnDSA were less likely to develop acute rejection than those with persistent dnDSA (P=.007). CONCLUSIONS: Early post-lung transplantation, dnDSA occurred in 1/4 of recipients, was associated with peri transplant risk factors and resulted in decreased survival. Spontaneous clearance of dnDSA, seen in one-third of recipients, was associated with a lower risk of acute rejection. PMID- 28658513 TI - The role of hospice in the transition from hospital to home for technology dependent children-A qualitative study. AB - AIMS AND OBJECTIVES: To report parent and professional perspectives of step-down care in assisting the transition from hospital to home, within one children's hospice in a constituent country of the United Kingdom. BACKGROUND: In recent years, increasing numbers of children-dependent on long term assisted ventilation have been noted. Meeting the complex physical, emotional and social needs of the child and family is challenging. Many of these children spend extended periods in hospital even when medically stable. DESIGN: This was a qualitative study using an inductive, semantic analytic approach within a realist epistemology. METHODS: Data collection was carried out in 2013. Interviews took place with parents (n = 5) and focus groups with professionals (n = 26) who had experience of step-down care. RESULTS: Multiple benefits of step-down in the hospice were clear. Both sets of accounts suggested that for children and families life was "on hold" in hospital. Hospice was considered a home-like environment where the child and family could "live again". Parents reflected that, in hospice they were "living, not existing" while professionals highlighted hospice as nurturing and empowering the whole family, promoting the child's development while safely meeting their clinical needs. CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: The study highlights a number of crucial benefits to the child and family both in the immediate and longer terms. The collective perspectives therefore endorse hospice as a potential viable choice for these children and their families during the always difficult, usually protracted transition from hospital to home. PMID- 28658514 TI - The role and therapeutic potential of melatonin in age-related ocular diseases. AB - The eye is continuously exposed to solar UV radiation and pollutants, making it prone to oxidative attacks. In fact, oxidative damage is a major cause of age related ocular diseases including cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy. As the nature of lens cells, trabecular meshwork cells, retinal ganglion cells, retinal pigment epithelial cells, and photoreceptors is postmitotic, autophagy plays a critical role in their cellular homeostasis. In age-related ocular diseases, this process is impaired, and thus, oxidative damage becomes irreversible. Other conditions such as low-grade chronic inflammation and angiogenesis also contribute to the development of retinal diseases (glaucoma, age-related macular degeneration and diabetic retinopathy). As melatonin is known to have remarkable qualities such as antioxidant/antinitridergic, mitochondrial protector, autophagy modulator, anti inflammatory, and anti-angiogenic, it can represent a powerful tool to counteract all these diseases. The present review analyzes the role and therapeutic potential of melatonin in age-related ocular diseases, focusing on nitro oxidative stress, autophagy, inflammation, and angiogenesis mechanisms. PMID- 28658515 TI - Antipsychotic combinations for schizophrenia. AB - BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with their initial antipsychotic drug treatment. Sometimes a second antipsychotic, in combination with the first, is used in these situations. OBJECTIVES: To examine whether:1. treatment with antipsychotic combinations is effective for schizophrenia; and2. treatment with antipsychotic combinations is safe for the same illness. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran searches in September 2010, August 2012 and January 2016. We checked for additional trials in the reference lists of included trials. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials comparing antipsychotic combinations with antipsychotic monotherapy for the treatment of schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CIs. For the meta-analysis we used a random-effects model. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for included studies. MAIN RESULTS: Sixty-two studies are included in the review, 31 of these compared clozapine monotherapy with clozapine combination. We considered the risk of bias in the included studies to be moderate to high. The majority of trials had unclear allocation concealment, method of randomisation and blinding, and were not free of selective reporting.There is some limited evidence that combination therapy is superior to monotherapy in improving clinical response (RR 0.73, 95% CI 0.63 to 0.85; participants = 2364; studies = 29, very low-quality evidence), although subgroup analyses show that the positive result was due to the studies with clozapine in both the monotherapy and combination groups (RR 0.66, 95% CI 0.53 to 0.83; participants = 1127; studies = 17). Few studies reported on rate of relapse, most likely due to the short length of the studies. Overall, a combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in preventing relapse (RR 0.63, 95% CI 0.31 to 1.29; participants = 512; studies = 3, very low-quality evidence), but the pooled data showed high heterogeneity (I2 = 82%). A combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in reducing the number of participants discontinuing treatment early (RR 0.89, 95% CI 0.73 to 1.07; participants = 3103; studies = 43, low-quality evidence). No difference was found between treatment groups in the number of participants hospitalised (RR 0.96, 95% CI 0.36 to 2.55; participants = 202; studies = 3, low-quality evidence) . We did not find evidence of a difference between treatment groups in serious adverse events or those requiring discontinuation (RR 1.05, 95% CI 0.65 to 1.69; participants = 2398; studies = 30, very low-quality evidence). There is as lack of evidence on clinically important change in quality of life, with only four studies reporting average endpoint or change data for this outcome on three different scales, none of which showed a difference between treatment groups. AUTHORS' CONCLUSIONS: Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials, limiting the assessment of long-term efficacy and safety. We found very low-quality evidence that a combination of antipsychotics may improve the clinical response. We also found low-quality evidence that a combination of antipsychotics is may make no difference at preventing participants from leaving the study early, preventing relapse and/or causing more serious adverse events than monotherapy. PMID- 28658516 TI - Patient-specific quantification of image quality: An automated technique for measuring the distribution of organ Hounsfield units in clinical chest CT images. AB - PURPOSE: To develop and validate an automated technique for measuring organ Hounsfield units (HUs) in clinical chest CT images. MATERIALS AND METHODS: An automated computer algorithm was developed to measure the distribution of HUs inside four major organs: the lungs, liver, aorta, and spine. These organs were first identified using image processing techniques. Each organ was segmented into multiple regions of interest (ROIs) and characterized in terms of HU values. The medians of the ROI histograms were computed for each dataset. The automated results were validated by assessing their correlation with manual measurements in fifteen contrast-enhanced and fifteen non-contrast-enhanced clinical chest CT datasets. The robustness of the measurements with respect to dependency on image noise and CTDIvol was ascertained. One utility of the approach was further demonstrated in assessing the variability in aorta HUs across 732 patients undergoing noncontrast and contrast-enhanced examinations. RESULTS: The algorithm successfully measured the histograms of the four organs in both contrast and non contrast-enhanced chest CT exams. The automated measurements were in agreement with manual measurements with a near unity slope of the relationship between automated and manual measurements with high coefficient of determination (slope = 0.931-1.003, R2 = 0.89-0.99). Organ median HU measurements were found to be largely independent of both image noise and CTDIvol (P > 0.05), as expected. Across patient cases, the program ran successfully across 95% (697/732) of cases. Aorta median HUs demonstrated five times more variability in contrast-enhanced exams compared to that in non-contrast-enhanced exams. CONCLUSIONS: Patient specific organ HUs can be measured from clinical datasets. The algorithm that was developed can be run on both contrast-enhanced and non-contrast-enhanced clinical datasets. The method can be applied to automatically extract image HU-contrast characteristics of clinical CT images, not captured in phantom data, whereby enabling quantification and optimization of image quality and contrast administration. PMID- 28658517 TI - Microfluidic Formation of Monodisperse Coacervate Organelles in Liposomes. AB - Coacervates have been widely studied as model compartments in protocell research. Complex coacervates composed of disordered proteins and RNA have also been shown to play an important role in cellular processes. Herein, we report on a microfluidic strategy for constructing monodisperse coacervate droplets encapsulated within uniform unilamellar liposomes. These structures represent a bottom-up approach to hierarchically structured protocells, as demonstrated by storage and release of DNA from the encapsulated coacervates as well as localized transcription. PMID- 28658518 TI - Two Completely Different Mechanisms for Highly Specific Na+ Recognition by DNAzymes. AB - Our view of the interaction between Na+ and nucleic acids was changed by a few recently discovered Na+ -specific RNA-cleaving DNAzymes. In addition to nonspecific electrostatic interactions, highly specific recognition is also possible. Herein, two such DNAzymes, named EtNa and Ce13d, are compared to elucidate their mechanisms of Na+ binding. Mutation studies indicate that they have different sequence requirements. Phosphorothioate (PS) substitution at the scissile phosphate drops the activity of EtNa 140-fold, and it cannot be rescued by thiophilic Cd2+ or Mn2+ , whereas the activity of PS-modified Ce13d can be rescued. Na+ -dependent activity assays indicate that two Na+ ions bind cooperatively in EtNa, and each Na+ likely interacts with a nonbridging oxygen atom in the scissile phosphate, whereas Ce13d binds only one Na+ ion in a well defined Na+ aptamer, and this Na+ ion does not directly interact with the scissile phosphate. Both DNAzymes display a normal pH-rate profile, with a single deprotonation reaction required for catalysis. For EtNa, Na+ fails to protect the conserved nucleotides from dimethyl sulfate attack, and no specific Na+ binding is detected by 2-aminopurine fluorescence, both of which are different from those observed for Ce13d. This work suggests that EtNa binds Na+ mainly through its scissile phosphate without significant involvement of the nucleotides in the enzyme strand, whereas Ce13d has a well-defined aptamer for Na+ binding. Therefore, DNA has at least two distinct ways to achieve highly selective Na+ binding. PMID- 28658519 TI - Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles. AB - Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27Kip1 , which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients. PMID- 28658520 TI - Cancer Stem Cell and Bulk Cancer Cell Active Copper(II) Complexes with Vanillin Schiff Base Derivatives and Naproxen. AB - Four copper(II) complexes, 1-4 containing regioisomeric vanillin Schiff base derivatives and the nonsteroidal anti-inflammatory drug (NSAID), naproxen, were synthesised and characterised. All complexes effectively cleave DNA in cell-free systems, with 4 displaying the highest nuclease activity. DNA binding studies suggest that 4 binds to DNA via the grooves prior to inducing oxidative DNA cleavage. Three of the complexes (1, 3, and 4) indiscriminately kill cancer stem cell (CSC)-enriched cells (HMLER-shEcad) and bulk cancer cells (HMLER) at micromolar concentrations. The most effective complex, 4 also reduced the formation and size of mammospheres to a similar extent as salinomycin, a well established CSC-potent agent. Mechanistic studies show that 4 is readily taken up by CSCs, elevates intracellular reactive oxygen species (ROS) levels, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 4 inhibits cyclooxygenase-2 (COX-2) expression and causes COX-2-dependent CSC death. The advantage of 4 over bulk cancer cell- or CSC-selective agents is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose. PMID- 28658521 TI - The in vitro mucolytic effect of xylitol and dornase alfa on chronic rhinosinusitis mucus. AB - BACKGROUND: The overproduction and stagnation of purulent mucus impair mucociliary clearance and exacerbate the symptoms of chronic rhinosinusitis (CRS). There is a clinical need for effective topical mucolytic agents to facilitate removal of mucus and improve postoperative outcomes. METHODS: The effects of xylitol (5%) and dornase alfa (1 mg/mL) on mucus and mucus crusts were investigated. Viscoelasticity and viscosity of wet mucus derived from 30 CRS patients was measured with a plate rheometer. Postoperative dried mucus crust dissolution was measured by examining peripheral transparency, central transparency, and border definition of treated crust samples from 17 CRS patients. RESULTS: Xylitol and dornase alfa reduced wet mucus viscoelasticity at a frequency of 0.1 Hz significantly more than the saline control. Treatments also produced significantly lower viscosities than saline at a shear rate of 10 and 100 seconds-1 . Xylitol and dornase alfa significantly decreased mucus crust border definition relative to saline. CONCLUSION: Xylitol and dornase alfa may be efficacious mucolytics, encouraging the breakdown of postoperative mucus crusts and the reduction of viscoelasticity and viscosity of wet mucus. In vivo study is required to evaluate the potential of these agents in treating recalcitrant CRS. PMID- 28658522 TI - Platelet activation by crushed and uncrushed muscle: a flow cytometry analysis. AB - BACKGROUND: Crushed autologous muscle is used in skull base surgery in the acute phase of major arterial hemorrhage to stop bleeding. The mechanism of this is not yet clear, but is thought to involve the formation of a platelet plug, which seals the vessel wall defect but still allows ongoing blood flow to the brain. METHODS: In this study we use flow cytometry to replicate the in-vivo actions of crushed muscle on platelets in whole blood. We compare the ratio of activation of platelets exposed to crushed and uncrushed muscle supernatant in control patients and in patients on antiplatelet agents. RESULTS: Crushed muscle activated platelets to a higher degree than uncrushed muscle: 5.18-fold greater in control blood (p = 0.002); 6.53-fold greater in aspirin-exposed blood (p < 0.0001); and 9.4-fold greater in clopidogrel-exposed blood (p < 0.0001). CONCLUSION: Crushed muscle caused a consistently increased ratio of platelet activation when compared with uncrushed muscle across all groups, adding to the evidence that at least part of its clinical effect is the result of platelet activation. PMID- 28658523 TI - Effect of tetramethylpyrazine (TMP) on Ca2+ signal transduction and cell viability in a model of renal tubular cells. AB - Tetramethylpyrazine (TMP) is a compound purified from herb. Its effect on Ca2+ concentrations ([Ca2+ ]i ) in renal cells is unclear. This study examined whether TMP altered Ca2+ signaling in Madin-Darby canine kidney (MDCK) cells. TMP at 100 800 MUM induced [Ca2+ ]i rises, which were reduced by Ca2+ removal. TMP induced Mn2+ influx implicating Ca2+ entry. TMP-induced Ca2+ entry was inhibited by 30% by modulators of protein kinase C (PKC) and store-operated Ca2+ channels. Treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert butylhydroquinone (BHQ) inhibited 93% of TMP-evoked [Ca2+ ]i rises. Treatment with TMP abolished BHQ-evoked [Ca2+ ]i rises. Inhibition of phospholipase C (PLC) abolished TMP-induced responses. TMP at 200-1000 MUM decreased viability, which was not reversed by pretreatment with the Ca2+ chelator 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester. Together, in MDCK cells, TMP induced [Ca2+ ]i rises by evoking PLC-dependent Ca2+ release from endoplasmic reticulum and Ca2+ entry via PKC-sensitive store-operated Ca2+ entry. TMP also caused Ca2+ -independent cell death. PMID- 28658524 TI - Determination of testosterone esters in the hair of male greyhound dogs using liquid chromatography-high resolution mass spectrometry. AB - The doping of greyhound dogs with testosterone is done in an attempt to improve their athletic performance, but such doping cannot easily be confirmed, especially in male dogs owing to the natural presence of endogenous testosterone. As testosterone is usually administered as its esters, their direct detection in hair would provide confirmatory evidence of the administration of a pharmaceutical product. This article demonstrates that the use of a liquid chromatography-high resolution mass spectrometry method with heated electrospray ionisation (HESI) combined with the use of amino solid-phase extraction (SPE) cartridges for sample clean-up, is suitable for the sensitive determination of propionate, phenyl propionate, isocaproate, decanoate, and enanthate esters of testosterone in greyhound hair. The method is linear over the range, 0.1 MUg/kg 10 MUg/kg, for all the testosterone esters analysed. The limits of detection (LOD) are 0.05 MUg/kg for testosterone phenyl propionate, isocaproate, and decanoate, 0.025 MUg/kg for testosterone propionate, and 0.25 MUg/kg for testosterone enanthate. This method was applied to hair samples collected from male greyhounds before and after a single administration of a product containing several testosterone esters, each of which could be detected up to 100 days post administration. The study also demonstrates that tail hair is the specimen of choice for the analysis of testosterone in dog hair and that washing of dogs does not impact the analysis of testosterone esters in hair. This method may be useful in racing regulation for the detection of illegitimate use of testosterone in all species. PMID- 28658525 TI - Sex matters in massive parallel sequencing: Evidence for biases in genetic parameter estimation and investigation of sex determination systems. AB - Using massively parallel sequencing data from two species with different life history traits, American lobster (Homarus americanus) and Arctic Char (Salvelinus alpinus), we highlight how an unbalanced sex ratio in the samples and a few sex linked markers may lead to false interpretations of population structure and thus to potentially erroneous management recommendations. Here, multivariate analyses revealed two genetic clusters separating samples by sex instead of by expected spatial variation: inshore and offshore locations in lobster, or east and west locations in Arctic Char. To further investigate this, we created several subsamples artificially varying the sex ratio in the inshore/offshore and east/west groups and then demonstrated that significant genetic differentiation could be observed despite panmixia in lobster, and that FST values were overestimated in Arctic Char. This pattern was due to 12 and 94 sex-linked markers driving differentiation for lobster and Arctic Char, respectively. Removing sex-linked markers led to nonsignificant genetic structure in lobster and a more accurate estimation of FST in Arctic Char. The locations of these markers and putative identities of genes containing or nearby the markers were determined using available transcriptomic and genomic data, and this provided new information related to sex determination in both species. Given that only 9.6% of all marine/diadromous population genomic studies to date have reported sex information, we urge researchers to collect and consider individual sex information. Sex information is therefore relevant for avoiding unexpected biases due to sex-linked markers as well as for improving our knowledge of sex determination systems in nonmodel species. PMID- 28658526 TI - Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav 1.7 mutation I234T. AB - BACKGROUND AND PURPOSE: Pharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Nav 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Nav 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav channel mutants is still unknown. EXPERIMENTAL APPROACH: We used structural modelling, patch clamp and multi-electrode array (MEA) recording to assess the effects of carbamazepine on Nav 1.7-I234T mutant channels and on the firing of dorsal root ganglion (DRG) sensory neurons expressing these mutant channels. KEY RESULTS: In a reverse engineering approach, structural modelling showed that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation and that activation of Nav 1.7-I234T mutant channels, from patients who are known to respond to carbamazepine, is partly normalized with a clinically relevant concentration (30 MUM) of carbamazepine. There was significantly higher firing in intact sensory neurons expressing Nav 1.7-I234T channels, compared with neurons expressing the normal channels (Nav 1.7-WT). Pre incubation with 30 MUM carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Nav 1.7-I234T channels. Although the expected use-dependent inhibition of Nav 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Nav 1.7 I234T mutant channels. CONCLUSION AND IMPLICATIONS: These results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 28658528 TI - Continent versus incontinent diversion for obstetric fistula. PMID- 28658527 TI - Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway. AB - Maternal obesity in humans is associated with poor outcomes across the reproductive spectrum. Emerging evidence indicates that these defects are likely attributed to factors within the oocyte. Although various molecules and pathways may contribute to impaired oocyte quality, prevention of fertility issues associated with maternal obesity is a challenge. Using mice fed a high-fat diet (HFD) as an obesity model, we document spindle disorganization, chromosome misalignment, and elevated reactive oxygen species (ROS) levels in oocytes from obese mice. Oral administration of melatonin to HFD mice not only reduces ROS generation, but also prevents spindle/chromosome anomalies in oocytes, consequently promoting the developmental potential of early embryos. Consistent with this finding, we find that melatonin supplement during in vitro maturation also markedly attenuates oxidative stress and meiotic defects in HFD oocytes. Finally, by performing morpholino knockdown and acetylation-mimetic mutant overexpression assays, we reveal that melatonin ameliorates maternal obesity induced defective phenotypes in oocytes through the SIRT3-SOD2-dependent mechanism. In sum, our data uncover the marked beneficial effects of melatonin on oocyte quality from obese females; this opens a new area for optimizing culture system as well as fertility management. PMID- 28658529 TI - AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis. AB - BACKGROUND AND PURPOSE: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. EXPERIMENTAL APPROACH: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg.kg-1 .d-1 , p.o.) or dexamethasone (1 mg.kg-1 .d-1 , i.p.) were given to CD 1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX 1125 (3, 10 or 30 mg.kg-1 .d-1 , p.o.) or pirfenidone (90 mg.kg-1 .d-1 , p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. KEY RESULTS: Given prophylactically, AQX-1125 (10 and 30 mg.kg-1 ) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-beta immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg.kg-1 ) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg.kg-1 , the effects of AQX-1125 were similar to those of pirfenidone (90 mg.kg-1 ) with corresponding improvements in disease severity. CONCLUSIONS AND IMPLICATIONS: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone. PMID- 28658530 TI - The role of biomechanical anatomical modeling via computed tomography for identification of restrictive allograft syndrome. AB - Chronic lung allograft dysfunction (CLAD) reduces long-term graft survival. It is important to distinguish CLAD subtypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) as RAS has a worse prognosis and accurate subtyping could facilitate targeted treatments. However, the current diagnosis of CLAD subtypes is based on pulmonary function test (PFT) results that reflect global estimates of lung function; anatomical modeling based on computed tomography (CT) has the potential to provide detailed analysis of global and regional lung function. The purpose of this study is to evaluate the utility of CT-based anatomical modeling for the identification of RAS. This retrospective study included 51 patients (CLAD: 17 BOS and 17 RAS, control: 17 No-CLAD). CT data were assessed using a biomechanical model-based platform (MORFEUS) to characterize changes in lung deformation between baseline and disease onset. Lung deformation demonstrated high sensitivity and specificity (>80%) in differentiating RAS from BOS (P<.0001) and No-CLAD (P<.0001). There were matching radiological reading and inward deformation abnormalities in 79% of lung sections in patients with RAS. Anatomical modeling is complementary to conventional assessment in the diagnosis of RAS and potentially provides quantitative data that can help in the characterization and detailed assessment of heterogeneous lung parenchymal disease. PMID- 28658532 TI - Genetically encoded calcium indicators for fluorescence imaging in the moss Physcomitrella: GCaMP3 provides a bright new look. PMID- 28658531 TI - Assessment of acquired mucociliary clearance defects using micro-optical coherence tomography. AB - BACKGROUND: Dehydration of airway surface liquid (ASL) disrupts normal mucociliary clearance (MCC) in sinonasal epithelium, which may lead to chronic rhinosinusitis (CRS). Abnormal chloride (Cl- ) transport is one such mechanism that contributes to this disorder and can be acquired secondary to environmental perturbations, such as hypoxia at the tissue surface. The objective of this study was to assess the technological feasibility of the novel micro-optical coherence tomography (MUOCT) imaging technique for investigating acquired MCC defects in cultured human sinonasal epithelial (HSNE) cells. METHODS: Primary HSNE cell cultures were subjected to a 1% oxygen environment for 12 hours to induce acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Ion transport characteristics were assessed with pharmacologic manipulation in Ussing chambers. ASL, periciliary fluid (PCL), and ciliary beat frequency (CBF) were evaluated using MUOCT. RESULTS: Amiloride-sensitive transport (DeltaISC ) was greater in cultures exposed to hypoxia (hypoxia: -13.2 +/- 0.6 MUA/cm2 ; control: -6.5 +/- 0.1 MUA/cm2 ; p < 0.01), whereas CFTR-mediated anion transport was significantly diminished (hypoxia: 28.6 +/- 0.3 MUA/cm2 ; control: 36.2 +/- 1.6 MUA/cm2 ; p < 0.01), consistent with acquired CFTR dysfunction and sodium hyperabsorption. Hypoxia diminished all markers of airway surface function microanatomy as observed with MUOCT, including ASL (hypoxia: 5.0 +/- 0.4 MUm; control: 9.0 +/- 0.9 MUm; p < 0.01) and PCL depth (hypoxia: 2.5 +/- 0.1 MUm; control: 4.8 +/- 0.3 MUm; p < 0.01), and CBF (hypoxia: 8.7 +/- 0.3 Hz; control: 10.2 +/- 0.3 Hz; p < 0.01). CONCLUSION: Hypoxia-induced defects in epithelial anion transport in HSNE led to predictable effects on markers of MCC measured with novel MUOCT imaging. This imaging method represents a technological leap forward and is feasible for assessing acquired defects impacting the airway surface. PMID- 28658534 TI - Transplant-Specific Quality Improvement Program Enters Beta Phase. PMID- 28658533 TI - Postoperative outcomes and management strategies for coronary artery disease in patients in need of a lung transplantation. AB - BACKGROUND: Patients requiring lung transplantation (LTx) may also have coronary artery disease (CAD). The peri-operative management and long-term outcomes of these patients are not well established. METHODS: Patients referred for LTx from 2008 to 2014 were included in this study. CAD was defined by angiography as no CAD (stenosis <20%), moderate CAD (20%-69%), and significant CAD (stenosis >=70%). Revascularization was per recommendations of local heart team. Postoperative cardiovascular outcomes and long-term survival are reported. RESULTS: A total of 1493 patients were screened for LTx during this period and 656 received a transplant. Of the patients that underwent LTx, 51% had no CAD, 33% had moderate non-obstructive CAD, and 16% had obstructive CAD. Forty-three patients underwent revascularization. There was a no increased risk of peri operative cardiovascular events or for adjusted mortality for patients with obstructive CAD (HR=1.24, 95% CI: 0.83-1.86, P=.290) including those requiring revascularization. CONCLUSIONS: There is a high prevalence of coronary disease in the population of patients with advanced lung disease requiring lung transplantation. Careful evaluation and treatment can allow for patients with all severities of CAD including those requiring revascularization to successfully undergo LTx. PMID- 28658535 TI - Human Papillomavirus Manifestation After Kidney-Pancreas Transplantation. PMID- 28658536 TI - State HCV Incidence and Policies Related to HCV Preventive and Treatment Services For Persons Who Inject Drugs - United States, 2015-2016. PMID- 28658537 TI - The Bugs That Keep Us Safe. PMID- 28658538 TI - A Membrane-Free Redox Flow Battery with Two Immiscible Redox Electrolytes. AB - Flexible and scalable energy storage solutions are necessary for mitigating fluctuations of renewable energy sources. The main advantage of redox flow batteries is their ability to decouple power and energy. However, they present some limitations including poor performance, short-lifetimes, and expensive ion selective membranes as well as high price, toxicity, and scarcity of vanadium compounds. We report a membrane-free battery that relies on the immiscibility of redox electrolytes and where vanadium is replaced by organic molecules. We show that the biphasic system formed by one acidic solution and one ionic liquid, both containing quinoyl species, behaves as a reversible battery without any membrane. This proof-of-concept of a membrane-free battery has an open circuit voltage of 1.4 V with a high theoretical energy density of 22.5 Wh L-1 , and is able to deliver 90 % of its theoretical capacity while showing excellent long-term performance (coulombic efficiency of 100 % and energy efficiency of 70 %). PMID- 28658539 TI - A call for critical examination of endoscopically guided cultures in chronic rhinosinusitis. PMID- 28658540 TI - Colorimetric Recognition of Aldehydes and Ketones. AB - A colorimetric sensor array has been designed for the identification of and discrimination among aldehydes and ketones in vapor phase. Due to rapid chemical reactions between the solid-state sensor elements and gaseous analytes, distinct color difference patterns were produced and digitally imaged for chemometric analysis. The sensor array was developed from classical spot tests using aniline and phenylhydrazine dyes that enable molecular recognition of a wide variety of aliphatic or aromatic aldehydes and ketones, as demonstrated by hierarchical cluster, principal component, and support vector machine analyses. The aldehyde/ketone-specific sensors were further employed for differentiation among and identification of ten liquor samples (whiskies, brandy, vodka) and ethanol controls, showing its potential applications in the beverage industry. PMID- 28658541 TI - The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic skin disorder characterized by pruritus and recurrent eczematous lesions that are accompanied by T-helper (Th)2-dominated inflammation. AD Etiology is not yet completely understood, but it is multifactorial. Moreover, the disease is characterized by complex interactions between genetic and environmental factors, such as skin barrier dysfunctions, allergy/immunity, and pruritus. For example, filaggrin is a key protein involved in skin barrier function. Th2 cells produce interleukin (IL)-31, which provokes pruritus, and other Th2 cytokines decrease filaggrin expression by keratinocytes. Dupilumab has recently been developed for AD treatment; its mechanism of action is to bind to IL-4 receptor alpha and inhibit downstream signaling induced by IL 4 and IL-13. This review summarizes the etiopathogenesis of AD and provides the rationale for selecting a novel targeted therapy. PMID- 28658542 TI - The nutrition-gut microbiome-physiology axis and allergic diseases. AB - Dietary and bacterial metabolites influence immune responses. This raises the question whether the increased incidence of allergies, asthma, some autoimmune diseases, cardiovascular disease, and others might relate to intake of unhealthy foods, and the decreased intake of dietary fiber. In recent years, new knowledge on the molecular mechanisms underpinning a 'diet-gut microbiota-physiology axis' has emerged to substantiate this idea. Fiber is fermented to short chain fatty acids (SCFAs), particularly acetate, butyrate, and propionate. These metabolites bind 'metabolite-sensing' G-protein-coupled receptors such as GPR43, GPR41, and GPR109A. These receptors play fundamental roles in the promotion of gut homeostasis and the regulation of inflammatory responses. For instance, these receptors and their metabolites influence Treg biology, epithelial integrity, gut homeostasis, DC biology, and IgA antibody responses. The SCFAs also influence gene transcription in many cells and tissues, through their inhibition of histone deacetylase expression or function. Contained in this mix is the gut microbiome, as commensal bacteria in the gut have the necessary enzymes to digest dietary fiber to SCFAs, and dysbiosis in the gut may affect the production of SCFAs and their distribution to tissues throughout the body. SCFAs can epigenetically modify DNA, and so may be one mechanism to account for diseases with a 'developmental origin', whereby in utero or post-natal exposure to environmental factors (such as nutrition of the mother) may account for disease later in life. If the nutrition-gut microbiome-physiology axis does underpin at least some of the Western lifestyle influence on asthma and allergies, then there is tremendous scope to correct this with healthy foodstuffs, probiotics, and prebiotics. PMID- 28658544 TI - Allergic airway inflammation: key players beyond the Th2 cell pathway. AB - Allergic asthma is characterized by eosinophilic airway inflammation, mucus hyperproduction, and airway hyperreactivity, causing reversible airway obstruction. Accumulating evidence indicates that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate these pathognomonic features of asthma. However, over the past decade, the understanding of asthma pathogenesis has made a significant shift from a Th2 cell-dependent, IgE-mediated disease to a more complicated heterogeneous disease. Recent studies clearly show that not only Th2 cytokines but also other T cell-related cytokines such as IL 17A and IL-22 as well as epithelial cell cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are involved in the pathogenesis of asthma. In this review, we focus on the roles of these players beyond Th2 pathways in the pathogenesis of asthma. PMID- 28658545 TI - Development of allergic immunity in early life. AB - The growth and maturity of the peripheral immune system and subsequent development of pulmonary immunity in early life is dictated by host, environmental and microbial factors. Dysregulation during the critical window of immune development in the postnatal years results in disease which impacts on lifelong lung health. Asthma is a common disease in childhood and is often preceded by wheezing illnesses during the preschool years. However, the mechanisms underlying development of wheeze and how and why only some children progress to asthma is unknown. Human studies to date have generally focused on peripheral immune development, with little assessment of local tissue pathology in young children. Moreover, mechanisms underlying the interactions between inflammation and tissue repair at mucosal surfaces in early life remain unknown. Disappointingly, mechanistic studies in mice have predominantly used adult models. This review will consider the aspects of the neonatal immune system which might contribute to the development of early life wheezing disorders and asthma, and discuss the external environmental factors which may influence this process. PMID- 28658546 TI - Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders. AB - Homeostasis in the gastrointestinal tract relies on a sensitive equilibrium between permissive and protective functions. This is closely reflected in the regulation of the intestinal immune system and especially T cells in the gut. This balance, however, is susceptible to disturbances as demonstrated by pathological conditions like food allergy, celiac disease, or inflammatory bowel disease. In these allergic and chronic inflammatory bowel disorders, luminal antigens get access to the lamina propria where they trigger a dysregulated immune response with crucial involvement of different T cell subsets. We will begin this review with some comprehensive remarks on current concepts on the pathogenesis of these diseases before taking a closer look at the life cycle of intestinal T cells consisting of priming, homing, differentiation and proliferation and apoptosis respectively. Subsequently we will discuss the specific implication of distinct T cell subsets in allergic and chronic inflammatory conditions of the gastrointestinal tract in detail and comment on current and future approaches to targeted therapy in this context. PMID- 28658547 TI - Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. AB - Allergy is a major public health problem with a high socio-economic impact. The number of allergic patients is expected to reach to four billion within two decades when the World's population reaches to 10 billion. Our knowledge on the molecular mechanisms underlying allergic diseases and allergen tolerance induction had significant advances during the last years. Nowadays, it is well accepted that the generation and maintenance of allergen-specific regulatory T cells (Tregs) and regulatory B cells (Bregs) and the involvement of their suppressive cytokines and surface molecules are essential for the induction of allergen tolerance. These mechanisms play essential roles for the restoration of healthy immune responses to allergens in allergen-specific immunotherapy (AIT) and healthy immune response during high-dose antigen exposure in beekeepers and cat owners. AIT remains as the only disease-modifying and curative treatment for allergic diseases and represents a perfect model to investigate the antigen specific immune responses in humans. A large number of clinical trials demonstrated AIT as an effective treatment in many patients, but it still faces several drawbacks in relation to efficacy, safety, long duration, and patient adherence. Novel strategies to overcome these inconveniences, such as the development of novel adjuvants and alternative routes of administration are being developed. The better understanding of the molecular mechanism governing the generation of Treg and Breg cells during allergen tolerance might well open new avenues for alternative therapeutic interventions in allergic diseases and help better understanding of other immune-tolerance-related diseases. PMID- 28658548 TI - Introduction to "allergic inflammation". PMID- 28658543 TI - Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma. AB - In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4+ T-helper type-2 lymphocytes (TH 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical TH 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of TH 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote TH 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of TH 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. PMID- 28658549 TI - Recent advances in understanding basophil-mediated Th2 immune responses. AB - Basophils, the least common granulocytes, represent only ~0.5% of peripheral blood leukocytes. Because of the small number and some similarity with mast cells, the functional significance of basophils remained questionable for a long time. Recent studies using newly-developed analytical tools have revealed crucial and non-redundant roles for basophils in various immune responses, particularly Th2 immunity including allergy and protective immunity against parasitic infections. In this review, we discuss the mechanisms how basophils mediate Th2 immune responses and the nature of basophil-derived factors involved in them. Activated basophils release serine proteases, mouse mast cell protease 8 (mMCP 8), and mMCP-11, that are preferentially expressed by basophils rather than mast cells in spite of their names. These proteases elicit microvascular hyperpermeability and leukocyte infiltration in affected tissues, leading to inflammation. Basophil-derived IL-4 also contributes to eosinophil infiltration while it acts on tissue-infiltrating inflammatory monocytes to promote their differentiation into M2 macrophages that in turn dampen inflammation. Although basophils produce little or no MHC class II (MHC-II) proteins, they can acquire peptide-MHC-II complexes from dendritic cells via trogocytosis and present them together with IL-4 to naive CD4 T cells, leading to Th2 cell differentiation. Thus, basophils contribute to Th2 immunity at various levels. PMID- 28658550 TI - Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in the pathogenesis of airway inflammation. AB - CD69 has been known as an early activation marker of lymphocytes; whereas, recent studies demonstrate that CD69 also has critical functions in immune responses. Early studies using human samples revealed the involvement of CD69 in various inflammatory diseases including asthma. Moreover, murine disease models using Cd69-/- mice and/or anti-CD69 antibody (Ab) treatment have revealed crucial roles for CD69 in inflammatory responses. However, it had not been clear how the CD69 molecule contributes to the pathogenesis of inflammatory diseases. We recently elucidated a novel mechanism, in which the interaction between CD69 and its ligands, myosin light chain 9, 12a and 12b (Myl9/12) play a critical role in the recruitment of activated T cells into the inflammatory lung. In this review, we first summarize CD69 function based on its structure and then introduce the evidence for the involvement of CD69 in human diseases and murine disease models. Then, we will describe how we discovered CD69 ligands, Myl9 and Myl12, and how the CD69-Myl9 system regulates airway inflammation. Finally, we will discuss possible therapeutic usages of the blocking Ab to the CD69-Myl9 system. PMID- 28658552 TI - Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma. AB - Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma. PMID- 28658554 TI - Are ILC2s Jekyll and Hyde in airway inflammation? AB - Asthma is a complex heterogeneous disease of the airways characterized by lung inflammation, airway hyperreactivity (AHR), mucus overproduction, and remodeling of the airways. Group 2 innate lymphoid cells (ILC2s) play a crucial role in the initiation and propagation of type 2 inflammatory programs in allergic asthma models, independent of adaptive immunity. In response to allergen, helminths or viral infection, damaged airway epithelial cells secrete IL-33, IL-25, and thymic stromal lymphopoietin (TSLP), which activate ILC2s to produce type 2 cytokines such as IL-5, IL-13, and IL-9. Furthermore, ILC2s coordinate a network of cellular responses and interact with numerous cell types to propagate the inflammatory response and repair lung damage. ILC2s display functional plasticity in distinct asthma phenotypes, enabling them to respond to very different immune microenvironments. Thus, in the context of non-allergic asthma, triggered by exposure to environmental factors, ILC2s transdifferentiate to ILC1-like cells and activate type 1 inflammatory programs in the lung. In this review, we summarize accumulating evidence on the heterogeneity, plasticity, regulatory mechanisms, and pleiotropic roles of ILC2s in allergic inflammation as well as mechanisms for their suppression in the airways. PMID- 28658555 TI - IL-25 in allergic inflammation. AB - IL-25, also known as IL-17E, is a member of the IL-17 cytokine family mostly produced by epithelial cells and innate immune cells. After binding to the IL 17RB/IL-17RA complex, IL-25 induces downstream signaling responses in epithelial cells and type 2 lymphocytes, which initiates, propagates, and sustains type 2 immunity. The function of IL-25 in allergic diseases such as asthma has been well established, and now also is extended to diseases such as inflammatory bowel disease and cancer. This review summarizes the literature on IL-25 and discusses the unsolved questions. Our knowledge on IL-25 will pave the pathway for targeting this cytokine in inflammatory diseases. PMID- 28658556 TI - Epigenetic regulation of T-helper cell differentiation, memory, and plasticity in allergic asthma. AB - An estimated 300 million people currently suffer from asthma, which causes approximately 250 000 deaths a year. Allergen-specific T-helper (Th) cells produce cytokines that induce many of the hallmark features of asthma including airways hyperreactivity, eosinophilic and neutrophilic inflammation, mucus hypersecretion, and airway remodeling. Cytokine-producing Th subsets including Th1 (IFN-gamma), Th2 (IL-4, IL-5, IL-13), Th9 (IL-9), Th17 (IL-17), Th22 (IL-22), and T regulatory (IL-10) cells have all been suggested to play a role in the development of asthma. Th differentiation involves genetic regulation of gene expression through the concerted action of cytokines, transcription factors, and epigenetic regulators. We describe how Th differentiation and plasticity is regulated by epigenetic histone and DNA modifications, with a focus on the regulation of histone methylation by members of the polycomb and trithorax complexes. In addition, we outline environmental influences that could influence epigenetic regulation of Th cells and discuss the potential to regulate Th plasticity and function through drugs targeting the epigenetic machinery. It is also becoming apparent that epigenetic regulation of allergen-specific memory Th cells may be important in the development and persistence of chronic allergies. Finally, we describe how epigenetic modifiers regulate cytokine memory in Th cells and describe recently identified hybrid, plastic, and pathogenic memory Th subsets the context of allergic asthma. PMID- 28658553 TI - Type two innate lymphoid cells: the Janus cells in health and disease. AB - Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2, and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity, and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by co stimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. PMID- 28658551 TI - Spectrum of T-lymphocyte activities regulating allergic lung inflammation. AB - Despite advances in the treatment of asthma, optimization of symptom control remains an unmet need in many patients. These patients, labeled severe asthma, are responsible for a substantial fraction of the disease burden. In these patients, research is needed to define the cellular and molecular pathways contributing to disease which in large part are refractory to corticosteroid treatment. The causes of steroid-resistant asthma are multifactorial and result from complex interactions of genetics, environmental factors, and innate and adaptive immunity. Adaptive immunity, addressed here, integrates the activities of distinct T-cell subsets and by definition is dynamic and responsive to an ever changing environment and the influences of epigenetic modifications. These T-cell subsets exhibit different susceptibilities to the actions of corticosteroids and, in some, corticosteroids enhance their functional activation. Moreover, these subsets are not fixed in lineage differentiation but can undergo transcriptional reprogramming in a bidirectional manner between protective and pathogenic effector states. Together, these factors contribute to asthma heterogeneity between patients but also in the same patient at different stages of their disease. Only by carefully defining mechanistic pathways, delineating their sensitivity to corticosteroids, and determining the balance between regulatory and effector pathways will precision medicine become a reality with selective and effective application of targeted therapies. PMID- 28658557 TI - Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin. AB - The prevalence of asthma is increasing over the years and it has become obvious that a thorough understanding of mechanisms leading to Th2 sensitization and to asthma is urgently needed to provide better ways to treat the disease. This articles reviews the different players involved in the initiation of allergic reactions in the lung and in the skin, and highlights the importance of a crosstalk between antigen-presenting dendritic cells and structural cell-derived signals in this process. Our increasing understanding of these mechanisms indicates that structural cells, such as airway epithelial cells and skin keratinocytes, need to be considered as more than a simple physical barrier since they are very upstream of the entire Th2 cascade and therefore might represent crucial targets for new therapies. PMID- 28658559 TI - Innate and adaptive type 2 immunity in lung allergic inflammation. AB - Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic inflammatory disease resulting in bronchial hyper reactivity. Atopic asthma is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic asthma there is no allergen-specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL-4 and IL-13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross-talk between innate and adaptive inflammatory responses. PMID- 28658561 TI - Spermatogenic Cycle and Steroidogenic Control of Spermatogenesis in Mytilus galloprovincialis Collected in the Bay of Naples. AB - The aim of the present article was to study the spermatogenic cycle of Mytilus galloprovincialis collected in the Bay of Naples during a whole year and to acquire new insights into the mechanism of control. Knowledge of the Mytilus cycle in this geographic area is of particular interest as, to the best of our knowledge, the male gonad cycle has been hitherto unexplored. Testis organization was evaluated together with the localization of the enzymes 3beta-HSD, 17beta HSD, and P450-aromatase, which are strictly connected to the synthesis of two key hormones involved in the testis activity: testosterone and 17beta-estradiol. It was demonstrated that: (1) the spermatogenic cycle starts in late Summer-early Fall and continues until early Winter, when the first spawning occurs; after rapid gonad restoration, several spawning events take place until June, when the testis becomes non-active again; (2) in the testis, true Leydig and Sertoli cells are present; (3) during the reproductive period, Sertoli, Leydig, germ, and adipogranular cells (ADGs) are positive to 3beta-HSD and 17beta-HSD, while only germ cells are positive to P450 aromatase; by contrast, during the resting period, only ADGs are positive to 3beta-HSD and 17beta-HSD, and P450-aromatase is no longer recognizable. The presence of a hermaphrodite sample is also described. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1881-1894, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28658562 TI - MOTHERS' EXPERIENCES OF MOTHER-INFANT PSYCHOANALYTIC TREATMENT-A QUALITATIVE STUDY. AB - As part of a larger research project in Sweden, a qualitative study investigated mother-infant psychoanalysis (MIP). Earlier, a randomized controlled trial compared two mother-infant groups. One received MIP, and the other received standard child health center care. Previous articles have reported long-term effects: MIP-group mothers were less depressed throughout a 3-year posttreatment period, and their children demonstrated better global functioning and psychological well-being (Winberg Salomonsson, Sorjonen, & Salomonsson, ). The present study's objectives were to describe the mothers' experiences of MIP and deepen the understanding of the MIP process. Six months after treatment started, all mothers were interviewed. Transcribed interviews of 10 (of 33) MIP-group participants were randomly selected and analyzed in detail. Thematic analysis was used on the interview data. Two main themes emerged: (a) transition to motherhood and (b) relationships with the infant and family. MIP facilitated mother-infant relationship development and familial relationship development and clarified mothers' views of how their personal histories were connected with their motherhood experiences. Mothers reported that the analysts had succeeded in balancing the mothers' own needs and those of the infant. Their accounts of therapy matched the published descriptions of MIP. PMID- 28658558 TI - The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. AB - Atopic dermatitis often precedes the development of other atopic diseases. The atopic march describes this temporal relationship in the natural history of atopic diseases. Although the pathophysiological mechanisms that underlie this relationship are poorly understood, epidemiological and genetic data have suggested that the skin might be an important route of sensitization to allergens. Animal models have begun to elucidate how skin barrier defects can lead to systemic allergen sensitization. Emerging data now suggest that epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL 33, and IL-25 may drive the progression from atopic dermatitis to asthma and food allergy. This review focuses on current concepts of the role of skin barrier defects and epithelial cell-derived cytokines in the initiation and maintenance of allergic inflammation and the atopic march. PMID- 28658563 TI - Synthesis, Characterization, and Electrochemistry of Open-Chain Pentapyrroles and Sapphyrins with Highly Electron-Withdrawing meso-Tetraaryl Substituents. AB - A series of open-chain pentapyrroles and sapphyrins with highly electron withdrawing substituents (i.e., CN, CF3 , or CO2 Me) on the meso-phenyl rings was synthesized and characterized as to the spectral properties, protonation reactions, and electrochemistry in non-aqueous media. The investigated compounds are represented as (Ar)4 PPyH3 and (Ar)4 SapH3 where PPy and Sap correspond to the tri-anion of the open-chain pentapyrrole and sapphyrin, respectively, and Ar=p-CNPh, p-CF3 Ph, or p-CO2 MePh. UV/Vis and 1 H NMR spectroscopy as well as mass spectrometry data are given for the confirmation of the structures for the newly synthesized compounds. An X-ray structure for one of the pentapyrroles, that is, (p-CF3 Ph)4 PPyH3 (2), is also presented. The protonation processes were examined by UV/Vis absorption spectroscopy during the titration of the compounds with trifluoroacetic acid (TFA) in CH2 Cl2 . Equilibrium constants for the protonation reactions were calculated by using both the Hill equation and the mole ratio method. The protonation-initiated conversion of pentapyrroles to sapphyrins upon oxidation was also investigated. Cyclic voltammetry was used to measure the redox potentials in CH2 Cl2 , PhCN, and/or pyridine (Py). Electrochemical properties, protonation constants, and chemical reactions of the six compounds in the two series were then analyzed as a function of the solvent properties and the type of the electron-withdrawing groups on the meso-phenyl rings. PMID- 28658560 TI - IL-33: biological properties, functions, and roles in airway disease. AB - Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases. PMID- 28658565 TI - Current controversies with oral emergency contraception. AB - : Emergency contraception (EC) is a method to be used in the case of unprotected sexual intercourse, failure of a regular contraceptive method, or after rape to try to prevent an unintended pregnancy. Oral EC remains surrounded by controversy, much due to myths and misconceptions among the public, policy makers and healthcare providers. This has resulted in restrictions on its availability in many parts of the world and restrictions on women's access to it. The aim of this article is to provide an evidence-based view on some of these common controversial issues surrounding oral EC in clinical practice. TWEETABLE ABSTRACT: Controversy about emergency contraception restricts access for women. PMID- 28658564 TI - A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood. OBJECTIVE: To clarify the best discriminators of the asthma-COPD overlap phenotype from asthma and COPD subgroups using a clustering approach. METHODS: This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell related transcription factors, namely TBX21 (Th1), GATA3 (Th2), RORC (Th17) and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n=152) and in COPD patients (n=50). Clusters were determined using k-means clustering. Exacerbations of asthma and COPD were recorded during the 1-year follow-up period. RESULTS: The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma-COPD overlap phenotype; cluster 3, patients with non-atopic and late-onset asthma; and cluster 4, patients with early-onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval [CI], 1.1-5.6) in cluster 1 and 2.3 (95% CI, 1.0-5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level >=310 IU/mL, blood eosinophil counts >=280 cells/MUL, a higher ratio of TBX21/GATA3, FEV1 /FVC ratio <0.67 and smoking >=10 pack-years with an area under the curve of 0.94 (95% CI, 0.90-0.98) in the receiver operating characteristic analysis. CONCLUSIONS AND CLINICAL RELEVANCE: The asthma-COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2-low endotype. PMID- 28658567 TI - Issue Information-Declaration of Helsinki. PMID- 28658566 TI - Profiling ephedrine prepared from N-methylalanine via the Akabori-Momotani reaction. AB - Novel methods for synthesising methylamphetamine precursors are appearing in clandestine laboratories within Australia. One such laboratory involved the synthesis of ephedrine from N-methylalanine and benzaldehyde via the Akabori Momotani reaction. This article presents chiral and stable isotope ratios of ephedrine synthesised via this method, along with a chemical profile of methylamphetamine produced from this ephedrine. Based on the chiral results and the delta13 C, delta15 N, and delta2 H values, it is possible to distinguish ephedrine made via the Akabori-Momotani reaction from ephedrine of a "natural", "semi-synthetic", or "fully-synthetic" origin. Methylamphetamine and ephedrine samples synthesised from benzaldehyde having an enriched delta2 H value (ie, > 00/00), via the Akabori-Momotani reaction, had an isotopic profile which set them apart from all other methylamphetamine samples. It was noted, however, that using stable isotope ratios alone to determine the precursor of methylamphetamine is limited; they could not with confidence differentiate between methylamphetamine and ephedrine synthesised from benzaldehyde having a depleted delta2 H value (ie, <00/00) from other ephedrine sources and phenyl-2-propanone based methylamphetamine samples profiled. PMID- 28658568 TI - Fragility and Strength in Nanoparticle Glasses. AB - Glasses formed from nano- and microparticles form a fascinating testing ground to explore and understand the origins of vitrification. For atomic and molecular glasses, a wide range of fragilities have been observed; in colloidal systems, these effects can be emulated by adjusting the particle softness. The colloidal glass transition can range from a superexponential, fragile increase in viscosity with increasing density for hard spheres to a strong, Arrhenius-like transition for compressible particles. However, the microscopic origin of fragility and strength remains elusive, both in the colloidal and in the atomic domains. Here, we propose a simple model that explains fragility changes in colloidal glasses by describing the volume regulation of compressible colloids in order to maintain osmotic equilibrium. Our simple model provides a microscopic explanation for fragility, and we show that it can describe experimental data for a variety of soft colloidal systems, ranging from microgels to star polymers and proteins. Our results highlight that the elastic energy per particle acts as an effective fragility order parameter, leading to a universal description of the colloidal glass transition. PMID- 28658569 TI - Surfactant-Free Synthesis of Carbon-Supported Palladium Nanoparticles and Size Dependent Hydrogen Production from Formic Acid-Formate Solution. AB - Steerable hydrogen generation from the hydrogen storage chemical formic acid via heterogeneous catalysis has attracted considerable interest given the safety and efficiency concerns in handling H2. Herein, a series of carbon-supported capping agent-free Pd nanoparticles (NPs) with mean sizes tunable from 2.0 to 5.2 nm are developed due to the demand for more efficient dehydrogenation from a formic acid formate solution of pH 3.5 at room temperature. The trick for the facile size controlled synthesis of Pd/C catalysts is the selective addition of Na2CO3, NH3.H2O, or NaOH to a Pd(II) solution to attain initial pH values of 7-9.5. For comparison, cuboctahedron modeling and electrochemical COads stripping methods are applied to evaluate active surface Pd sites for turnover frequency (TOF) calculation. Both mass activity and specific activity (TOF) of hydrogen production are not only time-dependent but also Pd-size-dependent. An initial H2 production rate of 246 L.h-1.gPd-1 is achieved on 2.0 nm Pd/C at 303 K, together with a TOF of 1815 h-1 on the basis of cuboctahedron modeling of surface-active Pd sites. The initial TOF exhibits a significant rise from 3.5 down to 2.8 nm and then levels off below 2.8 nm and even shows a maxima at ca. 2.2 nm using the electrochemical surface area for calculation. The volcano-shaped dependence of TOF on Pd NP size may be better attributed to the changing ratios of terrace sites to defect sites on Pd NPs. PMID- 28658570 TI - Enhanced Photocatalytic Activity of Heterostructured Ferroelectric BaTiO3/alpha Fe2O3 and the Significance of Interface Morphology Control. AB - We have used a ferroelectric BaTiO3 substrate with a hematite (alpha-Fe2O3) nanostructured surface to form a heterogeneous BaTiO3/alpha-Fe2O3 photocatalyst. In this study we show that varying the mass ratio of alpha-Fe2O3 on BaTiO3 has a significant influence on photoinduced decolorization of rhodamine B under simulated sunlight. The highest photocatalytic activity was obtained for BaTiO3 Fe2O3-0.001M, with the lowest mass ratio of alpha-Fe2O3 in our study. This catalyst exhibited a 2-fold increase in performance compared to pure BaTiO3 and a 5-fold increase when compared to the higher-surface-area pure alpha-Fe2O3. The increases in performance become more marked upon scaling for the lower surface area of the heterostructured catalyst. Performance enhancement is associated with improved charge-carrier separation at the interface between the ferroelectric surface, which exhibits ferroelectric polarization, and the hematite. Increasing the mass ratio of hematite increases the thickness of this layer, lowers the number of triple-point locations, and results in reduced performance enhancement. We show that the reduced performance is due to a lack of light penetrating into BaTiO3 and to relationships between the depolarization field from the ferroelectric and carriers in the hematite. Our findings demonstrate that it is possible to use the built-in electric field of a ferroelectric material to promote charge-carrier separation and boost photocatalytic efficiency. PMID- 28658572 TI - Nanowire Kinking Modulates Doping Profiles by Reshaping the Liquid-Solid Growth Interface. AB - Dopants modify the electronic properties of semiconductors, including their susceptibility to etching. In semiconductor nanowires doped during growth by the vapor-liquid-solid (VLS) process, it has been shown that nanofaceting of the liquid-solid growth interface influences strongly the radial distribution of dopants. Hence, the combination of facet-dependent doping and dopant selective etching provides a means to tune simultaneously the electronic properties and morphologies of nanowires. Using atom-probe tomography, we investigated the boron dopant distribution in Au catalyzed VLS grown silicon nanowires, which regularly kink between equivalent ?112? directions. Segments alternate between radially uniform and nonuniform doping profiles, which we attribute to switching between a concave and convex faceted liquid-solid interface. Dopant selective etching was used to reveal and correlate the shape of the growth interface with the observed anisotropic doping. PMID- 28658571 TI - Triazine-based Polyelectrolyte as an Efficient Cathode Interfacial Material for Polymer Solar Cells. AB - A novel polyelectrolyte containing triazine (TAZ) and benzodithiophene (BDT) scaffolds with polar phosphine oxide (P?O) and quaternary ammonium ions as pendant groups, respectively, in the polymer backbone (PBTAZPOBr) was synthesized to use it as a cathode interfacial layer (CIL) for polymer solar cell (PSC) application. Owing to the high electron affinity of the TAZ unit and P?O group, PBTAZPOBr could behave as an effective electron transport material. Due to the polar quaternary ammonium and P?O groups, the interfacial dipole moment created by PBTAZPOBr substantially reduced the work function of the metal cathode to afford better energy alignment in the device, thus enabling electron extraction and reducing recombination of excitons at the photoactive layer/cathode interface. Consequently, the PSC devices based on the poly[4,8-bis(2 ethylhexyloxyl)benzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt-ethylhexyl-3 fluorothithieno[3,4-b]thiophene-2-carboxylate-4,6-diyl]:[6,6]-phenyl-C71-butyric acid methyl ester (PTB7:PC71BM) system with PBTAZPOBr as CIL displayed simultaneously enhanced open-circuit voltage, short-circuit current density, and fill factor, whereas the power conversion efficiency increased from 5.42% to 8.04% compared to that of the pristine Al device. The outstanding performance of PBTAZPOBr is attributed not only to the polar pendant groups of BDT unit but also to the TAZ unit linked with the P?O group of PBTAZPOBr, demonstrating that functionalized TAZ building blocks are very promising cathode interfacial materials (CIMs). The design strategy proposed in this work will be helpful to develop more efficient CIMs for high performance PSCs in the future. PMID- 28658573 TI - Role of Water Solidification Concepts in Designing Nano-Textured Anti-Icing Surfaces. AB - Creating anti-icing surfaces has proven to be a challenging task. With such a wide range of impacting parameters it is important to quantify ones with a large effect. Water solidification mechanisms play a fundamental role in designing anti icing surfaces. In this Review Article, we will consider the effects of surface roughening on the mechanisms of nucleation and ice growth to show how surface roughening can be an alternative to overcome the limitations of icing of superhydrophobic coatings and surfaces. The results from various studies of anti icing properties of superhydrophobic surfaces are reviewed and expanded to incorporate water solidification mechanisms to provide a more comprehensive approach to the design of anti-icing surfaces. The literature within this review shows that by applying the necessary roughness to either hydrophilic or hydrophobic surfaces and adjusting the surface topography, we can significantly suppress ice nucleation on various surfaces. PMID- 28658574 TI - 3-Hydroxy-1H-quinazoline-2,4-dione as a New Scaffold To Develop Potent and Selective Inhibitors of the Tumor-Associated Carbonic Anhydrases IX and XII. AB - In this paper, we describe the discovery of the 3-hydroxyquinazoline-2,4-dione as a useful scaffold to obtain potent inhibitors of the tumor-associated human carbonic anhydrases (hCAs) IX and XII. A set of derivatives (1-29), bearing different substituents on the fused benzo ring (Cl, NO2, NH2, CF3, ureido, amido, heterocycles), were synthesized, and several of them showed nanomolar activity in inhibiting the hCA IX and XII isoforms, while they were ineffective against the cytosolic enzymes hCAs I and II. Some selected compounds were tested for their antiproliferative activity against HT-29 colon cancer cell lines. After 48 h of treatment with the lower dose (30 MUM), derivatives 12, 14, 15, and 19 were significantly active, inducing a mortality by about 50% in both normoxia and hypoxia. This finding led us to hypothesize for these compounds more than one mechanism of action involving both CAs IX and XII and other not yet identified target(s). PMID- 28658575 TI - Engineering Compartmentalized Biomimetic Micro- and Nanocontainers. AB - Compartmentalization of biological content and function is a key architectural feature in biology, where membrane bound micro- and nanocompartments are used for performing a host of highly specialized and tightly regulated biological functions. The benefit of compartmentalization as a design principle is behind its ubiquity in cells and has led to it being a central engineering theme in construction of artificial cell-like systems. In this review, we discuss the attractions of designing compartmentalized membrane-bound constructs and review a range of biomimetic membrane architectures that span length scales, focusing on lipid-based structures but also addressing polymer-based and hybrid approaches. These include nested vesicles, multicompartment vesicles, large-scale vesicle networks, as well as droplet interface bilayers, and double-emulsion multiphase systems (multisomes). We outline key examples of how such structures have been functionalized with biological and synthetic machinery, for example, to manufacture and deliver drugs and metabolic compounds, to replicate intracellular signaling cascades, and to demonstrate collective behaviors as minimal tissue constructs. Particular emphasis is placed on the applications of these architectures and the state-of-the-art microfluidic engineering required to fabricate, functionalize, and precisely assemble them. Finally, we outline the future directions of these technologies and highlight how they could be applied to engineer the next generation of cell models, therapeutic agents, and microreactors, together with the diverse applications in the emerging field of bottom-up synthetic biology. PMID- 28658576 TI - Elaborate Manipulation for Sub-10 nm Hollow Catalyst Sensitized Heterogeneous Oxide Nanofibers for Room Temperature Chemical Sensors. AB - Room-temperature (RT) operation sensors are constantly in increasing demand because of their low power consumption, simple operation, and long lifetime. However, critical challenges such as low sensing performance, vulnerability under highly humid state, and poor recyclability hinder their commercialization. In this work, sub-10 nm hollow, bimetallic Pt-Ag nanoparticles (NPs) were successfully formed by galvanic replacement reaction in bioinspired hollow protein templates and sensitized on the multidimensional SnO2-WO3 heterojunction nanofibers (HNFs). Formation of hollow, bimetallic NPs resulted in the double side catalytic effect, rendering both surface and inner side chemical reactions. Subsequently, SnO2-WO3 HNFs were synthesized by incorporating 2D WO3 nanosheets (NSs) with 0D SnO2 sphere by c-axis growth inhibition effect and fluid dynamics of liquid Sn during calcination. Hierarchically assembled HNFs effectively modulate surface depletion layer of 2D WO3 NSs by electron transfers from WO3 to SnO2 stemming from creation of heterojunction. Careful combination of bimetallic catalyst NPs with HNFs provided an extreme recyclability under exhaled breath (95 RH%) with outstanding H2S sensitivity. Such sensing platform clearly distinguished between the breath of healthy people and simulated halitosis patients. PMID- 28658577 TI - Transferred Overhauser DNP: A Fast, Efficient Approach for Room Temperature 13C ODNP at Moderately Low Fields and Natural Abundance. AB - Overhauser dynamic nuclear polarization (ODNP) is investigated at a moderately low field (1.2 T) for natural abundance 13C NMR of small molecules in solution state at room temperature. It is shown that ODNP transferred from 1H to 13C by NMR coherence transfer is in general significantly more efficient than direct ODNP of 13C. Compared to direct 13C ODNP, we demonstrate over 4-fold higher 13C sensitivity (signal-to-noise ratio, SNR), achieved in one-eighth of the measurement time by transferred ODNP (t-ODNP). Compared to the 13C signal arising from Boltzmann equilibrium in a fixed measurement time, this is equivalent to about 1500-fold enhancement of 13C signal by t-ODNP, as against a direct 13C ODNP signal enhancement of about 45-fold, both at a moderate ESR saturation factor of about 0.25. This owes in part to the short polarization times characteristic of 1H. Typically, t-ODNP reflects the essentially uniform ODNP enhancements of all protons in a molecule. Although the purpose of this work is to establish the superiority of t-ODNP vis-a-vis direct 13C ODNP, a comparison is also made of the SNR in t-ODNP experiments with standard high resolution NMR as well. Finally, the potential of t-ODNP experiments for 2D heteronuclear correlation spectroscopy of small molecules is demonstrated in 2D 1H-13C HETCOR experiments at natural abundance, with decoupling in both dimensions. PMID- 28658578 TI - In Situ Measurement of Electrosorption-Induced Deformation Reveals the Importance of Micropores in Hierarchical Carbons. AB - Dimensional changes in carbon-based supercapacitor electrodes were investigated using a combination of electrochemical dilatometry and in situ small-angle X-ray scattering. A novel hierarchical carbon material with ordered mesoporosity was synthesized, providing the unique possibility to track electrode expansion and shrinkage on the nanometer scale and the macroscopic scale simultaneously. Two carbons with similar mesopore structure but different amounts of micropores were investigated, employing two different aqueous electrolytes. The strain of the electrodes was always positive, but asymmetric with respect to positive and negative applied voltages. The asymmetry strongly increased with increasing microporosity, giving hints to the possible physical origin of electrosorption induced pore swelling. PMID- 28658579 TI - Connecting Protein Conformation and Dynamics with Ligand-Receptor Binding Using Three-Color Forster Resonance Energy Transfer Tracking. AB - Specific binding between biomolecules, i.e., molecular recognition, controls virtually all biological processes including the interactions between cells and biointerfaces, both natural and synthetic. Such binding often relies on the conformation of biomacromolecules, which can be highly heterogeneous and sensitive to environmental perturbations, and therefore difficult to characterize and control. An approach is demonstrated here that directly connects the binding kinetics and stability of the protein receptor integrin alphavbeta3 to the conformation of the ligand fibronectin (FN), which are believed to control cellular mechanosensing. Specifically, we investigated the influence of surface adsorbed FN structure and dynamics on alphavbeta3 binding using high-throughput single-molecule three-color Forster resonance energy transfer (FRET) tracking methods. By controlling FN structure and dynamics through tuning surface chemistry, we found that as the conformational and translational dynamics of FN increased, the rate of binding, particularly to folded FN, and stability of the bound FN-alphavbeta3 complex decreased significantly. These findings highlight the importance of the conformational plasticity and accessibility of the arginine glycine-aspartic acid (RGD) binding site in FN, which, in turn, mediates cell signaling in physiological and synthetic environments. PMID- 28658580 TI - Toward a Long-Chain Perfluoroalkyl Replacement: Water and Oil Repellency of Polyethylene Terephthalate (PET) Films Modified with Perfluoropolyether-Based Polyesters. AB - Original perfluoropolyethers (PFPE)-based oligomeric polyesters (FOPs) of different macromolecular architecture were synthesized via polycondensation as low surface energy additives to engineering thermoplastics. The oligomers do not contain long-chain perfluoroalkyl segments, which are known to yield environmentally unsafe perfluoroalkyl carboxylic acids. To improve the compatibility of the materials with polyethylene terephthalate (PET) we introduced isophthalate segments into the polyesters and targeted the synthesis of lower molecular weight oligomeric macromolecules. The surface properties such as morphology, composition, and wettability of PET/FOP films fabricated from solution were investigated using atomic force microscopy, X-ray photoelectron spectroscopy, and contact angle measurements. It was demonstrated that FOPs, when added to PET film, readily migrate to the film surface and bring significant water and oil repellency to the thermoplastic boundary. We have established that the wettability of PET/FOP films depends on three main parameters: (i) end-groups of fluorinated polyesters, (ii) the concentration of fluorinated polyesters in the films, and (iii) equilibration via annealing. The most effective water/oil repellency FOP has two C4F9-PFPE-tails. The addition of this oligomeric polyester to PET allows (even at relatively low concentrations) reaching a level of oil repellency and surface energy comparable to that of polytetrafluorethylene (PTFE/Teflon). Therefore, the materials can be considered suitable replacements for additives containing long-chain perfluoroalkyl substances. PMID- 28658581 TI - Modulation of procaspase-7 self-activation by PEST amino acid residues of the N terminal prodomain and intersubunit linker. AB - Procaspase-7 zymogen polypeptide is composed of a short prodomain, a large subunit (p20), and a small subunit (p10) connected to an intersubunit linker. Caspase-7 is activated by an initiator caspase-8 and -9, or by autocatalysis after specific cleavage at IQAD198?S located at the intersubunit linker. Previously, we identified that PEST regions made of amino acid residues Pro (P), Glu (E), Asp (D), Ser (S), Thr (T), Asn (N), and Gln (Q) are conserved flanking amino acid residues in the cleavage sites within a prodomain and intersubunit linker of all caspase family members. Here we tested the impact of alanine substitution of PEST amino acid residues on procaspase-7 proteolytic self activation directly in Escherichia coli. The p20 and p10 subunit cleavage were significantly delayed in double caspase-7 mutants in the prodomain (N18A/P26A) and intersubunit linker (S199A/P201A), compared with the wild-type caspase-7. The S199A/P201A mutants effectively inhibited the p10 small subunit cleavage. However, the mutations did not change the kinetic parameters (kcat/KM) and optimal tetrapeptide specificity (DEVD) of the purified mutant enzymes. The results suggest a role of PEST-amino acid residues in the molecular mechanism for prodomain and intersubunit cleavage and caspase-7 self-activation. PMID- 28658582 TI - Effect of acute nitrate ingestion on VO2 response at different exercise intensity domains. AB - While nitrate supplementation influences oxygen uptake (VO2) response to exercise, this effect may be intensity dependent. The purpose of this study was to investigate the effect of acute nitrate supplementation on VO2 response during different exercise intensity domains in humans. Eleven men ingested 10 mg.kg-1 body mass (8.76 +/- 1.35 mmol) of sodium nitrate or sodium chloride (placebo) 2.5 h before cycling at moderate (90% of gas exchange threshold; GET), heavy (GET + 40% of the difference between GET and peak oxygen uptake (VO2peak), Delta 40) or severe (GET + 80% of the difference between GET and VO2peak, Delta 80) exercise intensities. Volunteers performed exercise for 10 min (moderate), 15 min (heavy) or until exhaustion (severe). Acute nitrate supplementation had no effect on any VO2 response parameters during moderate and severe exercise intensities. However, the VO2 slow amplitude (nitrate: 0.93 +/- 0.36 L.min-1 vs. placebo: 1.13 +/- 0.59 L.min-1, p = 0.04) and VO2 slow gain (nitrate: 5.81 +/- 2.37 mL.min-1.W-1 vs. placebo: 7.09 +/- 3.67 mL.min-1.W-1, p = 0.04) were significantly lower in nitrate than in placebo during the heavy exercise intensity. There was no effect of nitrate on plasma lactate during any exercise intensity (p > 0.05). Time to exhaustion during the severe exercise intensity was also not affected by nitrate (p > 0.05). In conclusion, acute nitrate supplementation reduced the slow component of VO2 only when performing heavy-intensity exercise, which might indicate an intensity-dependent effect of nitrate on VO2 response. PMID- 28658583 TI - Risk of Engagement of Bipolar Bone Defects in Posterior Shoulder Instability. AB - BACKGROUND: The risk of re-engagement of bipolar bone defects in posterior shoulder instability has not yet been investigated. HYPOTHESIS: Posterior glenoid defects can lead to the engagement of supposedly noncritical reverse Hill-Sachs lesions (RHSLs). STUDY DESIGN: Descriptive laboratory study. METHODS: In a retrospective multicenter study, 102 cases of posterior shoulder dislocations and resulting RHSLs were collected. Of these cases, all patients with available computed tomography (CT) scans, with a reduced shoulder joint, and without bony posterior glenoid rim defects or concomitant dislocated fractures of the humeral head were included. The gamma angle (measure of the critical size and localization of RHSLs) and the delta angle (measure of the degree of internal rotation necessary for engagement to occur) of the RHSLs were determined on standardized CT scans. Virtual posterior glenoid defects were created, and the effect of increasing defect size on the delta angle was determined. RESULTS: The mean gamma angle of the 19 patients included in this study was 94.5 degrees (range, 69.7 degrees -124.8 degrees ). After creation of the virtual posterior glenoid defects, a mean reduction of the delta angle by 2.3 degrees +/- 0.2 degrees (range, 1.9 degrees -2.9 degrees ) per millimeter defect was observed. The cumulative change in the delta angle showed a highly significant correlation with the absolute and relative size of the glenoid defect ( R = 0.982, P < .001 and R = 0.974, P < .001, respectively). CONCLUSION: Concomitant posterior glenoid defects might lead to the engagement of noncritical RHSLs. When measuring the gamma angle to identify critical RHSLs, posterior glenoid bone loss should be accounted for. PMID- 28658584 TI - Sodium tanshinone IIA sulfonate prevents lipopolysaccharide-induced inflammation via suppressing nuclear factor-kappaB signaling pathway in human umbilical vein endothelial cells. AB - Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, has been demonstrated to have potent anti-inflammatory properties. However, the protective effects of STS on lipopolysaccharide (LPS)-induced inflammation in endothelial cells remain to be elucidated. In the present study, human umbilical vein endothelial cells (HUVECs) were used to explore the effects of STS on LPS induced inflammation and the molecular mechanism involved. HUVECs were pretreated with STS for 2 h, followed by stimulation with LPS. Then expression and secretion of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, and the activation of nuclear factor-kappaB (NF-kappaB) were assessed. The results demonstrated that STS significantly decreased LPS-induced TNF-alpha and IL-1beta protein expression in HUVECs. Similarly, the increased levels of TNF-alpha and IL 1beta in cell supernatants stimulated by LPS were also significantly inhibited by STS. Furthermore, STS inhibited LPS-induced NF-kappaB p65 phosphorylation and nuclear translocation. All the results suggest that STS prevents LPS-induced inflammation through suppressing NF-kappaB signaling pathway in endothelial cells, indicating the potential utility of STS for the treatment of inflammatory diseases. PMID- 28658585 TI - Transport and flow characteristics of an oscillating cylindrical fiber for total artificial lung application. AB - Mass transport and fluid dynamics characteristics in the vicinity of an oscillating cylindrical fiber with an imposed pulsatile inflow condition are computationally investigated in the present study. The work is motivated by a recently proposed design modification to the Total Artificial Lung (TAL) device, which is expected to provide better gas exchange. Navier-Stokes computations, coupled with convection-diffusion equation are performed to assess flow dynamics and mass transport behavior around the oscillating fiber. The oscillations and the pulsatile free stream velocity are represented by two sinusoidal functions. The resulting non-dimensional parameters are Keulegan-Carpenter number (KC), Schmidt number (Sc), Reynolds number (Re), pulsatile inflow amplitude ([Formula: see text]), and amplitude of cylinder oscillation ([Formula: see text]). Results are computed for [Formula: see text], Sc = 1000, Re = 5 and 10, [Formula: see text] and 0.7 and 0.25 [Formula: see text][Formula: see text][Formula: see text] 5.25. The pulsatile inflow parameters correspond to the flow velocities found in human pulmonary artery while matching the operating TAL Reynolds number. Mass transport from the surface of the cylinder to the bulk fluid is found to be primarily dependent on the size of surface vortices created by the movement of the cylinder. Time-averaged surface Sherwood number (Sh) is dependent on the amplitude and KC of cylinder oscillation. Compared to the fixed cylinder case, a significant gain up to 380% in Sh is achieved by oscillating the cylinder even at the small displacement amplitude (AD = 0.75D). Moreover, with decrease in KC the oscillating cylinder exhibits a lower drag amplitude compared with the fixed cylinder case. Inflow pulsation amplitude has minor effects on the mass transport characteristics. However, an increase in [Formula: see text] results in an increase in the amplitude of the periodic drag force on the cylinder. This rise in the drag amplitude is similar to that measured for the fixed cylinder case. Quantifications of shear stress distribution in the bulk fluid suggest that the physiological concerns of platelet activation and injury to red blood cells due to cylinder oscillation are negligible. PMID- 28658586 TI - Small-bubble transport and splitting dynamics in a symmetric bifurcation. AB - Simulations of small bubbles traveling through symmetric bifurcations are conducted to garner information pertinent to gas embolotherapy, a potential cancer treatment. Gas embolotherapy procedures use intra-arterial bubbles to occlude tumor blood supply. As bubbles pass through bifurcations in the blood stream nonhomogeneous splitting and undesirable bioeffects may occur. To aid development of gas embolotherapy techniques, a volume of fluid method is used to model the splitting process of gas bubbles passing through artery and arteriole bifurcations. The model reproduces the variety of splitting behaviors observed experimentally, including the bubble reversal phenomenon. Splitting homogeneity and maximum shear stress along the vessel walls is predicted over a variety of physical parameters. Small bubbles, having initial length less than twice the vessel diameter, were found unlikely to split in the presence of gravitational asymmetry. Maximum shear stresses were found to decrease exponentially with increasing Reynolds number. Vortex-induced shearing near the bifurcation is identified as a possible mechanism for endothelial cell damage. PMID- 28658587 TI - Recognizing Sepsis as a Global Health Priority - A WHO Resolution. PMID- 28658588 TI - Utility of 1% Tropicamide in Improving the Quality of Images for Tele-Screening of Diabetic Retinopathy in Patients with Dark Irides. AB - PURPOSE: To compare the quality of fundus photographs taken before and after instillation of one drop of tropicamide. METHODS: The 45o fundus photographs were taken with a non-mydriatic fundus camera in three conditions of the pupil; pre mydriatic, 10 minutes after one drop of tropicamide, and fully dilated. Two photographs were taken in each condition; one centered on the macula and the other on the optic disc. Two vitreoretinal specialists graded the images. RESULTS: A total of 1768 fundus photographs of 149 diabetic patients with dark irides were included. There were more ungradable images (38.1% and 50.3%, graders 1 and 2, respectively) in the non-mydriatic state than partially- (4.6% and 11.5%) or fully-dilated (15.4% and 10.0%) conditions (p < 0.001, both graders). Partially and fully dilated states had similar rates of ungradable images (p = 0.56 and p = 0.54, graders 1 and 2, respectively). Test-retest reliability (repeatability) was 92.5% and 74.3% for the two graders, respectively. Inter grader agreement was moderate (Kappa = 0.50). CONCLUSION: Non-mydriatic fundus photographs have a high rate of ungradable images in patients with dark irides. Instillation of only one drop of tropicamide improves the quality of fundus photographs, which is not furthered by adding more drops. This strategy can be used in tele-ophthalmology programs. PMID- 28658589 TI - The Prevalence of Age-Related Eye Disease in an Elderly Population. AB - PURPOSE: To determine the prevalence of cataracts, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR) in Iranians over the age of 54 years. METHODS: Through a cross-sectional study using randomized cluster sampling, 60 clusters were selected in Sari, a city in the North of Iran. In each cluster, 20 people over 54 years of age were chosen systematically and were invited to participate in the study. After enrollment, all participants had optometric and ophthalmologic exams including slit lamp biomicroscopy and fundoscopy. RESULTS: Of the 1185 selected persons, 937 (79.1%) participated in this study (age range 55-87 years). The prevalence of cataracts, AMD, glaucoma, and DR in at least one eye was 29.6% (95% confidence interval [CI] 26.6-32.5), 5.8% (95% CI: 4.3-7.3), 3.7% (95% CI: 2.5-5.0), and 2.7% (95% CI: 1.6-3.7), respectively. All prevalences significantly increased with aging. AMD was more prevalent in men (7.4%) than women (4.4%) (p = 0.054). Overall, 35.8% (95% CI: 32.7-38.8) of participants had at least one of the four conditions; this rate was 27.4% for the 55-59-year old age group and 52.4% for those over 75 years of age. CONCLUSION: Overall, 35.8% of the studied population had at least one of the four diseases. Cataracts, followed by AMD, are the most common age-related eye diseases in the Iranian population, and thus, precise planning along with enhanced diagnostic and therapeutic facilities are necessary. PMID- 28658590 TI - Factors associated with prehospital death among traffic accident patients in Osaka City, Japan: A population-based study. AB - OBJECTIVE: Although it is important to assess the factors associated with traffic accident fatalities to decrease them as a matter of public health, such factors have not been fully identified. METHODS: Using a large-scale data set of ambulance records in Osaka City, Japan, we retrospectively analyzed all traffic accident patients transported to hospitals by emergency medical service personnel from 2013 to 2014. In this study, prehospital death was defined as that occurring at the scene or in the emergency department immediately after hospital arrival. We assessed prehospital factors associated with prehospital death due to traffic accidents by logistic regression models. RESULTS: This study enrolled 28,903 emergency patients involved in traffic accidents, of whom 68 died prehospital. In a multivariate model, elderly patients aged >=75 years (adjusted odds ratio [AOR] = 4.34; 95% confidence interval [CI], 2.29-8.23), nighttime (AOR = 2.75; 95% CI, 1.65-4.70), and type of injured person compared to bicyclists such as pedestrians (AOR = 9.58; 95% CI, 5.07-17.99), motorcyclists (AOR = 2.75; 95% CI, 1.21-6.24), and car occupants (AOR = 2.98; 95% CI, 1.39-6.40) were significantly associated with prehospital death due to traffic accidents. In addition, the AOR for automobile versus nonautomobile as the collision opponent was 4.76 (95% CI, 2.30 9.88). CONCLUSIONS: In this population, the factors associated with prehospital death due to traffic accidents were elderly people, nighttime, and pedestrian as the type of patient. The proportion of prehospital deaths due to traffic accidents was also high when the collision component was an automobile. PMID- 28658591 TI - Exploring the Relationship of Task Performance and Physical and Cognitive Fatigue During a Daylong Light Precision Task. AB - OBJECTIVE: Our aim was to explore the relationship between fatigue and operation system performance during a simulated light precision task over an 8-hr period using a battery of physical (central and peripheral) and cognitive measures. BACKGROUND: Fatigue may play an important role in the relationship between poor ergonomics and deficits in quality and productivity. However, well-controlled laboratory studies in this area have several limitations, including the lack of work relevance of fatigue exposures and lack of both physical and cognitive measures. There remains a need to understand the relationship between physical and cognitive fatigue and task performance at exposure levels relevant to realistic production or light precision work. METHOD: Errors and fatigue measures were tracked over the course of a micropipetting task. Fatigue responses from 10 measures and errors in pipetting technique, precision, and targeting were submitted to principal component analysis to descriptively analyze features and patterns. RESULTS: Fatigue responses and error rates contributed to three principal components (PCs), accounting for 50.9% of total variance. Fatigue responses grouped within the three PCs reflected central and peripheral upper extremity fatigue, postural sway, and changes in oculomotor behavior. CONCLUSION: In an 8-hr light precision task, error rates shared similar patterns to both physical and cognitive fatigue responses, and/or increases in arousal level. APPLICATION: The findings provide insight toward the relationship between fatigue and operation system performance (e.g., errors). This study contributes to a body of literature documenting task errors and fatigue, reflecting physical (both central and peripheral) and cognitive processes. PMID- 28658593 TI - Effects of Soy Lecithin Extender on Dog Sperm Cryopreservation. AB - Semen cryopreservation is an essential biotechnology in canine reproduction and during the cryopreservation process commonly egg yolk are used. The discrepancy in the egg yolk composition and the potential risk of disease dissemination are obstacles for semen exportation and use. Therefore, studies aiming to substitute egg yolk are extremely important. In this context, soy lecithin contains a low density lipoprotein fraction, is an interesting alternative. Thus, the objective of this study was to compare extenders based on soy lecithin (several concentrations and forms) with egg yolk during the cryopreservation process of dog sperm. For this purpose, we used twelve dogs. Semen was evaluated at different time points (after refrigeration, glycerolization, and thawing), by motility analysis (CASA) and functional tests (e.g., membrane integrity eosin/nigrosin, acrosome integrity-fast green/Bengal rose, mitochondrial activity 3'3 diaminobenzidine, Chromatin susceptibility to acid-induced denaturation-SCSA, and susceptibility to oxidative stress-thiobarbituric acid reactive substances). The results indicated that egg yolk and lower concentrations of lecithin had similar effects on mitochondrial activity and motility. Thus, soy lecithin is a potentially viable alternative to egg yolk for the cryopreservation of dog semen. PMID- 28658592 TI - Dectin-1 plays an important role in host defense against systemic Candida glabrata infection. AB - Candida glabrata is the second most common pathogen of severe candidiasis in immunocompromised hosts, following C. albicans. Although C. glabrata and C. albicans belong to the same genus, they are phylogenetically distinct. C-type lectin receptors (CLRs), acting as pattern-recognition receptors (PRRs), play critical roles in host defense against C. albicans infections. However, our understanding of the specific roles of CLRs in host defense against C. glabrata is limited. Here, we explored the potential roles of the C-type lectins Dectin-1 and Dectin-2 in host defense against C. glabrata. We found that both Dectin-1 deficient mice (Dectin-1-/-) and Dectin-2-deficient mice (Dectin-2-/-) are more susceptible to C. glabrata infection. Dectin-1confers host higher sensitivity for sensing C. glabrata infections, while the effect of Dectin-2 in the host defense against C. glabrata is infection dose dependent. Dectin-1 is required for host myeloid cells recognition, killing of C. glabrata, and development of subsequent Th1 and Th17 cell-mediated adaptive immune response. Significantly impaired inflammatory responses such as inflammatory cells recruitment and cytokines release that were induced by C. glabrata were manifested in Dectin-1-deficient mice. Together, our study demonstrates that Dectin-1 plays an important role in host defense against systemic Candida glabrata infections, indicating a previous unknown control mechanism for this particular type of infection in host. Our study, therefore, provides new insights into the host defense against C. glabrata. PMID- 28658594 TI - Targeting protein localization for anti-infective therapy. PMID- 28658595 TI - Flexor Digitorum Superficialis Tenodesis for Traumatic Digit Amputation at the Level of the Proximal Phalanx. AB - BACKGROUND: Traumatic amputation of the digit requiring revision amputation at the level of the proximal phalanx provides the opportunity to improve flexor function via tenodesis of the remaining flexor digitorum superficialis (FDS) tendon. Salvage of the remaining FDS and performing flexor tenodesis to the proximal phalanx allows increased flexion at the metacarpophalangeal (MCP) joint. METHODS: This series reviews FDS tenodesis, outlining its surgical technique with clinical and functional outcomes. Institutional review board-approved retrospective study was performed. Twelve digits in 8 patients were included. RESULTS: Average flexion-extension arc of affected MCP joint was 82 degrees , and average grip strength was 70% of unaffected extremity. No patients required revision surgery or revision amputation. One patient had a minor wound infection treated successfully with oral antibiotics. CONCLUSIONS: FDS tenodesis is a reliable motion-preserving procedure for patients with amputations at the level of the proximal phalanx to maintain flexion at the MCP joint. PMID- 28658596 TI - Corrigendum. PMID- 28658598 TI - Erratum. PMID- 28658597 TI - Galleria mellonella as a host model to study Candida glabrata virulence and antifungal efficacy. PMID- 28658599 TI - ScipionCloud: An integrative and interactive gateway for large scale cryo electron microscopy image processing on commercial and academic clouds. AB - New instrumentation for cryo electron microscopy (cryoEM) has significantly increased data collection rate as well as data quality, creating bottlenecks at the image processing level. Current image processing model of moving the acquired images from the data source (electron microscope) to desktops or local clusters for processing is encountering many practical limitations. However, computing may also take place in distributed and decentralized environments. In this way, cloud is a new form of accessing computing and storage resources on demand. Here, we evaluate on how this new computational paradigm can be effectively used by extending our current integrative framework for image processing, creating ScipionCloud. This new development has resulted in a full installation of Scipion both in public and private clouds, accessible as public "images", with all the required preinstalled cryoEM software, just requiring a Web browser to access all Graphical User Interfaces. We have profiled the performance of different configurations on Amazon Web Services and the European Federated Cloud, always on architectures incorporating GPU's, and compared them with a local facility. We have also analyzed the economical convenience of different scenarios, so cryoEM scientists have a clearer picture of the setup that is best suited for their needs and budgets. PMID- 28658600 TI - Rheological characterization of human brain tissue. AB - : The rheology of ultrasoft materials like the human brain is highly sensitive to regional and temporal variations and to the type of loading. While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior under various loading conditions remains insufficiently understood. Here we combine cyclic and relaxation testing under multiple loading conditions, shear, compression, and tension, to understand the rheology of four different regions of the human brain, the cortex, the basal ganglia, the corona radiata, and the corpus callosum. We establish a family of finite viscoelastic Ogden-type models and calibrate their parameters simultaneously for all loading conditions. We show that the model with only one viscoelastic mode and a constant viscosity captures the essential features of brain tissue: nonlinearity, pre-conditioning, hysteresis, and tension compression asymmetry. With stiffnesses and time constants of MUinfinity=0.7kPa, MU1=2.0kPa, and tau1=9.7s in the gray matter cortex and MUinfinity=0.3kPa, MU1=0.9kPa and tau1=14.9s in the white matter corona radiata combined with negative parameters alphainfinity and alpha1, this five-parameter model naturally accounts for pre-conditioning and tissue softening. Increasing the number of viscoelastic modes improves the agreement between model and experiment, especially across the entire relaxation regime. Strikingly, two cycles of pre conditioning decrease the gray matter stiffness by up to a factor three, while the white matter stiffness remains almost identical. These new insights allow us to better understand the rheology of different brain regions under mixed loading conditions. Our family of finite viscoelastic Ogden-type models for human brain tissue is simple to integrate into standard nonlinear finite element packages. Our simultaneous parameter identification of multiple loading modes can inform computational simulations under physiological conditions, especially at low to moderate strain rates. Understanding the rheology of the human brain will allow us to more accurately model the behavior of the brain during development and disease and predict outcomes of neurosurgical procedures. STATEMENT OF SIGNIFICANCE: While recent experiments have shaped our understanding of the time independent, hyperelastic response of human brain tissue, its time-dependent behavior at finite strains and under various loading conditions remains insufficiently understood. In this manuscript, we characterize the rheology of human brain tissue through a family of finite viscoelastic Ogdentype models and identify their parameters for multiple loading modes in four different regions of the brain. We show that even the simplest model of this family, with only one viscoelastic mode and five material parameters, naturally captures the essential features of brain tissue: its characteristic nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. For the first time, we simultaneously identify a single parameter set for shear, compression, tension, shear relaxation, and compression relaxation loading. This parameter set is significant for computational simulations under physiological conditions, where loading is naturally of mixed mode nature. Understanding the rheology of the human brain will help us predict neurosurgical procedures, inform brain injury criteria, and improve the design of protective devices. PMID- 28658601 TI - Early arterial calcification does not correlate with bone loss in pseudoxanthoma elasticum. AB - BACKGROUND AND AIMS: Pseudoxanthoma elasticum (PXE; OMIM 264800, prevalence 1/25,000 to 1/50,000) is an autosomal recessive multisystem disease due to deficiency in ABCC6, an ATP-binding cassette, sub-family C transporter. The PXE phenotype is mainly characterized by progressive ectopic calcification of connective tissues (namely skin, retinal Bruch's membrane and peripheral arteries) but the impact of PXE on bone structure is currently unknown. The present study sought to investigate bone mineralization and its potential link with vascular calcification in a large cohort of PXE patients with inherited mutations of the ABCC6 gene. METHODS AND RESULTS: 96 patients (61 women) matching the PXE criteria participated in this study. Their clinical history and status and bone biological markers were collected. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry and expressed as T- and Z-scores. Osteoporotic fractures were identified by X-ray, and coronary (CAC) and lower limb arterial calcification (LLAC) scores were determined by CT scan. RESULTS: 44% of the women were menopausal. Osteopenia was disclosed in 46% (17 women) while 23% (9 women) exhibited osteoporosis, 3 with severe osteoporosis. Fractures of an osteoporotic nature were authenticated in 3 patients (1 woman). Markers of bone remodelling processes (CTX, BSAP and osteocalcin) were within the normal range for our laboratory standards. Severe vitamin D deficiency (<25nmol/L) was found in 15%, while 51% exhibited no vitamin D deficiency (vitamin D>=50nmol/L). LLAC and CAC scores were significantly higher in the patients with a low T- and/or Z-score, although this difference disappeared in multivariate analysis with age as a confounding factor. There was no significant difference in LLAC and CAC between PXE patients with and without osteoporotic fractures. There was no statistically significant association between BMD, LLAC and CAC and any of the bone remodelling factors. CONCLUSIONS: This is the first report on the bone mineralization process in PXE patients. Our data shows that PXE patients are not markedly prone to exaggerated bone demineralization and fracture risk, and prevalence of osteoporosis remains within the normal range for the general population. Furthermore, the relationships between LLAC, but not CAC, and BMD with age are similar to those observed in the general population. Therefore, despite its pivotal role in ectopic calcification, ABCC6 deficiency does not interfere with the bone-vascular axis. The lack of PXE-related disturbances between BMD and arterial calcification also supports vitamin D supplementation in PXE patients with vitamin D deficiency. ClinicalTrials.gov Identifier: NCT01446393. PMID- 28658602 TI - Direct effects of RFRP-1, a mammalian GnIH ortholog, on ovarian activities of the cyclic mouse. AB - Arg(R)-Phe(F)-amide related peptide-1 (RFRP-1) and -3 (RFRP-3) are known as mammalian orthologs of gonadotropin-inhibitory hormone (GnIH). In mammals, these RFRPs are expressed not only in the hypothalamus and but also in gonads. Inhibitory roles of the hypothalamic and gonadal RFRP-3 in reproduction have been documented in mammals. However, functional roles of the hypothalamic and gonadal RFRP-1 in reproduction are still unclear in mammals. Therefore, in vitro studies were conducted to elucidate the direct effect of RFRP-1, a mammalian GnIH ortholog, on ovarian activities, such as steroidogenesis, apoptosis, cell proliferation and metabolism in the cyclic mouse. The ovaries collected from the proestrus mice were cultured in vitro with different doses (Control, 1ng/ml, 10ng/ml and 100ng/ml) of RFRP-1 for 24h at 37 degrees C. A significant dose dependent increase in estradiol release from the ovary was detected after the treatment of RFRP-1. Therefore, changes in the ovarian activities, such as steroidogenic markers (luteinizing hormone receptors; LH-R and 3beta hydroxysteroid dehydrogenase; 3beta-HSD), apoptotic markers [Poly(ADP-ribose) polymerase-1; PARP-1 and cysteine-aspartic protease; caspase-3], a cell proliferation marker (proliferating cell nuclear antigen; PCNA) and metabolic markers (GLUT-4; glucose uptake) were assessed by the treatment of RFRP-1 in the proestrus ovary. The densitometry analysis showed the treatment of RFRP-1 significantly increased the expressions of LH-R and 3beta-HSD, steroidogenic markers. In contrast, the expressions of PCNA, a cell proliferation maker; PARP-1 and caspase-3, apoptotic markers were significantly decreased. Interestingly, RFRP-1 treatment further increases significantly glucose uptake and GLUT-4 receptor expression. These findings indicate that RFRP-1 possesses a stimulatory effect on ovarian steroidogenesis in the proestrus mouse. This is the first evidence showing the direct action of RFRP-1 on steroidogenesis in any vertebrate. In addition, RFRP-1 may also act directly on ovarian folliculogenesis as an inhibitory factor. PMID- 28658603 TI - Physiological approaches to assess diminished sympathetic activity in the conscious rat. AB - The purpose of this study was to evaluate functional measures of diminished sympathetic activity after postganglionic neuronal loss in the conscious rat. To produce variable degrees of sympathetic postganglionic neuronal loss, adult rats were treated daily with toxic doses of guanethidine (100mg/kg) for either 5days or 11days, followed by a recovery period of at least 18days. Heart rate, blood pressure, cardiac baroreflex responsiveness, urinalysis (for catecholamine metabolite, 3-methoxy-4-hydroxyphenylethylenglycol; MHPG), and pupillometry were performed during the recovery period. At the end of the recovery period stereology of superior cervical ganglia (SCG) was performed to determine the degree of neuronal loss. Total number of SCG neurons was correlated to physiological outcomes using regression analysis. Whereas guanethidine treatment for 11days caused significant reduction in the number of neurons (15,646+/-1460 vs. 31,958+/-1588), guanethidine treatment for 5days caused variable levels of neuronal depletion (26,009+/-3518). Regression analysis showed that only changes in urinary MHPG levels and systolic blood pressure significantly correlated with reduction of SCG neurons (r2=0.45 and 0.19, both p<0.05). Although cardiac baroreflex-induced reflex tachycardia (345.7+/-19.6 vs. 449.7+/-20.3) and pupil/iris ratio (0.50+/-0.03% vs. 0.61+/-0.02%) were significantly attenuated in the 11-day guanethidine treated rats there was no significant relationship between these measurements and the number of remaining SCG neurons after treatment (p>0.05). These data suggest that basal systolic blood pressure and urinary MHPG levels predict drug-induced depletion of sympathetic activity in vivo. PMID- 28658604 TI - Smurf1 targets Securin for ubiquitin-dependent degradation and regulates the metaphase-to-anaphase transition. AB - The HECT E3 ligase Smurf1 (Smad ubiquitination regulatory factor 1) plays a critical role in several important biological pathways by targeting many proteins for ubiquitination and degradation, such as Smad1/5, MEKK2 and RhoA. However, the function of Smurf1 in metaphase-to-anaphase transition remains unclear. Here, we show that Smurf1 interacts with and targets Securin, an inhibitor of sister chromatid separation, for poly-ubiquitination and proteasomal degradation. Further results demonstrate that Securin is a physiological substrate of Smurf1 in MEF cells. Knockdown of Smurf1 results in sister-chromatid separation inhibition and delay of anaphase onset. This study provides the first evidence that Smurf1 functions as a novel regulator for the metaphase-to-anaphase transition. PMID- 28658605 TI - Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944. AB - Childhood absence epilepsy (CAE) is associated with interictal co-morbid symptoms including abnormalities in social behaviour. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a model of CAE that exhibits physiological and behavioural alterations characteristic of the human disorder. However, it is unknown if GAERS display the social deficits often observed in CAE. Sociability in rodents is thought to be mediated by neural circuits densely populated with T-type calcium channels and GAERS contain a missense mutation in the Cav3.2 T-type calcium channel gene. Thus, the objective of this study was to examine the effects of the clinical stage pan-T-type calcium channel blocker, Z944, on sociability behaviour in male and female GAERS and non-epileptic control (NEC) animals. Female GAERS showed reduced sociability in a three-chamber sociability task whereas male GAERS, male NECs, and female NECs all showed a preference for the chamber containing a stranger rat. In drug trials, pre-treatment with 5mg/kg of Z944 normalized sociability in female GAERS. In contrast, female NECs showed impaired sociability following Z944 treatment. Dose-dependent decreases in locomotor activity were noted following Z944 treatment in both strains. Treatment with 10mg/kg of Z944 altered exploration such that only 8 of the 16 rats tested explored both sides of the testing chamber. In those that explored the chamber, significant preference for the stranger rat was observed in GAERS but not NECs. Overall, the data suggest that T-type calcium channels are critical in regulating sociability in both GAERS and NEC animals. Future research should focus on T-type calcium channels in the treatment of sociability deficits observed in disorders such as CAE. PMID- 28658607 TI - Phylogenomics and comparative genomic studies delineate six main clades within the family Enterobacteriaceae and support the reclassification of several polyphyletic members of the family. AB - The family Enterobacteriaceae harbors many important pathogens, however it has proven difficult to reliably distinguish different members of this family or discern their interrelationships. To understand the interrelationships among the Enterobacteriaceae species, we have constructed two comprehensive phylogenetic trees for 78 genome-sequenced Enterobacteriaceae species based on 2487 core genome proteins, and another set of 118 conserved proteins. The genome sequences of Enterobacteriaceae species were also analyzed for genetic relatedness based on average amino acid identity and 16S rRNA sequence similarity. In parallel, comparative genomic studies on protein sequences from the Enterobacteriaceae have identified 88 molecular markers in the form of conserved signature indels (CSIs) that are uniquely shared by specific members of the family. All of these multiple lines of investigations provide consistent evidence that most of the species/genera within the family can be assigned to 6 different subfamily level clades which are designated as the "Escherichia clade", "Klebsiella clade", "Enterobacter clade", "Kosakonia clade", "Cronobacter clade" and "Cedecea clade". The members of the six described clades, in addition to their distinct branching in phylogenetic trees, can now be reliably demarcated in molecular terms on the basis of multiple identified CSIs that are exclusively shared by the group members. Several additional CSIs identified in this work that are either specific for individual genera (viz. Kosakonia, Kluyvera and Escherichia-Shigella), or are present at various taxonomic depths, offer information regarding the interrelationships among the different clades. The described molecular markers provide novel means for diagnostic as well as genetic and biochemical studies on the Enterobacteriaceae species and for resolving the polyphyly of its several genera viz. Escherichia, Enterobacter and Kluyvera. On the bases of our results, we are proposing the reclassification of Escherichia vulneris and Enterobacter massiliensis into two novel genera viz. Pseudescherichia gen. nov. and Metakosakonia gen. nov., respectively. Additionally, our results also support the transfer of "Enterobacter lignolyticus" and "Kluyvera intestini" to the genera Pluralibacter and Metakosakonia, respectively. PMID- 28658606 TI - A comparative assessment of e-cigarette aerosols and cigarette smoke on in vitro endothelial cell migration. AB - Cigarette smoking is a risk factor for several diseases. There has been a steep increase in the use of e-cigarettes that may offer a safer alternative to cigarette smoking. In vitro models of smoking-related diseases may provide valuable insights into disease mechanisms associated with tobacco use and could be used to assess e-cigarettes. We previously reported the application of a 'scratch wound' assay, measuring endothelial cell migration rate following artificial wounding, in the presence or absence of cigarette smoke extracts. This study reports the comparative effects of two commercial e-cigarette products (Vype ePen and Vype eStick) and a scientific reference cigarette (3R4F) on endothelial migration in vitro. Puff-matched extracts were generated using the Health Canada Intense (HCI) regime for cigarettes and a modified HCI for e cigarettes. Exposure to 3R4F extract (20h) induced concentration-dependent inhibition of endothelial cell migration, with complete inhibition at concentrations >20%. E-cigarette extracts did not inhibit migration, even at double the 3R4F extract nicotine concentration, allowing cells to migrate into the wounded area. Our data demonstrate that e-cigarettes do not induce the inhibition of endothelial cell migration in vitro when compared to 3R4F. The scratch wound assay enables the comparative assessment between tobacco and nicotine products in vitro. PMID- 28658608 TI - Cigarette smoking risk-reducing beliefs: Findings from the United States Health Information National Trends Survey. AB - Cigarette smoking risk-reducing beliefs are ideas that certain health promoting behaviors (e.g., exercise) may mitigate the risks associated with smoking. The objective of this study was to describe smoking risk-reducing beliefs and the belief that quitting can reduce the harmful effects of smoking among the U.S. adult population and the associations between these beliefs, current smoking status, and sociodemographics. Data were from the Health Information National Trends Survey 4 (HINTS 4) Cycles 3 and 4 (2013-2014; N=6862). Descriptive analyses were conducted to examine bivariate associations among the quit smoking belief, smoking risk-reducing beliefs, and covariates. Weighted ordinal logistic regression models examined the adjusted associations between smoking status and sociodemographics, with quit smoking belief and risk-reducing beliefs. Eighty-two percent of the population reported that quitting cigarette smoking can help reduce the harmful effects of smoking a lot: former smokers and individuals with higher educational attainment were more likely to endorse this belief than never smokers and those with lower educational attainment. Many people endorsed smoking risk-reducing beliefs about exercise (79.3%), fruits and vegetables (71.8%), vitamins (67.2%), and sleep (68.5%). Former smokers were less likely to subscribe to these beliefs than never smokers. Vulnerable populations who may be most at risk of smoking attributable morbidity and mortality were more likely to endorse risk-reducing beliefs. Future studies are needed to better understand how risk reducing beliefs are formed and if modifying these beliefs may help to reduce cigarette smoking in the U.S. PMID- 28658609 TI - Postharvest changes in LIN5-down-regulated plants suggest a role for sugar deficiency in cuticle metabolism during ripening. AB - The cell wall invertase gene (LIN5) was reported to be a key enzyme influencing sugar uptake of tomato (Solanum lycopersicum) fruit. It was additionally revealed to be a key regulator of total soluble solids content in fruit as well as for reproductive development, being mainly involved in flower development, early fruit and seed development but also in ripening. Here, we demonstrate that silencing of the LIN5 gene promotes changes affecting fruit cuticle development which has a direct effect on postharvest properties. Transformants were characterized by reduced transpirational water loss in mature fruits accompanied by several other changes in the cuticle. Quantitative chemical composition, coupled with microscopy of isolated cuticle fruits revealed that the cuticle of the transformants were characterized by an increase of the thickness as well as significant increase in the content of cuticle components (cutin, phenolic compounds, and waxes). Furthermore, detailed analysis of the waxes revealed that the transformants displayed changes in waxes composition, showing higher levels of n-alkanes and triterpenoids which can shift the proportion of crystalline and amorphous waxes and change the water flux through the cuticle. Expression of the genes involved in cuticle biosynthesis indicated that LIN5 influences the biosynthesis of components of the cuticle, indicating that this process is coupled to sugar uploading via a mechanism which links carbon supply with the capacity for fruit expansion. PMID- 28658610 TI - Aberrant signaling and senescence associated protein degradation. AB - Senescent cells accumulate with age and contribute to pathologies associated to old age. The senescent program can be induced by pro-cancer stimuli or is developmentally controlled. In cells forced to senesce by expression of oncogenes or short telomeres, aberrant activation of the ERK/MAP kinase signaling pathway leads to selective protein degradation by the ubiquitin proteasome system. The proteins affected by this process control key cellular processes known to be defective in senescent cells. We discuss the evidence supporting a general role for aberrant signaling and senescence associated protein degradation for organismal aging. PMID- 28658611 TI - Interventions to slow cardiovascular aging: Dietary restriction, drugs and novel molecules. AB - Cardiovascular aging is a highly dynamic process. Despite the fact that cardiovascular function and structure change with age, they can still be modulated even in aged humans. The most prominent approaches to improve age dependent vascular changes include dietary restriction and pharmacologic agents interacting with signaling pathways implicated in this context. These include inhibition of TOR, glycolysis, and GH/IGF-1, activation of sirtuins, and AMPK, as well as modulators of inflammation, epigenetic pathways, and telomeres. Promising nutritional approaches include Mediterranean diet and novel dietary bioactives including flavanols, anthocyanins, and lignins. Many plant bioactives improve cardiovascular parameters implied in vascular healthy aging including endothelial function, arterial stiffness, blood pressure, cholesterol, and glycemic control. However, the mechanism of action of most bioactives is not established and it remains to be elucidated whether they act as dietary restriction mimetics or via other modes of action. Even more importantly, whether these interventions can slow or even reverses components of cardiovascular aging itself and can increase healthspan or longevity in humans needs to be determined. PMID- 28658612 TI - Senescence-associated microRNAs target cell cycle regulatory genes in normal human lung fibroblasts. AB - Senescence recapitulates the ageing process at the cell level. A senescent cell stops dividing and exits the cell cycle. MicroRNAs (miRNAs) acting as master regulators of transcription, have been implicated in senescence. In the current study we investigated and compared the expression of miRNAs in young versus senescent human fibroblasts (HDFs), and analysed the role of mRNAs expressed in replicative senescent HFL-1 HDFs. Cell cycle analysis confirmed that HDFs accumulated in G1/S cell cycle phase. Nanostring analysis of isolated miRNAs from young and senescent HFL-1 showed that a distinct set of 15 miRNAs were significantly up-regulated in senescent cells including hsa-let-7d-5p, hsa-let-7e 5p, hsa-miR-23a-3p, hsa-miR-34a-5p, hsa-miR-122-5p, hsa-miR-125a-3p, hsa-miR-125a 5p, hsa-miR-125b-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-503 5p, hsa-miR-574-3p, hsa-miR-574-5p and hsa-miR-4454. Importantly, pathway analysis of miRNA target genes down-regulated during replicative senescence in a public RNA-seq data set revealed a significant high number of genes regulating cell cycle progression, both G1/S and G2/M cell cycle phase transitions and telomere maintenance. The reduced expression of selected miRNA targets, upon replicative and oxidative-stress induced senescence, such as the cell cycle effectors E2F1, CcnE, Cdc6, CcnB1 and Cdc25C was verified at the protein and/or RNA levels. Induction of G1/S cell cycle phase arrest and down-regulation of cell cycle effectors correlated with the up-regulation of miR-221 upon both replicative and oxidative stress-induced senescence. Transient expression of miR 221/222 in HDFs promoted the accumulation of HDFs in G1/S cell cycle phase. We propose that miRNAs up-regulated during replicative senescence may act in concert to induce cell cycle phase arrest and telomere erosion, establishing a senescent phenotype. PMID- 28658613 TI - mTORC1 Controls Synthesis of Its Activator GTP. AB - In this issue of Cell Reports, Emmanuel et al. (2017) report that mTORC1 activity is regulated by purine availability. This increases the number of mTORC1 regulators to include metabolites whose synthesis mTORC1 controls. PMID- 28658614 TI - A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross Presentation. AB - Cross-presentation initiates immune responses against tumors and viral infections by presenting extracellular antigen on MHC I to activate CD8+ T cell-mediated cytotoxicity. In vitro studies in dendritic cells (DCs) established SNARE protein SEC22B as a specific regulator of cross-presentation. However, the in vivo contribution of SEC22B to cross-presentation has not been tested. To address this, we generated DC-specific Sec22b knockout (CD11c-Cre Sec22bfl/fl) mice. Contrary to the paradigm, SEC22B-deficient DCs efficiently cross-present both in vivo and in vitro. Although in vitro small hairpin RNA (shRNA)-mediated Sec22b silencing in bone-marrow-derived dendritic cells (BMDCs) reduced cross presentation, treatment of SEC22B-deficient BMDCs with the same shRNA produced a similar defect, suggesting the Sec22b shRNA modulates cross-presentation through off-target effects. RNA sequencing of Sec22b shRNA-treated SEC22B-deficient BMDCs demonstrated several changes in the transcriptome. Our data demonstrate that contrary to the accepted model, SEC22B is not necessary for cross-presentation, cautioning against extrapolating phenotypes from knockdown studies alone. PMID- 28658615 TI - PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion. AB - RAS genes are frequently mutated in cancers, yet an effective treatment has not been developed, partly because of an incomplete understanding of signaling within Ras-related tumors. To address this, we performed a genetic screen in Drosophila, aiming to find mutations that cooperate with oncogenic Ras (RasV12) to induce tumor overgrowth and invasion. We identified fiery mountain (fmt), a regulatory subunit of the protein phosphatase 6 (PP6) complex, as a tumor suppressor that synergizes with RasV12 to drive c-Jun N-terminal kinase (JNK)-dependent tumor growth and invasiveness. We show that Fmt negatively regulates JNK upstream of dTAK1. We further demonstrate that disruption of PpV, the catalytic subunit of PP6, mimics fmt loss-of-function-induced tumorigenesis. Finally, Fmt synergizes with PpV to inhibit JNK-dependent tumor progression. Our data here further highlight the power of Drosophila as a model system to unravel molecular mechanisms that may be relevant to human cancer biology. PMID- 28658616 TI - Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase. AB - Pharmacologic agents that interfere with nucleotide metabolism constitute an important class of anticancer agents. Recent studies have demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. Here, we demonstrate that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools. Cellular treatment with AG2037, an inhibitor of the purine biosynthetic enzyme GARFT, profoundly inhibits mTORC1 activity via a reduction in the level of GTP-bound Rheb, an obligate upstream activator of mTORC1, because of a reduction in intracellular guanine nucleotides. AG2037 treatment provokes both mTORC1 inhibition and robust tumor growth suppression in mice bearing non-small-cell lung cancer (NSCLC) xenografts. These results indicate that alterations in purine nucleotide availability affect mTORC1 activity and suggest that inhibition of mTORC1 contributes to the therapeutic effects of purine biosynthesis inhibitors. PMID- 28658619 TI - Peripheral Sensory Deprivation Restores Critical-Period-like Plasticity to Adult Somatosensory Thalamocortical Inputs. AB - Recent work has shown that thalamocortical (TC) inputs can be plastic after the developmental critical period has closed, but the mechanism that enables re establishment of plasticity is unclear. Here, we find that long-term potentiation (LTP) at TC inputs is transiently restored in spared barrel cortex following either a unilateral infra-orbital nerve (ION) lesion, unilateral whisker trimming, or unilateral ablation of the rodent barrel cortex. Restoration of LTP is associated with increased potency at TC input and reactivates anatomical map plasticity induced by whisker follicle ablation. The reactivation of TC LTP is accompanied by reappearance of silent synapses. Both LTP and silent synapse formation are preceded by transient re-expression of synaptic GluN2B-containing N methyl-D-aspartate (NMDA) receptors, which are required for the reappearance of TC plasticity. These results clearly demonstrate that peripheral sensory deprivation reactivates synaptic plasticity in the mature layer 4 barrel cortex with features similar to the developmental critical period. PMID- 28658618 TI - A Presynaptic Glutamate Receptor Subunit Confers Robustness to Neurotransmission and Homeostatic Potentiation. AB - Homeostatic signaling systems are thought to interface with other forms of plasticity to ensure flexible yet stable levels of neurotransmission. The role of neurotransmitter receptors in this process, beyond mediating neurotransmission itself, is not known. Through a forward genetic screen, we have identified the Drosophila kainate-type ionotropic glutamate receptor subunit DKaiR1D to be required for the retrograde, homeostatic potentiation of synaptic strength. DKaiR1D is necessary in presynaptic motor neurons, localized near active zones, and confers robustness to the calcium sensitivity of baseline synaptic transmission. Acute pharmacological blockade of DKaiR1D disrupts homeostatic plasticity, indicating that this receptor is required for the expression of this process, distinct from developmental roles. Finally, we demonstrate that calcium permeability through DKaiR1D is necessary for baseline synaptic transmission, but not for homeostatic signaling. We propose that DKaiR1D is a glutamate autoreceptor that promotes robustness to synaptic strength and plasticity with active zone specificity. PMID- 28658617 TI - Reliable and Elastic Propagation of Cortical Seizures In Vivo. AB - Mapping the fine-scale neural activity that underlies epilepsy is key to identifying potential control targets of this frequently intractable disease. Yet, the detailed in vivo dynamics of seizure progression in cortical microcircuits remain poorly understood. We combine fast (30-Hz) two-photon calcium imaging with local field potential (LFP) recordings to map, cell by cell, the spread of locally induced (4-AP or picrotoxin) seizures in anesthetized and awake mice. Using single-layer and microprism-assisted multilayer imaging in different cortical areas, we uncover reliable recruitment of local neural populations within and across cortical layers, and we find layer-specific temporal delays, suggesting an initial supra-granular invasion followed by deep layer recruitment during lateral seizure spread. Intriguingly, despite consistent progression pathways, successive seizures show pronounced temporal variability that critically depends on GABAergic inhibition. We propose an epilepsy circuit model resembling an elastic meshwork, wherein ictal progression faithfully follows preexistent pathways but varies flexibly in time, depending on the local inhibitory restraint. PMID- 28658620 TI - Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy. AB - Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels. PMID- 28658621 TI - Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel CGRP-Jdp2 Axis. AB - Candida albicans can enter skeletal tissue through a skin wound in an immunocompromised host or by contamination during orthopedic surgery. Such Candida osteomyelitis is accompanied by severe pain and bone destruction. It is established that nociceptor innervation occurs in skin and bone, but the mechanisms of nociceptive modulation in fungal inflammation remain unclear. In this study, we show that C. albicans stimulates Nav1.8-positive nociceptors via the beta-glucan receptor Dectin-1 to induce calcitonin gene-related peptide (CGRP). This induction of CGRP is independent of Bcl-10 or Malt-1 but dependent on transient receptor potential cation channel subfamily V member 1 (TRPV1)/transient receptor potential cation channel subfamily A member 1 (TRPA1) ion channels. Hindpaw beta-glucan injection after Nav1.8-positive nociceptor ablation or in TRPV1/TRPA1 deficiency showed dramatically increased osteoinflammation accompanied by impaired CGRP production. Strikingly, CGRP suppressed beta-glucan-induced inflammation and osteoclast multinucleation via direct suppression of nuclear factor-kappaB (NF-kappaB) p65 by the transcriptional repressor Jdp2 and inhibition of actin polymerization, respectively. These findings clearly suggest a role for Dectin-1-mediated sensocrine pathways in the resolution of fungal osteoinflammation. PMID- 28658622 TI - Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. AB - Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14alpha-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNbeta-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNbeta-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity. PMID- 28658624 TI - Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase. AB - Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP+ ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triple-null) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity. PMID- 28658623 TI - NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. AB - Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2 deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF kappaB, ERK, and STAT3 are significantly higher in Nod2-/- mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2-/- colons. In vitro studies demonstrate that, while NOD2 activates the NF-kappaB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-kappaB and MAPK. Notably, NOD2-mediated downregulation of NF-kappaB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways. PMID- 28658625 TI - In Vivo Regulation of the Zebrafish Endoderm Progenitor Niche by T-Box Transcription Factors. AB - T-box transcription factors T/Brachyury homolog A (Ta) and Tbx16 are essential for correct mesoderm development in zebrafish. The downstream transcriptional networks guiding their functional activities are poorly understood. Additionally, important contributions elsewhere are likely masked due to redundancy. Here, we exploit functional genomic strategies to identify Ta and Tbx16 targets in early embryogenesis. Surprisingly, we discovered they not only activate mesodermal gene expression but also redundantly regulate key endodermal determinants, leading to substantial loss of endoderm in double mutants. To further explore the gene regulatory networks (GRNs) governing endoderm formation, we identified targets of Ta/Tbx16-regulated homeodomain transcription factor Mixl1, which is absolutely required in zebrafish for endoderm formation. Interestingly, we find many endodermal determinants coordinately regulated through common genomic occupancy by Mixl1, Eomesa, Smad2, Nanog, Mxtx2, and Pou5f3. Collectively, these findings augment the endoderm GRN and reveal a panel of target genes underlying the Ta, Tbx16, and Mixl1 mutant phenotypes. PMID- 28658626 TI - Functional Dissection of the Pol V Largest Subunit CTD in RNA-Directed DNA Methylation. AB - Plant multisubunit RNA polymerase V (Pol V) transcription recruits Argonaute small interfering RNA (siRNA) complexes that specify sites of RNA-directed DNA methylation (RdDM) for gene silencing. Pol V's largest subunit, NRPE1, evolved from the largest subunit of Pol II but has a distinctive C-terminal domain (CTD). We show that the Pol V CTD is dispensable for catalytic activity in vitro yet essential in vivo. One CTD subdomain (DeCL) is required for Pol V function at virtually all loci. Other CTD subdomains have locus-specific effects. In a yeast two-hybrid screen, the 3'-> 5' exoribonuclease RRP6L1 was identified as an interactor with the DeCL and glutamine-serine (QS)-rich subdomains located downstream of an Argonaute-binding subdomain. Experimental evidence indicates that RRP6L1 trims the 3' ends of Pol V transcripts sliced by Argonaute 4 (AGO4), suggesting a model whereby the CTD enables the spatial and temporal coordination of AGO4 and RRP6L1 RNA processing activities. PMID- 28658627 TI - TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling. AB - Accessory proteins in Frizzled (FZD) receptor complexes are thought to determine ligand selectivity and signaling amplitude. Genetic evidence indicates that specific combinations of accessory proteins and ligands mediate vascular beta catenin signaling in different CNS structures. In the retina, the tetraspanin TSPAN12 and the ligand norrin (NDP) mediate angiogenesis, and both genes are linked to familial exudative vitreoretinopathy (FEVR), yet the molecular function of TSPAN12 remains poorly understood. Here, we report that TSPAN12 is an essential component of the NDP receptor complex and interacts with FZD4 and NDP via its extracellular loops, consistent with an action as co-receptor that enhances FZD4 ligand selectivity for NDP. FEVR-linked mutations in TSPAN12 prevent the incorporation of TSPAN12 into the NDP receptor complex. In vitro and in Xenopus embryos, TSPAN12 alleviates defects of FZD4 M105V, a mutation that destabilizes the NDP/FZD4 interaction. This study sheds light on the poorly understood function of accessory proteins in FZD signaling. PMID- 28658628 TI - The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes. AB - Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown. Through amphotericin B-based selection, we isolated two cholesterol transport-defective cell lines. Subsequent whole transcriptome-sequencing analysis revealed two cell lines bearing the same mutation in the vacuolar protein sorting 53 (Vps53) gene. Depletion of VPS53 or other subunits of the Golgi-associated retrograde protein (GARP) complex impaired NPC2 sorting to lysosomes and caused cholesterol accumulation. GARP deficiency blocked the retrieval of the cation-independent mannose 6-phosphate receptor (CI MPR) to the trans-Golgi network. Further, Vps54 mutant mice displayed reduced cellular NPC2 protein levels and increased cholesterol accumulation, underscoring the physiological role of the GARP complex in cholesterol transport. We conclude that the GARP complex contributes to intracellular cholesterol transport by targeting NPC2 to lysosomes in a CI-MPR-dependent manner. PMID- 28658629 TI - Definition of a High-Confidence Mitochondrial Proteome at Quantitative Scale. AB - Mitochondria perform central functions in cellular bioenergetics, metabolism, and signaling, and their dysfunction has been linked to numerous diseases. The available studies cover only part of the mitochondrial proteome, and a separation of core mitochondrial proteins from associated fractions has not been achieved. We developed an integrative experimental approach to define the proteome of yeast mitochondria. We classified > 3,300 proteins of mitochondria and mitochondria associated fractions and defined 901 high-confidence mitochondrial proteins, expanding the set of mitochondrial proteins by 82. Our analysis includes protein abundance under fermentable and nonfermentable growth, submitochondrial localization, single-protein experiments, and subcellular classification of mitochondria-associated fractions. We identified mitochondrial interactors of respiratory chain supercomplexes, ATP synthase, AAA proteases, the mitochondrial contact site and cristae organizing system (MICOS), and the coenzyme Q biosynthesis cluster, as well as mitochondrial proteins with dual cellular localization. The integrative proteome provides a high-confidence source for the characterization of physiological and pathophysiological functions of mitochondria and their integration into the cellular environment. PMID- 28658630 TI - An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling. AB - Building an integrated view of cellular responses to environmental cues remains a fundamental challenge due to the complexity of intracellular networks in mammalian cells. Here, we introduce an integrative biochemical and genetic framework to dissect signal transduction events using multiple data types and, in particular, to unify signaling and transcriptional networks. Using the Toll-like receptor (TLR) system as a model cellular response, we generate multifaceted datasets on physical, enzymatic, and functional interactions and integrate these data to reveal biochemical paths that connect TLR4 signaling to transcription. We define the roles of proximal TLR4 kinases, identify and functionally test two dozen candidate regulators, and demonstrate a role for Ap1ar (encoding the Gadkin protein) and its binding partner, Picalm, potentially linking vesicle transport with pro-inflammatory responses. Our study thus demonstrates how deciphering dynamic cellular responses by integrating datasets on various regulatory layers defines key components and higher-order logic underlying signaling-to transcription pathways. PMID- 28658631 TI - PAX7 Targets, CD54, Integrin alpha9beta1, and SDC2, Allow Isolation of Human ESC/iPSC-Derived Myogenic Progenitors. AB - Pluripotent stem (PS)-cell-derived cell types hold promise for treating degenerative diseases. However, PS cell differentiation is intrinsically heterogeneous; therefore, clinical translation requires the development of practical methods for isolating progenitors from unwanted and potentially teratogenic cells. Muscle-regenerating progenitors can be derived through transient PAX7 expression. To better understand the biology, and to discover potential markers for these cells, here we investigate PAX7 genomic targets and transcriptional changes in human cells undergoing PAX7-mediated myogenic commitment. We identify CD54, integrin alpha9beta1, and Syndecan2 (SDC2) as surface markers on PAX7-induced myogenic progenitors. We show that these markers allow for the isolation of myogenic progenitors using both fluorescent- and CGMP compatible magnetic-based sorting technologies and that CD54+alpha9beta1+SDC2+ cells contribute to long-term muscle regeneration in vivo. These findings represent a critical step toward enabling the translation of PS-cell-based therapies for muscle diseases. PMID- 28658633 TI - Membrane biofilm communities in full-scale membrane bioreactors are not randomly assembled and consist of a core microbiome. AB - Finding efficient biofouling control strategies requires a better understanding of the microbial ecology of membrane biofilm communities in membrane bioreactors (MBRs). Studies that characterized the membrane biofilm communities in lab-and pilot-scale MBRs are numerous, yet similar studies in full-scale MBRs are limited. Also, most of these studies have characterized the mature biofilm communities with very few studies addressing early biofilm communities. In this study, five full-scale MBRs located in Seattle (Washington, U.S.A.) were selected to address two questions concerning membrane biofilm communities (early and mature): (i) Is the assembly of biofilm communities (early and mature) the result of random immigration of species from the source community (i.e. activated sludge)? and (ii) Is there a core membrane biofilm community in full-scale MBRs? Membrane biofilm (early and mature) and activated sludge (AS) samples were collected from the five MBRs, and 16S rRNA gene sequencing was applied to investigate the bacterial communities of AS and membrane biofilms (early and mature). Alpha and beta diversity measures revealed clear differences in the bacterial community structure between the AS and biofilm (early and mature) samples in the five full-scale MBRs. These differences were mainly due to the presence of large number of unique but rare operational taxonomic units (~13% of total reads in each MBR) in each sample. In contrast, a high percentage (~87% of total reads in each MBR) of sequence reads was shared between AS and biofilm samples in each MBR, and these shared sequence reads mainly belong to the dominant taxa in these samples. Despite the large fraction of shared sequence reads between AS and biofilm samples, simulated biofilm communities from random sampling of the respective AS community revealed that biofilm communities differed significantly from the random assemblages (P < 0.001 for each MBR), indicating that the biofilm communities (early and mature) are unlikely to represent a random sample of the AS community. In addition to the presence of unique operational taxonomic units in each biofilm sample (early or mature), comparative analysis of operational taxonomic units and genera revealed the presence of a core biofilm community in the five full-scale MBRs. These findings provided insight into the membrane biofilm communities in full-scale MBRs. More comparative studies are needed in the future to elucidate the factors shaping the core and unique biofilm communities in full-scale MBRs. PMID- 28658634 TI - Dietary human exposure to mercury in two artisanal small-scale gold mining communities of northwestern Colombia. AB - Artisanal and small-scale gold mining (ASGM) is the largest anthropogenic source of mercury pollution worldwide, posing a grave threat to human health. The present study identifies current levels of mercury in the human population from mining areas of the Choco Department, Colombia, through total mercury (THg) and methylmercury (MeHg) measurements in human hair. Mercury exposure of the local population was assessed in two towns affected by ASGM and was related to different variables of interest. Concentrations of THg in human hair ranged from 0.06 to 17.54ppm and the mean value for the subjects under study was 2.48ppm. Men had significantly higher levels than women in both towns (3.29ppm vs. 0.77ppm). Fish consumption was related to a marked increase of THg in hair, with mean values close to five times higher in frequent fish consumers (5-7 times/week) than in non-fish consumers (4.80ppm vs. 0.90ppm). A multiple linear regression model was fitted successfully (R=0.671) and reveals that gender, fish consumption and location of residence were significant indicators of Hg levels in hair, while no significant relationship was found for age. Approximately 60% of subjects tested had THg levels that exceeded the U.S. Environmental Protection Agency reference dose of 1.0ppm, while 25% surpassed that of the World Health Organization (2.2ppm). PMID- 28658635 TI - Adipose-derived stem cell sheets functionalized by hybrid baculovirus for prolonged GDNF expression and improved nerve regeneration. AB - Peripheral nerve regeneration requires coordinated functions of supporting cells (e.g. Schwann cells) and neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF), but nerve regeneration is usually far from complete. Here we constructed a Cre/loxP-based hybrid baculovirus (BV) vector which enabled intracellular formation of episomal DNA minicircle for effective transduction of rat adipose-derived stem cells (ASCs) and prolonged expression of functional GDNF capable of recruiting Schwann cells. The GDNF expression persisted for >20 days with the peak level (~128 ng/ml) tremendously exceeding the picogram levels of GDNF secreted by neuroprogenitor cells. We further developed a facile method to fabricate and transduce cell sheets composed of undifferentiated ASCs in 2 days, without the need of thermo-responsive polymer commonly used for cell sheet fabrication. Implantation of the hybrid BV-engineered, GDNF-expressing ASCs sheets into sciatic nerve transection site in rats significantly improved the nerve repair, as judged from the enhanced functional recovery, nerve reinnervation, electrophysiological functionality, Schwann cells proliferation/infiltration, axon regeneration, myelination and angiogenesis. The hybrid BV is able to functionalize ASCs sheets by intracellular episomal DNA minicircle formation that circumvents undesired gene integration, and the ASCs sheets fabrication is rapid and simple. These data and features implicate the potentials of ASCs sheets functionalized by the hybrid BV for peripheral nerve regeneration. PMID- 28658636 TI - Emission factors and congener-specific characterization of PCDD/Fs, PCBs, PBDD/Fs and PBDEs from an off-road diesel engine using waste cooking oil-based biodiesel blends. AB - Few studies have been performed up to now on the emission factors and congener profiles of persistent organic pollutants (POPs) emitted from off-road diesel engines. This investigation elucidates the emission factors and congener profiles of various POPs, namely polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyl (PCBs), polybrominated dibenzo-p-dioxins and polybrominated dibenzofurans (PBDD/Fs) and polybrominated diphenyl ethers (PBDEs), in the exhausts of a diesel generator fueled with different waste cooking oil-based biodiesel (WCO-based biodiesel) blends. The PCDD/Fs contributed 87.2% of total dioxin-like toxicity (PCDD/Fs+PCBs+PBDD/Fs) in the exhaust, while the PCBs and PBDD/Fs only contributed 8.2% and 4.6%, respectively. Compared with petroleum diesel, B20 (20vol% WCO-based biodiesel+80vol% diesel) reduced total toxicity by 46.5% for PCDD/Fs, 47.1% for PCBs, and 24.5% for PBDD/Fs, while B40 (40vol% WCO-based biodiesel+60vol% diesel) reduced it by 89.5% for PCDD/Fs, 57.1% for PCBs, and 63.2% for PBDD/Fs in POP emission factors. The use of WCO-based biodiesel not only solves the problem of waste oil disposal, but also lowers POP emissions from diesel generators. PMID- 28658637 TI - Assessing multigenerational effects of prednisolone to the freshwater snail, Physa acuta (Gastropoda: Physidae). AB - Prednisolone (PDS), a potent synthetic glucocorticoid is widely prescribed for its exceptional anti-inflammatory properties. Several studies have detected the environmental presence of PDS in water bodies which has led to an ecological concern for its toxicity to non-target aquatic biota. The present study investigated the effects of exposure to PDS on different life-cycle stages and generations of the freshwater snail, Physa acuta. This continuous exposure over a period of multiple generations resulted in generational impairments at measured endpoints. LOEC values (p<0.001) for PDS exposure ranged from 32 to 4MUg/L in exposed F0-F2 generations. Global DNA methylation (% 5-methyl cytosine) of adult progeny was found to be affected at higher test concentrations in comparison to the parent snails. Partially formed to completely missed growth components of shell structure and shell thinning in abnormally underdeveloped PDS exposed snails of F1 and F2 generation, was also observed in this multigenerational exposure experiment. The multigenerational study confirmed P. acuta as a promising bioindicator since critical effects of the long term glucocorticoid exposure opens up the way for further investigations on transgenerational toxicity in environmental toxicology and risk assessment and to monitor glucocorticoid pollution in aqueous ecosystem. PMID- 28658638 TI - Soil attenuation of the seepage potential of metallic elements (Cu, Zn, As(V), Cd, and Pb) at abandoned mine sites: A batch equilibrium sorption and seepage column study. AB - Soil attenuation of off-site leaching potential of metallic elements at the two abandoned mine sites was investigated using batch sorption and layered column studies. In batch study, the leachate concentration-specific sorption (Kd*) by downgradient clean soils was in the order of Pb>Cu>Cd>Zn>As for DY site and Pb>As>Cu>Cd>Zn for BS site. In the layered (mine+clean) soil column, element elution was significantly reduced (e.g., no initial flush, retarded peak arrival, and lower peak concentration) while sulfate elution can be an indicator of the dissolution of sulfur-bearing minerals in mine soils. The greatest reduction was observed for Pb and Cu while the lowest was for Cd (2-19%) and Zn (6-51%), consistent with the batch data. Both the reduced elution at slow seepage and concentration drop after flow interruption support the time-limited propensity. In column segments, the sorptive elements (Cu, Pb, and As) were dominantly found in the inlet while less sorptive ones (Zn and Cd) in the outlet. Both batch and column data suggest that the element leaching with mine leachate movement can be greatly attenuated by the interactions with the surrounding downgradient soil during the seepage process. PMID- 28658632 TI - Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. PMID- 28658639 TI - Experimental evaluation and analysis of methane fire and explosion mitigation using isolation valves integrated with a vent system. AB - There has been a surge of interest from the extractive industries in the application of mechanical means to the mitigation of flame deflagration. To verify the implementation and performance of passive and active mitigation protection, a comprehensive experimental investigation has been conducted on a large scale detonation tube, 30m long and 0.5m in diameter, with two mitigation valves (passive and active) and a burst panel venting system. The valves were used alternately to mitigate the flame deflagration of methane in concentrations ranging from 1.25% to 7.5%. The experimental work revealed that locating the passive mitigation valve at 22m distance from the ignition source mitigates the flame by fully isolating the tube. However, closing the valve structure in the axial direction generated another pressure wave upstream, which was approximately the same value as for the original pressure wave upstream. In the case of the active mitigation system, the system perfectly isolated upstream from downstream with no further pressure wave generation. When the vent was located at 6.5m from the ignition source, the total pressure was reduced by 0.48bar. Due to the counter flow of the reflected pressure wave the flame was extinguished at 12.5m from the ignition source. PMID- 28658640 TI - Biogenic manganese oxides generated by green algae Desmodesmus sp. WR1 to improve bisphenol A removal. AB - Biogenic manganese oxides (BioMnOx) have attracted considerable attention as active oxidants, adsorbents, and catalysts. This study investigated the characteristics of algae-generated BioMnOx and determined its oxidative activity towards bisphenol A (BPA), an endocrine disrupter. Amorphous nanoparticles with a primary Mn valency of +3 were found in BioMnOx produced by Desmodesmus sp. WR1. The mechanism might be that algal growth created conditions favorable to Mn oxidation through increasing DO and pH. Initial Mn2+ concentrations of 6, 30, and 50mgL-1 produced a maximum of 5, 13, and 11mgL-1 of BioMnOx, respectively. Mn2+ enriched cultures exhibited the highest BPA removal efficiency (~78%), while controls only reached about 27%. BioMnOx may significantly promote BPA oxidation in algae culture, enhancing the accumulation of substrates for glycosylation. Moreover, continuous BioMnOx increase and Mn2+ decrease during BPA oxidation confirmed Mn oxide regeneration. In conclusion, Mn oxide formation by microalgae has the potential to be used for environmental remediation. PMID- 28658641 TI - Enhanced anaerobic degradability of highly polluted pesticides-bearing wastewater under thermophilic conditions. AB - This work presents a sustainable and cost-competitive solution for hardly biodegradable pesticides-bearing wastewater treatment in an anaerobic expanded granular sludge bed (EGSB) reactor at mesophilic (35 degrees C) and thermophilic (55 degrees C). The reactor was operated in continuous mode during 160days, achieving an average COD removal of 33 and 44% under mesophilic and thermophilic conditions, respectively. The increase of temperature improved the biomass activity and the production of methane by 35%. Around 96% of pesticides identified in raw wastewater were not detected in both mesophilic and thermophilic effluents. A dramatic selection of the microbial population in anaerobic granules was caused by the presence of pesticides, which also changed significantly when the temperature was increased. Pesticides caused a significant inhibition on methanogenesis, especially over acetoclastic methanogens. Aerobic biodegradability tests of the resulting anaerobic effluents revealed that aerobic post-treatment is also a feasible and effective option, yielding more than 60% COD reduction. PMID- 28658643 TI - Implicit assumptions underlying simple harvest models of marine bird populations can mislead environmental management decisions. AB - Assessing the potential impact of additional mortality from anthropogenic causes on animal populations requires detailed demographic information. However, these data are frequently lacking, making simple algorithms, which require little data, appealing. Because of their simplicity, these algorithms often rely on implicit assumptions, some of which may be quite restrictive. Potential Biological Removal (PBR) is a simple harvest model that estimates the number of additional mortalities that a population can theoretically sustain without causing population extinction. However, PBR relies on a number of implicit assumptions, particularly around density dependence and population trajectory that limit its applicability in many situations. Among several uses, it has been widely employed in Europe in Environmental Impact Assessments (EIA), to examine the acceptability of potential effects of offshore wind farms on marine bird populations. As a case study, we use PBR to estimate the number of additional mortalities that a population with characteristics typical of a seabird population can theoretically sustain. We incorporated this level of additional mortality within Leslie matrix models to test assumptions within the PBR algorithm about density dependence and current population trajectory. Our analyses suggest that the PBR algorithm identifies levels of mortality which cause population declines for most population trajectories and forms of population regulation. Consequently, we recommend that practitioners do not use PBR in an EIA context for offshore wind energy developments. Rather than using simple algorithms that rely on potentially invalid implicit assumptions, we recommend use of Leslie matrix models for assessing the impact of additional mortality on a population, enabling the user to explicitly define assumptions and test their importance. PMID- 28658642 TI - Folic acid conjugated polymeric micelles loaded with a curcumin difluorinated analog for targeting cervical and ovarian cancers. AB - The current study utilizes folic acid conjugated poly(styrene-co-maleic anhydride) block copolymer (FA-SMA) to enhance the solubility of a hydrophobic but very potent synthetic curcumin-difluorinated (CDF) analog and its targeted delivery to folate receptor-alpha overexpressing cancers. The nanomicelles showed high aqueous solubility. Importantly, the encapsulation of CDF in nanomicelles resulted in high photo-stability of the otherwise photo-labile drug. When the nanomicelles were tested in folate-receptor overexpressing ovarian and cervical cancer cells they exhibited high anticancer activity causing significant cell population to undergo apoptosis due to upregulation of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibition of nuclear factor kappa-B (NFkappaB), which further confirmed the targeting ability and anticancer potentials of folate-targeted formulations. PMID- 28658644 TI - EGCG inhibits the oligomerization of amyloid beta (16-22) hexamer: Theoretical studies. AB - An extensive replica exchange molecular dynamics (REMD) simulation was performed to investigate the progress patterns of the inhibition of (-)-epigallocatechin-3 gallate (EGCG) on the Abeta16-22 hexamer. Structural variations of the oligomers without and with EGCG were monitored and analyzed in detail. It has been found that EGCG prevents the formation of Abeta oligomer through two different ways by either accelerating the Abeta oligomerization or reducing the beta-content of the hexamer. It also decreases the potential "highly toxic" conformations of Abeta oligomer, which is related to the conformations having high order beta-sheet sizes. Both electrostatic and van der Waals interaction energies are found to be involved to the binding process. Computed results using quantum chemical methods show that the pi-pi stacking is a critical factor of the interaction between EGCG and the peptides. As a result, the binding free energy of the EGCG to the Abeta peptides is slightly larger than that of the curcumin. PMID- 28658645 TI - Bioresponsive interfaces composed of calmodulin and poly(ethylene glycol): Toggling the interfacial film thickness by protein-ligand binding. AB - Responsive interfaces are often realized by polymer films that change their structure and properties upon changing the pH-value, ionic strength or temperature. Here, we present a bioresponsive interfacial structure that is based on a protein, calmodulin (CaM), which undergoes a huge conformational change upon ligand binding. At first, we characterize the conformational functionality of a double Cys mutant of CaM by small-angle X-ray scattering (SAXS) and Fourier transform infrared (FTIR) spectroscopy. The CaM mutant is then used to cross-link poly(ethylene glycol) (PEG) chains, which are bound covalently to a supporting planar Si surface. These films are characterized by X-ray reflectometry (XR) in a humidity chamber providing full hydration. It is well known that Ca2+-saturated holo-CaM binds trifluoperazine (TFP) and changes its conformation from an open, dumbbell-shaped to a closed, globular one in solution. At the interface, we observe an increase of the PEG-CaM film thickness, when TFP is binding and inducing the closed conformation, whereas the removal of Ca2+-ions and a concomitant release of TFP is associated with a decrease of the film thickness. This toggling of the film thickness is largely reversible. In this way, a structural change of the interface is achieved via protein functionality which has the advantage of being selective for ligand molecules without changing the environmental conditions in a harsh way via physico-chemical parameters. PMID- 28658646 TI - Help me if I can't: Social interaction effects in adult contextual word learning. AB - A major challenge in second language acquisition is to build up new vocabulary. How is it possible to identify the meaning of a new word among several possible referents? Adult learners typically use contextual information, which reduces the number of possible referents a new word can have. Alternatively, a social partner may facilitate word learning by directing the learner's attention toward the correct new word meaning. While much is known about the role of this form of 'joint attention' in first language acquisition, little is known about its efficacy in second language acquisition. Consequently, we introduce and validate a novel visual word learning game to evaluate how joint attention affects the contextual learning of new words in a second language. Adult learners either acquired new words in a constant or variable sentence context by playing the game with a knowledgeable partner, or by playing the game alone on a computer. Results clearly show that participants who learned new words in social interaction (i) are faster in identifying a correct new word referent in variable sentence contexts, and (ii) temporally coordinate their behavior with a social partner. Testing the learned words in a post-learning recall or recognition task showed that participants, who learned interactively, better recognized words originally learned in a variable context. While this result may suggest that interactive learning facilitates the allocation of attention to a target referent, the differences in the performance during recognition and recall call for further studies investigating the effect of social interaction on learning performance. In summary, we provide first evidence on the role joint attention in second language learning. Furthermore, the new interactive learning game offers itself to further testing in complex neuroimaging research, where the lack of appropriate experimental set-ups has so far limited the investigation of the neural basis of adult word learning in social interaction. PMID- 28658647 TI - Quaternion-based disorientation coloring of orientation maps. AB - The authors of the present work propose a color coding technique using quaternions for the display of crystallographic orientation data such as EBSD maps. The main difference to existing color coding techniques in this field is that it creates a color space, within which the perceived color differences are approximately proportional to Euclidean distances in the corresponding 3D quaternion vector space, and thus approximately proportional to mutual disorientation angles. Since all disorientation parameters (axis and angle pairs, but represented as quaternions) are taken into account, color ambiguities appearing in maps created by other techniques are successfully avoided, and the sub-grain orientation differences within grains can be unambiguously visualized. PMID- 28658649 TI - Simultaneous ocular and muscle artifact removal from EEG data by exploiting diverse statistics. AB - Electroencephalography (EEG) recordings are frequently contaminated by both ocular and muscle artifacts. These are normally dealt with separately, by employing blind source separation (BSS) techniques relying on either second-order or higher-order statistics (SOS & HOS respectively). When HOS-based methods are used, it is usually in the setting of assuming artifacts are statistically independent to the EEG. When SOS-based methods are used, it is assumed that artifacts have autocorrelation characteristics distinct from the EEG. In reality, ocular and muscle artifacts do not completely follow the assumptions of strict temporal independence to the EEG nor completely unique autocorrelation characteristics, suggesting that exploiting HOS or SOS alone may be insufficient to remove these artifacts. Here we employ a novel BSS technique, independent vector analysis (IVA), to jointly employ HOS and SOS simultaneously to remove ocular and muscle artifacts. Numerical simulations and application to real EEG recordings were used to explore the utility of the IVA approach. IVA was superior in isolating both ocular and muscle artifacts, especially for raw EEG data with low signal-to-noise ratio, and also integrated usually separate SOS and HOS steps into a single unified step. PMID- 28658648 TI - Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient Derived Xenografts. AB - Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX) or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID) mice from Epstein-Barr virus (EBV)-infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patient's ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45 positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab) to 5.6% (n = 160 with rituximab), and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth. PMID- 28658651 TI - An IR investigation of solid amorphous ethanol - Spectra, properties, and phase changes. AB - Mid- and far-infrared spectra of condensed ethanol (CH3CH2OH) at 10-160K are presented, with a special focus on amorphous ethanol, the form of greatest astrochemical interest, and with special attention given to changes at 155-160K. Infrared spectra of amorphous and crystalline forms are shown. The refractive index at 670nm of amorphous ethanol at 16K is reported, along with three IR band strengths and a density. A comparison is made to recent work on the isoelectronic compound ethanethiol (CH3CH2SH), and several astrochemical applications are suggested for future study. PMID- 28658650 TI - The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors. AB - BACKGROUND AND AIM: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study. METHODS AND MATERIAL: Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup. RESULTS: One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + (P = .030), positive M status (P < .001), and lymph node ratio (LNR) > 0.1 (P = .045) to impair overall survival. Independent prognostic factors were CAF grade (P = .050) and positive M status (P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = -0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation-dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs. CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies. PMID- 28658652 TI - Beyond differences between the body schema and the body image: insights from body hallucinations. AB - The distinction between the body schema and the body image has become the stock in trade of much recent work in cognitive neuroscience and philosophy. Yet little is known about the interactions between these two types of body representations. We need to account not only for their dissociations in rare cases, but also for their convergence most of the time. Indeed in our everyday life the body we perceive does not conflict with the body we act with. Are the body image and the body schema then somehow reshaping each other or are they relatively independent and do they only happen to be congruent? On the basis of the study of bodily hallucinations, we consider which model can best account for the body schema/body image interactions. PMID- 28658653 TI - Perceived need for restrictions on activity for children with epilepsy. AB - BACKGROUND: Children and youth with epilepsy have long been subjected to excessive restrictions on extracurricular activities due to concerns over risk of injury. Over time physicians and medical regulatory associations have liberalized the advice given for people with epilepsy to promote independence, self-esteem and general health benefits of physical activity. Current evidence suggests that few restrictions are needed for children with epilepsy beyond water-related precautions and avoidance of very high-risk activities. However, more stringent restrictions on daily activities may be imposed by caregivers. This study was aimed at exploring current perceptions of parents regarding restrictions on activity for children with epilepsy and the child's perspective on restrictions related to the diagnosis. METHODS: A self-administered questionnaire was offered to a sample of parent-child dyads of children/youth with epilepsy attending summer camp for children with epilepsy age 8-18years. A 10-item validated HARCES Parent Scale of Childhood Epilepsy was completed by the parent/guardian and a modified-HARCES completed by the child. The primary objective was to assess the degree of restrictions placed on children with epilepsy from the perspective of child and parent assessed independently. Agreement of perceived restrictions between parent-child dyads was also determined. RESULTS: 21 parent/guardian-child pairs were recruited with mean age of children/youth 12.7years (range 9-16years). Total HARCES scores for parents and guardians ranged from 11-26 (x=16.5; SD 4.9) while total scores for children with epilepsy similarly ranged from 10-25 (x=15.2; SD 4.9). There were no differences in total parent scores when analyzed by child's age (<13 or >13years), gender, age of seizure onset, seizure frequency or seizure type. Total HARCES scores showed no agreement between parent and child pairs with correlation of 0.2798 (95% CI -0.173-0.635). CONCLUSIONS: Children and youth with epilepsy often face activity restrictions based on fear of perceived risk of injury. This small sample shows evidence that even more permissive parents and his/her children still feel limited by such restrictions. Parents and children do not perceive these restrictions in the same way despite similar education by physicians highlighting an important secondary role of epilepsy camps in targeting misperceptions and educating families on appropriate precautions. PMID- 28658654 TI - Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: A TBI Model Systems analysis. AB - PURPOSE: Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk. However, MH relationships to post traumatic epilepsy (PTE) have not been explored. Thus, the objective of this study was to assess associations between PTE and frequency of depression and/or anxiety in a cohort of individuals with moderate-to-severe TBI who received acute inpatient rehabilitation. METHODS: Multivariate regression models were developed using a recent (2010-2012) cohort (n=867 unique participants) from the TBI Model Systems (TBIMS) National Database, a time frame during which self-reported seizures, depression [Patient Health Questionnaire (PHQ)-9], and anxiety [Generalized Anxiety Disorder (GAD-7)] follow-up measures were concurrently collected at year-1 and year-2 after injury. RESULTS: PTE did not significantly contribute to depression status in either the year-1 or year-2 cohort, nor did it contribute significantly to anxiety status in the year-1 cohort, after controlling for other known depression and anxiety predictors. However, those with PTE in year-2 had 3.34 times the odds (p=.002) of having clinically significant anxiety, even after accounting for other relevant predictors. In this model, participants who self-identified as Black were also more likely to report clinical symptoms of anxiety than those who identified as White. PTE was the only significant predictor of comorbid depression and anxiety at year-2 (Odds Ratio 2.71; p=0.049). CONCLUSIONS: Our data suggest that PTE is associated with MH outcomes 2years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition. PMID- 28658655 TI - Continuous thermal control of hydrophilicity/hydrophobicity changes of hybrid films and of their directionality: Kinetics and substrate effects. AB - A successful methodology for obtaining hybrid films which allow thermal triggering and continuous, irreversible, control of their hydrophilicity/hydrophobicity nature was developed. Two types of poly(dimethylsiloxane)-silica (PDMS@SiO2) films were prepared for that purpose: A hydrophilic film in which the thermal treatment causes an irreversible gradual increase of hydrophobicity; and a hydrophobic film that turns more hydrophilic upon thermal treatment. The opposite directionality of the change is dictated by the film substrate, on which the same hybrid is deposited. In both cases the thermal treatment induced a phase separation which caused the change in hydrophobicity. The magnitude of change in hydrophilicity/hydrophobicity is continuously controllable in both types of films by either the temperature or heating time. The films were characterized before and after heating by a variety of methods, including contact angle (CA) measurements with the sessile drop and the tilting plate methods, and by X-ray photoelectron spectroscopy (XPS) analysis. A thorough kinetic study was carried out, following the progress of the changes in the wettability property of the surfaces. The kinetics analyses proved that the changes in the wettability in all cases are due to phase separation processes, the directionality of which is determined by the treatment of the substrate on which the films are deposited. By monitoring the change of wettability (DeltaCA) at various temperatures, an Arrhenius plot was obtained from which the activation energy and Arrhenius pre-exponential factor for the phase separation were derived, corroborating the proposed mechanism. To the best of our knowledge, this is the first use of phase separation behavior of a hybrid film in order to apply irreversible, thermally controllable change of surface wettability, tailored to proceed in opposite directions, and the first kinetic study of such a process. PMID- 28658656 TI - Solubility products of sparingly soluble barium perborates in aqueous solution that contains B(OH)3 and H2O2 at 25 degrees C. AB - Chemical oxo-precipitation (COP) has become a promising method for treating boron wastewater at room temperature; it uses hydrogen peroxide to convert boric acid to perborate species, which are precipitated using alkaline earth metals. In this work, solubility models of barium perborates were established to predict residual boron levels from COP. The solubility product constants (pKsp) of two major barium perborates - amorphous Ba(B(OH)3OOH)2 (A-BaPB) and crystalline BaB(OH)2(OO)2B(OH)2 (C-BaPB) - were experimentally estimated (8.335+/-0.109 and 9.190+/-0.057, respectively) to define the solubility curves of BaPBs at given pH, ionic strength and concentrations of barium and peroxide species. The characterization of precipitates that were formed by COP confirmed that the boron levels in aqueous solution were governed by the phase transformation of A-BaPB to C-BaPB. The predictive solubility models of barium perborates can perfectly predict the residual concentration of boron after COP treatment and can be used to optimize the process for reducing boron concentrations in wastewater. PMID- 28658657 TI - Acute stress in residents playing different roles during emergency simulations: a preliminary study. AB - Objectives: To investigate acute stress response in residents playing nurse and physician roles during emergency simulations. Methods: Sixteen second-year internal medicine residents participated in teams of four (two playing physician roles and two playing nurse roles). Stress markers were assessed in 24 simulations at baseline (T1) and immediately after the scenario (T2), using heart rate, systolic and diastolic blood pressure, salivary alpha-amylase, salivary cortisol and salivary interleukin-1beta. The State-Trait Anxiety Inventory was applied at T2. Continuous data were summarized for the median (1st-3rd interquartile ranges), and the Mann-Whitney U Test was used to compare the groups. Results: The percent variations of the stress markers in the physician and nurse roles, respectively, were the following: heart rate: 70.5% (46.0-136.5) versus 53.0% (29.5-117.0), U=89.00, p=0.35; systolic blood pressure: 3.0% (0.0 10.0) versus 2.0% (-2.0-9.0), U=59.50, p=0.46; diastolic blood pressure: 5.5% (0.0-13.5) versus 0.0% (0.0-11.5), U=91.50, p=0.27; alpha-amylase: -5.35% (-62.70 73.90) versus 42.3% (12.4-133.8), U=23.00, p=0.08; cortisol: 35.3% (22.2-83.5) versus 42.3% (12.4-133.8), U=64.00, p=0.08); and interleukin-1beta: 54.4% (21.9 109.3) versus 112.55% (29.7-263.3), U= 24.00, p=0.277. For the physician and nurse roles, respectively, the average heart rate was 101.5 (92.0-104.0) versus 91.0 (83.0-99.5) beats per minute, U=96.50, p=0.160; and the state anxiety inventory score was 44.0 (40.0-50.0) versus 42.0 (37.50-48.0) points, U= 89.50, p=0.319. Conclusions: Different roles during emergency simulations evoked similar participants' engagement, as indicated by acute stress levels. Role-play strategies can provide high psychological fidelity for simulation-based training, and these results reinforce the potential of role-play methodologies in medical education. PMID- 28658674 TI - Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFkappaB. AB - Sepsis is a severe systemic inflammatory response to infection. Endothelial activation and dysfunction play a critical role in the pathophysiology of sepsis and represent an important therapeutic target to reduce sepsis mortality. Interferon regulatory factor 1 (IRF-1) was recently identified as a downstream target of TNF-alpha-mediated signal transduction in endothelial cells. The aim of this study was to explore the importance of IRF-1 as a regulator of lipopolysaccharide (LPS)-induced endothelial proinflammatory activation. We found that renal IRF-1 was upregulated by LPS in vivo as well as in LPS-stimulated endothelial cells in vitro. Furthermore, we identified intracellular retinoic acid inducible gene-I (RIG-I) as a regulator of LPS-mediated IRF-1 induction. IRF 1 depletion specifically resulted in diminished induction of VCAM-1 in response to LPS, but not of E-selectin or ICAM-1, which was independent of NFkappaB signaling. When both IRF-1 and the RIG-I adapter protein mitochondrial antiviral signaling (MAVS) were absent, VCAM-1 induction was not additionally inhibited, suggesting that MAVS and IRF-1 reside in the same signaling pathway. Surprisingly, E-selectin and IL-6 induction were no longer inhibited by MAVS knockdown when IRF-1 was also absent, revealing a redundant endothelial activation pathway. In summary, we report an IRF-1-mediated proinflammatory signaling pathway that specifically regulates LPS-mediated VCAM-1 expression, independent of NFkappaB. PMID- 28658675 TI - Caries Experience in Children with and without Molar-Incisor Hypomineralisation: A Case-Control Study. AB - AIM: The aim of this study was to compare the caries experience of children with and without molar-incisor hypomineralisation (MIH). METHODS: A case-control study was designed in which 130 children aged between 7 and 13 years with MIH (cases) were matched with 130 children without the condition (controls) according to age, sex, and school. Dental caries and MIH were assessed using the Caries Assessment Spectrum and Treatment (CAST) and European Academy of Paediatric Dentistry (EAPD) criteria, respectively, by three examiners. CAST was converted into DMFT/dmft; the Kruskal-Wallis test was performed to analyse whether dmft/DMFT was influenced by the severity of MIH. Associations between MIH and dental caries were analysed at child and tooth levels: between and within subjects, respectively. To correlate MIH severity and the occurrence of dental caries, the Cochran-Armitage test was used. RESULTS: The mean age of the children was 9.63 +/- 1.29 years. The mean dmft for cases was 1.23 +/- 1.99 and for controls 1.71 +/- 2.22 (p > 0.05). For the DMFT, the mean scores for cases and controls were 0.45 +/- 0.90 and 0.07 +/- 0.25, respectively (p < 0.001). The between-subject analysis showed no difference in relation to enamel carious lesions; however, the prevalence of dentine carious lesions was significantly higher in children with MIH than in those without the condition. The same pattern was seen for the within-subject analysis. It was observed that the increase in MIH severity resulted in more teeth being affected by dentine carious lesions (p = 0.0003). CONCLUSION: Children with MIH presented a higher experience of caries in the permanent dentition than those without the condition. MIH was considered a risk factor for caries development. PMID- 28658676 TI - A Novel Homozygous SACS Mutation Identified by Whole-Exome Sequencing in a Consanguineous Family with Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a hereditary neurological disorder mostly manifested with a classical triad: progressive early-onset cerebellar ataxia, lower limb pyramidal signs, and peripheral neuropathy. We employed whole-exome sequencing and bioinformatics to identify the genetic cause in an ARSACS patient from a consanguineous family. Based on whole-exome sequences of the patient and her healthy parents, a novel homozygous deletion variant (NM_014363: c.9495_9508del; p.F3166Tfs*9) in the SACS gene was identified in the patient. This frameshift mutation is predicted to generate a truncated sacsin protein, which results in the loss of the C-terminal 1,406 amino acids. Our study provides a potential genetic diagnosis for the patient and expands the spectrum of SACS mutations. PMID- 28658677 TI - Similar but Different: How Reflectance Confocal Microscopy May Help in the Diagnosis of Pink Lesions. AB - BACKGROUND: Among skin neoplasms, solitary pink tumors represent challenging lesions in clinical practice since they can mimic melanocytic and nonmelanocytic lesions or even inflammatory ones. OBJECTIVE: In this case series we described dermoscopic and confocal features of 2 couples of similar lesions in order to achieve the correct diagnosis and the best therapeutic approach. METHODS: During clinical routine practice, 2 couples of clinically and dermoscopically similar lesions were examined by means of confocal microscopy. RESULTS: All lesions revealed no clear-cut diagnostic features on dermoscopy. However, confocal microscopy revealed tumor islands with palisading cells and a dark clefting at the periphery in basal cell carcinomas. In the other "false twin" lesions, atypical cells and elongated junctional nests were observed and the diagnosis of amelanotic melanomas was rendered. CONCLUSIONS: In the current case series, the combined use of dermoscopy and reflectance confocal microscopy was an optimal workup for difficult-to-diagnose lesions such as pink tumors. PMID- 28658678 TI - Revisiting Communicative Competence in Augmentative and Alternative Communication. AB - OBJECTIVE: This tutorial paper is to explore the novel nature of communicative competence in augmentative and alternative communication (AAC) practice by comparing it to communicative competence in naturally verbal dyadic communication. PATIENTS AND METHODS: This paper first reviews the four domains of communicative competence in AAC practice. Second, it examines competence in dyadic communications between naturally verbal people without disabilities, deriving new insights and using these to analyze the evolution of communicative competence in AAC practice. RESULTS: Communicative competence in AAC practice should be reconceptualized from a new perspective as dyadic, learned, co constructed, and of relative value, ascertained through performance. CONCLUSION: In the past decades, the study of communicative competence in AAC practice has primarily focused on individual persons who use AAC. However, the conceptualization of communicative competence should shift away from an individualized construct toward a dyadic construct. This leads to a discussion of potential implications and future research directions. This paper might offer AAC researchers and practitioners an opportunity to deepen their understanding of communicative competence and promote more positive outcomes for people who use AAC. PMID- 28658679 TI - Modified submucosal tunneling endoscopic resection for submucosal tumors in the esophagus and gastric fundus near the cardia. AB - Background and study aims Submucosal tunneling endoscopic resection with double opening (DO-STER) was developed by our group for the resection of submucosal tumors in the esophagus and gastric fundus near the cardia. This study aimed to provide a preliminary evaluation of feasibility and safety of DO-STER. Methods The key to DO-STER is the creation of a tunnel opening in the mucosa over the inferior border of the tumor. During resection, the tumor can be gradually pushed out of the submucosal tunnel through the opening, leaving enough space for operation within the tunnel. A total of 10 tumors resected by DO-STER were retrospectively reviewed. Results All tumors were successfully resected by DO STER. One tumor was located at the lower esophagus, four at the esophagogastric junction, and five at the gastric fundus near the cardia. Tumor size ranged from 1.0 * 1.2 cm to 3.5 * 5.0 cm, and all tumors originated from the muscularis propria. Operative times ranged from 45 to 150 minutes. No delayed bleeding or perforation occurred. Conclusion DO-STER seems to provide an alternative approach for resection of tumors in the esophagus and gastric fundus near the cardia. PMID- 28658681 TI - [Status of Selective Laser Trabeculoplasty (SLT)]. AB - Purpose Worldwide, in recent years, selective laser trabeculoplasty (SLT) has developed into a very successful therapy for glaucoma. Material and Methods The article provides a review of the literature from PubMed and clinical experience. Results SLT is equally efficacious to argon laser trabeculoplasty (ALT) and to a first-line glaucoma medication. SLT can be used in most common forms of open angle glaucoma and ocular hypertension. In contrast to ALT, SLT is repeatable and requires much less energy. SLT has been reported to be also successful in some rare forms of ocular hypertension/glaucoma. There is no negative influence of SLT to other forms of glaucoma treatment. Complications are rare and include intraocular pressure spikes, corneal scarring or corneal decompensation due to endothelial cell damage and cystoid macular edema. The potential of SLT as a first-line treatment of glaucoma is now under investigation. Conclusion SLT is a low-risk procedure to treat glaucoma in a broad range of indications. Advantages of SLT include the potential to use SLT more and more as a primary treatment procedure. Therefore, SLT is now under intensive investigation worldwide. PMID- 28658680 TI - Submucosal fibrosis in achalasia patients is a rare cause of aborted peroral endoscopic myotomy procedures. AB - Background and aims Peroral endoscopic myotomy (POEM) is now an established treatment for esophageal achalasia. The standard protocol ensures a smooth operation in most patients, but technical challenges and failures exist and little is known about the incidence, causes, and impact of aborted procedures. Here, using a large patient cohort, we attempted to answer these questions. Methods All patients admitted for planned POEM between August 2010 and July 2015 underwent chart review. Aborted POEM was defined as the inability to finish the procedure after submucosal injection. The cause of the failure, clinical course, management, and follow-up data were analyzed. Results Thirteen of the 1693 POEMs (0.77 %) were aborted. Out of the 13 failures, 12 (92.3 %) were due to severe submucosal fibrosis, which precluded tunneling, and one (7.7 %) was due to atrial fibrillation related to the electric current of the endoscopic knife. Submucosal fibrosis, prior Heller myotomy, and age ( >= 60 years) were related to technical failure, while a disease duration of >= 6 years, sigmoid esophagus, mucosal edema, and prior interventions were risk factors for the presence of fibrotic changes. In turn, fibrosis was correlated with a prolonged operation, longer hospital stay, more mucosal injuries, and more major perioperative adverse events. Finally, the yearly frequency of aborted POEMs decreased after the second year as operators became more experienced. Conclusions Aborted POEM is a rare event and is largely due to the presence of submucosal fibrosis, which not only causes increased procedural difficulties, but also gives rise to major adverse events. PMID- 28658683 TI - High Tibial Osteotomy following Biologic Replacement of the Knee. PMID- 28658682 TI - Variceal Bleeds in Patients with Biliary Atresia. AB - INTRODUCTION: Portal hypertension often occurs in biliary atresia (BA). The subsequent development of esophageal varices and bleeding from these varices are a well-known complication. We aim to describe the incidence and severity of variceal bleeding in patients with BA. In addition, we describe the characteristics of patients who experienced variceal bleeds. MATERIALS AND METHODS: We included all infants treated for BA at our center between March 1987 and August 2015. Variceal bleeding was defined as hematemesis and/or melena with presence of varices at endoscopy. Findings at endoscopy and ultrasound, laboratory tests, clearance of jaundice, fibrosis-grade at Kasai portoenterostomy, and several varices prediction scores were documented. Routine endoscopies were not performed. RESULTS: In this study, 74 patients were included. During follow-up, 18 out of 74 patients (24%) developed variceal bleeding at an age of 9 months (range, 4-111). Twelve patients were listed for liver transplantation at the time of bleeding. Patients who did not clear their jaundice developed variceal bleeds more often and earlier in life. Bleeds were treated with sclerotherapy, banding, or octreotide. Four patients did not receive treatment. No bleeding-related mortality occurred. CONCLUSION: One-fourth of the children diagnosed with BA experience variceal bleeds during follow-up. Most of these children are younger than 1 year and often already listed for transplantation. Major complications did not occur after variceal bleeding. PMID- 28658684 TI - Video Comment on Amir Klein et al. PMID- 28658685 TI - Video Comment on Daniel C. Steinemann et al. PMID- 28658686 TI - Video Comment on Yun Nah Lee et al. PMID- 28658687 TI - Video Comment on Muhammad Ali Khan et al. PMID- 28658688 TI - Will Reflux Kill POEM? PMID- 28658689 TI - Eradication of Barrett's neoplasia: endoscopy vs. laparoscopy. PMID- 28658690 TI - Cholangioscopic imaging: distinguishing good from bad. PMID- 28658691 TI - Is sedation really to blame? PMID- 28658692 TI - Reply to Ferreira et al. PMID- 28658695 TI - [French comment on article Gastroesophageal reflux after peroral endoscopic myotomy: a multicenter case-control study1]. PMID- 28658696 TI - [French comment on article Relook endoscopy predicts the development of esophageal and antropyloric stenosis better than immediate endoscopy in patients with caustic ingestion1]. PMID- 28658697 TI - [French comment on article Performance of a fully disposable, digital, single operator cholangiopancreatoscope1 ]. PMID- 28658698 TI - [French comment on article Endoscopic resection of large duodenal and papillary lateral spreading lesions is clinically and economically advantageous compared with surgery1]. PMID- 28658699 TI - Extra Pulmonary Toxicity Assessment of Gold and Silver Nanorods Following Intra Tracheal Instillation in Rats. AB - The gold nanorods (GNRs) and silver nanorods (SNRs) are utilized in various types of industrial and commercial applications. But, there is limited availability of extra pulmonary toxicity data regarding these nanorods. The present investigation evaluated the extra pulmonary toxicity induced by 10 and 25 nm GNRs and SNRs in rats following intra tracheal instillation. The serum biochemical analysis results have shown elevated levels of serum alanine transaminase (ALT) and serum creatinine following 1 day and 1 week post instillation. GNRs have shown greatly increased serum ALT levels at 1 day, 1 week and 1 month post exposure periods compared to SNRs and quartz (QTZ) treated rats. In case of serum creatinine levels, both GNRs and SNRs have shown similar elevated levels. Histopathology studies of rat liver tissues following exposure of GNRs and SNRs displayed that congestion of central vein, shrinkage and ballooning of hepatocytes and lymphocytic infiltration leading to degeneration after 1 week and 1 month post instillation periods. The histopathology of rat kidney tissue was showed tubular dilation, degeneration and necrosis with 10 nm SNRs and 10 nm GNRs after 1 month post instillation period. The 10 nm GNRs and SNRs have shown great changes in serum biochemical analysis and histopathological studies compared to 25 nm test nanorods. These observations suggest the size and dose dependent translocation and extra pulmonary toxicity of both GNRs and SNRs. PMID- 28658700 TI - Prevalence of Human Papillomavirus Infection and Cervical Cancer Screening among Riverside Women of the Brazilian Amazon. AB - Purpose The aim of this study was to evaluate the overall and type-specific prevalence of human papillomavirus (HPV) infection among females living in riverside communities in the state of Para, in the Eastern Brazilian Amazon. These communities are inhabited by low-income people, and are accessible only by small boats. Cervical cytology and risk factors for HPV infection were also assessed. Methods Cervical samples from 353 women of selected communities were collected both for Papanicolau (Pap) test and HPV detection. Conventional polymerase chain reaction (PCR) and real-time PCR were used to assess the overall and type-specific prevalence of HPV-16 and HPV-18, the main oncogenic types worldwide. Epidemiological questionnaires were used for the assessment of the risk factors for HPV infection. Results The mean age of the participants was 37 years (standard deviation [SD] +/- 13.7). Most were married or with a fixed sexual partner (79%), and had a low educational level (80%) and family monthly income (< U$ 250; 53%). Overall, HPV prevalence was 16.4% (n = 58), with 8 cases of HPV-16 (2.3%) and 5 of HPV-18 (1.4%). Almost 70% of the women surveyed had never undergone the Pap test. Abnormal cytology results were found in 27.5% (n = 97) of the samples, with higher rates of HPV infection according to the severity of the lesions (p = 0.026). Conclusions The infections by HPV-16 and HPV-18 were not predominant in our study, despite the high prevalence of overall HPV infection. Nevertheless, the oncogenic potential of these types and the low coverage of the Pap test among women from riverside communities demonstrate a potential risk for the development of cervical lesions and their progression to cervical cancer, since the access to these communities is difficult and, in most cases, these women do not have access to primary care and public health services. PMID- 28658701 TI - Margareta D. Pisarska, MD. PMID- 28658702 TI - Fertility Status and Overall Health. PMID- 28658703 TI - Abnormal Placentation Associated with Infertility as a Marker of Overall Health. PMID- 28658704 TI - Female Genomics: Infertility and Overall Health. PMID- 28658705 TI - How to Map the Genetic Basis for Conditions that are Comorbid with Male Infertility. PMID- 28658706 TI - Ovary as a Biomarker of Health and Longevity: Insights from Genetics. PMID- 28658707 TI - Environmental Contaminants Affecting Fertility and Somatic Health. PMID- 28658708 TI - A Canary in the Coal Mine: Reproductive Health and Cardiovascular Disease in Women. PMID- 28658709 TI - Hypothalamic Amenorrhea and the Long-Term Health Consequences. PMID- 28658710 TI - The Systemic Effects of Endometriosis. PMID- 28658711 TI - Polycystic Ovarian Syndrome: Long-Term Health Consequences. PMID- 28658712 TI - Male Infertility and Risk of Nonmalignant Chronic Diseases: A Systematic Review of the Epidemiological Evidence. PMID- 28658713 TI - Fertility Status and Cancer. PMID- 28658714 TI - Male Infertility and Risk of Cancer. PMID- 28658715 TI - Perinatal and Childhood Outcomes Associated with Infertility. PMID- 28658716 TI - Sustained secretion of anti-tumor necrosis factor alpha monoclonal antibody from ex vivo genetically engineered dermal tissue demonstrates therapeutic activity in mouse model of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory, cytokines including tumor necrosis factor (TNF)-alpha. Adalimumab is a monoclonal antibody (mAb) that binds TNF-alpha, and is widely used to treat RA. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages, including the requirement for repeated bolus injections and the appearance of treatment limiting anti-drug antibodies. To address these issues, we have developed an innovative ex vivo gene therapy approach, termed transduced autologous restorative gene therapy (TARGT), to produce and secrete adalimumab for the treatment of RA. METHODS: Helper-dependent (HD) adenovirus vector containing adalimumab light and heavy chain coding sequences was used to transduce microdermal tissues and cells of human and mouse origin ex vivo, rendering sustained secretion of active adalimumab. The genetically engineered tissues were subsequently implanted in a mouse model of RA. RESULTS: Transduced human microdermal tissues implanted in SCID mice demonstrated 49 days of secretion of active adalimumab in the blood, at levels of tens of microgram per milliliter. In addition, transduced autologous dermal cells were implanted in the RA mouse model and demonstrated statistically significant amelioration in RA symptoms compared to naive cell implantation and were similar to recombinant adalimumab bolus injections. CONCLUSIONS: The results of the present study report microdermal tissues engineered to secrete active adalimumab as a proof of concept for sustained secretion of antibody from the novel ex vivo gene therapy TARGT platform. This technology may now be applied to a range of antibodies for the therapy of other diseases. PMID- 28658717 TI - Bone marrow-on-a-chip: Long-term culture of human haematopoietic stem cells in a three-dimensional microfluidic environment. AB - Multipotent haematopoietic stem and progenitor cells (HSPCs) are the source for all blood cell types. The bone marrow stem cell niche in which the HSPCs are maintained is known to be vital for their maintenance. Unfortunately, to date, no in vitro model exists that accurately mimics the aspects of the bone marrow niche and simultaneously allows the long-term culture of HSPCs. In this study, a novel three-dimensional coculture model is presented, based on a hydroxyapatite coated zirconium oxide scaffold, comprising of human mesenchymal stromal cells (MSCs) and cord blood derived HSPCs, enabling successful HSPC culture for a time span of 28 days within the microfluidic multiorgan chip. The HSPCs were found to stay in their primitive state (CD34+ CD38- ) and capable of granulocyte, erythrocyte, macrophage, megakaryocyte colony formation. Furthermore, a microenvironment was formed bearing molecular and structural similarity to the in vivo bone marrow niche containing extracellular matrix and signalling molecules known to play an important role in HSPC homeostasis. Here, a novel human in vitro bone marrow model is presented for the first time, capable of long-term culture of primitive HSPCs in a microfluidic environment. PMID- 28658718 TI - Leaf water 18 O and 2 H maps show directional enrichment discrepancy in Colocasia esculenta. AB - Spatial patterns of leaf water isotopes are challenging to predict because of the intricate link between vein and lamina water. Many models have attempted to predict these patterns, but to date, most have focused on monocots with parallel veins. These provide a simple system to study, but do not represent the majority of plant species. Here, a new protocol is developed using a Picarro induction module coupled to a cavity ringdown spectrometer to obtain maps of the leaf water isotopes (18 O and 2 H). The technique is applied to Colocasia esculenta leaves. The results are compared with isotope ratio mass spectrometry. In C. esculenta, a large enrichment in the radial direction is observed, but not in the longitudinal direction. The string-of-lakes model fails to predict the observed patterns, while the Farquhar-Gan model is more successful, especially when enrichment is accounted for along the radial direction. Our results show that reticulate-veined leaves experience a larger enrichment along the axis of the secondary veins than along the midrib. We hypothesize that this is due to the lower major/minor vein ratio that leads to longer pathways between major veins and sites of evaporation. PMID- 28658719 TI - Patient education in the management of coronary heart disease. AB - BACKGROUND: Coronary heart disease (CHD) is the single most common cause of death globally. However, with falling CHD mortality rates, an increasing number of people live with CHD and may need support to manage their symptoms and improve prognosis. Cardiac rehabilitation is a complex multifaceted intervention which aims to improve the health outcomes of people with CHD. Cardiac rehabilitation consists of three core modalities: education, exercise training and psychological support. This is an update of a Cochrane systematic review previously published in 2011, which aims to investigate the specific impact of the educational component of cardiac rehabilitation. OBJECTIVES: 1. To assess the effects of patient education delivered as part of cardiac rehabilitation, compared with usual care on mortality, morbidity, health-related quality of life (HRQoL) and healthcare costs in patients with CHD.2. To explore the potential study level predictors of the effects of patient education in patients with CHD (e.g. individual versus group intervention, timing with respect to index cardiac event). SEARCH METHODS: We updated searches from the previous Cochrane review, by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 6, 2016), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) in June 2016. Three trials registries, previous systematic reviews and reference lists of included studies were also searched. No language restrictions were applied. SELECTION CRITERIA: 1. Randomised controlled trials (RCTs) where the primary interventional intent was education delivered as part of cardiac rehabilitation.2. Studies with a minimum of six-months follow-up and published in 1990 or later.3. Adults with a diagnosis of CHD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on the above inclusion criteria. One author extracted study characteristics from the included trials and assessed their risk of bias; a second review author checked data. Two independent reviewers extracted outcome data onto a standardised collection form. For dichotomous variables, risk ratios and 95% confidence intervals (CI) were derived for each outcome. Heterogeneity amongst included studies was explored qualitatively and quantitatively. Where appropriate and possible, results from included studies were combined for each outcome to give an overall estimate of treatment effect. Given the degree of clinical heterogeneity seen in participant selection, interventions and comparators across studies, we decided it was appropriate to pool studies using random-effects modelling. We planned to undertake subgroup analysis and stratified meta-analysis, sensitivity analysis and meta-regression to examine potential treatment effect modifiers. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the quality of the evidence and the GRADE profiler (GRADEpro GDT) to create summary of findings tables. MAIN RESULTS: This updated review included a total of 22 trials which randomised 76,864 people with CHD to an education intervention or a 'no education' comparator. Nine new trials (8215 people) were included for this update. We judged most included studies as low risk of bias across most domains. Educational 'dose' ranged from one 40 minute face-to-face session plus a 15 minute follow-up call, to a four-week residential stay with 11 months of follow up sessions. Control groups received usual medical care, typically consisting of referral to an outpatient cardiologist, primary care physician, or both.We found evidence of no difference in effect of education-based interventions on total mortality (13 studies, 10,075 participants; 189/5187 (3.6%) versus 222/4888 (4.6%); random effects risk ratio (RR) 0.80, 95% CI 0.60 to 1.05; moderate quality evidence). Individual causes of mortality were reported rarely, and we were unable to report separate results for cardiovascular mortality or non cardiovascular mortality. There was evidence of no difference in effect of education-based interventions on fatal and/or non fatal myocardial infarction (MI) (2 studies, 209 participants; 7/107 (6.5%) versus 12/102 (11.8%); random effects RR 0.63, 95% CI 0.26 to 1.48; very low quality of evidence). However, there was some evidence of a reduction with education in fatal and/or non-fatal cardiovascular events (2 studies, 310 studies; 21/152 (13.8%) versus 61/158 (38.6%); random effects RR 0.36, 95% CI 0.23 to 0.56; low quality evidence). There was evidence of no difference in effect of education on the rate of total revascularisations (3 studies, 456 participants; 5/228 (2.2%) versus 8/228 (3.5%); random effects RR 0.58, 95% CI 0.19 to 1.71; very low quality evidence) or hospitalisations (5 studies, 14,849 participants; 656/10048 (6.5%) versus 381/4801 (7.9%); random effects RR 0.93, 95% CI 0.71 to 1.21; very low quality evidence). There was evidence of no difference between groups for all cause withdrawal (17 studies, 10,972 participants; 525/5632 (9.3%) versus 493/5340 (9.2%); random effects RR 1.04, 95% CI 0.88 to 1.22; low quality evidence). Although some health-related quality of life (HRQoL) domain scores were higher with education, there was no consistent evidence of superiority across all domains. AUTHORS' CONCLUSIONS: We found no reduction in total mortality, in people who received education delivered as part of cardiac rehabilitation, compared to people in control groups (moderate quality evidence). There were no improvements in fatal or non fatal MI, total revascularisations or hospitalisations, with education. There was some evidence of a reduction in fatal and/or non-fatal cardiovascular events with education, but this was based on only two studies. There was also some evidence to suggest that education-based interventions may improve HRQoL. Our findings are supportive of current national and international clinical guidelines that cardiac rehabilitation for people with CHD should be comprehensive and include educational interventions together with exercise and psychological therapy. Further definitive research into education interventions for people with CHD is needed. PMID- 28658720 TI - Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. AB - BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: Primary objective 1. To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates Secondary objectives 1. To determine the effects of lactoferrin supplementation to enteral feeds to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later2. To determine the adverse effects of lactoferrin supplementation for prophylaxis of neonatal sepsis and/or NECWhen data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants)3. Type of feeding: breast milk versus formula milk SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group (CNRG) to update our search in December 2016. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trial registries and conference proceedings. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: Review authors used standard methods of the CNRG. MAIN RESULTS: This review includes six RCTs. Trial results show that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical risk ratio (RR) 0.59, 95% confidence interval (CI) 0.40 to 0.87; typical risk difference (RD) -0.06, 95% CI -0.10 to 0.02; number needed to treat for an additional beneficial outcome (NNTB) 17, 95% CI 10 to 50; six trials, 886 participants; low-quality evidence) and NEC stage II or III (typical RR 0.40, 95% CI 0.18 to 0.86; typical RD -0.04, 95% CI -0.06 to 0.01; NNTB 25, 95% CI 17 to 100; four studies, 750 participants; low-quality evidence). Lactoferrin supplementation did not have an effect on "all-cause mortality" (typical RR 0.65, 95% CI 0.37 to 1.11; typical RD -0.02, 95% CI -0.05 to 0; six studies, 1041 participants; low-quality evidence).Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants; low-quality evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants; low-quality evidence), but not "all cause mortality" (low-quality evidence).Lactoferrin supplementation to enteral feeds with or without probiotics decreased bacterial and fungal sepsis but not CLD or length of hospital stay (low-quality evidence). Investigators reported no adverse effects and did not evaluate long-term neurological outcomes and PVL. AUTHORS' CONCLUSIONS: Evidence of low quality suggests that lactoferrin supplementation to enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III in preterm infants without adverse effects. Completed ongoing trials will provide data from more than 6000 preterm neonates, which may enhance the quality of the evidence. Clarification regarding optimal dosing regimens, types of lactoferrin (human or bovine), and long-term outcomes is needed. PMID- 28658722 TI - [Clinical-epidemiological profile of oral allergy syndrome in the population aged 6 to 18 years]. AB - BACKGROUND: Oral allergy syndrome (OAS) or pollen-fruit syndrome is a type of food allergy. Its characteristics and associated allergens vary according to the studied population. There are few studies in Mexico about this topic, none in children. OBJECTIVE: To describe clinical and epidemiological characteristics of OAS among children in Mexico. METHODS: A descriptive, observational, transversal and prospective study was conducted. We included every patient from 6 to 18 years old with diagnostic suspicion of OAS, in which complete clinical history, skin test to food and pollens, and oral food challenge were performed. RESULTS: We found a prevalence of 5.3% (29 patients): 55% were males. Average age was 10 +/- 3 years, and average number of food implicated were 6.8 +/- 4.1. Apple, peach and banana, were the most frequent food associated, and sensitization to oak and European privet, the more prevalent pollens found in OAS. CONCLUSION: OAS is a common type of food allergy, transient and mild in nature. In more than 90% of the cases is associated with allergic rhinitis and sensitization to pollens. In our population, profilins may be involved in its pathogenesis. However, more studies are required to prove this. PMID- 28658721 TI - [Prevalence of allergic diseases in children with secondary renal tubular acidosis attending a tertiary care pediatric center]. AB - BACKGROUND: It has been suggested a high prevalence of allergic disease in children with RTA. OBJECTIVE: To describe the prevalence of allergic diseases in children with secondary RTA (renal tubular acidosis) in the nephrology department of the National Institute of Pediatrics (NIP), Mexico. METHODS: An observational, prospective, cross-sectional, descriptive study. Children with secondary RTA < 18 years who attended the outpatient nephrology service in the NIP for 24 months, were included. ISAAC questionnaire and the EAACI guidelines were applied. To prove a suspected allergy, skin tests, total and specific IgE, patch testing and food challenge were performed. Using SPSS 19, frequency of allergic diseases was described. RESULTS: 113 patients were included. Age 8 to 168 months. Male: 53.9 %. RTA types: Distal (64.6 %), proximal (26.5 %), mixed (1.8 %) and undetermined (7 %). Age of onset between 1 and 96 months. Serum bicarbonate 10.1 to 20 mEq/L. Allergic diseases were found in 24.8 %: allergic rhinitis (18.4 %), food allergy (9.7 %), atopic dermatitis (8 %), asthma (8 %) and allergic conjunctivitis (6.1 %). Total IgE was increased in 9 patients. Positive skin tests in 14.2 %. Positive chemiluminescence in 18 children; positive open food challenge in 11 children and patch tests in 4. CONCLUSION: Secondary RTA is common in children attending tertiary care hospitals. The prevalence of allergic disease in children with secondary ATR, is similar to that described in the general population. PMID- 28658723 TI - Sensitization to 10 mites in a tropic area. Der p and Der f are important risk factor for sensitization to other mites from Pyroglyphidae, Acaridae, Chortoglyphidae, and Glyciphagidae families. AB - BACKGROUND: Much is known about the frequency of sensitization to Blomia tropicalis, Dermatophagoides pteronyssinus and Dermatophagoides farinae, although less is known about sensitization to other species and their possible interactions. OBJECTIVE: In patients with allergic manifestations, to evaluate the frequency of sensitization to 10 species of mites in a tropical area and their possible interactions. METHODS: Cross-sectional study. Sensitization was evaluated by skin tests. A generalized linear Poisson regression model with robust variance was used. Based on the sensitization probability reasons and social networking analysis, explorations of relationship for 10 mites were performed. RESULTS: 147 patients were included. The highest sensitization was found to mites' family Pyroglyphidae (> 70 %) and less frequently was the Glycyphagidae family (< 50 %). Sensitization to any mites significantly increased the likelihood of sensitization to others. Sensitization to Der f or Der p increased, more than 20 times the likelihood of sensitization to other mites of the Pyroglyphidae family and more than 10 times to mites from other families. Sensitization to mites from Glycyphagidae, Chortoglyphidae or Acaridae family also increased the risk of sensitization to other mites but less than 5 times. CONCLUSION: Sensitization to mites is frequent in tropical area. Pyroglyphidae sensitization is the main risk factor for polysensitization with other mites from Glycyphagidae, Chortoglyphidae or Acaridae. These results must be considered at diagnosis and treatment of allergy diseases. PMID- 28658724 TI - [Prevalence of urticaria in Cartagena, Colombia]. AB - BACKGROUND: In Colombia, there have been studies on the prevalence of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Prevalence studies of urticaria in Colombia are scarce. OBJECTIVE: Our objective objective of this study was to estimate the prevalence of urticaria in Cartagena (Colombia) in order to contribute to national epidemiological estimates of disease. METHODS: A multicenter cross-sectional study in the city of Cartagena was conducted and 547 patients aged 1-58 years treated at the Allergy specialist consultation in care centers selected for this study between April and July 2015 were included, through non-probabilistic sampling. RESULTS: The prevalence of urticaria in the care centers selected of city of Cartagena (Colombia) was 7.1 % (4 % children and adults 3.1 %). 3.4 % prevalence of acute urticaria and 3.6 % of chronic urticaria was estimated. CONCLUSION: 46.1 % reported having a poor quality of life associated with urticaria. PMID- 28658725 TI - [Management of anaphylaxis in Latin America: current situation]. AB - BACKGROUND: Anaphylaxis is a systemic and severe allergic reaction, which can be fatal. The first-line treatment of choice, according to international guidelines, is intramuscular adrenaline. However, different studies show that the performance of health professionals managing anaphylaxis is often inadequate. OBJECTIVE: To assess the current resources available in Latin American countries for the diagnosis and treatment of anaphylaxis. METHODS: Online survey promoted by the Latin American Society of Allergy and Immunology to representatives of the national allergy societies of Latin American countries. RESULTS: Responses were received from 10 countries out of the 14 countries invited to participate. Only five of the countries have clinical practice guidelines in anaphylaxis. Adrenaline autoinjectors are available only in two countries, Argentina and Brazil, but are not subsidized by public health systems. In all countries, adrenaline is available in ampoules, which is the presentation usually prescribed to patients for self-administration. The use of adrenaline was estimated to be less than 50 % of cases in five countries, while antihistamines and corticosteroids are almost always used. The determination of serum tryptase is possible in some health centers, often private, in five of the countries surveyed. CONCLUSION: It is necessary to improve resources related to the diagnosis and management of anaphylaxis in Latin American countries. PMID- 28658726 TI - [Prevalence of vitamin D insufficiency and deficiency in Mexican adults with allergic asthma]. AB - BACKGROUND: Hypovitaminosis D has been associated with various chronic diseases such as infections, autoimmune diseases, chronic obstructive pulmonary disease, cancer and asthma Objective: The objective at hand is to determine the prevalence of vitamin D (VD) insufficiency and deficiency in adults with allergic asthma. OBJECTIVE: Objective: The objective at hand is to determine the prevalence of vitamin D (VD) insufficiency and deficiency in adults with allergic asthma. METHODS: Through a cross-sectional study, we analyzed corresponding data amongst 135 patients. VD concentration was categorized as sufficient (>= 30 ng/mL), insufficient (21-29 ng/mL), and deficient (<= 20 ng/mL). The level of VD deficiency was measured through chemo-luminescence. We estimated the prevalence of VD alterations and their respective confidence intervals at 95 % (CI 95 %). RESULTS: Within the analyzed population, there were 99/135 women (73.3 %); the mean age was 34.5 +/- 10.3 years. The mean concentration of VD was 17.9 +/- 6.9 ng/mL and the median was 17 ng/mL. The prevalence of VD insufficiency and deficiency was 25.2 % (CI 95 %, 18.6-33.2 %) and 71.1 % (CI 95 %, 62.9-78.1 %), respectively; VD concentrations <= 10 ng/mL had 13.3 % (CI 95 %, 8.5-20.2 %) and >= 30 ng/mL at 3.7 % (CI 95 %: 1.4-8.6 %). When we contrasted the men to the women, the median concentration of VD did not differ significantly (16 ng/mL vs. 18 ng/mL, p = 0.71). CONCLUSION: In this study, patients with allergic asthma had distinctively reduced VD concentration levels; future research will determine if and how VD affects the severity of asthma. PMID- 28658727 TI - [Prevalence of asthma in Latin America. Critical look at ISAAC and other studies]. AB - Currently, the ISAAC (International Study of Asthma and Allergies in Childhood) project is a global approach to assess the prevalence of asthma and other allergies in different latitudes. One of the great advantages of this project is that it compares using the same methodology, the prevalence of asthma in more than 50 cities during the same period of time, nevertheless the reproducibility of these results when compared with other studies of prevalence in each region has not been evaluated. In this review we aim to compare the epidemiological data provided by the ISAAC against the data identified in some regional cohort studies and by means of a critical evaluation to highlight the main similarities and to analyze the differences between these epidemiological data. PMID- 28658728 TI - [Mediators of inflammatory response in asthma and its association with obesity]. AB - There is an increase in the prevalence of asthma and obesity, constituting a public health problem at national and global levels. The association between the two pathologies has not been clearly determined; however, a certain synergy has been proposed, which leads to more severe bronchospasms, longer recovery time, and more prolonged use of medications in obese asthmatic patients. The discovery of leptin, an adipokine that is directly related to the amount of total body fat and the production of proinflammatory cytokines, has generated greater interest in white adipose tissue. Our objective was to describe the possible mechanisms involved and the association between obesity and asthma. A bibliographic search was conducted in the scientific literature using the National Biotechnology Information Center (NCBI) database of the USA as a search tool; keywords used were: asthma, leptin, obesity and inflammation. There are numerous clinical and experimental studies that explore the role of obesity as an inflammatory entity in asthma, some of which have evaluated the role of "shared" genetic polymorphisms in both pathologies. Apparently, the interaction between asthma and obesity is complex, there are mechanisms that link both pathologies, these can influence the improvement or exacerbation of symptoms. PMID- 28658729 TI - [Senescence of the immune system and alterations related with asthma]. AB - Senescence is an irreversible process by which cells enter to a permanent cell cycle arrest with generalized molecular changes. Senescent cells remain metabolically active and most of them show a secretory phenotype; through its secretion may induce senescence or cancer in other cells. The secretory cells in the so-called transient senescence may participate in embryogenesis, tissue regeneration and immune response. The deleterious changes associated with age affect the immune system members and the immune senescence cause poor response to vaccines and susceptibility to cancer and infections. These latter are a frequent cause of asthma mostly in the elderly, the incidence is increasing in old people, and it may be related with those anatomical, physiological and immune changes caused by age, asthma chronicity and external agents. Comorbidity in the elderly worsens the ailment and hinders diagnosis, therefore, knowledge and handling of these clinical entities must be in control by the physicians responsible of the first level attention to old patients. PMID- 28658730 TI - [The research protocol V: The calculation of sample size]. AB - Sample size refers to the number of participants to be included in a research study. If the calculation is carried out properly, not only conclusions will be established with statistical support and the potential risks to the subjects included in the investigation will be limited, but also the study can be properly planned to optimize economic and time costs. Calculation of sample size requires information that must be supported by the research protocol. This information includes that the objectives (descriptive study or a study to establish differences between groups) and hypotheses are well elaborated (with magnitude and direction), the scale of measurement of the outcome variable(s) must be defined, and type I error and type II error appropriately identified. This review describes how to specify the requirements needed for sample size calculation, including examples in clinical research designs. PMID- 28658731 TI - [Angioedema as initial manifestation of hypogammaglobulinemia]. AB - Common variable immunodeficiency is characterized by hypogammaglobulinemia and the inability to respond to vaccines. Patients mostly manifest infections, however only less than 5 % have pathological conditions as autoimmunity, granulomatous inflammation, and splenomegaly or lymphoproliferative disease among others, without showing infections. We report the case of a woman who debuted with localized cutaneous affection, facial angioedema, without other early symptoms. After diagnosis splenomegaly and bronchiectasis were documented. Angioedema and bronchiectasis responded with IVIG replacement. We also review the dermatological manifestations associated with CVID. PMID- 28658732 TI - [Good's syndrome. Report of case]. AB - BACKGROUND: Good's syndrome is an association of thymoma and immunodeficiency. The symptoms are recurrent sinopulmonary infections in addition to the compressive side of thymoma. A laboratory finding is notable for the absence or decrease of B lymphocytes, hypogammaglobulinemia, inversion ratio CD4/CD8 and abnormal proliferative response to mitogens. CASE REPORT: Female, 49-year-old started five months earlier with lower limb edema, postprandial vomiting, dysphagia, chronic diarrhea and weight loss. A second endoscopy ruled gastric neoplasia. Chest radiography with mediastinal widening, Thoraco-abdominal CT with bilateral pleural effusion and a mass in the anterior mediastinum, histopathological report of the tumor: B1 thymoma. Laboratory findings: IgG 349 mg/dL, IgA 70.3 mg/dL, 37.1 IgM mg/dL, Ca125 631 UI/mL, leukocytes 7890 mm3, hemoglobin 13.2 g/dL, lymphocytes 2060 mm3, CD16+CD56+ 122 cells/uL, CD19 77 cells/uL, CD3 2052 cells/uL, CD4 977 cells/uL, CD8 998 cells/uL; ratio CD4/CD8 0.98, hepatitis C, B and HIV negative. They requested valuation to Clinical Immunology and Allergy due to hypogammaglobulinemia, the diagnosis of Good's syndrome was confirmed and initiated with intravenous gamma globulin replacement to immunomodulatory dose of 1 g/kg, she reached replacement goal in the third dose of immunoglobulin intravenous, with clinical improvement. She died four months later from cardiac complications. CONCLUSIONS: Despite the variability of presentation, Good's syndrome should be suspected as part of the paraneoplastic manifestations of thymoma. PMID- 28658733 TI - Thyroid disease in children and adolescents. PMID- 28658734 TI - Ultrasonographic features differentiating thyroglossal duct cysts from dermoid cysts. AB - PURPOSE: The purpose of this study was to identify ultrasonographic features that can be used to differentiate between thyroglossal duct cysts (TGDCs) and dermoid cysts (DCs). METHODS: We searched surgical pathology reports completed between January 2004 and October 2015 and identified 66 patients with TGDCs or DCs who had undergone preoperative ultrasonography. The ultrasound images were reviewed by two radiologists who were blinded to the pathological diagnosis. They evaluated the following parameters: dimensions, shape, margin, location in relation to the midline, level in relation to the hyoid bone, attachment to the hyoid bone, the depth of the lesion in relation to the strap muscles, internal echogenicity, internal echogenic dots, multilocularity, the presence of a longitudinal extension into the tongue base, posterior acoustic enhancement, the presence of internal septae, and intralesional vascularity. RESULTS: There were 50 TGDCs and 16 DCs. TGDCs were significantly more likely than DCs to have an irregular shape, an ill-defined margin, attachment to the hyoid bone, an intramuscular location, heterogeneous internal echogenicity, multilocularity, and longitudinal extension into the tongue base. CONCLUSION: Ultrasound findings may inform the differential diagnosis between TGDCs and DCs. PMID- 28658735 TI - Effects of pH and H2O2 on ammonia, nitrite, and nitrate transformations during UV254nm irradiation: Implications to nitrogen removal and analysis. AB - In order to achieve better removal and analyses of three dissolved inorganic nitrogen (DIN) species via ultraviolet-activated hydrogen peroxide (UV/H2O2) process, this study systematically investigated the rates of photo-oxidations of ammonia/ammonium (NH3/NH4+) and nitrite (NO2-) as well as the photo-reduction of nitrate (NO3-) at varying pH and H2O2 conditions. The results showed that the mass balances of nitrogen were maintained along irradiation despite of interconversions of DIN species, suggesting that no nitrogen gas (N2) or other nitrogen-containing compound was formed. NH3 was more reactive than NH4+ with hydroxyl radical (OH), and by a stepwise H2O2 addition method NH3/NH4+ can be completely converted to NOx-; NO2- underwent rapid oxidation to form NO3- when H2O2 was present, suggesting that it is an intermediate compound linking NH3/NH4+ and NO3-; but once H2O2 was depleted, NO3- can be gradually photo-reduced back to NO2- at high pH conditions. Other than H2O2, the transformation kinetics of DINs were all dependent on pH, but to varying aspects and extents: the NH3 photo oxidation favored a pH of 10.3, which fell within the pKa values of NH4+ (9.24) and H2O2 (11.6); the NO3- photo-reduction increased with increasing pH provided that it exceeds the pKa of peroxynitrous acid (6.8); while the NO2- photo oxidation remained stable unless the pH neared the pKa of H2O2 (11.6). The study thereby demonstrates a picture of the evolutions of DIN species together during UV/H2O2 irradiation process, and for the first time presents a method to achieve complete conversion of NH4+ to NO3- with UV/H2O2 process. PMID- 28658736 TI - Greywater-induced soil hydrophobicity. AB - Greywater (GW) reuse for irrigation is a common method of reducing domestic consumption of fresh water. Most of the scientific research and legislation efforts have focused on GW's health risks, while less attention has been given to its environmental outcomes. One of the environmental risks of GW irrigation is its possible effect on soil hydraulic properties. This research examined the ability of GW to induce soil hydrophobicity, as well as its degree and persistence. Fresh water (control) and three model GW solutions representing raw, treated and highly treated GW were used to wet fine-grained sand. Every treatment was subjected to five cycles of wetting, incubation (at 5 degrees C or 30 degrees C) and drying (60 degrees C). After each cycle, capillary rise was measured and the contact angle (CA) was calculated. Samples were also tested by the Wilhelmy plate method to retrieve advancing and receding CA and reservoir surface tension. Water repellence of the sand, as implied from the CA, increased with increasing GW concentration and was highest in the sand coated with the model raw GW and incubated at 5 degrees C. However, none of the treatments resulted in what is considered to be "water-repellent soil". Furthermore, when raw GW-coated sand was immersed in water, its surface tension was significantly reduced relative to the other treatments, implying a release of surface-active compounds from the sand into the water. It was postulated that untreated GW may induce sub-critical water repellence in sand. However, this effect is sensitive to biodegradation and washing processes and is therefore temporary. PMID- 28658737 TI - Rhodamine B in dissolved and nano-bound forms: Indicators for light-based advanced oxidation processes. AB - Rhodamine B (RhB) is a water-soluble fluorescent dye that is often used to determine flux and flow direction in biotechnological and environmental applications. In the current research, RhB in soluble (termed free) and virus bound (termed nano-bound) forms was used as an efficiency indicator for three environmental processes. The degradation of free and nano-bound RhB by (i) direct UV photolysis and (ii) UV/H2O2 advanced oxidation process (AOP) was studied in a collimated beam apparatus equipped with medium-pressure mercury vapor lamp. The degradation by (iii) solar light-induced photocatalysis was studied in a solar simulator with titanium dioxide and bismuth photocatalysts. Results showed negligible RhB degradation by direct UV and solar light, and its nearly linear degradation by UV/H2O2 and photocatalysis/photosensitization in the presence of a solid catalyst. Considerable adsorption of free RhB on bismuth-based catalyst vs. no adsorption of nano-bound RhB on this catalyst or of any form of the dye on titanium dioxide produced two important conclusions. First, the better degradation of free RhB by the bismuth catalyst suggests that close proximity of a catalyst hole and the decomposing molecule significantly influences degradation. Second, the soluble form of the dye might not be the best option for its use as an indicator. Nano-bound RhB showed high potential as an AOP indicator, featuring possible separation from water after the analysis. PMID- 28658738 TI - Continuous low-level aquatic monitoring (CLAM) samplers for pesticide contaminant screening in urban runoff: Analytical approach and a field test case. AB - Monitoring of surface waters for organic contaminants is costly. Grab water sampling often results in non-detects for organic contaminants due to missing a pulse event or analytical instrumentation limitations with a small sample size. Continuous Low-Level Aquatic Monitoring (CLAM) samplers (C.I.Agent(r) Solutions) continually extract and concentrate organic contaminants in surface water onto a solid phase extraction disk. Utilizing CLAM samplers, we developed a broad spectrum analytical screen for monitoring organic contaminants in urban runoff. An intermediate polarity solid phase, hydrophobic/lipophilic balance (HLB), was chosen as the sorbent for the CLAM to target a broad range of compounds. Eighteen urban-use pesticides and pesticide degradates were targeted for analysis by LC/MS/MS, with recoveries between 59 and 135% in laboratory studies. In field studies, CLAM samplers were deployed at discrete time points from February 2015 to March 2016. Half of the targeted chemicals were detected with reporting limits up to 90 times lower than routine 1-L grab samples with good precision between field replicates. In a final deployment, CLAM samplers were compared to 1-L water samples. In this side-by-side comparison, imidacloprid, fipronil, and three fipronil degradates were detected by the CLAM sampler but only imidacloprid and fipronil sulfone were detected in the water samples. However, concentrations of fipronil sulfone and imidacloprid were significantly lower with the CLAM and a transient spike of diuron was not detected. Although the CLAM sampler has limitations, it can be a powerful tool for development of more focused and informed monitoring efforts based on pre-identified targets in the field. PMID- 28658739 TI - Targeted screening and safety evaluation of 276 agrochemical residues in raisins using buffered ethyl acetate extraction and liquid chromatography-tandem mass spectrometry analysis. AB - A buffered ethyl acetate extraction method was optimized and validated in raisin matrix to monitor 276 pesticides by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The final method involved homogenization of raisinsalong with water 1:1 raisins: water followed by extraction using ethyl acetate (10 mL/10 g raisins homogenate in presence of 0.1 mL acetic acid, 0.5 g sodium acetate and 10 g sodium sulfate, and cleanup by dispersive solid phase extraction with primary secondary amine sorbent (25 mg/5 mL extract). 276 pesticides were estimated within 20 min of chromatographic run time by retention time dependent 'scheduled multiple reaction monitoring' (sMRM) by LC-MS/MS.The method was validated as per European guideline, DG-SANTE/11945/2015, at 2, 10, and 25 ng/g spiking levels where the method precision in terms of repeatability was <15% at 10 ng/g for 93.8% of the compounds. The Limit of quantification (LOQ) ranged between 0.01 and 10 ng/g with recoveries 70-120% with <=20% RSD for 93.5% of compounds at regulatory default MRL of 10 ng/g. The matrix induced signal suppressions or enhancement were moderate (60-130% accuracy against solvent standard) for 85% compounds in white raisins and 67% compounds in black raisins. The method was successfully applied for screening of 94 market samples of raisins for the target analytes. The dietaryexposures calculated against the average concentrations detected were wellbelow the maximum permissible intake (MPI) values and the collected raisin samples were considered safe for human consumption without any acute toxicity hazard. PMID- 28658740 TI - Fungal treatment for the removal of endocrine disrupting compounds from reverse osmosis concentrate: Identification and monitoring of transformation products of benzotriazoles. AB - The removal of 27 endocrine-disrupting compounds and related compounds (suspect effect) from a reverse osmosis concentrate using an alternative decontamination method based on a fungal treatment involving Trametes versicolor was assessed. In addition to chemical analysis, the toxicity of the treated water during the treatment was monitored using a bioluminescence inhibition test and estrogenic and anti-estrogenic tests. The compounds 1H-benzotriazole (BTZ) and two tolyltriazoles (TTZs), 4-methyl-1H-benzotriazole (4-MBTZ) and 5-methyl-1H benzotriazole (5-MBTZ), were present in the reverse osmosis concentrate at the highest concentrations (7.4 and 12.8 MUg L-1, respectively) and were partially removed by the fungal treatment under sterile conditions (58% for BTZ and 92% for TTZs) and non-sterile conditions, although to lesser extents (32% for BTZ and 50% for TTZs). Individual biotransformation studies of BTZ and the TTZs by T. versicolor in a synthetic medium and further analysis via on-line turbulent flow chromatography coupled to an HRMS-Orbitrap allowed the tentative identification of the transformation products (TPs). Six TPs were postulated for BTZ, two TPs were postulated for 4-MBTZ, and four TPs were postulated for 5-MBTZ. Most of these TPs are suggested to have been generated by conjugation with some sugars and via the methylation of the triazole group. Only TP 148 A, postulated to be derived from the biotransformation of BTZ, was observed in the effluent of the bioreactor treating the reverse osmosis concentrate. PMID- 28658741 TI - Role of Fe(III)-carboxylates in AMZ photodegradation: A response surface study based on a Doehlert experimental design. AB - Photochemical redox reactions of Fe(III) complexes in surface waters are important sources of radical species, therefore contributing to the sunlight driven elimination of waterborne recalcitrant contaminants. In this study, the effects of three Fe(III)-carboxylates (i.e., oxalate, citrate, and tartrate) on the UVA photoinduced oxidation of the herbicide amicarbazone (AMZ) were investigated. A Doehlert experimental design was applied to find the Fe(III):ligand ratios and pH that achieved the fastest AMZ degradation rate. The results indicated optimal ratios of 1:10 (Fe(III):oxalate), 1:4 (Fe(III):citrate), and 1:1 (Fe(III):tartrate), with the [Fe(III)]0 set at 0.1 mmol L-1 and the best pH found to be 3.5 for all the complexes. In addition, a statistical model that predicts the observed degradation rate constant (kobs) as a function of pH and Fe(III):carboxylate ratio was obtained for each complex, enabling AMZ-photodegradation predictions based on these two variables. To the best of our knowledge, this is the first time that such models are proposed. Not only the pH-dependent speciation of Fe(III) in solution but also the time profiles of photogenerated OH, Fe(II), and H2O2 gave appropriate support to the experimental results. Additional experiments using a sampled sewage treatment plant effluent suggest that the addition of aqua and/or Fe(III)-oxalate complexes to the matrix may also be effective for AMZ removal from natural waters in case their natural occurrence is not high enough to promote pollutant degradation. Therefore, the inclusion of Fe(III)-complexes in investigations dealing with the environmental fate of emerging pollutants in natural waterbodies is strongly recommended. PMID- 28658742 TI - Hydrogen production by tailoring the brookite and Cu2O ratio of sol-gel Cu-TiO2 photocatalysts. AB - Cu-TiO2 photocatalysts were prepared by the sol-gel method. Copper loadings from, 1.0 to 5.0 wt % were used. The materials were annealed at different temperatures (from 400 to 600 degrees C) to study the formation of brookite and copper ionic species. The photocatalysts were characterized by X-ray diffraction, UV-vis, Raman and XPS spectroscopies, H2-temperature programmed reduction (TPR), N2 physisorption, and SEM-EDS to quantify the actual copper loadings and characterize morphology. The photocatalysts were evaluated during the hydrogen photocatalytic production using an ethanolic solution (50% v/v) under UV and visible radiation. The best hydrogen production was performed by Ti-Cu 1.0 with an overall hydrogen production that was five times higher than that obtained with photolysis. This sample had an optimal thermal treatment at 500 degrees C, and at this temperature, the Cu2O and brookite/anatase ratio boosted the photocatalytic production of hydrogen. In addition, a deactivation test was carried out for the most active sample (TiO2-Cu 1.0), showing unchanged H2 production for three cycles with negligible Cu lixiviation. The activity of hydrogen-through-copper production reported in this research work is comparable with the one featured by noble metals and that reported in the literature for doped TiO2 materials. PMID- 28658743 TI - Correlation of Prostate Gland Size and Uroflowmetry in Patients with Lower Urinary Tract Symptoms. AB - INTRODUCTION: Benign Prostatic Hyperplasia (BPH) is a common entity among men over 40 years of age with significant disability. It is a condition that occurs when the enlarged prostate gland compresses the urethra leading to Bladder Outlet Obstruction (BOO). AIM: To correlate the size of the prostate gland and uroflowmetry parameters in patients with Lower Urinary Tract Symptoms (LUTS). MATERIALS AND METHODS: One hundred and twenty randomly selected male patients, from the ages of 41 to 70 years, with LUTS, and underwent trans abdominal sonogram and uroflowmetry were included in the study. The samples were divided into three groups according to the age; Group 1: 41 to 50 years, Group 2: 51 to 60 years, Group 3: 61 to 70 years. RESULTS: In Group 1 (41 to 50 years), there were totally 28 patients with LUTS, out of which seven patients had BPH, indicating that about 5% of patients with LUTS have BPH. In Group 2 (51-60 years) there were totally 31 patients with LUTS, out of which 10 patients had BPH, indicating that 8% of patients with LUTS have BPH. In Group 3 (61-70 years) there were totally 61 patients with LUTS, out of which 33 patients had BPH, indicating that 27% of patients with LUTS had BPH. The mean age of patients with LUTS was 60 years with mean prostate size of 45 cm3. Enlarged prostate gland was present in 41% of patients with mean Q max of 14 ml/sec and post voidal volume of 48 ml. CONCLUSION: This study concludes that the LUTS in older patients are mostly due to BPH leading to BOO. Also, patients with BPH in early ages can lead to increased Post voidal Residual Volume (PVR) following uroflowmetry. Thus, screening male patients with LUTS, at 40 years and above, is an ideal way to detect prostatic problems at an early stage. PMID- 28658744 TI - Accessory Grooves on the Diaphragmatic Surface of the Liver: A Cadaveric Study. AB - INTRODUCTION: Usually liver does not possess any grooves on its diaphragmatic surface, but there are reports on the presence of grooves on this surface. AIM: The present study was conducted to study the gross features of diaphragmatic surface of the liver and document the presence of any grooves on it and also to correlate our study with the previous studies. MATERIALS AND METHODS: Ninety seven formalin embalmed livers stored in 10% formaldehyde were observed for the presence of grooves on diaphragmatic surface. RESULTS: Fifteen (15.46%) livers had at least one groove on the diaphragmatic surface. Left lobe did not reveal the presence of any abnormal grooves. Presence of a single groove was observed in six (6.18%) livers; Double grooves were found in five (5.15%) livers; Triple grooves were found in three (3.09%) livers and four grooves were found in one (1.03%) liver. The deepest among all the grooves was measured 1.5 cm. CONCLUSION: The knowledge of these grooves is of importance to radiologists and surgeons during their routine procedures. PMID- 28658745 TI - MRI Study on Spinal Canal Morphometry: An Indian Study. AB - INTRODUCTION: A large proportion of adults suffer from neck pain at some points of their life and show altered ranges of spinal canal morphometry in various studies. The differences in values are also seen due to genetic, hormonal and other factors too. Torg's ratio is a widely accepted measurement to eliminate such discrepancies. The measurement of Space Available for Cord (SAC) is also gaining importance as spinal stenosis is a contributor to neck pain. AIM: (1) To examine the cervical spinal canal and spinal cord morphometric determinants in symptomatic sub-Himalayan North Bengal population and to compare the obtained data with other populations; (2) To determine whether Torg's ratio vary with gender or not; (3) To determine SAC values in symptomatic individuals. MATERIALS AND METHODS: Magnetic Resonance Imaging (MRI) based on midsagittal diameter of vertebral body, spinal canal, spinal cord and its Torg's ratio and SAC value of the lower cervical spine (C3-C7) from 71 symptomatic adults were recorded at the Radiology Department of North Bengal Medical College and Hospital, Bengal, India. Individuals with any evidence of trauma, infection, neoplasia or any congenital anomalies related to spinal canal and below 18 years of age were excluded from the study. RESULTS: The average diameter for vertebral body was significantly larger in males. The average diameter for spinal canal, spinal cord and values of Torg's ratio and SAC has no significant gender difference. But the mean value of Torg's ratio is greater in females is due to smaller vertebral body size in females. CONCLUSION: It is interpreted from our study that sagittal spinal canal diameter, Torg's ratio and SAC value did not show any significant gender difference. But sagittal vertebral body's diameter showed sexual dimorphism which influenced the mean value of Torg's ratio. PMID- 28658746 TI - A Unique Triad of Muscular, Vascular and Nervous Variations in Upper Limb. AB - Multiple muscular and neurovascular anomalies in upper limb are reported continuously in medical literature because of their clinical significance. A unique case of the triad of variations was encountered during routine dissection activity. The variations observed were: 1) Accessory third head of biceps brachii; 2) High division of Brachial Artery; 3) Communication between Musculocutaneous Nerve and Median Nerve. Taken independently these variations are common but it is rare in a single cadaver. These abnormalities were found unilaterally on the right arm of the cadaver. The third head of biceps brachii was seen to be originating from the medial border and adjacent area on the anteromedial surface of the humerus at the level of insertion of coracobrachialis fusing with main muscle belly just before it forms the tendon. Additional head of biceps brachii was supplied by a branch from the Median Nerve. This branch after supplying the additional head of biceps was seen to join the Musculocutaneous Nerve. Further, a higher bifurcation of brachial artery was observed at the level of insertion of coracobrachialis. The medial division was traced distally as radial artery and the lateral division was traced as ulnar artery. The knowledge of these variations is of immense importance to correlate abnormal displacement of fractured bone segments, avoiding fatal injuries to vital structures, transradial angiography and diagnostic clinical neurophysiology. PMID- 28658747 TI - Correspondence: Abnormal Nuclear Variations in Response to Radiotherapy: As a Tool in Treatment Planning and Assessment of Prognosis. PMID- 28658748 TI - Diabetes Mellitus in Thalassaemia Major Patients: A Report from the Southeast of Iran. AB - INTRODUCTION: Diabetes Mellitus (DM) represents a major concern in Thalassaemia Major (TM) patients. AIM: The present study was conducted to evaluate the frequency of Impaired Fasting Glucose (IFG) and DM in TM patients in Southeast of Iran. MATERIALS AND METHODS: Fasting Blood Glucose (FBS) was determined using fasting blood samples in 148 TM patients. Demographical data was collected by a questionnaire. Clinical and laboratory variables including cell blood counts, pre transfusion Haemoglobin (Hb) level, and five-year ferritin were extracted from medical records. Statistical analysis was performed in SPSS19.0 software using chi-square, student t-test and logistic regression. RESULTS: Females and males comprised 83 (56.1%) and 65 (43.9%) subjects respectively. The mean age and mean five-year ferritin were 17.3+/-6.1 year-old and 5060.6+/-2395 ng/ml respectively. Overall, 39 (26.4%) patients had IFG, while 13 (8.8%) were diagnosed with DM. Significant differences were identified in the mean age, volume of transfused blood per occasion, and mean five-years ferritin between the patients with IFG or DM and the patients with normal fasting glucose level. Patients with age >25-year old had an increased risk of both IFG (OR=4.7,95% CI: 1.3-17, p=0.01) and DM (OR= 7.1, 95% CI: 1-49.2, p=0.04). In addition, splenectomized patients showed a higher risk for IFG (OR=4.3, 95% CI: 1.5-12.1, p=0.005), and ferritin value >6000 ng/ml were associated with an elevated risk of DM (OR=7, 95% CI: 0.8-60.1, p=0.07). CONCLUSION: Our results indicated that higher age, mean five-years ferritin, volume of blood transfused per occasion, as well as splenectomy were risk factors of IFG and DM in TM patients. PMID- 28658750 TI - Retrospective Comparison of Estimated GFR using 2006 MDRD, 2009 CKD-EPI and Cockcroft-Gault with 24 Hour Urine Creatinine Clearance. AB - INTRODUCTION: The assessment of Glomerular Filtration Rate (GFR) is essential for clinical practice in assessing kidney function, drug dosing, detecting and estimating the prognosis of Chronic Kidney Disease (CKD). The most common practical method for assessing GFR is performed with a 24 hour/timed urine collection for creatinine clearance evaluation. The estimation of eGFR by creatinine based formulae is known to be a rapid and reliable means of approximation of creatinine clearance. AIM: To compare eGFR using three commonly used Formulae {Modification of Diet in Renal Disease Study Equation (MDRD 2006), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2009) and Cockcroft Gault Formula} with 24 hour creatinine clearance and to identify which amongst the 3 formulae for eGFR closely correlates with 24 hour creatinine clearance in a secondary care hospital. MATERIALS AND METHODS: We retrospectively collected laboratory data requested for 24 hour creatinine clearance in the period from January 2014 to August 2016. Totally 91 laboratory request for 24 hour creatinine clearance data were obtained. The paired-t-test was used for comparison since all parameters used in the study were numerical, all patients came from same population and all had paired results. RESULTS: The eGFR by MDRD formulae had a statistically insignificant p-value (p > 0.05) i.e., good approximation in the IInd, IIIrd, IVth and Vth stages of CKD on comparison with 24 hour creatinine clearance. The eGFR by CKD-EPI formulae had a statistically insignificant p-value (p > 0.05) in the IInd, IVth and Vth stages of CKD. The eGFR by Cockcroft-Gault Formulae had a statistically insignificant p-value (p > 0.05) in the Ist, IInd and Vth stages of CKD. CONCLUSION: The Creatinine based GFR estimation provides a more accurate assessment of 24 hour creatinine clearance and kidney function than measuring serum creatinine alone but have certain limitations in few clinical circumstances. No single equation will be optimal for all populations. But the result of this study showed MDRD 2006 formulae to be more accurate than CKD-EPI 2009 and Cockcroft-Gault formulae in estimating GFR, detection of CKD, drug dosing and estimating prognosis. PMID- 28658749 TI - Analysis of Isocitrate Dehydrogenase -2 (IDH-2) Activity in Human Serum as a Biomarker in Chemotherapy Patients of Breast Carcinoma: A Case-Control Study. AB - INTRODUCTION: Breast cancer represents a major public health problem in women worldwide. For many cancers, serum tumour markers play an important role in patient treatment and monitoring. Isocitrate dehydrogenase enzyme is also used as a biomarker for various types of cancer. AIM: The purpose of this study was to determine serum Isocitrate dehydrogenase-2 (IDH-2) enzyme activity in breast cancer patients (pre and post chemotherapy) and also correlate the changes in enzyme activity with stages of cancer and control groups. MATERIALS AND METHODS: In this case-control study, histologically confirmed 40 female patients aged 28 80 years who fulfilled the criteria for diagnosis of invasive breast cancer were selected in our study groups from surgery outpatient department of SS Hospital, BHU, Varanasi, India, and 40 healthy age matched females were selected between October 2013 to July 2015. The estimation of serum IDH-2 enzyme activity in before and after two cycles of neoadjuvant chemotherapy patients was performed by spectrophotometry assay. RESULTS: The mean serum IDH-2 activity in cases (Mean+/ SD) was significantly more than control group (p<0.001). The mean serum IDH-2 activity in cases was significantly decrease after neo-adjuvant chemotherapy (p=0.019). In stage II pre chemotherapy patients serum IDH-2 activity was higher than post chemotherapy (p<0.05), but in stage III the correlation between pre and post chemotherapy patients serum IDH-2 activity was not significant (p value>0.05). CONCLUSION: The serum IDH-2 can be a potential biomarker in breast carcinoma and can be used for prognosis and monitoring the chemotherapy response of the patients. PMID- 28658751 TI - Fasting Insulin is Better Partitioned according to Family History of Type 2 Diabetes Mellitus than Post Glucose Load Insulin of Oral Glucose Tolerance Test in Young Adults. AB - INTRODUCTION: Hyperinsulinemia is contributed by insulin resistance, hepatic insulin uptake, insulin secretion and rate of insulin degradation. Family history of type 2 diabetes mellitus has been reported to cause hyperinsulinemia. AIM: Correlation of fasting insulin with post glucose load Oral Glucose Tolerance Test (OGTT) insulin in young adults and their partitioning according to family history of type 2 diabetes. MATERIALS AND METHODS: In this observational cross-sectional study, clinical evaluation and biochemical assays of insulin and diabetes related parameters, and secondary clinical influences on type 2 diabetes in volunteers were done for inclusion as participants (n=90) or their exclusion. Cut off levels of quantitative biochemical variables were fixed such that they included the effects of insulin resistance, but excluded other secondary clinical influences. Distribution was analysed by Shapiro-Wilk test; equality of variances by Levene's test; Log10 transformations for conversion of groups to Gaussian distribution and for equality of variances in the groups compared. When the groups compared had Gaussian distribution and there was equality of variance, parametric methods were used. Otherwise, non parametric methods were used. RESULTS: Fasting insulin was correlating significantly with 30, 60 and 120 minute OGTT insulin showing that hyperinsulinemia in the fasting state was related to hyperinsulinemia in the post glucose load states. When fasting and post glucose load OGTT insulin were partitioned into those without and with family history of type 2 diabetes, maximum difference was seen in fasting insulin (p<0.001), followed by 120 (p=0.001) and 60 (p= 0.002) minute OGTT insulin. The 30 minute insulin could not be partitioned (p=0.574). CONCLUSION: Fasting, 60 and 120 minute OGTT insulin can be partitioned according to family history of type 2 diabetes, demonstrating stratification and heterogeneity in the insulin sample. Of these, fasting insulin was better partitioned and could be used for baseline reference interval calculations. PMID- 28658752 TI - Relationship between Neutrophil-to-Lymphocyte Ratio and Stress in Multiple Sclerosis Patients. AB - INTRODUCTION: Multiple Sclerosis (MS), a disease of autoimmunity and inflammation, is characterized by deterioration of the myelin sheath that protects the nerve fibers. The high levels of neutrophils in serum may be related to the chronic inflammation and caused by other triggers such as infections that have been associated with relapses in MS. AIM: To investigate the value of Neutrophil/Lymphocyte Ratio (NLR) as a possible marker and relationship with Depression, Anxiety and Stress (DAS) score in MS patients. MATERIALS AND METHODS: A total of 60 MS patients and 60 age and sex matched healthy controls were recruited for the present study. We measured DAS score, NLR, calcium, phosphate, magnesium, chloride, alkaline phosphatase, albumin in serum levels in MS patients and in healthy controls. RESULTS: The mean age was not significantly different in both case and control groups. The case and control groups were similar in terms of sex; however, the majority of the MS group was female. The NLR values of MS patients were significantly higher than those of the healthy controls (p=<0.001). The NLR values were also significantly (p<0.001) correlated with stress score. CONCLUSION: NLR could be considered as a quick, cheap, easily measurable and inflammatory marker for assessment of inflammation in MS patients. The role of NLR in MS must be explored further. PMID- 28658753 TI - Effect of Menstrual Cycle Phases on Plasma Lipid and Lipoprotein Levels in Regularly Menstruating Women. AB - INTRODUCTION: Physiological cyclic variability in levels of sex hormones during a menstrual cycle may possibly have an impact on lipids, lipoprotein levels and therefore on cardiovascular health status of females. AIM: To ascertain the effect of menstrual cycle phases on the levels of cardiovascular risk predictors i.e., plasma lipids and lipoproteins in healthy menstruating women. MATERIALS AND METHODS: In the present study, 111 healthy regularly menstruating females aged 15 45 years were examined at two points of a menstrual cycle i.e., in the follicular phase (10th day) and in the luteal phase (22nd day) to find out the plasma levels of lipids and lipoproteins. The data were statistically analysed using paired t test. RESULTS: A significant decrease in the mean levels of Total Cholesterol (TC) (p=0.006), Low Density Lipoprotein Cholesterol (LDL-C) (p=0.004), TC/High Density Lipoprotein Cholesterol (HDL-C) (p=0.006), Low Density Lipoprotein Cholesterol (LDL)/HDL (p=0.01), and Triglyceride (TG)/HDL (p=0.02) was observed in the luteal phase compared to the follicular phase while TG (p=0.18), HDL-C (p=0.16). VLDL-C (p=0.17) did not show a significant difference although lower levels were observed in the luteal phase of TG and VLDL-C and higher levels for HDL-C. CONCLUSION: The present findings reveal high levels of oestrogen in the luteal phase compared to follicular phase of menstrual cycle. Clinicians should take menstrual cycle phase in account when inferring a women biomarker measurement in the analysis of cardiovascular diseases, particularly females possessing marginal levels. Moreover research studies should take the menstrual cycle phase in consideration which may be a confounding factor in framing and concluding studies on reproductive age group women. PMID- 28658754 TI - Effect of Recumbent Body Positions on Dynamic Lung Function Parameters in Healthy Young Subjects. AB - INTRODUCTION: The change in body position can alter pulmonary functions parameters, therefore it is important to understand the physiological basis of these alteration. Ideally, spirometry is done in sitting position until the subject is unable to do so. Hospitalized patients often assume recumbent body positions irrespective of underlying pathology. Hence, need arises to find out best recumbent body positions for the benefit of these patients to make breathing comfortable for them. AIM: The aim of this study was to find out whether the change from the supine position to crook lying and Fowler's position (45 degrees dorsal elevation) causes change in spirometric parameters. MATERIALS AND METHODS: The present work was carried out at Department of Physiology, King George's Medical University, Lucknow. A total 131 apparently healthy individuals were enrolled in this cross-sectional study. Lung function was assessed using a PC based spirometer according to American Thoracic Society guideline in the supine, crook lying and Fowler's position (45 degrees dorsal elevation). RESULTS: The study consisted of 131 subjects (male 66%, female 34%), with mean age of 20.15+/ 2.71 years and BMI 21.20+/-3.28 Kg/m2. Repeated measures ANOVA with post hoc Bonferroni test was used to compare the mean values between each body position. Compared with the other two positions, Fowler's position showed significantly (p<0.05) higher values for FVC, FEV1, PEF, FEF25-75%. CONCLUSION: Recumbent body position influences spirometric parameters in young healthy subjects. We demonstrated that spirometric values are higher in the Fowler's position than in the supine or crook lying position. The results of this study will help in the selection of the best alternative position for the spirometry in bed ridden patients. PMID- 28658755 TI - Occurrence of COPD in Patients with Respiratory Allergy: A Clinico-Spirometric Evaluation in a Tertiary Hospital, Kolkata. AB - INTRODUCTION: Smoking is established as the most important causative factor responsible for Chronic Obstructive Pulmonary Disease (COPD). Occurrence of allergy in COPD patients causes acute exacerbation of this disease, but role of allergy is not established in aetiopathogenesis of COPD. AIM: The present study was aimed at evaluation of occurrence of COPD in patients having symptoms suggestive of respiratory allergy. MATERIALS AND METHODS: An observational cross sectional study was conducted to evaluate occurrence of COPD in patients having respiratory allergic symptoms by routine spirometric screening. Five hundred and fifty urban patients aged 18-60 years (both gender) ailing from chronic respiratory symptoms like cough, wheeze and Shortness Of Breath (SOB), who were referred from OPDs of RGKMCH, Kolkata, were included in this study. After obtaining detailed clinical profile, patients were divided into two groups: subjects having additional clinical symptoms suggestive of respiratory allergy (n=260) like nasal catarrh, nasal stuffiness and sneezing and subjects with no symptoms suggestive of respiratory allergy (n=290). Thereafter, routine spirometry was carried out following recommendations of ATS/ERS (2005). Patients were then categorized based on FVC, FEV1, FEV1/FVC, FEF25-75 and PEFR percent predicted values. RESULTS: Study revealed that 18.97% of non-allergic population was suffering from COPD whereas only 7.69% of allergic subjects had COPD. This difference was statistically highly significant (p=0.0001). Although there was no significant difference in prevalence of respiratory symptoms between these two groups. CONCLUSION: Present study concludes that patients with respiratory allergy may have coexistent COPD but occurrence of COPD is much less than that in patients with no respiratory allergy. PMID- 28658756 TI - Unusual Severe Extra-Intestinal Manifestations of a Common Enteric Pathogen Aeromonas Spp. AB - INTRODUCTION: Aeromonas spp. are halophilic, Gram-negative bacilli. They are widely distributed in the soil and aquatic environment and have been associated with various extra-intestinal infections, such as skin and soft-tissue infections, meningitis, bacteraemia etc. The most common species associated with extra-intestinal infection is Aeromonas hydrophila. AIM: To get the overview of clinical presentations, underlying predisposing factors associated with the extra intestinal infections caused by Aeromonas species and their antimicrobial susceptibility pattern. MATERIALS AND METHODS: Extra-intestinal cases of Aeromonas spp. admitted during December 2015 to October 2016 in the tertiary care hospital of South Karnataka coastal region were analysed retrospectively. The isolates were identified by Matrix Assisted Laser Desorption Ionization Time-of Flight (MALDI-TOF) VITEK(r)MS and antimicrobial susceptibility testing was performed by VITEK(r)2 system (bioMerieux, Inc., Durham, NC) respectively. Clinical manifestations and management of the cases were noted from the clinical records. Clinical and microbiological findings presented as mean+/-standard deviation, frequency and percentage. RESULTS: We included 26 cases in this study, from whom Aeromonas spp. were isolated alone or with another microorganism. Most widespread infection was Skin and Soft Tissue Infection (SSTI) (24, 92.3%). In 50% (12/24) cases, SSTI developed due to trauma. In 45.8% (11/24), underlying co morbid conditions were present. The common site of infection was lower extremities (16/24, 66.7%) and 62.5% (15/24) of them presented with severe gangrene of the affected site. Other than SSTI, we encountered with two cases of keratitis and cholangitis respectively. A. hydrophila were frequently isolated species (23/26, 88.5%). The analysis of antimicrobial susceptibility showed, 13% isolates were Multidrug Resistant (MDR). Carbapenem resistance was also noted. CONCLUSION: We had isolated Aeromonas spp. from different extra-intestinal sites. Most common extra-intestinal manifestation by this organism was post-traumatic wound infection. Clinical spectrum of this infection confused the clinician with other organisms like group B Streptococcus, Clostridium spp. etc., and mislead them in empirical management. Finally with the microbiological support all the cases were treated either conservatively or in combination with surgical debridement or amputation depending on the situation. PMID- 28658757 TI - Molecular Strain Typing of Clinical Isolates, Trichophyton rubrum using Non Transcribed Spacer (NTS) Region as a Molecular Marker. AB - INTRODUCTION: Dermatophytes are a group of fungi which infect keratinized tissues and causes superficial mycoses in humans and animals. The group comprises of three major genera, Trichophyton, Microsporum and Epidermophyton. Among them Trichophyton rubrum is a predominant anthropophilic fungi which causes chronic infections. Although, the infection is superficial and treatable, reinfection/coinfection causes inflation in the treatment cost. Identifying the source and mode of transmission is essential to prevent its transmission. Accurate discrimination is required to understand the clinical (relapse or reinfection) and epidemiological implications of the genetic heterogeneity of this species. Polymorphism in the Non Transcribed Spacer (NTS) region of ribosomal DNA (rDNA) clusters renders an effective way to discriminate strains among T. rubrum. AIM: To carry out the strain typing of the clinical isolates, Trichophyton rubrum using NTS as a molecular marker. MATERIALS AND METHODS: Seventy T.rubrum clinical isolates obtained from April-2011-March 2013, from Sri Ramachandra Medical Centre, Chennai, Tamil Nadu, India, were identified by conventional phenotypic methods and included in this prospective study. The isolates were then subjected to Polymerase Chain Reaction (PCR) targeting two subrepeat elements (SREs), TRS-1 and TRS-2 of the NTS region. RESULTS: Strain specific polymorphism was observed in both subrepeat loci. Total, nine different strains were obtained on combining both TRS-1 and TRS-2, SREs. CONCLUSION: The outcome has given a strong representation for using NTS region amplification in discriminating the T. rubrum clinical isolates. The method can be adapted as a tool for conducting epidemiology and population based study in T. rubrum infections. This will help in future exploration of the epidemiology of T. rubrum. PMID- 28658758 TI - A Stratified Analysis of Clinical Manifestations and Different Diagnostic Methods of Neurocysticercosis-Suspected Tamilian Population Residing in and Around Puducherry. AB - INTRODUCTION: Human beings are accidental hosts for Cysticercus cellulosae showing varied clinical manifestations based on the site harbored by the parasitic cyst because of which disease profile remains unexplored at large. Besides this, diagnosis of the disease with a single conventional method is problematic due to lack of specificity and sensitivity. AIM: To assess the varied clinical manifestations and stratify based on imaging and serological methods for diagnosis of Neurocysticercosis (NCC) in our study population. MATERIALS AND METHODS: A hospital-based study was carried out at Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), the tertiary care centre caters patients from Puducherry and surrounding regions of Tamil Nadu. This is a cross sectional analysis of clinically and radiologically suspected cases of NCC (n=119) for a period of three years (2012 to 2015). The collection of detailed clinical history and imaging findings (MRI or CT) along with the lifestyle parameters was done after obtaining informed consent. Enzyme-Linked Immune Electro Transfer Blot (EITB) was carried out for the samples collected from study subjects. RESULTS: Based on dietary and environmental factors non-vegetarians, pork eaters, raw vegetable consumers and open-field defecation showed significant seropositivity. The clinical manifestations like seizures, blurring of vision and chronic headache with nausea followed by neck pain, cognitive deficits and movement disorder have higher seropositivity respectively. Generalized seizures were found to be more than focal seizures. While comparing the imaging and serological tests for NCC diagnosis, the positivity rate was 46.2% considering positive by both methods; but 18.5% of sero-positive cases were imaging negative, and 16% of the sero-negative cases were imaging positive. The study showed a predominance of multiple cysts (62%) in cases with cystic lesions. CONCLUSION: This study is first of its kind in associating varied and less commonly explored clinical manifestations with two different diagnostic measures in practice and its importance among our study settings. These manifestations must be considered as strong disease entities of NCC, which has to be suggested for differential diagnosis, and cannot be left ignored. Combinatorial diagnostic methods like serology and imaging techniques should be followed in diagnosis and assessing the disease burden. PMID- 28658760 TI - Shigella sonnei Sepsis in an Infant: A Case Report. AB - Shigella bacteraemia is a complication of gastroenteritis caused by Shigella spp. which occurs mainly in immunocompromised children. Other risk factors may include young malnourished children, patients with chronic disease, post transplant patients etc. We present a case of six-month-old infant who developed an episode of gastroenteritis caused by Shigella sonnei which was followed by septicaemia. The patient was managed well and he recovered. Shigella sonnei was isolated in both stool as well as blood culture. S.sonnei bacteraemia is a rare condition but we should always be vigilant. Blood cultures as well as stool cultures should be performed in patients presenting with acute febrile gastroenteritis, whether immunocompromised or not. This simple, early and prompt investigation may help in precise diagnosis, which will guide the clinician about appropriate intervention like antibiotic therapy and supportive care. PMID- 28658759 TI - Revisiting the Utility of Histopathological Examination of Biopsy: A Necessity in Microbiology. AB - INTRODUCTION: Culture is the gold standard, while potassium hydroxide mount is simplest technique used for diagnosis of fungal pathogens. Histopathological examination is the only definitive means to identify certain uncultivable fungi. AIM: To analyse role of histopathological examination and potassium hydroxide (KOH) mount for diagnosing fungal infections by correlating them with culture. MATERIALS AND METHODS: In this nine year retrospective study, all biopsy specimens submitted for microbiological examination were included. Histopathological examination of biopsies of cases with positive microbiological findings on either KOH mount or culture was carried out. Any discrepancy between histopathology interpretation and microbiology KOH or culture results, taking culture as the gold standard, were noted. STATISTICAL ANALYSIS: Open Epi software was used for statistical analysis. Comparisons between groups were made by using the chi-square test. A p-value < 0.05 was considered statistically significant. Cohen's Kappa coefficient (kappa) was calculated as a measure of agreement between different variables. RESULTS: Concurrent pathology specimen could be obtained in 70 samples positive for fungal elements in either KOH or culture. Thirty-two cases were positive for fungi in culture, of which 16 were correctly identified by histopathological examination. Histopathological examination was strongly associated with culture result. KOH mount was in good agreement with positive culture result for yeast. Eleven culture negative but KOH and histopathology positive cases included seven samples with hyphae suggestive of zygomycosis, and two cases of rhinosporidiosis. Allergic mucin was strongly associated with Aspergillus species. KOH mount and detection of allergic mucin on histopathological examination were found to be excellent complementary tools for diagnosing Aspergillus species. Necrosis was highly specific for fungal growth in culture and had good positive predictive value. CONCLUSION: We advocate using histopathology, culture and KOH examination in an integral manner to avoid potential lapses in patient management. PMID- 28658761 TI - Ebola Vaccine: How Far are we? AB - Ebola viruses have been identified as an emerging threat as it causes severe haemorrhagic fever in human with mortality rates ranging from 50 to 90%. In addition to being a global health concern, the virus also is considered a potential biological threat agent. As for now, no licensed vaccine is available for pre or post exposure treatment. Recent epidemic of this disease in South Africa has led to concern towards development of an effective vaccine on a priority basis. This review is an attempt to look upon current progress in the development of Ebola virus vaccines and highlights strategies that have the greatest potential for commercial development. PMID- 28658762 TI - Role of Immunofluorescence in Adult Onset Nephrotic Syndrome-A Study in a Tertiary Care Centre of Western India. AB - INTRODUCTION: Study of renal Immunofluorescence (IF) is an ancillary but essential technique in evaluation of renal biopsies in glomerulopathies and also it enlightens on the pathogenesis of nephrotic syndrome. AIM: To determine the role of IF in evaluating definite subtyping and diagnosis of adult onset nephrotic syndrome and attempting clinicopathological correlation. MATERIALS AND METHODS: A total of 52 patients of adult onset nephrotic syndrome were evaluated clinically and with pertinent investigations; and subjected to USG guided percutaneous renal biopsy which was processed and stained for light microscopy and for immunofluorescence by direct method (DIF) using antibodies against IgG, IgM, IgA and C3. RESULTS: The predominant age group affected was 18-47 years (78.85%). Male:female ratio was 1:0.63. The most frequent glomerular lesion encountered was Focal Segmental Glomerulosclerosis (FSGS, 36.54%) followed by lupus nephritis (26.92%) and IgA nephropathy (9.62%). The most common glomerular lesion in males was FSGS and that in females was lupus nephritis. DIF was mainly coarsely granular whenever present. One case of lupus nephritis and diabetic nephropathy, showed non specific IF. It was negative in all cases of FSGS, Minimal Change Disease (MCD) and renal amyloidosis. The IF helped in differentiating eight cases that were normal on light microscopy as IgA nephropathy (n=5) and authentic MCD (n=3). It helped in endorsing 19 cases of FSGS to be a progression of MCD. It was also of help in sub-typing all cases of Membranoproliferative Glomerulonephritis (MPGN) (n=3) as MPGN-Type I. CONCLUSION: IF was of great help in diagnosing exact type of glomerulopathy in adult onset nephrotic syndrome and provided insight in its pathogenesis. PMID- 28658763 TI - Erythrocytes and Platelets: A Critical Analysis of their Ontogenic Relationship through Automated Parameters. AB - INTRODUCTION: Erythrocytes and platelets share an intimate development history, due to which special interest is centered on their relationship. Mature Red Blood Cells (RBCs) and platelets show a similar physiological rhythm, and are concurrently involved in numerous pathologic states. AIM: To identify subtle relationships between various RBC and platelet parameters with an objective to analyse if a linear correlation co-exists between and among them in physiological/pathological states. MATERIALS AND METHODS: A prospective analysis of 1250 EDTA blood samples was conducted. The five RBC parameters (RBC count, HCT, MCV, RDW, Hb) and four platelet parameters (platelet count, PCT, MPV, PDW) obtained from each case were statistically analysed for linear dependence. RESULTS: A statistically significant direct linear relationship was found between RDW with platelet count and PCT. A statistically significant inverse linear relationship was noticed between the following parameters: i) HCT with platelet count and PCT; ii) MCV with platelet count and PCT; iii) Haemoglobin and platelet count. CONCLUSION: A linear correlation, either direct or inverse, was seen among various parallel RBC and platelet parameters. PMID- 28658764 TI - Evaluation of Histologically and Histochemically Proven Cases of Vitiligo and its Correlation with CD4+ and CD8+ Lymphocyte Counts using Flow Cytometry. AB - INTRODUCTION: Vitiligo is an acquired cutaneous disorder characterized by progressive and selective destruction of melanocytes from the epidermis. Autoimmunity is strongly implicated in its pathogenesis. The destruction of melanocytes has a correlation with the peripheral blood lymphocyte imbalance mainly including Cytotoxic T cells (CD8+cells) and Helper T cells (CD4+cells). The progression of vitiligo is associated with higher CD8+ counts and lower CD4+ counts thus, altering CD4+: CD8+ ratio. AIM: To evaluate the clinically suspected cases of vitiligo histopathologically and histochemically and to establish the co relation of autoimmunity with the flow cytometric analysis of CD8+ and CD4+ lymphocyte counts. MATERIALS AND METHODS: In this study, 40 patients with proven vitiligo were taken. The destruction of melanocytes was confirmed by Haematoxylin & Eosin (H & E) and by histochemical stains using Dihydroxyphenylacetic Acid (DOPA) reaction. Blood sample from these vitiligo patients and 10 control subjects was taken. Flow Cytometry was used for the determination of CD8+ and CD4+ counts in the vitiligo patients and control subjects. Then CD4+: CD8+ ratio was calculated and comparison between vitiligo patients and control subjects was done. T-test was used for the statistical analysis. RESULTS: There was statistically significant decrease in CD4+: CD8+ ratio. CD4+: CD8+ ratio was decreased in 57.5% cases of vitiligo with increase in CD8+ counts and decreased CD4+ counts. CONCLUSION: It was concluded from this study that cellular immunity might have a role to play in the pathogenesis of vitiligo causing the destruction of melanocytes. PMID- 28658765 TI - Prevalence of Lung Lesions at Autopsy: A Histopathological Study. AB - INTRODUCTION: Autopsies are carried out to establish the identity, cause of death, time of death, and ante-mortem or post-mortem nature of death. These help in establishing the cause of death and ascertain the disease process which led to death. AIM: To study the prevalence and pattern of lung diseases in medicolegal autopsies, confirmed by histopathological examination. MATERIALS AND METHODS: This retrospective study was carried out in the Department of Pathology. Tissue bits from lungs, retrieved at the time of autopsy, were preserved in 10% formalin. These were processed and examined microscopically. A total of 86 cases were received during the period of study. RESULTS: Among these 86 cases, in 4 cases (4.8%) the tissue was autolysed and in another 26 cases (30.1%) histopathology was unremarkable. Significant microscopic findings were found in 56 cases (65.1%). Wide spectrum of microscopic findings were seen, the commonest being oedema and congestion (28.5%) followed by changes in interstitium (11.9%). There were 9.5% cases of granulomatous inflammation and 5.9% cases each of acute pneumonia and emphysema. There were 1.2% cases each of Hyaline Membrane Disease (HMD), Meconium Aspiration Syndrome (MAS) and Acute Respiratory Distress Syndrome (ARDS) in the series. The series also had 1.2% cases of young adult having fungal colonies surrounded by necrosis and abscess formation. Possibility of mucormycosis was suggested in that case. CONCLUSION: This study highlights various lesions in lungs confirmed by histopathology, which were either incidental or direct cause of death. The short coming in present study was non receipt of whole organ or representative sample at the time of autopsy, which if overcome will set much higher standard of autopsy reporting and would be a more useful tool in understanding cause of death. PMID- 28658766 TI - Clinicopathological Study of Carcinoma of the Ampulla of Vater with Special Reference to MUC1, MUC2 and MUC5AC Expression. AB - INTRODUCTION: The ampulla of Vater consists of papilla, common channel, distal common bile duct and the distal main pancreatic duct. Ampullary carcinomas arise from two different types of mucosa, reflecting their broad histomorphological spectrum. Adenocarcinomas originating in the ampulla of Vater are classified as having either 'Intestinal' or 'Pancreatobiliary' type of differentiation. Pancreatobiliary type has consistently shown a worse prognosis. Various types of mucins are distributed in normal tissues and gastrointestinal tumours. MUC1, MUC2 and MUC5AC are known to be the most important amongst all. AIM: To study clinicopathological features of different types of carcinoma of ampulla with MUC1, MUC2 and MUC5AC expression. MATERIALS AND METHODS: We included 20 cases of ampullary adenocarcinoma in this study, diagnosed after radical surgery. The histopathological slides were reviewed and the tumours were classified into intestinal type, pancreatobilliary and other types. Representative block of tumours was subjected to immunohistochemical (IHC) study with MUC1, MUC2 and MUC5AC antibodies. Results were subsequently analysed. RESULTS: Pancreaticobiliary type of ampullary carcinoma cases predominated (50%) over intestinal type (25%). Carcinomas of "other types" included one case each of mucinous carcinoma, adenosquamous carcinoma and undifferentiated carcinoma and well differentiated neuroendocrine tumours. Pancreatobiliary type of carcinomas was associated with higher tumour stage and grade and lymph node metastasis. All the pancreatobiliary type expressed MUC1 and all intestinal type carcinomas expressed MUC2. MUC 5AC expression was seen predominantly in pancreatobiliary type of ampullary carcinomas. CONCLUSION: Mucin markers are associated with two different subtypes of ampullary carcinomas which have different prognosis. Immunohistochemical study of mucin expression can define the different types of carcinomas of ampulla of Vater with better objective criteria. PMID- 28658767 TI - Serial Changes in Complete Blood Counts in Patients with Leptospirosis: Our Experience. AB - INTRODUCTION: Leptospirosis is an infectious disease caused by Leptospira interrogans. It is endemic in many parts of the world. The symptoms vary between milder forms to severe type with organ dysfunction. The disease presents with diagnostic challenge as it clinically mimics acute febrile illness due to other causes. AIM: To study serial changes in complete blood counts in patients with leptospirosis. MATERIALS AND METHODS: A retrospectively collected data was prospectively studied for clinical and laboratory data of leptospirosis patients proven by raised IgM titres by ELISA on day 2 (counted from day of admission of patient to hospital) of unexplained fever. The changes in complete blood counts from admission upto the discharge of the patient were studied. SPSS version 13 (SPSS Inc. Chicago) was used for data analysis. The collected data was analysed using frequency, percentage, mean, median, standard deviation and Mann-Whitney test. A p-value less than 0.05 were considered significant. RESULTS: Mean haemoglobin concentration showed a progressive decline (<12.5 gm/dl) from day 1 to day 7 in both mild and severe disease. Platelet counts were significantly low (p=0.002), (<1,50,000 cells/mm3) in severe disease and showed a declining trend as compared to mild disease. Total leukocyte counts were significantly higher (p=0.001), (>11,000 cells/m3) in patients with severe disease from day 4 to day 5 of the illness. CONCLUSION: Complete blood count is a routine test done in the monitoring of patients with leptospirosis. Declining haemoglobin, marked thrombocytopenia and a normal to high total leukocyte count will help in early detection of severe disease and thus preventing mortality by timely management. PMID- 28658768 TI - Clinicopathological Analysis of Glomerular Disease of Adult Onset Nephrotic Syndrome in an Indian Cohort- A Retrospective Study. AB - INTRODUCTION: Primary glomerular disease presenting with adult onset nephrotic syndrome are a major cause of chronic renal failure worldwide. The spectrum of renal disease presenting with nephrotic syndrome has undergone a gradual change globally over the course of time. However, there still exist regional differences in the incidence of primary glomerular diseases causing adult onset nephrotic syndrome. AIM: To observe the spectrum of renal diseases presenting with adult onset nephrotic syndrome with comparative analysis of changing trends over the last five decades with regards to Western and Indian literature. MATERIALS AND METHODS: Subjects included patients with age of 18-80 years presenting with nephrotic syndrome. Renal biopsies with immunofluoroscence studies were performed in all patients. Baseline clinical parameters of serum urea, creatinine, albumin, globulin, cholesterol, 24 hour urine protein and urine microscopy were recorded. Descriptive statistics was used and results were expressed as frequencies, percentages, and mean+/-standard deviation. RESULTS: A total of 227 patients (72% males) were included for the study. Primary glomerular diseases formed 74.01% of total cases and majority of patients included males in the 4th decade. Minimal Change Disease (MCD) (15.8%) including its variants was the most common primary glomerular disease for adult onset of nephrotic syndrome followed by Mesangial proliferative Glomerulonephritis (MSGN) (13.2%). Membranous nephropathy and Type I Membranoproliferative Glomerulonephritis (MPGN) individually accounted for 12.3% of patients. Focal and Segmental Glomerulosclerosis (FSGS) accounted for only 11% of patients. Although, increased incidence of FSGS has been observed worldwide, there exist important regional differences in primary glomerular diseases in Indian population. MCD remains a major glomerular disease for adult onset nephrotic syndrome in different parts of India. CONCLUSION: Our study over three years represents important data of regional variations of primary glomerular diseases presenting with adult onset nephrotic syndrome. PMID- 28658769 TI - Expression of Podoplanin in Laryngeal Squamous Cell Carcinoma and Dysplasia. AB - INTRODUCTION: In human cancers, podoplanin expression and its correlation with tumour invasive potential raise its possible role as a diagnostic and prognostic marker for cancer. AIM: To investigate the immunohistochemical expression of podoplanin in laryngeal Squamous Cell Carcinoma (SCC) and dysplasia. MATERIALS AND METHODS: This study included a total of 60 archived, formalin fixed, paraffin embedded tissue blocks of 40 cases of laryngeal SCC and 20 cases of dysplastic lesions. The samples were immunohistochemically analysed for podoplanin expression. RESULTS: Podoplanin expression was significantly higher in laryngeal SCC (90%) than laryngeal dysplastic lesions (55%) (p-value=0.002). The expression of podoplanin was significantly increased with the higher grades of dysplasia (p value=0.016). A significant positive correlation was detected between podoplanin expression in laryngeal SCC and depth of tumour invasion (p-value=0.035), and stage (p-value=0.026). CONCLUSION: The high expression of podoplanin in laryngeal SCC and its significant correlation with poor prognostic parameters recommends podoplanin as a prognostic marker in laryngeal SCC. In addition, increased podoplanin expression with higher grades of dysplasia, supports its role in malignant transformation and allows us to recommend its evaluation in premalignant lesions. PMID- 28658770 TI - Diagnostic Utility of Epithelial Membrane Antigen (EMA) and Calretinin (CAL) in Effusion Cytology. AB - INTRODUCTION: Fluid cytology and subsequent utilization of immunocytology on cell block is being used commonly for increasing the diagnostic accuracy in effusion cytology. AIM: To do cytological analysis of fluids and evaluate the role of Epithelial Membrane Antigen (EMA) and Calretinin (CAL) to differentiate between reactive and malignant cell in pleural and peritoneal fluids. MATERIALS AND METHODS: This was a prospective study carried out in Department of Pathology, Shri Guru Ram Rai Institue of Medical and Health Science, for a period of 18 months from January 2014 to June 2015. A total of 253 samples of pleural and peritoneal fluid were studied by May-Gruenwald-Giemsa (MGG) stain and Papanicolaou (Pap) staining. In 73 cases which were suspicious for malignancy, cell blocks were prepared and IHC was done using two immunomarkers- EMA and CAL. RESULTS: A total of 253 cases of effusion cytology were studied out of which 73 were found positive for malignant cells. Maximum cases of malignant cells or atypical cells were seen in peritoneal fluid. A total of 34 cases were histologically positive for malignancy. All these cases showed strong membranous and cytoplasmic positivity for EMA. Most of cases also showed 2%-5% positivity for CAL. There were 38 cases categorized as atypical or reactive mesothelial cell hyperplasia. These cases showed nuclear and cytoplasmic staining for calretinin and none of these were positive for EMA, although 5 cases showed score 2-3, which was considered as negative. CONCLUSION: The distinction between reactive and malignant mesothelial cells in cytological specimens can be problematic. A combination of CAL and EMA may help in accurate diagnosis. PMID- 28658771 TI - A1 and A2 Sub-Types of Blood Group 'A': A Reflection of their Prevalence in North Karnataka Region. AB - INTRODUCTION: Landsteiner ABO system of blood groups is most important for transfusion medicine and has subtypes of A Antigen, A1 and A2, upon which further groups of A and AB have been classified. Of individuals with A antigen, approximately 20% belong to A2 while rest 80% belong to A1. Anti-A1 Lectin, a cold agglutinin which destroys A1 cells is clinically significant when they react at 37 degrees C, causing transfusion reactions. AIM: To assess the prevalence of A1 and A2 subgroups in the population. MATERIALS AND METHODS: This was two year retrospective analysis of blood groups of donors coming to the blood bank of Karnataka Institute of Medical Science, Hubli, Karnataka, India. The data of the subgroups A and AB was analysed. RESULTS: 20,864 donors were analysed. Of 5466 (26.20%) of A group, 5406 (98.90%) belonged to A1 subgroup and only 60 (1.10%) belonged to A2 subgroup. Of 1708 donors with blood group AB, 1532 (89.70%) belonged to A1B subgroup and 176 (10.30%) belonged to A2B. It was noted that A2 in AB blood-group, as A2B, was more frequent in occurrence than presence of A2 as an A blood group. Rhesus negative frequency in these subgroups was also reported. CONCLUSION: Having known the prevalence of A1 and A2 subgroups and incorporating them into the ABO grouping system can limit these minor, yet dangerous, transfusion incompatibilities. PMID- 28658773 TI - Haemostatic Disorder in Women with Unexplained Menorrhagia: A Tertiary Care Centre Experience from Northern India. AB - INTRODUCTION: Menorrhagia is a common gynaecological problem and its cause remains unexplained in a significant proportion of females. AIM: The present study was done to diagnose a wide range of haemostatic disorders which can give rise to menorrhagia in women of adolescent, postadolescent and perimenopausal age group. MATERIALS AND METHODS: A total of 1100 women presenting to gynaecological emergency with complaints of menorrhagia underwent comprehensive evaluation. After excluding local pelvic pathology and hormonal disorders as a cause of menorrhagia 104 women were included in this study. Screening investigations including bleeding time, prothrombin time, activated partial thromboplastin time, platelet count and morphology were done. The following diagnostic investigations were carried out as and when required. Platelet aggregation tests using adenosine diphosphate and ristocetin, platelets function tests, specific factor analysis as and when required. RESULTS: Age of patients ranged from 13 years to 46 years. Eighteen patients had menorrhagia since menarche. Seven patients had family history of abnormal bleeding. Twenty three patients were found to have systemic haemostatic disorder (10 patients of Von Willebrand Disease (vWD), seven of Glanzmann-Thrombasthenia, one of Bernard- Soulier syndrome and five of immune thrombocytopenic purpura). CONCLUSION: From this study it is concluded that systemic haemostatic disorders are found in substantial number of women presenting with menorrhagia. Hence, after excluding organic/hormonal cause, haemostatic disorders should be considered before taking patient for invasive surgical procedures. PMID- 28658772 TI - Immunohistochemical Expression of Human Epidermal Growth Factor Receptor 2 (HER2) and p53 in Gastric Adenocarcinoma: A Pilot Study from Northern India. AB - INTRODUCTION: After the recent approval of Trastuzumab (anti-HER2 antibody) for the treatment of HER2 overexpressed Gastric Adenocarcinoma (GA), importance of HER2 testing is increasingly recognized. However, there is paucity of studies for HER2 overexpression in the Indian patients of GA. Similarly, study of p53 expression in the Indian patients of GA is infrequent. AIM: To study immunohistochemical expression of HER2 and p53 in GA biopsy samples. MATERIALS AND METHODS: This was a cross-sectional observational study. The expression of HER2 and p53 by immunohistochemistry were analyzed in 50 cases of GA. The HER2 expression was scored as negative (0 and 1+), equivocal (2+), and overexpression (3+). The p53 expression was quantified as negative (0-9% tumour cells) and positive (>=10% tumour cells). The intensity of p53 expression was assessed as strong and weak. RESULTS: Mean age of the patients was 56.8+/-14.8 years. Male:female ratio was 2:1. Histological types of adenocarcinoma were intestinal (68%), diffuse (28%), and indeterminate (4%). HER2 overexpression and equivocal results were present in 10% cases, each. Overall, a positive expression of p53 was seen in 72% (strong and weak intensities: 66.7% and 33.3% cases, respectively). CONCLUSION: As compared to HER2 overexpression, a higher incidence of p53 expression was seen (10% vs.72%) in GA. PMID- 28658774 TI - Squamous Cell Carcinoma of Cervix with Isolated Metastasis to Ethmoidal Sinus: A Rare Occurrence. AB - Squamous Cell Carcinoma (SCC) of the cervix is a highly prevalent malignancy. Its spread and metastasis is mostly loco-regional. The occurrence of distant extra pelvic metastases is exceedingly rare, particularly with the involvement of paranasal sinus. This case report documents an unusual presentation of a 45-year old female diagnosed and treated for squamous cell carcinoma of cervix with metastatic deposits in the ethmoidal sinus without deposits in any intervening foci. PMID- 28658775 TI - Lymphovascular Malformation - A Report of Two Cases. AB - Congenital Vascular Malformations (CVM) represents a group of vascular anomalies that are the result of defective development of the vascular system. Lymphatic malformation consists of dilated lymphatic vessels caused by occlusion of the lymphatic drainage system due to congenital malformations or acquired causes such as the effects of trauma, infection, or surgery. Lymphaticovenous Malformation (LVM) is composed of lymphatic and venous channels. The most common sites are the neck and axilla. We report two cases of a four and a half-year-old and a seven year-old child who presented with complaints of swelling in arm and groin respectively. A provisional diagnosis was made on radiological investigations. Excision was done and the diagnosis was confirmed on histopathology and immunohistochemistry. The cases which were presented as LVMs are rare congenital tumours and require a high index of suspicion on part of pathologist and surgeon to reach a definitive diagnosis. PMID- 28658776 TI - Acinic Cell Carcinoma Papillary-Cystic Variant: Diagnostic Pitfalls in Fine Needle Aspiration Cytology. AB - Acinic cell carcinoma is a rare tumour comprising 1%-3% of all salivary gland neoplasms. Acinic Cell Carcinoma Papillary Cystic Variant (ACC-PCV) is a distinct subtype and shows variegated appearance on cytology. It is important to differentiate it from other malignant lesions because of its poor prognosis. We describe a case of 20-year-old female with swelling on left cheek for the last four months. Fine needle aspiration was done and diagnosed as intermediate grade mucoepidermoid carcinoma on cytology. Histological study of the resected tumour showed features of ACC-PCV. We are presenting this case to illustrate the diagnostic problems encountered in cytology and important points to be kept in mind while reporting FNA of salivary gland tumours. PMID- 28658777 TI - Detection of Compound Heterozygous Sickle Cell-beta+ Thalassaemia in a Patient with Extreme Weakness, Mild Jaundice and Moderate Anaemia - A Case Report. AB - A 16-year-old female complained of extreme weakness. She had moderate anaemia; her Haemoglobin (Hb) was 7.7 gm/dl. Peripheral blood smear showed few sickled red cells. Sickle cell test was positive. High-Performance Liquid Chromatography (HPLC) revealed elevated levels of HbS (38.4%) and HbF (15.7%). In addition, HbA2 concentration was 3.8% and HbA concentration was 42.1%. Results suggested a diagnosis of compound heterozygous sickle cell-beta+ thalassaemia. Sickle cell test was also positive with blood of patient's brother; Hb HPLC examination showed relatively low concentration of HbS (25.2%) suggesting a diagnosis of sickle cell trait. Chromatogram of patient's step sister suggested a diagnosis of thalassaemia trait. Findings of this study suggested that abnormal genes were inherited in the patient from both the parents. It was interpreted that repeated haemolysis in the patient might have contributed to anaemia, weakness, rise in indirect bilirubin and jaundice. Furthermore, high level of HbF (>12%) may interfere with polymerization of sickle haemoglobin suggesting beneficial effects of HbF-inducing agents which may inhibit sickling. PMID- 28658778 TI - Pure Primary Extragonadal Retroperitoneal Yolk Sac Tumour in a Young Child: A Case Report. AB - Germ Cell Tumours (GCTs) in children are uncommon, constituting approximately only 3% of all malignancies in children younger than 15 years of age. Primary extragonadal GCTs constitute only 1-5% of all GCTs and a retroperitoneal site is seen only in 4% of all extragonadal GCTs. Extragonadal GCTs arise from local transformation of primordial germ cells which have been misplaced during the migration of these cells through the midline dorsal mesentery in the fourth-sixth week of embryogenesis. GCTs in children show remarkable variability in age, site, presentation and histology. This is the case of a three-year-old male child who presented with a history of an abdominal swelling which was rapidly progressive in nature. Radiology showed a large retroperitoneal mass and lesions in the liver. Histopathology, immunohistochemistry and serum Alpha-fetoprotein (AFP) values confirmed a diagnosis of pure primary extragonadal yolk sac tumour. PMID- 28658779 TI - Sclerosing Mediastinitis Presenting as Complete Heart Block. AB - Sclerosing Mediastinitis (SM) is a rare condition which is characterized by the presence of dense fibrosis which infiltrates and encroaches upon various structures in the mediastinal cavity. Depending on the extent and the predominant organ of involvement, the patient presents with symptomatology of dysphagia, superior vena cava compression syndrome or dyspnoea. However, the involvement of the heart is rarely seen. Aetiologies of SM are several, with infections being the most common. We discuss a case of SM involving the oesophagus, descending aorta, hilum of lungs and the heart secondary to mucormycosis in an immunocompetent male. PMID- 28658780 TI - Pericardial Haemangioma: A Common Tumour in an Unusual Location: Case Report and Review of Literature. AB - Overall incidence of primary cardiac tumour ranges from 0.0017% and 0.27% at autopsy. Cardiac haemangiomas are rare, and account for 2.8% of benign cardiac tumours. Pericardial haemangiomas, in particular are extremely rare. Pericardial haemangiomas are reported to present with a variety of symptoms such as dyspnea, palpitation, atypical chest pain. Other symptoms like obstruction of blood vessels, cardiac tamponade, or pericardial effusion may result due to compression of surrounding structures. Here, we report a case of pericardial haemangioma in a patient who presented with breathlessness and cough. PMID- 28658781 TI - Synchronous Primary Endometrial Carcinoma and Metastatic Malignant Melanoma in Cervical Lymph Node. AB - The occurrence of dual malignancies is not rare but concurrent occurrence of two malignancies with different histogenesis and different anatomical sites is not known. In the studies which have been conducted so far, none of them has shown the simultaneous occurrence of metastatic malignant melanoma and primary endometrial carcinoma. We report herein a case of a 42-year-old female diagnosed with metastatic malignant melanoma in cervical lymph node with unknown developing primary endometrial carcinoma within two months. No foci of primary malignant melanoma were found in uterus. Dual primary malignancy is being suggested by the presence of two malignancies in a patient with different morphological picture on histopathological examination, at anatomically distinct sites. Malignant melanoma and endometrial carcinoma, being a rare combination, prompted us to report the case. PMID- 28658782 TI - Unusually Detected Anti-M Antibody Presenting as Cross Match Incompatibility in a Female Child Diagnosed with Small Round Cell Tumour. AB - MNS antigen system is one of the human blood group systems. Anti-M antibody is a relatively common, naturally occurring antibody of IgM variety. Clinically significant anti-M antibody is reactive at 37 degrees C in the anti-human globulin phase due to high thermal amplitude of IgM component or presence of IgG component. If anti-M antibody is activated at 37 degrees C or in the anti-human globulin phase, it may cause delayed haemolytic transfusion reactions or haemolytic disease of newborn, which suggest variable clinical significance. We report a case of an unusually detected anti-M antibody presenting as cross match incompatibility in a one-year-old female child with a lump in the right lumbar region, which was later diagnosed as small round cell tumour in the right kidney. PMID- 28658783 TI - Sinonasal Schwannoma - A Case Report. AB - Schwannomas are benign peripheral nerve sheath tumours that may occur throughout the body. They rarely occur in the nasal cavity. Paranasal schawannomas are uncommon lesions, representing less than 4% of all head and neck schawannomas. Here we report a case of sinonasal schwannoma in a 35-year-old man who presented with a history of nasal blockage since two years. The mass was removed successfully without any postoperative complication and there was no recurrence within a year of follow up. PMID- 28658784 TI - An Extremely Rare Case of Small Cell Carcinoma in Submandibular Salivary Gland. AB - Small Cell Carcinoma (SCC) of the salivary gland is a rare and aggressive tumour accounting for about less than 1% of the salivary gland tumours. Submandibular gland involvement is extremely rare. These tumours frequently present with metastasis to lymph node and distant organs. We report a case of a 30-year-old male patient who presented with a swelling on the left side of the face below the jaw and the floor of the mouth. The tumour was excised followed by histopathological evaluation and diagnosed as SCC of left submandibular gland. Immunohistochemistry was positive for pan cytokeratin, synaptophysin, chromogranin, Ki-67, CK5/6, and negative for Thyroid Transcription Factor (TTF-1) which confirmed that the tumour was SCC of submandibular salivary gland. PMID- 28658785 TI - Cystic Sertoli-Leydig Cell Tumour in a Postmenopausal Woman with Absent Virilising Symptoms: A Diagnostic Challenge. AB - A 60-year-old postmenopausal woman, presented with a left ovarian cystic mass with mildly elevated CA125 levels. An intraoperative frozen section showed oedematous ovarian stroma with interspersed large aggregates of spindle shaped stromal cells. Subsequently, the excised specimen was reported as Sertoli-Leydig Cell Tumour (SLCT) of intermediate differentiation. The leydig cells were identified in the imprint smears, but were misinterpreted as luteinized cells. The lack of tubular differentiated cells in frozen section had contributed to the misdiagnosis. Immunohistochemistry (IHC) played an important diagnostic role in the absence of clinical suspicion and lack of virilising features that are classically described in association with SLCTs. This case is unusual, as the tumour was seen in a postmenopausal woman in the absence of virilising symptoms. The cytomorphological features, IHC findings and the reasons for misdiagnosis are discussed in this case report. PMID- 28658786 TI - Xanthogranulomatous Cholecystitis with Florid Ducts of Luschka: Double Trouble Mimicking Malignancy. AB - Xanthogranulomatous Cholecystitis (XGC) is an uncommon inflammatory condition of gall bladder, which is often misdiagnosed as malignancy preoperatively, leading to extensive surgical resections which may not be necessary for the patient. Ducts of Luschka are a rare developmental variant of the biliary tree, which are prone to injury and bile leak during cholecystectomy. We report a case of a 52 year-old male patient who was taken up for surgery with a provisional diagnosis of chronic calculous cholecystitis. Intraoperative finding of dense adhesions, made the surgeons suspect malignancy. On histopathological examination, it was not only diagnosed as a case of XCG, but it also had florid ducts of Luschka, another rare variant needing documentation as it is a close mimicker of malignancy. PMID- 28658787 TI - Gastric Glomus Tumour Misdiagnosed as Gastric Carcinoid: An Unfamiliar Entity with Aids to Diagnosis and Review of Literature. AB - Glomus tumour (GT) is a rare mesenchymal tumour of the stomach with Gastrointestinal Stromal Tumour (GIST), leiomyoma and schwannoma being far more common and comprising more than 90% of all gastric mesenchymal tumours. As glomus bodies are located in the peripheral parts of the human body, these tumours are peripherally located, classically the subungual region, hands, feet and trunk. While being evaluated for renal problems, a middle aged lady was incidentally found to have a gastric tumour. This was submucosal in location and was excised by a wedge resection and reported elsewhere as carcinoid tumour. The patient came to our hospital for further management. The biopsy was reviewed here and the modified diagnosis given was GT, confirmed by panel of immunohistochemistry. Two years after regular clinical follow up the patient is free of disease or any distant metastasis. In this paper the authors discuss the potential pitfalls, differential diagnoses and diagnostic clues that help in diagnosing this gastric tumour. PMID- 28658788 TI - Pure Uterine Lipoma: A Common Tumour at an Uncommon Site. AB - Although lipomas are very common tumours, pure uterine lipomas are extremely rare. Their reported incidence is 0.03-0.2%. They commonly present with symptoms similar to that due to leiomyoma except that they occur in post menopausal elderly females. We report a case of 70-year-old elderly female, who presented with third degree uterovaginal descent. A total vaginal hysterectomy was done for her. The hysterectomy specimen showed presence of a well circumscribed uterine fundal lipoma. We report this case because of its rare occurrence in the uterine fundus. PMID- 28658789 TI - Cytological Diagnosis of Primary Cutaneous Aspergillosis Masquerading as Lipoma in a Known Case of Lepromatous Leprosy. AB - Primary cutaneous aspergillosis is a rare disease, caused by organisms like Aspergillus flavus and Aspergillus fumigatus. Fine Needle Aspiration Cytology (FNAC) is a simple and well established tool for the diagnosis of mycotic infections. We report a case of forearm swelling that presented clinically as lipoma in a known case of lepromatous leprosy. It was diagnosed as primary cutaneous aspergillosis on FNAC, which was subsequently confirmed on culture. Cutaneous aspergillosis co-existing with leprosy has rarely been reported in the literature and early diagnosis of aspergillosis in immunocompromised patients is mandatory. PMID- 28658790 TI - Bilateral Primary Papillary Serous Carcinoma of the Fallopian Tube. AB - Primary fallopian tube carcinoma is considered one of the rarest female genital cancers, and its bilateral occurrence is even rarer. Because of the rarity of fallopian tube carcinomas as well as the clinical presentation which simulates an ovarian cancer, a correct preoperative diagnosis of fallopian tube carcinoma is seen only in 4% of cases, and is usually first appreciated by Pathologists. We are reporting our experience of a case of bilateral primary serous carcinoma of the fallopian tube in a 36-year-old female. PMID- 28658791 TI - Ectopic Parathyroid Adenoma Presenting as a Mediastinal Mass. AB - A parathyroid adenoma present in an ectopic site, in the anterior mediastinum, is a rare cause of persistent hyperparathyroidism. Though its occurrence in the mediastinum is unusual, existence has been noted in literature for more than a century. We describe a case of a 35-year-old male presenting with complaints of pain abdomen, clinically diagnosed as acute necrotizing pancreatitis, with raised serum calcium. Patient received symptomatic treatment for the pancreatitis which subsided. However, high levels of serum calcium persisted. Suspecting hyperparathyroidism, ultrasound neck was done, revealing apical thoracic mass. CT scan of neck revealed a large heterogeneous enhancing mass in superior mediastinum. Fine Needle Aspiration (FNA) of the mass done endoscopically was confusing as it showed features suggestive of a cystic teratoma. However, persistently raised calcium levels along with raised parathormone warranted a Technetium - 99 (Tc-99m) sestamibi scan which revealed positive uptake involving right inferior parathyroid extending to superior mediastinum. The mass was surgically excised and it was diagnosed as a parathyroid adenoma. This case helps bring to light the necessity to consider ectopic parathyroid adenoma as an important differential diagnosis in mediastinal tumour with persistent hypercalcaemia, and as a cause of hyperparathyroidism. PMID- 28658792 TI - Serous Microcystic Adenoma of Pancreas: A Case Series from a Tertiary Care Centre in Southern India. AB - Serous microcystic adenoma is a rare exocrine tumour of the cystic neoplasm of pancreas seen predominantly in the elderly population. The first patient was a 56 year-old diabetic woman with abdominal pain, constipation and loss of weight since two months. The second patient was a 73-year-old female with complaints of abdominal pain and back pain since one year. The third patient was a 72-year-old diabetic man with complaints of burning sensation in the right lumbar region since two months. Clinical and laboratory examinations were normal. The radiological examinations of the first two patients showed multiloculated cystic lesion in the pancreas and of the third patient was suggestive of islet cell tumour. The histopathological examination of the three patients showed multiple cysts of varying sizes lined by cuboidal epithelium, showing no atypia. All the three patients were diagnosed as serous microcystic adenoma of pancreas. On follow up, all three patients had no recurrence. Serous epithelial neoplasms need to be differentiated from their non-neoplastic counterparts and other neoplastic lesions with cystic changes, in view of the differences in management. Serous microcystic adenomas have excellent prognosis. PMID- 28658793 TI - Mucoepidermoid Carcinoma of Salivary Gland: Limitations and Pitfalls on FNA. AB - Mucoepidermoid Carcinoma (MEC) is the most common malignant neoplasm of salivary gland origin. However, its morphologic heterogeneity poses difficulty in interpretation. In the present series we discuss the morphologic features of MEC, limitations and pitfalls in its diagnosis on Fine Needle Aspiration Cytology (FNAC). Fourteen cases of suspected MEC were evaluated cytologically followed by histopathological examination for confirmation. A definite cytological diagnosis was rendered in nine cases; three of the remaining five were underdiagnosed as abscess, pleomorphic adenoma and mucus cyst. Of the remaining two cases, one case each of sebaceous carcinoma and sialadenitis was mislabeled as MEC on cytology. A satisfactory aspirate composed of intermediate cells, mucin secreting cells and squamous cells in a mucinous background may not be obtained in all cases of low grade MEC. High grade MEC can be classified as squamous cell carcinoma. Hence, awareness of confounding factors with clinicopathologic correlation and judicious use of frozen section can help in minimizing errors. PMID- 28658794 TI - A Comparative Study on Clinical and Biochemical Parameters in Amlodipine and Cilnidipine Treated Hypertensive Patients. AB - INTRODUCTION: Hypertension is a major health issue worldwide. Calcium Channel Blockers (CCBs) are the most commonly used antihypertensive agents. CCBs act on voltage-dependent calcium channels and they were categorized into two subclasses, Dihydropyridine (DHP) and non-Dihydropyridine (non-DHP) derivative. Amlodipine is a third generation L-type of DHP and Cilnidipine is a novel L/N-type of DHP CCB, both drugs have excellent pharmacological profiles with the unique actions. AIM: To study the clinical and biochemical profile in Amlodipine and Cilnidipine treated mild to moderate hypertensive patients. MATERIALS AND METHODS: The present study was a cross-sectional study. A total of 140 mild to moderate hypertensive patients (HTN classified according to Joint National Committee-8 (JNC-8) HTN guideline), 70 were in Amlodipine group (Group-A), and other 70 patients were in Cilnidipine group (Group-B). Group-A receiving Tab Amlodac 5 mg/day and Group-B receiving Tab Cilacar 10 mg/day, and both the group receiving respective medications since more than six months. Patients enrolled into the study with due consideration of eligibility criteria. Demographic, clinical and biochemical parameters were noted and compared. RESULTS: Demographic parameters are matched, there was no significant difference seen between two study groups. Systolic and Diastolic Blood Pressure (SBP and DBP) showed a significant difference (p<0.001). There was no significant difference in pulse rate between the two groups, both QT/QTc showed statistically significant difference (p<0.001). The biochemical parameters like serum creatinine, albumin, globulin, total protein, serum Na+, fractional excretion of Na+, serum osmolality, vanillyl mandelic acid, were compared between two study groups, there was no significant difference seen between the two groups. CONCLUSION: The Amlodipine and Cilnidipine both are equally effective antihypertensive drugs. Cilnidipine treated group showed more reduction in blood pressure than the Amlodipine treated group and there was no significant change in heart rate between the two groups. Cilnidipine group showed comparatively shortened QT/QTc interval than the Amlodipine group. PMID- 28658796 TI - Comparison of Antiemetic Effectiveness of Palonosetron Versus Ondansetron in Patients on Cancer Chemotherapy: A Prospective Observational Study in South Indians. AB - INTRODUCTION: Chemotherapy Induced Nausea and Vomiting (CINV) is the most distressing side effect of cancer chemotherapy. It can seriously produce an impact on patient's quality of life. Prevention of CINV is far more effective than treatment of an established CINV. If the patient receives an optimal antiemetic regimen during the initial course of chemotherapy, the likelihood of developing emesis is greatly reduced. Although, all first generation 5HT3 antagonists demonstrate reasonable efficacy in preventing acute CINV, delayed CINV still remains a problem. AIM: To compare the effectiveness and safety of palonosetron versus ondansetron as an antiemetic agent in patients receiving cancer chemotherapy. MATERIALS AND METHODS: A prospective observational study was conducted in 106 patients in each treatment arm. Study duration was 12 months from January 2013 to January 2014. Consecutive patients diagnosed with cancer satisfying inclusion criteria, who were about to receive moderately or highly emetogenic chemotherapy were enrolled into the study after getting informed written consent. Each patient received either Intravenous (IV) palonosetron 0.25 mg or ondansetron 8 mg half an hour before chemotherapy as antiemetic. Patients were followed up for a period of five days following chemotherapy. Number of episodes, severity of vomiting and nausea and antiemetic rescue given if any were recorded. The data were graded using NCI-CTCAE (VERSION 3.0). Proportion of patients with nausea and vomiting during acute (0-24 hours), delayed (24-120 hours) and overall period (0-120 hours) in both the study groups were compared. Outcome was assessed in terms of symptom control and response. Data were analysed using SPSS-16.0 statistical software (IBM). Chi-square test was used to compare the difference in clinical response. RESULTS: Complete response during acute phase in ondansetron group was 80.2%, while for palonosetron it was 89.6%. During delayed phase, ondansetron and palonosetron produced complete response in 70.8% and 86.8% respectively. A total of 65.1% and 82.1% of subjects experienced complete response during the overall period in the ondansetron and palonosetron groups respectively. The difference in the response to antiemetic prophylaxis was statistically significant between the two groups for delayed (p-value = 0.006) and overall phase (p-value = 0.008). CONCLUSION: Palonosetron is clinically more efficacious than ondansetron in controlling CINV especially in delayed phase and overall period of emesis. PMID- 28658795 TI - Restricted Parenteral Antibiotics Usage Policy in a Tertiary Care Teaching Hospital in India. AB - INTRODUCTION: The indoor hospital use of antibiotic irrationally has been a growing concern in the recent past. For the patients and providers of health care services this kind of drug consumption account for a major chunk of the budget. AIM: To assess the outcome of restriction on the use of parenteral antibiotics with respect to their utilization and monetary benefits, in a tertiary care hospital in India. MATERIALS AND METHODS: Data details were collected regarding drug utilization two months before and after restriction respectively. A total 1605 patient records assessed. Drug utilization was expressed as DDD/100 patient bed days. Use of Carbapenems were restricted to culture positive cases only. Antibiotics started for patients as per clinical judgment were issued for only five days. Culture sensitivity reports verified physically on a special indent form, before every antibiotic issued thereafter. RESULTS: Piperacillin-tazobactum (DDD/100 BD 1.72 before and 1.29 after restrictions) was the commonly used antibiotic. Considering values expressed in DDD/100 BD before and after restriction respectively, substantial decrease in consumption of antibiotics like Imipenem- Cilastin (0.22 to 0.16), meropenem (0.30 to 0.09), piperacillin tazobactum (1.72 to 1.29), teicoplanin (0.24 to 0.05) and vancomycin (0.69 to 0.40) was observed. An increase in consumption of amoxicillin-clavulanic acid (0.90 to 1.04) and clarithromycin (0.44 to 0.55) noted, pointing to a shift in antibiotic use. Restriction decreased expenditure burden on these antibiotics by INR 1,45,911 (17.31%). CONCLUSION: Restriction of antibiotics cuts down consumption and benefits hospital budget immensely. PMID- 28658797 TI - Effect of Single Dose Betamethasone Administration in Pregnancy on Maternal and Newborn Parameters. AB - INTRODUCTION: Antenatal corticosteroids play an important role in preventing Respiratory Distress Syndrome (RDS) but benefits related to time between corticosteroid administration and delivery need to be explored. AIM: To observe the effect of betamethasone administration in pregnant women at risk of preterm delivery and on foetal parameters, in terms of development of RDS. MATERIALS AND METHODS: It was a prospective observational study on pregnant women at risk of preterm delivery who were administered a single dose 24 mg injection betamethasone. Outcome of 111 newborns of enrolled mothers was observed in terms of respiratory distress, Downe's and Silverman Anderson score, need of NICU admission and ventilation. Paired t-test was used to compare means of maternal parameters before and after betamethasone. Independent sample t-test for comparison of scores for respiratory distress in neonates was used. RESULTS: There was a significant decrease in maternal haematological parameters like mean Red Blood Cell (RBC) and mean Platelet Count (PC) whereas increase in mean Total leucocyte Count (TC) after betamethasone administration. Out of 111 newborn babies, 71 were born within 24 hours and rest were born after 24 hours of betamethasone administration. Twelve out of 71 newborns who were born within 24 hours of betamethasone administration, developed RDS. Mean Downe's score and mean Silverman Anderson score in neonates born within 24 hours of injection administration were significantly higher than those born after 24 hours. CONCLUSION: Betamethasone administration affects the haematological parameters in mothers in antenatal period nearing term. A minimum of 24 hours have to elapse between corticosteroid administration and delivery of the preterm for benefits to occur. PMID- 28658798 TI - Anti-Atherosclerotic Potential of Aqueous Extract of Cinnamomum Zeylanicum Bark against Glucocorticoid Induced Atherosclerosis in Wistar Rats. AB - INTRODUCTION: Atherosclerosis is one of the major causes of disability of blood vessels which can result in development of many cardiovascular disorders. There is a strong association between atherosclerosis and insulin resistance and dyslipidemia. AIM: To study the anti-atherosclerotic potential of C. zeylanicum bark extract in insulin resistance associated atherosclerosis and worsened Atherogenic Index (AI) associated with dyslipidemia, which are the predominant complications of steroid diabetes in Wistar rats. MATERIALS AND METHODS: A sum of 36 rats were categorized into five study groups and one plain control. In a 12 day study period, respective drug treatments were given every day throughout the study period whereas, dexamethasone dosage was started from day seven onwards. On day 12, fasting blood samples were collected and processed for lipid estimation and the determined values were also used to assess AI further. Animals were sacrificed under ether anaesthesia and the aorta was dissected away for its measurement and histopathological findings. One-way ANOVA was used to analyse the data and multiple comparison was done, interpreted based on Post-Hoc Scheffe test. RESULTS: High dose of dexamethasone (8 mg/kg/i.p) in Dexa Control (DC) group produced significant dyslipidemia, increased risk of atherogenicity (p<0.05) and caused severe thickening (78.5% compared to Plain Control (PC) of wall of aorta. Rosiglitazone (ROSI) (8 mg/kg and 16 mg/kg) and C. zelanicum (CZE) extract treatments (500 mg/kg and 250 mg/kg) significantly prevented dyslipidemia, well maintained AI compared to dexa control (p<0.05). However, both the CZE treatments protected the aorta from atherosclerosis (40.3% and 30.2% compared to DC) and significantly prevented the dyslipidemia and reduced the risk of atherogenicity compared to ROSI treatment (p<0.05). Although, the CZE did not show difference in significance in maintaining very low density lipoprotein when compared to ROSI (p>0.05). The atherosclerotic changes were completely absent in both the CZE treatments whereas, ROSI treatments did not prevented the atherosclerosis of aorta completely as they showed moderate and mild atherosclerotic changes in the aorta. CONCLUSION: The aqueous extract of C. zelanicum bark exhibited marked protection against dexamethasone induced atherosclerosis and also minimized the atherogenic risk in Wistar rats. PMID- 28658799 TI - A Prospective Study of Adverse Drug Reactions in Patients with Bipolar Disorder in Psychiatry Outpatient Department of a Tertiary Care Hospital. AB - INTRODUCTION: Bipolar disorder is a chronic, debilitating psychiatric disorder. Mood stabilizers and atypical antipsychotics are first line drugs for bipolar disorder. They have significant adverse effects. AIM: The study was conducted with an aim to evaluate the pattern of occurrence of Adverse Drug Reactions (ADRs) in the patients with bipolar disorder and to assess their causality, severity and preventability. MATERIALS AND METHODS: A prospective and observational study - carried out in the psychiatry outpatient department of New Civil Hospital, Surat for 15 months. All patients diagnosed with bipolar disorder and receiving pharmacotherapy were included. Udvalg for Kliniske Undersogelser (UKU) side effect rating scale and Abnormal Involuntary Movement Scale (AIMS) were used for documenting ADRs and tardive dyskinesia, respectively. Assessment of causality, severity and preventability of recorded ADRs was done using Naranjo's algorithm and WHO-UMC scale, modified Hartwig and Seigel Scale and modified Schumock and Thornton scale, respectively. Descriptive statistics was used (percentage, mean+/-standard deviation) for presentation of demographics and other numerical data; Chi Square test and Fisher's exact test were used to assess association between variables. A p-value < 0.05 was considered significant. RESULTS: A total of 703 ADRs were recorded from 175 patients. The most common ADRs observed were asthenia (11.95%) and sedation (10.24%). Majority of ADRs were mild on assessment with UKU scale. Mood stabilizers (59.46%) were most frequently associated with ADRs and lithium was most common single drug responsible. Upon causality assessment, majority of the reactions were probable (54.77% with WHO UMC scale, and 56.33% with Naranjo's algorithm). The association of results between the two scales was statistically significant (p<0.001). Majority of ADRs (70.27%) were assessed as mild and 64.30% of the ADRs were not preventable. CONCLUSION: ADRs are a frequent occurrence in patients with bipolar disorder which are mild in most cases. Incidence of ADRs can be decreased and compliance as well as quality of life of patient can be improved by early detection and management. PMID- 28658800 TI - A Post-Marketing Surveillance Study to Evaluate Performance of the EXIMOTM Blood Glucose Monitoring System. AB - INTRODUCTION: The performance of Blood Glucose Monitoring System (BGMS) is critical as the information provided by the system guide the patient or health care professional in making treatment decisions. However, besides evaluating accuracy of the BGMS in laboratory setting, it is equally important that the intended users (healthcare professionals and patients) should be able to achieve blood glucose measurements with similar level of high accuracy. AIM: To assess the performance of EXIMOTM (Meril Diagnostics Pvt. Ltd., Vapi, Gujarat, India) BGMS as per International Organization for Standardization (ISO) 15197:2013 section 8 user performance criteria. MATERIALS AND METHODS: This was a non randomized and post-marketing study conducted at a tertiary care centre of India. A total of 1005 patients with diabetes themselves performed fingertip blood glucose measurement using EXIMOTM BGMS. Immediately after capillary blood glucose measurement using the blood glucose monitoring system, venous blood sample from each patient was obtained by a trained technician which was assessed by reference laboratory method- Cobas Integra 400 plus (Roche Instrument Centre, Rotkreuz, Switzerland). All the blood glucose measurements assessed by EXIMOTM were compared with laboratory results. Performance of the system was assessed as per ISO 15197:2013 criteria using Bland-Altman plot, Parkes-Consensus Error Grid (CEG) and Surveillance Error Grid analyses (SEG). RESULTS: A total of 1005 patients participated in the study. Average age of the patients was 44.93+/-14.65 years. Evaluation of capillary fingertip blood glucose measurements demonstrated that 95.82% measurements fulfilled ISO 15197:2013 section 8 user performance criteria. All the results lie within clinically non-critical zones; Zone A (99.47%; n=1000) and Zone B (0.53%; n=05) of the CEG analysis. As per SEG analysis, majority of the results fell within "no-risk" zone (risk score 0 to 0.5; 90.42%). CONCLUSION: The result of the study confirmed that intended users are able to obtain accurate glucose measurements when operating EXIMOTM BGMS, given only the instructions and training materials routinely provided with the system, in clinical practice. PMID- 28658801 TI - Hypolipidaemic Effects of Gymnema sylvestre on High Fat Diet Induced Dyslipidaemia in Wistar Rats. AB - INTRODUCTION: Hyperlipidaemia is a well known risk factor for cardiovascular diseases. Lifestyle modification can be the initial step to reduce cholesterol levels. There are various drugs which are used to control dyslipidaemia. Treatment of lipid abnormalities is a lifelong battle. Moreover, the safety and effectiveness of long term lipid lowering treatment are questionable. Gymnema Sylvestre (GS) is a well known herb with various medicinal properties. AIM: To explore the hypolipidaemic activity of GS leaves extract. MATERIALS AND METHODS: Adult healthy female wistar rats, 30 in number, divided into five groups, weighing 150- 200 g were used. Dyslipidaemia was induced in rats by feeding them on high fat diet for four weeks. For the next four weeks GS extract was used as test drug while Atorvastatin was used as standard drug. Blood sample was collected for estimation of lipid profile on day 0, week 4 and week 8. Data was recorded as mean+/-SEM (Standard error of mean). Paired t-test and one way Analysis of Variance (ANOVA) followed by Dunnett's post hoc test was used for comparison. A p-value <0.05 was considered statistically significant. SPSS Statistics 20 (IBM software) was used for the analysis. RESULTS: Feeding rats with high fat diet for four weeks led to obesity and dyslipidaemia in rats. GS at both the doses (100mg/kg and 200mg/kg) significantly improved the lipid profile. Total Cholesterol (TC), Triglycerides (TG), Very Low Density Lipoprotein (VLDL) and Low Density Lipoprotein (LDL) values reduced significantly while that of High Density Lipoprotein (HDL) increased significantly. GS 200 mg/kg was found more effective than GS 100 mg/kg. GS improved the value of lipid profile significantly but the effect was found inferior to Atorvastatin. CONCLUSION: From the present study it can be concluded that GS possess an effective hypolipidaemic effect. Hence it can be included as an add on therapy in dyslipidaemia after further confirmatory studies. PMID- 28658802 TI - The Impact of Oxidative Stress on Testicular Function and the Role of Antioxidants in Improving it: A Review. AB - Oxidative stress is an important factor for development of male infertility because of very high rate of cell division and mitochondrial oxygen consumption in testicular tissue as well as comparably higher levels of unsaturated fatty acids in this tissue than in other tissues. Moreover, the level of oxygen pressure is low due to the weakness of testicular artery; therefore, there is a severe cell competition for oxygen. Therefore, the testicular tissue and male reproductive system are particularly susceptible to oxidative stress. On the other hand, exposure to X-ray, toxins and chemicals found in the environment as well as specific physical conditions such as varicocele can exacerbate the oxidative stress and induce apoptosis of germ cells and subsequently spermatogenesis. However, under normal conditions, the body's capacity to produce antioxidants for inhibiting adverse effects of oxidative stress is affected by metabolic process and genetic structure. Besides that, environmental factors such as diet, pollutants, and chemicals can affect this capacity. Thus, the body's antioxidant system alone is not able to neutralize all free radicals and prevent harmful complications of oxidative stress. Therefore, use of antioxidants and development of antioxidant therapy can break down the oxidative chain reaction and play a very significant role in increasing the body's capacity to fight free radical-induced oxidative stress, and therefore improve the process of spermatogenesis. PMID- 28658803 TI - Factors Influencing Nursing Students' Clinical Judgment: A Qualitative Directed Content Analysis in an Iranian Context. AB - INTRODUCTION: Clinical judgment is necessary for clinical decision making and enhancing it in nursing students improves health care quality. Since clinical judgment is an interactive phenomenon and dependent on context and culture, it can be affected by many different factors. AIM: To understand the experiences of Iranian nursing students and teachers about the factors influencing nursing students' clinical judgment. MATERIALS AND METHODS: A qualitative study was conducted using a directed content analysis approach. In this study, purposive sampling and semi-structured interviews were applied with seven nursing students, six faculty member teachers and four clinical instructors from Guilan University of Medical Sciences, Gilan, Iran. RESULTS: The factors influencing nursing students' clinical judgment consisted of five main categories including thoughtful behaviour, professional ethics, use of evidence based care, the context of learning environment and individual and professional features of clinical teachers. CONCLUSION: Relying on the results of this research, teachers can create an appropriate educational condition and a safe psychological atmosphere, use instructional strategies strengthening deep thought processes, applying professional ethics and scientific evidence and principles to establish clinical judgment in nursing students. PMID- 28658804 TI - Smartphone, the New Learning Aid amongst Medical Students. AB - INTRODUCTION: The use of smartphone is increasing day by day for personal as well as professional purpose. They are becoming a more suitable tool for advancing education in developing countries. Mobile access to information and many applications are successfully harnessed in health care. Smartphones are also becoming popular as an effective educational tool. AIM: The present study was conducted to evaluate the use of smartphones as an educational tool amongst the medical students. The study also aimed at identifying the common medical application used by the students. MATERIALS AND METHODS: It was an observational cross-sectional study carried out amongst medical students of private medical institute in India. A validated 16 point, structured, open-ended, questionnaire regarding ownership and use of smart phones was self-administered to 446 medical students. Data were analysed using SPSS and open ended questions were analysed by summative content analysis. RESULTS: Among the study population, 96% owned a smartphone -Android based 72.4%, i phone 13.0%, Windows based Nokia phones 7% and Blackberry 3.6%. Common medical applications used by the students were Anatomy and Medical Dictionary in First MBBS; Medical Dictionary, Medscape and Google/Wikipedia in Second MBBS; and Medscape, Google/Wikipedia and Prognosis/Diagnosis in Third MBBS. More than 90% students, reported to have technological skills to use smartphones, for medical education, communication and instant access during bedside teaching. Advertently, 37.2% students felt if smartphones are used for clinical purposes, they will need to spend less time with patients. Almost 79.4% felt that smartphones should be introduced in MBBS course. CONCLUSION: Smartphone use amongst medical students as learning aid for various medical applications is rapidly advancing. But it will be worthwhile to study whether use of smartphones has any impact on the grades of the students before introducing them in medical schools. PMID- 28658805 TI - Critical Appraisal of Clinical Research. AB - Evidence-based practice is the integration of individual clinical expertise with the best available external clinical evidence from systematic research and patient's values and expectations into the decision making process for patient care. It is a fundamental skill to be able to identify and appraise the best available evidence in order to integrate it with your own clinical experience and patients values. The aim of this article is to provide a robust and simple process for assessing the credibility of articles and their value to your clinical practice. PMID- 28658806 TI - Development and Validation of Health Education Tools and Evaluation Questionnaires for Improving Patient Care in Lifestyle Related Diseases. AB - Lifestyle related diseases continue to be a significant burden on the health care system. Health education is a combination of educational strategies that promote voluntary adoption of healthy lifestyle choices and dietary behaviour. The use of simple and validated education and evaluation tools is now increasing in routine clinical practice to aid health status evaluation and communication between the patient, dietitian and the health care provider. Development of effective health education materials is a systematic process which starts with setting up the goals for education, followed by literature review and focus group discussion, content selection, designing the rough draft, seeking expert comments and validation. Questionnaire development should follow a logical and structured approach. Item generation should be based on extensive literature search and target group participation. Validation by the experts makes the questionnaire more meaningful, trustworthy and applicable. Considerable effort goes into designing and testing of these tools in order to ensure that they are effective. For enhancing clinical, dietetic and educational practice, it is pertinent to learn the process of developing these tools scientifically. PMID- 28658807 TI - Effect of Yoga on Psychological Functioning of Nursing Students: A Randomized Wait List Control Trial. AB - INTRODUCTION: Nursing students experience considerable amount of stress to meet their professional demands. Yoga is an effective practice to reduce stress and improve psychological well being. However, improvement in psychological well being aids in stress management. AIM: To evaluate the effectiveness of eight week yoga intervention on psychological functioning of nursing students. MATERIALS AND METHODS: This was a randomised Wait List Control (WLC) trial, we recruited total 100 students from Kempegowda Institute of Nursing, Bengaluru, Karnataka, India and randomized them into two groups (yoga=50 and WLC=50 students). The following instruments were used to collect the data, Freiburg Mindfulness Inventory (FMI), Self-Compassion Scale- Short Form (SCS-SF), Connor-Davidson Resilience Scale (CD RISC), Satisfaction with Life Scale (SWLS), Jefferson Scale of Empathy HPS Version (JSE-HPS), and Perceived Stress Scale (PSS). Data was analysed using Repeated Measures Analysis of Variance (RM-ANOVA) followed by post-hoc Bonferroni correction for all psychological variables. RESULTS: The results of our study report that eight week yoga intervention was significantly effective in improving self compassion and mindfulness among nursing students in experimental group than compared to WLC group. Even though there were improvements in resilience, satisfaction in life and perceived stress, results were not statistically significant. CONCLUSION: Overall, results of the present study have demonstrated impact of eight week yoga intervention on the psychological functioning of nursing students. Yoga intervention can be inculcated in the nursing education to meet demands of the profession. PMID- 28658808 TI - Pharmacophore Mapping Approach for Drug Target Identification: A Chemical Synthesis and in Silico Study on Novel Thiadiazole Compounds. AB - INTRODUCTION: Compounds containing thiadiazole moiety are cognized to possess with variety of clinical and therapeutic activity. Finding a suitable drug target for newly synthesized compounds remain a major bottle neck in current high throughout medicinal chemistry era. AIM: To effectively synthesize di substituted thiadiazole compounds and demonstrate drug target identification using an in silico pharmacophore probing approach. Moreover, we also aim to validate the suitability of identified drug target. MATERIALS AND METHODS: A cost-effective and environmental friendly chemical synthesis scheme for production of di substituted thiadiazole compounds was employed. Target identification was conducted by Pharmmapper software. Validation was accomplished by performing molecular docking and further Molecular Hydrophobic Potential (MHP) analysis. RESULTS: Pharmacophore probing base approach identified hepatocyte growth factor receptor (c-Met) as a suitable biological target for newly synthesized compounds. Binding free energy values indicate that compound 4b, 4e, 4g and 4h has tremendous potential to be further used as lead compound to design selective inhibitors of c-Met receptor. MHP data from current study supports the possibility that hydrophobic contacts might act as major factor stabilizing thiadiazole- c-Met complex. Moreover, in silico observations of current study are in absolute accordance with previously described in vitro and crystallographic analysis. CONCLUSION: We demonstrate that thiadiazole compounds synthesized in current investigation has high potential to act in modulation of hepatocyte growth factor receptor (c-Met) activity and thereby act as putative therapeutic agent in cancer therapy. PMID- 28658809 TI - Adolescents Confusion in Receiving Health Services: A Qualitative Study. AB - INTRODUCTION: Providing health services for adolescents requires exploration of hidden factors from the perspective of adolescents, providers, and key individuals. Understanding the process of providing health services from adolescents point of view will help receiving and continuation of services. Although many studies have been conducted in Iran on adolescents health needs, few studies have dealt with provision of these services to adolescents. AIM: The present study aimed to explain the adolescents and key informants' perception of healthcare provision. MATERIALS AND METHODS: The present qualitative study was conducted according to grounded theory. Data were collected using deep semi structured individual interviews and group discussion. Participants were selected through purposive sampling followed by theoretical sampling. Participants in present study were 65 adolescents, nine youths (19-24-year-old), and 19 parents and key people involved in providing health services. Adolescents and their parents were selected from different parts of Tehran. Data collection continued until data saturation, and was analysed using Corbin-Strauss (2008) method. RESULTS: Issues relating to adolescents perception of the process of providing services included health concerns, society's inappropriate behaviours, and weakness of the health services system in responding to adolescents needs, which as underlying factors contributed to adolescents confusion in receiving services and their proper coping with puberty. CONCLUSION: Due to lack of education on how to manage puberty by parents, schools, society, and the health system, participating adolescents from Tehran were confused about receiving information and unable to manage puberty problems. Solving this problem requires continuity of services and interaction of family, school and community. PMID- 28658810 TI - Quality Assessment of Family Planning Sterilization Services at Health Care Facilities: Case Record Audit. AB - INTRODUCTION: Quality of sterilization services is a matter of concern in India because population control is a necessity. Family Planning Sterilization (FPS) services provided at public health care facilities need to be as per Standard Operating Procedures. AIM: To assess the quality of FPS services by audit of case records at selected health care facilities. MATERIALS AND METHODS: This cross sectional study was conducted for two and a half year duration at selected public health care facilities of central India by simple random sampling where FPS services were provided. As per the standards of Government of India, case records were audited and compliance was calculated to assess the quality of services. RESULTS: Results of record audit were satisfactory but important criteria like previous contraceptive history and postoperative counselling were found to be deviated from standards. At Primary Health Centres (PHCs) only 89.5% and at Community Health Centres (CHCs) 58.7% of records were having details of previous contraceptive history. Other criteria like mental illness (only 70% at CHCs) assessment were also inadequate. Although informed consent was found to be having 100% compliance in all records. CONCLUSION: Quality of care in FPS services is the matter of concern in present scenario for better quality of services. This study may enlighten the policy makers regarding improvements needed for providing quality care. PMID- 28658811 TI - Social Security Measures for Elderly Population in Delhi, India: Awareness, Utilization and Barriers. AB - INTRODUCTION: World population of elderly is increasing at a fast pace. The number of elderly in India has increased by 54.77% in the last 15 years. A number of social security measures have been taken by Indian government. AIM: To assess awareness, utilization and barriers faced while utilizing social security schemes by elderly in a secondary care hospital situated in a rural area in Delhi, India. MATERIALS AND METHODS: A cross-sectional study was conducted among 360 individuals aged 60 years and above in a secondary care hospital situated in a rural area in Delhi. A pre-tested, semi-structured schedule prepared in local language was used. Data was analysed using SPSS software (version 17.0). Chi square test was used to observe any statistical association between categorical variables. The results were considered statistically significant if p-value was less than 0.05. RESULTS: A majority of study subjects were females (54.2%), Hindu (89.7%), married (60.3%) and were not engaged in any occupation (82.8%). Awareness about Indira Gandhi National Old Age Pension Scheme (IGNOAPS) was present among 286 (79.4%) and Annapurna scheme in 193 (53.6%) subjects. Among 223 subjects who were below poverty line, 179 (80.3%) were aware of IGNOAPS; while, 112 (50.2%) were utilizing the scheme. There was no association of awareness with education status, occupation, religion, family type, marital status and caste (p>0.05). Corruption and tedious administrative formalities were major barriers reported. CONCLUSION: Awareness generation, provision of information on how to approach the concerned authority for utilizing the scheme and ease of administrative procedures should be an integral part of any social security scheme or measure. In the present study, about 79.4% of elderly were aware and 45% of the eligible subjects were utilizing pension scheme. Major barriers reported in utilization of schemes were corruption and tedious administrative procedures. PMID- 28658812 TI - Factors Associated with Physical Inactivity among Adult Urban Population of Puducherry, India: A Population Based Cross-sectional Study. AB - INTRODUCTION: Physical inactivity is the fourth leading cause of death worldwide. Increase in physical activity decreases the incidence of cardiovascular diseases, Type 2 diabetes, stroke, and improves psychological wellbeing. AIM: To study the level of physical inactivity among the adult population in an urban area of Puducherry in India and its associated risk factors. MATERIALS AND METHODS: This cross-sectional study was conducted among 569 adult participants from an urban area of Pondicherry. The level of physical inactivity was measured by using WHO standard Global Physical Activity Questionnaire (GPAQ). RESULTS: Overall prevalence of physical inactivity in our study was 49.7% (CI: 45.6-53.8). Among the physically active people, contribution of physical activity by work was 77.4%, leisure time activities were 11.6% and transport time was 11%. Both men and women were equally inactive {Physically inactive among women was 50% (CI:44.1 55.9)} and {Physically inactive among men was 49.5% (CI:43.8-55.2)}. Prevalence of physical inactivity was increasing with increasing age. Non tobacco users were two times more active than tobacco users {Adjusted Odds Ratio: 2.183 (1.175- 4.057)}. Employed were more active as compared to retired {Adjusted Odds Ratio: 0.412 (0.171-0.991)}, students {Adjusted Odds Ratio: 0.456 (0.196-1.060)}, house wives {Adjusted Odds Ratio: 0.757 (0.509-1.127)} and unemployed {Adjusted Odds Ratio: 0.538 (0.271-1.068)}. Non alcoholics were only 0.34 times as active as alcoholics. CONCLUSION: Level of physical activity was found to be insufficient among adult urban population of Puducherry. Working adult population found to be active, that too due to their work pattern. There is a need to promote leisure time and travelling time physical activity. PMID- 28658813 TI - How Non Consumers Differ from Consumers: A Qualitative Approach to Synthesize the Attributes of Iron Folic Acid End Users. AB - INTRODUCTION: Anaemia continues to be a major hurdle to achieve optimum health in Indian population context. Although government continues to promote Iron Folic Acid (IFA) supplementation as one of the key strategies to combat with burden of anaemia, the expected level of IFA consumption and subsequent anaemia reduction could not be achieved. This study tries to investigate those influences, concerns, experiences and behaviour from an end user perspective through a qualitative methodology which may affect the IFA consumption ambi-directionally. AIM: To explore and understand the several aspects related with anaemia and IFA supplementation with special emphasis to reveal the contributory factors behind low level of IFA consumption at consumer end. MATERIALS AND METHODS: A community based qualitative study was conducted in clusters identified through multileveled stratification from a state of central India. A conceptual construct was made in priory for this study. As the research question was related with policy, this study adapted a framework technique for making interview topic guides. Two consumers and two non consumers from each identified cluster were interviewed in depth. The data obtained through 160 in depth interviews (from 80 consumers and 80 non consumers) was utilized for thematic framework, linkage association and to typify the phenomenon. RESULTS: Ignorance, difficult intake, meaninglessness, misconceptions and discontentment with the system were the major dimensions (sub themes) associated with discontinuation. All these sub themes were further converged into major theme of informational discontinuity. Investigators further typified the users/non users into persistent user, potential defaulters, impending defaulters and absolute non users. CONCLUSION: Informational gap seems to be the fundamental factor behind sub optimum IFA consumption. On a policy perspective, all the attempts should be done to instigate arise felt need' among target groups for IFA consumption. PMID- 28658814 TI - Occupation Hazards - Pattern, Awareness and Preventive Measures among Welders from an Unorganized Sector in India. AB - INTRODUCTION: Welding is an occupation associated with tremendous physical and chemical hazards. In spite of the risk involved, usage of Personal Protective Gears (PPGs) among welders in developing countries has been reported to be poor, due to their limited awareness of occupational hazards. AIM: To assess morbidity pattern, awareness of occupational hazards and usage practices of protective gears among welders. MATERIALS AND METHODS: Cross-sectional study was conducted at welding sites from unorganized sector situated in and around Mangalore. A total of 155 welders chosen randomly from as many sites were interviewed at their workplace using a pilot tested structured interview schedule with both closed and open ended questions. Clinical examination of the participant and inspection of the work site was also done by the investigators. Statistical analysis used for analysis was Chi-Square test, unpaired t-test and ANOVA test. RESULTS: Working >8 hours a day was reported by 30 (19.4%) welders. Overcrowding was present at 10.3%, ventilation status was inadequate at 6.9% and exhaust ventilation was not present at 25.9% sites. Awareness about occupational health hazards associated with welding was present among 97(62.6%) welders. Periodicity of medical examination was associated with awareness of occupational hazards among welders (p=0.032). First aid kit was present at 60 (38.7%) sites. The most common morbidity over the past year was wounds 119 (76.8%). Non-usage of most essential protective gears such as face shields, masks or eye goggles was seen among 18 (11.6%) welders. Mean number of morbidities over the past one month was found to be more, in those welders doing continuous work of >=6 hours (p=0.05), at sites with overcrowding (p=0.002) and at sites where >10 welders work together (p=0.031). CONCLUSION: The period prevalence of morbidity was high among the welders surveyed. Ignorance of health hazards associated with occupation and non usage of protective gears was reported by number of them. Therefore, health education and safety policies need to be strengthened at welding sites. PMID- 28658815 TI - Assessment of Insulin Sensitivity and its Convalescence with Dietary Rehabilitation in Undernourished Rural West Bengal Population. AB - INTRODUCTION: Metabolic syndrome involving diabetes is acquiring the eminence of prospective epidemic in India with dramatic rise in rural population prevalence where majority are undernourished and creates significant healthcare burden. AIM: To investigate the prevalence of the insulin resistance amongst the undernourished rural population, involving children, adolescents and adult volunteers of the West Bengal and the effect of nutritional supplementation in the parameters echoing insulin sensitivity. MATERIALS AND METHODS: A prospective interventional study was carried out on 120 volunteers in three age groups; Group 1 (5-12 years), Group 2 (13-18 years) and Group 3 (19-40 years), each with 40 subjects who fulfilled the inclusion criteria, under informed consent over six months. Baseline data regarding demography, family history including parental history of diabetes, medical history, physical, activity, anthropometrical status and blood parameters echoing insulin sensitivity were obtained from volunteers. Intervention included daily nutritional supplementation with eggs and banana. After six months of food supplementation, parameters reflecting insulin sensitivity were assessed. RESULTS: Initial low figures of fasting insulin and blood sugar levels improvised with the nutritional supplementation alongside the absence of wasting in Group 1. HOMA-IR and IRI values of the Group 2 improved from the initial figures (3.19, 2.87) to (2.204, 1.99) and that of Group 3 from (5.0, 4.52) to (4.08, 3.67) respectively over six months (p<.05). Average Fasting Blood Sugar (FBS) enhanced from 85.5+/-9.6 mg/dl to 78.4+/-7.3 mg/dl and from 90.1+/-10.2 mg/dl to 84.8+/-8.4 mg/dl in Group 2 and 3 respectively by the end of the supplementation study (p<.05). CONCLUSION: Six months study revealed the existence of insulin resistance and malnourishment in the selected rural population in three groups. Decrement in HOMA-IR, IRI, FBS and serum insulin alongside the improvement in the body mass, in comparison to that of initial values is evocative of restoration of insulin sensitivity with nutrition supplementation. PMID- 28658816 TI - Prevalence of Anaemia in Kerala State, Southern India - A Systematic Review. AB - INTRODUCTION: Anaemia is the most common nutritional problem affecting children, adolescents and women. A systematic review was undertaken to find out the prevalence of anaemia and to identify the trend in the prevalence of anaemia in Kerala state, Southern India. AIM: The aim of the review was to identify the prevalence of anaemia in Kerala and to comment on its trend across last 25 years. MATERIALS AND METHODS: PubMed and google scholar searches and scanning of reference lists were used to identify studies. All population based studies on anaemia from Kerala, irrespective of its designs, published between Jan 1st 1990 to Dec 31st 2015 were included. Data extraction and quality assessment were carried out using structured proformas. Due to the heterogeneity of reviewed studies, meta-analysis was not done. A narrative approach was used. RESULTS: A total of 10 studies in addition to two major survey reports- National Family Health Survey (NFHS) and District Level Household Survey (DLHS) were included in the final analysis. Prevalence of anaemia among adolescents from recent study reports was around 30% and prevalence of severe anaemia was less than 1% in all studies. Anaemia among tribal women and children were in the range of 78.3% to 96.5%. A key finding of this review was the paucity of data and inconsistency in haemoglobin estimation methods and population characteristics which made comparisons impossible. CONCLUSION: The current prevalence of anaemia in Kerala is unclear. Though, there are many studies and reports regarding prevalence of anaemia in the state, those results could not be combined due to non uniform haemoglobin estimation methods. Standardised prospective study of general population including subgroups will be necessary. PMID- 28658817 TI - Salient Features of a Proposed Adolescent Health Policy Draft for India. AB - India is one of the most populous countries in the world. The adolescent population in India constitutes about one fifth of the total Indian population. Adolescent phase is a transitional phase in life and the adolescents are neither child nor adult at this stage and are full of energy, have significant drive and new ideas. The relatively lower death rate and relatively good health status of the adolescents has always been a misleading measure to adolescent health and thus given lesser priorities. In order to respond effectively to the needs of adolescent health and development, it is important to place adolescence in a life span perspective within dynamic sociological, cultural and economic realities. For this, government of India has started a national programme known as "Rashtriya Kishor Swathya Karyakram" in 2014. However, India as a country does not have an adolescent health policy till date and hence the country requires a national adolescent health policy. The key priorities should include sexual and reproductive health, nutritional problems (both under and over nutrition), substance abuse, mental health, road traffic accidents, intentional violence and non-communicable diseases. In addition to key priorities, the policy draft should include pertinent components such as a preamble, guiding principles, coordinating agencies, monitoring and evaluation, research and documentation components. PMID- 28658818 TI - A Prospective Study of Different Methods of Inferior Turbinate Reduction. AB - INTRODUCTION: All the functions of nasal cavities are performed through mucosa and contours of the turbinates. Hypertrophied inferior turbinate is one of the major and common causes of nasal obstruction. In these patients nasal obstruction is relieved by inferior turbinate reduction. Many procedures on turbinate reduction have been described earlier. AIM: To compare and evaluate the better method for inferior turbinate reduction among submucosal diathermy using monopolar cautery and bipolar cautery, complete turbinectomy, inj. sodium tetradecylsulphate infiltration. MATERIALS AND METHODS: Eighty patients of either sex between 17-50 years of age having inferior turbinate hypertrophy were included in the study. The patients were divided into four groups with 20 patients in each group. Each group had 20 patients. Group A was subjected to submucosal diathermy using monopolar cautery, Group B to bipolar cautery, Group C to complete inferior turbinectomy and group D to injection sodium tetradecylsulphate. Patients were assessed for nasal patency and symptomatic relief, postoperative bleeding, pain, crusting and synachiae. Follow up was done on 7th day, 21st day and 3rd month postoperatively. Statistical analysis was carried out using IBM SPSS Version 20.0 for windows. Mean and standard deviations were calculated for quantitative data, for categorical variables frequencies and percentages were calculated, within the group comparisons were done with paired t tests. RESULTS: The mean reduction in postoperative nasal obstruction was found to be maximum with bipolar cautery when compared with the other modalities and this difference was found to be statistically significant (p<0.001). Bipolar cautery was found to be associated with minimum after effects when compared to other modalities except for postoperative pain which was found more in the patients operated by the bipolar cautery method. CONCLUSION: We found inferior turbinate reduction using bipolar cautery was better and safe method, when compared to monopolar cautery, complete turbinectomy and inj. sodium tetradecylsulphate, however further studies are required with larger sample size. PMID- 28658819 TI - Osteoma of the Middle Turbinate Presenting with Frontal Lobe Abscess and Seizure. AB - Osteomas are the most common benign tumours of the sinonasal tract. Even though their location in the sinuses is well known, turbinate osteomas are quite rare. We report one such case of a 26-year-old female who presented with neurological complaints of a seizure rather than nasal complaints. The cause of the seizure was found to be a small abscess in her frontal lobe, secondary to frontal sinusitis due to a bony hard nasal mass arising from the middle turbinate. She underwent endoscopic excision of the mass which was confirmed on histopathology as an osteoma. The case highlights an unusual presentation of a middle turbinate osteoma. PMID- 28658820 TI - A Misdiagnosed Laryngeal Web: Treated with an Innovative Self-Made Keel. AB - Laryngeal web is a rare congenital anomaly. Late presentation at the age of 10 years as in our case, with misleading diagnosis of asthma in a Cohen's type III glottic web is even rarer. In cases of congenital laryngeal web the aim is to provide a patent airway and to achieve a good voice quality. Regardless of the technique used; the primary concern is recurrence. Traditionally, the treatment of choice for laryngeal web was laryngofissure with placement of a keel however; endoscopic laser excision of the web with keel placement is now the preferred technique for thin anterior glottic webs. This endoscopic technique not only requires a Lichtenberger needle carrier but also the ready-made keel, which many of the government set-ups in our country cannot provide. For an alternative to this problem, we have described an innovative, minimally invasive technique for placement of a self-made silicone keel without any sophisticated instruments. PMID- 28658821 TI - Intracorneal Amphotericin B Injection in a Case of Indolent Candidal Keratitis. AB - Ocular candidiasis is one of the opportunistic infection occurring in human body. Pathogenesis wise, Candida is very virulent and slow growing organism. We report a case of 76-year-old female with left eye candidal stromal abscess, not responding to topical and oral antifungal drugs. Patient was administered intrastromal amphotericin B injection in the affected eye. Four midstromal injections were given in the areas surrounding the corneal abscess. A total of approximately 0.05 mL of amphotericin B, 5 MUg per 0.1 mL, was administered. Within next four weeks, the eye became completely quiet with healed epithelial defect and corneal scarring. Intracorneal injection of amphotericin B is a safe and effective treatment option for recurrent and recalcitrant fungal infections. PMID- 28658822 TI - Recurrent Optic Nerve Pilocytic Astrocytoma: A Rare Case. AB - Pilocytic astrocytoma is a low grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is often associated with Neurofibromatosis Type I (NFI). A 40-year-old male presented with left sided axial proptosis and exposure keratopathy. MRI revealed a mass in left proximal orbit, extending posteriorly abutting the chiasma and the right optic nerve on MRI. Enucleation of the left eye along with near total excision of intracranial part of the mass was performed. Histopathology report was suggestive of pilocytic astrocytoma (WHO Grade I). Interestingly, his records showed evidence of surgery for removal of the optic nerve pilocytic astrocytoma twice (27 years and six years ago). We hereby, present an unusual case of recurrent pilocytic astrocytoma of the optic nerve in absence of NFI. PMID- 28658823 TI - Scintigraphic Profile of Thyrotoxicosis Patients and Correlation with Biochemical and Sonological Findings. AB - INTRODUCTION: Thyrotoxicosis is a spectrum of disorder with a rather common clinical presentation with different aetiologies. The aetiological diagnosis is important as the management differs. It is essential to accurately diagnose the cause before starting treatment. Scintigraphy of thyroid helps in differentiating accurately the various causes. USG is routinely being advocated and T3/T4 ratio has also been used. AIM: This study aims to evaluate the scintigraphic profile of thyrotoxicosis patients and to correlate biochemical and USG findings with scintigraphy. MATERIALS AND METHODS: A total of 60 newly diagnosed thyrotoxicosis patients based on biochemical reports were included in the study. They underwent further evaluation with ultrasonography and 99mTc scintigraphy. RESULTS: Of 60 patients of thyrotoxicosis, 45 cases were of Grave's disease, 10 cases were of thyroiditis and five cases were of Toxic Multinodular Goiter (MNG). The clinical characteristics were helpful in establishing the diagnosis in only six (10%) patients who presented with classic features of Grave's disease with ophthalmopathy. T3/T4 ratio greater than 20 was seen only in 29 (66%) patients of Grave's disease and also in three (33.33%) of thyroiditis patients. USG had a sensitivity and specificity of 81.82% and 93.75% in diagnosing Graves' disease and 100% and 82.4% in diagnosing thyroiditis respectively. CONCLUSION: Clinical findings do not help in accurately delineating aetiological diagnosis of thyrotoxicosis. Serum T3/T4 ratio when used as a criterion has marked overlap between the various conditions causing thyrotoxicosis. USG has reasonable sensitivity however, misses many cases of early Grave's disease. Follow up scintigraphy helps in a small population with resolving thyroiditis or early Grave's disease where the initial scintiscan is normal or inconclusive. PMID- 28658824 TI - Prevalence of Non Alcoholic Fatty Liver Disease and its Association with Diabetic Nephropathy in Patients with Type 2 Diabetes Mellitus. AB - INTRODUCTION: Non Alcoholic Fatty Liver Disease (NAFLD) and Type 2 Diabetes Mellitus (T2DM) are two common problems affecting global health as these two conditions can influence each other. There is very little information about the possible association between NAFLD and diabetic microvascular complications such as diabetic nephropathy. AIM: The aim of this study was to evaluate the prevalence of NAFLD in patients with T2DM and to investigate the association between NAFLD and diabetic nephropathy in these patients. MATERIALS AND METHODS: This cross-sectional study was conducted on 255 patients with T2DM, with minimum age being 30 years. Hepatic ultrasonography using a 3.5 MHz probe was performed in all subjects. Fatty liver based on standard criteria was diagnosed with liver brightness, contrast between the echogenicity of the liver, kidneys and the blood vessels fading rate. Screening for microalbuminuria was performed by the preferred method, measurement of the Urine Albumin-To-Creatinine (UACR) ratio in a random spot collection. RESULTS: In this study, 255 patients with T2DM were enrolled of which 173 (68%) were females and 82 (32%) were males. Of these 221 subjects (86.66%) had NAFLD. Diabetic nephropathy was observed among 33% of individuals, microalbuminuria among 32% and macroalbuminuria in 10% of all individuals. Duration of diabetes, Body Mass Index (BMI), hypertriglyceridemia, and HbA1c were significantly associated with incidence of NAFLD. Also, duration of diabetes and HbA1c were significantly associated with diabetic nephropathy in patients with T2DM. CONCLUSION: NAFLD in patients with T2DM is extremely common. NAFLD is not considered as a risk factor for diabetic nephropathy. To better understand the pathogenesis of NAFLD and its causal relationship with complications of diabetes such as diabetic nephropathy, prospective studies and long term follow up are needed. PMID- 28658825 TI - Uncovering Metabolic Syndrome among Chronic Obstructive Pulmonary Disease Patients in a Tertiary Care Hospital, India. AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is known to cause various systemic problems including Metabolic Syndrome (MetS). MetS is a group of cardiovascular risk factors. By assessing MetS, one can assess the cardiovascular disease risk. There is increasing evidence of MetS in COPD patients. However, the frequency of MetS and its individual components are not still been clearly shown which is likely to vary in different population. AIM: To know the extent of association of metabolic syndrome and its components in patients with COPD. MATERIAL AND METHODS: This study was designed as an analytical case control study. Ninety cases of COPD satisfying the inclusion criteria and 45 healthy volunteer subjects as controls were recruited over 18 months duration. Simple random sampling method was used to select all cases attending outdoor and indoor medicine department. All subjects (cases and controls) were matched for age, sex, occupation and socioeconomic status. Prior to participation in the study, written informed consent was taken from all subjects. All included subjects underwent a detailed history, clinical examination and laboratorial analysis. All subjects were assessed for MetS by using National Cholesterol Education Program-Third Adult Treatment Panel (NCEP ATP III) and International Diabetic Federation (IDF) criteria. RESULTS: The present study demonstrated Metabolic Syndrome (MetS) in COPD according to NCEP ATP III and IDF criteria as 14 (15.56%) and 30 (33.33%) while there was no association of MetS with controls. The frequency of its component such as abdominal obesity, systolic blood pressure, diastolic blood pressure, elevated triglyceride, reduced HDL-C and elevated fasting glucose respectively was 71 (78.89%), 25 (26.67%), 12 (13.33%), 18 (20%), 23 (25.56%) and 17 (18.78%) respectively. Dyslipidemia was found in 36 (40%) cases of COPD including 16 (17.78%) cases of elevated LDL cholesterol. CONCLUSION: Our study concluded that MetS is frequent in COPD patients as compared to general population. Therefore, a comprehensive medical approach to screen all COPD patients for MetS should be done there to lower the significant risk of cardiovascular events in patients with COPD. PMID- 28658826 TI - Analysis of 12 Months Clinical Outcomes Associated with Implantation of Ultrathin (60 MUm) Bare Metal Stent in an Unselected Real-world Population with Coronary Artery Disease. AB - INTRODUCTION: In the era of drug-eluting stents, Bare Metal Stent (BMS) has worked its way up to be recognized in several indications. Moreover, literature suggests that strut thickness has been directly related to the restenosis rate. AIM: We intended to evaluate the clinical performance of the ultrathin (60 MUm) Flexinnium stent (Sahajanand Medical Technologies Pvt. Ltd. Surat, India) for treatment of a wide range of patients with coronary artery disease in routine clinical practice. MATERIALS AND METHODS: This was an observational, non randomized, retrospective, single-arm study carried out in real-world patients at three clinical centres of India. A total of 419 consecutive patients' data was collected for the study, who underwent treatment for coronary lesions by implantation of Flexinnium stent, between April 2013 and December 2014. The primary endpoint of the study was Major Adverse Cardiac Events (MACE), a conglomerate of cardiac death, Myocardial Infarction (MI) (Q-wave and non-Q wave), Target Lesion Revascularization (TLR) and Target Vessel Revascularization (TVR). Any incidence of Stent Thrombosis (ST) was also observed as safety endpoint. These endpoints were observed during in-hospital stay, at 30 days, six months and at 12 months follow up. All data were analysed using the Statistical Package for Social Sciences (SPSS; Chicago, IL, USA) program, version 15. RESULTS: A total of 491 lesions were treated in 419 patients having mean age of 54.1 years. A total of 525 Flexinnium stents were implanted. There were 243 (58.0%) patients with hypertension. At 12 months the total incidences of MACE were 14 (3.5%). These included 9 (2.3%) cardiac deaths, 1 (0.3%) MI, 3 (0.8%) TLRs and 1 (0.3%) TVR. There was one incidence of definite ST at 12 months follow up. CONCLUSION: Our results demonstrate that the Flexinnium stent is associated with a low 12 months incidence of MACE in a wide range of real-world population. Long-term follow up would further confirm its clinical performance profile. PMID- 28658827 TI - Neck Circumference and Leg Length as Surrogate Markers of Coronary Artery Disease - Simplifying Cardiac Risk Stratification. AB - INTRODUCTION: Coronary angiography is the gold standard for quantification of coronary atherosclerosis. But, being invasive, it has inherent complications. Hence, we examined the accuracy of prediction of coronary angiography using simple anthropometric indices. AIM: To identify a patient friendly method to predict coronary artery disease using simple anthropometric parameters, by testing their correlation with coronary artery disease severity scoring system. MATERIALS AND METHODS: We conducted a cross-sectional study on patients undergoing elective coronary angiography. A total of 48 patients were included in the study. Neck circumference and leg length of the patients were noted. The severity of coronary atherosclerosis was quantified using Jenkin's scoring system. Mean and standard deviation for each continuous variable was calculated. The correlation between Jenkins' score, neck circumference and leg length was tested. The data analysis was done using IBM-SPSS software. RESULTS: Mean leg length among the study population was 88.70 cm (+/-2.51 cm) among males, 79.04 cm (+/-4.32 cm) among females and 83.66 cm (+/-3.26 cm) overall. Mean neck circumference was 36.87 cm (+/-4.37 cm) among males, 36.04 cm (+/-3.65 cm) among females and 36.44 cm (+/-3.99 cm) when combined together. There was no correlation of Jenkin's scores with leg length. But, there was significant correlation between Jenkin's scores and neck circumference. CONCLUSION: Neck circumference can be used as a simple and effective tool and is better than leg length for risk stratification of patients with coronary heart disease. PMID- 28658828 TI - Successful Outcome with Transradial Primary Percutaneous Coronary Intervention During Cardiopulmonary Resuscitation. AB - Transradial access for ST Elevation Myocardial Infarction (STEMI) has been shown to reduce mortality, major adverse cardiac events and bleeding, when compared with femoral access. Often patients with STEMIs present in the setting of cardiogenic shock and cardiac arrest. Prior published work has established the mortality benefit with early percutaneous coronary intervention in patients presenting with out of hospital cardiac arrests. However, the utility of transradial intervention in such patients is still under study. We present a case of transradial primary intervention performed during cardiopulmonary resuscitation for a patient who presented with an antero-septal MI. PMID- 28658829 TI - Acute Ischaemic Stroke as a Manifestation of Pituitary Apoplexy in a Young Lady. AB - Pituitary Apoplexy (PA) is defined as a clinical syndrome comprising headache, visual deficits and altered sensorium, which can result from haemorrhage or infarction of the pituitary gland. Acute ischaemic stroke following PA is very rare. We are presenting a 35-year-old young otherwise healthy lady who presented with neuro ophthalmological and vascular symptoms on a background of PA. Imaging revealed a pituitary macro adenoma with parasellar extension with internal bleed. Cerebral angiography revealed that the mass compressed the bilateral cavernous sinuses (left more than right), resulting in obliteration of the cavernous portion of the left Internal Carotid Artery (ICA). She was treated with steroids and surgical debulking of the tumour through trans-sphenoidal approach and postoperative imaging showed recanalization of the ICA with reduction of the tumour size. The histopathological diagnosis was consistent with pituitary macro adenoma. Patient improved in level of sensorium, eye movement and the patient showed almost full recovery after the operation. PA resulting in ICA occlusion is very rare. Early intervention is required for reducing mortality and morbidity and to improve quality of life. PMID- 28658830 TI - Blue Finger Syndrome: An Unusual Presentation of Rheumatoid Arthritis. AB - Blue Finger Syndrome (BFS) is a benign and rare condition with an idiopathic aetiology. It is characterised by an acute bluish discoloration of fingers which may be accompanied by pain. This is a case of a middle aged female who presented with painless bluish discoloration of right hand and was diagnosed to have BFS. Though BFS is idiopathic, our patient on evaluation was found to have an underlying Rheumatoid Arthritis (RA). Patients with RA are subject to Raynaud's phenomenon; but BFS presenting in a patient with RA is a rare scenario. PMID- 28658831 TI - Enteric Cholestatic Hepatitis with Ascites: A Rare Entity. AB - Typhoid fever is a very common illness in developing countries. Patients most often present with a history of fever, vomiting, anorexia, abdominal pain, etc. Rarely there is hepatic involvement due to the disease process. This is a case report of a 26-year-old male who had presented with fever, jaundice and ascites. The widal titres were found to be within normal limits (1:80) however the patient was found to have Salmonella typhi on ascitic fluid culture. The patient was treated with the appropriate antibiotics and was later discharged. PMID- 28658832 TI - Influenza as a Cause of SIADH Related Hyponatremia: A Case Report. AB - Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) is one of the most common causes of hyponatremia in hospitalized patients. The distinct aetiologies and co-morbidities associated with hyponatremia pose substantial challenges in identifying and managing this disorder. Several infectious causes of SIADH are reported but hyponatremia associated with SIADH and influenza virus infection is less commonly seen. We present a case of hyponatremia associated with influenza, which was subsequently diagnosed as SIADH. PMID- 28658833 TI - Insulin (Technique) Induced Hypoglycaemia. AB - The most common side effect of insulin therapy is hypoglycaemia apart from weight gain. It occurs commonly due to insulin overdose, faulty injection site, technique and meal-insulin mismatch. In lean individuals even the needle size can be a contributing factor to hypoglycaemia. Here we report a case who presented with recurrent episodes of hypoglycaemia due to a combination of wrong insulin site, technique as well as needle size. On examination, he was found to have spotted dermopathy on his forearms (insulin injection site) which was consistent with intradermal insulin administration. Recently, insulin infusion through intradermal route has been found to reach the systemic circulation faster than even the conventional subcutaneous injection. This case emphasizes that hypoglycaemias can occur due to less common causes. It warrants a good clinical examination and patient education. PMID- 28658834 TI - A Case of a Rapidly Enlarging Neck Mass with Airway Compromise. AB - Anaplastic Thyroid Carcinoma (ATC) is one of the most lethal tumours in humans, extremely rare in occurrence and very aggressive in nature. We hereby present a rare case of ATC with airway compromise. A 66-year-old male, presented complaining of a non-tender anterior neck mass rapidly increasing in size associated with dry cough, hoarseness and voice changes. Imaging studies revealed a large heterogeneous centrally necrotic lobulated left thyroid mass with metastatic lymph nodes and rightward tracheal deviation. Core biopsy and immunohistochemistry stains revealed a profile consistent with ATC. Patient's airway was compromised. Options for treatment and prognosis were discussed. Patient was discharged home with home hospice. A high index of suspicion for ATC is necessary in patients presenting with a rapidly enlarging neck mass. A prompt cytologic evaluation with metastatic work up is important to establish diagnosis. Due to its poor prognosis, an honest discussion regarding end-of-life issues must be initiated at diagnosis. Novel therapies toward genetic and epigenetic pathways have been developed, which is the basis of current clinical trials that are intended to improve clinical outcomes in the coming years. PMID- 28658835 TI - Simultaneous Occurrence of Thyroiditis in Ectopic and Eutopic Thyroid Masquerading as Thyroglossal Cyst. AB - Ectopic thyroid gland is a rare condition usually presenting with neck swelling or hypothyroidism. In most cases, ectopic thyroid tissue is the only functioning thyroid tissue, but it may rarely be associated with normal thyroid gland. Thyroiditis in an ectopic thyroid gland is very rare. Here, we describe a 13-year old girl who was initially suspected, as a having a thyroglossal cyst. Thyroid functions were suggestive of thyrotoxicosis. She was diagnosed to have simultaneous occurrence of thyroiditis in the ectopic and eutopic thyroid glands. This case was exceedingly rare since this patient presented with thyrotoxicosis unlike previous reported cases who were either euthyroid or hypothyroid. PMID- 28658836 TI - Upper Gastrointestinal Bleeding Due to Idiopathic Oesophageal Ulceration in the Era of HAART: A Vanishing yet Pernicious Aetiology. AB - Oesophageal ulcers are a rare cause of upper Gastrointestinal Bleeding (GIB). In patients with Acquired Immune Deficiency Syndrome (AIDS), oesophageal diseases including oesophageal ulcers are very common. Idiopathic Oesophageal Ulcers (IOU) comprises a subgroup of oesophageal ulcers with no identifiable cause. IOU mainly present as odynophagia, retrosternal chest pain, decreased oral intake, and weight loss. Upper GIB is a rare presentation. In the era of Highly Active Anti Retroviral Therapy (HAART), with improvement in CD4 count, this entity is almost forgotten. PMID- 28658837 TI - Leriche Syndrome: Acute Onset Painful Paraplegia of Vascular Origin with Catastrophic Consequences. AB - Acute Aorto-Iliac Occlusive Disease (AIOD) is a rare clinical entity which when presents with buttock claudication, erectile dysfunction and absent femoral pulses is termed as Leriche syndrome. A 59-year-old male patient with past history of smoking and dyslipidaemia presented with acute onset lower back pain, paraplegia, intense lower limb pain and was initially evaluated for compressive myelopathy. On further clinical examination there were absent femoral pulses and Computed Tomography (CT) aortogram was done which confirmed the diagnosis of diffuse AIOD. Clinically, it is often challenging to differentiate between vascular or neurogenic origin of acute onset painful paraplegia. A high index of suspicion and careful clinical examination is therefore essential to avoid misdiagnosis of a major vascular event which can result in significant morbidity and mortality. PMID- 28658838 TI - Hemi-Chorea in a Patient with Ketotic Hyperglycemia: An Unusual Presentation. AB - Chorea has often been associated with lesions in the basal ganglia and in the sub thalamic nucleus. It is possible for a patient with chorea-ballismus to have hyperglycemia at the initial presentation. We hereby present a case of an 81-year old female, who was on treatment for type 2 diabetes mellitus and presented to us with sub acute onset of abnormal movements of right side of the body. She had semi purposeful, rapid and jerky movements of right upper limb and lower limb along with abnormal tongue movements. Laboratory data showed very high blood glucose levels, urine ketones were positive and pH of arterial blood was normal. MRI brain showed hyperintensities in right basal ganglia. So, hyperglycemia induced hemichorea was considered as a possibility and she was treated with insulin. These abnormal movements decreased subsequently with treatment and patient is doing better in the follow-up visits. This presentation is extremely rare, as review of literature showed similar presentations in patients with non ketotic hyperglycemia but not reported so far in diabetic ketosis. PMID- 28658839 TI - Lymphangitic Pulmonary Metastasis: A Rare Finding in Gastric Carcinoma. PMID- 28658840 TI - Hoffmann's Syndrome- A Rare Form of Hypothyroid Myopathy. PMID- 28658841 TI - Respiratory Symptoms as Prominent Manifestation of Brucellosis: A Case Series. AB - Brucellosis is a zoonotic infection primarily affecting the reticuoendothelial system: spleen, liver and bone marrow. Despite the fact that multisystem infection in brucellosis is usually reported, pulmonary involvement is considered to be very rare. We report four cases (three male and one female, farm workers) of pulmonary brucellosis who presented with signs and symptoms of lower respiratory infection. All of them underwent thorough clinical examination and laboratory tests before the diagnosis of pulmonary brucellosis was confirmed. All patients were hospitalized for at least eight days and given appropriate antibiotic therapy. Follow up after 12-24 months showed no lasting effects from the infection and laboratory tests were found within the normal limits. PMID- 28658842 TI - A Case Series of Young Patients with Completely Reversed Severe Pulmonary Hypertension. AB - Pulmonary Arterial Hypertension (PAH) is a progressive symptomatic disorder, which may ultimately lead to death if left untreated. Although majority of PAH cases are idiopathic, pulmonary hypertension resulting due to certain underlying conditions are also observed frequently. In such cases, it becomes essential to identify any potentially treatable or reversible causes for PAH. There have been significant advances in the medical management of PAH and various medicines have been approved by US Food and Drug Administration (FDA) for various stages of PAH. With these therapies, there can be varying degrees of improvement in the pulmonary artery pressures and hemodynamic profile. Therefore, physiologic reversal can and does occur, sometimes to the point of normalization. We hereby present three such cases of severe PAH in patients below 50 years of age due to various aetiologies like left heart disease, isolated unilateral absence of right pulmonary artery with hypoplastic right lung and factor V Leiden mutation associated pulmonary thromboembolism, all of whose pulmonary artery pressures are completely normalised with adequate treatment of the underlying disease and with optimised medications for PAH, ultimately leading to tapering and stoppage of PAH medications. PMID- 28658843 TI - Anatrophic Nephrolithotomy in the Management of Large Staghorn Calculi - A Single Centre Experience. AB - INTRODUCTION: With advances in endourology, open stone surgery for staghorn calculi has markedly diminished. Anatrophic Nephrolithotomy (AN) is performed for complex staghorn stones which cannot be cleared by a reasonable number of Percutaneous Nephrolithotomy (PNL) attempts. AIM: To assess the indications and outcomes of AN in the modern era. MATERIALS AND METHODS: Between April 2008 and July 2015, AN was done in 14 renal units in 13 patients. In this retrospective study, demography, stone characteristics, operative details, clearance and long term outcomes were assessed. RESULTS: AN was performed for complex staghorn calculi involving pelvis and all calyces in 10 patients, infundibular stenosis in two patients and failed PNL in one patient. Mean (SD) in situ cold ischemia time was 47.64 (5.27) minutes. Retroperitoneal drain and double J stent were placed in all 13 patients. Median (IQR) estimated blood loss was 130 (75) ml. There was no perioperative mortality. Surgical site infection was seen in 2 patients and urosepsis in 2 patients. Drain was removed at a mean (SD) of 9.11 (6.15) days. Mean (SD) postoperative length of hospitalization was 15.44 (7.14) days. Stent removal was done in all patients between 2-8 weeks. Median (IQR) clearance was 95 (7.5%). There was no renal failure or new calculi during the follow up period {median (IQR): 1(3) years}. CONCLUSION: AN is effective in management of large staghorn calculi failed minimally invasive approaches and achieves 80%-100% clearance without much need for secondary interventions. Renal function is preserved and with emergence of laparoscopy and robotics, postoperative stay is minimized with expedited recovery and comparable results with open surgery. PMID- 28658844 TI - An Uncommon Case of Cervical Thymopharyngeal Duct Cyst. AB - Thymopharyngeal duct cyst is one of the most uncommon benign cervical lesions encountered in the paediatric population. Due to its rarity, it almost always escapes a correct preoperative diagnosis and is usually misdiagnosed as a branchial cyst or lymphangioma. Furthermore, although located at the neck it may present with retrosternal or mediastinal extension. In this case report here we present a case of a young boy with a right cervical mass, diagnosis of thymopharyngeal duct cyst was confirmed during histopathological examination of the excised specimen. Furthermore, preoperative ultrasonography and MRI did not detect the thin cord and the lower part of the lesion, which rendered operative treatment more demanding. Apropos to these findings, we reflect on the crucial points of awareness that affect the diagnostic and surgical process of this lesion. PMID- 28658845 TI - Large Multicystic Dysplastic Kidney Mimicking a Large Cystic Renal Neoplasm. AB - Multicystic Dysplastic Kidney (MCDK) is one of the most common renal conditions seen in paediatric population. The natural history typically involves involution and many of the patients with unilateral disease may actually never become symptomatic. The initial evaluation is usually done on Ultrasonography (USG) while cross-sectional imaging and nuclear scan are reserved for diagnostic dilemmas. Management is conservative and surgery is done for selected patients with symptomatic cysts or suspicion of neoplasm. We present an interesting case of MCDK in a nine-month-old female hypertensive child presenting with a large abdominal mass increasing in size with imaging features similar to cystic neoplasm and managed with nephrectomy. PMID- 28658846 TI - Concomitant Presence of Carcinoma of Breast in a Patient with Early-Onset Cataract: First Case Report of a Potential Association. AB - A recent nation-wide population based retrospective cohort study from Taiwan in 2014 suggested a propensity of developing breast cancer in young females with early-onset cataract. We report here a case of a young non-obese female who presented to us with a large lump in the right breast with skin nodules and bilateral painless progressive diminution of vision. Patient was diagnosed to be suffering from locally advanced carcinoma of right breast with axillary metastasis (Stage III B) and bilateral early-onset nuclear cataract. Patient was started on taxane and anthracycline based neoadjuvant chemotherapy and after three cycles of chemotherapy patient showed partial response (~50% reduction of tumour mass). Patient underwent small incision cataract surgery in left eye after the first cycle of chemotherapy. However, the patient was lost before any operative intervention could be done as she died in a road traffic accident. Possible mechanism of development of breast cancer in patients with early-onset cataract is discussed. This is the first reported case of a patient of early onset cataract developing breast cancer as well as the first reported case of concomitant presence of early-onset bilateral cataract with breast cancer. PMID- 28658847 TI - Massive Benign Phyllodes Tumour of Breast Complicating Pregnancy. AB - Phyllodes tumour of the breast, earlier called cystosarcomaphyllodes, is a rare fibroepithelial breast neoplasm that occurs in all age groups from adolescents to elderly. Phyllodes tumour occurring during pregnancy and associated with lactating breast is extremely rare. Giant phyllodes tumours or giant fibroadenomas are those measuring more than 10 cms in diameter and weighing more than 500 gm. Phyllodes tumour typically exhibits an exclusive intracanalicular growth pattern of fibroepithelial cells with classical, deep leaf-like stromal projections into dilated lumens from which its name "phyllodes" is derived. A 32 year-old primigravida at 38 weeks of gestation, presented with massive and heavy swelling of the left breast, growing over the last eight months. Physical examination revealed a massively enlarged left breast with palpable, firm, nodular mass measuring 10 x 20 cm and occupying whole of the left breast. A trucut biopsy demonstrated a fibroepithelial lesion suggestive of benign phyllodes tumour. Simple mastectomy was performed six days after the delivery of the baby by caesarean section. The histopathological report confirmed the diagnosis as benign phyllodes tumour with ductal hyperplasia and no atypia. We are reporting this case because of its massive size, associated with lactating breast and difficulty in histopathological differentiation from Giant fibroadenoma. PMID- 28658848 TI - Parietal Wall Abscess Perforating to Transverse Colon: A Rare Presentation. AB - Extrapulmonary tuberculosis affects an isolated organ or presents secondary to pulmonary involvement. Lymph nodes are the common sites for extrapulmonary tuberculosis. Primary extrapulmonary tuberculosis involving parietal wall is an unusual presentation. Tubercular abscess of the abdominal wall perforating to large bowel has not been reported. Here, we are reporting a very rare case of anterior abdominal wall abscess of tubercular origin in a 57-year-old female patient who presented with complaints of pain in upper abdomen for four months. CT scan and intraoperative findings revealed perforation of the abscess into transverse colon. Histopathology report confirmed the aetiology and origin of the abscess. PMID- 28658849 TI - Renal Pelvis Leiomyoma- An Infrequent Clinical Case. AB - Renal pelvis leiomyomas are infrequent benign tumours. These tumours are more frequent in women, usually asymptomatic and difficult to distinguish from malign kidney masses. A 27-year-old female presented with an asymptomatic renal mass discovered after abdominal ultrasound during routine check-up. Percutaneous renal biopsy was performed and reported urothelial carcinoma. After open nephroureterectomy, histopathological evaluation and immunohistochemistry were positive for Smooth Muscle Actin (SMA), Ki67 <5%, and negative for cytokeratin and HMB-45. Thus, confirming the diagnosis of renal leiomyoma. The diagnosis of these infrequent tumours is often difficult and it is usually made by immunohistochemistry after surgical treatment. PMID- 28658850 TI - An Unusual Presentation of Congenital Cystoadenomatoid Malformation of Lung. PMID- 28658851 TI - Risk Factors and Incidence of Puerperal Genital Haematomas. AB - INTRODUCTION: Puerperal genital haematomas although an uncommon entity but is elusive. This painful condition is not only distressing and dangerous to patient but is embarrassing to the obstetrician who has conducted the delivery. AIM: This study has been planned to evaluate the incidence and risk factors for puerperal genital haematomas. MATERIALS AND METHODS: A case control study was done from August 2005 to August 2015, of all puerperal genital haematomas. All patients, who had undergone drainage for the puerperal genital haematoma, were enrolled as cases. Two controls were chosen for each case, who had delivered immediately after the case. All the patients were evaluated for the characteristics of haematoma and the management of the same. Cases and controls were compared for the evaluation of risk factors for puerperal genital haematoma. RESULTS: During the study period 27,826 vaginal deliveries were performed in our institute. Thirty nine haematomas were drained during this period. Incidence of haematomas was one in 1,113 deliveries, in our institute. Among the puerperal haematomas, vulvovaginal was the most common type. Perineal pain was the most common complaint. To evaluate the risk factors, 77 controls were enrolled. Primigravida, hypertensive disease of pregnancy and coagulopathy were the significant risk factors with p-value of <0.01, 0.01 and 0.03 respectively. Episiotomy too was a risk factor with a p-value of 0.002. CONCLUSION: Primigravida, hypertensive disease of pregnancy, coagulopathy and episiotomy are still the most common risk factors. PMID- 28658852 TI - Severe Puerperal Sepsis-A Simmering Menace. AB - INTRODUCTION: Even decades after the development of effective low-cost antibiotics, sepsis persists as the foremost cause of preventable maternal death worldwide. In developing countries like India, where the paramount impediment to intervention is poverty, maternal mortality due to sepsis is a continuing representation of maternal health inequality. AIM: To determine the incidence, risk factors and mortality in women presenting with puerperal sepsis in a tertiary care health facility in India. MATERIALS AND METHODS: This retrospective study was carried out in VMMC and Safdarjung Hospital, New Delhi, India, from January 2016 to June 2016 in Department of Obstetrics and Gynaecology. Case records of all eligible patients of puerperal sepsis were reviewed and data were extracted regarding demographic profile, clinical profile on admission, course in hospital, management, complications and cause of mortality (in case of death). Inclusion criteria were any patient presenting either immediately after delivery or miscarriage or within 42 days of these events with fever and any of the following: pain abdomen, malodorous lochia, abdominal distention, uterine tenderness, pelvic abscess, peritonitis, mechanical or foreign body injury, any system/organ failure or shock. Exclusion criteria consisted of patients presenting with fever during pregnancy or more than 42 days after delivery or miscarriage, or patients presenting with fever due to medical conditions, wound infection, mastitis, UTI or thrombophlebitis. Data were entered in predesigned proformas and analysed. A p-value of less than 0.05 was considered significant. RESULTS: During the study period, a total of 33 cases met the inclusion criteria. Of these, 90% were referred cases. Anaemia, prolonged labour, delivery by an untrained person and unsafe abortion were the main identifiable risk factors. Surgical management was required in 75% cases, while 70% women succumbed to their illness, mostly due to multiorgan failure. CONCLUSION: Maternal mortality due to maternal sepsis is very high; Lack of safe and hygienic practices for conducting delivery and abortion are important contributory factors. PMID- 28658853 TI - Difference in Perception of Pregnancy Risk in Two Maternal Age Groups. AB - INTRODUCTION: Various health risks and complications may happen during pregnancy for both the mother and her child. Women should be informed of the risk associated with their pregnancy. AIM: To compare the differences of perception of pregnancy risk of two maternal age groups of healthy nulliparous women. MATERIALS AND METHODS: In an analytical, descriptive cross-sectional study, 240 nulliparous pregnant women (160 women aged 18 to 35 years as a normal age group and 80 women < 18 years as a high risk age group) were randomly selected. Women were asked to complete questionnaire which included sociodemographic characteristics, pregnancy history, perception of pregnancy risk and pregnancy related anxiety. RESULTS: Overall, women of < 18 years (high-risk group) perceived the risks of pregnancy higher than those of 18-35 years age women (reference group). Women in high-risk group rated their risks for herself, having haemorrhaging, having a cesarean birth and dying during pregnancy to be significantly higher than reference group. There was a statistically significant relationship between maternal age and perception of pregnancy risk (p<0.003). There was also a statistically significant relationship between pregnancy related anxiety and perception of pregnancy risk (p<0.002). CONCLUSION: Women's perception of pregnancy risk is different in various maternal age groups. Maternal age can be considered as one of the important factors affecting perception of pregnancy risk. By routine screening of perception of pregnancy risk during prenatal care more effective risk consulting model could be designed. PMID- 28658854 TI - Marital Intimacy and Predictive Factors Among Infertile Women in Northern Iran. AB - INTRODUCTION: Infertility is a stressful state that may decrease attachment between spouses. Marital intimacy is a real need in infertile women. AIM: The aim of this study was to evaluate marital intimacy and predictive factors among infertile women in Northern Iran. MATERIALS AND METHODS: This cross-sectional study was conducted at Fatemeh Zahra Infertility and Reproductive Health Center of Babol Medical Sciences University in 2014. A total of 221 infertile women participated in this study. The instrument used in this research was Marital Intimacy Need Questionnaire (MINQ). Statistical analyses was performed using linear and logistic regression with p<0.05 indicating statistical significance. RESULTS: An 88.5% of infertile women had good marital intimacy. The mean and standard deviation of the marital intimacy was 349.11+/-49.26 and in marital intimacy domains including: emotional (42.28+/-7.23), psychological (41.84+/ 7.59), intellectual (42.56+/-7.46), sexual (42.90+/-7.41), physical (43.59+/ 6.96), spiritual (51.61+/-8.06), aesthetic (42.66+/-6.75), and social intimacy (42.59+/-6.89). The highest mean of marital intimacy domains is related to spirituality in infertile women. Physical and sexual domains had the high mean in infertile women. The lowest mean in marital intimacy domains was psychological intimacy. There was a significant correlation between the domains of marital intimacy. The strongest correlation was between the physical and sexual intimacy (r=0.85). There was a significant inverse association in marital intimacy with the age difference of spouses (p<0.01), and tobacco use (p<0.02). There was a statistically significant association in the marital intimacy with husband's occupation, and cause of infertility (p<0.02). CONCLUSION: Early screening and psychosocial intervention strategies suggest in the setting of female infertility to identify and prevent the predictive factors that may cause marital conflict. PMID- 28658855 TI - Pure Primary Squamous Cell Carcinoma of Ovary - A Rare Case Report. AB - Primary Squamous Cell Carcinoma (SCC) is a rare tumour which arises in a mature cystic teratoma, endometrioma or Brenner tumour. The pure variety arises from metaplasia of surface epithelium of ovary and it is the rarest type. For optimal management no definitive treatment protocol is available till date. Also, there is no agreement concerning the postoperative therapy-chemotherapy or radiotherapy. We present a rare case of pure primary SCC of ovary which was managed by aggressive cytoreductive surgery followed by chemotherapy. PMID- 28658856 TI - Long Cord: A Knotty Affair. PMID- 28658857 TI - Application of a Mixed Material Graft to Posterior Intravaginal Slingoplasty Procedure: Preliminary Pilot Series. AB - Good anatomic outcomes have been achieved with transvaginal synthetic materials in pelvic organ prolapse, but mesh-related complications are a major health concern. Therefore, developing new synthetic or biological materials with increased tissue strength and decreased complications are major challenges. This paper presents preliminary pilot series of Posterior Intravaginal Slingoplasty (PIVS) procedure performed with mixed material graft containing both autologous tissue and a synthetic material. Six women with symptomatic Utero-Vaginal Prolapse (UVP) >= stage 2 underwent the PIVS procedure. Pelvic floor symptoms were assessed with the Pelvic Organ Prolapse Quantification (POP-Q) system, Pelvic Floor Distress Inventory (PFDI), and the Pelvic Floor Impact Questionnaire (PFIQ) both before the procedure and 36 months after the surgery. There were no mesh-related complications or recurrence and all the patients had good functional and anatomic outcomes. These preliminary results are promising, but further long term studies with a larger series are needed. PMID- 28658858 TI - Clinical Outcome of Treatment of Diaphyseal Fractures of Humerus Treated by Titanium Elastic Nails in Adult Age Group. AB - INTRODUCTION: Humerus shaft fracture is one of the most common injuries to the musculoskeletal system, which are managed both conservatively and surgically. There are pitfalls, advantages and disadvantages in each method. The individual fracture analysis determines the therapeutic options. AIM: To assess the clinical outcome of treatment of diaphyseal fractures of humerus treated by Titanium elastic nail in adult age group by DASH scoring. MATERIALS AND METHODS: It was a prospective study of 20 cases of diaphyseal fracture of humerus admitted to Era's Lucknow Medical College and Hospital between October 2014 and September 2015 treated with close reduction and internal fixation with titanium elastic nail. Functional outcome was evaluated using DASH scoring system and radiological outcome was evaluated by serial radiographs. The data was processed with SPSS software version 16.0 (Chicago, inc. USA) and it was summarized in proportion and percentage. RESULTS: In our series of 20 patients, 17 were males and three were females. Most of the patients were between 30-50 years of age (mean 38 years). Most common mode of injury, side of involvement, level of fracture and fracture type were road traffic accidents (60%), right side (53.3%) and mid one third (75%), transverse (60%) respectively. So, in 65% of the patients, there was no disability of arm shoulder and hand as DASH score was within normal range and in 15% of the patients the disability was mild to moderate as scoring was slightly higher than normal and in 20% the disability was severe as the DASH score could not be calculated because of non union. CONCLUSION: Elastic nail fixation require very minimal soft tissue dissection and being a close reduction, the biology of the fracture is also not disturbed and the chances of nerve injury are much less and as the non union was seen in oblique and spiral fracture type hence it should be used with caution or else other alternative methods of fixation should be used. PMID- 28658859 TI - Is the Cage an Additional Hardware in Lumbar Interbody Fusion for Low Grade Spondylolisthesis? A Prospective Study. AB - INTRODUCTION: Lumbar interbody fusion has become the standard of care for the management of lumbar instability, where fusion is achieved using bone grafts, cages, etc. AIM: The aim of the study was to compare the outcomes of the interbody fusion using interbody cage technique and stand alone local bone graft technique. MATERIALS AND METHODS: A total of 30 patients, operated for single level instability with low grade lytic and degenerative spondylolisthesis of L4 5/L5-S1, were selected and grouped into two groups: Group I (stand alone grafts) and Group II (interbody cage and graft) based on computer generated random numbers. All patients who underwent interbody fusion through conventional open posterior approach were included in the study. Data regarding the time taken for interbody fusion, formaninal height maintenance, disc height restoration, translation, functional scores (VAS,ODI) and operative complications were analysed using in both the groups was collected and a student's-t test was performed to evaluate the difference. RESULTS: The mean age of patients in Group I was 46.7 years whereas, the mean age of patients in Group II was 43.5 years with mean age of 46.7 years and 43.5 years respectively. Interbody fusion, was achieved in seven and eight months in Group I and II respectively (p>0.05). The clinical results of both groups were comparable and there was no significant difference between the two groups in VAS score (p-0.147) and ODI score (p-0.983). Radiological parameters were also comparable and there was no significant difference between the postoperative measurements of the two groups (p=0.348 for translation, p=0.310 for intervertebral disc height and p=0.135 for foraminal height). One patient in Group I had transient foot drop which recovered, while one in Group II had infection, wound was managed with wound wash and antibiotics and another patient in Group II had pseudoarthrosis. CONCLUSION: Lumbar interbody fusion with standalone local bone grafts is sufficient in single level low grade spondylolisthesis treated by conventional open surgery. PMID- 28658860 TI - Muscle Activation Profiles and Co-Activation of Quadriceps and Hamstring Muscles around Knee Joint in Indian Primary Osteoarthritis Knee Patients. AB - INTRODUCTION: Osteoarthritis (OA) of knee is a common joint disease. It is associated with reduced knee joint stability due to impaired quadriceps strength, pain, and an altered joint structure. There is altered muscle activation in knee OA patients, which interferes with normal load distribution around the knee and facilitates disease progression. AIM: Our primary aim was to determine activation patterns of the muscles i.e., quadriceps and hamstrings in knee OA patients during walking. We also studied co-activation of muscles around knee joint in primary OA knee patients including directed medial and lateral co-contractions. MATERIALS AND METHODS: This observational study was done at Department of Physical Medicine and Rehabilitation, All India Institute of Medical Sciences, New Delhi, India. Fourty-four patients with medial compartment primary knee OA were included in study after satisfying inclusion and exclusion criteria. All the patients were assessed for mean, peak and integrated Root Mean Square (RMS), EMG values, muscle activation patterns and co-activation of muscles around knee joint by surface Electromyography (EMG) analysis of Vastus Medialis Obliques (VMO), Vastus Lateralis (VL), Semitendinosus (SMT) and Biceps Femoris (BF) muscles during gait cycle. The EMG waveform for each muscle was amplitude normalized and time normalized to 100% of gait cycle and plotted on graph. Quantitative variables were assessed for normal distribution and accordingly mean+/-SD or median (range), as appropriate, was computed. RESULTS: For primary OA knee, mean age 61+/-5 years, mean weight 63.7+/-10.1 kg, mean height 153.9+/-7.2 cm, and mean Body Mass Index (BMI) 26.8+/-3.0 kg/m2 was found. The muscle activity of hamstrings (SMT muscle and BF) was increased during midstance, late stance and early swing phase of gait cycle as compared to quadriceps (VMO and VL) muscle activity respectively, suggesting co-contraction of opposing muscles around knee joint. CONCLUSION: Patients with knee OA walk with increased hamstring muscle activity (during late stance and early swing phase) and reduced quadriceps recruitment. Altered neuro-muscular control around knee interferes with normal load distribution and facilitates disease progression in knee joint. PMID- 28658861 TI - Comparative Efficacy of Platelet Rich Plasma Injection, Corticosteroid Injection and Ultrasonic Therapy in the Treatment of Periarthritis Shoulder. AB - INTRODUCTION: Periarthritis (PA) shoulder characterised by pain and restricted range of motion has a plethora of treatment options with inconclusive evidence. Platelet Rich Plasma (PRP) is an emerging treatment option and its efficacy needs to be examined and compared with other routine interventions. AIM: To assess the efficacy of PRP injection and compare it with corticosteroid injection and ultrasonic therapy in the treatment of PA shoulder. MATERIALS AND METHODS: Patients with PA shoulder (n=195) were randomised to receive single injection of PRP (2 ml) or corticosteroid (80 mg of methylprednisolone) or ultrasonic therapy (seven sittings in two weeks; 1.5 W/cm2, 1 MHz, continuous mode). All participants were also advised to perform a home based 10 minute exercise therapy. The primary outcome measure was active range of motion of the shoulder. Secondary outcome measures used were Visual Analogue Scale (VAS) for pain and a shortened version of Disabilities of the Arm, Shoulder and Hand (QuickDASH) for function. Participants were evaluated at 0, 3, 6 and 12 weeks. Chi-square test, one way and repeated measures of ANOVA tests were used to determine significant differences. RESULTS: PRP treatment resulted in statistically significant improvements over corticosteroid and ultrasonic therapy in active as well as passive range of motion of shoulder, VAS and QuickDASH at 12 weeks. At six weeks, PRP treatment resulted in statistically significant improvements over ultrasonic therapy in VAS and QuickDASH. No major adverse effects were observed. CONCLUSION: This study demonstrates that single injection of PRP is effective and better than corticosteroid injection or ultrasonic therapy in treatment of PA shoulder. PMID- 28658863 TI - Complicated Hydatid Cyst of Ulna- A Rare Case Report. AB - Although hydatidosis is not uncommon in tropical countries, still bony involvement is comparatively rare. The aetiological agent is Echinococcus granulosus, a parasite belonging to cestode group with dog as definitive host and man as incidental host. We present a case of young male, who consulted us for painless, multiple swellings in his right forearm of three years duration, with restricted wrist movements. On examination multiple non tender, soft to firm swellings were noted with restricted terminal pronation. X-rays and MRI of right forearm showed multiple lobulated soft tissue components in intermuscular, subcutaneous and cutaneous planes and the main ulnar intramedullary cystic mass extending out as extramedullary cyst through proximal ulnar cortical breach. Proximal 2/3rd radius were also affected. On surgical exploration of forearm, cystic swelling measuring 8 * 6 * 5 cm sprouting out from proximal ulnar erosion was found. Intraoperative histopathology showed multiple endocysts suggestive of hydatid cyst; hence with protective measures wound closed back in layers and six weeks of oral albendazole 400 mg daily was given. At six weeks follow-up wrist movements improved but serous discharge persisted at drain site. Patient is still under regular follow-up. Thus, a differential diagnosis of bony hydatidosis should be considered while evaluating soft tissue swellings. PMID- 28658862 TI - Extra Articular Supracondylar Femur Fractures Managed with Locked Distal Femoral Plate or Supracondylar Nailing: A Comparative Outcome Study. AB - INTRODUCTION: Despite recent evolution in the operating techniques and surgical implants, debate continues around the choice of implant for management of distal femur fractures. High rates of complications and union difficulties continues to make them a momentous therapeutic challenge. AIM: To compare the outcome of locked compressive plating versus retrograde nailing in the management of extra articular supracondylar femur fractures. MATERIALS AND METHODS: In this randomized prospective study, 42 patients with extra-articular distal femur fractures were segregated into two groups based on internal fixation with distal femoral locking plate (n=22) and retrograde nail (n=20). Clinical and radiological parameters were studied and functional evaluation was done at 18 months with KSS score. RESULTS: A significant difference in terms of mean duration of surgery and intraoperative blood loss was discerned in favour of plating group although complication rates were equivalent between the groups. Mean duration until union was 26.5 weeks (SD=12.9; range 12 to 64 weeks) in the locked plating and 22.6 weeks (SD=13.1: range 12 to 60 weeks) in the retrograde nail group. The difference came out to be statistically insignificant. Fractures in nailed patients united earlier but the difference was not statistically significant with similar overall union rates. Functional scores too were comparable between them. We deduce that surgical planning and expertise rather than the choice of implant are more crucial for optimal results. CONCLUSION: Nailing proved more cumbersome intraoperatively due to escalated operating time and blood loss and successive anterior knee pain necessitating implant removal but this detriment may be offset by an inclination towards earlier union. With Less Invasive Stabilization System (LISS), technical errors are more common and less forgiving and must be overcome with proper preoperative planning and intraoperative attention to detail. PMID- 28658864 TI - Bilateral Solitary Glomus Tumour of Thumb: A Case Report. AB - Glomus tumours are benign neoplastic lesions of glomus body, a thermoregulatory apparatus of cutaneous microvasculature. These tumours can arise at any location of the body but most commonly seen in subungual region of fingers. Bilateral solitary glomus tumour of hand is a rare entity. We report a case of 54-year-old female who presented with complaints of pain in the right thumb since three years and left thumb pain since 20 years. Clinical examination revealed acute tenderness of both the thumbs. Love's pin test and Hildreth's test were positive. MRI revealed characteristic features of glomus tumour. Excision of both the lesions was done and proceeds forwarded to histopathology which confirmed diagnosis. Patient was symptom free immediately following surgery. No nail deformities were noticed and there was no recurrence of symptoms in one year follow up. Glomus tumours of the hand are a rare entity and often missed. PMID- 28658865 TI - Lasegue's Sign. AB - Lasegue's sign is an interesting and important clinical sign in medicine for the last 150 years. The Lasegue test is commonly used in the physical examination of patients with low back pain. It is a test for lower lumbosacral nerve root irritation for example, due to disc prolapse. It is evident that the method of performance of this diagnostic sign varies with the physician. This article reviews the historical background and method of eliciting the sign. PMID- 28658866 TI - Unusual Presentation of Atypical Infantile Pompe Disease in the Newborn Period with Left Ventricular Hypertrophy. AB - Pompe disease, also known as glycogen storage disease Type II, is a lysosomal storage disorder caused by alpha-glucosidase deficiency. In general, the clinical spectrum varies with respect to the age of onset, residual enzyme activity and organ involvement. Infantile onset disease has two subtypes: classical and non classical (atypical). This case report describes the case of a newborn who presented with generalized hypotonia and elevated serum enzyme levels of aspartate aminotransferase 93 IU/L, lactate dehydrogenase 888 IU/L and creatine kinase 670 MUg/L. The electrocardiogram showed short PR interval with large QRS complexes with echocardiography suggesting evidence of left ventricular hypertrophy with infiltration in its walls. On the basis of the clinical signs and laboratory results, dried blood spots from the baby were tested to determine the acid alpha-glucosidase (GAA) activity, and the result confirmed that the GAA activity was only 1.42 units, normal range 5.5 to 29.6 units, leading to a diagnosis of Pompe disease (atypical infantile). Recognizing this disease and initiating enzyme replacement therapy in infants at the earliest can improve the quality of life of patients. PMID- 28658868 TI - An Unusual Presentation of B Cell Acute Lymphoblastic Leukaemia in a Child. PMID- 28658867 TI - Diagnostic Dilemma in a 15-Year-Old Boy with Recurrent Pneumococcal Meningitis. AB - Recurrent bacterial meningitis is very rare phenomenon in paediatric age group. Finding the aetiology of recurrent meningitis often poses diagnostic challenge to clinicians. Among the several aetiologies, structural deficiencies at the base of skull, congenital or acquired, are readily correctable ones and hence it's imperative to find out the location of the gap in order to surgically repair it. We report the diagnostic dilemma faced while managing a 15-year-old boy with recurrent pneumococcal meningitis. Aetiology could only be found after exclusion of immunodeficiency and performing a series of imaging studies. CT cisternogram clinched the diagnosis and patient was cured successfully. A single imaging modality, be it CT/MRI scan, although proven to be better than others according to literature, might not be sufficient while finding the cause of recurrent bacterial meningitis in an immunocompetent host. PMID- 28658869 TI - Role of Multi Detector Computed Tomography (MDCT) in Preoperative Staging of Pancreatic Carcinoma. AB - INTRODUCTION: Pancreatic carcinoma is one of the leading causes of cancer related death in advanced countries and has shown rising trends in developing countries like India. Increase in the incidence has been linked to risk factors like lifestyle modification associated with increased alcohol consumption and rapid urbanization. Most patients at the time of diagnosis present with an advanced condition. Surgical resection offers the only chance for cure in them and imaging plays a crucial role in the early diagnosis of the condition. AIM: To compare the staging of pancreatic carcinoma by MDCT (Multi Detector Computed Tomography) with surgery in a preoperative setting in a tertiary referral centre in Kerala. MATERIALS AND METHODS: A cross-sectional observational study was performed between November 2014 and October 2016, 25 patients (12 men, 13 women), with a mean age of 54.2 years, were evaluated. MDCT was performed using 16 slice, 64 slice and 256 slice multi detector CT machines. The gold standard for diagnosis was histopathology and operative data. All statistical analysis was done using IBM SPSS version 20.0. Validity parameters like sensitivity, specificity, accuracy and Positive Predictive Value (PPV) / Negative Predictive Value (NPV) were computed for MDCT with respect to surgery. RESULTS: Of the 25 patients who were evaluated for surgery, 15 (60%) cases were classified as resectable tumours, 3 (12%) as borderline resectable and 7 (28%) as unresectable tumours. CT showed a sensitivity of 82.3% with a specificity of 87.5%. However, for assessing vascular invasion, CT showed sensitivity and specificity of 100% and 93.3% respectively. Three (12%) patients in the study who were classified as borderline resectable pancreatic tumours underwent surgery. CONCLUSION: Contrast-enhanced multiphase pancreatic imaging using MDCT plays a pivotal role in diagnosing and assessing resectability and vascular invasion of pancreatic tumours. It is very useful for determining borderline resectable tumours pre-operatively, which aids for better treatment planning. PMID- 28658870 TI - Failed Back Surgery Syndrome: Evaluation with Magnetic Resonance Imaging. AB - INTRODUCTION: Failed Back Surgery Syndrome (FBSS) is a generalized term used to describe varied spinal symptoms of patients who have had unsuccessful results after spinal surgery. The treatment of FBSS is challenging and varies from conservative management to reoperation. Imaging plays a crucial role in identifying the cause and helps to guide the appropriate therapy. Contrast enhanced Magnetic Resonance Imaging (MRI) with its superior resolution is the imaging modality of choice. AIM: To evaluate the spectrum of imaging findings on postoperative MRI in FBSS. MATERIALS AND METHODS: A total of 30 postoperative symptomatic patients of FBSS were included in this cross-sectional study. Of these, 26 had undergone surgery for degenerative disc disease and four had spinal fixation surgery for spondylolisthesis or trauma. Patients were subjected to detailed clinical examination. All patients underwent MRI which was done on 1.5 Tesla scanner with standard sequences in all planes. Contrast was administered in all cases. Non Contrast Computed Tomography (NCCT) scan was done in patients with metallic implants to better delineate the placement of the implant. Patients with contraindication to MRI scanning were excluded from the study. RESULTS: Of the total 30 cases (23 males and seven females) of FBSS that were evaluated with contrast enhanced MRI of the spine, 16 patients had recurrent/residual disc herniation, six had epidural scar tissue, three patients had recurrent disc herniation and scar tissue, two had evidence of post surgery arachnoiditis, two patients had postoperative discitis and one patient had implant mal alignment. Eight patients underwent reoperation for recurrent disc herniation and one patient for implant malalignment after imaging. CONCLUSION: MRI is the modality of choice for evaluating the postoperative spine. It helps to identify the cause and guide the appropriate treatment. PMID- 28658871 TI - Accuracy of Diffusion Weighted Images and MR Spectroscopy in Prostate Lesions - Our Experience with Endorectal Coil on 1.5 T MRI. AB - INTRODUCTION: Prostatic cancer is most commonly seen in individuals greater than 65 years of age. The incidence rates are constantly increasing. AIM: To assess the accuracy of the non-contrast sequences {Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopy (MRS)} in the multiparametric Magnetic Resonance Imaging (mp-MRI) in identifying and differentiating benign and malignant prostate lesions using endorectal coil on 1.5 T MRI. MATERIALS AND METHODS: Twenty-six patients with clinical indications for prostate lesions were evaluated using endorectal coil on 1.5 T MRI. DWI and MRS were obtained in all the lesions. Signal change on T2 weighted images, Apparent Diffusion Coefficient (ADC) values and choline + creatinine to citrate ratios (Cho+Cr/Ci) of the lesions were obtained for all the patients. All the patients underwent Transrectal Ultrasound (TRUS) guided biopsy within one week of MRI study. Signal change on T2 weighted images, DWI and Cho+Cr/Ci ratios were correlated with the histopathological findings using appropriate statistical analysis (Wilson score). RESULTS: Of the 26 patients, seven had benign pathology and 19 had malignant pathology on the histopathological examination. Sensitivity and specificity (89.5% and 85.7% respectively) of the diagnosis of malignancy based on DWI were quite good. Positive and negative predictive values were also very much acceptable (94.4% and 75% respectively). Though, MRS had good sensitivity and Positive Predictive Value (PPV) (84.2% and 76.2% respectively), specificity and Negative Predictive Value (NPV) were poor (28.6% and 40% respectively). Accuracy of imaging diagnosis based on combining T2, DWI and MRS was same as that of results based on T2 signal alone (80.8%) and had higher sensitivity and lower specificity than DWI alone (94.7% and 42.9% respectively). Receiver Operating Characteristic (ROC) curves were calculated for ADC values and Cho+Cr/Ci ratios. The Area Under the Curve (AUC) for ADC is 0.74 and for Cho+Cr/Ci is 0.70. CONCLUSION: Comparing the accuracy of the non-contrast sequences T2, DWI and MRS in identifying and differentiating benign and malignant lesions, giving weightage to the MRS in mp-MRI reduces the negative predictive value. The diagnosis of malignancy based on diffusion restriction was quite good and it can be the workhorse for prostate cancer detection as a shortened mp-MRI. PMID- 28658872 TI - MRI Evaluation of Local Extent of Carcinoma Cervix - Is Post Contrast Imaging Needed in Every Case? AB - INTRODUCTION: Carcinoma cervix is widely prevalent among women in developing countries. Post contrast Magnetic Resonance Imaging (MRI) utilising spin echo T1 weighted sequence with fat suppression is widely practiced as part of evaluation of carcinoma cervix. However, it is unclear if such post contrast imaging provides any additional information other than adding to the cost of imaging. AIM: To find accuracy of T1 and T2 weighted non contrast MRI protocol in comparison with post contrast spin echo T1 weighted fat suppressed imaging in evaluating the local extent of the carcinoma cervix. MATERIALS AND METHODS: A prospective study was conducted in the Department of Radiodiagnosis, JJM Medical College and Hospital, Davangere, Karnataka, India, between June 2016 and December 2016. A total of 45 females with a mean age of 50.7 years with biopsy proven cervical malignancy and predetermined clinical staging underwent MRI of pelvis. Prior to the scan, 10-15 ml of lignocaine jelly was instilled into the vagina. Sagittal T2 weighted images of the pelvis were acquired to identify the plane of the uterus and cervix. Axial and coronal imaging were planned perpendicular and parallel to the plane of cervix. Post contrast fat suppressed Spin Echo T1 weighted images were also obtained. Two radiologists evaluated the non contrast and contrast enhanced MR images of all patients separately. Interobserver variability and statistical significance was calculated. RESULTS: There was 100% agreement between the two radiologists in interpreting non contrast scans and 91.1% interobserver agreement for post contrast images. Interruption of T2 hypointense cervical stroma with or without hyperintensity in adjacent parametrium, and interruption of the hypointense inner walls of urinary bladder and rectum could be more easily and reliably identified than the extension of enhancement outside the confines of the cervix. Four patients with a clinical staging of 1b and 2a who underwent surgery showed extension into parametrium on non contrast MRI image as well as peroperatively. In patients who had not underwent surgery, both the non contrast and post contrast MRI imaging findings were in agreement with each other. Twenty out of 45 cases showed pelvic nodes which were identified on both non contrast and post contrast images. CONCLUSION: Routine post contrast T1 weighted imaging pro-vides no added advantage in comparison with non contrast T1 and T2 weighted imaging in evaluation of carcinoma cervix and need not be acquired routinely. However, only in selective cases with ambiguity on non contrast images, dynamic post contrast imaging may be used as a problem solving tool. PMID- 28658873 TI - Detection and Differentiation of Focal Intracranial Calcifications and Chronic Microbleeds Using MRI. AB - INTRODUCTION: Differentiating calcification from chronic micro-bleeds on imaging may have important clinical implications. AIM: The present study aimed to evaluate the role and relative advantages of Magnetic Resonance Imaging (MRI) in the detection and differentiation of intracranial calcifications and chronic microbleeds. MATERIALS AND METHODS: The retrospective study comprised of 100 patients having either intracranial calcifications or microhaemorrhages selected on the basis of Computerized Tomography (CT) and MRI using predefined criteria. Two independent blinded observers evaluated the images qualitatively and quantitatively. Single pixel values were taken in the circular Region of Interest (ROI) on magnitude SWI, phase Susceptibility Weighted Imaging (SWI) and Diffusion Weighted Imaging (DWI) for quantitative analysis. RESULTS: Fifty patients with 76 focal calcifications and another 50 patients with 245 chronic microbleeds formed part of the study. Overall sensitivity of SWI in detection of calcification was 93.9% with good inter observer agreeability (k= 0.7) on phase SWI. All the chronic microbleeds were seen on SWI but there was only moderate inter observer agreeability in evaluation of signal on phase component (k= 0.5). Average pixel values of calcifications and chronic microbleeds were -312.5+/-187 SD and 541.9+/ 301.7 SD respectively on phase SWI, (p=0.0001, <0.05). CONCLUSION: SWI can play a pivotal role in the detection of intracranial calcifications and chronic microbleeds and resolving the ambiguity in their diagnosis. PMID- 28658874 TI - MR Imaging of Rotator Cuff Tears: Correlation with Arthroscopy. AB - INTRODUCTION: Rotator cuff tears are quite common and can cause significant disability. Magnetic Resonance Imaging (MRI) has now emerged as the modality of choice in the preoperative evaluation of patients with rotator cuff injuries, in view of its improved inherent soft tissue contrast and resolution. AIM: To evaluate the diagnostic accuracy of routine MRI in the detection and characterisation of rotator cuff tears, by correlating the findings with arthroscopy. MATERIALS AND METHODS: This prospective study was carried out between July 2014 and August 2016 at the AJ Institute of Medical Sciences, Mangalore, Karnataka, India. A total of 82 patients were diagnosed with rotator cuff injury on MRI during this period, out of which 45 patients who underwent further evaluation with arthroscopy were included in this study. The data collected was analysed for significant correlation between MRI diagnosis and arthroscopic findings using kappa statistics. The sensitivity, specificity, predictive value and accuracy of MRI for the diagnosis of full and partial thickness tears were calculated using arthroscopic findings as the reference standard. RESULTS: There were 27 males and 18 females in this study. The youngest patient was 22 years and the oldest was 74 years. Majority of rotator cuff tears (78%) were seen in patients above the age of 40 years. MRI showed a sensitivity of 89.6%, specificity of 100%, positive predictive value of 100% and negative predictive value of 83.3% for the diagnosis of full thickness rotator cuff tears. For partial thickness tears, MRI showed a sensitivity of 100%, specificity of 86.6%, positive predictive value of 78.9% and negative predictive value of 100%. The accuracy was 93.1% for full thickness tears and 91.1% for partial thickness tears. The p-value was less than 0.01 for both full and partial thickness tears. There was good agreement between the MRI and arthroscopic findings, with kappa value of 0.85 for full thickness tears and 0.81 for partial thickness tears. CONCLUSION: MRI revealed high sensitivity and specificity for the diagnosis of rotator cuff tears with accuracy of 93.1% for full thickness tears and 91.1% for partial thickness tears. MRI provides useful information about the size and extent of the tear, involvement of adjacent structures, presence of muscle atrophy and tendon retraction, all of which have important therapeutic and prognostic implications. PMID- 28658875 TI - Efficacy of Perfusion Computed Tomography (PCT) in Differentiating High-Grade Gliomas from Low Grade Gliomas, Lymphomas, Metastases and Abscess. AB - INTRODUCTION: Tumoural angioneogenesis and its quantification are important in predicting the tumour grade and in the management with respect to the treatment available and to assess the response to treatment and the prognosis. It also plays major role in the growth and spread of tumours. Hence, a need arises for non-invasive in vivo methods to assess tumour angioneogenesis and tumour grade at the time of presentation and for monitoring the response during treatment and follow up. In this regard Perfusion Computed Tomography (PCT) can be easily added into routine CT studies to obtain such information on lesion physiology along with its morphology. AIM: Prospective evaluation of the efficacy of PCT in differentiating high grade gliomas from low grade glioma lymphomas, metastases and abscess. MATERIALS AND METHODS: Perfusion CT was performed in 68 patients (17 high-grade gliomas, 10 low-grade gliomas, 7 lymphomas, 27 metastases and 7 abscess). Perfusion parameters which include Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF), Mean Transit Time (MTT) and Time To Peak (TTP) were derived both from the lesion and the normal parenchyma and were Normalized (n) by obtaining the ratio. Statistical analysis for high grade versus low-grade gliomas, high grade gliomas versus lymphomas, metastases and abscess was performed. RESULTS: Difference in the mean nCBV and nCBF in high grade gliomas were statistically significant from low grade gliomas with cut off of > 3.07 for nCBV and > 2.08 for nCBF yielding good sensitivity and specificity. Difference in the mean nCBV and nMTT in the lymphomas were statistically significant from high grade gliomas (p<0.05) with cut off of <3.40 for nCBV and >1.83 for nMTT yielding good sensitivity and specificity. Difference in the mean nCBV and nMTT in the metastases were statistically significant from high grade gliomas (p<0.05) with cut off of >4.95 for nCBV and >1.88 for nMTT yielding a fair sensitivity and specificity. No statistical significant difference seen among the parameters in differentiating high grade gliomas and abscess. CONCLUSION: Cerebral PCT greatly adds to the diagnostic accuracy when the diagnosis of a common intra-axial lesion based on morphological characters becomes uncertain. PMID- 28658876 TI - Combined Left Recurrent Laryngeal Nerve and Phrenic Nerve Palsy: A Rare Presentation of Thoracic Aortic Aneurysm. AB - Hoarseness of voice due to Vocal Cord Palsy (VCP) resulting from aortic aneurysm is a rare entity. Hoarseness due to left Recurrent Laryngeal Nerve (RLN) paralysis caused by identifiable cardiovascular disease has been described as Ortner's syndrome or Cardiovocal syndrome. Very rarely, thoracic aortic aneurysm can cause Phrenic Nerve (PN) palsy causing hemidiaphragm paralysis. But, aortic aneurysm causing both RLN and PN palsy is an extremely rare occasion. Our literature review showed only three cases of combined RLN and PN palsy due to thoracic aortic aneurysm. Here we report a 70-year-old patient having hoarseness of voice for six years for which he was on symptomatic treatment. He presented to us with cough and blood tinged sputum, left sided chest pain, loss of appetite and weakness since two months duration. Based on clinical history and chest radiograph, lung malignancy was suspected. To our surprise, Contrast Enhanced Computed Tomography (CECT) revealed partially thrombosed saccular thoracic aneurysm originating distal to origin of left subclavian artery. He was referred to the cardiothoracic vascular surgeon for surgical treatment, but was reluctant to go for surgery. He is now being followed up by cardiothoracic vascular surgery and cardiology department and his condition has remained the same. PMID- 28658877 TI - Bilateral Testicular Metastases from Occult Primary Prostate Cancer in a Young Adult: A Rare Case Report. AB - Testicular metastases are detected incidentally in upto 4% cases after orchiectomy for Prostate Carcinoma (PCa). Most of the secondaries to testes are due to PCa, only few patients have clinically manifested metastases to bilateral testes. Metastases to bilateral testis is unusual while unilateral involvement of the testis is seen usually. We report a case of primary PCa with bilateral testicular metastases which presented with palpable mass in the right testis. A 43-year-old male patient presented with two-month history of swelling in right inguino-scrotal region. On digital rectal examination, the prostate was enlarged. The Serum Prostate-Specific Antigen (PSA) level was >100 ng/ml. Ultrasound (USG) revealed metastatic deposits in bilateral testis, however prostate was having relatively normal echo pattern. Contrast Enhanced Computed Tomography (CECT) abdomen revealed primary malignancy of prostate gland with secondary metastases in bilateral testes and metastatic lymph nodes. Transrectal biopsy from prostate and excisional biopsy of right inguinal node showed prostate gland adenocarcinoma and deposits of adenocarcinoma respectively. Patient underwent bilateral orchiectomy. Histopathology showed that bilateral testes were infiltrated by metastatic adenocarcinoma with Gleason score 8. The patient is currently on chemotherapy. This is a rare case of primary PCa with clinically manifested bilateral testicular metastases in the form of palpable mass in right testis. PMID- 28658878 TI - Role of MRI in a Series of Cases with Biceps Injuries of the Shoulder. AB - Dislocation and injury of the biceps is associated with acute and chronic trauma, degenerative changes, repetitive microtrauma, or injuries associated with recurrent and neglected cases of shoulder dislocation. The cases of displaced biceps injuries are relatively rare (only 1/6th of all rotator cuff injuries). The dislocation of biceps is manifested with pain and restriction of movements. The X-ray shoulder is not of much help in this condition barring for ruling out the fractures of humerus and scapula. Ultrasound is an important tool in the dislocation and shows empty bicipital groove which raises the suspicion of the soft tissue injures. Ultrasound is a problem solving tool when the equivocal findings in MRI (Magnetic Resonance Imaging) in other muscular injuries also. MRI is the modality of choice in these conditions. The bone and anatomy is better visualised on the T1WI images and the pathology is better visualised on the PDFS (Proton Density Fat Saturation) and the STIR (Short Tau Inversion Recovery) images. The role of Non Contrast Computed Tomography (NCCT) is important in associated suspicious bony abnormalities as highlighted in the article. The biceps region is a hidden area and challenging on arthroscopy due to poor visualisation of the extra-articular tendon part. MRI study helps the orthopaedicians for better management of the hidden areas. This series highlights the role of each modality in the diagnosis and management of the biceps lesions. PMID- 28658879 TI - Attenuation of Haemodynamic Parameters in Response to Pneumoperitoneum during Laparoscopic Cholecystectomy: A Randomized Controlled Trial Comparing Infusions of Propofol and Dexmedetomidine. AB - INTRODUCTION: Effective control of sympathetic response to pneumoperitoneum is vital to avoid morbidity in patients undergoing laparoscopic surgeries. This control must be achieved without any side effects of the drugs being used as well as ensuring a raid recovery from anaesthesia in order to maximise operation theatre utility. AIM: To study the effectiveness of dexmedetomidine in attenuating the haemodynamic response to pneumoperitoneum during laparoscopic cholecystectomy (using only the maintenance dose) with that of propofol and compare time to extubation, haemodynamics on extubation, sedation score after extubation and any incidence of side effects between the two study drug. MATERIALS AND METHODS: Sixty American Society of Anaesthesiologist (ASA) I and II patients undergoing laparoscopic cholecystectomy between age of 20-60 years were randomly divided into two groups of 30 patients each: Group D to receive dexmedetomidine in dose of 0.2-0.7 MUg/kg/hr titrated as per clinical response and Group P to receive propofol in dose of 25-75 MUg/kg/min (1.5-4.5 mg/kg/hr) titrated as per clinical response after standard anaesthetic induction. Data recording was done for changes in haemodynamic parameters, time to extubation and post extubation sedation score. Statistical analysis was done using student's test and Chi-square test with p-value of< 0.05 was considered significant. RESULTS: Attenuation of haemodynamic parameters by dexmedetomidine during the intraoperative period even without the loading dose was comparable to that by propofol (p-value >0.05). Time to extubation was similar in both the groups (p value >0.05). Haemodynamics on extubation was better controlled in dexmedetomidine group (p-value <0.05) while the sedation score was better in propofol group (p-value <0.05). Mean dose of dexmedetomidine and propofol used were 0.504+/-0.09 MUg/kg/hr and 3.19+/-0.7 mg/kg/hr respectively. CONCLUSION: Dexmedetomidine in a dose of 0.2-0.7 MUg/kg/hr provides a stable haemodynamics without any side effects in patients undergoing laparoscopic cholecystectomy. PMID- 28658880 TI - Ultrasonographic Estimation of Endotracheal Tube Size in Paediatric Patients and its Comparison with Physical Indices Based Formulae: A Prospective Study. AB - INTRODUCTION: Choosing the correct Endotracheal Tube (ETT) size is important in paediatric anaesthesia. The subglottic diameter being the narrowest diameter of the paediatric upper airway plays an important role in appropriate ETT size selection. AIM: This study was planned to determine the accuracy of Ultrasonography (USG) to assess the appropriate ETT size and compare it with physical indices based formulae. The secondary outcome was to assess the number of times the tube was changed based on air leak test for USG estimated tube size. MATERIALS AND METHODS: After ethical committee approval, a prospective clinical observational study for a period of one year was conducted on 75 children (power of study 80%, confidence interval 95%) aged one to 14 years of American Society of Anaesthesiologists Physical Status (ASA) I and II undergoing elective surgery under general anaesthesia with orotracheal intubation. Parental consent was obtained. Pre-anaesthetic ultrasonography was performed on every patient at the subglottic region. The tracheal subglottic diameter was estimated to select the ETT size for cuffed and uncuffed tubes. The size estimated by USG and that based on age and height based formulae were compared with clinically used appropriate tube size. Data analysis was done using IBM Statistical Package for the Social Sciences (SPSS) version 20.0; One-way Analysis of Variance (ANOVA) and t-test for comparison were used. RESULTS: USG predicted the appropriate ETT size (p<0.05) better than physical indices based formulae for cuffed and uncuffed tubes. The age based formula predicted the clinically used ETT size well (p=0.58) and the height based formula did not correlate with clinically used tube size (p=0.0002 - a statistically significant value). Eight patients required change of tube once. CONCLUSION: Ultrasonographic estimation of subglottic diameter is useful for optimal paediatric ETT size selection. USG is effective in estimating the appropriate sized ETT both for cuffed and uncuffed tubes. PMID- 28658881 TI - Cross Sectional Observational Study Performed to See for Relation of Mallampati Score and Extended Mallampati Score with Body Mass Index. AB - INTRODUCTION: There is increasing incidence of obesity worldwide. Since obese patients have an increased fatty tissue distributed in a truncal fashion, they may have an important and negative impact on the airway patency and respiratory function. Various scoring systems have been used to predict difficult airway, the most commonly used universal bedside tool is the Modified Mallampati Scoring (MMS). It was shown that the Extended Mallampati Score (EMS) predicted difficult laryngoscopy better than the MMS in the obese populations. AIM: To evaluate the association of Mallampati score and EMS in adults. MATERIALS AND METHODS: This cross-sectional prospective observational study was performed on 323 subjects. The selection method included convenience sampling technique. Patient data which included name, age, sex, weight, height, Body Mass Index (BMI) and Neck Circumference (NC), Mallampati Score, and EMS were collected by two observers, anaesthesiologists. The observers noted their findings of MMS and EMS on the same patient independently. Their findings were entered independently and disclosed only during analysis. RESULTS: There was good agreement between the observers (kappa value 0.635) for MMS and EMS. The intraobserver correlation coefficient was 0.8 for MMS (p<0.001) and 0.7 (p=0.004) for EMS which was significant. A positive correlation between sex and NC with BMI, MMS and EMS was seen. CONCLUSION: From this study we concluded that there was no difference between the MMS and EMS. There was interobserver agreement between MMS and EMS and a positive correlation of body mass index with MMS and EMS was seen. PMID- 28658882 TI - Recognition of the Lateral Pterygoid Muscle and Plate during Ultrasound-Guided Trigeminal Nerve Block. PMID- 28658883 TI - Artificial Neural Network (ANN) Model to Predict Depression among Geriatric Population at a Slum in Kolkata, India. AB - INTRODUCTION: Depression is one of the most important causes of mortality and morbidity among the geriatric population. Although, the aging brain is more vulnerable to depression, it cannot be considered as physiological and an inevitable part of ageing. Various sociodemographic and morbidity factors are responsible for the depression among them. Using Artificial Neural Network (ANN) model depression can be predicted from various sociodemographic variables and co morbid conditions even at community level by the grass root level health care workers. AIM: To predict depression among geriatric population from sociodemographic and morbidity attributes using ANN. MATERIALS AND METHODS: An observational descriptive study with cross-sectional design was carried out at a slum under the service area of Bagbazar Urban Health and Training Centre (UHTC) in Kolkata. Among 126 elderlies under Bagbazar UHTC, 105 were interviewed using predesigned and pretested schedule. Depression status was assessed using 30 item Geriatric Depression Scale. WEKA 3.8.0 was used to develop the ANN model and test its performance. RESULTS: Prevalence of depression among the study population was 45.7%. Various sociodemographic variables like age, gender, literacy, living spouse, working status, personal income, family type, substance abuse and co morbid conditions like visual problem, mobility problem, hearing problem and sleeping problem were taken into consideration to develop the model. Prediction accuracy of this ANN model was 97.2%. CONCLUSION: Depression among geriatric population can be predicted accurately using ANN model from sociodemographic and morbidity attributes. PMID- 28658884 TI - Post Stroke Psychosis Following Lesions in Basal Ganglion. AB - Stroke is the second most common cause of death and fourth leading cause of disability worldwide. Post stroke behavioural manifestations are often not recognized, undiagnosed and hence remain untreated. They may even suffer from misdiagnosis of functional disorders before coming at conclusion of organic pathology. Early diagnosis and prompt treatment helps in lowering the overall morbidity related to stroke and improves quality of life of these patients with rare manifestations. Here, we report two cases of elderly female patients presenting with delusions and hallucinations subsequent to stroke, with lesions in basal ganglia detected on neuro-imaging. PMID- 28658885 TI - Psychosis in a Case of Dandy-Walker Syndrome: A Case Report. AB - Dandy Walker Syndrome (DWS) is a congenital malformation with brain abnormalities, intellectual disabilities, epilepsy and visible structural changes in particular brain structures. We present here a case of psychosis in an 18-year old male with DWS, epilepsy and intellectual disability. The purpose of this paper is to discuss the clinically relevant issues, psychopharmacological issues, neuropsychiatric manifestations and consultation liaison issues involved. PMID- 28658886 TI - Delirious State and Agitation Following Heparin Induced Stevens-Johnson Syndrome. PMID- 28658887 TI - A Screening Study on Dermatoses in Pregnancy. AB - INTRODUCTION: Pregnancy produces many cutaneous changes, some of which are specifically related to pregnancy (dermatoses of pregnancy), some are modifiable by pregnancy and others that are common are named physiologic. These physiologic skin changes, usually do not impair the health of the mother or the fetus but some of them can be cosmetically significant and of importance to the dermatologist. AIM: The present study was undertaken to find out the prevalence of the physiological and pathological skin changes in pregnancy, and to correlate the prevalence of the major cutaneous changes and diseases in relation to different trimesters of pregnancy and with gravidity. MATERIALS AND METHODS: A cross-sectional study was conducted during the period of August 2008 to August 2010. Ethical clearance was sought from Institutional Ethical Committee. Five hundred pregnant women were randomly selected, irrespective of the duration of pregnancy and gravidity. Detailed history and complete dermatological examination was done. Results were tabulated and analysed. Statistical analysis was done by Fisher's exact test and Chi square test. RESULTS: Physiological skin changes were seen in 94.8% of cases, with pigmentary changes being more common (90.8%). Specific dermatoses of pregnancy were observed in 14% of cases with pruritus gravidarum being the most common (10.4%). Prevalence of infection was found to 30.8% with fungal infection being the most common (23.8%). Exacerbations of systemic lupus erythematosus and neurofibromatosis was observed. Pigmentary changes, striae gravidarum and specific dermatoses of pregnancy were observed in statistically significant proportion in primigravidas and during third trimester. CONCLUSION: This study emphasizes that the prevalence of physiological skin changes (94.8%) was much higher than specific dermatoses (14%), stressing the fact that in most instances, the skin problems during pregnancy needs only reassurance. But meticulous observation and examination should be done, as pregnancy can influence many dermatological diseases and infections. PMID- 28658888 TI - Oral Isotretinoin May Improve the Symptoms of Chronic Rhinosinusitis. PMID- 28658889 TI - Unilateral Blaschkoian Lichen Planus: A Series of Cases with Review of literature. AB - A number of congenital and acquired dermatological diseases are known to follow lines of Blaschko. Lichen Planus (LP), commonly acquired inflammatory dermatosis, presents with various morphological forms but Blaschkoian variant is very less published in literature. We herein report a case series of six patients of various age groups with Blaschkoian LP, without any underlying predisposing factors. All these cases presented with asymptomatic to mildly pruritic, violaceous to hyperpigmented papules and plaques following the Blaschko lines. In all the patients, lesions responded well to topical steroids and oral antihistamines, leading to gradual resolution of lesions with post-inflammatory hyperpigmentation. Blaschkoian LP is not a rare condition and may remain under reported because of its insignificant clinical features especially the absence of pruritus. Thus, the physician should always keep this entity in mind while considering the lesions following lines of blaschko. PMID- 28658890 TI - Chemoresponse Assay in Head and Neck Cancer Patients: A Three-Year Follow Up. AB - INTRODUCTION: The majority of patients with advanced head and neck cancer receiving chemotherapy show partial response or frank resistance. Therefore, assessing the individuals' tumour reactivity to the eligible chemotherapeutic compounds carries the potential of personalizing the patient treatment and minimizing ineffective regimens which lead to excess toxicity and cost, treatment delays and possibly causing the tumour to be cross resistant to additional drugs. AIM: To determine the effectiveness of a phenotypic chemoresponse assay in predicting response to chemotherapy in a retrospective series of head and neck cancer patients whose tumour specimens had been tested with ChemoFx assay (Precision Theraputic Inc.). MATERIALS AND METHODS: Twenty-two tumour specimens were submitted to Precision Theraputics Inc. for chemoresponse testing, all of which have been histologically confirmed as squamous cell carcinoma of the head and neck. Selection of treatment was at the discretion of the treating physician and the results of the assay were not used to determine the therapy. A portion of the patients' solid tumour was established in primary culture, then exposed to increasing doses of different chemotherapeutic agents. The resultant cell counts in the treated wells were used to indicate the tumours' response to the agent and based on the dose response score curve, the test was scored as "responsive," "intermediate response," or "non-responsive." RESULTS: Of the 22 tumour samples submitted, 16 (72.7%) showed adequate cell yield in cultures and subsequently underwent in vitro chemoresponse assays and are reported in this study. Of the 16 cases reviewed, 5 were excluded due to inadequate follow up. A predictable response assay was either a good response to chemotherapy in patients whose tumour specimens showed sensitivity to the chemotherapeutic agents or failure in patients whose tumours showed either intermediate response or non responsiveness to the chemotherapeutic agent/agents. Of the 11 patients reported in this study, nine showed a predictable chemoresponse assay (81.8% predictability of effective treatment). Three patients had a predictable good response and six who failed their chemotherapy regimen within six months of treatment and their chemoresponse assay showed an inadequate response to the chemotherapeutic agents they were treated with. At three years follow up, all patients who had a predictable poor response succumbed to their disease except one, whose test showed intermediate response. CONCLUSION: While the current report has its limitation, we conclude, based on our findings, that chemoresponse assays may be useful adjuncts in the guiding the selection of chemotherapeutic agents in patients with head and neck cancer. PMID- 28658891 TI - Comparative Study of Adjuvant Temozolomide Six Cycles Versus Extended 12 Cycles in Newly Diagnosed Glioblastoma Multiforme. AB - INTRODUCTION: Studies have shown promising survival with the use of Extended Temozolomide (E-TMZ) as compared to Conventional six cycles of Temozolomide (C TMZ) in malignant gliomas; however, the reports are mostly limited to retrospective studies with significant bias. AIM: This study assesses the impact of six versus 12 cycles of adjuvant Temozolomide (TMZ) on Overall Survival (OS) in newly diagnosed postoperative patients of Glioblastoma Multiforme (GBM). MATERIALS AND METHODS: Between January 2012 and July 2013, 40 postoperative patients of GBM between age 18-65 years and Karnofsky Performance Score (KPS) >=70 were included. Patients were randomized to receive radiation (60 Gray in 30 fractions over six weeks) with concomitant TMZ (75 mg/m2/day) and adjuvant therapy with either six (C-TMZ arm) or 12 cycles (E-TMZ arm) of TMZ (150-200 mg/m2 for five days, repeated four weekly). Twenty patients were treated in each arm. Toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. OS and Progression Free Survival (PFS) were calculated from the time of diagnosis. Kaplan Meier method was used for survival analysis. A p value of <0.05 was taken as significant and SPSS version 12.0 was used for all statistical analysis. RESULTS: Median number of adjuvant TMZ cycles was six and 12 in C-TMZ and E-TMZ arm respectively. Overall, 5% and 15% patients respectively in C-TMZ and E-TMZ arm had haematological toxicity >= 3 in grade. Median follow up in C-TMZ and E-TMZ arm were 14.65 months and 19.85 months. Median PFS was 12.8 months and 16.8 months in C-TMZ and E-TMZ arm respectively (p=0.069). Median OS was 15.4 months vs. 23.8 months in C-TMZ and E-TMZ arm respectively (p=0.044). CONCLUSION: Our study showed that E-TMZ is well tolerated and leads to a significant increase in PFS as well as OS in newly diagnosed patients of GBM. Further prospective randomized studies are needed to validate the findings of our study. PMID- 28658892 TI - Poorly Differentiated Sertoli-Leydig Cell Tumour of Ovary with Heterologous Elements. AB - Sertoli-Leydig Cell Tumour (SLCT) is included under sex-cord stromal tumour of testis or ovary. Ovarian pathology is an extremely rare entity constituting less than 0.5% of all ovarian neoplasms. Majority of the cases present at younger age group, i.e., 2nd and 3rd decade of life. The clinical presentation depends on either mass effect or excess hormone production. Virillization symptoms are the most common presentation and depend upon the quantity of androgen production. Most of the patients have a unilateral mass without extraovarian spread and present at stage-I. Treatment and prognosis depends on the degree of the differentiation and the stage of the disease. Here, we report a case of SLCT of the ovary in a young female. The patient initially presented with pain abdomen due to mass effect and was treated with conservative surgery followed by adjuvant chemotherapy due to the presence of poorly differentiated pathology with heterologous elements. PMID- 28658893 TI - Salvage Surgery for Metastatic Gall Bladder Cancer with Vanishing Liver Metastasis Following Palliative 5-Fluorouracil Metronomic Chemotherapy. AB - Gall Bladder Cancer (GBC) is an aggressive malignancy. The prognosis of metastatic GBC is dismal. Until recently, there are no standard treatment guidelines for management of patients with metastatic GBC. But the ultimate aim of any treatment modality is to improve the overall survival with good quality of life. We hereby report a long term survivor of metastatic GBC treated with initial six cycles of gemcitabine + cisplatin combination chemotherapy, but did not show any response. In view of chemotoxicity and as a matter of physician preference patient was started on low dose weekly 5- Fluorouracil monotherapy based on a metronomic chemotherapy principle. There was complete resolution of all the liver metastasis and salvage radical cholecystectomy was done. The patient is disease free on imaging at eight months of follow up. A very few such cases have been reported in the world literature, till date. Metastatic disease must not be considered incurable as there are no objective measures to predict tumour biology. Further research on metronomic chemotherapy and tumour genetics in such patients will open a new era of individualised cancer therapy based on objective measures that will predict tumour biology. PMID- 28658894 TI - Reliability of the Infraspinatus Test in Carpal Tunnel Syndrome: A Clinical Study. AB - INTRODUCTION: Recently, a standardized provocation tests for the infraspinatus muscle, the Infraspinatus test (IsT), aimed at clinically confirming Carpal Tunnel Syndrome (CTS), was validated in a multiple-blind, controlled study. AIM: The present study was conducted to investigate inter-rater reliability of the IsT under conditions as they occur in daily clinical practice, since this is essential for acceptance of any new test. MATERIALS AND METHODS: Two raters from different medical disciplines used the IsT in the same group of subjects at different localities and with an interval of two to four weeks. Arms with symptoms of CTS were examined and compared with a control group of arms without symptoms. Nerve conduction studies were performed in all the subjects. Statistical analysis was performed with Cohen's Kappa (for inter-rater reliability) and McNemar's test (for determining dependencies between arms and raters). RESULTS: A total of 34 subjects (age 35-86 years) were investigated with the IsT by two raters in a blinded fashion. There was a high agreement between raters with a Kappa statistic of kappa=0.868, when performing this new provocation test. The McNemar test did not reveal dependencies between Rater A and Rater B (p=0.6171), nor between the left and right arms of subjects (Rater A: p=0.4533, Rater B: p=0.5023). CONCLUSION: The new provocation test of the infraspinatus muscle is not only capable of confirming CTS, as was shown before, but is also a reliable method for use by different examiners under customary conditions. PMID- 28658895 TI - Legendary Hero: Dr. G.V. Black (1836-1915). PMID- 28658896 TI - Evaluation of Impact of Pregnancy on Oral Health Status and Oral Health Related Quality of Life among Women of Kashmir Valley. AB - INTRODUCTION: Oral health is a key component of overall health and wellbeing of women throughout life; and particularly important prior to conception and during pregnancy. Pregnancy affects both general health as well as the oral health related quality of life. AIM: To assess the difference in oral health status and related quality of life among pregnant, postpartum and non pregnant women of Kashmir valley. MATERIALS AND METHODS: The present cross-sectional study was conducted among a convenient sample of 900 women (22-37 years) attending Sheri Kashmir Institute of Medical Sciences (SKIMS) Maternity Hospital, Srinagar, Jammu and Kashmir, India. Sample included 300 pregnant, 280 postpartum women and 320 non pregnant women of matched age group. Pretested and validated proforma for Oral Health Related Quality of Life (OHRQoL) Questionnaire designed in local language was used. Oral health was assessed using Oral Hygiene Index Simplified Index (OHIS), Gingival Index (GI) and Decayed Missing Filled Teeth/Surface Index (DMFT/DMFS). Mean differences were carried out using Kruskal-Wallis one-way ANOVA. Correlation analysis was performed to analyse their relationship with Oral Health Impact Profile (OHIP-14) score. Post-hoc Tukey test was employed for comparing the means within the three trimesters of the pregnant group. RESULTS: Pregnant women presented with significantly higher periodontal disease (p<=0.05). Decayed Missing and Filled Teeth index (DMFT) showed no difference within the groups. Comparison for the mean OHIP-14 presented significantly poorer scores among the pregnant women. CONCLUSION: Pregnancy had an influence only on the gingiva and not on periodontal attachment levels. However, oral health status and perceived OHRQoL were poorer among pregnant women. The present study draws attention toward the need for highlighting the importance of conserving oral health during pregnancy. PMID- 28658897 TI - Evaluation of Plaque pH Changes Following Consumption of Health Drinks by Children: A Pilot Study. AB - INTRODUCTION: With increased trend among people to choose a healthy diet, there is an increased consumption of health drinks by children. Thus, it is important to know their cariogenicity. AIM: To evaluate the effect of consumption of health drinks viz., Horlicks, Boost and Complan on plaque pH in children. MATERIALS AND METHODS: The study consisted of four groups: Group I (control)- 10% sucrose solution, Group II- Horlicks, Group III- Boost, Group IV- Complan. Samples of plaque from representative teeth were collected and pH was measured using an electrode outside the mouth. After baseline pH was recorded, children were given their respective drinks and were asked to consume slowly over a period of three to five minutes following swish with 20 ml of the test drink for one minute. The pH was then recorded after 10, 20, 30, 40 and 60 minutes of the post consumption period. Obtained values were subjected to one-way ANOVA test for multiple group comparison followed by Post-Hoc Tukey's test for group wise comparison. RESULTS: Twenty minutes after consumption of Complan and Boost, pH was decreased, but not to the critical pH value as in case of sucrose. The pH was found to be slightly increased, 20 minutes post Horlicks consumption. Post 60 minutes consumption of all the drinks including sucrose solution, the pH was increased in comparison to post 20 minutes. However, 60 minutes post consumption of Boost and Horlicks, pH increased above the baseline. CONCLUSION: Consumption of health drinks viz., Complan and Boost did not lower the plaque pH to the level of critical pH. Consumption of Horlicks increased the plaque pH. PMID- 28658898 TI - Estimation of Pentraxin 3 and Porphyromonas Gingivalis Levels in Patients with Rheumatoid Arthritis and Periodontitis- An Observational Study. AB - INTRODUCTION: Periodontal diseases are inflammatory in nature involving interplay between the bacterial plaque and the micro-organisms, with the response of the host playing a pivotal role in either attenuating or eliminating the disease. Rheumatoid Arthritis (RA) is also a chronic inflammatory disease which shares common risk factors with periodontitis. Porphyromonas Gingivalis and Pentraxin 3 (an acute inflammatory protein) have been observed to be associated with both the diseases. AIM: This study was done to determine if there was any association between Pophyromonas Gingivalis and Pentraxin 3 levels in patients with RA and Chronic Periodontitis in comparison with Healthy controls. MATERIALS AND METHODS: This observational study was conducted on 90 subjects (42 Males and 48 Females) aged between 30-60 years. The subjects were selected from the out patient ward of a tertiary referral care hospital. The selected subjects were equally divided into three groups. Group I: Comprising of 30 patients with RA and chronic periodontitis who were in turn, subdivided into Group I- A (n=15) -Patients just diagnosed with RA and Group I- B (n=15) Patients under medications for more than three months. Group II: Patients with Chronic Periodontitis (n=30) and Group III: Healthy Controls (n=30) Intergroup comparison for continuous data was done by One way analysis of variance test followed by Bonferroni's post-hoc test. Intragroup comparison for continuous data was done by paired t-test. RESULTS: Intergroup comparison between Group I and Group II did not show any statistical difference pertaining to the clinical parameters except for the Gingival Index (GI) which was found to be higher in Group II (Mean= 2.07) when compared to Group I (Mean=1.59). Intragroup comparison between Group IA and Group IB was statistically significant for GI, Plaque Index (PI), and Clinical Attachment Levels (CAL). Intragroup comparison between Group I-A and Group I-B showed that both Porphyromonas gingivalis and Pentraxin 3 Levels were higher in Group I- A. CONCLUSION: In this study, it was observed that there was a positive association between Porphyromonas gingivalis and Pentraxin 3 levels in patients with rheumatoid arthritis and periodontitis. PMID- 28658899 TI - Correlation between Maxillary Canine Calcification and Skeletal Maturation. AB - INTRODUCTION: Skeletal maturation assessment has a great role in many health professions especially in Orthodontics & Dentofacial Orthopedics. Functional appliances have proved to be more effective when used at the peak of mandibular growth, rather than before. AIM: The aim of this study was to evaluate whether the calcification stages of permanent maxillary canine are useful to assess skeletal maturity. MATERIALS AND METHODS: In this cross-sectional study, samples were derived from panoramic radiographs and lateral cephalograms of 300 subjects (137 males and 163 females) with their age ranging from 9 to 18 years. Dental maturity {Demirjian Index (DI)} and skeletal maturity {Cervical Stages (CS)} were assessed from radiographs. The Pearson chi-square test (chi2) and Sakoda adjusted Pearson contingency coefficient (C*) were calculated to determine the correlation between DI and CS. RESULTS: A highly significant association (C* = 0.851, p<.001for males and 0.879, p<.001 for females) was found between DI and CS. DI stage E coincided with CS2 (pre-peak of pubertal growth spurt) & DI stage F coincided with CS3 (peak of pubertal growth spurt) for all the subjects. DI stage H corresponded to CS5 and CS6 (end of peak of pubertal growth spurt). CONCLUSION: A highly significant association was found between DI and CS. Maxillary canine DI stages could be useful to assess skeletal maturity. PMID- 28658900 TI - Does Change in Thread Shape Influence the Pull Out Strength of Mini Implants? An In vitro Study. AB - INTRODUCTION: Mini implants form a valuable source for absolute anchorage thereby helping in achieving ideal treatment outcome. Stability of the mini implant is one of the important factors affecting the success of mini implants. Thread shape is a critical factor in the engineering design of mini implant, which affects the primary stability. AIM: To evaluate the effects of thread shape on the pull out strength of mini implants. MATERIALS AND METHODS: Mini implants of five different designs in thread shape (reverse buttress, buttress, 75 degrees joint profile with flutes, trapezoidal and trapezoidal fluted) were used with 10 screws in each group. The mini implants were loaded on to the polyurethane foam block (Sawbones pacific research lab, USA) perpendicular to the surface and the pull out strength was tested using the Instrom testing machine. The control group consisted of mini implants with reverse buttress thread shape. One-way ANOVA and Tukey post-hoc tests were used to compare the pull out strength of the mini implants within as well as between the different groups. RESULTS: The mean in the pull out tests ranged from 13.45 N (trapezoidal) to 61 N (trapezoidal fluted). The tukey post hoc tests showed a statistically significant difference of 34.5 N between the control group and the trapezoidal fluted group. The level of statistical significance showed p< 0.05. CONCLUSION: Trapezoidal fluted mini implants showed the highest pull out strength when compared to mini implants with other thread designs used in this study. Further studies with the use of Finite Element Method (FEM) and foam blocks of higher density would be required to evaluate the performance of this new thread design. PMID- 28658901 TI - The Status of Knowledge Related to the Emergency Management of Avulsed Tooth amongst the Medical Practitioners of Nagpur, Central India. AB - INTRODUCTION: Tooth avulsion is a frequently reported traumatic injury amongst young children and whenever it occurs, the parents or teachers of those children often seek the help of Medical Practitioners to provide the first line of treatment. Therefore, the general physician's knowledge regarding the same is an important issue to be taken into consideration. AIM: To assess the knowledge, attitude and practice of general medical practitioners of Nagpur city of Central India regarding emergency management of avulsed tooth and highlight the importance of avulsed tooth education in schools and medical colleges in order to increase the knowledge of the same among teachers, parents and general physicians. MATERIALS AND METHODS: A cross-sectional survey was carried out amongst 1045 medical doctors after a comprehensive search made in Google database using the keywords "Medical", "doctors" "Nagpur". Data regarding the emergency management of avulsed tooth was collected using a self administered close ended questionnaire. RESULTS: A total of 1045 medical practitioners (718 males, 327 females) voluntarily participated in this survey. It was observed that 56.8% of the medical practitioners had no prior knowledge of management of an avulsed tooth. A 81.6% of practitioners were unaware of transport medium for an avulsed tooth whereas, more than half practitioners (64.7%) were naive about an ideal time for replantation of an avulsed tooth. A little more than one third of the practitioners (26.5%) were unacquainted about the method of holding an avulsed tooth. CONCLUSION: Regardless of the level of education, the general medical practitioners of Nagpur lack most of the knowledge required for the emergency management of an avulsed teeth. Keeping the in mind the present scenario, it was recommended that education regarding avulsed tooth should be incorporated in school and medical curriculum to increase awareness among parents, teachers and medical practitioners. Also, it is the responsibility of the dentist to make the society aware of this situation. PMID- 28658902 TI - Correlation of Vascular and Inflammatory Index in Oral Pyogenic Granuloma and Periapical Granuloma - An Insight into Pathogenesis. AB - INTRODUCTION: Angiogenesis is vital in the aetiology and pathogenesis of a number of pathological processes that include solid reactive lesions like pyogenic granuloma and chronic inflammatory disorders like periapical granuloma. Vascular Endothelial Growth Factor (VEGF) is a potent proangiogenic cytokine secreted by many cell types which present several pivotal functions in physiologic and pathologic angiogenesis. AIM: The aim of the present study was to evaluate and compare the expression of VEGF in oral Pyogenic Granuloma (PG) and Periapical Granuloma (PAG) and also to correlate with the inflammatory cell infiltrate. MATERIALS AND METHODS: Paraffin embedded tissue blocks of histologically diagnosed cases of PG and PAG, 20 of each were retrieved from the archives. The cases were selected randomly to evaluate the expression of VEGF marker and to assess the Mean Vascular Count (MVC) index and inflammation by Morphological Index (MI). The results were analysed using Unpaired t-test, Mann-Whitney U test and spearman correlation coefficient-test. RESULTS: The PG showed higher expression of VEGF when compared to PAG with no significant difference in inflammation. PG showed positive correlation and PAG showed negative correlation between inflammation and VEGF expression. CONCLUSION: Histologically similar PG and PAG are different not only by their clinical presentation but also by their mechanisms of formation and molecular sketch. Thereby raised expression of VEGF marker was established in PG emphasizing the fact that all histologically similar lesions need not have similar clinical course and molecular depiction. PMID- 28658903 TI - A Survey on Nickel Titanium Rotary Instruments and their Usage Techniques by Endodontists in India. AB - INTRODUCTION: The preference and usage of nickel titanium rotary instruments varies from individual to individual based on their technique, experience with the rotary systems and the clinical situation. Very limited information is available to explain the adoption of changing concepts with respect to nickel titanium rotary instruments pertaining to the endodontists in India. AIM: The aim of this study was to conduct a questionnaire survey to acquire the knowledge concerning different NiTi rotary instruments and their usage techniques by endodontists in India. MATERIALS AND METHODS: A Survey questionnaire was designed which consisted of 32 questions regarding designation, demographics, experience with rotary instruments, usage of different file systems, usage techniques, frequency of reuse, occurrence of file fracture, reasons and their management was distributed by hand in the national postgraduate convention and also disseminated via electronic medium to 400 and 600 endodontists respectively. Information was collected from each individual to gain insight into the experiences and beliefs of endodontists concerning the new endodontic technology of rotary NiTi instrumentation based on their clinical experience with the rotary systems. The questions were designed to ascertain the problems, patterns of use and to identify areas of perceived or potential concern regarding the rotary instruments and the data acquired was statistically evaluated using Fisher's-exact test and the Chi-Square test. RESULTS: Overall 63.8% (638) endodontists responded. ProTaper was one of the most commonly used file system followed by M two and ProTaper Next. There was a significant co relation between the years of experience and the file re use frequency, preparation technique, file separation, management of file separation. CONCLUSION: A large number of Endodontists prefer to reuse the rotary NiTi instruments. As there was an increase in the experience, the incidence of file separation reduced with increasing number of re use frequency and with experience, the management of separated file was better. PMID- 28658904 TI - Elective Tracheostomy in Head and Neck Surgery: Our Experience. AB - INTRODUCTION: Tracheostomy is commonly used to secure the airway during the immediate postoperative period in maxillofacial oncological operations. We conducted a study to review the utility of elective tracheostomy in head and neck surgery. AIM: To review the incidence of intraoperative, perioperative and postoperative complications and its management in elective tracheostomy and to analyse its utility in head and neck surgery. MATERIALS AND METHODS: The study included review of 50 patients, who were treated for head and neck cancers in the Department of Oral And Maxillofacial Surgery of our centre between January 2011 to December 2014. RESULTS: The study showed a male predilection with mean tracheostomy time of 25 minutes and operative time of 11 hours. The patients had an ICU stay of two days and elective ventilation of one day with mild tracheal secretion seen postoperatively. No other complications were noted intraoperatively or postoperatively. CONCLUSION: Elective tracheostomy even though an invasive tool when used properly in selected patients, can be safe and beneficial to the patients. PMID- 28658905 TI - Knowledge and Attitude of Parents towards Avulsed Permanent Tooth of their Children and its Emergency Management in Bhopal City. AB - INTRODUCTION: Dental avulsion is a commonly reported traumatic injury causing pain, aesthetic, functional, psychological and mental impairment. Since parents are in the immediate vicinity of children in such situations, their knowledge regarding the same is of great importance. AIM: The aim of present study was to assess the level of parental knowledge and their attitude towards dental avulsion and its emergency management. MATERIALS AND METHODS: A 10-stemmed questionnaire was prepared for this study which was modified form of questionnaire used by Raphael and Gregory. The questionnaire consisted of two parts and was provided in both English and Hindi languages. Parents had to mark one option provided to them in multiple choice questions, which they found to be right. A written consent according to ethical guidelines was taken by all the participants before filling up the questionnaire. The survey consisted of 550 parents who accompanied their children aged between 6 to 13 years in the Department of Pedodontics and Preventive Dentistry, Peoples Dental Academy, Bhopal, Madhya Pradesh, India. Chi- square test was applied to evaluate the associations in this study. RESULTS: Statistically it was observed that 34.5% of male participants exhibited more knowledge regarding the necessity of reimplantation of avulsed tooth in comparison to female participants. Also parents with higher educational background have showed positive response toward knowledge and attitude of emergency treatment of avulsed permanent tooth. About 25.6% of higher secondary level, 20.9% of undergraduate level, 10.9% of elementary school level and 0.4% of illiterate participants responded that reimplantation of avulsed permanent tooth is possible. CONCLUSION: It was concluded from the study that regardless of the age, education level or other factors, parental knowledge of tooth avulsion management was found to be very low in our society. Parents who participated in this study reported having insufficient knowledge about dental trauma and unskilled to provide emergency care to their child. PMID- 28658906 TI - The Effect of Cavity Design on Fracture Resistance and Failure Pattern in Monolithic Zirconia Partial Coverage Restorations - An In vitro Study. AB - INTRODUCTION: Cavity preparations of posterior teeth have been frequently associated with decreased fracture strength of the teeth. Choosing the correct indirect restoration and the cavity design when restoring the posterior teeth i.e., premolars was difficult as it involves aesthetic, biomechanical and anatomical considerations. AIM: To evaluate the fracture resistance and failure pattern of three different cavity designs restored with monolithic zirconia. MATERIALS AND METHODS: Human maxillary premolars atraumatically extracted for orthodontic reasons were chosen. A total of 40 teeth were selected and divided into four groups (n=10). Group I-Sound teeth (control with no preparation). Group II-MOD Inlay, Group III-Partial Onlay, Group IV-Complete Onlay. Restorations were fabricated with monolithic partially sintered zirconia CAD (SAGEMAX- NexxZr). All the 30 samples were cemented using Multilink Automix (Ivoclar) and subjected to fracture resistance testing using Universal Testing Machine (UTM) (Instron) with a steel ball of 3.5 mm diameter at crosshead speed of 0.5 mm/minute. Stereomicroscope was used to evaluate the modes of failure of the fractured specimen. Fracture resistance was tested using parametric one way ANOVA test, unpaired t-test and Tukey test. Fracture patterns were assessed using non parametric Chi-square test. RESULTS: Group IV (Complete Onlay) presented highest fracture resistance and showed statistical significant difference. Group II (MOD Inlay) and Group III (Partial Onlay) showed significantly lower values than the Group I (Sound teeth). However, Groups I, II and III presented no significant difference from each other. Coming to the modes of failure, Group II (MOD Inlay) and Group III (Partial Onlay) presented mixed type of failures; Group IV (Complete Onlay) demonstrated 70% Type I failures. CONCLUSION: Of the three cavity designs evaluated, Complete Onlay had shown a significant increase in the fracture resistance than the Sound teeth. PMID- 28658907 TI - Effect of 5% Chlorine Dioxide Irrigant on Micro Push Out Bond Strength of Resin Sealer to Radicular Dentin: An In Vitro Study. AB - INTRODUCTION: Chlorine dioxide (ClO2) has been recently investigated as a possible root canal irrigant due to its broad spectrum of antimicrobial action, tissue dissolution and smear layer removal properties. Literature is scarce on the effect of chlorine dioxide irrigation on the resin sealer dentin bond strength. AIM: To compare 5% chlorine dioxide (ClO2) with or without Ethylene Diamine Tetra Acetic acid (EDTA) with 3% Sodium hypochlorite (NaOCl) and EDTA combination as endodontic irrigants on the adhesion of AH Plus sealer to radicular dentin using micro- Push out Bond Strength (uPBS) test. MATERIALS AND METHODS: Forty freshly extracted central incisors were decoronated and randomly divided into four groups based on the different irrigation regimes followed during irrigation: Group I - 3% NaOCl + 17% EDTA, Group II - 5% ClO2 + 17% EDTA, Group III - 5% ClO2 and Group IV - Saline, and canal enlarged till Protaper F3. All the samples were obturated with F3 gutta-percha cones using AH Plus sealer and sectioned perpendicular to long axis to obtain 1mm thick slices from the middle and coronal portions for uPBS measurement in universal testing machine followed by assessment of failure pattern under stereomicroscope. Data was analysed using One-way analysis of variance (ANOVA), Bonferroni and t-test. RESULTS: Bond strength values were in the following order: Group I>Group II>Group III>Group IV, with no statistically significant difference amongst experimental groups on intergroup comparison, except with saline. The uPBS values were more in coronal third than middle third in all specimens, with no statistical significant difference. Mode of failure showed mixed patterns in all experimental groups except saline. CONCLUSION: In the present study, the bond strength values of ClO2 were comparable with conventional NaOCl and EDTA combination and hence, ClO2 can be considered as an effective alternative endodontic irrigant. PMID- 28658908 TI - An In vitro Comparative Evaluation of Disinfectants on Standard and Clinical Microbial Strains on Heat Cure Resins. AB - INTRODUCTION: Oral cavity is colonised by numerous micro-organisms that form a biofilm on the acrylic resin. Hence, routine hygiene is essential to prevent oral mucosal inflammation and lesions. Knowledge of appropriate disinfecting agents for acrylic resins is crucial in this context. AIM: To compare and evaluate the effectiveness of four commercially available disinfectants on heat cure acrylic resin specimens contaminated with standard and clinical strains of two micro organisms commonly inhabiting the oral microflora. MATERIALS AND METHODS: Two hundred acrylic resin specimens (n=200), 10 in each group were contaminated in vitro with 1x106 cells/ml suspensions of standard and clinical strains of micro organisms (Candida albicans and Streptococcus mutans) and were immersed in four disinfectants (1% sodium hypochlorite, 2% chlorhexidine digluconate, 2% glutaraldehyde and 3.8% sodium perborate) for 10 minutes. The control group was not subjected to any disinfection process. For collection of clinical strains, oral swab was passed over the buccal mucosa and grown on blood agar culture media. Organism confirmation was done by growing them on selective culture media. Final counts of micro-organisms per ml were performed by plating method for evaluation of microbial level reduction. Results obtained were subjected to ANOVA and Tukey's test. RESULTS: Standard strains of Candida albicans (C) and Streptoccocus mutans (S) subjected to various disinfectants showed varied mean Colony Forming Units per ml (CFU/ml) from <10,000 to 25,000 and <10000 to <50,000 respectively. Clinical strains and of Candida albicans (C) and Streptococcus mutans (S) subjected to various disinfectants showed varied mean CFU/ml from <10,000 to 50,000 and from 10,000 to 50,000 respectively. Control groups showed maximum mean CFU/ml (>105). All intergroup comparisons were highly significant (p<0.001; HS) and intragroup comparisons were significant (p<0.05; S) except the comparison of clinical strains of Streptococcusmutans subjected to 2% chlorhexidine digluconate and 2% glutaraldehyde which was found to be non significant (p>0.05; NS). CONCLUSION: Almost 1% sodium hypochlorite was found to be the most effective disinfectant for both Candida albicans and Streptococcus mutans. The least effective disinfectant being: 3.8% sodium perborate. PMID- 28658909 TI - Effect of Motives for Food Choice on Oral Health among Primary School Children in Mangalore: An Analytical Survey. AB - INTRODUCTION: Parents influence children's eating behaviours by making some foods available than others and by acting as models of eating behaviour. Food selected by parents influence general and oral health of their children. AIM: Aim of this study was to assess oral health parameters among primary school children and motives for food choice among their parents in Mangalore. MATERIALS AND METHODS: A total of 759 primary school children aged 5-10 years, and their parents participated in this study. Motives for food choice among parents of children were evaluated by using Food Choice Questionnaire (FCQ). Oral health status of students was assessed by using World Health Organisation (WHO) Basic Oral Health Assessment Form. Data pertaining to dietary habits and demographics was also collected. Descriptive and inferential statistics along with Pearson's correlation and Binary logistic regression were executed for the present study and level of significance was fixed at p<0.05. RESULTS: Caries prevalence was 10.8% and 68.9% in permanent and primary dentitions, respectively. Mean Decayed, Missing And Filled Tooth (DMFT) index scores among study subjects were 0.21+/ 0.72 and 3.08+/-3.11 for permanent and primary dentitions, respectively. Increase in caries prevalence was significantly associated with decrease in total FCQ scores. FCQ domains 'health', 'natural content' and 'weight control' were significantly correlated with dental caries experience. FCQ also showed significant correlation with socio-economic variables. CONCLUSIONS: Overall, dental caries experience was found to be high. Parental food choice motives positively influenced dietary patterns and caries experience of their children. Caries experience was less in children whose parents reported higher scores on FCQ. Understanding the barriers, identification of risk factors for poor food choices and targeting interventions might formulate ways by which the desired behaviour can be achieved. PMID- 28658910 TI - Relation between Clinical Oral Dryness Score and Denture Satisfaction among Patients' in a Tertiary Care Centre, India. AB - INTRODUCTION: Xerostomia is a subjective feeling of dryness commonly seen in elderly populations which impairs the quality of life. Due to loss of lubricating property of saliva the buccal mucosa, tongue and lips tend to stick leading to dry, freckled, ulcerated and sore mucosa which is of major concern to the patient to use complete denture. AIM: The aim of the study was to assess the relation between oral dryness score and denture satisfaction among elderly patients. MATERIALS AND METHODS: A cross-sectional study was conducted in prosthodontics department of a dental institution. Patients wearing dentures for at least six months were invited to participate in study. Visual Analogue Scale (VAS) with scores ranging from 0-100 was used to assess patient's satisfaction and clinical oral dryness score was assessed using the criteria described by Osailan SM et al., with scores ranging from 0-10. Data was analysed with SPSS software (version 20) and Kendall's tau-b correlation was used to determine the relationship between mean denture satisfactions and mean clinical oral dryness scores. RESULTS: A total of 220 participants were included in the study based on inclusion criteria. Mean dryness score of the participants was 1.8+/-0.6 and mean VAS-score for denture satisfaction was 74.32+/-21.20 for aesthetics, for chewing ability the mean score was 62.31+/-19.64 and for phonetics it was 67.82+/-30.60. Strong negative correlation between VAS-scores and oral dryness scores was observed. CONCLUSION: Clinical oral dryness score is one of the important factors which influence denture satisfaction. Dentist should consider in predicting prognosis. PMID- 28658911 TI - Effect of Green Coffee Bean Extract on Streptococcus mutans Count: A Randomised Control Trial. AB - INTRODUCTION: Mouth rinses have been popularly used as a supplementary oral hygiene aid. A lot of commercially available mouth rinses possess few adverse effects, which has necessitated the search for alternative and herbal mouth rinses. AIM: The aim of the study was to assess the effect of rinsing with green coffee bean extract in comparison with chlorhexidine mouthwash and sterile water on salivary Streptococcus mutans count. MATERIALS AND METHODS: A randomized parallel controlled clinical trial was planned and 45 subjects aged between 18-22 years were selected. The subjects were divided into three groups (n=15 in each group): Group A: Study group: 2% Green coffee bean extract, Group B: Positive control: 0.2% Chlorhexidine (CHX), Group C: Negative control: Sterile water. Group A subjects rinsed mouth with 5 ml of 2% Green coffee bean extract for one minute. Group B subjects rinsed mouth with 5 ml 0.2% CHX mouthwash for one minute. Group C subjects rinsed mouth with 5 ml of Sterile water for one minute twice daily for two weeks. Baseline samples (Pre rinse) were collected on day 1 and post rinsing saliva samples were collected after 14 days. The samples were cultured using Mitis Salivarius Agar enriched with Bacitracin and colonies were counted using a hand held digital colony counter. The statistical analysis was done using paired t-test, One-way variance ANOVA and Post-Hoc tests. RESULTS: The Green coffee bean extract group showed a statistical significant reduction in Streptococcus mutans colony count before and after intervention which was comparable with CHX group. CONCLUSION: Green coffee bean extract as a mouthwash can be explored as a safe and effective alternative to CHX mouthwash. PMID- 28658912 TI - Polymorphism in the Eruption Sequence of Primary Dentition: A Cross-sectional Study. AB - INTRODUCTION: Primary teeth have shown wide variations in their eruption time among different population. Population specific eruption ages are provided as mean with standard deviations or median ages with its percentile range. This alone will be insufficient for prediction of tooth eruption sequence because they provide no information on the frequency of sequence variation within the pairs of teeth. Norms of polymorphic variation in the eruption sequence can be more useful. AIM: This study aims at providing norms for the sequence polymorphism in primary teeth among the children of Mysore population. MATERIALS AND METHODS: A cross-sectional study was designed with 1392 children, recruited from December 2015 to June 2016 by simple random sampling method. Tooth was recorded as present or absent. Across the entire possible intra quadrant tooth pair, cases of present present, absent-absent, present-absent and absent-present and were counted and computed as percentages. RESULTS: Sequence polymorphisms were more common in 82 84 pairs of teeth. Significant polymorphic reverse sequence was observed in 52-54 (9%), 82-84 (35%) in males and 82-84 (18%) in females. There was no polymorphism in maxillary arch in females. CONCLUSION: The present study provides the baseline data values for sequence variation in primary teeth eruption. To the best of investigators knowledge, there are no previous studies describing the sequence polymorphism in primary teeth in Indian population. The results of this study helps in assessment of eruption sequence problems in paediatric dentistry and in evaluation and prediction of tooth eruption sequence in individual child. PMID- 28658913 TI - Microgap Evaluation of Novel Hydrophilic and Hydrophobic Obturating System: A Scanning Electron Microscope Study. AB - INTRODUCTION: The purpose of an endodontic obturation is to obtain a fluid tight hermetic seal of the entire root canal system. There has been an evolution of different materials and techniques to achieve this desired gap free fluid tight seal due to presence of anatomic complexity of the root canal system. AIM: To compare the microgap occurring in root canals obturated with hydrophilic versus hydrophobic systems using scanning electron microscope. MATERIALS AND METHODS: Sixty extracted human single-rooted premolars were decoronated, instrumented using NiTi rotary instruments. The samples (n=20) were divided into three groups and obturated with Group A - (control group) gutta-percha with AH Plus, Group B - C-point with Smartpaste Bio and Group C - gutta-percha with guttaflow 2. The samples were split longitudinally into two halves and microgap was observed under scanning electron microscope in the apical 3 mm of the root canal. RESULTS: Group A (control) showed a mean difference of 8.54 as compared to 5.76 in group C. Group B showed the lowest mean difference of 0.83 suggesting that the hydrophilic system (C-point/Smartpaste Bio) produced least microgap as compared to the hydrophobic groups. CONCLUSION: Novel hydrophilic obturating system (C-points/ Smart-paste Bio) showed better seal and least microgap as compared to gutta percha/guttaflow 2 and gutta-percha/ AH plus which showed gap at the sealer dentin interface due to less penetration and bonding of these hydrophobic obturating system. PMID- 28658914 TI - Photogrammetric Correlation of Face with Frontal Radiographs and Direct Measurements. AB - INTRODUCTION: Photogrammetry is a science of making measurements from photographs. As cephalometric analysis till date has focused mainly on skeletal relationships, photogrammetry may provide a means to reliably assess and compare soft tissue and hard tissue measurements. AIM: To compare and correlate linear measurements taken directly from subject's faces and from standardized frontal cephalometric radiographs and to correlate them with standardized frontal facial photographs of Indian population and to obtain mean values. MATERIALS AND METHODS: A cross-sectional study was conducted on 30 subjects of Indian origin. Frontal cephalograms and standardized frontal photographs were obtained from subjects in the age group of 18- 25 years. Vernier calipers were used to obtain facial measurements directly. Photographs and radiographs were uploaded and measured using Nemoceph software. Analogous cephalometric, photographic and direct measurements were compared by one-way ANOVA to assess Pearson correlation coefficients for 12 linear measurements (6 vertical, 6 horizontal). Bonferroni post-hoc test was done for pair wise comparison. RESULTS: Among all measurements used, OR-OL (orbitale right-orbitale left) showed a high correlation r = 0.76, 0.70, 0.71. There was moderate correlation with EnR-EnL (endocanthion rt - endocanthion lt) r2 = 0.62, 0.68, 0.68. Highly significant correlation was evident with N-Sn, EnR-EnL and AgR-AgL with p<0.001. CONCLUSION: A statistically significant correlation was found between photographic, radiographic and direct measurements. Therefore, photogrammetry has proven to be an alternative diagnostic tool that can be used in epidemiologic studies when there is a need for a simple, basic, non-invasive and cost-effective method. PMID- 28658915 TI - Memory T Cells (CD45RO) Role and Evaluation in Pathogenesis of Lichen Planus and Lichenoid Mucositis. AB - INTRODUCTION: Memory T cells have the ability to survive in a quiescent state for longer periods and are responsible for the rapid responses on subsequent exposure to antigen. Analyzing memory T cells in Oral Lichen planus (OLP) and Lichenoid Mucositis (LM) suggest that these cells may play a role in the immunopathogenic mechanisms. AIM: To identify and evaluate Memory T cells in Lichen Planus (LP), Lichenoid Mucositis (LM) and Normal Mucosa (NM) using CD45RO monoclonal antibody immunohistochemically. MATERIALS AND METHODS: A total of 30 cases (15 cases of OLP and 15 cases of LM) clinically and histopathologically diagnosed, and 10 cases of NM were stained for CD45RO monoclonal antibody, immunohistochemically using Biotin Streptavidin method. Staining intensity of CD45RO expression was statistically analysed using Chi-square Test. RESULTS: The present study demonstrated a higher expression of CD45RO in connective tissue layer of OLP (53.3% intense staining) when compared to LM (20% intense staining) and no intense staining in NM. The difference in staining intensity pattern between the study groups was statistically significant (p=0.014). CONCLUSION: This study demonstrates a statistically significant rise in memory T cells in LP than in LM, indicating the possible different immunopathogenic mechanisms. PMID- 28658916 TI - Evaluation of Surface Microhardness Following Chemical and Microwave Disinfection of Commercially Available Acrylic Resin Denture Teeth. AB - INTRODUCTION: Denture disinfection is an indispensable procedure for preventing cross contamination and the maintenance of a healthy oral mucosa in patients rehabilitated with removable dental prosthesis. Nevertheless, they are known to cause changes in the physical and mechanical properties of denture base resins and acrylic resin denture teeth following immersion of a denture in a suitable chemical disinfectant solution or by undergoing microwave irradiation. One such mechanical property indicator for artificial tooth materials is hardness. AIM: To assess the surface hardness of acrylic resin teeth of three different commercial brands (Ivoclar, Newace, Acryrock) following chemical (2% glutaraldehyde, 1% sodium hypochlorite) and microwave disinfections. MATERIALS AND METHODS: Ten specimens of each of the three commercial brands were made for control and each simulated disinfection type and stored in distilled water at room temperature for 24 hours. After water storage, specimens were immersed in 2% glutaraldehyde and 1% sodium hypochlorite (one and three cycles) at room temperature for 10 minutes. Irradiation with microwave (one and three cycles) was done in domestic microwave for three minutes with the specimens immersed in 150 ml of distilled water. The specimens were stored in distilled water at room temperature for seven days after each disinfection cycle. Vickers hardness measurements were made using a hardness indenter under a load of 50 g force for 10 seconds. Data was subjected to repeated measure two-way ANOVA test and Tukey's test. RESULTS: There were statistically significant differences for the variables disinfection, tooth, and cycle (p<0.05 for teeth & disinfectant interaction, p<0.05 cycle and disinfectant interaction). The mean surface hardness following one microwave disinfection cycle was lower than control, glutaraldehyde and sodium hypochlorite. Comparison among cycles revealed that microhardness was significantly decreased for three cycles of microwave disinfection. CONCLUSION: It was concluded that there was no significant difference in microhardness when the teeth were subjected to chemical disinfection but three cycles of microwave disinfection produced decrease in the microhardness of different types of artificial teeth. PMID- 28658917 TI - Early Stage Oral Submucous Fibrosis is Characterized by Increased Vascularity as Opposed to Advanced Stages. AB - INTRODUCTION: The degree of vascularity of the diseased mucosa in Oral Submucous Fibrosis (OSMF) has always been a matter of debate with conflicting results. Knowledge of this aspect is important to understand pathogenesis of OSMF, which in future could be translated into therapeutic strategies. AIM: In the present study, attempt has been made to investigate parameters like Mean Vascular Density (MVD), Total Vascular Area (TVA) and Mean Vascular Area (MVA) using CD34 antibody. MATERIALS AND METHODS: Forty five previously untreated histopathologically diagnosed cases of OSMF were retrieved from archives and fifteen age and sex matched healthy volunteers without habits were included in the control group. Sections were immunohistochemically stained for CD 34 and morphometric analysis was performed. For statistical analysis ANOVA, Kruskal Wallis test and Mann Whitney U tests were used and p-values <0.05 were considered statistically significant. RESULTS: MVD was more in Stage I OSMF followed by Control, Stage II and Stage III with statistically significant differences (p< 0.001). Statistically significant differences were observed in the MVD between control versus Stage III OSMF. Similarly, TVA was statistically significant when compared between control versus OSMF, control versus Stage II OSMF, control versus Stage III OSMF, Stage I versus Stage II OSMF, Stage I versus Stage III OSMF, and Stage II versus Stage III OSMF. For MVA, significant differences were between control versus OSMF, control versus Stage II OSMF, control versus Stage III OSMF, Stage I versus Stage III OSMF and Stage II versus Stage III OSMF. CONCLUSION: Angiogenesis is seen in early stages of OSMF with decreasing trend in advanced stages. Decreased vascular areas seen in advanced stages could be attributed to the increasing fibrosis surrounding the blood vessels. PMID- 28658918 TI - Efficacy of Neem Extract and Three Antimicrobial Agents Incorporated into Tissue Conditioner in Inhibiting the Growth of C. Albicans and S. Mutans. AB - INTRODUCTION: Denture stomatitis is an inflammatory condition which compromises the mucosal surface beneath dentures. The aetiology of denture stomatitis is usually multifactorial which varies from trauma from ill fitting denture to poor immune system. There are evidences that denture stomatitis is an outcome of multispecies biofilms that include Candida albicans and Streptococcus mutans. Tissue conditioners are found to be more susceptible to colonisation by micro organisms. AIM: The purpose of this study was to compare the efficacy of neem leaf extract and three other antimicrobial agents incorporated in a tissue conditioner against both Candida albicans and Streptococcus mutans. MATERIALS AND METHODS: Standard strain of Candida albicans and Streptococcus mutans were inoculated into Sabouraud Dextrose broth and Mitis-Salivarius-Bacitracin broth respectively incubated at 37 degrees C. Tissue conditioner (Viscogel) mixed with two different concentrations of ketoconazole, nystatin and chlorhexidine diacetate (5%, 10% w/w) and neem leaf extract (7.5% w/w and 15% w/w) and control group (plain tissue conditioner) were placed into punch hole (6 mm diameter) agar plate inoculated with Candida albicans and Streptococcus mutans. A total of 216 samples were prepared for both Candida albicans and Streptococcus mutans. Mean Inhibition Diameter (MID) across each punch holes were measured in millimetres at 24 hours and seven days and data were statistically analysed using Kruskal Wallis test followed by Mann-Whitney U test. RESULTS: Both ketoconazole and nystatin (10% w/w) showed maximum inhibition of 32 mm and mean of 31.75 followed by 15% w/w neem leaf extract with an inhibition of 21 mm and mean of 20.67 after 24 hours against Candida albicans whereas chlorhexidine diacetate (10% w/w) showed mean of 25.67 followed by chlorhexidine diacetate (5% w/w) and neem extract (15% w/w) which showed mean of 24.17 and 23.67 respectively against Streptococcus mutans. CONCLUSION: Neem leaf extract exhibited considerable potential to be an efficacious antimicrobial agent against both Candida albicans and Streptococcus mutans. PMID- 28658919 TI - Lichenoid Dysplasia-A Case Report with a Review of Differential Diagnosis. AB - Lichenoid Dysplasia (LD) is often regarded as lichen planus with dysplastic features, as it mimics lichen planus clinically and histologically. Although it has been confirmed that these two entities are entirely different with not so similar etiopathogenesis, yet the confusion still exists. The separation between the two is of utmost importance as each of them has their own prognosis and treatment plan. We report one such case, where a 51-year-old male with excessive burning sensation had similar clinical picture as that of lichen planus but was histologically diagnosed as LD. PMID- 28658920 TI - Management of an Unusual Ectopic Eruption of Maxillary Canine. AB - Transposition of teeth is a rare condition, with a prevalence of 0.3-0.4% in general population. They are more commonly observed in females, and may occur unilaterally/bilaterally with greater frequency of left side occurrence in unilateral transposition cases. A 17-year-old female patient reported with the chief complaint of unaesthetic smile. On clinical examination the patient was diagnosed with Angle's class I malocclusion with an ectopically erupted maxillary left canine labial to the left central incisor with retained deciduous canine. The treatment plan decided was to extract the retained deciduous canine, level and align the ectopic canine using an R-loop. The treatment for the patient was finished in 14 months and was retained using a fixed lingual retainer in the upper and lower arches. PMID- 28658921 TI - An Unusual Radiographic Presentation of Aneurysmal Bone Cyst of the Zygoma: A Rare Case Report. AB - Aneurysmal Bone Cyst (ABC) is an uncommon benign lesion affecting mainly the long bones and vertebral column. Its occurrence in the maxillofacial skeleton is rare. So far only five cases of ABC in the zygoma have been reported in the literature. Radiographic features of ABC are not pathognomonic. There can be expansion of bone and it may manifest as cystic lesion with honeycomb or soap bubble appearance. There can be perforation or destruction of cortex of the bone as well. Therefore the differential diagnosis of ABC is quite conflicting with other types of maxillary bone lesions. Here we report a case of ABC in 30-year-old female, at the left zygoma region showing periosteal reaction with sunray effect, which according to the literature is the first case reported based on location and radiographic appearance. PMID- 28658922 TI - Lip and Lower Lid Supporting Prosthetic Appliance: A Unique Approach of Treating Unilateral Facial Paralysis. AB - Along with function, aesthetics plays an important role in treating partially or completely edentulous patients. Ageing, trauma, tooth loss and neuromuscular disorders have a high impact on tonicity of facial musculature, elasticity of skin as well as function of muscles. Patients affected with Bell's palsy face functional, aesthetic as well as psychological impairment. Common problems are the partial closure of upper eyelid, sagging of lower eyelid and drooping of angle of mouth leading to facial asymmetry, along with difficulty in eating, drinking and speaking. The key to aesthetic restoration is to support and harmonize the collapsed facial musculature with the help of various prosthodontic treatment approaches. This case report attempts to focus on treating completely edentulous patient affected with Bell's palsy with special prosthesis supporting angle of mouth and lower eyelid using novel technique. PMID- 28658923 TI - Sturge Weber Syndrome: A Case Study. AB - The aim of this case review was to touch upon the various clinical presentations and diagnostic features of Sturge-Weber syndrome (SWS) as seen in the dental/medical practice. Sturge-Weber syndrome is a rare congenital disorder that belongs to a group of disorders collectively known as the phakomatoses. The characteristic pathological elements of the disease include leptomeninges angioma extending out to cerebral cortex with angiomatous lesions on the same side and unilateral facial nevus that affects trigeminal nerve division. The classic oral lesions involve haemangiomatous gingival lesion limited on the same side of upper or lower jaw. An 18-year-old female patient reported to the Department of Oral Medicine and Radiology with oral manifestations of SWS. The evaluation of the patient, radiological findings as well as the management is discussed in this case report. It is important for the dental physician to be aware of the non-oral manifestations of SWS in order to identify and manage it appropriately. The challenge here is to see the oral manifestation as part of the syndrome and not as an isolated oral condition. Early diagnosis and appropriate treatment plan is imperative to prevent development of complications. PMID- 28658924 TI - A Case Report of Rare Carcinoma Ex Pleomorphic Adenoma of Submandibular Gland and its Detailed Description. AB - A 65-year-old female patient reported with a chief complaint of swelling in the left lower region of the jaw since two years. On clinical examination, the swelling was present on the mandibular left posterior region and measuring approximately 6.2 cm antero-posteriorly * 6.2 cm mediolaterally * 8.7 cm superioinferiorly. Initially, it was non tender but eventually it became tender. Fine needle aspiration was done to rule out any salivary gland pathology and report obtained was carcinoma ex pleomorphic adenoma. Then, excisional biopsy was taken and tissue sent for histopathology. Histopathological diagnosis was benign adenoma with carcinoma. Later serial sections of tissue were studied and came to the conclusion of carcinoma ex pleomorphic adenoma which was non invasive type and showed bizarre cells with neoplastic changes. Benign part was composed of myxomatous area with partial capsule. Neoplastic cells showed invasion into capsule and few necrotic areas were also present. Overall interpretation was favoured Non invasive carcinoma ex pleomorphic adenoma. So here, we reported a case of Carcinoma ex Pleomorphic Adenoma (CAEXPA) which is a deadly and rare variant of salivary gland malignancy. PMID- 28658925 TI - Effect of Cell Phone Radiations on Orofacial Structures: A Systematic Review. AB - INTRODUCTION: The widespread use of cell phone in recent years has raised many questions whether their use is safe to operator who is exposed to Electromagnetic Waves (EMV). AIM: To find out the effect of cell phone emitted radiations on the orofacial structures. MATERIALS AND METHODS: To identify suitable literature, an electronic search was performed using Medline, Pubmed and EBSCO host database in December 2016. The search was focused on effect of cell phone on orofacial structures. Among the literature available in English, the screening of the related titles and abstracts was done, and only those articles were selected for full text reading that fulfilled the inclusion criteria. RESULTS: The initial literature search resulted in 360 articles out of which only 24 articles fulfilled the inclusion criteria and were included in this systematic review. CONCLUSION: Cell phone emitted radiations had their adverse effect on salivary glands and facial nerves. Studies showed that cell phone emitted radiations had effects on oral mucosal cells and causes changes in salivary flow rate. It was still unclear that cell phone radiations cause tumours of the salivary glands. PMID- 28658926 TI - Role of Vitamin E and Vitamin A in Oral Mucositis Induced by Cancer Chemo/Radiotherapy- A Meta-analysis. AB - INTRODUCTION: Oral mucositis is known to hamper the quality of life in patients treated for oral cancer. Many pharmacological agents have been tried and tested in its management, especially vitamin supplements including A, E and their combinations. AIM: A Meta-analysis was carried out to evaluate the efficacy of vitamins individually used for prevention or treatment of oral mucositis separately for chemotherapy, concurrent chemo radiotherapy, radiotherapy and Haematopoietic Stem Cell Transplantation (HSCT) individuals. MATERIALS AND METHODS: The literature study was done using PUBMED, MEDLINE, EBSCO, GOOGLE SCHOLAR and COCHRANE data bases with keywords vitamin A, vitamin E, vitamin B, vitamin C, Oral mucositis, Chemotherapy, Radiotherapy, Concurrent chemo radiotherapy and Haematopoietic stem cell transplantation individually, from the year 1980 to 2016. Only randomized controlled trials were included. The data was extracted, tabulated and was subjected to statistical analysis with CI of 95%. RESULTS: Among 201 subjects the analysis clearly demonstrated a male predominance to females in studies where male to female ratio was given. Out of 8 studies, 2 were studies in children and remaining 6 studies concentrated on adult population. WHO and NCI-CTC criteria were followed except for one study which used customised assessment. A meta-analysis was performed regarding usage of topical medication of Vitamin E group in all three cancer treatment modalities, which showed significant reduction in oral mucositis (p < 0.001). There was reduced oral mucositis in a small group of patients with Vitamin A when compared to controls. No information on the agent used for chemotherapy, the dose of radiotherapy and the type of tumours in 4 studies. CONCLUSION: Topical Vitamin E had performed better on oral mucositis than Vitamin E systemic administration. Though the efficacy of topical treatment with Vitamin A showed reduction in oral mucositis, it was evaluated in a very small sample which cannot be attributed to a larger sitting. PMID- 28658927 TI - A Speedy Yet Simple Tip to Align Imbricated Anterior Teeth. AB - Correction of dental crowding can be achieved with several orthodontic procedures like extraction of teeth, proximal stripping etc. In contemporary orthodontic practice, resolution of incisor crowding is most commonly achieved by the use of canine lacebacks. This method takes time, requires frequent activations and taxes anchorage since it involves the "PULL" mechanics. In order to overcome these disadvantages, mostly the time factor, we devised a method of using open coil NiTi spring on 0.016" SS wire piggy backed on the 0.014" heat activated NiTi base arch wire ligated only at the canines. This method, resolved the incisor crowding in almost one third of the time taken with the use of canine lacebacks. Moreover, the result was more physiologic since light continuous force was applied with the spring and it essentially eliminated the anchorage loss since it involved "PUSH" mechanics. PMID- 28658928 TI - Staged Approach for Advanced Gingival Recession: Free Gingival Autograft Followed by Coronally Advanced Flap with PRF Membrane. PMID- 28658929 TI - Light Microscopic Features of Type II Dens Invaginatus in A Deciduous Mandibular Molar. PMID- 28658930 TI - Broad Thumb-Hallux Syndrome: A Diagnosis Made on Clinical Findings. PMID- 28658931 TI - Fibrolipoma of the Oral Cavity: Treatment Choice in a Case with an Unusual Location. PMID- 28658932 TI - All Premolars with Three Roots Confirmed with Cone Beam Computed Tomography: A Rare Anatomical Variation. PMID- 28658933 TI - Intraoral Approaches for Maxillary Molar Distalization: Case Series. AB - Correction of Class II malocclusion by distalization of maxillary molars with intraoral appliances is a non-extraction treatment approach, which has been described as an alternative to Head Gear. From the past few years, the procedures have undergone rectification to achieve treatment objective more precisely. This has been made possible by a better understanding of bone physiology, tooth movement, biomechanics and newer biomaterials. Nowadays newer distalizing appliances, like the Jones Jig, Lokar distalizer and Carriere distalizer, have been developed which have compact designs and cause minimal discomfort to the patient. Refinement in these appliances is concentrated mainly on achieving bodily movement of the molar rather than simple tipping. These appliances are also operator friendly as these are easy to insert and remove. The present case series presents the efficacy of these appliances in Class II malocclusion patients with a mean age of 16 years (age range of 15-17 years) that reported with the chief complaint of irregular upper front teeth, since non-extraction approach in correcting Class II malocclusion is gaining a lot of attention. PMID- 28658934 TI - Image Updating for Brain Shift Compensation During Resection. AB - BACKGROUND: In open-cranial neurosurgery, preoperative magnetic resonance (pMR) images are typically coregistered for intraoperative guidance. Their accuracy can be significantly degraded by intraoperative brain deformation, especially when resection is involved. OBJECTIVE: To produce model updated MR (uMR) images to compensate for brain shift that occurred during resection, and evaluate the performance of the image-updating process in terms of accuracy and computational efficiency. METHODS: In 14 resection cases, intraoperative stereovision image pairs were acquired after dural opening and during resection to generate displacement maps of the surgical field. These data were assimilated by a biomechanical model to create uMR volumes of the evolving surgical field. A tracked stylus provided independent measurements of feature locations to quantify target registration errors (TREs) in the original coregistered pMR and uMR as surgery progressed. RESULTS: Updated MR TREs were 1.66 +/- 0.27 and 1.92 +/- 0.49 mm in the 14 cases after dural opening and after partial resection, respectively, compared to 8.48 +/- 3.74 and 8.77 +/- 4.61 mm for pMR, respectively. The overall computational time for generating uMRs after partial resection was less than 10 min. CONCLUSION: We have developed an image-updating system to compensate for brain deformation during resection using a computational model with data assimilation of displacements measured with intraoperative stereovision imaging that maintains TREs less than 2 mm on average. PMID- 28658935 TI - Minimal Impact by Antenatal Subpatent Plasmodium falciparum Infections on Delivery Outcomes in Malawian Women: A Cohort Study. AB - Antenatal malaria screening with a rapid diagnostic test (RDT) and treatment only of women with positive RDT findings may potentially prevent low birth weight resulting from malaria. The consequences of subpatent antenatal infections below the detection limit of RDTs are incompletely understood. In Malawi, pregnant women of any gravidity status were tested at each antenatal visit for Plasmodium falciparum, using an RDT and polymerase chain reaction analysis, and were followed until delivery. Associations between antenatal infections and delivery outcomes were assessed with Poisson regression or analysis of variance. Compared with women with no detected antenatal P. falciparum infection, women with positive RDT findings delivered babies with a lower mean birth weight (2960 vs 2867 g; mean difference, -93 g [95% confidence interval {CI}, -27 to -159]; P = .006); this was not observed among women with only subpatent infections (mean birth weight, 3013 g; mean difference, 54 [95% CI, -33-140]; P = .2268). These differences were apparent early in pregnancy, during the second trimester: compared with uninfected women, women with positive RDT findings delivered babies with a lower mean birth weight (mean difference, -94 g [95% CI, -31 to -156]; P = .003), but women with subpatent infections did not (mean difference, 36 g [95% CI, -49-122]; P = .409). Subpatent antenatal P. falciparum infections were not associated with adverse delivery outcomes. The association of patent infections at enrollment with low birth weight suggests the importance of preventing P. falciparum infection early in pregnancy. PMID- 28658936 TI - Associations of Multimorbid Medical Conditions and Health-Related Quality of Life Among Older African American Men. AB - Background: African American (AA) men battling multiple morbidities are tasked with managing the components of each condition and are at greater risk for adverse outcomes such as poor health-related quality of life (QOL), disability, and higher mortality rates. Method: Baseline data for AA men from the University of Alabama at Birmingham Study of Aging were utilized. Factor analysis was used to categorize medical conditions and create factor scores. Covariate-adjusted regression models assessed the relationships between categories of conditions and physical and mental health-related QOL as assessed by the SF-12. Results: The mean age of the sample of 247 AA men was 75.36 years and 49% lived in rural areas. Medical conditions fit into three factors: metabolic syndrome, kidney failure and neurological complications, and COPD and heart disease. Covariate adjusted models revealed that low education, higher levels of income difficulty, and higher scores on metabolic syndrome and COPD and heart disease factors were associated with lower scores on physical health-related QOL, p's < .05. Higher levels of income difficulty were also associated with lower scores on mental health-related QOL. Discussion: These findings suggest the importance of examining clusters of comorbid medical conditions and their relationships to outcomes within older African American men. PMID- 28658937 TI - Loneliness, Social Integration, and Incident Dementia Over 6 Years: Prospective Findings From the English Longitudinal Study of Ageing. AB - Objectives: Social relationships are important for the maintenance of cognitive function at older ages, with both objective features of social networks and perceived social connections (loneliness) being relevant. There is limited evidence about how different aspects of social experience predict diagnosed dementia. Methods: The sample comprised 6,677 dementia-free individuals at baseline (2004) from the English Longitudinal Study of Ageing. Baseline information on loneliness, number of close relationships, marital status, and social isolation (contact with family and friends and participation in organizations) was analyzed in relation to incident dementia over an average 6.25 years using Cox regression, controlling for potential confounding factors. Results: Two hundred twenty participants developed dementia during follow-up. In multivariable analyses, dementia risk was positively related to greater loneliness (hazard ratio 1.40, 95% confidence interval 1.09-1.80, p = .008), and inversely associated with number of close relationships (p < .001) and being married (p = .018). Sensitivity analyses testing for reverse causality and different criteria for diagnosing dementia confirmed the robustness of these findings. There was no association with social isolation. Discussion: Dementia risk is associated with loneliness and having fewer close relationships in later life. The underlying mechanisms remain to be elucidated, but efforts to enhance older peoples' relationship quality may be relevant to dementia risk. PMID- 28658938 TI - Low Thyroid Hormone Levels Disrupt Thyrotrope Development. AB - Low thyroid hormone (TH) conditions caused by a variety of prenatal and perinatal problems have been shown to alter postnatal regulatory thyrotropin (TSH) responsiveness to TH in humans and rodents. The mechanisms underlying this pituitary TH resistance remain unknown. Here we use the evolutionarily conserved zebrafish model to examine the effects of low TH on thyrotrope development and function. Zebrafish were exposed to the goitrogen 6-propyl-2-thiouracil (PTU) to block TH synthesis, and this led to an approximately 50% increase in thyrotrope numbers and an 8- to 10-fold increase in tshb mRNA abundance in 2-week-old larvae and 1-month-old juveniles. Thyrotrope numbers returned to normal 3 weeks after cessation of PTU treatment, demonstrating that these effects were reversible and revealing substantial plasticity in pituitary-thyroid axis regulation. Using a T4 challenge assay, we found that development under low-TH conditions did not affect the ability of T4 to suppress tshb mRNA levels despite the thyrotrope hyperplasia that resulted from temporary low-TH conditions. Together, these studies show that low developmental TH levels can lead to changes in thyrotrope number and function, providing a possible cellular mechanism underlying elevated TSH levels seen in neonates with either permanent or transient congenital hypothyroidism. PMID- 28658939 TI - Use of Stereovision for Intraoperative Coregistration of a Spinal Surgical Field: A Human Feasibility Study. AB - BACKGROUND: The use of image guidance during spinal surgery has been limited by several anatomic factors such as intervertebral segment motion and ineffective spine immobilization. In its current form, the surgical field is coregistered with a preoperative computed tomography (CT), often obtained in a different spinal confirmation, or with intraoperative cross-sectional imaging. Stereovision offers an alternative method of registration. OBJECTIVE: To demonstrate the feasibility of stereovision-mediated coregistration of a human spinal surgical field using a proof-of-principle study, and to provide preliminary assessments of the technique's accuracy. METHODS: A total of 9 subjects undergoing image-guided pedicle screw placement also underwent stereovision-mediated coregistration with preoperative CT imaging. Stereoscopic images were acquired using a tracked, calibrated stereoscopic camera system mounted on an operating microscope. Images were processed, reconstructed, and segmented in a semi-automated manner. A multistart registration of the reconstructed spinal surface with preoperative CT was performed. Registration accuracy, measured as surface-to-surface distance error, was compared between stereovision registration and a standard registration. RESULTS: The mean surface reconstruction error of the stereovision acquired surface was 2.20 +/- 0.89 mm. Intraoperative coregistration with stereovision was performed with a mean error of 1.48 +/- 0.35 mm compared to 2.03 +/- 0.28 mm using a standard point-based registration method. The average computational time for registration with stereovision was 95 +/- 46 s (range 33 184 s) vs 10to 20 min for standard point-based registration. CONCLUSION: Semi automated registration of a spinal surgical field using stereovision is possible with accuracy that is at least comparable to current landmark-based techniques. PMID- 28658940 TI - Superior Prognostic Value of Cumulative Intracranial Tumor Volume Relative to Largest Intracranial Tumor Volume for Stereotactic Radiosurgery-Treated Brain Metastasis Patients. AB - BACKGROUND: Two intracranial tumor volume variables have been shown to prognosticate survival of stereotactic-radiosurgery-treated brain metastasis patients: the largest intracranial tumor volume (LITV) and the cumulative intracranial tumor volume (CITV). OBJECTIVE: To determine whether the prognostic value of the Scored Index for Radiosurgery (SIR) model can be improved by replacing one of its components-LITV-with CITV. METHODS: We compared LITV and CITV in terms of their survival prognostication using a series of multivariable models that included known components of the SIR: age, Karnofsky Performance Score, status of extracranial disease, and the number of brain metastases. Models were compared using established statistical measures, including the net reclassification improvement (NRI > 0) and integrated discrimination improvement (IDI). The analysis was performed in 2 independent cohorts, each consisting of ~3000 patients. RESULTS: In both cohorts, CITV was shown to be independently predictive of patient survival. Replacement of LITV with CITV in the SIR model improved the model's ability to predict 1-yr survival. In the first cohort, the CITV model showed an NRI > 0 improvement of 0.2574 (95% confidence interval [CI] 0.1890-0.3257) and IDI of 0.0088 (95% CI 0.0057-0.0119) relative to the LITV model. In the second cohort, the CITV model showed a NRI > 0 of 0.2604 (95% CI 0.1796-0.3411) and IDI of 0.0051 (95% CI 0.0029-0.0073) relative to the LITV model. CONCLUSION: After accounting for covariates within the SIR model, CITV offers superior prognostic value relative to LITV for stereotactic radiosurgery treated brain metastasis patients. PMID- 28658941 TI - Comparing Smoking Topography and Subjective Measures of Usual Brand Cigarettes Between Pregnant and Non-Pregnant Smokers. AB - Introduction: Most pregnant smokers report abruptly reducing their cigarettes per day (CPD) by ~50% after learning of pregnancy and making further smaller reductions over the remainder of their pregnancy. Laboratory and naturalistic studies with non-pregnant smokers have found that these types of reductions often lead to changes in smoking topography (i.e., changes in smoking intensity to maintain a desired blood-nicotine level). If pregnant women smoke more intensely, they may expose themselves and their offspring to similar levels of toxicants despite reporting reductions in CPD. Methods: Pregnant and non-pregnant female smokers (n = 20 and 89, respectively) participated. At the experimental session, after biochemical confirmation of acute abstinence, participants smoked one usual brand cigarette ad lib through a Borgwaldt CReSS Desktop Smoking Topography device. Carbon monoxide (CO) and measures of nicotine withdrawal, craving, and reinforcement derived from smoking were also collected. Results: The two groups did not differ on demographic or smoking characteristics at screening, except nicotine metabolism rate, which as expected, was faster in pregnant smokers. Analyses suggest that none of the smoking topography parameters differed between pregnant and non-pregnant smokers, although pregnant smokers had a significantly smaller CO boost. Both groups reported similar levels of relief of withdrawal and craving after smoking, but other subjective effects suggest that pregnant smokers find smoking less reinforcing than non-pregnant smokers. Conclusions: Pregnant smokers do not smoke cigarettes differently than non-pregnant women, but appear to find smoking comparatively less pleasurable. Implications: This is the first study to assess smoking topography in pregnant women. Pregnant women appear to be at increased risk for smoking cigarettes with more intensity because of (1) their tendency to make significant abrupt reductions in the number of cigarettes they smoke each day after learning of pregnancy and (2) an increase in nicotine metabolism induced by pregnancy. Despite these changes, the present results suggest that pregnant women do not smoke cigarettes more intensely or in a way that causes more toxicant exposure, perhaps due to a reportedly less pleasurable smoking experience. PMID- 28658943 TI - Commentary on: Long-Term Quality-of-Life Outcomes After Body Contouring Surgery: Phase IV Results for the Body-QoL(r) Cohort. PMID- 28658942 TI - Cellular Senescence Biomarker p16INK4a+ Cell Burden in Thigh Adipose is Associated With Poor Physical Function in Older Women. AB - Background: Ample evidence implicates cellular senescence as a contributor to frailty and functional decline in rodents, but considerable effort remains to translate these findings to human aging. Methods: We quantified senescence biomarker p16INK4a-expressing cells in thigh adipose tissue obtained from older women previously enrolled in a 5-month resistance training intervention, with or without caloric restriction (RT +/- CR, n = 11 baseline, 8 pre-post-intervention pairs). Women in this subsample were older (72.9 +/- 3.4 y) and overweight/obese (body mass index: 30.6 +/- 2.4 kg/m2). p16INK4a+ cells were identified from 12 to 20 random visual fields/sample at 20* magnification (immunohistochemical, nuclear staining) and were present in all adipose samples. Results: Cross-sectional associations were observed between p16INK4a+ cell burden and physical function, including grip strength (r = -0.74), 400-m walk time (r = 0.74), 4-m gait speed (r = -0.73), and self-perceived mobility (r = -0.78) (p <= .05). These relationships remained significant after independent adjustments for age and adiposity (p <= .05). p16INK4a+ cell abundance was lower following the intervention (pre: 5.47 +/- 3.4%, post: 2.17 +/- 1.1% count p16INK4a+ cells, p <= .05). Conclusions: These results provide proof-of-concept that p16INK4a+ cells in thigh adipose are associated with physical function, and may be sensitive to change with RT +/- CR in overweight/obese older women. PMID- 28658944 TI - Hydraulic retention time and pH affect the performance and microbial communities of passive bioreactors for treatment of acid mine drainage. AB - For acceleration of removing toxic metals from acid mine drainage (AMD), the effects of hydraulic retention time (HRT) and pH on the reactor performance and microbial community structure in the depth direction of a laboratory-scale packed bed bioreactor containing rice bran as waste organic material were investigated. The HRT was shortened stepwise from 25 to 12 h, 8 h, and 6 to 5 h under the neutral condition using AMD neutralized with limestone (pH 6.3), and from 25 to 20 h, 12 h, and 8 to 7 h under the acid condition using AMD (pH 3.0). Under the neutral condition, the bioreactor stably operated up to 6 h HRT, which was shorter than under the acid condition (up to 20 h HRT). During stable sulfate reduction, both the organic matter-remaining condition and the low oxidation reduction potential condition in lower parts of the reactor were observed. Principal coordinate analysis of Illumina sequencing data of 16S rRNA genes revealed a dynamic transition of the microbial communities at the boundary between stable and unstable operation in response to reductions in HRT. During stable operation under both the neutral and acid conditions, several fermentative operational taxonomic units (OTUs) from the phyla Firmicutes and Bacteroidetes dominated in lower parts of the bioreactor, suggesting that co-existence of these OTUs might lead to metabolic activation of sulfate-reducing bacteria. In contrast, during unstable operation at shorter HRTs, an OTU from the candidate phylum OP11 were found under both conditions. This study demonstrated that these microorganisms can be used to monitor the treatment of AMD, which suggests stable or deteriorated performance of the system. PMID- 28658945 TI - Comparison of duplex PCR and phenotypic analysis in differentiating Candida dubliniensis from Candida albicans from oral samples. AB - Candida dubliniensis shares a wide range of phenotypic characteristics with Candida albicans including a common trait called germ tube positivity. Hence, laboratory differentiation of these two species is cumbersome. Duplex PCR analyses for C. albicans and C. dubliniensis was performed directly on DNA extracted from a total of 122 germ tube positive isolates derived from 100 concentrated oral rinse samples from a random cohort of diabetics attending a clinic in Sri Lanka. These results were confirmed by DNA sequencing of internal transcribed spacer (ITS) region of rDNA of the yeasts. Performance efficacy of duplex PCR was then compared with phenotypic identification using a standard battery of phenotypic tests. Of the 122 germ tube positive isolates three were identified by duplex PCR as C. dubliniensis and the remainder as C. albicans. On the contrary, when the standard phenotypic tests, sugar assimilation and chlamydospore formation, were used to differentiate the two species 13 germ tube positive isolates were erroneously identified as C. dubliniensis. Duplex PCR was found to be rapid, sensitive and more specific than phenotypic identification methods in discriminating C. dubliniensis from C. albicans. This is also the first report on the oral carriage of C. dubliniensis in a Sri Lankan population. PMID- 28658946 TI - Heating-Enhanced Dielectrophoresis for Aligned Single-Walled Carbon Nanotube Film of Ultrahigh Density. AB - In this paper, we demonstrate that the alignment density of individualized single walled carbon nanotubes (SWCNTs) can be greatly improved by heating-enhanced dielectrophoresis (HE-DEP) process. The observations by scanning electron microscope (SEM) suggest ultrahigh alignment density and good alignment quality of SWCNTs. The intuitive alignment density of individualized SWCNTs is much higher than the currently reported best results. The reason of this HE-DEP process is explained by simulation work and ascribed to the heating-enhanced convection process, and the "convection force" induced by the heating effect is assessed in a novel way. PMID- 28658947 TI - Zika Virus: A Threat to Pregnancy PMID- 28658948 TI - Post-Brexit: challenges and opportunities for rehabilitation beyond the European Union. PMID- 28658949 TI - Sink or Swim: Ions and Organics at the Ice-Air Interface. AB - The ice-air interface is an important locus of environmental chemical reactions. The structure and dynamics of the ice surface impact the uptake of trace gases and kinetics of reactions in the atmosphere and snowpack. At tropospheric temperatures, the ice surface is partially premelted. Experiments indicate that ions increase the liquidity of the ice surface but hydrophilic organics do not. However, it is not yet known the extent of the perturbation solutes induce at the ice surface and what is the role of the disordered liquid-like layer in modulating the interaction between solutes and their mobility and aggregation at the ice surface. Here we use large-scale molecular simulations to investigate the effect of ions and glyoxal, one of the most abundant oxygenated volatile organic compounds in the atmosphere, on the structure, dynamics, and solvation properties of the ice surface. We find that the premelted surface of ice has unique solvation properties, different from those of liquid water. The increase in surface liquidity resulting from the hydration of ions leads to a water-mediated attraction of ions at the ice surface. Glyoxal molecules, on the other hand, perturb only slightly the surface of ice and do not experience water-driven attraction. They nonetheless accumulate as dry agglomerates at the ice surface, driven by direct interactions between the organic molecules. The enhanced attraction and clustering of ions and organics at the ice surface may play a significant role in modulating the mechanism and rate of heterogeneous chemical reactions occurring at the surface of atmospheric ice particles. PMID- 28658950 TI - Correction to Ultrahigh Resolution Titanium Deep Reactive Ion Etching. PMID- 28658951 TI - Qualitative and Quantitative Analysis of Proteome and Peptidome of Human Follicular Fluid Using Multiple Samples from Single Donor with LC-MS and SWATH Methodology. AB - Human follicular fluid (hFF) is a natural environment of oocyte maturation, and some components of hFF could be used to judge oocyte capability for fertilization and further development. In our pilot small-scale study three samples from four donors (12 samples in total) were analyzed to determine which hFF proteins/peptides could be used to differentiate individual oocytes and which are patient-specific. Ultrafiltration was used to fractionate hFF to high-molecular weight (HMW) proteome (>10 kDa) and low-molecular-weight (LMW) peptidome (<10 kDa) fractions. HMW and LMW compositions were analyzed using LC-MS in SWATH data acquisition and processing methodology. In total we were able to identify 158 proteins, from which 59 were never reported before as hFF components. 55 (45 not reported before) proteins were found by analyzing LMW fraction, 67 (14 not reported before) were found by analyzing HMW fraction, and 36 were identified in both fractions of hFF. We were able to perform quantitative analysis for 72 proteins from HMW fraction of hFF. We found that concentrations of 11 proteins varied substantially among hFF samples from single donors, and those proteins are promising targets to identify biomarkers useful in oocyte quality assessment. PMID- 28658953 TI - Aggregation of Oligomeric Surfactant Constructed by Four-Armed Carboxylic Acid Sodium and Cationic Surfactant. AB - A star-shaped oligomeric-like surfactant with variable oligomeric degrees has been formed with a four-arm carboxylate salt (4EOCOONa) and cationic single chain surfactant dodecyl trimethylammonium bromide (DTAB). The aggregation of the 4EOCOONa/(DTAB)n complexes has been investigated by surface tension, electrical conductivity, isothermal titration microcalorimetry, zeta potential, dynamic light scattering, 1H NMR spectroscopy, and steady-state fluorescence measurements. The calorimetric result shows that 4EOCOONa interacts strongly with DTAB and each 4EOCOONa molecule binds with six DTAB molecules, wherein four DTAB molecules electrostatically bind to one 4EOCOONa molecule and additional two DTAB molecules further bind to the 4EOCOONa/(DTAB)n complex by hydrophobic interaction. The critical micelle concentration (CMC) of the 4EOCOONa/(DTAB)n complexes is remarkably lower than the CMC of DTAB, similar to synthesized star shaped oligomeric surfactants. The micelle properties of the DTAB/4EOCOONa mixtures depend on the component changes of the 4EOCOONa/(DTAB)n complexes. By increasing the DTAB/4EOCOONa molar ratio and/or concentration, the DTAB/4EOCOONa mixtures gradually form the complexes of 4EOCOO(DTA)13-, 4EOCOO(DTA)22-, 4EOCOO(DTA)3-, 4EOCOO(DTA)4, and 4EOCOO(DTA)62+, and the corresponding aggregates are small anionic micelles with loose molecular packing, and nearly nonionic or positively charged small micelles with more compact packing. Moreover, the positive charge of the small micelles increases with the increase of the concentration and the DTAB/4EOCOONa molar ratio. Therefore, constructing oligomeric-like surfactants by adding appropriate organic salts into conventional surfactants is a convenient method to achieve desired properties of surfactant aggregates. PMID- 28658952 TI - Noncovalent Control of the Electrostatic Potential of Quantum Dots through the Formation of Interfacial Ion Pairs. AB - This paper describes the role of tetraalkylammonium counterions [NR4+, R = -CH3, CH2CH3, -(CH2)2CH3, or -(CH2)3CH3] in gating the electrostatic potential at the interface between the 6-mercaptohexanoate (MHA) ligand shell of a PbS quantum dot (QD) and water. The permeability of this ligand shell to a negatively charged anthraquinone derivative (AQ), measured from the yield of electron transfer (eT) from the QD core to AQ, increases as the steric bulk of NR4+ increases (for a given concentration of NR4+). This result indicates that bulkier counterions screen repulsive interactions at the ligand/solvent interface more effectively than smaller counterions. Free energy scaling analysis and molecular dynamics simulations suggest that ion pairing between the ligand shell of the QD and NR4+ results from a combination of electrostatic and van der Waals components, and that the van der Waals interaction promotes ion pairing with longer-chain counterions and more effective screening. This work provides molecular-level details that dictate a nanoparticle's electrostatic potential and demonstrates the sensitivity of the yield of photoinduced charge transfer between a QD and a molecular probe to even low-affinity binding events at the QD/solvent interface. PMID- 28658954 TI - Preparation and Characterization of Biomimetic beta-Lens Crystallins Using Single Chain Polymeric Nanoparticles. AB - Presbyopia, the inability to focus at arm's length, and cataracts that cloud vision are associated primarily with changes in the mechanical and optical properties of the lens. The optical properties, particularly the refractive index, of the human lens originate from the cytoplasm of the lens fiber, which contains a highly concentrated solution (~40%) of globular proteins referred to as alpha, beta, and gamma crystallins, of which beta is the most abundant. In this study, we focus on the synthesis and characterization of a beta-crystallin biomimetic in an effort to understand and develop treatments for presbyopia and cataract. Polyacrylamide was used as a protein analogue. The side chains were endowed with aromatic and acidic functionality. Acrylic acid was incorporated into the copolymer and cross-linked with diamines to form nanoparticles. The composition and cross-linking condition of the biomimetic copolymers were optimized to match the hydrodynamic radius (Rh), refractive index, size, density, and intrinsic and dynamic viscosities with those of betahigh lens crystallins. The refractive indices and densities of the nanoparticles' dispersion at different concentrations matched that of betahigh lens crystallins, and the viscosity of the nanoparticles approached that of betahigh lens crystallins. The biocompatibility findings for primary porcine retinal pigment epithelial (ppRPE) cells and porcine lens epithelial (pLE) cells showed both cell types tolerated up to 30 mg/mL of nanoparticles. These materials have the potential for use as replacements for the crystallins in developing an accommodating intraocular lens nanocomposite hydrogel that closely replicates the natural autofocusing ability of the original. PMID- 28658955 TI - Salt-Induced Regenerative Surface for Bacteria Killing and Release. AB - Antibacterial surfaces with both bacteria killing and release functions show great promise in biological and biomedical applications, in particular for reusable medical devices. However, these surfaces either require a sophisticated technique to create delicate structures or need rigorous stimuli to trigger the functions, greatly limiting their practical application. In this study, we made a step forward by developing a simple system based on a salt-responsive polyzwitterionic brush. Specifically, the salt-responsive brush of poly(3 (dimethyl (4-vinylbenzyl) ammonium) propyl sulfonate) (polyDVBAPS) was endowed with bactericidal function by grafting an effective bactericide, i.e., triclosan (TCS). This simple functionalization successfully integrated the bacteria attach/release function of polyDVBAPS and bactericidal function of TCS. As a result, the surface could kill more than 95% attached bacteria and, subsequently, could rapidly detach ~97% bacteria after gently shaking in 1.0 M NaCl for 10 min. More importantly, such high killing efficiency and release rate could be well retained (unchanged effectiveness of both killing and release after four severe killing/release cycles), indicating the highly efficient regeneration and long term reusability of this system. This study not only contributes zwitterionic polymers by conferring new functions but also provides a new, highly efficient and reliable surface for "killing-release" antibacterial strategy. PMID- 28658956 TI - Protein Interactions with Nanoengineered Polyoxazoline Surfaces Generated via Plasma Deposition. AB - Protein adsorption to biomaterials is critical in determining their suitability for specific applications, such as implants or biosensors. Here, we show that surface nanoroughness can be tailored to control the covalent binding of proteins to plasma-deposited polyoxazoline (PPOx). Nanoengineered surfaces were created by immobilizing gold nanoparticles varying in size and surface density on PPOx films. To keep the surface chemistry consistent while preserving the nanotopography, all substrates were overcoated with a nanothin PPOx film. Bovine serum albumin was chosen to study protein interactions with the nanoengineered surfaces. The results demonstrate that the amount of protein bound to the surface is not directly correlated with the increase in surface area. Instead, it is determined by nanotopography-induced geometric effects and surface wettability. A densely packed array of 16 and 38 nm nanoparticles hinders protein adsorption compared to smooth PPOx substrates, while it increases for 68 nm nanoparticles. These adaptable surfaces could be used for designing biomaterials where proteins adsorption is or is not desirable. PMID- 28658957 TI - Preface: In Focus Issue on Protein Structures at Biointerfaces. PMID- 28658958 TI - Collagen affinity coating for surface binding of decorin and other biomolecules: Surface characterization. AB - The development of biomaterials that promote tissue reconstruction and regeneration can reduce the low level, chronic inflammation and encapsulation that impact the performance of today's medical devices. Specifically, in the case of implantable sensors, the host response often leads to poor device performance that discourages permanent implantation. Our goal is to present on medical implants bioactive molecules that can promote healing rather than scarring. Localized delivery of these molecules would also minimize the possibility of adverse tissue reactions elsewhere in the body. Toward this end, the authors have developed a collagen affinity coating that binds a number of potential healing molecules and can be attached to the surface of an implanted biomaterial. This allows the creation of a wide variety of natural surface coatings that can be evaluated and tailored to promote the desired healing response. To demonstrate the efficacy of this collagen affinity coating to biospecifically bind promising healing molecules to type I collagen in vivo, the antifibrotic proteoglycan decorin was utilized. Decorin binds and renders ineffective the protein transforming growth factor beta (TGFbeta) that induces collagen scar production. Thus, an assembled, supramolecular structure of biomaterial-collagen-decorin TGFbeta is formed. A decorin surface coating was created and characterized, illustrating the potential of this type I collagen affinity coating for widespread use with a variety of promising healing molecules. Future studies will test the implant efficacy of this type of coating. PMID- 28658959 TI - Vitamin C attenuates methotrexate-induced oxidative stress in kidney and liver of rats. AB - Like several other anticancer drugs, methotrexate (MTX) causes side effects, such as neuropathic pain, hepatotoxicity, and nephrotoxicity. Abnormal production of reactive oxygen species has been suspected in the pathophysiology of MTX-induced hepatorenal toxicity. Therefore, the aim of this study was to investigate the probable protective role of vitamin C (Vit C) on oxidative stress induced by MTX in the liver and kidney tissues of rats. A total of 32 rats were randomly and equally divided into four groups. The first group served as the control group. The second group received a single dose of 20 mg/kg of MTX intraperitoneally. To demonstrate our hypothesis, the third and the fourth groups received 250 mg/kg of Vit C for 3 days by oral gavage, with or without MTX treatment. At the end of the study, the liver and kidney tissues of the rats were collected and examined using histology. Both the tissues were assayed for malondialdehyde concentration and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities. In hepatic and renal tissues, lipid peroxidation levels were increased, whereas SOD, CAT, and GSH-Px levels were decreased by MTX. All parameters, including CAT levels in hepatic tissue, were significantly restored after the administration of Vit C for 3 days. Similar to the biochemical findings, evidence of oxidative damage was examined in both types of tissues by histopathological examination. From the results of this study, we were able to observe that Vit C administration modulates the antioxidant redox system and reduces the renal and hepatic oxidative stress induced by MTX. Vit C can ameliorate the toxic effect of MTX in liver and kidney tissues of rat. PMID- 28658960 TI - The influence of game genre on Internet gaming disorder. AB - Background and aims Although Internet gaming disorder (IGD) has been investigated in detail, minimal research has been conducted regarding the influence of different game genres on IGD. The aim of this study is to compare the characteristics of members of game genre-specific groups with IGD and to identify factors associated with IGD status in each group in a large sample of adults. Methods Internet games were categorized into four genres: real-time strategy games, massive multiplayer online role-playing games (MMORPG), sport games, and first-person shooter (FPS) games. Participants (n = 2,923) who usually played one of these games completed an anonymous online survey that collected sociodemographic, game usage pattern, and psychopathological assessment data. Results MMORPG and FPS game players more frequently met the criteria for IGD than participants in the other two groups. Differences between the IGD-suspected gamers within the genre-specific groups were observed for a few items, such as average game-playing time and the subscales of the behavioral activation system; however, the factors that contributed to the development of IGD within each game genre-specific group were found to be considerably different. Discussion and conclusions The findings of this study suggest that IGD is a stable psychiatric diagnosis encompassing users of a broad range of game genres. In addition, the development of strategies for the prevention of and early intervention on individuals at high risk for developing IGD may require consideration of the distinct characteristics identified as effective predictors of IGD in users of each game genre. PMID- 28658961 TI - Type 2 diabetes and cognitive dysfunction in minorities: a review of the literature. AB - OBJECTIVES: The purpose of this review was to summarize the current status of knowledge regarding cognitive dysfunction and diabetes in minorities. Literature on the interaction of cognitive dysfunction and diabetes was analyzed to (a) examine the number and characteristics of studies in minority populations; (b) identify tests used to assess cognitive function in diabetes; (c) consider the impact of diabetes on cognitive function; and (d) assess the moderators of the association between diabetes and cognitive function. DESIGN: A literature review and thematic analysis was conducted. Studies were mapped to describe their design, target population, instruments used, and the physiologic, psychosocial, and socioeconomic findings related to cognitive function and diabetes. Twelve studies met the inclusion criteria. RESULTS: Hispanics were studied more than any other ethnic group. Rates and degree of cognitive dysfunction were more prevalent in minorities than non-Hispanic whites. Overall, 28 different tests were administered to evaluate cognitive function. There was some variation among findings regarding the relationship of cognitive function and diabetes. Risk for cognitive decline was associated with the diagnosis of diabetes alone, regardless of whether the diabetes was treated or untreated. Higher rates of discrimination were associated with greater cognitive decline Conclusion: Given the context of minority health, there is a potential for higher negative health impact due to the increased prevalence of diabetes and cognitive dysfunction and other related health disparities. Reduction of physiological risk factors for diabetes, consistency in assessment, as well as elimination of structural barriers such as access to care should be helpful in decreasing the incidence of both diabetes and cognitive decline. More research is needed to determine whether the observed differences are modifiable and to identify factors involved in the interaction of diabetes and cognitive decline-not only physiological factors, but factors related to socioeconomic status and quality of life. PMID- 28658962 TI - Scoping Review of Nursing Case Management in the United States. AB - The purpose of this study is to identify issues of case management (CM) interventions in the United States in recent studies and to identify implications for future research into CM. This study was guided by the following framework for a scoping review. Multiple electronic databases were searched to identify studies published between 2007 and 2016 in the United States and related to nursing CM. Five weaknesses were identified: no clear and consistent definition of CM, lack of theoretical frameworks, lack of standard guidelines in CM practice, lack of precise CM dosage and of process measures, and limited reports of explicit role of nurse case managers and role confusion by nurses. Three strengths were also identified. More rigorous and continuous efforts to develop theoretical frameworks and evaluation tools, as well as clear definitions and precise role descriptions, are required for future research and practice into CM. PMID- 28658963 TI - Chemical composition and physicochemical properties of Phaeodactylum tricornutum microalgal residual biomass. AB - The production of photosynthetic biofuels using microalgae is a promising strategy to combat the use of non-renewable energy sources. The microalgae residual biomass is a waste by-product of biofuel production; however, it could prove to have utility in the development of sustainable nutraceuticals and functional foods. In this study, a comprehensive characterisation of the under utilised Phaeodactylum tricornutum microalgae residual biomass is presented. Proximal composition, antioxidant capacity (using three different antioxidant assays; oxygen radical absorbance capacity; radical cation activity, ABTS; and radical scavenging activity, DPPH), and total phenolic content of free and bound polyphenols were determined. Additionally, the physicochemical properties of water activity, pH, water absorption index, water solubility index, and dispersibility were evaluated. Results revealed that P. tricornutum microalgae residual biomass exhibits a relatively high protein and carbohydrate content, with values of 36.67% and 46.78%, respectively; and most carbohydrates were found as total dietary fibre (45.57%), of which insoluble dietary fibre was the most predominant (43.54%). Antioxidant capacity values for total phytochemicals of 106.22, 67.93, 9.54 uM TE g-1 dw were determined by oxygen radical absorbance capacity, ABTS, and DPPH assays, respectively. Total phenolic content was found to be 2.90 mg GAE g-1 dw. Interestingly, antioxidant capacity and total phenolic content were higher in bound than in free phytochemical extracts. The physicochemical analysis showed P. tricornutum microalgae residual biomass to have suitable properties for the generation of a beverage with Aw, pH, water absorption index, water solubility index, and dispersibility values of 0.45, 7.12, 3.40 g gel g-1 dw, 2.5 g solids 100 g-1 dw, and 90%, respectively. Hence, P. tricornutum microalgae residual biomass could be considered a potential source of bioactive compounds suitable for the production of functional food exhibiting antioxidant capacity and high dietary fibre content. PMID- 28658964 TI - Products of chickpea processing as texture improvers in gluten-free bread. AB - Recent market developments raised the need for alternatives to hydrocolloids as texture improver in gluten-free bread. Chickpea exerts several physicochemical properties (water- and oil-binding, emulsifying and foaming) that might address this need. Therefore, the effect of processing on chickpea functionality was tested on low ingredient dose, comparably to that of common hydrocolloids. Control bread was small, hard and with low gas retention ability as shown by microscopy, depicting holes inside crumb pores. Addition of chickpea flour in low dose (2% w/w) enhanced loaf volume by 20% and reduced crumb hardness by 40%, due to increased gas retention (no holes within pores) and superior homogeneity of the starch-protein network. On the contrary, chickpea paste deleteriously affected bread quality due to loss of solubility upon cooking. Interestingly, both soaking and cooking water significantly reduced crumb hardness, although to a lower extent than the flour. More homogeneous crumb structure and gas retention were observed in the micrographs, possibly due to the emulsifying activity of flavonoids and saponins (soaking) and insoluble fibre (cooking). Chickpea ingredients are promising substitute of hydrocolloids such as xanthan gum for texture improvement of gluten-free bread, although acting with different mechanisms. PMID- 28658965 TI - Self-rated health among multiracial young adults in the United States: findings from the add health study. AB - OBJECTIVE: The multiracial adult population is one of the fastest growing segments of the U.S. population, yet much remains to be learned about multiracial health. Considerable research finds racial/ethnic disparities in self-rated health, however subgroups within the multiracial population have not been consistently described. DESIGN: We use data from the National Longitudinal Survey of Adolescent Health (Add Health) and multivariate logistic regression analyses to compare self-rated health of multiracial and monoracial young adults (n = 7880). RESULTS: Overall, there were no significant differences in poor self-rated health status of multiracial adults as a single group odds ratio 0.84 (95% CI: 0.52-1.36) compared to monoracial White adults. Analyses further revealed important variations in health-status by specific subgroups and show that some multiracial subgroups may not fit existing patterns of health disparities. For instance, Asian-White multiracial adults do not fit documented patterns of health disparities and report better health than monoracial Asian and monoracial White adults. CONCLUSION: This study illustrates that the inclusion of specific multiracial categories provides evidence to enhance understanding of the pathways that are linked to health outcomes and the implications for health disparities. PMID- 28658966 TI - Actinin-4 protein overexpression as a predictive biomarker in adjuvant chemotherapy for resected lung adenocarcinoma. AB - AIM: Although several clinical trials demonstrated the benefits of platinum combination adjuvant chemotherapy for stage II-IIIA lung adenocarcinoma, predictive biomarkers for the efficacy of such therapy have not yet been identified. We evaluated protein overexpression of actinin-4 as a predictive biomarker of the efficacy of adjuvant chemotherapy in resected lung adenocarcinoma. MATERIALS & METHODS: We measured actinin-4 protein levels in patients with completely resected stage II-IIIA lung adenocarcinoma using immunohistochemistry and then retrospectively compared survival between adjuvant chemotherapy and observation groups. RESULTS: A total of 148 eligible patients were classified into actinin-4 positive or negative cases by immunohistochemistry. In the former, patients with adjuvant chemotherapy survived significantly longer than those with observation (hazard ratio [HR]: 0.307; p = 0.028). But, no significant survival benefit was noted with adjuvant chemotherapy (HR: 0.926; p = 0.876) in the latter. CONCLUSION: This marker could predict the efficacy of adjuvant chemotherapy for resected lung adenocarcinoma patients. PMID- 28658968 TI - Scientific Sessions - Oral presentations - Program Overview. PMID- 28658967 TI - Bridging the ocean: Kiribati Australia alliance in mental health. AB - OBJECTIVE: The objective of this study was to demonstrate the benefits of collaboration between Australia and Kiribati, a Pacific island nation, to enhance Kiribati's mental health system. METHOD: The collaboration involved a training program for a Kiribati senior mental health leader in Melbourne, Australia, and service planning including prioritisation of key areas for development. RESULTS: As well as receiving general training in community-based mental health, the Kiribati mental health leader gained skills in modification of the inpatient environment, with plans for implementation in Kiribati within the current limited resources. Future planning will focus on shifting from an emphasis on acute psychiatric treatment and custodial care to a recovery-oriented approach. CONCLUSION: The international exchange was a positive experience for both the Kiribati participants and their Australian colleagues. Knowledge transfer was achieved in a short time, and service development appropriate and realistic for the Kiribati environment was planned. PMID- 28658969 TI - Resilience and Coping Strategies Influencing the Quality of Life in Patients With Brain Tumor. AB - The study purpose was to evaluate how much of the variance in quality of life (QOL) among Taiwanese patients with brain tumor could be accounted for by resilience and coping strategy. This cross-sectional study included 95 patients who had undergone a treatment of operations or chemotherapy or radiotherapy relevant to brain tumor after at least 1 month and completed the European Organization for Research and Treatment of Cancer QOL Questionnaire-Brain Cancer Module (EORTC QLQ-BN20), Resilience Scale (RS), and Ways of Coping Checklist Revised (WCC-R). There was a significant negative correlation between resilience and future uncertainty QOL and motor dysfunction QOL. In addition, there was a significant positive correlation between the emotion-focused coping and future uncertainty QOL, as well as a significant negative correlation between problem focused coping and motor dysfunction QOL. Resilience accounted for 4.8% and the emotion-focused coping accounted for 10.20% of the variance in separately predicting the future uncertainty QOL. This study highlights the potential importance of resilience and coping strategies in patients' QOL, which is relevant to brain tumor treatment. PMID- 28658971 TI - Case Series: A Kindred With Eruptive Vellus Hair Cysts and Systemic Features. AB - Eruptive vellus hair cysts (EVHCs) often occur on the trunk and limbs. Facial involvement is uncommon. Autosomal dominant inheritance has been described, but associated extracutaneous anomalies have not. We describe a 4-patient kindred presenting with multiple facial EVHCs and an association of preauricular pits, lipomas, joint hypermobility, and cardiac defects. Histopathologic examination confirmed the diagnosis of EVHCs in 3 affected individuals. We propose that facial EVHCs may indicate the presence of an inherited autosomal dominant disorder with extracutaneous manifestations. Extracutaneous manifestations noted in the kindred have been sporadically described in association with steatocystoma multiplex (SM), a condition occasionally noted in the presence of EVHCs, further supporting an association between these disorders. PMID- 28658972 TI - Programming microphysiological systems for children's health protection. AB - Microphysiological systems (MPS) and computer simulation models that recapitulate the underlying biology and toxicology of critical developmental transitions are emerging tools for developmental effects assessment of drugs/chemicals. Opportunities and challenges exist for their application to alternative, more public health relevant and efficient chemical toxicity testing methods. This is especially pertinent to children's health research and the evaluation of complex embryological and reproductive impacts of drug/chemical exposure. Scaling these technologies to higher throughput is a key challenge and drives the need for in silico models for quantitative prediction of developmental toxicity to inform safety assessments. One example is cellular agent-based models, constructed from extant embryology, that produce data useful to simulate critical developmental transitions and thereby predict phenotypic consequences of disruption in silico. Biologically inspired MPS models built from human induced pluripotent stem (iPS) derived cells and synthetic matrices that recapitulate organ-specific physiologies and native tissue architectures are providing exciting new research opportunities to advance the assessment of developmental toxicity and offer the possibility of deriving a full 'human on a chip' system, or a 'Homunculus.' Impact statement This 'commentary' summarizes research needs and opportunities for engineered MPS models for developmental and reproductive toxicity testing. Emerging concepts can be taken forward to a virtual tissue modeling framework for assessing chemical (and non-chemical) stressors on human development. These models will advance children's health research, both basic and translational and new ways to evaluate complex embryological and reproductive impacts of drug and chemical exposures to inform safety assessments. PMID- 28658974 TI - One new cytochalasin metabolite isolated from a mangrove-derived fungus Daldinia eschscholtzii HJ001. AB - One new cytochalasin metabolite [11]-cytochalasa-5(6),13-diene-1,21-dione-7,18 dihydroxy-16,18-dimethyl-10-phenyl-(7S*,13E,16S*,18R*) (1), together with three known compounds (2-4) were obtained from the EtOAc extract of the endophytic fungus Daldinia eschscholtzii HJ001 isolated from the mangrove Brguiera sexangula var. rhynchopetala collected in the South China Sea. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. Compounds 1 and 2 were evaluated for their antibacterial and cytotoxic activities. PMID- 28658973 TI - The Relation Between Physical Activity and Cognitive Change in Older Latinos. AB - Cognitive impairment in older Latinos is of concern due to the rapid growth of this population and their increased risk for dementia due to chronic disease. Evidence, primarily from studies of non-Latino Whites, suggests that physical activity (PA) may reduce cognitive decline. Few longitudinal studies have included older Latinos, objective measures of PA, or neurocognitive tests that assess domains of cognition. The purpose of this longitudinal study was to explore the relationship between changes in PA and cognitive decline in older Latinos over an average of 5 years. Inclusion criteria for the baseline sample were age >=50 years, Latino ethnicity (English or Spanish speaking), no ambulation disability, no evidence of dementia, and Chicago address. Of the 174 baseline participants, 59 (33.9%) participated at follow-up. PA was measured by questionnaire and accelerometer worn for 7 days. A battery of neurocognitive tests assessed episodic memory, perceptual speed, and semantic memory. Change in cognitive function was dichotomized to maintenance versus decline. Binary logistic regression results indicated that those who had less decline from baseline to follow-up in self-reported light PA maintained episodic memory, odds ratio ( OR) = 1.16 (95% confidence interval [CI] [1.03, 1.32]), while those who had less decline in accelerometer moderate-vigorous bouts maintained semantic memory, OR = 16.08 (95% CI [1.53, 168.89]), controlling for baseline age, chronic health problems, depressive symptoms, and acculturation. These findings suggest that maintenance of PA with aging may prevent cognitive decline. This work can inform future intervention development that aims to maintain PA in order to prevent cognitive decline. PMID- 28658975 TI - Synthesis and biological evaluation of novel A-seco-taxoids derived from 1 deoxybaccatin VI. AB - Three novel nor-seco-taxoids 13, 15, 23 in which the A rings are cleaved but the B, C, and D rings are retained were prepared from 1-deoxybaccatin VI via its nor dioxo derivative and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. Oxidative introduction of C-1 hydroxyl to 1-deoxybaccatin VI with oxidising agent KBrO3 and catalyst RuCl3 led to the dioxo derivative 6 and its structure is determined by X-ray crystallographic analysis. A-seco taxoids 13, 15, 23 with a C-13 ester linkage were tested for cytotoxic activity and all compounds showed no measurable cytotoxic activity against HCT-116 cell line. However, 1-deoxy-9a-dihydrotaxane analogue 4 semi-synthesised from 1 deoxybaccatin VI is 10-fold less cytotoxic than paclitaxel, indicating the indispensible nature of the A ring double bond for the bioactivity of paclitaxel. PMID- 28658976 TI - Application of anthocyanins as natural dye extracted from Brassica oleracea L. var. capitata f. rubra: dyeing studies of wool and silk fibres. AB - Brassica oleracea L. var. capitata f. rubra (Red Cabbage) dye is composed mainly of natural pigment called anthocyanins used as a natural colourant. Wool and silk fibres were dyed with the aqueous extract obtained from red cabbage. The dyeing process was investigated and the combined effects of dyeing conditions on the colour yield parameter (K/S) were studied. Resulted fastness to wash, rubbing and light of the dyed fabrics were evaluated. Chemical Oxygen Demand (COD) and Biological Oxygen Demand (BOD5) of the residual effluent were measured. Best dyeing conditions were found to be: 50 g/100 mL, pH 2, 60 min and 100 degrees C, respectively, for the red cabbage weight, pH, dyeing duration and temperature. Good fastnesses properties were found in both cases: for wool and silk fabrics. It was found also that the calculated biodegradability ratio (COD/BOD5) of the residual bath of dyeing wool and silk with red cabbage extract are lower than 1.5 which means that these baths are biodegradable. PMID- 28658978 TI - Surgical considerations in posterior C1-2 instrumentation in the presence of vertebral artery anomalies: case illustration and review of literature. AB - Vascular anomalies involving the V3 segment of the vertebral artery are common and may complicate posterior atlantoaxial instrumentation. We report a patient with a fenestrated vertebral artery that underwent successful C1-2 instrumentation and fusion. Various vertebral artery anomalies are discussed with a review of pertinent literature. PMID- 28658977 TI - N-hydroxymethylglycinate with EDTA is an efficient eye drop preservative with very low toxicity: an in vitro comparative study. AB - PURPOSE: Preservatives are used in multi-dose ophthalmic topical medications in order to prevent contamination by bacteria and fungi. However, prolonged use of preserved eye drops, as it may happen in dry eye or glaucoma, may damage cells of the ocular surface. Therefore, an important goal is to find preservatives with low toxicity which are mild to host cells, still able to prevent drug contamination so to maintain their sterility and efficacy. Hence, aim of this study has been to compare the relative toxicity on a rabbit corneal cell line of a new preservative, made by the association of N-hydroxy-methyl-glycinate (NIG) with disodium-ethylene diamine tetra-acetate (EDTA), with other known and widely used eye-drops preservatives. MATERIALS AND METHODS: Rabbit corneal cells (SIRC) were tested either in 96-well plates or in suspension culture. Treatments with preservatives (used at known bacteriostatic concentrations) included: benzalkonium chloride (BAK), polyquaternium-1 (PQ-1), sodium perborate (SP: NaBO3 * H2O), and NIG +/- EDTA at different concentrations (0.001% and 0.002%), and different treatment times (from 30 minutes to 120 hours). At the end of treatment, cell survival was evaluated by a specific spectrophotometric method through the metabolic conversion of MTT [3-(4,5-dimethylthiazol-2-yl) 2, 5 diphenyltetrazolium bromide] into formazan crystals. RESULTS: Almost no cell toxicity was evident for NIG and SP at either concentration (0.001% or 0.002%), while a low toxicity was observed for PQ-1 (62% at the highest dose at 120 hours). BAK, as expected, showed the highest toxicity (60-80% at 30 minutes, and over 90% from eight hours onward). EDTA 0.1% alone or in combination with NIG 0.002%, showed no toxicity at 24 hours, and even resulted in cell growth promotion (46% and 38%, respectively), after 48 hours of treatment. CONCLUSIONS: These data show that the new preservative NIG/EDTA, at doses known to have effective antimicrobial properties, has a very low toxicity on corneal cells, and so it can be safely used in multi-dose eye drops. PMID- 28658979 TI - Addendum. PMID- 28658981 TI - Pharmacotherapy of alcoholism - an update on approved and off-label medications. AB - INTRODUCTION: Only a few medications are available for the treatment of alcohol use disorders (AUDs). Areas covered: This paper discusses approved AUD medications, including the opioid antagonists naltrexone and nalmefene (the latter is licensed for reduction of alcohol consumption only), the putative glutamate receptor antagonist acamprosate and the aldehyde dehydrogenase inhibitor disulfiram. It also covers off-label medications of interest, including topiramate, gabapentin, ondansetron, varenicline, baclofen, sodium oxybate and antidepressants. Clinical implications, benefits and risks of treatment are discussed. Expert opinion: Acamprosate, naltrexone, nalmefene and disulfiram are the only approved 'alcohol-specific' drugs. Acamprosate and naltrexone have been evaluated in numerous clinical trials and represent evidence-based treatments in AUDs. Nalmefene use, however, is controversial. Supervised disulfiram is a second line treatment approach. Compounds developed and licensed for different neuropsychiatric disorders are potential alternatives. Encouraging results have been reported for topiramate, gabapentin and also varenicline, which might be useful in patients with comorbid nicotine dependence. The GABA (gamma aminobutyric acid)-B receptor agonist baclofen has shown mixed results; it is currently licensed for the treatment of AUDs in France only. Gabapentin may be close to approval in the USA. Further studies of these novel treatment approaches in AUDs are needed. PMID- 28658982 TI - Cerebral protection devices for transcatheter aortic valve replacement. AB - INTRODUCTION: Stroke is a devastating, potential complication of any cardiovascular procedure including transcatheter aortic valve implantation (TAVI). Even clinically silent lesions as detected by magnetic resonance imaging have been associated with poor long-term cognitive outcomes. As a result, extensive efforts have been focused on developing stroke preventative strategies including the development of novel embolic protection devices. These devices aim to reduce this risk by capturing or deflecting emboli away from the cerebral circulation. Areas covered: This review provides an insight into the incidence and mechanisms of neurologic events during TAVI, explores the design features and initial human experience of each of the cerebral embolic protection devices that have been used during TAVI, and carefully explains the major clinical trials of each of these devices with a focus on safety, efficacy and other reported outcomes. Expert commentary: The potential benefit of neuroprotection cannot be ignored as TAVI widens its scope to include younger and lower-risk patients wherein preventing a procedure related cerebral injury would potentially prevent long-term morbidity and mortality. PMID- 28658983 TI - Melphalan hydrochloride for the treatment of multiple myeloma. AB - INTRODUCTION: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections. Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment. Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice. Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents. PMID- 28658984 TI - Cedrin identified from Cedrus deodara (Roxb.) G. Don protects PC12 cells against neurotoxicity induced by Abeta1-42. AB - Alzheimer's disease is a severe neurodegenerative disease affecting elder worldwide and closely related to the neurotoxicity induced by amyloid beta. To find efficient therapeutics, we have investigated the protective effects of cedrin from Cedrus deodara (Roxb.) G. Don on PC12 cells against the neurotoxicity induced by amyloid beta1-42. The results have shown the viability of PC12 cells injured by amyloid beta1-42 can be improved by cedrin. Cedrin can reduce reacrive oxygen species overproduction, increase the activity of superoxide dismutase and decrease malondialdehyde content. Meanwhile, the loss of mitochondrial membrane potential and mitochondrial permeability transition pore opening in PC12 cells, and elevated Caspase-3 activity, downregulated Bcl-2 and upregulated Bax are meliorated. These results demonstrate the protective effect of cedrin is related to the inhibition of oxidative stress, improvement of mitochondrial dysfunction and suppression of apoptosis. This investigation gives evidences for the application of cedrin in practice and further investigation in vivo. PMID- 28658985 TI - Platelet-rich plasma and peripheral nerve regeneration: a potential contraindication to its use after tumor excision. PMID- 28658986 TI - Ocrelizumab: a B-cell depleting therapy for multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown. PMID- 28658987 TI - Parkinsonism after chronic subdural haematoma followed by ventriculoperitoneal shunt for obstructive hydrocephalus: a case report. AB - Parkinsonism has been reported as a complication of a ventriculoperitoneal shunt (VPS) or clinical symptoms of chronic subdural haematoma (CSDH). We report an interesting case of parkinsonism in a patient with CSDH secondary to placement of a VPS for obstructive hydrocephalus, and we discuss the possible pathophysiological mechanisms and treatment. PMID- 28658988 TI - Updates on the treatment of gout, including a review of updated treatment guidelines and use of small molecule therapies for difficult-to-treat gout and gout flares. AB - INTRODUCTION: Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues. Areas covered: In this article, we describe the role of currently available drug therapies for managing acute gout flares and used in reducing serum urate levels. Further, we explore the role of novel small molecular therapies and biologic agents in the treatment of refractory or severe gout symptoms. A literature search of MEDLINE and MEDLINE In-Process & Other Non Indexed Citations Databases (1996-June 2017) was conducted utilizing the key words 'gout', 'interleukin-1 inhibitors', 'acute gout', 'gout treatment', 'urate lowering therapies', 'hyperuricemia', 'colchicine', 'pegloticase', 'lesinurad', 'xanthine oxidase', 'xanthine oxidase inhibitors', 'allopurinol', 'febuxostat', 'uricosurics', 'probenecid', and 'benzbromarone'. All published articles regarding therapeutic management of gout and hyperuricemia were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed. Expert opinion: Numerous therapies are currently available to managing acute gout flares and for lowering serum urate levels; advances in the understanding of the pathophysiology of this disorder has led to the emergence of targeted therapies and novel biologic preparations currently in development which may improve the clinical management of severe or refractory cases of disease that fail to respond to traditional therapies. PMID- 28658989 TI - Serum albumin level in spontaneous subarachnoid haemorrhage: More than a mere nutritional marker! AB - BACKGROUND: The role of nutritional markers on outcome following subarachnoid hemorrhage (SAH) has been scarcely described. METHODS: This is a prospective study of 273 patients with SAH, in which haemoglobin, serum protein and albumin were measured within 24 hours and again at one week following ictus, and analysed with respect to other variables. New neurologic deficits (NND), infarct, mortality and Glasgow outcome scale (GOS) at 3 months were assessed. RESULTS: The values of haemoglobin, total protein and albumin showed significant (p < .001) decline over the first week of SAH. Patients who developed NND had significantly lower serum albumin levels at admission compared to others (median 3.6 vs 3.9 g/dL, p < .001). Patients having lower albumin (<=3.5 gm/dL) levels at admission had significantly higher rates of NND (52% vs 20%), infarct (35% vs 23%), mortality (28% vs 16%) and unfavourable GOS (38% vs 25%). Hunt & Hess (H&H) grade and Fisher grade also affected all the outcome parameters significantly. Percentage decrease in albumin levels at one week following ictus significantly affected mortality and unfavourable GOS. On multivariate analyses, Fisher grade and lower admission albumin levels had significant impact on NND, while percentage decrease in albumin levels had significant impact on mortality and unfavourable GOS, independent of other nutritional markers and known prognostic variables. CONCLUSIONS: Serum albumin levels following SAH can be useful to predict development of NND, while its further weekly decrease correlates independently with unfavourable outcome at 3 months. Albumin assessment being readily available may serve as more than a mere nutritional parameter in SAH. PMID- 28658990 TI - Optimisation of peptides that actively cross the tympanic membrane by random amino acid extension: a phage display study. AB - Local treatment of middle ear (ME) disease currently requires surgical penetration of the tympanic membrane (TM). We previously discovered 12-mer peptides that are actively transported across the intact TM, a process that could be used for non-invasive drug delivery into the ME. To optimise transport and provide further understanding of the peptides transport mechanism, we extended two of the candidate peptides by six additional amino acids at random, and screened the resulting 18-mers libraries on TMs of rats with active bacterial otitis media (OM) for transport efficiency using phage display. Six identified peptides were individually tested in vivo for trans-TM transport to verify the tissue specificity. Three exhibited enhanced transport compared to their parent 12-mer scaffold, with the best showing an approximately nine-fold increase. Sequence analysis revealed anchor residues and structural features associated with enhanced transport. This included the prominent display of conserved sequence motifs at the extended free ends of the predicted peptide structures. PMID- 28658991 TI - Chemical composition and antimicrobial activity of the essential oil of Mentha mozaffarianii Jamzad growing wild and cultivated in Iran. AB - The aerial parts of wild and cultivated Mentha mozaffarianii Jamzad were collected at full flowering stage from two provinces (Hormozgan and Fars) of Iran. The essential oils were extracted by a Clevenger approach and analysed using GC and GC-MS. The main components in wild plants were piperitenone (33.85%), piperitone (21.18%), linalool (6.89%), pulegone (5.93%), 1, 8.cineole (5.49%), piperitenone oxide (5.17%) and menthone (4.69%) and in cultivated plants, cis-piperitone epoxide (28.89%), linalool (15.36%), piperitone (11.57%), piperitenone oxide (10.14%), piperitenone (8.42%),1,8-cineole (3.60%) were the main constituents in essential oil. The in vitro antimicrobial activity of the essential oil of M. mozaffarianii was studied against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Candida albicans. The results of the bioassays showed that the oil exhibited high antimicrobial activity against all the tested pathogens. PMID- 28658992 TI - Biophysics: for HTS hit validation, chemical lead optimization, and beyond. AB - INTRODUCTION: There are many challenges to the drug discovery process, including the complexity of the target, its interactions, and how these factors play a role in causing the disease. Traditionally, biophysics has been used for hit validation and chemical lead optimization. With its increased throughput and sensitivity, biophysics is now being applied earlier in this process to empower target characterization and hit finding. Areas covered: In this article, the authors provide an overview of how biophysics can be utilized to assess the quality of the reagents used in screening assays, to validate potential tool compounds, to test the integrity of screening assays, and to create follow-up strategies for compound characterization. They also briefly discuss the utilization of different biophysical methods in hit validation to help avoid the resource consuming pitfalls caused by the lack of hit overlap between biophysical methods. Expert opinion: The use of biophysics early on in the drug discovery process has proven crucial to identifying and characterizing targets of complex nature. It also has enabled the identification and classification of small molecules which interact in an allosteric or covalent manner with the target. By applying biophysics in this manner and at the early stages of this process, the chances of finding chemical leads with novel mechanisms of action are increased. In the future, focused screens with biophysics as a primary readout will become increasingly common. PMID- 28658993 TI - Influence of Val16Ala-SOD2 polymorphism on sperm quality parameters. AB - The purpose of this study was to investigate the association between the Val16Ala superoxide dismutase manganese-dependent (SOD2) single nucleotide polymorphism (SNP) and sperm reproductive parameters in a sample of Brazilian men. A potential association between this polymorphism and some oxidative biochemical parameters as well as sperm plasma cell-free DNA (cfDNA) levels were also evaluated. The study was performed using semen samples obtained from male patients that had undergone semen analysis according to the 2010 World Health Organisation (WHO) recommendations and the Val16Ala-SOD2 SNP was genotyped by polymerase chain reaction (PCR). Oxidative parameters as well as cfDNA levels were spectrophotometrically and fluorimetrically determined. Statistical analysis included chi-square test, analysis of variance followed by Bonferroni post hoc test, as well as logistic regression multivariate analysis. Semen samples from 169 men (35.89 +/- 7.33 years) were genotyped. The allelic frequencies were V= 0.485 (n = 97), A = 0.515 (n = 103), with statistically similar allelic frequencies to those of samples obtained from a general population: V = 0.509; A= 0.591. In general, AV samples presented lower numbers of sperm-altered parameters than homozygous sperm. Lipoperoxidation was higher in homozygous than heterozygous sperm samples. The results suggest that genetically caused S-HP imbalance could contribute to poor sperm quality and affect male fertility. PMID- 28658994 TI - Socioeconomic disadvantage and schizophrenia in migrants under mental health detention orders. AB - BACKGROUND: Migrants with mental hospital orders according to section 63 of the German criminal code are overrepresented in relation to their numbers in the general population. Subgroups originating from certain world regions are diagnosed with schizophrenia at a much higher rate than others. In the present literature, there is a strong evidence for a substantial correlation between migration, social disadvantage and the prevalence of schizophrenia. AIMS: This study investigates the relationship between countries of origin, the risk of becoming a forensic patient and the proportion of schizophrenia spectrum disorders. METHOD: Data from a comprehensive evaluation tool of forensic inpatients in the German federal state of Baden-Wurttemberg (FoDoBa) were compared with population statistics and correlated with the Human Development Index (HDI) and Multidimensional Poverty Index (MPI). RESULTS: For residents with migration background, the risk ratio to receive a mental hospital order is 1.3 in comparison to non-migrants. There was a highly significant correlation between the HDI of the country of origin and the risk ratio for detention in a forensic psychiatric hospital. The proportion of schizophrenia diagnoses also correlated significantly with the HDI. In contrast, the MPI country rankings were not associated with schizophrenia diagnoses. CONCLUSION: Two lines of explanations are discussed: first, higher prevalence of schizophrenia in migrants originating from low-income countries, and second, a specific bias in court rulings with regard to involuntary forensic treatment orders for these migrant groups. PMID- 28658995 TI - Lay beliefs about the causes and cures of schizophrenia. AB - BACKGROUND: Lay beliefs about schizophrenia are an important factor associated with treatment-seeking behavior. AIMS: This study was conducted to investigate the lay beliefs about the causes and treatments of schizophrenia in South Korea. METHODS: A total of 654 adults (mean age, 35.96 +/- 11.33 years) completed two questionnaires assessing their views on the causes and cures of schizophrenia. The factor structures of lay beliefs about the causes and treatments of schizophrenia were then analyzed and the correlations between the resultant factors investigated. RESULTS: From the cause items, four factors were extracted: Health/Lifestyle, God/Fate, Social/Environmental and Biological. Four factors were also extracted from the treatment items: Self-Help/Stress Management, Physical Treatment/Health Management, Religious Help and Mental Health Service Utilization. Notably, most participants believed that items in the Social/Environmental and Biological factors were the causes of schizophrenia, while they believed that items in the Mental Health Service Utilization and Self Help/Stress Management factors were the treatments. Participants' beliefs about the causes and treatments of schizophrenia were systematically correlated. CONCLUSION: Overall, laypeople have reasonably accurate beliefs and a multidimensional view of the causes and treatments of schizophrenia. Nevertheless, our results suggest that public education about the etiology and treatment of schizophrenia are necessary to increase actual usage of mental health services and treatments for schizophrenia. PMID- 28658996 TI - T.R.U.S.T. Model for Inclusive Spiritual Care: Critique of Middle-Range Theory. AB - Spiritual care has been recognized as an integral component to holistic health care promotion. Several middle-range theories in the recent years have been developed in an attempt to promote spiritual care in nursing practice and to guide research in spiritual nursing. However, there is still reluctance from nurses in addressing spiritual care needs for their patients. Fear of intrusion and a lack of technical know-how are among the reasons for this dilemma. The development of the T.R.U.S.T. Model for Inclusive Spiritual Care is to provide caregivers with a relevant, nonintrusive mode of care in their approach to spiritual nursing practice. The T.R.U.S.T. model provides guidelines to help address and accommodate different spiritual worldviews with the aim of promoting optimum healing. The following article is a critique of the T.R.U.S.T. Model for Inclusive Spiritual Care using Fawcett's criteria for evaluation. PMID- 28658997 TI - Evaluation of the potential of kartogenin encapsulated poly(L-lactic acid-co caprolactone)/collagen nanofibers for tracheal cartilage regeneration. AB - Tracheal stenosis is one of major challenging issues in clinical medicine because of the poor intrinsic ability of tracheal cartilage for repair. Tissue engineering provides an alternative method for the treatment of tracheal defects by generating replacement tracheal structures. In this study, we fabricated coaxial electrospun fibers using poly(L-lactic acid-co-caprolactone) and collagen solution as shell fluid and kartogenin solution as core fluid. Scanning electron microscope and transmission electron microscope images demonstrated that nanofibers had uniform and smooth structure. The kartogenin released from the scaffolds in a sustained and stable manner for about 2 months. The bioactivity of released kartogenin was evaluated by its effect on maintain the synthesis of type II collagen and glycosaminoglycans by chondrocytes. The proliferation and morphology analyses of mesenchymal stems cells derived from bone marrow of rabbits indicated the good biocompatibility of the fabricated nanofibrous scaffold. Meanwhile, the chondrogenic differentiation of bone marrow mesenchymal stem cells cultured on core-shell nanofibrous scaffold was evaluated by real-time polymerase chain reaction. The results suggested that the core-shell nanofibrous scaffold with kartogenin could promote the chondrogenic differentiation ability of bone marrow mesenchymal stem cells. Overall, the core-shell nanofibrous scaffold could be an effective delivery system for kartogenin and served as a promising tissue engineered scaffold for tracheal cartilage regeneration. PMID- 28658998 TI - Patient-reported outcomes in topical field treatment of actinic keratosis in Swedish and Danish patients. AB - Topical treatments in dermatology can be long, complex and lead to nonadherence and nonpersistence to prescribed treatment. Clinical efficacy observed in randomized clinical trials (RCT) may therefore be reduced in real-world clinical practice. The objective of this study was to analyze patient-reported treatment adherence, treatment satisfaction and health-related quality of life (HRQoL) with topical treatments of actinic keratosis (AK) in routine clinical practice in Denmark and Sweden. Adult patients prescribed field-directed topical AK treatments with diclofenac gel, imiquimod or ingenol mebutate per routine clinical practice were eligible for the observational RAPID-ACT study. Data were collected through physician and patient questionnaires that included validated instruments to measure treatment satisfaction (TSQM-9), treatment adherence (MMAS) and HRQoL (EQ-5D-5L, EQ-VAS, AKQoL). In total, 446 patients from Denmark and Sweden were included. Ingenol mebutate patients reported a higher satisfaction with treatment effectiveness compared to patients treated with diclofenac (p = .006) while no other differences in treatment satisfaction could be determined. Treatment adherence was generally high, but higher for ingenol mebutate compared to both diclofenac (p < .001) and imiquimod (p = .007), possibly due to shorter treatment duration. No differences in improved HRQoL were found. More research is needed about the link between treatment adherence and real-world effectiveness. PMID- 28658999 TI - Predictive Validity of the HKT-R Risk Assessment Tool: Two and 5-Year Violent Recidivism in a Nationwide Sample of Dutch Forensic Psychiatric Patients. AB - This study has examined the predictive validity of the Historical Clinical Future [ Historisch Klinisch Toekomst] Revised risk assessment scheme in a cohort of 347 forensic psychiatric patients, which were discharged between 2004 and 2008 from any of 12 highly secure forensic centers in the Netherlands. Predictive validity was measured 2 and 5 years after release. Official reconviction data obtained from the Dutch Ministry of Security and Justice were used as outcome measures. Violent reoffending within 2 and 5 years after discharge was assessed. With regard to violent reoffending, results indicated that the predictive validity of the Historical domain was modest for 2 (area under the curve [AUC] = .75) and 5 (AUC = .74) years. The predictive validity of the Clinical domain was marginal for 2 (admission: AUC = .62; discharge: AUC = .63) and 5 (admission: AUC = .69; discharge: AUC = .62) years after release. The predictive validity of the Future domain was modest (AUC = .71) for 2 years and low for 5 (AUC = .58) years. The total score of the instrument was modest for 2 years (AUC = .78) and marginal for 5 (AUC = .68) years. Finally, the Final Risk Judgment was modest for 2 years (AUC = .78) and marginal for 5 (AUC = .63) years time at risk. It is concluded that this risk assessment instrument appears to be a satisfactory instrument for risk assessment. PMID- 28659000 TI - Recurrent neural network-based modeling of gene regulatory network using elephant swarm water search algorithm. AB - Correct inference of genetic regulations inside a cell from the biological database like time series microarray data is one of the greatest challenges in post genomic era for biologists and researchers. Recurrent Neural Network (RNN) is one of the most popular and simple approach to model the dynamics as well as to infer correct dependencies among genes. Inspired by the behavior of social elephants, we propose a new metaheuristic namely Elephant Swarm Water Search Algorithm (ESWSA) to infer Gene Regulatory Network (GRN). This algorithm is mainly based on the water search strategy of intelligent and social elephants during drought, utilizing the different types of communication techniques. Initially, the algorithm is tested against benchmark small and medium scale artificial genetic networks without and with presence of different noise levels and the efficiency was observed in term of parametric error, minimum fitness value, execution time, accuracy of prediction of true regulation, etc. Next, the proposed algorithm is tested against the real time gene expression data of Escherichia Coli SOS Network and results were also compared with others state of the art optimization methods. The experimental results suggest that ESWSA is very efficient for GRN inference problem and performs better than other methods in many ways. PMID- 28659001 TI - Evaluation of the cytotoxic potential of a new pentacyclic triterpene from Rhododendron arboreum stem bark. AB - CONTEXT: Traditionally, Rhododendron arboreum Sm. (Ericaceae) is a very important medicinal plant having oxytocic, estrogenic, anti-inflammatory, analgesic and hepatoprotective activities; it also inhibits the prostaglandin synthetase. OBJECTIVES: This study determines the cytotoxic potential of 15-oxoursolic acid isolated from R. arboreum against selected human cancer cell lines. MATERIALS AND METHODS: Extraction from stem bark (5 kg) of R. arboreum was performed with methanol, which was successively partitioned into hexane, dichloromethane and ethyl acetate fractions, respectively. The new antitumor agent [15-oxoursolic acid (1)] was isolated from ethyl acetate fraction through column chromatography. Structure elucidation of new compound was performed through extensive spectroscopy i.e., IR, MS and 1D and 2D NMR. Cytotoxicity of isolated compound was determined at doses 5-100 MUM for a period of 72 h on specified human cancer cell lines [renal cell carcinoma (A498), non-small cell lung (NCI-H226), squamous cell carcinoma (H157) and human ovarian carcinoma (MDR-2780AD)]. RESULTS: Structure of isolated compound was characterized as 15-oxoursolic acid on the basis of various extensive spectroscopic techniques. 15-Oxoursolic acid revealed considerable anticancer activity with IC50 values of 2.3 +/- 0.1 MUM, 4.9 +/- 0.2 MUM, 9.2 +/- 0.2 MUM and 10.3 +/- 0.1 MUM against MDR 2780AD, Hep G2, H157 and NCI-H226, respectively, while in the case of A498, the activity was good (IC50 32.8 +/- 1.2 MUM). CONCLUSIONS: This study highlighted the potential of 15 oxoursolic acid to be further explored as a new lead compound for cancer chemotherapy. PMID- 28659002 TI - In vitro and in vivo antidiabetic potential of extracts and a furostanol saponin from Balanites aegyptiaca. AB - CONTEXT: Balanites aegyptiaca Del. (Zygophyllaceae) fruits are well-known antidiabetic drug in Egyptian folk medicine. Nevertheless, its mechanism of action is still unclear. OBJECTIVES: Searching for the possible mechanisms of action of the plant and identification of its bioactive compounds. MATERIALS AND METHODS: A bio-guided protocol based on the evaluation of alpha-glucosidase (AG) and aldose reductase (AR) inhibitory activities was adopted to isolate the biologically active compounds from the methanol extract (MeEx). An in vivo antidiabetic study was conducted for the active extract, fraction and compound using streptozotocin-induced diabetic male albino Wistar rats at two dose levels (100 and 200 mg/kg.b/wt) for 2 weeks. RESULTS: Three compounds were isolated and identified: a sterol, (1) stigmasterol-3-O-beta-d-glucopyranoside; a pregnane glucoside, (2) pregn-5-ene-3beta,16beta,20(R)-trio1-3-O-beta-d-glucopyranoside; a furostanol saponin, (3) 26-(O-beta-d-glucopyranosyl)-22-O-methylfurost-5-ene 3beta,26-diol-3-O-beta-d-glucopyranosyl-(1 -> 4)-[alpha-l-rhamnopyranosyl-(1 -> 2)]-beta-d-glucopyranoside. Only compound 3 possessed significant AG and AR inhibitory activities (IC50 = 3.12 +/- 0.17 and 1.04 +/- 0.02 MUg/mL, respectively), while compounds 1 and 2 were inactive. The in vivo antidiabetic study revealed that MeEx and furostanol saponin 3 possessed significant activities at a dose of 200 mg/kg through reducing the fasting plasma glucose level by 46.14% and 51.39%, respectively, as well as reducing the total cholesterol by 24.44% and 31.90%, respectively. Compound 3 also caused increment in insulin and C-peptide levels by 63.56% and 65%, respectively. DISCUSSION AND CONCLUSIONS: We presented a scientific base for using Balanites aegyptiaca, and shed the light on one of its saponins, as an antidiabetic agent in fasting and postprandial hyperglycaemia along with the improvement of diabetic complications. PMID- 28659003 TI - Secular trends in salt and soy sauce intake among Chinese adults, 1997-2011. AB - Salt and soy sauce are the main ways of sodium intake in Chinese dietary. In this study, we used the data of the China Health and Nutrition Surveys to describe the secular trends of salt and soy sauce intake among Chinese adults from 1997 to 2011. Trends were tested by multiple linear regression models. During the past 14 years, the consumption of sodium, salt and soy sauce intake values decreased significantly across the six study periods (p < .0001) among both men and women. Averaged salt values decreased by 4.9 g/d in men and 4.1 g/d in women. Mean soy sauce intake values decreased by 9.0 g/d among men and 7.3 g/d among women. Similar significant trends were observed in all age groups, activity levels and regions (p < .0001). PMID- 28659004 TI - Role of HIF-1alpha in response of tumors to a combination of hyperthermia and radiation in vivo. AB - PURPOSE: Mild temperature hyperthermia (MTH) increases blood flow and oxygenation in tumours. On the other hand, high-dose-per-fraction irradiation damages blood vessels, decreases blood flow and increases hypoxia in tumours. The radiation induced hypoxia in tumours activates hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes, such as vascular endothelial growth factor (VEGF), promoting revascularization and recurrence. In the present study, we examined the hypothesis that MTH inhibits radiation-induced upregulation of HIF-1alpha and its target genes by increasing tumour oxygenation. MATERIALS AND METHODS: FSaII fibrosarcoma tumours grown subcutaneously in the legs of C3H mice were used. Tumours were irradiated with 15 Gy using a 60Co irradiator or heated at 41 degrees C for 30 min using an Oncothermia heating unit. Blood perfusion and hypoxia in tumours were assessed with Hoechst 33342 and pimonidazole staining, respectively. Expression levels of HIF-1alpha and VEGF were determined using immunohistochemical techniques. Apoptosis of tumour cells was quantitated via TUNEL staining and the effects of treatments on tumour growth rate were assessed by measuring tumour diameters. RESULTS: Irradiation of FSaII tumours with a single dose of 15 Gy led to significantly decreased blood perfusion, increased hypoxia and upregulation of HIF-1alpha and VEGF. On the other hand, MTH at 41 degrees C for 30 min increased blood perfusion and tumour oxygenation, thereby suppressing radiation-induced HIF-1alpha and VEGF in tumours, leading to enhanced apoptosis of tumour cells and tumour growth delay. CONCLUSION: MTH enhances the anti-tumour effect of high-dose irradiation, at least partly by inhibiting radiation-induced upregulation of HIF-1alpha. PMID- 28659005 TI - Preinjury characteristics of children with mild traumatic brain injury: Is "other injury" an appropriate comparison group"? AB - BACKGROUND: Mild traumatic brain injury (mTBI) has been associated with ongoing problems in children and young people. However, there remains to be considerable debate regarding whether outcomes are a result of brain impairment, or simply reflect preinjury characteristics of the child or family. To reliably assess outcomes, an appropriate control group is required. AIMS: This study aimed to identify the preinjury characteristics of children with mTBI, and to examine whether an "other injury to the head" group is an appropriate comparison to control for preinjury characteristics of children with mTBI. METHOD: Parents of 290 children admitted to the emergency department with either a diagnosis of mTBI (n = 186, M = 6.44 years) or a superficial injury to the head (SIH) (n = 104, M = 5.40 years) were assessed. Parents completed three questionnaires examining behavioral problems (Clinical Assessment of Behavior), parental stress (Parenting Stress Index), and background variables (e.g., medical issues, socioeconomic factors). RESULTS: A series of chi-square analyses and multivariate analysis of variance tests revealed no differences for behavior, parental stress, and other preexisting problems between children with mTBI and those with SIH. CONCLUSIONS: Children who experience a mTBI event present similarly to individuals with a SIH, and SIH is an appropriate comparison group to examine the outcomes of childhood mTBI, as it may help minimize any confounding effects of preexisting issues associated with mTBI. PMID- 28659006 TI - Training hospital staff on spiritual care in palliative care influences patient reported outcomes: Results of a quasi-experimental study. AB - BACKGROUND: Spiritual care is reported to be important to palliative patients. There is an increasing need for education in spiritual care. AIM: To measure the effects of a specific spiritual care training on patients' reports of their perceived care and treatment. DESIGN: A pragmatic controlled trial conducted between February 2014 and March 2015. SETTING/PARTICIPANTS: The intervention was a specific spiritual care training implemented by healthcare chaplains to eight multidisciplinary teams in six hospitals on regular wards in which patients resided in both curative and palliative trajectories. In total, 85 patients were included based on the Dutch translation of the Supportive and Palliative Care Indicators Tool. Data were collected in the intervention and control wards pre- and post-training using questionnaires on physical symptoms, spiritual distress, involvement and attitudes (Spiritual Attitude and Involvement List) and on the perceived focus of healthcare professionals on patients' spiritual needs. RESULTS: All 85 patients had high scores on spiritual themes and involvement. Patients reported that attention to their spiritual needs was very important. We found a significant ( p = 0.008) effect on healthcare professionals' attention to patients' spiritual and existential needs and a significant ( p = 0.020) effect in favour of patients' sleep. No effect on the spiritual distress of patients or their proxies was found. CONCLUSION: The effects of spiritual care training can be measured using patient-reported outcomes and seemed to indicate a positive effect on the quality of care. Future research should focus on optimizing the spiritual care training to identify the most effective elements and developing strategies to ensure long-term positive effects. This study was registered at the Dutch Trial Register: NTR4559. PMID- 28659007 TI - Pancarditis: an unusual complication of a group B streptococcal infection. AB - Pancarditis is a rare condition with a poor prognosis combining endocarditis, myocarditis with abscess formation, and purulent pericarditis. Diagnosis is often delayed and the clinical signs are predominantly those of the embolic complications. Literature is scarce. We present a unique and rare case of pancarditis, complicating a Streptococcal B infection in an immunocompetent, healthy, 54 year-old woman. The evolution was favourable under medical therapy alone and thanks to multimodality cardiac imaging diagnosis and follow-up. PMID- 28659008 TI - Pain Mechanisms in Peritoneal Diseases Might Be Partially Regulated by Estrogen. AB - To identify factors influencing the differential pain pathogenesis in peritoneal endometriosis (pEM) and peritoneal carcinomatosis in ovarian cancer (pOC), we undertook an experimental study. Tissue samples of 18 patients with pEM, 15 patients with pOC, and 15 unaffected peritoneums as controls were collected during laparoscopy or laparotomy. Immunohistochemical stainings were conducted to identify nerve fibers and neurotrophins in the tissue samples. Additionally, 23 pEM fluids, 25 pOC ascites fluids, and 20 peritoneal fluids of patients with myoma uteri as controls were collected. In these fluids, the expression of neurotrophins was evaluated. The effects of peritoneal fluids and ascites on the neurite outgrowth of chicken sensory ganglia were estimated by using a neuronal growth assay. An electrochemiluminescence immunoassay was carried out to determine the expression of estrogen in the peritoneal fluids and ascites. The total and sensory nerve fiber density was significantly higher in pEM than in pOC ( P < .001 and P < .01). All neurotrophins tested were present in tissue and fluid samples of pEM and pOC. Furthermore, the neurotrophic properties of pEM and pOC fluids were demonstrated, leading to sensory nerve fiber outgrowth. Estrogen concentration in the peritoneal fluids of pEM was significantly higher compared to ascites of pOC ( P < .001). The total and sensory nerve fiber density in the tissue samples as well as the estrogen expression in the peritoneal fluid of pEM was considerably higher than that in pOC, representing the most notable difference found in both diseases. This might explain the differential pain perception in pEM and pOC. Therefore, estrogen might be a key factor in influencing the genesis of pain in endometriosis. PMID- 28659009 TI - Upregulation of Interleukin 35 in Patients With Endometriosis Stimulates Cell Proliferation. AB - In this study, we investigated the expression of interleukin 35 (IL-35) and its receptors in endometriosis, analyzed the function of IL-35 in primary culture model of endometrial stromal cells (ESCs), and evaluated their clinicapathological significance. Peripheral blood (PB) and peritoneal fluid (PF) were collected from 37 women with endometriosis and 24 control women. The ectopic endometrium was obtained from patients with endometriosis undergoing laparoscopic surgery. The eutopic and normal endometrium were collected by endometrial biopsy. Levels of IL-35 in PB and PF were evaluated by enzyme-linked immunosorbent assay. Women with endometriosis had higher levels of IL-35 compared to controls both in PB and in PF. Levels of n IL-35 were increased in patients with advanced stage endometriosis compared to those with early stages in PF. A significant upregulation of IL-35 was observed in patients with ovarian endometriosis accompanied with pelvic implants (PI) compared to those without PI in PB and PF. The relative messenger RNA and protein expression of EBi3 and p35, the subunits of IL-35, were significantly higher in ectopic endometrium than in eutopic and healthy endometrium as measured by immunohistochemistry and quantitative polymerase chain reaction. The ESCs from endometriosis displayed a remarkable overexpression of IL-35 receptor subunits, IL12Rbeta2 and gp130, compared to those from controls . Moreover, recombined human IL-35 protein stimulated the upregulation of IL12Rbeta2 and gp130 and facilitated proliferation of ESCs. Our study provides the first evidence that IL-35 was involved in the pathogenesis of endometriosis through suppressing immunoreaction and promoting proliferation of ESCs. IL-35 may potentially serve as a biomarker for endometriosis. PMID- 28659010 TI - Copper Deficiency Myelopathy After Upper Gastrointestinal Surgery. AB - A well-functioning alimentary canal is required for adequate nutrient absorption. Disruption to the upper gastrointestinal tract through surgery can lead to micronutrient malnourishment. Copper deficiency has been noted in up to 10% of those undergoing Roux-en-Y gastric bypass surgery, but sequalae are not frequently reported. The resultant deficiency states can have profound and long term consequences if not realized early and managed appropriately. Here we present a case of copper deficiency myelopathy, a condition indistinguishable from subacute combined degeneration of the spinal cord, following upper gastrointestinal bypass surgery for gastric ulceration, further complicated by inadequate nutrition. PMID- 28659011 TI - Using social exchange theory to understand non-terminal palliative care referral practices for Parkinson's disease patients. AB - BACKGROUND: A palliative approach is recommended in the care of Parkinson's disease patients; however, many patients only receive this care in the form of hospice at the end of life. Physician attitudes about palliative care have been shown to influence referrals for patients with chronic disease, and negative physician perceptions may affect early palliative referrals for Parkinson's disease patients. AIM: To use Social Exchange Theory to examine the association between neurologist-perceived costs and benefits of palliative care referral for Parkinson's disease patients and their reported referral practices. DESIGN: A cross-sectional survey study of neurologists. SETTING/PARTICIPANTS: A total of 62 neurologists recruited from the National Parkinson Foundation, the Medical Association of Georgia, and the American Academy of Neurology's clinician database. RESULTS: Participants reported significantly stronger endorsement of the rewards ( M = 3.34, SD = 0.37) of palliative care referrals than the costs ( M = 2.13, SD = 0.30; t(61) = -16.10, p < 0.0001). A Poisson regression found that perceived costs, perceived rewards, physician type, and the number of complementary clinicians in practice were significant predictors of palliative care referral. CONCLUSION: Physicians may be more likely to refer patients to non terminal palliative care if (1) they work in interdisciplinary settings and/or (2) previous personal or patient experience with palliative care was positive. They may be less likely to refer if (1) they fear a loss of autonomy in patient care, (2) they are unaware of available programs, and/or (3) they believe they address palliative needs. Initiatives to educate neurologists on the benefits and availability of non-terminal palliative services could improve patient access to this care. PMID- 28659012 TI - Natural radionuclides in electronic waste: an initial approach. AB - Some radionuclides are present in trace amount in the raw material of electronic devices that suffer obsolescence and are improperly disposed of. Obsolete personal computers become electronic waste and may contain potential environmental contaminants. Furthermore, there may be an additional concern: the ionizing radiation emission. This study aimed to assess qualitatively the possibility of alpha and beta particles and gamma rays reaching somehow workers involved in the handling of such wastes. Using gamma spectrometry method, we analyzed a set of 10 microprocessors randomly taken from motherboards incorrectly discarded. The analysis resulted in the occurrence of primordial radioisotopes in the microchips. PMID- 28659013 TI - 'There's a Catch-22' - The complexities of pain management for people with advanced dementia nearing the end of life: A qualitative exploration of physicians' perspectives. AB - BACKGROUND: Pain management is a cornerstone of palliative care. The clinical issues encountered by physicians when managing pain in patients dying with advanced dementia, and how these may impact on prescribing and treatment, are unknown. AIM: To explore physicians' experiences of pain management for patients nearing the end of life, the impact of these on prescribing and treatment approaches, and the methods employed to overcome these challenges. DESIGN: Qualitative, semi-structured interview study exploring barriers to and facilitators of pain management, prescribing and treatment decisions, and training needs. Thematic analysis was used to elicit key themes. SETTING/PARTICIPANTS: A total of 23 physicians, responsible for treating patients with advanced dementia approaching the end of life, were recruited from primary care ( n = 9), psychiatry ( n = 7) and hospice care ( n = 7). RESULTS: Six themes emerged: diagnosing pain, complex prescribing and treatment approaches, side effects and adverse events, route of administration, importance of sharing knowledge and training needs. Knowledge exchange was often practised through liaison with physicians from other specialities. Cross-speciality mentoring and the creation of knowledge networks were believed to improve pain management in this patient population. CONCLUSION: Pain management in end-stage dementia is complex, requiring cross-population of knowledge between palliative care specialists and non-specialists, in addition to collateral information provided by other health professionals and patients' families. Regular, cost- and time effective mentoring and ongoing professional development are perceived to be essential in empowering physicians to meet clinical challenges in this area. PMID- 28659014 TI - Optimizing Nutrition in Pediatric Heart Failure: The Crisis Is Over and Now It's Time to Feed. AB - Pediatric heart failure is a complex disease occurring when cardiac output is unable to meet the metabolic demands of the body. With improved surgical interventions and medical therapies, survival rates have improved, and care has shifted from focusing on survival to optimizing quality of life and health outcomes. Based on current literature, this review addresses the nutrition needs of infants and children in heart failure and describes the pathophysiology and metabolic implications of this disease. The prevalence of wasting in pediatric heart failure has been reported to be as high as 86%, highlighting the importance of nutrition assessment through all stages of treatment to provide appropriate intake of energy, protein, and micronutrients. The etiology of malnutrition in pediatric heart failure is multifactorial and involves hypermetabolism, decreased intake, increased nutrient losses, inefficient utilization of nutrients, and malabsorption. Children in heart failure often present with tachypnea, tachycardia, fatigue, nausea, and vomiting and consequently may not be able to meet their nutrition requirements through oral intake alone. Nutrition support, including enteral nutrition and parenteral nutrition, should be considered an essential part of routine care. The involvement of multiple allied health professionals may be needed to create a feeding therapy plan to support patients and their families. With appropriate nutrition interventions, clinical outcomes and quality of life can be significantly improved. PMID- 28659015 TI - Advanced treatment of sodium dithionite wastewater using the combination of coagulation, catalytic ozonation, and SBR. AB - A combined process of coagulation-catalytic ozonation-anaerobic sequencing batch reactor (ASBR)-SBR was developed at lab scale for treating a real sodium dithionite wastewater with an initial chemical oxygen demand (COD) of 21,760 22,450 mg/L. Catalytic ozonation with the prepared cerium oxide (CeO2)/granular activated carbon catalyst significantly enhances wastewater biodegradability and reduces wastewater microtoxicity. The results show that, under the optimum conditions, the removal efficiencies of COD and suspended solids are averagely 99.3% and 95.6%, respectively, and the quality of final effluent can meet the national discharge standard of China. The coagulation and ASBR processes remove a considerable proportion of organic matter, while the SBR plays an important role in post-polish of final effluent. The ecotoxicity of the wastewater is greatly reduced after undergoing the hybrid treatment. This work demonstrates that the hybrid system has the potential to be applied for the advanced treatment of high strength industrial wastewater. PMID- 28659016 TI - Calcipotriene betamethasone dipropionate aerosol foam in the treatment of plaque psoriasis: a review of the literature. AB - Psoriasis is a common chronic immune-mediated skin disease which has a significant impact on patients' quality of life, and is associated with numerous comorbidities (i.e., psoriatic arthritis, Crohn's disease and cardiovascular disease). A greater understanding of its immunopathogenesis has guided the development of novel, more targeted therapies. Nonetheless, traditional treatment with topical agents, phototherapy and systemic medications is used in the management of the majority of psoriasis patients. Mainstay topical treatments include corticosteroids and vitamin D derivatives. Calcipotriene/betamethasone dipropionate aerosol foam is a novel single product combination, which seeks to provide superior therapeutic efficacy in addition to enhanced cosmetic properties. This article reviews the literature on the pharmacology and clinical data in terms of safety, efficacy and patient satisfaction of this topical medication. PMID- 28659017 TI - Effect of TiO2/GAC and water vapor on chloroform decomposition in a hybrid plasma catalytic system. AB - This paper presents the combination of TiO2/GAC catalyst and NTP for the decomposition of chloroform using a DBD reactor. The experiments were performed using an AC transformer as the power supply system to determine the optimal conditions of the chloroform conversion in the presence of a hydrogen-rich substance, that is, water vapor. TiO2/GAC enhanced the removal efficiency and also CO2 selectivity significantly, leading to an acceptable conversion rate at SIEs higher than 400 J L-1. The adsorption property of GAC was noticed to be an effective factor for catalytic activity by increasing the residence time, although the higher retention time prevented the accurate determination of chlorine and carbon balance. Selectivity toward HCl was improved considerably from 24.3% to 64.3% over catalyst when water was fed as a hydrogen-rich compound. At the same time, the harmful chlorinated by-products such as TCBA and TCE declined significantly. A noticeable enhancement in the selectivity toward CO2 was observed when both catalyst and water were introduced, regardless of the inlet concentration. Our findings suggest that the hybrid of NTP with TiO2/GAC will highly be effective in the abatement of chloroform, and the addition of H2O will successfully decline harmful chlorinated by-products. PMID- 28659018 TI - Polycyclic aromatic hydrocarbons in milk powders marketed in Uruguay. AB - Polycyclic aromatic hydrocarbons (PAHs) occurrence in forty-four samples of milk powder, marketed in Uruguay, was determined. A high-performance liquid chromatography (HPLC) method was applied with fluorescence detector (FLD) and UV VIS diodes array detector (DAD). Milk powder was fortified with PAHs at three levels producing average recovery higher than 78.6% for all levels. The highest concentration of benzo(a)pyrene (BaP) was 2.85 MUg kg-1 in milk powder. Contamination of samples expressed as the sum of 16 analysed PAHs varied between 5.77 and 427.28 MUg kg-1 and as PAH4 (BaP, chrysene, benzo(a)anthracene and benzo(b)fluoranthene) was between below LOD and 11.54 MUg kg-1. Only one sample exceeded the maximum limit for BaP, but 84% of the commercial milk powders did not comply with the European Union maximum limit for PAH4. PMID- 28659020 TI - Advanced analytic and statistical methods in health psychology. PMID- 28659019 TI - Does Early-Life Misfortune Increase the Likelihood of Psychotropic Medication Use in Later Life? AB - Life-course research has linked childhood experiences to adult mental illness, but most studies focus on anxiety or depressive symptoms, which may be transient. Therefore, this study investigates whether childhood misfortune is associated with taking psychotropic medication, a measure reflecting an underlying chronic mental disorder. Data are from three waves of a national survey of 2,999 U.S. men and women aged 25-74 years. Four domains of childhood misfortune (childhood socioeconomic status, family structure, child maltreatment, and poor health) are considered-specified as separate domains and a single additive measure-as key predictors of psychotropic medication use. Findings reveal an association between additive childhood misfortune and adult psychotropic medication use, net of adult risk factors. Psychotropic medication use is also more likely during the 20-year study for adults who experienced maltreatment and poor health during childhood. These results reveal the importance of early intervention to reduce consumption of psychotropic medications and associated costs. PMID- 28659021 TI - Parental experiences with a paediatric palliative care team: A qualitative study. AB - BACKGROUND: Parents of children with a life-limiting disease have to rely on themselves at home while adequate paediatric palliative care is lacking. In several countries, paediatric palliative care teams are introduced to ensure continuity and quality of care and to support the child and the family. Yet, little is known about how parents experience such multidisciplinary teams. AIM: To obtain insight into the support provided by a new paediatric palliative care team from the parents' perspective. DESIGN: An interpretative qualitative interview study using thematic analysis was performed. SETTING/PARTICIPANTS: A total of 47 single or repeated interviews were undertaken with 42 parents of 24 children supported by a multidisciplinary paediatric palliative care team located at a university children's hospital. The children suffered from malignant or non malignant diseases. RESULTS: In advance, parents had limited expectations of the paediatric palliative care team. Some had difficulty accepting the need for palliative care for their child. Once parents experienced what the team achieved for their child and family, they valued the team's involvement. Valuable elements were as follows: (1) process-related aspects such as continuity, coordination of care, and providing one reliable point of contact; (2) practical support; and (3) the team members' sensitive and reliable attitude. As a point of improvement, parents suggested more concrete clarification upfront of the content of the team's support. CONCLUSION: Parents feel supported by the paediatric palliative care team. The three elements valued by parents probably form the structure that underlies quality of paediatric palliative care. New teams should cover these three valuable elements. PMID- 28659022 TI - How continuity of care is experienced within the context of integrated palliative care: A qualitative study with patients and family caregivers in five European countries. AB - BACKGROUND: Patients with advanced diseases often experience deficient continuity of care. Although integrated palliative care promotes continuity of care, it is not clear how it can be optimized to improve continuity of care experiences. AIM: To examine how relational, informational and management continuity of care are experienced by patients with advanced diseases and their family caregivers receiving care from several integrated palliative care initiatives in five European countries. DESIGN: We adopted a longitudinal qualitative study design including two interviews (interval 3 months) with patients and family caregivers focusing on how health care professionals responded to their needs. Interviews were audio-recorded and transcribed verbatim. Analysis involved a two-step qualitative content approach. SETTING/PARTICIPANTS: A total of 22 integrated palliative care initiatives (established local palliative care collaborations) were selected in Belgium, Germany, Hungary, the Netherlands and the United Kingdom. We recruited 152 patients (63% cancer, 24% chronic obstructive pulmonary disease, 13% heart failure; life expectancy <1 year; mean age 68 years, 56% female) and 92 family caregivers (mean age 61 years, 66% female). RESULTS: Trusted relationships with a small number of key health care professionals to receive tailored care and easily access help were essential. Relational continuity was often deficient, especially with general practitioners. Although informational and management continuity was often lacking in care provision, collaborative integrated palliative care initiatives were related to consistent and coherent care. CONCLUSION: Patients and family caregivers most likely experience continuity of care by having a small number of trusted health care professionals who are available, provide multidisciplinary care and regularly transfer information to all health care professionals involved. Optimizing continuity of care requires further integration of integrated palliative care initiatives with other health care professionals involved in the patients' care networks. PMID- 28659023 TI - 'Powerlessness' or 'doing the right thing' - Moral distress among nursing home staff caring for residents at the end of life: An interpretive descriptive study. AB - BACKGROUND: Caring for dying people can contribute to moral distress experienced by healthcare professionals. Moral distress can occur when this caring is restricted by organisational processes, resources or the provision of futile care. These factors apply to end of life care in nursing homes but research is lacking. AIM: To describe how nursing home staff experience moral distress when caring for residents during and at the end of life. METHODS: An interpretive descriptive design, using the critical incident technique in semi-structured interviews to collect data from nursing home staff. Data were analysed using a thematic analysis approach. SETTING: Four nursing homes in one large metropolitan area. PARTICIPANTS: A total of 16 staff: 2 nurse managers, 4 nurses and 10 care assistants. FINDINGS: Participants described holding 'good dying' values which influenced their practice. The four practice-orientated themes of advocating, caring, communicating and relating with residents were found to influence interactions with residents, relatives, general practitioners, and colleagues. These led staff to be able to 'do the right thing' or to experience 'powerlessness', which could in turn lead to staff perceiving a 'bad death' for residents. CONCLUSION: When there are incongruent values concerning care between staff and others involved in the care of residents, staff feel powerless to 'do the right thing' and unable to influence care decisions in order to avoid a 'bad death'. This powerlessness is the nature of their moral distress. PMID- 28659024 TI - Moderate alcohol use and apolipoprotein E-4 (ApoE-4): Independent effects on cognitive outcomes in later life. AB - OBJECTIVES: Substantive past research suggests that moderate alcohol use confers beneficial health outcomes. The study of moderate alcohol use and cognition has produced variable findings. The primary goal was to examine the relationship between alcohol use and cognitive aging over time (Experiment 1), in a demographically representative, longitudinal survey of older adults. Experiment 2 examined the hypothesis that apolipoprotein E-4 (ApoE-4) would moderate the relationship between moderate drinking and performance on cognitive domains. METHOD: The sample was drawn from the Aging, Demographics, and Memory Study (ADAMS) supplement of the Health and Retirement Study (HRS) and included 856 participants over age 65 in 2001. Follow-up data were from 2002, 2006, and 2008. Alcohol use was measured via self-report. Control variables included gender, age, race, number of years of education, medical burden (total number of medical diseases), and marital status. RESULTS: Results of Experiment 1 indicated that moderate alcohol use was significantly associated with better baseline functioning across cognitive measures (p <= .05), but had no significant effect on rate of change over time across cognitive domains. Results of Experiment 2 indicated that while ApoE-4 carriage did not moderate the relationship between alcohol use and cognitive performance, generally, both ApoE-4 and moderate alcohol use were significant predictors of cognitive performance. CONCLUSIONS: Overall, findings from this study support past findings that moderate alcohol use is associated with better cognitive functioning among community-dwelling older adults, and these relative benefits appear to persist throughout later life. However, the role of individual differences on manifestation of benefit remain very poorly understood. Future research should further examine the respective roles of demographic differences associated with cognitive aging, genetic moderators, and the influence of social interaction. PMID- 28659025 TI - Respite in dementia: An evolutionary concept analysis. AB - Aim There is a lack of conceptual clarity around 'respite' as it relates to people with dementia and their carers. This study provides clarification on the use and meaning of the term and considers the concept in relation to the dominant care paradigm in dementia, i.e. person-centred care. Methods Rodgers' (1989) evolutionary framework was employed. A systematic search was conducted on the Pubmed/MedLine, Embase, Cinahl, PsychInfo, Scopus, Web of Science and Cochrane databases (1980-2016, English) with fixed search terms relating to 'respite' and 'dementia'. Papers with primary qualitative data and literature reviews were included. This search was supplemented with snowballing techniques (back/forward searching, generic search engines). Data were analysed thematically, through an iterative process of constant comparison. Results Respite is understood both as a service that provides a physical break for the carer and as a psychological outcome, i.e. a mental break for the carer, which can be facilitated by formal services, under certain conditions. The conceptual model outlines how client factors (dyadic relations, recognising/accepting need, carer psychosocial issues, restorative occupation, and stigma) and service factors (model/characteristics, care quality, staff expertise, meaningful occupation for people with dementia and communication and support), interact to influence a respite outcome. The key antecedent for a positive respite experience is that the carer perceives that mutual benefit is garnered from service use. Conclusion The term respite can be interpreted as both a service and an outcome. However, it is clear that 'respite', as currently understood, acknowledges the relational experience of the carer only; it is, therefore, potentially damaging to the planning and delivery of person-centred dementia care. We suggest 'restorative care' as a potential alternative nomenclature to respite care, thereby highlighting the importance of providing mutual, personalised health and social care services that serve to enhance care relationships rather than diminish them. PMID- 28659026 TI - Colonization and infection with extended-spectrum beta-lactamase producing Enterobacteriaceae in patients with malignancy. AB - INTRODUCTION: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL PE) constitute a global threat and are prevalent in both nosocomial and community settings. These pathogens have been associated with delays in initiation of appropriate antimicrobial therapy and worse clinical outcomes. Patients with solid or hematologic malignancy represent a high-risk population for both colonization and infection with ESBL-PE. Areas covered: A description of the microbiology and epidemiology of the ESBL-PE is presented. Also, we explore studies on ESBL-PE colonization and infection, and examine areas where future research is needed. Expert commentary: ESBL-PE constitute an increasing threat to patients with malignancy. Unfortunately, substantial geographic variations as well as knowledge gaps in certain regions of the world limit our ability to reach conclusions that are valid globally. Furthermore, there is limited evidence regarding the optimal ways to prevent and manage infections caused by ESBL-PE. Research is urgently needed to elucidate these areas and allow the institution of appropriate infection control and antimicrobial stewardship policies and recommendations. PMID- 28659027 TI - Eclipta prostrata Improves DSS-Induced Colitis through Regulation of Inflammatory Response in Intestinal Epithelial Cells. AB - Eclipta prostrata (EP) and its compounds are known to have several pharmacological effects including anti-inflammatory effects. In the present study, we demonstrated that EP improves the dextran sulfate sodium (DSS)-induced colitis symptoms such as body weight loss, colon length shortening and disease activity index. In DSS-induced colitis tissue, EP controls the protein expressions of cyclooxygenase-2 (COX-2) and hypoxia inducible factor-1[Formula: see text] (HIF-1[Formula: see text]). In addition, the release of prostaglandin E2 and vascular endothelial growth factor-A were significantly reduced by EP administration. EP also inhibited COX-2 and HIF-1[Formula: see text] expressions in the tumor necrosis factor-[Formula: see text] stimulated HT-29 cells. These inhibitory effects of EP occurred by reducing the phosphorylation of I[Formula: see text]B and the translocation of the nuclear factor-[Formula: see text]B (NF [Formula: see text]B). Additionally, we found through HPLC analysis that wedelolactone, which is an inhibitor of NF-[Formula: see text]B transcription, was contained in water extract of EP. These results indicate that EP can improve colitis symptoms through the modulation of immune function in intestinal epithelial cells and suggests that EP has the potential therapeutic effect to intestinal inflammation. PMID- 28659028 TI - Efficacy and Mechanisms of Chinese Medicine on the Modulation of Myocardial Autophagy in Cardiovascular Disease. AB - Autophagy refers to the process in which the cellular lysosome degrades the cell's own damaged organelles and related macromolecule substances. It plays important roles in the homeostasis of organs, cell survival, and stable development. Previous studies indicate that the process of cardiopathology is closely associated with autophagy and some of Chinese medicines (active compounds and formulae) are found to have beneficial effects on injured cardiomyocytes via the modulation of autophagy. This review highlights the efficacy of the action of Chinese medicine on the regulation of myocardial autophagy and summarizes the related molecular and signal mechanisms. Our study discovers that some active compounds and formulae of Chinese medicines react on the specific targets of autophagy in related signal pathways to exert protective effects in the processes of ischemia and reperfusion, as well as, in other cardiopathological models. Parts of these compounds even have the characteristics of multiple targets in autophagic signal pathways and dual-directional regulated actions on autophagy, suggesting that Chinese medicines, which possess the ability to modulate autophagy, might improve effective cardio protection in the treatment of cardiovascular disease. PMID- 28659029 TI - The Mixture of Anemarrhena asphodeloides and Coptis chinensis Attenuates High-Fat Diet-Induced Colitis in Mice. AB - Anemarrhena asphodeloides (AA, family Liliaceae) inhibits macrophage activation by inhibiting IRAK1 phosphorylation and helper T (Th)17 differentiation. Coptis chinensis (CC, family Ranunculaceae), which inhibits macrophage activation by inhibiting the binding of lipopolysaccharide (LPS) on toll-like receptor 4 and inducing regulatory T (Treg) cell differentiation. The mixture of AA and CC (AC mix) synergistically attenuates 2,4,6-trinitrobenzenesulfonic acid or dextran sulfate sodium-induced colitis in mice by inhibiting NF-[Formula: see text]B activation and regulating Th17/Treg balance. In the present study, we examined the effect of AC-mix on high-fat diet (HFD)-induced colitis in mice, which induced NF-[Formula: see text]B activation and disturbed Th17/Treg balance. Long term feeding of HFD in mice caused colitis, including increased macroscopic score and myeloperoxidase activity. Oral administration of AC-mix (20[Formula: see text]mg/kg) suppressed HFD-induced myeloperoxidase activity by 68% ([Formula: see text]). Furthermore, treatment with the AC-mix (20[Formula: see text]mg/kg) inhibited HFD-induced activation of NF-[Formula: see text]B and expression of cyclooxygenase-2, inducible NO synthase, interleukin (IL)-17, and tumor necrosis factor-alpha but increased HFD- suppressed expression of IL-10. AC-mix suppressed HFD-induced differentiation into Th17 cells by 46% ([Formula: see text]) and increased HFD-induced differentiation into regulatory T cells 2.2-fold ([Formula: see text]). AC-mix also suppressed the HFD-induced Proteobacteria/Bacteroidetes ratio on the gut microbiota by 48% ([Formula: see text]). These findings suggest that AC-mix can ameliorate HFD-induced colitis by regulating innate and adaptive immunities and correcting the disturbance of gut microbiota. PMID- 28659030 TI - Tongxinluo Inhibits Renal Fibrosis in Diabetic Nephropathy: Involvement of the Suppression of Intercellular Transfer of TGF-[Formula: see text]1-Containing Exosomes from GECs to GMCs. AB - Glomerular mesangial cells (GMCs) activation is implicated in the pathogenesis of diabetic nephropathy (DN). Our previous study revealed that high glucose (HG) treated glomerular endothelial cells (GECs) produce an increased number of TGF [Formula: see text]1-containing exosomes to activate GMCs through the TGF [Formula: see text]1/Smad3 signaling pathway. We also identified that Tongxinluo (TXL), a traditional Chinese medicine, has beneficial effects on the treatment of DN in DN patients and type 2 diabetic mice. However, it remained elusive whether TXL could ameliorate renal structure and function through suppression of intercellular transfer of TGF-[Formula: see text]1-containing exosomes from GECs to GMCs. In this study, we demonstrate that TXL can inhibit the secretion of TGF [Formula: see text]1-containing exosomes from HG-treated GECs. Furthermore, exosomes produced by HG induced-GECs treated with TXL cannot trigger GMC activation, proliferation and extracellular matrix (ECM) overproduction both in vitro and in vivo. These results suggest that TXL can prevent the transfer of TGF [Formula: see text]1 from GECs to GMCs via exosomes, which may be one of the mechanisms of TXL in the treatment of DN. PMID- 28659031 TI - Gypenosides Ameliorate Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the Differentiation of Hepatic Progenitor Cells into Myofibroblasts. AB - Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl[Formula: see text] three times a week for two weeks. Then, CCl4 was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-[Formula: see text]1) with or without GPs for 48[Formula: see text]h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ([Formula: see text]-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). In the 5M CCl4 group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ([Formula: see text], [Formula: see text]). Immunostaining showed that the number of Sox9 and [Formula: see text]-SMA double-positive cells was higher in the 5M CCl4 group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of [Formula: see text]-SMA and Col I was significantly increased after treatment with TGF-[Formula: see text], whereas in the GPs treatment group, expression was markedly decreased ([Formula: see text]). The levels of TGF-[Formula: see text] and TGF-[Formula: see text]R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl4-induced liver fibrosis via the inhibition of TGF-[Formula: see text] signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts. PMID- 28659032 TI - Epimedin C Promotes Vascularization during BMP2-Induced Osteogenesis and Tumor Associated Angiogenesis. AB - Epimedin C is one of the chemical markers and major flavonoids in Herba Epimedii (Yinyanghuo), which is traditionally used to treat bone diseases and gonadal dysfunction in China. Our previous study indicated that epimedin C could induce endothelial-like, but not osteogenic differentiation of C3H/10T1/2 cells in vitro. As vasculogenesis plays a pivotal role in bone formation, this study used the bone morphogenetic protein 2 (BMP2) induced ectopic bone formation model and mice 4T1 breast cancer cells co-implanted with luciferase labeled C3H/10T1/2 cells (4T1 [Formula: see text] C3H/10T1/2-Luc) model to examine the in vivo effects of Epimedin C on vasculogenesis. As a result, Epimedin C significantly increased the bone weight and blood perfusion of mice in the BMP2 induced ectopic osteogenesis model, and the bone in Epimedin C [Formula: see text] BMP2 group was more mature than that in BMP2 group. In addition, the tumor weight, blood perfusion and tumor-associated angiogenesis were also significantly increased in the Epimedin C treated 4T1 tumor bearing mice. The mRNA levels of endothelial markers, such as the platelet endothelial adhesive factor-1(CD31), the endothelial cell specific molecule-1(ESM-1), and the vascular von Willebrand factor (vWF) in mouse 4T1 mammary tumor tissue, were commonly found to occur alongside the luciferase (labeled in C3H/10T1/2 cells) expression and significantly increased after Epimedin C treatment. Taken together, Epimedin C can effectively promote vascularization both in the BMP2-depended bone formation model and in the 4T1 mammary tumor-bearing model by inducing an endothelial-like differentiation of C3H/10T1/2 in BALB/c nude mice. PMID- 28659033 TI - Electro-Acupuncture is Beneficial for Knee Osteoarthritis: The Evidence from Meta Analysis of Randomized Controlled Trials. AB - Knee osteoarthritis (KOA) is a common chronic degenerative disease of the elderly. Electro-acupuncture (EA) is considered as a beneficial treatment for KOA, but the conclusion is controversial. This systematic review compiled the evidence from 11 randomized controlled trials to objectively assess the effectiveness and safety of EA for KOA. Eight databases including PubMed, Cochrane Library, Clinic trials, Foreign Medical Literature Retrial Service (FMRS), Science Direct, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang Data were extensively searched up to 5 July 2016. The outcomes included the evaluation of effectiveness, pain and physical function. Risk of bias was evaluated according to the Cochrane risk of bias tool. Eleven RCTs with 695 participants were included. Meta-analysis indicated that EA was more effective than pharmacological treatment (RR [Formula: see text] 1.14; 95% CI [Formula: see text] 1.01,1.28; [Formula: see text]) and manual acupuncture (RR [Formula: see text] 1.12; 95% CI [Formula: see text] 1.02,1.22; [Formula: see text]). Also, EA had a more significant effect in reducing the pain intensity (SMD [Formula: see text]; 95% CI [Formula: see text]; [Formula: see text]) and improving the physical function in the perspective of WOMAC (MD [Formula: see text]; 95% CI [Formula: see text], 5.56; [Formula: see text]) and LKSS (pharmacological treatment: MD [Formula: see text]; 95% CI [Formula: see text], 6.64; [Formula: see text]). Furthermore, these studies implied that EA should be performed for at least 4 weeks. Conclusively, the results indicate that EA is a great opportunity to remarkably alleviate the pain and improve the physical function of KOA patients with a low risk of adverse reaction. Therefore, more high quality RCTs with rigorous methods of design, measurement and evaluation are needed to confirm the long-term effects of EA for KOA. PMID- 28659034 TI - A Review on Annona squamosa L.: Phytochemicals and Biological Activities. AB - Annona squamosa L. (Annonaceae) is a fruit tree with a long history of traditional uses. A. squamosa is an evergreen plant mainly located in tropical and subtropical regions. Srikayas, the fruits of A. squamosa, are extensively used to prepare candies, ice creams and beverages. A wide range of ethno medicinal uses has been related to different portions of A. squamosa, such as tonic, apophlegmatisant, cool medicine, abortient and heart sedative. Numerous research projects on A. squamosa have found that it has anticancer, anti-oxidant, antidiabetic, antihypertensive, hepatoprotective, antiparasitic, antimalarial, insecticidal, microbicidel and molluscicidal activities. Phytochemistry investigations on A. squamosa have considered annonaceous acetogenins (ACGs), diterpenes (DITs), alkaloids (ALKs) and cyclopeptides (CPs) as the main constituents. Until 2016, 33 DITs, 19 ALKs, 88 ACGs and 13 CPs from this species were reported. On the basis of the multiple researches on A. squamosa, this review strives to integrate available information on its phytochemicals, folklore uses and bioactivities, hoping to promote a better understanding of its medicinal values. PMID- 28659036 TI - Cinnamomum cassia Prevents High-Fat Diet-Induced Obesity in Mice through the Increase of Muscle Energy. AB - The cortex of Cinnamomum cassia Presl (Cinnamomi Cortex: CC) has commonly been used for weight control in traditional medicines, but without a scientific basis. Therefore, this study was undertaken to investigate the anti-obesity effect of CC extract in a high-fat diet (HFD)-induced obese mouse model and in C2C12 mouse skeletal muscle cells. Male C57BL/6 mice were fed a normal diet or a HFD for 16 consecutive weeks, and orally administered CC extract (100 or 300[Formula: see text]mg/kg) or metformin (250[Formula: see text]mg/kg; positive control) daily for 16 weeks. CC extract administration significantly decreased body weights, food intakes, and serum levels of glucose, insulin, total cholesterol and ALT levels, prevented oral glucose tolerance and insulin resistance, inhibited the protein expressions of MyHC and PGC1[Formula: see text] and the phosphorylation of AMPK, suppressed lipid accumulation in liver, decreased adipocyte size and increased muscle mass in obese mice. For this in vitro study, C2C12 myoblasts were differentiated into the myotubes for five days, and then treated with CC extract (0.1 or 0.2[Formula: see text]mg/ml) for 24[Formula: see text]h. CC extract significantly increased ATP levels by increasing the mRNA expressions of mitochondrial biogenesis-related factors, such as, PGC1[Formula: see text], NRF 1, and Tfam, and the phosphorylations of AMPK and ACC. Our results suggest CC extract controls weight gain in obese mice by inhibiting lipid accumulation and increasing energy expenditure, and that its action mechanism involves the up regulation of mitochondrial biogenesis in skeletal muscle cells. PMID- 28659035 TI - Geraniin Promotes Recovery of Hematopoietic Cells after Radiation Injury. AB - Cells of the hematopoietic system are uniquely radiosensitive due to their rapid proliferation. Consequently, immune suppression readily and undesirably results from irradiation. Our previous studies demonstrated that geraniin isolated from Nymphaea tetragona var. angusta (water lily) had a protective effect on the splenocytes and intestinal tract of irradiated mice. This study was designed to assess the effectiveness of geraniin, an ellagitannin isolated from the water lily, in decreasing gamma ray irradiation-induced destruction of the hematopoietic system in mice. Geraniin treatment improved the survival time of bone marrow cells and maintained bone marrow integrity and also up-regulated the expression of stem cell receptors and the extent of cell mitosis. Geraniin also enhanced the proliferation and differentiation of immune cells that had been suppressed by irradiation. These results suggest geraniin is a promising agent for reconstituting hematopoietic cells after exposure to irradiation. PMID- 28659037 TI - Myrcene, an Aromatic Volatile Compound, Ameliorates Human Skin Extrinsic Aging via Regulation of MMPs Production. AB - Myrcene is an aromatic volatile compound that is commercially well-known as a flavor ingredient in the food industry and a fragrance in the soap and detergent industry. Given the worldwide interest in natural antiphotoaging products, we investigated the protective effects of myrcene in UVB-irradiated human dermal fibroblasts (NHDFs). NHDFs were subjected to 144[Formula: see text]mJ/cm2of UVB irradiation. The expression of intracellular reactive oxygen species (ROS), matrix metalloproteinase-1 (MMP-1), MMP-3, interleukin-6 (IL-6), transforming growth factor (TGF-[Formula: see text]1) and type I procollagen were examined. We showed that myrcene decreased the production of ROS, MMP-1, MMP-3, and IL-6, and increased TGF-[Formula: see text]1 and type I procollagen secretions. Furthermore, myrcene treatment (0.1-10[Formula: see text][Formula: see text]M) dramatically reduced the activation of MAPK-related signaling molecules such as p ERK, p-p38, and p-JNK and AP-1 including p-c-Jun and p-c-Fos. Our data indicate that myrcene has a potential protective effect on UVB-induced human skin photoaging. Therefore, myrcene might have applications in the skincare industry. PMID- 28659038 TI - A Randomized Controlled Trial of Medication and Cognitive-Behavioral Therapy for Hypochondriasis. AB - OBJECTIVE: Prior studies of hypochondriasis demonstrated benefits for pharmacotherapy and for cognitive-behavioral therapy (CBT). This study examined whether joint treatment offers additional benefit. METHOD: Patients with DSM-IV hypochondriasis (N=195) were randomly assigned to one of four treatments-placebo, CBT, fluoxetine, or joint treatment with both fluoxetine and CBT. Evaluations assessed hypochondriasis, other psychopathology, adverse events, functional status, and quality of life. The primary analysis assessed outcome at week 24 among the intent-to-treat sample, with responders defined as having a 25% or greater improvement over baseline on both the Whiteley Index and a modified version of the Yale-Brown Obsessive Compulsive Scale for hypochondriasis (H-YBOCS M). The Cochran-Armitage trend test assessed the hypothesized pattern of response: joint treatment > CBT or fluoxetine treatment > placebo treatment. RESULTS: The predicted pattern of response was statistically significant, as shown by the following responder rates: joint treatment group, 47.2%; single active treatment group, 41.8%; and placebo group, 29.6%. Responder rates for each active treatment were not significantly different from the rate for placebo. Secondary analyses of the Whiteley Index as a continuous measure revealed that, compared with placebo, fluoxetine (but not CBT) was significantly more effective at week 24 in reducing hypochondriasis and had a significantly faster rate of improvement over 24 weeks. Fluoxetine also resulted in significantly less anxiety and better quality of life than placebo. Dropout rates did not differ between groups, and treatment-emergent adverse events were evenly distributed. CONCLUSIONS: This study supports the safety, tolerance, and efficacy of fluoxetine for hypochondriasis. Joint treatment provided a small incremental benefit. Because approximately 50% of patients did not respond to the study treatments, new or more intensive approaches are needed. PMID- 28659039 TI - ADHD Medication and Substance-Related Problems. AB - OBJECTIVE: Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events. METHOD: The authors analyzed 2005-2014 commercial health care claims from 2,993,887 (47.2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not. RESULTS: In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64-0.67), and female patients had 31% lower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67-0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78-0.85), and female patients had 14% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95% CI= 0.82-0.91). Sensitivity analyses supported most findings but were less consistent for long term associations among women. CONCLUSIONS: These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events. PMID- 28659041 TI - Teaching End-of-Life Communication in Intensive Care Medicine: Review of the Existing Literature and Implications for Future Curricula. AB - OBJECTIVES: End-of-life (EOL) situations are common in the intensive care unit (ICU). Poor communication in respective situations may result in conflict and/or post-traumatic stress disorder in patients' next of kin. Thus, training for EOL communication seems pivotal. Primary objective of the current report was to identify approaches for educational programs in the ICU with regard to EOL communication as well as to conclude on implications for future curricula. MATERIALS AND METHODS: A literature review in MEDLINE, EMBASE, and PsychINFO was performed. A total of 3484 articles published between 2000 until 2016 were assessed for eligibility. Nine articles reporting on education in EOL communication in the ICU were identified and analyzed further. RESULTS: The duration of EOL workshops ranged from 3 hours to 3 days, with several different educational methods being applied. Mounting data suggest improved comfort, preparedness, and communication performance in EOL providers following specific EOL training. Due to missing data, the effect of EOL training programs on respective patients' next of kin remains unclear. CONCLUSION: Few scientific investigations focus on EOL communication in intensive care medicine. The available evidence points to increased comfort and EOL communication performance following specific individual EOL training. Given the general importance of EOL communication, we suggest implementation of educational EOL programs. When developing future educational programs, educators should consider previous experience of participants, clearly defined objectives based on institutional needs, and critical care society recommendations to ensure best benefit of all involved parties. PMID- 28659040 TI - Defining the Neural Substrate of the Adult Outcome of Childhood ADHD: A Multimodal Neuroimaging Study of Response Inhibition. AB - OBJECTIVE: Understanding the neural processes tied to the adult outcome of childhood attention deficit hyperactivity disorder (ADHD) could guide novel interventions to improve its clinical course. It has been argued that normalization of prefrontal cortical activity drives remission from ADHD, while anomalies in subcortical processes are "fixed," present even in remission. Using multimodal neuroimaging of inhibitory processes, the authors tested these hypotheses in adults followed since childhood, contrasting remitted against persistent ADHD. METHOD: Adult participants (persistent ADHD, N=35; remit-ted ADHD, N=47; never affected, N=99) were scanned with functional MRI (fMRI) (N=85), magnetoencephalography (N=33), or both (N=63) during a response inhibition task. RESULTS: In fMRI analyses, during inhibition, right caudate anomalies reflected a childhood ADHD history and were present even among those who remitted. By contrast, differences related to adult outcome emerged in cortical (right inferior frontal and inferior parietal/precuneus) and cerebellar regions. The persistent ADHD group showed under-activation, whereas the remitted ADHD group did not differ significantly from the never-affected group. Magnetoencephalography showed that the association between adult symptom severity and prefrontal neuronal activity was confined to the time window covering the act of inhibition (300 ms-350 ms). Group differences in cerebellar and parietal neuronal activity occurred during the time window of performance monitoring processes (500 ms-600 ms). CONCLUSIONS: By combining fMRI and magnetoencephalography, the location and time window of neuronal activity that underpins the adult outcome of ADHD was pinpointed. Thus, the cortico-cerebellar processes tied to the clinical course of ADHD are separated from the subcortical processes that are not. PMID- 28659043 TI - Three new oleanane-type triterpenoid saponins from the seeds of Celosia cristata L. AB - Phytochemical investigation of the 1-butanol soluble fraction of 60% ethanol extract of the seeds of Celosia cristata L. led to the identification of three new oleanane-type triterpenoid saponins. Using 1D and 2D NMR experiment methods, ESI-MS analysis and acid hydrolysis, their structures were identified as 3-O [beta-D-xylopyranosyl-(1 -> 3)-beta-D-glucuronopyranosyl]-2beta-hydroxy-oleanolic acid-28-O-beta-D-glucopyranoside (1), 3-O-[beta-D-xylopyranosyl-(1 -> 3)-beta-D glucuronopyranosyl]-2beta, 23-dihydroxy-oleanolic acid-28-O-beta-D glucopyranoside (2) and 3-O-[beta-D-glucopyranosyl-(1 -> 4)-beta-D glucopyranosyl]-2-hydroxyl-medicagenic acid-28-O-beta-D-glucopyranosyide (3), respectively. PMID- 28659044 TI - Practice patterns in longitudinal lupus care provision: patient and physician perspectives. AB - Background/purpose To plan a quality improvement project, we need to understand the practice patterns of physicians. We undertook an online survey of systemic lupus erythematosus (SLE) patients and physicians providing care to SLE patients to determine the patterns of medical care provided to SLE patients. Materials and methods Two self-report surveys were developed. A 12-item survey for the patients and a 13-item survey for physicians enquired about longitudinal care for SLE. Surveys were administered online to physicians providing care to SLE patients, and to patients who self-identified as having SLE, through the Lupus Society of Illinois. Patient and physician data were analyzed for physician practice patterns for SLE care, using chi square tests and t tests. A P value of 0.05 or less was considered significant on two-tailed tests. Results A total of 283 patients completed the survey. Mean (SD) age and disease duration of patients were 45.9 (13.2) and 12.7 (9.7) years. Half of the participants were being seen at 3-4-month intervals. More than 70% of patients reported being tested for antinuclear antibody (ANA), and 20-30% anti-ENA antibody and Sjogren's (SSA/SSB) antibodies, respectively, at each follow-up visit. Eighty-six rheumatologists completed the surveys. Mean (SD) age was 55 (12) years and 56% were men. More than half (54%) provided care only in a private practice setting. More than 80% of physicians reported seeing their SLE patients at 3-4-month interval. Only 2% reported performing ANA tests at each visit, while 4-5% performed anti-ENA and anti-SSA/SSB antibody tests at each visit for their SLE patients. More than 75% of physicians in private practice also ordered sedimentation rate at each visit for their SLE patients. Conclusions Unnecessary laboratory investigations may be being ordered routinely for patients at every visit. These results indicate a need for physician education on indications and utility of some of the laboratory tests such as ANA. PMID- 28659045 TI - Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies. AB - The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial ( n = 6) and venous ( n = 9) thrombosis (median follow-up period 69 months). Cox's proportional hazards model showed that older age at SLE onset and IgG anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01-0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis. PMID- 28659046 TI - Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men. AB - B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study was to investigate whether renal tubular epithelial cells (TEC) are an important source of BAFF and thus may contribute to the pathogenesis and progression of SLE. We found BAFF expression both in cultured murine and human TEC. These results could be verified with in situ data from the kidney. Moreover, BAFF expression in the kidneys of lupus-prone MRL- Faslpr mice correlated with disease activity, and BAFF expression on TEC in biopsies of patients with diffuse proliferative lupus nephritis showed a correlation with the histopathological activity index. In vitro functional assays revealed an autocrine loop of BAFF with its binding receptors on TEC, resulting in a strong induction of colony stimulating factor-1. Finally, we identified divergent effects of BAFF on TEC depending on the surrounding milieu ('inflammatory versus non-inflammatory'). Taken together, our findings indicate that renal-derived BAFF may play an important role in the pathophysiology of the systemic autoimmune disease SLE. PMID- 28659047 TI - Health status and concomitant prescription of immunosuppressants are risk factors for hydroxychloroquine non-adherence in systemic lupus patients with prolonged inactive disease. AB - Background/objective The objectives of this paper are to assess the extent of and the factors associated with hydroxychloroquine (HCQ) non-adherence in systemic lupus erythematosus (SLE) patients with prolonged inactive disease and to investigate relationships between blood HCQ concentration and quality of life (QoL). Methods Consecutive SLE patients, in remission for at least one year and taking a stable dose of HCQ were investigated. At study entry (T0) and six months later (T6) a blood venous sample was taken to measure whole blood concentration of [HCQ] and desethylchloroquine ([DCQ]). Moreover, at T0 each patient completed validated questionnaires assessing QoL, disability, anxiety, depression and visual analogue scales for fatigue, pain, general health (GH), and self assessment of disease activity. Results Eighty-three patients with a median [HCQ] of 327 ng/ml were enrolled. At T0, 24 (29%) were defined as non-adherent ([HCQ] < 100 ng/ml). At multiple logistic regression analysis the physical summary of SF 36 ( p = 0.038), and the concomitant use of immunosuppressants ( p = 0.010) were independently associated with non-adherence. A significant increase of HCQ adherence was observed at T6 ( p < 0.05). Conclusions A better health status and the concomitant prescription of immunosuppressants represent risk factors for HCQ non-adherence in SLE patients in remission. Monitoring HCQ levels might represent an important opportunity to improve adherence. PMID- 28659048 TI - Blocking the VISTA pathway enhances disease progression in (NZB * NZW) F1 female mice. AB - V-domain Ig suppressor of T-cell activation (VISTA) is a critical negative checkpoint molecule involved in regulating the immune response. Targeting the pathway with an antagonist anti-VISTA antibody designated 13F3 has been shown to enhance disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. To determine if VISTA plays a role in murine lupus, New Zealand Black * New Zealand White (BWF1) mice were treated with 13F3 or control hamster Ig and disease monitored. Onset of proteinuria was earlier and renal damage more profound in mice treated with 13F3. Cell subset analysis showed an increase of activated splenic T cells and inflammatory splenic myeloid cells, but no effect on B cells, in mice receiving 13F3. Examination of the kidney showed an increase in inflammatory myeloid cell infiltration with 13F3 treatment. This study along with previous EAE data, suggests that interventions that enhance VISTA regulatory activity may be effective for the treatment of autoimmune disease. PMID- 28659049 TI - Interferon alpha gene expression and serum level association with low vitamin D levels in Egyptian female patients with systemic lupus erythematosus. AB - Background Patients with systemic lupus erythematosus (SLE) are prone to develop vitamin D (25(OH) D3) deficiency, due to several factors and there is an association between lower vitamin D levels and higher SLE disease activity. The aim of this research was to assess the prevalence of vitamin D deficiency in Egyptian female patients with SLE. Furthermore, we analyzed the potential relationship between this deficiency and SLE manifestations, disease activity, and its effect on interferon alpha (IFN-alpha) gene expression and serum level. Methods We evaluated the serum levels of vitamin D 25(OH)D3 and IFN-alpha by enzyme-linked immunosorbent assay (ELISA). IFN-alpha gene expression was measured by real-time polymerase chain reaction (PCR) assay in 123 Egyptian female patients with SLE and in 100 females as a healthy control group. Results Vitamin D deficiency was prevalent in 20.30%, while insufficiency was prevalent in 42.40% of the total group of patients. Serum levels of 25(OH)D3 were significantly decreased in the group of severe disease, and in the group of patients with lupus nephritis. 25(OH)D3 showed highly significant negative correlation with the SLE Disease Activity Index (SLEDAI) in the high activity group and lupus nephritis group. There was a significant negative correlation between 25(OH)D3 and IFN alpha serum level and gene expression in all patients; more significant in the group with lupus nephritis. Conclusions The deficiency of 25(OH)D3 has a direct relationship with increase disease activity and nephritis in Egyptian SLE patients, suggesting the need for vitamin D supplementation in these patients. Also, it is directly correlated with increased secretion and gene expression of IFN-alpha, suggesting its role in pathogenesis of lupus nephritis, to be confirmed by further longitudinal observational studies. PMID- 28659050 TI - Inter-arch digital model vs. manual cast measurements: Accuracy and reliability. AB - OBJECTIVES: The purpose of this study was to evaluate the accuracy and reliability of inter-arch measurements using digital dental models and conventional dental casts. METHODS: Thirty sets of dental casts with permanent dentition were examined. Manual measurements were done with a digital caliper directly on the dental casts, and digital measurements were made on 3D models by two independent examiners. Intra-class correlation coefficients (ICC), a paired sample t-test or Wilcoxon signed-rank test, and Bland-Altman plots were used to evaluate intra- and inter-examiner error and to determine the accuracy and reliability of the measurements. RESULTS: The ICC values were generally good for manual and excellent for digital measurements. The Bland-Altman plots of all the measurements showed good agreement between the manual and digital methods and excellent inter-examiner agreement using the digital method. CONCLUSION: Inter arch occlusal measurements on digital models are accurate and reliable and are superior to manual measurements. PMID- 28659051 TI - Prediction of pathologic femoral fractures in patients with lung cancer using machine learning algorithms: Comparison of computed tomography-based radiological features with clinical features versus without clinical features. AB - PURPOSE: The purpose of this article is to compare the predictive power of two models trained with computed tomography (CT)-based radiological features and both CT-based radiological and clinical features for pathologic femoral fractures in patients with lung cancer using machine learning algorithms. METHODS: Between January 2010 and December 2014, 315 lung cancer patients with metastasis to the femur were included. Among them, 84 patients who underwent CT scan and were followed up for more than 3 months were enrolled. We examined clinical and radiological risk factors affecting pathologic fracture through logistic regression. Predictive analysis was performed using five different supervised learning algorithms. The power of predictive model trained with CT-based radiological features was compared to those trained with both CT-based radiological and clinical features. RESULTS: In multivariate logistic regression, female sex (odds ratio = 0.25, p = 0.0126), osteolysis (odds ratio = 7.62, p = 0.0239), and absence of radiation therapy (odds ratio = 10.25, p = 0.0258) significantly increased the risk of pathologic fracture in proximal femur. The predictive model trained with both CT-based radiological and clinical features showed the highest area under the receiver operating characteristic curve (0.80 +/- 0.14, p < 0.0001) through gradient boosting algorithm. CONCLUSION: We believe that machine learning algorithms may be useful in the prediction of pathologic femoral fracture, which are multifactorial problem. PMID- 28659052 TI - Magnetic resonance guided focused ultrasound for treatment of bone tumors. AB - AIMS: Magnetic resonance guided focused ultrasound (MRgFUS) is a new modality in the management of primary and secondary bone tumors. We aimed to investigate the safety, efficacy, and feasibility of using MRgFUS for the treatment of (1) benign bone tumors with the intent of complete tumor ablation, (2) primary malignant bone tumors with the intent to assess its effectiveness in causing tumor necrosis, and (3) metastatic bone disease with the intent of pain relief. METHOD: Twenty-four patients with benign bone tumors, primary malignant bone tumors, and metastatic bone disease were treated with one session of MRgFUS. Contrast enhanced (CE) magnetic resonance imaging (MRI) was carried out post-procedure to assess and quantify the area of ablation. Those with malignant primary tumors had the tumors resected 2 weeks after the treatment and the ablated areas were examined histopathologically (HPE). The other patients were followed up for 3 months to assess for the side effects and pain scores. RESULTS: Significant volume of ablation was noted on CE MRI after the treatment. Benign bone tumors were ablated with minimal adverse effects. Metastatic bone disease was successfully treated with significant decrease in pain scores. Ablated primary malignant tumors showed significant coagulative necrosis on MRI and the HPE showed 100% necrosis. Pain scores significantly decreased 3 months after the procedure. Only two patients had superficial skin blistering and three patients had increase in pain scores immediately after treatment. CONCLUSION: MRgFUS is effective, safe, and noninvasive procedure that can be an adjunct in the management of primary and metastatic bone tumors. PMID- 28659053 TI - Posterior hip approach yields better functional results vis-a-vis anterolateral approach in total hip arthroplasty for patients with severe hip dysplasia: A prospective randomized controlled clinical study. AB - OBJECTIVES: We aimed to compare functional outcomes of two common hip approaches for patients with severe hip dysplasia in total hip replacement (THR) surgery. MATERIALS AND METHODS: Seventy hips of 68 patients randomized into two groups with regard to hip approach as posterior (group I) and anterolateral (group II). All patients underwent THR surgery with femoral shortening osteotomy. The groups were compared for operation time, preoperative and 6 months after abductor muscle strengths (AMSs), gait disorders, union time of the osteotomied site and dislocation rates. RESULTS: There were two early dislocations in group I, and two early and one late dislocations in group II. No significant difference was observed regarding hip dislocations. Mean union time of the osteotomied site was 113.9 +/- 51 days in group I while 111.1 +/- 29.3 days in group II ( p = 0.774). Six months after surgery, group I had higher AMS than group II ( p < 0.0001). More patients in group II had Trendelenburg gait pattern ( p = 0.043), while no difference was observed regarding antalgic and deviated gait patterns between groups. CONCLUSION: THR surgery for patients with severe developmental dysplasia of hip is a challenging procedure, and posterior approach provides better functional outcomes regarding gait and AMSs. PMID- 28659054 TI - Self-reducing proximal humerus fractures. AB - BACKGROUND: Proximal humeral fractures are common in the elderly and can present with multiple fracture configurations. Our case series describes a three-part valgus-impacted fracture pattern of the proximal humerus that underwent spontaneous reduction by nonsurgical management with good functional outcomes. METHODS: Seven patients who sustained low-energy three-part valgus-impacted fractures of the proximal humerus were studied. We retrospectively reviewed serial anteroposterior radiographs of each patient taken as part of routine follow-up. For clinical outcomes, patients were assessed by a physical examination of both shoulders. A Disability of Arm, Shoulder, and Hand (DASH) questionnaire assessed the functional outcomes. RESULTS: In all seven patients, fractures reduced spontaneously without any complications. Radiologically, the neck-shaft angle decreased from an average of 169 degrees to 141 degrees . In the six patients examined, range of motion was decreased in all planes in the affected shoulder relative to the contralateral shoulder. Two patients exhibited no loss of power in the affected arm, while the rest exhibited Medical Research Council grade 4 of 5 power in the affected arm. The mean DASH score obtained in our patients was 18.17. None of our patients reported any significant limitations in their activities of daily living and all achieved premorbid functional levels. CONCLUSION: Low-energy three-part valgus-impacted fracture pattern of the proximal humerus has the ability to spontaneously reduce by nonsurgical management with good functional outcomes. PMID- 28659055 TI - Chronic calcific periarthritis of the elbow treated by cimetidine administration: Five cases. AB - Calcific periarthritis or calcific tendinitis occurs most frequently in the shoulder and rarely in the elbow. Cimetidine was previously reported to be effective for chronic calcific periarthritis of the shoulder. Here, we present five patients with chronic calcific periarthritis of the elbow treated by administration of cimetidine; there were six affected elbows in these five patients. Although all patients had been treated with nonsteroidal anti inflammatory drugs for at least 3 months, their symptoms were not relieved. All patients took oral administration of cimetidine 400 mg daily. The pain was completely relieved in an average of 1.8 months after the administration of cimetidine, and the calcification of the elbow disappeared in an average of 5.1 months. During the follow-up period, there were no symptoms suggesting a recurrence. Although the detailed mechanism of action of cimetidine on periarticular calcifications remains to be understood, cimetidine appears to be a potential therapeutic agent for chronic calcific periarthritis. PMID- 28659056 TI - The influence of bicipital groove morphology on the stability of the long head of the biceps tendon. AB - PURPOSE: We aimed to evaluate the influence of the bony morphology of the bicipital groove on the stability of the long head of the biceps tendon (LHBT). METHODS: Among the patients who underwent magnetic resonance imaging of the shoulder at our outpatient clinic in 2012, those aged >40 years were included. After excluding cases with complete tear or unclear positioning of the biceps tendon, 464 shoulders were analyzed according to the position of the LHBT with respect to the bicipital groove. Shoulders with subluxation or dislocation of the LHBT were labeled as having unstable LHBT, while those with the LHBT located in the bicipital groove were labeled as having stable LHBT. The bony morphology of the bicipital groove was measured in terms of opening angle, medial wall angle, and depth. A shallow bicipital groove was defined as having an opening angle >94 degrees , concurrent with earlier studies. We compared shoulders with stable and unstable LHBT regarding bicipital bony morphology. We also compared shoulders with normal and shallow grooves regarding tendon stability. RESULTS: Shoulders with stable and unstable LHBT differed significantly regarding bony morphology. Shoulders with unstable LHBT showed a shallower mean depth (by 0.3 mm; p = 0.008), a smaller mean medial angle (by 2.2 degrees ; p = 0.014), and a larger mean opening angle (by 3.7 degrees ; p = 0.016). Bony morphology characterized by a shallow groove was significantly associated with increased prevalence of instability defined as LHBT subluxation or dislocation ( p = 0.011). CONCLUSION: A shallow bicipital groove, identified by the larger opening angle, smaller medial angle, and shallower depth, may represent a predisposing factor for biceps tendon instability. PMID- 28659057 TI - Anatomical shoulder arthroplasty in epileptic patients with instability arthropathy and persistent seizures. AB - PURPOSE: Epileptic seizures can cause shoulder dislocation, recurrent instability and eventually arthritis. The purpose of this study was to report the results, complications and rate of revision surgery following anatomical shoulder arthroplasty in epileptic patients with instability arthropathy. METHODS: A consecutive series of eight patients with epilepsy underwent anatomical shoulder arthroplasty for recurrent shoulder instability and were retrospectively reviewed after a mean of 4.7 years (range, 2-7.5 years). These included three total shoulder replacements and five humeral resurfacing hemiarthroplasty procedures. RESULTS: Mean age of the cohort was 33 years (range, 17-44). All patients experienced post-operative grand mal seizures. Two patients with hemiarthroplasty required further surgery due to painful glenoid erosion. No residual cases of instability were noted. Mean active forward elevation and external rotation improved following surgery. The Oxford Shoulder Score improved from 15 pre operatively (range, 7-22) to 26 post-operatively (range, 12-45) ( p = 0.031). This was accompanied by an increase in the mean Subjective Shoulder Value, which improved from 29 (range, 10-80) pre-operatively to 53 (range, 15-90) post operatively ( p=0.042). CONCLUSIONS: Anatomical shoulder arthroplasty may offer a solution for the treatment of instability arthropathy in patients with epilepsy and persistent seizures. PMID- 28659058 TI - Diagnosis and treatment of developmental dysplasia of the hip: A current practice of paediatric orthopaedic surgeons. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is one of the prevalent musculoskeletal conditions in young adults and is a leading cause of hip osteoarthrosis in this age group. The optimum age for surgical intervention when needed is not well established in the literature and the lack of management guidelines and standard practice of DDH leads to different practices worldwide. This study aims to investigate the current practice of paediatric orthopaedic surgeons in diagnosing and treating DDH worldwide and identify points of agreement and disagreement. METHODS: A cross-sectional study utilizing an online questionnaire was designed to examine the different points of view and current practice of paediatric orthopaedic surgeons worldwide regarding DDH diagnosis and treatment. RESULTS: Ninety-one surgeons responded, with an overall response of 45.5%. The vast majority of respondents use ultrasonography in children less than 3 months of age and pelvic radiography in over 3 months to diagnose DDH. Pavlik harness is the most popular DDH treatment for children younger than 6 months. For older children, closed reduction with hip spica cast is the most preferable treatment. The maximum duration of first-line treatment has a broad range. The treatment of bilateral DDH varies widely among surgeons. CONCLUSION: This study shows clearly that paediatric orthopaedic surgeons do not agree on the diagnosis and treatment protocol of DDH, hence different approaches to this common disease are practised. The lack of an international guideline should motivate paediatric orthopaedic surgeons to discuss and formulate a uniform and evidence-based protocol for the diagnosis and treatment of DDH. PMID- 28659059 TI - Endovascular Treatment of Visceral Artery Aneurysms and Pseudoaneurysms in 100 Patients: Covered Stenting vs Transcatheter Embolization. AB - PURPOSE: To retrospectively report a large single-center experience of visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) treated with covered stenting (CS) as the first therapeutic option vs transcatheter embolization (TE). METHODS: One hundred patients (mean age 59+/-14 years; 58 men) underwent 59 elective and 41 emergent endovascular procedures to treat 51 VAAs and 49 VAPAs. Seventy patients had TE and 30 received CS (27 Viabahn and 3 coronary stent grafts). Both TE and CS were performed in 10 cases. RESULTS: Technical success was 96% (97% CS, 96% TE), and 30-day clinical success was 83% (87% CS, 81.4% TE). Four major complications occurred; 30-day mortality was 7%, mainly due to septic shock following pancreatic surgery. The midterm follow-up was 20.8 months in the total population and 32.8 months in the CS group. More than 6 months after CS all aneurysms remained excluded; stent patency was achieved in 88%. Twelve CS patients with >3 years' follow-up had maintained stent patency. CONCLUSION: In endovascular treatment of visceral aneurysms, covered stenting was feasible in 30%. CS showed a slightly better efficacy than TE and good midterm patency. The Viabahn covered stent seems to be suitable for endovascular repair of tortuous visceral arteries affected by true or false aneurysms. PMID- 28659060 TI - Mental Imagery and School Readiness. AB - The aim of this study was to investigate the relationships between the skills that constitute school readiness, such as linguistic, phonological, logical mathematical and psychomotor skills, and mental imagery processes in preschool children. The participants were 100 healthy children (50 boys and 50 girls) aged four to five. Two batteries of tests were used to assess school readiness and different aspects of the mental imagery processes. The mental imagery battery measured mental imagery generation, inspection, and rotation of images. The results showed a relationship between the generation and inspection processes and the level of skills that constitute school readiness. These findings emphasize the potential usefulness of screening all preschoolers and kindergarteners for imagery ability, with the aim of adopting effective measures to increase their mental imagery abilities. PMID- 28659061 TI - Dendropsophin 1, a novel antimicrobial peptide from the skin secretion of the endemic Colombian frog Dendropsophus columbianus. AB - In efforts to find new antimicrobial peptides (AMPs), we studied the skin secretion of the endemic Colombian frog Dendropsophus columbianus belonging to a genus that has not been investigated previously. From HPLC-fractionated secretion, we identified one peptide with slightly antibacterial activity. Its peptide sequence showed no sequence similarity to current annotated peptides. We named this novel peptide dendropsophin 1 (Dc1). Afterward, two analogues were designed (Dc1.1 and Dc1.2) to improve the cationic and amphipathic features. Then, their antiproliferative and cytotoxic properties were evaluated against several pathogens including bacteria, fungi, protozoa and also mammalian cells. Dc1 and its two analogues exhibited moderate antibacterial activities and no hemolytic and cytotoxic effects on mammalian cells. Analogue Dc1.2 showed slightly improved antibacterial properties. Their secondary structures were characterised using CD spectroscopy and Dc1.2 displayed a higher alpha-helix content and thermal stability compared to Dc1 and Dc1.1 in hydrophobic experimental conditions. PMID- 28659062 TI - Layered double hydroxide films on nanoporous anodic aluminum oxide/aluminum wire: a new fiber for rapid analysis of Origanum vulgare essential oils. AB - Zn/Al layered double hydroxide (LDH) films were fabricated in situ with anodic aluminium oxide aluminium as both the substrate and the sole aluminium source by means of urea hydrolysis. Headspace solid phase microextraction using LDH fibre in combination with capillary GC-MS was utilised as a monitoring technique for the collection and detection of the volatile compounds of Origanum vulgare. Experimental parameters, including the sample weight, microwave power, extraction time and humidity effect, were examined and optimised. PMID- 28659063 TI - University Students' Relationship-Based Mentoring in School Settings. AB - How university students perform the tasks of mentoring, and the kinds of activities that are successful and unsuccessful in relationship-based mentoring interactions when mentors are instructed to "first establish relationships and then use the relationship to promote prosocial thinking and behaviors," remains an unfamiliar area of youth mentoring. Thus, the purpose of this study is to develop some understanding of steps criminal justice majors took and the behavioral goals and objectives they pursued during their semester-long mentoring interactions with primary, middle, and high school pupils within a local school district. Conventional content analysis methods were used to systematically identify, classify, and code themes and patterns of self-reported activities. Results show that student-mentors overwhelmingly engaged in activities that addressed known risk factors associated with antisocial thinking, attitudes, and behaviors. The results provide insights into the dynamics of this form of mentoring that emphasizes the importance of healthy relationships between proteges and mentors and advance reasons for further investigation of the effectiveness of a relationship-based mentoring approach. PMID- 28659064 TI - Impact of the type of emulsifier on the physicochemical characteristics of the prepared fish oil-loaded microcapsules. AB - Fish oil microcapsules were successfully prepared from fish oil-in-water emulsions using chitosan as shell material and anionic surfactants sodium dodecyl sulphate (SDS), sodium dodecylbenzenesulfonate (SDBS), sodium cholate (cholate), and sodium deoxycholate (DOC) as emulsifiers. The type of emulsifier influenced the physicochemical characteristics of the prepared microcapsules to different extents. The microcapsules formed with DOC showed the least mean effective diameter (MED) of 500 nm. Emulsion formed with DOC exhibited the smallest MED of 100 nm. The emulsions showed negative zeta potential values which became positive after encapsulation with chitosan. The surfactants showed little influence on thermal stability. Microcapsule suspensions showed creaming over storage. Fish oil at higher loading in SDS microcapsules showed higher primary and secondary oxidation. All microcapsules showed sustained release but the values varied depending upon the surfactants. The emulsion and microcapsules formed with DOC showed better morphology and stability despite its lower loading and encapsulation efficiency. PMID- 28659065 TI - Prevalence and risk factors for cats testing positive for feline immunodeficiency virus and feline leukaemia virus infection in cats entering an animal shelter in New Zealand. AB - AIMS To estimate the prevalence of cats testing positive for antibodies to feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) antigens in domestic cats entering a New Zealand animal shelter, based on a commercial point of-care ELISA, to identify risk factors associated with cats testing positive, and to compare the results obtained from the ELISA with those obtained using PCR based testing. METHOD A cross-sectional study was performed on 388 cats entering the Royal New Zealand Society for the Prevention of Cruelty to Animals animal shelter in Auckland, New Zealand between 7 February 2014 and 30 May 2014. Whole blood samples were collected from each cat and tested for FIV antibody and FeLV antigen using a commercial point-of-care ELISA. Information on the signalment and health status of the cat at the time of entry was also recorded. Blood and saliva samples from a subset of cats were tested for FIV and FeLV proviral DNA using a real-time PCR assay. RESULTS Of the 388 cats in the study sample, 146 (37.6%) had been relinquished by owners, 237 (62.4%) were strays, and 5 (1.3%) were of unknown origin. Overall, 53/388 (13.7%) cats tested positive for FIV antibodies and 4/388 (1.0%) were positive for FeLV antigen. Stray cats had a higher FIV seroprevalence than relinquished cats (42/237 (17.8%) vs. 11/146 (7.5%); p=0.008). Of 53 cats that were FIV-seropositive, 51 (96%) tested positive for FIV proviral DNA using PCR testing of blood. Of these 51 cats, 28 (55%) were positive by PCR testing of saliva. Of the four cats that were FeLV antigen-positive by ELISA, two (50%) were positive for FeLV proviral DNA by PCR testing of blood. The odds of a cat being seropositive for FIV were greater for intact compared to desexed cats (OR=3.3; 95% CI=1.6-7.4) and for male compared to female cats (OR=6.5; 95% CI=3.2-14.0). CONCLUSIONS AND CLINICAL RELEVANCE The seroprevalence for FIV was 14% among cats entering an animal shelter in Auckland, whereas the prevalence of FeLV antigen-positive cats was only 1%. These findings suggest differences in the transmission dynamics of each virus in free-roaming cat populations in New Zealand. Our study also highlights the potential role of desexing cats in reducing transmission of FIV. However, further data from first opinion veterinary practices are required to confirm that these findings may be generalised to the wider domestic cat population in New Zealand. PMID- 28659066 TI - The potential synergistic behaviour of inter- and intra-genus probiotic combinations in the pattern and rate of short chain fatty acids formation during fibre fermentation. AB - This study compared the rate of short chain fatty acid (SCFA) production by different probiotic combinations of Lactobacillus and Bifidobacterium to determine any synergistic effects. Six different fibre fractions were fermented with nine combinations of Lactobacillus rhamnosus (LR), Lactobacillus acidophilus (LA), Bifidobacterium longum (BL) and Bifidobacterium breve (BB) for 0, 6, 24 and 48 h. SCFAs were quantified by gas chromatography. Inter-genus combinations of bacteria produced more SCFA, especially BB + BL + LR, compared to intra-genus that yielded the lowest SCFA production. Acetate was the most abundant, while propionate and butyrate were the most utilised. The SCFA formation was as acetate > propionate > butyrate and the total dietary fibre produced most of the SCFA. Most combinations utilised 60-80% of the fibre; BB + BL + LR digested the fibre completely. The quantity, pattern and the time of release of SCFA depends on the genus, but the combination of pre and probiotics is of great importance for the outcome. PMID- 28659067 TI - Dignity realization of patients with stroke in hospital care: A grounded theory. AB - BACKGROUND: Dignity is seen as an important but complex concept in the healthcare context. In this context, the discussion of dignity includes concepts of other ethical principles such as autonomy and privacy. Patients consider dignity to cover individuality, patient's feelings, communication, and the behavior of healthcare personnel. However, there is a lack of knowledge concerning the realization of patients' dignity in hospital care and the focus of the study is therefore on the realization of dignity of the vulnerable group of patients with stroke. AIM: The aim of the study was to create a theoretical construct to describe the dignity realization of patients with stroke in hospital care. Research design and participants: Patients with stroke (n = 16) were interviewed in 2015 using a semi-structured interview containing open questions concerning dignity. The data were analyzed using constant comparison of Grounded Theory. Ethical considerations: Ethical approval for the research was obtained from the Ethics Committee of the University. The permission for the research was given by the hospital. Informed consent was obtained from participants. FINDINGS: The "Theory of Dignity Realization of Patients with Stroke in Hospital Care" consists of a core category including generic elements of the new situation and dignity realization types. The core category was identified as "Dignity in a new situation" and the generic elements as health history, life history, individuality and stroke. Dignity of patients with stroke is realized through specific types of realization: person-related dignity type, control-related dignity type, independence-related dignity type, social-related dignity type, and care-related dignity type. DISCUSSION: The theory has similar elements with the previous literature but the whole construct is new. The theory reveals possible special characteristics in dignity realization of patients with stroke. CONCLUSION: For healthcare personnel, the theory provides a frame for a better understanding and recognition of how dignity of patients with stroke is realized. PMID- 28659068 TI - Ethical climate in nursing environment. AB - BACKGROUND: In the past two decades, interest in the concept of ethical climate and in its research has increased in healthcare. Ethical climate is viewed as a type of organizational work climate, and defined as the shared perception of ethically correct behavior, and how ethical issues should be handled in the organization. Ethical climate as an important element of nursing environment has been the focus of several studies. However, scoping reviews of ethical climate research in nursing have not been conducted to guide further research in this area. OBJECTIVE: The purpose of this scoping review is to describe and analyze studies focusing on ethical climate in nursing environment to elicit an overall picture of the research in this field. METHODS: A scoping review methodology guided by Arksey and O'Malley and Levac et al. was used. Studies were identified by conducting electronic searches on PubMed/MEDLINE, CINAHL, Web of Science Core Collection, PsycINFO, and Scopus and Philosophers' Index databases. Of 1051 citations, 56 articles matched the inclusion criteria. Ethical considerations: This study was conducted according to good scientific guidelines. FINDINGS: Ethical climate is a topical research area which has been explored with different methods and outcomes, in different environments, and has mainly been perceived positively. The focus of the studies was on finding associations between ethical climate and work-related factors such as job satisfaction, moral distress, and turnover intentions. Methodologically, research was rather homogeneous using quantitative, descriptive, and correlative research designs. CONCLUSION: Novel perspectives and more diverse methodological approaches paying attentions to issues affecting generalizability of the findings could expand our knowledge in this area. PMID- 28659069 TI - HIV/AIDS discourses in Kyrgyzstan's policy arena. AB - This article explores the major discourses on HIV/AIDS in the policy arena in Kyrgyzstan, a former Soviet country in Central Asia that has experienced a rapid rise in HIV infections since the early 2000s. Based on an analysis of policy documents and 54 semi-structured in-depth interviews with key stakeholders in the area of HIV/AIDS policies in Kyrgyzstan, we distinguish a number of key discourses, competing for legitimacy and authority. While some of these discourses have been used in other countries (such as those presenting HIV/AIDS as a biomedical, social or moral issue), others are more specific to Kyrgyzstan (such as a discourse presenting the country as a regional pioneer in HIV/AIDS prevention efforts). Our analysis shows how HIV/AIDS discourses in the policy arena overlap and complement each other and how stakeholders employ a number of tools and strategies to promote and secure their agendas and positions of power. Our findings help to better understand HIV/AIDS discourses in Kyrgyzstan and elsewhere. They highlight the importance of understanding which discourses are prevailing, who drives them and why, how they change over time, and how they can be framed to achieve policy objectives. PMID- 28659070 TI - Noninvasive Stimulation of the Human Brain: Activation of Multiple Cortical Circuits. AB - Noninvasive brain stimulation methods, such as transcranial electric stimulation and transcranial magnetic stimulation are widely used tools for both basic research and clinical applications. However, the cortical circuits underlying their effects are poorly defined. Here we review the current knowledge based on data mostly coming from experiments performed on human subjects, and also to a lesser extent on rodent or primate models. The data suggest that multiple mechanisms are likely to be involved, such as the direct activation of layer V pyramidal neurons, but also of different types of GABAergic interneurons. In this regard, we propose a key role for a specific type of interneuron known as neurogliaform cell. PMID- 28659071 TI - Using systems thinking in patient safety: a case study on medicines management. AB - Systems thinking is used as a way of understanding behaviours and actions in complex healthcare organisations. An important premise of the concept is that every action in a system causes a reaction elsewhere in that system. These reactions can lead to unintended consequences, sometimes long after the original action, and so are not always attributed to them. This article applies systems thinking to a medicines management case study, to highlight how quality improvement practitioners can use the approach to underpin planning and implementation of patient-safety initiatives. The case study is specific to transcribing in children's hospices, but the strategies can be applied to other areas. The article explains that, while root cause analysis tools are useful for identifying the cause of, and possible solutions to, problems, they need to be considered carefully in terms of unintended consequences, and how the system into which the solution is implemented can be affected by the change. Analysis of problems using a systems-thinking approach can help practitioners to develop robust and well informed business cases to present to decision makers. PMID- 28659072 TI - Improving interdepartmental communication following a patient death. AB - When patients die in emergency departments (EDs), it is important to record information that can be shared with staff in other departments, such as the mortuary and bereavement office. This can be a time-consuming exercise but, if information is omitted, it can increase families' distress by delaying documents such as death certificates. This article describes how a new, tick-box-style death-in-department checklist was introduced in a London hospital adult ED to increase and improve communication and information sharing between the ED, the mortuary and the bereavement office. Audits undertaken before and after the introduction of the checklist show a 75% increase in the recording and sharing of information between relevant departments. The positive effect of the new checklist has led to its introduction in another, associated ED, and it has been incorporated into the trust's end of life care policy. PMID- 28659073 TI - Safe staffing. AB - The Scottish Government is consulting on safe and effective staffing in health and social care. The proposals set out in the consultation document focus on the application of evidence-based approaches to nursing and midwifery workload and workforce planning. PMID- 28659074 TI - Health secretary 'sympathetic' about nurses' case for pay rise. AB - Health secretary Jeremy Hunt (pictured) used his address to the NHS Confederation conference last month to announce renewed talks with the RCN over nurses' pay. PMID- 28659075 TI - Nurses' commitment should be rewarded. AB - The extraordinary commitment of healthcare staff cannot be expected to continue if the pay cap remains in place, the head of the membership body for NHS providers has said. PMID- 28659076 TI - Patient involvement. AB - New guidance for clinical commissioning groups has been published to help staff involve patients and the public in their work to improve services. The guidance also outlines the legal duty for NHS England to involve patients and the public in its commissioning processes and decisions, and links to an extensive range of resources. PMID- 28659077 TI - Addressing high turnover rates in senior nurse roles. AB - Heather Caudle is leaving her position as chief nurse at Ashford and St Peter's NHS Foundation Trust, Surrey, to take up the role of director of nursing for improvement at NHS England. PMID- 28659078 TI - What the election means for the NHS. AB - In many ways it is curious that the NHS did not feature more prominently in the election campaign. Polling consistently showed it was the most important issue for the electorate after Brexit. PMID- 28659079 TI - Enabling professionalism in practice. AB - Essential facts Helping nurses provide the best care possible is at the heart of new guidance on professionalism from the Nursing and Midwifery Council (NMC) and chief nursing officers from across the UK. PMID- 28659080 TI - 'Happy patients are as important as happy staff'. AB - What is your job? I am a pre-assessment lead nurse at Newcastle upon Tyne Hospitals NHS Foundation Trust. There is a misconception that I'm an 'ob and swab nurse' but in fact the role involves balancing patient assessment for elective surgery, service development and pathway expertise for a diverse patient group with the management of various grades of staff, including nurse practitioners, operating department practitioners, assistant practitioners, healthcare assistants and administration team. PMID- 28659081 TI - Integrated services: the plan for the future. AB - Sustainability and transformation plans (STPs) represent a move away from the purchaser-provider relationship adopted by the NHS in England to plan its services. PMID- 28659082 TI - Ambulation of patients who are mechanically ventilated: nurses' views. AB - Aims Equipment and skills in intensive care have advanced dramatically, and early rehabilitation and ambulation for patients in intensive care units (ICUs) are part of their journey to recovery. The aim of this study is to understand better nurses' perspectives on ambulating mechanically ventilated patients, and to determine why this is not a routine part of ICU patient care. Method Interpretative phenomenological analysis was used to extract data from semi structured interviews. The questions were piloted twice before being used in the main study. Results Two overarching themes, staff anxiety and organisational culture, were identified, within which there are several subthemes. The study also found that education and training programmes could increase staff confidence and consequently result in routine ambulation of mechanically ventilated patients. Conclusion The study identified that nursing staff are aware of the benefits of ambulation for patients in ICUs, but the personal satisfaction gained from undertaking this activity does not outweigh the anxiety it causes. This is compounded by the organisational culture of ICUs; for example, the hierarchical pyramid of leadership, which dictates that consultants decide when patients are ready to ambulate. PMID- 28659083 TI - Social Media Toolkit Skills for Health. AB - Created with support from Public Health Wales, Skills for Health's Social Media Toolkit offers advice and best practice on using social media effectively. PMID- 28659085 TI - Delivering person-centred care in people's homes. AB - There is much information in the literature, in presentations and in government related initiatives about moving to patient- or person-centred care. In the various settings for healthcare, including hospitals and rehabilitation centres, it is sometimes hard to apply the concepts of such care. PMID- 28659086 TI - Integration and collaboration. AB - In developing new models of care, the NHS is moving away from competition towards integration and collaboration. PMID- 28659088 TI - Urgent care. AB - Staff working in emergency departments (EDs) are expected to deal with any clinical emergency, perform complex procedures and arrange the administration of unusual medications in a time-sensitive but thorough manner. PMID- 28659087 TI - Final acts. AB - 'Last offices' is the term traditionally used in nursing to describe the final acts of care for a deceased person or someone who is about to die. The chief nursing officer for Ireland has published guidance on nurses' responsibilities before, at the time of and immediately after the person's death. PMID- 28659090 TI - Now more than ever, nurses need resilience. AB - I have been heartened over recent weeks by the many nurses and healthcare staff who have led the care of those caught up in the terrorist attacks in London and Manchester, as well as the catastrophic fire in London's Grenfell Tower. PMID- 28659089 TI - Others' perspectives. AB - A Mile in My Shoes is an interactive installation project by the Health Foundation and the Empathy Museum that invites people to 'put themselves in health and social care workers' and users' shoes', by listening to audio recordings of their experiences. The exhibit, a giant shoe box displaying the storytellers' shoes, has toured various health-sector events. PMID- 28659091 TI - STPs 'not ready for implementation'. AB - Academics have released a damning report on sustainability and transformation plans (STPs), claiming that none of them is ready for implementation. PMID- 28659092 TI - Head of WHO pledges nurses in top team. AB - 'I fully understand the critical role nurses play in health systems and agree that we must devote more attention and resources to nursing.' PMID- 28659093 TI - Queen's Birthday Honours. AB - Queen's Nursing Institute (QNI) chief executive Crystal Oldman has been made a CBE for services to the charity and community nursing. Dr Oldman is among more than 25 nurses recognised for their achievements in the 2017 Queen's Birthday Honours. PMID- 28659095 TI - 'Ambassadors' could encourage students to take up careers in health and social care. AB - NHS organisations in the UK should invest more in the skills of the domestic population, according to NHS Employers. PMID- 28659097 TI - Most vulnerable trusts losing nurses from EU. AB - More than half of NHS trusts in England most vulnerable to workforce problems after Brexit have seen falls in the number of nurses from other EU countries. PMID- 28659098 TI - Around the world. AB - 1 Fifth Annual Worldwide Nursing Conference 24-25 July, Singapore tinyurl.com/WNC 2017. PMID- 28659100 TI - Improving Indigenous health through education. PMID- 28659102 TI - Caring for country and the health of Aboriginal and Torres Strait Islander Australians. PMID- 28659103 TI - Recognising the communication gap in Indigenous health care. PMID- 28659104 TI - Embedding cultural safety in Australia's main health care standards. PMID- 28659105 TI - Disparities in experiences and outcomes of hospital care between Aboriginal and non-Aboriginal patients in New South Wales. PMID- 28659106 TI - Perspectives on the complexity of Indigenous child health. PMID- 28659107 TI - The health of Indigenous Australians. PMID- 28659108 TI - Dignity, social investment and the Indigenous health gap. PMID- 28659109 TI - Including minority populations in research: we must do better. PMID- 28659110 TI - "Has he eaten salt?": communication difficulties in health care. PMID- 28659111 TI - Progress in closing the gap in life expectancy at birth for Aboriginal people in the Northern Territory, 1967-2012. AB - OBJECTIVES: To compare long term changes in mortality and life expectancy at birth (LE) of Aboriginal people in the Northern Territory and of the overall Australian population; to determine the contributions of changes in mortality in specific age groups to changes in LE for each population. DESIGN, SETTING, PARTICIPANTS: Retrospective trend analysis of death and LE data for the NT Aboriginal and Australian populations, 1967-2012. MAIN OUTCOME MEASURES: LE estimates based on abridged life tables; mortality estimates (deaths per 100 000 population); and age decomposition of LE changes by sex and time period. RESULTS: Between 1967 and 2012, LE increased for both NT Aboriginal and all Australians; the difference in LE between the two populations declined by 4.6 years for females, but increased by one year for males. Between 1967-1971 and 1980-1984, LE of NT Aboriginal people increased rapidly, particularly through reduced infant mortality; from 1980-1984 to 1994-1998, there was little change; from 1994-1998 to 2008-2012, there were modest gains in older age groups. Decomposition by age group identified the persistent and substantial contribution of the 35-74-year age groups to the difference in LE between NT Aboriginal people and all Australians. CONCLUSIONS: Early gains in LE for NT Aboriginal people are consistent with improvements in nutrition, maternal and infant care, and infectious disease control. A rapid epidemiological transition followed, when LE gains in younger age groups plateaued and non-communicable diseases became more prevalent. Recent LE gains, across all adult age groups, are consistent with improved health service access and chronic disease management. If LE is to continue improving, socio-economic disadvantage and its associated risks must be reduced. PMID- 28659112 TI - Fall-related hospitalisations of older Aboriginal and Torres Strait Islander people and other Australians. AB - OBJECTIVES: To compare the socio-demographic characteristics and type of injury sustained, the use of hospital resources and rates of hospitalisation by injury type, and survival following fall injuries to older Aboriginal people and non Indigenous Australian people hospitalised for fall-related injuries. DESIGN: Population-based retrospective cohort data linkage study. Setting, participants: New South Wales residents aged 50 years or more admitted to a public or private NSW hospital for a fall-related injury during 1 January 2003 - 31 December 2012. MAIN OUTCOME MEASURES: Proportions of patients with defined injury types, mean hospital length of stay (LOS), 30-day mortality, age-standardised hospitalisation rates and age-adjusted rate ratios, 28-day re-admission rates. RESULTS: There were 312 758 fall-related injury hospitalisations for 234 979 individuals; 2660 admissions (0.85%) were of Aboriginal people. The proportion of hospitalisations for fall-related fracture injuries was lower for Aboriginal than for non Indigenous Australians (49% v 60% of fall-related hospitalisations; P < 0.001). The major injury type for Aboriginal patients was non-fracture injury to head or neck (19% of hospitalisations); for non-Indigenous patients it was hip fractures (18%). Age-adjusted LOS was lower for Aboriginal than for non-Indigenous patients (9.1 v 14.0 days; P < 0.001), as was 30-day mortality (2.9% v 4.2%; P < 0.001). For Aboriginal people, fall injury hospitalisations increased at an annual rate of 5.8% (95% CI, 4.0-7.7%; P < 0.001); for non-Indigenous patients, the mean annual increase was 2.5% (95% CI, 2.1-3.0; P < 0.001). CONCLUSIONS: The patterns of injury and outcomes of fall injury hospitalisations were different for older Aboriginal people and other older Australians, suggesting that different approaches are required to prevent and treat fall injuries. PMID- 28659113 TI - Exclusions from clinical trials in Australia based on proficiency in English. PMID- 28659114 TI - The general health of a cohort of Aboriginal children (0-7 years) in Sydney. PMID- 28659115 TI - The gap reversed: a review of site of death in the Top End. PMID- 28659116 TI - Cardiac care for Indigenous Australians: practical considerations from a clinical perspective. AB - Indigenous Australians have a much high burden of cardiovascular disease, which occurs at an earlier age than in the non-Indigenous population. Comorbidities such as diabetes are common. Early diagnosis of ischaemic heart disease may be difficult because of barriers such as distance to medical centres, communication problems and family and cultural responsibilities. Disparities in cardiac care between Indigenous and non-Indigenous populations are well documented, with examples including reduced angiography and revascularisation rates in Indigenous patients. Indigenous patients can have poor health literacy and need careful explanation of procedures, with the assistance of Aboriginal health workers, visual aids and family members. Acute rheumatic fever and chronic rheumatic heart disease remain ongoing health problems in Indigenous communities, especially in remote areas. Ambulatory care of Indigenous Australians with chronic cardiovascular disease is challenging. It requires well supported health care systems, including Aboriginal health workers and cardiac nurse coordinators to case-manage patients. A holistic approach to care, with attention directed towards both cardiac and non-cardiac comorbidities, is crucial for optimal management of cardiovascular disease in Indigenous Australians. Multidisciplinary care, involving an empowered and supported primary care team working together with specialists through outreach services or telehealth, is important for patients who are at high clinical risk and those living in remote areas. Indigenous Australians deserve the same level of evidence-based cardiovascular health care and access to care as non-Indigenous Australians. PMID- 28659117 TI - The excess burden of severe sepsis in Indigenous Australian children: can anything be done? PMID- 28659118 TI - The excess burden of severe sepsis in Indigenous Australian children: can anything be done? PMID- 28659119 TI - The excess burden of severe sepsis in Indigenous Australian children: can anything be done? PMID- 28659120 TI - Trends in cancer incidence and survival for Indigenous and non-Indigenous people in the Northern Territory. PMID- 28659121 TI - Indigenous champion honoured. PMID- 28659122 TI - Effects of combined spinal epidural labor analgesia on episiotomy: a retrospective cohort study. AB - BACKGROUND: According to some published studies, neuraxial analgesia may be associated with prolonged labor and an increased risk for instrumental vaginal delivery. However, its effects on episiotomy are unknown. This study aimed to examine the incidence of episiotomy with and without combined spinal-epidural analgesia (CSEA) during labor. METHODS: This was a retrospective cohort study, in which the computerized medical records of nulliparous women with singleton, cephalic and live births were reviewed and women with and without CSEA were matched based on their propensity scores. Univariate and multivariate analyses were used to examine the association between CSEA and the incidence of episiotomy during vaginal delivery. RESULTS: In the cohort study with 11,994 vaginal deliveries, 5748 received CSEA and 6246 did not receive CSEA. 4116 CSEA women were successfully matched with 4116 Non-CSEA women. In the univariate analysis, the incidence of episiotomy was 47.4% in the CSEA group and 44.7% in the Non-CSEA group. However, after a multivariable logistic regression analysis, CSEA did not increase the risk of episiotomy (adjusted OR, 1.080; 95% confidence interval [CI], 0.988-1.180). CONCLUSIONS: The use of CSEA during labor and vaginal delivery did not increase the risk of episiotomy. PMID- 28659123 TI - Semi-automated quantitative Drosophila wings measurements. AB - BACKGROUND: Drosophila melanogaster is an important organism used in many fields of biological research such as genetics and developmental biology. Drosophila wings have been widely used to study the genetics of development, morphometrics and evolution. Therefore there is much interest in quantifying wing structures of Drosophila. Advancement in technology has increased the ease in which images of Drosophila can be acquired. However such studies have been limited by the slow and tedious process of acquiring phenotypic data. RESULTS: We have developed a system that automatically detects and measures key points and vein segments on a Drosophila wing. Key points are detected by performing image transformations and template matching on Drosophila wing images while vein segments are detected using an Active Contour algorithm. The accuracy of our key point detection was compared against key point annotations of users. We also performed key point detection using different training data sets of Drosophila wing images. We compared our software with an existing automated image analysis system for Drosophila wings and showed that our system performs better than the state of the art. Vein segments were manually measured and compared against the measurements obtained from our system. CONCLUSION: Our system was able to detect specific key points and vein segments from Drosophila wing images with high accuracy. PMID- 28659124 TI - Cataract and optic disk drusen in a patient with glycogenosis and di George syndrome: clinical and molecular report. AB - BACKGROUND: We report the ophthalmic findings of a patient with type Ia glycogen storage disease (GSD Ia), DiGeorge syndrome (DGS), cataract and optic nerve head drusen (ONHD). CASE PRESENTATION: A 26-year-old white woman, born at term by natural delivery presented with a post-natal diagnosis of GSD Ia. Genetic testing by array-comparative genomic hybridization (CGH) for DGS was required because of her low levels of serum calcium. The patient has been followed from birth, attending the day-hospital every six months at the San Paolo Hospital, Milan, outpatient clinic for metabolic diseases and previously at another eye center. During the last day-hospital visit, a complete eye examination showed ONHD and cataract in both eyes. Next Generation Sequencing (NGS) was subsequently done to check for any association between the eye problems and metabolic aspects. CONCLUSIONS: This is the first description of ocular changes in a patient with GSD Ia and DGS. Mutations explaining GSD Ia and DGS were found but no specific causative mutation for cataract and ONHD. The metabolic etiology of her lens changes is known, whereas the pathogenesis of ONHD is not clear. Although the presence of cataract and ONHD could be a coincidence; the case reported could suggest that hypocalcemia due to DGS could be the common biochemical pathway. PMID- 28659125 TI - Certainty and safe consequence responses provide additional information from multiple choice question assessments. AB - BACKGROUND: Clinicians making decisions require the ability to self-monitor and evaluate their certainty of being correct while being mindful of the potential consequences of alternative actions. For clinical students, this ability could be inferred from their responses to multiple-choice questions (MCQ) by recording their certainty in correctness and avoidance of options that are potentially unsafe. METHODS: Response certainty was assessed for fifth year medical students (n = 330) during a summative MCQ examination by having students indicate their certainty in each response they gave on the exam. Incorrect responses were classified as to their inherent level of safeness by an expert panel (response consequence). Analyses compared response certainty, response consequence across student performance groupings. RESULTS: As students' certainty in responses increased, the odds they answered correctly increased and the odds of giving unsafe answers decreased. However, from some ability groups the odds of an incorrect response being unsafe increased with high certainty. CONCLUSIONS: Certainty in, and safeness of, MCQ responses can provide additional information to the traditional measure of a number correct. In this sample, even students below standard demonstrated appropriate certainty. However, apart from those scoring lowest, student's incorrect responses were more likely to be unsafe when they expressed high certainty. These findings suggest that measures of certainty and consequence are somewhat independent of the number of correct responses to MCQs and could provide useful extra information particularly for those close to the pass-fail threshold. PMID- 28659126 TI - Paroxysmal freezing of gait in a patient with mesial frontal transient ischemic attacks. AB - BACKGROUND: Rare patients have been reported who developed a mixture of gait disturbances following a focal lesion in the frontal lobe. Thus, the exact location of frontal lesion responsible for a specific gait disturbance is not well defined. CASE PRESENTATION: We describe a 47-year-old man who experienced two episodes of paroxysmal freezing of gait of the right leg. During the attacks, he had no motor weakness, sensory change, or disequilibrium. He had past history of panic attacks. Recently, he had been under severe emotional stress. T2 and diffusion brain magnetic resonance imaging scans were normal. So far, the most likely clinical diagnosis might be functional freezing of gait. However, magnetic resonance angiography showed atherosclerosis in the proximal left anterior cerebral artery. Perfusion scans showed a delayed mean transit time in the left mesial frontal lobe. He developed two more attacks during the four months of follow up. CONCLUSIONS: The presented case illustrates that the mesial frontal lobe may be important in the pathophysiology of freezing of gait. We speculate that the supplementary motor area may generate a neuronal command for the initiation of locomotion that in our case may have been inhibited by a transient ischemia. PMID- 28659127 TI - General vs. neuraxial anaesthesia in hip fracture patients: a systematic review and meta-analysis. AB - BACKGROUND: Hip fracture is a trauma of the elderly. The worldwide number of patients in need of surgery after hip fracture will increase in the coming years. The 30-day mortality ranges between 4 and 14%. Patients' outcome may be improved by anaesthesia technique (general vs. neuraxial anaesthesia). There is a dearth of evidence from randomised studies regarding to the optimal anaesthesia technique. However, several large non-randomised studies addressing this question have been published from the onset of 2010. METHODS: To compare the 30-day mortality rate, in-hospital mortality rate and length of hospital stay after neuraxial (epidural/spinal) or general anaesthesia in hip fracture patients (>= 18 years old) we prepared a systematic review and meta-analysis. A systematic search for appropriate retrospective observational and prospective randomised studies in Embase and PubMed databases was performed in the time-period from 01.01.2010 to 21.11.2016. Additionally a forward searching in google scholar, a level one reference list searching and a formal searching of trial registries was performed. RESULTS: Twenty retrospective observational and three prospective randomised controlled studies were included. There was no difference in the 30 day mortality [OR 0.99; 95% CI (0.94 to 1.04), p = 0.60] between the general and the neuraxial anaesthesia group. The in-hospital mortality [OR 0.85; 95% CI (0.76 to 0.95), p = 0.004] and the length of hospital stay were significantly shorter in the neuraxial anaesthesia group [MD -0.26; 95% CI (-0.36 to -0.17); p < 0.00001]. CONCLUSION: Neuraxial anaesthesia is associated with a reduced in hospital mortality and length of hospitalisation. However, type of anaesthesia did not influence the 30-day mortality. In future there is a need for large randomised studies to examine the association between the type of anaesthesia, post-operative complications and mortality. PMID- 28659129 TI - SLMSuite: a suite of algorithms for segmenting genomic profiles. AB - BACKGROUND: The identification of copy number variants (CNVs) is essential to study human genetic variation and to understand the genetic basis of mendelian disorders and cancers. At present, genome-wide detection of CNVs can be achieved using microarray or second generation sequencing (SGS) data. Although these technologies are very different, the genomic profiles that they generate are mathematically very similar and consist of noisy signals in which a decrease or increase of consecutive data represent deletions or duplication of DNA. In this framework, the most important step of the analysis consists of segmenting genomic profiles for the identification of the boundaries of genomic regions with increased or decreased signal. RESULTS: Here we introduce SLMSuite, a collection of algorithms, based on shifting level models (SLM), to segment genomic profiles from array and SGS experiments. The SLM algorithms take as input the log transformed genomic profiles from SGS or microarray experiments and output segmentation results. We apply our method to the analysis of synthetic genomic profiles and real whole genome sequencing data and we demonstrate that it outperforms the state of the art circular binary segmentation algorithm in terms of sensitivity, specificity and computational speed. CONCLUSION: The SLMSuite contains an R library with the segmentation methods and three wrappers that allow to use them in Python, Ruby and C++. SLMSuite is freely available at https://sourceforge.net/projects/slmsuite . PMID- 28659128 TI - CMISG1701: a multicenter prospective randomized phase III clinical trial comparing neoadjuvant chemoradiotherapy to neoadjuvant chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) (NCT03001596). AB - BACKGROUND: Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0). METHODS/DESIGN: CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment related complications, postoperative mortality as well as quality of life. DISCUSSION: The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE. TRIAL REGISTRATION: NCT03001596 (December 17, 2016). PMID- 28659130 TI - What makes a successful species? Traits facilitating survival in altered tropical forests. AB - BACKGROUND: Ongoing conversion, disturbance and fragmentation of tropical forests stress this ecosystem and cause the decline or disappearance of many species. Particular traits have been identified which indicate an increasing extinction risk of a species, but traits facilitating survival in altered habitats have mostly been neglected. Here we search for traits that make a species tolerant to disturbances, thus independent of pristine forests. We identify the fauna that have an increasing effect on the ecosystem and its functioning in our human dominated landscapes. METHODS: We use a unique set of published data on the occurrences of 243 frog species in pristine and altered forests throughout the tropics. We established a forest dependency index with four levels, based on these occurrence data and applied Random Forest classification and binomial Generalized Linear Models to test whether species life history traits, ecological traits or range size influence the likelihood of a species to persist in disturbed habitats. RESULTS: Our results revealed that indirect developing species exhibiting a large range size and wide elevational distribution, being independent of streams, and inhabiting the leaf litter, cope best with modifications of their natural habitats. CONCLUSION: The traits identified in our study will likely persist in altered tropical forest systems and are comparable to those generally recognized for a low species extinction risk. Hence our findings will help to predict future frog communities in our human-dominated world. PMID- 28659131 TI - Childhood pesticide poisoning in Zhejiang, China: a retrospective analysis from 2006 to 2015. AB - BACKGROUND: Pesticide poisoning in children has been a serious public health issue around the world, especially in the developing countries where agriculture is still one of the largest economic sectors. The purpose of this study was to analyze epidemiological characteristics of acute pesticide poisoning in children from Zhejiang province, China. METHODS: The pesticide poisoning cases for children were retrieved from Occupational Disease Surveillance and Reporting System, Zhejiang Provincial Center for Disease Control and Prevention, China. The incident cases, deaths, and fatality rate of child pesticide poisoning from 2006 through 2015 were calculated. RESULTS: During the study period, totally 2952 children were poisoned by pesticides, with 66 deaths, resulting in a fatality rate of 2.24%. Among them, there were 1607 male cases with 28 deaths, and 1345 female cases with 38 deaths. Most of the cases occurred in preschool children (1349) and adolescent age group (1269). Organophosphate and carbamate insecticides were the cause of most poisonings (1130), leading to 34 deaths. The highest fatality rate (3.13%) was due to poisoning by herbicides and fungicides, causing 14 deaths out of 448 cases. Poisoning occurred mostly in rural areas (78%). And most pesticide poisoning occurred in the summer (896) and fall (811), while fewest poisoning cases in the winter (483) but with the highest fatality rate (3.52%). CONCLUSIONS: This study shows that pesticide poisoning of children is a major health problem in Zhejiang, suggesting preventive strategies should be conducted to control childhood pesticide poisoning. PMID- 28659132 TI - Identification and profiling of growth-related microRNAs in Chinese perch (Siniperca chuatsi). AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous small non-coding RNAs that play important roles in the regulation of diverse biological processes in eukaryotes. Chinese perch (Siniperca chuatsi) is one of the most economically important fish species widely cultured in China. Growth is an extremely important characteristic in fish. Individual differences in body size are common in Siniperca chuatsi, which significantly influence the aquaculture production of Siniperca chuatsi. However, the underline growth-related regulatory factors, such as miRNAs, are still unknown. RESULTS: To investigate the growth-related miRNAs in Siniperca chuatsi, two RNA libraries from four growth-related tissues (brain, pituitary, liver, and muscle) of Siniperca chuatsi at 6-month stage with relatively high or low growth rates (big-size group or small-size group) were obtained and sequenced using Solexa sequencing. A total of 252 known miRNAs and 12 novel miRNAs were identified. The expression patterns of these miRNAs in big-size group and small size group were compared, and the results showed that 31 known and 5 novel miRNAs were differently expressed (DE). Furthermore, to verify the Solexa sequencing, five DE miRNAs were randomly selected and quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The results showed that their expression patterns were consistent with those of Solexa sequencing. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of target genes of DE miRNAs was performed. It showed that the target genes were involved in multiple biological processes including metabolic process, suggesting that metabolic process played an important role in growth of fish. CONCLUSIONS: Siniperca chuatsi is a popular and economically important species in aquaculture. In this study, miRNAs in Siniperca chuatsi with different growth rates were identified, and their expression profiles were compared. The data provides the first large-scale miRNA profiles related to growth of Siniperca chuatsi, which is expected to contribute to a better understanding of the role of miRNAs in regulating the biological processes of growth and possibly useful for Siniperca chuatsi breeding. PMID- 28659134 TI - Evaluating non-responders of a survey in the Swedish fracture register: no indication of different functional result. AB - BACKGROUND: The Swedish Fracture Register (SFR) currently contains information on more than 190,000 fractures. Patient Reported Outcome Measures (PROMs) are used for monitoring functional results after fracture treatment. One weakness, as in many surveys, is a low response rate. The aim of the current study was to examine if non-responders of a survey in the SFR differ in PROMs scores, how age and gender influence the response rate and reasons for not responding. METHODS: Patients with fractures of radius, ulna or humerus between June and August 2013 and registered in the SFR were included in the study. The non-responders to both the pre-injury and the 1-year survey were contacted by phone and reminded to reply. A comparison of the results of both EQ-5D and Short Musculoskeletal Function Assessment (SMFA) could be made between the responders after a phone reminder and the initial responders. The response rate for the register as a whole was extracted in order to identify how age and gender affect the response rate. RESULTS: Three hundred seventeen of the patients included in the study responded initially. After phone reminder another 94 patients answered the pre injury survey. Two hundred sixty eight responded initially to the 1-year follow up survey and 42 after phone reminder. No significant difference was identified in the score of the pre-injury survey between initial responders and responders after phone reminder neither in the EQ-5D nor in the Short Musculoskeletal Function Assessment (SMFA). Regarding the 1-year survey, responders after a phone reminder reported a significantly better outcome in crude data of SMFA score. This difference disappeared after controlling for confounding factors through case control matching. The highest response rate to PROMs in the SFR was among females in the age range 60-69 years. CONCLUSION: This study indicates that both in the preinjury survey as well as in the 1-year survey the non-responders in the SFR report similar function compared to the initial responders. Age and gender of patients affect the response rate of the survey which needs to be taken into consideration in analysis of data from the SFR. PMID- 28659135 TI - Bilateral Morganella Morganii keratitis in a patient with facial topical corticosteroid-induced rosacea-like dermatitis: a case report. AB - BACKGROUND: Bilateral keratitis rarely occurs in individuals without predisposing factors. Here we describe the clinical course of a patient who developed a bilateral keratitis caused by Morganella. morganii which might be associated with long term using of topical corticosteroids-containing preparations on the face. CASE PRESENTATION: A 52-year-old female patient presented with marked bilateral corneal infiltration and hypopyon without any usual predisposing factors for bilateral infectious keratitis. There was diffuse erythema with itching on face before the onset of eye discomforts. Microbiological culture of materials from both corneas revealed significant growth of Morganella morganii. Topical corticosteroid-induced rosacea-like dermatitis was diagnosed by dermatologist because of the characteristic eruptions and long history of using the corticosteroids-containing cosmetic creams on her face. The corneal ulcers responded well to levofloxacin eye drops and ofloxacin ointment and healed with opacity and neovascularization. CONCLUSION: This case illustrates that bilateral bacterial corneal infection can develop in patients with long term using of topical corticosteroids-containing preparations on the face. To our knowledge, this is the first case of bilateral keratitis caused by Morganella morganii. PMID- 28659133 TI - A multicentre double-blind randomised controlled trial evaluating the efficacy of daily use of antibacterial mouthwash against oropharyngeal gonorrhoea among men who have sex with men: the OMEGA (Oral Mouthwash use to Eradicate GonorrhoeA) study protocol. AB - BACKGROUND: Gonorrhoea is one of the most common sexually transmissible infections in men who have sex with men (MSM). Gonorrhoea rates have increased substantially in recent years. There is concern that increasing gonorrhoea prevalence will increase the likelihood of worsening antibiotic resistance in Neisseria gonorrhoeae. A recent randomised controlled trial (RCT) demonstrated that a single-dose of mouthwash has an inhibitory effect against oropharyngeal gonorrhoea. We are conducting the first RCT to evaluate whether daily use of mouthwash could reduce the risk of acquiring oropharyngeal gonorrhoea. METHODS/DESIGN: The OMEGA (Oral Mouthwash use to Eradicate GonorrhoeA) study is a double-blind RCT and will be conducted at several sexual health clinics and high caseload General Practice (GP) clinics in Melbourne and Sydney, Australia. A total of 504 MSM attending the participating sites will be recruited. Participants will be randomised to either using 'Study mouthwash A' or 'Study mouthwash B' for 12 weeks. Study mouthwash A was inhibitory against N. gonorrhoeae in vitro, whereas study mouthwash B was not. Participants will be instructed to rinse and gargle the study mouthwash for 60 seconds every day. The primary outcome is the proportion of participants with oropharyngeal gonorrhoea detected by nucleic acid amplification test by 12 weeks. DISCUSSION: The results from this trial may provide a novel way to reduce gonorrhoea prevalence and transmission without the use of antibiotics that may be associated with development of resistance. If shown to be effective, the widespread use of mouthwash will reduce the prevalence of oropharyngeal gonorrhoea, which plays key role in driving the emergence of gonococcal antimicrobial resistance through DNA exchange with oral commensal bacteria. The anticipated net effect will be interruption of onward transmission of N. gonorrhoeae within high density sexual networks within MSM populations. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000247471 , registered on 23rd February 2016. PMID- 28659136 TI - Risk of chronic liver disease in post-menopausal women due to body mass index, alcohol and their interaction: a prospective nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). AB - BACKGROUND: We investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to the UKCTOCS trial. METHODS: 95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none, <1-15, 16-20 and >=21 units/week), and followed for an average of 5.1 years. Hazard ratios (HR) were calculated for incident liver-related events (LRE). RESULTS: First LREs were reported in 325 (0.34%) participants. Compared to women with normal BMI, HR = 1.44 (95% CI; 1.10 1.87) in the overweight group and HR = 2.25 (95% CI; 1.70-2.97) in the obese group, adjusted for alcohol and potential confounders. Compared to those abstinent from alcohol, HR = 0.70 (95% CI; 0.55-0.88) for <1-15 units/week, 0.93 (95% CI; 0.50-1.73) for 16-20 units/week and 1.82 (95% CI; 0.97-3.39) for >=21 units/week adjusted for BMI and potential confounders. Compared to women with normal BMI drinking no alcohol, HR for LRE in obese women consuming >=21 units/week was 2.86 (95% CI; 0.67-12.42), 1.58 (95% CI; 0.96-2.61) for obese women drinking <1-15 units/week and 1.93 (95% CI; 0.66-5.62) in those with normal BMI consuming >=21 units/week after adjustment for potential confounders. We found no significant interaction between BMI and alcohol. CONCLUSION: High BMI and alcohol consumption and abstinence are risk factors for CLD in post menopausal women. However, BMI and alcohol do not demonstrate significant interaction in this group. TRIAL REGISTRATION: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000. PMID- 28659137 TI - Factors influencing decision regret regarding placement of a PEG among substitute decision-makers of older persons in Japan: a prospective study. AB - BACKGROUND: A tube feeding decision aid designed at the Ottawa Health Research Institute was specifically created for substitute decision-makers who must decide whether to allow placement of a percutaneous endoscopic gastrostomy (PEG) tube in a cognitively impaired older person. We developed a Japanese version and found that the decision aid promoted the decision-making process of substitute decision makers to decrease decisional conflict and increase knowledge. However, the factors that influence decision regret among substitute decision-makers were not measured after the decision was made. The objective of this study was to explore the factors that influence decision regret among substitute decision-makers 6 months after using a decision aid for PEG placement. METHODS: In this prospective study, participants comprised substitute decision-makers for 45 inpatients aged 65 years and older who were being considered for placement of a PEG tube in hospitals, nursing homes and patients' homes in Japan. The Decisional Conflict Scale (DCS) was used to evaluate decisional conflict among substitute decision makers immediately after deciding whether to introduce tube feeding and the Decision Regret Scale (DRS) was used to evaluate decisional regret among substitute decision-makers 6 months after they made their decision. Normalized scores were evaluated and analysis of variance was used to compare groups. RESULTS: The results of the multiple regression analysis suggest that PEG placement (P < .01) and decision conflict (P < .001) are explanatory factors of decision regret regarding placement of a PEG among substitute decision-makers. CONCLUSIONS: PEG placement and decision conflict immediately after deciding whether to allow PEG placement have an influence on decision regret among substitute decision-makers after 6 months. PMID- 28659138 TI - The effect of geriatric intervention in frail elderly patients receiving chemotherapy for colorectal cancer: a randomized trial (GERICO). AB - BACKGROUND: Better surgical techniques, chemotherapy and biological therapy have improved survival in patients with colorectal cancer (CRC), most markedly in younger patients. About half of patients over 70 years receive dose reductions or early treatment discontinuation of the planned adjuvant or first-line treatment due to side effects. The Comprehensive Geriatric Assessment (CGA) is a multidisciplinary evaluation of an elderly individual's health status. This assessment in older patients with cancer can predict survival, chemotherapy toxicity and morbidity. METHODS: This randomized phase II trial (GERICO) is designed to investigate whether comprehensive geriatric assessment and intervention before and during treatment with chemotherapy in frail elderly patients with stages II-IV CRC will increase the number of patients completing chemotherapy. All patients >=70 years in whom chemotherapy for CRC is planned to start at Herlev and Gentofte Hospital are screened for frailty using the G8 questionnaire at the first visit to the outpatient clinic. The G8 questionnaire is a multi-domain screening tool to identify frail or vulnerable patients at risk of increased toxicity and morbidity. Frail patients are offered inclusion and are then randomized to two groups (the intervention group and the control group). Patients in the intervention group receive a full geriatric assessment of comorbidity, medication, psycho-cognitive function, physical, functional and nutrition status, and interventions are undertaken on identified health issues. Simultaneously, they are treated for their cancer according to international guidelines. Patients in the control group receive the same chemotherapy regimens and standard of care. Primary outcome is number of patients completing scheduled chemotherapy at starting dose. Secondary outcomes are dose reductions, treatment delays, toxicity, time to recurrence, survival, cancer-related mortality and quality of life. DISCUSSION: This ongoing trial is one of the first to evaluate the effect of geriatric intervention in frail elderly patients with CRC. The trial will provide new and valuable knowledge about whether it is beneficial for the elderly patient undergoing chemotherapy to be treated simultaneously by a geriatrician. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02748811 . The trial was registered retrospectively; registration date 04/28/2016. PMID- 28659139 TI - The unique value of cardiovascular magnetic resonance in patients with suspected acute coronary syndrome and culprit-free coronary angiograms. AB - BACKGROUND: Patients with chest pain, elevated troponin, and unobstructed coronary disease present a clinical dilemma. The purpose of this study was to investigate the incremental diagnostic value of cardiovascular magnetic resonance (CMR) in a cohort of patients with suspected acute coronary syndrome (ACS) and unobstructed coronary arteries. RESULTS: Data files of patients meeting the inclusion criteria in two cardiology centres were searched and analysed. The inclusion criteria included: 1) thoracic pain suspected with ACS; 2) a significant increase in the high-sensitive Troponin T value; 3) ECG changes; 4) coronary arteries without any significant stenosis; 5) a CMR examination included in the diagnostic process; 6) an uncertain diagnosis before the CMR exam; and 7) the absence of known CMR and contrast media contraindications. Special attention was paid to the benefits of CMR in determining the final diagnosis. In total, 136 patients who underwent coronary angiography for chest pain were analysed. The most frequent underlying causes were myocarditis (38%) and perimyocarditis (18%), followed by angiographically unrecognised acute myocardial infarction (18%) and Takotsubo cardiomyopathy (15%). The final diagnosis remained unclear in 6% of the patients. The contribution of CMR in determining the final diagnosis determination was crucial in 57% of the patients. In another 35% of the patients, CMR confirmed the suspicion and, only 8% of the CMR examinations did not help at all and had no influence on diagnosis or treatment. CONCLUSION: CMR provided a powerful incremental diagnostic value in the cohort of patients with suspected ACS and unobstructed coronary arteries. CMR is highly recommended to be incorporated as an inalienable part of the diagnostic algorithms in these patients. PMID- 28659140 TI - Amblyopia treatment of adults with dichoptic training using the virtual reality oculus rift head mounted display: preliminary results. AB - BACKGROUND: The gold standard treatments in amblyopia are penalizing therapies, such as patching or blurring vision with atropine that are aimed at forcing the use of the amblyopic eye. However, in the last years, new therapies are being developed and validated, such as dichoptic visual training, aimed at stimulating the amblyopic eye and eliminating the interocular supression. PURPOSE: To evaluate the effect of dichoptic visual training using a virtual reality head mounted display in a sample of anisometropic amblyopic adults and to evaluate the potential usefulness of this option of treatment. METHODS: A total of 17 subjects (10 men, 7 women) with a mean age of 31.2 years (range, 17-69 year) and anisometropic amblyopia were enrolled. Best corrected visual acuity (BCVA) and stereoacuity (Stereo Randot graded circle test) changes were evaluated after 8 sessions (40 min per session) of dichoptic training with the computer game Diplopia Game (Vivid Vision) run in the Oculus Rift OC DK2 virtual reality head mounted display (Oculus VR). RESULTS: Mean BCVA in amblyopic eye improved significantly from a logMAR value of 0.58 +/- 0.35 before training to a post training value of 0.43 +/- 0.38 (p < 0.01). Forty-seven percent of the participants achieved BCVA of 20/40 or better after the training as compared to 30% before the training. Mean stereoacuity changed from a value of 263.3 +/- 135.1 before dichoptic training to a value of 176.7 +/- 152.4 s of arc after training (p < 0.01). A total of 8 patients (47.1%) before dichoptic treatment had unmeasurable stereoacuity while this only occurred in 2 patients (11.8%) after training. CONCLUSIONS: Dichoptic training using a virtual reality head mounted display seems to be an effective option of treatment in adults with anisometropic amblyopia. Future clinical trials are needed to confirm this preliminary evidence. TRIAL REGISTRATION: Trial ID: ISRCTN62086471 . Date registered: 13/06/2017. Retrospectively registered. PMID- 28659141 TI - ISVASE: identification of sequence variant associated with splicing event using RNA-seq data. AB - BACKGROUND: Exon recognition and splicing precisely and efficiently by spliceosome is the key to generate mature mRNAs. About one third or a half of disease-related mutations affect RNA splicing. Software PVAAS has been developed to identify variants associated with aberrant splicing by directly using RNA-seq data. However, it bases on the assumption that annotated splicing site is normal splicing, which is not true in fact. RESULTS: We develop the ISVASE, a tool for specifically identifying sequence variants associated with splicing events (SVASE) by using RNA-seq data. Comparing with PVAAS, our tool has several advantages, such as multi-pass stringent rule-dependent filters and statistical filters, only using split-reads, independent sequence variant identification in each part of splicing (junction), sequence variant detection for both of known and novel splicing event, additional exon-exon junction shift event detection if known splicing events provided, splicing signal evaluation, known DNA mutation and/or RNA editing data supported, higher precision and consistency, and short running time. Using a realistic RNA-seq dataset, we performed a case study to illustrate the functionality and effectiveness of our method. Moreover, the output of SVASEs can be used for downstream analysis such as splicing regulatory element study and sequence variant functional analysis. CONCLUSIONS: ISVASE is useful for researchers interested in sequence variants (DNA mutation and/or RNA editing) associated with splicing events. The package is freely available at https://sourceforge.net/projects/isvase/ . PMID- 28659142 TI - Association of BUD13 polymorphisms with metabolic syndrome in Chinese population: a case-control study. AB - BACKGROUND: BUD13 homolog (BUD13), one of submits of the retention and splicing complex, was identified in yeast as a splicing factor that affected nuclear pre mRNA retention. While more and more studies demonstrated that BUD13 played a potential role in the pathogenesis of metabolic syndrome (MetS). This objective was to reassess whether novel locus of BUD13 were linked to MetS and individual complements in the northeast of China. METHODS: A total of 3850 individuals were recruited in this case-control study, including 1813 MetS cases and 2037 healthy controls. The diagnostic criteria was according to the International Diabetes Federation (IDF). Metabolic complements such as waist circumference (WC), triglyceride, high-density lipoprotein cholesterol (HDL-C), systolic and diastolic blood pressure (SBP and DBP), and fasting glucose were measured. We explored the association between two novel single nucleotide polymorphism (SNPs) of BUD13 (rs7118999 and rs10488698) and MetS and its complements. RESULTS: Using binary logistic regression analysis we found that there were no significant associations between SNPs and MetS in different heritance models (all P > 0.05). However, novel locus of BUD13 were linked to individual complements in MetS cases. Rs7118999 conferred to risk of WC (P = 0.016) and the carrier of TT might have higher susceptibility to MetS. While rs10488698 was associated with HDL-C (P = 0.001) and the carrier of TT was significantly associated with higher level of HDL-C. CONCLUSIONS: We concluded that novel mutations in BUD13 did not confer risk for MetS in our study population, but these mutations changed the level of metabolic complements. PMID- 28659143 TI - Explaining time elapsed prior to cancer diagnosis: patients' perspectives. AB - BACKGROUND: Cancer is the leading cause of death in Canada. Early cancer diagnosis could improve patients' prognosis and quality of life. This study aimed to analyze the factors influencing elapsed time between the first help-seeking trigger and cancer diagnosis with respect to the three most common and deadliest cancer types: lung, breast, and colorectal. METHODS: This paper presents the qualitative component of a larger project based on a sequential explanatory design. Twenty-two patients diagnosed were interviewed, between 2011 to 2013, in oncology clinics of four hospitals in the two most populous regions in Quebec (Canada). Transcripts were analyzed using the Model of Pathways to Treatment. RESULTS: Pre-diagnosis elapsed time and phases are difficult to appraise precisely and vary according to cancer sites and symptoms specificity. This observation makes the Model of Pathways to Treatment challenging to use to analyze patients' experiences. Analyses identified factors contributing to elapsed time that are linked to type of cancer, to patients, and to health system organization. CONCLUSIONS: This research allowed us to identify avenues for reducing the intervals between first symptoms and cancer diagnosis. The existence of inequities in access to diagnostic services, even in a universal healthcare system, was highlighted. PMID- 28659145 TI - Erratum to: A four-part working bibliography of neuroethics: Part 4 - Ethical issues in clinical and social applications of neuroscience. PMID- 28659144 TI - Impaired right ventricular contractile function in childhood obesity and its association with right and left ventricular changes: a cine DENSE cardiac magnetic resonance study. AB - BACKGROUND: Pediatric obesity is a growing public health problem, which is associated with increased risk of cardiovascular disease and premature death. Left ventricular (LV) remodeling (increased myocardial mass and thickness) and contractile dysfunction (impaired longitudinal strain) have been documented in obese children, but little attention has been paid to the right ventricle (RV). We hypothesized that obese/overweight children would have evidence of RV remodeling and contractile dysfunction. METHODS: One hundred and three children, ages 8-18 years, were prospectively recruited and underwent cardiovascular magnetic resonance (CMR), including both standard cine imaging and displacement encoding with stimulated echoes (DENSE) imaging, which allowed for quantification of RV geometry and function/mechanics. RV free wall longitudinal strain was quantified from the end-systolic four-chamber DENSE image. Linear regression was used to quantify correlations of RV strain with LV strain and measurements of body composition (adjusted for sex and height). Analysis of variance was used to study the relationship between RV strain and LV remodeling types (concentric remodeling, eccentric/concentric hypertrophy). RESULTS: The RV was sufficiently visualized with DENSE in 70 (68%) subjects, comprising 36 healthy weight (13.6 +/ 2.7 years) and 34 (12.1 +/- 2.9 years) obese/overweight children. Obese/overweight children had a 22% larger RV mass index (8.2 +/- 0.9 vs 6.7 +/- 1.1 g/m2.7, p < 0.001) compared to healthy controls. RV free wall longitudinal strain was impaired in obese/overweight children (-16 +/- 4% vs -19 +/- 5%, p = 0.02). Ten (14%) out of 70 children had LV concentric hypertrophy, and these children had the most impaired RV longitudinal strain compared to those with normal LV geometry (-13 +/- 4% vs -19 +/- 5%, p = 0.002). RV longitudinal strain was correlated with LV longitudinal strain (r = 0.34, p = 0.004), systolic blood pressure (r = 0.33, p = 0.006), as well as BMI z-score (r = 0.28, p = 0.02), waist (r = 0.31, p = 0.01), hip (r = 0.40, p = 0.004) and abdominal (r = 0.38, p = 0.002) circumference, height and sex adjusted. CONCLUSIONS: Obese/overweight children have evidence of RV remodeling (increased RV mass) and RV contractile dysfunction (impaired free wall longitudinal strain). Moreover, RV longitudinal strain correlates with LV longitudinal strain, and children with LV concentric hypertrophy show the most impaired RV function. These results suggest there may be a common mechanism underlying both remodeling and dysfunction of the left and right ventricles in obese/overweight children. PMID- 28659147 TI - Health as a bridge to peace and trust in Myanmar: The 21st Century Panglong Conference. AB - The twenty-first Century Panglong Conference, proposed by Aung San Suu Kyi and her National League for Democracy, has concluded with unsatisfactory results. This five-day conference attracted global attention and wide endorsements from the United Nations and many other key stakeholders. The broad framework of the peace dialogue included various social and economic issues. However, the implication of the conference on the health system strengthening efforts in ethnic areas was largely unknown. Although a "convergence model" was proposed by organizations in Thai-Myanmar borders as a roadmap for integrations of the national and ethnic health systems years ago, the genuine bottlenecks beneath have not been addressed. This commentary discussed the Panglong Conference and its implication for the health systems in ethnic regions, as well as the bottlenecks of a "peace process" in health sector. It outlined a few key steps to achieve health system convergence between national and ethnic health systems, the outcome of which will not only improve the health status of the ethnic regions, but also help strengthen mutual trust and understanding among peoples, as a powerful bridge for peace. PMID- 28659146 TI - Antibody targeting of claudin-1 as a potential colorectal cancer therapy. AB - BACKGROUND: Metastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti CLDN1 monoclonal antibody (mAb). METHODS: Gene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells. RESULTS: Compared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation. CONCLUSION: Our data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target. PMID- 28659149 TI - Estimating canine cancer incidence: findings from a population-based tumour registry in northwestern Italy. AB - BACKGROUND: Canine cancer registry data can be put to good use in epidemiological studies. Quantitative comparison of tumour types may reveal unusual cancer frequencies, providing directions for research and generation of hypotheses of cancer causation in a specific area, and suggest leads for identifying risk factors. Here we report canine cancer incidence rates calculated from a population-based registry in an area without any known specific environmental hazard. RESULTS: In its 90 months of operation from 2001 to 2008 (the observation period in this study), the population-based Piedmont Canine Cancer Registry collected data on 1175 tumours confirmed by histopathological diagnosis. The incidence rate was 804 per 100,000 dog-years for malignant tumours and 897 per 100,000 dog-years for benign tumours. Higher rates for all cancers were observed in purebred dogs, particularly in Yorkshire terrier and Boxer. The most prevalent malignant neoplasms were cutaneous mastocytoma and hemangiopericytoma, and mammary gland complex carcinoma and simplex carcinoma. CONCLUSIONS: The Piedmont canine cancer registry is one of few of its kind whose operations have been consistently supported by long-term public funding. The registry-based cancer incidence rates were estimated with particular attention to the validity of data collection, thus minimizing the potential for bias. The findings on cancer incidence rates may provide a reliable reference for comparison studies. Researches conducted on dogs, used as sentinels for community exposure to environmental carcinogens, can be useful to detect excess risks in the incidence of malignant tumours in the human population. PMID- 28659148 TI - PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation. AB - BRAF inhibitors (BRAFi) are standard of care for the treatment of BRAF V600 mutation-driven metastatic melanoma, but can lead to paradoxical activation of the mitogen-activated protein kinase (MAPK) signalling pathway. This can result in the promotion of precancerous lesions and secondary neoplasms, mainly (but not exclusively) associated with pre-existing mutations in RAS genes. We previously reported a patient with synchronous BRAF-mutated metastatic melanoma and BRAF wt /KRAS G12D-metastatic colorectal cancer (CRC), whose CRC relapsed and progressed when treated with the BRAF inhibitor dabrafenib (GSK2118436). We used tissue from the resected CRC metastasis to derive a cell line, LM-COL-1, which directly and reliably mimicked the clinical scenario including paradoxical activation of the MAPK signalling pathway resulting in increased cell proliferation upon dabrafenib treatment. Novel BRAF inhibitors (PLX8394 and PLX7904), dubbed as "paradox breakers", were developed to inhibit V600 mutated oncogenic BRAF without causing paradoxical MAPK pathway activation. In this study we used our LM-COL-1 model alongside multiple other CRC cell lines with varying mutational backgrounds to demonstrate and confirm that the paradox breaker PLX8394 retains on-target inhibition of mutated BRAF V600 without paradoxically promoting MAPK signalling. PMID- 28659150 TI - Early diagnosis and care is achieved but should be improved in infants with Prader-Willi syndrome. AB - BACKGROUND: PWS is a severe neurodevelopmental genetic disorder now usually diagnosed in the neonatal period from hypotonia and feeding difficulties. Our study analyzed the birth incidence and care of infants with early diagnosis. METHODS: Data were collected on 61 infants with a molecular diagnosis of PWS born in 2012 and 2013 in France. RESULTS: Thirty-eight infants with PWS were born in 2013. The median age at diagnosis was 18 days. Birth incidence calculated for 2013 was 1/21,000 births. No case was diagnosed prenatally, despite 9 amniocenteses, including 4 for polyhydramnios. Five infants had delayed diagnosis, after 3 months of life. For 2 of them, the diagnosis was not suspected at birth and for 3, FISH analysis in the neonatal period was normal, with no further molecular studies. Ninety-three percent of the neonates were hospitalized, and 84% needed nasogastric tube feeding for a median of 38 days. Swallowing assessment was performed for 45%, at a median age of 10 days. Physiotherapy was started for 76% during hospitalization. Eighty percent of those diagnosed within the first 3 months were seen by a pediatric endocrinologist within the first week of life. CONCLUSION: Our study is the first to assess the birth incidence of PWS in France, at 1/21,000 births. Some prenatal or neonatal cases remain undiagnosed because of unrecognized clinical signs and the inappropriate choice of the initial molecular test. We also underscore the need to optimize neonatal care of infants with PWS. PMID- 28659151 TI - Pain and quality of life evaluation in patients with localized epidermolysis bullosa simplex. AB - BACKGROUND: A localized form of epidermolysis bullosa simplex (EBS-l) is considered one of the mildest forms of epidermolysis bullosa (EB), with blisters limited to the palms and soles. However, these lesions can be very painful. The aim of the study was to characterize pain in patients with EBS-l and evaluate its impact on quality of life (QoL). Patients were contacted via the Research Group of the French Society of Pediatric Dermatology and the association of EB patients (DEBRA France). One investigator used a standardized questionnaire that included validated scales for pain and QoL for a telephone interview. RESULTS: We included 57 patients (27 children). All patients had pain: the mean pain on a 10-mm visual analog scale was >5 for most adults (90%) and children >=8 years old (94%) when blisters were present and for most adults (73%) and about half of the children >= age 8 (53%) during dressing changes. Similar results were found for younger patients. Overall, 75% of patients had neuropathic pain; for 55% of children and 73% of adults, the pain had a moderate to severe impact on QOL. Only seven patients used premedication before changing dressings and seven regularly used oral treatment for chronic pain. A total of 21% and 23% of patients used non steroidal anti-inflammatory drugs and grade 2 analgesics, respectively. These treatments were not effective for neuropathic pain. Six patients tried 5% lidocaine plasters on their feet, with good efficacy. CONCLUSIONS: EBS-l patients have frequent and severe pain with neuropathic characteristics. This pain is undertreated and affects QoL. PMID- 28659152 TI - Idelalisib may have the potential to increase radiotherapy side effects. AB - INTRODUCTION: Idelalisib is approved for the treatment of relapsed chronic lymphocytic leukemia together with Rituximab and for monotherapy of follicular B cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. It is a potent and selective phosphatidylinositol 3-kinase-delta (PI3K-delta) inhibitor. PI3K-delta primarily is expressed in B-cells and prevents effectively proliferation in malignant B-cells. METHODS: We provide a detailed report on treatment history and photo documentation of acute adverse effects of radiation therapy with simultaneous Idelalisib medication in one case of B-CLL. Radiosensitivity tests were performed for the index patient under Idelalisib and after the addition of Idelalisib to healthy individuals' blood. Radiosensitivity in human lymphocytes was analyzed with a three color in situ hybridization assay. Primary skin fibroblasts were studied after a treatment with Idelalisib for apoptosis, necrosis and cell cycle using flow cytometry. DNA double-strand break repair was analyzed by gammaH2AX immunostaining. RESULTS: The index patient presented a strong grade 2 radiodermatitis and grade 3 mucositis after irradiation with 20 Gy and a simultaneous intake of Idelalisib. Irradiations without Idelalisib medication were well tolerated and resulted in not more than grade 1 radiodermatitis. The index patient under Idelalisib had a radiosensitivity of 0.62 B/M which is in the range of clearly radiosensitive patients. A combined treatment of lymphocytes with 2 Gy and 10 nmol/l Idelalisib showed a tendency to an increased radiosensitivity. We found a clear increase of apoptosis as a result of the combined treatment in the Idelalisib dose range of 1 to 100 nmol/l compared to solely irradiated cells or solely Idelalisib treated cells (p = 0.05). CONCLUSION: A combined Idelalisib radiotherapy treatment has an increased risk of side effects. However, combined therapy seems to be feasible when patients are monitored closely. PMID- 28659153 TI - Advanced glycation end products (AGEs) increase renal lipid accumulation: a pathogenic factor of diabetic nephropathy (DN). AB - BACKGROUND: Advanced glycation end products (AGEs) are pathogenic factors of diabetic nephropathy (DN), causing renal damage in various ways. The aim of this study is to investigate the ectopic lipid accumulation caused by AGEs in human renal tubular epithelial cell line (HK-2) cells and the kidney of type 2 diabetic rats. METHODS: In vivo study, diabetes was induced in male Sprague-Dawley rats through intraperitoneal injection of high-fat/high-sucrose diet and low-dose streptozocin (STZ). Two weeks after STZ injection, the diabetic rats were randomly divided into two groups, namely, untreated diabetic and Aminoguanidine Hydrochloride (AG, an AGEs formation inhibitor)-treated (100 mg/Kg/day, i.g., for 8 weeks) group. In vitro study, according to the different treatments, HK-2 were divided into 6 groups. Intracellular cholesterol content was assessed by Oil Red O staining and cholesterol enzymatic assay. Expression of mRNA and protein of molecules controlling cholesterol homeostasis in the treated cells was examined by real-time quantitative PCR and western blotting, respectively. SREBP cleavage activating protein (SCAP) translocation was detected by confocal microscopy. RESULTS: Here we found Nepsilon-(carboxymethyl) lysine (CML, a member of the AGEs family) increased Oil Red O staining and intracellular cholesterol ester (CE) in HK-2 cells; Anti-RAGE (AGEs receptor) reduced lipid droplets and the CE level. A strong staining of Oil Red O was also found in the renal tubules of the diabetic rats, which could be alleviated by AG. CML upregulated both mRNA and protein expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), LDL receptor (LDLr), sterol regulatory element binding protein-2 (SREBP-2) and SCAP, which were inhibited by anti-RAGE. The upregulation of these molecules in the kidney of the diabetic rats was also ameliorated by AG. Furthermore, AG reduced serum and renal CML deposition, and improved urine protein and u-NGAL in type 2 diabetic rats. CONCLUSIONS: Overall, these results suggest that CML caused DN might be via disturbing the intracellular feedback regulation of cholesterol. Inhibition of CML-induced lipid accumulation might be a potential renoprotective role in the progression of DN. PMID- 28659154 TI - Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia. AB - BACKGROUND: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. RESULTS: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3 12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. CONCLUSIONS: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition. PMID- 28659155 TI - Building capacity for information and communication technology use in global health research and training in China: a qualitative study among Chinese health sciences faculty members. AB - BACKGROUND: The demand to use information and communications technology (ICT) in education and research has grown fast among researchers and educators working in global health. However, access to ICT resources and the capacity to use them in global health research remains limited among developing country faculty members. In order to address the global health needs and to design an ICT-related training course, we herein explored the Chinese health science faculty members' perceptions and learning needs for ICT use. METHODS: Nine focus groups discussions (FGDs) were conducted during December 2015 to March 2016, involving 63 faculty members working in areas of health sciences from six universities in China. All FGDs were audio recorded and analysed thematically. RESULTS: The findings suggest that the understandings of ICT were not clear among many researchers; some thought that the concept of ICT was too wide and ambiguous. Most participants were able to cite examples of ICT application in their research and teaching activities. Positive attitudes and high needs of ICT use and training were common among most participants. Recommendations for ICT training included customised training programmes focusing on a specific specialty, maintaining a balance between theories and practical applications, more emphasis on the application of ICT, and skills in finding the required information from the bulk information available in the internet. Suggestions regarding the format and offering of training included short training programmes, flexible timing, lectures with practicum opportunities, and free of charge or with very minimal cost to the participants. Two participants suggested the linking of ICT-related training courses with faculty members' year-end assessment and promotion. CONCLUSIONS: This study among health sciences faculty members in China demonstrated a high level of need and interest in learning about ICT use in research and training. The results have important implications for the design and implementation of ICT-related educational programmes in China and other developing countries. PMID- 28659156 TI - The Arm Movement Detection (AMD) test: a fast robotic test of proprioceptive acuity in the arm. AB - BACKGROUND: We examined the validity and reliability of a short robotic test of upper limb proprioception, the Arm Movement Detection (AMD) test, which yields a ratio-scaled, objective outcome measure to be used for evaluating the impact of sensory deficits on impairments of motor control, motor adaptation and functional recovery in stroke survivors. METHODS: Subjects grasped the handle of a horizontal planar robot, with their arm and the robot hidden from view. The robot applied graded force perturbations, which produced small displacements of the handle. The AMD test required subjects to respond verbally to queries regarding whether or not they detected arm motions. Each participant completed ten, 60s trials; in five of the trials, force perturbations were increased in small increments until the participant detected motion while in the others, perturbations were decreased until the participant could no longer detect motion. The mean and standard deviation of the 10 movement detection thresholds were used to compute a Proprioceptive Acuity Score (PAS). Based on the sensitivity and consistency of the estimated thresholds, the PAS quantifies the likelihood that proprioception is intact. Lower PAS scores correspond to higher proprioceptive acuity. Thirty-nine participants completed the AMD test, consisting of 25 neurologically intact control participants (NIC), seven survivors of stroke with intact proprioception in the more affected limb (HSS+P), and seven survivors of stroke with impaired or absent proprioception in the more affected limb (HSS-P). RESULTS: Significant group differences were found, with the NIC and HSS+P groups having lower (i.e., better) PAS scores than the HSS-P group. A subset of the participants completed the AMD test multiple times and the AMD test was found to be reliable across repetitions. CONCLUSIONS: The AMD test required less than 15 min to complete and provided an objective, ratio-scaled measure of proprioceptive acuity in the upper limb. In the future, this test could be utilized to evaluate the contributions of sensory deficits to motor recovery following stroke. PMID- 28659157 TI - Supporting medication discontinuation: provider preferences for interventions to facilitate deprescribing. AB - BACKGROUND: One approach to prevent adverse drug events is to discontinue ("deprescribe") medications that are outdated, not indicated, or of limited benefit relative to risk for a particular patient. However, there is little guidance to clinicians about how to integrate the process of deprescribing into the workflow of clinical practice. We sought to determine clinical prescribers' preferences for interventions that would improve their ability to appropriately and proactively discontinue medications. METHODS: We conducted a national web based survey of 2475 prescribers [physicians, nurse practitioners (NP), physician assistants (PA), and clinical pharmacy specialists] practicing in US Veterans Affairs (VA) primary care clinics. One survey question presented 15 potential changes to medication-related practices and respondents ranked their top three choices for changes that would "most improve [their] ability to discontinue medications." We summed the weighted rankings for each of the 15 response options. Preferences were determined for the whole sample and within subgroups of respondents defined by demographic and background characteristics, medication relevant experience, and beliefs. RESULTS: Among the 326 respondents who provided rankings, the top choice for a change that would help improve their ability to discontinue medications was "Requiring all medication prescriptions to have an associated 'indication for use.'" This preference was followed by "Assistance with follow-up of patients as they taper or discontinue medications is performed by another member of the Patient Aligned Care Team (PACT)" and "Increased patient involvement in prescribing decisions." This combination of options, albeit in varying rank order, was the most commonly selected, with 250 respondents (77%) who answered the question including at least one of these items in their three highest ranked choices, regardless of their demographics, experience, or beliefs. CONCLUSIONS: Continued efforts to improve clinicians' ability to make prescribing decisions, especially around deprescribing, have many potential benefits, including decreased pharmaceutical and health care costs, fewer adverse drug events and complications, and improved patient involvement and satisfaction with their care. Future work, whether as research or quality improvement, should incorporate clinicians' preferences for interventions, as greater buy-in from front-line staff leads to better adoption of changes. PMID- 28659158 TI - Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics. AB - BACKGROUND: Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. RESULTS: We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, delta-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. CONCLUSION: The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development. PMID- 28659159 TI - Searching for management approaches to reduce HAI transmission (SMART): a study protocol. AB - BACKGROUND: Healthcare-associated infections (HAIs) impact patients' lives through prolonged hospitalization, morbidity, and death, resulting in significant costs to both health systems and society. Central line-associated bloodstream infections (CLABSIs) and catheter-associated urinary tract infections (CAUTIs) are two of the most preventable HAIs. As a result, these HAIs have been the focus of significant efforts to identify evidence-based clinical strategies to reduce infection rates. The Comprehensive Unit-based Safety Program (CUSP) provides a formal model for translating CLABSI-reduction evidence into practice. Yet, a national demonstration project found organizations experienced variable levels of success using CUSP to reduce CLABSIs. In addition, in Fiscal year 2019, Medicare will expand use of CLABSI and CAUTI metrics beyond ICUs to the entire hospital for reimbursement purposes. As a result, hospitals need guidance about how to successfully translate HAI-reduction efforts such as CUSP to non-ICU settings (clinical practice), and how to shape context (management practice)-including culture and management strategies-to proactively support clinical teams. METHODS: Using a mixed-methods approach to evaluate the contribution of management factors to successful HAI-reduction efforts, our study aims to: (1) Develop valid and reliable measures of structural management practices associated with the recommended CLABSI Management Strategies for use as a survey (HAI Management Practice Guideline Survey) to support HAI-reduction efforts in both medical/surgical units and ICUs; (2) Develop, validate, and then deploy the HAI Management Practice Guideline Survey, first across Ohio hospitals, then nationwide, to determine the positive predictive value of the measurement instrument as it relates to CLABSI- and CAUTI-prevention; and (3) Integrate findings into a Management Practices Toolkit for HAI reduction that includes an organization-specific data dashboard for monitoring progress and an implementation program for toolkit use, and disseminate that Toolkit nationwide. DISCUSSION: Providing hospitals with the tools they need to successfully measure management structures that support clinical care provides a powerful approach that can be leveraged to reduce the incidence of HAIs experienced by patients. This study is critical to providing the information necessary to successfully "make health care safer" by providing guidance on how contextual factors within a healthcare setting can improve patient safety across hospitals. PMID- 28659160 TI - Inhibition of mirtazapine metabolism by Ecstasy (MDMA) in isolated perfused rat liver model. AB - BACKGROUND: Nowadays MDMA (3,4-methylendioxymethamphetamine), known as ecstasy, is widely abused among the youth because of euphoria induction in acute exposure. However, abusers are predisposed to depression in chronic consumption of this illicit compound. Mirtazapine (MRZ), an antidepressant agent, may be prescribed in MDMA-induced depression. MRZ is extensively metabolized in liver by CYP450 isoenzymes. 8-hydroxymirtazapine (8-OH) is mainly produced by CYP2D6. N desmethylmirtazapine (NDES) is generated by CYP3A4. MDMA is also metabolized by the mentioned isoenzymes and demonstrates mechanism-based inhibition (MBI) in association with CYP2D6. Several studies revealed that MDMA showed inhibitory effects on CYP3A4. In the present study, our aim was to evaluate the impact of MDMA on the metabolism of MRZ in liver. Therefore, isolated perfused rat liver model was applied as our model of choice in this assessment. METHODS: The subjects of the study were categorized into two experimental groups. Rats in the control group received MRZ-containing Krebs-Henselit buffer (1 MUg/ml). Rats in the treatment group received aqueous solution of 1 mg/ml MDMA (3 mg/kg) intraperitoneally 1 hour before receiving MRZ. Perfusate samples were analyzed by HPLC. RESULTS: Analyses of perfusate samples showed 80% increase in the parent drug concentrations and 50% decrease in the concentrations of both metabolites in our treatment group compared to the control group. In the treatment group compared to the control group, AUC(0-120) of the parent drug demonstrated 50% increase and AUC(0-120) of 8-OH and NDES showed 70% and 60% decrease, respectively. Observed decrease in metabolic ratios were 83% and 79% for 8-OH and NDES in treatment group compared to control group, respectively. Hepatic clearance (CLh) and intrinsic clearance (Clint) showed 20% and 60% decrease in treatment group compared to control group. CONCLUSION: All findings prove the inhibitory effects of ecstasy on both CYP2D6 and CYP3A4 hepatic isoenzymes. In conclusion, this study is the first investigation of MRZ metabolism in presence of MDMA in isolated perfused rat liver model. PMID- 28659161 TI - Associations between cerebral amyloid and changes in cognitive function and falls risk in subcortical ischemic vascular cognitive impairment. AB - BACKGROUND: To determine the association between amyloid-beta (Abeta) plaque deposition and changes in global cognition, executive functions, information processing speed, and falls risk over a 12-month period in older adults with a primary clinical diagnosis of subcortical ischemic vascular cognitive impairment (SIVCI). METHODS: This is a secondary analysis of data acquired from a subset of participants (N = 22) who were enrolled in a randomized controlled trial of aerobic exercise (NCT01027858). The subset of individuals completed an 11C Pittsburgh compound B (PIB) scan. Cognitive function and falls risk were assessed at baseline, 6-months, and 12-months. Global cognition, executive functions, and information processing speed were measured using: 1) ADAS-Cog; 2) Trail Making Test; 3) Digit Span Test; 4) Stroop Test, and 5) Digit Symbol Substitution Test. Falls risk was measured using the Physiological Profile Assessment. Hierarchical multiple linear regression analyses determined the unique contribution of Abeta on changes in cognitive function and falls risk at 12-months after controlling for experimental group (i.e. aerobic exercise training or usual care control) and baseline performance. To correct for multiple comparisons, we applied the Benjamini-Hochberg procedure to obtain a false discovery rate corrected threshold using alpha = 0.05. RESULTS: Higher PIB retention was significantly associated with greater decrements in set shifting (Trail Making Test, adjusted R2 = 35.3%, p = 0.002), attention and conflict resolution (Stroop Test, adjusted R2 = 33.4%, p = 0.01), and information processing speed (Digit Symbol Substitution Test, adjusted R2 = 24.4%, p = 0.001) over a 12-month period. Additionally, higher PIB retention was significantly associated with increased falls risk (Physiological Profile Assessment, adjusted R2 = 49.1%, p = 0.04). PIB retention was not significantly associated with change in ADAS-Cog and Verbal Digit Span Test (p > 0.05). CONCLUSIONS: Symptoms associated with SIVCI may be amplified by secondary Abeta pathology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01027858 , December 7, 2009. PMID- 28659162 TI - Acupuncture paired with herbal medicine for prediabetes: study protocol for a randomized controlled trial. AB - BACKGROUND: Type-2 diabetes has become a major disease and is known to seriously impair people's health worldwide. Prediabetes includes impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and is the most critical period for preventing type-2 diabetes, as it can be identified and reversed. Studies in the past decade have indicated that acupuncture and Chinese herbal medicine may be beneficial for treating prediabetes. However, a randomized controlled trial (RCT) should be conducted to obtain more clinical evidence on this topic. METHODS/DESIGN: An RCT will be implemented in this study, using a72-week study period (24 weeks for the intervention and 48 weeks for follow-up). Participants will be recruited from the Fifth Affiliated Hospital of Guangzhou Medical University in China. Eighty participants will be randomized to the treatment group (acupuncture plus herbal medicine and health education) or the control group (health education only), 40 participants in each. People included in this study must have been diagnosed with prediabetes using Western medicine criteria. The endpoint indices include the incidence of diabetes mellitus and the reversion rate. The primary outcome is fasting plasma glucose (FPG) level, 2-h plasma glucose (2-hPG) level after a 75-g oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) level. Secondary outcomes include the following: Body Mass Index (BMI); hemorheology, including shear rates of whole-blood viscosity and plasma viscosity. Safety indices include hepatic (ALT, AST) and renal function (BUN, Cr) and records of adverse events, including diarrhoea, colds, pharyngitis, and sleep disorders. Quality control will be implemented, including quality control of the laboratory, researchers, participants, investigational drugs, data and documents, occurrence of bias, supervision, among others, according to uniform standard operating procedures (SOPs) which have been established by the Good Clinical Practice (GCP) office of the Fifth Affiliated Hospital of Guangzhou Medical University. DISCUSSION: The aim of this study is to evaluate the efficacy and safety of acupuncture paired with herbal medicine for the treatment of patients with prediabetes. TRIAL REGISTRATION: Chinese clinical trials register ChiCTR-INR-16008891 . Registered on 23 July 2016. PMID- 28659163 TI - The association between child and adolescent emotional disorder and poor attendance at school: a systematic review protocol. AB - BACKGROUND: Anxiety and depression are common in young people and are associated with a range of adverse outcomes. Research has suggested a relationship between emotional disorder and poor school attendance, and thus poor attendance may serve as a red flag for children at risk of emotional disorder. This systematic review aims to investigate the association between child and adolescent emotional disorder and poor attendance at school. METHODS: We will search electronic databases from a variety of disciplines including medicine, psychology, education and social sciences, as well as sources of grey literature, to identify any quantitative studies that investigate the relationship between emotional disorder and school attendance. Emotional disorder may refer to diagnoses of mood or anxiety disorders using standardised diagnostic measures, or measures of depression, anxiety or "internalising symptoms" using a continuous scale. Definitions for school non-attendance vary, and we aim to include any relevant terminology, including attendance, non-attendance, school refusal, school phobia, absenteeism and truancy. Two independent reviewers will screen identified papers and extract data from included studies. We will assess the risk of bias of included studies using the Newcastle-Ottawa Scale. Random effects meta-analysis will be used to pool quantitative findings when studies use the same measure of association, otherwise a narrative synthesis approach will be used. DISCUSSION: This systematic review will provide a detailed synthesis of evidence regarding the relationship between childhood emotional disorder and poor attendance at school. Understanding this relationship has the potential to assist in the development of strategies to improve the identification of and intervention for this vulnerable group. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016052961. PMID- 28659164 TI - Antioxidant properties, antimicrobial and anti-adhesive activities of DCS1 lipopeptides from Bacillus methylotrophicus DCS1. AB - BACKGROUND: The present work aims to investigate the antioxidant and antimicrobial activities as well as the potential of DCS1 lipopeptides produced by Bacillus methylotrophicus DCS1 strain at inhibition and disruption of biofilm formation. RESULTS: The produced biosurfactants were characterized as lipopeptides molecules by using thin layer chromatography (TLC) and Fourier transform infrared spectroscopy (FT-IR). The DCS1 lipopeptides were assayed for their antioxidant activity through five different tests. The scavenging effect on DPPH radicals at a concentration of 1 mg mL-1 was 80.6%. The reducing power reached a maximum value of 3.0 (OD700 nm) at 2 mg mL-1. Moreover, the DCS1 lipopeptides exhibited a strong inhibition of beta-carotene bleaching by linoleic acid assay with 80.8% at 1 mg mL-1 and showed good chelating ability and lipid peroxidation inhibition. The in vitro antimicrobial activity of DCS1 lipopeptides showed that they display significant antibacterial and antifungal activities. The anti-adhesive activity of DCS1 lipopeptides was evaluated against several pathogenic microorganisms. The lipopeptides showed excellent anti-adhesive activity, even at low concentrations, in a polystyrene surface pre-treatment against all the microorganisms tested. Further, they can disrupt performed biofilms. CONCLUSION: This study shows the potentiality of DCS1 lipopeptides as natural antioxidants, antimicrobial and/or anti-adhesive agent for several biomedical and industrial applications. PMID- 28659165 TI - Longitudinal survey on the distribution of Biomphalaria sudanica and B. choanomophala in Mwanza region, on the shores of Lake Victoria, Tanzania: implications for schistosomiasis transmission and control. AB - BACKGROUND: Schistosomiasis is hyper-endemic in the Lake Victoria basin; with intestinal schistosomiasis plaguing communities adjacent to the lake, where the intermediate host snails live. The two intermediate host species of Schistosoma mansoni in the Mwanza region are Biomphalaria sudanica, found on the banks of the lakes, and B. choanomphala, found in the lake itself. There are few longitudinal surveys documenting changing abundance and differential transmission patterns of these Biomphalaria snails across seasons and years. We undertook 15 field surveys at 26 sites over four years to determine the parameters that influence Biomphalaria abundance, presence of S. mansoni-shedding snails and impact of schistosomiasis treatment interventions on transmission potential in the Mwanza region. RESULTS: Statistical analysis revealed seasonal difference in the abundance of B. sudanica with the highest number of snails found in the dry season (Kruskal-Wallis chi 2 = 37.231, df = 3, P < 0.0001). Water measurements were not associated with B. sudanica abundance; however, high levels of rainfall did have a negative effect on B. sudanica [coefficient effect -0.1405, 95% CI ( 0.2666, -0.0144)] and B. choanomphala abundance [coefficient effect -0.4388, 95% CI (-0.8546, -0.0231)] potentially due to inundation of sites "diluting" the snails and influencing collection outcome. Biomphalaria sudanica snails were found at all sites whereas B. choanomphala were far more focal and only found in certain sites. Shedding Biomphalaria did not show any variation between dry and rainy seasons; however, a decrease in shedding snails was observed in year 4 of the study. CONCLUSIONS: Biomphalaria sudanica is uniformly present in the Mwanza region whereas B. choanomphala is far more focal. Seasonality plays a role for B. sudanica abundance, likely due to its habitat preference on the banks of the lake, but not for B. choanomphala. The decrease in shedding Biomphalaria abundance in Year 4 could be linked to ongoing schistosomiasis treatment efforts in the neighbouring human populations. The highest number of shedding Biomphalaria was observed at sites with high levels of human movement. Prioritising snail control at such sites could greatly reduce transmission in these high-risk areas. PMID- 28659166 TI - Familiar ethical issues amplified: how members of research ethics committees describe ethical distinctions between disaster and non-disaster research. AB - BACKGROUND: The conduct of research in settings affected by disasters such as hurricanes, floods and earthquakes is challenging, particularly when infrastructures and resources were already limited pre-disaster. However, since post-disaster research is essential to the improvement of the humanitarian response, it is important that adequate research ethics oversight be available. METHODS: We aim to answer the following questions: 1) what do research ethics committee (REC) members who have reviewed research protocols to be conducted following disasters in low- and middle-income countries (LMICs) perceive as the key ethical concerns associated with disaster research?, and 2) in what ways do REC members understand these concerns to be distinct from those arising in research conducted in non-crisis situations? This qualitative study was developed using interpretative description methodology; 15 interviews were conducted with REC members. RESULTS: Four key ethical issues were identified as presenting distinctive considerations for disaster research to be implemented in LMICs, and were described by participants as familiar research ethics issues that were amplified in these contexts. First, REC members viewed disaster research as having strong social value due to its potential for improving disaster response, but also as requiring a higher level of justification compared to other research settings. Second, they identified vulnerability as an overarching concern for disaster research ethics, and a feature that required careful and critical appraisal when assessing protocols. They noted that research participants' vulnerabilities frequently change in the aftermath of a disaster and often in unpredictable ways. Third, they identified concerns related to promoting and maintaining safety, confidentiality and data security in insecure or austere environments. Lastly, though REC members endorsed the need and usefulness of community engagement, they noted that there are significant challenges in a disaster setting over and above those typically encountered in global health research to achieve meaningful community engagement. CONCLUSION: Disaster research presents distinctive ethical considerations that require attention to ensure that participants are protected. As RECs review disaster research protocols, they should address these concerns and consider how justification, vulnerability, security and confidentially, and community engagement are shaped by the realities of conducting research in a disaster. PMID- 28659167 TI - Deviations from the expected relationship between serum FGF23 and other markers in children with CKD: a cross-sectional study. AB - BACKGROUND: High levels of fibroblast growth factor-23 (FGF23) are associated with mortality. In chronic kidney disease (CKD), FGF23 levels rise as renal function declines. We analyzed the contribution of laboratory values to the variance of FGF23 levels in relationship to a curve of expected FGF23 levels for a given GFR. METHODS: Following approval by the research ethics boards, we measured FGF23, CysC eGFR, creatinine, urea, albumin, calcium, phosphate, vitamin D metabolites, PTH, alkaline phosphatase, CRP, and venous gases in 141 pediatric CKD patients (45, 37, 32, 13 and 14 CKD stages I, II, III, IV, and V, respectively). Data were expressed as median (25th, 75th percentile). RESULTS: FGF23 correlated significantly with CysC, CysC eGFR, PTH, 1.25 (OH)2 vitamin D, phosphate, and pH. The correlation of the latter three remained significant in the multivariate analysis. We calculated a formula for the expected FGF23 value for a given level of eGFR which reads Y = 1295 * e-0.07247*X + 38.35. Deviation by more than 20% from the curve also depended on phosphate, 1.25 (OH)2 vitamin D and pH. CONCLUSIONS: Our data emphasize the importance of phosphate and 1.25 (OH)2 vitamin D levels. The impact of acidosis on FGF23 warrants further studies. PMID- 28659170 TI - The transcriptome of a "sleeping" invader: de novo assembly and annotation of the transcriptome of aestivating Cornu aspersum. AB - BACKGROUND: Cornu aspersum is a quite intriguing species from the point of view of ecology and evolution and its potential use in medical and environmental applications. It is a species of economic importance since it is farmed and used for culinary purposes. However, the genomic tools that would allow a thorough insight into the ecology, evolution, nutritional and medical properties of this highly adaptable organism, are missing. In this work, using next-generation sequencing (NGS) techniques we assessed a significant portion of the transcriptome of this non-model organism. RESULTS: Out of the 9445 de novo assembled contigs, 2886 (30.6%) returned significant hits and for 2261 (24%) of them Gene Ontology (GO) terms associated to the hits were retrieved. A high percentage of the contigs (69.4%) produced no BLASTx hits. The GO terms were grouped to reflect biological processes, molecular functions and cellular components. Certain GO terms were dominant in all groups. After scanning the assembled transcriptome for microsatellites (simple sequence repeats, SSRs), a total of 563 SSRs were recovered. Among the identified SSRs, trinucleotide repeats were the predominant followed by tetranucleotide and dinucleotide repeats. CONCLUSION: The annotation success of the transcriptome of C. aspersum was relatively low. This is probably due to the very limited number of annotated reference genomes existing for mollusc species, especially terrestrial ones. Several biological processes being active in the aestivating species were revealed through the association of the transcripts to enzymes relating to the pathways. The genomic tools provided herein will eventually aid in the study of the global genomic diversity of the species and the investigation of aspects of the ecology, evolution, behavior, nutritional and medical properties of this highly adaptable organism. PMID- 28659169 TI - The novel compound PBT434 prevents iron mediated neurodegeneration and alpha synuclein toxicity in multiple models of Parkinson's disease. AB - Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of alpha synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral alpha-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T alpha-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD. PMID- 28659171 TI - Comparison of endoscopic evacuation, stereotactic aspiration and craniotomy for the treatment of supratentorial hypertensive intracerebral haemorrhage: study protocol for a randomised controlled trial. AB - BACKGROUND: Hypertensive intracerebral haemorrhage (HICH) is the most common form of haemorrhagic stroke with the highest morbidity and mortality of all stroke types. The choice of surgical or conservative treatment for patients with HICH remains controversial. In recent years, minimally invasive surgeries, such as endoscopic evacuation and stereotactic aspiration, have been attempted for haematoma removal and offer promise. However, research evidence on the benefits of endoscopic evacuation or stereotactic aspiration is still insufficient. METHODS/DESIGN: A multicentre, randomised controlled trial will be conducted to compare the efficacy of endoscopic evacuation, stereotactic aspiration and craniotomy in the treatment of supratentorial HICH. About 1350 eligible patients from 10 neurosurgical centres will be randomly assigned to an endoscopic group, a stereotactic group and a craniotomy group at a 1:1:1 ratio. Randomisation is undertaken using a 24-h randomisation service accessed by telephone or the Internet. All patients will receive the corresponding surgery based on their grouping. They will be followed-up at 1, 3 and 6 months after surgery. The primary outcome is the modified Rankin Scale at 6-month follow-up. Secondary outcomes include: haematoma clearance rate; Glasgow Coma Scale 7 days after surgery; rebleeding rate; intracranial infection rate; hospitalisation time; mortality at 1 month and 3 months after surgery; the Barthel Index and the WHO quality of life at 3 months and 6 months after surgery. DISCUSSION: The trial aims to investigate whether endoscopic evacuation and stereotactic aspiration could improve the outcome of supratentorial HICH compared with craniotomy. The trial will help to determine the best surgical method for the treatment of supratentorial HICH. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02811614 . Registered on 20 June 2016. PMID- 28659172 TI - What will make a difference? Assessing the impact of policy and non-policy scenarios on estimations of the future GP workforce. AB - BACKGROUND: Health workforce planning is based on estimates of future needs for and supply of health care services. Given the pipeline time lag for the training of health professionals, inappropriate workforce planning or policies can lead to extended periods of over- or under-supply of health care providers. Often these policy interventions focus on one determinant of supply and do not incorporate other determinants such as changes in population health which impact the need for services. The aim of this study is to examine the effect of the implementation of various workforce policies on the estimated future requirements of the GP workforce, using South Australia as a case study. This is examined in terms of the impact on the workforce gap (excess or shortage), the cost of these workforce policies, and their role in addressing potential non-policy-related future scenarios. METHODS: An integrated simulation model for the general practice workforce in South Australia was developed, which determines the supply and level of services required based on the health of the population over a projection period 2013-2033. The published model is used to assess the effects of various policy and workforce scenarios. For each policy scenario, associated costs were estimated and compared to baseline costs with a 5% discount rate applied. RESULTS: The baseline scenario estimated an excess supply of GPs of 236 full-time equivalent (FTE) in 2013 but this surplus decreased to 28 FTE by 2033. The estimates based on single policy scenarios of role substitution and increased training positions continue the surplus, while a scenario that reduces the number of international medical graduates (IMGs) recruited estimated a move from surplus to shortage by 2033. The best-case outcome where the workforce achieves balance by 2023 and remains balanced to 2033, arose when GP participation rates (a non policy scenario) were combined with the policy levers of increased GP training positions and reduced IMG recruitment. The cost of each policy varied, with increased role substitution and reduced IMG recruitment resulting in savings (AUD$752,946,586 and AUD$3,783,291 respectively) when compared to baseline costs. Increasing GP training costs over the projection period would cost the government an additional AUD$12,719,798. CONCLUSIONS: Over the next 20 years, South Australia's GP workforce is predicted to remain fairly balanced. However, exogenous changes, such as increased demand for GP services may require policy intervention to address associated workforce shortfalls. The workforce model presented in this paper should be updated at regular intervals to inform the need for policy intervention. PMID- 28659173 TI - Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling. AB - BACKGROUND: Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown. METHODS: lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs. RESULTS: The microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway. CONCLUSIONS: MRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC. PMID- 28659168 TI - Gene expression profiles and signaling mechanisms in alpha2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells. AB - BACKGROUND: alpha2-adrenoceptors are important regulators of vascular tone and blood pressure. Regulation of cell proliferation is a less well investigated consequence of alpha2-adrenoceptor activation. We have previously shown that alpha2B-adrenoceptor activation stimulates proliferation of vascular smooth muscle cells (VSMCs). This may be important for blood vessel development and plasticity and for the pathology and therapeutics of cardiovascular disorders. The underlying cellular mechanisms have remained mostly unknown. This study explored pathways of regulation of gene expression and intracellular signaling related to alpha2B-adrenoceptor-evoked VSMC proliferation. RESULTS: The cellular mechanisms and signaling pathways of alpha2B-adrenoceptor-evoked proliferation of VSMCs are complex and include redundancy. Functional enrichment analysis and pathway analysis identified differentially expressed genes associated with alpha2B-adrenoceptor-regulated VSMC proliferation. They included the upregulated genes Egr1, F3, Ptgs2 and Serpine1 and the downregulated genes Cx3cl1, Cav1, Rhoa, Nppb and Prrx1. The most highly upregulated gene, Lypd8, represents a novel finding in the VSMC context. Inhibitor library screening and kinase activity profiling were applied to identify kinases in the involved signaling pathways. Putative upstream kinases identified by two different screens included PKC, Raf 1, Src, the MAP kinases p38 and JNK and the receptor tyrosine kinases EGFR and HGF/HGFR. As a novel finding, the Src family kinase Lyn was also identified as a putative upstream kinase. CONCLUSIONS: alpha2B-adrenoceptors may mediate their pro-proliferative effects in VSMCs by promoting the activity of bFGF and PDGF and the growth factor receptors EGFR, HGFR and VEGFR-1/2. The Src family kinase Lyn was also identified as a putative upstream kinase. Lyn is known to be expressed in VSMCs and has been identified as an important regulator of GPCR trafficking and GPCR effects on cell proliferation. Identified Ser/Thr kinases included several PKC isoforms and the beta-adrenoceptor kinases 1 and 2. Cross-talk between the signaling mechanisms involved in alpha2B-adrenoceptor-evoked VSMC proliferation thus appears to involve PKC activation, subsequent changes in gene expression, transactivation of EGFR, and modulation of kinase activities and growth factor-mediated signaling. While many of the identified individual signals were relatively small in terms of effect size, many of them were validated by combining pathway analysis and our integrated screening approach. PMID- 28659174 TI - CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. AB - BACKGROUND: GPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species. METHODS: We determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a "humanized" mouse GPRC6A containing the K..Y sequence by immunofluorescence. We assessed functions of GPRC6A in PC-3 cells expressing endogenous GPRC6A and in GPRC6A-deficient PC-3 cells created using CRISPR/Cas9 technology. The effect of GPRC6A on basal and ligand stimulated cell proliferation and migration was evaluated in vitro in wild-type and PC-3 deficient cell lines. The effect of editing GPRC6A on prostate cancer growth and progression in vivo was assessed in a Xenograft mouse model implanted with wild type and PC-3 deficient cells and treated with the GPRC6A ligand osteocalcin. RESULTS: We found that all of the human prostate cancer cell lines tested endogenously express the "K..Y" polymorphism in the 3rd IL. Comparison of mouse wild-type GPRC6A with a "humanized" mouse GPRC6A construct created by replacing the "RKLP" with the "K..Y" sequence, found that both receptors were predominantly expressed on the cell surface. The transfected "humanized" GPRC6A receptor, however, preferentially activated mTOR compared to ERK signaling in HEK-293 cells. In contrast, in PC-3 cells expressing the endogenous GPRC6A with the "K..Y" polymorphism, the ligand osteocalcin stimulated ERK, AKT and mTOR phosphorylation, promoted cell proliferation and migration, and upregulated genes regulating testosterone biosynthesis. Targeting GPRC6A in PC-3 cells by CRISPR/Cas9 significantly blocked these responses in vitro. In addition, GPRC6A deficient PC-3 xenografts exhibited significantly less growth and were resistant to osteocalcin-induced prostate cancer progression compared to control PC-3 cells expressing GPRC6A. CONCLUSIONS: Human GPRC6A is a functional osteocalcin and testosterone sensing receptor that promotes prostate cancer progression. GPRC6A may contribute to racial disparities in prostate cancer, and is a potential therapeutic target to develop antagonists to treat prostate cancer. PMID- 28659175 TI - Allergens in red ginseng extract induce the release of mediators associated with anaphylactoid reactions. AB - BACKGROUND: Anaphylactoid reactions induced by preparations containing red ginseng have been reported. The aim of this study is to evaluate the allergenicity and screen potential allergens in red ginseng extract thoroughly. METHODS: Red ginseng extract (RGE) and different fractions of RGE were prepared and evaluated by measuring the degranulation and viability of rat basophilic leukemia 2H3 (RBL-2H3) cells. Potential allergens were screened by RBL-2H3 cell extraction and allergenicity verified in RBL-2H3 cells, mouse peritoneal mast cells, Laboratory of Allergic Disease 2 (LAD2) human mast cells and mice, respectively. RESULTS: 80% ethanol extract of red ginseng extract induced mast cell degranulation with less cytotoxicity, but 40% ethanol extract could not. Ginsenoside Rd and 20(S)-Rg3 could induce a significant increase in beta hexosaminidase release, histamine release and translocation of phosphatidylserine in RBL-2H3 cells. Ginsenoside Rd and 20(S)-Rg3 also increased beta-hexosaminidase release and the intracellular Ca2+ concentration in mouse peritoneal mast cells and LAD2 cells. In addition, histamine levels in serum of mice were elevated dose dependently. CONCLUSIONS: Ginsenoside Rd and 20(S)-Rg3 are potential allergens that induce the release of mediators associated with anaphylactoid reactions. Our study could guide optimization of methods associated with Rd/20(S)-Rg3-containing preparations and establishment of quality standards for safe application of Traditional Chinese Medicines. PMID- 28659176 TI - ISOWN: accurate somatic mutation identification in the absence of normal tissue controls. AB - BACKGROUND: A key step in cancer genome analysis is the identification of somatic mutations in the tumor. This is typically done by comparing the genome of the tumor to the reference genome sequence derived from a normal tissue taken from the same donor. However, there are a variety of common scenarios in which matched normal tissue is not available for comparison. RESULTS: In this work, we describe an algorithm to distinguish somatic single nucleotide variants (SNVs) in next generation sequencing data from germline polymorphisms in the absence of normal samples using a machine learning approach. Our algorithm was evaluated using a family of supervised learning classifications across six different cancer types and ~1600 samples, including cell lines, fresh frozen tissues, and formalin-fixed paraffin-embedded tissues; we tested our algorithm with both deep targeted and whole-exome sequencing data. Our algorithm correctly classified between 95 and 98% of somatic mutations with F1-measure ranges from 75.9 to 98.6% depending on the tumor type. We have released the algorithm as a software package called ISOWN (Identification of SOmatic mutations Without matching Normal tissues). CONCLUSIONS: In this work, we describe the development, implementation, and validation of ISOWN, an accurate algorithm for predicting somatic mutations in cancer tissues in the absence of matching normal tissues. ISOWN is available as Open Source under Apache License 2.0 from https://github.com/ikalatskaya/ISOWN . PMID- 28659177 TI - A Bayesian network and heuristic approach for systematic characterization of radiotherapy receipt after breast-conservation surgery. AB - BACKGROUND: Breast-conservation surgery with radiotherapy is a treatment highly recommended by the guidelines from the National Comprehensive Cancer Network. However, several variables influence the final receipt of radiotherapy and it might not be administered to breast cancer patients. Our objective is to propose a systematic framework to identify the clinical and non-clinical variables that influence the receipt of unexpected radiotherapy treatment by means of Bayesian networks and a proposed heuristic approach. METHODS: We used cancer registry data of Detroit, San Francisco-Oakland, and Atlanta from years 2007-2012 downloaded from the Surveillance, Epidemiology, and End Results Program. The samples had patients diagnosed with in situ and early invasive cancer with 14 clinical and non-clinical variables. Bayesian networks were fitted to the data of each region and systematically analyzed through the proposed Zoom-in heuristic. A comparative analysis with logistic regressions is also presented. RESULTS: For Detroit, patients under stage 0, grade undetermined, histology lobular carcinoma in situ, and age between 26-50 were found more likely to receive breast-conservation surgery without radiotherapy. For stages I, IIA, and IIB patients with age between 51-75, and grade II were found to be more likely to receive breast conservation surgery with radiotherapy. For San Francisco-Oakland, patients under stage 0, grade undetermined, and age >75 are more likely to receive BCS. For stages I, IIA, and IIB patients with age >75 are more likely to receive breast conservation surgery without radiotherapy. For Atlanta, patients under stage 0, grade undetermined, year 2011, and primary site C509 are more likely to receive breast-conservation surgery without radiotherapy. For stages I, IIA, and IIB patients in year 2011, and grade III are more likely to receive breast conservation surgery without radiotherapy. CONCLUSION: For in situ breast cancer and early invasive breast cancer, the results are in accordance with the guidelines and very well demonstrates the usefulness of the Zoom-in heuristic in systematically characterizing a group receiving a treatment. We found a subset of the population from Detroit with ductal carcinoma in situ for which breast conservation surgery without radiotherapy was received, but potential reasons for this treatment are still unknown. PMID- 28659178 TI - Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome dependent inflammation. AB - BACKGROUND: Azithromycin, an antibiotic used for multiple infectious disorders, exhibits anti-inflammatory effects, but the molecular basis for this activity is not well characterized. Azithromycin inhibits IL-1beta-mediated inflammation that is dependent, in part, on inflammasome activity. Here, we investigated the effects of azithromycin on the NACHT, LRR, and PYD domains-containing protein 3 (NALP3) protein, which is the sensing component of the NALP3 inflammasome, in human monocytes. METHODS: THP-1 cells were treated with azithromycin alone, LPS alone, or both. NALP3 and IL-1beta protein levels were determined by immunoblotting. NLRP3 gene (encoding NALP3) transcript levels were determined by quantitative qPCR. In order to measure NLRP3 transcript decay, actinomycin D was used to impair gene transcription. THP-1 Lucia cells which contain an NF-kappaB responsive luciferase element were used to assess NF-kappaB activity in response to azithromycin, LPS, and azithromycin/LPS by measuring luminescence. To confirm azithromycin's effects on NLRP3 mRNA and promoter activity conclusively, HEK cells were lipofected with luciferase reporter constructs harboring either the 5' untranslated region (UTR) of the NLRP3 gene which included the promoter, the 3' UTR of the gene, or an empty plasmid prior to treatment with azithromycin and/or LPS, and luminescence was measured. RESULTS: Azithromycin decreased IL-1beta levels and reduced NALP3 protein levels in LPS-stimulated THP-1 monocytes through a mechanism involving decreased mRNA stability of the NALP3 - coding NLRP3 gene transcript as well as by decreasing NF-kappaB activity. Azithromycin accelerated NLRP3 transcript decay confirmed by mRNA stability and 3'UTR luciferase reporter assays, and yet the antibiotic had no effect on NLRP3 promoter activity in cells containing a 5' UTR reporter. CONCLUSIONS: These studies provide a unique mechanism whereby azithromycin exerts immunomodulatory actions in monocytes by destabilizing mRNA levels for a key inflammasome component, NALP3, leading to decreased IL-1beta-mediated inflammation. PMID- 28659180 TI - Multiparametric imaging for detection and characterization of hepatocellular carcinoma using gadoxetic acid-enhanced MRI and perfusion-CT: which parameters work best? AB - BACKGROUND: MRI and perfusion-CT (PCT) are both useful imaging techniques for detection and characterization of liver lesions. The aim of this study was to compare the diagnostic accuracy of imaging parameters derived from PCT and gadoxetic acid-enhanced MRI in patients with hepatocellular carcinoma (HCC). METHODS: 36 patients with liver cirrhosis and a total of 67 lesions referred to our hospital for multi-parametric diagnosis of HCC-suspected liver lesions in the setting of liver cirrhosis were prospectively enrolled and underwent PCT and MRI. HCC diagnosis was confirmed either by histology (n = 60) or interval growth (n = 7). For PCT, mean/max blood flow (BF), blood volume (BV), k-trans, arterial liver perfusion (ALP), portal venous perfusion (PVP) and hepatic perfusion index (HPI) were quantified. Two readers identified the lesions based on single maps each being blinded to the number of lesions. MRI-protocol included fat-suppressed T1w VIBE sequences obtained before, 2, 5, 10 and 20 min after the injection of gadoxetic acid as well as non-enhanced coronal HASTE, axial T1w-VIBE, fat suppressed T2w-TSE and DWI. Quantitative analysis was performed using enhancement ratios between tumor and liver parenchyma for post-contrast in the hepatobiliary phase (RIRHB), arterial (ERa) and late-venous (ERv) phases as well as signal intensity ratios (liver/parenchyma) on T1w (RIRT1) and T2w (RIRT2). RESULTS: In PCT analysis, all lesions exhibited high BFmax values (63-250 mL/100 g tissue) and were visible on HPI maps with high degrees of arterial blood supply of (HPI > 96%). In MRI, RIRHB was negative in 8/67. 12/67 HCCs were missed on DWI. 46/67 HCCs showed wash-in and 47/67 HCC showed wash-out of contrast agent. 6/67 HCCs were missed on T1w and 11/67 were missed on T2w-sequences when analyzed separately, while analysis of multiparametric MRI combining typical enhancement pattern, visibility on hepatobiliary phase and T1w-images the same number of lesions as PCT irrespective of their size (1-19 cm) were detected. Quantification of early enhancement by ERa or ERv did not improve detection rates. CONCLUSIONS: Perfusion-CT and gadoxetic acid-enhanced MRI were comparable in detecting HCC lesions. For PCT a mean HPI > 96% proved to be a very robust parameter for detection and characterization of HCC. PMID- 28659179 TI - Coping with living in the soil: the genome of the parthenogenetic springtail Folsomia candida. AB - BACKGROUND: Folsomia candida is a model in soil biology, belonging to the family of Isotomidae, subclass Collembola. It reproduces parthenogenetically in the presence of Wolbachia, and exhibits remarkable physiological adaptations to stress. To better understand these features and adaptations to life in the soil, we studied its genome in the context of its parthenogenetic lifestyle. RESULTS: We applied Pacific Bioscience sequencing and assembly to generate a reference genome for F. candida of 221.7 Mbp, comprising only 162 scaffolds. The complete genome of its endosymbiont Wolbachia, was also assembled and turned out to be the largest strain identified so far. Substantial gene family expansions and lineage specific gene clusters were linked to stress response. A large number of genes (809) were acquired by horizontal gene transfer. A substantial fraction of these genes are involved in lignocellulose degradation. Also, the presence of genes involved in antibiotic biosynthesis was confirmed. Intra-genomic rearrangements of collinear gene clusters were observed, of which 11 were organized as palindromes. The Hox gene cluster of F. candida showed major rearrangements compared to arthropod consensus cluster, resulting in a disorganized cluster. CONCLUSIONS: The expansion of stress response gene families suggests that stress defense was important to facilitate colonization of soils. The large number of HGT genes related to lignocellulose degradation could be beneficial to unlock carbohydrate sources in soil, especially those contained in decaying plant and fungal organic matter. Intra- as well as inter-scaffold duplications of gene clusters may be a consequence of its parthenogenetic lifestyle. This high quality genome will be instrumental for evolutionary biologists investigating deep phylogenetic lineages among arthropods and will provide the basis for a more mechanistic understanding in soil ecology and ecotoxicology. PMID- 28659181 TI - Prognostic and predictive factors in patients with metastatic or recurrent cervical cancer treated with platinum-based chemotherapy. AB - BACKGROUND: Recognizing resistance or susceptibility to the current standard cisplatin and paclitaxel treatment could improve therapeutic outcomes of metastatic or recurrent cervical cancer. METHODS: Forty-five tissue samples from patients participating in a phase II trial of cisplatin and ifosfamide, with or without paclitaxel were collected for retrograde analysis. Immunohistochemistry and genotyping was performed to test ERCC1, III beta-tubulin, COX-2, CD4, CD8 and ERCC1 (C8092A and N118 N) and MDR1 (C3435T and G2677 T) gene polymorphisms, as possible predictive and prognostic markers. Results were statistically analyzed and correlated with patient characteristics and outcomes. RESULTS: Patients with higher levels of ERCC1 expression had shorter PFS and OS than patients with low ERCC1 expression (mPFS:5.1 vs 10.2 months, p = 0.027; mOS:10.5 vs. 21.4 months, p = 0.006). Patients with TT in the site of ERCC1 N118 N and GT in the site of MDR1 G2677 T polymorphisms had significantly longer PFS (p = 0.006 and p = 0.027 respectively). ERCC1 expression and the ERCC1 N118 N polymorphism remained independent predictors of PFS. Interestingly, high III beta tubulin expression was associated with chemotherapy resistance and fewer responses [5/20 (25%)] compared to lower III beta-tubulin expression [15/23 (65.2%)] (p = 0.008). Finally, IotaIotaIota beta-tubulin levels and chemotherapy regimen were independent predictors of response to treatment. CONCLUSIONS: ERCC1 expression proved to be a significant prognostic factor for survival in our metastatic or recurrent cervical cancer population treated with cisplatin based chemotherapy. ERCC1 N118 N and MDR1 G2677 T polymorphism also proved of prognostic significance for disease progression, while overexpression of III beta-tubulin was positively correlated with chemotherapy resistance. PMID- 28659182 TI - Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed. METHODS: We used reverse transcription RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin. RESULTS: The present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage. CONCLUSIONS: The current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression. PMID- 28659183 TI - What determines the effects and costs of breast cancer screening? A protocol of a systematic review of reviews. AB - BACKGROUND: Multiple reviews demonstrated high variability in effectiveness and cost-effectiveness outcomes among studies on breast cancer screening (BCS) programmes. No study to our knowledge has summarized the current evidence on determinants of effectiveness and cost-effectiveness of the most used BCS approaches or tried to explain differences in conclusions of systematic reviews on this topic. Based on published reviews, this systematic review aims to assess the degree of variability of determinants for (a) effectiveness and (b) cost effectiveness of BCS programmes using mammography, clinical breast examination, breast self-examination, ultrasonography, or their combinations among the general population. METHODS: We will perform a comprehensive systematic literature search in Cochrane, Scopus, Embase, and Medline (via Pubmed). The search will be supplemented with hand searching of references of the included reviews, with hand searching in the specialized journals, and by contacting prominent experts in the field. Additional search for grey literature will be conducted on the websites of international cancer associations and networks. Two trained research assistants will screen titles and abstracts of publications independently, with at least random 10% of all abstracts being also screened by the principal researcher. The full texts of the systematic reviews will then be screened independently by two authors, and disagreements will be solved by consensus. The included reviews will be grouped by publication year, outcomes, designs of original studies, and quality. Additionally, for reviews published since 2011, transparency in reporting will be assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for the review on determinants of effectiveness and a modified PRISMA checklist for the review on determinants for cost-effectiveness. The study will apply the Assessing the Methodological Quality of Systematic Reviews checklist to assess the methodological quality of systematic reviews. We will report the data extracted from the systematic reviews in a systematic format. Meta-meta-analysis of extracted data will be conducted when feasible. DISCUSSION: This systematic review of reviews will examine the degree of variability in the effectiveness and cost-effectiveness of BCS programmes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016050764 and CRD42016050765. PMID- 28659184 TI - RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF kappaB signaling pathway in nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types. METHODS: RERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2'-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines. RESULTS: RERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818-0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-kappaB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts. CONCLUSIONS: Our results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-kappaB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy. PMID- 28659185 TI - The genome-wide transcription response to telomerase deficiency in the thermotolerant yeast Hansenula polymorpha DL-1. AB - BACKGROUND: In the course of replication of eukaryotic chromosomes, the telomere length is maintained due to activity of telomerase, the ribonucleoprotein reverse transcriptase. Abolishing telomerase function causes progressive shortening of telomeres and, ultimately, cell cycle arrest and replicative senescence. To better understand the cellular response to telomerase deficiency, we performed a transcriptomic study for the thermotolerant methylotrophic yeast Hansenula polymorpha DL-1 lacking telomerase activity. RESULTS: Mutant strain of H. polymorpha carrying a disrupted telomerase RNA gene was produced, grown to senescence and analyzed by RNA-seq along with wild type strain. Telomere shortening induced a transcriptional response involving genes relevant to telomere structure and maintenance, DNA damage response, information processing, and some metabolic pathways. Genes involved in DNA replication and repair, response to environmental stresses and intracellular traffic were up-regulated in senescent H. polymorpha cells, while strong down-regulation was observed for genes involved in transcription and translation, as well as core histones. CONCLUSIONS: Comparison of the telomerase deletion transcription responses by Saccharomyces cerevisiae and H. polymorpha demonstrates that senescence makes different impact on the main metabolic pathways of these yeast species but induces similar changes in processes related to nucleic acids metabolism and protein synthesis. Up-regulation of a subunit of the TORC1 complex is clearly relevant for both types of yeast. PMID- 28659186 TI - Low-volume resuscitation with normal saline is associated with microvascular endothelial dysfunction after hemorrhage in rats, compared to colloids and balanced crystalloids. AB - BACKGROUND: Restoration of endothelial glycocalyx (EG) barrier may be an essential therapeutic target for successful resuscitation. The aim of this study was to compare in vivo the effects of resuscitation with normal saline (NS) to lactated Ringer's solution (LR), 5% albumin and fresh frozen plasma (FFP) on their ability to maintain EG and barrier function integrity, mitigate endothelial injury and inflammation, and restore vascular homeostasis after hemorrhagic shock. METHODS: Anesthetized rats (N = 36) were subjected to hemorrhagic shock (bled 40% of total blood volume), followed by resuscitation with 45 ml/kg NS or LR, or 15 ml/kg 5% albumin or FFP. Microhemodynamics, EG thickness, permeability, leukocyte rolling and adhesion were assessed in >180 vessels from cremaster muscle, as well as systemic measures. RESULTS: After hypotensive resuscitation, arterial pressure was 25% lower than baseline in all cohorts. Unlike FFP, resuscitation with crystalloids failed to restore EG thickness to baseline post shock and shedding of glycocalyx proteoglycan was significantly higher after NS. NS decreased blood flow and shear, and markedly increased permeability and leukocyte rolling/adhesion. In contrast, LR had lesser effects on increased permeability and leukocyte rolling. Albumin stabilized permeability and white blood cell (WBC) rolling/adhesion post shock, comparable to FFP. CONCLUSIONS: Resuscitation with NS failed to inhibit syndecan-1 shedding and to repair the EG, which led to loss of endothelial barrier function (edema), decline in tissue perfusion and pronounced leukocyte rolling and adhesion. Detrimental effects of NS on endothelial and microvascular stabilization post shock may provide a pathophysiological basis to understand and prevent morbidity associated with iatrogenic resuscitation after hemorrhagic shock. PMID- 28659187 TI - Tuberculous meningoencephalitis associated with brain tuberculomas during pregnancy: a case report. AB - BACKGROUND: Tuberculous meningitis is globally highly prevalent and is commoner in resource-limited countries and in patients with immunosuppression. Central nervous system tuberculosis is one of the severest forms of extrapulmonary tuberculosis during pregnancy and associated brain tuberculomas have been rarely reported. With the availability of neuroimaging at our hospital center, we present the first case of tuberculous meningoencephalitis associated with brain tuberculomas during pregnancy. CASE PRESENTATION: In this case report we present a 25-year-old, Albanian, pregnant woman living in an urban area in Kosovo, who at 24 weeks of twin pregnancy manifested signs and symptoms of meningoencephalitis with decreased level of consciousness, hemiparesis, and generalized recurrent seizures. Based on medical history, origin from a region of high prevalence of tuberculosis, clinical presentation, especially neurological examination, cytobiochemical changes in cerebrospinal fluid (mild mononuclear pleocytosis with decreased level of glucose and elevated proteins), and elevated level of interferon-gamma release assay in cerebrospinal fluid, antituberculous therapy was initiated on the fourth day of admission. After 3 weeks of treatment, at 27 weeks of pregnancy, she had a preterm delivery and both twins, with low birthweight, died after 24 and 72 hours. Although findings on chest radiography were normal, brain magnetic resonance imaging showed signs of meningoencephalitis and multiple intracerebral tuberculomas, while Koch's bacillus was isolated from urine cultures. On long-term follow-up after delivery, she was cured with no sequelae and became pregnant again without any additional complications. CONCLUSIONS: In countries with a high prevalence of tuberculosis, screening for central nervous system tuberculosis should be considered in the differential diagnosis of meningitis in pregnancy. Cerebral imaging is essential to establish the diagnosis of brain tuberculomas in such a case of suspected tuberculous meningoencephalitis during pregnancy. PMID- 28659188 TI - Comparative transcriptome analysis of shoot and root tissue of Bacopa monnieri identifies potential genes related to triterpenoid saponin biosynthesis. AB - BACKGROUND: Bacopa monnieri commonly known as Brahmi is utilized in Ayurveda to improve memory and many other human health benefits. Bacosides enriched standardized extract of Bacopa monnieri is being marketed as a memory enhancing agent. In spite of its well known pharmacological properties it is not much studied in terms of transcripts involved in biosynthetic pathway and its regulation that controls the secondary metabolic pathway in this plant. The aim of this study was to identify the potential transcripts and provide a framework of identified transcripts involved in bacosides production through transcriptome assembly. RESULTS: We performed comparative transcriptome analysis of shoot and root tissue of Bacopa monnieri in two independent biological replicate and obtained 22.48 million and 22.0 million high quality processed reads in shoot and root respectively. After de novo assembly and quantitative assessment total 26,412 genes got annotated in root and 18,500 genes annotated in shoot sample. Quality of raw reads was determined by using SeqQC-V2.2. Assembled sequences were annotated using BLASTX against public database such as NR or UniProt. Searching against the KEGG pathway database indicated that 37,918 unigenes from root and 35,130 unigenes from shoot were mapped to 133 KEGG pathways. Based on the DGE data we found that most of the transcript related to CYP450s and UDP glucosyltransferases were specifically upregulated in shoot tissue as compared to root tissue. Finally, we have selected 43 transcripts related to secondary metabolism including transcription factor families which are differentially expressed in shoot and root tissues were validated by qRT-PCR and their expression level were monitored after MeJA treatment and wounding for 1, 3 and 5 h. CONCLUSIONS: This study not only represents the first de novo transcriptome analysis of Bacopa monnieri but also provides information about the identification, expression and differential tissues specific distribution of transcripts related to triterpenoid sapogenin which is one of the most important pharmacologically active secondary metabolite present in Bacopa monnieri. The identified transcripts in this study will establish a foundation for future studies related to carrying out the metabolic engineering for increasing the bacosides biosynthesis and its regulation for human health benefits. PMID- 28659189 TI - Clinical predictors of dengue fever co-infected with leptospirosis among patients admitted for dengue fever - a pilot study. AB - BACKGROUND: Dengue and leptospirosis infections are currently two major endemics in Malaysia. Owing to the overlapping clinical symptoms between both the diseases, frequent misdiagnosis and confusion of treatment occurs. As a solution, the present work initiated a pilot study to investigate the incidence related to co-infection of leptospirosis among dengue patients. This enables the identification of more parameters to predict the occurrence of co-infection. METHOD: Two hundred sixty eight serum specimens collected from patients that were diagnosed for dengue fever were confirmed for dengue virus serotyping by real time polymerase chain reaction. Clinical, laboratory and demographic data were extracted from the hospital database to identify patients with confirmed leptospirosis infection among the dengue patients. Thus, frequency of co infection was calculated and association of the dataset with dengue-leptospirosis co-infection was statistically determined. RESULTS: The frequency of dengue co infection with leptospirosis was 4.1%. Male has higher preponderance of developing the co-infection and end result of shock as clinical symptom is more likely present among co-infected cases. It is also noteworthy that, DENV 1 is the common dengue serotype among all cases identified as dengue-leptospirosis co infection in this study. CONCLUSION: The increasing incidence of leptospirosis among dengue infected patients has posed the need to precisely identify the presence of co-infection for the betterment of treatment without mistakenly ruling out either one of them. Thus, anticipating the possible clinical symptoms and laboratory results of dengue-leptospirosis co-infection is essential. PMID- 28659190 TI - Tribute to Mark Wainberg. PMID- 28659191 TI - An ultrasound transient elastography system with coded excitation. AB - BACKGROUND: Ultrasound transient elastography technology has found its place in elastography because it is safe and easy to operate. However, it's application in deep tissue is limited. The aim of this study is to design an ultrasound transient elastography system with coded excitation to obtain greater detection depth. METHODS: The ultrasound transient elastography system requires tissue vibration to be strictly synchronous with ultrasound detection. Therefore, an ultrasound transient elastography system with coded excitation was designed. A central component of this transient elastography system was an arbitrary waveform generator with multi-channel signals output function. This arbitrary waveform generator was used to produce the tissue vibration signal, the ultrasound detection signal and the synchronous triggering signal of the radio frequency data acquisition system. The arbitrary waveform generator can produce different forms of vibration waveform to induce different shear wave propagation in the tissue. Moreover, it can achieve either traditional pulse-echo detection or a phase-modulated or a frequency-modulated coded excitation. A 7-chip Barker code and traditional pulse-echo detection were programmed on the designed ultrasound transient elastography system to detect the shear wave in the phantom excited by the mechanical vibrator. Then an elasticity QA phantom and sixteen in vitro rat livers were used for performance evaluation of the two detection pulses. RESULTS: The elasticity QA phantom's results show that our system is effective, and the rat liver results show the detection depth can be increased more than 1 cm. In addition, the SNR (signal-to-noise ratio) is increased by 15 dB using the 7-chip Barker coded excitation. CONCLUSIONS: Applying 7-chip Barker coded excitation technique to the ultrasound transient elastography can increase the detection depth and SNR. Using coded excitation technology to assess the human liver, especially in obese patients, may be a good choice. PMID- 28659192 TI - Independent associations between arterial bicarbonate, apnea severity and hypertension in obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea is characterized by intermittent hypoxia and hypercapnia. CO2 production, transport and elimination are influenced by the carbonic anhydrase enzyme. We hypothesized that elevated standard bicarbonate, a proxy for increased carbonic anhydrase activity, is associated with apnea severity and higher blood pressure in patients with obstructive sleep apnea. METHODS: A retrospective analysis of a sleep apnea cohort (n = 830) studied by ambulatory polygraphy. Office systolic/diastolic blood pressure, lung function, and arterial blood gases were assessed during daytime. RESULTS: Arterial standard bicarbonate was increased with apnea severity (mild/moderate/severe 24.1 +/- 1.8, 24.4 +/- 1.7 and 24.9 +/- 2.9 mmol/l, respectively, Kruskal-Wallis test p < 0.001). Standard bicarbonate was independently associated with apnea hypopnea index after adjustment for sex, age, body mass index, smoking, alcohol, hypertension, pO2 and pCO2 (standard bicarbonate quartile 1 vs. quartile 4, beta = 10.6, p < 0.001). Log-transformed standard bicarbonate was associated with a diagnosis of hypertension or diastolic blood pressure but not systolic blood pressure adjusting for cofounders (p = 0.007, 0.048 and 0.45, respectively). CONCLUSIONS: There was an independent association between sleep apnea severity and arterial standard bicarbonate. The link between high standard bicarbonate and daytime hypertension suggests that carbonic anhydrase activity may constitute a novel mechanism for blood pressure regulation in sleep apnea. PMID- 28659193 TI - Feasibility of a prototype newborn resuscitation monitor to study transition at birth, measuring heart rate and ventilator parameters, an animal experimental study. AB - BACKGROUND: Every year, an estimated 10 million babies are born, non-breathing and in need of resuscitation. Advances in management have been made over the past decades, however, approximately 700.000 yearly deaths result from this global problem. A prototype newborn resuscitation monitor (NRM) (Laerdal Global Health, Stavanger, Norway) has been developed with the purpose of studying newborn resuscitation. The monitor has the ability to continuously display HR using dry electrode ECG technology, to measure tidal volume, pressure and end tidal CO2, and to store the results for later analysis. Such monitor could enhance the care providers performance, and hence survival of neonates, by displaying the quality and response of the given care. The aim of this preclinical study was to describe the abilities of the NRM to measure ventilation and heart rate parameters against pathophysiological responses to different induced conditions in a piglet i.e. increased deadspace, pressure and washout of surfactant. METHODS: Piglets were chosen for the study, as they have tidal volumes of approximately 6 ml/kg, resembling the human neonate. Five piglets were anesthetized and intubated before starting positive pressure ventilation (PPV). The dry electrode ECG sensor of the NRM was placed over the abdomen, and experiments performed: (1) inducing different ventilation scenarios and (2) lavage of surfactant. RESULTS: The NRM was capable of continuously displaying HR and detecting inflicted changes in ventilation and compliance of piglets. It could measure inflated and exhaled volume, the pressure of the ventilations and also the end tidal CO2. CONCLUSIONS: The NRM provides objective feedback in anesthetized animals, and may be used in clinical studies and hopefully generate new knowledge on neonatal transition and resuscitation. The monitor may be further developed for use in both low and high resource settings. PMID- 28659194 TI - Out of hospital Cardio-pulmonary arrest - Is there a role for the primary healthcare teams? AB - Out of hospital cardiac arrest (OHCA) remains a major cause of morbidity and mortality. The survival rates are poor and even more frustrating are the rates of neurologically favorable outcomes at hospital discharge. In a recent IJHPR article, Einav et al. concluded that many primary care clinics are underequipped and the physicians underprepared to initiate life-saving services. The chance of having an OHCA in a primary care clinic is very low. But although the impact is small, primary care teams as well as other out-of-hospital healthcare personal should be familiar with the telephone number for summoning emergency medical services (EMS), be aware of the location of the defibrillator in their clinic, and know how to use it. The literature about effective ways to keep long-standing competencies in cardiopulmonary resuscitation among medical personnel outside the hospital is scarce. It is very difficult to evaluate the actual effectiveness of interventions on better outcome; the events are rare and unique in their nature and it hard to generalize the conclusions. The "chain of survival" concept involves a series of steps that should be taken at the scene in the community: early recognition of symptoms and activation of an emergency response system; early bystander cardiopulmonary resuscitation; rapid defibrillation, if needed; early advanced cardiac life support and integrated post-resuscitation care. In this "chain" there is an important role for healthcare personal in the community via improving their own skills and performance and via a deeper involvement in the education of the public. We should take all the needed steps so that community clinic personnel can be role models for effective and successful out of hospital cardiac resuscitation (OHCR). PMID- 28659195 TI - Development and testing of Schisto and LaddersTM, an innovative health educational game for control of schistosomiasis in schoolchildren. AB - BACKGROUND: Schistosomiasis remains a public health problem in many regions of the world, including Nigeria. Current control strategy involves mass drug administration with praziquantel to the endemic population. To complement and sustain on-going preventive chemotherapy, we developed a health educational game named Schisto and LaddersTM and tested its potential for the control of schistosomiasis among schoolchildren living in Imala-Odo, a highly endemic community near Abeokuta, Nigeria. METHODS: One hundred school children were randomly selected and divided into intervention and control groups through balloting. Their knowledge, attitudes and practices (KAP) concerning schistosomiasis transmission, control and prevention were assessed using structured questionnaires. Schisto and LaddersTM game were given to the intervention group and the popular Snake and LaddersTM game to the control group. Both games were played for 2 months under the supervision of their class teachers. A post-KAP assessment was carried out in both groups, including focus group discussions (FGDs) to investigate knowledge and the impact of the games. RESULTS: Knowledge about urinary schistosomiasis and its transmission significantly improved (P = 0.000) in the intervention group (68.0%) compared to the control group (8.0%). FGDs showed that the frequency of visits to dam water also significantly reduced (P = 0.048) in the intervention group (18.0%) compared to the control group (40.0%). There was a significant increase in knowledge regarding risk behaviours, prevention and control of schistosomiasis among the intervention group, but no new knowledge gained in the control group. CONCLUSIONS: This study demonstrates the potential of the health education game Schisto and LaddersTM for teaching basic health education and promoting behavioural changes among schoolchildren in endemic communities. PMID- 28659197 TI - [Prognosis after diagnosis of multiple sclerosis]. AB - - Even at a young age, multiple sclerosis often profoundly impacts a patient's daily activities.- Treatment is complicated because disease course is different for each patient.- Early treatment has the best results, in the short term as well as the long term, but the most effective treatments can have severe and sometimes irreversible side effects and are very costly.- It is therefore important to determine the prognosis at an early stage, in order to limit increasing future invalidity with appropriate treatment.- For this literature review, we have examined short- and long-term disease course as well as possible prognostic factors. PMID- 28659196 TI - [Medical Psychiatric Units in the Netherlands: an investigation into distribution and quality]. AB - OBJECTIVE: One of the spearheads of psychiatric healthcare in the Netherlands is hospital care for patients with a psychiatric comorbidity. In 2014, the Netherlands Psychiatric Association published ten field standards for Medical Psychiatric Units (MPUs). We catalogued healthcare in the Netherlands on the basis of these field standards. DESIGN: Telephone screening, followed by a questionnaire investigation. METHOD: In the period May-August 2015, psychiatrists in 90 hospitals in the Netherlands were approached by telephone with 4 screening questions. If the department complied with the screening criteria for an MPU, a structured interview comprising 51 questions followed. The interview script was tested against the field standards using the Delphi method. RESULTS: The screening identified 40 potential MPUs; 37 (92.5%) wards participated in the complete interview. CONCLUSION: MPUs are unevenly distributed across the country; care content is adequate, but education, tighter multidisciplinary cooperation and availability of somatic nursing expertise on every shift could improve care on MPUs. The departments should also pay more attention to care chain arrangements. The field standards are too stringent; these could be improved by defining 'essential care' and application of differentiated assessment of subcriteria. PMID- 28659198 TI - [Henry Beecher and medical science: the 50th anniversary of a famous article]. AB - In 2016, it had been exactly half a century ago that Henry Beecher published his article 'Ethics and clinical research' in The New England Journal of Medicine. Today, this article is considered a turning point in the history of medical research ethics. On the occasion of the fiftieth anniversary of this famous article, we are looking back on this turbulent period in the history of medicine. PMID- 28659199 TI - [Support of damaged heart with the Impella pump]. AB - Temporary mechanical circulatory support is increasingly used, particularly in patients with cardiogenic shock or during high-risk percutaneous coronary interventions. In the last five years there have been numerous developments in this field. Experience has been gained from usage of temporary heart pumps, and new pumps have arrived on the market. Until recently, the intra-aortal balloon pump was the standard treatment for patients with cardiogenic shock; however, results from the latest research into the effectiveness of this pump have rendered it less popular. An alternative modality is the Impella system. Since 2012, usage of a heart pump in cardiogenic shock treatment is reimbursed by healthcare insurers in the Netherlands. Recently, the FDA approved the Impella system for said indication. PMID- 28659200 TI - [An unrecognized cause of dyspnoea]. AB - BACKGROUND: Neuralgic amyotrophy is characterised by pain in the neck or shoulder region, followed by neuropathy of both motor and sensory nerves of the brachial plexus. The incidence of this condition is estimated at 1/1000 per year. In a rare variant of the syndrome, involvement of both phrenic nerves can occur, leading to diaphragmatic paralysis and severe orthopnoea. CASE DESCRIPTION: A 67 year-old woman was referred to us with acute orthopnoea. Imaging studies showed bilateral diaphragmatic paralysis, and electromyography (EMG) confirmed neuropathy of both phrenic nerves. The diagnosis was bilateral neuralgic amyotrophy. The patient received nocturnal ventilation support via nasal high flow oxygen therapy. This symptomatic treatment had a positive effect. CONCLUSION: Isolated phrenic nerve neuropathy is a rare variant of neuralgic amyotrophy, leading to orthopnoea. Recovery is slow and frequently incomplete. Supportive treatment with non-invasive ventilation support is necessary to improve the patient's quality of life. PMID- 28659201 TI - [Embrace, integrated primary care for older adults]. AB - OBJECTIVE: To examine the impact of Embrace (Dutch: SamenOud), a new primary care model for community-living people aged over 75 years on perceived quality of care. DESIGN: Randomized controlled trial in 15 general practices in the East Groningen region of the Netherlands. METHOD: In the period January 2012-March 2013, 1456 general practice patients aged 75 years and older were stratified on the basis of self-reporting into 3 risk profiles: 'robust', 'frail' and 'complex care needs', and then randomized to the intervention or the control arm. Intervention consisted of care and support from an elderly-care team consisting of a specialist in Gerontology, a district nurse, and a social worker. Intensity and duration of the care and support were dependent on risk profile. The primary outcome measure was quality of care as reported by participants; the secondary outcome measure was the extent of implementation as reported by the caregivers. RESULTS: The level of perceived quality of care after 12 months was slightly higher in the intervention arm than in the control arm, but the effect size was quite small. The difference was significant in elderly people with the risk profiles 'frail' and 'complex care needs'; robust elderly people did not experience a significant difference. The caregivers reported increased implementation of integrated care (effect size 0.71, that means average). CONCLUSION: Embrace slightly improved the perceived quality of care, particularly for elderly people with complex care needs for whom case management was organised. Caregivers judged implementation of integrated care to be greatly improved, though there was still room for further improvement. Further research should be carried out into the effectiveness of integrated primary care for the elderly on health, service-use and healthcare costs. PMID- 28659202 TI - [Polycythaemia in a patient with uterus myomatosus]. AB - BACKGROUND: Myomatous erythrocytosis syndrome (MES) is characterised by a combination of polycythaemia, uterus myomatosus and the normalisation of erythrocyte count after hysterectomy. CASE DESCRIPTION: A 58-year-old postmenopausal woman was referred to the gynaecologist with symptoms of vaginal blood loss, increased abdominal circumference and pollakiuria. Physical examination indicated her uterus was enlarged to the size of a 24-week gestation. Endometrial malignancy was excluded and ultrasound showed a myoma. In consultation with the patient a hysterectomy was planned. Pre-operative blood tests showed increased haemoglobin levels (14.2 mmol/l). No indications of polycythaemia vera or secondary polycythaemia were found after which the diagnosis of MES was made. Haemoglobin levels normalised after hysterectomy without any further intervention. CONCLUSION: MES is common, although relatively unknown. Its pathophysiology is most likely based on ectopic production of erythropoietin by leiomyoma tissue. The combination of polycythaemia and uterus myomatosus should alert clinicians to this syndrome, especially as polycythaemia normalises after hysterectomy. PMID- 28659203 TI - [A baby with progressive skin lesions on the scalp]. AB - An eight-month-old girl was referred to the dermatologist with a progressive desquamative and purulent eruption on the scalp. Laboratory tests confirmed the diagnosis kerion celsi and the girl was successfully treated with an antimycoticum. Kerion celsi is a deep inflammatory fungal infection on the scalp. Early diagnosis is essential to prevent irreversible hair loss. PMID- 28659204 TI - [Tracheotomy in the intensive care unit is a tailor-made decision]. AB - Tracheotomy is one of the oldest interventions in medical sciences. It is a procedure that is frequently used in patients who have been admitted to the intensive care unit. Over the last twenty years, the use of the dilation technique has increased in frequency. We believe that the timing of a tracheostoma placement should be evaluated individually for every patient and should always be weighed against the potential risks of an operative intervention. This is illustrated with case reports of four patients with respiratory problems; in the case of one of these patients, the decision was made not to perform tracheotomy, which nonetheless resulted in a favourable clinical outcome. PMID- 28659205 TI - [The standard mid-pregnancy anomaly scan in the Netherlands: what is its effect?] AB - - The mid-pregnancy anomaly scan was introduced into the Netherlands in 2007. The scan is performed at 18- 21 weeks of pregnancy.- The detection rate of open spina bifida is 94%.- In the Netherlands, 60% of all congenital heart defects are diagnosed prenatally compared with 35-40% in other countries. There is a strong relationship between the severity of the heart defect and the detection rate, as more than 95% of all univentricular heart defects are detected.- The detection rate of isolated cleft lip and cleft palate has increased from 32% to 87%.- The absolute number of abortions has not increased since the implementation of the anomaly scan. However, perinatal morbidity and mortality have decreased.- To further increase the quality of the screening programme, prenatal and postnatal congenital defect registries should be linked and studies into the effect of intensive training of sonographists with modern teaching methods should be performed. PMID- 28659206 TI - [Quantifying the biomedical research agenda of the Netherlands]. AB - In October 2016, the Health Council of the Netherlands has published the 'Research that makes you better' report. This report gives an overview of a future scenario in which UMCs (university medical centres) are investing more in research into quality and efficiency of care and prevention. This scenario is based on interviews and a review of the literature. In this article, we quantify biomedical research in the Netherlands and give a summary of the implications of the Health Council proposals. Our conclusion is that there is only a limited correlation between the Dutch research portfolio versus burden of disease and cost of care. This means there is a challenge for policy makers and researchers to push currently underexposed themes higher up the Dutch research agenda. PMID- 28659207 TI - ['Ecstasy-light' - not as light as its name suggests: toxic effects of 4 fluoroamphetamine]. AB - BACKGROUND: The use of 4-fluoroamphetamine (4-FA) has shown a marked increase, especially because users perceive its effects to be relatively mild. 4-FA is also known as ecstacy-light, but is probably not as light as its name suggests. From April 2017 its use has therefore been forbidden in the Netherlands. CASE DESCRIPTION: In a short time, we saw three patients at our emergency department who had signs of a severe intoxication with 4-FA. A 21-year-old male developed a tonic-clonic seizure, bruxism, mydriasis, and rhabdomyolysis. A 19-year-old female was confused and was longing for death. A 22-year-old male needed to be admitted to intensive care to be intubated, sedated and cooled due to tachycardia, hypertension and hyperthermia. CONCLUSION: Because of its relatively mild effects, 4-FA is gaining in popularity in the Netherlands. However, the use of this designer drug can lead to severe problems such as severe confusion, hyperthermia and tonic-clonic seizures. PMID- 28659208 TI - [Intoxication with new psychoactive substances: drug unknown, but complications are still treatable]. AB - Abuse of new psychoactive substances (NPS) and the number of patients presenting to the ER with intoxication are increasing. Treatment may at first sight seem complicated because of limited knowledge of the substance involved, but should be based on a general supportive approach recognising the relatively predictable spectrum of symptoms caused by adrenergic, serotonergic and dopaminergic stimulation. In this article, we discuss the vital elements of this approach and possible complications of NPS intoxication. This is illustrated by two 20-year old male patients with NPS intoxication who presented to our ER as participants in a group intoxication. Patient A suffered from mild symptoms and tested positive for 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (2C-I-NBOMe) only. Patient B presented with agitated delirium and tested positive for both 2C I-NBOMe and cocaine. While patient A was treated with benzodiazepines and rehydration, patient B required sedation, intubation and short-term ventilation. PMID- 28659209 TI - [Approaching psychological problems like a general practitioner]. AB - An important cause of the high prescription levels of psychotropic medication for psychological symptoms is that these symptoms are assessed according to the same model as applied for physical symptoms, the disease model. This has led to a one sided medical approach to psychological symptoms. A person-centred approach offers an alternative; the positive aspects of the disease-centred approach are retained and attention for the patient and his/her context become the central focal point for the general practitioner. Important elements of the person centred approach are empathy, a good doctor-patient relationship, a shared approach to problem definition and understanding of the patient's problem, development of a therapeutic alliance, and a focus on the patient's hopes and expectations. If additional primary care-based treatment by mental health practice nurses is indicated, this model could be suitable since it is based on patients' strengths and focuses on personal growth rather than reduction of symptoms. PMID- 28659210 TI - [Non-publication is common among phase 1, single-center, not prospectively registered, or early terminated clinical drug trials]. AB - The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands. All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials. PMID- 28659211 TI - [The life cycle of clinical drug research]. AB - Recently, it was shown that more than 40% of the clinical drug trials in the Netherlands does not reach the stage of publication. Although the non-publication rate of clinical trials seems to have improved compared to previous studies, it is still far from optimal, in particular among phase I trials. In this article the life cycle of clinical drug research is discussed, in order to explain the non-publication rate in the Netherlands and to point out how the publication rate of phase I trials could be improved. PMID- 28659212 TI - Helminth-induced apoptosis: a silent strategy for immunosuppression. AB - During microbial infections, both innate and adaptive immunity are activated. Viruses and bacteria usually induce an acute inflammation in the first setting of infection, which helps the eliciting an effective immune response. In contrast, macroparasites such as helminths are a highly successful group of invaders known to be capable of maintaining a chronic infestation with the minimum instigation. Undoubtedly, generating such an immunoregulatory environment requires the exploitation of various immunosuppressive mechanisms to debilitate host immunity supporting their survival and replication. Several mechanisms have been recognized whereby helminths prolong their infections including an increase of immunoregulatory cells, inhibition of Th1 or Th2 responses, targeting pattern recognition receptors (PRRs) and lowering the immune cells quantity via induction of apoptosis. Apoptosis is a programmed intracellular process involving a series of consecutive downstream signalling event evolved to cell death. It plays a pivotal role in several immunological reactions in particular deletion of autoreactive immune cells. Helminth-triggered apoptosis in immune cells exhausts host immunity, which paves the way for generating a permissive environment and chronic infection. This review provides a compilation of recent investigations discussing the apoptotic mechanisms exploited by different worms and the immunological consequences of immune cell death. Finally, the anti-cancer effects of some worm-derived molecules due to their apoptotic effects are discussed, highlighting as potentially druggable candidates to combat cancer. PMID- 28659213 TI - Breast-feeding counselling mitigates the negative association of domestic violence on exclusive breast-feeding duration in rural Bangladesh. The MINIMat randomized trial. AB - OBJECTIVE: To determine if exclusive breast-feeding counselling modifies the association of experience of any lifetime or specific forms of domestic violence (DV) on duration of exclusive breast-feeding (EBF). DESIGN: In the MINIMat trial pregnant women were randomized to receive either usual health messages (UHM) or usual health messages with breast-feeding counselling (BFC) in eight visits. During pregnancy (30 weeks), lifetime experience of any or specific forms of DV was measured. Infant feeding practice information was collected from 0 to 6 months at 15 d intervals. SETTING: Matlab, Bangladesh. SUBJECTS: Pregnant and postpartum women (n 3186) and their infants. RESULTS: Among women in the UHM group, those who had experienced any lifetime DV exclusively breast-fed for a shorter duration than women who did not experience any lifetime DV (P=0.02). There was no difference, however, in duration of EBF among women in the BFC group based on their experience of any lifetime DV exposure (P=0.48). Using Cox regression analysis, there was an interaction of exposure to any lifetime DV, sexual violence and controlling behaviour, and counselling group with duration of breast-feeding at or before 6 months (P-interaction<=0.08). Among the UHM group, experience of any lifetime DV, sexual violence or controlling behaviour was associated with fewer days of EBF (P<0.05). In contrast, among the BFC group, experience of DV was not associated with duration of EBF. CONCLUSIONS: The experience of DV compromises EBF and the support of breast-feeding counselling programmes could assist this vulnerable group towards better infant feeding practices. PMID- 28659214 TI - The risk of stroke after prenatal exposure to famine. AB - Prenatal exposure to famine is associated with an increased risk of metabolic and cardiovascular diseases in the offspring at adult age. The aim of this study was to assess whether prenatal exposure to undernutrition increases the risk of stroke. This study was performed in the Dutch famine birth cohort, which consist of 2414 members who were born between 1943 and 1947 in the Netherlands. In a subsample of 1177 individuals, interviews were conducted using standardized questionnaires to obtain information about medical history (which included specific questions regarding stroke) and lifestyle. Information on stroke-related mortality was collected by linking the cohort with Statistics Netherlands. A Cox's proportional hazard analysis was performed to calculate hazard ratios (HRs) comparing the incidence of non-fatal stroke between participants who were exposed, subdivided into early, mid and late gestation, and unexposed to famine prenatally. Three cohort members died of stroke. Of the 1177 subjects who responded to the questionnaires 49 (4.2%) survived a stroke. Unadjusted and adjusted HRs for the risk of non-fatal stroke did not show a significant difference between the unexposed and exposed subjects: HR 1.23 (95% CI 0.53 2.83), HR 1.23 (95% CI 0.53-2.82), HR 1.12 (95% CI 0.46-2.71) for those exposed in late, mid and early gestation, respectively. We were unable to find evidence for a major effect of prenatal exposure to famine on the risk of stroke in later life, although one should be aware that this study was underpowered and the study population too selected and young to identify smaller risks. PMID- 28659215 TI - How Evacuees Obtained Health Care Information After the Great East Japan Earthquake: A Qualitative Interview Study. AB - OBJECTIVE: To explore how evacuees obtained health care information at their evacuation destinations after the Great East Japan Earthquake. METHODS: We conducted semi-structured interviews of 11 evacuees who moved to City A in Kyoto Prefecture following the Great East Japan Earthquake. The interviews explored how the evacuees obtained health care information, including the main factors of influence. The interviews were transcribed and analyzed to identify trends by using the constant comparative method. RESULTS: Four categories emerged from 6 concepts. Mother-children evacuees and family evacuees tended to obtain health care information in different ways. Family evacuees had moved as a family unit and had obtained their health care information from local neighbors. Mother children evacuees were mothers who had moved with their children, leaving behind other family members. These evacuees tended to obtain information from other mother-children evacuees. At the time of evacuation, we found 2 factors, emotions and systems, influencing how mother-children evacuees obtained health care information. CONCLUSIONS: We found 2 different ways of obtaining health care information among mother-children evacuees and other evacuees. At the time of evacuation, 2 factors, emotions and systems, influenced how mother-children evacuees obtained health care information. Community-building support should be a priority from an early stage after a disaster for health care management. (Disaster Med Public Health Preparedness. 2017;11:729-734). PMID- 28659216 TI - Response to the letters addressing "Much ado about nothing". PMID- 28659217 TI - Ambiguities and Violations of Patient Autonomy from Ontario's Prehospital "Do Not Resuscitate" Form. PMID- 28659218 TI - Effect of dietary consumption as a modifier on the association between FTO gene variants and excess body weight in children from an admixed population in Brazil: the Social Changes, Asthma and Allergy in Latin America (SCAALA) cohort study. AB - Previous studies have shown associations of variants of the FTO gene with body weight, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the north-eastern Brazilian population. This study evaluated the association between SNP in the FTO gene and excess weight in Salvador, Bahia, Brazil. In addition, the effect of diet as a modifier on this association was also investigated. This cross-sectional study included 1191 participants aged 4-11 years, who were genotyped for 400 variants of the FTO gene. Direct anthropometric measures were made and dietary data were obtained by 24-h food recall. Multivariate logistic regression analyses were used to assess the associations of interest. Overall, 11.2 % of the individuals included in the study were overweight/obese. Interactions were identified between the percentage energy intake from proteins and obesity risk linked to the rs62048379 SNP (P interaction=0.01) and also between fat intake (PUFA:SFA ratio) and obesity risk linked to the rs62048379 SNP (P interaction=0.01). The T allele for the variant rs62048379 was positively associated with overweight/obesity in individuals whose percentage energy intake from protein was above the median (OR 2.00; 95 % CI 1.05, 3.82). The rs62048379 SNP was also associated with overweight/obesity in individuals whose PUFA:SFA ratio was below the median (OR 1.63; 95 % CI 1.05, 2.55). The association between FTO gene variants and excess body weight can be modulated by dietary characteristics, particularly by fatty acid distribution and dietary protein intake in children. PMID- 28659219 TI - Evaluating physician awareness of common health care costs in the emergency department. AB - BACKGROUND: Health care costs are on the rise in Canada and the sustainability of our health care system is at risk. As gatekeepers to patient care, emergency department (ED) physicians have a direct impact on health care costs. We aimed to identify current levels of cost awareness among ED physicians. By understanding the current level of physician cost awareness, we hope to identify areas where cost education would provide the greatest benefit in reducing ordering costs. METHODS: We conducted a survey evaluating current awareness of common ordering costs among ED physicians from two tertiary teaching hospitals. Our study population was comprised of 124, certified emergency medicine staff physicians and emergency medicine resident physicians. Our survey asked ED physicians to estimate the costs of 41 items across four categories of day-to-day ordering: imaging investigations, materials, laboratory tests, and pharmaceuticals. Items were selected based on frequency of use, availability of cost-effective alternatives, and tests considered to be "low yield". The primary outcome was percentages of underestimates, correct estimates, and overestimates for ED costs among ED physicians. RESULTS: The average percentage of correct cost estimates among ED physicians was 14% across the four ordering categories. Where cost effective alternatives exist, ED physicians overestimated the cost of the more cost-effective item. They also underestimated the cost of low-yield tests.InterpretationED physicians demonstrated limited cost awareness of common health care costs. Further studies that characterize utilization of hospital resources based on ED physician awareness of cost-effective alternatives and cost of "low yield" tests are needed. PMID- 28659220 TI - Evacuations as a Result of Hurricane Sandy: Analysis of the 2014 New Jersey Behavioral Risk Factor Survey. AB - OBJECTIVE: We characterized evacuations related to Hurricane Sandy, which made landfall in New Jersey on October 29, 2012. METHODS: We analyzed data from the 2014 New Jersey Behavioral Risk Factor Survey. The proportion of respondents reporting evacuation was used to estimate the number of New Jersey adults who evacuated. We determined evacuation rates in heavily impacted and less-impacted municipalities, as well as evacuation rates for municipalities under and not under mandatory evacuation orders. We tested associations between demographic and health factors, such as certain chronic health conditions, and evacuation. RESULTS: Among respondents, 12.7% (95% CI: 11.8%-13.6%) reported evacuating, corresponding to approximately 880,000 adults. In heavily impacted municipalities, 17.0% (95% CI: 15.2%-18.7%) evacuated, compared with 10.1% (95% CI: 9.0%-11.2%) in less-impacted municipalities. In municipalities under mandatory evacuation orders, 42.5% (95% CI: 35.1%-49.8%) evacuated, compared with 11.8% (95% CI: 10.9%-12.9%) in municipalities not under mandatory orders. Female gender (odds ratio [OR]: 1.36; 95% CI: 1.14-1.64), unmarried status (OR: 1.22; 95% CI: 1.02-1.46), shorter length of residence (OR: 1.28; 95% CI: 1.03-1.60), and living in a heavily impacted municipality (OR: 1.84; 95% CI: 1.54-2.20) were significantly associated with evacuation. History of stroke (OR: 1.61; 95% CI: 1.02-2.53) was the only chronic condition associated with evacuation. CONCLUSIONS: Approximately 880,000 New Jersey adults evacuated because of Hurricane Sandy. Those in heavily impacted municipalities and municipalities under mandatory evacuation orders had higher evacuation rates; however, still fewer than half evacuated. These findings can be used for future disaster planning. (Disaster Med Public Health Preparedness. 2017;11:720-728). PMID- 28659221 TI - QTc interval in patients with schizophrenia receiving antipsychotic treatment as monotherapy or polypharmacy. AB - OBJECTIVE: Antipsychotics are associated with a polymorphic ventricular tachycardia, torsades de pointes, which, in the worst case, can lead to sudden cardiac death. The QT interval corrected for heart rate (QTc) is used as a clinical proxy for torsades de pointes. The QTc interval can be prolonged by antipsychotic monotherapy, but it is unknown if the QTc interval is prolonged further with antipsychotic polypharmaceutical treatment. Therefore, this study investigated the associations between QTc interval and antipsychotic monotherapy and antipsychotic polypharmaceutical treatment in schizophrenia, and measured the frequency of QTc prolongation among patients. METHODS: We carried out an observational cohort study of unselected patients with schizophrenia visiting outpatient facilities in the region of Central Jutland, Denmark. Patients were enrolled from January of 2013 to June of 2015, with follow-up until June of 2015. Data were collected from clinical interviews and clinical case records. RESULTS: Electrocardiograms were available for 65 patients, and 6% had QTc prolongation. We observed no difference in average QTc interval for the whole sample of patients receiving no antipsychotics, antipsychotic monotherapy, or antipsychotic polypharmaceutical treatment (p=0.29). However, women presented with a longer QTc interval when receiving polypharmacy than when receiving monotherapy (p=0.01). A limitation of this study was its small sample size. CONCLUSIONS: We recommend an increased focus on monitoring the QTc interval in women with schizophrenia receiving antipsychotics as polypharmacy. PMID- 28659222 TI - Changes to the Korean Disaster Medical Assistance System After Numerous Multi casualty Incidents in 2014 and 2015. AB - OBJECTIVE: A number of multiple-casualty incidents during 2014 and 2015 brought changes to Korea's disaster medical assistance system. We report these changes here. METHODS: Reports about these incidents, revisions to laws, and the government's revised medical disaster response guidelines were reviewed. RESULTS: The number of DMAT (Disaster Medical Assistance Team) staff members was reduced to 4 from 8, and the mobilization method changed. An emergency response manual was created that contains the main content of the DMAT, and there is now a DMAT training program to educate staff. The government created and launched a national 24-hour Disaster Emergency Medical Service Situation Room, and instead of the traditional wireless communications, mobile instant smart phone messaging has been added as a new means of communication. The number of disaster base hospitals has also been doubled. CONCLUSION: Although there are still limitations that need to be remedied, the changes to the current emergency medical assistance system are expected to improve the system's response capacity. (Disaster Med Public Health Preparedness. 2017;11:526-530). PMID- 28659223 TI - The provision of ultra-processed foods and their contribution to sodium availability in Australian long day care centres. AB - OBJECTIVES: To categorize and assess all foods, beverages and ingredients provided over one week at Australian long day care (LDC) centres according to four levels of food processing and to assess the contribution of Na from each level of processing. DESIGN: Cross-sectional. SETTING: Menus for lunch, morning and afternoon snacks were collected from LDC centres. The level of food processing of all foods, beverages and ingredients was assessed utilizing a four level food processing classification system: minimally processed (MP), processed culinary ingredients (PCI), processed (P) and ultra-processed (ULP). RESULTS: A total of thirty-five menus (lunch, n 35; snacks, n 70) provided to 1-5-year-old children were collected from seven LDC centres. Proportions of foodstuffs classified as MP, PCI, P and ULP were 54, 10, 15 and 21 %, respectively. All lunches were classified as MP. ULP foods accounted for 6 % of morning snacks; 41 % of afternoon snacks. Mean daily amount of Na provided per child across all centres was 633 (sd 151) mg. ULP foods provided 40 % of Na, followed by P (35 %), MP (23 %) and PCI (2 %). CONCLUSIONS: Centres provided foods resulting in a mean total daily Na content that represented 63 % of the recommended Upper Level of Intake for Na in this age group. A significant proportion of ULP snack foods were included, which were the major contributor to total daily Na intake. Replacement of ULP snack foods with MP lower-Na alternatives is recommended. PMID- 28659224 TI - Ageing, resilience and depression: adding life to years as well as years to life. PMID- 28659225 TI - Mediterranean food consumption patterns: low environmental impacts and significant health-nutrition benefits. AB - The Mediterranean dietary patterns comply better with recommended nutrient and micronutrient intakes. The Mediterranean diet (MD) was associated with reduced mortality and lower risk for metabolic chronic diseases. It has also low ecological, carbon and water footprints due to its high share of plant-based foods. In fact, the share of plant-based dietary energy is higher in the Mediterranean than in Northern Europe. The Mediterranean hotspot is a major centre of plant and crop diversity. Mediterranean people gather and consume about 2300 plant species. This review paper aims at highlighting the nutrition-health benefits of the MD and analysing the main environmental impacts of the Mediterranean food consumption patterns. There is a growing body of scientific evidence that the MD has significant health-nutrition benefits and low environmental footprints, so there is urgent need to reverse the ongoing erosion of the MD heritage and to promote it as a sustainable diets model. PMID- 28659226 TI - Description of a method for inducing fetal growth restriction in the spiny mouse. AB - Intrauterine or fetal growth restriction (IUGR) is a major complication of pregnancy and leads to significant perinatal morbidities and mortality. Typically, induction of IUGR in animals involves the complete occlusion or ablation of vessels to the uterus or placenta, acutely impairing blood flow and fetal growth, usually with high fetal loss. We aimed to produce a model of reduced fetal growth in the spiny mouse with minimal fetal loss. At 27 days gestational age (term is 38-39 days), a piece of silastic tubing was placed around the left uterine artery to prevent the further increase of uterine blood flow with advancing gestation to induce IUGR (occluded). Controls were generated from sham surgeries without placement of the tubing. Dams were humanely euthanized at 37 days gestational age and all fetuses and placentas were weighed and collected. Of the 17 dams that underwent surgery, 15 carried their pregnancies to 37 days gestational age and 95% of fetuses survived to this time. The difference in fetal body weight between occluded and control was ~21% for fetuses in the left uterus side: there were no differences for fetuses in the right uterus side. Offspring from the occluded group had significantly lower brain, liver, lung, kidney and carcass weights compared with shams. Preventing the gestation-related increase of uterine blood flow induced significant growth restriction in the fetal spiny mouse, with minimal fetal loss. This technique could be readily adapted for other small animal. PMID- 28659227 TI - The role of genetic liability in the association of urbanicity at birth and during upbringing with schizophrenia in Denmark. AB - BACKGROUND: Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case-control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. METHODS: Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. RESULTS: Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], but not at birth (OR 1.09, 95% CI 0.95-1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18-2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97-1.78; overall p = 0.148). CONCLUSIONS: While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia. PMID- 28659228 TI - Are we failing clinical trials? A case for strong aggregate outcomes. AB - Clinical trials in psychiatry inherit methods for design and statistical analysis from evidence-based medicine. However, trials in other clinical disciplines benefit from a more specific relationship between instruments that measure disease state (e.g. biomarkers, clinical signs), the underlying pathology and diagnosis such that primary outcomes can be readily defined. Trials in psychiatry use diagnosis (i.e. a categorical label for a syndrome) as a proxy for the underlying disorder, and outcomes are defined, for example, as a percentage change in a univariate total score on some clinical instrument. We label this approach to defining outcomes weak aggregation of disease state. Univariate measures are necessary, because statistical methodology is both tractable and well-developed for scalar outcomes, but we show that weak aggregate approaches do not capture disease state sufficiently, potentially leading to loss of information about response to intervention. We demonstrate how multivariate disease state can be captured using geometric concepts of spaces defined over routine clinical instruments, and show how clinically meaningful disease states (e.g. representing different profiles of symptoms, recovery or remission) can be defined as prototypes (geometric locations) in these spaces. Then, we show how to derive univariate (scalar) measures, which capture patient's relationships to these prototypes and argue these represent strong aggregates of disease state that may be a better basis for outcome measures. We demonstrate our proposal using a large publically available dataset. We conclude by discussing the impact of strong aggregates for analyses in traditional and novel trial designs. PMID- 28659229 TI - Homeopathic potencies of Arnica montana L. change gene expression in a Tamm Horsfall protein-1 cell line in vitro model: the role of ethanol as a possible confounder and statistical bias. AB - Marzotto et al. showed that homeopathic preparations of Arnica montana L. acted directly on gene expression of Tamm-Horsfall protein-1 (THP-1) monocyte/macrophage cell lines activated with phorbol12-myristate13-acetate and interleukin-4 (IL-4). A. montana homeopathic dilutions are used in complementary and alternative medicine to treat inflammation disorders and post-traumatic events as well as for wound repair. The French Pharmacopoeia of these remedies uses 0.3% ethanol in each centesimal dilution. In this paper, we discuss how ethanol-containing A. montana homeopathic centesimal dilutions can change gene expression in IL-4-treated monocyte/macrophage THP-1. We assessed the role of ethanol in the Arnica homeopathic dilutions containing this alcohol by investigating its action on gene expression of THP-1 cell. Evidence would strongly suggest that the presence of ethanol in these remedies might play a fundamental role in the dilutions ability to affect gene expression, particularly for doses from 5c to 15c. Where, rather than playing a major role in the mesoscopic structure of water, the ethanol might have a chemical-physical role in the induction of THP-1 gene expression, apoptosis, and deoxyribonucleic acid function. This evidence generates a debate about the suggestion that the use of a binary-mixed solvent in homeopathic chemistry, used by Hahnemann since 1810, may be fundamental to explain the activity of homeopathy on cell models. PMID- 28659230 TI - SEEDi1.0-3.0 strategies for major noncommunicable diseases in China. AB - The purpose of this article is to briefly introduce the status and challenges of major noncommunicable diseases (mNCDs), which include cardiovascular disease, diabetes and cancer, as well as related risk factors, such as environmental pollution, smoking, obesity and sleep disorders. "S-E-E-D" rules or the strategies of "S-E-E-D" intervention (SEEDi) consist of four core healthy elements: sleep, emotion, exercise and diet. The history of SEEDi1.0-3.0 is also introduced, which includes versions 1.0, 1.5, 2.0 and 3.0 of the program. These guidelines are suitable for prevention and control of mNCDs. Not only the "Healthy China" initiated in China's "13th Five-year Plan," but also the "Healthy World" philosophy needs SEEDi1.0-3.0 strategies for control of mNCDs. PMID- 28659231 TI - Exercise and gut microbiota: clinical implications for the feasibility of Tai Chi. AB - Recent studies have shown exercise is associated with changes in the gut microbiota in humans as well as in experimental animals. Tai Chi is an exercise that integrates a martial art, deep breathing and mediation, and has various beneficial effects for health. This review summarizes current knowledge and recent literature on the association between exercise and gut microbiota, and explores the feasibility of Tai Chi for improving gut microbiota composition and function. PubMed/MEDLINE was used to search the English literature for the keywords exercise and gut microbiota. Fourteen relevant studies were identified. In humans, exercise increases the gut microbial diversity. However, the evidence for this association is weak, as previous studies were small-scale, non controlled studies of short duration or cross-sectional design. In animals, exercise alters the composition of gut microbiota, with some studies suggesting exercise increases the Bacteroidetes/Firmicutes ratio. However, these results are controversial, partly because host genetics and physical fitness also influence gut microbiota. Furthermore, the intensity of exercise may play a key role in how exercise affects gut microbiota. Tai Chi is a moderate-intensity exercise that improves immune function and inflammation of the gut. Tai Chi may also affect gut microbiota through vagal modulation and mediating the hypothalamic-pituitary adrenal axis. However, no studies have investigated the association between Tai Chi and gut microbiota. Well designed studies exploring the effects of Tai Chi on gut microbiota are needed. PMID- 28659232 TI - Progress in research on the effects of traditional Chinese medicine on the tumor microenvironment. AB - Tumor microenvironment (TME) has received more and more attention as modern medical research has begun to understand its importance in tumorigenesis. The occurrence, development, metastasis and drug resistance of tumors are closely related to TME. TME is a complicated system, including nontumor cells, their secreted cytokines, extracellular matrix, among other components. The concepts of wholism and multitarget regulation in traditional Chinese medicine (TCM) make it well suited to the regulation of TME. In this paper, the authors reviewed the progress of TME research and the effect of TCM on TME, providing some views of Chinese medicine in antitumor research. PMID- 28659233 TI - The meaning of complementary, alternative and traditional medicine among the Indonesian psychology community: a pilot study. AB - OBJECTIVE: Complementary, alternative and traditional medicine (CATM) is a new field, as well as a promising area of study and practice in psychology. It is important to research the cultural context and meaning of CATM, including its definitions and examples, among different communities of psychology because CATM's use is dependent on how it is understood by the members. The aim of this pilot study is to provide an interpretation of the Indonesian psychology community's understanding of CATM through a qualitative approach. METHODS: Online interviews with open-ended questions and purposive sampling were used. Participants were dominantly psychologists or lecturers in clinical psychology area. Ten males and 12 females with an average age of 28.0 +/- 2.5 years voluntarily participated in this study. Interviews were audio-recorded, transcribed verbatim, and reviewed and analysed by the two authors to ensure accuracy of interpretation. RESULTS: It was found that there was no single meaning of CATM among the Indonesian community of psychology. Participants were not familiar enough with the terms and tended to use them with overlap. It can be suggested that "complementary medicine" and "alternative medicine" or "complementary-alternative medicine" combined provides more suitable terminology for use among Indonesian psychology community when communicating with other health care professionals. CONCLUSION: The understanding of the terms and examples of CATM were diverse and were often used interchangeably in the projects/interviews. It was also found that Indonesian psychologists required more education regarding CATM. In addition, future studies with more participants from various aspects of the psychology community should be conducted to capture a more representative sample. PMID- 28659234 TI - Use of ginger versus stretching exercises for the treatment of primary dysmenorrhea: a randomized controlled trial. AB - BACKGROUND: Dysmenorrhea is a common gynecologic problem. In some cases, non medical treatments are considered to be more effective, with fewer side effects. Ginger and exercise are alternative treatments for dysmenorrhea, but in the present study they were not combined. OBJECTIVE: In this study, the effects of ginger and exercise on primary dysmenorrhea were compared. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This randomized controlled trial was performed in Mazandaran University of Medical Sciences, Iran. Two groups of female students were recruited by simple random allocation. In each group, 61 students with moderate to severe primary dysmenorrhea with regular menstrual cycles and without a history of regular exercise were assessed. The ginger group received 250 mg ginger capsules from the onset of menstruation. In the exercise group, belly and pelvic stretching exercises were performed for 10 min, 3 times per week. MAIN OUTCOME MEASURES: Intensity of pain was assessed according to a visual analogue scale after the first and the second month. RESULTS: Exercise was significantly more effective than ginger for pain relief (31.57 +/- 16.03 vs 38.19 +/- 20.47, P = 0.02), severity of dysmenorrhea (63.9% vs 44.3% mild dysmenorrhea, P = 0.02) and decrease in menstrual duration (6.08 +/- 1.22 vs 6.67 +/- 1.24, P = 0.006), in the second cycle. CONCLUSION: Stretching exercises, as a safe and low-cost treatment, are more effective than ginger for pain relief in primary dysmenorrhea. TRIAL REGISTRATION: The trial was registered in www.IRCT.ir with No. 201203118822N2. PMID- 28659235 TI - Comparison of antioxidant activity of insulin, Ocimum gratissimum L., and Vernonia amygdalina L. in type 1 diabetic rat model. AB - OBJECTIVE: Diabetes mellitus (DM) is known to be associated with increase of oxidative stress products. The direction of effect of any treatment on these products could therefore be a reliable measure of its efficacy on DM. So the aim of this study was to investigate the activity of insulin, Ocimum gratissimum L. (OG) and Vernonia amygdalina L. (VA) on oxidative stress products. METHODS: Thirty-six female Wistar rats weighing 150-200 g were randomly divided into six groups of six rats each. Thirty rats were induced for type 1 DM (DM1) with a single intraperitoneal administration of 65 mg/kg body weight of streptozotocin. Group 1 was normal control and was administered distilled water while Group 2 served as DM1 control group; Groups 3, 4, 5 and 6 were diabetic rats treated with 208 mg/kg OG (DM1 + OG), 52 mg/kg VA (DM1 + VA), 208 mg/kg OG + 52 mg/kg VA (DM1 + OG + VA) and 0.16 IU insulin (DM1 + insulin) respectively. Determination of methemoglobin and sulfhemoglobin was achieved by the absorption spectrum principle. Red blood cell (RBC) catalase was assayed by continuous spectrophotometric method. RESULTS: The RBC catalase concentration was significantly decreased in the DM1 and DM1 + VA groups when compared with the normal control. DM1 + OG significantly increased RBC-catalase when compared to DM1. The methemoglobin concentration was significantly reduced in the DM1, DM1 + VA, DM1 + OG + VA and DM1 + insulin groups when compared to the normal control group. The sulfhemoglobin concentration was significantly increased in the diabetic control and the diabetic treated groups when compared to the normal control. DM1 + OG reduced the sulfhemoglobin concentration when compared to DM1. The blood glucose concentration of all the diabetic groups was significantly raised compared to normal control. OG, VA and insulin significantly reduced the blood glucose concentration with the efficacy of OG and VA higher than insulin. CONCLUSION: Adverse alteration of oxidative indices were observed in type 1 DM model. Treatment with OG and insulin showed potent antioxidant activity, while the hypoglycemic efficacy of OG and VA were higher than insulin. PMID- 28659236 TI - Antioxidant activities and phytochemical constituents of Antidesma thwaitesianum Mull. Arg. leaf extracts. AB - OBJECTIVE: To investigate the antioxidant activities as well as phytochemical constituents of Antidesma thwaitesianum Mull. Arg. leaf extracts. METHODS: The leaves of A. thwaitesianum were extracted using three different methods: blending with distilled water, maceration with ethanol and decoction. The chemical antioxidant activity of the plant leaf extracts was evaluated using 2,2-diphenyl 1-picryhydrazyl (DPPH) radical and 2,2'-azinobis(3-ethylbenzo-thiazoline-6 sulfonic acid) diammonium salt (ABTS+) radical scavenging assays, as well as the ferric reducing antioxidant power assay. Cellular antioxidant activity was determined by superoxide and nitric oxide scavenging assays. The cytotoxicity of the leaf extracts in RAW 264.7 and differentiated HL-60 cells was tested in parallel using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium assays, respectively. The total phenolic and flavonoid contents were also assessed by spectrophotometric analysis. Phytochemical constituents of the most potent extract were investigated by liquid chromatography with an electrospray ionization quadrupole time-of-flight mass spectrometer (LC-ESI-QTOF MS/MS). RESULTS: The ethanolic (ME) and decoction (LW) extracts of dried leaves had the highest chemical scavenging activity against DPPH and ABTS+ free radicals with half maximal effective concentration (EC50) values ranging from 3.54 to 6.44 MUg/mL. ME and LW exerted moderate ferric reducing activity, with ferric reducing antioxidant power values of 847.41 and 941.26 mg Fe2+/g extract, respectively. Similarly, ME showed potent cellular scavenging activity against superoxide and nitric oxide radicals with EC50 values of 58.12 and 71.90 MUg/mL, respectively. However, LW exhibited only strong nitric oxide scavenging activity with an EC50 value of 91.20 MUg/mL. The cell viability of RAW 264.7 and HL-60 cells was greater than 70% in all tested concentrations of both extracts, thus confirming the absence of their cytotoxicity. ME and LW contained high total phenolic contents of 231.14 and 274.42 mg gallic acid equivalents per gram, respectively, as well as high total flavonoid contents of 18.82 and 22.17 mg quercetin equivalents per gram, respectively. LC-ESI-QTOF-MS/MS analysis revealed the presence of 52 structurally characterized compounds in ME, 43 of which were tentatively identified. Hydroxycinnamic acids such as caffeic acid and its derivatives were the predominant phenolic compounds. CONCLUSION: This is the first report describing potent chemical and cellular antioxidant effects of the ethanolic leaf extract of A. thwaitesianum. The extract contained high total phenolic and flavonoid contents. LC-ESI-QTOF-MS/MS analysis further revealed an abundance of caffeic acid derivatives and flavonoids. These data support its potential use as dietary supplements in oxidative stress prevention. PMID- 28659237 TI - In vivo antianxiety and antidepressant activity of Murraya paniculata leaf extracts. AB - OBJECTIVE: Different parts of Murraya paniculata have been used traditionally for treating several ailments including mental disorders. The present study was designed to evaluate the antianxiety and antidepressant potential of M. paniculata leaves using elevated plus maze model and forced swim test, respectively. METHODS: Extracts of M. paniculata made with petroleum ether (60-80 degrees C), chloroform, ethanol and water were evaluated for antianxiety and antidepressant activity. The anxiolytic chloroform extract was subjected to column chromatography, yielding five fractions (F1-F5). Fraction F5 (100 mg/kg), which showed notable anxiolytic activity, was further chromatographed to get four subfractions (F5.1-F5.4). Simultaneously, the ethanol extract was partitioned with ethyl acetate to obtain ethyl acetate soluble fraction (EASF) and ethyl acetate insoluble fraction. Phytochemical screening of bioactive extracts/fractions and detection of mahanimbine in M. paniculata leaf extract by thin-layer chromatography was also carried out. RESULTS: Fraction F5.3 (25 mg/kg) and EASF (20 mg/kg) showed significant anxiolytic and antidepressant activity, respectively. Thin-layer chromatography and phytochemical screening demonstrated the absence of mahanimbine in M. paniculata leaves. Coumarins were observed to be responsible for the anxiolytic activity. CONCLUSION: The results validate the traditional use of M. paniculata leaves in the treatment of mental disorders. PMID- 28659238 TI - Hwangryunhaedoktang exerts anti-inflammation on LPS-induced NO production by suppressing MAPK and NF- kappaB activation in RAW264.7 macrophages. AB - OBJECTIVE: This study aimed to evaluate whether Hwangryunhaedoktang (HHT), a herbal compound, has an inhibitory effect on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. METHODS: The effects of HHT were evaluated by confirming nitric oxide (NO) production and expression of inducible NO synthase (iNOS) and mitogen-activated protein kinases (MAPKs) in LPS-stimulated RAW264.7 macrophages via the Griess assay, Western blotting, and real-time reverse transcription quantitative polymerase chain reaction. Western blot analyses and luciferase assays were used to evaluate whether HHT has an effect on the phosphorylation and translocation of nuclear factor-kappaB (NF-kappaB). The secretion and expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined via enzyme-linked immunosorbent assay and Western blot analyses. RESULTS: HHT suppressed LPS-induced NO production and expression of iNOS in a dose-dependent manner. Additionally, MAPKs activation was also attenuated via inhibition of phosphorylation of extracellular signal regulated kinases 1/2, c-Jun N-terminal kinase and p38 which were related to inflammatory pathway. Furthermore, HHT also effectively attenuated NF-kappaB activation and its translocation to the nucleus, a process that is closely linked to inflammation. LPS normally induced the expression of inflammatory cytokines such as TNF-alpha and IL-6, but the secretion and expression of TNF-alpha and IL 6 were significantly attenuated by pretreating the cells with HHT. CONCLUSION: HHT suppressed LPS-induced NO production by blocking the activation of NF-kappaB and MAPK signaling pathways in RAW264.7 macrophages. Furthermore, HHT may have an anti-inflammatory effect by suppressing the LPS-induced secretion of TNF-alpha and IL-6. Therefore, the traditional herbal formula HHT might be a useful potential therapeutic agent for inflammation. PMID- 28659240 TI - Children's second-hand tobacco smoke exposure: the silent killer. PMID- 28659239 TI - A causality algorithm to guide diagnosis and treatment of catatonia due to autoimmune conditions in children and adolescents. AB - OBJECTIVES: Pediatric catatonia is a rare and life-threatening syndrome. Around 20% of juvenile catatonia is associated with organic condition (Consoli et al., 2012). Autoimmune conditions represent a diagnostic and therapeutic challenge since specific antibodies can be missed. To facilitate decision making, we recently formulated a causality assessment score (CAUS) using a stepwise approach and an immunosuppressive therapeutic challenge (Ferrafiat et al., 2016). Our objectives were to validate retrospectively CAUS and to define its threshold for an accurate distinction between organic catatonia and non-organic catatonia, and specifically between autoimmune catatonia and non-organic catatonia. METHOD: To obtain a sufficient number of cases with organic catatonia, we pooled two samples (N=104) - one from a child psychiatry center, the other from neuro-pediatrics center - expert in catatonia and autoimmune conditions. Organic conditions were diagnosed using a multidisciplinary approach and numerous paraclinical investigations. Given the binary classification needs, we used receiver operating characteristic (ROC) analysis (Peacock and Peacock, 2010) to calculate the best classification threshold. RESULTS: The cohort included 67 cases of non-organic catatonia and 37 cases of organic catatonia. ROC analysis showed that the CAUS performance in discriminating both organic catatonia vs. non-organic catatonia, and autoimmune catatonia vs. non-organic catatonia was excellent (Area Under the Curve=0.99). In both analyses, for a CAUS threshold>=5, accuracy equaled to 0.96. CONCLUSION: Regarding juvenile catatonia, the use of the CAUS score algorithm combining a therapeutic challenge and a threshold>=5 may help to diagnose and treat autoimmune conditions even without formal identification of auto antibodies. PMID- 28659241 TI - Primary Melanoma of the Third Metatarsal. AB - Melanoma is a well-known malignant neoplasm of the skin, although it can also arise from other structures. Bone metastasis is not an uncommon event associated with melanoma, although primary osseous melanoma is very rare. In the present report, we describe a case of primary melanoma arising from the left third metatarsal in an adult male. The lesion was treated with surgical excision without adjunct chemotherapy, and recurrence developed approximately 12 months after the foot surgery. The patient died of the cancer 34 months after it had been identified. Primary melanoma arising in a metatarsal is rare, and we wished to highlight this unusual presentation. PMID- 28659242 TI - Minimally Invasive Achilles Tendon Stripping for the Management of Tendinopathy of the Main Body of the Achilles Tendon. AB - Achilles tendinopathy is a common cause of disability. New nerves fibers grow from the paratenon into the Achilles tendon, and they could play a central role in the development of pain. We report the results of minimally invasive Achilles tendon stripping for Achilles tendinopathy in 47 active patients. The Victorian Institute of Sports Assessment-Achilles questionnaire score improved from 53.8 preoperatively to 85.3 postoperatively (p < .001). After a mean follow-up period of 40.5 months, 41 patients had resumed sporting activities at an average of 3.5 months postoperatively. A sural nerve injury was recorded in 5 patients (10.6%), and all 5 complications occurred during the first 12 cases. As a result, the technique was slightly modified, and no sural nerve neuropathy was observed subsequently. One superficial infection (2.1%) was recorded. Minimally invasive Achilles tendon stripping seems to be an effective, technically simple, and inexpensive treatment of Achilles tendinopathy. Further randomized controlled trials involving more patients are needed to confirm these outcomes. PMID- 28659243 TI - The impact of using an intraoperative goal directed fluid therapy protocol on clinical outcomes in patients undergoing total pancreatectomy and islet cell autotransplantation. AB - BACKGROUND: Patients undergoing total pancreatectomy and islet cell autotransplant (TPIAT) for treatment of pancreatitis are at risk for complications of over and under resuscitation. We hypothesized that using a goal directed fluid therapy (GDFT) protocol might impact clinical outcomes. MATERIALS AND METHODS: A consecutive series of adult patients undergoing TPIAT were managed intraoperatively using either standard fluid therapy (SFT, n = 44) or GDFT (n = 23) as part of a pilot study between January 2013 and May 2015. Patient characteristics, intraoperative, and postoperative data were recorded prospectively, then retrospectively analyzed for differences between the groups. RESULTS: The GDFT group had lower total fluid resuscitation (3,240 cc vs 5,173 cc, p < 0.0001) and transfusion requirements (1.0 cc/kg vs 3.3 cc/kg, p = 0.050) compared to the SFT group. The pre to postop nadir hemoglobin change was significantly less for GDFT (4.2 vs 5.1 gm/dl, p = 0.021) despite less transfusion. CONCLUSIONS: Compared to SFT, using an intraoperative GDFT protocol in TPIAT patients was associated with significantly decreased intraoperative fluid resuscitation, blood transfusion and less postoperative dilutional anemia, without any difference in complications of underresuscitation. This pilot study suggests that GDFT is likely safe and further investigation is warranted. PMID- 28659244 TI - Long-term physical health consequences of perceived inequality: Results from a twin comparison design. AB - RATIONALE: Previous research has identified long-term exposure to stress as a risk factor for negative mental and physical health outcomes. This pattern of findings suggests that environmental stimuli that evoke feelings of stress or strain may also result in physiological responses, which may accumulate over the life course and ultimately increase the overall risk of various physical health conditions. This physiological "wear and tear" resulting from sustained levels of stress or strain has been previously operationalized as allostatic load (AL), a comprehensive indicator of stress exposure. OBJECTIVE: The current study examines the association between one potential environmental stressor-perceived inequality and AL with a research design aimed at addressing both observed and unobserved sources of confounding; it also employs a more comprehensive AL measure (comprised of 24 biomarkers tapping seven physiological systems) than previous studies. METHOD: The biomarker twin sample from the Midlife Development in the United States (MIDUS) study was used to estimate a series of twin comparison models, which include controls for latent sources of influence that cluster within families. The sibling comparison models also included additional controls for lifestyle choices, overall physical health, and demographics which may confound the examined associations. RESULTS: The results revealed significant associations between greater perceptions of inequality and greater overall levels of AL. The association persisted even after including controls for both observed and unobserved influences that may confound the examined associations but was limited to more recent measures of perceived inequality. Associations involving earlier measures of perceived inequality, along with a lifetime measure, failed to reach conventional levels of significance. CONCLUSION: Perceived inequality appears to be a robust predictor of AL and potentially contributes to subsequent physical health problems, particularly for more proximate forms of perceived inequality. PMID- 28659245 TI - Newborn screening for hyperargininemia due to arginase 1 deficiency. AB - Hyperargininemia caused by Arginase 1 deficiency is a rare disorder of the urea cycle that can be diagnosed by elevation of arginine in newborn screening blood spots when analyzed by tandem mass spectrometry. Hyperargininemia is currently included as a secondary target on the U.S. Recommended Uniform Screening Panel, which directly influences state-based newborn screening. Because of the apparent low disease frequency and lack of case detection and treatment data, detailed attention has not been given to a model newborn screening algorithm including appropriate analytical cutoff values for disease indicators. In this paper we assess the frequency of hyperargininemia in the U.S. identified by newborn screening to date and document the current status and variability of hyperargininemia newborn screening across U.S. newborn screening programs. We also review other data that support improved screening efficacy by utilizing the arginine/ornithine ratio and other amino acid ratios as discriminators in the screening algorithm. Analysis of archived California screening data showed that an arginine cutoff of 50MUM combined with an arginine/ornithine ratio of 1.4 would have resulted in a recall rate of 0.01%. Using an arginine cutoff of 60MUM and an arginine/(phenylalanine x leucine) ratio of 1.4, reportedly used in one screening program, or the R4S Tool Runner, would have resulted in a recall rate of <0.005%. All 9 diagnosed patients would have been found for either protocol. Thus, use of appropriate ratios as part of the screening algorithm has the potential to increase both screening sensitivity and specificity. Improved newborn screening effectiveness should lead to better case detection and more rapid treatment to lower plasma arginine levels hence improving long term outcome of individuals with hyperargininemia. PMID- 28659246 TI - Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays. AB - Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48MUM and 1.61MUM, respectively. They were much potent than the reference drug ddI (EC50=76.0MUM) and comparable to 3TC (EC50=2.54MUM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed. PMID- 28659247 TI - Two emergency departments, 6000km apart: Differences in patient flow and staff perceptions about crowding. AB - INTRODUCTION: Emergency department (ED) crowding is a worldwide public health issue. In this study, patient flow and staff perceptions of crowding were assessed in Pakistan (Aga Khan University Hospital (AKUH)) and in the Netherlands (Haaglanden Medical Centre Westeinde (HMCW)). Bottlenecks affecting ED patient flow were identified. METHODS: First, a one-year review of patient visits was performed. Second, staff perceptions about ED crowding were collected using face to-face interviews. Non-participant observation and document review were used to interpret the findings. RESULTS: At AKUH 58,839 (160visits/day) and at HMCW 50,802 visits (140visits/day) were registered. Length of stay (LOS) at AKUH was significantly longer than at HMCW (279min (IQR 357) vs. 100min (IQR 152)). There were major differences in patient acuities, admission and mortality rates, indicating a sicker population at AKUH. Respondents from both departments experienced hampered patient flow on a daily basis, and perceived similar causes for crowding: increased patients' complexity, long treatment times, and poor availability of inpatient beds. CONCLUSION: Despite differences in environment, demographics, and ED patient flow, respondents perceived similar bottlenecks in patient flow. Interventions should be tailored to specific ED and hospital needs. For both EDs, improving the outflow of boarded patients is essential. PMID- 28659250 TI - Cutaneous Kaposi sarcoma during treatment with superpotent topical steroids and methotrexate for bullous pemphigoid: three cases. AB - Iatrogenic Kaposi sarcoma (KS) has previously been reported in patients with bullous pemphigoid (BP), in relation to systemic steroids. To report three cases of previously unreported cutaneous KS during treatment with superpotent topical steroids (STS) and methotrexate (MTX). All patients were elderly men with BP treated with STS for 2 to 32 months (cumulative doses: 2,700-9,150 g) before MTX was introduced (dosage: 10-12.5 mg/week). KS occurred one to nine months after the combined therapy. In one case, KS rapidly resolved after withdrawal of MTX. In two cases, vinblastine and/or radiotherapy were required to achieve regression of KS. Human herpes virus 8 (HHV8) latency-associated nuclear antigen was not expressed in BP lesions biopsied prior to development of KS (n = 3), but HHV8 DNA was detected in BP lesions from the patient with the most aggressive KS. Several predisposing factors were identified, including sex and age, high cumulative doses of STS, combination with MTX, and impaired immune status. In such cases, serum antibodies against HHV8 infection may be investigated in BP patients before introduction of MTX in order to guide clinical monitoring. PMID- 28659251 TI - Web-Based Alcohol Intervention: Study of Systematic Attrition of Heavy Drinkers. AB - BACKGROUND: Web-based alcohol interventions are a promising way to reduce alcohol consumption because of their anonymity and the possibility of reaching a high numbers of individuals including heavy drinkers. However, Web-based interventions are often characterized by high rates of attrition. To date, very few studies have investigated whether individuals with higher alcohol consumption show higher attrition rates in Web-based alcohol interventions as compared with individuals with lower alcohol consumption. OBJECTIVES: The aim of this study was to examine the attrition rate and predictors of attrition in a Web-based intervention study on alcohol consumption. METHODS: The analysis of the predictors of attrition rate was performed on data collected in a Web-based randomized control trial. Data collection took place at the University of Konstanz, Germany. A total of 898 people, which consisted of 46.8% males (420/898) and 53.2% females (478/898) with a mean age of 23.57 years (SD 5.19), initially volunteered to participate in a Web-based intervention study to reduce alcohol consumption. Out of the sample, 86.9% (781/898) were students. Participants were classified as non-completers (439/898, 48.9%) if they did not complete the Web-based intervention. Potential predictors of attrition were self-reported: alcohol consumption in the last seven days, per week, from Monday to Thursday, on weekends, excessive drinking behavior measured with the Alcohol Use Disorder Identification Test (AUDIT), and drinking motives measured by the Drinking Motive Questionnaire (DMQ-R SF). RESULTS: Significant differences between completers and non-completers emerged regarding alcohol consumption in the last seven days (B=-.02, P=.05, 95% CI [0.97-1.00]), on weekends (B=-.05, P=.003, 95% CI [0.92-0.98]), the AUDIT (B=-.06, P=.007, 95% CI [0.90-0.98], and the status as a student (B=.72, P=.001, 95% CI [1.35-3.11]). Most importantly, non-completers had a significantly higher alcohol consumption compared with completers. CONCLUSIONS: Hazardous alcohol consumption appears to be a key factor of the dropout rate in a Web-based alcohol intervention study. Thus, it is important to develop strategies to keep participants who are at high risk in Web-based interventions. PMID- 28659252 TI - Mobile Phone Short Messages to Improve Exclusive Breastfeeding and Reduce Adverse Infant Feeding Practices: Protocol for a Randomized Controlled Trial in Yangon, Myanmar. AB - BACKGROUND: Myanmar has a high burden of mortality for children aged younger than 5 years in which undernutrition plays a major role. Despite current efforts, the exclusive breastfeeding rate for children under 6 months is only 24%. To date there have been no interventions using mobile phones to improve breastfeeding and other feeding practices in Myanmar. OBJECTIVE: This study aims to implement a breastfeeding promotion intervention using mobile phone text messages in Yangon, Myanmar, and evaluate its impact on breastfeeding practices. METHODS: M528 is a 2 group parallel-arm randomized controlled trial with 9 months follow-up from recruitment until 6 months post-delivery. A total of 353 pregnant women between 28 and 34 weeks' gestation who had access to a mobile phone and were able to read and write have been recruited from the Central Women's Hospital, Yangon, and allocated randomly to an intervention or control group in a 1:1 ratio. The intervention group received breastfeeding promotional SMS messages 3 times a week while the control group received maternal and child health care messages (excluding breastfeeding-related messages) once a week. The SMS messages were tailored for the women's stage of gestation or the child's age. A formative qualitative study was conducted prior to the trial to inform the study design and text message content. We hypothesize that the exclusive breastfeeding rate in the intervention group will be double that in the control group. The primary outcome is exclusive breastfeeding from birth to 6 months and secondary outcomes are median durations of exclusive breastfeeding and other infant feeding practices. Both primary and secondary outcomes were assessed by monthly phone calls at 1 to 6 months postdelivery in both groups. Participants' delivery status was tracked through text messages, phone calls, and hospital records, and delivery characteristics were assessed 1 month after delivery. Child morbidity and breastfeeding self-efficacy scores were assessed at 1, 3, and 5 months postdelivery. Social desirability was measured at 5 months, and text messages expressing delivery success and user experience were assessed at the end of the study. RESULTS: The targeted 353 pregnant women were recruited between January and March 2015. Baseline data have been collected; SMS messages have been developed and pretested and sent to the women from both groups. Follow-up data collection via phone calls has been completed. Data analysis is being done and results are expected soon. This is the first RCT study examining the effects of mobile text messaging for promoting exclusive breastfeeding. CONCLUSIONS: This trial is timely in Myanmar following the telecommunications market opening in 2014. Our results will help determine whether text messaging is an effective and feasible method for promoting appropriate feeding practices and will inform further research to assess how this model could be replicated in the broader community. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12615000063516; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367704 (Archived by WebCite at http://www.webcitation.org/ 6rGif3l81). PMID- 28659254 TI - Tracing the Potential Flow of Consumer Data: A Network Analysis of Prominent Health and Fitness Apps. AB - BACKGROUND: A great deal of consumer data, collected actively through consumer reporting or passively through sensors, is shared among apps. Developers increasingly allow their programs to communicate with other apps, sensors, and Web-based services, which are promoted as features to potential users. However, health apps also routinely pose risks related to information leaks, information manipulation, and loss of information. There has been less investigation into the kinds of user data that developers are likely to collect, and who might have access to it. OBJECTIVE: We sought to describe how consumer data generated from mobile health apps might be distributed and reused. We also aimed to outline risks to individual privacy and security presented by this potential for aggregating and combining user data across apps. METHODS: We purposively sampled prominent health and fitness apps available in the United States, Canada, and Australia Google Play and iTunes app stores in November 2015. Two independent coders extracted data from app promotional materials on app and developer characteristics, and the developer-reported collection and sharing of user data. We conducted a descriptive analysis of app, developer, and user data collection characteristics. Using structural equivalence analysis, we conducted a network analysis of sampled apps' self-reported sharing of user-generated data. RESULTS: We included 297 unique apps published by 231 individual developers, which requested 58 different permissions (mean 7.95, SD 6.57). We grouped apps into 222 app families on the basis of shared ownership. Analysis of self-reported data sharing revealed a network of 359 app family nodes, with one connected central component of 210 app families (58.5%). Most (143/222, 64.4%) of the sampled app families did not report sharing any data and were therefore isolated from each other and from the core network. Fifteen app families assumed more central network positions as gatekeepers on the shortest paths that data would have to travel between other app families. CONCLUSIONS: This cross-sectional analysis highlights the possibilities for user data collection and potential paths that data is able to travel among a sample of prominent health and fitness apps. While individual apps may not collect personally identifiable information, app families and the partners with which they share data may be able to aggregate consumer data, thus achieving a much more comprehensive picture of the individual consumer. The organizations behind the centrally connected app families represent diverse industries, including apparel manufacturers and social media platforms that are not traditionally involved in health or fitness. This analysis highlights the potential for anticipated and voluntary but also possibly unanticipated and involuntary sharing of user data, validating privacy and security concerns in mobile health. PMID- 28659253 TI - Informing the Design of "Lifestyle Monitoring" Technology for the Detection of Health Deterioration in Long-Term Conditions: A Qualitative Study of People Living With Heart Failure. AB - BACKGROUND: Health technologies are being developed to help people living at home manage long-term conditions. One such technology is "lifestyle monitoring" (LM), a telecare technology based on the idea that home activities may be monitored unobtrusively via sensors to give an indication of changes in health-state. However, questions remain about LM technology: how home activities change when participants experience differing health-states; and how sensors might capture clinically important changes to inform timely interventions. OBJECTIVE: The objective of this paper was to report the findings of a study aimed at identifying changes in activity indicative of important changes in health in people with long-term conditions, particularly changes indicative of exacerbation, by exploring the relationship between home activities and health among people with heart failure (HF). We aimed to add to the knowledge base informing the development of home monitoring technologies designed to detect health deterioration in order to facilitate early intervention and avoid hospital admissions. METHODS: This qualitative study utilized semistructured interviews to explore everyday activities undertaken during the three health-states of HF: normal days, bad days, and exacerbations. Potential recruits were identified by specialist nurses and attendees at an HF support group. The sample was purposively selected to include a range of experience of living with HF. RESULTS: The sample comprised a total of 20 people with HF aged 50 years and above, and 11 spouses or partners of the individuals with HF. All resided in Northern England. Participant accounts revealed that home activities are in part shaped by the degree of intrusion from HF symptoms. During an exacerbation, participants undertook activities specifically to ease symptoms, and detailed activity changes were identified. Everyday activity was also influenced by a range of factors other than health. CONCLUSIONS: The study highlights the importance of careful development of LM technology to identify changes in activities that occur during clinically important changes in health. These detailed activity changes need to be considered by developers of LM sensors, platforms, and algorithms intended to detect early signs of deterioration. Results suggest that for LM to move forward, sensor set-up should be personalized to individual circumstances and targeted at individual health conditions. LM needs to take account of the uncertainties that arise from placing technology within the home, in order to inform sensor set-up and data interpretation. This targeted approach is likely to yield more clinically meaningful data and address some of the ethical issues of remote monitoring. PMID- 28659255 TI - Mobile Device Accuracy for Step Counting Across Age Groups. AB - BACKGROUND: Only one in five American meets the physical activity recommendations of the Department of Health and Human Services. The proliferation of wearable devices and smartphones for physical activity tracking has led to an increasing number of interventions designed to facilitate regular physical activity, in particular to address the obesity epidemic, but also for cardiovascular disease patients, cancer survivors, and older adults. However, the inconsistent findings pertaining to the accuracy of wearable devices for step counting needs to be addressed, as well as factors known to affect gait (and thus potentially impact accuracy) such as age, body mass index (BMI), or leading arm. OBJECTIVE: We aim to assess the accuracy of recent mobile devices for counting steps, across three different age groups. METHODS: We recruited 60 participants in three age groups: 18-39 years, 40-64 years, and 65-84 years, who completed two separate 1000 step walks on a treadmill at a self-selected speed between 2 and 3 miles per hour. We tested two smartphones attached on each side of the waist, and five wrist-based devices worn on both wrists (2 devices on one wrist and 3 devices on the other), as well as the Actigraph wGT3X-BT, and swapped sides between each walk. All devices were swapped dominant-to-nondominant side and vice-versa between the two 1000 step walks. The number of steps was recorded with a tally counter. Age, sex, height, weight, and dominant hand were self-reported by each participant. RESULTS: Among the 60 participants, 36 were female (60%) and 54 were right-handed (90%). Median age was 53 years (min=19, max=83), median BMI was 24.1 (min=18.4, max=39.6). There was no significant difference in left- and right-hand step counts by device. Our analyses show that the Fitbit Surge significantly undercounted steps across all age groups. Samsung Gear S2 significantly undercounted steps only for participants among the 40-64 year age group. Finally, the Nexus 6P significantly undercounted steps for the group ranging from 65-84 years. CONCLUSIONS: Our analysis shows that apart from the Fitbit Surge, most of the recent mobile devices we tested do not overcount or undercount steps in the 18-39-year-old age group, however some devices undercount steps in older age groups. This finding suggests that accuracy in step counting may be an issue with some popular wearable devices, and that age may be a factor in undercounting. These results are particularly important for clinical interventions using such devices and other activity trackers, in particular to balance energy requirements with energy expenditure in the context of a weight loss intervention program. PMID- 28659256 TI - Users' Adoption of Mental Health Apps: Examining the Impact of Information Cues. AB - BACKGROUND: Numerous mental health apps have been developed and made available to users on the current app market. Users may find it difficult and overwhelming to select apps from the hundreds of choices that are available in the app marketplace. Clarifying what information cues may impact a user's selection and adoption of mental health apps is now a critical and pressing issue. OBJECTIVE: The aim of this study was to investigate the impact of information cues on users' adoption of anxiety apps using observational data from the Android app market. METHODS: A systematic search of anxiety apps was conducted on the Android app store by using keywords search. The title and metadata information of a total of 274 apps that met our criteria were collected and analyzed. Three trained researchers recorded the app rankings from the search results page on different dates and Web browsers. RESULTS: Our results show that ratings (r=.56, P<.001) and reviews (r=.39, P<.001) have significant positive correlations with the number of installs, and app prices have significant negative correlations with installs (r=-.36). The results also reveal that lower-priced apps have higher ratings (r=-.23, P<.001) and a greater number of app permission requests (r=.18, P=.002) from the device. For app titles, we found that apps with titles related to symptoms have significantly lower installs than apps with titles that are not related to symptoms (P<.001). CONCLUSIONS: This study revealed a relationship between information cues and users' adoption of mental health apps by analyzing observational data. As the first of its kind, we found impactful indicators for mental health app adoptions. We also discovered a labeling effect of app titles that could hinder mental health app adoptions and which may provide insight for future designs of mental health apps and their search mechanisms. PMID- 28659257 TI - Telemedicine Services for the Arctic: A Systematic Review. AB - BACKGROUND: Telemedicine services have been successfully used in areas where there are adequate infrastructures such as reliable power and communication lines. However, despite the increasing number of merchants and seafarers, maritime and Arctic telemedicine have had limited success. This might be linked with various factors such as lack of good infrastructure, lack of trained onboard personnel, lack of Arctic-enhanced telemedicine equipment, extreme weather conditions, remoteness, and other geographical challenges. OBJECTIVE: The purpose of this review was to assess and analyze the current status of telemedicine services in the context of maritime conditions, extreme weather (ie, Arctic weather), and remote accidents and emergencies. Moreover, the paper aimed to identify successfully implemented telemedicine services in the Arctic region and in maritime settings and remote emergency situations and present state of the art systems for these areas. Finally, we identified the status quo of telemedicine services in the context of search and rescue (SAR) scenarios in these extreme conditions. METHODS: A rigorous literature search was conducted between September 7 and October 28, 2015, through various online databases. Peer reviewed journals and articles were considered. Relevant articles were first identified by reviewing the title, keywords, and abstract for a preliminary filter with our selection criteria, and then we reviewed full-text articles that seemed relevant. Information from the selected literature was extracted based on some predefined categories, which were defined based on previous research and further elaborated upon via iterative brainstorming. RESULTS: The initial hits were vetted using the title, abstract, and keywords, and we retrieved a total of 471 papers. After removing duplicates from the list, 422 records remained. Then, we did an independent assessment of the articles and screening based on the inclusion and exclusion criteria, which eliminated another 219 papers, leaving 203 relevant papers. After a full-text assessment, 36 articles were left, which were critically analyzed. The inter-rater agreement was measured using Cohen Kappa test, and disagreements were resolved through discussion. CONCLUSIONS: Despite the increasing number of fishermen and other seafarers, Arctic and maritime working conditions are mainly characterized by an absence of access to health care facilities. The condition is further aggravated for fishermen and seafarers who are working in the Arctic regions. In spite of the existing barriers and challenges, some telemedicine services have recently been successfully delivered in these areas. These services include teleconsultation (9/37, 24%), teleradiology (8/37, 22%), teledermatology and tele-education (3/37, 8%), telemonitoring and telecardiology (telesonography) (1/37, 3%), and others (10/37, 27%). However, the use of telemedicine in relation to search and rescue (SAR) services is not yet fully exploited. Therefore, we foresee that these implemented and evaluated telemedicine services will serve as underlying models for the successful implementation of future search and rescue (SAR) services. PMID- 28659258 TI - Acceptance of Mobile Health in Communities Underrepresented in Biomedical Research: Barriers and Ethical Considerations for Scientists. AB - BACKGROUND: The rapid expansion of direct-to-consumer wearable fitness products (eg, Flex 2, Fitbit) and research-grade sensors (eg, SenseCam, Microsoft Research; activPAL, PAL Technologies) coincides with new opportunities for biomedical and behavioral researchers. Underserved communities report among the highest rates of chronic disease and could benefit from mobile technologies designed to facilitate awareness of health behaviors. However, new and nuanced ethical issues are introduced with new technologies, which are challenging both institutional review boards (IRBs) and researchers alike. Given the potential benefits of such technologies, ethical and regulatory concerns must be carefully considered. OBJECTIVE: Our aim was to understand potential barriers to using wearable sensors among members of Latino, Somali and Native Hawaiian Pacific Islander (NHPI) communities. These ethnic groups report high rates of disparate health conditions and could benefit from wearable technologies that translate the connection between physical activity and desired health outcomes. Moreover, these groups are traditionally under-represented in biomedical research. METHODS: We independently conducted formative research with individuals from southern California, who identified as Latino, Somali, or Native Hawaiian Pacific Islander (NHPI). Data collection methods included survey (NHPI), interview (Latino), and focus group (Somali) with analysis focusing on cross-cutting themes. RESULTS: The results pointed to gaps in informed consent, challenges to data management (ie, participant privacy, data confidentiality, and data sharing conventions), social implications (ie, unwanted attention), and legal risks (ie, potential deportation). CONCLUSIONS: Results shed light on concerns that may escalate the digital divide. Recommendations include suggestions for researchers and IRBs to collaborate with a goal of developing meaningful and ethical practices that are responsive to diverse research participants who can benefit from technology enabled research methods. TRIAL REGISTRATION: ClinicalTrials.gov NCT02505165; https://clinicaltrials.gov/ct2/show/NCT02505165 (Archived by WebCite at http://www.Webcitation.org/6r9ZSUgoT). PMID- 28659260 TI - BMA annual meeting: GPs working at unsafe levels should issue "black alert"-style warnings, says BMA. PMID- 28659259 TI - Initial Progress Toward Development of a Voice-Based Computer-Delivered Motivational Intervention for Heavy Drinking College Students: An Experimental Study. AB - BACKGROUND: Computer-delivered interventions have been shown to be effective in reducing alcohol consumption in heavy drinking college students. However, these computer-delivered interventions rely on mouse, keyboard, or touchscreen responses for interactions between the users and the computer-delivered intervention. The principles of motivational interviewing suggest that in-person interventions may be effective, in part, because they encourage individuals to think through and speak aloud their motivations for changing a health behavior, which current computer-delivered interventions do not allow. OBJECTIVE: The objective of this study was to take the initial steps toward development of a voice-based computer-delivered intervention that can ask open-ended questions and respond appropriately to users' verbal responses, more closely mirroring a human delivered motivational intervention. METHODS: We developed (1) a voice-based computer-delivered intervention that was run by a human controller and that allowed participants to speak their responses to scripted prompts delivered by speech generation software and (2) a text-based computer-delivered intervention that relied on the mouse, keyboard, and computer screen for all interactions. We randomized 60 heavy drinking college students to interact with the voice-based computer-delivered intervention and 30 to interact with the text-based computer delivered intervention and compared their ratings of the systems as well as their motivation to change drinking and their drinking behavior at 1-month follow-up. RESULTS: Participants reported that the voice-based computer-delivered intervention engaged positively with them in the session and delivered content in a manner consistent with motivational interviewing principles. At 1-month follow up, participants in the voice-based computer-delivered intervention condition reported significant decreases in quantity, frequency, and problems associated with drinking, and increased perceived importance of changing drinking behaviors. In comparison to the text-based computer-delivered intervention condition, those assigned to voice-based computer-delivered intervention reported significantly fewer alcohol-related problems at the 1-month follow-up (incident rate ratio 0.60, 95% CI 0.44-0.83, P=.002). The conditions did not differ significantly on perceived importance of changing drinking or on measures of drinking quantity and frequency of heavy drinking. CONCLUSIONS: Results indicate that it is feasible to construct a series of open-ended questions and a bank of responses and follow-up prompts that can be used in a future fully automated voice-based computer delivered intervention that may mirror more closely human-delivered motivational interventions to reduce drinking. Such efforts will require using advanced speech recognition capabilities and machine-learning approaches to train a program to mirror the decisions made by human controllers in the voice-based computer delivered intervention used in this study. In addition, future studies should examine enhancements that can increase the perceived warmth and empathy of voice based computer-delivered intervention, possibly through greater personalization, improvements in the speech generation software, and embodying the computer delivered intervention in a physical form. PMID- 28659262 TI - Yemen's cholera epidemic may have peaked, says WHO. PMID- 28659264 TI - Can Healthcare Expansion Rapidly Reduce Out-of-Hospital Cardiac Arrest? PMID- 28659263 TI - Health Insurance Expansion and Incidence of Out-of-Hospital Cardiac Arrest: A Pilot Study in a US Metropolitan Community. AB - BACKGROUND: Health insurance has many benefits including improved financial security, greater access to preventive care, and better self-perceived health. However, the influence of health insurance on major health outcomes is unclear. Sudden cardiac arrest prevention represents one of the major potential benefits from health insurance, given the large impact of sudden cardiac arrest on premature death and its potential sensitivity to preventive care. METHODS AND RESULTS: We conducted a pre-post study with control group examining out-of hospital cardiac arrest (OHCA) among adult residents of Multnomah County, Oregon (2015 adult population 636 000). Two time periods surrounding implementation of the Affordable Care Act were evaluated: 2011-2012 ("pre-expansion") and 2014-2015 ("postexpansion"). The change in OHCA incidence for the middle-aged population (45-64 years old) exposed to insurance expansion was compared with the elderly population (age >=65 years old) with constant near-universal coverage. Rates of OHCA among middle-aged individuals decreased from 102 per 100 000 (95% CI: 92-113 per 100 000) to 85 per 100 000 (95% CI: 76-94 per 100 000), P value 0.01. The elderly population experienced no change in OHCA incidence, with rates of 275 per 100 000 (95% CI: 250-300 per 100 000) and 269 per 100 000 (95% CI: 245-292 per 100 000), P value 0.70. CONCLUSIONS: Health insurance expansion was associated with a significant reduction in OHCA incidence. Based on this pilot study, further investigation in larger populations is warranted and feasible. PMID- 28659265 TI - BMA annual meeting: Department of Health must stop sharing patient details with immigration enforcers, says BMA. PMID- 28659267 TI - Bedroom TVs and obesity. PMID- 28659266 TI - Higher IQ in childhood is linked to a longer life. PMID- 28659268 TI - Rare worm in an infant's nappy. PMID- 28659269 TI - Practical management of chronic fatigue syndrome or myalgic encephalomyelitis in childhood. AB - Paediatric chronic fatigue syndrome or myalgic encephalomyelitis affects at least 1% of secondary school children in the UK and is very disabling. Treatment is effective but few children get a diagnosis or access treatment. This paper summarises what we currently know about diagnosing and treating this important illness in childhood. PMID- 28659270 TI - Fifteen years of genetic testing from a London developmental clinic. AB - OBJECTIVE: To evaluate genetic disease among children referred to a community paediatric clinic. DESIGN: Retrospective cohort study. SETTING: Community paediatric clinic, Tower Hamlets, London. PATIENTS: All patients seen for first time in the Child Development Team (CDT) clinic between 1999 and 2013. INTERVENTIONS: Clinical notes were reviewed. Genetic test results were obtained. Exploratory Excel analysis was performed. Patients without an identified genetic disorder were labelled 'more likely genetic cause' if they had at least two out of three risk factors: developmental delay, congenital abnormality or parental consanguinity, and 'unlikely genetic cause' if they had one or no risk factors, or an obvious alternative cause. MAIN OUTCOME MEASURES: Prevalence of genetic diagnoses and parental consanguinity, undertaking of genetic tests, predicted likelihood of a genetic cause among unsolved patients. RESULTS: 749 patients were included. 404 (53.9%) had undergone genetic testing and 158 of those tested (39.1%) had a confirmed genetic diagnosis. Parental relatedness was documented in 461 patients, of which 128 (27.8%) had first-cousin parents. The number of patients undergoing genetic testing increased over time. Aneuploidies and syndromic/Mendelian disorders were most common. Of the 591 patients without a genetic diagnosis, 29.9% were classified 'more likely genetic cause'. Patients with consanguineous parents were significantly more likely to have a diagnosed genetic disorder than those with non-consanguineous parents (43/128 vs 72/333), particularly an autosomal recessive condition (27/43 vs 6/72). CONCLUSIONS: Genetic disease was common and genetic testing is important in evaluating children in this clinic. Consanguinity increases the likelihood of autosomal recessive disease. PMID- 28659271 TI - Insect bites and fever: what is your diagnosis? PMID- 28659272 TI - p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction. AB - Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study has shown that mitochondrial fission contributed to mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro. In an animal model of aldosterone-induced nephropathy, inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction, and podocyte apoptosis. Furthermore, aldosterone dose dependently induced p53 expression. Knockdown of p53 inhibited aldosterone induced Drp1 expression, mitochondrial dysfunction, and podocyte apoptosis. These findings implicated that aldosterone induced mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury. PMID- 28659273 TI - Maggie's cancer centre wins award. PMID- 28659274 TI - Childhood intelligence in relation to major causes of death in 68 year follow-up: prospective population study. AB - Objectives To examine the association between intelligence measured in childhood and leading causes of death in men and women over the life course.Design Prospective cohort study based on a whole population of participants born in Scotland in 1936 and linked to mortality data across 68 years of follow up.Setting Scotland.Participants 33 536 men and 32 229 women who were participants in the Scottish Mental Survey of 1947 (SMS1947) and who could be linked to cause of death data up to December 2015.Main outcome measures Cause specific mortality, including from coronary heart disease, stroke, specific cancer types, respiratory disease, digestive disease, external causes, and dementia.Results Childhood intelligence was inversely associated with all major causes of death. The age and sex adjusted hazard ratios (and 95% confidence intervals) per 1 SD (about 15 points) advantage in intelligence test score were strongest for respiratory disease (0.72, 0.70 to 0.74), coronary heart disease (0.75, 0.73 to 0.77), and stroke (0.76, 0.73 to 0.79). Other notable associations (all P<0.001) were observed for deaths from injury (0.81, 0.75 to 0.86), smoking related cancers (0.82, 0.80 to 0.84), digestive disease (0.82, 0.79 to 0.86), and dementia (0.84, 0.78 to 0.90). Weak associations were apparent for suicide (0.87, 0.74 to 1.02) and deaths from cancer not related to smoking (0.96, 0.93 to 1.00), and their confidence intervals included unity. There was a suggestion that childhood intelligence was somewhat more strongly related to coronary heart disease, smoking related cancers, respiratory disease, and dementia in women than men (P value for interactions <0.001, 0.02, <0.001, and 0.02, respectively).Childhood intelligence was related to selected cancer presentations, including lung (0.75, 0.72 to 0.77), stomach (0.77, 0.69 to 0.85), bladder (0.81, 0.71 to 0.91), oesophageal (0.85, 0.78 to 0.94), liver (0.85, 0.74 to 0.97), colorectal (0.89, 0.83 to 0.95), and haematopoietic (0.91, 0.83 to 0.98). Sensitivity analyses on a representative subsample of the cohort observed only small attenuation of the estimated effect of intelligence (by 10-26%) after adjustment for potential confounders, including three indicators of childhood socioeconomic status. In a replication sample from Scotland, in a similar birth year cohort and follow-up period, smoking and adult socioeconomic status partially attenuated (by 16-58%) the association of intelligence with outcome rates.Conclusions In a whole national population year of birth cohort followed over the life course from age 11 to age 79, higher scores on a well validated childhood intelligence test were associated with lower risk of mortality ascribed to coronary heart disease and stroke, cancers related to smoking (particularly lung and stomach), respiratory diseases, digestive diseases, injury, and dementia. PMID- 28659276 TI - KLF1 drives the expression of fetal hemoglobin in British HPFH. AB - beta-Hemoglobinopathies are among the most common single-locus inherited diseases. In this condition, high fetal hemoglobin (HbF) levels have been found to be beneficial, and boosting HbF expression is seen as an attractive therapy. Naturally occurring mutations in the fetal globin promoter can result in high HbF persisting into adulthood in a benign condition known as hereditary persistence of fetal hemoglobin (HPFH). Individuals with one form of HPFH, British HPFH, carry a T to C substitution at position -198 of the fetal globin gene promoter. These individuals exhibit HbF levels of up to 20%, enough to ameliorate the symptoms of beta-hemoglobinopathies. Here, we use clustered regularly interspaced short palindromic repeat-mediated genome editing to introduce the -198 substitution into human erythroid HUDEP-2 cells and show that this mutation is sufficient to substantially elevate expression of HbF. We also examined the molecular mechanism underlying the increase in fetal globin expression. Through a combination of in vitro and in vivo studies, we demonstrate that the mutation creates a de novo binding site for the important erythroid gene activator Kruppel like factor 1 (KLF1/erythroid KLF). Our results indicate that introducing this single naturally occurring mutation leads to significantly boosted HbF levels. PMID- 28659275 TI - Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. AB - Prolonged exposure to thiopurines (eg, mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL), but is also associated with frequent dose-limiting hematopoietic toxicities, which is partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (eg, TPMT). Recently, our group and others identified germ line genetic variants in NUDT15 as another major cause of thiopurine-related myelosuppression, particularly in Asian and Hispanic people. In this article, we describe 3 novel NUDT15 coding variants (p.R34T, p.K35E, and p.G17_V18del) in 5 children with ALL enrolled in frontline protocols in Singapore, Taiwan, and at St. Jude Children's Research Hospital. Patients carrying these variants experienced significant toxicity and reduced tolerance to MP across treatment protocols. Functionally, all 3 variants led to partial to complete loss of NUDT15 nucleotide diphosphatase activity and negatively influenced protein stability. In particular, the p.G17_V18del variant protein showed extremely low thermostability and was completely void of catalytic activity, thus likely to confer a high risk of thiopurine intolerance. This in frame deletion was only seen in African and European patients, and is the first NUDT15 risk variant identified in non-Asian, non-Hispanic populations. In conclusion, we discovered 3 novel loss-of-function variants in NUDT15 associated with MP toxicity, enabling more comprehensive pharmacogenetics-based thiopurine dose adjustments across diverse populations. PMID- 28659277 TI - Five things I wish I'd known at the start of my career as a GP. PMID- 28659280 TI - A Test of the Stereausis Hypothesis for Sound Localization in Mammals. AB - The relative arrival times of sounds at both ears constitute an important cue for localization of low-frequency sounds in the horizontal plane. The binaural neurons of the medial superior olive (MSO) act as coincidence detectors that fire when inputs from both ears arrive near simultaneously. Each principal neuron in the MSO is tuned to its own best interaural time difference (ITD), indicating the presence of an internal delay, a difference in the travel times from either ear to the MSO. According to the stereausis hypothesis, differences in wave propagation along the cochlea could provide the delays necessary for coincidence detection if the ipsilateral and contralateral inputs originated from different cochlear positions, with different frequency tuning. We therefore investigated the relation between interaural mismatches in frequency tuning and ITD tuning during in vivo loose-patch (juxtacellular) recordings from principal neurons of the MSO of anesthetized female gerbils. Cochlear delays can be bypassed by directly stimulating the auditory nerve; in agreement with the stereausis hypothesis, tuning for timing differences during bilateral electrical stimulation of the round windows differed markedly from ITD tuning in the same cells. Moreover, some neurons showed a frequency tuning mismatch that was sufficiently large to have a potential impact on ITD tuning. However, we did not find a correlation between frequency tuning mismatches and best ITDs. Our data thus suggest that axonal delays dominate ITD tuning.SIGNIFICANCE STATEMENT Neurons in the medial superior olive (MSO) play a unique role in sound localization because of their ability to compare the relative arrival time of low-frequency sounds at both ears. They fire maximally when the difference in sound arrival time exactly compensates for the internal delay: the difference in travel time from either ear to the MSO neuron. We tested whether differences in cochlear delay systematically contribute to the total travel time by comparing for individual MSO neurons the best difference in arrival times, as predicted from the frequency tuning for either ear, and the actual best difference. No systematic relation was observed, emphasizing the dominant contribution of axonal delays to the internal delay. PMID- 28659278 TI - Pathologists' diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. AB - Objective To quantify the accuracy and reproducibility of pathologists' diagnoses of melanocytic skin lesions.Design Observer accuracy and reproducibility study.Setting 10 US states.Participants Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart.Main outcome measures Pathologists' interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, >=pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses.Results In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted.Conclusion Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists' visual assessments. PMID- 28659281 TI - Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity. AB - Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS+ and a DS-, respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS+ to reinstate cocaine seeking behavior. The DS+ was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS+ We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability. PMID- 28659282 TI - Experience-Dependent Plasticity in Accessory Olfactory Bulb Interneurons following Male-Male Social Interaction. AB - Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC-interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate early gene Arc after male-male social experience. Following the resident-intruder paradigm, Arc-expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc-expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated IH currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident-intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc-expressing interneurons.SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male-male social chemosensory encounters. We show that the plasticity-associated immediate-early gene Arc is selectively expressed in IGCs from resident males following the resident-intruder assay. After behavior, Arc-expressing IGCs are more strongly excited by sensory input stimulation and MC activation is suppressed. Arc-expressing IGCs do not show increased excitatory synaptic drive but instead show increased intrinsic excitability. These data indicate that MC-IGC plasticity is induced after male male social chemosensory encounters, resulting in enhanced MC suppression by Arc expressing IGCs. PMID- 28659284 TI - Renal vascular and glomerular pathologies associated with spontaneous hypertension in the nonhuman primate Chlorocebus aethiops sabaeus. AB - Hypertension is a complex, multifactorial disease affecting an estimated 78 million adults in the United States. Despite scientific gains, the etiology of human essential hypertension is unknown and current experimental models do not recapitulate all the behavioral and physiological characteristics of the pathology. Researchers should assess the translational capacity of these models and look to other animal models for the discovery of new therapies. Chlorocebus aethiops sabaeus, the African Green Monkey (AGM), is a nonhuman primate that develops spontaneous hypertension and may provide a novel translational model for the study of hypertension and associated diseases. In a randomly selected group of 424 adult AGMs, 37% (157/424) exhibited systolic blood pressures (SBP) >140 mmHg (SBP: 172.0 +/- 2.2 mmHg) and were characterized as hypertensive (HT). 44% (187/424) were characterized as normotensive with SBP <120 mmHg (NT, SBP: 99.6 +/ 1.0 mmHg) and the remaining 18% (80/424) as borderline hypertensive (BHT, SBP: 130.6 +/- 0.6 mmHg). When compared with NT animals, HT AGMs are older (8.7 +/- 0.6 vs. 12.4 +/- 0.7 yr, P < 0.05) with elevated heart rates (125.7 +/- 2.0 vs. 137.7 +/- 2.2 beats/min, P < 0.05). BHT animals had average heart rates of 138.2 +/- 3.1 beats/min (P < 0.05 compared with NT) and were 11.00 +/- 0.9 yr old. NT and HT animals had similar levels of angiotensinogen gene expression, plasma renin activity, and renal cortical renin content (P > 0.05). HT monkeys exhibit renal vascular remodeling (wall-to-lumen ratio NT 0.11 +/- 0.01 vs. HT 0.15 +/- 0.02, P < 0.05) and altered glomerular morphology (Bowman's capsular space: NT 30.9 +/- 1.9% vs. HT 44.4 +/- 3.1%, P < 0.05). The hypertensive AGM provides a large animal model that is highly similar to humans and should be studied to identify novel, more effective targets for the treatment of hypertension. PMID- 28659283 TI - Identified Serotonergic Modulatory Neurons Have Heterogeneous Synaptic Connectivity within the Olfactory System of Drosophila. AB - Modulatory neurons project widely throughout the brain, dynamically altering network processing based on an animal's physiological state. The connectivity of individual modulatory neurons can be complex, as they often receive input from a variety of sources and are diverse in their physiology, structure, and gene expression profiles. To establish basic principles about the connectivity of individual modulatory neurons, we examined a pair of identified neurons, the "contralaterally projecting, serotonin-immunoreactive deutocerebral neurons" (CSDns), within the olfactory system of Drosophila Specifically, we determined the neuronal classes providing synaptic input to the CSDns within the antennal lobe (AL), an olfactory network targeted by the CSDns, and the degree to which CSDn active zones are uniformly distributed across the AL. Using anatomical techniques, we found that the CSDns received glomerulus-specific input from olfactory receptor neurons (ORNs) and projection neurons (PNs), and networkwide input from local interneurons (LNs). Furthermore, we quantified the number of CSDn active zones in each glomerulus and found that CSDn output is not uniform, but rather heterogeneous, across glomeruli and stereotyped from animal to animal. Finally, we demonstrate that the CSDns synapse broadly onto LNs and PNs throughout the AL but do not synapse upon ORNs. Our results demonstrate that modulatory neurons do not necessarily provide purely top-down input but rather receive neuron class-specific input from the networks that they target, and that even a two cell modulatory network has highly heterogeneous, yet stereotyped, pattern of connectivity.SIGNIFICANCE STATEMENT Modulatory neurons often project broadly throughout the brain to alter processing based on physiological state. However, the connectivity of individual modulatory neurons to their target networks is not well understood, as modulatory neuron populations are heterogeneous in their physiology, morphology, and gene expression. In this study, we use a pair of identified serotonergic neurons within the Drosophila olfactory system as a model to establish a framework for modulatory neuron connectivity. We demonstrate that individual modulatory neurons can integrate neuron class-specific input from their target network, which is often nonreciprocal. Additionally, modulatory neuron output can be stereotyped, yet nonuniform, across network regions. Our results provide new insight into the synaptic relationships that underlie network function of modulatory neurons. PMID- 28659286 TI - BMA annual meeting: Doctors who carry out abortions should not face criminal sanctions, says BMA. PMID- 28659285 TI - Upregulation of circulating myomiR following short-term energy restriction is inversely associated with whole body protein synthesis. AB - The objective of the present investigation was to determine whether energy restriction (ER) influences expression of skeletal muscle-specific microRNA (miRNA) in circulation (c-myomiR) and whether changes in c-myomiR are associated with rates of whole body protein synthesis. Sixteen older (64 +/- 2 yr) overweight (28.5 +/- 1.2 kg/m2) men enrolled in this 35-day controlled feeding trial. A 7-day weight maintenance (WM) period was followed by 28 days of 30% ER. Whole body protein turnover was determined from [15N]glycine enrichments in 24-h urine collections, and c-myomiR (miR-1-3p, miR-133a-3p, miR-133b, and miR-206) expression was assessed from serum samples by RT-quantitative PCR upon completion of the WM and ER periods. Participants lost 4.4 +/- 0.3 kg body mass during ER (P < 0.05). After 28 days of ER, miR-133a and miR-133b expression was upregulated (P < 0.05) compared with WM. When all four c-myomiR were grouped as c-myomiR score (sum of the median fold change of all myomiR), overall expression of c-myomiR was higher (P < 0.05) at ER than WM. Backward linear regression analysis of whole body protein synthesis and breakdown and carbohydrate, fat, and protein oxidation determined protein synthesis to be the strongest predictor of c-myomiR score. An inverse association (P < 0.05) was observed with ER c-myomiR score and whole body protein synthesis (r = -0.729, r2 = -0.530). Findings from the present investigation provide evidence that upregulation of c-myomiR expression profiles in response to short-term ER is associated with lower rates of whole body protein synthesis. PMID- 28659288 TI - Overload-mediated skeletal muscle hypertrophy is not impaired by loss of myofiber STAT3. AB - Although the signal pathways mediating muscle protein synthesis and degradation are well characterized, the transcriptional processes modulating skeletal muscle mass and adaptive growth are poorly understood. Recently, studies in mouse models of muscle wasting or acutely exercised human muscle have suggested a potential role for the transcription factor signal transducer and activator of transcription 3 (STAT3), in adaptive growth. Hence, in the present study we sought to define the contribution of STAT3 to skeletal muscle adaptive growth. In contrast to previous work, two different resistance exercise protocols did not change STAT3 phosphorylation in human skeletal muscle. To directly address the role of STAT3 in load-induced (i.e., adaptive) growth, we studied the anabolic effects of 14 days of synergist ablation (SA) in skeletal muscle-specific STAT3 knockout (mKO) mice and their floxed, wild-type (WT) littermates. Plantaris muscle weight and fiber area in the nonoperated leg (control; CON) was comparable between genotypes. As expected, SA significantly increased plantaris weight, muscle fiber cross-sectional area, and anabolic signaling in WT mice, although interestingly, this induction was not impaired in STAT3 mKO mice. Collectively, these data demonstrate that STAT3 is not required for overload-mediated hypertrophy in mouse skeletal muscle. PMID- 28659287 TI - Reduced SCD1 activity alters markers of fatty acid reesterification, glyceroneogenesis, and lipolysis in murine white adipose tissue and 3T3-L1 adipocytes. AB - White adipose tissue (WAT) has a critical role in lipid handling. Previous work demonstrated that SCD1 is an important regulator of WAT fatty acid (FA) composition; however, its influence on the various interconnected pathways influencing WAT lipid handling remains unclear. Our objective was to investigate the role of SCD1 on WAT lipid handling using Scd1 knockout (KO) mice and SCD1 inhibited 3T3-L1 adipocytes by measuring gene, protein, and metabolite markers related to FA reesterification, glyceroneogenesis, and lipolysis. Triacylglycerol (TAG) content was higher in inguinal WAT (iWAT) from KO mice compared with wild type, but significantly lower in epididymal WAT (eWAT). The SCD1 desaturation index was decreased in both WAT depots in KO mice. FA reesterification, as measured with a NEFA:glycerol ratio, was reduced in both WAT depots in KO mice, as well as SCD1-inhibited 3T3-L1 adipocytes. Pck1, Atgl, and Hsl gene expression was reduced in both WAT depots of KO mice, while Pck2 and Pdk4 gene expression showed depot-specific regulation. Pck1, Atgl, and Hsl gene expression was reduced, and phosphoenolpyruvate carboxykinase protein content was ablated, in SCD1-inhibited adipocytes. Our data provide evidence that SCD1 has a broad impact on WAT lipid handling by altering TAG composition in a depot-specific manner, reducing FA reesterification, and regulating markers of lipolysis and glyceroneogenesis. PMID- 28659289 TI - Moving forward with steady strokes in paralympic sports medicine. PMID- 28659290 TI - Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20). PMID- 28659291 TI - Characterizing the Pyrenophora teres f. maculata-Barley Interaction Using Pathogen Genetics. AB - Pyrenophora teres f. maculata is the cause of the foliar disease spot form net blotch (SFNB) on barley. To evaluate pathogen genetics underlying the P. teres f. maculata-barley interaction, we developed a 105-progeny population by crossing two globally diverse isolates, one from North Dakota and the other from Western Australia. Progeny were phenotyped on a set of four barley genotypes showing a differential reaction to the parental isolates, then genotyped using a restriction site-associated-genotype-by-sequencing (RAD-GBS) approach. Genetic maps were developed for use in quantitative trait locus (QTL) analysis to identify virulence-associated QTL. Six QTL were identified on five different linkage groups and individually accounted for 20-37% of the disease variation, with the number of significant QTL ranging from two to four for the barley genotypes evaluated. The data presented demonstrate the complexity of virulence involved in the P. teres f. maculata-barley pathosystem and begins to lay the foundation for understanding this important interaction. PMID- 28659292 TI - Dissecting the Satellite DNA Landscape in Three Cactophilic Drosophila Sequenced Genomes. AB - Eukaryote genomes are replete with repetitive DNAs. This class includes tandemly repeated satellite DNAs (satDNA) which are among the most abundant, fast evolving (yet poorly studied) genomic components. Here, we used high-throughput sequencing data from three cactophilic Drosophila species, D. buzzatii, D. seriema, and D. mojavensis, to access and study their whole satDNA landscape. In total, the RepeatExplorer software identified five satDNAs, three previously described (pBuM, DBC-150 and CDSTR198) and two novel ones (CDSTR138 and CDSTR130). Only pBuM is shared among all three species. The satDNA repeat length falls within only two classes, between 130 and 200 bp or between 340 and 390 bp. FISH on metaphase and polytene chromosomes revealed the presence of satDNA arrays in at least one of the following genomic compartments: centromeric, telomeric, subtelomeric, or dispersed along euchromatin. The chromosomal distribution ranges from a single chromosome to almost all chromosomes of the complement. Fiber-FISH and sequence analysis of contigs revealed interspersion between pBuM and CDSTR130 in the microchromosomes of D. mojavensis Phylogenetic analyses showed that the pBuM satDNA underwent concerted evolution at both interspecific and intraspecific levels. Based on RNA-seq data, we found transcription activity for pBuM (in D. mojavensis) and CDSTR198 (in D. buzzatii) in all five analyzed developmental stages, most notably in pupae and adult males. Our data revealed that cactophilic Drosophila present the lowest amount of satDNAs (1.9-2.9%) within the Drosophila genus reported so far. We discuss how our findings on the satDNA location, abundance, organization, and transcription activity may be related to functional aspects. PMID- 28659293 TI - Lower systolic blood pressure at age 7 y in low-birth-weight children who received iron supplements in infancy: results from a randomized controlled trial. AB - Background: Low birth weight (LBW) (<=2500 g) is associated with iron deficiency in infancy and high blood pressure (BP) later in life.Objective: We investigated the effect of iron supplementation that was given to LBW infants on midchildhood BP.Design: The study was a randomized, double-blind, controlled trial that included 285 marginally LBW (2000-2500-g) infants at 2 Swedish centers between May 2004 and November 2007. The infants were randomly assigned to receive a placebo or 1 or 2 mg Fe . kg-1 . d-1 from 6 wk to 6 mo of age. In secondary analyses at the age of 7 y, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the prevalence of children with BP within the hypertensive range (>90th percentile) were compared between the groups.Results: BP was analyzed via intention to treat in 189 children (66%). The mean +/- SD SBP was 103 +/- 8.1, 101 +/- 7.5, and 101 +/- 7.8 mm Hg in children who had received the placebo (n = 70), 1 mg Fe . kg-1 . d-1 (n = 54), or 2 mg Fe . kg-1 . d-1 (n = 65), respectively. When the iron-supplemented groups were combined in covariate adjusted analyses, the mean SBP in LBW children who had received iron supplementation in infancy was 2.2 mm Hg (95% CI: 0.3, 4.2 mm Hg) lower than in those who were unsupplemented (P = 0.026). Multivariate logistic regression showed that iron supplementation in infancy reduced the odds of having an SBP within the hypertensive range at 7 y of age (OR: 0.32; 95% CI: 0.11, 0.96). For DBP, there were no significant differences between the intervention groups.Conclusions: LBW children who receive iron supplementation (1 or 2 mg Fe . kg-1 . d-1) in infancy have lower SBP at 7 y. This (to our knowledge) novel observation suggests that the increased risk of hypertension that is observed in children and adults who are born small might be reduced with early micronutrient interventions. This trial was registered at clinicaltrials.gov as NCT00558454. PMID- 28659294 TI - Artificially sweetened beverages, sugar-sweetened beverages, plain water, and incident diabetes mellitus in postmenopausal women: the prospective Women's Health Initiative observational study. AB - Background: Sugar-sweetened beverages (SSBs) have been associated with an increased risk of diabetes mellitus (DM), whereas the association with artificially sweetened beverages (ASBs) is unclear.Objective: We aimed to evaluate the associations of ASB and SSB consumption with the risk of developing DM and the potential benefit of replacing SSBs with ASBs or water.Design: The national Women's Health Initiative recruited a large prospective cohort of postmenopausal women between 1993 and 1998. ASB, SSB, and water consumption was measured by lifestyle questionnaires, and DM was self-reported.Results: Of 64,850 women, 4675 developed diabetes over an average of 8.4 y of follow-up. ASBs and SSBs were both associated with an increased risk of DM with an HR of 1.21 (95% CI: 1.08, 1.36) comparing ASB consumption of >=2 serving/d to never or <3 serving/mo, and an HR of 1.43 (95% CI: 1.17, 1.75) comparing SSB consumption of >=2 serving/d to <1 serving/wk (1 serving = one 12-ounce can or 355 mL). Subgroup analysis found an increased risk of DM associated with ASBs only in the obese group. Modeling the substitution of SSBs with an equal amount of ASBs did not significantly reduce the risk of developing DM. However, statistically substituting 1 serving of ASBs with water was associated with a significant risk reduction of 5% (HR: 0.95; 95% CI: 0.91, 0.99), whereas substituting 1 serving of SSBs with water was associated with a risk reduction of 10% (HR: 0.90; 95% CI: 0.85, 0.95).Conclusions: ASBs were associated with a 21% increased risk of developing DM, approximately half the magnitude of SSBs (associated with a 43% increased risk). Replacing ASBs and SSBs with water could potentially reduce the risk. However, caution should be taken in interpreting these results as causal because both residual confounding and reverse causation could explain these results. PMID- 28659295 TI - Infant feeding and growth trajectory patterns in childhood and body composition in young adulthood. AB - Background: Growth patterns of breastfed and formula-fed infants may differ, with formula-fed infants growing more rapidly than breastfed infants into childhood and adulthood.Objective: Our objectives were to identify growth patterns and investigate early nutritional programming potential on growth patterns at 6 y and on body composition at 20 y.Design: The West Australian Pregnancy Cohort (Raine) Study and 3 European cohort studies (European Childhood Obesity Trial, Norwegian Human Milk Study, and Prevention of Coeliac Disease) that collaborate in the European Union-funded Early Nutrition project combined, harmonized, and pooled data on full breastfeeding, anthropometry, and body composition. Latent growth mixture modeling was applied to identify growth patterns among the 6708 individual growth trajectories. The association of full breastfeeding for <3 mo compared with >=3 mo with the identified trajectory classes was assessed by logistic regression. Differences in body composition at 20 y among the identified trajectory classes were tested by analysis of variance.Results: Three body mass index (BMI; in kg/m2) trajectory patterns were identified and labeled as follows class 1: persistent, accelerating, rapid growth (5%); class 2: early, nonpersistent, rapid growth (40%); and class 3: normative growth (55%). A shorter duration of full breastfeeding for <3 mo was associated with being in rapid growth class 1 (OR: 2.66; 95% CI: 1.48, 4.79) and class 2 (OR: 1.96; 95% CI: 1.51, 2.55) rather than the normative-growth class 3 after adjustment for covariates. Both rapid-growth classes showed significant associations with body composition at 20 y (P < 0.0001).Conclusions: Full breastfeeding for <3 mo compared with >=3 mo may be associated with rapid growth in early childhood and body composition in young adulthood. Rapid-growth patterns in early childhood could be a mediating link between infant feeding and long-term obesity risk. PMID- 28659296 TI - An observational cohort study of weight- and length-derived anthropometric indicators with body composition at birth and 5 mo: the Healthy Start study. AB - Background: Despite widespread use of weight- and length-based anthropometric indexes as proxies for adiposity, little is known regarding the extent to which they correspond with fat mass (FM) or fat-free mass (FFM) during infancy.Objective: This study aimed to examine associations of 3 derived indicators-weight-for-age z score (WFAZ), weight-for-length score (WFLZ), and body mass index z score (BMIZ)-with FM, percentage of FM, and FFM measured by air displacement plethysmography during the first 5 mo of life.Design: Applying prospectively collected data from 1027 infants in a Colorado prebirth cohort, we used multivariate regression to evaluate associations between the derived indicators and body composition at birth and at 5 mo, and with change (Delta) during follow-up.Results: At birth, all 3 derived indicators were more strongly associated with FFM than with FM. Each unit of WFAZ corresponded with 0.342 kg FFM (95% CI: 0.331, 0.351 kg FFM), compared with 0.121 kg FM (95% CI: 0.114, 0.128 kg FM) (P < 0.0001); similar trends were observed for WFLZ and BMIZ. By 5 mo, WFLZ and BMIZ were more strongly associated with FM than with FFM, whereas WFAZ correlated similarly with the 2 components of body composition. DeltaWFLZ and DeltaBMIZ were both more strongly related to DeltaFM than to DeltaFFM; however, a direct comparison of the 2 indexes with respect to change in the percentage of FM indicated that DeltaBMIZ was the optimal proxy of adiposity gain (P < 0.0001, pairwise difference).Conclusions: Weight- and length-based indexes are poor surrogates for newborn adiposity. However, at 5 mo, WFLZ and BMIZ are suitable proxies of FM. When assessing adiposity gain, DeltaBMIZ is the best indicator of fat accrual during the first 5 postnatal months. This trial was registered at clinicaltrials.gov as NCT02273297. PMID- 28659297 TI - Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants. AB - Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood.Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC.Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidemiologique sur les Petits Ages Gestationnels), including preterm infants born at <32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensity-matched case-control study, EPIFLORE (Etude Epidemiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing.Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002).Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698. PMID- 28659299 TI - Associations of infant feeding with trajectories of body composition and growth. AB - Background: The extent to which breastfeeding is protective against later-life obesity is controversial. Little is known about differences in infant body composition between breastfed and formula-fed infants, which may reflect future obesity risk.Objective: We aimed to assess associations of infant feeding with trajectories of growth and body composition from birth to 7 mo in healthy infants.Design: We studied 276 participants from a previous study of maternal vitamin D supplementation during lactation. Mothers used monthly feeding diaries to report the extent of breastfeeding. We measured infants' anthropometrics and used dual-energy X-ray absorptiometry to assess body composition at 1, 4, and 7 mo. We compared changes in infant size (z scores for weight, length, and body mass index [BMI (in kg/m2)]) and body composition (fat and lean mass, body fat percentage) between predominantly breastfed and formula-fed infants, adjusting in linear regression for sex, gestational age, race/ethnicity, maternal BMI, study site, and socioeconomic status.Results: In this study, 214 infants (78%) were predominantly breastfed (median duration: 7 mo) and 62 were exclusively formula fed. Formula-fed infants had lower birth-weight z scores than breastfed infants ( 0.22 +/- 0.86 and 0.16 +/- 0.88, respectively; P < 0.01) but gained more in weight and BMI through 7 mo of age (weight z score difference: 0.37; 95% CI: 0.04, 0.71; BMI z score difference: 0.35; 95% CI: 0, 0.69), with no difference in linear growth (z score difference: 0.05; 95% CI: -0.24, 0.34). Formula-fed infants gained more lean mass (difference: 303 g; 95% CI: 137, 469 g) than breastfed infants, but not fat mass (difference: -42 g; 95% CI: -299, 215 g).Conclusions: Formula-fed infants gained weight more rapidly and out of proportion to linear growth than did predominantly breastfed infants. These differences were attributable to greater accretion of lean mass, rather than fat mass. Any later obesity risk associated with infant feeding does not appear to be explained by differential adiposity gains in infancy. PMID- 28659298 TI - Nutritional metabolomics and breast cancer risk in a prospective study. AB - Background: The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators.Objective: The aim of this study was to evaluate associations of diet related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.Design: We examined prediagnostic serum concentrations of diet-related metabolites in a nested case control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (P-correlation < 1.47 * 10-6) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate <0.2).Results: Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk (621 cases): caprate (10:0), a saturated fatty acid (OR: 1.77; 95% CI = 1.28, 2.43); gamma-carboxyethyl hydrochroman (gamma CEHC), a vitamin E (gamma-tocopherol) derivative (OR: 1.64; 95% CI: 1.18, 2.28); and 4-androsten-3beta,17beta-diol-monosulfate (1), an androgen (OR: 1.61; 95% CI: 1.20, 2.16). Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER+) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and alpha-hydroxyisovalerate (OR: 2.23; 95% CI: 1.50, 3.32); 3 vitamin E (tocopherol) derivatives (e.g., gamma-CEHC; OR: 1.80; 95% CI: 1.20, 2.70); butter-associated caprate (10:0) (OR: 1.81; 95% CI: 1.23, 2.67); and fried food-associated 2-hydroxyoctanoate (OR: 1.46; 95% CI: 1.03, 2.07). No metabolites were significantly associated with ER-negative breast cancer (144 cases).Conclusions: Prediagnostic serum concentrations of metabolites related to alcohol, vitamin E, and animal fats were moderately strongly associated with ER+ breast cancer risk. Our findings show how nutritional metabolomics might identify diet-related exposures that modulate cancer risk. This trial was registered at clinicaltrials.gov as NCT00339495. PMID- 28659301 TI - Metabolism of uniformly labeled 13C-eicosapentaenoic acid and 13C-arachidonic acid in young and old men. AB - Background: Plasma eicosapentaenoic acid (EPA) and arachidonic acid (AA) concentrations increase with age.Objective: The aim of this study was to evaluate EPA and AA metabolism in young and old men by using uniformly labeled carbon-13 (13C) fatty acids.Design: Six young (~25 y old) and 6 old (~75 y old) healthy men were recruited. Each participant consumed a single oral dose of 35 mg 13C-EPA and its metabolism was followed in the course of 14 d in the plasma and 28 d in the breath. After the washout period of >=28 d, the same participants consumed a single oral dose of 50 mg 13C-AA and its metabolism was followed for 28 d in plasma and breath.Results: There was a time * age interaction for 13C-EPA (Ptime * age = 0.008), and the shape of the postprandial curves was different between young and old men. The 13C-EPA plasma half-life was ~2 d for both young and old men (P = 0.485). The percentage dose recovered of 13C-EPA per hour as 13CO2 and the cumulative beta-oxidation of 13C-EPA did not differ between young and old men. At 7 d, however, old men had a >2.2-fold higher plasma 13C-DHA concentration synthesized from 13C-EPA compared with young men (Page = 0.03). 13C-AA metabolism was not different between young and old men. The 13C-AA plasma half-life was ~4.4 d in both young and old participants (P = 0.589).Conclusions: The metabolism of 13C-AA was not modified by age, whereas 13C-EPA metabolism was slightly but significantly different in old compared with young men. The higher plasma 13C-DHA seen in old men may be a result of slower plasma DHA clearance with age. This trial was registered at clinicaltrials.gov as NCT02957188. PMID- 28659300 TI - Dietary fat intake and risk of non-Hodgkin lymphoma in 2 large prospective cohorts. AB - Background: Dietary fat intake may contribute to non-Hodgkin lymphoma (NHL) pathogenesis by influencing carcinogen exposure or through immune modulation.Objective: We aimed to evaluate NHL risk associated with total and specific dietary fat intake.Design: We evaluated associations within the Nurses' Health Study (NHS) (n = 88,598) and the Health Professionals Follow-Up Study (HPFS) (n = 47,531) using repeated validated dietary assessments. We confirmed 1802 incident NHL diagnoses through 2010. Using multivariable Cox proportional hazards models, we estimated hazard ratios (HRs) for all NHL and common subtypes associated with a 1-SD increase in cumulative mean intakes of total, animal, saturated, trans, and vegetable fats and marine fatty acids. We pooled sex specific HRs using random-effects meta-analysis.Results: Over 24-30 y of follow up, neither total nor specific dietary fats were significantly associated with NHL risk overall. Higher total, animal, and saturated fat intakes were positively associated with the risk of the chronic lymphocytic leukemia/small lymphocytic lymphoma subtype among women only (253 cases; P-trend <= 0.05), driven by strong associations during 1980-1994. From baseline through 1994, among women and men combined, total fat intake was borderline-significantly positively associated with NHL overall (pooled HR per SD: 1.13; 95% CI: 0.99, 1.29) and was significantly associated with diffuse large B cell lymphoma (pooled HR per SD: 1.47; 95% CI: 1.06, 2.05), with similar trends for animal and saturated fat intake. For women only, trans fat was significantly positively associated with all NHL. In contrast, during 1994-2010, there was little evidence for associations of dietary fat intake with NHL overall or by subtype.Conclusion: Previous observations of an increased risk of NHL associated with intakes of total, animal, saturated, and trans fat with 14 y of follow-up did not persist with longer follow-up. PMID- 28659302 TI - Higher dietary cholesterol and omega-3 fatty acid intakes are associated with a lower success rate of Helicobacter pylori eradication therapy in Japan. AB - Background:Helicobacter pylori infection is a known risk factor for duodenal ulcers, gastritis, and gastric cancer. The eradication of H. pylori is successful in treating these disorders; however, the success rate of eradication therapy is declining. There may be an interaction with nutrient intake to account for this decline.Objective: We investigated the influence of food and nutrient intake on H. pylori eradication therapy.Design: In this study, 4014 subjects underwent endoscopy, were tested for serum antibodies to H. pylori (2046 positive; 51.0%), and had their food intake assessed with the use of a food-frequency questionnaire (FFQ). Of the positive subjects, endoscopies showed that 389 (19.0%) had gastritis and/or duodenal ulcers and were also positive for a 13C-urea breath test (UBT). These 389 subjects received 1-wk H. pylori eradication therapy with lansoprazole, amoxicillin, and clarithromycin and a second UBT 8 wk after treatment. Complete demographic characteristics, serum lipid, insulin, glycated hemoglobin, C-reactive protein (CRP), and creatinine concentrations as well as complete FFQs were available for 352 subjects. Multivariate logistic regression analyses were performed to determine factors that were associated with successful H. pylori eradication therapy.Results: The success rate of eradication therapy was 60.4% (235 of 389). Factors associated with the failure of eradication therapy included increased age (P = 0.02), higher CRP concentrations (P < 0.01), higher dietary cholesterol (P < 0.01) or egg intake (P < 0.01), higher omega-3 (n 3) fatty acid (P = 0.02) or fish intake (P = 0.01), and higher vitamin D intake (P = 0.02). Moreover, the higher vitamin D intake was strongly linked to higher fish intake. A limitation of the study is that we did not assess the antibiotic resistance of H. pyloriConclusions: Our results indicate that higher egg and fish intake may be negatively correlated with successful H. pylori eradication therapy in H. pylori-positive subjects with gastritis and/or duodenal ulcers. PMID- 28659303 TI - Video recording in the emergency department: a pathway to success. PMID- 28659304 TI - Heritability of resting heart rate and association with mortality in middle-aged and elderly twins. PMID- 28659305 TI - Effects of rearing salinity on expression and function of ion-motive ATPases and ion transport across the gastric caecum of Aedes aegypti larvae. AB - Larvae of Aedes aegypti, the yellow fever vector, inhabit a variety of aquatic habitats ranging from freshwater to brackish water. This study focuses on the gastric caecum of the larvae, an organ that has not been widely studied. We provide the first measurements of H+, K+ and Na+ fluxes at the distal and proximal gastric caecum, and have shown that they differ in the two regions, consistent with previously reported regionalization of ion transporters. Moreover, we have shown that the regionalization of vacuolar H+-ATPase and Na+/K+ ATPase is altered when larvae are reared in brackish water (30% seawater) relative to freshwater. Measurements of luminal Na+ and K+ concentrations also show a 5-fold increase in Na+/K+ ratio in the caecal lumen in larvae reared in brackish water relative to freshwater, whereas transepithelial potential and luminal pH were unchanged. Calculated electrochemical potentials reveal changes in the active accumulation of Na+ and K+ in the lumen of the gastric caecum of freshwater versus brackish water larvae. Together with the results of previous studies of the larval midgut, our results show that the caecum is functionally distinct from the adjacent anterior midgut, and may play an important role in osmoregulation as well as uptake of nutrients. PMID- 28659306 TI - Monoaminergic integration of diet and social signals in the brains of juvenile spadefoot toads. AB - Social behavior often includes the production of species-specific signals (e.g. mating calls or visual displays) that evoke context-dependent behavioral responses from conspecifics. Monoamines are important neuromodulators that have been implicated in context-dependent social behavior, yet we know little about the development of monoaminergic systems and whether they mediate the effects of early life experiences on adult behavior. We examined the effects of diet and social signals on monoamines early in development in the plains spadefoot toad (Spea bombifrons), a species in which diet affects the developmental emergence of species recognition and body condition affects the expression of adult mating preferences. To do so, we manipulated the diet of juveniles for 6 weeks following metamorphosis and collected their brains 40 min following the presentation of either a conspecific or a heterospecific call. We measured levels of monoamines and their metabolites using high pressure liquid chromatography from tissue punches of the auditory midbrain (i.e. torus semicircularis), hypothalamus and preoptic area. We found that call type affected dopamine and noradrenaline signaling in the auditory midbrain and that diet affected dopamine and serotonin in the hypothalamus. In the preoptic area, we detected an interaction between diet and call type, indicating that diet modulates how the preoptic area integrates social information. Our results suggest that the responsiveness of monoamine systems varies across the brain and highlight preoptic dopamine and noradrenaline as candidates for mediating effects of early diet experience on later expression of social preferences. PMID- 28659307 TI - Passive regeneration of glutathione: glutathione reductase regulation in the freeze-tolerant North American wood frog, Rana sylvatica. AB - Wood frogs inhabit a broad range across North America, extending from the southern tip of the Appalachian Mountains to the northern boreal forest. Remarkably, they can survive the winter in a frozen state, where as much as 70% of their body water is converted into ice. Whilst in the frozen state, their hearts cease to pump blood, causing their cells to experience ischemia, which can dramatically increase the production of reactive oxygen species within the cell. To overcome this, wood frogs have elevated levels of glutathione, a primary antioxidant. We examined the regulation of glutathione reductase, the enzyme involved in recycling glutathione, in both the frozen and unfrozen (control) state. Glutathione reductase activity from both the control and frozen state showed a dramatic reduction in substrate specificity (Km) for oxidized glutathione (50%) when measured in the presence of glucose (300 mmol l-1) and a increase (157%) when measured in the presence of levels of urea (75 mmol l-1) encountered in the frozen state. However, when we tested the synergistic effect of urea and glucose simultaneously, we observed a substantial reduction in the Km for oxidized glutathione (43%) to a value similar to that with glucose alone. In fact, we found no observable differences in the kinetic and structural properties of glutathione reductase between the two states. Therefore, a significant increase in the affinity for oxidized glutathione in the presence of endogenous levels of glucose suggests that increased glutathione recycling may occur as a result of passive regulation of glutathione reductase by rising levels of glucose during freezing. PMID- 28659308 TI - Estimation of distance and electric impedance of capacitive objects in the weakly electric fish Gnathonemus petersii. AB - During active electrolocation, the weakly electric fish Gnathonemus petersii judges the distance and impedance of nearby objects. Capacitive objects, which modulate local amplitude and waveform of the fish's electric probing signals, cast amplitude and waveform images onto the fish's electroreceptive skin. For an unambiguous estimation of the impedance and distance of an object, the animal has to deal with multiple dependencies of object and image parameters. Based on experimentally recorded amplitude and waveform images, we investigated possible strategies of the fish to unequivocally determine both the distance and the impedance of capacitive objects. We show that the relative slope in amplitude images, but not in waveform images, is independent of object impedance and is a measure of object distance. Distance-invariant impedance estimators were obtained by two different analytical strategies. The peak modulations of both image types were 'calibrated' with the relative slope of the amplitude image. Impedance estimators were obtained whenever these pairs of image features (peak and relative slope) were related dynamically over two consecutive distances. A static impedance estimator termed 'electric colour' is postulated to arise from the relationship of an amplitude and waveform image. Our results confirm that electric colour is indeed unaffected by object distance. For electric colour estimation we suggest a minimalistic approach of just relating the peak modulations of both image types to the basal amplitude and waveform condition. Our results are discussed with regard to the anatomical and physiological organization of the fish's electrosensory neuronal pathways and behavioural strategies of electrolocating fish. PMID- 28659309 TI - Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus. AB - OBJECTIVE: Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. We aimed to investigate whether eradication of HCV infection with direct-acting antiviral (DAA) agents is associated with improved glycemic control in patients with diabetes. RESEARCH DESIGN AND METHODS: We identified 2,435 patients with diabetes who underwent interferon-free and ribavirin-free DAA-based antiviral treatment for HCV in the national Veterans Affairs health care system. Changes in average hemoglobin A1c (HbA1c) level and use of antidiabetic medications 1 year before and after antiviral treatment were compared between patients who achieved sustained virologic response (SVR) and those who did not. RESULTS: Among patients with elevated baseline HbA1c, the drop in HbA1c associated with antiviral treatment was greater in those who achieved SVR (0.98%) than in those who sustained treatment failure (0.65%) (adjusted mean difference 0.34, P = 0.02). Use of antidiabetic medications decreased more in patients who achieved SVR than in those who sustained treatment failure, especially for the use of insulin, which dropped significantly from 41.3% to 38% in patients achieving SVR compared with a slight increase from 49.8% to 51% in those who sustained treatment failure. CONCLUSIONS: DAA-based eradication of HCV is associated with improved glycemic control in patients with diabetes as evidenced by decreased mean HbA1c and decreased insulin use. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes. PMID- 28659310 TI - DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Kruppel-Like Factor 4 Expression. AB - Purpose: The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the underlying molecules remain unknown. We investigated the mechanistic underexpression of Kruppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment.Experimental Design: Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by IHC and the genetic and epigenetic alterations of KLF4 in and KLF4's impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3'-diindolylmethane (DIM) on miR 152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal models.Results: Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. In addition, DIM treatment caused significant inhibition of cell growth in vitro and tumorigenesis in animal models of pancreatic cancer.Conclusions: This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers. Clin Cancer Res; 23(18); 5585-97. (c)2017 AACR. PMID- 28659311 TI - Memory T Cells Expressing an NKG2D-CAR Efficiently Target Osteosarcoma Cells. AB - Purpose: NKG2D ligands (NKG2DL) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. Various immune cells express NKG2D receptors, including natural killer (NK) cells and CD8+ T cells. Interactions between NKG2DL and NKG2D receptors are essential for NK-cell elimination of osteosarcoma tumor initiating cells. In this report, we used NKG2D-NKG2DL interactions to optimize an immunotherapeutic strategy against osteosarcoma. We evaluated in vitro and in vivo the safety and cytotoxic capacity against osteosarcoma cells of CD45RA- memory T cells expressing an NKG2D-4-1BB-CD3z chimeric antigen receptor (CAR).Experimental Design: CD45RA- cells from healthy donors were transduced with NKG2D CARs containing 4-1BB and CD3z signaling domains. NKG2D CAR expression was analyzed by flow cytometry. In vitro cytotoxicity of NKG2D-CAR+ CD45RA- T cells against osteosarcoma was evaluated by performing conventional 4-hour europium-TDA release assays. For the in vivo orthotopic model, 531MII YFP-luc osteosarcoma cells were used as targets in NOD-scid IL2Rgnull mice.Results: Lentiviral transduction of NKG2D-4-1BB-CD3z markedly increased NKG2D surface expression in CD45RA- cells. Genetic stability was preserved in transduced cells. In vitro, NKG2D-CAR+ memory T cells showed significantly increased cytolytic activity than untransduced cells against osteosarcoma cell lines, while preserving the integrity of healthy cells. NKG2D-CAR+ memory T cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas untransduced T cells were ineffective.Conclusions: Our results demonstrate NKG2D-4-1BB-CD3z CAR-redirected memory T cells target NKG2DL-expressing osteosarcoma cells in vivo and in vitro and could be a promising immunotherapeutic approach for patients with osteosarcoma. Clin Cancer Res; 23(19); 5824-35. (c)2017 AACR. PMID- 28659313 TI - Diagnosing minor illness outside the emergency department. PMID- 28659314 TI - John Dean: Committed to quality improvement. PMID- 28659312 TI - Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition. AB - Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044-53. (c)2017 AACR. PMID- 28659316 TI - The Invisible Army. AB - The "invisible army" of clinical microbiologists is facing major changes and challenges. The rate of change in both the science and technology is accelerating with no end in sight, putting pressure on our army to learn and adapt as never before. Health care funding in the United States is undergoing dramatic change which will require a new set of assumptions about how clinical microbiology is practiced here. A major challenge facing the discipline is the replacement of a generation of clinical microbiologists. In my opinion, it is incumbent on us in the invisible army to continue to work with the American Society for Microbiology (ASM) in meeting the future challenges faced by our discipline. In this commentary, I will first discuss some recent history of clinical microbiology within ASM and then some current challenges we face. PMID- 28659315 TI - Association of Atypical Enteropathogenic Escherichia coli with Diarrhea and Related Mortality in Kittens. AB - Diarrhea is responsible for the death of approximately 900,000 children per year worldwide. In children, typical enteropathogenic Escherichia coli (EPEC) is a common cause of diarrhea and is associated with a higher hazard of death. Typical EPEC infection is rare in animals and poorly reproduced in experimental animal models. In contrast, atypical EPEC (aEPEC) infection is common in both children and animals, but its role in diarrhea is uncertain. Mortality in kittens is often attributed to diarrhea, and we previously identified enteroadherent EPEC in the intestines of deceased kittens. The purpose of this study was to determine the prevalence and type of EPEC in kittens and whether infection was associated with diarrhea, diarrhea-related mortality, gastrointestinal pathology, or other risk factors. Kittens with and without diarrhea were obtained from two shelter facilities and determined to shed atypical EPEC at a culture-based prevalence of 18%. In contrast, quantitative PCR detected the presence of the gene for intimin (eae) in feces from 42% of kittens. aEPEC was isolated from kittens with and without diarrhea. However, kittens with diarrhea harbored significantly larger quantities of aEPEC than kittens without diarrhea. Kittens with aEPEC had a significantly greater severity of small intestinal and colonic lesions and were significantly more likely to have required subcutaneous fluid administration. These findings identify aEPEC to be prevalent in kittens and a significant primary or contributing cause of intestinal inflammation, diarrhea, dehydration, and associated mortality in kittens. PMID- 28659317 TI - Whole-Genome Sequencing Overrules a Suspected Case of Carbapenem-Resistant Enterobacter cloacae Transmission. PMID- 28659318 TI - Reliable Detection of Group B Streptococcus in the Clinical Laboratory. AB - Group B streptococcus (GBS) is a leading cause of invasive neonatal infections and a significant pathogen in immunocompromised adults. Screening to detect GBS colonization in pregnant women determines the need for antibiotic prophylaxis in that pregnancy. Efficient determination of the GBS colonization status of pregnant women is crucial. Methods that maximize the probability of GBS recovery are needed. The availability of technologies such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), molecular techniques, and chromogenic culture media, including Granada-type media, have changed the scenario for GBS detection and identification. This review presents and evaluates novel diagnostic tools, as well as classic identification techniques, for GBS species determination. PMID- 28659319 TI - Laboratory Diagnosis of Infective Endocarditis. AB - Infective endocarditis is life-threatening; identification of the underlying etiology informs optimized individual patient management. Changing epidemiology, advances in blood culture techniques, and new diagnostics guide the application of laboratory testing for diagnosis of endocarditis. Blood cultures remain the standard test for microbial diagnosis, with directed serological testing (i.e., Q fever serology, Bartonella serology) in culture-negative cases. Histopathology and molecular diagnostics (e.g., 16S rRNA gene PCR/sequencing, Tropheryma whipplei PCR) may be applied to resected valves to aid in diagnosis. Herein, we summarize recent knowledge in this area and propose a microbiologic and pathological algorithm for endocarditis diagnosis. PMID- 28659320 TI - Development of a One-Step Multiplex PCR Assay for Differential Detection of Major Mycobacterium Species. AB - The prevalence of tuberculosis continues to be high, and nontuberculous mycobacterial (NTM) infection has also emerged worldwide. Moreover, differential and accurate identification of mycobacteria to the species or subspecies level is an unmet clinical need. Here, we developed a one-step multiplex PCR assay using whole-genome analysis and bioinformatics to identify novel molecular targets. The aims of this assay were to (i) discriminate between the Mycobacterium tuberculosis complex (MTBC) and NTM using rv0577 or RD750, (ii) differentiate M. tuberculosis (M. tuberculosis) from MTBC using RD9, (iii) selectively identify the widespread M. tuberculosis Beijing genotype by targeting mtbk_20680, and (iv) simultaneously detect five clinically important NTM (M. avium, M. intracellulare, M. abscessus, M. massiliense, and M. kansasii) by targeting IS1311, DT1, mass_3210, and mkan_rs12360 An initial evaluation of the multiplex PCR assay using reference strains demonstrated 100% specificity for the targeted Mycobacterium species. Analytical sensitivity ranged from 1 to 10 pg for extracted DNA and was 103 and 104 CFU for pure cultures and nonhomogenized artificial sputum cultures, respectively, of the targeted species. The accuracy of the multiplex PCR assay was further evaluated using 55 reference strains and 94 mycobacterial clinical isolates. Spoligotyping, multilocus sequence analysis, and a commercial real-time PCR assay were employed as standard assays to evaluate the multiplex PCR assay with clinical M. tuberculosis and NTM isolates. The PCR assay displayed 100% identification agreement with the standard assays. Our multiplex PCR assay is a simple, convenient, and reliable technique for differential identification of MTBC, M. tuberculosis, M. tuberculosis Beijing genotype, and major NTM species. PMID- 28659321 TI - Performance of a Quantitative PCR-Based Assay and Beta-d-Glucan Detection for Diagnosis of Invasive Candidiasis in Very-Low-Birth-Weight Preterm Neonatal Patients (CANDINEO Study). AB - An epidemiological, multicenter, noninterventional, observational case-control study was conducted to describe the performance of serum beta-d-glucan (BDG) and Candida PCR in blood, serum, and sterile samples for the diagnosis of invasive candidiasis (IC) in very-low-birth-weight (VLBW) preterm neonates and to compare these techniques with culture of samples from blood and other sterile sites. Seventeen centers participated in the study, and the number of episodes analyzed was 159. A total of 9 episodes of IC from 9 patients (7 confirmed and 2 probable) and 150 episodes of suspected sepsis from 117 controls were identified. The prevalence of IC was 5.7% (95% confidence interval [95% CI], 2.1 to 9.3). The mortality was significantly higher in episodes of IC (44.4%) than in the non-IC episodes (11.1%, P < 0.01). The sensitivity and specificity of the PCR performed on blood/serum samples were 87.5% and 81.6%, respectively. The sensitivity and specificity of the BDG results were lower (75.0% and 64.6%). For cases with negative culture results, the PCR and the BDG results were positive in 27 (17.4%) and 52 (33.5%) episodes, respectively. The presence of multiorgan failure, improvement with empirical antifungal therapy, thrombocytopenia, and Candida colonization were significantly associated (P < 0.01) with PCR or BDG positivity regardless of the results of the cultures. Serum BDG analysis and Candida PCR could be used as complementary diagnostic techniques to detect IC in VLBW neonates. PMID- 28659322 TI - The Effect of Preoperative Antimicrobial Prophylaxis on Intraoperative Culture Results in Patients with a Suspected or Confirmed Prosthetic Joint Infection: a Systematic Review. AB - Obtaining reliable cultures during revision arthroplasty is important to adequately diagnose and treat a prosthetic joint infection (PJI). The influence of antimicrobial prophylaxis on culture results remains unclear. Since withholding prophylaxis increases the risk for surgical site infections, clarification on this topic is critical. A systematic review was performed with the following research question: in patients who undergo revision surgery of a prosthetic joint, does preoperative antimicrobial prophylaxis affect the culture yield of intraoperative samples in comparison with nonpreoperative antimicrobial prophylaxis? Seven articles were included in the final analysis. In most studies, standard diagnostic culture techniques were used. In patients with a PJI, pooled analysis showed a culture yield of 88% (145/165) in the prophylaxis group versus 95% (344/362) in the nonprophylaxis group (P = 0.004). Subanalysis of patients with chronic PJIs showed positive cultures in 88% (78/89) versus 91% (52/57), respectively (P = 0.59). In patients with a suspected chronic infection, a maximum difference of 4% in culture yield between the prophylaxis and nonprophylaxis groups was observed. With the use of standard culture techniques, antimicrobial prophylaxis seems to affect cultures in a minority of patients. Along with the known risk of surgical site infections due to inadequate timing of antimicrobial prophylaxis, we discourage the postponement of prophylaxis until tissue samples are obtained in revision surgery. Future studies are necessary to conclude whether the small percentage of false-negative cultures after prophylaxis can be further reduced with the use of more-sensitive culture techniques, like sonication. PMID- 28659323 TI - WciG O-Acetyltransferase Functionality Differentiates Pneumococcal Serotypes 35C and 42. AB - Streptococcus pneumoniae expresses capsular polysaccharides (CPSs) to protect itself from opsonophagocytic killing. The genes responsible for capsules synthesized by the Wzy-dependent mechanism, which accounts for 96 of the 98 known pneumococcal capsule types, are in a chromosomal region known as the cps locus. The nucleotide sequence in this region has been determined for all serotypes. In contrast, not all CPS structures have been defined. The structure of the serotype 35C polysaccharide was recently reported, but the presence of O-acetyltransferase genes in the serotype 35C cps locus suggested that it could be incomplete, as the reported structure contains no O-acetylation. In addition, the genetic distinction of serotype 35C from the closely related serotype 42 was unclear, as their reported cps loci are nearly identical. To clarify these discrepancies, we obtained serotype 35C and 42 clinical and reference isolates and studied their serological and genetic properties, as well as the structures of CPSs purified from reference isolates. We demonstrated that the O-acetyltransferase WciG was functional in serotype 35C but nonfunctional in serotype 42 due to a deletion in wciG Serotype 35C was O-acetylated at the 5- and 6-positions of 3-beta galactofuranose, as well as the 2-position of 6-beta-galactofuranose. However, serotype 42 has only O-acetylation at 3-beta-galactofuranose, an observation consistent with its loss of WciG functionality, which is associated with O acetylation at the 2-position and subsequent reaction with typing antiserum 35a. These findings provide a comprehensive view of the genetic, biochemical structural, and serological bases of serotypes 35C and 42. PMID- 28659325 TI - Identification of an Atypical Enzootic Bovine Leukosis in Japan by Using a Novel Classification of Bovine Leukemia Based on Immunophenotypic Analysis. AB - Bovine leukemia is classified into two types: enzootic bovine leukosis (EBL) and sporadic bovine leukosis (SBL). EBL is caused by infection with bovine leukemia virus (BLV), which induces persistent lymphocytosis and B-cell lymphoma in cattle after a long latent period. Although it has been demonstrated that BLV-associated lymphoma occurs predominantly in adult cattle of >3 to 5 years, suspicious cases of EBL onset in juvenile cattle were recently reported in Japan. To investigate the current status of bovine leukemia in Japan, we performed immunophenotypic analysis of samples from 50 cattle that were clinically diagnosed as having bovine leukemia. We classified the samples into five groups on the basis of the analysis and found two different types of EBL: classic EBL (cEBL), which has the familiar phenotype commonly known as EBL, and polyclonal EBL (pEBL), which exhibited neoplastic proliferation of polyclonal B cells. Moreover, there were several atypical EBL cases even in cEBL, including an early onset of EBL in juvenile cattle. A comparison of the cell marker expressions among cEBL, pEBL, and B-cell-type SBL (B-SBL) revealed characteristic patterns in B-cell leukemia, and these patterns could be clearly differentiated from those of healthy phenotypes, whereas it was difficult to discriminate between cEBL, pEBL, and B SBL only by the expression patterns of cell markers. This study identified novel characteristics of bovine leukemia that should contribute to a better understanding of the mechanism underlying tumor development in BLV infection. PMID- 28659326 TI - A Cation-binding Surface Protein as a Vaccine Antigen to Prevent Moraxella catarrhalis Otitis Media and Infections in Chronic Obstructive Pulmonary Disease. AB - Moraxella catarrhalis is an exclusively human respiratory tract pathogen that is a common cause of otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. A vaccine to prevent these infections would have a major impact in reducing the substantial global morbidity and mortality in these populations. Through a genome mining approach, we identified AfeA, an ~32 kDa substrate binding protein of an ABC transport system as an excellent candidate vaccine antigen. Recombinant AfeA was expressed and purified and binds ferric, ferrous, manganese and zinc ions as demonstrated by thermal shift assays. It is a highly conserved protein that is present in all strains of M. catarrhalis Immunization with recombinant, purified AfeA induces high titer antibodies that recognize the native M. catarrhalis protein. AfeA expresses abundant epitopes on the bacterial surface and induces protective responses in the mouse pulmonary clearance model following aerosol challenge with M. catarrhalis. Finally, AfeA is expressed during human respiratory tract infection of adults with COPD. Based on these observations, AfeA is an excellent vaccine antigen to be included in a vaccine to prevent infections caused by M. catarrhalis. PMID- 28659324 TI - Multimethod Longitudinal HIV Drug Resistance Analysis in Antiretroviral-Therapy Naive Patients. AB - The global intensification of antiretroviral therapy (ART) can lead to increased rates of HIV drug resistance (HIVDR) mutations in treated and also in ART-naive patients. ART-naive HIV-1-infected patients from Cameroon were subjected to a multimethod HIVDR analysis using amplification-refractory mutation system (ARMS) PCR, Sanger sequencing, and longitudinal next-generation sequencing (NGS) to determine their profiles for the mutations K103N, Y181C, K65R, M184V, and T215F/Y. We processed 66 ART-naive HIV-1-positive patients with highly diverse subtypes that underlined the predominance of CRF02_AG and the increasing rate of F2 and other recombinant forms in Cameroon. We compared three resistance testing methods for 5 major mutation sites. Using Sanger sequencing, the overall prevalence of HIVDR mutations was 7.6% (5/66) and included all studied mutations except K65R. Comparing ARMS-PCR with Sanger sequencing as a reference, we obtained a sensitivity of 100% (5/5) and a specificity of 95% (58/61), caused by three false-positive calls with ARMS-PCR. For 32/66 samples, we obtained NGS data and we observed two additional mismatches made up of minority variants (7% and 18%) that might not be clinically relevant. Longitudinal NGS analyses revealed changes in HIVDR mutations in all five positive subjects that could not be attributed to treatment. In one of these cases, superinfection led to the temporary masking of a resistant virus. HIVDR mutations can be sensitively detected by ARMS-PCR and sequencing methods with comparable performances. Longitudinal changes in HIVDR mutations have to be considered even in the absence of treatment. PMID- 28659327 TI - Phosphoinositide-dependent enrichment of actin monomers in dendritic spines regulates synapse development and plasticity. AB - Dendritic spines are small postsynaptic compartments of excitatory synapses in the vertebrate brain that are modified during learning, aging, and neurological disorders. The formation and modification of dendritic spines depend on rapid assembly and dynamic remodeling of the actin cytoskeleton in this highly compartmentalized space, but the precise mechanisms remain to be fully elucidated. In this study, we report that spatiotemporal enrichment of actin monomers (G-actin) in dendritic spines regulates spine development and plasticity. We first show that dendritic spines contain a locally enriched pool of G-actin that can be regulated by synaptic activity. We further find that this G-actin pool functions in spine development and its modification during synaptic plasticity. Mechanistically, the relatively immobile G-actin pool in spines depends on the phosphoinositide PI(3,4,5)P3 and involves the actin monomer binding protein profilin. Together, our results have revealed a novel mechanism by which dynamic enrichment of G-actin in spines regulates the actin remodeling underlying synapse development and plasticity. PMID- 28659329 TI - Shared Motivational Functions of Ventral Striatum D1 and D2 Medium Spiny Neurons. PMID- 28659328 TI - Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes. AB - The spindle pole body (SPB) of budding yeast duplicates once per cell cycle. In G1, the satellite, an SPB precursor, assembles next to the mother SPB (mSPB) on the cytoplasmic side of the nuclear envelope (NE). How the growing satellite subsequently inserts into the NE is an open question. To address this, we have uncoupled satellite growth from NE insertion. We show that the bridge structure that separates the mSPB from the satellite is a distance holder that prevents deleterious fusion of both structures. Binding of the gamma-tubulin receptor Spc110 to the central plaque from within the nucleus is important for NE insertion of the new SPB. Moreover, we provide evidence that a nuclear pore complex associates with the duplicating SPB and helps to insert the SPB into the NE. After SPB insertion, membrane-associated proteins including the conserved Ndc1 encircle the SPB and retain it within the NE. Thus, uncoupling SPB growth from NE insertion unmasks functions of the duplication machinery. PMID- 28659330 TI - Mapping the Role of MAP7 in Axon Collateral Branching. PMID- 28659331 TI - Correction: Crittenden et al. "Task Encoding across the Multiple Demand Cortex Is Consistent with a Frontoparietal and Cingulo-Opercular Dual Networks Distinction". PMID- 28659333 TI - Failure of long-term lamivudine prophylaxis in patients with resolved hepatitis B infection undergoing chemotherapy and allogenic hematopoietic stem cell transplantation for hematological malignancies: two case reports. PMID- 28659334 TI - Peripheral T-cell lymphoma cell line T8ML-1 highlights conspicuous targeting of PVRL2 by t(14;19)(q11.2;q13.3). PMID- 28659335 TI - Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. AB - A subset of patients with familial platelet disorder with propensity to myeloid malignancy and germline RUNX1 mutation develops hematological malignancies, often myelodysplastic syndrome/acute myeloid leukemia, currently recognized in the 2016 WHO classification. Patients who develop hematologic malignancies are typically young, respond poorly to conventional therapy, and need allogeneic stem cell transplant from non-familial donors. Understanding the spectrum of bone marrow morphologic and genetic findings in these patients is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of hematologic malignancies, particularly myelodysplastic syndrome. However, bone marrow features remain poorly characterized. To address this knowledge gap, we analyzed the clinicopathologic and genetic findings of 11 patients from 7 pedigrees. Of these, 6 patients did not develop hematologic malignancies over a 22-month follow up period; 5 patients developed hematologic malignancies (3 acute myeloid leukemia; 2 myelodysplastic syndrome). All patients had thrombocytopenia at initial presentation. All 6 patients who did not develop hematologic malignancies showed baseline bone marrow abnormalities: low-for-age cellularity (n=4), dysmegakaryopoiesis (n=5), megakaryocytic hypoplasia/hyperplasia (n=5), and eosinophilia (n=4). Two patients had multiple immunophenotypic alterations in CD34-positive myeloblasts; 1 patient had clonal hematopoiesis. In contrast, patients who developed hematologic malignancies had additional cytopenia(s) (n=4), abnormal platelet granulation (n=5), bone marrow hypercellularity (n=4), dysplasia in >=2 lineages including megakaryocytes (n=3) and acquired clonal genetic aberrations (n=5). In conclusion, our study demonstrated that specific bone marrow abnormalities and acquired genetic alterations may be harbingers of progression to hematological malignancies in patients with familial platelet disorder with germline RUNX1 mutation. PMID- 28659336 TI - Ibrutinib may impair serological responses to influenza vaccination. PMID- 28659337 TI - Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene. AB - Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is characterized by 2p23/ALK aberrations, including the classic t(2;5)(p23;q35)/NPM1 ALK rearrangement present in ~80% of cases and several variant t(2p23/ALK) occurring in the remaining cases. The ALK fusion partners play a key role in the constitutive activation of the chimeric protein and its subcellular localization. Using various molecular technologies, we have characterized ALK fusions in eight recently diagnosed anaplastic large cell lymphoma cases with cytoplasmic-only ALK expression. The identified partner genes included EEF1G (one case), RNF213/ALO17 (one case), ATIC (four cases) and TPM3 (two cases). Notably, all cases showed copy number gain of the rearranged ALK gene, which is never observed in NPM1-ALK positive lymphomas. We hypothesized that this could be due to lower expression levels and/or lower oncogenic potential of the variant ALK fusions. Indeed, all partner genes, except EEF1G, showed lower expression in normal and malignant T cells, in comparison with NPM1 In addition, we investigated the transformation potential of endogenous Npm1-Alk and Atic-Alk fusions generated by clustered regularly interspaced short palindromic repeats/Cas9 genome editing in Ba/F3 cells. We found that Npm1-Alk has a stronger transformation potential than Atic Alk, and we observed a subclonal gain of Atic-Alk after a longer culture period, which was not observed for Npm1-Alk Taken together, our data illustrate that lymphomas driven by the variant ATIC-ALK fusion (and likely by RNF213-ALK and TPM3-ALK), but not the classic NPM1-ALK, require an increased dosage of the ALK hybrid gene to compensate for the relatively low and insufficient expression and signaling properties of the chimeric gene. PMID- 28659338 TI - High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia. AB - The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment. Stroma reprogrammed signaling networks and modified the sensitivity of acute myeloid leukemia samples to all three targeted inhibitors. Stroma activated AKT at Ser473 in the majority of samples treated with single-agent ABT737 or Nutlin-3a. This survival mechanism was partially abrogated by concomitant treatment with temsirolimus plus ABT737 or Nutlin-3a. Mapping the signaling networks revealed that combinations of two inhibitors increased the number of affected proteins in the targeted pathways and in multiple parallel signaling, translating into facilitated cell death. These results demonstrated that a mechanism-based selection of combined inhibitors can be used to guide clinical drug selection and tailor treatment regimens to eliminate microenvironment-mediated resistance in acute myeloid leukemia. PMID- 28659340 TI - The long non-coding RNA GAS5 regulates transforming growth factor beta (TGF-beta) induced smooth muscle cell differentiation via RNA Smad-binding elements. AB - Smooth muscle cell (SMC) differentiation is essential for vascular development, and TGF-beta signaling plays a critical role in this process. Although long non coding RNAs (lncRNAs) regulate various cellular events, their functions in SMC differentiation remain largely unknown. Here, we demonstrate that the lncRNA growth arrest-specific 5 (GAS5) suppresses TGF-beta/Smad3 signaling in smooth muscle cell differentiation of mesenchymal progenitor cells. We found that forced expression of GAS5 blocked, but knockdown of GAS5 increased, the expression of SMC contractile proteins. Mechanistically, GAS5 competitively bound Smad3 protein via multiple RNA Smad-binding elements (rSBEs), which prevented Smad3 from binding to SBE DNA in TGF-beta-responsive SMC gene promoters, resulting in suppression of SMC marker gene transcription and, consequently, in inhibition of TGF-beta/Smad3-mediated SMC differentiation. Importantly, other lncRNAs or artificially synthesized RNA molecules that contained rSBEs also effectively inhibited TGF-beta/Smad3 signaling, suggesting that lncRNA-rSBE may be a general mechanism used by cells to fine-tune Smad3 activity in both basal and TGF-beta stimulated states. Taken together, our results have uncovered an lncRNA-based mechanism that modulates TGF-beta/Smad3 signaling during SMC differentiation. PMID- 28659339 TI - Structure of the competence pilus major pilin ComGC in Streptococcus pneumoniae. AB - Type IV pili are important virulence factors on the surface of many pathogenic bacteria and have been implicated in a wide range of diverse functions, including attachment, twitching motility, biofilm formation, and horizontal gene transfer. The respiratory pathogen Streptococcus pneumoniae deploys type IV pili to take up DNA during transformation. These "competence pili" are composed of the major pilin protein ComGC and exclusively assembled during bacterial competence, but their biogenesis remains unclear. Here, we report the high resolution NMR structure of N-terminal truncated ComGC revealing a highly flexible and structurally divergent type IV pilin. It consists of only three alpha-helical segments forming a well-defined electronegative cavity and confined electronegative and hydrophobic patches. The structure is particularly flexible between the first and second alpha-helix with the first helical part exhibiting slightly slower dynamics than the rest of the pilin, suggesting that the first helix is involved in forming the pilus structure core and that parts of helices two and three are primarily surface-exposed. Taken together, our results provide the first structure of a type IV pilin protein involved in the formation of competence-induced pili in Gram-positive bacteria and corroborate the remarkable structural diversity among type IV pilin proteins. PMID- 28659341 TI - Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass. AB - Bone and skeletal muscle mass are highly correlated in mammals, suggesting the existence of common anabolic signaling networks that coordinate the development of these two anatomically adjacent tissues. The activin signaling pathway is an attractive candidate to fulfill such a role. Here, we generated mice with conditional deletion of activin receptor (ACVR) type 2A, ACVR2B, or both, in osteoblasts, to determine the contribution of activin receptor signaling in regulating bone mass. Immunohistochemistry localized ACVR2A and ACVR2B to osteoblasts and osteocytes. Primary osteoblasts expressed activin signaling components, including ACVR2A, ACVR2B, and ACVR1B (ALK4) and demonstrated increased levels of phosphorylated Smad2/3 upon exposure to activin ligands. Osteoblasts lacking ACVR2B did not show significant changes in vitro However, osteoblasts deficient in ACVR2A exhibited enhanced differentiation indicated by alkaline phosphatase activity, mineral deposition, and transcriptional expression of osterix, osteocalcin, and dentin matrix acidic phosphoprotein 1. To investigate activin signaling in osteoblasts in vivo, we analyzed the skeletal phenotypes of mice lacking these receptors in osteoblasts and osteocytes (osteocalcin-Cre). Similar to the lack of effect in vitro, ACVR2B-deficient mice demonstrated no significant change in any bone parameter. By contrast, mice lacking ACVR2A had significantly increased femoral trabecular bone volume at 6 weeks of age. Moreover, mutant mice lacking both ACVR2A and ACVR2B demonstrated sustained increases in trabecular bone volume, similar to those in ACVR2A single mutants, at 6 and 12 weeks of age. Taken together, these results indicate that activin receptor signaling, predominantly through ACVR2A, directly and negatively regulates bone mass in osteoblasts. PMID- 28659342 TI - Proton transfer reactions in the red light-activatable channelrhodopsin variant ReaChR and their relevance for its function. AB - Channelrhodopsins (ChRs) are light-gated ion channels widely used for activating selected cells in large cellular networks. ChR variants with a red-shifted absorption maximum, such as the modified Volvox carteri ChR1 red-activatable channelrhodopsin ("ReaChR," lambdamax = 527 nm), are of particular interest because longer wavelengths allow optical excitation of cells in deeper layers of organic tissue. In all ChRs investigated so far, proton transfer reactions and hydrogen bond changes are crucial for the formation of the ion-conducting pore and the selectivity for protons versus cations, such as Na+, K+, and Ca2+ (1). By using a combination of electrophysiological measurements and UV-visible and FTIR spectroscopy, we characterized the proton transfer events in the photocycle of ReaChR and describe their relevance for its function. 1) The central gate residue Glu130 (Glu90 in Chlamydomonas reinhardtii (Cr) ChR2) (i) undergoes a hydrogen bond change in D -> K transition and (ii) deprotonates in K -> M transition. Its negative charge in the open state is decisive for proton selectivity. 2) The counter-ion Asp293 (Asp253 in CrChR2) receives the retinal Schiff base proton during M-state formation. Starting from M, a photocycle branching occurs involving (i) a direct M -> D transition and (ii) formation of late photointermediates N and O. 3) The DC pair residue Asp196 (Asp156 in CrChR2) deprotonates in N -> O transition. Interestingly, the D196N mutation increases 15 syn-retinal at the expense of 15-anti, which is the predominant isomer in the wild type, and abolishes the peak current in electrophysiological measurements. This suggests that the peak current is formed by 15-anti species, whereas 15-syn species contribute only to the stationary current. PMID- 28659343 TI - The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles. AB - The host-cell restriction factor SERINC5 potently suppresses the infectivity of HIV, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which SERINC5 restricts HIV-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of HIV particles is a major determinant of the infectious potential of the particles, we tested whether SERINC5-mediated restriction of HIV particle infectivity involves alterations of membrane lipid composition. We produced and purified HIV-1 particles from SERINC5293T cells with very low endogenous SERINC5 levels under conditions in which ectopically expressed SERINC5 restricts HIV-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS. SERINC5 restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and HIV particles. Sphingosine metabolism kinetics were also unaltered by SERINC5 expression. Moreover, the levels of phosphatidylserine on the surface of HIV-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of SERINC5 or Nef. Finally, saturating the phosphatidylserine-binding sites on HIV target cells did not affect SERINC5 restriction or Nef antagonism. These results demonstrate that the restriction of HIV-1 particle infectivity by SERINC5 does not depend on alterations in lipid composition and organization of HIV-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of SERINC5. PMID- 28659345 TI - Ablation of Neuropilin 1 in Myeloid Cells Exacerbates High-Fat Diet-Induced Insulin Resistance Through Nlrp3 Inflammasome In Vivo. AB - Neuropilin 1 (Nrp1), a coreceptor for class 3 semaphorins and growth factors, is highly expressed in vascular cells and myeloid cells, including macrophages. Unlike well-characterized proangiogenic functions of endothelial cell Nrp1, the contributions of macrophage Nrp1 within the context of metabolic dysfunction remain to be established. The aim of this study was to determine the contributions of macrophage Nrp1 in high-fat diet (HFD)-instigated insulin resistance in vivo. Insulin sensitivity and Nlrp3 inflammasome activation were monitored in wild-type (WT) and myeloid cell-specific Nrp1 knockout (Nrp1myel-KO) mice fed an HFD (60% kcal) for 16 weeks. HFD-fed mice exhibited insulin resistance with reduced levels of Nrp1 in macrophages compared with chow-fed mice. Further, HFD-fed Nrp1myel-KO mice displayed accentuated insulin resistance, enhanced systemic inflammation, and dramatically increased Nlrp3 inflammasome priming and activation. Importantly, knockout of Nlrp3 ablated HFD-induced insulin resistance and inflammation in Nrp1myel-KO mice, indicating that Nrp1 reduction in macrophages instigates insulin resistance by increasing macrophage Nlrp3 inflammasome activation. Mechanistically, Nrp1 deletion activates the nuclear factor-kappaB pathway, which in turn accentuates the priming of Nlrp3, promotes Nlrp3-ASC inflammasome assembly, and results in the activation of Nlrp3. We conclude that the HFD-instigated Nrp1 reduction in macrophages exacerbates insulin resistance by promoting Nlrp3 inflammasome priming and activation. PMID- 28659344 TI - Guanylyl cyclase sensitivity to nitric oxide is protected by a thiol oxidation driven interaction with thioredoxin-1. AB - Nitric oxide (NO) modulates many physiological events through production of cGMP from its receptor, the NO-sensitive guanylyl cyclase (GC1). NO also appears to function in a cGMP-independent manner, via S-nitrosation (SNO), a redox-based modification of cysteine thiols. Previously, we have shown that S-nitrosated GC1 (SNO-GC1) is desensitized to NO stimulation following prolonged NO exposure or under oxidative/nitrosative stress. In animal models of nitrate tolerance and angiotensin II-induced hypertension, decreased vasodilation in response to NO correlates with GC1 thiol oxidation, but the physiological mechanism that resensitizes GC1 to NO and restores basal activity is unknown. Because GC1 interacts with the oxidoreductase protein-disulfide isomerase, we hypothesized that thioredoxin-1 (Trx1), a cytosolic oxidoreductase, could be involved in restoring GC1 basal activity and NO sensitivity because the Trx/thioredoxin reductase (TrxR) system maintains thiol redox homeostasis. Here, by manipulating activity and levels of the Trx1/TrxR system and by using a Trx1-Trap assay, we demonstrate that Trx1 modulates cGMP synthesis through an association between Trx1 and GC1 via a mixed disulfide. A proximity ligation assay confirmed the endogenous Trx1-GC1 complex in cells. Mutational analysis suggested that Cys609 in GC1 is involved in the Trx1-GC1 association and modulation of GC1 activity. Functionally, we established that Trx1 protects GC1 from S-nitrosocysteine induced desensitization. A computational model of Trx1-GC1 interaction illustrates a possible mechanism for Trx1 to maintain basal GC1 activity and prevent/rescue GC1 desensitization to NO. The etiology of some oxidative vascular diseases may very well be explained by the dysfunction of the Trx1-GC1 association. PMID- 28659347 TI - Author's reply to Hill-Smith. PMID- 28659348 TI - Non-coding regulatory variations: the dark matter of pancreatic cancer genomics. PMID- 28659346 TI - Starch Digestion-Related Amylase Genetic Variant Affects 2-Year Changes in Adiposity in Response to Weight-Loss Diets: The POUNDS Lost Trial. AB - Salivary and pancreatic amylases (encoded by AMY1 and AMY2 genes, respectively) are responsible for digesting starchy foods. AMY1 and AMY2 show copy number variations that affect differences in amylase amount and activity, and AMY1 copies have been associated with adiposity. We investigated whether genetic variants determining amylase gene copies are associated with 2-year changes in adiposity among 692 overweight and obese individuals who were randomly assigned to diets varying in macronutrient content. We found that changes in body weight (BW) and waist circumference (WC) were significantly different according to the AMY1-AMY2 rs11185098 genotype. Individuals carrying the A allele (indicating higher amylase amount and activity) showed a greater reduction in BW and WC at 6, 12, 18, and 24 months than those without the A allele (P < 0.05 for all). The association was stronger for long-term changes compared with short-term changes of these outcomes. The genetic effects on these outcomes did not significantly differ across diet groups. In conclusion, the genetic variant determining starch metabolism influences the response to weight-loss dietary intervention. Overweight and obese individuals carrying the AMY1-AMY2 rs11185098 genotype associated with higher amylase activity may have greater loss of adiposity during low-calorie diet interventions. PMID- 28659349 TI - Randomised controlled trial of transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND Study). AB - OBJECTIVE: Non-randomised studies suggest that endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM), but EMR might be more cost-effective and safer. This trial compares the clinical outcome and cost-effectiveness of TEM and EMR for large rectal adenomas. DESIGN: Patients with rectal adenomas >=3 cm, without malignant features, were randomised (1:1) to EMR or TEM, allowing endoscopic removal of residual adenoma at 3 months. Unexpected malignancies were excluded postrandomisation. Primary outcomes were recurrence within 24 months (aiming to demonstrate non-inferiority of EMR, upper limit 10%) and the number of recurrence free days alive and out of hospital. RESULTS: Two hundred and four patients were treated in 18 university and community hospitals. Twenty-seven (13%) had unexpected cancer and were excluded from further analysis. Overall recurrence rates were 15% after EMR and 11% after TEM; statistical non-inferiority was not reached. The numbers of recurrence-free days alive and out of hospital were similar (EMR 609+/-209, TEM 652+/-188, p=0.16). Complications occurred in 18% (EMR) versus 26% (TEM) (p=0.23), with major complications occurring in 1% (EMR) versus 8% (TEM) (p=0.064). Quality-adjusted life years were equal in both groups. EMR was approximately ?3000 cheaper and therefore more cost-effective. CONCLUSION: Under the statistical assumptions of this study, non-inferiority of EMR could not be demonstrated. However, EMR may have potential as the primary method of choice due to a tendency of lower complication rates and a better cost effectiveness ratio. The high rate of unexpected cancers should be dealt with in further studies. PMID- 28659350 TI - Endothelial dysfunction: what is the role of the microbiota? PMID- 28659351 TI - Doctors can allow terminally ill baby to die after parents' appeal to European court fails. PMID- 28659352 TI - Cancer incidence attributable to air pollution in Alberta in 2012. AB - BACKGROUND: The International Agency for Research on Cancer has classified outdoor air pollution (fine particulate matter [PM2.5]) as a Group 1 lung carcinogen in humans. We aimed to estimate the proportion of lung cancer cases attributable to PM2.5 exposure in Alberta in 2012. METHODS: Annual average concentrations of PM2.5 in 2011 for 22 communities across Alberta were extracted from the Clean Air Strategic Alliance Data Warehouse and were population-weighted across the province. Using 7.5 ug/m3 and 3.18 ug/m3 as the annual average theoretical minimum risk concentrations of PM2.5, we estimated the proportion of the population above this cut-off to determine the population attributable risk of lung cancer due to PM2.5 exposure. RESULTS: The mean population-weighted concentration of PM2.5 for Alberta in 2011 was 10.03 ug/m3. We estimated relative risks of 1.02 and 1.06 for theoretical minimum risk PM2.5 concentration thresholds of 7.5 ug/m3 and 3.18 ug/m3, respectively. About 1.87%-5.69% of incident lung cancer cases in Alberta were estimated to be attributable to PM2.5 exposure. INTERPRETATION: Our estimate of attributable burden is low compared to that reported in studies in other areas of the world owing to the relatively low levels of PM2.5 recorded in Alberta. Reducing PM2.5 emissions in Alberta should continue to be a priority to help decrease the burden of lung cancer in the population. PMID- 28659353 TI - Alterations in the Thymic Selection Threshold Skew the Self-Reactivity of the TCR Repertoire in Neonates. AB - Neonatal and adult T cells differ in their effector functions. Although it is known that cell-intrinsic differences in mature T cells contribute to this phenomenon, the factors involved remain unclear. Given emerging evidence that the binding strength of a TCR for self-peptide presented by MHC (self-pMHC) impacts T cell function, we sought to determine whether altered thymic selection influences the self-reactivity of the TCR repertoire during ontogeny. We found that conventional and regulatory T cell subsets in the thymus of neonates and young mice expressed higher levels of cell surface CD5, a surrogate marker for TCR avidity for self-pMHC, as compared with their adult counterparts, and this difference in self-reactivity was independent of the germline bias of the neonatal TCR repertoire. The increased binding strength of the TCR repertoire for self-pMHC in neonates was not solely due to reported defects in clonal deletion. Rather, our data suggest that thymic selection is altered in young mice such that thymocytes bearing TCRs with low affinity for self-peptide are not efficiently selected into the neonatal repertoire, and stronger TCR signals accompany both conventional and regulatory T cell selection. Importantly, the distinct levels of T cell self-reactivity reflect physiologically relevant differences based on the preferential expansion of T cells from young mice to fill a lymphopenic environment. Therefore, differences in thymic selection in young versus adult mice skew the TCR repertoire, and the relatively higher self-reactivity of the T cell pool may contribute to the distinct immune responses observed in neonates. PMID- 28659354 TI - Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes. AB - The T cell repertoire is a function of thymic V(D)J rearrangement and of peripheral selection. The mature repertoire embodies TCR sequences that are important for survival and can identify important structural aspects of the TCR. Analysis of the circulating TCRBV19 CD8 T cell repertoire showed that a majority of NDN-encoded CDR3 amino acid motifs start at CDR3 position four, well within the V region. Rearrangement at this position indicates that the DNA hairpin loop is not opened at the position adjacent to the recombination signal sequence, but rather is trimmed back three or more bases. In this article, we show that the rearrangement frequency distribution within the V region reveals selection on CDR3 position four. The selection is already established in single-positive CD8 thymocytes. Crystal structures reveal a possible basis for this selection due to the location of this residue in a bend that positions the remaining portion of CDR3 to interact with the peptide and MHC. Examination of other TCRBV families also shows selection for rearrangement within the V region of a number of genes and for CD8 and CD4 cells. The exact profile of rearrangement within the V region appears to be V gene specific. The frequent observation of side chains associated with turn motifs at CDR3 positions three and four fits with the structural need for a bend. The data are discussed in terms of the generation of a structural turn motif, the rearrangement mechanism, and selection of the repertoire on the peptide and MHC. PMID- 28659355 TI - Deficiency of Phosphatidylinositol 3-Kinase delta Signaling Leads to Diminished Numbers of Regulatory T Cells and Increased Neutrophil Activity Resulting in Mortality Due to Endotoxic Shock. AB - Despite decades of clinical and biomedical research, the pathogenesis of sepsis and its spectrum of diseases (severe sepsis and septic shock), which are leading causes of death in intensive care units, are still poorly understood. In this article, we show that signaling via the p110delta isoform of PI3K is critical for survival in experimental sepsis. Mice with an inactive knock-in mutation in the p110delta gene (p110deltaD910A) succumbed acutely to nonlethal dose LPS challenge. The susceptibility of p110deltaD910A mice to LPS was associated with increased neutrophil numbers and activities in the tissues, due in part to delayed apoptosis resulting mostly from inherent reduced regulatory T cell (Treg) numbers. Adoptive transfer of wild-type or p110deltaD910A Tregs abrogated exaggerated neutrophil activity, increased neutrophil apoptosis, and rescued p110deltaD910A mice from mortality after LPS challenge. We confirmed the clinical relevance of these findings by showing that human Tregs also regulate neutrophil function and survival. Collectively, our results show that PI3K delta is essential for survival during sepsis. In addition, our data highlight the importance of Tregs in regulating the pathogenesis of sepsis and septic shock via their effects on neutrophil survival and function, and provide evidence of regulation of innate immunity by cells of the adaptive immune system. PMID- 28659356 TI - Wnt5a Signaling Promotes Host Defense against Leishmania donovani Infection. AB - Leishmania donovani infects macrophages, disrupting immune homeostasis. The underlying mechanism that sustains infection remains unresolved. In view of the potential of Wnt5a signaling to support immune homeostasis, we evaluated the interrelationship of Wnt5a signaling and Leishmania donovani infection. Upon infecting macrophages separately with antimony drug-sensitive and -resistant L. donovani, we noted disruption in the steady-state level of Wnt5a. Moreover, inhibition of Wnt5a signaling by small interfering RNA transfection in vitro or by use of inhibitor of Wnt production in vivo led to an increase in cellular parasite load. In contrast, treatment of macrophages with recombinant Wnt5a caused a decrease in the load of antimony-sensitive and -resistant parasites, thus confirming that Wnt5a signaling antagonizes L. donovani infection. Using inhibitors of the Wnt5a signaling intermediates Rac1 and Rho kinase, we demonstrated that Wnt5a-mediated inhibition of parasite infection in macrophages is Rac1/Rho dependent. Furthermore, phalloidin staining and reactive oxygen species estimation of Wnt5a-treated macrophages suggested that a Wnt5a-Rac/Rho mediated decrease in parasite load is associated with an increase in F- actin assembly and NADPH oxidase activity. Moreover, live microscopy of L. donovani infected macrophages treated with Wnt5a demonstrated increased endosomal/lysosomal fusions with parasite-containing vacuoles (parasitophorous vacuoles [PV]). An increase in PV-endosomal/lysosomal fusion accompanied by augmented PV degradation in Wnt5a-treated macrophages was also apparent from transmission electron microscopy of infected cells. Our results suggest that, although L. donovani evades host immune response, at least in part through inhibition of Wnt5a signaling, revamping Wnt5a signaling can inhibit L. donovani infection, irrespective of drug sensitivity or resistance. PMID- 28659357 TI - Menin Controls the Memory Th2 Cell Function by Maintaining the Epigenetic Integrity of Th2 Cells. AB - Posttranslational modifications of histones are well-established epigenetic modifications that play an important role in gene expression and regulation. These modifications are partly mediated by the Trithorax group (TrxG) complex, which regulates the induction or maintenance of gene transcription. We investigated the role of Menin, a component of the TrxG complex, in the acquisition and maintenance of Th2 cell identity using T cell-specific Menin deficient mice. Our gene expression analysis revealed that Menin was involved in the maintenance of the high expression of the previously identified Th2-specific genes rather than the induction of these genes. This result suggests that Menin plays a role in the maintenance of Th2 cell identity. Menin directly bound to the Gata3 gene locus, and this Menin-Gata3 axis appeared to form a core unit of the Th2-specific gene regulatory network. Consistent with the phenotype of Menin deficient Th2 cells observed in vitro, Menin deficiency resulted in the attenuation of effector Th2 cell-induced airway inflammation. In addition, in memory Th2 (mTh2) cells, Menin was found to play an important role in the maintenance of the expression of Th2-specific genes, including Gata3, Il4, and Il13 Consequently, Menin-deficient mTh2 cells showed an impaired ability to recruit eosinophils to the lung, resulting in the attenuation of mTh2 cell induced airway inflammation. This study confirmed the critical role of Menin in Th2 cell-mediated immune responses. PMID- 28659358 TI - B Cell-Extrinsic Myd88 and Fcer1g Negatively Regulate Autoreactive and Normal B Cell Immune Responses. AB - MyD88 and FcR common gamma-chain (Fcer1g, FcRgamma) elicit proinflammatory responses to exogenous Ags. Deletion of these receptors in autoimmune models has generally led to reduced overall disease. In B cells, Myd88 is required for anti DNA and anti-RNA autoantibody responses, whereas Fcer1g is not expressed in these cells. The roles of these receptors in myeloid cells during B cell autoimmune activation remain less clear. To investigate the roles of Myd88 and Fcer1g in non B cells, we transferred anti-self-IgG (rheumatoid factor) B cells and their physiologic target Ag, anti-chromatin Ab, into mice lacking Fcer1g, Myd88, or both and studied the extrafollicular plasmablast response. Surprisingly, we found a markedly higher and more prolonged response in the absence of either molecule; this effect was accentuated in doubly deficient recipients, with a 40-fold increase compared with wild-type recipients at day 10. This enhancement was dependent on CD40L, indicating that Myd88 and FcRgamma, presumably on myeloid APCs, were required to downregulate T cell help for the extrafollicular response. To extend the generality, we then investigated a classic T cell-dependent response to (4-hydroxy-3-nitrophenyl)acetyl conjugated to chicken gamma globulin and found a similar effect. Thus, these results reveal novel regulatory roles in the B cell response for receptors that are typically proinflammatory. PMID- 28659359 TI - International Sports Federation's fight to protect the clean athlete: are we doing enough in the fight against doping? PMID- 28659360 TI - Lung ultrasound immediately after birth to describe normal neonatal transition: an observational study. AB - OBJECTIVE: Lung ultrasound (LUS) has shown promise as a diagnostic tool for the evaluation of the newborn with respiratory distress. No study has described LUS during 'normal' transition. Our goal was to characterise the appearance of serial LUS in healthy newborns from the first minutes after birth until airway liquid clearance is achieved. STUDY DESIGN: Prospective observational study. SETTING: Single-centre tertiary perinatal centre in Australia. PATIENTS: Of 115 infants born at >=35 weeks gestational age, mean (SD) gestational age of 386/7 weeks+/-11 days, mean birth weight of 3380+/-555 g, 51 were delivered vaginally, 14 via caesarean section (CS) after labour and 50 infants via elective CS. INTERVENTIONS: We obtained serial LUS videos via the right and left axillae at 1 10 min, 11-20 min and 1, 2, 4 and 24 hours after birth. MAIN OUTCOME MEASURES: LUS videos were graded for aeration and liquid clearance according to a previously validated system. RESULTS: We analysed 1168 LUS video recordings. As assessed by LUS, lung aeration and airway liquid clearance occurred quickly. All infants had an established pleural line at the first examination (median=2 (1-4) min). Only 14% of infants had substantial liquid retention at 10 min after birth. 49%, 78% and 100% of infants had completed airway liquid clearance at 2, 4 and 24 hours, respectively. CONCLUSIONS: In healthy transitioning newborn infants, lung aeration and partial liquid clearance are achieved on the first minutes after birth with complete liquid clearance typically achieved within the first 4 hours of birth. TRIAL REGISTRATION NUMBER: ANZCT 12615000380594. PMID- 28659361 TI - Parenting stress trajectories in mothers of very preterm infants to 2 years. AB - OBJECTIVE: To examine levels of parenting stress in mothers of preterm and term infants when the children were 2 years old; to determine the trajectory of stress over three time periods and to examine the association of maternal and neonatal factors and developmental outcomes with parenting stress. DESIGN: It is a prospective longitudinal study to determine parenting stress in mothers of preterm and term infants with outcomes having been previously obtained at 4 and 12 months. At 2 years, 79 preterm mothers (96 babies) and 64 term mothers (77 babies) participated. The mothers completed the Parenting Stress Index-Short Form (PSI-SF), the Depression, Anxiety, Stress Scale (DASS) and the Child Behaviour Checklist (CBCL). The infants had a neurological examination and the Bayley-III scales were administered. RESULTS: The mean total PSI-SF at 2 years was significantly higher for the preterm group compared with the term group of mothers (p=0.007). There was a significant increase in the mean total PSI over time for the preterm mothers (p<0.001). For mothers at 2 years, there was an association with high levels of parenting stress and abnormal scores on the DASS (p<0.001) and high total T-scores on the CBCL (internalising p<0.001; externalising p=0.006). There was no association between parenting stress and maternal demographics, neonatal factors or Bayley-III results. CONCLUSIONS: Parenting stress in mothers of preterm infants continues to be high at 2 years having increased over time. Maternal mental health problems and infant behavioural issues contribute to the stress. PMID- 28659362 TI - Volume guaranteed? Accuracy of a volume-targeted ventilation mode in infants. AB - OBJECTIVES: Volume-targeted ventilation (VTV) is widely used and may reduce lung injury, but this assumes the clinically set tidal volume (VTset) is accurately delivered. This prospective observational study aimed to determine the relationship between VTset, expiratory VT (VTe) and endotracheal tube leak in a modern neonatal -volume-targeted ventilator (VTV) and the resultant partial arterial pressure of carbon dioxide (PaCO2) relationship with and without VTV. DESIGN: Continuous inflations were recorded for 24 hours in 100 infants, mean (SD) 34 (4) weeks gestation and 2483 (985) g birth weight, receiving synchronised mechanical ventilation (SLE5000, SLE, UK) with or without VTV and either the manufacturer's V4 (n=50) or newer V5 (n=50) VTV algorithm. The VTset, VTe and leak were determined for each inflation (maximum 90 000/infant). If PaCO2 was sampled (maximum of 2 per infant), this was compared with the average VTe data from the preceding 15 min. RESULTS: A total of 7 497 137 inflations were analysed. With VTV enabled (77 infants), the VTset-VTe bias (95% CI) was 0.03 ( 0.12 to 0.19) mL/kg, with a median of 80% of VTe being +/-1.0 mL/kg of VTset. Endotracheal tube leak up to 30% influenced VTset-VTe bias with the V4 (r2=-0.64, p<0.0001; linear regression) but not V5 algorithm (r2=0.04, p=0.21). There was an inverse linear relationship between VTe and PaCO2 without VTV (r2=0.26, p=0.004), but not with VTV (r2=0.04, p=0.10), and less PaCO2 within 40-60 mm Hg, 53% versus 72%, relative risk (95% CI) 1.7 (1.0 to 2.9). CONCLUSION: VTV was accurate and reliable even with moderate leak and PaCO2 more stable. VTV algorithm differences may exist in other devices. PMID- 28659363 TI - Spontaneous rupture of the bladder during vomiting. AB - A 46-year-old woman with no urological history or comorbidities presented with an acute abdomen with haematuria after a spell of protracted vomiting. The initial cystogram was negative; however, CT imaging highly suggested an intraperitoneal bladder perforation, which was confirmed during laparotomy and subsequently repaired. Cystoscopic evaluation prior to laparotomy revealed no concurrent bladder pathology, and the ureteric orifices were intact. A cystogram 2 weeks after repair demonstrated no leaks, and her catheters were removed. She recovered well, with expectant postoperative pain and lower urinary tract symptoms settling on 3-month review. Spontaneous bladder rupture is a rare entity, with very few reports in the literature. PMID- 28659364 TI - Acute cor pulmonale due to pulmonary tumour thrombotic microangiopathy from renal cell carcinoma. AB - We report the case of a previously healthy man who presented with subacute dyspnoea after a long drive. He developed hypoxic respiratory failure, thought secondary to a massive pulmonary embolism and was treated with tissue plasminogen activator but died in the hospital despite aggressive medical measures. Autopsy revealed pulmonary tumour thrombotic microangiopathy (PTTM) from papillary renal cell carcinoma. PTTM is a rare clinicopathological syndrome that clinically results in symptoms of dyspnoea and right heart failure. Pathologically, a localised paraneoplastic process evolves from tumour microemboli in the pulmonary arterioles, resulting in fibrocellular proliferation and narrowing of the vessels, causing subacute right heart failure. To our knowledge, this is the first case of PTTM due to papillary renal cell carcinoma. PMID- 28659365 TI - Presacral mass in the setting of an ovarian cyst and abdominal pain. AB - Tailgut cysts, also known as retrorectal hamartomas, are very rare neoplasms located in the presacral/retrorectal space that originate from the embryonic hindgut. Although a majority of lesions in this location are benign, 30% of the reported cases in the literature were found to be malignant. This report describes a case of a presacral mass found on CT of a 37-year-old woman who initially presented with worsening abdominal pain and a history of ovarian cyst rupture. This patient's clinical picture was complicated by an enlarging ovarian cyst. The risk of progression to malignancy warranted excision. She recovered well with resolution of her presenting symptoms. We report this case along with a brief review of the literature with a focus on the surgical considerations. PMID- 28659366 TI - Successful repeat ECMO in a patient with AIDS and ARDS. AB - Veno-venous extracorporeal membrane oxygenation (ECMO) is being more commonly used in patients with acute respiratory distress syndrome (ARDS) due to potentially reversible illnesses. Survival from ARDS using ECMO has been reported even in patients with AIDS. However, the indications for ECMO for ARDS due to immune reconstitution inflammatory syndrome (IRIS) in patients with AIDS are unknown. A 23-year-old man with AIDS and Pneumocystis jirovecii pneumonia was admitted to the intensive care unit with severe ARDS refractory to mechanical ventilator support requiring ECMO. Although ECMO was discontinued, a second treatment with ECMO was necessary due to IRIS-associated ARDS, resulting in an excellent patient outcome. This patient's clinical course suggests two important messages. First, ECMO is a reasonable option for the treatment of patients with ARDS even in a patient with AIDS. Second, ECMO may be effective for the treatment of patients with IRIS. PMID- 28659367 TI - Heroin-induced acute myelopathy with extreme high levels of CSF glial fibrillar acidic protein indicating a toxic effect on astrocytes. AB - A man aged 33 years with previous heroin substance abuse was found unconscious lying in a bush. The patient had been without heroin for some time but had just started to use intravenous heroin again, 0.5-2 g daily. The patient had almost complete paraplegia and a sensory loss for all modalities below the mamillary level and a urine retention of 1.5 L. Acute MRI of the spine revealed an expanded spinal cord with increased intramedullary signal intensity, extending from C7-T9. The cerebrospinal fluid showed extremely high levels of nerve injury markers particularly glial fibrillar acidic protein (GFAP): 2 610 000/ng/L (ref. <750). The patient was empirically treated with intravenous 1 g methylprednisolone daily for 5 days and improved markedly. Very few diseases are known to produce such high levels of GFAP, indicating a toxic effect on astrocytes. Measuring GFAP could possibly aid in the diagnosis of heroin-induced myelopathy. PMID- 28659368 TI - Giant lipoma of the hand causing median nerve compression. AB - Lipomas are benign neoplasms derived from adipose tissue composed of mature adipocytes. They account for almost 50% of all soft-tissue neoplasms and occur in up to 2% of the population. They usually present asymptomatically as solitary discrete mobile lumps found most commonly on the neck, upper back, proximal limbs and chest. In less than 1% of cases, they can be found in the distal extremities.We discuss the case of a 65-year-old man who presented with a 2-year history of a slowly enlarging left palm swelling, with recent-onset numbness and loss of power in the distribution of the median nerve. MRI studies showed that the 5*4*2.7 cm lipoma had a component extending into the distal aspect of the carpal tunnel, compressing the median nerve. It was successfully excised, and at follow-up the patient reported complete resolution of his symptoms. PMID- 28659369 TI - Insidious perforation of the rectum by a fallopian tube: the need to keep 'an open mind' when dealing with deep infiltrating endometriosis (DIE). AB - Endometriosis is a benign chronic disease which can have different degrees of severity and can potentially affect any organ. Intestinal endometriosis occurs in 3%a?"37% of the cases, being more frequent in the rectosigmoid transition. Transmural involvement of intestinal endometriosis is extremely rare and is usually associated with recurrent abdominal pain. Due to the cyclical hormone influence, endometriosis implants may infiltrate the deeper layers of the intestinal wall and may lead to bowel obstruction or perforation. We present a case of transmural perforation of the rectum wall by an adjacent organ (left fallopian tube) that occurred insidiously in a patient with deep infiltrative endometriosis. A complete set of images is presented, regarding the preoperative, intraoperative and postoperative findings. PMID- 28659370 TI - When your patient clicks: a loud clicking sound as a key sign to the diagnosis. AB - A 19-year-old male patient was referred by his general practitioner with a new 'cardiac murmur'. For 1 week, he had been able to provoke a clicking sound, which was in time with his heart beat and originated from his chest. The physical examination and laboratory tests were normal. The sound was initially interpreted as most likely due to a valve condition such as mitral valve prolapse, but a transthoracic echocardiogram was normal. A cardiac CT was obtained, which showed left-sided ventral pneumothorax.The Hamman's sign is a loud precordial pulse synchronous sound, which is often postural. It is pathognomonic for left-sided pneumothorax or pneumomediastinum. Hamman's sign as a presenting symptom is rare, but if present is key to diagnosis. The awareness of rare clinical findings is important and will prevent unnecessary diagnostic tests. PMID- 28659371 TI - Mild androgen insensitivity syndrome (MAIS): the identification of c.1783C>T mutation in two unrelated infertile men. AB - Two unrelated men complaining of primary male infertility presented to Orient Hospital in Damascus city. Physical examination showed moderate hypoandrogenic features. Both men were azoospermic. Hormone profiles revealed an elevation of follicle-stimulating hormone in one patient, but all the other hormones tested were within normal limits for both patients. Further genetic analyses, including karyotype and microdeletions in the AZF region of the Y chromosome, were normal in both patients. Mild androgen insensitivity syndrome was expected in the two patients. Sequencing analysis of the first exon in the androgen receptor (AR) gene have shown c.1783C>T mutation in the two patients with azoospermia. This paper sheds light on the need to screen for mutations in the AR gene, causing male infertility whenever mild hypoandrogenic features are present with unexplained male infertility. PMID- 28659372 TI - Fever and asplenia: a dangerous association. PMID- 28659373 TI - Vibrio vulnificus tonsillitis after swimming in the Gulf of Mexico. PMID- 28659374 TI - Urine fluorescence in antifreeze poisoning. PMID- 28659376 TI - A new twist to Sin3 complexes in pluripotent cells. PMID- 28659375 TI - Role of glutamine and interlinked asparagine metabolism in vessel formation. AB - Endothelial cell (EC) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in ECs is unknown. Here, we show that depriving ECs of glutamine or inhibiting glutaminase 1 (GLS1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in ECs did not cause energy distress, but impaired tricarboxylic acid (TCA) cycle anaplerosis, macromolecule production, and redox homeostasis. Only the combination of TCA cycle replenishment plus asparagine supplementation restored the metabolic aberrations and proliferation defect caused by glutamine deprivation. Mechanistically, glutamine provided nitrogen for asparagine synthesis to sustain cellular homeostasis. While ECs can take up asparagine, silencing asparagine synthetase (ASNS, which converts glutamine-derived nitrogen and aspartate to asparagine) impaired EC sprouting even in the presence of glutamine and asparagine. Asparagine further proved crucial in glutamine-deprived ECs to restore protein synthesis, suppress ER stress, and reactivate mTOR signaling. These findings reveal a novel link between endothelial glutamine and asparagine metabolism in vessel sprouting. PMID- 28659377 TI - ERCC1-XPF endonuclease-positioned to cut. PMID- 28659379 TI - Glutamine fuels proliferation but not migration of endothelial cells. AB - Endothelial metabolism is a key regulator of angiogenesis. Glutamine metabolism in endothelial cells (ECs) has been poorly studied. We used genetic modifications and 13C tracing approaches to define glutamine metabolism in these cells. Glutamine supplies the majority of carbons in the tricyclic acid (TCA) cycle of ECs and contributes to lipid biosynthesis via reductive carboxylation. EC specific deletion in mice of glutaminase, the initial enzyme in glutamine catabolism, markedly blunts angiogenesis. In cell culture, glutamine deprivation or inhibition of glutaminase prevents EC proliferation, but does not prevent cell migration, which relies instead on aerobic glycolysis. Without glutamine catabolism, there is near complete loss of TCA intermediates, with no compensation from glucose-derived anaplerosis. Mechanistically, addition of exogenous alpha-ketoglutarate replenishes TCA intermediates and rescues cellular growth, but simultaneously unveils a requirement for Rac1-dependent macropinocytosis to provide non-essential amino acids, including asparagine. Together, these data outline the dependence of ECs on glutamine for cataplerotic processes; the need for glutamine as a nitrogen source for generation of biomass; and the distinct roles of glucose and glutamine in EC biology. PMID- 28659378 TI - The AAA+ ATPase TRIP13 remodels HORMA domains through N-terminal engagement and unfolding. AB - Proteins of the conserved HORMA domain family, including the spindle assembly checkpoint protein MAD2 and the meiotic HORMADs, assemble into signaling complexes by binding short peptides termed "closure motifs". The AAA+ ATPase TRIP13 regulates both MAD2 and meiotic HORMADs by disassembling these HORMA domain-closure motif complexes, but its mechanisms of substrate recognition and remodeling are unknown. Here, we combine X-ray crystallography and crosslinking mass spectrometry to outline how TRIP13 recognizes MAD2 with the help of the adapter protein p31comet We show that p31comet binding to the TRIP13 N-terminal domain positions the disordered MAD2 N-terminus for engagement by the TRIP13 "pore loops", which then unfold MAD2 in the presence of ATP N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro, and in cells causes spindle assembly checkpoint defects consistent with loss of TRIP13 function. Similar truncation of HORMAD1 in mouse spermatocytes compromises its TRIP13 mediated removal from meiotic chromosomes, highlighting a conserved mechanism for recognition and disassembly of HORMA domain-closure motif complexes by TRIP13. PMID- 28659380 TI - Deubiquitylation of deubiquitylases. AB - Deubiquitylating enzymes (DUBs) reverse the ubiquitylation of target proteins, thereby regulating diverse cellular functions. In contrast to the plethora of research being conducted on the ability of DUBs to counter the degradation of cellular proteins or auto-ubiquitylated E3 ligases, very little is known about the mechanisms of DUB regulation. In this review paper, we summarize a novel possible mechanism of DUB deubiquitylation by other DUBs. The available data suggest the need for further experiments to validate and characterize this notion of 'Dubbing DUBs'. The current studies indicate that the idea of deubiquitylation of DUBs by other DUBs is still in its infancy. Nevertheless, future research holds the promise of validation of this concept. PMID- 28659381 TI - SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease. AB - Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran-sulfate-sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples (N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD. PMID- 28659382 TI - Domain Cell Theory supports the independent evolution of the Eukarya, Bacteria and Archaea and the Nuclear Compartment Commonality hypothesis. AB - In 2015, the Royal Society of London held a meeting to discuss the various hypotheses regarding the origin of the Eukarya. Although not all participants supported a hypothesis, the proposals that did fit into two broad categories: one group favoured 'Prokaryotes First' hypotheses and another addressed 'Eukaryotes First' hypotheses. Those who proposed Prokaryotes First hypotheses advocated either a fusion event between a bacterium and an archaeon that produced the first eukaryote or the direct evolution of the Eukarya from the Archaea. The Eukaryotes First proponents posit that the eukaryotes evolved initially and then, by reductive evolution, produced the Bacteria and Archaea. No mention was made of another previously published hypothesis termed the Nuclear Compartment Commonality (NuCom) hypothesis, which proposed the evolution of the Eukarya and Bacteria from nucleated ancestors (Staley 2013 Astrobiol Outreach1, 105 (doi:10.4172/2332-2519.1000105)). Evidence from two studies indicates that the nucleated Planctomycetes-Verrucomicrobia-Chlamydia superphylum members are the most ancient Bacteria known (Brochier & Philippe 2002 Nature417, 244 (doi:10.1038/417244a); Jun et al. 2010 Proc. Natl Acad. Sci. USA107, 133-138 (doi:10.1073/pnas.0913033107)). This review summarizes the evidence for the NuCom hypothesis and discusses how simple the NuCom hypothesis is in explaining eukaryote evolution relative to the other hypotheses. The philosophical importance of simplicity and its relationship to truth in hypotheses such as NuCom and Domain Cell Theory is presented. Domain Cell Theory is also proposed herein, which contends that each of the three cellular lineages of life, the Archaea, Bacteria and Eukarya domains, evolved independently, in support of the NuCom hypothesis. All other proposed hypotheses violate Domain Cell Theory because they posit the evolution of different cellular descendants from ancestral cellular types. PMID- 28659383 TI - Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats. AB - O-linked N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognizes its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity-signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site. PMID- 28659385 TI - CEP19 cooperates with FOP and CEP350 to drive early steps in the ciliogenesis programme. AB - Primary cilia are microtubule-based sensory organelles necessary for efficient transduction of extracellular cues. To initiate cilia formation, ciliary vesicles (CVs) are transported to the vicinity of the centrosome where they dock to the distal end of the mother centriole and fuse to initiate cilium assembly. However, to this date, the early steps in cilia formation remain incompletely understood. Here, we demonstrate functional interplay between CEP19, FOP and CEP350 in ciliogenesis. Using three-dimensional structured-illumination microscopy (3D-SIM) imaging, we mapped the relative spatial distribution of these proteins at the distal end of the mother centriole and show that CEP350/FOP act upstream of CEP19 in their recruitment hierarchy. We demonstrate that CEP19 CRISPR KO cells are severely impaired in their ability to form cilia, analogous to the loss of function of CEP19 binding partners FOP and CEP350. Notably, in the absence of CEP19 microtubule anchoring at centromes is similar in manner to its interaction partners FOP and CEP350. Using GFP-tagged deletion constructs of CEP19, we show that the C-terminus of CEP19 is required for both its localization to centrioles and for its function in ciliogenesis. Critically, this region also mediates the interaction between CEP19 and FOP/CEP350. Interestingly, a morbid-obesity associated R82* truncated mutant of CEP19 cannot ciliate nor interact with FOP and CEP350, indicative of a putative role for CEP19 in ciliopathies. Finally, analysis of CEP19 KO cells using thin-section electron microscopy revealed marked defects in the docking of CVs to the distal end of the mother centrioles. Together, these data demonstrate a role for the CEP19, FOP and CEP350 module in ciliogenesis and the possible effect of disrupting their functions in ciliopathies. PMID- 28659386 TI - Fate predetermination of cardiac myocytes during zebrafish heart regeneration. AB - Adult zebrafish have the remarkable ability to regenerate their heart upon injury, a process that involves limited dedifferentiation and proliferation of spared cardiomyocytes (CMs), and migration of their progeny. During regeneration, proliferating CMs are detected throughout the myocardium, including areas distant to the injury site, but whether all of them are able to contribute to the regenerated tissue remains unknown. Here, we developed a CM-specific, photoinducible genetic labelling system, and show that CMs labelled in embryonic hearts survive and contribute to all three (primordial, trabecular and cortical) layers of the adult zebrafish heart. Next, using this system to investigate the fate of CMs from different parts of the myocardium during regeneration, we show that only CMs immediately adjacent to the injury site contributed to the regenerated tissue. Finally, our results show an extensive predetermination of CM fate during adult heart regeneration, with cells from each myocardial layer giving rise to cells that retain their layer identity in the regenerated myocardium. Overall, our results indicate that adult heart regeneration in the zebrafish is a rather static process governed by short-range signals, in contrast to the highly dynamic plasticity of CM fates that takes place during embryonic heart regeneration. PMID- 28659387 TI - Foreign-born blacks no different from whites for odds of stroke. AB - BACKGROUND: Blacks have higher risk for stroke than whites. However, combining foreign-born and US-born blacks could mask important health differences. We examined the relationship between nativity and stroke risk in US adults. METHODS: Data were obtained from the National Health Interview Survey, 2006-2014. Study population (n=189, 409) included non-Hispanic whites and non-Hispanic blacks born in the Caribbean, and non-Hispanic blacks born in Africa. Logistic regression models were used to assess the association between stroke and race/nativity, adjusting for covariates such as insurance status, hypertension, age and duration of US residence. RESULTS: Foreign-born blacks had similar odds of stroke (95% CI 0.58 to 1.60 for non-Hispanic blacks from the Caribbean, and 95% CI 0.17 to 1.10 for blacks from Africa), while US-born blacks had increased odds of stroke (95% CI 1.22 to 1.46) compared with non-Hispanic whites. When compared with US-born blacks, both non-Hispanic blacks from the Caribbean and Africa showed reduced odds of stroke: 95% CI 0.50 to 0.94 and 95% CI 0.21 to 0.75, respectively. After adding a race/nativity * age interaction term to the model however, compared with non-Hispanic whites, blacks from Africa aged <65 years had lower odds of stroke (95% CI 0.13 to 0.72) while blacks from the Caribbean had similar odds of stroke at all ages. CONCLUSIONS: Homogenising 'Blacks' may mask important differences based on nativity. Public health prevention efforts should consider the heightened risk of stroke among younger US-born blacks and focus on primary prevention for immigrant blacks. Also, national surveys should incorporate more ethnicity-related variables. PMID- 28659384 TI - Cell signalling pathway regulation by RanBPM: molecular insights and disease implications. AB - RanBPM (Ran-binding protein M, also called RanBP9) is an evolutionarily conserved, ubiquitous protein which localizes to both nucleus and cytoplasm. RanBPM has been implicated in the regulation of a number of signalling pathways to regulate several cellular processes such as apoptosis, cell adhesion, migration as well as transcription, and plays a critical role during development. In addition, RanBPM has been shown to regulate pathways implicated in cancer and Alzheimer's disease, implying that RanBPM has important functions in both normal and pathological development. While its functions in these processes are still poorly understood, RanBPM has been identified as a component of a large complex, termed the CTLH (C-terminal to LisH) complex. The yeast homologue of this complex functions as an E3 ubiquitin ligase that targets enzymes of the gluconeogenesis pathway. While the CTLH complex E3 ubiquitin ligase activity and substrates still remain to be characterized, the high level of conservation between the complexes in yeast and mammals infers that the CTLH complex could also serve to promote the degradation of specific substrates through ubiquitination, therefore suggesting the possibility that RanBPM's various functions may be mediated through the activity of the CTLH complex. PMID- 28659388 TI - Incidence, risk factors and management of intractable diplopia. AB - AIMS: There is a paucity of literature concerning intractable diplopia. The aims of this study were to determine the incidence of intractable diplopia in the UK, identify the causes and any associated risk factors, establish how cases are managed and if the treatment is successful and tolerated. METHODS: A 1-year prospective observational study was undertaken via the British Ophthalmological Surveillance Unit (BOSU). This involved implementation of a reporting mechanism, which then triggered distribution of an incident questionnaire to explore clinical details concerning each case and a follow-up questionnaire 6 months later to explore how the case had been managed. RESULTS: The incidence of intractable diplopia was 53 cases per year. The most common preceding events were strabismus surgery (32%), no known preceding event, that is,spontaneous (25%), severe head trauma (8%), cataract surgery (6%) and vitrectomy (6%). In the at risk age group of 7 years and above, the incidence of intractable diplopia following strabismus surgery is 1 in 494 (95% CI; 1 in 296 to 790) cases. A total of nine different treatments were used in the management, with many patients receiving between two and four different methods. The overall success rate was poor, but most effective were opaque intraocular lenses (IOLs) (86%) and opaque contact lenses (50%). CONCLUSION: Intractable diplopia is a relatively rare but important condition. The main risk factor is a pre-existing strabismus, and careful counselling is needed when planning surgical correction in patients with no demonstrable binocular function. Treatment success of intractable diplopia is high when using opaque IOLs, although with additional risk, but is often disappointing via other methods where it can be difficult to eradicate the diplopia successfully. PMID- 28659389 TI - Diagnosis of Lyme-associated uveitis: value of serological testing in a tertiary centre. AB - AIMS: To determine the frequency and clinical presentation of Lyme disease in patients with uveitis and to assess the value of Borrelia burgdorferi serological testing. METHODS: Retrospective study on all patients with uveitis who were referred to our tertiary hospital were serologically tested for Lyme in our laboratory between 2003 and 2016. Screening consisted of determining B. burgdorferi serum IgG and IgM by ELISA method. The patient's serology was considered as positive if the ELISA-positive result in IgM and/or IgG was confirmed by an immunoblot positive in IgM and/or IgG. Lyme-associated uveitis was diagnosed based on serological results as well as response to antibiotics and exclusion of other diagnosis. RESULTS: Of the 430 patients with uveitis (60% women, mean age 49 years) fulfilling inclusion criteria, 63 (14.7%) had an ELISA positive serology, confirmed by immunoblot for 34 patients (7.9%). The diagnosis of Lyme-associated uveitis was finally retained in seven patients (1.6%). These patients reported either a previous exposure including tick bite or forest walks (n=5), symptoms suggestive of Lyme disease (n=5) and resistance to local and/or systemic steroids (n=7). Among the remaining 27 positive patients, 22 had other established aetiologies and 5 other were unclassified. CONCLUSION: The seroprevalence of B. burgdorferi among our patients with uveitis was 7.9% compared with 6 to 8.5% in the general French population which leads to a low predictive value of serological testing. Its use should be reserved for patients with unexplained uveitis, an exposure history, systemic findings suggestive of Lyme disease and steroids resistance. PMID- 28659390 TI - Risk of bias assessment of randomised controlled trials in high-impact ophthalmology journals and general medical journals: a systematic review. AB - Evidence-based treatments in ophthalmology are often based on the results of randomised controlled trials. Biased conclusions from randomised controlled trials may lead to inappropriate management recommendations. This systematic review investigates the prevalence of bias risk in randomised controlled trials published in high-impact ophthalmology journals and ophthalmology trials from general medical journals. Using Ovid MEDLINE, randomised controlled trials in the top 10 high-impact ophthalmology journals in 2015 were systematically identified and critically appraised for the prevalence of bias risk. Included randomised controlled trials were assessed in all domains of bias as defined by the Cochrane Collaboration. In addition, the prevalence of conflict of interest and industry sponsorship was investigated. A comparison with ophthalmology articles from high impact general medical journals was performed. Of the 259 records that were screened from ophthalmology-specific journals, 119 trials met all inclusion criteria and were critically appraised. In total, 29.4% of domains had an unclear risk, 13.8% had a high risk and 56.8% had a low risk of bias. In comparison, ophthalmology articles from general medical journals had a lower prevalence of unclear risk (17.1%), higher prevalence of high risk (21.9%) and a higher prevalence of low risk domains (61.9%). Furthermore, 64.7% of critically appraised trials from ophthalmology-specific journals did not report any conflicts of interest, while 70.6% did not report an industry sponsor of their trial. In closing, it is essential that authors, peer reviewers and readers closely follow published risk of bias guidelines. PMID- 28659391 TI - Primary enucleation for group D retinoblastoma in the era of systemic and targeted chemotherapy: the price of retaining an eye. AB - BACKGROUND: Chemotherapy is increasingly used as primary treatment for group D retinoblastoma, whereas primary enucleation is considered to have a diminishing role. This study aimed to compare the management course, including number of examinations under anaesthesia (EUAs), of group D patients treated by enucleation versus chemotherapy. METHODS: A retrospective analysis of 92 group D patients, of which 40 (37 unilateral) underwent primary enucleation and 52 (17 unilateral) were treated with intravenous chemotherapy. Number of EUAs was compared between the treatment groups with respect to the whole cohort, using univariate and multivariate analysis, and to unilateral cases only. RESULTS: Patients were followed up for a median of 61 months (mean: 66, range: 14-156), in which time primary enucleated patients had on average seven EUAs and chemotherapy-treated patients 21 EUAs (p<0.001). Chemotherapy, young age, bilateral disease, multifocal tumours, familial and germline retinoblastoma were found on univariate analysis to correlate with increased number of EUAs (p<=0.019). On multivariate analysis, however, only treatment type and presentation age were found significant (p<=0.001). On subanalysis of the unilateral cases, patients undergoing primary enucleation had in average seven EUAs, as compared with 16 in the chemotherapy group (p<0.001). Of the 55 unilateral-presenting patients, a new tumour developed in the fellow eye only in a single familial case. CONCLUSION: Group D patients' families should be counselled regarding the significant difference in number of EUAs following primary enucleation versus chemotherapy when deciding on a treatment strategy. In this regard, primary enucleation would be most beneficial for older patients with unilateral disease. PMID- 28659392 TI - Change in vision-related quality of life and influencing factors in Asians receiving treatment for neovascular age-related macular degeneration. AB - AIM: To assess the change in vision-related quality of life (VRQoL) after treatment for neovascular age-related macular degeneration (nAMD) and factors influencing this change in an Asian population. METHODS: In this longitudinal study, 116 patients (mean age+/-SD=66.5+/-9.9 years; 59.5% male) who underwent treatment for nAMD were recruited from a tertiary eye centre in Singapore. Best corrected visual acuity (BCVA) and the Impact of Vision Impairment (IVI) questionnaire were evaluated at baseline and month 12. We defined three categories of BCVA change in the treated eye: BCVA gain >=2 lines; no change in BCVA; BCVA loss >=2 lines. The main outcome measures were the Rasch-derived IVI Reading, Mobility, and Emotional Scores. Multivariable linear regression analyses assessed the influence of sociodemographic, clinical and treatment-related factors on change in VRQoL. RESULTS: Following treatment, mean treated-eye BCVA improved by almost 2 lines (-0.22+/-0.40 logMAR, p<0.001) and 43% (n=50) patients reported a gain in BCVA of >=2 lines. Mean+/-SD scores for Reading, Mobility and Emotional demonstrated positive changes of 0.43+/-1.73, 0.45+/-1.54 and 0.66+/ 1.6, respectively (p<0.001 for all). In multivariable models, a >=2 line improvement in BCVA was independently associated with a 47% (beta=0.20; CI 0.01 to 0.39) increase in Reading Scores, but was not independently associated with Mobility or Emotional Scores. CONCLUSION: Nearly half of patients undergoing treatment for nAMD reported a 2-line improvement in vision which was, in turn, associated with substantial positive increases in Reading Scores. Improvements in Mobility and Emotional Scores appear to be driven by factors other than visual acuity. PMID- 28659393 TI - Interaction between APOE-E4 and HMGB1 is associated with widespread cortical thinning in mild cognitive impairment. PMID- 28659394 TI - Pulse-wave velocity is associated with cognitive impairment in haemodialysis patients. AB - Chronic kidney disease (CKD) is common, its prevalence increasing with age. Cognitive impairment is common in the elderly, in CKD and in those on maintenance haemodialysis. As cognitive impairment is the precursor to dementia, the identification of reversible risk factors for cognitive decline is the key to reducing dementia risk. Arterial stiffness is one such potential risk factor. It is independently associated with cardiovascular outcome in dialysis patients. Importantly, the recent demonstration of an independent association between arterial stiffness and cognitive impairment in these patients suggests that vascular stiffness might be potentially causative in the development of cognitive impairment and also be an opportune target for interventions. Whether unstiffening of blood vessels in patients on maintenance haemodialysis can reduce the incidence of cognitive impairment or indeed slow its progression to dementia, remain unanswered questions. In this issue of the Clinical Science, Angermann and colleagues present thought-provoking data related to cognitive impairment in haemodialysis patients. PMID- 28659395 TI - Cellular and molecular mechanisms of asthma and COPD. AB - Asthma and chronic obstructive pulmonary disease (COPD) both cause airway obstruction and are associated with chronic inflammation of the airways. However, the nature and sites of the inflammation differ between these diseases, resulting in different pathology, clinical manifestations and response to therapy. In this review, the inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted. These differences account for the differences in clinical manifestations of asthma and COPD and their response to therapy. Although asthma and COPD are usually distinct, there are some patients who show an overlap of features, which may be explained by the coincidence of two common diseases or distinct phenotypes of each disease. It is important to better understand the underlying cellular and molecular mechanisms of asthma and COPD in order to develop new treatments in areas of unmet need, such as severe asthma, curative therapy for asthma and effective anti-inflammatory treatments for COPD. PMID- 28659396 TI - A Man with Recurrent Ascites after Laparoscopic Cholecystectomy. PMID- 28659397 TI - Commentary. PMID- 28659398 TI - Commentary. PMID- 28659399 TI - Confusing Hyperkalemia. PMID- 28659400 TI - Glistening Urine Sample from a Patient with Delirium. PMID- 28659401 TI - Electronics That Flex Themselves. PMID- 28659402 TI - An Autumn Sunset Scene in Edinburgh. PMID- 28659403 TI - Posters: Interfacing Art, Science, Commerce, and Entertainment. PMID- 28659404 TI - Heart failure - or a failure of imagination? PMID- 28659405 TI - Fish Oil Contaminated with Persistent Organic Pollutants Induces Colonic Aberrant Crypt Foci Formation and Reduces Antioxidant Enzyme Gene Expression in Rats. AB - Background: Epidemiologic, clinical, and experimental studies have suggested that fish oil (FO), a rich source of n-3 (omega-3) polyunsaturated fatty acids, protects against colon cancer. However, this message is confounded by the FDA's warning that the consumption of certain types of fish should be restricted because of contamination with persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs) and organochlorine pesticides.Objective: We examined FO contaminated with POPs (PCBs, dichlorodiphenyltrichloroethane, and chlordane) compared with unmodified FO on the risk factors of colon cancer development.Methods: Male Sprague-Dawley rats aged 28 d (n = 30) were allocated into 3 groups and fed 15% corn oil (CO), FO, or POP-contaminated FO for 9 wk with a subcutaneous injection of colon carcinogen azoxymethane at weeks 3 and 4. Colonic aberrant crypt foci (ACF) and cell proliferation were enumerated, and the gene expression of inflammation, antioxidant enzymes, and repair enzymes were determined with the use of real-time quantitative polymerase chain reaction analysis.Results: FO-fed rats had a lower number of ACF (mean +/- SE: 29 +/- 4.0 for FO compared with 53 +/- 8.4 for CO and 44 +/- 4.6 for POP FO) and higher multiplicity ACF than the CO and POP FO groups (4.7 +/- 0.9 for FO compared with 11 +/- 1.5 for CO and 9.6 +/- 1.8 for POP FO) (P < 0.05). FO feeding lowered the proliferation index compared with the CO and POP FO feeding groups (18% +/- 1.1% for FO compared with 25% +/- 1.6% for CO and 23% +/- 0.7% for POP FO) (P = 0.009). Superoxide dismutase [2.4 +/- 0.6 relative quantification (RQ) for FO compared with 1.2 +/- 0.2 RQ for CO and 1.3 +/- 0.3 RQ for POP FO] and catalase gene expression (10 +/- 2.0 RQ for FO compared with 5.4 +/- 1.1 RQ for CO and 6.6 +/- 1.5 RQ for POP FO) were higher in the FO group than in the CO and POP FO groups (P < 0.05). There were no differences between CO and POP FO on the variables.Conclusion: These results indicate that POPs in FO reduce the preventive effects of FO on colon carcinogenesis by increasing preneoplastic lesion formation through the downregulation of antioxidant enzyme expression and increasing cell proliferation in rats. PMID- 28659406 TI - Early Postnatal Diets Affect the Bioregional Small Intestine Microbiome and Ileal Metabolome in Neonatal Pigs. AB - Background: Breastfeeding is known to be protective against gastrointestinal disorders and may modify gut development. Although the gut microbiome has been implicated, little is known about how early diet affects the small intestine microbiome.Objective: We hypothesized that disparate early diets would promote unique microbial profiles in the small intestines of neonatal pigs.Methods: Male and female 2-d-old White Dutch Landrace pigs were either sow fed or provided dairy (Similac Advance powder; Ross Products Abbott Laboratories) or soy (Enfamil Prosobee Lipil powder; Mead Johnson Nutritionals) infant formulas until day 21. Bacterial ecology was assessed in the contents of the small intestine through the use of 16S ribosomal RNA sequencing. alpha-Diversity, beta-diversity, and differential abundances of operational taxonomic units were assessed by ANOVA, permutational ANOVA, and negative binomial regression, respectively. Ileum tissue metabolomics were measured by LC-mass spectrometry and assessed by weighted correlation network analysis.Results: Greater alpha-diversity was observed in the duodena of sow-fed compared with formula-fed neonatal pigs (P < 0.05). No differences were observed in the ilea. Firmicutes represented the most abundant phylum across all diets in duodena (78.8%, 80.1%, and 53.4% relative abundance in sow, dairy, and soy groups, respectively), followed by Proteobacteria in sow (12.2%) and dairy (12.4%) groups and Cyanobacteria in soy-fed (36.2%) pigs. In contrast to those in the duodenum, Proteobacteria was the dominant phylum in the ileum, with >60% relative abundance in all of the groups. In the duodenum, 77 genera were altered by diet, followed by 48 in the jejunum and 19 in the ileum. Metabolomics analyses revealed associations between ileum tissue metabolites (e.g., acylcarnitines, 3-aminoisobutyric acid) and diet-responsive microbial genera.Conclusions: These results indicate that the neonatal diet has regional effects on the small intestine microbiome in pigs, with the most pronounced effects occurring in the duodena. Regional effects may be important factors when considering gut tissue metabolism and development in the postnatal period. PMID- 28659408 TI - The Nitrogen Moieties of Dietary Nonessential Amino Acids Are Distinctively Metabolized in the Gut and Distributed to the Circulation in Rats. AB - Background: Although previous growth studies in rodents have indicated the importance of dietary nonessential amino acids (NEAAs) as nitrogen sources, individual NEAAs have different growth-promoting activities. This phenomenon might be attributable to differences in the nitrogen metabolism of individual NEAAs. Objective: The aim of this study was to compare nitrogen metabolism across dietary NEAAs with the use of their 15N isotopologues.Methods: Male Fischer rats (8 wk old) were given 1.0 g amino acid-defined diets containing either 15N labeled glutamate, glutamine (amino or amide), aspartate, alanine, proline, glycine, or serine hourly for 5-6 h. Then, steady-state amino acid concentrations and their 15N enrichments in the gut and in portal and arterial plasma were measured by an amino acid analyzer and LC tandem mass spectrometry, respectively.Results: The intestinal 15N distribution and portal-arterial balance of 15N metabolites indicated that most dietary glutamate nitrogen (>90% of dietary input) was incorporated into various amino acids, including alanine, proline, and citrulline, in the gut. Dietary aspartate nitrogen, alanine nitrogen, and amino nitrogen of glutamine were distributed similarly to other amino acids both in the gut and in the circulation. In contrast, incorporation of the nitrogen moieties of dietary proline, serine, and glycine into other amino acids was less than that of other NEAAs, although interconversion between serine and glycine was very active. Cluster analysis of 15N enrichment data also indicated that dietary glutamate nitrogen, aspartate nitrogen, alanine nitrogen, and the amino nitrogen of glutamine were distributed similarly to intestinal and circulating amino acids. Further, the analysis revealed close relations between intestinal and arterial 15N enrichment for each amino acid. The steady-state 15N enrichment of arterial amino acids indicated that substantial amounts of circulating amino acid nitrogen are derived from dietary NEAAs.Conclusions: The present results revealed similarities and differences among NEAAs in terms of their intestinal nitrogen metabolism in rats and indicated substantial entry of dietary NEAA nitrogen into circulating amino acid nitrogen, presumably primarily through metabolism in the gut. PMID- 28659407 TI - An Empirical Dietary Inflammatory Pattern Score Enhances Prediction of Circulating Inflammatory Biomarkers in Adults. AB - Background: Two indexes exist to describe dietary inflammatory potential: an empirical dietary inflammatory pattern (EDIP) composed of food groups as reported on a food-frequency questionnaire (FFQ) and a literature-derived dietary inflammatory index (DII) composed mainly of nutrients.Objective: We compared the ability of the 2 indexes to predict concentrations of inflammatory markers and hypothesized that the EDIP would be more predictive because it was derived on the basis of circulating inflammatory markers.Methods: Both EDIP and DII scores were calculated from FFQ data reported by 5826 women in the Nurses' Health Study II and 5227 men in the Health Professionals Follow-Up Study. We used multivariable adjusted linear regression analyses to calculate relative differences in concentrations of 4 plasma inflammatory markers-C-reactive protein (CRP; milligrams per liter), interleukin 6 (IL-6; picograms per milliliter), tumor necrosis factor alpha receptor 2 (TNFalphaR2; picograms per milliliter), and adiponectin (nanograms per milliliter)-in quintiles of the dietary indexes.Results: Spearman correlations between the EDIP and DII scores were modest (r = 0.29 and 0.21 for women and men, respectively; all P < 0.0001). Higher scores on both dietary indexes were associated with higher concentrations of inflammatory markers, although they were associated with lower adiponectin concentrations and there was no association between the DII and adiponectin in men. For example, percentage differences in concentrations of biomarkers in quintile 5 generally were higher (lower for adiponectin) than in quintile 1 (for the EDIP and DII, respectively-women: CRP, +60% and +49%; IL-6, +23% and +21%; TNFalphaR2, +7% and +4%; adiponectin, -21% and -14%; men: CRP, +38% and +29%; IL 6, +14% and +24%; TNFalphaR2, +9% and +5%; adiponectin, -16% and -4%.)Conclusion: Despite design differences, the EDIP and DII both assess dietary inflammatory potential in men and women, with the EDIP showing a greater ability to predict concentrations of plasma inflammatory markers. PMID- 28659409 TI - Prevalence of Mycobacterium avium subspecies paratuberculosis and hepatitis E in New World camelids in Austria. AB - Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent ofparatuberculosis in domestic ruminants and New World Camelids (NWC). Hepatitis E virus(HEV) is an important public health concern worldwide. The virus has been identified inseveral species, some of them serving as a reservoir for zoonotic HEV strains. Husbandry andbreeding of llamas and alpacas have increased in Austria in recent years. Therefore, the aimof the present study was to evaluate the prevalence of MAP and HEV in NWC in Austria.Altogether 445 animals, originating from 78 farms were enrolled in the study. Of the animalssampled, 184 (41.35%) were llamas and 261 (58.65%) were alpacas. 443 blood samples forMAP ELISA and 399 faecal samples for quantitative PCR (qPCR) and culture for MAP as well asfor HEV detection by RT-qPCR have been collected. All of the 399 animals tested for sheddingof MAP were negative by faecal solid culture. Using qPCR, 15 (3.8%) of the animals wereMAP positive and 384 (96.2%) negative. Out of the 443 serum samples examined for specificantibodies against MAP by ELISA, 6 (1.4%) were positive, 1 (0.2%) was questionable and 436(98.4%) samples were negative. All faecal samples were tested negative for HEV. PMID- 28659410 TI - Addressing current challenges in cancer immunotherapy with mathematical and computational modelling. AB - The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development. PMID- 28659411 TI - Leaping lizards landing on leaves: escape-induced jumps in the rainforest canopy challenge the adhesive limits of geckos. AB - The remarkable adhesive capabilities of geckos have garnered attention from scientists and the public for centuries. Geckos are known to have an adhesive load-bearing capacity far in excess (by 100-fold or more) of that required to support their body mass or accommodate the loading imparted during maximal locomotor acceleration. Few studies, however, have investigated the ecological contexts in which geckos use their adhesive system and how this may influence its properties. Here we develop a modelling framework to assess whether their prodigious adhesive capacity ever comes under selective challenge. Our investigation is based upon observations of escape-induced aerial descents of canopy-dwelling arboreal geckos that are rapidly arrested by clinging to leaf surfaces in mid-fall. We integrate ecological observations, adhesive force measurements, and body size and shape measurements of museum specimens to conduct simulations. Using predicted bending mechanics of petioles and leaf midribs, we find that the drag coefficient of the gecko, the size of the gecko and the size of the leaf determine impact forces. Regardless of the landing surface, safety factors for geckos range from a maximum of just over 10 to a minimum of well under one, which would be the point at which the adhesive system fails. In contrast to previous research that intimates that gecko frictional adhesive capacity is excessive relative to body mass, we demonstrate that realistic conditions in nature may result in frictional capacity being pushed to its limit. The rapid arrest of the lizard from its falling velocity likely results in the maximal loading to which the adhesive system is exposed during normal activities. We suggest that such activities might be primary determinants in driving their high frictional adhesive capacity. PMID- 28659412 TI - Uncovering the underlying mechanism of cancer tumorigenesis and development under an immune microenvironment from global quantification of the landscape. AB - The study of the cancer-immune system is important for understanding tumorigenesis and the development of cancer and immunotherapy. In this work, we build a comprehensive cancer-immune model including both cells and cytokines to uncover the underlying mechanism of cancer immunity based on landscape topography. We quantify three steady-state attractors, normal state, low cancer state and high cancer state, for the innate immunity and adaptive immunity of cancer. We also illustrate the cardinal inhibiting cancer immunity interactions and promoting cancer immunity interactions through global sensitivity analysis. We simulate tumorigenesis and the development of cancer and classify these into six stages. The characteristics of the six stages can be classified further into three groups. These correspond to the escape, elimination and equilibrium phases in immunoediting, respectively. Under specific cell-cell interactions strength oscillations emerge. We found that tumorigenesis and cancer recovery processes may need to go through cancer-immune oscillation, which consumes more energy. Based on the cancer-immune landscape, we predict three types of cells and two types of cytokines for cancer immunotherapy as well as combination immunotherapy. This landscape framework provides a quantitative way to understand the underlying mechanisms of the interplay between cancer and the immune system for cancer tumorigenesis and development. PMID- 28659413 TI - Modelling the spread of innovation in wild birds. AB - We apply three plausible algorithms in agent-based computer simulations to recent experiments on social learning in wild birds. Although some of the phenomena are simulated by all three learning algorithms, several manifestations of social conformity bias are simulated by only the approximate majority (AM) algorithm, which has roots in chemistry, molecular biology and theoretical computer science. The simulations generate testable predictions and provide several explanatory insights into the diffusion of innovation through a population. The AM algorithm's success raises the possibility of its usefulness in studying group dynamics more generally, in several different scientific domains. Our differential-equation model matches simulation results and provides mathematical insights into the dynamics of these algorithms. PMID- 28659414 TI - How do prosthetic stiffness, height and running speed affect the biomechanics of athletes with bilateral transtibial amputations? AB - Limited available information describes how running-specific prostheses and running speed affect the biomechanics of athletes with bilateral transtibial amputations. Accordingly, we quantified the effects of prosthetic stiffness, height and speed on the biomechanics of five athletes with bilateral transtibial amputations during treadmill running. Each athlete performed a set of running trials with 15 different prosthetic model, stiffness and height combinations. Each set of trials began with the athlete running on a force-measuring treadmill at 3 m s-1, subsequent trials incremented by 1 m s-1 until they achieved their fastest attainable speed. We collected ground reaction forces (GRFs) during each trial. Prosthetic stiffness, height and running speed each affected biomechanics. Specifically, with stiffer prostheses, athletes exhibited greater peak and stance average vertical GRFs (beta = 0.03; p < 0.001), increased overall leg stiffness (beta = 0.21; p < 0.001), decreased ground contact time (beta = -0.07; p < 0.001) and increased step frequency (beta = 0.042; p < 0.001). Prosthetic height inversely associated with step frequency (beta = -0.021; p < 0.001). Running speed inversely associated with leg stiffness (beta = -0.58; p < 0.001). Moreover, at faster running speeds, the effect of prosthetic stiffness and height on biomechanics was mitigated and unchanged, respectively. Thus, prosthetic stiffness, but not height, likely influences distance running performance more than sprinting performance for athletes with bilateral transtibial amputations. PMID- 28659415 TI - Single-molecule imaging of the BAR-domain protein Pil1p reveals filament-end dynamics. AB - Molecular assemblies can have highly heterogeneous dynamics within the cell, but the limitations of conventional fluorescence microscopy can mask nanometer-scale features. Here we adapt a single-molecule strategy to perform single-molecule recovery after photobleaching (SRAP) within dense macromolecular assemblies to reveal and characterize binding and unbinding dynamics within such assemblies. We applied this method to study the eisosome, a stable assembly of BAR-domain proteins on the cytoplasmic face of the plasma membrane in fungi. By fluorescently labeling only a small fraction of cellular Pil1p, the main eisosome BAR-domain protein in fission yeast, we visualized whole eisosomes and, after photobleaching, localized recruitment of new Pil1p molecules with ~30-nm precision. Comparing our data to computer simulations, we show that Pil1p exchange occurs specifically at eisosome ends and not along their core, supporting a new model of the eisosome as a dynamic filament. This result is the first direct observation of any BAR-domain protein dynamics in vivo under physiological conditions consistent with the oligomeric filaments reported from in vitro experiments. PMID- 28659417 TI - Human adipose stem cells induced to osteogenic differentiation by an innovative collagen/hydroxylapatite hybrid scaffold. AB - Novel biomaterials are of paramount importance for bone regrowth. In this study, we investigated human adipose stem cells (hASCs) for osteogenic, osteoconductivity, and osteoinductivity effects of an innovative collagen/hydroxylapatite hybrid scaffold. In hASCs that were grown on this scaffold, osteogenic genes were analyzed for their expression profiles, together with adhesion and extracellular matrix genes. In hASC integrins, basement membrane constituents and collagens were up-regulated, together with cell proliferation. In addition, expression of osteopontin and activated focal adhesion kinase was studied at the protein level. Our in vitro data indicate that hASCs, together with hybrid biomaterial, is an important model of study to investigate in vitro bone induction.-Mazzoni, E., D'Agostino, A., Manfrini, M., Maniero, S., Puozzo, A., Bassi, E., Marsico, S., Fortini, C., Trevisiol, L., Patergnani, S., Tognon, M. Human adipose stem cells induced to osteogenic differentiation by an innovative collagen/hydroxylapatite hybrid scaffold. PMID- 28659416 TI - Haspin inhibition reveals functional differences of interchromatid axis-localized AURKB and AURKC. AB - Aneuploidy is the leading genetic abnormality contributing to infertility, and chromosome segregation errors are common during female mammalian meiosis I (MI). Previous results indicate that haspin kinase regulates resumption of meiosis from prophase arrest, chromosome condensation, and kinetochore-microtubule attachments during early prometaphase of MI. Here we report that haspin inhibition in late prometaphase I causes acceleration of MI, bypass of the spindle assembly checkpoint (SAC), and loss of interchromatid axis-localized Aurora kinase C. Meiotic cells contain a second chromosomal passenger complex (CPC) population, with Aurora kinase B (AURKB) bound to INCENP. Haspin inhibition in oocytes from Aurkc-/- mice, where AURKB is the sole CPC kinase, does not alter MI completion timing, and no change in localization of the SAC protein, MAD2, is observed. These data suggest that AURKB on the interchromatid axis is not needed for SAC activation and illustrate a key difference between the functional capacities of the two AURK homologues. PMID- 28659418 TI - Perception of animacy in dogs and humans. AB - Humans have a tendency to perceive inanimate objects as animate based on simple motion cues. Although animacy is considered as a complex cognitive property, this recognition seems to be spontaneous. Researchers have found that young human infants discriminate between dependent and independent movement patterns. However, quick visual perception of animate entities may be crucial to non-human species as well. Based on general mammalian homology, dogs may possess similar skills to humans. Here, we investigated whether dogs and humans discriminate similarly between dependent and independent motion patterns performed by geometric shapes. We projected a side-by-side video display of the two patterns and measured looking times towards each side, in two trials. We found that in Trial 1, both dogs and humans were equally interested in the two patterns, but in Trial 2 of both species, looking times towards the dependent pattern decreased, whereas they increased towards the independent pattern. We argue that dogs and humans spontaneously recognized the specific pattern and habituated to it rapidly, but continued to show interest in the 'puzzling' pattern. This suggests that both species tend to recognize inanimate agents as animate relying solely on their motions. PMID- 28659420 TI - Comment: Does patient sex affect decision-making after hemorrhagic stroke? PMID- 28659419 TI - Aggressiveness of care following intracerebral hemorrhage in women and men. AB - OBJECTIVE: To compare comorbidities and use of surgery and palliative care between men and women with intracerebral hemorrhage (ICH). METHODS: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter, case-control study of ICH risk factors and outcomes. We compared comorbidities, treatments, and use of do-not-resuscitate (DNR) orders in men vs women. Multivariate analysis was used to assess the likelihood of ICH surgery and palliative care after adjustment for variables that were p < 0.1 in univariate analyses and backward elimination to retain those that were significant (p < 0.05). RESULTS: Women were older on average (65.0 vs 59.9, p < 0.0001), and higher proportions of women had previous stroke (24.1% vs 19.3%, p = 0.002), had dementia (6.1% vs 3.4%, p = 0.0007), lived alone (23.1% vs 18.0%, p = 0.0005), and took anticoagulants (12.8% vs 10.1% p = 0.02), compared with men. Men had higher rates of alcohol and cocaine use. After adjusting for age, hematoma volume, and ICH location, there was no difference in rates of surgical treatment by sex (odds ratio [OR] 0.93 for men vs women, 95% confidence interval [CI] 0.68-1.28, p = 0.67), and there was no difference in DNR/comfort care decisions after adjustment for ICH score, prior stroke, and dementia (OR 0.96, CI 0.77-1.22, p = 0.76). CONCLUSIONS: After ICH, women do not receive less aggressive care than men after controlling for the substantial comorbidity differences. Future studies on sex bias should include the presence of comorbidities, prestroke disability, and other factors that may influence management. PMID- 28659422 TI - Adolescent weight gain confers long-term increased stroke risk: Weighty matters. PMID- 28659421 TI - Slowing gait and risk for cognitive impairment: The hippocampus as a shared neural substrate. AB - OBJECTIVE: To identify the shared neuroimaging signature of gait slowing and cognitive impairment. METHODS: We assessed a cohort of older adults (n = 175, mean age 73 years, 57% female, 65% white) with repeated measures of gait speed over 14 years, MRI for gray matter volume (GMV) at year 10 or 11, and adjudicated cognitive status at year 14. Gait slowing was calculated by bayesian slopes corrected for intercepts, with higher values indicating faster decline. GMV was normalized to intracranial volume, with lower values indicating greater atrophy for 10 regions of interest (hippocampus, anterior and posterior cingulate, primary and supplementary motor cortices, posterior parietal lobe, middle frontal lobe, caudate, putamen, pallidum). Nonparametric correlations adjusted for demographics, comorbidities, muscle strength, and knee pain assessed associations of time to walk with GMV. Logistic regression models calculated odds ratios (ORs) of gait slowing with dementia or mild cognitive impairment with and without adjustment for GMV. RESULTS: Gait slowing was associated with cognitive impairment at year 14 (OR per 0.1 s/y slowing 1.47; 95% confidence interval 1.04 2.07). The right hippocampus was the only region that was related to both gait slowing (rho = -0.16, p = 0.03) and cognitive impairment (OR 0.17, p = 0.009). Adjustment for right hippocampal volume attenuated the association of gait slowing with cognitive impairment by 23%. CONCLUSIONS: The association between gait slowing and cognitive impairment is supported by a shared neural substrate that includes a smaller right hippocampus. This finding underscores the value of long-term gait slowing as an early indicator of dementia risk. PMID- 28659424 TI - Improving practice through neurovascular board. PMID- 28659423 TI - BMI increase through puberty and adolescence is associated with risk of adult stroke. AB - OBJECTIVE: To evaluate the contribution of prepubertal childhood body mass index (BMI) and BMI change through puberty and adolescence, 2 distinct developmental BMI parameters, for risk of adult stroke in men. METHODS: In this population based study in Gothenburg, Sweden, men born in 1945-1961 with information on both childhood BMI at age 8 and BMI change through puberty and adolescence (BMI at age 20-BMI at age 8) were followed until December 2013 (n = 37,669). Information on stroke events was retrieved from high-quality national registers (918 first stroke events, 672 ischemic stroke events [IS], 207 intracerebral hemorrhage events [ICH]). RESULTS: BMI increase through puberty and adolescence (hazard ratio [HR] 1.21 per SD increase; 95% confidence interval [CI] 1.14-1.28), but not childhood BMI, was independently associated with risk of adult stroke. Subanalyses revealed that BMI increase through puberty and adolescence was associated with both IS (HR per SD increase 1.19; 95% CI 1.11-1.28) and ICH (HR per SD increase 1.29; 95% CI 1.15-1.46). High BMI increase during puberty was strongly associated with increased risk of adult hypertension (odds ratio per SD increase 1.35; 95% CI 1.32-1.39). CONCLUSIONS: BMI increase through puberty and adolescence is associated with risk of adult IS and ICH in men. We propose that greater BMI increases during puberty contribute to increased risk of adult stroke at least partly via increased blood pressure. PMID- 28659425 TI - Missed diagnosis of prehospital status epilepticus: Is it serious, doctor? PMID- 28659426 TI - Emergency response to out-of-hospital status epilepticus: A 10-year observational cohort study. AB - OBJECTIVE: To determine the implications of first responses of emergency medical services (EMS) to out-of-hospital status epilepticus (SE) on outcome. METHODS: From 2005 to 2014, prehospital and in-hospital data were assessed in consecutive adults admitted to an academic medical center with out-of-hospital SE. Logistic regression was performed to identify variables with a robust association between missed epileptic events by the EMS and no recovery to functional baseline in survivors. RESULTS: Among 213 SE patients, 150 were admitted via EMS. While nonconvulsive SE (NCSE) was missed by the EMS in 63.7%, convulsive SE (CSE) was not missed except in 4 patients with transformation into subtle SE. Missed NCSE was more likely with older age (odds ratio [OR]per year 1.06, 95% confidence interval [CI] 1.02-1.10, p = 0.003) and no seizure history (OR 6.64, 95% CI 2.43 18.1, p < 0.001). The area under the receiver operating characteristic curve for prediction of missed NCSE by these variables was 0.839. Independent predictors for not receiving benzodiazepines were increasing age (ORper year 1.05, 95% CI 1.01-1.08, p = 0.008) and higher Glasgow Coma Scale score (ORper increasing unit 1.21, 95% CI 1.09-1.36, p = 0.001). Missed NCSE was independently associated with increased odds for no return to functional baseline in survivors (OR 3.83, 95% CI 1.22-11.98, p = 0.021). CONCLUSIONS: Among patients admitted with out-of-hospital SE, CSE is mostly recognized while NCSE is frequently missed especially in patients with increasing age and no seizure history. This calls for heightened awareness for out-of-hospital NCSE in such patients, as missed NCSE is associated with lack of treatment and less recovery to functional baseline in survivors independent of established outcome predictors. PMID- 28659427 TI - Effects of increasing IV tPA-treated stroke mimic rates at CT-based centers on clinical outcomes. AB - OBJECTIVE: To determine to what degree stroke mimics skew clinical outcomes and the potential effects of incorrect stroke diagnosis. METHODS: This retrospective analysis of data from 2005 to 2014 included IV tissue plasminogen activator (tPA) treated adults with clinical suspicion for acute ischemic stroke who were transferred or admitted directly to our 2 hub hospitals. Primary outcome measures compared CT-based spoke hospitals' and MRI-based hub hospitals' mimic rates, hemorrhagic transformation, follow-up modified Rankin Scale (mRS), and discharge disposition. Secondary outcomes were compared over time. RESULTS: Of the 725 thrombolysis-treated patients, 29% were at spoke hospitals and 71% at hubs. Spoke hospital patients differed from hubs by age (mean 62 +/- 15 vs 72 +/- 15 years, p < 0.0001), risk factors (atrial fibrillation, 17% vs 32%, p < 0.0001; alcohol consumption, 9% vs 4%, p = 0.007; smoking, 23% vs 13%, p = 0.001), and mimics (16% vs 0.6%, p < 0.0001). Inclusion of mimics resulted in better outcomes for spokes vs hubs by mRS <=1 (40% vs 27%, p = 0.002), parenchymal hematoma type 2 (3% vs 7%, p = 0.037), and discharge home (47% vs 37%, p = 0.01). Excluding mimics, there were no significant differences. Comparing epochs, spoke stroke mimic rate doubled (9%-20%, p = 0.03); hub rate was unchanged (0%-1%, p = 0.175). CONCLUSIONS: Thrombolysis of stroke mimics is increasing at our CT-based spoke hospitals and not at our MRI-based hub hospitals. Caution should be used in interpreting clinical outcomes based on large stroke databases when stroke diagnosis at discharge is unclear. Inadvertent reporting of treated stroke mimics as strokes will artificially elevate overall favorable clinical outcomes with additional downstream costs to patients and the health care system. PMID- 28659428 TI - Real-world experience of treatment decision-making in carotid stenosis in a neurovascular board. AB - OBJECTIVE: To describe our experience with consensus-based decision-making for treatment of internal carotid artery (ICA) stenosis by neurologists, interventional neuroradiologists, vascular surgeons, and neurosurgeons in a multidisciplinary neurovascular board and to study adherence to treatment recommendations in the context of uncertainty with respect to the best treatment option. METHODS: We established a multidisciplinary neurovascular board meeting twice a week with structured documentation of consensus decisions. Over a time period of 53 months, 614 cases with ICA stenosis were discussed, with 285 (46%) symptomatic and 279 (45%) asymptomatic cases. RESULTS: Recommendation for symptomatic ICA stenosis was revascularization in 76%, medical management alone in 8%, and further diagnostics in 16%. For asymptomatic ICA stenosis, recommendation was randomization in a clinical trial in 29%, revascularization in 27%, medical management alone in 23%, and further diagnostics in 22%. Treatment recommendations were followed in 94% of symptomatic ICA stenosis and 69% of asymptomatic ICA stenosis. Patients in whom carotid artery stenting was recommended for revascularization were younger and showed a higher rate of severe (>=70%) ICA stenosis. CONCLUSIONS: Interdisciplinary board decisions are a helpful and transparent tool to assure adherence to guideline recommendations, and to provide consensus-based individualized treatment strategies in clinical practice in the absence of unequivocal evidence. PMID- 28659430 TI - Upgoing thumb sign: A sensitive indicator of brain involvement? AB - OBJECTIVE: To assess the frequency of this finding in patients with minor stroke and TIAs compared to those with stroke mimics and to evaluate the level of agreement between examiners to detect an upgoing thumb sign. METHODS: We previously reported an upgoing thumb sign as a subtle clinical finding in patients with transient ischemic attacks or minor stroke. In this study conducted between March 2016 and October 2016 at the Stroke Prevention Clinic at University Hospital, University of Western Ontario, London, Canada, participants were examined independently by stroke faculty and fellows who were blinded to each other's findings. The frequency of the upgoing thumb sign in patients with minor or threatened stroke was compared to that in patients with stroke mimics, and the level of agreement between examiners and clinical findings was assessed with the Cohen kappa test. RESULTS: The upgoing thumb sign was observed more frequently in those with minor stroke/TIA than in those with stroke mimics (p = 0.001). A substantial level of agreement between examiners was recorded in the detection of the thumb sign (kappa: right 0.71, left 0.78). In addition, an upgoing thumb sign showed a substantial level of agreement with the patient's symptoms (examiner 1: kappa = 0.65, p < 0.01; examiner 2: kappa = 0.64; p < 0.01). CONCLUSIONS: An upgoing thumb sign is a sensitive and reliable indicator of brain involvement. This examination is noninvasive, easy, reliable, and highly compatible with and confirmatory of the patient's symptoms. PMID- 28659429 TI - Permanent CSF shunting after intraventricular hemorrhage in the CLEAR III trial. AB - OBJECTIVE: To study factors associated with permanent CSF diversion and the relationship between shunting and functional outcomes in spontaneous intraventricular hemorrhage (IVH). METHODS: Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III), a randomized, multicenter, double-blind, placebo-controlled trial, was conducted to determine if pragmatically employed external ventricular drainage (EVD) plus intraventricular alteplase improved outcome, in comparison to EVD plus saline. Outcome measures were predictors of shunting and blinded assessment of mortality and modified Rankin Scale at 180 days. RESULTS: Among the 500 patients with IVH, CSF shunting was performed in 90 (18%) patients at a median of 18 (interquartile range [IQR] 13-30) days. Patient demographics and IVH characteristics were similar among patients with and without shunts. In the multivariate analysis, black race (odds ratio [OR] 1.98; 95% confidence interval [CI] 1.18-3.34), duration of EVD (OR 1.10; CI 1.05-1.15), placement of more than one EVD (OR 1.93; CI 1.13-3.31), daily drainage CSF per 10 mL (OR 1.07; CI 1.04-1.10), and intracranial pressure >30 mm Hg (OR 1.70; CI 1.09-2.88) were associated with higher odds of permanent CSF shunting. Patients who had CSF shunts had similar odds of 180-day mortality, while survivors with shunts had increased odds of poor functional outcome, compared to survivors without shunts. CONCLUSIONS: Among patients with spontaneous IVH requiring emergency CSF diversion, those with early elevated intracranial pressure, high CSF output, and placement of more than one EVD are at increased odds of permanent ventricular shunting. Administration of intraventricular alteplase, early radiographic findings, and CSF measures were not useful predictors of permanent CSF diversion. PMID- 28659431 TI - Odor identification as a biomarker of preclinical AD in older adults at risk. AB - OBJECTIVE: To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia. METHODS: In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with beta-amyloid (Abeta1-42). Adjusted analyses considered age, cognition, APOE epsilon4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models. RESULTS: Reduced OI was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau and P181-tau to Abeta1-42 (all p < 0.02). However, the observed associations of OI with age and cognition were unapparent in adjusted models that restricted observations to CSF donors and included AD biomarkers. OI showed little association with CSF Abeta1-42 alone except in APOE epsilon4 carriers having lowest-quartile Abeta1-42 levels. CONCLUSIONS: These findings from healthy high-risk older individuals suggest that OI reflects degree of preclinical AD pathology, while its relationships with age and cognition result from the association of these latter variables with such pathology. Diminished OI may be a practical and affordable biomarker of AD pathology. PMID- 28659433 TI - Effect of communication skills training on outcomes in critically ill patients with life-limiting illness referred for intensive care management: a before-and after study. AB - OBJECTIVES: To describe the effect of a communication skills training programme on patient-centred goals of care documentation and clinical outcomes in critically ill patients with life-limiting illnesses (LLI) referred for intensive care management. METHODS: Prospective before-and-after cohort study in a tertiary teaching hospital in Australia. The population was 222 adult patients with LLI referred to the intensive care unit (ICU). The study was divided into two periods, before (1 May to 31 July 2015) and after (15 September to 15December 2015) the intervention. The intervention was a 2-day, small group, simulated patient, communication skills course, and process of care for patients with LLI. The primary outcome was documentation of patient-centred goals of care discussion (PCD) within 48 hours of referral to the ICU. Secondary outcomes included clinical outcomes and 90-day mortality. RESULTS: The intervention was associated with increased documentation of a PCD from 50% to 69% (p=0.004) and 43% to 94% (p<0.0001) in patients deceased by day 90. A significant decrease in critical care as the choice of resuscitation goal (61% vs 42%, p=0.02) was observed. Although there was no decrease in admission to ICU, there was a significant decrease in medical emergency team call prevalence (87% vs 73%, p=0.009). The cancer and organ failure groups had a significant decrease in 90-day mortality (75% vs 44%, p=0.02; 42% vs 16%, p=0.01), and the frailty group had a significant decrease in 90-day readmissions (48% vs 19%, p=0.003). CONCLUSIONS: The intervention was associated with increased PCD documentation and decrease in the choice of critical care as the resuscitation goal. Admissions to ICU did not decrease, and although limited by study design, condition-specific trajectory changes, clinical interventions and outcomes warrant further study. PMID- 28659434 TI - Responding to the public's voice: changing cornea donation practice in a hospice. PMID- 28659432 TI - A Novel Theranostic Strategy for MMP-14-Expressing Glioblastomas Impacts Survival. AB - Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM-initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP 14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of MMP 14-expressing GBM, induced GIC apoptosis, and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled in vivo drug tracking with MR imaging. Treatment with CLIO-ICT plus temozolomide achieved tumor remission and significantly increased survival of human GBM-bearing mice by more than 2 fold compared with treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation. Mol Cancer Ther; 16(9); 1909-21. (c)2017 AACR. PMID- 28659435 TI - Highly Accurate Detection of Cancer In Situ with Intraoperative, Label-Free, Multimodal Optical Spectroscopy. AB - Effectiveness of surgery as a cancer treatment is reduced when all cancer cells are not detected during surgery, leading to recurrences that negatively impact survival. To maximize cancer cell detection during cancer surgery, we designed an in situ intraoperative, label-free, optical cancer detection system that combines intrinsic fluorescence spectroscopy, diffuse reflectance spectroscopy, and Raman spectroscopy. Using this multimodal optical cancer detection system, we found that brain, lung, colon, and skin cancers could be detected in situ during surgery with an accuracy, sensitivity, and specificity of 97%, 100%, and 93%, respectively. This highly sensitive optical molecular imaging approach can profoundly impact a wide range of surgical and noninvasive interventional oncology procedures by improving cancer detection capabilities, thereby reducing cancer burden and improving survival and quality of life. Cancer Res; 77(14); 3942-50. (c)2017 AACR. PMID- 28659436 TI - Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. AB - Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naive human populations throughout the globe. Broad spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future. PMID- 28659437 TI - Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-beta. AB - Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-gamma (IFN-gamma) signature. Conversely, IFN-gamma-deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-beta (TGF-beta) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-beta and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-beta alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLD collaboratively with TGF-beta in the liver. PMID- 28659439 TI - Fortifying the BBB: Border control by increasing regulators. AB - Treatment with exogenous regulatory T cells fortifies the blood-brain barrier after tissue plasminogen activator therapy in models of acute ischemic stroke. PMID- 28659440 TI - Surf's up for ER stress. AB - A new type of biological clock regulates the unfolded protein response. PMID- 28659438 TI - Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice. AB - LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is the most frequent form of early-onset, fatal congenital muscular dystrophies. It is caused by mutations in LAMA2, the gene encoding laminin-alpha2, the long arm of the heterotrimeric (alpha2, beta1, and gamma1) basement membrane protein laminin-211 (Lm-211). We establish that despite compensatory expression of laminin-alpha4, giving rise to Lm-411 (alpha4, beta1, and gamma1), muscle basement membrane is labile in LAMA2 MD biopsies. Consistent with this deficit, recombinant Lm-411 polymerized and bound to cultured myotubes only weakly. Polymerization and cell binding of Lm-411 were enhanced by addition of two specifically designed linker proteins. One, called alphaLNNd, consists of the N-terminal part of laminin-alpha1 and the laminin-binding site of nidogen-1. The second, called mini-agrin (mag), contains binding sites for laminins and alpha-dystroglycan. Transgenic expression of mag and alphaLNNd in a mouse model for LAMA2 MD fully restored basement membrane stability, recovered muscle force and size, increased overall body weight, and extended life span more than five times to a maximum survival beyond 2 years. These findings provide a mechanistic understanding of LAMA2 MD and establish a strong basis for a potential treatment. PMID- 28659441 TI - Epigenetics make transient states of cancer therapy resistance permanent. AB - Resistance to targeted cancer therapies is mediated by stabilization of transient insensitive states. PMID- 28659442 TI - Strengthening brittle bones. AB - Decreased WNT1 signaling weakens bones but is partially reversed by blocking the WNT1 inhibitory regulator sclerostin. PMID- 28659444 TI - Positive First Trial of Enasidenib for AML. AB - The first clinical trial of the investigational drug enasidenib, which targets IDH2 mutations, suggests that it is safe and may improve survival in patients with relapsed or refractory acute myeloid leukemia. It induced responses in 40.3% of patients, yielding a median overall survival of 9.3 months. PMID- 28659445 TI - Body, Make Thy Own Bispecific Antibody. AB - Synthetic mRNA that's been optimized, modified, and formulated to spur the production of bispecific antibodies in the liver can eradicate large tumors in mice. The strategy circumvents some of the manufacturing challenges associated with conventional antibody production and creates a therapeutic that's easier and more convenient to administer. PMID- 28659443 TI - Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. AB - Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2 Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of function mutation (EZH2Y641X ). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies. PMID- 28659446 TI - A comprehensive allometric analysis of 2nd digit length to 4th digit length in humans. AB - It has been widely reported that men have a lower ratio of the 2nd and 4th human finger lengths (2D : 4D). Size-scaling ratios, however, have the seldom appreciated potential for providing biased estimates. Using an information theoretic approach, we compared 12 candidate models, with different assumptions and error structures, for scaling untransformed 2D to 4D lengths from 154 men and 262 women. In each hand, the two-parameter power function and the straight line with intercept models, both with normal, homoscedastic error, were superior to the other models and essentially equivalent to each other for normalizing 2D to 4D lengths. The conventional 2D : 4D ratio biased relative 2D length low for the generally bigger hands of men, and vice versa for women, thereby leading to an artefactual indication that mean relative 2D length is lower in men than women. Conversely, use of the more appropriate allometric or linear regression models revealed that mean relative 2D length was, in fact, greater in men than women. We conclude that 2D does not vary in direct proportion to 4D for both men and women, rendering the use of the simple 2D : 4D ratio inappropriate for size-scaling purposes and intergroup comparisons. PMID- 28659447 TI - Unravelling the relationship between the tsetse fly and its obligate symbiont Wigglesworthia: transcriptomic and metabolomic landscapes reveal highly integrated physiological networks. AB - Insects with restricted diets rely on obligate microbes to fulfil nutritional requirements essential for biological function. Tsetse flies, vectors of African trypanosome parasites, feed exclusively on vertebrate blood and harbour the obligate endosymbiont Wigglesworthia glossinidia. Without Wigglesworthia, tsetse are unable to reproduce. These symbionts are sheltered within specialized cells (bacteriocytes) that form the midgut-associated bacteriome organ. To decipher the core functions of this symbiosis essential for tsetse's survival, we performed dual-RNA-seq analysis of the bacteriome, coupled with metabolomic analysis of bacteriome and haemolymph collected from normal and symbiont-cured (sterile) females. Bacteriocytes produce immune regulatory peptidoglycan recognition protein (pgrp-lb) that protects Wigglesworthia, and a multivitamin transporter (smvt) that can aid in nutrient dissemination. Wigglesworthia overexpress a molecular chaperone (GroEL) to augment their translational/transport machinery and biosynthesize an abundance of B vitamins (specifically B1-, B2-, B3- and B6 associated metabolites) to supplement the host's nutritionally deficient diet. The absence of Wigglesworthia's contributions disrupts multiple metabolic pathways impacting carbohydrate and amino acid metabolism. These disruptions affect the dependent downstream processes of nucleotide biosynthesis and metabolism and biosynthesis of S-adenosyl methionine (SAM), an essential cofactor. This holistic fundamental knowledge of the symbiotic dialogue highlights new biological targets for the development of innovative vector control methods. PMID- 28659448 TI - Bright birds are cautious: seasonally conspicuous plumage prompts risk avoidance by male superb fairy-wrens. AB - Increased predation risk is considered a cost of having conspicuous colours, affecting the anti-predator behaviour of colourful animals. However, this is difficult to test, as individual factors often covary with colour and behaviour. We used alarm call playback and behavioural observations to assess whether individual birds adjust their response to risk according to their plumage colour. Male superb fairy-wrens (Malurus cyaneus) change from a dull brown to conspicuous blue plumage each year, allowing the behaviour of different coloured birds to be compared while controlling for within-individual effects. Because the timing of colour change varies among males, blue and brown birds can also be compared at the same time of year, controlling for seasonal effects on behaviour. While blue, fairy-wrens fled more often in response to alarm calls, and took longer to emerge from cover. Blue fairy-wrens also spent more time foraging in cover and being vigilant. Group members appeared to benefit from the presence of blue males, as they reduced their response to alarms, and allocated less time to sentinel behaviour when a blue male was close by. We suggest that fairy-wrens perceive themselves to be at a higher risk of predation while in conspicuous plumage and adjust their behaviour accordingly. PMID- 28659449 TI - Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance. AB - Early initiation of antiretroviral therapy (ART) reduces the risk of drug sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing. PMID- 28659450 TI - Warming has a greater effect than elevated CO2 on predator-prey interactions in coral reef fish. AB - Ocean acidification and warming, driven by anthropogenic CO2 emissions, are considered to be among the greatest threats facing marine organisms. While each stressor in isolation has been studied extensively, there has been less focus on their combined effects, which could impact key ecological processes. We tested the independent and combined effects of short-term exposure to elevated CO2 and temperature on the predator-prey interactions of a common pair of coral reef fishes (Pomacentrus wardi and its predator, Pseudochromis fuscus). We found that predator success increased following independent exposure to high temperature and elevated CO2 Overall, high temperature had an overwhelming effect on the escape behaviour of the prey compared with the combined exposure to elevated CO2 and high temperature or the independent effect of elevated CO2 Exposure to high temperatures led to an increase in attack and predation rates. By contrast, we observed little influence of elevated CO2 on the behaviour of the predator, suggesting that the attack behaviour of P. fuscus was robust to this environmental change. This is the first study to address how the kinematics and swimming performance at the basis of predator-prey interactions may change in response to concurrent exposure to elevated CO2 and high temperatures and represents an important step to forecasting the responses of interacting species to climate change. PMID- 28659451 TI - Costs and benefits of maternally inherited algal symbionts in coral larvae. AB - Many marine invertebrates provide their offspring with symbionts. Yet the consequences of maternally inherited symbionts on larval fitness remain largely unexplored. In the stony coral Favia fragum (Esper 1797), mothers produce larvae with highly variable amounts of endosymbiotic algae, and we examined the implications of this variation in symbiont density on the performance of F. fragum larvae under different environmental scenarios. High symbiont densities prolonged the period that larvae actively swam and searched for suitable settlement habitats. Thermal stress reduced survival and settlement success in F. fragum larvae, whereby larvae with high symbiont densities suffered more from non lethal stress and were five times more likely to die compared with larvae with low symbiont densities. These results show that maternally inherited algal symbionts can be either beneficial or harmful to coral larvae depending on the environmental conditions at hand, and suggest that F. fragum mothers use a bet hedging strategy to minimize risks associated with spatio-temporal variability in their offspring's environment. PMID- 28659452 TI - Fear creates an Allee effect: experimental evidence from seasonal populations. AB - Allee effects driven by predation can play a strong role in the decline of small populations but are conventionally thought to occur when generalist predators target specific prey (i.e. type II functional response). However, aside from direct consumption, fear of predators could also increase vigilance and reduce time spent foraging as population size decreases, as has been observed in wild mammals living in social groups. To investigate the role of fear on fitness in relation to population density in a species with limited sociality, we exposed varying densities of Drosophila melanogaster to mantid predators either during an experimental breeding season or non-breeding season. The presence of mantids in either season decreased the reproductive performance of individuals but only at low breeding densities, providing evidence for an Allee effect. We then used our experimental results to parametrize a mathematical model to examine the population consequences of fear at low densities. Fear tended to destabilize population dynamics and increase the risk of extinction up to sevenfold. Our study provides unique experimental evidence that the indirect effects of the presence of predators can cause an Allee effect and has important consequences for our understanding of the dynamics of small populations. PMID- 28659453 TI - Human impacts reduce morphological diversity in an insular species of lizard. AB - Fossil remains provide useful insights into the long-term impact of anthropogenic phenomena on faunas and are often used to reveal the local (extirpations) or global (extinctions) losses of populations or species. However, other phenomena such as minor morphological changes can remain inconspicuous in the fossil record depending on the methodology used. In this study, we used the anole of Marie Galante Island (Anolis ferreus) in Guadeloupe (French, West Indies) as a model to demonstrate how the morphological evolution of an insular lizard can be tracked through the Pleistocene/Holocene climatic transition and the recent anthropization of the island. We used a fossil assemblage of nearly 30 000 remains and a combination of anatomical description, traditional morphometry and geometric morphometrics. These fossils are attributed to a single taxon, most likely to be A. ferreus on the basis of morphological and morphometric arguments. Our results show the disappearance of a distinct (sub)population of large specimens that were about 25% larger than the modern representatives of A. ferreus We also demonstrate an apparent size stability of the main fossil population of this species since the Late Pleistocene but with the possible occurrence of a reduction in morphological diversity during the Late Holocene. These results highlight the impact of anthropic disturbances on a lizard whose morphology otherwise remained stable since the Late Pleistocene. PMID- 28659454 TI - Correction to: Wind and rain are the primary climate factors driving changing phenology of an aerial insectivore. PMID- 28659455 TI - Calcified embolus mimics patent middle cerebral artery on CT angiogram. PMID- 28659456 TI - Pilot RCT Results of an mHealth HIV Prevention Program for Sexual Minority Male Adolescents. AB - BACKGROUND: Guy2Guy (G2G) is the first comprehensive HIV prevention program developed for sexual minority males as young as 14 years old and is delivered nationally via text messaging. Here, we report the results of the pilot randomized control trial. METHODS: G2G was tested against an attention-matched "healthy lifestyle" control (eg, self-esteem). Both programs lasted 5 weeks and delivered 5 to 10 text messages daily. A 1-week booster was delivered 6 weeks subsequently. Participants were cisgender males ages 14 to 18 years old who were gay, bisexual, and/or queer and had an unlimited text messaging plan. Youth were recruited across the United States via Facebook and enrolled by telephone from October 2014 to April 2015. Ninety-day postintervention outcomes were condomless sex acts (CSA) and abstinence and, secondarily, HIV testing. We also examined these outcomes at intervention end and stratified them by sexual experience. RESULTS: At 90 days postintervention, there were no significant differences in CSAs or abstinence noted. Among participants who were sexually active at baseline, intervention participants were significantly more likely to report getting an HIV test (adjusted odds ratio = 3.42, P = .001). They were also less likely than control youth to be abstinent (adjusted odds ratio = 0.48, P = .05). CSAs were significantly lower for those in the intervention versus control at intervention end (incident rate ratio = 0.39, P = .04), although significance was lost once age was added to the analysis (incident rate ratio = 0.58, P = .26). CONCLUSIONS: G2G appears promising in increasing adolescent HIV testing rates. Sex-positive intervention messages appear to have increased the participants' comfort with having sex (ie, less abstinence) while not increasing their potential for HIV transmission (ie, more CSAs). Additional content or features may be needed to invigorate condom use. PMID- 28659457 TI - Effect of whisker geometry on contact force produced by vibrissae moving at different velocities. AB - Rats and mice are able to perform a variety of subtle tactile discriminations with their mystacial vibrissae. Increasingly, the design and interpretation of neurophysiological and behavioral studies are inspired by and linked to a more precise understanding of the detailed physical properties of the whiskers and their associated hair follicles. Here we used a piezoelectric sensor (bimorph) to examine how contact forces are influenced by the geometry of individual whisker hairs. For a given point along a whisker, bimorph signals are linearly related to whisker movement velocity. The slope of this linear function, called velocity sensitivity (VS), diminishes nonlinearly as whisker diameter decreases. Whiskers differ in overall length, thickness, and proximal-distal taper. Thus VS varies along an individual whisker and among different whiskers on the mystacial pad. Thinner, shorter whiskers, such as those located rostrally in rats and those in mice, have lower overall VSs, rendering them potentially less effective for mediating discriminations that rely on subtle velocity cues. The nonlinear effect of diameter combined with the linear effect of arc length produces radial distance tuning curves wherein small differences in the proximal-distal location of impacts yields larger differences in signal magnitude. Such position-dependent cues could contribute to the localization of objects near the face. Proximal-to distal changes in contact location during whisking sweeps could also provide signals that aid texture discrimination.NEW & NOTEWORTHY This study describes the geometry of facial whiskers distributed across the mystacial pad with emphasis on velocity encoding of object strikes. Findings indicate how the shapes, lengths, and thicknesses of individual hairs can contribute to sophisticated vibrissa based tactile discrimination. PMID- 28659458 TI - Impaired visuomotor generalization by inconsistent attentional contexts. AB - In daily life, people are constantly presented with situations in which they have to learn and acquire new motor skills in complex environments, where attention is often distracted by other events. Being able to generalize and perform the acquired motor action in different environments is a crucial part of visuomotor learning. The current study examined whether attentional distraction impairs generalization of visuomotor adaptation or whether consistent distraction can operate as an internal cue to facilitate generalization. Using a dual-task paradigm combining visuomotor rotational adaptation and an attention-demanding secondary task, we showed that switching the attentional context from training (dual-task) to generalization (single-task) reduced the range of transfer of visuomotor adaptation to untrained directions. However, when consistent distraction was present throughout training and generalization, visuomotor generalization was equivalent to without distractions at all. Furthermore, this attentional context-dependent generalization was evident even when sensory modality of distractions differed between training and generalization. Therefore, the general nature of the dual tasks, rather than the specific stimuli, is associated with visuomotor memory and serves as a critical cue for generalization. Taken together, we demonstrated that attention plays a critical role during sensorimotor adaptation in selecting and associating multisensory signals with motor memory. This finding provides insight into developing learning programs that are generalizable in complex daily environments.NEW & NOTEWORTHY Learning novel motor actions in complex environments with attentional distraction is a critical function. Successful motor learning involves the ability to transfer the acquired skill from the trained to novel environments. Here, we demonstrate attentional distraction does not impair visuomotor adaptation. Rather, consistency in the attentional context from training to generalization modulates the degree of transfer to untrained locations. The role of attention and memory must, therefore, be incorporated into existing models of visuomotor learning. PMID- 28659459 TI - Task-specific, dimension-based attentional shaping of motion processing in monkey area MT. AB - Nonspatially selective attention is based on the notion that specific features or objects in the visual environment are effectively prioritized in cortical visual processing. Feature-based attention (FBA), in particular, is a well-studied process that dynamically and selectively addresses neurons preferentially processing the attended feature attribute (e.g., leftward motion). In everyday life, however, behavior may require high sensitivity for an entire feature dimension (e.g., motion), but experimental evidence for a feature dimension specific attentional modulation on a cellular level is lacking. Therefore, we investigated neuronal activity in macaque motion-selective mediotemporal area (MT) in an experimental setting requiring the monkeys to detect either a motion change or a color change. We hypothesized that neural activity in MT is enhanced when the task requires perceptual sensitivity to motion. In line with this, we found that mean firing rates were higher in the motion task and that response variability and latency were lower compared with values in the color task, despite identical visual stimulation. This task-specific, dimension-based modulation of motion processing emerged already in the absence of visual input, was independent of the relation between the attended and stimulating motion direction, and was accompanied by a spatially global reduction of neuronal variability. The results provide single-cell support for the hypothesis of a feature dimension-specific top-down signal emphasizing the processing of an entire feature class.NEW & NOTEWORTHY Cortical processing serving visual perception prioritizes information according to current task requirements. We provide evidence in favor of a dimension-based attentional mechanism addressing all neurons that process visual information in the task-relevant feature domain. Behavioral tasks required monkeys to attend either color or motion, causing modulations of response strength, variability, latency, and baseline activity of motion-selective monkey area MT neurons irrespective of the attended motion direction but specific to the attended feature dimension. PMID- 28659460 TI - Intermuscular coherence reflects functional coordination. AB - Coherence analysis has the ability to identify the presence of common descending drive shared by motor unit pools and reveals its spectral properties. However, the link between spectral properties of shared neural drive and functional interactions among muscles remains unclear. We assessed shared neural drive between muscles of the thumb and index finger while participants executed two mechanically distinct precision pinch tasks, each requiring distinct functional coordination among muscles. We found that shared neural drive was systematically reduced or enhanced at specific frequencies of interest (~10 and ~40 Hz). While amplitude correlations between surface EMG signals also exhibited changes across tasks, only their coherence has strong physiological underpinnings indicative of neural binding. Our results support the use of intermuscular coherence as a tool to detect when coactivated muscles are members of a functional group or synergy of neural origin. Furthermore, our results demonstrate the advantages of considering neural binding at 10, ~20, and >30 Hz, as indicators of task dependent neural coordination strategies.NEW & NOTEWORTHY It is often unclear whether correlated activity among muscles reflects their neural binding or simply reflects the constraints defining the task. Using the fact that high-frequency coherence between EMG signals (>6 Hz) is thought to reflect shared neural drive, we demonstrate that coherence analysis can reveal the neural origin of distinct muscle coordination patterns required by different tasks. PMID- 28659461 TI - Response preparation and execution during intentional bimanual pattern switching. AB - During continuous bimanual coordination, in-phase (IP; 0 degrees relative phase) and anti-phase (AP; 180 degrees relative phase) patterns can be stably performed without practice. Paradigms in which participants are required to intentionally switch between these coordination patterns have been used to investigate the interaction between the performer's intentions and intrinsic dynamics of the body's preferred patterns. The current study examined the processes associated with switching preparation and execution through the use of a startling acoustic stimulus (SAS) as the switch stimulus. A SAS is known to involuntarily trigger preprogrammed responses at a shortened latency and, thus, can be used to probe advance preparation. Participants performed cyclical IP and AP bimanual elbow extension-flexion movements in which they were required to switch patterns in response to an auditory switch cue, which was either nonstartling (80 dB) or a SAS (120 dB). Results indicated that reaction time to the switch stimulus (i.e., switch onset) was significantly reduced on startle trials, indicative of advance preparation of the switch response. Similarly, switching time was reduced on startle trials, which was attributed to increased neural activation caused by the SAS. Switching time was also shorter for AP to IP trials, but only when the switching stimulus occurred at either the midpoint or reversal locations within the movement cycle, suggesting that the switch location may affect the intrinsic dynamics of the system.NEW & NOTEWORTHY The current study provides novel information regarding preparation and execution of intentional switching between in-phase and anti-phase bimanual coordination patterns. Using a startling acoustic stimulus, we provide strong evidence that the switching response is prepared before the switch stimulus, and switch execution is accelerated by the startling stimulus. In addition, the time required to switch between patterns and relative limb contribution is dependent upon where in the movement cycle the switch stimulus occurred. PMID- 28659462 TI - Discrimination of curvature from motion during smooth pursuit eye movements and fixation. AB - Smooth pursuit and motion perception have mainly been investigated with stimuli moving along linear trajectories. Here we studied the quality of pursuit movements to curved motion trajectories in human observers and examined whether the pursuit responses would be sensitive enough to discriminate various degrees of curvature. In a two-interval forced-choice task subjects pursued a Gaussian blob moving along a curved trajectory and then indicated in which interval the curve was flatter. We also measured discrimination thresholds for the same curvatures during fixation. Motion curvature had some specific effects on smooth pursuit properties: trajectories with larger amounts of curvature elicited lower open-loop acceleration, lower pursuit gain, and larger catch-up saccades compared with less curved trajectories. Initially, target motion curvatures were underestimated; however, ~300 ms after pursuit onset pursuit responses closely matched the actual curved trajectory. We calculated perceptual thresholds for curvature discrimination, which were on the order of 1.5 degrees of visual angle ( degrees ) for a 7.9 degrees curvature standard. Oculometric sensitivity to curvature discrimination based on the whole pursuit trajectory was quite similar to perceptual performance. Oculometric thresholds based on smaller time windows were higher. Thus smooth pursuit can quite accurately follow moving targets with curved trajectories, but temporal integration over longer periods is necessary to reach perceptual thresholds for curvature discrimination.NEW & NOTEWORTHY Even though motion trajectories in the real world are frequently curved, most studies of smooth pursuit and motion perception have investigated linear motion. We show that pursuit initially underestimates the curvature of target motion and is able to reproduce the target curvature ~300 ms after pursuit onset. Temporal integration of target motion over longer periods is necessary for pursuit to reach the level of precision found in perceptual discrimination of curvature. PMID- 28659463 TI - Integration of visual and tactile information in reproduction of traveled distance. AB - In the natural world, self-motion always stimulates several different sensory modalities. Here we investigated the interplay between a visual optic flow stimulus simulating self-motion and a tactile stimulus (air flow resulting from self-motion) while human observers were engaged in a distance reproduction task. We found that adding congruent tactile information (i.e., speed of the air flow and speed of visual motion are directly proportional) to the visual information significantly improves the precision of the actively reproduced distances. This improvement, however, was smaller than predicted for an optimal integration of visual and tactile information. In contrast, incongruent tactile information (i.e., speed of the air flow and speed of visual motion are inversely proportional) did not improve subjects' precision indicating that incongruent tactile information and visual information were not integrated. One possible interpretation of the results is a link to properties of neurons in the ventral intraparietal area that have been shown to have spatially and action-congruent receptive fields for visual and tactile stimuli.NEW & NOTEWORTHY This study shows that tactile and visual information can be integrated to improve the estimates of the parameters of self-motion. This, however, happens only if the two sources of information are congruent-as they are in a natural environment. In contrast, an incongruent tactile stimulus is still used as a source of information about self motion but it is not integrated with visual information. PMID- 28659464 TI - Impact of glutamatergic and serotonergic neurotransmission on diaphragm muscle activity after cervical spinal hemisection. AB - Incomplete cervical spinal cord hemisection at C2 (SH) disrupts descending excitatory drive to phrenic motoneurons, paralyzing the ipsilateral diaphragm muscle. Spontaneous recovery over time is associated with increased phrenic motoneuron expression of glutamatergic N-methyl-d-aspartate (NMDA) and serotonergic 5-HT2A receptors. We hypothesized that NMDA and 5-HT2A receptor mediated neurotransmission play a role in ipsilateral diaphragm muscle activity post-SH. Adult male Sprague-Dawley rats were implanted with bilateral diaphragm EMG electrodes for chronic EMG recordings up to 28 days post-SH (SH 28D). The extent of recovery was calculated by peak root-mean-square (RMS) EMG amplitude. In all animals, absence of ipsilateral activity was verified at 3 days post-SH. Diaphragm EMG activity was also recorded during exposure to hypoxia-hypercapnia (10% O2-5% CO2). In SH animals displaying recovery of ipsilateral diaphragm EMG activity at SH 28D, cervical spinal cord segments containing the phrenic motor nucleus (C3-C5) were surgically exposed and either the NMDA receptor antagonist d 2-amino-5-phosphonovalerate (d-AP5; 100 mM, 30 MUl) or 5-HT2A receptor antagonist ketanserin (40 mM, 30 MUl) was instilled intrathecally. Following d-AP5, diaphragm EMG amplitude was reduced ipsilaterally, during both eupnea (42% of pre d-AP5 value; P = 0.007) and hypoxia-hypercapnia (31% of pre-d-AP5 value; P = 0.015), with no effect on contralateral EMG activity or in uninjured controls. Treatment with ketanserin did not change ipsilateral or contralateral RMS EMG amplitude in SH animals displaying recovery at SH 28D. Our results suggest that spinal glutamatergic NMDA receptor-mediated neurotransmission plays an important role in ipsilateral diaphragm muscle activity after cervical spinal cord injury.NEW & NOTEWORTHY Spontaneous recovery following C2 spinal hemisection (SH) is associated with increased phrenic motoneuron expression of glutamatergic and serotonergic receptors. In this study, we show that pharmacological inhibition of glutamatergic N-methyl-d-aspartate (NMDA) receptors blunts ipsilateral diaphragm activity post-SH. In contrast, pharmacological inhibition of serotonergic 5-HT2A receptors does not change diaphragm EMG activity post-SH. Our results suggest that NMDA receptor-mediated glutamatergic neurotransmission plays an important role in enhancing rhythmic respiratory-related diaphragm activity after spinal cord injury. PMID- 28659465 TI - Removal of endogenous neuromodulators in a small motor network enhances responsiveness to neuromodulation. AB - We studied the changes in sensitivity to a peptide modulator, crustacean cardioactive peptide (CCAP), as a response to loss of endogenous modulation in the stomatogastric ganglion (STG) of the crab Cancer borealis Our data demonstrate that removal of endogenous modulation for 24 h increases the response of the lateral pyloric (LP) neuron of the STG to exogenously applied CCAP. Increased responsiveness is accompanied by increases in CCAP receptor (CCAPr) mRNA levels in LP neurons, requires de novo protein synthesis, and can be prevented by coincubation for the 24-h period with exogenous CCAP. These results suggest that there is a direct feedback from loss of CCAP signaling to the production of CCAPr that increases subsequent response to the ligand. However, we also demonstrate that the modulator-evoked membrane current (IMI) activated by CCAP is greater in magnitude after combined loss of endogenous modulation and activity compared with removal of just hormonal modulation. These results suggest that both receptor expression and an increase in the target conductance of the CCAP G protein-coupled receptor are involved in the increased response to exogenous hormone exposure following experimental loss of modulation in the STG.NEW & NOTEWORTHY The nervous system shows a tremendous amount of plasticity. More recently there has been an appreciation for compensatory actions that stabilize output in the face of perturbations to normal activity. In this study we demonstrate that neurons of the crustacean stomatogastric ganglion generate apparent compensatory responses to loss of peptide neuromodulation, adding to the repertoire of mechanisms by which the stomatogastric nervous system can regulate and stabilize its own output. PMID- 28659466 TI - Caffeine accelerates recovery from general anesthesia via multiple pathways. AB - Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP]i) elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A2A receptor blockade and [cAMP]i elevation play a role in caffeine's ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response.NEW & NOTEWORTHY Currently, there is no method to accelerate emergence from anesthesia. Patients "wake" when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that caffeine is effective even at high levels of anesthetic. We also show that caffeine operates by both elevating intracellular cAMP levels and by blocking adenosine receptors. This complicated pharmacology makes caffeine especially effective in accelerating emergence from anesthesia. PMID- 28659467 TI - Motor learning in a complex balance task and associated neuroplasticity: a comparison between endurance athletes and nonathletes. AB - Studies suggested that motor expertise is associated with functional and structural brain alterations, which positively affect sensorimotor performance and learning capabilities. The purpose of the present study was to unravel differences in motor skill learning and associated functional neuroplasticity between endurance athletes (EA) and nonathletes (NA). For this purpose, participants had to perform a multimodal balance task (MBT) training on 2 sessions, which were separated by 1 wk. Before and after MBT training, a static balance task (SBT) had to be performed. MBT-induced functional neuroplasticity and neuromuscular alterations were assessed by means of functional near-infrared spectroscopy (fNIRS) and electromyography (EMG) during SBT performance. We hypothesized that EA would showed superior initial SBT performance and stronger MBT-induced improvements in SBT learning rates compared with NA. On a cortical level, we hypothesized that MBT training would lead to differential learning dependent functional changes in motor-related brain regions [such as primary motor cortex (M1)] during SBT performance. In fact, EA showed superior initial SBT performance, whereas learning rates did not differ between groups. On a cortical level, fNIRS recordings (time * group interaction) revealed a stronger MBT-induced decrease in left M1 and inferior parietal lobe (IPL) for deoxygenated hemoglobin in EA. Even more interesting, learning rates were correlated with fNIRS changes in right M1/IPL. On the basis of these findings, we provide novel evidence for superior MBT training-induced functional neuroplasticity in highly trained athletes. Future studies should investigate these effects in different sports disciplines to strengthen previous work on experience-dependent neuroplasticity.NEW & NOTEWORTHY Motor expertise is associated with functional/structural brain plasticity. How such neuroplastic reorganization translates into altered motor learning processes remains elusive. We investigated endurance athletes (EA) and nonathletes (NA) in a multimodal balance task (MBT). EA showed superior static balance performance (SBT), whereas MBT-induced SBT improvements did not differ between groups. Functional near-infrared spectroscopy recordings revealed a differential MBT training-induced decrease of deoxygenated hemoglobin in left primary motor cortex and inferior parietal lobe between groups. PMID- 28659468 TI - Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling. AB - Antigen-triggered T-cell receptor (TCR) phosphorylation is the first signaling event in T cells to elicit adaptive immunity against invading pathogens and tumor cells. Despite its physiological importance, the underlying mechanism of TCR phosphorylation remains elusive. Here, we report a key mechanism regulating the initiation of TCR phosphorylation. The major TCR kinase Lck shows high selectivity on the four CD3 signaling proteins of TCR. CD3epsilon is the only CD3 chain that can efficiently interact with Lck, mainly through the ionic interactions between CD3epsilon basic residue-rich sequence (BRS) and acidic residues in the Unique domain of Lck. We applied a TCR reconstitution system to explicitly study the initiation of TCR phosphorylation. The ionic CD3epsilon-Lck interaction controls the phosphorylation level of the whole TCR upon antigen stimulation. CD3epsilon BRS is sequestered in the membrane, and antigen stimulation can unlock this motif. Dynamic opening of CD3epsilon BRS and its subsequent recruitment of Lck thus can serve as an important switch of the initiation of TCR phosphorylation. PMID- 28659469 TI - ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. AB - BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the Brca1S1598F mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in Brca1S1598F cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of Brca1S1598F mice. Whereas both ATM and BRCA1 promote end resection, which can be regulated by 53BP1, 53bp1 deletion does not rescue the HDR defects of Atm mutant cells, in contrast to Brca1 mutant cells. These results demonstrate that ATM has a role in HDR independent of the BRCA1-53BP1 antagonism and that its HDR function can become critical in certain contexts. PMID- 28659470 TI - Hepatitis C Virus NS5A Targets Nucleosome Assembly Protein NAP1L1 To Control the Innate Cellular Response. AB - Hepatitis C virus (HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral nonstructural protein NS5A, which, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified nucleosome assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A. Here we confirmed this interaction and mapped it to the C terminus of NS5A of both genotype 1 and 2. NS5A sequesters NAP1L1 in the cytoplasm, blocking its nuclear translocation. However, only NS5A from genotype 2 HCV, and not that from genotype 1, targets NAP1L1 for proteosome-mediated degradation. NAP1L1 is a nuclear chaperone involved in chromatin remodeling, and we demonstrated the NAP1L1-dependent regulation of specific pathways involved in cellular responses to viral infection and cell survival. Among those, we showed that lack of NAP1L1 leads to a decrease of RELA protein levels and a strong defect of IRF3 TBK1/IKKepsilon-mediated phosphorylation, leading to inefficient RIG-I and Toll like receptor 3 (TLR3) responses. Hence, HCV is able to modulate the host cell environment by targeting NAP1L1 through NS5A.IMPORTANCE Viruses have evolved to replicate and to overcome antiviral countermeasures of the infected cell. Hepatitis C virus is capable of establishing a lifelong chronic infection in the liver, which could develop into cirrhosis and cancer. Chronic viruses are particularly able to interfere with the cellular antiviral pathways by several different mechanisms. In this study, we identified a novel cellular target of the viral nonstructural protein NS5A and demonstrated its role in antiviral signaling. This factor, called nucleosome assembly protein 1-like 1 (NAP1L1), is a nuclear chaperone involved in the remodeling of chromatin during transcription. When it is depleted, specific signaling pathways leading to antiviral effectors are affected. Therefore, we provide evidence for both a novel strategy of virus evasion from cellular immunity and a novel role for a cellular protein, which has not been described to date. PMID- 28659471 TI - The Nucleocapsid Protein and Nonstructural Protein 10 of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Enhance CD83 Production via NF-kappaB and Sp1 Signaling Pathways. AB - Porcine reproductive and respiratory syndrome, caused by porcine reproductive and respiratory syndrome virus (PRRSV), is a panzootic disease that is one of the most economically costly diseases to the swine industry. A key aspect of PRRSV virulence is that the virus suppresses the innate immune response and induces persistent infection, although the underlying mechanisms are not well understood. The dendritic cell (DC) marker CD83 belongs to the immunoglobulin superfamily and is associated with DC activation and immunosuppression of T cell proliferation when expressed as soluble CD83 (sCD83). In this study, we show that PRRSV infection strongly stimulates CD83 expression in porcine monocyte-derived DCs (MoDCs) and that the nucleocapsid (N) protein and nonstructural protein 10 (nsp10) of PRRSV enhance CD83 promoter activity via the NF-kappaB and Sp1 signaling pathways. R43A and K44A amino acid substitution mutants of the N protein suppress the N protein-mediated increase of CD83 promoter activity. Similarly, P192-5A and G214-3A mutants of nsp10 (with 5 and 3 alanine substitutions beginning at residues P192 and G214, respectively) abolish the nsp10-mediated induction of the CD83 promoter. Using reverse genetics, four mutant viruses (rR43A, rK44A, rP192-5A, and rG214-3A) and four revertants [rR43A(R), rK44A(R), rP192-5A(R), and rG214-3A(R)] were generated. Decreased induction of CD83 in MoDCs was observed after infection by mutants rR43A, rK44A, rP192-5A, and rG214-3A, in contrast to the results obtained using rR43A(R), rK44A(R), rP192-5A(R), and rG214-3A(R). These findings suggest that PRRSV N and nsp10 play important roles in modulating CD83 signaling and shed light on the mechanism by which PRRSV modulates host immunity.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically costly pathogens affecting the swine industry. It is unclear how PRRSV inhibits the host's immune response and induces persistent infection. The dendritic cell (DC) marker CD83 belongs to the immunoglobulin superfamily and has previously been associated with DC activation and immunosuppression of T cell proliferation and differentiation when expressed as soluble CD83 (sCD83). In this study, we found that PRRSV infection induces sCD83 expression in porcine MoDCs via the NF-kappaB and Sp1 signaling pathways. The viral nucleocapsid protein, nonstructural protein 1 (nsp1), and nsp10 were shown to enhance CD83 promoter activity. Amino acids R43 and K44 of the N protein, as well as residues 192 to 196 (P192-5) and 214 to 216 (G214-3) of nsp10, play important roles in CD83 promoter activation. These findings provide new insights into the molecular mechanism of immune suppression by PRRSV. PMID- 28659472 TI - Crystal Structure and Thermostability Characterization of Enterovirus D68 3Dpol. AB - Enterovirus D68 (EV-D68) is one of the many nonpolio enteroviruses that cause mild to severe respiratory illness. The nonstructural protein 3Dpol is an RNA dependent RNA polymerase (RdRP) of EV-D68 which plays a critical role in the replication of the viral genome and represents a promising drug target. Here, we report the first three-dimensional crystal structure of the RdRP from EV-D68 in complex with the substrate GTP to 2.3-A resolution. The RdRP structure is similar to structures of other viral RdRPs, where the three domains, termed the palm, fingers, and thumb, form a structure resembling a cupped right hand. Particularly, an N-terminal fragment (Gly1 to Phe30) bridges the fingers and the thumb domains, which accounts for the enhanced stability of the full-length enzyme over the truncation mutant, as assessed by our thermal shift assays and the dynamic light scattering studies. Additionally, the GTP molecule bound proximal to the active site interacts with both the palm and fingers domains to stabilize the core structure of 3Dpol Interestingly, using limited proteolysis assays, we found that different nucleoside triphosphates (NTPs) stabilize the polymerase structure by various degrees, with GTP and CTP being the most and least stabilizing nucleosides, respectively. Lastly, we derived a model of the core structure of 3Dpol stabilized by GTP, according to our proteolytic studies. The biochemical and biophysical characterizations conducted in this study help us to understand the stability of EV-D68-3Dpol, which may extend to other RdRPs as well.IMPORTANCE Enterovirus D68 (EV-D68) is an emerging viral pathogen, which caused sporadic infections around the world. In recent years, epidemiology studies have reported an increasing number of patients with respiratory diseases globally due to the EV-D68 infection. Moreover, the infection has been associated with acute flaccid paralysis and cranial nerve dysfunction in children. However, there are no vaccines and antiviral treatments specifically targeting the virus to date. In this study, we solved the crystal structure of the RNA-dependent RNA polymerase of EV-D68 and carried out systematic biophysical and biochemical characterizations on the overall and local structural stability of the wild-type (WT) enzyme and several variants, which yields a clear view on the structure activity relationship of the EV-D68 RNA polymerase. PMID- 28659473 TI - Pace of Coreceptor Tropism Switch in HIV-1-Infected Individuals after Recent Infection. AB - HIV-1 entry into target cells influences several aspects of HIV-1 pathogenesis, including viral tropism, HIV-1 transmission and disease progression, and response to entry inhibitors. The evolution from CCR5- to CXCR4-using strains in a given human host is still unpredictable. Here we analyzed timing and predictors for coreceptor evolution among recently HIV-1-infected individuals. Proviral DNA was longitudinally evaluated in 66 individuals using Geno2pheno[coreceptor] Demographics, viral load, CD4+ and CD8+ T cell counts, CCR5Delta32 polymorphisms, GB virus C (GBV-C) coinfection, and HLA profiles were also evaluated. Ultradeep sequencing was performed on initial samples from 11 selected individuals. A tropism switch from CCR5- to CXCR4-using strains was identified in 9/49 (18.4%) individuals. Only a low baseline false-positive rate (FPR) was found to be a significant tropism switch predictor. No minor CXCR4-using variants were identified in initial samples of 4 of 5 R5/non-R5 switchers. Logistic regression analysis showed that patients with an FPR of >40.6% at baseline presented a stable FPR over time whereas lower FPRs tend to progressively decay, leading to emergence of CXCR4-using strains, with a mean evolution time of 27.29 months (range, 8.90 to 64.62). An FPR threshold above 40.6% determined by logistic regression analysis may make it unnecessary to further determine tropism for prediction of disease progression related to emergence of X4 strains or use of CCR5 antagonists. The detection of variants with intermediate FPRs and progressive FPR decay over time not only strengthens the power of Geno2pheno in predicting HIV tropism but also indirectly confirms a continuous evolution from earlier R5 variants toward CXCR4-using strains.IMPORTANCE The introduction of CCR5 antagonists in the antiretroviral arsenal has sparked interest in coreceptors utilized by HIV-1. Despite concentrated efforts, viral and human host features predicting tropism switch are still poorly understood. Limited longitudinal data are available to assess the influence that these factors have on predicting tropism switch and disease progression. The present study describes longitudinal tropism evolution in a group of recently HIV-infected individuals to determine the prevalence and potential correlates of tropism switch. We demonstrated here that a low baseline FPR determined by the Geno2pheno[coreceptor] algorithm can predict tropism evolution from CCR5 to CXCR4 coreceptor use. PMID- 28659475 TI - A Small Viral PPxY Peptide Motif To Control Antiviral Autophagy. AB - Autophagy is an essential metabolic program that is also used for clearing intracellular pathogens. This mechanism, also termed selective autophagy, is well characterized for invasive bacteria but remains poorly documented for viral infections. Here we highlight our recent work showing that endosomolytic adenoviruses trigger autophagy when entering cells. Our study revealed how adenoviruses exploit a capsid-associated small PPxY peptide motif to manipulate the autophagic machinery to prevent autophagic degradation and to promote endosomal escape and nuclear trafficking. PMID- 28659474 TI - Phylogeography of Coxsackievirus A16 Reveals Global Transmission Pathways and Recent Emergence and Spread of a Recombinant Genogroup. AB - Coxsackievirus A16 (CV-A16; Picornaviridae) is an enterovirus (EV) type associated with hand, foot, and mouth disease (HFMD) in children. To investigate the spatial spread of CV-A16, we used viral sequence data sampled during a prospective sentinel surveillance of HFMD in France (2010 to 2014) and phylogenetic reconstruction. A data set of 168 VP1 sequences was assembled with 416 publicly available sequences of various geographic origins. The CV-A16 sequences reported were assigned to two clades, genogroup B and a previously uncharacterized clade D. The time origins of clades B and D were assessed in 1978 (1973 to 1981) and 2004 (2001 to 2007), respectively. The shape of the global CV A16 phylogeny indicated worldwide cocirculation of genetically distinct virus lineages over time and across geographic regions. Phylogenetic tree topologies and Bayes factor analysis indicated virus migration. Virus transportation events in clade B within Europe and Asia and between countries of the two geographic regions were assessed. The sustained transmission of clade D viruses over 4 years was analyzed at the township level in France and traced back to Peru in South America. Comparative genomics provided evidence of recombination between CV-A16 clades B and D and suggested an intertype recombinant origin for clade D. Time resolved phylogenies and HFMD surveillance data indicated that CV-A16 persistence is sustained by continuing virus migration at different geographic scales, from community transmission to virus transportation between distant countries. The results showed a significant impact of virus movements on the epidemiological dynamics of HFMD that could have implications for disease prevention.IMPORTANCE Coxsackievirus A16 is one of the most prevalent enterovirus types in hand, foot, and mouth disease outbreaks reported in Southeast Asia. This study is based on epidemiological and viral data on HFMD caused by CV-A16 in a European country. The phylogeographic data complemented the syndromic surveillance with virus migration patterns between geographic regions in France. The results show how viral evolutionary dynamics and global virus spread interact to shape the worldwide pattern of an EV disease. CV-A16 transmission is driven by movements of infected individuals at different geographic levels: within a country (local dynamics), between neighboring countries (regional dynamics), and between distant countries (transcontinental dynamics). The results are consistent with our earlier data on EV-A71 and confirm the epidemiological interconnection of Asia and Europe with regard to EV infections. PMID- 28659476 TI - Entry and release of hepatitis C virus in polarized human hepatocytes. AB - Hepatitis C virus (HCV) infects primarily hepatocytes that are highly polarized cells. The relevance of cell polarity in the HCV life cycle has only been addressed in distant models and remains poorly understood. Although polarized epithelial cells have a rather simple morphology with a basolateral and an apical domain, hepatocytes exhibit complex polarization structures. However, it has been reported that some selected polarized HepG2 cell clones can exhibit a honeycomb pattern of distribution of the tight-junction proteins, typical of columnar polarized epithelia which can be used as a simple model to study the role of cell polarization in viral infection of hepatocytes. To obtain similar clones, HepG2 cells expressing CD81 (HepG2-CD81) were used and clones were isolated by limiting dilutions. Two clones exhibiting a simple columnar polarization capacity when grown on semi-permeable support were isolated and characterized. To test the polarity of HCV entry and release, our polarized HepG2-CD81 clones were infected with cell culture derived HCV. Our data indicate that HCV binds equally to both sides of the cells, but productive infection occurs mainly when the virus is added at the basolateral domain. Furthermore, we also observed that HCV virions are released from the basolateral domain of the cells. Finally, when polarized cells were treated with oleic acid and U0126, a MEK inhibitor, to promote lipoprotein secretion, a higher proportion of infectious viral particles of lower density was secreted. This cell culture system provides an excellent model to investigate the influence of cell polarization on the HCV life cycle.IMPORTANCE Hepatitis C is a major health burden with approximately 170 million persons infected worldwide. Hepatitis C virus (HCV) infects primarily hepatocytes that are highly polarized cells with a complex organization. The relevance of cell polarity in the HCV life cycle has been addressed in distant models and remains unclear. Hepatocyte organization is complex with multiple apical and basolateral surfaces. A simple culture model of HepG2 cells expressing CD81 that are able to polarize with a unique apical and basolateral domain was developed to study HCV infection. With this model, we demonstrated that HCV enters and exits hepatocytes by the basolateral domain. Furthermore, lower density viral particles were produced in conditions that promote lipoprotein secretion. This cell culture system provides a useful model to study the influence of cell polarization on HCV infection. PMID- 28659477 TI - West Nile Virus NS1 Antagonizes Interferon Beta Production by Targeting RIG-I and MDA5. AB - West Nile virus (WNV) is a mosquito-borne flavivirus that causes epidemics of encephalitis and viscerotropic disease worldwide. This virus has spread rapidly and has posed a significant public health threat since the outbreak in New York City in 1999. The interferon (IFN)-mediated antiviral response represents an important component of virus-host interactions and plays an essential role in regulating viral replication. Previous studies have suggested that multifunctional nonstructural proteins encoded by flaviviruses antagonize the host IFN response via various means in order to establish efficient viral replication. In this study, we demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes IFN-beta production, most likely through suppression of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) activation. In a dual luciferase reporter assay, WNV NS1 significantly inhibited the activation of the IFN-beta promoter after Sendai virus infection or poly(I.C) treatment. NS1 also suppressed the activation of the IFN-beta promoter when it was stimulated by interferon regulatory factor 3 (IRF3)/5D or its upstream molecules in the RLR signaling pathway. Furthermore, NS1 blocked the phosphorylation and nuclear translocation of IRF3 upon stimulation by various inducers. Mechanistically, WNV NS1 targets RIG-I and melanoma differentiation-associated gene 5 (MDA5) by interacting with them and subsequently causing their degradation by the proteasome. Furthermore, WNV NS1 inhibits the K63-linked polyubiquitination of RIG-I, thereby inhibiting the activation of downstream sensors in the RLR signaling pathway. Taken together, our results reveal a novel mechanism by which WNV NS1 interferes with the host antiviral response.IMPORTANCE WNV Nile virus (WNV) has received increased attention since its introduction to the United States. However, the pathogenesis of this virus is poorly understood. This study demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes the induction of interferon beta (IFN-beta) by interacting with and degrading retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), which are crucial viral sensors in the host innate immune system. Further experiments suggested that NS1-mediated inhibition of the RIG-I-like receptor (RLR) signaling pathway involves inhibition of RIG-I K63-linked polyubiquitination and that the proteasome plays a role in RIG-I degradation. This study provides new insights into the regulation of WNV NS1 in the RLR signaling pathway and reveals a novel mechanism by which WNV evades the host innate immune response. The novel findings may guide us to discover new therapeutic targets and develop effective vaccines for WNV infections. PMID- 28659478 TI - Enfuvirtide (T20)-Based Lipopeptide Is a Potent HIV-1 Cell Fusion Inhibitor: Implications for Viral Entry and Inhibition. AB - The peptide drug enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy for HIV-1 infection, but it has relatively low antiviral activity and easily induces drug resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors, such as LP-11 and LP-19, which mainly target the gp41 pocket site, have greatly improved antiviral potency and in vivo stability. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site. First, the C-terminal tryptophan-rich motif (TRM) of T20 was verified to be essential for its target binding and inhibition; then, a novel lipopeptide, termed LP-40, was created by replacing the TRM with a fatty acid group. LP-40 showed markedly enhanced binding affinity for the target site and dramatically increased inhibitory activity on HIV-1 membrane fusion, entry, and infection. Unlike LP-11 and LP-19, which required a flexible linker between the peptide sequence and the lipid moiety, addition of a linker to LP-40 sharply reduced its potency, implying different binding modes with the extended N-terminal helices of gp41. Also, interestingly, LP-40 showed more potent activity than LP-11 in inhibiting HIV-1 Env-mediated cell-cell fusion while it was less active than LP-11 in inhibiting pseudovirus entry, and the two inhibitors displayed synergistic antiviral effects. The crystal structure of LP-40 in complex with a target peptide revealed their key binding residues and motifs. Combined, our studies have not only provided a potent HIV-1 fusion inhibitor, but also revealed new insights into the mechanisms of viral inhibition.IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection; however, T20 requires high doses and has a low genetic barrier for resistance, and its inhibitory mechanism and structural basis remain unclear. Here, we report the design of LP-40, a T20 based lipopeptide inhibitor that has greatly improved anti-HIV activity and is a more potent inhibitor of cell-cell fusion than of cell-free virus infection. The binding modes of two classes of membrane-anchoring lipopeptides (LP-40 and LP-11) verify the current fusion model in which an extended prehairpin structure bridges the viral and cellular membranes, and their complementary effects suggest a vital strategy for combination therapy of HIV-1 infection. Moreover, our understanding of the mechanism of action of T20 and its derivatives benefits from the crystal structure of LP-40. PMID- 28659479 TI - Crystal Structure of the Marburg Virus Nucleoprotein Core Domain Chaperoned by a VP35 Peptide Reveals a Conserved Drug Target for Filovirus. AB - Filovirus nucleoprotein (NP), viral protein 35 (VP35), and polymerase L are essential for viral replication and nucleocapsid formation. Here, we identify a 28-residue peptide (NP binding peptide [NPBP]) from Marburg virus (MARV) VP35 through sequence alignment with previously identified Ebola virus (EBOV) NPBP, which bound to the core region (residues 18 to 344) of the N-terminal portion of MARV NP with high affinity. The crystal structure of the MARV NP core/NPBP complex at a resolution of 2.6 A revealed that NPBP binds to the C-terminal region of the NP core via electrostatic and nonpolar interactions. Further structural analysis revealed that the MARV and EBOV NP cores hold a conserved binding pocket for NPBP, and this pocket could serve as a promising target for the design of universal drugs against filovirus infection. In addition, cross binding assays confirmed that the NP core of MARV or EBOV can bind the NPBP from the other virus, although with moderately reduced binding affinities that result from termini that are distinct between the MARV and EBOV NPBPs.IMPORTANCE Historically, Marburg virus (MARV) has caused severe disease with up to 90% lethality. Among the viral proteins produced by MARV, NP and VP35 are both multifunctional proteins that are essential for viral replication. In its relative, Ebola virus (EBOV), an N-terminal peptide from VP35 binds to the NP N terminal region with high affinity. Whether this is a common mechanism among filoviruses is an unsolved question. Here, we present the crystal structure of a complex that consists of the core domain of MARV NP and the NPBP peptide from VP35. As we compared MARV NPBP with EBOV NPBP, several different features at the termini were identified. Although these differences reduce the affinity of the NP core for NPBPs across genera, a conserved pocket in the C-terminal region of the NP core makes cross-species binding possible. Our results expand our knowledge of filovirus NP-VP35 interactions and provide more details for therapeutic intervention. PMID- 28659480 TI - Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection. AB - Mitochondria are crucial to proper neuronal function and overall brain health. Mitochondrial dysfunction within the brain has been observed in many neurodegenerative diseases, including prion disease. Several markers of decreased mitochondrial activity during prion infection have been reported, yet the bioenergetic respiratory status of mitochondria from prion-infected animals is unknown. Here we show that clinically ill transgenic mice overexpressing hamster prion protein (Tg7) infected with the hamster prion strain 263K suffer from a severe deficit in mitochondrial oxygen consumption in response to the respiratory complex II substrate succinate. Characterization of the mitochondrial proteome of purified brain mitochondria from infected and uninfected Tg7 mice showed significant differences in the relative abundance of key mitochondrial electron transport proteins in 263K-infected animals relative to that in controls. Our results suggest that at clinical stages of prion infection, dysregulation of respiratory chain proteins may lead to impairment of mitochondrial respiration in the brain.IMPORTANCE Mitochondrial dysfunction is present in most major neurodegenerative diseases, and some studies have suggested that mitochondrial processes may be altered during prion disease. Here we show that hamster prion infected transgenic mice overexpressing the hamster prion protein (Tg7 mice) suffer from mitochondrial respiratory deficits. Tg7 mice infected with the 263K hamster prion strain have little or no signs of mitochondrial dysfunction at the disease midpoint but suffer from a severe deficit in mitochondrial respiration at the clinical phase of disease. A proteomic analysis of the isolated brain mitochondria from clinically affected animals showed that several proteins involved in electron transport, mitochondrial dynamics, and mitochondrial protein synthesis were dysregulated. These results suggest that mitochondrial dysfunction, possibly exacerbated by prion protein overexpression, occurs at late stages during 263K prion disease and that this dysfunction may be the result of dysregulation of mitochondrial proteins. PMID- 28659481 TI - Hepatitis C Virus Strain-Dependent Usage of Apolipoprotein E Modulates Assembly Efficiency and Specific Infectivity of Secreted Virions. AB - Hepatitis C virus (HCV) is extraordinarily diverse and uses entry factors in a strain-specific manner. Virus particles associate with lipoproteins, and apolipoprotein E (ApoE) is critical for HCV assembly and infectivity. However, whether ApoE dependency is common to all HCV genotypes remains unknown. Therefore, we compared the roles of ApoE utilizing 10 virus strains from genotypes 1 through 7. ApoA and ApoC also support HCV assembly, so they may contribute to virus production in a strain-dependent fashion. Transcriptome sequencing (RNA-seq) revealed abundant coexpression of ApoE, ApoB, ApoA1, ApoA2, ApoC1, ApoC2, and ApoC3 in primary hepatocytes and in Huh-7.5 cells. Virus production was examined in Huh-7.5 cells with and without ApoE expression and in 293T cells where individual apolipoproteins (ApoE1, -E2, -E3, -A1, -A2, -C1, and C3) were provided in trans All strains were strictly ApoE dependent. However, ApoE involvement in virus production was strain and cell type specific, because some HCV strains poorly produced infectious virus in ApoE-expressing 293T cells and because ApoE knockout differentially affected virus production of HCV strains in Huh-7.5 cells. ApoE allelic isoforms (ApoE2, -E3, and -E4) complemented virus production of HCV strains to comparable degrees. All tested strains assembled infectious progeny with ApoE in preference to other exchangeable apolipoproteins (ApoA1, -A2, -C1, and -C3). The specific infectivity of HCV particles was similar for 293T- and Huh-7.5-derived particles for most strains; however, it differed by more than 100-fold in some viruses. Collectively, this study reveals strain dependent and host cell-dependent use of ApoE during HCV assembly. These differences relate to the efficacy of virus production and also to the properties of released virus particles and therefore govern viral fitness at the level of assembly and cell entry.IMPORTANCE Chronic HCV infections are a major cause of liver disease. HCV is highly variable, and strain-specific determinants modulate the response to antiviral therapy, the natural course of infection, and cell entry factor usage. Here we explored whether host factor dependency of HCV in particle assembly is modulated by strain-dependent viral properties. We showed that all examined HCV strains, which represent all seven known genotypes, rely on ApoE expression for assembly of infectious progeny. However, the degree of ApoE dependence is modulated in a strain-specific and cell type-dependent manner. This indicates that HCV strains differ in their assembly properties and host factor usage during assembly of infectious progeny. Importantly, these differences relate not only to the efficiency of virus production and release but also to the infectiousness of virus particles. Thus, strain-dependent features of HCV modulate ApoE usage, with implications for virus fitness at the level of assembly and cell entry. PMID- 28659482 TI - Complete Genome Sequencing of Influenza A Viruses within Swine Farrow-to-Wean Farms Reveals the Emergence, Persistence, and Subsidence of Diverse Viral Genotypes. AB - Influenza A viruses (IAVs) are endemic in swine and represent a public health risk. However, there is limited information on the genetic diversity of swine IAVs within farrow-to-wean farms, which is where most pigs are born. In this longitudinal study, we sampled 5 farrow-to-wean farms for a year and collected 4,190 individual nasal swabs from three distinct pig subpopulations. Of these, 207 (4.9%) samples tested PCR positive for IAV, and 124 IAVs were isolated. We sequenced the complete genomes of 123 IAV isolates and found 31 H1N1, 26 H1N2, 63 H3N2, and 3 mixed IAVs. Based on the IAV hemagglutinin, seven different influenza A viral groups (VGs) were identified. Most of the remaining IAV gene segments allowed us to differentiate the same VGs, although an additional viral group was identified for gene segment 3 (PA). Moreover, the codetection of more than one IAV VG was documented at different levels (farm, subpopulation, and individual pigs), highlighting the environment for potential IAV reassortment. Additionally, 3 out of 5 farms contained IAV isolates (n = 5) with gene segments from more than one VG, and 79% of all the IAVs sequenced contained a signature mutation (S31N) in the matrix gene that has been associated with resistance to the antiviral amantadine. Within farms, some IAVs were detected only once, while others were detected for 283 days. Our results illustrate the maintenance and subsidence of different IAVs within swine farrow-to-wean farms over time, demonstrating that pig subpopulation dynamics are important to better understand the diversity and epidemiology of swine IAVs.IMPORTANCE On a global scale, swine are one of the main reservoir species for influenza A viruses (IAVs) and play a key role in the transmission of IAVs between species. Additionally, the 2009 IAV pandemics highlighted the role of pigs in the emergence of IAVs with pandemic potential. However, limited information is available regarding the diversity and distribution of swine IAVs on farrow-to-wean farms, where novel IAVs can emerge. In this study, we studied 5 swine farrow-to-wean farms for a year and characterized the genetic diversity of IAVs among three different pig subpopulations commonly housed on this type of farm. Using next-generation sequencing technologies, we demonstrated the complex distribution and diversity of IAVs among the pig subpopulations studied. Our results demonstrated the dynamic evolution of IAVs within farrow-to-wean farms, which is crucial to improve health interventions to reduce the risk of transmission between pigs and from pigs to people. PMID- 28659483 TI - Human Bocavirus 1 Is a Novel Helper for Adeno-Associated Virus Replication. AB - Human bocavirus 1 (HBoV1) is an autonomous parvovirus that infects well differentiated primary human airway epithelia (HAE) in vitro. In human embryonic kidney (HEK) 293 cells, transfection of a duplex HBoV1 genome initiates viral DNA replication and produces progeny virions that are infectious in HAE. HBoV1 takes advantage of signaling pathways in the DNA damage response for efficient genome amplification in both well-differentiated (non-dividing) HAE and dividing HEK293 cells. On the other hand, adeno-associated virus 2 (AAV2) is a helper-dependent dependoparvovirus, and productive AAV2 replication requires co-infection with a helper virus (e.g., adenovirus or herpesvirus) or treatment with genotoxic agents. Here, we report that HBoV1 is a novel helper virus for AAV2 replication. HBoV1 and AAV2 co-infection rescued AAV2 replication in HAE cells. The helper function of HBoV1 for AAV2 is not only limited to HAE cells but also includes HEK293 and HeLa cells. Importantly, the HBoV1's helper function for AAV2 neither relies on HBoV1 replication nor DNA damage response. Following transfection of HEK293 cells, the minimal requirements for replication of AAV2 duplex DNA genome and production of progeny virions included HBoV1 NP1 and NS4 proteins, and the newly identified viral long non-coding RNA (BocaSR). However, following infection of HEK293 and HeLa cells with AAV2 virions, HBoV1 NS2 (but not NS4), NP1, and BocaSR were required for AAV2 DNA replication and progeny virion formation. These new methods for packaging AAV2 genome may be useful for generating recombinant AAV packaging cell lines and directed-evolution of AAV capsids.IMPORTANCE We first report that an autonomous parvovirus HBoV1 helps replication of a dependoparvovirus AAV2 in differentiated human airway epithelia. We identified the minimal sets of HBoV1 genes required to facilitate replication of AAV2 duplex genome and for AAV2 infection. Notably, together with expression of NP1 and BocaSR genes, HBoV1 NS2 is required for AAV2 productive infection in HEK293 and HeLa cells; whereas, NS4 is sufficient for viral DNA replication of an AAV2 duplex genome. The identification of HBoV1 as a helper virus for AAV2 replication has implications for improvement of recombinant AAV production in HEK293 cells and cell types that do not express adenovirus E1 gene, as well as for rescue of wild-type AAV genomes from tissues during directed-evolution in the absence of wild type adenovirus. Further understanding the mechanism underlying HBoV1 helper dependent AAV2 replication may also provide insights into their functions in HBoV1 replication. PMID- 28659484 TI - Case-Control Comparison of Enteric Viromes in Captive Rhesus Macaques with Acute or Idiopathic Chronic Diarrhea. AB - Diarrhea is the major cause of non-research-associated morbidity and mortality affecting the supply of rhesus macaques and, potentially, their responses to experimental treatments. Idiopathic chronic diarrhea (ICD) in rhesus macaques also resembles ulcerative colitis, one form of human inflammatory bowel disease. To test for viral etiologies, we characterized and compared the fecal viromes from 32 healthy animals, 31 animals with acute diarrhea, and 29 animals with ICD. The overall fractions of eukaryotic viral reads were 0.063% for the healthy group, 0.131% for the acute-diarrhea group, and 0.297% for the chronic-diarrhea group. Eukaryotic viruses belonging to 6 viral families, as well as numerous circular Rep-encoding single-stranded DNA (CRESS DNA) viral genomes, were identified. The most commonly detected sequences were from picornaviruses, making up 59 to 88% of all viral reads, followed by 9 to 17% for CRESS DNA virus sequences. The remaining 5 virus families, Adenoviridae, Astroviridae, Anelloviridae, Picobirnaviridae, and Parvoviridae, collectively made up 1 to 3% of the viral reads, except for parvoviruses, which made up 23% of the viral reads in the healthy group. Detected members of the families Picornaviridae and Parvoviridae were highly diverse, consisting of multiple genera, species, and genotypes. Coinfections with members of up to six viral families were detected. Complete and partial viral genomes were assembled and used to measure the number of matching short sequence reads in feces from the 92 animals in the two clinical and the healthy control groups. Several enterovirus genotypes and CRESS DNA genomes were associated with ICD relative to healthy animals. Conversely, higher read numbers from different parvoviruses were associated with healthy animals. Our study reveals a high level of enteric coinfections with diverse viruses in a captive rhesus macaque colony and identifies several viruses positively or negatively associated with ICD. PMID- 28659485 TI - Cytomegalovirus Late Protein pUL31 Alters Pre-rRNA Expression and Nuclear Organization during Infection. AB - The replication cycle of human cytomegalovirus (CMV) leads to drastic reorganization of domains in the host cell nucleus. However, the mechanisms involved and how these domains contribute to infection are not well understood. Our recent studies defining the CMV-induced nuclear proteome identified several viral proteins of unknown functions, including a protein encoded by the UL31 gene. We set out to define the role of UL31 in CMV replication. UL31 is predicted to encode a 74-kDa protein, referred to as pUL31, containing a bipartite nuclear localization signal, an intrinsically disordered region overlapping arginine-rich motifs, and a C-terminal dUTPase-like structure. We observed that pUL31 is expressed with true late kinetics and is localized to nucleolin-containing nuclear domains. However, pUL31 is excluded from the viral nuclear replication center. Nucleolin is a marker of nucleoli, which are membrane-less regions involved in regulating ribosome biosynthesis and cellular stress responses. Other CMV proteins associate with nucleoli, and we demonstrate that pUL31 specifically interacts with the viral protein, pUL76. Coexpression of both proteins altered pUL31 localization and nucleolar organization. During infection, pUL31 colocalizes with nucleolin but not the transcriptional activator, UBF. In the absence of pUL31, CMV fails to reorganize nucleolin and UBF and exhibits a replication defect at a low multiplicity of infection. Finally, we observed that pUL31 is necessary and sufficient to reduce pre-rRNA levels, and this was dependent on the dUTPase-like motif in pUL31. Our studies demonstrate that CMV pUL31 functions in regulating nucleolar biology and contributes to the reorganization of nucleoli during infection.IMPORTANCE Nucleolar biology is important during CMV infection with the nucleolar protein, with nucleolin playing a role in maintaining the architecture of the viral nuclear replication center. However, the extent of CMV-mediated regulation of nucleolar biology is not well established. Proteins within nucleoli regulate ribosome biosynthesis and p53 dependent cellular stress responses that are capable of inducing cell cycle arrest and/or apoptosis, and they are proposed targets for cancer therapies. This study establishes that CMV protein pUL31 is necessary and sufficient to regulate nucleolar biology involving the reorganization of nucleolar proteins. Understanding these processes will help define approaches to stimulate cellular intrinsic stress responses that are capable of inhibiting CMV infection. PMID- 28659486 TI - Differential Innate Immune Signaling in Macrophages by Wild-Type Vaccinia Mature Virus and a Mutant Virus with a Deletion of the A26 Protein. AB - The Western Reserve (WR) strain of mature vaccinia virus contains an A26 envelope protein that mediates virus binding to cell surface laminin and subsequent endocytic entry into HeLa cells. Removal of the A26 protein from the WR strain mature virus generates a mutant, WRDeltaA26, that enters HeLa cells through plasma membrane fusion. Here, we infected murine bone marrow-derived macrophages (BMDM) with wild-type strain WR and the WRDeltaA26 mutant and analyzed viral gene expression and cellular innate immune signaling. In contrast to previous studies, in which both HeLa cells infected with WR and HeLa cells infected with WRDeltaA26 expressed abundant viral late proteins, we found that WR expressed much less viral late protein than WRDeltaA26 in BMDM. Microarray analysis of the cellular transcripts in BMDM induced by virus infection revealed that WR preferentially activated type 1 interferon receptor (IFNAR)-dependent signaling but WRDeltaA26 did not. We consistently detected a higher level of soluble beta interferon secretion and phosphorylation of the STAT1 protein in BMDM infected with WR than in BMDM infected with WRDeltaA26. When IFNAR-knockout BMDM were infected with WR, late viral protein expression increased, confirming that IFNAR-dependent signaling was differentially induced by WR and, in turn, restricted viral late gene expression. Finally, wild-type C57BL/6 mice were more susceptible to mortality from WRDeltaA26 infection than to that from WR infection, whereas IFNAR knockout mice were equally susceptible to WR and WRDeltaA26 infection, demonstrating that the ability of WRDeltaA26 to evade IFNAR signaling has an important influence on viral pathogenesis in vivoIMPORTANCE The vaccinia virus A26 protein was previously shown to mediate virus attachment and to regulate viral endocytosis. Here, we show that infection with strain WR induces a robust innate immune response that activates type 1 interferon receptor (IFNAR) dependent cellular genes in BMDM, whereas infection with the WRDeltaA26 mutant does not. We further demonstrated that the differential activation of IFNAR dependent cellular signaling between WR and WRDeltaA26 not only is important for differential host restriction in BMDM but also is important for viral virulence in vivo Our study reveals a new property of WRDeltaA26, which is in regulating host antiviral innate immunity in vitro and in vivo. PMID- 28659487 TI - Mumps Virus SH Protein Inhibits NF-kappaB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes. AB - The mumps virus (MuV) small hydrophobic protein (SH) is a type I membrane protein expressed in infected cells. SH has been reported to interfere with innate immunity by inhibiting tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis and NF-kappaB activation. To elucidate the underlying mechanism, we generated recombinant MuVs (rMuVs) expressing the SH protein with an N-terminal FLAG epitope or lacking SH expression due to the insertion of three stop codons into the SH gene. Using these viruses, we were able to show that SH reduces the phosphorylation of IKKbeta, IkappaBalpha, and p65 as well as the translocation of p65 into the nucleus of infected A549 cells. Reporter gene assays revealed that SH interferes not only with TNF-alpha-mediated NF-kappaB activation but also with IL-1beta- and poly(I.C)-mediated NF-kappaB activation, and that this inhibition occurs upstream of the NF-kappaB pathway components TRAF2, TRAF6, and TAK1. Since SH coimmunoprecipitated with tumor necrosis factor receptor 1 (TNFR1), RIP1, and IRAK1, we hypothesize that SH exerts its inhibitory function by interacting with TNFR1, interleukin-1 receptor type 1 (IL-1R1), and TLR3 complexes in the plasma membrane of infected cells.IMPORTANCE The MuV SH has been shown to impede TNF alpha-mediated NF-kappaB activation and is therefore thought to contribute to viral immune evasion. However, the mechanisms by which SH mediates NF-kappaB inhibition remained largely unknown. In this study, we show that SH interacts with TNFR1, IL-1R1, and TLR3 complexes in infected cells. We thereby not only shed light on the mechanisms of SH-mediated NF-kappaB inhibition but also reveal that SH interferes with NF-kappaB activation induced by interleukin-1beta (IL 1beta) and double-stranded RNA. PMID- 28659488 TI - Inhibition of Poxvirus Gene Expression and Genome Replication by Bisbenzimide Derivatives. AB - Virus infection of humans and livestock can be devastating for individuals and populations, sometimes resulting in large economic and societal impact. Prevention of virus disease by vaccination or antiviral agents is difficult to achieve. A notable exception was the eradication of human smallpox by vaccination over 30 years ago. Today, humans and animals remain susceptible to poxvirus infections, including zoonotic poxvirus transmission. Here we identified a small molecule, bisbenzimide (bisbenzimidazole), and its derivatives as potent agents against prototypic poxvirus infection in cell culture. We show that bisbenzimide derivatives, which preferentially bind the minor groove of double-stranded DNA, inhibit vaccinia virus infection by blocking viral DNA replication and abrogating postreplicative intermediate and late gene transcription. The bisbenzimide derivatives are potent against vaccinia virus and other poxviruses but ineffective against a range of other DNA and RNA viruses. The bisbenzimide derivatives are the first inhibitors of their class, which appear to directly target the viral genome without affecting cell viability.IMPORTANCE Smallpox was one of the most devastating diseases in human history until it was eradicated by a worldwide vaccination campaign. Due to discontinuation of routine vaccination more than 30 years ago, the majority of today's human population remains susceptible to infection with poxviruses. Here we present a family of bisbenzimide (bisbenzimidazole) derivatives, known as Hoechst nuclear stains, with high potency against poxvirus infection. Results from a variety of assays used to dissect the poxvirus life cycle demonstrate that bisbenzimides inhibit viral gene expression and genome replication. These findings can lead to the development of novel antiviral drugs that target viral genomes and block viral replication. PMID- 28659489 TI - Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model. AB - There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8+ T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease.IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs using a mouse model of disease. We found that DENV infection induced metabolic dysregulation and inflammatory responses and affected the immune cell content of the spleen and liver. The use of the mast cell stabilization drug ketotifen reversed many of these responses and induced additional changes in the transcriptome and immune cell repertoire that contribute to decreased dengue disease. PMID- 28659490 TI - RhoA Inhibitor Treatment At Acute Phase of Spinal Cord Injury May Induce Neurite Outgrowth and Synaptogenesis. AB - The therapeutic use of RhoA inhibitors (RhoAi) has been experimentally tested in spinal cord injury (SCI). In order to decipher the underlying molecular mechanisms involved in such a process, an in vitro neuroproteomic-systems biology platform was developed in which the pan-proteomic profile of the dorsal root ganglia (DRG) cell line ND7/23 DRG was assessed in a large array of culture conditions using RhoAi and/or conditioned media obtained from SCI ex vivo derived spinal cord slices. A fine mapping of the spatio-temporal molecular events of the RhoAi treatment in SCI was performed. The data obtained allow a better understanding of regeneration/degeneration induced above and below the lesion site. Results notably showed a time-dependent alteration of the transcription factors profile along with the synthesis of growth cone-related factors (receptors, ligands, and signaling pathways) in RhoAi treated DRG cells. Furthermore, we assessed in a rat SCI model the in vivo impact of RhoAi treatment administered in situ via alginate scaffold that was combined with FK506 delivery. The improved recovery of locomotion was detected only at the early postinjury time points, whereas after overall survival a dramatic increase of synaptic contacts on outgrowing neurites in affected segments was observed. We validate these results by in vivo proteomic studies along the spinal cord segments from tissue and secreted media analyses, confirming the increase of the synaptogenesis expression factors under RhoAi treatment. Taken together, we demonstrate that RhoAi treatment seems to be useful to stimulate neurite outgrowth in both in vitro as well in vivo environments. However, for in vivo experiments there is a need for sustained delivery regiment to facilitate axon regeneration and promote synaptic reconnections with appropriate target neurons also at chronic phase, which in turn may lead to higher assumption for functional improvement. PMID- 28659492 TI - On the Inside. PMID- 28659493 TI - Salt Tolerance in Crops: Not Only a Matter of Gene Regulation. PMID- 28659494 TI - Application of FTIR spectroscopy for traumatic axonal injury: a possible tool for estimating injury interval. AB - Traumatic axonal injury (TAI) is a progressive and secondary injury following traumatic brain injury (TBI). Despite extensive investigations in the field of forensic science and neurology, no effective methods are available to estimate TAI interval between injury and death. In the present study, Fourier transform IR (FTIR) spectroscopy with IR microscopy was applied to collect IR spectra in the corpus callosum (CC) of rats subjected to TAI at 12, 24, and 72 h post-injury compared with control animals. The classification amongst different groups was visualized based on the acquired dataset using hierarchical cluster analysis (HCA) and partial least square (PLS). Furthermore, the established PLS models were used to predict injury interval of TAI in the unknown sample dataset. The results showed that samples at different time points post-injury were distinguishable from each other, and biochemical changes in protein, lipid, and carbohydrate contributed to the differences. Then, the established PLS models provided a satisfactory prediction of injury periods between different sample groups in the external validation. The present study demonstrated the great potential of FTIR-based PLS algorithm as an objective tool for estimating injury intervals of TAI in the field of forensic science and neurology. PMID- 28659491 TI - Physiological and Molecular Understanding of Bacterial Polysaccharide Monooxygenases. AB - Bacteria have long been known to secrete enzymes that degrade cellulose and chitin. The degradation of these two polymers predominantly involves two enzyme families that work synergistically with one another: glycoside hydrolases (GHs) and polysaccharide monooxygenases (PMOs). Although bacterial PMOs are a relatively recent addition to the known biopolymer degradation machinery, there is an extensive amount of literature implicating PMO in numerous physiological roles. This review focuses on these diverse and physiological aspects of bacterial PMOs, including facilitating endosymbiosis, conferring a nutritional advantage, and enhancing virulence in pathogenic organisms. We also discuss the correlation between the presence of PMOs and bacterial lifestyle and speculate on the advantages conferred by PMOs under these conditions. In addition, the molecular aspects of bacterial PMOs, as well as the mechanisms regulating PMO expression and the function of additional domains associated with PMOs, are described. We anticipate that increasing research efforts in this field will continue to expand our understanding of the molecular and physiological roles of bacterial PMOs. PMID- 28659496 TI - Secretion of interleukin-6 by bone marrow mesenchymal stem cells promotes metastasis in hepatocellular carcinoma. AB - Mesenchymal stem cells (MSCs) interact with tumor cells and regulate tumorigenesis and metastasis. As one of the important components of the tumor microenvironment, MSC-secreted cytokines play a critical role in cancer development. However, whether and how bone marrow MSCs (BMSCs) and their secreted cytokines participate in hepatocellular carcinoma (HCC) progression, still remains largely unknown. In the present study, we first measured the concentration of interleukin-6 (IL-6) in BMSC conditioned medium (BMSC-CM). Next, we assessed the changes of invasion ability in response to treatment of BMSC-CM or recombinant IL-6 in two human HCC cell lines Bel-7404 and HepG2. Then we analyzed the level of key components of the IL-6 signal pathway, including IL-6 receptor and signal transducer (i.e. IL-6R and gp130), a transcription factor STAT3 (signal transducer and activator of transcription 3), as well as its target genes BCL2, CCND1, MCL1 and MMP2, in BMSC-CM or recombinant IL-6 treated Bel-7404 and HepG2 cells. Results showed that a considerable amount of IL-6 was secreted by BMSCs, and BMSC-CM markedly elevated Bel-7404 cell invasion rate and stimulated the signal transduction of IL-6/STAT3 pathway. Neutralizing the secreted IL-6 bioactivity by the anti-IL-6 antibody diminished the invasion promoting effect and down-regulated IL-6/STAT3 pathway of BMSC-CM treated Bel 7404 cells. In conclusion, we found that BMSCs may activate the IL-6/STAT3 signaling pathway and promote cell invasion in Bel-7404 cells, suggesting that this protumor effect should be seriously considered before clinical application of MSC-mediated cancer therapy. PMID- 28659497 TI - Immune checkpoints in chronic obstructive pulmonary disease. AB - Cell-mediated immune responses are vital to the body's defence against infection and play a key role in tumour immunity. T-cell activation and cytotoxic function is tightly regulated by a series of immune-regulatory receptor-ligand interactions or immune checkpoints. These controls limit immune-mediated damage, particularly in the context of chronic infection. However, prolonged signalling through these axes can lead to progressive loss of T-cell function, termed exhaustion.Understanding of the biology of checkpoints and that exhaustion is reversible has been key to the development of new therapies directed at reversing the dysfunctional status of T-cells, which are dramatically improving outcomes of cancer treatment.Emerging data suggest that immune checkpoint axes are dysregulated in chronic obstructive pulmonary disease (COPD). T-cells from diseased lungs express the key receptor programmed death (PD)1 and demonstrate loss of cytotoxic function. However, the picture is complex with evidence of downregulation of the associated ligand PDL1 on alveolar macrophages. The resulting impact may be excessive T-cell inflammation as a consequence of acute infection, which may contribute to the pattern of exacerbation and lung damage characteristic of COPD. More work is needed to understand these immune controls in COPD before the therapeutic advances seen in lung cancer can be explored. PMID- 28659498 TI - Shared epithelial pathways to lung repair and disease. AB - Chronic lung diseases present tremendous health burdens and share a common pathobiology of dysfunctional epithelial repair. Lung adenocarcinoma, the leading cancer killer worldwide, is caused mainly by chemical carcinogens of tobacco smoke that induce mutations in pulmonary epithelial cells leading to uncontrolled epithelial proliferation. Lung epithelial cells that possess the capacity for self-renewal and regeneration of other lung cell types are believed to underlie the pathobiology of chronic obstructive, fibrotic and neoplastic lung disorders. However, the understanding of lung epithelial progenitor cell hierarchy and turnover is incomplete and a comprehensive model of the cellular and transcriptional events that underlie lung regeneration and carcinogenesis is missing. The mapping of these processes is extremely important, since their modulation would potentially allow effective cure and/or prevention of chronic lung diseases. In this review we describe current knowledge on cellular and molecular pathways at play during lung repair and carcinogenesis and summarise the critical lung cell populations with regenerative and cancerous potential. PMID- 28659495 TI - Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death. AB - Ceramides are essential precursors of sphingolipids with a dual role as mediators of apoptotic cell death. Previous work revealed that the ER-resident ceramide phosphoethanolamine (CPE) synthase SMSr/SAMD8 is a suppressor of ceramide mediated apoptosis in cultured cells. Anti-apoptotic activity of SMSr requires a catalytically active enzyme but also relies on the enzyme's N-terminal sterile alpha-motif or SAM domain. Here, we demonstrate that SMSr itself is a target of the apoptotic machinery. Treatment of cells with staurosporine or the death receptor ligand FasL triggers caspase-mediated cleavage of SMSr at a conserved aspartate located downstream of the enzyme's SAM domain and upstream of its first membrane span. Taking advantage of reconstitution experiments with SMSr produced in a cell-free expression system, specific caspase-inhibitors and gene silencing approaches, we show that SMSr is a novel and specific substrate of caspase-6, a non-conventional effector caspase implicated in Huntington's and Alzheimer's diseases. Our findings underscore a role of SMSr as negative regulator of ceramide-induced cell death and, in view of a prominent expression of the enzyme in brain, raise questions regarding its potential involvement in neurodegenerative disorders. PMID- 28659499 TI - Intersections of lung progenitor cells, lung disease and lung cancer. AB - The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials. PMID- 28659500 TI - Mechanistic overlap between chronic lung injury and cancer: ERS Lung Science Conference 2017 report. PMID- 28659502 TI - Pulmonary hypertensive vasculopathy in parenchymal lung diseases and/or hypoxia: Number 1 in the Series "Pathology for the clinician" Edited by Peter Dorfmuller and Alberto Cavazza. AB - Pulmonary hypertension (PH) with complicating chronic lung diseases and/or hypoxia falls into group 3 of the updated classification of PH. Patients with chronic obstructive lung disease (COPD), diffuse lung disease (such as idiopathic pulmonary fibrosis (IPF)) and with sleep disordered breathing are particularly exposed to the risk of developing PH. Although PH in such a context is usually mild, a minority of patients exhibit severe haemodynamic impairment, defined by a mean pulmonary arterial pressure (mPAP) of >=35 mmHg or mPAP values ranging between 25 mmHg and 35 mmHg with a low cardiac index (<2 L.min-1.m-2). The overlap between lung parenchymal disease and PH heavily affects life expectancy in such a patient population and complicates their therapeutic management. In this review we illustrate the pathological features and the underlying pathophysiological mechanisms of pulmonary circulation in chronic lung diseases, with an emphasis on COPD, IPF and obstructive sleep apnoea syndrome. PMID- 28659501 TI - Diet and exercise in the management of obstructive sleep apnoea and cardiovascular disease risk. AB - Obstructive sleep apnoea (OSA) is associated with increased cardiovascular disease (CVD) morbidity and mortality. It is accepted that OSA and obesity commonly coexist. The American Academy of Sleep Medicine recommends dietary induced weight loss and exercise as lifestyle treatment options for OSA. However, most clinical trials upon which this recommendation is based have focused on establishing the effectiveness of calorie-restricted, often low-fat diets for improving OSA severity, whereas less attention has been given to the means through which weight loss is achieved (e.g. altered dietary quality) or whether diet or exercise mediates the associations between reduced weight, improved OSA severity and the CVD substrate. The current evidence suggests that the benefits of a low-carbohydrate or Mediterranean diet in overweight and obese individuals go beyond the recognised benefits of weight reduction. In addition, exercise has an independent protective effect on vascular health, which may counter the increased oxidative stress, inflammation and sympathetic activation that occur in OSA patients. This review aims to expand our understanding of the effects of diet and exercise on OSA and associated CVD complications, and sets the stage for continued research designed to explore optimal lifestyle strategies for reducing the CVD burden in OSA patients. PMID- 28659503 TI - Nonsmall cell lung carcinoma: diagnostic difficulties in small biopsies and cytological specimens: Number 2 in the Series "Pathology for the clinician" Edited by Peter Dorfmuller and Alberto Cavazza. AB - The pathological and molecular classification of lung cancer has become substantially more complex over the past decade. For diagnostic purposes on small samples, additional stains are frequently required to distinguish between squamous cell carcinoma and adenocarcinoma. Subsequently, for advanced nonsquamous cell nonsmall cell lung carcinoma (NSCLC) patients, predictive analyses on epidermal growth factor receptor, anaplastic lymphoma kinase and ROS1 are required. In NSCLCs negative for these biomarkers, programmed death ligand-1 immunohistochemistry is performed. Small samples (biopsy and cytology) require "tissue" management, which is best achieved by the interaction of all physicians involved. PMID- 28659504 TI - Endoplasmic reticulum stress in lung disease. AB - Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled pollutants have devastating effects on the genome, it is now recognised that additional effects on protein folding also drive the development of lung disease. Protein misfolding in the endoplasmic reticulum affects the pathogenesis of many diseases, ranging from pulmonary fibrosis to cancer. It is therefore important to understand how cells respond to endoplasmic reticulum stress and how this affects pulmonary tissues in disease. These insights may offer opportunities to manipulate such endoplasmic reticulum stress pathways and thereby cure lung disease. PMID- 28659505 TI - Lung pathology for the clinician: a comprehensive approach. PMID- 28659506 TI - Cell therapy for lung disease. AB - Besides cancer and cardiovascular diseases, lung disorders are a leading cause of morbidity and death worldwide. For many disease conditions no effective and curative treatment options are available. Cell therapies offer a novel therapeutic approach due to their inherent anti-inflammatory and anti-fibrotic properties. Mesenchymal stem/stromal cells (MSC) are the most studied cell product. Numerous preclinical studies demonstrate an improvement of disease associated parameters after MSC administration in several lung disorders, including chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Furthermore, results from clinical studies using MSCs for the treatment of various lung diseases indicate that MSC treatment in these patients is safe. In this review we summarise the results of preclinical and clinical studies that indicate that MSCs are a promising therapeutic approach for the treatment of lung diseases. Nevertheless, further investigations are required. PMID- 28659508 TI - Resolution of Refractory Bipolar Disorder With Psychotic Features and Suicidality Through Lifestyle Interventions: A Case Report. AB - Background * This case illustrates the relationship between gut, hormonal, and brain function in that dietary change, mindfulness interventions, and detoxification led to resolution of disabling luteally exacerbated psychiatric symptoms. Summary * A 45-y-old, married, Caucasian female with a history of diagnosed bipolar disorder with psychotic features, premenstrual dysphoric disorder, panic disorder, and repeated occurrence of suicide attempts and self mutilating behavior presented for outpatient management. She reported limited gains through conventional treatment consisting of medication. The patient was prescribed a dietary, detox, and meditation regimen for 1 mo, after which supplementation was added to support detoxification, digestion, hormonal balance, and nervous system structure and function. Additional lifestyle management therapeutics included daily meditation, dry-skin brushing, and coffee enemas. Conclusion * This case exemplifies dramatic clinical remission after cessation of medication treatment and engagement of lifestyle interventions, which include dietary change, meditation, and detoxification. When medication demonstrates limited results, tapering combined with dietary interventions as the first-line therapy should be considered. PMID- 28659509 TI - The Impact of Self-directed Voice of Love Messages on Anger: A Pilot Study. AB - Context * Buddhist texts direct practitioners to generate a feeling of love to stop the affliction of anger. Modern self-help practices and clinical psychology have demonstrated that generating emotions of love can reduce anger. More studies are needed, however, to identify the active components of interventions and their applicability in clinical populations. Objective * The study investigated the hypothesis that enhancing self-love through frequent listening to recorded self loving messages can reduce anger. Design * The pilot study was designed to measure changes in anger level between baseline and postintervention in the course of 12 wk. Setting * The study occurred at Moa Oasis, Israel. Participants * Participants were adults enrolled in a program of study on advanced Tibetan Buddhism. Intervention * Participants were directed to record statements expressing love and appreciation of themselves in their own voices, inserting their names as the recipients of the messages. Participants listened to their recording for 2 min every morning, for 12 wk. Outcome Measures * At baseline and postintervention, the participants completed a self-reported questionnaire, the clinical anger score (CAS). Every 2 wk, they completed the short dimensions of anger reactions (DAR-5) scale to assess temporal changes in anger. Results * Eighty-six participants, 69 women and 17 men with a median age of 45 y and a range from 20 to 70 y, enrolled in the study. Fifty-six completed all designated tests. The mean CAS score decreased significantly, from 10.4 to 6.7 (P < .001). The analysis of variance demonstrated a time-X-practice effect, with 6 wk of practice being necessary to achieve a significant reduction in the DAR-5 score. Conclusions * The present study provided encouraging preliminary evidence on the effectiveness of a daily regimen of listening to a short recording of self-love and appreciation in reducing anger. The findings indicate that the technique merits replication in larger controlled studies. If supported, it could be applied in conflict resolution. PMID- 28659507 TI - Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress. AB - Aging is commonly associated with chronic low-grade inflammation and hypertension but it is unknown whether a cause-effect relationship exists between them. We compared the sensitivity of young adult (8-12 w) and aged (23-31 mo) male C57Bl6J mice to develop hypertension in response to a slow-pressor dose of angiotensin II (Ang II; 0.28 mg/kg/d; 28 d). In young mice, the pressor response to Ang II was gradual and increased to 142+/-8 mmHg over 28 d. However, in aged mice, Ang II promptly increased SBP and reached 155+/-12 mmHg by 28 d. Aging increased renal but not brain expression of Ang II receptors (At1ar and At2r) and elevated AT1R:AT2R expression ratio in mesenteric artery. Maximal contractile responses of mesenteric arteries to Ang II were enhanced in aged mice and were not affected by L-NAME, indomethacin or tempol. Mesenteric arteries and thoracic aortae from aged mice exhibited higher Nox2-dependent superoxide production. Despite having higher renal expression of Nlrp3, Casp-1 and Il-1beta, Ang II-induced hypertension (SBP: 139+/-7 mmHg) was unaffected by co-infusion of the NLRP3 inflammasome inhibitor, MCC950 (10 mg/kg/d; SBP: 145+/-10 mmHg). Thus, increased vascular AT1R:AT2R expression, rather than NLRP3 inflammasome activation, may contribute to enhanced responses to Ang II in aging. PMID- 28659510 TI - Swedish Massage: A Systematic Review of its Physical and Psychological Benefits. AB - Context * Swedish massage is the systematic application of manual pressure and the movement of soft tissue, with rhythmical pressure and stroking to obtain or maintain health. Studies have revealed its many benefits. Objective * The aim of the current study was to determine the results of past studies that evaluated the benefits of Swedish massage for various populations and to highlight its relevance as an alternative medical practice in health promotion and disease prevention. Methods * The research team performed a review of the literature using the key terms massage, relaxation, and benefits of massage. Original case reports and literature reviews of manual therapy published from 2004 to 2014 were included in the current review. The search was conducted using the SciELO, PubMed, and Medline databases. Setting * The study was performed at the Central Library of the Federal University of Sergipe, in Sao Cristovao, Sergipe, Brazil. Participants * Participants in the reviewed studies included varied populations, such as nurses in hospitals, infants and older children, pregnant women, older adults, and cancer patients. Results * A total of 4516 articles were identified for consideration through the electronic database searches. After screening, 117 potentially relevant articles were identified for full review, and 11 studies met the inclusion criteria. The studies showed beneficial results in most cases, including improved nasal breathing and cleanliness in children, reduced lower back pain for nurses, and improved adrenocortical function in infants. Massage is not completely risk free, however, and should be done by a professional very cautiously. Conclusions * Swedish massage has shown beneficial effects for multiple populations and can be used as a therapy. Its use in disease prevention is highly recommended. PMID- 28659511 TI - Ronald Epstein, MD: Bringing Mindfulness Into the Examination Room. AB - Advances in Mind-Body Medicine (Advances): You have come out with a book recently, titled Attending: Medicine, Mindfulness, and Humanity. What was the motive for writing this book? Dr Epstein: I knew that it was time to expand beyond writing for medical audiences and peer-reviewed journals when 2 realizations struck me. One is that important change in medicine often comes from the outside in as opposed to from the inside out. The degree to which the public is educated and energized about an issue can produce a change in medicine. The second is that the issue of being present, attentive, and curious and having a beginner's mind goes well beyond medical practice. I think the message is relevant to anyone who does work that involves people. PMID- 28659512 TI - Isotherms, thermodynamic and mechanism studies of removal of low concentration uranium (VI) by Aspergillus niger. AB - In order to develop an effective and economical method for removing low concentration radioactive wastewater of uranium, the biomass of 'CMCC(F)-98003' Aspergillus niger was investigated in a batch system. The maximum uranium adsorption capacity of 12.5 mg g-1 was obtained at the initial uranium concentration of 0.75 mg L-1. The biosorption data on a biomass concentration of 0.029 g L-1 fitted well to the Freundlich isotherm with a correlation coefficient (R2) of 0.987. The calculated thermodynamic parameters showed that the biosorption of uranium ions was endothermic (DeltaH degrees < 0). The results of scanning electron microscope and Fourier transform infrared spectrometry analysis revealed that nano-particles of uranium precipitation were formed on the cell surfaces after biosorption, and the functional groups of -CH, N-H, -COOH, P = O and the carbohydrates and alcohols were involved in the biosorption process between A. niger and uranium ions. PMID- 28659513 TI - Removal efficiencies and kinetic rate constants of xenobiotics by ozonation in tertiary treatment. AB - This study gives a full overview of the chemical oxidation by ozone of selected xenobiotics usually present in effluents of conventional wastewater treatment plants. A qualitative and quantitative overview of literature data was made, and describes the ozonation efficiency and processes for the elimination of 12 xenobiotics (pesticides and pharmaceuticals). A database was built, compiling literature results of experimental ozonation assays in laboratory and real-scale conditions. Special attention was paid to selecting the data and compiling reliable results on removal efficiencies and kinetic parameters. An original study was performed in a semi-batch reactor applying ozone on secondary effluent spiked beforehand with a cocktail of 12 xenobiotics. The results of this study were compared with the literature data to evaluate the influence of the kinetic competition of xenobiotics in spiked wastewater in the determination of kinetic rate constants. These 12 xenobiotics were classified into three groups (high /medium-/low-oxidizable) according to the ranges of their direct kinetic rate constants (kO3). A best effective ozone dose between 0.2 and 0.4 gO3 gDOC-1 is proposed for the elimination of xenobiotics. The predominant elimination pathway between direct and indirect oxidation was identified for each xenobiotic. PMID- 28659514 TI - Adsorption characteristic of As(III) on goethite waste generated from hydrometallurgy of zinc. AB - In this paper, goethite waste from hydrometallurgy of zinc was used as a raw material for arsenic adsorbent preparation. The goethite waste adsorbent (GWA) was characterized with scanning electron microscope (SEM), X-ray powder diffraction (XRD), and particle size distribution analysis. The adsorption of As(III) on GWA was studied as a function of contact time, pH, and coexisting anions. The safety of GWA usage in the wastewater treatment process was assessed by toxicity characteristic leaching procedure (TCLP) tests. The equilibrium adsorption data fitted well with the Langmuir isotherm model, and the maximum adsorption capacity of As(III) on GWA was 51.47 mg.g-1. GWA showed higher adsorption capacity at weak alkaline pH values (7.0-9.5). The coexisting PO43- and SiO32- presented significant adsorption competition with As(III) in aquatic systems. No significant heavy metals leaching was observed for GWA and As(III) loaded GWA in TCLP tests, which implied the safety of GWA as an adsorbent for arsenic containing wastewater treatment. PMID- 28659515 TI - Fabrication of sponge biomass adsorbent through UV-induced surface-initiated polymerization for the adsorption of Ce(III) from wastewater. AB - The recovery of rare earth ions from industrial wastewater has aroused wide concern in recent years. In present work, we synthesized a novel three dimensional adsorbent (denoted as LF-AA) by grafting loofah fiber with acrylic acid via ultraviolet radiation. The LF-AA was washed by boiling water and subjected to soxhlet extraction with acetone and then fully characterized by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). Rare earth ion (Ce(III)) was selected as a model to validate its adsorption property. The saturation adsorption capacity for Ce(III) reaches 527.5 mg/g. Not only was this material highly efficient at adsorbing Ce(III) from aqueous solutions, it also proved to have ideal performance in regeneration; the total adsorption capacity of LF-AA for Ce(III) after six successive cycles decreased only 6.40% compared with the initial capacity of LF-AA. More importantly, the LF-AA can be easily separated from aqueous solutions because of its three-dimensional sponge natural structure. This study provides a new insight into the fabrication of biomass adsorbent and demonstrated that the LF-AA can be used as excellent adsorbent for the recovery of rare earth ions from wastewater. PMID- 28659516 TI - Surface modified polythiophene nanocomposite using HPC and DBSNa for heavy metal ion removal. AB - In the present work, surface modified nanocomposite adsorbents polythiophene (PTh)/rice husk ash (RHA) have successfully been synthesized in the presence of hydroxyl propyl cellulose (HPC) and sodium dodecyl benzene sulfonate (DBSNa) as surfactants. The synthesized nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR), and the synthesized nanocomposite adsorbents were applied as an efficient sorbent for Pb(II) ion removal from contaminated water and the removal efficiency was compared to pure PTh/RHA composite. Several variables affecting the extraction efficiency of the nanoadsorbent i.e., adsorbent dosage, metal ion concentration, extraction time, and adsorption conditions were investigated. The highest efficiency of adsorption (98.12%) was achieved with 0.05 g of PTh/RHA/HPC nanocomposite adsorbent in 50 mL of 10 mg/L Pb(II) solution. Equilibrium studies were also performed with known linear and non-linear adsorption isotherms including Langmuir, Freundlich and Sips from which the best result was achieved with Freundlich and Sips isotherms representing multilayer adsorption on heterogeneous structure of the adsorbent. The pseudo-first-order model and the pseudo-second-order model were adopted to analyze the adsorption kinetics of Pb(II) on PTh/RHA/HPC and PTh/RHA/DBSNa. The consistency of the experimental adsorption capacity with the ones calculated from the pseudo-second-order kinetic model illustrated that the adsorption of Pb(II) onto both adsorbents at initial concentration of 50 mg/L was probably controlled by chemical adsorption. PMID- 28659517 TI - A novel growth method for diatom algae in aquaculture waste water for natural food development and nutrient removal. AB - Diatom algae are known to play an important role as primary producers in many diverse ecosystems, including artificial aquaculture ponds where they also aid in maintaining water quality by consuming excess nutrients. But factors influencing their growth are still poorly understood. In the present study the effect of micronutrients, N:P ratio and silica concentration on benthic diatom Synedra sp. grown in fish pond waste water was studied along with nutrient removal efficiency. We have studied nine different treatments, of which addition of micronutrient mixture Nualgi along with adjusted N:P to 6:1 resulted in highest cell density, followed by silicate enrichment, whereas only N:P adjustment and Nualgi addition had no significant effect on diatom growth. At the end of the growth experiment, the N removal efficiencies of treatment groups (50.23%-65.44%) were significantly higher (P < 0.05) than that of the control group (43.56%), whereas phosphate removal efficiency was significantly higher (P < 0.05) with Nualgi and N:P adjustment (53.37%-68.98%). The silicate consumption was significantly higher in the control group, at 63.87%, than in other experimental groups. These results will give us a new insight into important factors influencing beneficial algae growth and simultaneous nutrient removal from aquaculture waste water. PMID- 28659518 TI - The decolorization and mineralization of orange II by microwave-assisted ball milling. AB - This study proposed an integrated technique of reduction coupled with an oxidation process in order to acquire simultaneously both decolorization and mineralization of orange II under the condition of microwave-assisted milling. Experimental variables of initial dye concentration, iron dosage, microwave power, solution pH and initial H2O2 concentration were systematically studied. Under the optimal operational parameters (100 mg/L aqueous solution of pH 3 containing 400 mg/L H2O2 while controlling microwave power at 400 W), the results showed that the decolorization efficiency is up to 91% after reaction for 2 min and the total organic carbon removal efficiencies were 72.7% and 80.5% at a reaction time of 10 min and 60 min, respectively. It indicated that the decolorization and mineralization of orange II were largely enhanced by the reduction of zero-valent iron in the ball milling process and the oxidation of hydroxyl radicals generated by hydrogen peroxide. It suggested that microwave assisted ball milling technology has potential application for degradation of azo dye in wastewater. PMID- 28659519 TI - Multi-objective evolutionary polynomial regression-based prediction of energy consumption probing. AB - Electrocoagulation (EC) is employed to investigate the energy consumption (EnC) of synthetic wastewater. In order to find the best process conditions, the influence of various parameters including initial pH, initial dye concentration, applied voltage, initial electrolyte concentration, and treatment time are investigated in this study. EnC is considered the main criterion of process evaluation in investigating the effect of the independent variables on the EC process and determining the optimum condition. Evolutionary polynomial regression is combined with a multi-objective genetic algorithm (EPR-MOGA) to present a new, simple and accurate equation for estimating EnC to overcome existing method weaknesses. To survey the influence of the effective variables, six different input combinations are considered. According to the results, EPR-MOGA Model 1 is the most accurate compared to other models, as it has the lowest error indices in predicting EnC (MARE = 0.35, RMSE = 2.33, SI = 0.23 and R2 = 0.98). A comparison of EPR-MOGA with reduced quadratic multiple regression methods in terms of feasibility confirms that EPR-MOGA is an effective alternative method. Moreover, the partial derivative sensitivity analysis method is employed to analyze the EnC variation trend according to input variables. PMID- 28659520 TI - Adsorption behavior of methyl orange onto an aluminum-based metal organic framework, MIL-68(Al). AB - MIL-68(Al), a powdered aluminum-based metal organic framework (MOF), was synthesized and used to explore its adsorption behavior toward methyl orange (MO). The adsorption isotherm, thermodynamics, kinetics, and some key operating factors as well as changes in the material's structure were investigated. The adsorption isotherm conformed to the Langmuir isotherm model and the maximum equilibrium adsorption capacity was 341.30 mg g-1. Thermodynamic data demonstrated that the adsorption process was spontaneous, endothermic and showed positive entropy. For kinetics, the process of MO adsorption onto MIL-68(Al) was more suitably described by a pseudo-second-order model. Electrostatic and hydrogen-bonding interactions contributed to dye adsorption, with electrostatic interactions considered to be the principal binding force between adsorbent and adsorbate. Furthermore, MIL-68(Al) maintained a stable structure after adsorption. From these results, MIL-68(Al) was suggested here to be a stable MOF adsorbent for removing MO from aqueous solution. PMID- 28659521 TI - Removal and recovery of ammonia from chicken manure. AB - The feasibility of the conversion of organic nitrogen available in raw chicken manure (CM) into ammonia via hydrolysis and the removal of ammonia from anaerobically digested manure were evaluated in this study. Firstly, the hydrolysis experiments were performed and the effects of temperature, total solids (TS) content and retention time were investigated. The results showed that 90% of the organic nitrogen in CM can be converted into ammonia via biological hydrolysis within 3.6 days at 35 degrees C and 10-12.5% TS content. In addition to high ammonification efficiency, partial acidification of the CM was also experienced during this period. Secondly, removal of ammonia from anaerobically digested CM was examined by flushing the head space of a vigorously stirred bottle partially filled with digestate. At 35 degrees C, after 45 hours 77% of the influent ammonia was removed. PMID- 28659522 TI - Biofilm carrier migration model describes reactor performance. AB - The accuracy of a biofilm reactor model depends on the extent to which physical system conditions (particularly bulk-liquid hydrodynamics and their influence on biofilm dynamics) deviate from the ideal conditions upon which the model is based. It follows that an improved capacity to model a biofilm reactor does not necessarily rely on an improved biofilm model, but does rely on an improved mathematical description of the biofilm reactor and its components. Existing biofilm reactor models typically include a one-dimensional biofilm model, a process (biokinetic and stoichiometric) model, and a continuous flow stirred tank reactor (CFSTR) mass balance that [when organizing CFSTRs in series] creates a pseudo two-dimensional (2-D) model of bulk-liquid hydrodynamics approaching plug flow. In such a biofilm reactor model, the user-defined biofilm area is specified for each CFSTR; thereby, Xcarrier does not exit the boundaries of the CFSTR to which they are assigned or exchange boundaries with other CFSTRs in the series. The error introduced by this pseudo 2-D biofilm reactor modeling approach may adversely affect model results and limit model-user capacity to accurately calibrate a model. This paper presents a new sub-model that describes the migration of Xcarrier and associated biofilms, and evaluates the impact that Xcarrier migration and axial dispersion has on simulated system performance. Relevance of the new biofilm reactor model to engineering situations is discussed by applying it to known biofilm reactor types and operational conditions. PMID- 28659523 TI - Hydrological performance of dual-substrate-layer green roofs using porous inert substrates with high sorption capacities. AB - Given that the common medium in existing green roofs is a single layer composed of organic and inorganic substrates, seven pilot-scale dual-substrate-layer extensive green roofs (G1-G7), which include nutrition and adsorption substrate layers, were constructed in this study. The effectiveness of porous inert substrates (activated charcoal, zeolite, pumice, lava, vermiculite and expanded perlite) used as the adsorption substrate for stormwater retention was investigated. A single-substrate-layer green roof (G8) was built for comparison with G1-G7. Despite the larger total rainfall depth (mm) of six types of simulated rains (43.2, 54.6, 76.2, 87.0, 85.2 and 86.4, respectively), the total percent retention of G1-G7 varied between 14% and 82% with an average of 43%, exhibiting better runoff-retaining capacity than G8 based on the maximum potential rainfall storage depth per unit height of adsorption substrate. Regression analysis showed that there was a logarithmic relationship between cumulative rainfall depth with non-zero runoff and stormwater retention for G1-G4 and a linear relationship for G5-G8. To enhance the water retention capacity and extend the service life of dual-substrate-layer extensive green roofs, the mixture of activated charcoal and/or pumice with expanded perlite and/or vermiculite is more suitable as the adsorption substrate than the mixture containing lava and/or zeolite. PMID- 28659524 TI - Batch equilibrium and kinetics of mercury removal from aqueous solutions using polythiophene/graphene oxide nanocomposite. AB - Polythiophene/graphene oxide (PTh/GO) nanocomposite (NC) was prepared through polymerisation of thiophene in the presence of GO and was used for mercury ions (Hg2+) adsorption in aqueous solutions. Equilibrium studies showed that mercury removal was strongly influenced by solution pH and GO composition in the NC. The equilibrium data were well described by both Langmuir and Freundlich isotherm models, with a Langmuir maximum adsorption capacity of 113.6 mg/g. Adsorption kinetics were rapid and correlated well with the pseudo-second-order model. The thermodynamic studies indicated that the adsorption was spontaneous and endothermic in nature, and occurred through a physicochemical mechanism. Desorption studies revealed that PTh/GO NC could be used repeatedly for three adsorption-desorption cycles without a significant loss in its capacity. Competing ions reduced mercury uptake although considerable values were still attained. The findings of this study suggest that PTh/GO NC is a potential adsorbent for Hg2+ removal from aqueous solutions. PMID- 28659525 TI - Comparative evaluation of conventional and microwave hydrothermal carbonization of human biowaste for value recovery. AB - This paper compares conventional and microwave hydrothermal carbonization (HTC) of human biowaste (HBW) at 160 degrees C, 180 degrees C and 200 degrees C as a potential technology to recover valuable carbonaceous solid fuel char and organic rich liquor. Also discussed are the influence of HTC heating methods and temperature on HBW processing conversion into solid fuel char, i.e. yield and post-HTC management, dewaterability rates, particle size distribution and the carbon and energy properties of solid fuel char. While HTC temperatures influenced all parameters investigated, especially yield and properties of end products recovered, heating source effects were noticeable on dewatering rates, char particle sizes and HBW processing/end product recovery rate and, by extension, energy consumed. The microwave process was found to be more efficient for dewatering processed HBW and for char recovery, consuming half the energy used by the conventional HTC method despite the similarity in yields, carbon and energy properties of the recovered char. However, both processes reliably overcame the heterogeneity of HBW, converting them into non-foul end products, which were easily dewatered at <3 seconds/g total solids (TS) (c.f. 50.3 seconds/g TS for a raw sample) to recover energy-densified chars of ~17 MJ/kg calorific value and up to 1.4 g/l of ammonia concentration in recovered liquor. PMID- 28659526 TI - Response surface modeling of bioremediation of acid black 52 dye using Aspergillus flavus. AB - Bioremediation is an efficient process to remove metals and dyes from solutions using different micro-organisms. In the present study, the efficiency of growing Aspergillus flavus (isolated from the effluent of an electroplating industry) to treat a synthetic solution of acid black 52 dye (a trivalent chromium complex dye) was investigated. Maximum removal of dye and chromium was observed to be 390 and 17.22 mg/L, respectively, at an initial dye concentration of 750 mg/L and at pH 4.5 in 50 hours in a batch bioreactor. The biomass concentration was reduced from 4.1 to 0.4 g/L with increasing dye concentration from 100 to 2,000 mg/L. The response surface modeling for color removal was performed using the range of initial dye concentration 200-400 mg/L, pH 4-6 and time 35-50 hours. The optimum conditions for maximum color removal (76.52%) were observed at initial dye concentration: 200 mg/L, pH: 4.75 and time: 50 hours. The deviation (-0.02%) showed a close agreement between the experimental and predicted values of color removal. The scanning electron microscopic and energy dispersive X-ray analyses indicated bioremediation of the dye. PMID- 28659527 TI - Advanced phosphorus removal via coagulation, flocculation and microsieve filtration in tertiary treatment. AB - The applicability of microsieve technology together with coagulation and flocculation for advanced phosphorus removal was investigated. A pilot unit including a microsieve with 10 MUm mesh size was operated continuously with secondary effluent from Ruhleben wastewater treatment plant in Berlin. By applying a pretreatment of 0.07-0.09 mmol/L (as metal) coagulant and 1.5-2 mg/L cationic polymer, total phosphorus values below 80 MUg/L were achieved. Coagulation with polyaluminum chloride (PACl) produced a better effluent quality compared to FeCl3, as less suspended solids and less residual coagulant were found in the microsieve effluent. In addition, the transmittance of UV radiation through the water was improved by using PACl. The produced amount of backwash water was always below 3% (on average 1.6%). Under optimized mixing conditions, polymer doses of 0.6 mg/L were possible without losses in water quality and filtration performance. Microsieving with chemical pretreatment is a viable option for high quality effluent polishing. PMID- 28659528 TI - Dual bioremediation of phenol and Cr(VI) by mixed microbial cultures in the presence of molasses. AB - Simultaneous phenol and Cr(VI) bioremoval by two different mixed cultures, from petroleum-contaminated soil (PS) and boron-contaminated wastewater (BW), was investigated in regard to different culture media, pH levels (6-8), initial phenol (25-100 mg/L) and Cr(VI) (15-50 mg/L) concentrations. The optimum medium was found to be mineral salt medium tested, which contained 1% (v/v) molasses (MSM). Optimum pH values were 6 for PS and 8 for BW. All of the phenol present in the samples was mineralized regardless of its concentrations tested, Cr(VI) bioremoval was enhanced by the increase in phenol concentrations, and molasses also exerted a positive effect on Cr(VI) removal, and the yields reached 100% for both pollutants, even at 13.1 mg/L Cr(VI) and 91.1 mg/L phenol concentration in PS samples. In MSM containing PS samples approximate efficiency was 100% for phenol removal; but Cr(VI) removal ratios were 64.9% and 41.7% at 25.8 mg/L and 41.3 mg/L concentrations, respectively. Finally it can be concluded that molasses stimulated Cr(VI) bioremoval at elevated phenolic conditions in the mixed microbial culture, and molasses might be of use for the bioremediation of phenol and Cr(VI) polluted wastewaters. PMID- 28659529 TI - Combined ultrafiltration-electrodeionization technique for production of high purity water. AB - Electrodeionization (EDI) is the most common method to produce high purity water used for boiler feed water, microelectronic, and pharmaceutical industries. Commonly, EDI is combined with reverse osmosis (RO) to meet the requirement of EDI feed water, with hardness less than 1 ppm. However, RO requires a relatively high operating pressure and ultrafiltration (UF) as pretreatment which results in high energy consumption and high complexity in piping and instrumentation. In this work, UF was used as the sole pretreatment of EDI to produce high purity water. Tap water with conductivity 248 MUS/cm was fed to UF-EDI system. The UF EDI system showed good performance with ion removal more than 99.4% and produced water with low conductivity from 0.2 to 1 MUS/cm and total organic compounds less than 0.3 ppm. Generally, product conductivity decreased with the increase of current density of EDI and the decrease of feed velocity and UF pressure. The energy consumption for UF-EDI system in this work was 0.89-2.36 kWh/m3. These results proved that UF-EDI system meets the standards of high purity water for pharmaceutical and boiler feed water with lower investment and energy consumption than RO-EDI system. PMID- 28659530 TI - Inhibitory effect of thiourea on biological nitrification process and its eliminating method. AB - Thiourea is a typical nitrification inhibitor that shows a strong inhibitory effect against the biological nitrification process. The 50% inhibitory concentration (IC50) of thiourea on nitrification was determined to be 0.088 mg g VSS-1, and nitrifiers recovered from the thiourea inhibition after it was completely degraded. The thiourea-degrading ability of the sludge system was improved to 3.06 mg gVSS-1 h-1 through cultivation of thiourea-degrading bacteria by stepwise increasing the influent thiourea concentration. The dominant thiourea degrading bacteria strain that used thiourea as the sole carbon and nitrogen source in the sludge system was identified as Pseudomonas sp. NCIMB. The results of this study will facilitate further research of the biodegradation characteristics of thiourea and similar pollutants. PMID- 28659531 TI - Effects of HRT on the efficiency of denitrification and carbon source release in constructed wetland filled with bark. AB - Constructed wetland is widely used to treat municipal sewage. However, lack of carbon source always constraints the application of constructed wetland in advanced tailwater treatment process. Bark was used as the filler and external carbon source of constructed wetland in the study, and the effects of hydraulic retention time (HRT) on NO3--N removal efficiency and carbon release velocity were explored. Results showed that the NO3--N removal process was steady in the constructed wetland filled with bark without additional carbon source. The NO3--N removal efficiency and NO3--N concentration presented a first-order reaction. The reaction rate constant k was 0.4 day-1. The relationship between NO3--N removal efficiency (eta) and HRT (t) was eta = 1-e-0.4t, and eta was increased with increasing of HRT. eta reached a maximum of 77% at HRT of 4.48 days. eta obtained the minimum of 20% at HRT of 0.75 days. The relationship between the carbon source releasing velocity (v) by bark and HRT was v = 0.53(1.62/t-1/t2) + 0.32. v increased first and then decreased with HRT increasing. The maximum v was detected at t = 1.12 days. PMID- 28659532 TI - Water masses surface temperatures assessment and their effect on surrounding environment. AB - The aim of this study was to evaluate the effect of water masses on the surface temperature with direct impact on the surrounding area. Three systems were used for the study: a fully vegetated system (subsurface flow constructed wetland (CW)), a lake with no vegetation and a lake partially vegetated with Lemna minor. Infrared thermography was applied for the different systems analysis, allowing the determination of the surface temperature spatial distribution. In general, the presence of plants and water in the analyzed systems contributed to lowering the surface temperatures when comparing to its surroundings. Differences up to about 22 degrees C were observed in the temperature between the CW canopy and the surrounding soil, and up to about 19 degrees C between the lake and the surrounding border. Different plant species (Canna flaccida, Canna indica and Zantedeschia aethiopica) inhabiting the CW were also compared and slightly higher average surface temperatures were observed for C. indica. The above mentioned results are relevant in terms of supporting a strategy for water systems inclusion, for example a lake or a CW, in a site as means of having influence in the surface temperature and to some extent in the heat island effect supporting a sustainable environmental management. PMID- 28659533 TI - Ecology of duckweed ponds used for nutrient recovery from wastewater. AB - The microorganism community that grows under duckweed shelter can play an important role on treatment processes. Therefore, the present study aimed to assess the zooplankton dynamic and microbial community in duckweed ponds (DPs) applied for domestic wastewater treatment under open field conditions. A pilot system comprised of two DPs in series (DP1 and DP2), with 10 m2 each, received domestic wastewater through a flow rate of 200 L.day-1. Thus, the system was monitored during 314 days through samples collected and analysed weekly. Also, the zooplankton organisms were identified and quantified. DNA sequencing was performed in order to identify the bacterial populations. The findings showed a high efficiency of nutrient removal with 93% and 91% of total phosphorus and total nitrogen, respectively. A high density of microcrustaceans was observed in DP1 reaching 4,700 org.100 mL-1 and rotifers (over than 32,000 org.100 mL-1) in DP2, that could be related to the low suspended solids concentration (<30 mg.L-1) and turbidity (<10 NTU). The bacterial community showed a strong heterogeneity between samples collected along the seasons. Through these findings, it is possible to realise that the understanding of ecology could help to enhance the operation and designs of DPs. PMID- 28659534 TI - Photo-degradation ibuprofen by UV/H2O2 process: response surface analysis and degradation mechanism. AB - The removal of ibuprofen (IBP) in aqueous solution using UV/H2O2 process was evaluated. The response surface methodology (RSM) and Box-Behnken design were employed to investigate the effects of process parameters on IBP removal, including the initial IBP concentration, H2O2 dosage, UV light intensity, and initial pH value of solution. The RSM model developed herein fits well with the experiments, and provides a good insight into the OH radical irritated degradation mechanisms and kinetics. High resolution accurate mass spectrometry coupled with liquid chromatography was used to identify the degradation intermediates. A total of 23 degradation products were identified, including mono hydroxylated products and dihydroxylated products. A series of OH radical initiated reactions, including hydroxylation, dihydroxylation, decarboxylation, demethylation, ring break, lead to the final mineralization of IBP to CO2 and H2O. UV/H2O2 technology could be a promising technology for IBP removal in aqueous solution. PMID- 28659535 TI - Gaussian process regression for monitoring and fault detection of wastewater treatment processes. AB - Monitoring and fault detection methods are increasingly important to achieve a robust and resource efficient operation of wastewater treatment plants (WWTPs). The purpose of this paper was to evaluate a promising machine learning method, Gaussian process regression (GPR), for WWTP monitoring applications. We evaluated GPR at two WWTP monitoring problems: estimate missing data in a flow rate signal (simulated data), and detect a drift in an ammonium sensor (real data). We showed that GPR with the standard estimation method, maximum likelihood estimation (GPR MLE), suffered from local optima during estimation of kernel parameters, and did not give satisfactory results in a simulated case study. However, GPR with a state-of-the-art estimation method based on sequential Monte Carlo estimation (GPR-SMC) gave good predictions and did not suffer from local optima. Comparisons with simple standard methods revealed that GPR-SMC performed better than linear interpolation in estimating missing data in a noisy flow rate signal. We conclude that GPR-SMC is both a general and powerful method for monitoring full-scale WWTPs. However, this paper also shows that it does not always pay off to use more sophisticated methods. New methods should be critically compared against simpler methods, which might be good enough for some scenarios. PMID- 28659536 TI - Rethinking micropollutant removal assessment methods for wastewater treatment plants - how to get more robust data? AB - This paper covers the pitfalls, recommendations and a new methodology for assessing micropollutant removal efficiencies in wastewater treatment plants. The proposed calculation rules take into account the limit of quantification and the analytical and sampling uncertainty of measured concentrations. We identified six cases for which a removal efficiency value is reliable and four other cases where result is highly variable (uncertain) due to very low or unquantified concentrations in effluent or when the influent-effluent concentrations differential is below the measurement uncertainty. The influence of the proposed calculation rules on removal efficiency values was scrutinized using actual results from a research project. The paper arrives at detailed recommendations for limiting the impact of other sources of uncertainty during sampling (sampling strategy, cleaning and field blank), chemical analyses (suspended solids and sludge) and data processing according to the targeted objectives. PMID- 28659537 TI - Serum 25-hydroxyvitamin D concentrations in dogs with suspected acute pancreatitis. AB - The present study aimed to determine whether circulating serum concentrations of 25-hydroxyvitamin D [25-(OH) D] differed between healthy dogs and dogs with acute pancreatitis (AP). Twenty-two healthy dogs and twenty client-owned dogs with AP were enrolled in the study. Serum concentrations of 25-(OH) D, blood ionized calcium (iCa), and serum C-reactive protein (CRP) were measured. Concentrations of serum 25-(OH) D and blood iCa in dogs with AP were significantly lower than those of healthy dogs, and serum concentrations of CRP in dogs with AP were significantly higher than those of healthy dogs. A significant difference in 25 (OH) D serum concentrations was observed between survivor and non-survivor dogs with AP. After resolution of clinical signs, concentrations of serum 25-(OH) D, blood iCa, and serum CRP did not differ compared to those before treatment. This study shows that dogs with AP exhibit decreased 25-(OH) D levels, which might be associated with calcium imbalances and mortality rate in canine AP. PMID- 28659539 TI - Progesterone dose-dependently modulates hepatocyte growth factor production in 3T3-L1 mouse preadipocytes. AB - It is well documented that estrogen is predominant inducer of hepatocyte growth factor (HGF) in a variety of cell types. However, the effect of progesterone (P) remains to be elusive. Thus, in the present study, we examined the effect of P and combined effect of P and 17beta-estradiol (E2) on HGF expression and production in 3T3-L1 fibroblastic preadipocytes and mature adipocytes, as a model of stromal cells. Northern blot analysis showed that hgf mRNA expressed in preadipocytes was notably higher than that of mature adipocytes, and increased by treatment of preadipocytes with E2 or 10 nM P, but not with 1,000 nM P. The E2 induced hgf mRNA expression was enhanced by 10 nM P, but suppressed by 1,000 nM P. Western blot analysis revealed that biological active forms of HGF protein was found in the preadipocyte culture medium, while the lesser amount of HGF precursor protein was detected in the mature adipocyte culture medium. The amounts of HGF were changed dependently on the hgf mRNA expression levels. These results indicate that HGF production is intricately regulated by E2 and P at the transcriptional levels in 3T3-L1 cells, and may explain the changes in the HGF production during the mammary gland development, especially decrease in HGF expression during pregnancy when P concentration is high. PMID- 28659538 TI - Pyothorax induced by an intrathoracic foreign body in a miniature dachshund: Migration of a popsicle stick from the stomach. AB - A four-year-old dachshund presented with a two-week history of pyrexia, depression, and cough. Four months earlier, the owner observed the dog swallow a whole popsicle stick, but the animal showed no clinical signs at that time. Radiography, ultrasonography, and computed tomography confirmed an intrathoracic linear foreign body and pleural effusion in the right thorax. The pleural fluid was bloody and purulent, and contained inflammatory cells and Escherichia coli. The dog was diagnosed with pyothorax induced by a foreign body, and was treated successfully by surgical removal of the foreign body, partial lung lobectomy, thoracic lavage, and antibiotics. The foreign body was identified as a popsicle stick that the dog had eaten. PMID- 28659541 TI - Very Late Strut Overhang on Coronary Angioscopy After Bioresorbable Vascular Scaffold Implantation in a Clinically Stable Patient. PMID- 28659540 TI - An alert of Mycobacterium tuberculosis infection of rhesus macaques in a wild zoo in China. AB - Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), is becoming increasingly recognized as an important cause of fatal chronic illnesses in China. In this study, we report an infectious disease among 84 rhesus macaques at a Chinese zoo. Their clinical signs and symptoms were very similar with the manifestations of TB in humans. To determine the potential pathogens of this outbreak, many methods were used. First, tuberculin skin tests showed that none of the monkeys displayed significant skin reactions. Subsequently, the sera were tested for specific antibody IgG; 29 (34.5%) and 39 (46.4%) blood samples tested positive by TB-IgG and TB-DOT, respectively. Radiographic examination showed characteristic imageology changes in 14 (16.7%) monkeys. One individual determined as positive by the above three methods was euthanized, and histopathological analysis demonstrated typical granulomas and caseous necrosis in the lung, liver, spleen, and intestine. Furthermore, the pathogenic mycobacteria were isolated from lung lobe, cultured on acidic Lowenstein-Jensen culture medium, and identified as M. tuberculosis by real-time PCR and DNA sequencing. Nevertheless, the origin of the infection remained unknown. These findings emphasize the need to strengthen the management and training of staff, especially those working at animal shelters. PMID- 28659542 TI - Asymptomatic Lower Extremity Deep Vein Thrombosis - Clinical Characteristics, Management Strategies, and Long-Term Outcomes. AB - BACKGROUND: The prognosis of asymptomatic deep vein thrombosis (DVT) is uncertain and there is no consensus on the necessity of detection and treatment.Methods and Results:We retrospectively evaluated 300 patients with asymptomatic lower extremity DVT screened from 4,514 consecutive patients on ultrasound at Kyoto University Hospital between January 2010 and September 2015. The subjects had concomitant active cancer in 40%, unprovoked DVT in 59%, and distal DVT in 70%. The cumulative 5-year incidences of symptomatic recurrent venous thromboembolism (VTE); major bleeding; and all-cause death were 14.5%, 16.6%, and 34.1%, respectively. Among 232 patients (77%) with prolonged anticoagulant therapy, anticoagulants were discontinued in 48.4% at 1 year. Anticoagulant therapy was associated with a significantly higher incidence of major bleeding compared with the non-anticoagulant group (20.5% vs. 1.5%, P=0.01) with no significant effect on the incidence of VTE. In patients with active cancer, the favorable effect of anticoagulants relative to no anticoagulants for VTE was significant (HR, 0.22; 95% CI: 0.05-0.95). CONCLUSIONS: Prolonged anticoagulants therapy was implemented in the majority of patients with asymptomatic DVT, but was associated with a significantly higher risk for major bleeding. On subgroup analysis in patients with active cancer, however, there appeared to be a benefit of prolonged anticoagulant therapy in decreasing the rate of symptomatic recurrent VTE. PMID- 28659543 TI - SOX2 nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism. AB - Hypogonadotropic hypogonadism (HH) is a genetically heterogeneous condition that occurs either as an isolated disorder or as a component of congenital malformation syndromes. SOX2 is a causative gene of syndromic HH characterized by anophthalmia, microphthalmia, or coloboma and other neurological defects such as epilepsy. To date, the causal relationship between SOX2 abnormalities and non syndromic HH remains speculative. Here, we identified a nonsense mutation of SOX2 in a male patient clinically diagnosed with non-syndromic HH. The patient had epilepsy but no additional clinical features. Ophthalmological examination revealed no abnormalities except for decreased thickness of the retinal nerve fiber layer. Audiometry showed mild sensorineural hearing impairment of both ears. Hormonal evaluation suggested isolated gonadotropin deficiency. Next generation sequencing-based mutation screening of 13 major causative genes for HH identified a p.Lys35* mutation in SOX2 and excluded pathogenic mutations in other tested genes. The p.Lys35* mutation appeared to encode a non-functioning SOX2 protein that lacks 283 of 317 amino acids. The SOX2 mutation was absent in the maternal DNA sample, while a paternal sample was unavailable for sequence analysis. These results expand the clinical consequences of SOX2 haploinsufficiency to include non-syndromic HH. Systematic mutation screening using a next-generation sequencer and detailed evaluation of nonspecific ocular/neurological features may help identify SOX2 mutation-positive individuals among HH patients. PMID- 28659545 TI - Baicalein Protects against Rotenone-Induced Neurotoxicity through Induction of Autophagy. AB - Baicalein, a typical flavonoid compound, has neuroprotective properties in several neurological disorders. Autophagy plays a central role in maintaining the cellular homeostasis, and is involved in the pathogenesis of Parkinson's disease (PD). Recently, baicalein has been reported to induce autophagy. Therefore, the current study was designed to investigate whether baicalein could protect against rotenone-induced neurotoxicity via induction of autophagy both in SH-SY5Y cells and in a mouse model. A chronic PD mouse model was established by continuous intragastric administration of rotenone for 12 weeks. Baicalein was administrated from 7 to 12 week. Our results showed that baicalein prevented rotenone-induced behavioral deficits, dopaminergic neuronal loss, apoptosis and mitochondrial dysfunction. Furthermore, baicalein restored rotenone-impaired autophagy, and blocking the baicalein-induced autophagy using 3-methyladenine inhibited the neuroprotective effects of bacalein. Baicalein increased cell viability and restored mitochondrial function in SH-SY5Y cells. The beneficial effect of baicalein was abrogated by 3-methyladenine treatment. Furthermore, rapamycin increased autopahgy and reduced the rotenone-induced neurotoxicity in SH-SY5Y cells. Collectively, these results suggest that baicalein could prevent rotenone induced neurotoxicity via restoring autophagy. PMID- 28659544 TI - Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma. AB - Although advanced thyroid carcinoma patients who cannot be cured by conventional therapy have lacked effective treatment, multitargeted tyrosine kinase inhibitors have recently become available. Phase 3 trials of lenvatinib showed a median time to objective response of 2 (95 % confidence interval (CI) 1.9-3.5) months, demonstrating that shrinks tumors rapidly. The phenomenon of immediate tumor shrink is known as early tumor shrinkage (ETS) which is related to clinical outcome in other malignancies. However, precisely when within 8 weeks lenvatinib starts to affect tumors remains unclear. In tumors near the carotid arteries, trachea, or esophagus, a rapid therapeutic effect can induce fistula formation or arterial bleeding. To prevent such treatment-emergent serious adverse events (SAE), early imaging evaluation seems to be very important. In this study, the point in time when lenvatinib started to shrink tumors was retrospectively investigated. The subjects were 16 patients who started lenvatinib administration between May and August 2015. Tumor size was evaluated by computed tomography (CT) scans frequently within the first 8 weeks according to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline. Initial tumor response was defined as >= 10% tumor reduction. Serum thyroglobulin (Tg) level was monitored in 8 differentiated thyroid carcinoma (DTC) without TgAb patients. At the first evaluation, 13 patients (83.3 %) showed tumor reduction and that decreased with time. Thirteen patients (83.3 %) showed >10 % tumor reduction within 8 weeks. In all DTC patients, serum Tg level was markedly decreased. In conclusion, lenvatinib immediately shrinks tumors, the so-called ETS phenomenon. Therefore, careful attention should be paid to fistula formation from the early phase. PMID- 28659546 TI - Focused Ultrasound Treatment, Present and Future. AB - The discovery that ultrasound waves could be focused inside the skull and heated to high temperatures at a focal point goes back to 1944. However, because the skull causes the ultrasound waves to attenuate and scatter, it was believed that application of this technology would be difficult, and that it would be impossible to use this approach in the surgical treatment of intracranial diseases. Eventually, magnetic resonance image guided focused ultrasound (MRgFUS) surgery began being used to treat uterine fibroids, breast cancer and bone metastasis and locally confined prostate cancer. In the first ten years of the 21st century, new developments in this technology have been achieved, broadening the scope of practical application, and treatment is now being performed in various countries around the world. In 2011, third-generation transcranial focused ultrasound made it possible to use thermocoagulation and create intracranial lesions measuring 2 to 6 mm in diameter with a precision of around 1 mm. It was also possible to produce MR images which relay information of temperature changes in real time, enabling a shift from reversible test heating to irreversible therapeutic heating. This gave rise to the possibility of a minimally-invasive treatment with outcomes similar to those of conventional brain surgery. This method is paving the way to a new future not only in functional neurosurgery, but in cranial neurosurgery targeting conditions such as epilepsy and brain tumors, among others. In this paper, we describe the current state and future outlook of magnetic resonance image guided focused ultrasound, which uses computed tomography (CT) bone images in combination with MRI monitoring of brain temperature. PMID- 28659547 TI - Balloon Kyphoplasty under Three-dimensional Radiography Guidance. AB - Percutaneous balloon kyphoplasty (PBKP) is generally performed under two dimensional (2D) radiography guidance (lateral- and anteroposterior (A-P) views) using C-arm fluoroscopy. However, 2D images taken by single-plane or bi-plane fluoroscopy cannot provide information regarding axial views, particularly the Z axis. Lack of information regarding the Z axis prevents the creation of three dimensional (3D) images. Currently, there has been a progress in interventional X ray systems, and they are capable of providing 3D radiographic images using a rotational angiography mode which is used to create 3D angiographies. In this report, we described the usefulness of 3D radiography guidance. Patients treated by PBKP was designed to evaluate the efficacy of 3D radiography guidance. These patients experienced osteoporotic vertebral fractures with severe pain. We retrospectively analyzed patients who underwent PBKP from February to December 2016. All patients had a single-level vertebral fracture and underwent surgery by 2D or 3D radiography guidance. We performed 16 patients in 3D radiography guidance, and 10 patients in traditional 2D radiography guidance. This 3D radiography guided PBKP increase the amount of the polymethyl methacrylate (PMMA) injection compared with ordinary 2D method. As a result, postoperative vertebral height and alignment were significantly improved. Both groups have no complication. To confirm the final results and make PBKP more effective, 3D radiography guidance is feasible and safe for balloon kyphoplasty. PMID- 28659548 TI - Pathogenicity of Enterococci. AB - Enterococci belong to the group of lactic acid bacteria (LAB), and inhabit the gastrointestinal tracts of a wide variety of animals from insects and to human, and the commensal organism in humans and animals. The commensal/probiotic role of enterococci has evolved through thousands of years in mutual coexistence. Enterococcus have many favorable traits that have been appreciated in food fermentation and preservation, and many serve as probiotics to promote health. While lactobacillus have been shown to confer numerous benefits on and often regarded as health bringing organisms, enterococci have become more recognized as emerging human pathogens in recent years. Mac Callum and Hastings characterized an organism, now known to be Enterococcal faecalis, which was isolated from a lethal case of endocarditis on 1899. The report was the first detailed description of its pathogenic capabilities. Over the past few decades, multi-drug resistance enterococci have become as important health-care associated pathogen, and leading causes of drug resistance infection. The modern life style including the broad use of antibiotics in medical practice and animal husbandry have selected for the convergence of potential virulence factors to the specific enterococcus species such as E. faecium and E. faecalis. The development of modern medical care of intensive and invasive medical therapies and treatments for human disease, and existence of severe compromised patients in hospitals has contributed to the increased prevalence of these opportunistic organisms. The virulence factors converged in E. faecalis and E. faecium which have been isolated in nosocomial infections, include antibiotic resistance, extracellular proteins (toxins), extrachromosome and mobile genetic elements, cell wall components, biofilm formation, adherence factors, and colonization factor such as bacteriocin, etc. In these potential virulence factors, I presented characteristics of enterococcal conjugative plasmid, cytolysin, collagen binding protein of adhesion, bacteriocins, and drug resistances. I made reference to our original reports, and review books for this review. The review books are "Enterococci: from Commensals to Leading Causes of Drug Resistant Infection, NCBI Bookshelf. A service of the National Library of Medicine, National Institute of Health. Ed. by Michael S Gilmore, Don B Clewell, Yasuyoshi Ike, and Nathan Shankar", and "The Enterococci: Pathogenesis, Molecular Biology, and Antibiotic Resistance, Gilmore M., Clewell D., Courvadin P., Dunny G., Murray B., Rice L., (ed) 2002. ASM Press". PMID- 28659549 TI - Predictors and Clinical Impact of Functional Mitral Stenosis Induced by Restrictive Annuloplasty for Ischemic and Functional Mitral Regurgitation. AB - BACKGROUND: There are few reports of the determinants of "functional" mitral stenosis in terms of a residual mitral valve (MV) pressure gradient >5 mmHg following restrictive mitral annuloplasty (RMA) or the effect on long-term outcome in patients with functional mitral regurgitation (MR).Methods and Results:Serial cardiac catheterization and echocardiographic studies were performed in 55 patients with functional MR who underwent RMA using a 24/26-mm semi-rigid complete ring. The mean postoperative (1 month) catheter-measured MV gradient was 3.4+/-1.6 mmHg, which was independently associated with corresponding cardiac output [standardized partial regression coefficient (SPRC)=0.59] and indexed effective orifice area (SPRC=-0.25). Body surface area (BSA) had the greatest contribution to MV gradient (SPRC=0.38), followed by use of a 24-mm ring (SPRC=0.33) and hemodialysis (SPRC=0.26). Receiver-operating characteristic curve analysis demonstrated an optimal BSA cutoff value of 1.86 m2to predict post-MV stenosis (21% for <1.86 m2vs. 86% for >=1.86 m2, P=0.002). During follow-up (75+/-32 months), freedom from adverse events did not differ between patients with (n=16) and without (n=39) an MV gradient >=5 mmHg (log-rank P=0.24). CONCLUSIONS: Post-RMA MV gradient was determined not only by the degree of annular reduction but also by patients' hemodynamic factors (e.g., cardiac output). Implantation of a 24/26-mm annuloplasty ring for patients with BSA >=1.86 m2indicated a high likelihood of post-MV stenosis. However, mild MV stenosis did not adversely affect late outcome after RMA. PMID- 28659550 TI - Significant Prognostic Value of Acute Preload Stress Echocardiography Using Leg Positive Pressure Maneuver for Patients With Symptomatic Severe Aortic Stenosis Awaiting Aortic Valve Intervention. AB - BACKGROUND: Although aortic valve intervention is recommended for virtually all symptomatic patients with aortic stenosis (AS), how urgently the intervention should be performed remains controversial. The aim of this study was thus to determine whether the preload reserve in response to leg-positive pressure (LPP) maneuver could serve for decision-making for AS patients awaiting aortic valve intervention.Methods and Results:Sixty-eight patients with symptomatic AS, who were referred for aortic valve intervention, were recruited. Stroke volume (SV) was assessed by means of pulsed-wave Doppler, and the ratio between transmitral E wave and mitral annular velocity (e') was calculated to estimate ventricular filling pressure. While waiting for intervention, 11 patients experienced preoperative cardiac events. During acute preload stress, forward SV for patients without cardiac events increased significantly (from 43+/-9 to 49+/-10 mL/m2, P<0.01) along with a minimal change in filling pressure (E/e': from 20+/-8 to 21+/-9, NS). For patients with cardiac events, the Frank-Starling mechanism was significantly impaired (SVi: from 40+/-9 to 38+/-7 mL/m2, NS), while filling pressure increased to the critical level (E/e': from 24+/-8 to 31+/-8, P<0.001). Both the patients without flow reserve (?SVi <4.5 mL/m2) and those without diastolic reserve (?E/e' >=2.9) exhibited significantly worse event-free survival than the others (P<0.05, respectively). CONCLUSIONS: Assessment of preload reserve during LPP stress could facilitate risk stratification of patients with severe AS waiting for aortic valve intervention. PMID- 28659551 TI - Impact of Stent Type and Presence of Vasospastic Angina on Long-Term Prognosis. AB - BACKGROUND: Little is known about the impact of stent type on the prognosis of vasospastic angina (VSA) in patients who undergo stent implantation.Methods and Results:We evaluated consecutive patients undergoing coronary angiography with positive (n=650; VSA) and negative (n=2,872; non-VSA) ergonovine testing. Among them, 304 patients undergoing stent implantation for organic stenosis were classified for comparison into 3 respective VSA and non-VSA groups based on stent type (68 and 78 with bare-metal stent [BMS]; 21 and 49 with sirolimus-eluting stent [SES]; 26 and 62 with newer generation drug-eluting stent [N-DES]). The primary outcome was defined as target lesion revascularization, target vessel revascularization, emergency coronary angiography, and cardiac death. The 2-year cumulative incidence of the primary outcome was significantly higher in the VSA group than non-VSA group after SES implantation (38.1% vs. 16.1%, P=0.03), whereas there were no differences between the 2 groups after both BMS implantation and N-DES implantation. The difference in the percent diameter stenosis from mid-term to late-term follow-up was significantly higher in the VSA group than non-VSA group (10.0% vs. 2.3%, P=0.045) after SES implantation, whereas there were no differences between the 2 groups after both BMS implantation and N-DES implantation. CONCLUSIONS: The impact of VSA on clinical and angiographic outcomes was observed only in SES implantation, but not after N DES or BMS implantation. PMID- 28659552 TI - Differential Effects of Myocardial Afadin on Pressure Overload-Induced Compensated Cardiac Hypertrophy. AB - BACKGROUND: Pressure overload induces cardiac hypertrophy, which often ends in heart failure. Afadin is an adaptor protein that is ubiquitously expressed and, in the heart, it localizes at intercalated disks. The current study aimed to examine the afadin-mediated cardiac phenotype in mice exposed to different types of pressure overload: transverse aortic constriction (TAC) burden and angiotensin II (Ang II) stimulation.Methods and Results:Conditional knockout mice with selective deletion of afadin (afadin cKO) in cardiomyocytes were generated. TAC operated and Ang II-infused mice at 4 weeks had a similar degree of pressure overload and cardiac hypertrophy in the heart. In afadin cKO mice, TAC operation caused progressive left ventricular dysfunction and heart failure, while Ang II infusion did not deteriorate cardiac function. Furthermore, TAC operation produced more fibrosis and apoptosis in the heart than Ang II infusion, and the expression of growth differentiation factor 15, which can promote apoptosis, in the afadin cKO heart was higher in TAC-operated mice than Ang II-infused ones. CONCLUSIONS: In the 2 pressure overload models, myocardial afadin is involved in mechanical stress-induced, but not pharmacological Ang II-related, compensated cardiac hypertrophy. PMID- 28659553 TI - Microbial Fouling in a Water Treatment Plant and Its Control Using Biocides. AB - Water treatment plants (WTP) are vital in the food, pharmaceutical and chemical process industries. This investigation describes the dense microbial fouling by microbes and organic compounds in a WTP of a heavy water producing industrial unit. On-site observations showed severe algal and bacterial growth in the various units of the WTP which are open to the atmosphere and very dense fungal fouling in the closed vacuum degasser unit. Digital and microscopic images showed that the microbial fouling problem was primarily due to a fungus. Microbiological analysis showed a count of ~105 cfu mL-1 in various sections of the WTP. On the contrary, slime/biofilm scrapings had very high bacterial populations (>109 cfu cm-2). High organic carbon values in the system (5.0 to 19.5 ppm) had supported the growth of the fouling fungus in various sections of the WTP along with bacteria. Chlorination was found to be inadequate in controlling the biofouling problem. Consequently chlorine dioxide was tested and found to be a better biocide in controlling the bacterial population. A 2.0% Sodium-2-pyridinethiol-1 oxide solution had completely inhibited the fouling fungus. The paper discusses the importance of fungal adaptation in an industrial unit and highlights the biodeterioration of various sections of the WTP unit. PMID- 28659554 TI - Importance of the High-Expression of Proline Transporter PutP to the Adaptation of Escherichia coli to High Salinity. AB - The effect of the amount of the proline transporter PutP expression on the mechanism of adaptation of E. coli cells to high salinity was analyzed. The PutP gene derived from the E. coli expression plasmid was introduced into the E. coli cell, and a high PutP expression strain was developed. At 1.2 M NaCl culture condition, the growth of normal E. coli cells was inhibited, whereas high ProP expression cells showed growth under 2.5 M NaCl conditions. The uptake of proline by E. coli as a compatible solute and substrate for metabolization was in good accordance with those seen in cell growth. These data suggested that the amount of the proline transporter PutP expression played an important role in the adaptation of E. coli cells to high saline conditions. PMID- 28659555 TI - The Effects of Temperature on the Growth and Heat Resistance of Cronobacter spp. AB - The growth and survival of Cronobacter isolates were examined under incubation at different temperatures, and their thermal death behavior was investigated at high temperature conditions of above 50C. Seventy three strains isolated from fresh vegetables, dried foods and soil were tested: 28 of Cronobacter sakazakii, 5 of C. dublienensis, 27 of C. malonaticus and 13 of C. turicensis. All Cronobacter strains grew and multiplied predominantly at 35 and 44C until 16 hours of incubation, but showed poor growth at 15C, and no growth at 5C. At 48C, the bacteria grew slightly during 6 to 8 h-incubation but decreased or were inactivated after 16 h-incubation. The heat resistance of Cronobacter spp. was measured under the conditions of 50, 55, 60, 65 and 70C. Cronobacter strains survived almost without decrement for 30 min at 50C, but decreased suddenly and perished completely within 10 to 20 min at 55C and within 2 - 5 min at above 60C. Some food materials should be stored below 5C until the preparation, and dried food including powdered infant milk formula should be utilized immediately after reconstitution and preparation. PMID- 28659556 TI - A Novel Double Subculture Method and Its Theory for the Enumeration of Injured Cells in Stressed Microbial Population. AB - A novel double subculture method, termed DiVSaL (Differential Viabilities between Solid and Liquid media) method, for the enumeration of injured cell population of a microorganism, which occurs after some sublethal to lethal treatment, was proposed. In this method injured cells were enumerated as the differential value between viabilities determined with two different techniques, the conventional plate counting using a solid agar medium and the growth delay analysis using a liquid medium. In the former technique, the viable cell number is obtained as colony forming unit (CFU) formed on an agar medium where sublethally injured cells are as much rescued as possible. In the latter technique, on the other hand," the integrated viability" defined by Takano and Tsuchido (1982) is introduced and is calculated from the growth delay of a stressed population, referred to unstressed one. For the growth delay analysis, in this paper, not only the original theoretical model, where the specific growth rate (and therefore the defined G10 value) does not change after the exposure to a stress treatment, but also a novel modified theory, where the parameter changes, is proposed. On the theoretical background, this DiVSaL method as a double subculture method can be used to enumerate the injured cells without selection by addition of some inhibitor or by nutritional shortage. PMID- 28659557 TI - Biocontrol Science Vol.21, No.2 June, 2016. AB - There are three mistakes in Biocontrol Science, Vol.21 (2), p.81-89 (2016). The detail is as follows. PMID- 28659558 TI - Biopreservative Efficacy of Bacteriocin BacFL31 in Raw Ground Turkey Meat in terms of Microbiological, Physicochemical, and Sensory Qualities. AB - The effect of the semi purified bacteriocin BacFL31 at 200 and 400 AU/g on the shelf life of refrigerated raw ground turkey meat was investigated. The microbiological, physicochemical, and sensory properties of the meat samples were examined during refrigerated storage. The findings indicated that BacFL31 treatments were effective (p<0.05) against the proliferation of various spoilage microorganisms and suppressed the growth of Listeria monocytogenes and Salmonella Typhimurium. The pH, % Met-MB, and TBA-RS values of the treated samples were lower (p<0.05) than those of their control samples. The addition of BacFL31 extended the shelf life and enhanced the sensory attributes of the turkey meat samples during refrigerated storage. These results suggest that BacFL31 could be considered a promising candidate for future application as an additive to preserve the raw turkey meat during storage at 4C. PMID- 28659559 TI - Microflora in the Soft Tissue of the Pacific Oyster Crassostrea gigas Exposed to the Harmful Microalga Heterosigma akashiwo. AB - A marine raphidophyte Heterosigma akashiwo is a causative agent of harmful microalgal blooms, which often cause the massive mortality of aquacultured finfish. In the present study, the Pacific oyster Crassostrea gigas was reared with H. akashiwo, and effect of the microalga on filter-feeding behavior and microflora of the gastrointestinal tract was investigated. The intake of the raphidophyte cells inhibited the molluscan filter-feeding activities, suggesting the negative physiological effect of the microalgal cell contents. However, the bivalves ingested the H. akashiwo cells to the same extent as the diatom Chaetoceros calcitrans, a non-harmful indicator to estimate the filtration rate, showing a continuation of their non-selective ingestion of the phytoplankton. Microflora of the oyster soft tissue was dominated by bacteria affiliated with the family Rhodobacteraceae, some of which are associated with microalgae. In addition, the Bacteroidetes species, in which algicidal bacteria are included, were also found in the bivalve individuals exposed to H. akashiwo. These results suggested that the ingested phytoplankton affected the microbial flora in the gastrointestinal tracts, some constituents of which helped the mollusc assimilate the ingested red tide phytoplankton. This study will provide beneficial information to clarify mechanisms by which the oyster evades the ichthyotoxicity of harmful microalgae and the participation of the intestinal microorganisms in these processes. PMID- 28659560 TI - Environmental Impact of Tributyltin-Resistant Marine Bacteria in the Indigenous Microbial Population of Tributyltin-Polluted Surface Sediments. AB - We compared the TBT-resistant ability of resting cells prepared from isolates that formed colonies on nutrient agar plates containing 100 uM tributyltin (TBT) chloride, such as Photobacterium sp. TKY1, Halomonas sp. TKY2, and Photobacterium sp. NGY1, with those from taxonomically similar type strains. Photobacterium sp. TKY1 showed the highest ability among those three isolates. The number of surviving Photobacterium sp. TKY1 cells was hardly decreased after 1 h of exposure to 100 uM TBTCl, regardless of the number of resting cells in the range from 109.4 to 104.2 CFU mL-1. In such an experimental condition, the maximum number of TBT molecules available to associate with a single cell was estimated to be approximately 6.0 x 1011.8. Resting cells prepared from type strains Photobacterium ganghwense JCM 12487T and P. halotolerans LMG 22194T, which have 16S rDNA sequences highly homologous with those of Photobacterium sp. TKY1, showed sensitivity to TBT, indicating that TBT-resistant marine bacterial species are not closely related in spite of their taxonomic similarity. We also estimated the impact of TBT-resistant bacterial species to indigenous microbial populations of TBT-polluted surface sediments. The number of surviving TBT-sensitive Vibrio natriegens ATCC 14048T cells, 106.2+/-0.3 CFU mL-1, was reduced to 104.4+/-0.4 CFU mL-1 when TBT-resistant Photobacterium sp. TKY1 cells, 109.1+/-0.2 CFU mL-1, coexisted with 109.4+/-0.2 CFU mL-1 of V. natriegens ATCC 14048T cells in the presence of 100 uM TBTCl. These results indicate that the toxicity of TBT to TBT sensitive marine bacterial populations might be enhanced when a TBT-resistant marine bacterial species inhabits TBT-polluted surface sediments. PMID- 28659561 TI - Detection of Fungi from an Indoor Environment using Loop-mediated Isothermal Amplification (LAMP) Method. AB - Loop-mediated isothermal amplification (LAMP) is a useful DNA detection method with high specificity and sensitivity. The LAMP reaction is carried out within a short time at a constant temperature without the need for thermal cycling. We developed a LAMP primer set for detecting a wide range of fungi by aligning the sequences of the large subunit ribosomal RNA gene of Candida albicans (Ascomycota), Cryptococcus neoformans (Basidiomycota), and Mucor racemosus (Mucorales). The threshold of C. albicans rDNA as template with our LAMP primer set was in the range of 10-100 copies per a reaction. In this study, we evaluated the correlation between colony forming units (CFU) and LAMP detection rate using the LAMP method for environmental fungi. The LAMP method should be a useful means of detecting fungi in indoor environments, disaster areas, or even in confined manned spacecraft to prevent allergies or infections caused by fungi. PMID- 28659570 TI - Tyrosine Phosphorylation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 20 and Its Functional Role. AB - Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20 is an immunoglobulin-superfamily transmembrane protein that contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic region. However, the mechanism for tyrosine phosphorylation of, or the physiological function of, this protein remains largely unknown. Here we have shown that CEACAM20 is indeed tyrosine-phosphorylated by either treatment with pervanadate or forced expression of c-Src. In addition, Tyr522, Tyr559 or Tyr570, the latter two of which are within the ITAM, is likely important for such tyrosine phosphorylation. Forced expression of Myc-tagged wild-type CEACAM20 promoted the phagocytic activity of cultured cells for microbeads coupled with anti-Myc antibodies. By contrast, such phagocytic activity was markedly reduced when a mutant form of CEACAM20, in which Tyr559 and Tyr570 were substituted with phenylalanine, was expressed. Furthermore, the CEACAM20-mediated phagocytic activity was markedly prevented by the treatment with an inhibitor for either Src family kinases (SFKs), Syk, phosphoinositide 3-kinase (PI3K) or phospholipase C-gamma (PLCgamma). Inhibition of actin polymerization by Cytochalasin D significantly inhibited the CEACAM20 mediated phagocytosis. These results thus suggest that tyrosine phosphorylation of CEACAM20 likely promotes phagocytic activity of the cells. The CEACAM20 mediated phagocytic activity requires the activation of SFKs, Syk, PI3K or PLCgamma. PMID- 28659571 TI - Chest Pain and Sudden-Onset Paraplegia at the Emergency Department: An Uncommon Presentation. AB - BACKGROUND Coarctation of the aorta is characterized by narrowing of the descending aorta. The narrowing typically is at the isthmus, the segment just distal to the left subclavian artery. Adults with undiagnosed aortic coarctation are asymptomatic or may present with nonspecific hypertension. We present a case that highlights the uncommon complication of aortic coarctation with spinal compression syndrome. CASE REPORT A 45-year-old male presented to the emergency department (ED) with acute-onset chest pain; he experienced urinary incontinence and bilateral lower limb weakness during his ED visit. Chest CT showed coarctation of the aorta and MRI of the spine showed an epidural nodular lesion. He received emergency aortic stent placement surgery, followed by successful hematoma removal and was discharged with residual lower-extremity paraplegia. CONCLUSIONS Chest pain with lower limb paraplegia presentation should consider aortic coarctation complicated with spinal hemorrhage as a possible cause. PMID- 28659572 TI - Effect of Vitamin D and Tacrolimus Combination Therapy on IgA Nephropathy. AB - BACKGROUND To explore the effects and the mechanism of vitamin D (VD) and tacrolimus (TAC) combinatorial therapy in the treatment of IgA nephropathy (IgAN) in a rat model. MATERIAL AND METHODS IgAN rat models constructed by oral immunization with bovine serum albumin (BSA) and lipopolysaccharide (LPS) (n=30) and were treated with: saline (model group), TAC (TAC group), or TAC+VD therapy (TAC+VD group) through gavage daily for 14 days. Serum creatinine (Scr), albumin (ALB), blood urea nitrogen (BUN), and urinary protein (UAE) levels were determined. Histopathology of renal tissues was examined after hematoxylin and eosin (H&E) staining. The levels of cytokines TGF-beta1, IL-5, IFN-gamma, and IL 4 in serum were detected by enzyme-linked immunosorbent assay (ELISA). Changes in TLR4/NF-kappaB pathway were evaluated by western blot. RESULTS Both TAC and TAC+VD treatment significantly restored the dysregulated Scr, ALB, BUN, and UAE levels in IgAN rats. TAC+VD therapy more prominently restored Scr and UAE levels (p<0.05). TAC+VD therapy demonstrated superior efficacy in reducing glomerular mesangial cells hyperplasia, reducing thickening of the glomerular basement membrane and glomerular infiltration of inflammatory cells. Thymus and spleen indexes were also increased (p<0.05). The levels of TGF-beta1, IL-5, and IL-4 of the TAC+VD group were also lower than those of the TAC group (p<0.05). The TAC+VD group also demonstrated increased IFN-gamma, and decreased p-P65/P65 and TLR4 compared to the TAC group. CONCLUSIONS TAC+VD combinatorial therapy can effectively alleviate renal tissue damage in IgAN rats by regulating immune response and the NF-kappaB/TLR4 pathway. PMID- 28659573 TI - Multilevel Evolutionary Algorithm that Optimizes the Structure of Scale-Free Networks for the Promotion of Cooperation in the Prisoner's Dilemma game. AB - Understanding the emergence of cooperation has long been a challenge across disciplines. Even if network reciprocity reflected the importance of population structure in promoting cooperation, it remains an open question how population structures can be optimized, thereby enhancing cooperation. In this paper, we attempt to apply the evolutionary algorithm (EA) to solve this highly complex problem. However, as it is hard to evaluate the fitness (cooperation level) of population structures, simply employing the canonical evolutionary algorithm (EA) may fail in optimization. Thus, we propose a new EA variant named mlEA-CPD-SFN to promote the cooperation level of scale-free networks (SFNs) in the Prisoner's Dilemma Game (PDG). Meanwhile, to verify the preceding conclusions may not be applied to this problem, we also provide the optimization results of the comparative experiment (EAcluster), which optimizes the clustering coefficient of structures. Even if preceding research concluded that highly clustered scale-free networks enhance cooperation, we find EAcluster does not perform desirably, while mlEA-CPD-SFN performs efficiently in different optimization environments. We hope that mlEA-CPD-SFN may help promote the structure of species in nature and that more general properties that enhance cooperation can be learned from the output structures. PMID- 28659574 TI - Validation of weak biological effects by round robin experiments: cytotoxicity/biocompatibility of SiO2 and polymer nanoparticles in HepG2 cells. AB - All over the world, different types of nanomaterials with a diversified spectrum of applications are designed and developed, especially in the field of nanomedicine. The great variety of nanoparticles (NPs), in vitro test systems and cell lines led to a vast amount of publications with conflicting data. To identify the decisive principles of these variabilities, we conducted an intercomparison study of collaborating laboratories within the German DFG Priority Program SPP1313, using well-defined experimental parameters and well characterized NPs. The participants analyzed the in vitro biocompatibility of silica and polymer NPs on human hepatoma HepG2 cells. Nanoparticle mediated effects on cell metabolism, internalization, and inflammation were measured. All laboratories showed that both nanoparticle formulations were internalized and had a low cytotoxicity profile. Interestingly, small variations in nanoparticle preparation, cell handling and the type of culture slide influenced the nanoparticle stability and the outcomes of cell assays. The round robin test demonstrated the importance of the use of clearly defined and characterized NPs and parameters for reproducible results across laboratories. Comparative analyses of in vitro screening methods performed in multiple laboratories are absolutely essential to establish robust standard operation procedure as a prerequisite for sound hazard assessment of nanomaterials. PMID- 28659577 TI - Elitist Binary Wolf Search Algorithm for Heuristic Feature Selection in High Dimensional Bioinformatics Datasets. AB - Due to the high-dimensional characteristics of dataset, we propose a new method based on the Wolf Search Algorithm (WSA) for optimising the feature selection problem. The proposed approach uses the natural strategy established by Charles Darwin; that is, 'It is not the strongest of the species that survives, but the most adaptable'. This means that in the evolution of a swarm, the elitists are motivated to quickly obtain more and better resources. The memory function helps the proposed method to avoid repeat searches for the worst position in order to enhance the effectiveness of the search, while the binary strategy simplifies the feature selection problem into a similar problem of function optimisation. Furthermore, the wrapper strategy gathers these strengthened wolves with the classifier of extreme learning machine to find a sub-dataset with a reasonable number of features that offers the maximum correctness of global classification models. The experimental results from the six public high-dimensional bioinformatics datasets tested demonstrate that the proposed method can best some of the conventional feature selection methods up to 29% in classification accuracy, and outperform previous WSAs by up to 99.81% in computational time. PMID- 28659575 TI - Interaction of tankyrase and peroxiredoxin II is indispensable for the survival of colorectal cancer cells. AB - Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. Here we demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. PrxII deletion in mice with inactivating mutation of adenomatous polyposis coli (APC) gene reduces intestinal adenomatous polyposis via Axin/beta-catenin axis and thereby promotes survival. In human colorectal cancer cells with APC mutations, PrxII depletion consistently reduces the beta catenin levels and the expression of beta-catenin target genes. Essentially, PrxII depletion hampers the PARP-dependent Axin1 degradation through tankyrase inactivation. Direct binding of PrxII to tankyrase ARC4/5 domains seems to be crucial for protecting tankyrase from oxidative inactivation. Furthermore, a chemical compound targeting PrxII inhibits the expansion of APC-mutant colorectal cancer cells in vitro and in vivo tumor xenografts. Collectively, this study reveals a redox mechanism for regulating tankyrase activity and implicates PrxII as a targetable antioxidant enzyme in APC-mutation-positive colorectal cancer.2 Cys peroxiredoxin (Prx) enzymes are highly expressed in most cancers but how they promote cancer progression is unclear. Here the authors show that in colorectal cancers with APC mutation, PrxII binds to tankyrase and prevents its oxidative inactivation, thereby preventing Axin1-dependent degradation of 2b-catenin. PMID- 28659578 TI - Photocatalytic hollow TiO2 and ZnO nanospheres prepared by atomic layer deposition. AB - Carbon nanospheres (CNSs) were prepared by hydrothermal synthesis, and coated with TiO2 and ZnO nanofilms by atomic layer deposition. Subsequently, through burning out the carbon core templates hollow metal oxide nanospheres were obtained. The substrates, the carbon-metal oxide composites and the hollow nanospheres were characterized with TG/DTA-MS, FTIR, Raman, XRD, SEM-EDX, TEM SAED and their photocatalytic activity was also investigated. The results indicate that CNSs are not beneficial for photocatalysis, but the crystalline hollow metal oxide nanospheres have considerable photocatalytic activity. PMID- 28659576 TI - Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission. AB - Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO2-induced ischemia and that LA-derived 13 hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke. PMID- 28659579 TI - Sex Hormones, Gonadotropins, and Sex Hormone-binding Globulin in Infants Fed Breast Milk, Cow Milk Formula, or Soy Formula. AB - Measurement of endogenous hormones in early life is important to investigate the effects of hormonally active environmental compounds. To assess the possible hormonal effects of different feeding regimens in different sample matrices of infants, 166 infants were enrolled from two U.S hospitals between 2006 and 2009. The children were classified into exclusive soy formula, cow milk formula or breast milk regimens. Urine, saliva and blood samples were collected over the first 12 months of life. Estradiol, estrone, testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) levels were measured in the three matrices. Lower estradiol and LH levels were found in urine and saliva samples of soy formula-fed boys compared to cow formula fed boys. Higher LH level was found in urine samples of soy formula-fed girls compared to cow formula-fed girls. However, we found neither a neonatal testosterone rise in the boys nor a gender-specific difference in testosterone levels, which suggests that urinary testosterone levels may not accurately reflect blood levels during mini-puberty. Nevertheless, our study shows that blood, urine and saliva samples are readily collectible and suitable for multi hormone analyses in children and allow examination of hypotheses concerning endocrine effects from dietary compounds. PMID- 28659581 TI - The emergence and transient behaviour of collective motion in active filament systems. AB - Most living systems, ranging from animal flocks, self-motile microorganisms to the cytoskeleton rely on self-organization processes to perform their own specific function. Despite its importance, the general understanding of how individual active constituents initiate the intriguing pattern formation phenomena on all these different length scales still remains elusive. Here, using a high density actomyosin motility assay system, we show that the observed collective motion arises from a seeding process driven by enhanced acute angle collisions. Once a critical size is reached, the clusters coarsen into high and low density phases each with fixed filament concentrations. The steady state is defined by a balance of collision induced randomization and alignment effects of the filaments by multi-filament collisions within ordered clusters.Self organization is observed in cytoskeletal systems but emergence of order from disorder is poorly understood. Using a high density actomyosin system, the authors capture the transition from disorder to order, which is driven by enhanced alignment effects caused by increase in multi-filament collisions. PMID- 28659580 TI - Palmitic Acid-BSA enhances Amyloid-beta production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1alpha and Akt/NF kappaB pathways. AB - The pathophysiological actions of fatty acids (FAs) on Alzheimer's disease (AD), which are possibly mediated by genomic effects, are widely known; however, their non-genomic actions remain elusive. The aim of this study was to investigate the non-genomic mechanism of extra-cellular palmitic acid (PA) regulating beta amyloid peptide (Abeta) production, which may provide a link between obesity and the occurrence of AD. In an obese mouse model, a high-fat diet (HFD) significantly increased the expression levels of APP and BACE1 as well as the AD pathology in the mouse brain. We further found that PA conjugated with bovine serum albumin (PA-BSA) increased the expression of APP and BACE1 and the production of Abeta through the G protein-coupled receptor 40 (GPR40) in SK-N-MC cells. PA-BSA coupling with GPR40 significantly induced Akt activation which is required for mTOR/p70S6K1-mediated HIF-1alpha expression and NF-kappaB phosphorylation facilitating the transcriptional activity of the APP and BACE1 genes. In addition, silencing of APP and BACE1 expression significantly decreased the production of Abeta in SK-N-MC cells treated with PA-BSA. In conclusion, these results show that extra-cellular PA coupled with GPR40 induces the expression of APP and BACE1 to facilitate Abeta production via the Akt-mTOR-HIF 1alpha and Akt-NF-kappaB pathways in SK-N-MC cells. PMID- 28659582 TI - Deciphering biodiversity and interactions between bacteria and microeukaryotes within epilithic biofilms from the Loue River, France. AB - Epilithic river biofilms are complex matrix-enclosed communities harboring a great diversity of prokaryotic and eukaryotic microorganisms. Interactions between these communities and the relative impacts of environmental factors on their compositions are poorly understood. In this study, we assessed the spatio temporal variation in the diversity and composition of bacterial and microeukaryotic communities within biofilms in a French river. Significant changes were found in the composition of these microbial communities over the sampling period and between the upstream and downstream stations. In addition, the beta diversity of the bacterial community tended to decrease along the river, mostly as a result of turnover. These changes could be caused by the different water temperatures and geological and hydrological river contexts at the sampling sites (from karst landscape to river plain). Finally, our network analysis showed multiple correlations among dominant OTUs. Among them, negative correlations between Rhodobacteraceae and two other dominant groups of photosynthetic microorganisms (cyanobacteria and diatoms) were particularly interesting, which raises the question of what environmental factors trigger the changes occurring in benthic microbial photosynthetic communities. PMID- 28659583 TI - Trait-based model development to support breeding programs. A case study for salt tolerance and rice. AB - Eco-physiological models are increasingly used to analyze G * E * M interactions to support breeding programs via the design of ideotypes for specific contexts. However, available crop models are only partly suitable for this purpose, since they often lack clear relationships between parameters and traits breeders are working on. Taking salt stress tolerance and rice as a case study, we propose a paradigm shift towards the building of ideotyping-specific models explicitly around traits involved in breeding programs. Salt tolerance is a complex trait relying on different physiological processes that can be alternatively selected to improve the overall crop tolerance. We developed a new model explicitly accounting for these traits and we evaluated its performance using data from growth chamber experiments (e.g., R2 ranged from 0.74 to 0.94 for the biomass of different plant organs). Using the model, we were able to show how an increase in the overall tolerance can derive from completely different physiological mechanisms according to soil/water salinity dynamics. The study demonstrated that a trait-based approach can increase the usefulness of mathematical models for supporting breeding programs. PMID- 28659584 TI - The gender difference and mortality-to-incidence ratio relate to health care disparities in bladder cancer: National estimates from 33 countries. AB - The variation in the mortality-to-incidence ratio (MIR) between countries and genders reflects the complex etiology and intervention of bladder cancer. In this study, we investigated the MIR variation between genders and health care disparities among countries. Cancer incidence and mortality were obtained from the GLOBOCAN 2012 database. The ranking and the total expenditure on health of countries were obtained from the World Health Organization. Linear regression was used to estimate the significance between variables. We estimated the role of MIRs from 33 countries. Bladder cancer incidence and mortality rates were higher in more developed regions, Europe, and the Americas. The MIRs were higher in less developed regions. Analysis according to country revealed Germany to have the lowest MIR. High relative MIRs (female MIR/male MIR) for bladder cancer were noted in many developed countries. A correlation between MIR and health care disparities among countries was indicated by a significant association between the World Health Organization ranking and total expenditure on health/GDP with the MIR and relative MIR. Low bladder cancer MIR is prone to be more prevalent in countries with good health care system. PMID- 28659585 TI - Evidence for Rapid Oxidative Phosphorylation and Lactate Fermentation in Motile Human Sperm by Hyperpolarized 13C Magnetic Resonance Spectroscopy. AB - Poor sperm motility is a common cause of male infertility for which there are no empirical therapies. Sperm motility is powered by adenosine triphosphate but the relative importance of lactate fermentation and Oxidative Phosphorylation (OxPhos) is debated. To study the relationship between energy metabolism and sperm motility we used dissolution Dynamic Nuclear Polarization (dDNP) for the first time to show the rapid conversion of 13C1-pyruvate to lactate and bicarbonate, indicating active glycolytic and OxPhos metabolism in sperm. The magnitude of both lactate and bicarbonate signals were positively correlated with the concentration of progressively motile sperm. After controlling for sperm concentration, increased progressive sperm motility generated more pyruvate conversion to lactate and bicarbonate. The technique of dDNP allows 'snapshots' of sperm metabolism to be tracked over the different stages of their life. This may provide help to uncover the causes of poor sperm motility and suggest new approaches for novel treatments or therapies. PMID- 28659586 TI - PGC-1alpha attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3beta inactivation mediated by activated p38 in HK-2 Cells. AB - Ischemia/reperfusion injury triggers acute kidney injury (AKI) by aggravating oxidative stress mediated mitochondria dysfunction. The peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) is a master player that regulates mitochondrial biogenesis and the antioxidant response. We postulated that PGC-1alpha functions as cytoprotective effector in renal cells and that its regulation mechanism is coordinated by nuclear factor erythroid 2-related factor 2 (Nrf-2). In this study, to understand the effect and molecular mechanisms of PGC-1alpha, we developed an empty vector or PGC-1alpha-overexpressing stable cell lines in HK-2 cells (Mock or PGC-1alpha stable cells). PGC-1alpha overexpression increased the viability of cells affected by H2O2 mediated injury, protected against H2O2-mediated apoptotic events and inhibited reactive oxygen species accumulation in the cytosol and mitochondria as compared to that in Mock cells. The cytoprotective effect of PGC-1alpha was related to Nrf-2 upregulation, which was counteracted by Nrf-2-specific knockdown. Using inhibitor of p38, we found that regulation of the p38/glycogen synthase kinase 3beta (GSK3beta)/Nrf-2 axis was involved in the protective effects of PGC-1alpha. Taken together, we suggest that PGC-1alpha protects human renal tubule cells from H2O2-mediated apoptotic injury by upregulating Nrf-2 via GSK3beta inactivation mediated by activated p38. PMID- 28659587 TI - Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Autoimmune Uveitis. AB - We previously demonstrated that mesenchymal stem cells (MSCs) ameliorated experimental autoimmune uveoretinitis (EAU) in rats. Recently, MSC-derived exosomes (MSC-Exo) were thought to carry functions of MSCs. In this study, we tested the effect of local administration of human MSC-Exo on established EAU in the same species. Rats with EAU induced by immunization with interphotoreceptor retinol-binding protein 1177-1191 peptide were treated by periocular injections of increasing doses of MSC-Exo starting at the disease onset for 7 consecutive days. The in vitro effects of MSC-Exo on immune cell migration and responder T cell proliferation were examined by chemotactic assays and lymphocyte proliferation assays, respectively. We found that MSC-Exo greatly reduced the intensity of ongoing EAU as their parent cells by reducing the infiltration of T cell subsets, and other inflammatory cells, in the eyes. Furthermore, the chemoattractive effects of CCL2 and CCL21 on inflammatory cells were inhibited by MSC-Exo. However, no inhibitory effect of MSC-Exo on IRBP-specific T cell proliferation was observed. These results suggest that MSC-Exo effectively ameliorate EAU by inhibiting the migration of inflammatory cells, indicating a potential novel therapy of MSC-Exo for uveitis. PMID- 28659588 TI - The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo. AB - Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining beta-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet beta-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase beta-cell proliferation and up-regulate genes involved in improved beta-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors. PMID- 28659589 TI - Vitamin D Modulation of TRAIL Expression in Human Milk and Mammary Epithelial Cells. AB - The vitamin D levels in mothers affect the health status of both the mother and breastfeeding infant. Vitamin D deficient mothers' infants are prone to rickets. While tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been implicated in cellular growth/apoptosis, immune cell function and bone-resorbing osteoclast formation, the expression of TRAIL in human milk as a function of vitamin D status in mothers remains unknown. We hypothesized that vitamin D deficiency alters TRAIL protein levels in human breast milk and mammary epithelial cells. Milk from vitamin D deficient mothers showed high levels of TRAIL (alpha and beta) proteins compared to milk from vitamin D replete women. Western blot analysis of total cell lysate obtained from normal human mammary epithelial (HME-1) cells treated with variable doses (0-20 nM) of vitamin D for 24 h demonstrated that low levels (0.5 to 5 nM) significantly increased the TRAIL alpha but no change in beta expression. In contrast, vitamin D at 20 nM concentration suppressed the expression of both TRAIL alpha and beta proteins. Consistently, vitamin D regulated TRAIL mRNA expression in HME-1 cells. Our results indicate that vitamin D status in mothers modulates TRAIL expression in breast milk, which may have implications for both mother and infant health. PMID- 28659590 TI - One-dimensional electron gas in strained lateral heterostructures of single layer materials. AB - Confinement of the electron gas along one of the spatial directions opens an avenue for studying fundamentals of quantum transport along the side of numerous practical electronic applications, with high-electron-mobility transistors being a prominent example. A heterojunction of two materials with dissimilar electronic polarisation can be used for engineering of the conducting channel. Extension of this concept to single-layer materials leads to one-dimensional electron gas (1DEG). MoS2/WS2 lateral heterostructure is used as a prototype for the realisation of 1DEG. The electronic polarisation discontinuity is achieved by straining the heterojunction taking advantage of dissimilarities in the piezoelectric coupling between MoS2 and WS2. A complete theory that describes an induced electric field profile in lateral heterojunctions of two-dimensional materials is proposed and verified by first principle calculations. PMID- 28659591 TI - Alpha-lipoic Acid suppresses P2X receptor activities and visceral hypersensitivity to colorectal distention in diabetic rats. AB - The present study was designed to investigate the roles of P2X3 receptors in dorsal root ganglion (DRG) neurons in colonic hypersensitivity and the effects of alpha-lipoic acid (ALA) on P2X3 receptor activity and colonic hypersensitivity of diabetic rats. Streptozotocin (STZ) was used to induce diabetic model. Abdominal withdrawal reflex (AWR) responding to colorectal distention (CRD) was recorded as colonic sensitivity. ATP-induced current density of colon-specific DRG (T13-L2 DRGs) neurons was measured with whole-cell patch clamp. The expression of P2X3Rs of T13-L2 DRGs was measured by western blot analysis. The results showed that AWR scores significantly increased after STZ injection. P2X3R expression and ATP current density of T13-L2 DRG neurons were enhanced in diabetic rats. Intraperitoneal injection with ALA once a day for 1 week remarkably reduced P2X3R expression and ATP current density in diabetic rats. Importantly, ALA treatment attenuated colonic hypersensitivity in diabetic rats. Our data suggest that STZ injection increases expression and function of P2X3 receptors of colon-specific DRG neurons, thus contributing to colonic hypersensitivity in diabetic rats. Administration of ALA attenuates diabetic colonic hypersensitivity, which is most likely mediated by suppressing expression and function of P2X3 receptors in DRGs of diabetic rats. PMID- 28659592 TI - Ultra-broadband enhancement of nonlinear optical processes from randomly patterned super absorbing metasurfaces. AB - Broadband light trapping and field localization is highly desired in enhanced light-matter interaction, especially in harmonic generations. However, due to the limited resonant bandwidth, most periodic plasmonic nanostructures cannot cover both fundamental excitation wavelength and harmonic generation wavelength simultaneously. Therefore, most previously reported plasmonic nonlinear optical processes are low in conversion efficiency. Here, we report a strong enhancement of second harmonic generation based on a three-layered super absorbing metasurface structure consisting of a dielectric spacer layer sandwiched by an array of random metallic nanoantennas and a metal ground plate. Intriguingly, the strong light trapping band (e.g. >80%) was realized throughout the entire visible to near-infrared spectral regime (i.e., from 435 nm to 1100 nm), enabling plasmonically enhanced surface harmonic generation and frequency mixing across a broad range of excitation wavelengths, which cannot be achieved with narrow band periodic plasmonic structures. By introducing hybrid random antenna arrays with small metallic nanoparticles and ultra-thin nonlinear optical films (e.g. TiO2) into the nanogaps, the nonlinear optical process can be further enhanced. This broadband light-trapping metastructure shows its potential as a building block for emerging nonlinear optical meta-atoms. PMID- 28659594 TI - Spectral proof for the 4-aminophenyl disulfide plasma assisted catalytic reaction. AB - 4-Aminophenyl disulfide (APDS) forms on the surface of silver nanoparticles due to chemical adsorption and disulfide bond breakage. This leads to the formation of new silver chemical bonds to result in the new compound NH2-C6H6-S-Ag. This novel material produces enhanced Raman spectra under weak laser light irradiation. When irradiated a plasma-assisted catalytic coupling reaction of NH2 C6H6-S-Ag occurs leading to the formation of 4,4-dimercaptoazobenzene (DMAB). Raman spectroscopy was used to monitor this reaction process, showing clear spectral changes associated with each step after addition of Ag nanoparticles onto the APDS powder. This method clearly shows the mechanism of the plasma assisted catalytic reaction and may also be useful for spectral imaging purposes. PMID- 28659593 TI - A Quantitative Study of Internal and External Interactions of Homodimeric Glucocorticoid Receptor Using Fluorescence Cross-Correlation Spectroscopy in a Live Cell. AB - Glucocorticoid receptor (GRalpha) is a well-known ligand-dependent transcription regulatory protein. The classic view is that unliganded GRalpha resides in the cytoplasm, relocates to the nucleus after ligand binding, and then associates with a specific DNA sequence, namely a glucocorticoid response element (GRE), to activate a specific gene as a homodimer. It is still a puzzle, however, whether GRalpha forms the homodimer in the cytoplasm or in the nucleus before DNA binding or after that. To quantify the homodimerization of GRalpha, we constructed the spectrally different fluorescent protein tagged hGRalpha and applied fluorescence cross-correlation spectroscopy. First, the dissociation constant (Kd) of mCherry2 fused hGRalpha or EGFP-fused hGRalpha was determined in vitro. Then, Kd of wild type hGRalpha was found to be 3.00 MUM in the nucleus, which was higher than that in vitro. Kd of a DNA-binding-deficient mutant was 3.51 MUM in the nucleus. This similarity indicated that GRalpha homodimerization was not necessary for DNA binding but could take place on GRE by means of GRE as a scaffold. Moreover, cytoplasmic homodimerization was also observed using GRalpha mutated in the nuclear localization signal. These findings support the existence of a dynamic monomer pathway and regulation of GRalpha function both in the cytoplasm and nucleus. PMID- 28659595 TI - Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2. AB - Matrix metalloproteinases (MMPs) are regulated at multiple transcriptional and post-transcriptional levels, among which receptor-mediated endocytic clearance. We previously showed that low-density lipoprotein receptor-related protein-1 (LRP 1) mediates the clearance of a complex between the zymogen form of MMP-2 (proMMP 2) and tissue inhibitor of metalloproteinases, TIMP-2, in HT1080 human fibrosarcoma cells. Here we show that, in BN16 rat yolk sac cells, proMMP-2:TIMP 2 complex is endocytosed through a distinct LRP member, megalin/LRP-2. Addition of receptor-associated protein (RAP), a natural LRP antagonist, caused accumulation of endogenous proMMP-2 and TIMP-2 in conditioned media. Incubation with RAP also inhibited membrane binding and cellular uptake of exogenous iodinated proMMP-2:TIMP-2. Moreover, antibodies against megalin/LRP-2, but not against LRP-1, inhibited binding of proMMP-2:TIMP-2 to BN16 cell surface. BIAcore analysis confirmed direct interaction between the complex and megalin/LRP-2. Conditional renal invalidation of megalin/LRP-2 in mice resulted in accumulation of proMMP-2 and TIMP-2 in their urine, highlighting the physiological relevance of the binding. We conclude that megalin/LRP-2 can efficiently mediate cell surface binding and endocytosis of proMMP-2:TIMP-2 complex. Therefore megalin/LRP 2 can be considered as a new actor in regulation of MMP-2 activity, an enzyme crucially involved in many pathological processes. PMID- 28659596 TI - Novel approaches for Spatial and Molecular Surveillance of Porcine Reproductive and Respiratory Syndrome Virus (PRRSv) in the United States. AB - The US swine industry has been impaired over the last 25 years by the far reaching financial losses caused by the porcine reproductive and respiratory syndrome (PRRS). Here, we explored the relations between the spatial risk of PRRS outbreaks and its phylodynamic history in the U.S during 1998-2016 using ORF5 sequences collected from swine farms in the Midwest region. We used maximum entropy and Bayesian phylodynamic models to generate risk maps for PRRS outbreaks and reconstructed the evolutionary history of three selected phylogenetic clades (A, B and C). High-risk areas for PRRS were best-predicted by pig density and climate seasonality and included Minnesota, Iowa and South Dakota. Phylodynamic models demonstrated that the geographical spread of the three clades followed a heterogeneous spatial diffusion process. Furthermore, PRRS viruses were characterized by typical seasonality in their population size. However, endemic strains were characterized by a substantially slower population growth and evolutionary rates, as well as smaller spatial dispersal rates when compared to emerging strains. We demonstrated the prospects of combining inferences derived from two unique analytical methods to inform decisions related to risk-based interventions of an important pathogen affecting one of the largest food animal industries in the world. PMID- 28659597 TI - In Vivo Photoacoustic Imaging of Anterior Ocular Vasculature: A Random Sample Consensus Approach. AB - Visualizing ocular vasculature is important in clinical ophthalmology because ocular circulation abnormalities are early signs of ocular diseases. Photoacoustic microscopy (PAM) images the ocular vasculature without using exogenous contrast agents, avoiding associated side effects. Moreover, 3D PAM images can be useful in understanding vessel-related eye disease. However, the complex structure of the multi-layered vessels still present challenges in evaluating ocular vasculature. In this study, we demonstrate a new method to evaluate blood circulation in the eye by combining in vivo PAM imaging and an ocular surface estimation method based on a machine learning algorithm: a random sample consensus algorithm. By using the developed estimation method, we were able to visualize the PA ocular vascular image intuitively and demonstrate layer by-layer analysis of injured ocular vasculature. We believe that our method can provide more accurate evaluations of the eye circulation in ophthalmic applications. PMID- 28659598 TI - Differential effects of developmental thermal plasticity across three generations of guppies (Poecilia reticulata): canalization and anticipatory matching. AB - Developmental plasticity can match offspring phenotypes to environmental conditions experienced by parents. Such epigenetic modifications are advantageous when parental conditions anticipate offspring environments. Here we show firstly, that developmental plasticity manifests differently in males and females. Secondly, that under stable conditions, phenotypic responses (metabolism and locomotion) accumulate across several generations. Metabolic scope in males was greater at warmer test temperatures (26-36 degrees C) in offspring bred at warm temperatures (29-30 degrees C) compared to those bred at cooler temperatures (22 23 degrees C), lending support to the predictive adaptive hypothesis. However, this transgenerational matching was not established until the second (F2) generation. For other responses, e.g. swimming performance in females, phenotypes of offspring bred in different thermal environments were different in the first (F1) generation, but became more similar across three generations, implying canalization. Thirdly, when environments changed across generations, the grandparental environment affected offspring phenotypes. In females, the mode of the swimming thermal performance curve shifted to coincide with the grandparental rather than the parental or offspring developmental environments, and this lag in response may represent a cost of plasticity. These findings show that the effects of developmental plasticity differ between traits, and may be modulated by the different life histories of males and females. PMID- 28659599 TI - PARP-1 overexpression contributes to Cadmium-induced death in rat proximal tubular cells via parthanatos and the MAPK signalling pathway. AB - Parthanatos is a newly discovered form of PARP-1-dependent programmed cell death. It has been reported to play an important role in several cancer or tumour cells; however, few studies have been performed in normal cells. Cadmium is a highly toxic pollutant and is reported to induce autophagy and apoptosis in multiple cell types. Although cadmium toxicity induces cell death, the underlying mechanism is not fully understood. Therefore, in this study we aimed to investigate the mechanism of Cadmium -induced cell damage using rat proximal tubular cell line NRK-52E and primary rat proximal tubular (rPT) cells. Our results indicated that parthanatos and the MAPK signalling pathway contribute to Cadmium-induced cell death, and that oxidative stress and mitochondrial damage play key roles in this process. In addition, parthanatos with oxidative stress has a synergistic effect on apoptosis, and JNK1/2 and p38 contribute to parthanatos. PMID- 28659600 TI - Comparative genetic, proteomic and phosphoproteomic analysis of C. elegans embryos with a focus on ham-1/STOX and pig-1/MELK in dopaminergic neuron development. AB - Asymmetric cell divisions are required for cellular diversity and defects can lead to altered daughter cell fates and numbers. In a genetic screen for C. elegans mutants with defects in dopaminergic head neuron specification or differentiation, we isolated a new allele of the transcription factor HAM-1 [HSN (Hermaphrodite-Specific Neurons) Abnormal Migration]. Loss of both HAM-1 and its target, the kinase PIG-1 [PAR-1(I)-like Gene], leads to abnormal dopaminergic head neuron numbers. We identified discrete genetic relationships between ham-1, pig-1 and apoptosis pathway genes in dopaminergic head neurons. We used an unbiased, quantitative mass spectrometry-based proteomics approach to characterise direct and indirect protein targets and pathways that mediate the effects of PIG-1 kinase loss in C. elegans embryos. Proteins showing changes in either abundance, or phosphorylation levels, between wild-type and pig-1 mutant embryos are predominantly connected with processes including cell cycle, asymmetric cell division, apoptosis and actomyosin-regulation. Several of these proteins play important roles in C. elegans development. Our data provide an in depth characterisation of the C. elegans wild-type embryo proteome and phosphoproteome and can be explored via the Encyclopedia of Proteome Dynamics (EPD) - an open access, searchable online database. PMID- 28659601 TI - A thermophilic cell-free cascade enzymatic reaction for acetoin synthesis from pyruvate. AB - Acetoin (3-hydroxy-2-butanone) is an important bio-based platform chemical with wide applications. In vitro enzyme catalysed synthesis exhibits great feasibility in the production of chemicals with high purity. In the present work, a synthetic pathway involving a two-step continuous reaction was constructed in vitro for acetoin production from pyruvate at improved temperature. Thermostable candidates, acetolactate synthase (coAHASL1 and coAHASL2 from Caldicellulosiruptor owensensis OL) and alpha-acetolactate decarboxylase (bsALDC from Bacillus subtilis IPE5-4) were cloned, heterologously expressed, and characterized. All the enzymes showed maximum activities at 65-70 degrees C and pH of 6.5. Enzyme kinetics analysis showed that coAHASL1 had a higher activity but lower affinity against pyruvate than that of coAHASL2. In addition, the activities of coAHASL1 and bsALDC were promoted by Mn2+ and NADPH. The cascade enzymatic reaction was optimized by using coAHASL1 and bsALDC based on their kinetic properties. Under optimal conditions, a maximum concentration of 3.36 +/- 0.26 mM acetoin was produced from 10 mM pyruvate after reaction for 24 h at 65 degrees C. The productivity of acetoin was 0.14 mM h-1, and the yield was 67.80% compared with the theoretical value. The results confirmed the feasibility of synthesis of acetoin from pyruvate with a cell-free enzyme catalysed system at improved temperature. PMID- 28659602 TI - Cellulose-based magnetoelectric composites. AB - Since the first magnetoelectric polymer composites were fabricated more than a decade ago, there has been a reluctance to use piezoelectric polymers other than poly(vinylidene fluoride) and its copolymers due to their well-defined piezoelectric mechanism and high piezoelectric coefficients that lead to superior magnetoelectric coefficients of >1 V cm-1 Oe-1. This is the current situation despite the potential for other piezoelectric polymers, such as natural biopolymers, to bring unique, added-value properties and functions to magnetoelectric composite devices. Here we demonstrate a cellulose-based magnetoelectric laminate composite that produces considerable magnetoelectric coefficients of ~1.5 V cm-1 Oe-1, comprising a Fano resonance that is ubiquitous in the field of physics, such as photonics, though never experimentally observed in magnetoelectric composites. The work successfully demonstrates the concept of exploring new advances in using biopolymers in magnetoelectric composites, particularly cellulose, which is increasingly employed as a renewable, low-cost, easily processable and degradable material.Magnetoelectric materials by converting a magnetic input to a voltage output holds promise in contactless electrodes that find applications from energy harvesting to sensing. Zong et al. report a promising laminate composite that combines a piezoelectric biopolymer, cellulose, and a magnetic material. PMID- 28659603 TI - Site-specific gene expression analysis using an automated tissue micro-dissection punching system. AB - Site-specific gene expression analyses are important for understanding tissue functions. Despite rapid developments in DNA-related technologies, the site specific analysis of whole genome expression for a tissue remains challenging. Thus, a new tool is required for capturing multiple tissue micro-dissections or single cells while retaining the positional information. Here, we describe the development of such a system, which can pick up micro-dissections by punching a tissue repeatedly in a very short period, e.g., 5 s/sampling cycle. A photo of the punched tissue provides information on the dissected positions, allowing site specific gene expression analysis. We demonstrate the site-specific analysis of a frozen tissue slice of mouse brain by analyzing many micro-dissections produced from the tissue at a 300-MUm pitch. The site-specific analysis provided new insights into the gene expression profiles in a tissue and on tissue functions. The analysis of site-specific whole genome expression may therefore, open new avenues in life science. PMID- 28659604 TI - Long-Term Monitoring of Dolphin Biosonar Activity in Deep Pelagic Waters of the Mediterranean Sea. AB - Dolphins emit short ultrasonic pulses (clicks) to acquire information about the surrounding environment, prey and habitat features. We investigated Delphinidae activity over multiple temporal scales through the detection of their echolocation clicks, using long-term Passive Acoustic Monitoring (PAM). The Istituto Nazionale di Fisica Nucleare operates multidisciplinary seafloor observatories in a deep area of the Central Mediterranean Sea. The Ocean noise Detection Experiment collected data offshore the Gulf of Catania from January 2005 to November 2006, allowing the study of temporal patterns of dolphin activity in this deep pelagic zone for the first time. Nearly 5,500 five-minute recordings acquired over two years were examined using spectrogram analysis and through development and testing of an automatic detection algorithm. Echolocation activity of dolphins was mostly confined to nighttime and crepuscular hours, in contrast with communicative signals (whistles). Seasonal variation, with a peak number of clicks in August, was also evident, but no effect of lunar cycle was observed. Temporal trends in echolocation corresponded to environmental and trophic variability known in the deep pelagic waters of the Ionian Sea. Long-term PAM and the continued development of automatic analysis techniques are essential to advancing the study of pelagic marine mammal distribution and behaviour patterns. PMID- 28659605 TI - Mmm-derived lipid-associated membrane proteins activate IL-1beta production through the NF-kappaB pathway via TLR2, MyD88, and IRAK4. AB - Mycoplasma mycoides subsp.mycoides (Mmm) is a pathogen that causes pneumonia, otitis media, and arthritis in young calves. Its pathogenesis is attributed in part to excessive immune responses. Mmm-derived lipid-associated membrane proteins (LAMPs) are potent inducers of the host innate immune system; however, interactions between Mmm-derived LAMPs as pathogenic agents, toll-like receptors (TLRs), and the signaling pathways responsible for activating inflammation and nuclear factor (NF)-kappaB have not been fully elucidated. Here, we analyzed the expression kinetics of interleukin (IL)-1beta in Mmm-derived LAMP-stimulated embryonic bovine lung (EBL) cells and found that Mmm-derived LAMPs induced IL 1beta expression. Subcellular localization analysis revealed the nuclear translocation of the NF-kappaB p65 subunit after EBL cells were stimulated with Mmm-derived LAMPs. Furthermore, a specific inhibitor assay demonstrated that NF kappaB is required for Mmm-derived LAMP-induced IL-1beta expression. Additionally, overexpression of TLR2, myeloid differentiation primary response gene 88 (MyD88), and IL-1 receptor-associated kinase 4 (IRAK4) increased IL-1beta expression during LAMP stimulation, and TLR2-neutralizing antibodies reduced IL 1beta expression in EBL cells during LAMP stimulation. Furthermore, LAMPs inhibited IL-1beta expression following transfection with dominant-negative MyD88 and IRAK4 variants. These results suggested that Mmm-derived LAMPs activate IL 1beta production through the NF-kappaB pathway via TLR2, MyD88, and IRAK4. PMID- 28659606 TI - The right to health in Brazil: A Constitutional guarantee threatened by fiscal austerity. AB - After 25 years of expanding coverage and improving the quality of preventive public health measures and publicly financed medical care associated with positive outcomes for the health of Brazil's population, our country suffers from deterioration of social policies. Among the areas of policy affected by new economic austerity measures is health-with potential to damage lives. These threats stem mainly from the 2016 approval of a Constitutional amendment that limits, for the next 20 years, public investments in health, education, social assistance, and social security. This viewpoint addresses how the changes have come about and the possible consequences. PMID- 28659607 TI - Policy and advocacy for informal caregivers: How state policy influenced a community initiative. AB - With a growing proportion of elderly in the global population, the role of 'informal caregivers' gains importance. Informal caregivers are unpaid family members or friends who provide assistance to home-dwelling adults with health related needs or limitations. Internationally, informal caregivers provide important medical support to those with a variety of diseases. While informal caregivers will remain vital to the growing aging population's pursuit of healthy aging, they often suffer from 'caregiver burnout,' a state of physical, emotional, and mental exhaustion caused by their caregiving work. Policy and legislation are needed to diminish the burden on caregivers and to help assure that resources are allocated for these caregivers. We describe an initiative aimed at providing appropriate social support for caregivers by partnering among local organizations, hospitals, and health authorities. PMID- 28659608 TI - The life-course impact of smoking on hypertension, myocardial infarction and respiratory diseases. AB - The objective of this study was to examine the impact of smoking on respiratory diseases, hypertension and myocardial infarction, with a particular focus from a life-course perspective. In this study, 28,577 males from a Chinese longitudinal survey were analysed. The effects of smoking on the risk of respiratory diseases, hypertension and myocardial infarction were assessed from a life-course perspective and a current view separately. No significant associations were found between smoking and the risk of incident respiratory diseases, hypertension and myocardial infarction in the group younger than 35. Among study participants aged between 36-55 and 56-80, smoking was positively associated with the risk of incident respiratory diseases, hypertension and myocardial infarction from the life-course perspective, and the risk increased with age. In contrast, the results from a current view showed inverse associations between smoking and the risk of the diseases mentioned above. Our findings highlight that it is essential to quantify the effects of smoking from a life-course perspective in future research and to suggest that smokers quit smoking as soon as possible, regardless of the temporary side effects of quitting. PMID- 28659609 TI - Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2, dual specificity phosphatase 1 and tristetraprolin. AB - In many different cell types, pro-inflammatory agonists induce the expression of cyclooxygenase 2 (COX-2), an enzyme that catalyzes rate-limiting steps in the conversion of arachidonic acid to a variety of lipid signaling molecules, including prostaglandin E2 (PGE2). PGE2 has key roles in many early inflammatory events, such as the changes of vascular function that promote or facilitate leukocyte recruitment to sites of inflammation. Depending on context, it also exerts many important anti-inflammatory effects, for example increasing the expression of the anti-inflammatory cytokine interleukin 10 (IL-10), and decreasing that of the pro-inflammatory cytokine tumor necrosis factor (TNF). The tight control of both biosynthesis of, and cellular responses to, PGE2 are critical for the precise orchestration of the initiation and resolution of inflammatory responses. Here we describe evidence of a negative feedback loop, in which PGE2 augments the expression of dual specificity phosphatase 1, impairs the activity of mitogen-activated protein kinase p38, increases the activity of the mRNA-destabilizing factor tristetraprolin, and thereby inhibits the expression of COX-2. The same feedback mechanism contributes to PGE2-mediated suppression of TNF release. Engagement of the DUSP1-TTP regulatory axis by PGE2 is likely to contribute to the switch between initiation and resolution phases of inflammation. PMID- 28659610 TI - Upregulation of arylsulfatase B in carotid atherosclerosis is associated with symptoms of cerebral embolization. AB - The aim of this study was to identify genes for which the expression within carotid atherosclerosis was reproducibly associated with the symptoms of cerebral embolization. Two publically available microarray datasets E-MEXP-2257 and GSE21545 were analysed using GeneSpring 11.5. The two datasets utilized a total of 22 and 126 carotid atherosclerosis samples, obtained from patients with and without symptoms of cerebral embolization, respectively. To assess whether the findings were reproducible we analysed carotid atherosclerosis samples from another 8 patients with and 7 patients without symptoms of cerebral embolization using real-time PCR. In vitro studies using VSMC were performed to assess the functional relevance of one of the validated genes. We identified 1624 and 135 differentially expressed genes within carotid atherosclerosis samples of symptomatic compared to asymptomatic patients using the E-MEXP-2257 and GSE21545 datasets, respectively (>=1.15-absolute fold-change, P < 0.05). Only 7 differentially expressed genes or 0.4% (7/1,752) were consistent between the datasets. We validated the differential expression of ARSB which was upregulated 1.15-fold (P = 0.029) in atherosclerosis from symptomatic patients. In vitro incubation of VSMCs with the ARSB inhibitor L-ascorbic acid resulted in marked upregulation of SIRT1 and AMPK. This study suggests that ARSB may represent a novel target to limit carotid embolization. PMID- 28659611 TI - A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women. AB - Haptoglobin (HP) protein plays a critical role in binding and removing free hemoglobin from blood. A deletion in the HP gene affects the protein structure and function. A recent study developed a novel method to impute this variant and discovered significant association of this variant with low-density lipoprotein (LDL) and total cholesterol levels among European descendants. In the present study, we investigated this variant among 3608 Chinese women. Consistent with findings from Europeans, we found significant associations between the deletion with lower cholesterol levels; women homozygous for the deletion allele (HP1 HP1), had a lower level of total cholesterol (-4.24 mg dl-1, P=0.02) and LDL cholesterol (-3.43 mg dl-1, P=0.03) than those not carrying the deletion allele (HP2-HP2). Especially, women carrying the HP1S-HP1S, had an even lower level of total cholesterol (-5.59 mg dl-1, P=7.0 * 10-3) and LDL cholesterol (-4.68 mg dl 1, P=8.0 * 10-3) compared to those carrying HP2-HP2. These associations remained significant after an adjustment for an established cholesterol level-related variant, rs2000999. Our study extends the previous findings regarding the association of HP structure variant with blood cholesterol levels to East Asians and affirms the validity of the new methodology for assessing HP structure variation. PMID- 28659612 TI - Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma. AB - Analysis of our microRNA (miRNA) expression signatures of human cancers based on RNA sequencing have shown that both strands of pre-miR-150, miR-150-5p (the guide strand) and miR-150-3p (the passenger strand), are significantly reduced in cancer tissues. We have investigated the functional significance of both strands of pre-miR-150 in cancer cells. The aim of this study was to investigate the antitumor function of these miRNAs and how these miRNAs regulated oncogenic targets in esophageal squamous cell carcinoma (ESCC). Ectopic expression studies demonstrated that both strands of pre-miR-150 miRNA inhibited ESCC cancer cell migration and invasion, indicating that both miR-150-5p and miR-150-3p acted as antitumor miRNAs. A combination of genome-wide gene expression analyses and in silico database searches showed that SPOCK1 (SPARC/osteonectin, cwcv and kazal like domains proteoglycan 1) was a candidate target of miR-150-5p and miR-150-3p in ESCC cells. Luciferase reporter assays showed that SPOCK1 was directly regulated by these miRNAs. Silencing of SPOCK1 by small interfering RNA inhibited cancer cell migration and invasion. Overexpression of SPOCK1/SPOCK1 was confirmed by real-time PCR methods and immunohistochemistry. Taken together, downregulation of both strands of pre-miR-150 and overexpression of SPOCK1 are involved in ESCC pathogenesis. The involvement of passenger strand miRNAs in the regulation of cancer cell aggressiveness is a novel concept in RNA research. PMID- 28659613 TI - Maternal smoking and autism spectrum disorder: meta-analysis with population smoking metrics as moderators. AB - While exposure to nicotine during developmental periods can significantly affect brain development, studies examining the association between maternal smoking and autism spectrum disorder (ASD) in offspring have produced conflicting findings, and prior meta-analyses have found no significant association. Our meta-analysis used a novel approach of investigating population-level smoking metrics as moderators. The main meta-analysis, with 22 observational studies comprising 795,632 cases and 1,829,256 control participants, used a random-effects model to find no significant association between maternal smoking during pregnancy and ASD in offspring (pooled odds ratio (OR) = 1.16, 95% CI: 0.97-1.40). However, meta regression analyses with moderators were significant when we matched pooled ORs with adult male smoking prevalence (z = 2.55, p = 0.01) in each country, using World Health Organization data. Our study shows that using population-level smoking metrics uncovers significant relationships between maternal smoking and ASD risk. Correlational analyses show that male smoking prevalence approximates secondhand smoke exposure. While we cannot exclude the possibility that our findings reflect the role of paternal or postnatal nicotine exposure, as opposed to maternal or in utero nicotine exposure, this study underlines the importance of investigating paternal and secondhand smoking in addition to maternal smoking in ASD. PMID- 28659614 TI - Dopamine-dependent changes of cortical excitability induced by transcranial static magnetic field stimulation in Parkinson's disease. AB - Transcranial static magnetic field stimulation (tSMS) is a recent low-cost non invasive brain stimulation technique that decreases cortical excitability in healthy subjects. The objective of the present study was to test the ability of tSMS to modulate cortical excitability in patients with Parkinson's disease. We performed a randomized double-blind sham-controlled cross-over study to assess cortical excitability before and immediately after tSMS (or sham) applied for 10 min to the more affected motor cortex of patients with Parkinson's disease. Cortical excitability was quantified by the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS). tSMS significantly decreased MEP amplitudes in patients OFF medication (after overnight withdrawal of dopaminergic drugs), but not ON medication (after an acute dose of levodopa). The between-patients variability of tSMS-induced changes was significantly greater ON medication. The variability ON medication could be partly explained by disease progression, i.e. the more advanced the patient, the more likely it was to observe a switch from inhibitory tSMS plasticity OFF medication to paradoxical facilitatory plasticity ON medication. These results suggest that tSMS induces dopamine-dependent changes of cortical excitability in patients with Parkinson's disease. PMID- 28659615 TI - Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration. AB - Disorders in cell signaling mediated by ATP or histamine, activating specific membrane receptors, have been frequently associated with tumorigenesis. Among the elements of response to purinergic (and histaminergic) signaling, ion channel activation controls essential cellular processes in cancer, such as cell proliferation, motility, and death. Here, we studied the effects that ATP had on electrical properties of human ovarian adenocarcinoma cells named SKOV-3. ATP caused increase in intracellular Ca2+ concentration ([Ca2+]i) and, concurrently, it evoked a complex electrical response with a conspicuous outward component. This current was generated through P2Y2 receptor activation and opening of K+ channels, KCa3.1, as indicated by electrophysiological and pharmacological analysis, as well as by immunodetection and specific silencing of P2Y2 or KCa3.1 gene by esiRNA transfection. Low uM ATP concentration increased SKOV-3 cell migration, which was strongly inhibited by KCa3.1 channel blockers and by esiRNA generated P2Y2 or KCa3.1 downregulation. Finally, in human ovarian tumors, the P2Y2 and KCa3.1 proteins are expressed and co-localized in neoplastic cells. Thus, stimulation of P2Y2 receptors expressed in SKOV-3 cells promotes motility through KCa3.1 activation. Since P2Y2 and KCa3.1 are co-expressed in primary tumors, our findings suggest that they may play a role in cancer progression. PMID- 28659616 TI - A novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism. AB - Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites, but the remaining murine hepatocytes contain an expanded set of P450 cytochromes that form the major class of drug-metabolizing enzymes. We therefore generated a conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene combined with Il2rg - /- /Rag2 - /- /Fah - /- (PIRF) mice. Here we show that homozygous PIRF mouse livers are readily repopulated with human hepatocytes, and when the murine Por gene is deleted (<5%), they predominantly use human cytochrome metabolism. When given the anticancer drug gefitinib or the retroviral drug atazanavir, the Por-deleted humanized PIRF mice develop higher levels of the major human metabolites than current models. Humanized, murine Por-deficient PIRF mice can thus predict human drug metabolism and should be useful for preclinical drug development.Human liver chimeric mice are increasingly used for drug testing in preclinical development, but express residual murine p450 cytochromes. Here the authors generate mice lacking the Por gene in the liver, and show that human cytochrome metabolism is used following repopulation with human hepatocytes. PMID- 28659617 TI - Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism. AB - Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24 hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis. PMID- 28659618 TI - An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma. AB - Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30+ lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30+ diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas. PMID- 28659619 TI - Nano-engineering the Antimicrobial Spectrum of Lantibiotics: Activity of Nisin against Gram Negative Bacteria. AB - Lantibiotics, bacteria-sourced antimicrobial peptides, are very good candidates for effective and safe food additives. Among them, nisin is already approved by the EU and FDA, and has been used in food preservation for the past 40 years. Now, there is a possibility and strong interest to extend its applicability to biomedicine for designing innovative alternatives to antibiotics. The main obstacle is, however, its naturally narrow spectrum of antimicrobial activity, focused on Gram positive bacteria. Here we demonstrate broadening nisin's spectrum to Gram negative bacteria using a nano-engineering approach. After binding nisin molecules to the surface of gold nano-features, uniformly deposited on spherical carbon templates, we created a nanocomposite with a high density of positively charged groups. Before assembly, none of the components of the nanocomposite showed any activity against bacterial growth, which was changed after assembly in the form of the nanocomposite. For the first time we showed that this type of structure enables interactions capable of disintegrating the wall of Gram negative bacteria. As confirmed by the nisin model, the developed approach opens up new horizons for the use of lantibiotics in designing post antibiotic drugs. PMID- 28659620 TI - Combined influence of poor health behaviours on the prevalence and 15-year incidence of age-related macular degeneration. AB - We aimed to establish the collective influence of four lifestyle practices (physical activity, diet, smoking and alcohol consumption) on the prevalence and incidence of AMD. At baseline, 2428 participants aged 49+ with complete lifestyle and AMD data were examined, and of these, 1903 participants were re-examined 15 years later. AMD was assessed from retinal photographs. A health behaviour score was calculated, allocating 1 point for each poor behaviour: current smoking; fruits and vegetables consumed <4 serves daily; <3 episodes of physical activity per week; and >2 alcoholic drinks per day. Cross-sectional analysis showed that participants who engaged in all 4 poor health behaviours (n = 29) versus those who did not engage in unhealthy behaviours (reference group; n = 677) had greater odds of any and late AMD: multivariable-adjusted OR, 5.14 (95% CI, 1.04-25.45) and OR 29.53 (95% CI 2.72-321.16), respectively. A marginally non-significant association was observed between increasing number of poor health behaviours and 15-year incidence of early AMD (multivariable-adjusted P-trend = 0.08). Our data suggests that motivating patients with AMD to eat better, exercise more, limit alcohol intake and avoid smoking seems advisable to decelerate the development or worsening of existing AMD. PMID- 28659621 TI - A Dynamic Precision Evaluation Method for the Star Sensor in the Stellar-Inertial Navigation System. AB - Integrating the advantages of INS (inertial navigation system) and the star sensor, the stellar-inertial navigation system has been used for a wide variety of applications. The star sensor is a high-precision attitude measurement instrument; therefore, determining how to validate its accuracy is critical in guaranteeing its practical precision. The dynamic precision evaluation of the star sensor is more difficult than a static precision evaluation because of dynamic reference values and other impacts. This paper proposes a dynamic precision verification method of star sensor with the aid of inertial navigation device to realize real-time attitude accuracy measurement. Based on the gold standard reference generated by the star simulator, the altitude and azimuth angle errors of the star sensor are calculated for evaluation criteria. With the goal of diminishing the impacts of factors such as the sensors' drift and devices, the innovative aspect of this method is to employ static accuracy for comparison. If the dynamic results are as good as the static results, which have accuracy comparable to the single star sensor's precision, the practical precision of the star sensor is sufficiently high to meet the requirements of the system specification. The experiments demonstrate the feasibility and effectiveness of the proposed method. PMID- 28659622 TI - Determination of Aspergillus pathogens in agricultural products by a specific nanobody-polyclonal antibody sandwich ELISA. AB - Aspergillus and its poisonous mycotoxins are distributed worldwide throughout the environment and are of particular interest in agriculture and food safety. In order to develop a specific method for rapid detection of Aspergillus flavus to forecast diseases and control aflatoxins, a nanobody, PO8-VHH, highly reactive to A. flavus was isolated from an immunized alpaca nanobody library by phage display. The nanobody was verified to bind to the components of extracellular and intracellular antigen from both A. flavus and A. parasiticus. To construct a sandwich format immunoassay, polyclonal antibodies against Aspergillus were raised with rabbits. Finally, a highly selective nanobody-polyclonal antibody sandwich enzyme-linked immunosorbent assay was optimized and developed. The results revealed that the detection limits of the two fungi were as low as 1 MUg mL-1, and that it is able to detect fungal concentrations below to 2 MUg mg-1 of peanut and maize grains in both artificially and naturally contaminated samples. Therefore, we here provided a rapid and simple method for monitoring Aspergillus spp. contamination in agricultural products. PMID- 28659623 TI - A systematic review and meta-analysis of traditional insect Chinese medicines combined chemotherapy for non-surgical hepatocellular carcinoma therapy. AB - On the background of high morbidity and mortality of hepatocellular carcinoma (HCC) and rapid development of traditional Chinese medicine (TCM), we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement to assess the clinical effectiveness and safety of traditional insect Chinese medicine and related preparation for non-surgical HCC. RCTs were searched based on standardized searching rules in mainstream medical databases from the inception up to May 2016. Ultimately, a total of 57 articles with 4,651 patients enrolled in this meta-analysis. We found that traditional insect Chinese medicine and related preparation combined chemotherapy show significantly effectiveness and safety in objective response rate (P < 0.001), survival time extension [12 months (P < 0.001); 18 months (P < 0.001); 24 months (P < 0.001); 36 months (P < 0.001)], amelioration for life quality [QoL scores improvement (P < 0.001); KPS improvement (P < 0.001); AFP improvement (P < 0.001)] and reduction of therapeutic toxicity [WBC decrease (P = 0.04); gastrointestinal adverse reactions (P < 0.001)]. In conclusion, traditional insect Chinese medicine and related preparations could be recommended as auxiliary therapy combined chemotherapy for HCC therapy. PMID- 28659625 TI - Free-standing plasmonic metal-dielectric-metal bandpass filter with high transmission efficiency. AB - Plasmonic spectrum filtering devices based on metallic nanostructures have attracted wide attention due to their good reliability, ease of fabrication, and wideband tunability. However, the presence of thick substrate significantly limits the structure's longitudinal size for further optoelectronic integration and reduces the devices' performance. Here we propose and demonstrate an ultra thin plasmonic bandpass filter based on free-standing periodic metal-dielectric metal stack geometry working in the near-infrared wavelength range. The coupling between free-space electromagnetic waves and spatially confined plasmonic modes in the designed structure is systematically investigated. As demonstrated in the calculation and experiment, the free-standing plasmonic filters have more than 90% transmission efficiency and superior angular tolerance. The experimental results are in good agreement with the theoretical calculations. These artificial nanostructured filtering devices may find potential applications in the extremely compact device architectures. PMID- 28659624 TI - Alcohol Recognition by Flexible, Transparent and Highly Sensitive Graphene-Based Thin-Film Sensors. AB - Chemical sensors detect a variety of chemicals across numerous fields, such as automobile, aerospace, safety, indoor air quality, environmental control, food, industrial production and medicine. We successfully assemble an alcohol-sensing device comprising a thin-film sensor made of graphene nanosheets (GNs) and bacterial cellulose nanofibers (BCNs). We show that the GN/BCN sensor has a high selectivity to ethanol by distinguishing liquid-phase or vapor-phase ethanol (C2H6O) from water (H2O) intelligently with accurate transformation into electrical signals in devices. The BCN component of the film amplifies the ethanol sensitivity of the film, whereby the GN/BCN sensor has 12400% sensitivity for vapor-phase ethanol compared to the pure GN sensor, which has only 21% sensitivity. Finally, GN/BCN sensors demonstrate fast response/recovery times and a wide range of alcohol detection (10-100%). The superior sensing ability of GN/BCN compared to GNs alone is due to the improved wettability of BCNs and the ionization of liquids. We prove a facile, green, low-cost route for the assembly of ethanol-sensing devices with potential for vast application. PMID- 28659626 TI - Live Imaging of Micro-Wettability Experiments Performed for Low-Permeability Oil Reservoirs. AB - Low-permeability (unconventional) hydrocarbon reservoirs exhibit a complex nanopore structure and micro (um) -scale variability in composition which control fluid distribution, displacement and transport processes. Conventional methods for characterizing fluid-rock interaction are however typically performed at a macro (mm) -scale on rock sample surfaces. In this work, innovative methods for the quantification of micro-scale variations in wettability and fluid distribution in a low-permeability oil reservoir was enabled by using an environmental scanning electron microscope. Live imaging of controlled water condensation/evaporation experiments allowed micro-droplet contact angles to be evaluated, while imaging combined with x-ray mapping of cryogenically frozen samples facilitated the evaluation of oil and water micro-droplet contact angles after successive fluid injection. For the first time, live imaging of fluids injected through a micro-injection system has enabled quantification of sessile and dynamic micro-droplet contact angles. Application of these combined methods has revealed dramatic spatial changes in fluid contact angles at the micro-scale, calling into question the applicability of macro-scale observations of fluid-rock interaction. PMID- 28659627 TI - Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance. AB - Visceral leishmaniasis (VL) remains a major public health problem worldwide. Cytokine balance is thought to play a critical role in the development of this disease. Here, we perform a prospective exploratory study addressing whether simultaneous assessment of circulating levels of different lipid mediators and cytokines could highlight specific pathways involved with VL pathogenesis. VL patients displayed substantial increases in serum levels of Prostaglandin F2alpha (PGF2alpha), Leukotriene B4 (LTB4), Resolvin D1 (RvD1), IL-1beta, IL-6, IL-8, IL 10, IL-12p70 and TNF-alpha compared with uninfected endemic control group, while exhibiting decreased levels of TGF-beta1. Hierarchical cluster analysis of the prospective changes in the expression level of theses parameters upon anti Leishmania treatment initiation revealed that the inflammatory profile observed in active disease gradually changed over time and was generally reversed at day 30 of therapy. Furthermore, not only the individual concentrations of most of the inflammatory biomarkers changed upon treatment, but the correlations between those and several biochemical parameters used to characterize VL disease activity were also modified over time. These results demonstrate that an inflammatory imbalance hallmarks active VL disease and open perspective for manipulation of these pathways in future studies examining a potential host-directed therapy against VL. PMID- 28659628 TI - Hybrid Resonators and Highly Tunable Terahertz Metamaterials Enabled by Vanadium Dioxide (VO2). AB - Hybrid metamaterials that exhibit reconfigurable responses under external stimulus, such as electric fields and light radiation, have only recently been demonstrated by combining active media with patterned metallic structures. Nevertheless, hybrid terahertz (THz) metamaterials whose spectral performance can be dynamically tuned over a large scale remain rare. Compared with most active media (for instance, silicon) that provide limited activity, vanadium dioxide (VO2), which exhibits an insulator-to-metal transition, has been recently explored to facilitate dynamically tunable metamaterials. More importantly, the phase transition yields a three orders of magnitude increase in THz electrical conductivity, which suggests the potential for creating VO2 based hybrid resonators that operate at THz frequencies. Here, we show that an integration of VO2 structures and conventional metallic resonating components can enable a class of highly tunable THz metamaterials. Considering the widely studied phase transition dynamics in VO2, the proposed hybrid metamaterials are capable of offering ultrafast modulation of THz radiation. PMID- 28659629 TI - Engineering Biodegradable and Biocompatible Bio-ionic Liquid Conjugated Hydrogels with Tunable Conductivity and Mechanical Properties. AB - Conventional methods to engineer electroconductive hydrogels (ECHs) through the incorporation of conductive nanomaterials and polymers exhibit major technical limitations. These are mainly associated with the cytotoxicity, as well as poor solubility, processability, and biodegradability of their components. Here, we describe the engineering of a new class of ECHs through the functionalization of non-conductive polymers with a conductive choline-based bio-ionic liquid (Bio IL). Bio-IL conjugated hydrogels exhibited a wide range of highly tunable physical properties, remarkable in vitro and in vivo biocompatibility, and high electrical conductivity without the need for additional conductive components. The engineered hydrogels could support the growth and function of primary cardiomyocytes in both two dimentinal (2D) and three dimensional (3D) cultures in vitro. Furthermore, they were shown to be efficiently biodegraded and possess low immunogenicity when implanted subcutaneously in rats. Taken together, our results suggest that Bio-IL conjugated hydrogels could be implemented and readily tailored to different biomedical and tissue engineering applications. PMID- 28659630 TI - Relationship between sexual position and severity of penile fracture. AB - The objective of the study was to evaluate the relationship between the sexual position and severity of penile fracture (PF). We studied 90 patients with PF. The mechanism of injury and the sexual position was assessed. We divided our sample by the etiology of the fracture in six groups: (a) masturbation or penile manipulation; (b) 'man-on-top' position; (c) 'doggy style' position; (d) 'woman on-top' position; (d) blunt trauma; and (e) 'rolling over' fracture. We used the chi2-test for contingency analysis of the populations under study (P<0.05). The patient's age ranged from 18 to 66 years (mean 39 years). Investigation of the injury mechanism identified sexual trauma as the main etiological factor, involved in 69 cases (76.5%). The sexual position at the time of injury varied, with 23 cases (25.5%) occurring in the 'man-on-top', 37cases (41%) in the 'doggy style' and 9 cases (10%) in the 'woman-on-top'. We do not observe differences between the severity of the PF between the 'doggy style' and 'man-on-top' (P=0.9595), but the 'doggy style' had more severity of PF when compared with 'woman-on-top' (P=0.0396) and penile manipulation (P=0.0026). The 'man-on-top' and 'doggy style' positions showed more associations with bilateral fractures of the corpus cavernosum and urethral lesions. PMID- 28659631 TI - A retrospective analysis of risk factors for IPP reservoir entry into the peritoneum after abdominal wall placement. AB - Placement of an inflatable penile prosthesis (IPP) is the most effective treatment modality for men with ED refractory to medical management. We have previously demonstrated a protocol for IPP reservoir placement within the abdominal wall musculature, which was shown to be a safer location than traditional placement in the retropubic space of Retzius. The aim of this study was to review our complications with IPP reservoir entry into the peritoneum after abdominal wall placement of the reservoir. We retrospectively reviewed our two patients with peritoneal entry of the reservoir after posterior to transversalis fascia and anterior to transversalis fascia placement during virgin and compromised IPP cases, respectively. Our goal was to assess common inherent patient and surgical factors that resulted in this complication in order to develop a management algorithm to prevent future occurrence during alternative reservoir placement. Peritoneal reservoir entry was identified in two patients. These patients were both noted to be thin (mean body mass index (BMI) 18.5 kg/m2), current or former smokers. Peritoneal entry was identified early after reservoir placement. Neither of the patients suffered bowel injury and both subsequently underwent successful reservoir removal and IPP replacement. Both are currently doing well with functional IPPs on follow-up. Peritoneal entry of the reservoir occurs very rarely and, in our series, occurred in a cohort of patients with low BMI and tobacco use history. We recommend early identification of similar patients and subsequent reservoir placement anterior to transversalis fascia with caution to prevent peritoneal entry. PMID- 28659632 TI - Assessment of erectile dysfunction and associated psychological distress in Chinese men with type 2 diabetes mellitus. AB - To estimate the prevalence of erectile dysfunction (ED) and the level of psychological distress and to assess the inter-associations of them among type 2 diabetic men, a cross-sectional observational study of 335 men with type 2 diabetes and 284 men without diabetes from a hospital in Hefei city, Anhui province, China, was conducted. The erectile function was assessed using the five item version of the International Index of Erectile Function scale (IIEF-5). The evaluation of psychological distress was completed using a self-administered questionnaire, the Symptom Checklist 90-Revised (SCL-90-R). In this study, ED was more prevalent in type 2 diabetic men than that in the control group (58.51% vs 26.76%, P<0.001). All subscale scores of SCL-90-R were significantly higher in the group with type 2 diabetes (N=335) than those in the group without type 2 diabetes (N=284). All scores of SCL-90-R subscales were inversely correlated with IIEF-5 score. ED and psychological distress were strongly correlated in type 2 diabetic patients. Clinicians should be aware of the association between ED and psychological distress when treating men with type 2 diabetes. PMID- 28659633 TI - Wall-thickness-dependent strength of nanotubular ZnO. AB - We fabricate nanotubular ZnO with wall thickness of 45, 92, 123 nm using nanoporous gold (np-Au) with ligament diameter at necks of 1.43 MUm as sacrificial template. Through micro-tensile and micro-compressive testing of nanotubular ZnO structures, we find that the exponent m in [Formula: see text], where [Formula: see text] is the relative strength and [Formula: see text] is the relative density, for tension is 1.09 and for compression is 0.63. Both exponents are lower than the value of 1.5 in the Gibson-Ashby model that describes the relation between relative strength and relative density where the strength of constituent material is independent of external size, which indicates that strength of constituent ZnO increases as wall thickness decreases. We find, based on hole-nanoindentation and glazing incidence X-ray diffraction, that this wall thickness-dependent strength of nanotubular ZnO is not caused by strengthening of constituent ZnO by size reduction at the nanoscale. Finite element analysis suggests that the wall-thickness-dependent strength of nanotubular ZnO originates from nanotubular structures formed on ligaments of np-Au. PMID- 28659634 TI - DACH1 suppresses breast cancer as a negative regulator of CD44. AB - Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma. PMID- 28659636 TI - Erratum: SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. AB - This corrects the article DOI: 10.1038/ncb3514. PMID- 28659635 TI - Method for preparing DNA from feces in guanidine thiocyanate solution affects 16S rRNA-based profiling of human microbiota diversity. AB - Metagenomic analysis based on the 16S rRNA gene is generally performed to examine the diversity and abundance of commensal bacteria in feces, which is now recognized to be associated with human health and diseases. Guanidine thiocyanate (GuSCN) solution is used as a less onerous way compared with a frozen method to transport and stock fecal samples at room temperature for DNA analysis; however, optimal methods to measure fecal bacterial composition in GuSCN solution remain to be investigated. Here, we examined the influence of various factors such as pretreatment (e.g., removing GuSCN solution and washing feces with phosphate buffered saline (PBS) before mechanical lysis), fecal concentration in the GuSCN solution, storage time, and position of fecal subsampling on the 16S rRNA-based analysis of fecal bacteria in GuSCN solution. We found that pretreatment and fecal concentration affected the bacterial composition, and a little change was noted with subsampling position. Based on these results, we propose a basic protocol, including fecal sampling, sample storage, and DNA extraction, for the 16S rRNA-based analysis of bacterial composition in feces suspended in GuSCN solution. PMID- 28659637 TI - Inter-organ regulation of haem homeostasis. AB - Haem is an iron-containing cofactor required for life. Many cellular processes rely on haem and failure to maintain iron homeostasis results in numerous pathological conditions. A study now identifies a Caenorhabditis elegans inter organ signalling pathway in which secreted intestinal HRG-7 and neuronally secreted BMP signals coordinate animal haem homeostasis. PMID- 28659638 TI - Revolving around constriction by ESCRT-III. AB - The endosomal sorting complex required for transport (ESCRT)-III is critical for membrane abscission; however, the mechanism underlying ESCRT-III-mediated membrane constriction remains elusive. A study of the dynamic assembly and disassembly of the ESCRT-III machinery in vitro and in vivo now suggests that the turnover of the observed spiralling filaments is critical for membrane abscission during cytokinesis. PMID- 28659640 TI - Enhancing the quality and transparency of reporting. PMID- 28659639 TI - Erratum: The metabolic co-regulator PGC1alpha suppresses prostate cancer metastasis. AB - This corrects the article DOI: 10.1038/ncb3357. PMID- 28659641 TI - Lgr5 joins the club of gastric stem cell markers in the corpus. AB - Several markers of gastric stem cells have been identified in recent years. Now a study demonstrates that Lgr5 marks a population of reserve stem cells located at the base of the corpus glands of the gastric epithelium, and that these cells can also act as a cell-of-origin for gastric tumorigenesis. PMID- 28659642 TI - snoRNAs contribute to myeloid leukaemogenesis. AB - The mechanism of action of oncogenes in acute myeloid leukaemia is poorly understood. A study now shows that the fusion oncoprotein AML1-ETO regulates leukaemogenesis by increasing the expression of small nucleolar RNAs through post transcriptional mechanisms, resulting in increased ribosomal RNA methylation, protein translation, and promotion of leukaemic-cell self-renewal and growth. PMID- 28659643 TI - Erratum: Microtubule minus-end regulation at spindle poles by an ASPM-katanin complex. AB - This corrects the article DOI: 10.1038/ncb3511. PMID- 28659644 TI - Are goblet cell carcinoids a group of heterogeneous tumors? AB - BACKGROUND: Goblet cell carcinoids belong to neuroendocrine tumors, according to the WHO classification. The tumors are diagnosed based on a typical histological pattern and using neuroendocrine markers. However, some tumors do not react with these markers and yet expression of proliferative markers is high. Do these tumors belong to G1 and G2 neuroendocrine tumors? METHODS: The sample comprised nine cases of tumors of the appendix identified by immunohistological methods as goblet cell carcinoids or adenocarcinoma ex goblet cell carcinoid. RESULTS: In six cases, hematoxylin and eosin staining revealed tumors completely or 90% made of characteristic large tumor cells observed in typical goblet cell carcinoids. The remaining three cases were identified as adenocarcinomas arising ex goblet cell carcinoids. Immunohistological examination revealed that in four cases of typical goblet cell carcinoids, expression of neuroendocrine markers was low or completely negative. Yet in two cases, the Ki-67 proliferative index exceeded the 20% cut-off for inclusion in the G1 and G2 category. CONCLUSIONS: Goblet cell carcinoids are a heterogeneous group of tumors that may express neuroendocrine markers in a small number of tumor cells or are negative to these markers. However, high expression of the proliferative marker Ki-67 exceeds the criteria for G1 and G2 neuroendocrine tumors. It is our opinion that these tumors may be classified as a specific type of carcinoma. PMID- 28659645 TI - Single giant mediastinal rhabdomyoma as a sole manifestation of TSC in foetus. AB - BACKGROUND: Presence of multiple cardiac rhabdomyomas is one of the major features of Tuberous sclerosis (TSC), but isolated progressing single giant rhabdomyoma is very rare and not typical of TSC. CASE REPORT: This report presents family without obvious history of TSC with occurrence of giant mediastinal rhabdomyoma affecting the haemodynamics in male foetus, without other TSC symptoms. Girl from the next gravidity had prenatally detected multiple rhabdomyomas and small subcortical tuber of brain detected after birth. DNA analysis found novel c.4861A>T TSC2 variant and large deletion in TSC2 in tumour tissue from male foetus. The novel TSC2 variant was also present in the girl and her healthy father, in silico analysis suggested its functional effect on TSC2. Brain MRI of the father detected mild TSC specific abnormality. CONCLUSION: We suggest the novel TSC2 mutation is a cause of mild TSC in this family and has reduced expression. The clinical and molecular findings in this family also emphasize that TSC diagnosis should be also evaluated in case of single giant foetal cardiac rhabdomyoma. PMID- 28659646 TI - Synthesis of the Right-Side Structure of Type B Physalins. AB - We present a full account of our synthetic studies on the racemic DEFGH-ring moiety of physalins, featuring domino ring transformation of a tricyclic key intermediate. We also report the results of a detailed mechanistic examination of the domino ring transformation, as well as a reoptimization of the 2,3-Wittig rearrangement and methylation steps. Furthermore, we have newly established a method for the preparation of an optically active synthetic intermediate by enzymatic kinetic resolution. Our work provides access to both natural and nonnatural right-side physalin structures. PMID- 28659647 TI - PICS bags safely store unshelled and shelled groundnuts in Niger. AB - We conducted an experiment in Niger to evaluate the performance of hermetic triple layer (Purdue Improved Crop Storage- PICS) bags for the preservation of shelled and unshelled groundnut Arachis hypogaea L. Naturally-infested groundnut was stored in PICS bags and woven bags for 6.7 months. After storage, the average oxygen level in the PICS bags fell from 21% to 18% (v/v) and 21%-15% (v/v) for unshelled and shelled groundnut, respectively. Identified pests present in the stored groundnuts were Tribolium castaneum (Herbst), Corcyra cephalonica (Stainton) and Cryptolestes ferrugineus (Stephens). After 6.7 months of storage, in the woven bag, there was a large increase in the pest population accompanied by a weight loss of 8.2% for unshelled groundnuts and 28.7% for shelled groundnut. In PICS bags for both shelled and unshelled groundnuts, by contrast, the density of insect pests did not increase, there was no weight loss, and the germination rate was the same compared to that recorded at the beginning of the experiment. Storing shelled groundnuts in PICS bags is the most cost-effective way as it increases the quantity of grain stored. PMID- 28659648 TI - Impact of storage environment on the efficacy of hermetic storage bags. AB - Small hermetic bags (50 and 100 kg capacities) used by smallholder farmers in several African countries have proven to be a low-cost solution for preventing storage losses due to insects. The complexity of postharvest practices and the need for ideal drying conditions, especially in the Sub-Sahara, has led to questions about the efficacy of the hermetic bags for controlling spoilage by fungi and the potential for mycotoxin accumulation. This study compared the effects of environmental temperature and relative humidity at two locations (Indiana and Arkansas) on dry maize (14% moisture content) in woven polypropylene bags and Purdue Improved Crop Storage (PICS) hermetic bags. Temperature and relative humidity data loggers placed in the middle of each bag provided profiles of environmental influences on stored grain at the two locations. The results indicated that the PICS bags prevented moisture penetration over the three-month storage period. In contrast, maize in the woven bags increased in moisture content. For both bag types, no evidence was obtained indicating the spread of Aspergillus flavus from colonized maize to adjacent non-colonized maize. However, other storage fungi did increase during storage. The number of infected kernels did not increase in the PICS bags, but the numbers in the woven bags increased significantly. The warmer environment in Arkansas resulted in significantly higher insect populations in the woven bags than in Indiana. Insects in the PICS bags remained low at both locations. This study demonstrates that the PICS hermetic bags are effective at blocking the effects of external humidity fluctuations as well as the spread of fungi to non-infected kernels. PMID- 28659649 TI - An Alternative to the RNA World. PMID- 28659651 TI - Poverty among Foster Children: Estimates Using the Supplemental Poverty Measure. AB - We use data from the Current Population Survey and the new Supplemental Poverty Measure (SPM) to provide estimates for poverty among foster children over the period 1992 to 2013. These are the first large-scale national estimates for foster children who are not included in official poverty statistics. Holding child and family demographics constant, foster children have a lower risk of poverty than other children. Analyzing income in detail suggests that foster care payments likely play an important role in reducing the risk of poverty in this group. In contrast, we find that children living with grandparents have a higher risk of poverty than other children, even after taking demographics into account. Our estimates suggest that this excess risk is likely linked to their lower likelihood of receiving foster care or other income supports. PMID- 28659652 TI - Young child poverty in the United States: Analyzing trends in poverty and the role of anti-poverty programs using the Supplemental Poverty Measure. AB - Between 1968 and 2013, the poverty rate of young children age 0 to 5 years fell by nearly one third, in large part because of the role played by anti-poverty programs. However, young children in the U.S. still face a much higher rate of poverty than do older children in the U.S. They also continue to have a much higher poverty rate than do young children in other developed countries around the world. In this paper, we provide a detailed analysis of trends in poverty and the role of anti-poverty programs in addressing poverty among young children, using an improved measure of poverty, the Supplemental Poverty Measure. We examine changes over time and the current status, both for young children overall and for key subgroups (by child age, and by child race/ethnicity). Our findings can be summarized in three key points. First, poverty among all young children age 0-5 years has fallen since the beginning of our time series; but absent the safety net, today's poverty rate among young children would be identical to or higher than it was in 1968. Second, the safety net plays an increasing role in reducing the poverty of young children, especially among Black non-Hispanic children, whose poverty rate would otherwise be 20.8 percentage points higher in 2013. Third, the composition of support has changed from virtually all cash transfers in 1968, to about one third each of cash, credit and in-kind transfers today. PMID- 28659653 TI - Effects of semantic context on access to words of low imageability in deep phonological dysphasia: a treatment case study. AB - BACKGROUND: Deep dysphasia is a relatively rare subcategory of aphasia, characterised by word repetition impairment and a profound auditory-verbal short term memory (STM) limitation. Repetition of words is better than nonwords (lexicality effect) and better for high-image than low-image words (imageability effect). Another related language impairment profile is phonological dysphasia, which includes all of the characteristics of deep dysphasia except for the occurrence of semantic errors in single word repetition. The overlap in symptoms of deep and phonological dysphasia has led to the hypothesis that they share the same root cause, impaired maintenance of activated representation of words, but that they differ in severity of that impairment, with deep dysphasia being more severe. AIMS: We report a single-subject multiple baseline, multiple probe treatment study of a person who presented with a pattern of repetition that was consistent with the continuum of deep-phonological dysphasia: imageability and lexicality effects in repetition of single and multiple words and semantic errors in repetition of multiple-word utterances. The aim of this treatment study was to improve access to and repetition of low-imageability words by embedding them in modifier-noun phrases that enhanced their imageability. METHODS & PROCEDURES: The treatment involved repetition of abstract noun pairs. We created modifier abstract noun phrases that increased the semantic and syntactic cohesiveness of the words in the pair. For example, the phrases "long distance" and "social exclusion" were developed to improve repetition of the abstract pair "distance exclusion". The goal of this manipulation was to increase the probability of accessing lexical and semantic representations of abstract words in repetition by enriching their semantic -syntactic context. We predicted that this increase in accessibility would be maintained when the words were repeated as pairs, but without the contextual phrase. OUTCOMES & RESULTS: Treatment outcomes indicated that increasing the semantic and syntactic cohesiveness of low-imageability and low-frequency words later improved this participant's ability to repeat those words when presented in isolation. CONCLUSIONS: This treatment approach to improving access to abstract word pairs for repetition was successful for our participant with phonological dysphasia. The approach exemplifies the potential value in manipulating linguistic characteristics of stimuli in ways that improve access between phonological and lexical-semantic levels of representation. Additionally, this study demonstrates how principles of a cognitive model of word processing can be used to guide treatment of word processing impairments in aphasia. PMID- 28659654 TI - Real time implementation of anti-scatter grid artifact elimination method for high resolution x-ray imaging CMOS detectors using Graphics Processing Units (GPUs). AB - Scatter is one of the most important factors effecting image quality in radiography. One of the best scatter reduction methods in dynamic imaging is an anti-scatter grid. However, when used with high resolution imaging detectors these grids may leave grid-line artifacts with increasing severity as detector resolution improves. The presence of such artifacts can mask important details in the image and degrade image quality. We have previously demonstrated that, in order to remove these artifacts, one must first subtract the residual scatter that penetrates through the grid followed by dividing out a reference grid image; however, this correction must be done fast so that corrected images can be provided in real-time to clinicians. In this study, a standard stationary Smit Rontgen x-ray grid (line density - 70 lines/cm, grid ratio - 13:1) was used with a high-resolution CMOS detector, the Dexela 1207 (pixel size - 75 micron) to image anthropomorphic head phantoms. For a 15 * 15 cm field-of-view (FOV), scatter profiles of the anthropomorphic head phantoms were estimated then iteratively modified to minimize the structured noise due to the varying grid line artifacts across the FOV. Images of the head phantoms taken with the grid, before and after the corrections, were compared, demonstrating almost total elimination of the artifact over the full FOV. This correction is done fast using Graphics Processing Units (GPUs), with 7-8 iterations and total time taken to obtain the corrected image of only 87 ms, hence, demonstrating the virtually real time implementation of the grid-artifact correction technique. PMID- 28659655 TI - Expression and Clinical Significance of Cancer Stem Cell Markers CD24, CD44, and CD133 in Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis. AB - Cancer stem cells (CSC) play an important role in pancreatic carcinogenesis and prognosis. The study aimed at examining the expression of CD24, CD44, and CD133 in human PDAC and CP in order to evaluate its clinicopathological correlations and the clinical significance. Surgical specimens from 23 patients with PDAC and 15 patients with chronic pancreatitis after pancreatic resection were stained with CD24, CD44, and CD133 antibodies. The intensity of staining was scored from 0 (negative) to 3 (strongly positive). Results. Mean CD24 staining score in PDAC was 1.38 +/- 0.76 and was significantly higher than that in CP: 0.70 +/- 0.53 (p < 0.01); CD44 score in PDAC was 2.23 +/- 0.42 and was significantly higher than that in CP: 1.87 +/- 0.55 (p < 0.05); CD133 score 0.93 +/- 0.58 was not different from CP: 0.71 +/- 0.43 (p > 0.05). CD44 immunoreactivity was significantly higher (p < 0.05) in pT1 and pT2 patients together as regards pT3: 2.45 +/- 0.37 versus 2.06 +/- 0.38 as well as in N0 patients compared to N1 patients: 2.5 +/- 0.38 versus 2.04 +/- 0.34. Conclusions. CD24 and CD44 are upregulated in human pancreatic cancer compared to chronic pancreatitis. CD44 immunoreactivity decreases with the tumor advancement and may represent the negative PDAC prognostic factor. Each CSC marker was differently related to PDAC advancement. CD133 may lack clinical significance in PDAC. PMID- 28659656 TI - Type II Endometrial Cancer Overexpresses NILCO: A Preliminary Evaluation. AB - OBJECTIVE: The expression of NILCO molecules (Notch, IL-1, and leptin crosstalk outcome) and the association with obesity were investigated in types I and II endometrial cancer (EmCa). Additionally, the involvement of NILCO in leptin induced invasiveness of EmCa cells was investigated. METHODS: The expression of NILCO mRNAs and proteins were analyzed in EmCa from African-American (n = 29) and Chinese patients (tissue array, n = 120 cases). The role of NILCO in leptin induced invasion of Ishikawa and An3ca EmCa cells was investigated using Notch, IL-1, and leptin signaling inhibitors. RESULTS: NILCO molecules were expressed higher in type II EmCa, regardless of ethnic background or obesity status of patients. NILCO proteins were mainly localized in the cellular membrane and cytoplasm of type II EmCa. Additionally, EmCa from obese African-American patients showed higher levels of NILCO molecules than EmCa from lean patients. Notably, leptin-induced EmCa cell invasion was abrogated by NILCO inhibitors. CONCLUSION: Type II EmCa expressed higher NILCO molecules, which may suggest it is involved in the progression of the more aggressive EmCa phenotype. Obesity was associated with higher expression of NILCO molecules in EmCa. Leptin-induced cell invasion was dependent on NILCO. Hence, NILCO might be involved in tumor progression and could represent a new target/biomarker for type II EmCa. PMID- 28659657 TI - Serum Gamma-Glutamyl Transferase and Ferritin Synergistically Associated with the Rate of Chronic Kidney Disease. AB - The present study investigated the effects of GGT and SF on the risk of CKD. 1024 participants (436 men and 588 women) were divided into three groups according to GGT and SF levels: group 1 (both GGT and SF not in the fourth quartile), group 2 (only GGT or SF in the fourth quartile), and group 3 (both GGT and SF in the fourth quartile). The risks of CKD in different levels of GGT and SF and in groups 2-3 compared with group 1 were analyzed by multiple logistic regression. GGT or SF in the highest quartile was associated with increased risk of CKD. Such associations attenuated after adjustment for confounding factors. The incidences of CKD, especially albuminuria, increased across the three groups. Correspondingly, malondialdehyde (MDA) levels gradually increased from group 1 to group 3. The risks of CKD were higher in groups 2 and 3 than that in group 1. In group 3, the increased rate was independent of age, BMI, alcohol drinking, diabetes mellitus, hypertension, hypertriglyceridemia, and metabolic syndrome (odds ratios from 1.887 to 2.293, P < 0.05). In summary, this study suggested that GGT and SF synergistically influence the rate of CKD. PMID- 28659658 TI - Enabling Incremental Query Re-Optimization. AB - As declarative query processing techniques expand to the Web, data streams, network routers, and cloud platforms, there is an increasing need to re-plan execution in the presence of unanticipated performance changes. New runtime information may affect which query plan we prefer to run. Adaptive techniques require innovation both in terms of the algorithms used to estimate costs, and in terms of the search algorithm that finds the best plan. We investigate how to build a cost-based optimizer that recomputes the optimal plan incrementally given new cost information, much as a stream engine constantly updates its outputs given new data. Our implementation especially shows benefits for stream processing workloads. It lays the foundations upon which a variety of novel adaptive optimization algorithms can be built. We start by leveraging the recently proposed approach of formulating query plan enumeration as a set of recursive datalog queries; we develop a variety of novel optimization approaches to ensure effective pruning in both static and incremental cases. We further show that the lessons learned in the declarative implementation can be equally applied to more traditional optimizer implementations. PMID- 28659659 TI - How Family Status and Social Security Claiming Options Shape Optimal Life Cycle Portfolios. AB - We show how optimal household decisions regarding work, retirement, saving, portfolio allocations, and life insurance are shaped by the complex financial options embedded in U.S. Social Security rules and uncertain family transitions. Our life cycle model predicts sharp consumption drops on retirement, an age-62 peak in claiming rates, and earlier claiming by wives versus husbands and single women. Moreover, life insurance is mainly purchased on men's lives. Our model, which takes Social Security rules seriously, generates wealth and retirement outcomes that are more consistent with the data, in contrast to earlier and less realistic models. PMID- 28659660 TI - Robotics in Lower-Limb Rehabilitation after Stroke. AB - With the increase in the elderly, stroke has become a common disease, often leading to motor dysfunction and even permanent disability. Lower-limb rehabilitation robots can help patients to carry out reasonable and effective training to improve the motor function of paralyzed extremity. In this paper, the developments of lower-limb rehabilitation robots in the past decades are reviewed. Specifically, we provide a classification, a comparison, and a design overview of the driving modes, training paradigm, and control strategy of the lower-limb rehabilitation robots in the reviewed literature. A brief review on the gait detection technology of lower-limb rehabilitation robots is also presented. Finally, we discuss the future directions of the lower-limb rehabilitation robots. PMID- 28659661 TI - Different Cognitive Profiles of Patients with Severe Aphasia. AB - Cognitive dysfunction frequently occurs in aphasic patients and primarily compromises linguistic skills. However, patients suffering from severe aphasia show heterogeneous performance in basic cognition. Our aim was to characterize the cognitive profiles of patients with severe aphasia and to determine whether they also differ as to residual linguistic abilities. We examined 189 patients with severe aphasia with standard language tests and with the CoBaGA (Cognitive Test Battery for Global Aphasia), a battery of nonverbal tests that assesses a wide range of cognitive domains such as attention, executive functions, intelligence, memory, visual-auditory recognition, and visual-spatial abilities. Twenty patients were also followed longitudinally in order to assess their improvement in cognitive skills after speech therapy. Three different subgroups of patients with different types and severity of cognitive impairment were evidenced. Subgroups differed as to residual linguistic skills, in particular comprehension and reading-writing abilities. Attention, reasoning, and executive functions improved after language rehabilitation. This study highlights the importance of an extensive evaluation of cognitive functions in patients with severe aphasia. PMID- 28659662 TI - IL-34 Upregulated Th17 Production through Increased IL-6 Expression by Rheumatoid Fibroblast-Like Synoviocytes. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease which is characterized by synovial inflammation and cartilage damage for which causes articular dysfunction. Activation of fibroblast-like synoviocytes (FLS) is a critical step that promotes disease progression. In this study, we aimed to explore the effect of interleukin-34 (IL-34) on RA FLS as a proinflammatory factor and IL-34 stimulated FLS on the production of Th17. We found that serum IL-34 levels were increased compared to those of the healthy controls and had positive correlations with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and anticyclic citrullinated peptide (CCP) antibody accordingly. CSF 1R was also highly expressed on RA FLS. The interaction of IL-34 and CSF-1R promoted a dramatic production of IL-6 by FLS through JNK/P38/NF-kappaB signaling pathway. Further, the IL-34-stimulated IL-6 secretion by RA FLS was found to upregulate the number of Th17. The treatment of IL-6R antagonist could attenuate the production of Th17 mediated by IL-34-stimulated RA FLS. Our results suggest that the increased IL-34 levels were closely related to the disease activity of RA. Additionally, the overexpression of IL-6 in the IL-34-stimulated FLS promoted the generation of Th17. Therefore, IL-34 was supposed to be involved in the pathogenesis of RA. The inhibition of IL-34 might provide a novel target for therapies of RA. PMID- 28659663 TI - A Role of the ABCC4 Gene Polymorphism in Airway Inflammation of Asthmatics. AB - The ATP-binding cassette subfamily C member 4 gene encodes a transmembrane protein involved in the export of proinflammatory molecules, including leukotriene, prostaglandin, and sphingosine-1-phosphate across the plasma membrane. Those metabolites play important roles in asthma. We investigated the potential associations between ABCC4 gene polymorphisms and asthma phenotype. In total, 270 asthma patients and 120 normal healthy controls were enrolled for a genetic association study. Two polymorphisms (-1508A>G and -642C>G) in the ABCC4 promoter were genotyped. The functional variability of the promoter polymorphisms was analyzed by luciferase reporter assay. Inflammatory cytokine levels were measured by enzyme-linked immunosorbent assay. Serum and urinary eicosanoid metabolites, sphingosine-1-phosphate, were evaluated by quadrupole time-of-flight mass spectrometry. Asthma patients carrying the G allele at -1508A>G had significantly higher serum levels of periostin, myeloperoxidase, and urinary levels of 15-hydroxyeicosatetraenoic acid and sphingosine-1-phosphate (P = 0.016, P = 0.027, P = 0.032, and P = 0.010, resp.) compared with noncarrier asthma patients. Luciferase activity was significantly enhanced in human epithelial A549 cells harboring a construct containing the -1508G allele (P < 0.01 for each) compared with a construct containing the -1508A allele. A functional polymorphism in the ABCC4 promoter, -1508A>G, may increase extracellular 15 hydroxyeicosatetraenoic acid, sphingosine-1-phosphate, and periostin levels, contributing to airway inflammation in asthmatics. PMID- 28659664 TI - Inherited Variation in Cytokine, Acute Phase Response, and Calcium Metabolism Genes Affects Susceptibility to Infective Endocarditis. AB - Infective endocarditis (IE) is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1beta and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE. PMID- 28659666 TI - miR-155 Promotes ox-LDL-Induced Autophagy in Human Umbilical Vein Endothelial Cells. AB - As an evolutionarily conserved metabolic process, autophagy is involved in the process of atherosclerosis (AS). MicroRNA-155 (miR-155), a multifunctional miRNA, plays an important role in many physiological and pathological conditions, including AS and autophagy. However, the effect of miR-155 on the regulation of autophagy in endothelial cells has not been reported to date. Therefore, the objective of our study was to investigate the role of miR-155 in autophagy induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs). Our results demonstrated that ox-LDL induced autophagy in HUVECs and increased the expression of miR-155 significantly. Overexpression of miR-155 improved autophagic activity, whereas low expression of miR-155 inhibited autophagic activity. Therefore, the data demonstrated that miR 155 has a modulating effect on the autophagy of vascular endothelial cells. PMID- 28659667 TI - Individual Surgeon Outcomes and the Public. PMID- 28659668 TI - Lateral Internal Partial Sphincterotomy Technique for Chronic Anal Fissure. AB - Lateral internal sphincterotomy is used for the treatment of a chronic anal fissure. There is a lack of consensus for the amount of internal sphincter division necessary in the surgical treatment of an anal fissure. The anatomy of the anal sphincters and the subcutaneous partial sphincterotomy technique are presented with fresh anal canal specimen photographs. Lateral internal partial sphincterotomy is performed in 43 patients in the office between 2012 and 2013. The patients were questioned about their bowel habitus and any problem with anal control before the operation. Postoperatively, the patients were followed up by office visits and telephone calls at 1 week, 1 month, and 6 months. Data were collected prospectively. Forty of the patients (93 %) were pain free in 1 week after the operation. Further sphincter fibers were divided in three patients (7 %) because of the persistent pain. The most common complication was the sensation of burning (n = 9, 20.9 %) around the anus. Bleeding in three patients, itching around the anus in two patients, and incontinence to flatus in one patient were the other complications. None of the patients developed fecal incontinence in the follow-up period. Lateral internal partial sphincterotomy is a safe, effective, and reproducible technique for the management of chronic anal fissure pain. PMID- 28659665 TI - Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics. AB - Tuberculosis (TB) still represents an important issue for public health in underdeveloped countries, but the use of antitumor necrosis factor agents (anti TNF) for the treatment of inflammatory rheumatic disorders has reopened the problem also in countries with low TB incidence, due to the increased risk of TB reactivation in subjects with latent tuberculosis infection (LTBI). Over the last 5 years, several non-anti-TNF-targeted biologics have been licensed for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. We reviewed the epidemiology of TB, the role of different cytokines and of the immune system cells involved in the immune response against TB infection, the methods to detect LTBI, and the risk of TB reactivation in patients exposed to non-anti-TNF-targeted biologics. Given the limited role exerted by the cytokines different from TNF, as expected, data from controlled trials, national registries of biologics, and postmarketing surveillance show that the risk of TB reactivation in patients receiving non-anti-TNF-targeted biologics is negligible, hence raising the question whether the screening procedures for LTBI would be necessary. PMID- 28659669 TI - The Importance of Rockall Scoring System for Upper Gastrointestinal Bleeding in Long-Term Follow-Up. AB - The aim of the study is to examine the importance of Rockall scoring system in long-term setting to estimate re-bleeding and mortality rate due to upper gastrointestinal bleeding. A total of 321 patients who had been treated for upper gastrointestinal bleeding were recruited to the study. Patients' demographic and clinical data, the amount of blood transfusion, endoscopy results, and Rockall scores were retrieved from patients' charts. The re-bleeding, morbidity, and mortality rates were noted after 3 years of follow-up with telephone. Re-bleeding rate was statistically significantly higher in Rockall 4 group compared to Rockall 0 group. Mortality rate was also statistically significantly higher in Rockall 4 group. Rockall risk scoring system is a valuable tool to predict re bleeding and mortality rates for patients with upper gastrointestinal bleeding in long-term setting. PMID- 28659670 TI - Is the Routine Use of Impedance Analysis for the Diagnosis of Gastro-Esophageal Reflux Disease More Expensive than Conventional pH Monitoring? Cost Analysis of Two Procedures. AB - Conventional 24-h pH monitoring is the gold standard for the diagnosis of non erosive, non-acidic gastro-esophageal reflux disease. Multichannel Intraluminal Impedance (MII) analysis markedly improves diagnostic accuracy of non-erosive, non-acidic gastro-esophageal reflux disease. However, MII catheters are more expensive than standard catheters. This study aimed to determine the rates of acid or non-acid reflux and by making a retrospective projection, to predict the costs of two algorithms. We retrospectively reviewed the medical data of 102 patients who presented to our hospital with suspected non-erosive GERD and underwent 24 h impedance/pH-monitoring. Demographic characteristics, Demeester scores, number of reflux episodes, and results of impedance analysis were recorded. According to these data, cost was calculated either for the scenario in which impedance measurement was performed solely or following a negative conventional pH monitoring. Thirty-seven of all 102 patients (36.3 %) had a Demeester score greater than 14.7. These patients were assigned as group 1 (acid reflux). The impedance analysis of the remaining 65 patients detected 34 patients (33.3 %) to have more than 50 reflux episodes over a period of 24 h and assigned as Group 2, and 31 patients (30.4 %) had no reflux (group 3). The cost of the single- step algorithm using MII catheter was calculated as $15,300, while the total cost of two-step scenario would have been predicted as $16,890. Our study showed that an initial conventional pH monitoring can make the diagnosis of GERD in only one third of the patients with suspected non-erosive GERD. In nearly two thirds of patients, however, repeated procedures and use of impedance catheters are needed. It is clear that this algorithm has certain drawbacks with regard to cost, patient comfort, and workforce loss. PMID- 28659671 TI - Penetrating Injuries to the Abdomen: a Single Institutional Experience with Review of Literature. AB - Penetrating abdominal trauma forms an important component of surgical emergencies, most of the victims being young aged in the prime of their life. Over the past century, the diagnosis and management of this common problem has seen drastic changes, finally reaching the destination of selective approach. We present our experience in the management of this group of patients in the rural setup. This is a prospective observational study done at our hospital between 1 April 2013 and 31 March 2015 including patients who presented with penetrating abdominal injury. The clinical presentation, imaging features, diagnosis, management, and complications of all these patients are analyzed. The mean age was 33.5 years with majority being males. Homicidal stab injuries accounted for most of the injuries (62.5 %). Forty-eight patients underwent laparotomy, and among which, the procedure was therapeutic in 36 patients. Peritoneal penetration was the best predictor of a therapeutic laparotomy with a high sensitivity and positive predictive value (100 and 80 %, respectively). The small intestine was the most commonly injured organ. The mean postoperative stay was 8.25 days, and there was no mortality. Though the management of these patients should aim at minimizing the rate of negative laparotomies, this should not be done at the expense of delayed diagnosis and treatment. Diagnostic laparoscopy may avoid unnecessary laparotomies; however, it requires adequate skills in laparoendoscopy. Management is best tailor made for each individual based on the nature of injury, findings at presentation, and the organ injured. PMID- 28659672 TI - Effect of Splenectomy to Short Bowel Syndrome in Rats. AB - The aim of this study was to determine the effect of splenectomy in the short bowel syndrome. Twenty-four Wistar-albino rats weighing between 210 and 375 g were used. They were divided into three groups. In group A, short bowel syndrome (SBS) was created by 75 % bowel resection. In group B, SBS and splenectomy was performed. In group C, after transecting the bowel, it was anastomosed. Before and 45 days after the procedures, all rats were weighed. In all three groups, the first and final weight of the rats, the final bowel weight and length, the ileal and jejunal crypt depths, the villus height, the luminal diameter, the bowel wall thickness, and the number of apoptotic cells and mitosis per 100 crypt cell were compared. Periportal fibrosis, infiltration, bile stasis, and bile duct proliferation were detected in liver samples. The rat intestinal length and weight was the least in group B while the jejunal crypt depth was higher in group B than in group A and it was exactly the opposite for the jejunal and ileal villus heights. The ileal and jejunal luminal diameter, the ileal bowel wall thickness, the jejunal and ileal apoptotic cell number, the jejunal mitosis, and the periportal fibrosis were highest in group B. Adding splenectomy to an SBS model has a negative impact on bowel adaptation. PMID- 28659673 TI - Emergency Laparotomies at a Tertiary Care Center-a Hospital-Based Cross-Sectional Study. AB - Emergency laparotomy is a common high-risk surgical procedure, but with a few outcome data and few data on postoperative care. This was a hospital-based descriptive study of 376 consecutive emergency midline laparotomies performed in a tertiary care center. The aim of the study was to identify the clinical presentation, surgical indications, preoperative delay, intraoperative findings, and postoperative complications. Majority of the patients belonged to the 40-80 year age group. Broadly, the indications could be divided into acute abdomen and trauma. Most of the cases (82 %) presented with acute abdomen, out of which 57 % cases had gastrointestinal perforation, and 33 % had intestinal obstruction. In trauma laparotomies, 63 % of cases were done for blunt abdominal trauma and the rest for penetrating injury. The clinical features were analyzed, of which most frequent were abdominal tenderness (88.8 %), abdominal distension (88 %), tachycardia (74.2 %), and guarding (70.7 %). Nearly three fourths of the patients underwent laparotomy within 24 h of entry to the casualty. The most common condition that resulted in an emergency laparotomy was duodenal perforation which was seen in 93 patients, followed by gastric perforation in 60 patients. Postoperatively, 54.5 % of patients did not develop any complication. The most common complication encountered was wound infection (26.6 %). Mortality following emergency laparotomy was 13 %. Age-specific mortality was maximum in patients with age more than 80 years. The diagnosis-specific mortality was higher for large bowel perforation and mesenteric ischemia among the acute abdomen cases, and liver injury or great vessel injury among the trauma cases. PMID- 28659674 TI - Blunt Diaphragmatic Injuries: Pericardial Ruptures. AB - Blunt traumatic diaphragmatic injuries (BTDIs) can be misdiagnosed. Careful evaluation of associated injuries in BTDI is important. In this study, we evaluated treatment options and difficulties in the diagnosis of patients with BTDI. We evaluated ten patients retrospectively with BTDI admitted to our departments, between January 2004 and 2015. Age, gender, trauma type, symptoms, radiological findings, diagnosis time, location and grade of the diaphragmatic injury, surgical type of repair, associated injuries and pericardial rupture, and morbidity and mortality rates were recorded. The mean age of the patients was 46.7 years, and all were males. Ninety percent of BTDI was left sided, and 10 % was on the right side. The diagnosis was confirmed with chest radiograph in 50 % and computed tomography in 70 %. Radiological examination revealed hemothorax in 80 %, the loss of diaphragmatic shadow in 60 %, and visceral organ herniation to the thorax in 60 %. Multiple organ injuries were present in 90 % of cases. Pericardial rupture seen in 30 % was remarkable. Early surgery was performed for eight patients and late surgery for two patients. There were six patients with grade 4 or 5 central diaphragmatic injuries (CDIs). Multiorgan injury was present in all patients developing acute CDI. Multiple organ injury is much higher in patients with severe acute blunt trauma with CDI. Pericardial rupture rate is high in cases with acute BTDI and CDI. Proper diagnosis and early surgical management reduce morbidity and mortality. PMID- 28659675 TI - Validation of Different Techniques in Physical Examination of Breast. AB - The majority of patients attending breast clinics are found to be suffering from benign conditions. The detailed investigations of every patient would add to the cost of care and burden the laboratories. A detailed clinical evaluation might limit the use of thorough investigations for suspicious lesions only. This cross sectional study involved the patients with various benign and malignant conditions of breast, who attended outpatient clinic and surgical ward at All India Institute of Medical Sciences, New Delhi from June 2009 to May 2011. The study started with a training of the resident (observer 2) in various breast examination techniques by a professor of surgery (observer 1), who was well trained in the discipline of breast surgery by internationally renowned breast experts. The different techniques of breast examination were validated after calculation of intra and inter-observer variation. Excellent agreement was observed between both the observers. The diagnostic accuracy ratio for most variables ranges from 0.9 to 1. The dimpling of skin on inspection had a low kappa (coefficient of agreement = 0.48) and consistency of lymph node on palpation had a kappa 0.38. All other variables showed high agreement. The present study was successful in training the resident and validating the different techniques in physical examination of breast. PMID- 28659676 TI - Outcomes of 101 Consecutive Surgical Resections of Gastroenteropancreatic Neuroendocrine Tumours (GEPNETs) at Tata Memorial Hospital: a Referral Bias for Nonfunctional Duodenopancreatic Tumours and the Need for Greater Awareness of GEPNETs as a Distinct Entity. AB - Data from India regarding the disease spectrum and surgical results of neuroendocrine tumours (GEPNETs) are sparse. Tempered surgical radicality in a high-volume oncology centre, conforming to existing guidelines, may further our understanding of tumour characteristics and behavioural patterns of nonfunctional GEPNETs. Surgical outcomes of patients with histopathologically confirmed GEPNETs from January 2003 to December 2013 were analyzed from a prospectively maintained database. Tumour grade, organ of primary tumour, perioperative factors, quality/radicality of resection and presence of metastatic disease were correlated with perioperative outcomes, overall survival and disease-free survival. Ninety of the 101 operated patients had nonfunctional tumours. These comprised radical resections (n = 69), organ-preserving procedures (n = 16) and inoperable tumours (n = 5). The primary tumour sites were pancreatic in 48 patients and gastroenteric in 42 patients. The overall perioperative morbidity and mortality rates were 30 and 3 %, respectively. Fifteen patients harboured metastatic disease at presentation. At a median follow-up of 22 months, 18 patients had residual disease, 7 developed recurrences and 10 patients died. The estimated actuarial 5-year overall survival was 81.6 %, and disease-free survival was 67.2 %. Tumour grade and organ of origin (pancreatic vs. gastroenteric) did not influence long-term survival (p = 0.315 and p = 0.624, respectively), but presence of metastatic disease at presentation significantly affected long-term survival (p = 0.009). Nonfunctional pancreatic/duodenal neuroendocrine tumours (NETs) accounted for 76 % of surgical resections at our centre with the minority being other resections. In selected patients with nonfunctional NETs, organ preserving surgery may provide equivalent long-term survival with decreased operative morbidity. Although tumour grade is considered to be an important prognostic factor, the presence of metastatic disease at presentation also determines long-term survival. The referral bias suggests the need for greater awareness given the favourable long-term outcomes of these tumours. There is a need to correct this referral bias by increasing the awareness of GEPNETs in India. PMID- 28659677 TI - Colorectal Cancer: Postoperative Follow-up and Surveillance. AB - Follow-up and surveillance form an important aspect of care in patients with colorectal cancers (CRC). Most recurrences will occur within 2 years of surgery and 90% by 5 years. Follow up protocols have not been well defined in stage I disease and the approach should be individualized. As 40% of patients with stages II and III will develop recurrences, intensive postoperative follow-up strategy is recommended for them. It includes visit to the clinician for clinical examination, serum carcinoembryonic antigen (CEA), computed tomography (CT) of the chest and abdomen, colonoscopy, and flexible proctosigmoidoscopy in rectal cancers. Surveillance should be undertaken in those who are medically fit for repeat surgical procedures or for chemoradiotherapy. The concept of intensive post operative surveillance is based on the fact that some of these patients can have resectable/curable recurrence. PMID- 28659678 TI - 'Never Events in Surgery': Mere Error or an Avoidable Disaster. AB - Never events in surgery is not an uncommon occurrence. It is difficult to find any surgeon who never had an experience of one or another kind of mistake, committed while delivering the surgical care to the patient. Whatever the reports come out through news media or other sources are just a tip of iceberg. Collectively, its results, not only as a huge suffering and financial burden for the patients but also its impact on the operating surgeon and sometimes to related institute, are very far reaching and extremely negative. In spite of all of this, every one of us thinks this as an individual problem or one of the anecdotal media coverage. The aim of this study is to create an awareness among surgeon's fraternity and bring the attention of associations of surgeon bodies to this serious issue so that collective steps can be initiated to address it. In an attempt to find all the related information, an extensive search of literature in English language was performed using online search engines: PubMed NCBI database, Google search, and other digital sources available online. Error may be in the form of an act of commission, act of omission, error of planning, or error of execution, but whatever the reason, ultimate impacts are not less than disastrous, affecting individuals to global level. In addition to the enforcing authorities, all other stake holders should wake up and must take collective and comprehensive approach to create a safety system inside the health care organisations. PMID- 28659680 TI - Isolated Double Gastric Perforation in Blunt Abdominal Trauma-a Case Report. AB - Blunt abdominal trauma mostly results from motor vehicle accidents, recreational accidents, falls or assaults with commonly injured internal organs being the spleen, liver, retroperitoneum, small bowel, kidneys, bladder, colorectal, diaphragm and pancreas. Gastric rupture is quite uncommon. Isolated gastric perforations following blunt trauma to the abdomen are mostly seen in paediatric patients. It is uncommon in adult patients and even rarer is the occurrence of double gastric perforations. We report here with a case of isolated double gastric perforation in a 24-year-old male patient following vehicular accident. PMID- 28659679 TI - Distal Duodenal Obstruction: a Surgical Enigma. AB - The postbulbar segment also known as the distal duodenum is a separate clinical entity in terms of the intrinsic pathologies of this region and its varied anatomical relations. The common bile duct and the pancreatic duct open through the major papilla, which marks the beginning of this segment. Distal duodenal obstruction can be defined as a clinicoradiological entity that is characterized by features of gastric outlet obstruction with recurrent bilious vomiting and a radiological evidence of postbulbar obstruction. A Medline search for distal duodenal obstruction revealed 1409 entries, mostly in the form of case reports. In the last 10 years, 310 cases are reported. Clinical features like abdominal pain, nausea, and vomiting are non-specific and quite similar to gastric outlet obstruction. Clinical findings are also non-specific and do not aid in diagnosis. Laboratory findings also do not add much. Contrast-enhanced CT scan and MR enterography are diagnostic modalities of choice. Distal duodenal obstruction is a clinical entity that has a wide list of differential diagnosis which requires due consideration in terms of its management and follow-up. Most of these lesions require adequate workup with the help of a multidisciplinary team consisting of radiologists, gastroenterologists, and pathologists to adequately diagnose and stage the disease before a treatment plan is formulated. A thorough knowledge is a must regarding the treatment options available for each of the conditions so that the management can be personalized leading to better results. PMID- 28659681 TI - An Unusual Presentation of a Breast Lump. AB - Trichilemmal cyst also known as pilar cyst is a rare cyst arising from the external root sheath of the hair follicle. These cysts are observed on the scalp most commonly in females. The occurrence of trichilemmal cysts in areas other than the scalp is extremely rare. We report a case of an 80-year-old female with trichilemmal cyst of the breast which was first misdiagnosed as a sebaceous cyst because of the unusual disease site and our unfamiliarity with the disease. The patient underwent excision of cyst along with the cyst wall and histopathological diagnosis was trichilemmal cyst of the breast. A review of literature shows that trichilemmal cyst of the breast is an extremely rare condition which accounts for 0.1 % of the skin biopies reported till to date. We report a case of trichilemmal cyst of the breast with relevant discussion on trichilemmal cysts. PMID- 28659682 TI - Benevolent Renal Angiomyolipoma with Intra-cardiac Extension-A Challenge in Diagnosis and Management. AB - While intra-caval and intra-cardiac extension of retroperitoneal tumors is extremely rare, it is almost unheard-of in benign tumors. We report the challenges in diagnosis and management of the first case of a renal angiomyolipoma (AML) with intra-ventricular extension in a young man who presented with pain and a lump in the abdomen. PMID- 28659683 TI - Successful Transplant of Two Kidneys Harvested from a Young Brain-Dead Liver Transplant Recipient. AB - Efforts to increase the dismal deceased renal transplantation (DRT): live renal transplantation (LRT) ratio in our country have gathered momentum recently, with governmental and non-governmental projects focussing on building public awareness and capacity-building, and appropriate legislation. Worldwide, efforts at increasing the number of organs from the deceased pool have focussed on the use of 'expanded criteria donors', including deceased cardiac donors (DCD). 'Reuse' transplant, where an organ is transplanted after removal from the first recipient, is a rare strategy, used more commonly in liver than in kidney transplantation. Exceptional circumstances, where other organs have been harvested from transplant recipients, are rare. We describe the successful transplants of two renal grafts obtained from a 19-year-old brain-dead liver transplant recipient; this is probably the second case in English-language literature. A 19-year-old male patient with hepatitis E-induced fulminant hepatic failure underwent live-related liver transplantation. On postoperative day 2, cerebral edema set in, and the patient was declared brain-dead. Despite the economical and emotional trauma, the family opted for donation of the well perfused kidneys. The kidneys were transported in HTK solution (histidine tryptophan-ketoglutarate) to our centre. Recipient 1 was a 32-year-old woman (B positive) and recipient 2 was a 29-year-old man (also B positive); the kidneys were placed extraperitoneally and anastomosed end-to-side to the external iliac artery and vein. Recipient 2 experienced delayed graft function; however, both are doing well 15 months posttransplant. PMID- 28659684 TI - Medical Professionals and Smartphone Applications. AB - Ever since the advent of Smartphones, Smartphone applications (SAs) are revolutionizing the contemporary medicine. Smartphone application which was created in view of swift communications among the general public has now intruded the medical fraternity. But the ethics for using these applications to transfer patients' medical records through SA is bewildering among the medical professionals (MPs). PMID- 28659685 TI - Jarcho's Syndrome: Bone Marrow Infiltrates from a Gastric Malignancy. AB - Bone and bone marrow metastasis is extremely rare in adenocarcinoma particularly from the stomach. We present a case of gastric carcinoma primarily manifesting as anemia and pancytopenia. On evaluation, he was found to have bone marrow secondaries from a gastric primary tumor. Though such metastasis is rare, patients with refractory anemia must be evaluated to search for solid organ malignancy like the stomach. PMID- 28659686 TI - An Obstructive Wind Sock Web Deformity of the Proximal Duodenum. AB - We herein present a case of a wind sock web deformity of the proximal duodenum causing episodic duodenal obstruction in a 43-year-old male patient. PMID- 28659687 TI - Management of Epithelioid Sarcoma of the Inguinal Region with Vascular Invasion. PMID- 28659688 TI - Evidence-Based Management to Optimize Oncological Outcome: the Need of the Hour! PMID- 28659690 TI - Mental health awareness: The Indian scenario. PMID- 28659689 TI - Emerging immunotherapeutics in adenocarcinomas: A focus on CAR-T cells. AB - More than 80% of all cancers arise from epithelial cells referred to as carcinomas. Adenocarcinomas are the most common type of carcinomas arising from the specialized epithelial cells that line the ducts of our major organs. Despite many advances in cancer therapies, metastatic and treatment-refractory cancers remain the 2nd leading cause of death. Immunotherapy has offered potential opportunities with specific targeting of tumor cells and inducing remission in many cancer patients. Numerous therapies using antibodies as antagonists or checkpoint inhibitors/immune modulators, peptide or cell vaccines, cytokines, and adoptive T cell therapies have been developed. The most innovative immunotherapy approach so far has been the use of engineered T cell, also referred to as chimeric antigen receptor T cells (CAR-T cells). CAR-T cells are genetically modified naive T cells that express a chimeric molecule which comprises of the antigen-recognition domains (scFv) of an anti-tumor antibody and one, two, or three intracellular signaling domains of the T cell receptor (TCR). When these engineered T cells recognize and bind to the tumor antigen target via the scFv fragment, a signal is sent to the intracellular TCR domains of the CAR, leading to activation of the T cells to become cytolytic against the tumor cells. CAR-T cell therapy has shown tremendous success for certain hematopoietic malignancies, but this success has not been extrapolated to adenocarcinomas. This is due to multiple factors associated with adenocarcinoma that are different from hematopoietic tumors. Although many advances have been made in targeting multiple cancers by CAR-T cells, clinical trials have shown adverse effects and toxicity related to this treatment. New strategies are yet to be devised to manage side effects associated with CAR-T cell therapies. In this review, we report some of the promising immunotherapeutic strategies being developed for treatment of most common adenocarcinomas with particular emphasis on the future generation of CAR-T cell therapy. PMID- 28659691 TI - Negative symptoms in schizophrenia. AB - The negative symptoms have been described in association with schizophrenia since the early days of it being recognized as an entity. However, their elusive nature kept them unacknowledged until there was a revival of interest in them following the development of specific quantifying measures. Over the past three decades, there has been a tremendous surge in research on their types, measurements, status in the present classificatory system, and their implications. The developments in modern investigatory methods have provided the researchers with fresh insights into the underlying mechanisms, and a distributed functioning of the neuronal networks has emerged as the major abnormality. Accordingly, a variety of pharmacological and other treatment modalities have been developed which go beyond the traditional. Nevertheless, a lot remain unanswered. The present paper summarizes important concepts with regard to negative symptoms in schizophrenia. PMID- 28659692 TI - "One level more:" A narrative review on internet gaming disorder. AB - Due to explosive growth in technology and internet usage in the last few years, internet gaming disorder (IGD) has manifested as rapidly growing public health problem mainly affecting the teen and preteen population worldwide. It has a negative impact upon physical, psychological, social, and occupational functioning of the affected individual, often leading to severe consequences. It was only recently that it has been recognized as a separate diagnosable disorder in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Not much data is available regarding the exact prevalence and the various sociodemographic, clinical, and other risk factors to identify the individuals vulnerable to develop this disorder, especially in the developing countries such as India. According to a recent report, India ranks 22nd in the list of highest revenue-generating countries from gaming-related businesses, thus highlighting the magnitude of risk faced by Indian population. The aim of this review is to provide an insight about the disorder to identify the risk factors and clinical features, to understand the effect of IGD upon the psychological and physical health with a special focus on neural changes, and to provide information on the various upcoming preventive and treatment strategies. PMID- 28659693 TI - Insomnia, dreams, and suicide: Connecting links. AB - INTRODUCTION: A growing empirical literature has examined insomnia symptoms as a possible risk factor for a range of suicidal behavior. Not much literature is available in normal adolescent population. AIMS: The aim is to find insomnia prevalence, studying various dream factors, and suicidality prevalence among students of various courses. To check if there is a relation between insomnia and suicidal behavior and dreams, particularly nightmares and suicide. MATERIALS AND METHODS: A total of 400 students of various courses were assessed using Insomnia Severity Index and The Mannheim Dream Questionnaire and Suicide Behaviour Questionnaire. RESULTS: Insomnia was present in 11%, 23%, 19%, and 19% and suicide behavior in 16%, 17%, 12%, and 22%, respectively, in medical, commerce, engineering, and arts students. Statistically significant correlation was found between suicide and insomnia severity and various dream factors. CONCLUSIONS: Insomnia and dreams had relation with suicidality in normal adolescent population. PMID- 28659694 TI - Predictors of the work-related depressive symptoms among blue-collar male employees of an industrial unit in Iran. AB - BACKGROUND AND AIM: Possible associations between depressive symptoms and work related parameters have frequently been discussed in the literature. The present study was aimed to evaluate the work-related depressive symptoms and their possible-related parameters among male employees of Esfahan Steel Company (ESCO) as one of the most important industrial sites in Iran. MATERIALS AND METHODS: With a cross-sectional design and a stratified random sampling method in 2010, a total of 400 male employees were enrolled from the operational parts of the ESCO. RESULTS: Among 400 participated employees, 245 (61.3%) were rotational duty employees and 358 (89.5%) were reported making <$500. After applying the linear regression model, some variables including: economic difficulties (P = 0.022, odds ratio [OR] = 0.558, 95% confidence interval [CI] =0.339-0.919), family related problems (P = 0.003, OR = 0.303, 95% CI = 0.138-0.669), and work environment (P < 0.001, OR = 0.244, 95% CI = 0.140-0.426) were found to be significantly associated with higher depressive symptoms among the participants. CONCLUSION: The present study brought to light the predictors of occupational depressive symptoms among blue-collar employees of ESCO. More research is needed to find the causal relations between mental health and work-related parameters among Iranian employees. PMID- 28659695 TI - Depression and risk of suicide in patients with obsessive-compulsive disorder: A hospital-based study. AB - BACKGROUND: Obsessive Compulsive Disorder (OCD) is a chronic, distressing, anxiety disorder associated with significant functional impairment. Patient with OCD often suffer from one or more co-morbid disorders. Major depression has been the most common co-morbid syndrome. Comorbid Axis I disorders along with increased severity of comorbid depressive and anxiety symptoms, increased severity of obsessions, feelings of hopelessness and past history of suicide attempts have been associated with worsening levels of suicidality in OCD (Angelakis I, Gooding P., 2015). As per data Thirty-six percent of the patients of OCD report lifetime suicidal thoughts and 11% have a history of attempted suicide(Torres AR, Ramos-Cerqueira AT, et al, 2011). There is a reasonable probability that the patient of OCD have suicidal thoughts, plans or actually attempt suicide. AIM: To assess depression and suicidality in OCD patients. METHOD: This study was conducted on 50 patients diagnosed with OCD as per ICD 10 criteria, both outpatient & indoor, from department of psychiatry, Dayanand Medical College & Hospital, Ludhiana, Punjab, India. A socio-demographic proforma (containing demographic details), Hamilton Depression Rating & Scale, Columbia suicide severity rating scale (CSSRS) & Yale Brown Obsessive Compulsive Scale Symptom Checklist (YBOCS) were administered. RESULTS: Mild depression was found out to be 40% whereas 16% were suffering from moderate depression and 10% and 14% had severe and very severe depression respectively. Suicidal ideation was found in 52 % of patients.16% of patients had history of actual attempt. Data showed that 70% of females had suicidal ideations. It was also found that in cases of severe and very severe depression associated with OCD all the patients had suicidal ideations as compared to 35% in mild and 87.5% in moderate depressive patients. It was found that 40% of severe depressive and 28.57% of very severe depressive patients had attempted suicide one or more times during the course of illness. Also suicidality was found to be maximum in those with symptoms of cleanliness and contamination (57%) followed by religious obsessions (45%), sexual obsessions (33%), repeated rituals (31%) and other obsessions like need to touch, ask (26%) respectively. CONCLUSION: OCD is associated with high risk not only depression but also of suicidal behavior. It is vital that patients of OCD undergo detailed assessment for suicide risk and associated depression. Aggressive treatment of depression may be warranted to modify the risk of suicide. Behavioral and cognitive techniques along with pharmacotherapy should be used to target co-existing depressive symptoms so as to decrease morbidity and mortality. PMID- 28659696 TI - Employability of mentally ill persons in India: A self-report-based population study. AB - INTRODUCTION: The employment status of mentally ill patients is a reflection of their productivity, control of illness besides providing therapeutic benefits and integration into mainstream society. Owing to the associated stigma, self reporting of mental illness (SRMI) often is rare. Census exercise of India in 2011 provides an insight of SRMI and employment status of such people. This study was undertaken to consider the role of gender, age group, and place on the employment status of SRMI. METHODOLOGY: Frequency of SRMI, age group, gender, and employment status was gathered from Indian 2011 census sources. Descriptive statistics and logistic regression were employed. P <= 0.05 was taken as significant. RESULTS: Majority (68.6%) of the SRMI people resides in rural areas, in the economically productive age group of 15-59 years (75.88%) and often males (57.51%). Of the SRMI as reported in the data, 78.62% were not employed while 2.4% of them were currently employed. The employability frequency distributions of SMRIs were statistically different in terms of area, age group, and gender with significance. DISCUSSION: Although the mental illness data of 2011 census was rejected by mental health professionals citing discrepancy and underestimating of the prevalence of mental illness, it provides a robust estimate of the employability, self-reporting tendency of mental illness. The association of the factors provides a unique insight into SRMIs in India. CONCLUSION: Understanding the interplay of factors may yield robust estimates and clues for policy framers to formulate employment-related policies for employment opportunities for mentally ill patients. PMID- 28659697 TI - A cross-sectional assessment of stress, coping, and burnout in the final-year medical undergraduate students. AB - BACKGROUND: Medical students undergo significant stress during training which may lead to own suffering or problem in patient care. High level of burnouts and depression is also not uncommon. The transition from preclinical to clinical training has been regarded as crucial to student in relation to the stress. METHODOLOGY: An assessment of perceived stress and its relation to general psychopathology, the pattern of coping, and burnout in the final-year medical student was done to bring out clear nature, pattern, and extent of the problem. RESULTS: Perceived stress had statistically significant association with general psychopathology and depressive-anxiety component of burnout. Acceptance, positive reframing, humor, planning, and active coping correlated with lower score on perceived stress. CONCLUSION: Higher score on perceived stress was associated with higher scores on general psychopathology and burnout. Age of joining MBBS course and doctor in the family did not affect the stress significantly. People who displayed positive coping strategies had lesser stress and general psychopathology. PMID- 28659698 TI - Assessment of psychological problems in schoolgoing adolescents of Aligarh. AB - BACKGROUND: Adolescence is a period of physical, nutritional, and sexual transition, also remarkable for the accompanying psychological changes. Worldwide, 20% of children and adolescents suffer from a disabling mental illness. Therefore, knowledge of the prevalence of these disorders can be used to design intervention strategies. The present study was conducted in the 13-15 years' age group schoolgoing adolescents, with the objective to estimate the prevalence of psychological morbidity, employing Strength and Difficulties Questionnaire (SDQ). MATERIALS AND METHODS: A cross-sectional analytical study was conducted in three different schools of Aligarh, in the 13-15 years' age group, with a prior permission from the school authorities. The study was approved by a multidisciplinary Institutional Ethics and Research Advisory Committee. RESULTS: A total of 1456 students were sampled for the study. The prevalence of psychological morbidity on the basis of total difficulties score was found to be 9.75% (95% confidence interval - 8.33-11.39). The prevalence of emotional, conduct, hyperactivity, peer, and prosocial problems was 5.42%, 5.56%, 3.78%, 4.40%, and 4.26%, respectively. CONCLUSIONS: Psychological problems are fairly common in the adolescent age group. Despite the need, there is a dearth studies conducted in this crucial age group in India. Of the studies available, a wide variance is reported either due to the difference in diagnostic tools or due to the types of psychological disorders considered in different researches. For the purpose of uniformity and comparability, SDQ stands as a good option. PMID- 28659699 TI - Effect of environmental factors on intelligence quotient of children. AB - INTRODUCTION: A child's intelligence quotient (IQ) is determined by both genetic and environmental factors that start from the prenatal period itself. There is a lack of data on the factors which influence IQ in Indian children; therefore, we conducted a multicenter questionnaire-based study to determine the environmental factors which influence IQ in Indian children. PARTICIPANTS AND METHODS: In this cross-sectional observational study, we recruited 1065 schoolchildren between the age of 12 and 16 years from 2 government and 13 private schools in 5 towns, 6 cities, and 2 villages across India. All the children were administered a questionnaire consisting of various environmental factors such as parents' education, occupation, income, and the physical activity of the students. IQ scores were assessed using Ravens Standard Progressive Matrices. An approximate IQ score was calculated using the score on the Ravens test. IQ scores were divided into three groups: below normal IQ (0-79), normal IQ (80-119), and high IQ (above 120). The data were analyzed using SPSS software. RESULTS: In this study, it was observed that the environmental factors such as place of residence, physical activity, family income, parental education, and occupation of the father had an impact on the IQ of the children. Children living in cities (P = 0.001), children having physical activity more than 5 h/weeks (P = 0.001), children with parents having a postgraduate or graduate level of education (P = 0.001), children whose father having a professional job (P = 0.001), and those with a higher family income (P = 0.001) were more likely to have high IQ. CONCLUSIONS: In the present study, we found that various environmental factors such as place of residence, physical exercise, family income, parents' occupation and education influence the IQ of a child to a great extent. Hence, a child must be provided with an optimal environment to be able to develop to his/her full genetic potential. PMID- 28659700 TI - Coping, perceived stress, and job satisfaction among medical interns: The mediating effect of mindfulness. AB - BACKGROUND: Past research studies on the exploration of attributes to the stress of doctors/medical interns were reported more often than the types of coping strategies, healthy practices to strengthen their internal resources to deal effectively with the stressful situations. OBJECTIVES: The present study was conducted to find such internal resource - "mindfulness" as a mediator of coping, perceived stress, and job satisfaction among medical interns. METHODS: A cross sectional descriptive study comprised 120 medical interns forms from various medical colleges in Mangalore were recruited and completed the assessment on mindfulness, cognitive-emotive regulation, coping strategies, perceived stress, and job satisfaction from doctoral interns were collected. RESULTS: Initial correlation analysis results indicate that adaptive coping strategies significantly associate with greater mindfulness and less perceived stress. In turn, mindfulness is negatively correlated with nonadaptive coping strategies and perceived. Job satisfaction showed no significant relationship with any of the other variables. Mediational models indicate that the relationship between adaptive coping strategies and perceived stress was significantly mediated by mindfulness. Furthermore, partial mediation between nonadaptive strategies and perceived stress through mindfulness indicates that respondents reported a high level of nonadaptive strategy experience and a lower level of mindfulness can be counterproductive as they encourage the ineffective way to deal with the stresses. CONCLUSION: The implication of the results were discussed with suggesting a possible intervention to improve the adaptive strategies and mindfulness among the medical interns. PMID- 28659701 TI - Psychometric assessment of anxiety with the Modified Dental Anxiety Scale among central Indian adults seeking oral health care to a dental school. AB - BACKGROUND: Anxiety toward dental treatment can cause people to delay or avoid seeking oral health care despite being in need of treatment. Therefore, recognizing such anxious patients and their appropriate management plays important aspects in clinical practice. AIM: The aim of this study was to investigate the level of dental anxiety (DA), factors affecting it, and anxiety toward dental extraction among adults seeking dental care to a dental school in Central India. MATERIALS AND METHODS: The study sample consisted of 1360 consecutive patients aged 18-70 years. Participants completed a questionnaire while in the waiting room, which included the Modified Dental Anxiety Scale (MDAS) to assess the level of DA. An additional item was included which asked participants to rate the anxiety felt on having a tooth extracted. RESULTS: Among the study group, 65.1% were men and 34.9% were women. Based on the MDAS score, 41.8% of the participants were identified to be less anxious, 53.2% were moderately or extremely anxious, and 5% were suffering from dental phobia. Female participants and younger patients were more anxious (P = 0.0008). Patients who were anxious had postponed their dental visit (P = 0.0008). Participants who had negative dental experience were more anxious (P = 0.03). Nearly, 83% reported anxiety toward extraction procedure. A significant association was observed between anxiety toward dental extraction and the patients' gender (P = 0.03), age (P = 0.0007), education level (P = 0.03), employment status (P = 0.0006), income (P = 0.0007), self-perceived oral health status (P = 0.03), and their history of visit to dentist (P = 0.02). CONCLUSION: Majority of patients in this population revealed high levels of DA. Factors such as age, gender, education level, occupation, financial stability, and previous bad dental experience influence DA to various levels. Extraction followed by injection of local anesthetics and drilling of tooth provoked more anxiety. PMID- 28659702 TI - A comparative study of quality of life and disability among schizophrenia and obsessive-compulsive disorder patients in remission. AB - BACKGROUND: Persons with long-term psychiatric disorders have greater deficits in living skills as well as greater problems in employment and relationship to their social environment. Thus, chronic psychiatric illnesses have psychosocial consequences such as disability and impaired quality of life (QOL) due to their symptomatology and chronic course. OBJECTIVES: Assessment and comparison of disability and QOL of patients suffering from schizophrenia and obsessive compulsive disorder (OCD) in remission phase. MATERIALS AND METHODS: A cross sectional study carried out in the psychiatry outpatient Department of Mental Health Institute, S.C.B. Medical College and Neuropsychiatric Consultation Centre, Cuttack. The study sample consisted of fifty cases of each groups (schizophrenia and OCD), which included both males and females. All of them were assessed through the World Health Organization-QOL BREF and Indian Disability Evaluation and Assessment Scale. RESULTS: Results revealed that schizophrenics have poor QOL and greater disability burden than patients of OCD. CONCLUSION: These psychiatric illnesses, i.e. schizophrenia and OCD, affect all areas of daily functioning leading to greater disability, and thus increasing the burden on the family, imposing greater challenges for the rehabilitation of these patients and their inclusion in the mainstream of the family and society. PMID- 28659703 TI - Mental health in mass gatherings. AB - BACKGROUND: Hajj pilgrimage, in Saudi Arabia, is one of the world's largest religious mass gatherings. We have similar mass gathering scenarios in India such as the Amarnath Yatra and Kumbh. A unique combination of physical, physiological, and psychological factors makes this pilgrimage a very stressful milieu. We studied the emergence of psychopathology and its determinants, in this adverse environment in mass gathering situation, in Indian pilgrims on Hajj 2016. MATERIALS AND METHODS: This is a descriptive study analyzing the mental morbidity in 1.36 lakh Indian pilgrims during Hajj 2016, using SPSS software version 19. RESULTS: Totally 182 patients reported psychological problems. Twenty-two patients (12%) required admission. Twelve (6.8%) pilgrims reported a past history of a mental illness. One hundred and sixty-five (93.2%) patients never had any mental symptoms earlier in life. The most common illnesses seen were stress related (45.7%) followed by psychosis (9.8%), insomnia (7.3%), and mood disorders (5.6%). The most common symptoms recorded were apprehension (45%), sleep (55%), anxiety (41%), and fear of being lost (27%). Psychotropics were prescribed for 46% of pilgrims. All patients completed their Hajj successfully and returned to India. CONCLUSIONS: Cumulative stress causes full spectrum of mental decompensation, and prompt healing is aided by simple nonpharmacological measures including social support and counseling in compatible sociolinguistic milieu. PMID- 28659704 TI - High-dose zolpidem dependence - Psychostimulant effects? A case report and literature review. AB - Zolpidem, an imidazoline nonbenzodiazepine sedative drug, is used widely. Initial reports showed minimal abuse potential. However, multiple reports have appeared of dose escalation and abuse. Subjective effects of high-dose zolpidem are not known. In light of accumulating evidence of abuse potential, we hereby report a case of high-dose dependence and a review of relevant literature. A 33-year-old male presented with 5 years of daily use of 600-1700 mg of zolpidem tartrate. He reported subjective effects of euphoria, intense craving, and inability to stop use. Loss of receptor specificity, pharmacokinetic factors, and different receptor distributions can explain paradoxical stimulatory effects of high-dose zolpidem. Further studies are required to characterize subjective effects of high dose zolpidem. PMID- 28659705 TI - Aripiprazole-induced skin rash. AB - Adverse skin reactions are an important type of adverse drug reactions which have been reported with a wide variety of psychotropics including both typical and atypical antipsychotics. Like typical antipsychotics, atypical antipsychotics such as olanzapine, risperidone, and paliperidone have been documented to cause skin reactions. Reports of aripiprazole-induced skin reactions are sparse. We report a case of skin rash that developed after starting aripiprazole in a male patient suffering from schizophrenia and which remitted after the drug was stopped. PMID- 28659706 TI - Two cases of male genital self-mutilation. AB - Male genital self-mutilation (GSM) is a rare but serious phenomenon. Some of the risk factors for this act are the presence of religious delusions, command hallucinations, low self-esteem, and feelings of guilt associated with sexual offences. Other risk factors include failures in the male role, problems in the early developmental period, such as experiencing difficulties in male identification and persistence of incestuous desires, depression, and having a history of GSM. The eponym Klingsor Syndrome, which involves the presence of religious delusions, is proposed for GSM. Psychiatric case reports of male GSM in the literature are rare and mostly anecdotal. PMID- 28659707 TI - Meige's syndrome. AB - Meige's syndrome consists of idiopathic blepharospasm and oromandibular dystonia. The exact etiology is not known and various hypotheses have been proposed for its causation. The hypothesis suggesting dopaminergic and cholinergic hyperactivity is most widely accepted. There is no curative drug for Meige's syndrome although a variety of treatments have been proposed. We report a case which responded to tetrabenazine. PMID- 28659708 TI - Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1. AB - PURPOSE: A region within chromosome 10q26 has a set of single nucleotide polymorphisms (SNPs) that define a haplotype that confers high risk for age related macular degeneration (AMD). We used a bioinformatics approach to search for genes in this region that may be responsible for risk for AMD by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in the retinal pigment epithelium (RPE) that might include one or more of the SNPs. METHODS: We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in 10q26 strongly associated with AMD. We used the HaploReg and LDlink databases to find sets of SNPs with alleles in linkage disequilibrium and used the Genotype Tissue Expression (GTEx) database to search for correlations between genotypes at individual SNPs and the relative level of expression of the genes. We also accessed Encyclopedia of DNA Elements (ENCODE) to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER, PROMO, and RegulomeDB software programs. RESULTS: There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r2>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, PLEKHA1, ARMS2, and HTRA1 varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For PLEKHA1, 44 tissues have an expression pattern with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10-5 in ovary). With regard to ARMS2, the variation is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express ARMS2 at lower levels than homozygotes with the low-AMD-risk haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10-24). For HTRA1, the expression pattern is the opposite; the high-AMD-risk haplotype has higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 * 10-7 in testes). None of the other 22 genes within one megabase of rs10490924, or any gene in the entire genome, have mRNA expression levels that correlate with the high-AMD-risk haplotype. More than 100 other SNPs in the 10q26 region affect the expression of PLEKHA1 and ARMS2 but not that of HTRA1; none of these SNPs affects the risk for AMD according to published genome-wide association studies (GWASs). Two of the AMD-risk SNPs (rs36212732 and rs36212733) affect transcription factor binding sites in proximity to a DNase I hypersensitive region (i.e., a region of open chromatin) in RPE cells. CONCLUSIONS: SNPs in chromosome 10q26 that influence the expression of only PLEKHA1 or ARMS2 are not associated with risk for AMD, while most SNPs that influence the expression of HTRA1 are associated with risk for AMD. Two of the AMD-risk SNPs affect transcription factor binding sites that may control expression of one of the linked genes in the RPE. These findings suggest that the variation in the risk for AMD associated with chromosome 10q26 is likely due to variation in HTRA1 expression. Modulating HTRA1 activity might be a potential therapy for AMD. PMID- 28659709 TI - Meclofenamic acid improves the signal to noise ratio for visual responses produced by ectopic expression of human rod opsin. AB - PURPOSE: Retinal dystrophy through outer photoreceptor cell death affects 1 in 2,500 people worldwide with severe impairment of vision in advanced stages of the disease. Optogenetic strategies to restore visual function to animal models of retinal degeneration by introducing photopigments to neurons spared degeneration in the inner retina have been explored, with variable degrees of success. It has recently been shown that the non-steroidal anti-inflammatory and non-selective gap-junction blocker meclofenamic acid (MFA) can enhance the visual responses produced by an optogenetic actuator (channelrhodopsin) expressed in retinal ganglion cells (RGCs) in the degenerate retina. Here, we set out to determine whether MFA could also enhance photoreception by another optogenetic strategy in which ectopic human rod opsin is expressed in ON bipolar cells. METHODS: We used in vitro multielectrode array (MEA) recordings to characterize the light responses of RGCs in the rd1 mouse model of advanced retinal degeneration following intravitreal injection of an adenoassociated virus (AAV2) driving the expression of human rod opsin under a minimal grm6 promoter active in ON bipolar cells. RESULTS: We found treated retinas were light responsive over five decades of irradiance (from 1011 to 1015 photons/cm2/s) with individual RGCs covering up to four decades. Application of MFA reduced the spontaneous firing rate of the visually responsive neurons under light- and dark-adapted conditions. The change in the firing rate produced by the 2 s light pulses was increased across all intensities following MFA treatment, and there was a concomitant increase in the signal to noise ratio for the visual response. Restored light responses were abolished by agents inhibiting glutamatergic or gamma-aminobutyric acid (GABA)ergic signaling in the MFA-treated preparation. CONCLUSIONS: These results confirm the potential of MFA to inhibit spontaneous activity and enhance the signal to noise ratio of visual responses in optogenetic therapies to restore sight. PMID- 28659710 TI - Fluid Shear Stress and Fibroblast Growth Factor-2 Increase Endothelial Cell Associated Vitronectin. AB - Vitronectin is a matricellular protein that plays an important role in both coagulation and angiogenesis through its effects on cell adhesion and the plasminogen system. Vitronectin is known to bind to endothelial cells upon integrin activation. However, the effect of integrin activation by shear stress and growth factors on cell-associated vitronectin and plasminogen system activity has not yet been studied. We therefore exposed human umbilical vein endothelial cells to steady laminar flow, oscillating disturbed flow, or fibroblast growth factor-2 (FGF-2) for 24 hours. We then measured cell-associated vitronectin by Western blot and plasminogen system activity using a Chromozym assay. Steady laminar flow, oscillating disturbed flow, and FGF-2 all increased cell-associated vitronectin, although the vitronectin molecular weight varied among the different conditions. FGF-2 also increased cell-associated vitronectin in microvascular endothelial cells and vascular smooth muscle cells. The increase in cell associated vitronectin increased plasminogen system activity. Confocal microscopy showed that vitronectin was primarily located in the basal and intracellular regions. alphavbeta5 integrin inhibition via genistein, an anti-alphavbeta5 antibody, or beta5 siRNA knockdown abrogated the FGF-2-induced increase in cell associated vitronectin and increased plasminogen system activity. These data show that shear stress and growth factors increase cell-associated vitronectin through integrin activation, which may affect coagulation and angiogenesis. PMID- 28659711 TI - Conservation of Repeats at the Mammalian KCNQ1OT1-CDKN1C Region Suggests a Role in Genomic Imprinting. AB - KCNQ1OT1 is located in the region with the highest number of genes showing genomic imprinting, but the mechanisms controlling the genes under its influence have not been fully elucidated. Therefore, we conducted a comparative analysis of the KCNQ1/KCNQ1OT1-CDKN1C region to study its conservation across the best assembled eutherian mammalian genomes sequenced to date and analyzed potential elements that may be implicated in the control of genomic imprinting in this region. The genomic features in these regions from human, mouse, cattle, and dog show a higher number of genes and CpG islands (detected using cpgplot from EMBOSS), but lower number of repetitive elements (including short interspersed nuclear elements and long interspersed nuclear elements), compared with their whole chromosomes (detected by RepeatMasker). The KCNQ1OT1-CDKN1C region contains the highest number of conserved noncoding sequences (CNS) among mammals, where we found 16 regions containing about 38 different highly conserved repetitive elements (using mVista), such as LINE1 elements: L1M4, L1MB7, HAL1, L1M4a, L1Med, and an LTR element: MLT1H. From these elements, we found 74 CNS showing high sequence identity (>70%) between human, cattle, and mouse, from which we identified 13 motifs (using Multiple Em for Motif Elicitation/Motif Alignment and Search Tool) with a significant probability of occurrence, 3 of which were the most frequent and were used to find transcription factor-binding sites. We detected several transcription factors (using JASPAR suite) from the families SOX, FOX, and GATA. A phylogenetic analysis of these CNS from human, marmoset, mouse, rat, cattle, dog, horse, and elephant shows branches with high levels of support and very similar phylogenetic relationships among these groups, confirming previous reports. Our results suggest that functional DNA elements identified by comparative genomics in a region densely populated with imprinted mammalian genes may be related to the regulation of imprinted gene expression. PMID- 28659712 TI - The Model-Based Study of the Effectiveness of Reporting Lists of Small Feature Sets Using RNA-Seq Data. AB - Ranking feature sets for phenotype classification based on gene expression is a challenging issue in cancer bioinformatics. When the number of samples is small, all feature selection algorithms are known to be unreliable, producing significant error, and error estimators suffer from different degrees of imprecision. The problem is compounded by the fact that the accuracy of classification depends on the manner in which the phenomena are transformed into data by the measurement technology. Because next-generation sequencing technologies amount to a nonlinear transformation of the actual gene or RNA concentrations, they can potentially produce less discriminative data relative to the actual gene expression levels. In this study, we compare the performance of ranking feature sets derived from a model of RNA-Seq data with that of a multivariate normal model of gene concentrations using 3 measures: (1) ranking power, (2) length of extensions, and (3) Bayes features. This is the model-based study to examine the effectiveness of reporting lists of small feature sets using RNA-Seq data and the effects of different model parameters and error estimators. The results demonstrate that the general trends of the parameter effects on the ranking power of the underlying gene concentrations are preserved in the RNA-Seq data, whereas the power of finding a good feature set becomes weaker when gene concentrations are transformed by the sequencing machine. PMID- 28659713 TI - Making Meaningful Clinical Use of Biomarkers. AB - This review discusses the current state of biomarker discovery for the purposes of diagnostics and therapeutic monitoring. We underscore relevant challenges that have defined the gap between biomarker discovery and meaningful clinical use. We highlight recent advancements in and propose a way to think about future biomarker development. PMID- 28659714 TI - CellTrans: An R Package to Quantify Stochastic Cell State Transitions. AB - Many normal and cancerous cell lines exhibit a stable composition of cells in distinct states which can, e.g., be defined on the basis of cell surface markers. There is evidence that such an equilibrium is associated with stochastic transitions between distinct states. Quantifying these transitions has the potential to better understand cell lineage compositions. We introduce CellTrans, an R package to quantify stochastic cell state transitions from cell state proportion data from fluorescence-activated cell sorting and flow cytometry experiments. The R package is based on a mathematical model in which cell state alterations occur due to stochastic transitions between distinct cell states whose rates only depend on the current state of a cell. CellTrans is an automated tool for estimating the underlying transition probabilities from appropriately prepared data. We point out potential analytical challenges in the quantification of these cell transitions and explain how CellTrans handles them. The applicability of CellTrans is demonstrated on publicly available data on the evolution of cell state compositions in cancer cell lines. We show that CellTrans can be used to (1) infer the transition probabilities between different cell states, (2) predict cell line compositions at a certain time, (3) predict equilibrium cell state compositions, and (4) estimate the time needed to reach this equilibrium. We provide an implementation of CellTrans in R, freely available via GitHub (https://github.com/tbuder/CellTrans). PMID- 28659715 TI - Advanced Collaborative Emissions Study Auxiliary Findings on 2007-Compliant Diesel Engines: A Comparison With Diesel Exhaust Genotoxicity Effects Prior to 2007. AB - Since its beginning, more than 117 years ago, the compression-ignition engine, or diesel engine, has grown to become a critically important part of industry and transportation. Public concerns over the health effects from diesel emissions have driven the growth of regulatory development, implementation, and technological advances in emission controls. In 2001, the United States Environmental Protection Agency and California Air Resources Board issued new diesel fuel and emission standards for heavy-duty engines. To meet these stringent standards, manufacturers used new emission after-treatment technology, and modified fuel formulations, to bring about reductions in particulate matter and nitrogen oxides within the exhaust. To illustrate the impact of that technological transition, a brief overview of pre-2007 diesel engine exhaust biomarkers of genotoxicity and health-related concerns is provided, to set the context for the results of our research findings, as part of the Advanced Collaborative Emissions Study (ACES), in which the effects of a 2007-compliant diesel engine were examined. In agreement with ACES findings reported in other tissues, we observed a lack of measurable 2007-compliant diesel treatment associated DNA damage, in lung tissue (comet assay), blood serum (8-hydroxy-2' deoxyguanosine [8-OHdG] assay), and hippocampus (lipid peroxidation assay), across diesel exhaust exposure levels. A time-dependent assessment of 8-OHdG and lipid peroxidation also suggested no differences in responses across diesel exhaust exposure levels more than 24 months of exposure. These results indicated that the 2007-compliant diesel engine reduced measurable reactive oxygen species associated tissue derangements and suggested that the 2007 standards-based mitigation approaches were effective. PMID- 28659717 TI - Accuracy of [18Fluorine]-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography Computed Tomography Response Assessment Following (Chemo)radiotherapy for Locally Advanced Laryngeal/Hypopharyngeal Carcinoma. AB - INTRODUCTION: The accuracy of response assessment positron emission tomography (PET)-computed tomography (CT) following radiotherapy with or without chemotherapy for laryngeal/hypopharyngeal squamous cell carcinoma is uncertain. METHODS: In all, 35 patients with laryngeal or hypopharyngeal squamous cell carcinoma who were treated between 2009 and 2014 with (chemo)radiotherapy were identified. The accuracy of response assessment PET-CT was made by correlation with clinical follow-up and pathological findings. RESULTS: Of the 35 patients, 20 (57%) had an overall complete metabolic response. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for response assessment [18Fluorine]-fluoro-2-deoxy-d-glucose (FDG) PET-CT for primary and nodal sites, respectively, were 100%, 73%, 46%, and 100% and 83%, 95%, 83%, and 95%. CONCLUSIONS: Response assessment FDG PET-CT following (chemo)radiotherapy for laryngeal and hypopharyngeal carcinomas has a high NPV for both primary site and lymph nodes and can be used to guide treatment decisions. The PPV of residual FDG uptake at the primary tumour site is limited and requires examination and biopsy confirmation. PMID- 28659716 TI - Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale. AB - Increasing evidence underscores the interesting ability of tryptophan to regulate immune responses. However, the exact mechanisms of tryptophan's immune regulation remain to be determined. Tryptophan catabolism via the kynurenine pathway is known to play an important role in tryptophan's involvement in immune responses. Interestingly, quinolinic acid, which is a neurotoxic catabolite of the kynurenine pathway, is the major pathway for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+, a natural coenzyme found in all living cells, regulates immune responses and creates homeostasis via a novel signaling pathway. More importantly, the immunoregulatory properties of NAD+ are strongly related to the overexpression of tryptophan hydroxylase 1 (Tph1). This review provides recent knowledge of tryptophan and NAD+ and their specific and intriguing roles in the immune system. Furthermore, it focuses on the mechanisms by which tryptophan regulates NAD+ synthesis as well as innate and adaptive immune responses. PMID- 28659718 TI - Pasteurized Autograft-Prosthesis Composite Reconstruction May Not Be a Viable Primary Procedure for Large Skeletal Defects after Resection of Sarcoma. AB - BACKGROUND: Among various types of composite biological reconstruction, pasteurized autograft-prosthesis composite (PPC) is popular when allograft is unavailable. Previous limited cohort study indicated result comparable to tumor prosthesis. However, as case number and follow-up increase, we experienced more complications than anticipated. We questioned the usefulness of PPC as a viable reconstructive option. METHODS: We reviewed 142 PPCs and analyzed overall and location-related survival and factors associated with the failure of PPC. RESULTS: Twenty-year survival rate of 142 PPCs was 39.8 +/- 10.0%. Fifty-two (36.6%) of 142 PPCs showed failure. Among various locations, the proximal femur showed best survival: 78.0 +/- 9.9%. Final status of the 52 failed PPCs was modular tumor prosthesis in 23 (43%), arthrodesis in 11 (21%), pseudarthrosis in 7 (13%), amputation in 7 (13%), and allograft-prosthesis composite in 4 (8%). Tumor volume > 200 cc (p = 0.001), pasteurization length <= 10 cm (p = 0.002), male sex (p = 0.02), and locations in pelvis or tibia (p = 0.029) were poor prognostic factors. CONCLUSIONS: Long-term survival of PPCs was below expectations. Despite the complexity of the procedure, there is little survival gain over tumor prosthesis. PPC may be indicated when a modular prosthesis is not readily available. PMID- 28659719 TI - Somatic Mutation Analyses in Studies of the Clonal Evolution and Diagnostic Targets of Prostate Cancer. AB - Prostate cancer (PC) is the most common uro-oncological disease in the global population and still requires a more efficient laboratory diagnosis. Point mutations of oncogenes and tumor sup-pressor genes are the most frequent molecular genetic events in carcinogenesis. The mutations are re-sponsible, to a great extent, for the clonal evolution of cancer and can be considered as primary candi-date molecular markers of PC. Using next-generation sequencing to analyze the mutations in PC, the main molecular PC subtypes were identified, which depended on the presence of fusion genes and FOXA1, CHD1, and SPOP point mutations; other driver mutations responsible for the progression of PC subclones were also characterized. This review summarizes the data on early PC genetic markers (an mtDNA deletion, and TMPRSS2:ERG expression), as well as these somatic mutations at later stages of PC. Emphasis is placed on a switch in AR synthesis to a constitutively active variant and the point muta-tions that facilitate PC transition to a castration-refractory state that is resistant to new AR inhibitors. Based on the current whole-exome sequencing data, the frequencies and localizations of the somatic mu-tations that may provide new genetic diagnostic markers and drug targets are described. PMID- 28659720 TI - The Genetics of Papillary Microcarcinomas of the Thyroid: Diagnostic and Prognostic Implications. AB - Papillary microcarcinoma of the thyroid (mPTC) is defined by the WHO as a papillary thy-roid cancer measuring 10mm or less in diameter and it is nowadays a topic of intense debate among the members of the medical community due to its apparent "epidemic" rise. Although these tumors follow almost always an indolent clinical course and carry an excellent prognosis, it is known that a small sub set may display a potentially aggressive behavior. Nevertheless, we still lack an accurate way of predict-ing those which will cause significant disease. In an attempt to address this problem, a number of clini-co-pathologic features have been studied as poor prognostic markers in mPTC, and their association with known genetic alterations in thyroid cancer has been evaluated. Herein we review the present knowledge concerning mPTC's genetic profile, namely the prevalence of BRAF (V600E), RAS and TERT promoter mutations and RET/PTC and PAX8-PPARG rearrangements and report the results of the evaluation in the putative prognostic value of these genetic alterations in mPTC. PMID- 28659722 TI - Comparison of Alternative Splicing Junction Detection Tools Using RNA-Seq Data. AB - BACKGROUND: Alternative splicing (AS) is a posttranscriptional process that produces differ-ent transcripts from the same gene and is important to produce diverse protein products in response to environmental stimuli. AS occurs at specific sites on the mRNA sequence, some of which have been de-fined. Multiple bioinformatics tools have been developed to detect AS from experimental data. OBJECTIVES: The goal of this review is to help researchers use specific tools to aid their research and to develop new AS detection tools based on these previously established tools. METHOD: We selected 15 AS detection tools that were recently published; we classified and delineated them on several aspects. Also, a performance comparison of these tools with the same starting input was conducted. RESULT: We reviewed the following categorized features of the tools: Publication information, working principles, generic and distinct workflows, running platform, input data requirement, sequencing depth dependency, reads mapped to multiple locations, isoform annotation basis, precise detected AS types, and performance benchmarks. CONCLUSION: Through comparisons of these tools, we provide a panorama of the advantages and short-comings of each tool and their scopes of application. PMID- 28659721 TI - MtDNA As a Cancer Marker: A Finally Closed Chapter? AB - Sequence alterations of the mitochondrial DNA (mtDNA) have been identified in many tu-mor types. Their nature is not entirely clear. Somatic mutation or shifts of heteroplasmic mtDNA vari-ants may play a role. These sequence alterations exhibit a sufficient frequency in all tumor types investi-gated thus far to justify their use as a tumor marker. This statement is supported by the high copy num-ber of mtDNA, which facilitates the detection of aberrant tumor-derived DNA in bodily fluids. This will be of special interest in tumors, which release a relatively high number of cells into bodily fluids, which are easily accessible, most strikingly in urinary bladder carcinoma. Due to the wide distribution of the observed base substitutions, deletions or insertions within the mitochondrial genome, high efforts for whole mtDNA sequencing (16.5 kb) from bodily fluids would be required, if the method would be in-tended for initial tumor screening. However, the usage of mtDNA for sensitive surveillance of known tumor diseases is a meaningful option, which may allow an improved non-invasive follow-up for the urinary bladder carcinoma, as compared to the currently existing cytological or molecular methods. Fol-lowing a short general introduction into mtDNA, this review demonstrates that the scenario of a sensi-tive cancer follow-up by mtDNA analysis deserves more attention. It would be most important to inves-tigate precisely in the most relevant tumor types, if sequencing approaches in combination with simple PCR-assays for deletions/insertions in homopolymeric tracts has sufficient sensitivity to find most tu-mor-derived mtDNAs in bodily fluids. PMID- 28659723 TI - Helitrons and Retrotransposons Are Co-localized in Bos taurus Genomes. AB - BACKGROUND: DNA transposons helitrons are mobile genetic elements responsible for major movements of the genetic material within and across different genomes. This ability makes helitrons suitable candidate elements for the development of new approaches of multilocus genotyping of live-stock animals, along with the well known microsatellite loci. OBJECTIVE: We aimed to estimate the informativeness of helitron and microsatellite markers in assessing the consolidation and the "gene pool" standards of two commercial dairy cattle breeds (Ayrshire breed and holsteinized Black-and-White cattle) and one local breed of Kalmyk cattle, and to reveal any inter-breed difference in the organization of genomic regions flanked by helitrons in the studied cattle breeds. METHOD: We used the combination of two highly-polymorphic genomic elements - helitrons and trinu-cleotide microsatellites (AGC)6G and (GAG)6C, respectively - for genome scanning of the sampled groups of cattle. Also, we pyrosequenced the genomic regions flanked by the inverted repeats of 3'-end of Heligloria family of helitron fragments. RESULTS: Generally, the both combinations of markers generated polymorphic spectra, based on which certain interbreed differentiation could be observed. The analysis of the identified interspersed repeats suggests that in factory and local cattle the genomic regions flanked by helitron fragments are shaped differently and contain different superfamilies of transposable elements, especially retrotransposons. CONCLUSION: Despite the well-known fact of retrotransposon-dependent microsatellite expansion, our data suggest that, in the cattle genome, the DNA transposons and microsatellites can also be found in close neighbourhood, and that helitrons and retrotransposons may form domains of increased variability - targets for factors of artificial selection. PMID- 28659724 TI - Identification of Sets of Cytoskeletal Related and Adhesion-related Coding Region Mutations in the TCGA Melanoma Dataset that Correlate with a Negative Outcome. AB - BACKGROUND: Relatively little cancer genome atlas data has been associated with clinically relevant stratifications of individual cancers. RESULTS: Mutations in two subsets of a cytoskeletal related and adhesion-related protein coding region set (CAPCRs) were determined to have strong associations with a negative outcome for melanoma, in-cluding a subset constituted by: DSCAM, FAT3, MUC17 and PCDHGC5 (p < 0.0001). CONCLUSION: Roles for CAPCR mutations in cancer progression raise a question about the potential dominant negative impact of these mutations for multi-meric subcellular and extra-cellular protein struc-tures. PMID- 28659725 TI - System Level Meta-analysis of Microarray Datasets for Elucidation of Diabetes Mellitus Pathobiology. AB - BACKGROUND: Type 2 diabetes (T2D) is a common multi-factorial disease that is primarily ac-counted to ineffective insulin action in lowering blood glucose level and later escalates to impaired insu-lin secretion by pancreatic beta cells. Deregulation in insulin signaling to its target organs is attributed to this disease phenotype. Various genome-wide microarray studies from multiple insulin responsive tis-sues have been conducted in past but due to inherent noise in microarray data and heterogeneity in dis-ease etiology; reproduction of prioritized pathways/genes is very low across various studies. OBJECTIVE: In this study, we aim to identify consensus signaling and metabolic pathways through system level meta-analysis of multiple expression-sets to elucidate T2D pathobiology. METHOD: We used 'R', an open source statistical environment, which is routinely used for Microarray data analysis particularly using special sets of packages available at Bioconductor. We primarily focused on gene-set analysis methods to elucidate various aspects of T2D. RESULT: Literature-based evidences have shown the success of our approach in exploring various known aspects of diabetes pathophysiology. CONCLUSION: Our study stressed the need to develop novel bioinformatics workflows to advance our understanding further in insulin signaling. PMID- 28659726 TI - Evaluating Application of Knowledge and Skills: The Use of Consensus Expert Review to Assess Conference Abstracts of Field Epidemiology Training Participants. AB - BACKGROUND: Often evaluations of training programs are limited - with many focusing on the aspects that are easy to measure (e.g., reaction of trainees) without addressing the important outcomes of training, such as how trainees applied their new knowledge, skills, and attitudes. Numerous evaluations fail to measure training's effect on job performance because few effective methods are available to do so. Particularly difficult is the problem of evaluating multisite training programs that vary considerably in structure and implementation from one site to another. PURPOSE: NA. SETTING: NA. INTERVENTION: NA. RESEARCH DESIGN: We devised a method of a consensus expert review to evaluate the quality of conference abstracts submitted by participants in Field Epidemiology Training Programs - an approach that can provide useful information on how well trainees apply knowledge and skills gained in training, complementing data obtained from other sources and methods. This method is practical, minimally intrusive, and resource-efficient, and it may prove useful for evaluation practice in diverse fields that require training. DATA COLLECTION AND ANALYSIS: NA. FINDINGS: NA. PMID- 28659727 TI - Visualization of Hyperconjugation and Subsequent Structural Distortions through 3D Printing of Crystal Structures. AB - BACKGROUND: Structural distortions due to hyperconjugation in organic molecules, like norbornenes, are well captured through X-ray crystallographic data, but are sometimes difficult to visualize especially for those applying chemical knowledge and are not chemists. METHODS: Crystal structure from the Cambridge database were downloaded and converted to .stl format. The structures were then printed at the desired scale using a 3D printer. RESULTS: Replicas of the crystal structures were accurately reproduced in scale and any resulting distortions were clearly visible from the macroscale models. Through space interactions or effect of through space hyperconjugation was illustrated through loss of symmetry or distortions thereof. CONCLUSION: The norbornene structures exhibits distortion that cannot be observed through conventional ball and stick modelling kits. We show that 3D printed models derived from crystallographic data capture even subtle distortions in molecules. We translate such crystallographic data into scaled-up models through 3D printing. PMID- 28659728 TI - Hedonic eating in Prader-Willi syndrome is associated with blunted PYY secretion. AB - Hedonic and homeostatic hunger represent two different forms of eating: just for pleasure or following energy deprivation, respectively. Consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and some specific endocannabinoids in normal weight subjects and patients with morbid obesity. To date, the effects of palatable food on these mediators in Prader-Willi syndrome (PWS) are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, cholecystokinin (CCK), peptide YY (PYY), anandamide (AEA), 2-arachidonoyl glycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) in eight satiated adult PWS patients after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same macronutrient composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with decreased circulating levels of PYY. An increase in PEA levels was also observed. By contrast, circulating levels of ghrelin, CCK, AEA, 2 AG and OEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were similar in the hedonic and non-palatable sessions. In conclusion, when motivation to eat is promoted by highly palatable foods, a depressed post-prandial PYY secretion is observed in PWS. Although preliminary, these findings seem to hypothesize a possible role of PYY agonists in the management of PWS patients. Abbreviations: AEA, Anandamide; 2 AG, 2-arachidonoyl-glycerol; CB1, cannabinoid receptor type 1; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; PWS: Prader-Willi syndrome; VAS, visual analog scales. PMID- 28659729 TI - Some current applications, limitations and future perspectives of lactic acid bacteria as probiotics. AB - Several mechanism and non-mechanism-based studies supporting the claim that lactic acid bacteria (LAB) strains confer health benefits and play immune modulatory roles were examined in this review. Probiotic applications of LAB on global burdens such as obesity and type-2 diabetes were discussed as well as the use of yoghurt and ice cream as important vehicles to convey several beneficial LAB strains. Probiotic and symbiotic dairy products may be used in the nearest future to treat a variety of health disorders. Current studies suggest that lactic acid bacteria possess anti-obesity and anti-diabetic propensities on their hosts and thus can play a crucial role in human health care. Research in the rheological and physicochemical properties of ice cream as well as its applications are also on the increase. These applications face certain hurdles including technological (for less developed countries), consumer acceptability of new functional foods may be influenced by culture, ethics or religion. There is need for more studies on the genetic basis for probiotic properties which will give further understanding regarding novel manipulation skills and applicability in nutrition and health sectors. More studies confirming the direct effects of probiotic LABs in lowering the spread of food-borne and other pathogens are also anticipated. PMID- 28659730 TI - Acute selective bioactivity of grape seed proanthocyanidins on enteroendocrine secretions in the gastrointestinal tract. AB - Background: Enteroendocrine cells respond to food components by secreting an array of hormones that regulate several functions. We have previously shown that grape seed proanthocyanidins (GSPE) modulate GLP-1 levels. Objective: To deepen on the knowledge of the mechanisms used by GSPE to increase GLP-1, and extend it to its role at modulation of other enterohormones. Design: We used an ex vivo system to test direct modulation of enterohormones; STC-1 cells to test pure phenolic compounds; and rats to test the effects at different gastrointestinal segments. Results: GSPE compounds act at several locations along the gastrointestinal tract modulating enterohormone secretion depending on the feeding condition. GSPE directly promotes GLP-1 secretion in the ileum, while unabsorbed/metabolized forms do so in the colon. Such stimulation requires the presence of glucose. GSPE enhanced GIP and reduced CCK secretion; gallic acid could be partly responsible for this effect. Conclusions: The activity of GSPE modulating enterohormone secretion may help to explain its effects on metabolism. GSPE acts through several mechanisms; its compounds and their metabolites are GLP 1 secretagogues in ileum and colon, respectively. In vivo GLP-1 secretion might also be mediated by indirect pathways involving modulation of other enterohormones that in turn regulate GLP-1 release. PMID- 28659731 TI - Modulatory effect of intestinal polyamines and trace amines on the spontaneous phasic contractions of the isolated ileum and colon rings of mice. AB - Background: Gastrointestinal motility modulatory factors include substances of the intestinal content, such as polyamines and trace amines (TAs), the focus of this study. Methods: The amines of food, intestinal content and from faecal bacteria of Swiss mice were determined by HPLC and functionally characterised in isolated distal ileum and medial colon rings. Results: Mouse food and intestinal content contain polyamines (spermidine>putrescine>spermine) and TAs (isoamylamine>cadaverine). Intestinal bacteria mainly produce putrescine and cadaverine. The amines inhibited the spontaneous motility of the ileum (0.1-3 mM) and colon rings (0.01-3 mM, with lower IC50), with: spermine~isoamylamine~spermidine. Spermine inhibition was tetrodotoxin (TTX) insensitive, while isoamylamine was TTX-sensitive, suggesting neural control. Mainly in the ileum, isoamylamine (3 mM) elicited acute effects modified by TTX, atropine and propranolol, and suppressed by spermine (3 mM), not being localized at the smooth muscle level. The amines assayed (3 mM), except putrescine and cadaverine in the ileum and isoamylamine in the colon, antagonised acetylcholine (ACh, 0.1 mM)-elicited phasic contractions. Isoamylamine and spermine in colon relaxed KCl (100 mM)-elicited tonic contractions, suggesting an effect on smooth muscle, but did not justify the suppression of motility caused by spermine and isoamylamine. Conclusions: Polyamines and TAs of the intestinal content might act on chemosensors and modulate intestinal peristalsis. PMID- 28659732 TI - Pressure ulcer is associated with malnutrition as assessed by Nutritional Risk Screening (NRS 2002) in a mixed hospital population. AB - Background and aim: Pressure ulcers (PUs) and malnutrition represent a significant health problem for hospital inpatients. Satisfactory nutritional status is crucial for proper wound healing. Risk of malnutrition can be identified using standardized screening tools, such as the Nutritional Risk Screening (NRS) 2002. Objective: The objective of this study was to examine whether nutritional status based on the NRS 2002 is associated with PU in hospital inpatients. Design: The data for this cross-sectional analysis were based on 10 screening days between September 2012 and May 2014. All adult inpatients admitted to a medical or surgical ward on the screening days were evaluated for eligibility. Nursing students and ward nurses conducted the NRS 2002 initial screening and skin examinations for PU classification (Stages I-IV). A registered clinical dietician conducted all NRS 2002 final screenings. Results: The sample consisted of 651 patients, with mean age 62.9 years. Skin examinations indicated an 8% PU prevalence. Factors associated with PUs included age >= 70 years, low body mass index (BMI) and hospitalization in the medical department. Based on the initial screening, 48% were at 'Low risk' for malnutrition and 52% were at 'Possible risk'. After final screening, 34% of the sample was identified as 'At risk' for malnutrition. Patients identified at 'Possible risk' by the initial screening or 'At risk' by the final screening were more likely than patients at 'Low risk' to have a PU (OR = 2.58 and 2.55, respectively). Each of the three initial screening items was significantly associated PU, with 'Is BMI<20?' and 'Ate less past week?' having the strongest associations. Conclusion: Nutritional risk using the NRS 2002 is associated with the presence of PU in a mixed hospital population. The final screening had a slightly stronger association with PU compared to the initial screening. PMID- 28659733 TI - Attenuation of postprandial blood glucose in humans consuming isomaltodextrin: carbohydrate loading studies. AB - Background: Isomaltodextrin (IMD) is a novel highly branched alpha-glucan and its function as a soluble dietary fiber is expected. Objective: The goal of this study was to evaluate the effects of IMD on postprandial glucose excursions in healthy people and to make the mechanism clear. Design: Twenty-nine subjects ingested a solution containing maltodextrin (MD) or sucrose with or without IMD. Fourteen subjects ingested a solution containing glucose with or without IMD. Blood glucose concentrations were then compared between the groups. Furthermore, in vitro digestion, inhibition of digestive enzymes, and glucose absorption tests were conducted. Results: IMD attenuated blood glucose elevation in the subjects with blood glucose excursions at the high end of normal following the ingestion of MD or sucrose or glucose alone. This effect of 5 g IMD was most clear. IMD was digested partially only by small intestinal mucosal enzymes, and maltase and isomaltase activities were weakly inhibited. Furthermore, IMD inhibited the transport of glucose from mucosal side to serosal side. Conclusions: IMD attenuated postprandial blood glucose, after the ingestion of MD or sucrose or glucose. As one of the mechanism, it was suggested that IMD inhibited the absorption of glucose on small intestinal mucosal membrane. PMID- 28659734 TI - Effects of epigallocatechin-3-gallate on thermogenesis and mitochondrial biogenesis in brown adipose tissues of diet-induced obese mice. AB - Background: Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea and has been considered a natural agent that can help to reduce the risk of obesity. Objective: The aim of this study was to investigate the effects of EGCG on thermogenesis and mitochondrial biogenesis in brown adipose tissue (BAT) of diet-induced obese mice. Methods: Male C57BL/6J mice were provided a high-fat diet for 8 weeks to induce obesity, following which they were divided into two groups: one on a high-fat control diet and the other on a 0.2% EGCG (w/w) supplemented high-fat diet for another 8 weeks. Results: The EGCG-supplemented group showed decreased body weight gain, and plasma and liver lipids. EGCG-fed mice exhibited higher body temperature and mitochondrial DNA (mtDNA) content in BAT. The messenger RNA levels of genes related to thermogenesis and mitochondrial biogenesis in BAT were increased by EGCG. Moreover, adenosine monophosphate activated protein kinase (AMPK) activity in BAT was stimulated by EGCG. Conclusions: The results suggest that EGCG may have anti-obesity properties through BAT thermogenesis and mitochondria biogenesis, which are partially associated with the regulation of genes related to thermogenesis and mitochondria biogenesis, and the increase in mtDNA replication and AMPK activation in BAT of diet-induced obese mice. PMID- 28659735 TI - Pulmonary Pseudomonas aeruginosa infection induces autophagy and proteasome proteolytic pathways in skeletal muscles: effects of a pressurized whey protein based diet in mice. AB - Background: Pulmonary Pseudomonas aeruginosa infection in cystic fibrosis patients is associated with skeletal muscle atrophy. In this study, we investigated the effects of P. aeurginosa infection and a whey protein-rich diet on skeletal muscle proteolytic pathways. Design: An agar bead model of pulmonary P. aeurginosa infection was established in adult C57/Bl6 mice. Protein ubiquitinaiton, lipidation of LC3B protein and expressions of autophagy-related genes and ubiquitin E3 ligases were quantified using immunoblotting and qPCR. The effects of pressure-treated whey protein diet on muscle proteolysis were also evaluated. Results: Pulmonary P. aeurginosa infection reduced diaphragm, tibialis anterior, and soleus muscle weights and increased protein ubiquitination, LC3B protein lipidation, and the expressions of Lc3b, Gabarapl1, Bnip3, Parkin, Atrogin-1, and MuRF1 genes in each muscle. These changes were greater in the tibialis as compared to soleus and diaphragm. Proteolysis indicators increased within one day of infection but were not evident after seven days of infection. A pressurized whey diet attenuated LC3B protein lipidation, expressions of autophagy-related genes (BNIP3), pro-inflammatory cytokines, and protein ubiquitination. Conclusions: We conclude that pulmonary P. aeruginosa infection activates the autophagy, and the proteasome pathways in skeletal muscles and that a pressurized whey protein diet attenuates muscle proteolysis in this model. PMID- 28659736 TI - Folate intake in a Swedish adult population: Food sources and predictive factors. AB - Introduction: Folate plays an important role in cell metabolism, but international studies show that intake is currently below recommendations, especially among women. The study objective was to identify folate food sources by food group, gender, and age group, and to identify factors influencing folate intake, based on food consumption data for Swedish adults in the 2010-11 Riksmaten study. Methods: The sample included a representative Swedish population aged 18-80 years (n = 1657; 56.3% female). Food and nutrient intakes were estimated from self-reported food records during 4 consecutive days. Food consumption was categorized into 26 food groups. Stepwise regression was used to analyze food groups as folate sources for participants. Factors predicting the highest folate intake (third tertile) were determined by logistic regression analysis. Results: Vegetables and pulses represented the most important folate source for all age groups and both genders, especially in women aged 45-64 years (49.7% of total folate intake). The next folate source in importance was dairy products for the youngest group (18-30 years), bread for men, and fruit and berries for women. The likelihood of being in the highest tertile of folate intake (odds ratio = 1.69, 95% confidence interval 1.354-2.104) was higher for men. Influencing factors for folate intake in the highest tertile were low body mass index and high educational level in the men, and high educational level, vegetarian diet, organic product consumption, non-smoking, and alcohol consumption within recommendations in the women. Conclusion: This study describes the folate intake per food group of Swedish adults according to the 2010-11 Riksmaten survey, identifying vegetables and pulses as the most important source. Data obtained on factors related to folate consumption may be useful for the development of specific nutrition education programs to increase the intake of this vitamin in high-risk groups. PMID- 28659737 TI - Association of diet quality with dietary inflammatory potential in youth. AB - Background: Diet plays a crucial role in the regulation of chronic inflammation. The sparse evidence available in adult populations indicates that diet quality is linked to the dietary inflammatory potential; however, this association has not been established in youth. Design: Data were obtained from a representative national sample of 2889 children and young people in Spain, aged 6-24 years. The dietary inflammatory potential was measured by the dietary inflammatory index (DII), and diet quality by three conceptually different measures: the Mediterranean Diet Quality Index for children and adolescents (KIDMED), energy density, and total dietary antioxidants capacity. Results: The mean DII was 1.96 +/- 0.76 units Scoring for the KIDMED index and the total dietary antioxidant capacity significantly decreased (p < 0.001 and p = 0.030, respectively) across quintiles of the DII, whereas the opposite was true for energy density (p < 0.001). The effect size of these associations was strongest for energy density, followed by the KIDMED index and total dietary antioxidant capacity. Conclusion: A healthy diet characterized by high adherence to the Mediterranean diet, high total dietary antioxidant capacity, or low energy density was linked to greater anti-inflammatory potential of the diet, as measured by the DII. PMID- 28659739 TI - The effect of egg supplementation on growth parameters in children participating in a school feeding program in rural Uganda: a pilot study. AB - Background: School feeding programs have gained popularity in developing countries . Eggs are an inexpensive source of micronutrients and high-quality protein. Therefore, the objective of this study was to gain preliminary data regarding the impact of egg supplementation on growth in primary school students participating in a school feeding program in rural Uganda. Methods: Children (ages 6-9; n = 241) were recruited from three different schools located throughout the Kitgum District of Uganda. All participants in the same school received the same dietary intervention: control (no eggs (0 eggs); n = 56), one egg five days per week (1 egg; n = 89), or two eggs five days per week (2 eggs; n = 96). Height, weight, tricep skinfold thickness (TSF), and mid-upper arm circumference (MUAC) were measured monthly over 6 months. Results: Following six months of egg supplementation, participants receiving 2 eggs had a greater increase in height and weight compared to the 0 eggs and 1 egg groups (P < 0.05). In addition, participants receiving 1 egg and 2 eggs had a significantly higher (P < 0.05) increase in MUAC at six months compared to 0 eggs. Conclusion: These results suggest that supplementation with eggs can improve parameters of growth in school-aged children participating in school feeding programs in rural Uganda. Abbreviations: MUAC: Mid-Upper Arm Circumference; TSF: Tricep Skinfold Thickness. PMID- 28659738 TI - Rosmarinic acid suppresses adipogenesis, lipolysis in 3T3-L1 adipocytes, lipopolysaccharide-stimulated tumor necrosis factor-alpha secretion in macrophages, and inflammatory mediators in 3T3-L1 adipocytes. AB - Background: Rosmarinic acid (RA) is a natural phenol carboxylic acid with many promising biological effects. It may be a suitable candidate for improving obesity-related adipose tissue dysfunction. Objective: We aimed to investigate the therapeutic use of RA as an anti-obesity agent by measuring its effects on adipogenesis, lipolysis, and messenger RNA (mRNA) expression of major adipokines in 3T3-L1 adipocytes; and its effects on lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) secretion in macrophages and inflammatory mediators in 3T3-L1 adipocytes incubated with macrophage-conditioned medium (MCM). Methods: 3T3-L1 preadipocytes were used to explore how RA affects adipogenesis, as well as the involvement of phosphorylated extracellular signal regulated kinase-1/2 (p-ERK1/2) and mothers against decapentaplegic homolog 3 (p Smad3). 3T3-L1 preadipocytes were also differentiated into mature adipocytes to explore how RA affects basal and isoproterenol- and forskolin-stimulated lipolysis; and how RA affects key adipokines' mRNA expression. RAW 264.7 macrophages were stimulated with LPS in the absence or presence of RA to explore RA's effects on TNF-alpha secretion. MCM was collected and 3T3-L1 adipocytes were incubated with MCM to explore RA's effects on interleukin-6 (IL-6), IL-1beta, monocyte chemoattractant protein-1 (MCP-1), and RANTES mRNA expression. Results: During the preadipocyte differentiation process, RA suppressed peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer binding protein-alpha, and activated p-ERK1/2 and p-Smad3; inhibition of adipogenesis by RA was partially restored following treatment with p-ERK1/2 and p-Smad3 inhibitors. In mature adipocytes, RA inhibited basal lipolysis; phosphodiesterase-3 inhibitor reversed this. RA also inhibited isoproterenol- and forskolin-stimulated glycerol and free fatty acid release, and the phosphorylation of hormone-sensitive lipase and perilipin. RA had no effects on leptin, adiponectin, resistin, or visfatin mRNA expression. RA suppressed TNF-alpha mRNA expression and secretion in LPS stimulated RAW 264.7 macrophages; and reduced LPS-MCM-induced IL-6, IL-1beta, MCP 1, and RANTES mRNA expression in 3T3-L1 adipocytes. Conclusions: RA exerts inhibitory effects on adipogenesis, lipolysis, and inflammation. RA could be a promising natural product for improving adipose mobilization in obesity. PMID- 28659740 TI - Biochemical, physiological, and performance response of a functional watermelon juice enriched in L-citrulline during a half-marathon race. AB - Background: Watermelon is a rich natural source of l-citrulline. This non essential amino acid increases exercise performance. Objective: Evaluate the effect of Fashion watermelon juice enriched in l-citrulline (CWJ) (3.45 g per 500 mL) in physical performance and biochemical markers after a half-marathon race. Design: A randomised, double blind, crossover design where 2 h after drinking 500 mL of CWJ or placebo (PLA, beverage without l-citrulline) amateur male runners performed two half-marathon races. Jump height, heart rate and rating of perceived exertion were evaluated before and after the races. Moreover, muscle soreness and plasma markers of muscle damage and metabolism were evaluated for 72 h after the races. Results: Muscle soreness perception was significantly lower from 24 to 72 h after the race with CWJ beverage. Immediately after the races, runners under CWJ condition showed plasma lactate and glucose concentrations significantly lower and higher lactate dehydrogenase and l-arginine concentration than runners under PLA. A maintenance of jump heights after the races under CWJ supplementation was found, decreasing significantly with PLA. Conclusion: A single Fashion watermelon juice enriched in l-citrulline dose diminished muscle soreness perception from 24 to 72 h after the race and maintained lower concentrations of plasma lactate after an exhausting exercise. PMID- 28659741 TI - Impact of palm olein in infant formulas on stool consistency and frequency: a meta-analysis of randomized clinical trials. AB - Background: Meta-analysis studies have documented that palm olein (PALM) predominant formulas reduce calcium and fat absorption, and bone mineralization in infants, but none have been documented for stool consistency and frequency. Objective: The study objective was to conduct a meta-analysis of published randomized clinical trials (RCTs) on the effect of PALM-based formulas on stool consistency and frequency in infants. Design: A literature search was conducted in BIOSIS Previews(r), Embase(r), Embase(r) Alert, MEDLINE(r) and Cochrane databases. PALM-based RCTs with available stool outcomes were selected and meta analyzed. Mean rank stool consistency (MRSC, primary outcome) and stool frequency (secondary outcome) were compared between infants fed PALM-based and PALM-free formulas (NoPALM), using random effects model. Results: Nine out of identified16 studies were meta-analyzed. The mean MRSC (scale of 1 = watery to 5 = hard) in the NoPALM-fed infants was lower (softer stools) compared to the PALM-fed infants (mean difference -0.355, 95% Confidence Interval [CI] of -0.472 to -0.239, p < 0.001). Difference for stool frequency was not significant (p = 0.613). Conclusion: Meta-analysis of RCTs indicated that NoPALM-fed infants have significantly softer stools but similar stool frequencies versus PALM-fed infants, despite differences in study types and design. Future meta-analysis could benefit from including comparison with human milk-fed infants. PMID- 28659743 TI - In vitro inhibition of lipid accumulation induced by oleic acid and in vivo pharmacokinetics of chitosan microspheres (CTMS) and chitosan-capsaicin microspheres (CCMS). AB - Chitosan and capsaicin are compounds extracted from natural products and have been indicated to lower body weight and prevent fatty liver. However, their applications are limited by poor oral bioavailability, low compliance and some serious side effects. To solve these problems, we successfully prepared chitosan microspheres (CTMS) and chitosan-capsaicin microspheres (CCMS) in previous study. Therefore, in the present study, we evaluated the ability of CTMS and CCMS to eliminate lipid accumulation in hepatocytesand also characterized their pharmacokinetic parameters after administration. The results showed that the two microspheres could significantly reduce intracellular lipid accumulation and dose dependently improve the triglyceride (TG) content in HepG2 cells. A pharmacokinetic study indicated that CTMS and CCMS were distributed in almost all of the measured tissues, especially liver and kidney, and that their absorption was better than those of chitosan and capsaicin. Simultaneously, the prolonged circulating half-lives, the lower clearance and higher plasma concentration of CTMS and CCMS showed that their bioavailability was effectively enhanced. All of the results indicated that the lipid accumulation inhibition of CTMS and CCMS was better than that of chitosan and capsaicin, and that these microspheres can be developed as preventive agents for fatty liver or obesity. PMID- 28659742 TI - Dietary fructose causes defective insulin signalling and ceramide accumulation in the liver that can be reversed by gut microbiota modulation. AB - Objective: The link between metabolic derangement of the gut-2013liver-visceral white adipose tissue (v-WAT) axis and gut microbiota was investigated. Methods: Rats were fed a fructose-rich diet and treated with an antibiotic mix. Inflammation was measured in portal plasma, ileum, liver, and v-WAT, while insulin signalling was analysed by measuring levels of phosphorylated kinase Akt. The function and oxidative status of hepatic mitochondria and caecal microbiota composition were also evaluated. Results: Ileal inflammation, increase in plasma transaminases, plasma peroxidised lipids, portal concentrations of tumour necrosis factor alpha, lipopolysaccharide, and non-esterified fatty acids, were induced by fructose and were reversed by antibiotic. The increased hepatic ceramide content, inflammation and decreased insulin signaling in liver and v-WAT induced by fructose was reversed by antibiotic. Antibiotic also blunted the increase in hepatic mitochondrial efficiency and oxidative damage of rats fed fructose-rich diet. Three genera, Coprococcus, Ruminococcus, and Clostridium, significantly increased, while the Clostridiaceae family significantly decreased in rats fed a fructose-rich diet, and antibiotic abolished these variations Conclusions: When gut microbiota modulation by fructose is prevented by antibiotic, inflammatory flow from the gut to the liver and v-WAT are reversed. PMID- 28659744 TI - How is dietary diversity related to haematological status of preschool children in Ghana? AB - Background: The role of dietary diversity on blood biomarkers may be significant, but the evidence is limited. Objective: This study assessed the association between dietary diversity and haematological status of children aged 6-59 months controlling for various known confounders. Design: The analysis in this study is based on the 2014 Ghana Demographic and Health survey data.The study involved 2,388 pre-school children aged 6-59 months who constituted the sub-sample for anaemia assessment. Results: The mean haemoglobin concentration (Hb) was 10.2 g/dl +/- 1.50 (95 % CI: 10.1 to 10.3), and anaemia prevalence (Hb < 11 g/dl) among children aged 6-59 months was 66.8 % (CI: 63.7 to 69.8). In multivariable logistic regression analysis,continued breastfeeding [Adjusted odds ratio (AOR) = 1.9 (95% CI: 1.19-2.91], 12-23 months of age (AOR = 2.4 (95% CI: 1.40-3.98), having fever in last two weeks (AOR = 1.7 (95% CI: 1.20-2.45, birth interval <= 24 months (AOR = 1.9 (1.20-2.84), and poorest wealth quintile (AOR = 2.6 (95% CI: 1.48-4.48) were positively associated with anaemia. Conclusion: The current study showed that factors other than poor dietary diversity predicted anaemia among children aged 6-59 months in Ghana. PMID- 28659745 TI - Protective effects of tea polyphenols on exhaustive exercise-induced fatigue, inflammation and tissue damage. AB - Background: The beneficial properties of tea polyphenols have been extensively studied; however, less attention has been paid to their effects, especially anti inflammatory effect during exhaustive exercise. Objective: The present study assessed the potential protective effects of tea polyphenols against the fatigue, inflammation and tissue injury caused by an exhaustive exercise bout in rats. Design: Twenty-four healthy male rats were divided into three groups. Group C was a sedentary control group, Groups E+TP and Group E performed a single exhaustive swimming test; all groups had normal diets, but Group E+TP was supplemented with tea polyphenols. All rats were immediately euthanized after exhaustive exercise, and biochemical and inflammatory parameters, including lactic acid (LA), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-10 (IL-10), lactic dehydrogenase (LDH), and creatine kinase (CK) activity levels, were measured. Reverse transcription (RT) and Real-Time PCR was employed to evaluate the mRNA expression of IL-1beta in the liver. Results: The results showed a decrease in serum LA levels (22%, p < 0.05) in rats that consumed dietary tea polyphenols. Interestingly, dietary tea polyphenols decreased the serum levels of pro-inflammatory factors (TNF-alpha: 13%, p < 0.05; IL-1beta: 10%, p < 0.05; and IL-6: 48%, p < 0.05) and shifted the serum IL-10/TNF alpha ratio to a predominantly anti-inflammatory milieu (0.52 +/- 0.07 vs. 0.67 +/- 0.10, p < 0.01). Furthermore, the polyphenols effectively inhibited the release of tissue damage markers (CK: 24%, p < 0.05 and LDH: 28%, p < 0.05) in the serum and decreased IL-1beta mRNA expression in the liver. Conclusions: This study indicated that tea polyphenols could significantly protect rats from the fatigue, inflammation and tissue damage induced by acute exhaustive exercise. PMID- 28659746 TI - Effects of baked and raw salmon fillet on lipids and n-3 PUFAs in serum and tissues in Zucker fa/fa rats. AB - Knowledge of the health impact of consuming heat-treated versus raw fish fillet is limited. To investigate effects of baked or raw salmon fillet intake on lipids and n-3 PUFAs in serum and tissues, obese Zucker fa/fa rats were fed diets containing 25% of protein from baked or raw salmon fillet and 75% of protein from casein, or casein as the sole protein source (control group) for four weeks. Salmon diets had similar composition of amino and fatty acids. Growth and energy intake were similar in all groups. Amounts of lipids and n-3 PUFAs in serum, liver and skeletal muscle were similar between rats fed baked or raw salmon fillet. When compared to the control group, rats fed baked salmon had lower serum total and LDL cholesterol and higher serum triacylglycerol levels. Both raw and baked salmon groups had lower HDL cholesterol level when compared to control rats. In conclusion, baking as a preparation method does not alter protein and fat qualities of salmon fillets, and intake of baked and raw salmon fillets gave similar effects on lipids and n-3 PUFAs in serum and tissues from rats. PMID- 28659747 TI - Compliance to the recommended use of folic acid supplements for women in Sweden is higher among those under treatment for infertility than among fertile controls and is also related to socioeconomic status and lifestyle. AB - Background: Folate has been discussed in relation to fertility among women, but studies on women under treatment for infertility are lacking. Objective: The objective of this study was to investigate folic acid supplement use and folate status among women under treatment for infertility (hereafter infertile) and fertile women also in regard to socioeconomic and lifestyle factors. Design: Lifestyle and dietary habits, and use of dietary supplements were assessed using a questionnaire. Blood samples were obtained for analysis of folate status. 24 hour recall interviews were also performed. Results: Highly educated, employed and infertile women were most prone to using folic acid supplements. The infertile women had a significantly better folate status than the fertile women. Folate status did not correlate with socioeconomic or lifestyle factors. The infertile women were physically more active, smoked less and were employed. Our questionnaire data had only fair agreement with the data from 24-hour recalls, but the folate status data was clearly correlated to our questionnaire results. Conclusions: Infertile women were most prone to using folic acid supplements and had better folate status than the controls. High educational and employment status were found to be key factors for high compliance to the recommended use folic acid supplements. PMID- 28659748 TI - Anti-fatigue effects of dietary nucleotides in mice. AB - As the building blocks of nucleic acids, nucleotides are conditionally essential nutrients that exhibit multifaceted activities. The present study aimed to evaluate the anti-fatigue effects of dietary nucleotides (NTs) on mice and explore the possible underlying mechanism. Mice were randomly divided into four experimental sets to detect different indicators. Each set of mice was then divided into four groups: (i) one control group and (ii) three NTs groups, which were fed diets supplemented with NTs at concentrations of 0%, 0.04%, 0.16%, and 0.64% (wt/wt). NTs could significantly increase the forced swimming time, enhance lactate dehydrogenase activity and hepatic glycogen levels, as well as delay the accumulation of blood urea nitrogen and blood lactic acid in mice after 30 days of treatment. NTs also markedly improved fatigue-induced alterations in oxidative stress biomarkers and antioxidant enzymes. Notably, NTs increased the mitochondrial energy metabolic enzyme activities in the skeletal muscles of mice. These results suggest that NTs exert anti-fatigue effects, which may be attributed to the inhibition of oxidative stress and the improvement of mitochondrial function in skeletal muscles. NTs could be used as a novel natural agent for relieving exercise fatigue. Abbreviations: ATP: adenosine triphosphate; BLA: blood lactic acid; GSH-Px: glutathione peroxidase; LDH: lactate dehydrogenase; MDA: malondialdehyde; NTs: dietary nucleotides; SDH: succinate dehydrogenase; SOD: superoxide dismutase; BUN: blood urea nitrogen. PMID- 28659749 TI - Anti-adipogenic effects of Tropaeolum majus (nasturtium) ethanol extract on 3T3 L1 cells. AB - Background: Edible flowers, Tropaeolum majus has been used as a disinfectant and an antibiotic, and for wound healing, but the anti-obesity effects of this plant have not been reported previously Objective: We investigated the anti-adipogenic effects of T. majus ethanol extract (TME) on 3T3-L1 cells. Design: 3T3-L1 cells were differentiated in the presence of different concentrations of TME. Lipid accumulation levels were determined using Oil-Red O staining and a triglyceride content assay. Changes in the expression of proteins related to adipocyte differentiation in 3T3-L1 cells were determined by SDS-PAGE and western blotting. Results: The highest inhibition of lipid accumulation was observed at a TME concentration of 300 ug/mL. Additionally, TME concentrations ranging from 20 ug/mL to 500 ug/mL led to a decrease in the expression of adipocyte differentiation regulators, peroxisome proliferator-activated receptor gamma, CCAAT element binding protein alpha, and sterol regulatory element binding transcription factor 1. This decrease was shown to be concentration-dependent. Discussion: Taken together, the results of this study demonstrate that TME inhibits lipid accumulation and reduces the expression PPARG, CEBPA, and SREBF1, which regulate adipocyte differentiation in 3T3-L1 cells. Conclusions: TME may be a potential novel therapeutic agent for the prevention and treatment of obesity. PMID- 28659750 TI - Development of Performance and ERPs in a Flanker Task in Children and Adolescents with Tourette Syndrome-A Follow-Up Study. AB - Background: Tourette Syndrome (TS) is a neurodevelopmental disorder with childhood-onset, with a typical decline in tic severity, as well as an increasing ability to suppress tics in late childhood and adolescence. These processes develop in parallel with general improvement of self-regulatory abilities, and performance monitoring during this age-span. Hence, changes in performance monitoring over time might provide insight into the regulation of tics in children and adolescents with TS. Method: We measured reaction time, reaction time variability, accuracy, and event-related potentials (ERP) in 17 children with TS, including 10 children with comorbid Attention-Deficit/Hyperactivity Disorder (ADHD), 24 children with ADHD, and 29 typically developing children, using a modified Eriksen Flanker task in two testing sessions administered on average 4.5 years apart. We then compared task performance, as well as ERP components across groups, and over time using regression models. Results: Task performance improved in all groups with age, and behavioral differences between children with TS and controls diminished at second assessment, while differences between controls and children with ADHD largely persisted. In terms of ERP, the early P3 developed earlier in children with TS compared with controls at the first assessment, but trajectories converged with maturation. ERP component amplitudes correlated with worst-ever tic scores. Conclusions: Merging trajectories between children with TS and controls are consistent with the development of compensatory self-regulation mechanisms during early adolescence, probably facilitating tic suppression, in contrast to children with ADHD. Correlations between ERP amplitudes and tic scores also support this notion. PMID- 28659752 TI - Electrocorticographic Temporal Alteration Mapping: A Clinical Technique for Mapping the Motor Cortex with Movement-Related Cortical Potentials. AB - We propose electrocorticographic temporal alteration mapping (ETAM) for motor cortex mapping by utilizing movement-related cortical potentials (MRCPs) within the low-frequency band [0.05-3] Hz. This MRCP waveform-based temporal domain approach was compared with the state-of-the-art electrocorticographic frequency alteration mapping (EFAM), which is based on frequency spectrum dynamics. Five patients (two epilepsy cases and three tumor cases) were enrolled in the study. Each patient underwent intraoperative direct electrocortical stimulation (DECS) procedure for motor cortex localization. Moreover, the patients were required to perform simple brisk wrist extension task during awake craniotomy surgery. Cross validation results showed that the proposed ETAM method had high sensitivity (81.8%) and specificity (94.3%) in identifying sites which exhibited positive DECS motor responses. Moreover, although the sensitivity of the ETAM and EFAM approaches was not significantly different, ETAM had greater specificity compared with EFAM (94.3 vs. 86.1%). These results indicate that for the intraoperative functional brain mapping, ETAM is a promising novel approach for motor cortex localization with the potential to reduce the need for cortical electrical stimulation. PMID- 28659751 TI - A New Perspective for the Training Assessment: Machine Learning-Based Neurometric for Augmented User's Evaluation. AB - Inappropriate training assessment might have either high social costs and economic impacts, especially in high risks categories, such as Pilots, Air Traffic Controllers, or Surgeons. One of the current limitations of the standard training assessment procedures is the lack of information about the amount of cognitive resources requested by the user for the correct execution of the proposed task. In fact, even if the task is accomplished achieving the maximum performance, by the standard training assessment methods, it would not be possible to gather and evaluate information about cognitive resources available for dealing with unexpected events or emergency conditions. Therefore, a metric based on the brain activity (neurometric) able to provide the Instructor such a kind of information should be very important. As a first step in this direction, the Electroencephalogram (EEG) and the performance of 10 participants were collected along a training period of 3 weeks, while learning the execution of a new task. Specific indexes have been estimated from the behavioral and EEG signal to objectively assess the users' training progress. Furthermore, we proposed a neurometric based on a machine learning algorithm to quantify the user's training level within each session by considering the level of task execution, and both the behavioral and cognitive stabilities between consecutive sessions. The results demonstrated that the proposed methodology and neurometric could quantify and track the users' progresses, and provide the Instructor information for a more objective evaluation and better tailoring of training programs. PMID- 28659753 TI - Neural Correlates of Verbal Episodic Memory and Lexical Retrieval in Logopenic Variant Primary Progressive Aphasia. AB - Objective: Logopenic variant primary progressive aphasia (lvPPA) is commonly associated with Alzheimer's disease (AD) pathology. But lvPPA patients display different cognitive and anatomical profile from the common clinical AD patients, whose verbal episodic memory is primarily affected. Reports of verbal episodic memory difficulty in lvPPA are inconsistent, and we hypothesized that their lexical retrieval impairment contributes to verbal episodic memory performance and is associated with left middle temporal gyrus atrophy. Methods: We evaluated patients with lvPPA (n = 12) displaying prominent word-finding and repetition difficulties, and a demographically-matched cohort of clinical Alzheimer's disease (AD, n = 26), and healthy seniors (n = 16). We assessed lexical retrieval with confrontation naming and verbal episodic memory with delayed free recall. Whole-brain regressions related naming and delayed free recall to gray matter atrophy. Medial temporal lobe (MTL) subfields were examined using high in-plane resolution imaging. Results: lvPPA patients had naming and delayed free recall impairments, but intact recognition memory. In lvPPA, delayed free recall was related to naming; both were associated with left middle temporal gyrus atrophy but not MTL atrophy. Despite cerebrospinal fluid evidence consistent with AD pathology, examination of MTL subfields revealed no atrophy in lvPPA. While AD patients displayed impaired delayed free recall, this deficit did not correlate with naming. Regression analyses related delayed free recall deficits in clinical AD patients to MTL subfield atrophy, and naming to left middle temporal gyrus atrophy. Conclusion: Unlike amnestic AD patients, MTL subfields were not affected in lvPPA patients. Verbal episodic memory deficit observed in lvPPA was unlikely to be due to a hippocampal-mediated mechanism but appeared to be due to poor lexical retrieval. Relative sparing of MTL volume and intact recognition memory are consistent with previous reports of hippocampal-sparing variant cases of AD pathology, where neurofibrillary tangles are disproportionately distributed in cortical areas with relative sparing of the hippocampus. This suggests that AD neuropathology in lvPPA may originate in neuronal networks outside of the MTL, which deviates from the typical Braak staging pattern of spreading pathology in clinical AD. PMID- 28659754 TI - NADPH Oxidase Isoform 2 (NOX2) Is Involved in Drug Addiction Vulnerability in Progeny Developmentally Exposed to Ethanol. AB - Ethanol exposure increases oxidative stress in developing organs, including the brain. Antioxidant treatment during maternal ethanol ingestion improves behavioral deficits in rodent models of fetal alcohol spectrum disorder (FASD). However, the impact of general antioxidant treatment in their adult offspring and the Specific Reactive Species (ROS)-dependent mechanism, are not fully understood. We hypothesized that pre and early postnatal ethanol exposure (PEE) modifies redox homeostasis, in particular NOX2 function during reward signaling in the mesocorticolimbic pathway, which reinforces the effects of alcohol. We developed a FASD rat model which was evaluated during adolescence (P21) and adulthood (P70). We first studied whether redox homeostasis is affected in PEE animals, by analyzing mRNA expression of SOD1, CAT, and Gpx1. We found that PEE reduced the mRNA levels of these three anti-oxidant enzymes in PFC and HIPP at P21 and in the VTA at P70. We also analyzed basal mRNA and protein expression of NOX2 subunits such as gp91phox, p22 phox, and p47 phox, in mesocorticolimbic brain areas of PEE rat brains. At P21, gp91 phox, and p47 phox levels in the VTA were decreased. At P70, gp91 phox mRNA levels was decreased in HIPP and both mRNA and protein levels were decreased in PFC. Since NOX2 is regulated by the N-methyl D-aspartate Receptor (NMDAR), we analyzed NMDAR mRNA expression and found differential expression of NMDAR subunits (NR1 and NR2B) in the PFC that was age dependent, with levels decreased at P21 and increased at P70. The analysis also revealed decreased NR2B mRNA expression in HIPP and VTA at P70. Offspring from maternal ethanol users consumed 25% more ethanol in a free choice alcohol consumption test than control rats, and showed place preference for an alcohol paired compartment. In vivo inhibition of NOX2 using apocynin in drinking water, or infusion of blocked peptide gp91 phox ds in the VTA normalized alcohol place preference, suggesting that NOX2 plays an important role in addictive like behavior. Taken together, PEE significantly affects the expression of antioxidant enzymes, NOX2, NMDAR in an age, and brain region dependent manner. Moreover, we demonstrate that NOX2 regulates alcohol seeking behavior. PMID- 28659755 TI - Osthole Stimulated Neural Stem Cells Differentiation into Neurons in an Alzheimer's Disease Cell Model via Upregulation of MicroRNA-9 and Rescued the Functional Impairment of Hippocampal Neurons in APP/PS1 Transgenic Mice. AB - Alzheimer's disease (AD) is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost), a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD in vitro and in vivo. Recently, microRNAs (miRNAs) have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP)-expressing neural stem cells (NSCs) as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR)-9 and inhibiting the Notch signaling pathway in vitro. In addition, Ost treatment in APP/PS1 double transgenic (Tg) mice markedly restored cognitive functions, reduced Abeta plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases. PMID- 28659756 TI - Proprioceptive Feedback through a Neuromorphic Muscle Spindle Model. AB - Connecting biologically inspired neural simulations to physical or simulated embodiments can be useful both in robotics, for the development of a new kind of bio-inspired controllers, and in neuroscience, to test detailed brain models in complete action-perception loops. The aim of this work is to develop a fully spike-based, biologically inspired mechanism for the translation of proprioceptive feedback. The translation is achieved by implementing a computational model of neural activity of type Ia and type II afferent fibers of muscle spindles, the primary source of proprioceptive information, which, in mammals is regulated through fusimotor activation and provides necessary adjustments during voluntary muscle contractions. As such, both static and dynamic gamma-motoneurons activities are taken into account in the proposed model. Information from the actual proprioceptive sensors (i.e., motor encoders) is then used to simulate the spindle contraction and relaxation, and therefore drive the neural activity. To assess the feasibility of this approach, the model is implemented on the NEST spiking neural network simulator and on the SpiNNaker neuromorphic hardware platform and tested on simulated and physical robotic platforms. The results demonstrate that the model can be used in both simulated and real-time robotic applications to translate encoder values into a biologically plausible neural activity. Thus, this model provides a completely spike-based building block, suitable for neuromorphic platforms, that will enable the development of sensory-motor closed loops which could include neural simulations of areas of the central nervous system or of low-level reflexes. PMID- 28659757 TI - The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors. AB - Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K+ currents (M-current, IM ), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions. PMID- 28659759 TI - Optimized Method for Robust Transcriptome Profiling of Minute Tissues Using Laser Capture Microdissection and Low-Input RNA-Seq. AB - Obtaining high quality RNA from complex biological tissues, such as the brain, is needed for establishing high-fidelity cell-type specific transcriptomes. Although combining genetic labeling techniques with laser capture microdissection (LCM) is generally sufficient, concerns over RNA degradation and limited yields call into question results of many sequencing studies. Here we set out to address both of these issues by: (1) developing a fluorescence-assisted LCM protocol that yields high quality RNA from fresh-frozen tissues; and (2) determining a suitable RNA Seq library generation method for limited amounts of RNA (1-5 ng total RNA). The latter focused on comparing commercially available kits able to produce libraries of sufficient concentration and complexity while limiting PCR amplification biases. We find that high quality RNA (RNA integrity number, RIN, >9) of sufficient concentration can be isolated from laser-captured material from thinly sectioned tissues when digestion time and temperature are minimized. Furthermore, we found that library generation approaches that retain ribosomal RNA (rRNA) through cDNA library generation required fewer cycles of PCR, minimizing bias in the resulting libraries. Lastly, end stage depletion of rRNA prior to sequencing enriches for target RNAs, thereby increasing read depth and level of gene detection while decreasing sequencing costs. Here we describe our protocol for generating robust RNA-Seq libraries from laser-captured tissue and demonstrate that with this method, we obtain samples with RNA quality superior to the current standard in the LCM field, and show that low-input RNA-Seq kits that minimize PCR bias produce high fidelity sequencing metrics with less variability compared to current practices. PMID- 28659758 TI - Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness. AB - Memory and mood dysfunction are the key symptoms of Gulf war illness (GWI), a lingering multi-symptom ailment afflicting >200,000 veterans who served in the Persian Gulf War-1. Research probing the source of the disease has demonstrated that concomitant exposures to anti-nerve gas agent pyridostigmine bromide (PB), pesticides, and war-related stress are among the chief causes of GWI. Indeed, exposures to GWI-related chemicals (GWIR-Cs) and mild stress in animal models cause memory and mood impairments alongside reduced neurogenesis and chronic low level inflammation in the hippocampus. In the current study, we examined whether exposure to GWIR-Cs and stress causes chronic changes in the expression of genes related to increased oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus. We also investigated whether GWI is linked with chronically increased activation of Nrf2 (a master regulator of antioxidant response) in the hippocampus, and inflammation and enhanced oxidative stress at the systemic level. Adult male rats were exposed daily to low-doses of PB and pesticides (DEET and permethrin), in combination with 5 min of restraint stress for 4 weeks. Analysis of the hippocampus performed 6 months after the exposure revealed increased expression of many genes related to oxidative stress response and/or antioxidant activity (Hmox1, Sepp1, and Srxn1), reactive oxygen species metabolism (Fmo2, Sod2, and Ucp2) and oxygen transport (Ift172 and Slc38a1). Furthermore, multiple genes relevant to mitochondrial respiration (Atp6a1, Cox6a1, Cox7a2L, Ndufs7, Ndufv1, Lhpp, Slc25a10, and Ucp1) and neuroinflammation (Nfkb1, Bcl6, Csf2, IL6, Mapk1, Mapk3, Ngf, N-pac, and Prkaca) were up-regulated, alongside 73-88% reduction in the expression of anti-inflammatory genes IL4 and IL10, and nuclear translocation and increased expression of Nrf2 protein. These hippocampal changes were associated with elevated levels of pro-inflammatory cytokines and chemokines (Tnfa, IL1b, IL1a, Tgfb, and Fgf2) and lipid peroxidation byproduct malondialdehyde in the serum, suggesting the presence of an incessant systemic inflammation and elevated oxidative stress. These results imply that chronic oxidative stress, inflammation, and mitochondrial dysfunction in the hippocampus, and heightened systemic inflammation and oxidative stress likely underlie the persistent memory and mood dysfunction observed in GWI. PMID- 28659760 TI - Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3. AB - Mecp2 is a DNA methylation reader that plays a critical role in experience dependent plasticity. Increasing evidence supports a role for epigenetic modifications in activity-induced gene expression. Hence, candidate genes related to such phenomena are of great interest. Ryanodine receptors are intracellular calcium channels that contribute to hippocampal synaptic plasticity, dendritic spine remodeling, and participate in learning and memory processes. Here we exposed mice to the enriched environment (EE) paradigm, which through increased stimulation induces experience dependent-plasticity, to explore a role for methyl cytosines, and Mecp2 in directing Ryanodine receptor 3 (Ryr3) transcriptional activity. EE induced a hippocampal-specific increase in the methylation of discrete cytosines located at a Ryr3 isoform promoter; chromatin immunoprecipitation experiments revealed that EE increased Mecp2 binding to this Ryr3 isoform promoter. Interestingly, the experimental paradigm induced robust Ryr3 upregulation, accompanied by miR132-dependent suppression of p250GAP, a pathway driving synaptogenesis. In contrast to WT mice, Mecp2-null mice showed diminished levels of Ryr3 and displayed impaired EE-induced Ryr3 upregulation, compromising miR132 dependent suppression of p250GAP and experience-dependent structural plasticity. Based on these results, we propose that Mecp2 acts as a transcriptional activator of Ryr3, contributing to experience-dependent plasticity. PMID- 28659761 TI - Commentary: Identification of diverse astrocyte populations and their malignant analogs. PMID- 28659762 TI - Genetically-Informed Patient Selection for iPSC Studies of Complex Diseases May Aid in Reducing Cellular Heterogeneity. AB - Induced pluripotent stem cell (iPSC) technology is more and more used for the study of genetically complex human disease but is challenged by variability, sample size and polygenicity. We discuss studies involving iPSC-derived neurons from patients with Schizophrenia (SCZ), to exemplify that heterogeneity in sampling strategy complicate the detection of disease mechanisms. We offer a solution to controlling variability within and between iPSC studies by using specific patient selection strategies. PMID- 28659763 TI - NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons. AB - N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB). We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders. PMID- 28659764 TI - Associative Memory Extinction Is Accompanied by Decayed Plasticity at Motor Cortical Neurons and Persistent Plasticity at Sensory Cortical Neurons. AB - Associative memory is essential for cognition, in which associative memory cells and their plasticity presumably play important roles. The mechanism underlying associative memory extinction vs. maintenance remains unclear, which we have studied in a mouse model of cross-modal associative learning. Paired whisker and olfaction stimulations lead to a full establishment of odorant-induced whisker motion in training day 10, which almost disappears if paired stimulations are not given in a week, and then recovers after paired stimulation for an additional day. In mice that show associative memory, extinction and recovery, we have analyzed the dynamical plasticity of glutamatergic neurons in layers II-III of the barrel cortex and layers IV-V of the motor cortex. Compared with control mice, the rate of evoked spikes as well as the amplitude and frequency of excitatory postsynaptic currents increase, whereas the amplitude and frequency of inhibitory postsynaptic currents (IPSC) decrease at training day 10 in associative memory mice. Without paired training for a week, these plastic changes are persistent in the barrel cortex and decayed in the motor cortex. If paired training is given for an additional day to revoke associative memory, neuronal plasticity recovers in the motor cortex. Our study indicates persistent neuronal plasticity in the barrel cortex for cross-modal memory maintenance as well as the dynamical change of neuronal plasticity in the motor cortex for memory retrieval and extinction. In other words, the sensory cortices are essential for long-term memory while the behavior-related cortices with the inability of memory retrieval are correlated to memory extinction. PMID- 28659765 TI - Synaptic Impairment and Robustness of Excitatory Neuronal Networks with Different Topologies. AB - Synaptic deficiencies are a known hallmark of neurodegenerative diseases, but the diagnosis of impaired synapses on the cellular level is not an easy task. Nonetheless, changes in the system-level dynamics of neuronal networks with damaged synapses can be detected using techniques that do not require high spatial resolution. This paper investigates how the structure/topology of neuronal networks influences their dynamics when they suffer from synaptic loss. We study different neuronal network structures/topologies by specifying their degree distributions. The modes of the degree distribution can be used to construct networks that consist of rich clubs and resemble small world networks, as well. We define two dynamical metrics to compare the activity of networks with different structures: persistent activity (namely, the self-sustained activity of the network upon removal of the initial stimulus) and quality of activity (namely, percentage of neurons that participate in the persistent activity of the network). Our results show that synaptic loss affects the persistent activity of networks with bimodal degree distributions less than it affects random networks. The robustness of neuronal networks enhances when the distance between the modes of the degree distribution increases, suggesting that the rich clubs of networks with distinct modes keep the whole network active. In addition, a tradeoff is observed between the quality of activity and the persistent activity. For a range of distributions, both of these dynamical metrics are considerably high for networks with bimodal degree distribution compared to random networks. We also propose three different scenarios of synaptic impairment, which may correspond to different pathological or biological conditions. Regardless of the network structure/topology, results demonstrate that synaptic loss has more severe effects on the activity of the network when impairments are correlated with the activity of the neurons. PMID- 28659767 TI - Hornets Have It: A Conserved Olfactory Subsystem for Social Recognition in Hymenoptera? AB - Eusocial Hymenoptera colonies are characterized by the presence of altruistic individuals, which rear their siblings instead of their own offspring. In the course of evolution, such sterile castes are thought to have emerged through the process of kin selection, altruistic traits being transmitted to following generation if they benefit relatives. By allowing kinship recognition, the detection of cuticular hydrocarbons (CHCs) might be instrumental for kin selection. In carpenter ants, a female-specific olfactory subsystem processes CHC information through antennal detection by basiconic sensilla. It is still unclear if other families of eusocial Hymenoptera use the same subsystem for sensing CHCs. Here, we examined the existence of such a subsystem in Vespidae (using the hornet Vespa velutina), a family in which eusociality emerged independently of ants. The antennae of both males and female hornets contain large basiconic sensilla. Sensory neurons from the large basiconic sensilla exclusively project to a conspicuous cluster of small glomeruli in the antennal lobe, with anatomical and immunoreactive features that are strikingly similar to those of the ant CHC sensitive subsystem. Extracellular electrophysiological recordings further show that sensory neurons within hornet basiconic sensilla preferentially respond to CHCs. Although this subsystem is not female-specific in hornets, the observed similarities with the olfactory system of ants are striking. They suggest that the basiconic sensilla subsystem could be an ancestral trait, which may have played a key role in the advent of eusociality in these hymenopteran families by allowing kin recognition and the production of altruistic behaviors toward relatives. PMID- 28659768 TI - Neuroelectric Tuning of Cortical Oscillations by Apical Dendrites in Loop Circuits. AB - Bundles of relatively long apical dendrites dominate the neurons that make up the thickness of the cerebral cortex. It is proposed that a major function of the apical dendrite is to produce sustained oscillations at a specific frequency that can serve as a common timing unit for the processing of information in circuits connected to that apical dendrite. Many layer 5 and 6 pyramidal neurons are connected to thalamic neurons in loop circuits. A model of the apical dendrites of these pyramidal neurons has been used to simulate the electric activity of the apical dendrite. The results of that simulation demonstrated that subthreshold electric pulses in these apical dendrites can be tuned to specific frequencies and also can be fine-tuned to narrow bandwidths of less than one Hertz (1 Hz). Synchronous pulse outputs from the circuit loops containing apical dendrites can tune subthreshold membrane oscillations of neurons they contact. When the pulse outputs are finely tuned, they function as a local "clock," which enables the contacted neurons to synchronously communicate with each other. Thus, a shared tuning frequency can select neurons for membership in a circuit. Unlike layer 6 apical dendrites, layer 5 apical dendrites can produce burst firing in many of their neurons, which increases the amplitude of signals in the neurons they contact. This difference in amplitude of signals serves as basis of selecting a sub-circuit for specialized processing (e.g., sustained attention) within the typically larger layer 6-based circuit. After examining the sustaining of oscillations in loop circuits and the processing of spikes in network circuits, we propose that cortical functioning can be globally viewed as two systems: a loop system and a network system. The loop system oscillations influence the network system's timing and amplitude of pulse signals, both of which can select circuits that are momentarily dominant in cortical activity. PMID- 28659766 TI - Neuroanatomical Substrates of Rodent Social Behavior: The Medial Prefrontal Cortex and Its Projection Patterns. AB - Social behavior encompasses a number of distinctive and complex constructs that form the core elements of human imitative culture, mainly represented as either affiliative or antagonistic interactions with conspecifics. Traditionally considered in the realm of psychology, social behavior research has benefited from recent advancements in neuroscience that have accelerated identification of the neural systems, circuits, causative genes and molecular mechanisms that underlie distinct social cognitive traits. In this review article, I summarize recent findings regarding the neuroanatomical substrates of key social behaviors, focusing on results from experiments conducted in rodent models. In particular, I will review the role of the medial prefrontal cortex (mPFC) and downstream subcortical structures in controlling social behavior, and discuss pertinent future research perspectives. PMID- 28659769 TI - Propofol, Sevoflurane, and Ketamine Induce a Reversible Increase in Delta-Gamma and Theta-Gamma Phase-Amplitude Coupling in Frontal Cortex of Rat. AB - Studies from human and non-human species have demonstrated a breakdown of functional corticocortical connectivity during general anesthesia induced by anesthetics with diverse molecular, neurophysiological, and pharmacological profiles. Recent studies have demonstrated that changes in long-range neural communication, and by corollary, functional connectivity, might be influenced by cross-frequency coupling (CFC) between the phase of slow oscillations and the amplitude of local fast oscillations. Phase-amplitude coupling (PAC) between slow oscillations and alpha rhythm during general anesthesia reveal distinct patterns depending on the anesthetic. In this study, we analyzed the effect of three clinically used anesthetics (propofol: n = 6, sevoflurane: n = 10, and ketamine: n = 8) with distinct molecular mechanisms on changes in PAC in the frontal cortex of rat. The loss of righting reflex was used as a surrogate for unconsciousness. PAC was calculated using the modulation index (MI) algorithm between delta (1-4 Hz), theta (4-10 Hz), low gamma (25-55 Hz), and high gamma (65-125 Hz) bands. A linear mixed model with fixed effects was used for statistical comparisons between waking, anesthetized, and post-anesthesia recovery epochs. All three anesthetics increased the coupling between delta and low gamma (p < 0.0001) as well as between theta and low gamma (p < 0.0001) oscillations, which returned to baseline waking levels during the post-anesthetic recovery period. In addition, a reversible reduction in high gamma power (p < 0.0001) was a consistent change during anesthesia induced by all three agents. The changes in delta-high gamma and theta-high gamma PAC as well as power spectral changes in delta, theta, and low gamma bandwidths did not show a uniform response across the three anesthetics. These results encourage the study of alternative PAC patterns as drug-invariant markers of general anesthesia in humans. PMID- 28659770 TI - Evaluation of AZD1446 as a Therapeutic in DYT1 Dystonia. AB - DYT1 dystonia is an early-onset, hyperkinetic movement disorder caused by a deletion in the gene TOR1A, which encodes the protein torsinA. Several lines of evidence show that in animal models of DTY1 dystonia, there is impaired basal dopamine (DA) release and enhanced acetylcholine tone. Clinically, anticholinergic drugs are the most effective pharmacological treatment for DYT1 dystonia, but the currently used agents are non-selective muscarinic antagonists and associated with side effects. We used a DYT1 ?GAG knock-in mouse model (DYT1 KI) to investigate whether nicotine and/or a non-desensitizing nicotinic agonist, AZD1446, would increase DA output in DYT1 dystonia. Using in vivo microdialysis, we found that DYT1 KI mice showed significantly increased DA output and greater sensitivity to nicotine compared to wild type (WT) littermate controls. In contrast, neither systemic injection (0.25-0.75 mg/kg) or intrastriatal infusion (30 MUM-1 mM) of AZD1446 had a significant effect on DA efflux in WT or DYT1 KI mice. In vitro, we found that AZD1446 had no effect on the membrane properties of striatal spiny projection neurons (SPNs) and did not alter the spontaneous firing of ChI interneurons in either WT or DYT1 KI mice. We did observe that the firing frequency of dopaminergic neurons was significantly increased by AZD1446 (10 MUM), an effect blocked by dihydro-beta-erythroidine (DHbetaE 3 MUM), but the effect was similar in WT and DYT1 KI mice. Our results support the view that DYT1 models are associated with abnormal striatal cholinergic transmission, and that the DYT1 KI animals have enhanced sensitivity to nicotine. We found little effect of AZD1446 in this model, suggesting that other approaches to nicotinic modulation should be explored. PMID- 28659771 TI - Cognitive Impairment in Patients with Chronic Neuropathic or Radicular Pain: An Interaction of Pain and Age. AB - A growing body of empirical research has confirmed an association between chronic pain and cognitive dysfunction. The aim of the present study was to determine whether cognitive function is affected in patients with a diagnosis of chronic neuropathic or radicular pain relative to healthy control participants matched by age, gender, and years of education. We also examined the interaction of pain with age in terms of cognitive performance. Some limitations of previous clinical research investigating the effects of chronic pain on cognitive function include differences in the pain and cognitive scale materials used, and the heterogeneity of patient participants, both in terms of their demographics and pathological conditions. To address these potential confounds, we have used a relatively homogenous patient group and included both experimental and statistical controls. We have also specifically investigated the interaction effect of pain and age on cognitive performance. Patients (n = 38) and controls (n = 38) were administered a battery of cognitive tests measuring IQ, spatial and verbal memory, attention, and executive function. Educational level, depressive symptoms, and state anxiety were assessed as were medication usage, caffeine, and nicotine consumption to control for possible confounding effects. Both the level of depressive symptoms and the state anxiety score were higher in chronic pain patients than in matched control participants. Chronic pain patients had a lower estimated IQ than controls, and showed impairments on measures of spatial and verbal memory. Attentional responding was altered in the patient group, possibly indicative of impaired inhibitory control. There were significant interactions between chronic pain condition and age on a number of cognitive outcome variables, such that older patients with chronic pain were more impaired than both age-matched controls and younger patients with chronic pain. Chronic pain did not appear to predict performance on the Wisconsin Card Sorting Task, which was used a measure of executive function. This study supports and extends previous research indicating that chronic pain is associated with impaired memory and attention. Perspective: Compared to healthy control participants, patients with chronic neuropathic or radicular pain showed cognitive deficits which were most pronounced in older pain patients. PMID- 28659772 TI - Parameter Optimization Analysis of Prolonged Analgesia Effect of tDCS on Neuropathic Pain Rats. AB - Background: Transcranial direct current stimulation (tDCS) is widely used to treat human nerve disorders and neuropathic pain by modulating the excitability of cortex. The effectiveness of tDCS is influenced by its stimulation parameters, but there have been no systematic studies to help guide the selection of different parameters. Objective: This study aims to assess the effects of tDCS of primary motor cortex (M1) on chronic neuropathic pain in rats and to test for the optimal parameter combinations for analgesia. Methods: Using the chronic neuropathic pain models of chronic constriction injury (CCI), we measured pain thresholds before and after anodal-tDCS (A-tDCS) using different parameter conditions, including stimulation intensity, stimulation time, intervention time and electrode located (ipsilateral or contralateral M1 of the ligated paw on male/female CCI models). Results: Following the application of A-tDCS over M1, we observed that the antinociceptive effects were depended on different parameters. First, we found that repetitive A-tDCS had a longer analgesic effect than single stimulus, and both ipsilateral-tDCS (ip-tDCS) and contralateral-tDCS (con-tDCS) produce a long-lasting analgesic effect on neuropathic pain. Second, the antinociceptive effects were intensity-dependent and time-dependent, high intensities worked better than low intensities and long stimulus durations worked better than short stimulus durations. Third, timing of the intervention after injury affected the stimulation outcome, early use of tDCS was an effective method to prevent the development of pain, and more frequent intervention induced more analgesia in CCI rats, finally, similar antinociceptive effects of con- and ip-tDCS were observed in both sexes of CCI rats. Conclusion: Optimized protocols of tDCS for treating antinociceptive effects were developed. These findings should be taken into consideration when using tDCS to produce analgesic effects in clinical applications. PMID- 28659773 TI - Increased Alpha Band Functional Connectivity Following the Quadrato Motor Training: A Longitudinal Study. AB - Quadrato Motor Training (QMT) is a new training paradigm, which was found to increase cognitive flexibility, creativity and spatial cognition. In addition, QMT was reported to enhance inter- and intra-hemispheric alpha coherence as well as Fractional Anisotropy (FA) in a number of white matter pathways including corpus callosum. Taken together, these results seem to suggest that electrophysiological and structural changes induced by QMT may be due to an enhanced interplay and communication of the different brain areas within and between the right and the left hemisphere. In order to test this hypothesis using the exact low-resolution brain electromagnetic tomography (eLORETA), we estimated the current neural density and lagged linear connectivity (LLC) of the alpha band in the resting state electroencephalography (rsEEG) recorded with open (OE) and closed eyes (CE) at three different time points, following 6 and 12 weeks of daily QMT. Significant changes were observed for the functional connectivity. In particular, we found that limbic and fronto-temporal alpha connectivity in the OE condition increased after 6 weeks, while it enhanced at the CE condition in occipital network following 12-weeks of daily training. These findings seem to show that the QMT may have dissociable long-term effects on the functional connectivity depending on the different ways of recording rsEEG. OE recording pointed out a faster onset of Linear Lag Connectivity modulations that tend to decay as quickly, while CE recording showed sensible effect only after the complete 3-months training. PMID- 28659774 TI - Electromyographic Pattern during Gait Initiation Differentiates Yoga Practitioners among Physically Active Older Subjects. AB - During gait initiation, postural adjustments are needed to deal with balance and movement. With aging, gait initiation changes and reflects functional degradation of frailty individuals. However, physical activities have demonstrated beneficial effects of daily motor tasks. The aim of our study was to compare center of pressure (COP) displacement and ankle muscle co-activation during gait initiation in two physically active groups: a group of walkers (n = 12; mean age +/- SD 72.6 +/- 3.2 years) and a yoga group (n = 11; 71.5 +/- 3.8 years). COP trajectory and electromyography of leg muscles were recorded simultaneously during five successive trials of gait initiation. Our main finding was that yoga practitioners had slower COP displacements (p < 0.01) and lower leg muscles % of coactivation (p < 0.01) in comparison with walkers. These parameters which characterized gait initiation control were correlated (r = 0.76; p < 0.01). Our results emphasize that lengthy ankle muscle co-activation and COP path in gait initiation differentiate yoga practitioners among physically active subjects. PMID- 28659775 TI - Editorial: The Evolution of Rhythm Cognition: Timing in Music and Speech. PMID- 28659777 TI - Deep Brain Stimulation of the H Fields of Forel Alleviates Tics in Tourette Syndrome. AB - The current rationale for target selection in Tourette syndrome revolves around the notion of cortico-basal ganglia circuit involvement in the pathophysiology of the disease. However, despite extensive research, the ideal target for deep brain stimulation (DBS) is still under debate, with many structures being neglected and underexplored. Based on clinical observations and taking into account the prevailing hypotheses of network processing in Tourette syndrome, we chose the fields of Forel, namely field H1, as a target for DBS. The fields of Forel constitute the main link between the striatopallidal system and the thalamocortical network, relaying pallidothalamic projections from core anatomical structures to the thalamic ventral nuclear group. In a retrospective study we investigated two patients suffering from chronic, medically intractable Tourette syndrome who underwent bilateral lead implantation in field H1 of Forel. Clinical scales revealed significant alleviation of tics and comorbid symptoms, namely depression and anxiety, in the postoperative course in both patients. PMID- 28659776 TI - Cholinergic Potentiation and Audiovisual Repetition-Imitation Therapy Improve Speech Production and Communication Deficits in a Person with Crossed Aphasia by Inducing Structural Plasticity in White Matter Tracts. AB - Donepezil (DP), a cognitive-enhancing drug targeting the cholinergic system, combined with massed sentence repetition training augmented and speeded up recovery of speech production deficits in patients with chronic conduction aphasia and extensive left hemisphere infarctions (Berthier et al., 2014). Nevertheless, a still unsettled question is whether such improvements correlate with restorative structural changes in gray matter and white matter pathways mediating speech production. In the present study, we used pharmacological magnetic resonance imaging to study treatment-induced brain changes in gray matter and white matter tracts in a right-handed male with chronic conduction aphasia and a right subcortical lesion (crossed aphasia). A single-patient, open label multiple-baseline design incorporating two different treatments and two post-treatment evaluations was used. The patient received an initial dose of DP (5 mg/day) which was maintained during 4 weeks and then titrated up to 10 mg/day and administered alone (without aphasia therapy) during 8 weeks (Endpoint 1). Thereafter, the drug was combined with an audiovisual repetition-imitation therapy (Look-Listen-Repeat, LLR) during 3 months (Endpoint 2). Language evaluations, diffusion weighted imaging (DWI), and voxel-based morphometry (VBM) were performed at baseline and at both endpoints in JAM and once in 21 healthy control males. Treatment with DP alone and combined with LLR therapy induced marked improvement in aphasia and communication deficits as well as in selected measures of connected speech production, and phrase repetition. The obtained gains in speech production remained well-above baseline scores even 4 months after ending combined therapy. Longitudinal DWI showed structural plasticity in the right frontal aslant tract and direct segment of the arcuate fasciculus with both interventions. VBM revealed no structural changes in other white matter tracts nor in cortical areas linked by these tracts. In conclusion, cholinergic potentiation alone and combined with a model-based aphasia therapy improved language deficits by promoting structural plastic changes in right white matter tracts. PMID- 28659779 TI - Temporality of Features in Near-Death Experience Narratives. AB - Background: After an occurrence of a Near-Death Experience (NDE), Near-Death Experiencers (NDErs) usually report extremely rich and detailed narratives. Phenomenologically, a NDE can be described as a set of distinguishable features. Some authors have proposed regular patterns of NDEs, however, the actual temporality sequence of NDE core features remains a little explored area. Objectives: The aim of the present study was to investigate the frequency distribution of these features (globally and according to the position of features in narratives) as well as the most frequently reported temporality sequences of features. Methods: We collected 154 French freely expressed written NDE narratives (i.e., Greyson NDE scale total score >= 7/32). A text analysis was conducted on all narratives in order to infer temporal ordering and frequency distribution of NDE features. Results: Our analyses highlighted the following most frequently reported sequence of consecutive NDE features: Out-of-Body Experience, Experiencing a tunnel, Seeing a bright light, Feeling of peace. Yet, this sequence was encountered in a very limited number of NDErs. Conclusion: These findings may suggest that NDEs temporality sequences can vary across NDErs. Exploring associations and relationships among features encountered during NDEs may complete the rigorous definition and scientific comprehension of the phenomenon. PMID- 28659778 TI - Effects of More-Affected vs. Less-Affected Motor Cortex tDCS in Parkinson's Disease. AB - Objective: To evaluate therapeutic potential of different montages of transcranial direct current stimulation (tDCS) in Parkinson's Disease (PD) patients with asymmetric motor symptoms. Materials and Methods: Fourteen patients with asymmetric PD underwent, while on treatment, seven separate sessions including electrophysiological and clinical evaluation at baseline and after anodal, cathodal and sham tDCS of the primary motor cortex (M1) of the two hemispheres. Changes in motor cortical excitability were evaluated by transcranial magnetic stimulation (TMS). Effects on motor symptoms were assessed by testing finger tapping (FT) and upper limb bradykinesia, and by using the Italian validated Movement Disorder Society revision of the Unified PD Rating Scale (MDS-UPDRS). Results: Only anodal tDCS of the more-affected M1 (contralateral to the more-affected body side) and cathodal tDCS of the less affected M1 (contralateral to the less-affected body side) were able to induce significant changes in cortical excitability, i.e., facilitation and inhibition of the motor evoked potentials respectively. The motor performances of both hands significantly improved after anodal tDCS of the more-affected M1, as well as after cathodal tDCS of the less-affected one. Conclusion: Our findings support the potential usefulness of tDCS as add-on treatment for asymmetric PD, also providing interesting clues on the possible pathophysiological role played by an asymmetric activation of homologous motor cortical areas in PD. PMID- 28659780 TI - Estimation of Human Workload from the Auditory Steady-State Response Recorded via a Wearable Electroencephalography System during Walking. AB - Workload in the human brain can be a useful marker of internal brain state. However, due to technical limitations, previous workload studies have been unable to record brain activity via conventional electroencephalography (EEG) and magnetoencephalography (MEG) devices in mobile participants. In this study, we used a wearable EEG system to estimate workload while participants walked in a naturalistic environment. Specifically, we used the auditory steady-state response (ASSR) which is an oscillatory brain activity evoked by repetitive auditory stimuli, as an estimation index of workload. Participants performed three types of N-back tasks, which were expected to command different workloads, while walking at a constant speed. We used a binaural 500 Hz pure tone with amplitude modulation at 40 Hz to evoke the ASSR. We found that the phase-locking index (PLI) of ASSR activity was significantly correlated with the degree of task difficulty, even for EEG data from few electrodes. Thus, ASSR appears to be an effective indicator of workload during walking in an ecologically valid environment. PMID- 28659781 TI - Coarse-Grained Descriptions of Dynamics for Networks with Both Intrinsic and Structural Heterogeneities. AB - Finding accurate reduced descriptions for large, complex, dynamically evolving networks is a crucial enabler to their simulation, analysis, and ultimately design. Here, we propose and illustrate a systematic and powerful approach to obtaining good collective coarse-grained observables-variables successfully summarizing the detailed state of such networks. Finding such variables can naturally lead to successful reduced dynamic models for the networks. The main premise enabling our approach is the assumption that the behavior of a node in the network depends (after a short initial transient) on the node identity: a set of descriptors that quantify the node properties, whether intrinsic (e.g., parameters in the node evolution equations) or structural (imparted to the node by its connectivity in the particular network structure). The approach creates a natural link with modeling and "computational enabling technology" developed in the context of Uncertainty Quantification. In our case, however, we will not focus on ensembles of different realizations of a problem, each with parameters randomly selected from a distribution. We will instead study many coupled heterogeneous units, each characterized by randomly assigned (heterogeneous) parameter value(s). One could then coin the term Heterogeneity Quantification for this approach, which we illustrate through a model dynamic network consisting of coupled oscillators with one intrinsic heterogeneity (oscillator individual frequency) and one structural heterogeneity (oscillator degree in the undirected network). The computational implementation of the approach, its shortcomings and possible extensions are also discussed. PMID- 28659782 TI - Cliques of Neurons Bound into Cavities Provide a Missing Link between Structure and Function. AB - The lack of a formal link between neural network structure and its emergent function has hampered our understanding of how the brain processes information. We have now come closer to describing such a link by taking the direction of synaptic transmission into account, constructing graphs of a network that reflect the direction of information flow, and analyzing these directed graphs using algebraic topology. Applying this approach to a local network of neurons in the neocortex revealed a remarkably intricate and previously unseen topology of synaptic connectivity. The synaptic network contains an abundance of cliques of neurons bound into cavities that guide the emergence of correlated activity. In response to stimuli, correlated activity binds synaptically connected neurons into functional cliques and cavities that evolve in a stereotypical sequence toward peak complexity. We propose that the brain processes stimuli by forming increasingly complex functional cliques and cavities. PMID- 28659783 TI - Multistability and Long-Timescale Transients Encoded by Network Structure in a Model of C. elegans Connectome Dynamics. AB - The neural dynamics of the nematode Caenorhabditis elegans are experimentally low dimensional and may be understood as long-timescale transitions between multiple low-dimensional attractors. Previous modeling work has found that dynamic models of the worm's full neuronal network are capable of generating reasonable dynamic responses to certain inputs, even when all neurons are treated as identical save for their connectivity. This study investigates such a model of C. elegans neuronal dynamics, finding that a wide variety of multistable responses are generated in response to varied inputs. Specifically, we generate bifurcation diagrams for all possible single-neuron inputs, showing the existence of fixed points and limit cycles for different input regimes. The nature of the dynamical response is seen to vary according to the type of neuron receiving input; for example, input into sensory neurons is more likely to drive a bifurcation in the system than input into motor neurons. As a specific example we consider compound input into the neuron pairs PLM and ASK, discovering bistability of a limit cycle and a fixed point. The transient timescales in approaching each of these states are much longer than any intrinsic timescales of the system. This suggests consistency of our model with the characterization of dynamics in neural systems as long-timescale transitions between discrete, low-dimensional attractors corresponding to behavioral states. PMID- 28659784 TI - Effects of Assist-As-Needed Upper Extremity Robotic Therapy after Incomplete Spinal Cord Injury: A Parallel-Group Controlled Trial. AB - BACKGROUND: Robotic rehabilitation of the upper limb following neurological injury has been supported through several large clinical studies for individuals with chronic stroke. The application of robotic rehabilitation to the treatment of other neurological injuries is less developed, despite indications that strategies successful for restoration of motor capability following stroke may benefit individuals with incomplete spinal cord injury (SCI) as well. Although recent studies suggest that robot-aided rehabilitation might be beneficial after incomplete SCI, it is still unclear what type of robot-aided intervention contributes to motor recovery. METHODS: We developed a novel assist-as-needed (AAN) robotic controller to adjust challenge and robotic assistance continuously during rehabilitation therapy delivered via an upper extremity exoskeleton, the MAHI Exo-II, to train independent elbow and wrist joint movements. We further enrolled seventeen patients with incomplete spinal cord injury (AIS C and D levels) in a parallel-group balanced controlled trial to test the efficacy of the AAN controller, compared to a subject-triggered (ST) controller that does not adjust assistance or challenge levels continuously during therapy. The conducted study is a stage two, development-of-concept pilot study. RESULTS: We validated the AAN controller in its capability of modulating assistance and challenge during therapy via analysis of longitudinal robotic metrics. For the selected primary outcome measure, the pre-post difference in ARAT score, no statistically significant change was measured in either group of subjects. Ancillary analysis of secondary outcome measures obtained via robotic testing indicates gradual improvement in movement quality during the therapy program in both groups, with the AAN controller affording greater increases in movement quality over the ST controller. CONCLUSION: The present study demonstrates feasibility of subject adaptive robotic therapy after incomplete spinal cord injury, but does not demonstrate gains in arm function occurring as a result of the robot-assisted rehabilitation program, nor differential gains obtained as a result of the developed AAN controller. Further research is warranted to better quantify the recovery potential provided by AAN control strategies for robotic rehabilitation of the upper limb following incomplete SCI. ClinicalTrials.gov registration number: NCT02803255. PMID- 28659785 TI - The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies. PMID- 28659786 TI - Flavonoid Hesperidin Induces Synapse Formation and Improves Memory Performance through the Astrocytic TGF-beta1. AB - Synapse formation and function are critical events for the brain function and cognition. Astrocytes are active participants in the control of synapses during development and adulthood, but the mechanisms underlying astrocyte synaptogenic potential only began to be better understood recently. Currently, new drugs and molecules, including the flavonoids, have been studied as therapeutic alternatives for modulation of cognitive processes in physiological and pathological conditions. However, the cellular targets and mechanisms of actions of flavonoids remain poorly elucidated. In the present study, we investigated the effects of hesperidin on memory and its cellular and molecular targets in vivo and in vitro, by using a short-term protocol of treatment. The novel object recognition test (NOR) was used to evaluate memory performance of mice intraperitoneally treated with hesperidin 30 min before the training and again before the test phase. The direct effects of hesperidin on synapses and astrocytes were also investigated using in vitro approaches. Here, we described hesperidin as a new drug able to improve memory in healthy adult mice by two main mechanisms: directly, by inducing synapse formation and function between hippocampal and cortical neurons; and indirectly, by enhancing the synaptogenic ability of cortical astrocytes mainly due to increased secretion of transforming growth factor beta-1 (TGF-beta1) by these cells. Our data reinforces the known neuroprotective effect of hesperidin and, by the first time, characterizes its synaptogenic action on the central nervous system (CNS), pointing astrocytes and TGF-beta1 signaling as new cellular and molecular targets of hesperidin. Our work provides not only new data regarding flavonoid's actions on the CNS but also shed light on possible new therapeutic alternative based on astrocyte biology. PMID- 28659787 TI - Better Correlation of Cognitive Function to White Matter Integrity than to Blood Supply in Subjects with Leukoaraiosis. AB - Leukoaraiosis is associated with increased risk of cognitive impairment, but its pathophysiological pathway is unclear. The aim of the present study was to determine whether brain structural damage or cerebral blood supply better correlated with the global cognitive outcome in subjects with leukoaraiosis. Seventy-five subjects with leukoaraiosis were included in present study, with age ranged from 43 to 85 years, with mean white matter hyperintensities (WMH) volume 30.69 +/- 24.35 mL. Among them, 19(25.33%) subjects presented with cerebral microbleeds (CMB) and 40 (53.33%) subjects presented with lacunes. These participants received arterial spin labeling perfusion MRI, diffusion-tensor imaging (DTI) and diffusion Kurtosis imaging. We analyzed the cerebral blood flow (CBF) by dividing the brain tissue into three regions: WMH, normal appearing white matter (NAWM) and cortex. After adjusting for age and gender, the CBF of NAWM was significantly correlated with fractional anisotropy (FA) (r = 0.336, p = 0.004) and mean diffusion (MD) (r = -0.271, p = 0.020) of NAWM, while there lacked of association between CBF of cortex and mean kurtosis (MK) of cortex (r = -0.015, p = 0.912). Meanwhile, both NAWM-FA (r = -0.443, p < 0.001) and NAWM-MD (r = 0.293, p = 0.012), as well as cortex-MK (r = -0.341, p = 0.012) was significantly correlated with WMH volume. Univariate regression analysis demonstrated that global cognitive function was significantly associated with mean FA or MD of both WMH and NAWM, and cortex-CBF, but neither with the cortex MK, nor the presences of CMB or lacunes. Finally, multiple linear regression analysis revealed that global cognitive function was independently associated with NAWM-FA (standardized beta = 0.403, p < 0.001) and WMH-FA (Standardized beta = 0.211, p = 0.017), but not with the cortex-CBF. A model that contained NAWM-FA, WMH-FA and years of education explained 49% of the variance of global cognitive function. Cerebral perfusion status might have a significant impact on the maintenance of white matter integrity in subjects with leukoaraiosis. Global cognitive function was more strongly associated with white matter integrity than with blood supply. DTI parameters, especially FA could serve as a potent imaging indicator for detecting the invisible alteration of white matter integrity and implying its potential cognitive relevance. PMID- 28659789 TI - A Chinese Chan-based Mind-Body Intervention Improves Memory of Older Adults. AB - There is growing interest in the adoption of lifestyle interventions to remediate age-related declines in memory functioning and physical and psychological health among older adults. This study aimed to investigate whether a Chinese Chan-based lifestyle intervention, the Dejian Mind-Body Intervention (DMBI), leads to positive benefits for memory functioning in older adults. Fifty-six adults aged 60 years or older with subjective memory complaints (SMC) were randomly assigned to receive the DMBI or a control intervention (i.e., a conventional memory intervention; MI) once a week for 10 weeks; 48 of the adults completed the intervention. Participants' verbal and visual memory functioning before and after the intervention were compared. In addition, changes in the participants' subjective feelings about their memory performance and physical and psychological health after the intervention were examined. The results showed that both the DMBI and MI resulted in significant improvements in both verbal and visual memory functioning and that the extent of the improvements was correlated with participants' level of performance at baseline. In addition, compared to the MI group, the DMBI group had significantly greater improvements in subjective physical and psychological health after the intervention. In summary, the present findings support the potential of the DMBI as an alternative lifestyle intervention for improving memory functioning, subjective physical and psychological health of older adults with SMC. PMID- 28659788 TI - Oscillatory Activities in Neurological Disorders of Elderly: Biomarkers to Target for Neuromodulation. AB - Non-invasive brain stimulation (NIBS) has been under investigation as adjunct treatment of various neurological disorders with variable success. One challenge is the limited knowledge on what would be effective neuronal targets for an intervention, combined with limited knowledge on the neuronal mechanisms of NIBS. Motivated on the one hand by recent evidence that oscillatory activities in neural systems play a role in orchestrating brain functions and dysfunctions, in particular those of neurological disorders specific of elderly patients, and on the other hand that NIBS techniques may be used to interact with these brain oscillations in a controlled way, we here explore the potential of modulating brain oscillations as an effective strategy for clinical NIBS interventions. We first review the evidence for abnormal oscillatory profiles to be associated with a range of neurological disorders of elderly (e.g., Parkinson's disease (PD), Alzheimer's disease (AD), stroke, epilepsy), and for these signals of abnormal network activity to normalize with treatment, and/or to be predictive of disease progression or recovery. We then ask the question to what extent existing NIBS protocols have been tailored to interact with these oscillations and possibly associated dysfunctions. Our review shows that, despite evidence for both reliable neurophysiological markers of specific oscillatory dis-functionalities in neurological disorders and NIBS protocols potentially able to interact with them, there are few applications of NIBS aiming to explore clinical outcomes of this interaction. Our review article aims to point out oscillatory markers of neurological, which are also suitable targets for modification by NIBS, in order to facilitate in future studies the matching of technical application to clinical targets. PMID- 28659790 TI - Aging Microglia-Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases. AB - Aging of the central nervous system (CNS) is one of the major risk factors for the development of neurodegenerative pathologies such as Parkinson's disease (PD) and Alzheimer's disease (AD). The molecular mechanisms underlying the onset of AD and especially PD are not well understood. However, neuroinflammatory responses mediated by microglia as the resident immune cells of the CNS have been reported for both diseases. The unique nature and developmental origin of microglia causing microglial self-renewal and telomere shortening led to the hypothesis that these CNS-specific innate immune cells become senescent. Age-dependent and senescence-driven impairments of microglia functions and responses have been suggested to play essential roles during onset and progression of neurodegenerative diseases. This review article summarizes the current knowledge of microglia phenotypes and functions in the aging CNS and further discusses the implications of these age-dependent microglia changes for the development and progression of AD and PD as the most common neurodegenerative diseases. PMID- 28659791 TI - Pentazocine Protects SN4741 Cells Against MPP+-Induced Cell Damage via Up Regulation of the Canonical Wnt/beta-Catenin Signaling Pathway. AB - The Wnt/beta-catenin signaling pathway has been linked to many neurodegenerative diseases including Parkinson's disease (PD). A glycoprotein named Dickkopf-1 (Dkk1) can combine with the receptor complex on cell membrane to inhibit Wnt/beta catenin signaling. Opioids, a series of compounds including morphine, fentanyl and pentazocine, have been reported to contribute to the up-regulation of Wnt/beta-catenin signaling. Naloxone is an antagonist that has been used as an antidote to opioids through mu-opioid receptor. 1-methyl-4-phenylpyridinium (MPP+), which serves as a selective toxin for dopaminergic neurons, has been used to create experimental models of PD. In our study, we examined the protective effects of pentazocine against MPP+-induced cell death in the nigral dopaminergic cell line, SN4741 and tried to elucidate the molecular mechanisms underlying such protective effects. The data showed that pretreatment with pentazocine significantly rescued the SN4741 cell against MPP+. Moreover, the MPP+-exposed SN4741 cells exhibited a down-regulation of beta-catenin, which could be restored by treatment with pentazocine. However, Dkk1 but not naloxonewas associated with the abrogation of protective effect of pentazocine. These results suggest that pentazocine alleviates MPP+-induced SN4741 cells apoptosis via the up-regulation of canonical Wnt/beta-catenin signaling. PMID- 28659792 TI - The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity-A Functional MRI Study in the Awake Rat. AB - The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients. PMID- 28659793 TI - Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin 1alpha and -1beta, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis. AB - Background: Innate immune response components such as toll-like receptors (TLRs) and NLRP3-inflammasome act in concert to increase IL-1alpha/beta secretion by synovial macrophages. Previous results suggest that IL-1alpha/beta could be an important mediator involved in the pathogenesis of osteoarthritis (OA). Objectives: The aim of our study was to evaluate the role of NLRP3, IL-1beta, and IL-1alpha in the menisectomy (MNX) model of murine OA. Methods: Murine chondrocytes (CHs) and bone marrow-derived machrophages (BMDM) were stimulated with hydroxyapatite (HA) crystals, a form of calcium-containing crystal found in human OA, and IL-1beta and IL-6 secretion assayed by ELISA.Conversely, the ability of IL-1beta and IL-6 to induce CHs calcification was assessed in vitro by Alizarin red staining. Knees from 8 to 10 weeks old C57Bl/6J wild-type (WT) (n = 7), NLRP3-/- (n = 9), IL-1alpha-/- (n = 5), and IL-1beta-/- (n = 5) mice were menisectomized, using the sham-operated contralateral knee as control. 8 weeks later, knee cartilage degradation and synovial inflammation were evaluated by histology. In addition, apoptotic chondrocytes, metalloproteases activity, and collagen-type 2 expression were evaluated in all mice. Joint calcification and subchondral bone parameters were quantified by CT-scan in WT and IL-1beta-/- menisectomized knees. Results:In vitro, HA crystals induced significant increased IL-6 secretion by CHs, while IL-1beta remained undetectable.Conversely, both IL-6 and IL-1beta were able to increase chondrocytes mineralization. In vivo, operated knees exhibited OA features compared to sham-operated knees as evidenced by increased cartilage degradation and synovial inflammation. In menisectomized KO mice, severity and extent of cartilage lesions were similar (IL-1alpha-/- mice) or exacerbated (IL-1beta-/- and NLRP3-/- mice) compared to that of menisectomized WT mice. Metalloproteases activity, collagen-type 2 expression, chondrocytes apoptosis, and synovial inflammation were similar between KO and WT mice menisectomized knees. Moreover, the extent of joint calcification in osteoarthritic knees was comparable between IL-1beta-/- and WT mice. Conclusions: MNX knees recapitulated features of OA, i.e, cartilage destruction, synovial inflammation, cell death, and joint calcification. Deficiency of IL-1alpha did not impact on the severity of these features, whereas deficiency of IL-1beta or of NLRP3 led to increased cartilage erosion. Our results suggest that IL-1alpha and IL-1beta are not key mediators in this murine OA model and may explain the inefficiency of IL-1 targeted therapies in OA. PMID- 28659794 TI - Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies. AB - Thymoquinone (TQ), the main bioactive component of Nigella sativa, has been found to exhibit anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Moreover, TQ can specifically sensitize tumor cells toward conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells. In this review, we summarized the adjuvant potential of TQ as observed in various in vitro and in vivo animal models and discussed the pharmacological properties of TQ to rationalize its supplementary role in potentiating the efficacy of standard therapeutic modalities namely surgery, radiotherapy, chemotherapy, and immunotherapy. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical levels to delineate its implied utility as a novel complementary adjuvant therapy for cancer treatment. PMID- 28659796 TI - Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is an acute leukemia common in most adults; its prevalence intensifies with age. The overall survival of AML is very poor because of therapeutic resistance. Azelaic acid (AZA) is non-toxic, non-teratogenic, and non-mutagenic and its antitumor effect on various tumor cells is well established; Nonetheless, its therapeutic effects in AML cells are largely unknown. In this study, it was shown that AZA significantly inhibits the cell viability and induces apoptosis in AML cells in a dose-dependent manner. Additionally, AZA suppressed the expression of phosphorylated Akt, Jab1 and Trx, and this suppression was enhanced by treatment with Jab1 siRNA. Furthermore, AZA sensitized AML cells to Ara-c chemotherapy. The suppressive effect of AZA on tumor growth was examined in vivo by subcutaneously inoculated AML cells in a tumor model using nude mice. These findings indicate that AZA is useful as an effective ingredient in antineoplastic activity. PMID- 28659795 TI - Exosomes: A Novel Strategy for Treatment and Prevention of Diseases. AB - An "exosome" is a nanoscale membrane vesicle derived from cell endocytosis that functions as an important intercellular communication mediator regulating the exchange of proteins and genetic materials between donor and surrounding cells. Exosomes secreted by normal and cancer cells participate in tumor initiation, progression, invasion, and metastasis. Furthermore, immune cells and cancer cells exert a two-way bidirectional regulatory effect on tumor immunity by exchanging exosomes. Current studies on exosomes have further expanded their known functions in physiological and pathological processes. The purpose of this review is to describe their discovery and biological functions in the context of their enormous potential in the clinical diagnosis, prevention, and treatment of cancer as well as bacterial and viral infectious diseases. PMID- 28659797 TI - Specific Combination of Salvianolic Acids As Core Active Ingredients of Danhong Injection for Treatment of Arterial Thrombosis and Its Derived Dry Gangrene. AB - Although single-targeting anti-platelet agents are used extensively in clinics, their limitations in resistance and bleeding have started a trend of combination therapy. Danhong injection (DHI) is a widely prescribed injection medicine for cardiovascular and cerebrovascular diseases in China. However, its precise clinical efficacy and functional components remain unexplored. In this study, we investigated the anti-thrombotic role and its chemical basis of DHI. In a photochemically-induced thrombosis model, DHI effectively dissolved thrombus and ameliorated its derived dry gangrene. DHI inhibited multiple GPCR agonists induced platelet adhesion, aggregation and downstream Ca2+ and cAMP signaling pathways. A functional screen of DHI library identified its major active components as a cluster of seven salvianolic acids. A combination of salvianolic acid A and C synergistically inhibited platelet aggregation in vitro while salvianolic acid B antagonized this effect. Our study revealed the anti thrombotic activity of DHI. The multi-targeting mechanism of DHI proves the effectiveness of a natural anti-thrombotic combination therapy. The identification of salvianolic acids as a core anti-thrombotic activity of DHI and the discovery that their different combinations could either synergistically or antagonistically provide a better guidance for safer clinical application and paves the way for further development of DHI. PMID- 28659798 TI - IL-1beta Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus. AB - Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of beta-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1beta, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL 1beta. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1beta inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1beta inhibitors as novel therapeutic tools for treating these patients. PMID- 28659800 TI - Socioeconomic Factors Associated with Psychoactive Substance Abuse by Adolescents in Serbia. PMID- 28659799 TI - Antimicrobial Activity and Resistance: Influencing Factors. AB - Rational use of antibiotic is the key approach to improve the antibiotic performance and tackling of the antimicrobial resistance. The efficacy of antimicrobials are influenced by many factors: (1) bacterial status (susceptibility and resistance, tolerance, persistence, biofilm) and inoculum size; (2) antimicrobial concentrations [mutant selection window (MSW) and sub inhibitory concentration]; (3) host factors (serum effect and impact on gut micro biota). Additional understandings regarding the linkage between antimicrobial usages, bacterial status and host response offers us new insights and encourage the struggle for the designing of antimicrobial treatment regimens that reaching better clinical outcome and minimizing the emergence of resistance at the same time. PMID- 28659801 TI - Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis. AB - Tyrosine kinase inhibitors (TKIs) are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1-100 MUM) for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis), all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism), imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib), and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism. PMID- 28659802 TI - Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study. AB - Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD). Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity. Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot's score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment. PMID- 28659803 TI - Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia. AB - Indoxyl sulfate (IS) is a protein-bound uremic toxin resulting from the metabolism of dietary tryptophan which accumulates in patients with impaired renal function, such as chronic kidney disease (CKD). IS is a well-known nephrovascular toxin but little is known about its effects on central nervous system (CNS) cells. Considering the growing interest in the field of CNS comorbidities in CKD, we studied the effect of IS on CNS cells. IS (15-60 MUM) treatment in C6 astrocyte cells increased reactive oxygen species release and decreased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, and heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 expression. Moreover, IS increased Aryl hydrocarbon Receptor (AhR) and Nuclear Factor-kB (NF-kB) activation in these cells. Similiar observations were made in primary mouse astrocytes and mixed glial cells. Inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression, tumor necrosis factor-alpha and interleukin 6 release and nitrotyrosine formation were increased by IS (15-60 MUM) in primary mouse astrocytes and mixed glial cells. IS increased AhR and NF-kB nuclear translocation and reduced Nrf2 translocation and HO-1 expression in primary glial cells. In addition, IS induced cell death in neurons in a dose dependent fashion. Injection of IS (800 mg/kg, i.p.) into mice induced histological changes and increased COX-2 expression and nitrotyrosine formation in thebrain tissue. Taken together, our results show a significant contribution of IS in generating a neurotoxic enviroment and it could also have a potential role in neurodegeneration. IS could be considered also a potential therapeutical target for CKD-associated neurodegenerative complications. PMID- 28659804 TI - In Vitro Antiproliferative Activity of Extracts of Carlina acaulis subsp. caulescens and Carlina acanthifolia subsp. utzka. AB - Various species of the Carlina genus have been used in traditional medicine in many countries to treat numerous skin disorders, including cancer. The objective of this work was to assess the anticancer properties of root and leaf extracts from Carlina acaulis subsp. caulescens and C. acanthifolia subsp. utzka. Anti tumor properties of the extracts were explored using a tetrazolium-based cell viability assay and flow cytometric apoptosis analysis, followed by immunodetection of phosphoactive ERK1/2 in UACC-903, C32, and UACC-647 human melanoma cell lines. Normal human fibroblasts were used as a control. Leaf extracts inhibited the viability of all tested melanoma cell lines in a dose dependent fashion while the fibroblasts were less sensitive to such extract. The root extracts inhibited the proliferation of UACC-903 and UACC-647 cells only at the highest doses (300 MUg/mL). However, the C32 and fibroblast cells exhibited an increase in the cellular proliferation rate and no caspase activity was observed in response to the root extracts (100 MUg/mL). An increase in caspase activity was observed in melanoma cells treated with the leaf extracts of both Carlina species. Leaf extracts from C. acaulis subsp. caulescens (100 MUg/mL) inhibited proliferatory ERK1/2 in UACC-903 and C32 cells, as demonstrated by the decrease in ERK1/2 phosphorylation. No reduction in phospho-ERK1/2 was observed in the tested cell lines treated with the root extracts, apart from UACC-647 after incubation with the C. acanthifolia subsp. utzka root extract (100 MUg/mL). There was no change in ERK1/2 phosphorylation in the fibroblasts. The extracts from the leaves and roots were analyzed by HPLC and the analysis showed the presence of triterpenes and phenolic acids as the main extract components. The research demonstrated that the extracts from the leaves of the plants were cytotoxic against the human melanoma line and induced apoptosis of the cells. The triterpene fraction present in the tested extracts may be responsible for this activity. PMID- 28659805 TI - Statins and New-Onset Diabetes Mellitus: LDL Receptor May Provide a Key Link. AB - Numerous studies have noted that populations treated with statins have increased risk for new-onset diabetes mellitus; however, the underlying molecular mechanisms are not fully understood. Interestingly, familial hypercholesterolemia (FH) patients with mutations in the low-density lipoprotein receptor (LDLR) gene are protected against diabetes mellitus (DM), despite these patients being subjected to long-term statin therapy. Since the common pathway between FH and statin therapy is LDLR-mediated cellular cholesterol uptake, the arising question is whether the LDLR plays an important role in the diabetogenic effect of statins. Indeed, given that statins can regulate the LDLR expression in liver and peripheral tissue, there is a possible mechanism that the increased LDLR causes cellular cholesterol accumulation and dysfunction in pancreatic islets, explaining why statins fail to increase the risk of DM in FH patients. In this paper, with regarded to recent literatures, we highlight the role of LDLR in the pathophysiology of cholesterol-induced pancreatic islets dysfunction, which may provide the key link between statins treatment and the increased risk of new onset diabetes mellitus. PMID- 28659806 TI - Erythrodiol, an Olive Oil Constituent, Increases the Half-Life of ABCA1 and Enhances Cholesterol Efflux from THP-1-Derived Macrophages. AB - Cholesterol efflux (ChE) from macrophages is an initial step of reverse cholesterol transport (RCT). The ATP-binding cassette transporter A1 (ABCA1) is a key transporter for ChE and its increased expression is regarded to attenuate atherosclerosis. Thus, the identification and characterization of molecules raising ABCA1 and thereby stimulating ChE is of pharmacological relevance. In this study, we tested dietary compounds from olive oil for their capacity of enhancing cellular ABCA1 protein level. We identified erythrodiol (Olean-12-ene 3beta,28-diol) as an ABCA1 stabilizer and revealed its positive influence on ChE in THP-1-derived human macrophages. Among the nine tested compounds from olive oil, erythrodiol was the sole compound raising ABCA1 protein level (at 10 MUM). None of the tested compounds impaired viability of THP-1 macrophages from 5 to 20 MUM as determined by resazurin conversion. Western blot analyses of key membrane transporters contributing to ChE showed that the protein level of ABCG1 and scavenger receptor class B member 1 (SR-B1) remain unaffected by erythrodiol. Besides, erythrodiol (10 MUM) did not influence the mRNA level of ABCA1, ABCG1, and SR-B1, as determined by quantitative reverse transcription PCR, but significantly inhibited the degradation of ABCA1 as evident by an increased half life of the protein in the presence of cycloheximide, an inhibitor of de novo protein synthesis. Therefore, erythrodiol promotes ChE from THP-1-derived human macrophages by stabilizing the ABCA1 protein. This bioactivity makes erythrodiol a good candidate to be further explored for therapeutic or preventive application in the context of atherosclerosis. PMID- 28659808 TI - Expression of Concern: Topical Ophthalmic Formulation of Trichostatin A and SurR9 C84A for Quick Recovery Post-alkali Burn of Corneal Haze. PMID- 28659807 TI - Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings. AB - Although arctigenin (AG) has diverse bioactivities, such as anti-oxidant, anti inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug delivery manners, including intravenous (i.v), hypodermic injection (i.h), and sublingual (s.l) administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h), a high absorption degree (absolute bioavailability > 100%), and a strong elimination ability (t1/2 < 2 h). The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak) and wide (detectable in almost all tissues and organs). The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro, AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min). The percentages of AG remaining in four species' liver microsomes were human (62 +/- 6.36%) > beagle dog (25.9 +/- 3.24%) > rat (15.7 +/- 9%) > monkey (3.69 +/- 0.12%). This systematic investigation of pharmacokinetic profiles of arctigenin (AG) in vivo and in vitro is worthy of further exploration. PMID- 28659809 TI - Corrigendum: High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated with Mitochondrial Abnormalities. AB - [This corrects the article on p. 275 in vol. 8, PMID: 28559847.]. PMID- 28659810 TI - Expression, Localization of SUMO-1, and Analyses of Potential SUMOylated Proteins in Bubalus bubalis Spermatozoa. AB - Mature spermatozoa have highly condensed DNA that is essentially silent both transcriptionally and translationally. Therefore, post translational modifications are very important for regulating sperm motility, morphology, and for male fertility in general. Protein sumoylation was recently demonstrated in human and rodent spermatozoa, with potential consequences for sperm motility and DNA integrity. We examined the expression and localization of small ubiquitin related modifier-1 (SUMO-1) in the sperm of water buffalo (Bubalus bubalis) using immunofluorescence analysis. We confirmed the expression of SUMO-1 in the acrosome. We further found that SUMO-1 was lost if the acrosome reaction was induced by calcium ionophore A23187. Proteins modified or conjugated by SUMO-1 in water buffalo sperm were pulled down and analyzed by mass spectrometry. Sixty proteins were identified, including proteins important for sperm morphology and motility, such as relaxin receptors and cytoskeletal proteins, including tubulin chains, actins, and dyneins. Forty-six proteins were predicted as potential sumoylation targets. The expression of SUMO-1 in the acrosome region of water buffalo sperm and the identification of potentially SUMOylated proteins important for sperm function implicates sumoylation as a crucial PTM related to sperm function. PMID- 28659811 TI - Resolving Ambiguities in the LF/HF Ratio: LF-HF Scatter Plots for the Categorization of Mental and Physical Stress from HRV. AB - It is generally accepted that the activities of the autonomic nervous system (ANS), which consists of the sympathetic (SNS) and parasympathetic nervous systems (PNS), are reflected in the low- (LF) and high-frequency (HF) bands in heart rate variability (HRV)-while, not without some controversy, the ratio of the powers in those frequency bands, the so called LF-HF ratio (LF/HF), has been used to quantify the degree of sympathovagal balance. Indeed, recent studies demonstrate that, in general: (i) sympathovagal balance cannot be accurately measured via the ratio of the LF- and HF- power bands; and (ii) the correspondence between the LF/HF ratio and the psychological and physiological state of a person is not unique. Since the standard LF/HF ratio provides only a single degree of freedom for the analysis of this 2D phenomenon, we propose a joint treatment of the LF and HF powers in HRV within a two-dimensional representation framework, thus providing the required degrees of freedom. By virtue of the proposed 2D representation, the restrictive assumption of the linear dependence between the activity of the autonomic nervous system (ANS) and the LF-HF frequency band powers is demonstrated to become unnecessary. The proposed analysis framework also opens up completely new possibilities for a more comprehensive and rigorous examination of HRV in relation to physical and mental states of an individual, and makes possible the categorization of different stress states based on HRV. In addition, based on instantaneous amplitudes of Hilbert-transformed LF- and HF-bands, a novel approach to estimate the markers of stress in HRV is proposed and is shown to improve the robustness to artifacts and irregularities, critical issues in real-world recordings. The proposed approach for resolving the ambiguities in the standard LF/HF-ratio analyses is verified over a number of real-world stress-invoking scenarios. PMID- 28659812 TI - Strength Training Decreases Inflammation and Increases Cognition and Physical Fitness in Older Women with Cognitive Impairment. AB - Introduction: Cognitive impairment that affects older adults is commonly associated with an inflammatory imbalance, resulting in decreased physical fitness. Exercise has been pointed to mitigate immunosenescence and cognitive impairment associated with aging, while increase in physical fitness. However, few studies explored the relationship between changes in cytokine concentration and improvement on cognition due to elastic band strength training. The aim of this study was to investigate the effects of strength training on pro-and anti inflammatory cytokines, hematological markers and physical fitness of older women with cognitive impairment. Methods: Thirty-three women (82.7 +/- 5.7 years old) participated in the study and were divided in two groups: strength exercise training group (ST; n = 16) and Control Group (CG; n = 17) and were evaluated before and after 28 weeks of the exercise program. The CG did not undergo any type of exercise programs. Data for IL-10, TNF-alpha, IFN-gamma, C-Reactive Protein (CRP), white blood counts (WBC), red blood counts (RBC), Mini Mental State Examination (MMSE) and physical fitness tests were analyzed in both moments. Results: IL-10 increased in the ST group without changes in CG. TNF alpha and CRP increased in the control group while no changes were observed for IFN-gamma in both groups. Strength training decreased leukocyte and lymphocyte counts and increase hemoglobin, mean cell volume and mean cell hemoglobin concentration. The MMSE score increased in strength training group but remained unchanged in the control group. A correlation between the variation of granulocyte counts and the MMSE scores was also observed within the total sample. An improvement in physical fitness was observed with strength training. Conclusion: Resistance exercise promoted better anti-inflammatory balance and physical performance simultaneously with an increase in cognitive profile in older women with cognitive impairment. PMID- 28659813 TI - Human Peritoneal Mesothelial Cell Death Induced by High-Glucose Hypertonic Solution Involves Ca2+ and Na+ Ions and Oxidative Stress with the Participation of PKC/NOX2 and PI3K/Akt Pathways. AB - Chronic peritoneal dialysis (PD) therapy is equally efficient as hemodialysis while providing greater patient comfort and mobility. Therefore, PD is the treatment of choice for several types of renal patients. During PD, a high glucose hyperosmotic (HGH) solution is administered into the peritoneal cavity to generate an osmotic gradient that promotes water and solutes transport from peritoneal blood to the dialysis solution. Unfortunately, PD has been associated with a loss of peritoneal viability and function through the generation of a severe inflammatory state that induces human peritoneal mesothelial cell (HPMC) death. Despite this deleterious effect, the precise molecular mechanism of HPMC death as induced by HGH solutions is far from being understood. Therefore, the aim of this study was to explore the pathways involved in HGH solution-induced HPMC death. HGH-induced HPMC death included influxes of intracellular Ca2+ and Na+. Furthermore, HGH-induced HPMC death was inhibited by antioxidant and reducing agents. In line with this, HPMC death was induced solely by increased oxidative stress. In addition to this, the cPKC/NOX2 and PI3K/Akt intracellular signaling pathways also participated in HGH-induced HPMC death. The participation of PI3K/Akt intracellular is in agreement with previously shown in rat PMC apoptosis. These findings contribute toward fully elucidating the underlying molecular mechanism mediating peritoneal mesothelial cell death induced by high glucose solutions during peritoneal dialysis. PMID- 28659815 TI - Multi-Level Integration of Environmentally Perturbed Internal Phenotypes Reveals Key Points of Connectivity between Them. AB - The genotype and external phenotype of organisms are linked by so-called internal phenotypes which are influenced by environmental conditions. In this study, we used five existing -omics datasets representing five different layers of internal phenotypes, which were simultaneously measured in dietarily perturbed mice. We performed 10 pair-wise correlation analyses verified with a null model built from randomized data. Subsequently, the inferred networks were merged and literature mined for co-occurrences of identified linked nodes. Densely connected internal phenotypes emerged. Forty-five nodes have links with all other data-types and we denote them "connectivity hubs." In literature, we found proof of 6% of the 577 connections, suggesting a biological meaning for the observed correlations. The observed connectivities between metabolite and cytokines hubs showed higher numbers of literature hits as compared to the number of literature hits on the connectivities between the microbiota and gene expression internal phenotypes. We conclude that multi-level integrated networks may help to generate hypotheses and to design experiments aiming to further close the gap between genotype and phenotype. We describe and/or hypothesize on the biological relevance of four identified multi-level connectivity hubs. PMID- 28659814 TI - Crosstalk between Photoreceptor and Sugar Signaling Modulates Floral Signal Transduction. AB - Over the past decade, integrated genetic, cellular, proteomic and genomic approaches have begun to unravel the surprisingly crosstalk between photoreceptors and sugar signaling in regulation of floral signal transduction. Although a number of physiological factors in the pathway have been identified, the molecular genetic interactions of some components are less well understood. The further elucidation of the crosstalk mechanisms between photoreceptors and sugar signaling will certainly contribute to our better understanding of the developmental circuitry that controls floral signal transduction. This article summarizes our current knowledge of this crosstalk, which has not received much attention, and suggests possible directions for future research. PMID- 28659816 TI - Cardioprotective Effects of SIRT6 in a Mouse Model of Transverse Aortic Constriction-Induced Heart Failure. AB - SIRT6, a member of the NAD (+)-dependent class III deacetylase sirtuin family, plays important roles in the maintenance of cardiovascular homeostasis. Telomere shortening is a risk factor for age-associated diseases, including heart disease. In the present study, we investigated the role of SIRT6 and telomerase in a mouse model of transverse aortic constriction (TAC)-induced heart failure. SIRT6, telomerase reverse transcriptase (TERT), and telomere repeat binding factor (TRF) 1 were significantly downregulated in TAC mice compared with their expression in sham-operated mice. Lentiviral vector-mediated overexpression of SIRT6 upregulated TERT and TRF1 and increased the survival of mice after TAC. Echocardiography and hemodynamic measurements as well as histological analyses indicated that SIRT6 overexpression attenuated TAC-induced heart dysfunction and decreased TAC-induced cardiac inflammatory responses, reducing cardiac fibrosis and decreasing infarct size. Taken together, our findings indicate that SIRT6 protects the myocardium against damage and this effect may be mediated by the modulation of telomeres. Our findings linking SIRT6 and telomere integrity in the heart warrant further investigation into the underlying mechanisms and support SIRT6 as a promising therapeutic target for the treatment of cardiovascular diseases. PMID- 28659817 TI - Cobalt Chloride Upregulates Impaired HIF-1alpha Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats. AB - Previous studies from our group have demonstrated that sevoflurane post conditioning (SPC) protects against myocardial ischemia reperfusion injury via elevating the intranuclear expression of hypoxia inducible factor-1 alpha (HIF 1alpha). However, diabetic SPC is associated with decreased myocardial protection and disruption of the HIF-1 signaling pathway. Previous studies have demonstrated that cobalt chloride (CoCl2) can upregulate HIF-1alpha expression under diabetic conditions, but whether myocardial protection by SPC can be restored afterward remains unclear. We established a rat model of type 2 diabetes and a Langendorff isolated heart model of ischemia-reperfusion injury. Prior to reperfusion, 2.4% sevoflurane was used as a post-conditioning treatment. The diabetic rats were treated with CoCl2 24 h before the experiment. At the end of reperfusion, tests were performed to assess myocardial function, infarct size, mitochondrial morphology, nitric oxide (NO), Mitochondrial reactive oxygen species (ROS), mitochondrial respiratory function and enzyme activity, HIF-1alpha, vascular endothelial growth factor (VEGF) and endothelial NO synthase (eNOS) protein levels. In addition, myocardial protection by SPC was monitored after the blood glucose levels were lowered by insulin. The diabetic state was associated with deficient SPC protection and decreased HIF-1alpha expression. After treating the diabetic rats with CoCl2, SPC significantly upregulated the expression of HIF 1alpha, VEGF and eNOS, which markedly improved cardiac function, NO, mitochondrial respiratory function, and enzyme activity and decreased the infarction areas and ROS. In addition, these effects were not influenced by blood glucose levels. This study proved that CoCl2activates the HIF-1alpha signaling pathway, which restores SPC-dependent myocardial protection under diabetic conditions, and the protective effects of SPC were independent of blood glucose levels. PMID- 28659818 TI - Managing Thoracic Aortic Aneurysm in Patients with Bicuspid Aortic Valve Based on Aortic Root-Involvement. AB - Bicuspid aortic valve (BAV) can be both sporadic and hereditary, is phenotypically variable, and genetically heterogeneous. The clinical presentation of BAV is diverse and commonly associated with a high prevalence of valvular dysfunction producing altered hemodynamics and aortic abnormalities (e.g., aneurysm and dissection). The thoracic aortic aneurysm (TAA) in BAV frequently involves the proximal aorta, including the aortic root, ascending aorta, and aortic arch, but spares the aorta distal to the aortic arch. While the ascending aortic aneurysm might be affected by both aortopathy and hemodynamics, the aortic root aneurysm is considered to be more of a consequence of aortopathy rather than hemodynamics, especially in younger patients. The management of aortic aneurysm in BAV has been very controversial because the molecular mechanism is unknown. Increasing evidence points toward the BAV root phenotype [aortic root dilation with aortic insufficiency (AI)] as having a higher risk of catastrophic aortic complications. We propose more aggressive surgical approaches toward the BAV with root phenotype. PMID- 28659819 TI - Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta. AB - Amelogenesis imperfecta (AI) designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene (MMP20) produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues), pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI. PMID- 28659822 TI - Visual Ecology and the Development of Visually Guided Behavior in the Cuttlefish. AB - Cuttlefish are highly visual animals, a fact reflected in the large size of their eyes and visual-processing centers of their brain. Adults detect their prey visually, navigate using visual cues such as landmarks or the e-vector of polarized light and display intense visual patterns during mating and agonistic encounters. Although much is known about the visual system in adult cuttlefish, few studies have investigated its development and that of visually-guided behavior in juveniles. This review summarizes the results of studies of visual development in embryos and young juveniles. The visual system is the last to develop, as in vertebrates, and is functional before hatching. Indeed, embryonic exposure to prey, shelters or complex background alters postembryonic behavior. Visual acuity and lateralization, and polarization sensitivity improve throughout the first months after hatching. The production of body patterning in juveniles is not the simple stimulus-response process commonly presented in the literature. Rather, it likely requires the complex integration of visual information, and is subject to inter-individual differences. Though the focus of this review is vision in cuttlefish, it is important to note that other senses, particularly sensitivity to vibration and to waterborne chemical signals, also play a role in behavior. Considering the multimodal sensory dimensions of natural stimuli and their integration and processing by individuals offer new exciting avenues of future inquiry. PMID- 28659821 TI - Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. AB - Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter >= 4.0 cm in adults, or a Z-score >= 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype. PMID- 28659823 TI - Assessment of Exercise Capacity and Oxygen Consumption Using a 6 min Stepper Test in Older Adults. AB - It is often necessary to assess physical function in older adults to monitor disease progression, rehabilitation or decline in function with age. However, increasing frailty and poor balance that accompany aging are common barriers to exercise testing protocols. We investigated whether a 6-min stepper test (6MST) was acceptable to older adults and provided a measure of exercise capacity and a predicted value for peak aerobic capacity (VO2max). 635 older adults from a tri ethnic UK population-based cohort were screened to undertake a self-paced 6MST. Expired gas analysis, heart rate and blood pressure monitoring were carried out. A sub-set of 20 participants performed a second 6MST for assessment of reproducibility and a further sub-set of 10 performed the 6-min walk test as verification against a well-recognized and accepted self-paced exercise test. 518 (82%) participants met inclusion criteria and undertook the 6MST (299 men, mean age 71.2 +/- 6.4). Step rate showed a strong positive correlation with measured VO2 (r = 0.75, p < 0.001) and VO2 was lower in women (male-female difference in VO2 = 2.61 (95% confidence interval -3.6, -1.7) ml/min/kg; p < 0.001). 20 participants repeated a 6MST, step rate was higher in the second test but the predicted VO2max showed good agreement (mean difference = 0.1 [3.72, 3.95] ml/min/kg). In 10 participants who completed a 6MST and a 6-min walk test there was a strong positive correlation between walking rate and step rate (r = 0.77; p < 0.009) and weaker positive correlations between the tests for measured VO2 and peak heart rate. In conclusion, the 6MST is a convenient, acceptable method of assessing exercise capacity in older adults that allows VO2max to be predicted reproducibly. The test shows good correlation between performance and measured physiological markers of performance and can detect the expected gender differences in measured VO2. Furthermore, the 6MST results correlate with a previously verified and established self-paced exercise test. PMID- 28659820 TI - Viral Delivery of dsRNA for Control of Insect Agricultural Pests and Vectors of Human Disease: Prospects and Challenges. AB - RNAi is applied as a new and safe method for pest control in agriculture but efficiency and specificity of delivery of dsRNA trigger remains a critical issue. Various agents have been proposed to augment dsRNA delivery, such as engineered micro-organisms and synthetic nanoparticles, but the use of viruses has received relatively little attention. Here we present a critical view of the potential of the use of recombinant viruses for efficient and specific delivery of dsRNA. First of all, it requires the availability of plasmid-based reverse genetics systems for virus production, of which an overview is presented. For RNA viruses, their application seems to be straightforward since dsRNA is produced as an intermediate molecule during viral replication, but DNA viruses also have potential through the production of RNA hairpins after transcription. However, application of recombinant virus for dsRNA delivery may not be straightforward in many cases, since viruses can encode RNAi suppressors, and virus-induced silencing effects can be determined by the properties of the encoded RNAi suppressor. An alternative is virus-like particles that retain the efficiency and specificity determinants of natural virions but have encapsidated non-replicating RNA. Finally, the use of viruses raises important safety issues which need to be addressed before application can proceed. PMID- 28659824 TI - Hypersensitivity of Vagal Pulmonary Afferents Induced by Tumor Necrosis Factor Alpha in Mice. AB - Tumor necrosis factor alpha (TNFalpha), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFalpha also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFalpha caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFalpha on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFalpha (10 MUg/ml, 0.03 ml) and vehicle (Veh; phosphate buffered saline (PBS), 0.03 ml) were administered by intra-tracheal instillation in each mouse of treated (TNF) and control (Veh) groups, respectively, the peak activity of pulmonary C-fibers in response to an intravenous bolus injection of a low dose of capsaicin (Cap; 0.5 MUg/kg) was significantly elevated in TNF group (6.5 +/- 1.3 impulses/s, n = 12) 24-48 h later, compared to that in Veh group (2.2 +/- 0.5 impulses/s, n = 11; P < 0.05). Interestingly, the same low dose of Cap injection also evoked a distinct burst of discharge (2.4 +/- 0.7 impulses/s) in 75% of the silent rapidly adapting receptors (RARs), a subtype of RARs exhibiting no phasic activity, in TNF group, but did not stimulate any of the silent RARs in Veh group. To further determine if this sensitizing effect involves a direct action of TNFalpha on these sensory nerves, the change in intracellular Ca2+ concentration in response to Cap challenge was measured in isolated mouse vagal pulmonary sensory neurons. The Cap-evoked Ca2+ influx was markedly enhanced in the neurons incubated with TNFalpha (50 ng/ml) for ~24 h, and this sensitizing effect was attenuated in the neurons isolated from the TNF-receptor double homozygous mutant mice. In conclusion, the TNFalpha pretreatment enhanced the Cap sensitivity in both pulmonary C-fibers and silent RARs, and the action was mediated through TNF receptors. These sensitizing effects of TNFalpha may contribute, at least in part, to the pathogenesis of airway hyperresponsiveness induced by this cytokine. PMID- 28659825 TI - Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew). AB - Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pK b values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1 Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrally-located H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control. PMID- 28659826 TI - No Additional Benefits of Block- Over Evenly-Distributed High-Intensity Interval Training within a Polarized Microcycle. AB - Introduction: The current study aimed to investigate the responses to block- versus evenly-distributed high-intensity interval training (HIT) within a polarized microcycle. Methods: Twenty well-trained junior cross-country skiers (10 males, age 17.6 +/- 1.5 and 10 females, age 17.3 +/- 1.5) completed two, 3 week periods of training (EVEN and BLOCK) in a randomized, crossover-design study. In EVEN, 3 HIT sessions (5 * 4-min of diagonal-stride roller-skiing) were completed at a maximal sustainable intensity each week while low-intensity training (LIT) was distributed evenly around the HIT. In BLOCK, the same 9 HIT sessions were completed in the second week while only LIT was completed in the first and third weeks. Heart rate (HR), session ratings of perceived exertion (sRPE), and perceived recovery (pREC) were recorded for all HIT and LIT sessions, while distance covered was recorded for each HIT interval. The recovery-stress questionnaire for athletes (RESTQ-Sport) was completed weekly. Before and after EVEN and BLOCK, resting saliva and muscle samples were collected and an incremental test and 600-m time-trial (TT) were completed. Results: Pre- to post testing revealed no significant differences between EVEN and BLOCK for changes in resting salivary cortisol, testosterone, or IgA, or for changes in muscle capillary density, fiber area, fiber composition, enzyme activity (CS, HAD, and PFK) or the protein content of VEGF or PGC-1alpha. Neither were any differences observed in the changes in skiing economy, [Formula: see text] or 600-m time trial performance between interventions. These findings were coupled with no significant differences between EVEN and BLOCK for distance covered during HIT, summated HR zone scores, total sRPE training load, overall pREC or overall recovery-stress state. However, 600-m TT performance improved from pre- to post training, irrespective of intervention (P = 0.003), and a number of hormonal and muscle biopsy markers were also significantly altered post-training (P < 0.05). Discussion: The current study shows that well-trained junior cross-country skiers are able to complete 9 HIT sessions within 1 week without compromising total work done and without experiencing greater stress or reduced recovery over a 3-week polarized microcycle. However, the findings do not support block-distributed HIT as a superior method to a more even distribution of HIT in terms of enhancing physiological or performance adaptions. PMID- 28659827 TI - Increased Postnatal Cardiac Hyperplasia Precedes Cardiomyocyte Hypertrophy in a Model of Hypertrophic Cardiomyopathy. AB - Rationale: Hypertrophic cardiomyopathy (HCM) occurs in ~0.5% of the population and is a leading cause of sudden cardiac death (SCD) in young adults. Cardiomyocyte hypertrophy has been the accepted mechanism for cardiac enlargement in HCM, but the early signaling responsible for initiating hypertrophy is poorly understood. Mutations in cardiac myosin binding protein C (MYBPC3) are among the most common HCM-causing mutations. Ablation of Mybpc3 in an HCM mouse model (cMyBP-C-/-) rapidly leads to cardiomegaly by postnatal day (PND) 9, though hearts are indistinguishable from wild-type (WT) at birth. This model provides a unique opportunity to explore early processes involved in the dramatic postnatal transition to hypertrophy. Methods and Results: We performed microarray analysis, echocardiography, qPCR, immunohistochemistry (IHC), and isolated cardiomyocyte measurements to characterize the perinatal cMyBP-C-/- phenotype before and after overt hypertrophy. cMyBP-C-/- hearts showed elevated cell cycling at PND1 that transitioned to hypertrophy by PND9. An expanded time course revealed that increased cardiomyocyte cycling was associated with elevated heart weight to body weight ratios prior to cellular hypertrophy, suggesting that cell cycling resulted in cardiomyocyte proliferation. Animals heterozygous for the cMyBP-C deletion trended in the direction of the homozygous null, yet did not show increased heart size by PND9. Conclusions: Results indicate that altered regulation of the cell cycling pathway and elevated proliferation precedes hypertrophy in the cMyBP-C-/- HCM model, and suggests that increased cardiomyocyte number contributes to increased heart size in cMyBP-C-/- mice. This pre-hypertrophic period may reflect a unique time during which the commitment to HCM is determined and disease severity is influenced. PMID- 28659828 TI - Formal Modeling of mTOR Associated Biological Regulatory Network Reveals Novel Therapeutic Strategy for the Treatment of Cancer. AB - Cellular homeostasis is a continuous phenomenon that if compromised can lead to several disorders including cancer. There is a need to understand the dynamics of cellular proliferation to get deeper insights into the prevalence of cancer. Mechanistic Target of Rapamycin (mTOR) is implicated as the central regulator of the metabolic pathway involved in growth whereas its two distinct complexes mTORC1 and mTORC2 perform particular functions in cellular propagation. To date, mTORC1 is a well defined therapeutic target to inhibit uncontrolled cell division, while the role of mTORC2 is not well characterized. Therefore, the current study is designed to understand the signaling dynamics of mTOR and its partner proteins such as PI3K, PTEN, mTORC2, PKB (Akt), mTORC1, and FOXO. For this purpose, a qualitative model of mTOR-associated Biological Regulatory Network (BRN) is constructed to predict its regulatory behaviors which may not be predictable otherwise. The depleted expression of PTEN and FOXO along with the overexpression of PI3K, mTORC2, mTORC1 and Akt is predicted as a stable steady state which is in accordance with their observed expression levels in the progression of various cancers. The qualitative model also predicts the homeostasis of all the entities in the form of qualitative cycles. The significant qualitative (discrete) cycle is identified by analyzing betweenness centralities of the qualitative (discrete) states. This cycle is further refined as a linear hybrid automaton model with the production (activation) and degradation (inhibition) time delays in order to analyze the real-time constraints for its existence. The analysis of the hybrid model provides a formal proof that during homeostasis the inhibition time delay of Akt is less than the inhibition time delay of mTORC2. In conclusion, our observations characterize that in homeostasis Akt is degraded with a faster rate than mTORC2 which suggests that the inhibition of Akt along with the activation of mTORC2 may be a better therapeutic strategy for the treatment of cancer. PMID- 28659829 TI - Risk-Conferring Glutamatergic Genes and Brain Glutamate Plus Glutamine in Schizophrenia. AB - BACKGROUND: The proton magnetic resonance spectroscopy (1H-MRS) signals from glutamate (or the combined glutamate and glutamine signal-Glx) have been found to be greater in various brain regions in people with schizophrenia. Recently, the Psychiatric Genetics Consortium reported that several common single-nucleotide polymorphisms (SNPs) in glutamate-related genes confer increased risk of schizophrenia. Here, we examined the relationship between presence of these risk polymorphisms and brain Glx levels in schizophrenia. METHODS: 1H-MRS imaging data from an axial, supraventricular tissue slab were acquired in 56 schizophrenia patients and 67 healthy subjects. Glx was measured in gray matter (GM) and white matter (WM) regions. The genetic data included six polymorphisms genotyped across an Illumina 5M SNP array. Only three of six glutamate as well as calcium-related SNPs were available for examination. These included three glutamate-related polymorphisms (rs10520163 in CLCN3, rs12704290 in GRM3, and rs12325245 in SLC38A7), and three calcium signaling polymorphisms (rs1339227 in RIMS1, rs7893279 in CACNB2, and rs2007044 in CACNA1C). Summary risk scores for the three glutamate and the three calcium polymorphisms were calculated. RESULTS: Glx levels in GM positively correlated with glutamate-related genetic risk score but only in younger (<=36 years) schizophrenia patients (p = 0.01). Glx levels did not correlate with calcium risk scores. Glx was higher in the schizophrenia group compared to levels in controls in GM and WM regardless of age (p < 0.001). CONCLUSION: Elevations in brain Glx are in part, related to common allelic variants of glutamate-related genes known to increase the risk for schizophrenia. Since the glutamate risk scores did not differ between groups, some other genetic or environmental factors likely interact with the variability in glutamate related risk SNPs to contribute to an increase in brain Glx early in the illness. PMID- 28659830 TI - Depression Reduces Accuracy While Parkinsonism Slows Response Time for Processing Positive Feedback in Patients with Parkinson's Disease with Comorbid Major Depressive Disorder Tested on a Probabilistic Category-Learning Task. AB - Major depressive disorder (MDD) is the most common non-motor manifestation of Parkinson's disease (PD) affecting 50% of patients. However, little is known about the cognitive correlates of MDD in PD. Using a computer-based cognitive task that dissociates learning from positive and negative feedback, we tested four groups of subjects: (1) patients with PD with comorbid MDD, (2) patients with PD without comorbid MDD, (3) matched patients with MDD alone (without PD), and (4) matched healthy control subjects. Furthermore, we used a mathematical model of decision-making to fit both choice and response time data, allowing us to detect and characterize differences between the groups that are not revealed by cognitive results. The groups did not differ in learning accuracy from negative feedback, but the MDD groups (PD patients with MDD and patients with MDD alone) exhibited a selective impairment in learning accuracy from positive feedback when compared to the non-MDD groups (PD patients without MDD and healthy subjects). However, response time in positive feedback trials in the PD groups (both with and without MDD) was significantly slower than the non-PD groups (MDD and healthy groups). While faster response time usually correlates with poor learning accuracy, it was paradoxical in PD groups, with PD patients with MDD having impaired learning accuracy and PD patients without MDD having intact learning accuracy. Mathematical modeling showed that both MDD groups (PD with MDD and MDD alone) were significantly slower than non-MDD groups in the rate of accumulation of information for stimuli trained by positive feedback, which can lead to lower response accuracy. Conversely, modeling revealed that both PD groups (PD with MDD and PD alone) required more evidence than other groups to make responses, thus leading to slower response times. These results suggest that PD patients with MDD exhibit cognitive profiles with mixed traits characteristic of both MDD and PD, furthering our understanding of both PD and MDD and their often-complex comorbidity. To the best of our knowledge, this is the first study to examine feedback-based learning in PD with MDD while controlling for the effects of PD and MDD. PMID- 28659831 TI - Stress and Burnout in Health-Care Workers after the 2009 L'Aquila Earthquake: A Cross-Sectional Observational Study. AB - Burnout is a work-related mental health impairment, which is now recognized as a real problem in the context of the helping professions due to its adverse health outcomes on efficiency. To our knowledge, the literature on the postdisaster scenario in Italy is limited by a focus on mental health professionals rather than other health-care workers. Our cross-sectional study aims to evaluate the prevalence of burnout and psychopathological distress in different categories of health-care workers, i.e., physicians, nurses, and health-care assistants, working in different departments of L'Aquila St. Salvatore General Hospital 6 years after the 2009 earthquake in order to prevent and reduce work-related burnout. With a two-stage cluster sampling, a total of 8 departments out of a total of 28 departments were selected and the total sample included 300 health care workers. All the participants completed the following self-reporting questionnaires: a sociodemographic data form, a Maslach Burnout Inventory and a General Health Questionnaire 12 Items (GHQ-12). Statistically significant differences emerged between the total scores of the GHQ-12: post hoc analysis showed that the total average scores of the GHQ-12 were significantly higher in doctors than in health-care assistants. A high prevalence of burnout among doctors (25.97%) emerged. Using multivariate analysis, we identified a hostile relationship with colleagues, direct exposure to the L'Aquila earthquake and moderate to high levels of distress as being burnout predictors. Investigating the prevalence of burnout and distress in health-care staff in a postdisaster setting and identifying predictors of burnout development such as stress levels, time-management skills and work-life balance will contribute to the development of preventative strategies and better organization at work with a view to improving public health efficacy and reducing public health costs, given that these workers live in the disaster-affected community as survivors and serve as disaster relief workers at the same time. PMID- 28659832 TI - Rehabilitation Interventions to Promote Recovery from Schizophrenia: A Systematic Review. AB - Only one out of seven patients recovers after a first episode of psychosis despite psychiatric care. Rehabilitation interventions have been developed to improve functional outcomes and to promote recovery. We conducted a systematic review of the effectiveness of the main psychiatric rehabilitation interventions following a search of the electronic databases Pubmed, ScienceDirect, and Google Scholar using combinations of terms relating to cognitive remediation, psychoeducation, cognitive-behavioral therapies, and schizophrenia. Eighty articles relevant to the topic of interest were found. According to results, cognitive remediation has been found to be effective in reducing the impact of cognitive impairment, social skills in the learning a variety of skills and to a lesser extent in reducing negative symptoms, psychoeducation in improving compliance and reducing relapses, and cognitive therapy in reducing the intensity of or distress related to positive symptoms. All psychosocial rehabilitation interventions should be considered as evidence-based practices for schizophrenia and need to become a major part of the standard treatment of the disease. PMID- 28659833 TI - Neuropeptide Y and Calcitonin Gene-Related Peptide in Cerebrospinal Fluid in Parkinson's Disease with Comorbid Depression versus Patients with Major Depressive Disorder. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. The diagnosis of PD is based on movement dysfunctions. Many patients also suffer from comorbid depression in spite of adequate treatment with dopamine replacement, indicating that also other non-dopaminergic mechanisms are involved. Indeed, neuropeptides are critically implicated in the pathophysiology of major depressive disorder (MDD). To increase our understanding of the biochemical basis of depression in PD patients, we examined the levels of neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) in cerebrospinal fluid (CSF) from PD patients, with or without comorbid depression, and compared them to the levels in patients with MDD. We also compared the levels of NPY and CGRP with 5 hydroxyindoleacetic acid (5-HIAA), the major serotonin metabolite. Both NPY and CGRP were higher in PD patients with comorbid depression compared to MDD patients. No similar difference was found in 5-HIAA levels. Accordingly, there were no correlations between NPY and 5-HIAA or CGRP and 5-HIAA levels. The finding of higher NPY and CGRP CSF levels in PD patients with MDD raises the possibility that different pathophysiological processes may underlie depression in PD and MDD. PMID- 28659835 TI - Vitamin D Levels in Different Severity Groups of Schizophrenia. AB - BACKGROUND: Vitamin D deficiency (VDD) continues to be associated with schizophrenia, but there is the dearth of information on the relationship between the severity of schizophrenia and plasma levels of vitamin D. This study, therefore, determined the plasma levels of vitamin D in different severity groups of schizophrenia. MATERIALS AND METHODS: Plasma level of vitamin D was determined in 60 patients with schizophrenia and 30 apparently healthy individuals who served as controls. Patients with schizophrenia were classified into mildly ill, moderately ill, markedly ill, and severely ill groups using the Positive and Negative Syndrome Scale (PANSS). RESULTS: The mean level of vitamin D was significantly lower in patients with schizophrenia compared with the controls. Similarly, there was a significant association between VDD and schizophrenia. The mean plasma levels of vitamin D were not significantly different when the mildly, moderately, markedly, and severely ill groups were compared with one another and there was no significant correlation between vitamin D level and PANSS scores. Furthermore, patients on atypical antipsychotics had an insignificantly lower level of vitamin D compared with the patients on typical antipsychotics. CONCLUSION: It could be concluded from this study that patients with schizophrenia have low plasma vitamin D level which does not appear to be associated with the severity of schizophrenia and type of antipsychotics. Therefore, regular screening for vitamin D status of patients with schizophrenia is suggested in order to allow for the institution of appropriate clinical intervention when necessary. PMID- 28659834 TI - How Accurate Appraisal of Behavioral Costs and Benefits Guides Adaptive Pain Coping. AB - Coping with pain is a complex phenomenon encompassing a variety of behavioral responses and a large network of underlying neural circuits. Whether pain coping is adaptive or maladaptive depends on the type of pain (e.g., escapable or inescapable), personal factors (e.g., individual experiences with coping strategies in the past), and situational circumstances. Keeping these factors in mind, costs and benefits of different strategies have to be appraised and will guide behavioral decisions in the face of pain. In this review we present pain coping as an unconscious decision-making process during which accurately evaluated costs and benefits lead to adaptive pain coping behavior. We emphasize the importance of passive coping as an adaptive strategy when dealing with ongoing pain and thus go beyond the common view of passivity as a default state of helplessness. In combination with passive pain coping, we highlight the role of the reward system in reestablishing affective homeostasis and discuss existing evidence on a behavioral and neural level. We further present neural circuits involved in the decision-making process of pain coping when circumstances are ambiguous and, therefore, costs and benefits are difficult to anticipate. Finally, we address the wider implications of this topic by discussing its relevance for chronic pain patients. PMID- 28659836 TI - A Deficit in Movement-Derived Sentences in German-Speaking Hearing-Impaired Children. AB - Children with hearing impairment (HI) show disorders in syntax and morphology. The question is whether and how these disorders are connected to problems in the auditory domain. The aim of this paper is to examine whether moderate to severe hearing loss at a young age affects the ability of German-speaking orally trained children to understand and produce sentences. We focused on sentence structures that are derived by syntactic movement, which have been identified as a sensitive marker for syntactic impairment in other languages and in other populations with syntactic impairment. Therefore, our study tested subject and object relatives, subject and object Wh-questions, passive sentences, and topicalized sentences, as well as sentences with verb movement to second sentential position. We tested 19 HI children aged 9;5-13;6 and compared their performance with hearing children using comprehension tasks of sentence-picture matching and sentence repetition tasks. For the comprehension tasks, we included HI children who passed an auditory discrimination task; for the sentence repetition tasks, we selected children who passed a screening task of simple sentence repetition without lip reading; this made sure that they could perceive the words in the tests, so that we could test their grammatical abilities. The results clearly showed that most of the participants with HI had considerable difficulties in the comprehension and repetition of sentences with syntactic movement: they had significant difficulties understanding object relatives, Wh-questions, and topicalized sentences, and in the repetition of object who and which questions and subject relatives, as well as in sentences with verb movement to second sentential position. Repetition of passives was only problematic for some children. Object relatives were still difficult at this age for both HI and hearing children. An additional important outcome of the study is that not all sentence structures are impaired-passive structures were not problematic for most of the HI children. PMID- 28659837 TI - Paper vs. Pixel: Can We Use a Pen-and-Paper Method to Measure Athletes' Implicit Doping Attitude? PMID- 28659839 TI - Effects of an Additional Sequence of Color Stimuli on Visuomotor Sequence Learning. AB - Through practice, people are able to integrate a secondary sequence (e.g., a stimulus-based sequence) into a primary sequence (e.g., a response-based sequence), but it is still controversial whether the integrated sequences lead to better learning than only the primary sequence. In the present study, we aimed to investigate the effects of a sequence that integrated space and color sequences on early and late learning phases (corresponding to effector-independent and effector-dependent learning, respectively) and how the effects differed in the integrated and primary sequences in each learning phase. In the task, the participants were required to learn a sequence of button presses using trial-and error and to perform the sequence successfully for 20 trials (m * n task). First, in the baseline task, all participants learned a non-colored sequence, in which the response button always turned red. Then, in the learning task, the participants were assigned to two groups: a colored sequence group (i.e., space and color) or a non-colored sequence group (i.e., space). In the colored sequence, the response button turned a pre-determined color and the participants were instructed to attend to the sequences of both location and color as much as they could. The results showed that the participants who performed the colored sequence acquired the correct button presses of the sequence earlier, but showed a slower mean performance time than those who performed the non-colored sequence. Moreover, the slower performance time in the colored sequence group remained in a subsequent transfer task in which the spatial configurations of the buttons were vertically mirrored from the learning task. These results indicated that if participants explicitly attended to both the spatial response sequence and color stimulus sequence at the same time, they could develop their spatial representations of the sequence earlier (i.e., early development of the effector independent learning), but might not be able to enhance their motor representations of the sequence (i.e., late development of the effector-dependent learning). Thus, the undeveloped effector-dependent representations in the colored sequence group directly led to a long performance time in the transfer sequence. PMID- 28659838 TI - The Robust Running Ape: Unraveling the Deep Underpinnings of Coordinated Human Running Proficiency. AB - In comparison to other mammals, humans are not especially strong, swift or supple. Nevertheless, despite these apparent physical limitations, we are among Natures most superbly well-adapted endurance runners. Paradoxically, however, notwithstanding this evolutionary-bestowed proficiency, running-related injuries, and Overuse syndromes in particular, are widely pervasive. The term 'coordination' is similarly ubiquitous within contemporary coaching, conditioning, and rehabilitation cultures. Various theoretical models of coordination exist within the academic literature. However, the specific neural and biological underpinnings of 'running coordination,' and the nature of their integration, remain poorly elaborated. Conventionally running is considered a mundane, readily mastered coordination skill. This illusion of coordinative simplicity, however, is founded upon a platform of immense neural and biological complexities. This extensive complexity presents extreme organizational difficulties yet, simultaneously, provides a multiplicity of viable pathways through which the computational and mechanical burden of running can be proficiently dispersed amongst expanded networks of conditioned neural and peripheral tissue collaborators. Learning to adequately harness this available complexity, however, is a painstakingly slowly emerging, practice-driven process, greatly facilitated by innate evolutionary organizing principles serving to constrain otherwise overwhelming complexity to manageable proportions. As we accumulate running experiences persistent plastic remodeling customizes networked neural connectivity and biological tissue properties to best fit our unique neural and architectural idiosyncrasies, and personal histories: thus neural and peripheral tissue plasticity embeds coordination habits. When, however, coordinative processes are compromised-under the integrated influence of fatigue and/or accumulative cycles of injury, overuse, misuse, and disuse-this spectrum of available 'choice' dysfunctionally contracts, and our capacity to safely disperse the mechanical 'stress' of running progressively diminishes. Now the running work burden falls increasingly on reduced populations of collaborating components. Accordingly our capacity to effectively manage, dissipate and accommodate running-imposed stress diminishes, and vulnerability to Overuse syndromes escalates. Awareness of the deep underpinnings of running coordination enhances conceptual clarity, thereby informing training and rehabilitation insights designed to offset the legacy of excessive or progressively accumulating exposure to running-imposed mechanical stress. PMID- 28659840 TI - Multiplicity: An Explorative Interview Study on Personal Experiences of People with Multiple Selves. AB - Background and aims: Personality psychology research relies on the notion that humans have a single self that is the result of the individual's thoughts, feelings, and behaviors that can be reliably described (i.e., through traits). People who identify themselves as "multiple" have a system of multiple or alternative, selves, that share the same physical body. This is the first study to explore the phenomenon of multiplicity by assessing the experiences of people who identify themselves as "multiple." Methods: First, an Internet forum search was performed using the terms "multiplicity" and "multiple system." Based on that search, people who identified themselves as multiple were contacted. Interviews were conducted by a consultant psychiatrist, which produced six case vignettes. Results: Multiplicity is discussed on Twitter, Tumblr, Google+ and several other personal websites, blogs, and forums maintained by multiples. According to the study's estimates, there are 200-300 individuals who participate in these forums and believe they are multiple. Based on the six interviews, it appears that multiples have several selves who are relatively independent of each other and constitute the personality's system. Each "resident person" or self, has their own unique behavioral pattern, which is triggered by different situations. However, multiples are a heterogeneous group in terms of their system organization, memory functions, and control over switching between selves. Conclusions: Multiplicity can be placed along a continuum between identity disturbance and dissociative identity disorder (DID), although most systems function relatively well in everyday life. Further research is needed to explore this phenomenon, especially in terms of the extent to which multiplicity can be regarded as a healthy way of coping. PMID- 28659841 TI - Comprehension and Hemispheric Processing of Irony in Schizophrenia. AB - Studies focusing on the comprehension of figurative language among schizophrenia patients (SZ) reveal their difficulties comprehending such language and their tendency to interpret it literally. The present study investigated hemispheric processing and comprehension of irony in 16 SZ patients and 18 typically developing (TD) adults. Two experimental tasks were used: an online divided visual field experiment and an offline irony questionnaire. The results show an atypical reversal of hemispheric processing of irony in SZ patients as compared to TD adults. While the TD group demonstrated a right hemisphere advantage in processing irony, SZ patients demonstrated a left hemisphere advantage. Greater comprehension of irony was associated with decreased negative symptoms. In addition, under conditions that not involving a time restriction, the SZ patients' performance improved. Our findings reinforce those of previous studies suggesting that brain lateralization is atypical in SZ patients. PMID- 28659842 TI - Functional Synchronization: The Emergence of Coordinated Activity in Human Systems. AB - The topical landscape of psychology is highly compartmentalized, with distinct phenomena explained and investigated with recourse to theories and methods that have little in common. Our aim in this article is to identify a basic set of principles that underlie otherwise diverse aspects of human experience at all levels of psychological reality, from neural processes to group dynamics. The core idea is that neural, behavioral, mental, and social structures emerge through the synchronization of lower-level elements (e.g., neurons, muscle movements, thoughts and feelings, individuals) into a functional unit-a coherent structure that functions to accomplish tasks. The coherence provided by the formation of functional units may be transient, persisting only as long as necessary to perform the task at hand. This creates the potential for the repeated assembly and disassembly of functional units in accordance with changing task demands. This perspective is rooted in principles of complexity science and non-linear dynamical systems and is supported by recent discoveries in neuroscience and recent models in cognitive and social psychology. We offer guidelines for investigating the emergence of functional units in different domains, thereby honoring the topical differentiation of psychology while providing an integrative foundation for the field. PMID- 28659843 TI - Leaky Pipeline Myths: In Search of Gender Effects on the Job Market and Early Career Publishing in Philosophy. AB - That philosophy is an outlier in the humanities when it comes to the underrepresentation of women has been the occasion for much discussion about possible effects of subtle forms of prejudice, including implicit bias and stereotype threat. While these ideas have become familiar to the philosophical community, there has only recently been a surge of interest in acquiring field specific data. This paper adds to quantitative findings bearing on hypotheses about the effects of unconscious prejudice on two important stages along career pathways: tenure-track hiring and early career publishing. PMID- 28659844 TI - Transferability of Dual-Task Coordination Skills after Practice with Changing Component Tasks. AB - Recent research has demonstrated that dual-task performance with two simultaneously presented tasks can be substantially improved as a result of practice. Among other mechanisms, theories of dual-task practice-relate this improvement to the acquisition of task coordination skills. These skills are assumed (1) to result from dual-task practice, but not from single-task practice, and (2) to be independent from the specific stimulus and response mappings during the practice situation and, therefore, transferable to new dual task situations. The present study is the first that provides an elaborated test of these assumptions in a context with well-controllable practice and transfer situations. To this end, we compared the effects of dual-task and single-task practice with a visual and an auditory sensory-motor component task on the dual-task performance in a subsequent transfer session. Importantly, stimulus and stimulus-response mapping conditions in the two component tasks changed repeatedly during practice sessions, which prevents that automatized stimulus-response associations may be transferred from practice to transfer. Dual-task performance was found to be improved after practice with the dual tasks in contrast to the single-task practice. These findings are consistent with the assumption that coordination skills had been acquired, which can be transferred to other dual-task situations independently on the specific stimulus and response mapping conditions of the practiced component tasks. PMID- 28659845 TI - Identifying the Micro-relations Underpinning Familiarity Detection in Dynamic Displays Containing Multiple Objects. AB - We identified the important micro-relations that are perceived when attempting to recognize patterns in stimuli consisting of multiple dynamic objects. Skilled and less-skilled participants were presented with point light display sequences representing dynamic patterns in an invasion sport and were subsequently required to make familiarity based recognition judgments in three different conditions, each of which contained only a select number of features that were present at initial viewing. No differences in recognition accuracy were observed between skilled and less-skilled participants when just objects located in the periphery were presented. Yet, when presented with the relative motions of two centrally located attacking objects only, skilled participants were significantly more accurate than less-skilled participants and their recognition accuracy improved further when a target object was included against which these relative motions could be judged. Skilled participants can perceive and recognize global patterns on the basis of centrally located relational information. PMID- 28659846 TI - Editorial: Methodological Quality of Interventions in Psychology. PMID- 28659847 TI - Electrophysiological Correlates of Cue-Related Processing in a Gambling Task: Early Outcome Evaluation or Outcome Expectation? AB - Several recent studies have suggested that cues that predict outcomes elicit a feedback-related-like negativity (FRN-like negativity) reflecting initial appraisals of whether desired outcomes are probable. Some other studies, however, have found that the cues that predict outcomes elicited event-related potentials (ERPs) that reflect the expectation to outcomes (e.g., outcome expectations). Given these mixed findings, this study aimed to examine whether the brain activity elicited by predictive cues in a gambling task reflected the initial evaluations of the outcomes, the outcome expectations, or both. We used a gambling task in which the participants were told to guess which of two doors hid a reward. At the beginning of each trial, a cue was presented to inform the participants of how many doors hid a reward. We found that these predictive cues elicited a FRN-like negativity at the frontal sites within around 200-300 ms. However, this negativity did not significantly differ between the cues that fully predicted gains and the cues that fully predicted losses. Furthermore, predictive cues elicited an expectation-related slow wave, and cues that predicted gains with a 50% probability elicited a larger expectation-related slow wave than cues that fully predicted gains or losses. Our results suggest that cues predicting outcomes reflect outcome expectations rather than initial evaluations of the forthcoming outcomes. PMID- 28659848 TI - Construct Validity and Reliability of a New Spanish Empathy Questionnaire for Children and Early Adolescents. AB - Empathy is a basic socio-emotional process of human development that involves the ability to perceive, share, and understand the emotional states of others. This process is essential to successful social functioning. However, despite its significance, empathy has been difficult to define and measure, particularly when incorporating both its emotional and cognitive aspects. The purpose of this study was to develop an Empathy Questionnaire for children aged 9-12 years based on a model of social cognitive neuroscience and to analyze its construct validity and reliability. This questionnaire aimed to integrate the following aspects: emotional contagion, self-other awareness, perspective-taking, emotional regulation, and empathic action. Three studies were conducted. Study 1 evaluated the discriminative power of the items and studied the underlying structure of the instrument using exploratory factor analysis. In Study 2, confirmatory factor analysis was performed to test the model obtained. Finally, the goal of Study 3 was to analyze the convergent and discriminant validity of the questionnaire and the internal consistency of its dimensions. The final version of the instrument contained 15 items that operationalized the previously listed dimensions. The results of the 3 studies indicated that the questionnaire had good validity and reliability. This study has important implications for research and clinical practice. Given its simplicity and brevity, this new self-report scale may work well as a screening method to evaluate the key psychological issues underlying numerous child behaviors that predict the success or failure of social relationships, individual quality of life, and mental well-being. PMID- 28659849 TI - The Use of Velocity Information in Movement Reproduction. AB - Background: Previous studies suggested that movement velocity influence space perception. Aim and Objectives: We examined whether healthy participants used velocity information when they were asked to reproduce a previously performed movement. Two experiments were carried out. Methods: In Experiment 1, blindfolded participants actively performed an arm movement (criterion movement, CM) at a natural velocity, or quickly, or slowly. After a brief delay, participants were asked to reproduce (reproduction movement, RM) CM-amplitude. No velocity constraints were imposed in making RM. In Experiment 2, CM was performed quickly or slowly. After a brief delay, the participants were asked to reproduce not only CM-amplitude but also CM-velocity. Results: Experiment 1: in Natural condition, RM-velocity did not differ from CM-velocity and the participants accurately reproduced CM-amplitude. Conversely, in Fast and Slow condition, RM-velocities differed from CM-velocities and in Slow condition RM-amplitude was greater than CM-amplitude. Experiment 2: both RM-amplitude and -velocity did not differ from CM-amplitude and -velocity. Conclusion: The present study confirms the view that movement velocity influences selectively space perception and suggests that this influence is stronger for slow than fast movements. Furthermore, although velocity information is crucial in accurately reproducing CM-amplitude, it was not used spontaneously when movements were performed at unnatural velocities. PMID- 28659851 TI - Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval. AB - Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR. PMID- 28659850 TI - Increased Complexities in Visual Search Behavior in Skilled Players for a Self Paced Aiming Task. AB - The badminton serve is an important shot for winning a rally in a match. It combines good technique with the ability to accurately integrate visual information from the shuttle, racket, opponent, and intended landing point. Despite its importance and repercussive nature, to date no study has looked at the visual search behaviors during badminton service in the singles discipline. Unlike anticipatory tasks (e.g., shot returns), the serve presents an opportunity to explore the role of visual search behaviors in movement control for self-paced tasks. Accordingly, this study examined skill-related differences in visual behavior during the badminton singles serve. Skilled (n = 12) and less skilled (n = 12) participants performed 30 serves to a live opponent, while real-time eye movements were captured using a mobile gaze registration system. Frame-by-frame analyses of 662 serves were made and the skilled players took a longer preparatory time before serving. Visual behavior of the skilled players was characterized by significantly greater number of fixations on more areas of interest per trial than the less skilled. In addition, the skilled players spent a significantly longer time fixating on the court and net, whereas the less skilled players found the shuttle to be more informative. Quiet eye (QE) duration (indicative of superior sports performance) however, did not differ significantly between groups which has implications on the perceived importance of QE in the badminton serve. Moreover, while visual behavior differed by skill level, considerable individual differences were also observed especially within the skilled players. This augments the need for not just group-level analyses, but individualized analysis for a more accurate representation of visual behavior. Findings from this study thus provide an insight to the possible visual search strategies as players serve in net-barrier games. Moreover, this study highlighted an important aspect of badminton relating to deception and the implications of interpreting visual behavior of players. PMID- 28659852 TI - Psychosocial Interventions for Depressive and Anxiety Symptoms in Individuals with Chronic Kidney Disease: Systematic Review and Meta-Analysis. AB - Purpose: Depressive and anxiety symptoms are common amongst individuals with chronic kidney disease and are known to affect quality of life adversely. Psychosocial interventions have been shown to decrease depressive and anxiety symptoms in various chronic diseases, but few studies have examined their efficacy in people with chronic kidney disease and no meta-analysis has been published. Thus, the aim of the present systematic review and meta-analysis was to evaluate the effects of psychosocial interventions on depressive and anxiety symptoms as well as quality of life in individuals diagnosed with chronic kidney disease and/or their carers. Methods: In this systematic review and meta analysis, we included published randomized controlled trials comparing psychosocial interventions versus usual care for impacting depressive and anxiety symptoms and quality of life. Results: Eight studies were included in the systematic review and six of these were subjected to meta-analysis. Psychosocial interventions were associated with a medium effect size for reduction in depressive symptoms and a small effect size for improved quality of life in the in individuals with chronic-kidney-disease and their carers. Some evidence suggested a reduction in anxiety. Conclusion: Psychosocial interventions appear to reduce depressive symptoms and improve quality of life in patients with chronic-kidney-disease and their carers and to have some beneficial impact on anxiety. However, the small number of identified studies indicates a need for further research in this field. PMID- 28659853 TI - Can Functional Magnetic Resonance Imaging Generate Valid Clinical Neuroimaging Reports? PMID- 28659855 TI - Upper Extremity Motor Impairments and Microstructural Changes in Bulbospinal Pathways in Chronic Hemiparetic Stroke. AB - Following hemiparetic stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement, or abnormal limb synergies, which can negatively impact functional use of the paretic arm. One hypothesis for the expression of these synergies is an increased dependence on bulbospinal pathways such as the rubrospinal (RubST) tract and especially the reticulospinal (RetST) tracts, which co-activate multiple muscles of the shoulder, elbow, wrist, and fingers. Despite indirect evidence supporting this hypothesis in humans poststroke, it still remains unclear whether it is correct. Therefore, we used high-resolution diffusion tensor imaging (DTI) to quantify white matter microstructure in relation to severity of arm synergy and hand-related motor impairments. DTI was performed on 19 moderately to severely impaired chronic stroke individuals and 15 healthy, age-matched controls. In stroke individuals, compared to controls, there was significantly decreased fractional anisotropy (FA) and significantly increased axial and radial diffusivity in bilateral corona radiata and body of the corpus callosum. Furthermore, poststroke, the contralesional (CL) RetST FA correlated significantly with both upper extremity (UE) synergy severity (r = -0.606, p = 0.003) and hand impairment (r = -0.609, p = 0.003). FA in the ipsilesional RubST significantly correlated with hand impairment severity (r = -0.590, p = 0.004). For the first time, we separately evaluate RetST and RubST microstructure in chronic stroke individuals with UE motor impairment. We demonstrate that individuals with the greatest UE synergy severity and hand impairments poststroke have the highest FA in the CL RetST a pattern consistent with increased myelination and suggestive of neuroplastic reorganization. Since the RetST pathway microstructure, in particular, is sensitive to abnormal joint coupling and hand-related motor impairment in chronic stroke, it could help test the effects of specific, and novel, anti-synergy neurorehabilitation interventions for recovery from hemiparesis. PMID- 28659856 TI - Do Patients with Multiple Sclerosis Derive More Benefit from Robot-Assisted Gait Training Compared with Conventional Walking Therapy on Motor Function? A Meta analysis. AB - OBJECTIVE: To determine whether robot-assisted gait training (RAGT) is more effective in improving mobility, endurance, gait performance, and balance in patients with multiple sclerosis (MS) compared with conventional walking rehabilitation treatment (CWT). DATA SOURCES: Sources included the Cochrane Library, PubMed, Embase, and Science Direct databases. REVIEW METHOD: All possible articles were retrieved by two independent investigators and relevant articles were gathered. Studies on adult patients (older than 19 years old) suffering from MS were included, regardless the subtype of MS diagnosis. Finally, we identified seven studies that comprised 205 patients with MS. RESULTS: We identified seven studies comprising 205 patients with MS in our meta-analysis. The pooled mean difference (MD) for the six-minute walk test (6MWT) was 14.25 [95% confidence interval (CI) 3.19 to 25.32, Z = 2.53, P = 0.01, I2 = 54%], which indicates that RAGT is superior to CWT on improving endurance. No significant improvement on using RAGT was found regarding the Berg Balance Scale (MD = -0.59, 95% CI: -2.7 to 1.52, Z = 0.55, P = 0.58, I2 = 51%), 10-meter walk test [standard mean difference (SMD) = 0.03, 95% CI: -0.26 to 0.31, Z = 0.18, P = 0.86, I2 = 48%] timed up and go (TUG) test (MD = -1.04, 95% CI: -8.68 to 6.60, Z = 0.27, P = 0.79), or stride length (SMD = 0.36, 95% CI: -0.13 to 0.85, Z = 0.73, P = 0.15). CONCLUSION: We can conclude that RAGT can bring more benefits on improving 6MWT among MS patients, but it is not enough to make a clinically significance conclusion. Considering the limitation of our study, it takes reservations about recommending all MS patients to take RAGT as primary rehabilitation intervention. Unless patients with progressive MS can take conventional rehabilitation in early time, RAGT would be a suitable substitute. PMID- 28659854 TI - Role of Interleukin-10 in Acute Brain Injuries. AB - Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation. PMID- 28659857 TI - A New Rat Model of Epileptic Spasms Based on Methylazoxymethanol-Induced Malformations of Cortical Development. AB - Malformations of cortical development (MCDs) can cause medically intractable epilepsies and cognitive disabilities in children. We developed a new model of MCD-associated epileptic spasms by treating rats prenatally with methylazoxymethanol acetate (MAM) to induce cortical malformations and postnatally with N-methyl-d-aspartate (NMDA) to induce spasms. To produce cortical malformations to infant rats, two dosages of MAM (15 mg/kg, intraperitoneally) were injected to pregnant rats at gestational day 15. In prenatally MAM-exposed rats and the controls, spasms were triggered by single (6 mg/kg on postnatal day 12 (P12) or 10 mg/kg on P13 or 15 mg/kg on P15) or multiple doses (P12, P13, and P15) of NMDA. In prenatally MAM-exposed rats with single NMDA-provoked spasms at P15, we obtain the intracranial electroencephalography and examine the pretreatment response to adrenocorticotropic hormone (ACTH) or vigabatrin. Rat pups prenatally exposed to MAM exhibited a significantly greater number of spasms in response to single and multiple postnatal NMDA doses than vehicle-exposed controls. Vigabatrin treatment prior to a single NMDA dose on P15 significantly suppressed spasms in MAM group rats (p < 0.05), while ACTH did not. The MAM group also showed significantly higher fast oscillation (25-100 Hz) power during NMDA-induced spasms than controls (p = 0.047). This new model of MCD-based epileptic spasms with corresponding features of human spasms will be valuable for future research of the developmental epilepsy. PMID- 28659858 TI - Biometric Digital Health Technology for Measuring Motor Function in Parkinson's Disease: Results from a Feasibility and Patient Satisfaction Study. AB - OBJECTIVES: To assess the feasibility, predictive value, and user satisfaction of objectively quantifying motor function in Parkinson's disease (PD) through a tablet-based application (iMotor) using self-administered tests. METHODS: PD and healthy controls (HCs) performed finger tapping, hand pronation-supination and reaction time tasks using the iMotor application. RESULTS: Thirty-eight participants (19 with PD and 17 HCs) were recruited in the study. PD subjects were 53% male, with a mean age of 67.8 years (+/-8.8), mean disease duration of 6.5 years (+/-4.6), Movement Disorders Society version of the Unified Parkinson Disease Rating Scale III score 26.3 (+/-6.7), and Hoehn & Yahr stage 2. In the univariate analysis, most tapping variables were significantly different in PD compared to HC. Tap interval provided the highest predictive ability (90%). In the multivariable logistic regression model reaction time (reaction time test) (p = 0.021) and total taps (two-target test) (p = 0.026) were associated with PD. A combined model with two-target (total taps and accuracy) and reaction time produced maximum discriminatory performance between HC and PD. The overall accuracy of the combined model was 0.98 (95% confidence interval: 0.93-1). iMotor use achieved high rates of patients' satisfaction as evaluated by a patient satisfaction survey. CONCLUSION: iMotor differentiated PD subjects from HCs using simple alternating tasks of motor function. Results of this feasibility study should be replicated in larger, longitudinal, appropriately designed, controlled studies. The impact on patient care of at-home iMotor-assisted remote monitoring also deserves further evaluation. PMID- 28659859 TI - Pre-Stroke Modified Rankin Scale: Evaluation of Validity, Prognostic Accuracy, and Association with Treatment. AB - BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) was designed to measure poststroke recovery but is often used to describe pre-stroke disability. We sought to evaluate three aspects of pre-stroke mRS: validity as a measure of pre stroke disability; prognostic accuracy and association of pre-stroke mRS scores, and process of care. METHODS: We used data from a large, UK clinical registry. For analysis of validity, we compared pre-stroke mRS against other markers of pre stroke function (age, comorbidity index, care needs). For analysis of prognostic accuracy, we described univariable and multivariable models comparing pre-stroke mRS and other prognostic variables against a variety of outcomes (early and late mortality, length of stay, institutionalization, incident complications). Finally, we described association of pre-stroke mRS and components of evidence based stroke care (early neuroimaging, admission to stroke unit, assessment of swallow). RESULTS: We analyzed data of 2,491 stroke patients. Concurrent validity analyses suggested statistically significant, but modest correlations between pre stroke mRS and chosen variables (rho >0.40; p < 0.0001 for all). Every point increase of pre-stroke mRS was associated with poorer outcomes for our prognostic variables (unadjusted p < 0.001). This association held when corrected for other covariates. For example, pre-stroke mRS 4-5 odds ratio (OR): 6.84 (95% CI: 4.24 11.03) for 1 year mortality compared to mRS 0 in adjusted model. There was a difference between pre-stroke mRS and treatment, with higher pre-stroke mRS more likely to receive evidence-based care. CONCLUSION: Results suggest that pre stroke mRS has some concurrent validity and is a robust predictor of prognosis. This association is not explained by the influence of pre-stroke mRS on care pathways. PMID- 28659860 TI - Spinocerebellar Ataxia Type 2 Is Associated with the Extracellular Loss of Superoxide Dismutase but Not Catalase Activity. AB - BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an inherited and still incurable neurodegenerative disorder. Evidence suggests that pro-oxidant agents as well as factors involved in antioxidant cellular defenses are part of SCA2 physiopathology. AIM: To assess the influence of superoxide dismutase (SOD3) and catalase (CAT) enzymatic activities on the SCA2 syndrome. METHOD: Clinical, molecular, and electrophysiological variables, as well as SOD3 and CAT enzymatic activities were evaluated in 97 SCA2 patients and in 64 age- and sex-matched control individuals. RESULTS: Spinocerebellar ataxia type 2 patients had significantly lower SOD3 enzymatic activity than the control group. However, there were no differences between patients and controls for CAT enzymatic activity. The effect size for the loss of patients' SOD3 enzymatic activity was 0.342, corresponding to a moderate effect. SOD3 and CAT enzymatic activities were not associated with the CAG repeat number at the ATXN2 gene. SOD3 and CAT enzymatic activities did not show significant associations with the age at onset, severity score, or the studied electrophysiological markers. CONCLUSION: There is a reduced SOD3 enzymatic activity in SCA2 patients with no repercussion on the clinical phenotype. PMID- 28659861 TI - The Effect of Systemic Nitroglycerin Administration on the Kynurenine Pathway in the Rat. AB - The primary headache disorders include migraine, which is one of the most frequent neurological disorders, which influences more than 14% of the whole population. Despite the research efforts, its exact pathomechanism is not fully revealed, but evidence points to the role of glutamate and its receptors. Kynurenic acid is an endogenous glutamate receptor antagonist produced by the kynurenine pathway (KP). Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO) convert l-tryptophan to N-formyl-l-kynurenine, to be further transformed to l-kynurenine. Kynurenine aminotransferase-II (KAT-II), l kynurenine hydrolase (KYNU), and l-kynurenine 3-monooxygenase (KMO) are key enzymes in the later steps of the KP. Nitroglycerin (NTG) administration serves as both human and animal model of migraine, causing the activation and sensitization in the trigeminal system. A previous study demonstrated a reduction of KAT-II expression following NTG administration in animals. The goal of current tests was to identify the potential modulatory effect of NTG on other metabolizing enzymes of the KP in the caudal trigeminal nucleus (TNC) of rats. Four hours following the intraperitoneal injection of NTG (10 mg/kg), the rats were perfused transcardially and the TNC was extracted for Western blotting. Western blot studies revealed that the expression of TDO2, IDO1, KYNU, and KMO decreased in the TNC. The results demonstrated that NTG is able to downregulate the KP, with a potential influence on the glutamatergic system as well, contributing to the development of trigeminal activation and sensitization in animals. PMID- 28659862 TI - Usability of Three-dimensional Augmented Visual Cues Delivered by Smart Glasses on (Freezing of) Gait in Parkinson's Disease. AB - External cueing is a potentially effective strategy to reduce freezing of gait (FOG) in persons with Parkinson's disease (PD). Case reports suggest that three dimensional (3D) cues might be more effective in reducing FOG than two dimensional cues. We investigate the usability of 3D augmented reality visual cues delivered by smart glasses in comparison to conventional 3D transverse bars on the floor and auditory cueing via a metronome in reducing FOG and improving gait parameters. In laboratory experiments, 25 persons with PD and FOG performed walking tasks while wearing custom-made smart glasses under five conditions, at the end-of-dose. For two conditions, augmented visual cues (bars/staircase) were displayed via the smart glasses. The control conditions involved conventional 3D transverse bars on the floor, auditory cueing via a metronome, and no cueing. The number of FOG episodes and percentage of time spent on FOG were rated from video recordings. The stride length and its variability, cycle time and its variability, cadence, and speed were calculated from motion data collected with a motion capture suit equipped with 17 inertial measurement units. A total of 300 FOG episodes occurred in 19 out of 25 participants. There were no statistically significant differences in number of FOG episodes and percentage of time spent on FOG across the five conditions. The conventional bars increased stride length, cycle time, and stride length variability, while decreasing cadence and speed. No effects for the other conditions were found. Participants preferred the metronome most, and the augmented staircase least. They suggested to improve the comfort, esthetics, usability, field of view, and stability of the smart glasses on the head and to reduce their weight and size. In their current form, augmented visual cues delivered by smart glasses are not beneficial for persons with PD and FOG. This could be attributable to distraction, blockage of visual feedback, insufficient familiarization with the smart glasses, or display of the visual cues in the central rather than peripheral visual field. Future smart glasses are required to be more lightweight, comfortable, and user friendly to avoid distraction and blockage of sensory feedback, thus increasing usability. PMID- 28659863 TI - Neural Plasticity in Moderate to Severe Chronic Stroke Following a Device Assisted Task-Specific Arm/Hand Intervention. AB - Currently, hand rehabilitation following stroke tends to focus on mildly impaired individuals, partially due to the inability for severely impaired subjects to sufficiently use the paretic hand. Device-assisted interventions offer a means to include this more severe population and show promising behavioral results. However, the ability for this population to demonstrate neural plasticity, a crucial factor in functional recovery following effective post-stroke interventions, remains unclear. This study aimed to investigate neural changes related to hand function induced by a device-assisted task-specific intervention in individuals with moderate to severe chronic stroke (upper extremity Fugl-Meyer < 30). We examined functional cortical reorganization related to paretic hand opening and gray matter (GM) structural changes using a multimodal imaging approach. Individuals demonstrated a shift in cortical activity related to hand opening from the contralesional to the ipsilesional hemisphere following the intervention. This was driven by decreased activity in contralesional primary sensorimotor cortex and increased activity in ipsilesional secondary motor cortex. Additionally, subjects displayed increased GM density in ipsilesional primary sensorimotor cortex and decreased GM density in contralesional primary sensorimotor cortex. These findings suggest that despite moderate to severe chronic impairments, post-stroke participants maintain ability to show cortical reorganization and GM structural changes following a device-assisted task specific arm/hand intervention. These changes are similar as those reported in post-stroke individuals with mild impairment, suggesting that residual neural plasticity in more severely impaired individuals may have the potential to support improved hand function. PMID- 28659864 TI - Editorial: ACTH Action in the Adrenal Cortex: From Molecular Biology to Pathophysiology. PMID- 28659865 TI - Review of Evidence for Adult Diabetic Ketoacidosis Management Protocols. AB - BACKGROUND: Diabetic ketoacidosis (DKA) is an endocrine emergency with associated risk of morbidity and mortality. Despite this, DKA management lacks strong evidence due to the absence of large randomised controlled trials (RCTs). OBJECTIVE: To review existing studies investigating inpatient DKA management in adults, focusing on intravenous (IV) fluids; insulin administration; potassium, bicarbonate, and phosphate replacement; and DKA management protocols and impact of DKA resolution rates on outcomes. METHODS: Ovid Medline searches were conducted with limits "all adult" and published between "1973 to current" applied. National consensus statements were also reviewed. Eligibility was determined by two reviewers' assessment of title, abstract, and availability. RESULTS: A total of 85 eligible articles published between 1973 and 2016 were reviewed. The salient findings were (i) Crystalloids are favoured over colloids though evidence is lacking. The preferred crystalloid and hydration rates remain contentious. (ii) IV infusion of regular human insulin is preferred over the subcutaneous route or rapid acting insulin analogues. Administering an initial IV insulin bolus before low-dose insulin infusions obviates the need for supplemental insulin. Consensus-statements recommend fixed weight-based over "sliding scale" insulin infusions although evidence is weak. (iii) Potassium replacement is imperative although no trials compare replacement rates. (iv) Bicarbonate replacement offers no benefit in DKA with pH > 6.9. In severe metabolic acidosis with pH < 6.9, there is lack of both data and consensus regarding bicarbonate administration. (v) There is no evidence that phosphate replacement offers outcome benefits. Guidelines consider replacement appropriate in patients with cardiac dysfunction, anaemia, respiratory depression, or phosphate levels <0.32 mmol/L. (vi) Upon resolution of DKA, subcutaneous insulin is recommended with IV insulin infusions ceased with an overlap of 1-2 h. (vii) DKA resolution rates are often used as end points in studies, despite a lack of evidence that rapid resolution improves outcome. (viii) Implementation of DKA protocols lacks strong evidence for adherence but may lead to improved clinical outcomes. CONCLUSION: There are major deficiencies in evidence for optimal management of DKA. Current practice is guided by weak evidence and consensus opinion. All aspects of DKA management require RCTs to affirm or redirect management and formulate consensus evidence-based practice to improve patient outcomes. PMID- 28659867 TI - Increased Short-Term Beat-to-Beat QT Interval Variability in Patients with Impaired Glucose Tolerance. AB - Prediabetic states and diabetes are important risk factors for cardiovascular morbidity and mortality. Determination of short-term QT interval variability (STVQT) is a non-invasive method for assessment of proarrhythmic risk. The aim of the study was to evaluate the STVQT in patients with impaired glucose tolerance (IGT). 18 IGT patients [age: 63 +/- 11 years, body mass index (BMI): 31 +/- 6 kg/m2, fasting glucose: 6.0 +/- 0.4 mmol/l, 120 min postload glucose: 9.0 +/- 1.0 mmol/l, hemoglobin A1c (HbA1c): 5.9 +/- 0.4%; mean +/- SD] and 18 healthy controls (age: 56 +/- 9 years, BMI: 27 +/- 5 kg/m2, fasting glucose: 5.2 +/- 0.4 mmol/l, 120 min postload glucose: 5.5 +/- 1.3 mmol/l, HbA1c: 5.4 +/- 0.3%) were enrolled into the study. ECGs were recorded, processed, and analyzed off-line. The RR and QT intervals were expressed as the average of 30 consecutive beats, the temporal instability of beat-to-beat repolarization was characterized by calculating STVQT as follows: STVQT = Sigma|QTn + 1 - QTn| (30x?2)-1. Autonomic function was assessed by means of standard cardiovascular reflex tests. There were no differences between IGT and control groups in QT (411 +/- 43 vs 402 +/- 39 ms) and QTc (431 +/- 25 vs 424 +/- 19 ms) intervals or QT dispersion (44 +/- 13 vs 42 +/- 17 ms). However, STVQT was significantly higher in IGT patients (5.0 +/- 0.7 vs 3.7 +/- 0.7, P < 0.0001). The elevated temporal STVQT in patients with IGT may be an early indicator of increased instability of cardiac repolarization during prediabetic conditions. PMID- 28659868 TI - Issues in Continuous 24-h Core Body Temperature Monitoring in Humans Using an Ingestible Capsule Telemetric Sensor. AB - BACKGROUND: There is increasing interest in the use of pill-sized ingestible capsule telemetric sensors for assessing core body temperature (Tc) as a potential indicator of variability in metabolic efficiency and thrifty metabolic traits. The aim of this study was to investigate the feasibility and accuracy of measuring Tc using the CorTemp(r) system. METHODS: Tc was measured over an average of 20 h in 27 human subjects, with measurements of energy expenditure made in the overnight fasted state at rest, during standardized low-intensity physical activity and after a 600 kcal mixed meal. Validation of accuracy of the capsule sensors was made ex vivo against mercury and electronic thermometers across the physiological range (35-40 degrees C) in morning and afternoon of 2 or 3 consecutive days. Comparisons between capsule sensors and thermometers were made using Bland-Altman analysis. Systematic bias, error, and temperature drift over time were assessed. RESULTS: The circadian Tc profile classically reported in free-living humans was confirmed. Significant increases in Tc (+0.2 degrees C) were found in response to low-power cycling at 40-50 W (~3-4 METs), but no changes in Tc were detectable during low-level isometric leg press exercise (<2 METs) or during the peak postprandial thermogenesis induced by the 600 kcal meal. Issues of particular interest include fast "turbo" gut transit with expulsion time of <15 h after capsule ingestion in one out of every five subjects and sudden erratic readings in teletransmission of Tc. Furthermore, ex vivo validation revealed a substantial mean bias (exceeding +/-0.5 degrees C) between the Tc capsule readings and mercury or electronic thermometers in half of the capsules. When examined over 2 or 3 days, the initial bias (small or large) drifted in excess of +/-0.5 degrees C in one out of every four capsules. CONCLUSION: Since Tc is regulated within a very narrow range in the healthy homeotherm's body (within 1 degrees C), physiological investigations of Tc require great accuracy and precision (better than 0.1 degrees C). Although ingestible capsule methodology appears of great interest for non-invasively monitoring the transit gut temperature, new technology requires a reduction in the inherent error of measurement and elimination of temperature drift and warrants more interlaboratory investigation on the above factors. PMID- 28659869 TI - Resting Metabolic Rate Does Not Change in Response to Different Types of Training in Subjects with Type 2 Diabetes. AB - BACKGROUND AND OBJECTIVES: Ambiguous results have been reported regarding the effects of training on resting metabolic rate (RMR), and the importance of training type and intensity is unclear. Moreover, studies in subjects with type 2 diabetes (T2D) are sparse. In this study, we evaluated the effects of interval and continuous training on RMR in subjects with T2D. Furthermore, we explored the determinants for training-induced alterations in RMR. METHODS: Data from two studies, both including T2D subjects, were encompassed in this manuscript. Study 1 was a randomized, crossover study where subjects (n = 14) completed three, 2 week interventions [control, continuous walking training (CWT), interval-walking training (IWT)] separated by washout periods. Training included 10 supervised treadmill sessions, 60 min/session. CWT was performed at moderate walking speed [aiming for 73% of walking peak oxygen uptake (VO2peak)], while IWT was performed as alternating 3-min repetitions at slow (54% VO2peak) and fast (89% VO2peak) walking speed. Study 2 was a single-arm training intervention study where subjects (n = 23) were prescribed 12 weeks of free-living IWT (at least 3 sessions/week, 30 min/session). Before and after interventions, RMR, physical fitness, body composition, and glycemic control parameters were assessed. RESULTS: No overall intervention-induced changes in RMR were seen across the studies, but considerable inter-individual differences in RMR changes were seen in Study 2. At baseline, total body mass (TBM), fat-free mass (FFM), and fat mass were all associated with RMR. Changes in RMR were associated with changes in TBM and fat mass, and subjects who decreased body mass and fat mass also decreased their RMR. No associations were seen between changes in physical fitness, glycemic control, or FFM and changes in RMR. CONCLUSION: Neither short-term continuous or interval-type training, nor longer term interval training affects RMR in subjects with T2D when no overall changes in body composition are seen. If training occurs concomitant with a reduction in fat mass, however, RMR is decreased. CLINICAL TRIALS REGISTRATION WWWCLINICALTRIALSGOV: NCT02320526 and NCT02089477. PMID- 28659866 TI - Overlapping Neural Endophenotypes in Addiction and Obesity. AB - Impulsivity refers to a tendency to act rapidly without full consideration of consequences. The trait is thought to result from the interaction between high arousal responses to potential rewards and poor self-control. Studies have suggested that impulsivity confers vulnerability to both addiction and obesity. However, results in this area are unclear, perhaps due to the high phenotypic complexity of addictions and obesity. Focusing on impulsivity, the aim of this review is to tackle the putative overlaps between addiction and obesity in four domains: (1) personality research, (2) neurocognitive tasks, (3) brain imaging, and (4) clinical evidence. We suggest that three impulsivity-related domains are particularly relevant for our understanding of similarities between addiction and obesity: lower self-control (high Disinhibition/low Conscientiousness), reward sensitivity (high Extraversion/Positive Emotionality), and negative affect (high Neuroticism/Negative Emotionality). Neurocognitive studies have shown that obesity and addiction are both associated with increased impulsive decision making and attention bias in response to drug or food cues, respectively. Mirroring this, obesity and different forms of addiction seem to exhibit similar alterations in functional MRI brain activity in response to reward processing and during self-control tasks. Overall, our review provides an integrative approach to understand those facets of obesity that present similarities to addictive behaviors. In addition, we suggest that therapeutic interventions targeting inhibitory control may represent a promising approach for the prevention and/or treatment of obesity. PMID- 28659870 TI - The Biogeographic Pattern of Microbial Functional Genes along an Altitudinal Gradient of the Tibetan Pasture. AB - As the highest place of the world, the Tibetan plateau is a fragile ecosystem. Given the importance of microbial communities in driving soil nutrient cycling, it is of interest to document the microbial biogeographic pattern here. We adopted a microarray-based tool named GeoChip 4.0 to investigate grassland microbial functional genes along an elevation gradient from 3200 to 3800 m above sea level open to free grazing by local herdsmen and wild animals. Interestingly, microbial functional diversities increase with elevation, so does the relative abundances of genes associated with carbon degradation, nitrogen cycling, methane production, cold shock and oxygen limitation. The range of Shannon diversities (10.27-10.58) showed considerably smaller variation than what was previously observed at ungrazed sites nearby (9.95-10.65), suggesting the important role of livestock grazing on microbial diversities. Closer examination showed that the dissimilarity of microbial community at our study sites increased with elevations, revealing an elevation-decay relationship of microbial functional genes. Both microbial functional diversity and the number of unique genes increased with elevations. Furthermore, we detected a tight linkage of greenhouse gas (CO2) and relative abundances of carbon cycling genes. Our biogeographic study provides insights on microbial functional diversity and soil biogeochemical cycling in Tibetan pastures. PMID- 28659871 TI - Comparative Genome Analysis Provides Insights into Both the Lifestyle of Acidithiobacillus ferrivorans Strain CF27 and the Chimeric Nature of the Iron Oxidizing Acidithiobacilli Genomes. AB - The iron-oxidizing species Acidithiobacillus ferrivorans is one of few acidophiles able to oxidize ferrous iron and reduced inorganic sulfur compounds at low temperatures (<10 degrees C). To complete the genome of At. ferrivorans strain CF27, new sequences were generated, and an update assembly and functional annotation were undertaken, followed by a comparative analysis with other Acidithiobacillus species whose genomes are publically available. The At. ferrivorans CF27 genome comprises a 3,409,655 bp chromosome and a 46,453 bp plasmid. At. ferrivorans CF27 possesses genes allowing its adaptation to cold, metal(loid)-rich environments, as well as others that enable it to sense environmental changes, allowing At. ferrivorans CF27 to escape hostile conditions and to move toward favorable locations. Interestingly, the genome of At. ferrivorans CF27 exhibits a large number of genomic islands (mostly containing genes of unknown function), suggesting that a large number of genes has been acquired by horizontal gene transfer over time. Furthermore, several genes specific to At. ferrivorans CF27 have been identified that could be responsible for the phenotypic differences of this strain compared to other Acidithiobacillus species. Most genes located inside At. ferrivorans CF27-specific gene clusters which have been analyzed were expressed by both ferrous iron-grown and sulfur attached cells, indicating that they are not pseudogenes and may play a role in both situations. Analysis of the taxonomic composition of genomes of the Acidithiobacillia infers that they are chimeric in nature, supporting the premise that they belong to a particular taxonomic class, distinct to other proteobacterial subgroups. PMID- 28659872 TI - Replications of Two Closely Related Groups of Jumbo Phages Show Different Level of Dependence on Host-encoded RNA Polymerase. AB - Ralstonia solanacearum phages PhiRP12 and PhiRP31 are jumbo phages isolated in Thailand. Here we show that they exhibit similar virion morphology, genome organization and host range. Genome comparisons as well as phylogenetic and proteomic tree analyses support that they belong to the group of PhiKZ-related phages, with their closest relatives being R. solanacearum phages PhiRSL2 and PhiRSF1. Compared with PhiRSL2 and PhiRSF1, PhiRP12 and PhiRP31 possess larger genomes (ca. 280 kbp, 25% larger). The replication of PhiRP12 and PhiRP31 was not affected by rifampicin treatment (20 MUg/ml), suggesting that phage-encoded RNAPs function to start and complete the infection cycle of these phages without the need of host-encoded RNAPs. In contrast, PhiRSL2 and PhiRSF1, encoding the same set of RNAPs, did not produce progeny phages in the presence of rifampicin (5 MUg/ml). This observation opens the possibility that some PhiRP12/PhiRP31 factors that are absent in PhiRSL2 and PhiRSF1 are involved in their host-independent transcription. PMID- 28659873 TI - Microbial Community Structure of Deep-sea Hydrothermal Vents on the Ultraslow Spreading Southwest Indian Ridge. AB - Southwest Indian Ridge (SWIR) is a typical oceanic ultraslow spreading ridge with intensive hydrothermal activities. The microbial communities in hydrothermal fields including primary producers to support the entire ecosystem by utilizing geochemical energy generated from rock-seawater interactions. Here we have examined the microbial community structures on four hydrothermal vents from SWIR, representing distinct characteristics in terms of temperature, pH and metal compositions, by using Illumina sequencing of the 16S small subunit ribosomal RNA (rRNA) genes, to correlate bacterial and archaeal populations with the nature of the vents influenced by ultraslow spreading features. Epsilon-, Gamma-, Alpha-, and Deltaproteobacteria and members of the phylum Bacteroidetes and Planctomycetes, as well as Thaumarchaeota, Woesearchaeota, and Euryarchaeota were dominant in all the samples. Both bacterial and archaeal community structures showed distinguished patterns compared to those in the fast-spreading East Pacific Ridge or the slow-spreading Mid-Atlantic Ridge as previously reported. Furthermore, within SWIR, the microbial communities are highly correlated with the local temperatures. For example, the sulfur-oxidizing bacteria were dominant within bacteria from low-temperature vents, but were not represented as the dominating group recovered from high temperature (over 300 degrees C) venting chimneys in SWIR. Meanwhile, Thaumarchaeota, the ammonium oxidizing archaea, only showed high relative abundance of amplicons in the vents with high-temperature in SWIR. These findings provide insights on the microbial community in ultraslow spreading hydrothermal fields, and therefore assist us in the understanding of geochemical cycling therein. PMID- 28659874 TI - The Deep-Sea Microbial Community from the Amazonian Basin Associated with Oil Degradation. AB - One consequence of oil production is the possibility of unplanned accidental oil spills; therefore, it is important to evaluate the potential of indigenous microorganisms (both prokaryotes and eukaryotes) from different oceanic basins to degrade oil. The aim of this study was to characterize the microbial response during the biodegradation process of Brazilian crude oil, both with and without the addition of the dispersant Corexit 9500, using deep-sea water samples from the Amazon equatorial margin basins, Foz do Amazonas and Barreirinhas, in the dark and at low temperatures (4 degrees C). We collected deep-sea samples in the field (about 2570 m below the sea surface), transported the samples back to the laboratory under controlled environmental conditions (5 degrees C in the dark) and subsequently performed two laboratory biodegradation experiments that used metagenomics supported by classical microbiological methods and chemical analysis to elucidate both taxonomic and functional microbial diversity. We also analyzed several physical-chemical and biological parameters related to oil biodegradation. The concomitant depletion of dissolved oxygen levels, oil droplet density characteristic to oil biodegradation, and BTEX concentration with an increase in microbial counts revealed that oil can be degraded by the autochthonous deep-sea microbial communities. Indigenous bacteria (e.g., Alteromonadaceae, Colwelliaceae, and Alcanivoracaceae), archaea (e.g., Halobacteriaceae, Desulfurococcaceae, and Methanobacteriaceae), and eukaryotic microbes (e.g., Microsporidia, Ascomycota, and Basidiomycota) from the Amazonian margin deep-sea water were involved in biodegradation of Brazilian crude oil within less than 48-days in both treatments, with and without dispersant, possibly transforming oil into microbial biomass that may fuel the marine food web. PMID- 28659875 TI - Predicting Species-Resolved Macronutrient Acquisition during Succession in a Model Phototrophic Biofilm Using an Integrated 'Omics Approach. AB - The principles governing acquisition and interspecies exchange of nutrients in microbial communities and how those exchanges impact community productivity are poorly understood. Here, we examine energy and macronutrient acquisition in unicyanobacterial consortia for which species-resolved genome information exists for all members, allowing us to use multi-omic approaches to predict species' abilities to acquire resources and examine expression of resource-acquisition genes during succession. Metabolic reconstruction indicated that a majority of heterotrophic community members lacked the genes required to directly acquire the inorganic nutrients provided in culture medium, suggesting high metabolic interdependency. The sole primary producer in consortium UCC-O, cyanobacterium Phormidium sp. OSCR, displayed declining expression of energy harvest, carbon fixation, and nitrate and sulfate reduction proteins but sharply increasing phosphate transporter expression over 28 days. Most heterotrophic members likewise exhibited signs of phosphorus starvation during succession. Though similar in their responses to phosphorus limitation, heterotrophs displayed species-specific expression of nitrogen acquisition genes. These results suggest niche partitioning around nitrogen sources may structure the community when organisms directly compete for limited phosphate. Such niche complementarity around nitrogen sources may increase community diversity and productivity in phosphate-limited phototrophic communities. PMID- 28659877 TI - Dynamic Acquisition and Loss of Dual-Obligate Symbionts in the Plant-Sap-Feeding Adelgidae (Hemiptera: Sternorrhyncha: Aphidoidea). AB - Sap-sucking insects typically engage in obligate relationships with symbiotic bacteria that play nutritional roles in synthesizing nutrients unavailable or in scarce supply from the plant-sap diets of their hosts. Adelgids are sap-sucking insects with complex life cycles that involve alternation between conifer tree species. While all adelgid species feed on spruce during the sexual phase of their life cycle, each adelgid species belongs to a major lineage that feeds on a distinct genus of conifers as their alternate host. Previous work on adelgid symbionts had discovered pairs of symbionts within each host species, and unusual diversity across the insect family, but left several open questions regarding the status of bacterial associates. Here, we explored the consistency of symbionts within and across adelgid lineages, and sought evidence for facultative vs. obligate symbiont status. Representative species were surveyed for symbionts using 16S ribosomal DNA gene sequencing, confirming that different symbiont pairs were consistently present within each major adelgid lineage. Several approaches were used to establish whether symbionts exhibited characteristics of long-term, obligate mutualists. Patterns of symbiont presence across adelgid species and diversification with host insects suggested obligate relationships. Fluorescent in situ hybridization and electron microscopy localized symbionts to bacteriocyte cells within the bacteriome of each species (with one previously known exception), and detection of symbionts in eggs indicated their vertical transmission. Common characteristics of long-term obligate symbionts, such as nucleotide compositional bias and pleomorphic symbiont cell shape were also observed. Superimposing microbial symbionts on the adelgid phylogeny revealed a dynamic pattern of symbiont gains and losses over a relatively short period of time compared to other symbionts associated with sap-sucking insects, with each adelgid species possessing an older, "senior" symbiont and a younger "junior" symbiont. A hypothesis relating adelgid life cycles to relaxed constraints on symbionts is proposed, with the degradation of senior symbionts and repeated acquisition of more junior symbionts creating opportunities for repeated colonization of new alternate-conifer hosts by adelgids. PMID- 28659876 TI - Improvement Strategies, Cost Effective Production, and Potential Applications of Fungal Glucose Oxidase (GOD): Current Updates. AB - Fungal glucose oxidase (GOD) is widely employed in the different sectors of food industries for use in baking products, dry egg powder, beverages, and gluconic acid production. GOD also has several other novel applications in chemical, pharmaceutical, textile, and other biotechnological industries. The electrochemical suitability of GOD catalyzed reactions has enabled its successful use in bioelectronic devices, particularly biofuel cells, and biosensors. Other crucial aspects of GOD such as improved feeding efficiency in response to GOD supplemental diet, roles in antimicrobial activities, and enhancing pathogen defense response, thereby providing induced resistance in plants have also been reported. Moreover, the medical science, another emerging branch where GOD was recently reported to induce several apoptosis characteristics as well as cellular senescence by downregulating Klotho gene expression. These widespread applications of GOD have led to increased demand for more extensive research to improve its production, characterization, and enhanced stability to enable long term usages. Currently, GOD is mainly produced and purified from Aspergillus niger and Penicillium species, but the yield is relatively low and the purification process is troublesome. It is practical to build an excellent GOD producing strain. Therefore, the present review describes innovative methods of enhancing fungal GOD production by using genetic and non-genetic approaches in depth along with purification techniques. The review also highlights current research progress in the cost effective production of GOD, including key advances, potential applications and limitations. Therefore, there is an extensive need to commercialize these processes by developing and optimizing novel strategies for cost effective GOD production. PMID- 28659878 TI - Detection and Physicochemical Characterization of Membrane Vesicles (MVs) of Lactobacillus reuteri DSM 17938. AB - Membrane vesicles (MVs) are bilayer structures which bleb from bacteria, and are important in trafficking biomolecules to other bacteria or host cells. There are few data about MVs produced by the Gram-positive commensal-derived probiotic Lactobacillus reuteri; however, MVs from this species may have potential therapeutic benefit. The aim of this study was to detect and characterize MVs produced from biofilm (bMVs), and planktonic (pMVs) phenotypes of L. reuteri DSM 17938. MVs were analyzed for structure and physicochemical characterization by Scanning Electron Microscope (SEM) and Dynamic Light Scattering (DLS). Their composition was interrogated using various digestive enzyme treatments and subsequent Transmission Electron Microscopy (TEM) analysis. eDNA (extracellular DNA) was detected and quantified using PicoGreen. We found that planktonic and biofilm of L. reuteri cultures generated MVs with a broad size distribution. Our data also showed that eDNA was associated with pMVs and bMVs (eMVsDNA). DNase I treatment demonstrated no modifications of MVs, suggesting that an eDNA-MVs complex protected the eMVsDNA. Proteinase K and Phospholipase C treatments modified the structure of MVs, showing that lipids and proteins are important structural components of L. reuteri MVs. The biological composition and the physicochemical characterization of MVs generated by the probiotic L. reuteri may represent a starting point for future applications in the development of vesicles based therapeutic systems. PMID- 28659879 TI - Co-registered Geochemistry and Metatranscriptomics Reveal Unexpected Distributions of Microbial Activity within a Hydrothermal Vent Field. AB - Despite years of research into microbial activity at diffuse flow hydrothermal vents, the extent of microbial niche diversity in these settings is not known. To better understand the relationship between microbial activity and the associated physical and geochemical conditions, we obtained co-registered metatranscriptomic and geochemical data from a variety of different fluid regimes within the ASHES vent field on the Juan de Fuca Ridge. Microbial activity in the majority of the cool and warm fluids sampled was dominated by a population of Gammaproteobacteria (likely sulfur oxidizers) that appear to thrive in a variety of chemically distinct fluids. Only the warmest, most hydrothermally-influenced flows were dominated by active populations of canonically vent-endemic Epsilonproteobacteria. These data suggest that the Gammaproteobacteria collected during this study may be generalists, capable of thriving over a broader range of geochemical conditions than the Epsilonproteobacteria. Notably, the apparent metabolic activity of the Gammaproteobacteria-particularly carbon fixation-in the seawater found between discrete fluid flows (the intra-field water) suggests that this area within the Axial caldera is a highly productive, and previously overlooked, habitat. By extension, our findings suggest that analogous, diffuse flow fields may be similarly productive and thus constitute a very important and underappreciated aspect of deep-sea biogeochemical cycling that is occurring at the global scale. PMID- 28659880 TI - Alkyl Protocatechuate-Loaded Nanostructured Lipid Systems as a Treatment Strategy for Paracoccidioides brasiliensis and Paracoccidioides lutzii In Vitro. AB - Dodecyl protocatechuate (dodecyl) is a derivative of protocatechuic acid (3,4 dihydroxybenzoic acid) that possesses anti-oxidant and antifungal properties. Nanostructured lipid systems (NLS) can potentiate the action of many antifungal agents, reducing the required dose and side effects by improving their activity. This work aimed to evaluate dodecyl protocatechuate loaded into a NLS (NLS+dodecyl) as a strategy for the treatment of Paracoccidioides brasiliensis and P. lutzii in vitro. Antifungal activity against P. brasiliensis and P. lutzii was evaluated using the microdilution technique. NLS+dodecyl showed high antifungal activity with a minimum inhibitory concentration ranging from 0.06 to 0.03 MUg/mL; 4- to 16-fold higher than that of free dodecyl. NLS+dodecyl was able to inhibit fungal adhesion of the extracellular artificial matrix proteins (laminin and fibronectin), resulting in 82.4 and 81% inhibition, respectively, an increase of 8-17% compared with free dodecyl. These findings corroborate previous results demonstrating 65 and 74% inhibition of fungal adhesion in pulmonary fibroblast cells by dodecyl and NLS+dodecyl, respectively, representing a 9% increase in inhibition for NLS+dodecyl. Subsequently, cytotoxicity was evaluated using the 0.4% sulforhodamine B assay. NLS+dodecyl did not exhibit cytotoxicity in MRC5 (human pneumocyte) and HepG2 (human hepatic carcinoma) cells, thus increasing the selectivity index for NLS+dodecyl. In addition, cytotoxicity was evaluated in vivo using the Caenorhabditis elegans model; neither dodecyl nor NLS+dodecyl exhibited any toxic effects. Taken together, these results suggest that NLS can be used as a strategy to improve the activity of dodecyl against P. brasiliensis and P. lutzii because it improves antifungal activity, increases the inhibition of fungal adhesion in lung cells and the extracellular matrix in vitro, and does not exhibit any toxicity both in vitro and in vivo. PMID- 28659881 TI - RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Active and Latent Mycobacterium tuberculosis Infection. AB - Tuberculosis (TB) has exceeded HIV as the most lethal infectious disease globally for two consecutive years. Moreover, one third of the world's population is estimated to have latent tuberculosis infection (LTBI). This is mainly because of difficulties associated with diagnosis and treatment for both TB and LTBI patients. Exosomes provide a promising research tool for TB diagnosis and treatment because they are released from various cells containing valuable biochemical information related to disease. In this study, we performed RNA sequencing analysis on exosomes derived from clinical specimens of healthy controls (HC), active tuberculosis (ATB), and LTBI patients. Our results revealed the distinct gene expression profiles of the exosomes from LTBI and ATB patients. (1) We identified many distinct up-regulated and down-regulated differentially expressed genes (DEGs) in LTBI and ATB samples, and further screened the top-20 DEGs which might provide a potential panel for differentiation of HC, LTBI, and ATB. (2) We classified all the DEGs into six expression patterns, screened the top-20 genes in each pattern, and mainly focused on those highly expressed in LTBI and ATB. (3) Some Mycobacterium tuberculosis (Mtb) RNAs were only enriched in the exosomes of LTBI samples. (4) Pathway and function analysis further indicated down-regulated signaling pathways/immune response and up-regulated apoptosis/necrosis. Our findings indicate the selective packaging of RNA cargoes into exosomes under different stages of Mtb infection, while facilitating the development of potential targets for the diagnosis, prevention and treatment of tuberculosis. PMID- 28659882 TI - Dendritic Cells Primed with Paracoccidioides brasiliensis Peptide P10 Are Therapeutic in Immunosuppressed Mice with Paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is an endemic systemic mycosis in Latin America, with the highest prevalence in Brazil, Colombia, and Venezuela. Fungi of the Paracoccidioides genus are etiologic agents of the disease. The 15 amino acid peptide P10 is derived from gp43, the main diagnostic antigen of Paracoccidioides brasiliensis. We previously reported that P10-pulsed dendritic cells (DCs) induce a protective response against P. brasiliensis. Presently, dexamethasone-treated BALB/c mice were intratracheally infected with P. brasiliensis Pb18 to establish the therapeutic efficacy of P10-pulsed DCs. Immunosuppressed and infected animals that received DCs had a reduction in their fungal burden, and this result was most pronounced in mice receiving DCs primed with P10. The efficacy of therapeutic DCs was significantly augmented by concomitant treatment with trimethoprim-sulfamethoxazole. Additionally, primed-DCs with or without the antifungal drug induced a beneficial Th1-biased immune response and significantly reduced tissue damage. In conclusion, these studies with immunocompromised mice demonstrate that P10-pulsed DCs with or without concomitant antifungal drugs are potently effective in combating invasive PCM. These findings support further translational studies to validate the use of P10-primed DCs for PCM in immunocompetent and immunosuppressed hosts. PMID- 28659883 TI - Transcriptional Alterations of Virulence-Associated Genes in Extended Spectrum Beta-Lactamase (ESBL)-Producing Uropathogenic Escherichia coli during Morphologic Transitions Induced by Ineffective Antibiotics. AB - It is known that an ineffective antibiotic treatment can induce morphological shifts in uropathogenic Escherichia coli (UPEC) but the virulence properties during these shifts remain to be studied. The present study examines changes in global gene expression patterns and in virulence factor-associated genes in an extended spectrum beta-lactamase (ESBL)-producing UPEC (ESBL019) during the morphologic transitions induced by an ineffective antibiotic and in the presence of human primary bladder epithelial cells. Microarray results showed that the different morphological states of ESBL019 had significant transcriptional alterations of a large number of genes (Transition; 7%, Filamentation; 32%, and Reverted 19% of the entities on the array). All three morphological states of ESBL019 were associated with a decreased energy metabolism, altered iron acquisition systems and altered adhesion expression. In addition, genes associated with LPS synthesis and bacterial motility was also altered in all the morphological states. Furthermore, the transition state induced a significantly higher release of TNF-alpha from bladder epithelial cells compared to all other morphologies, while the reverted state was unable to induce TNF-alpha release. Our findings show that the morphological shifts induced by ineffective antibiotics are associated with significant transcriptional virulence alterations in ESBL-producing UPEC, which may affect survival and persistence in the urinary tract. PMID- 28659884 TI - Fungal Glucosylceramide-Specific Camelid Single Domain Antibodies Are Characterized by Broad Spectrum Antifungal Activity. AB - Chemical crop protection is widely used to control plant diseases. However, the adverse effects of pesticide use on human health and environment, resistance development and the impact of regulatory requirements on the crop protection market urges the agrochemical industry to explore innovative and alternative approaches. In that context, we demonstrate here the potential of camelid single domain antibodies (VHHs) generated against fungal glucosylceramides (fGlcCer), important pathogenicity factors. To this end, llamas were immunized with purified fGlcCer and a mixture of mycelium and spores of the fungus Botrytis cinerea, one of the most important plant pathogenic fungi. The llama immune repertoire was subsequently cloned in a phage display vector to generate a library with a diversity of at least 108 different clones. This library was incubated with fGlcCer to identify phages that bind to fGlcCer, and VHHs that specifically bound fGlcCer but not mammalian or plant-derived GlcCer were selected. They were shown to inhibit the growth of B. cinerea in vitro, with VHH 41D01 having the highest antifungal activity. Moreover, VHH 41D01 could reduce disease symptoms induced by B. cinerea when sprayed on tomato leaves. Based on all these data, anti-fGlcCer VHHs show the potential to be used as an alternative approach to combat fungal plant diseases. PMID- 28659885 TI - Importance of Campylobacter jejuni FliS and FliW in Flagella Biogenesis and Flagellin Secretion. AB - Flagella-driven motility enables bacteria to reach their favorable niche within the host. The human foodborne pathogen Campylobacter jejuni produces two heavily glycosylated structural flagellins (FlaA and FlaB) that form the flagellar filament. It also encodes the non-structural FlaC flagellin which is secreted through the flagellum and has been implicated in host cell invasion. The mechanisms that regulate C. jejuni flagellin biogenesis and guide the proteins to the export apparatus are different from those in most other enteropathogens and are not fully understood. This work demonstrates the importance of the putative flagellar protein FliS in C. jejuni flagella assembly. A constructed fliS knockout strain was non-motile, displayed reduced levels of FlaA/B and FlaC flagellin, and carried severely truncated flagella. Pull-down and Far Western blot assays showed direct interaction of FliS with all three C. jejuni flagellins (FlaA, FlaB, and FlaC). This is in contrast to, the sensor and regulator of intracellular flagellin levels, FliW, which bound to FlaA and FlaB but not to FlaC. The FliS protein but not FliW preferred binding to glycosylated C. jejuni flagellins rather than to their non-glycosylated recombinant counterparts. Mapping of the binding region of FliS and FliW using a set of flagellin fragments showed that the C-terminal subdomain of the flagellin was required for FliS binding, whereas the N-terminal subdomain was essential for FliW binding. The separate binding subdomains required for FliS and FliW, the different substrate specificity, and the differential preference for binding of glycosylated flagellins ensure optimal processing and assembly of the C. jejuni flagellins. PMID- 28659887 TI - Integrated Interventions to Tackle Antimicrobial Usage in Animal Production Systems: The ViParc Project in Vietnam. AB - Antimicrobial usage and antimicrobial resistance (AMR) in animal production is now recognized to be an important contributor to the global problem of AMR. Initiatives to curb indiscriminate antimicrobial use in animal production are currently being discussed in many low- and middle-income countries. Well designed, scientifically sound interventions aimed to tackle excessive antimicrobial usage should provide scientists and policy makers with evidence of the highest quality to guide changes in policy and to formulate better targeted research initiatives. However, since large-scale interventions are costly, they require careful planning in order not to waste valuable resources. Here, we describe the components of the ViParc project (www.viparc.org), one of the first large-scale interventions of its kind to tackle excessive antimicrobial usage in Southeast Asian animal production systems. The project has been formulated as a "randomized before-and-after controlled study" targeting small-scale poultry farms in the Mekong Delta region of Vietnam. It aims to provide farmers with a locally-adapted veterinary support service to help them reduce their reliance on antimicrobials. ViParc has been developed in the backdrop of efforts by the Government of Vietnam to develop a National Action Plan to reduce Antimicrobials in Livestock and Aquaculture. Crucially, the project integrates socio-economic analyses that will provide insights into the drivers of antimicrobial usage, as well as an assessment of the cost-effectiveness of the proposed intervention. Information generated from ViParc should help the Government of Vietnam refine its policies to curb excessive antimicrobial usage in poultry production, while lessons from ViParc will help tackle excessive antimicrobial usage in other productions systems in Vietnam and in the broader Southeast Asian region. PMID- 28659886 TI - Molecular Epidemiology and Risk Factors of Carbapenem-Resistant Klebsiella pneumoniae Infections in Eastern China. AB - Background: The increasing prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses an immediate threat to treatment worldwide. This retrospective study assessed the molecular epidemiology and determined the risk factors for and outcomes of CRKP infections in a general teaching hospital in Shanghai, China. Methods: From January 2013 to July 2015, 100 consecutive unique CRKP isolates isolated from hospitalized patients were collected. Isolates were screened for antibiotic resistance genes by polymerase chain reaction and molecular typing was performed by pulsed-field gel electrophoresis (PFGE). Patients infected with CRKP comprised the case group and were compared to the control group of patients infected with carbapenem-susceptible Klebsiella pneumoniae. Therapeutic effects were compared in the CRKP infection group. Results: Among the 100 CRKP isolates, the percentages of multidrug-resistant, extensively drug-resistant (XDR), and pandrug-resistant were 50.0, 50.0, and 0%, respectively. All the CRKP isolates produced KPC-2 and could be divided into 18 PFGE clusters (A-O) and 70 subtypes. No dominant intra-hospital PFGE type was detected using a cutoff of 80% similarity. The ratio of CRKP infection to colonization was 51 to 49. Risk factors correlated with CRKP infection included pulmonary disease (p = 0.038), ICU stay (p = 0.002), invasive ventilation (p = 0.009), blood transfusion (p = 0.028), parenteral nutrition (p = 0.004), sputum suction (p = 0.006), medical history of previous hospitalization (p = 0.022), exposure to antibiotics 90 days before infection (p = 0.030), and antibiotic exposure during hospital stay including carbapenems (p = 0.013), enzyme inhibitors (p = 0.021), nitroimidazoles (p = 0.029), and glycopeptides (p = 0.000). Multivariable analysis showed that sputum suction (odds ratio 3.090, 95% confidence intervals 1.004-9.518, p = 0.049) was an independent risk factor for CRKP infections. Patients infected with CRKP with longer carbapenems treatment course (p = 0.002) showed better outcome. Conclusion: This study showed the severity of CRKP infection in eastern China. Sputum suction was an independent risk factor for CRKP infection. Prolonged duration of treatment with carbapenems benefited the patients infected with CRKP. PMID- 28659889 TI - Rapid Phenotypic Detection of Microbial Resistance in Gram-Positive Bacteria by a Real-Time Laser Scattering Method. AB - We developed a methodology for antimicrobial susceptibility testing (AST) based on the BacterioScanTM216R laser scattering technology, using methicillin resistance in Staphylococcus aureus and vancomycin resistance in enterococci as exemplar for important resistance phenotypes. Fifty methicillin-resistant (MRSA) and 50 methicillin-susceptible (MSSA) S. aureus, as well as 50 vancomycin resistant enterococci (VRE) and 50 vancomycin-susceptible enterococci (VSE) isolates were used for the study. Optimal test conditions were derived by investigating the effects of inoculum size, medium, incubation temperature and broth filtration. We proposed four different statistical approaches for rapid discrimination between resistant and susceptible bacteria. The statistical approach based on raw measurements of bacterial concentrations delivered sensitivity of 100% and specificity of 94% for discrimination between MRSA and MSSA already after 3 hours of incubation. Categorical agreement of >=90% was achieved after 140 min with this approach. Differentiation between VRE and VSE was possible with 98% sensitivity and 92% specificity after 3 hours, using a sophisticated statistical approach based on concentration slopes derived from the raw concentration measurements. This approach provided categorical agreement of >=90% after 165 min. The sensitivity and specificity estimates were confirmed by leave-one-out cross validation. In conclusion, the phenotypic AST methods developed in this study are promising for rapid detection of MRSA and VRE. The development and application of this technology would allow early detection of the resistant pathogens, thus facilitating swift change to the targeted antimicrobial treatment as well as timely initiation of appropriate infection control measures. Further studies are warranted to validate this approach for the detection of other resistance phenotypes, including direct testing from clinical specimens. PMID- 28659888 TI - Genome-Wide Analysis of Secondary Metabolite Gene Clusters in Ophiostoma ulmi and Ophiostoma novo-ulmi Reveals a Fujikurin-Like Gene Cluster with a Putative Role in Infection. AB - The emergence of new microbial pathogens can result in destructive outbreaks, since their hosts have limited resistance and pathogens may be excessively aggressive. Described as the major ecological incident of the twentieth century, Dutch elm disease, caused by ascomycete fungi from the Ophiostoma genus, has caused a significant decline in elm tree populations (Ulmus sp.) in North America and Europe. Genome sequencing of the two main causative agents of Dutch elm disease (Ophiostoma ulmi and Ophiostoma novo-ulmi), along with closely related species with different lifestyles, allows for unique comparisons to be made to identify how pathogens and virulence determinants have emerged. Among several established virulence determinants, secondary metabolites (SMs) have been suggested to play significant roles during phytopathogen infection. Interestingly, the secondary metabolism of Dutch elm pathogens remains almost unexplored, and little is known about how SM biosynthetic genes are organized in these species. To better understand the metabolic potential of O. ulmi and O. novo-ulmi, we performed a deep survey and description of SM biosynthetic gene clusters (BGCs) in these species and assessed their conservation among eight species from the Ophiostomataceae family. Among 19 identified BGCs, a fujikurin like gene cluster (OpPKS8) was unique to Dutch elm pathogens. Phylogenetic analysis revealed that orthologs for this gene cluster are widespread among phytopathogens and plant-associated fungi, suggesting that OpPKS8 may have been horizontally acquired by the Ophiostoma genus. Moreover, the detailed identification of several BGCs paves the way for future in-depth research and supports the potential impact of secondary metabolism on Ophiostoma genus' lifestyle. PMID- 28659890 TI - Pre-cultivation with Selected Prebiotics Enhances the Survival and the Stress Response of Lactobacillus rhamnosus Strains in Simulated Gastrointestinal Transit. AB - In our study, we dwelled upon combinations of lactobacilli/prebiotics, considering four different strains belonging to the Lactobacillus rhamnosus species, including Lactobacillus rhamnosus GG (LGG), and different prebiotics often found in commercial synbiotic products, such as inulin, lactulose and polyols mannitol and sorbitol. In the first step of the research, the survival, the growth kinetic parameters and the protein expression of Lb. rhamnosus strains cultivated in presence of the different prebiotics as a unique carbon source were evaluated. In the second step, the influence of pre-cultivation in medium added of metabolizable prebiotics on the strains survival to simulated gastrointestinal (GI) transit, assayed without prebiotics addition, was estimated. Our results showed that the presence in the medium of certain low fermented prebiotics, specific for each strain, represents a stress factor that significantly affects the growth of Lb. rhamnosus strains, inducing the up-regulation of several proteins. In detail, all added prebiotics used as unique carbon source caused a growth retard compared with glucose, as testified by increased values of the lag phase and decreased values of the MUmax. Mannitol evidenced intermediate MUmax values between those registered with glucose and those detected with the other assayed prebiotics. Moreover, the cultivation with prebiotics induced the over expression of 7 protein bands. Interestingly, we found a correlation between the up-regulation of two specific stress proteins, called P4 (ATP-binding subunit Clpx) and P7 (GrpE), and the death kinetic parameters (resistance and cells viability) registered during the simulated GI transit of strains pre-cultivated with specific, low fermented prebiotics. Specifically, the highest resistance and gastric-vitality scores were highlighted for the strain AT195 when pre-cultivated in presence of sorbitol. Conversely, the lowest values were found in the case of DSM20021 pre-cultivated with mannitol. Among the up-regulated stress proteins, P7 resulted involved in the response to the starvation. Finally, it is possible to conclude that the pre-cultivation with certain prebiotics as a unique carbon source represents a strain-specific, sub-lethal stress able to enhance the resistance of Lb. rhamnosus strains and consequently their viability under simulated GI transit. PMID- 28659891 TI - Original XPCTM Effect on Salmonella Typhimurium and Cecal Microbiota from Three Different Ages of Broiler Chickens When Incubated in an Anaerobic In Vitro Culture System. AB - Feed supplements are utilized in the poultry industry as a means for improving growth performance and reducing pathogens. The aim of the present study was to evaluate the effects of Diamond V Original XPCTM (XPC, a fermented product generated from yeast cultures) on Salmonella Typhimurium ST 97 along with its potential for modulation of the cecal microbiota by using an anaerobic in vitro mixed culture assay. Cecal slurries obtained from three broiler chickens at each of three sampling ages (14, 28, and 42 days) were generated and exposed to a 24 h pre-incubation period with the various treatments: XPC (1% XPC, ceca, and feeds), CO (ceca only), and NC (negative control) group consisting of ceca and feeds. The XPC, CO, and NC were each challenged with S. Typhimurium and subsequently plated on selective media at 0, 24, and 48 h. Plating results indicated that the XPC treatment significantly reduced the survival of S. Typhimurium at the 24 h plating time point for both the 28 and 42 days bird sampling ages, while S. Typhimurium reduction in the NC appeared to eventually reach the same population survival level at the 48 h plating time point. For microbiome analysis, Trial 1 revealed that XPC, CO, and NC groups exhibited a similar pattern of taxa summary. However, more Bacteroidetes were observed in the CO group at 24 and 48 h. There were no significant differences (P > 0.05) in alpha diversity among samples based on day, hour and treatment. For beta diversity analysis, a pattern shift was observed when samples clustered according to sampling hour. In Trial 2, both XPC and NC groups exhibited the highest Firmicutes level at 0 h but the Bacteroidetes group became dominant at 6 h. Complexity of alpha diversity was increased in the initial contents from older birds and became less complex after 6 h of incubation. Beta diversity analysis was clustered as a function of treatment NC and XPC groups and by individual hours including 6, 12, 24, and 48 h. Overall, addition of XPC influenced microbiome diversity in a similar fashion to the profile of the NC group. PMID- 28659892 TI - A Complex Endomembrane System in the Archaeon Ignicoccus hospitalis Tapped by Nanoarchaeum equitans. AB - Based on serial sectioning, focused ion beam scanning electron microscopy (FIB/SEM), and electron tomography, we depict in detail the highly unusual anatomy of the marine hyperthermophilic crenarchaeon, Ignicoccus hospitalis. Our data support a complex and dynamic endomembrane system consisting of cytoplasmic protrusions, and with secretory function. Moreover, we reveal that the cytoplasm of the putative archaeal ectoparasite Nanoarchaeum equitans can get in direct contact with this endomembrane system, complementing and explaining recent proteomic, transcriptomic and metabolomic data on this inter-archaeal relationship. In addition, we identified a matrix of filamentous structures and/or tethers in the voluminous inter-membrane compartment (IMC) of I. hospitalis, which might be responsible for membrane dynamics. Overall, this unusual cellular compartmentalization, ultrastructure and dynamics in an archaeon that belongs to the recently proposed TACK superphylum prompts speculation that the eukaryotic endomembrane system might originate from Archaea. PMID- 28659893 TI - Live Probiotic Lactobacillus johnsonii BS15 Promotes Growth Performance and Lowers Fat Deposition by Improving Lipid Metabolism, Intestinal Development, and Gut Microflora in Broilers. AB - Numerous studies have focused on the beneficial effects of probiotics in animals. Even so, additional information should be obtained about the mechanisms by which a useful probiotic strain successfully exerts such beneficial effects. In this study, we evaluated the effect of the dietary supplementation of both live and disrupted Lactobacillus johnsonii (LJ) strain BS15 in broilers at different ages. Specifically, growth performance, lipid metabolism, gut microbiota, intestinal development, and digestive ability of the broilers were assessed. A total of 180 1-day-old Cobb 500 chicks were randomly distributed into three groups. These chicks were fed diets supplemented with 1 * 106 colony-forming units (cfu) LJ per gram of feed (LJ group); 1 * 106 cfu disrupted LJ per gram of feed (D-LJ group); and de Man, Rogosa, and Sharpe liquid medium (control group), respectively, throughout a 42-day experimental period. The results demonstrated that LJ supplementation of feed had a positive effect on the average daily gain and starter feed conversion ratio. In addition, LJ supplementation of feed decreased serum triglyceride and low-density lipid cholesterol levels, as well as abdominal fat deposition. LJ also reduced the mRNA levels of lipoprotein lipase in adipose tissue and stearoyl-CoA desaturase-1 in the liver. LJ diminished the mRNA quantities of the sterol regulatory element binding protein-1c and fatty acid synthase, as well as increased the level of serum high-density lipid cholesterol. LJ increased the mRNA quantities of peroxisome proliferator-activated receptor alpha, acyl-CoA oxidase in the liver, and carnitine palmitoyltransferase-1. LJ also improved the intestinal development and digestive ability mainly by increasing the villus height/crypt depth ratio in the ileum. The probiotic increased the levels of epidermal growth factor and insulin-like growth factor-1, as well as the activities of trypsin and lipase in the jejunum and ileum. LJ exerted beneficial effects on the intestinal flora. Specifically, LJ markedly enhanced the population of Bacteroidetes and Lactobacillus spp. Moreover, the probiotic reduced the population of Enterobacteriaceae and the Firmicutes/Bacteroidetes ratio. Slight changes caused by disrupted LJ were detected. These findings indicated that live LJ supplementation may promote growth performance and lower fat deposition in broilers. PMID- 28659894 TI - Thyme Oil Reduces Biofilm Formation and Impairs Virulence of Xanthomonas oryzae. AB - Xanthomonas oryzae pv. oryzae (Xoo), a common bacterial plant pathogen regulates its virulence and biofilm formation attribute via a chemical method of communication. Disabling this mechanism offers a promising alternative to reduce the virulence and pathogencity of the microorganism. In this study, the effect of thyme (THY) oil on Quorum Sensing mediated synthesis of various virulence factors and biofilm formation was analyzed. Treatment of Xoo with 500 ppm THY oil displayed a significant diminution in swimming, swarming, exopolysaccharide and xanthomonadin secretion. However, no effect was observed on bacterial growth kinetics and metabolic activity of the cells. Results were further authenticated by RT-qPCR as significant reduction in motA, motB, and flgE genes was observed upon THY oil treatment. Similarly, the expression of some extracellular enzyme genes such as endoglucanase, xylanase, cellobiosidase, and polygalacturonase was also found to be significantly reduced. However, biochemical plate assays revealed insignificant effect of 500 ppm THY oil on secretion of protease, cellulase, and lipase enzymes. The rpfF gene known to play a crucial role in the virulence of the phytopathogenic bacteria was also significantly reduced in the THY oil treated Xoo cells. HPTLC analysis further revealed significant reduction in DSF and BDSF signaling molecules when Xoo cells were treated with 500 ppm THY oil. Disease reduction was observed in in vitro agar plate assay as lesion length was reduced in THY oil treated Xoo cells when compared with the alone treatment. GC-MS result revealed thymol as the active and major component of THY oil which showed potential binding with rpfF gene. Application of 75 MUM thymol resulted in downregulation of gumC, motA, estA, virulence acvB and pglA along with rpfF. The other genes such as cheD, flgA, cheY, and pilA, were not found to be significantly affected. Overall, the results clearly indicated THY oil and its active component Thymol to be a potential candidate for the development of anti virulence agent which in future when applied in combination with conventional bactericides might not only help in lowering the dose of bactericides but also be successful in curbing the disease progression in rice. PMID- 28659895 TI - Autoinducer-2 Quorum Sensing Influences Viability of Escherichia coli O157:H7 under Osmotic and In Vitro Gastrointestinal Stress Conditions. AB - Bacteria use autoinducer molecules to communicate both at intra-species and inter species levels by quorum sensing. One such cell density-dependent signaling system is the luxS-mediated universal quorum sensing using autoinducer-2 (AI-2). Virulence of several pathogens is determined by an AI-2 system and is related to colonization and infection of the host. From this concept, numerous papers have suggested that AI-2 inhibition is an important strategy toward designing of new antimicrobial agents. However, recent studies indicate that the AI-2 system is also involved in adaptation and survival under environmental stress conditions. Therefore, we hypothesized that interaction between quorum sensing and environmental conditions may be critical in influencing predicted results in a control and when combating of target pathogens. We investigated the growth of enterohemorrhagic Escherichia coli O157:H7 (EHEC) and its luxS-deficient (non AI 2 producing) mutant strain under various stress conditions, and found significant differences in the growth rate under osmotic stress. Moreover, we could also show the impact of the AI-2 molecule on viability in the gastrointestinal tract model representing a complex environmental condition. Differences in vital responses of the strains suggest that AI-2 quorum sensing has a significant influence on the viability of EHEC under environmental stress conditions. PMID- 28659896 TI - The Impact of Hydration and Temperature on Bacterial Diversity in Arid Soil Mesocosms. AB - Hot desert ecosystems experience rare and unpredictable rainfall events that resuscitate the arid flora and fauna. However, the effect of this sudden abundance of water on soil microbial communities is still under debate. We modeled varying rainfall amounts and temperatures in desert soil mesocosms and monitored the microbial community response over a period of 21 days. We studied two different wetting events, simulating heavy (50 mm) and light (10 mm) rain, as well as three different temperature regimes: constant 25 degrees or 36 degrees C, or a temperature diurnal cycle alternating between 36 and 10 degrees C. Amplicon sequencing of the bacterial ribosomal RNA revealed that rain intensity affects the soil bacterial community, but the effects are mitigated by temperature. The combination of water-pulse intensity with lower temperature had the greatest effect on the bacterial community. These experiments demonstrated that the soil microbial response to rain events is dependent not only on the intensity of the water pulse but also on the ambient temperature, thus emphasizing the complexity of bacterial responses to highly unpredictable environments. PMID- 28659897 TI - Comparison of Biochemical Properties of HIV-1 and HIV-2 Capsid Proteins. AB - Timely disassembly of viral core composed of self-assembled capsid (CA) in infected host cells is crucial for retroviral replication. Extensive in vitro studies to date on the self-assembly/disassembly mechanism of human immunodeficiency virus type 1 (HIV-1) CA have revealed its core structure and amino acid residues essential for CA-CA intermolecular interaction. However, little is known about in vitro properties of HIV-2 CA. In this study, we comparatively analyzed the polymerization properties of bacterially expressed HIV 1 and HIV-2 CA proteins. Interestingly, a much higher concentration of NaCl was required for HIV-2 CA to self-assemble than that for HIV-1 CA, but once the polymerization started, the reaction proceeded more rapidly than that observed for HIV-1 CA. Analysis of a chimeric protein revealed that N-terminal domain (NTD) is responsible for this unique property of HIV-2 CA. To further study the molecular basis for different in vitro properties of HIV-1 and HIV-2 CA proteins, we determined thermal stabilities of HIV-1 and HIV-2 CA NTD proteins at several NaCl concentrations by fluorescent-based thermal shift assays. Experimental data obtained showed that HIV-2 CA NTD was structurally more stable than HIV-1 CA NTD. Taken together, our results imply that distinct in vitro polymerization abilities of the two CA proteins are related to their structural instability/stability, which is one of the decisive factors for viral replication potential. In addition, our assay system described here may be potentially useful for searching for anti-CA antivirals against HIV-1 and HIV-2. PMID- 28659899 TI - A Novel Method to Titrate Herpes Simplex Virus-1 (HSV-1) Using Laser-Based Scanning of Near-Infrared Fluorophores Conjugated Antibodies. AB - Among several strategies used for Herpes simplex virus (HSV) detection in biological specimens, standard plaque assay (SPA) remains the most reliable method to evaluate virus infectivity and quantify viral replication. However, it is a manual procedure, thereby affected by operator subjectivity, and it may be particularly laborious for multiple sample analysis. Here we describe an innovative method to perform the titration of HSV type 1 (HSV-1) in different samples, using the "In-Cell WesternTM" Assay (ICW) from LI-COR, a quantitative immunofluorescence assay that exploits laser-based scanning of near infrared (NIR). In particular, we employed NIR-immunodetection of viral proteins to monitor foci of HSV-1 infection in cell monolayers, and exploited an automated detection of their fluorescence intensity to evaluate virus titre. This innovative method produced similar and superimposable values compared to SPA, but it is faster and can be performed in 96 well plate, thus allowing to easily and quickly analyze and quantify many samples in parallel. These features make our method particularly suitable for the screening and characterization of antiviral compounds, as we demonstrated by testing acyclovir (ACV), the main anti-HSV-1 drug. Moreover, we developed a new data analysis system that allowed to overcome potential bias due to unspecific florescence signals, thus improving data reproducibility. Overall, our method may represents a useful tool for both clinical and research purposes. PMID- 28659898 TI - Biological Characterizations of H5Nx Avian Influenza Viruses Embodying Different Neuraminidases. AB - The H5 subtype virus of Highly Pathogenic Avian Influenza Virus has caused huge economic losses to the poultry industry and is a threat to human health. Until 2010, H5N1 subtype virus was the major genotype in China. Since 2011, reassortant H5N2, H5N6, and H5N8 viruses were identified in domestic poultry in China. The clade 2.3.4.4 H5N6 and H5N8 AIV has now spread to most of China. Clade 2.3.4.4 H5N6 virus has caused 17 human deaths. However, the prevalence, pathogenicity, and transmissibility of the distinct NA reassortment with H5 subtypes viruses (H5Nx) is unknown. We constructed five clade 2.3.4.4 reassortant H5Nx viruses that shared the same HA and six internal gene segments. The NA gene segment was replaced with N1, N2, N6, DeltaN6 (with an 11 amino acid deletion at the 58th to 68th of NA stalk region), and N8 strains, respectively. The reassortant viruses with distinct NAs of clade 2.3.4.4 H5 subtype had different degrees of fitness. All reassortant H5Nx viruses formed plaques on MDCK cell monolayers, but the DeltaH5N6 grew more efficiently in mammalian and avian cells. The reassortant H5Nx viruses were more virulent in mice as compared to the H5N2 virus. The H5N6 and H5N8 reassortant viruses exhibited enhanced pathogenicity and transmissibility in chickens as compared to the H5N1 reassortant virus. We suggest that comprehensive surveillance work should be undertaken to monitor the H5Nx viruses. PMID- 28659900 TI - Efficacy of Live-Attenuated H9N2 Influenza Vaccine Candidates Containing NS1 Truncations against H9N2 Avian Influenza Viruses. AB - H9N2 avian influenza virus is a zoonotic agent with a broad host range that can contribute genetic information to H5 or H7N9 subtype viruses, which are significant threats to both humans and birds. Thus, there is a great need for a vaccine to control H9N2 avian influenza. Three mutant viruses of an H9N2 virus A/chicken/Taixing/10/2010 (rTX-NS1-73, rTX-NS1-100, and rTX-NS1-128) were constructed with different NS1 gene truncations and confirmed by western blot analysis. The genetic stability, pathogenicity, transmissibility, and host immune responses toward these mutants were evaluated. The mutant virus rTX-NS1-128 exhibited the most attenuated phenotype and lost transmissibility. The expression levels of interleukin 12 in the nasal and tracheal tissues from chickens immunized with rTX-NS1-128 were significantly upregulated on day 3 post immunization and the IgA and IgG antibody levels were significantly increased on days 7, 14, and 21 post-immunization when compared to chickens that received an inactivated vaccine. rTX-NS1-128 also protected chickens from challenge by homologous and heterologous H9N2 avian influenza viruses. The results indicate that rTX-NS1-128 can be used as a potential live-attenuated vaccine against H9N2 avian influenza. PMID- 28659901 TI - Prevalence and Antimicrobial Susceptibility of Vibrio parahaemolyticus Isolated from Short Mackerels (Rastrelliger brachysoma) in Malaysia. AB - Numerous prevalence studies and outbreaks of Vibrio parahaemolyticus infection have been extensively reported in shellfish and crustaceans. Information on the quantitative detection of V. parahaemolyticus in finfish species is limited. In this study, short mackerels (Rastrelliger brachysoma) obtained from different retail marketplaces were monitored with the presence of total and pathogenic strains of V. parahaemolyticus. Out of 130 short mackerel samples, 116 (89.2%) were detected with the presence of total V. parahaemolyticus and microbial loads of total V. parahaemolyticus ranging from <3 to >105 MPN/g. Prevalence of total V. parahaemolyticus was found highest in wet markets (95.2%) followed by minimarkets (89.1%) and hypermarkets (83.3%). Pathogenic V. parahaemolyticus strains (tdh+ and/or trh+) were detected in 16.2% (21 of 130) of short mackerel samples. The density of tdh+ V. parahaemolyticus strains were examined ranging from 3.6 to >105 MPN/g and microbial loads of V. parahaemolyticus strains positive for both tdh and trh were found ranging from 300 to 740 MPN/g. On the other hand, antibiotic susceptibility profiles of V. parahaemolyticus strains isolated from short mackerels were determined through disc diffusion method in this study. Assessment of antimicrobial susceptibility profile of V. parahaemolyticus revealed majority of the isolates were highly susceptible to ampicillin sulbactam, meropenem, ceftazidime, and imipenem, but resistant to penicillin G and ampicillin. Two isolates (2.99%) exhibited the highest multiple antibiotic resistance (MAR) index value of 0.41 which shown resistance to 7 antibiotics. Results of the present study demonstrated that the occurrence of pathogenic V. parahaemolyticus strains in short mackerels and multidrug resistance of V. parahaemolyticus isolates could be a potential public health concerns to the consumer. Furthermore, prevalence data attained from the current study can be further used to develop a microbial risk assessment model to estimate health risks associated with the consumption of short mackerels contaminated with pathogenic V. parahaemolyticus. PMID- 28659902 TI - Erythritol Availability in Bovine, Murine and Human Models Highlights a Potential Role for the Host Aldose Reductase during Brucella Infection. AB - Erythritol is the preferential carbon source for most brucellae, a group of facultative intracellular bacteria that cause a worldwide zoonosis. Since this polyol is abundant in genital organs of ruminants and swine, it is widely accepted that erythritol accounts at least in part for the characteristic genital tropism of brucellae. Nevertheless, proof of erythritol availability and essentiality during Brucella intracellular multiplication has remained elusive. To investigate this relationship, we compared DeltaeryH (erythritol-sensitive and thus predicted to be attenuated if erythritol is present), DeltaeryA (erythritol tolerant but showing reduced growth if erythritol is a crucial nutrient) and wild type B. abortus in various infection models. This reporting system indicated that erythritol was available but not required for B. abortus multiplication in bovine trophoblasts. However, mice and humans have been considered to lack erythritol, and we found that it was available but not required for B. abortus multiplication in human and murine trophoblastic and macrophage-like cells, and in mouse spleen and conceptus (fetus, placenta and envelopes). Using this animal model, we found that B. abortus infected cells and tissues contained aldose reductase, an enzyme that can account for the production of erythritol from pentose cycle precursors. PMID- 28659903 TI - Antibacterial Activity of Silver Nanoparticles against Staphylococcus warneri Synthesized Using Endophytic Bacteria by Photo-irradiation. AB - Diseases caused by Staphylococcus warneri have a significant impact on human health. We evaluated the antibacterial activity of silver nanoparticles (synthesized using the endophytic strain SYSU 333150) against S. warneri. The strain SYSU 333150 was isolated from the roots of Borszczowia aralocaspica Bunge. The 16S rRNA sequence results suggest that SYSU 333150 belongs to the genus Isoptericola and is likely a new species. Photo-irradiation was used to synthesize silver nanoparticles, which were characterized using UV-visible spectroscopy, transmission electron microscopy and X-ray diffraction. The nanoparticles were spherical and measured to be11 to 40 nm. X-ray diffraction revealed four peaks corresponding to the 111, 200, 220, and 311 planes of the face-centered cubic lattice, indicating a crystalline nature. Fourier transform infrared spectroscopy suggested that the metabolites in the culture supernatant were likely reducing and capping agents. The silver nanoparticles possessed antimicrobial activity (14 mm zone of inhibition) against S. warneri, which was likely a result of DNA cleavage. The synthesized silver nanoparticles have potent antibacterial activity against S. warneri and can be used to control infection. PMID- 28659904 TI - Antimicrobial Potential of Bacteria Associated with Marine Sea Slugs from North Sulawesi, Indonesia. AB - Nudibranchia, marine soft-bodied organisms, developed, due to the absence of a protective shell, different strategies to protect themselves against putative predators and fouling organisms. One strategy is to use chemical weapons to distract predators, as well as pathogenic microorganisms. Hence, these gastropods take advantage of the incorporation of chemical molecules. Thereby the original source of these natural products varies; it might be the food source, de novo synthesis from the sea slug, or biosynthesis by associated bacteria. These bioactive molecules applied by the slugs can become important drug leads for future medicinal drugs. To test the potential of the associated bacteria, the latter were isolated from their hosts, brought into culture and extracts were prepared and tested for antimicrobial activities. From 49 isolated bacterial strains 35 showed antibiotic activity. The most promising extracts were chosen for further testing against relevant pathogens. In that way three strains showing activity against methicillin resistant Staphylococcus aureus and one strain with activity against enterohemorrhagic Escherichia coli, respectively, were identified. The obtained results indicate that the sea slug associated microbiome is a promising source for bacterial strains, which hold the potential for the biotechnological production of antibiotics. PMID- 28659905 TI - Long-Term Survey Is Necessary to Reveal Various Shifts of Microbial Composition in Corals. AB - The coral holobiont is the assemblage of coral host and its microbial symbionts, which functions as a unit and is responsive to host species and environmental factors. Although monitoring surveys have been done to determine bacteria associated with coral, none have persisted for >1 year. Therefore, potential variations in minor or dominant community members that occur over extended intervals have not been characterized. In this study, 16S rRNA gene amplicon pyrosequencing was used to investigate the relationship between bacterial communities in healthy Stylophora pistillata in tropical and subtropical Taiwan over 2 years, apparently one of the longest surveys of coral-associated microbes. Dominant bacterial genera in S. pistillata had disparate changes in different geographical setups, whereas the constitution of minor bacteria fluctuated in abundance over time. We concluded that dominant bacteria (Acinetobacter, Propionibacterium, and Pseudomonas) were stable in composition, regardless of seasonal and geographical variations, whereas Endozoicomonas had a geographical preference. In addition, by combining current data with previous studies, we concluded that a minor bacteria symbiont, Ralstonia, was a keystone species in coral. Finally, we concluded that long-term surveys for coral microbial communities were necessary to detect compositional shifts, especially for minor bacterial members in corals. PMID- 28659906 TI - Combined Effects of Elevated pCO2 and Warming Facilitate Cyanophage Infections. AB - Elevated pCO2 and warming are generally expected to influence cyanobacterial growth, and may promote the formation of blooms. Yet, both climate change factors may also influence cyanobacterial mortality by favoring pathogens, such as viruses, which will depend on the ability of the host to adapt. To test this hypothesis, we grew Plectonema boryanum IU597 under two temperature (25 and 29 degrees C) and two pCO2 (400 and 800 MUatm) conditions for 1 year, after which all treatments were re-exposed to control conditions for a period of 3 weeks. At several time points during the 1 year period, and upon re-exposure, we measured various infection characteristics of it associated cyanophage PP, including the burst size, latent period, lytic cycle and the efficiency of plaquing (EOP). As expected, elevated pCO2 promoted growth of P. boryanum equally over the 1 year period, but warming did not. Burst size increased in the warm treatment, but decreased in both the elevated pCO2 and combined treatment. The latent period and lytic cycle both became shorter in the elevated pCO2 and higher temperature treatment, and were further reduced by the combined effect of both factors. Efficiency of plaquing (EOP) decreased in the elevated pCO2 treatment, increased in the warm treatment, and increased even stronger in the combined treatment. These findings indicate that elevated pCO2 enhanced the effect of warming, thereby further promoting the virus infection rate. The re-exposure experiments demonstrate adaptation of the host leading to higher biomass build-up with elevated pCO2 over the experimental period, and lower performance upon re exposure to control conditions. Similarly, virus burst size and EOP increased when given warm adapted host, but were lower as compared to the control when the host was re-exposed to control conditions. Our results demonstrate that adaptation but particularly physiological acclimation to climate change conditions favored viral infections, while limited host plasticity and slow adaptation after re-exposure to control conditions impeded host biomass build-up and viral infections. PMID- 28659907 TI - The Effect of Phenazine-1-Carboxylic Acid on Mycelial Growth of Botrytis cinerea Produced by Pseudomonas aeruginosa LV Strain. AB - One of the most important postharvest plant pathogens that affect strawberries, grapes and tomatoes is Botrytis cinerea, known as gray mold. The fungus remains in latent form until spore germination conditions are good, making infection control difficult, causing great losses in the whole production chain. This study aimed to purify and identify phenazine-1-carboxylic acid (PCA) produced by the Pseudomonas aeruginosa LV strain and to determine its antifungal activity against B. cinerea. The compounds produced were extracted with dichloromethane and passed through a chromatographic process. The purity level of PCA was determined by reversed-phase high-performance liquid chromatography semi-preparative. The structure of PCA was confirmed by nuclear magnetic resonance and electrospray ionization mass spectrometry. Antifungal activity was determined by the dry paper disk and minimum inhibitory concentration (MIC) methods and identified by scanning electron microscopy and confocal microscopy. The results showed that PCA inhibited mycelial growth, where MIC was 25 MUg mL-1. Microscopic analysis revealed a reduction in exopolysaccharide (EPS) formation, showing distorted and damaged hyphae of B. cinerea. The results suggested that PCA has a high potential in the control of B. cinerea and inhibition of EPS (important virulence factor). This natural compound is a potential alternative to postharvest control of gray mold disease. PMID- 28659908 TI - Pterostilbene, a Methoxylated Resveratrol Derivative, Efficiently Eradicates Planktonic, Biofilm, and Intracellular MRSA by Topical Application. AB - Pterostilbene is a methoxylated derivative of resveratrol originated from natural sources. We investigated the antibacterial activity of pterostilbene against drug resistant Staphylococcus aureus and the feasibility of using it to treat cutaneous bacteria. The antimicrobial effect was evaluated using an in vitro culture model and an in vivo mouse model of cutaneous infection. The minimum inhibitory concentration (MIC) assay demonstrated a superior biocidal activity of pterostilbene compared to resveratrol (8~16-fold) against methicillin-resistant S. aureus (MRSA) and clinically isolated vancomycin-intermediate S. aureus (VISA). Pterostilbene was found to reduce MRSA biofilm thickness from 18 to 10 MUm as detected by confocal microscopy. Pterostilbene showed minimal toxicity to THP-1 cells and was readily engulfed by the macrophages, facilitating the eradication of intracellular MRSA. Pterostilbene exhibited increased skin absorption over resveratrol by 6-fold. Topical pterostilbene application improved the abscess formation produced by MRSA by reducing the bacterial burden and ameliorating the skin architecture. The potent anti-MRSA capability of pterostilbene was related to bacterial membrane leakage, chaperone protein downregulation, and ribosomal protein upregulation. This mechanism of action was different from that of resveratrol according to proteomic analysis and molecular docking. Pterostilbene has the potential to serve as a novel class of topically applied agents for treating MRSA infection in the skin while demonstrating less toxicity to mammalian cells. PMID- 28659909 TI - Commentary: Superoxide Generation and Its Involvement in the Growth of Mycobacterium smegmatis. PMID- 28659910 TI - Microbial Eukaryote Diversity and Activity in the Water Column of the South China Sea Based on DNA and RNA High Throughput Sequencing. AB - To study the diversity and metabolic activity of microbial eukaryotes in the water column of the South China Sea, genomic DNA and RNA were co-extracted from samples collected down to bathyal depth at two sites. V9 regions of both SSU rRNA gene and its transcript (cDNA) were amplified and sequenced using high throughput sequencing. Our study revealed: (1) DNA and RNA datasets showed significant differences in microbial eukaryote community composition, with the variability between the two datasets for the same sample exceeding that between samples within each dataset, indicating that nucleic acid source overrode environmental factors in determining the composition of microeukaryotes; (2) despite the differences in community composition between the two datasets, both DNA and RNA revealed similar depth-related distribution patterns of microbial eukaryotes; (3) using the ratio of RNA: DNA as a proxy of relative metabolic activity, a depth related pattern was found for the relative metabolic activity of some but not all groups of microbial eukaryotes, with the highest activity for the groups with depth-related pattern usually found in the middle water layers; and (4) the presence of live and active photoautotrophic microbial eukaryotes in the deep ocean was confirmed, indicating that they play an important role in controlling the deep-sea organic carbon pool. Overall, our study sheds light on the diversity and activity of microbial eukaryotes in the water column of a tropical oligotrophic ocean and their potential contributions in the downward transportation of organic material from the surface ocean to the deep via the biological pump. PMID- 28659911 TI - Corrigendum: Identification and Characterization of miRNAs in Response to Leishmania donovani Infection: Delineation of Their Roles in Macrophage Dysfunction. AB - [This corrects the article on p. 314 in vol. 8, PMID: 28303124.]. PMID- 28659912 TI - C-Terminal Domain of Hemocyanin, a Major Antimicrobial Protein from Litopenaeus vannamei: Structural Homology with Immunoglobulins and Molecular Diversity. AB - Invertebrates rely heavily on immune-like molecules with highly diversified variability so as to counteract infections. However, the mechanisms and the relationship between this variability and functionalities are not well understood. Here, we showed that the C-terminal domain of hemocyanin (HMC) from shrimp Litopenaeus vannamei contained an evolutionary conserved domain with highly variable genetic sequence, which is structurally homologous to immunoglobulin (Ig). This domain is responsible for recognizing and binding to bacteria or red blood cells, initiating agglutination and hemolysis. Furthermore, when HMC is separated into three fractions using anti-human IgM, IgG, or IgA, the subpopulation, which reacted with anti-human IgM (HMC-M), showed the most significant antimicrobial activity. The high potency of HMC-M is a consequence of glycosylation, as it contains high abundance of alpha-d-mannose relative to alpha d-glucose and N-acetyl-d-galactosamine. Thus, the removal of these glycans abolished the antimicrobial activity of HMC-M. Our results present a comprehensive investigation of the role of HMC in fighting against infections through genetic variability and epigenetic modification. PMID- 28659913 TI - Lactobacillus johnsonii N6.2 Modulates the Host Immune Responses: A Double-Blind, Randomized Trial in Healthy Adults. AB - : Lactobacillus johnsonii N6.2 mitigates the onset of type 1 diabetes (T1D) in biobreeding diabetes-prone rats, in part, through changes in kynurenine:tryptophan (K:T) ratios. The goal of this pilot study was to determine the safety, tolerance, and general immunological response of L. johnsonii N6.2 in healthy subjects. A double-blind, randomized clinical trial in 42 healthy individuals with no known risk factors for T1D was undertaken to evaluate subject responses to the consumption of L. johnsonii N6.2. Participants received 1 capsule/day containing 108 colony-forming units of L. johnsonii N6.2 or placebo for 8 weeks. Comprehensive metabolic panel (CMP), leukocyte subpopulations by complete blood count (CBC) and flow cytometry, serum cytokines, and relevant metabolites in the indoleamine-2,3-dioxygenase pathway were assessed. L. johnsonii N6.2 survival and intestinal microbiota was analyzed. Daily and weekly questionnaires were assessed for potential effects of probiotic treatment on general wellness. The administration of L. johnsonii N6.2 did not modify the CMP or CBC of participants suggesting general safety. In fact, L. johnsonii N6.2 administration significantly decreased the occurrence of abdominal pain, indigestion, and cephalic syndromes. As predicted, increased serum tryptophan levels increased resulting in a decreased K:T ratio was observed in the L. johnsonii N6.2 group. Interestingly, immunophenotyping assays revealed that monocytes and natural killer cell numbers were increased significantly after washout (12 weeks). Moreover, an increase of circulating effector Th1 cells (CD45RO+CD183+CD196-) and cytotoxic CD8+ T cells subset was observed in the L. johnsonii N6.2 group. Consumption of L. johnsonii N6.2 is well tolerated in adult control subjects, demonstrates systemic impacts on innate and adaptive immune populations, and results in a decreased K:T ratio. These data provide support for the safety and feasibility of using L. johnsonii N6.2 in prevention trials in subjects at risk for T1D. TRIAL REGISTRATION: This trial was registered at http://clinicaltrials.gov as NCT02349360. PMID- 28659914 TI - Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. AB - Type I and type III interferons (IFNs) are crucial components of the first-line antiviral host response. While specific receptors for both IFN types exist, intracellular signaling shares the same Jak-STAT pathway. Due to its receptor expression, IFN-lambda responsiveness is restricted mainly to epithelial cells. Here, we display IFN-stimulated gene induction at the single cell level to comparatively analyze the activities of both IFN types in intestinal epithelial cells and mini-gut organoids. Initially, we noticed that the response to both types of IFNs at low concentrations is based on a single cell decision-making determining the total cell intrinsic antiviral activity. We identified histone deacetylase (HDAC) activity as a crucial restriction factor controlling the cell frequency of IFN-stimulated gene (ISG) induction upon IFN-lambda but not IFN-beta stimulation. Consistently, HDAC blockade confers antiviral activity to an elsewise non-responding subpopulation. Second, in contrast to the type I IFN system, polarization of intestinal epithelial cells strongly enhances their ability to respond to IFN-lambda signaling and raises the kinetics of gene induction. Finally, we show that ISG induction in mini-gut organoids by low amounts of IFN is characterized by a scattered heterogeneous responsiveness of the epithelial cells and HDAC activity fine-tunes exclusively IFN-lambda activity. This study provides a comprehensive description of the differential response to type I and type III IFNs and demonstrates that cell polarization in gut epithelial cells specifically increases IFN-lambda activity. PMID- 28659915 TI - Graphene and the Immune System: A Romance of Many Dimensions. AB - Graphene-based materials (GBMs) are emerging as attractive materials for biomedical applications. Understanding how these materials are perceived by and interact with the immune system is of fundamental importance. Phagocytosis is a major mechanism deployed by the immune system to remove pathogens, particles, and cellular debris. Here, we discuss recent studies on the interactions of GBMs with different phagocytic cells, including macrophages, neutrophils, and dendritic cells. The importance of assessing GBMs for endotoxin contamination is discussed as this may skew results. We also explore the role of the bio-corona for interactions of GBMs with immune cells. Finally, we highlight recent evidence for direct plasma membrane interactions of GBMs. PMID- 28659918 TI - Guanabenz Prevents d-Galactosamine/Lipopolysaccharide-Induced Liver Damage and Mortality. AB - Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-alpha) expression. Consequently, drugs interfering with eIF2alpha phosphorylation may represent potential candidates for the treatment of such pathologies. We, therefore, used Guanabenz (GBZ), a small compound with enhancing eIF2alpha phosphorylation activity to evaluate its effect on bacterial LPS sensing and endotoxemia. GBZ is confirmed here to have an anti inflammatory activity by increasing in vitro interleukin-10 (IL-10) production by LPS-stimulated dendritic cells. We further show that in the d-galactosamine (d galN)/LPS-dependent lethality model, intraperitoneal injection of GBZ promoted mice survival, prevented liver damage, increased IL-10 levels, and inhibited TNF alpha production. GBZ and its derivatives could therefore represent an interesting pharmacological solution to control systemic inflammation and associated acute liver failure. PMID- 28659916 TI - HLA-Bw4-I-80 Isoform Differentially Influences Clinical Outcome As Compared to HLA-Bw4-T-80 and HLA-A-Bw4 Isoforms in Rituximab or Dinutuximab-Based Cancer Immunotherapy. AB - Killer-cell immunoglobulin-like receptors (KIRs) are a family of glycoproteins expressed primarily on natural killer cells that can regulate their function. Inhibitory KIRs recognize MHC class I molecules (KIR-ligands) as ligands. We have reported associations of KIRs and KIR-ligands for patients in two monoclonal antibody (mAb)-based trials: (1) A Children's Oncology Group (COG) trial for children with high-risk neuroblastoma randomized to immunotherapy treatment with dinutuximab (anti-GD2 mAb) + GM-CSF + IL-2 + isotretinion or to treatment with isotretinoin alone and (2) An Eastern Cooperative Oncology Group (ECOG) trial for adults with low-tumor burden follicular lymphoma responding to an induction course of rituximab (anti-CD20 mAb) and randomized to treatment with maintenance rituximab or no-maintenance rituximab. In each trial, certain KIR/KIR-ligand genotypes were associated with clinical benefit for patients randomized to immunotherapy treatment (immunotherapy in COG; maintenance rituximab in ECOG) as compared to patients that did not receive the immunotherapy [isotretinoin alone (COG); no-maintenance (ECOG)]. Namely, patients with both KIR3DL1 and its HLA-Bw4 ligand (KIR3DL1+/HLA-Bw4+ genotype) had improved clinical outcomes if randomized to immunotherapy regimens, as compared to patients with the KIR3DL1+/HLA-Bw4+ genotype randomized to the non-immunotherapy regimen. Conversely, patients that did not have the KIR3DL1+/HLA-Bw4+ genotype showed no evidence of a difference in outcome if receiving the immunotherapy vs. no-immunotherapy. For each trial, HLA Bw4 status was determined by assessing the genotypes of three separate isoforms of HLA-Bw4: (1) HLA-B-Bw4 with threonine at amino acid 80 (B-Bw4-T80); (2) HLA-B Bw4 with isoleucine at amino acid 80 (HLA-B-Bw4-I80); and (3) HLA-A with a Bw4 epitope (HLA-A-Bw4). Here, we report on associations with clinical outcome for patients with KIR3DL1 and these separate isoforms of HLA-Bw4. Patients randomized to immunotherapy with KIR3DL1+/A-Bw4+ or with KIR3DL1+/B-Bw4-T80+ had better outcome vs. those randomized to no-immunotherapy, whereas for those with KIR3DL1+/B-Bw4-I80+ there was no evidence of a difference based on immunotherapy vs. no-immunotherapy. Additionally, we observed differences within treatment types (either within immunotherapy or no-immunotherapy) that were associated with the genotype status for the different KIR3DL1/HLA-Bw4-isoforms. These studies suggest that specific HLA-Bw4 isoforms may differentially influence response to these mAb-based immunotherapy, further confirming the involvement of KIR-bearing cells in tumor-reactive mAb-based cancer immunotherapy. PMID- 28659917 TI - A Two-Phase Expansion Protocol Combining Interleukin (IL)-15 and IL-21 Improves Natural Killer Cell Proliferation and Cytotoxicity against Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children. Despite intensive research in recent decades the prognosis for patients with metastatic or relapsed diseases has hardly improved. New therapeutic concepts in anti-tumor therapy aim to modulate the patient's immune system to increase its aggressiveness or targeted effects toward tumor cells. Besides surgery, radiotherapy and chemotherapy, immune activation by direct application of cytokines, antibodies or adoptive cell therapy are promising approaches. In the last years, adoptive transfer of natural killer (NK) cells came into the focus of translational medicine, because of their high cytotoxic potential against transformed malignant cells. A main challenge of NK cell therapy is that it requires a high amount of functional NK cells. Therefore, ex vivo NK cell expansion protocols are currently being developed. Many culturing strategies are based on the addition of feeder or accessory cells, which need to be removed prior to the clinical application of the final NK cell product. In this study, we addressed feeder cell-free expansion methods using common gamma-chain cytokines, especially IL-15 and IL-21. Our results demonstrated high potential of IL-15 for NK cell expansion, while IL-21 triggered NK cell maturation and functionality. Hence, we established a two-phase expansion protocol with IL-15 to induce an early NK cell expansion, followed by short exposure to IL-21 that boosted the cytotoxic activity of NK cells against RMS cells. Further functional analyses revealed enhanced degranulation and secretion of pro-inflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha. In a proof of concept in vivo study, we also observed a therapeutic effect of adoptively transferred IL-15 expanded and IL-21 boosted NK cells in combination with image guided high precision radiation therapy using a luciferase-transduced RMS xenograft model. In summary, this two-phased feeder cell-free ex vivo culturing protocol combined efficient expansion and high cytolytic functionality of NK cells for treatment of radiation-resistant RMS. PMID- 28659919 TI - The beta-d-Endoglucuronidase Heparanase Is a Danger Molecule That Drives Systemic Inflammation and Correlates with Clinical Course after Open and Endovascular Thoracoabdominal Aortic Aneurysm Repair: Lessons Learnt from Mice and Men. AB - Thoracoabdominal aortic aneurysm (TAAA) is a highly lethal disorder requiring open or endovascular TAAA repair, both of which are rare, but extensive and complex surgical procedures associated with a significant systemic inflammatory response and high post-operative morbidity and mortality. Heparanase is a beta-d endoglucuronidase that remodels the endothelial glycocalyx by degrading heparan sulfate in many diseases/conditions associated with systemic inflammation including sepsis, trauma, and major surgery. We hypothesized that (a) perioperative serum levels of heparanase and heparan sulfate are associated with the clinical course after open or endovascular TAAA repair and (b) induce a systemic inflammatory response and renal injury/dysfunction in mice. Using a reverse-translational approach, we assessed (a) the serum levels of heparanase, heparan sulfate, and the heparan sulfate proteoglycan syndecan-1 preoperatively as well as 6 and 72 h after intensive care unit (ICU) admission in patients undergoing open or endovascular TAAA repair and (b) laboratory and clinical parameters and 90-day survival, and (c) the systemic inflammatory response and renal injury/dysfunction induced by heparanase and heparan sulfate in mice. When compared to preoperative values, the serum levels of heparanase, heparan sulfate, and syndecan-1 significantly transiently increased within 6 h of ICU admission and returned to normal within 72 h after ICU admission. The kinetics of any observed changes in heparanase, heparan sulfate, or syndecan-1 levels, however, did not differ between open and endovascular TAAA-repair. Postoperative heparanase levels positively correlated with noradrenalin dose at 12 h after ICU admission and showed a high predictive value of vasopressor requirements within the first 24 h. Postoperative heparan sulfate showed a strong positive correlation with interleukin-6 levels day 0, 1, and 2 post-ICU admission and a strong negative correlation with lactate clearance during the first 6 h post-ICU admission. Moreover, systemic administration of heparanase and heparan sulfate induced an inflammatory response and a small degree of renal dysfunction in mice. In conclusion, these results suggest that heparanase and heparan sulfate exhibit a substantial role as clinically relevant danger molecules and may serve as both, promising biomarkers and therapeutic targets in patients undergoing open or endovascular TAAA repair and, indeed, other conditions associated with significant systemic inflammation. PMID- 28659920 TI - Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy. AB - Decidual CD4+ T (dCD4 T) cells are crucial for the maternal-fetal immune tolerance required for a healthy pregnancy outcome. However, their molecular and functional characteristics are not well elucidated. In this study, we performed the first analysis of transcriptional and alternative splicing (AS) landscapes for paired decidual and peripheral blood CD4+ T (pCD4 T) cells in human early pregnancy using high throughput mRNA sequencing. Our data showed that dCD4 T cells are endowed with a unique transcriptional signature when compared to pCD4 T cells: dCD4 T cells upregulate 1,695 genes enriched in immune system process whereas downregulate 1,011 genes mainly related to mRNA catabolic process and the ribosome. Moreover, dCD4 T cells were observed to be at M phase, and show increased activation, proliferation, and cytokine production, as well as display an effector-memory phenotype and a heterogenous nature containing Th1, Th17, and Treg cell subsets. However, dCD4 T cells undergo a comparable number of upregulated and downregulated AS events, both of which are enriched in the genes related to cellular metabolic process. And the changes at the AS event level do not reflect measurable differences at the gene expression level in dCD4 T cells. Collectively, our findings provide a comprehensive portrait of the unique transcriptional signature and AS profile of CD4+ T cells in human decidua and help us gain more understanding of the functional characteristic of these cells during early pregnancy. PMID- 28659921 TI - Patient's Natural Killer Cells in the Era of Targeted Therapies: Role for Tumor Killers. AB - Natural killer (NK) cells are potent antitumor effectors, involved in hematological malignancies and solid tumor immunosurveillance. They infiltrate various solid tumors, and their numbers are correlated with good outcome. The function of NK cells extends their lytic capacities toward tumor cells expressing stress-induced ligands, through secretion of immunoregulatory cytokines, and interactions with other immune cells. Altered NK cell function due to tumor immune escape is frequent in advanced tumors; however, strategies to release the function of NK infiltrating tumors are emerging. Recent therapies targeting specific oncogenic mutations improved the treatment of cancer patients, but patients often relapse. The actual development consists in combined therapeutic strategies including agents targeting the proliferation of tumor cells and others restorating functional antitumor immune effectors for efficient and durable efficacy of anticancer treatment. In that context, we discuss the recent results of the literature to propose hypotheses concerning the potential use of NK cells, potent antitumor cytotoxic effectors, to design novel antitumor strategies. PMID- 28659923 TI - Subcutaneous Immunization with Fusion Protein DnaJ-DeltaA146Ply without Additional Adjuvants Induces both Humoral and Cellular Immunity against Pneumococcal Infection Partially Depending on TLR4. AB - Subunit vaccines that are poorly immunogenic are often combined with adjuvants for immunization. Our previous research identified a pneumolysin variant (DeltaA146Ply), a Toll-like receptor 4 agonist, that was an effective adjuvant in the protection of fusion protein DnaJ-DeltaA146Ply against mucosal Streptococcus pneumoniae infections. For pneumococcal vaccines, World Health Organization recommend injection as a regular vaccination approach. Subcutaneous immunization is a common and effective method of injection, so we explored the immunity mechanism of subcutaneous immunization with DnaJ-DeltaA146Ply. We found that mice immunized subcutaneously with fusion proteins DeltaA146Ply-DnaJ and DnaJ DeltaA146Ply produced a higher anti-DnaJ IgG titer than when DnaJ alone was administered. DnaJ-DeltaA146Ply induced both B-cell and T-cell-dependent protection against both colonization and lethal pneumococcal infections. Levels of IFN-gamma, IL-4, and IL-17A were also elevated in DnaJ-DeltaA146Ply immunized mice. However, all these effects were negated in TLR4-/- mice compared to WT mice immunized with DnaJ-DeltaA146Ply. B-cell-deficient MUMT mice, nude mice, IFN gamma-/-, and IL-4-/- mice immunized with DnaJ-DeltaA146Ply could not resist infection with pneumococci. IL-17A-/- and TLR4-/- mice did not benefit from DnaJ DeltaPly immunization in colonization experiments although their survival was not impaired compared with WT mice. Collectively, our data indicated that DeltaA146Ply can be a potential subcutaneous adjuvant, and the DnaJ-DeltaA146Ply fusion protein induces both humoral and cellular immune response to resist S. pneumoniae infection. The protective effect of colonization also depends on TLR4. PMID- 28659922 TI - A Poly(Lactic-co-Glycolic) Acid Nanovaccine Based on Chimeric Peptides from Different Leishmania infantum Proteins Induces Dendritic Cells Maturation and Promotes Peptide-Specific IFNgamma-Producing CD8+ T Cells Essential for the Protection against Experimental Visceral Leishmaniasis. AB - Visceral leishmaniasis, caused by Leishmania (L.) donovani and L. infantum protozoan parasites, can provoke overwhelming and protracted epidemics, with high case-fatality rates. An effective vaccine against the disease must rely on the generation of a strong and long-lasting T cell immunity, mediated by CD4+ TH1 and CD8+ T cells. Multi-epitope peptide-based vaccine development is manifesting as the new era of vaccination strategies against Leishmania infection. In this study, we designed chimeric peptides containing HLA-restricted epitopes from three immunogenic L. infantum proteins (cysteine peptidase A, histone H1, and kinetoplastid membrane protein 11), in order to be encapsulated in poly(lactic-co glycolic) acid nanoparticles with or without the adjuvant monophosphoryl lipid A (MPLA) or surface modification with an octapeptide targeting the tumor necrosis factor receptor II. We aimed to construct differentially functionalized peptide based nanovaccine candidates and investigate their capacity to stimulate the immunomodulatory properties of dendritic cells (DCs), which are critical regulators of adaptive immunity generated upon vaccination. According to our results, DCs stimulation with the peptide-based nanovaccine candidates with MPLA incorporation or surface modification induced an enhanced maturation profile with prominent IL-12 production, promoting allogeneic T cell proliferation and intracellular production of IFNgamma by CD4+ and CD8+ T cell subsets. In addition, DCs stimulated with the peptide-based nanovaccine candidate with MPLA incorporation exhibited a robust transcriptional activation, characterized by upregulated genes indicative of vaccine-driven DCs differentiation toward type 1 phenotype. Immunization of HLA A2.1 transgenic mice with this peptide-based nanovaccine candidate induced peptide-specific IFNgamma-producing CD8+ T cells and conferred significant protection against L. infantum infection. Concluding, our findings supported that encapsulation of more than one chimeric multi-epitope peptides from different immunogenic L. infantum proteins in a proper biocompatible delivery system with the right adjuvant is considered as an improved promising approach for the development of a vaccine against VL. PMID- 28659924 TI - Brucella Dysregulates Monocytes and Inhibits Macrophage Polarization through LC3 Dependent Autophagy. AB - Brucellosis is caused by infection with Brucella species and exhibits diverse clinical manifestations in infected humans. Monocytes and macrophages are not only the first line of defense against Brucella infection but also a main reservoir for Brucella. In the present study, we examined the effects of Brucella infection on human peripheral monocytes and monocyte-derived polarized macrophages. We showed that Brucella infection led to an increase in the proportion of CD14++CD16- monocytes and the expression of the autophagy-related protein LC3B, and the effects of Brucella-induced monocytes are inhibited after 6 weeks of antibiotic treatment. Additionally, the production of IL-1beta, IL-6, IL 10, and TNF-alpha from monocytes in patients with brucellosis was suppressed through the LC3-dependent autophagy pathway during Brucella infection. Moreover, Brucella infection inhibited macrophage polarization. Consistently, the addition of 3-MA, an inhibitor of LC3-related autophagy, partially restored macrophage polarization. Intriguingly, we also found that the upregulation of LC3B expression by rapamycin and heat-killed Brucella in vitro inhibits M2 macrophage polarization, which can be reversed partially by 3-MA. Taken together, these findings reveal that Brucella dysregulates monocyte and macrophage polarization through LC3-dependent autophagy. Thus, targeting this pathway may lead to the development of new therapeutics against Brucellosis. PMID- 28659925 TI - Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging. AB - Aging is associated with an increased susceptibility to infection and a failure to control latent viruses thought to be driven, at least in part, by alterations in CD8 T cell function. The aging T cell repertoire is characterized by an accumulation of effector CD8 T cells, many of which express the negative regulatory receptor CD85j. To define the biological significance of CD85j expression on CD8 T cells and to address the question whether presence of CD85j in older individuals is beneficial or detrimental for immune function, we examined the specific attributes of CD8 T cells expressing CD85j as well as the functional role of CD85j in antigen-specific CD8 T cell responses during immune aging. Here, we show that CD85j is mainly expressed by terminally differentiated effector (TEMRAs) CD8 T cells, which increase with age, in cytomegalovirus (CMV) infection and in males. CD85j+ CMV-specific cells demonstrate clonal expansion. However, TCR diversity is similar between CD85j+ and CD85j- compartments, suggesting that CD85j does not directly impact the repertoire of antigen-specific cells. Further phenotypic and functional analyses revealed that CD85j identifies a specific subset of CMV-responsive CD8 T cells that coexpress a marker of senescence (CD57) but retain polyfunctional cytokine production and expression of cytotoxic mediators. Blocking CD85j binding enhanced proliferation of CMV specific CD8 T cells upon antigen stimulation but did not alter polyfunctional cytokine production. Taken together, these data demonstrate that CD85j characterizes a population of "senescent," but not exhausted antigen-specific effector CD8 T cells and indicates that CD85j is an important checkpoint regulator controlling expansion of virus-specific T cells during aging. Inhibition of CD85j activity may be a mechanism to promote stronger CD8 T cell effector responses during immune aging. PMID- 28659926 TI - The Epimmunity Theory: The Single Cell Defenses against Infectious and Genetic Diseases. AB - Single cell defense against diseases defines "epimmunity." Epimmunity is complementary to the immune system and can neither be substituted by innate nor by acquired immunity. Epimmunity, the proposed new branch of immunity, is further explored and analyzed for enucleated mature mammalian erythrocytes and nucleated erythrocytes of non-mammalian vertebrates leading to the development of "The Epimmunity Theory." Enucleation of mammalian erythroblast and inactivation of nuclei in erythrocytes of non-mammalian vertebrates are major contributors to the collective immunity: epimmunity, innate, and acquired. The fact that diseases of mature erythrocytes (MEs) are rare supports the notion that a single cell can resist microbial and genetic diseases; MEs are refractory to malaria and cancer. Nucleated cells, such as B-cells, T-cells, hepatocytes, and cell developmental stages are susceptible to genetic and specific microbial diseases depending on their nuclear activities and the receptors they express; such cells show lower epimmunity relative to MEs. Epimmunity is important as a disease insulator that prevents the spread of diseases from an infected tissue to the majority of other tissues. Breakdown of epimmunity may lead to disease development. PMID- 28659927 TI - The Role of Innate Lymphoid Cells in Immune-Mediated Liver Diseases. AB - Innate lymphoid cells (ILCs) are a recently identified group of innate immune cells lacking antigen-specific receptors that can mediate immune responses and regulate tissue homeostasis and inflammation. ILCs comprise group 1 ILCs, group 2 ILCs, and group 3 ILCs. These ILCs usually localize at mucosal surfaces and combat pathogens by the rapid release of certain cytokines. However, the uncontrolled activation of ILCs can also lead to damaging inflammation, especially in the gut, lung, and skin. Although the physiological and pathogenic roles of ILCs in liver diseases have been attracting increasing attention recently, there has been no systematic review regarding the roles of ILCs in immune-mediated liver diseases. Here, we review the relationships between the ILC subsets and their functions in immune-mediated liver diseases, and discuss their therapeutic potential based on current knowledge about the functional roles of these cells in liver diseases. PMID- 28659928 TI - Gestational Diabetes Mellitus Is Associated with Altered Neutrophil Activity. AB - Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-alpha levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-alpha antagonist, we observed that the pro NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia. PMID- 28659929 TI - Involvement of MicroRNAs in Probiotics-Induced Reduction of the Cecal Inflammation by Salmonella Typhimurium. AB - The microRNAs (miRNAs) have been shown to play important roles in the development of the immune system and in regulation of host inflammation responses. Probiotics can effectively alleviate the inflammation caused by Salmonella in chickens. However, whether and how miRNAs are involved in modulation of the inflammation response in the gut of chickens have not been reported. In this study, the impact of a probiotics, Lactobacillus plantarum Z01 (LPZ01), was investigated on the cecal miRNAs and cytokine secretions in Salmonella Typhimurium (S. Typhimurium) infected chickens at the age of 3 days. Newly hatched chicks were assigned to four groups (1): NC (basal diet) (2): S (basal diet + S. Typhimurium challenged) (3): SP (basal diet + S. Typhimurium challenged + LPZ01) (4): P (basal diet + LPZ01). In comparison with the S group, chicks in the SP group reduced the number of S. Typhimurium and had lower levels of interferon-gamma and lipopolysaccharide induced tumor necrosis factor alpha factor (LITAF) in ceca post challenge. Expression of 14 miRNAs was significantly affected by the presence of S. Typhimurium and/or lactobacillus. Five differential expression miRNAs (gga-miR 215-5p, gga-miR-3525, gga-miR-193a-5p, gga-miR-122-5p, and gga-miR-375) were randomly selected for confirmation by the RT-PCR. Predicted target genes of differentially expressed miRNAs were enriched in regulation of cAMP-dependent protein kinase activity, stress-activated MAPK cascade, immune system development and regulation of immune system process as well as in immune related pathways such as MAPK and Wnt signaling pathways. The relationship between changes of miRNAs and changes of cytokines was explored. Finally, 119 novel miRNAs were identified in 36 libraries totally. Identification of novel miRNAs significantly expanded the repertoire of chicken miRNAs and provided the basis for understanding the function of miRNAs in the host. Our results suggest that the probiotics reduce the inflammation of the S. Typhimurium infection in neonatal broiler chicks, at least partially, through regulation of miRNAs expression. PMID- 28659931 TI - Establishment, Growth, and Yield Potential of the Perennial Grass Miscanthus * Giganteus on Degraded Coal Mine Soils. AB - Miscanthus * giganteus is a giant C4 grass native to Asia. Unlike most C4 species, it is relatively cold tolerant due to adaptations across a wide range of altitudes. These grasses are characterized by high productivity and low input requirements, making them excellent candidates for bioenergy feedstock production. The aim of this study was to investigate the potential for growing Miscanthus on extremely marginal soils, degraded by open lignite (brown coal) mining. Field experiments were established within three blocks situated on waste heaps originating from the lignite mine. Analyses were conducted over the first 3 years following Miscanthus cultivation, focusing on the effect of organic and mineral fertilization on crop growth, development and yield in this extreme environment. The following levels of fertilization were implemented between the blocks: the control plot with no fertilization (D0), a plot with sewage sludge (D1), a plot with an identical amount of sewage sludge plus one dose of mineral fertilizer (D2) and a plot with an identical amount of sewage sludge plus a double dose of mineral fertilizer (D3). Crop development and characteristics (plant height, tillering, and biomass yield [dry matter]) were measured throughout the study period and analyzed using Analysis of Variance (ANOVA). Significant differences were apparent between plant development and 3rd year biomass production over the course of the study (0.964 kg plant-1 for DO compared to 1.503 kg plant-1 for D1). Soil analyses conducted over the course of the experiment showed that organic carbon levels within the soil increased significantly following the cultivation of Miscanthus, and overall, pH decreased. With the exception of iron, macronutrient concentrations remained stable throughout. The promising yields and positive effects of Miscanthus on the degraded soil suggests that long term plantations on land otherwise unsuitable for agriculture may prove to be of great environmental and economic significance. PMID- 28659930 TI - Functional and Homeostatic Impact of Age-Related Changes in Lymph Node Stroma. AB - Adults over 65 years of age are more vulnerable to infectious disease and show poor responses to vaccination relative to those under 50. A complex set of age related changes in the immune system is believed to be largely responsible for these defects. These changes, collectively termed immune senescence, encompass alterations in both the innate and adaptive immune systems, in the microenvironments where immune cells develop or reside, and in soluble factors that guide immune homeostasis and function. While age-related changes in primary lymphoid organs (bone marrow, and, in particular, the thymus, which involutes in the first third of life) have been long appreciated, changes affecting aging secondary lymphoid organs, and, in particular, aging lymph nodes (LNs) have been less well characterized. Over the last 20 years, LN stromal cells have emerged as key players in maintaining LN morphology and immune homeostasis, as well as in coordinating immune responses to pathogens. Here, we review recent progress in understanding the contributions of LN stromal cells to immune senescence. We discuss approaches to understand the mechanisms behind the decline in LN stromal cells and conclude by considering potential strategies to rejuvenate aging LN stroma to improve immune homeostasis, immune responses, and vaccine efficacy in the elderly. PMID- 28659932 TI - Seaweed Extracts Enhance Salam Turfgrass Performance during Prolonged Irrigation Intervals and Saline Shock. AB - The negative effects of the ongoing climate change include unusual prolonged droughts and increased salinity pressures on the agricultural lands. Consequently, crops are facing unprecedented environmental pressure, and this calls for more research toward controlling such major stresses. The current study investigates the effects of seaweed extract sprays of Ascophyllum nodosum (5 and 7 mL.L-1; 6 day intervals) on Paspalum vaginatum Salam' during prolonged irrigation intervals (2 and 6 day) and saline growing conditions (1 and 49.7 dS.m 1) for 6 weeks in containers under greenhouse conditions. Control plants showed reduced turf quality, photochemical efficiency, root length and dry weight, total non-structural carbohydrates, and K and Ca compositions. Seaweed extracts increased turf quality, leaf photochemical efficiency, root length and dry weight, total non-structural carbohydrates, K, Ca, and proline in treated plants during prolonged irrigation intervals as well as saline shock conditions. There were also increases in the antioxidant defensive mechanisms such as catalase (CAT), superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities and non-enzymatic antioxidants as well as reduced lipid peroxidation. The application of SWE at 7 mL.L-1 showed higher performance in treated plants during prolonged irrigation intervals as well as saline conditions. Our findings imply that several mechanisms including drought tolerance, osmotic adjustment and antioxidant defense system may interact to enhance the performance of plants in the face of environmental stress following SWE treatments. PMID- 28659933 TI - Genome Wide Identification and Expression Profiling of Ethylene Receptor Genes during Soybean Nodulation. AB - It has long been known that the gaseous plant hormone ethylene plays a key role in nodulation in legumes. The perception of ethylene by a family of five membrane localized receptors is necessary to trigger the ethylene signaling pathway, which regulates various biological responses in Arabidopsis. However, a systematic analysis of the ethylene receptors in leguminous plants and their roles in nodule development is lacking. In this study, we performed a characterization of ethylene receptor genes based on the latest Glycine max genome sequence and a public microarray database. Eleven ethylene receptor family genes were identified in soybean through homology searches, and they were divided into two subgroups. Exon-intron analysis showed that the gene structures are highly conserved within each group. Further analysis of their expression patterns showed that these ethylene receptor genes are differentially expressed in various soybean tissues and organs, including functional nodules. Notably, the ethylene receptor genes showed different responses to rhizobial infection and Nod factors, suggesting a possible role for ethylene receptors and ethylene signaling in rhizobia-host cell interactions and nodulation in soybean. Together, these data indicate the functional divergence of ethylene receptor genes in soybean, and that some of these receptors mediate nodulation, including rhizobial infection, nodule development, and nodule functionality. These findings provide a foundation for further elucidation of the molecular mechanism by which the ethylene signaling pathway regulates nodulation in soybean, as well as other legumes. PMID- 28659936 TI - A Global Assessment of the Chemical Recalcitrance of Seagrass Tissues: Implications for Long-Term Carbon Sequestration. AB - Seagrass ecosystems have recently been identified for their role in climate change mitigation due to their globally-significant carbon sinks; yet, the capacity of seagrasses to sequester carbon has been shown to vary greatly among seagrass ecosystems. The recalcitrant nature of seagrass tissues, or the resistance to degradation back into carbon dioxide, is one aspect thought to influence sediment carbon stocks. In this study, a global survey investigated how the macromolecular chemistry of seagrass leaves, sheaths/stems, rhizomes and roots varied across 23 species from 16 countries. The goal was to understand how this seagrass chemistry might influence the capacity of seagrasses to contribute to sediment carbon stocks. Three non-destructive analytical chemical analyses were used to investigate seagrass chemistry: thermogravimetric analysis (TGA) and solid state 13C-NMR and infrared spectroscopy. A strong latitudinal influence on carbon quality was found, whereby temperate seagrasses contained 5% relatively more labile carbon, and tropical seagrasses contained 3% relatively more refractory carbon. Sheath/stem tissues significantly varied across taxa, with larger morphologies typically containing more refractory carbon than smaller morphologies. Rhizomes were characterized by a higher proportion of labile carbon (16% of total organic matter compared to 8-10% in other tissues); however, high rhizome biomass production and slower remineralization in anoxic sediments will likely enhance these below-ground tissues' contributions to long-term carbon stocks. Our study provides a standardized and global dataset on seagrass carbon quality across tissue types, taxa and geography that can be incorporated in carbon sequestration and storage models as well as ecosystem valuation and management strategies. PMID- 28659935 TI - NaCl Induces Flavonoid Biosynthesis through a Putative Novel Pathway in Post harvest Ginkgo Leaves. AB - The flavonoids in the extracts of Ginkgo leaves have been shown to have great medical value: thus, a method to increase the flavonoid contents in these extracts is of significant importance for human health. In the present study, we investigated the changes in flavonoid contents and the corresponding gene expression levels in post-harvest Ginkgo leaves after various treatments. We found that both ultraviolet-B and NaCl treatment induced flavonoid accumulation. However, gene expression analysis showed that the increases in flavonoid contents were achieved by different pathways. Furthermore, post-harvest Ginkgo leaves responded differently to NaCl treatment compared with naturally grown leaves in both flavonoid contents and corresponding gene expression. In addition, combined treatment with ultraviolet-B and NaCl did not further increase the flavonoid contents compared with ultraviolet-B or NaCl treatment alone. Our results indicate the existence of a novel mechanism in response to NaCl treatment in post harvest Ginkgo leaves, and provide a technique to increase flavonoid content in the pharmaceutical industry. PMID- 28659937 TI - Assessment of the Effect of Seed Infection with Ascochyta pisi on Pea in Western Canada. AB - The role of seed infection with Ascochyta pisi using naturally infected seeds with an incidence from 0.5 to 14.5% was studied in field pea experiments in western Canada at locations with historically low inoculum pressure. A significant effect of A. pisi seed infection on the emergence of seedlings was observed in one experiment and when all data were pooled, but emergence was only reduced minimally, and symptoms of A. pisi on the aerial parts of the seedlings were rarely observed. The level of seed infection at planting had no impact on A. pisi disease severity on mature plants, on seed yield and size, or on the incidence of A. pisi infection of harvested seeds although A. pisi was the dominant species recovered from seeds. Results suggest that the disease did not progress significantly from seeds to seedlings, hence did not contribute to infection of aerial parts of the plants, and therefore infected seeds cannot be regarded as a source of inoculum in the epidemiology of this pathogen under western Canadian growing conditions. Assessing seed components of seeds with varying levels of A. pisi infection and seed staining revealed that the pathogen was present in all components of the seed, regardless of the severity of seed staining. This indicates that infected seeds may be an important way for the pathogen to survive in nature. PMID- 28659934 TI - Morphological Plant Modeling: Unleashing Geometric and Topological Potential within the Plant Sciences. AB - The geometries and topologies of leaves, flowers, roots, shoots, and their arrangements have fascinated plant biologists and mathematicians alike. As such, plant morphology is inherently mathematical in that it describes plant form and architecture with geometrical and topological techniques. Gaining an understanding of how to modify plant morphology, through molecular biology and breeding, aided by a mathematical perspective, is critical to improving agriculture, and the monitoring of ecosystems is vital to modeling a future with fewer natural resources. In this white paper, we begin with an overview in quantifying the form of plants and mathematical models of patterning in plants. We then explore the fundamental challenges that remain unanswered concerning plant morphology, from the barriers preventing the prediction of phenotype from genotype to modeling the movement of leaves in air streams. We end with a discussion concerning the education of plant morphology synthesizing biological and mathematical approaches and ways to facilitate research advances through outreach, cross-disciplinary training, and open science. Unleashing the potential of geometric and topological approaches in the plant sciences promises to transform our understanding of both plants and mathematics. PMID- 28659938 TI - Functional Characterization of Tea (Camellia sinensis) MYB4a Transcription Factor Using an Integrative Approach. AB - Green tea (Camellia sinensis, Cs) abundantly produces a diverse array of phenylpropanoid compounds benefiting human health. To date, the regulation of the phenylpropanoid biosynthesis in tea remains to be investigated. Here, we report a cDNA isolated from leaf tissues, which encodes a R2R3-MYB transcription factor. Amino acid sequence alignment and phylogenetic analysis indicate that it is a member of the MYB4-subgroup and named as CsMYB4a. Transcriptional and metabolic analyses show that the expression profile of CsMYB4a is negatively correlated to the accumulation of six flavan-3-ols and other phenolic acids. GFP fusion analysis shows CsMYB4a's localization in the nucleus. Promoters of five tea phenylpropanoid pathway genes are isolated and characterized to contain four types of AC-elements, which are targets of MYB4 members. Interaction of CsMYB4a and five promoters shows that CsMYB4a decreases all five promoters' activity. To further characterize its function, CsMYB4a is overexpressed in tobacco plants. The resulting transgenic plants show dwarf, shrinking and yellowish leaf, and early senescence phenotypes. A further genome-wide transcriptomic analysis reveals that the expression levels of 20 tobacco genes involved in the shikimate and the phenylpropanoid pathways are significantly downregulated in transgenic tobacco plants. UPLC-MS and HPLC based metabolic profiling reveals significant reduction of total lignin content, rutin, chlorogenic acid, and phenylalanine in CsMYB4a transgenic tobacco plants. Promoter sequence analysis of the 20 tobacco genes characterizes four types of AC-elements. Further CsMYB4a-AC element and CsMYB4a-promoter interaction analyses indicate that the negative regulation of CsMYB4a on the shikimate and phenylpropanoid pathways in tobacco is via reducing promoter activity. Taken together, all data indicate that CsMYB4a negatively regulates the phenylpropanoid and shikimate pathways. Highlight: A tea (Camellia sinensis) MYB4a is characterized to encode a R2R3-MYB transcription factor. It is shown to repressively control the phenylpropanoid and shikimate pathway. PMID- 28659939 TI - Application of Nuclear Volume Measurements to Comprehend the Cell Cycle in Root Knot Nematode-Induced Giant Cells. AB - Root-knot nematodes induce galls that contain giant-feeding cells harboring multiple enlarged nuclei within the roots of host plants. It is recognized that the cell cycle plays an essential role in the set-up of a peculiar nuclear organization that seemingly steers nematode feeding site induction and development. Functional studies of a large set of cell cycle genes in transgenic lines of the model host Arabidopsis thaliana have contributed to better understand the role of the cell cycle components and their implication in the establishment of functional galls. Mitotic activity mainly occurs during the initial stages of gall development and is followed by an intense endoreduplication phase imperative to produce giant-feeding cells, essential to form vigorous galls. Transgenic lines overexpressing particular cell cycle genes can provoke severe nuclei phenotype changes mainly at later stages of feeding site development. This can result in chaotic nuclear phenotypes affecting their volume. These aberrant nuclear organizations are hampering gall development and nematode maturation. Herein we report on two nuclear volume assessment methods which provide information on the complex changes occurring in nuclei during giant cell development. Although we observed that the data obtained with AMIRA tend to be more detailed than Volumest (Image J), both approaches proved to be highly versatile, allowing to access 3D morphological changes in nuclei of complex tissues and organs. The protocol presented here is based on standard confocal optical sectioning and 3-D image analysis and can be applied to study any volume and shape of cellular organelles in various complex biological specimens. Our results suggest that an increase in giant cell nuclear volume is not solely linked to increasing ploidy levels, but might result from the accumulation of mitotic defects. PMID- 28659940 TI - SUMO-Dependent Synergism Involving Heat Shock Transcription Factors with Functions Linked to Seed Longevity and Desiccation Tolerance. AB - A transcriptional synergism between HaHSFA9 (A9) and HaHSFA4a (A4a) contributes to determining longevity and desiccation tolerance of sunflower (Helianthus annuus, L.) seeds. Potential lysine SUMOylation sites were identified in A9 and A4a and mutated to arginine. We show that A9 is SUMOylated in planta at K38. Although we did not directly detect SUMOylated A4a in planta, we provide indirect evidence from transient expression experiments indicating that A4a is SUMOylated at K172. Different combinations of wild type and SUMOylation site mutants of A9 and A4a were analyzed by transient expression in sunflower embryos and leaves. Although most of the precedents in literature link SUMOylation with repression, the A9 and A4a synergism was fully abolished when the mutant forms for both factors were combined. However, the combination of mutant forms of A9 and A4a did not affect the nuclear retention of A4a by A9; therefore, the analyzed mutations would affect the synergism after the mutual interaction and nuclear co localization of A9 and A4a. Our results suggest a role for HSF SUMOylation during late, zygotic, embryogenesis. The SUMOylation of A9 (or A4a) would allow a crucial, synergic, transcriptional effect that occurs in maturing sunflower seeds. PMID- 28659941 TI - Insight into MAS: A Molecular Tool for Development of Stress Resistant and Quality of Rice through Gene Stacking. AB - Rice yield is subjected to severe losses due to adverse effect of a number of stress factors. The most effective method of controlling reduced crop production is utilization of host resistance. Recent technological advances have led to the improvement of DNA based molecular markers closely linked to genes or QTLs in rice chromosome that bestow tolerance to various types of abiotic stresses and resistance to biotic stress factors. Transfer of several genes with potential characteristics into a single genotype is possible through the process of marker assisted selection (MAS), which can quicken the advancement of tolerant/resistant cultivars in the lowest number of generations with the utmost precision through the process of gene pyramiding. Overall, this review presented various types of molecular tools including MAS that can be reasonable and environmental friendly approach for the improvement of abiotic and biotic stress resistant rice with enhanced quality. PMID- 28659942 TI - Identification of Two New Mechanisms That Regulate Fruit Growth by Cell Expansion in Tomato. AB - Key mechanisms controlling fruit weight and shape at the levels of meristem, ovary or very young fruit have already been identified using natural tomato diversity. We reasoned that new developmental modules prominent at later stages of fruit growth could be discovered by using new genetic and phenotypic diversity generated by saturated mutagenesis. Twelve fruit weight and tissue morphology mutants likely affected in late fruit growth were selected among thousands of fruit size and shape EMS mutants available in our tomato EMS mutant collection. Their thorough characterization at organ, tissue and cellular levels revealed two major clusters controlling fruit growth and tissue morphogenesis either through (i) the growth of all fruit tissues through isotropic cell expansion or (ii) only the growth of the pericarp through anisotropic cell expansion. These likely correspond to new cell expansion modules controlling fruit growth and tissue morphogenesis in tomato. Our study therefore opens the way for the identification of new gene regulatory networks controlling tomato fruit growth and morphology. PMID- 28659943 TI - Winter Night-Warming Improves Post-anthesis Physiological Activities and Sink Strength in Relation to Grain Filling in Winter Wheat (Triticum aestivum L.). AB - The diurnal and seasonal temperature rising patterns "asymmetric warming," plays an important role in crop distribution and productivity. Asymmetric warming during the early growth periods of winter wheat (Triticum aestivum L.) profoundly affects vegetative growth and post-anthesis grain productivity, but the underlying physiological mechanism is still unclear. We conducted field experiments from 2012 to 2014 using two wheat cultivars, namely, Yangmai-13 (vernal type) and Yannong-19 (semi-winter type), to investigate the influences of night-warming during the winter (warming by 1.56-1.67 degrees C from tillering to jointing) or during the spring (warming by 1.78-1.92 degrees C from jointing to booting) on post-anthesis physiological activities and grain-filling processes. Both night-warming treatments enhanced the source activity by increasing flag leaf area, chlorophyll content, and photosynthetic capability in both cultivars compared with those of the control. The night-warming treatments caused an increase in the antioxidant activities of superoxide dismutase (SOD), peroxidase, and catalase (CAT) in the flag leaves of both cultivars, while ROS contents such as superoxide anion radical ([Formula: see text]) and hydrogen peroxide (H2O2) decreased. Moreover, the expression levels of Rubisco activase B (RcaB), major chlorophyll a/b-binding protein (Cab), chloroplast Cu/Zn superoxide dismutase (Cu/Zn-SOD), mitochondrial manganese superoxide dismutase (Mn-SOD), and CAT genes were upregulated at anthesis and were associated with higher photosynthetic capacity and antioxidant activities. Furthermore, night-warming improved sink activities by increasing the concentrations of grain indole-3-acetic acid and cytokinins as well as the sucrose synthase activity for both cultivars. Winter night-warming showed greater potential for improving source strength and grain filling, with consistent performance in both cultivars compared with that of spring night-warming. We concluded form these results that night-warming can improve source and sink capacities in winter wheat, and winter night-warming has greater advantages in this respect than does spring warming. PMID- 28659944 TI - OsSAPK2 Confers Abscisic Acid Sensitivity and Tolerance to Drought Stress in Rice. AB - SNF 1-RELATED PROTEIN KINASE 2 (SnRK2) is a family of plant-specific protein kinases which is the key regulator of hyper-osmotic stress signaling and abscisic acid (ABA)-dependent development in various plants. Among the rice subclass-I and -II SnRK2s, osmotic stress/ABA-activated protein kinase 2 (SAPK2) may be the primary mediator of ABA signaling. However, SAPK2 has not been comprehensively characterized. In this study, we elucidated the functional properties of SAPK2 using loss-of-function mutants produced with the CRISPR/Cas9 system. The SAPK2 expression level was strongly upregulated by drought, high-salinity, and polyethylene glycol (PEG) treatments. The sapk2 mutants exhibited an ABA insensitive phenotype during the germination and post-germination stages, suggesting that SAPK2 had a pivotal role related to ABA-mediated seed dormancy. The sapk2 mutants were more sensitive to drought stress and reactive oxygen species (ROS) than the wild-type plants, indicating that SAPK2 was important for responses to drought conditions in rice. An additional investigation revealed that SAPK2 increased drought tolerance in the following two ways: (i) by reducing water loss via the accumulation of compatible solutes, promoting stomatal closure, and upregulating the expression levels of stress-response genes such as OsRab16b, OsRab21, OsbZIP23, OsLEA3, OsOREB1 and slow anion channel (SLAC) associated genes such as OsSLAC1 and OsSLAC7; (ii) by inducing the expression of antioxidant enzyme genes to promote ROS-scavenging abilities that will ultimately decrease ROS damages. Moreover, we also observed that SAPK2 significantly increased the tolerance of rice plants to salt and PEG stresses. These findings imply that SAPK2 is a potential candidate gene for future crop improvement studies. PMID- 28659945 TI - Expression of the Aeluropus littoralis AlSAP Gene Enhances Rice Yield under Field Drought at the Reproductive Stage. AB - We evaluated the yields of Oryza sativa L. 'Nipponbare' rice lines expressing a gene encoding an A20/AN1 domain stress-associated protein, AlSAP, from the halophyte grass Aeluropus littoralis under the control of different promoters. Three independent field trials were conducted, with drought imposed at the reproductive stage. In all trials, the two transgenic lines, RN5 and RN6, consistently out-performed non-transgenic (NT) and wild-type (WT) controls, providing 50-90% increases in grain yield (GY). Enhancement of tillering and panicle fertility contributed to this improved GY under drought. In contrast with physiological records collected during previous greenhouse dry-down experiments, where drought was imposed at the early tillering stage, we did not observe significant differences in photosynthetic parameters, leaf water potential, or accumulation of antioxidants in flag leaves of AlSAP-lines subjected to drought at flowering. However, AlSAP expression alleviated leaf rolling and leaf drying induced by drought, resulting in increased accumulation of green biomass. Therefore, the observed enhanced performance of the AlSAP-lines subjected to drought at the reproductive stage can be tentatively ascribed to a primed status of the transgenic plants, resulting from a higher accumulation of biomass during vegetative growth, allowing reserve remobilization and maintenance of productive tillering and grain filling. Under irrigated conditions, the overall performance of AlSAP-lines was comparable with, or even significantly better than, the NT and WT controls. Thus, AlSAP expression inflicted no penalty on rice yields under optimal growth conditions. Our results support the use of AlSAP transgenics to reduce rice GY losses under drought conditions. PMID- 28659946 TI - The Banana Fruit SINA Ubiquitin Ligase MaSINA1 Regulates the Stability of MaICE1 to be Negatively Involved in Cold Stress Response. AB - The regulation of ICE1 protein stability is important to ensure effective cold stress response, and is extensively studied in Arabidopsis. Currently, how ICE1 stability in fruits under cold stress is controlled remains largely unknown. Here, we reported the possible involvement of a SEVEN IN ABSENTIA (SINA) ubiquitin ligase MaSINA1 from banana fruit in affecting MaICE1 stability. MaSINA1 was identified based on a yeast two-hybrid screening using MaICE1 as bait. Further yeast two-hybrid, pull-down, bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation (CoIP) assays confirmed that MaSINA1 interacted with MaICE1. The expression of MaSINA1 was repressed by cold stress. Subcellular localization analysis in tobacco leaves showed that MaSINA1 was localized predominantly in the nucleus. In vitro ubiquitination assay showed that MaSINA1 possessed E3 ubiquitin ligase activity. More importantly, in vitro and semi-in vivo experiments indicated that MaSINA1 can ubiquitinate MaICE1 for the 26S proteasome-dependent degradation, and therefore suppressed the transcriptional activation of MaICE1 to MaNAC1, an important regulator of cold stress response of banana fruit. Collectively, our data reveal a mechanism in banana fruit for control of the stability of ICE1 and for the negative regulation of cold stress response by a SINA E3 ligase via the ubiquitin proteasome system. PMID- 28659947 TI - MicroRNAs and Their Regulatory Role in Sugarcane. AB - Sugarcane, one of the most photosynthetically efficient crops, is an important source of sugar and feedstock for green energy and co-generation. The high level of polyploidy and genomic peculiarities in this crop point towards a complex mechanism of regulation for the economically important traits like sugar content, cane yield related traits, resistance to biotic and abiotic stresses etc. The regulatory pathways for these traits comprise of a number of genes, transcription factors and different categories of RNAs like small interference RNAs (siRNAs), and Micro RNAs (miRNAs). MicroRNAs (miRNAs) are found to play an important regulatory role in many crops. As in other crops, several miRNAs have been identified in sugarcane too and these are speculated to have a role in regulating the various metabolic processes. Role of miRNAs in relation to drought tolerance has been studied to a great extent in this crop. miRNAs have been predicted to be linked to expression of other traits like disease resistance, salinity tolerance, waterlogging and axillary bud growth in sugarcane. miRNAs can have a significant role in biomass production in sugarcane, as reported in several biofuel crops. Till now, miRNAs linked to sugar accumulation have not been identified in sugarcane, but studies suggest an important role for miRNAs in sugar metabolic pathway in crops like Sorghum and switch grass. It is presumed that in sugarcane too, sugar accumulation as well as the other important metabolic pathways might be regulated to some extent by the miRNAs. The review examines the progress made in understanding the miRNA regulation in sugarcane and the extent to which miRNA mediated regulation can be utilized in sugarcane improvement. PMID- 28659948 TI - The Multitalented MEDIATOR25. AB - The multi-subunit Mediator complex, which links DNA-bound transcription factors to RNA Pol II during transcription, is an essential regulator of gene expression in all eukaryotes. Individual subunits of the Mediator complex integrate numerous endogenous and exogenous signals. In this paper, diverse regulatory functions performed by MEDIATOR25 (MED25), one of the subunits of the plant Mediator complex are reviewed. MED25 was first identified as a regulator of flowering time and named PHYTOCHROME AND FLOWERING TIME1 (PFT1). Since then, MED25 has been implicated in a range of other plant functions that vary from hormone signaling (JA, ABA, ethylene, and IAA) to biotic and abiotic stress tolerance and plant development. MED25 physically interacts with transcriptional activators (e.g., AP2/ERFs, MYCs, and ARFs), repressors (e.g., JAZs and Aux/IAAs), and other Mediator subunits (MED13 and MED16). In addition, various genetic and epigenetic interactions involving MED25 have been reported. These features make MED25 one of the most multifunctional Mediator subunits and provide new insights into the transcriptional control of gene expression in plants. PMID- 28659949 TI - Quantitative Trait Locus Mapping of Salt Tolerance and Identification of Salt Tolerant Genes in Brassica napus L. AB - Salinity stress is one of typical abiotic stresses that seriously limit crop production. In this study, a genetic linkage map based on 532 molecular markers covering 1341.1 cM was constructed to identify the loci associated with salt tolerance in Brassica napus. Up to 45 quantitative trait loci (QTLs) for 10 indicators were identified in the F2:3 populations. These QTLs can account for 4.80-51.14% of the phenotypic variation. A major QTL, qSPAD5 on LG5 associated with chlorophyll can be detected in three replicates. Two intron polymorphic (IP) markers in this QTL region were developed successfully to narrow down the QTL location to a region of 390 kb. A salt tolerance related gene Bra003640 was primary identified as the candidate gene in this region. The full length of the candidate gene was 1,063 bp containing three exons and two introns in B. napus L. The open reading frame (ORF) is 867 bp and encodes 287 amino acids. Three amino acid differences (34, 54, and 83) in the conserved domain (B-box) were identified. RT-qPCR analysis showed that the gene expression had significant difference between the two parents. The study laid great foundation for salt tolerance related gene mapping and cloning in B. napus L. PMID- 28659950 TI - Mapping and Characterization of the fefe Gene That Controls Iron Uptake in Melon (Cucumis melo L.). AB - Iron (Fe) deficiency in plants limits crop growth and productivity. Molecular mechanisms that plants use to sense and respond to Fe deficiency by coordinated expression of Fe-uptake genes are not fully understood. The C940-fe chlorotic melon (Cucumis melo) mutant known as fefe is unable to upregulate Fe-uptake genes, however, the FeFe gene had not been identified. In this study, we used two F2 mapping populations to map and identify the FeFe gene as bHLH38, a homolog of subgroup Ib bHLH genes from Arabidopsis thaliana that are involved in transcriptional regulation of Fe-uptake genes in partnership with the FIT gene. A Ty1-copia type retrotransposon insertion of 5.056 kb within bHLH38 is responsible for the defect in bHLH38 in fefe, based on sequencing and expression analysis. This retrotransposon insertion results in multiple non-functional transcripts expected to result in an altered and truncated protein sequence. Hairy root transformation of fefe plants using wild-type bHLH38 resulted in functional complementation of the chlorotic fefe phenotype. Using a yeast-2-hybrid assay, the transcription factor Fit interacted with the wild-type bHLH38 protein, but did not interact with the fefe bHLH38 protein, suggesting that heterodimer formation of Fit/bHLH38 to regulate Fe-uptake genes does not occur in fefe roots. The second subgroup Ib bHLH gene in the melon genome is not functionally redundant to bHLH38, in contrast to Arabidopsis where four subgroup Ib bHLH genes are functionally redundant. Whereas the Arabidopsis bHLH transcript levels are upregulated by Fe deficiency, melon bHLH38 was not regulated at the transcript level. Thus, the fefe mutant may provide a platform for studying bHLH38 genes and proteins from other plant species. PMID- 28659951 TI - ANGUSTIFOLIA, a Plant Homolog of CtBP/BARS Localizes to Stress Granules and Regulates Their Formation. AB - The ANGUSTIFOLIA (AN) gene in Arabidopsis is important for a plethora of morphological phenotypes. Recently, AN was also reported to be involved in responses to biotic and abiotic stresses. It encodes a homolog of the animal C terminal binding proteins (CtBPs). In contrast to animal CtBPs, AN does not appear to function as a transcriptional co-repressor and instead functions outside nucleus where it might be involved in Golgi-associated membrane trafficking. In this study, we report a novel and unexplored role of AN as a component of stress granules (SGs). Interaction studies identified several RNA binding proteins that are associated with AN. AN co-localizes with several messenger ribonucleoprotein granule markers to SGs in a stress dependent manner. an mutants exhibit an altered SG formation. We provide evidence that the NAD(H) binding domain of AN is relevant in this context as proteins carrying mutations in this domain localize to a much higher degree to SGs and strongly reduce AN dimerization and its interaction with one interactor but not the others. Finally, we show that AN is a negative regulator of salt and osmotic stress responses in Arabidopsis suggesting a functional relevance in SGs. PMID- 28659953 TI - Overexpressing the Sedum alfredii Cu/Zn Superoxide Dismutase Increased Resistance to Oxidative Stress in Transgenic Arabidopsis. AB - Superoxide dismutase (SOD) is a very important reactive oxygen species (ROS) scavenging enzyme. In this study, the functions of a Cu/Zn SOD gene (SaCu/Zn SOD), from Sedum alfredii, a cadmium (Cd)/zinc/lead co-hyperaccumulator of the Crassulaceae, was characterized. The expression of SaCu/Zn SOD was induced by Cd stress. Compared with wild-type (WT) plants, overexpression of SaCu/Zn SOD gene in transgenic Arabidopsis plants enhanced the antioxidative defense capacity, including SOD and peroxidase activities. Additionally, it reduced the damage associated with the overproduction of hydrogen peroxide (H2O2) and superoxide radicals (O2*-). The influence of Cd stress on ion flux across the root surface showed that overexpressing SaCu/Zn SOD in transgenic Arabidopsis plants has greater Cd uptake capacity existed in roots. A co-expression network based on microarray data showed possible oxidative regulation in Arabidopsis after Cd induced oxidative stress, suggesting that SaCu/Zn SOD may participate in this network and enhance ROS-scavenging capability under Cd stress. Taken together, these results suggest that overexpressing SaCu/Zn SOD increased oxidative stress resistance in transgenic Arabidopsis and provide useful information for understanding the role of SaCu/Zn SOD in response to abiotic stress. PMID- 28659954 TI - Segregation of Hydroxycinnamic Acid Esters Mediating Sweetpotato Weevil Resistance in Storage Roots of Sweetpotato. AB - Resistance to sweetpotato weevils (Cylas spp.) has been identified in several sweetpotato (Ipomoea batatas) landraces from East Africa and shown to be conferred by hydroxycinnamic acids that occur on the surface of storage roots. The segregation of resistance in this crop is unknown and could be monitored using these chemical traits as markers for resistance in F1 offspring from breeding programs. For the first time in a segregating population, we quantified the plant chemicals that confer resistance and evaluated levels of insect colonization of the same progeny in field and laboratory studies. We used a bi parental mapping population of 287 progenies from a cross between I. batatas 'New Kawogo,' a weevil resistant Ugandan landrace and I. batatas 'Beauregard' a North American orange-fleshed and weevil susceptible cultivar. The progenies were evaluated for resistance to sweetpotato weevil, Cylas puncticollis at three field locations that varied climatically and across two seasons to determine how environment and location influenced resistance. To augment our field open-choice resistance screening, each clone was also evaluated in a no choice experiment with weevils reared in the laboratory. Chemical analysis was used to determine whether differences in resistance to weevils were associated with plant compounds previously identified as conferring resistance. We established linkage between field and laboratory resistance to Cylas spp. and sweetpotato root chemistry. The data also showed that resistance in sweetpotato was mediated by root chemicals in most but not all cases. Multi-location trials especially from Serere data provided evidence that the hydroxycinnamic acid esters are produced constitutively within the plants in different clonal genotypes and that the ecological interaction of these chemicals in sweetpotato with weevils confers resistance. Our data suggest that these chemical traits are controlled quantitatively and that ultimately a knowledge of the genetics of resistance will facilitate management of these traits, enhance our understanding of the mechanistic basis of resistance and speed the development of new sweetpotato varieties with resistance to sweetpotato weevil. PMID- 28659952 TI - Alteration in Auxin Homeostasis and Signaling by Overexpression Of PINOID Kinase Causes Leaf Growth Defects in Arabidopsis thaliana. AB - In plants many developmental processes are regulated by auxin and its directional transport. PINOID (PID) kinase helps to regulate this transport by influencing polar recruitment of PIN efflux proteins on the cellular membranes. We investigated how altered auxin levels affect leaf growth in Arabidopsis thaliana. Arabidopsis mutants and transgenic plants with altered PID expression levels were used to study the effect on auxin distribution and leaf development. Single knockouts showed small pleiotropic growth defects. Contrastingly, several leaf phenotypes related to changes in auxin concentrations and transcriptional activity were observed in PID overexpression (PIDOE ) lines. Unlike in the knockout lines, the leaves of PIDOE lines showed an elevation in total indole-3 acetic acid (IAA). Accordingly, enhanced DR5-visualized auxin responses were detected, especially along the leaf margins. Kinematic analysis revealed that ectopic expression of PID negatively affects cell proliferation and expansion rates, yielding reduced cell numbers and small-sized cells in the PIDOE leaves. We used PIDOE lines as a tool to study auxin dose effects on leaf development and demonstrate that auxin, above a certain threshold, has a negative affect on leaf growth. RNA sequencing further showed how subtle PIDOE -related changes in auxin levels lead to transcriptional reprogramming of cellular processes. PMID- 28659955 TI - Five Fatty Acyl-Coenzyme A Reductases Are Involved in the Biosynthesis of Primary Alcohols in Aegilops tauschii Leaves. AB - The diploid Aegilops tauschii is the D-genome donor to hexaploid wheat (Triticum aestivum) and represents a potential source for genetic study in common wheat. The ubiquitous wax covering the aerial parts of plants plays an important role in protecting plants against non-stomatal water loss. Cuticular waxes are complex mixtures of very-long-chain fatty acids, alkanes, primary and/or secondary alcohols, aldehydes, ketones, esters, triterpenes, sterols, and flavonoids. In the present work, primary alcohols were identified as the major components of leaf cuticular wax in Ae. tauschii, with C26:0-OH being the dominant primary alcohol. Analysis by scanning electron microscope revealed that dense platelet shaped wax crystals were deposited on leaf surfaces of Ae. tauschii. Ten putative wax biosynthetic genes encoding fatty acyl-coenzyme A reductase (FAR) were identified in the genome of Ae. tauschii. Five of these genes, Ae.tFAR1, Ae.tFAR2, Ae.tFAR3, Ae.tFAR4, and Ae.tFAR6, were found expressed in the leaf blades. Heterologous expression of the five Ae.tFARs in yeast (Saccharomyces cerevisiae) showed that Ae.tFAR1, Ae.tFAR2, Ae.tFAR3, Ae.tFAR4, and Ae.tFAR6 were predominantly responsible for the accumulation of C16:0, C18:0, C26:0, C24:0, and C28:0 primary alcohols, respectively. In addition, nine Ae.tFAR paralogous genes were located on D chromosome of wheat and the wheat nullisomic-tetrasomic lines with the loss of Ae.tFAR3 and Ae.tFAR4 paralogous genes had significantly reduced levels of primary alcohols in the leaf blades. Collectively, these data suggest that Ae.tFAR1, Ae.tFAR2, Ae.tFAR3, Ae.tFAR4, and Ae.tFAR6 encode alcohol-forming FARs involved in the biosynthesis of primary alcohols in the leaf blades of Ae. tauschii. The information obtained in Ae. tauschii enables us to better understand wax biosynthesis in common wheat. PMID- 28659956 TI - Identification of Genes Associated with Lemon Floral Transition and Flower Development during Floral Inductive Water Deficits: A Hypothetical Model. AB - : Water deficit is a key factor to induce flowering in many woody plants, but reports on the molecular mechanisms of floral induction and flowering by water deficit are scarce. Here, we analyzed the morphology, cytology, and different hormone levels of lemon buds during floral inductive water deficits. Higher levels of ABA were observed, and the initiation of floral bud differentiation was examined by paraffin sections analysis. A total of 1638 differentially expressed genes (DEGs) were identified by RNA sequencing. DEGs were related to flowering, hormone biosynthesis, or metabolism. The expression of some DEGs was associated with floral induction by real-time PCR analysis. However, some DEGs may not have anything to do with flowering induction/flower development; they may be involved in general stress/drought response. Four genes from the phosphatidylethanolamine binding protein family were further investigated. Ectopic expression of these genes in Arabidopsis changed the flowering time of transgenic plants. Furthermore, the 5' flanking region of these genes was also isolated and sequence analysis revealed the presence of several putative cis-regulatory elements, including basic elements and hormone regulation elements. The spatial and temporal expression patterns of these promoters were investigated under water deficit treatment. Based on these findings, we propose a model for citrus flowering under water deficit conditions, which will enable us to further understand the molecular mechanism of water deficit-regulated flowering in citrus. HIGHLIGHT: Based on gene activity during floral inductive water deficits identified by RNA sequencing and genes associated with lemon floral transition, a model for citrus flowering under water deficit conditions is proposed. PMID- 28659958 TI - Extra Large G-Protein Interactome Reveals Multiple Stress Response Function and Partner-Dependent XLG Subcellular Localization. AB - The three-member family of Arabidopsis extra-large G proteins (XLG1-3) defines the prototype of an atypical Galpha subunit in the heterotrimeric G protein complex. Recent evidence indicate that XLG subunits operate along with its Gbetagamma dimer in root morphology, stress responsiveness, and cytokinin induced development, however downstream targets of activated XLG proteins in the stress pathways are rarely known. To assemble a set of candidate XLG-targeted proteins, a yeast two-hybrid complementation-based screen was performed using XLG protein baits to query interactions between XLG and partner protein found in glucose treated seedlings, roots, and Arabidopsis cells in culture. Seventy two interactors were identified and >60% of a test set displayed in vivo interaction with XLG proteins. Gene co-expression analysis shows that >70% of the interactors are positively correlated with the corresponding XLG partners. Gene Ontology enrichment for all the candidates indicates stress responses and posits a molecular mechanism involving a specific set of transcription factor partners to XLG. Genes encoding two of these transcription factors, SZF1 and 2, require XLG proteins for full NaCl-induced expression. The subcellular localization of the XLG proteins in the nucleus, endosome, and plasma membrane is dependent on the specific interacting partner. PMID- 28659960 TI - Editorial: Roots-The Hidden Provider. PMID- 28659959 TI - Moderate Drought Stress Induces Increased Foliar Dimethylsulphoniopropionate (DMSP) Concentration and Isoprene Emission in Two Contrasting Ecotypes of Arundo donax. AB - The function of dimethylsulphoniopropionate (DMSP) in plants is unclear. It has been proposed as an antioxidant, osmolyte and overflow for excess energy under stress conditions. The formation of DMSP is part of the methionine (MET) pathway that is involved in plant stress responses. We used a new analytical approach to accurately quantify the changes in DMSP concentration that occurred in two ecotypes of the biomass crop Arundo donax subject to moderate drought stress under field conditions. The ecotypes of A. donax were from a hot semi-arid habitat in Morocco and a warm-humid environment in Central Italy. The Moroccan ecotype showed more pronounced reductions in photosynthesis, stomatal conductance and photochemical electron transport than the Italian ecotype. An increase in isoprene emission occurred in both ecotypes alongside enhanced foliar concentrations of DMSP, indicative of a protective function of these two metabolites in the amelioration of the deleterious effects of excess energy and oxidative stress. This is consistent with the modification of carbon within the methyl-erythritol and MET pathways responsible for increased synthesis of isoprene and DMSP under moderate drought. The results of this study indicate that DMSP is an important adaptive component of the stress response regulated via the MET pathway in A. donax. DMSP is likely a multifunctional molecule playing a number of roles in the response of A. donax to reduced water availability. PMID- 28659957 TI - Auxin Signaling in Regulation of Plant Translation Reinitiation. AB - The mRNA translation machinery directs protein production, and thus cell growth, according to prevailing cellular and environmental conditions. The target of rapamycin (TOR) signaling pathway-a major growth-related pathway-plays a pivotal role in optimizing protein synthesis in mammals, while its deregulation triggers uncontrolled cell proliferation and the development of severe diseases. In plants, several signaling pathways sensitive to environmental changes, hormones, and pathogens have been implicated in post-transcriptional control, and thus far phytohormones have attracted most attention as TOR upstream regulators in plants. Recent data have suggested that the coordinated actions of the phytohormone auxin, Rho-like small GTPases (ROPs) from plants, and TOR signaling contribute to translation regulation of mRNAs that harbor upstream open reading frames (uORFs) within their 5'-untranslated regions (5'-UTRs). This review will summarize recent advances in translational regulation of a specific set of uORF-containing mRNAs that encode regulatory proteins-transcription factors, protein kinases and other cellular controllers-and how their control can impact plant growth and development. PMID- 28659961 TI - Bulked Segregant RNA-seq Reveals Differential Expression and SNPs of Candidate Genes Associated with Waterlogging Tolerance in Maize. AB - Waterlogging has increasingly become one of the major constraints to maize productivity in some maize production zones because it causes serious yield loss. Bulked segregant RNA-seq (BSR-seq) has been widely applied to profile candidate genes and map associated Single Nucleotide Polymorphism (SNP) markers in many species. In this study, 10 waterlogging sensitive and eight tolerant inbred lines were selected from 60 maize inbred lines with waterlogging response determined and preselected by the International Maize and Wheat Improvement Center (CIMMYT) from over 400 tropical maize inbred lines. BSR-seq was performed to identify differentially expressed genes and SNPs associated with waterlogging tolerance. Upon waterlogging stress, 354 and 1094 genes were differentially expressed in the tolerant and sensitive pools, respectively, compared to untreated controls. When tolerant and sensitive pools were compared, 593 genes were differentially expressed under untreated and 431 genes under waterlogged conditions, of which 122 genes overlapped. To validate the BSR-seq results, the expression levels of six genes were determined by qRT-PCR. The qRT-PCR results were consistent with BSR-seq results. Comparison of allelic polymorphism in mRNA sequences between tolerant and sensitive pools revealed 165 (normal condition) and 128 (waterlogged condition) high-probability SNPs. We found 18 overlapping SNPs with genomic positions mapped. Eighteen SNPs were contained in 18 genes, and eight and nine of 18 genes were responsive to waterlogging stress in tolerant and sensitive lines, respectively. Six alleles of the 18 originated from tolerant pool were significantly up-regulated under waterlogging, but not those from sensitive pool. Importantly, one allele (GRMZM2G055704) of the six genes was mapped between umc1619 and umc1948 on chromosome 1 where a QTL associated with waterlogging tolerance was identified in a previous research, strongly indicating that GRMZM2G055704 is a candidate gene responsive to waterlogging. Our research contributes to the knowledge of the molecular mechanism for waterlogging tolerance in maize. PMID- 28659963 TI - Comparative Transcriptome Analysis Reveal Candidate Genes Potentially Involved in Regulation of Primocane Apex Rooting in Raspberry (Rubus spp.). AB - Raspberries (Rubus spp.) exhibit a unique rooting process that is initiated from the stem apex of primocane, conferring an unusual asexual mode of reproduction to this plant. However, the full complement of genes involved in this process has not been identified. To this end, the present study analyzed the transcriptomes of the Rubus primocane and floricane stem apex at three developmental stages by Digital Gene Expression profiling to identify genes that regulate rooting. Sequencing and de novo assembly yielded 26.82 Gb of nucleotides and 59,173 unigenes; 498, 7,346, 4,110, 7,900, 9,397, and 4,776 differently expressed genes were identified in paired comparisons of SAF1 (floricane at developmental stage 1) vs. SAP1 (primocane at developmental stage 1), SAF2 vs. SAP2, SAF3 vs. SAP3, SAP1 vs. SAP2, SAP1 vs. SAP3, and SAP2 vs. SAP3, respectively. SAP1 maintains an extension growth pattern; SAP2 then exhibits growth arrest and vertical (downward) gravitropic deflection; and finally, short roots begin to form on the apex of SAP3. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis of SAP1 vs. SAP2 revealed 12 pathways that were activated in response to shoot growth arrest and root differentiation, including circadian rhythm-plant (ko04712) and plant hormone signal transduction (ko04075). Our results indicate that genes related to circadian rhythm, ethylene and auxin signaling, shoot growth, and root development are potentially involved in the regulation of primocane apex rooting in Rubus. These findings provide a basis for elucidating the molecular mechanisms of primocane apex rooting in this economically valuable crop. PMID- 28659962 TI - Molecular Characterization, Gene Evolution, and Expression Analysis of the Fructose-1, 6-bisphosphate Aldolase (FBA) Gene Family in Wheat (Triticum aestivum L.). AB - Fructose-1, 6-bisphosphate aldolase (FBA) is a key plant enzyme that is involved in glycolysis, gluconeogenesis, and the Calvin cycle. It plays significant roles in biotic and abiotic stress responses, as well as in regulating growth and development processes. In the present paper, 21 genes encoding TaFBA isoenzymes were identified, characterized, and categorized into three groups: class I chloroplast/plastid FBA (CpFBA), class I cytosol FBA (cFBA), and class II chloroplast/plastid FBA. By using a prediction online database and genomic PCR analysis of Chinese Spring nulli-tetrasomic lines, we have confirmed the chromosomal location of these genes in 12 chromosomes of four homologous groups. Sequence and genomic structure analysis revealed the high identity of the allelic TaFBA genes and the origin of different TaFBA genes. Numerous putative environment stimulus-responsive cis-elements have been identified in 1,500-bp regions of TaFBA gene promoters, of which the most abundant are the light regulated elements (LREs). Phylogenetic reconstruction using the deduced protein sequence of 245 FBA genes indicated an independent evolutionary pathway for the class I and class II groups. Although, earlier studies have indicated that class II FBA only occurs in prokaryote and fungi, our results have demonstrated that a few class II CpFBAs exist in wheat and other closely related species. Class I TaFBA was predicted to be tetramers and class II to be dimers. Gene expression analysis based on microarray and transcriptome databases suggested the distinct role of TaFBAs in different tissues and developmental stages. The TaFBA 4-9 genes were highly expressed in leaves and might play important roles in wheat development. The differential expression patterns of the TaFBA genes in light/dark and a few abiotic stress conditions were also analyzed. The results suggested that LRE cis-elements of TaFBA gene promoters were not directly related to light responses. Most TaFBA genes had higher expression levels in the roots than in the shoots when under various stresses. Class I cytosol TaFBA genes, particularly TaFBA10/12/18 and TaFBA13/16, and three class II TaFBA genes are involved in responses to various abiotic stresses. Class I CpFBA genes in wheat are apparently sensitive to different stress conditions. PMID- 28659965 TI - A Novel Lens orientalis Resistance Source to the Recently Evolved Highly Aggressive Australian Ascochyta lentis Isolates. AB - Substantial yield losses and poor seed quality are frequently associated with Ascochyta blight infection of lentil caused by Ascochyta lentis. Recently reported changes in aggressiveness of A. lentis have led to decreased resistance within cultivars, such as Northfield and Nipper in Australia. Furthermore, the narrow genetic base of the current breeding program remains a risk for further selective pathogen evolution to overcome other currently used resistances. Therefore, incorporation of potentially novel and diverse resistance genes into the advanced lines will aid to improve cultivar stability. To identify these, 30 genotypes sourced from five wild species (Lens orientalis, L. odomensis, L. ervoides, L. nigricans and L. lamottei), including eight previously reported resistance sources, were screened for disease reaction to two recently isolated and highly aggressive isolates. Subsequently, two L. orientalis accessions were found highly resistant and a further six L. nigricans, one L. odomensis, one L. ervoides, one L. lamottei, and one L. orientalis accessions were moderately resistant. Several of these were more resistant than the currently deployed resistance source, ILL 7537. Furthermore, L. orientalis accession ILWL 180 was consistently resistant against other highly aggressive isolates recovered from diverse geographical lentil growing regions and host genotypes, suggesting stability and potential for future use of this accession in the Australian lentil breeding program. PMID- 28659964 TI - Transcription Factor Repertoire of Necrotrophic Fungal Phytopathogen Ascochyta rabiei: Predominance of MYB Transcription Factors As Potential Regulators of Secretome. AB - Transcription factors (TFs) are the key players in gene expression and their study is highly significant for shedding light on the molecular mechanisms and evolutionary history of organisms. During host-pathogen interaction, extensive reprogramming of gene expression facilitated by TFs is likely to occur in both host and pathogen. To date, the knowledge about TF repertoire in filamentous fungi is in infancy. The necrotrophic fungus Ascochyta rabiei, that causes destructive Ascochyta blight (AB) disease of chickpea (Cicer arietinum), demands more comprehensive study for better understanding of Ascochyta-legume pathosystem. In the present study, we performed the genome-wide identification and analysis of TFs in A. rabiei. Taking advantage of A. rabiei genome sequence, we used a bioinformatic approach to predict the TF repertoire of A. rabiei. For identification and classification of A. rabiei TFs, we designed a comprehensive pipeline using a combination of BLAST and InterProScan software. A total of 381 A. rabiei TFs were predicted and divided into 32 fungal specific families of TFs. The gene structure, domain organization and phylogenetic analysis of abundant families of A. rabiei TFs were also carried out. Comparative study of A. rabiei TFs with that of other necrotrophic, biotrophic, hemibiotrophic, symbiotic, and saprotrophic fungi was performed. It suggested presence of both conserved as well as unique features among them. Moreover, cis-acting elements on promoter sequences of earlier predicted A. rabiei secretome were also identified. With the help of published A. rabiei transcriptome data, the differential expression of TF and secretory protein coding genes was analyzed. Furthermore, comprehensive expression analysis of few selected A. rabiei TFs using quantitative real-time polymerase chain reaction revealed variety of expression patterns during host colonization. These genes were expressed in at least one of the time points tested post infection. Overall, this study illustrates the first genome-wide identification and analysis of TF repertoire of A. rabiei. This work would provide the basis for further studies to dissect role of TFs in the molecular mechanisms during A. rabiei-chickpea interactions. PMID- 28659966 TI - Local Populations of Arabidopsis thaliana Show Clear Relationship between Photoperiodic Sensitivity of Flowering Time and Altitude. AB - Adaptation of plants to local conditions that vary substantially within their geographic range is essential for seasonal timing of flowering, a major determinant of plant reproductive success. This study investigates photoperiodic responses in natural populations of Arabidopsis thaliana from high northern latitudes and their significance for local adaptation. Thirty lineages from ten local A. thaliana populations, representing different locations across an altitudinal gradient (2-850 m a.s.l.) in Norway, were grown under uniform controlled conditions, and used to screen for responses to five different photoperiods. We studied relationships between variation in photoperiodic sensitivity of flowering time, altitude, and climatic factors associated with the sites of origin. We found that variation in response to photoperiod is significantly correlated with altitude and climatic variables associated with the sites of origin of the populations. Populations originating from lower altitudes showed stronger photoperiodic sensitivity than populations from higher altitudes. Our results indicate that the altitudinal climatic gradient generates clinal variation in adaptive traits in A. thaliana. PMID- 28659968 TI - The Human Microbiome and the Missing Heritability Problem. AB - The "missing heritability" problem states that genetic variants in Genome-Wide Association Studies (GWAS) cannot completely explain the heritability of complex traits. Traditionally, the heritability of a phenotype is measured through familial studies using twins, siblings and other close relatives, making assumptions on the genetic similarities between them. When this heritability is compared to the one obtained through GWAS for the same traits, a substantial gap between both measurements arise with genome wide studies reporting significantly smaller values. Several mechanisms for this "missing heritability" have been proposed, such as epigenetics, epistasis, and sequencing depth. However, none of them are able to fully account for this gap in heritability. In this paper we provide evidence that suggests that in order for the phenotypic heritability of human traits to be broadly understood and accounted for, the compositional and functional diversity of the human microbiome must be taken into account. This hypothesis is based on several observations: (A) The composition of the human microbiome is associated with many important traits, including obesity, cancer, and neurological disorders. (B) Our microbiome encodes a second genome with nearly a 100 times more genes than the human genome, and this second genome may act as a rich source of genetic variation and phenotypic plasticity. (C) Human genotypes interact with the composition and structure of our microbiome, but cannot by themselves explain microbial variation. (D) Microbial genetic composition can be strongly influenced by the host's behavior, its environment or by vertical and horizontal transmissions from other hosts. Therefore, genetic similarities assumed in familial studies may cause overestimations of heritability values. We also propose a method that allows the compositional and functional diversity of our microbiome to be incorporated to genome wide association studies. PMID- 28659969 TI - Complementary Network-Based Approaches for Exploring Genetic Structure and Functional Connectivity in Two Vulnerable, Endemic Ground Squirrels. AB - The persistence of small populations is influenced by genetic structure and functional connectivity. We used two network-based approaches to understand the persistence of the northern Idaho ground squirrel (Urocitellus brunneus) and the southern Idaho ground squirrel (U. endemicus), two congeners of conservation concern. These graph theoretic approaches are conventionally applied to social or transportation networks, but here are used to study population persistence and connectivity. Population graph analyses revealed that local extinction rapidly reduced connectivity for the southern species, while connectivity for the northern species could be maintained following local extinction. Results from gravity models complemented those of population graph analyses, and indicated that potential vegetation productivity and topography drove connectivity in the northern species. For the southern species, development (roads) and small-scale topography reduced connectivity, while greater potential vegetation productivity increased connectivity. Taken together, the results of the two network-based methods (population graph analyses and gravity models) suggest the need for increased conservation action for the southern species, and that management efforts have been effective at maintaining habitat quality throughout the current range of the northern species. To prevent further declines, we encourage the continuation of management efforts for the northern species, whereas conservation of the southern species requires active management and additional measures to curtail habitat fragmentation. Our combination of population graph analyses and gravity models can inform conservation strategies of other species exhibiting patchy distributions. PMID- 28659970 TI - Effects of Genotype by Environment Interaction on Genetic Gain and Genetic Parameter Estimates in Red Tilapia (Oreochromis spp.). AB - The extent to which genetic gain achieved from selection programs under strictly controlled environments in the nucleus that can be expressed in commercial production systems is not well-documented in aquaculture species. The main aim of this paper was to assess the effects of genotype by environment interaction on genetic response and genetic parameters for four body traits (harvest weight, standard length, body depth, body width) and survival in Red tilapia (Oreochromis spp.). The growth and survival data were recorded on 19,916 individual fish from a pedigreed population undergoing three generations of selection for increased harvest weight in earthen ponds from 2010 to 2012 at the Aquaculture Extension Center, Department of Fisheries, Jitra in Kedah, Malaysia. The pedigree comprised a total of 224 sires and 262 dams, tracing back to the base population in 2009. A multivariate animal model was used to measure genetic response and estimate variance and covariance components. When the homologous body traits in freshwater pond and cage were treated as genetically distinct traits, the genetic correlations between the two environments were high (0.85-0.90) for harvest weight and square root of harvest weight but the estimates were of lower magnitudes for length, width and depth (0.63-0.79). The heritabilities estimated for the five traits studied differed between pond (0.02 to 0.22) and cage (0.07 to 0.68). The common full-sib effects were large, ranging from 0.23 to 0.59 in pond and 0.11 to 0.31 in cage across all traits. The direct and correlated responses for four body traits were generally greater in pond than in cage environments (0.011-1.561 vs. -0.033-0.567 genetic standard deviation units, respectively). Selection for increased harvest body weight resulted in positive genetic changes in survival rate in both pond and cage culture. In conclusion, the reduced selection response and the magnitude of the genetic parameter estimates in the production environment (i.e., cage) relative to those achieved in the nucleus (pond) were a result of the genotype by environment interaction and this effect should be taken into consideration in the future breeding program for Red tilapia. PMID- 28659967 TI - Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models. AB - Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of alpha-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans. PMID- 28659971 TI - Computational Methods for Characterizing Cancer Mutational Heterogeneity. AB - Advances in DNA sequencing technologies have allowed the characterization of somatic mutations in a large number of cancer genomes at an unprecedented level of detail, revealing the extreme genetic heterogeneity of cancer at two different levels: inter-tumor, with different patients of the same cancer type presenting different collections of somatic mutations, and intra-tumor, with different clones coexisting within the same tumor. Both inter-tumor and intra-tumor heterogeneity have crucial implications for clinical practices. Here, we review computational methods that use somatic alterations measured through next generation DNA sequencing technologies for characterizing tumor heterogeneity and its association with clinical variables. We first review computational methods for studying inter-tumor heterogeneity, focusing on methods that attempt to summarize cancer heterogeneity by discovering pathways that are commonly mutated across different patients of the same cancer type. We then review computational methods for characterizing intra-tumor heterogeneity using information from bulk sequencing data or from single cell sequencing data. Finally, we present some of the recent computational methodologies that have been proposed to identify and assess the association between inter- or intra-tumor heterogeneity with clinical variables. PMID- 28659973 TI - Forest Pruning Based on Branch Importance. AB - A forest is an ensemble with decision trees as members. This paper proposes a novel strategy to pruning forest to enhance ensemble generalization ability and reduce ensemble size. Unlike conventional ensemble pruning approaches, the proposed method tries to evaluate the importance of branches of trees with respect to the whole ensemble using a novel proposed metric called importance gain. The importance of a branch is designed by considering ensemble accuracy and the diversity of ensemble members, and thus the metric reasonably evaluates how much improvement of the ensemble accuracy can be achieved when a branch is pruned. Our experiments show that the proposed method can significantly reduce ensemble size and improve ensemble accuracy, no matter whether ensembles are constructed by a certain algorithm such as bagging or obtained by an ensemble selection algorithm, no matter whether each decision tree is pruned or unpruned. PMID- 28659972 TI - Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets. AB - Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor gamma- (PPARgamma-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARgamma agonists, selective PPARgamma modulators (sPPARgammaMs), PPARgamma-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARgamma, along with agents, such as heat shock protein (HSP) inducers, 5'-adenosine monophosphate-activated protein kinase (AMPK) activators, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers. PMID- 28659975 TI - Influence of Dietary Factors on Helicobacter pylori and CagA Seroprevalence in Bulgaria. AB - The aim of this study was to assess the association between some dietary factors and prevalence of H. pylori infection or strain virulence in 294 adult asymptomatic blood donors. Methods. Seroprevalence was evaluated using ELISA. Logistic regression was used. Results. Anti-H. pylori IgG prevalence was 72.4%, and CagA IgG seroprevalence was 49.3%. In the multivariate analyses, the frequent (>5 days per week) honey consumption was associated with both reduced H. pylori seroprevalence OR, 0.68 with 95% confidence interval (CI), 0.473-0.967 and reduced CagA IgG seroprevalence OR, 0.65 with 95% CI, 0.486-0859. Frequent (>5 days per week) yoghurt consumption also was associated with lower H. pylori virulence of the strains (CagA IgG OR, 0.56 with 95% CI, 0.341-0.921). Smoking and consumption of the other dietary factors resulted in no significant differences in the prevalence of H. pylori IgG and CagA IgG within the subject groups. Conclusion. To the best of our knowledge, this is the first report revealing reverse associations between honey or yoghurt consumption and CagA IgG prevalence as well as between frequent honey consumption and lower prevalence of the H. pylori infection. Regular honey and yoghurt consumption can be of value as a supplement in the control of H. pylori therapy. PMID- 28659976 TI - Organs Blood Flow during Elevation of Body Temperature in Sevoflurane Anesthetized Rats. AB - The aim of this study is to investigate how elevation of body temperature changes organs blood flow during sevoflurane anesthesia. We conducted in vivo research on 14 male Wistar rats to monitor pulse rate and arterial blood pressure and measure hepatic, small intestinal, renal, and descending aortic blood flow using a laser Doppler blood flowmeter. We assessed the changes in organ blood flow, pulse rate, and arterial blood pressure during elevation of the rats' body temperatures up to 41.5 degrees C under anesthesia with 2.0% or 3.0% sevoflurane. We concluded that elevation of body temperature up to 39.5 degrees C does not change hepatic, small intestinal, and renal blood flow during 2.0 and 3.0% sevoflurane anesthesia. PMID- 28659974 TI - Esophageal Cancer Metastases to Unexpected Sites: A Systematic Review. AB - The most common pattern of esophageal cancer metastases (ECM) is to the lymph nodes, lung, liver, bones, adrenal glands, and brain. On the other hand, unexpected metastasis (UM) spread to uncommon sites has increasingly reported and consequently affected the pathway of diagnosis, staging, and management. Using the PubMed database, a systematic search of the following headings "Esophageal" and "Metastasis" or "Metastases" was performed, 10049 articles were identified, and the articles were included if they demonstrated unexpected ECM. 84% of cases were men with an average age of 60.7 years. EC was located in the lower third in 65%. Two-thirds of the UM originated from the lower esophagus, and the two major histological types were adenocarcinoma 40% and squamous cell carcinoma 60%. Metastases were disseminated toward five main anatomical sites: the head and neck (42%), thoracic (17%), abdomen and pelvis (25%), extremities (9%), and multiple skin and muscle metastases (7%). The EC metastases were found to be synchronous 42% and metachronous 58%, isolated in 53.5% and multiple in 46.5%. The overall survival rate was 10.2 months. Since distant metastases are responsible for most EC-related deaths, understanding of ECM dissemination patterns needs more extensive studies. These critical data are the cornerstone of optimal cancer approach and treatment. PMID- 28659977 TI - Facial Mobility after Maxilla-Mandibular Advancement in Patients with Severe Obstructive Sleep Apnea Syndrome: A Three-Dimensional Study. AB - Introduction. The functional results of surgery in terms of facial mobility are key elements in the treatment of patients. Little is actually known about changes in facial mobility following surgical treatment with maxillomandibular advancement (MMA). Objectives. The three-dimensional (3D) methods study of basic facial movements in typical OSAS patients treated with MMA was the topic of the present research. Materials and Methods. Ten patients affected by severe obstructive sleep apnea syndrome (OSAS) were engaged for the study. Their facial surface data was acquired using a 3D laser scanner one week before (T1) and 12 months after (T2) orthognathic surgery. The facial movements were frowning, grimace, smiling, and lip purse. They were described in terms of surface and landmark displacements (mm). The mean landmark displacement was calculated for right and left sides of the face, at T1 and at T2. Results. One year after surgery, facial movements were similar to presurgical registrations. No modifications of symmetry were present. Conclusions. Despite the skeletal maxilla mandible expansion, orthognathic surgical treatment (MMA) of OSAS patients does not seem to modify facial mobility. Only an enhancement of amplitude in smiling and knitting brows was observed. These results could have reliable medical and surgical applications. PMID- 28659979 TI - The Cognitive and Psychological Factors (Personality, Driving Behavior, and Mental Illnesses) As Predictors in Traffic Violations. AB - Objective: Driving is a complex behavior and is affected by several factors. This cohort study aimed at representing the main determinants such as personality features, driving behavior, and mental illnesses on driving violation based on logistic regression. Method: In this cohort study, 800 heavy truck and lorry drivers were recruited. Participants were selected from those individuals who referred to Imam Sajjad hospital in Tehran, Iran during fall 2013 to summer 2015. Manchester Driving Behavior Questionnaire (MDBQ), Big Five Personality Test (NEO Personality Inventory), and SADS (Semi-Structural Interview) were used in this study. After 2 years, we checked all traffic violations caused by human factors involving the drivers. SPSS Version 18 was used for data analysis; t test and logistic regression (OR) was also used. Results: The findings of the present study revealed significant differences between the 2 groups of drivers (those who were and were not involved in driving offenses) with respect to controlling the effective and demographic variables. Moreover, it was found that depression and anxiety could increase the chance of accidents (2.4 and 2.7 accidents odds, respectively) (P = 0.04, P = 0.004). Furthermore, just neuroticism could increase 1.1 odds of traffic offences (P = 0.009), but other personality traits did not have an effect on the equation. Conclusion: Consistent with previous examinations, some mental disorders may affect traffic violations. Considering the magnitude and sensitivity of driving behavior, it is essential to evaluate multiple psychological factors in drivers before and after receiving or renewing their driver's licenses. PMID- 28659980 TI - Comparing Facial Emotional Recognition in Patients with Borderline Personality Disorder and Patients with Schizotypal Personality Disorder with a Normal Group. AB - Objective: No research has been conducted on facial emotional recognition on patients with borderline personality disorder (BPD) and schizotypal personality disorder (SPD). The present study aimed at comparing facial emotion recognition in these patients with the general population. The neurocognitive processing of emotions can show the pathologic style of these 2 disorders. Method: Twenty BPD patients, 16 SPD patients, and 20 healthy individuals were selected by available sampling method. Structural Clinical Interview for Axis II, Millon Personality Inventory, Beck Depression Inventory and Facial Emotional Recognition Test was were conducted for all participants. Discussion: The results of one way ANOVA and Scheffe's post hoc test analysis revealed significant differences in neuropsychology assessment of facial emotional recognition between BPD and SPD patients with normal group (p = 0/001). A significant difference was found in emotion recognition of fear between the 2 groups of BPD and normal population (p = 0/008). A significant difference was observed between SPD patients and control group in emotion recognition of wonder (p = 0/04(. The obtained results indicated a deficit in negative emotion recognition, especially disgust emotion, thus, it can be concluded that these patients have the same neurocognitive profile in the emotion domain. PMID- 28659978 TI - Cell Connections by Tunneling Nanotubes: Effects of Mitochondrial Trafficking on Target Cell Metabolism, Homeostasis, and Response to Therapy. AB - Intercellular communications play a major role in tissue homeostasis and responses to external cues. Novel structures for this communication have recently been described. These tunneling nanotubes (TNTs) consist of thin-extended membrane protrusions that connect cells together. TNTs allow the cell-to-cell transfer of various cellular components, including proteins, RNAs, viruses, and organelles, such as mitochondria. Mesenchymal stem cells (MSCs) are both naturally present and recruited to many different tissues where their interaction with resident cells via secreted factors has been largely documented. Their immunosuppressive and repairing capacities constitute the basis for many current clinical trials. MSCs recruited to the tumor microenvironment also play an important role in tumor progression and resistance to therapy. MSCs are now the focus of intense scrutiny due to their capacity to form TNTs and transfer mitochondria to target cells, either in normal physiological or in pathological conditions, leading to changes in cell energy metabolism and functions, as described in this review. PMID- 28659981 TI - Effectiveness of Cognitive Behavioral Therapy on Spiritual Well-Being and Emotional Intelligence of the Elderly Mourners. AB - Objective: Grief is one of the most painful experiences of the humans after linking emotions. In the literature of trauma, grief and mourning can be seen on many topics. Intervention and treatment of grief seems necessary as the period of mourning is prolonged. Thus, this study aimed at understanding the effectiveness of cognitive behavioral therapy on spiritual well-being and emotional intelligence in the elderly bereavement. Method: This was an experimental study with pre-and posttest design, and control group. The population of this study was the elderly mourners in city of Ardabil in 15-2014. After conducting clinical interviews and diagnostic tests using the sampling method, 30 elderly mourners selected. Spiritual Well-Being questionnaire and Emotional Intelligence questionnaire were used for data collection. The questionnaire and pretest posttest were used in this study. Data were analyzed using multivariate analysis of covariance. Results: The results of the data analysis revealed that cognitive behavioral therapy increased spiritual well-being and emotional intelligence of the mourners was not significantly different between the 2 groups (P<0.01). However, the means of Spiritual Well-Being and Emotional Intelligence at pretest was not significant in the intervention group compared with the control group (P>0.05). Conclusion: Method of cognitive behavioral therapy helps confront the emotional drain and grief acceptance, increasing the spiritual well-being and emotional intelligence of the elderly bereavement.?. PMID- 28659982 TI - The Reliability and Validity of the Persian Version of Three-Factor Eating Questionnaire-R18 (TFEQ-R18) in Overweight and Obese Females. AB - Objective: The Three-Factor Eating Questionnaire Reduced (TFEQ-R18) is one of the most widely used instruments for assessing eating behavior worldwide. The present study aimed at confirming the reliability and validity of the Persian version of TFEQ-R18 among overweight and obese females in Iran. Method: In the present study, 168 overweight and obese females consented to participate. We estimated the anthropometric indices and asked the participants to complete the TFEQ-R18. Beck Depression Inventory (BDI), Spielberger Anxiety Scale, Appetite Visual Analogue Rating Scale, Food Craving Questionnaire (FCQ), Compulsive Eating Scale (CES), and Restraint Eating Visual Analogue Rating Scale were performed simultaneously to assess concurrent validity. Two weeks later, TFEQ-R18 was repeated for 126 participants to assess test-retest reliability. Moreover, we reported the internal consistency and factor analysis of this questionnaire. Results: Using the results of the reliability analysis and exploratory factor analysis of the principal component by varimax rotation, we extracted 3 factors: hunger, cognitive restraint, and emotional eating. After removing the Items 16 and 18, the Cronbach's alpha was increased to 0.73 (The Cronbach's alpha of the factors was 0.84, 0.64, and 0.7, respectively). The results of the Pearson correlation revealed a consistency of 0.87 between the test and retest administrations (p = 0.001). Significant positive correlations were observed between TFEQ-R18 and BDI, Spielberger Anxiety Scale, FCQ, CES, appetite, body weight, fat percentage, and calorie intake. Moreover, a negative correlation was observed in Restraint Eating Visual Analogue Rating Scale and muscle percentage.Conclusion: This study aimed at presenting preliminary support for the reliability and validity of the Persian version of TFEQ-R18 and its psychometric characteristics. This instrument may be helpful in clinical practice and research studies of obesity, appetite, and eating behavior. PMID- 28659983 TI - The Psychometric Properties of Attentional Control Scale and Its Relationship with Symptoms of Anxiety and Depression: A Study on Iranian Population. AB - Objectives: The attentional control scale is a self- report questionnaire that assesses individual differences in attentional control. Despite its extensive use, the psychometric properties of the Persian version of the ACS are not well understood. Thus, the present study aimed at investigating the psychometric properties of the attentional control scale and its relationship with symptoms of anxiety and depression in Iranian population. Method: Using quota sampling, we asked a community sample of 524 to respond to Attentional Control Scale, mindfulness, emotion regulation, social anxiety, depression, generalized anxiety, worry, and rumination. SPSS (Version 23) was used for data analysis. Results: Exploratory factor analysis yielded 2 factors of focusing and shifting, which accounted for 30.93% of the total variance. The results of convergent validity revealed that reappraisal, as an emotion regulation strategy and mindfulness facets, had a positive relationship with focusing, shifting, and the total score of the attentional control scale. Furthermore, worry, rumination, depression, generalized anxiety, and social anxiety symptoms all had negative relationships with focusing, rumination, and the total score of the attentional control scale. In addition, the results of incremental validity revealed that focusing, not shifting, uniquely predicted depression and generalized anxiety symptoms. Furthermore, both focusing and shifting uniquely predicted social anxiety symptoms. Test- retest reliability of focusing and shifting was 0.80 and 0. 76, respectively. Conclusion: Attentional control scale has been demonstrated to have acceptable validity and reliability in Iranian population. However, further studies are needed to evaluate other aspects of the ACS like CFA. PMID- 28659984 TI - The Effect of Multidimensional Motivation Interventions on Cognitive and Behavioral Components of Motivation: Testing Martin's Model. AB - Objective: The present study aimed at examining the effect of multidimensional motivation interventions based on Martin's model on cognitive and behavioral components of motivation. Method: The research design was prospective with pretest, posttest, and follow-up, and 2 experimental groups. In this study, 90 students (45 participants in the experimental group and 45 in the control group) constituted the sample of the study, and they were selected by available sampling method. Motivation interventions were implemented for fifteen 60-minute sessions 3 times a week, which lasted for about 2 months. Data were analyzed using repeated measures multivariate variance analysis test. Results: The findings revealed that multidimensional motivation interventions resulted in a significant increase in the scores of cognitive components such as self-efficacy, mastery goal, test anxiety, and feeling of lack of control, and behavioral components such as task management. The results of one-month follow-up indicated the stability of the created changes in test anxiety and cognitive strategies; however, no significant difference was found between the 2 groups at the follow up in self-efficacy, mastery goals, source of control, and motivation. Conclusion: The research evidence indicated that academic motivation is a multidimensional component and is affected by cognitive and behavioral factors; therefore, researchers, teachers, and other authorities should attend to these factors to increase academic motivation. PMID- 28659985 TI - The Effect of Spiritual Intelligence Training on Job Satisfaction of Psychiatric Nurses. AB - Objective: Nurses are the most important staff in the health care system, thus, their job satisfaction is important in nursing management. The present study aimed at determining the impact of teaching spiritual intelligence on the job satisfaction of psychiatric nurses. Method: The participants were divided into 2 groups by random allocation. Data were collected in 3 stages of before intervention, 4 weeks, and 8 weeks post intervention using Brayfield & Rother Job Satisfaction Questionnaire. Results: The results of this study revealed that the mean score of job satisfaction in the experimental group was 65.5+/-9.9 in the pre intervention stage, which increased to 69.8+/-6.3 one month after the intervention and to 72.5+/-8.9 in 2 months after the intervention, and it was significantly more than that of the control group. Conclusion: The job satisfaction rate of the control group decreased admirably in both 1 month and 2 months after the intervention stage. Thus, spiritual intelligence training is an effective method to increase job satisfaction, and it is suggested that managers consider spiritual intelligence training to increase job satisfaction in nurses. PMID- 28659986 TI - Efficacy of N-Acetylcysteine Augmentation on Obsessive Compulsive Disorder: A Multicenter Randomized Double Blind Placebo Controlled Clinical Trial. AB - Objective: Glutamate is considered a target for treating obsessive-compulsive disorder (OCD). The efficacy and safety of the nutritional supplement of N Acetylcysteine (NAC) as an adjuvant to serotonin reuptake inhibitor (SSRI) for treating children and adolescents with OCD has never been examined. Method: This was a 10-week randomized double-blind placebo-controlled clinical trial with 34 OCD outpatients. The patients received citalopram plus NAC or placebo. Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Pediatric Quality of Life Inventory (PedsQLTM) were used. Adverse effects were monitored. Results: YBOCS score was not different between the two groups at baseline, but the score was different between the two groups at the end of this trial (P<0.02). The YBOCS score of NAC group significantly decreased from 21.0(8.2) to 11.3(5.7) during this study. However, no statistically significant decrease of YBOCS was found in the placebo group. The Cohen's d effect size was 0.83. The mean change of score of resistance/control to obsessions in the NAC and placebo groups was 1.8(2.3) and 0.8(2.1), respectively (P = 0.2). However, the mean score of change for resistance/control to compulsion in the NAC and placebo groups was 2.3(1.8) and 0.9(2.3), respectively. Cohen's d effect size was 0.42. The score of three domains of quality of life significantly decreased in N-Acetylcysteine group during this trial. However, no statistically significant decrease was detected in the placebo group. No serious adverse effect was found in the two groups. Conclusion: This trial suggests that NAC adds to the effect of citalopram in improving resistance/control to compulsions in OCD children and adolescents. In addition, it is well tolerated. PMID- 28659987 TI - The Potential Role of Naltrexone in Borderline Personality Disorder. AB - Objective: Management of borderline personality disorder (BPD) is a difficult challenge due to the complex features of this disorder. This article reviews the use of naltrexone in the treatment of BPD. Method: Published articles and clinical trials were searched in Google Scholar, MedLine, ELSEVIER, and Cochrane database of systematic reviews abstracts in English language between 1990 and 2017. Results: Naltrexone (NTX), a nonspecific competitive opiate antagonist, has been noted to be helpful in controlling self-injurious behavior (SIB) and dissociative symptoms in patients with BPD. Conclusion: Further studies should be conducted on the effects of naltrexone to confirm the role of this medication in the treatment of BPD. PMID- 28659988 TI - Systems Pharmacological Approach of Pulsatillae Radix on Treating Crohn's Disease. AB - In East Asian traditional medicine, Pulsatillae Radix (PR) is widely used to treat amoebic dysentery and renowned for its anti-inflammatory effects. This study aimed to confirm evidence regarding the potential therapeutic effect of PR on Crohn's disease using a system network level based in silico approach. Study results showed that the compounds in PR are highly connected to Crohn's disease related pathways, biological processes, and organs, and these findings were confirmed by compound-target network, target-pathway network, and gene ontology analysis. Most compounds in PR have been reported to possess anti-inflammatory, anticancer, and antioxidant effects, and we found that these compounds interact with multiple targets in a synergetic way. Furthermore, the mRNA expressions of genes targeted by PR are elevated significantly in immunity-related organ tissues, small intestine, and colon. Our results suggest that the anti inflammatory and repair and immune system enhancing effects of PR might have therapeutic impact on Crohn's disease. PMID- 28659989 TI - The Efficacy of Acupuncture for the Treatment of Cervical Vertigo: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: This study aims to evaluate the efficacy and safety of acupuncture for the treatment of cervical vertigo (CV). METHODS: Randomized controlled trials (RCTs) regarding effectiveness of acupuncture for treating CV were searched in 7 comprehensive databases prior to April 2016. The data analysis was performed by using RevMan version 5.3. RESULTS: A total of 10 studies with 914 participants were included. Results showed that acupuncture was more effective than conventional medicine therapy (CMT) in effectiveness, improvement rate of vertigo and headache, and increased average blood flow velocity of vertebral-basilar artery. In the subgroup analysis, the results did not change in different acupuncture methods and drug categories substantially. Sensitivity analysis demonstrated that the results of this meta-analysis were stable. Meanwhile, the long-term safety of acupuncture for CV still remains uncertain. GRADE analysis indicated that the quality of evidence for all outcomes was from very low to low which limited the value of the meta-analysis. CONCLUSION: Based on the systematic review, acupuncture appeared to be a promising therapeutic approach for CV based on low or very low quality of evidence. However, large-scale and high-quality trials are required to provide stronger evidence for the conclusion. PMID- 28659990 TI - Antihepatocarcinoma Effect of Portulaca oleracea L. in Mice by PI3K/Akt/mTOR and Nrf2/HO-1/NF-kappaB Pathway. AB - The purpose of the present study was to evaluate the pharmacological effects of Portulaca oleracea L. (Purslane) (PL) on N-nitrosodiethylamine- (NDEA-) induced hepatocellular carcinomas (HCC) and explore its potential mechanism. Mice were randomly assigned to four groups: control group, NDEA group, NDEA + Purslane (100 mg/kg) group, and NDEA + Purslane (200 mg/kg) group. The animal of each group was given NDEA (100 ppm) in drinking water. 1 h later, Purslane dissolved in PBS was intragastrically administered for continuous seven days. The results showed that Purslane reduced the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in liver and serum. Purslane also reduced the contents of interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and methane dicarboxylic aldehyde (MDA) and restored the activity of superoxygen dehydrogenises (SOD) in serum. Purslane could obviously attenuate the hepatic pathological alteration. Furthermore, treatment with Purslane effectively inhibited the phosphorylations of phosphatidylinositol 3 kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), nuclear factor-kappa B (NF kappaB), and inhibitor of NF-kappaBalpha (IkappaBalpha) and upregulated the expressions of NF-E2-related factor 2 (Nrf2) and heme oxygenase- (HO-) 1. In conclusion, our research suggested that Purslane exhibited protective effects on NDEA-induced hepatocellular carcinomas by anti-inflammatory and antioxidative properties via the PI3K/Akt/mTOR and Nrf2/HO-1/NF-kappaB pathway. PMID- 28659991 TI - Bupropion Maintenance Treatment in Refractory Bipolar Depression: A Case Report. AB - BACKGROUND: The optimal duration of antidepressant treatment in bipolar depression appears to be controversial due to a lack of quality evidence, and guideline recommendations are either vague or contradictive. This is especially true for second line treatments such as bupropion that had not been subject to rigourous long term studies in Bipolar Disorder. CASE PRESENTATION: We report the case of a 75 year old woman who presented with treatment refractory bipolar depression. Because of insufficient response to previous mood stabilizer treatment and refractory depressive symptoms, bupropion was added to venlafaxine and lamotrigine. From there onwards, the patient improved continuously without experiencing deterioration of depression or a switch into hypomania. Our patient being on antidepressants for allmost four years experienced an obvious benefit from longterm antidepressant administration. CONCLUSION: Noradrenergic/dopaminergic mechanisms of action may play a more prominent role in bipolar depression, and may still be underused as a therapeutic strategy in the acute phase as well as in long-term maintenance in at least a subgroup of bipolar patients. There is still a lack of evidence from RCTs, but this case report further supports antidepressant long-term continuation and the usefulness of a noradrenergic/dopaminergic antidepressant in the acute and maintenance treatment of bipolar disorder. PMID- 28659992 TI - Analysis of Urine Flow in Three Different Ureter Models. AB - The ureter provides a way for urine to flow from the kidney to the bladder. Peristalsis in the ureter partially forces the urine flow, along with hydrostatic pressure. Ureteral diseases and a double J stent, which is commonly inserted in a ureteral stenosis or occlusion, disturb normal peristalsis. Ineffective or no peristalsis could make the contour of the ureter a tube, a funnel, or a combination of the two. In this study, we investigated urine flow in the abnormal situation. We made three different, curved tubular, funnel-shaped, and undulated ureter models that were based on human anatomy. A numerical analysis of the urine flow rate and pattern in the ureter was performed for a combination of the three different ureters, with and without a ureteral stenosis and with four different types of double J stents. The three ureters showed a difference in urine flow rate and pattern. Luminal flow rate was affected by ureter shape. The side holes of a double J stent played a different role in detour, which depended on ureter geometry. PMID- 28659993 TI - A Feasibility Study of Geometric-Decomposition Coil Compression in MRI Radial Acquisitions. AB - Receiver arrays with a large number of coil elements are becoming progressively available because of their increased signal-to-noise ratio (SNR) and enhanced parallel imaging performance. However, longer reconstruction time and intensive computational cost have become significant concerns as the number of channels increases, especially in some iterative reconstructions. Coil compression can effectively solve this problem by linearly combining the raw data from multiple coils into fewer virtual coils. In this work, geometric-decomposition coil compression (GCC) is applied to radial sampling (both linear-angle and golden angle patterns are discussed) for better compression. GCC, which is different from directly compressing in k-space, is performed separately in each spatial location along the fully sampled directions, then followed by an additional alignment step to guarantee the smoothness of the virtual coil sensitivities. Both numerical simulation data and in vivo data were tested. Experimental results demonstrated that the GCC algorithm can achieve higher SNR and lower normalized root mean squared error values than the conventional principal component analysis approach in radial acquisitions. PMID- 28659994 TI - The influence of air quality model resolution on health impact assessment for fine particulate matter and its components. AB - Health impact assessments for fine particulate matter (PM2.5) often rely on simulated concentrations generated from air quality models. However, at the global level, these models often run at coarse resolutions, resulting in underestimates of peak concentrations in populated areas. This study aims to quantitatively examine the influence of model resolution on the estimates of mortality attributable to PM2.5 and its species in the USA. We use GEOS-Chem, a global 3-D model of atmospheric composition, to simulate the 2008 annual average concentrations of PM2.5 and its six species over North America. The model was run at a fine resolution of 0.5 * 0.66 degrees and a coarse resolution of 2 * 2.5 degrees , and mortality was calculated using output at the two resolutions. Using the fine-modeled concentrations, we estimate that 142,000 PM2.5-related deaths occurred in the USA in 2008, and the coarse resolution produces a national mortality estimate that is 8 % lower than the fine-model estimate. Our spatial analysis of mortality shows that coarse resolutions tend to substantially underestimate mortality in large urban centers. We also re-grid the fine-modeled concentrations to several coarser resolutions and repeat mortality calculation at these resolutions. We found that model resolution tends to have the greatest influence on mortality estimates associated with primary species and the least impact on dust-related mortality. Our findings provide evidence of possible biases in quantitative PM2.5 health impact assessments in applications of global atmospheric models at coarse spatial resolutions. PMID- 28659995 TI - Maxillary Overdenture Retained with an Implant Support CAD-CAM Bar: A 4 Years Follow Up Case. AB - INTRODUCTION: Oral rehabilitation with overdenture on implants of upper jaw must be taken into consideration a variety of anatomical and biomechanical issues. It is possible to provide for rehabilitation with two or more implants, in different positions, solidarizing them with a bar. MATERIALS & METHODS: The present study involved a patient rehabilitated with 4 Xive implants (Friadent GmbH, Mannheim, Germany) solidarized with a titanium bar crafted with CAD-CAM technology for maximal comfort, precision and structural lightness. RESULTS & DISCUSSION: The follow-up was 54 months, with an implant survival of 100%. Based on our clinical evidence, bars engineered with CAD-CAM technology are promising in terms of precision and comfort despite higher costs. PMID- 28659996 TI - The Immunomodulatory Effect of Trichophyton Rubrum Exoantigens in the Treatment of Experimental Septic Arthritis. AB - BACKGROUND: Understanding the nature and function of fungal exoantigens might lead to novel approaches in the treatment and prophylaxis of some infectious diseases. Septic arthritis represents a serious problem for medicine due to the high incidence rate and severe complications. OBJECTIVE: The present study aimed at assessing the immunomodulatory effects of Trichophyton rubrum culture filtrate as a novel compound in experimental septic arthritis. METHOD: The septic arthritis was haematogenously induced in Sprague-Dawley rats by a single intravenous injection of 109 colony forming units of the human clinical isolate Staphylococcus aureus producing toxic shock syndrome toxin-1. Trichophyton rubrum culture filtrate at two different doses 20 and 40 mg/kg was administered intraperituneally two days after bacterial inoculation in the treatment groups and concurrently with the appearance of clinical signs in the patient groups. The administration of Trichophyton rubrum solution was continued every other day for 10 injections. RESULTS: The clinical evaluation showed that Trichophyton rubrum treated rats were significantly protected from disease development compared with untreated controls. This finding was correlated with results of radiological evaluation of the involved joints. Although, the inflammatory cell infiltration, cartilage/bone destruction and synovial hypertrophy had been decreased in the treatment groups in comparison with arthritic controls however, the histological changes were not significant in these two groups. CONCLUSION: It is possible that Trichophyton rubrum antigens may play a role in modulating the immune responses and would be efficient in septic arthritis treatment. PMID- 28659997 TI - 24-Hour Hypoxia and Pulmonary Hypertension in Patients with Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: The quantification of hypoxia based on resting partial pressure of arterial oxygen (PaO2) may underestimate hypoxia related to activities of daily living or sleep and thus not accurately reflect pulmonary hypertension (PH). The aim of the present study was to investigate the association of resting PaO2 with percent time of SpO2 below 90% (T90) and 88% (T88) in 24 hours. We also evaluated the capacity of hypoxia measures to predict PH in patients with idiopathic pulmonary fibrosis (IPF). METHOD: This cross-sectional study included 27 patients with IPF presenting PaO2 >= 55 mmHg and not receiving home oxygen therapy. All were submitted to blood gas measurement, 24-h oximetry, and transthoracic Doppler echocardiography to estimate systolic pulmonary artery pressure (SPAP). Patients were divided into three groups according to resting PaO2: 55-55.9 mmHg (A); 60 60.9 mmHg (B); >= 70 mmHg (C). PH was defined as "likely" if SPAP > 50 mmHg, and as possible for SPAP between 37 and 50 mmHg. RESULTS: T90 and T88 in Groups A, B, and C were as follows: 59.9+/-29% and 44.1+/-34%; 49.3+/-34% and 29.9+/-31%; 17.1+/-25% and 8.8+/-18% respectively, with significant differences between the groups for both T90 (p <= 0.01) and T88 (p = 0.02). PaO2 was inversely correlated with T90 (r = -0.398; p = 0.04) and T88 (r = -0.351; p = 0.07). Hypoxia variables did not correlate with SPAP, and were not able to predict PH. CONCLUSION: Percent time of SpO2 below 90% and 88% in 24 hours revealed periods of severe hypoxia even in patients with borderline-normal resting PaO2. However, none of the present hypoxia variables was capable of predicting PH. PMID- 28659998 TI - Axial Spondyloarthritis and Cigarette Smoking. AB - BACKGROUND: Smoking is one of the main environmental risk factors involved in several rheumatic diseases according to ACR 2014, it is included among the risk factors for severe axial spondyloarthritis. OBJECTIVES: The objective is to study the association between smoking and the activity of the disease, the functional impact and the severity of the axial spondyloarthritis. METHODS: It is a transversal study with a descriptive and analytical aim, during the period between January 2014 and December 2015 conducted in the department of rheumatology at the CHU Hassan II of Fes. The data was recorded and analyzed using SPSS v20 univariate and bivariate analysis A value of p <0.005 has been used to identify factors associated with smoking. RESULTS: The study included 214 patients, 130 men and 84 women. The mean age was 39.77 +/- 13.06 (16-68) years with an average disease duration of 7.97 +/- 6.4 (2-35) years. The prevalence of smoking in patients with spondyloarthritis was 36%. According to the univariate and bivariate analysis: Smoking was associated with the male sex (p<=0.0001), with a functional impairment BASFI (p = 0.038) and activity BASDAI (p=0.004) and ASDAS CRP, (p=0.036). Multivariate logistic regression analysis suggested that smoking was associated with male sex and the severity of the disease. CONCLUSION: Our study suggests that there is a significant association between smoking and male sex and the severity of the disease. PMID- 28659999 TI - Biological Effects of Phosphocitrate on Osteoarthritic Articular Chondrocytes. AB - BACKGROUND: Phosphocitrate (PC) inhibits osteoarthritis (OA) in Hartley guinea pigs. However, the underlying molecular mechanisms remain poorly understood. OBJECTIVE: This study sought to examine the biological effect of PC on OA chondrocytes and test the hypothesis that PC may exert its OA disease modifying effect, in part, by inhibiting the expression of genes implicated in OA disease process and stimulating the production of extracellular matrices. METHOD: OA chondrocytes were cultured in the absence or presence of PC. Total RNA was extracted and subjected to microarray analyses. The effect of PC on proliferation and chondrocyte-mediated calcification were examined in monolayer culture. The effect of PC on the production of extracellular matrices was examined in micromass culture. RESULTS: PC downregulated the expression of numerous genes classified in proliferation and apoptosis while upregulating the expression of many genes classified in transforming growth factor-beta (TGF-beta) receptor signaling pathway and ossification. PC also downregulated the expressions of many genes classified in inflammatory response and Wnt receptor signaling pathways. Consistent with its effect on the expression of genes classified in proliferation, ossification, and skeletal development, PC inhibited the proliferation of OA chondrocytes and chondrocyte-mediated calcification while stimulating the production of extracellular matrices. CONCLUSION: PC may exert its OA disease modifying effect, in part, through a crystal-independent mechanism or by inhibiting the expressions of many genes implicated in OA disease process, and at the same time, stimulating the expression of genes implicated in chondroprotection and production of extracellular matrices. PMID- 28660000 TI - Coronal Knee Alignment 40 Years after Total Meniscectomy in Adolescents: A Prospective Cohort Study. AB - INTRODUCTION: Meniscectomies result in altered knee biomechanics and increase contact forces on the operated knee joint. METHODS: We assessed coronal knee alignment in relation to radiological osteoarthritis grading, clinical range of movement and patient reported outcome measures 40 years after total open meniscectomies in adolescence. Thirty eight knees (30 patients) that underwent total open meniscectomy were assessed on standardised weight-bearing anteroposterior radiographs for deviation from 'physiological valgus angle' in either direction (magnitude of malalignment). These values were analysed as per site of meniscectomy for correlations with radiographic scoring systems, range of motion and patient reported outcome measures. RESULTS: Tibiofemoral angle was significantly more varus, and the magnitude of malalignment was significantly higher for the medial meniscectomy patients. The range of flexion was lower for those patients who underwent medial and lateral meniscectomies of the same knee. The patients who underwent meniscectomies of both knees had worse scores for IKDC and KOOS quality of life. Tibiofemoral angle, magnitude of malalignment and range of flexion strongly correlated with Ahlback, and Kellgren and Laurence scores, but patient reported that outcome measures did not correlate. CONCLUSION: Meniscectomy induced malalignment corresponds to the site of meniscectomy and the radiographic degree of osteoarthritis. While malalignment and reduced range of movement correlate well with worsening radiographic signs of arthritis, patient reported outcome measures do not correlate. PMID- 28660001 TI - A Retrospective Study Comparing Crossed and Lateral Wire Configurations in Paediatric Supracondylar Fractures. AB - BACKGROUND: Supracondylar fractures are common in children and are associated with significant morbidity. The purpose of our study was to assess and compare the clinical and radiological outcome of management of supracondylar fractures by both wire configurations, along with identifying factors that predispose to complications. MATERIALS & METHODS: We retrospectively reviewed all paediatric cases admitted with a supracondylar fracture over a five year period. We reviewed case notes, theatre records and radiographs to determine the age of the patient, classification of fracture, treatment method, delay to theatre, duration of surgery, wire configuration, Baumann's angle, radiocapitellar alignment, anterior humeral alignment and complications. RESULTS: During the five year period we admitted 132 patients and complete notes were available for 123 patients for analyses. For all the patients managed with wire stabilisation 23% developed complications, including 13% with significant complications including nerve injuries and fracture displacements. All five nerve injuries had crossed wires, whereas all for fracture displacements had lateral wires. Baumann's angle was 76.7 degrees in the group with no complication and 72.2 degrees in the significant complication group (p=0.02). Radiocapitellar line and anterior humeral line were not satisfactory in 5% and 15% of the group with no complications, and 17% and 33% of the group with significant complications. CONCLUSION: We found more complications in lateral pinning configurations, although all nerve injuries were in patients with crossed wire configurations. The factors we believe are associated with a higher likelihood of complications are inadequate post-operative radiological appearance. PMID- 28660002 TI - Does Total Wrist Arthroplasty for Treatment of Posttraumatic Wrist Joint Osteoarthritis in Young Patients Always Lead to Restriction of High-demand Activities of Daily Living? Case Report and Brief Review of Recent Literature. AB - BACKGROUND: Posttraumatic ulnar carpal translocation is a very rare condition that is caused either by fracture-dislocation injury or by purely ligamentous injury of the wrist. Its prognosis is poor and development of posttraumatic pancarpal wrist joint osteoarthritis is inevitable, and options for treatment are total wrist fusion or total wrist arthroplasty. METHODS: A 24-year-old male sustained a fracture-related injury in his left wrist that was accompanied with a second ligamentous distorsion-related injury 1 year later in the same wrist. Seven years after first injury, a posttraumatic pancarpal wrist joint osteoarthritis has developed that was caused by posttraumatic ulnar carpal translocation. The patient was treated by total wrist arthroplasty with use of the MaestroTM Wrist Reconstructive System. RESULTS: With our patient, it is unclear whether posttraumatic ulnar carpal translocation occurred either as result of the first fracture-related injury or as result of the second ligamentous distorsion-related injury or as result of both injuries. The 31-year old patient could be reemployed completely in his original occupation as a mechanic for big agriculture machines and load his wrist with more than 10 pounds. In order to preserve motion, the patient reported that he would undergo the same total wrist arthroplasty a second time were it necessary. CONCLUSION: We report on a young male receiving total wrist arthroplasty and resulting in good restoration of his high-demand claims in activities of daily living, respectively. However, it cannot be concluded that total wrist arthroplasty is to be preferred generally over total wrist fusion in young patients. Essential prerequisite for this motion-preserving procedure is the compliance of patients. PMID- 28660003 TI - Fracture of the Body of the Hamate With Dorsal Dislocation of the 4th and 5th Metacarpals: A Case Report. AB - BACKGROUND: Solitary fractures of the body of the hamate are rare. Their diagnosis is difficult and requires a high clinical suspicion and a proper radiological examination. CASE REPORT: We present a case of a 36-year-old male patient who sustained an intraarticular fracture of the body of the hamate along with dorsal dislocation of the 4th and 5th metacarpals on his right dominant hand. Through a dorsal surgical approach, he underwent ORIF of the hamate with screws and stabilization of the dislocated 4th and 5th metacarpals with KW. At his last follow-up appointment, 18 months postoperatively, he had no pain, almost full range of motion on his fingers and a Mayo Wrist score of 90 points. CONCLUSIONS: Hamate fractures are rare entities that can cause significant patient morbidity if not recognized and treated appropriately. PMID- 28660004 TI - Management Of Recent Elbow Dislocations: Functional Treatment Versus Immobilization; A Prospective Study About 60 Cases. AB - OBJECTIVE: To determine our therapeutic posture trough a comparison of functional treatment results versus immobilization in two different periods. INTRODUCTION: For years, the treatment of recent elbow dislocations consisted of reduction and immobilization during 21 days. Given the frequency of stiffness other methods have been tried out. METHOD: A prospective study was carried out from January 2010 to December 2014. Sixty patients averaging 28.3 years of age underwent elbow dislocation reduction. They were categorized into three separate groups. Patients in the first group had their elbow immobilized for 21 days whereas Group 2 patients were immobilized for 10 days. Group 3 patients were applied a functional treatment followed by a functional rehabilitation. Patients were evaluated according to the Mayo Clinic Elbow Performance Index and the results analyzed with statistical software (SPSS, version 18). RESULTS: During the first month, the functional results of the patients were excellent and good in 19%, 94.7% and 90% respectively for Groups 1, 2 and 3. The pain was intense (10 on the visual analogue scale) in group 3 associated with swelling. At day 90, the results of the patients in Groups 2 and 3 were excellent in 100% of the cases versus 90% for Group 1. At 6 months, all the results were the same. We have not noted any instability, or recurrence or periarticular ossification in our patients. CONCLUSION: The treatment of stable elbow dislocations remains orthopedic. The risk of instability and pain motivates a short 10-day immobilization period followed by early mobilization. PMID- 28660005 TI - Histological Findings in the Trabecular Meshwork of a Patient with Atopic Glaucoma. AB - PURPOSE: The aim of this study was to report a case of atopic dermatitis showing elevated intraocular pressure (IOP) beyond the baseline levels followed by a modified 360-degree suture trabeculotomy, and to analyze the histological findings in the trabecular meshwork. METHODS: A 40-year-old male suffered from blurred vision in the right eye (OD). He had a medical history of severe atopic dermatitis and intraocular lens implantation OU due to atopic cataract. At the initial presentation, the visual acuity was 0.03, and IOP was 35 mmHg OD. Slit lamp examination demonstrated corneal epithelial edema OD. Increased IOP was refractory to several topical medications. The patient underwent a modified 360 degree suture trabeculotomy. The visual field defect, however, deteriorated with persistently high IOP. The patient underwent trabeculectomy together with drainage implant surgery. In the outflow routes, although there seemed to be an opening of Schlemm's canal into the anterior chamber, there was no endothelium of the canal in the region of its opening. The fibrotic changes were conspicuous around Schlemm's canal. CONCLUSION: The histological results indicated that trabeculotomy might not be an appropriate treatment for patients with atopic glaucoma, possibly because of excessive repair to the newly created uveoscleral outflow in addition to the increased postoperative fibrosis in the trabecular meshwork and Schlemm's canal. PMID- 28660006 TI - Convexity Subarachnoid Hemorrhage, Pseudomonas Aeruginosa (PA) Infective Endocarditis and Left Atrial Appendage Occluder (LAAO) Device Infection. A Case Report. AB - An 83 year-old-man with left atrial appendage occluder (LAAO) developed Pseudomonas Aeruginosa (PA) infective endocarditis. MRI at day 3 of onset showed distal small infarcts in both middle cerebral arteries and left postero-inferior cerebellar artery territories. MRI at day 6 revealed two sites of convexity subarachnoid hemorrhage (cSAH). MRA and CTA failed to reveal a Mycotic aneurysm. The radiologic findings favor the assumption of necrosis of distal branches of mca or of pial arteries wall. This case present three unusual features: the presence of localized cSAH after initiation of antibiotherapy without mycotic aneurysm being individualized; the late occurrence of infective endocarditis after LAAO implantation; the very rare occurrence of PA in prosthetic infections. PMID- 28660007 TI - MicroRNAs Modulate Oxidative Stress in Hypertension through PARP-1 Regulation. AB - Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA) expression between African American (AA) and white women with hypertension. Here, we found that the poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension. To explore this mechanism, we identified two miRNAs, miR-103a-2-5p and miR-585-5p, that are differentially expressed with hypertension and were predicted to target PARP1. Through overexpression of each miRNA-downregulated PARP-1 mRNA and protein levels and using heterologous luciferase reporter assays, we demonstrate that miR-103a-2-5p and miR-585-5p regulate PARP1 through binding within the coding region. Given the important role of PARP-1 in DNA repair, we assessed whether overexpression of miR 103a-2-5p or miR-585-5p affected DNA damage and cell survival. Overexpression of these miRNAs enhanced DNA damage and decreased both cell survival and colony formation. These findings highlight the role for PARP-1 in regulating oxidative DNA damage in hypertension and identify important new miRNA regulators of PARP-1 expression. These insights may provide additional avenues to understand hypertension health disparities. PMID- 28660008 TI - Paradoxical Effect of Nonalcoholic Red Wine Polyphenol Extract, ProvinolsTM, in the Regulation of Cyclooxygenases in Vessels from Zucker Fatty Rats (fa/fa). AB - The aim of this work was to study the vascular effects of dietary supplementation of a nonalcoholic red wine polyphenol extract, Provinols, in Zucker fatty (ZF) obese rats. ZF or lean rats received diet supplemented or not with Provinols for 8 weeks. Vasoconstriction in response to phenylephrine (Phe) was then assessed in small mesenteric arteries (SMA) and the aorta with emphasis on the contribution of cyclooxygenases (COX). Although no difference in vasoconstriction was observed between ZF and lean rats both in SMA and the aorta, Provinols affected the contribution of COX-derived vasoconstrictor agents. The nonselective COX inhibitor, indomethacin, reduced vasoconstriction in vessels from both groups; however, lower efficacy was observed in Provinols-treated rats. This was associated with a reduction in thromboxane-A2 and 8-isoprostane release. The selective COX-2 inhibitor, NS398, reduced to the same extent vasoconstriction in aortas from ZF and Provinols-treated ZF rats. However, NS398 reduced response to Phe only in SMA from ZF rats. This was associated with a reduction in 8 isoprostane and prostaglandin-E release. Paradoxically, Provinols decreased COX-2 expression in the aorta, while it increased its expression in SMA. We provide here evidence of a subtle and paradoxical regulation of COX pathway by Provinols vessels from obese rats to maintain vascular tone within a physiological range. PMID- 28660009 TI - Assessing Free-Radical-Mediated DNA Damage during Cardiac Surgery: 8-Oxo-7,8 dihydro-2'-deoxyguanosine as a Putative Biomarker. AB - Coronary artery bypass grafting (CABG), one of the most common cardiac surgical procedures, is characterized by a burst of oxidative stress. 8-Oxo-7,8-dihydro-2' deoxyguanosine (8-oxodG), produced following DNA repairing, is used as an indicator of oxidative DNA damage in humans. The effect of CABG on oxidative induced DNA damage, evaluated through the measurement of urinary 8-oxodG by a developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in 52 coronary artery disease (CAD) patients, was assessed before (T0), five days (T1), and six months (T2) after CABG procedure. These results were compared with those obtained in 40 subjects with cardiovascular risk factors and without overt cardiovascular disease (CTR). Baseline (T0) 8-oxodG was higher in CAD than in CTR (p = 0.035). A significant burst was detected at T1 (p = 0.019), while at T2, 8-oxodG levels were significantly lower than those measured at T0 (p < 0.0001) and comparable to those found in CTR (p = 0.73). A similar trend was observed for urinary 8-iso-prostaglandin F2alpha (8-isoPGF2alpha ), a reliable marker of oxidative stress. In the whole population baseline, 8-oxodG significantly correlated with 8-isoPGF2alpha levels (r = 0.323, p = 0.002). These data argue for CABG procedure in CAD patients as inducing a short-term increase in oxidative DNA damage, as revealed by 8-oxodG concentrations, and a long-term return of such metabolite toward physiological levels. PMID- 28660010 TI - Liver immunology and herbal treatment. AB - Beyond the metabolic functions, the liver recently has been defined as an organ of immune system (IS), which have central regulatory role for innate and adaptive immunity. The liver keeps a delicate balance between hepatic screening of pathogenic antigens and immune tolerance to self-antigens. Herbal treatments with immunological effects have potential to alter this hepatic immune balance towards either therapeutic side or diseases side by inducing liver injury via hepatotoxicity or initiation of autoimmune diseases. Most commonly known herbal treatments, which have therapeutic effect on liver and IS, have proven via in vitro, in vivo, and/or clinical studies were summarized in this review. PMID- 28660011 TI - Risk factors and outcomes associated with alcohol relapse after liver transplantation. AB - Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT) in the United States and Europe. Unlike other indications for LT, transplantation for ALD may be controversial due to the concern for alcohol relapse and non-compliance after LT. However, the overall survival in patients transplanted for ALD is comparable or higher than in patients transplanted for other etiologies of liver disease. While the rate of alcohol use after liver transplantation does not differ among various etiologies of liver disease, alcohol relapse after transplantation for ALD has been associated with complications such as graft rejection, graft loss, recurrent alcoholic cirrhosis and reduced long-term patient survival. Given these potential complications, our review aimed to discuss risk factors associated with alcohol relapse and the efficacy of various interventions attempted to reduce the risk of alcohol relapse. We also describe the impact of alcohol relapse on post-transplant outcomes including graft and patient survival. Overall, alcohol liver disease remains an appropriate indication for liver transplantation, and long-term mortality in this group of patients is primarily attributed to cardiovascular disease or de novo malignancies rather than alcohol related hepatic complications, among those who relapse. PMID- 28660012 TI - Angiotensin II or epinephrine hemodynamic and metabolic responses in the liver of L-NAME induced hypertension and spontaneous hypertensive rats. AB - AIM: To study hepatic vasoconstriction and glucose release induced by angiotensin (Ang)II or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat (SHR). METHODS: Isolated liver perfusion was performed following portal vein and vena cava cannulation; AngII or epinephrine (Epi) was injected in bolus and portal pressure monitored; glucose release was measured in perfusate aliquots. RESULTS: The portal hypertensive response (PHR) and the glucose release induced by AngII of L-NAME were similar to normal rats (WIS). On the other hand, the PHR induced by Epi in L-NAME was higher whereas the glucose release was lower compared to WIS. Despite the similar glycogen content, glucose release induced by AngII was lower in SHR compared to Wistar-Kyoto rats although both PHR and glucose release induced by Epi in were similar. CONCLUSION: AngII and Epi responses are altered in different ways in these hypertension models. Our results suggest that inhibition of NO production seems to be involved in the hepatic effects induced by Epi but not by AngII; the diminished glucose release induced by AngII in SHR is not related to glycogen content. PMID- 28660013 TI - Use of aspartate aminotransferase to platelet ratio to reduce the need for FibroScan in the evaluation of liver fibrosis. AB - AIM: To evaluate the performance of aspartate aminotransferase to platelet ratio (APRI) score against FibroScan in predicting the presence of fibrosis. METHODS: Data of patients who concurrently had APRI score, FibroScan and liver biopsy to assess their hepatitis C virus (HCV) and hepatitis B virus (HBV) over 6 years were retrospectively reviewed and details of their disease characteristics and demographics were recorded. Advanced fibrosis was defined as >= F3. RESULTS: Of the 3619 patients (47.5 +/- 11.3 years, 97M:36F) who had FibroScans and APRI for HCV and HBV, 133 had concurrent liver biopsy. Advanced liver fibrosis was found in 27/133 (20%, F3 = 21 and F4 = 6) patients. Although APRI score (P < 0.001, AUC = 0.83) and FibroScan (P < 0.001, AUC = 0.84) predicted the presence of advanced fibrosis, the sensitivities and specificities were only modest (APRI score: 51.9% sensitivity, 84.9% specificity; FibroScan: 63% sensitivity, 84% specificity). Whilst 13/27 (48%) patients with advanced fibrosis had APRI <= 1.0, no patients with APRI <= 0.5 had advanced fibrosis, with 100% sensitivity. The use of APRI <= 0.5 would avoid the need for FibroScan in 43% of patients. CONCLUSION: APRI score and FibroScan performed equally well in predicting advanced fibrosis. A proposed APRI cut-off score of 0.5 could be used as a screening tool for FibroScan, as cut off score of 1.0 will miss up to 48% of patients with advanced fibrosis. Further prospective validation studies are required to confirm this finding. PMID- 28660014 TI - Apolipoprotein E - A Multifunctional Protein with Implications in Various Pathologies as a Result of Its Structural Features. AB - Apolipoprotein E (apoE), a 34 kDa glycoprotein, mediates hepatic and extrahepatic uptake of plasma lipoproteins and cholesterol efflux from lipid-laden macrophages. In humans, three structural different apoE isoforms occur, with subsequent functional changes and pathological consequences. Here, we review data supporting the involvement of apoE structural domains and isoforms in normal and altered lipid metabolism, cardiovascular and neurodegenerative diseases, as well as stress-related pathological states. Studies using truncated apoE forms provided valuable information regarding the regions and residues responsible for its properties. ApoE3 renders protection against cardiovascular diseases by maintaining lipid homeostasis, while apoE2 is associated with dysbetalipoproteinemia. ApoE4 is a recognized risk factor for Alzheimer's disease, although the exact mechanism of the disease initiation and progression is not entirely elucidated. ApoE is also implicated in infections with herpes simplex type-1, hepatitis C and human immunodeficiency viruses. Interacting with both viral and host molecules, apoE isoforms differently interfere with the viral life cycle. ApoE exerts anti-inflammatory effects, switching macrophage phenotype from the proinflammatory M1 to the anti-inflammatory M2, suppressing CD4+ and CD8+ lymphocytes, and reducing IL-2 production. The anti-oxidative properties of apoE are isoform-dependent, modulating the levels of various molecules (Nrf2 target genes, metallothioneins, paraoxonase). Mimetic peptides were designed to exploit apoE beneficial properties. The "structure correctors" which convert apoE4 into apoE3-like molecules have pharmacological potential. Despite no successful strategy is yet available for apoE-related disorders, several promising candidates deserve further improvement and exploitation. PMID- 28660015 TI - Metal complexes as potential modulators of inflammatory and autoimmune responses. AB - Over the past few decades, the realm of inorganic medicinal chemistry has been dominated by the study of the anti-cancer properties of transition metal complexes, particularly those based on platinum or ruthenium. However, comparatively less attention has been focused on the development of metal complexes for the treatment of inflammatory or autoimmune diseases. Metal complexes possess a number of advantages that render them as attractive alternatives to organic small molecules for the development of therapeutic agents. In this perspective, we highlight recent examples in the development of transition metal complexes as modulators of inflammatory and autoimmune responses. The studies presented here serve to highlight the potential of transition metal complexes in modulating inflammatory or immune pathways in cells. PMID- 28660016 TI - Observation of quantum dynamical resonances in near cold inelastic collisions of astrophysical molecules. AB - This mini review summarizes experimental findings of quantum dynamical resonances in inelastic collisions at energies equivalent to temperatures of a few to a few tens of Kelvin, corresponding to physical conditions prevailing in dense molecular clouds of the interstellar medium. Information obtained is thus relevant to collision energy transfer modelling in such media. Crossed-beam scattering experiments performed at Bordeaux university for inelastic collisions of important astrophysical molecules such as CO with H2 or He and O2 with H2 are described. The peaks that show up in the collision energy dependence of the state to-state integral cross sections for the lowest rotational excitation transitions reveal the quantum nature of such processes. They are ascribed as shape and Feshbach resonances by comparison with the results of close coupling quantum mechanical calculations performed concomitantly on accurate potential energy surfaces. PMID- 28660017 TI - The rise of 3-d single-ion magnets in molecular magnetism: towards materials from molecules? AB - Single-molecule magnets (SMMs) that contain one spin centre (so-called single-ion magnets) theoretically represent the smallest possible unit for spin-based electronic devices. The realisation of this and related technologies, depends on first being able to design systems with sufficiently large energy barriers to magnetisation reversal, Ueff, and secondly, on being able to organise these molecules into addressable arrays. In recent years, significant progress has been made towards the former goal - principally as a result of efforts which have been directed towards studying complexes based on highly anisotropic lanthanide ions, such as Tb(iii) and Dy(iii). Since 2013 however, and the remarkable report by Long and co-workers of a linear Fe(i) system exhibiting Ueff = 325 K, single-ion systems of transition metals have undergone something of a renaissance in the literature. Not only do they have important lessons to teach us about anisotropy and relaxation dynamics in the quest to enhance Ueff, the ability to create strongly coupled spin systems potentially offers access to a whole of host of 1, 2 and 3-dimensional materials with interesting structural and physical properties. This perspective summarises recent progress in this rapidly expanding sub-genre of molecular magnetism from the viewpoint of the synthetic chemist, with a particular focus on the lessons that have so far been learned from single ion magnets of the d-block, and, the future research directions which we feel are likely to emerge in the coming years. PMID- 28660018 TI - Glycosylation, an effective synthetic strategy to improve the bioavailability of therapeutic peptides. AB - Glycosylation of peptides is a promising strategy for modulating the physicochemical properties of peptide drugs and for improving their absorption through biological membranes. This review highlights various methods for the synthesis of glycoconjugates and recent progress in the development of glycosylated peptide therapeutics. Furthermore, the impacts of glycosylation in overcoming the existing barriers that restrict oral and brain delivery of peptides are described herein. PMID- 28660019 TI - Reversible quantitative guest sensing via spin crossover of an iron(ii) triazole. AB - A new phenyl-triazole-pyrazine ligand, 4-p-tolyl-3-(phenyl)-5-(2-pyrazinyl)-1,2,4 triazole (tolpzph), was prepared in order to enforce pyrazine coordination of the iron(ii) centre in the resulting complex, [FeII(tolpzph)2(NCS)2].THF (1.THF). Structure determinations carried out on this discrete mononuclear complex, 1.THF, at 273 K (mostly high spin) and 100 K (mostly low spin) demonstrate this was successful, and that spin crossover (SCO) occurred on cooling. Subsequent magnetic measurements on 1.THF revealed that it shows highly sensitive and reversible solvent-dependent SCO, with T1/2(1.THF) = 255 K vs. T1/2(1) = 212 K (with SCO of 1 more abrupt and occurring with a 4 K hysteresis loop), a drop of 43 K due to THF loss. This is reversible over at least 10 cycles of re-solvating with THF followed by re-drying, so 1 <-> 1.THF can be considered an 'on-off' THF sensor, monitored by the T1/2 reversibly shifting (by 43 K). Furthermore, quantitative sensing of the fractional amount of THF present in 1.nTHF, 0 <= n <= 1, is demonstrated. Monitoring the T1/2 and using TGA to quantify n(THF) revealed a linear dependence (25 data points; Pearson r2 = 0.93): T1/2 = 41.1n(THF) + 219. Finally, 1 is also shown to take up CHCl3 [T1/2(1.CHCl3) = 248 K], with a logarithmic T1/2 dependence on the fractional amount of CHCl3 present (10 data points; Pearson r2 = 0.98): T1/2 = 27.0 log10[n(CHCl3)] + 243. This study is a proof of principle that a (multi-use) quantitative sensor material based on spin crossover is feasible. PMID- 28660020 TI - Polymer coordination promotes selective CO2 reduction by cobalt phthalocyanine. AB - Cobalt phthalocyanine (CoPc) is a known electrocatalyst for the carbon dioxide reduction reaction (CO2RR) that, when adsorbed onto edge-plane graphite (EPG) electrodes, shows modest activity and selectivity for CO production along with co generation of H2. In contrast, electrodes modified with CoPc immobilized in a poly-4-vinylpridine (P4VP) film show dramatically enhanced activity and selectivity compared to those modified with CoPc alone. CoPc-P4VP films display a faradaic efficiency of ~90% for CO, with a turnover frequency of 4.8 s-1 at just 0.75 V vs. RHE. Two properties of P4VP contribute to enhancing the activity of CoPc: (1) the ability of individual pyridine residues to coordinate to CoPc and (2) the high concentration of uncoordinated pyridine residues throughout the film which may enhance the catalytic activity of CoPc through secondary and other outer coordination sphere effects. Electrodes modified with polymer-free, five coordinate CoPc(py) films (py = pyridine) and with CoPc catalysts immobilized in non-coordinating poly-2-vinylpyridine films were prepared to independently investigate the role that each property plays in enhancing CO2RR performance of CoPc-P4VP. These studies show that a synergistic relationship between the primary and outer coordination sphere effects is responsible for the enhanced catalytic activity of CoPc when embedded in the P4VP membrane. PMID- 28660021 TI - Conjugating a groove-binding motif to an Ir(iii) complex for the enhancement of G quadruplex probe behavior. AB - In this study, the reported G-quadruplex groove binder benzo[d,e]isoquinoline was linked to a cyclometallated Ir(iii) complex to generate a highly selective DNA probe 1 that retains the favorable photophysical properties of the parent complex. The linked complex 1 showed advantages of both parent complex 2 and groove binder 3. Similar to 3, the conjugated complex 1 exhibits a superior affinity and selectivity for G-quadruplex DNA over other conformations of DNA or proteins, with the fold enhancement ratio obviously improved compared with parent complex 2. The molecular modelling revealed a groove-binding mode between complex 1 and G-quadruplex. Meanwhile 1 also possesses the prominent advantages of transition metal complex probes such as a large Stokes shift and long lifetime phosphorescence, which could be recognized in strong fluorescence media through time-resolved emission spectroscopy (TRES). We then employed 1 to develop a detection assay for AGR2, a potential cancer biomarker, as a "proof-of-principle" demonstration of the application of a linked complex for DNA-based detection in diluted fetal bovine serum. We anticipate that this conjugation method may be further employed in the development of DNA probes and have applications in label free DNA-based diagnostic platforms. PMID- 28660023 TI - A complex with nitrogen single, double, and triple bonds to the same chromium atom: synthesis, structure, and reactivity. AB - A nitrogen-based analogue of the Schrock and Clark "yl-ene-yne" complex, W(CBu t )(CHBu t )(CH2Bu t )(dmpe), has been prepared. The new complex is the nitrido, imido, amido anion [NCr(NPh)(NPri2)2]-, which was structurally characterized with the [K(crypt-2.2.2)]+ counterion. The "Cr-N 1-2-3" complex was prepared from NCr(NHPh)(NPri2)2, which exists as this nitrido-amido tautomer, rather than the bis(imido) Cr(NH)(NPh)(NPri2)2. By selection of electrophile, the nitrido-imido salt K[NCr(NPh)(NPri2)2] can undergo reaction at either the imido or the nitrido to form unusual examples of nitrido or bis(imido) complexes. PMID- 28660022 TI - [C-H...anion] interactions mediate the templation and anion binding properties of topologically non-trivial metal-organic structures in aqueous solutions. AB - Two synthetic approaches-temperature variation and anion templation-allowed for the selective formation of a [2]catenane ([2]C4+ ) or a trefoil knot (TK6+ ), or for the enhanced formation of a Solomon link (SL8+ ), all from a simple set of starting materials (Zn(ii) acetate, diformylpyridine (DFP) and a diamino-2,2' bipyridine (DAB)) in mixed aqueous solutions. The catenane formed exclusively at 90 degrees C in a 1 : 1 mixed solvent of D2O and MeOD. In the presence of bromide ion as template, TK6+ formed exclusively at 50 degrees C in the same solvent. In the solid state, TK6+ hosts two bromide ions in its central cavity by forming six Csp2 -H hydrogen bonds. In D2O, TK6+ , which was originally prepared as a trifluoroacetate (TFA) salt, was found to exchange two TFA counterions for two monovalent anions of different sizes and shapes, which lodged within the knot's central cavity. In contrast to bromide, the larger triflate anion (CF3SO3 ) promoted the formation of SL8+ , which was characterized by 1H NMR spectroscopy and mass spectrometry. Two dimensional heteronuclear 19F-1H-HOSEY NMR experiments detected CH...F interactions inside the cavity of SL8+ . Thus, the product distribution of this dynamic link forming system is sensitive to temperature and the size and shape of the anion template, and one of the products, TK6+ , is capable of binding a variety of monovalent anions in D2O with high affinity (with log beta2 values of 4 to 6 being typical). PMID- 28660025 TI - Bond fission in monocationic frameworks: diverse fragmentation pathways for phosphinophosphonium cations. AB - A series of phosphinophosphonium cations ([R2PPMe3]+; R = Me, Et, i Pr, t Bu, Cy, Ph and N i Pr2) have been prepared and examined by collision-induced dissociation (CID) to determine the fragmentation pathways accessible to these prototypical catena-phosphorus cations in the gas-phase. Experimental evidence for fission of P-P and P-E (E = P, C) bonds, and beta-hydride elimination has been obtained. Comparison of appearance potentials for the P-P bond dissociation fragments [R2P]+ (P-P heterolysis) and [PMe3]+ (P-P homolysis) shows that heterolytic P-P cleavage is more sensitive than P-P homolysis towards changes in substitution at the trivalent phosphorus center. The facility of beta-hydride elimination increases with the steric bulk of R in [R2PPMe3]+. A density functional theory (DFT) study modelling these observed processes in gas-phase, counterion- and solvent-free conditions, to mimic the mass spectrometric environment, was performed for derivatives of [R2PPMe3]+ (R = Me, Et, i Pr, t Bu, Ph and N i Pr2), showing good agreement with experimental trends. The unusual observation of both homolytic and heterolytic cleavage pathways for the P-P and P-C bonds reveals new insight into the fundamental aspects of bonding in monocations and undermines the use of simplistic bonding models. PMID- 28660024 TI - Metal-free electrocatalytic hydrogen oxidation using frustrated Lewis pairs and carbon-based Lewis acids. AB - Whilst hydrogen is a potentially clean fuel for energy storage and utilisation technologies, its conversion to electricity comes at a high energetic cost. This demands the use of rare and expensive precious metal electrocatalysts. Electrochemical-frustrated Lewis pairs offer a metal-free, CO tolerant pathway to the electrocatalysis of hydrogen oxidation. They function by combining the hydrogen-activating ability of frustrated Lewis pairs (FLPs) with electrochemical oxidation of the resultant hydride. Here we present an electrochemical-FLP approach that utilises two different Lewis acids - a carbon-based N methylacridinium cation that possesses excellent electrochemical attributes, and a borane that exhibits fast hydrogen cleavage kinetics and functions as a "hydride shuttle". This synergistic interaction provides a system that is electrocatalytic with respect to the carbon-based Lewis acid, decreases the required potential for hydrogen oxidation by 1 V, and can be recycled multiple times. PMID- 28660026 TI - A new Pseudomonas quinolone signal (PQS) binding partner: MexG. AB - The opportunistic pathogen Pseudomonas aeruginosa utilises the cell-cell signalling mechanism known as quorum sensing to regulate virulence. P. aeruginosa produces two quinolone-based quorum sensing signalling molecules; the Pseudomonas quinolone signal (PQS) and its biosynthetic precursor 2-heptyl-4(1H)-quinolone (HHQ). To date, only one receptor (the PqsR protein) has been identified that is capable of binding PQS and HHQ. Here, we report on the synthesis of PQS and HHQ affinity probes for chemical proteomic studies. The PQS affinity probe very effectively captured PqsR in vitro. In addition, we also identified an interaction between PQS and the "orphan" RND efflux pump protein, MexG. The PQS MexG interaction was further confirmed by purifying MexG and characterizing its ability to bind PQS and HHQ in vitro. Our findings suggest that PQS may have multiple binding partners in the cell and provide important new tools for studying quinolone signalling in P. aeruginosa and other organisms. PMID- 28660027 TI - Designed multi-stranded heme binding beta-sheet peptides in membrane. AB - Designed peptides demonstrating well-defined structures and functioning in membrane environment are of significant interest in developing novel proteins for membrane active biological processes including enzymes, electron transfer, ion channels and energy conversion. Heme proteins' ability to carry out multiple functions in nature has inspired the design of several helical heme binding peptides and proteins soluble in water and also recently in membrane. Naturally occurring beta-sheet proteins are both water and membrane soluble, and are known to bind heme, however, designed heme binding beta-sheet proteins are yet to be reported, plausibly because of the complex folding and difficulty in introducing heme binding sites in the beta-sheet structures. Here, we describe the design, NMR structures and biochemical functional characterization of four stranded and six stranded membrane soluble beta-sheet peptides that bind heme and di-heme, respectively. The designed peptides contain either DP-G or DP-DA residues for the nucleation of beta-turns intended to stabilize multi-stranded beta-sheet topologies and ligate heme with bis-His coordination between adjacent antiparallel beta-strands. Furthermore, we have optimized a high affinity heme binding pocket, Kd ~ nM range, in the adjacent beta-strands by utilizing a series of four stranded beta-sheet peptides employing beta- and omega-amino acids. We find that there is a progressive increase in cofactor binding affinity in the designed peptides with the alkyl chain length of omega-amino acids. Notably, the six stranded beta-sheet peptide binds two molecules of heme in a cooperative fashion. The designed peptides perform peroxidase activity with varying ability and efficiently carried out electron transfer with membrane associated protein cytochrome c. The current study demonstrates the designing of functional beta sheet proteins in a membrane environment and expands the repertoire of heme protein design. PMID- 28660028 TI - Sub-5 nm lanthanide-doped lutetium oxyfluoride nanoprobes for ultrasensitive detection of prostate specific antigen. AB - It remains challenging to develop ultrasmall (<5 nm) but highly luminescent bioprobes with a large linear detection range for the early diagnosis and monitoring of prostate cancer (PCa). Benefiting from the high molar density of lanthanide ions in an oxyfluoride matrix and the superior dissolution capability of Lu6O5F8 nanoparticles in the enhancer solution, we demonstrated the successful use of novel sub-5 nm Lu6O5F8:Eu3+ nanoprobes for the detection of prostate specific antigen (PSA) in clinical serum samples. The limit of detection for PSA is as low as 0.52 pg mL-1, which is almost a 200-fold improvement relative to that of a commercial dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) kit. The PSA levels detected in 23 patient serum samples were consistent with those measured independently by the DELFIA kit, showing the assay's reliability with a correlation coefficient of 97%. A linear range of 4 orders of magnitude ranging from 8.5 * 10-4 to 5.6 ng mL-1 for the assay of PSA was achieved, which is highly promising for the early diagnosis of PCa and monitoring of PCa relapse of patients after radical prostatectomy. PMID- 28660029 TI - Experimental and computational study of alkane dehydrogenation catalyzed by a carbazolide-based rhodium PNP pincer complex. AB - A rhodium complex based on the bis-phosphine carbazolide pincer ligand was investigated in the context of alkane dehydrogenation and in comparison with its iridium analogue. (carb-PNP)RhH2 was found to catalyze cyclooctane/t butylethylene (COA/TBE) transfer dehydrogenation with a turnover frequency up to 10 min-1 and turnover numbers up to 340, in marked contrast with the inactive Ir analogue. TONs were limited by catalyst decomposition. Through a combination of mechanistic, experimental and computational (DFT) studies the difference between the Rh and Ir analogues was found to be attributable to the much greater accessibility of the 14-electron (carb-PNP)M(i) fragment in the case of Rh. In contrast, Ir is more strongly biased toward the M(iii) oxidation state. Thus (carb-PNP)RhH2 but not (carb-PNP)IrH2 can be dehydrogenated by sacrificial hydrogen acceptors, particularly TBE. The rate-limiting segment of the (carb PNP)Rh-catalyzed COA/TBE transfer dehydrogenation cycle is found to be the dehydrogenation of COA. Within this segment, the rate-determining step is calculated to be (carb-PNP)Rh(cyclooctyl)(H) undergoing formation of a beta-H agostic intermediate, while the reverse step (loss of a beta-H agostic interaction) is rate-limiting for hydrogenation of the acceptors TBE and ethylene. Such a step has not previously been proposed as rate-limiting in the context of alkane dehydrogenation, nor, to our knowledge, has the reverse step been proposed as rate-limiting for olefin hydrogenation. PMID- 28660030 TI - Palladium(ii)-catalyzed synthesis of dibenzothiophene derivatives via the cleavage of carbon-sulfur and carbon-hydrogen bonds. AB - A new process has been developed for the palladium(ii)-catalyzed synthesis of dibenzothiophene derivatives via the cleavage of C-H and C-S bonds. In contrast to the existing methods for the synthesis of this scaffold by C-H functionalization, this new catalytic C-H/C-S coupling method does not require the presence of an external stoichiometric oxidant or reactive functionalities such as C-X or S-H, allowing its application to the synthesis of elaborate pi systems. Notably, the product-forming step of this reaction lies in an oxidative addition step rather than a reductive elimination step, making this reaction mechanistically uncommon. PMID- 28660031 TI - Exploiting recognition-mediated assembly and reactivity in [2]rotaxane formation. AB - A small molecular reaction network exploits recognition-mediated reactive processes in order to drive the assembly and formation of both a self-replicating linear template (thread) and a [2]rotaxane, in which the linear template is encircled by a diamide macrocycle. Complementary recognition sites, placed at strategic positions on the reactive building blocks, drive these assembly and replication processes. Template-instructed experiments show that the thread is capable of efficient self-replication and that no cross-catalytic relationships exist between the thread and the [2]rotaxane. The rate of [2]rotaxane formation is insensitive to the addition of a preformed template, however, [2]rotaxane formation does show enhanced diastereoselectivity, most likely originating from its recognition-mediated formation through a ternary reactive complex. PMID- 28660032 TI - Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods. AB - Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki-Miyaura, cyanation and Buchwald-Hartwig amination. PMID- 28660034 TI - Whipped oil stabilised by surfactant crystals. AB - We describe a protocol for preparing very stable air-in-oil foams starting with a one-phase oil solution of a fatty acid (myristic acid) in high oleic sunflower oil at high temperature. Upon cooling below the solubility limit, a two-phase mixture consisting of fatty acid crystals (length around 50 MUm) dispersed in an oil solution at its solubility is formed which, after whipping, coat air bubbles in the foam. Foams which do not drain, coalesce or coarsen may be produced either by increasing the fatty acid concentration at fixed temperature or aerating the mixtures at different temperatures at constant concentration. We prove that molecular fatty acid is not surface-active as no foam is possible in the one phase region. Once the two-phase region is reached, fatty acid crystals are shown to be surface-active enabling foam formation, and excess crystals serve to gel the continuous oil phase enhancing foam stability. A combination of rheology, X ray diffraction and pulsed nuclear magnetic resonance is used to characterise the crystals and oil gels formed before aeration. The crystal-stabilised foams are temperature-sensitive, being rendered completely unstable on heating around the melting temperature of the crystals. The findings are extended to a range of vegetable oil foams stabilised by a combination of adsorbed crystals and gelling of the oil phase, which destabilise at different temperatures depending on the composition and type of fatty acid chains in the triglyceride molecules. PMID- 28660033 TI - Catenation and encapsulation induce distinct reconstitutions within a dynamic library of mixed-ligand Zn4L6 cages. AB - Two new Zn4L6 cages composed of diamine subcomponents containing either naphthalene diimide (NDI) or porphyrin moieties are described. Their structural differences allow these cages to exhibit distinct interactions with different chemical stimuli, yielding different supramolecular products. The electron-poor NDI subunits of the first cage were observed to thread through electron-rich aromatic crown-ether macrocycles, forming mechanically-interlocked species up to a [3]catenane, whereas the porphyrin ligands of the second cage interacted favourably with C70, causing it to be bound as a guest. When mixed, the two cages were observed to form a dynamic combinatorial library (DCL) of seven constitutionally distinct mixed-ligand Zn4L6 cages. The DCL was observed to reconstitute in opposing ways when treated with either the crown ether or C70: the electron-rich macrocycle templated the formation of heteroleptic catenanes, whereas C70 caused the DCL to self-sort into homoleptic structures. PMID- 28660035 TI - High conductivity Ag-based metal organic complexes as dopant-free hole-transport materials for perovskite solar cells with high fill factors. AB - Hole-transport materials (HTMs) play an important role as hole scavenger materials in the most efficient perovskite solar cells (PSCs). Here, for the first time, two Ag-based metal organic complexes (HA1 and HA2) are employed as a new class of dopant-free hole-transport material for application in PSCs. These HTMs show excellent conductivity and hole-transport mobility. Consequently, the devices based on these two HTMs exhibit unusually high fill factors of 0.76 for HA1 and 0.78 for HA2, which are significantly higher than that obtained using spiro-OMeTAD (0.69). The cell based on HA1-HTM in its pristine form achieved a high power conversion efficiency of 11.98% under air conditions, which is comparable to the PCE of the cell employing the well-known doped spiro-MeOTAD (12.27%) under the same conditions. More importantly, their facile synthesis and purification without using column chromatography makes these new silver-based HTMs highly promising for future commercial applications of PSCs. These results provide a new way to develop more low-cost and high conductivity metal-complex based HTMs for efficient PSCs. PMID- 28660036 TI - The importance of nickel oxyhydroxide deprotonation on its activity towards electrochemical water oxidation. AB - Nickel oxyhydroxide (NiOOH) is extensively used for energy storage and it is a very promising catalyst for the oxygen evolution reaction (OER). However, the processes occurring on the NiOOH surface during charge accumulation and OER are not well understood. This work presents an in situ Surface Enhanced Raman Spectroscopy (SERS) study of the pH dependent interfacial changes of the NiOOH catalyst under the working conditions used for OER. We demonstrate the important effect of the electrolyte pH on the degree of surface deprotonation of NiOOH, which crucially affects its OER activity. Our results show that the deprotonation of NiOOH produces negatively charged (or proton-deficient) surface species, which are responsible for the enhanced OER activity of NiOOH in highly alkaline pH. Moreover, we provide spectroscopic evidence obtained in an 18O-labeled electrolyte that allows us to assign this surface species to a superoxo-type species (Ni-OO-). Furthermore, we propose a mechanism for the OER on NiOOH which is consistent with the observed pH-sensitivity, and that also explains why NiOOH is not a suitable catalyst for applications in neutral or moderately alkaline pH (in the range 7-11), apart from the lower stability of the catalyst under these conditions. PMID- 28660037 TI - 'Traceless' tracing of proteins - high-affinity trans-splicing directed by a minimal interaction pair. AB - Protein trans-splicing mediated by split inteins is a powerful technique for site specific protein modification. Despite recent developments there is still an urgent need for ultra-small high-affinity intein tags for in vitro and in vivo approaches. To date, only very few in-cell applications of protein trans-splicing have been reported, all limited to C-terminal protein modifications. Here, we developed a strategy for covalent N-terminal intein-mediated protein labeling at (sub) nanomolar probe concentrations. Combined with a minimal synthetic lock-and key element, the affinity between the intein fragments was increased more than 50 fold to 10 nM. Site-specific and efficient 'traceless' protein modification by high-affinity trans-splicing is demonstrated at nanomolar concentrations in living mammalian cells. PMID- 28660038 TI - Accelerating chemoselective peptide bond formation using bis(2-selenylethyl)amido peptide selenoester surrogates. AB - Given the potential of peptide selenoesters for protein total synthesis and the paucity of methods for the synthesis of these sensitive peptide derivatives, we sought to explore the usefulness of the bis(2-selenylethyl)amido (SeEA) group, i.e. the selenium analog of the bis(2-sulfanylethyl)amido (SEA) group, for accelerating peptide bond formation. A chemoselective exchange process operating in water was devised for converting SEA peptides into the SeEA ones. Kinetic studies show that SeEA ligation, which relies on an initial N,Se-acyl shift process, proceeds significantly faster than SEA ligation. This property enabled the design of a kinetically controlled three peptide segment assembly process based on the sequential use of SeEA and SEA ligation reactions. The method was validated by the total synthesis of hepatocyte growth factor K1 (85 AA) and biotinylated NK1 (180 AA) domains. PMID- 28660039 TI - Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds. AB - Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin containing four disulfide bridges, is a high affinity blocker of the voltage-gated potassium channel Kv1.3, but also blocks Kv1.2. To improve potential therapeutic use of the toxin, we have designed a double substituted analog, [N17A/F32T]-AnTx, which showed comparable Kv1.3 affinity to the wild-type peptide, but also a 2500-fold increase in the selectivity for Kv1.3 over Kv1.2. In the present study we have achieved the chemical synthesis of a Sec-analog in which all cysteine (Cys) residues have been replaced by selenocysteine (Sec) forming four diselenide bonds. To the best of our knowledge this is the first time to replace, by chemical synthesis, all disulfide bonds with isosteric diselenides in a peptide/protein. Gratifyingly, the key pharmacological properties of the Sec-[N17A/F32T]-AnTx are retained since the peptide is functionally active. We also propose here a combined experimental and theoretical approach including NOE- and 77Se-based NMR supplemented by MD simulations for conformational and dynamic characterization of the Sec [N17A/F32T]-AnTx. Using this combined approach allowed us to attain unequivocal assignment of all four diselenide bonds and supplemental MD simulations allowed characterization of the conformational dynamics around each disulfide/diselenide bridge. PMID- 28660040 TI - A visible-light-promoted radical reaction system for azidation and halogenation of tertiary aliphatic C-H bonds. AB - A highly tunable radical-mediated reaction system for the functionalization of tertiary aliphatic C-H bonds was developed. Reactions of various substrates with the Zhdankin azidoiodane reagent 1, Ru(bpy)3Cl2, and visible light irradiation at room temperature gave C-H azidated or halogenated products in an easily controllable fashion. These reactions are efficient, selective, and compatible with complex substrates. They provide a potentially valuable tool for selectively labeling tertiary C-H bonds of organic and biomolecules with tags of varied chemical and biophysical properties for comparative functional studies. PMID- 28660041 TI - Catalysis of "outer-phase" oxygen atom exchange reactions by encapsulated "inner phase" water in {V15Sb6}-type polyoxovanadates. AB - Antimonato polyoxovanadate (POV) cluster compounds {M(en)3}3[V15Sb6O42(H2O) x ].nH2O (M = FeII, CoII, NiII and x = 0 or 1) obtained under solvothermal conditions exhibit unusual high water solubility making these compounds promising synthons for generation of new POV structure types. Electrospray ionization mass spectrometry provides evidence (i) for a water molecule encapsulated inside the cavity of a fraction of the spherical cluster shells, (ii) for a post functionalization in water, namely a slow exchange of VO against Sb2O, (iii) for the inner-phase reactivity of the encapsulated water that is capable of opening an oxo-bridge, and (iv) for a significant acceleration of the 16O/18O exchange reactions of oxygen atoms in the cluster periphery with surrounding H218O, when encapsulated water is present. To the best of our knowledge, this is the first example in polyoxovanadate chemistry for the transduction of inner-phase reactivity of an encapsulated guest molecule into changes in the outer-phase reactivity of the cluster. Magnetic susceptibility measurements reflect the individual contributions of the frustrated {V15} spin polytope and the {M(en)3}2+ complexes, with very weak coupling between these groups. PMID- 28660042 TI - Direct and multiplex quantification of protein biomarkers in serum samples using an immuno-magnetic platform. AB - A direct and ultrasensitive multiplex assay using an immuno-magnetic platform has been developed for the quantification of trace amounts of circulating cancer associated antigens in serum. The detection is based on the specific immuno interactions among the target antigen, detection antibody and capture antibody that is immobilized on the surface of magnetic nanoparticles. The sandwiched immuno-assembly is then labelled with turn-on fluorophores and detected with a fluorescence imaging system. To afford a high signal-to-noise ratio, three turn on fluorophores with unique optical properties have been designed and synthesized to label the target antigens. The developed assay has achieved a remarkable LOD down to the femto-molar regime without sample pre-treatment. This versatile assay can efficiently differentiate the target antigen from a protein matrix and simultaneously quantify multiple cancer-associated antigens, for instance, alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), and prostate specific antigen (PSA) using only 6 MUL of serum sample in an hour. This novel system has a high applicability to serve as a universal and useful tool for early disease diagnostics. PMID- 28660043 TI - Solvent-dependent conductance decay constants in single cluster junctions. AB - Single-molecule conductance measurements have focused primarily on organic molecular systems. Here, we carry out scanning tunneling microscope-based break junction measurements on a series of metal chalcogenide Co6Se8 clusters capped with conducting ligands of varying lengths. We compare these measurements with those of individual free ligands and find that the conductance of these clusters and the free ligands have different decay constants with increasing ligand length. We also show, through measurements in two different solvents, 1 bromonaphthalene and 1,2,4-trichlorobenzene, that the conductance decay of the clusters depends on the solvent environment. We discuss several mechanisms to explain our observations. PMID- 28660044 TI - The total synthesis of K-252c (staurosporinone) via a sequential C-H functionalisation strategy. AB - A synthesis of the bioactive indolocarbazole alkaloid K-252c (staurosporinone) via a sequential C-H functionalisation strategy is reported. The route exploits direct functionalisation reactions around a simple arene core and comprises of two highly-selective copper-catalysed C-H arylations, a copper-catalysed C-H amination and a palladium-catalysed C-H carbonylation, which build up the structural complexity of the natural product framework. PMID- 28660045 TI - Enhanced aging properties of HKUST-1 in hydrophobic mixed-matrix membranes for ammonia adsorption. AB - Metal-organic frameworks (MOFs) in their free powder form have exhibited superior capacities for many gases when compared to other materials, due to their tailorable functionality and high surface areas. Specifically, the MOF HKUST-1 binds small Lewis bases, such as ammonia, with its coordinatively unsaturated copper sites. We describe here the use of HKUST-1 in mixed-matrix membranes (MMMs) prepared from polyvinylidene difluoride (PVDF) for the removal of ammonia gas. These MMMs exhibit ammonia capacities similar to their hypothetical capacities based on the weight percent of HKUST-1 in each MMM. HKUST-1 in its powder form is unstable toward humid conditions; however, upon exposure to humid environments for prolonged periods of time, the HKUST-1 MMMs exhibit outstanding structural stability, and maintain their ammonia capacity. Overall, this study has achieved all of the critical and combined elements for real-world applications of MOFs: high MOF loadings, fully accessible MOF surfaces, enhanced MOF stabilization, recyclability, mechanical stability, and processability. This study is a critical step in advancing MOFs to a stable, usable, and enabling technology. PMID- 28660046 TI - Nickel(ii)-catalyzed enantioselective cyclopropanation of 3-alkenyl-oxindoles with phenyliodonium ylide via free carbene. AB - A chiral Lewis acid-promoted enantioselective cyclopropanation using phenyliodonium ylide as the carbene precursor was developed. A variety of spirocyclopropane-oxindoles with contiguous tertiary and all carbon quaternary centers were obtained in excellent outcomes (up to 99% yield, >19 : 1 d.r., up to 99% ee). EPR spectroscopy study supported a stepwise biradical mechanism. PMID- 28660047 TI - DNA orientation-specific adhesion and patterning of living mammalian cells on self-assembled DNA monolayers. AB - To better understand cell behaviors on substrates, the precise control of density and orientation of cell-specific ligands remains a great challenge. In this study, we established an easy-to-use approach to manipulate the adhesion and patterning of mammalian cells on gold substrates. We prepared DNA self-assembled monolayers (DNA-SAMs) on gold substrates and found that the sequence-specific orientation of DNA-SAMs played an important role in modulating cell adhesion. We also found that the DNA-SAMs on gold substrates could be used as a potentially universal cell culture substrate, which showed properties similar to cationic polymers (e.g. poly-l lysine, PLL) substrates. Furthermore, we could manipulate cell adhesion by tuning the length of poly adenine (polyA) in the DNA sequence. We also prepared a DNA aptamer-based SAM to regulate cell adhesion by exploiting stimuli-responsive conformational change of the aptamer. By using the well established DNA spotting technology, we patterned cells on DNA-SAMs to form a spot matrix and four English letters "CELL". Our findings suggest that DNA-SAMs on gold substrates are potentially useful for making smart surfaces for cell studies, thus introducing a new platform for cell/tissue engineering research. PMID- 28660049 TI - A seawater triggered dynamic coordinate bond and its application for underwater self-healing and reclaiming of lipophilic polymer. AB - In this work, water triggered dynamic catechol-Fe3+ coordinate bonds are revealed and studied at atomic, molecular and macroscopic levels using Mossbauer spectroscopy, rheological analysis, etc. DOPA-iron complexation is found to be dynamic in the presence of water, and this dynamic manner is immobilized after removing water. Accordingly, a water saturated lipophilic polymer containing catechol-Fe3+ crosslinks, rather than the dry version, exhibits dynamic coordination-dissociation behavior. In addition, a migration of iron proves to be enabled in the catechol-Fe3+ crosslinked polymer immersed in seawater. Rearrangement of the dynamic catechol-Fe3+ coordinate bonds among different molecules is thus favored. Based on these results, we develop a bulk lipophilic polymer solid capable of repeated autonomic recovery of strength in seawater without manual intervention. When the polymer is damaged in seawater, reshuffling of the mobile hyperbranched polymer networks across the crack interface, owing to the dynamic catechol-Fe3+ crosslinkages activated by the alkaline circumstances, rebinds the damaged site. By taking advantage of the same mechanism, the polymer can be remolded with the help of seawater and this recycled polymer is still self healable in seawater. Unlike in the case of conventional polymers where water would shield macromolecules from interacting, here, seawater is a necessary environmental assistant for the material interaction to take effect. The outcomes are beneficial for deepening the understanding of coordinate bonds, and the development of robust underwater self-healing lipophilic polymers. PMID- 28660048 TI - A pendant proton shuttle on [Fe4N(CO)12]- alters product selectivity in formate vs. H2 production via the hydride [H-Fe4N(CO)12]. AB - Proton relays are known to increase reaction rates for H2 evolution and lower overpotentials in electrocatalytic reactions. In this report we describe two electrocatalysts, [Fe4N(CO)11(PPh3)]- (1-) which has no proton relay, and hydroxyl-containing [Fe4N(CO)11(Ph2P(CH2)2OH)]- (2-). Solid state structures indicate that these phosphine-substituted clusters are direct analogs of [Fe4N(CO)12]- where one CO ligand has been replaced by a phosphine. We show that the proton relay changes the selectivity of reactions: CO2 is reduced selectively to formate by 1- in the absence of a relay, and protons are reduced to H2 under a CO2 atmosphere by 2-. These results implicate a hydride intermediate in the mechanism of the reactions and demonstrate the importance of controlling proton delivery to control product selectivity. Thermochemical measurements performed using infrared spectroelectrochemistry provided pKa and hydricity values for [HFe4N(CO)11(PPh3)]-, which are 23.7, and 45.5 kcal mol-1, respectively. The pKa of the hydroxyl group in 2- was determined to fall between 29 and 41, and this suggests that the proximity of the proton relay to the active catalytic site plays a significant role in the product selectivity observed, since the acidity alone does not account for the observed results. More generally, this work emphasizes the importance of substrate delivery kinetics in determining the selectivity of CO2 reduction reactions that proceed through metal-hydride intermediates. PMID- 28660050 TI - Stereoselective synthesis of protected l- and d-dideoxysugars and analogues via Prins cyclisations. AB - A de novo approach for the rapid construction of orthogonally protected l- and d deoxysugars and analogues is described. A novel and robust silicon-acetal undergoes Prins cyclisations with a series of homoallylic alcohols in high yield and excellent stereocontrol. Modified Tamao-Fleming oxidation of the resulting silyltetrahydropyrans gives direct access to deoxyglycoside analogues and the approach was showcased in the synthesis of protected l-oliose, a component of the anticancer agent aclacinomycin A. PMID- 28660051 TI - Printable hybrid hydrogel by dual enzymatic polymerization with superactivity. AB - A new approach has been developed to fabricate tough hybrid hydrogels by employing dual enzyme-mediated redox initiation to achieve post-self-assembly cross-linking polymerization. The resulting hydrogel combines the merits of supramolecular hydrogels with polymeric hydrogels to achieve higher mechanical strength and porous networks. Designed 3D constructs were fabricated via in situ 3D printing. The in situ immobilized GOx/HRP in Gel II exhibited superactivity compared to free enzymes, which might be attributed to the synergistic effect of co-localized GOx and HRP minimizing the distances for mass transport between the gel and the bulk solution. This mechanically strong hybrid hydrogel maintained high reusability and thermal stability as well. In addition, in situ 3D cell culture was demonstrated, thus indicating that this biodegradable hybrid hydrogel is biocompatible with cells. The subsequent 3D cell printing further indicates that the hybrid hydrogel is a promising scaffold for bio-related applications such as biocatalysis and tissue engineering. PMID- 28660052 TI - beta-Turn mimetic-based stabilizers of protein-protein interactions for the study of the non-canonical roles of leucyl-tRNA synthetase. AB - For the systematic perturbation of protein-protein interactions, we designed and synthesized tetra-substituted hexahydro-4H-pyrazino[2,1-c][1,2,4]triazine-4,7(6H) diones as beta-turn mimetics. We then devised a new synthetic route to obtain beta-turn mimetic scaffolds via tandem N-acyliminium cyclization and constructed a 162-member library of tetra-substituted pyrazinotriazinediones with an average purity of 90% using a solid-phase parallel synthesis platform. Each library member was subjected to ELISA-based modulator screening for the LRS-RagD interaction, which plays a pivotal role in the nutrient-dependent mTORC1 signalling pathway. Western blot analysis of phosphorylated S6K1 as well as FRET based imaging confirmed that 5c{3,9} stabilizes the direct interaction between LRS and RagD and activates mTORC1 in live cells under leucine-deprived conditions. Thus, 5c{3,9} can be used as a new research tool for studying the non canonical role of LRS. PMID- 28660053 TI - Enantioselective assembly of tertiary stereocenters via multicomponent chemoselective cross-coupling of geminal chloro(iodo)alkanes. AB - Tertiary stereocenters represent a ubiquitous and highly important motif in many pharmaceutically active compounds and natural products. Development of efficient and straightforward approaches to their enantioselective construction from readily available simple substrates is an important yet challenging goal for synthetic chemistry. Herein we describe an efficient, versatile and facile method for the highly enantioselective construction of tertiary stereocenters via unprecedented consecutive one-pot Suzuki reactions of non-activated racemic 1 chloro-1-iodoalkanes with alkylboranes. It represents the first cross-coupling approach which employs simple and readily available primary alkyl substrates for the direct multicomponent assembly of enantioenriched tertiary stereocenters. A simple and effective preparation of 1-chloro-1-iodoalkanes from ubiquitous alpha chloroalkanoic acids is also described. Collectively, the developed methods open a door to efficient catalytic enantioselective synthesis of alkanes bearing tertiary stereocenters from carboxylic acids just in few steps. PMID- 28660054 TI - Flat-on ambipolar triphenylamine/C60 nano-stacks formed from the self organization of a pyramid-sphere-shaped amphiphile. AB - A giant amphiphile, which is constructed with an amorphous nano-pyramid (triphenylamine, TPA) and a crystalline nano-sphere (C60), was synthesized. Structural characterization indicates that this pyramid-sphere-shaped amphiphile (TPA-C60 ) forms a solvent-induced ordered phase, in which the two constituent units self-assemble into alternating stacks of two-dimensional (2D) TPA and C60 nano-sheets. Due to the complexity of the molecular structure and the amorphous nature of the nano-pyramid, phase formation was driven by intermolecular C60-C60 interactions and the ordered phase could not be reformed from the TPA-C60 melt. Oriented crystal arrays of TPA-C60 , which contain flat-on TPA/C60 nano-stacks, can be obtained via a PDMS-assisted crystallization (PAC) technique. The flat-on dual-channel supramolecular structure of TPA-C60 delivered ambipolar and balanced charge-transport characteristics with an average MUe of 2.11 * 10-4 cm2 V-1 s-1 and MUh of 3.37 * 10-4 cm2 V-1 s-1. The anisotropic charge-transport ability of the pyramid-sphere-shaped amphiphile was further understood based on the lattice structure and the lattice orientation of TPA-C60 revealed from electron diffraction analyses. PMID- 28660055 TI - Structural and spectroscopic studies of a rare non-oxido V(v) complex crystallized from aqueous solution. AB - A non-oxido V(v) complex with glutaroimide-dioxime (H3L), a ligand for recovering uranium from seawater, was synthesized from aqueous solution as Na[V(L)2].2H2O, and the structure determined by X-ray diffraction. It is the first non-oxido V(v) complex that has been directly synthesized in and crystallized from aqueous solution. The distorted octahedral structure contains two fully deprotonated ligands (L3-) coordinating to V5+, each in a tridentate mode via the imide N (RV N = 1.96 A) and oxime O atoms (RV-O = 1.87-1.90 A). Using 17O-labelled vanadate as the starting material, concurrent 17O/51V/1H/13C NMR, in conjunction with ESI MS, unprecedentedly demonstrated the stepwise displacement of the oxido V 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O bonds by glutaroimide-dioxime and verified the existence of the "bare" V5+/glutaroimide dioxime complex, [V(L)2]-, in aqueous solution. In addition, the crystal structure of an intermediate 1 : 1 V(v)/glutaroimide-dioxime complex, [VO2(HL)]-, in which the oxido bonds of vanadate are only partially displaced, corroborates the observations by NMR and ESI-MS. Results from this work provide important insights into the strong sorption of vanadium on poly(amidoxime) sorbents in the recovery of uranium from seawater. Also, because vanadium plays important roles in biological systems, the syntheses of the oxido and non-oxido V5+ complexes and the unprecedented demonstration of the displacement of the oxido VO bonds help with the on-going efforts to develop new vanadium compounds that could be of importance in biological applications. PMID- 28660056 TI - Facile syntheses of [3]-, [4]- and [6]catenanes templated by orthogonal supramolecular interactions. AB - A water soluble [6]catenane consisting of two interlocking [3]catenanes was synthesised in 91% yield using readily accessible precursors. The new strategy features the simultaneous use of orthogonal Cu+-phenanthroline and CB[6]-ammonium interactions for preorganising the precursors and the efficient CB[6]-catalysed azide-alkyne cycloaddition as bond forming reactions for ring closing, resulting in high structural complexity and fidelity of the products without compromising interlocking efficiency. A related [4]catenane with three different types of macrocycles was also obtained in good yield. PMID- 28660057 TI - Palladium-catalyzed ligand-promoted site-selective cyanomethylation of unactivated C(sp3)-H bonds with acetonitrile. AB - The direct cyanomethylation of unactivated sp3 C-H bonds of aliphatic amides was achieved via palladium catalysis assisted by a bidentate directing group with good functional group compatibility. This process represents the first example of the direct cross-coupling of sp3 C-H bonds with acetonitrile. Considering the importance of the cyano group in medicinal and synthetic organic chemistry, this reaction will find broad application in chemical research. PMID- 28660058 TI - A rationally designed metal-binding helical peptoid for selective recognition processes. AB - Metal-binding biopolymers play a significant role in processes, such as regulation, recognition and catalysis, due to their high affinity towards specific metal ions, which they bind selectively from the cellular pool. Many enzymes can bind two or more metal ions, each at a specific binding site, to enable efficient cooperative function. Imitating these recognition abilities might lead to the production of biomimetic materials such as unique chelators and catalysts. Herein, we report a rationally designed helical peptoid bearing two distinct metal binding ligands at positions i and i + 3 (Helix HQT i + 3), which enables the selective recognition of one or two metal ions depending on its environment. Using various spectroscopic techniques, we describe (1) the selective intramolecular binding of Cu2+ and its extraction from a mixture of neighboring metal ions in high concentrations, and (2) the selective intermolecular binding of two different metal ions, including the pair Cu2+ and Zn2+, one at each binding site, for the generation of hetero-bimetallic peptoid duplexes. Thorough analysis and comparison between the spectroscopic data and association constants of the metal complexes formed by Helix HQT i + 3 and those formed by non-helical peptoids, or helical peptoids in which the two metal binding ligands are not pre-organized, revealed that the unique recognition processes performed by Helix HQT i + 3 are controlled by both the sequence and the structure of the peptoid. PMID- 28660059 TI - Design and synthesis of biphenyl and biphenyl ether inhibitors of sulfatases. AB - Inhibitors of sulfatase-2 are putative anticancer agents, but the discovery of potent small molecules targeting this enzyme has proved challenging. Based on molecular modelling, two series of sulfatase-2 inhibitors have been developed with biphenyl and biphenyl ether scaffolds judiciously substituted with sulfamate, carboxylate and other polar groups (e.g. amino). Inhibition of aryl sulfatase A and B was also determined. The biphenyl ether derivatives were less selective for sulfatase-2 over aryl sulfatase B than the biphenyl series. All biphenyl ether derivatives inhibited aryl sulfatase A, whereas only amino derivatives inhibited aryl sulfatase B significantly. In the biphenyl series few derivatives exhibited activity against aryl sulfatase B. The trichloroethylsulfamate group was identified as a new pharmacophore enabling potent inhibition of all of the sulfatases studied. PMID- 28660060 TI - Coupling functionalized cobalt ferrite nanoparticle enrichment with online LC/MS/MS for top-down phosphoproteomics. AB - Phosphorylation plays pivotal roles in cellular processes and dysregulated phosphorylation is considered as an underlying mechanism in many human diseases. Top-down mass spectrometry (MS) analyzes intact proteins and provides a comprehensive analysis of protein phosphorylation. However, top-down MS-based phosphoproteomics is challenging due to the difficulty in enriching low abundance intact phosphoproteins as well as separating and detecting the enriched phosphoproteins from complex mixtures. Herein, we have designed and synthesized the next generation functionalized superparamagnetic cobalt ferrite (CoFe2O4) nanoparticles (NPs), and have further developed a top-down phosphoproteomics strategy coupling phosphoprotein enrichment enabled by the functionalized CoFe2O4 NPs with online liquid chromatography (LC)/MS/MS for comprehensive characterization of phosphoproteins. We have demonstrated the highly specific enrichment of a minimal amount of spike-in beta-casein from a complex tissue lysate as well as effective separation and quantification of its phosphorylated genetic variants. More importantly, this integrated top-down phosphoproteomics strategy allows for enrichment, identification, quantification, and comprehensive characterization of low abundance endogenous phosphoproteins from complex tissue extracts on a chromatographic time scale. PMID- 28660061 TI - Reversible on-surface wiring of resistive circuits. AB - Whilst most studies in single-molecule electronics involve components first synthesized ex situ, there is also great potential in exploiting chemical transformations to prepare devices in situ. Here, as a first step towards this goal, we conduct reversible reactions on monolayers to make and break covalent bonds between alkanes of different lengths, then measure the conductance of these molecules connected between electrodes using the scanning tunneling microscopy based break junction (STM-BJ) method. In doing so, we develop the critical methodology required for assembling and disassembling surface-bound single molecule circuits. We identify effective reaction conditions for surface-bound reagents, and importantly demonstrate that the electronic characteristics of wires created in situ agree with those created ex situ. Finally, we show that the STM-BJ technique is unique in its ability to definitively probe surface reaction yields both on a local (~50 nm2) and pseudo-global (>=10 mm2) level. This investigation thus highlights a route to the construction and integration of more complex, and ultimately functional, surface-based single-molecule circuitry, as well as advancing a methodology that facilitates studies beyond the reach of traditional ex situ synthetic approaches. PMID- 28660062 TI - Photo-switchable two-dimensional nanofluidic ionic diodes. AB - The bottom-up assembly of ion-channel-mimetic nanofluidic devices and materials with two-dimensional (2D) nano-building blocks paves a straightforward way towards the real-world applications of the novel transport phenomena on a nano- or sub-nanoscale. One immediate challenge is to provide the 2D nanofluidic systems with adaptive responsibilities and asymmetric ion transport characteristics. Herein, we introduce a facile and general strategy to provide a graphene-oxide-based 2D nanofluidic system with photo-switchable ionic current rectification (ICR). The degree of ICR can be prominently enhanced upon UV irradiation and it can be perfectly retrieved under irradiation with visible light. A maximum ICR ratio of about 48 was achieved. The smart and functional nanofluidic devices have applications in energy conversion, chemical sensing, water treatment, etc. PMID- 28660063 TI - CuH-catalysed hydroamination of arylalkynes with hydroxylamine esters - a computational scrutiny of rival mechanistic pathways. AB - An in-depth computational mechanistic probe of the CuH-mediated hydroamination of internal arylalkynes with an archetype hydroxylamine ester and hydrosilane by a (Xantphos)CuH catalyst (Xantphos = {P^P} = 4,5-bis(diphenylphosphino)-9,9 dimethylxanthene) is presented. This first comprehensive computational study of the CuH-mediated electrophilic alkyne hydroamination has identified the most accessible pathway for the rival avenues for direct and reductive hydroamination. The mechanistic picture derived from smooth energy profiles obtained by employing a reliable computational protocol applied to a realistic catalyst model conforms to all available experimental data. The crucial vinyl- and alkylcopper intermediates were found to display a distinct chemodivergence in their reactivity towards amine electrophile and alcohol, which ensures the successful formation of alpha-branched alkylamines together with (E)-enamines. On the one hand, the vinylcopper is somewhat preferably approached by the alcohol, thereby rendering the reductive hydroamination avenue favourable in the presence of both amine electrophile and alcohol. In contrast, the greater kinetic demands for protonation versus electrophilic amination predicted for the alkylcopper prevents the reductive hydroamination avenue to become non-productive. Electronically modified hydroxylamine esters are found to influence the chemoselectivity in reactivity towards amine electrophile and alcohol achievable for the vinyl- and alkylcopper, thereby offering an opportunity for process improvement. PMID- 28660064 TI - Enrichment and fluorogenic labelling of 5-formyluracil in DNA. AB - Recently, the detection of natural thymine modified 5-formyluracil has attracted widespread attention. Herein, we introduce a new insight into designing reagents for both the selective biotin enrichment and fluorogenic labelling of 5 formyluracil in DNA. Biotinylated o-phenylenediamine directly tethered to naphthalimide can switch on 5-formyluracil, under physiological conditions, which can then be used in cell imaging after exposure to gamma-irradiation. In addition, its labelling property caused the polymerase extension to stop in the 5 formyluracil site, which gave us more information than the fluorescence did itself. The idea of detecting 5-formyluracil might be used in the synthesis of other modified diaminofluoresceins. PMID- 28660065 TI - Micrometre and nanometre scale patterning of binary polymer brushes, supported lipid bilayers and proteins. AB - Binary polymer brush patterns were fabricated via photodeprotection of an aminosilane with a photo-cleavable nitrophenyl protecting group. UV exposure of the silane film through a mask yields micrometre-scale amine-terminated regions that can be derivatised to incorporate a bromine initiator to facilitate polymer brush growth via atom transfer radical polymerisation (ATRP). Atomic force microscopy (AFM) and imaging secondary ion mass spectrometry (SIMS) confirm that relatively thick brushes can be grown with high spatial confinement. Nanometre scale patterns were formed by using a Lloyd's mirror interferometer to expose the nitrophenyl-protected aminosilane film. In exposed regions, protein-resistant poly(oligo(ethylene glycol)methyl ether methacrylate) (POEGMEMA) brushes were grown by ATRP and used to define channels as narrow as 141 nm into which proteins could be adsorbed. The contrast in the pattern can be inverted by (i) a simple blocking reaction after UV exposure, (ii) a second deprotection step to expose previously intact protecting groups, and (iii) subsequent brush growth via surface ATRP. Alternatively, two-component brush patterns can be formed. Exposure of a nitrophenyl-protected aminosilane layer either through a mask or to an interferogram, enables growth of an initial POEGMEMA brush. Subsequent UV exposure of the previously intact regions allows attachment of ATRP initiator sites and growth of a second poly(cysteine methacrylate) (PCysMA) brush within photolithographically-defined micrometre or nanometre scale regions. POEGMEMA brushes resist deposition of liposomes, but fluorescence recovery after photobleaching (FRAP) studies confirm that liposomes readily rupture on PCysMA "corrals" defined within POEGMEMA "walls". This leads to the formation of highly mobile supported lipid bilayers that exhibit similar diffusion coefficients to lipid bilayers formed on surfaces such as glass. PMID- 28660066 TI - An N-nitrosation reactivity-based two-photon fluorescent probe for the specific in situ detection of nitric oxide. AB - In situ fluorescence imaging of nitric oxide (NO) is a powerful tool for studying the critical roles of NO in biological events. However, the selective imaging of NO is still a challenge because most currently available fluorescent probes rely on the o-phenylenediamine (OPD) recognition site, which reacts with both NO and some abundant reactive carbonyl species (RCS) (such as dehydroascorbic acid and methylglyoxal) and some reactive oxygen/nitrogen species (ROS/RNS). To address this problem, a new fluorescent probe, NCNO, based on the N-nitrosation of aromatic secondary amine was designed to bypass the RCS, ROS, and RNS interference. As was expected, the probe NCNO could recognize NO with pronounced selectivity and sensitivity among ROS, RNS, and RCS. The probe was validated by detecting NO in live cells and deep tissues owing to its two-photon excitation and red-light emission. It was, hence, applied to monitor NO in ischemia reperfusion injury (IRI) in mice kidneys by two-photon microscopy for the first time, and the results vividly revealed the profile of NO generation in situ during the renal IRI process. PMID- 28660067 TI - Gold(iii)-arene complexes by insertion of olefins into gold-aryl bonds. AB - The synthesis and characterization of the first gold(iii)-arene complexes are described. Well-defined (P,C)-cyclometalated gold(iii)-aryl complexes were prepared and characterized by NMR spectroscopy. These complexes swiftly and cleanly reacted with norbornene and ethylene to provide cationic gold(iii)-alkyl complexes, in which the remote phenyl ring was eta2-coordinated to gold. The interaction between the aromatic ring and the gold(iii) center was thoroughly analyzed by NMR spectroscopy, X-ray diffraction, and DFT calculations. The pi arene coordination was found to significantly influence the stability and reactivity of low coordinated gold(iii) alkyl species. PMID- 28660068 TI - Turning the Other Lobe: Directional Biases in Brain Diagrams. AB - Past research shows that in drawn or photographic portraits, people are significantly more likely to be posed facing to their right than their left. We examined whether the same type of bias exists among sagittal images of the human brain. An exhaustive search of Google images using the term 'brain sagittal view' yielded 425 images of a left or right facing brain. The direction of each image was coded and revealed that 80% of the brains were right-facing. This bias was present in images that did not contain any representation of a human head. It is argued that the effect might be aesthetic in nature, the result of the Western tradition of reading left to right or due to the facial factors that underlie the bias previously found in portraits. PMID- 28529711 TI - We can shift academic culture through publishing choices. AB - Researchers give papers for free (and often actually pay) to exploitative publishers who make millions off of our articles by locking them behind paywalls. This discriminates not only against the public (who are usually the ones that paid for the research in the first place), but also against the academics from institutions that cannot afford to pay for journal subscriptions and the 'scholarly poor'. I explain exploitative and ethical publishing practices, highlighting choices researchers can make right now to stop exploiting ourselves and discriminating against others. PMID- 28620460 TI - A putative antiviral role of plant cytidine deaminases. AB - BACKGROUND: A mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade. Host cytidine deaminases ( e.g., APOBEC3 proteins) edit viral genomes, giving rise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis. By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity. To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation. The model plant Arabidopsis thaliana genome encodes nine cytidine deaminases ( AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well. METHODS: Here we tested the effects of expression of AtCDAs on the pararetrovirus Cauliflower mosaic virus (CaMV). Two different experiments were carried out. First, we transiently overexpressed each one of the nine A. thalianaAtCDA genes in Nicotianabigelovii plants infected with CaMV, and characterized the resulting mutational spectra, comparing them with those generated under normal conditions. Secondly, we created A. thaliana transgenic plants expressing an artificial microRNA designed to knock-out the expression of up to six AtCDA genes. This and control plants were then infected with CaMV. Virus accumulation and mutational spectra where characterized in both types of plants. RESULTS: We have shown that the A. thalianaAtCDA1 gene product exerts a mutagenic activity, significantly increasing the number of G to A mutations in vivo, with a concomitant reduction in the amount of CaMV genomes accumulated. Furthermore, the magnitude of this mutagenic effect on CaMV accumulation is positively correlated with the level of AtCDA1 mRNA expression in the plant. CONCLUSIONS: Our results suggest that deamination of viral genomes may also work as an antiviral mechanism in plants. PMID- 28660071 TI - Comparison of two-dimensional strain analysis using vendor-independent and vendor specific software in adult and pediatric patients. AB - INTRODUCTION: Two-dimensional strain analysis is a powerful analysis modality, however, clinical utilization has been limited by variability between different analysis systems and operators. We compared strain in adults and children using vendor-specific and vendor-independent software to evaluate variability. METHODS: One hundred and ten subjects (50/110 pediatric, 80/110 normal left ventricular function) had echocardiograms with a General Electric ultrasound scanner between September 2010 and January 2012. Left ventricular longitudinal strain was derived with EchoPAC (General Electric, v10.8.1), a vendor-specific software, and Velocity Vector Imaging (Siemens, v3.5), which is vendor-independent. Three independent readers analyzed all the echocardiograms yielding 330 datasets. RESULTS: Mean left ventricular global longitudinal Lagrangian strain was -18.1 +/ SD 4.4% for EchoPAC and -15.3 +/- SD 4.1% for Velocity Vector Imaging. Velocity Vector Imaging yielded lower absolute global longitudinal Lagrangian strain by mean 2.9 (+/-SD 2.7, p < 0.0001), and lower regional longitudinal strain. These differences persisted in normal subjects versus those with cardiomyopathy. Longitudinal strain differences were slightly higher in the pediatric cohort. There was no significant difference in inter-observer longitudinal strain and a small difference in intra-observer strain between analysis systems. On repeat measurements, a significant change in global longitudinal Lagrangian strain occurred after the difference exceeded 3-5 strain points for EchoPAC and Velocity Vector Imaging, respectively. CONCLUSION: Velocity Vector Imaging produces lower left ventricular longitudinal strain values versus EchoPAC for the same echo images. Both systems have similar inter-observer variability, Velocity Vector Imaging slightly higher intra-observer variability. A statistically significant change in global longitudinal Lagrangian strain occurs with changes >3-5 strain points on repeat measurements. Strain values between the systems are not interchangeable. PMID- 28660072 TI - Study of Cardiovascular Outcomes in Renal Transplantation: A Prospective, Multicenter Study to Determine the Incidence of Cardiovascular Events in Renal Transplant Recipients in Ontario, Canada. AB - BACKGROUND: Renal transplant recipients (RTRs) are at significantly higher risk for morbidity and mortality compared with the general population, largely attributed to cardiovascular disease (CVD). Previous estimates of CVD events have come from health care databases and retrospective studies. OBJECTIVE: The objective of this study was to prospectively determine the prevalence of risk factors and incidence of CVD events in a Canadian cohort of RTRs. DESIGN: Study of Cardiovascular Outcomes in Renal Transplantation (SCORe) was a prospective, longitudinal, multicenter observational study. SETTING: Adult RTRs were recruited from 6 participating transplant sites in Ontario, Canada. PATIENTS: Eligible patients were those receiving a living or deceased donor renal transplant. Patients who received simultaneous transplant of any other organ were excluded. MEASUREMENTS: Primary outcomes included myocardial infarction (MI) defined by American College of Cardiology (ACC-MI) criteria, and major adverse cardiac events (MACE), defined as cardiovascular (CV) death, ACC-MI, coronary revascularization, and nonhemorrhagic stroke. CV events were adjudicated by a single, independent cardiologist. METHODS: CV and transplant-specific risk factors that predict MACE and ACC-MI were identified by stepwise regression analysis using the Cox proportional hazards model. RESULTS: A total of 1303 patients enrolled across 6 transplant centers were followed for 4.5 +/- 1.6 years (mean +/- SD). Incidence of MACE was 7.0%, with significant independent predictors/risk factors including age, diabetes, coronary revascularization, nonhemorrhagic stroke, and renal replacement therapy (RRT). ACC-MI incidence was 4.0%, with significant independent predictors/risk factors including age, coronary revascularization, and duration of RRT in excess of the median value (2.91 years). LIMITATIONS: Patients were recruited from a single province, so may not reflect the experience of RTRs in other areas of Canada. CONCLUSIONS: Using a prospective design and rigorous methodology, this study found that the incidence of CV events after renal transplantation was elevated relative to the general Canadian population and was comparable with that reported in patient registries, thus helping validate the utility of retrospective analysis in this field. SCORe highlights the importance of monitoring RTRs for traditional cardiac and transplant-specific CV risk factors to help prevent CV morbidity and mortality. Further research is needed to investigate a broader range of potential risk factors and their combined effects on incident CV events. PMID- 28660073 TI - Ryk regulates Wnt5a repulsion of mouse corticospinal tract through modulating planar cell polarity signaling. AB - It was previously reported a role for Ryk in mediating Wnt5a repulsion of the corticospinal tract (CST) in mice. Recent evidence has shown that Ryk regulates planar cell polarity (PCP) signaling through interacting with Vangl2. Here, in vivo, in vitro and biochemical analyses were applied to investigate the molecular cross-talk between the Ryk and PCP signaling pathways, revealing that PCP pathway components play important roles in CST anterior-posterior guidance. Ryk-Vangl2 interactions are crucial for PCP signaling to mediate Wnt5a repulsion of CST axons. Cytoplasmic distribution of Ryk is increased under high concentrations of Wnt5a and facilitates the cytoplasmic distribution of Vangl2, leading to inhibition of Frizzled3 translocation to cytoplasm. Alternatively, Ryk stabilizes Vangl2 in the plasma membrane under low Wnt5a concentrations, which promotes cytoplasmic translocation of Frizzled3. We propose that Ryk regulates PCP signaling through asymmetric modulation of Vangl2 distribution in the cytoplasm and plasma membrane, which leads to repulsion of CST axons in response to the Wnt gradient. PMID- 28660074 TI - Treatment of hallux valgus deformity. AB - Hallux valgus deformity is a very common pathological condition which commonly produces painful disability. It is characterised as a combined deformity with a malpositioning of the first metatarsophalangeal joint caused by a lateral deviation of the great toe and a medial deviation of the first metatarsal bone.Taking the patient's history and a thorough physical examination are important steps. Anteroposterior and lateral weight-bearing radiographs of the entire foot are crucial for adequate assessment in the treatment of hallux valgus.Non-operative treatment of the hallux valgus cannot correct the deformity. However, insoles and physiotherapy in combination with good footwear can help to control the symptoms.There are many operative techniques for hallux valgus correction. The decision on which surgical technique is used depends on the degree of deformity, the extent of degenerative changes of the first metatarsophalangeal joint and the shape and size of the metatarsal bone and phalangeal deviation. The role of stability of the first tarsometatarsal joint is controversial.Surgical techniques include the modified McBride procedure, distal metatarsal osteotomies, metatarsal shaft osteotomies, the Akin osteotomy, proximal metatarsal osteotomies, the modified Lapidus fusion and the hallux joint fusion. Recently, minimally invasive percutaneous techniques have gained importance and are currently being evaluated more scientifically.Hallux valgus correction is followed by corrective dressings of the great toe post-operatively. Depending on the procedure, partial or full weight-bearing in a post-operative shoe or cast immobilisation is advised. Post-operative radiographs are taken in regular intervals until osseous healing is achieved. Cite this article: Fraissler L, Konrads C, Hoberg M, Rudert M, Walcher M. Treatment of hallux valgus deformity. EFORT Open Rev 2016;1:295-302. DOI: 10.1302/2058-5241.1.000005. PMID- 28660075 TI - The bile acid receptor FXR attenuates acinar cell autophagy in chronic pancreatitis. AB - The functional relationship between bile acid (BA) and autophagy has not been evaluated in the context of pancreatitis. Here we investigated whether BA and their nuclear farnesoid X receptor (FXR) modulate autophagy and the development of pancreatitis. FXR expression, autophagy, apoptosis and necroptosis were determined in human chronic pancreatitis (CP) tissue in vivo and in pancreatic cells lines in vitro by means of real-time PCR, immunoblots and immunofluorescence. Pancreatic cell lines exposed to the most abundant BAs glycochenodeoxycholate (GCDC) and taurocholic acid (TCA) increased the expression of nuclear FXR and diminished that of the essential autophagy-related protein ATG7. BA was also elevated in pancreatic tissues from CP patients, correlating with elevated FXR and curtailed ATG7 expression with locally reduced autophagic activity. This was accompanied by an increased manifestation of CP hallmarks including apoptosis, necroptosis, inflammation and fibrosis. The present results suggest a cascade of events in which local accumulation of BA signals via FXR to suppress autophagy in pancreatic acinar cells, thereby unleashing acinar cell apoptosis and necroptosis. Thus, BA may cause CP by suppressing autophagy and exacerbating acinar cell apoptosis and necroptosis. PMID- 28660076 TI - Intraocular Pressure, Axial Length, and Refractive Changes after Phacoemulsification and Trabeculectomy for Open-Angle Glaucoma. AB - PURPOSE: To compare changes in intraocular pressure (IOP), axial eye length (AEL), and refractive outcome in primary open-angle glaucoma patients undergoing cataract surgery and trabeculectomy in dependence of the sequence of surgeries. MATERIALS AND METHODS: We retrospectively analysed 48 eyes. The changes in refraction, intraocular pressure, and axial eye length were analysed after surgery. In group A (21 subjects), phacoemulsification was performed before trabeculectomy, and in group B (27 subjects), trabeculectomy was performed before phacoemulsification with a minimum time span between interventions of 6 months. RESULTS: The reduction in IOP and the decrease in AEL after trabeculectomy were significant after 6 and 12 months postsurgery (p < 0.001 each). The decrease in AEL was 0.42 +/- 0.11% at 6 months after surgery and 0.40 +/- 0.13% after 12 months from surgery; this decrease in AEL was comparable between the groups. The refractive outcome was significantly different between the groups (group A: 0.35 +/- 0.75 dpt, group B: -0.05 +/- 0.36 dpt, p = 0.018); in group A, trabeculectomy caused a hyperopic shift of 0.34 +/- 0.44 dpt (p = 0.002) at 12 months postsurgery. CONCLUSION: IOP reduction after trabeculectomy causes AEL shortening. The effect on refractive outcome depends on the sequence of surgeries. Better refractive outcome is achieved if phacoemulsification is performed after trabeculectomy. PMID- 28660077 TI - Relationship between Retinal Nerve Fiber Layer Thickness and Hemoglobin Present in the Optic Nerve Head in Glaucoma. AB - PURPOSE: To observe the relationship between topographic hemoglobin levels in the optic nerve head (ONH), the rim thickness (BMO-MRW), and retinal nerve fiber layer (RNFL) thickness. METHODS: 96 normal eyes and 82 glaucomas were examined using TOP strategy (Octopus 300 perimeter), SPECTRALIS OCT, and Laguna ONhE program which estimates hemoglobin from conventional color photographs (Horus Scope DEC 200 fundus camera). RESULTS: The correlation between Laguna ONhE glaucoma discriminant function (GDF) and SPECTRALIS BMO-MRW was R = 0.81 (P < 0.0001), similar to that between the BMO-MRW and BMO-RNFL thicknesses (R = 0.85, P < 0.0001) (P = 0.227 between both R values). GDF correlated well with RNFL thicknesses in the 360 degrees around the nerve, similar to mean perimetric sensitivity (MS) and BMO-MRW. The amount of hemoglobin in the nasal and temporal sectors showed low correlation with superior and inferior RNFL thicknesses. The superotemporal and inferotemporal sectors located on the vertical diameter of the disk showed good intercorrelation but without a clear RNFL topographic relationship. CONCLUSION: GDF showed high correlation with RNFL thickness. Except in the nasal and temporal sectors, ONH hemoglobin correlated well with RNFL thickness. PMID- 28660078 TI - Anatomical and Functional Results Following 23-Gauge Primary Pars Plana Vitrectomy for Rhegmatogenous Retinal Detachment: Superior versus Inferior Breaks. AB - PURPOSE: In this retrospective study, we evaluated the anatomical and functional outcomes of patients with rhegmatogenous retinal detachment primarily treated with pars plana vitrectomy in regard to the location of the breaks. Methods. 160 eyes were enrolled in this study, divided into two groups based on break location: the superior break group (115 eyes) and the inferior break group (45 eyes). The main endpoint of our study was the anatomical success at 3 months following surgery. RESULTS: Primary retinal reattachment was achieved in 96.5% of patients in group A and in 93.3% in group B (no statistically significant difference, OR 1.98, 95% CI: 0.4, 7.7). Mean BCVA change and intraoperative complication rate were also not statistically significantly different between the two groups (p > 0.05, OR: 1.0, 95% CI: 0.9, 1.01, resp.). Statistical analyses showed that macula status, age, and preoperative BCVA had a significant effect on mean BCVA change (p = 0.0001, p = 0.005, and p = 0.001, resp.). CONCLUSION: This study supports that acceptable reattachment rates can be achieved using PPV for uncomplicated RRD irrespective of the breaks location and inferior breaks do not constitute an independent risk factor for worse anatomical or functional outcome. PMID- 28660079 TI - Umbilical Cord Patch Transplantation for Corneal Perforations and Descemetoceles. AB - PURPOSE: To evaluate the clinical outcome of umbilical cord patch (UCP) transplantation for deep corneal ulcers with perforations and descemetoceles. METHODS: In this retrospective, noncomparative, interventional case series, 11 eyes of 11 patients with corneal perforation or descemetocele were included. The thickness and microstructure of UCP were measured. All eyes were treated with UCP and amniotic membrane transplantation for corneal reconstruction. Corneal ulcer healing, corneal thickness, anterior chamber formation, and best-corrected visual acuity (BCVA) were recorded and analyzed. RESULTS: The thickness of human UCP is 398.6 +/- 102.8 MUm (n = 5) with compact aligned fibers. The average age was 56.2 +/- 15.8 (ranging from 22 to 75) years. The mean follow-up period was 7.1 +/- 1.7 (ranging from 5 to 10) months. Four patients had descemetocele and 7 had perforation. The anterior chambers in all the 7 perforated corneas were formed at postoperative day 1. All patients regained a normal corneal thickness and smooth corneal surface within the first postoperative month. The vision improved in 10 eyes and remained unchanged in 1 eye. No recurrence nor side effects occurred during the follow-up. CONCLUSIONS: UCP can serve as an alternative material in the treatment of corneal perforations and descemetoceles. This treatment option is also beneficial in those countries with limited cornea donors and eye bank services. PMID- 28660080 TI - Neovascular Age-Related Macular Degeneration in the Very Old (>=90 Years): Epidemiology, Adherence to Treatment, and Comparison of Efficacy. AB - PURPOSE: To investigate neovascular age-related macular degeneration (AMD) in patients aged >=90 years from several perspectives for a comprehensive overview: prevalence, presenting characteristics, treatment adherence, reasons for discontinuation, and efficacy of antivascular endothelial growth factor (VEGF) treatment comparing Ranibizumab and Aflibercept. METHODS: In this retrospective chart review, we determined the prevalence and presenting characteristics by reviewing all data for patients referred to our department with treatment-naive neovascular AMD. By looking at historical cohorts, we determined adherence to treatment, reasons for discontinuation, and treatment outcomes after loading dose, 12 months, and 24 months. RESULTS: Patients aged >=90 years constituted 7% of the patients. Treatment was discontinued in 51%, primarily because of death and treatment burden. Mean change in best-corrected visual acuity was 3.2, 1.5, and -2.2 ETDRS letters at 4, 12, and 24 months, respectively. Aflibercept was superior to Ranibizumab in visual and anatomic outcomes. After two years of treatment, patients losing >=15 ETDRS letters made up 19% in the Aflibercept group and 26% in the Ranibizumab group. CONCLUSIONS: We propose that the very old patients with neovascular AMD may constitute a distinctive group warranting special attention and possibilities for individualized therapy. Possible differences between anti-VEGF agents need further investigations. PMID- 28660081 TI - Analysis of Peripapillary Retinal Vessel Diameter in Unilateral Normal-Tension Glaucoma. AB - PURPOSE: This study sought to analyze peripapillary retinal vessel diameter and evaluate its correlation with retinal nerve fiber layer (RNFL) thickness in patients with unilateral normal-tension glaucoma (NTG). METHODS: This retrospective study included 37 patients with unilateral NTG and 40 healthy controls. The unilateral NTG patients were selected based on RNFL photography and unilateral visual field (VF) defects from the Humphrey central 30-2 threshold test. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured and calculated using retinal photographs and a computer-assisted calculation program. The RNFL thickness was measured using spectral domain optical coherence tomography. RESULTS: The mean CRAE and CRVE were significantly narrower in the glaucomatous and fellow eyes of the unilateral NTG patients than they were in the normal subjects (p < 0.001). There was no significant correlation between CRAE/CRVE and RNFL thickness. There was only a significant correlation between VF severity and RNFL thickness in unilateral NTG eyes. CONCLUSIONS: Both NTG-affected eyes and NTG-fellow eyes in the unilateral NTG patients had narrower central retinal vessel diameters than did the eyes of normal subjects. Our results show that vascular factors may play a role in the NTG pathogenesis. PMID- 28660082 TI - Autistic Traits Affect P300 Response to Unexpected Events, regardless of Mental State Inferences. AB - Limited use of contextual information has been suggested as a way of understanding cognition in people with autism spectrum disorder (ASD). However, it has also been argued that individuals with ASD may have difficulties inferring others' mental states. Here, we examined how individuals with different levels of autistic traits respond to contextual deviations by measuring event-related potentials that reflect context usage. The Autism Spectrum Quotient (AQ) was used to quantify autistic-like traits in 28 university students, and 19 participants were defined as Low or High AQ groups. To additionally examine inferences about mental state, two belief conditions (with or without false belief) were included. Participants read short stories in which the final sentence included either an expected or an unexpected word and rated the word's degree of deviation from expectation. P300 waveform analysis revealed that unexpected words were associated with larger P300 waveforms for the Low AQ group, but smaller P300 responses in the High AQ group. Additionally, AQ social skill subscores were positively correlated with evaluation times in the Unexpected condition, whether a character's belief was false or not. This suggests that autistic traits can affect responses to unexpected events, possibly because of decreased availability of context information. PMID- 28660083 TI - Visual Plasticity in Adults. PMID- 28660084 TI - A Case of Thermal Esophageal Injury Induced by Sodium Picosulfate with Magnesium Citrate. AB - Although thermal esophageal injuries caused by hot food or tea have been reported, thermal esophageal injury due to sodium picosulfate with magnesium citrate (PSMC) used for bowel preparation is rarely reported. We report the case of a 56-year-old man who presented with esophageal injury after ingestion of PSMC. Instead of dissolving the PSMC in water before ingestion, he drank water immediately after swallowing PSMC powder. As soon as he drank water, he developed severe chest pain and hematemesis. Upper endoscopy revealed severe hemorrhagic, ulcerative mucosal change from upper to mid-esophagus. He was hospitalized for nine days, received conservative treatment (fasting and parenteral nutrition), and recovered without complications. When PSMC is used as a colonic cleansing agent, patients should be educated to take it after dissolving it sufficiently in 150 mL of water to avoid esophageal thermal injury. PMID- 28660085 TI - Dermatomyositis Associated with Myelofibrosis following Polycythemia Vera. AB - Dermatomyositis (DM) is a unique inflammatory myopathy with clinical findings of proximal muscle weakness, characteristic rash, and elevated muscle enzymes. The association of DM and malignancy, most commonly adenocarcinoma, is well known. There have been few case reports of primary myelofibrosis associated with DM. We present the case of a 69-year-old male with a history of polycythemia vera (PV) who developed proximal muscle weakness, dysphagia, and rash. He was found to have elevated creatinine kinase and skin biopsy was consistent with DM. Due to persistent pancytopenia a bone marrow biopsy was performed and showed postpolycythemic myelofibrosis. To our knowledge, this is the first case reported of this unique association. PMID- 28660086 TI - Successful Use of Ectopic Pelvic Kidney for Living Related Donation Technical Aspects and Literature Review. AB - Ectopic pelvic kidneys can provide an additional source of organs for transplantation. They are often excluded from donation in living donation programs mainly due to aberrant vascular and urinary anatomies. We present a donor with an ectopic left kidney, who successfully donated his kidney. The use of ectopic pelvic kidney for living kidney transplantation is a highly demanding surgical procedure but after extensive preoperative investigation in high volume centers with surgical expertise in vascular reconstruction and access surgery, ectopic pelvic kidneys should not be a contraindication for donation and should be considered as a viable option. PMID- 28660087 TI - A Novel Technique of Stenting of the Renal Artery In-Stent Restenosis with GuideLiner(r) through Radial Approach. AB - In-stent restenosis of the renal arteries is relatively common and its management is not well studied. An 83-year-old female with bilateral renal artery stenosis and balloon angioplasty and stenting bilaterally one year ago was found to have recurrent severe elevations in the blood pressure despite medical management. Renal artery duplex showed 60-99% stenosis of the right renal artery and 20-59% stenosis of the left renal artery. A subsequent angiography of the right renal artery revealed 80% in-stent restenosis at the ostium. We describe a new approach of balloon angioplasty and stenting through radial access site with the assistance of a GuideLiner in a complex in-stent restenosis of the renal artery. PMID- 28660088 TI - High Vitamin D Levels May Downregulate Inflammation in Patients with Behcet's Disease. AB - Vitamin D plays a significant role in the immune system modulation and may confer a protective role in autoimmune diseases. We conducted a case-control study to compare 25(OH)D levels in patients with BD who were managed at a regional rheumatology programme in the midwest region of Ireland compared to matched controls. Healthy controls were selected from the Irish health system and matched in 1 : 5 ratio for age, sex, and the month of the year. 25(OH)D levels <20 nmol/L were classified as deficient while levels between 20 and 40 nmol/L were classified as insufficient. Differences between groups were assessed using Mann Whitney test and associations between cases and controls were expressed as odds ratios and 95% confidence intervals. Nineteen patients with BD were compared with 95 controls matched by age, sex, and month of blood draw. 25(OH)D levels were significantly higher in patients in BD than in matched controls (median values: 45 nmol/L versus 22 nmol/L, p < 0.005) and tended to be lower in patients with active disease than in those without (median values: 35 nmol/L (IQR: 22.75-47.25 nm/L) versus 50 nmol/L (IQR: 35-67 nmol/L), p = 0.11). Compared to controls, patients with BD were significantly less likely to have 25(OH)D deficiency or insufficiency (OR: 0.09, 95% CI: 0.03-0.28, p < 0.001). Our findings suggest a possible role for 25(OH)D in modifying the inflammatory response in BD and uncover a potential opportunity to assess whether correction of Vit D deficiency confers protective benefits. PMID- 28660090 TI - Colonic Oxidative and Mitochondrial Function in Parkinson's Disease and Idiopathic REM Sleep Behavior Disorder. AB - OBJECTIVE: To determine potential mitochondrial and oxidative alterations in colon biopsies from idiopathic REM sleep behavior disorder (iRBD) and Parkinson's disease (PD) subjects. METHODS: Colonic biopsies from 7 iRBD subjects, 9 subjects with clinically diagnosed PD, and 9 healthy controls were homogenized in 5% w/v mannitol. Citrate synthase (CS) and complex I (CI) were analyzed spectrophotometrically. Oxidative damage was assessed either by lipid peroxidation, through malondialdehyde and hydroxyalkenal content by spectrophotometry, or through antioxidant enzyme levels of superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (Gpx1), and catalase (CAT) by western blot. The presence of mitochondrial DNA (mtDNA) deletions was assessed by long PCR and electrophoresis. RESULTS: Nonsignificant trends to CI decrease in both iRBD (45.69 +/- 18.15; 23% decrease) and PD patients (37.57 +/- 12.41; 37% decrease) were found compared to controls (59.51 +/- 12.52, p: NS). Lipid peroxidation was maintained among groups (iRBD: 27.46 +/- 3.04, PD: 37.2 +/- 3.92, and controls: 31.71 +/- 3.94; p: NS). Antioxidant enzymes SOD2 (iRBD: 2.30 +/- 0.92, PD: 1.48 +/- 0.39, and controls: 1.09 +/- 0.318) and Gpx1 (iRBD 0.29 +/- 0.12, PD: 0.56 +/ 0.33, and controls: 0.38 +/- 0.16) did not show significant differences between groups. CAT was only detected in 2 controls and 1 iRBD subject. One iRBD patient presented a single mtDNA deletion. PMID- 28660089 TI - Does Inhalation of Virgin Coconut Oil Accelerate Reversal of Airway Remodelling in an Allergic Model of Asthma? AB - Many studies have been done to evaluate the effect of various natural products in controlling asthma symptoms. Virgin coconut oil (VCO) is known to contain active compounds that have beneficial effects on human health and diseases. The objective of this study was to evaluate the effect of VCO inhalation on airway remodelling in a rabbit model of allergic asthma. The effects of VCO inhalation on infiltration of airway inflammatory cells, airway structures, goblet cell hyperplasia, and cell proliferation following ovalbumin induction were evaluated. Allergic asthma was induced by a combination of ovalbumin and alum injection and/or followed by ovalbumin inhalation. The effect of VCO inhalation was then evaluated via the rescue or the preventive route. Percentage of inflammatory cells infiltration, thickness of epithelium and mucosa regions, and the numbers of goblet and proliferative cells were reduced in the rescue group but not in preventive group. Analysis using a gas chromatography-mass spectrometry found that lauric acid and capric acid were among the most abundant fatty acids present in the sample. Significant improvement was observed in rescue route in alleviating the asthma symptoms, which indicates the VCO was able to relieve asthma-related symptoms more than preventing the onset of asthma. PMID- 28660091 TI - Can a Biodegradable Implanted Bilayered Drug Delivery System Loaded with BMP 2/BMP-12 Take an Effective Role in the Biological Repair Process of Bone-Tendon Injuries? A Preliminary Report. AB - BACKGROUND: Use of biodegradable and biocompatible materials in the orthopedic surgery is gaining popularity. In this research, the rate of controlled release of a bilayered prototype biomaterial designed to promote osteoblastic and tenoblastic activity was calculated using pharmacochemical methods. METHODS: The first part of the design, composed of a sodium tetraborate, polyvinyl alcohol, and starch based hydrogel, was loaded with bone morphogenic protein-2. The second part which was composed of a sodium tetraborate, polyvinyl alcohol, and chitosan based hydrogel was loaded with bone morphogenic protein-12. Osteochondral and tendon tissue specimens were obtained from patients with a diagnosis of gonarthrosis and primary bone cells and tendon cells cultures were prepared following treatment with collagenase enzyme. Cell samples were collected from the groups by means of an invert light microscope and environmental scanning electron microscope underwent at the 1st and 21st days. The level of osteogenic differentiation was measured by the activity of alkaline phosphatase. For the statistical evaluation of the obtained data, groups were compared with post hoc Tukey test following analysis of variance. Level of significance was accepted to be <0,01. RESULTS: Both osteogenic and tenogenic stimulation were observed in the cultured specimens. In comparison to the control groups, the rate of proliferation of healthy cells was found to be higher in the groups to which the design was added (p < 0.01). CONCLUSIONS: Our research is a preliminary report that describes a study conducted in an in vitro experimental setting. We believe that such prototype systems may be pioneers in targeted drug therapies after reconstructional surgeries. PMID- 28660092 TI - Novel HPLC Analysis of Hydrocortisone in Conventional and Controlled-Release Pharmaceutical Preparations. AB - An isocratic sensitive and precise reverse phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination and quantification of hydrocortisone in controlled-release and conventional (tablets and injections) pharmaceutical preparations. Chromatographic separation was achieved on an ODS (C18), 5 MUm, 4.6 * 150 mm, with an isocratic elution using a freshly prepared mobile phase of composition methanol : water : acetic acid (60 : 30 : 10, v/v/v) at a flow rate of 1.0 ml/min. The detection of the drug was successfully achieved at a wavelength of 254 nm. The retention time obtained for the drug was 2.26 min. The proposed method produced linear detectable responses in the concentration range of 0.02 to 0.4 mg/ml of hydrocortisone. High recoveries of 98-101% were attained at concentration levels of 80%, 100%, and 120%. The intraday and interday precision (RSD) were 0.19-0.55% and 0.33-0.71%, respectively. A comparison of hydrocortisone analyses data from the developed method and the official USP method showed no significant difference (p > 0.05) at a 95% confidence interval. The method was successfully applied to the determination and quantification of hydrocortisone in six controlled-release and fifteen conventional release pharmaceutical preparations. PMID- 28660094 TI - Aqueous Deficient Dry Eye Syndrome Post Orbital Radiotherapy: A 10-Year Retrospective Study. AB - PURPOSE: Despite advances in orbital radiotherapy (XRT), a significant proportion of patients develop ophthalmic complication like dry eye syndrome (DES). The study evaluates the prevalence of aqueous deficient DES (ADDE) and lacrimal gland (LG) changes through histologic evaluation and ex-vivo expansion potential postorbital XRT. METHODS: With the approval of the institutional review board, medical records of patients who underwent orbital XRT as management protocol were reviewed for evidence of ADDE using DEWS (Dry Eye Workshop) 2007 criteria (n = 51). HuLG was harvested from three of these patients who underwent subsequent orbital exenteration and used for histological studies/ex-vivo culture. RESULTS: ADDE was noted in 47.07% of the patients, status postorbital XRT, with a prediction of nearly 50% developing it within 0.5 to 2.9 years. ADDE severity was grade 2 (18%), grade 3 (14%), and grade 4 (17%). Other comorbidities were radiation retinopathy (33.4%), radiation-induced cataract (24.9%), and radiation keratopathy (20.8%). Multivariate and univariate analysis showed that fraction of radiation and dose of radiation/fraction were significant risk factors; male gender and young age were protective factors. The post-XRT exenterated HuLG showed near-total effacement of histoarchitecture with intra/periductal and intra/interlobular fibrosis, loss of acini, and reduced secretory activity. The potential of the LG to expand and grow in culture was impaired with loss of stem cells as compared to normal HuLG. CONCLUSION: This study documents that orbital XRT is associated with morphological and functional loss of lacrimal function in nearly 50% of the patients with a prediction of two-third developing ADDE by the end of 5 years. TRANSLATIONAL RELEVANCE: The study provides objective clinical evidence for DES development due to architectural/functional damage to the LG postorbital XRT. Based on recent findings that the LG can be cultured in-vitro, with preservation of stem cells and secretory potential, it would be logical to harvest a portion of LG before radiation, and expand and transplant it to rescue the damaged gland if indicated. PMID- 28660095 TI - Development of the FitSight Fitness Tracker to Increase Time Outdoors to Prevent Myopia. AB - PURPOSE: To develop a fitness tracker (FitSight) to encourage children to increase time spent outdoors. To evaluate the wear pattern for this tracker and outdoor time pattern by estimating light illumination levels among children. METHODS: The development of the FitSight fitness tracker involved the designing of two components: (1) the smartwatch with custom-made FitSight watch application (app) to log the instant light illuminance levels the wearer is exposed to, and (2) a companion smartphone app that synchronizes the time outdoors recorded by the smartwatch to smartphone via Bluetooth communication. Smartwatch wear patterns and tracker-recorded daily light illuminance levels data were gathered over 7 days from 23 Singapore children (mean +/- standard deviation age: 9.2 +/- 1.4 years). Feedback about the tracker was obtained from 14 parents using a three level rating scale: very poor/poor/good. RESULTS: Of the 14 parents, 93% rated the complete "FitSight fitness tracker" as good and 64% rated its wearability as good. While 61% of 23 children wore the watch on all study days (i.e., 0 nonwear days), 26% had 1 nonwear day, and 4.5% children each had 3, 4, and 5 nonwear days, respectively. On average, children spent approximately 1 hour in light levels greater than 1000 lux on weekdays and 1.3 hours on weekends (60 +/- 46 vs. 79 +/- 53 minutes, P = 0.19). Mean number of outdoor "spurts" (light illuminance levels >1000 lux) per day was 8 +/- 3 spurts with spurt duration of 34 +/- 32 minutes. CONCLUSION: The FitSight tracker with its novel features may motivate children to increase time outdoors and play an important role in supplementing community outdoor programs to prevent myopia. TRANSLATIONAL RELEVANCE: If the developed noninvasive, wearable, smartwatch-based fitness tracker, FitSight, promotes daytime outdoor activity among children, it will be beneficial in addressing the epidemic of myopia. PMID- 28660093 TI - The Taste of Caffeine. AB - Many people avidly consume foods and drinks containing caffeine, despite its bitter taste. Here, we review what is known about caffeine as a bitter taste stimulus. Topics include caffeine's action on the canonical bitter taste receptor pathway and caffeine's action on noncanonical receptor-dependent and -independent pathways in taste cells. Two conclusions are that (1) caffeine is a poor prototypical bitter taste stimulus because it acts on bitter taste receptor independent pathways, and (2) caffeinated products most likely stimulate "taste" receptors in nongustatory cells. This review is relevant for taste researchers, manufacturers of caffeinated products, and caffeine consumers. PMID- 28660096 TI - Da Vinci Xi Robot-Assisted Penetrating Keratoplasty. AB - PURPOSE: This study aims (1) to investigate the feasibility of robot-assisted penetrating keratoplasty (PK) using the new Da Vinci Xi Surgical System and (2) to report what we believe to be the first use of this system in experimental eye surgery. METHODS: Robot-assisted PK procedures were performed on human corneal transplants using the Da Vinci Xi Surgical System. After an 8-mm corneal trephination, four interrupted sutures and one 10.0 monofilament running suture were made. For each procedure, duration and successful completion of the surgery as well as any unexpected events were assessed. The depth of the corneal sutures was checked postoperatively using spectral-domain optical coherence tomography (SD-OCT). RESULTS: Robot-assisted PK was successfully performed on 12 corneas. The Da Vinci Xi Surgical System provided the necessary dexterity to perform the different steps of surgery. The mean duration of the procedures was 43.4 +/- 8.9 minutes (range: 28.5-61.1 minutes). There were no unexpected intraoperative events. SD-OCT confirmed that the sutures were placed at the appropriate depth. CONCLUSIONS: We confirm the feasibility of robot-assisted PK with the new Da Vinci Surgical System and report the first use of the Xi model in experimental eye surgery. Operative time of robot-assisted PK surgery is now close to that of conventional manual surgery due to both improvement of the optical system and the presence of microsurgical instruments. TRANSLATIONAL RELEVANCE: Experimentations will allow the advantages of robot-assisted microsurgery to be identified while underlining the improvements and innovations necessary for clinical use. PMID- 28660100 TI - Editorial. PMID- 28660097 TI - Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment. AB - PURPOSE: Retinal detachment disrupts the rod-bipolar synapse in the outer plexiform layer by retraction of rod axons. We showed that breakage is due to RhoA activation whereas inhibition of Rho kinase (ROCK), using Y27632, reduces synaptic damage. We test whether the ROCK inhibitor fasudil, used for other clinical applications, can prevent synaptic injury after detachment. METHODS: Detachments were made in pigs by subretinal injection of balanced salt solution (BSS) or fasudil (1, 10 mM). In some animals, fasudil was injected intravitreally after BSS-induced detachment. After 2 to 4 hours, retinae were fixed for immunocytochemistry and confocal microscopy. Axon retraction was quantified by imaging synaptic vesicle label in the outer nuclear layer. Apoptosis was analyzed using propidium iodide staining. For biochemical analysis by Western blotting, retinal explants, detached from retinal pigmented epithelium, were cultured for 2 hours. RESULTS: Subretinal injection of fasudil (10 mM) reduced retraction of rod spherules by 51.3% compared to control detachments (n = 3 pigs, P = 0.002). Intravitreal injection of 10 mM fasudil, a more clinically feasible route of administration, also reduced retraction (28.7%, n = 5, P < 0.05). Controls had no photoreceptor degeneration at 2 hours, but by 4 hours apoptosis was evident. Fasudil 10 mM reduced pyknotic nuclei by 55.7% (n = 4, P < 0.001). Phosphorylation of cofilin and myosin light chain, downstream effectors of ROCK, was decreased with 30 MUM fasudil (n = 8-10 explants, P < 0.05). CONCLUSIONS: Inhibition of ROCK signaling with fasudil reduced photoreceptor degeneration and preserved the rod-bipolar synapse after retinal detachment. TRANSLATIONAL RELEVANCE: These results support the possibility, previously tested with Y27632, that ROCK inhibition may attenuate synaptic damage in iatrogenic detachments. PMID- 28660099 TI - Presurgery Weight Loss Goals, Depressive Symptoms, and Weight Loss Among Women Undergoing Bariatric Surgery. AB - Purpose: To determine whether preoperative weight loss goals are associated with postoperative weight loss and whether the effect is modified by preoperative depressive symptoms. Methods: Sixty-three women from an ongoing cohort study who were undergoing first-time bariatric surgery at a large, academic hospital in Pittsburgh, PA, were included in this subanalysis. They were assessed preoperatively and 12 months postoperatively in regard to anthropometric and biobehavioral factors. Multivariable linear regression models were used to estimate associations between weight loss goals, expressed as percentage excess body mass index loss (%EBMIL), and postoperative %EBMIL, as well as test effect modification by depressive symptoms. Findings: Presurgery weight loss goals were positively associated with %EBMIL 12 months after bariatric surgery (beta = 1.0, p < 0.01), adjusting for preoperative body mass index, age, race, and marital status; this relationship was negatively modified by depressive symptoms (beta = 0.1, p = 0.02). The association between goal %EBMIL and postoperative %EBMIL was attenuated when type of surgery was added to the model. Conclusions: This initial report suggests that weight loss goals and depressive symptoms may be associated with achieved weight loss after bariatric surgery. If confirmed in larger cohorts, these findings may indicate that more personalized approaches will be needed when discussing weight loss goals with patients. PMID- 28660098 TI - Gait Implications of Visual Field Damage from Glaucoma. AB - PURPOSE: To evaluate fall-relevant gait features in older glaucoma patients. METHODS: The GAITRite Electronic Walkway was used to define fall-related gait parameters in 239 patients with suspected or manifest glaucoma under normal usual pace walking conditions and while carrying a cup or tray. Multiple linear regression models assessed the association between gait parameters and integrated visual field (IVF) sensitivity after controlling for age, race, sex, medications, and comorbid illness. RESULTS: Under normal walking conditions, worse IVF sensitivity was associated with a wider base of support (beta = 0.60 cm/5 dB IVF sensitivity decrement, 95% confidence interval [CI] = 0.12-1.09, P = 0.016). Worse IVF sensitivity was not associated with slower gait speed, shorter step or stride length, or greater left-right drift under normal walking conditions (P > 0.05 for all), but was during cup and/or tray carrying conditions (P < 0.05 for all). Worse IVF sensitivity was positively associated with greater stride-to stride variability in step length, stride length, and stride velocity (P < 0.005 for all). Inferior and superior IVF sensitivity demonstrated associations with each of the above gait parameters as well, though these associations were consistently similar to, or weaker than, the associations noted for overall IVF sensitivity. CONCLUSION: Glaucoma severity was associated with several gait parameters predictive of higher fall risk in prior studies, particularly measures of stride-to-stride variability. Gait may be useful in identifying glaucoma patients at higher risk of falls, and in designing and testing interventions to prevent falls in this high-risk group. TRANSLATIONAL RELEVANCE: These findings could serve to inform the development of the interventions for falls prevention in glaucoma patients. PMID- 28660101 TI - Large Compressive Pseudomeningocele Causing Early Major Neurologic Deficit After Spinal Surgery. AB - STUDY DESIGN: Retrospective review. OBJECTIVES: Large compressive pseudomeningocele causing a major neurologic deficit is a very rare complication that is not well described in the existing literature. METHODS: Institutional review board consent was obtained to study 2552 consecutive extradural spinal surgical cases performed by a single senior spinal surgeon during a 10-year period. The surgeon's database for the decade was retrospectively reviewed and 3 cases involving postoperative major neurologic deficits caused by large compressive pseudomeningocele were identified. RESULTS: The incidence of postoperative compressive pseudomeningocele causing major neurologic deficit was 0.12% (3/2552) per decade of spinal surgery with approximately 1.3% of cases incurring incidental durotomy. Average age of the patients was 57 years (range 45 78). One patient had posterior cervical spine surgery, and 2 patients had posterior lumbar surgery. All 3 patients had intraoperative incidental durotomy repaired during their index procedure. Large compressive pseudomeningocele causing major neurologic deficit occurred in the early 2-week postoperative period in all patients and was clearly identified on postoperative magnetic resonance imaging. All 3 patients were treated with emergent decompression and repair of the dural defect. All patients recovered neurologic function after revision surgery. CONCLUSIONS: Incidental durotomy and repair causing a large compressive pseudomeningocele after spine surgery is a rare and potentially devastating event. Early postoperative magnetic resonance imaging assists in the diagnosis. Emergent decompression combined with revision dural repair surgery may result in improved outcomes. Surgeons should be cognizant of this rare cause of early postoperative major neurologic deficit in patients who had previous dural repair. PMID- 28660102 TI - Impact of the Economic Downturn on Elective Lumbar Spine Surgery in the United States: A National Trend Analysis, 2003 to 2013. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: The impact of the 2008 2009 economic downtown on elective lumbar spine surgery is unknown. Our objective was to investigate the effect of the economic downturn on the overall trends of elective lumbar spine surgery in the United States. METHODS: The Nationwide Inpatient Sample (NIS) was used in conjunction with US Census and macroeconomic data to determine historical trends. The economic downturn was defined as 2008 to 2009. Codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), were used in order to identify appropriate procedures. Confidence intervals were determined using subgroup analysis techniques. RESULTS: From 2003 to 2012, there was a 19.8% and 26.1% decrease in the number of lumbar discectomies and laminectomies, respectively. Over the same time period, there was a 56.4% increase in the number of lumbar spinal fusions. The trend of elective lumbar spine surgeries per 100 000 persons in the US population remained consistent from 2008 to 2009. The number of procedures decreased by 4.5% from 2010 to 2011, 7.6% from 2011 to 2012, and 3.1% from 2012 to 2013. The R2 value between the number of surgeries and the S&P 500 Index was statistically significant (P <= .05). CONCLUSIONS: The economic downturn did not affect elective lumbar fusions, which increased in total from 2003 to 2013. The relationship between the S&P 500 Index and surgical trends suggests that during recessions, individuals may utilize other means, such as insurance, to cover procedural costs and reduce out-of-pocket expenditures, accounting for no impact of the economic downturn on surgical trends. These findings can assist multiple stakeholders in better understanding the interconnectedness of macroeconomics, policy, and elective lumbar spine surgery trends. PMID- 28660103 TI - Thirty-Day Readmission Risk Factors Following Single-Level Transforaminal Lumbar Interbody Fusion (TLIF) for 4992 Patients From the ACS-NSQIP Database. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To describe the readmission rate and identify risk factors associated with 30-day readmission after transforaminal lumbar interbody fusion (TLIF) surgery. METHODS: Patients who underwent elective single level TLIF surgery from 2011 to 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Emergency or trauma cases were excluded. Preoperative, intraoperative, and postoperative variables were extracted. A multivariate binary regression identified predictors correlated with 30-day readmission. RESULTS: A total of 4992 patients were included in the analysis. The overall 30-day readmission rate was 5.51% (275/4992) for readmissions reported between 2011 to 2013. The mean age of patients readmitted was 62.40 years (standard error [SE] = 0.78) and 60.92 years (SE = 0.20) among those whom were not readmitted (P = .05). The top three causes for readmission included postoperative pain control, deep or superficial surgical site infections. Predictors associated with 30-day readmission in a multivariate analysis included female gender (odds ratio [OR] = 1.27, 95% CI = 0.97-1.65), history of severe chronic obstructive pulmonary disease (OR = 1.81, 95% CI = 1.11-2.96), and in the postoperative period, American Society of Anesthesiologists class (OR = 1.30, 95% CI = 1.04-1.63), presence of superficial surgical site infection (OR= 18.23, 95% CI = 10.36 32.08), or urinary tract infection (OR = 4.93, 95% CI = 2.84-8.58). CONCLUSIONS: The readmission rate, risk factors, and causes following TLIF surgery are comparable to other lumbar spinal procedures reported from the ACS-NSQIP database. PMID- 28660104 TI - Use of Bivector Traction for Stabilization of the Head and Maintenance of Optimal Cervical Alignment in Posterior Cervical Fusions. AB - STUDY DESIGN: Retrospective analysis of consecutive case series. OBJECTIVE: To introduce a novel method of stabilizing the cranium using bivector traction in posterior cervical fusions. METHODS: A retrospective review of 50 consecutive patients undergoing instrumented posterior cervical arthrodesis was performed. All patients had at least 3 levels of subaxial fusion using the bivector traction apparatus. Patients' demographic data was recorded for the following: pre- and postoperative cervical lordosis, pre- and postoperative cervical sagittal vertical alignment (cSVA), and intraoperative complications from pin placements. RESULTS: A total of 50 patients were studied. There were 31 females and 19 males. The mean age at the time of surgery was 49 years (range 35-79). A mean 5.8 levels were fused. The most common levels fused were C2-T3 in 14 patients followed by C2 T2 in 7 patients. In no case did the surgeon or assistant have to scrub out to adjust the alignment. The mean pre- and postoperative cervical lordosis was -6.0 degrees and -10 degrees , respectively (P = .04). The mean pre-and postoperative cSVA was 30.5 mm and 32 mm, respectively (P = .6). There were no complications related to placement of the Gardner-Well tongs. CONCLUSION: The bivector traction is an easy, safe, and effective method of stabilizing the head and obtaining adequate cervical sagittal alignment. PMID- 28660105 TI - Significance of Vertebral Endplate Failure in Symptomatic Lumbar Disc Herniation. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: Endplate lesions though have been implicated in the genesis of lumbar disc herniation (LDH), very little is known regarding their clinical course. Thus, the present study is aimed to investigate the incidence and types of endplate failure (EPF) in LDH and its correlation with the clinical symptoms and prognosis. METHODS: Clinical and magnetic resonance imaging (MRI) features of 66 patients with isolated single level LDH were studied. Three-dimensional fast spoiled gradient (3D FSPGR) MRI and computed tomography scans were used to identify the bony and cartilaginous EPF. Twenty-five patients were operated on and 41 patients were treated conservatively. Changes in the pain score, function and neurology were noted at 3, 6, 12, 24, and 36 weeks. RESULTS: Endplate lesions were observed in 64 patients (96.9%), including bony endplate failure (bony failure) in 47 patients (71.2%) and isolated cartilaginous endplate lesions in 17 patients (25.7%). Bony failure group had similar pain and functional scores but more severe neurological deficit at the initial evaluation. Clinical parameters improved in all groups, but the recovery was lesser in conservatively treated bony failure patients. CONCLUSION: Endplate lesions are commonly associated with symptomatic LDH. Presence of bony failure can increase neurological deficit and reduce the chance of recovery with conservative management. The 3D FSPGR sequence of MRI can be successfully used for detection of the endplate lesions in the herniated disc. PMID- 28660106 TI - Biomechanical Evaluation of Unilateral Versus Bilateral C1 Lateral Mass-C2 Intralaminar Fixation. AB - STUDY DESIGN: Biomechanical, cadaveric study. OBJECTIVES: To compare the relative stiffness of unilateral C1 lateral mass-C2 intralaminar fixation to intact specimens and bilateral C1 lateral mass-C2 intralaminar constructs. METHODS: The biomechanical integrity of a unilateral C1 lateral mass-C2 intralaminar screw construct was compared to intact specimens and bilateral C1 lateral mass-C2 intralaminar screw constructs. Five human cadaveric specimens were used. Range of motion and stiffness were tested to determine the stiffness of the constructs. RESULTS: Unilateral fixation significantly decreased flexion/extension range of motion compared to intact (P < .001) but did not significantly affect axial rotation (P = .3) or bending range of motion (P = .3). There was a significant decrease in stiffness in extension for both unilateral and bilateral fixation techniques compared to intact (P = .04 and P = .03, respectively). There was also a significant decrease in stiffness for ipsilateral rotation for the unilateral construct compared to intact (P = .007) whereas the bilateral construct significantly increased ipsilateral rotation stiffness compared to both intact and unilateral fixation (P < .001). CONCLUSION: Bilateral constructs did show improved biomechanical properties compared to the unilateral constructs. However, unilateral C1-C2 fixation using a C1 lateral mass and C2 intralaminar screw-rod construct decreased range of motion and improved stiffness compared to the intact state with the exception of extension and ipsilateral rotation. Hence, a unilateral construct may be acceptable in clinical situations in which bilateral fixation is not possible, but an external orthosis may be necessary to achieve a fusion. PMID- 28660107 TI - Optimal Timing of Surgery for Intramedullary Cavernous Hemangioma of the Spinal Cord in Relation to Preoperative Motor Paresis, Disease Duration, and Tumor Volume and Location. AB - STUDY DESIGN: Prospective study. OBJECTIVE: Investigate factors associated with preoperative motor paresis, recovery, ambulatory status, and intraoperative neurophysiological monitoring (IONM) among patients with no preoperative paresis (N group), complete preoperative motor recovery (CR group), and no complete recovery (NCR group) in patients with intramedullary spinal cavernous hemangioma to determine the optimal timing of surgery. METHODS: The study evaluated 41 surgical cases in our institute. Disease duration, tumor lesion, manual muscle testing (MMT), and gait at onset, just before surgery, and final follow-up (FU), tumor and lesion volume, IONM, extent of tumor resection, and tumor recurrence were evaluated among N, CR, and NCR groups. RESULTS: Motor paresis at onset was found in 26 patients (63%), with 42% of those in CR group. Disease duration from onset negatively affected stable gait just before surgery and FU as well as lower preoperative MMT (P < .05). Thoracic tumors were associated with patients with unstable gait before surgery (P < .05). Tumor volume was larger in NCR group (P < .05). IONM significantly decreased in NCR and CR groups than in N group (P < .05). The NCR group had residual mild motor paresis at FU (P < .05). Stable gait at FU was similar in N group and CR group, though lower in NCR group (P < .05). CONCLUSIONS: Early surgery is generally recommended for thoracic tumors and large tumors during stable gait without motor paresis before long disease duration. Surgery may be postponed until patients recover from preoperative motor paresis to allow optimal surgical outcome. IONM should be carefully monitored in patients with a history of preoperative paresis even with preoperative complete motor recovery. PMID- 28660108 TI - Distal Fusion Level Selection in Scheuermann's Kyphosis: A Comparison of Lordotic Disc Segment Versus the Sagittal Stable Vertebrae. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To compare 2 methods of selecting the lowest instrumented vertebra (LIV) on the rates of revision surgery for distal junctional kyphosis (DJK) following treatment for Scheuermann's kyphosis (SK). METHODS: A retrospective review of patients who have undergone surgical treatment for SK was performed. Forty-four patients were divided into 2 groups based on intervention: Group 1 (n = 26) included patients who had an LIV distal to or at the sagittal stable vertebrae (SSV), and Group 2 (n = 18) included patients who had an LIV proximal to the SSV. For each group, demographic, radiographic, and revision surgery data was analyzed. RESULTS: The average follow up was 3.1 years. There were no differences among demographic variables between the groups. Preoperative and postoperative thoracic kyphosis, lumbar lordosis, and sagittal balance were not different between groups. Postoperatively, Group 1 demonstrated a significantly greater average lordotic disc angle below the LIV compared with Group 2 (Group 1, -6.2 +/- 4.3 degrees vs Group 2, -2.9 +/- 5.8 degrees ; P = .02). In a subgroup analysis, extending fusions to the sagittal stable vertebra rather than the first lordotic disc resulted in fewer distal LIV complications necessitating revision surgery compared with fusing short of the SSV (5% vs 36.3%, P = .04). CONCLUSION: The SSV method may reduce complications secondary to distal junctional failure, but at the expense of incorporating additional motion segments in a typically young population. PMID- 28660109 TI - Usefulness of Tokuhashi Score in Survival Prediction of Patients Operated for Vertebral Metastatic Disease. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: Spinal metastasis can produce pain, deformity, neurological compromise and can decrease life expectancy. Surgical management is usually indicated for pain control, neurological decompression, and to avoid deformity progression. Tokuhashi et al created a scoring system to estimate survival and stratify surgical treatment based on established parameters. Our objective was to evaluate the usefulness of Tokuhashi scoring (TS) system by comparing the predicted and real survival times and analyze the survival time according to the type of tumor. METHODS: From 2004 to 2014, 105 patients with vertebral metastasis who underwent surgical treatment were enrolled and retrospectively analyzed. Preoperative TS was performed in all cases. Patients were classified into 3 groups according to TS; group 1 (TS 0-8), group 2 (TS 9-11), and group 3 (TS 12-15). Patients' average age was 61.5 years, main primary tumor site were as follows: kidney (23%), lung (19%), and breast (18%). RESULTS: The Tokuhashi general concordance was 67.6%. Per group concordance was as follows: group 1 80%, in group 2, only 33% of concordance was observed. In group 3, 100% of concordance was observed. In group 2, the most common primary sites were breast and kidney and the mean survival was 20 and 22.3 months, respectively, both longer than that expected for this group. CONCLUSIONS: Tokuhashi concordance was acceptable in our study, particularly in lower and higher scores. The lesser concordance observed in group 2 (33.3%) was observed in almost all tumors. For our practice, TS constitutes an acceptable tool to define survival, particularly in lower and higher scores. PMID- 28660110 TI - Assessing Foraminal Stenosis in the Cervical Spine: A Comparison of Three Dimensional Computed Tomographic Surface Reconstruction to Two-Dimensional Modalities. AB - STUDY DESIGN: Retrospective radiographic study. OBJECTIVE: The optimal radiographic modality for assessing cervical foraminal stenosis is unclear. Determination on conventional axial cuts is made difficult due in part to the complex, oblique orientation of the cervical neuroforamen. The utility of 3 dimensonal (3D) computed tomography (CT) reconstruction in improving neuroforaminal assessment is not well understood. The objective of this study is to determine inter-rater variability in grading cervical foraminal stenosis using 3 different CT imaging modalities: 3D CT surface reconstructions (3DSR), 2D sagittal oblique multiplanar reformations (2D-SOMPR), and conventional 2D axial CT imaging. METHODS: Pretreatment CT scans of 25 patients undergoing surgery for cervical spondylotic radiculopathy were analyzed at 2 levels: C5-C6 and C6-C7. Simple interrater agreement and kappa-Fleiss coefficients were calculated for each imaging modality and stenosis grade. Image reviewers (attending spine surgeon, attending neuroradiologist, spine fellow) interpreted each CT scan in 3 different formats: axial, 2D-SOMPR, and 3DSR. Four cervical foramina at 2 spinal levels were graded as normal (no stenosis), mild (<=25% stenosis), moderate (25% 50% stenosis), or severe (>50% stenosis). RESULTS: Across all imaging modalities, interrater reliability was fair when grading foraminal stenosis (kappa < 0.4). Agreement was lowest for the axial images (kappa = 0.119) and highest for the 3D CT reconstructions (kappa = 0.334). 2D-SOMPR images also led to improved interrater reliability when compared with axial images (kappa = 0.255). CONCLUSION: Grading cervical foraminal stenosis using conventional axial CT imaging is difficult with low interrater reliability. CT modalities that provide a circumferential view of the cervical foramen, such as 2D-SOMPR and 3D CT reconstruction, had higher rates of interobserver reliability in grading foraminal stenosis than conventional axial cuts, with 3D having the highest. As these 3D reconstructions can be obtained at no additional cost or radiation exposure over a conventional CT scan, and because they can provide useful information in determining levels being considered for surgical decompression, we recommend they be utilized when evaluating cervical foramina. PMID- 28660111 TI - Corticosteroid Treatment for Metastatic Spinal Cord Compression: A Review. AB - STUDY DESIGN: Narrative review. OBJECTIVE: Metastatic spinal cord compression (MSCC) is a very frequent complication among cancer patients. Presenting commonly as nocturnal back pain, MSCC typically progresses to lower extremity paresis, loss of ambulatory capabilities, and paraplegia. In addition to standard treatment modalities, corticosteroid administration has been utilized in preclinical and clinical settings as adjunctive therapy to reduce local spinal cord edema and improve clinical symptoms. This article serves as a review of existing literature regarding corticosteroid management of MSCC and seeks to provide potential avenues of research on the topic. METHODS: A literature search was performed using PubMed in order to consolidate existing information regarding dexamethasone treatment of MSCC. Of all search results, 7 articles are reviewed, establishing the current understanding of metastatic spine disease and dexamethasone treatment in both animal models and in clinical trials. RESULTS: Treatment with high-dose corticosteroids is associated with an increased rate of potentially serious systemic side effects. For this reason, definitive guidelines for the use of dexamethasone in the management of MSCC are unavailable. CONCLUSIONS: It is still unclear what role dexamethasone plays in the treatment of MSCC. It is evident that new, more localizable therapies may provide more acceptable treatment strategies using corticosteroids. Looking forward, the potential for more targeted, localized application of the steroid through the use of nanotechnology would decrease the incidence of adverse effects while maintaining the drug's efficacy. PMID- 28660113 TI - Study Analysis: Revelation of Truth, or Murder by Numbers? PMID- 28660112 TI - Vertebral Column Resection for Rigid Spinal Deformity. AB - STUDY DESIGN: Broad narrative review. OBJECTIVE: To review the evolution, operative technique, outcomes, and complications associated with posterior vertebral column resection. METHODS: A literature review of posterior vertebral column resection was performed. The authors' surgical technique is outlined in detail. The authors' experience and the literature regarding vertebral column resection are discussed at length. RESULTS: Treatment of severe, rigid coronal and/or sagittal malalignment with posterior vertebral column resection results in approximately 50-70% correction depending on the type of deformity. Surgical site infection rates range from 2.9% to 9.7%. Transient and permanent neurologic injury rates range from 0% to 13.8% and 0% to 6.3%, respectively. Although there are significant variations in EBL throughout the literature, it can be minimized by utilizing tranexamic acid intraoperatively. CONCLUSION: The ability to correct a rigid deformity in the spine relies on osteotomies. Each osteotomy is associated with a particular magnitude of correction at a single level. Posterior vertebral column resection is the most powerful posterior osteotomy method providing a successful correction of fixed complex deformities. Despite meticulous surgical technique and precision, this robust osteotomy technique can be associated with significant morbidity even in the most experienced hands. PMID- 28660114 TI - A Rare Complication of TEVAR Performed for Complex Acute Stanford B Aortic Dissection. AB - Management of aortic dissection with a novel endovascular technique known as thoracic endovascular aortic repair (TEVAR) paired with surgical debranching as a less invasive alternative to conventional repair has gained widespread acceptance. However, experience for complicated, Stanford type B dissection involving the aortic arch is still limited. PMID- 28660115 TI - Heterogeneous Electron-Transfer Rates for the Reduction of Viologen Derivatives at Platinum and Bismuth Electrodes in Acetonitrile. AB - The standard heterogeneous rate constants for the reduction of a series of viologen derivatives with a range of inter-ring torsion angles were measured at Bi and Pt electrodes. The electrode potentials for the first one-electron reduction of the viologens vary from -684 mV to -1070 mV vs. Ag/0.01 m Ag+; this enabled a comparison of the behaviour of metallic (Pt) and semi-metallic (Bi) electrodes over a wide range of applied potentials. The differential capacitance (6.5 MUF cm-2) of Bi/MeCN,TBAPF6 interfaces at the potential of zero charge (pzc= 0.60 V) is at least an order of magnitude greater than that calculated on the basis of the bulk Bi carrier density (3*1017 cm-3) and the differential capacitance (9.5 MUF cm-2) of Pt/MeCN interfaces at their pzc (-0.43 V) is of the same order. The series of viologen derivatives exhibited simple one-electron redox behaviour and showed similar rate constants at Pt (1.8*10-4-1.6*10-3 cm s 1) and Bi electrodes (1.1*10-4-1.9*10-3 cm s-1) after application of the Frumkin correction. These results demonstrate that the density of states at the Bi surface is much higher than in bulk. Finally, the Frumkin-corrected standard rate constants were observed to be inversely correlated with the inter-ring torsion angle of the viologens. PMID- 28660116 TI - Facile Morphology-Controlled Synthesis of Organolead Iodide Perovskite Nanocrystals Using Binary Capping Agents. AB - Controlling the morphology of organolead halide perovskite crystals is crucial to a fundamental understanding of the materials and to tune their properties for device applications. Here, we report a facile solution-based method for morphology-controlled synthesis of rod-like and plate-like organolead halide perovskite nanocrystals using binary capping agents. The morphology control is likely due to an interplay between surface binding kinetics of the two capping agents at different crystal facets. By high-resolution scanning transmission electron microscopy, we show that the obtained nanocrystals are monocrystalline. Moreover, long photoluminescence decay times of the nanocrystals indicate long charge diffusion lengths and low trap/defect densities. Our results pave the way for large-scale solution synthesis of organolead halide perovskite nanocrystals with controlled morphology for future device applications. PMID- 28660117 TI - Comparing geographic area-based and classical population-based incidence and prevalence rates, and their confidence intervals. AB - To quantify the HIV epidemic, the classical population-based prevalence and incidence rates (P rates) are the two most commonly used measures used for policy interventions. However, these P rates ignore the heterogeneity of the size of geographic region where the population resides. It is intuitive that with the same P rates, the likelihood for HIV can be much greater to spread in a population residing in a crowed small urban area than the same number of population residing in a large rural area. With this limitation, Chen and Wang (2017) proposed the geographic area-based rates (G rates) to complement the classical P rates. They analyzed the 2000-2012 US data on new HIV infections and persons living with HIV and found, as compared with other methods, using G rates enables researchers to more quickly detect increases in HIV rates. This capacity to reveal increasing rates in a more efficient and timely manner is a crucial methodological contribution to HIV research. To enhance this newly proposed concept of G rates, this article presents a discussion of 3 areas for further development of this important concept: (1) analysis of global HIV epidemic data using the newly proposed G rates to capture the changes globally; (2) development of the associated population density-based rates (D rates) to incorporate the heterogeneities from both geographical area and total population-at-risk; and (3) development of methods to calculate variances and confidence intervals for the P rates, G rates, and D rates to capture the variability of these indices. PMID- 28660118 TI - Intervening during and after pregnancy to prevent weight retention among African American women. AB - Efforts to prevent postpartum weight retention in extant clinical trials of African American women have proven exceedingly challenging. The primary purpose of this pilot study was to determine whether a behavioral intervention implemented in early pregnancy through 6 months postpartum could increase the proportion of African American women who were at or below their early pregnancy weights by 6 months postpartum. We additionally evaluated whether mothers' postpartum weight loss could be maintained at 12 months postpartum. Participants were 66 socioeconomically disadvantaged African American women (36% overweight, 64% obese) randomly assigned to a behavioral intervention or usual care group. The intervention, implemented from early pregnancy to 6 months postpartum, promoted weight control through: (1) empirically supported behavior change goals; (2) interactive self-monitoring text messages; (3) weekly to monthly health coach calls; and (4) skills training and support through Facebook. In modified intent to-treat analyses, participants assigned to the intervention were significantly more likely to be at or below their early pregnancy weights by 6 months postpartum compared to usual care (56% vs. 29%, p = 0.04). At 12 months postpartum, the maternal weight difference between intervention and usual care groups was not maintained (41% vs. 38% respectively at or below early pregnancy weights, p = 0.83). Findings suggest that a combined pregnancy and postpartum weight control intervention improves 6 month weight outcomes in socioeconomically disadvantaged African American women with obesity. Longer interventions may be needed to overcome late postpartum weight gain among this high risk group. Clinical trial registration number: ClinicalTrials.gov identifier NCT01530776. PMID- 28660119 TI - Different types of housing and respiratory health outcomes. AB - Evidence has shown that housing conditions may substantially influence the health of residents. Different types of housing have different structures and construction materials, which may affect indoor environment and housing conditions. This study aimed to investigate whether people living in different types of housing have different respiratory health outcomes. The data from the 1999-2006 National Health and Nutrition Examination Survey were used for the analyses. The types of housing included houses, townhouses, apartments, and mobile homes. Respiratory symptoms included wheezing, coughing, sputum, and dyspnea; respiratory diseases included asthma, chronic bronchitis, emphysema, and chronic obstructive pulmonary disease (COPD). Multiple logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI) after adjustment for potential confounding factors. A total of 11,785 participants aged 40 years and older were included in the analyses. Compared with those living in single family houses, participants living in mobile homes were more likely to have respiratory conditions, the OR (95% CI) was 1.38 (1.13-1.69) for wheezing, and 1.49 (1.25-1.78) for dyspnea; whereas participants living in apartments were less likely to have respiratory conditions, the OR (95% CI) was 0.58 (0.36-0.91) for chronic bronchitis, and 0.69 (0.49-0.97) for COPD. Compared with living in single family houses, living in mobile home was associated with worse, whereas living in apartments was associated with better, respiratory health outcomes. Further research is needed to better understand the underlying mechanisms and prevent adverse respiratory effects associated with living in mobile homes. PMID- 28660120 TI - Objectively measured physical activity level and sedentary behavior in Norwegian children during a week in preschool. AB - Although many studies have reported on physical activity (PA) levels using accelerometers, a thorough description of the PA pattern in preschool children during their stay in the preschool, is lacking in the current literature. Furthermore, there remains a lack of understanding of the PA level and pattern in children in the lower end of the PA continuum. The first aim of this study was therefore to describe the PA pattern during a week-long stay in a preschool in all children born in 2011 (either three or four-year-olds) attending public preschools in a municipality in Norway. The second aim was to describe the PA level and pattern of the children who are the least physically active. This cross sectional study included baseline data from 95% of children (N = 111) participating in a randomized controlled physical activity intervention (Active Kindergarten - Active Children study). The participants wore an Actigraph accelerometer, in week 39 in 2015, from when they arrived at the preschool on Monday morning and throughout their stay of five consecutive days. The amount of moderate- to vigorous-intensity PA (MVPA) per day ranged from 16 min to 116 min, and sedentary time ranged from 2.7 h to 6.5 h per day in the least and most sedentary child, respectively. The least physically active 25% of children were less active throughout the entire day, and only a few of them managed to achieve the recommended level of MVPA on any weekday. The physical activity levels and patterns among the least active children described in this study may help to inform interventions targeting this group. PMID- 28660121 TI - Point-of-care testing to promote cardiovascular disease risk assessment: A proof of concept study. AB - Updated cholesterol guidelines emphasize multivariable cardiovascular disease (CVD) risk estimation to guide treatment decision-making in primary prevention. This study tested the preliminary feasibility, acceptability and efficacy of point-of-care testing (POCT) and quantitative CVD risk assessment in high-risk adults to increase guideline-recommended statin use in primary prevention. Participants were aged 40-75 years, without CVD or diabetes mellitus, and potentially-eligible for consideration of statins based on estimated 10-year CVD risk from last-measured risk factor levels in the electronic health record. We performed POCT to facilitate quantitative CVD risk assessment with the Pooled Cohort Equations immediately before a scheduled primary care provider (PCP) visit. Outcomes were: physician documentation of a CVD risk discussion and statin prescription on the study date. We also assessed acceptability of the intervention through structured questionnaire. We recruited 18 participants (8 from an academic practice and 10 from a federally-qualified health clinic). After the intervention, 83% of participants discussed CVD risk with their PCP, 47% received a statin recommendation from their PCP, and 29% received a new statin prescription during the PCP visit. Participants reported high levels of satisfaction with the intervention. This study demonstrates that in initial testing pre-visit POCT and quantitative CVD risk assessment appears to be a feasible and acceptable intervention that may promote guideline-recommended statin initiation in primary prevention. Future research with an adequately powered trial is warranted to determine the effectiveness of this approach in clinical practice. PMID- 28660122 TI - Family carers: A role in addressing chronic disease risk behaviours for people with a mental illness? AB - People with a mental illness experience greater chronic disease morbidity and mortality compared to those without mental illness. Family carers have the potential to promote the health behaviours of those they care for however factors which may influence the extent to which they do so have not been reported. An exploratory study was conducted to investigate carers': 1) promotion of fruit and vegetable consumption, physical activity, quitting smoking, and reducing alcohol consumption; 2) perceptions of their role and ability to promote such behaviours; 3) and the association between carer perceptions and the promotion of such behaviours. A cross-sectional survey was conducted with mental health carers (N = 144, 37.6% response rate) in New South Wales, Australia in 2013. Associations between current promotion of health behaviours and carer perceptions were explored through multivariate regression analysis in 2016. A majority of respondents promoted fruit and vegetable consumption (63.8%), physical activity (60.3%), quitting smoking (56.3%), and reducing alcohol consumption (56.2%) to the person they cared for. A perception that it was 'very important' to have a positive influence on these behaviours was positively related with promotion of each of the four behaviours, with those holding such a view being more likely to promote such behaviours, than those who did not (odds ratio: 9.47-24.13, p < 0.001). The majority (56.2%-63.8%) of carers reported promoting the health behaviours of those they cared for, demonstrating a need and opportunity to build the capacity of carers to contribute to reducing the health risk behaviours among people with a mental illness. PMID- 28660123 TI - Constructing tailored parental monitoring strategy profiles to predict adolescent disclosure and risk involvement. AB - *Many parents use multiple monitoring strategies in different combinations over time to monitor their adolescents.*Adolescents of parents who use multiple strategies reported greater risk involvement.*Parents who solicited information only from adolescents had greater knowledge and adolescent disclosure. PMID- 28660124 TI - Shopping pattern and food purchase differences among Supplemental Nutrition Assistance Program (SNAP) households and Non-supplemental Nutrition Assistance Program households in the United States. AB - *SNAP households are influenced by proximity to stores in predicting store choice.*Store choice among SNAP households predicted beverage purchases.*SNAP households are more likely to purchase sugar-sweetened beverages at supercenters and convenience stores. PMID- 28660125 TI - The effect of health insurance coverage and the doctor-patient relationship on health care utilization in high poverty neighborhoods. AB - African Americans have higher rates of mortality than whites who are the same age and sex. We hypothesize that in low socioeconomic status neighborhoods, having health insurance coverage and a regular health care provider increases the likelihood of receiving diagnostic tests for cardiovascular disease and diabetes. We use data from a random two-stage cluster sample of 230 adults living in high poverty census tracts to examine the effects of insurance coverage and having a regular doctor on the likelihood receiving diagnostic tests for high cholesterol, high blood sugar, and blood pressure. We find that health insurance coverage increases the odds of having a regular health care provider (p < 0.05) and of receiving the diagnostic tests (p < 0.05). Having a regular doctor mediates the effect of insurance coverage on the likelihood of receiving the tests, especially when the participant can report the physician's name. PMID- 28660126 TI - Sternoclavicular joint osteomyelitis extending to lung abscess complicated by Staphylococcal infective endocarditis. PMID- 28660127 TI - Multiorgan Echinococcus infection: Treatment of an immigrant in the United States. AB - We discuss the clinical presentation and management of a 36-year-old woman presenting with a 12-year history of recurrent hydatid disease, a disease caused by Echinococcus granulosus and other Echinococcal species, which is rarely seen in the contiguous United States. She has had multiple procedures since her diagnosis in 2005 and is still closely being followed for possible disease recurrence. PMID- 28660128 TI - Medical and surgical management of Pasteurella canis infectious keratitis. AB - INTRODUCTION: We describe a case of refractory Pasteurella Canis keratitis that initially failed antimicrobial treatment but was successfully treated with a conjunctival flap followed by a penetrating keratoplasty. CASE DISCUSSION: A 70 year-old male had persistent corneal edema related to previous herpes zoster keratouveitis with visual acuity of 20/400. An endothelial keratoplasty was performed with improvement in vision to 20/25. Several months after this surgery the patient developed a corneal infiltrate and cultures grew Pasturella canis. The infection persisted despite topical treatment with broad spectrum fortified vancomycin, tobramycin and fluoroquinolones. A conjunctival flap combined with corneal cryotherapy was performed to help mitigate symptoms and to allow the ulcer to heal. A penetrating keratoplasty was done several months later. DISCUSSION: The patient achieved pain relief immediately after the flap was placed. Medications were tapered off in the following few months after the procedure. A penetrating keratoplasty was performed 4 months later. The patient has remained almost entirely symptom free, and the graft remained clear one year after surgery. CONCLUSIONS: A keratitis caused by Pasteurella canis that is resistant to medical therapy can be treated successfully with a conjunctival flap and cryotherapy followed by a penetrating keratoplasty. PMID- 28660129 TI - Haemophilus influenzae peritonitis in a girl on automated peritoneal dialysis: Case report and review of the literature. AB - Haemophilus influenzae is a rare cause of peritonitis in patients on peritoneal dialysis (PD). We report a case of peritonitis due to non-typeable H. influenzae in a 5-year-old girl on automated PD. The patient was successfully treated with intraperitoneal cefepime and cefazolin. The isolate was multilocus sequence type 3 and contained the hmw and hia genes but was IS1016-negative. Seven of the eight reported cases were female, indicating that sex-associated factors may be important in H. influenzae peritonitis in patients on PD. Determination of the pathogenesis of PD-associated H. influenzae peritonitis requires gene analysis and a swab sample from the vaginal introitus. PMID- 28660130 TI - Mesenteric lymphadenitis as a presenting feature of Whipple's disease. AB - Detecting Whipple's disease, a "great imitator", requires a high index of suspicion so that antimicrobial treatment can be initiated in a timely manner; a missed diagnosis can be fatal. Although an uncommon cause, Whipple's disease must be considered in adults with mesenteric lymphadenitis. We report the case of a 39 year-old African American man who presented with chronic joint pain, chronic weight loss, and acute onset epigastric pain. Contrast-enhanced computed tomography of the abdomen and pelvis showed extensive mesenteric lymphadenopathy. A diagnosis of Whipple's disease was made based upon demonstration of PAS positive macrophages in the mesenteric lymph node and duodenal biopsies. Antimicrobial therapy resulted in weight gain and resolution of abdominal pain and arthralgia at six months follow-up. Whipple's disease can be fatal without antibacterial therapy and it always needs to be considered in individuals presenting with any combination of abdominal pain, weight loss, and diarrhea in the background of nonspecific arthritis or arthralgia. Whipple's disease must also be considered in adults presenting with mesenteric lymphadenitis. Review of CT scans may be helpful, as Whipple's disease characteristically causes low attenuation mesenteric lymphadenopathy. PMID- 28660131 TI - Successful treatment of multidrug resistant Klebsiella pneumoniae using dual carbapenem regimen in immunocompromised patient. AB - This report describes a longitudinal case of immunocompromised patient post kidney transplant who was admitted to our institution repeatedly for treatment of various infections caused by multi-drug resistant Klebsiella pneumoniae. The patient was successfully treated with a combination of ertapenem/meropenem on multiple occasions despite the elevated MICs. Our observations corroborate previous preclinical studies and case reports showing the efficacy of double carbapenem regimens against resistant Enterobacteriaceae. PMID- 28660133 TI - Resolution of a Debilitating Paraneoplastic Parkinson-like Neurological Syndrome Following Tyrosine Inhibitor Therapy and Consolidative Nephrectomy in a Patient with Advanced Clear Cell Renal Cell Carcinoma. AB - Paraneoplastic syndromes are commonly encountered in renal cell carcinoma, but neurological manifestations are rare. Herein we report a case of a patient with locally advanced renal cell carcinoma who presented with Parkinson-like symptoms which prohibited surgery due to poor performance status. However, a significant improvement was noted after tyrosine kinase inhibitor therapy, allowing the patient to proceed to curative surgery. PMID- 28660132 TI - New Delhi metallo-beta-lactamase-1 (NDM-1) Escherichia coli isolated from household vacuum cleaner-Oregon, 2013. AB - The first Oregon case of New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Escherichia coli was reported during November 2013. Epidemiologic investigation revealed only local outpatient medical care and no travel outside Oregon for both the patient and his household contact. Environmental sampling discovered a matching isolate from the patient's household vacuum cleaner, suggesting environmental persistence. PMID- 28660134 TI - Cumulus cell mitochondrial activity in relation to body mass index in women undergoing assisted reproductive therapy. AB - Most studies have considered the negative influence of obesity on fertility in both genders. In the present study, we assessed mitochondrial activity expressed as the mitochondrial potential index (MPI) in cumulus cells from obese women and women with a normal body mass index (BMI) during assisted reproductive therapy. The results revealed a significant reduction of MPI with increased body mass. The lower MPI levels in cumulus cells from obese women may reflect mitochondrial dysfunction caused by oxidative stress, which can affect the cumulus-oocyte complex and have an impact on oocyte development. PMID- 28660136 TI - Sternal metastasis - the forgotten column and its effect on thoracic spine stability. AB - Sternal metastases are not studied extensively in the literature. There is a paucity of information on their role in metastatic disease. The concept of the fourth column was described by Berg in 1993, and has been proven in case report, clinically and biomechanical studies. The role of the sternum as a support to the thoracic spine is well documented in the trauma patients, but not much is known about its role in cancer patients. This review examines what is known on the role of the fourth column. Following this we have identified two likely scenarios that sternal metastases may impact management: (1) sternal pathological fracture increases the mobility of the semi-rigid thorax with the loss of the biomechanical support of the sternum-rib-thoracic spine complex; and (2) a sternal metastasis increases the risk of fracture, and while being medical treated the thoracic spine should be monitored for acute kyphosis and neurological injury secondarily to the insufficiency of the fourth column. PMID- 28660137 TI - Role of fetuin A in the diagnosis and treatment of joint arthritis. AB - Osteoarthritis is a slowly progressive disease which includes the intervention of several cytokines, macrophage metalleinoproteinases reaction, leading to the degradation of the local cartilage but also having an impact on the serum acute phase proteins (APPs). Subsequently, biomarkers seem to be essential to estimate its progression and the need for any surgical intervention such as total arthroplasty, but also can be used as therapeutic agents. Recently, among APPs, fetuin A drew attention regarding its possible anti-inflammatory role in animal models but also as a therapeutic agent in the inflammatory joint disease in clinical trials. In contrast with other APPs such as C-reactive protein, fetuin A appears to be lower in the serum of patients with degenerative joint disease in comparison with the healthy ones, and also acts as an antagonist of the anti proliferative potential of transforming growth factor-beta (TGF-beta) cytokines. Because of its lower serum levels in arthritis, an unregulated binding of TGF beta and bone morphogenetic proteins takes place leading to further arthritic lesions. The purpose of the present review is to assess the current evidence regarding the multipotent role of the alpha-2-HS-glycoprotein or as also known Fetuin-a in animal models but also as a biomarker of the degenerative joint arthritis in clinical trials. PMID- 28660135 TI - Perioperative blood management strategies for patients undergoing total knee replacement: Where do we stand now? AB - Total knee replacement (TKR) is one of the most common surgeries over the last decade. Patients undergoing TKR are at high risk for postoperative anemia and furthermore for allogeneic blood transfusions (ABT). Complications associated with ABT including chills, rigor, fever, dyspnea, light-headedness should be early recognized in order to lead to a better prognosis. Therefore, perioperative blood management program should be adopted with main aim to reduce the risk of blood transfusion while maximizing hemoglobin simultaneously. Many blood conservation strategies have been attempted including preoperative autologous blood donation, acute normovolemic haemodilution, autologous blood transfusion, intraoperative cell saver, drain clamping, pneumatic tourniquet application, and the use of tranexamic acid. For practical and clinical reasons we will try to classify these strategies in three main stages/pillars: Pre-operative optimization, intra-operative and post-operative protocols. The aim of this work is review the strategies currently in use and reports our experience regarding the perioperative blood management strategies in TKR. PMID- 28660138 TI - Emergent reintubation following elective cervical surgery: A case series. AB - AIM: To review cases of emergent reintubation after cervical surgery. METHODS: Patients who were emergently intubated in the post-operative period following cervical surgery were identified. The patients' prospectively documented demographic parameters, medical history and clinical symptoms were ascertained. Pre-operative radiographs were examined for the extent of their pathology. The details of the operative procedure were discerned. RESULTS: Eight hundred and eighty patients received anterior- or combined anterior-posterior cervical surgery from 2008-2013. Nine patients (1.02%) required emergent reintubation. The interval between extubation to reintubation was 6.2 h [1-12]. Patients were kept intubated after reintubation for 2.3 d [2-3]. Seven patients displayed moderate postoperative edema. One patient was diagnosed with a compressive hematoma which was subsequently evacuated in the OR. Another patient was diagnosed with a pulmonary effusion and treated with diuretics. One patient received a late debridement for an infected hematoma. Six patients reported residual symptoms and three patients made a complete recovery. CONCLUSION: Respiratory compromise is a rare but potentially life threatening complication following cervical surgery. Patients at increased risk should be monitored closely for extended periods of time post-operatively. If the airway is restored adequately in a timely manner through emergent re-intubation, the outcome of the patients is generally favorable. PMID- 28660139 TI - Two-stage surgical treatment for septic non-union of the forearm. AB - AIM: To investigate the effectiveness of a two-stage surgical procedure for the treatment of septic forearm non-union. METHODS: Septic non-unions are rare complications of forearm fractures. When they occur, they modify the relationship between forearm bones leading to a severe functional impairment. Treatment is challenging and surgery and antibiotic therapy are required to achieve infection resolution. It is even harder to obtain non-union healing with good functional results. The aim of this study is to present a two stages surgical treatment for septic forearm non-union with revision and temporary stabilization of the non union until infection has cleared and subsequently perform a new synthesis with plate, opposite bone graft strut and intercalary graft. We retrospectively reviewed 18 patients with a mean age at the time of primary injury of 34.5 years (19-57 years) and a mean follow-up of 6 years (2-10 years). All patients presented an atrophic non-union with a mean length of the bone defect of 1.8 cm (1.2-4 cm). Complications and clinical results after surgical treatment were recorded. RESULTS: Mean time to resolution of the infectious process was 8.2 wk (range 4-20 wk) after the first surgery and specific antibiotic therapy. All the non-union healed with an average time of 5 mo (range 2-10 mo) after the second step surgery. Cultures on intraoperative samples were positive in all cases. No major intraoperative complications occurred. Two patients developed minor complications and one needed a second surgical debridement for infection resolution. At the last follow-up functional results were excellent in 5 (27.8%) patients, satisfactory in 10 (55.5%) and unsatisfactory in 3 (16.7%) patients. No activities of daily living (ADLs) limitations were reported by 12 (66.6%) patients, slight by 3 (16.6%) and severe limitation by 3 (16.6%) patients. Mean visual analog scale at the last follow-up was 1 (0-3). CONCLUSION: The two-step technique has proven to be effective to achieve resolution of the infectious process and union with good functional results and low rate of complications. PMID- 28660140 TI - Upper extremity disorders in heavy industry workers in Greece. AB - AIM: To investigate the disability due to musculoskeletal disorders of the upper extremities in heavy industry workers. METHODS: The population under study consisted of 802 employees, both white- and blue-collar, working in a shipyard industry in Athens, Greece. Data were collected through the distribution of questionnaires and the recording of individual and job-related characteristics during the period 2006-2009. The questionnaires used were the Quick Disabilities of the Arm, Shoulder and Hand (QD) Outcome Measure, the Work Ability Index (WAI) and the Short-Form-36 (SF-36) Health Survey. The QD was divided into three parameters - movement restrictions in everyday activities, work and sports/music activities - and the SF-36 into two items, physical and emotional. Multiple linear regression analysis was performed by means of the SPSS v.22 for Windows Statistical Package. RESULTS: The answers given by the participants for the QD did not reveal great discomfort regarding the execution of manual tasks, with the majority of the participants scoring under 5%, meaning no disability. After conducting multiple linear regression, age revealed a positive association with the parameter of restrictions in everyday activities (b = 0.64, P = 0.000). Basic education showed a statistically significant association regarding restrictions during leisure activities, with b = 2.140 (P = 0.029) for compulsory education graduates. WAI's final score displayed negative charging in the regression analysis of all three parameters, with b = -0.142 (P = 0.0), b = -0.099 (P = 0.055) and b = -0.376 (P = 0.001) respectively, while the physical and emotional components of SF-36 associated with movement restrictions only in daily activities and work. The participants' specialty made no statistically significant associations with any of the three parameters of the QD. CONCLUSION: Increased musculoskeletal disorders of the upper extremity are associated with older age, lower basic education and physical and mental/emotional health and reduced working ability. PMID- 28660141 TI - Medial tibial plateau morphology and stress fracture location: A magnetic resonance imaging study. AB - AIM: To determine the location of medial tibial plateau stress fractures and its relationship with tibial plateau morphology using magnetic resonance imaging (MRI). METHODS: A retrospective review of patients with a diagnosis of stress fracture of the medial tibial plateau was performed for a 5-year period. Fourteen patients [three female and 11 male, with an average age of 36.4 years (range, 15 50 years)], who underwent knee MRI, were included. The appearance of the tibial plateau stress fracture and the geometry of the tibial plateau were reviewed and measured on MRI. RESULTS: Thirteen of 14 stress fractures were linear, and one of them stellated on MRI images. The location of fractures was classified into three types. Three fractures were located anteromedially (AM type), six posteromedially (PM type), and five posteriorly (P type) at the medial tibial plateau. In addition, tibial posterior slope at the medial tibial plateau tended to be larger when the fracture was located more posteriorly on MRI. CONCLUSION: We found that MRI showed three different localizations of medial tibial plateau stress fractures, which were associated with tibial posterior slope at the medial tibial plateau. PMID- 28660142 TI - Clinical application of concentrated bone marrow aspirate in orthopaedics: A systematic review. AB - AIM: To examine the evidence behind the use of concentrated bone marrow aspirate (cBMA) in cartilage, bone, and tendon repair; establish proof of concept for the use of cBMA in these biologic environments; and provide the level and quality of evidence substantiating the use of cBMA in the clinical setting. METHODS: We conducted a systematic review according to PRISMA guidelines. EMBASE, MEDLINE, and Web of Knowledge databases were screened for the use of cBMA in the repair of cartilage, bone, and tendon repair. We extracted data on tissue type, cBMA preparation, cBMA concentration, study methods, outcomes, and level of evidence and reported the results in tables and text. RESULTS: A total of 36 studies met inclusion/exclusion criteria and were included in this review. Thirty-one of 36 (86%) studies reported the method of centrifugation and preparation of cBMA with 15 (42%) studies reporting either a cell concentration or an increase from baseline. Variation of cBMA application was seen amongst the studies evaluated. Twenty-one of 36 (58%) were level of evidence IV, 12/36 (33%) were level of evidence III, and 3/36 (8%) were level of evidence II. Studies evaluated full thickness chondral lesions (7 studies), osteochondral lesions (10 studies), osteoarthritis (5 studies), nonunion or fracture (9 studies), or tendon injuries (5 studies). Significant clinical improvement with the presence of hyaline-like values and lower incidence of fibrocartilage on T2 mapping was found in patients receiving cBMA in the treatment of cartilaginous lesions. Bone consolidation and time to bone union was improved in patients receiving cBMA. Enhanced healing rates, improved quality of the repair surface on ultrasound and magnetic resonance imaging, and a decreased risk of re-rupture was demonstrated in patients receiving cBMA as an adjunctive treatment in tendon repair. CONCLUSION: The current literature demonstrates the potential benefits of utilizing cBMA for the repair of cartilaginous lesions, bony defects, and tendon injuries in the clinical setting. This study also demonstrates discrepancies between the literature with regards to various methods of centrifugation, variable cell count concentrations, and lack of standardized outcome measures. Future studies should attempt to examine the integral factors necessary for tissue regeneration and renewal including stem cells, growth factors and a biologic scaffold. PMID- 28660143 TI - Distal triceps injuries (including snapping triceps): A systematic review of the literature. AB - AIM: To review current literature on types of distal triceps injury and determine diagnosis and appropriate management. METHODS: We performed a systematic review in PubMed, Cochrane and EMBASE using the terms distal triceps tears and snapping triceps on the 10th January 2017. We excluded all animal, review, foreign language and repeat papers. We reviewed all papers for relevance and of the papers left we were able to establish the types of distal triceps injury, how these injuries are diagnosed and investigated and the types of management of these injuries including surgical. The results are then presented in a review paper format. RESULTS: Three hundred and seventy-nine papers were identified of which 65 were relevant to distal triceps injuries. After exclusion we had 47 appropriate papers. The papers highlighted 2 main distal triceps injuries: Distal triceps tears and snapping triceps. Triceps tear are more common in males than females occurring in the 4th-5th decade of life and often due to a direct trauma but are also strongly associated with weightlifting and American football. The tears are diagnosed by history and clinically with a palpable gap. Diagnosis can be confirmed with the use of ultrasound (US) and magnetic resonance imaging. Treatment depends on type of tear. Partial tears can be treated conservatively with bracing and physio whereas acute tears need repair either open or arthroscopic using suture anchor or bone tunnel techniques with similar success. Chronic tears often need augmenting with tendon allograft or autograft. Snapping triceps are also seen more in men than women but at a mean age of 32 years. They are characterized by a snapping sensation mostly medially and can be associated with ulna nerve subluxation and ulna nerve symptoms. US is the diagnostic modality of choice due to its dynamic nature and to differentiate between snapping triceps tendon or ulna nerve. Treatment is conservative initially with activity avoidance and if that fails surgical management includes resection of triceps edge or transposition of the tendon plus or minus ulna nerve transposition. CONCLUSION: Distal triceps injuries are uncommon. This systematic review examines the evidence base behind diagnosis, imaging and treatment options of distal triceps injuries including tears and snapping triceps. PMID- 28660144 TI - Worldwide orthopaedic research activity 2010-2014: Publication rates in the top 15 orthopaedic journals related to population size and gross domestic product. AB - AIM: To perform a bibliometric analysis of publications rates in orthopedics in the top 15 orthopaedic journals. METHODS: Based on their 2015 impact factor, the fifteen highest ranked orthopaedic journals between January 2010 and December 2014 were used to establish the total number of publications; cumulative impact factor points (IF) per country were determined, and normalized to population size, GDP, and GDP/capita, comparison to the median country output and the global leader. RESULTS: Twenty-three thousand and twenty-one orthopaedic articles were published, with 66 countries publishing. The United States had 8149 publications, followed by the United Kingdom (1644) and Japan (1467). The highest IF was achieved by the United States (24744), United Kingdom (4776), and Japan (4053). Normalized by population size Switzerland lead. Normalized by GDP, Croatia was the top achiever. Adjusting GDP/capita, for publications and IF, China, India, and the United States were the leaders. Adjusting for population size and GDP, 28 countries achieved numbers of publications to be considered at least equivalent with the median academic output. Adjusting GDP/capita only China and India reached the number of publications to be considered equivalent to the current global leader, the United States. CONCLUSION: Five countries were responsible for 60% of the orthopaedic research output over this 5-year period. After correcting for GDP/capita, only 28 of 66 countries achieved a publication rate equivalent to the median country. The United States, United Kingdom, South Korea, Japan, and Germany were the top five countries for both publication totals and cumulative impact factor points. PMID- 28660145 TI - Non-Hodgkin Lymphoma of the Liver: A US Population-based Analysis. AB - Background and Aims: Non-Hodgkin lymphoma (NHL) of the liver is a rare lymphoid malignancy, accounting for less than 1% of extranodal lymphomas. Methods: I conducted an analysis of the U.S Surveillance, Epidemiology, and End Results (SEER) database to evaluate the histological subtypes and the survival outcomes of 785 cases with hepatic NHL between 1973 and 2012. Results: There were 785 of 312 459 cases with NHL had a first primary hepatic NHL (0.25%). Of the total 785 cases, the median age at diagnosis was 61 years (range 3-95 years) and male female ratio of 1.7:1. The most common subtype was diffuse large B cell lymphoma (63.2%). In all patients, the median overall survival (OS) was 33 months (95%CI, 22-48 months). The 5-year OS rate for indolent B-cell NHLs was 62%, compared with 44% for an aggressive B-cell NHLs and 42% for T-cell NHLs. The median OS improved from 19 months in patients diagnosed in a period 1996-2000 to 60 months when diagnosed between 2006 and 2012 (p < .001). In a multivariable Cox regression analysis, the age >=80 years (adjusted hazard ratio [aHR] 3.21, p < .001), male gender (aHR 1.26, p = .02), Black race (aHR, 1.70, p < .001), and T-cell NHL variants (aHR 1.73, p = .03) were unfavourable prognostic factors. Conclusion: NHL of the liver comprises about 0.3% of all NHLs and survival was improved in the recent calendar period. PMID- 28660146 TI - Bile Cast Nephropathy in Patients with Acute Kidney Injury Due to Hepatorenal Syndrome: A Postmortem Kidney Biopsy Study. AB - Background and Aims: The role of bile cast nephropathy (BCN) in pathogenesis of hepatorenal syndrome (HRS) in decompensated cirrhosis and acute on chronic liver failure (ACLF) is unknown. This study aimed to determine the frequency of BCN detected on postmortem renal biopsy among patients with decompensated cirrhosis and ACLF who had been admitted with acute kidney injury due to HRS (HRA-AKI) and expired during that hospitalization. Methods: One-hundred-twenty-seven postmortem renal biopsies with adequate size (>1 cm in length) were included for analysis. These were obtained from 84 patients with decompensated cirrhosis and 43 patients with ACLF. Results: BCN was detected in 57 of the total 127 (44.8%) renal biopsy specimens. Patients with BCN had significantly higher levels of serum total bilirubin, total leukocyte count and model for end-stage liver disease score, as compared to those without BCN. BCN was detected in 32/43 (74.4%) of the patients with ACLF, as compared to 25/84 (29.7%) of the patients with decompensated cirrhosis (p < 0.001). On multivariate analysis, direct bilirubin (OR (95% CI): 1.27 (1121-1.698); p < 0.001) and presence of ACLF (OR (95% CI): 2.603 (1.054 7.111); p = 0.041) were found to be significant predictors of BCN on postmortem renal biopsy. Conclusion: BCN was found in 72.1% of patients with ACLF and 27.4% patients with decompensated cirrhosis who had been hospitalized with an admitting diagnosis of HRS-AKI and who expired during that hospitalization and underwent postmortem renal biopsy. Direct serum bilirubin and presence of ACLF were found to be significant predictors of BCN on postmortem renal biopsy. PMID- 28660147 TI - Effectiveness of Ledipasvir/Sofosbuvir with/without Ribavarin in Liver Transplant Recipients with Hepatitis C. AB - Background and Aims: Recurrent infection of hepatitis C virus (HCV) in liver transplant (LT) recipients is universal and associated with significant morbidity and mortality. Methods: We retrospectively evaluated the safety and efficacy of ledipasvir/sofosbuvir with and without ribavirin in LT recipients with recurrent genotype 1 hepatitis C. Results: Eighty-five LT recipients were treated for recurrent HCV with ledipasvir/sofosbuvirwith and without ribavirin for 12 or 24 weeks. The mean (+/- standard deviation [SD]) time from LT to treatment initiation was 68 (+/-71) months. The mean (+/- SD) age of the cohort was 63 (+/ 8.6) years old. Most recipients were male (70%). Baseline alanine transaminase, total bilirubin, and HCV ribonucleic acid (RNA) values (+/- SD) were 76.8 (+/ 126) mg/dL, 0.8 (+/-1.3) U/L, and 8,010,421.9 (+/-12,420,985) IU/mL, respectively. Five of 43 recipients who were treated with ribavirin required drug cessation due to side effects, with 4 of those being anemia complications. No recipient discontinued the ledipasvir/sofosbuvir. Eighty-one percent of recipients had undetectable viral levels at 4 weeks after starting therapy, and all recipients had complete viral suppression at the end of therapy. The sustained viral response at 12 weeks after completion of therapy was 94%. Conclusion : Ledipasvir and sofosbuvir with and without ribavirin therapy is an effective and well-tolerated interferon-free treatment for recurrent HCV infection after LT. Anemia is not uncommon in LT recipients receiving ribavirin. PMID- 28660148 TI - Evaluation of Biomarkers in Egyptian Patients with Different Grades of Nonalcoholic Fatty Liver Disease. AB - Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a silent disease; its spectrum includes simple steatosis, nonalcoholic steatohepatitis and fibrosis. Pro- and anti-inflammatory cytokines play roles in the pathogenesis of NAFLD and insulin resistance (IR). Moreover, plasma cell antigen-1 (PC-1) is related to IR and associated with NAFLD progression. Therefore, we aimed to detect biomarkers, ultrasonographic and anthropometric findings capable of differentiating NAFLD grades, since most previous investigators were concerned more with NAFLD patients without classifying them into grades. Methods: A total of 87 NAFLD patients (31 with grade 1 (mild NAFLD), 26 with grade 2 (moderate NAFLD) and 30 with grade 3 (severe NAFLD) were included in the study, in addition to 47 controls (grade 0). All subjects underwent ultrasonographic examination for NAFLD diagnosis. Serum interleukin-10 (IL-10), plasma interleukin-18 (IL-18) and plasma PC-1 levels were determined using enzyme-linked immunosorbent assay. Results: Homoeostasis model assessment (HOMA)-IR was higher in different NAFLD grades than in controls. Ultrasonographic and anthropometric findings and lipid profile indices (except for high-density lipoprotein cholesterol, which was decreased) were increased with NAFLD progression. Grade 3 patients showed significant increase in levels of IL-18 and significant decrease in IL-10 and PC 1 levels when compared to grade 1 patients. Conclusion: Anthropometric and ultrasonographic findings were valuable in differentiating NAFLD grades. IR is very important in NAFLD pathogenesis. IL-18, HOMA-index and PC-1 levels could be used to differentiate between NAFLD grades, together with other measurements. PMID- 28660149 TI - Mechanisms and Prevention of Vertical Transmission in Chronic Viral Hepatitis. AB - Vertical transmission (VT) is the primary route of transmission of viral hepatitis in children. The rate of VT ranges from 1-28% with hepatitis B virus (HBV) and 3-15% with hepatitis C virus (HCV). VT for both viruses can occur during the intrauterine or peripartum period. VT of HBV primarily occurs by intrauterine transmission (IUT). Hepatitis B surface antigen is unable to cross the placenta and, therefore, relies on processes like transplacental leakage, placental infection, cellular transmission by peripheral blood mononuclear cells, and germline transmission. HCV can also infect the fetus by IUT. Both viruses also have the potential for transmission during delivery, when there is increase chance of maternal-fetal blood exposure. HBV and HCV share some common risk factors for VT, including maternal viral load, human immunodeficiency virus co infection and neonatal sex. Prevention of VT differs greatly between HBV and HCV. There are several alternatives for prevention of HBV VT, including antiviral medications during the third trimester of pregnancy and HBV vaccine, as well as hepatitis B immunoglobulin administration to infants post-partum. In contrast, there are no preventative interventions available for HCV. Despite these differences, the key to prevention with both viruses is screening women prior to and during pregnancy. PMID- 28660150 TI - Expanding Treatment Access for Chronic Hepatitis C with Task-shifting in the Era of Direct-acting Antivirals. AB - In the United States, the fight to eradicate hepatitis C virus (HCV) infection has been ongoing for many years, but the results have been less than ideal. Historically, patients with chronic hepatitis C (CHC) were treated with interferon-based regimens, which were associated with frequent adverse effects, suboptimal response rates, and long durations of treatment - of up to 48 weeks. Expertise from specialist-physicians, such as hepatologists and gastroenterologists, was needed to closely follow patients on these medications so as to monitor laboratory values and manage adverse effects. However, the emergence of direct-acting antiviral (DAA) agents against HCV infection have heralded outstanding progress in terms of safety, tolerability, lack of adverse effects, efficacy, and truncated duration of therapy - 12 weeks or less - thereby making the need for close monitoring by specialist-physicians obsolete. With the recent approval of DAA agents by the Food and Drug Administration, the treatment model for CHC no longer relies on the limited number of specialist-physicians, which represented a major barrier to treatment access in the past, especially in underserved areas of the United States. We propose and share our experiences in adapting a task-shifting treatment model, one that utilizes a relatively larger pool of non-specialist healthcare providers, such as nursing staff (medical assistants, vocational licensed nurses, registered nurses, etc.) and advanced practice providers (nurse practitioners and physician assistants), to perform a variety of important clinical functions in an effort to make DAA-based antiviral therapy widely available against HCV infection. Most recently, task-shifting was implemented by the United States and World Health Organization in the fight against the human immunodeficiency virus and showed encouraging results. Based on our experiences in implementing this model at our outreach clinics, the majority of HCV-infected patients treated with DAA agents can be easily monitored by non specialist healthcare providers and physician extenders. Task-shifting can effectively address one of the major rate-limiting factors in expanding treatment access for HCV infection. PMID- 28660151 TI - Nonalcoholic Fatty Liver Disease (NAFLD) and Risk of Cardiac Arrhythmias: A New Aspect of the Liver-heart Axis. AB - Nonalcoholic fatty liver disease (NAFLD) is a pathologic condition frequently observed in clinical practice. To date, the prevalence of NAFLD is approximately 25-30% among adults of the general population in Western countries but increases to approximately 70-75% among patients with type 2 diabetes mellitus. In the last decade, accumulating evidence has clearly demonstrated that patients with NAFLD have not only an increased liver-related morbidity and mortality but also an increased risk of fatal and non-fatal cardiovascular events. In particular, several studies have documented the existence of an independent association among NAFLD and cardiac changes in structure and function in both non-diabetic and diabetic patients. In addition, mounting evidence also suggests that there is a strong relationship between NAFLD and cardiac arrhythmias, such as atrial fibrillation, QTc prolongation and ventricular arrhythmias. This is of clinical interest, as it could explain, at least in part, the increased risk of death for cardiovascular disease in patients with NAFLD. Therefore, seeing that cardiovascular disease complications are the leading cause of disability and death in NAFLD patients, the recent European clinical practice guidelines advised to check the cardiovascular system in all patients with NAFLD. This clinical mini review will briefly describe the increasing body of evidence regarding the association between NAFLD and cardiac arrhythmias, and discuss the potential biological mechanisms underlying this association. PMID- 28660152 TI - Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. AB - Hepatic encephalopathy is a spectrum of reversible neuropsychiatric abnormalities, seen in patients with liver dysfunction and/or portosystemic shunting. One of the most debilitating complications of cirrhosis, encephalopathy affects 30-45% of cirrhotics. In addition to significantly affecting the lives of patients and their caregivers, it is also associated with increased morbidity and mortality as well as significant utilization of health care resources. In this paper, we provide an overview on the pathophysiology, diagnosis, management and newer therapies of hepatic encephalopathy. PMID- 28660153 TI - Vascular Diseases of the Spleen: A Review. AB - Vascular diseases of the spleen are relatively uncommon in the clinical practice. However, the reported incidence has been progressively increasing, probably due to advances in the imaging modalities used to detect them. This disease condition often presents with non-specific clinical manifestations, but can be associated with significant morbidity and mortality. This review article aims to provide updated clinical information on the different vascular diseases of the splenic vasculature-splenic vein thrombosis, splenic vein aneurysm, splenic artery aneurysm, splenic arteriovenous fistula, and spontaneous splenorenal shunt-in order to aid clinicians in early diagnosis and management. PMID- 28660154 TI - The Number of Positive Tumor Marker Status Is Beneficial for the Selection of Therapeutic Modalities in Patients with Hepatocellular Carcinoma. AB - Hepatic resection (HR) and radiofrequency ablation (RFA) are popular local therapies for early-stage hepatocellular carcinoma (HCC). Alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-c-carboxy prothrombin are well-known and useful tumor markers for HCC. The positive number status of these tumor markers has recently been demonstrated as beneficial for predicting outcome for HCC patients treated with local therapy. Although the normal ranges reported have differed by institution, the positivity of tumor markers is consistent and can easily be assessed. Kumamoto and Wakayama's group clearly demonstrated the following: 1) Regardless of the degree of tumor stage, a triple-positive tumor marker profile can predict poor outcome in HCC patients undergoing HR; 2) For RFA alone, HCC patients with double- and triple-positive status, having less than three lesions and lesions <=3 cm in diameter show comparably insufficient outcomes; 3) For HCC patients with lesions <=5 cm in Child-Pugh grade A, HR is preferred over RFA; 4) Microvascular invasion rates increased even in the double-positive patients, while poorly differentiated HCC was frequently observed only in the triple-positive patients; and 5) RFA with chemoembolization, anatomical liver resection, and postoperative adjuvant chemoembolization or hepatic arterial chemotherapy might improve the outcome for patients with highly malignant HCC with multiple positive tumor markers. However, the impacts of these therapies still need to be evaluated in prospective comparative studies. PMID- 28660157 TI - Comment on 'Ascitic Fluid Analysis in the Differential Diagnosis of Ascites: Focus on Cirrhotic Ascites'. PMID- 28660155 TI - New Evidence and Perspectives on the Management of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. AB - Portal vein tumor thrombosis (PVTT) is an intractable condition but common phenomenon in hepatocellular carcinoma (HCC). HCC patients with PVTT may have worse liver function, a higher chance of comorbidity related to portal hypertension, lower tolerance to treatment and poorer prognoses. In Western guidelines, patients are offered palliative treatment with sorafenib or other systemic agents because HCC with PVTT is grouped together with metastatic HCC during the planning of its management. In recent years, various treatment options have become available for patients with HCC and PVTT. Therapy has also shifted toward evidence-based treatment. However, policies for the management of HCC with PVTT have not been established. This comprehensive literature review aims to present current and available management options for patients with HCC and PVTT. Evidence is mainly based on studies published after 2010. PMID- 28660158 TI - What's New in Critical Illness and Injury Science? We must lead by hope.... PMID- 28660156 TI - A Review of Non-operative Treatments for Hepatocellular Carcinoma with Advanced Portal Vein Tumor Thrombus. AB - Portal vein tumor thrombus (PVTT) frequently occurs with the progression of hepatocellular carcinoma (HCC) and is an important factor in determining the prognosis of HCC. In many cases of HCC with advanced PVTT, treatment is difficult because the tumor has considerable extension into the liver, and portal hypertension is a frequent complication. The standard therapy for unresectable HCC with advanced PVTT is sorafenib therapy in patients with good hepatic function. However, the outcomes of sorafenib therapy are not completely satisfactory, making the development of another therapy an urgent task. Therefore, this review aims to summarize non-operative treatments for HCC with advanced PVTT and discuss future perspectives based on those therapies, including therapies still being developed. PMID- 28660159 TI - Opioids as co-induction agents - the pros and cons. PMID- 28660160 TI - The 2017 Academic College of Emergency Experts and Academy of Family Physicians of India position statement on preventing violence against health-care workers and vandalization of health-care facilities in India. AB - There have been multiple incidents where doctors have been assaulted by patient relatives and hospital facilities have been vandalized. This has led to mass agitations by Physicians across India. Violence and vandalism against health-care workers (HCWs) is one of the biggest public health and patient care challenge in India. The sheer intensity of emotional hijack and the stress levels in both practicing HCWs and patient relative's needs immediate and detail attention. The suffering of HCWs who are hurt, the damage to hospital facilities and the reactionary agitation which affects patients who need care are all together doing everything to damage the delivery of health care and relationship between a doctor and a patient. This is detrimental to India where illnesses and Injuries continue to be the biggest challenge to its growth curve. The expert group set by The Academic College of Emergency Experts and The Academy of Family Physicians of India makes an effort to study this Public Health and Patient Care Challenge and provide recommendations to solve it. PMID- 28660161 TI - Posttraumatic stress disorder after myocardial infarction and coronary artery bypass grafting. AB - Post traumatic stress disorder is a psychiatric disease that is usually precipitated by life threatening stressors. Myocardial infarction, especially in the young can count as one such event. The development of post traumatic stress after a coronary event not only adversely effects psychiatric health, but leads to increased cardiovascular morbidity and mortality. There is increasing evidence that like major depression, post traumatic stress disorder is also a strong coronary risk factor. Early diagnosis and treatment of this disease in patients with acute manifestations of coronary artery disease can improve patient outcomes. PMID- 28660162 TI - Keys to successful organ procurement: An experience-based review of clinical practices at a high-performing health-care organization. AB - Organ procurement (OP) from donors after brain death and circulatory death represents the primary source of transplanted organs. Despite favorable laws and regulations, OP continues to face challenges for a number of reasons, including institutional, personal, and societal barriers. This focused review presents some of the key components of a successful OP program at a large, high-performing regional health network. This review focuses on effective team approaches, aggressive resuscitative strategies, optimal communication, family support, and community outreach efforts. PMID- 28660163 TI - Effective environmental factors on geographical distribution of traffic accidents on pedestrians, downtown Tehran city. AB - INTRODUCTION: In most countries, occurrence of traffic causalities is high in pedestrians. The aim of this study is to geographically analyze the traffic casualties in pedestrians in downtown Tehran city. METHODS: The study population consisted of traffic injury accidents in pedestrians occurred during 2015 in Tehran city. Data were extracted from offices of traffic police and municipality. For analysis of environmental factors and site of accidents, ordinary least square regression models and geographically weighted regression were used. Fitness and performance of models were checked using the Akaike information criteria, Bayesian information criteria, deviance, and adjusted R2. RESULTS: Totally, 514 accidents were included in this study. Of them, site of accidents was arterial streets in 370 (71.9%) cases, collector streets in 133 cases (25.2%), and highways in 11 cases (2.1%). Geographical units of traffic accidents in pedestrians had statistically significant relationship with a number of bus stations, number of crossroads, and recreational areas. CONCLUSION: Distribution of injury traffic accidents in pedestrians is different in downtown Tehran city. Neighborhoods close to markets are considered as most dangerous neighborhoods for injury traffic accidents. Different environmental factors are involved in determining the distribution of these accidents. The health of pedestrians in Tehran city can be improved by proper traffic management, control of environmental factors, and educational programs. PMID- 28660164 TI - Epidemiology of trauma victims admitted to a level 2 trauma center of North India. AB - BACKGROUND: Good quality information on characteristics of victims, types, and frequency of injuries, causes of accidents, vehicles involved in injury and outcome is essential for understanding and planning required for managing the trauma epidemic. The objective of this study was to describe the characteristics of trauma victims admitted to King George's Medical University trauma center. METHODS: This observational study enrolled trauma victims over a 1-year period. Characteristics recorded were age, sex, systolic blood pressure at admission, respiratory rate at admission, Glasgow Coma Scale (GCS) score at the time of admission, time since injury to admission, referral, specific injury, Injury Severity Score (ISS), chronic medical condition, mechanism of injury, and the regions involved. Outcome at the end of hospital stay was recorded. RESULTS: A total of 3280 injuries were recorded in 2288 patients. Mean age 40.81 +/- 16.3 years, predominantly male (83.57%), mean ISS 12.56 +/- 7.3, mean GCS 12.20 +/- 4.1. Mean time to admission (hospitalization) to trauma center was 54.22 +/- 185.2 h. Head was the most commonly involved region (32.44%). Patients referred from peripheral hospitals had significantly lower GCS, higher time to admission to trauma center, and longer duration of hospital stay. Road traffic accidents were responsible for 1514 (66.40%) injuries. Five hundred and ten (22.37%) patients sustained injury due to a fall. Three hundred and ninety (68.59%) patients were discharged, 67 (11.69%) left the hospital against medical advice, 8 absconded from the trauma center, and 104 expired within the hospital. CONCLUSION: Traumatic brain injuries and orthopedic injuries constitute a majority of injured admitted to the trauma center. Motorcycle collision with other vehicles and pedestrian hits by other vehicles are the most common causes of traumatic brain injuries. In contrast to west, the most common cause of spinal cord injury was falls. Pedestrians, bicyclists, and motorcyclists are the vulnerable road users. Long time to admission is an alarming finding. PMID- 28660165 TI - The Incidence of hypotension with continuous infusion atracurium compared to cisatracurium in the Intensive Care Unit. AB - BACKGROUND: A drug shortage of cisatracurium led to use of atracurium as an alternative neuromuscular blocker (NMB). Cisatracurium may be preferred due to less histamine release and potentially less hypotension. The study purpose is to compare the incidence of hypotension with continuous infusion atracurium to continuous infusion cisatracurium in ICU patients. MATERIALS AND METHODS: This retrospective cohort analysis reviewed 119 ICU patients who received either continuous infusion atracurium (56) or cisatracurium (63). The primary outcome was the incidence of hypotension (mean arterial pressure <60mmHg). Secondary outcomes included: incidence of blood pressure decrease of >20% from baseline, time to first hypotensive episode, treatment for hypotension during NMB use, hospital mortality, ICU and hospital length of stay (LOS), duration of mechanical ventilation (MV), and NMB duration. RESULTS: Hypotension occurred in 64.3% of atracurium patients and 58.7% of cisatracurium patients (P = 0.58), with 60.7% experiencing >20% drop in blood pressure in atracurium group and 54.0% in cisatracurium (P = 0.58). Median time to first hypotensive episode was 9.4[Interquartile range 1.17-19.7] hours atracurium and 4.4[1.5-13.9] hours cisatracurium (P = 0.36). There were no differences between atracurium and cisatracurium groups respectively for median ICU LOS (10.5 days and 12.4 days, P = 0.34), hospital LOS (14.0 days and 17.7 days, P = 0.37), MV duration (9.3 days and 10.5 days, P = 0.43), infusion duration (34.5 hours and 25 hours P = 0.27), or hospital mortality (62.5% and 53.9%, P = 0.336). Hypotension treatment was similar between groups. CONCLUSIONS: The incidence of hypotension was similar between atracurium and cisatracurium. Critical drug shortages may provide an opportunity to study alternative drug therapy. PMID- 28660166 TI - Neuroleptic malignant syndrome in the trauma intensive care unit: Diagnosis and management of a rare disease in a challenging population. AB - Neuroleptic malignant syndrome (NMS) is a life-threatening neurological disorder associated with the use of antipsychotic medications. Many of its classic signs, such as fever and altered mental status, are nonspecific in trauma intensive care unit (ICU) patients, and its rarity makes it a difficult diagnosis in this population. However, delays in treatment can be costly both in terms of hospital resources and patient outcomes. We herein report a case of a 54-year-old trauma patient with NMS precipitated by a combination of cocaine withdrawal and neuroleptic medications. Few cases of NMS in the intubated polytrauma patient have been described in the literature previously. Given the poor outcomes associated with this disorder, ICU patients would benefit from risk stratification and avoidance of neuroleptic medications in those at highest risk for NMS, particularly patients who are withdrawing from dopaminergic agents. PMID- 28660167 TI - Tissue plasminogen activator and pulmozyme for postoperative-retained hemothorax: A safe alternative to postoperative re-exploration. AB - Successful treatment of traumatic hemothoraces is imperative to reduce morbidity and mortality among patients. Treatment modalities range from more conservative to invasive measures, including antibiotic therapy, thoracostomy tube placement, video-assisted thoracoscopic surgery, or thoracotomy. Various studies have documented success in using fibrinolytics such as tissue plasminogen activator (tPA) in conjunction with deoxyribonuclease administered through a chest tube to resolve a hemothorax. The optimal dose and frequency of fibrinolytic therapy have not yet been determined although most studies report administering therapy two times a day for 3 days. We report a successful case of a one-time dose of fibrinolytic therapy through thoracostomy tube which could support that a single dose may be ideal and sufficient enough to resolve a hemothorax. We also performed this in the acute postoperative period, which has not been well studied, and believe fibrinolytic therapy can be safe to use in this setting. PMID- 28660168 TI - Spontaneous intraventricular rupture of a craniopharyngioma cyst: A case report. AB - Intraventricular rupture of craniopharyngioma cysts is an unusual event which is associated with a high risk of loculated or communicating hydrocephalus. A 75 year-old woman presented at the Emergency Department of our hospital with mental status deterioration due to chemical ventriculitis and acute hydrocephalus following the intraventricular rupture of a craniopharyngioma cyst. The patient was treated with stress-dose steroid therapy. In addition, she underwent placement of an external ventricular drain and endoscopy-assisted intra-cystic placement of an Ommaya reservoir for the aspiration of the cystic fluid. The patient's condition improved; she was shunted in an expeditious fashion and discharged from the Intensive Care Unit within 2 weeks of her admission with the reservoir in place for the continued drainage of the cyst. PMID- 28660169 TI - Distribution of shock index and age shock index score among trauma patients in India. PMID- 28660170 TI - Low Grade Neuroendocrine Tumors of the Lung. AB - The lung is the second most common site of neuroendocrine tumors (NETs). Typical and atypical carcinoids are low-grade NETs of the lung. They present a favorable prognosis comported to the more common high-grade NETs. The low- and high-grade NETs require different treatment strategies; effective management of these tumors is essential to prolong survival and to manage the symptoms in patients with secretory or functional tumors. These rare tumors have received little attention and education is needed for treating physicians. This mini-review will concentrate mainly on advanced low-grade lung NETs. The article describes the classification of lung NETs and the diagnostic work-up. Different treatment methods including somatostatin analogs, peptide receptor radioligand therapy, and biologic systemic therapy are discussed. Promising results from recent trials are presented and discussed in the context of the lung primary site. PMID- 28660171 TI - The Feasibility and Safety of Surgery in Patients Receiving Immune Checkpoint Inhibitors: A Retrospective Study. AB - Immune checkpoint inhibitors (ICI) are revolutionizing care for cancer patients. The list of malignancies for which the Food and Drug Administration is granting approval is rapidly increasing. Furthermore, there is a concomitant increase in clinical trials incorporating ICI. However, the safety of ICI in patients undergoing surgery remains unclear. Herein, we assessed the safety of ICI in the perioperative setting at a single center. We conducted a retrospective review of patients who underwent planned surgery while receiving ICI in the perioperative setting from 2012 to 2016. We collected 30-day postoperative morbidity and mortality utilizing the Clavien-Dindo classification system. We identified 17 patients who received perioperative ICI in 22 operations. Patients were diagnosed with melanoma (n = 14), renal cell carcinoma (n = 2), and urothelial carcinoma (n = 1). Therapies included pembrolizumab (n = 10), ipilimumab (n = 5), atezolizumab (n = 5), and ipilimumab/nivolumab (n = 2). Procedures included cutaneous/subcutaneous resection (n = 6), lymph node resection (n = 5), small bowel resection (n = 5), abdominal wall resection (n = 3), other abdominal surgery (n = 3), orthopedic surgery (n = 1), hepatic resection (n = 1), and neurosurgery (n = 2). There were no Grade III-IV Clavien-Dindo complications. There was one death secondary to ventricular fibrillation in the setting of coronary artery disease. ICI appear safe in the perioperative setting, involving multiple different types of surgery, and likely do not need to be stopped in the perioperative setting. Further studies are warranted to confirm these findings. PMID- 28660172 TI - Pineal Region Glioblastoma, a Case Report and Literature Review. AB - INTRODUCTION: Pineal region glioblastoma multiforme (GBM) is a rare disease entity with a generally poor prognosis. We present a case of a patient with an unresectable pineal region GBM treated with chemoradiation with favorable outcome. CASE BACKGROUND: A 65-year-old patient who was presented with visual symptoms was found to have a pineal region tumor on imaging. A stereotactic biopsy showed a World Health Organization Grade IV GBM, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, isocitrate dehydrogenase 1 and 2 wild type. The patient was treated with radiotherapy with concurrent temozolomide, followed by adjuvant temozolomide. Disease progression occurred at 58 weeks post-biopsy, which prompted the initiation of bevacizumab. The patient was alive and functioning well as of his last follow up, 166 weeks from the initial biopsy. DISCUSSION: On our review of the literature, 24 cases of pineal region GBM have been reported. The median reported survival for these previously reported cases was 6 months (range, 2-24 months). This patient has the longest overall survival reported to date for a patient with this diagnosis. This is the first patient in the literature with pineal region GBM who has been reported to have MGMT promoter methylation. CONCLUDING REMARKS: Although pineal region GBM is a rare disease entity with a generally poor prognosis, long-term survival is achievable for select patients. MGMT promoter methylation may potentially have prognostic value. Favorable control of recurrent disease with the use of bevacizumab is possible. PMID- 28660173 TI - Evaluating Post-Radiotherapy Laryngeal Function with Laryngeal Videostroboscopy in Early Stage Glottic Cancer. AB - OBJECTIVE: Dysphonia is common among patients with early stage glottic cancer. Laryngeal videostroboscopy (LVS) has not been routinely used to assess post radiotherapy (RT) voice changes. We hypothesized that LVS would demonstrate improvement in laryngeal function after definitive RT for early-stage glottic cancer. STUDY DESIGN: Blinded retrospective review of perceptual voice and stroboscopic parameters for patients with early glottic cancer and controls. SETTING: High-volume, single-institution academic medical center. SUBJECTS AND METHODS: Fifteen patients underwent RT for Tis-T2N0M0 glottic cancer and were evaluated with serial LVS exams pre- and post-RT. Stroboscopic assessment included six parameters: vocal fold (VF) vibration, VF mobility, erythema/edema, supraglottic compression, glottic closure, and secretions. Grade, roughness, breathiness, asthenia, strain (GRBAS) voice perceptual scale was graded in tandem with LVS score. Assessments were grouped by time interval from RT: pre-RT, 0-4, 4 12, and >12 months post-RT. RESULTS: 60 LVS exams and corresponding GRBAS assessments were reviewed. There were significant improvements in ipsilateral VF motion (P = 0.03) and vibration (P = 0.001) and significant worsening in contralateral VF motion (P < 0.001) and vibration (P = 0.008) at >12 months post RT. Glottic closure significantly worsened, most prominent >12 months post-RT (P = 0.01). Composite GRBAS scores were significantly improved across all post-RT intervals. CONCLUSION: LVS proved to be a robust tool for assessing pre- and post RT laryngeal function. We observed post-RT improvement in ipsilateral VF function, a decline in contralateral VF function, and decreased glottic closure. These results demonstrate that LVS can detect meaningful changes in VF and glottic function and support its use for post-RT evaluation of glottic cancer patients. PMID- 28660174 TI - Parasite Carbohydrate Vaccines. AB - Vaccination is an efficient means of combating infectious disease burden globally. However, routine vaccines for the world's major human parasitic diseases do not yet exist. Vaccines based on carbohydrate antigens are a viable option for parasite vaccine development, given the proven success of carbohydrate vaccines to combat bacterial infections. We will review the key components of carbohydrate vaccines that have remained largely consistent since their inception, and the success of bacterial carbohydrate vaccines. We will then explore the latest developments for both traditional and non-traditional carbohydrate vaccine approaches for three of the world's major protozoan parasitic diseases-malaria, toxoplasmosis, and leishmaniasis. The traditional prophylactic carbohydrate vaccine strategy is being explored for malaria. However, given that parasite disease biology is complex and often arises from host immune responses to parasite antigens, carbohydrate vaccines against deleterious immune responses in host-parasite interactions are also being explored. In particular, the highly abundant glycosylphosphatidylinositol molecules specific for Plasmodium, Toxoplasma, and Leishmania spp. are considered exploitable antigens for this non-traditional vaccine approach. Discussion will revolve around the application of these protozoan carbohydrate antigens for vaccines currently in preclinical development. PMID- 28660177 TI - An Evaluation of the Online Universal Programme COPING Parent: A Feasibility Study. AB - BACKGROUND: COPING parent (Confident Parent Internet Guide) is an online universal parenting programme designed for parents of children aged 3-8 who are interested in learning positive parenting strategies to address everyday parenting challenges. Most people now have access to the internet and many parents seek online parenting advice, so it is important to ensure that advice is both evidence-based and freely available. The 10-week online COPING parent programme presents information and activities based on core social learning theory principles. The programme provides information and video examples of parenting skills, uses quizzes to test knowledge and suggests home practice activities. This study was undertaken to obtain feedback on the usefulness and acceptability of the programme to inform its further development. DESIGN AND METHODS: The programme was created using the LifeGuide software and participants (n=20) were asked to complete one chapter of the programme each week and provide feedback. This feasibility study was undertaken to highlight any technical issues and suggest modifications prior to a more rigorous evaluation. RESULTS: Both participant feedback and programme usage data are reported. Thirteen feedback forms were returned and programme usage data was downloaded for all participants. Feedback suggested modifications that included adaptations to enable the programme to be accessed by tablet users, an option to look back over previously completed chapters, the inclusion of more video examples of positive parenting and text message prompting to address attrition challenges. PMID- 28660175 TI - Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response. AB - Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting pigs, cattle and other domestic, and wild animals worldwide. The aim of the host interferon (IFN) response is to limit viral replication and spread. Detection of the viral genome and products by specialized cellular sensors initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I- and type III-IFNs and other antiviral cytokines with antiproliferative and immunomodulatory functions. During co evolution with their hosts, viruses have acquired strategies to actively counteract host antiviral responses and the balance between innate response and viral antagonism may determine the outcome of disease and pathogenesis. FMDV proteases Lpro and 3C have been found to antagonize the host IFN response by a repertoire of mechanisms. Moreover, the putative role of other viral proteins in IFN antagonism is being recently unveiled, uncovering sophisticated immune evasion strategies different to those reported to date for other members of the Picornaviridae family. Here, we review the interplay between antiviral responses induced by FMDV infection and viral countermeasures to block them. Research on strategies used by viruses to modulate immunity will provide insights into the function of host pathways involved in defense against pathogens and will also lead to development of new therapeutic strategies to fight virus infections. PMID- 28660176 TI - Chlamydia trachomatis Infection Is Associated with E-Cadherin Promoter Methylation, Downregulation of E-Cadherin Expression, and Increased Expression of Fibronectin and alpha-SMA-Implications for Epithelial-Mesenchymal Transition. AB - Chlamydia trachomatis (Ct) can induce scarring disease of the ocular mucosa, known as trachoma, the most common infectious cause of blindness worldwide. We hypothesized that epithelial-mesenchymal transition (EMT) contributes to the fibrotic process in trachomatous scarring. Infection of human conjunctival epithelial cells (HCjE) with Ct activated signaling pathways involved in EMT induction, which was correlated with decreased expression of E-cadherin, guardian of the epithelial phenotype. In addition, Ct infection was associated with increased expression of two mesenchymal cell markers: fibronectin and alpha-SMA. The DNA methylation statuses of selected regions of E-cadherin, fibronectin, and alpha-SMA genes revealed that Ct infection was accompanied with changes in DNA methylation of the E-cadherin promoter, while the expression of the two mesenchymal markers was not related with this epigenetic event. Our data suggest that Ct infection of conjunctival epithelial cells induces EMT-like changes that go along with modification of the methylation profile of the E-cadherin promoter and could, as one of the earliest events, contribute to processes triggering conjunctival scarring. PMID- 28660178 TI - Clinical Laboratory Automation: A Case Study. AB - BACKGROUND: This paper presents a case study of an automated clinical laboratory in a large urban academic teaching hospital in the North of Italy, the Spedali Civili in Brescia, where four laboratories were merged in a unique laboratory through the introduction of laboratory automation. MATERIALS AND METHODS: The analysis compares the preautomation situation and the new setting from a cost perspective, by considering direct and indirect costs. It also presents an analysis of the turnaround time (TAT). The study considers equipment, staff and indirect costs. RESULTS: The introduction of automation led to a slight increase in equipment costs which is highly compensated by a remarkable decrease in staff costs. Consequently, total costs decreased by 12.55%. The analysis of the TAT shows an improvement of nonemergency exams while emergency exams are still validated within the maximum time imposed by the hospital. CONCLUSIONS: The strategy adopted by the management, which was based on re-using the available equipment and staff when merging the pre-existing laboratories, has reached its goal: introducing automation while minimizing the costs. PMID- 28660180 TI - Constructing a Global Learning Partnership in Physiotherapy: An Ireland-Uganda Initiative. AB - BACKGROUND AND AIM: There is a strong correlation between disability and poverty and it is acknowledged that until disability issues are addressed, the goal of poverty reduction in low-income countries is unlikely to be achieved. Despite the high prevalence of disability in developing countries, there remains a significant shortage of rehabilitation professionals as highlighted by the WHO report, Human resources for Health (2006). The purpose of this project was to develop a collaborative and sustainable partnership to strengthen educational and research capacity in global health, disability, and rehabilitation between two physiotherapy schools; University College Dublin, Ireland, and Mbarara University of Science and Technology, Uganda. This article aims to describe the approach used and initial project outcomes. METHODS: This project involved a bilateral visit to both institutions by two members of staff of respective physiotherapy programs. These visits entailed stakeholder meetings, clinical site visits, and workshops to identify the priorities for the partnership and shape the collaboration going forward. Appreciative inquiry methodology was used during the workshops and the four-dimensional framework for curriculum development was used to guide analysis and underpin findings. FINDINGS: The key priorities identified were (i) development of joint global health learning initiative, (ii) to explore the possibility of postgraduate learning and research opportunities for Ugandan colleagues, and (iii) to develop joint clinical placements. The rationale and context and a plan of action is described. DISCUSSION AND CONCLUSION: The project is ambitious and in order to be sustainable, the importance of long-term interinstitutional commitment and further funding cannot be ignored. This work provides a framework for other universities and institutions wishing to undertake similar activities. Such partnerships provide rich learning opportunities for students and health professionals and facilitate a deeper understanding of global health issues, social and cultural health determinants, and development of enhanced professional skills. PMID- 28660179 TI - Monitoring Cerebral and Renal Oxygenation Status during Neonatal Digestive Surgeries Using Near Infrared Spectroscopy. AB - BACKGROUND: Depending on the initial pathology, hypovolemia, intra-abdominal hypertension, and sepsis are often encountered in neonatal digestive surgery. Accurate newborn monitoring during and after surgery is essential to adapt resuscitation protocols. Near infrared spectroscopy (NIRS) is non-invasive and can detect hypoperfusion which indicates a low circulatory blood flow, regardless of the cause. OBJECTIVE: Evaluating changes in cerebral and renal regional oxygen saturation during neonatal digestive surgeries, conducted according to normal practices, with commonly used monitoring parameters. Analyzing retrospectively the inter-relationships between NIRS values and mean arterial pressure (MAP) values as well as pre-ductal SpO2. METHODS: Prospective, descriptive, monocentric study. All neonates referred for surgery were included. NIRS allows the measurement of cerebral and renal oxygenation fluctuations, as well as calculating difference in intraoperative and postoperative values. RESULTS: Nineteen patients were included. Cerebral regional oxygen saturation (C rSO2) values were stable while renal regional oxygen saturation (R rSO2) values tended to decrease with time during surgery. Indeed, 72% of rSO2 decline episodes occurred after the first 30 min of surgery, without any significant statistical differences for the next 90 min of surgery. After surgery, the lowest average C and R rSO2 values were evidenced during the first 6 h, with 60% of C rSO2 and R rSO2 anomalies occurring in that time frame. There was no significant statistical difference observed in the following 18 h. There was a significant correlation between R rSO2 and SpO2 values (p < 0.01), but not with C rSO2 values. There was no correlation with the MAP either for the C rSO2 values or R rSO2 ones. CONCLUSION: NIRS is a promising non-invasive bedside tool to monitor cerebral and tissue perfusion, analyzing tissue microcirculation. NIRS has its interest to guide neonatal digestive surgeries (bowel manipulation, viscera reduction) and may represent an early warning for identifying patients requiring resuscitation during or after these surgeries. PMID- 28660181 TI - Psychosocial Challenges Associated with Caregiving in the Context of Pediatric HIV in Rural Eastern Cape. AB - BACKGROUND: While survival among human immunodeficiency virus (HIV)-infected children has increased due to combination antiretroviral therapy, many children remain vulnerable to the adverse effects of poverty and family disruptions as a result of the loss of one or both biological parents to acquired immunodeficiency syndrome. The aim of this qualitative study was to develop an understanding of the psychosocial challenges experienced by caregivers caring for a child with perinatally acquired HIV. METHOD: A series of interviews were conducted with 44 HIV-positive and -negative primary caregivers of HIV+ children. Data were analyzed through interpretative phenomenological analysis using NVivo8 software. FINDINGS: The findings suggest that caregiving is compromised by inadequate, financial resources and single-headed households where mainly grandparents assume the role of primary caregivers of HIV+ children. HIV remains a stigmatized illness that weakens support networks, as well as timeous and free accessibility to healthcare. This has a negative impact on the mental health of caregivers, with the majority of women in the study displaying symptoms of depression. CONCLUSION: The findings highlight the contextual challenges of caregiving in the presence of HIV, which impacts negatively on social ecology of the families. The need for interventions to enhance resilience and coping in families confronted with HIV is indicated. PMID- 28660182 TI - Research on the Translation and Implementation of Stepping On in Three Wisconsin Communities. AB - OBJECTIVE: Falls are a leading cause of injury death. Stepping On is a fall prevention program developed in Australia and shown to reduce falls by up to 31%. The original program was implemented in a community setting, by an occupational therapist, and included a home visit. The purpose of this study was to examine aspects of the translation and implementation of Stepping On in three community settings in Wisconsin. METHODS: The investigative team identified four research questions to understand the spread and use of the program, as well as to determine whether critical components of the program could be modified to maximize use in community practice. The team evaluated program uptake, participant reach, program feasibility, program acceptability, and program fidelity by varying the implementation setting and components of Stepping On. Implementation setting included type of host organization, rural versus urban location, health versus non-health background of leaders, and whether a phone call could replace the home visit. A mixed methodology of surveys and interviews completed by site managers, leaders, guest experts, participants, and content expert observations for program fidelity during classes was used. RESULTS: The study identified implementation challenges that varied by setting, including securing a physical therapist for the class and needing more time to recruit participants. There were no implementation differences between rural and urban locations. Potential differences emerged in program fidelity between health and non-health professional leaders, although fidelity was high overall with both. Home visits identified more home hazards than did phone calls and were perceived as of greater benefit to participants, but at 1 year no differences were apparent in uptake of strategies discussed in home versus phone visits. CONCLUSION: Adaptations to the program to increase implementation include using a leader who is a non-health professional, and omitting the home visit. Our research demonstrated that a non-health professional leader can conduct Stepping On with adequate fidelity, however non-health professional leaders may benefit from increased training in certain aspects of Stepping On. A phone call may be substituted for the home visit, although short-term benefits are greater with the home visit. PMID- 28660183 TI - Quantitative Lateral Flow Assays for Salivary Biomarker Assessment: A Review. AB - Saliva is an emerging biofluid with a significant number of applications in use across research and clinical settings. The present paper explores the reasons why saliva has grown in popularity in recent years, balancing both the potential strengths and weaknesses of this biofluid. Focusing on reasons why saliva is different from other common biological fluids such as blood, urine, or tears, we review how saliva is easily obtained, with minimal risk to the donor, and reduced costs for collection, transportation, and analysis. We then move on to a brief review of the history and progress in rapid salivary testing, again reviewing the strengths and weaknesses of rapid immunoassays (e.g., lateral flow immunoassay) compared to more traditional immunoassays. We consider the potential for saliva as an alternative biofluid in a setting where rapid results are important. We focus the review on salivary tests for small molecule biomarkers using cortisol as an example. Such salivary tests can be applied readily in a variety of settings and for specific measurement purposes, providing researchers and clinicians with opportunities to assess biomarkers in real time with lower transportation, collection, and analysis costs, faster turnaround time, and minimal training requirements. We conclude with a note of cautious optimism that the field will soon gain the ability to collect and analyze salivary specimens at any location and return viable results within minutes. PMID- 28660184 TI - Diabetes Screening and Prevention in a High-Risk, Medically Isolated Border Community. AB - INTRODUCTION: A project in a Texas border community setting, Prevention Organized against Diabetes and Dialysis with Education and Resources (POD2ER), offered diabetes prevention information, screening, and medical referrals. The setting was a large, longstanding flea market that functions as a shopping mall for low income people. The priority population included medically underserved urban and rural Mexican Americans. Components of the program addressed those with diabetes, prediabetes, and accompanying relatives and friends. BACKGROUND: People living in the Lower Rio Grande Valley (LRGV) face challenges of high rates of type 2 diabetes, lack of knowledge about prevention, and inadequate access to medical care. Recent statistics from actual community-wide screenings indicate a high diabetes prevalence, 30.7% among adults in the LRGV compared with 12.3% nationwide. METHODS: A diverse team composed of public health faculty, students, a physician, a community health worker, and community volunteers conceived and developed the project with a focus on cultural and economic congruence and a user friendly atmosphere. The program provided screening for prediabetes and diabetes with a hemoglobin A1c test. Screening was offered to those who were at least 25 years of age and not pregnant. When results indicated diabetes, a test for kidney damage was offered (urinary albumin-to-creatinine ratio). A medical appointment at a community clinic within a week was provided to those who tested positive for diabetes and lacked a medical home. Health education modules addressed all family members. DISCUSSION: The project was successful in recruiting 2,332 high-risk people in 26 months in a community setting, providing clinic referrals to those without a doctor, introducing them to treatment, and providing diabetes prevention information to all project participants. Implications for research and practice are highlighted. CONCLUSION: This study shows that a regular access point in a place frequented by large numbers of medically marginalized people in a program designed to eliminate cultural and economic barriers can succeed in providing a hard-to-reach community with diabetes prevention services. Aspects of this program can serve as a model for other service provision for similar populations and settings. PMID- 28660185 TI - Dedifferentiated Chondrocytes in Composite Microfibers As Tool for Cartilage Repair. AB - Tissue engineering (TE) approaches using biomaterials have gain important roles in the regeneration of cartilage. This paper describes the production by microfluidics of alginate-based microfibers containing both extracellular matrix (ECM)-derived biomaterials and chondrocytes. As ECM components gelatin or decellularized urinary bladder matrix (UBM) were investigated. The effectiveness of the composite microfibers has been tested to modulate the behavior and redifferentiation of dedifferentiated chondrocytes. The complete redifferentiation, at the single-cell level, of the chondrocytes, without cell aggregate formation, was observed after 14 days of cell culture. Specific chondrogenic markers and high cellular secretory activity was observed in embedded cells. Notably, no sign of collagen type 10 deposition was determined. The obtained data suggest that dedifferentiated chondrocytes regain a functional chondrocyte phenotype when embedded in appropriate 3D scaffold based on alginate plus gelatin or UBM. The proposed scaffolds are indeed valuable to form a cellular microenvironment mimicking the in vivo ECM, opening the way to their use in cartilage TE. PMID- 28660186 TI - Use of Imaging Techniques to Illuminate Dynamics of Hematopoietic Stem Cells and Their Niches. AB - Continuous generation of blood cells over an organism's lifetime is supported by hematopoietic stem/progenitor cells (HSPCs) capable of producing all hematopoietic cell subtypes. Adult mammalian HSPCs are localized to bone marrow and regulated by their neighboring microenvironment, or "niche." Because interactions of HSPCs with their niches are highly dynamic and complex, the recent development of imaging technologies provides a powerful new tool to understand stem cell/niche biology. In this review, we discuss recent advances in our understanding of dynamic HSPC/niche interactions during development, homeostasis, disease states or aging with a focus on studies advanced by imaging analysis. We also summarize methods to visualize HSPCs and niche cells in vivo, including use of HSPC reporter mice and chemical probes. Findings emerging from these investigations could suggest novel therapies for diseases and aging. PMID- 28660187 TI - Advancing Public Health Using Regulatory Science to Enhance Development and Regulation of Medical Products: Food and Drug Administration Research at the Center for Biologics Evaluation and Research. AB - Center for Biologics Evaluation and Research enhances and supports regulatory decision-making and policy development. This work contributes to our regulatory mission, advances medical product development, and supports Food and Drug Administration's regulatory response to public health crises. This review presents some examples of our diverse scientific work undertaken in recent years to support our regulatory and public health mission. PMID- 28660189 TI - Eosinophil Activation Status in Separate Compartments and Association with Asthma. AB - Asthma is frequently characterized by eosinophil-rich airway inflammation. Airway eosinophilia is associated with asthma exacerbations and likely plays a part in airway remodeling. Eosinophil recruitment from the bloodstream depends on circulating eosinophils becoming activated, which leads to eosinophil arrest on activated endothelium, extravasation, and continued movement through the bronchial tissue by interaction with the extracellular matrix (ECM). Circulating eosinophils can exist at different activation levels, which include non-activated or pre-activated (sensitized or "primed"). Further, the bloodstream may lack pre activated cells, due to such eosinophils having arrested on endothelium or extravasated into tissue. Increased expression, and in some instances, decreased expression of cell-surface proteins, including CD44, CD45, CD45R0, CD48, CD137, neuropeptide S receptor, cytokine receptors, Fc receptors, and integrins (receptors mediating cell adhesion and migration by interacting with ligands on other cells or in the ECM), and activated states of integrins or Fc receptors on blood eosinophils have been reported to correlate with aspects of asthma. A subset of these proteins has been reported to respond to intervention, e.g., with anti-interleukin (IL)-5. How these surface proteins and the activation state of the eosinophil respond to other interventions, e.g., with anti-IL-4 receptor alpha or anti-IL-13, is unknown. Eosinophil surface proteins suggested to be biomarkers of activation, particularly integrins, and reports on correlations between eosinophil activation and aspects of asthma are described in this review. Intermediate activation of beta1 and beta2 integrins on circulating eosinophils correlates with decreased pulmonary function, airway inflammation, or airway lumen eosinophils in non-severe asthma. The correlation does not appear in severe asthma, likely due to a higher degree of extravasation of pre-activated eosinophils in more severe disease. Bronchoalveolar lavage (BAL) eosinophils have highly activated integrins and other changes in surface proteins compared to blood eosinophils. The activation state of eosinophils in lung tissue, although likely very important in asthma, is largely unknown. However, some recent articles, mainly on mice but partly on human cells, indicate that tissue eosinophils may have a surface phenotype(s) different from that of sputum or BAL eosinophils. PMID- 28660190 TI - Commentary: Renal Function Estimation and Cockcroft-Gault Formulas for Predicting Cardiovascular Mortality in Population-Based, Cardiovascular Risk, Heart Failure and Post-Myocardial Infarction Cohorts: The Heart 'OMics' in AGEing (HOMAGE) and the High-Risk Myocardial Infarction Database Initiatives. PMID- 28660191 TI - The Therapeutic Role of Interleukin-1 Inhibition in Idiopathic Recurrent Pericarditis: Current Evidence and Future Challenges. AB - Recurrent pericarditis is a common complication of acute pericarditis (15-30%) for which, in most cases, no underlying etiology is found [idiopathic recurrent pericarditis (IRP)]. IRP is currently viewed as an autoinflammatory disease with characteristic recurrent episodes of sterile inflammation. According to the most recent Guidelines, the initial treatment regimen consists of a combination of aspirin or non-steroidal anti-inflammatory drugs with colchicine followed by the addition of corticosteroids in resistant or intolerant cases. Despite this treatment approach, a number of patients either do not respond or cannot tolerate the above therapies. For this refractory group, small case series and a recent randomized controlled trial have shown that interleukin-1 inhibition with anakinra is a rapidly acting, highly efficient, steroid-sparing, and safe therapeutic intervention. In this perspective, we discuss the available clinical evidence and our own clinical experience as well as the future prospects of this novel therapeutic approach for patients with IRP. PMID- 28660192 TI - Global Phosphorus Fertilizer Market and National Policies: A Case Study Revisiting the 2008 Price Peak. AB - The commodity market super-cycle and food price crisis have been associated with rampant food insecurity and the Arab spring. A multitude of factors were identified as culprits for excessive volatility on the commodity markets. However, as it regards fertilizers, a clear attribution of market drivers explaining the emergence of extreme price events is still missing. In this paper, we provide a quantitative assessment of the price spike of the global phosphorus fertilizer market in 2008 focusing on diammonium phosphate (DAP). We find that fertilizer market policies in India, the largest global importer of phosphorus fertilizers and phosphate rock, turned out to be a major contributor to the global price spike. India doubled its import of P-fertilizer in 2008 at a time when prices doubled. The analysis of a wide set of factors pertinent to the 2008 price spike in phosphorus fertilizer market leads us to the discovery of a price spike magnification and triggering mechanisms. We find that the price spike was magnified on the one hand by protective trade measures of fertilizer suppliers leading to a 19% drop in global phosphate fertilizer export. On the other hand, the Indian fertilizer subsidy scheme led to farmers not adjusting their demand for fertilizer. The triggering mechanism appeared to be the Indian production outage of P-fertilizer resulting in the additional import demand for DAP in size of about 20% of annual global supply. The main conclusion is that these three factors have jointly caused the spike, underscoring the need for ex ante improvements in fertilizer market regulation on both national and international levels. PMID- 28660188 TI - microRNA in Cardiovascular Aging and Age-Related Cardiovascular Diseases. AB - Over the last decades, life expectancy has significantly increased although several chronic diseases persist in the population, with aging as the leading risk factor. Despite improvements in diagnosis and treatment, many elderlies suffer from cardiovascular problems that are much more frequent in an older, more fragile organism. In the long term, age-related cardiovascular diseases (CVDs) contribute to the decline of quality of life and ability to perform normal activities of daily living. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level in both physiological and pathological conditions. In this review, we will focus on the role of miRNAs in aging and age-related CVDs as heart failure, hypertension, atherosclerosis, atrial fibrillation, and diabetes mellitus. miRNAs are key regulators of complex biological mechanisms, representing an exciting potential therapeutic target in CVDs. Moreover, one major challenge in geriatric medicine is to find reliable biomarkers for diagnosis, prognosis, and prediction of the response to specific drugs. miRNAs represent a very promising tool due to their stability in the circulation and unique signature in CVDs. However, further studies are needed to investigate their translational potential in the real clinical practice. PMID- 28660193 TI - Abscisic Acid: A Novel Nutraceutical for Glycemic Control. AB - Abscisic acid is naturally present in fruits and vegetables, and it plays an important role in managing glucose homeostasis in humans. According to the latest U.S. dietary survey, about 92% of the population might have a deficient intake of ABA due to their deficient intake of fruits and vegetables. This review summarizes the in vitro, preclinical, mechanistic, and human translational findings obtained over the past 15 years in the study of the role of ABA in glycemic control. In 2007, dietary ABA was first reported to ameliorate glucose tolerance and obesity-related inflammation in mice. The most recent findings regarding the topic of ABA and its proposed receptor lanthionine synthetase C like 2 in glycemic control and their interplay with insulin and glucagon-like peptide-1 suggest a major role for ABA in the physiological response to a glucose load in humans. Moreover, emerging evidence suggests that the ABA response might be dysfunctional in diabetic subjects. Follow on intervention studies in healthy individuals show that low-dose dietary ABA administration exerts a beneficial effect on the glycemia and insulinemia profiles after oral glucose load. These recent findings showing benefits in humans, together with extensive efficacy data in mouse models of diabetes and inflammatory disease, suggest the need for reference ABA values and its possible exploitation of the glycemia-lowering effects of ABA for preventative purposes. Larger clinical studies on healthy, prediabetic, and diabetic subjects are needed to determine whether addressing the widespread dietary ABA deficiency improves glucose control in humans. PMID- 28660195 TI - A Dairy Herd Case Investigation with Very Low Dietary Cation-Anion Difference in Prepartum Dairy Cows. AB - During the periparturient period, subclinical hypocalcemia (total plasma Ca concentration <2.0 mmol/l) is a potential problem for the dairy cow; consequently, its prevention is essential for success of fertility and productive performance. Dietary cation-anion difference (DCAD) has been defined as the difference in milliequivalents of cations (Na, K) and anions (Cl, S) per kilogram of dry matter (DM) and has a direct impact on blood acid-base metabolism. Diets rich in K and Na induce metabolic alkalosis, interfering with tissue sensitivity to parathyroid hormone, and diets rich in Cl and S (anionic salts) cause metabolic acidosis, reducing the risk of hypocalcemia. Consequently, the use of anionic salts has become a popular method to prevent hypocalcemia in dairy cattle. Monitoring diets with anionic salts can be done by measuring urine pH, with optimal values between 6.2 and 6.8 for Holstein cows. The objective of this report is to present a herd case investigation involving a dairy farm feeding a very low DCAD (-143 mEq/kg DM), expecting improved Ca homeostasis. The diet of 143 mEq/kg (urine pH 5.2-5.8) was changed to a diet with -53 mEq/kg DM (urine pH 6.2-6.8). Blood samples were taken at the time of calving for 10 cows that calved before and then for 10 cows that calved after changing the diet. Cows with extremely low DCAD had Ca concentrations of 2.11 +/- 0.22 mmol/l and cows with a more moderated DCAD, 2.11 +/- 0.16 mmol/l (P > 0.05). Several other blood metabolites (P, Mg, Na, K, Cl, albumin, globulins, blood urea nitrogen, creatinine, and GGT) were also similar between groups. This very low DCAD during the prepartum period may severely compromise animal physiology unnecessarily, with little advantage over normal calcium concentrations at parturition, when compared with a less negative DCAD (-53 mEq/kg DM). Feeding a less negative DCAD ration (-53 mEq/kg DM) did not decrease plasma Ca levels right after parturition compared to a DCAD ration of -143 mEq/kg DM, reinforcing the lack of benefit of a more negative DCAD. PMID- 28660194 TI - Dietary Patterns Characterized by High Meat Consumption Are Associated with Other Unhealthy Life Styles and Depression Symptoms. AB - OBJECTIVE: We aimed to identify dietary patterns (DPs) of Portuguese adults, to assess their socioeconomic, demographic, lifestyle determinants, and to identify their impact on health. DESIGN: EpiDoC 2 study included 10,153 Portuguese adults from the EpiDoC Cohort, a population-based study. In this study, trained research assistants using computer-assisted telephone interview collected socioeconomic, demographic, dietary, lifestyles, and health information from March 2013 to July 2015. Cluster analysis was performed, based on questions regarding the number of meals, weekly frequency of soup consumption, vegetables, fruit, meat, fish, dairy products, and daily water intake. Factors associated with DP were identified through logistic regression models. RESULTS: Two DPs were identified: the "meat dietary pattern" and the "fruit & vegetables dietary pattern." After multivariable adjustment, women (OR = 0.52; p < 0.001), older adults (OR = 0.97; p < 0.001), and individuals with more years of education (OR = 0.96; p = 0.025) were less likely to adopt the "meat dietary pattern," while individuals in a situation of job insecurity/unemployment (OR = 1.49; p = 0.013), Azores island residents (OR = 1.40; p = 0.026), current smoking (OR = 1.58; p = 0.001), daily alcohol intake (OR = 1.46; p = 0.023), and physically inactive (OR = 1.86; p < 0.001) were positively and significantly associated with "meat dietary pattern." Moreover, individuals with depression symptoms (OR = 1.50; p = 0.018) and the ones who did lower number of medical appointments in the previous year (OR = 0.98; p = 0.025) were less likely to report this DP. CONCLUSION: Our results suggest that unhealthy DPs (meat DP) are part of a lifestyle behavior that includes physical inactivity, smoking habits, and alcohol consumption. Moreover, depression symptoms are also associated with unhealthy DPs. PMID- 28660196 TI - Endovascular Repair of Traumatic Isthmic Ruptures: Special Concerns. AB - Injury of the aortic isthmus is the second most frequent cause of death in cases of blunt traumatic injury. Conventional open repair is related to significant morbidity and mortality. Thoracic endovascular aortic repair (TEVAR) has increasing role in traumatic isthmic rupture, as it avoids the thoracotomy related morbidity, aortic cross clamping, and cardiopulmonary bypass. Additionally to the technical difficulties of open repair, multi-trauma patients may not tolerate the manipulations necessary to undergo open surgery, due to concomitant injuries. TEVAR is a procedure easier to perform compared to open surgery, despite that a considerable degree of expertise is necessary. Direct comparison of the two methods is difficult, but TEVAR appears to offer better results than open repair in terms of mortality, incidence of spinal cord ischemia, renal insufficiency, and graft infection. TEVAR is related to a statistically not significant-trend for higher re-intervention rates during the follow-up period. Current guidelines support TEVAR as a first-line repair method for traumatic isthmic rupture. Certain specific considerations related to TEVAR, such as the timing of the procedure, the type and oversizing of the endograft, heparinization during the procedure, the necessity of cerebrospinal fluid drainage, type of anesthesia, and the necessary follow-up strategy remain to be clarified. TEVAR should be considered advantageous compared to open surgery, but future developments in endovascular materials, along with accumulating long-term clinical data, will eventually improve TEVAR results in traumatic aortic isthmic rupture (TAIR) cases. This publication reviews the role, outcomes, and relevant issues linked to TEVAR in the repair of TAIR. PMID- 28660198 TI - Transforming Growth Factor-beta2 Downregulates Major Histocompatibility Complex (MHC) I and MHC II Surface Expression on Equine Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Other Phenotypic Cell Surface Markers. AB - Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Effective and safe allogeneic therapy may be hindered, however, by recipient immune recognition and rejection of major histocompatibility complex (MHC)-mismatched MSCs. Development of strategies to prevent immune rejection of MHC-mismatched MSCs in vivo is necessary to enhance cell survival and potentially increase the efficacy and safety of allogeneic MSC therapy. The purposes of this study were to evaluate if transforming growth factor-beta2 (TGF-beta2) downregulated MHC expression on equine MSCs and to determine if TGF-beta2 treatment altered the phenotype of MSCs. Equine bone marrow-derived MSCs from 12 horses were treated with 1, 5, or 10 ng/ml TGF-beta2 from initial isolation until MHC expression analysis. TGF-beta2-treated MSCs had reduced MHC I and MHC II surface expression compared to untreated controls. TGF beta2 treatment also partially blocked IFN-gamma-induced upregulation of MHC I and MHC II. Constitutive and IFN-gamma-induced MHC I and MHC II expression on equine MSCs was dynamic and highly variable, and the effect of TGF-beta2 was significantly dependent on the donor animal and baseline MHC expression. TGF beta2 treatment did not appear to change morphology, surface marker expression, MSC viability, or secretion of TGF-beta1, but did significantly increase the number of cells obtained from culture. These results indicate that TGF-beta2 treatment has promise for regulating MHC expression on MSCs to facilitate allogeneic therapy, but further work is needed to maintain MHC stability when exposed to an inflammatory stimulus. PMID- 28660199 TI - Histological Characteristics, Fatty Acid Composition of Lipid Fractions, and Cholesterol Content of Semimembranosus and Triceps Brachii Muscles in Maremmana and Limousine Bovine Breeds. AB - This study examined the histological properties of Semimembranosus and Triceps brachii muscle in two different bovine breeds, Maremmana (Ma) (an autochthonous breed from Tuscany, Italy) and Limousine (Lm). The animals were grazed in two adjoining pastures, received the same feed supplementation, and were weighed monthly. The experimental period lasted from weaning (6 months old) to slaughter (19 months old). Muscle samples were collected immediately after slaughter, before carcass cooling. Regarding the histological properties, the number of muscle fibers (TNF), mean sarcolemma perimeter (MSP), cross-sectional area, and total sarcolemma perimeter (TSP) were determined. Samples were also analyzed for proximate composition, fatty acid profile of total lipids (TLs), phospholipids (PLs), and neutral lipids (NLs), and for total cholesterol content. Breed was a significant variation factor for the performance parameter and histological muscle fiber properties. Interestingly, despite that Ma being a less extensively genetically improved breed than Lm, it showed higher weight at slaughter (+18%) and daily weight gain (+19%). Ma also showed smaller muscle fibers than Lm and, consequently, the TSP was higher. This difference affected the lipid fraction distribution (Lm was higher in PLs and lower in NLs than Ma) and, consequently, the fatty acid composition of TLs (Lm was high in polyunsaturated fatty acids, while Ma was high in monounsaturated fatty acids). The results of this experiment highlight the importance of environmental and management conditions on the full expression of genotypic potential. PMID- 28660200 TI - A Fast and Inexpensive Protocol for Empirical Verification of Neutralizing Epitopes in Microbial Toxins and Enzymes. AB - In vivo targeting of peptides to antigen-presenting cells by use of agonistic anti-CD40 monoclonal antibodies has been used successfully as an immune response enhancing strategy. When tested in chickens, the antibody-guided platform was capable of inducing specific IgG production within 1 week postimmunization. However, use of this method beyond its initial conception as a vaccine delivery tool has not been fully exploited. In this study, Clostridium perfringens alpha toxin was used as a model microbial toxin for epitope mapping by using the antibody-guided immunization method to generate a panel of antibodies against specific, regions of the toxin in an attempt to identify crucial determinants on the toxin which, once bound, would hinder downstream toxicity. Alpha-toxin, which possesses both hemolytic and phospholipase C (PLC) enzymatic activities, has long been known to be one of the key destructive etiological agents of necrotic enteritis disease in poultry. Previous attempts to identify crucial antigenic determinants on the toxin mediating its enzymatic activities have been performed using expensive and labor-intensive site-directed mutagenesis techniques. To create a panel of antibodies, 23 short candidate alpha-toxin peptide regions were selected in silico using B-cell epitope prediction algorithms in the public domain and were custom synthesized to load onto the antibody-guided complex for immunization in birds for antisera production. Peptide-specific antibody responses were generated against all candidate neutralizing epitopes and used for in vitro toxin neutralization tests. Antisera against all 23 peptides were able to neutralize the toxin's hemolytic activity, with neutralization titers ranging from 80 to 320, but none were effective in blocking PLC. The novel approach of antibody-guided immunization introduces a new, inexpensive method for polyclonal IgG production and de facto identification of neutralizing epitopes in microbial toxins and enzymes within 2 weeks from in silico analysis of a putative target sequence. PMID- 28660197 TI - A Mighty "Protein Extractor" of the Cell: Structure and Function of the p97/CDC48 ATPase. AB - p97/VCP (known as Cdc48 in S. cerevisiae or TER94 in Drosophila) is one of the most abundant cytosolic ATPases. It is highly conserved from archaebacteria to eukaryotes. In conjunction with a large number of cofactors and adaptors, it couples ATP hydrolysis to segregation of polypeptides from immobile cellular structures such as protein assemblies, membranes, ribosome, and chromatin. This often results in proteasomal degradation of extracted polypeptides. Given the diversity of p97 substrates, this "segregase" activity has profound influence on cellular physiology ranging from protein homeostasis to DNA lesion sensing, and mutations in p97 have been linked to several human diseases. Here we summarize our current understanding of the structure and function of this important cellular machinery and discuss the relevant clinical implications. PMID- 28660202 TI - Integrative modules for efficient genome engineering in yeast. AB - We present a set of vectors containing integrative modules for efficient genome integration into the commonly used selection marker loci of the yeast Saccharomyces cerevisiae. A fragment for genome integration is generated via PCR with a unique set of short primers and integrated into HIS3, URA3, ADE2, and TRP1 loci. The desired level of expression can be achieved by using constitutive (TEF1p, GPD1p), inducible (CUP1p, GAL1/10p), and daughter-specific (DSE4p) promoters available in the modules. The reduced size of the integrative module compared to conventional integrative plasmids allows efficient integration of multiple fragments. We demonstrate the efficiency of this tool by simultaneously tagging markers of the nucleus, vacuole, actin, and peroxisomes with genomically integrated fluorophores. Improved integration of our new pDK plasmid series allows stable introduction of several genes and can be used for multi-color imaging. New bidirectional promoters (TEF1p-GPD1p, TEF1p-CUP1p, and TEF1p-DSE4p) allow tractable metabolic engineering. PMID- 28660204 TI - Protein aggregation triggers a declining libido in elder yeasts that still have a lust for life. AB - Many organisms have to face a physiological decline that is associated with age. Humans and even budding yeast accumulate scars and cellular damages. A single yeast cell can only produce a limited number of daughter cells and thus has a finite replicative lifespan. Many studies have now identified molecular ageing factors and defects in organelle functions linked to the ageing process. However, at the cellular level, the most striking phenotype of yeast elders is their loss of mating ability. This sterility in old cells has been linked to a loss of response to mating pheromone, the peptide that haploid yeast cells send to opposite mating type cells in order to signal their presence and readiness to mate. Our results (Schlissel et al., 2017) demonstrate that old cells are unable to respond to mating pheromone due to age-induced aggregation of the protein Whi3. We recently discovered that Whi3 changes conformation and coalesces when cells experience and memorise a deceptive mating attempt. Together, these results prompt the question of how proteins physiologically aggregating behave during ageing, induce age associated phenotypes and influence the ageing process itself. PMID- 28660201 TI - The Potential Link between Thermal Resistance and Virulence in Salmonella: A Review. AB - In some animals, the typical body temperature can be higher than humans, for example, 42 degrees C in poultry and 40 degrees C in rabbits which can be a potential thermal stress challenge for pathogens. Even in animals with lower body temperatures, when infection occurs, the immune system may increase body temperature to reduce the chance of survival for pathogens. However, some pathogens can still easily overcome higher body temperatures and/or rise in body temperatures through expression of stress response mechanisms. Salmonella is the causative agent of one of the most prevalent foodborne illnesses, salmonellosis, and can readily survive over a wide range of temperatures due to the efficient expression of the heat (thermal) stress response. Therefore, thermal resistance mechanisms can provide cross protection against other stresses including the non specific host defenses found within the human body thus increasing pathogenic potential. Understanding the molecular mechanisms associated with thermal responses in Salmonella is crucial in designing and developing more effective or new treatments for reducing and eliminating infection caused by Salmonella that have survived heat stress. In this review, Salmonella thermal resistance is assessed followed by an overview of the thermal stress responses with a focus on gene regulation by sigma factors, heat shock proteins, along with the corresponding thermosensors and their association with virulence expression including a focus on a potential link between heat resistance and potential for infection. PMID- 28660203 TI - The neuroprotective steroid progesterone promotes mitochondrial uncoupling, reduces cytosolic calcium and augments stress resistance in yeast cells. AB - The steroid hormone progesterone is not only a crucial sex hormone, but also serves as a neurosteroid, thus playing an important role in brain function. Epidemiological data suggest that progesterone improves the recovery of patients after traumatic brain injury. Brain injuries are often connected to elevated calcium spikes, reactive oxygen species (ROS) and programmed cell death affecting neurons. Here, we establish a yeast model to study progesterone-mediated cytoprotection. External supply of progesterone protected yeast cells from apoptosis-inducing stress stimuli and resulted in elevated mitochondrial oxygen uptake accompanied by a drop in ROS generation and ATP levels during chronological aging. In addition, cellular Ca2+ concentrations were reduced upon progesterone treatment, and this effect occurred independently of known Ca2+ transporters and mitochondrial respiration. All effects were also independent of Dap1, the yeast orthologue of the progesterone receptor. Altogether, our observations provide new insights into the cytoprotective effects of progesterone. PMID- 28660205 TI - Pneumothoraces in collagen VI-related dystrophy: a case series and recommendations for management. AB - Collagen VI-related dystrophy (collagen VI-RD) is a rare neuromuscular condition caused by mutations in the COL6A1, COL6A2 or COL6A3 genes. The phenotypic spectrum includes early-onset Ullrich congenital muscular dystrophy, adult-onset Bethlem myopathy and an intermediate phenotype. The disorder is characterised by distal hyperlaxity and progressive muscle weakness, joint contractures and respiratory insufficiency. Respiratory insufficiency is attributed to chest wall contractures, scoliosis, impaired diaphragmatic function and intercostal muscle weakness. To date, intrinsic parenchymal lung disease has not been implicated in the inevitable respiratory decline of these patients. This series focuses on pneumothorax, an important but previously under-recognised disease manifestation of collagen VI-RD. We describe two distinct clinical presentations within collagen VI-RD patients with pneumothorax. The first cohort consists of neonates and children with a single pneumothorax in the setting of large intrathoracic pressure changes. The second group is made up of adult patients with recurrent pneumothoraces, associated with chest computed tomography scan evidence of parenchymal lung disease. We describe treatment challenges in this unique population with respect to expectant observation, tube thoracostomy and open pleurodesis. Based on this experience, we offer recommendations for early identification of lung disease in collagen VI-RD and definitive intervention. PMID- 28660206 TI - Attitudes and preferences of home mechanical ventilation users from four European countries: an ERS/ELF survey. AB - Home mechanical ventilation is increasingly used by people with chronic respiratory failure. However, there are few reports on attitudes towards treatment. A web-based survey in eight languages was disseminated across 11 European countries to evaluate the perception of home mechanical ventilation provision in ventilator-assisted individuals and caregivers. Out of 787 responders from 11 European countries, 687 were patients and 100 were caregivers. 95% of patients and 94% of caregivers were from only 4 countries (Germany, the Netherlands, Italy, Spain). The majority of respondents were male and aged 46-65 years. Obstructive lung diseases were proportionally more represented among respondent patients (46%), and neuromuscular diseases (65%) were more represented among patients of respondent caregivers. About 20% of respondent patients and caregivers were not sure of the modality of ventilation. Different interfaces were used, with a minority of respondents in all countries using invasive home mechanical ventilation by tracheostomy. These results may be useful for healthcare providers and policy makers to improve the quality of patients' daily lives. PMID- 28660208 TI - Comment on "Intraoperative Contrast Enhanced Ultrasound Evaluates the Grade of Glioma". PMID- 28660207 TI - Chlamydia muridarum Infection of Macrophages Stimulates IL-1beta Secretion and Cell Death via Activation of Caspase-1 in an RIP3-Independent Manner. AB - Chlamydiae are Gram-negative bacteria, which replicate exclusively in the infected host cells. Infection of the host cells by Chlamydiae stimulates the innate immune system leading to an inflammatory response, which is manifested not only by secretion of proinflammatory cytokines such as IL-1beta from monocytes, macrophages, and dendritic cells, but also possibly by cell death mediated by Caspase-1 pyroptosis. RIP3 is a molecular switch that determines the development of necrosis or inflammation. However, the involvement of RIP3 in inflammasome activation by Chlamydia muridarum infection has not been clarified. Here, we assessed the role of RIP3 in synergy with Caspase-1 in the induction of IL-1beta production in BMDM after either LPS/ATP or Chlamydia muridarum stimulation. The possibility of pyroptosis and necroptosis interplays and the role of RIP3 in IL 1beta production during Chlamydia muridarum infection in BMDM was investigated as well. The data indicated that RIP3 is involved in NLRP3 inflammasome activation in LPS/ATP-stimulated BMDMs but not in Chlamydia muridarum infection. Pyroptosis occurred in BMDM after LPS/ATP stimulation or Chlamydia muridarum infection. Moreover, the results also illuminated the important role of the Caspase-1 mediated pyroptosis process which does not involve RIP3. Taken together, these observations may help shed new light on details in inflammatory signaling pathways activated by Chlamydia muridarum infection. PMID- 28660209 TI - Intravenous Thrombolysis in Acute Ischemic Stroke with Active Cancer. AB - Ischemic stroke patients with active cancer are known to have poor clinical outcomes. However, the efficacy and safety of intravenous alteplase (IV t-PA) in this group are still unclear. In this study, we aimed to evaluate whether stroke patients with cancer had poor clinical outcomes after use of IV t-PA. We reviewed ischemic stroke patients with active cancer treated with isolated IV t-PA between April 2010 and March 2015 at three national university hospitals from the registry for ischemic stroke in Korea. The clinical outcomes of early neurological deterioration (END), hemorrhagic transformation, in-hospital mortality, 3-month modified Rankin scale (mRS), the National Institutes of Health Stroke Scale (NIHSS) discharge score, and duration of hospitalization were compared. We enrolled a total of 12 patients, and the cohort showed poor outcomes including 4 (33%) END events, 7 (58%) hemorrhagic transformations, 3 (25%) in hospital mortality cases, and 7 (58%) poor mRS (3-6) scores. Additionally, the cryptogenic stroke group (n = 6) more frequently had high mRS scores (P = 0.043) as well as tendencies for frequent END events, hemorrhagic transformations, in hospital mortality cases, and higher discharge NIHSS scores without statistical significance. In conclusion, ischemic stroke patients with active cancer, especially those with a cryptogenic mechanism, showed poor clinical outcomes after use of IV t-PA. PMID- 28660210 TI - Kinetics of Tyrosinase Inhibitory Activity Using Vitis vinifera Leaf Extracts. AB - Natural medical plant is considered as a good source of tyrosinase inhibitors. Red vine leaf extract (RVLE) can be applied to a wide variety of medical disciplines, such as treatments for chronic venous insufficiency over many decades. This study investigated the tyrosinase inhibitory activity of RVLE containing gallic acid, chlorogenic acid, epicatechin, rutin, and resveratrol which are effective for skin hyperpigmentation. The five components contents are 1.03, 0.2, 18.55, 6.45, and 0.48 mg/g for gallic acid, chlorogenic acid, epicatechin, rutin, and resveratrol. The kinetic study showed the tyrosinase inhibitory of RVLE via a competitive reaction mechanism. RVLE solution has an IC50 (the half inhibitory concentration) value of 3.84 mg/mL for tyrosinase inhibition, that is, an effective tyrosinase inhibitory activity, and can be used as a whitening agent for cosmetic formulations in the future. PMID- 28660211 TI - Noninvasive Electroencephalogram Based Control of a Robotic Arm for Writing Task Using Hybrid BCI System. AB - A novel hybrid brain-computer interface (BCI) based on the electroencephalogram (EEG) signal which consists of a motor imagery- (MI-) based online interactive brain-controlled switch, "teeth clenching" state detector, and a steady-state visual evoked potential- (SSVEP-) based BCI was proposed to provide multidimensional BCI control. MI-based BCI was used as single-pole double throw brain switch (SPDTBS). By combining the SPDTBS with 4-class SSEVP-based BCI, movement of robotic arm was controlled in three-dimensional (3D) space. In addition, muscle artifact (EMG) of "teeth clenching" condition recorded from EEG signal was detected and employed as interrupter, which can initialize the statement of SPDTBS. Real-time writing task was implemented to verify the reliability of the proposed noninvasive hybrid EEG-EMG-BCI. Eight subjects participated in this study and succeeded to manipulate a robotic arm in 3D space to write some English letters. The mean decoding accuracy of writing task was 0.93 +/- 0.03. Four subjects achieved the optimal criteria of writing the word "HI" which is the minimum movement of robotic arm directions (15 steps). Other subjects had needed to take from 2 to 4 additional steps to finish the whole process. These results suggested that our proposed hybrid noninvasive EEG-EMG-BCI was robust and efficient for real-time multidimensional robotic arm control. PMID- 28660212 TI - Anatomical Footprint of the Tibialis Anterior Tendon: Surgical Implications for Foot and Ankle Reconstructions. AB - This study aimed to analyze precisely the dimensions, shapes, and variations of the insertional footprints of the tibialis anterior tendon (TAT) at the medial cuneiform (MC) and first metatarsal (MT1) base. Forty-one formalin-fixed human cadaveric specimens were dissected. After preparation of the TAT footprint, standardized photographs were made and the following parameters were evaluated: the footprint length, width, area of insertion, dorsoplantar location, shape, and additional tendon slips. Twenty feet (48.8%) showed an equal insertion at the MC and MT1, another 20 feet (48.8%) had a wide insertion at the MC and a narrow insertion at the MT1, and 1 foot (2.4%) demonstrated a narrow insertion at the MC and a wide insertion at the MT1. Additional tendon slips inserting at the metatarsal shaft were found in two feet (4.8%). Regarding the dorsoplantar orientation, the footprints were located medial in 29 feet (70.7%) and medioplantar in 12 feet (29.3%). The most common shape at the MT1 base was the crescent type (75.6%) and the oval type at the MC (58.5%). The present study provided more detailed data on the dimensions and morphologic types of the tibialis anterior tendon footprint. The established anatomical data may allow for a safer surgical preparation and a more anatomical reconstruction. PMID- 28660213 TI - How to Use CA-125 More Effectively in the Diagnosis of Deep Endometriosis. AB - Deep infiltrative endometriosis (DIE) is a severe form of the disease. The median time interval from the onset of symptoms to diagnosis of endometriosis is around 8 years. In this prospective study patients were divided into two groups: cases (34 DIE patients) and control (20 tubal ligation patients). The main objective of this study was to evaluate the performance of CA-125 measurement in the menstrual and midcycle phases of the cycle, as well as the difference in its levels between the two phases, for the early diagnosis of DIE. Area Under the Curve (AUC) of CA 125 in menstrual phase and of the difference between menstrual and midcycle phases had the best performance (both with AUC = 0.96), followed by CA-125 in the midcycle (AUC = 0.89). The ratio between menstrual and midcycle phases had the worst performance. CA-125 may be useful for the diagnosis of deep endometriosis, especially when both are collected during menstruation and in midcycle. These may help to decrease the long interval until the definitive diagnosis of DIE. Multicentric studies with larger samples should be performed to better evaluate the cost-effectiveness of measuring CA-125 in two different phases of the menstrual cycle. PMID- 28660214 TI - Liver-Specific Overexpression of Gamma-Glutamyltransferase Ameliorates Insulin Sensitivity of Male C57BL/6 Mice. AB - In the current study, we developed a liver-specific GGT-overexpressing mice model by rapid injection pLIVE-GGT vector through tail vein and investigated the effects of GGT elevation on glucose metabolism and insulin sensitivity. The serum GGT activity was significantly increased after 7 days of pLIVE-GGT1 vector delivery and lasted for about 3 weeks. GGT overexpression reduced the levels of GSSG and GSH in the liver and serum and had no effects on total antioxidative capacity in the liver, kidney, and skeletal muscle except for the pancreas. Increased GGT activity had no effect on the glucose tolerance but could facilitate blood glucose lowering after intraperitoneal insulin administration. The results of Western blotting showed that increased GGT activity enhanced insulin-induced AKT phosphorylation at Ser473. Furthermore, GGT inhibitor could attenuate the changes of insulin-induced blood glucose uptake and AKT phosphorylation in the liver. In summary, the present study developed a liver specific GGT-overexpressing mice model and found that GGT elevation in short term had no effects on glucose metabolism but could increase insulin sensitivity through enhancing the activity of insulin signaling pathway. PMID- 28660215 TI - Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study. AB - Herein, we summarize our recent findings from the international Collaborative Transplant Study (CTS) and Heidelberg Transplant Center regarding the role of HLA antibodies in kidney transplantation and their application into the clinical routine. Based on the antibody findings from the CTS serum study, an algorithm was developed in 2006 for the transplantation of high-risk sensitized patients at the Heidelberg Transplant Center which includes seven different pre- and posttransplant measures. Using this algorithm, the number of transplantations could be increased in high-risk presensitized patients and the previously existing impact of antibodies on graft survival could greatly be diminished but not totally eliminated. More recent findings led to the hypothesis that T cell help from a preactivated immune system supports the harmful effects of pretransplant donor-specific HLA antibodies that otherwise disappear in many cases after transplantation without any consequence. PMID- 28660216 TI - Chitinase-3-Like Protein 1 (YKL-40) Reflects the Severity of Symptoms in Atopic Dermatitis. AB - Chitinase-3-like protein 1 (YKL-40) is suggested to be associated with type 2 T helper response and atopy. The aim of the study was the evaluation of serum YKL 40 level in atopic dermatitis. The study was performed on 59 patients: 27 males and 32 females, aged from 18 to 64 years. The severity of the disease was assessed by the SCORAD and objective SCORAD indexes. The severity of pruritus was measured by the visual analogue scale. Blood samples were taken to examine serum level of YKL-40, total IgE level, C-reactive protein level, white blood cell count, and neutrophil count. YKL-40 serum levels were significantly higher in patients with atopic dermatitis compared to the controls. There was a positive correlation between YKL-40 concentration and SCORAD, objective SCORAD, and pruritus. This study has shown that YKL-40 serum level is increased in patients with atopic dermatitis and reflects the severity of symptoms. PMID- 28660217 TI - A Prospective Study Comparing Functional Imaging (18F-FDG PET) Versus Anatomical Imaging (Contrast Enhanced CT) in Dosimetric Planning for Non-small Cell Lung Cancer. AB - OBJECTIVES: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) is a well-used and established technique for lung cancer staging. Radiation therapy requires accurate target volume delineation, which is difficult in most cases due to coexisting atelectasis. The present study was performed to compare the 18F-FDG PET-CT with contrast enhanced computed tomography (CECT) in target volume delineation and investigate their impacts on radiotherapy planning. METHODS: Eighteen patients were subjected to 18F- FDG PET CT and CECT in the same position. Subsequently, the target volumes were separately delineated on both image sets. In addition, the normal organ doses were compared and evaluated. RESULTS: The comparison of the primary gross tumour volume (GTV) between the 18F-FDG PET-CT and CECT imaging revealed that 88.9% (16/18) of the patients had a quantitative change on the 18F-FDG PET-CT. Out of these patients, 77% (14/18) of the cases had a decrease in volume, while 11% (2/18) of them had an increase in volume on the 18F-FDG PET-CT. Additionally, 44.4% (8/18) of the patients showed a decrease by > 50 cm 3 on the 18F-FDG PET CT. The comparison of the GTV lymph node between the 18F-FDG PET-CT and CECT revealed that the volume changed in 89% (16/18) of the patients: it decreased and increased in 50% (9/18) and 39% (7/18) on the 18F-FDG PET-CT. New nodes were identified in 27% (5/18) of the patients on the 18F-FDG PET-CT. The decrease in the GTV lymph node on the 18F-FDG PET-CT was statistically significant. The decreased target volumes made radiotherapy planning easier with improved sparing of normal tissues. CONCLUSION: GTV may either increase or decrease with the 18F FDG PET-CT, compared to the CECT. However, the 18F-FDG PET-CT-based contouring facilitates the accurate delineation of tumour volumes, especially at margins, and detection of new lymph node volumes. The non-FDG avid nodes can be omitted to avoid elective nodal irradiation, which can spare the organs at risk and improve accurate staging and treatment. PMID- 28660218 TI - Diagnosis of Brain Tumors Using Amino Acid Transport PET Imaging with 18F fluciclovine: A Comparative Study with L-methyl-11C-methionine PET Imaging. AB - OBJECTIVES: 18F-fluciclovine (trans-1-amino-3-[18F] fluorocyclobutanecarboxylic acid, [FACBC]) is an artificial amino acid radiotracer used for positron emission tomography (PET) studies, which is metabolically stable in vivo and has a long half-life. It has already been shown that FACBC-PET is useful for glioma imaging. However, there have been no reports evaluating the efficiency of FACBC-PET in the diagnosis of brain tumors in comparison with other PET tracers in clinical studies. The purpose of this study was to investigate the efficacy of FACBC-PET imaging in glioma diagnosis, compared to L-methyl- 11 C-methionine (MET)-PET. METHODS: Six consecutive patients (four male, two female), who were clinically suspected of having high- or low-grade glioma, received both FACBC-PET and MET PET within a two-week interval. T1-weighted, contrast-enhanced, T1-weighted, and fluid-attenuated inversion recovery magnetic resonance imaging was performed to assist with subsequent tissue resection. Visual findings and semi-quantitative analyses of FACBC and MET uptake, using standardized uptake values (SUVs) and lesion-to-contralateral normal brain tissue (LN) ratios, were evaluated to compare PET images. RESULTS: SUVs for FACBC were lower than those for MET in the non-lesion cerebral cortex, brain stem, and cerebellar hemisphere. There was a weak positive correlation between FACBC and MET uptake in glioma tissue, although L/N ratios for FACBC were higher than those for MET in all the cases. CONCLUSION: FACBC-PET showed higher contrast than MET-PET by both visual and semi quantitative analyses and may therefore provide better assessment for the detection of glioma. This study was registered as clinical trial (No. JapicCTI 132289). PMID- 28660219 TI - Seventy FDG-PET/CT Cases in Which Nuclear Medicine Physicians Suspected Lymphoma: How Reliable Are We? AB - OBJECTIVES: To validate the reliability of nuclear medicine physicians in diagnosing lymphoma using positron emission tomography/computed tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) and to determine findings that reliably suggest lymphoma. METHODS: Seventy patients suspected of having lymphoma using FDG-PET/CT were enrolled in this retrospective study. Two nuclear medicine physicians read all the interpretation reports and graded the degree of suspicion by consensus (3: definitely suspicious, 2: probably suspicious, and 1: possibly suspicious). The following factors were also investigated for each patient: maximum standardized uptake value (SUVmax) of the lesions, serum level of soluble interleukin-2 receptor (sIL-2R), and the presence of splenic FDG uptake higher than that of the liver. RESULTS: The study group consisted of 34 lymphomas, 18 other malignancies, and 18 benign lesions according to histopathological diagnosis. No patient with a Grade 1 degree of suspicion was diagnosed as lymphoma. SUVmax and the serum level of sIL-2R could not distinguish lymphoma from other diseases. Of the 11 patients who presented with elevated splenic FDG uptake, 10 were diagnosed as having lymphoma. CONCLUSION: When the degree of suspicion by nuclear medicine physicians is low, the possibility of lymphoma is also low. On the other hand, elevated splenic FDG uptake may suggest lymphoma. PMID- 28660220 TI - F-18 FDG PET/CT Imaging of Eccrine Sweat Gland Carcinoma of the Scrotum with Extensive Regional and Distant Metastases. AB - Eccrine carcinoma is an extremely rare malignant skin cancer arising from eccrine sweat glands with a high metastatic potential. It mainly occurs in the elderly, with equal incidence in both sexes. It usually spreads to regional lymph nodes, with liver, lungs, and bones being the most common sites of distant metastasis. Because of tumor rarity, little is known about the value of F-18 FDG PET/CT in evaluating this disease. Our case report aims to increase current knowledge of F 18 FDG PET/CT in eccrine sweat gland carcinoma as a noninvasive imaging tool for assessing the extension of the disease and detecting distant metastases. We reported a 96-year-old man who presented with as lowly progressive, ill-margined erythematous papules and nodules with a crusted and eroded involving multiple sites of groin, scrotum, penis, left pelvic wall, left hip and left thigh for >3 years, which became extensive in the past 2 months. The histologic investigation confirmed the diagnosis of an eccrine carcinoma. He was performed F-18 FDG PET/CT to further evaluate the lesions. FDG PET/CT imaging revealed FDG uptake at the extensive skin lesion, involvement of lymph nodes, and multiple FDG-avid of liver, skeletal and lung metastases. PMID- 28660221 TI - Triage of Limited Versus Extensive Disease on 18F-FDG PET/CT Scan in Small Cell lung Cancer. AB - OBJECTIVES: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, which accounts for 10-15% of pulmonary cancers and exhibits early metastatic spread. This study aimed to determine the added value of 18F-FDG PET/CT imaging in tumor, node, and metastasis (TNM) staging of SCLC, compared to the conventional computed tomography (CT) scan and its potential role as a prognosticator. METHODS: This retrospective review was conducted on 23 patients, who were histopathologically diagnosed to have SCLC and referred for undergoing 18F-FDG PET/CT scanning during October 2009-December 2015. The rate of agreement between the CT and 18F-FDG PET/CT findings for TNM staging was calculated using the Cohen's kappa (kappa). The median follow-up time was eight months, ranging 27 3 months). The overall and disease-free survival rates were calculated based on the extent of disease. RESULTS: 19 cases were male and four female with the mean age of 58+/-9 years. The 18F-FDG PET/CT identified limited and extensive diseases in 2 (8.7%) and 21 (91.3%) patients, respectively. In addition, the results of the Cohen's kappa demonstrated a strong (kappa=0.82), fair (kappa=0.24), and poor (kappa=0.12) agreement between the PET/CT and CT findings for determining tumor, node, and metastasis stages, respectively. The 18F-FDG PET/CT scans upstaged disease in 47% of the cases with visceral and osseous metastasis. The disease free survival rates for the limited and extensive diseases were 100% and 23% within the 12-month follow-up. In addition, 8 (35%) patients expired during the follow-up period. CONCLUSION: Improved nodal and metastatic disease identification highlights the role of 18F-FDG PET/CT scanning in initial staging of SCLC with prognostic implications. PMID- 28660222 TI - 99mTc-TRODAT-1 SPECT Imaging in Early and Late Onset Parkinson's Disease. AB - OBJECTIVES: 99mTc-TRODAT-1, which binds to the dopamine transporter, could be used to image the dopaminergic system in diagnosis of Parkinson's disease (PD). PD can be classified into two groups: late onset Parkinson's disease (LOPD) and early onset Parkinson's disease (EOPD). In this study we tried to determine the TRODAT SPECT findings in EOPD as compared to LOPD. METHODS: Fifteen patients were studied. The diagnosis of PD was defined by clinical criteria based on UK Parkinson's Disease Society Brain Bank criteria. Six patients whose age at onset of PD were younger than 50 were defined as patients with EOPD and 9 patients with older than 50 years were defined as patients with LOPD. All patients underwent 99mTc-TRODAT Brain SPECT. RESULTS: There was a significant decrease of striatal 99mTc-TRODAT-1 (TRODAT) binding in PD patients in both EOPD and LOPD. No significant difference was noticed between EOPD and LOPD in disease stage and symptoms. In visual analysis, 20 (66.67%) caudate nucleuses had decreased tracer uptake while all 30 (100%) putamens had decreased or absent tracer uptake. No significant difference between EOPD and LOPD was noticed in visual analysis. Striatum, Caudate and Putamen uptake ratio to background were calculated. No significant difference was noticed between EOPD and LOPD in these ratios. However there was significant difference in visual analysis (tracer uptake) as well as in uptake ratio between putamen and caudate nucleuses in both groups (P=0.001). On the other word, we found more diminished uptake in putamen as compared the caudate. Frequency and severity of putamen involvement were much more than caudate. CONCLUSION: 99mTc-TRODAT-1 SPECT imaging showed lower presynaptical dopami-nergical terminals density in both EOPD and LOPD. There was no difference between EOPD and LOPD in TRODAT uptake. Putamen showed more involvement and more diminished TRODAT uptake. PMID- 28660223 TI - Development and Evaluation of Image Reconstruction Algorithms for a Novel Desktop SPECT System. AB - OBJECTIVE S: Various iterative reconstruction algorithms in nuclear medicine have been introduced in the last three decades. For each new imaging system, it is wise to select appropriate image reconstruction algorithms and evaluate their performance. In this study, three approaches of image reconstruction were developed for a novel desktop open-gantry SPECT system, PERSPECT, to assess their performance in terms of the quality of the resultant reconstructed images. METHODS: In the present work, a proposed image reconstruction algorithm for the PERSPECT, referred to as quasi-simultaneous multiplicative algebraic reconstruction technique (qSMART), together with two popular image reconstruction methods, maximum-likelihood expectation-maximization (MLEM) and ordered-subsets EM (OSEM), were implemented and compared. Analytic and Monte Carlo simulations were applied for data acquisition of various phantoms including a micro-Derenzo phantom. All acquired data were reconstructed by the three algorithms using different number of iterations (1-40 ). A thorough set of figures-of-merit was utilized to quantitatively compare the generated images. RESULTS: OSEM depicted reconstructed images of higher (or matching) quality in comparison to qSMART. MLEM also reached nearly similar quality as OSEM but at higher number of iterations. The graph of data discrepancy revealed that the ranking of the three approaches in terms of convergence speed is as qSMART, OSEM, and MLEM. Furthermore, bias-versus-noise curves indicated that optimal bias-noise results were achieved using OSEM. CONCLUSION: The results showed that although qSMART can be applied for image reconstruction if being halted in the early iterations (up to 5), the best achievable quality of images is obtained using the OSEM. PMID- 28660224 TI - Edge Artifacts in Point Spread Function-based PET Reconstruction in Relation to Object Size and Reconstruction Parameters. AB - OBJECTIVES: We evaluated edge artifacts in relation to phantom diameter and reconstruction parameters in point spread function (PSF)-based positron emission tomography (PET) image reconstruction. METHODS: PET data were acquired from an original cone-shaped phantom filled with 18F solution (21.9 kBq/mL) for 10 min using a Biograph mCT scanner. The images were reconstructed using the baseline ordered subsets expectation maximization (OSEM) algorithm and the OSEM with PSF correction model. The reconstruction parameters included a pixel size of 1.0, 2.0, or 3.0 mm, 1-12 iterations, 24 subsets, and a full width at half maximum (FWHM) of the post-filter Gaussian filter of 1.0, 2.0, or 3.0 mm. We compared both the maximum recovery coefficient (RCmax) and the mean recovery coefficient (RCmean) in the phantom at different diameters. RESULTS: The OSEM images had no edge artifacts, but the OSEM with PSF images had a dense edge delineating the hot phantom at diameters 10 mm or more and a dense spot at the center at diameters of 8 mm or less. The dense edge was clearly observed on images with a small pixel size, a Gaussian filter with a small FWHM, and a high number of iterations. At a phantom diameter of 6-7 mm, the RCmax for the OSEM and OSEM with PSF images was 60% and 140%, respectively (pixel size: 1.0 mm; FWHM of the Gaussian filter: 2.0 mm; iterations: 2). The RCmean of the OSEM with PSF images did not exceed 100%. CONCLUSION: PSF-based image reconstruction resulted in edge artifacts, the degree of which depends on the pixel size, number of iterations, FWHM of the Gaussian filter, and object size. PMID- 28660225 TI - Incidental Unilateral Tuberculous Sacroiliitis Detected by 18F-FDG PET/CT in a Patient with Abdominal Tuberculosis. AB - Tuberculosis is a systemic disease which involves skeletal and articular system very rarely. Osteoarticular tuberculosis commonly occurs in the vertebral column and more rarely in the sacroiliac joints. In this study, we report a 44-years-old male patient with low-grade fever, malabsorption syndrome, abdominal and pelvic ascites and low-back pain, that underwent 18F-FDG PET/CT for identifying the cause of signs and symptoms after a negative abdominal CT and negative thorax radiography. The study revealed increased tracer uptake at the peritoneal ascites and at the right sacroiliac joint in absence of bone alteration suggesting a sacroiliitis. Staining of the ascitic fluid was positive for acid-fast bacilli (Ziehl-Neelsen) and in the subsequent abdominal paracentesis Mycobacterium Tuberculosis was isolated; the final diagnosis was abdominal tuberculosis with a sacroiliac joint involvement. The patient started antitubercular therapy for 6 months and the clinical conditions were resolved, in particular both back pain and ascites disappeared. PMID- 28660226 TI - Generalized Lymph Node Activation after Influenza Vaccination on 18F FDG-PET/CT Imaging, an Important Pitfall in PET Interpretation. AB - We report on a 59-year-old female patient with an infected vascular graft investigated with 18F FDG-PET/CT. The first of two studies showed FDG activity in the left deltoid and ipsilateral axillary lymph nodes explained by influenza vaccination the day prior. The second 18F FDG-PET/CT showed multiple FDG-avid lymph nodes on both sides of the diaphragm without tracer accumulation at the vaccination site. Three months later the CT was negative for lymphadenopathy within the chest or abdominal region. Although influenza vaccination is a potential source of false positive results in FDG PET studies, generalised lymph node activation post vaccination is a rare finding with only one prior published report in individuals infected with HIV-1. This case emphasizes the necessity of taking a history of vaccination prior to a FDG PET study, and consideration of a vaccine-related immune response even without evidence of tracer activity at the vaccination site when generalised FDG-avid lymphadenopathy is encountered. PMID- 28660227 TI - Sectional Anatomy Quiz. AB - This image based series comprises of a quiz pertaining to the identification of salient anatomical structures expected to be seen at a given level on the computed tomography (CT) followed by examples of multiple representative pathologies that can be seen at the same level in a routine clinical setting. It is expected that this will improve confidence of nuclear physicians in interpretation of the CT component of the single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. PMID- 28660228 TI - Necrotizing Autoimmune Myopathy: A Rare Variant of Idiopathic Inflammatory Myopathies. AB - Idiopathic inflammatory myopathies are an unusual group of myopathies with annual incidence of 1 in 100 000 people in the United States. Necrotizing autoimmune myopathy comprises only 16% of this group. It usually presents with severe proximal weakness, lower extremity weakness, and severe fatigue while very rarely does it present with dysphagia and respiratory muscle weakness. Statin use, cancer, and connective tissue disorder are the usual associated risk factors. Anti-signal recognition particle and 3-hydroxy-3-methylglutaryl-coenzyme A reductase are the 2 most common autoantibodies associated with necrotizing autoimmune myopathy. In this article, we present a very rare case of a 66-year old male who presented with shortness of breath and dysphagia requiring intubation and ventilator support. Creatine kinase was 23 000, myoglobin was 7000, and ANA was positive. All other autoimmune and infectious workup including Lyme disease was unremarkable. Muscle biopsy turned out remarkable for necrotizing myopathy. No evidence of statin use, active malignancy, or connective tissue disease was found. He was treated with high-dose corticosteroids and a short course of intravenous immunoglobulin with very mild improvement in symptoms. Anti-signal recognition particle and 3-hydroxy-3-methylglutaryl coenzyme A reductase could not be performed as the patient refused to pursue further medical testing. This is a very rare case of idiopathic inflammatory myopathy presenting with bulbar and respiratory muscle weakness requiring ventilator support. PMID- 28660229 TI - Lateral Meniscus Posterior Root and Meniscofemoral Ligaments as Stabilizing Structures in the ACL-Deficient Knee: A Biomechanical Study. AB - BACKGROUND: The biomechanical effects of lateral meniscal posterior root tears with and without meniscofemoral ligament (MFL) tears in anterior cruciate ligament (ACL)-deficient knees have not been studied in detail. PURPOSE: To determine the biomechanical effects of the lateral meniscus (LM) posterior root tear in ACL-intact and ACL-deficient knees. In addition, the biomechanical effects of disrupting the MFLs in ACL-deficient knees with meniscal root tears were evaluated. STUDY DESIGN: Controlled laboratory study. METHODS: Ten paired cadaveric knees were mounted in a 6-degrees-of-freedom robot for testing and divided into 2 groups. The sectioning order for group 1 was (1) ACL, (2) LM posterior root, and (3) MFLs, and the order for group 2 was (1) LM posterior root, (2) ACL, and (3) MFLs. For each cutting state, displacements and rotations of the tibia were measured and compared with the intact state after a simulated pivot-shift test (5-N.m internal rotation torque combined with a 10-N.m valgus torque) at 0 degrees , 20 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion; an anterior translation load (88 N) at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion; and internal rotation (5 N.m) at 0 degrees , 30 degrees , 60 degrees , 75 degrees , and 90 degrees . RESULTS: Cutting the LM root and MFLs significantly increased anterior tibial translation (ATT) during a pivot-shift test at 20 degrees and 30 degrees when compared with the ACL-cut state (both Ps < .05). During a 5-N.m internal rotation torque, cutting the LM root in ACL-intact knees significantly increased internal rotation by between 0.7 degrees +/- 0.3 degrees and 1.3 degrees +/- 0.9 degrees (all Ps < .05) except at 0 degrees (P = .136). When the ACL + LM root cut state was compared with the ACL-cut state, the increase in internal rotation was significant at greater flexion angles of 75 degrees and 90 degrees (both Ps < .05) but not between 0 degrees and 60 degrees (all Ps > .2). For an anterior translation load, cutting the LM root in ACL-deficient knees significantly increased ATT only at 30 degrees (P = .007). CONCLUSION: The LM posterior root was a significant stabilizer of the knee for ATT during a pivot-shift test at lower flexion angles and internal rotation at higher flexion angles. CLINICAL RELEVANCE: Increased knee anterior translation and rotatory instability due to posterior lateral meniscal root disruption may contribute to increased loads on an ACL reconstruction graft. It is recommended that lateral meniscal root tears be repaired at the same time as an ACL reconstruction to prevent possible ACL graft overload. PMID- 28660230 TI - Long-Term Outcomes in Anterior Cruciate Ligament Reconstruction: A Systematic Review of Patellar Tendon Versus Hamstring Autografts. AB - BACKGROUND: Much controversy still exists surrounding graft choice in anterior cruciate ligament (ACL) reconstruction. Over the past decade, an increase in comparative studies with longer follow-up has enhanced our understanding of current graft options and outcomes. PURPOSE: To describe the long-term comparative outcomes of ACL reconstruction with autograft bone-patellar tendon bone (BPTB) versus autograft hamstring (HS) ACL reconstruction with regard to clinical and radiographic outcomes. STUDY DESIGN: Systematic review; Level of evidence, 2. METHODS: A search of the PubMed, MEDLINE, Cochrane, and Scopus databases was performed to identify studies in the English language with outcome data comparing ACL reconstruction utilizing autograft BPTB and autograft HS; only studies with a minimum 5-year follow-up were included. Outcome data included failure and complications, manual and instrumented laxity, patient-reported outcomes, and radiographic risk of osteoarthritis. RESULTS: Twelve studies with a total of 953 patients met the inclusion criteria. Of these studies, 8 were level 1 evidence and 2 were level 2. Mean follow-up was 8.96 years (range, 5-15.3 years). No differences in graft failure or manual or instrumented laxity were seen in any studies. Lower clinical outcomes scores and greater motion loss were seen in BPTB patients in 1 and 2 studies, respectively. Two of 4 studies reporting on anterior knee pain, and 3 of 7 that recorded kneeling pain found it more frequently among BPTB patients. One study found significantly increased reoperation rates in HS patients, while another found a similar result in BPTB, and 1 study reported a significant increase in contralateral ACL tears in BPTB patients. Three of 5 studies reporting on radiographic evidence of osteoarthritis noted significantly increased rates in BPTB patients. CONCLUSION: This systematic review comparing long-term outcomes after ACL reconstruction with either autograft BPTB or autograft HS suggests no significant differences in manual/instrumented laxity and graft failures between graft types. An increase in long-term anterior knee pain, kneeling pain, and higher rates of osteoarthritis were noted with BPTB graft use. PMID- 28660231 TI - The Impact of Data Dependence on Speaker Recognition Evaluation. AB - The data dependency due to multiple use of the same subjects has impact on the standard error (SE) of the detection cost function (DCF) in speaker recognition evaluation. The DCF is defined as a weighted sum of the probabilities of type I and type II errors at a given threshold. A two-layer data structure is constructed: target scores are grouped into target sets based on the dependency, and likewise for non-target scores. On account of the needed equal probabilities for scores being selected when resampling, target sets must contain the same number of target scores, and so must non-target sets. In addition to the bootstrap method with i.i.d. assumption, the nonparametric two-sample one-layer and two-layer bootstrap methods are carried out based on whether the resampling takes place only on sets, or subsequently on scores within the sets. Due to the stochastic nature of the bootstrap, the distributions of the SEs of the DCF estimated using the three different bootstrap methods are created and compared. After performing hypothesis testing, it is found that data dependency increases not only the SE but also the variation of the SE, and the two-layer bootstrap is more conservative than the one-layer bootstrap. The rationale regarding the different impacts of the three bootstrap methods on the estimated SEs is investigated. PMID- 28660232 TI - Adoptive Transfer of Lung Antigen Presenting Cells. AB - Our protocol describes adoptive transfer of antigen presenting cells (APCs) isolated from the lungs by enzymatic digestion and magnetic enrichment. This protocol can be used to study APC functions and trafficking. PMID- 28660233 TI - Chase Assay of Protein Stability in Haloferax volcanii. AB - Highly regulated and targeted protein degradation plays a fundamental role in almost all cellular processes. Determination of the protein half-life by the chase assay serves as a powerful and popular strategy to compare the protein stability and study proteolysis pathways in cells. Here, we describe a chase assay in Haloferax volcanii, a halophilic archaeon as the model organism. PMID- 28660234 TI - Isolation of Exosomes from Semen for in vitro Uptake and HIV-1 Infection Assays. AB - Exosomes are membranous extracellular nanovesicles of endocytic origin. Exosomes are known to carry host and pathogen-derived genomic, proteomic, lipidomic cargos and other extraneous molecules. Exosomes are secreted by diverse cell types into the extracellular milieu and are subsequently internalized by recipient neighboring or distal cells. Upon internalization, exosomes condition recipient cells by donating their cargos and/or activating various signal transduction pathways, consequently regulating physiological and pathophysiological processes. Exosomes facilitate intercellular communication, modulate cellular phenotype, and regulate microbial pathogenesis. We have previously shown that semen exosomes (SE) inhibit HIV-1 replication in various cell types. Here, we describe detailed protocols for characterizing SE. This protocol can be adapted or modified and used for evaluation of other extracellular vesicles of interest. PMID- 28660235 TI - A Co-culture Model for Determining the Target Specificity of the de novo Generated Retinal Ganglion Cells. AB - In glaucoma, the output neurons of the retina, the retinal ganglion cells (RGCs), progressively degenerate, leading to irreversible blindness (Ahram et al., 2015). The ex vivo stem cell method to replace degenerated RGCs remains a potentially viable approach (Levin et al., 2004). However, the success of the approach depends upon the ability of the de novo generated RGCs to connect over the long distance with specific targets in the central visual pathway. Here, we describe a protocol to examine the target specificity of the de novo generated RGCs using a co-culture approach where the RGCs neurites are allowed to choose between specific (superior colliculus; SC) and non-specific (inferior colliculus; IC) tectal targets. PMID- 28660236 TI - Expression, Purification and Crystallisation of the Adenosine A2A Receptor Bound to an Engineered Mini G Protein. AB - G protein-coupled receptors (GPCRs) promote cytoplasmic signalling by activating heterotrimeric G proteins in response to extracellular stimuli such as light, hormones and nucleosides. Structure determination of GPCR-G protein complexes is central to understanding the precise mechanism of signal transduction. However, these complexes are challenging targets for structural studies due to their conformationally dynamic and inherently transient nature. We recently developed an engineered G protein, mini-Gs, which addressed these problems and allowed the formation of a stable GPCR-G protein complex. Mini-Gs facilitated the structure determination of the human adenosine A2A receptor (A2AR) in its G protein-bound conformation at 3.4 A resolution. Here, we describe a step by step protocol for the expression and purification of A2AR, and crystallisation of the A2AR-mini-Gs complex. PMID- 28660237 TI - Analysis of Replicative Intermediates of Adeno-associated Virus through Hirt Extraction and Southern Blotting. AB - Adeno-associated virus (AAV) is a small single-stranded DNA virus that requires the presence of a helper virus, such as adenovirus or herpes virus, to efficiently replicate its genome. AAV DNA is replicated by a rolling-hairpin mechanism (Ward, 2006), and during replication several DNA intermediates can be detected. This detailed protocol describes how to analyze the AAV DNA intermediates formed during AAV replication using a modified Hirt extract (Hirt, 1967) procedure and Southern blotting (Southern, 1975). PMID- 28660238 TI - Uncovering Factors Influencing Interpersonal Health Communication. AB - Talking to friends, family, or peers about health issues might, among other things, increase knowledge of social norms and feelings of self-efficacy in adopting a healthier lifestyle. We often see interpersonal health communication as an important mediating factor in the effects of health campaigns on health behavior. No research has been done so far, however, on factors that influence whether and how people talk about health issues without being exposed to a health campaign first. In this exploratory study, we interviewed 12 participants about their communication behavior concerning six different health themes, like smoking and exercising. The results suggest that at least four types of interpersonal health communication can be distinguished, each influenced by different factors, like conversational partner and objective of the conversation. Future research should take this diversity of interpersonal health communication into account, and focus on designing health campaigns that aim to trigger dialogue within target populations. PMID- 28660239 TI - Factors Influencing Diabetes Self-Management Among Medically Underserved Patients With Type II Diabetes. AB - In this study, researchers compare and contrast issues regarding diabetes self management between persons in good versus poor glycemic control. The sample comprises low-income racially diverse adults with diabetes from four mid-western community health centers; 44 patients participated in eight focus groups divided by control status (HbA1c of > 9 [uncontrolled] or < 7 [controlled]). Themes common to both groups included the impact of dietary restrictions on social interactions, food cravings, the impact of mental health on self-management, and the importance of formal and informal (friends and family) support. Those in the uncontrolled groups described fear about being able to control their diabetes, confusion about self-management, and difficulty managing their diabetes while caring for family members. Although those in the controlled groups acknowledged difficulties, they discussed resisting cravings, making improvements with small changes, positive feelings about their ability to control their diabetes, and enjoying new foods and exercise. Interventions should include mental health support, incorporate formal and informal patient support structures, and address literacy issues. Health care providers and intervention personnel should be very concrete about how to do self-management tasks and guide patients on how to alter their diabetes regimens for social and other important life events. PMID- 28660240 TI - Sarcopenia and Predictors of Skeletal Muscle Mass in Elderly Men With and Without Obesity. AB - Objectives: The aim of this study was to determine the variables which show the highest association with muscle mass and to identify the most important predictors for muscle mass in elderly men with and without sarcopenia. Methods: A total of 71 men participated, aged >=65 years. Sarcopenia was assessed using the definition of the European Working Group on Sarcopenia in Older People with determining skeletal muscle index (SMI), hand-grip strength (HGS), and Short Physical Performance Battery. In addition, maximum strength at upper and lower extremities and physical activity were measured. Results: Strong correlations existed between SMI and gait speed, HGS, maximum isometric strength at leg and chest press. Physical activity showed low correlations with muscle strength. Regression analysis revealed HGS and gait speed as key predictors for SMI. Discussion: The recommendation is measuring gait speed and HGS in clinical practice at first followed by measuring muscle mass for determining sarcopenia. PMID- 28660241 TI - Are Psychosocial Resources Associated With Perceived Facial Aging in Men? AB - Background: Looking younger than actual age has been related to a variety of health outcomes. Optimism, self-esteem, and relationship satisfaction are important psychosocial resources for mental health. Little is known about their relation with a younger facial appearance. Objective: This study analyzed whether these psychosocial resources are associated with a younger facial appearance and if their effects were mediated through mental health. Method: A sample of N = 223 self-reporting healthy men aged 40 to 75 years filled in questionnaires to assess optimism (Life Orientation Test-Revised), self-esteem (Multidimensional Self Esteem Scale), relationship satisfaction (Relationship Assessment Scale), and mental health (Short-Form Health Survey). Five female raters estimated the visual age of each participant from a frontal face photograph. Results: Looking younger (compared with chronological age) was correlated with optimism, relationship satisfaction, and mental health. Mediation analyses and structural equation modeling indicated that mental health mediated the association between each psychosocial resource and a younger appearance. Discussion: The results emphasize the importance of promoting psychosocial resources and mental health in men 40+ for the maintenance of good health and the deceleration of facial aging. PMID- 28660242 TI - Bacterial Autophagy: Offense and Defense at the Host-Pathogen Interface. AB - Autophagy is a fundamental cellular process used for the turnover and recycling of cytosolic components and damaged organelles. Originally characterized as a response to cellular stress, it now is well established that autophagy also is used as a defensive mechanism to combat the infection of host cells by intracellular pathogens. However, although this defensive strategy does limit the proliferation of most pathogens within their host cells, successful pathogens have evolved countermeasures that subvert or circumvent the autophagic response. In this review, we discuss the mechanisms used by a number of these pathogens to escape autophagy, with a particular focus on Salmonella enterica serovar Typhimurium, which has been the most extensively studied example. We also discuss the consequences of bacterial autophagy for the broader innate immune response. PMID- 28660243 TI - Effects of Selective Deletion of Tyrosine Hydroxylase from Kisspeptin Cells on Puberty and Reproduction in Male and Female Mice. AB - The neuropeptide kisspeptin, encoded by Kiss1, regulates reproduction by stimulating GnRH secretion. Kiss1-syntheizing neurons reside primarily in the hypothalamic anteroventral periventricular (AVPV/PeN) and arcuate (ARC) nuclei. AVPV/PeN Kiss1 neurons are sexually dimorphic, with females expressing more Kiss1 than males, and participate in estradiol (E2)-induced positive feedback control of GnRH secretion. In mice, most AVPV/PeN Kiss1 cells coexpress tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis (in this case, dopamine). Dopamine treatment can inhibit GnRH neurons, but the function of dopamine signaling arising specifically from AVPV/PeN Kiss1 cells is unknown. We generated a novel TH flox mouse and used Cre-Lox technology to selectively ablate TH specifically from Kiss1 cells. We then examined the effects of selective TH knock-out on puberty and reproduction in both sexes. In control mice, 90% of AVPV/PeN Kiss1 neurons coexpressed TH, whereas in mice lacking TH exclusively in Kiss1 cells (termed Kiss THKOs), TH was successfully absent from virtually all Kiss1 cells. Despite this absence of TH, both female and male Kiss THKOs displayed normal body weights, puberty onset, and basal gonadotropin levels in adulthood, although testosterone (T) was significantly elevated in adult male Kiss THKOs. The E2-induced LH surge was unaffected in Kiss THKO females, and neuronal activation status of kisspeptin and GnRH cells was also normal. Supporting this, fertility and fecundity were normal in Kiss THKOs of both sexes. Thus, despite high colocalization of TH and Kiss1 in the AVPV/PeN, dopamine produced in these cells is not required for puberty or reproduction, and its function remains unknown. PMID- 28660244 TI - Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions. AB - Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral "notch" of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing. PMID- 28660245 TI - Plasticity in the Structure of Visual Space. AB - Visual space embodies all visual experiences, yet what determines the topographical structure of visual space remains unclear. Here we test a novel theoretical framework that proposes intrinsic lateral connections in the visual cortex as the mechanism underlying the structure of visual space. The framework suggests that the strength of lateral connections between neurons in the visual cortex shapes the experience of spatial relatedness between locations in the visual field. As such, an increase in lateral connection strength shall lead to an increase in perceived relatedness and a contraction in perceived distance. To test this framework through human psychophysics experiments, we used a Hebbian training protocol in which two-point stimuli were flashed in synchrony at separate locations in the visual field, to strengthen the lateral connections between two separate groups of neurons in the visual cortex. After training, participants experienced a contraction in perceived distance. Intriguingly, the perceptual contraction occurred not only between the two training locations that were linked directly by the changed connections, but also between the outward untrained locations that were linked indirectly through the changed connections. Moreover, the effect of training greatly decreased if the two training locations were too close together or too far apart and went beyond the extent of lateral connections. These findings suggest that a local change in the strength of lateral connections is sufficient to alter the topographical structure of visual space. PMID- 28660246 TI - GABA-B Controls Persistent Na+ Current and Coupled Na+-Activated K+ Current. AB - The GABA-B receptor is densely expressed throughout the brain and has been implicated in many CNS functions and disorders, including addiction, epilepsy, spasticity, schizophrenia, anxiety, cognitive deficits, and depression, as well as various aspects of nervous system development. How one GABA-B receptor is involved in so many aspects of CNS function remains unanswered. Activation of GABA-B receptors is normally thought to produce inhibitory responses in the nervous system, but puzzling contradictory responses exist. Here we report that in rat mitral cells of the olfactory bulb, GABA-B receptor activation inhibits both the persistent sodium current (INaP) and the sodium-activated potassium current (IKNa), which is coupled to it. We find that the primary effect of GABA-B activation is to inhibit INaP, which has the secondary effect of inhibiting IKNa because of its dependence on persistent sodium entry for activation. This can have either a net excitatory or inhibitory effect depending on the balance of INaP/IKNa currents in neurons. In the olfactory bulb, the cell bodies of mitral cells are densely packed with sodium-activated potassium channels. These channels produce a large IKNa which, if constitutively active, would shunt any synaptic potentials traversing the soma before reaching the spike initiation zone. However, GABA-B receptor activation might have the net effect of reducing the IKNa blocking effect, thus enhancing the effectiveness of synaptic potentials. PMID- 28660247 TI - Phototransduction in Drosophila Is Compromised by Gal4 Expression but not by InsP3 Receptor Knockdown or Mutation. AB - Drosophila phototransduction is mediated by phospholipase C, leading to activation of transient receptor potential (TRP) and TRP-like (TRPL) channels by mechanisms that are unresolved. A role for InsP3 receptors (IP3Rs) had been excluded because IP3R mutants (itpr) appeared to have normal light responses; however, this was recently challenged by Kohn et al. ("Functional cooperation between the IP3 receptor and phospholipase C secures the high sensitivity to light of Drosophila photoreceptors in vivo," Journal of Neuroscience 35:2530), who reported defects in phototransduction after IP3R-RNAi knockdown. They concluded that InsP3-induced Ca2+ release plays a critical role in facilitating channel activation, and that previous failure to detect IP3R phenotypes resulted from trace Ca2+ in electrodes substituting for InsP3-induced Ca2+ release. In an attempt to confirm this, we performed electroretinograms, whole-cell recordings, and GCaMP6f Ca2+ imaging from both IP3R-RNAi flies and itpr-null mutants. Like Kohn et al., we used GMRGal4 to drive expression of UAS-IP3R-RNAi, but we also used controls expressing GMRGal4 alone. We describe several GMRGal4 phenotypes suggestive of compromised development, including reductions in sensitivity, dark noise, potassium currents, and cell size and capacitance, as well as extreme variations in sensitivity between cells. However, we found no effect of IP3R RNAi or mutation on photoreceptor responses or Ca2+ signals, indicating that the IP3R plays little or no role in Drosophila phototransduction. PMID- 28660249 TI - Tracking Down Nonresponsive Cortical Neurons in Cochlear Implant Stimulation. PMID- 28660248 TI - Optogenetic Evidence for a Direct Circuit Linking Nociceptive Transmission through the Parabrachial Complex with Pain-Modulating Neurons of the Rostral Ventromedial Medulla (RVM). AB - The parabrachial complex (PB) is a functionally and anatomically complex structure involved in a range of homeostatic and sensory functions, including nociceptive transmission. There is also evidence that PB can engage descending pain-modulating systems, the best characterized of which is the rostral ventromedial medulla (RVM). Two distinct classes of RVM neurons, "ON-cells" and "OFF-cells," exert net pronociceptive and anti-nociceptive effects, respectively. PB was recently shown to be a relay of nociceptive information to RVM ON- and OFF cells. The present experiments used optogenetic methods in a lightly anesthetized rat and an adult RVM slice to determine whether there are direct, functionally relevant inputs to RVM pain-modulating neurons from PB. Whole-cell patch-clamp recordings demonstrated that PB conveys direct glutamatergic and GABAergic inputs to RVM neurons. Consistent with this, in vivo recording showed that nociceptive evoked responses of ON- and OFF-cells were suppressed by optogenetic inactivation of archaerhodopsin (ArchT)-expressing PB terminals in RVM, demonstrating that a net inhibitory input to OFF-cells and net excitatory input to ON-cells are engaged by acute noxious stimulation. Further, the majority of ON- and OFF-cells responded to optogenetic activation of channelrhodopsin (ChR2)-expressing terminals in the RVM, confirming a direct PB influence on RVM pain-modulating neurons. These data show that a direct connection from the PB to the RVM conveys nociceptive information to the pain-modulating neurons of RVM under basal conditions. They also reveal additional inputs from PB with the capacity to activate both classes of RVM pain-modulating neurons and the potential to be recruited under different physiological and pathophysiological conditions. PMID- 28660250 TI - Shape Selectivity of Middle Superior Temporal Sulcus Body Patch Neurons. AB - Functional MRI studies in primates have demonstrated cortical regions that are strongly activated by visual images of bodies. The presence of such body patches in macaques allows characterization of the stimulus selectivity of their single neurons. Middle superior temporal sulcus body (MSB) patch neurons showed similar stimulus selectivity for natural, shaded, and textured images compared with their silhouettes, suggesting that shape is an important determinant of MSB responses. Here, we examined and modeled the shape selectivity of single MSB neurons. We measured the responses of single MSB neurons to a variety of shapes producing a wide range of responses. We used an adaptive stimulus sampling procedure, selecting and modifying shapes based on the responses of the neuron. Forty percent of shapes that produced the maximal response were rated by humans as animal-like, but the top shape of many MSB neurons was not judged as resembling a body. We fitted the shape selectivity of MSB neurons with a model that parameterizes shapes in terms of curvature and orientation of contour segments, with a pixel-based model, and with layers of units of convolutional neural networks (CNNs). The deep convolutional layers of CNNs provided the best goodness of-fit, with a median explained explainable variance of the neurons' responses of 77%. The goodness-of-fit increased along the convolutional layers' hierarchy but was lower for the fully connected layers. Together with demonstrating the successful modeling of single unit shape selectivity with deep CNNs, the data suggest that semantic or category knowledge determines only slightly the single MSB neuron's shape selectivity. PMID- 28660251 TI - Avoidant Responses to Interpersonal Provocation Are Associated with Increased Amygdala and Decreased Mentalizing Network Activity. AB - When intentionally pushed or insulted, one can either flee from the provoker or retaliate. The implementation of such fight-or-flight decisions is a central aspect in the genesis and evolution of aggression episodes, yet it is usually investigated only indirectly or in nonsocial situations. In the present fMRI study, we aimed to distinguish brain regions associated with aggressive and avoidant responses to interpersonal provocation in humans. Participants (thirty six healthy young women) could either avoid or face a highly (HP) and a lowly (LP) provoking opponent in a competitive reaction time task: the fight-or-escape (FOE) paradigm. Subjects avoided the HP more often, but retaliated when facing her. Moreover, they chose to fight the HP more quickly, and showed increased heart rate (HR) right before confronting her. Orbitofrontal cortex (OFC) and sensorimotor cortex were more active when participants decided to fight, whereas the mentalizing network was engaged when deciding to avoid. Importantly, avoiding the HP relative to the LP was associated with both higher activation in the right basolateral amygdala and lower relative activity in several mentalizing regions [e.g., medial and inferior frontal gyrus (IFG), temporal-parietal junction (TPJ)]. These results suggest that avoidant responses to provocation might result from heightened threat anticipation and are associated with reduced perspective taking. Furthermore, our study helps to reconcile conflicting findings on the role of the mentalizing network, the amygdala, and the OFC in aggression. PMID- 28660252 TI - Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. AB - OBJECTIVE: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). METHODS: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20). RESULTS: Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR. CONCLUSIONS: In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases. PMID- 28660253 TI - Non-auditory neurocognitive skills contribute to speech recognition in adults with cochlear implants. AB - OBJECTIVE: Unexplained variability in speech recognition outcomes among postlingually deafened adults with cochlear implants (CIs) is an enormous clinical and research barrier to progress. This variability is only partially explained by patient factors (e.g., duration of deafness) and auditory sensitivity (e.g., spectral and temporal resolution). This study sought to determine whether non-auditory neurocognitive skills could explain speech recognition variability exhibited by adult CI users. STUDY DESIGN: Thirty postlingually deafened adults with CIs and thirty age-matched normal-hearing (NH) controls were enrolled. METHODS: Participants were assessed for recognition of words in sentences in noise and several non-auditory measures of neurocognitive function. These non-auditory tasks assessed global intelligence (problem solving), controlled fluency, working memory, and inhibition-concentration abilities. RESULTS: For CI users, faster response times during a non-auditory task of inhibition-concentration predicted better recognition of sentences in noise; however, similar effects were not evident for NH listeners. CONCLUSIONS: Findings from this study suggest that inhibition-concentration skills play a role in speech recognition for CI users, but less so for NH listeners. Further research will be required to elucidate this role and its potential as a novel target for intervention. PMID- 28660254 TI - CB1 allosteric modulator Org27569 is an antagonist/inverse agonist of ERK1/2 signaling. AB - Allosteric modulation of cannabinoid type-1 receptors (CB1) is a novel means through which signaling bias may be exerted. Org27569 remains the most characterized CB1 allosteric modulator yet there are conflicting reports regarding its effects on extracellular signal-regulated kinase (ERK) signaling. We conducted a systematic evaluation of Org27569 signaling through ERK. We have found that Org27569 is an antagonist of human CB1 (hCB1) mediated ERK signaling in HEK293 cells where it fully blocks CP55,940- but does not completely inhibit THC- and 2-AG-stimulated ERK1/2 activation. In hCB1 HEK293 cells, CP55,940 (1 MUM) treatment produced a significant increase in puncta at 20, 40, 60, and 120 min, consistent with receptor internalization. Org27569 (10 MUM) co-treatment prevented internalization at each time point and alone had no effect. These data demonstrate that Org27569 can block the CP55,940- induced internalization of CB1 receptors. Org27569 reduced basal ERK phosphorylation in hCB1 HEK293 cells but not in untransfected cells, demonstrating that Org27569 acts via the CB1 receptor to produce this effect. Furthermore, inverse agonism was through inhibition of Gi/o as overnight treatment with pertussis toxin abated this response. Finally, to delineate Org27569's effects on ERK1/2 in subcellular compartments, subcellular fractionation was performed; Org27569 produced a significant decrease in ERK phosphorylation in the nuclear-enriched and cytosolic fractions. Altogether, these data are consistent with previous studies demonstrating that CB1-mediated ERK1/2 activation is Gi/o-dependent and that Org27569 is an inverse agonist of CB1 receptors. To our knowledge this is the first reported demonstration of inverse agonism of ERK signaling by Org27569. PMID- 28660255 TI - Employee and customer handling of nicotine-containing e-liquids in vape shops. AB - INTRODUCTION: Vape shops sell electronic cigarettes and related products such as e-liquids, which may contain nicotine. Direct contact with nicotine can lead to adverse health effects, and few regulations exist on how nicotine is handled in vape shops. This study examined how customers and employees come into contact with, and handle, nicotine-containing e-liquids in vape shops with the goal of informing potential future regulation of nicotine handling in vape shops. METHODS: Data were collected from 77 vape shops in the Los Angeles basin. Characteristics of the shops were documented by employee interviews and in store observations. Data collection was focused on shops located in areas with high concentrations of communities of interest; 20 shops from African-American communities, 17 from Hispanic communities, 18 from Korean communities, and 22 from non-Hispanic White communities. RESULTS: Half of the vape shops allowed customers to sample e-liquids with nicotine. Most of the shops (83%) provided self-service sampling stations for customers. A majority of shop employees (72%) reported that spills of e-liquids containing nicotine had occurred in the past. While 64% of the shops provided safety equipment, only 34% provided equipment for proper nicotine handling. Furthermore, 62% of shop employees reported handling nicotine without gloves or other safety equipment. CONCLUSIONS: Regulation on the handling of nicotine by customers and vape shop employees is important to prevent unsafe practices and subsequent injury. The frequent occurrence of spills and limited availability of safety equipment in vape shops highlights the need for the creation and enforcement of regulations to protect employees and customers. Appropriate safety training and equipment should be provided to employees to prevent accidental exposure to nicotine. Information on ways to safely handle nicotine should be communicated to vape shop employees and customers. PMID- 28660256 TI - A Comparison of Inpatient Cost Per Day in General Surgery Patients with Type 2 Diabetes Treated with Basal-Bolus versus Sliding Scale Insulin Regimens. AB - BACKGROUND: The identification of cost-effective glycaemic management strategies is critical to hospitals. Treatment with a basal-bolus insulin (BBI) regimen has been shown to result in better glycaemic control and fewer complications than sliding scale regular insulin (SSI) in general surgery patients with type 2 diabetes mellitus (T2DM), but the effect on costs is unknown. OBJECTIVE: We conducted a post hoc analysis of the RABBIT Surgery trial to examine whether total inpatient costs per day for general surgery patients with T2DM treated with BBI (n = 103) differed from those for patients with T2DM treated with SSI (n = 99) regimens. METHODS: Data were collected from patient clinical and hospital billing records. Charges were adjusted to reflect hospital costs. General linearized models were used to estimate the risk-adjusted effects of BBI versus SSI treatment on average total inpatient costs per day. RESULTS: Risk-adjusted average total inpatient costs per day were $US5404. Treatment with BBI compared with SSI reduced average total inpatient costs per day by $US751 (14%; 95% confidence interval [CI] 20-4). Being treated in a university medical centre, being African American or having a bowel procedure or higher-volume pharmacy use significantly reduced costs per day. CONCLUSIONS: In general surgery patients with T2DM, a BBI regimen significantly reduced average total hospital costs per day compared with an SSI regimen. BBI has been shown to improve outcomes in a randomized controlled trial. Those results, combined with our findings regarding savings, suggest that hospitals should consider adopting BBI regimens in patients with T2DM undergoing surgery. PMID- 28660257 TI - Inducing Domain-Specific Sentiment Lexicons from Unlabeled Corpora. AB - A word's sentiment depends on the domain in which it is used. Computational social science research thus requires sentiment lexicons that are specific to the domains being studied. We combine domain-specific word embeddings with a label propagation framework to induce accurate domain-specific sentiment lexicons using small sets of seed words. We show that our approach achieves state-of-the-art performance on inducing sentiment lexicons from domain-specific corpora and that our purely corpus-based approach outperforms methods that rely on hand-curated resources (e.g., WordNet). Using our framework, we induce and release historical sentiment lexicons for 150 years of English and community-specific sentiment lexicons for 250 online communities from the social media forum Reddit. The historical lexicons we induce show that more than 5% of sentiment-bearing (non neutral) English words completely switched polarity during the last 150 years, and the community-specific lexicons highlight how sentiment varies drastically between different communities. PMID- 28660258 TI - Polarisation-controlled single photon emission at high temperatures from InGaN quantum dots. AB - Solid-state single photon sources with polarisation control operating beyond the Peltier cooling barrier of 200 K are desirable for a variety of applications in quantum technology. Using a non-polar InGaN system, we report the successful realisation of single photon emission with a g(2)(0) of 0.21, a high polarisation degree of 0.80, a fixed polarisation axis determined by the underlying crystallography, and a GHz repetition rate with a radiative lifetime of 357 ps at 220 K in semiconductor quantum dots. The temperature insensitivity of these properties, together with the simple planar epitaxial growth method and absence of complex device geometries, demonstrates that fast single photon emission with polarisation control can be achieved in solid-state quantum dots above the Peltier temperature threshold, making this system a potential candidate for future on-chip applications in integrated systems. PMID- 28660259 TI - Ultrasensitive surface-enhanced Raman scattering detection of urea by highly ordered Au/Cu hybrid nanostructure arrays. AB - We report a simple approach to fabricate cost-effective and highly sensitive surface-enhanced Raman scattering substrates based on Au/Cu hybrid nanostructure arrays for the detection of urea, an important molecule in biological and medical fields. By effectively adjusting the gap size between neighbouring nanorods into the sub-10 nm regime, a high density of hot-spots was generated, enabling the substrates to detect urea signals at a concentration as low as 1 mM with great reproducibility. PMID- 28660260 TI - Aromatic stacking - a key step in nucleation. AB - Crystal nucleation from solution is of central importance in the chemical and biological sciences. Linking nucleation kinetics to the properties of solutes and solvents remains a grand-challenge in physical chemistry. Through a unique dataset of compounds able to self-assemble via both hydrogen-bonds and aromatic stacking, we are able to compare the importance of these two types of interaction in driving the nucleation process. Contrary to previous reports in which solution chemistry and hydrogen bonding have been seen as controlling factors, we are now able to show that cluster growth via aromatic stacking holds the key. PMID- 28660261 TI - Iron-catalyzed cascade reaction of 2-aminobenzyl alcohols with benzylamines: synthesis of quinazolines by trapping of ammonia. AB - A novel approach to construct 2-aryl/heteroaryl quinazolines was developed through an iron-catalyzed cascade reaction of 2-aminobenzyl alcohols with benzylamines under aerobic oxidative conditions. The reaction proceeds via the formation of N-benzylidenebenzylamines followed by oxidative trapping of ammonia/intramolecular cyclization in a one-pot manner. This method exhibits a broad substrate scope and a high tolerance level for sensitive functional groups, and is amenable to gram scale synthesis. PMID- 28660262 TI - Pyrene-tagged carbohydrate-based mixed P/S ligand: spacer effect on the Rh(i) catalyzed hydrogenation of methyl alpha-acetamidocinnamate. AB - The post-functionalization of a chiral catalyst offers the advantage of providing it with additional physical characteristics that, together with its enantioselective capacity, increase its overall synthetic value. Taking advantage of the modularity and polyfunctionality of carbohydrate-derived ligands, herein we report the synthesis of two mixed P/S catalysts functionalized with a pyrene group through the 6 position of the sugar by carbon chains of different lengths. Using the hydrogenation of methyl (Z)-alpha-acetamidocinnamate as the model reaction has shown that the proximity of the pyrenyl group to the catalytic center is detrimental to the activity and enantioselectivity of the hydrogenation process, the most efficient catalyst being the complex derived from pyrenebutyric acid 12. The study of the supramolecular pi-pi interaction of the most active complex 12 with SWCNTs by UV-Vis spectroscopy shows, that in ethyl acetate complex 12 is totally adsorbed onto the SWCNT surface, while in methylene chloride there is an equilibrium between the adsorbed and the free form of the complex, allowing the use of complex 12 and SWCNTs in a catch and release process. Interestingly, it has been determined that the nanocatalyst 12/SWCNT is more enantioselective than complex 12 alone, affording (S)-N-acetylphenyl alanine 16 in quantitative yield and 96% ee. PMID- 28660263 TI - A paper-based colorimetric spot test for the identification of adulterated whiskeys. AB - A colorimetric point-of-care paper-based analytical device (PAD) is developed for detecting adulterated beverages using whiskey falsified with caramel color as a model. Combining principal component analysis and calibration curves facilitated identification of adulteration in samples seized by the Brazilian Federal Police, at only ~$0.02 per sample. PMID- 28660264 TI - Platinated porphyrin as a new organelle and nucleus dual-targeted photosensitizer for photodynamic therapy. AB - Organelle and nucleus dual-targeted anticancer drugs are being increasingly used for efficient cancer therapy as they can attack the double vital sites of tumor cells. In this work, we synthesized and characterized two new porphyrin compounds Pt-Por-RB and Me-Por-RB. The spectral titration results suggest that both Pt-Por RB and Me-Por-RB bind to DNA efficiently in an intercalation binding mode. Upon irradiation, Pt-Por-RB with low dark-cytotoxicity can rapidly generate singlet oxygen to damage the tumor cells through the process of photodynamic therapy. Compared with Me-Por-RB, Pt-Por-RB was not only internalized in the organelles, but also in the nuclei of HeLa cells, probably due to the presence of platinum complexes, as analyzed using the confocal laser scanning microscope. Thus, with the combination of organelle and nucleus dual-targeting property and high efficiency of singlet oxygen generation, Pt-Por-RB showed a significant therapeutic activity against tumor cells. PMID- 28660265 TI - Correction: Arbuscular mycorrhizal fungi enhance the copper tolerance of Tagetes patula through the sorption and barrier mechanisms of intraradical hyphae. AB - Correction for 'Arbuscular mycorrhizal fungi enhance the copper tolerance of Tagetes patula through the sorption and barrier mechanisms of intraradical hyphae' by Xishi Zhou et al., Metallomics, 2017, DOI: . PMID- 28660266 TI - Monodispersed gold nanoparticles supported on a zirconium-based porous metal organic framework and their high catalytic ability for the reverse water-gas shift reaction. AB - A highly active and selective Au@UIO-67 catalyst has been assembled. Gold nanoparticles (AuNPs) are monodispersed on the UIO-67 surface of a porous metal organic framework, the micropores in UIO-67 as templates for adsorbing Au ions and enhancing interaction between AuNPs and UIO-67, favoring the formation of isolated and well-dispersed AuNPs. The catalyst exhibits high catalytic activity and CO selectivity for the reverse water-gas shift reaction in a fixed-bed flow reactor. PMID- 28660267 TI - Ru(ii)-Metal complex immobilized mesoporous SBA-15 hybrid for visible light induced photooxidation of chlorophenolic compounds in aqueous medium. AB - The work focuses on room-temperature photocatalytic degradation of phenolic compounds by Ru(ii)-complex immobilized mesoporous silica SBA-15 under visible light in an aqueous medium. The immobilization of [Ru(bpy)3]Cl2 complex on an SBA 15 surface is carried out, and the as-synthesized hybrid is characterized by X ray Diffraction (XRD), Fourier Transformation IR Spectroscopy (FTIR), Diffuse Reflectance Spectroscopy (DRS), Brunauer-Emmett-Teller analysis (BET), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray analysis (EDX) and X-ray Photoelectron Spectroscopy (XPS). Kinetic studies of photodegradation reactions are followed by High Performance Liquid Chromatography (HPLC). Control studies are performed to elucidate the nature of the photodegradation process. The maximum degradation of DCP reached 95% for 10 ppm concentration of the contaminants with an optimum amount of catalyst being 1 g L-1 in 150 min of light irradiation. The long-lived intermediates are identified by HPLC, and the final products are identified by GC-MS. From a series of experiments, the mechanistic steps of the photodegradation process are identified. PMID- 28660268 TI - Cancer bioimprinting and cell shape recognition for diagnosis and targeted treatment. AB - Cancer incidence and mortality have both increased in the last decade and are predicted to continue to rise. Diagnosis and treatment of cancers are often hampered by the inability to specifically target neoplastic cells. Bioimprinting is a promising new approach to overcome shortfalls in cancer targeting. Highly specific recognition cavities can be made into polymer matrices to mimic lock-and key actions seen in in vivo biological systems. Early studies concentrated on molecules and were inhibited by template size complexity. Surface imprinting allows the capture of increasingly complex motifs from polypeptides to single cell organisms and mammalian cells. Highly specific cell shape recognition can also be achieved by cell interaction with imprints that can be made into polymer matrices to mimic biological systems at a molecular level. Bioimprinting has also been used to achieve nanometre scale resolution imaging of cancer cells. Studies of bioimprint-based drug delivery on cancer cells have been recently trialled in vitro and show that this approach can potentially improve existing chemotherapeutic approaches. This review focuses on the possible applications of bioimprinting with particular regards to cancer understanding, diagnosis and therapy. Cell imprints, incorporated into biosensors can allow the limits of detection to be improved or negate the need for extensive patient sample processing. Similar cell imprinting platforms can be used for nanoscale imaging of cancer morphology, as well as to investigate topographical signalling of cancer cells in vitro. Lastly, bioimprints also have applications as selective drug delivery vehicles to tumours with the potential to decrease chemotherapy related side effects. PMID- 28660273 TI - Efficacy of cardiac magnetic resonance imaging in a sub-aortic aneurysm case. AB - Sub-aortic (SA) aneurysms are a rare entity of variable aetiology. We report the first case of a SA aneurysm assessed using cardiac magnetic resonance imaging (MRI). A 33-year-old female with human immunodeficiency virus and on highly active antiretroviral treatment presented with syncope and dyspnoea. Clinical examination suggested moderate to severe aortic regurgitation (AR) confirmed by transthoracic and transoesophageal echocardiograms. However, echocardiography was suboptimal in defining the precise mechanism and severity of AR. A cardiac MRI was done to elucidate the aetiology, severity and mechanism of regurgitation. It confirmed the presence of a SA aneurysm below the left coronary cusp and its retraction, resulting in an eccentric AR jet. An assessment of moderate AR, based on regurgitant volume, was made. Furthermore, the anatomical relationships of the aneurysm were clearly defined. Cardiac MRI allowed comprehensive assessment of this SA aneurysm. PMID- 28660274 TI - Pupillary Light Reflexes in Severe Photoreceptor Blindness Isolate the Melanopic Component of Intrinsically Photosensitive Retinal Ganglion Cells. AB - Purpose: Pupillary light reflex (PLR) is driven by outer retinal photoreceptors and by melanopsin-expressing intrinsically photosensitive retinal ganglion cells of the inner retina. To isolate the melanopic component, we studied patients with severe vision loss due to Leber congenital amaurosis (LCA) caused by gene mutations acting on the outer retina. Methods: Direct PLR was recorded in LCA patients (n = 21) with known molecular causation and severe vision loss. Standard stimuli (2.5 log scot-cd.m-2; ~13 log quanta.cm-2.s-1; achromatic full-field) with 0.1- or 5-second duration were used in all patients. Additional recordings were performed with higher luminance (3.9 log scot-cd.m-2) in a subset of patients. Results: The LCA patients showed no detectable PLR to the standard stimulus with short duration. With longer-duration stimuli, a PLR was detectable in the majority (18/21) of patients. The latency of the PLR was 2.8 +/- 1.3 seconds, whereas normal latency was 0.19 +/- 0.02 seconds. Peak contraction amplitude in patients was 1.1 +/- 0.9 mm at 6.2 +/- 2.3 seconds, considerably different from normal amplitude of 4.2 +/- 0.4 mm at 3.0 +/- 0.4 seconds. Recordings with higher luminance demonstrated that PLRs in severe LCA could also be evoked with short-duration stimuli. Conclusions: The PLR in severe LCA patients likely represents the activation of the melanopic circuit in isolation from rod and cone input. Knowledge of the properties of the human melanopic PLR allows not only comparison to those in animal models but also serves to define the fidelity of postretinal transmission in clinical trials targeting patients with no outer retinal function. PMID- 28660275 TI - The Magnitude of Hypotony and Time Course of Intraocular Pressure Recovery Following Anterior Chamber Cannulation in Nonhuman Primates. AB - Purpose: To determine the magnitude of ocular hypotony and the length of recovery time to 6 and 10 mm Hg IOP following anterior chamber (AC) cannulation. Methods: Bilateral IOP was recorded 500 times per second via telemetry immediately before, during, and immediately after AC cannulation with a 27-G needle in 10 different sessions at least 2 weeks apart in four male rhesus macaques (nonhuman primates; NHPs) aged 3- to 6-years old. Bilateral IOP was recorded continuously using a proven telemetry system while the NHPs were under general anesthesia during IOP transducer calibration experiments involving manometric control of IOP via AC cannulation, then continuously after the AC needles were removed until IOP recovered to precannulation levels. The change in IOP from baseline to AC cannulation was tested using the signed-rank test. The times necessary for IOP to recover to 6 and 10 mm Hg, respectively, were calculated. Results: Average precannulation IOP was 11.5 mm Hg and significantly decreased to an average of 2.3 mm Hg immediately following AC needle removal (P = 0.0156). On average, IOP recovered from 2.3 to 6 and 10 mm Hg in 32.4 and 63.7 minutes, respectively. Recovery times of IOP were not affected by repeated AC cannulations every 2 weeks. Conclusions: Generally, IOP recovers relatively quickly after repeated AC cannulation, and did not result in extended duration hypotony. It is important to consider hypotony in animal experiments and clinical procedures involving AC cannulation and paracentesis when consideration of IOP or its effects is important. PMID- 28660276 TI - Determining the Contribution of Retinotopic Discrimination to Localization Performance With a Suprachoroidal Retinal Prosthesis. AB - Purpose: With a retinal prosthesis connected to a head-mounted camera, subjects can perform low vision tasks using a combination of electrode discrimination and head-directed localization. The objective of the present study was to investigate the contribution of retinotopic electrode discrimination (perception corresponding to the arrangement of the implanted electrodes with respect to their position beneath the retina) to visual performance for three recipients of a 24-channel suprachoroidal retinal implant. Proficiency in retinotopic discrimination may allow good performance with smaller head movements, and identification of this ability would be useful for targeted rehabilitation. Methods: Three participants with retinitis pigmentosa performed localization and grating acuity assessments using a suprachoroidal retinal prosthesis. We compared retinotopic and nonretinotopic electrode mapping and hypothesized that participants with measurable acuity in a normal retinotopic condition would be negatively impacted by the nonretinotopic condition. We also expected that participants without measurable acuity would preferentially use head movement over retinotopic information. Results: Only one participant was able to complete the grating acuity task. In the localization task, this participant exhibited significantly greater head movements and significantly lower localization scores when using the nonretinotopic electrode mapping. There was no significant difference in localization performance or head movement for the remaining two subjects when comparing retinotopic to nonretinotopic electrode mapping. Conclusions: Successful discrimination of retinotopic information is possible with a suprachoroidal retinal prosthesis. Head movement behavior during a localization task can be modified using a nonretinotopic mapping. Behavioral comparisons using retinotopic and nonretinotopic electrode mapping may be able to highlight deficiencies in retinotopic discrimination, with a view to address these deficiencies in a rehabilitation environment. (ClinicalTrials.gov number, NCT01603576). PMID- 28660277 TI - Prediction of Anti-VEGF Treatment Requirements in Neovascular AMD Using a Machine Learning Approach. AB - Purpose: The purpose of this study was to predict low and high anti-VEGF injection requirements during a pro re nata (PRN) treatment, based on sets of optical coherence tomography (OCT) images acquired during the initiation phase in neovascular AMD. Methods: Two-year clinical trial data of subjects receiving PRN ranibizumab according to protocol specified criteria in the HARBOR study after three initial monthly injections were included. OCT images were analyzed at baseline, month 1, and month 2. Quantitative spatio-temporal features computed from automated segmentation of retinal layers and fluid-filled regions were used to describe the macular microstructure. In addition, best-corrected visual acuity and demographic characteristics were included. Patients were grouped into low and high treatment categories based on first and third quartile, respectively. Random forest classification was used to learn and predict treatment categories and was evaluated with cross-validation. Results: Of 317 evaluable subjects, 71 patients presented low (<=5), 176 medium, and 70 high (>=16) injection requirements during the PRN maintenance phase from month 3 to month 23. Classification of low and high treatment requirement subgroups demonstrated an area under the receiver operating characteristic curve of 0.7 and 0.77, respectively. The most relevant feature for prediction was subretinal fluid volume in the central 3 mm, with the highest predictive values at month 2. Conclusions: We proposed and evaluated a machine learning methodology to predict anti-VEGF treatment needs from OCT scans taken during treatment initiation. The results of this pilot study are an important step toward image-guided prediction of treatment intervals in the management of neovascular AMD. PMID- 28660278 TI - Trachomatous Scarring and Infection With Non-Chlamydia Trachomatis Bacteria in Women in Kongwa, Tanzania. AB - Purpose: To assess for an association between conjunctival infection with nonchlamydial bacterial species and the presence of trachomatous scarring (TS) in women in central Tanzania. Methods: Cross-sectional data were collected from a random sample of women ages 18 and older in 47 trachoma-endemic communities in Kongwa, Tanzania. Each participant completed a survey, provided a conjunctival swab sample, and received an ocular exam to assess for TS. Biologic samples were cultured for bacterial growth and speciation. Contingency tables were used to assess the associations between TS and bacterial carriage. Results: Complete data was provided by 3882 women (80.7% of invitees). Of all samples, 14% resulted in a positive bacterial isolate. There was no association between TS and nonchlamydial bacterial carriage, whether assessed by species, pathogenicity, or in aggregate. There was a significant association between increasing age and TS severity, but not between age and bacterial carriage. No Corynebacterium was found in the swabs. Conclusions: This study found no association between TS and nonchlamydial ocular infections, although associations with Corynebacterium cannot be ruled out. PMID- 28660279 TI - Mineral Depositions of Calcifying Skin Disorders are Predominantly Composed of Carbonate Apatite. AB - Subcutaneous calcifications can lead to complications, including pain, inflammation, ulceration and immobilization. Studies on the pathophysiology of mineral compositions and effective treatment modalities are limited. We therefore studied 14 patients with subcutaneous calcifications. Mineral material was collected and analysed by Fourier transform infrared spectrometry. Blood analyses were run to evaluate systemic alterations of mineral metabolism. Carbonate apatite (CAP) was found to be the single constituent in the majority of patients (n = 9, 64.3%), 3 cases (21.4%) had a composition of CAP and calcium oxalate dihydrate and one case had a combination of CAP and magnesium ammonium phosphate, whereas CAP was the major component in all 4 cases. Only one case showed predominantly calcium oxalate. Thus, CAP was found to be the only or predominant component in most cases of subcutaneous calcifications. Chemical analyses of the mineral compositions may aid in the development of new treatment regimes to improve the solubility of mineral components and to decrease extraosseous calcifications. PMID- 28660280 TI - Evaluation of a Rapid, Fully Automated Platform for Detection of BRAF and NRAS Mutations in Melanoma. AB - BRAF and NRAS genetic analyses are time-consuming and can delay treatment choices in patients with metastatic melanomas presenting with acute deterioration. We compared the rapid, real-time, fully automated molecular diagnosis platform IdyllaTM with next-generation sequencing (NGS) and immunohistochemistry for detection of BRAF and NRAS mutations in 36 patients with metastatic melanomas. The IdyllaTM NRAS-BRAF-EGFRS492R mutation assay (110 min per sample) detected BRAF and NRAS mutations in 15 and 17 samples, respectively. One NRAS mutation was different between NGS and IdyllaTM (NRASG13C vs. NRASG12A/D). Four samples were BRAF and NRAS wild-type. The global concordance between NGS and IdyllaTM assays was 97.2% (35/36 cases). Immunohistochemistry was positive only in 9/9 BRAFV600E- and 6/6 NRASQ61R-mutated samples with VE1 and SP174 antibodies, respectively. The IdyllaTM platform is a valuable rapid molecular diagnosis tool to reduce the delay in BRAF and NRAS analyses-related treatment choices for patients with metastatic melanoma presenting with acute deterioration. PMID- 28660281 TI - Quality of Life in Greek Patients with Autoimmune Bullous Diseases Assessed with ABQOL and TABQOL Indexes. AB - is missing (Short communication). PMID- 28660282 TI - A Pinkish-Blue Exophytic Nodule on the Arm of an Elderly Man: A Quiz. Melanocytic matricoma. PMID- 28660283 TI - A new method for predicting uric acid composition in urinary stones using routine single-energy CT. AB - Urinary stones composed of uric acid can be treated medically. Prediction of uric acid stone type is, therefore, desirable when a urinary stone is diagnosed with unenhanced CT. The purpose of the present study was to describe single-energy thin slice quantitative CT parameters of urinary stones correlated to chemical stone type and to develop a method to distinguish pure uric acid stones (UA) from other stones (non-UA/Mix). Unenhanced thin slice single-energy CT images of 126 urinary stones (117 patients) with known chemical stone type were retrospectively included in the study. Among the included stones, 22 were UA and 104 were non UA/Mix. The included CT images and Laplacian filtered images of the stones were quantitatively analyzed using operator-independent methods. A post hoc classification method for pure UA stones was created using a combination of cutoff values for the peak attenuation and peak point Laplacian. The stone types differed in most quantitative image characteristics including mean attenuation (p < 0.001), peak attenuation (p < 0.001), and peak point Laplacian (p < 0.001). The sensitivity for the post hoc-developed peak attenuation-peak point Laplacian method for classifying pure UA stones was 95% [21/22, 95% CI (77-100%)] and the specificity was 99% [103/104, 95% CI (95-100%)]. In conclusion, quantitative image analysis of thin slice routine single-energy CT images is promising for predicting pure UA content in urinary stones, with results comparable to double energy methods. PMID- 28660284 TI - Primary hyperoxaluria in populations of Pakistan origin: results from a literature review and two major registries. AB - Primary hyperoxalurias (PH) are devastating, autosomal recessive diseases causing renal stones. Undifferentiated hyperoxaluria is seen in up to 43% of Pakistani paediatric stone patients. High rates of consanguinity in Pakistan suggest significant local prevalence. There is no detailed information regarding number of cases, clinical features, and genetics in Pakistan-origin (P-o) patients. We reviewed available information on P-o PH patients recorded in the literature as well as from two major PH registries (the Rare Kidney Stone Consortium PH Registry (RKSCPHR) and the OxalEurope PH Registry (OxER); and the Aga Khan University Hospital in Pakistan. After excluding overlaps, we noted 217 P-o PH subjects (42 in OxER and 4 in RKSCPHR). Presentations were protean. Details of mutations were available for 94 patients of 201 who had genetic analyses. Unique mutations were noted. Mutation [c.508G>A (p. Gly170Arg)] (present in up to 25% in the West) was reported in only one case. In one series, only 30% had mutations on exons 1,4,7 of AGXT. Of 42 P-o patients in OxER, 52.4% were PH1, 45.2% PH2, and 2.4% PH3. Of concern is that diagnosis was made after renal transplant rejection (four cases) and on bone-marrow aspiration (in five). Lack of consideration of PH as a diagnosis, late diagnosis, and loss of transplanted kidneys mandates that PH be searched for diligently. Mutation analysis will need to extend to all exons and include PH 1,2,3. There is a need to spread awareness and identify patients through a scoring or screening system that alerts physicians to consider a diagnosis of PH. PMID- 28660285 TI - Exploring the quiet eye in archery using field- and laboratory-based tasks. AB - The 'quiet eye' (QE)-a period of extended gaze fixation on a target-has been reported in many tasks that require accurate aiming. Longer quiet eye durations (QEDs) are reported in experts compared to non-experts and on successful versus less successful trials. The QE has been extensively studied in the field; however, the cognitive mechanisms underlying the QE are not yet fully understood. We investigated the QEDs of ten expert and ten novice archers in the field and in the laboratory using a computer-based archery task. The computer task consisted of shooting archery targets using a joystick. Random 'noise' (visual motion perturbation) was introduced at high and low levels to allow for the controlled examination of the effects of task complexity and processing demands. In this computer task, we also tested an additional group of ten non-archers as controls. In both field and computer tasks, eye movements were measured using electro oculography. The expert archers exhibited longer QED compared to the novice archers in the field task. In the computer task, the archers again exhibited longer QEDs and were more accurate compared to non-archers. Furthermore, expert archers showed earlier QE onsets and longer QEDs during high noise conditions compared to the novices and non-archers. Our findings show skill-based effects on QED in field conditions and in a novel computer-based archery task, in which online (visual) perturbations modulated experts' QEDs. These longer QEDs in experts may be used for more efficient programming in which accurate predictions are facilitated by attention control. PMID- 28660286 TI - Hydrocinnamic Acid Inhibits the Currents of WT and SQT3 Syndrome-Related Mutants of Kir2.1 Channel. AB - Gain of function in mutations, D172N and E299V, of Kir2.1 will induce type III short QT syndrome. In our previous work, we had identified that a mixture of traditional Chinese medicine, styrax, is a blocker of Kir2.1. Here, we determined a monomer, hydrocinnamic acid (HA), as the effective component from 18 compounds of styrax. Our data show that HA can inhibit the currents of Kir2.1 channel in both excised inside-out and whole-cell patch with the IC50 of 5.21 +/- 1.02 and 10.08 +/- 0.46 mM, respectively. The time course of HA blockage and washout are 2.3 +/- 0.6 and 10.5 +/- 2.6 s in the excised inside-out patch. Moreover, HA can also abolish the currents of D172N and E299V with the IC50 of 6.66 +/- 0.57 and 5.81 +/- 1.10 mM for D172N and E299V, respectively. Molecular docking results determine that HA binds with Kir2.1 at K182, K185, and K188, which are phosphatidylinositol 4,5-bisphosphate (PIP2) binding residues. Our results indicate that HA competes with PIP2 to bind with Kir2.1 and inhibits the currents. PMID- 28660287 TI - Adverse outcome pathways: a concise introduction for toxicologists. AB - Adverse outcome pathways (AOPs) are designed to provide a clear-cut mechanistic representation of critical toxicological effects that propagate over different layers of biological organization from the initial interaction of a chemical with a molecular target to an adverse outcome at the individual or population level. Adverse outcome pathways are currently gaining momentum, especially in view of their many potential applications as pragmatic tools in the fields of human toxicology, ecotoxicology, and risk assessment. A number of guidance documents, issued by the Organization for Economic Cooperation and Development, as well as landmark papers, outlining best practices to develop, assess and use AOPs, have been published in the last few years. The present paper provides a synopsis of the main principles related to the AOP framework for the toxicologist less familiar with this area, followed by two case studies relevant for human toxicology and ecotoxicology. PMID- 28660288 TI - Influence of water management on the active root-associated microbiota involved in arsenic, iron, and sulfur cycles in rice paddies. AB - In recent years, the role of microorganisms inhabiting rice rhizosphere in promoting arsenic contamination has emerged. However, little is known concerning the species and metabolic properties involved in this phenomenon. In this study, the influence of water management on the rhizosphere microbiota in relation to arsenic dissolution in soil solution was tested. Rice plants were cultivated in macrocosms under different water regimes: continuous flooding, continuous flooding with a 2-week period drainage before flowering, and dry soil watered every 10 days. The active bacterial communities in rhizosphere soil and in rhizoplane were characterized by 16S rRNA pyrosequencing. An in-depth analysis of microbial taxa with direct or indirect effects on arsenic speciation was performed and related contribution was evaluated. Continuous flooding promoted high diversity in the rhizosphere, with the plant strongly determining species richness and evenness. On the contrary, under watering the communities were uniform, with little differences between rhizosphere soil and rhizoplane. Arsenic releasing and arsenite-methylating bacteria were selected by continuous flooding, where they represented 8% of the total. On the contrary, bacteria decreasing arsenic solubility were more abundant under watering, with relative abundance of 10%. These values reflected arsenic concentrations in soil solution: 135 MUg L-1 and negligible in continuous flooding and under watering, respectively. When short-term drainage was applied before flowering, intermediate conditions were achieved. This evidence strongly indicates an active role of the rhizosphere microbiota in driving arsenic biogeochemistry in rice paddies, influenced by water management, explaining amounts and speciation of arsenic often found in rice grains. PMID- 28660289 TI - Monoamine oxidase and transaminase screening: biotransformation of 2-methyl-6 alkylpiperidines by Neopestalotiopsis sp. CBMAI 2030. AB - High-throughput screening detected transaminases (TAs) and monoamine oxidases (MAOs) in fungi by applying a fluorogenic probe. Strains F026, F037, F041, F053, and F057 showed the highest enzymatic conversions (31, 60, 30, 40, and 32%, respectively) and where evaluated for their ability to transform piperidines. Strain F053 (Neopestalotiopsis sp. CBMAI 2030) revealed unusual enzymatic activity to deracemize 2-methyl-6-alkylpiperidines. Neopestalotiopsis sp. CBMAI 2030 was capable to convert 2-methyl-6-propylpiperidine, 2-methyl-6 butylpiperidine, and 2-methyl-6-pentylpiperidine in piperideine with 11, 14, and 24% conversion, respectively. The activity was enhanced by cultivating the fungus with 2-methyl-6-pentylpiperidine (38% conversion and 73% ee). PMID- 28660290 TI - A retrospective survey into the presence of Plasmodium spp. and Toxoplasma gondii in archived tissue samples from New Zealand raptors: New Zealand falcons (Falco novaeseelandiae), Australasian harriers (Circus approximans) and moreporks (Ninox novaeseelandiae). AB - Human colonisation of New Zealand has resulted in the introduction of emerging diseases, such as avian malaria and toxoplasmosis, which arrived with their exotic avian and mammalian hosts. Plasmodium spp. and Toxoplasma gondii have a wide host range, and several species of endemic New Zealand birds have developed a fatal disease following infection with either pathogen. However, no reports of either toxoplasmosis or avian malaria in New Zealand raptors, namely, the New Zealand falcons (Falco novaeseelandiae), Australasian harriers (Circus approximans) and moreporks (Ninox novaeseelandiae) exist in the literature. Therefore, this study was designed to determine if these two pathogens are present in these raptors through a retrospective analysis of archived tissue samples. Detection and isolate identification of these pathogens was determined using established histological and molecular techniques. All three species of New Zealand raptors tested positive for the presence of Plasmodium spp. (10/117; 8.5%) and an atypical genotype of T. gondii (9/117; 7.7%). Plasmodium lineages identified include P. elongatum GRW6, P. relictum SGS1, P. relictum PADOM02 and Plasmodium sp. LINN1. Two Australasian harriers and one morepork tested positive for the presence of both Plasmodium spp. and T. gondii. However, the pathogenicity of these organisms to the raptors is unclear as none of the tissues showed histological evidence of clinical disease associated with Plasmodium spp. and T. gondii infections. Thus, these results demonstrate for the first time that these two potential pathogens are present in New Zealand's raptors; however, further research is required to determine the prevalence and pathogenicity of these organisms among the living populations of these birds in the country. PMID- 28660291 TI - Adjuvant hysterectomy after radiochemotherapy for locally advanced cervical cancer. AB - BACKGROUND: External beam radiation therapy (EBRT) with concomitant chemotherapy (cCT) (=RCT) plus intracavitary (+/-interstitial) brachytherapy (iBT) is standard of care for advanced cervical cancer. The aim of this study was to evaluate morbidity and survival outcome of simple adjuvant hysterectomy (AH) after EBRT/cCT and to compare it with the standard treatment. PATIENTS AND METHODS: Patients with FIGO stage III cervical cancer were treated with EBRT/cCT and then divided in two groups: group 1 was further treated with standard intracavitary/interstitial BT, while group 2 underwent AH. RESULTS: From 881 women with cervical cancer, 248 were eligible for analysis: 161 received iBT and 87 underwent AH. The median follow-up of the study was 53 months. Clinical and pathological characteristics were well balanced in the two groups. After EBRT/cCT, complete clinical response was observed in 121 (48.8%) of 246 patients. Clinical complete response was observed in 81 (50.3%) of 161 patients in group 1. At 6 weeks after EBRT/cCT, 40 (46.0%) of 87 patients in the surgery group had pathological complete response. Intra- and postoperative complications were observed in 10 (11.5%) of 87 cases. The rates of locoregional recurrence and metastasis were similar in both groups. Progression-free (PFS) and disease specific overall survival (DOS) for these patients were similar between the control and surgery group. Interestingly, PFS and DOS were significantly improved by AH for the patients with residual tumor. CONCLUSION: AH could improve survival in patients with residual disease after RCT and is characterized by a low complication rate. PMID- 28660292 TI - Bartonella in Rodents and Ectoparasites in the Canary Islands, Spain: New Insights into Host-Vector-Pathogen Relationships. AB - Bartonella genus is comprised of several species of zoonotic relevance and rodents are reservoirs for some of these Bartonella species. As there were no data about the range of Bartonella species circulating among rodents in the Canary Islands, our main aim was to overcome this lack of knowledge by targeting both the citrate synthase (gltA) and the RNA polymerase beta subunit (rpoB) genes. A total of 181 small mammals and 154 ectoparasites were obtained in three of the Canary Islands, namely Tenerife, La Palma, and Lanzarote. The overall prevalence of Bartonella DNA in rodents was 18.8%, whereas the prevalence in ectoparasites was 13.6%. Bartonella sequences closely related to the zoonotic species Bartonella elizabethae, Bartonella tribocorum, and Bartonella rochalimae were identified in rodents, whereas two different gltA haplotypes similar to B. elizabethae were also detected in fleas. Furthermore, Bartonella queenslandensis DNA was also identified in rodents. A strong host specificity was observed, since B. elizabethae DNA was only found in Mus musculus domesticus, whereas gltA and rpoB sequences closely related to the rest of Bartonella species were only identified in Rattus rattus, which is probably due to the host specificity of the arthropod species that act as vectors in these islands. Our results indicate that humans may contract Bartonella infection by contact with rodents in the Canary Islands. PMID- 28660293 TI - Variations on a theme in fruit development: the PLE lineage of MADS-box genes in tomato (TAGL1) and other species. AB - MAIN CONCLUSION: This article focuses on the role of TOMATO AGAMOUS-LIKE 1 (TAGL1) on a wide range of ripening functions in tomato. We also examine orthologs of this gene in related species that produce different fruit types and discuss some evolutionary implications. TOMATO AGAMOUS-LIKE 1 (TAGL1) is a MADS box transcription factor gene that belongs to the PLENA (PLE) lineage within the AGAMOUS (AG) clade. The most well-studied genes in this lineage are the SHATTERPROOF (SHP) genes in Arabidopsis, known to be involved in dehiscence zone formation during silique development. In tomato, TAGL1 has been shown to control several aspects of tomato fruit ripening. Most notably, carotenoid synthesis seems to be controlled by TAGL1, likely via the ethylene synthesis and signaling pathway and in combination with RIPENING INHIBITOR (RIN). In addition, TAGL1 regulates genes involved in cell cycle regulation, flavonoid and lignin biosynthesis, and cuticle development. We discuss many of the genes in these different pathways that are likely controlled by TAGL1, directly or indirectly. We also examine the relationship of TAGL1 with known and putative interaction partners. PLE lineage genes have also been examined in other species such as Antirrhinum, Petunia, and Nicotiana and provide an interesting example of conservation and diversification of function in species that produce very different types of fleshy and dry fruits. The control of lignification may be a common mechanism for this group of genes. Lastly, we discuss future work needed to elucidate the TAGL1 regulatory pathway in tomato and to help better understand the functional diversification of genes in this lineage in related species. PMID- 28660296 TI - [When a name becomes a unit: Louis Harold Gray]. PMID- 28660294 TI - Influence of estrous cycle hormonal fluctuations and gonadal hormones on the ventilatory response to hypoxia in female rats. AB - Sex hormones may influence many physiological processes. Recently, we demonstrated that hormonal fluctuations of cycling female rats do not affect respiratory parameters during hypercapnia. However, it is still unclear whether sex hormones and hormonal fluctuations that occur during the estrous cycle can affect breathing during a hypoxic challenge. Our study aimed to evaluate respiratory, metabolic, and thermal responses to hypoxia in female rats on different days of the estrous cycle (proestrus, estrus, metestrus, and diestrus) and in ovariectomized rats that received replacement with oil (OVX), estradiol (OVX + E2), or a combination of estradiol and progesterone (OVX + E2P). Ventilation (V E), tidal volume (V T), respiratory frequency (fR), oxygen consumption (VO2), and V E/VO2 were not different during the estrous cycle in normoxia or hypoxia. Body temperature (Tb) was higher during estrus, but decreased similarly in all groups during hypoxia. Compared with intact females in estrus, gonadectomized rats also had lower Tb in normoxia, but not in hypoxia. OVX rats experienced a significant drop in the ventilatory response to hypoxia, but hormonal replacement did not restore values to the levels of an intact animal. Our data demonstrate that the different phases of the estrous cycle do not alter ventilation during normoxia and hypoxia, but OVX animals display lower ventilatory responses to hypoxia compared with ovary-intact rats. Because estradiol and progesterone replacement did not cause significant differences in ventilation, our findings suggest that a yet-to-be-defined non-steroidal ovarian hormone is likely to stimulate the ventilatory responses to hypoxia in females. PMID- 28660295 TI - [Prostate gland - what would urologists like to know from radiologists?] AB - A more than 100-year period, where the prostate was only seen and treated as a whole is coming to an end right now. Finally, high resolution imaging is providing deep insights and detailed information so that new therapeutic procedures can aim for the smallest targets within the gland. The long-standing wish of patients for individual noninvasive diagnostics and treatment of prostate diseases can now be fulfilled by providing new tailored concepts; however, in order to transfer the enormous amount of new information into the specific clinical patient situation, a closely knit interdisciplinary approach is required. In this setting, the traditional outpatient consultation service is overstretched in every aspect. It is now the time for new innovative constructs. The current one-sided service concept for urologists, radiologists and radiation therapists is therefore behind the times and the development of a "prostate management team" with equally cooperating partners from each specialty is the task for the future. PMID- 28660297 TI - [Radiation protection in medical research : Licensing requirement for the use of radiation and advice for the application procedure]. AB - BACKGROUND: In Germany, persons who are to be exposed to radiation for medical research purposes are protected by a licensing requirement. However, there are considerable uncertainties on the part of the applicants as to whether licensing by the competent Federal Office for Radiation Protection is necessary, and regarding the choice of application procedure. AIM: The article provides explanatory notes and practical assistance for applicants and an outlook on the forthcoming new regulations concerning the law on radiation protection of persons in the field of medical research. MATERIALS AND METHODS: Questions and typical mistakes in the application process were identified and evaluated. RESULTS AND DISCUSSION: The qualified physicians involved in a study are responsible for deciding whether a license is required for the intended application of radiation. The decision can be guided by answering the key question whether the study participants would undergo the same exposures regarding type and extent if they had not taken part in the study. When physicians are still unsure about their decision, they can seek the advisory service provided by the professional medical societies. Certain groups of people are particularly protected through the prohibition or restriction of radiation exposure. A simplified licensing procedure is used for a proportion of diagnostic procedures involving radiation when all related requirements are met; otherwise, the regular licensing procedure should be used. The new radiation protection law, which will enter into force on the 31st of december 2018, provides a notification procedure in addition to deadlines for both the notification and the licensing procedures. In the article, the authors consider how eligible studies involving applications of radiation that are legally not admissible at present may be feasible in the future, while still ensuring a high protection level for study participants. PMID- 28660298 TI - Standardize or Diversify Experimental Conditions in Ecotoxicology? A Case Study on Herbicide Toxicity to Larvae of Two Anuran Amphibians. AB - Despite a steeply increasing number of ecotoxicological studies on the effects of pesticides on nontarget organisms, studies assessing the adequacy and reliability of different experimental approaches have remained scarce. We scrutinized effects of a glyphosate-based herbicide on larvae of two European anuran amphibians by estimating species-specific LC50 values, assessing how an additional stress factor may influence outcomes, and investigating whether replicate experiments yielded qualitatively the same results. We exposed Rana dalmatina and Bufo bufo tadpoles to two predator treatments (no predator vs. predator chemical cues) combined with varying herbicide concentrations, repeated the experiment with a subset of the experimental treatments and partly with slight modifications 1 week later and assessed survival. Our results indicated that the herbicide was moderately toxic to tadpoles. The presence of predator chemical cues did not affect the lethality of the herbicide in either species. The estimated sensitivity of R. dalmatina tadpoles varied considerably across experiments, whereas in case of B. bufo LC50 values remained very similar. Our results suggest that differences in the experimental setup may often have no influence on the measured effects of pesticides, whereas replicated experiments can deliver widely differing results in other cases, perhaps depending on the studied species, the population origin of the tested individuals, or the test conditions. This draws attention to the suggestion that strict standardization may not deliver widely applicable insights into the toxicity of contaminants and, instead, intentionally introducing variation into the design of ecotoxicological experiments and replicating entire experiments may prove highly beneficial. PMID- 28660299 TI - Physiological crosstalk between the AC/PKA and PLC/PKC pathways modulates melatonin-mediated, monochromatic-light-induced proliferation of T-lymphocytes in chickens. AB - Previous study has demonstrated that melatonin plays a critical role in monochromatic-light-induced lymphocyte proliferation in response to T cell mitogen concanavalin A (ConA). However, its intracellular mechanism is still unclear. In this study, we investigate the intracellular signal pathways of melatonin receptor-mediated T-lymphocyte proliferation in the spleens of chicks exposed to different light wavelengths. Results showed that green light enhanced T-lymphocyte proliferation by 2.46-6.83% and increased splenic mRNA and protein expressions of melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) by 16.05 40.43% compared with the white, red and blue light groups. However, pinealectomy resulted in a decrease in T-lymphocyte proliferation and melatonin receptor expression with no statistically significant differences between the different light groups. In vitro experiments showed that the Mel1b selective antagonist 4P PDOT, the Mel1c selective antagonist prazosin and the mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor PD98059 suppressed both melatonin-induced lymphocyte proliferation in response to ConA and melatonin- and ConA-stimulated extracellular signal-regulated kinase 1/2 (ERK1/2) activity but that the Mel1a/Mel1b non-selective antagonist luzindole did not. In addition, pretreatment with forskolin (FSK, the adenylyl cyclase activator), H89 (the PKA inhibitor), U73122 (the PLC inhibitor) or Go6983 (the broad spectrum PKC inhibitor) markedly attenuated melatonin- and ConA-stimulated T-lymphocyte proliferation and ERK1/2 activity. These results demonstrate that melatonin mediates green-light-induced T lymphocyte proliferation via the Mel1b and Mel1c receptors by triggering crosstalk between the cAMP/PKA and PLC/PKC signal pathways followed by ERK1/2 activation. PMID- 28660300 TI - Cell type-specific localization of Ephs pairing with ephrin-B2 in the rat postnatal pituitary gland. AB - Sox2-expressing stem/progenitor cells in the anterior lobe of the pituitary gland form two types of micro-environments (niches): the marginal cell layer and dense cell clusters in the parenchyma. In relation to the mechanism of regulation of niches, juxtacrine signaling via ephrin and its receptor Eph is known to play important roles in various niches. The ephrin and Eph families are divided into two subclasses to create ephrin/Eph signaling in co-operation with confined partners. Recently, we reported that ephrin-B2 localizes specifically to both pituitary niches. However, the Ephs interacting with ephrin-B2 in these pituitary niches have not yet been identified. Therefore, the present study aims to identify the Ephs interacting with ephrin-B2 and the cells that produce them in the rat pituitary gland. In situ hybridization and immunohistochemistry demonstrated cell type-specific localization of candidate interacting partners for ephrin-B2, including EphA4 in cells located in the posterior lobe, EphB1 in gonadotropes, EphB2 in corticotropes, EphB3 in stem/progenitor cells and EphB4 in endothelial cells in the adult pituitary gland. In particular, double immunohistochemistry showed cis-interactions between EphB3 and ephrin-B2 in the apical cell membranes of stem/progenitor cell niches throughout life and trans interactions between EphB2 produced by corticotropes and ephrin-B2 located in the basolateral cell membranes of stem/progenitor cells in the early postnatal pituitary gland. These data indicate that ephrin-B2 plays a role in pituitary stem/progenitor cell niches by selective interaction with EphB3 in cis and EphB2 in trans. PMID- 28660301 TI - Evolution of GSTD1 in Cactophilic Drosophila. AB - GSTD1 is an insect glutathione S-transferase that has received considerable attention because of its role in detoxification of xenobiotic compounds, specifically pesticides and plant allelochemicals involved in detoxification, or in the use of some substrates as a nutritional source. GSTD1 has been implicated in the adaptation to a new cactus host in Drosophila mojavensis and thus constitutes an interesting candidate to study ecological genetics of adaptation in Drosophila. We conducted population genetic and molecular evolution analyses of the GstD1 gene in the context of association with different cactus hosts (Opuntia sp. vs. Columnar) in nine Drosophila species from the repleta group. We observed strong evidence of selection in GstD1 from D. hexastigma. This species is associated with a diverse set of columnar cacti with very complex chemistries. GstD1 sequences from D. hexastigma show evidence of a recent selective sweep, and positive selection at one residue just outside of the active site of the enzyme. The substitution (Q116T) at the site under selection leads to a conformational change in the enzyme that could have important consequences for substrate binding efficiency. Our results suggest that GSTD1 from D. hexastigma may have evolved improved substrate binding in order to adapt to the diverse chemical environments that this species encounters in the wild. PMID- 28660302 TI - Tumor angiogenesis and vascular normalization: alternative therapeutic targets. AB - Tumor blood vessels are a key target for cancer therapeutic management. Tumor cells secrete high levels of pro-angiogenic factors which contribute to the creation of an abnormal vascular network characterized by disorganized, immature and permeable blood vessels, resulting in poorly perfused tumors. The hypoxic microenvironment created by impaired tumor perfusion can promote the selection of more invasive and aggressive tumor cells and can also impede the tumor-killing action of immune cells. Furthermore, abnormal tumor perfusion also reduces the diffusion of chemotherapeutic drugs and radiotherapy efficiency. To fight against this defective phenotype, the normalization of the tumor vasculature has emerged as a new therapeutic strategy. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. In this review, we investigate the mechanisms involved in tumor angiogenesis and describe strategies used to achieve vascular normalization. PMID- 28660303 TI - The role of EEG recordings in children undergoing cardiac surgery for congenital heart disease. AB - BACKGROUND: Neurological dysfunction may occur after corrective cardiac surgery using cardio-pulmonary bypass (CPB) with or without circulatory arrest. Different neurophysiological monitoring systems have been employed to detect neurological complications and possible brain injury in infants and children during and after cardiac surgery. The value of Elecetroencephalogram (EEG) in infants and children at risk for neurological sequelae has not been systematically studied. METHODS: Sequential performance of two EEGs before and after cardiac surgery at a tertiary University Hospital to screen for possible brain injury after cardiac surgery in neonates and children undergoing CPB surgery. In addition, a complete neurological examination and assessment by a physiotherapist was performed. RESULTS: Over a 4-year period, in 313 patients (age: 54.2 +/- 55.7 months; normal initial EEG) after cardiac surgery CPB (duration of surgery: 146.0 +/- 58.9 min; aortic cross clamp time: 34.1 +/- 19.1 min), a 19-channel EEG recording was performed 2.4 +/- 1.8 days prior to and 11.6 +/- 5.3 days after cardiac surgery. An abnormal EEG was detected in only 8 of 313 patients (2.5%; focal slowing: 1, generalised slowing: 5, epiletiform discharges: 2) after cardiac surgery, while the EEG was normal in the remaining 305 patients (97.5%). In 1 patient, an intra cerebral pathology was seen on MRI (ischemic); in 5 patients, follow-up EEGs were performed, which revealed normalized findings. None of the 8 patients demonstrated new focal neurological deficits on physical examination, but 33 (9.7%) children demonstrated minor abnormalities (e.g., subtle motor asymmetry, increase in muscle tone, etc.), which were unrelated to abnormal EEG findings. CONCLUSIONS: According to the used protocol, pathological EEG findings were very infrequent in our study cohort. The routine and indiscriminative recording of EEGs in children before and after corrective or palliative cardiac surgery for congenital heart disease using CPB is not recommended. Further intra-operative neuromonitoring methods with immediate intervention should be evaluated. PMID- 28660304 TI - Differences in the renal antifibrotic cGMP/cGKI-dependent signaling of serelaxin, zaprinast, and their combination. AB - Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild type (WT) and cGKI knockout (KO) mice. Renal antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by alpha-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive antifibrotic effects compared to the monotherapy. Due to antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for antifibrotic signaling of zaprinast. PMID- 28660305 TI - Comparison of medical-grade and calibrated consumer-grade displays for diagnosis of subtle bone fissures. AB - OBJECTIVE: To compare the diagnostic accuracy of medical-grade and calibrated consumer-grade digital displays for the detection of subtle bone fissures. METHODS: Three experienced radiologists assessed 96 digital radiographs, 40 without and 56 with subtle bone fissures, for the presence or absence of fissures in various bones using one consumer-grade and two medical-grade displays calibrated according to the DICOM-Grayscale Standard Display Function. The reference standard was consensus reading. Subjective image quality was also assessed by the three readers. Statistical analysis was performed using receiver operating characteristic analysis and by calculating the sensitivity, specificity, and Youden's J for each combination of reader and display. Cohen's unweighted kappa was calculated to assess inter-rater agreement. Subjective image quality was compared using the Wilcoxon signed-rank test. RESULTS: No significant differences were found for the assessment of subjective image quality. Diagnostic performance was similar across all readers and displays, with Youden's J ranging from 0.443 to 0.661. The differences were influenced more by the reader than by the display used for the assessment. CONCLUSION: No significant differences were found between medical-grade and calibrated consumer-grade displays with regard to their diagnostic performance in assessing subtle bone fissures. Calibrated consumer-grade displays may be sufficient for most radiological examinations. KEY POINTS: * Diagnostic performance of calibrated consumer-grade displays is comparable to medical-grade displays. * There is no significant difference with regard to subjective image quality. * Use of calibrated consumer-grade displays could cut display costs by 60-80%. PMID- 28660306 TI - Shear wave velocity measurement of upper trapezius muscle by color Doppler shear wave imaging. AB - PURPOSE: Skeletal muscle stiffness is thought to be the result of increased tissue hardness, but measurement accuracy has been dependent on operator technique. We have proposed a novel shear wave real-time imaging method (color Doppler shear wave imaging: CD SWI) with continuous shear waves excited from the tissue surface by a mechanical vibrator. METHODS: Using the method, shear wave velocity was measured for the upper trapezius muscle. Adaptive shear wave velocity measurement by means of quality estimation of shear wave wavefront was adopted. We recruited 23 male volunteers with no history of orthopedic disease and recorded shear wave propagation to assess the intra- and inter-observer reliability. For intra-observer reliability, one observer took two measurements separated by a time delay, and the intra-class correlation coefficient (ICC) was calculated (1,1). For inter-observer reliability, ICC (2,1) was calculated from both observers' measurements. RESULTS: Mean propagation speed was 3.75 +/- 0.47 (first) and 3.71 +/- 0.49 m/s (second) for Observer A (ICC (1,1) = 0.91 [95% CI 0.76-0.96]) and 3.80 +/- 0.53 m/s for Observer B (ICC (2,1) = 0.83 [95% CI 0.56 0.94]). CONCLUSIONS: This result suggests that our technique is satisfactorily reliable and has potential for future application in various fields, such as evaluation of muscle condition or the effects of rehabilitation. PMID- 28660307 TI - [The new GOA and its pitfalls]. AB - The German Medical Association is working out a new fee scale for medical invoicing, which has to be reformed because the contents and the ratings are not up to date. The secretary of state for health in Germany demands that the new draft be coordinated with private insurance companies; as a result, they can influence indirectly the relationship between physicians and their patients. The new specifications will narrow the gap between private and social insurance in Germany. We discuss the consequences for the physician-patient relationship and the implications for the political plans to reform the whole insurance system in Germany. PMID- 28660308 TI - Relationship between RAGE gene polymorphisms and cardiovascular disease prognosis in the Chinese Han population. AB - Cardiovascular disease (CVD) is the leading cause of death in China. This study aimed to investigate whether RAGE gene polymorphisms are associated with the prognosis of various cardiovascular diseases in the Chinese Han population. This study was conducted from July 2004 to December 2005 and a total of 425 subjects from Guangdong province were enrolled. Genotyping of the three polymorphisms ( 429T/C, 1704G/T, and G82S) in the RAGE gene was performed with polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Patients were followed for 6.5 years to watch for the development of cardiovascular events and mortality. Subjects with the S mutation of the G82S polymorphism had a significantly higher risk of all-cause mortality and acute myocardial infarction (AMI) than did those with wild-type homozygosity. Logistic regression analysis and Kaplan-Meier analysis all revealed that the G82S polymorphism of the RAGE gene was associated with a significantly increased risk of all-cause mortality and AMI. However, the -429T/C and 1704G/T polymorphisms were not shown to have any effect on prognosis. In conclusion, the G82S variant of the RAGE gene was significantly associated with an increased risk of all-cause mortality and AMI in the Chinese Han population. PMID- 28660309 TI - Genome-wide comparative analysis of four Indian Drosophila species. AB - Comparative analysis of multiple genomes of closely or distantly related Drosophila species undoubtedly creates excitement among evolutionary biologists in exploring the genomic changes with an ecology and evolutionary perspective. We present herewith the de novo assembled whole genome sequences of four Drosophila species, D. bipectinata, D. takahashii, D. biarmipes and D. nasuta of Indian origin using Next Generation Sequencing technology on an Illumina platform along with their detailed assembly statistics. The comparative genomics analysis, e.g. gene predictions and annotations, functional and orthogroup analysis of coding sequences and genome wide SNP distribution were performed. The whole genome of Zaprionus indianus of Indian origin published earlier by us and the genome sequences of previously sequenced 12 Drosophila species available in the NCBI database were included in the analysis. The present work is a part of our ongoing genomics project of Indian Drosophila species. PMID- 28660310 TI - Advanced glycation endproducts induce self- and cross-tolerance in monocytes. AB - INTRODUCTION: Advanced glycation endproducts (AGEs) are well-known inflammatory mediators, which are recognized by immune cells through their corresponding receptor RAGE and have been shown to participate in the pathophysiology of a variety of acute as well as chronic inflammatory diseases. Nevertheless, no data are available on the aftermath of AGE recognition on immune cells. MATERIALS AND METHODS: We used the monocytic cell line MonoMac6 as well as primary human monocytes for double stimulation experiments. We measured secreted as well as intracellular levels of TNF-alpha using ELISA and flow cytometry. In addition, gene expression of surface receptors (RAGE and TLR4) and TNF were measured by qPCR. RESULTS: Stimulation with AGE leads to a dose-dependent induction of self- and cross-tolerance in both primary monocytes as well as the MonoMac6 cell line. The AGE tolerance depended neither on a decreased expression of RAGE or TLR4, nor on a decrease of TNF-alpha expression. Nevertheless, intracellular TNF-alpha was decreased, hinting towards a posttranscriptional regulation. CONCLUSION: High levels of AGEs are capable to activate immune cells at first, but induce a secondary state of hypo-responsiveness in these cells. Based on the origin of its causal agent, we propose this phenomenon to be "metabolic tolerance". PMID- 28660311 TI - Astragalus polysaccharides inhibits cell growth and pro-inflammatory response in IL-1beta-stimulated fibroblast-like synoviocytes by enhancement of autophagy via PI3K/AKT/mTOR inhibition. AB - The hyperplastic growth of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and inflammatory response are pathological hallmarks of RA. It has been reported that Astragalus polysaccharides (APS) possess appreciable anti inflammatory activity against adjuvant-induced arthritis. Nevertheless, little is known about the role and detailed mechanism underlying the therapeutic effects of APS in RA. This study demonstrated that administration of APS dose-dependently impaired cell viability, increased cell apoptosis by decreasing Bcl-2 expression, increasing Bax expression and Caspase3 activity in IL-1beta-stimulated RSC-364 cells and RA-FLS. Simultaneously, IL-1beta-induced production of pro-inflammatory cytokines IL-6 and TNF-alpha was significantly decreased after APS treatment. Furthermore, preconditioning with APS dramatically enhanced autophagy activity by increasing Beclin-1 and LC3II/LC3I expression coupled with decreasing p62 expression and augmenting the number of LC3 puncta in IL-1beta-stimulated RSC-364 cells. More importantly, autophagy inhibitor 3-methyladenine (3-MA) partly abolished APS-triggered inhibitory effects on cell growth and production of pro inflammatory cytokines. APS also repressed the activation of PI3K/Akt/mTOR signaling pathway in IL-1beta-stimulated RSC-364 cells. Moreover, treatment with insulin-like growth factor-1 (IGF-1), an activator of PI3K/Akt signaling, partly reversed the therapeutic effects of APS in IL-1beta-stimulated RSC-364 cells. Collectively, we concluded that APS might attenuate the pathological progression of RA by exerting the pro-apoptotic and anti-inflammatory effects in IL-1beta stimulated FLSs by regulating the PI3K/AKT/mTOR-autophagy pathway. PMID- 28660313 TI - Early motor delays as diagnostic clues in autism spectrum disorder. AB - : Early identification of autism facilitates referral for early intervention services, shown to be effective in enhancing parent-child interaction as well as adaptive behavior, communication, and socialization. Traditional hallmarks for the diagnosis of autism spectrum disorder (ASD) include deficits in social communication and social interaction as well as stereotypic or repetitive behavioral patterns. Research during the past decade suggests that developmental motor delays during early childhood may also be important predictors of this difficult-to-make diagnosis. The purpose of this short communication is to describe specific research findings about developmental motor delays and other neuromotor concerns that may contribute to the early diagnosis of ASD and thus hasten referral for early therapeutic intervention. CONCLUSION: In that there is reasonable consensus that motor delays during the first year of life may represent a prodrome of ASD, pediatricians should not rule out the possibility of ASD in infants with concerning motor behaviors. What is Known: * Early identification of autism facilitates referral for early intervention services. * Traditional hallmarks for diagnosis of autism spectrum disorder (ASD) include deficits in social communication and social interaction as well as repetitive patterns of behavior. What is New: * Recent research suggests that developmental motor delays during early childhood may also be important predictors of ASD. * Pediatricians should consider the possibility of ASD in infants with motor delays or other concerning motor behaviors. PMID- 28660312 TI - Neonatal outcome of small for gestational age preterm infants. AB - : Small for gestational age (SGA) preterm neonates (birth weight < -2 SDS) are considered to have increased risk of bronchopulmonary dysplasia (BPD) compared to appropriate for GA (AGA) neonates. It is unclear if SGA infants have increased risk for respiratory distress syndrome (RDS) and mortality. We analyzed data from 515 neonates born <30 weeks GA, 98(19%) were SGA. SGA were compared to AGA by univariate analysis and logistic regression analysis (LRA). Significant variables at univariate analysis were IUGR (67 vs 7%, p = 0.000), chorioamnionitis (1 vs 13%, p = 0.017), pre-eclampsia (62 vs 18%, p = 0.000), surfactant retreatment (47 vs 25%, p = 0.000), BPD (32 vs 20%, p = 0.015), death (30 vs 12%, p = 0.000), SatO2/FiO2 on day 3 (376 vs 433, p = 0.013), and SatO2/FiO2 ratio on day 28 (400 vs 448, p = 0.000). LRA found the following associations: regarding mortality, a decreased Sat/FiO2 ratio on day 3 (OR 1.99, 95% CI 1.26-3.16, p = 0.003); regarding BPD, surfactant retreatment (3.70, 2.11-6.49, p = 0.000), being SGA (2.69, 1.36-5.36, p = 0.005), decreasing GA (1.05, 1.03-1.08, p = 0.000), decreasing SatO2/FiO2 ratio on day 3 (1.25, 1.11-1.40, p = 0.000); and regarding severe RDS, pre-eclampsia (2.68, 1.58-4.55, p = 0.000) and decreasing GA (1.06, 1.04-1.08, p = 0.000). CONCLUSIONS: In our cohort of preterm infants, being SGA was significantly associated with BPD, but not with increased risk of mortality or RDS due to multiple pathophysiologic mechanisms. What is Known: * Small for gestational age preterm neonates are considered to have increased risk of bronchopulmonary dysplasia (BPD) compared to appropriate for GA neonates. * It is still unclear if SGA infants have increased risk for respiratory distress syndrome (RDS) and mortality. What is New: * In our cohort of 515 preterm infants (19% SGA), being SGA was significantly associated with BPD, but not with increased risk of mortality or RDS. * These results may be explained by the heterogeneity of mechanisms leading to SGA condition and by multiple mechanisms involving lung growth impairment and other factors. PMID- 28660314 TI - Nicotine chewing gum for the prevention of postoperative ileus after colorectal surgery: a multicenter, double-blind, randomised, controlled pilot study. AB - PURPOSE: When postoperative ileus is not resolved after 5 days or recurs after resolution, prolonged POI (PPOI) is diagnosed. PPOI increases discomfort, morbidity and hospitalisation length, and is mainly caused by an inflammatory response following intestinal manipulation. This response can be weakened by targeting the cholinergic anti-inflammatory pathway, with nicotine as essential regulator. Chewing gum, already known to stimulate gastrointestinal motility itself, combined with nicotine is hypothesised to improve gastrointestinal recovery and prevent PPOI. This pilot study is the first to assess efficacy and safety of nicotine gum in colorectal surgery. METHODS: Patients undergoing elective oncological colorectal surgery were enrolled in this double-blind, parallel-group, controlled trial and randomly assigned to a treatment protocol with normal or nicotine gum (2 mg). Patient reported outcomes (PROMS), clinical characteristics and blood samples were collected. Primary endpoint was defined as time to first passage of faeces and toleration of solid food for at least 24 h. RESULTS: In total, 40 patients were enrolled (20 vs. 20). In both groups, six patients developed PPOI. Time to primary endpoint (4.50 [3.00-7.25] vs. 3.50 days [3.00-4.25], p = 0.398) and length of stay (5.50 [4.00-8.50] vs. 4.50 days [4.00 6.00], p = 0.738) did not differ significantly between normal and nicotine gum. There were no differences in PROMS, inflammatory parameters and postoperative complications. CONCLUSIONS: We proved nicotine gum to be safe but ineffective in improving gastrointestinal recovery and prevention of PPOI after colorectal surgery. Other dosages and administration routes of nicotine should be tested in future research. PMID- 28660315 TI - Characterization of the Dihydroorotase from Methanococcus jannaschii. AB - The gene that codes for the putative dihydroorotase in the hyperthermophilic archaeon Methanococcus jannaschii was subcloned in pET-21a and expressed in Escherichia coli. A purification protocol was devised. The purity of the protein was evaluated by SDS-PAGE and the protein was confirmed by sequencing using LC MS. The calculated molecular mass is 48104 Da. SEC-LS suggested that the protein is a monomer in solution. ICP-MS showed that there are two Zn ions per monomer. Kinetic analysis of the recombinant protein gave hyperbolic kinetics with Vmax = 12.2 umol/min/mg and Km = 0.14 mM at 25 degrees C. Furthermore the activity of the protein increased with temperature consistent with the hyperthermophilic nature of the organism. A homology model was constructed using the mesophilic Bacillus anthracis protein as the template. Residues known to be critical for Zn and substrate binding were conserved. The activity of the enzyme at 85 and 90 degrees C was found to be relatively constant over 160 min and this correlates with the temperature of optimal growth of the organism of 85 degrees C. The amino acid sequences and structures of the two proteins were compared and this gave insight into some of the factors that may confer thermostability-more Lys and Ile, fewer Ala, Thr, Gln and Gly residues, and shorter N- and C-termini. Additional and better insight into the thermostabilization strategies adopted by this enzyme will be provided when its crystal structure is determined. PMID- 28660316 TI - Expression of Flp Protein in a Baculovirus/Insect Cell System for Biotechnological Applications. AB - The Saccharomyces cerevisiae Flp protein is a site-specific recombinase that recognizes and binds to the Flp recognition target (FRT) site, a specific sequence comprised of at least two inverted repeats separated by a spacer. Binding of four monomers of Flp is required to mediate recombination between two FRT sites. Because of its site-specific cleavage characteristics, Flp has been established as a genome engineering tool. Amongst others, Flp is used to direct insertion of genes of interest into eukaryotic cells based on single and double FRT sites. A Flp-encoding plasmid is thereby typically cotransfected with an FRT harboring donor plasmid. Moreover, Flp can be used to excise DNA sequences that are flanked by FRT sites. Therefore, the aim of this study was to determine whether Flp protein and its step-arrest mutant, FlpH305L, recombinantly expressed in insect cells, can be used for biotechnological applications. Using a baculovirus system, the proteins were expressed as C-terminally 3 * FLAG-tagged proteins and were purified by anti-FLAG affinity selection. As demonstrated by electrophoretic mobility shift assays (EMSAs), purified Flp and FlpH305L bind to FRT-containing DNA. Furthermore, using a cell assay, purified Flp was shown to be active in recombination and to mediate efficient insertion of a donor plasmid into the genome of target cells. Thus, these proteins can be used for applications such as DNA-binding assays, in vitro recombination, or genome engineering. PMID- 28660317 TI - Ischemic stroke after radiation therapy for pituitary adenomas: a systematic review. AB - Radiation therapy is widely used for the treatment of residual and recurrent pituitary adenomas and proved to effectively control tumor growth. However, it is suggested that this treatment might result in an increased risk of ischemic stroke. This review aims to evaluate the radiotherapy-related risk of stroke in pituitary adenoma patients. PubMed and Embase databases were systematically searched for current literature on ischemic stroke risk after radiotherapy in pituitary adenoma, in accordance with the PRISMA statement. Two authors independently selected eligible studies and extracted data. The New Castle Ottawa scale was used for quality assessment. Out of 264 publications, 11 studies were selected, including 4394 irradiated patients. Incidence of ischemic stroke ranged from 0 to 11.6% (mean 6.7%). While one large, long term follow-up study showed a threefold increased risk of stroke after radiation therapy, another nationwide study of high quality found no significant difference in stroke risk after irradiation. Four studies, which applied stereotactic radiosurgery (SRS) or Gamma knife surgery (GKS), found no ischemic strokes. Included studies described different radiation techniques and regimens and different lengths of follow-up. In conclusion, complications of cerebral ischemia after radiotherapy for pituitary adenoma are infrequently reported. Moreover, after correction for several confounders, no significant difference in ischemic stroke rate between irradiated and non-irradiated patients could be identified. PMID- 28660318 TI - Reduced-volume radiotherapy for patients with localized intracranial nongerminoma germ cell tumors. AB - Craniospinal irradiation is standard radiotherapy (RT) for localized intracranial nongerminoma germ cell tumors (NGGCT). Given its toxicity, there is interest in using smaller fields. We examined outcomes of NGGCT patients receiving reduced volume RT at a single institution. Records of 16 patients who received reduced volume RT as part of definitive treatment between 1996 and 2016 were reviewed. Median age at presentation was 10.8 years (range 4.6-41.0 years). Ten patients had pineal tumors and 6 had suprasellar tumors. All received chemotherapy and 9 patients received second-look surgery thereafter. RT volume was tumor-only to a median of 54 Gy (range 50.4-54 Gy) in 3 patients and whole-ventricle irradiation to a median of 30.6 Gy (range 30.6-36 Gy) with a boost to 54 Gy in 13 patients. Median follow-up was 4.1 years (range 1.9-19.3 years). Three patients recurred locally at a median 9.9 months (range 9.6-10.6 months) after diagnosis, and one of these developed leptomeningeal relapse after 30 months. One patient expired from disease 2.6 years post-diagnosis and another due to stroke 19.3 years post diagnosis. Fourteen patients are alive with no evidence of disease. Kaplan-Meier estimates of the 4-year overall survival and failure-free survival are 92% (95% confidence interval [CI], 57-99%) and 81% (95% CI 53-94%), respectively. Excellent disease control was observed in these patients with no initial relapses outside of these RT fields. The results of ACNS1123 may better delineate patterns of failure and identify subgroups likely to benefit from this approach. PMID- 28660320 TI - Acceptance of Ambulatory Laparoscopic Cholecystectomy in Central Switzerland. AB - BACKGROUND: Currently, most patients undergoing laparoscopic cholecystectomy (LC) in Switzerland are inpatients for 2-3 days. Due to a lack of available hospital beds, we asked whether day-case surgery would be an option for patients in central Switzerland. The questions of acceptability of outpatient LC and factors contributing to the acceptability thus arose. METHODS: Hundred patients suffering from symptomatic cholecystolithiasis, capable of communicating in German, and between 18 and 65 years old, were included. Patients received a pre-operative questionnaire on medical history and social situation when informed consent on surgery and participation in the study was obtained. Exclusion criteria were patients suffering from acute cholecystitis or any type of cancer; having a BMI >40 kg/m2; needing conversion to open cholecystectomy or an intraoperative drainage; and non-German speakers. Surgery was performed laparoscopically. Both surgeon and patient filled in a postoperative questionnaire. The surgeon's questionnaire listed medical and technical information, and the patients' questionnaire listed medical information, satisfaction with the treatment and willingness to be released on the same day. These data from both questionnaires were grouped into social and medical factors and analysed on their influence upon willingness to accept an ambulatory procedure. No outpatient follow-up apart from checking for readmission to our hospital within 1 month after discharge was performed. RESULTS: Of the 100 participants, one-third was male. More than two thirds were Swiss citizens. Only one participant was ineligible for rapid release evaluation due to need of a drainage. Among the social factors contributing to the acceptability of ambulatory care, we found nationality to be relevant; Swiss citizens preferred an inpatient procedure, whereas non-Swiss citizens were significantly more willing to return home on the same day. Household size, sex and age did not correlate with a preference for inpatient care in our study population. Furthermore, medical input factors such as the surgeon's level of experience, operation time or use of local anaesthesia at the end of surgery had also no significant influence on whether patients preferred inpatient care or not. Medical output factors not found to contribute to the patients' decisions included co-morbidities or postoperative nausea and vomiting (PONV). Patients of experienced surgeons reported significantly less pain at the operation site. This was correlated with a somewhat increased willingness to accept ambulatory treatment. CONCLUSION: Given the choice, about half of the LC patients in central Switzerland prefer to stay in hospital overnight. PONV, age, sex or social surroundings were not predictive of the preferred treatment modality. Only being a non-Swiss citizen and experiencing little pain at the operation site due to the surgeon's skills seem to be factors that lead to a preference for ambulatory LC (ALC). Therefore, ALC in central Switzerland is most acceptable to non-Swiss citizens, operated upon by experienced surgeons. PMID- 28660319 TI - The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5) specific CAR T cells is limited by poor persistence and transient pre conditioning-dependent respiratory toxicity. AB - The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5+ malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5+-specific CAR T cells after fludarabine pre conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNgamma and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies. PMID- 28660321 TI - Overweight and obesity are progressively associated with lower work ability in the general working population: cross-sectional study among 10,000 adults. AB - PURPOSE: Obesity is associated with many diseases and functional limitations. Workplaces are not always designed to accommodate this challenge. This study investigated the association between body mass index (BMI) and work ability in the general working population. METHODS: Currently employed wage earners (N = 10,427) from the 2010 round of the Danish Work Environment Cohort Study (DWECS) replied to questions about work and health. Cumulative logistic regression analyses controlling for age, gender, physical and psychosocial work factors, lifestyle, and chronic diseases modeled the associations between BMI and work ability. RESULTS: BMIs above the normal range were progressively associated with lower work ability in relation to the physical demands of the job. Odds ratios for having lower work ability were 1.11 (95% CI 1.01-1.22), 1.17 (95% CI 1.01 1.34), 1.43 (95% CI 1.09-1.88), 1.69 (95% CI 1.10-2.62) for overweight and obesity classes I, II, and III, respectively. In subgroup analyses, the associations between BMI and work ability were more pronounced among individuals with mainly sedentary work than among those with physically active work. BMI was not associated with work ability in relation to the mental demands of the work. CONCLUSIONS: BMIs above the normal range are progressively associated with lower work ability in relation to the physical demands of the job, especially among individuals with mainly sedentary work. Ergonomic research on how to optimally design workstations for workers with obesity are needed. PMID- 28660323 TI - [A rare case of intestinal perforation]. PMID- 28660322 TI - Associations between organizational injustice and work ability, self-reported disability days, and medical consultations: cross-sectional findings from employees with prior sickness absence payments. AB - PURPOSE: The aim of the study was to identify associations between organizational injustice and work ability, disability days, and consultations with general practitioners. METHODS: Cross-sectional data of persons previously receiving sickness absence benefits were used for analyses. Organizational injustice was assessed using a German version of the "organizational justice questionnaire". Dependent variables were the Work Ability Index, self-reported disability days, and consultations with general practitioners. Associations were adjusted for sociodemographic characteristics, behavioral health risks, neuroticism, effort reward imbalance, and overcommitment. RESULTS: The analysis included 2983 employed persons (54.1% women, mean age: 47.9 years). High organizational injustice was associated with poor work ability (OR = 2.04, 95% CI 1.55-2.69). There were also slight associations with frequent self-reported disability days (OR = 1.34, 95% CI 1.06-1.68). The dependent variables were also associated with the effort-reward ratio and overcommitment. CONCLUSION: Organizational injustice is associated with work ability, self-reported disability days, and health-care utilization. Results support the notion of a complementary role of the models of organizational justice and effort-reward imbalance. PMID- 28660324 TI - [R1 resection for gastric carcinoma]. AB - The results reported in the literature in the context of an R1 situation for a resected gastric carcinoma are not uniform. An R1 situation worsens the prognosis for the long-term survival of patients. This is significant especially for low T stages and lymph node metastasis with 0-<=3 lymph node metastases. In higher tumor stages with extensive lymph node metastases, the survival difference between R0 and R1 resections is lower and frequently no longer significant. The frequency of R1 resection is approximately 5% (range 1.8-9%) and for adenocarcinoma of the esophagogastric junction (AEG tumors)> 10%. The data are mainly related to the oral and aboral resection line but there are only a few specifications on the circumferential margin. The risk of an infiltrated resection line increases with the size of the tumor (>5 cm), T3+4 and pN2/pN3 stages. Poorly differentiated signet ring cell or mucinous adenocarcinomas and carcinomas of the Bormann type 3+4 also lead to an increased R1 rate. In order to achieve an R0 resection, an intraoperative frozen section is the standard approach. Immediate reoperation should be performed in the case of tumor infiltration. If an R1 resection is detected only in the definitive histology, surgical re-excision to achieve an R0 resection is the standard approach in publications. Nevertheless, a reoperation is rare. Only 1 study showed 122 patients with 100% re-operations, which were successfully performed in 50 patients (41% R0). For the R0 group, median survival was extended from 18 months to 23 months. There are only sporadic literature data and no evidence for postoperative additive treatment (chemotherapy, radiotherapy and radiochemotherapy). PMID- 28660325 TI - ["I will do laparoscopy somewhere else" : Total, highly immersive virtual reality without side effects?] AB - BACKGROUND: For virtual reality laparosopic simulation we developed a new, highly immersive simulation mode. The goal of the current pilot study was to investigate if kinetosis or other negative vegetative side effects can be caused by a total virtual training set-up (TVRL). METHODS: In this study 20 participants with varying degrees of expertise in laparoscopy performed 3 tasks (i.e. ring exchange, fine dissection and cholecystectomy) in regular (VRL) and immersive mode (TVRL) with a head-mounted display (HMD) on a laparoscopic simulator. Aside from performance scores, the heart rate was recorded and the occurrence of vertigo was investigated. RESULTS: Surgical performance was independent of the VR mode (VRL or TVRL). Participants' heart rate was higher in TVRL without reaching statistical significance. Kinetosis occurred in two participants (10%) with a history of motion sickness. CONCLUSION: Laparoscopic training can take place in a total virtual environment with limited nagative vegetative side effects. Special attention should be paid to participants with a history of motion sickness. The development of TVRL enables new perspectives for surgical training. PMID- 28660326 TI - [Pyloric stenosis due to unclear tumor of the distal gastric wall]. PMID- 28660327 TI - [Robot-assisted surgery - Progress or expensive toy? : Matched-pair comparative analysis of robot-assisted cholecystectomy vs. laparoscopic cholecystectomy]. AB - AIM AND METHODS: By means of a matched-pair analysis comparing data obtained from laparoscopic cholecystectomy (LC) and robot-assisted laparoscopic cholecystectomy (RAC), the value of both methods as well as the advantages and disadvantages of both approaches were elucidated. The consideration was carried out by evaluation of postoperative surgical results, a cost analysis and a subjective survey of the patients using a questionnaire. Thus, from the 35 consecutive RAC, 35 (parallel) retrospectively matched pairs were established. RESULTS: Postoperative surgical results did not show any significant differences between LC and RAC. In the individual assessment by each patient, there were also no significant differences; however, there was a tendency towards the assessment of the RAC to be slightly worse. A striking difference was found with respect to the cost analysis at the time of surgery. CONCLUSION: The RAC operation alone is significantly more expensive compared to LC with respect to maintenance and acquisition costs. In addition, RAC can at present not be completely reimbursed under the current German diagnosis-related system. The postulated advantages of RAC comprise mainly the precise preparation within narrow confinements and the favorable ergonomic handling for the surgeon. The basic prerequisites are control of the costs and a reasonable reflection in the current reimbursement system. PMID- 28660329 TI - Clinical need for bone morphogenetic proteins. PMID- 28660328 TI - Radiological study of the secondary reduction effect of early functional exercise on displaced intra-articular calcaneal fractures after internal compression fixation. AB - PURPOSE: Early post-operative exercise and weight-bearing activities are found to improve the functional recovery of patients with displaced intra-articular calcaneal fractures (DIACFs). We hypothesized that early functional exercise after surgery might have a secondary reduction effect on the subtalar joint, in particular the smaller fracture fragments that were not fixed firmly. A prospective study was conducted to verify this hypothesis. METHODS: From December 2012 to September 2013, patients with unilateral DIACFs were enrolled and received a treatment consisting of percutaneous leverage and minimally invasive fixation. After surgery, patients in the study group started exercising on days two to three, using partial weight bearing starting week three, and full weight bearing starting week 12. Patients in the control group followed a conventional post-operative protocol of partial weight bearing after week six and full weight bearing after the bone healed. Computed tomography (CT) scanning was performed at post-operative day one, week four, week eight, and week 12 to reconstruct coronal, sagittal, and axial images, on which the maximal residual displacements of the fractures were measured. Function was evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) scoring scale at the 12th post operative month. RESULTS: Twenty-eight patients in the study group and 32 in the control group were followed up for more than 12 months; their data were collected and used for the final analysis. Repeated-measures analysis of variance (ANOVA) of the maximal residual displacements of the fracture measured on CT images revealed significant differences between the study and the control groups. There were interaction effects between group and time point. Except for the first time point, the differences between the groups at all studied time points were significant. In the study group, the differences between all studied time points were significant. Strong correlations were observed between the AOFAS score at post-operative month 12 and the maximal residual displacement of the fractures on the CT images at postoperative week 12. CONCLUSIONS: Early functional exercise and weight bearing activity can smooth and shape the subtalar joint and reduce the residual displacement of the articular surface, improving functional recovery of the affected foot. Therefore, early rehabilitation functional exercise can be recommended in clinical practice. PMID- 28660331 TI - The arrowhead appearance of bile ducts in recurrent pyogenic cholangitis. PMID- 28660330 TI - Quantitative MRI of kidneys in renal disease. AB - PURPOSE: To evaluate the reproducibility and utility of quantitative magnetic resonance imaging (MRI) sequences for the assessment of kidneys in young adults with normal renal function (eGFR ranged from 90 to 130 mL/min/1.73 m2) and patients with early renal disease (autosomal dominant polycystic kidney disease). MATERIALS AND METHODS: This prospective case-control study was performed on ten normal young adults (18-30 years old) and ten age- and sex-matched patients with early renal parenchymal disease (autosomal dominant polycystic kidney disease). All subjects underwent a comprehensive kidney MRI protocol, including qualitative imaging: T1w, T2w, FIESTA, and quantitative imaging: 2D cine phase contrast of the renal arteries, and parenchymal diffusion weighted imaging (DWI), magnetization transfer imaging (MTI), blood oxygen level dependent (BOLD) imaging, and magnetic resonance elastography (MRE). The normal controls were imaged on two separate occasions >=24 h apart (range 24-210 h) to assess reproducibility of the measurements. RESULTS: Quantitative MR imaging sequences were found to be reproducible. The mean +/- SD absolute percent difference between quantitative parameters measured >=24 h apart were: MTI-derived ratio = 4.5 +/- 3.6%, DWI-derived apparent diffusion coefficient (ADC) = 6.5 +/- 3.4%, BOLD-derived R2* = 7.4 +/- 5.9%, and MRE-derived tissue stiffness = 7.6 +/- 3.3%. Compared with controls, the ADPKD patient's non-cystic renal parenchyma (NCRP) had statistically significant differences with regard to quantitative parenchymal measures: lower MTI percent ratios (16.3 +/- 4.4 vs. 23.8 +/- 1.2, p < 0.05), higher ADCs (2.46 +/- 0.20 vs. 2.18 +/- 0.10 * 10-3 mm2/s, p < 0.05), lower R2*s (14.9 +/- 1.7 vs. 18.1 +/- 1.6 s-1, p < 0.05), and lower tissue stiffness (3.2 +/ 0.3 vs. 3.8 +/- 0.5 kPa, p < 0.05). CONCLUSION: Excellent reproducibility of the quantitative measurements was obtained in all cases. Significantly different quantitative MR parenchymal measurement parameters between ADPKD patients and normal controls were obtained by MT, DWI, BOLD, and MRE indicating the potential for detecting and following renal disease at an earlier stage than the conventional qualitative imaging techniques. PMID- 28660332 TI - Making the invisible visible: improving conspicuity of noncalcified gallstones using dual-energy CT. AB - PURPOSE: To determine whether virtual monochromatic imaging (VMI) increases detectability of noncalcified gallstones on dual-energy CT (DECT) compared with conventional CT imaging. MATERIALS AND METHODS: This retrospective IRB-approved, HIPAA-compliant study included consecutive patients who underwent DECT of the abdomen in the Emergency Department during a 30-month period (July 1, 2013 December 31, 2015), with a comparison US or MR within 1-year. 51 patients (36F, 15M; mean age 52 years) fulfilled the inclusion criteria. All DECT were acquired on a dual-source 128 * 2 slice scanner using either 80/Sn140 or 100/Sn140 kVp pairs. Source images at high and low kVp were used for DE post-processing with VMI. Within 3 mm reconstructed images, regions of interest of 0.5 cm2 were placed on noncalcified gallstones and bile to record hounsfield units (HU) at VMI energy levels ranging between 40 and 190 keV. RESULTS: Noncalcified gallstones uniformly demonstrated lowest HU at 40 keV and increase at higher keV; the HU of bile varied at higher keV. Few of the noncalcified stones are visible at 70 keV (simulating a conventional 120 kVp scan), with measured contrast (bile-stone HU difference) <10 HU in 78%, 10-20 HU in 20%, and >20 HU in 2%. Contrast was maximal at 40 keV, where 100% demonstrated >20 HU difference from surrounding bile, 75% >44 HU difference, and 50% >60 HU difference. A paired t test demonstrated a significant difference (p < 0.0001) between this stone-bile contrast at 40 vs. 70 keV and 70 vs. 190 keV. CONCLUSION: Low keV virtual monochromatic imaging increased conspicuity of noncalcified gallstones, improving their detectability. PMID- 28660333 TI - Paraduodenal pancreatitis: benign and malignant mimics at MRI. AB - Paraduodenal pancreatitis, also known as groove pancreatitis, is a rare form of chronic pancreatitis that masquerades as pancreatic adenocarcinoma affecting the pancreaticoduodenal groove, a potential space between the head of the pancreas, duodenum, and common bile duct. Two forms of groove pancreatitis have been described. The segmental form involves the pancreatic head with development of scar tissue within the groove, whereas the pure form affects the groove only, sparing the pancreatic head. Imaging findings of groove pancreatitis often overlap with primary duodenal, ampullary, or pancreatic neoplasms, which often results in a diagnostic challenge. In addition, paraduodenal pancreatitis can be mistaken for cystic pancreatic lesions, especially when there is involvement of the duodenal wall. Preoperative recognition of this entity is very important in order to avoid unnecessary procedures, although surgery, such as pancreaticoduodenectomy, may still be required to relieve obstructive symptoms. In this article, the pathophysiology and magnetic resonance imaging characteristics of paraduodenal pancreatitis and important benign and malignant mimics are discussed. PMID- 28660334 TI - Follow-up of acute pyelonephritis: what causes the diffusion-weighted magnetic resonance imaging recovery to lag clinical recovery? AB - PURPOSE: To analyze with diffusion-weighted magnetic resonance imaging (DW-MRI) the evolution and progress to resolution of acute pyelonephritis (APN) foci over a period of 3 months after onset. METHODS: 30 women (age 22-51 years) with clinical, laboratory (white blood cell and C-reactive protein), and DW-MRI (4b values 0, 50, 600, 1000 s/mm2) diagnosis of APN were prospectively enrolled. Two double-blinded radiologists evaluated the number of APN foci, and for each of them dimension (D), absolute diffusion coefficient (ADC), and its ratio R to the ADC of unaffected parenchyma. Signature of radiological recovery was focus no longer visible (DW-) and ADC of its site not inferior to the ADC of the unaffected parenchyma, i.e., R >= 0.9. Clinical and DW-MRI follow-ups (FU) were performed at 1 and 3 months. RESULTS: At the acute stage (t 0), 187 APN foci were found, with ADC0 = 1.3 +/- 0.2 * 10-3 mm2/s, R 0 = 0.65 +/- 0.12, and D 0 = 14 +/ 7.5 mm. By the 1-month FU (t 1), all patients had no symptoms and physiological laboratory values; despite this, only 80 (43%) foci were solved, increasing to 138 (74%) by at the 3-month FU. The ROC curve (AUC >= 0.80) identified R 0 <= 0.6 and D 0 > 15 mm as forecast of slow radiologic resolution. About 80% of foci unsolved at 1 month but with R 1 >= 0.8 and D 1 <= 10 mm reached solution at 3 months. CONCLUSIONS: DW-MRI recovery of APN foci does not always coincide with clinical recovery. The evolution of an APN focus is shaped by its initial values R 0 and D 0. About half of the foci still visible at 1 month reached radiological resolution in the two following months. PMID- 28660335 TI - The IVC contrast level sign. AB - The inferior vena cava (IVC) contrast level sign refers to a contrast-fluid level seen in the IVC on an arterial phase contrast-enhanced computed tomography (CT) scan. This sign has been documented in conditions including cardiac tamponade, myocardial infarction, and cardiac arrest. When this sign is detected, the patient requires immediate attention, with resuscitation initiated as needed, and the referring clinician alerted as soon as possible. PMID- 28660336 TI - Revisiting shape selectivity in liquid chromatography for polycyclic aromatic hydrocarbons (PAHs) - six-ring and seven-ring Cata-condensed PAH isomers of molecular mass 328 Da and 378 Da. AB - The relationship of reversed-phase liquid chromatography (RPLC) retention on a polymeric C18 stationary phase and the shape of polycyclic aromatic hydrocarbons (PAHs) was investigated for three-ring to seven-ring cata-condensed isomers. We report the first RPLC separation for six-ring and seven-ring cata-condensed PAH isomers. Correlations of LC retention and shape parameters (length-to-breath ratio, L/B and thickness, T) were investigated for 2 three-ring isomers (molecular mass 178 Da), 5 four-ring isomers (molecular mass 228 Da), 11 five ring isomers (molecular mass 278 Da), 17 six-ring isomers (molecular mass 328 Da), and 20 seven-ring isomers (molecular mass 378 Da). Significant linear correlations were found for all isomer groups (r = 0.71 to 0.94). Nonplanarity of the PAH isomers was found to influence retention (i.e., nonplanar isomers eluting earlier than expected based on L/B) and linear correlations of retention vs. T for isomer groups containing nonplanar isomers were significant (r = 0.71 to 0.86). Graphical abstract. PMID- 28660337 TI - Differential mobility spectrometry tandem mass spectrometry with multiple ion monitoring for the bioanalysis of liraglutide. AB - Liraglutide is a glucagon-like peptide-1 analog for the treatment of type 2 diabetes. Major interference in plasma of human and animals and low fragment signal in tandem mass spectrometry are the main difficulties encountered in the bioanalysis of liraglutide. In this study, by combining differential mobility spectrometry (DMS) with multiple ion monitoring detection (MIM), a liquid chromatography differential mobility spectrometry tandem mass spectrometry with multiple ion monitoring detection (LC-DMS-MIM) method was developed for the quantitation of liraglutide in dog plasma. Mixed anion-exchange solid-phase extraction was used for sample preparation. The parameters of DMS were meticulously optimized to increase the signal-to-noise ratio of the analyte. The assay was linear in the range 1-100 ng/mL with good accuracy and precision. The lower limit of quantitation (LLOQ, the lowest standard on the calibration curve) of this method was 1 ng/mL. The research reveals that DMS is an effective tool for the elimination of interference in bioanalysis and that LC-DMS-MIM has better specificity and higher signal-to-noise ratio than classical liquid chromatography tandem mass spectrometry (LC-MS/MS) for the bioanalysis of liraglutide. Graphical abstract Process for the bioanalysis of liraglutide by liquid chromatography differential mobility spectrometry tandem mass spectrometry with multiple ion monitoring detection. PMID- 28660338 TI - Trends in analysis of gunshot residue for forensic purposes. AB - Detection and identification of organic and inorganic components of gunshot residue are well established within forensic chemistry because of highly characteristic and uncommon features of the products of ammunition discharge at the time and place of a shooting incident in comparison to other materials present in daily life of people. Both types of residue play an important role in establishing various circumstances of a shooting crime, though the most vital one concerns the possibility of relating a suspect with the activity of shooting. In this aspect, solid, inorganic particles, nowadays called characteristic, have been utilized. Their specific features result from the primer mixture composition, including compounds of heavy metals, lead, antimony, and barium, and from the extraordinarily dynamic conditions of their formation, taking place at the moment of the primer detonation. Scanning electron microscopy and X-ray microanalysis techniques proved to be necessary and sufficient to reveal the content and the spherical morphology of the particles for this purpose. Recently, the recommendation that the potential for lead exposure be minimized was followed in the production of ammunition cal. 9 mm Luger, 0.40 S&W, 0.380 Auto, and 0.38 Special. These modern types of ammunition expel less characteristic particles, the identification of which can be a challenge for the examiners. At least two solutions to strengthen the residue identity are taken into account: additional insights into the internal structure of inorganic particles, e.g., by means of electron backscattered diffraction and focused ion beam, as well as complementary examinations of organic residues with sensitive mass spectrometric techniques. PMID- 28660339 TI - A multifunctional fluorescent aptamer probe for highly sensitive and selective detection of cadmium(II). AB - We report a highly sensitive and selective strategy for Cd(II) assay using a singly labeled multifunctional probe consisting of a Cd(II)-specific aptamer (CAP), which acted as a recognition element for Cd(II) and a signal reporter. The presence of Cd(II) can induce the conformational switching of the CAP, accompanied by a change in fluorescence intensity. Thereby, a fluorescence strategy for Cd(II) assay was established. The proposed method has a detection limit of 2.15 nM, which is much lower than the detection limits reported in related literature. This strategy involves only an aptamer probe, and the use of such a G4-based quencher avoids the dual labeling of the CAP with fluorophore/quencher units. It is obviously more convenient and economical than the other aptamer-based biosensors for Cd(II) detection. The mechanism by which Cd(II) induces the CAP to change from a random coil sequence to a stem-loop structure was studied in a series of control experiments. This strategy would be helpful in the design of a sensitive analytical platform for various target assays in environmental and biomedical fields. Graphical Abstract The presence of Cd2+ leads to the conformational change of CAP from a random coil sequence to a stem-loop structure, resulting in a quenching in the fluorescence. PMID- 28660340 TI - Electroencephalographic Patterns in Neurocritical Care: Pathologic Contributors or Epiphenomena? PMID- 28660341 TI - Low-dose Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage with INR Less Than 2.0. AB - BACKGROUND: Prothrombin complex concentrates (PCCs) have become the first-line therapy for warfarin reversal in the setting of central nervous system (CNS) hemorrhage. Randomized, controlled studies comparing agents for warfarin reversal excluded patients with international normalized ratio (INR) <2, yet INR values of 1.6-1.9 are also associated with poor outcomes. METHODS: We retrospectively reviewed our use of a low-dose (15 units/kg) strategy of 4-factor PCC (4F-PCC) on warfarin reversal (INR 1.6-1.9) in the setting of both traumatic and spontaneous intracranial bleeding. RESULTS: A total of 21/134 (15.7%) patients with either spontaneous or traumatic intracranial hemorrhage presented with an INR value of 1.6-1.9. Nine patients (43%) presented with traumatic bleeding and 12 (57%) with spontaneous bleeding. The median (IQR) presenting INR was 1.8 (1.7, 1.9) which decreased to 1.3 (1.2, 1.3) following the administration of low-dose 4F-PCC (median dose = 1062 units; 15.2 units/kg). A total of 19/20 (95%) patients achieved a goal INR value of <=1.5 on the first check following dosing and 17/20 (85%) achieved an INR value <=1.3. One patient did not have follow-up INR testing due to withdrawal of life support. No patient experienced hematoma expansion within 48 h of 4F-PCC, and there were no thromboembolic events within 72 h of administration. CONCLUSIONS: The administration of low dose (15 units/kg) of 4F PCC for urgent warfarin reversal in the setting of CNS hemorrhage was effective in correcting the INR in patients presenting with INR values of 1.6-1.9. Further assessment of low-dose PCC for urgent reversal of modest INR elevation is warranted. PMID- 28660342 TI - Digital divide, biometeorological data infrastructures and human vulnerability definition. AB - The design and implementation of any climate-related health service, nowadays, imply avoiding the digital divide as it means having access and being able to use complex technological devices, massive meteorological data, user's geographic location and biophysical information. This article presents the co-creation, in detail, of a biometeorological data infrastructure, which is a complex platform formed by multiple components: a mainframe, a biometeorological model called Pronbiomet, a relational database management system, data procedures, communication protocols, different software packages, users, datasets and a mobile application. The system produces four daily world maps of the partial density of the atmospheric oxygen and collects user feedback on their health condition. The infrastructure is shown to be a useful tool to delineate individual vulnerability to meteorological changes as one key factor in the definition of any biometeorological risk. This technological approach to study weather-related health impacts is the initial seed for the definition of biometeorological profiles of persons, and for the future development of customized climate services for users in the near future. PMID- 28660343 TI - Tissue mineral density measured at the sub-millimetre scale can provide reliable statistics of elastic properties of bone matrix. AB - Reliability of multiscale models of bone is related to the accuracy of the experimental information available on bone microstructure. X-ray-based imaging techniques allow to inspect bone structure and mineralization in vitro at the micrometre scale. However, spatial resolution achievable in vivo is much coarser and can produce blurry, uncertain information on bone microstructure. Working with uncertain data calls for new modelling paradigms able to propagate uncertainty through the scales. In this paper we investigate the effects of uncertain bone mineralization on the elastic coefficients of the bone matrix. To this aim, some stochastic concepts were developed and compared with one another in order to identify the best way to account for uncertain input data. These concepts step from a deterministic micromechanical model of bone matrix which was extended in order to account for uncertain bone composition. Uncertainty was introduced by assuming to know only mean value and dispersion of the parameters describing bone composition. Thus, these parameters were modelled as random variables and their distribution functions were obtained using the maximum entropy principle. Either the tissue mineral density (TMD) or the ensuing volume fractions of collagen and mineral were used to describe uncertain bone composition. Moreover, mean value and dispersion were estimated at the scales of either 10 or a few 100 [Formula: see text]m, representative of standard in vitro and in vivo spatial resolutions, respectively. Analysis of these modelling concepts suggests that TMD measured at the sub-millimetre scale can be used to obtain reliable statistical information about the elastic coefficients of bone matrix. PMID- 28660344 TI - Response to the Letter by Lucijanic et al., regarding our manuscript "Management and outcome of gastro-intestinal bleeding in patients taking oral anticoagulants or antiplatelet drugs". PMID- 28660345 TI - [Expectations of visceral surgeons from the results of clinical autopsies]. PMID- 28660347 TI - Bioinspired magnetic reception and multimodal sensing. AB - Several animals use Earth's magnetic field in concert with other sensor modes to accomplish navigational tasks ranging from local homing to continental scale migration. However, despite extensive research, animal magnetic reception remains poorly understood. Similarly, the Earth's magnetic field offers a signal that engineered systems can leverage to navigate in environments where man-made positioning systems such as GPS are either unavailable or unreliable. This work uses a behavioral strategy inspired by the migratory behavior of sea turtles to locate a magnetic goal and respond to wind when it is present. Sensing is performed using a number of distributed sensors. Based on existing theoretical biology considerations, data processing is performed using combinations of circles and ellipses to exploit the distributed sensing paradigm. Agent-based simulation results indicate that this approach is capable of using two separate magnetic properties to locate a goal from a variety of initial conditions in both noiseless and noisy sensory environments. The system's ability to locate the goal appears robust to noise at the cost of overall path length. PMID- 28660346 TI - Adeno-associated viral gene therapy for mucopolysaccharidoses exhibiting neurodegeneration. AB - The mucopolysaccharidoses (MPS) are a subgroup of lysosomal storage disorders that are caused by mutations in the genes involved in glycosaminoglycan breakdown. Multiple organs and tissues are affected, including the central nervous system. At present, hematopoietic stem cell transplantation and enzyme replacement therapies are approved for some of the (non-neurological) MPS. Treatments that effectively ameliorate the neurological aspects of the disease are being assessed in clinical trials. This review will focus on the recent outcomes and planned viral vector-mediated gene therapy clinical trials, and the pre-clinical data that supported these studies, for MPS-I (Hurler/Scheie syndrome), MPS-II (Hunter syndrome), and MPS-IIIA and -IIIB (Sanfilippo syndrome). PMID- 28660348 TI - The role of F-18 FDG PET/CT in evaluating the impact of HIV infection on tumor burden and therapy outcome in patients with Hodgkin lymphoma. AB - BACKGROUND: To evaluate the impact of HIV infection on tumor burden and therapy outcome following treatment with chemotherapy in patients with Hodgkin lymphoma. METHODS: A total of 136 patients with classical Hodgkin lymphoma were studied (mean age +/- SD = 32.31 +/- 1.39 years, male = 86, female = 50). Advanced disease (stage III and IV) was present in 64% of patients. HIV infection was present in 57 patients while 79 patients were HIV-negative. Baseline F-18 FDG PET/CT was obtained in all patients. SUVmax, MTV and TLG were determined on the baseline scan to evaluate for tumor burden. All patients completed a standard regimen of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). After a median period of 8 weeks (range = 6 to 17 weeks), a repeat F-18 FDG PET/CT scan was obtained to evaluate response to therapy using Deauville 5-point scoring system. RESULTS: The HIV-positive and HIV-negative groups were similar with regards to age and disease stage. The groups were heterogeneous with respect to gender (p = 0.029). The SUVmax, MTV and TLG of lesions were not significant different between the two groups. Complete response was seen in 72.8% of the study population. Presence of HIV infection was associated with higher rate of treatment failure with 40.4% of the HIV-positive patients having treatment failure while only 17.7% of the HIV-negative patients had treatment failure (p = 0.0034). HIV infection was a significant predictor of response to chemotherapy. Effects of SUVmax, MTV, TLG and Ann Arbor stage of the disease were not statistically significant as predictors of therapy outcome. In a multiple logistic regression, presence of HIV infection still remained an independent predictor of therapy outcome in the presence of other factors such as SUVmax, MTV, TLG and the Ann Arbor stage of the disease. CONCLUSIONS: HIV infection is not associated with a higher tumor burden in patients with Hodgkin lymphoma. HIV infection is, however, a strong predictor of poor therapy outcome in patients treated with standard regimen of ABVD. PMID- 28660350 TI - The effects of oncology massage on symptom self-report for cancer patients and their caregivers. AB - BACKGROUND: Massage has shown benefit for symptomatic relief in cancer patients and their caregivers. We explored the effects of a single massage session on self reported symptoms in an outpatient clinic at a comprehensive cancer center. METHODS: Patients and caregivers receiving oncology massage treatments (30 or 60 min duration) at our Integrative Medicine Center outpatient clinic from September 2012 to January 2015 completed the Edmonton Symptom Assessment Scale (ESAS; 0-10 scale, 10 most severe) pre and post massage. ESAS individual items and subscales of physical distress (PHS), psychological distress (PSS), and global distress (GDS) were analyzed. We used paired t tests with a p value correction (i.e., p < .001) to examine symptoms pre/post massage. RESULTS: Initial massage visits for 343 patients and 87 caregivers were analyzed. The highest symptom burdens (means) at baseline for patients were sleep 4.22, fatigue 3.57, and pain 2.94; for caregivers, sleep 3.77, well-being 3.01, and pain 2.59. Although patients reported significantly greater global distress and physical symptoms (p < .0001) compared to caregivers at baseline, groups did not differ in regard to psychological symptom burden (p = .66) and individual symptom scores (e.g., pain, sleep, spiritual pain). Massage therapy was associated with statistically (p < .0001) and clinically significant improvements in symptoms of pain, fatigue, anxiety, well-being, and sleep and ESAS subscales for both patients and caregivers. Greater massage duration (30 vs 60 min) did not lead to greater symptom reduction. CONCLUSIONS: Patients and caregivers reported a moderately high symptom burden. A single massage treatment resulted in acute relief of self reported symptoms in both groups. Further study is warranted regarding optimal massage dose and frequency. PMID- 28660349 TI - Tumor-Associated Macrophages as Target for Antitumor Therapy. AB - It is well known that the microenvironment of solid tumors is rich in inflammatory cells that influence tumor growth and development. Macrophages, called tumor-associated macrophages (TAMs), are the most abundant immune cell population present in tumor tissue. Several studies have demonstrated that the density of TAMs is associated with a poor prognosis and positively correlates with tumor growth. Several studies have proved that TAMs may activate and protect tumor stem cells, stimulate their proliferation as well as promote angiogenesis and metastasis. Furthermore, TAMs-derived cytokines and other proteins, such as CCL-17, CCL-22, TGF-beta, IL-10, arginase 1, and galectin-3, make a significant contribution to immunosuppression. Since TAMs influence various aspects of cancer progression, there are many attempts to use them as a target for immunotherapy. The numerous studies have shown that the primary tumor growth and the number of metastatic sites can be significantly decreased by decreasing the population of macrophages in tumor tissue, for example, by blocking recruitment of monocytes or eliminating TAMs already present in the tumor tissue. Moreover, there are attempts at reprogramming TAMs into proinflammatory M1 macrophages or neutralizing the protumoral products of TAMs. Another approach uses TAMs for anticancer drug delivery into the tumor environment. In this review, we would like to summarize the clinical and preclinical trials that were focused on macrophages as a target for anticancer therapies. PMID- 28660351 TI - Moxifloxacin versus levofloxacin or ciprofloxacin prophylaxis in acute myeloid leukemia patients receiving chemotherapy. AB - PURPOSE: Patients receiving intensive chemotherapy regimens are at high risk for infectious complications due to prolonged neutropenia and hospital stay. Fluoroquinolone antibiotics, mainly levofloxacin and ciprofloxacin, are the mainstay of prophylactic therapy for these patients. There is limited data regarding the utilization of other quinolone antibiotics including moxifloxacin in this setting. METHODS: A retrospective chart review was completed comparing the use of prophylactic moxifloxacin to that of levofloxacin or ciprofloxacin during periods of prolonged neutropenia. Adult patients admitted to a community teaching hospital while receiving induction or reinduction chemotherapy for acute myeloid leukemia were included. RESULTS: One hundred and forty-one patients were included in this study. The two groups displayed slight heterogeneity: patients receiving moxifloxacin were approximately 10 years younger (54 vs. 64 years, p = 0.01), more likely to receive granulocyte colony stimulating factor (GCSF) (45 vs. 19%, p = 0.001), and neutropenic for a longer duration (23 vs. 19 days, p = 0.009). The incidence of febrile neutropenia (76 vs. 81%, RR 0.93, 95% CI 0.78 1.11, p = 0.42) and of documented infections (27 vs. 33%, RR 0.82, 95% CI 0.49 1.36, p = 0.44) was similar between those receiving moxifloxacin and levofloxacin/ciprofloxacin, respectively. Hospital readmission for an infectious issue within 30 days of hospital discharge (9 vs. 5%, p = 0.39) was also similar between groups as was the incidence of Clostridium difficile (9 vs. 9%, p = 0.96). CONCLUSIONS: Moxifloxacin may be an alternative to levofloxacin or ciprofloxacin in patients with a prolonged risk of febrile neutropenia requiring prophylaxis. PMID- 28660354 TI - Working with the Hmong Population in a Genetics Setting: Genetic Counselor Perspectives. AB - The Hmong language lacks words for many familiar Western medical genetic concepts which may impact genetic counseling sessions with individuals of Hmong ancestry who have limited English proficiency. To study this interaction, a qualitative, semi-structured interview was designed to address genetic counselors' experiences of genetic counseling sessions working with individuals with Hmong ancestry. Genetic counselors in the three states with the largest population of Hmong individuals (California, Minnesota and Wisconsin) were invited via email to participate in a telephone interview. Eleven counselors' interviews were transcribed and analyzed for emergent themes. Each of the counselors had served Hmong patients in a variety of clinics and possessed counseling experience ranging from approximately one to greater than 20 years. Interviews highlighted strengths and challenges in genetic counseling sessions with Hmong patients with limited English proficiency in each of five categories: 1) relevant training during graduate school, 2) session preparation, 3) content of the counseling session, 4) perception of Hmong culture, and 5) reflections on working with Hmong interpreters. Cultural awareness and education in training programs were highlighted by all genetic counselors as valued components to patient care. All interviewees had worked with professional Hmong medical interpreters, but had different expectations for the interpreter with whom they worked. To help improve genetic services for Hmong individuals in the United States, we offer suggestions to improve some of the challenges mentioned, and recommend further studies to investigate the genetic counselor and interpreter relationship. PMID- 28660352 TI - Erratum to: Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features. PMID- 28660355 TI - Left Spatial Neglect Evoked by Electrostimulation of the Right Inferior Fronto occipital Fasciculus. AB - Left spatial neglect is a debilitating condition that may occur after lesion of many cortical territories in the right hemisphere. At the subcortical level, the second and third branches of the right superior longitudinal fasciculus has emerged as strong candidates in conveying information exchanges within the attention networks as their damage has been repeatedly associated to spatial neglect in neuromodulation and neuropsychological studies. Yet, a few cases of spatial neglect have also been observed after damage to the right inferior fronto occipital fasciculus (IFOF), suggesting an involvement of this associative connectivity in spatial attention. Here we report three rare cases of patients having undergone a wide-awake craniotomy with direct electrostimulation for right temporal glioma. An intraoperative monitoring of spatial cognition was performed using a standard line bisection task. Responsive cortical sites were observed in the supramarginal gyrus and the posterior part of both the middle and superior temporal gyri. Critically, in all patients, significant rightward deviations were observed by the stimulation of the white matter deep in the temporal lobe, along the roof of the inferior horn of the lateral ventricle-a well-known anatomical landmark to identify the IFOF. Disconnection analyses confirmed the high probability of IFOF disconnection during neglect-related stimulations. Taken together, our findings provide support for a role of the right IFOF in spatial cognition. We discuss these results in the light of the newly discovered fronto parietal connections of the IFOF and suggest that some subcomponents of this tract might be involved in between-system integration within the attention network. PMID- 28660356 TI - Community-acquired lower respiratory tract infections in HIV-infected patients on antiretroviral therapy: predictors in a contemporary cohort study. AB - : Community-acquired pneumonia represents the most frequent bacterial infection in patients with HIV/AIDS. PURPOSE: We aimed to assess variables associated with lower respiratory tract infection (LRTI) among HIV-infected adults using ART. METHODS: A cohort study of HIV-infected patients aged >=18 years, enrolled from 2000 to 2015, on ART for at least 60 days, with primary outcome as the 1st episode of LRTI during follow-up. The independent variables included were sex at birth, age, race/skin color, educational level, tobacco smoking, alcohol use, cocaine use, diabetes mellitus, CD4 count, HIV viral load, influenza and pneumococcal vaccination. Extended Cox proportional hazards models accounting for time-updated variables were fitted to assess LRTI predictors. RESULTS: 2669 patients were included; median follow-up was 3.9 years per patient. LRTI was diagnosed in 384 patients; incidence rate was 30.7/1000 PY. In the unadjusted Cox extended models, non-white race [crude hazard ratio (cHR) 1.28, p = 0.020], cocaine use (cHR 2.01, p < 0.001), tobacco smoking (cHR 1.34, p value 0.007), and HIV viral load >=400 copies/mL (cHR 3.40, p < 0.001) increased the risk of LRTI. Lower risk of LRTI was seen with higher educational level (cHR 0.61, p < 0.001), rise in CD4 counts (cHR 0.81, p < 0.001, per 100 cells/mm3 increase), influenza (cHR 0.60, p = 0.002) and pneumococcal vaccination (cHR 0.57, p < 0.001). In the adjusted model, aHR for CD4 count was 0.86, for cocaine use 1.47 and for viral load >=400 copies 2.20. CONCLUSIONS: LRTI has a high incidence in HIV-infected adults using ART. Higher CD4 counts and undetectable viral loads were protective, as were pneumococcal and influenza vaccines. PMID- 28660357 TI - Sociodemographic disparities in survival for adolescents and young adults with cancer differ by health insurance status. AB - PURPOSE: To investigate associations of sociodemographic factors-race/ethnicity, neighborhood socioeconomic status (SES), and health insurance-with survival for adolescents and young adults (AYAs) with invasive cancer. METHODS: Data on 80,855 AYAs with invasive cancer diagnosed in California 2001-2011 were obtained from the California Cancer Registry. We used multivariable Cox proportional hazards regression to estimate overall survival. RESULTS: Associations of public or no insurance with greater risk of death were observed for 11 of 12 AYA cancers examined. Compared to Whites, Blacks experienced greater risk of death, regardless of age or insurance, while greater risk of death among Hispanics and Asians was more apparent for younger AYAs and for those with private/military insurance. More pronounced neighborhood SES disparities in survival were observed among AYAs with private/military insurance, especially among younger AYAs. CONCLUSIONS: Lacking or having public insurance was consistently associated with shorter survival, while disparities according to race/ethnicity and neighborhood SES were greater among AYAs with private/military insurance. While health insurance coverage associates with survival, remaining racial/ethnic and socioeconomic disparities among AYAs with cancer suggest additional social factors also need consideration in intervention and policy development. PMID- 28660358 TI - Aspartame and Soft Drink-Mediated Neurotoxicity in Rats: Implication of Oxidative Stress, Apoptotic Signaling Pathways, Electrolytes and Hormonal Levels. AB - A significant association between fructose corn syrup in sweetened beverages consumption and increased risk of detrimental central nervous system effects has been recently reported. We hypothesized that the aspartame and soft drink induced disturbances in energy production and endocrine function, which play a role in the induction of brain damage. Therefore, we aimed to assess the effect of aspartame and soft drink on brain function and the link between energy status in the brain, oxidative stress and molecular pathways of apoptosis. Thirty rats were randomly assigned to drink water, aspartame (240 mg/kg orally) and cola soft drinks (free access) daily for two months. Subchronic intake of aspartame and soft drink significantly disrupted the brain energy production, as indicated by inhibited serum and brain creatine kinase, specifically in soft drink-received rats. Moreover, they substantially altered serum electrolytes (increased Ca and Na, and depleted Cu, Fe, Zn and K levels), and accordingly the related hormonal status (increased T4 and PTH, and lowered T3 and aldosterone levels), particularly in soft drink-received rats reflecting brain damage. Additionally, significant increment of acetylcholine esterase activity concomitant with the reduction of antioxidant molecules (SOD, CAT, GSH-Px and GSH), and induction of malondialdehyde level are precisely indicative of oxidative brain damage. Brain mRNA transcripts of target genes showed that aspartame and soft drink induced upregulation of BAX, Casp3, P27 and Mdm2 (1.5-fold) and down-regulation of Bcl2, suggesting an activation of cellular apoptosis. Collectively, subchronic aspartame and soft drink-induced brain damage in rats may be driven via a mechanism that involves energy production disruption, electrolytes and hormonal imbalance, increased oxidative stress and activation of molecular pathway of neuronal apoptosis. PMID- 28660359 TI - Non-alcoholic Wernicke's encephalopathy with cortical involvement and polyneuropathy following gastrectomy. AB - In this study, we present the clinical manifestations, brain magnetic resonance imaging (MRI) and concurrent polyneuropathies in two patients with non-alcoholic Wernicke's encephalopathy (WE) after gastrojejunostomy (Billroth II) anastomosis procedures. These patients developed sub-acute onset of disorientation and disturbance of consciousness following several weeks of poor intake. Peripheral neuropathy of varying severity was noted before and after the onset of WE. Brain MRI of the patients showed cerebellar vermis and symmetric cortical abnormalities in addition to typical WE changes. Electrophysiological studies demonstrated axonal sensorimotor polyneuropathy. Prompt thiamine supplement therapy was initiated and both patients gradually recovered, however mild amnesia was still noted 6 months later. We reviewed non- alcoholic WE with atypical cortical abnormalities in English language literatures and identified 29 more cases. Eight out of 31 (25.8%) patients died during follow-up. Nine patients with gait disturbance or motor paresis had showed hyporeflexia in neurological examinations. In addition to classic triad, seizure was recorded in seven patients. Dietary deprivation is a risk factor for non-alcoholic WE among elderly patients receiving gastrointestinal surgery. The prognosis is good after thiamine supplement therapy. Recognizing the MRI features and predisposing factors in patients who have undergone gastrectomy can aid in the diagnosis and management. PMID- 28660360 TI - Neuro- and nephrotoxicity of subchronic cadmium chloride exposure and the potential chemoprotective effects of selenium nanoparticles. AB - Cadmium (Cd) exposure leads to production of reactive oxygen species (ROS), which are associated with Cd-induced neurotoxicity and nephrotoxicity. Selenium nanoparticles (Se-NPs) have high bioavailability and antioxidant activities so it attracted wide spread attention. The present study examined the possible ameliorative effect of Se-NPs with diameters of 3-5 nm and 10-20 nm against cadmium chloride (CdCl2)-induced neuro- and nephrotoxicity in rats. Rats were treated with Se-NPs (0 or 0.5 mg/kg BW, s.c.) one hour prior to the CdCl2 (0 or 5 mg/kg BW, p.o.). Pretreatment with Se-NPs significantly decreased CdCl2-induced elevation of serum kidney and brain damage biomarkers; lipid peroxidation; the percent of DNA fragmentation and nearly normalized the activity of acetylcholinesterase (AchE) and significantly increased the activity and expression of antioxidant biomarkers in the RNA and protein levels. Se-NPs also attenuated CdCl2-induced upregulation of kidney and brain pro-apoptotic B-cell CLL/lymphoma 2 associated X (Bax) RNA and protein levels with preventing the increased body burden of Cd and the altered Fe and Cu homeostasis. Histopathological analysis confirmed the biochemical and molecular outcomes. Our data stated that Se-NPs appear to be effective in ameliorating the adverse neurological and nephrotoxic effects induced by CdCl2 partially through the scavenging of free radicals, metal ion chelation, averting apoptosis and altering the cell-protective pathways. The results indicated that Se-NPs could potentially included as an additive to Cd-based industries to control Cd-induced brain and renal injury. PMID- 28660361 TI - Establishment of a markerless gene deletion system in Chromohalobacter salexigens DSM 3043. AB - Chromohalobacter salexigens DSM 3043 can grow over a wide range of salinity, which makes it as an excellent model organism for understanding the mechanism of prokaryotic osmoregulation. Functional analysis of C. salexigens genes is an essential way to reveal their roles in cellular osmoregulation. However, the lack of an effective markerless gene deletion system has prevented construction of multiple gene deletion mutants for the members in the genus. Here, we report the development of a markerless gene deletion system in C. salexigens using allelic exchange method. In this system, the in vitro mutant allele of target gene was inserted into a pK18mobsacB-based integrative vector pMDC21, which contained a chloramphenicol resistance cassette as the positive selection marker and a sacB gene from Bacillus subtilis as the counterselectable marker. To validate this system, two single-gene deletion mutants and a double-gene deletion mutant were constructed. In addition, our results showed that growth of the merodiploids and sucrose screening at 25 degrees C were more effective to decrease the occurrence of spontaneous sucrose resistance colonies than at higher temperature (30 or 37 degrees C), and growth of the merodiploids in mineral salt medium instead of the complex medium was critical to increase the recovery rate of deletion mutants. PMID- 28660362 TI - Antarctic rocks from continental Antarctica as source of potential human opportunistic fungi. AB - We assessed the diversity of culturable fungi associated with rocks of continental Antarctica to evaluate their physiological opportunistic virulence potential in vitro. The seventy fungal isolates obtained were identified as nine species of Acremonium, Byssochlamys, Cladosporium, Debaryomyces, Penicillium, and Rhodotorula. Acremonium sp., D. hansenii, P. chrysogenum, P. citrinum, P. tardochrysogenum, and R. mucilaginosa were able to grow at 37 degrees C; in addition, B. spectabilis displayed a high level of growth at 37 and 45 degrees C. Thirty-one isolates of P. chrysogenum, P. citrinum, and P. tardochrysogenum were able to produce partial haemolysis on blood agar at 37 degrees C. Acremonium sp., P. citrinum, and P. tardochrysogenum showed spore sizes ranging from 2.81 to 5.13 um diameters at 37 degrees C. Of these, P. chrysogenum and P. tardochrysogenum displayed macro- and micro morphological polymorphism. Our results suggest that rocks of the ultra-extreme cold and dry environment of Antarctica harbour cryptic fungi phylogenetically close to opportunistic pathogenic and mycotoxigenic taxa with physiologic virulence characteristics in vitro. PMID- 28660363 TI - Adaptation of root growth to increased ambient temperature requires auxin and ethylene coordination in Arabidopsis. AB - KEY MESSAGE: A fresh look at the roles of auxin, ethylene, and polar auxin transport during the plant root growth response to warmer ambient temperature (AT). The ambient temperature (AT) affects plant growth and development. Plants can sense changes in the AT, but how this change is transduced into a plant root growth response is still relatively unclear. Here, we found that the Arabidopsis ckrc1-1 mutant is sensitive to higher AT. At 27 degrees C, the ckrc1-1 root length is significantly shortened and the root gravity defect is enhanced, changes that can be restored with addition of 1-naphthaleneacetic acid, but not indole-3-acetic acid (IAA). AUX1, PIN1, and PIN2 are involved in the ckrc1-1 root gravity response under increased AT. Furthermore, CKRC1-dependent auxin biosynthesis was critical for maintaining PIN1, PIN2, and AUX1 expression at elevated temperatures. Ethylene was also involved in this regulation through the ETR1 pathway. Higher AT can promote CKRC1-dependent auxin biosynthesis by enhancing ETR1-mediated ethylene signaling. Our research suggested that the interaction between auxin and ethylene and that the interaction-mediated polar auxin transport play important roles during the plant root growth response to higher AT. PMID- 28660364 TI - How Can Supervisors Contribute to the Return to Work of Employees Who have Experienced Depression? AB - Background In Western countries, work disability due to depression is a widespread problem that generates enormous costs. Objective The goal of this study was to determine the types and prevalence of supervisor contributions during the different phases of the return-to-work (RTW) process (before and during the sick-leave absence, and during the RTW preparations) of employees diagnosed with depression. Moreover, we sought to determine which contributions actually facilitate employees' RTW, and to identify the work accommodations most frequently implemented by supervisors at the actual time of their employee's RTW. Methods Telephone interviews were conducted in Quebec (Canada) with 74 supervisors working with employees who were already back at work or still on sick leave due to depression. A sub-sample of 46 supervisors who had already taken measures to facilitate their employees' RTW was questioned about the work accommodations implemented. Results Most of the supervisors got along well with their employees before their sick leave and 72% stayed in contact with them during their leave. Nearly 90% of the supervisors encouraged their employees to focus primarily on their recovery before their RTW, but 43% pressured their employees to RTW as soon as possible. Cox regression analyses performed for the entire sample revealed that "the supervisors' intention to take measures to facilitate their employees' RTW" was the only significant predictor of the RTW at the time of the interview. The Kaplan-Meier survival curve showed that 50% of the employees were expected to RTW within the first 8 months of absence. Four of the most frequently implemented work accommodations were actions directly involving the supervisor (i.e. providing assistance, feedback, recognition, and emotional support to the employee). Conclusions This study shed light on the less explored point of view of the supervisor involved in the RTW process of employees post depression. It highlighted the most frequent and effective supervisor contributions to the process. These results can be used to develop concrete action plans for training supervisors to contribute to the sustainable RTW of employees on sick leave due to depression. PMID- 28660365 TI - Do Work Characteristics Predict Health Deterioration Among Employees with Chronic Diseases? AB - Purpose In our ageing workforce, the increasing numbers of employees with chronic diseases are encouraged to prolong their working lives. It is important to prevent health deterioration in this vulnerable group. This study aims to investigate whether work characteristics predict health deterioration over a 3 year period among employees with (1) chronic diseases, and, more specifically, (2) musculoskeletal and psychological disorders. Methods The study population consisted of 5600 employees aged 45-64 years with a chronic disease, who participated in the Dutch Study on Transitions in Employment, Ability and Motivation (STREAM). Information on work characteristics was derived from the baseline questionnaire. Health deterioration was defined as a decrease in general health (SF-12) between baseline and follow-up (1-3 years). Crude and adjusted logistic regression analyses were performed to investigate prediction of health deterioration by work characteristics. Subgroup analyses were performed for employees with musculoskeletal and psychological disorders. Results At follow-up, 19.2% of the employees reported health deterioration (N = 1075). Higher social support of colleagues or supervisor predicted health deterioration in the crude analyses in the total group, and the groups with either musculoskeletal or psychological disorders (ORs 1.11-1.42). This effect was not found anymore in the adjusted analyses. The other work characteristics did not predict health deterioration in any group. Conclusions This study did not support our hypothesis that work characteristics predict health deterioration among employees with chronic diseases. As our study population succeeded continuing employment to 45 years and beyond, it was probably a relatively healthy selection of employees. PMID- 28660366 TI - Nationwide conversion to generic tacrolimus in pediatric kidney transplant recipients. AB - BACKGROUND: Bioequivalence between Tacrolimus Prograf(r) and generic tacrolimus formulations has been demonstrated in adult populations, however clinical experience and safety data regarding generic tacrolimus in pediatric transplant recipients is limited. This study aimed to evaluate conversion from Tacrolimus Prograf(r) to Sandoz(r) in pediatric renal transplant recipients nationwide. The primary outcome was a change in mean trough tacrolimus concentration. Additionally, changes in tacrolimus intra-patient coefficient of variation (CoV), allograft function, requirement for dose adjustments, and episodes of biopsy proven rejection were evaluated. METHODS: Retrospective cohort study in 37 pediatric renal transplant recipients who switched to Tacrolimus Sandoz(r). Each patient had three pre-conversion tacrolimus trough and creatinine concentrations within the 4 months prior and three post-conversion concentrations on day 3, 10, and the next subsequent level. Mean pre- and post-conversion tacrolimus trough concentrations and glomerular filtration rate (eGFR) were calculated. Tacrolimus concentration, CoV, and creatinine differences were compared by paired t test. RESULTS: Thirty-seven patients (41% females, age 3-18 years) were included. Average intra-patient difference in trough tacrolimus concentration was 0.05MUg/l (95% CI -0.37 to 0.47). Average intra-patient difference in eGFR was -1.20 ml/min/1.732 (95% CI -3.53 to 1.13). Three patients had acute rejection during 12 months post-conversion compared to none during 12 months pre-conversion. CONCLUSIONS: Pediatric renal transplant recipients can be converted from Tacrolimus Prograf(r) to Sandoz(r) with negligible change in trough concentration, dose adjustments, or immediate allograft function. Of concern was the number of acute rejection episodes, however non-adherence contributed to at least one episode and this difference was determined clinically and statistically not significant. PMID- 28660367 TI - Whole exome sequencing: a state-of-the-art approach for defining (and exploring!) genetic landscapes in pediatric nephrology. AB - The genesis of whole exome sequencing as a powerful tool for detailing the protein coding sequence of the human genome was conceptualized based on the availability of next-generation sequencing technology and knowledge of the human reference genome. The field of pediatric nephrology enriched with molecularly unsolved phenotypes is allowing the clinical and research application of whole exome sequencing to enable novel gene discovery and provide amendment of phenotypic misclassification. Recent studies in the field have informed us that newer high-throughput sequencing techniques are likely to be of high yield when applied in conjunction with conventional genomic approaches such as linkage analysis and other strategies used to focus subsequent analysis. They have also emphasized the need for the validation of novel genetic findings in large collaborative cohorts and the production of robust corroborative biological data. The well-structured application of comprehensive genomic testing in clinical and research arenas will hopefully continue to advance patient care and precision medicine, but does call for attention to be paid to its integrated challenges. PMID- 28660368 TI - High production of genistein diglucoside derivative using cyclodextrin glycosyltransferase from Paenibacillus macerans. AB - Genistein has been regarded as one important soy isoflavone with multiple health benefits, whereas its applications are limited by the low hydrophilicity. To improve the water solubility, codon optimized cyclodextrin glycosyltransferase from Paenibacillus macerans was employed for genistein transglycosylation in this study. At least four transglycosylation products were produced and identified by HPLC and LC-MS: genistein monoglucoside, diglucoside, triglucoside, and tetraglucoside derivatives. Obviously, the yields of genistein monoglucoside and genistein diglucoside exhibited great superiority compared with other two products. To maximize the yield of genistein diglucoside, various reaction conditions such as genistein dissolvents, glycosyl donors, substrates concentrations and ratios, enzyme concentrations, reaction pH, temperature, and time were optimized. Finally, the yield of genistein diglucoside was enhanced by 1.5-fold under the optimum reaction system. Our study demonstrates that the production of genistein diglucoside could be specifically enhanced, which is one important genistein derivative with better water solubility and stability. PMID- 28660370 TI - The Impact of Coverage Restrictions on Antipsychotic Utilization Among Low-Income Medicare Part D Enrollees. AB - Prior research demonstrates substantial access problems associated with utilization management and formulary exclusions for antipsychotics in Medicaid, but the use and impact of coverage restrictions for these medications in Medicare Part D remains unknown. We assess the effect of coverage restrictions on antipsychotic utilization in Part D by exploiting a unique natural experiment in which low-income beneficiaries are randomly assigned to prescription drug plans with varying levels of formulary generosity. Despite considerable variation in use of coverage restrictions across Part D plans, we find no evidence that these restrictions significantly deter utilization or reduce access to antipsychotics for low-income beneficiaries. PMID- 28660369 TI - Accurate analysis of fusion expression of Pichia pastoris glycosylphosphatidylinositol-modified cell wall proteins. AB - Glycosylphosphatidylinositol (GPI)-anchored glycoproteins have diverse intrinsic functions in yeasts, and they also have different uses in vitro. The GPI-modified cell wall proteins GCW21, GCW51, and GCW61 of Pichia pastoris were chosen as anchoring proteins to construct co-expression strains in P. pastoris GS115. The hydrolytic activity and the amount of Candida antarctica lipase B (CALB) displayed on cell surface increased significantly following optimization of the fusion gene dosage and combination of the homogeneous or heterogeneous cell wall proteins. Maximum CALB hydrolytic activity was achieved at 4920 U/g dry cell weight in strain GS115/CALB-GCW (51 + 51 + 61 + 61) after 120 h of methanol induction. Changes in structural morphology and the properties of the cell surfaces caused by co-expression of fusion proteins were observed by transmission electron microscopy (TEM) and on plates containing cell-wall-destabilizing reagent. Our results suggested that both the outer and inner cell layers were significantly altered by overexpression of GPI-modified cell wall proteins. Interestingly, quantitative analysis of the inner layer components showed an increase in beta-1,3-glucan, but no obvious changes in chitin in the strains overexpressing GPI-modified cell wall proteins. PMID- 28660371 TI - Effects of River Discharge and Land Use and Land Cover (LULC) on Water Quality Dynamics in Migina Catchment, Rwanda. AB - Agricultural intensification may accelerate the loss of wetlands, increasing the concentrations of nutrients and sediments in downstream water bodies. The objective of this study was to assess the effects of land use and land cover and river discharge on water quality in the Migina catchment, southern Rwanda. Rainfall, discharge and water quality (total nitrogen, total phosphorus, total suspended solids, dissolved oxygen, conductivity, pH, and temperature) were measured in different periods from May 2009 to June 2013. In 2011, measurements were done at the outlets of 3 sub-catchments (Munyazi, Mukura and Akagera). Between May 2012 and May 2013 the measurements were done in 16 reaches of Munyazi dominated by rice, vegetables, grass/forest or ponds/reservoirs. Water quality was also measured during two rainfall events. Results showed seasonal trends in water quality associated with high water flows and farming activities. Across all sites, the total suspended solids related positively to discharge, increasing 2-8 times during high flow periods. Conductivity, temperature, dissolved oxygen, and pH decreased with increasing discharge, while total nitrogen and total phosphorus did not show a clear pattern. The total suspended solids concentrations were consistently higher downstream of reaches dominated by rice and vegetable farming. For total nitrogen and total phosphorus results were mixed, but suggesting higher concentration of total nitrogen and total phosphorus during the dry and early rainy (and farming) season, and then wash out during the rainy season, with subsequent dilution at the end of the rains. Rice and vegetable farming generate the transport of sediment as opposed to ponds/reservoir and grass/forest. PMID- 28660372 TI - A finite element study of traditional Chinese cervical manipulation. AB - PURPOSE: Traditional Chinese cervical manipulation (TCCM) has been claimed as an effective treatment for diseases of the cervical spine, but its biomechanical effects on the vertebral body and intervertebral discs remain unclear. The aim of this study was to develop and validate a detailed finite element model of cervical spine, which was then used to investigate the biomechanical response of the cervical spine to TCCM. METHODS: The model of a C2-T1 cervical spine was constructed based on CT images of a healthy male volunteer and validated against published in vitro studies under different loading conditions. The detailed force time data of TCCM were measured on the same volunteer through dynamometric diaphragms. The data were applied on the validated finite element model to simulate TCCM. RESULTS: The current model could offer potentials to effectively reflect the behavior of human cervical spine suitable for biomechanics studies of TCCM. Under simulated TCCM condition, the stress distributions in cervical spine and intervertebral discs could not be completely explained through the traditional theory. CONCLUSION: Spinal manipulation, or TCCM, might play no role in reducing intradiscal pressure for treating cervical spondylosis. It could cause less stress concentration in intervertebral discs while operating spinal manipulation or TCCM when the adjustment points was chosen near the root of spinous process than the top of spinous process. PMID- 28660373 TI - Cervical laminectomy of limited width prevents postoperative C5 palsy: a multivariate analysis of 263 muscle-preserving posterior decompression cases. AB - PURPOSE: Between 2006 and 2010, we performed wide laminectomy (wide LAM) alone, with decompression performed between the bilateral medial margin of the zygapophyseal joints, or double-door laminoplasty (DL) combined with wide LAM for cervical compressive myelopathy (CCM). From 2010, instead of wide LAM and DL, we began to perform narrow LAM, where the laminectomy width was no more than 2-3 mm wider than the spinal cord width (SW). This study aimed to elucidate the risk factors for C5 palsy by reviewing surgical outcomes. METHODS: The clinical features and radiological findings of 263 CCM patients with or without C5 palsy were compared. Risk factors for C5 palsy were assessed using logistic regression analysis. The decompression width (DW) was defined as the laminectomy width or the width between the bilateral medial margins of the bony gutters in DL. RESULTS: Narrow LAM reduced the incidence of C5 palsy from 9.2 to 1.2%. DL was performed more frequently in the C5 palsy group. The difference between the DW and the SW (DW - SW) was significantly greater in the C5 palsy group. Posterior spinal cord shift, aging, and the number of consecutive laminae surgically treated were significantly higher in the C5 palsy group. The diameter of the foramen (DF) at C4/5 was significantly smaller in the C5 palsy patients. The logistic regression analysis revealed that DL, DW - SW, DF, and aging were risk factors for C5 palsy. CONCLUSIONS: Cervical laminectomy of limited width prevented postoperative C5 palsy without compromising the functional recovery. PMID- 28660374 TI - Response to "Clinical Evaluation of Bone Strength and Fracture Risk". AB - We read with great interest the recent review by de Bakker et al that summarized the state of several existing and emerging technologies for estimating bone strength and fracture risk in vivo. Much of their review focused on how well the measurements of selected technologies predicted experimental measurements of bone strength by ex vivo quasistatic mechanical testing (QMT) and on how well they tracked changes in mechanical properties of bone. The authors noted that the association of many common skeletal health measurements (e.g., DXA measures of trabecular bone score and areal and volumetric BMD) are only moderately associated with bone strength. The authors did not include mechanical response tissue analysis (MRTA) in their review. MRTA is a dynamic mechanical bending test that uses a vibration analysis technique to make immediate, direct, functional measurements of the mechanical properties (mass, stiffness, and damping) of long bones in humans in vivo. In this article we note our interest in the ability of MRTA to detect large changes in bone stiffness that go undetected by DXA. We also highlight results of our proprietary improvements to MRTA technology that have resulted in unmatched accuracy in QMT-validated measurements of the bending stiffness and estimates of the bending strength (both R2 = 0.99) of human ulna bones. To distinguish our improved technique from the legacy MRTA technology, we refer to it as Cortical Bone Mechanics Technology (CBMT). Further research will determine whether such CBMT measurements are clinically useful. PMID- 28660375 TI - The Combined Effect of Blackcurrant Powder and Wholemeal Flours to Improve Health Promoting Properties of Cookies. AB - A diet with high glycaemic index, which causes rapid spikes in blood sugar level, can lead to disorders such as significantly increased risk for type 2 diabetes, cardiovascular disease and obesity. These conditions are also linked to the progression of cognitive decline and neurodegenerative diseases including Alzheimer's disease. Blackcurrant powder (BC) is a rich source of dietary fibre and bioactive compounds. Wholemeal wheat, barley and oat flours contain high amount of fibre. In this study, a model food (cookie) was developed and used to investigate the in vitro glycaemic glucose equivalent and antioxidant activities of the cookies made with three different wholemeal flours (wheat, barley and oat) with different replacement levels (5, 10 and 15%) of blackcurrant powder. Increasing the proportion of blackcurrant powder in the cookie resulted in a significant (P < 0.05) decrease in glucose release after in vitro digestion compared to the control. In addition, incorporation of blackcurrant powder in cookies up to 15% increased the antioxidant capacity. The combination of wholemeal flour and the bioactive compound rich blackcurrant has the potential to improve the nutritional value and reduce the glycaemic index of such foods. PMID- 28660376 TI - Bone metabolism markers and angiogenic cytokines as regulators of human hematopoietic stem cell mobilization. AB - Hematopoietic stem cell (HSC) mobilization involves cleavage of ligands between HSC and niche components. However, there are scarce data regarding the role of bone cells in human HSC mobilization. We studied biochemical markers of bone metabolism and angiogenic cytokines during HSC mobilization in 46 patients' sera with lymphoma and multiple myeloma, by ELISA. Significant changes between pre mobilization and collection samples were found: (1) Bone alkaline phosphatase (BALP) increased, indicating augmentation of bone formation; (2) Receptor activator of Nf-kappaB ligand/osteoprotegerin ratio (RANKL/OPG) increased, showing osteoclastic differentiation and survival; however, there was no evidence of increased osteoclastic activity; and (3) Angiopoietin-1/Angiopoietin-2 ratio (ANGP-1/ANGP-2) decreased, consistent with vessel destabilization. Poor mobilizers had significantly higher carboxy-terminal telopeptide of collagen type I (CTX) and lower ANGP-1 at pre-mobilization samples, compared to good ones. CTX, amino-terminal telopeptide of collagen type I (NTX) and ANGP-1 pre-mobilization levels correlated significantly with circulating CD34+ peak cell counts. Our results indicate that bone formation and vessel destabilization are the two major events during human HSC mobilization. Osteoblasts seem to be the orchestrating cells, while osteoclasts are stimulated but not fully active. Moreover, ANGP-1, CTX and NTX may serve as predictors of poor mobilization. PMID- 28660378 TI - Mineral metabolism abnormalities in patients with prostate cancer: a systematic case controlled study. AB - PURPOSE: Prostate cancer is the most common tumor in men. To the best of our knowledge a systematic assessment of bone and mineral abnormalities has not been performed in prostatic cancer patients consecutively enrolled. METHODS: This study was therefore carried out to investigate changes of skeletal and mineral metabolism in patients with prostate cancer (n = 69). A population of patients with cancer of various origin was also investigated as a control group (n = 53), since a comparison with non-prostate cancer patients has not been previously reported. RESULTS: In the prostatic cancer group, one patient had extremely high values of C-terminal Fibroblast Growth Factor 23, low values of tubular reabsorption of phosphate and very high values of bone alkaline phosphatase, suggesting the diagnosis of oncogenic osteomalacia. We found nine patients with primary hyperparathyroidism in the group of prostate cancer vs. only one in cancer patients group (p < 0.026). We stratified the population on the basis of Gleason score, prostate specific antigen and hormonal therapy. Using a generalized linear model with a logit link to predict the probability of developing primary hyperparathyroidism, only Gleason score, C-terminal fibroblast growth factor 23 and hormonal therapy had a significant effect (p < 0.05). Controlling for other covariates, a rise in fibroblast growth factor 23 increases the odds of developing primary hyperparathyroidism by 2% (p = 0.017), while patients with higher values of Gleason score have a much greater probability of developing primary hyperparathyroidism (log-odds = 3.6, p < 0.01). The probability decreases with higher values of Gleason score while on hormonal therapy; a further decrease was observed in patients on hormonal treatment and lower values of GS. Finally, lower grade of Gleason score without hormonal therapy have a significant protective factor (p < 0.01) decreasing the odds of developing primary hyperparathyroidism by 8%. CONCLUSION: We showed a remarkable prevalence of primary hyperparathyroidism in men with prostate cancer; the multivariate analysis demonstrates that higher aggressiveness of prostate cancer, as determined by Gleason score, is a significant predictor of increased risk of developing primary hyperparathyroidism. PMID- 28660379 TI - HIV Incidence and Care Linkage among MSM First-Time-Testers in Shenyang, China 2012-2014. AB - HIV testing is the first step to the fulfillment of Treat as Prevention (TasP) and reaching the 90-90-90 goal in HIV control. However, there are still a large number of Men who have Sex with Men (MSM) have never been tested for HIV before, and little is known about the HIV incidence and care linkage among this population. A Mixed method was used to recruit MSM who had never tested for HIV before from January 2012 to December 2014 in Shenyang, China. Potential MSM participants were invited to attend the enrollment for HIV and syphilis testing at a general hospital-based voluntary counseling and test (VCT). HIV confirmed positive subjects were further tested by BED HIV-1 capture enzyme immunoassay (BED-CEIA) to determine the HIV incidence. Syphilis was screened by the rapid plasma reagent test (RPR) and confirmed by Treponema pallidum particle assay (TPPA). All the HIV positive subjects were referred to the local Center for Disease Control and Prevention (CDC) and clinics for HIV primary care and follow ups. In total 646 HIV first-time-testers of MSM (FMSM) attended this study, 73.4% (474/646) were aged under 31-year-old and 57.3% (370/646) and used the Internet as their major cruising avenue for seeking male sexual partners. The average prevalence of HIV and current syphilis infection was 10.8% (70/646) and 11.0% (71/646), respectively. The HIV incidence was 10.3 (95% confidence interval [CI] 6.1-14.5)/100PY. Multivariate logistic analysis showed that factors such as use of the Internet as the major cruising avenue (adjusted OR [AOR] 2.7, 95% CI 0.9 7.6) and having a current syphilis infection (AOR 4.2, 95% CI 1.8-12.2) were independent correlates of a recent HIV infection. Of the 95 HIV screening test positive FMSM, 73.7% (70/95) returned and be confirmed positive, 92.9% (65/70) of confirmed patients were linked to care. Among those retained and underwent CD4+ T cell test, 76.3% (42/55) started HIV antiretroviral therapy. Among the unconfirmed, 84.0% (21/25) were non-local migrants. The HIV incidence of FMSM in Shenyang was high. Future HIV testing program needs to keep on expanding among the MSM who have never been tested for HIV yet. The Internet-based campaigns and syphilis testing and treatment could represent an opportunity to get access to this hard-to-reach population and link them to HIV care. Future linkage to HIV care of this population should underscore the usage of HIV rapid diagnostic tests to prevent lost at early steps of linkage. PMID- 28660377 TI - Local administration of WP9QY (W9) peptide promotes bone formation in a rat femur delayed-union model. AB - The WP9QY peptide (W9) consists of nine amino acids. It binds to RANKL and blocks RANKL-induced increases in bone resorption and osteoclastogenesis. W9 has a unique effect on the coupling mechanism between osteoclasts and osteoblasts, which promotes bone formation while working to suppress bone resorption. In this study, with the aim of clinical application of W9 for fracture treatment, we aimed to clarify the bone repair-promoting effect of W9 when administered locally to a rat femur model of delayed union. Using Sprague-Dawley rats, a model of delayed union was created in the right femur by cauterizing the periosteum. Injection of W9 (1 mg in 100 MUl) or phosphate-buffered saline (PBS) (100 MUl) at the fracture site was performed at the operation and every week thereafter until death (sacrifice). The bone union rate was 14% in the PBS group and 57% in the W9 group at 8 weeks postoperatively. The X-ray score of the W9 group was significantly higher than that of the PBS group at 8 weeks postoperatively. When bone morphometry was analyzed by micro-computed tomography (CT), total callus volume (TV) and mineralized callus bone volume (BV) were measured. TV showed no significant difference between the two groups, but BV/TV was significantly higher in the W9 group. This finding suggests that local administration of W9 can promote bone maturation from callus and can be considered to contribute to fracture healing. These results reveal that W9 has an effect on fractures of promoting healing and could be applied as a fracture treatment. PMID- 28660380 TI - Informing Targeted Interventions to Optimize the Cascade of HIV Care Using Cluster Analyses of Health Resource Use Among People Living with HIV/AIDS. AB - Increased awareness of the secondary preventive benefits of antiretroviral treatment (ART) has strengthened the desire to optimize health care systems' response to HIV/AIDS. We identified clusters of health resource utilization (HRU) among people living with HIV (PLHIV) to inform targeted interventions aimed to optimize the cascade of HIV care. Using linked population-level health databases in British Columbia, Canada, we selected two analytic samples of PLHIV with 3 years of follow-up between 2006-2011 that were classified as intermittently retained in care or intermittently engaged in ART, and executed a probabilistic model-based clustering analysis for each sample with 5 and 9 quarterly HRU variables, respectively. We found clear HRU profile differences among both samples with similar HIV-related care: one featured active involvement in non-HIV care, the other little or no health care interaction following linkage to care. Differential reengagement intervention strategies capitalizing on missed opportunities in non-HIV care and further engaging physicians delivering HIV care are needed to optimize the response to the HIV epidemic. PMID- 28660381 TI - Overlooked Threats to Respondent Driven Sampling Estimators: Peer Recruitment Reality, Degree Measures, and Random Selection Assumption. AB - Intensive sociometric network data were collected from a typical respondent driven sample (RDS) of 528 people who inject drugs residing in Hartford, Connecticut in 2012-2013. This rich dataset enabled us to analyze a large number of unobserved network nodes and ties for the purpose of assessing common assumptions underlying RDS estimators. Results show that several assumptions central to RDS estimators, such as random selection, enrollment probability proportional to degree, and recruitment occurring over recruiter's network ties, were violated. These problems stem from an overly simplistic conceptualization of peer recruitment processes and dynamics. We found nearly half of participants were recruited via coupon redistribution on the street. Non-uniform patterns occurred in multiple recruitment stages related to both recruiter behavior (choosing and reaching alters, passing coupons, etc.) and recruit behavior (accepting/rejecting coupons, failing to enter study, passing coupons to others). Some factors associated with these patterns were also associated with HIV risk. PMID- 28660382 TI - Epidemiology behavior of leptospirosis in Cienaga de Oro, Cordoba (Colombia). AB - The purpose of this study was to determine the epidemiology of leptospirosis in rural areas of Cienaga de Oro, Cordoba, Colombia, a convenience sampling was carried out on 13 farms. The sample size was 325 reproductive age cows, 11 canine samples, and 20 humans. The samples were subjected to MAT analysis with 11 serogroups of Leptospira interrogans sensu lato. Once the MAT results were received, urine samples were collected from 78 cows, along with 39 water samples, for bacteriological cultures and PCR for the 16S rRNA gene in L. interrogans sensu lato. Positive PCR samples were sequenced to determine the possible genome species. The leptospirosis seroprevalence was 74.5% in the cattle, 70.0% in the dogs, and 45.5% in the humans. Although isolation was not achieved, L. interrogans sensu lato was detected by PCR in three urine samples and in a sample of wastewater. The sequencing confirmed the circulation of pathogenic species. The high prevalence of antibodies for L. interrogans sensu lato and the molecular evidence led to the inference that the rural areas of Cienaga de Oro are endemic and that cattle can act as renal carriers and contaminate water sources, which increases the risk of contracting leptospirosis. PMID- 28660383 TI - Risk estimation and annual fluxes of emerging contaminants from a Scottish priority catchment to the estuary and North Sea. AB - Emerging contaminants (ECs) such as endocrine-disrupting chemicals (EDCs) and pharmaceuticals and personal care products (PPCPs) attracted global concern during the last decades due to their potential adverse effects on humans and ecosystems. This work is the first study to assess the spatiotemporal changes, annual fluxes and ecological risk of ECs (4 EDCs and 6 PPCPs) by different monitoring strategies (spot and passive sampling) over 12 months in a Scottish priority catchment (River Ugie, Scotland, 335 km2). Overall, the total concentration in water ranged from 1. This suggests that mitigation measures might need to be taken to reduce the input of emerging contaminants into the river and its adjacent estuary and sea. PMID- 28660386 TI - Environmental Decision Making on Acid Mine Drainage Issues in South Africa: An Argument for the Precautionary Principle. AB - This paper examines the issue of acid mine drainage in South Africa and environmental decision making processes that could be taken to mitigate the problem in the context of both conventional risk assessment and the precautionary principle. It is argued that conventional risk assessment protects the status quo and hence cannot be entirely relied upon as an effective tool to resolve environmental problems in the context of South Africa, a developing country with complex environmental health concerns. The complexity of the environmental issues is discussed from historical and political perspectives. An argument is subsequently made that the precautionary principle is an alternative tool, and its adoption can be used to empower local communities. This work, therefore, adds to new knowledge by problematising conventional risk assessment and proposing the framing of the acid mine drainage issues in a complex and contextual scenario of a developing country-South Africa. PMID- 28660385 TI - Genetic improvement of Magnetospirillum gryphiswaldense for enhanced biological removal of phosphate. AB - OBJECTIVES: To improve its phosphate accumulating abilities for phosphate recycling from wastewater, a magnetotactic bacterium, Magnetospirillum gryphiswaldense, was genetically modified to over-express polyphosphate kinase. RESULTS: Polyphosphate kinase was over-expressed in the bacterium. The recombinant strain accumulated ninefold more polyphosphate from synthetic wastewater compared to original wild type. The magnetic property of the recombinant M. gryphiswaldense strain was retained. CONCLUSIONS: The recombinant M. gryphiswaldense can be used for phosphate removal and recovery in bioremediation. PMID- 28660384 TI - Increased hepatic ABCA1 transporter is associated with hypercholesterolemia in a cholestatic rat model and primary biliary cholangitis patients. AB - Hepatic ATP-binding cassette A1 (ABCA1) transporter is the modulator of intrahepatic cholesterol levels via the efflux of cholesterol into plasma. This study aimed to determine the expression of hepatic ABCA1 levels in a cholestatic rat model and patients with primary biliary cholangitis (PBC). A cholesterol efflux study was conducted with Abca1 knock down using siRNA in WIF9 cells. Cholesterol levels in the ABCA1 siRNA cells in the medium were significantly decreased compared with those in controls (P < 0.05). Hepatic ABCA1 mRNA levels were significantly higher in BDL rats than in control rats (P < 0.05). Furthermore, the protein expression level of hepatic ABCA1 was also significantly increased by 200% in BDL rats (P < 0.05). In PBC patients, expression of hepatic ABCA1 mRNA was 2.2-fold higher than that in controls (P < 0.05). The level of hepatic liver X receptor (LXR)beta mRNA was correlated with ABCA1 mRNA levels in PBC patients. The expression of hepatic ABCA1 transporter was upregulated in both the cholestatic rat model and PBC patients. Upregulated hepatic ABCA1 may lead to efflux of cholesterol into plasma, thus explaining the mechanism of cholestasis leading to hypercholesterolemia. PMID- 28660387 TI - 3D Bioprinting Technology: Scientific Aspects and Ethical Issues. AB - The scientific development of 3D bioprinting is rapidly advancing. This innovative technology involves many ethical and regulatory issues, including theoretical, source, transplantation and enhancement, animal welfare, economic, safety and information arguments. 3D bioprinting technology requires an adequate bioethical debate in order to develop regulations in the interest both of public health and the development of research. This paper aims to initiate and promote ethical debate. The authors examine scientific aspects of 3D bioprinting technology and explore related ethical issues, with special regard to the protection of individual rights and transparency of research. In common with all new biotechnologies, 3D bioprinting technology involves both opportunities and risks. Consequently, several scientific and ethical issues need to be addressed. A bioethical debate should be carefully increased through a multidisciplinary approach among experts and also among the public. PMID- 28660388 TI - Is cardiac magnetic resonance necessary for prediction of left ventricular remodeling in patients with reperfused ST-segment elevation myocardial infarction? AB - As cardiac magnetic resonance imaging (CMR) has become widely used for evaluation of myocardial viability after acute myocardial infarction, the additional value of CMR parameters for prediction of left ventricle (LV) remodeling has been receiving interest. The aim of the study was to investigate the additional predictive value of CMR parameters for LV remodeling after successful reperfusion of ST-segment elevation myocardial infarction (STEMI) using multiple predictive models. LV remodeling was defined as >=20% increase in end-diastolic volume at 6 month follow-up echocardiography. Using multiple stepwise regression analysis, conventional risk model was classified as following; model 1 (clinical factors), model 2 (model 1 + angiographic factors), model 3 (model 2 + echocardiographic factors) and CMR-added model; model 4 (model 3 + CMR factors). Among 262 enrolled patients, 25.1% showed LV remodeling. There were significant increments of c statistics from the predictive model 1 to model 3 (AUC; 0.675 [0.60-0.75], 0.708 [0.64-0.78], 0.756 [0.69-0.82], respectively. all p < 0.05). However, model 4, which added the CMR variables, did not show any increase in predictive value compared with model 3 (AUC; 0.763 [0.70-0.83] versus 0.756 [0.69-0.82], p = 0.11). During the 28.2 months of median follow up, the incidence of hospitalization for heart failure was significantly higher in the patients with LV remodeling (6.1% vs. 0.5%, p = 0.02). CMR parameters did not provide incremental predictive value above the assessment by conventional echocardiography-based risk model in patients with STEMI. PMID- 28660389 TI - Clinical and Molecular Characterization of Prader-Willi Syndrome. AB - OBJECTIVES: To describe the clinical presentations and molecular diagnosis to aid the clinicians in early diagnosis and appropriate management of Prader-Willi syndrome (PWS). METHODS: Thirty-four clinically diagnosed PWS cases were enrolled after obtaining informed consent/assent. Demographic details, clinical data and anthropometry were recorded using structured proforma. The facial dysmorphology was evaluated. Appropriate genetic testing was performed to confirm the diagnosis. RESULTS: At diagnosis, the most common clinical features included obesity (59%) and short stature (53%). Distinct dysmorphic features were observed in 67%. Neonatal hypotonia with feeding difficulty, delayed development in infancy and childhood behavioral problems were reported in 94%, 94% and 74% respectively. Food seeking behavior and hyperphagia was reported in 67%. Seizures were reported in 47%. All children had underdeveloped external genitalia. Growth hormone (GH) deficiency and impaired glucose tolerance were found in 56% and 50% respectively. Sleep related problems were seen in 67%. Skin and rectal picking were reported in 67%. FISH confirmed micro-deletion was found in 64.7% and abnormal methylation in 35%, of which uniparental disomy was confirmed in 14.7%. CONCLUSIONS: Clinical suspicion is vital for early detection of PWS. Confirmation of the diagnosis requires complex multi-tier molecular genetic testing. PMID- 28660390 TI - Paecilomyces as a Cause of Lymph Nodes Enlargement in Hodgkin's Lymphoma. PMID- 28660392 TI - Exploring Health Service Underutilization: A Process Evaluation of the Newcomer Women's Health Clinic. AB - The BC Women's Hospital and Health Centre's Newcomer Women's Health Clinic (NWHC) opened in 2014 to fill a gap in services for newcomer women to Canada residing in Metro Vancouver. After 1 year the NWHC was operating at only 50% capacity. An evaluation was conducted to better understand the underutilization of clinic services. Evaluation data was collected via patient intake forms, patient feedback surveys, and one-to-one interviews with both newcomer women and service providers who work with newcomer women. Results highlight the heterogeneity in newcomer women's experiences including different perceptions of health, health needs, and health-seeking behaviours. Despite the population's diversity, some common experiences exist, including difficulties navigating and accessing a new health system and lack of awareness of the NWHC. Findings provide insight for improving the delivery of NWHC services, and contribute to a rich and ongoing dialogue concerning the diversity of experiences of newcomer women in Canada. PMID- 28660391 TI - Retention of Ethnic Participants in Longitudinal Studies. AB - We aimed to identify effective participant retention strategies utilized in longitudinal studies of ethnic groups, specifically those from South Asian and Chinese communities. We conducted a systematic review of the literature focusing on the retention of ethnic minorities in longitudinal studies, up until April 2017. Only peer-reviewed research was included. 11,316 citations were retrieved, of which 4808 were duplicates and 51 met the inclusion criteria. Financial incentives, involving key community members, flexible scheduling, developing trust and personal connections with participants, and having extensive participant contact information are key facilitators. We also describe our extensive experience of retaining South Asian and Chinese participants in longitudinal studies. Key retention strategies for these groups include involving family members, informing participants about potential personal and community benefits, being flexible in how and when the interviews are conducted, and providing multiple language options. There is little published evidence or direction regarding how to retain study participants from South Asian or Chinese communities. However, there can be some learning from studies focused on other ethnic groups. Establishing an evidence-based approach, including facilitators and barriers to retention of these groups in longitudinal studies would help to determine study feasibility, validity, and ultimately to reduce health disparities among South Asian or Chinese communities. PMID- 28660393 TI - Re-evaluating concepts of biological function in clinical medicine: towards a new naturalistic theory of disease. AB - Naturalistic theories of disease appeal to concepts of biological function, and use the notion of dysfunction as the basis of their definitions. Debates in the philosophy of biology demonstrate how attributing functions in organisms and establishing the function-dysfunction distinction is by no means straightforward. This problematization of functional ascription has undermined naturalistic theories and led some authors to abandon the concept of dysfunction, favoring instead definitions based in normative criteria or phenomenological approaches. Although this work has enhanced our understanding of disease and illness, we need not necessarily abandon naturalistic concepts of function and dysfunction in the disease debate. This article attempts to move towards a new naturalistic theory of disease that overcomes the limitations of previous definitions and offers advantages in the clinical setting. Our approach involves a re-evaluation of concepts of biological function employed by naturalistic theories. Drawing on recent insights from the philosophy of biology, we develop a contextual and evaluative account of function that is better suited to clinical medicine and remains consistent with contemporary naturalism. We also show how an updated naturalistic view shares important affinities with normativist and phenomenological positions, suggesting a possibility for consilience in the disease debate. PMID- 28660394 TI - Optic chiasm distortions in craniopharyngiomas: a sign of hypothalamic involvement. PMID- 28660395 TI - Comparison of anti-siphon devices-how do they affect CSF dynamics in supine and upright posture? AB - BACKGROUND: Three different types of anti-siphon devices (ASDs) have been developed to counteract siphoning-induced overdrainage in upright posture. However, it is not known how the different ASDs affect CSF dynamics under the complex pressure environment seen in clinic due to postural changes. We investigated which ASDs can avoid overdrainage in upright posture best without leading to CSF accumulation. METHODS: Three shunts each of the types Codman Hakim with SiphonGuard (flow-regulated), Miethke miniNAV with proSA (gravitational), and Medtronic Delta (membrane controlled) were tested. The shunts were compared on a novel in vitro setup that actively emulates the physiology of a shunted patient. This testing method allows determining the CSF drainage rates, resulting CSF volume, and intracranial pressure in the supine, sitting, and standing posture. RESULTS: The flow-regulated ASDs avoided increased drainage by closing their primary flow path when drainage exceeded 1.39 +/- 0.42 mL/min. However, with intraperitoneal pressure increased in standing posture, we observed reopening of the ASD in 3 out of 18 experiment repetitions. The adjustable gravitational ASDs allow independent opening pressures in horizontal and vertical orientation, but they did not provide constant drainage in upright posture (0.37 +/- 0.03 mL/min and 0.26 +/- 0.03 mL/min in sitting and standing posture, respectively). Consequently, adaptation to the individual patient is critical. The membrane-controlled ASDs stopped drainage in upright posture. This eliminates the risk of overdrainage, but leads to CSF accumulation up to the volume observed without shunting when the patient is upright. CONCLUSIONS: While all tested ASDs reduced overdrainage, their actual performance will depend on a patient's specific needs because of the large variation in the way the ASDs influence CSF dynamics: while the flow-regulated shunts provide continuous drainage in upright posture, the gravitational ASDs allow and require additional adaptation, and the membrane-controlled ASDs show robust siphon prevention by a total stop of drainage. PMID- 28660396 TI - Resolution of traumatic vertebral artery dissection and occlusion after repositioning and posterior C1-ring osteosynthesis of a displaced Jefferson burst fracture. AB - A 70-year-old male sustained a Jefferson burst fracture with unilateral vertebral artery dissection and occlusion by displaced fragments. We performed reduction and posterior C1-ring osteosynthesis. We present a description of the intraoperative manual assessment of atlantoaxial stability. The vertebral artery was found with a good anterograde flow posteroperatively, and MRA showed reperfusion of the vessel. The patient was free of pain with preserved C1-C2 rotation after 6 weeks. Function-preserving posterior C1-ring osteosynthesis after reduction in a displaced Jefferson burst fracture complicated by vertebral artery dissection and occlusion may restore blood flow. PMID- 28660397 TI - No evidence for binding of items to task-irrelevant backgrounds in visual working memory. AB - When representing visual features such as color and shape in visual working memory (VWM), participants also represent the locations of those features as a spatial configuration of the locations of those features in the display. In everyday life, we encounter objects against some background, yet it is unclear whether the configural representation in memory obligatorily constitutes the entire display, including that (often task-irrelevant) background information. In three experiments, participants completed a change detection task on color and shape; the memoranda were presented in front of uniform gray backgrounds, a textured background (Exp. 1), or a background containing location placeholders (Exps. 2 and 3). When whole-display probes were presented, changes to the objects' locations or feature bindings impacted memory performance-implying that the spatial configuration of the probes influenced participants' change decisions. Furthermore, when only a single item was probed, the effect of changing its location or feature bindings was either diminished or completely extinguished, implying that single probes do not necessarily elicit the entire spatial configuration. Critically, when task-irrelevant backgrounds were also presented that may have provided a spatial configuration for the single probes, the effect of location or bindings was not moderated. These findings suggest that although the spatial configuration of a display guides VWM-based recognition, this information does not necessarily always influence the decision process during change detection. PMID- 28660398 TI - What is in a name? Does cancer subtyping help or hinder in epidemiology research? PMID- 28660399 TI - Microdialysis Coupled with LC-MS/MS for In Vivo Neurochemical Monitoring. AB - Microdialysis is a powerful sampling technique used to monitor small molecules in vivo. Despite the many applications of microdialysis sampling, it is limited by the method of analyzing the resulting samples. An emerging technique for analysis of microdialysis samples is liquid chromatography-tandem mass spectrometry (LC MS/MS). This technique is highly versatile, allowing multiplexed analysis of neurotransmitters, metabolites, and neuropeptides. Using LC-MS/MS for polar neurotransmitters is hampered by weak retention reverse phase LC columns. Several derivatization reagents have been utilized to enhance separation and resolution of neurochemicals in dialysate samples including benzoyl chloride (BzCl), dansyl chloride, formaldehyde, ethylchloroformate, and propionic anhydride. BzCl reacts with amine and phenol groups so that many neurotransmitters can be labeled. Besides improving separation on reverse phase columns, this reagent also increases sensitivity. It is available in a heavy form so that it can be used to make stable-isotope labeled internal standard for improved quantification. Using BzCl with LC-MS/MS has allowed for measuring as many as 70 neurochemicals in a single assay. With slightly different conditions, LC-MS/MS has also been used for monitoring endocannabinoids. LC-MS/MS is also useful for neuropeptide assay because it allows for highly sensitive, sequence specific measurement of most peptides. These advances have allowed for multiplexed neurotransmitter measurements in behavioral, circuit analysis, and drug effect studies. PMID- 28660400 TI - Development of a Two-Dimensional Model for Predicting Transdermal Permeation with the Follicular Pathway: Demonstration with a Caffeine Study. AB - PURPOSE: The development of a new two-dimensional (2D) model to predict follicular permeation, with integration into a recently reported multi-scale model of transdermal permeation is presented. METHODS: The follicular pathway is modelled by diffusion in sebum. The mass transfer and partition properties of solutes in lipid, corneocytes, viable dermis, dermis and systemic circulation are calculated as reported previously [Pharm Res 33 (2016) 1602]. The mass transfer and partition properties in sebum are collected from existing literature. None of the model input parameters was fit to the clinical data with which the model prediction is compared. RESULTS: The integrated model has been applied to predict the published clinical data of transdermal permeation of caffeine. The relative importance of the follicular pathway is analysed. Good agreement of the model prediction with the clinical data has been obtained. The simulation confirms that for caffeine the follicular route is important; the maximum bioavailable concentration of caffeine in systemic circulation with open hair follicles is predicted to be 20% higher than that when hair follicles are blocked. CONCLUSIONS: The follicular pathway contributes to not only short time fast penetration, but also the overall systemic bioavailability. With such in silico model, useful information can be obtained for caffeine disposition and localised delivery in lipid, corneocytes, viable dermis, dermis and the hair follicle. Such detailed information is difficult to obtain experimentally. PMID- 28660401 TI - Individual Bayesian Information Matrix for Predicting Estimation Error and Shrinkage of Individual Parameters Accounting for Data Below the Limit of Quantification. AB - PURPOSE: In mixed models, the relative standard errors (RSE) and shrinkage of individual parameters can be predicted from the individual Bayesian information matrix (MBF). We proposed an approach accounting for data below the limit of quantification (LOQ) in MBF. METHODS: MBF is the sum of the expectation of the individual Fisher information (MIF) which can be evaluated by First-Order linearization and the inverse of random effect variance. We expressed the individual information as a weighted sum of predicted MIF for every possible design composing of measurements above and/or below LOQ. When evaluating MIF, we derived the likelihood expressed as the product of the likelihood of observed data and the probability for data to be below LOQ. The relevance of RSE and shrinkage predicted by MBF in absence or presence of data below LOQ were evaluated by simulations, using a pharmacokinetic/viral kinetic model defined by differential equations. RESULTS: Simulations showed good agreement between predicted and observed RSE and shrinkage in absence or presence of data below LOQ. We found that RSE and shrinkage increased with sparser designs and with data below LOQ. CONCLUSIONS: The proposed method based on MBF adequately predicted individual RSE and shrinkage, allowing for evaluation of a large number of scenarios without extensive simulations. PMID- 28660402 TI - Bisphosphonate-induced zebra lines in fibrous dysplasia of bone: histo radiographic correlation in a case of McCune-Albright syndrome. AB - Bisphosphonates (BPs) are currently used in the treatment of diverse bone diseases including fibrous dysplasia of bone (FD). In pediatric patients, a radiographic consequence of cyclical administration of BPs is the development of apo-, epi-, and meta-physeal sclerotic bands, otherwise known as zebra lines, which result from the temporary inhibition of osteoclastic activity at the time of drug treatment. We report here on a child with McCune-Albright syndrome (FD in addition to hyperfunctioning endocrinopathies and skin hyperpigmentation) treated with cyclical intravenous infusions of pamidronate in which conventional radiography, contact microradiography, histology, and backscattered electron image analysis demonstrated that zebra lines formed only where bone was normal, were arrested at the boundary between FD-unaffected and FD-affected bone where bone is sclerotic, and were absent within the undermineralized FD bone. Moreover, in spite of the treatment, the FD lesions continued to expand. This case report is unique because no previously published studies correlated the radiographic and the histologic features of BP-induced zebra lines in the metaphysis of an FD affected long bone of the limbs. PMID- 28660403 TI - MR imaging features of hemispherical spondylosclerosis. AB - OBJECTIVE: Hemispherical spondylosclerosis (HS) is a rare degenerative entity characterized by dome-shaped sclerosis of a single vertebral body that may pose a diagnostic dilemma. The goal of this study was to describe the MR imaging features of HS. MATERIALS AND METHODS: We identified spine radiographs and CT examinations of subjects with HS who also had MR imaging for correlation. Two musculoskeletal radiologists independently assessed sclerosis characteristics, presence of endplate erosions, marrow signal intensity, and disk degeneration (Pfirrmann scale). RESULTS: We identified 11 subjects (six males, five females, mean 48 +/- 10 years) with radiographic/CT findings of HS. The most commonly affected vertebral body was L4 (6/11; 55%). On MR imaging, variable signal intensity was noted, being most commonly low on T1 (8/11, 73%) and high on fat suppressed T2-weighted (8/11, 73%) images. In two subjects, diffuse post-contrast enhancement was seen in the lesion. Moderate disk degeneration and endplate bone erosions adjacent to sclerosis were present in all subjects. Erosions of the opposite endplate were present in two subjects (2/11, 18%). CT data from nine subjects showed the mean attenuation value of HS was 472 +/- 96 HU. CONCLUSIONS: HS appearance on MR imaging is variable and may not correlate with the degree of sclerosis seen on radiographs or CT. Disk degenerative changes and asymmetric endplate erosions are consistent markers of HS. PMID- 28660404 TI - Isolated peroneal tenosynovial lipoma arborescens: multimodality imaging features. AB - Synovial lipoma arborescens is a rare and benign fatty proliferative lesion of the synovium that is most commonly seen within the suprapatellar pouch of the knee, but increasingly reported to involve tendon sheaths, including those of the ankle. We present the third known case of tenosynovial lipoma arborescens isolated to the peroneal tendon sheath without ankle joint involvement. To our knowledge, this is the first to report this entity utilizing a unique combination of radiographic, sonographic, and MR imaging, along with intraoperative and histologic correlation. Knowledge of this case is important when interpreting radiographic or sonographic images of this condition to raise the possibility of the rare entity of lipoma arborescens involving the peroneal tendon sheath. PMID- 28660405 TI - Xanthogranulomatous osteomyelitis of the humerus in a pediatric patient with Alagille syndrome: a case report and literature review. AB - Xanthogranulomatous osteomyelitis (XO) is an exceedingly rare disease characterized by infiltration of histiocytes and foamy macrophages. Both on gross examination and on radiographs, XO can mimic malignancy. We describe the case of a 5-year-old female with Alagille syndrome who presented with a pathologic fracture of the right humerus. Initial radiographs revealed multiple osteolytic lesions in the distal humerus while MRI showed a large soft tissue mass. Biopsy confirmed the diagnosis of XO, which has hitherto not been described in a patient with Alagille syndrome. The patient was admitted for IV antibiotics and taken to the operating room for an incision and debridement. Tissue cultures were obtained and grew Salmonella. Antibiotic therapy was tapered, and the patient responded to treatment. She was doing well at her 6-month follow-up visit. In the discussion section, we explore how osteopenia and immune dysregulation caused by Alagille syndrome can affect the development of XO. We summarize all previously reported cases of XO and conclude that XO presents as an osteolytic lesion that expands rapidly over the course of a few weeks. We highlight that XO can mimic sarcoma because of its mass effect but can be distinguished radiographically by the presence of surrounding sclerosis. Given the rapid onset of XO, we classify it as an acute osteomyelitis. We discuss how leukemia and Ewing sarcoma can present similarly to acute osteomyelitis. We then emphasize key features that can be used to distinguish these malignancies from acute osteomyelitis. PMID- 28660406 TI - Evaluation of Potentially Prolactin-Related Adverse Events and Sexual Maturation in Adolescents with Schizophrenia Treated with Paliperidone Extended-Release (ER) for 2 Years: A Post Hoc Analysis of an Open-Label Multicenter Study. AB - BACKGROUND: Elevated prolactin levels (hyperprolactinemia) are a frequent adverse effect of antipsychotic medications, especially in young populations. Prolonged hyperprolactinemia may affect sexual functioning and the onset and progression of puberty. OBJECTIVE: This study assessed potentially prolactin-related treatment emergent adverse events (PPRL-TEAEs) and sexual maturation during long-term treatment of adolescents with paliperidone extended-release (ER). METHODS: This post hoc analysis of a 2-year open-label multicenter study (NCT00488319) included patients of either sex aged 12-17 years at study enrollment, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]) for >=1 year, who had received one or more adequate antipsychotic treatment prior to enrollment but had not responded sufficiently. Patients were initially treated with 6 mg/day paliperidone ER and further titrated between 1.5 and 12 mg/day based on clinical response and tolerability. The primary objective was to determine the relationship between characteristics (including sex, age at study entry, ethnicity, geographic region, age at diagnosis, duration of illness, number of prior hospitalizations, serum prolactin, and baseline Tanner stages) and onset or risk of PPRL-TEAEs. The secondary objective was to assess sexual maturation during long-term treatment with paliperidone ER. RESULTS: In total, 400 patients were enrolled in the study and 184 patients completed the 2-year study; the majority were boys (61%), White (66%), and aged >14 years at study enrolment (73%) with mean (standard deviation [SD]) body mass index (BMI) of 21.96 (4.375) kg/m2 at baseline. Girls (18.5%) had a higher incidence of PPRL TEAEs than did boys (3.3%). Most of these events were mild to moderate in severity, and none were serious; four patients discontinued the study due to PPRL TEAEs. Mean prolactin levels in the total population of boys and girls increased early during treatment then stabilized with time. Mean +/- SD maximum changes in prolactin levels from baseline were higher in girls and boys with PPRL-TEAEs than in those without (Girls: 74.7 +/- 32.3 ng/ml [n = 28] vs. 50.5 +/- 44.9 ng/ml [n = 114]; p = 0.008. Boys: 33.6 +/- 23.7 ng/ml [n = 8] vs. 31.0 +/- 24.5 ng/ml [n = 205]; p = 0.77). No clinically significant mean changes from baseline in growth adjusted z-score for weight, height, or BMI were observed. Overall, ~90% of the patients who completed the 2-year study achieved Tanner stages 4-5 by study endpoint. Female sex, age at diagnosis (13-14 years), girls of Hispanic ethnicity, and region (EU and North America) were associated with a greater risk for PPRL-TEAEs; higher baseline Tanner stages for pubic hair (boys and girls) and breast development (stage 3 vs. 4 or 5) also seemed to be associated with a higher incidence of PPRL-TEAEs. CONCLUSIONS: Female sex appeared to be associated with an increased risk for PPRL-TEAEs. Other potential predictors, such as ethnicity, region, age at diagnosis, and Tanner stage 4 or 5, all seemed to be related to sex. Evidence from this study was insufficient to definitively conclude that prolactin values at baseline and change during treatment were predictive of PPRL-TEAEs, although there is a signal that this may be the case in girls. These results are exploratory in nature, and confirmatory studies are needed to confirm these observations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00488319. PMID- 28660407 TI - Examining the Relationship Between Parent and Child Psychopathology in Treatment Seeking Veterans. AB - This study aimed to examine: (1) the relationship between parental psychopathology and child psychopathology in military families and (2) parenting sense of competence as a mediator of the relationship between veteran psychopathology and child psychopathology. As part of their standard clinical evaluations, 215 treatment-seeking veterans who reported having a child between the ages of 4 and 17 were assessed for psychopathology (posttraumatic stress disorder, depression, anxiety, and stress), their sense of competence as a parent, and their child's psychopathology (internalizing, externalizing, and attentional symptoms). A path analysis model examining parenting sense of competence as a mediator of the relationship between veteran psychopathology and child psychopathology showed significant indirect effects of veteran depression on all child psychopathology outcomes via parenting sense of competence. Parental sense of competence may be a critical mechanism linking veteran depression and child psychopathology, and may therefore be an important target for intervention. PMID- 28660408 TI - Phosphorylated Mechanistic Target of Rapamycin (p-mTOR) and Noncoding RNA Expression in Follicular and Hurthle Cell Thyroid Neoplasm. AB - Oncocytic (Hurthle cell) and follicular neoplasms are related thyroid tumors with distinct molecular profiles. Diagnostic criteria separating adenomas and carcinomas for these two types of neoplasms are similar, but there may be some differences in the biological behavior of Hurthle cell and follicular carcinomas. Recent studies have shown that noncoding RNAs may have diagnostic and prognostic utility in separating benign and malignant Hurthle cell and follicular neoplasms. In this study, we examined expression of various noncoding RNAs including metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and miR-RNA-885 5p (miR-885) in distinguishing between benign and malignant neoplasms. In addition, the expression of phosphorylated mechanistic receptor of rapamycin (p mTOR) was also analyzed in these two groups of tumors. Tissue microarrays (TMAs) with archived tissue samples were analyzed using in situ hybridization (ISH) for MALAT1 and miR-885 and immunohistochemistry (IHC) for p-mTOR. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was also performed on a subset of the cases.MALAT1 and miR-885 were increased in all neoplastic groups compared to the normal thyroid tissues (p < 0.05). MALAT1 was more highly expressed in HCCs compared to FTCs, although the differences were not statistically significant (p = 0.06). MiR-885 was expressed at similar levels in FTCs and HCCs. P-mTOR protein was more highly expressed in FTCs than in HCCs (p<0.001). qRT-PCR analysis of noncoding RNAs supported the ISH findings. These results indicate that the noncoding RNAs MALAT1 and miR-885 show increased expression in neoplastic follicular and Hurthle cell thyroid neoplasms compared to normal thyroid tissues. P-mTOR was most highly expressed in FTC but was also increased in HCC, suggesting that drugs targeting this pathway may be useful for treatment of tumors unresponsive to conventional therapies. PMID- 28660409 TI - Histological type predicts mediastinal metastasis and surgical outcome in resected cN1 non-small cell lung cancer. AB - OBJECTIVES: Non-small cell lung cancer (NSCLC) patients at cN1 have unfavorable outcomes. It has been reported that a substantial proportion of cN1 patients have occult mediastinal disease, and treatment guidelines suggest invasive preoperative mediastinal evaluation. However, the population that would most benefit from invasive staging has not been defined. The aims of this study are to identify factors predicting mediastinal metastasis and outcomes in cN1 NSCLC patients to select appropriate candidates for invasive mediastinal evaluation. METHODS: We retrospectively studied 164 patients with radiologically diagnosed cN1 NSCLC. Clinicopathological factors including radiological nodal findings were reviewed. Factors predicting the pN2 status, disease-free survival (DFS), and overall survival (OS) were investigated. RESULTS: Among 164 patients with cN1 disease, pN2 was diagnosed in 43 (26.4%). This pN2 subgroup included a higher proportion of cases with adenocarcinoma (AD) histology than the pN0/1 subgroup (60.5 vs. 38.8%, p = 0.012). Logistic regression analyses revealed AD as an independent predictor of the pN2 status, while radiological nodal findings were unrelated. Cox regression analyses identified lower preoperative serum CEA, non AD, and pN0/1 status as favorable factors of DFS and adjuvant therapy to be associated with OS. Five-year DFS was much lower in the pN2 subgroup than the pN0/1 subgroup of AD patients (p < 0.001), while DFS was independent of pN status in non-AD patients. CONCLUSIONS: Adenocarcinoma is predictive of pN2 and poor prognosis in radiologically diagnosed cN1 NSCLC. Accurate mediastinal staging may be more beneficial for prognoses and optimal treatment planning in NSCLC patients with AD histology. PMID- 28660410 TI - Effect of fetal hypothyroidism on MyomiR network and its target gene expression profiles in heart of offspring rats. AB - Thyroid hormone deficiency during fetal life (fetal hypothyroidism) causes intrauterine growth restriction (IUGR). Fetal hypothyroidism (FH) could attenuate normal cardiac functions in the later life of the offspring rats. The aim of this study was to evaluate the contribution of myomiR network and its target gene expression in cardiac dysfunction in fetal hypothyroid rats. Six Pregnant female rats were divided into two groups: Control consumed tap water, and the hypothyroid group received water containing 0.025% 6-propyl-2-thiouracil during gestation. Hearts from male offspring rats in adulthood (month 3) were tested with Langendorff apparatus for measuring hemodynamic parameters. Expressions of miR-208a, -208b, and -499 and its target genes including thyroid hormone receptor 1 (Thrap1), sex-determining region Y-box 6 (Sox6), and purine-rich element binding protein beta (Purbeta) were measured by qPCR. FH rats had lower LVDP (%20), +dp/dt (%26), -dp/dt (%20), and heart rate (%21) than controls. FH rats at month 3 had a higher expression of beta-MHC (190%), Myh7b (298%), and lower expression of alpha-MHC (36%) genes in comparison with controls. FH rats at month 3 had a higher expression of miR-499 (520%) and miR-208b (439%) and had lower expression of miR-208a (74%), Thrap1 (47%), Sox6 (49%), and Purbeta (45%) compared with controls. Our results showed that thyroid hormone deficiency during fetal life changes the pattern of gene expression of myomiR network and its target genes in fetal heart, which, in turn, resulted in increased beta-MHC expression and associated cardiac dysfunction in adulthood. PMID- 28660412 TI - [Erratum to: Difficulties with children of abnormal weight]. PMID- 28660411 TI - HIF1A overexpression using cell-penetrating DNA-binding protein induces angiogenesis in vitro and in vivo. AB - Hypoxia-inducible factor-1 alpha (HIF1A) is an important transcription factor for angiogenesis. Recent studies have used the protein transduction domain (PTD) to deliver genes, but the PTD has not been used to induce the expression of HIF1A. This study aimed at using a novel PTD (Hph-1-GAL4; ARVRRRGPRR) to overexpress the HIF1A and identify the effects on angiogenesis in vitro and in vivo. Overexpression of HIF1A was induced using Hph-1-GAL4 in human umbilical vein/vascular endothelium cells (HUVEC). The expression levels of genes were analyzed by the quantitative real-time polymerase chain reaction (qPCR) after 2 and 4 days, respectively. An in vitro tube formation was performed using Diff Quik staining. HIF1A and Hph-1-GAL4 were injected subcutaneously into the ventral area of each 5-week-old mouse. All of the plugs were retrieved after 1 week, and the gene expression levels were evaluated by qPCR. Each Matrigel plug was evaluated using the hemoglobin assay and hematoxylin and eosin (HE) staining. The expression levels of HIF1A and HIF1A target genes were significantly higher in HIF1A-transfected HUVEC than in control HUVEC in vitro. In the in vivo Matrigel plug assay, the amount of hemoglobin was significantly higher in the HIF1A treatment group than in the PBS-treatment group. Blood vessels were identified in the HIF1A-treatment group. The expression levels of HIF1A, vascular endothelial growth factor (Vegf), and Cd31 were significantly higher in the HIF1A-treatment group than in the PBS-treatment group. These findings suggest that using Hph-1 G4D to overexpress HIF1A might be useful for transferring genes and regenerating tissues. PMID- 28660413 TI - [Sharpen the classical view of septic cardiomyopathy]. PMID- 28660414 TI - [Stocks of dantrolene in anesthesia and intensive care units in Germany : Nationwide online survey with 1673 participants]. AB - BACKGROUND: A malignant hyperthermia (MH) crisis is a potentially fatal complication in anesthesia and intensive care units (ICU). Rapid administration and adequate dosage of dantrolene is the only known effective pharmacological and causal treatment of an MH crisis. International anesthesiology societies recommend an initial dose of 2.0-2.5 mg/kg body weight (BW). The necessary total dosage should be titrated up to 10 mg/kg BW depending on the effectiveness. OBJECTIVE: The goal of this study was an analysis of the stocking situation of dantrolene in Germany. A national survey was conducted amongst members of the German Society of Anaesthesia and Intensive Care (DGAI). MATERIAL AND METHODS: A questionnaire consisting of 19 items was posted online to all DGAI members from 2 September to 30 September 2015. The questionnaire dealt with characterization of the participants, the administration of triggering substances in the operating room and in the ICU of the respective hospitals. The main part covered the amount of stocked dantrolene, the place of storage and emergency availability of stocked dantrolene from elsewhere. RESULTS: The questionnaire was posted online to 12,415 DGAI members with a response rate of 13.5% (n = 1673). The highest response rate was from 259 directors and heads of anesthesiology units representing 28.3%. In total 93,7% of participants use volatile anesthetics and 82,3% use succinylcholine. In the event of an MH-crisis 40.4% of participants have 36 or more vials of dantrolene available within 5 min, 27.4% have only 24 vials and 18.7% only have 12 vials. Of the anesthesiologists in outpatient surgery 70.6% have a dantrolene stock of less than 36 vials. In those cases with insufficient dantrolene stock, 35.5% of hospitals have no agreement with neighboring hospitals. In the ICU setting, 51.8% of responding participants indicated the use of volatile anesthetics, but only 25.7% stock dantrolene in the ICU. For succinylcholine, 77.3% stated using the drug in the ICU, and 26.0% have a dantrolene stock in the ICU. CONCLUSION: Almost all anesthesiologists participating in the online survey use volatile anesthethics and/or succinylcholine. Whereas almost all participants have access to dantrolene, more than half of the units have a stock of dantolene, which is less than that recommended by the DGAI. In the case of low dantrolene stock, only 61% of anesthesia departments have access to additional dantrolene within a time frame of 15min . The results of this online survey demonstrate that the stock of dantrolene may be insufficient in some German hospitals and anesthesiology practices. PMID- 28660415 TI - [New onset atrial fibrillation in patients with sepsis]. AB - BACKGROUND: Atrial fibrillation is the most common new onset arrhythmia in patients hospitalized with sepsis; however, there are no specific treatment guidelines and the ideal therapeutic approaches still remain unclear. OBJECTIVES: To begin with the current state of knowledge concerning the underling mechanisms, the incidence and prognostic impact of new onset atrial fibrillation during sepsis are presented. Then a possible therapeutic algorithm for the special situation of sepsis is derived with respect to the currently existing atrial fibrillation guidelines. Finally necessary future research topics are outlined. MATERIAL ANS METHODS: A systematic literature search was conducted in MEDLINE. All publications (reviews and studies) relevant for the summary of the current knowledge regarding new onset atrial fibrillation in septic patients were included. RESULTS: The underlying patchomechanism is primarily systemic inflammation. Approximately 8% of patients with sepsis and more than 20% of patients with septic shock develop new onset atrial fibrillation. The occurrence of atrial fibrillation is associated with increased morbidity and mortality. The necessity of rhythm control therapy is dependent on the hemodynamic stability. The success rate of electrical cardioversion can be increased by the administration of amiodarone. The necessity of systemic anticoagulation is based on the individual risk of thromboembolism. CONCLUSION: Further research is needed to unveil the optimal therapeutic strategies for patients with new onset atrial fibrillation during sepsis. PMID- 28660416 TI - [Botulinum toxin A injections in neuropathic pain : A post-hoc subgroup analysis of patients with peripheral nerve injury]. AB - The randomized controlled trial (RCT) presented in this article showed significant relief in neuropathic pain following subcutaneous injections of botulinum toxin A over 24 weeks compared to placebo. This result was confirmed in a novel post-hoc analysis of the subgroup of 46 patients with peripheral nerve injury. Relevant adverse effects did not occur during the RCT. PMID- 28660418 TI - Basal forebrain activation enhances between-trial reliability of low-frequency local field potentials (LFP) and spiking activity in tree shrew primary visual cortex (V1). AB - Brain state has profound effects on neural processing and stimulus encoding in sensory cortices. While the synchronized state is dominated by low-frequency local field potential (LFP) activity, low-frequency LFP power is suppressed in the desynchronized state, where a concurrent enhancement in gamma power is observed. Recently, it has been shown that cortical desynchronization co-occurs with enhanced between-trial reliability of spiking activity in sensory neurons, but it is currently unclear whether this effect is also evident in LFP signals. Here, we address this question by recording both spike trains and LFP in primary visual cortex during natural movie stimulation, and using isoflurane anesthesia and basal forebrain (BF) electrical activation as proxies for synchronized and desynchronized brain states. We show that indeed, low-frequency LFP modulations ("LFP events") also occur more reliably following BF activation. Interestingly, while being more reliable, these LFP events are smaller in amplitude compared to those generated in the synchronized brain state. We further demonstrate that differences in reliability of spiking activity between cortical states can be linked to amplitude and probability of LFP events. The correlated temporal dynamics between low-frequency LFP and spiking response reliability in visual cortex suggests that these effects may both be the result of the same neural circuit activation triggered by BF stimulation, which facilitates switching between processing of incoming sensory information in the desynchronized and reverberation of internal signals in the synchronized state. PMID- 28660417 TI - [What does pain intensity mean from the patient perspective? : A qualitative study on the patient perspective of pain intensity as an outcome parameter in treatment evaluation and on the interpretability of pain intensity measurements]. AB - BACKGROUND: Pain intensity (PI) is a common outcome parameter in effectiveness studies on interdisciplinary multimodal pain therapy (IMPT), despite the fact that IMPT highlights dealing with rather than reducing chronic pain. Moreover, the measurement of pain intensity as a highly subjective experience is problematic. Patient participation is absolutely essential to examine the relevance of PI as a criterion of treatment success as well as to select/develop suitable measurement methods. METHOD: A qualitative multicenter study was conducted using focus groups with 69 patients (18-77 years; 80% female) at four different IMPT centers in Germany to discuss pain intensity as a therapy outcome parameter in IMPT, as well as the interpretability and feasibility of common measurement methods. RESULTS: The discussions emphasized that PI is a relevant, but not the primary, outcome in IMPT for patients. Patients' statements also demonstrate that there are some problems in measuring PI, for instance with regard to pain attacks. CONCLUSIONS: The focus group discussions suggested that, due to the highly subjective nature of PI, as well as (verbal) inaccuracies and a lack of standardization in common instruments, the measurement of pain intensity is a challenging task. These limitations should be taken into account in future studies. PMID- 28660419 TI - Per oral endoscopic myotomy vs. laparoscopic Heller myotomy, does gastric extension length matter? AB - OBJECTIVE: To report our experience in POEM vs. LHM, with particular focus on myotomy extension. BACKGROUND: POEM has been adopted worldwide as a treatment for achalasia. While resolution of dysphagia is above 90%, postoperative reflux ranges from 10 to 57%. Myotomy length has been a controversial topic. METHODS: Thirty-five cases of POEM were prospectively analyzed and compared retrospectively to the last 35 patients that underwent LHM, from December 2010 to August 2016. Mean follow-up was 10 months (6/32) for POEM and 20 months (6/68) for LHM. All patients with LHM had a myotomy extension >=3 cm on the gastric side. In POEM cases, extension was defined by direct vision (Hill type II) and never exceeded 2 cm. RESULTS: Follow-up was completed in 100% of patients. Efficacy (ES <= 3) was 33/35 (94.2%) for POEM and 32/35 (91.4%) for LHM in a short-term follow-up (p = 1.000) and 31/35 (88.6%) and 27/35 (77.1%), respectively, in a long-term follow-up (p = 1.000), with average ES drop from 9 to 1.2 (p = 0.0001) in POEM vs. 9.2 to 1.3 (p = 0.0001) in LHM. Major Postoperative complications occurred in 1 patient (leak) for LHM and 1 patient (massive capnothorax) in POEM. Hospital stay was shorter for POEM than for LHM (1.3 vs. 2.1, respectively) (p = 0.0001). Symptomatic reflux cases included 7/35 POEM (20%) vs. 6/35 LHM (17.1%) (p = 0.4620). Esophagitis signs in endoscopy appeared in 1/21 POEM (4.7%) vs. 1/22 LHM (4.5%) (p = 1.000). Patients requiring PPI included 8/35 POEM (22.8%) vs. 7/35 LHM (20%) (p = 0.6642). Further treatment (endoscopic dilation) was performed in 10/35 POEM (28.5%) vs. 8/35 LHM (22.8%). CONCLUSIONS: A shorter myotomy on the gastric side in POEM may contribute to an acceptable reflux rate with comparable relief of dysphagia. Although our follow up for POEM is shorter than for LHM, the trends are promising and warrant future prospective studies to address this topic. PMID- 28660420 TI - Effects of combined orthodontic-orthognathic treatment for class II and III correction on posterior airway space : Comparison of mono- and bignathic osteotomies. AB - OBJECTIVES: Comparison of treatment effects on the posterior airway space (PAS) in patients treated with combined orthodontic-orthognathic surgical treatment. METHODS: Pre- and postsurgical lateral cephalograms of 53 (34 females, 19 males) Caucasian patients were analyzed using a customized set of measurements. According to malocclusion (Class II or III) and surgical approach (either monognathic or bignathic), patients were allocated into four groups. PAS was assessed from cranial to caudal at six levels (P1-P6). Paired t tests were used for intragroup and t tests for independent samples for intergroup comparisons. Results were considered statistically significant at p < 0.05. RESULTS: In patients treated for Class II malocclusion, PAS retropalatally (P1 level) almost remained unchanged, whereas measurements at levels P2-P6 showed a mean increase ranging from approximately 2-5.5 mm. Significant changes were most pronounced in monognathic Class II patients (group 1) at levels P2-P4 with mean values ranging from approximately 3.7-5.5 mm. In patients treated for Class III malocclusion (groups 3 and 4), measurements at the P1 level almost remained unchanged in patients who underwent mandibular setback surgery (group 3), whereas the same measurements exhibited significant increase (>6 mm) in patients treated with bignathic surgery (group 4). CONCLUSIONS: Bignathic surgery led to smaller changes of pharyngeal depth in Class II and III patients than monognathic surgery. Alterations of the PAS due to orthognathic surgery should be considered during orthodontic and presurgical treatment planning. PMID- 28660421 TI - Incidence and severity of gingival invaginations associated with early versus late initiation of orthodontic space closure after tooth extraction : A multicenter pilot and randomized controlled trial. AB - OBJECTIVE: Gingival invaginations are a common side effect of orthodontic extraction-space closure. The timing of initiating the closure of an extraction space varies greatly in clinical practice. In this multicenter pilot and randomized controlled trial, we prospectively investigated whether initiating space closure in the early stage of wound healing would benefit the incidence and severity of invaginations developing in the extraction sites. METHODS: A total of 368 patients were screened for indications to extract at least one mandibular premolar. Those recruited were randomly assigned to one of two treatment arms: initiation of space closure either 2-4 weeks (arm A) or >=12 weeks (arm B) after tooth extraction. Clinical data regarding treatment process and periodontal tissue response were recorded during and after space closure and analyzed by a specialized biometrics unit. The study was performed under continuous surveillance by an independent study control center. RESULTS: A total of 74 extraction sites were analyzed. Regarding the incidence of gingival invaginations, there were no significant intergroup differences [p = 0.13; group A comprising 37/44 (84.1%) and group B 29/30 (96.7%) invaginated sites]. The same was true based on either maxillary (p = 0.52) or mandibular (p = 0.21) sites only, and the severity of the invaginations did not differ between the treatment arms. CONCLUSIONS: As to the incidence and severity of gingival invaginations, we did not notice any statistically significant differences between the two timeframes. Our data do, however, provide a basis to identify additional confounders and to improve the accuracy of case-load estimations for future trials. PMID- 28660422 TI - Effect of orthognathic surgery on profile esthetics in Class II:1 malocclusions. AB - OBJECTIVES: To measure the effect of orthognathic surgery on Class II:1 profile silhouette esthetics and to identify pretreatment parameters and thresholds for consistent esthetic improvement. METHODS: Pre- and posttreatment black profile silhouettes of 20 patients with Class II:1 malocclusion who had received combined orthodontic/orthognathic treatment were evaluated retrospectively by 20 European orthodontists and laypeople each using a visual analogue scale (VAS). A variety of pretreatment skeletal and facial angles were measured cephalometrically and on the silhouette profiles. Descriptive statistics and Pearson's correlation coefficients were calculated. RESULTS: The population showed a mean VAS improvement of 12.6%. VAS changes were significantly and directly related to pretreatment ANB in all evaluator groups (r = 0.48-0.59), whereas the interrelation with the degree of pretreatment profile convexity angle was less clear and statistically significant for the orthodontic evaluators only (r = 0.34 to -0.51). The highest correlation coefficients in all evaluator groups were seen for the relationship with pretreatment VAS scores (r = -0.64 to -0.73). CONCLUSION: The lower the pretreatment VAS score and the profile convexity angles or the larger the pretreatment ANB angles were, the more the VAS improved. Pretreatment thresholds for consistent improvements were as follows: VAS score < 20 mm, ANB > 8 degrees , and profile angle <= 155 degrees . PMID- 28660423 TI - Ixazomib: A Review in Relapsed and/or Refractory Multiple Myeloma. AB - The oral proteasome inhibitor ixazomib (Ninlaro(r)) is approved in the USA, EU and Japan in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In adults with relapsed and/or refractory MM who had received one to three prior therapies, progression-free survival (PFS) was significantly prolonged in patients who received the ixazomib- versus placebo-based triple therapy in the pivotal, global TOURMALINE-MM1 trial and its regional expansion (China continuation study). A significantly longer time to progression and favourable hazard ratios for PFS were observed across all prespecified subgroups, including patients with high cytogenetic risk. Overall response was achieved in a significantly higher proportion of patients receiving ixazomib- than placebo based treatment. Ixazomib had a manageable tolerability profile in patients with MM. Ixazomib is the first orally-administered proteasome inhibitor approved for patients with MM, and in combination with lenalidomide and dexamethasone represents an important new option for use in patients with relapsed and/or refractory MM who have previously received at least one prior therapy. PMID- 28660424 TI - How to become a Bayesian in eight easy steps: An annotated reading list. AB - In this guide, we present a reading list to serve as a concise introduction to Bayesian data analysis. The introduction is geared toward reviewers, editors, and interested researchers who are new to Bayesian statistics. We provide commentary for eight recommended sources, which together cover the theoretical and practical cornerstones of Bayesian statistics in psychology and related sciences. The resources are presented in an incremental order, starting with theoretical foundations and moving on to applied issues. In addition, we outline an additional 32 articles and books that can be consulted to gain background knowledge about various theoretical specifics and Bayesian approaches to frequently used models. Our goal is to offer researchers a starting point for understanding the core tenets of Bayesian analysis, while requiring a low level of time commitment. After consulting our guide, the reader should understand how and why Bayesian methods work, and feel able to evaluate their use in the behavioral and social sciences. PMID- 28660425 TI - The Fate of Mengovirus on Fiberglass Filter of Air Handling Units. AB - One of the most important topics that occupy public health problems is the air quality. That is the reason why mechanical ventilation and air handling units (AHU) were imposed by the different governments in the collective or individual buildings. Many buildings create an artificial climate using heating, ventilation, and air-conditioning systems. Among the existing aerosols in the indoor air, we can distinguish the bioaerosol with biological nature such as bacteria, viruses, and fungi. Respiratory viral infections are a major public health issue because they are usually highly infective. We spend about 90% of our time in closed environments such as homes, workplaces, or transport. Some studies have shown that AHU contribute to the spread and transport of viral particles within buildings. The aim of this work is to study the characterization of viral bioaerosols in indoor environments and to understand the fate of mengovirus eukaryote RNA virus on glass fiber filter F7 used in AHU. In this study, a set-up close to reality of AHU system was used. The mengovirus aerosolized was characterized and measured with the electrical low pressure impact and the scanner mobility particle size and detected with RT-qPCR. The results about quantification and the level of infectivity of mengovirus on the filter and in the biosampler showed that mengovirus can pass through the filter and remain infectious upstream and downstream the system. Regarding the virus infectivity on the filter under a constant air flow, mengovirus was remained infectious during 10 h after aerosolization. PMID- 28660426 TI - Recent Developments in the Probes and Assays for Measurement of the Activity of NADPH Oxidases. AB - NADPH oxidases are a family of enzymes capable of transferring electrons from NADPH to molecular oxygen. A major function of NADPH oxidases is the activation of molecular oxygen into reactive oxygen species. Increased activity of NADPH oxidases has been implicated in various pathologies, including cardiovascular disease, neurological dysfunction, and cancer. Thus, NADPH oxidases have been identified as a viable target for the development of novel therapeutics exhibiting inhibitory effects on NADPH oxidases. Here, we describe the development of new assays for measuring the activity of NADPH oxidases enabling the high-throughput screening for NADPH oxidase inhibitors. PMID- 28660428 TI - A step-by-step oncoplastic breast conservation surgical atlas of reproducible dissection techniques and anatomically ideal incision placement. AB - PURPOSE: To develop an atlas for oncoplastic surgery (OPS) with template dissection techniques via anatomically ideal incisions for breast conservation surgery. The evolution of breast conservation techniques has evolved from placing an incision directly over the lesion to the incorporation of a thoughtful decision making process utilizing oncoplastic surgical (OPS) techniques to combining OPS with incision placement in anatomically advantageous sites. The high survival rates of breast cancer and effect of breast surgery on quality of life reinforce emphasis of optimal oncologic as well as aesthetic outcome. OPS results in greater patient satisfaction, fewer surgeries, and is oncologically safe. Today's breast surgeon is tasked with optimizing both oncologic and aesthetic outcomes. METHODS: Presentation of reproducible dissection techniques and incision placement strategies to afford surgeons a step-by-step approach of OPS via anatomically ideal incisions in breast conservation surgery. RESULTS: Demonstration of reproducible techniques to facilitate the decision making process of optimal breast conservation surgery, eliminate knowledge gaps for surgeons, optimize outcome for individuals undergoing breast conservation surgery, and decrease disparity of care. CONCLUSION: Adoption of OPS techniques utilizing an anatomically ideal incision in breast conservation surgery is a feasible and reproducible practice for breast surgeons. Application of these techniques results in maintained optimal shape, size, and contour without the typical overlying skin envelope scars. OPS techniques performed under the skin envelope result in expected OPS oncologic and aesthetic outcomes with the addition of the resulting scar(s) in anatomically discrete position(s). PMID- 28660427 TI - Cholesterol Bilayer Domains in the Eye Lens Health: A Review. AB - The most unique biochemical characteristic of the eye lens fiber cell plasma membrane is its extremely high cholesterol content, the need for which is still unclear. It is evident, however, that the disturbance of Chol homeostasis may result in damages associated with cataracts. Electron paramagnetic resonance methods allow discrimination of two types of lipid domains in model membranes overloaded with Chol, namely, phospholipid-cholesterol domains and pure Chol bilayer domains. These domains are also detected in human lens lipid membranes prepared from the total lipids extracted from lens cortices and nuclei of donors from different age groups. Independent of the age-related changes in phospholipid composition, the physical properties of phospholipid-Chol domains remain the same for all age groups and are practically identical for cortical and nuclear membranes. The presence of Chol bilayer domains in these membranes provides a buffering capacity for cholesterol concentration in the surrounding phospholipid Chol domains, keeping it at a constant saturating level and thus keeping the physical properties of the membrane consistent with and independent of changes in phospholipid composition. It seems that the presence of Chol bilayer domains plays an integral role in the regulation of cholesterol-dependent processes in fiber cell plasm membranes and in the maintenance of fiber cell membrane homeostasis. PMID- 28660429 TI - Erratum to: Fertility preservation with ovarian stimulation and time to treatment in women with stage II-III breast cancer receiving neoadjuvant therapy. PMID- 28660430 TI - Mammographic breast density decreases after bariatric surgery. AB - PURPOSE: Breast density (BD), an important risk factor for breast cancer, can change over time in some women, but the underlying mechanism is unclear. Very little is known about the impact of surgical weight loss on BD. Our hypothesis is that weight loss after bariatric surgery is associated with a significant and favorable change in mammographic BD. METHODS: We identified 1097 women 40 years of age or older who underwent gastric bypass or sleeve gastrectomy at our institution from 2010 to 2014. Women who did not have either pre- and post bariatric surgery mammograms performed at our institution were excluded; 110 had both mammograms and comprised the cohort. Breast density was determined both qualitatively, using reported BI-RADS density, and quantitatively, using the Laboratory for Individualized Breast Radiodensity Assessment. RESULTS: Qualitative BI-RADS density, quantitative breast area, and percent BD significantly decreased in post-bariatric surgery mammograms (p = 0.009, <0.001, and <0.001, respectively). CONCLUSIONS: Our retrospective study demonstrated that surgical weight loss was associated with a significant decrease in breast density. Additional studies are warranted to validate our findings and elucidate the molecular mechanisms underlying breast density change after weight loss surgery. PMID- 28660431 TI - The Identification and Tracking of Uterine Contractions Using Template Based Cross-Correlation. AB - The purpose of this paper is to outline a novel method of using template based cross-correlation to identify and track uterine contractions during labour. A purpose built six-channel Electromyography (EMG) device was used to collect data from consenting women during labour and birth. A range of templates were constructed for the purpose of identifying and tracking uterine activity when cross-correlated with the EMG signal. Peak finding techniques were applied on the cross-correlated result to simplify and automate the identification and tracking of contractions. The EMG data showed a unique pattern when a woman was contracting with key features of the contraction signal remaining consistent and identifiable across subjects. Contraction profiles across subjects were automatically identified using template based cross-correlation. Synthetic templates from a rectangular function with a duration of between 5 and 10 s performed best at identifying and tracking uterine activity across subjects. The successful application of this technique provides opportunity for both simple and accurate real-time analysis of contraction data while enabling investigations into the application of techniques such as machine learning which could enable automated learning from contraction data as part of real-time monitoring and post analysis. PMID- 28660432 TI - Human microdosing and mice xenograft data of AGM-130 applied to estimate efficacious doses in patients. AB - PURPOSE: AGM-130 is a cyclin-dependent kinase inhibitor that exhibits dose dependent efficacy in xenograft mouse models. During preclinical pharmacokinetic (PK) studies, mice and rats showed comparable PK parameters while dogs showed unusually high clearance (CL), which has made human PK prediction challenging. To address this discrepancy, we performed a human microdosing PK and developed a mouse PK/PD model in order to guide the first-in-human studies. METHODS: A microdose of AGM-130 was given via intravenous injection to healthy subjects. Efficacy data obtained using MCF-7 breast cancer cells implanted in mice was analyzed using pre-existing tumor growth inhibition models. We simulated a human PK/PD profile with the PK parameters obtained from the microdose study and the PD parameters estimated from the xenograft PK/PD model. RESULTS: The human CL of AGM 130 was 3.08 L/h/kg, which was comparable to CL in mice and rats. The time courses of tumor growth in xenograft model was well described by a preexisting model. Our simulation indicated that the human doses needed for 50 and 90% inhibition of tumor growth were about 100 and 400 mg, respectively. CONCLUSIONS: This is the first report of using microdose PK and xenograft PK/PD model to predict efficacious doses before the first-in-human trial in cancer patients. In addition, this work highlights the importance of integration of all of information in PK/PD analysis and illustrates how modeling and simulation can be used to add value in the early stages of drug development. PMID- 28660433 TI - Fetal Androgens and Human Sexual Orientation: Searching for the Elusive Link. PMID- 28660434 TI - Decortication and osteotomy for the correction of multiplanar deformity in the treatment of malunion in adult diaphyseal femoral deformity: a case series and technique description. AB - AIM: To review patients that have undergone correction of a symptomatic femoral malunion using osteotomy combined with decortication. METHODS: A retrospective review of all patients who have undergone decortication and multiplanar osteotomy, looking at the pre-operative deformity, correction achieved, time to union and complications. RESULTS: Seven patients underwent correction under the senior author from 2003 to 2012. Average age was 46 years (range 32-60 years). All had femoral shortening deformity (average 2.7 cm, range 2-4 cm). Each also had at least one other plane of deformity with rotation being the next most commonly encountered in 5 out of the 7 (average 33 degrees , range 0 degrees -45 degrees ). Two had tri-planar deformity with the five having bi-planar deformity. Average time to union was 16.3 months (range 7-39 months) with an average of 1.5 operations (range 1-3 operations) to union. One patient has a non-union after five corrective operations. CONCLUSION: Correction of multiplanar deformity of the femur is challenging. Osteotomy with decortication provides a technique to achieve significant femoral multiplanar deformity correction in a single operation. This publication provides technical description of the operative technique, guidance and results. PMID- 28660435 TI - Non-operative management of distal humerus fractures in the elderly: a review of functional outcomes. AB - Comminuted distal humerus fractures in the elderly have traditionally been managed by ORIF or total elbow arthroplasty (TEA). This poses a treatment dilemma in elderly patients where anaesthetic and surgical risks combine with poor bone and wound healing. We aimed to assess the functional outcomes in patients managed non-operatively, with TEA being used as the salvage procedure. Retrospective analysis of patients over 65 years presenting to our unit between 2005 and 2015 was undertaken. Sixty-two patients were identified, 38 had died, and 5 were lost to follow-up leaving 5 with immediate TEA and 14 non-operatively managed, available for review. Mean follow-up was 55 months (range 17-131). Patient outcomes were measured using VAS scores for pain at rest and during activity, and the Oxford elbow score (OES) for TEA and non-operatively managed patients. Conversion to TEA for non-operative treatment and complications were also recorded. Notes interrogation of patients who had died or were lost to follow-up to ascertain outcomes was undertaken. The mean age at injury was 76 years (range 65-90) of which 79% (11/14) were females. The mean score on the OES was 46.2 (range 29-48). The mean VAS score at rest was 0.4 (range 0-6), and the mean VAS score during activity was 1.3 (range 0-9). 93% (13/14) of patients reported no pain in their injured elbow at rest and 79% (11/14) reported no pain during activity. No patients converted to TEA, and there were no complications. Of deceased patients, notes demonstrated one who had ongoing stiffness after physiotherapy, but no conversions to TEA were undertaken. Those managed primarily with TEA had worse OES (mean 40.8), but slightly better pain scores with means 0.2 at rest and 0.8 at activity. Non-operative management of comminuted distal humerus fractures should be considered for elderly patients, avoiding surgical risks whilst giving satisfactory functional outcomes in this low-demand group. PMID- 28660436 TI - Adventure sports and sexual freedom hip replacement: the tripolar hip. AB - Certain athletic activities and lifestyles require a completely stable and very mobile hip. Total hip replacement with a natural femoral head size and two mobile bearing surfaces (i.e., a "tripolar" prosthesis) is the most stable prosthesis. Elegant design and wear-resistant bearing surfaces are the keys to long-term implant survivorship. The hypothesis is that a ceramic-coated tripolar prosthesis using highly cross-linked polyethylene can provide full function and complete stability with low wear. This study sought to determine: (1) patient-reported outcomes, (2) functional outcomes, (3) implant survivorship and complications, and (4) postoperative sexual limitations. Between 1998 and 2011, the author performed 160 primary total hip replacements using tripolar prostheses in patients participating in adventure sports and other physically demanding activities. The institutional review board approved this study. The inclusion criteria were patients who needed unrestricted activity and who were not candidates for or did not choose hip resurfacing. Patients were followed every second year and assessed with radiographs, Harris Hip Score, WOMAC, SF-12, and UCLA functional outcome scores. Patients were asked about symptoms of instability and satisfaction with their hip replacement. Patients were asked both preoperatively and 2 years postoperatively four questions about their sexual activity. Mean follow-up was 11 years. At 2 years' postoperatively, 98% of patients reported their satisfaction as excellent or good and 99% were not limited for sexual activity following surgery. Seventy-four percent of patients reported they were recovered within 6 weeks of surgery. There were no dislocations. There were three revision procedures for implant loosening, infection, and periprosthetic fracture, but there were no failures of the tripolar articulation. The mean postoperative UCLA score was the highly athletic score of 8. There were no signs of osteolysis, wear, or metal sensitivity reactions. The range of motion achieved, sexual, and functional outcomes were higher than with other types of total hip replacement. This ceramic-coated tripolar prosthesis using highly cross-linked polyethylene provides full function, complete stability, and low wear to younger, active patients, thus confirming the hypothesis and clinical relevance. PMID- 28660437 TI - Optimization of technique for insertion of implants at the supra-acetabular corridor in pelvis and acetabular surgery. AB - The technique for application of implants at the sciatic buttress has been well described in the pelvic and acetabular fracture reconstruction literature. We described a new use of the inlet-obturator oblique view for the identification of the anterior inferior iliac spine, which is the entry point of implants, and we provide a detailed fluoroscopic and radiographic description of this view. A small series of 15 patients who underwent an application of an anterior inferior pelvic external (supra-acetabular) fixator via this technique is presented. We consider the use of the obturator oblique for the identification of the entry point unnecessary, and we advocate for the use of only the inlet-obturator oblique and iliac oblique views when implants are applied to the sciatic buttress. PMID- 28660438 TI - Lower material stiffness in rupture-repaired Achilles tendon during walking: transmission-mode ultrasound for post-surgical tendon evaluation. AB - PURPOSE: This cross-sectional study used transmission-mode ultrasound to evaluate dynamic tendon properties during walking in surgically repaired and contralateral Achilles tendon (AT), with a median (range) post-operative period of 22 (4-58) months. It was hypothesised that the axial transmission speed of ultrasound (TSOU) during walking would be slower, indicating lower material stiffness in repaired compared with contralateral AT. METHODS: Ten patients [median (range) age 47 (37-69) years; height 180 (170-189) cm; weight 93 (62-119) kg], who had undergone open surgical repair of the AT and were clinically recovered according to their treating clinicians, walked barefoot on a treadmill at self-selected speed (1.0 +/- 0.2 m/s). Synchronous measures of TSOU, sagittal ankle motion, vertical ground reaction force (GRF), and spatiotemporal gait parameters were recorded during 20 s of steady-state walking. Paired t tests were used to evaluate potential between-limb differences in TSOU, GRF, ankle motion, and spatiotemporal gait parameters. RESULTS: TSOU was significantly lower (~175 m/s) in the repaired than in the contralateral AT over the entire gait cycle (P < 0.05). Sagittal ankle motion was significantly greater (~3 degrees ) in the repaired than in the contralateral limb (P = 0.036). There were no significant differences in GRF or spatiotemporal parameters between limbs. CONCLUSIONS: Repaired AT was characterised by a lower TSOU, reflecting a lower material stiffness in the repaired tendon than in the contralateral tendon. A lower material stiffness may underpin greater ankle joint motion of the repaired limb during walking and long-term deficits in the muscle-tendon unit reported with AT repair. Treatment and rehabilitation approaches that focus on increasing the material stiffness of the repaired AT may be clinically beneficial. Transmission mode ultrasound would seem useful for quantifying tendon properties post AT rupture repair and may have the potential to individually guide rehabilitation programmes, thereby aiding safer return to physical activity. LEVEL OF EVIDENCE: II. PMID- 28660439 TI - Talus bipartitus: a systematic review and report of two cases with arthroscopic treatment. AB - PURPOSE: The aim of this study was to provide a literature review on talus bipartitus and to introduce an arthroscopic treatment option. METHODS: A systematic review of published case reports and small case series was performed. Medline, Embase, CINAHL, Google Scholar and Web of Science databases were searched for relevant publications. In addition, three cases of talus bipartitus treated in our institute were discussed. RESULTS: Eleven articles were identified, reporting on 23 patients, of whom one patient had a bilateral talus bipartitus. Fourteen were males (61%). The median age at presentation was 15.5 years (IQR 14-24.3). In 21 of the symptomatic cases (96%), the patient experienced ankle pain, and 13 had a restricted range of motion (54%). In our institution, two patients were treated arthroscopically and had excellent short- and long-term outcomes. CONCLUSION: Talus bipartitus is a rare anatomical anomaly. Symptoms are characterized by pain and restricted subtalar motion in young patients. Surgical treatment is focused on either fixation or excision of the bony fragment. Our two cases have demonstrated that an arthroscopic approach can be a safe and effective treatment option in patients with a symptomatic talus bipartitus. LEVEL OF EVIDENCE: IV. PMID- 28660440 TI - Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation. PMID- 28660441 TI - Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter. AB - OBJECTIVES: Based on a novel paclitaxel-resveratrol drug matrix, the safety and efficacy to inhibit intimal hyperplasia were studied in symptomatic claudicants with morphologically challenging lesions. BACKGROUND: The treatment of peripheral artery occlusive disease (PAOD) with percutaneous transluminal angioplasty is limited by occurrence of vessel recoil and neointimal hyperplasia. Drug-coated balloons (DCB) deliver drugs to the arterial wall to potentially reduce the restenosis rate. A number of paclitaxel-coated balloon technologies are available to treat peripheral lesions. METHODS: In this randomized controlled trial, a total of 153 patients with symptomatic PAOD in femoro-popliteal lesions were randomized either to DCB or plain old balloon angioplasty (POBA). RESULTS: The mean lesion length was 13.2 +/- 10.4 cm with target lesion total occlusions in 26.1% of all patients (40/153). The primary endpoint of in-lesion late lumen loss (LLL) at 6 months was significantly reduced in the DCB group as compared to the POBA group (0.35 mm CI [0.19; 0.79 mm] vs. 0.72 mm CI [0.68; 1.22 mm], p = 0.006). At 12 months, the TLR rate in the DCB group was significantly lower as compared to the POBA group (17.8 vs. 37.7% p = 0.008). The censored walking distance increase suggests a benefit for patients who underwent DCB angioplasty as compared to the standard POBA treatment (12 months 165 +/- 105 vs. 94 +/- 136 m, p = 0.012). CONCLUSION: The use of paclitaxel-resveratrol-matrix-coated peripheral balloon angioplasty as compared to POBA was associated with significantly reduced in-lesion LLL and reduced TLR rates. ClinicalTrials.gov identifier NCT01970579. PMID- 28660442 TI - Limbal rebound tonometry: clinical comparisons and applications. AB - PURPOSE: The accuracy of contact tonometry may be compromised in cases with disorders affecting central corneal bio-mechanical properties. This study examined the reliability of rebound tonometry (RT) on the area of corneo-scleral limbus, instead of the conventional central corneal area, and the correlation of findings with ocular biometric parameters. METHODS: This is a prospective cross sectional study performed at the Department of Ophthalmology of the University Hospital of Heraklion, in Crete, Greece. Consecutive cataract surgery candidates without concomitant ocular pathology, apart from cataract, were included. RT was performed on the central cornea (central RT, CRT) as well as on the limbus and scleral spur area (limbal RT, LRT). Findings were correlated with Goldmann applanation tonometry (GAT) as well as axial length (AL), central corneal thickness (CCT), and corneal curvature (CC) measurements. RESULTS: LRT readings were significantly correlated with central CRT as well as with GAT readings, whereas respective correlations with other parameters examined were not statistically significant. CONCLUSIONS: LRT may be used as an alternative tool in clinical practice to determine intraocular pressure when conventional devices and techniques might be inadequate or unreliable. PMID- 28660443 TI - Isoforms of TGF-beta in the aqueous humor of patients with pseudoexfoliation syndrome and a possible association with the long-term stability of the capsular bag after cataract surgery. AB - BACKGROUND: Pseudoexfoliation syndrome (PEXS) may go along with capsular bag shrinkage and luxation. In the present study, we focus on an association of isoforms of TGF-beta with capsular bag luxation. METHODS: Aqueous humor was collected intraoperatively from 20 healthy controls and from 73 otherwise healthy patients with PEXS [PEXS without complications (PEX, n = 33), late PEXS with glaucoma (PEXG, n = 30) and with IOL and capsular bag luxation (PEXL, n = 10)]. The concentrations of TGF-beta1, TGF-beta2 and TGF-beta3 were compared using the Bio-Plex(r) multiplex beads system based on the non-parametric Kruskal-Wallis H test (p < 0.01). RESULTS: Concentrations of TGF-beta 1, TGF-beta 2 and TGF-beta 3 were higher in the sub-groups PEX and PEXG than in controls (TGF-beta 1; p = 0.009 and 0.0005; TGF-beta 2; p = 0.002 and 0.005 and TGF-beta 3; 0.0005 and 0.0005; respectively), whereas for TGF beta2, no significant difference between controls and PEXL was revealed (p = 1.0). TGF-beta2 concentrations were elevated in a similar degree in early PEX and PEXG, but not in PEXL compared to controls (p = 0.002). The concentrations of of TGF-beta 1 and TGF-beta 3 increased in parallel with the progression of disease. The levels of TGF-beta 3, however, did not attain pathophysiological levels (>100 pg/ml) in any group. CONCLUSIONS: A stage-dependent increase in the concentrations of TGF-beta1 and TGF-beta3, but not of TGF-beta2, accords to the shrinkage of the capsular bag. This could increase the tension on the zonular fibers and contribute to luxation of the capsular bag. PMID- 28660444 TI - Rituximab in primary membranous nephropathy: beyond a B-cell-centered paradigm? PMID- 28660445 TI - Serum adipocyte fatty acid-binding protein level is associated with arterial stiffness quantified with cardio-ankle vascular index in kidney transplant patients. AB - BACKGROUND: Arterial stiffness is an established marker of cardiovascular risk and an independent predictor of cardiovascular disease (CVD) events and mortality in kidney transplant (KT) patients. Adipocyte fatty acid-binding protein (A FABP), a novel adipokine, is positively associated with atherosclerosis. The present study evaluated the relationship between fasting circulating A-FABP and peripheral arterial stiffness using the cardio-ankle vascular index (CAVI) in KT patients. METHODS: Fasting blood samples were collected from 74 KT patients, and serum A-FABP levels were measured using an enzyme immunoassay. CAVI was calculated using a waveform device (CAVI-VaSera VS-1000). The cutoff values for high and low levels of arterial stiffness were defined by the CAVI values of >=9 and <9, respectively. RESULTS: Thirty-four patients (45.9%) were classified into the high arterial stiffness group. Compared with the low arterial stiffness group, the high arterial stiffness group had higher values for age (p = 0.015), systolic blood pressure (p < 0.001), pulse pressure (p < 0.001), duration of kidney transplantation (p = 0.005), serum total cholesterol and triglyceride levels (p = 0.033 and 0.047, respectively), glomerular filtration rate (p = 0.019), fasting glucose levels (p = 0.012), and serum A-FABP levels (p < 0.001). Multivariate forward stepwise linear regression analysis showed that age (p = 0.004), systolic blood pressure (p = 0.001), and serum A-FABP levels (p = 0.003) were independent predictors of CAVI value in KT patients. CONCLUSION: Serum fasting A-FABP level is positively associated with peripheral arterial stiffness in KT patients. PMID- 28660447 TI - Hypolipidaemic and hypoglycaemic properties of pumpkin polysaccharides. AB - Both hyperglycaemia and hyperlipidaemia are major risk factors for the development of coronary artery diseases and atherosclerosis, and therefore therapeutic drugs must be developed for treatment of them. Pumpkin polysaccharides (PPs) are biomacromolecules with varying bioactivities. In this study, PPs were extracted with commercial thermostable alpha-amylase, and their hypolipidaemic and hypoglycaemic activities were evaluated. Twenty four KKAy mice were divided into two groups: control was fed with high-fat diet; while the PP group was fed with high-fat diet with the addition of PPs at the same time, for 6 weeks. PP diet reduced body weight gain, the levels of plasma insulin, serum triglyceride, cholesterol, low-density lipoprotein cholesterol and blasting blood glucose in mice and improved the level of high-density lipoprotein cholesterol and liver glycogen. Results indicate that PPs had high hypolipidaemic and hypoglycaemic activities and could be used as potential drugs for treatment of hyperlipidaemia and hyperglycaemia. PMID- 28660446 TI - Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial). AB - BACKGROUND: Renal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified. METHODS: This ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index. RESULTS: The subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated. CONCLUSION: By clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non dialysis CKD patients. PMID- 28660448 TI - Enhanced n-butanol production by Clostridium beijerinckii MCMB 581 in presence of selected surfactant. AB - Extractive butanol fermentation with non-ionic surfactant, a recently explored area, has shown promising results with several advantages but is relatively less investigated. This work reports the extractive fermentation with selected non ionic surfactants (L62 and L62D) to enhance butanol production using a high butanol producing strain (Clostridium beijerinckii MCMB 581). Biocompatibility studies with both the surfactants showed growth. Higher concentrations of surfactant (>5%) affected the cell count. 15.3 g L-1 of butanol and 21 g L-1 of total solvents were obtained with 3% (v/v) L62 which was respectively, 43% (w/w) and 55% (w/w), higher than control. It was found that surfactant addition at 9th h doubled the productivity (from 0.13 to 0.31 g L-1 h-1 and 0.17 to 0.39 g L-1 h 1, respectively for butanol and total solvent). Butanol productivity obtained was 2-3 times higher than similar studies on extractive fermentation with non-ionic surfactants. Interestingly, mixing did not improve butanol production. PMID- 28660449 TI - Proximate composition and nutritional evaluation of the adductor muscle of pen shell. AB - The proximate composition of pen shell adductor muscle (PSAM) was determined, and its nutrition value was evaluated. Proximate composition analysis indicated that PSAM contained 91.07% (w/w) protein, 5.77% (w/w) ash, and 2.46% (w/w) fat. Calcium was the predominant mineral followed by zinc and then iron. The amino acid profile was in accordance with the recommended pattern of FAO/WHO except for histidine. At the same time, the first limiting amino acid was histidine. Fatty acid composition showed that docosahexaenoic acid was the major fatty acid, followed by palmitic, stearic, and arachidonic acids. Results indicated that PSAM was rich in nutrition and may be developed as a functional food. PMID- 28660450 TI - Evaluating water deficit and glyphosate treatment on the accumulation of phenolic compounds and photosynthesis rate in transgenic Codonopsis lanceolata (Siebold & Zucc.) Trautv. over-expressing gamma-tocopherol methyltransferase (gamma-tmt) gene. AB - The effect of water stress and herbicide treatment on the phenolic compound concentration and photosynthesis rate in transgenic Codonopsis lanceolata plants over-expressing the gamma-tmt gene was investigated and compared to that in control non-transgenic C. lanceolata plants. The total phenolic compound content was investigated using high-performance liquid chromatography combined with diode array detection in C. lanceolata seedlings 3 weeks after water stress and treatment with glyphosate. Changes in the composition of phenolic compounds were observed in leaf and root extracts from transformed C. lanceolata plants following water stress and treatment with glyphosate. The total concentration of phenolic compounds in the leaf extracts of transgenic samples after water stress ranged from 3455.13 +/- 40.48 to 8695.00 +/- 45.44 ug g-1 dry weight (DW), whereas the total concentration phenolic compound in the leaf extracts of non transgenic control samples was 5630.83 +/- 45.91 ug g-1 DW. The predominant phenolic compounds that increased after the water stress in the transgenic leaf were (+) catechin, benzoic acid, chlorogenic acid, ferulic acid, gallic acid, rutin, vanillic acid, and veratric acid. The total concentration of phenolic compounds in the leaf extracts of transgenic samples after glyphosate treatment ranged from 4744.37 +/- 81.81 to 12,051.02 +/- 75.00 ug g-1 DW, whereas the total concentration of the leaf extracts of non-transgenic control samples after glyphosate treatment was 3778.28 +/- 59.73 ug g-1 DW. Major phenolic compounds that increased in the transgenic C. lanceolata plants after glyphosate treatment included kaempherol, gallic acid, myricetin, p-hydroxybenzjoic acid, quercetin, salicylic acid, t-cinnamic acid, catechin, benzoicacid, ferulic acid, protocatechuic acid, veratric acid, and vanillic acid. Among these, vanillic acid showed the greatest increase in both leaf and root extracts from transgenic plants relative to those from control C. lanceolata plants following treatment with glyphosate, which could affect the 5-enol-pyruvyl shikimate-3-phosphate (EPSP) synthase, an enzyme in the shikimate pathway. We observed enhanced stomatal conductance (gs) and photosynthesis rate (A) in the transgenic plants treated with water stress and glyphosate treatment. The results of this study demonstrated large variations in the functioning of secondary metabolites pathway in response glyphosate and water stress in transgenic C. lanceolata. PMID- 28660451 TI - Daphnia magna demonstrated sufficient sensitivity in techno-economic optimization of lignocellulose bioethanol production. AB - Notable progress has been achieved in the past two decades regarding production of different enzymatic mixtures for hydrolysis of the lignocellulose matrix. Nevertheless, the hydrolysing mixtures remain slow and require tempering, which results in high-energy demands and bad financial results. Use of acids or alkali at a very high temperature and pressure accelerates the process more than ten times wherein the energy requirements are approximately equal. However, these elevated reaction conditions might cause the breakdown of complex lignin formula into substances that have the potential to inhibit subsequent fermentation processes. Formation of these breakdown products may be prevented by selecting the optimum process parameters, but their acquisition requires either a large number of expensive analytical techniques or equally large amounts of slow fermentation tests. An inexpensive and time saving alternative that is based on the sensitivity of chosen organisms to these inhibitors was designed and financially assessed. It was confirmed that the method is technically feasible and economically viable with significant potential to reduce the bioethanol production cost. PMID- 28660452 TI - Bamboo shoots as a nutritive boon for Northeast India: an overview. AB - With about 136 species, India is one among the richest countries in bamboo resources that help mankind in more than 1500 diverse ways. Although the utilization of juvenile shoots of bamboo in tribal diet of Northeast India is a very old observable fact, its numerous health benefits and potentiality remains uncharted. Apart from being delicious, the bamboo shoots are also rich in minerals and nutrient components such as carbohydrates, proteins, fiber and are low in fat and sugar which could be helpful in mitigating the problem of malnutrition. Few studies also revealed the health benefits of bamboo shoots for the treatment of cancer and cardiovascular diseases, weight loss and to improve digestion. Over and above the nutritional values of different species of bamboo shoots, the increasing inclinations towards health awareness among the consumers have emphasized its utilization in modern diet as a health food for boosting the nutritional security. Thus, in the present review, the nutraceutical potentiality of bamboo shoots is explored alongside its various qualities. PMID- 28660453 TI - Peach gum polysaccharides-based edible coatings extend shelf life of cherry tomatoes. AB - Cherry tomato is a nutritious, but highly perishable fruit. Peach gum polysaccharides (PGPs) can form edible films with antioxidant and antibacterial activities. The effects of PGP-based edible coatings on cherry tomatoes during hypothermic storage (4 degrees C) were investigated. PGP-based edible coatings effectively maintained firmness, decreased weight loss, inhibited respiration rate and delayed the changes in total acidity, ascorbic acid and sugar content of cherry tomatoes during hypothermic storage (4 degrees C) compared with those of the control (p < 0.05). The results indicate that using PGP-based edible coating is a promising method to extend the shelf life of cherry tomatoes. PMID- 28660454 TI - An improved method suitable for isolation of high-quality metagenomic DNA from diverse soils. AB - Standardization of metagenomic DNA extraction protocol is a pre-requisite for a successful metagenomic study aiming to screen and exploit the variety of microorganisms inhabiting a particular soil environment. Six methods reported earlier were used for isolation of metagenomic DNA in the present study. These methods suffered with regard to either poor yield or quality of DNA. Therefore, we developed an improved method for isolation of high-molecular weight and good quality metagenomic DNA from different soil samples. Our protocol combines the enzymatic (lysozyme and proteinase K) and chemical (CTAB and CaCl2) strategies to ensure efficient cell lysis and use of PEG and isopropanol for precipitation of humic impurities-free DNA. Our improved method gave high yield of good quality metagenomic DNA from diverse soils collected from garden, domestic waste dumping site, cellulose waste dumping site, sewage site, and tannery waste site. The good quality of the metagenomic DNA was evident by spectrophotometry data, PCR amplification of 16S rRNA gene and restriction digestion. PMID- 28660455 TI - Investigation of in vitro digestibility of dietary microalga Chlorella vulgaris and cyanobacterium Spirulina platensis as a nutritional supplement. AB - Microalgal proteins are promising sources for functional nutrition and a sustainable candidate for nutraceutical formulations. They also gain importance due to emerging focus on a healthy nutrition and increase in the number of chronic diseases. In this study, dried dietary species of microalga, Chlorella vulgaris, and cyanobacterium Spirulina platensis were hydrolyzed with pancreatin enzyme to obtain protein hydrolysates. The hydrolysis yield of biomass was 55.1 +/- 0.1 and 64.8 +/- 3.6% for C. vulgaris and S. platensis; respectively. Digestibility, as an indicator for dietary utilization, was also investigated. In vitro protein digestibility (IVPD) values depicted that cell wall structure due to the taxonomical differences affected both hydrolysis and digestibility yield of the crude biomass (p < 0.05). Epithelial cells (Vero) maintained their viability around 70%, even in relatively higher concentrations of hydrolysates in the culture. The protein hydrolysates showed no any antimicrobial activities. This study clearly shows that the conventional protein sources in nutraceutical formulations such as soy, whey, and fish proteins can be replaced by enzymatic hydrolysates of microalgae, which shows elevated digestibility values as a sustainable and reliable source. PMID- 28660456 TI - Sorghum husk biomass as a potential substrate for production of cellulolytic and xylanolytic enzymes by Nocardiopsis sp. KNU. AB - Nocardiopsis sp. KNU was found to degrade various lignocellulosic waste materials, namely, sorghum husk, sugarcane tops and leaves, wheat straw, and rice husk very efficiently. The strain was found to produce high amounts of cellulase and hemicellulase. Augmentation of cotton seed cake as an organic nitrogen source revealed inductions in activities of endoglucanase, glucoamylase, and xylanase up to 70.03, 447.89, and 275.10 U/ml, respectively. Nonionic surfactant Tween-80 addition was found to enhance the activity of endoglucanase enzyme. Cellulase produced by Nocardiopsis sp. KNU utilizing sorghum husk as a substrate was found to retain its stability in various surfactants up to 90%. The produced enzyme was further tested for saccharification of mild alkali pretreated rice husk. The changes in morphology and functional group were analyzed using scanning electron microscopy and Fourier transform infrared spectroscopy. Enzymatic saccharification confirmed the hydrolytic potential of crude cellulase. The hydrolysate products were analyzed by high-performance thin layer chromatography. PMID- 28660457 TI - Marker-assisted breeding for introgression of opaque-2 allele into elite maize inbred line BML-7. AB - Improvement of quality protein maize (QPM) along with high content of lysine and tryptophan had foremost importance in maize breeding program. The efficient and easiest way of developing QPM hybrids was by backcross breeding in marker aided selection. Hence, the present investigation aimed at conversion of elite maize inbred line BML-7 into QPM line. CML-186 was identified to be a donor variety as it revealed high-quality polymorphism with BML-7 for opaque-2 gene specific marker umc1066. Non-QPM inbred line BML-7 was crossed with QPM donor CML-186 and produced F1 followed by the development of BC1F1 and BC2F1 population. Foreground selection was carried out with umc1066 in F1, and selected plants were used for BC1F1 and BC2F1 populations. Two hundred plants were screened in both BC1F1 and BC2F1 population with umc1066 for foreground selection amino acid modifiers. Foreground selected plants for both opaque-2 and amino acid modifiers were screened for background selection for BML-7 genome. Recurrent parent genome (RPG) was calculated for BC2F1 population plants. Two plants have shown with RPG 90-93% in two generation with back cross population. Two BC2F2 populations resulted from marker recognized BC2F1 individuals subjected toward foreground selection followed by tryptophan estimation. The tryptophan and lysine concentration was improved in all the plants. BC2F2 lines developed from hard endosperm kernels were selfed for BC2F2 lines and finest line was selected to illustrate the QPM version of BML-7, with 0.97% of tryptophan and 4.04% of lysine concentration in protein. Therefore, the QPM version of BML-7 line can be used for the development of single cross hybrid QPM maize version. PMID- 28660458 TI - Hypoglycaemic and hypolipidaemic properties of peach gum polysaccharides. AB - Hyperglycaemia and hyperlipidaemia are major risk factors for coronary artery diseases and atherosclerosis. Peach gum polysaccharides (PGPs) possess various bioactivities. In this study, PGPs were extracted with thermostable alpha-amylase and investigated in terms of hypolipidaemic and hypoglycaemic activities. KKAy mice were gavaged once daily with either PGPs or distilled water (control group) for 3 weeks. Oral administration of PGPs decreased the levels of serum triglyceride, cholesterol low-density lipoprotein cholesterol, fasting blood glucose, plasma insulin, C-peptide, and HbAlc in mice. Moreover, treatment with PGPs increased the insulin sensitivity index in KKAy mice. Results indicated that PGPs possess significant hypoglycaemic effects and could be developed as a drug for preventing hyperlipidaemia and hyperglycaemia. PMID- 28660460 TI - Bioactive profile, free-radical scavenging potential, DNA damage protection activity, and mycochemicals in Aspergillus awamori (MTCC 548) extracts: a novel report on filamentous fungi. AB - Biomass of Aspergillus awamori was investigated for mycochemicals, total phenolic compounds (TPC), condensed tannin content (CTC), free-radical scavenging potential (FRSP), and DNA damage protection activity. FRSP was determined using DPPH, ABTS, FRAP (Ferric reducing antioxidant power), metal chelating activity, and cupric reducing antioxidant capacity) assays. Water (Aq), aqueous ethanol 50% (AqE), and methanol were used as extraction phase at 44.5 degrees C for 23.8 min. AqE shows the presence of maximum mycochemicals (coumarins, glucose, saponins, flavonoids, and tannin). Further quantitative analysis shows maximum TPC (23.17 mg GAE/g dwb) in AqE and CTC (.89 mg CE/g dwb) in ME. Qualitative and quantitative analysis for identification of specific bioactive compound in AqE was carried out using HPLC. HPLC analysis confirmed the presence of bioactive compounds: p'-Coumaric acid (5.96 mg/g dwb), cinnamic acid (4.31 mg/g dwb), gallic acid (2.27 mg/g dwb), and ascorbic acid (.98 mg/g dwb). All the extracts show significant DNA damage protection activity; however, AqE showed the maximum activity. Pearson correlations were also calculated to find the relationships between bioactive compounds and antioxidant potential. PMID- 28660459 TI - Plant-derived antimicrobials to fight against multi-drug-resistant human pathogens. AB - Antibiotic resistance is becoming a pivotal concern for public health that has accelerated the search for new antimicrobial molecules from nature. Numbers of human pathogens have inevitably evolved to become resistant to various currently available drugs causing considerable mortality and morbidity worldwide. It is apparent that novel antibiotics are urgently warranted to combat these life threatening pathogens. In recent years, there have been an increasing number of studies to discover new bioactive compounds from plant origin with the hope to control antibiotic-resistant bacteria. This review attempts to focus and record the plant-derived compounds and plant extracts against multi-drug-resistant (MDR) pathogens including methicillin-resistant Staphylococcus aureus (MRSA), MDR Mycobacterium tuberculosis and malarial parasites Plasmodium spp. reported between 2005 and 2015. During this period, a total of 110 purified compounds and 60 plant extracts were obtained from 112 different plants. The plants reviewed in this study belong to 70 different families reported from 36 countries around the world. The present review also discusses the drug resistance in bacteria and emphasizes the urge for new drugs. PMID- 28660461 TI - Addition of Rubber to soil damages the functional diversity of soil. AB - Rubber is a polymer of isoprene, consisting mainly of cis-1,4-polyisoprene units. The unmanageable production and its irresponsible disposal pose severe threats to environmental ecology. Therefore, the current study focuses extensively on the ill-effects of Rubber disposal on soil microbial functional diversity as it reflects the health of ecosystem by acting as a key component in ecosystem productivity. To investigate the effect of Rubber on soil microbial functional diversity, soil samples were collected from landfill sites and three different soil microcosms (Rubber treated, untreated, and sterile soil) were prepared. The soil enzymatic activity was determined by fluorescein diacetate hydrolysis followed by the determination of the microbial metabolic potential and functional diversity by average well color development and Shannon-Weaver index (H), respectively. BiOLOG ECO plates were used for determining the microbial functional diversity of the soil microcosms. Higher heterotrophic microbial count as well as higher soil microbial activity was observed in Rubber untreated soil than Rubber treated soil microcosm. The result indicated that the addition of Rubber to soil reduced soil heterotrophic microbial count and soil microbial activity considerably. Similarly, soil microbial metabolic potential as well as microbial functional diversity of soil had been decreased by the addition of Rubber gloves in it. Variation in soil microbial metabolic spectrum between Rubber treated and untreated microcosm was confirmed by multivariate analysis. Collectively, all the results demonstrated that the addition of Rubber to soil reduced the soil microbial functional diversity considerably. Therefore, it is necessary for the commission of serious steps regarding Rubber disposal and protection of the environment from serious environmental issues. PMID- 28660462 TI - Fabrication and characterization of chitosan nanoparticles and collagen-loaded polyurethane nanocomposite membrane coated with heparin for atrial septal defect (ASD) closure. AB - Atrial septal defect (ASD) constitutes 30-40% of all congenital heart diseases in adults. The most common complications in the treatment of ASD are embolization of the device and thrombosis formation. In this research, an occluding patch was developed for ASD treatment using a well-known textile technology called electrospinning. For the first time, a cardiovascular occluding patch was fabricated using medical grade polyurethane (PU) loaded with bioactive agents namely chitosan nanoparticles (Cn) and collagen (Co) which is then coated with heparin (Hp). Fourier transform infrared spectrum showed characteristic vibrations of several active constituents and changes in the absorbance due to the inclusion of active ingredients in the patch. The contact angle analysis demonstrated no significant decrease in contact angle compared to the control and the composite patches. The structure of the electrospun nanocomposite (PUCnCoHp) was examined through scanning electron microscopy. A decrease in nanofiber diameter between control PU and PUCnCoHp nanocomposite was observed. Water uptake was found to be decreased for the PUCnCoHp nanocomposite against the control. The hemocompatibility properties of the PUCnCoHp ASD occluding patch was inferred through in vitro hemocompatibility tests like activated partial thromboplastin time (APTT), prothrombin time (PT) and hemolysis assay. It was found that the PT and APTT time was significantly prolonged for the fabricated PUCnCoHp ASD occluding patch compared to the control. Likewise, the hemolysis percentage was also decreased for the PUCnCoHp ASD patch against the control. In conclusion, the developed PUCnCoHp patch demonstrates potential properties to be used for ASD occlusion. PMID- 28660463 TI - Resilience to health challenges is related to different ways of thinking: mediators of physical and emotional quality of life in a heterogeneous rare disease cohort. AB - BACKGROUND: We sought to understand what distinguishes people who confront health challenges but still manage to thrive. This study investigated whether resilience helps to explain the impact of health challenges on quality of life (QOL) outcomes, and how resilience relates to appraisal. METHODS: A web-based survey of rare-disease panel participants included the Centers for Disease Control Healthy Days Core Module, the PROMIS-10, and comorbidities. The QOL Appraisal Profile-v2 assessed cognitive processes underlying QOL. Resilience was operationalized statistically using residual modeling, and hierarchical regressions tested the mediation hypothesis that resilience accounts for a significant amount of the relationship of appraisal to QOL. RESULTS: The study sample (n = 3,324; mean age 50; 86% female; 90% White) represented a range of diagnostic codes, with cancer and diseases of the nervous system being the most prevalent health conditions. After adjusting for comorbidities (catalysts), resilience was associated with better physical and emotional functioning, and different appraisal processes were associated with better or worse physical or emotional functioning. After controlling for catalysts, 62% of the association of Physical Functioning and 23% of the association between Emotional Functioning and appraisal were mediated by resilience. Physical and emotional resilience comprised some of the same appraisal processes, but physically resilient people were characterized by more appraisal processes than their emotionally resilient counterparts. CONCLUSIONS: Resilient people employ different appraisal processes than non-resilient people, and these processes differ for physical and emotional outcomes. Resilience was a stronger mediator of the relationship between physical rather than emotional functioning and appraisal. PMID- 28660464 TI - Respiratory Tract Infection Caused by Fonsecaea monophora After Kidney Transplantation. AB - Fonsecaea spp. are melanized fungi which cause most cases of chromoblastomycosis. The taxonomy of this genus has been revised, now encompassing four species, with different pathogenic potential: F. pedrosoi, F. nubica, F. pugnacius, and F. monophora. The latter two species present wider clinical spectrum and have been associated with cases of visceral infection, most often affecting the brain. To our knowledge, this is the first report of proven case of F. monophora respiratory tract infection. A Brazilian 57-year-old-female patient underwent kidney transplantation on January 12, 2013. On the fourth postoperative month, the patient presented with fever, productive cough, and pleuritic pain in the right hemithorax. A thoracic CT scan showed a subpleural 2.2-cm nodular lesion in the right lung lower lobe, with other smaller nodules (0.5-0.7 cm) scattered in both lungs. Bronchoscopy revealed a grayish plaque on the right bronchus which was biopsied. Microscopic examination demonstrated invasion of bronchial mucosa by pigmented hyphae. Culture from the bronchial biopsy and bronchoalveolar lavage samples yielded a melanized mold, which was eventually identified as F. monophora. She started treatment with voriconazole (400 mg q.12h on the first day, followed by 200 mg q.12h). After 4 weeks of therapy, voriconazole dose was escalated to 200 mg q.8h and associated with amphotericin B (deoxycolate 1 mg/kg/day) because of a suspected dissemination to the brain. The patient eventually died of sepsis 8 weeks after the start of antifungal therapy. In conclusion, F. monophora may cause respiratory tract infection in solid organ transplant recipients. PMID- 28660465 TI - Is Marine Dispersion of the Lethargic Crab Disease Possible? Assessing the Tolerance of Exophiala cancerae to a Broad Combination of Salinities, Temperatures, and Exposure Times. AB - Since 1997, an emergent fungal disease named lethargic crab disease (LCD) has decimated stocks of the edible mangrove land crab Ucides cordatus (Linnaeus, 1763) (Brachyura: Ocypodidae) along the Brazilian coast, threatening the mangrove ecosystem and causing socioeconomic impacts. Evidence from a variety of sources suggests that the black yeast Exophiala cancerae (Herpotrichiellaceae, Chaetothyriales) has been responsible for such epizootic events. Based on the spatiotemporal patterns of the LCD outbreaks, the well-established surface ocean currents, and the range of ecological traits of Exophiala spp., a marine dispersal hypothesis may be proposed. Using in vitro experiments, we tested the survival and growth of E. cancerae CBS 120420 in a broad combination of salinities, temperatures, and exposure times. While variation in salinity did not significantly affect the growth of colony-forming units (CFUs) (P > 0.05), long exposure times visibly influenced an increase in CFUs growth (P < 0.05). However, higher temperature (30 degrees C) caused a reduction of about 1.2-fold in CFUs growth (P < 0.05). This result suggests that sea surface temperatures either above or below the optimum growth range of E. cancerae could play a key role in the apparent north-south limits in the geographical distribution of LCD outbreaks. In light of our results, we conclude that a fundamental step toward the understanding of LCD epidemiological dynamics should comprise a systematic screening of E. cancerae in estuarine and coastal waters. PMID- 28660466 TI - Identity Elements of tRNA as Derived from Information Analysis. AB - The decipherment of the tRNA's operational code, known as the identity problem, requires the location of the sites in the tRNA structure that are involved in their correct recognition by the corresponding aminoacyl-tRNA synthetase. In this work, we determine the identity elements of each tRNA isoacceptor by means of the variation of information measure from information theory. We show that all isoacceptors exhibit sites associated with some bases of the anticodon. These sites form clusters that are scattered along the tRNA structure. The clusters determine the identity elements of each tRNA. We derive a catalogue of clustered sites for each tRNA that expands previously reported elements. PMID- 28660467 TI - Influence of dexmedetomidine on cardiac complications in non-cardiac surgery: a meta-analysis of randomized trials. AB - Background The cardiac protection of dexmedetomidine (Dex) in peri-operative period of patients with non-cardiac surgery is still controversial. Aim of the Review We aimed to evaluate the influence of Dex on cardiac complications in peri operative period of non-cardiac surgery by using a meta-analysis. Methods PubMed, Embase, the Cochrane library and Springer databases were searched for relevant studies. Patients in the eligible studies were divided into Dex group and placebo group. Relative risk (RR) and the 95 % confidence interval (CI) were calculated to evaluate the outcomes including all-cause mortality, myocardial infarction, myocardial ischaemia, hypotension and bradycardia. Subgroup analysis was performed based on the dosage of Dex. Publication bias was assessed by Egger's test. Results Twenty double-blind randomized controlled trials containing 1157 patients were included in this meta-analysis. The pooled results showed no significant difference between Dex group and placebo group in peri-operative myocardial infarction, myocardial ischaemia and all-cause mortality. However, Dex group showed higher risk of hypotension (RR = 1.46, 95 % CI 1.07, 2.01) and bradycardia (RR = 1.98, 95 % CI 1.33, 2.95) than that of placebo group. In addition, significant publication bias was found among studies involving hypotension and bradycardia. In subgroup analysis, the risk of bradycardia was significantly higher in 1.0 MUg/kg Dex group than that in placebo group. Besides, a higher risk of hypotension in 0.5 MUg/kg Dex group than that in placebo group was found. Conclusions Dex supplement might not reduce the risk of cardiac complications but increases the risk of hypotension and bradycardia in peri operative period of patients who underwent non-cardiac surgeries. PMID- 28660468 TI - How do targets, nontargets, and scene context influence real-world object detection? AB - Humans excel at finding objects in complex natural scenes, but the features that guide this behaviour have proved elusive. We used computational modeling to measure the contributions of target, nontarget, and coarse scene features towards object detection in humans. In separate experiments, participants detected cars or people in a large set of natural scenes. For each scene, we extracted target associated features, annotated the presence of nontarget objects (e.g., parking meter, traffic light), and extracted coarse scene structure from the blurred image. These scene-specific values were then used to model human reaction times for each novel scene. As expected, target features were the strongest predictor of detection times in both tasks. Interestingly, target detection time was additionally facilitated by coarse scene features but not by nontarget objects. In contrast, nontarget objects predicted target-absent responses in both person and car tasks, with contributions from target features in the person task. In most cases, features that speeded up detection tended to slow down rejection. Taken together, these findings demonstrate that humans show systematic variations in object detection that can be understood using computational modeling. PMID- 28660469 TI - Childhood socioeconomic circumstances and depressive symptom burden across 15 years of follow-up during midlife: Study of Women's Health Across the Nation (SWAN). AB - Childhood socioeconomic disadvantage may contribute to adult depression. Understanding pathways by which early socioeconomic adversity may shape adult depression is important for identifying areas for intervention. Studies to date have focused on one potential pathway, adult socioeconomic status (SES), and assessed depression at only one or a few time points. Our aims were to examine (a) the association between childhood SES (low vs. high) and depressive symptom burden in midlife and (b) whether adult socioeconomic, psychosocial, and physical health characteristics are important pathways. Using annual data from a cohort of 1109 black and white US women recruited in 1996-1997, we evaluated the association between childhood SES and depressive symptom burden across 15 years in midlife and whether adult characteristics-financial difficulty, lower education, stressful events, low social support, low role functioning, medical conditions, and bodily pain-mediated the association. Depressive symptom burden was estimated by calculating area under the curve of annual scores across 15 years of the Center for Epidemiological Studies Depression (CES-D). In unadjusted models, low childhood SES was associated with greater depressive burden (P = 0.0002). Each hypothesized mediator, individually, did not reduce the association. However, when five of the hypothesized mediators were included together in the same analysis, they explained more than two thirds of the association between childhood SES and depressive symptom burden reducing the P value for childhood SES to non-significance (P = 0.20). These results suggest that childhood SES influences midlife depressive symptom burden through a cluster of economic stress, limited social resources, and physical symptoms in adulthood. PMID- 28660470 TI - Psychosis secondary to an incidental teratoma: a "heads-up" for psychiatrists and gynecologists. AB - Anti-N-methyl-D-aspartate receptor encephalitis is a potentially fatal form of autoimmune encephalitis that originates secondary to a host immune response to neural tissue within a teratoma. We describe the case of a 17-year old girl who presented with acute onset psychosis, catatonic movements, urinary incontinence, fever, tachycardia, and fluctuating periods of hypotension and hypertension. A CT scan demonstrated an incidental 6 cm ovarian teratoma. The patient fully recovered after ovarian cystectomy, followed by medical management with intravenous immunoglobins and plasmapheresis. Anti-N-methyl-D-aspartate receptor encephalitis is an important differential diagnosis to consider for young patients presenting with acute onset psychiatric symptoms, who develop seizures, movement disorders, or autonomic instability. It is important for psychiatrist and gynecologist to be aware of this diagnosis as delay in recognition can have serious consequences including patient death. PMID- 28660471 TI - Spirituality/Religiosity (SpR), Leisure-Time Physical Activity, and Sedentary Behaviour in Students at a Catholic University. AB - Some studies have found an association between spirituality and/or religiosity (SpR) and cardiovascular health, for reasons which remain unclear. This study explores whether SpR is linked to physical activity whilst young, which in turn is linked to long-term cardiovascular health. Students at a Catholic University in Australia completed a survey combining the SpREUK-P SF 17 SpR questionnaire with elements of the long-form 7-day recall International Physical Activity Questionnaire. Respondents who scored highly in the unconventional spiritual practices components of SpREUK-P engaged in moderate intensity physical activity more frequently. This finding may have implications for health promotion. PMID- 28660472 TI - Associations between Screen-Based Activity, Spiritual Well-Being, and Life Satisfaction among Adolescents. AB - The current study examined how screen-based activity is related to spiritual well being and life satisfaction among Czech adolescents, age ranged between 11 and 15 years. Results indicated that spending time on screen-based activities was predictive for spiritual well-being, but did not have a decisive effect on life satisfaction. We also found that spiritual well-being was significantly related to life satisfaction. Findings suggest that we ought to pay more attention to the influence of time spending on screen-based activities on spiritual well-being among adolescents to promote positive youth development. PMID- 28660473 TI - Assessing the Value of Biosimilars: A Review of the Role of Budget Impact Analysis. AB - Biosimilar drugs are highly similar to an originator (reference) biologic, with no clinically meaningful differences in terms of safety or efficacy. As biosimilars offer the potential for lower acquisition costs versus the originator biologic, evaluating the economic implications of the introduction of biosimilars is of interest. Budget impact analysis (BIA) is a commonly used methodology. This review of published BIAs of biosimilar fusion proteins and/or monoclonal antibodies identified 12 unique publications (three full papers and nine congress posters). When evaluated alongside professional guidance on conducting BIA, the majority of BIAs identified were generally in line with international recommendations. However, a lack of peer-reviewed journal articles and considerable shortcomings in the publications were identified. Deficiencies included a limited range of cost parameters, a reliance on assumptions for parameters such as uptake and drug pricing, a lack of expert validation, and a limited range of sensitivity analyses that were based on arbitrary ranges. The rationale for the methods employed, limitations of the BIA approach, and instructions for local adaptation often were inadequately discussed. To understand fully the potential economic impact and value of biosimilars, the impact of biosimilar supply, manufacturer-provided supporting services, and price competition should be included in BIAs. Alternative approaches, such as cost minimization, which requires evidence demonstrating similarity to the originator biologic, and those that integrate a range of economic assessment methods, are needed to assess the value of biosimilars. PMID- 28660474 TI - Ahead of Our Time: Collaboration in Modeling Then and Now. PMID- 28660476 TI - A review of the atrial upper rate algorithms of St. Jude Medical (Abbott) cardiac implantable electronic devices : Incidence of repetitive nonreentrant ventriculoatrial synchrony (RNRVAS). AB - This review focuses on the manifestations of the three triggered atrial upper rate functions of St Jude Medical cardiac implantable electronic devices. The occurrence of repetitive nonreentrant ventriculoatrial synchrony (RNRVAS) is also evaluated as a basis for the development of automatic mode switching (AMS) and as a trigger for atrial tachycardia/atrial fibrillation (AT/AF) event recordings. RNRVAS is a common trigger for AMS because all the atrial events or intervals are used to calculate the filtered atrial rate interval (FARI). Once AMS is initiated, it will also effectively stop RNRVAS because entry into AMS also shortens the postventricular atrial refractory period (PVARP). Recent design developments to eliminate or minimize unusual upper rare responses include the following: (1) P waves in the PVARP are no longer counted towards the FARI if they are followed by an atrial paced event. (2) In new devices the AT/AF detection algorithm substitutes the Moving Average Interval (a relatively complex calculation) with the new FARI average. (3) Improved design of the rate responsive PVARP with a far more aggressive response than in the past (enhanced atrial protection interval). PMID- 28660475 TI - Eating Disorders and Disordered Weight and Shape Control Behaviors in Sexual Minority Populations. AB - PURPOSE OF REVIEW: This review summarized trends and key findings from empirical studies conducted between 2011 and 2017 regarding eating disorders and disordered weight and shape control behaviors among lesbian, gay, bisexual, and other sexual minority (i.e., non-heterosexual) populations. RECENT FINDINGS: Recent research has examined disparities through sociocultural and minority stress approaches. Sexual minorities continue to demonstrate higher rates of disordered eating; disparities are more pronounced among males. Emerging data indicates elevated risk for disordered eating pathology among sexual minorities who are transgender or ethnic minorities. Dissonance-based eating disorder prevention programs may hold promise for sexual minority males. Continued research must examine the intersections of sexual orientation, gender, and ethnic identities, given emergent data that eating disorder risk may be most prominent among specific subgroups. More research is needed within sexual minorities across the lifespan. There is still a lack of eating disorder treatment and prevention studies for sexual minorities. PMID- 28660477 TI - Correlation of serum metal ion levels with pathological changes of ARMD in failed metal-on-metal-hip-resurfacing arthroplasties. AB - BACKGROUND: Metal-on-metal-hip-resurfacing arthroplasties (MoMHRAs) have been associated with an increased failure rates due to an adverse-response-to-metal debris (ARMD) associated with a spectrum of pathological features. Serum levels of cobalt (Co) and chromium (Cr) are used to assess MoMHRAs, with regard to ARMD, but it is not certain whether ion levels correlate with pathological changes in periprosthetic tissues. METHODS: Serum Co and Cr levels were correlated with histological findings in 38 revised MoMHRAs (29 pseudotumour cases and 9 non pseudotumour cases revised for pain). The extent of necrosis and macrophage infiltrate as well as the aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) response was assessed semi-quantitatively; the prosthesis linear wear rate (PLWR) was also determined in ten cases. RESULTS: Cr levels were elevated in 82% and Co levels elevated in 53% of cases; the PLWR correlated with Cr level (rho = 0.8, p = 0.006). Tissue necrosis and macrophage infiltration were noted in all, most of which also exhibited significant ALVAL. Although a discrete correlation was not seen between Co and/or Cr ion levels and the extent of necrosis, degree of macrophage infiltration, or ALVAL score, it was noted that cases with acceptable metal ions levels had high ALVAL score. CONCLUSION: Histological features of both innate and adaptive immune response to metal wear are seen in periprosthetic tissues in cases with both elevated and non-elevated metal ion levels. MoMHRA failures with acceptable ion levels exhibited a pronounced ALVAL response. Although metal ion levels are elevated in most cases of MoMHRA failure due to ARMD, the finding of a normal metal ion level does not exclude this diagnosis. PMID- 28660479 TI - Nerve Growth Factor Antagonists: Is the Future of Monoclonal Antibodies Becoming Clearer? AB - Although there is an unmet need for pain medications that are both effective and safe, virtually no novel analgesics have been approved over the past two decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the clinical development of humanised anti-nerve growth factor monoclonal antibodies (anti-NGF mAbs) aroused particular interest. However, the US Food and Drug Administration (FDA) placed a clinical hold on anti-NGF mAb clinical studies in late 2010, first because of reports of serious joint-related adverse events, and afterwards because of sympathetic nervous system safety concerns. The development programmes of tanezumab and fasinumab resumed after the FDA lifted its hold in March 2015, whereas other anti-NGF mAbs were dropped by their sponsors. This article provides an updated review on the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies and public information from websites, and discusses the possible future role of these agents in managing chronic pain. The efficacy of anti-NGF mAbs was highly variable depending on the chronic pain condition studied. The most consistent and convincing results were obtained in patients with symptomatic osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain and peripheral neuropathic pain generated mixed results. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in cancer pain and urological chronic pelvic pain syndromes. Treatment-emergent adverse events were similar across anti-NGF mAbs, thus being suggestive of 'class-specific effects'. Although most patients tolerated anti-NGF agents well, neurosensory symptoms occurred frequently, and some patients developed new or worsened peripheral neuropathies. However, the most problematic safety issue was rapidly destructive arthropathies, leading to joint replacement surgery. To date, the aetiologies of joint-related side effects and their pathophysiology have not been clearly elucidated. However, some risk factors have been identified, such as higher doses of anti-NGF mAbs and longer drug exposure, concurrent nonsteroidal anti inflammatory drug use and pre-existing subchondral insufficiency fractures. Taken together, the present data suggest that low-dose anti-NGF mABs may exhibit a favourable risk-benefit ratio in selected patients with certain chronic pain conditions, especially symptomatic osteoarthritis. PMID- 28660478 TI - Drugs in Development for Hepatitis B. AB - With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions. Included among the DAAs being developed are RNA interference therapies, covalently closed circular DNA (cccDNA) formation and transcription inhibitors, core/capsid inhibitors, reverse transcriptase inhibitors, hepatitis B surface antigen (HBsAg) release inhibitors, antisense oligonucleotides, and helioxanthin analogues. Included among the host-targeting agents are entry inhibitors, cyclophilin inhibitors, and multiple immunomodulatory agents, including Toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and several cytokine agents, including recombinant human interleukin-7 (CYT107) and SB 9200, a novel therapy that is believed to both have direct antiviral properties and to induce endogenous interferon. In this review we discuss agents that are currently in the clinical stage of development for CHB treatment as well as strategies and agents currently at the evaluation and discovery phase and potential future targets. Effective approaches to CHB may require suppression of viral replication combined with one or more host-targeting agents. Some of the recent research advances have led to the hope that with such a combined approach we may have a functional cure for CHB in the not distant future. PMID- 28660481 TI - A Dialogic Vaccine to Bridge Opposing Cultural Viewpoints Based on Bakhtin's Views on Dialogue and Estrangement. AB - Today, we face global conflicts between opposing ideologies that may be described in terms of cultural viewpoints and value judgments. It is difficult for individuals to determine whether ideologies are right or wrong because each ideology has its own worldview and sense of justice. Psychologists have an urgent mission to defuse the likelihood of fatal clashes between opposing cultural perspectives (ideologies), and to propose paradigms for peaceful coexistence. This paper examines the series of papers (Oh, Integrative Psychological and Behavioral Science, 51, 2017; Sakakibara, Integrative Psychological and Behavioral Science, 51, 2017; Watanabe, Integrative Psychological & Behavioral Science, 51, 2017) contributed to this volume that investigate the effects of high school and university educational programs promoting productive dialogue aimed at bridging, or transcending, conflicting perspectives among Japanese, Chinese, and Korean students. Here, I have evaluated the capacity of these educational programs to coordinate opposing cultural ideologies using the framework of Bakhtin's theories of dialogue and estrangement. Bakhtin viewed discourse with others who had opposing viewpoints as an opportunity to learn to overcome the one-sidedness of ideology, which ensues from automatic value judgments made by each speaker according to their culture, and he affirmed the value of flexible attitudes toward opposing viewpoints. In this paper, I review Bakhtin's theories relating to communication in a context of different cultural viewpoints, assess the general values of the educational practices mentioned above, and propose new concepts for applying these methods to other educational fields in the future using Bakhtin's theoretical viewpoints. PMID- 28660480 TI - Dendritic cell-based immunotherapy: a basic review and recent advances. AB - Dendritic cells (DCs) are considered a very promising arm to activate the immune system in immunotherapeutic strategies against cancer. DCs are the most powerful antigen-presenting cells (APCs), being highly efficient at generating robust immune responses. They are also considered the center of the immune system, since they provide a crucial link between both innate and adaptive immune responses. Thus, DC-based cancer immunotherapy aims to take advantage of these unique characteristics of DCs to better fight cancer. During the last decade, they have been the subject of numerous studies intending to develop immunotherapeutic strategies against cancer through vaccination. For this purpose, it is essential to gain a better insight into DC immunobiology, regulation of innate and adaptive immune systems, and tumor microenvironment, as well as applying the latest advances in science in order to boost their enormous anti-tumor immunotherapeutic potential. In this review, we will hold focus on DC immunobiology (from their origin, location, and special properties and distinct subsets to the innate and adaptive immunity), on the new concept of cancer immunoediting, and on the knowledge given by clinical trials using DC vaccines. Finally, future perspectives for this emerging field are highlighted. PMID- 28660482 TI - Efficacy of tyrosine kinase inhibitors in EGFR-mutant lung cancer women in a real world setting: the WORLD07 database. AB - BACKGROUND: The WORLD07 project is a female specific database to assess the characteristics of women with lung cancer. METHODS: WORLD07 database sets up in 2007, and prospectively stores clinical characteristics, treatment, outcome, and follow-up of lung cancer women. All women with epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) were selected for this analysis. RESULTS: From October 2007 to December 2012, a total of 1775 NSCLC women were recruited. EGFR mutation was identified in 34.4% of patients. Upfront EGFR tyrosine kinase inhibitor (TKI) reported a response rate of 60%, a median progression-free survival of 11.7 months, and median overall survival of 23.0 months. EGFR TKI, EGFR-mutation type, and smoking status did not impact in the outcome of treated women. CONCLUSION: Prevalence of EGFR mutation in women with NSCLC is higher than overall population with NSCLC. Efficacy of EGFR TKI in this real-world setting is similar to that previously reported. PMID- 28660483 TI - Erratum to: Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke. PMID- 28660485 TI - CRMP2 Phosphorylation Drives Glioblastoma Cell Proliferation. AB - Glioblastoma (GBM) is an aggressive primary brain tumor. The rapid growth and the privileged provenance of the tumor within the brain contribute to its aggressivity and poor therapeutic targeting. A poor prognostic factor in glioblastoma is the deletion or mutation of the Nf1 gene. This gene codes for the protein neurofibromin, a tumor suppressor gene that is known to interact with the collapsin response mediator protein 2 (CRMP2). CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 have recently been implicated in cancer progression. The CRMP2-neurofibromin interaction protects CRMP2 from its phosphorylation by cyclin-dependent kinase 5 (Cdk5), an event linked to cancer progression. In three human glioblastoma cell lines (GL15, A172, and U87), we observed an inverse correlation between neurofibromin expression and CRMP2 phosphorylation levels. Glioblastoma cell proliferation was dependent on CRMP2 expression and phosphorylation by Cdk5 and glycogen synthase kinase 3 beta (GSK3beta). The CRMP2 phosphorylation inhibitor (S)-lacosamide reduces, in a concentration-dependent manner, glioblastoma cell proliferation and induced apoptosis in all three GBM cell lines tested. Since (S)-lacosamide is bioavailable in the brain, we tested its utility in an in vivo orthotopic model of GBM using GL261-LucNeo glioma cells. (S)-lacosamide decreased tumor size, as measured via in vivo bioluminescence imaging, by ~54% compared to vehicle control. Our results introduce CRMP2 expression and phosphorylation as a novel player in GBM proliferation and survival, which is enhanced by loss of Nf1. PMID- 28660484 TI - Therapeutic Strategies for Leukodystrophic Disorders Resulting from Perinatal Asphyxia: Focus on Myelinating Oligodendrocytes. AB - Perinatal asphyxia results from the action of different risk factors like complications during pregnancy, preterm delivery, or long and difficult labor. Nowadays, it is still the leading cause of neonatal brain injury known as hypoxic ischemic encephalopathy (HIE) and resulting neurological disorders. A temporal limitation of oxygen, glucose, and trophic factors supply results in alteration of neural cell differentiation and functioning and/or leads to their death. Among the affected cells are oligodendrocytes, responsible for myelinating the central nervous system (CNS) and formation of white matter. Therefore, one of the major consequences of the experienced HIE is leukodystrophic diseases resulting from oligodendrocyte deficiency or malfunctioning. The therapeutic strategies applied after perinatal asphyxia are aimed at reducing brain damage and promoting the endogenous neuroreparative mechanisms. In this review, we focus on the biology of oligodendrocytes and discuss present clinical treatments in the context of their efficiency in preserving white matter structure and preventing cognitive and behavioral deficits after perinatal asphyxia. PMID- 28660487 TI - Erratum to: Effectiveness and Safety of CT-P13 (Biosimilar Infliximab) in Patients with Inflammatory Bowel Disease in Real Life at 6 Months. PMID- 28660486 TI - Hutchinson-Gilford Progeria Syndrome: A Premature Aging Disease. AB - Progeria is sporadic, very rare, autosomal dominant, deadly childhood disorder. It is one of the progeroid syndromes also known as Hutchinson-Gilford progeria syndrome (HGPS). Aging is a developmental process that begins with fertilization and ends up with death involving a lot of environmental and genetic factors. The disease firstly involves premature aging and then death from complications of atherosclerosis such as myocardial infarction, stroke, atherosclerosis, or heart failure. The lifespan of the patient is normally up to teen age or early twenties. It is usually not inherited because a patient normally dies before the age of reproduction. The most important genetic linkage between progeria and aging is shortening of telomere ends with each replication cycle. The patients are normally observed to have extremely short telomeres. Currently, 90% of the patients are said to have de novo point mutations in the LMNA gene that substitute cytosine with thymine and have been found in individuals with HGPS. Lmna encodes lamins A and C, and the A-type lamins have important structural function in the nuclear envelope. The most common type of HGPS mutation is located at codon 608 (G608G). It could not be diagnosed at birth, but after the age of 2 years, visible, prominent symptoms can be observed. Still, lot of research is needed to solve this mystery; hopefully, future research on HGPS would provide important clues for progeria and other fatal age-related disorders. PMID- 28660488 TI - Patient-Reported Outcome Measures in Routine Clinical Care: The PROMise of a Better Future? PMID- 28660489 TI - Novel Approach to Fecal Occult Blood Testing by Assay of Erythrocyte-Specific microRNA Markers. AB - BACKGROUND: Fecal occult blood testing (FOBT) has historically relied on methods to detect hemoglobin with no fundamental innovations in decades. AIM: To examine microRNA (miRNA) as a new marker class for FOBT. METHODS: Candidate miRNA markers were identified by small RNA sequencing of human whole blood compared to colorectal epithelia. Markers were tested in human blood cell subsets and blood from non-human species. We assessed assay linearity in blood spiking and marker stability in stool over incubation experiments. Levels of candidate erythrocyte markers were explored in stools from colorectal cancer (CRC) cases and controls. RESULTS: Based on small RNA sequencing and validation RT-qPCR, expression level of each of the top blood-enriched markers (hsa-miR-144-3p, 144-5p, 451a, 486-5p, 363-3p, 20b-5p) could perfectly discriminate blood from colorectal epithelia. All six markers arose from and showed specificity to human erythrocytes. Marker levels increased linearly with erythrocyte concentration in saline or stool and demonstrated a broader dynamic range than did immunochemical test for hemoglobin. Degradation of markers occurred in stool but was reduced with preservative buffers. Erythrocyte marker candidates for stool testing were selected in an exploratory set of stools (20 CRC, 40 normal). Candidates were then further tested in a feasibility set (29 CRC, 31 advanced adenoma, and 115 normal); a miRNA panel (hsa-miR-451a, 144-5p, and 200b-3p as normalizer) yielded an AUC of 0.89 (95% CI 0.82-0.95, P < .0001) for CRC. CONCLUSIONS: A novel miRNA-based approach accurately quantifies fecal blood levels over a broad, clinically relevant range. PMID- 28660490 TI - Arjunolic Acid Improves the Serum Level of Vitamin B12 and Folate in the Process of the Attenuation of Arsenic Induced Uterine Oxidative Stress. AB - Continuation of prolonged treatment against arsenicosis with conventional chelating therapy is a global challenge. The present study was intended to evaluate the defensive effect of arjunolic acid against arsenic-induced oxidative stress and female reproductive dysfunction. Wistar strain adult female rats were given sodium arsenite (10 mg/kg body weight) in combination with arjunolic acid (10 mg/kg body weight) orally for two estrous cycles. Electrozymographic analysis explored that arjunolic acid co-treatment counteracted As3+-induced ROS production in uterine tissue by stimulating the activities of endogenous enzymatic antioxidants. Arjunolic acid was able to enhance the protection against mutagenic uterine DNA breakage, necrosis, and ovarian-uterine tissue damages in arsenicated rats by improving the ovarian steroidogenesis. The mechanisms might be coupled with the augmentation of antioxidant defense system, partly through the elimination of arsenic with the involvement of S-adenosyl methionine pool where circulating levels of vitamin B12, folic acid, and homocysteine play critical roles as evidenced from our present investigation. PMID- 28660491 TI - The role of structured education in the management of hypoglycaemia. AB - The role of intensive glycaemic control in preventing microvascular disease in diabetes is well established. Iatrogenic hypoglycaemia is, however, a major barrier to effective treatment. Hypoglycaemia is associated with a significant level of morbidity and, despite pharmacological and technological therapeutic advances, reported rates of severe hypoglycaemia in clinical practice have not fallen over the last 20 years. This suggests that human factors are of major relevance and that ensuring the effective self-management of diabetes is an important strategy for the reduction of hypoglycaemic risk. Most of the evidence for the impact of this strategy on hypoglycaemia risk is confined to adults with type 1 diabetes although, in this review, we also cite studies that have specifically addressed this in type 2 diabetes. There are relatively few adequately powered RCTs that have rigorously evaluated the effectiveness of structured education and training programmes on hypoglycaemia; however, the available data suggest a subsequent reduction in severe hypoglycaemia rates of around 50%, a rate reduction that is comparable with that observed following technological interventions. Furthermore, longitudinal observational cohorts support these data, showing similar reductions in rates of hypoglycaemia following structured education. Those who continue to experience recurrent hypoglycaemia and impaired awareness of hypoglycaemia despite education and training in diabetes self-management may benefit from technological interventions and/or interventions that specifically address psychological factors that contribute to hypoglycaemia risk; however, there is urgent need for further research in this area. In the meantime, structured education for effective self management of diabetes should be part of routine therapy for all those with type 1 diabetes. PMID- 28660492 TI - Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice. AB - AIMS/HYPOTHESIS: Obesity is associated with glucose intolerance and insulin resistance and is closely linked to the increasing prevalence of type 2 diabetes. In mouse models of diet-induced obesity (DIO) and type 2 diabetes, an increased fat intake results in adipose tissue expansion and the secretion of proinflammatory cytokines. The innate immune system not only plays a crucial role in obesity-associated chronic low-grade inflammation but it is also proposed to play a role in modulating energy metabolism. However, little is known about how the modulation of metabolism by the immune system may promote increased adiposity in the early stages of increased dietary intake. Here we aimed to define the role of type I IFNs in DIO and insulin resistance. METHODS: Mice lacking the receptor for IFN-alpha (IFNAR-/-) and deficient in plasmacytoid dendritic cells (pDCs) (B6.E2-2 fl/fl .Itgax-cre) were fed a diet with a high fat content or normal chow. The mice were analysed in vivo and in vitro using cellular, biochemical and molecular approaches. RESULTS: We found that the development of obesity was inhibited by an inability to respond to type I IFNs. Furthermore, the development of obesity and insulin resistance in this model was associated with pDC recruitment to the fatty tissues and liver of obese mice (a 4.3-fold and 2.7-fold increase, respectively). Finally, we demonstrated that the depletion of pDCs protects mice from DIO and from developing obesity-associated metabolic complications. CONCLUSIONS/INTERPRETATION: Our results provide genetic evidence that pDCs, via type I IFNs, regulate energy metabolism and promote the development of obesity. PMID- 28660493 TI - Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study. AB - AIMS/HYPOTHESIS: Recent European guidelines for non-alcoholic fatty liver disease (NAFLD) call for reference values for HOMA-IR. In this study, we aimed to determine: (1) the upper limit of normal HOMA-IR in two population-based cohorts; (2) the HOMA-IR corresponding to NAFLD; (3) the effect of sex and PNPLA3 genotype at rs738409 on HOMA-IR; and (4) inter-laboratory variations in HOMA-IR. METHODS: We identified healthy individuals in two population-based cohorts (FINRISK 2007 [n = 5024] and the Programme for Prevention of Type 2 Diabetes in Finland [FIN D2D; n = 2849]) to define the upper 95th percentile of HOMA-IR. Non-obese individuals with normal fasting glucose levels, no excessive alcohol use, no known diseases and no use of any drugs were considered healthy. The optimal HOMA IR cut-off for NAFLD (liver fat >=5.56%, based on the Dallas Heart Study) was determined in 368 non-diabetic individuals (35% with NAFLD), whose liver fat was measured using proton magnetic resonance spectroscopy (1H-MRS). Samples from ten individuals were simultaneously analysed for HOMA-IR in seven European laboratories. RESULTS: The upper 95th percentiles of HOMA-IR were 1.9 and 2.0 in healthy individuals in the FINRISK (n = 1167) and FIN-D2D (n = 459) cohorts. Sex or PNPLA3 genotype did not influence these values. The optimal HOMA-IR cut-off for NAFLD was 1.9 (sensitivity 87%, specificity 79%). A HOMA-IR of 2.0 corresponded to normal liver fat (<5.56% on 1H-MRS) in linear regression analysis. The 2.0 HOMA-IR measured in Helsinki corresponded to 1.3, 1.6, 1.8, 1.8, 2.0 and 2.1 in six other laboratories. The inter-laboratory CV% of HOMA-IR was 25% due to inter-assay variation in insulin (25%) rather than glucose (5%) measurements. CONCLUSIONS/INTERPRETATION: The upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat. Standardisation of insulin assays would be the first step towards definition of normal values for HOMA-IR. PMID- 28660496 TI - Role of Cost on Failure to Access Prescribed Pharmaceuticals: The Case of Statins. AB - BACKGROUND: In Australia, as in many other Western countries, patient surveys suggest the costs of medicines lead to deferring or avoiding filling of prescriptions. The Australian Pharmaceutical Benefits Scheme provides approved prescription medicines at subsidised prices with relatively low patient co payments. The Pharmaceutical Benefits Scheme defines patient co-payment levels per script depending on whether patients are "concessional" (holding prescribed pension or other government concession cards) or "general", and whether they have reached a safety net defined by total out-of-pocket costs for Pharmaceutical Benefits Scheme-approved medicines. OBJECTIVE: The purpose of this study was to explore the impact of costs on adherence to statins in this relatively low-cost environment. METHODS: Using data from a large-scale survey of older Australians in the state of New South Wales linked to administrative data from the national medical and pharmaceutical insurance schemes, we explore the relationships between adherence to medication regimes for statins and out-of-pocket costs of prescribed pharmaceuticals, income, other health costs, and a wide set of demographic and socio-economic control variables using both descriptive analysis and logistic regressions. RESULTS: Within the general non-safety net group, which has the highest co-payment, those with lowest income have the lowest adherence, suggesting that the general safety threshold may be set at a level that forms a major barrier to statin adherence. This is reinforced by over 75% of those who were not adherent before reaching the safety net threshold becoming adherent after reaching the safety net with its lower co-payments. CONCLUSION: The main financial determinant of adherence is the concessional/general and safety net category of the patient, which means the main determinant is the level of co payment. PMID- 28660495 TI - Determinants of bone mineral density in young Australian women; results from the Safe-D study. AB - : The study aimed to explore determinants of bone parameters in young women. Most bone parameters were associated with height and lean mass. Bone parameters were not associated with vitamin D status. Future research should address whether interventions aimed at improving lean mass are beneficial to bone health in young women. INTRODUCTION: The implementation of prevention strategies during young adulthood may be crucial for osteoporosis prevention in later life, yet literature examining the determinants of bone health in premenopausal women is limited. We aimed to assess determinants of bone health, including serum 25 hydroxyvitamin D (25OHD), in females aged 16-25 years, living in Victoria, Australia, recruited through Facebook advertising. METHODS: Serum 25OHD was measured by liquid chromatography-tandem mass spectrometry and bone health was measured using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) in 326 participants. RESULTS: Mean (+/- standard deviation) serum 25OHD was 69 +/- 28 nmol/L and the prevalence of vitamin D deficiency (serum 25OHD <50 nmol/L) was 26%. Seven percent of participants (n = 23) reported taking a vitamin D supplement. Two percent of participants had low lumbar spine bone mineral density (Z-score <-2.0), 5% at the hip and 7% at the femoral neck. Serum 25OHD levels were not associated with DXA bone parameters, nor with pQCT bone parameters. Most bone parameters were positively associated with height and lean mass. CONCLUSION: Vitamin D status was not associated with bone health in young women in the current study. Our findings suggest that targeting other modifiable factors, such as lean body mass, is likely to be beneficial to bone health in young women. Longitudinal studies examining the association between vitamin D status and bone health in young women are necessary to confirm our findings. In addition, whether raising 25OHD levels is advantageous for young women's bone health is yet to be determined. PMID- 28660497 TI - McArdle disease: a "pediatric" disorder presenting in an adult with acute kidney injury. AB - Rhabdomyolysis is characterized by the acute breakdown of skeletal muscle, resulting in the release of muscle cell contents, subsequent myoglobinuria, and in severe cases, acute renal failure. A number of etiologies have been identified in acute rhabdomyolysis, in which drugs and trauma account for the majority of cases. One etiological category that is commonly overlooked in the adult population is an underlying genetic defect. This may be challenging to diagnose due to its rarity in the adult demographic and the marked heterogeneity, often requiring a high level of clinical suspicion before investigation is pursued. Once diagnosed, however, appropriate steps can be taken to reduce future episodes of rhabdomyolysis, further renal injury, and other systemic complications. Here, we report a case of an adult patient presenting with acute rhabdomyolysis secondary to McArdle disease, a genetic disease causing defective glycogenolysis. The case highlights the importance of recognizing the potential of undiagnosed "pediatric" disorders in adulthood and particularly for underlying genetic causes of rhabdomyolysis. PMID- 28660498 TI - Effect of Degarelix, a Gonadotropin-Releasing Hormone Receptor Antagonist for the Treatment of Prostate Cancer, on Cardiac Repolarisation in a Randomised, Placebo and Active Comparator Controlled Thorough QT/QTc Trial in Healthy Men. AB - BACKGROUND AND OBJECTIVES: Degarelix is a gonadotropin-releasing hormone antagonist registered for the treatment of advanced hormone-dependent prostate cancer. Treatment causing androgen deprivation is associated with QT prolongation and this study investigated whether degarelix at supratherapeutic concentrations has an intrinsic effect per se on cardiac repolarisation and the QT interval. METHODS: This was a single-centre, randomised, crossover study comparing the effect of degarelix, placebo, and the positive control moxifloxacin on the QT interval. Degarelix and placebo treatments were double-blind, whereas moxifloxacin treatment was open-label. Eighty healthy men, aged 18-45 years, received single intravenous doses of degarelix 2.8 mg, and placebo, as well as a single oral dose of moxifloxacin 400 mg. Electrocardiograms were collected up to 24 h after the start of administration, with the QT interval assessed and plasma concentrations of degarelix concomitantly analysed. RESULTS: Time-matched, one sided 95% upper confidence boundaries for baseline-corrected average changes from placebo for the QT interval, corrected using the Fridericia method (DeltaDeltaQTcF), did not exceed 10 ms at any timepoint, with maximum degarelix concentrations reaching approximately threefold the concentrations seen in the treatment of prostate cancer. Furthermore, concentration-exposure analysis indicated absence of any QT prolongation effects of degarelix. No significant effect on any other cardiac parameter was observed. The lower bound of the 98.3% confidence interval for moxifloxacin DeltaDeltaQTcF exceeded 5 ms, thus verifying assay sensitivity. CONCLUSION: The results showed that the study was validated to detect a significant effect on the QT interval, and that degarelix by itself does not have any effect on the QT interval and cardiac repolarisation at supratherapeutic concentrations. PMID- 28660499 TI - Good Intentions, But What About Unintended Consequences? PMID- 28660500 TI - Surface Acoustic Wave Nebulisation Mass Spectrometry for the Fast and Highly Sensitive Characterisation of Synthetic Dyes in Textile Samples. AB - Surface acoustic wave nebulisation (SAWN) mass spectrometry (MS) is a method to generate gaseous ions compatible with direct MS of minute samples at femtomole sensitivity. To perform SAWN, acoustic waves are propagated through a LiNbO3 sampling chip, and are conducted to the liquid sample, which ultimately leads to the generation of a fine mist containing droplets of nanometre to micrometre diameter. Through fission and evaporation, the droplets undergo a phase change from liquid to gaseous analyte ions in a non-destructive manner. We have developed SAWN technology for the characterisation of organic colourants in textiles. It generates electrospray-ionisation-like ions in a non-destructive manner during ionisation, as can be observed by the unmodified chemical structure. The sample size is decreased by tenfold to 1000-fold when compared with currently used liquid chromatography-MS methods, with equal or better sensitivity. This work underscores SAWN-MS as an ideal tool for molecular analysis of art objects as it is non-destructive, is rapid, involves minimally invasive sampling and is more sensitive than current MS-based methods. Graphical Abstract ?. PMID- 28660501 TI - The anti-Mullerian hormone (AMH) induces forkhead box L2 (FOXL2) expression in primary culture of human granulosa cells in vitro. AB - PURPOSE: Anti-Mullerian hormone (AMH) and forkhead box L2 (FOXL2) are two pivotal genes expressed in human granulosa cells (hGCs) where both genes share similar inhibitory functions on activation and follicular growth in order to preserve the ovarian follicle reserve. Furthermore, AMH and FOXL2 contribute to inhibit steroidogenesis, decreasing or preventing the activation of gonadotrophin dependent aromatase CYP19A1 cytochrome P450 family 19 subfamily A member 1 (CYP19A1). The purpose of this study is to evaluate the role of AMH in regulating the expression of FOXL2. METHODS: Primary cultures of hGCs were treated with increasing concentrations of recombinant human AMH (rhAMH; range 10-100 ng/ml) for 3 h. Negative controls were performed using corresponding amounts of AMH vehicle. Total RNA or proteins were purified and quantified by spectrophotometry. FOXL2 and CYP19A1 gene expression, normalized by reference gene ribosomal protein S7 (RpS7), was evaluated by RT-qPCR. Each reaction was repeated in triplicate. Statistical analysis was performed. Extracted proteins were analyzed by immunoblot using anti-FOXL2 and anti-beta-actin as primary antibodies. RESULTS: rhAMH treatments tested did not modulate the basal expression of aromatase CYP19A1 gene. rhAMH (50 ng/ml) was able to increase FOXL2 gene expression and its intracellular content. CONCLUSIONS: This study demonstrated the existence of an AMH-FOXL2 relationship in hGCs. AMH is capable of increasing both gene and protein expression of FOXL2. Because FOXL2 induces AMH transcription, these ovarian factors could be finely regulated by a positive feedback loop mechanism to preserve the ovarian follicle reserve. PMID- 28660502 TI - Down-regulation of PARP1 by miR-891b sensitizes human breast cancer cells to alkylating chemotherapeutic drugs. AB - PURPOSE: Breast cancer is the most common invasive type of cancer among women. Role of different microRNAs (miRNAs) and poly(ADP-ribose) polymerases (PARPs) in breast cancer has been well established. This study aimed to explore the effects of miR-891b on sensitizing breast cancer cells to alkylating chemotherapeutic drugs through PARPs. METHODS: The expression of miR-891b and PARP1 in human breast cancer cells HCC1806 was overexpressed by transfection with their mimics or expressing vector. Then, the transfected cells were exposed to 40 uM N-methyl N-nitro-N-nitrosoguanidine (MNNG) for 1 h. The correlation between miR-891b and PARP1 was detected by RT-qPCR, western blot, and dual-luciferase reporter assay. Besides, MTT assay and Annexin V assay were done to measure cell proliferation and apoptosis, respectively. RESULTS: PARP1 was a target of miR-891b, and it was negatively regulated by miR-891b. MiR-891b increased the sensitivity of the HCC1806 cells to the cytotoxic effects of MNNG through suppressing cell proliferation and increasing the percentage of apoptotic cells. Restoration of PARP1 activity in the HCC1806 cells led to loss of miR-891b mediated sensitivity of the HCC1806 cells to MNNG. CONCLUSION: MiR-891b increases the sensitivity of the breast cancer cells (HCC1806) to the cytotoxic effects of the chemotherapeutic agent MNNG by suppressing the expression of PARP1. PMID- 28660503 TI - Controllable synthesis Fe3O4@POHABA core-shell nanostructure as high-performance recyclable bifunctional magnetic antimicrobial agent. AB - We demonstrated a method to form magnetic antimicrobial POHABA (poly-N,N'-[(4,5 dihydroxy-1,2-phenylene)bis(methylene)]bisacrylamide)-based core-shell nanostructure by free-radical polymerization of OHABA on the Fe3O4 core surface. The magnetic antimicrobial agent Fe3O4@POHABA can be used in domestic water treatment against bacterial pathogens. The thickness of POHABA shell could be controlled from 10.4 +/- 1.2 to 56.3 +/- 11.7 nm by the dosage of OHABA. The results of antimicrobial-activity test indicated that POHABA-based core-shell nanostructure had broad-spectrum inhibitory against Gram-negative, Gram-positive bacteria and fungi. The minimum inhibitory concentration (MIC) values of Fe3O4@POHABA nanostructure against Escherichia coli and Bacillus subtilis were both 0.4 mg/mL. Fe3O4@POHABA nanostructures responded to a permanent magnet and were easily recycled. Fe3O4@POHABA nanoparticles retained 100% antimicrobial efficiency for both Gram-negative and Gram-positive bacteria throughout eight recycle procedures. PMID- 28660505 TI - De novo formation of dioxins from milled model fly ash. AB - Municipal solid waste incineration (MSWI) fly ash has been classified as hazardous waste and needs treatment in an environmentally safe manner. Mechanochemical (MC) treatment is such a detoxification method, since it destroys dioxins and solidifies heavy metals. Milling, however, also introduces supplemental metals (Fe, Ni, Cr, Mn...), following wear of both steel balls and housing. Milling moreover reduces the particle size of fly ash and disperses catalytic metal, potentially rising the reactivity of fly ash to form and destroy 'dioxins', i.e. polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD + PCDF or PCDD/F). To test this issue, model fly ash (MFA) samples were composed by mixing of silica, sodium chloride, and activated carbon, and doped with CuCl2. Then, these samples were first finely milled without any additives for 0 h (original sample), 1 h and 8 h, and the effect of milling time (and hence particle size) was investigated on the formation of polycyclic aromatic hydrocarbons (PAHs), and of polychlorinated phenols (CP), benzenes (CBz), biphenyls (PCB) and dioxins (PCDD + PCDF) during de novo tests at 300 degrees C for 1 h, thus simulating the conditions prevailing in the post-combustion zone of an incinerator, where dioxins are formed and destroyed. These compounds are all characterized by their rate of generation (ng/g MFA) and their signature, i.e. internal distribution over congeners as a means of gathering mechanistic indications. PAH and CBz total yield did not decrease in MC treated MFA with milling time, while total pentachlorophenol (PeCP), PCB and PCDD/F yield decreased up to 86, 94 and 97%, respectively. International Toxic Equivalents (I TEQ) concentration decreased more than 90%, while degree of chlorination varied inconsistently for PCB and PCDD/F, and average congener patterns of PCDD/F do not vary considerably with milling time for both gas and solid phase. PMID- 28660504 TI - Distribution of six anticancer drugs and a variety of other pharmaceuticals, and their sorption onto sediments, in an urban Japanese river. AB - The distributions of 31 pharmaceuticals grouped into nine therapeutic classes, including six anticancer drugs, were investigated in the waters and sediments of an urban river in Japan. The coefficients of sorption (logK d) to the river sediments were also determined from the results of a field survey and laboratory scale experiment. Three anticancer drugs-bicalutamide, doxifluridine, and tamoxifen-were detected in the river sediments at maximum concentrations of 391, 392, and 250 ng/kg, respectively. In addition, the transformation products of psychotropic carbamazepine (2-hydroxy carbamazepine, acridine, and acridone) were detected in the range of 108 ng/kg (2-hydroxy carbamazepine) to 2365 ng/kg (acridine), and the phytoestrogen glycitein was detected in the range of N.D. to 821 ng/kg. The logK d values of the targeted pharmaceuticals in river sediments in the field survey ranged from 0.5 (theophylline) to 3.3 (azithromycin). These results were in accord with those of the laboratory-scale sorption experiment. To the best of our knowledge, this is the first report of the detection of the anticancer drugs bicalutamide and tamoxifen, the transformation products of carbamazepine (2-hydroxy carbamazepine, acridine, and acridone), and the phytoestrogen genistein in river sediments. PMID- 28660506 TI - Remote estimation of cyanobacterial blooms using the risky grade index (RGI) and coverage area index (CAI): a case study in the Three Gorges Reservoir, China. AB - Harmful cyanobacterial blooms are exemplified as a major environmental concern due to producing toxin, and have generated a serious threat to public health. Knowledge on the spatial-temporal distribution of cyanobacterial blooms is therefore crucial for public health organizations and environmental agencies. In this study, field data and charge coupled device (CCD) image were collected in Lakes Gaoyang and Hanfeng of the Three Gorges Reservoir (TGR), China. We conducted the risky grade index (RGI) and coverage area index to develop a feasible estimation framework of cyanobacterial blooms. First, the close relationships between CCD reflectance spectral indices and water quality parameters were constructed based on water optical classification. Then, a regional algorithm for the RGI classification was established by density peaks. Finally, our proposed algorithm was applied to investigate dynamics of cyanobacterial blooms in the two lakes from 6-year series of CCD images. Encouraging results demonstrated that satellite remote sensing in conjunction with field observation can aid in the estimation of cyanobacterial blooms in the TGR. PMID- 28660507 TI - Raw sugarcane bagasse as carbon source for xylanase production by Paenibacillus species: a potential degrader of agricultural wastes. AB - Paenibacillus species isolated from a variety of natural sources have shown to be important glycoside hydrolases producers. These enzymes play a key role in bio refining applications, as they are central biocatalysts for the processing of different types of polymers from vegetal biomass. Xylanase production by three native isolates belonging to the genus Paenibacillus was approached by utilizing mineral-based medium and agricultural by-products as a convenient source to produce biocatalysts suitable for their degradation. While varieties of alkali pretreated sugarcane bagasse were useful substrates for the strains from Paenibacillus genus evaluated, raw sugarcane bagasse was the most effective substrate for endoxylanase production by Paenibacillus sp. AR247. This strain was then selected to further improvement of its enzyme production by means of a two step statistical approach. It was determined that the carbon source, provided as an inexpensive agro-waste, as well as phosphate and magnesium were the culture media components that most influenced the enzyme production, which was improved three times compared to the screening results. PMID- 28660508 TI - Sorption specificity and desorption hysteresis of gibberellic acid on ferrihydrite compared to goethite, hematite, montmorillonite, and kaolinite. AB - The pesticide gibberellic acid (GA3) is a potential endocrine disruptor and environmental toxin; therefore, research into its environmental fate is warranted. Batch studies were conducted to investigate the sorption and desorption characteristics of GA3 on aquifer media. The results demonstrated special sorption characteristic of GA3 on ferrihydrite compared to goethite, hematite, montmorillonite, and kaolinite, where the sorption kinetics of GA3 on ferrihydrite was fitted well with the pseudo-second-order, Elovich, and intra particle diffusion models. The sorption kinetics of GA3 on ferrihydrite indicated an initial high sorption rate followed by a slow reaction process. The initial high GA3 sorption rate may be related to electrostatic sorption and surface complexation reactions on the outer surfaces and at the macropore entrances of ferrihydrite. While the slow step was controlled by GA3 diffusion into mesopore of ferrihydrite. Analysis of the desorption hysteresis indicated a high hysteresis index (HI) ranging from 0.68 to 17.32, and a low desorption percentage ranging from 18 to 48%. After sufficient desorption, the calculated maximum residual GA3 quantity due to surface complexation reactions with the ferrihydrite coordinated unsaturated sites was 9.05 +/- 0.12 mg g-1. The calculated maximum quantity of GA3 trapped within the mesopore was 16.23 +/- 0.91 mg g-1. Graphical Abstract Schematic overview of GA3 sorption and desorption on five minerals in groundwater. PMID- 28660509 TI - Pollution-induced community tolerance in benthic macroinvertebrates of a mildly lead-contaminated lake. AB - Pollution-induced community tolerance (PICT) has been used to demonstrate effects of sediment contamination on microbes and meiofauna. Our study explored the potential to detect PICT in benthic macroinvertebrates of a lake with long-term mild lead (Pb) contamination. We collected macrobenthos from two areas in Caddo Lake, Texas, a control area (CO) with a mean sediment Pb level of 11 MUg/g and Goose Prairie (GP) where sediment Pb levels averaged 74 MUg/g. Upon return to the laboratory, we exposed macroinvertebrates to a lethal lead concentration and assessed 48-h mortality. Mortality of CO macrobenthos was significantly higher than that of GP macrobenthos, providing evidence that these communities differed in their tolerance to lead. A comparison of macrobenthos community composition between the areas showed that the GP macrobenthos lacked metal-sensitive taxa such as gastropods and amphipods (which were present at CO). Similarly, a higher proportion of the GP benthos belonged to metal-tolerant taxa such as isopods and chironomids. Thus, changes in community composition appeared to be at least partly responsible for differences in community tolerance. Our results showed that a sediment Pb concentration below effect-based sediment quality guidelines had a measurable impact on macrobenthos, thus demonstrating that results from single-species toxicity tests may underestimate impacts on communities. This study also confirms that the PICT approach with macroinvertebrates is a feasible and potentially powerful approach for detecting contaminant impacts. PMID- 28660511 TI - Environmental Metabolic Footprinting (EMF) vs. half-life: a new and integrative proxy for the discrimination between control and pesticides exposed sediments in order to further characterise pesticides' environmental impact. AB - Pesticides are regularly used for a variety of applications and are disseminated throughout the environment. These substances may have significant negative impacts. To date, the half-life, t1/2, was often used to study the fate of pesticides in environmental matrices (water, soil, sediment). However, this value gives limited information. First, it does not evaluate the formation of by products, resulting in the need for additional experiments to be performed to evaluate biodegradation and biotransformation products. T1/2 also fails to consider the chemical's impact on biodiversity. Resilience time, a new and integrative proxy, was recently proposed as an alternative to t1/2, with the potential to evaluate all the post-application effects of the chemical on the environment. The 'Environmental Metabolic Footprinting' (EMF) approach, giving an idea of the resilience time, was used to evaluate the impact of botanicals on soil. The goal is to optimise the EMF to study the impact of a microbial insecticide, the Bacillus thuringiensis israelensis (Bti), on sediment. The difficulty of this work lies in the commercial solution of Bti that is really complex, and this complexity yields chromatograms that are extremely difficult to interpret; t1/2 cannot be used. No methodologies currently exist to monitor the impact of these compounds on the environment. We will test the EMF to determine if it is sensitive enough to tolerate such complex mixtures. A pure chemical insecticide, the alpha-cypermethrin, will be also studied. The article shows that the EMF is able to distinguish meta-metabolome differences between control and exposed (with Bti) sediments. PMID- 28660510 TI - Taurine mitigates nitrite-induced methemoglobin formation and oxidative damage in human erythrocytes. AB - Nitrite is present as a noxious contaminant in drinking water and causes oxidative damage in various tissues of humans and animals. It is a well-known methemoglobin-forming agent that has been shown to damage blood cells. The protective effect of taurine, a semi-essential sulfur-containing amino acid, was studied on sodium nitrite (NaNO2)-induced oxidative damage in human erythrocytes. Erythrocytes were incubated with NaNO2, in the presence and absence of taurine, and changes in oxidative stress parameters determined. Pretreatment with taurine significantly ameliorated NaNO2-induced oxidative damage to lipids, proteins, and plasma membrane. It also reduced the NaNO2-induced increase in methemoglobin levels and ROS production. Taurine improved the antioxidant capacity of cells, restored the alterations in the activities of various metabolic enzymes, and prevented morphological changes in erythrocytes. Thus, taurine can be potentially used as a protective agent against the damaging effects of nitrite. PMID- 28660512 TI - Transformer oils as a potential source of environmental exposure to polychlorinated biphenyls (PCBs): an assessment in three central provinces of Iran. AB - Polychlorinated biphenyl (PCB) contamination of oils from all transformers of the national electrical grid in Tehran, Qom, and Alborz, three central provinces of Iran, was assessed. The concentration of PCBs in transformer oils was determined by gas chromatography. At the national level, the proportions of transformers with oil PCB contents of <5, 5-49, 50-499, 500-4999, and >5000 ppm were determined to be 85.7, 12.4, 1.6, 0.1, and 0.1%, respectively. About 0.5% of transformer oils (66,000 kg out of 13,342,000 kg) exhibited PCB levels higher than 50 ppm that based on the Stockholm Convention should be phased out before 2025. The contaminated oils contained 91.4% of detected PCBs (132 kg PCBs out of 144 kg PCBs) and were located in 1.9% of transformers (27 transformers out of 1449 transformers). Statistical analysis indicated that the year of manufacture and manufacturing company provided significant effects on PCB contamination (p value <0.001). PCB contamination of transformer oils in Tehran was higher than that of the other provinces that could be mainly caused by the older average year of manufacture. PCB levels higher than 499 ppm were also observed only in Tehran. This study provided valuable information for future studies on identification of PCB-contaminated transformers as well as planning and design of waste management facilities for PCB-contaminated oils at the national level. PMID- 28660513 TI - The biological responses and metal phytoaccumulation of duckweed Spirodela polyrhiza to manganese and chromium. AB - The phytoaccumulation ability of duckweed Spirodela polyrhiza on manganese (Mn) and chromium (Cr) was assessed by exposing the plant to various concentrations of single or dual metals (5-70 mg L-1 Mn, 2-12 mg L-1 Cr(VI)) under laboratory conditions. The results showed that S. polyrhiza can tolerate Mn at high concentrations of up to 70 mg L-1, and its growth rate was barely affected by Mn. The effects of Cr on S. polyrhiza growth were dose-dependent, and the growth was completely inhibited in the presence of 12 mg L-1 Cr. Analysis of metal content in the plant biomass revealed a high accumulation of Mn (up to 15.75 mg per g of duckweed dry weight). The Cr bioaccumulation (from below detection limit to 2.85 mg Cr (11.84 mg Cr2O72-) per g of duckweed dry weight) increased with cultivation time and metal concentration in the medium. Further study with the concurrence of Mn and Cr showed increased toxicity to plant growth and photosynthesis. The metal accumulations in the dual metal treatments were also significantly decreased as compared to the single metal treatments. Nevertheless, the phytoaccumulation of these two metals in S. polyrhiza in the dual metal treatments were still comparable to or higher than in previous reports. Thus, it was concluded that duckweed S. polyrhiza has the potential to be used as a phytoremediator in aquatic environments for Mn and Cr removal. PMID- 28660515 TI - Predicting microalgae growth and phosphorus removal in cold region waste stabilization ponds using a stochastic modelling approach. AB - A stochastic ecological model with an integrated equilibrium temperature model was developed to predict microalgae growth and phosphorus removal in cold region waste stabilization ponds (WSPs). The model utilized a Monte Carlo simulation to account for parameter uncertainty. The equilibrium temperature model was parameterized using field data collected from two WSPs in Nunavut, Canada, from 2012 to 2014. The equilibrium temperature model provided good agreement with field data on a daily time step. The full model was run using historic (1956 2005) temperature and solar radiation data from five communities (Baker Lake, Cambridge Bay, Coral Harbour, Hall Beach, Resolute) in Nunavut, Canada. The communities represented a range of geographical locations and environmental conditions. Logistic regression on pooled model outputs showed that mean July temperature and mean treatment season temperature (June 1-September 15, ice-free period) provided the best predictors for microalgae growth. They had a predictive success rate of 93 and 88%, respectively. The modelled threshold (50% probability from the Monte Carlo simulation) for microalgae growth was 8.7 and 5.6 degrees C for the July temperature and mean treatment season temperature, respectively. The logistic regression was applied to each community (except Sanikiluaq) in Nunavut using historic climate data and a probability of microalgae growth was calculated. Based on the model results, soluble phosphorus concentrations consistent with secondary treatment could be achieved if WSP depth is less than 2 m. The model demonstrated a robust method to predict whether a microalgae bloom will occur under a range of model parameters. PMID- 28660514 TI - Monitoring of organic pollutants in marine environment by semipermeable membrane devices and mussels: accumulation and biochemical responses. AB - This study involves the monitoring of organic pollutants using transplanted mussels (Mytilus galloprovincialis) as bioindicator organisms and semipermeable membrane devices (SPMDs) as passive samplers. Mussels and SPMDs were deployed to marinas, shipyards and shipbreaking yards on the coastal area of Turkey and retrieved after 60 days. Polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and organochlorine pesticide (OCP) compounds were analysed with high-resolution GC-MS. Total PAH concentrations in SPMDs and mussels ranged from 200 to 4740 ng g sampler-1 and from 7.0 to 1130 ng g-1 in wet weight (ww). PCB and OCP concentrations in SPMDs changed between 0.04-200 and 4.0-26 ng g sampler 1, respectively. The highest PCB (190 ng g-1 ww) and OCP (200 ng g-1 ww) concentrations in mussels were measured at shipyard stations. A strong correlation was observed between the PAH and PCB concentrations in SPMDs and mussels. Enzyme assays (acetylcholinesterase, ethoxyresorufin-O-deethylase, glutathione S-transferase, glutathion reductase and carboxylesterase activities) were performed as biomarkers to reveal the effects of pollution on the mussels. There was no clear relationship found between the enzyme levels and the pollutant concentrations in mussels. Integrated biomarker responses were calculated to interpret the overall effect of pollutants. PMID- 28660516 TI - Impacts of hydrologic variations on chemical weathering and solute sources in the Min River basin, Himalayan-Tibetan region. AB - Feedback between hydrologic variations and chemical weathering is thought to play a crucial role in modulating global carbon cycling. The mechanisms associated with the impacts of hydrologic variations on solute sources and chemical weathering were evaluated by examining the relationships between river discharge and hydrochemistry based on high-frequency sampling of the Min River, which originates in the Himalayan-Tibetan region. Fluid transit times and flow pathways vary with changes in discharge, thereby affecting various biogeochemical processes. Although shorter transit times occur during the high-flow season than during the low-flow season, concentrations of chemical weathering products exhibit chemostatic behaviour (less variation than changes in discharge) in response to increasing discharge due to hydrologic flushing of minerals, which increases the amount of reactive mineral surface area. The contributions of various sources to dissolved loads in the Min River were estimated using a forward model. The calculated annual carbonate and silicate weathering fluxes are 24.1 and 9.6 t/km2 year, respectively. Atmospheric contributions increase with increasing discharge, whereas the contributions of silicate weathering decrease with increasing discharge. Both the carbonate weathering flux (FCarb) and silicate weathering flux (FSil) are positively correlated with the discharge, indicating that temporal variations in chemical weathering fluxes in the Min River are highly affected by hydrologic variations. The slope of the relationship between FCarb and discharge is much greater than that between FSil and discharge due to the rapid dissolution of carbonate minerals, suggesting that carbonate weathering is more sensitive than silicate weathering to hydrologic variations. This study demonstrates that high-frequency sampling is necessary when investigating solute sources and chemical weathering processes in river basins influenced by a monsoon climate. PMID- 28660517 TI - Dynamic water quality evaluation based on fuzzy matter-element model and functional data analysis, a case study in Poyang Lake. AB - Comprehensively evaluating water quality with a single method alone is challenging because water quality evaluation involves complex, uncertain, and fuzzy processes. Moreover, water quality evaluation is limited by finite water quality monitoring that can only represent water quality conditions at certain time points. Thus, the present study proposed a dynamic fuzzy matter-element model (D-FME) to comprehensively and continuously evaluate water quality status. D-FME was first constructed by introducing functional data analysis (FDA) theory into a fuzzy matter-element model and then validated using monthly water quality data for the Poyang Lake outlet (Hukou) from 2011 to 2012. Results showed that the finite water quality indicators were represented as dynamic functional curves despite missing values and irregular sampling time. The water quality rank feature curve was integrated by the D-FME model and revealed comprehensive and continuous variations in water quality. The water quality in Hukou showed remarkable seasonal variations, with the best water quality in summer and worst water quality in winter. These trends were significantly correlated with water level fluctuations (R = -0.71, p < 0.01). Moreover, the extension weight curves of key indicators indicated that total nitrogen and total phosphorus were the most important pollutants that influence the water quality of the Poyang Lake outlet. The proposed D-FME model can obtain scientific and intuitive results. Moreover, the D-FME model is not restricted to water quality evaluation and can be readily applied to other areas with similar problems. PMID- 28660519 TI - Alterations in liver marker enzymes and recovery ability of cyprinids as indicators of aquatic pollution. AB - Information on the detection of pesticides in fresh water Lakes of Kashmir (Dal and Mansbal) through GC-MS technique is scarce, and also the recovery in biochemical parameters (AST, ALT and ALP) of fish after transferring them to clean media has not been reported yet. The water samples were collected from three sites and analyzed for their pesticide profile by dispersive liquid-liquid micro extraction (DLLME) followed by GC-MS. Influence of pesticides on liver marker enzymes of Cyprinus carpio and Carassius carassius was also investigated. The results obtained showed the presence of three main pesticides viz. chlorpyrifros, dimethoate and dichlorvos in waters of Dal Lake whereas no pesticide was detected in waters of Mansbal. The higher values for AST, ALT and ALP activities and decrease in protein content were obtained in the samples from the Dal Lake compared with those from Mansbal Lake (p < 0.05). These data when compared with the values found in C. carpio and C. carassius from both the Dal Lake and Mansbal Lake kept under laboratory conditions after 15, 30, 45 and 60 days of maintenance in clean media found that during depuration, all the enzyme activities came down significantly (p < 0.05) indicating the compensatory response by the fish against the pesticide stress. Therefore, these parameters could be used as indicators of pesticide pollution in aquatic organisms and were recommended for environmental monitoring for investigating the mechanism involved in the recovery pattern. PMID- 28660521 TI - Primary Squamous Cell Carcinoma of the Pancreas: a Case Report and Literature Review. PMID- 28660520 TI - Comparison of Complications Following Laparoscopic and Endoscopic Gastrostomy Placements. AB - INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) and laparoscopic gastrostomy (LG) placements provide enteral access to patients unable to tolerate oral feeds. Limited data comparing PEG and LG outcomes is available in adults. This study compares complications between PEG and LG placements. MATERIALS AND METHODS: A retrospective chart review was completed for patients undergoing PEG or LG placement at a single academic center between 2007 and 2014. Patient demographics, comorbidities, and Charlson Comorbidity Index (CCI) were compared. Logistic regression was utilized to identify independent predictors for complication. RESULTS: Two hundred and twenty-four patients (164 PEGs and 60 LGs) were evaluated. Patients undergoing LG had a higher incidence of prior surgery (42 vs 20%; P < 0.01) and age-adjusted CCI (5 vs 4; P = 0.01). Return to the OR was more common following PEG than LG (5.5 vs 0%) but did not achieve significance (P = 0.12). There were no differences in 30-day mortality; however, age-adjusted CCI was predictive of 30-day mortality (OR 1.3, 95% CI 1.1-1.6). CONCLUSION: Despite increased comorbidities, LG tubes are at least as safe as PEGs. Research should focus on identifying predictive factors associated with post-operative complications to identify which patients would have superior outcomes with LG placement. PMID- 28660523 TI - Posterior Reversible Encephalopathy Syndrome During Treatment with Aflibercept, 5 Fluorouracil, Leucovorin, and Irinotecan for Metastatic Colorectal Cancer. PMID- 28660518 TI - Parasites and pollution: the effectiveness of tiny organisms in assessing the quality of aquatic ecosystems, with a focus on Africa. AB - The aquatic environment represents the final repository for many human-generated pollutants associated with anthropogenic activities. The quality of natural freshwater systems is easily disrupted by the introduction of pollutants from urban, industrial and agricultural processes. To assess the extent of chemical perturbation and associated environmental degradation, physico-chemical parameters have been monitored in conjunction with biota in numerous biological monitoring protocols. Most studies incorporating organisms into such approaches have focussed on fish and macroinvertebrates. More recently, interest in the ecology of parasites in relation to environmental monitoring has indicated that these organisms are sensitive towards the quality of the macroenvironment. Variable responses towards exposure to pollution have been identified at the population and component community level of a number of parasites. Furthermore, such responses have been found to differ with the type of pollutant and the lifestyle of the parasite. Generally, endoparasite infection levels have been shown to become elevated in relation to poorer water quality conditions, while ectoparasites are more sensitive, and exposure to contaminated environments resulted in a decline in ectoparasite infections. Furthermore, endoparasites have been found to be suitable accumulation indicators for monitoring levels of several trace elements and metals in the environment. The ability of these organisms to accumulate metals has further been observed to be of benefit to the host, resulting in decreased somatic metal levels in infected hosts. These trends have similarly been found for host-parasite models in African freshwater environments, but such analyses are comparatively sparse compared to other countries. Recently, studies on diplozoids from two freshwater systems have indicated that exposure to poorer water quality resulted in decreased infections. In the Vaal River, the poor water quality resulted in the extinction of the parasite from a site below the Vaal River Barrage. Laboratory exposures have further indicated that oncomiracidia of Paradiplozoon ichthyoxanthon are sensitive to exposure to dissolved aluminium. Overall, parasites from African freshwater and marine ecosystems have merit as effect and accumulation indicators; however, more research is required to detail the effects of exposure on sensitive biological processes within these organisms. PMID- 28660522 TI - Rectal Cancer Surveillance-Recurrence Patterns and Survival Outcomes from a Cohort Followed up Beyond 10 Years. AB - AIM: The intensity and duration of surveillance for rectal cancer after surgical resection remain contentious. We evaluated the pattern of recurrences in a rectal cancer cohort followed up beyond 10 years. METHODS: An analysis was performed on a retrospective database of 326 patients with rectal cancer who underwent curative surgical resection from 1999 to 2007. The above study duration was chosen to ensure at least 10 years of follow-up. Data on patient demographics, peri-operative details, and follow-up outcomes were extracted from the database. The pattern of recurrences and investigative modality that detected recurrences was identified. Patients were followed up until either year 2016 or the day of their demise. RESULTS: Two hundred seventeen patients (66.6%) were male and 109 patients (33.3%) female. Median age was 64 years old. Close to a third of the patients received adjuvant therapy (34%). Among the 326 patients studied, 29.8% of (97/326) patients developed recurrence. 7.7% (25/326) had loco-regional recurrence while 22.1% (72/326) had distant metastasis. Median time to recurrence was 16 months (4-83) and 18 months (3-81), respectively. Computed tomography scan was the best modality to detect both loco-regional and distant recurrences (48% in loco-regional and 41.7% in distant metastasis). The most common site of distant metastasis is the lung (34.7%). The salvage rate for loco-regional and distant recurrences was 52 and 12.5%, respectively. CONCLUSION: The predominant pattern of recurrence in rectal cancer is distant disease. Surveillance regimes may need to be altered to increase early detection of distant metastases. PMID- 28660524 TI - Acinar Cell Carcinoma of Pancreas: a Case Report and Review of Literature. PMID- 28660525 TI - Diffuse, Aggressive Metastatic Progression after Minimally Invasive Local Resection of Primary Gastric Synovial Sarcoma: a Case Report and Systematic Review of the Literature. PMID- 28660526 TI - Colon Metastasis, 8 years after Gastrectomy, for Stage I Gastric Cancer. PMID- 28660527 TI - Core curriculum illustration: abdominal wood impalement injury from motor vehicle collision. AB - This is the 42nd installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at http://www.erad.org/page/CCIP_TOC . PMID- 28660528 TI - Lipid transfers to HDL are diminished in long-term bedridden patients: association with low HDL-cholesterol and increased inflammatory markers. AB - Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long-term care (>90 days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193 +/- 36 vs 160 +/- 43, p = 0.005), LDL (124 +/- 3 vs 96 +/- 33 p = 0.003) and HDL-cholesterol (45 +/- 10 vs 36 +/- 13, p = 0.008), apolipoprotein A-I (134 +/- 20 vs 111 +/- 24, p = 0.001) and oxidized LDL (53 +/- 13 vs 43 +/- 12, p = 0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL-cholesterol levels. Concentrations of IL-1beta, IL-6, IL-8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL-cholesterol, apolipoprotein A-I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition. PMID- 28660530 TI - Hemorrhagic polyps formed like fundic gland polyps during long-term proton pump inhibitor administration. AB - We report a rare case of hemorrhagic gastric polyps resulting in anemia during long-term proton pump inhibitor (PPI) administration that endoscopically looked like a fundic gland polyp (FGP). A 44-year-old man presented complaining of anemia and tarry stools. Esophagogastroduodenoscopy (EGD) demonstrated multiple white edematous polyps in the corpus and antrum, which were considered to be FGPs. We attempted endoscopic hemostasis but hemorrhaging increased because of hemorrhagic polyps and vulnerable gastric mucosa. Re-bleeding occurred several times. Polyp resection was performed at 24 polyp sites. We also ceased the administration of PPI. Microscopically, polyps showed characteristics of hyperplasia in the foveolar epithelium, extensions of fundic glands, and edema of the stroma. The proliferation of parietal and chief cells was also observed. Immunohistochemically, aquaporin-4 (AQP4) and KCNQ1-positive parietal cells and dilated mucous glands were found from the basal side to the apical side of the mucosa. These findings were compatible with the development of lesions associated with the long-term administration of PPI. EGD revealed an improvement in the vulnerability of gastric mucosa and the development of polyps, with no further gastric polyps observed 1 year after discharge. Bleeding from polyps resembling FGPs is generally rare, with indications that long-term PPI administration may induce such bleeding. PMID- 28660529 TI - Inhibition of Polyunsaturated Fatty Acids Synthesis Decreases Growth Rate and Membrane Fluidity of Rhodosporidium kratochvilovae at Low Temperature. AB - The intention of this study was to investigate the role of polyunsaturated fatty acids (PUFA) in the cold adaptation of Rhodosporidium kratochvilovae YM25235 by knockout of the Delta12/Delta15-fatty acid desaturase gene (RKD12) to inactivate Delta12/Delta15-fatty acid desaturase. Polymerase chain reaction (PCR) amplification was used to detect the genomic structure of RKD12 gene in YM25235. The RKD12 gene was knocked out by DNA homologous recombination to inhibit the biosynthesis of PUFA. Then, the contents of linoleic acid (LNA) and alpha linolenic acid (ALA) after gene knockout were investigated using a gas chromatography-mass spectrometer, followed by determination of the growth rate and membrane fluidity of YM25235 at low temperature. After PCR amplification, a 1611 bp genomic fragment was amplified from YM25235. When the RKD12 gene was knocked out, the contents of LNA and ALA in YM25235 significantly decreased. The growth rate and membrane fluidity of YM25235 decreased significantly at low temperature. Inhibition of PUFA biosynthesis by RKD12 gene knockout influenced cold adaptation of YM25235 by decreasing the PUFA content in cell membranes and reducing the growth rate and membrane fluidity of YM25235 at low temperature. PMID- 28660532 TI - Influence of single and dual tasks on gait stability and gait speed in the elderly : An explorative study. AB - BACKGROUND: Gait stability during dual tasks is important for elderly persons, especially for elderly individuals in need of care. A study was conducted to assess gait stability by using Lyapunov exponents (lambdaS) during single task and dual task conditions in independently living elderly people (Go-Goes) and elderly people in need of care (No-Goes). MATERIAL AND METHODS: This study was conducted with 26 participants (average age 82 +/- 9.4 years) who were allocated to the Go-Goes or No-Goes group. Outcomes were mediolateral and vertical Lyapunov exponents (lambdaS) from accelerometer data and gait speed under single task and dual task conditions. RESULTS: In both groups significantly higher mediolateral and vertical Lyapunov exponent values as well as significantly lower walking speeds under dual task conditions were found in both groups. The effect sizes were small to moderate for mediolateral lambdaS and large for vertical lambdaS and these differences remained when the analyses were adjusted for walking speed. CONCLUSION: Elderly people showed lower gait stability and gait speed under dual task conditions compared to single task conditions. PMID- 28660531 TI - Decision-making neural circuits mediating social behaviors : An attractor network model. AB - We propose a mathematical model of a continuous attractor network that controls social behaviors. The model is examined with bifurcation analysis and computer simulations. The results show that the model exhibits stable steady states and thresholds for steady state transitions corresponding to some experimentally observed behaviors, such as aggression control. The performance of the model and the relation with experimental evidence are discussed. PMID- 28660533 TI - Analysis of cytopenia in geriatric inpatients. AB - BACKGROUND: Peripheral blood dyscrasias in older patients are repeatedly seen in geriatric clinical practice; however, there is substantial lack of data about the epidemiology, possible causes and treatment options in this patient group. Proton pump inhibitors (PPI) are extensively used in older patients and associated with leukopenia. The primary objective of this study was the assessment of encoded cytopenia prevalence in a geriatric patient cohort and the secondary objective was the assessment of putative causes and the analysis of PPI administration in patients with cytopenia. METHODS: Retrospective evaluation of patients admitted to the geriatric department of a German urban hospital between 2010 and 2012. Electronic patient data were screened for encoded diagnosis of cytopenia according to the International Classification of Diseases (ICD) 10. Inclusion criteria were ICD code D69.0-9 and/or D70.0-7, age >=60 years and exclusion criteria were no ICD code D69.0-9 and/or D70.0-7 and age <60 years. Out of 9328 screened inpatients 54 patients remained for analysis. Study parameters included hemoglobin (Hb), red blood cell count (RBC), leucocytes, platelets, mean cell volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), presence of leukopenia (<4000/ul), presence of thrombocytopenia (<140,000/ul) and presence of anemia according to the World Health Organization (WHO). Substitution of blood products, medication with PPI and potential causes for dyscrasias were evaluated based on electronic patient records. RESULTS: The mean age was 78.3 +/- 6.5 years (27 females, 27 males), anemia was seen in 78%, leukopenia was encoded in13% and thrombocytopenia in 44.4%. In most of the patients no substitution of blood products was documented. In most of the patients (20.4%) cytopenia was attributed to either heparin-induced thrombocytopenia (HIT) or hemato-oncologic (20.4%) diseases, followed by drug association in 18.5%. In 70.8% of the study patients PPIs were administered but the indication for PPI administration remained unclear in 20.4%. CONCLUSION: The results encourage accurate assessment of blood dyscrasias and appropriate documentation as well as indication check for PPI treatment in geriatric inpatients. PMID- 28660534 TI - [Mild head injuries in the elderly]. AB - In the elderly, particularly those over 80 years old, head injuries often occur as a result of falls. The majority suffer from mild head injury. After clarification of the initial symptoms in these patients, the main aim is to recognize or exclude intracranial injuries (bleeding). Demonstration of intracranial bleeding is possible with cranial computed tomography (CCT), which in contrast to magnetic resonance imaging (MRI) can be quickly carried out in most cases; however, most patients with mild head injury show no intracranial bleeding. The performance of CCT and the often necessary hospital admission place a severe physical and psychological burden on the elderly. The plasma parameter S100B, combined with the clinical findings, is a valuable instrument for decision making in the management of elderly patients with mild head injury. PMID- 28660536 TI - In Silico Identification of Novel microRNAs and Targets Using EST Analysis in Allium cepa L. AB - microRNAs (miRNAs) are a newly discovered class of non-coding small RNAs roughly 22 nucleotides long. Increasing evidence has shown that miRNAs play multiple roles in biological processes, including development, cell proliferation, apoptosis and stress responses. The identification of miRNAs and their targets is an important need to understand their roles in the development and physiology of sweet onion (Allium cepa). In this research, several computational approaches were combined to make concise prediction of the potential miRNAs and their targets. We used previously known miRNAs from other plant species against Expressed Sequence Tags (EST) database to search for the potential miRNAs. As a result, nine potential miRNAs were identified in eight ESTs of A. cepa, belonging to eight families. We could further BLAST the mRNA database and found total 154 number of the potential targets in A. cepa based on these potential miRNAs. According to the mRNA target information provided by NCBI, most of the target mRNAs appeared to be involved in plant growth, signal transduction, development, and stress responses. Gene ontology (GO) analysis implicated these targets in 32 biological processes such as protein ubiquitination, plant hormone signalling pathways and heme biosynthesis. PMID- 28660535 TI - The Stability of Type D Personality in Dialysis Patients. AB - PURPOSE: Type D personality has been identified as an independent risk factor for survival in cardiovascular disease (CVD) patients. As CVD is present in about 50% of dialysis patients, it is of clinical interest to assess the prevalence of type D personality, the association with depressive and anxiety symptoms, and stability of type D personality in dialysis patients. METHODS: Data was used from two consecutive measurements of the DIVERS study, a prospective cohort study among chronic dialysis patients in the Netherlands. Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and the Type D Scale-14 (DS14) were used to assess depressive and anxiety symptoms and type D personality, respectively. The association of type D personality was assessed with analysis of variance F test. Stability of type D personality, depressive, and anxiety symptoms were determined by calculating Cohen's kappa, and by determining the positive agreement. RESULTS: In total, 349 patients were included of which 249 patients had two measurement points. The prevalence of type D personality was 21% and type D personality was associated with depressive and anxiety symptoms (P < 0.01). Over a 6-month period, Cohen's kappa was 0.52, 0.56, and 0.61 for type D personality, depressive, and anxiety symptoms, respectively. Sixty-one, 73, and 73% had a stable type-D personality, depressive, and anxiety symptoms, respectively. CONCLUSION: The presence of type D personality varies over time in dialysis patients. Therefore, type D personality is possibly more a state instead of a trait phenomenon. PMID- 28660537 TI - In Silico Analysis of nsSNPs of Carp TLR22 Gene Affecting its Binding Ability with Poly I:C. AB - Immune response mediated by toll-like receptor 22 (TLR22), only found in teleost/amphibians, is triggered by double-stranded RNA binding to its LRR (leucine-rich repeats) ecto-domain. Accumulated evidences suggested that missense mutations in TLR genes affect its function. However, information on mutation linked pathogen recognition for TLR22 was lacking. The present study was commenced for predicting the effect of non-synonymous single-nucleotide polymorphisms (nsSNPs) on the pathogen recognizable LRR domain of TLR22 of farmed carp, Labeo rohita. The sequence-based algorithms (SIFT, PROVEAN and I-Mutant2.0) indicated that three SNPs (out of 27) such as p.L159F (rs76759876) and p.L529P (rs749355507) of LRR, and p.I836M (rs750758397) of intracellular motifs could potentially disrupt protein function. The 3D structure was generated using MODELLER 9.13 and further validated by SAVEs server. The simulated molecular docking of native TLR22 and mutants with poly I:C ligand indicated that mutations positioned at p.L159F and p.L529P of the LRR region affects the binding affinity significantly. This is the first kind of study of predicting nsSNPs of teleost TLR22 with disturbed ligand binding affinity with its extra-cellular LRR domain and thereby likely hindrance in subsequent signal transduction. This study serves as a guide for in vivo evaluation of impact of mutation on immune response mediated by teleost TLR22 gene. PMID- 28660539 TI - The "P" Is Silent. PMID- 28660538 TI - Effect of low-intensity whole-body vibration on bone defect repair and associated vascularization in mice. AB - Low-intensity whole-body vibration (LIWBV) may stimulate bone healing, but the involvement of vascular ingrowth, which is essential for bone regeneration, has not been well examined. We thus investigated the LIWBV effect on vascularization during early-stage bone healing. Mice aged 13 weeks were subjected to cortical drilling on tibial bone. Two days after surgery (day 0), mice were exposed daily to sine-wave LIWBV at 30 Hz and 0.1 g peak-to-peak acceleration for 20 min/day (Vib) or were sham-treated (sham). Following vascular casting with a zirconium based contrast agent on days 6, 9, or 12 and sacrifice, vascular and bone images were obtained by K-edge subtraction micro-CT using synchrotron lights. Bone regeneration advanced more in the Vib group from days 9 to 12. The vascular volume fraction decreased from days 6 to 9 in both groups; however, from days 9 to 12, it was increased in shams, while it stabilized in the Vib group. The vascular volume fraction tended to be or was smaller in the Vib group on days 6 and 12. The vessel number density was higher on day 9 but lower on day 12 in the Vib group. These results suggest that the LIWBV-promoted bone repair is associated with the modulation of vascularization, but additional studies are needed to determine the causality of this association. PMID- 28660540 TI - Integrating Clinical Neurosciences in a Psychiatry Residency Training Program: A Brief Report with Pilot Data. AB - OBJECTIVE: A novel neuroscience curriculum was developed attempting to address the growing consensus that increased attention be given to incorporating clinical neuroscience in psychiatric residencies. METHODS: Eight 2-h sessions delivered over 2 academic years were incorporated into the teaching curriculum at one institution in which residents participated in case-based clinical neuroscience learning. Each session utilized multimodal teaching methods facilitated by two senior psychiatry residents with support from a faculty mentor. A survey assessing resident comfort with clinical neurosciences was gathered over four timepoints during the 2-year period. RESULTS: There were 69 attendees in total across the four time points, with a 100% response rate to the surveys. There was a significant overall effect found, F(3,16) = 12.64, p < .01, on resident comfort level between the four timepoints. There was a significant increase in comfort level at the third timepoint compared to the first two timepoints; however, there was a notable drop in comfort level between the third and fourth timepoint such that there was no statistically significant difference between the first and last timepoint. Nevertheless, despite mixed positive and negative responses on qualitative analysis, all residents supported the continuation of the course. CONCLUSION: Resident comfort level did not change appreciably with this curriculum; however, there was unanimous support for the continuation of the course in future years. Incorporating this type of curriculum is feasible in a medium-sized psychiatry residency program. Given that subjective comfort ratings are not indicative of actual competency, future work should include objective, competency-based outcomes. PMID- 28660541 TI - Environmental water demand assessment under climate change conditions. AB - Measures taken to cope with the possible effects of climate change on water resources management are key for the successful adaptation to such change. This work assesses the environmental water demand of the Karkheh river in the reach comprising Karkheh dam to the Hoor-al-Azim wetland, Iran, under climate change during the period 2010-2059. The assessment of the environmental demand applies (1) representative concentration pathways (RCPs) and (2) downscaling methods. The first phase of this work projects temperature and rainfall in the period 2010 2059 under three RCPs and with two downscaling methods. Thus, six climatic scenarios are generated. The results showed that temperature and rainfall average would increase in the range of 1.7-5.2 and 1.9-9.2%, respectively. Subsequently, flows corresponding to the six different climatic scenarios are simulated with the unit hydrographs and component flows from rainfall, evaporation, and stream flow data (IHACRES) rainfall-runoff model and are input to the Karkheh reservoir. The simulation results indicated increases of 0.9-7.7% in the average flow under the six simulation scenarios during the period of analysis. The second phase of this paper's methodology determines the monthly minimum environmental water demands of the Karkheh river associated with the six simulation scenarios using a hydrological method. The determined environmental demands are compared with historical ones. The results show that the temporal variation of monthly environmental demand would change under climate change conditions. Furthermore, some climatic scenarios project environmental water demand larger than and some of them project less than the baseline one. PMID- 28660542 TI - Comparing two periphyton collection methods commonly used for stream bioassessment and the development of numeric nutrient standards. AB - Periphyton is an important component of stream bioassessment, yet methods for quantifying periphyton biomass can differ substantially. A case study within the Arkansas Ozarks is presented to demonstrate the potential for linking chlorophyll a (chl-a) and ash-free dry mass (AFDM) data sets amassed using two frequently used periphyton sampling protocols. Method A involved collecting periphyton from a known area on the top surface of variably sized rocks gathered from relatively swift-velocity riffles without discerning canopy cover. Method B involved collecting periphyton from the entire top surface of cobbles systematically gathered from riffle-run habitat where canopy cover was intentionally avoided. Chl-a and AFDM measurements were not different between methods (p = 0.123 and p = 0.550, respectively), and there was no interaction between method and time in the repeated measures structure of the study. However, significantly different seasonal distinctions were observed for chl-a and AFDM from all streams when data from the methods were combined (p < 0.001 and p = 0.012, respectively), with greater mean biomass in the cooler sampling months. Seasonal trends were likely the indirect results of varying temperatures. Although the size and range of this study were small, results suggest data sets collected using different methods may effectively be used together with some minor considerations due to potential confounding factors. This study provides motivation for the continued investigation of combining data sets derived from multiple methods of data collection, which could be useful in stream bioassessment and particularly important for the development of regional stream nutrient criteria for the southern Ozarks. PMID- 28660544 TI - A Discrete Dynamical System Approach to Pathway Activation Profiles of Signaling Cascades. AB - In living organisms, cascades of covalent modification cycles are one of the major intracellular signaling mechanisms, allowing to transduce physical or chemical stimuli of the external world into variations of activated biochemical species within the cell. In this paper, we develop a novel method to study the stimulus-response of signaling cascades and overall the concept of pathway activation profile which is, for a given stimulus, the sequence of activated proteins at each tier of the cascade. Our approach is based on a correspondence that we establish between the stationary states of a cascade and pieces of orbits of a 2D discrete dynamical system. The study of its possible phase portraits in function of the biochemical parameters, and in particular of the contraction/expansion properties around the fixed points of this discrete map, as well as their bifurcations, yields a classification of the cascade tiers into three main types, whose biological impact within a signaling network is examined. In particular, our approach enables to discuss quantitatively the notion of cascade amplification/attenuation from this new perspective. The method allows also to study the interplay between forward and "retroactive" signaling, i.e., the upstream influence of an inhibiting drug bound to the last tier of the cascade. PMID- 28660545 TI - Further Mathematical Modelling of Mating Sex Ratios & Male Strategies with Special Relevance to Human Life History. AB - Influential models of male reproductive strategies have often ignored the importance of mate guarding, focusing instead on trade-offs between fitness gained through care for dependants in a pair bond versus fitness from continued competition for additional mates. Here we follow suggestions that mate guarding is a distinct alternative strategy that plays a crucial role, with special relevance to the evolution of our own lineage. Human pair bonding may have evolved in concert with the evolution of our grandmothering life history, which entails a shift to male-biased sex ratios in the fertile ages. As that sex ratio becomes more male biased, payoffs for mate-guarding increase due to partner scarcity. We present an ordinary differential equation model of mutually exclusive strategies (dependant care, multiple mating, and mate guarding), calculate steady-state frequencies and perform bifurcation analysis on parameters of care and guarding efficiency. Mate guarding triumphs over alternate strategies when populations are male biased, and guarding is fully efficient. When guarding does not ensure complete certainty of paternity, and multiple maters are able to gain some paternity from guarders, multiple mating can coexist with guarding. At female-biased sex ratios, multiple mating takes over, unless the benefit of care to the number of surviving offspring produced by the mates of carers is large. PMID- 28660543 TI - Therapeutic Strategies Targeting Inherited Cardiomyopathies. AB - PURPOSE OF REVIEW: Cardiomyopathies due to genetic mutations are a heterogeneous group of disorders that comprise diseases of contractility, myocardial relaxation, and arrhythmias. Our goal here is to discuss a limited list of genetically inherited cardiomyopathies and the specific therapeutic strategies used to treat them. RECENT FINDINGS: Research into the molecular pathophysiology of the development of these cardiomyopathies is leading to the development of novel treatment approaches. Therapies targeting these specific mutations with gene therapy vectors are on the horizon, while other therapies which indirectly affect the physiologic derangements of the mutations are currently being studied and used clinically. Many of these therapies are older medications being given new roles such as mexiletine for Brugada syndrome and diflunisal for transthyretin amyloid cardiomyopathy. A newer targeted therapy, the inhibitor of myosin ATPase MYK-461, has been shown to suppress the development of ventricular hypertrophy, fibrosis, and myocyte disarray and is being studied as a potential therapy in patients with hypertrophic cardiomyopathy. While this field is too large to be completely contained in a single review, we present a large cross section of recent developments in the field of therapeutics for inherited cardiomyopathies. New therapies are on the horizon, and their development will likely result in improved outcomes for patients inflicted by these conditions. PMID- 28660546 TI - A Bayesian Computational Approach to Explore the Optimal Duration of a Cell Proliferation Assay. AB - Cell proliferation assays are routinely used to explore how a low-density monolayer of cells grows with time. For a typical cell line with a doubling time of 12 h (or longer), a standard cell proliferation assay conducted over 24 h provides excellent information about the low-density exponential growth rate, but limited information about crowding effects that occur at higher densities. To explore how we can best detect and quantify crowding effects, we present a suite of in silico proliferation assays where cells proliferate according to a generalised logistic growth model. Using approximate Bayesian computation we show that data from a standard cell proliferation assay cannot reliably distinguish between classical logistic growth and more general non-logistic growth models. We then explore, and quantify, the trade-off between increasing the duration of the experiment and the associated decrease in uncertainty in the crowding mechanism. PMID- 28660547 TI - Long-Term Outcome of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Acute Myeloid Leukemia (AML)- Single Center Retrospective Analysis. AB - For patients with acute myeloid leukemia (AML) in complete remission without an acceptable HLA donor, the autologous hematopoietic stem cell transplantation (AHSCT) may remain a therapeutic option as remission consolidation, however its role is still a subject of continued debate. One hundred and twenty patients who underwent AHSCT for AML were included in this retrospective single center analysis. The procedure was performed over a 19 years period and transplanted patients were in first complete remission (CR1; n = 109) or in second CR (CR2; n = 11). The median age at transplant was 37 years (range 18-64). The source of stem cells was bone marrow (n = 61; 50.8%), peripheral blood (n = 36; 30%) and bone marrow with peripheral blood (n = 23; 19.2%). The median time from AML diagnosis to AHSCT was 0.8 year (range 0.3-4.4) and the median follow-up after AHSCT for surviving patients was 12.8 years (range 3.1-20.5). The median LFS was 1.1 year. The probability of LFS calculated at 5 years and 10 years after transplantation was 28% (95%CI, 22%-32%) and 21% (95%CI, 18%-24%), respectively. The last relapse occurred 14.8 years after AHSCT and among patients who survived >2 years, 28.4% (27/95) had leukemia recurrence. The median OS was 1.7 years. The probability of OS after 5 years and 10 years was 29% and 22%, respectively. There was a tendency for increased LFS for patients younger than 50 years at transplant if compared to older population. AHSCT for AML was safe with acceptable toxicity profile. Leukemia recurrence remained the leading cause of death. PMID- 28660548 TI - Chemotherapy-induced cardiomyopathy caused by Pemetrexed. AB - Chemotherapy-related cardiac toxicity is a rare but serious adverse event in patients with cancer. Thus far, no case of serious cardiac toxicity of pemetrexed has been reported. We describe the case of a patient with advanced lung cancer and cardiomyopathy due to pemetrexed. A 59-year-old woman visited our hospital, and we found abnormal findings on a chest radiograph. She was diagnosed as having stage IV lung adenocarcinoma. Chemotherapy with cisplatin and pemetrexed every 3 weeks was initiated. After four cycles of chemotherapy, maintenance chemotherapy with pemetrexed was administered every 3 weeks. During the seventeenth cycle of pemetrexed, she had shortness of breath in her daily life. A chest radiograph showed an enlarged cardiothoracic ratio (66%), and the transthoracic echocardiogram demonstrated expansion of the left ventricle (diastolic diameter, 67 mm), severe global hypokinesis, and reduced left ventricular ejection fraction (28%). The coronary angiogram showed no coronary constriction. There was no delayed accumulation on the contrast-enhanced cardiac magnetic resonance imaging scan. After right heart catheterization, pathological results of a myocardial biopsy from the ventricular septum indicated no cardiac muscle hypertrophy, cardiac fibrosis, inflammatory cell infiltration, or myocyte disarray. Eventually, she was diagnosed as having pemetrexed-induced cardiomyopathy. Pemetrexed was discontinued, and furosemide, enalapril, and carvedilol were started. Then her symptoms and cardiac function improved. Early detection and discontinuation of causative agents are the most important treatment strategies in similar patients. Diuretics, angiotensin-conversion enzyme inhibitors, and beta-blockers may be effective for treating heart failure. PMID- 28660549 TI - Safety and effectiveness of eribulin in Japanese patients with locally advanced or metastatic breast cancer: a post-marketing observational study. AB - Background This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m2) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (>=15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade >= 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk benefit balance when used in real-world clinical settings. PMID- 28660550 TI - Clinical and Economic Evaluation of Repository Corticotropin Injection: A Narrative Literature Review of Treatment Efficacy and Healthcare Resource Utilization for Seven Key Indications. AB - INTRODUCTION: Repository corticotropin injection (RCI; H.P. Acthar(r) Gel; Mallinckrodt Pharmaceuticals Inc., Hampton, NJ) is a highly purified, prolonged release porcine preparation of adrenocorticotropic hormone (ACTH) analogue that is FDA-approved for treatment of 19 autoimmune and inflammatory disorders. The diverse physiological actions of RCI at the melanocortin receptors (MCRs) affect processes involved in inflammation, pigmentation, steroidogenesis, and immunomodulation. Although RCI has been approved to treat inflammatory and autoimmune diseases for more than 60 years, recent progress in understanding both MCRs and the effects of RCI in modulating immune responses has led to increased interest in RCI as a therapeutic choice. The objective of this narrative literature review is to summarize key clinical and economic data on RCI treatment of seven disorders: infantile spasms (IS), multiple sclerosis (MS) relapses, proteinuria in nephrotic syndrome, rheumatoid arthritis (RA), dermatomyositis/polymyositis (DM/PM), systemic lupus erythematosus (SLE), and symptomatic sarcoidosis based on published literature and product information. An extended report is available as the Academy of Managed Care Pharmacy (AMCP) Formulary dossier for H.P. Acthar(r) Gel. METHODS: Key studies of clinical efficacy and healthcare utilization and cost from 1956 to 2016 are summarized. RESULTS: The evidence supports the efficacy of RCI across the seven indications. RCI is effective as a first-line therapy for IS. For the other six conditions, RCI may improve clinical outcomes during exacerbations or when the condition is resistant to conventional treatments. Use of RCI is associated with reduced use of biologics, corticosteroids, and disease-modifying antirheumatic drugs. Initiation of RCI therapy in patients with IS, MS, RA, SLE, or DM/PM has been associated with lower post-therapy healthcare utilization and medical costs, including decreases in hospitalizations, hospital length of stay, outpatient visits, and emergency department visits. CONCLUSION: The evidence suggests that RCI may improve inflammatory and autoimmune disease control and patient quality of life, particularly in complex patients, and yield healthcare cost savings that demonstrate the medicine's value. FUNDING: Mallinckrodt Pharmaceuticals Inc. PMID- 28660551 TI - Infants with head injuries-do all need hospital admission? AB - BACKGROUND: Head injury in a young infant is a common presentation in paediatric emergency departments and clinicians often admit these young infants (less than 12 months of age) for further neuro-observation due to lack of strong evidence base and standard recommendations about the management of such a young patient with head injury. AIMS: We performed this retrospective observational study to find out whether inpatient admission is really necessary in those infants who present with minor head injury to the paediatric emergency departments. METHODS: Electronic patient record system and handwritten patient records were retrospectively accessed of the infants admitted with minor head injury to the paediatric ward of the Midland Regional Hospital, Mullingar over a period of the previous 5 years. RESULTS: A total of 256 infants less than 12 months of age met the criteria of minor head injury at admission and none of them showed any clinical indicators indicating serious intracranial injury whilst under observation in the paediatric ward. They all remained well and were discharged later after a period of observation. CONCLUSIONS: Barring few clinical circumstances which put these young infants at increased risk of clinically important traumatic brain injury, a vast majority of minor head injury in infants can be safely observed at home with reliable caretakers and proper discharge instructions. PMID- 28660553 TI - Comment on: "Intranasal Dexmedetomidine for Procedural Sedation in Children, a Suitable Alternative to Chloral Hydrate". PMID- 28660552 TI - Adverse Remodeling and Reverse Remodeling After Myocardial Infarction. AB - PURPOSE OF REVIEW: The purpose of this review it to summarize the current literature on remodeling after myocardial infarction, inclusive of pathophysiological considerations, imaging modalities, treatment strategies, and future directions. RECENT FINDINGS: As patients continue to live longer after myocardial infarction (MI), the prevalence of post-MI heart failure continues to rise. Changes in the left ventricle (LV) after MI involve complex interactions between cellular and extracellular components, under neurohormonal regulation. Treatments to prevent adverse LV remodeling and promote reverse remodeling in the post-MI setting include early revascularization, pharmacotherapy aimed at neurohormonal blockade, and device-based therapies that address ventricular dyssynchrony. Despite varying definitions of adverse LV remodeling examined across multiple imaging modalities, the presence of an enlarged LV cavity and/or reduced ejection fraction is consistently associated with poor clinical outcomes. Advances in our knowledge of the neurohormonal regulation of adverse cardiac remodeling have been instrumental in generating therapies aimed at arresting adverse remodeling and promoting reserve remodeling. Further investigation into other specific mechanisms of adverse LV remodeling and pathways to disrupt these mechanisms is ongoing and may provide incremental benefit to current evidence based therapies. PMID- 28660554 TI - Authors' Reply to M.S. Raghuraman: "Intranasal Dexmedetomidine for Procedural Sedation in Children, a Suitable Alternative to Chloral Hydrate". PMID- 28660555 TI - The impact of visual symptoms on the quality of life of patients with early to moderate glaucoma. AB - PURPOSE: To investigate the visual symptoms and to determine the impact of visual symptoms on vision-related quality of life (QoL) in patients with early to moderate glaucoma. METHODS: A retrospective, hospital-based, cross-sectional study was conducted from July 1 to August 31, 2014, at a university referral center. A total of 176 patients with early to moderate glaucoma underwent a comprehensive ocular examination, including Humphrey visual field testing. The patients were divided into six groups based on visual symptoms that could be verified by forced-choice questions. Vision-related QoL was assessed by the Korean version of the National Eye Institute Visual Function Questionnaire 25 (K NEI-VFQ-25). We compared the mean deviation (MD) and questionnaire scores among the groups. RESULTS: Of 352 eyes, 107 (30.4%) were symptomatic. The most common visual symptoms were partial blurring (15.91%), followed by a missing part (7.67%) and a black part (5.97%) of the image. The symptomatic groups (blurred part and missing part) had a significantly worse MD than the asymptomatic group. The symptomatic groups tended to have more visual field defects than the asymptomatic group. The overall NEI-VFQ-25 score in the symptomatic group (black part) was significantly lower than that in the asymptomatic group. Similar effects were observed for other subscale scores, including social functioning, mental health, role difficulties, dependency, and peripheral vision. CONCLUSIONS: Vision-related QoL may be severely compromised in glaucoma patients with visual symptoms. Patients with visual disorders should be evaluated for glaucoma and QoL. PMID- 28660556 TI - The Effect of Endothelin Receptor Antagonists in Patients with Eisenmenger Syndrome: A Systematic Review. AB - INTRODUCTION: The efficacy of endothelin receptor antagonists (ERAs) in the management of Eisenmenger syndrome (ES) remains controversial. The aim of this study is to systemically review the safety and effects of ERAs in improving the quality of life and basic cardiac functions of these patients. METHODS: Twelve databases were searched, including PubMed, Web of Science, Scopus, Virtual Health Library, World Health Organization (WHO) Global Health Library, Google Scholar, POPLINE, Systems for Information of Grey Literature in Europe, New York Academy of Medicine, ClinicalTrials.gov, metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform, through August 2016. We included randomized clinical trials addressing the effect of ERAs on cardiac functions in patients with ES. The quality of studies was assessed using the Cochrane Collaboration tool. RESULTS: We included two trials represented by four papers, of which three papers reported the efficacy of bosentan against placebo and one paper reported the results of a combination of bosentan and sildenafil versus placebo and bosentan. One trial showed a significant effect of bosentan treatment over placebo on indexed pulmonary vascular resistance and mean pulmonary artery pressure, but a non-significant increase in 6-min walk distance and a non significant effect on systemic pulse oximetry. The other trial reported the safe but non-significant effect of combination therapy of bosentan and sildenafil compared with bosentan and placebo. CONCLUSIONS: This study demonstrated safety and improved hemodynamic effects of bosentan in ES, with a controversial effect on exercise capacity. Further randomized controlled trials with longer follow-up duration are needed to confirm these results. PMID- 28660557 TI - Long-Term Follow-up of Patients with Coronary Slow Flow Phenomenon. PMID- 28660558 TI - Morphometric changes in the spinal cord during prenatal life: a stereological study in sheep. AB - This study describes the volumetric changes in the spinal cord during prenatal life in sheep using quantitative stereological methods. Twenty healthy sheep fetuses were included in the present study, divided into four groups representing 9-11, 12-14, 15-17, and 18-20 weeks of gestation. In each group, the spinal cord was dissected out and sampled according to the unbiased systematic random sampling method then used for stereological estimations. The total volume of spinal cord, volume of gray matter (GM), volume of white matter (WM), ratio of GM volume to WM volume, and volume of central canal (CC) were estimated in the whole spinal cord and its various regions using Cavalieri's principle. The total volume of the spinal cord increased 8 times from week 9 to week 20. The cervical region showed the greatest (9.7 times) and the sacral region the least (6.3 times) volumetric change. The CC volume of the whole spinal cord increased 5.8 times from week 9 to week 20. The cervical region developed faster (8.2 times) and the thoracic region slower (4.4 times) than the total spinal cord. During development, the volume ratio of GM to WM decreased from lower toward upper regions. The greatest volume changes occurred mostly in weeks 9-11 and 12-14. The cervical region showed the greatest volume changes in comparison with other regions of the spinal cord. PMID- 28660559 TI - The changing comet. PMID- 28660560 TI - Jetstream atherectomy and balloon angioplasty with distal embolic protection for Angio-Seal related vascular access complications. AB - Arteriotomy closure devices (ACDs) are routinely used for vascular closure during invasive cardiovascular procedures. They decrease time to hemostasis as well as length of stay. Major complications such as arterial ischemia and occlusion can be encountered in a minority of patients. We are describing a series of 3 patients with access site closure using Angio-Seal after coronary angiography who developed intermittent claudication within 2-3 weeks of follow-up. Access site thrombosis/stenosis in the CFA was found in all the three cases. They were successfully revascularized using Jetstream atherectomy with embolic protection filter followed by balloon angioplasty. This technique can treat extensive thrombus burden as well as extract the collagen and foot plate of Angio-Seal through atherectomy with cutting blades and thrombectomy via rheolytic macerating aspiration port. All cases had excellent angiographic and clinical results. PMID- 28660561 TI - Hormonal effect on the relationship between migraine and female sexual dysfunction. AB - It is not a well-established finding in migraine that female sexual dysfunction (FSD) emerging as a natural course of disease, as a result of accompanying depression/anxiety, or an underlying endocrinological abnormality. Our aim is evaluating the relationship among frequency and severity of migraine, FSD, depression, anxiety, and related hormones in migrainous women. We examined 80 migrainous female and 62 controls cross sectionally. Beck Depression and Anxiety Inventories, Female Sexual Dysfunction Inventory, Migraine Disability Assessment Test, and hormonal analysis were done. Independent risk factors were identified by logistic regression analysis and cut-off values were measured with Receiver Operating Curve. FSD was not related to frequency or severity of migraine. Although depression and anxiety was related to arousal and lubrication, they had limited effect in FSD. There were correlations between prolactin (PRL), desire and lubrication, follicular-stimulating hormone FSH and orgasm, luteinizing hormone (LH), and pain. Also FSH-LH combination and PRL were found as independent factors for FSD. FSH-LH combination and PRL were found as independent factors which had effect on FSD in migraine. Our study is a precursor study about the effect of several hormones on FSD and migraine relationship. Hormonal effect on FSD in migraine will be clearer with future studies. PMID- 28660562 TI - Continuous quantitative monitoring of physical activity in Parkinson's disease patients by using wearable devices: a case-control study. AB - The objective of this study was to explore the feasibility of using wearable devices to quantitatively measure the daily activity in patients with Parkinson's disease (PD) and to monitor medication-induced motor fluctuations. In this case controlled study, we used monitored daily movement function in 21 patients with Parkinson's disease and 20 healthy volunteers. We analyzed the exercise types and sleep duration in the two groups and evaluated the correlation between daily movement function and age, gender, education, disease duration, Hohn-Yahr stage, UPDRS-II score, UPDRS-III score, and levodopa dose. We also determined the amount of exercise performed by PD patients at 1 h after taking levodopa and at 1 h before the next dose. The type of activity, average speed, and sleep duration in patients were significantly lower in PD patients than in healthy controls (P < 0.05). One hour after taking levodopa, patients were significantly more active than 1 h before the next dose (P < 0.05).Correlation analysis showed that age, gender, education, disease duration, Hohn-Yahr stage, UPDRS-II and UPDRS-III scores, and dosage of levodopa do not correlate with the daily movement function (P > 0.05) in patients with Parkinson's disease. In the control group, age and education were associated with daily movement function (P < 0.05), while gender was unrelated (P > 0.05). Continuous monitoring of daily activity may be useful to reveal medication-induced motor fluctuations in Parkinson's disease. The daily movement function may depend on age and education, but not on other parameters. PMID- 28660563 TI - Serum uric acid concentrations are directly associated with the presence of benign multiple sclerosis. AB - It has been reported that patients with multiple sclerosis (MS) exhibit lower serum uric acid levels; however, the association between uric acid concentrations and benign MS (BMS) has not been assessed. Hence, the objective of the present study was to determine whether the serum concentrations of uric acid are associated with the presence of BMS. Men and non-pregnant women over 16 years of age with diagnosis of MS were enrolled in a cross-sectional study. Expanded Disability Status Scale score < 3, progression of disease <=10 years, diabetes, renal or hepatic diseases, gout, malignancy, alcohol intake, and treatment with thiazide diuretics and/or acetylsalicylic acid were exclusion criteria. According to subtype of disease, the eligible patients were allocated into groups with BMS and other varieties of MS. A logistic regression analysis was conducted in order to evaluate the association between serum concentrations of uric acid and BMS. A total of 106 patients were included, 39 in the group with BMS and 67 in the group with other varieties of MS. The logistic regression analysis adjusted by age, sex, and disease duration showed that increased concentrations of uric acid, indeed within the physiological levels, are significantly associated with the presence of BMS (OR = 2.60; 95% CI: 1.55-4.38, p < 0.001). The results of the present study suggest that elevated concentrations of uric acid, indeed within the physiological range, are likely linked to the presence of BMS. PMID- 28660564 TI - A smartphone application to determine body length for body weight estimation in children: a prospective clinical trial. AB - The aim of this study was to test the feasibility and accuracy of a smartphone application to measure the body length of children using the integrated camera and to evaluate the subsequent weight estimates. A prospective clinical trial of children aged 0-<13 years admitted to the emergency department of the University Children's Hospital Zurich. The primary outcome was to validate the length measurement by the smartphone application "Optisizer". The secondary outcome was to correlate the virtually calculated ordinal categories based on the length measured by the app to the categories based on the real length. The third and independent outcome was the comparison of the different weight estimations by physicians, nurses, parents and the app. For all 627 children, the Bland Altman analysis showed a bias of -0.1% (95% CI -0.3-0.2%) comparing real length and length measured by the app. Ordinal categories of real length were in excellent agreement with categories virtually calculated based upon app length (kappa = 0.83, 95% CI 0.79-0.86). Children's real weight was underestimated by physicians (-3.3, 95% CI -4.4 to -2.2%, p < 0.001), nurses (-2.6, 95% CI -3.8 to -1.5%, p < 0.001) and parents (-1.3, 95% CI -1.9 to -0.6%, p < 0.001) but overestimated by categories based upon app length (1.6, 95% CI 0.3-2.8%, p = 0.02) and categories based upon real length (2.3, 95% CI 1.1-3.5%, p < 0.001). Absolute weight differences were lowest, if estimated by the parents (5.4, 95% CI 4.9-5.9%, p < 0.001). This study showed the accuracy of length measurement of children by a smartphone application: body length determined by the smartphone application is in good agreement with the real patient length. Ordinal length categories derived from app-measured length are in excellent agreement with the ordinal length categories based upon the real patient length. The body weight estimations based upon length corresponded to known data and limitations. Precision of body weight estimations by paediatric physicians and nurses were comparable and not different to length based estimations. In this non-emergency setting, parental weight estimation was significantly better than all other means of estimation (paediatric physicians and nurses, length based estimations) in terms of precision and absolute difference. PMID- 28660566 TI - Screening of BMPR1a for pathogenic mutations in familial colorectal cancer type X families from Newfoundland. AB - The Canadian province of Newfoundland and Labrador (NL) reports one of the highest incidence rates of familial colorectal cancer (CRC) worldwide. The NL population is an invaluable resource for studying genetic disorders because of a unique ancestry, and a willingness to participate in research studies. Familial colorectal cancer type X (FCCTX) describes a cluster of families with strong predisposition for CRC, of unknown etiology. A putative link between FCCTX and BMPR1a mutations has been identified in the Finnish population; however these findings have not been independently replicated. To investigate a potential connection between BMPR1a and FCCTX, we screened a cohort of 22 probands from unrelated NL FCCTX families using Sanger sequencing. This analysis did not independently replicate findings seen in Finland; as no candidate pathogenic BMPR1a mutations were uncovered. Our findings highlight that BMPR1a mutations are not a major contributor of FCCTX incidence in NL. Further investigation of additional FCCTX populations may assist in delineating a role for BMPR1a, if any, in FCCTX globally. PMID- 28660568 TI - Lipid Sample Preparation for Biomedical Research. AB - We describe here a step-by-step protocol for extraction of lipids from tissue/cell samples for biomedical research. The protocol described here works well for biological samples that contain lipids, which are less than 2% of weight compared to total wet weight of tissue or cells. The protocols described here are suitable and incremental modification of previously published protocols. These protocols have been developed based on our experience with different tissues and cells, and yield estimates determined using class-specific mass spectrometry either using direct infusion or after chromatographic separation. PMID- 28660565 TI - Biopsychosocial Aspects of Weight Management in Type 1 Diabetes: a Review and Next Steps. AB - PURPOSE OF REVIEW: This review aims to summarize the type 1 diabetes (T1D) and weight literature with an emphasis on barriers associated with weight management, the unique T1D-specific factors that impact weight loss success, maladaptive and adaptive strategies for weight loss, and interventions to promote weight loss. RECENT FINDINGS: Weight gain is associated with intensive insulin therapy. Overweight and obese weight status in individuals with T1D is higher than the general population and prevalence is rising. A variety of demographic (e.g., female sex), clinical (e.g., greater insulin needs), environmental (e.g., skipping meals), and psychosocial (e.g., depression, stress) factors are associated with overweight/obese weight status in T1D. Fear of hypoglycemia is a significant barrier to engagement in physical activity. Studies evaluating adaptive weight loss strategies in people with T1D are limited. There is a growing literature highlighting the prevalence and seriousness of overweight and obesity among both youth and adults with T1D. There is an urgent need to develop evidence-based weight management guidelines and interventions that address the unique concerns of individuals with T1D and that concurrently address glycemic control. PMID- 28660567 TI - The Best of Both Worlds: An Example Mixed Methods Approach to Understand Men's Preferences for the Treatment of Lower Urinary Tract Symptoms. AB - BACKGROUND: Discrete choice experiments (DCEs) are widely used to quantify individuals' preferences for healthcare. Guidelines recommend the design of DCEs should be informed by qualitative research. However, only a few studies go beyond guidelines by fully presenting qualitative and quantitative research jointly together in a mixed methods approach (MMA). OBJECTIVES: Using an example study about men's preferences for medical treatment of lower urinary tract symptoms (LUTS), we demonstrate how qualitative research can complement DCEs to gain a rich understanding of individuals' preferences. METHODS: We were the first to combine online discussion groups (ODGs) with an online DCE. A thematic analysis of the ODGs and a conceptual map provided insights into men's quality of life (QoL) with LUTS and relevant treatment attitudes. This was used to design the DCE. Men's willingness to pay (WTP) for these attributes was estimated. Findings from ODGs and DCE were compared to understand WTP and preference heterogeneity. KEY FINDINGS: Men mostly valued medicine that reduced urgency and night-time frequencies of urination but avoided sexual side effects. We find heterogeneity in the effect of sexual side effects on men's preferences. The ODGs suggest this is because several men may be sexually inactive due to their age, being widowed or having comorbidities. The ODGs also raised concern about men's awareness of LUTS. CONCLUSION: We argue that the insights gained into men's preferences for treatment and how LUTS affects men's QoL could not have been obtained by either the qualitative research or the DCE alone. PMID- 28660569 TI - Lipid Extraction Techniques for Stable Isotope Analysis and Ecological Assays. AB - Lipid extraction is an important component of many ecological and ecotoxicological measurements. For instance, percent lipid is often used as a measure of body condition, under the assumption that those individuals with higher lipid reserves are healthier. Likewise, lipids are depleted in 13C compared with protein, and it is consequently a routine to remove lipids prior to measuring carbon isotopes in ecological studies so that variation in lipid content does not obscure variation in diet. We provide detailed methods for two different protocols for lipid extraction: Soxhlet apparatus and manual distillation. We also provide methods for polar and nonpolar solvents. Neutral (nonpolar) solvents remove some lipids but few non-lipid compounds, whereas polar solvents remove most lipids but also many non-lipid compounds. We discuss each of the methods and provide guidelines for best practices. We recommend that, for stable isotope analysis, researchers test for a relationship between the change in carbon stable isotope ratio and the amount of lipid extracted to see if the degree of extraction has an impact on isotope ratios. Stable isotope analysis is widely used by ecologists, and we provide a detailed methodology that minimizes known biases. PMID- 28660570 TI - Isolation of Lipid Raft Proteins from CD133+ Cancer Stem Cells. AB - Pancreatic cancer cells expressing the surface markers CD133 have been widely reported as cancer stem cells and mainly responsible for tumor recurrence and chemoresistance in pancreatic cancer. In spite of its role as a stem cell marker in pancreatic cancer, its function remains elusive. CD133 (also known as prominin 1) is a pentaspan glycoprotein predominantly localized in lipid rafts, specialized membrane microdomains enriched in crucial signaling proteins. Coexistence of CD133 with these signaling proteins can modulate various signaling pathways that might be responsible for aggressive phenotype of CD133+ cells. This chapter describes a detailed protocol to isolate lipid rafts from CD133+ tumor initiating cells. Purified lipid rafts can be investigated further for protein or lipid composition by mass spectrometry that can shed some light on functional role of CD133 protein in these cancer stem cells. PMID- 28660571 TI - Isolation of Neuronal Synaptic Membranes by Sucrose Gradient Centrifugation. AB - Sucrose gradient centrifugation is a very useful technique for isolating specific membrane types based on their size and density. This is especially useful for detecting fatty acids and lipid molecules that are targeted to specialized membranes. Without fractionation, these types of molecules could be below the levels of detection after being diluted out by the more abundant lipid molecules with a more ubiquitous distribution throughout the various cell membranes. Isolation of specific membrane types where these lipids are concentrated allows for their detection and analysis. We describe herein our synaptic membrane isolation protocol that produces excellent yield and clear resolution of five major membrane fractions from a starting neural tissue homogenate: P1 (Nuclear), P2 (Cytoskeletal), P3 (Neurosynaptosomal), PSD (Post-synaptic Densities), and SV (Synaptic Vesicle). PMID- 28660572 TI - Sample Preparation and Analysis for Imaging Mass Spectrometry. AB - Imaging mass spectrometry (IMS) is a novel quantitative technique used to investigative diverse biomolecules in tissue sections. Specifically, IMS uses analytical separation of mass spectrometry to determine the spatial distribution of certain lipids and/or proteins located directly on biological sections from a single tissue sample. Typically, IMS is combined with histological analysis to reveal additional distribution details of characterized biomolecules including cell type and/or subcellular localization. In this chapter, we describe the use of Matrix-Assisted Laser Desorption/Ionization (MALDI) Time-Of-Flight/Time-Of Flight (TOF/TOF) to analyze various cholesterol and phosphatidylcholine species in atherosclerotic plaque of murine heart aortic valves. In particular, we detail animals used, tissue collection, preparation, matrix application, spectra acquisition for generating a color-coded image based on IMS spectral characteristics. PMID- 28660573 TI - Direct Measurement of Free and Esterified Cholesterol Mass in Differentiated Human Podocytes: A TLC and Enzymatic Assay-Based Method. AB - Esterified cholesterol content is often lower than free cholesterol content in biological systems and thus the determination of the esterified cholesterol content of cells is often challenging. Traditional methods use enzymatic assays in which an indirect measurement of the esterified cholesterol content is obtained by subtracting the measurements of the free from the total cholesterol content. However, this approach fails in the case where the total cholesterol content of cells is unchanged while the ratio of free to esterified cholesterol changes such that total and free cholesterol content are very similar and thus the difference may fall within the background noise of the enzymatic assay. To overcome this challenge, we here describe a method that utilizes a TLC-based technique to isolate esterified cholesterol. Isolated esterified cholesterol can then be measured using traditional enzymatic methods. Therefore, this method provides a practical and more sensitive assay to measure esterified cholesterol content in cellular extracts. PMID- 28660574 TI - High-Performance Chromatographic Separation of Cerebrosides. AB - High-performance thin-layer chromatography (HPTLC) is a very robust, fast, and inexpensive technique that enables separation of complex mixtures. Here, we describe the analytical separation of glucosylceramide and galactosylceramide by HPTLC. This technique can be used for quantitation purposes but also with small modification for subsequent mass spectrum analyses for structural determination. PMID- 28660575 TI - Lipid Identification by Untargeted Tandem Mass Spectrometry Coupled with Ultra High-Pressure Liquid Chromatography. AB - Lipidomics refers to the large-scale study of lipids in biological systems (Wenk, Nat Rev Drug Discov 4(7):594-610, 2005; Rolim et al., Gene 554(2):131-139, 2015). From a mass spectrometric point of view, by lipidomics we understand targeted or untargeted mass spectrometric analysis of lipids using either liquid chromatography (LC) (Castro-Perez et al., J Proteome Res 9(5):2377-2389, 2010) or shotgun (Han and Gross, Mass Spectrom Rev 24(3):367-412, 2005) approaches coupled with tandem mass spectrometry. This chapter describes the former methodology, which is becoming rapidly the preferred method for lipid identification owing to similarities with established omics workflows, such as proteomics (Washburn et al., Nat Biotechnol 19(3):242-247, 2001) or genomics (Yadav, J Biomol Tech: JBT 18(5):277, 2007). The workflow described consists in lipid extraction using a modified Bligh and Dyer method (Bligh and Dyer, Can J Biochem Physiol 37(8):911 917, 1959), ultra high pressure liquid chromatography fractionation of lipid samples on a reverse phase C18 column, followed by tandem mass spectrometric analysis and in silico database search for lipid identification based on MSMS spectrum matching (Kind et al., Nat Methods 10(8):755-758, 2013; Yamada et al., J Chromatogr A 1292:211-218, 2013; Taguchi and Ishikawa, J Chromatogr A 1217(25):4229-4239, 2010; Peake et al., Thermoscientifices 1-3, 2015) and accurate mass of parent ion (Sud et al., Nucleic Acids Res 35(database issue):D527-D532, 2007; Wishart et al., Nucleic Acids Res 35(database):D521-D526, 2007). PMID- 28660576 TI - Utility of Moderate and High-Resolution Mass Spectrometry for Class-Specific Lipid Identification and Quantification. AB - The study of lipidomics has been dramatically enhanced by using mass spectrometry techniques.With the purpose of identification and/or quantification of the lipids object of study, mass spectrometry has been proven to be the best approach, where three main techniques are currently being used: electrospray ionization (ESI), liquid chromatography (LC/MS), and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (Han et al. Mass Spectrom Rev 31:134-178, 2012). In order to avoid the problems generated by gradient concentration using liquid chromatography, here we describe the method used for the lipidomics analysis using moderate and high-resolution mass spectrometry for class-specific lipid identification and quantification for phospholipid species using ESI-MS/MS. PMID- 28660578 TI - Combined Use of MALDI-TOF Mass Spectrometry and 31P NMR Spectroscopy for Analysis of Phospholipids. AB - Lipids are important and abundant constituents of all biological tissues and body fluids. In particular, phospholipids (PL) constitute a major part of the cellular membrane, play a role in signal transduction, and some selected PL are increasingly considered as potential disease markers. However, methods of lipid analysis are less established in comparison to techniques of protein analysis. Mass spectrometry (MS) is an increasingly used technique to analyze lipids, especially in combination with electrospray ionization (ESI) MS which is the so far best established ionization method. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS has itself proven to be also useful in the field of lipid analysis. 31P nuclear magnetic resonance (NMR) spectroscopy is another powerful method of PL analysis, represents a direct quantitative method, and does not suffer from suppression effects.This chapter gives an overview of methodological aspects of MALDI-TOF MS and 31P NMR in lipid research and summarizes the specific advantages and drawbacks of both methods. In particular, suppression effects in MS will be highlighted and possible ways to overcome this problem (use of different matrices, separation of the relevant lipid mixture prior to analysis) will be discussed. PMID- 28660577 TI - A Robust Lipidomics Workflow for Mammalian Cells, Plasma, and Tissue Using Liquid Chromatography High-Resolution Tandem Mass Spectrometry. AB - Lipids have been analyzed in applications including drug discovery, disease etiology elucidation, and natural products. The chemical and structural diversity of lipids requires a tailored lipidomics workflow for each sample type. Therefore, every protocol in the lipidomics workflow, especially those involving sample preparation, should be optimized to avoid the introduction of bias. The coupling of ultra-high-performance liquid chromatography (UHPLC) with high resolution mass spectrometry (HRMS) allows for the separation and identification of lipids based on class and fatty acid acyl chain. This work provides a comprehensive untargeted lipidomics workflow that was optimized for various sample types (mammalian cells, plasma, and tissue) to balance extensive lipid coverage and specificity with high sample throughput. For identification purposes, both data-dependent and data-independent tandem mass spectrometric approaches were incorporated, providing more extensive lipid coverage. Popular open-source feature detection, data processing, and identification software are also outlined. PMID- 28660579 TI - Global Monitoring of the Mammalian Lipidome by Quantitative Shotgun Lipidomics. AB - The emerging field of lipidomics presents the systems biology approach to identify and quantify the full lipid repertoire of cells, tissues, and organisms. The importance of the lipidome is demonstrated by a number of biological studies on dysregulation of lipid metabolism in human diseases such as cancer, diabetes, and neurodegenerative diseases. Exploring changes and regulations in the huge networks of lipids and their metabolic pathways requires a lipidomics methodology: Advanced mass spectrometry that resolves the complexity of the lipidome. Here, we report a comprehensive protocol of quantitative shotgun lipidomics that enables identification and quantification of hundreds of molecular lipid species, covering a wide range of lipid classes, extracted from cultured mammalian cells. PMID- 28660580 TI - Bioinformatics Pertinent to Lipid Analysis in Biological Samples. AB - Electrospray ionization mass spectrometry has revolutionized the way lipids are studied. In this work, we present a tutorial for analyzing class-specific lipid spectra obtained from a triple quadrupole mass spectrometer. The open-source software MZmine 2.21 is used, coupled with LIPID MAPS databases. Here, we describe the steps for lipid identification, ratiometric quantification, and briefly address the differences to the analyses when using direct infusion versus tandem liquid chromatography-mass spectrometry (LC-MS). We also provide a tutorial and equations for quantification of lipid amounts using synthetic lipid standards and normalization to a protein amount. PMID- 28660581 TI - LC-MS-Based Lipidomics and Automated Identification of Lipids Using the LipidBlast In-Silico MS/MS Library. AB - This protocol describes the analysis, specifically the identification, of blood plasma lipids. Plasma lipids are extracted using methyl tert-butyl ether (MTBE), methanol, and water followed by separation and data acquisition of isolated lipids using reversed-phase liquid chromatography coupled to quadrupole/time-of flight mass spectrometry (RPLC-QTOFMS) operated in MS/MS mode. For lipid identification, acquired MS/MS spectra are converted to the mascot generic format (MGF) followed by library search using the in-silico MS/MS library LipidBlast. Using this approach, lipid classes, carbon-chain lengths, and degree of unsaturation of fatty-acid components are annotated. PMID- 28660582 TI - Single-Step Capture and Targeted Metabolomics of Alkyl-Quinolones in Outer Membrane Vesicles of Pseudomonas aeruginosa. AB - Outer membrane vesicles (OMVs) are secreted by all Gram-ve pathogens. These nano scale delivery vehicles contain discrete arrays of prokaryotic pathogenic determinants, including a family of low molecular weight (MW) lipidic quorum signaling alkyl-quinolones (AQs). These are synthesized from beta-keto-fatty acids and function like primordial lipidic hormones, which regulate numerous pathogenic factors both inter-species and intra-species. Significantly, AQs can also directly exacerbate pathogenesis by cross-kingdom signaling with the host immune, metabolic, and other systems. In Pseudomonas aeruginosa more than 50 AQs are reported; many with pathogenic mechanisms that are largely unknown. Some of these AQs are exclusively associated with OMVs. Accurate characterization of these OMV-AQs may reveal novel mechanism of diseases and Pseudomonas aeruginosa presents an ideal model. Matrix-free laser desorption/ionization mass spectrometry (LDI-MS) technologies enjoy unique advantages in mass spectrometry (MS)-based imaging and low MW analysis. We report single-step isolation of Pseudomonas aeruginosa OMV on inert ceramic filters and high-resolution mass spectrometry (HRMS) analysis of AQs vesicle in situ. PMID- 28660583 TI - Analysis of Fatty Acid and Cholesterol Content from Detergent-Resistant and Detergent-Free Membrane Microdomains. AB - The compartmentalization of cellular membranes into discrete membrane microdomains (known as lipid rafts) challenged the original definition of membranes as containing randomly distributed lipid and protein components. The lipid microdomain hypothesis has generated significant controversy and rigorous inquiry based on the attractive idea that such domains concentrate machinery to mediate cellular events such as signaling and endocytosis. As such, numerous studies have used biochemical, cell biological, and biophysical methodologies to define the composition of such domains in a variety of experimental contexts. In this chapter, we describe methodologies to isolate membranes from cell or tissue sources with biophysical/biochemical properties of membrane microdomains that are amenable to subsequent classical or mass spectrometry-based lipid analytical approaches. PMID- 28660584 TI - Computational Functional Analysis of Lipid Metabolic Enzymes. AB - The computational analysis of enzymes that participate in lipid metabolism has both common and unique challenges when compared to the whole protein universe. Some of the hurdles that interfere with the functional annotation of lipid metabolic enzymes that are common to other pathways include the definition of proper starting datasets, the construction of reliable multiple sequence alignments, the definition of appropriate evolutionary models, and the reconstruction of phylogenetic trees with high statistical support, particularly for large datasets. Most enzymes that take part in lipid metabolism belong to complex superfamilies with many members that are not involved in lipid metabolism. In addition, some enzymes that do not have sequence similarity catalyze similar or even identical reactions. Some of the challenges that, albeit not unique, are more specific to lipid metabolism refer to the high compartmentalization of the routes, the catalysis in hydrophobic environments and, related to this, the function near or in biological membranes.In this work, we provide guidelines intended to assist in the proper functional annotation of lipid metabolic enzymes, based on previous experiences related to the phospholipase D superfamily and the annotation of the triglyceride synthesis pathway in algae. We describe a pipeline that starts with the definition of an initial set of sequences to be used in similarity-based searches and ends in the reconstruction of phylogenies. We also mention the main issues that have to be taken into consideration when using tools to analyze subcellular localization, hydrophobicity patterns, or presence of transmembrane domains in lipid metabolic enzymes. PMID- 28660585 TI - Isoprenylation of Monomeric GTPases in Human Trabecular Meshwork Cells. AB - Small monomeric GTPases, including those belonging to the Rho family, regulate a diverse array of intracellular signaling pathways which affect vesicle transport/trafficking, endocytosis, cell cycle progression, cell contractility, and formation of stress fibers or focal adhesions. Functional activation of newly synthesized small monomeric GTPases is facilitated by a multistep post translational process involving transferase-catalyzed addition of farnesyl or geranylgeranyl isoprenoids to conserved cysteine residues within a unique carboxy terminal CaaX motif. Here, using well-established and widely available contemporary methodologies, detailed protocols by which to semi-quantitatively evaluate the functional consequence of post-translational isoprenylation in human trabecular meshwork cells are described. We introduce the concept that isoprenylation alone is itself a key regulator of mammalian Rho GTPase expression and turnover. PMID- 28660586 TI - Purification and Validation of Lipid Transfer Proteins. AB - Understanding the holistic picture of lipid homeostasis not only involves the analysis of synthesis and breakdown of lipids but also requires a thorough understanding of their transport. The transport of lipid monomers in an aqueous environment is facilitated by different lipid transfer proteins. Their universal feature is the shielding or encapsulation of the hydrophobic part of the lipid, consequently overcoming the poor solubility of lipids in water. Here we describe a method to purify lipid transfer proteins using bacterial expression. We also present three methods to validate their transfer activity. PMID- 28660587 TI - Incorporation of Artificial Lipid-Anchored Proteins into Cultured Mammalian Cells. AB - Exogenous lipid-anchored proteins can be incorporated into the plasma membranes of living mammalian cells, allowing the chemical structure of the incorporated protein and its lipid anchor to be controlled (and varied) to a much greater degree than is possible for proteins expressed by the cells themselves. This technology offers a variety of potential applications, including incorporating novel and complex protein constructs into cell surfaces and exploring structure function relationships for biologically important lipid-anchored proteins such as glycosylphosphatidylinositol-anchored proteins. Here we describe detailed methods for stable incorporation of artificial lipid-anchored proteins into cultured mammalian cells under mild, nonperturbing conditions. PMID- 28660588 TI - Sonication-Based Basic Protocol for Liposome Synthesis. AB - Liposomes are spherical vesicles with a wide range of sizes from nano- to micrometer scale. For the past 7-8 decades, these vesicles have occupied the interest of a variety of scientists due to its physical, chemical, and mathematical properties and, to say the least, for its immense utility and potential as delivery vehicles for toxic and nontoxic excipients into biological tissues. Methods related to selection of reagents for creation of specific liposomes of certain properties are beyond the scope of this chapter, but here, we would outline a simplistic protocol to prepare and qualify an uniform batch of simple liposome with basic cargo. This chapter will attempt to provide the reader with a starting point for this immensely potent tool to build upon the right kind of liposome, appropriate for their studies. PMID- 28660589 TI - On Electrochemical Methods for Determination of Protein-Lipid Interaction. AB - Amyloid-beta (Abeta) peptides are important and reliable molecular biomarkers for the diagnosis and prognosis of Alzheimer's disease. Aggregation and fibrillization of Abeta peptides on ganglioside GM1 (GM1)-containing lipid membranes is considered a cause of neurodegenerative disease. Because GM1 is abundant in the central nervous system and plays a key role in the aggregation of Abeta, the interaction of Abeta with supported planar lipid bilayers (SPBs) containing GM1 is of great significance. We have prepared SPBs containing GM1 in order to study the electrochemical characteristics of GM1/sphingomyelin/cholesterol SPBs and their interaction with Abeta(1-40) by cyclic voltammetry and electrochemical impedance spectroscopy (EIS), which proves that electrochemical is a promising method for analyzing the interaction between peptides and lipid membranes. PMID- 28660590 TI - Angiogenesis Model of Cornea to Understand the Role of Sphingosine 1-Phosphate. AB - The role of sphingolipids, mainly sphingosine 1-phosphate (S1P) and the receptors for which it serves as a ligand, is an interesting and promising area in both sphingolipid and vascular biology. S1P is crucial for establishing blood flow competent blood vessels (Jung et al. Dev Cell 23(3):600-610, 2012). The role of S1P in neovascular pathology is of great interest and promising as a target for treatment. Here we describe an easy and affordable in vivo model of neovascularization by an alkali chemical burn to the cornea. This gives a consistent and easy way to quantitate methods for neovascularization. PMID- 28660591 TI - Society of Behavioral Medicine (SBM) position statement: SBM supports curbing summertime weight gain among America's youth. AB - The Society of Behavioral Medicine recommends adoption of policies at the district, state, and federal levels that minimize weight gain among youth over the summertime, particularly among low-income, minority school-age youth who appear to be at greater risk. Policies that facilitate (1) partnerships between school districts and community organizations to provide affordable summertime programming, (2) strategic efforts by schools and communities to encourage families to enroll and attend summertime programming via the creation of community-wide summertime offerings offices, (3) adoption of joint-use/shared use agreements in communities to promote use of indoor and outdoor school facilities to provide affordable programming during the summer months, and (4) implementation of strategies that help summer programs achieve the Healthy Eating and Physical Activity (HEPA) standards which have been endorsed by the Healthy Out-of-School Time (HOST) coalition. Research is needed to elucidate key mechanisms by which involvement in structured programming may reduce weight gain over the summer months. PMID- 28660592 TI - Erratum to: Osseointegration of standard and mini dental implants: a histomorphometric comparison. PMID- 28660593 TI - Is Obesity the New Hypertension? Parallels in the Evolution of Obesity and Hypertension as Recognized Disease States. AB - Obesity and hypertension are recognized disease states that share many similarities including complex physiology, therapeutic response to both lifestyle modification and pharmacotherapy, and the need for long-term management. Both were initially believed to be disorders of lifestyle rather than true disease entities, and initial efforts at developing medical and surgical therapies were criticized. Ultimately, both have proven to be amenable to treatments that control their underlying physiology. Both hypertension and obesity have complex pathophysiology involving multiple regulatory pathways that may require combination therapies in addition to lifestyle modification to reach therapeutic goals. While hypertension is now a mature field practiced widely in primary care with the availability of 127 antihypertensive drugs, the specialty of obesity medicine is still in its infancy and growing in terms of management and development of medications, devices, and minimally invasive surgical interventions. Although the medical antiobesity armamentarium is relatively limited at present to six FDA-approved drugs, the development of combination pharmacotherapies with lower doses of component agents has improved efficacy and tolerability. As we look to the future of obesity medicine, hypertension can be used as a template to educate the public, fund research, and develop further treatment strategies. PMID- 28660594 TI - Thalidomide combined with chemotherapy in treating elderly patients with advanced gastric cancer. AB - AIM: The current systemic chemotherapy brings toxicity to human body, which elder patients suffer more than young people. The effective and well-tolerated treatment methods are of great importance for elderly advanced GC patients. This paper proposed an effective way of combining thalidomide with chemotherapy to treat elderly advanced GC patients, on the purpose of improving life quality and the treatment efficacy. METHODS: In the control group, capecitabine was given with 2000 mg/m2 daily in a manner of 2 weeks on and 1 week off for elderly advanced GC patients. In the study group, thalidomide was given with 100 mg per day concurrently with chemotherapy additionally administered. RESULTS: No significant differences were observed in the major prognostic factors among 64 eligible patients between the study and control groups. The ORRs and DCRs of the treatment and control groups showed no significant difference (P > 0.05). PFS of the study and control groups were 5.3 months (95% CI 4.5-6.2) and 4.2 months (95% CI 3.4-5.1), respectively. PFS exhibited a significant difference between the two group (P = 0.03), while the overall survivals of the patients between the two groups (10.4 months vs. 9.7 months) resulted as statistically non-significant (P = 0.47). Adverse effects were minimal in the study group, only a few patients suffered the grade 3 toxicity. The rate of drowsiness, fatigue, constipation of the study group was higher than that of the control group, and the rate of anorexia was lower (P < 0.05). CONCLUSIONS: Our results demonstrated that thalidomide combined with capecitabine was mildly effective and safe for treating elderly patients with advanced GC. PMID- 28660595 TI - Mismatch between stiffness in elastic and muscular arteries as a predictor of vascular calcification in dialysis patients. AB - BACKGROUND: Vascular calcification is one of the risk factors for arterial stiffness in patients with chronic kidney disease. We hypothesized that a mismatch between elastic and muscular arteries, represented as pulse wave velocity (PWV) ratio, could depict the extent of vascular calcification in end stage renal disease. We also aimed to compare the predictive PWV ratio value to other factors possibly related to vascular calcification in dialysis population. METHODS: In this cross-sectional study, in 60 chronic dialysis patients without previous cerebrovascular events, cardiovascular disease and events or clinically evident peripheral artery disease (ankle-brachial index >0.9), carotid-femoral and carotid-radial PWV as well as central hemodynamic parameters were measured by applanation tonometry (SphygmoCor). The PWV ratio using carotid-femoral PWV divided by carotid-radial PWV was calculated. Each patient underwent blood tests and chest X-ray for aortic arch calcification scoring. Two experienced radiologists blinded to patient's medical data evaluated chest X-rays (Cohen's kappa coefficient 0.76) and calculated how many sectors were calcified (Ogawa et al. in Hemodial Int 13:301-306, 2009). Differently scored chest X-rays were repeatedly reviewed and a consensus was reached. RESULTS: The study population consisted of 31 (51.7%) males and 29 (48.3%) females, mean age 52.73 +/- 13.76 years. Increased risk for aortic arch calcification was associated with higher PWV ratio even after adjustment for age, height, heart rate, ferritin level and C reactive protein level (OR 2.59E+04, 95% CI 2.43E+01, 2.65E+09, p = 0.021). PWV ratio together with above-mentioned variables could predict the presence of aortic arch calcification with specificity of 93% (95% CI 78, 99%) and sensitivity of 53% (95% CI 34, 72%). CONCLUSION: The elastic and muscular arteries' stiffness mismatch was strongly associated with the extent of aortic arch calcification in this dialysis population and had better calcification predictive value compared to other demographic, hemodynamic and biochemical markers. PMID- 28660596 TI - Risk factors for mortality in elderly patients with hip fractures: a meta analysis of 18 studies. AB - BACKGROUND: Hip fracture is common and associated with poor outcomes in elderly patients. This meta-analysis aims to investigate the risk factors that might increase the mortality rate in elderly patients with hip fracture. METHODS: PubMed, Embase, and Web of Science were systematically searched for observational studies regarding the prognostic factors of mortality in elderly patients with hip fracture. A fixed-effects or random-effects model was used to calculate pooled hazard ratio (HR) and 95% confidence intervals (95% CIs). RESULTS: Eighteen cohort studies, involving 223,875 patients, were included in this meta analysis. The most prominent factors associated with mortality were higher age (HR 1.51, 95% CI 1.37, 1.67; P < 0.001), male gender (HR 1.91, 95% CI 1.67, 2.19; P < 0.001), cognitive impairment (HR 2.06, 95% CI 1.25, 3.40; P = 0.005), delirium (HR 2.14, 95% CI 1.50, 3.05; P < 0.001), dementia (HR 2.72, 95% CI 1.41, 5.26; P = 0.003), depression (HR 1.71, 95% CI 1.43, 2.05; P < 0.001), living with caregiver (HR 1.61, 95% CI 1.43, 1.82; P < 0.001), cardiovascular disease (HR 2.10, 95% CI 1.14, 3.86; P = 0.018), renal disease (HR 1.66, 95% CI 1.52, 1.82; P < 0.001), and malignancy (HR 1.75, 95% CI 1.30, 2.37; P = 0.031), whereas respiratory disease (HR 1.49, 95% CI 0.99, 2.24; P = 0.056), diabetes (HR 1.15, 95% CI 0.96, 1.37; P = 0.121), and smoking (HR 1.54, 95% CI 0.64, 3.71; P = 0.337) did not increase the risk of mortality. CONCLUSION: The current study investigated several factors that might increase the risk of mortality in elderly patients with hip fracture. Further studies are needed to evaluate the effectiveness of specific interventions to reduce the risk of mortality. PMID- 28660597 TI - Barrett's Oesophagus and Oesophageal Carcinogenesis Following Obesity Surgery: Helicobacter Pylori Must Be Eradicated? PMID- 28660598 TI - Reply to the Letter to the Editor on "Helicobacter Pylori Does Not Affect Postoperative Outcomes after Sleeve Gastrectomy". PMID- 28660600 TI - Comparing two methods for determining appropriateness of myocardial perfusion imaging: Criteria from the American College of Cardiology Foundation and the American College of Radiology. AB - BACKGROUND: Appropriate use criteria (AUC) developed by the American College of Cardiology Foundation and the appropriateness criteria (AC) developed by the American College of Radiology (ACR) are two existing methods of rating appropriateness of myocardial perfusion imaging (MPI). One study found poor agreement of ratings between the two methods. However, using the most contemporary AUC from 2013, it is unknown if poor agreement still exists. METHODS: Retrospective cohort investigation comparing patients undergoing nuclear MPI between June 2011 and September 2014. The appropriateness category was determined based on the 2013 AUC (Appropriate, may be appropriate, rarely appropriate) and the 2010 ACR AC (usually appropriate, maybe appropriate, usually not appropriate). The primary outcome was the degree of the agreement between the two methods. RESULTS: The kappa coefficient between ACR AC and AUC was 0.32, P < 0.0001, indicating poor agreement; 40 (8%) patients were classified by the AUC but could not be classified by the ACR AC. CONCLUSION: The two methods for rating the appropriateness of MPI have poor agreement; a potential for disagreement between providers and payers if only one method is used. PMID- 28660599 TI - Exploring Asian Indian and Pakistani views about cancer and participation in cancer genetics research: toward the development of a community genetics intervention. AB - Cancer is a leading cause of mortality among the three million Asian Indian/Pakistanis (AIPs) in the USA. AIPs have traditionally been underrepresented in cancer-related research, although reasons remain largely unexplored. We sought to understand AIP's awareness and perceptions of cancer to improve their participation in risk assessment and cancer genetics research. Four focus groups, stratified by gender and birthplace (US-born vs. foreign-born), were held at an AIP cultural center. Discussions focused on knowledge and awareness of cancer risk; how AIP culture influences cancer perceptions; access to health care services for cancer screening, diagnosis, or treatment; and willingness to or experiences with participating in cancer genetics research. Sessions were audio-recorded, transcribed verbatim, and content analyzed using NVivo(r)11 for dominant themes. Thirty-two AIP adults participated in a focus group. Information on family cancer history is challenging to obtain due to the desire for privacy, cancer stigma, and loss of medical records. Interest in genetic testing for cancer risk was mixed: some were in favor of knowing their personal risk, yet many noted that future generations in their family would benefit more by knowing their risk. Participants felt that the AIP community has largely been overlooked in recruitment efforts for research studies. Recommendations for improving recruitment efforts included partnering with community events and festivities, posting culturally and linguistically relevant recruitment materials, and focusing on population-wide health improvement. Understanding the culture and perceptions of AIPs, separate from Asian Americans at large, will allow for more tailored approaches for including this population in cancer genetics research. PMID- 28660601 TI - Cardiac resynchronization therapy in chronic heart failure: Effect on right ventricular function. PMID- 28660603 TI - Clinical and diagnostic features of trochanteric tuberculosis. AB - Trochanteric tuberculosis is a very rare localization of musculo-skeletal tuberculosis. The diagnosis is difficult and is often made in a late stage. The authors describe five cases of trochanteric tuberculosis. The mean age of patients was 46.6 years. Time to diagnosis was long (7.6 months on average). The tuberculosis was plurifocal in all cases. Diagnosis was based on positive Lowenstein culture in one case, on the presence of caseum granuloma in one case and through a pathognommonic manifestation in one case. For the remaining two cases, diagnosis was established on clinical and paraclinical arguments. The patients recovered after medical treatment alone. PMID- 28660602 TI - Immunotherapeutic Approaches to Biliary Cancer. AB - OPINION STATEMENT: Biliary tract cancers (BTCs) are rare aggressive neoplasms with a poor prognosis and a median survival of less than 1 year in the locally advanced or metastatic setting. Among the few patients who undergo curative resection the recurrence rates are high. About 90% of patients are detected at advanced stages, and systemic chemotherapy is the mainstay of their treatment. The treatment options for these patients are limited and multiple modalities of therapy from targeted therapy to immunotherapy and combination therapies (immunotherapy, targeted therapy, and chemotherapy) have been tested in this disease. Targeted therapies have failed to show a survival benefit. The deregulation of the immune system plays a significant role in the pathogenesis of BTCs. Therefore, immunotherapy, especially, immune checkpoint inhibitors hold great promise for this group of cancers. Numerous trials of immunotherapy in BTC are currently ongoing. In this review, we will discuss the available data and evidence for immunotherapy in BTC. PMID- 28660604 TI - HIV prevalence and behavioral studies among female sex workers in Togo in 2015. AB - The purpose of this study is to determine the seroprevalence of HIVamong female sex workers (FSWs) and to document the behavior in this target population four years after the last study and possibly readjust these interventions. We conducted from March 27 to April 4, 2015 a crosssectional study of 1197 FSWs. Behavior data were collected by interviewer-administered questionnaires. The FSWs were then subjected to blood tests to measure the prevalence of HIV. The average age of respondents FSWs was 28 years and 20% had their first sexual intercourse before 15 years old. Overall, 48% of the FSWs received between 1 and 7 customers per working day. The majority of FSWs (90%) had consistently used condoms during their last week of work. HIV seroprevalence was 11.7% for FSWs. HIV prevalence was higher in FSWs living in Lome, the capital city, (13.4%) than those living in the Kara region, in the North of the country (2%), P < 0.0001. The results of this study show the positive behavioral change in FSWs with a stabilization of HIV prevalence in this group after four years. PMID- 28660605 TI - Evaluation of depressive mood and cognitive functions in patients with acromegaly under somatostatin analogue therapy. AB - AIMS: Acromegaly is caused by a pituitary adenoma that releases excess growth hormone (GH) and a concomitant increase in insulin-like growth factor 1 (IGF-1). Acromegaly results not only in phenotypic changes, but also in neurologic complications as peripheral neuropathy and cognitive dysfunction. This study aimed to compare depressive mood and cognitive function in patients with acromegaly and in healthy controls as well as to determine the factors underlying cognitive dysfunction in the acromegalic patients. MATERIALS AND METHODS: This study included 42 patients with acromegaly that were receiving somatostatin analogue therapy and 44 healthy controls. Memory, attention, visuospatial function, inhibitory function, abstract thinking, verbal fluency, and depressive mood were measured in the patients and controls. RESULTS: Patients with acromegaly had lower learning (p = 0.01), planning (p = 0.03), complex attention and inhibitory function (p = 0.04) scores than the controls. There was no significant difference in depressive mood between the patients and controls (p > 0.05). Gamma knife radiosurgery did not negatively affect cognitive function (p > 0.05). CONCLUSION: The present findings show that acromegaly negatively affects learning, attention, and planning. PMID- 28660608 TI - The evidence base for seafarer pre-employment medical examinations (PEMEs). PMID- 28660607 TI - The effects of alpha-lipoic acid on diabetic myopathy. AB - PURPOSE: Increased oxidative stress and impaired antioxidant defense are important mechanisms in the pathogenesis of diabetic myopathy. Since diabetes mellitus type 1 decreases muscle regeneration capacity the present study was designed to determine the influence of alpha-lipoic acid (ALA), a potent biological antioxidant, on the process of regeneration of diabetic rat skeletal muscles. METHODS: 40 Wistar rats were divided into three groups: control (n = 8), untreated diabetic group (n = 16) and ALA treated diabetic group (n = 16). The regeneration process was provoked in streptozotocin-induced diabetic rats in both slow (m.soleus, SOL) and fast (m.extensor digitorum longus, EDL) skeletal muscles by intramuscular injection of myotoxin bupivacaine. At intervals of 10 days and 4 weeks, muscle histochemical and morphometrical analysis (fiber cross areas and fiber type distribution) was performed. RESULTS: Changes induced by diabetes are evident in redistribution of muscle fibers and in significant level of atrophy. After 4 weeks of diabetes, glycolytic muscle fibers are dominant in both slow and fast muscles. Muscle atrophy is present in all fiber types except in type I of slow skeletal muscle. Treatment with ALA reduce changes in the morphological properties caused by diabetes mellitus type 1 in slow and fast rat skeletal muscles during the process of regeneration. CONCLUSION: Treatment with lipoic acid during 4 weeks has shown effects on the redistribution of muscle fibers, and can prevent atrophy in slow and fast diabetic muscle. PMID- 28660609 TI - The changing economic structure of the maritime industry and its adverse effects on seafarers' health care rights. AB - BACKGROUND: This review seeks to understand whether and how seafarers can exercise their human right to health care and the factors that facilitate or impede that exercise. The general focus is on a critical policy analysis of labour policies from the mid-twentieth century through today, with a specific focus on how Filipino seafarers access their health care rights. MATERIALS AND METHODS: The methodology includes a critical policy analysis of seafaring, focusing on mid-twentieth century political shifts in the recognition and regulation of health care rights. The analysis of international and United States policy provides the backbone for understanding the health care experiences of seafarers by laying the ideological, theoretical, and political foundations of labour rights and precarious employment. RESULTS: Policy analysis shows that there are numerous laws, regulations, and human rights norms that have been established to protect seafarers, but uncertain and limited recourse to lay claim to such laws, regulations, and norms while at sea. Lack of recourse to policies and regulations, taken together with the changed conditions of labour and worker protections through technology and neoliberal policies, create the conditions that may increase the health inequity among seafarers'. CONCLUSIONS: Health policy discussions in the United States and internationally must not solely focus on the health of seafarers as an interruption to travel and trade, but policy makers should consider that their decisions may contribute to how seafarers can exercise their rights to health care. In this context, health is more than disease and access to care - economic and governance structures come to not only matter, but play an integral role in the facilitation or impediment of health care and to the health arrangements/conditions of workers. PMID- 28660606 TI - Drug-induced obesity and its metabolic consequences: a review with a focus on mechanisms and possible therapeutic options. AB - Weight gain is a common side effect of many widely used drugs. Weight gain of a few kilograms to an increase of 10% or more of initial body weight has been described. Not only the weight gain as such puts a burden on the health risks of the involved patients, the accompanying increase in the incidence of the metabolic syndrome, type 2 diabetes mellitus, and cardiovascular risk factors urges the caregiver to identify and to closely monitor the patients at risk. In this review, the different classes of drugs with significant weight gaining properties and the metabolic consequences are described. Specific attention is given to pathogenetic mechanisms underlying the metabolic effects and to potential therapeutic measures to prevent them. PMID- 28660610 TI - Risk-taking behaviours among fishermen in Morocco by the evaluation of "ordalique" functioning. AB - BACKGROUND: The aim was to investigate the potential fishermen's psychological functioning which induces risk-taking behaviours by evaluating the ordalique functioning. MATERIALS AND METHODS: This cross-sectional epidemiological study was conducted in three ports of northern Morocco in 2016 and concerned 1413 traditional fishermen working in small embarkations and 1049 administrative staff working in the maritime sector on land. Both groups were male, comparable for age and educational level. The survey support was an individual questionnaire covering socio-demographic characteristics, toxic habits and ordalique functioning questionnaire (le questionnaire de fonctionnement ordalique, QFO). It is composed of 42 items and four dimensions which are evaluated: risk-taking, transgression, positive representation of risk-taking and believes. RESULTS: The prevalence of the ordalique behaviour and its four dimensions was significantly higher among traditional fishermen than administrative staff on land; 66.4% vs. 33.6% (p < 0.0001) for risk-taking, 65.2% vs. 34.8% (p < 0.0001) for transgression, 60.4% vs. 39.6% (p < 0.0001) for positive representation, 59.8% vs. 51.2% (p < 0.0001) for believes. For all range ages, the prevalence of ordalique functioning was higher among fishermen than administrative staff on land. Among fishermen, the prevalence of the was significantly higher among the under 40 years old (69.1% vs. 54.7%, p < 0.0001). The prevalence of toxic habits among ordalique fishermen was significantly greater than no-ordalique ones: tobacco (54.5% vs. 48.6%, p < 0.035), alcohol (42.8% vs. 32.4%, p < 0.0001), cannabis (34.8% vs. 26.6%, p < 0.0001), psychotropic drugs (13.8% vs. 10.4%, p < 0.081) and a combination of toxic habits (27.7% vs. 19.6%, p < 0.0001). CONCLUSIONS: Ordalique behaviour among fishermen may explain the partial failure of preventive measures in this sector. Risk-taking behaviours into account in the safety system could reduce occupational hazards in the fishery. PMID- 28660611 TI - Decision aid for the use of additional tests during the pre-employment medical examination (PEME) of seafarers. AB - No laboratory tests and imaging techniques are recommended for routine use in the ILO/IMO Guidelines on the Pre-Employment Medical Examination (PEME) of Seafarers that form the basis for statutory certification. However, they are widely used as components of the PEME protocols developed by insurers, employers and national maritime authorities in an attempt to predict and reduce the risks from illness whilst working at sea. This may be justified on scientific, safety, economic or professional grounds. We propose a rational approach for deciding if and when tests can be justified for routine use in assessing a seafarer's fitness for work at sea. This is based on well-established methods for determining the validity of screening tests in public health as well as the seafarer demographics. We do not address the well-established use of similar tests where illness is suspected but only when they are used for routine PEME screening of all seafarers. PMID- 28660612 TI - Standards for quality assurance of pre-employment medical examinations of seafarers: the IMHA Quality experience. AB - Standards to assess the quality of doctors and clinics performing pre-employment medical examinations (PEMEs) were developed for International Maritime Health Association (IMHA) Quality, a not for profit organisation, created to provide an ethically sound and professional accepted accreditation system that would benefit seafarers having PEMEs and employers, insurers and national maritime authorities seeking valid assessments of seafarers' fitness for duty. These standards followed a format widely used in other healthcare settings, where assessment of clinical performance is desirable. Uptake of these standards by doctors and clinics was not as expected, as they did not see sufficient business benefits coming from accreditation to justify the costs. This was, at least in part, because there was some antagonism to a professionally based accreditation system from commercial interest groups such as insurers, while national maritime authorities did not come forward to use the system as a recommendation or requirement for approval of doctors. The IMHA Quality accreditation system has now been closed and for this reason we are making the standards publicly available. Those who helped to develop them hope that doctors and clinics will now use them as a means of improving the quality of their practice when performing PEME. PMID- 28660613 TI - The design of health promotion strategies for seafarers. AB - Health promoting interventions among seafarers have, to date, been limited in scope and their effectiveness is questionable. There is good knowledge base from a wide range of onshore settings that indicates how best to structure health promotion initiatives in ways that are accepted by those affected by them and where their effectiveness has been fully evaluated. Here we identify the main lessons to be learnt from experience in other sectors and note the special features of the settings in which seafarers live and work as the basis for strategic development. The history of health promoting initiatives in seafarers is also summarised. The aim of this review is to foster debate about the best means to formulate seafarer health promotion initiatives and to introduce them in such ways that their effectiveness can be evaluated. The review has its origins as a scoping document for a strategic review of seafarer health promotion supported by the Seafarers' Trust. PMID- 28660614 TI - Seafarers' depression and suicide. AB - This review assesses available evidence on the frequency of and trends in depression and suicide among seafarers. Investigations of depression and suicide are scarce and the findings are inconsistent, they do, nevertheless, show indications of improvement although some recent case series do indicate that suicide remains a problem. A review of additional indicators for mental distress and lack of wellbeing supports the decline in frequency of problems, but nuances this in terms of the relative risks in different groups of seafarers, showing internal variations in the frequency of mental health issues among seafarers, with markers such as rank, type of voyage, gender, age, nationality and crew multiculturalism being relevant variables. The methodological limitations that hinder the understanding of depression and suicide in the maritime sector are identified. PMID- 28660615 TI - Self-reported exercise behaviour and perception of its importance to recreational divers. AB - BACKGROUND: This study examined self-reported physical activity and perceptions of exercise importance among certified divers in two distinct age groups. MATERIALS AND METHODS: Questionnaires were distributed by hand at dive sites in three states of the United States, half to students from an academic programme in scuba diving at a regional university. The survey included questions about health status, dive history, certification levels, structured exercise activity levels and perceived importance of regular exercise to their health, diving ability, and safety. Also included was the Godin-Shephard Leisure-Time Physical Activity Questionnaire, a validated physical activity classification instrument for use among adults. RESULTS: Non-students were older than the students and had greater diving experience. There was no detectable difference between groups in perceived exercise importance to health (p = 0.69), diving ability (p = 0.75), or diving safety (p = 0.25). Fitting age, sex, occupation and number of dives to a generalised linear model to predict Godin-Shephard scores, number of dives was removed first (p = 0.43), followed by student status (p = 0.33). Remaining predictors of Godin-Shephard exercise scores were age (-0.004 per year, p < 0.0001) and sex (males = + 0.11, 95% CI 0.04-0.17, p = 0.0012). Both groups reported similar structured exercise regularity, overall health and perceived importance of regular exercise for health, diving and safety. CONCLUSIONS: Despite acknowledging the importance of exercise, Godin-Shephard scores for physical activity decrease with age. PMID- 28660616 TI - Added value of sending photograph in diagnosing a medical disease declared at sea: experience of the French Tele-Medical Assistance Service. AB - : The maritime medical tele-consultation carried out by a doctor from the Toulouse Tele-Medical Assistance Service is currently based on tele-consultation using radiotelegraphy and the complementary transmission of data (photographs, electrocardiogram) via the Internet. In a previous article, we presented the benefits of photograph transmission for trauma management in isolated areas. Through this new series of cases, we wanted to expose the aspect of the medical pathologies and the contribution of sending photographs in their management. CASE REPORTS: Case 1. Myocardial infarction. Case 2. Toxic epidermal necrolysis. Case 3. Tooth abscess. Case 4. Shingles. Case 5. Junctional tachycardia. The tele transmission of photographs provides a real diagnostic and follow-up tool for patients suffering from medical pathologies. The constant increase in the number of tele-consultations with the exchange of photographs shows its necessity and the interest of the participants in the development of these technologies. PMID- 28660617 TI - Exploring the core of crew resource management course: speak up or stay silent. AB - The Norwegian Costal Express travels 24/7 along a coast considered as one of the most dangerous littoral areas of the world. It is crucial for safe voyage to speak up when one of the crewmembers discovers a discrepancy or vital new information to the passage that needs to be shared and acted upon. Crew resource management courses are intended to increase safety and we suggest that the key is to enhance the ability to speak up. Watch keepers valued a 4-h course intended to enhance the ability to speak up and improve listening skills as highly relevant (89%) and educational (69%). These high scores indicate that this type of training is necessary to improve safety. PMID- 28660619 TI - Dermatological learning needs among aboriginal health workers in rural and remote Australia: A cross-sectional survey. PMID- 28660618 TI - High-Frequency Ultrasound in Blistering Skin Diseases: A Useful Method for Differentiating Blister Locations. AB - Bullous pemphigoid and pemphigus vulgaris, which belong to the group of subepidermal and intraepidermal bullae, respectively, are two potentially devastating blistering skin diseases. We used high-frequency ultrasound (US) in 3 cases of these diseases as prototypes to study the value of high-frequency US in discriminating blister locations. Our findings showed that high-frequency US has a strong correlation with histomorphometric findings because of its high resolution, and we hope that it will be helpful for differentiating blister locations. PMID- 28660620 TI - 3D Printed Photoresponsive Devices Based on Shape Memory Composites. AB - Compared with traditional stimuli-responsive devices with simple planar or tubular geometries, 3D printed stimuli-responsive devices not only intimately meet the requirement of complicated shapes at macrolevel but also satisfy various conformation changes triggered by external stimuli at the microscopic scale. However, their development is limited by the lack of 3D printing functional materials. This paper demonstrates the 3D printing of photoresponsive shape memory devices through combining fused deposition modeling printing technology and photoresponsive shape memory composites based on shape memory polymers and carbon black with high photothermal conversion efficiency. External illumination triggers the shape recovery of 3D printed devices from the temporary shape to the original shape. The effect of materials thickness and light density on the shape memory behavior of 3D printed devices is quantified and calculated. Remarkably, sunlight also triggers the shape memory behavior of these 3D printed devices. This facile printing strategy would provide tremendous opportunities for the design and fabrication of biomimetic smart devices and soft robotics. PMID- 28660621 TI - Changes in hip abductor moment 3 or more years after femoral derotation osteotomy among individuals with cerebral palsy. AB - AIM: To examine the effect of femoral derotation osteotomy (FDO) on dimensionless hip abductor moment during gait in children with cerebral palsy. METHODS: We retrospectively analyzed data from independent ambulators within our database. Postoperative visits 1 year (short-term) and at least 3 years (mid-term) were analyzed. We estimated the coronal plane hip abductor moment arm based on musculoskeletal modeling that accounted for anteversion and hip rotation. RESULTS: There were 140 individuals with a short-term analysis (77 males, 63 females; age at surgery 9y 11mo [range 4y 5mo-17y 5mo]) and 29 with mid-term analysis (15 males, 14 females; age at surgery 8y 7mo [range 4y 5mo-13y 1mo]). At short-term, anteversion and internal hip rotation decreased 35 degrees and 13 degrees respectively, which increased median (IQR) moment arms from 20 (23) per cent below normal to 2 (12) per cent above normal. Dimensionless mean hip abductor moment remained unchanged at short-term. Mid-term anteversion did not change but hip rotation increased 8 degrees and hip abductor moment increased to 0.040 (0.029). There was no change in pelvic and trunk obliquity, although hip abductor strength increased and walking velocity decreased at mid-term. INTERPRETATION: The unexpected lack of improvement in hip abductor moment from pre- to short-term may be caused by gait compensations that unload the hip. The increase in hip abductor moment beyond 3 years postoperatively underscores the benefits of an FDO into adolescence for independent ambulating individuals with cerebral palsy. PMID- 28660622 TI - Palliative care access for hospitalized patients with end-stage liver disease across the United States. AB - : Patients with end-stage liver disease (ESLD) often have a high symptom burden. Historically, palliative care (PC) services have been underused in this population. We investigated the use of PC services in patients with ESLD hospitalized across the United States. We used the Nationwide Inpatient Sample to conduct a retrospective nationwide cohort analysis. All patients >18 years of age admitted with ESLD, defined as those with at least two liver decompensation events, were included in the analysis. A multivariate logistic regression model predicting referral to PC was created. We analyzed 55,208,382 hospitalizations from the 2006-2012 Nationwide Inpatient Sample, with 39,349 (0.07%) patients meeting study inclusion. PC consultation was performed in 1,789 (4.5%) ESLD patients. The rate of PC referral in ESLD increased from 0.97% in 2006 to 7.1% in 2012 (P < 0.01). In multivariate analysis, factors associated with lower referral to PC were Hispanic race (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.66-0.89; P < 0.01) and insurance coverage (OR, 0.74; 95% CI, 0.65-0.84; P < 0.01). Factors associated with increased referral to PC were age (per 5-year increase, OR, 1.05; 95% CI, 1.03-1.08; P < 0.01), do-not-resuscitate status (OR, 16.24; 95% CI, 14.20-18.56; P < 0.01), treatment in a teaching hospital (OR, 1.25; 95% CI, 1.12-1.39; P < 0.01), presence of hepatocellular carcinoma (OR, 2.00; 95% CI, 1.71-2.33; P < 0.01), and presence of metastatic cancer (OR, 2.39; 95% CI, 1.80-3.18; P < 0.01). PC referral was most common in west coast hospitals (OR, 1.81; 95% CI, 1.53-2.14; P < 0.01) as well as large-sized hospitals (OR, 1.49; 95% CI, 1.22-1.82; P < 0.01). CONCLUSION: From 2006 to 2012 the use of PC in ESLD patients increased substantially; socioeconomic, geographical, and ethnic barriers to accessing PC were observed. (Hepatology 2017;66:1585-1591). PMID- 28660623 TI - Leprosy: An ancient disease that still threatens global health. PMID- 28660624 TI - How do hospital-specialty characteristics influence health system responsiveness? An empirical evaluation of in-patient care in the Italian region of Emilia Romagna. AB - Studies of health system responsiveness mostly focus on the demand side by investigating the association between sociodemographic characteristics of patients and their reported level of responsiveness. However, little is known about the influence of supply-side factors. This paper addresses that research gap by analysing the role of hospital-specialty characteristics in explaining variations in patients' evaluation of responsiveness from a sample of about 38,700 in-patients treated in public hospitals within the Italian Region of Emilia-Romagna. The analysis is carried out by adopting a 2-step procedure. First, we use patients' self-reported data to derive 5 measures of responsiveness at the hospital-specialty level. By estimating a generalised ordered probit model, we are able to correct for variations in individual reporting behaviour due to the health status of patients and their experience of being in pain. Second, we run cross-sectional regressions to investigate the association between patients' responsiveness and potential supply-side drivers, including waiting times, staff workload, the level of spending on non-clinical facilities, the level of spending on staff education and training, and the proportion of staff expenditure between nursing and administrative staff. Results suggest that responsiveness is to some extent influenced by the supply-side drivers considered. PMID- 28660625 TI - Recalcitrant ulcers associated with anti-small ubiquitin-like modifier activating enzyme-positive dermatomyositis treated with surgery followed by intravenous immunoglobulin. PMID- 28660626 TI - Hepatocellular malignant neoplasm, NOS: a clinicopathological study of 11 cases from a single institution. AB - AIMS: The primary aim of this study is to characterize hepatocellular malignant neoplasm, NOS (HEMNOS), a new provisional entity describing a subset of paediatric hepatocellular tumours, which have histological features of neither typical hepatoblastoma (HB) nor hepatocellular carcinoma (HCC). METHODS AND RESULTS: The clinicopathological features of 11 patients with HEMNOS were analysed retrospectively. The median age and serum alpha-fetoprotein level at diagnosis was 7 years and 182 000 ng/ml, respectively. Ten patients presented with pretreatment extent of disease (PRETEXT) stages III/IV multifocal tumours, eight with major vascular involvement, three with lung metastases and three with extrahepatic extension. The original pathology diagnoses were: HB in seven patients, HCC in two and HEMNOS in two. Our pathology review of pre-chemotherapy specimens showed that six tumours had equivocal/overlapping histological features of HB and HCC, four had predominant HB histology along with focal HCC-like histology and one had HB histology. Seven of nine post-chemotherapy resection specimens showed predominant HCC-like histology. Beta-catenin, glypican 3 and spalt-like transcription factor 4 immunostaining showed that all the tumours had a mixed HB/HCC immunophenotype. Telomerase reverse transcriptase immunostaining showed nuclear staining in nine of the 11 tumours. All patients received chemotherapy and achieved gross total primary tumour resection. Nine of the 11 patients were treated with established HB chemotherapy regimens. After a median follow-up of 6.1 years (range: 1.2-11.8 years), all patients were in remission. CONCLUSIONS: HEMNOS is a subtype of HB with focal HCC-like histology, a high-risk clinical profile but favourable outcome following chemotherapy and complete tumour resection. PMID- 28660627 TI - Four new species of Talaromyces from clinical sources. AB - The genus Talaromyces constitutes an important group of molds with species that are mainly found in soil, indoor environments and food products. Traditionally, it has been considered, together with Eupenicillium, the teleomorphic state of Penicillium. However, the taxonomy of these fungi has changed considerably, and Talaromyces currently includes sexually and asexually reproducing species. In a previous study of the occurrence of penicillium-like fungi from clinical samples in the USA, we used the combined phylogeny of the internal transcribed spacer (ITS) region of the rDNA and beta-tubulin (BenA) gene to identify 31 isolates of Talaromyces, 85 of Penicillium and two of Rasamsonia. However, seven isolates of Talaromyces were assigned to the corresponding sections but not to any particular species. In this study, we have resolved the taxonomy of these isolates through a multilocus sequence analysis of the ITS, fragments of the BenA, calmodulin (CaM), and RNA polymerase II second largest subunit (RPB2) genes, and a detailed phenotypic study. As a result, four new species are described and illustrated, ie Talaromyces alveolaris, T. georgiensis, T. minnesotensis and T. rapidus. PMID- 28660628 TI - Efficient estimation of binding free energies between peptides and an MHC class II molecule using coarse-grained molecular dynamics simulations with a weighted histogram analysis method. AB - We estimate the binding free energy between peptides and an MHC class II molecule using molecular dynamics (MD) simulations with the weighted histogram analysis method (WHAM). We show that, owing to its more thorough sampling in the available computational time, the binding free energy obtained by pulling the whole peptide using a coarse-grained (CG) force field (MARTINI) is less prone to significant error induced by inadequate-sampling than using an atomistic force field (AMBER). We further demonstrate that using CG MD to pull 3-4 residue peptide segments while leaving the remaining peptide segments in the binding groove and adding up the binding free energies of all peptide segments gives robust binding free energy estimations, which are in good agreement with the experimentally measured binding affinities for the peptide sequences studied. Our approach thus provides a promising and computationally efficient way to rapidly and reliably estimate the binding free energy between an arbitrary peptide and an MHC class II molecule. (c) 2017 Wiley Periodicals, Inc. PMID- 28660629 TI - Mixture models for undiagnosed prevalent disease and interval-censored incident disease: applications to a cohort assembled from electronic health records. AB - For cost-effectiveness and efficiency, many large-scale general-purpose cohort studies are being assembled within large health-care providers who use electronic health records. Two key features of such data are that incident disease is interval-censored between irregular visits and there can be pre-existing (prevalent) disease. Because prevalent disease is not always immediately diagnosed, some disease diagnosed at later visits are actually undiagnosed prevalent disease. We consider prevalent disease as a point mass at time zero for clinical applications where there is no interest in time of prevalent disease onset. We demonstrate that the naive Kaplan-Meier cumulative risk estimator underestimates risks at early time points and overestimates later risks. We propose a general family of mixture models for undiagnosed prevalent disease and interval-censored incident disease that we call prevalence-incidence models. Parameters for parametric prevalence-incidence models, such as the logistic regression and Weibull survival (logistic-Weibull) model, are estimated by direct likelihood maximization or by EM algorithm. Non-parametric methods are proposed to calculate cumulative risks for cases without covariates. We compare naive Kaplan-Meier, logistic-Weibull, and non-parametric estimates of cumulative risk in the cervical cancer screening program at Kaiser Permanente Northern California. Kaplan-Meier provided poor estimates while the logistic-Weibull model was a close fit to the non-parametric. Our findings support our use of logistic Weibull models to develop the risk estimates that underlie current US risk-based cervical cancer screening guidelines. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA. PMID- 28660630 TI - Cryopreservation of Nili-Ravi buffalo (Bubalus bubalis) semen in AndroMed(r) extender; in vitro and in vivo evaluation. AB - The study was designed to evaluate AndroMed(r) for the freezability and fertility of Nili-Ravi buffalo semen. Semen was collected from four adult Nili-Ravi buffalo (Bubalus bubalis) bulls for 3 weeks (replicate). Semen ejaculates from each buffalo bull were divided into three aliquots. One aliquot was used for evaluation of motility, plasma membrane integrity, livability, viability, DNA integrity and normal apical ridge. Remaining two aliquots were diluted (37 degrees C; 50 * 106 spermatozoa/ml) in tris-citric egg yolk or AndroMed(r) extender and cryopreserved in 0.5 ml French straws. After thawing, per cent post thaw motility (47.9 +/- 0.8, 49.2 +/- 1.7), plasma membrane integrity (44.4 +/- 1.2, 46.8 +/- 1.8) and normal apical ridge (81.4 +/- 0.3, 83.2 +/- 0.3) were recorded similar (p > .05) in tris-citric egg yolk and AndroMed(r) extender. Higher (p < .05) percentage of sperm livability (70.5 +/- 1.4 and 64.4 +/- 1.0), viability (67.5 +/- 1.5 and 61.5 +/- 0.6) and DNA integrity (97.0 +/- 0.3 and 93.4 +/- 0.21) were recorded in AndroMed(r) compared to tris-citric egg yolk post thaw. Values for all the aforementioned spermatozoal quality parameters were observed lower (p < .05) in frozen-thawed compared to fresh semen irrespective of the experimental extenders. Fertility rates of buffalo semen did not differ (p > .05) either cryopreserved in tris-citric egg yolk or AndroMed(r) extender (45.5% vs. 49%). It is concluded that AndroMed(r) is capable in protecting the buffalo bull sperm during freeze-thawing process and can be adopted safely for routine use replacing the tris-citric egg yolk extender in artificial insemination programme. PMID- 28660631 TI - Yes, health is important, but as much for its importance via social life: The direct and indirect effects of health on subjective well-being in chronically ill individuals. AB - There is an increasing evidence that health-related quality of life, income, and social relationships are important to our subjective well-being (SWB). Little is known, however, about the specific indirect pathways that link health to SWB via social relationships and income. On the basis of a unique data set of 7 disease groups from 6 OECD-countries (N = 6,173), we investigate the direct and indirect effects of health on SWB by using structural equation modeling. Three alternative measures of health are used: For generic instruments (EQ-5D-5L; SF-6D), the total indirect effect was stronger (0.226; 0.249) than its direct effect (0.157; 0.205). For the visual analogue scale, the direct effect was stronger (0.322) than its total indirect effect (0.179). Most of the indirect effect of improved health on SWB transmitted through social relationships. The effect via income was small. Nevertheless, the presence of unmeasured confounders may bias the estimates. An important lesson for researchers is to include meaningful items on social relationships when measuring the benefits from improved health. An important lesson for policy makers is that social isolation appears to be more detrimental to overall well-being than ill health. Hence, the Health and Care Services should facilitate social arenas for people with chronic conditions. PMID- 28660632 TI - Proposed new staging system for ampulla of Vater cancer with greater discriminatory ability: multinational study from eastern and western centers. AB - BACKGROUND: We built a multinational retrospective database of patients with ampulla of Vater cancer to develop a reliable new staging system. METHOD: This study included 841 patients with ampulla of Vater cancer after curative surgery at Seoul National University Hospital (n = 440) and Johns Hopkins University medical institutions (n = 401) between 1985 and 2013. RESULTS: The 5-year overall survival (OS) rates of patients staged according to the 7th American Joint Committee on Cancer staging system were 80.3%, 60.9%, 58.1%, 36.6%, 17.9%, and 25.0% for Stages IA (n = 140), IB (n = 194), IIA (n = 115), IIB (n = 348), III (n = 33), and IV (n = 4), respectively. Five-year OS rates were similar in patients with Stage IB (T2N0M0) and IIA (T3N0M0) tumors (P = 0.556), but differed significantly between other pairs of groups. The number of positive lymph nodes (PLN) enhanced prognosis when stratified as 0, 1-2 and >=3 (P < 0.001). The revised staging system consisted of Stages I (T1, PLN 0), IIA (T2-T3, PLN 0), IIB (T1-T3, PLN 1-2), III (PLN >=3 or any T4), and IV (any M1), with 5-year OS rates differing significantly in each pair of groups, including Stages I and IIA (P < 0.001). CONCLUSION: This new staging system has better discriminatory ability in stratifying 5-year OS rates based on a large multinational database. PMID- 28660633 TI - Cross-sectional study of psychological stress and skin symptoms in Australian university students. PMID- 28660634 TI - Effects of phylogeny and locomotor style on the allometry of body mass and pelvic dimensions in birds. AB - The pelvic girdle provides physical support and attachment for the hind limb musculature. In birds there is variability in pelvic morphology across different orders and this has been used as evidence for various types of locomotion. However, the morphological variation of pelvic bones has yet to be studied systematically in birds. Therefore, we investigated basic allometric relationships among female body mass (as a size proxy) and various pelvic measurements in a phylogenetic context. We also examined in detail the inter relationships among various pelvic measurements. Also considered were the effects of broader taxonomic relationships at the level of order, with further examination of the influence of style of terrestrial locomotion on the allometric relationships. Positive relationships were initially found among all pelvic linear measurements and female body mass (FBM). The relationships among measures of pelvic width and FBM were isometric, whereas those between pelvic length and FBM showed positive allometry. Also, FBM explained more of the variance in pelvic length than in width. Similarly, the angle of the pelvis had a significant negative relationship, but FBM only explained a very low proportion of the variation in pelvic angles. In general terms, ancova showed that the effect of FBM was smaller than the effect of locomotor style in this species set. Both the synsacrum and pelvic girdle play roles in weight support and therefore scale in proportion to body weight accordingly. All three parts of the pelvis (ilium, ischium and pubis) are attached around the acetabulum and also provide muscle attachment points, so it might be expected for them to scale in a similar manner. Increased angulation of the pelvis is linked to orders which employ their hind limbs in feeding, perching and running, although FBM also explains a very low proportion of the variation in pelvic angle. Muscle attachment and the confines on morphology presented by locomotion explain much of the variation exhibited by the relationships among pelvic measurements. PMID- 28660635 TI - Pyoderma gangrenosum arising during treatment of psoriasis with adalimumab: Effectiveness of ustekinumab. PMID- 28660636 TI - Pulmonary co-infections by Pneumocystis jirovecii and Aspergillus fumigatus in non-HIV patients: A report of two cases and literature review. AB - Pneumocystis jirovecii is the causative agent of Pneumocystis pneumonia (PcP), a common and often life-threatening opportunistic infection in HIV-infected patients. However, non-HIV, immunocompromised patients are at risk of PcP as well, whereas the mortality appears to be higher among these patients. Pneumocystis co-infections with other microorganisms are less frequent and only sparse reports of combined PcP and invasive pulmonary fungal infections exist in the literature, especially in the non-HIV patients. Two cases of pulmonary co infections by P. jirovecii and Aspergillus fumigatus are presented. Both patients were non-HIV infected, the first one was suffering from crescentic IgA nephropathy under immunosuppressive treatment and the second from resistant non Hodgkin lymphoma under chemotherapy. Both patients were treated with intravenous trimethoprim/sulphamethoxazole (TMP/SMX) combined with voriconazole. The first patient showed gradual clinical improvement while the outcome for the second patient was unfavourable. In addition, a literature review of the previous published cases of co-infection by P. jirovecii and other fungi in non-HIV patients was performed. Our target was to provide comprehensive information on this kind of infections, highlighting the importance of clinical suspicion. PMID- 28660637 TI - Sensory processes modulate differences in multi-component behavior and cognitive control between childhood and adulthood. AB - Many everyday tasks require executive functions to achieve a certain goal. Quite often, this requires the integration of information derived from different sensory modalities. Children are less likely to integrate information from different modalities and, at the same time, also do not command fully developed executive functions, as compared to adults. Yet still, the role of developmental age-related effects on multisensory integration processes has not been examined within the context of multicomponent behavior until now (i.e., the concatenation of different executive subprocesses). This is problematic because differences in multisensory integration might actually explain a significant amount of the developmental effects that have traditionally been attributed to changes in executive functioning. In a system, neurophysiological approach combining electroencephaloram (EEG) recordings and source localization analyses, we therefore examined this question. The results show that differences in how children and adults accomplish multicomponent behavior do not solely depend on developmental differences in executive functioning. Instead, the observed developmental differences in response selection processes (reflected by the P3 ERP) were largely dependent on the complexity of integrating temporally separated stimuli from different modalities. This effect was related to activation differences in medial frontal and inferior parietal cortices. Primary perceptual gating or attentional selection processes (P1 and N1 ERPs) were not affected. The results show that differences in multisensory integration explain parts of transformations in cognitive processes between childhood and adulthood that have traditionally been attributed to changes in executive functioning, especially when these require the integration of multiple modalities during response selection. Hum Brain Mapp 38:4933-4945, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28660638 TI - Using Search Engines to Investigate Shared Migraine Experiences. AB - OBJECTIVES: To investigate migraine patterns in the United States using Google search data and utilize this information to better understand societal-level trends. Additionally, we aimed to evaluate time-series relationships between migraines and social factors. BACKGROUND: Extensive research has been done on clinical factors associated with migraines, yet population-level social factors have not been widely explored. Migraine internet search data may provide insight into migraine trends beyond information that can be gleaned from other sources. METHODS: In this longitudinal analysis of open access data, we performed a time series analysis in which about 12 years of Google Trends data (January 1, 2004 to August 15, 2016) were assessed. Data points were captured at a daily level and Google's 0-100 adjusted scale was used as the primary outcome to enable the comparison of relative popularity in the migraine search term. We hypothesized that the volume of relative migraine Google searches would be affected by societal aspects such as day of the week, holidays, and novel social events. RESULTS: Several recurrent social factors that drive migraine searches were identified. Of these, day of the week had the most significant impact on the volume of Google migraine searches. On average, Mondays accumulated 13.31 higher relative search volume than Fridays (95% CI: 11.12-15.51, P <= .001). Surprisingly, holidays were associated with lower relative migraine search volumes. Christmas Day had 13.84 lower relative search volumes (95% CI: 6.26 21.43, P <= .001) and Thanks giving had 20.18 lower relative search volumes (95% CI: 12.55-27.82, P <= .001) than days that were not holidays. Certain novel social events and extreme weather also appear to be associated with relative migraine Google search volume. CONCLUSIONS: Social factors play a crucial role in explaining population level migraine patterns, and thus, warrant further exploration. PMID- 28660639 TI - The role of regulatory T cells in thymectomy-induced autoimmune ovarian disease. AB - PROBLEM: To evaluate the role of regulatory T (Treg) cells in autoimmune ovarian disease (AOD). METHOD OF STUDY: AOD model was set up by thymectomy of BALB/C mice on day 3 (d3tx). The variation of T lymphocyte subsets, especially the Treg cells were analyzed in the peripheral blood, spleen, para-aortic, and inguinal lymph nodes in d3tx mice. The effect of Treg cells on AOD was further evaluated by adoptive transfer of Treg cells into d3tx mice (d3tx+Treg). RESULTS: In d3tx mice, the ratio of Treg/CD4+ was significantly increased rapidly from 1st to 2nd week, rapidly declined in 3rd week, then decreased slowly until the 9th week. The CD3+ /T lymphocytes and the ratio of CD4+ /CD3+ were significantly decreased in the para-aortic and inguinal lymph nodes of d3tx mice, but the ratio of Treg/CD4+ and CD8+ /CD3+ were increased simultaneously. In d3tx mice with adoptive transfer of Treg cells (0.5*104 ~5*105 ), there was a significant increase in the Treg/CD4+ ratios in the spleen and peripheral blood. AOD score, especially adoptive transferred treg cells from the ovarian lymph nodes was significantly decreased. Oocytes were successfully obtained from d3tx+Treg mice, which could fertilize and develop to embryos normally. CONCLUSION: Treg cells involved in the pathogenesis of AOD. Sufficient numbers of Treg cells can modify AOD in the early phase in d3tx mice. PMID- 28660641 TI - Author response to the contributors to the discussion on "A critical evaluation of the current 'p-value controversy'". PMID- 28660640 TI - Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion dependent thalassaemia and HCV genotype 1 or 4 infection. AB - BACKGROUND: Patients with thalassaemia major depend on blood transfusions. In Italy, up to 80% of thalassaemia patients bear HCV antibodies due to HCV contaminated transfusions before 1990. Thalassaemia patients with HCV infection have high risk of developing HCC. Treatment based on Pegylated-IFN (Peg-IFN) and Ribavirin (RBV) was limited by relevant side effects. AIM: To evaluate the impact of Sofosbuvir/Ledipasvir (SOF/LDV) fixed dose combination for 12 weeks without RBV, in patients with thalassaemia major and HCV Genotype 1 or 4 (GT1/4). METHODS: Open label, historically-controlled, nationwide multicentre study in thalassaemia patients including naive with cirrhosis and prior treatment failure without cirrhosis. SOF/LDV single pill was administered for 12 weeks to 100 patients of whom 16% had cirrhosis. The control group included 96 patients with comparable baseline characteristics treated with Peg-IFN/RBV. The primary end point was sustained virologic response at follow-up week 12 or 24 after IFN-free or Peg-IFN/RBV, respectively. RESULTS: In the study group, sustained virological response (SVR) was reported in 98% of patients (95% CI 95.3%-100%). Cirrhotic as well as prior treatment failure achieved 100% SVR. In the control group, SVR was 47.9% (95% CI 37.9%-57.9%). Adverse events including fatigue, headache, nausea, decrease in haemoglobin or increase in ferritin levels were rare and significantly less common in the study than in the historical control group. CONCLUSIONS: In conclusion, SOF/LDV for 12 weeks provides simple, highly effective and safe Peg-IFN/RBV-free treatment for HCV GT1/4 thalassaemia patients. EUDRACT number 2015-002401-1. PMID- 28660642 TI - Towards inclusive occupational therapy: Introducing the CORE approach for inclusive and occupation-focused practice. AB - BACKGROUND/AIM: Occupation is a human right and a social determinant of health. It is also taken for granted. Having access to, and participating in, occupation, is intricately linked to positive health and wellbeing. Despite theory and evidence to support the link between occupation, health and wellbeing, occupational therapists can struggle with applying an occupation focus in practice and knowing how to use occupational frameworks to enable occupation. The purpose of this paper is to introduce the Capabilities, Opportunities, Resources and Environments (CORE) approach for inclusive and occupation-focused practice. It provides occupational therapists with a means of operationalising occupational enablement and facilitating social inclusion. METHODS: The CORE approach is introduced by linking its main ideas to Economist and Nobel Prize Laureate Amartya Sen's capabilities approach, as well as findings from the author's doctoral research into entrenched disadvantage and social inclusion. Practical questions guided by the CORE approach's acronym are given to explore how the approach can be utilised alongside other occupational models and frameworks to encourage strategies for effective enablement through occupation for social inclusion. CONCLUSION: As experts in enabling occupation, occupational therapists can use the CORE approach to design occupation-focused interventions and promote inclusive occupational therapy. PMID- 28660643 TI - Graduating into a downturn: Are physicians recession proof? AB - An extensive literature documents immediate and persistent adverse labor market outcomes for individuals graduating into an economic downturn, but these effects are heterogeneous across sectors, occupations, and skill levels. In particular, the impact of recessions on the labor market outcomes for new physician graduates remains unknown. We leverage a unique dataset on New York physicians to analyze if and how the Great Recession impacted the labor market of physicians who have completed their residency and fellowship training and are seeking their first job. We find that these physicians do not delay labor market entry and their job searches and other employment outcomes are unaffected by the business cycle. The collage of evidence demonstrates that new graduates were largely unfazed by the recent downturn, which sharply contrasts with other highly educated, high remunerating occupations. PMID- 28660644 TI - Motion control skill assessment based on kinematic analysis of robotic end effector movements. AB - BACKGROUND: The performance of robotic end-effector movements can reflect the user's operation skill difference in robot-assisted minimally invasive surgery. This study quantified the trade-off of speed-accuracy-stability by kinematic analysis of robotic end-effector movements to assess the motion control skill of users with different levels of experience. METHODS: Using 'MicroHand S' system, 10 experts, 10 residents and 10 novices performed single-hand test and bimanual coordination test. Eight metrics based on the movements of robotic end-effectors were applied to evaluate the users' performance. RESULTS: In the single-hand test, experts outperformed other groups except for movement speed; in the bimanual coordination test, experts also performed better except for movement time and movement speed. No statistically significant difference in performance was found between residents and novices. CONCLUSIONS: The kinematic differences obtained from the movements of robotic end-effectors can be applied to assess the motion control skill of users with different skill levels. PMID- 28660645 TI - Rapid response to clinical symptoms in early psoriatic onycho-pachydermo periostitis treated with infliximab. PMID- 28660646 TI - How reliable is the Assisting Hand Assessment for adolescents with unilateral cerebral palsy? PMID- 28660647 TI - Heteroresistance and fungi. AB - The concept of heteroresistance refers to the heterogeneous susceptibility to an antimicrobial drug in a microorganism population, meaning that some clones may be resistant and others are susceptible. This phenomenon has been widely studied in bacteria, but little attention has been given to its expression in fungi. We review the available literature on heteroresistance in fungi and invite the reader to recognise this phenomenon as a fungal mechanism to adapt to environmental stress, which may interfere both in resistance and virulence. Finally, heteroresistance may explain the treatment failures to eradicate mycosis in some patients treated with a seemingly appropriate antifungal. PMID- 28660648 TI - Lepromatous leprosy with Lucio's phenomenon. PMID- 28660649 TI - Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months. AB - BACKGROUND: Vaccination with Bacillus Calmette-Guerin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. METHODS: The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13 months of age. Subgroups of participants were offered blood sampling at 13 months of age. RESULTS: By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). CONCLUSION: In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age. PMID- 28660651 TI - A vicious circle in chronic lymphoedema pathophysiology? An adipocentric view. AB - Chronic lymphoedema is a disease caused by a congenital or acquired damage to the lymphatic system and characterized by complex chains of pathophysiologic events such as lymphatic fluid stasis, chronic inflammation, lymphatic vessels impairment, adipose tissue deposition and fibrosis. These events seem to maintain and reinforce themselves through a positive feedback loop: regardless of the initial cause of lymphatic stasis, the dysfunctional adipose tissue and its secretion products can worsen lymphatic vessels' function, aggravating lymph leakage and stagnation, which can promote further adipose tissue deposition and fibrosis, similar to what may happen in obesity. In addition to the current knowledge about the tight and ancestral interrelation between immunity system and metabolism, there is evidence for similarities between obesity-related and lymphatic damage-induced lymphoedema. Together, these observations indicate strong reciprocal relationship between lymphatics and adipose tissue and suggest a possible key role of the adipocyte in the pathophysiology of chronic lymphoedema's vicious circle. PMID- 28660650 TI - Rational Design of Domain-Swapping-Based c-Type Cytochrome Heterodimers by Using Chimeric Proteins. AB - The design of protein oligomers with multiple active sites has been gaining interest, owing to their potential use for biomaterials, which has encouraged researchers to develop a new design method. Three-dimensional domain swapping is the unique phenomenon in which protein molecules exchange the same structural region between each other. Herein, to construct oligomeric heme proteins with different active sites by utilizing domain swapping, two c-type cytochrome-based chimeric proteins have been constructed and the domains swapped. According to X ray crystallographic analysis, the two chimeric proteins formed a domain-swapped dimer with two His/Met coordinated hemes. By mutating the heme coordination structure of one of the two chimeric proteins, a domainswapped heterodimer with His/Met and His/H2 O coordinated hemes was formed. Binding of an oxygen molecule to the His/H2 O site of the heterodimer was confirmed by resonance Raman spectroscopy, in which the Fe-O2 stretching band was observed at 580 cm-1 for the reduced/oxygenated heterodimer (at 554 cm-1 under an 18 O2 atmosphere). These results show that domain swapping is a useful method to design multiheme proteins. PMID- 28660652 TI - Change in Use of Sleep Medications After Gastric Bypass Surgery or Intensive Lifestyle Treatment in Adults with Obesity. AB - OBJECTIVE: To examine the change in use of hypnotics and/or sedatives after gastric bypass surgery or intensive lifestyle modification in adults with obesity. METHODS: Adults with obesity who underwent gastric bypass surgery or initiated intensive lifestyle modification between 2007 and 2012 were identified through the Scandinavian Obesity Surgery Registry and a Swedish commercial weight loss database. The two cohorts were matched on BMI, age, sex, education, history of hypnotics and/or sedatives use, and treatment year (surgery n = 20,626; lifestyle n = 11,973; 77% women, mean age 41 years, mean BMI 41 kg/m2 ). The proportion of participants with filled hypnotics and/or sedatives prescriptions was compared yearly for 3 years. RESULTS: In the matched treatment cohorts, 4% had filled prescriptions for hypnotics and/or sedatives during the year before treatment. At 1 year follow-up, following an average weight loss of 37 kg and 18 kg in the surgery and intensive lifestyle cohorts, respectively, this proportion had increased to 7% in the surgery cohort but remained at 4% in the intensive lifestyle cohort (risk ratio 1.7; 95% CI: 1.4-2.1); at 2 years, the proportion had increased to 11% versus 5% (risk ratio 2.0; 95% CI: 1.7-2.4); and at 3 years, it had increased to 14% versus 6% (risk ratio 2.2; 95% CI: 1.9-2.6). CONCLUSIONS: Gastric bypass surgery was associated with increased use of hypnotics and/or sedatives compared with intensive lifestyle modification. PMID- 28660653 TI - Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant. AB - Cytomegalovirus (CMV) infection in clinical settings other than the allogeneic transplant represents a poorly explored issue. Thus, we performed a comprehensive review of the medical literature about CMV infection in patients undergoing autologous hematopoietic stem cell transplant and in other nontransplant-related hematologic patients. In autologous hematopoietic stem cell transplant, a CMV reactivation is reported to occur in up to 41% of CMV seropositive patients, when a prospective monitoring of antigenemia and/or viremia by polymerase chain reaction was adopted. However, more contained frequencies, up to 12%, have been reported when the monitoring criteria were based on a clinically driven diagnostic strategy. The most relevant risk factors appear to be CD34 + selected autografts, total body irradiation, and prior treatment with Alemtuzumab, Fludarabine, or Bortezomib, respectively. Other possible risk factors (ie, prior treatment with Rituximab, T-cell lymphomas, and pretransplant HBcIgG seropositivity) are still debated. In nontransplant settings, the data are very heterogeneous; thus, CMV infection incidence and risk factors are more difficult to establish. Overall, the rate of CMV infection/reactivation ranges between 2 and 67%. High-dose steroids, advanced disease, poor performance status, and treatment with Alemtuzumab, Fludarabine, Bortezomib, and Rituximab appear as the most relevant, though putative, risk factors. Intravenous Ganciclovir represents the gold standard for first-line treatment of CMV infection in these patients. Oral Valganciclovir and Foscarnet are other possible options. Extensive prophylaxis and preemptive therapy are not generally recommended, with the exception of high-risk patients. PMID- 28660654 TI - Teleultrasound: How Accurate Are We? AB - OBJECTIVES: Ultrasound serves an important role in the prenatal diagnosis of fetal structural anomalies. Recently, there has been increased use of teleultrasound protocols. We aimed to evaluate the sensitivity and accuracy of teleultrasound. METHODS: We conducted an Institutional Review Board-approved retrospective cohort study determining the sensitivity and accuracy of teleultrasound. In addition, we evaluated the number of ultrasound examinations required to complete an anatomic survey. Only ultrasound examinations performed for anatomic surveys were included. Studies were excluded if performed before 16 completed weeks' gestation, if they had multiple gestations, or for reasons other than anatomy (eg, Doppler studies and fluid assessment). Prenatal diagnoses were compared with postnatal diagnoses obtained from a robust mandatory birth defects surveillance program that records all birth defects in the entire state, from deliveries before 20 weeks' gestation through infants up to 2 years of age. RESULTS: A total of 2499 studies were evaluated; 2368 were included. The teleultrasound cohort had a congenital anomaly prevalence of 5.66%. The sensitivity of teleultrasound was 57.46%; the specificity was 98.21%; and the accuracy was 95.9%. Anatomic surveys were completed after 1 visit in 82% of patients, whereas 63% and 61% of the remaining patients required 2 and 3 visits, respectively. CONCLUSIONS: Teleultrasound for prenatal diagnosis has similar sensitivity and accuracy as the published literature for on-site ultrasound. Further studies are needed to compare the sensitivity and accuracy within the same population and further validate this potentially cost-saving modality. PMID- 28660655 TI - Association between total globozoospermia and sperm chromatin defects. AB - Globozoospermia is a severe sperm morphological anomaly leading to primary infertility and low fertilisation following intracytoplasmic sperm injection (ICSI). This phenotype is observed in less than 0.1% of infertile men and is determined by small, round-headed spermatozoa with absence of an acrosomal cap, acrosome protease and also cytoskeletal proteins. Failure of oocyte activation is considered as the main cause of fertilisation failure in these individuals post ICSI. Therefore, artificial oocyte activation (AOA) along with ICSI is commonly implemented. However, based on previous report, fertilisation rate remains low despite implementation of ICSI-AOA. Therefore, other mechanisms like sperm chromatin packaging and DNA fragmentation may account for low fertilisation and development post-ICSI-AOA. Therefore, this study aims to assess and compare the degree of sperm protamine deficiency and DNA fragmentation in large population of infertile men with total globozoospermia (30 globozoospermic men presenting with 100% round-headed spermatozoa) with 22 fertile individuals using chromomycin A3 and TUNEL assay respectively. Results clearly show that mean of sperm concentration and percentage of sperm motility were significantly lower, while percentage of sperm abnormal morphology, protamine-deficient and DNA-fragmented spermatozoa were significantly higher in infertile men with globozoospermia compared to fertile men. Therefore, increased sperm DNA damage in globozoospermia is likely related to defective DNA compaction and antioxidant therapy before ICSI AOA could be recommended as an appropriate option before ICSI-AOA. PMID- 28660657 TI - Pay less, consume more? The price elasticity of home care for the disabled elderly in France. AB - Little is known about the price sensitivity of demand for home care of the disabled elderly. We partially fill this knowledge gap by using administrative data on the beneficiaries of the main French home care subsidy program in a department and exploiting interindividual variation in provider prices. We address the potential endogeneity of prices by taking advantage of the unequal spatial coverage of providers and instrumenting price by the number of municipalities served by a provider. We estimate a price elasticity of around 0.4 that is significantly different from both 0 and -1. This less than proportionate response of consumption to price has implications for the efficiency and redistributive impact of variation in the level of copayments in home care subsidy schemes. PMID- 28660656 TI - Early Identification of Reading Difficulties: A Screening Strategy that Adjusts the Sensitivity to the Level of Prediction Accuracy. AB - Early screening for reading difficulties before the onset of instruction is desirable because it allows intervention that is targeted at prevention rather than remediation of reading difficulties. However, early screening may be too inaccurate to effectively allocate resources to those who need them. The present study compared the accuracy of early screening before the onset of formal reading instruction with late screening six months into the first year of instruction. The study followed 164 Danish students from the end of Grade 0 to the end of Grade 2. Early screening included measures of phonemic awareness, rapid naming, letter knowledge, paired associate learning, and reading. Late screening included only reading. Results indicated that reading measures improved substantially as predictors over the first six months of Grade 1, to the point where late reading measures alone provided as much information as the early measures combined. In the light of these results and a less than perfect early screening accuracy, a new strategy for screening is introduced and discussed. The strategy proposes multi-point screening with gradually increasing sensitivity to strike a balance between manageable screening procedures and outcomes and early identification of students who are most likely in need of extra resources. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28660658 TI - Cannabis and psychotic experiences. PMID- 28660659 TI - RNA structure, binding, and coordination in Arabidopsis. AB - From the moment of transcription, up through degradation, each RNA transcript is bound by an ever-changing cohort of RNA binding proteins. The binding of these proteins is regulated by both the primary RNA sequence, as well as the intramolecular RNA folding, or secondary structure, of the transcript. Thus, RNA secondary structure regulates many post-transcriptional processes. With the advent of next generation sequencing, several techniques have been developed to generate global landscapes of both RNA-protein interactions and RNA secondary structure. In this review, we describe the current state of the field detailing techniques to globally interrogate RNA secondary structure and/or RNA-protein interaction sites, as well as our current understanding of these features in the transcriptome of the model plant Arabidopsis thaliana. WIREs RNA 2017, 8:e1426. doi: 10.1002/wrna.1426 For further resources related to this article, please visit the WIREs website. PMID- 28660660 TI - Photovoltaic Rudorffites: Lead-Free Silver Bismuth Halides Alternative to Hybrid Lead Halide Perovskites. AB - Hybrid CPbX3 (C: Cs, CH3 NH3 ; X: Br, I) perovskites possess excellent photovoltaic properties but are highly toxic, which hinders their practical application. Unfortunately, all Pb-free alternatives based on Sn and Ge are extremely unstable. Although stable and non-toxic C2 ABX6 double perovskites based on alternating corner-shared AX6 and BX6 octahedra (A=Ag, Cu; B=Bi, Sb) are possible, they have indirect and wide band gaps of over 2 eV. However, is it necessary to keep the corner-shared perovskite structure to retain good photovoltaic properties? Here, we demonstrate another family of photovoltaic halides based on edge-shared AX6 and BX6 octahedra with the general formula Aa Bb Xx (x=a+3 b) such as Ag3 BiI6 , Ag2 BiI5 , AgBiI4 , AgBi2 I7 . As perovskites were named after their prototype oxide CaTiO3 discovered by Lev Perovski, we propose to name these new ABX halides as rudorffites after Walter Rudorff, who discovered their prototype oxide NaVO2 . We studied structural and optoelectronic properties of several highly stable and promising Ag-Bi-I photovoltaic rudorffites that feature direct band gaps in the range of 1.79-1.83 eV and demonstrated a proof-of-concept FTO/c-m-TiO2 /Ag3 BiI6 /PTAA/Au (FTO: fluorine doped tin oxide, PTAA: poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine], c: compact, m: mesoporous) solar cell with photoconversion efficiency of 4.3 %. PMID- 28660661 TI - Anionic Redox in Rechargeable Lithium Batteries. AB - The extraordinarily high capacities delivered by lithium-rich oxide cathodes, compared with conventional layered oxide electrodes, are a result of contributions from both cationic and anionic redox processes. This phenomenon has invoked a lot of research exploring new kinds of lithium-rich oxides with multiple-electron redox processes. Though proposed many years ago, anionic redox is now regarded to be crucial in further developing high-capacity electrodes. A basic overview of the previous work on anionic redox is given, and issues related to electronic and geometric structures are discussed, including the principles of activation, reversibility, and the energy barrier of anionic redox. Anionic redox also leads to capacity loss and structural degradation, as well as voltage hysteresis, which shows the importance of controlling anionic redox reactions. Finally, the techniques used for characterizing anionic redox processes are reviewed to aid the rational choice of techniques in future studies. Important perspectives are highlighted, which should instruct future work concerning anionic redox processes. PMID- 28660662 TI - Chlorogenic acid supplementation during in vitro maturation improves maturation, fertilization and developmental competence of porcine oocytes. AB - Chlorogenic acid (CGA) is a quinic acid conjugate of caffeic acid, and a phytochemical found in many fruits and beverages that acts as an antioxidant. The present study investigated the effects of CGA supplementation during in vitro maturation (IVM), on in vitro development of porcine oocytes, to improve the porcine in vitro production (IVP) system. Oocytes were matured either without (control) or with CGA (10, 50, 100 and 200 MUM). Subsequently, the matured oocytes were fertilized and cultured in vitro for 7 day. The rates of maturation, fertilization and blastocyst formation of oocytes matured with 50 MUM CGA were significantly (p < .05) higher than those of the control oocytes. Hydrogen peroxide (H2 O2 ) is one of the reactive oxygen species and induces DNA damage in porcine oocytes. When oocytes were matured with 1 mM H2 O2 to assess the protective effect of CGA, 50 MUM CGA supplementation improved the maturation rate and the proportion of DNA-fragmented nuclei in oocytes compared with control oocytes matured without CGA. Moreover, when oocytes were matured with either 50 MUM CGA (control) or caffeic acid (10, 50 and 100 MUM), the rates of maturation, fertilization and the blastocyst formation of oocytes matured with 50 MUM CGA were similar to those of oocytes matured with 10 and 50 MUM caffeic acid. Our results suggest that CGA has comparable effects to caffeic acid, and IVM with 50 MUM CGA is particularly beneficial to IVP of porcine embryos and protects oocytes from DNA damage induced by oxidative stress. Supplementation of CGA to the maturation medium has a potential to improve porcine IVP system. PMID- 28660663 TI - Review article: dyssynergic defaecation and biofeedback therapy in the pathophysiology and management of functional constipation. AB - BACKGROUND: Functional constipation is a common clinical presentation in primary care. Functional defaecation disorders are defined as the paradoxical contraction or inadequate relaxation of the pelvic floor muscles during attempted defaecation (dyssynergic defaecation) and/or inadequate propulsive forces during attempted defaecation. Prompt diagnosis and management of dyssynergic defaecation is hindered by uncertainty regarding nomenclature, diagnostic criteria, pathophysiology and efficacy of management options such as biofeedback therapy. AIM: To review the evidence pertaining to the pathophysiology of functional defaecation disorders and the efficacy of biofeedback therapy in the management of patients with dyssynergic defaecation and functional constipation. METHODS: Relevant articles addressing functional defaecation disorders and the efficacy of biofeedback therapy in the management of dyssynergic defaecation and functional constipation were identified from a search of Pubmed, MEDLINE Ovid and the Cochrane Library. RESULTS: The prevalence of dyssynergic defaecation in patients investigated for chronic constipation is as many as 40%. Randomised controlled trials have demonstrated major symptom improvement in 70%-80% of patients undergoing biofeedback therapy for chronic constipation resistant to standard medical therapy and have determined it to be superior to polyethylene glycol laxatives, diazepam or sham therapy. Long-term studies have shown 55%-82% of patients maintain symptom improvement. CONCLUSIONS: Dyssynergic defaecation is a common clinical condition in patients with chronic constipation not responding to conservative management. Biofeedback therapy appears to be a safe, successful treatment with sustained results for patients with dyssynergic defaecation. Further studies are required to standardise the diagnosis of dyssynergic defaecation in addition to employing systematic protocols for biofeedback therapy. PMID- 28660664 TI - Engaging Ly-6A/Sca-1 triggers lipid raft-dependent and -independent responses in CD4+ T-cell lines. AB - INTRODUCTION: The lymphocyte antigen 6 (Ly-6) supergene family encodes proteins of 12-14 kda in molecular mass that are either secreted or anchored to the plasma membrane through a glycosyl-phosphatidylinisotol (GPI) lipid anchor at the carboxy-terminus. The lipidated GPI-anchor allows localization of Ly-6 proteins to the 10-100 nm cholesterol-rich nano-domains on the membrane, also known as lipid rafts. Ly-6A/Sca-1, a member of Ly-6 gene family is known to transduce signals despite the absence of transmembrane and cytoplasmic domains. It is hypothesized that the localization of Ly-6A/Sca-1 with in lipid rafts allows this protein to transduce signals to the cell interior. METHODS AND RESULTS: In this study, we found that cross-linking mouse Ly-6A/Sca-1 protein with a monoclonal antibody results in functionally distinct responses that occur simultaneously. Ly 6A/Sca-1 triggered a cell stimulatory response as gauged by cytokine production with a concurrent inhibitory response as indicated by growth inhibition and apoptosis. While production of interleukin 2 (IL-2) cytokine by CD4+ T cell line in response to cross-linking Ly-6A/Sca-1 was dependent on the integrity of lipid rafts, the observed cell death occurred independently of it. Growth inhibited CD4+ T cells showed up-regulated expression of the inhibitory cell cycle protein p27kip but not of p53. In addition, Ly-6A/Sca-1 induced translocation of cytochrome C to the cytoplasm along with activated caspase 3 and caspase 9, thereby suggesting an intrinsic apoptotic cell death mechanism. CONCLUSIONS: We conclude that opposing responses with differential dependence on the integrity of lipid rafts are triggered by engaging Ly-6A/Sca-1 protein on the membrane of transformed CD4+ T cells. PMID- 28660666 TI - Factors associated with the pricing of childhood vaccines in the U.S. public sector. AB - Vaccine purchase cost has grown substantially over the last few decades. A closer look at vaccine prices reveals that not all vaccines shared the same increasing pattern. Various factors, such as vaccine attributes, competition, and supply shortages, could relate to price changes. In this study, we examined whether a variety of factors influenced the prices of noninfluenza childhood vaccines purchased in the public sector from 1996 to 2014. The association differed among price-capped vaccines and combination vaccines. There was an increasing time trend in real prices for non-price-capped vaccines, which was mostly offset by the effect of market longevity. The effect of competition in lowering prices was more pronounced among non-price-capped vaccines when manufacturer and vaccine component fixed effects were excluded. Supply shortage, manufacturer name change, and number of vaccine doses in series showed no effect. The results may help policy makers better understand price behaviors and make more informed decisions in vaccine planning and financing. PMID- 28660665 TI - Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion. AB - BACKGROUND: Curcumin (diferuloylmethane) has chemopreventive and therapeutic properties against many types of tumors, both in vitro and in vivo. Previous reports have shown that curcumin exhibits anti-invasive activities, but the mechanisms remain largely unclear. METHODS: In this study, both microRNA (miRNA) and messenger RNA (mRNA) expression profiles were used to characterize the anti metastasis mechanisms of curcumin in human non-small cell lung cancer A549 cell line. RESULTS: Microarray analysis revealed that 36 miRNAs were differentially expressed between the curcumin-treated and control groups. miR-330-5p exhibited maximum upregulation, while miR-25-5p exhibited maximum downregulation in the curcumin treatment group. mRNA expression profiles and functional analysis indicated that 226 differentially expressed mRNAs belonged to different functional categories. Significant pathway analysis showed that mitogen-activated protein kinase, transforming growth factor-beta, and Wnt signaling pathways were significantly downregulated. At the same time, axon guidance, glioma, and ErbB tyrosine kinase receptor signaling pathways were significantly upregulated. We constructed a miRNA gene network that contributed to the curcumin inhibition of metastasis in lung cancer cells. let-7a-3p, miR-1262, miR-499a-5p, miR-1276, miR 331-5p, and miR-330-5p were identified as key microRNA regulators in the network. Finally, using miR-330-5p as an example, we confirmed the role of miR-330-5p in mediating the anti-migration effect of curcumin, suggesting the importance of miRNAs in the regulation of curcumin biological activity. CONCLUSION: Our findings provide new insights into the anti-metastasis mechanism of curcumin in lung cancer. PMID- 28660667 TI - Pivotal role of hMT+ in long-range disambiguation of interhemispheric bistable surface motion. AB - It remains an open question whether long-range disambiguation of ambiguous surface motion can be achieved in early visual cortex or instead in higher level regions, which concerns object/surface segmentation/integration mechanisms. We used a bistable moving stimulus that can be perceived as a pattern comprehending both visual hemi-fields moving coherently downward or as two widely segregated nonoverlapping component objects (in each visual hemi-field) moving separately inward. This paradigm requires long-range integration across the vertical meridian leading to interhemispheric binding. Our fMRI study (n = 30) revealed a close relation between activity in hMT+ and perceptual switches involving interhemispheric segregation/integration of motion signals, crucially under nonlocal conditions where components do not overlap and belong to distinct hemispheres. Higher signal changes were found in hMT+ in response to spatially segregated component (incoherent) percepts than to pattern (coherent) percepts. This did not occur in early visual cortex, unlike apparent motion, which does not entail surface segmentation. We also identified a role for top-down mechanisms in state transitions. Deconvolution analysis of switch-related changes revealed prefrontal, insula, and cingulate areas, with the right superior parietal lobule (SPL) being particularly involved. We observed that directed influences could emerge either from left or right hMT+ during bistable motion integration/segregation. SPL also exhibited significant directed functional connectivity with hMT+, during perceptual state maintenance (Granger causality analysis). Our results suggest that long-range interhemispheric binding of ambiguous motion representations mainly reflect bottom-up processes from hMT+ during perceptual state maintenance. In contrast, state transitions maybe influenced by high-level regions such as the SPL. Hum Brain Mapp 38:4882-4897, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28660668 TI - fMRI capture of auditory hallucinations: Validation of the two-steps method. AB - Our purpose was to validate a reliable method to capture brain activity concomitant with hallucinatory events, which constitute frequent and disabling experiences in schizophrenia. Capturing hallucinations using functional magnetic resonance imaging (fMRI) remains very challenging. We previously developed a method based on a two-steps strategy including (1) multivariate data-driven analysis of per-hallucinatory fMRI recording and (2) selection of the components of interest based on a post-fMRI interview. However, two tests still need to be conducted to rule out critical pitfalls of conventional fMRI capture methods before this two-steps strategy can be adopted in hallucination research: replication of these findings on an independent sample and assessment of the reliability of the hallucination-related patterns at the subject level. To do so, we recruited a sample of 45 schizophrenia patients suffering from frequent hallucinations, 20 schizophrenia patients without hallucinations and 20 matched healthy volunteers; all participants underwent four different experiments. The main findings are (1) high accuracy in reporting unexpected sensory stimuli in an MRI setting; (2) good detection concordance between hypothesis-driven and data driven analysis methods (as used in the two-steps strategy) when controlled unexpected sensory stimuli are presented; (3) good agreement of the two-steps method with the online button-press approach to capture hallucinatory events; (4) high spatial consistency of hallucinatory-related networks detected using the two steps method on two independent samples. By validating the two-steps method, we advance toward the possible transfer of such technology to new image-based therapies for hallucinations. Hum Brain Mapp 38:4966-4979, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28660669 TI - Comparison of eye movement desensitization and reprocessing therapy, cognitive behavioral writing therapy, and wait-list in pediatric posttraumatic stress disorder following single-incident trauma: a multicenter randomized clinical trial. AB - BACKGROUND: Practice guidelines for childhood posttraumatic stress disorder (PTSD) recommend trauma-focused psychotherapies, mainly cognitive behavioral therapy (CBT). Eye movement desensitization and reprocessing (EMDR) therapy is a brief trauma-focused, evidence-based treatment for PTSD in adults, but with few well-designed trials involving children and adolescents. METHODS: We conducted a single-blind, randomized trial with three arms (n = 103): EMDR (n = 43), Cognitive Behavior Writing Therapy (CBWT; n = 42), and wait-list (WL; n = 18). WL participants were randomly reallocated to CBWT or EMDR after 6 weeks; follow-ups were conducted at 3 and 12 months posttreatment. Participants were treatment seeking youth (aged 8-18 years) with a DSM-IV diagnosis of PTSD (or subthreshold PTSD) tied to a single trauma, who received up to six sessions of EMDR or CBWT lasting maximally 45 min each. RESULTS: Both treatments were well-tolerated and relative to WL yielded large, intent-to-treat effect sizes for the primary outcomes at posttreatment: PTSD symptoms (EMDR: d = 1.27; CBWT: d = 1.24). At posttreatment 92.5% of EMDR, and 90.2% of CBWT no longer met the diagnostic criteria for PTSD. All gains were maintained at follow-up. Compared to WL, small to large (range d = 0.39-1.03) intent-to-treat effect sizes were obtained at posttreatment for negative trauma-related appraisals, anxiety, depression, and behavior problems with these gains being maintained at follow-up. Gains were attained with significantly less therapist contact time for EMDR than CBWT (mean = 4.1 sessions/140 min vs. 5.4 sessions/227 min). CONCLUSIONS: EMDR and CBWT are brief, trauma-focused treatments that yielded equally large remission rates for PTSD and reductions in the severity of PTSD and comorbid difficulties in children and adolescents seeking treatment for PTSD tied to a single event. Further trials of both treatments with PTSD tied to multiple traumas are warranted. PMID- 28660670 TI - Defaunation and habitat disturbance interact synergistically to alter seedling recruitment. AB - Vertebrate granivores destroy plant seeds, but whether animal-induced seed mortality alters plant recruitment varies with habitat context, seed traits, and among granivore species. An incomplete understanding of seed predation makes it difficult to predict how widespread extirpations of vertebrate granivores in tropical forests might affect tree communities, especially in the face of habitat disturbance. Many tropical forests are simultaneously affected by animal loss as well as habitat disturbance, but the consequences of each for forest regeneration are often studied separately or additively, and usually on a single plant demographic stage. The combined impacts of these threats could affect plant recruitment in ways that are not apparent when studied in isolation. We used wire cages to exclude large (elephants), medium, (sambar deer, bearded pigs, muntjac deer), and small (porcupines, chevrotains) ground-dwelling mammalian granivores and herbivores in logged and unlogged forests in Malaysian Borneo. We assessed the interaction between habitat disturbance (selective logging) and experimental defaunation on seed survival, germination, and seedling establishment in five dominant dipterocarp tree species spanning a 21-fold gradient in seed size. Granivore-induced seed mortality was consistently higher in logged forest. Germination of unpredated seeds was reduced in logged forest and in the absence of small to large-bodied mammals. Experimental defaunation increased germination and reduced seed removal but had little effect on seed survival. Seedling recruitment however, was more likely where logging and animal loss occurred together. The interacting effects of logging and hunting could therefore, actually increase seedling establishment, suggesting that the loss of mammals in disturbed forest could have important consequences for forest regeneration and composition. PMID- 28660671 TI - Do E-cigarettes induce weight changes and increase cardiometabolic risk? A signal for the future. AB - The prevalence of non-cigarette tobacco use in electronic cigarettes, also called vaping, is rapidly increasing, especially in adolescents and young adults, due to attractive marketing techniques promoting them as healthier alternatives to conventional tobacco cigarettes. Although smoking is associated with weight loss, it increases insulin resistance and attributes to other features of the metabolic syndrome, increasing the cardiometabolic risk profile. Whether vaping has the same deleterious effects on metabolic parameters as regular cigarette smoke has not yet been studied thoroughly in humans. However, animal model experiments attribute comparable effects of e-cigarette smoking, even without nicotine exposure, on weight and metabolic parameters as compared to smoking cigarettes. In this review paper, we want to give an overview of published data on the effects on weight and cardiometabolic parameters of e-cigarette use and formulate some mechanistic hypotheses. PMID- 28660673 TI - Patient-reported outcome measures in advanced musculoskeletal physiotherapy practice: a systematic review. AB - OBJECTIVE: Advanced practice physiotherapists (APPs), also known as extended scope physiotherapists, provide a new model of service delivery for musculoskeletal (MSK) disorders. Research to date has largely focused on health service efficiencies, with less emphasis on patient outcomes. The present systematic review aimed to identify the patient-reported outcome measures (PROMs) being utilized by APPs. METHOD: A wide search strategy was employed, including the PubMed, Embase, CINAHL, CENTRAL and PEDro databases, to identify studies relating to PROMs utilized by APPs in MSK healthcare settings. PROMs identified were classified into predetermined outcome domains, with additional contextual data extracted. RESULTS: Of the initial 12,302 studies, 38 met the inclusion criteria. These involved APPs across different settings, utilizing 72 different PROMs and most commonly capturing: Patient Satisfaction, Quality of Life (QoL), Functional Status, and Pain; and, less frequently: Global Status (i.e. overall improvement), Psychological Well-Being, Work ability, and Healthcare Consumption and Costs. The quality of the PROMs varied greatly, with Satisfaction most commonly measured utilizing non-standardized locally-devised tools; the EuroQol five-dimensions questionnaire (EuroQoL-5D) and 36-Item Short-Form (SF-36) cited most frequently to capture QoL; and the Visual Analogue Scale (VAS) to capture Pain. No key measure was identified to capture Functional Status, with 15 different tools utilized. CONCLUSION: APPs utilized a multiplicity of PROMs across a range of MSK disorders. The present review will act as an important resource, informing the selection of outcomes for MSK disorders, with a view to greater standardization of outcome measurement in MSK clinical practice, service evaluation and research. PMID- 28660672 TI - Food allergy response capabilities of mothers and related factors. AB - A parent's ability to confidently manage a child's food allergy (i.e. food allergy response capability) is considered instrumental toward treating this disorder; however, little is known regarding this measure and associated factors. A questionnaire survey among 280 qualified participants identified the greatest food allergy response capability as "spousal collaboration", followed by "elimination diet capacity", "gathering information from medical professionals", "knowledge about food allergies", and "stress coping". These capabilities were associated with maternal and household health status, food items eliminated and their number, anaphylaxis experience, and type of medical facility used. This measure represented a predictor of maternal quality of life and health status, household health status, and overall life stress (not related to childrearing). Thus, to improve food allergy response capability, multidisciplinary cooperation and support are required from professionals, such as physicians, nurses, nutritionists, and clinical psychologists. Nurses in particular must take an interest in the situations these mothers face and in their emotions; elicit their power to cope with stress; provide knowledge about food allergies; provide individualized, specific information about elimination diets; and conduct interventions to enable spousal cooperation. PMID- 28660674 TI - Comprehensive Network Map of ADME-Tox Databases. AB - In the last decade, many statistical-based approaches have been developed to improve poor pharmacokinetics (PK) and to reduce toxicity of lead compounds, which are one of the main causes of high failure rate in drug development. Predictive QSAR models are not always very efficient due to the low number of available biological data and the differences in the experimental protocols. Fortunately, the number of available databases continues to grow every year. However, it remains a challenge to determine the source and the quality of the original data. The main goal is to identify the relevant databases required to generate the most robust predictive models. In this study, an interactive network of databases was proposed to easily find online data sources related to ADME-Tox parameters data. In this map, relevant information regarding scope of application, data availability and data redundancy can be obtained for each data source. To illustrate the usage of data mining from the network, a dataset on plasma protein binding is selected based on various sources such as DrugBank, PubChem and ChEMBL databases. A total of 2,606 unique molecules with experimental values of PPB were extracted and can constitute a consistent dataset for QSAR modeling. PMID- 28660675 TI - Objectively improving appropriateness of absorbent products provision to patients with urinary incontinence: The DIAPPER study. AB - AIMS: To objectively assess and enhance the appropriateness of continence products provision to sufferers from urinary incontinence (UI) managed with containment strategies. METHODS: Incontinent patients of five Italian continence care services were included in this industry-supported study from 01/2012 to 03/2016. All patients/carers have been invited to perform a 48-h home-based pad test and to fill in a diary. The primary outcome was the product appropriateness defined as the use of a pad with maximum absorbent capacity (MAC) from 30% to 50% higher than the individually measured urine load. Pads provision was corrected accordingly. Meaningful factors affecting products appropriateness and patient's satisfaction with the new products were also assessed. RESULTS: The study included 14 493 subjects (mean age 78 years; 26% males, 74% females) using overall during the study days 98 362 pads. Sixty percent of the products were found to be not appropriate. In most of cases, (75%) products were inappropriate because too large. Age and pad weight gain, followed by gender, body weight, waist circumference, level of autonomy and mobility, pad wearing time, skin health status, and health district were independently associated to the propensity to inappropriateness. After correction of products prescription, a significant reduction (-31%) of the use of largest products was observed. At 6 months evaluation, 88% of evaluable participants were satisfied with the new prescription. CONCLUSIONS: Most of patients are provided with not appropriate containment products. The use of the 48-h pad test allows improving on an individual basis the appropriateness of products provision. PMID- 28660676 TI - Manipulator-driven selection of semi-active MR-visible markers. AB - BACKGROUND: A method for the identification of semi-active fiducial magnetic resonance (MR) markers is presented based on selectively optically tuning and detuning them. METHODS: Four inductively coupled solenoid coils with photoresistors were connected to light sources. A microcontroller timed the optical tuning/detuning of coils and image collection. The markers were tested on an MR manipulator linking the microcontroller to the manipulator control to visibly select the marker subset according to the actuated joint. RESULTS: In closed-loop control, the average and maximum were 0.76 degrees +/- 0.41 degrees and 1.18 degrees errors for a rotational joint, and 0.87 mm +/- 0.26 mm and 1.13 mm for the prismatic joint. CONCLUSIONS: This technique is suitable for MR compatible actuated devices that use semi-active MR-compatible markers. PMID- 28660677 TI - Variability of Delivery of Timolol for the Treatment of Infantile Hemangiomas. AB - BACKGROUND/OBJECTIVES: Topical timolol maleate solution or gel-forming solution is used alone or in conjunction with oral propranolol for the treatment of infantile hemangiomas. The consistency of the amount of timolol dispensed has never been evaluated. We evaluated the variability of drug delivery between different brands and formulations of timolol solution and gel-forming solution. METHODS: Five blinded volunteers sequentially dispensed five drops from each of the eight bottles containing timolol 0.5% solution or gel-forming solution. This was repeated three times per user for each bottle. The average amount of timolol dispensed was analyzed according to brand, formulation, and user for variability. The intra- and interuser variability of dispensing both formulations of timolol was also measured. RESULTS: Our study demonstrates statistically significant differences in the amount of timolol dispensed between timolol solution and gel forming solution, with the latter closer to manufacturer estimates. Significant differences in the amount of timolol dispensed were noted between users regardless of the formulation or brand. Variability in the amount of timolol dispensed was greater for gel-forming solution than 0.5% solution. Inter- and intrauser variability in the amount of timolol dispensed was greater for gel forming solution than 0.5% solution. CONCLUSION: Statistically significant differences were noted in the amount of timolol dispensed according to formulation, brand, and user. Whether this is clinically significant is unknown given the lack of pharmacokinetic data available for timolol. PMID- 28660679 TI - Do Avoidable Hospitalization Rates among Older Adults Differ by Geographic Access to Primary Care Physicians? AB - OBJECTIVE: To investigate the association between older adults' potentially avoidable hospitalization rates and both a geographic measure of primary care physician (PCP) access and a standard bounded-area measure of PCP access. DATA SOURCES: State physician licensure data from the Virginia Board of Medicine. Patient-level hospital discharge data from Virginia Health Information. Area level data from the American Community Survey and the Area Health Resources Files. Virginia Information Technologies Agency road network data. US Census Bureau TIGER/Line boundary files. STUDY DESIGN: We use enhanced two-step floating catchment area methods to calculate geographic PCP accessibility for each ZIP Code Tabulation Area in Virginia. We use spatial regression techniques to model potentially avoidable hospitalization rates. DATA COLLECTION/EXTRACTION: Geographic accessibility was calculated using ArcGIS. Physician locations were geocoded using TAMU GeoServices and ArcGIS. PRINCIPAL FINDINGS: Increased geographic access to PCPs is associated with lower rates of potentially avoidable hospitalization among older adults. This association is robust, allowing for spatial spillovers in spatial lag models. CONCLUSIONS: Compared to bounded-area density measures, unbounded geographic accessibility measures provide more robust evidence that avoidable hospitalization rates are lower in areas with more PCPs per person. Results from our spatial lag models reveal the presence of positive spatial spillovers. PMID- 28660678 TI - Safety and efficacy of venous reconstruction in liver resection using cryopreserved homologous veins. AB - BACKGROUND: Only a few studies have reported the resection and reconstruction of major hepatic veins during hepatectomy. Here, we present our strategy and techniques for venous reconstruction with cryopreserved homologous veins, and describe the surgical outcome. METHODS: Among 2,387 hepatectomy patients, 39 patients who required hepatic venous reconstruction were reviewed retrospectively. Venous reconstruction was performed to secure a non-congested liver remnant volume of at least 40% of the total liver volume. RESULTS: There was no operative mortality, and the severe morbidity rate was 5% in this series. A total of 41 veins were reconstructed; 30 with homologous veins (73.2%) and 11 with autologous veins (26.8%), with the middle hepatic vein being the most frequent (n = 23, 56%). Interposition grafting was performed more often (P = 0.003), the length of the venous resection was longer (P = 0.007), and pathologic wall infiltration of the vein was revealed more often (P = 0.002) in the homologous graft group than in the autologous graft group. The 1-, 2-, and 3-year overall patency of the reconstructed veins was 55.4%, 46.3%, and 46.3%, respectively. CONCLUSIONS: Aggressive venous reconstruction during hepatectomy using cryopreserved homologous veins is a feasible option with satisfactory short term outcomes, and may be warranted to improve operative safety. PMID- 28660680 TI - Text mining for search term development in systematic reviewing: A discussion of some methods and challenges. AB - Using text mining to aid the development of database search strings for topics described by diverse terminology has potential benefits for systematic reviews; however, methods and tools for accomplishing this are poorly covered in the research methods literature. We briefly review the literature on applications of text mining for search term development for systematic reviewing. We found that the tools can be used in 5 overarching ways: improving the precision of searches; identifying search terms to improve search sensitivity; aiding the translation of search strategies across databases; searching and screening within an integrated system; and developing objectively derived search strategies. Using a case study and selected examples, we then reflect on the utility of certain technologies (term frequency-inverse document frequency and Termine, term frequency, and clustering) in improving the precision and sensitivity of searches. Challenges in using these tools are discussed. The utility of these tools is influenced by the different capabilities of the tools, the way the tools are used, and the text that is analysed. Increased awareness of how the tools perform facilitates the further development of methods for their use in systematic reviews. PMID- 28660681 TI - The role of affective temperament as a predictor of relapse in alcohol dependence. AB - BACKGROUND: Personality traits have been proposed as relapse risk factors in alcohol use disorders. So far, no study has assessed the association between affective temperamental traits and the prospective relapse risk. METHODS: This was a 3-month prospective naturalistic study, designed to assess the impact of affective temperaments in relapse. A sample of 61 alcohol-dependent patients was collected from an ambulatory clinical setting. Socio-demographic information, drinking and substance use habits, drinking status, craving and affective temperament traits were assessed. RESULTS: Age, age of onset of alcohol abuse and dependence and drug consumption correlate with drinking status. Male alcohol dependent patients who relapsed presented higher scores on cyclothymic temperament than patients with an alcohol dependence diagnosis who remain sober. Hierarchical logistic regression indicates that cyclothymic temperament predicted relapse in a 3-month follow-up. However, the coefficient was marginally significant after controlling for all potential confounding predictors. CONCLUSIONS: Our results provide new insights about the role of affective temperaments in alcohol use disorders, specifically in predicting short-term relapse in detoxified male alcohol-dependent patients. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28660683 TI - Maculopapular type drug eruption caused by garenoxacin mesilate hydrate: A case report and literature review. PMID- 28660682 TI - Robotic versus thoracoscopic thymectomy: The current evidence. AB - BACKGROUND: The purpose of this study was to analyze all relevant comparative studies comparing robot-assisted minimally invasive thymectomy (RATS) and video assisted thoracic surgery thymectomy (VATS) in terms of surgical and short-term outcomes. METHODS: A systematic search for articles describing robot-assisted and video-assisted thymectomy and addressing surgical outcomes, operation time, length of hospitalization, intra-operative blood loss, conversion to sternotomy and post-operative complications was performed using the medical databases. RESULTS: Of the 478 studies from preliminary screening, five articles were included. By pooling these studies, we found no significant differences between the RATS and VATS (odds ratio 1.24 (95% CI 0.51, 3.03; p = 0.63)).There were no significant differences in comparison of conversion rates, operation time (26.29 min (95% CI -2.57, 55.35; p = 0.07)) and length of hospitalization (-1.58 days (95% CI -4.78, 1.62; p = 0.33)). There was a slightly higher blood loss in the RATS group. CONCLUSION: Our meta-analysis did not detect any statistically significant differences in surgery outcomes between the two groups. PMID- 28660684 TI - Antioxidative effect of BHA in soya bean lecithin-based extender containing Glycerol or DMSO on freezing capacity of goat semen. AB - The aim of this study was to evaluate the effects of butylated hydroxyanisole (0 or 4 mM) along with different concentrations (5 or 7%) of glycerol (G) and dimethyl sulphoxide (DMSO) as cryoprotectant (CPAs) on freezability of goat semen. Semen was collected from four bucks (3-4 years) twice a week for five weeks. The pooled ejaculates were diluted with extender containing two different concentrations of G or DMSO in combination with BHA. Afterwards, the diluted samples were loaded into 0.25 ml straws and frozen using a standard protocol. After thawing motility parameters, viability, membrane integrity and total abnormality were assessed. The Results showed that the presence of BHA in extender, type and level of CPAs as main factors had significant effects on goat sperm viability, total and progressive motility after freezing-thawing processes (p < .05). Also, the interaction of BHA (0 and 4 mM) and levels of G or DMSO (5 or 7%) had a significant effects (p < .05) on total motility, viability and some characteristic. In this case, the addition of 5% G or DMSO with BHA resulted in highest motility and viability than the other groups (p < .05). The addition of G5 (with and without BHA) increased VSL and reduced abnormality than the other groups (p < .05). The results showed that the main effects of CPAs and CPAs level on membrane functionality were significant (p < .05). Also there were no significance differences in the interactive effects of MDA, VCL, VAP, ALH, LIN and STR among the groups (p > .05). Finally, it can be concluded that the use of 5% CPAs with or without BHA may result in better post-thaw sperm quality of goat. PMID- 28660685 TI - Studying the relationship between a woman's reproductive lifespan and age at menarche using a Bayesian multivariate structured additive distributional regression model. AB - Studies addressing breast cancer risk factors have been looking at trends relative to age at menarche and menopause. These studies point to a downward trend of age at menarche and an upward trend for age at menopause, meaning an increase of a woman's reproductive lifespan cycle. In addition to studying the effect of the year of birth on the expectation of age at menarche and a woman's reproductive lifespan, it is important to understand how a woman's cohort affects the correlation between these two variables. Since the behavior of age at menarche and menopause may vary with the geographic location of a woman's residence, the spatial effect of the municipality where a woman resides needs to be considered. Thus, a Bayesian multivariate structured additive distributional regression model is proposed in order to analyze how a woman's municipality and year of birth affects a woman's age of menarche, her lifespan cycle, and the correlation of the two. The data consists of 212,517 postmenopausal women, born between 1920 and 1965, who attended the breast cancer screening program in the central region of Portugal. PMID- 28660686 TI - Infundibulocystic basal cell carcinoma of the eyelid. PMID- 28660687 TI - Retroperitoneal drainage versus no drainage after pelvic lymphadenectomy for the prevention of lymphocyst formation in women with gynaecological malignancies. AB - BACKGROUND: This is an updated version of an original Cochrane review published in Issue 6, 2014. Pelvic lymphadenectomy is associated with significant complications including lymphocyst formation and related morbidities. Retroperitoneal drainage using suction drains has been recommended as a method to prevent such complications. However, findings from recent studies have challenged this policy. OBJECTIVES: To assess the effects of retroperitoneal drainage versus no drainage after pelvic lymphadenectomy on lymphocyst formation and related morbidities in women with gynaecological cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2017) in the Cochrane Library, electronic databases MEDLINE (1946 to March Week 2, 2017), Embase (1980 to 2017 week 12), and the citation lists of relevant publications. We also searched the trial registries for ongoing trials on 20 May 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared the effect of retroperitoneal drainage versus no drainage after pelvic lymphadenectomy in women with gynaecological cancer. Retroperitoneal drainage was defined as placement of passive or active suction drains in pelvic retroperitoneal spaces. No drainage was defined as no placement of passive or active suction drains in pelvic retroperitoneal spaces. DATA COLLECTION AND ANALYSIS: We assessed studies using methodological quality criteria. For dichotomous data, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). We examined continuous data using mean difference (MD) and 95% CI. MAIN RESULTS: Since the last version of this review, we have identified no new studies for inclusion. The review included four studies with 571 women. Regarding short-term outcomes (within four weeks after surgery), retroperitoneal drainage was associated with a comparable rate of overall lymphocyst formation when all methods of pelvic peritoneum management were considered together (2 studies; 204 women; RR 0.76, 95% CI 0.04 to 13.35; moderate-quality evidence). When the pelvic peritoneum was left open, the rates of overall lymphocyst formation (1 study; 110 women; RR 2.29, 95% CI 1.38 to 3.79) and symptomatic lymphocyst formation (2 studies; 237 women; RR 3.25, 95% CI 1.26 to 8.37) were higher in the drained group. At 12 months after surgery, the rates of overall lymphocyst formation were comparable between the groups (1 study; 232 women; RR 1.48, 95% CI 0.89 to 2.45; high-quality evidence). However, there was a trend toward increased risk of symptomatic lymphocyst formation in the group with drains (1 study; 232 women; RR 7.12, 95% CI 0.89 to 56.97; low quality evidence). AUTHORS' CONCLUSIONS: Placement of retroperitoneal tube drains has no benefit in the prevention of lymphocyst formation after pelvic lymphadenectomy in women with gynaecological malignancies. When the pelvic peritoneum is left open, the tube drain placement is associated with a higher risk of short- and long-term symptomatic lymphocyst formation. We found the quality of evidence using the GRADE approach to be moderate to high for most outcomes, except for symptomatic lymphocyst formation at 12 months after surgery, and unclear or low risk of bias. PMID- 28660688 TI - Use of Contrast-Enhanced Ultrasound for Confirmation of Central Venous Catheter Placement: Systematic Review and Meta-analysis. AB - OBJECTIVES: The purpose of this meta-analysis was to determine the sensitivity, specificity, and positive and negative predictive values of contrast-enhanced ultrasound (US) for confirming the tip location and placement of central venous catheters in adult patients. METHODS: A systematic review was performed using electronic databases, including MEDLINE, ClinicalTrials.gov, Cochrane, Embase, PubMed, and Scopus. Inclusion criteria were studies conducted on adult patients receiving an internal jugular or a subclavian central venous catheter in the emergency department or intensive care unit. Furthermore, the catheter tip location had to be checked with the use of the agitated saline contrast-enhanced US technique. RESULTS: A total of 2245 articles were screened by title and abstract. Seventeen articles were retrieved and assessed for the predefined inclusion criteria. Four articles and 1 abstract were used in the final analysis. Contrast-enhanced US showed pooled sensitivity of 72% (95% confidence interval, 44%-91%), pooled specificity of 100% (95% confidence interval, 99%-100%), a positive predictive value of 92.1%, and a negative predictive value of 98.5% compared with chest radiography for confirming the placement of central venous catheters. CONCLUSIONS: In the setting of central venous catheter placement, postprocedural contrast-enhanced US imaging is a safe, efficient, and highly specific confirmatory test for the catheter tip location compared with chest radiography. PMID- 28660690 TI - Neonatal dysphonia caused by subglottic infantile hemangioma. PMID- 28660689 TI - A rare form of extremely wide QRS complex due to reversed homologous electrical ventricular separation of acute heart failure. AB - Electrical ventricular separation, as a special complete intraventricular block, denotes that ventricles be electrically separated into two or more parts caused by severe and wide damage of myocardium and conduction. Electrical ventricular separation can be divided into homologous and heterologous, homologous electrical ventricular separation is a rare phenomenon, literally the excitement of whole ventricle originate from supraventricle, on ECG, there are two different QRS waves which connect with an isoelectric line, one ST segment and T wave. We report a valve heart disease presented with complicated electrophysiological characteristics, which has reversed complex homologous electrical ventricular separation with second degree intraventricular block. PMID- 28660691 TI - Metagenomic analysis of the complex microbial consortium associated with cultures of the oil-rich alga Botryococcus braunii. AB - Microalgae are widely viewed as a promising and sustainable source of renewable chemicals and biofuels. Botryococcus braunii synthesizes and secretes significant amounts of long-chain (C30 -C40 ) hydrocarbons that can be subsequently converted into gasoline, diesel, and aviation fuel. B. braunii cultures are not axenic and the effects of co-cultured microorganisms on B. braunii growth and hydrocarbon yield are important, but sometimes contradictory. To understand the composition of the B. braunii microbial consortium, we used high throughput Illumina sequencing of metagenomic DNA to profile the microbiota within a well established, stable B. braunii culture and characterized the demographic changes in the microcosm following modification to the culture conditions. DNA sequences attributed to B. braunii were present in equal quantities in all treatments, whereas sequences assigned to the associated microbial community were dramatically altered. Bacterial species least affected by treatments, and more robustly associated with the algal cells, included members of Rhizobiales, comprising Bradyrhizobium and Methylobacterium, and representatives of Dyadobacter, Achromobacter and Asticcacaulis. The presence of bacterial species identified by metagenomics was confirmed by additional 16S rDNA analysis of bacterial isolates. Our study demonstrates the advantages of high throughput sequencing and robust metagenomic analyses to define microcosms and further our understanding of microbial ecology. PMID- 28660692 TI - Are the implanted ICD/CRT leads functioning normally? PMID- 28660693 TI - Relationship of temperament with oestrous behaviour, resumption of ovarian cyclicity and milk yield in post-partum Murrah buffaloes. AB - This study was designed to investigate the relationship of temperament with oestrus, resumption of ovarian cyclicity and milk yield in post-partum buffaloes. For this study, 102 post-partum Murrah buffaloes were observed for temperament in open paddock and during milking. Based on the temperament score (1-5 score), they were classified into docile, slightly restless, restless, aggressive and nervous. Oestrous behaviour was monitored twice daily in all the buffaloes along with milk yield (weekly), body weight (BW) and body condition score (BCS) at day 0, 30, 60 and 90 post-partum. Based on the temperament score, the number of buffaloes classified as docile, slightly restless, restless and aggressive was 37 (36.27%), 28 (27.45%), 30 (29.41%) and 7 (6.86%), respectively, but none under nervous category. Number of buffaloes resuming cyclicity in various temperaments groups were as follows: docile (n = 35; 94.59%), slightly restless (n = 22; 78.57%), restless (n = 20; 66.67%) and aggressive (n = 7; 85.71%). Temperament was not correlated (p = .128; r=-.152) with oestrous behaviour. But, temperament was correlated (p < .0001; r = .384) with the resumption of cyclicity as docile and slightly restless buffaloes resumed cyclicity (p < .0016) earlier. Temperament of buffaloes was weakly correlated (p = .0017; r=-.306) with milk production with higher (p < .0358) total milk yield in docile (1022 +/- 23.75 kg) and slightly restless buffaloes (948 +/- 35.86 kg) as compared to other temperament groups. In summary, temperament of post-partum buffaloes was related with resumption of ovarian cyclicity and milk yield, but not oestrous behaviour. PMID- 28660694 TI - Long-term serum bile acid concentrations in 51 dogs after complete extrahepatic congenital portosystemic shunt ligation. AB - OBJECTIVES: To report the long-term bile acid stimulation test results for dogs that have undergone complete suture ligation of a single congenital extrahepatic portosystemic shunt. MATERIALS AND METHODS: Data were collected from the hospital records of all dogs that had undergone a complete suture ligation of a single congenital extrahepatic portosystemic shunt. Owners were invited to return to the referral centre or their local veterinarian for repeat serum bile acid measurement. Dogs diagnosed with idiopathic epilepsy and undergoing bile acid stimulation tests were used as a comparison population. RESULTS: Fifty-one study dogs were included, with a mean follow-up time of 62 months. 48 dogs had no evidence of multiple acquired shunts and a significant reduction in the pre- and post-prandial serum bile acid concentrations at long-term follow-up compared with pre-operative measurements. Pre- and post-prandial serum bile acids were statistically significantly greater for dogs that had undergone a full ligation (with no evidence of multiple acquired shunts) at all time points compared to the control dogs (P<0.001 for all comparisons). CLINICAL SIGNIFICANCE: The results suggest that in dogs treated with complete suture ligation mild increases in serum bile acids are not clinically relevant if there are no physical examination abnormalities, a normal body condition score and no relapse in clinical signs. PMID- 28660695 TI - Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: Risk factors and management. AB - BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is a rare but serious complication of childhood acute lymphoblastic leukemia (ALL) therapy. No available consensus exists regarding its risk factors and appropriate management due to the rarity of cases. PROCEDURES: Out of 209 ALL patients aged 1-21 years treated at the Children's Cancer Center of Lebanon between May 2002 and May 2015, 13 developed CSVT during therapy. Patient characteristics, clinical management, and outcomes were studied. RESULTS: The incidence of CSVT was 6.2% (95% confidence interval [CI]: 3.4-10.4). Using univariate analysis, increased risk of CSVT was observed with age >10 years (odds ratio [OR]: 3.56, 95% CI: 1.13-11.2), T-cell immunophenotype (OR: 4.14, 95% CI: 1.16-14.7), and intermediate/high risk disease (OR: 3.4, 95% CI: 1.03-11.7). The only statistically significant risk factor by multivariate analysis was the treatment as per the intermediate-/high risk protocol (HR: 15.6, 95% CI: 1.43-171.3). Most cases (77%) occurred in the postinduction phases of treatment while receiving a combination of asparaginase and dexamethasone rather than prednisone. Treatment with low molecular weight heparin (LMWH) for a minimum of 3 months and until significant radiological improvement is observed resulted in 100% survival rate. All but one patient had complete neurological recovery. CONCLUSIONS: CSVT is an important complication of childhood ALL therapy. Postinduction combined asparaginase and dexamethasone intensive treatment for intermediate-/high-risk patients was the most important risk factor. Treatment with LMWH for a minimum of 3 months, and until asparginase therapy is over, with major radiological improvement seems to be effective and feasible. PMID- 28660696 TI - Fabrication of Metal Molybdate Micro/Nanomaterials for Electrochemical Energy Storage. AB - Currently, metal molybdates compounds can be prepared by several methods and are considered as prospective electrode materials in many fields because the metal ions possess the ability to exist in several oxidation states. These multiple oxidation states contribute to prolonging the discharge time, improving the energy density, and increasing the cycling stability. The high electrochemical performance of metal molybdates as electrochemical energy storage devices are discussed in this review. According to recent publications and research progress on relevant materials, the investigation of metal molybdate compounds are discussed via three main aspects: synthetic methods, material properties and measured electrochemical performance of these compounds as electrode materials. The recent progress in general metal molybdate nanomaterials for LIBs and supercapacitors are carefully presented here. PMID- 28660697 TI - Intra-Ethnic Coverage Disparities among Latinos and the Effects of Health Reform. AB - OBJECTIVE: To examine the patterns of insurance coverage among nine Latino subgroups and assess heterogeneous effects of the Affordable Care Act (ACA) among these groups. DATA SOURCES: American Community Survey (2010-2014). STUDY DESIGN: We examined pre-ACA disparities in coverage using linear probability models. Then, we used interrupted time series and triple-difference models to evaluate coverage changes associated with the ACA and Medicaid expansion, respectively. PRINCIPAL FINDINGS: Pre-ACA coverage disparities between Latino subgroups were nearly 30 percentage points-larger than the gap between whites and Latinos as a whole. Coverage changes associated with the ACA and Medicaid expansion differed significantly between subgroups, with the largest gains among South Americans, Central Americans, and Mexicans. CONCLUSIONS: Latino subgroups show marked heterogeneity in baseline coverage rates and responses to the ACA. PMID- 28660698 TI - Breastfeeding and the risk of childhood asthma: A two-stage instrumental variable analysis to address endogeneity. AB - BACKGROUND: Several explanations for the inconsistent results on the effects of breastfeeding on childhood asthma have been suggested. The purpose of this study was to investigate one unexplored explanation, which is the presence of a potential endogenous relationship between breastfeeding and childhood asthma. Endogeneity exists when an explanatory variable is correlated with the error term for reasons such as selection bias, reverse causality, and unmeasured confounders. Unadjusted endogeneity will bias the effect of breastfeeding on childhood asthma. METHODS: To investigate potential endogeneity, a cross sectional study of breastfeeding practices and incidence of childhood asthma in 87 pediatric patients in Georgia, the USA, was conducted using generalized linear modeling and a two-stage instrumental variable analysis. First, the relationship between breastfeeding and childhood asthma was analyzed without considering endogeneity. Second, tests for presence of endogeneity were performed and having detected endogeneity between breastfeeding and childhood asthma, a two-stage instrumental variable analysis was performed. The first stage of this analysis estimated the duration of breastfeeding and the second-stage estimated the risk of childhood asthma. RESULTS: When endogeneity was not taken into account, duration of breastfeeding was found to significantly increase the risk of childhood asthma (relative risk ratio [RR]=2.020, 95% confidence interval [CI]: [1.143-3.570]). After adjusting for endogeneity, duration of breastfeeding significantly reduced the risk of childhood asthma (RR=0.003, 95% CI: [0.000 0.240]). CONCLUSION: The findings suggest that researchers should consider evaluating how the presence of endogeneity could affect the relationship between duration of breastfeeding and the risk of childhood asthma. PMID- 28660699 TI - Development and Validation of a Decision Tool for Early Identification of Adult Patients with Severe and Complex Eating Disorder Psychopathology in Need of Highly Specialized Care. AB - Patients with complex and severe eating disorders often receive a number of ineffective or/and insufficient treatments. Direct referral of these patients to highly specialized tertiary treatment facilities in an earlier stage of the disorder is likely to be more (cost)-effective. The aim of the study was to develop a decision tool that aids clinicians in early identification of these patients. After identification of criteria that were indicative of severity and complexity of eating disorder psychopathology by means of a systematic review of literature and consultation of a focus group, a Delphi method was applied to obtain consensus from experts on the list of relevant criteria. Finally, the decision tool was validated in clinical practice, and cut-off criteria were established. The tool demonstrated good feasibility and validity to identify patients for highly specialized tertiary care. The final decision tool consisted of five criteria that can easily be implemented in clinical practice. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28660700 TI - Inga laurina trypsin inhibitor (ILTI) obstructs Spodoptera frugiperda trypsins expressed during adaptive mechanisms against plant protease inhibitors. AB - Plant protease inhibitors (PIs) are elements of a common plant defense mechanism induced in response to herbivores. The fall armyworm, Spodoptera frugiperda, a highly polyphagous lepidopteran pest, responds to various PIs in its diet by expressing genes encoding trypsins. This raises the question of whether the PI induced trypsins are also inhibited by other PIs, which we posed as the hypothesis that Inga laurina trypsin inhibitor (ILTI) inhibits PI-induced trypsins in S. frugiperda. In the process of testing our hypothesis, we compared its properties with those of selected PIs, soybean Kunitz trypsin inhibitor (SKTI), Inga vera trypsin inhibitor (IVTI), Adenanthera pavonina trypsin inhibitor (ApTI), and Entada acaciifolia trypsin inhibitor (EATI). We report that ILTI is more effective in inhibiting the induced S. frugiperda trypsins than SKTI and the other PIs, which supports our hypothesis. ILTI may be more appropriate than SKTI for studies regarding adaptive mechanisms to dietary PIs. PMID- 28660702 TI - Pattern of skin diseases among patients attending an outpatient dermatology clinic in a tertiary hospital in urban Malaysia. PMID- 28660701 TI - Accumulation of non-numerical evidence during nonsymbolic number processing in the brain: An fMRI study. AB - Behavioral evidence has shown that when performing a nonsymbolic number comparison task (e.g., deciding which of two dot arrays contains more dots), participants' responses are sensitive to affected by both numerical (e.g., number of items) and non-numerical magnitudes (i.e., area, density, etc.). Thus far it is unclear what brain circuits support this process of accumulating non-numerical variables during nonsymbolic number processing. To investigate this, 21 adult participants were asked to engage in a dot comparison task. To measure the neural correlates of accumulating numerical and non-numerical variables, we manipulated the number of the non-numerical magnitudes that were congruent (correlated with number) or incongruent (anticorrelated with number). In a control task, participants were asked to choose the darker of two gray rectangles (brightness task). The tasks were matched in terms of their difficulty. The results of a whole brain analysis for regions sensitive to the congruity of numerical and non numerical magnitudes revealed a region in the right inferior frontal gyrus (rIFG). Activation in this region was found to be correlated with the relative congruency of numerical and non-numerical magnitudes. In contrast, this region was not modulated by difficulty of the brightness control task. Accordingly in view of these findings, we suggest that the rIFG supports the accumulation of non numerical magnitudes that are positively correlated with number. Therefore taken together, this study reveals a brain region whose pattern of activity is influenced by the congruency between numerical and non-numerical variables during nonsymbolic number judgments. Hum Brain Mapp 38:4908-4921, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28660703 TI - HLA-DQB1*05:144, a novel allele, discovered in a Southeast Asian donor for stem cell transplantation. AB - HLA-DQB1*05:144 differs from HLA-DQB1*05:01:01 by a single substitution in exon 3. PMID- 28660704 TI - Dermoscopic features in three cases of rounded and velvety epidermal naevus. PMID- 28660705 TI - Pigmented squamous cell carcinoma in situ of the eyelid. PMID- 28660706 TI - Bicomponent Block Copolymers Derived from One or More Random Copolymers as an Alternative Route to Controllable Phase Behavior. AB - Block copolymers have been extensively studied due to their ability to spontaneously self-organize into a wide variety of morphologies that are valuable in energy-, medical-, and conservation-related (nano)technologies. While the phase behavior of bicomponent diblock and triblock copolymers is conventionally governed by temperature and individual block masses, it is demonstrated here that their phase behavior can alternatively be controlled through the use of blocks with random monomer sequencing. Block random copolymers (BRCs), i.e., diblock copolymers wherein one or both blocks are a random copolymer comprised of A and B repeat units, have been synthesized, and their phase behavior, expressed in terms of the order-disorder transition (ODT), has been investigated. The results establish that, depending on the block composition contrast and molecular weight, BRCs can microphase-separate. We also report that large variation in incompatibility can be generated at relatively constant molecular weight and temperature with these new soft materials. This sequence-controlled synthetic strategy is extended to thermoplastic elastomeric triblock copolymers differing in chemistry and possessing a random-copolymer midblock. PMID- 28660707 TI - Fluorescence sensing of dichlorvos pesticide by the luminescent Tb(III)-3-ally salicylohydrazide probe. AB - A fluorescent probe was developed and characterized, it consisted of terbium(III) with 3-ally-salicylohydrazide in ethanol, in which the 1:2 [Tb3+ :S1 ] molar ratio was the best stoichiometric ratio for the probe. The ligand 3-ally salicylohydrazide (S1 ) was synthesized, then was confirmed by IR, CHN, LC-MS and 1 H NMR. The sensitivity of the probe's fluorescence spectra towards the presence of eight organophosphorus pesticides in ethanolic solution was studied, in which the probe showed marked sensitivity towards dichlorvos pesticide. A tangible enhancement of the probe's fluorescence intensity was observed as a consequence of the gradual addition of dichlorvos pesticide. The calculated limit of detection (LOD) was 1.183 MUM and limit of quantitation (LOQ) was 3.94 MUM. Further characterization of the nature of forces acting in the interaction of the probe with dichlorvos was performed by calculation of binding constants at different temperatures according to the Benesi - Hildebrand equation, and the thermodynamic parameters DeltaH, DeltaS and DeltaG. In order to assess the analytical applicability of the method, the influence of various potentially interfering anion and cations that naturally occur in water and soil were calculated. PMID- 28660708 TI - Linear Unilateral Basaloid Follicular Hamartoma Following Blaschko's Lines: Two Case Reports and Review of the Literature. AB - Basaloid follicular hamartoma (BFH) is a rare follicular malformation characterized by variable clinical presentations and identical histopathologic features. We present the cases of a 3-month-old boy and an 8-year-old boy with linear unilateral BFH. To the best of our knowledge, only 14 cases of linear unilateral BFH have been described in the English-language literature. PMID- 28660710 TI - Physical activity participation and the association with work-related upper quadrant disorders (WRUQDs): A systematic review. AB - BACKGROUND: Workers in various occupations often report work-related upper quadrant disorders (WRUQDs). Research has shown that associative factors for WRUQDs include psychosocial and environmental elements, gender and physical activity levels. To date, no review has investigated whether physical activity participation is associated with and/or predicts the development of WRUQDs, so the present study set out to determine this. METHODS: A systematic review was conducted including searches of PubMed (MEDLINE), EMBASE and CINAHL from inception to 31 March 2017. Quantitative studies, including any outcome measure of physical activity participation and its association with and/or prediction of WRUQDs, were included. One reviewer conducted the search and two reviewers independently assessed eligibility and completed methodological quality assessment using a modified Downs and Black checklist. Data were analysed narratively. RESULTS: Eight studies were eligible for inclusion in the final review. The quality of these ranged from moderate to high quality. Three studies reported no statistical difference between physical activity participation and the risk of developing WRUQD. Three studies reported a negative and one study a positive association between physical activity participation and WRUQDs. One study reported that little or no physical exercise participation was a risk factor for WRUQD. CONCLUSIONS: There is limited evidence for a negative association between physical activity participation and the development of WRUQDs. However, this was not a consistent finding across all studies included. Further research is indicated in standardizing diagnostic criteria and the measurement of physical activity participation in this patient population. PMID- 28660709 TI - Patient characteristics, prognostic factors and outcome of dogs with high-grade primary mediastinal lymphoma. AB - The goals of this retrospective study were to determine the patient characteristics of dogs with high-grade primary mediastinal lymphoma and to determine outcome and associated prognostic factors. A total of 42 dogs were identified, in which 36 received treatment and had follow-up information available. The most common clinical signs included lethargy, anorexia and polyuria/polydipsia. Hypercalcemia and pleural effusion were common findings at diagnosis. The phenotype was almost exclusively T-cell, most often in association with lymphoblastic cytomorphology as defined by the World Health Organization (WHO) lymphoma classification scheme. The overall progression-free survival (PFS) and overall survival (OS) were 133 and 183 days, respectively. Treatment with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) protocol was associated with an improved PFS (144 days) and OS (194 days) when compared with dogs that received other medical therapies (P = .005 and P = .002, respectively); the absence of pleural effusion at diagnosis was associated with an increased OS but not PFS. These results suggest that while the prognosis for dogs with mediastinal lymphoma is poor, survival may be improved with treatment using a CHOP-based protocol. PMID- 28660711 TI - Mental health education in occupational therapy professional preparation programs: Alignment between clinician priorities and coverage in university curricula. AB - BACKGROUND/AIM: Occupational therapy programs must prepare graduates for work in mental health. However, this area of practice is complex and rapidly changing. This study explored the alignment between educational priorities identified by occupational therapists practising in mental health and level of coverage of these topics in occupational therapy programs in Australia and New Zealand. METHODS: Surveys were distributed to heads of all occupational therapy programs across Australia and New Zealand. The survey included educational priorities identified by occupational therapists in mental health from a previous study. Respondents were requested to identify the level of coverage given to each of these priorities within their curriculum. These data were analysed to determine a ranking of educational topics in terms of level of coverage in university programs. RESULTS: Responses were received for 19 programs from 16 universities. Thirty-four topics were given 'High-level coverage' in university programs, and these were compared against the 29 topics classified as 'Essential priorities' by clinicians. Twenty topics were included in both the 'Essential priorities' and 'High-level coverage' categories. Topics considered to be 'Essential priorities' by clinicians which were not given 'High-level coverage' in university programs included the following: mental health fieldwork experiences; risk assessment and management; professional self-care resilience and sensory approaches. CONCLUSION: While there appears to be overall good alignment between mental health curricula and priorities identified by practising occupational therapists, there are some discrepancies. These discrepancies are described and establish a strong foundation for further discussion between clinicians, academics and university administration to support curriculum review and revision. PMID- 28660712 TI - Reverse engineering development: Crosstalk opportunities between developmental biology and tissue engineering. AB - The fields of developmental biology and tissue engineering have been revolutionized in recent years by technological advancements, expanded understanding, and biomaterials design, leading to the emerging paradigm of "developmental" or "biomimetic" tissue engineering. While developmental biology and tissue engineering have long overlapping histories, the fields have largely diverged in recent years at the same time that crosstalk opportunities for mutual benefit are more salient than ever. In this perspective article, we will use musculoskeletal development and tissue engineering as a platform on which to discuss these emerging crosstalk opportunities and will present our opinions on the bright future of these overlapping spheres of influence. The multicellular programs that control musculoskeletal development are rapidly becoming clarified, represented by shifting paradigms in our understanding of cellular function, identity, and lineage specification during development. Simultaneously, advancements in bioartificial matrices that replicate the biochemical, microstructural, and mechanical properties of developing tissues present new tools and approaches for recapitulating development in tissue engineering. Here, we introduce concepts and experimental approaches in musculoskeletal developmental biology and biomaterials design and discuss applications in tissue engineering as well as opportunities for tissue engineering approaches to inform our understanding of fundamental biology. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2356-2368, 2017. PMID- 28660713 TI - Bacteria-Assisted Activation of Antimicrobial Polypeptides by a Random-Coil to Helix Transition. AB - The application of antimicrobial peptides (AMPs) is largely hindered by their non specific toxicity against mammalian cells, which is usually associated with helical structure, hydrophobicity, and charge density. A random coil-to-helix transition mechanism has now been introduced into the design of AMPs, minimizing the toxicity against mammalian cells while maintaining high antimicrobial activity. By incorporating anionic phosphorylated tyrosine into the cationic polypeptide, the helical structure of AMPs was distorted owing to the side-chain charge interaction. Together with the decreased charge density, the AMPs exhibited inhibited toxicity against mammalian cells. At the infectious site, the AMPs can be activated by bacterial phosphatase to restore the helical structure, thus contributing to strong membrane disruptive capability and potent antimicrobial activity. This bacteria-activated system is an effective strategy to enhance the therapeutic selectivity of AMPs. PMID- 28660714 TI - Gene-based interaction analysis shows GABAergic genes interacting with parenting in adolescent depressive symptoms. AB - BACKGROUND: Most gene-environment interaction studies (G * E) have focused on single candidate genes. This approach is criticized for its expectations of large effect sizes and occurrence of spurious results. We describe an approach that accounts for the polygenic nature of most psychiatric phenotypes and reduces the risk of false-positive findings. We apply this method focusing on the role of perceived parental support, psychological control, and harsh punishment in depressive symptoms in adolescence. METHODS: Analyses were conducted on 982 adolescents of Caucasian origin (Mage (SD) = 13.78 (.94) years) genotyped for 4,947 SNPs in 263 genes, selected based on a literature survey. The Leuven Adolescent Perceived Parenting Scale (LAPPS) and the Parental Behavior Scale (PBS) were used to assess perceived parental psychological control, harsh punishment, and support. The Center for Epidemiologic Studies Depression Scale (CES-D) was the outcome. We used gene-based testing taking into account linkage disequilibrium to identify genes containing SNPs exhibiting an interaction with environmental factors yielding a p-value per single gene. Significant results at the corrected p-value of p < 1.90 * 10-4 were examined in an independent replication sample of Dutch adolescents (N = 1354). RESULTS: Two genes showed evidence for interaction with perceived support: GABRR1 (p = 4.62 * 10-5 ) and GABRR2 (p = 9.05 * 10-6 ). No genes interacted significantly with psychological control or harsh punishment. Gene-based analysis was unable to confirm the interaction of GABRR1 or GABRR2 with support in the replication sample. However, for GABRR2, but not GABRR1, the correlation of the estimates between the two datasets was significant (r (46) = .32; p = .027) and a gene-based analysis of the combined datasets supported GABRR2 * support interaction (p = 1.63 * 10-4 ). CONCLUSIONS: We present a gene-based method for gene-environment interactions in a polygenic context and show that genes interact differently with particular aspects of parenting. This accentuates the importance of polygenic approaches and the need to accurately assess environmental exposure in G * E. PMID- 28660715 TI - Climate change vulnerability for species-Assessing the assessments. AB - Climate change vulnerability assessments are commonly used to identify species at risk from global climate change, but the wide range of methodologies available makes it difficult for end users, such as conservation practitioners or policymakers, to decide which method to use as a basis for decision-making. In this study, we evaluate whether different assessments consistently assign species to the same risk categories and whether any of the existing methodologies perform well at identifying climate-threatened species. We compare the outputs of 12 climate change vulnerability assessment methodologies, using both real and simulated species, and validate the methods using historic data for British birds and butterflies (i.e. using historical data to assign risks and more recent data for validation). Our results show that the different vulnerability assessment methods are not consistent with one another; different risk categories are assigned for both the real and simulated sets of species. Validation of the different vulnerability assessments suggests that methods incorporating historic trend data into the assessment perform best at predicting distribution trends in subsequent time periods. This study demonstrates that climate change vulnerability assessments should not be used interchangeably due to the poor overall agreement between methods when considering the same species. The results of our validation provide more support for the use of trend-based rather than purely trait-based approaches, although further validation will be required as data become available. PMID- 28660716 TI - Diagnostic utility of radiological heterogeneity in acute severe (fulminant) autoimmune hepatitis. AB - BACKGROUND: Histological examination is useful for the diagnosis of acute severe (fulminant) autoimmune hepatitis (AIH), but it is sometimes difficult to perform liver biopsy due to the complicated coagulopathy and ascites. We have shown that heterogeneous hypoattenuation on unenhanced computed tomography (CT) is a characteristic imaging feature of acute severe (fulminant) AIH. In the present study, we examined the utility of the imaging feature by applying the score to diagnose acute severe (fulminant) AIH. METHODS: Twenty-three patients with acute severe (fulminant) AIH were analyzed retrospectively. Modified AIH score was created by adding three points to AIH score with/without histological points in case of the presence of heterogeneous hypoattenuation on unenhanced CT. RESULTS: Areas of hypoattenuation were present in 15 (65%) patients, all of which were heterogeneous pattern. Five (22%) patients were diagnosed as "definite" AIH, 16 (69%) as "probable" and two (9%) as "non-diagnosis" by the revised original score without histological score. By adding three points, two of "non-diagnosis" changed to "probable" AIH, and all patients were diagnosed as AIH. CONCLUSIONS: Modified AIH score using heterogeneous CT image finding would be beneficial especially for patients in whom histological examinations cannot be performed because of complications. PMID- 28660718 TI - Clinical and dermoscopic features of targetoid haemosiderotic naevus: A peculiar melanoma simulator. PMID- 28660717 TI - Risk of Urolithiasis in Anorexia Nervosa: A Population-Based Cohort Study Using the Health Improvement Network. AB - This population-based retrospective cohort study sought to determine if anorexia nervosa (AN) is associated with a higher risk of urolithiasis. Nine thousand three hundred two females with AN were compared to 92 959 randomly selected age matched and practice-matched females. Cox regression was used to estimate the hazard ratio (HR) for urolithiasis and evaluate effect modification by age. Twenty-three participants with AN (0.25%) developed urolithiasis compared with 154 unexposed participants (0.17%) over a median of 4 years of observation. The risk of urolithiasis varied significantly with age (interaction p = 0.02). AN was associated with a more than threefold higher risk of urolithiasis in females <=25 years of age (HR 3.49, 95% CI: 1.56-7.81; p = 0.002), but not in females over 25 years (HR 1.18, 95% CI: 0.69-2.02; p = 0.54). The distribution of diagnosis codes for urolithiasis differed between groups (p = 0.04), with a higher proportion of codes for uric acid urolithiasis in the AN (16.2%) versus unexposed group (5.0%). Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28660719 TI - A Community Health Worker-Delivered Intervention in African American Women with Type 2 Diabetes: A 12-Month Randomized Trial. AB - OBJECTIVE: To evaluate the effectiveness of a community health worker (CHW) delivered lifestyle intervention for African American women with type 2 diabetes. METHODS: Participants were randomized to either 16 phone-based lifestyle intervention sessions aimed at making small changes in their diet and activity or 16 educational mailings sent across 12 months. Main outcomes included glycosylated hemoglobin (HbA1c), blood pressure (BP), and weight (kg) changes. RESULTS: Two hundred middle-aged (mean = 53 +/- 10.24 years), rural, African American women with moderate obesity (mean BMI = 37.7 +/- 8.02) and type 2 diabetes (mean HbA1c = 9.1 +/- 1.83) were enrolled. At 12 months, the intervention group exhibited no significant differences in HbA1c (-0.29 +/- 1.84 vs. + 0.005 +/- 1.61; P = 0.789) or BP (-1.01 +/- 20.46/+0.66 +/- 13.24 vs. + 0.22 +/- 25.33/-2.87 +/- 1.52; P = 0.100) but did exhibit greater weight loss ( 1.35 +/- 6.22 vs. -0.39 +/- 4.57 kg, respectively; P = 0.046) compared with controls. Exploratory post hoc analyses revealed that participants not using insulin had significantly greater reductions in HbA1c (-0.70 +/- 1.86 vs. + 0.07 +/- 2.01; P = 0.000), diastolic BP (-5.17 +/- 14.16 vs. -3.40 +/- 14.72 mmHg; P = 0.035), and weight (-2.36 +/- 6.59 vs. -1.64 +/- 4.36 kg; P = 0.003) compared to controls not on insulin. CONCLUSIONS: A phone-based CHW intervention resulted in no significant improvements in HbA1c or BP but did demonstrate modest improvements in weight. Women not using insulin showed significant improvements in all primary outcomes. PMID- 28660720 TI - Prednisolone for the first rhinovirus-induced wheezing and 4-year asthma risk: A randomized trial. AB - BACKGROUND: Previous findings show that corticosteroid treatment during the first acute wheezing episode may reduce recurrent wheezing in children with high rhinovirus genome load at 12-month follow-up. Longer-term effects have not been investigated prospectively. METHODS: After PCR confirmation of rhinovirus from nasopharyngeal aspirate, 79 children with the first acute wheezing episode were randomized to receive orally prednisolone or placebo for 3 days. The initiation of asthma control medication before the age of 5 years was confirmed from medical record and/or from parental interview. The outcome was the time to initiation of regular asthma control medication. Interaction analysis examined rhinovirus genome load. RESULTS: Fifty-nine (75%) children completed the follow-up. Asthma control medication was initiated in 40 (68%) children at the median age of 20 months. Overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo (P=.99). Rhinovirus load modified the effect of prednisolone regarding the time to initiation of asthma control medication (P-value for interaction=.04). In children with high rhinovirus load (>7000 copies/mL; n=23), the risk for initiation of medication was lower in the prednisolone group compared to the placebo group (P=.05). In the placebo group, asthma medication was initiated to all children with high rhinovirus load (n=9) during the 14 months after the first wheezing episode. CONCLUSIONS: Overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo. However, prednisolone may be beneficial in first-time wheezing children whose episode was severe and associated with high rhinovirus load. (ClinicalTrials.gov, NCT00731575). PMID- 28660721 TI - A cross-sectional, comparative study of home vs in-office NB-UVB phototherapy for vitiligo. PMID- 28660722 TI - In silico-designed novel non-peptidic ABAD LD hot spot mimetics reverse Abeta induced mitochondrial impairments in vitro. AB - Present work aimed to introduce non-peptidic ABAD loop D (LD ) hot spot mimetics as ABAD-Abeta inhibitors. A full-length atomistic model of ABAD-Abeta complex was built as a scaffold to launch the lead design and its topology later verified by cross-checking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime Abeta-binding LD residues-Tyr101, Thr108, and Thr110-were translated into specific pharmacophore features and this hypothesis subsequently used as a virtual screen query. ELISA-based screening of 20 hits identified two promising lead candidates, VC15 and VC19 with an IC50 of 4.4 +/- 0.3 and 9.6 +/- 0.1 MUm, respectively. They productively reversed Abeta induced mitochondrial dysfunctions such as mitochondrial membrane potential loss (JC-1 assay), toxicity (MTT assay), and ATP reduction (ATP assay) in addition to increased cell viabilities. This is the first reporting of LD hot spot-centric in silico scheme to discover novel compounds with promising ABAD-Abeta inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimer's disease (AD) therapeutics. PMID- 28660723 TI - Outcomes of treatment of stress urinary incontinence associated with female urethral diverticula: A selective approach. AB - AIMS: To assess surgical outcomes of concomitant treatment of SUI at time of transvaginal urethral diverticulectomy (TVUD) based on a selective approach. METHODS: Following Institutional Review Board (IRB) approval, we identified patients with a UD and SUI who underwent TVUD between July 2004 and January 2016. SUI was documented before and after surgery using subjective and objective parameters. Autologous pubovaginal slings (APVS) were used selectively based on surgeon and patient preference. RESULTS: A total of 61 patients underwent surgical treatment of urethral diverticula; 39 patients with UD and concomitant SUI. Mean age was 53 years. Mean follow-up was 16.2 months. There were 24 patients (62%) with SUI that underwent concomitant APVS. There was resolution of SUI in 20 of 24 patients (83%) who underwent a simultaneous APVS compared to 8 of 15 patients (53%) who underwent TVUD without APVS. Surgery resulted in the improvement or resolution of the majority of preoperative symptoms including recurrent urinary tract infection (UTI) (82% vs 15%), dyspareunia (64% vs 8%), and urgency (56% vs 13%) (preoperative vs postoperative). CONCLUSIONS: Female UD is often associated with SUI. Concomitant surgical treatment of UD and SUI often results in satisfactory control of bothersome SUI as well as other urinary symptoms such as UTI, dyspareunia and urgency. Treatment of SUI with APVS when undergoing TVUD is feasible with satisfactory outcomes. PMID- 28660724 TI - Forced- and Self-Rotation of Magnetic Nanorods Assembly at the Cell Membrane: A Biomagnetic Torsion Pendulum. AB - In order to provide insight into how anisotropic nano-objects interact with living cell membranes, and possibly self-assemble, magnetic nanorods with an average size of around 100 nm * 1 um are designed by assembling iron oxide nanocubes within a polymeric matrix under a magnetic field. The nano-bio interface at the cell membrane under the influence of a rotating magnetic field is then explored. A complex structuration of the nanorods intertwined with the membranes is observed. Unexpectedly, after a magnetic rotating stimulation, the resulting macrorods are able to rotate freely for multiple rotations, revealing the creation of a biomagnetic torsion pendulum. PMID- 28660725 TI - Automated robot-assisted surgical skill evaluation: Predictive analytics approach. AB - BACKGROUND: Surgical skill assessment has predominantly been a subjective task. Recently, technological advances such as robot-assisted surgery have created great opportunities for objective surgical evaluation. In this paper, we introduce a predictive framework for objective skill assessment based on movement trajectory data. Our aim is to build a classification framework to automatically evaluate the performance of surgeons with different levels of expertise. METHODS: Eight global movement features are extracted from movement trajectory data captured by a da Vinci robot for surgeons with two levels of expertise - novice and expert. Three classification methods - k-nearest neighbours, logistic regression and support vector machines - are applied. RESULTS: The result shows that the proposed framework can classify surgeons' expertise as novice or expert with an accuracy of 82.3% for knot tying and 89.9% for a suturing task. CONCLUSION: This study demonstrates and evaluates the ability of machine learning methods to automatically classify expert and novice surgeons using global movement features. PMID- 28660726 TI - Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. AB - Lanthanum carbonate (LaC) is used to prevent hyperphosphatemia in dialysis patients. It is commonly believed that there is little LaC absorption from the intestines. However, La deposition in the gastric mucosa, which we coined "gastric lanthanosis", was recently reported. We describe here the clinicopathological features of and a possible mechanism for gastric lanthanosis. This study included 23 patients with definite gastric lanthanosis. We extracted characteristic clinicopathological features of gastric lanthanosis by computed tomography (CT) imaging and endoscopic, histologic, electron-microscopic, and element analysis examinations. The Helicobacter pylori infection rate in the lanthanosis group was much lower than that among the general population. The clinicopathological features characteristic of gastric lanthanosis were mucosal high-density linear appearance by CT, reflective bright-white spots (BWS) by gastroscopy, eosinophilic histiocytes occasionally phagocytizing foreign materials by histology, and numerous electron-dense particles in the histiocytes. The particles had burr-like skeletons resembling La crystals. Gastric lanthanosis is an under-reported, but not a rare lesion. It is characterized by endoscopic BWS and histologic eosinophilic histiocytes in dialysis patients treated with LaC. The proposed mechanism for gastric lanthanosis is that LaC is dissolved by gastric juice, crystallized within the mucosa and is phagocytized by histiocytes. PMID- 28660727 TI - Preliminary evaluation of serum total cholesterol concentrations in dogs with osteosarcoma. AB - OBJECTIVES: To determine if total serum cholesterol concentrations were altered in dogs with osteosarcoma. To evaluate association of total serum cholesterol concentration with clinical outcomes in dogs with appendicular osteosarcoma. MATERIALS AND METHODS: Retrospective, multi-institutional study on 64 dogs with osteosarcoma. Control population consisted of dogs with traumatic bone fractures (n=30) and healthy patients of similar age and weight as those of the osteosarcoma cases (n=31). Survival analysis was done on 35 appendicular osteosarcoma patients that received the current standard of care. Statistical associations were assessed by univariable and multi-variable analysis. Information about age, sex, primary tumour location, total cholesterol concentration, monocytes and lymphocyte counts and alkaline phosphatase were also included. RESULTS: Total cholesterol was elevated above the reference interval (3.89 to 7.12 mmol/L) (150 to 275 mg/dL) in 29 of 64 (45.3%) osteosarcoma-bearing dogs, whereas similar elevations were found in only 3 of 30 (10%) fracture controls (P<0.0001) and 2 of 31 (6.5%) similar age/weight controls (P=0.0002). Elevated total cholesterol was significantly associated with a reduced hazard ratio (0.27, P=0.008) for overall mortality in dogs with osteosarcoma. CLINICAL SIGNIFICANCE: These results suggest that elevated total cholesterol is associated with canine osteosarcoma and may have prognostic significance. PMID- 28660728 TI - Necrobiosis lipoidica following Q-switched laser tattoo removal. PMID- 28660729 TI - Relative variations of gut microbiota in disordered cholesterol metabolism caused by high-cholesterol diet and host genetics. AB - Recent studies performed provide mechanistic insight into effects of the microbiota on cholesterol metabolism, but less focus was given to how cholesterol impacts the gut microbiota. In this study, ApoE-/- Sprague Dawley (SD) rats and their wild-type counterparts (n = 12) were, respectively, allocated for two dietary condition groups (normal chow and high-cholesterol diet). Total 16S rDNA of fecal samples were extracted and sequenced by high-throughput sequencing to determine differences in microbiome composition. Data were collected and performed diversity analysis and phylogenetic analysis. The influence of cholesterol on gut microbiota was discussed by using cholesterol dietary treatment as exogenous cholesterol disorder factor and genetic modification as endogenous metabolic disorder factor. Relative microbial variations were compared to illustrate the causality and correlation of cholesterol and gut microbiota. It turned out comparing to genetically modified rats, exogenous cholesterol intake may play more effective role in changing gut microbiota profile, although the serum cholesterol level of genetically modified rats was even higher. Relative abundance of some representative species showed that the discrepancies due to dietary variation were more obvious, whereas some low abundance species changed because of genetic disorders. Our results partially demonstrated that gut microbiota are relatively more sensitive to dietary variation. Nevertheless, considering the important effect of bacteria in cholesterol metabolism, the influence to gut flora by "genetically caused cholesterol disorder" cannot be overlooked. Manipulation of gut microbiota might be an effective target for preventing cholesterol-related metabolic disorders. PMID- 28660730 TI - Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens. AB - Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10 mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10 mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p < 0.001) and resulted in a strong post-nicotine elevation in DA levels (p < 0.01). However, there were no differences between the genotypes at higher doses. Furthermore, FAAH KO mice displayed a moderate enhancement of the effect of low dose nicotine on NAc 5-HT release (p < 0.05), with no differences between the genotypes at higher doses. Compared with vehicle-pretreated mice, mice pretreated with PF-3845 displayed an enhancement of the effect of low-dose nicotine on NAc DA release (p < 0.001), which resulted in a sustained increase in DA levels (p < 0.05). Similar to FAAH KO mice, PF-3845-pretreated mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.01). These observations in mice suggest that enhanced nicotine-induced NAc DA release might contribute to increased sensitivity to the conditioned rewarding effects of low-dose nicotine following FAAH inhibition, which has been previously reported. Future studies combining behavioral and neurochemical approaches are needed to elucidate the precise mechanism of these effects. PMID- 28660732 TI - "Part of the Team": Mapping the outcomes of training patients for new roles in health research and planning. AB - BACKGROUND: A patient research internship (Patient and Community Engagement Research program-PaCER) was created to support a provincial commitment by Alberta Health Services' Strategic Clinical NetworksTM to find new ways to engage patients in a new interdisciplinary organization to support evidence-informed improvements in clinical outcomes across the health system. OBJECTIVE: Implement and test a new research method and training curriculum to build patient capacity for engagement in health through peer-to-peer research. DESIGN: Programme evaluation using Outcome Mapping and the grounded theory method. SETTING AND PARTICIPANTS: Twenty-one patients with various chronic conditions completed one year of training in adapted qualitative research methods, including an internship where they designed and conducted five peer-to-peer inquiries into a range of health experiences. MAIN OUTCOME MEASURES: Outcomes were continually monitored and evaluated using an Outcome Mapping framework, in combination with grounded theory analysis, based on data from focus groups, observation, documentation review and semi-structured interviews (21 patient researchers, 15 professional collaborators). RESULTS: Key stakeholders indicated the increased capacity of patients to engage in health-care research and planning, and the introduction and acceptance of new, collaborative roles for patients in health research. The uptake of new patient roles in health-care planning began to impact attitudes and practices. CONCLUSIONS: Patient researchers become "part of the team" through cultural and relationship changes that occur in two convergent directions: (i) building the capacity of patients to engage confidently in a dialogue with clinicians and decision makers, and (ii) increasing the readiness for patient engagement uptake within targeted organizations. PMID- 28660731 TI - Zygomaticomaxillary suture maturation: Part II-The influence of sutural maturation on the response to maxillary protraction. AB - OBJECTIVE: To evaluate the influence of the maturational stages of zygomaticomaxillary sutures (ZMS) on the response to maxillary protraction. SUBJECTS AND METHODS: A total of 40 Class III patients were treated retrospectively with either a combination of rapid maxillary expansion and facial mask (RME/FM) or bone-anchored maxillary protraction (BAMP). The RME/FM group consisted of 18 patients (mean age 8.3 years), while the BAMP group was comprised of 22 patients (mean age 11.8 years). The initial CBCT images (T1) of the ZMSs were classified blindly. 3D models from CBCT images at the start and at the end of orthopaedic treatment were registered on the anterior cranial base, and corresponding structures were measured on colour-coded maps and semitransparent overlays. The amounts of protraction of the maxilla, zygoma, orbitale and maxillary first molars for both groups were analysed with two-way ANOVA with Holm Sidak post hoc test for multiple comparisons. RESULTS: A significant association was found between the early maturation stages of the ZMSs and the amount of maxillary protraction, regardless of the protraction method used. Class III patients with ZMS stages A and B showed greater maxillary protraction than patients at stage C. CONCLUSION: The maturational stages of ZMS are associated with the response maxillary protraction. PMID- 28660733 TI - Prospective measurement of quality of life in myotonic dystrophy type 1. AB - INTRODUCTION: Generic patient reported outcome measures have had varied success in tracking QoL in myotonic dystrophy type 1 (DM1). AIM: To analyze changes of Individualized Neuromuscular Quality of Life questionnaire (INQoL) scores in clinic patients with DM1 over a 6-year period. METHOD: Patients completed the INQoL at baseline and after a 6-year period through their attendance in a neurology outpatient clinic. Severity of muscular involvement in DM1 was analyzed using the Muscular Impairment Rating Scale (MIRS). RESULTS: Ninety-nine DM1 patients completed a baseline visit. Sixty-seven of these patients were retested at an interval time. The overall INQoL score improved in our sample of patients (P<.05) as did the following subscales: myotonia (P<.05), pain (P<.05), activities (P<.01), social relationships (P<.01), and body image (P<.05). No changes were observed for the independence and emotions scales. There were no differences in mean change of INQoL scores between patients with worsened MIRS and those with no change in MIRS scale after follow-up (P>.05). CONCLUSION: Individualized Neuromuscular Quality of Life questionnaire scores improved in our cohort of DM1 patients during a 6-year period. INQoL score did not correlate with progression of muscle weakness. This must be better understood before the selection of the instrument for use in trials to measure therapeutic benefit in DM1 patients. PMID- 28660736 TI - How to write abstracts for manuscripts, presentations, and grants: Maximizing information in a 30-s sound bite world. AB - BACKGROUND AND PURPOSE: Exponential growth of published conference and manuscript material, increasingly available electronic access, and heightened expectations for short, quick, and available information have propelled the written abstract into a position of extreme importance for nurse practitioners (NPs). NPs can leverage their abstract writing, to maximize exposure of their work, through presentations, publications, and grants. The purpose of this article is to detail the significance of abstract use and relevance for NPs, and to provide useful details and helpful hints for writing effective and strategic abstracts in a heavily electronic and 30-s sound bite world. METHODS: The manuscript is a brief report. Development procedures included detailed searches (PubMed, CINAHL, Google Scholar). Available literature was compiled and evaluated. Descriptions, examples, and helpful hints were developed and integrated into the manuscript. CONCLUSIONS: Attention to traditions and directions of the organization to which the abstract will be submitted is important. The process requires diligence, iterative writing, a focus on relevant content, and intended audience to maximize success. IMPLICATIONS FOR PRACTICE: A well-written abstract will move NP-relevant messages to heightened visibility for others. Leveraging the abstract is critical for NP patient care, professional growth, and profession overall. PMID- 28660734 TI - The association of QT interval components with atrial fibrillation. AB - BACKGROUND: Although abnormalities of the QT interval are associated with atrial fibrillation (AF), it is unclear whether ventricular depolarization (QRS duration) or repolarization (JT interval) is a more important marker of AF risk. METHODS: This analysis included 4,181 (95% white; 59% women) participants from the Cardiovascular Health Study (CHS) who were free of baseline AF and major intraventricular delay. A linear scale was used to compute heart rate adjusted QT (QTa), QRS (QRSa ), and JT (JTa ) intervals. Prolonged QTa , QRSa , and JTa were defined by values greater than the sex-specific 95th percentile for each measurement. AF events were ascertained during the annual study electrocardiograms and from hospitalization discharge data. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the associations of prolonged QTa , QRSa , and JTa with AF, separately. RESULTS: Over a mean follow-up of 12.1 years, a total of 1,236 (30%) AF events were detected. An increased risk of AF (HR = 1.50. 95% CI = 1.20, 1.88) was observed with prolonged QTa . When we examined the association between individual components of the QTa interval and AF, the risk of AF was limited to prolonged JTa (HR = 1.31, 95% CI = 1.04, 1.65) and not prolonged QRSa (HR = 1.00, 95% CI = 0.77, 1.30). Similar results were obtained per 1-SD increase in QTa (HR = 1.07, 95% CI = 1.01, 1.13), QRSa (HR = 0.99, 95% CI = 0.94, 1.06), and JTa (HR = 1.07, 95% CI = 1.01, 1.13). CONCLUSIONS: The JT interval is a more important marker of AF risk in the QT interval among persons who do not have ventricular conduction delays. PMID- 28660735 TI - Impact of standardized clinical assessment and management plans on resource utilization and costs in children after the arterial switch operation. AB - BACKGROUND: Standardized Clinical Assessment and Management Plans (SCAMPs) are a quality improvement initiative designed to reduce unnecessary utilization, decrease practice variation, and improve patient outcomes. We created a novel methodology, the SCAMP managed episode of care (SMEOC), which encompasses multiple encounters to assess the impact of the arterial switch operation (ASO) SCAMP on total costs. METHODS: All ASO SCAMP patients (dates March 2009 to July 2015) were compared to a control group of ASO patients (January 2001 to February 2009). Patients were divided into "younger" (<2 years) and "older" (2-18 years) subgroups. Utilization included all cardiology visits, tests, and procedures. Standardized costs were applied to each unit of utilization. RESULTS: There were 100 historical and 63 SCAMP patients in the younger subgroup, and 163 historical and 165 SCAMP patients in the older subgroup. In the younger subgroup, the SCAMP had a 28% reduction in outpatient clinic visits (P < .001), a 52% reduction in chest radiographs (P < .001), a 21% reduction in electrocardiograms (P < .001), and a 30% total reduction in costs. In the older subgroup, the SCAMP had a 21% reduction in outpatient clinic visits (P < .001), a 20% reduction in chest radiographs (P = .05), a 10% reduction in echocardiograms (P = .05), a 25% reduction in exercise stress tests (P = .01), and a 14% total reduction in costs. The total cost savings of the ASO SCAMP was $216 649 in the first 6 years of the SCAMP. There was no difference in clinical outcomes between the historical and SCAMP cohorts. CONCLUSION: SCAMPs can improve resource utilization and reduce costs after the ASO operation while maintaining quality of care. PMID- 28660737 TI - Ammonothermal Synthesis of Crystalline Oxonitride Perovskites LnTaON2 (Ln=La, Ce, Pr, Nd, Sm, Gd). AB - The perovskite type oxonitridotantalates LnTaON2 with Ln=La, Ce, Pr, Nd, Sm, and Gd were synthesized by the ammonothermal method employing custom-built autoclaves made of nickel-based superalloy. Metal powders were reacted with NaOH and NaN3 as mineralizers under supercritical conditions with purified ammonia at temperature range of 870-1070 K and pressure values of 150-300 MPa. Crystal structures and the space groups were determined by using powder X-ray diffraction and refined by the Rietveld method. The refined lattice parameters are for LaTaON2 (a=5.7156(1), b=8.0675(1), c=5.7465(1) A, Rwp =0.0471), CeTaON2 (a=5.6761(11), b=8.0386(16), c=5.7891(12) A, Rwp =0.183), PrTaON2 (a=5.6920(1), b=8.0197(1), c=5.6804(1) A, Rwp =0.0349), NdTaON2 (a=5.6884(1), b=8.0037(2), c=5.6554(1) A, Rwp =0.026), SmTaON2 (a=5.6827(1), b=7.9656(2), c=5.6103(1) A, Rwp =0.042), GdTaON2 (a=5.6160(10), b=7.9359(12), c=5.5962(10) A, Rwp =0.118). LaTaON2 crystallizes in space group Imma (no. 74) and the other compounds LnTaON2 with Ln=Pr, Nd, Sm, Gd in Pnma (no. 62). SEM measurements were performed to investigate the elemental composition and morphology of the oxonitride perovskites. The bandgap values of the oxonitrides (LaTaON2 1.8 eV, CeTaON2 1.7 eV; PrTaON2 1.9 eV, NdTaON2 2.0 eV, SmTaON2 2.0 eV, GdTaON2 1.8 eV) were estimated by using UV/Vis measurements and the Kubelka-Munk function. PMID- 28660738 TI - Pseudolymphoma in a cat on phenobarbital treatment. AB - A two-year-old female spayed domestic shorthair cat was presented with apathy, inappetence and generalised lymphadenomegaly. Anamnestic data included a generalised seizure disorder and phenobarbital treatment started one month before presentation. Routine blood analysis revealed only mild abnormalities and FeLV and FIV tests were negative. Both popliteal lymph nodes were aspirated and cytology was consistent with reactive lymph node hyperplasia. PCR for antigen receptor rearrangement testing diagnosed a polyclonal cell population. In the absence of another cause, lymphadenomegaly was attributed to an adverse drug reaction and phenobarbital was discontinued. The cat's condition improved and lymph node size normalised over the next 10 days. The retrospective diagnosis was phenobarbital-induced pseudolymphoma. PMID- 28660739 TI - Pooled efficacy and safety data for house dust mite sublingual immunotherapy tablets in adolescents. AB - BACKGROUND: House dust mite (HDM) respiratory allergy is a common and burdensome disease in children and adolescents. There are few HDM allergy immunotherapy trials in children with perennial allergic rhinitis. This post hoc analysis used pooled data to evaluate efficacy and safety of the SQ HDM sublingual immunotherapy (SLIT) tablet in adolescents (12-17 years). METHODS: In two double blind, placebo-controlled trials conducted in North America and Japan, respectively, subjects aged 12+ years with HDM allergic rhinitis were randomized to up to 1 year of treatment. The primary end-point in both trials was the average total combined rhinitis score (TCRS) during the last 8 weeks of treatment in the active group compared with placebo. Data from subjects aged 12-17 years were pooled (N=395). RESULTS: In the pooled adolescent subpopulation, average TCRS improved 22% with 12 SQ HDM vs placebo (absolute treatment difference of 1.04; P<.01). Rhinitis daily symptom score (DSS), conjunctivitis DSS and rhinitis daily medication score (DMS) were also significantly improved vs placebo in the pooled adolescent subpopulation (all P<.05). There were no new safety signals for adolescents. The frequency of adverse events was similar in adolescents and adults with the majority being mild application site-related events. CONCLUSIONS: Treatment with 12 SQ HDM appears to be effective and well tolerated in adolescents with HDM allergic rhinitis. PMID- 28660740 TI - Prolonged first-line PEG-asparaginase treatment in pediatric acute lymphoblastic leukemia in the NOPHO ALL2008 protocol-Pharmacokinetics and antibody formation. AB - BACKGROUND: As pegylated asparaginase is becoming the preferred first-line asparaginase preparation in the chemotherapy regimens of childhood acute lymphoblastic leukemia (ALL), there is a need to evaluate this treatment. METHODS: The aim of this study was to evaluate the pharmacokinetics of prolonged upfront biweekly PEG-asparaginase (where PEG is polyethylene glycol) treatment by measuring serum l-asparaginase activity and formation of anti-PEG-asparaginase antibodies. A total of 97 evaluable patients (1-17 years), diagnosed with ALL, and treated according to the NOPHO ALL2008 protocol (where NOPHO is Nordic Society of Paediatric Haematology and Oncology) were included. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG asparaginase (Oncaspar(r) ) 1,000 IU/m2/dose, at 2-week or 6-week intervals with a total of 30-week treatment (Clinical trials.gov. no.: NCT00819351). RESULTS: The pharmacological target of treatment (l-asparaginase activity above 100 IU/l) was reached in 612 of 652 (94%) samples obtained 14 +/- 2 days after PEG asparaginase administration. Mean l-asparaginase activity was 338 IU/l. Six patients had l-asparaginase activity below 50 IU/l in all samples. A total of 25 patients (26%) developed Immunoglobulin G (IgG) anti-PEG-asparaginase antibodies, but there was no correlation between anti-PEG-asparaginase antibodies and low levels of asparaginase activity. CONCLUSION: We conclude that prolonged first line biweekly PEG-asparaginase therapy, 1,000 IU/m2/dose was above the pharmacological target in the vast majority of patients. Presence of anti-PEG asparaginase antibodies was not a predictor of l-asparaginase activity. PMID- 28660741 TI - Split-brain phenomena in anterior communicating artery aneurysm rupture: A case report. AB - In 1976, a patient with an anterior communicating artery aneurysm (ACoAA) rupture (diagnosed on angiography) and sub-arachnoid hemorrhage (SAH) underwent serial neuropsychological testing revealing a classical anterior cerebral artery (ACA) spasm picture with severe anterograde amnesia of Korsakoff's type and dysexecutive syndrome. In addition, the patient demonstrated impaired hemispheric interaction with alien hand syndrome, dyscopia-dysgraphia, complete left ear neglect, and other, more complex, split-brain phenomena. He was evaluated by A. R. Luria in 1976. Following surgery the patient demonstrated gradual improvement. PMID- 28660742 TI - The "third abstraction" of the Chinese artist LaoZhu: Neural and behavioral indicators of aesthetic appreciation. AB - The eminent Chinese artist LaoZhu has created a homogeneous set of abstract pictures that are referred to as the "third abstraction." By definition, these pictures are meant to be representations of the artist's personal involvement and as such to create an internal point of view in the observer on an implicit level of processing. Aiming at investigating whether the artist's choice of a specific color is experienced in a specific way in the recipient, we assessed both explicit and implicit (i.e. neurocognitive) correlates in naive viewers of LaoZhu's pieces. The behavioral results reveal a preference of the original red paintings over color-changed counterparts in green or black. Paradoxically and inconsistent with predictions, we found higher levels of neural activation in several brain regions (predominantly in the frontal and parietal cortices) for the color-changed compared to the original red conditions. These observations add empirically to the complementarity of early visual pathways and higher-order cognition as well as of explicit and implicit information processing during aesthetic appreciation. We discuss our findings in light of processing effort and top-down control of the color-changed paintings. With regard to the third abstraction as defined by LaoZhu, in particular to the distinction between an external and internal point of view when viewing abstract art, our results contribute to an understanding of "abstraction and empathy" as a fundamental part of aesthetic appreciations. PMID- 28660743 TI - Single case studies as a prime example for exploratory research. PMID- 28660744 TI - Reconceptualizing mental disorders: From symptoms to organs. AB - Most mental pathologies are diagnosed on the sole basis of the symptoms reported by patients, such as "I'm feeling low." The thrust of this paper is the proposal to reconceptualize mental disorders as dysfunctions of brain subsystems. This shift from symptom to organ would bring psychiatry in line with the rest of medicine, and is analogous to the change in status of venereal infections from skin pathologies, such as chancres, to bacterial infections. The proposal in question is part of the reconceptualization of mental processes as brain processes, in line with the materialist conception of the mind as neural. A practical advantage of this conceptual change is that it suggests approaching mental disorders as brain dysfunctions treatable by biological and chemical means, in addition to social measures, such as accommodating mental patients in ordinary hospitals rather than in isolated "madhouses" at the mercy of amateurs or even charlatans. An additional advantage of the "embodiment" of mental diseases is that it suggests reframing some new research projects, such as explaining why the common cold causes mental fogginess, why hypertension can cause irritability, and why nicotine dependence can be even stronger than cocaine addiction. In other words, the present proposal is to complete the so-called "mapping of the mind onto the brain" by including the abnormal mental processes, which used to be treated by shamans at a time when the mind was conceived of as an immaterial entity detachable from the body. PMID- 28660745 TI - Prolidase is a critical enzyme for complete gliadin digestion in Tenebrio molitor larvae. AB - Prolidase is a proline-specific metallopeptidase that cleaves imidodipeptides with C-terminal Pro residue. Prolidase was purified and characterized from the Tenebrio molitor larval midgut. The enzyme was localized in the soluble fraction of posterior midgut tissues, corresponding to a predicted cytoplasmic localization of prolidase according to the structure of the mRNA transcript. Expression of genes encoding prolidase and the major digestive proline-specific peptidase (PSP)-dipeptidyl peptidase 4-were similar. The pH optimum of T. molitor prolidase was 7.5, and the enzyme was inhibited by Z-Pro, indicating that it belongs to type I prolidases. In mammals, prolidase is particularly important in the catabolism of a proline-rich protein-collagen. We propose that T. molitor larval prolidase is a critical enzyme for the final stages of digestion of dietary proline-rich gliadins, providing hydrolysis of imidodipeptides in the cytoplasm of midgut epithelial cells. We propose that the products of hydrolysis are absorbed from the luminal contents by peptide transporters, which we have annotated in the T. molitor larval gut transcriptome. The origin of prolidase substrates in the insect midgut is discussed in the context of overall success of grain feeding insects. PMID- 28660746 TI - Pronase treatment improves flow cytometry crossmatching results. AB - Flow cytometry crossmatching (FC-XM) is the most sensitive cell-based method for detecting donor-specific antibodies in clinical organ transplantation. Unfortunately, background FC-XM reactivity is elevated in assays with B lymphocytes-partly because of nonspecific immunoglobulin binding by Fc receptors and B-cell surface immunoglobulins. To reduce the background reactivity in a B cell FC-XM assay, we treated lymphocytes with pronase (1 mg/mL for 30 minutes). This treatment drastically reduced the presence of kappa light chains and Fc receptors (CD32b), while the concomitant decrease in CD19, CD20 and major histocompatibility complex (MHC) I and II expression on B-cells was acceptable. Higher pronase concentrations (>2 mg/mL) started to significantly affect CD19, CD20, MHC-I and -II expression on B-cells. In subsequent prospective experiments (on 42 donor cells tested with 102 sera), we found that pronase treatment was associated with a relative increase of the sensitivity and specificity in our B cell FC-XM assay. PMID- 28660747 TI - Reversible and Efficient Sequestration of Cesium from Water by the Layered Metal Thiophosphate K0.48 Mn0.76 PS3 ?H2 O. AB - Water body contamination with radioactive species is an important issue due to significant developments in nuclear energy. Cesium (137 Cs) radioisotope is a non actinide fission product of uranium and plutonium that is long-lived. Hence, selective removal/capture of cesium is essential for managing radioactive waste. Herein, a detailed Cs+ ion-exchange study on a potassium intercalated layered metal thiophosphate, K0.48 Mn0.76 PS3 ?H2 O (K-MPS-1), is reported. The sorption of Cs+ by K-MPS-1 follows the Langmuir model with a high capacity of 337.5 mg g-1 and high distribution coefficients in the order of about 104 mL g-1 . K-MPS-1 can sequester Cs+ efficiently, even from very low concentrations (ppb level). K MPS-1 exhibits high cesium uptake over a broad pH range of 2-12 and the ion exchange process reaches equilibrium within a short time (~15 min), following pseudo-second-order kinetics. Moreover, K-MPS-1 demonstrates selectivity towards Cs+ capture in the presence of complex solutions containing excess Na+ , Ca2+ , and Mg2+ ions; this is due to favorable interactions between Cs (soft Lewis acid) and S (soft Lewis base). K-MPS-1 reversibly captures Cs+ and it can be regenerated by treating Cs-MPS-1 with a solution of KCl. PMID- 28660749 TI - "Making the best of what we have": The lived experiences of community psychiatric nurses, day centre managers and social workers supporting clients with dementia attending a generic day care service. AB - AIM AND OBJECTIVES: This study explored the experiences and perspectives of community psychiatric nurses, day centre managers and social workers about supporting clients living with and without dementia attending a generic day care service. The purpose of the study was to elucidate approaches that enable clients living with dementia to access and derive benefit from the service. BACKGROUND: In the light of international ageing demographics and strategy towards social inclusion, it is anticipated that demand for generic day care services for clients living with and without dementia will increase. DESIGN AND METHODS: A descriptive qualitative design utilised three focus groups for data collection. Community psychiatric nurses (n = 4), day centre mangers (n = 4) and social workers (n = 12) participated in the study. Data analysis informed a narrative description of the approaches that support adults living with dementia in day care. FINDINGS: An exhaustive description is encapsulated in five key themes. These are "easing the transition to day care," "proactively managing supervision and complexity of need," "sustaining the person and family carer," making the best of what we have" and "encountering a need for change," The data conveyed a sensitivity to the life story and needs of clients with dementia. Whilst the data revealed deficits in the physical environment of the centres, there were indications of the generation of a positive social environment. CONCLUSIONS: A generic day care service that provides an integrated blend of care and treatment and social and recreational support to older adults, irrespective of whether they have or have not dementia, is realistic and manageable. The routine of day centre attendance may have value in sustaining clients with dementia and family care giving relationships. IMPLICATIONS FOR PRACTICE: Approaches to support the attendance of clients with dementia at day care include home visits, life story work, proactive supervision and careful planning of social groupings and recreational activities. PMID- 28660748 TI - Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation. AB - Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor- beta1 (TGF-beta1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80+ cells expressing TGF-beta1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO-BM)->WT showed suppressed formation of liver metastasis compared with WT BM->WT. However, the formation of metastasis was further suppressed in WT-BM >AT1aKO compared with AT1aKO-BM->WT. In addition, accumulated F4/80+ cells in the liver metastasis were not BM-derived F4/80+ cells, but mainly resident hepatic F4/80+ cells, and these resident hepatic F4/80+ cells were positive for TGF beta1. Angiotensin II enhanced TGF-beta1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF beta1+ F4/80+ cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-beta1 through AT1a signaling. PMID- 28660750 TI - Urinary manifestations in Isaacs's syndrome. Our experience in 8 cases. AB - INTRODUCTION: Isaacs's syndrome (IS), is a rare neurological disorder, characterized by sustained muscular activity, fasciculations, cramps, myokymia, excessive sweating, and occasional elevation of creatine phosphokinase (CPK) enzyme. AIM: To report our experience in patients with IS and urinary manifestations, describing clinical findings, test's results, and response to treatment. Methods An observational, retrospective analysis of patients with IS and urinary manifestations treated at German Hospital of Buenos Aires between 2001 and 2011 was done. Diagnosis was performed with clinical examination and electromyography (EMG) of external sphincter of the anus and/or urethra. Demographic, clinical, and treatment variables were analyzed. International Prognostic Scoring System (IPSS) at diagnosis and follow up was made. RESULTS: Eleven IS patients were recruited, of whom 8 (72.72%) were females with a mean age 47.87 years (DS +/- 13.95) and presented associated lower tract urinary symptoms (LUTS). Six of them (75%) had voiding and 2 (25%) filling symptoms. Urodynamic and electromyographic findings reproduced symptomatology in all patients. Patients with voiding symptomatology were treated with combination of alpha-blockers with benzodiazepines; membrane stabilizings agents; antiepileptics; neurotropic; corticoids; posterior tibial nerve stimulation and botulinum toxin, achieving improvement in 4/6. The two patients with storage symptoms were treated in first instance with anticholinergic drugs, one of which did not respond completely was added oral pentosansulfate and electrical stimulation, reversing the symptomatology. Four patients had associated pathologies: Hashimoto's thyroiditis; Sjogren's syndrome; dysautonomia, and myasthenia gravis. CONCLUSIONS: In our experience, IS urinary manifestations are common and usually has a good evolution with adequate treatment for each patient. PMID- 28660752 TI - Biased Duplications and Loss of Members in Tdrd Family in Teleost Fish. AB - Gene expansion and contraction are important evolution events. Some tdrd genes, especially multi-Tudor members, participate in Piwi-interacting RNA pathway and spermatogenesis. However, tdrd evolution and their functions in teleost fish are poorly understood. Here, we identified 14 tdrds in the teleost fish, swamp eel, which were clustered into 12 tdrd branches. Comparative synteny showed biased duplications and loss of members in the tdrd family. Both tdrd6 and tdrd7 were duplicated in the teleost fish, whereas tdrd8 was lost from the original locus. Expression analysis at both RNA and protein levels showed that tdrd6l, a duplicated multi-Tudor member, was gonad enriched. Expression pattern of tdrd6l in follicular epithelium and seminiferous epithelium during sex reversal supports its potential role in genome defense in germline. PMID- 28660751 TI - Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. AB - Charcot-Marie-Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole-exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 +/- 14 (range 0-59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co-occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is the most frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2-related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity. PMID- 28660753 TI - Response to the Letter by Natamba et al. PMID- 28660754 TI - Food insecurity and depressive symptoms in pregnant women with special reference to social support. PMID- 28660755 TI - Highly Efficient Inverted D:A1:A2 Ternary Blend Organic Photovoltaics Combining a Ladder-type Non-Fullerene Acceptor and a Fullerene Acceptor. AB - A formylated benzodi(cyclopentadithiophene) (BDCPDT) ladder-type structure with forced coplanarity is coupled with two 1,1-dicyanomethylene-3-indanone (IC) moieties via olefination to form a non-fullerene acceptor, BDCPDT-IC. The BDCPDT IC, as an acceptor (A1) with broad light-absorbing ability and excellent solution processability, is combined with a second PC71BM acceptor (A2) and a medium band gap polymer, PBDB-T, as the donor (D) to form a ternary blend with gradient HOMO/LUMO energy alignments and panchromatic absorption. The device with the inverted architecture using the D:A1:A2 ternary blend has achieved a highest efficiency of 9.79% with a superior Jsc of 16.84 mA cm-2. PMID- 28660756 TI - Photoelectrochemical Performance of the Ag(III)-Based Oxygen-Evolving Catalyst. AB - We report the electrosynthesis of a water oxidation catalyst based on Ag oxides (AgCat). The deposited AgCat is composed of mixed valence crystalline Ag oxides with the presence of particle aggregates whose size is ~1 MUm. This catalyst, coupled with TiO2 and hematite, and under photoelectrochemical conditions, substantially increases photocurrents in a wide range of applied potentials compared with bare and Co-Pi-modified photocatalysts. AgCat can sustain current densities comparable with other water oxidation catalysts. Dark bulk electrolysis demonstrated that AgCat is stable and can sustain high turnover number in operative conditions. Oxygen evolution from water occurs in mild conditions: pH = 2-13, room temperature and pressure, and moderate overpotentials (600 mV) compatible with the coupling with semiconducting oxides as sensitizers. Using hematite in sustained electrolysis O2 production is significant, both in the dark and under irradiation, after an initial slow induction time in which modification of surface species occurs. PMID- 28660757 TI - Pulsed Electron Paramagnetic Resonance Insights into the Ligand Environment of Copper in Drosophila Lysyl Oxidase. AB - Lysyl oxidase (LOX) is a copper amine oxidase that cross-links collagens and elastin in connective tissue and plays an important role in fibrosis, cancer development, and formation of the "metastatic niche". Despite its important biological functions, the structure of human LOX remains unknown (unlike that of an unrelated LOX, from Pichia pastoris). Here, we expressed active LOX from Drosophila melanogaster, DmLOXL1, a close homologue of human LOX, and characterized it by MS, UV-vis, activity, and inhibition assays. We then used bioinformatics, electron paramagnetic resonance, electron spin-echo envelope modulation, and hyperfine sublevel-correlation (HYSCORE) spectroscopies to probe Cu-ligand bonding finding direct evidence for pH-dependent Cu-His interactions. At pH = 9.3, the spectroscopic data indicated primarily a single His bound to Cu, but at pH = 7.5, there was evidence for a ~ 1:1 mixture of species containing 1 and 3 His ligands. We then used HYSCORE to probe possible interactions between the LOX inhibitor BAPN (beta-aminopropionitrile; 1-[13C15N]cyano-2-aminoethane) and the copper center-finding none. Overall, the results are of interest since they provide new spectroscopic information about the nature of the catalytic site in LOX, an important anticancer drug target. PMID- 28660758 TI - Intracellular Messenger RNA Triggered Catalytic Hairpin Assembly for Fluorescence Imaging Guided Photothermal Therapy. AB - We show a theranostic nanoplatform for messenger RNA (mRNA) triggered enhanced fluorescence imaging guided therapy. Catalytic hairpin assembly (CHA) and gold nanorods (AuNRs) are employed to fabricate the theranostic nanoplatform. Two hairpin DNAs and Cy5 labeled duplex DNA are integrated into the CHA for mRNA triggered fluorescence signal amplification via hybridization and displacement with mRNA. The AuNRs act both as the fluorescence quencher and the photothermal therapy (PTT) agent. The nanoplatform not only enables sensitive and specific imaging of target mRNA in living cells and good differentiating of the survivin mRNA expression levels in different cell lines but also offers excellent photothermal conversion efficiency for PTT. The developed nanoplatform has great potential for sensitive and specific intracellular mRNA imaging guided PTT. PMID- 28660759 TI - DNA Tetrahedral Nanostructure-Based Electrochemical miRNA Biosensor for Simultaneous Detection of Multiple miRNAs in Pancreatic Carcinoma. AB - Specific and sensitive biomarker detection is essential to early cancer diagnosis. In this study, we demonstrate an ultrasensitive electrochemical biosensor with the ability to detect multiple pancreatic carcinoma (PC)-related microRNA biomarkers. By employing DNA tetrahedral nanostructure capture probes to enhance the detection sensitivity as well as a disposable 16-channel screen printed gold electrode (SPGE) detection platform to enhance the detection efficiency, we were able to simultaneously detect four PC-related miRNAs: miRNA21, miRNA155, miRNA196a, and miRNA210. The detection sensitivity reached to as low as 10 fM. We then profiled the serum levels of the four miRNAs for PC patients and healthy individuals with our multiplexing electrochemical biosensor. Through the combined analyses of the four miRNAs, our results showed that PC patients could be discriminated from healthy controls with fairly high sensitivity. This multiplexing PCR-free miRNA detection sensor shows promising applications in early diagnosis of PC disease. PMID- 28660760 TI - Stacking Sequence and Acceptor Dependence of Photocurrent Spectra and Photovoltage in Organic Two-Junction Devices. AB - Both single-junction and tandem organic photovoltaic cells have been well developed. A tandem cell contains two junctions with a charge recombination layer (CRL) inserted between the two junctions. So far, there is no detailed report on how the device will perform that contains two junctions but without a CRL in between. In this work, we report the photocurrent spectra and photovoltage output of the devices that contains two bulk-heterojunctions (BHJ) stacked directly on top of each other without a CRL. The top active layer is prepared by transfer printing. The photocurrent response spectra and photovoltage are found to be sensitive to stacking sequence and the selection of electron acceptors. The open circuit voltage of the devices (up to 1.09 V) can be higher than the devices containing either junction layer. The new phenomenon in the new device architecture increases the versatility of the optoelectronic devices based on organic semiconductors. PMID- 28660761 TI - Bipolar Electrode Based Multicolor Electrochemiluminescence Biosensor. AB - We report a multicolor ECL device based on closed bipolar electrode (BPE) for the visualized sensing of prostate-specific antigen (PSA) in human blood serum. As the emission color of concomitant electrochemiluminophores is potential resolved, similar to a three-electrode system, selective excitation of ECL could be achieved by tuning the interfacial potential at the poles of BPE. Via modulating the resistance of BPE, multicolor ECL emission of [Ru(bpy)3]2+ and [Ir(ppy)3] mixture using tripropylamine (TPrA) as the co-reactant was observed at the anode and the principle was elaborated. The concept was utilized to the quantification of clinical biomarkers with the color variation. A PSA concentration dependent silver bridge was constructed in the gap of the BPEs as an electric conductivity modulator. On the basis of a multicolor BPE-ECL device, the cutoff values (4.0 and 10.0 ng/mL) of human PSA could be recognized with naked eyes by the green yellow-red ECL emission changing. As the first multicolor ECL device in biological analysis, BPE may raise the application of potential-resolved ECL to a new level. PMID- 28660762 TI - Efficient Synthesis of Glucosyl-beta-Cyclodextrin from Maltodextrins by Combined Action of Cyclodextrin Glucosyltransferase and Amyloglucosidase. AB - Instead of beta-cyclodextrin (beta-CD), branched beta-CDs have been increasingly used in many aspects as they possess better solubility and higher bioadaptability. But most commercialized branched beta-CDs were chemically synthesized. Thus, the glucosyl-beta-cyclodextrin (G1-beta-CD) prepared via enzymatic approach could be a nice substitute. However, the yield of G1-beta-CD was low. Here, we reported a controlled two-step reaction to efficiently prepare G1-beta-CD from maltodextrins by beta-cyclodextrin glucosyltransferase (beta CGTase) and amyloglucosidase (AG). Compared to the single beta-CGTase reaction, controlled two-step reaction caused a yield increase of G1-beta-CD by 130%. Additionally, the percentage of G1-beta-CD was enhanced from 2.4% to 24.0% and the side products alpha-CD and gamma-CD were hydrolyzed because of the coupling activity of beta-CGTase. Thus, this controlled two-step reaction might be an efficient approach for industrial production of pure G1-beta-CD. PMID- 28660763 TI - Ruthenium-Catalyzed C-H Hydroxylation in Aqueous Acid Enables Selective Functionalization of Amine Derivatives. AB - The identification, optimization, and evaluation of a new catalytic protocol for sp3 C-H hydroxylation is described. Reactions are performed in aqueous acid using a bis(bipyridine)Ru catalyst to enable oxidation of substrates possessing basic amine functional groups. Tertiary and benzylic C-H hydroxylation is strongly favored over N-oxidation for numerous amine derivatives. With terpene-derived substrates, similar trends in reactivity toward tertiary and benzylic C-H bonds are observed. Hydroxylation of chiral tertiary centers is enantiospecific in spite of the ionizing strength of the reaction medium. Preliminary kinetics experiments show a marked difference in reactivity between isomeric cis- and trans-Ru catalysts suggesting that the catalyst is configurationally stable under the reaction conditions. PMID- 28660764 TI - Tunable Cu Enrichment Enables Designer Syngas Electrosynthesis from CO2. AB - Using renewable energy to recycle CO2 provides an opportunity to both reduce net CO2 emissions and synthesize fuels and chemical feedstocks. It is of central importance to design electrocatalysts that both are efficient and can access a tunable spectrum of products. Syngas, a mixture of carbon monoxide (CO) and hydrogen (H2), is an important chemical precursor that can be converted downstream into small molecules or larger hydrocarbons by fermentation or thermochemistry. Many processes that utilize syngas require different syngas compositions: we therefore pursued the rational design of a family of electrocatalysts that can be programmed to synthesize different designer syngas ratios. We utilize in situ surface-enhanced Raman spectroscopy and first principles density functional theory calculations to develop a systematic picture of CO* binding on Cu-enriched Au surface model systems. Insights from these model systems are then translated to nanostructured electrocatalysts, whereby controlled Cu enrichment enables tunable syngas production while maintaining current densities greater than 20 mA/cm2. PMID- 28660765 TI - Copper(I)-Catalyzed Chemoselective Reduction of Benzofuran-2-yl Ketones to Alcohols with B2pin2 via a Domino-Borylation-Protodeboronation Strategy. AB - A novel copper(I)-catalyzed chemoselective reduction of the carbonyls of benzofuran-2-yl ketones over furan rings with B2pin2 has been developed. This reaction proceeded under mild conditions. High valuable secondary alcohol derivatives of benzofurans were obtained in good to excellent yields with a broad substrate scope. The mechanistic studies suggested that a domino-borylation protodeboronation pathway was involved in this reaction. PMID- 28660766 TI - One-Pot Synthesis of Hyperoside by a Three-Enzyme Cascade Using a UDP-Galactose Regeneration System. AB - Hyperoside exhibits many biological properties and is more soluble in water than quercetin. A uridine 5'-diphosphate (UDP) galactose regeneration system and one pot synthesis of hyperoside was described herein. Glycine max sucrose synthase (GmSUS) was coupled with Escherichia coli UDP-galactose 4-epimerase (GalE) to regenerate UDP-galactose from sucrose and UDP. Petunia hybrida glycosyltransferase (PhUGT) with high activity toward quercetin was used to synthesize hyperoside via the UDP-galactose regeneration system. The important factors for optimal synergistic catalysis were determined. Through the use of a fed-batch operation, the final titer of hyperoside increased to 2134 mg/L, with a corresponding molar conversion of 92% and maximum number of UDP-galactose regeneration cycles (RCmax) of 18.4 under optimal conditions. Therefore, the method described herein for the regeneration of UDP-galactose from UDP and sucrose can be widely used for the glycosylation of flavonoids and other bioactive substances. PMID- 28660768 TI - Comparison of peri and post-procedural complications in patients undergoing revascularisation of coronary artery multivessel disease by coronary artery bypass grafting or protected percutaneous coronary intervention with the Impella 2.5 device. AB - BACKGROUND: While coronary artery bypass grafting remains the standard treatment of complex multivessel coronary artery disease, the advent of peripheral ventricular assist devices has enhanced the safety of percutaneous coronary intervention. We therefore evaluated the safety in terms of inhospital outcome comparing protected high-risk percutaneous coronary intervention with the Impella 2.5 device and coronary artery bypass grafting in patients with complex multivessel coronary artery disease. METHODS: This retrospective study included patients with complex multivessel coronary artery disease (SYNTAX score >22) undergoing either coronary artery bypass grafting before the implementation of a protected percutaneous coronary intervention programme with a peripheral ventricular assist device or protected percutaneous coronary intervention with the Impella 2.5 device following the start of the programme. The primary endpoint consisted of inhospital major adverse cardiac and cerebrovascular events. The combined secondary endpoint included peri and post-procedural adverse events. RESULTS: A total of 54 patients (mean age 70.1+/-9.9 years, 92.6% men) were enrolled in the study with a mean SYNTAX score of 34.5+/-9.8. Twenty-six (48.1%) patients underwent protected percutaneous coronary intervention while 28 (51.9%) patients received coronary artery bypass grafting. The major adverse cardiac and cerebrovascular event rate was numerically higher in the coronary artery bypass grafting group (17.9 vs. 7.7%; P=0.43) but was not statistically significant. The combined secondary endpoint was not different between the groups; however, patients undergoing coronary artery bypass grafting experienced significantly more peri-procedural adverse events (28.6 vs. 3.8%; P<0.05). CONCLUSION: Patients with complex multivessel coronary artery disease undergoing protected percutaneous coronary intervention with the Impella 2.5 device experience similar intrahospital major adverse cardiac and cerebrovascular event rates when compared to coronary artery bypass grafting. Protected percutaneous coronary intervention represents a safe alternative to coronary artery bypass grafting in terms of inhospital adverse events. PMID- 28660767 TI - SpecOMS: A Full Open Modification Search Method Performing All-to-All Spectra Comparisons within Minutes. AB - The analysis of discovery proteomics experiments relies on algorithms that identify peptides from their tandem mass spectra. The almost exhaustive interpretation of these spectra remains an unresolved issue. At present, an important number of missing interpretations is probably due to peptides displaying post-translational modifications and variants that yield spectra that are particularly difficult to interpret. However, the emergence of a new generation of mass spectrometers that provide high fragment ion accuracy has paved the way for more efficient algorithms. We present a new software, SpecOMS, that can handle the computational complexity of pairwise comparisons of spectra in the context of large volumes. SpecOMS can compare a whole set of experimental spectra generated by a discovery proteomics experiment to a whole set of theoretical spectra deduced from a protein database in a few minutes on a standard workstation. SpecOMS can ingeniously exploit those capabilities to improve the peptide identification process, allowing strong competition between all possible peptides for spectrum interpretation. Remarkably, this software resolves the drawbacks (i.e., efficiency problems and decreased sensitivity) that usually accompany open modification searches. We highlight this promising approach using results obtained from the analysis of a public human data set downloaded from the PRIDE (PRoteomics IDEntification) database. PMID- 28660769 TI - Platelets as a surrogate disease model of neurodevelopmental disorders: Insights from Fragile X Syndrome. AB - Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Despite a large number of therapeutics developed in past years, there is currently no targeted treatment approved for FXS. In fact, translation of the positive and very promising preclinical findings from animal models to human subjects has so far fallen short owing in part to the low predictive validity of the Fmr1 ko mouse, an overly simplistic model of the complex human disease. This issue stresses the critical need to identify new surrogate human peripheral cell models of FXS, which may in fact allow for the identification of novel and more efficient therapies. Of all described models, blood platelets appear to be one of the most promising and appropriate disease models of FXS, in part owing to their close biochemical similarities with neurons. Noteworthy, they also recapitulate some of FXS neuron's core molecular dysregulations, such as hyperactivity of the MAPK/ERK and PI3K/Akt/mTOR pathways, elevated enzymatic activity of MMP9 and decreased production of cAMP. Platelets might therefore help furthering our understanding of FXS pathophysiology and might also lead to the identification of disease-specific biomarkers, as was shown in several psychiatric disorders such as schizophrenia and Alzheimer's disease. Moreover, there is additional evidence suggesting that platelet signaling may assist with prediction of cognitive phenotype and could represent a potent readout of drug efficacy in clinical trials. Globally, given the neurobiological overlap between different forms of intellectual disability, platelets may be a valuable window to access the molecular underpinnings of ASD and other neurodevelopmental disorders (NDD) sharing similar synaptic plasticity defects with FXS. Platelets are indeed an attractive model for unraveling pathophysiological mechanisms involved in NDD as well as to search for diagnostic and therapeutic biomarkers. PMID- 28660770 TI - To the ninetieth anniversary of Professor Istvan Nasz. PMID- 28660772 TI - Reporting More but Moving Less? The Complex Relationship between Acculturation and Physical Activity Among US Adults. AB - PURPOSE: To investigate the association between acculturation and physical activity (PA). DESIGN: Cross sectional. SETTING: The National Health and Nutrition Examination Surveys (NHANES) 2003 to 2006. SUBJECTS: A total of 4029 adults (aged 20-64), including 2063 men and 1966 women. MEASURES: The outcome measures included both self-reported PA and device-assessed PA. The acculturation measure was constructed based on nativity, language use at home, and length of residence in the United States. ANALYSIS: Regressions with domain analysis were conducted to adjust for the influence of confounding factors and complex survey design. RESULTS: For men, self-reported PA increased with acculturation, especially leisure-time PA. However, device-assessed PA decreased with acculturation. For women, the results were more mixed. CONCLUSION: All evidence considered, we concluded that PA decreased with acculturation for US men. PMID- 28660771 TI - Service Quality Assessment of Hospitals in Asian Context: An Empirical Evidence From Pakistan. AB - Hospitals vary from one another in terms of their specialty, services offered, and resource availability. Their services are widely measured with scales that gauge patients' perspective. Therefore, there is a need for research to develop a scale that measures hospital service quality in Asian hospitals, regardless of their nature or ownership. To address this research need, this study adapted the SERVQUAL instrument to develop a service quality measurement scale. Data were collected from inpatients and outpatients at 9 different hospitals, and the scale was developed using structural equation modeling. The developed scale was then validated by identifying service quality gaps and ranking the areas that require managerial effort. The findings indicated that all 5 dimensions of SERVQUAL are valid in Asian countries such as Pakistan, with 13 items retained. Reliability, tangibility, responsiveness, empathy, and assurance were ranked first, second, third, fourth, and fifth, respectively, in terms of the size of the quality gap. The gaps were statistically significant, with values <=.05; therefore, hospital administrators must focus on each of these areas. By focusing on the identified areas of improvement, health care authorities, managers, practitioners, and decision makers can bring substantial change within hospitals. PMID- 28660773 TI - Successful Treatment of Azole-Resistant Candida Esophagitis in an Immunocompromised Pregnant Woman Using Anidulafungin. PMID- 28660774 TI - Canalis basalis medianus with cerebrospinal fluid leak: rare presentation and literature review. AB - Canalis Basalis Medianus is a rare congenital normal anatomically variant of the clivus .We report a very rare case of cerebrospinal fluid leak from a canalis basilaris medianus in a 22-year-old male, who presented to our hospital with frontal headache and running nose two weeks after an elective septoplasty. PMID- 28660775 TI - The microbiome: current and future view of an ancient paradigm. PMID- 28660776 TI - Gender-Affirming Pharmacological Interventions for Youth With Gender Dysphoria: When Treatment Guidelines Are Not Enough. AB - Youth with gender dysphoria, also known as transgender youth, are increasingly presenting to multidisciplinary clinics within academic pediatric centers across the United States. Gender-affirming pharmacological interventions for adolescents with gender dysphoria may be used to promote positive psychological well-being and mental health outcomes. Interventions range from completely reversible to partially irreversible, based on the age and sexual maturity of the adolescent. For each intervention, dilemmas and controversies exist regarding age at treatment initiation, treatment duration, safety, and cost. Pharmacists' awareness of these considerations and interventions is important when providing evidence-based gender-affirming care to this underserved population. PMID- 28660777 TI - Diogenes Syndrome in Frontotemporal Dementia. AB - Diogenes syndrome refers to the combination of extreme self-neglect and excessive collecting with clutter and squalor, which is often present in patients with dementia. Diogenes syndrome may be particularly common in behavioral variant frontotemporal dementia (bvFTD), and the investigation of these patients may help clarify the nature of this syndrome. We describe 5 patients with bvFTD who exhibited a decline in self-care accompanied by hoarding behaviors. These patients, and a review of the literature, suggest a combination of frontal lobe disturbances: loss of insight or self-awareness with a failure to clean up or discard, a general compulsive drive, and an innate impulse to take environmental items. This impulse may be part of the environmental dependency syndrome in frontal disease, with specific involvement of a right frontolimbic-striatal system. Further investigation of the similarities and mechanisms of these symptoms in bvFTD could help in understanding Diogenes syndrome and lead to potential treatment options. PMID- 28660778 TI - Cardio-oncology: cardiovascular complications of cancer therapy. AB - This paper focuses on three classes of commonly used anticancer drugs, which can cause cardiotoxicity: anthracyclines, monoclonal antibodies exemplified by trastuzumab and tyrosine kinase inhibitors. Anthracyclines can induce cardiomyocyte necrosis and fibrosis. Trastuzumab can cause cardiac stunning. The tyrosine kinase inhibitors can increase systemic arterial pressure and impair myocyte contractility. In addition, radiation therapy to the mediastinum or left chest can exacerbate the cardiotoxicity of these anticancer drugs and can also cause accelerated atherosclerosis, myocardial infarction, heart failure and arrhythmias. Left ventricular ejection fraction measurements are most commonly used to assess cardiac function in patients who receive chemo- or radiation therapy. However, echocardiographic determinations of global longitudinal strain are more sensitive for detection of early left ventricular systolic dysfunction. Information on patient-risk stratification and monitoring is presented and guidelines for the medical treatment of cardiac dysfunction due to cancer therapies are summarized. PMID- 28660780 TI - Patients with male gender or greater body weight use smaller amounts of topical therapy in psoriasis. AB - OBJECTIVES AND METHODS: Topical therapy is the first-line treatment in mild and moderate psoriasis. We performed a real-life study on topical therapies in psoriasis and observed a variation in the amounts of ointment patients applied during the study. RESULTS: A statistically significant correlation was found between gender and the total amount of ointment used: women used more than men (p = .020). Also, heavier patients tended to use less ointment (p = .038). CONCLUSIONS: We look forward to seeing whether the current pressure to improve psoriasis treatment leads to more patients receiving systemic therapies or to better adherence to, and persistence with, topical therapies. PMID- 28660781 TI - Variability in biological behaviour, pathogenicity, protectotype and induction of virus neutralizing antibodies by different vaccination programmes to infectious bronchitis virus genotype Q1 strains from Chile. AB - In the period from July 2008 to 2010, a disease episode resulting in serious economic losses in the major production area of the Chilean poultry industry was reported. These losses were associated with respiratory problems, increase of condemnations, drops in egg production and nephritis in breeders, laying hens and broilers due to infections with infectious bronchitis virus (IBV). Twenty-five IBV isolates were genotyped and four strains were selected for further testing by pathotyping and protectotyping. Twenty-four IBV isolates were of the Q1 genotype. The experiments also included comparing the ability of six vaccination programmes to induce virus neutralizing antibodies (VNA) in layers against four selected Chilean strains. Despite the high genetic homology in the S1 gene between the four strains, the heterogeneity in biological behaviour of these different Q1 strains was substantial. These differences were seen in embryonated eggs, in cell culture, in pathogenicity and in level of cross-protection by IBV Massachusetts (Mass) vaccination. This variability underlines the importance of testing more than one strain per serotype or genotype to determine the characteristics of a certain serotype of genotype. The combination of Mass and 793B vaccine provided a high level of protection to the respiratory tract and the kidney for each strain tested in the young birds. The combination of broad live priming using Mass and 793B vaccines and boosting with multiple inactivated IBV antigens induced the highest level of VNA against Q1 strains, which might be indicative for higher levels of protection against Q1 challenge in laying birds. PMID- 28660782 TI - Violacein and bacterial predation: promising alternatives for priority multidrug resistant human pathogens. PMID- 28660783 TI - Interview with Justin Davies and Andrew Tochterman. AB - Justin Davies and Andrew Tochterman speak to Adam Price-Evans, Commissioning Editor of Future Cardiology: Justin Davies is a Senior Research Fellow and Honorary Consultant Cardiologist at the National Heart and Lung Institute, Imperial College London (UK). His main research interests include the development and application of pioneering technologies in engineering to aid understanding of disease mechanisms, and in the diagnosis of pathological disease states. After completing his undergraduate training at Imperial College, he was awarded a prestigious British Heart Foundation research fellowship to undertake his PhD at Imperial College. Since then, he has trained in interventional cardiology with a specialist interest in physiological and structural assessment of coronary disease states. In 2008, he was appointed as a Walport Clinical Lecturer to support his research activities alongside his ongoing clinical commitments. Born in Greentown, Indiana (USA), Andrew holds a BSc in Chemical Engineering from Rose Hulman Institute of Technology (IN, USA) and an MBA from the Wharton Business School (PA, USA). His experience includes roles in Quality Engineering, R&D, Clinical & Product Marketing, Marketing Management and Sales at Guidant Corporation/Abbott Vascular. Andrew joined Philips Image Guided Therapy (CA, USA) in 2012, helping launch the instant wave-free ratio (iFR) product in Europe and the United States before taking on greater responsibilities as the Physiology Segment Leader, and later assuming his current role as Coronary Segment Leader at Philips Image Guided Therapy (CA, USA). PMID- 28660784 TI - The novel Pseudomonas putida plasmid p12969-2 harbors an In127-carrying multidrug resistant region. AB - AIM: This study aims to characterize a multidrug-resistant (MDR) plasmid p12969-2 coexistent with the previously reported one p12969-DIM in clinical Pseudomonas putida. MATERIALS & METHODS: The complete sequence of p12969-2 was determined using next-generation sequencing technology. RESULTS: p12969-2 contains a 29.2 kb MDR region, which carries In127 harboring three resistance genes aadA2, qacED1 and sul1. The MDR region is derived from the connection of Tn5041D and Tn5045, which is facilitated by two copies of miniature inverted-repeat transposable element. Conclusion & future perspective: p12969-2 represents a novel lineage with the highest but limited nucleotide sequence similarity with the plasmid pGRT1 that does not carry any of the resistance genes. This is the first report of coexistence of two MDR plasmids in P. putida. PMID- 28660785 TI - Non-elastic taping, but not elastic taping, provides benefits for patients with knee osteoarthritis: systemic review and meta-analysis. AB - OBJECTIVE: To determine whether therapeutic taping, which includes elastic (Kinesio tape) and non-elastic (Leukotape) taping, is superior to control taping in improving pain and functions for patients with knee arthritis. To understand whether both elastic and non-elastic taping are beneficial. METHODS: We searched the PubMed and Scopus databases from their earliest record to 31 May 2017 for randomized controlled and cross-over studies that used taping to treat knee osteoarthritis. We extracted the mean differences and SD between baseline and posttreatment for selected outcomes measured in the experimental and control groups for subsequent meta-analyses. RESULTS: In total, 11 studies were included in the review. Of which, five Leukotaping and five Kinesio taping studies involving 379 participants were used in the meta-analysis. PEDro scores of the Leukotaping and Kinesio taping studies were 4.2 and 7.8, respectively. Overall, therapeutic taping exhibited significantly greater pain reduction than control taping with a significant weighted mean difference of 12.8 mm on a 0- to 100-mm visual analogue scale. Compared to control taping, Leukotaping produced a significant weighted mean difference of 11.6 mm regarding pain with a large effect size of 0.89 and I2 = 0%, while Kinesio taping produced a non-significant weighted mean difference of 12.1 mm and I2 = 93%. Leukotaping also exhibited a large and significant standard mean difference of 0.82, while Kinesio taping exhibited a non-significant standard mean difference of 1.34 regarding climbing stairs and stepping. CONCLUSION: Therapeutic taping seemed to be superior to control taping in pain control for knee osteoarthritis. Non-elastic taping, but not elastic taping, provides benefits in pain reduction and functional performance. PMID- 28660786 TI - Cost and Complications of Percutaneous Fixation of Hand Fractures in a Procedure Room Versus the Operating Room. AB - BACKGROUND: The purpose of this study was to compare closed reduction and percutaneous pinning of metacarpal and phalanx fractures performed in the operating room (OR) versus the procedure room of the emergency department with primary outcomes being infection rate, radiographic union, and monetary cost. METHODS: From January 2006 to December 2010, all closed reduction and percutaneous pinnings of metacarpal and phalanx fractures (CPT codes: 26608; 26727) by a single board-certified hand surgeon (A.M.H.) were retrospectively reviewed. Patients were placed into 2 groups: Group 1 was patients treated in the OR, and group 2 was patients in an emergency department procedure room. Infection, malunion, and nonunion rates were compared using a chi-square test. Charges were compared using a t-test, and cost of supplies and labor was evaluated. RESULTS: A total of 189 patients met final inclusion criteria for this study: 130 in group 1 and 59 in group 2. There was no statistically significant difference in infection rates ( P = .13), nonunion ( P = .40), malunion rates ( P = .89), and hardware failure with revision ( P = .94) between the 2 groups. The procedure room patients had an average hospital charge of $1358.55 compared with $3691.85 for OR-treated patients (P = .001). The total cost of supplies and nonphysician labor was $432.31 per OR case and $179.59 per procedure room case. CONCLUSIONS: Metacarpal and phalanx fractures of the hand amendable to closed reduction and percutaneous pinning can be treated in the procedure room with no increase in risk of infection, malunion, or nonunion rates. In addition, these surgeries can be performed in a procedure room with lower cost and less charges to patients than in the operating room. PMID- 28660787 TI - Comparison of pharmacokinetics and drug release in tissues after transarterial chemoembolization with doxorubicin using diverse lipiodol emulsions and CalliSpheres Beads in rabbit livers. AB - CalliSpheres(r) Beads (CB) is the first drug-eluting bead (DEB) product in China. Our aim was to compare the effect on the pharmacokinetics of doxorubicin (DOX) and its local concentration between lipiodol emulsions and CB in the process of TACE in rabbit livers. Twenty-five rabbits were distributed into two groups; Group 1 received lipiodol emulsions with DOX, and Group 2 received CB loaded with DOX (CBDOX). DOX was measured in the peripheral blood at different times after treatment. Livers were sampled at 1 week and 1 month for Group 2 after embolization. DOX concentration and distribution were measured in the liver. The administration of DOX by TACE with CBDOX resulted in peripheral blood DOX concentrations of 39.85 +/- 13.86 ng/mL at 5 min, with a gradual decrease to 6.89 +/- 1.62 ng/mL at 24 h, after treatment. Plasma concentration of DOX after chemoembolization with lipiodol was 225.91 +/- 64.88 ng/mL at 5 min and decreased with time by 24 h to 5.06 +/- 0.48 ng/mL. In CBDOX group, the drug impregnated an area as far as 200 MUm from the bead edge. The tissue concentration of doxorubicin (tissCDOX) ranged from 40.27 MUg/mL to 245.70 MUg/mL at 1 week and from 5.64 MUg/mL to 28.09 MUg/mL at 1 month. Plasma concentrations of DOX resulting from CBDOX embolization were significantly lower than that for cTACE. CB could deliver relatively high concentrations of DOX to an area as far as 200 MUm from the bead edge for at least 1 month. PMID- 28660788 TI - Evaluation of the effectiveness and safety of a genetically modified live vaccine in broilers challenged with Salmonella Heidelberg. AB - Salmonellosis ranks among the major diseases of commercial poultry, and its presence in poultry flocks is responsible for economic losses and risks related to public health. Vaccines are an important tool within integrated programmes to control salmonellosis. The purpose of this study was to assess cross-protection provided by the Poulvac(r) ST vaccine in the control of Salmonella Heidelberg in experimentally challenged 3- and 21-day-old birds. Eighty birds were identified and separated into four treatments (T1: vaccinated and challenged at 3 days of age, T2: unvaccinated and challenged at 3 days of age, T3: vaccinated and challenged at 21 days of age, and T4: unvaccinated and challenged at 21 days of age). The inoculum was produced from a Brazilian field strain of SH. At the end of the experiment, caecum and liver/spleen samples were collected for quantitative and qualitative analysis of SH, respectively. Analysis of the liver/spleen showed that Poulvac(r) ST significantly (P <= 0.05) reduced the percentage of SH positivity in the group challenged at 3 days of age, while in the group challenged at 21 days this difference was almost considered significant (P = 0.1818). On the other hand, there was no statistically significant difference in SH count in the caecum (CFU/g) in the group challenged at 3 days, but for the group challenged at 21 days the SH counts were significantly (P <= 0.05) lower in the vaccinated group when compared to the positive control. PMID- 28660789 TI - Glycemic Control With Early Initiation of Continuous Glucose Monitoring System in Adults With Recently Diagnosed Type 1A Diabetes. PMID- 28660791 TI - Long-term changes of salivary exoglycosidases and their applicability as chronic alcohol-drinking and dependence markers. AB - OBJECTIVES: Investigation of long-term dynamic changes of salivary activity/output of exoglycosidases, deglycosylation processes and their applicability as alcohol markers. METHODS: Exoglycosidase (alpha-fucosidase (FUC), beta-galactosidase (GAL), beta-glucuronidase (GLU), beta-hexosaminidase (HEX, HEX A and HEX B isoenzymes) and alpha-mannosidase (MAN)) activities were measured in the saliva of healthy social drinking controls (C), alcohol-dependent non-smokers (ANS) and alcohol-dependent smokers (AS) at the 1st, 15th, 30th and 50th day of abstinence after chronic alcohol drinking. RESULTS: The activity of exoglycosidases was 2-3-fold (MAN), 2-6 fold (FUC), 8-25-fold (HEX A) and 19-40 fold (GLU) higher in the ANS and AS groups than in controls, and had good/excellent sensitivity, specificity and accuracy. The higher outputs of exoglycosidases were in the AS and ANS groups than in controls at the 1st day (GLU, HEX A) and at the 50th day (GLU, FUC, MAN) of abstinence. We found numerous correlations between alcohol-drinking days with GLU and HEX A, alcohol amounts with HEX A and duration of alcohol dependence with FUC and MAN activity/output. CONCLUSIONS: Salivary exoglycosidases/deglycosylation processes were still very high up to 50 days after the end of alcohol consumption. We found markers of chronic alcohol consumption (HEX A), alcohol dependence (FUC and MAN) and chronic alcohol consumption and dependence (GLU). PMID- 28660792 TI - Left ventricular torsion in patients with obstructive sleep apnoea before and after continuous positive airway pressure therapy: assessment by two-dimensional speckle tracking echocardiography. AB - BACKGROUND: The purpose of the present study was to evaluate how obstructive sleep apnoea (OSA) influences left ventricular (LV) torsion and whether nasal continuous positive airway pressure (CPAP) therapy has any impact on LV torsion in OSA patients with established cardiovascular risk factors. METHODS: LV torsion was assessed by two-dimensional speckle tracking echocardiography (STE) in 162 participants without overt cardiovascular disease. The participants were categorized according to the apnoea-hypopnea index (AHI) as controls and mild, moderate and severe OSA patients. Forty-three patients with AHI greater than 30 were enrolled to receive CPAP therapy for 24 weeks. Twenty-eight patients received CPAP therapy effectively (compliance: 65%). After completion of CPAP therapy, STE was repeated to evaluate LV torsion. RESULTS: LV torsion was decreased in the severe OSA group compared to mild and moderate OSA but was similar to controls as a result of predominant decrease in apical rotation. AHI had no correlation with LV torsion in moderate OSA but a significant and mild negative correlation with LV torsion in severe OSA. When adjusted for potential confounding variables such as left ventricular mass index, diastolic dysfunction and the presence of hypertension, AHI and E/E' remained significant predictors of LV torsion in OSA patients. LV apical rotation tended to increase after effective CPAP therapy. On the other hand, LV basal rotation decreased significantly. CONCLUSIONS: LV torsion was altered in OSA patients with varying degrees according to the disease severity. Furthermore, there was no significant change of torsion after 24 weeks of CPAP therapy. PMID- 28660793 TI - Pulmonary hypertension in patients with chronic kidney disease: invasive hemodynamic etiology and outcomes. AB - Pulmonary hypertension (PH) is common in patients with chronic kidney disease (CKD) and associated with increased mortality but the hemodynamic profiles, clinical risk factors, and outcomes have not been well characterized. Our objective was to define the hemodynamic profile and related risk factors for PH in CKD patients. We extracted clinical and hemodynamic data from Vanderbilt's de identified electronic medical record on all patients undergoing right heart catheterization during 1998-2014. CKD (stages III-V) was defined by estimated glomerular filtration rate thresholds. PH was defined as mean pulmonary pressure >= 25 mmHg and categorized into pre-capillary and post-capillary according to consensus recommendations. In total, 4635 patients underwent catheterization: 1873 (40%) had CKD; 1518 (33%) stage 3, 230 (5%) stage 4, and 125 (3%) stage 5. PH was present in 1267 (68%) of these patients. Post-capillary (n = 965, 76%) was the predominant PH phenotype among CKD patients versus 302 (24%) for pre capillary ( P < 0.001). CKD was independently associated with pulmonary hypertension (odds ratio = 1.4, 95% confidence interval = 1.18-1.65). Mortality among CKD patients rose with worsening stage and was significantly increased by PH status. PH is common and independently associated with mortality among CKD patients referred for right heart catheterization. Post-capillary was the most common etiology of PH. These data suggest that PH is an important prognostic co morbidity among CKD patients and that CKD itself may have a role in the development of pulmonary vascular disease in some patients. PMID- 28660795 TI - Barriers to primary and emergency healthcare for trans adults. AB - Trans individuals are less healthy than the general population in part because of their avoidance and underutilisation of healthcare. Using qualitative research methods, the objective of this study was to explore the barriers trans adults encounter when pursuing primary and emergency care in Nova Scotia, Canada. Findings reveal that trans adults often feel discriminated against and socially excluded in primary and emergency care settings. This marginalisation is manifested in relationships with healthcare providers and within both the physical care and social care environments. The findings suggest that there is a 'discrimination continuum' with experiences of discrimination ranging from subtle to overt. Findings indicate that subtle discriminatory experiences may be encountered most frequently. Both kinds of experiences are reported to have detrimental consequences. The findings also indicate that trans adults are often burdened by the expectation that they will take on a more active role in their care than cisgender patients, including educating their healthcare providers and remaining resilient in the face of discrimination. PMID- 28660794 TI - Left main coronary artery compression by a dilated main pulmonary artery and left coronary sinus of Valsalva aneurysm in a patient with heritable pulmonary arterial hypertension and FLNA mutation. AB - Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient's sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A ( FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva. PMID- 28660796 TI - Increased stress and strain on the spinal cord due to ossification of the posterior longitudinal ligament in the cervical spine under flexion after laminectomy. AB - Myelopathy in the cervical spine due to cervical ossification of the posterior longitudinal ligament could be induced by static compression and/or dynamic factors. It has been suggested that dynamic factors need to be considered when planning and performing the decompression surgery on patients with the ossification of the posterior longitudinal ligament. A finite element model of the C2-C7 cervical spine in the neutral position was developed and used to generate flexion and extension of the cervical spine. The segmental ossification of the posterior longitudinal ligament on the C5 was assumed, and laminectomy was performed on C4-C6 according to a conventional surgical technique. For various occupying ratios of the ossified ligament between 20% and 60%, von-Mises stresses, maximum principal strains in the spinal cord, and cross-sectional area of the cord were investigated in the pre-operative and laminectomy models under flexion, neutral position, and extension. The results were consistent with previous experimental and computational studies in terms of stress, strain, and cross-sectional area. Flexion leads to higher stresses and strains in the cord than the neutral position and extension, even after decompression surgery. These higher stresses and strains might be generated by residual compression occurring at the segment with the ossification of the posterior longitudinal ligament. This study provides fundamental information under different neck positions regarding biomechanical characteristics of the spinal cord in cervical ossification of the posterior longitudinal ligament. PMID- 28660797 TI - Evaluating Cultural Competence of Pediatric Oncology Nurses at a Teaching Hospital: A Pilot Study. AB - This cross-sectional descriptive study evaluated registered nurses' self-ratings of cultural competence on the hematology/oncology unit at a large Northeastern urban children's hospital. The Inventory for Assessing the Process of Cultural Competence among Healthcare Professionals was used to measure 5 constructs of cultural competence. The study findings show that there were significant correlations between the knowledge and skill subscales (rho = .57, P < .001) and the knowledge and desire subscales (rho = .42, P < .05). The highest mean among the 5 subscales was cultural desire (mean = 15.5), indicating that nurses were motivated to engage in the process of becoming culturally competent. The lowest mean among the 5 subscales was cultural knowledge (mean = 11.2), followed by cultural skill (mean = 11.8), indicating that nurses did not perceive themselves to be well informed in these areas. The findings from this pilot study suggest that nurses on this pediatric oncology unit are most likely to possess cultural desire and cultural awareness, but there is certainly opportunity to engage and educate the staff. Targeted interventions to improve cultural competence on this inpatient unit are being explored and a larger scale study is being planned to assess the cultural competence of nurses across the hospital. PMID- 28660798 TI - The philosophy of 'unity of knowledge and action' in interventional neuroradiology teaching. AB - Despite the continuing emphasis on the importance of clinical skills, these skills do not appear to be improving and may actually be declining. The 'unity of knowledge and action' is a medicine directed precisely at this disease. The 'unity of knowledge and action' helps to learn from failure and successes, learn from mistakes of predecessors and institute a behaviour that prevents repetition of these mistakes. PMID- 28660799 TI - Factors to consider in pregnancy of unknown location. AB - The management of women with a pregnancy of unknown location (PUL) can vary significantly and often lacks a clear evidence base. Intensive follow-up is usually required for women with a final outcome of an ectopic pregnancy. This, however, only accounts for a small proportion of women with a pregnancy of unknown PUL location. There remains a clear clinical need to rationalize the follow-up of PUL so women at high risk of having a final outcome of an ectopic pregnancy are followed up more intensively and those PUL at low risk of having an ectopic pregnancy have their follow-up streamlined. This review covers the main management strategies published in the current literature and aims to give clinicians an overview of the most up-to-date evidence that they can take away into their everyday clinical practice when caring for women with a PUL. PMID- 28660800 TI - Hysterectomy for benign conditions: Complications relative to surgical approach and other variables that lead to post-operative readmission within 90 days of surgery. AB - OBJECTIVE: To examine variables associated with hysterectomy-related complications, relative to surgical approach and other variables, that lead to readmission within 90 days of surgery. METHODS: We conducted an observational cohort study for which data were extracted from electronic health records. Data were extracted of all patients (n = 3106) who underwent hysterectomies at 10 Kaiser Permanente Southern California medical centers between June 2010 and September 2011. Patients who were pregnant or had a cancer diagnosis were excluded from the study. To identify univariate associations between examined variables and procedure type, chi-square tests for categorical variables and t tests or analysis of variance for continuous variables were used. Generalized estimating equations methods were used to test associations between independent variables and primary outcomes of interest. Statistical significance was determined using a p-value <.05. RESULTS: Of 3106 patients, 109 experienced 168 post-operative complications. The most common post-operative complications were related to pelvic abscesses, bowel obstruction, or severe ileus, and the vaginal cuff. Pelvic abscesses were most frequent among total laparoscopic hysterectomy and total abdominal hysterectomy cases (p = .002), and vaginal cuff complications were most frequent among total laparoscopic hysterectomy cases (p = .015). Patients who underwent total vaginal hysterectomy (odds ratio = 2.13, confidence interval = 1.15-3.92), laparoscopic supracervical hysterectomy (odds ratio = 3.11, confidence interval = 1.13-8.57), and total laparoscopic hysterectomy (odds ratio = 5.60, confidence interval = 2.90-10.79) experienced increased occurrence of post-operative complications resulting in readmission. Other variables associated with an increased risk for readmission included high estimated blood loss (201-300 mL and 301+ mL, relative to 0-50 mL; odds ratio = 2.28, confidence interval = 1.24-4.18 and odds ratio = 2.63, confidence interval = 1.67-4.14) and long length of stay of 3 days or more (relative to 0 days; odds ratio = 2.93, confidence interval = 1.28-6.69). Pelvic specimen weight in the 151-300 g and 501+ g ranges appeared protective (odds ratio = 0.40, confidence interval = 0.25 0.64 and odds ratio = 0.54, confidence interval = 0.33-0.90). In a sub-analysis of 1294 patients, 74 hospital operative complications directly related to hysterectomy were identified among 59 patients. The most common hospital operative complications were excessive bleeding associated with surgery or injury to nearby structures. Among the sub-sample of 1294 patients, those with hospital operative complications were more likely to experience post-operative complications that lead to readmission (odds ratio = 3.82, confidence interval = 1.55-9.43, p = .004). CONCLUSION: The observed increased risk of complications among patients of Black race, who underwent laparoscopic supracervical hysterectomy or total laparoscopic hysterectomy, who experienced more than 300 mL surgical blood loss, who suffered hospital operative complications, and those whose hospitalization was 3 days or greater, offers an opportunity for higher scrutiny and preventive measures during usual hysterectomy care to prevent later readmission. PMID- 28660801 TI - Seizing the Moment: Experiences of School Nurses Caring for Students With Overweight and Obesity. AB - School nurses are well positioned to assess, intervene, and evaluate efforts to positively impact students who are overweight or obese. The purpose of this qualitative, descriptive study was to explore the experiences of school nurses providing care to children living with overweight and obesity. Data were collected through face-to-face, tape-recorded, in-depth, open-ended interviews with 10 school nurses from rural areas of North Carolina working with minority and low-income children in the public school setting. The text of the interviews was transcribed and analyzed into codes, categories, and themes. Three themes and eight subthemes were identified. The three themes were identified as (1) "jumping hurdles," (2) "seize the moment," and (3) "moral distress." The findings of this study can be used to provide a better understanding of the experiences of school nurses caring for children with overweight and obesity that is necessary for planning successful school-based interventions. PMID- 28660802 TI - Efficacy and safety of ustekinumab in the induction therapy of TNF-alpha refractory Crohn's disease patients: a systematic review and meta-analysis. AB - AIM: The aim of the systematic review and meta-analysis was to assess the efficacy and safety of ustekinumab in the induction therapy of anti-TNF-alpha failure patients with Crohn's disease. METHODS: A systematic literature search was conducted in Medline (PubMed), EMBASE, Cochrane Library until 30 December 2016. We included randomized controlled trials that compared efficacy (clinical response and remission) and safety profile of ustekinumab in TNF-alpha failure Crohn's disease patients; primary and secondary TNF-alpha nonresponders or intolerant patients were also assessed. Included studies were critically appraised according to the PRISMA statement protocol; data aggregation with a RevMan(r) software was performed. RESULTS: Three randomized controlled trials were revealed in the systematic review but only two of them (CERTIFI and UNITI-1) were homogenous to be included in the meta-analysis; aggregation of data only for induction phase of therapy was possible. Clinical response was significantly higher for patients who received ustekinumab compared with placebo patients in a group of TNF-alpha antagonist failure patients (relative benefit [RB] = 1.62; 95% CI: 1.28-2.04) and in the following subgroups: secondary nonresponders (RB = 1.98; 95% CI: 1.49-2.63), intolerant patients (RB = 1.47; 95% CI: 1.01-2.13) and patients who failed at least two TNF-alpha antagonists (RB = 2.19; 95% CI: 1.53 3.14) but in case of primary nonresponders it occurred insignificant (RB = 1.22; 95% CI: 0.76-1.98). The clinical remission in TNF-alpha antagonist failure population was significantly higher for patients who received ustekinumab compared with placebo (RB = 1.72; 95% CI: 1.17-2.53). Pooled analysis revealed that risk of adverse events in induction phase of therapy was not significantly different (risk ratio = 0.96; 95% CI: 0.86-1.06) between ustekinumab and placebo groups. CONCLUSION: The clinical response was significantly higher for TNF-alpha antagonist failure patients who received ustekinumab as well as in subgroups of secondary nonresponders or intolerant patients but not in case of primary nonresponders. Ustekinumab occurred as safe as placebo in the induction as well as in a maintenance phase of therapy. PMID- 28660803 TI - Spectroscopic Methods for Quantifying Gabapentin: Framing the Methods without Derivatization and Application to Different Pharmaceutical Formulations. AB - This work aimed at analyzing the performance of direct spectroscopic methods for the quantification of gabapentin (GABAp), given the lack of previous studies, in comparison with the more reviewed and complex derivatization techniques, discussing their susceptibility to the pharmaceutical formulations. All of the methods analyzed showed high selectivity for this pharmaceutical analyte, with recoveries close to 100%. Absorption spectroscopy without derivatization yielded better sensitivity and lower limits of detection and quantification of gabapentin in aqueous solution (AqSol method) when compared with other solvents, such as acidic solution or ethanol/water mixture. Derivatization with sodium hypochlorite presented the highest precision, whereas derivatization with vanillin exhibited the highest accuracy. The best method for GABAp quantification in terms of highest sensitivity, lowest limits of detection, and quantification, and also with good precision and accuracy, proved to be fluorescence with derivatization by 4-chloro-7-nitrobenzofurazan. The effect of the pharmaceutical formulation (nature of excipients) was tested for the most robust and sensitive methods, with and without derivatization, on capsules of five commercial brands. Recoveries in the range of 97.9-101.5% proved that there are no matrix interfering effects. Although not presenting the best performance in all the parameters evaluated, the AqSol method, due to its simplicity, proved to be suitable for the quantification of GABAp in capsules and tables containing the molecule as the active ingredient. PMID- 28660804 TI - Evaluation of the molecular mechanisms associated with cytotoxicity and inflammation after pulmonary exposure to different metal-rich welding particles. AB - Welding generates a complex aerosol of incidental nanoparticles and cytotoxic metals, such as chromium (Cr), manganese (Mn), nickel (Ni), and iron (Fe). The goal was to use both in vivo and in vitro methodologies to determine the mechanisms by which different welding fumes may damage the lungs. Sprague-Dawley rats were treated by intratracheal instillation (ITI) with 2.0 mg of gas metal arc-mild steel (GMA-MS) or manual metal arc-stainless steel (MMA-SS) fumes or saline (vehicle control). At 1, 3, and 10 days, bronchoalveolar lavage (BAL) was performed to measure lung toxicity. To assess molecular mechanisms of cytotoxicity, RAW264.7 cells were exposed to both welding fumes for 24 h (0-100 MUg/ml). Fume composition was different: MMA-SS (41% Fe, 29% Cr, 17% Mn, 3% Ni) versus GMA-MS (85% Fe, 14% Mn). BAL indicators of lung injury and inflammation were increased by MMA-SS at all time points and by GMA-MS at 3 and 10 days after exposure. RAW264.7 cells exposed to MMA-SS had elevated generation of reactive oxygen species (ROS), protein-HNE (P-HNE) adduct formation, activation of ERK1/2, and expression of cyclooxygenase-2 (COX-2) compared to GMA-MS and control. Increased generation of ROS due to MMA-SS exposure was confirmed by increased expression of Nrf2 and heme oxygenase-1 (HO-1). Results of in vitro studies provide evidence that stainless steel welding fume mediate inflammatory responses via activation of ROS/P-HNE/ERK1/2/Nrf2 signaling pathways. These findings were corroborated by elevated expression of COX-2, Nrf2, and HO-1 in homogenized lung tissue collected 1 day after in vivo exposure. PMID- 28660805 TI - Contrast-Induced Acute Kidney Injury Is Associated With Long-Term Adverse Events in Patients With Acute Coronary syndrome. AB - Contrast-induced acute kidney injury (CI-AKI) is associated with increased mortality, morbidity, and prolonged hospitalization. Patients with acute coronary syndrome (ACS) have a 3-fold higher risk of developing CI-AKI. The aim of our study was to evaluate the predictors of CI-AKI and long-term prognosis in patients with ACS who developed CI-AKI (1083 patients were enrolled). Contrast induced acute kidney injury was defined as an increase of >=0.5 mg/dL and/or an increase of >=25% of pre-percutaneous coronary intervention (PCI) to post-PCI serum creatinine levels within 48 to 72 hours after the procedure. Primary end point was defined as all-cause mortality, myocardial infarction, and cerebrovascular event at long-term follow-up (36 +/- 12 months). Contrast-induced acute kidney injury occurred in 178 (16.4%) of the 1083 patients. The primary end points were significantly high in patients with ACS who developed CI-AKI ( P < .001). The occurrence of CI-AKI was identified as an independent predictor of primary end point. Risk of CI-AKI development was more frequently seen in patients with ACS. Also, patients who developed CI-AKI have worse prognosis at long-term follow-up. Additional preventive treatment strategies need to be developed in this group of patients. PMID- 28660806 TI - Antiplatelet Therapy for Non-ST-Segment Elevation Myocardial Infarction in Complex "Real" Clinical Scenarios: A Consensus Document of the "Campania NSTEMI Study Group". AB - The incidence of ST-segment elevation myocardial infarction (STEMI) has significantly decreased. Conversely, the rate of non-STEMI (NSTEMI) has increased. Patients with NSTEMI have lower short-term mortality compared to patients with STEMI, whereas at long-term follow-up, the mortality becomes comparable. This might be due to the differences in baseline characteristics, including older age and a greater prevalence of comorbidities in the NSTEMI population. Although antithrombotic strategies used in patients with NSTEMI have been well studied in clinical trials and updated guidelines are available, patterns of use and outcomes in clinical practice are less well described. Thus, a panel of Italian cardiology experts assembled under the auspices of the "Campania NSTEMI Study Group" for comprehensive discussion and consensus development to provide practical recommendations, for both clinical and interventional cardiologists, regarding optimal management of antithrombotic therapy in patients with NSTEMI. This position article presents and discusses various clinical scenarios in patients with NSTEMI or unstable angina, including special subsets (eg, patients aged >=85 years, patients with chronic renal disease or previous cerebrovascular events, and patients requiring triple therapy or long-term antithrombotic therapy), with the panel recommendations being provided for each scenario. PMID- 28660807 TI - Factors Influencing IACUC Decision Making: Who Leads the Discussions? AB - Decisions about the appropriate use of animals in research are largely made by Institutional Animal Care and Use Committees (IACUCs). Several commentators claim that scientists exert excessive influence on IACUC decisions. We studied 87 protocol reviews from 10 IACUCs to assess whether any group of participants appeared to dominate the protocol discussions. Audio recordings of the meetings were coded to capture the topics of the discussions. We found that animal research scientists made the largest total number of topic mentions while community members made the fewest. On a per person basis, chairpersons and attending veterinarians made the most mentions. Scientists presented the largest number of protocols, and the subsequent discussions tended to contain the same topics mentioned in the presentations. The large number of protocols presented by scientists and their total number of comments made during protocol discussions suggest that scientists may significantly influence IACUC decision making. PMID- 28660808 TI - Spontaneous subdural hematoma associated with microcystic meningioma: first case report in the literature. AB - BACKGROUND: Non traumatic subdural hematomas are rare, especially those associated with intracranial meningiomas. Among the most common meningiomas associated with spontaneous bleeding are angioblastic and malignant meningioma variants. The pathophysiological mechanisms of this association are not yet fully understood. The association of chronic subdural hematoma with microcystic meningioma histological subtype has not yet been described in the literature. CASE REPORT: The authors present a case report of a patient with a spontaneous non traumatic chronic subdural hematoma associated with a microcystic subtype grade I meningioma of the parietal convexity. Epidemiological, etiology, natural history, pathophysiology, risk factors of bleeding and treatment options are reviewed. CONCLUSION: Spontaneous subdural hematomas associated with meningiomas are rare, specially related to the microcystic variant of meningioma. Careful pre operative consideration of specific anatomy and pathophysiological features are paramount to their full treatment. PMID- 28660809 TI - The effect of stage of HIV disease as determined by CD4 count on clinical outcomes of surgical sepsis in South Africa. AB - INTRODUCTION This paper reviews the impact of the stage of human immunodeficiency virus (HIV) disease on the outcome of surgical sepsis. METHODS All adult emergency general surgical patients (aged >15 years) who fulfilled the criteria for sepsis or septic shock, with a documented surgical source of infection, and who were HIV positive were reviewed. RESULTS During the 5-year study period, a total of 675 patients with a documented surgical source of sepsis were managed by our service; 142 (21%) of these were HIV positive. Among the individuals who were HIV positive, the CD4 count was <200 cells/ul in 21 patients and >=200 cells/ul in 121 patients. There was no difference between these two cohorts in terms of demography or spectrum of surgical conditions. The range of surgical procedures and complications was also similar in both groups. Nevertheless, patients with a CD count of <200 cells/ul had a significantly longer length of hospital stay than those in the cohort with >=200 cells/ul. For HIV positive patients with a CD4 count of <200 cells/ul, the mortality rate was 66.7% (14/21) while the mortality rate for individuals with HIV and a CD4 count of >=200 cells/ul was 2.5% (2/121). This difference was statistically significant (p<0.001). CONCLUSIONS The clinical presentation and spectrum of surgical sepsis disease in cases with stage 1 and stage 2 HIV is not markedly different. However, in patients with a CD4 count of <200 cells/ul, the length of hospital stay and mortality is significantly higher. Stage of HIV disease must be considered when stratifying patients' risk for surgery. PMID- 28660810 TI - Intravenous fluid and electrolyte administration in elective gastrointestinal surgery: mechanisms of excessive therapy. AB - INTRODUCTION While clinical guidelines stress the importance of the judicious perioperative intravenous fluid administration, data show that adherence to these protocols is poor. The reasons have not been identified. We therefore audited the magnitude and indications of fluid and electrolyte administration in a teaching hospital. We hypothesised that epidural analgesia is associated with excessive fluid therapy. MATERIALS AND METHODS Intravenous fluid and electrolyte administration during the day of surgery and the subsequent 2 days in consecutive patients undergoing elective gastrointestinal surgery between November 2013 and May 2014 were retrospectively audited. Timing, volumes and indications were recorded. RESULTS One hundred patients undergoing elective gastrointestinal resection were studied. Patients received 9030 ml +/- 2860 ml (mean +/- standard deviation) intravenous fluids containing a total of 1180 ml +/- 420 mmol sodium and resulting in a cumulative fluid balance of +5120 ml +/- 2510 ml; 44% +/- 14% of total volumes were given in theatre. Nearly all fluid was given for maintenance, 100% (96-100%, interquartile range), with 17 patients only receiving replacement or resuscitation. Independent predictors of increased volumes included open surgery, upper gastrointestinal surgery, increased duration and epidural analgesia but not body weight. Postoperative fluid volume was the only independent predictor of postoperative complication grade (P = 0.0044). CONCLUSIONS Despite published guidelines, perioperative fluid and electrolyte administration were excessive and were associated with postoperative morbidity. Substantial volumes were administered in theatre. Nearly all administration was for maintenance, yet patients received approximately five times the amount of sodium required. Epidural analgesia was an independent predictor of fluid volumes but body weight was not. PMID- 28660812 TI - Sex differences in the splenic flexure. AB - INTRODUCTION Anecdotally, surgeons claim splenic flexure mobilisation is more difficult in male patients. There have been no scientific studies to confirm or disprove this hypothesis. The implications in colorectal surgery could be profound. The aim of this study was to assess quantitatively whether there is an anatomical difference in the position of the splenic flexure between men and women using computed tomography (CT). METHODS Portal venous phase CT performed for preoperative assessment of colorectal malignancy was analysed using the hospital picture archiving and communication system. The splenic flexure was compared between men and women using two variables: anatomical height corresponding to the adjacent vertebral level (converted to ordinal values between 1 and 17) and distance from the midline. RESULTS In total, 100 CT images were analysed. Sex distribution was even. The mean ages of the male and female patients were 68.1 years and 66.7 years respectively (p=0.630). The mean vertebral level for men was 8.88, equating to the inferior half of the T11 vertebral body (range: 1-17 [superior half of T9 to inferior half of L2]), and 11.36 for women, equating to the inferior half of the T12 vertebral body (range: 4-16 [superior half of T10 to superior half of L2]). This difference was statistically significant (p=0.0001) and is equivalent to one whole vertebra. The mean distance from the midline was 160.8mm (range: 124-203mm) for men and 138.2mm (range: 107-185mm) for women (p<0.0001). CONCLUSIONS The splenic flexure is both higher and further from the midline in men than in women. This provides one theory as to why mobilising the splenic flexure may be more difficult in male patients. PMID- 28660811 TI - Lengthening the pedicle of the rectus abdominis myocutaneous flap for repair of upper chest and neck defects. AB - INTRODUCTION The aim of this study was to investigate whether the pedicle of the rectus abdominis flap can be lengthened by resecting the inferior costal cartilage segments or associated muscle when repairing upper body defects. A formula was generated that calculates the expected increase in pedicle length. METHODS Thirty patients underwent computed tomography. The width and thickness of the third to seventh inferior costal cartilage segments as well as the width of the respective intercostal spaces were recorded. Four patients underwent reconstruction of an upper body defect with the relevant flap. RESULTS The expected mean increases in pedicle length were 4.07cm (standard deviation [SD]: 0.31cm) and 4.63cm (SD: 0.54cm) following resection of the left and right sides respectively of the seventh inferior costal cartilage segment, 7.99cm (SD: 0.49cm) and 10.82cm (SD: 0.23cm) following resection of the left and right sides respectively of the sixth and seventh inferior costal cartilage segments while resection of the fourth to seventh inferior costal cartilage segments would equate to increases of 17.48cm (SD: 0.62cm) and 22.05cm (SD: 0.21cm) for the left and right sides respectively. In four patients who required reconstruction, three flaps survived without problems but one flap developed partial necrosis. CONCLUSIONS Resecting inferior costal cartilage segments or associated muscle can lengthen the pedicle of the rectus abdominis flap for reconstruction of defects on the upper chest and neck. PMID- 28660813 TI - Monophasic synovial sarcoma of the greater omentum: case report and review of literature. AB - Synovial sarcoma is a malignant spindle cell neoplasm normally arising from tissues around joints, bursa and tendon sheaths. Several reports involving the gastrointestinal tract, mainly the oesophagus and stomach, have been documented; however, the omentum remains an extremely unusual location. Monophasic type is composed exclusively of spindle cells arranged in fascicles. Establishing the correct diagnosis of these tumours could be challenging because of the similarities with gastrointestinal stromal tumours and other mesenchymal tumours with similar histology. PMID- 28660814 TI - Perianal rhabdomyomatous mesenchymal hamartoma. AB - A rhabdomyomatous mesenchymal hamartoma (RMH) is a rare benign soft tissue tumour found in the face and neck region of children. A three-month-old male infant was referred to our unit with a polypoid anal lesion that had been present from birth. Histopathological examination of the excised sample showed haphazard arrangement of mature striated skeletal muscle in among nerves and blood vessels, and immunohistochemistry confirmed the lesion to be a RMH. There was no evidence of recurrence during the follow-up period. This case emphasises two points: the unique histological characteristics associated with RMH and how this allows distinction from other differential diagnoses, and the consideration of RMH as a diagnosis in perianal lesions. PMID- 28660815 TI - A letter to Sir Heneage Ogilvie. PMID- 28660816 TI - The role of antimicrobial sutures in preventing surgical site infection. AB - INTRODUCTION Healthcare associated infections (HCAIs) are falling following widespread and enforced introduction of guidelines, particularly those that have addressed antibiotic resistant pathogens such as methicillin resistant Staphylococcus aureus or emergent pathogens such as Clostridium difficile, but no such decline has been seen in the incidence of surgical site infection (SSI), either in the UK, the EU or the US. SSI is one of the HCAIs, which are all avoidable complications of a surgical patient's pathway through both nosocomial and community care. METHODS This report is based on a meeting held at The Royal College of Surgeons of England on 21 July 2016. Using PubMed, members of the panel reviewed the current use of antiseptics and antimicrobial sutures in their specialties to prevent SSI. FINDINGS The group agreed that wider use of antiseptics in surgical practice may help in reducing reliance on antibiotics in infection prevention and control, especially in the perioperative period of open elective colorectal, hepatobiliary and cardiac operative procedures. The wider use of antiseptics includes preoperative showering, promotion of hand hygiene, (including the appropriate use of surgical gloves), preoperative skin preparation (including management of hair removal), antimicrobial sutures and the management of dehisced surgical wounds after infection. The meeting placed emphasis on the level I evidence that supports the use of antimicrobial sutures, particularly in surgical procedures after which the SSI rate is high (colorectal and hepatobiliary surgery) or when a SSI can be life threatening even when the rate of SSI is low (cardiac surgery). PMID- 28660817 TI - A novel use of QR code stickers after orthopaedic cast application. AB - INTRODUCTION We present a novel solution to ensure that information and contact details are always available to patients while in cast. An information sticker containing both telephone numbers and a Quick Response (QR) code is applied to the cast. When scanned with a smartphone, the QR code loads the plaster team's webpage. This contains information and videos about cast care, complications and enhancing recovery. METHODS A sticker was designed and applied to all synthetic casts fitted in our fracture clinic. On cast removal, patients completed a questionnaire about the sticker. A total of 101 patients were surveyed between November 2015 and February 2016. The questionnaire comprised ten binary choice questions. RESULTS The vast majority (97%) of patients had the sticker still on their cast when they returned to clinic for cast removal. Eighty-four per cent of all patients felt reassured by the presence of the QR code sticker. Nine per cent used the contact details on the cast to seek advice. Over half (56%) had a smartphone and a third (33%) of these scanned the QR code. Of those who scanned the code, 95% found the information useful. CONCLUSIONS This study indicates that use of a QR code reassures patients and is an effective tool in the proactive management of potential cast problems. The QR code sticker is now applied to all casts across our trust. In line with NHS England's Five Year Forward View calling for enhanced use of smartphone technology, our trust is continuing to expand its portfolio of patient information accessible via QR codes. Other branches of medicine may benefit from incorporating QR codes as portals to access such information. PMID- 28660818 TI - Systemic air embolism as a complication of percutaneous computed tomography guided transthoracic lung biopsy. AB - A 57-year-old man underwent prone position computed tomography (CT) guided percutaneous transthoracic lung biopsy. After removal of the 18-gauge biopsy needle, the patient lost consciousness and developed shock. CT showed signs of air embolism in descending aorta and left atrium. Cardiopulmonary resuscitation was unsuccessful. A postmortem CT scan confirmed a massive air embolism in the descending aorta, left ventricle and brain. Systemic air embolism occurs in around 0.001-0.003% of lung biopsy procedures. Recommendations to reduce the risk include requesting the patient to stop breathing during the procedure and preventing the exposure of the outer cannula of a coaxial biopsy needle to the atmosphere. PMID- 28660819 TI - Selective non-operative management of abdominal stab wounds is a safe and cost effective strategy: A South African experience. AB - INTRODUCTION Selective non-operative management (SNOM) of abdominal stab wounds is well established in South Africa. SNOM reduces the morbidity associated with negative laparotomies while being safe. Despite steady advances in technology (including laparoscopy, computed tomography [CT] and point-of-care sonography), our approach has remained clinically driven. Assessments of financial implications are limited in the literature. The aim of this study was to review isolated penetrating abdominal trauma and analyse associated incurred expenses. METHODS Patients data across the Pietermaritzburg Metropolitan Trauma Service (PMTS) are captured prospectively into the regional electronic trauma registry. A bottom-up microcosting technique produced estimated average costs for our defined clinical protocols. RESULTS Between January 2012 and April 2015, 501 patients were treated for an isolated abdominal stab wound. Over one third (38%) were managed successfully with SNOM, 5% underwent a negative laparotomy and over half (57%) required a therapeutic laparotomy. Over five years, the PMTS can expect to spend a minimum of ZAR 20,479,800 (GBP 1,246,840) for isolated penetrating abdominal stab wounds alone. CONCLUSIONS Provided a stringent policy is followed, in carefully selected patients, SNOM is effective in detecting those who require further intervention. It minimises the risks associated with unnecessary surgical interventions. SNOM will continue to be clinically driven and promulgated in our environment. PMID- 28660820 TI - Recurrence of hepatocellular carcinoma at surgical incision site: case series and review of literature. AB - First reported two decades ago, isolated incisional recurrence of hepatocellular carcinoma is an extremely rare clinical entity. We present two cases of recurrence: one recurring over 10 years after initial resection, and the second presenting with a port site recurrence 3.5 years following laparoscopic radiofrequency ablation. Clinical case presentation, including radiographical, pathological, laboratory and intraoperative images are reported, together with a review of the current literature surrounding this uncommon hepatocellular carcinoma presentation. PMID- 28660821 TI - Major haemorrhage requiring transarterial embolisation following open biopsy of an unusual neck mass. AB - A 65-year-old man presented with a right supraclavicular neck mass and right arm pain. Magnetic resonance imaging revealed a 96mm lesion in the upper thoracic paraspinal region extending into the deep supraclavicular fossa. The presentation was consistent with a sarcoma or lymphoma but fine needle aspiration was inconclusive. During open biopsy of the lesion, the patient had a rapid intraoperative haemorrhage of 1l from the tumour. Haemostasis could only be achieved by transarterial embolisation of the feeding vessel and the biopsy result confirmed Ewing's sarcoma. Open biopsy is considered the gold standard in the diagnosis of certain tumour types; however, the morbidity from haemorrhage must be considered. This case highlights the key role that transarterial embolisation can play in achieving haemostasis in the neck. PMID- 28660822 TI - Comparison of prognostic scoring systems in follicular thyroid cancer. AB - INTRODUCTION Many studies have addressed the accuracy of prognostic scoring systems in the treatment of differentiated thyroid cancers as a whole but few have addressed this issue in patients with follicular thyroid cancer (FTC) alone. The aim of this study was to establish the accuracy of the various scoring systems in determining the overall and disease free survival of FTC patients in Singapore. METHODS Retrospective review was undertaken of 82 patients with FTC treated at a single tertiary institution between January 2000 and December 2014. Demographic, clinical, pathological and treatment outcomes were analysed. Prognostic scoring systems evaluated for the cohort included TNM (Tumour, Nodes, Metastases), AGES (Age, Grade, Extent, Size), MACIS (Metastases, Age, Completeness of resection, Invasion, Size), AMES (Age, Metastases, Extent, Sex) and EORTC (European Organisation for Research and Treatment of Cancer). Statistical analysis was performed by plotting Kaplan-Meier survival curves and using the Cox proportional hazards model. RESULTS There were 29 male and 53 female patients with a mean age of 48 years. The mean follow-up duration was 88 months and there were 7 deaths (9%). The ten-year overall survival rate was 90%. Factors predictive of survival on univariate analysis were age, size of tumour, invasiveness, completeness of resection, metastasis, external beam radiotherapy, and risk scores using the AGES and MACIS scoring systems (p<0.05). On multivariate analysis, AGES and MACIS provided the best prognostic information. CONCLUSIONS MACIS is the best prognostic scoring system currently available for FTC and it is superior to other scoring systems in term of guiding management. The scoring systems require further development to accommodate variations in clinical practice globally and to improve the prognostic accuracy. PMID- 28660823 TI - Glisson's capsule cauterisation is associated with increased postoperative pain after laparoscopic cholecystectomy: a prospective case-control study. AB - INTRODUCTION Postoperative pain after laparoscopic cholecystectomy has three components: parietal, visceral and referred pain felt at the shoulder. Visceral peritoneal injury on the liver (Glisson's capsule) during cauterisation sometimes occurs as an unavoidable complication of the operation. Its effect on postoperative pain has not been quantified. In this study, we aimed to evaluate the association between Glisson's capsule injury and postoperative pain following laparoscopic cholecystectomy. METHODS The study was a prospective case-control of planned standard laparoscopic cholecystectomy with standardized anaesthesia protocol in patients with benign gallbladder disease. Visual analogue scale (VAS) abdominal pain scores were noted at 2 and 24 hours after the operation. One surgical team performed the operations. Operative videos were recorded and examined later by another team to detect presence of Glisson's capsule cauterisation. Eighty-one patients were enrolled into the study. After examination of the operative videos, 46 patients with visceral peritoneal injury were included in the study group, and the remaining 35 formed the control group. RESULTS VAS pain score at postoperative 2 and 24 hours was significantly higher in the study group than control (P = 0.027 and 0.017, respectively). CONCLUSIONS Glisson's capsule cauterisation in laparoscopic cholecystectomy is associated with increased postoperative pain. Additional efforts are recommended to prevent unintentional cauterisation. PMID- 28660824 TI - Laparoscopic treatment of cystic artery pseudoaneurysm in the presence of calculous cholecystitis. AB - Cystic artery pseudoaneurysm is a very rare disease in which there is an abnormal, focal dilatation of the artery supplying the gallbladder. The condition may occur as a consequence of a localised inflammatory response, such as in cholecystitis. Here, we present the case of a 56-year-old man who presented with chronic cholecystitis in whom a 1.8 cm * 2 cm cystic artery pseudoaneurysm was found incidentally during laparoscopic cholecystectomy. Prior to the operation, routine investigations such as ultrasound revealed no indication of cystic artery pseudoaneurysm, ruptured or otherwise. This case is reported to emphasise that cystic artery pseudoaneurysm may be caused by chronic or acute cholecystitis and that skilled surgeons may handle them laparoscopically. PMID- 28660825 TI - An unexpected diagnosis of breast malignancy. AB - Inflammatory breast cancer constitutes 5% of all breast cancer diagnoses. Diagnosis is based on clinical signs including skin changes, erythema and oedema, together with rapid progression and involvement of more than one-third of the affected breast. It is an aggressive tumour with great metastatic potential, metastases being present in 30% of patients at first presentation. Primary non Hodgkin's lymphoma of the breast is rare but is well reported. It accounts for 0.5% of all breast malignancies and 1% of all non-Hodgkin's diagnoses. Prognosis of primary breast lymphoma varies depending on the stage of disease with stage IE having a 5-year survival rate of 78-83% and stage IIE having a 5-year survival rate of 20-57%. We present a rare case of non-Hodgkin's lymphoma mimicking an inflammatory breast cancer. The aim of this case report is to highlight an unusual presentation of non-Hodgkin's lymphoma and the diagnostic difficulties that arise. PMID- 28660826 TI - Giant solitary fibrous tumour of the pleura an unpredictable entity: case series and literature review. AB - A small proportion of tumours can undergo malignant transformation. We report a case series of five patients diagnosed with giant solitary fibrous tumours of the pleura. These cases highlight the unpredictable nature of this disease process, with significant variability in clinical course observed, from indolence to aggressive progression. Three patients were found to have malignant disease on explant, with two of these having preoperative imaging and histology suggesting benign pathology. This finding emphasises that accurately differentiating between benign and malignant disease on imaging and/or biopsy has low specificity and sensitivity and cannot be relied upon in guiding the management of these tumours. Patients with solitary fibrous tumours of the pleura should be managed cautiously, owing to the unpredictable and potentially aggressive clinical course. We would advocate the position that all patients with solitary fibrous tumours of the pleura should be managed as if they have malignant disease. Prolonged follow-up is required due to the risk of disease recurrence, even in patients with benign disease. PMID- 28660827 TI - Seventy years of academic surgery. PMID- 28660828 TI - Predictors of direct home discharge following fractured neck of femur. AB - INTRODUCTION Direct home discharge (DHD) following hip fracture surgery represents a challenging proposition. The aim of this study was to identify factors influencing the discharge destination (home vs alternative location) for patients admitted from their own home with a fractured neck of femur. METHODS A retrospective cohort study of prospectively collected major trauma centre data was performed, identifying 10,044 consecutive hip fracture admissions between 2000 and 2012. RESULTS Two-thirds of the patients (n=6,742, 67%) were admitted from their own home. Half of these (n=3,509, 52%) returned directly to their own home while two-fifths (n=2,640, 39%) were discharged to an alternative location; 593 (9%) died. The following were identified as independent variables associated with a higher likelihood of DHD: younger patients, female sex, an abbreviated mental test score of 10, absence of certain co-morbidities, cohabiting, walking independently outdoors, no use of walking aids, no assistance required with basic activities of daily living and intracapsular fracture. CONCLUSIONS Identifying those at risk of being discharged to an alternative location following admission from home on the basis of identified preoperative indices could assist in streamlining the postoperative care phase. Pre-emptive action may help increase the numbers of patients discharged directly home and reduce the number requiring additional rehabilitation prior to discharge home with its associated socioeconomic effect. PMID- 28660829 TI - Incarcerated Bochdalek hernia causing bowel obstruction in an adult male patient. AB - Bochdalek hernias occur as a result of congenital fusion failure of the posterolateral muscular portion of the diaphragm derived from the embryonic pleuroperitoneal membrane. The vast majority of symptomatic Bochdalek hernias are diagnosed during the neonatal period. Congenital diaphragmatic hernias showing symptoms in adulthood are rare. We report the case of a 28-year-old man who presented with subacute bowel obstruction, later diagnosed to have a left-sided incarcerated Bochdalek hernia containing an ischaemic splenic flexure and the distal transverse colon. During laparotomy, he underwent primary repair of the diaphragmatic defect and an extended right hemicolectomy with ileocolic anastomosis. The patient made a good recovery and is well at three months following surgery. This case highlights the need for surgeons to be vigilant about rare types of congenital internal hernias as they may become symptomatic later in life. PMID- 28660830 TI - A letter to Major-General Philip Mitchiner. PMID- 28660831 TI - Diagnostic use of intramedullary reaming biopsy in metastatic long bone disease. AB - INTRODUCTION Bone is the third most common site of metastasis. A histological diagnosis is important in guiding therapy and prognosis. In up to 15% of cases of metastatic disease, the primary tumour remains unknown. This emphasises the importance of adequate, reliable and accurate sampling when performing any type of biopsy. Reaming biopsy is commonly performed during intramedullary nailing of metastatic long-bone disease but there is little published evidence on the diagnostic use and reliability of this technique. AIMS AND METHODS We reviewed 49 cases of confirmed metastatic bone disease to determine adequacy for analysis, diagnostic accuracy and factors affecting reliability. RESULTS Adequate tissue for histopathological analysis was obtained in 96% of cases but metastasis was confirmed in only 51% of cases. The presence of a pathological fracture had no effect on accuracy of the results but metastasis was more likely to be missed in the presence of tissue crushing and or necrosis (P = 0.015). DISCUSSION This study determines the use and accuracy of bone reaming biopsy in metastatic disease and, to the best of our knowledge, is the only study determining the effect of additional factors such as the presence of a pathological fracture and tissue necrosis or crushing on the diagnostic accuracy of this technique. CONCLUSIONS In spite of adequate tissue sampling, the diagnostic accuracy and, hence, reliability of intramedullary reaming biopsy in metastatic bone disease is less than optimal. A reaming histopathology report suggesting no evident metastasis should always be taken in clinical context. PMID- 28660832 TI - Rare presentation of idiopathic duodenoduodenal intussusception. AB - Enteroenteric intussusception is a condition in which the full-thickness bowel wall becomes telescoped into the lumen of distal bowel. Intussusception in adult occurs infrequently and varies from childhood intussusception, particularly in its presentation, aetiology and treatment. Duodenoduodenal intussusception is rare because the duodenum is fixed in the retroperitoneal position. It usually occurs secondary to tumour, lipoma, Brunner's gland hamartomatous polyp or adenoma. The diagnosis in adults is usually made at laparotomy, where presentation is with intestinal obstruction. In non-emergency presentation, it may be difficult to arrive at an accurate diagnosis as symptoms may be vague, self-limiting intermittent abdominal pain. Clinical examinations and investigations may not be conclusive and another working diagnosis such as irritable bowel syndrome would be made. We describe a case where a patient initially presented with symptoms mimicking pancreatitis but his symptoms persisted over the course of 2 weeks. When a laparotomy was performed, duodenoduodenal intussusception was discovered and confirmed with histopathology. In this case, a discernible leading point could not be identified. PMID- 28660833 TI - Novel technique of Mapping Biopsies during laparoscopic assisted transanal Soave endorectal pull-through surgery for Hirschsprung's disease's. PMID- 28660834 TI - The role of two-sided splinting for recalcitrant paediatric post-burn hand flexion contracture: a case report. AB - A 2-year-old boy presented to the plastic and reconstructive surgery outpatient clinic with bilateral post-burn hand flexion contracture. The contracture had been released twice elsewhere. The third surgical repair on one hand at a time was conducted by the author (TOHP). However, inadeq.uate compliance to the postoperative splinting and exercise led to the recurrence of the contracture in the following year. A customised two-sided splint was therefore created to ensure proper placement and compliance. Reinforcement to the parents to encourage the boy to practise active exercise on demand was also an integral part of the management. Good functional and cosmetic outcome were presented at 1-year follow up. This case highlights the value of a two-sided splint for the management of post-burn hand flexion contracture in children whose compliance is inevitably cannot be guaranteed. PMID- 28660835 TI - Rectal foreign body insertion as a rare cause of persistent lumbosacral plexus injury. AB - Rectal foreign body insertion is a common condition in emergency surgery, which often requires surgical intervention. Here we report a clinical case of rectal foreign body insertion as a rare cause of persistent lumbosacral plexus injury. A 72-year-old man presented to the emergency department complaining of acute bilateral paraplegia with loss of sensation in both legs, as well as total urinary retention. The patient underwent abdominal computed tomography, which showed a rectal foreign body measuring 13 * 11.5 * 10 cm in the lower abdomen and pelvis. Extraluminal assistance through a median laparotomy was required after unsuccessful attempts at transanal recovery alone. After removal of the foreign body, the rectal wall and anorectal sphincter were massively dilated, with severe bruising of the rectal mucosa on proctoscopy. A protective loop-ileostomy was performed. The sacral plexus is located posteriorly in the pelvis. Physiologically, the nerves are well protected by surrounding anatomical structures. Post-traumatic lumbosacral plexus injuries with paraplegia, urinary retention and anorectal sphincter insufficiency occur quite frequently after heavy traffic accidents. Lumbosacral plexus injury as a result of rectal foreign body insertion is rare. Severe neurological deficits through rectal foreign body insertion are rare but known medical conditions. To the best of our knowledge, this is the first reported case of severe and persistent post-traumatic lumbosacral plexus injury through a rectal foreign body. PMID- 28660836 TI - Superior mesenteric artery syndrome: a single centre experience of laparoscopic duodenojejunostomy as the operation of choice. AB - INTRODUCTION The superior mesenteric artery (SMA) syndrome, or Wilkie's syndrome, is a rare cause of postprandial epigastric pain, vomiting and weight loss caused by compression of the third part of the duodenum as it passes beneath the proximal superior mesenteric artery. The syndrome may be precipitated by sudden weight loss secondary to other pathologies, such as trauma, malignancy or eating disorders. Diagnosis is confirmed by angiography, which reveals a reduced aorto SMA angle and distance, and contrast studies showing duodenal obstruction. Conservative management aims to increase intra-abdominal fat by dietary manipulation and thereby increase the angle between the SMA and aorta. Where surgery is indicated, division of the ligament of Treitz, anterior transposition of the third part of the duodenum and duodenojejunostomy have been described. METHODS We present four cases of SMA syndrome where the intention of treatment was laparoscopic duodenojejunostomy. The procedure was completed successfully in three patients, who recovered quickly with no short-term complications. A fourth patient underwent open gastrojejunostomy (complicated by an anastomotic bleed) when dense adhesions prevented duodenojejunostomy. CONCLUSIONS The superior mesenteric artery syndrome should be considered in patients with epigastric pain, prolonged vomiting and weight loss. Laparoscopic duodenojejunostomy is a safe and effective operation for management of the syndrome. A multi-speciality team approach including gastrointestinal, vascular and radiological specialists should be invoked in the management of these patients. PMID- 28660837 TI - Effect of storage conditions on the calorific value of municipal solid waste. AB - Storage conditions are considered to be an important factor as far as waste material characteristics are concerned. This experimental investigation was conducted using municipal solid waste (MSW) with a high moisture content and varying composition of organic waste. The objective of this study was to understand the effect of storage conditions and temperature on the moisture content and calorific value of the waste. Samples were subjected to two different storage conditions and investigated at specified temperatures. The composition of sample materials investigated was varied for each storage condition and temperature respectively. Gross calorific value was determined experimentally while net calorific value was calculated using empirical formulas proposed by other researchers. Results showed minimal changes in moisture content as well as in gross and net calorific values when the samples were subjected to sealed storage conditions. Moisture content reduced due to the ventilation process and the rate of moisture removal increased with a rise in storage temperature. As expected, rate of moisture removal had a positive effect on gross and net calorific values. Net calorific values also increased at varying rates with a simultaneous decrease in moisture content. Experimental investigation showed the effectiveness of ventilation in improving the combustion characteristics of the waste. PMID- 28660839 TI - Editorial. PMID- 28660838 TI - Measuring lifetime stress exposure and protective factors in life course research on racial inequality and birth outcomes. AB - There has been a long-standing interest in better understanding how social factors contribute to racial disparities in health, including birth outcomes. A recent emphasis in this context has been on identifying the effects of stress exposure and protective factors experienced over the entire lifetime. Yet despite repeated calls for a life course approach to research on this topic, very few studies have actually assessed how stressors and protective factors occurring over women's lives relate to birth outcomes. We discuss this issue here by describing how challenges in the measurement of lifetime stress exposure and protective factors have prevented researchers from developing an empirically based life course perspective on health. First, we summarize prevailing views on racial inequality and birth outcomes; second, we discuss measurement challenges that exist in this context; and finally, we describe both new tools and needed tools for assessing lifetime stress exposure and suggest opportunities for integrating information on stress exposure and psychosocial protective factors. We conclude that more studies are needed that integrate information about lifetime stress exposures and the protective factors that promote resilience against such exposures to inform policy and practice recommendations to reduce racial disparities in birth outcomes. PMID- 28660840 TI - Does certificate of need law enhance competition in inpatient care market? An empirical analysis. AB - This article investigates the impact of Certificate of Need (CON) laws on competition in the inpatient care market. One of the major criticisms of these laws is that it may hinder competition in the health care market, which can lead to higher prices. However, from a theoretical standpoint, CON laws could also promote competition by limiting excessive expansion from incumbents. Our main conclusion is that CON laws by and large enhanced competition in the inpatient market during the period of our study. This indicates that the effects of CON laws to hinder predatory behavior could dominate its effects of preventing new entrants into the inpatient care market. We do not find statistically significant evidence to reject the exogeneity assumption of either CON laws or their stringency in our study. We also find factors such as proportion of population aged 18-44, proportion of Asian American population, obesity rate, political environment, etc., in a state significantly impact competition. Our findings could shed some light to public policy makers when deciding the appropriate health programs or legislative framework to promote health care market competition and thereby facilitate quality health care. PMID- 28660841 TI - The care experiences of patients who die in residential hospice: A qualitative analysis of the last three months of life from the views of bereaved caregivers. AB - OBJECTIVE: Despite the increasing prominence of residential hospices as a place of death and that, in many regards, this specialized care represents a gold standard, little is known about the care experience in this setting. Using qualitative survey data, we examined the positive and negative perceptions of care in hospices and in other prior settings. METHOD: Qualitative comments were extracted from the CaregiverVoice survey completed by bereaved caregivers of decedents who had died in 16 residential hospices in Ontario, Canada. On this survey, caregivers reported what was good and bad about the services provided during the last three months of life as separate open-text questions. A constant comparison method was employed to derive themes from the responses. RESULTS: A total of 550 caregivers completed the survey, 94% (517) of whom commented on either something good (84%) and/or bad (49%) about the care experience. In addition to residential hospice, the majority of patients represented also received palliative care in the home (69%) or hospital (59%). Overall, most positive statements were about care in hospice (71%), whereas the negative statements tended to refer to other settings (81%). The hospice experience was found to exemplify care that was compassionate and holistic, in a comforting environment, offered by providers who were personable, dedicated, and informative. These humanistic qualities of care and the extent of support were generally seen to be lacking from the other settings. SIGNIFICANCE OF RESULTS: Our examination of the good and bad aspects of palliative care received is unique in qualitatively exploring palliative care experiences across multiple settings, and specifically that in hospices. Investigation of these perspectives affirmed the elements of care that dying patients and their family caregivers most value and that the hospices were largely effective at addressing. These findings highlight the need for reinforcing these qualities in other end-of-life settings to create comforting and supportive environments. PMID- 28660842 TI - Sequencing, characterization and phylogenomics of the complete mitochondrial genome of Dactylogyrus lamellatus (Monogenea: Dactylogyridae). AB - Despite the worldwide distribution and pathogenicity of monogenean parasites belonging to the largest helminth genus, Dactylogyrus, there are no complete Dactylogyrinae (subfamily) mitogenomes published to date. In order to fill this knowledge gap, we have sequenced and characterized the complete mitogenome of Dactylogyrus lamellatus, a common parasite on the gills of grass carp (Ctenopharyngodon idella). The circular mitogenome is 15,187 bp in size, containing the standard 22 tRNA genes, 2 rRNA genes, 12 protein-encoding genes and a long non-coding region (NCR). There are two highly repetitive regions in the NCR. We have used concatenated nucleotide sequences of all 36 genes to perform the phylogenetic analysis using Bayesian inference and maximum likelihood approaches. As expected, the two dactylogyrids, D. lamellatus (Dactylogyrinae) and Tetrancistrum nebulosi (Ancyrocephalinae), were closely related to each other. These two formed a sister group with Capsalidae, and this cluster finally formed a further sister group with Gyrodactylidae. Phylogenetic affinity between Dactylogyrinae and Ancyrocephalinae was further confirmed by the similarity in their gene arrangement. The sequencing of the first Dactylogyrinae, along with a more suitable selection of outgroups, has enabled us to infer a much better phylogenetic resolution than recent mitogenomic studies. However, as many lineages of the class Monogenea remain underrepresented or not represented at all, a much larger number of mitogenome sequences will have to be available in order to infer the evolutionary relationships among the monogeneans fully, and with certainty. PMID- 28660843 TI - Rapidly progressive Fronto-temporal dementia (FTD) associated with Frontotemporal lobar degeneration (FTLD) in the presence of Fused in Sarcoma (FUS) protein: a rare, sporadic, and aggressive form of FTD. AB - Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD. PMID- 28660844 TI - Socioeconomic, emotional, and physical execution variables as predictors of cognitive performance in a Spanish sample of middle-aged and older community dwelling participants. AB - BACKGROUND: Cognitive performance is not easily predicted, since different variables play an important role in the manifestation of age-related declines. The objective of this study is to analyze the predictors of cognitive performance in a Spanish sample over 50 years from a multidimensional perspective, including socioeconomic, affective, and physical variables. Some of them are well-known predictors of cognition and others are emergent variables in the study of cognition. METHODS: The total sample, drawn from the "Longitudinal Study Aging in Spain (ELES)" project, consisted of 832 individuals without signs of cognitive impairment. Cognitive function was measured with tests evaluating episodic and working memory, visuomotor speed, fluency, and naming. Thirteen independent variables were selected as predictors belonging to socioeconomic, emotional, and physical execution areas. Multiple linear regressions, following the enter method, were calculated for each age group in order to study the influence of these variables in cognitive performance. RESULTS: Education is the variable which best predicts cognitive performance in the 50-59, 60-69, and 70-79 years old groups. In the 80+ group, the best predictor is objective economic status and education does not enter in the model. CONCLUSIONS: Age-related decline can be modified by the influence of educational and socioeconomic variables. In this context, it is relevant to take into account how easy is to modify certain variables, compared to others which depend on each person's life course. PMID- 28660845 TI - Caregivers' attitude toward disclosure of Alzheimer's disease diagnosis in Urban China. AB - BACKGROUND: Disclosing the diagnosis of Alzheimer's disease (AD) to a patient is controversial. There is significant stigma associated with a diagnosis of AD or dementia in China, but the attitude of the society toward disclosure of such a diagnosis had not been formally evaluated prior to our study. Therefore, we aimed to evaluate the attitude toward disclosing an AD diagnosis to patients in China with cognitive impairment from their caregivers, and the factors that may affect their attitude. METHODS: We designed a 17-item questionnaire and administered this questionnaire to caregivers, who accompanied patients with cognitive impairment or dementia in three major hospitals in Shanghai, China. The caregiver's attitude toward disclosing the diagnosis of AD as evaluated by the questionnaire was compared to that of disclosing the diagnosis of terminal cancer. RESULTS: A majority (95.7%) of the 175 interviewed participants (mean 14.2 years of education received) wished to know their own diagnosis if they were diagnosed with AD, and 97.6% preferred the doctor to tell their family members if they were diagnosed with AD. If a family member of the participants suffered from AD, 82.9% preferred to have the diagnosis disclosed to the patient. "Cognitive impairment" was the most accepted term by caregivers to disclose AD diagnosis in Chinese. CONCLUSION: This study suggests most of the well-educated individuals in a Chinese urban area favored disclosing the diagnosis when they or their family members were diagnosed with AD. PMID- 28660846 TI - Carbohydrate nutrition and risk of adiposity-related cancers: results from the Framingham Offspring cohort (1991-2013). AB - Higher carbohydrate intake, glycaemic index (GI), and glycaemic load (GL) are hypothesised to increase cancer risk through metabolic dysregulation of the glucose-insulin axis and adiposity-related mechanisms, but epidemiological evidence is inconsistent. This prospective cohort study investigates carbohydrate quantity and quality in relation to risk of adiposity-related cancers, which represent the most commonly diagnosed preventable cancers in the USA. In exploratory analyses, associations with three site-specific cancers: breast, prostate and colorectal cancers were also examined. The study sample consisted of 3184 adults from the Framingham Offspring cohort. Dietary data were collected in 1991-1995 using a FFQ along with lifestyle and medical information. From 1991 to 2013, 565 incident adiposity-related cancers, including 124 breast, 157 prostate and sixty-eight colorectal cancers, were identified. Cox proportional hazards models were used to evaluate the role of carbohydrate nutrition in cancer risk. GI and GL were not associated with risk of adiposity-related cancers or any of the site-specific cancers. Total carbohydrate intake was not associated with risk of adiposity-related cancers combined or prostate and colorectal cancers. However, carbohydrate consumption in the highest v. lowest quintile was associated with 41 % lower breast cancer risk (hazard ratio (HR) 0.59; 95 % CI 0.36, 0.97). High-, medium- and low-GI foods were not associated with risk of adiposity-related cancers or prostate and colorectal cancers. In exploratory analyses, low-GI foods, were associated with 49 % lower breast cancer risk (HR 0.51; 95 % CI 0.32, 0.83). In this cohort of Caucasian American adults, associations between carbohydrate nutrition and cancer varied by cancer site. Healthier low-GI carbohydrate foods may prevent adiposity-related cancers among women, but these findings require confirmation in a larger sample. PMID- 28660847 TI - Attended With and Head-Turning Sign can be clinical markers of cognitive impairment in older adults. AB - BACKGROUND: Comprehensive neurocognitive assessment may not be performed in clinical practice, as it takes too much time and requires special training. Development of easily applicable, time-saving, and cost effective screening methods has allowed identifying the individuals that require further evaluation. The aim of present study was to assess the diagnostic value of the Attended With (AW) and Head-Turning Sign (HTS) for screening cognitive impairment (CI). METHODS: Comprehensive geriatric assessment was performed in 529 elderly outpatients, and the presence or absence of AW and HTS was investigated in them all. RESULTS: Of the 529 patients, of whom the mean age was 75.67 +/- 8.29 years, 126 patients were considered as CI (102 dementia, 24 mild CI). The patients with positive AW had significantly lower scores on Mini-Mental State Examination, Cognitive State Test, and Montreal Cognitive Assessment, and activities of daily living compared to AW (-) patients (p < 0.001). Similar significant findings were obtained in the patients with positive and negative HTS (p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of AW in detecting CI were 92%, 37%, 31.4%, and 93.7%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of HTS were 80%, 64%, 41.8%, and 91.5%, respectively. The area under the receiver-operating characteristics curve was 0.90 for AW and 0.82 for HTS. CONCLUSION: AW and HTS are fast, simple, effective, and sensitive methods for detecting CI. Therefore, they can be used for older adults attending the primary care settings with memory loss. Those with positive AW or HTS can be referred to the relevant centers for detailed cognitive assessment. PMID- 28660848 TI - Effects of rapeseed meal fiber content on phosphorus and calcium digestibility in growing pigs fed diets without or with microbial phytase. AB - The optimization of dietary phosphorus (P) and calcium (Ca) supply requires a better understanding of the effect of dietary fiber content of co-products on the digestive utilization of minerals. This study was designed to evaluate the effects of dietary fiber content from 00-rapeseed meal (RSM) on P and Ca digestibility throughout the gastrointestinal tract in growing pigs fed diets without or with microbial phytase. In total, 48 castrated male pigs (initial BW=36.1+/-0.4 kg) were housed in metabolic crates for 29 days. After an 8-day adaptation period, pigs were allocated to one of the eight treatments. The impact of dietary fiber was modulated by adding whole RSM (wRSM), dehulled RSM (dRSM) or dRSM supplemented with 4.5% or 9.0% rapeseed hulls (dRSMh1 and dRSMh2). Diets contained 0 or 500 phytase unit of microbial phytase per kg. From day 14 to day 23, feces and urine were collected separately to determine apparent total tract digestibility (ATTD) and apparent retention (AR) of P and Ca. At the end of the experiment, femurs and digestive contents were sampled. No effect of variables of interest was observed on growth performance. Microbial phytase increased ATTD and AR of P (P<0.001) but the P equivalency with the wRSM diet was lower than expected. Moreover, stomach inorganic P (iP) solubility was improved by microbial phytase (P<0.001). The ATTD of Ca was not affected by microbial phytase which increased AR of Ca and femur characteristics (P<0.05). Ileal recovery of P was not affected by microbial phytase but cecal recovery was considerably reduced by microbial phytase (P<0.001). The decrease in digesta pH between the distal ileum and cecum (7.6 v. 5.9) enhanced the solubility of iP and may have improved its absorption, as supported by the negative relationship between soluble iP and pH (R 2=0.40, P<0.001 without microbial phytase and R 2=0.24, P=0.026 with microbial phytase). The inclusion of hulls improved the solubility of iP (P<0.05). In conclusion, dehulling does not largely increase nutrient digestibility although dRSM seems to improve the efficacy of microbial phytase in releasing phosphate in the stomach. Moreover, dietary fiber may affect solubilization process in the cecum which potentiates the effect of microbial phytase on P digestibility. PMID- 28660853 TI - Fluorescence lifetime based bioassays. AB - Fluorescence lifetime (FLT) is a robust intrinsic property and material constant of fluorescent matter. Measuring this important physical indicator has evolved from a laboratory curiosity to a powerful and established technique for a variety of applications in drug discovery, medical diagnostics and basic biological research. This distinct trend was mainly driven by improved and meanwhile affordable laser and detection instrumentation on the one hand, and the development of suitable FLT probes and biological assays on the other. In this process two essential working approaches emerged. The first one is primarily focused on high throughput applications employing biochemical in vitro assays with no requirement for high spatial resolution. The second even more dynamic trend is the significant expansion of assay methods combining highly time and spatially resolved fluorescence data by fluorescence lifetime imaging. The latter approach is currently pursued to enable not only the investigation of immortal tumor cell lines, but also specific tissues or even organs in living animals. This review tries to give an actual overview about the current status of FLT based bioassays and the wide range of application opportunities in biomedical and life science areas. In addition, future trends of FLT technologies will be discussed. PMID- 28660849 TI - Racial Differences in Neurocognitive Outcomes Post-Stroke: The Impact of Healthcare Variables. AB - OBJECTIVES: The present study examined differences in neurocognitive outcomes among non-Hispanic Black and White stroke survivors using the NIH Toolbox Cognition Battery (NIHTB-CB), and investigated the roles of healthcare variables in explaining racial differences in neurocognitive outcomes post-stroke. METHODS: One-hundred seventy adults (91 Black; 79 White), who participated in a multisite study were included (age: M=56.4; SD=12.6; education: M=13.7; SD=2.5; 50% male; years post-stroke: 1-18; stroke type: 72% ischemic, 28% hemorrhagic). Neurocognitive function was assessed with the NIHTB-CB, using demographically corrected norms. Participants completed measures of socio-demographic characteristics, health literacy, and healthcare use and access. Stroke severity was assessed with the Modified Rankin Scale. RESULTS: An independent samples t test indicated Blacks showed more neurocognitive impairment (NIHTB-CB Fluid Composite T-score: M=37.63; SD=11.67) than Whites (Fluid T-score: M=42.59, SD=11.54; p=.006). This difference remained significant after adjusting for reading level (NIHTB-CB Oral Reading), and when stratified by stroke severity. Blacks also scored lower on health literacy, reported differences in insurance type, and reported decreased confidence in the doctors treating them. Multivariable models adjusting for reading level and injury severity showed that health literacy and insurance type were statistically significant predictors of the Fluid cognitive composite (p<.001 and p=.02, respectively) and significantly mediated racial differences on neurocognitive impairment. CONCLUSIONS: We replicated prior work showing that Blacks are at increased risk for poorer neurocognitive outcomes post-stroke than Whites. Health literacy and insurance type might be important modifiable factors influencing these differences. (JINS, 2017, 23, 640-652). PMID- 28660854 TI - Quinone molecules encapsulated in SWCNTs for low-temperature Na ion batteries. AB - We have performed Li and Na ion charge-discharge experiments of 9,10-phenanthrene quinone (PhQ) molecules encapsulated in single-walled carbon nanotubes (SWCNTs) with mean tube diameters of 1.5 and 2.5 nm at room temperature and also at low temperatures. The Na ion reversible capacity of PhQ encapsulated in the larger diameter SWCNTs, measured at a low temperature of 0 degrees C, remained as high as that measured at room temperature (RT), while the capacity of PhQ in the smaller diameter SWCNTs at 0 degrees C was about a half of that at RT. The diameter dependence of the capacity should be attributed to the difference in the interactions between the encapsulated PhQ molecules and the host SWCNTs, which was revealed by Raman peak profile analysis. Charge-transfer reaction from metallic tubes to PhQ molecules encapsulated in the smaller diameter SWCNTs was detected by Raman measurements. The electrostatic interaction between charged SWCNTs and PhQ molecules, induced by the charge-transfer reaction, would partly contribute to the stabilization of PhQ molecules in the smaller diameter SWCNTs, while only van der Waals interaction stabilizes PhQ molecules in the larger diameter SWCNTs. The difference in stability was confirmed by thermogravimetric, x-ray photoelectron spectroscopy, and Raman measurements. Charge-discharge curves of PhQ encapsulated in SWCNTs were also discussed based on the stability difference. PMID- 28660850 TI - PUFA levels in erythrocyte membrane phospholipids are differentially associated with colorectal adenoma risk. AB - Dietary intake of PUFA has been associated with colorectal neoplasm risk; however, results from observational studies have been inconsistent. Most prior studies have utilised self-reported dietary measures to assess fatty acid exposure which might be more susceptible to measurement error and biases compared with biomarkers. The purpose of this study was to determine whether erythrocyte phospholipid membrane PUFA percentages are associated with colorectal adenoma risk. We included data from 904 adenoma cases and 835 polyp-free controls who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using GC. Conditional logistic regression was used to calculate adjusted OR for risk of colorectal adenomas with erythrocyte membrane PUFA. Higher erythrocyte membrane percentages of arachidonic acid was associated with an increased risk of colorectal adenomas (adjusted OR 1.66; 95 % CI 1.05, 2.62, P trend=0.02) comparing the highest tertile to the lowest tertile. The effect size for arachidonic acid was more pronounced when restricting the analysis to advanced adenomas only. Higher erythrocyte membrane EPA percentages were associated with a trend towards a reduced risk of advanced colorectal adenomas (P trend=0.05). Erythrocyte membrane arachidonic acid percentages are associated with an increased risk of colorectal adenomas. PMID- 28660855 TI - Ultra rapid direct heating synthesis of ZnO nanorods with improved light trapping from stacked photoanodes for high efficiency photocatalytic water splitting. AB - An ultra rapid growth method for vertically aligned ZnO nanorod (NR) thin films on metal meshes was developed using a direct heating synthesis technique. A typical NR growth rate of 10 MUm h-1 was achieved. The effects of the applied heating power and growth duration on the morphologies of ZnO nanostructures were examined. High density surface defects were formed on the ZnO NRs, which is responsible for slow charge recombination and high efficiency in the photoelectrochemical (PEC) water splitting process. The light absorption for a photoanode was significantly improved by light trapping using a 3D stacked metal mesh photoanode structure. With the internal reflection between the stacked photoanodes, the final light leakage is minimised. The light absorption in the stacked photoanode is improved without restricting the charge transportation. In comparison with a single mesh photoanode and a chemical bath deposition grown flat photoanode, the PEC water splitting efficiency from the stacked photoanode was increased by a factor of 2.6 and 6.1 respectively. PMID- 28660856 TI - Innovative exhaled breath analysis with old breathing manoeuvres-is there a problem or an advantage? AB - As the field of exhaled breath research is expanding, the question that arises is can the old usual method of spirometry be used in all cases? The answer is yes for some analysation methods and definitely not for others: it all depends on the result you are looking for. Exhaled breath condensate collection can be accomplished with silent tidal breathing, but not in the analysation of the amount of exhaled particles, as they become very low during tidal breathing. There are gases that are exhalation flow dependent, e.g. nitric oxide, acetone and ethanol, that require a special breathing manoeuvre with flow control. Physiological changes of the lung, i.e. inhalation to total lung capacity or forced exhalation such as during spirometry, will affect the result of exhaled biomarkers. The standardisation of exhaled breath requires further development, and there are many aspects to consider. PMID- 28660857 TI - Highly luminescent, stable, transparent and flexible perovskite quantum dot gels towards light-emitting diodes. AB - By controlling the hydrolysis of alkoxysilanes, highly luminescent, transparent and flexible perovskite quantum dot (QD) gels were synthesized. The gels could maintain the structure without shrinking and exhibited excellent stability comparing to the QDs in solution. This in situ fabrication can be easily scaled up for large-area/volume gels. The gels integrated the merits of the polymer matrices to avoid the non-uniformity of light output, making it convenient for practical LED applications. Monochrome and white LEDs were fabricated using these QD gels; the LEDs exhibited broader color gamut, demonstrating better property in the backlight display application. PMID- 28660858 TI - Fe2Ni2N nanosheet array: an efficient non-noble-metal electrocatalyst for non enzymatic glucose sensing. AB - It is very important to develop enhanced electrochemical sensing platforms for molecular detection and non-noble-metal nanoarray architecture, as electrochemical catalyst electrodes have attracted great attention due to their large specific surface area and easy accessibility to target molecules. In this paper, we demonstrate that an Fe2Ni2N nanosheet array grown on Ti mesh (Fe2Ni2N NS/TM) shows high electrocatalytic activity toward glucose electrooxidation in alkaline medium. As an electrochemical glucose sensor, such an Fe2Ni2N NS/TM catalyst electrode demonstrates superior sensing performance with a short response time of less than 5 s, a wide linear range of 0.05 MUM-1.5 mM, a low detection limit of 0.038 MUM (S/N = 3), a high sensitivity of 6250 MUA mM-1 cm-2, as well as high selectivity and long-term stability. PMID- 28660859 TI - Exhaled nitric oxide measurements in patients with acute-onset interstitial lung disease. AB - It is important to identify the underlying cause of acute-onset interstitial lung disease (ILD). This study aims to assess whether there are differences in the exhaled nitric oxide (eNO) level between different subtypes of acute-onset ILD. Forty patients with a combination of illness <=4 weeks in duration and diffuse radiographic infiltrates were classified into groups based on the etiology. The eNO at a flow rate of 50 ml s-1 (FeNO), the alveolar nitric oxide concentration (Calv), and the systemic inflammatory markers of the groups were compared. The median FeNO value of patients with acute eosinophilic pneumonia (AEP) (48.1 ppb) was significantly higher than that of the other groups (17.4 ppb in cryptogenic organizing pneumonia, 20.5 ppb in hypersensitivity pneumonia, and 12.0 ppb for sarcoidosis) (p < 0.0005) as well as blood eosinophils (p < 0.005) and Calv levels (p < 0.005). The area under the receiver's operating characteristic curve (AUC) for FeNO to identify AEP was 0.90 with a cut-off of 23.4 ppb. The AUC for Calv and blood eosinophils was 0.85 and 0.82, respectively. Even in patients with blood eosinophil numbers <5 * 105 cells MUl-1, FeNO maintained a good diagnostic value for AEP (AUC = 0.85). eNO can be useful for differentiating AEP from other types of acute-onset ILD, regardless of the blood eosinophil levels. PMID- 28660860 TI - Introducing the holo-TIE approach to cellular imaging. PMID- 28660861 TI - Three-dimensional single-cell imaging with X-ray waveguides in the holographic regime. AB - X-ray tomography at the level of single biological cells is possible in a low dose regime, based on full-field holographic recordings, with phase contrast originating from free-space wave propagation. Building upon recent progress in cellular imaging based on the illumination by quasi-point sources provided by X ray waveguides, here this approach is extended in several ways. First, the phase retrieval algorithms are extended by an optimized deterministic inversion, based on a multi-distance recording. Second, different advanced forms of iterative phase retrieval are used, operational for single-distance and multi-distance recordings. Results are compared for several different preparations of macrophage cells, for different staining and labelling. As a result, it is shown that phase retrieval is no longer a bottleneck for holographic imaging of cells, and how advanced schemes can be implemented to cope also with high noise and inconsistencies in the data. PMID- 28660863 TI - A first-prototype multi-determinant X-ray constrained wavefunction approach: the X-ray constrained extremely localized molecular orbital-valence bond method. AB - All the current variants of Jayatilaka's X-ray constrained wavefunction (XCW) approach work within the framework of the single-determinant wavefunction ansatz. In this paper, a first-prototype multi-determinant XCW technique is proposed. The strategy assumes that the desired XCW is written as a valence-bond-like expansion in terms of pre-determined single Slater determinants constructed with extremely localized molecular orbitals. The method, which can be particularly suitable to investigate systems with a multi-reference character, has been applied to determine the weights of the resonance structures of naphthalene at different temperatures by exploiting experimental high-resolution X-ray diffraction data. The results obtained have shown that the explicit consideration of experimental structure factors in the determination of the resonance structure weights may lead to results significantly different compared with those resulting only from the simple energy minimization. PMID- 28660862 TI - High-resolution X-ray diffraction with no sample preparation. AB - It is shown that energy-dispersive X-ray diffraction (EDXRD) implemented in a back-reflection geometry is extremely insensitive to sample morphology and positioning even in a high-resolution configuration. This technique allows high quality X-ray diffraction analysis of samples that have not been prepared and is therefore completely non-destructive. The experimental technique was implemented on beamline B18 at the Diamond Light Source synchrotron in Oxfordshire, UK. The majority of the experiments in this study were performed with pre-characterized geological materials in order to elucidate the characteristics of this novel technique and to develop the analysis methods. Results are presented that demonstrate phase identification, the derivation of precise unit-cell parameters and extraction of microstructural information on unprepared rock samples and other sample types. A particular highlight was the identification of a specific polytype of a muscovite in an unprepared mica schist sample, avoiding the time consuming and difficult preparation steps normally required to make this type of identification. The technique was also demonstrated in application to a small number of fossil and archaeological samples. Back-reflection EDXRD implemented in a high-resolution configuration shows great potential in the crystallographic analysis of cultural heritage artefacts for the purposes of scientific research such as provenancing, as well as contributing to the formulation of conservation strategies. Possibilities for moving the technique from the synchrotron into museums are discussed. The avoidance of the need to extract samples from high value and rare objects is a highly significant advantage, applicable also in other potential research areas such as palaeontology, and the study of meteorites and planetary materials brought to Earth by sample-return missions. PMID- 28660864 TI - Reduction of small-angle scattering profiles to finite sets of structural invariants. AB - This paper shows how small-angle scattering (SAS) curves can be decomposed in a simple sum using a set of invariant parameters called Kn which are related to the shape of the object of study. These Kn, together with a radius R, give a complete theoretical description of the SAS curve. Adding an overall constant, these parameters are easily fitted against experimental data giving a concise comprehensive description of the data. The pair distance distribution function is also entirely described by this invariant set and the Dmax parameter can be measured. In addition to the understanding they bring, these invariants can be used to reliably estimate structural moments beyond the radius of gyration, thereby rigorously expanding the actual set of model-free quantities one can extract from experimental SAS data, and possibly paving the way to designing new shape reconstruction strategies. PMID- 28660865 TI - Thermoelectric transport properties in magnetically ordered crystals. AB - The forms of the tensors describing thermoelectric transport properties in magnetically ordered crystals are given for frequently used orientations of the 122 space-time point groups up to second order in an applied magnetic field. It is shown which forms are interchanged for the point groups of the hexagonal crystal family by two different conventions for the connection between the Hermann-Mauguin symbol and the orientation of the Cartesian coordinate system. The forms are given in Nye notation, which conspicuously shows how the forms for different point groups are related. It is shown that the measurable effects in magnetically ordered crystals can be decomposed into an effect occurring in all crystals and one coming from the magnetic ordering. Errors in the literature are pointed out. PMID- 28660866 TI - Hard-sphere displacive model of deformation twinning in hexagonal close-packed metals. Revisiting the case of the (56 degrees , a) contraction twins in magnesium. AB - Contraction twinning in magnesium alloys leads to new grains that are misoriented from the parent grain by a rotation (56 degrees , a). The classical shear theory of deformation twinning does not specify the atomic displacements and does not explain why contraction twinning is less frequent than extension twinning. The paper proposes a new displacive model in line with our previous work on martensitic transformations and extension twinning. A continuous angular distortion matrix that transforms the initial hexagonal close-packed (h.c.p.) crystal into a final h.c.p. crystal is determined such that the atoms move as hard spheres and reach the final positions expected by the orientation relationship. The calculations prove that the distortion is not a simple shear when it is considered in its continuity. The ({0{?overline 1}1}) plane is untilted and restored, but it is not fully invariant because some interatomic distances in this plane evolve during the distortion process; the unit volume also increases up to 5% before coming back to its initial value when the twinning distortion is complete. Then, the distortion takes the form of a simple shear on the ({0{?overline 1}1}) plane with a shear along the direction [{18,{?overline 5},{?overline 5}}] of amplitude 0.358. Experiments are proposed to validate or disprove the model. PMID- 28660867 TI - Close-packed structures with finite-range interaction: computational mechanics of layer pair interaction. AB - The stacking problem is approached by computational mechanics, using an Ising next-nearest-neighbour model. Computational mechanics allows one to treat the stacking arrangement as an information processing system in the light of a symbol generating process. A general method for solving the stochastic matrix of the random Gibbs field is presented and then applied to the problem at hand. The corresponding phase diagram is then discussed in terms of the underlying E machine, or optimal finite-state machine. The occurrence of higher-order polytypes at the borders of the phase diagram is also analysed. The applicability of the model to real systems such as ZnS and cobalt is discussed. The method derived is directly generalizable to any one-dimensional model with finite-range interaction. PMID- 28660869 TI - A reliability and readability analysis of silicosis-related Italian websites: implications for occupational health. AB - BACKGROUND: Silicosis represents a "classical" occupational disease characterized by a renewed interest. New risk factors are emerging, such as sandblasting in the jeans industry or hydrofracking, leading to clusters of acute or massive cases. OBJECTIVES: Given that the Internet could represent a worker education and empowerment tool, and considering the increase in popularity of silicosis-related information, we aimed at systematically analyzing the reliability and readability of online silicosis-relevant information. METHODS: The search term "silicosi" was used to query 5 top search engines. The first 3 pages of results were screened using two validated readability tools: namely, the Gulpease and the ReadIt DyLanLab grade level scores. RESULTS: Seventy sites were analyzed. The Gulpease score differed among the types of websites: academic websites differed from institutional websites, as well as encyclopedia/dictionary pages from institutional sites. The Lexical Model - ReadIt DyLanLab grade level differed among the types of websites. Encyclopedia/dictionary pages differed from academic, commercial, health-related, institutional and news sites. Approximately, half of the websites were intended/designed for workers. Only the Global Model - Read-It DyLanLab grade level differed according to the intended/designed target. Only 1.4% of websites adhered to Health on the Net Foundation Code of Conduct. CONCLUSIONS: Our findings may have important practical implications for occupational physicians and health agencies/authorities. They should make efforts in strengthening their online presence, and producing appropriate material. This could lead to positive outcomes in term of occupational health promotion, potentially enabling workers to increase and to improve their work-related health and its determinants. PMID- 28660870 TI - The effect of Global Postural Reeducation on body weight distribution in sitting posture and on musculoskeletal pain. A pilot study. AB - OBJECTIVE: To quantify body weight distribution (BWD) in seated posture with an office chair instrumented with load cells and to evaluate the effects of ergonomic advice and Global Postural Reeducation (GPR) on seated BWD and on musculoskeletal pain. METHODS: Nineteen healthy females were randomly assigned: nine to the experimental group and 10 to the control group. Control group (CG) received only ergonomic verbal advice (EVA) regarding BWD in a seated position. Experimental group (EG) also received EVA and furthermore attended eight GPR sessions. Difference in the effects of the different therapeutic approaches was investigated using the non-parametric Wilcoxon-Mann-Whitney test. RESULTS: After treatments, there was no significant difference between the two groups as regards seated BWD. EG improved musculoskeletal pain significantly more than CG (p<0.005). Instead, musculoskeletal pain frequency decreased (p<0.005) only in EG (after EVA and GPR sessions), in neck, cervical, thoracic, lumbar, shoulders and wrists areas. CONCLUSIONS: Despite both interventions did not induce any significant improvement on seated BWD, adding GPR to EVA was related to a better reduction on musculoskeletal pain in young health females. PMID- 28660872 TI - Determinants of work-related accidents in Italian Regions. AB - OBJECTIVE: To identify the determinants of the regional differences in work injuries and mortality rates in Italy. METHODS: Several linear regression models were built assessing the association between regional differences in work mortality and injury rates (as dependent variables) and socio-demographic factors (occupation and population) and variables describing alcohol consumption, mean age and availability of health care (as independent variables). Data sources are from ISTAT, INAIL, Health for All database and the national report Osservasalute. The analysis was carried out using data coming from all the Italian Regions. RESULTS: The mean work mortality rate for the period 2006-2014 was 7.73 (DS 1.85) per 100,000 workers, while the injury rate was 4503.1 (DS 1413.5) per 100,000 workers. Socio-demographic variables and that related to health care (TC availability) were inversely associated with mortality rates, while for the work injury rates, significant associations with alcohol were found, while Gross domestic product and TC availability were inversely associated. CONCLUSIONS: The study pointed out the extreme heterogeneity between different geographical areas in the field of work injury, due to different socio-demographic and economic factors. In the future, health surveillance and work injury and mortality rates could be improved in areas at high risk. PMID- 28660871 TI - Increase of exposure and event acceleration. AB - INTRODUCTION: In a previous paper on acceleration of failure time we highlighted the difficulties of the application to the case of mesothelioma of the methodology proposed by Berry. In this contribution we elaborate further on the concept of anticipation/acceleration, taking into account the content of the III Italian Consensus Document. METHODS: We analyzed the ways in which the concept of anticipation/acceleration has been proposed and interpreted in the III Consensus Document. RESULTS: We show that the concept of anticipation of the III Consensus Document has to do with incidence (frequency) in a population (and not with acceleration of the pathological process in an individual case), and is a measure which is alternative to other measures of frequency effects. In addition, we show that the same epidemiological result is compatible with causal models where no cases, all the cases, or some of the cases are anticipated. DISCUSSION: This paper suggests that the concept of anticipation measurable through epidemiologic data has to do exclusively with the anticipation of a frequency indicator (more occurrencies and anticipated occurrencies are indistinguishable and alternative concepts) but not with the acceleration of the biological process in individual cases. In causal terms, without a biological support it is not possible to infer from the epidemiologic results if a causal model is in action with no, all, or some of cases anticipated. PMID- 28660873 TI - The community of practice as a place of prevention: the value of collective knowledge in occupational safety. AB - BACKGROUND: Occupational Health and Safety (OSH) inspectors of the Health Units of Piedmont Region wrote 47 case histories based on data gathered from injury investigations as part of the project "From the injury investigation reports to case histories: creation of a collection of case histories on occupational injuries". Afterwards a Community of Practice (CoP) was initiated with the aim of sharing recommendations for prevention of occupational injuries. OBJECTIVE: The aims of the article are: 1) to describe the implementation process of the CoP; 2) to evaluate the benefits of CoP regarding the improvement of professional practice of OSH inspectors. METHODS: Two injury case histories were peer reviewed during each meeting of the CoP. A focus group was set up to evaluate benefits of CoP. Seven OSH inspectors participated in this focus group. RESULTS: Eight CoP meetings were organized and about 70 OSH inspectors participated. Fourteen stories were peer reviewed and eight were published on www.dors.it. Operators involved in the focus groups reported that the main reasons for participation in the CoP were the need to compare and tackle new challenges. The criticalities are tied to the turnover of the participants and to the lack of recognition by management. Most of the operators felt it was too early to include professionals such as Workers' Safety Representatives and Prevention and Safety Service Managers in the CoP due to their different professional roles. CONCLUSIONS: OSH inspectors reported professional benefits of CoP experience. We believe that this approach might be transferred, integrated and developed in other regions and included in the next national prevention plan. PMID- 28660874 TI - Occupational exposure to fluorescent light in a pathologist with myopic complications and asthenopia onset. AB - BACKGROUND: Pathologic myopia is often associated with many complications, e.g. retinopathy, vitreous detachment and glaucoma. To date, occupational exposure of workers suffering from myopic co-morbidities to fluorescence light is not clearly linked to a worsening of retinal damage and eye symptoms. CASE REPORT: A 56-year old pathologist, suffering from myopic retinopathy and other ocular comorbidities, asked for medical examination due to worsening vision and burning eyes, after occupational exposure to fluorescence microscope. Eye examination performed by an ophthalmologist detected a severe chorio-retinal atrophy in peri papillar region and scotopic-photopic reduced voltages at electroretinogram. Moreover, a workplace inspection noted high light intensity from power source (9600 lux). Considering severity of the retinopathy, frequency of the ocular symptoms and steady occupational exposure both to low-intensity fluorescent light and high intensity light, we decided to declare the worker only fit for specific tasks which do not include the use of a fluorescence microscope. Almost six months later, the worker was recalled for a new examination and she reported the absence of the ocular discomfort that had led her to request the previous examination. CONCLUSION: In this unconventional case, we considered appropriated to use great caution, to avoid ocular fatigue and prevent possible retinal damage in the worker. PMID- 28660875 TI - Imaging the real space structure of the spin fluctuations in an iron-based superconductor. AB - Spin fluctuations are a leading candidate for the pairing mechanism in high temperature superconductors, supported by the common appearance of a distinct resonance in the spin susceptibility across the cuprates, iron-based superconductors and many heavy fermion materials. The information we have about the spin resonance comes almost exclusively from neutron scattering. Here we demonstrate that by using low-temperature scanning tunnelling microscopy and spectroscopy we can characterize the spin resonance in real space. We show that inelastic tunnelling leads to the characteristic dip-hump feature seen in tunnelling spectra in high temperature superconductors and that this feature arises from excitations of the spin fluctuations. Spatial mapping of this feature near defects allows us to probe non-local properties of the spin susceptibility and to image its real space structure. PMID- 28660876 TI - Understanding dynamic friction through spontaneously evolving laboratory earthquakes. AB - Friction plays a key role in how ruptures unzip faults in the Earth's crust and release waves that cause destructive shaking. Yet dynamic friction evolution is one of the biggest uncertainties in earthquake science. Here we report on novel measurements of evolving local friction during spontaneously developing mini earthquakes in the laboratory, enabled by our ultrahigh speed full-field imaging technique. The technique captures the evolution of displacements, velocities and stresses of dynamic ruptures, whose rupture speed range from sub-Rayleigh to supershear. The observed friction has complex evolution, featuring initial velocity strengthening followed by substantial velocity weakening. Our measurements are consistent with rate-and-state friction formulations supplemented with flash heating but not with widely used slip-weakening friction laws. This study develops a new approach for measuring local evolution of dynamic friction and has important implications for understanding earthquake hazard since laws governing frictional resistance of faults are vital ingredients in physically-based predictive models of the earthquake source. PMID- 28660877 TI - Sodium vanadium titanium phosphate electrode for symmetric sodium-ion batteries with high power and long lifespan. AB - Sodium-ion batteries operating at ambient temperature hold great promise for use in grid energy storage owing to their significant cost advantages. However, challenges remain in the development of suitable electrode materials to enable long lifespan and high rate capability. Here we report a sodium super-ionic conductor structured electrode, sodium vanadium titanium phosphate, which delivers a high specific capacity of 147 mA h g-1 at a rate of 0.1 C and excellent capacity retentions at high rates. A symmetric sodium-ion full cell demonstrates a superior rate capability with a specific capacity of about 49 mA h g-1 at 20 C rate and ultralong lifetime over 10,000 cycles. Furthermore, in situ synchrotron diffraction and X-ray absorption spectroscopy measurement are carried out to unravel the underlying sodium storage mechanism and charge compensation behaviour. Our results suggest the potential application of symmetric batteries for electrochemical energy storage given the superior rate capability and long cycle life. PMID- 28660878 TI - Jahn-Teller distortion driven magnetic polarons in magnetite. AB - The first known magnetic mineral, magnetite, has unusual properties, which have fascinated mankind for centuries; it undergoes the Verwey transition around 120 K with an abrupt change in structure and electrical conductivity. The mechanism of the Verwey transition, however, remains contentious. Here we use resonant inelastic X-ray scattering over a wide temperature range across the Verwey transition to identify and separate out the magnetic excitations derived from nominal Fe2+ and Fe3+ states. Comparison of the experimental results with crystal field multiplet calculations shows that the spin-orbital dd excitons of the Fe2+ sites arise from a tetragonal Jahn-Teller active polaronic distortion of the Fe2+O6 octahedra. These low-energy excitations, which get weakened for temperatures above 350 K but persist at least up to 550 K, are distinct from optical excitations and are best explained as magnetic polarons. PMID- 28660879 TI - Common mechanism of thermodynamic and mechanical origin for ageing and crystallization of glasses. AB - The glassy state is known to undergo slow structural relaxation, where the system progressively explores lower free-energy minima which are either amorphous (ageing) or crystalline (devitrification). Recently, there is growing interest in the unusual intermittent collective displacements of a large number of particles known as 'avalanches'. However, their structural origin and dynamics are yet to be fully addressed. Here, we study hard-sphere glasses which either crystallize or age depending on the degree of size polydispersity, and show that a small number of particles are thermodynamically driven to rearrange in regions of low density and bond orientational order. This causes a transient loss of mechanical equilibrium which facilitates a large cascade of motion. Combined with previously identified phenomenology, we have a complete kinetic pathway for structural change which is common to both ageing and crystallization. Furthermore, this suggests that transient force balance is what distinguishes glasses from supercooled liquids. PMID- 28660880 TI - Clustering of arc volcanoes caused by temperature perturbations in the back-arc mantle. AB - Clustering of arc volcanoes in subduction zones indicates along-arc variation in the physical condition of the underlying mantle where majority of arc magmas are generated. The sub-arc mantle is brought in from the back-arc largely by slab driven mantle wedge flow. Dynamic processes in the back-arc, such as small-scale mantle convection, are likely to cause lateral variations in the back-arc mantle temperature. Here we use a simple three-dimensional numerical model to quantify the effects of back-arc temperature perturbations on the mantle wedge flow pattern and sub-arc mantle temperature. Our model calculations show that relatively small temperature perturbations in the back-arc result in vigorous inflow of hotter mantle and subdued inflow of colder mantle beneath the arc due to the temperature dependence of the mantle viscosity. This causes a three dimensional mantle flow pattern that amplifies the along-arc variations in the sub-arc mantle temperature, providing a simple mechanism for volcano clustering. PMID- 28660882 TI - Understanding the mechanism of catalytic fast pyrolysis by unveiling reactive intermediates in heterogeneous catalysis. AB - Catalytic fast pyrolysis is a promising way to convert lignin into fine chemicals and fuels, but current approaches lack selectivity and yield unsatisfactory conversion. Understanding the pyrolysis reaction mechanism at the molecular level may help to make this sustainable process more economic. Reactive intermediates are responsible for product branching and hold the key to unveiling these mechanisms, but are notoriously difficult to detect isomer-selectively. Here, we investigate the catalytic pyrolysis of guaiacol, a lignin model compound, using photoelectron photoion coincidence spectroscopy with synchrotron radiation, which allows for isomer-selective detection of reactive intermediates. In combination with ambient pressure pyrolysis, we identify fulvenone as the central reactive intermediate, generated by catalytic demethylation to catechol and subsequent dehydration. The fulvenone ketene is responsible for the phenol formation. This technique may open unique opportunities for isomer-resolved probing in catalysis, and holds the potential for achieving a mechanistic understanding of complex, real-life catalytic processes. PMID- 28660881 TI - Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis. AB - Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; however, the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Ten-eleven translocation (Tet) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and its downstream derivatives. Here we show that 5hmC is elevated during the differentiation of adult neural stem cells (aNSCs), and Tet2 is primarily responsible for modulating 5hmC dynamics. Depletion of Tet2 leads to increased aNSC proliferation and reduced differentiation in vitro and in vivo. Genome-wide transcriptional analyses reveal important epigenetic roles of Tet2 in maintaining the transcriptome landscape related to neurogenesis. Mechanistically, transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet2 and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis. PMID- 28660883 TI - Interfacial engineering of metal-insulator-semiconductor junctions for efficient and stable photoelectrochemical water oxidation. AB - Solar-assisted water splitting can potentially provide an efficient route for large-scale renewable energy conversion and storage. It is essential for such a system to provide a sufficiently high photocurrent and photovoltage to drive the water oxidation reaction. Here we demonstrate a photoanode that is capable of achieving a high photovoltage by engineering the interfacial energetics of metal insulator-semiconductor junctions. We evaluate the importance of using two metals to decouple the functionalities for a Schottky contact and a highly efficient catalyst. We also illustrate the improvement of the photovoltage upon incidental oxidation of the metallic surface layer in KOH solution. Additionally, we analyse the role of the thin insulating layer to the pinning and depinning of Fermi level that is responsible to the resulting photovoltage. Finally, we report the advantage of using dual metal overlayers as a simple protection route for highly efficient metal-insulator-semiconductor photoanodes by showing over 200 h of operational stability. PMID- 28660884 TI - The association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysis. AB - There have been numerous case reports of severe adverse events including deaths following chronic licorice ingestion. The aim of the present study was to evaluate the effect of chronic ingestion of licorice on blood pressure, plasma potassium, plasma renin activity and plasma aldosterone. A search of MEDLINE, PubMed, EMBASE, CENTRAL, DARE, CINAHL and Current Contents Connect was performed from inception through to 26 April 2017. Trials that included a treatment group ingesting a product containing at least 100 mg of glycyrrhizic acid daily were selected. Pooled mean changes from baseline with 95% confidence intervals were calculated for diastolic blood pressure, systolic blood pressure, plasma potassium, plasma renin activity and plasma aldosterone using a random effects model. An assessment of dose-response was also undertaken. A total of 18 studies (n=337) were included in the meta-analysis. There was a statistically significant increase in mean systolic blood pressure (5.45 mm Hg, 95% CI 3.51-7.39) and diastolic blood pressure (3.19 mm Hg, 95% CI 0.10-6.29) after chronic ingestion of a product containing glycyrrhizic acid. Plasma potassium (-0.33 mmol l-1, 95% CI -0.42 to 0.23), plasma renin activity (-0.82 ngml-1 per hour, 95% CI -1.27 to 0.37) and plasma aldosterone (-173.24 pmol l-1, 95% CI -231.65 to -114.83) were all significantly decreased. A significant correlation was noted between daily dose of glycyrrhizic acid and systolic blood pressure (r2=0.55) and diastolic blood pressure (r2=0.65), but not for the other outcome measures. Hence, chronic licorice ingestion is associated with an increase in blood pressure and a drop in plasma potassium, even at modest doses. This is of particular relevance for individuals with existing cardiovascular disease. PMID- 28660885 TI - Factors associated with antihypertensive medication non-adherence: a systematic review. AB - Non-adherence to antihypertensive medication is the most important cause of uncontrolled blood pressure and is influenced by multiple interrelating factors. Understanding the complexity of medication non-adherence and its associated factors is important to determine intervention strategies. Therefore, a systematic review was performed aimed to identify factors associated with antihypertensive medication non-adherence. Different databases were searched for observational studies reporting on factors associated with non-adherence to antihypertensive medication. Titles, abstracts and full texts were reviewed by three researchers. Subsequently, the methodological quality of each study was assessed. Factors that were extracted from the included studies were categorised as factors with consistent or inconsistent evidence to put their potential importance into perspective. Forty-four studies were included. Higher co-payment, side effects and a poor patient-provider relationship were identified as factors with consistent evidence since consistent significant relationships were found for these factors whenever studied. The relationships between non-adherence and multiple other factors were inconsistent among the reviewed studies. However, some of these factors deserve some consideration. Since multiple potentially relevant factors were identified, patient-tailored interventions focussing on identifying and addressing patients' specific barriers to adherence are needed. Further research should clarify the influence of inconsistent factors on adherence and their potential to be addressed in interventions. PMID- 28660886 TI - Gallstone disease associated with increased risk of arterial stiffness in a Taiwanese population. AB - Arterial stiffness has similar risk factors to gallstone disease (GSD). However, there are few studies on the association between arterial stiffness and GSD. The aim of this study was to determine the relationship between arterial stiffness and GSD in a Taiwanese population. We enroled 6211 subjects from a health examination centre after excluding those who received medications for diabetes, hypertension and hyperlipidemia or had a history of cardiovascular disease, cerebrovascular disease, cancer, cholecystectomy or ankle-brachial index of ? 0.9 or?1.3. Increased arterial stiffness was defined as right brachial-ankle pulse wave velocity (baPWV) ?1400 cm s-1. The diagnosis of GSD was based on ultrasonographic findings. The prevalence of increased arterial stiffness was 47.2 and 31.9 % in subjects with and without GSD (P<0.001). A multiple linear regression analysis revealed that GSD, age, systolic blood pressure, fasting plasma glucose and current smoking were positively associated with baPWV, whereas male gender, BMI, habitual exercise and HDL-C were negatively related to baPWV after adjusting for other clinical variables. In conclusion, subjects with GSD are associated with an increased risk of arterial stiffness. PMID- 28660887 TI - Association between hypertensive disorders of pregnancy and the risk of postpartum hypertension: a cohort study in women with gestational diabetes. AB - Previous studies in general people indicated that hypertensive disorders of pregnancy (HDP) increased the risk of subsequent hypertension after delivery. Some studies found that women with gestational diabetes mellitus (GDM) had an increased risk of HDP. However, very few studies have assessed the association between HDP and the risk of postpartum hypertension among GDM women. To evaluate the association between HDP and the risk of postpartum hypertension among GDM women, a retrospective cohort study was conducted in 1261 women with prior GDM at their postpartum 1-5 years using the baseline data from Tianjin Gestational Diabetes Mellitus Prevention Program. Cox regression models were applied to assess the single and joint associations of having a history of HDP, maternal pre pregnancy Body mass index (BMI) (normal weight, overweight and obesity), and weight change from preconception to post-delivery with the risk of subsequent hypertension among the GDM women. We found that GDM women with a history of HDP, high pre-pregnancy BMI and weight gain >7 kg from preconception to post-delivery had an increased risk of postpartum hypertension. Joint effects analysis revealed that the positive association between a history of HDP in the index pregnancy and the risk of postpartum hypertension was consistent in GDM women with different levels of pre-pregnancy BMI or weight gain from preconception to post-delivery. In conclusion, a history of HDP, high pre-pregnancy BMI and weight gain >7 kg from preconception to post-delivery increase the risk of subsequent hypertension in postpartum 1-5 years among GDM women. PMID- 28660888 TI - Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys. AB - The gamma-2 herpesvirus of rhesus monkeys, rhesus monkey rhadinovirus (RRV), persists principally in B cells of its host. We constructed recombinant strains of RRV expressing the rhesus monkey-derived anti-SIV monoclonal antibodies 4L6 and 5L7 and compared the RRV-mediated in vivo delivery of these antibodies in rhesus monkeys with previous studies that utilized intramuscular delivery with an adeno-associated virus (AAV) vector. Recombinant RRV-4L6 and RRV-5L7 were both shown to stably produce the antibodies in persistently infected B-cell lines in culture. Two RRV-negative rhesus monkeys were experimentally infected with recombinant RRV-4L6 and two with recombinant RRV-5L7. Following infection, the appearance of the delivered antibody was readily detected in all four animals. However, the levels of the delivered antibody were considerably lower than what has been typically observed following intramuscular AAV delivery. Furthermore, three of the four monkeys had an antibody response to the delivered antibody as had been observed previously with intramuscular AAV delivery of these same antibodies. We conclude that this recombinant herpesvirus has no inherent advantage over AAV for delivery of potentially therapeutic monoclonal antibodies in a rhesus monkey model. PMID- 28660889 TI - Myosin 7 and its adaptors link cadherins to actin. AB - Cadherin linkages between adjacent stereocilia and microvilli are essential for mechanotransduction and maintaining their organization. They are anchored to actin through interaction of their cytoplasmic domains with related tripartite complexes consisting of a class VII myosin and adaptor proteins: Myo7a/SANS/Harmonin in stereocilia and Myo7b/ANKS4B/Harmonin in microvilli. Here, we determine high-resolution structures of Myo7a and Myo7b C-terminal MyTH4-FERM domain (MF2) and unveil how they recognize harmonin using a novel binding mode. Systematic definition of interactions between domains of the tripartite complex elucidates how the complex assembles and prevents possible self-association of harmonin-a. Several Myo7a deafness mutants that map to the surface of MF2 disrupt harmonin binding, revealing the molecular basis for how they impact the formation of the tripartite complex and disrupt mechanotransduction. Our results also suggest how switching between different harmonin isoforms can regulate the formation of networks with Myo7a motors and coordinate force sensing in stereocilia. PMID- 28660891 TI - Vascular disease: Treatment of ischaemic vascular disease with 3D-printed vessels. PMID- 28660890 TI - Vitamin B12 deficiency. AB - Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12-containing animal derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency. PMID- 28660893 TI - Diabetes: Lower risk of cardiovascular death with canagliflozin. PMID- 28660895 TI - Risk factors: Low educational attainment linked to high CVD risk. PMID- 28660896 TI - Valvular disease: Cadherin 11 in calcific aortic valve disease. PMID- 28660898 TI - Chinese biopharma starts feeding the global pipeline. PMID- 28660900 TI - Cancer immunotherapy: Macrophages steal the show. PMID- 28660892 TI - Reperfusion strategies in acute myocardial infarction and multivessel disease. AB - Approximately 50% of patients with ST-segment elevation myocardial infarction (STEMI) have multivessel disease. The optimal reperfusion strategy in these patients is still uncertain. Whether percutaneous coronary intervention (PCI) of only the culprit vessel or a strategy of complete revascularization, either in a simultaneous or staged multivessel PCI approach, should be performed remains unclear. Although a large number of observational studies have mostly shown worse clinical outcomes associated with a multivessel PCI approach, increasing evidence from randomized controlled trials suggests that multivessel PCI is safe, while reducing the need for revascularization in selected patients, compared with culprit vessel-only PCI. However, adequately-powered studies are still needed to determine the best treatment strategy in patients with STEMI and multivessel disease, particularly to demonstrate a reduction in the hard end point of death or myocardial infarction. In this Review, we provide a comprehensive summary of current evidence on the different treatment options for patients with STEMI and multivessel disease, highlighting current guideline recommendations and providing future directions on reperfusion strategies in these patients. PMID- 28660901 TI - Transporters: Natural product provides alternative transport for iron. PMID- 28660894 TI - Proteostasis in cardiac health and disease. AB - The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing. Failure of protein quality control involves impairment of chaperones, ubiquitin-proteosomal systems, autophagy, and loss of sarcomeric and cytoskeletal proteins, all of which relate to induction of cardiomyocyte senescence. Targeting protein quality control to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease. Currently marketed drugs are available to explore this concept in the clinical setting. PMID- 28660902 TI - Cardiovascular disease: BET inhibitor attenuates heart failure. PMID- 28660904 TI - Yong-Jun liu. PMID- 28660907 TI - Systemic lupus erythematosus: The promise of PROMIS - is it ready for prime time in SLE? PMID- 28660908 TI - Crystal arthritis: Combination therapy effective in tophaceous gout. PMID- 28660909 TI - Spondyloarthropathies: MIF drives inflammation and bone formation in AS. PMID- 28660910 TI - Rheumatoid arthritis: ACPA status influences RA development. PMID- 28660906 TI - Robotic surgical systems in maxillofacial surgery: a review. AB - Throughout the twenty-first century, robotic surgery has been used in multiple oral surgical procedures for the treatment of head and neck tumors and non malignant diseases. With the assistance of robotic surgical systems, maxillofacial surgery is performed with less blood loss, fewer complications, shorter hospitalization and better cosmetic results than standard open surgery. However, the application of robotic surgery techniques to the treatment of head and neck diseases remains in an experimental stage, and the long-lasting effects on surgical morbidity, oncologic control and quality of life are yet to be established. More well-designed studies are needed before this approach can be recommended as a standard treatment paradigm. Nonetheless, robotic surgical systems will inevitably be extended to maxillofacial surgery. This article reviews the current clinical applications of robotic surgery in the head and neck region and highlights the benefits and limitations of current robotic surgical systems. PMID- 28660911 TI - Paediatric rheumatic disease: What is the best definition of clinical remission in JIA? PMID- 28660913 TI - Systemic lupus erythematosus: Tackling complexity through immunophenotyping. PMID- 28660912 TI - Rheumatoid arthritis: Growing role for PADs in pathogenesis. PMID- 28660914 TI - Immunology: Inhibiting autophagy in dendritic cells. PMID- 28660915 TI - Therapy: Rheumatic disease after immune checkpoint inhibitor therapy. PMID- 28660916 TI - Rheumatoid arthritis: The benefits of early treatment after decades. PMID- 28660917 TI - Ligand induced structural isomerism in phosphine coordinated gold clusters revealed by ion mobility mass spectrometry. AB - Structural isomerism in ligated gold clusters is revealed using electrospray ionization ion mobility spectrometry mass spectrometry. Phosphine ligated Au8 clusters are shown to adopt more extended type structures with increasing exchange of methyldiphenylphosphine (MePPh2) for triphenylphosphine (PPh3). These ligand-dependant structure-property relationships are critical to theoretical modeling of clusters as well as their applications in catalysis and photovoltaics. PMID- 28660918 TI - Iodine-131-labeled, transferrin-capped polypyrrole nanoparticles for tumor targeted synergistic photothermal-radioisotope therapy. AB - Combining different therapeutic functions within single tumor-targeted nanoscale delivery systems is promising to overcome the limitations of conventional cancer therapies. Herein, transferrin that recognizes transferrin receptors up-regulated on tumor cells is pre-labeled with iodine-131 (131I) and then utilized as the stabilizer in the fabrication of polypyrrole (PPy) nanoparticles. The obtained transferrin-capped PPy@Tf-131I nanoparticles could be used for tumor-targeted radioisotope therapy (RIT) and photothermal therapy (PTT), by employing beta emission from 131I and the intrinsic high near-infrared (NIR) absorbance of PPy, respectively. Owing to the transferrin-mediated tumor targeting, PPy@Tf-131I nanoparticles exhibit obviously enhanced in vitro cancer cell binding and in vivo tumor uptake compared to its non-targeting counterpart. The combined RIT and PTT based on PPy@Tf-131I nanoparticles is then conducted, achieving a remarkable synergistic therapeutic effect. This work thus demonstrates a rather simple one step approach to fabricate tumor-targeting nanoparticles based on protein-capped conjugated polymers, promising for combination cancer therapy with great efficacy and high safety. PMID- 28660919 TI - Solid matrix transformation and tracer addition using molten ammonium bifluoride salt as a sample preparation method for laser ablation inductively coupled plasma mass spectrometry. AB - Solid sampling and analysis methods, such as laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), are challenged by matrix effects and calibration difficulties. Matrix-matched standards for external calibration are seldom available and it is difficult to distribute spikes evenly into a solid matrix as internal standards. While isotopic ratios of the same element can be measured to high precision, matrix-dependent effects in the sampling and analysis process frustrate accurate quantification and elemental ratio determinations. Here we introduce a potentially general solid matrix transformation approach entailing chemical reactions in molten ammonium bifluoride (ABF) salt that enables the introduction of spikes as tracers or internal standards. Proof of principle experiments show that the decomposition of uranium ore in sealed PFA fluoropolymer vials at 230 degrees C yields, after cooling, new solids suitable for direct solid sampling by LA. When spikes are included in the molten salt reaction, subsequent LA-ICP-MS sampling at several spots indicate that the spikes are evenly distributed, and that U-235 tracer dramatically improves reproducibility in U-238 analysis. Precisions improved from 17% relative standard deviation for U-238 signals to 0.1% for the ratio of sample U-238 to spiked U 235, a factor of over two orders of magnitude. These results introduce the concept of solid matrix transformation (SMT) using ABF, and provide proof of principle for a new method of incorporating internal standards into a solid for LA-ICP-MS. This new approach, SMT-LA-ICP-MS, provides opportunities to improve calibration and quantification in solids based analysis. Looking forward, tracer addition to transformed solids opens up LA-based methods to analytical methodologies such as standard addition, isotope dilution, preparation of matrix matched solid standards, external calibration, and monitoring instrument drift against external calibration standards. PMID- 28660920 TI - Faradaic oxygen evolution from SrTiO3 under nano- and femto-second pulsed light excitation. AB - During photocatalytic water oxidation, n-SrTiO3(100) demonstrated near 100% Faradaic efficiency for O2 evolution with nano- (30 ns) and femto- (150 fs) second pulsed laser excitation of the band gap, despite surface rearrangements attributed to the high peak power (300 MW cm-2). Therefore, these results establish a methodology for tracking intermediates of the water oxidation cycle at the n-SrTiO3(100) surface from the picosecond time scales of charge transfer through to the millisecond time scales of O2 evolution. PMID- 28660921 TI - Polysaccharide-derived mesoporous materials (Starbon(r)) for sustainable separation of complex mixtures. AB - The recovery and separation of high value and low volume extractives are a considerable challenge for the commercial realisation of zero-waste biorefineries. Using solid-phase extractions (SPE) based on sustainable sorbents is a promising method to enable efficient, green and selective separation of these complex extractive mixtures. Mesoporous carbonaceous solids derived from renewable polysaccharides are ideal stationary phases due to their tuneable functionality and surface structure. In this study, the structure-separation relationships of thirteen polysaccharide-derived mesoporous materials and two modified types as sorbents for ten naturally-occurring bioactive phenolic compounds were investigated. For the first time, a comprehensive statistical analysis of the key molecular and surface properties influencing the recovery of these species was carried out. The obtained results show the possibility of developing tailored materials for purification, separation or extraction, depending on the molecular composition of the analyte. The wide versatility and application span of these polysaccharide-derived mesoporous materials offer new sustainable and inexpensive alternatives to traditional silica-based stationary phases. PMID- 28660922 TI - Two-dimensional frameworks formed by pentagonal bipyramidal cobalt(ii) ions and hexacyanometallates: antiferromagnetic ordering, metamagnetism and slow magnetic relaxation. AB - We herein report the syntheses, structures, and magnetic properties of two isostructural two-dimensional (2D) coordination polymers based on a pentagonal bipyramidal CoII unit [Co(TODA)]2+ and two hexacyanometallates, namely [MIII(CN)6]2[CoII(TODA)]3.9H2O (M = Cr (1), Co (2), TODA = 1,4,10-trioxa-7,13 diazacyclopentadecane). Structure analyses show that both complexes have 2D honeycomb structures where the [Co(TODA)]2+ units are bridged by the [MIII(CN)6]3 groups through three cyano groups in the facial positions. Magnetic investigation reveals ferromagnetic coupling between the CrIII and CoII centres through cyanides in 1. Due to the antiferromagnetic interaction between the layers, compound 1 exhibits an antiferromagnetic ordering below 11.4 K, and shows a metamagnetic phase transition under an external dc field. Due to the disorder of the TODA ligands, compound 1 shows a spin glass behavior, which leads to slow magnetic relaxation in 1. A butterfly-shaped hysteresis loop at 1.8 K can be observed with a coercive field of 720 Oe, which is quite large for cyano-bridged Cr-Co molecular magnets. For compound 2 containing the diamagnetic [CoIII(CN)6]3- unit, field-induced slow magnetic relaxation was also verified, which makes compound 2 a rare example of an SIM assembled in a 2D network. An easy-plane magnetic anisotropy with a positive D value (29.9 cm-1 by PHI and 26.5 cm-1 by Anisofit2.0) was deduced for hepta-coordinated CoII centers. These results show the efficiency of the strategy of combining cyanometallates and pentagonal bipyramidal precursors for novel molecular magnetic materials. PMID- 28660923 TI - A magnetoreception system constructed by a dysprosium metallofullerene and nitroxide radical. AB - Endohedral lanthanide metallofullerene molecules exhibit various paramagnetic properties. In this study, we present a magnetoreception probe that can detect the magnetic properties of an endohedral metallofullerene via spin-paramagnet interaction between a nitroxide radical and Dy3N@C80. A cycloaddition reaction on the outer cage of Dy3N@C80 was employed to obtain two regioisomers linked with the nitroxide radical; the resultant adduct exhibits site-dependent signal intensity in the ESR spectra. This Dy3N@C80-nitroxide radical adduct has potential applications as a molecular compass with position-sensitive magnetoreception ability. PMID- 28660924 TI - A study of biocatalysts based on glucose oxidase. AB - During this work, we studied the possibility of glucose oxidase (GOx) covalent immobilization on a modified inorganic support. A series of GOx-based biocatalysts was synthesized by crosslinking the enzyme to a surface of modified silica or alumina. Polyelectrolyte layers were used as modifiers for the silica and alumina surfaces. These layers promote tight binding of the GOx to the support. The biocatalyst's activity and stability were studied using an oxidation reaction of d-glucose to d-gluconic acid. It was found that GOx immobilized on the modified SiO2 using glutardialdehyde as a crosslinking agent was the most active and stable catalytic system, showing an 85% yield of gluconic acid. A study of the synthesized biocatalyst structure using FTIR spectroscopy showed that the enzyme was covalently crosslinked to the surface of an inorganic support modified with chitosan and glutardialdehyde. In the case of SiO2, the quantity of the immobilized enzyme was higher than in the case of Al2O3. PMID- 28660925 TI - Correction: A universal strategy for visual chiral recognition of alpha-amino acids with l-tartaric acid-capped gold nanoparticles as colorimetric probes. AB - Correction for 'A universal strategy for visual chiral recognition of alpha-amino acids with l-tartaric acid-capped gold nanoparticles as colorimetric probes' by Guoxin Song et al., Analyst, 2016, 141, 1257-1265. PMID- 28660926 TI - Manual assembly of a rare-earth polyoxometalate microcrystal film showing highly polarized luminescence. AB - Currently, the realization of rationally designed architectures based on polyoxometalates (POMs) with designed functions has mostly been achieved through the preparation of functional films. However, the traditional approaches suffer from the drawbacks such as time-consuming processes, ill-defined structure and quality, random orientation of the POM molecules, and unsatisfactory performance. In this study, microcrystals of Ag9[EuW10O36].36H2O (denoted as Ag9[EuW10O36]) were synthesized via a titration method by treating Na9[EuW10O36].32H2O (denoted as Na9[EuW10O36]), selected as a prototype, with Ag+, leading to the formation of a water-insoluble crystalline powder with a uniform hexagonal platelet morphology. After this, a simple yet efficient manual assembly method was used to rapidly manufacture Ag9EuW10O36 microcrystal thin films on a glass substrate with high coverage, high crystallinity, and highly preferential orientation. Note that the as-prepared films emit orange polarized fluorescence with an anisotropy value of about 0.21, which places them among the materials of largest anisotropy. It is expected that the manual assembly approach can be generally adopted for the fabrication of many other kinds of polyoxometalate-based materials on various substrates for practical applications. PMID- 28660927 TI - Synthesis and complexation of superbulky imidazolium-2-dithiocarboxylate ligands. AB - The superbulky N-heterocyclic carbenes (NHCs) 2,6-bis(diphenylmethyl)-4 methylimidazol-2-ylidene (IDip*Me) and its 4-methoxy analogue (IDip*OMe) reacted instantaneously with carbon disulfide to afford the corresponding imidazolium-2 dithiocarboxylate zwitterions in high yields. These new dithiolate ligands were fully characterized and their coordination chemistry toward common Re(i) and Ru(ii) metal sources was thoroughly investigated. Neutral [ReBr(CO)3(S2C.NHC)] chelates featured three facially-arranged carbonyl groups on a distorted octahedron, whereas cationic [RuCl(p-cymene)(S2C.NHC)]PF6 complexes displayed a piano-stool geometry. The molecular structures of the six new compounds revealed that the NHC.CS2 inner salts were highly flexible. Indeed, the torsion angle between their anionic and cationic moieties varied between ca. 63 degrees in the free ligands and 3 degrees in the ruthenium complexes. Concomitantly, the S-C-S bite angle underwent a contraction from 131 degrees to 110-113 degrees upon chelation. Computation of the %VBur parameter showed that the dithiocarboxylate unit of the NHC.CS2 betaines chiefly determined the steric requirements of the imidazolium moieties, irrespective of the metal center involved in the complexation. The replacement of the p-methyl substituents of IDip*Me with p methoxy groups in IDip*OMe did not significantly affect the ligand bulkiness. The more electron-donating methoxy group led, however, to small changes in various IR wavenumbers used to probe the electron donor properties of the carbene moiety. PMID- 28660928 TI - Weak interactions and their impact on cellulose dissolution in an alkali/urea aqueous system. AB - Weak interactions, though sometimes easily ignored, play an important role in macromolecule dissolution. In this work, the characterization of weak interactions between urea and cellulose in a LiOH/urea aqueous solution was accomplished and confirmed in situ, for the first time, using PFG-SE NMR, FT-IR and solvatochromic methods, etc. The NMR results indicated the binding of urea with cellulose in the solution, demonstrating the existence of the weak interactions between them. Subsequently, the solvatochromic methods revealed that urea hardly affected the hydrogen bond donor (HBD acidity) and hydrogen bond acceptor (HBA basicity) properties of the solvent, but was related to its dipolarity and polarizability, indicating that dispersion forces existed therein, but not likely hydrogen bonding, which was also supported by the FT-IR. Furthermore, the impact of weak interactions between urea and cellulose was demonstrated to facilitate the dissolving process. The fine dispersion and good stability of cellulose in the solution were maintained by mitigating the effect of the hydrophobic portions from all the dilute, semi-dilute and concentrated regimes, supported by the results of dynamic light scattering (DLS), rheology, NMR, etc. Therefore, the transmittance and mechanical properties of the regenerated cellulose materials prepared from the cellulose solution in the alkali/urea aqueous system were enhanced, compared with those in the alkali only system. This work provided significant and new experimental insights into the non covalent weak interactions between urea and macromolecules from the viewpoints of polymer physics and physical chemistry, which could never be ignored and underestimated. The indispensable weak interactions in the system are also important for the green conversion of natural biomass into new materials via physical processes. PMID- 28660930 TI - A facile one-pot strategy for fabrication of carbon-based microwave absorbers: effects on annealing and paraffin content. AB - In this work, a one-pot strategy was proposed to synthesize carbon-coated Fe3O4 and carbon-coated Fe3C via the pyrolysis of colloidal Fe3O4 nanocrystals capped with oleic acid (OA) at different calcination temperatures. After exploring the microwave absorption performance of these composites, we found that carbon-coated Fe3C obtained at 700 degrees C possesses higher reflection loss (RL) and broader effective bandwidth (RL <= -10 dB) at low thickness. So the further investigation of the microwave absorption performance for carbon-capped Fe3C composites mixed with different mass percentages of paraffin was also carried out. The results demonstrated that the multi-dielectric relaxation process and better impedance matching, especially at low thickness and high frequency, contributed to the preferable microwave absorption greatly. PMID- 28660931 TI - Exciton dynamics in tungsten dichalcogenide monolayers. AB - The strong photoluminescence from monolayer WS2 and WSe2 paves the way for a range of optoelectronic applications and opens up the door for ultrafast carrier dynamics study. In this work, we observed that monolayer WS2 and WSe2 exhibited giant absorption in the visible frequency range. This phenomenon has been ascribed to the band nesting effect. We used time-resolved photoluminescence spectroscopy to study the absorption and recombination dynamics of the photocarriers in monolayer WS2 and WSe2. We found that some of the electron-hole pairs excited in the band nesting region initially relaxed to the K/K' point and then underwent radiative decay. The decay and recombination of the photocarriers occurred rapidly and terminated within the sub-nanosecond timescale. The observed experimental results indicate the great potential of these materials in optoelectronic devices. PMID- 28660932 TI - A chelating bis(aminophenol) ligand bridged by a 1,1'-ferrocene-bis(para phenylene) linker. AB - 1,1'-Bis(4-(2-hydroxy-3,5-di-tert-butylphenyl)aminophenyl)ferrocene (pFlipH4) is prepared in three steps from commercially available 1,1'-ferrocenediboronic acid or its pinacol ester. The suitability of the ligand to bind as a tetradentate ligand in a cis, planar fashion has been confirmed by formation of a square planar palladium bis-iminosemiquinone (pFlip)Pd. The linker unit appears to be structurally similar to 1,1'-ferrocenediyl, but the electronic interaction of the ferrocene with the aminophenols is minimal. PMID- 28660933 TI - On the effect of confined fluid molecular structure on nonequilibrium phase behaviour and friction. AB - A detailed understanding of the behaviour of confined fluids is critical to a range of industrial applications, for example to control friction in engineering components. In this study, a combination of tribological experiments and confined nonequilibrium molecular dynamics simulations has been used to investigate the effect of base fluid molecular structure on nonequilibrium phase behaviour and friction. An extensive parameter study, including several lubricant and traction fluid molecules subjected to pressures (0.5-2.0 GPa) and strain rates (104-1010 s 1) typical of the elastohydrodynamic lubrication regime, reveals clear relationships between the friction and flow behaviour. Lubricants, which are flexible, broadly linear molecules, give low friction coefficients that increase with strain rate and pressure in both the experiments and the simulations. Conversely, traction fluids, which are based on inflexible cycloaliphatic groups, give high friction coefficients that only weakly depend on strain rate and pressure. The observed differences in friction behaviour can be rationalised through the stronger shear localisation which is observed for the traction fluids in the simulations. Higher pressures lead to more pronounced shear localisation, whilst increased strain rates lead to a widening of the sheared region. The methods utilised in this study have clarified the physical mechanisms of important confined fluid behaviour and show significant potential in both improving the prediction of elastohydrodynamic friction and developing new molecules to control it. PMID- 28660934 TI - Introducing the triangular BN nanodot or its cooperation with the edge modification via the electron-donating/withdrawing group to achieve the large first hyperpolarizability in a carbon nanotube system. AB - Based on the ab initio calculations, we first investigated the nonlinear optical (NLO) properties of the doped carbon nanotube (CNT) systems with a triangular BN nanodot with the central B or N atom. Our computed results reveal that introducing the triangular BN nanodot can be considered as a new strategy to effectively enhance the first hyperpolarizability beta0 value of a CNT system, and the type and size of the triangular BN domain have an important effect on the beta0 value of the hybrid CNT system. In addition, the n-type doping by introducing the triangular BN nanodot with more N atoms, viewed as injecting electrons into the CNT system, can more effectively increase the beta0 value of the hybrid CNT system when the doped domains have the same size. Moreover, the beta0 value of the hybrid CNT system can be further enhanced by employing the electron-donating or -withdrawing group (NH2/NO2) to modify the appropriate nanotube-edged site to build the typical donor-pi-acceptor framework, in view of the occurrence of a more effective charge transfer process. Evidently, this type of cooperation of introducing the triangular BN nanodot and forming the donor-pi acceptor framework can be considered as another new strategy to significantly enhance the first hyperpolarizability of the CNT system. These appealing findings can provide valuable insights into the design of novel high-performance NLO materials based on carbon nanotubes. PMID- 28660935 TI - Targeted and efficient activation of channelrhodopsins expressed in living cells via specifically-bound upconversion nanoparticles. AB - Optogenetics is an innovative technology now widely adopted by researchers in different fields of biological sciences. However, most light-sensitive proteins adopted in optogenetics are excited by ultraviolet or visible light which has a weak tissue penetration capability. Upconversion nanoparticles (UCNPs), which absorb near-infrared (NIR) light to emit shorter wavelength light, can help address this issue. In this report, we demonstrated the target selectivity by specifically conjugating the UCNPs with channelrhodopsin-2 (ChR2). We tagged the V5 epitope to the extracellular N-terminal of ChR2 (V5-ChR2m) and functionalized the surface of UCNPs with NeutrAvidin (NAv-UCNPs). After the binding of the biotinylated antibody against V5 onto the V5-ChR2m expressed in the plasma membrane of live HEK293T cells, our results showed that the NAv-UCNPs were specifically bound to the membrane of cells expressing V5-ChR2m. Without the V5 epitope or NAv modification, no binding of UCNPs onto the cell membrane was observed. For the cells expressing V5-ChR2m and bound with NAv-UCNPs, both 488 nm illumination and the upconverted blue emission from UCNPs by 980 nm excitation induced an inward current and elevated the intracellular Ca2+ concentration. Our design reduces the distance between UCNPs and light-sensitive proteins to the molecular level, which not only minimizes the NIR energy required but also provides a way to guide the specific binding for optogenetics applications. PMID- 28660936 TI - The interaction of photoexcited carbon nanodots with metal ions disclosed down to the femtosecond scale. AB - Fluorescent carbon nanodots are a novel family of carbon-based nanoscale materials endowed with an outstanding combination of properties that make them very appealing for applications in nanosensing, photonics, solar energy harvesting and photocatalysis. One of the remarkable properties of carbon dots is their strong sensitivity to the local environment, especially to metal ions in solution. These interactions provide a testing ground for their marked photochemical properties, highlighted by many studies, and frequently driven by charge transfer events. Here we combine several optical techniques, down to femtosecond time resolution, to understand the interplay between carbon nanodots and aqueous metal ions such as Cu2+ and Zn2+. We find that copper inhibits the fluorescence of carbon dots through static and diffusional quenching mechanisms, and our measurements allow discriminating between the two. Ultrafast optical methods are then used to address the dynamics of copper-dot complexes, wherein static quenching takes place, and unveil the underlying complexity of their photocycle. We propose an initial increase of electronic charge on the surface of the dot, upon photo-excitation, followed by a partial electron transfer to the nearby ion, with 0.2 ps and 1.9 ps time constants, and finally a very fast (?1 ps) non-radiative electron-hole recombination which brings the system back to the ground state. Notably, we find that the electron transfer stage is governed by an ultrafast water rearrangement around photo-excited dots, pointing out the key role of solvent interactions in the photo-physics of these systems. PMID- 28660937 TI - A systematic computational study of the structure crossover and coordination number distribution of metallic nanoparticles. AB - In this study, we identified stable configurations for three nanoparticle structure motifs (icosahedral, decahedral and cuboctahedral) of eight transition metals (Cu, Ag, Au, Pd, Ni, Rh, Ir, and Pt) ranging in size from 140 to 3000 atoms. We made simple yet precise analytical approximations of the energy of the stable configurations as a function of nanoparticle size and calculated the structure crossover sizes from these approximations. We then analyzed the surface structure of the nanoparticles in terms of the distribution of the coordination numbers and active sites. We found that low-coordinated atoms are most preferable for cuboctahedral forms and for lighter metals - Cu, Ni and Rh. Compared to other considered metals, gold nanoparticles exhibited unique features as follows: the least amount of low-coordinated atoms, the largest fraction of (111) faces on its surface and a concave reconstruction of five-fold vertices. PMID- 28660938 TI - A Pd-catalyzed, boron ester-mediated, reductive cross-coupling of two aryl halides to synthesize tricyclic biaryls. AB - Tricyclic biaryls are important scaffold structures in many natural products and lead compounds in drug discovery. The formation of a biaryl unit is often the key step for the synthesis of tricyclic biaryls. Despite significant progress toward the synthesis of biaryl compounds in recent years, the direct cross-coupling of two different aryl halides is still challenging and robust methods are lacking. Herein we report a direct cross-coupling of two different aryl halides in the presence of a palladium catalyst and boron ester, which provides a new and useful complementary method to synthesize tricyclic biaryls. PMID- 28660939 TI - Genetic and chemical characterisation of the cornexistin pathway provides further insight into maleidride biosynthesis. AB - The biosynthesis of the herbicide cornexistin in the fungus Paecilomyces variotii was investigated by full sequencing of its genome, knockout of key genes within its biosynthetic gene cluster and isolation and identification of intermediate compounds. The general biosynthetic pathway resembles that of byssochlamic acid and other nonadrides in the early stages, but differs in requiring fewer enzymes in the key nonadride dimerisation step, and in the removal of one maleic anhydride moiety. PMID- 28660940 TI - The effect of l-DOPA hydroxyl groups on the formation of supramolecular hydrogels. AB - Fmoc-l-DOPA-d-Oxd-OH was prepared starting from commercially available l-DOPA. Its gelation ability was tested by comparison with Fmoc-l-Tyr-d-Oxd-OH and Fmoc-l Phe-d-Oxd-OH using ten different triggers. Among them, only GdL, CaCl2 and ZnCl2 form strong hydrogels with the three gelators. The analysis of the aerogels obtained by freeze drying the hydrogels show that the three gelators always induce the formation of dense networks, which strongly depend on the nature of the gelator. Rheological analysis of these samples demonstrates that stronger gels were obtained using the l-Tyr containing gelator, while the l-DOPA containing hydrogels were characterized by a storage modulus approximately one order of magnitude lower. Finally, the l-Phe containing gelators show a different trend with respect to the other samples depending on the trigger used. All the hydrogels show a thixotropic behaviour at the molecular level. These results indicate that hydrogel formation is sensitive to both the number of the hydroxyl moieties on the aromatic rings and trigger used. PMID- 28660941 TI - Application of a 2-aryl indenylphosphine ligand in the Buchwald-Hartwig cross coupling reactions of aryl and heteroaryl chlorides under the solvent-free and aqueous conditions. AB - An efficient solvent-free protocol for the Buchwald-Hartwig cross-coupling reaction of aryl and heteroaryl chlorides with primary and secondary amines using the Pd(dba)2/ligand 1 catalytic system has been developed. Notably, the catalytic system also efficiently catalyzed the reaction under aqueous conditions. PMID- 28660942 TI - Optimization of the Ag/PCBM interface by a rhodamine interlayer to enhance the efficiency and stability of perovskite solar cells. AB - Effective control of the interface between the metal cathode and the electron transport layer (ETL) is critical for achieving high performance p-i-n planar heterojunction perovskite solar cells (PSCs). Several organic molecules have been explored as interlayers between the silver (Ag) electrode and the ETL for the improvement in the photovoltaic conversion efficiency (PCE) of p-i-n planar PSCs. However, the role of these organic molecules in the charge transfer at the metal/ETL interface and the chemical degradation processes of PSCs has not yet been fully understood. In this work, we systematically explore the effects of the interfacial modification of the Ag/ETL interface on PSCs using rhodamine 101 as a model molecule. By the insertion of rhodamine 101 as an interlayer between Ag and fullerene derivatives (PC60BM and PC70BM) ETLs improve the PCE as well as the stability of p-i-n planar PSCs. Atomic force microscopy (AFM) characterization reveals that rhodamine passivates the defects at the PCBM layer and reduces the band bending at the PCBM surface. In consequence, charge transfer from the PCBM towards the Ag electrode is enhanced leading to an increased fill factor (FF) resulting in a PCE up to 16.6%. Moreover, rhodamine acts as a permeation barrier hindering the penetration of moisture towards the perovskite layer as well as preventing the chemical interaction of perovskite with the Ag electrode. Interestingly, the work function of the metal cathode remains more stable due to the rhodamine incorporation. Consequently, a better alignment between the quasi Fermi level of PCBM and the Ag work function is achieved minimizing the energy barrier for charge extraction. This work contributes to reveal the relevance of proper interfacial engineering at the metal-cathode/organic-semiconductor interface. PMID- 28660943 TI - A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways. AB - Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent. PMID- 28660944 TI - Direct versus ligand-exchange synthesis of [PtAg28(BDT)12(TPP)4]4- nanoclusters: effect of a single-atom dopant on the optoelectronic and chemical properties. AB - Heteroatom doping of atomically precise nanoclusters (NCs) often yields a mixture of doped and undoped products of single-atom difference, whose separation is extremely difficult. To overcome this challenge, novel synthesis methods are required to offer monodisperse doped NCs. For instance, the direct synthesis of PtAg28 NCs produces a mixture of [Ag29(BDT)12(TPP)4]3- and [PtAg28(BDT)12(TPP)4]4 NCs (TPP: triphenylphosphine; BDT: 1,3-benzenedithiolate). Here, we designed a ligand-exchange (LE) strategy to synthesize single-sized, Pt-doped, superatomic Ag NCs [PtAg28(BDT)12(TPP)4]4- by LE of [Pt2Ag23Cl7(TPP)10] NCs with BDTH2 (1,3 benzenedithiol). The doped NCs were thoroughly characterized by optical and photoelectron spectroscopy, mass spectrometry, total electron count, and time dependent density functional theory (TDDFT). We show that the Pt dopant occupies the center of the PtAg28 cluster, modulates its electronic structure and enhances its photoluminescence intensity and excited-state lifetime, and also enables solvent interactions with the NC surface. Furthermore, doped NCs showed unique reactivity with metal ions - the central Pt atom of PtAg28 could not be replaced by Au, unlike the central Ag of Ag29 NCs. The achieved synthesis of single-sized PtAg28 clusters will facilitate further applications of the LE strategy for the exploration of novel multimetallic NCs. PMID- 28660946 TI - Janus plasmonic-magnetic gold-iron oxide nanoparticles as contrast agents for multimodal imaging. AB - The design of compact nanoprobes for multimodal bioimaging is a current challenge and may have a major impact on diagnostics and therapeutics. Multicomponent gold iron oxide nanoparticles have shown high potential as contrast agents in numerous imaging techniques due to the complementary features of iron oxide and gold nanomaterials. In this paper we describe novel gold-iron oxide Janus magnetic plasmonic nanoparticles as versatile nanoprobes for multimodal imaging. The nanoparticles are characterized as contrast agents for different imaging techniques, including X-ray computed tomography (CT), T2-weighted nuclear magnetic resonance imaging (MRI), photoacoustic imaging (PA), dark-field and bright-field optical microscopy, transmission electron microscopy (TEM), and surface enhanced Raman spectroscopy (SERS). We discuss the effect of particle size and morphology on their performance as contrast agents and show the advantage of a Janus configuration. Additionally, the uptake of nanoparticles by cells can be simultaneously visualized in dark- and bright-field optical microscopy, SERS mapping, and electron microscopy. These complementary techniques allow a complete view of cell uptake in an artifact-free manner, with multiplexing capabilities, and with extra information regarding the nanoparticles' fate inside the cells. Altogether, the results obtained with these non-invasive techniques show the high versatility of these nanoparticles, the advantages of a Janus configuration, and their high potential in multipurpose biomedical applications. PMID- 28660947 TI - One-pot strategy of copper-catalyzed synthesis of 1,2-disubstituted benzimidazoles. AB - A simple, one-pot and copper-catalyzed coupling reaction for the construction of 1,2-disubstituted benzimidazole derivatives is described. A low-cost copper salt and a weak base K3PO4 were utilized in this reaction. A variety of 1,2 disubstituted benzimidazoles were obtained in moderate to excellent yields. PMID- 28660945 TI - Automated and controlled mechanical stimulation and functional imaging in vivo in C. elegans. AB - C. elegans is a useful genetic model system for investigating mechanisms involved in sensory behavior which are potentially relevant to human diseases. While utilities of advanced techniques such as microfluidics have accelerated some areas of C. elegans sensory biology such as chemosensation, studies of mechanosensation conventionally require immobilization by glue and manual delivery of stimuli, leading to low experimental throughput and high variability. Here we present a microfluidic platform that precisely and robustly delivers a wide range of mechanical stimuli and can also be used in conjunction with functional imaging and optical interrogation techniques. The platform is fully automated, thereby greatly enhancing the throughput and robustness of experiments. We show that the behavior of the well-known gentle and harsh touch neurons and their receptive fields can be recapitulated. Using calcium dynamics as a read-out, we demonstrate its ability to perform a drug screen in vivo. We envision that this system will be able to greatly accelerate the discovery of genes and molecules involved in mechanosensation and multimodal sensory behavior, as well as the discovery of therapeutics for related diseases. PMID- 28660948 TI - The magnetic proximity effect and electrical field tunable valley degeneracy in MoS2/EuS van der Waals heterojunctions. AB - We report the magnetic proximity effect (MPE) and valley non-degeneracy in monolayer MoS2 and magnetic semiconductor EuS thin film heterojunctions studied by density functional theory (DFT) with the vdW-DF2 correlations. Magnetic moments are observed in MoS2 due to the MPE when forming chemical or van der Waals (vdW) adsorption states with EuS. Spin-orbit coupling (SOC) leads to observable valley non-degeneracy of MoS2 at the K (K') points in the Brillouin zone. The valley Zeeman splitting energy Ez can reach 5.1 meV and 37.3 meV for the vdW and chemical adsorption states, corresponding to a magnetic exchange field (MEF) of 22 T and 160 T respectively. By applying a gate voltage across the MoS2/EuS interface, it is found that Ez can be tuned from 1.8 meV to 8.2 meV and from 24.5 meV to 53.8 meV for vdW and chemical adsorption states respectively. The strong MPE, large and tunable valley degeneracy in 2D material and ferromagnetic semiconductor/insulator vdW heterojunctions demonstrate their promising potential for novel optoelectronic and valleytronic device applications. PMID- 28660949 TI - Selenoproteins are involved in antioxidant defense systems in thalassemia. AB - Thalassemia major (TM) is a hereditary blood disease that affects the production of hemoglobin, resulting in severe anemia. Iron overload because of repeated blood transfusion and increased intestinal iron absorption and hemolysis are the major causes of increased oxidative stress in these patients. Growth and maturational delay, cardiomyopathy, endocrinopathies, and osteoporosis are the complications of thalassemia, secondary to anemia and iron overload. The human body has endogenous defense mechanisms to help protect against free radical induced cell damage. Selenoproteins are important enzymes involved in these antioxidant defense mechanisms. In thalassemia patients, selenoproteins are essential because of their potential defense against oxidative damage due to iron overload and hemolysis. The aim of this review is to provide an overview of data regarding selenoproteins including glutathione peroxidase, thioredoxin reductase and iodothyronine deiodinases in TM patients. We also underline some complications of thalassemia that may be associated with selenoproteins. PMID- 28660950 TI - Electron-deficient trifluoromethyl-substituted sub-components affect the properties of M4L4 tetrahedral cages. AB - Two supramolecular tetrahedral cages based on a new electron-deficient trifluoromethyl-substituted pyridylimine ligand are synthesised by sub-component self-assembly. Their structures are characterised by NMR und UV-Vis spectroscopy, high-resolution mass spectrometry and single crystal X-ray diffraction. The iron(ii) complex shows host-guest chemistry, complex-to-complex transformations and novel electronic properties. PMID- 28660952 TI - A novel generation of hybrid photochromic vinylidene-naphthofuran silica nanoparticles through fine-tuning of surface chemistry. AB - Novel photochromic 1-vinylidene-naphtho[2,1-b]furan derivatives (VNF-1 and VNF-2) were successfully anchored onto silica nanoparticles (SiO2 NPs) through direct adsorption (SiO2@VNF-1) and covalent post-grafting (SiO2@VNF-2). SiO2 NPs with different sizes (15 +/- 3 and 123 +/- 7 nm) and surface chemistry (pHpzc in the range of 5-9) were used, offering a wide range of possibilities to fabricate tailor-made photochromic materials. The characterization of VNF-based SiO2 NPs confirmed the efficient VNF immobilization and the integrity of both organic and inorganic components. The photochromic behavior of these new nanoparticles indicates that silica surface acidity and the type of VNF immobilization strategy (adsorption vs. covalent grafting) were crucial factors for the occurrence of photochromism in the VNF-based SiO2 NPs. Upon UV (lambda = 365 nm) or sunlight exposure for 1 min, only the SiO2@VNF-1 nanomaterials prepared by direct VNF adsorption onto SiO2 NPs with pHpzc ~ 6.0 showed direct and reversible photochromic properties, developing fast (in seconds) and intense salmon and violet coloration, with high values of total color difference () and optical densities (DeltaOD = 0.14-0.25). In contrast, all nanomaterials prepared by covalent grafting of VNF-2 onto SiO2 NPs (SiO2@VNF-2) did not exhibit photochromism. In the case of the photochromic SiO2@VNF-1 NPs, the decoloration process followed a bi-exponential decay with fast rate constants (k1 = 1.6 * 10-1 1.6 min-1 and k2 = 9.1 * 10-3-1.3 * 10-1 min-1), which were responsible for the loss of coloration in less than 10 min. Furthermore, they presented very good resistance to fatigue, showing reversibility between the colored/uncolored states without significant loss of their performance for at least 8 successive UV/dark cycles. PMID- 28660953 TI - Coordination behavior of bidentate bis(carbenes) at alkali metal bis(trimethylsilyl)amides. AB - Lithiation of HN(SiMe3)2 in hexane and crystallization in the presence of 2,2,5,5 tetramethyltetrahydrofuran (Me4THF) allows the isolation of crystalline tetrameric [LiN(SiMe3)2]4 (1) with an average Li-N distance of 208.9 pm. Deprotonation of a methylene-bridged bis(imidazolium) diiodide with NaN(SiMe3)2 in tetrahydrofuran (THF) yields 1,1'-diisopropyl-3,3'-methylene-diimidazole-2,2' diylidene (H2C(NHCiPr)2) and layering of this orange reaction mixture with pentane yield [{H2C(NHCiPr)2}{(thf)NaI}2]infinity (2). The reaction of this bis(imidazolium) diiodide with excess of KN(SiMe3)2 in THF leads to the formation of [{H2C(NHCiPr)2}KN(SiMe3)2]2 (3). Due to the fact that 2 and 3 are polymeric in the crystalline state, the bulkier 1,1'-bis(2,6-diisopropylphenyl)-3,3'-methylene diimidazole-2,2'-diylidene (H2C(NHCDipp)2) has been used. Thus, addition of H2C(NHCDipp)2 with the bulky 2,6-diisopropylphenyl (Dipp) groups to AN(SiMe3)2 (A = Li, Na, K) in toluene yields mononuclear [{H2C(NHCDipp)2}LiN(SiMe3)2] (4) and dinuclear [{H2C(NHCDipp)2}AN(SiMe3)2]2 for sodium (5) and potassium (6). The rather short alkali metal-carbon bonds lie in the range of alkylmetal derivatives. PMID- 28660954 TI - Electromagnetic theories of surface-enhanced Raman spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) and related spectroscopies are powered primarily by the concentration of the electromagnetic (EM) fields associated with light in or near appropriately nanostructured electrically-conducting materials, most prominently, but not exclusively high-conductivity metals such as silver and gold. This field concentration takes place on account of the excitation of surface-plasmon (SP) resonances in the nanostructured conductor. Optimizing nanostructures for SERS, therefore, implies optimizing the ability of plasmonic nanostructures to concentrate EM optical fields at locations where molecules of interest reside, and to enhance the radiation efficiency of the oscillating dipoles associated with these molecules and nanostructures. This review summarizes the development of theories over the past four decades pertinent to SERS, especially those contributing to our current understanding of SP-related SERS. Special emphasis is given to the salient strategies and theoretical approaches for optimizing nanostructures with hotspots as efficient EM near-field concentrating and far-field radiating substrates for SERS. A simple model is described in terms of which the upper limit of the SERS enhancement can be estimated. Several experimental strategies that may allow one to approach, or possibly exceed this limit, such as cascading the enhancement of the local and radiated EM field by the multiscale EM coupling of hierarchical structures, and generating hotspots by hybridizing an antenna mode with a plasmonic waveguide cavity mode, which would result in an increased local field enhancement, are discussed. Aiming to significantly broaden the application of SERS to other fields, and especially to material science, we consider hybrid structures of plasmonic nanostructures and other material phases and strategies for producing strong local EM fields at desired locations in such hybrid structures. In this vein, we consider some of the numerical strategies for simulating the optical properties and consequential SERS performance of particle-on-substrate systems that might guide the design of SERS-active systems. Finally, some current theoretical attempts are briefly discussed for unifying EM and non-EM contribution to SERS. PMID- 28660955 TI - Computing distance distributions from dipolar evolution data with overtones: RIDME spectroscopy with Gd(iii)-based spin labels. AB - Extraction of distance distributions between high-spin paramagnetic centers from relaxation induced dipolar modulation enhancement (RIDME) data is affected by the presence of overtones of dipolar frequencies. As previously proposed, we account for these overtones by using a modified kernel function in Tikhonov regularization analysis. This paper analyzes the performance of such an approach on a series of model compounds with the Gd(iii)-PyMTA complex serving as paramagnetic high-spin label. We describe the calibration of the overtone coefficients for the RIDME kernel, demonstrate the accuracy of distance distributions obtained with this approach, and show that for our series of Gd rulers RIDME technique provides more accurate distance distributions than Gd(iii) Gd(iii) double electron-electron resonance (DEER). The analysis of RIDME data including harmonic overtones can be performed using the MATLAB-based program OvertoneAnalysis, which is available as open-source software from the web page of ETH Zurich. This approach opens a perspective for the routine use of the RIDME technique with high-spin labels in structural biology and structural studies of other soft matter. PMID- 28660956 TI - In situ analysis of reaction kinetics of reduction promotion of NiMn2O4 under microwave H-field irradiation. AB - Reaction kinetics during microwave H-field heating and electric furnace heating were investigated to verify the effect of rapid heating and the non-thermal microwave effect. This work is focused on the ferromagnetic material NiMn2O4, and the reduction reaction under rapid heating is investigated using an in situ analysis device. The results showed that the activation energy varied with the heating rate under microwave H-field irradiation, and it was the same as that in an electric furnace when the heating rate was the same. On the other hand, under microwave H-field irradiation, the reduction reaction began from a significantly low temperature compared with that of electric furnace heating. The results suggest that the transition theory during microwave irradiation should be expanded to include the effect of spin waves excited by a microwave H-field on magnetic materials. PMID- 28660957 TI - Inverse electron demand Diels-Alder reactions in chemical biology. AB - The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science. PMID- 28660958 TI - Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis. AB - Chiral ligands play a central role in enantioselective transition-metal catalysis. The success of achiral N-heterocyclic carbenes (NHCs) as stable electron-rich neutral ligands in homogeneous catalysis led to the development of a manifold of chiral NHCs as stereodirecting ancillary ligands for various enantioselective transformations. Due to the modular design of NHCs and the ease of access to their azolium salt precursors, tailor-made NHCs are readily available. Many chiral NHC scaffolds have been synthesised and tested in catalysis. Herein, we highlight only those NHC structures which have enabled high degrees of enantioselectivity in transition-metal catalysis. Following a brief introduction to the field of chiral NHCs, this tutorial review introduces different categories of chiral NHCs and provides a guide to the structural fine tuning of ligand requirements and stereochemical models. PMID- 28660959 TI - Iron catalyzed diastereoselective hydrogenation of chiral imines. AB - Cyclopentadienone-based iron complexes were used for the first time to successfully catalyze the diastereoselective hydrogenation of enantiopure imines. Chiral amines, including valuable biologically active products, were obtained often as enantiomerically pure compounds. Computational studies helped to elucidate the chemical and stereochemical aspects of the iron-catalyzed reaction. PMID- 28660960 TI - Exploring DNA-protein interactions on the single DNA molecule level using nanofluidic tools. AB - DNA-protein interactions are at the core of the cellular machinery and single molecule methods have revolutionized the possibilities to study, and our understanding of these interactions on the molecular level. Nanofluidic channels have been extensively used for studying single DNA molecules during the last twelve years and in this review, we discuss how this experimental platform has been extended to studies of DNA-protein interactions. We first present how the design of the device can be tailored for the specific DNA-protein system studied and how the channels can be passivated to avoid non-specific binding of proteins. We then focus on describing the different kinds of DNA-interacting proteins that have been studied in nanofluidic devices, including proteins that compact DNA and proteins that form filaments on DNA. Our main objective is to highlight the diverse functionalities of DNA-protein systems that have been characterized using nanofluidic structures and hence demonstrate the versatility of these experimental tools. We finally discuss potential future directions studies of DNA protein complexes in nanochannels might take, including specific DNA-protein systems that are difficult to analyze with traditional techniques, devices with increased complexity, and fully integrated lab-on-a-chip devices for analysis of material extracted from (single) cells. PMID- 28660962 TI - Reinforcement of natural rubber latex using lignocellulosic nanofibers isolated from spinifex grass. AB - Reinforcement of natural rubber (NR) using nanofillers often results in an enhancement of the tensile strength, but at the expense of elongation at break and toughness. In this study, with the objective of strengthening NR without compromising its compliance, we investigate the reinforcement efficiency of a series of cellulose nanofibers (CNF) with variations in residual hemicellulose, lignin and therefore surface chemistry. Different types of high aspect ratio CNF isolated from Triodia pungens (T. pungens), an Australian arid grass commonly known as spinifex, were added at 0.1-2 wt% loadings into a pre-vulcanized NR latex. CNF/NR nanocomposites then were benchmarked against NR nanocomposites incorporating a well-known wood-derived CNF. It was found that the presence of residual lignin and hemicellulose, and the pretreatment with a deep eutectic solvent, a mixture of choline chloride and urea (CCU), could increase the compatibility of CNF with the NR matrix, while still enabling stability and handling of the colloidal latex mixture. Incorporation of 0.5 and 0.1 wt% of the sodium hydroxide treated CNF and choline chloride/urea treated CNF into the NR latex showed respectively 11 and 17% enhancement in tensile stress, and importantly without compromising viscoelastic properties; while addition of 0.1 wt% wood-derived CNF resulted in 18% decrease in both tensile stress and strain coupled with more pronounced latex stiffening. PMID- 28660963 TI - Ultra-high sensitivity infra-red detection and temperature effects in a graphene tellurium nanowire binary hybrid. AB - The optoelectronic performance of hybrid devices from graphene and optically sensitive semiconductors exceeds conventional photodetectors due to a large in built optical gain. Tellurium nanowire (TeNW), being a narrow direct band gap semiconductor (~0.65 eV), is as an excellent potential candidate for near infra red (NIR) detection. Here we demonstrate a new graphene-TeNW binary hybrid that exhibits a maximum photoresponsivity of ~106 A W-1 at 175 K in the NIR regime (920 nm-1720 nm), which exceeds the photoresponsivity of the most common NIR photodetectors. The resulting noise-equivalent power (NEP) is as low as 2 * 10-18 W Hz-1/2, and the specific detectivity (D*) exceeds 5 * 1013 cm Hz1/2 W-1 (Jones). The temperature range of optimal operation, which extends up to ~220 K and ~260 K for 1720 nm and 920 nm excitation, respectively, is primarily limited by the electrical conductivity of the TeNW layer, and can further be improved by lowering of the defect density as well as inter-wire electronic coupling. PMID- 28660964 TI - Boron clusters with 46, 48, and 50 atoms: competition among the core-shell, bilayer and quasi-planar structures. AB - Using a genetic algorithm combined with density functional theory calculations, we perform a global search for the lowest-energy structures of Bn clusters with n = 46, 48, 50. Competition among different structural motifs including a hollow cage, core-shell, bilayer, and quasi-planar, is investigated. For B46, a core shell B4@B42 structure resembling the larger Bn clusters with n >= 68 is found to compete with a quasi-planar structure with a central hexagonal hole. A quasi planar configuration with two connected hexagonal holes is most favorable for B50. More interestingly, an unprecedented bilayer structure is unveiled at B48, which can be extended to a two-dimensional bilayer phase exhibiting appreciable stability. Our results suggest alternatives to the cage motif as lower-energy Bn cluster structures with n > 50. PMID- 28660965 TI - Highly efficient dual-modal phosphorescence/computed tomography bioprobes based on an iridium complex and AuNP polyiohexol composite nanoparticles. AB - On the basis of finite-difference time-domain simulations, a novel strategy is developed to prepare highly efficient bis(2-(2'-benzothienyl)pyridinato-N, C3')iridium (BTP) and AuNP polyiohexol composite nanoparticles (BAPI NPs) as dual modal phosphorescence/computed tomography (CT) bioprobes. In these bioprobes, BTP and AuNPs are both encapsulated with polyiohexol NPs. All bioprobe components perform two functions here: AuNPs could be used as both a CT contrast agent and a phosphorescence enhancement reagent of BTP with a metal-enhancement fluorescence effect. The results showed that BAPI NPs were almost spherical in shape, with an average size of 50.36 +/- 3.8 nm and a higher total contrast agent loading ratio of 69.4%. Fourier transform infrared spectra confirmed that AuNPs and BTP are encapsulated in BAPI NPs. It is shown that they have lower toxicity for tissues and cells, their phosphorescence intensities are 8.27-fold that of BTP polyiohexol NPs (BPI NPs), the average phosphorescence intensity of the BAPI NPs was 1.46 times higher than that of BPI NPs and 5.85 times that of BTP alone in vivo. Improved CT imaging is obtained at a low dose of polyiohexol in vivo. These bioprobes not only have highly efficient and excellent dual-modal imaging, but they also save the use of various materials, indicating that these bioprobes are the potential dual-modal probes of the future. PMID- 28660966 TI - Fractional conversion of microalgae from water blooms. AB - Fractional conversion of natural algae cyanobacteria from Taihu Lake was conducted. The raw Taihu Lake algae (TLA) and pretreated samples were pyrolyzed at 290 degrees C and 450 degrees C according to the TGA results. Extraction of lipids or saccharides from the TLA was performed as a pretreatment to obtain lipid extracted algae (LEA) or saccharide extracted algae (SEA). The total yields of bio-oil from fractional pyrolysis were 40.9 wt% from TLA, 42.3 wt% from LEA, and 48.5 wt% from SEA. From TLA, the major components of the bio-oil were fatty acids, amides and hydrocarbons (heptadecane) at 290 degrees C whereas those at 450 degrees C were phenols and C10-C15 hydrocarbons. Following the lipid extraction, acids, amides and indoles accounted for a large proportion at 290 degrees C, while the main products obtained at 450 degrees C were phenols, indoles and pyrroles. It is worth mentioning that the yield of bio-oil from the LEA had increased, and the composition of the bio-oil was simplified. Moreover, the average molecular weight of the bio-oil obtained from LEA had decreased. Interestingly, the extraction of saccharides inhibited pyrolysis of the lipids, so the distribution of the bio-oil from SEA changed only a little. Fractional pyrolysis of pretreated microalgae not only increased the bio-oil yield but also improved the quality of the bio-oil. PMID- 28660967 TI - 2D-3D structural transition in sub-nanometer PtN clusters supported on CeO2(111). AB - Transition metal particles dispersed on oxide supports are used as heterogeneous catalysts in numerous applications. One example is platinum clusters supported on ceria which is used in automotive catalysis. Although control at the nm-scale is desirable to open new technological possibilities, there is limited knowledge both experimentally and theoretically regarding the geometrical structure and stability of sub-nanometer platinum clusters supported on ceria. Here we report a systematic, Density Functional Theory (DFT) study on the growth trends of CeO2(111) supported PtN clusters (N = 1-10). Using a global optimization methodology as a guidance tool to locate putative global minima, our results show a clear preference for 2D planar structures up to size Pt8. It is followed by a structural transition to 3D configurations at larger sizes. This remarkable trend is explained by the subtle competition between the formation of strong Pt-O bonds and the cluster internal Pt-Pt bonds. Our calculations show that the reducibility of CeO2(111) provides a mechanism to anchor PtN clusters where they become oxidized in a two-way charge transfer mechanism: (a) an oxidation process, where Osurface atoms withdraw charge from Pt atoms forming Pt-O bonds, (b) surface Ce4+ atoms are reduced, leading to Ce3+. The active role of the CeO2(111) support in modifying the structural and eventually the chemical properties of sub-nanometer PtN clusters is computationally demonstrated. PMID- 28660968 TI - Application of a strain rate gradient microfluidic device to von Willebrand's disease screening. AB - Von Willebrand's disease (VWD) is the most common inherited bleeding disorder caused by either quantitative or qualitative defects of von Willebrand factor (VWF). Current tests for VWD require relatively large blood volumes, have low throughput, are time-consuming, and do not incorporate the physiologically relevant effects of haemodynamic forces. We developed a microfluidic device incorporating micro-contractions that harnesses well-defined haemodynamic strain gradients to initiate platelet aggregation in citrated whole blood. The microchannel architecture has been specifically designed to allow for continuous real-time imaging of platelet aggregation dynamics. Subjects aged >=18 years with previously diagnosed VWD or who presented for evaluation of a bleeding disorder, where the possible diagnosis included VWD, were tested. Samples were obtained for device characterization as well as for pathology-based testing. Platelet aggregation in the microfluidic device is independent of platelet amplification loops but dependent on low-level platelet activation, GPIb/IX/V and integrin alphaIIbbeta3 engagement. Microfluidic output directly correlates with VWF antigen levels and is able to sensitively detect aggregation defects associated with VWD subtypes. Testing demonstrated a strong correlation with standard clinical laboratory-based tests. Head-to-head comparison with PFA100(r) demonstrated equivalent, if not improved, sensitivity for screening aggregation defects associated with VWD. This strain rate gradient microfluidic prototype has the potential to be a clinically useful, rapid and high throughput-screening tool for VWD as well as other strain-dependent platelet disorders. In addition, the microfluidic device represents a novel approach to examine the effects of high magnitude/short duration (ms) strain rate gradients on platelet function. PMID- 28660970 TI - Effect of methanol in controlling defunctionalization of the propyl side chain of phenolics from catalytic upstream biorefining. AB - In recent years, lignin valorization has gained upward momentum owing to advances in both plant bioengineering and catalytic processing of lignin. In this new horizon, catalysis is now applied to the 'pulping process' itself, creating efficient methods for lignocellulose fractionation or deconstruction (here referred to as Catalytic Upstream Biorefining or 'CUB'). These processes render, together with delignified pulps, lignin streams of low molecular weight (Mw) and low molecular diversity. Recently, we introduced a CUB process based on Early stage Catalytic Conversion of Lignin (ECCL) through H-transfer reactions catalyzed by RANEY(r) Ni. This approach renders a lignin stream obtained as a viscous oil, comprising up to 60 wt% monophenolic compounds (Mw < 250 Da). The remaining oil fraction (40 wt%) is mainly composed of lignin oligomers, and as minor products, holocellulose-derived polyols and lignin-derived species of high Mw (0.25-2 kDa). Simultaneously, the process yields a holocellulose pulp with a low content of residual lignin (<5 wt%). Despite the efficiency of aqueous solutions of 2-propanol as a solvent for lignin fragments and an H-donor, there is scant information regarding the CUB process carried out in the presence of primary alcohols, which often inhibit the catalytic activity of RANEY(r) Ni, as revealed in model compound studies performed at low temperature. Considering the composition of the lignin oils obtained from CUB based on ECCL, the processes commonly render ortho-(di)methoxy-4-propylphenol derivatives with a varied degree of defunctionalization of the propyl side chain. In this contribution, we present the role of the alcohol solvent (methanol or 2-propanol) and Ni catalyst (Ni/C or RANEY(r) Ni) in control over selectivity of phenolic products. The current results indicate that solvent effects on the catalytic processes could hold the key for improving control over the degree of functionalization of the propyl side chain in the lignin oil obtained from CUB, offering new avenues for lignin valorization at the extraction step. PMID- 28660972 TI - Copper-catalyzed radical cascade oxyalkylation of olefinic amides with simple alkanes: highly efficient access to benzoxazines. AB - A copper-catalyzed C(sp3)-H bond functionalization of simple alkanes with olefinic amides was developed for the efficient synthesis of important benzoxazine derivatives. It involves new C-C and C-O bond formation in one step via a radical cascade process. PMID- 28660973 TI - Exfoliation of two-dimensional polymer single crystals into thin sheets and investigations of their surface structure by high-resolution atomic force microscopy. AB - The acid-assisted wet-chemical and the adhesive-tape induced micromechanical exfoliation of differently sized single crystals of a 2D polymer (approx. 20 MUm and 100 MUm) is shown to result in thin sheet stacks. Tuning of the thickness is achieved via duration and frequency of the exfoliation, respectively. A color code is established that correlates interference colors of sheet stacks on SiO2(300 nm)/Si as observed under an optical microscope with their thicknesses measured by atomic force microscopy. This facilitates reliable monitoring of the exfoliation and quick identification of sheet stacks of a desired thickness. Furthermore, high resolution atomic force microscopy is applied to investigate the surfaces of starting crystals and both wet-chemically and micromechanically exfoliated sheet stacks aiming at exploring whether exfoliation proceeds with preservation of surface periodicity and with a low frequency of sheet rupturing. These investigations also aimed at uncovering possible point defects and domain (grain) boundaries in the surfaces. It appears that all investigated objects have a high molecular scale perfection and that both exfoliation methods proceed mild enough to largely preserve the molecular structure of the 2D polymer including the not covalently bonded template molecules being part of the crystal packing. PMID- 28660974 TI - Extending the limits of direct force measurements: colloidal probes from sub micron particles. AB - Direct force measurements by atomic force microscopy (AFM) in combination with the colloidal probe technique are widely used to determine interaction forces in colloidal systems. However, a number of limitations are still preventing a more universal applicability of this technique. Currently, one of the most significant limitations is that only particles with diameters of several micrometers can be used as probe particles. Here, we present a novel approach, based on the combination of nanofluidics and AFM (also referred to as FluidFM-technique), that allows to overcome this size limit and extend the size of suitable probe particles below diameters of 500 nanometers. Moreover, by aspiration of colloidal particles with a hollow AFM-cantilever, the immobilization process is independent of the particle's surface chemistry. Furthermore, the probe particles can be exchanged in situ. The applicability of the FluidFM-technique is demonstrated with silica particles, which are also the types of particles most often used for the preparation of colloidal probes. By comparing 'classical' colloidal probes, i.e. probes from particles irreversibly attached with glue, and various particle sizes aspirated by the FluidFM-technique, we can quantitatively evaluate the instrumental limits. Evaluation of the force profiles demonstrate that even for 500 nm silica particles the diffuse layer properties can be evaluated quantitatively. Therefore, direct force measurements on the level of particle sizes used in industrial formulations will become available in the future. PMID- 28660975 TI - The influence of the explosive decompression in steam-explosion pretreatment on the enzymatic digestibility of different biomasses. AB - For the production of second generation biofuels from lignocellulosic biomass, pretreatment of the biomass feedstock is necessary to overcome its recalcitrance in order to gain fermentable sugars. Due to many reasons, steam-explosion pretreatment is currently the most commonly used pretreatment method for lignocellulosic biomass on a commercial scale [S. Brethauer and M. H. Studer, CHIMIA, 2015, 69, 572-581]. In contrast to others, we showed that the explosive decompression at the end of this pretreatment step can have a positive influence on the enzymatic digestibility of softwood, especially in combination with high enzyme dosages [T. Pielhop, et al., Biotechnology for Biofuels, 2016, 9, 152]. In this study, the influence of the explosive decompression on the enzymatic digestibility of hardwood and herbaceous plants was systematically studied. Beech and corn stover were pretreated under different pretreatment conditions and enzymatically hydrolysed with different enzyme dosages. The maximum enhancement of the digestibility of corn stover was 16.53% after a 2.5 min pretreatment step at 15 barg steam pressure. For beech, a maximum relative enhancement of 58.29% after a 10 min pretreatment step at 15 barg steam pressure could be reached. With this, we show that the explosive decompression can also enhance the enzymatic cellulose digestibility of hardwood and herbaceous plants. PMID- 28660976 TI - Multicomponent diffusion coefficients from microfluidics using Raman microspectroscopy. AB - Diffusion is slow. Thus, diffusion experiments are intrinsically time-consuming and laborious. Additionally, the experimental effort is multiplied for multicomponent systems as the determination of multicomponent diffusion coefficients typically requires several experiments. To reduce the experimental effort, we present the first microfluidic diffusion measurement method for multicomponent liquid systems. The measurement setup combines a microfluidic chip with Raman microspectroscopy. Excellent agreement between experimental results and literature data is achieved for the binary system cyclohexane + toluene and the ternary system 1-propanol + 1-chlorobutane + heptane. The Fick diffusion coefficients are obtained from fitting a multicomponent convection-diffusion model to the mole fractions measured in experiments. Ternary diffusion coefficients can be obtained from a single experiment; high accuracy is already obtained from two experiments. Advantages of the presented measurement method are thus short measurement times, reduced sample consumption, and less experiments for the determination of a multicomponent diffusion coefficient. PMID- 28660977 TI - Synthesis of selectively 4-substituted 9,9'-spirobifluorenes and modulation of their photophysical properties. AB - Synthesis of selectively 4-substituted 9,9'-spirobifluorenes was accomplished by using catalytic [2 + 2 + 2]-cyclotrimerization of specifically substituted diynols with alkynes to the corresponding fluorenols. Further synthetic transformations provided the target molecules. The measurement of the photophysical properties of the prepared 4-substituted 9,9'-spirobifluorenes revealed that their emission maxima depended on the electronic properties of the substituents present in the para position: the presence of an electron accepting group strongly favored the maxima red shift toward the blue VIS region (CF3lambdamax = 361 nm vs. MeO lambdamax = 330 nm). Adding further substituents (aryl or arylethynyl moieties) on the phenyl ring in position 4 did not lead to a dramatic improvement in the emission maxima (CF3C6H4, lambdamax = 369 nm, CF3C6H4C[triple bond, length as m-dash]C, lambdamax = 370 nm), but increased their quantum yields considerably. In addition, a series of 9,9'-spirobifluorenes possessing various extended pi-systems (pyrene, anthracene, etc.) were synthesized. In general, the emission maxima pattern reflected that of the parent pi-systems, but they were red shifted by 10-30 nm. Finally, also a 1-[4-(9,9' spirobifluorene-4-yl)phenyl]-2-aryl-ortho-carborane was prepared. These data thus may provide guidelines for further design of 9,9'-spirobifluorenes with tailored properties. PMID- 28660978 TI - Tailoring the optical properties of atomically-thin WS2via ion irradiation. AB - Two-dimensional transition metal dichalcogenides (TMDCs) exhibit excellent optoelectronic properties. However, the large band gaps in many semiconducting TMDCs make optical absorption in the near-infrared (NIR) wavelength regime impossible, which prevents applications of these materials in optical communications. In this work, we demonstrate that Ar+ ion irradiation is a powerful post-synthesis technique to tailor the optical properties of the semiconducting tungsten disulfide (WS2) by creating S-vacancies and thus controlling material stoichiometry. First-principles calculations reveal that the S-vacancies give rise to deep states in the band gap, which determine the NIR optical absorption of the WS2 monolayer. As the density of the S-vacancies increases, the enhanced NIR linear and saturable absorption of WS2 is observed, which is explained by the results of first-principles calculations. We further demonstrate that by using the irradiated WS2 as a saturable absorber in a waveguide system, the passively Q-switched laser operations can be optimized, thus opening new avenues for tailoring the optical response of TMDCs by defect engineering through ion irradiation. PMID- 28660979 TI - Gel-seq: whole-genome and transcriptome sequencing by simultaneous low-input DNA and RNA library preparation using semi-permeable hydrogel barriers. AB - The advent of next generation sequencing has fundamentally changed genomics research. Unfortunately, standard protocols for sequencing the genome and the transcriptome are incompatible. This forces researchers to choose between examining either the DNA or the RNA for a particular sample. Here we describe a new device and method, collectively dubbed Gel-seq, that enables researchers to simultaneously sequence both DNA and RNA from the same sample. This technology makes it possible to directly examine the ways that changes in the genome impact the transcriptome in as few as 100 cells. The heart of the Gel-seq protocol is the physical separation of DNA from RNA. This separation is achieved electrophoretically using a newly designed device that contains several different polyacrylamide membranes. Here we report on the development and validation of this device. We present both the manufacturing protocol for the device and the biological protocol for preparing genetic libraries. Using cell lines with uniform expression (PC3 and Hela), we show that the libraries generated with Gel seq are similar to those developed using standard methods for either RNA or DNA. Furthermore, we demonstrate the power of Gel-seq by generating a matched genome and transcriptome library from a sample of 100 cells collected from a mouse liver tumor. PMID- 28660981 TI - Use of near infrared spectroscopy for the rapid low-cost analysis of waste papers and cardboards. AB - Analytical data and quantitative near infrared (NIR) spectroscopy models for various lignocellulosic components (including Klason lignin and the constituent sugars glucose, xylose, mannose, arabinose, galactose, and rhamnose), ash, and ethanol-soluble extractives were obtained for 53 samples of paper and cardboard. These samples were mostly the type of materials typically found in domestic wastes (e.g. newspapers, printing paper, glossy papers, food packaging). A number of the samples (48) were obtained by separating a sample, after milling, into two particle size fractions. It was found that the fractions containing the smaller particles typically had higher ash and Klason lignin contents and lower glucose and xylose contents than the larger particle size fractions. Nevertheless, all of the sample types had attractive total sugars contents (>50%), indicating that these could be suitable feedstocks for the production of biofuels and chemicals in hydrolysis-based biorefining technologies. NIR models of a high predictive accuracy (R2 of >0.9 for the independent validation set) were obtained for total sugars, glucose, xylose, Klason lignin, and ash, with values for the Root Mean Square Error of Prediction (RMSEP) of 2.36%, 2.64%, 0.56%, 1.98%, and 4.87%, respectively. Good NIR models (R2 of >0.8) were also obtained for mannose, arabinose, and galactose. These results suggest that NIR spectroscopy is a suitable method for the rapid, low-cost, analysis of the major lignocellulosic components of waste paper/cardboard samples. PMID- 28660980 TI - Presence and formation of fluorescence carbon dots in a grilled hamburger. AB - The presence of nanomaterials during food processing has attracted significant concern due to the physicochemical properties of nanomaterials. In this study, the presence and formation of nitrogen-containing fluorescence carbon dots (C dots) in a grilled hamburger at different temperatures (220, 260, and 300 degrees C) were investigated during the pyrolysis process. The size and morphology of the C-dots were found to be highly dependent on the heating temperatures, which again affected the functional groups on their surface. The C dots are strongly fluorescent with multicolor emission accompanied by a gradual decrease in fluorescence intensity. The fluorescence quantum yield of the C-dots produced at 260 degrees C was measured to be 23.25%. The potential cytotoxicity and biodistribution of the C-dots within live organisms were examined with the mouse osteoblasts cell line and mung bean sprout, respectively. The cell viability after 24 h incubation remained 79% for the C-dots obtained at 300 degrees C at a concentration of 3.2 mg mL-1, and no obvious phytotoxicity in the growing mung bean sprout was observed. The results showed an increased cytotoxicity of the C-dots formed at higher temperatures. PMID- 28660982 TI - Biochemical characteristics and gene expression profiles of two paralogous luciferases from the Japanese firefly Pyrocoelia atripennis (Coleoptera, Lampyridae, Lampyrinae): insight into the evolution of firefly luciferase genes. AB - Two paralogous genes of firefly luciferase, Luc1 and Luc2, have been isolated from the species in two subfamilies, Luciolinae and Photurinae, of the family Lampyridae. The gene expression profiles have previously been examined only in the species of Luciolinae. Here we isolated Luc1 and Luc2 genes from the Japanese firefly Pyrocoelia atripennis. This is the first report of the presence of both Luc1 and Luc2 genes in the species of the subfamily Lampyrinae and of the exon intron structure of Luc2 in the family Lampyridae. The luminescence of both gene products peaked at 547 nm under neutral buffer conditions, and the spectrum of Luc1, but not Luc2, was red-shifted under acidic conditions, as observed for Luc2 in the Luciolinae species. The semi-quantitative reverse transcription-polymerase chain reaction suggested that Luc1 was expressed in lanterns of all the stages except eggs, while Luc2 was expressed in the non-lantern bodies of eggs, prepupae, pupae, and female adults. These expression profiles are consistent with those in the Luciolinae species. Considering the distant phylogenetic relationship between Lampyrinae and Luciolinae in Lampyridae, we propose that fireflies generally possess two different luciferase genes and the biochemical properties and gene expression profiles for each paralog are conserved among lampyrid species. PMID- 28660983 TI - Minimal edge-transitive nets for the design and construction of metal-organic frameworks. AB - Highly-connected and minimal edge-transitive nets (with one or two kinds of edge) can be regarded as ideal blueprints for the rational design and construction of metal-organic frameworks (MOFs). Here we report and affirm the prominence of highly-connected nets as suitable targets in reticular chemistry for the design and synthesis of MOFs. Of special interest are augmented highly-connected binodal edge-transitive nets embedding a unique and precise positioning and connectivity of the net vertex figures, regarded as net-coded building units (net-cBUs). Explicitly, a definite net-cBU encompasses precise geometrical information that codes a selected net uniquely and matchlessly, a compelling perquisite for the rational design of MOFs. Interestingly, the double six-membered ring (d6R) building unit offers great potential to be used as a net-cBU for the deliberate reticulation of the sole two edge-transitive nets with a vertex figure as a d6R, namely the (4,12)-coordinated shp net (square and hexagonal prism) and the (6,12) coordinated alb net (aluminium diboride, hexagonal prism and trigonal prism). We envisioned and proposed various MOF structures based on the derived shp and alb nets. Gaining access to the requisite net-cBUs is essential for the successful practice of reticular chemistry; correspondingly organic and inorganic chemistries were deployed to afford concomitant molecular building blocks (MBBs) with the looked-for shape and connectivity. Practically, the combination of the 12-connected (12-c) rare-earth (RE) polynuclear, points of extension matching the 12 vertices of the hexagonal prism (d6R) with a 4-connected tetracarboxylate ligand or a 6-connected hexacarboxylate ligand afforded the targeted shp-MOF or alb-MOF, respectively. A dodecacarboxylate ligand can be conceived as, and is shown to be, a compatible 12-c MBB, plausibly affording the positioning of the carbon centers of the twelve carboxylate groups on the vertices of the desired hexagonal prism building unit, and combined with the complementary 4-c copper paddlewheel [Cu2(O2C-)4] cluster or 6-c metal trinuclear [M3O(O2C-)6] clusters/zinc tetranulcear [Zn4O(O2C-)6] clusters to credibly afford the construction of new MOF structures with underlying topologies based on derived shp and alb nets. PMID- 28660984 TI - Directed evolution of the periodic table: probing the electronic structure of late actinides. AB - Recent investigations of the coordination chemistry and physical properties of berkelium (Z = 97) and californium (Z = 98) have revealed fundamental differences between post-curium elements and lighter members of the actinide series. This review highlights these developments and chronicles key findings and concepts from the last half-century that have helped usher in a new understanding of the evolution of electronic structure in the periodic table. PMID- 28660985 TI - Evidence of electric field-tunable tunneling probability in graphene and metal contact. AB - The metal-graphene contact resistance has been identified to be a key bottleneck for achieving high performance of graphene transistors. It is crucial to understand the electrical properties of graphene and the carrier transport mechanism under the contact metal. Here, we have developed a new method of characterizing the electrical properties of graphene under the metal contact. It was found that the electrical properties of graphene under the metal can be tuned via the back-gate voltage and display ambipolar behavior. A quantum tunneling model for graphene-metal physical contact has been proposed. The probability of electric field-tunable tunneling has been derived from the results of measurements for the first time. The model predicts that even for physical contact the contact resistance can be much lower than 100 Omega MUm when graphene is more heavily doped and the interfacial layer is eliminated. This study paves the way to achieving ultralow graphene-metal contact resistance in graphene devices for terahertz applications. PMID- 28660986 TI - The "game" of glial fibrillary acidic and S100 proteins in pituitary adenomas: two players or several? AB - INTRODUCTION: S100 protein and GFAP expression in pituitary adenomas tumour cells is not well known; few correlations with other prognostic or therapeutic factors have previously been reported in pituitary adenomas. We aim to elucidate their involvement in the pathogenesis of pituitary adenomas and to establish the correlation of their expression with different growth factors and growth factor receptors known to have a prognostic and/or therapeutic role. MATERIAL AND METHODS: Sixty-one cases of pituitary adenomas were immunohistochemically assessed for the expression of GFAP and S100 protein in both tumour cells and FS cells, in close relationship with hormone profile, and correlated with vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression, previously studied by our team. RESULTS: GFAP and S100 protein were expressed both in tumour cells and FS cells. Differences between morphology, distribution, and density of GFAP+ FS cells and S100+ FS cells were observed according to the hormone profile of pituitary adenomas. GFAP and S100 protein expression in tumour cells was significantly related to hormone profile of pituitary adenomas and also with VEGF and EGFR expression. CONCLUSIONS: GFAP and S100 protein expressions in tumour cells from pituitary adenomas are influenced by hormone profile. Our re-sults support the presence of two molecular subtypes of FS cells GFAP+/VEGF+/S100 respectively and another one that is GFAP /S100+/EGFR+ simultaneously with the classical variant GFAP+/S100+. It is possible that S100+/EGFR+ pituitary adenomas represent a group of pituitary adenomas with an aggressive behaviour and a high ability of invasion and recurrence. PMID- 28660987 TI - Correlations between 10-year risk of death from cardiovascular diseases. AB - INTRODUCTION: Osteoporosis and cardiovascular diseases (CVD) are more common in the elderly population and have similar risk factors. THE GOAL: was an evaluation of the correlation between 10-year risk of death from CVD and 10-year bone fracture risk (FRAX). MATERIAL AND METHODS: A total of 79 patients of the Regional Centre of Menopause and Osteoporosis of the Military Teaching Hospital in Lodz (Poland), aged 50-83 years, consulted for osteoporosis were divided into two groups: study group - with osteoporosis (O; T-score <= -2.5 SD) and control - without osteoporosis (T-sc > -2.5). Bone mineral density was evaluated by densitometric scanning of spine (L2-L4 T-score) and/or femoral neck (Neck T score) and/or total hip (Total Hip T-score). Total cholesterol (TC), fasting glucose, arterial blood pressure, medical history, and family history were obtained. The risk of fatal-CVD was assessed by Euro Heart Score (EHS), and major osteoporotic (MOFR) and hip fracture risk (HFR) by the FRAX scale. RESULTS: 80% of the patients (32/40) with osteoporosis and 51% (20/39) of the patients without osteoporosis revealed a HeartScore >= 5%. There was correlation in the group of all patients between EHS and Neck T-score (p < 0.05; Spearman rank correlation coefficient (Rs) = -0.3806), L2-L4 T-score (p < 0.05; Rs = -0.2891), and Total Hip T-score (p < 0.005; Rs = -0.3561), and in the control group - between EHS and Neck T-score (p < 0.05; Rs = -0.3502). There was a 2.33% difference between the average EHS level to the disadvantage of patients with osteoporosis (p < 0.05). EHS positively correlated with MOFR (p < 0.001) and HFR (p < 0.001) in the whole study popula-tion and with MOFR (p < 0.05) and HFR (p < 0.01) in the group of osteoporotic patients. There were differences between groups in TC (p < 0.001) and BMI (p < 0.001) levels. CONCLUSIONS: The 10-year risk of fatal-CVD correlated with osteoporosis and with the 10-year osteoporotic fracture risk. This conclusion may help identify patients who require extended cardiotherapy protocols. PMID- 28660988 TI - Clinical and immunological changes in patients with active moderate-to-severe Graves' orbitopathy treated with very low-dose rituximab. AB - INTRODUCTION: Glucocorticoids represent the therapy of choice for active and moderate-to-severe Graves' orbitopathy (GO). In some patients, rituximab, a monoclonal antibody against the cluster of differentiation (CD) 20 receptor of B lymphocytes, can serve as a second-line or an alternative treatment. The effect of very low-dose of rituximab on the clinical activity of GO and corresponding clinical or laboratory changes is reported. MATERIAL AND METHODS: Changes of Clinical Activity Score (CAS) for GO, proptosis, levels of thyroid-stimulating hormone receptor antibodies, and depletion of CD19+ and CD20+ B-lymphocytes were determined in ten patients (two men and eight women) with active moderate-to severe GO treated with a single 100-mg dose of rituximab. Correlations between differences of clinical and laboratory parameters were performed. RESULTS: A significant decrease of CAS was found during subsequent examinations compared to the baseline values. A significant depletion of CD19+ and CD20+ B-lymphocytes was detected after rituximab administration. Differences between follow-up and baseline levels of CD20+ positively correlated with differences in CAS after six (p < 0.05) and 12 months (p < 0.01). Differences in CD19+ levels correlated with differences in CAS after 12 months (p < 0.05) of the treatment. Two patients developed dysthyroid optic neuropathy (DON) requiring orbital decompression. No other rituximab side effects were reported during the whole study duration. CONCLUSIONS: A single very low-dose of rituximab appears to be very well tolerated and effective enough to reduce clinical activity in active moderate-to severe GO patients without impending DON. PMID- 28660989 TI - Cinacalcet as symptomatic treatment of hypercalcaemia in primary hyperparathyroidism prior to surgery. AB - INTRIDUCTION: The aim of presented study was to assess the efficacy of cinacalcet in reducing serum calcium concentrations in primary hyperparathyroid (PHPT) patients with hypercalcaemia exceeding 12.5 mg/dL, awaiting parathyroidectomy. MATERIAL AND METHODS: The study included 23 patients with PHPT with hypercalcaemia > 12.5 mg/dL, qualified for surgery. We recorded clinical and biochemical data at baseline, and after every week of treatment. We also monitored adverse events. Cinacalcet was adminis-tered in increasing doses until the corrected serum calcium concentration was 11.3 mg/dL or less, the patient reached the highest possible dosage of 90 mg four times daily, or the patient experienced an adverse event that precluded further dosage increases. RESULTS: The primary end point of reduction in corrected serum calcium concentration to 11.3 mg/dL was achieved in 19 patients (83%), and normocalcaemia (S-Ca < 10.3 mg/dL) was achieved in 55% of patients. The medication was usually well tolerated (83.4%). Most common adverse events were nausea and vomiting, especially at the beginning of therapy; however, only one patient withdrew from the study because of adverse events. CONCLUSION: Cinacalcet rapidly reduced serum calcium in PHPT patients with severe hypercalcaemia and can be useful as a short-term pretreatment prior to surgery, allowing the completion of diagnostics and safe awaiting for operation. PMID- 28660990 TI - [Venopunction of the cubital vein as an alternative approach for CGRP plasma level evaluation in tmd patients]. AB - INTRODUCTION: Calcitonin gene-related peptide is an important vasodilator. It plays an important role in the metabolism of chewing muscles. The aim of the study was to evaluate the plasma level of CGRP in patients with myofascial pain (RDC/TMD Ia) and myofascial pain with limited opening (RDC/TMD Ib) before and after occlusal splint therapy (Michigan splint). MATERIAL AND METHODS: A randomised trial was performed including 39 patients (males = 3, females = 36). Blood samples were taken from the external jugular vein (JUG) and cubital vein (CUB) before and after 30 days of occlusal splint therapy. Plasma levels of CGRP were measured with ELISA KIT for Human Calcitonin Gene Related Peptide (CGRP) 96T (USCNK Business Co. Ltd.). RESULTS: The results of the study show that the plasma CGRP level was higher in the external jugular vein (JUG1 = 5.07pg/mL [SD = 1.99]) than in cubital vein (CUB1 = 4.3 pg/mL [SD = 1.6]). After 30 days of the occlusal splint therapy the levels in both veins increased: JUG2 = 6.07 pg/mL (SD = 2.19), and CUB2 = 4.9 pg/mL (SD = 1.4). The CGRP plasma level increase was statistically significant only in the external jugular vein (JUG) (p < 0.05). Statistically significant pain intensity reduction was observed: VAS1 = 5.4 (SD = 2.08) decreased to VAS2 = 1.7 (SD = 2.07) after splint therapy (p < 0.05). CONCLUSIONS: Venepuncture of an external jugular vein is more precise, than venepuncture of a cubital vein in evaluating CGRP plasma level changes in patients with TMD. PMID- 28660991 TI - Insulin resistance in endocrine disorders - treatment options. AB - Changes in sensitivity to insulin occur in the course of a number of endocrine disorders. Most of the hormones through their antagonistic action to insulin lead to increased hepatic glucose output and its decreased utilisation in peripheral tissues. Carbohydrate disorders observed in endocrine diseases result from the phenomenon of insulin resistance, and in some cases also a reduction in insulin secretion is present. Abnormalities of glucose metabolism are observed in acromegaly, but also in growth hormone deficiency, hypercortisolism in the course of Cushing's syndrome, hyper- or hypothyroidism, primary hyperparathyroidism, aldosteronism, pheochromocytoma, congenital hypertrophy of the adrenal glands, polycystic ovaries syndrome, hypogonadism, or other hormonally active neuroendocrine tumours. They are of a secondary nature in relation to impaired hormonal balance. Hyperglycaemia is therefore often reversible, and the most effective method of treatment of impaired insulin sensitivity is successful therapy of specific endocrinopathies. Insulin sensitisers, also with a good effect, are used. Most experiences to date can be attributed to metformin therapy. Attempts have been made at treatment with other agents that are also effective in reducing insulin resistance as incretins or glitazones. In the presented paper, the authors reviewed endocrine diseases in which there is a clinically significant change in insulin sensitivity. Moreover, methods of therapy of concomitant disturbed glucose metabolism were presented. PMID- 28660992 TI - All that glitters on PET is not cancer! 18F-deoxy-glucose avidity versus tumor biology: pituitary incidentaloma in a survivor of two previous unrelated malignancies. AB - INTRODUCTION: 18F-deoxy-glucose positron emission tomography combined with computed tomography (18F-FDG PET/CT) is routinely used in the detection of malignant disease based on the property of malignant cells to fuel their growth and replication by increased glucose uptake. Malignant lesions are rare in the sellar region, while pituitary adenomas are the most common pathology. These are benign neoplasms with insidious onset and low proliferation activity, and therefore are only exceptionally detected by 18F-FDG PET/CT. Studies that compare the biology of pituitary adenomas and their radiological properties using PET/CT are still lacking. CASE REPORT: We investigate and discuss tumour biology in light of increased 18F-FDG avidity in a symptom-free, 70-year-old male patient, previously treated for two different malignancies (lung and rectal). Increased tracer accumulation in the sellar region was incidentally detected on a follow-up 18F-FDG PET/CT scan. Additional MRI disclosed pituitary adenoma. Normal hormonal status was found, consistent with the diagnosis of non-functioning pituitary adenoma. Analysis of tumour tissue after pituitary surgery confirmed a silent gonadotroph adenoma with low proliferation index. Low expression of oncogene induced senescence markers did not support senescence as the explanation for the tumour's low proliferative activity although it was in consonance with the hormonal activity. CONCLUSIONS: Pituitary adenomas can manifest as hypermetabolic foci on 18F-FDG PET/CT imaging with increased tracer uptake even in indolent, clinically silent pituitary adenomas with low mitotic activity. Special attention should be paid to evaluation of 18F-FDG avid pituitary adenomas in patients with multiple malignancies, bearing in mind that avidity does not always mirror its biological behaviour. PMID- 28660993 TI - Diagnostic pitfalls of adrenal incidentaloma. AB - Adrenal incidentaloma (AI) includes all lesions with diameter >= 1 cm found incidentally during imaging examinations not associated with suspected adrenal pathology. Every adrenal incidentaloma requires a detailed hormonal and imaging assessment. Initial diagnosis includes radiological phenotypical evaluation (particularly in CT, or in case of contraindications - in MRI) and biochemical assessment of tumour hormonal activity (which includes cortisol circadian rhythm, salivary cortisol concentration, 24-hour urinary free-cortisol and metanephrines test, short cortisol and dexamethasone suppression test, ACTH level assessment, aldosterone and ARO concentration, adrenal androgen concentration). Each diagnostic step is associated with limitations and method imperfections. The influence of administered medications, age and concomitant diseases must be taken into account when interpreting test results. It is important to remember abovementioned factors may cause false positive or false negative test results. The following paper is to summarize the etiology of the most common diagnostic mishaps which frequently lead to misdiagnoses, an increase in patient's anxiety and, as a consequence, in the introduction of improper therapy or its discontinuation. The awareness of biochemical and imaging test limitations, and the knowledge of false positive and false negative result sources, allows for the optimisation of the diagnostic process. Simultaneously, the analyzed factors may contribute to a decrease in unnecessary and frequently repeated tests. Additionally, it may imply avoiding the costs of unjustified deep diagnostics. PMID- 28660994 TI - Altered expression of CTLA-4, CD28, VDR, and CD45 mRNA in T cells of patients with Hashimoto's thyroiditis - a pilot study. AB - INTRODUCTION: CD28/T-cell receptor (TCR)/cytotoxic T-lymphocyte antigen 4 (CTLA4) complex controls T-cell tolerance and autoimmunity in Hashimoto's thyroiditis (HT). In addition, CD45 protein tyrosine phosphatase (PTPase) and vitamin D receptor (VDR) cooperatively interact with the TCR complex to affect autoimmune processes central to the pathogenesis of HT. Nevertheless, their role in HT aetiology has been less well established. In this study, we aimed to explore mRNA expression levels of CTLA4, CD28, CD45, and VDR in T-cells, across different outcomes of HT. MATERIAL AND METHODS: The study included 45 HT patients and 13 euthyroid, healthy controls. T-lymphocytes were isolated from peripheral blood mononuclear cells, total mRNA was extracted from T-cells, and gene expression was studied by reverse transcription-polymerase chain reaction (RT-PCR) and ImageQuant method relative to glyceraldehyde-3-phosphate dehydrogenase RT-PCR products. RESULTS: Nominally higher expression levels of VDR, CTLA4, CD28, and CD45RAB mRNA were found in unsorted T-lymphocytes of healthy controls when compared to the HT patients. No difference was observed between hypothyroid/untreated, spontaneously euthyroid and LT4-treated HT patients. VDR mRNA expression was linked to both T3 levels and CTLA4 gene expression, whilst CD45RB mRNA expression coincided with CTLA4 and CD28 transcript levels. Conversely, older age and lower T3 levels were associated with increased abundance of CD45R0 isoform in HT patients. CONCLUSIONS: The results suggest a cross talk between endocrine and immune functions in HT pathology: an altered peripheral T cell mRNA profile with reduced VDR, CTLA4, CD28, and CD45RAB transcript levels is accompanied by age-related shift from naive to memory/late differentiated T cell CD45R mRNA signature and associated with thyroid hormone status in the HT patients. PMID- 28660995 TI - Age at diagnosis and gender modify the risk of 9q22 and 14q13 polymorphisms for papillary thyroid carcinoma. AB - INTRODUCTION: Papillary thyroid cancer (PTC) shows familial occurrence, and some susceptibility single nucleotide polymorphisms (SNPs) have been identified in FOXE1 and near the NKX2-1 locus. The aim of our study was to analyse the association of PTC risk with SNPs in FOXE1 (rs965513, rs1867277, rs1443434) and near the NKX2-1 locus (rs944289) in a Polish population, and, in the second step, the interac-tion between SNPs and patient-related factors (age at diagnosis and gender). MATERIAL AND METHODS: A total of 2243 DNA samples from PTC patients and 1160 controls were included in the study. The SNP analysis was performed with the allelic discrimination technique. RESULTS: There were significant associations of all SNPs with PTC (rs965513 odds ratio [OR] = 1.72, p = 8 * 10-7; rs1867277 OR = 1.59, p = 1 * 10-6; rs1443434 OR = 1.53, p = 1 * 10-5; rs944289 OR = 1.52, p = 4 * 10-5). Logistic regression analysis revealed an increased PTC risk in the interaction of rs944289 with age at diagnosis (OR = 1.01 per year, p = 6 * 10-4) and a decreased PTC risk in the interaction of male gender with the GGT FOXE1 protective haplotype (OR = 0.69, p = 0.01). CONCLUSIONS: the association between PTC and all analysed SNPs was confirmed. It was also shown that patient-related factors modify the predisposition to PTC by increasing the risk for rs944289 per year of age, and by enhancing the protective effect of the FOXE1 GGT haplotype in men. PMID- 28660996 TI - Models of cognitive functions with respect to selected parameters of functional state of the thyroid gland in post-menopausal women. AB - INTRODUCTION: The objective of the study was the development of models of cognitive functions in a group of post-menopausal women, according to the concentration of the selected laboratory parameters evaluating the functional state of the thyroid gland. MATERIAL AND METHODS: The study was conducted during 2012-2014, and covered women aged 50-65 years, minimum two years after the last menstruation, without chronic diseases, cancerous diseases, mental disorders, addiction to drugs or alcohol, and who did not use hormone replacement therapy. At the stage of qualification, a brief MoCA test was performed; 383 women were qualified for the study. Blood was collected for the determination of such parameters as: TSH, TT4, fT4, anti-TPO, anti-Tg, and AB-TSHR. Assessment of cognitive functions was performed using the diagnostic instrument Central Nervous System - Vital Signs (CNS-VS) (Polish version). The results were statistically analysed. RESULTS: The mean age of the women in the study was 56.4 +/- 3.4; the mean TSH was 1.91 +/- 1.35 mU/L, fT4 14.76 +/- 2.34 pmol/L, and TT4 99.12 +/- 16.98 nmol/L. Mean values were: 64.74 IU/L for anti-TPO, 100.69 IU/L for anti-Tg, and 1.40 IU/L for AB-TSHR. The examined women obtained the neurocognitive index (NCI) on the level of 84.4 scores, on average. The lowest results were obtained in tests assessing cognitive flexibility (mean 78.64 scores), processing speed (mean 79.25 scores), and executive functions (mean 79.75 scores). In the tests evaluating complex attention, the mean values were 82.24 scores, psychomotor speed - mean 83.42 scores, and reaction time - mean 86.87 scores. The women examined obtained the best results in tests assessing memory (mean 90.15 scores), including verbal (mean 91.22 scores), and visual (mean 93.37 scores). The NCI and cognitive function models were assessed from the aspect of thyroid gland examinations in post-menopausal women. Based on the analyses performed, the following conclusions were drawn: The developed models of cognitive functions indicate a considerable effect of TSH, fT4, AB-TSHR, and anti-TPO, as well as TT4 and anti-Tg, on the level of cognitive functions after menopause in the group examined. The conducted study suggests the need for examination of the functional state of the thyroid gland in post-menopausal women who show cognitive function disorders. PMID- 28660997 TI - Optical coherence tomography reveals the mechanisms of balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension. PMID- 28660998 TI - Subacute thrombosis of left main coronary artery after transcatheter aortic valve replacement. PMID- 28660999 TI - Audible alert protected patient from inappropriate cardiac-defibrillator shocks. PMID- 28661000 TI - Three-dimensional optical coherence tomography with the current version (E.4 [Build 10457]) of Metallic Stent Optimization Software is a mirror image. PMID- 28661001 TI - Thyroid storm: A rare and life-threatening cause of acute neurological manifestations during urgent percutaneous coronary intervention for acute coronary syndrome. PMID- 28661002 TI - An epidemiological study of cataracts in wild and farmed lumpfish (Cyclopterus lumpus L.) and the relation to nutrition. AB - Twelve groups of farmed lumpfish and one of wild lumpfish were screened for cataract and sampled for fish muscle tissue, whole heart and both eye lenses to investigate possible relations between cataract and tissue free amino acid concentrations. Cataract prevalence ranged from 20% to 100%, with the highest average score of 7.3 (max 8) and incidences of severe cataract (>5) in all groups. Cataract could not be explained by suboptimal histidine concentrations in the feed. Neither muscle nor cardiac tissues had concentrations of free histidine compounds. The lumpfish lens contained N-acetylhistidine (NAH), of which low concentrations were strongly related to cataract severity. However, no correlation between lens NAH and cataract severity was found in the present sample set. Wild lumpfish had higher levels compared to farmed lumpfish, suggesting that the farmed lumpfish may have been deficient in histidine or have a higher utilization of NAH due to osmotic problems. Thus, cataract in farmed lumpfish may be related to primary or secondary disturbed nutrient metabolism or malnutrition, shown by the high levels of specific amino acids in different tissues, which may cause osmotic imbalance and cataract development. This nutritional or environmental-related welfare problem deserves further research. PMID- 28661003 TI - No detection of Merkel cell polyomavirus in oral lichen planus: Results of a preliminary study in a French cohort of patients. AB - Oral lichen planus (OLP) is a chronic inflammatory disease considered as a CD8+ T lymphocyte-mediated autoimmune reaction, which may be triggered by undetermined virus. Recent reports have described the detection of Merkel cell polyomavirus (MCPyV) DNA in oral samples from healthy patients and in patients with different forms of oral cancers. We therefore investigated in a prospective way whether MCPyV was detectable in oral lesions of patients with active OLP. Our preliminary results do not support the hypothesis that OLP may be triggered by MCPyV infection. Further studies are needed to evaluate the involvement of other human polyomaviruses in OLP pathogenesis. PMID- 28661004 TI - Revisiting Young Children's Understanding of the Psychological Causes of Behavior. AB - In 1989, Miller and Aloise challenged the prevailing belief that preschoolers tend to explain others' behavior in terms of external events or a person's physical attributes and have little understanding of psychological causes. That review documented preschoolers' understanding of, and even preference for, psychological causes as part of an emerging renaissance in developmental social cognitive research. The present, updated review (97 articles, participant ages 3 months to 6 years) suggests the emergence of a transformative new perspective in which social-cognition is balanced between social and cognitive aspects rather than tilted toward cognition. Recent research on infants' awareness of mental states, young children's understanding of social categories and their judgments of the trustworthiness of informants, and cultural context reveals various ways in which preschoolers' social-causal reasoning is social. PMID- 28661006 TI - Using demographic characteristics of populations to detect spatial fragmentation following suspected ebola outbreaks in great apes. AB - OBJECTIVES: Demographic crashes due to emerging diseases can contribute to population fragmentation and increase extinction risk of small populations. Ebola outbreaks in 2002-2004 are suspected to have caused a decline of more than 80% in some Western lowland gorilla (Gorilla gorilla gorilla) populations. We investigated whether demographic indicators of this event allowed for the detection of spatial fragmentation in gorilla populations. MATERIALS AND METHODS: We collected demographic data from two neighbouring populations: the Lokoue population, suspected to have been affected by an Ebola outbreak (followed from 2001 to 2014), and the Romani population, of unknown demographic status before Ebola outbreaks (followed from 2005 to 2014). RESULTS: Ten years after the outbreak, the Lokoue population is slowly recovering and the short-term demographic indicators of a population crash were no longer detectable. The Lokoue population has not experienced any additional demographic perturbation over the past decade. The Romani population did not show any of the demographic indicators of a population crash over the past decade. Its demographic structure remained similar to that of unaffected populations. DISCUSSION: Our results highlighted that the Ebola disease could contribute to fragmentation of gorilla populations due to the spatially heterogeneous impact of its outbreaks. The demographic structure of populations (i.e., age-sex and group structure) can be useful indicators of a possible occurrence of recent Ebola outbreaks in populations without known history, and may be more broadly used in other emerging disease/species systems. Longitudinal data are critical to our understanding of the impact of emerging diseases on wild populations and their conservation. PMID- 28661005 TI - Endogenous bioelectric currents promote differentiation of the mammalian lens. AB - The functional roles of bioelectrical signals (ES) created by the flow of specific ions at the mammalian lens equator are poorly understood. We detected that mature, denucleated lens fibers expressed high levels of the alpha1 and beta1 subunits of Na+ /K+ -ATPase (ATP1A1 and ATP1B1 of the sodium pump) and had a hyperpolarized membrane potential difference (Vmem ). In contrast, differentiating, nucleated lens fiber cells had little ATP1A1 and ATP1B1 and a depolarized Vmem . Mimicking the natural equatorial ES with an applied electrical field (EF) induced a striking reorientation of lens epithelial cells to lie perpendicular to the direction of the EF. An EF also promoted the expression of beta-crystallin, aquaporin-0 (AQP0) and the Beaded Filament Structural Protein 2 (BFSP2) in lens epithelial cells (LECs), all of which are hallmarks of differentiation. In addition, applied EF activated the AKT and CDC2 and inhibition of AKT reduced the activation of CDC2. Our results indicate that the endogenous bioelectrical signal at the lens equator promotes differentiation of LECs into denucleated lens fiber cells via depolarization of Vmem. Development of methods and devices of EF application or amplification in vivo may supply a novel treatment for lens diseases and even promote regeneration of a complete new lens following cataract surgery. PMID- 28661007 TI - Serum thyroxine and thyroid-stimulating hormone concentration in hyperthyroid cats that develop azotaemia after radioiodine therapy. AB - OBJECTIVES: The objectives of this study were to determine which serum thyroid hormone test best identifies iatrogenic hypothyroidism in cats that develop azotaemia after radioiodine treatment and to determine which thyroid test best differentiates these azotaemic, hypothyroid cats from azotaemic, radioiodine treated euthyroid cats, as well as from azotaemic cats with chronic kidney disease and no history of thyroid disease. MATERIALS AND METHODS: A total of 42 hyperthyroid cats that developed azotaemia (serum creatinine e220 umol/L) after radioiodine treatment had serum concentrations of thyroxine and free thyroxine by dialysis and thyroid--stimulating hormone measured at 3, 6 and 12 months. Iatrogenic hypothyroidism was confirmed (n=28) or excluded (n=14) on the basis of thyroid scintigraphy. A total of 14 cats with chronic kidney disease and 166 clinically normal cats underwent similar serum thyroid testing and scintigraphy. RESULTS: Concentrations of thyroxine and free thyroxine were lower and thyroid stimulating hormone higher in hypothyroid cats than in all three groups of euthyroid cats (P<0.0001). Of the hypothyroid cats, thyroxine and free thyroxine concentrations were low in 15 (53.6%) and seven (25%), respectively. Low serum thyroxine and free thyroxine concentrations were also detected in seven (50%) and two (14.3%) of the cats with chronic kidney disease. Thyroid-stimulating hormone concentrations were elevated in all hypothyroid cats but remained within the reference interval in all three groups of euthyroid cats. Serum thyroid- stimulating hormone had a higher test sensitivity and specificity than either thyroxine or free thyroxine concentration. CLINICAL SIGNIFICANCE: The finding of high serum thyroid-stimulating hormone concentrations best identifies feline iatrogenic hypothyroidism and differentiates it from non-thyroidal illness syndrome in cats that develop azotaemia after treatment. PMID- 28661008 TI - Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. AB - BACKGROUND: Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. OBJECTIVES: To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). SEARCH METHODS: We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. SELECTION CRITERIA: We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events. MAIN RESULTS: IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders. AUTHORS' CONCLUSIONS: Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity. PMID- 28661010 TI - Cationic Chains of Parent Arsanylboranes and Substituted Phosphanylboranes. AB - The substituted monomeric phosphanylboranes Ph2 P-BH2 ?NMe3 (1) and tBuHP-BH2 ?NMe3 (2) have been used for the synthesis of cationic chain compounds built up by R2 P-BH2 units. With a simple synthesis route, the highly stable cations [Me3 N?H2 B-PR1 R2 -BH2 ?NMe3 ]+ (1 a, 2 a) and [Me3 N?H2 B-PR1 R2 -BH2 -PR1 R2 -BH2 ?NMe3 ]+ (1 b, 2 b) (R1 =R2 =Ph; R1 =H, R2 =tBu) are obtained as iodide (I- ) salts. The reaction of H2 As-BH2 ?NMe3 (3) with IBH2 ?SMe2 leads to [Me3 N?H2 B AsH2 -BH2 -AsH2 -BH2 ?NMe3 ][I] (3 a), the longest so far known arsanylborane chain. Compound 3 a reacts with acetonitrile through a formal hydroarsination reaction to form [cyclo-{As(BH2 ?NMe3 )(CMe=NH)2 (BH2 )}][I] (4). The reported synthetic strategy has proved to be a powerful tool for the formation of small, cationic oligomeric units. All products were comprehensively characterized by X ray structure analysis, NMR, IR spectroscopy, and mass spectrometry in cooperation with DFT calculations. PMID- 28661009 TI - The Effect of Geographic Location on Circannual Adrenocorticotropic Hormone Plasma Concentrations in Horses in Australia. AB - BACKGROUND: Longitudinal evaluation of plasma endogenous ACTH concentration in clinically normal horses has not been investigated in the Southern Hemisphere. OBJECTIVES: To longitudinally determine monthly upper reference limits for plasma ACTH in 2 disparate Australian geographic locations and to examine whether location affected the circannual rhythm of endogenous ACTH in the 2 groups of horses over a 12-month period. ANIMALS: Clinically normal horses <20 years of age from 4 properties (institutional herd and client owned animals) in Perth (n = 40) and Townsville (n = 41) were included in the study. METHODS: A prospective longitudinal descriptive study to determine the upper reference limit and confidence intervals for plasma ACTH in each geographic location using the ASVCP reference interval (RI) guidelines, for individual months and monthly groupings for 12 consecutive months. RESULTS: Plasma endogenous ACTH concentrations demonstrated a circannual rhythm. The increase in endogenous ACTH was not confined to the autumnal months but was associated with changes in photoperiod. During the quiescent period, plasma ACTH concentrations were lower, <=43 pg/mL (upper limit of the 90% confidence interval (CI)) in horses from Perth and <=67 pg/mL (upper limit of the 90% CI) in horses from Townsville, than at the acrophase, <=94 pg/mL (upper limit of the 90% CI) in horses from Perth, <=101 pg/mL (upper limit of the 90% CI) in horses from Townsville. CONCLUSIONS AND CLINICAL IMPORTANCE: Circannual rhythms of endogenous ACTH concentrations vary between geographic locations, this could be due to changes in photoperiod or other unknown factors, and upper reference limits should be determined for specific locations. PMID- 28661011 TI - Visual methods in health dialogues: A qualitative study of public health nurse practice in schools. AB - AIMS: We aimed to explore how using visual methods might improve or complicate the dynamics of the health dialogue between public health nurses (PHNs) and school pupils. This was done from the perspective of PHNs, specifically examining how they understood their role and practice as a PHN and the application of visual methods in this practice. BACKGROUND: The health dialogue is a method used by PHNs in school nursing in Norway. In this practice, there can be communicative barriers between pupils and PHNs. Investigating how PHNs understand their professional practice can lead to ways of addressing these communicative barriers, which can affect pupil satisfaction and achievement of health-related behaviours in the school context. Specifically, the use of visual methods by PHNs may address these communicative barriers. DESIGN: The research design was qualitative, using focus groups combined with visual methods. METHODS: We conducted focus group interviews using a semi-structured discussion guide and visual methods with five groups of PHNs (n = 31) working in northern Norwegian school health services. The data were collected during January and February 2016. Discussions were audio recorded, transcribed and coded into themes and sub-themes using systematic text condensation and drawings were analysed using interpretive engagement, a method of visual analysis. FINDINGS: Drawings and focus group discussions showed that PHNs perceived their professional practice as primarily a relational praxis. The PHNs used a variety of visual methods as part of the health dialogue with school pupils. This active use of visualization worked to build and strengthen relations when words were inadequate and served to enhance the flexible and relational practice employed by the PHNs. CONCLUSIONS: PHNs used different kinds of visualization methods to establish relations with school pupils, especially when verbalization by the pupils was difficult. PHNs were aware of both the benefits and challenges of using visualization with school pupils in health education. We recommend the use of visual methods in schools because they are useful for PHNs, other health professionals and teachers working with children and young people in developing relations, particularly where verbal communication may be a challenge. PMID- 28661012 TI - Mixed-Stack Charge Transfer Crystals of Pillar[5]quinone and Tetrathiafulvalene Exhibiting Ferroelectric Features. AB - Ferroelectric materials find extensive applications in the fabrication of compact memory devices and ultra-sensitive multifunctional detectors. Face-to-face alternate stacking of electron donors and acceptors effectuate long-range unidirectional ordering of charge-transfer (CT) dipoles, promising tunable ferroelectricity. Herein we report a new TTF-quinone system-an emerald green CT complex consisting pillar[5]quinone (P5Q) and tetrathiafulvalene (TTF). The CT crystals, as determined by single crystal synchrotron X-ray diffraction, adopt a 1:1 mixed-stack arrangement of donor and acceptor with alternating dimers of TTF and 1,4-dioxane encapsulated P5Q. The TTF-P5Q.dioxane crystal possesses a macroscopic polarization axis giving rise to ferroelectricity at room temperature. The CT complex manifests ferroelectric features such as optical polarization rotation, temperature-dependent phase transition and piezoelectric response in single crystals. Ferroelectric behavior observed in P5Q-based CT complex widens the scope for further work on this structurally intriguing and readily accessible cyclic pentaquinone. PMID- 28661013 TI - Pain associated with pressure injury: A qualitative study of community-based, home-dwelling individuals. AB - AIMS: The aim of this study was to provide deep insights into the pain associated with pressure injuries in home-dwelling individuals using narrative accounts. BACKGROUND: Pressure injuries or pressure ulcers are burdensome and costly. Prevalence data, surveys and systematic reviews demonstrate that pain associated with pressure injury is widespread, but voices of home-dwelling patients have remained largely unheard. DESIGN: Concurrent mixed methods case study of a UK community of approximately 50,000 adults. METHODS: Qualitative interviews, conducted in 2016, of 12 home-dwelling adult participants with a current pressure injury (n = 10), or a recently healed pressure injury (n = 2). FINDINGS: Pain had an adverse impact on activities of daily living, mobility and sleep. Participants described days that were clouded in pain; a pain they felt was poorly understood and often out of control. Thematic content analysis revealed two major themes; these are: Poorly controlled pain: "I just want the pain to go away"; and, Uncertainty for the future: "it almost seems insurmountable." CONCLUSION: Findings of our study support the need to develop an appropriate assessment tool for pressure injury patients in the community to enable healthcare professionals and patients to recognize and manage pressure injury-related pain effectively. PMID- 28661014 TI - Aromatic Thioethers as Novel Luminophores with Aggregation-Induced Fluorescence and Phosphorescence. AB - Here we report on a novel system based on aromatic thioethers with unique luminescence properties. Fifteen different compounds were investigated in detail on their luminescence properties using UV/Vis absorption and steady-state and time-resolved luminescence spectroscopy. Excited state lifetimes as well as quantum yields were determined, and the toxicity towards HeLa cells was investigated. Besides X-ray analyses also quantum chemical calculations were performed to gain deeper insights in the unique behavior of this facile system. The studied compounds reveal remarkable fluorescence emission ranging from 437 to 588 nm as well as phosphorescence (up to 5 MUs). PMID- 28661016 TI - Gender studies and the hoax paper: Could it happen in nursing? PMID- 28661015 TI - From intention to STI prevention: An online questionnaire on barriers and facilitators for discussing sexual risk behaviour among HIV nurses. AB - AIMS: We aimed to elucidate facilitators and barriers that HIV nurses experience in discussing sexual risk behaviour with HIV-positive men who have sex with men, using variables from a previous qualitative study and the theory of planned behaviour. BACKGROUND: HIV-positive men who have sex with men are frequently diagnosed with sexually transmitted infections, which can be reduced if HIV nurses discuss sexual risk behaviour. DESIGN: An online questionnaire was disseminated in April 2015 among all HIV nurses in the Netherlands. METHODS: We assessed variables, such as attitudes, shame, ability, knowledge and time concerns. A regression analysis was conducted with "intention to discuss sexual risk behaviour" as an outcome variable. RESULTS: The questionnaire was completed by 60 of 79 HIV nurses. Overall, participants reported high intentions to discuss sexual risk behaviour, and 38% of the variance was explained by attitude, sexual preference, knowing ways to introduce the topic and experiencing enough time or viewing it as a priority. In addition, high intenders significantly differed from low intenders in "experienced shame," "relation with patients," "non-verbal communication," "subjective norm" and "knowledge." CONCLUSION: Improving sexual health in HIV care translates into improving opportunities and the facilitating factors in initiating the discussion of sexual risk behaviour rather than removing barriers HIV nurses experience. Interventions should mainly focus on improving the HIV nurses' perceived ability to initiate the topic of sexual risk behaviour and to utilize the jargon and terminology that is commonly used among men who have sex with men. PMID- 28661017 TI - N-Type Superconductivity in an Organic Mott Insulator Induced by Light-Driven Electron-Doping. AB - The presence of interface dipoles in self-assembled monolayers (SAMs) gives rise to electric-field effects at the device interfaces. SAMs of spiropyran derivatives can be used as photoactive interface dipole layer in field-effect transistors because the photochromism of spiropyrans involves a large dipole moment switching. Recently, light-induced p-type superconductivity in an organic Mott insulator, kappa-(BEDT-TTF)2 Cu[N(CN)2 ]Br (kappa-Br: BEDT-TTF = bis(ethylenedithio)tetrathiafulvalene) has been realized, thanks to the hole carriers induced by significant interface dipole variation in the spiropyran-SAM. This report explores the converse situation by designing a new type of spiropyran monolayer in which light-induced electron-doping into kappa-Br and accompanying n type superconducting transition have been observed. These results open new possibilities for novel electronics utilizing a photoactive SAMs, which can design not only the magnitude but also the direction of photoinduced electric fields at the device interfaces. PMID- 28661018 TI - Clinical characterization of dystonia in adult patients with Huntington's disease. AB - BACKGROUND AND PURPOSE: Huntington's disease (HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterized by chorea. Dystonia is also recognized as part of the HD motor phenotype, although little work detailing its prevalence, distribution, severity and impact on functional capacity has been published to date. METHODS: Patients (>18 years of age) were recruited from the Cardiff (UK) HD clinic, each undergoing a standardized videotaped clinical examination and series of functional assessment questionnaires (Unified Huntington's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale and modified version of the Toronto Western Spasmodic Torticollis Rating Scale). The presence and severity of dystonia were scored by four independent neurologists using the Burke-Fahn-Marsden Dystonia Rating Scale and Unified Huntington's Disease Rating Scale. Statistical analysis included Fisher's exact test, Wilcoxon test, anova and calculation of correlation coefficients where appropriate. RESULTS: Forty-eight patients [91% (48/53)] demonstrated evidence of dystonia, with the highest prevalence in the left upper limb (n = 44, 83%), right upper limb most severely affected and eyes least affected. Statistically significant positive correlations (P < 0.05) were observed between dystonia severity and increasing HD disease stage and motor disease duration. Deterioration in functional capacity also correlated with increasing dystonia severity. No significant relationship was observed with age at motor symptom onset or CAG repeat length. CONCLUSIONS: We report a high prevalence of dystonia in adult patients with HD, with worsening dystonia severity with increasing HD disease stage and motor disease duration. The recognition and management of dystonic symptoms in routine clinical practice will aid overall symptomatic treatment and functional improvement. PMID- 28661020 TI - Enantioselective Organocatalytic Intramolecular Aza-Diels-Alder Reaction. AB - A highly efficient catalytic enantioselective intramolecular Povarov reaction was developed with primary anilines as 2-azadiene precursors. A wide variety of angularly fused azacycles were obtained without column chromatography in high to excellent yields and with excellent diastereo- and enantioselectivity (d.r.>99:1 and up to e.r. 99:1). Furthermore, the catalyst loading could be lowered to 1 mol %, and the obtained azacycles could be used as key intermediates for further transformations to generate additional molecular diversity. PMID- 28661019 TI - Prevalence of Methicillin-Resistant Staphylococcus aureus from Equine Nasopharyngeal and Guttural Pouch Wash Samples. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is recognized as a cause of nosocomial infections in both human and veterinary medicine. Studies that examine the nasopharynx and guttural pouches of the horse as carriage sites for MRSA have not been reported. HYPOTHESIS/OBJECTIVE: MRSA colonizes the nasopharynx and guttural pouch of horses. To determine the prevalence of MRSA in equine nasopharyngeal wash (NPW) and guttural pouch lavage (GPL) samples in a field population of horses. SAMPLES: One hundred seventy-eight samples (123 NPW and 55 GPL) from 108 horses. METHODS: Prospective study. Samples were collected from a convenience population of clinically ill horses with suspected Streptococcus equi subsp. equi (S. equi) infection, horses convalescing from a known S. equi infection, and asymptomatic horses undergoing S. equi screening. Samples were submitted for S. aureus aerobic bacterial culture with mannitol salt broth and two selective agars (cefoxitin CHROMagar as the PBP2a inducer and mannitol salt agar with oxacillin). Biochemical identification of Staphylococcus species and pulsed-field gel electrophoresis (PFGE), to determine clonal relationships between isolates, were performed. RESULTS: Methicillin-resistant Staphylococcus (MRS) was isolated from the nasopharynx of 7/108 (4%) horses. Three horses had MRSA (2.7%), and 4 had MR-Staphylococcus pseudintermedius (MRSP). MRSA was isolated from horses on the same farm. PFGE revealed the 3 MRSA as USA 500 strains. CONCLUSIONS AND CLINICAL IMPORTANCE: Sampling the nasopharynx and guttural pouch of community-based horses revealed a similarly low prevalence rate of MRSA as other studies sampling the nares of community-based horses. More study is required to determine the need for sampling multiple anatomic sites when screening horses for MRSA. PMID- 28661021 TI - Outcome of Cesarean scar pregnancy managed expectantly: systematic review and meta-analysis. AB - OBJECTIVE: To explore the outcome in women managed expectantly following the diagnosis of Cesarean scar pregnancy (CSP). METHODS: An electronic search of MEDLINE, EMBASE and ClinicalTrials.gov databases was performed utilizing combinations of relevant medical subject headings for 'Cesarean scar pregnancy' and 'outcome'. Reference lists of relevant articles and reviews were hand searched for additional reports. Observed outcomes included: severe first trimester vaginal bleeding; clinical symptoms (abdominal pain, vaginal bleeding) requiring treatment; uncomplicated miscarriage; complicated miscarriage requiring intervention; first- or second-trimester uterine rupture or hysterectomy; third trimester bleeding, uterine rupture or hysterectomy; maternal death; incidence of abnormally invasive placenta (AIP); prevalence of placenta percreta; ultrasound signs suggestive of AIP; and live birth. Meta-analyses of proportions using a random-effects model were used to combine data. Cases were stratified based on the presence or absence of embryonic/fetal heart activity at the time of diagnosis. RESULTS: A total of 17 studies (69 cases of CSP managed expectantly, 52 with and 17 without embryonic/fetal heart beat) were included. In women with CSP and embryonic/fetal heart activity, 13.0% (95% CI, 3.8-26.7%) experienced an uncomplicated miscarriage, while 20.0% (95% CI, 7.1-37.4%) required medical intervention. Uterine rupture during the first or second trimester of pregnancy occurred in 9.9% (95% CI, 2.9-20.4%) of cases, while hysterectomy was required in 15.2% (95% CI, 3.6-32.8%) of all cases. Forty (76.9% (95% CI, 65.4-86.5%)) women progressed to the third trimester of pregnancy, of whom 39.2% (95% CI, 15.4 66.2%) experienced severe bleeding. Finally, 74.8% (95% CI, 52.0-92.1%) had a surgical or pathological diagnosis of AIP at delivery and around two-thirds (69.7% (95% CI, 42.8-90.1%)) of them had placenta percreta. In women with CSP but no embryonic/fetal cardiac activity, an uncomplicated miscarriage occurred in 69.1% (95% CI, 47.4-87.1%) of cases, while surgical or medical intervention during or immediately after miscarriage was required in 30.9% (95% CI, 12.9 52.6%). Uterine rupture during the first trimester of pregnancy occurred in 13.4% (95% CI, 2.7-30.3%) of cases, but hysterectomy was not required in any case. CONCLUSIONS: CSP with positive embryonic/fetal heart activity managed expectantly is associated with a high burden of maternal morbidity including severe hemorrhage, early uterine rupture, hysterectomy and severe AIP. Despite this, a significant proportion of pregnancies complicated by CSP may progress to, or close to, term, thus questioning whether termination of pregnancy should be the only therapeutic option offered to these women. Expectant management of CSP with no cardiac activity may be a reasonable option in view of the low likelihood of maternal complications requiring intervention, although close surveillance is advisable to avoid adverse maternal outcome. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28661023 TI - Copper-Induced Topology Switching and Thrombin Inhibition with Telomeric DNA G Quadruplexes. AB - The topological diversity of DNA G-quadruplexes may play a crucial role in its biological function. Reversible control over a specific folding topology was achieved by the synthesis of a chiral, glycol-based pyridine ligand and its fourfold incorporation into human telomeric DNA by solid-phase synthesis. Square planar coordination to a CuII ion led to the formation of a highly stabilizing intramolecular metal-base tetrad, substituting one G-tetrad in the parent unimolecular G-quadruplex. For the Tetrahymena telomeric repeat, CuII -triggered switching from a hybrid-dominated conformer mixture to an antiparallel topology was observed. CuII -dependent control over a protein-G-quadruplex interaction was shown for the thrombin-tba pair (tba=thrombin-binding aptamer). PMID- 28661022 TI - Transdiagnostic emotional vulnerabilities linking obsessive-compulsive and depressive symptoms in a community-based sample of adolescents. AB - BACKGROUND: Transdiagnostic emotional vulnerabilities are suspected to underlie psychopathologic comorbidity but have received little attention in adolescent emotional pathology literature. We examined distress tolerance, anxiety sensitivity, and anhedonia as concomitant transdiagnostic mechanisms that account for (i.e., statistically mediate) the covariance between adolescent obsessive compulsive disorder (OCD) and major depressive disorder (MDD) symptoms. METHOD: Data on MDD, OCD, and the three aforementioned transdiagnostic vulnerabilities were collected from a community-based sample of 3,094 ninth graders in a large metropolitan area and analyzed using mixed effects modeling to evaluate mediation effects. RESULTS: Individually and when controlling for each other, all three transdiagnostic vulnerabilities mediated the relation between OCD and MDD symptoms both before and after adjusting for demographics. CONCLUSIONS: Distress tolerance, anxiety sensitivity, and anhedonia may be unique mechanisms accounting for comorbidity between OCD and MDD symptoms in youth. Longitudinal evaluation of these candidate transdiagnostic emotional vulnerabilities in adolescent OCD-MDD comorbidity is warranted. PMID- 28661024 TI - A follow-up study of selected biomarkers of health in cod Gadus morhua L. collected from the southern Baltic off the Polish coast. AB - Selected biomarkers of health were examined in 50 post-spawning cod Gadus morhua collected in November 2015 from the southern Baltic. The biomarkers included condition factor (CF), macroscopic lesions, histopathology of spleen, liver and gonads, and morphometry of follicular atresia and hepatic and splenic melanomacrophage cells (MMC). All fish appeared in good body condition. One fish had a dermal ulcer, and in seven, macroscopic nematodes were noted within body cavity. Microscopic lesions in the liver included biliary myxozoanosis, microsporidial and necrocentric granulomas, parasitic hepatitis, multifocal necrosis, foci of cellular alterations, spongiosis, peliosis and cytoplasmic fibrillar inclusions. The spleen and gonads had microsporidial and/or necrocentric granulomas. Some of the biomarkers showed differences as compared to spawning cod collected in May from the same location in 2012, most importantly values an order of magnitude lower for splenic MMC in post-spawning fish. In post spawning fish, there were statistically significant correlations between MMC, CF, follicular atresia, parasitic hepatitis and microsporidiosis. This is the first comparison of biomarkers of health in post-spawning and spawning Baltic cod. Future studies need to examine the relationships of biomarkers to levels of pollutants in the environment and in tissues of cod. PMID- 28661025 TI - Effect of three- vs four-dimensional ultrasonography on maternal attachment. PMID- 28661026 TI - Therapeutic potentials of adenosine receptors agonists and antagonists in colitis; Current status and perspectives. AB - Increasing evidence suggests that adenosine is dysregulated in ulcerative colitis (UC), potentially affecting UC pathogenesis, diagnosis, and therapy. Dysregulation of the activity of adenosine generating enzymes including adenosine deaminase in serum of patients with acute colitis supports the role of this omnipresent metabolite in the pathogenesis of colitis. Adenosine regulates inflammatory responses including epithelial barrier hyper-permeability, myeloperoxidase activity, and neuromuscular motility in colitis, supporting the therapeutic potency of adenosine receptors agonists and antagonists in this disease. Depending upon the adenosine receptor subtype, activation or suppression of the receptor with pharmacological agonists or antagonists attenuates colitis pathological symptoms in colitis model. This review summarizes the role of adenosine receptors agonists and antagonists in the pathogenesis of colitis for a better understanding and hence a better management of this disease. PMID- 28661027 TI - Silica Scaffold with Shifted "Plumber's Nightmare" Networks and their Interconversion into Diamond Networks. AB - Bicontinuous structures with hyperbolic surfaces have been found in a variety of natural and synthetic systems. Herein, we present the synthesis and structural study of the shifted double-primitive networks, which is known as the rare "plumber's nightmare", and its interconversion into diamond networks. The scaffold was prepared by self-assembly of an amphiphilic triblock terpolymer and silica precursors. Electron crystallography indicates that the structure consists of two sets of hollow primitive networks shifted along 0.75b and 0.25c axes (2pcu(38 63), space group Cmcm). The "side-by-side" epitaxial relationship of the primitive and diamond networks with unit cell ratio of about 1.30 has been directly observed with the intermediate surface related to the rPD family. These results bring new insights to previous theoretical studies. PMID- 28661028 TI - Increased use of heated humidified high flow nasal cannula is associated with longer oxygen requirements. AB - AIM: There has been an increased use of heated humidified high flow nasal canula (HFNC) in premature babies (PBs) admitted to our neonatal unit. The aim of this study is to identify clinical characteristics in PBs < 29 weeks gestational age (GA) that distinguish between those who did not or did receive HFNC. METHODS: This study compared prospectively collected data from 2010 to 2012. Comparisons were undertaken between PBs<29 weeks GA who received continuous positive airway pressure (CPAP: 44/72 (61.1%)) to those who received both CPAP and HFNC (28/72 (38.9%)). Data were analysed using general linear models. RESULTS: There were no significant differences in baseline characteristics between the groups (GA: 27.6 +/- 1.1 vs. 27.5 +/- 1.1 (weeks), birth weight: 1066 +/- 209 vs. 1057 +/- 304 (grams) respectively). When analysing outcome measures with multivariate analysis, we found the corrected GA to cease CPAP and oxygen were significantly longer in the HFNC group (31.2 +/- 2.1 vs. 32.7 +/- 2.0 weeks, P = 0.01 and 32.8 +/- 3.5 vs. 36.5 +/- 2.8 weeks, P < 0.0001 respectively). CONCLUSIONS: Increased use of HFNC has been associated with increased oxygen requirements. These findings highlight the need to review the use of HFNC in small PBs. PMID- 28661029 TI - Successful pregnancy outcome in woman with history of Triple-P procedure for placenta percreta. PMID- 28661030 TI - Red blood cell storage duration and long-term mortality in patients undergoing cardiac intervention: a Danish register study. AB - OBJECTIVES: To study the effect of red blood cell (RBC) storage duration on long term mortality in patients undergoing cardiac intervention. BACKGROUND: RBCs undergo numerous structural and functional changes during storage. Observational studies have assessed the association between RBC storage duration and patient outcomes with conflicting results. METHODS: Between January 2006 and December 2014, 82 408 patients underwent coronary angiography. Of these, 1856 patients received one to four RBC units within 30 days after this procedure. Patients were allocated according to length of RBC storage duration: short-term (<=11 days), intermediate (IM)-term (12-23 days) and long-term (>=24 days). The study endpoints were 30-day and long-term all-cause mortality. RESULTS: A total of 4168 RBC units were given to 1856 patients. The mean RBC storage duration was 8.5 +/- 2.1, 17.7 +/- 3.4 and 29.9 +/- 3.4 days in the short-term, IM-term and long-term storage groups, respectively. There was no difference in baseline characteristics between the groups. The long-term storage group received significantly more units (2.4 +/- 1.0 units) as compared to the short-term (2.0 +/- 1.0 units; P < 0.001) and IM-term storage group (2.2 +/- 1.0 units; P < 0.01). In the survival analysis, there was no significant difference in all-cause mortality between the groups (log-rank: 0.509 for 30-days mortality; 0.493 for 5-year mortality). Additional stratified analysis demonstrated no association between RBC storage duration and long-term mortality. CONCLUSION: This study did not find an association between RBC storage duration and 30-days or long-term mortality in patients undergoing cardiac intervention. PMID- 28661031 TI - Myeloid-derived suppressor cells: Important contributors to tumor progression and metastasis. AB - Myeloid-derived suppressor cells (MDSCs) are traditionally considered among the major components of the immunosuppressive tumor microenvironment (TME). However, there is currently increasing evidence indicating that MDSCs in addition to suppression of immune surveillance is also involved in an array of non immunological functions like augmenting metastatic potential of tumor cells. Indeed, MDSCs can promote metastasis in animal models and cancer patients through promoting premetastatic niche formation, tumor angiogenesis and invasion. Moreover, MDSC frequency and function have been associated with progressive disease and correlated with clinical outcome. This review will summarize and discusses the data demonstrating the role for MDSCs in tumor metastasis. PMID- 28661032 TI - Cotransporting Ion is a Trigger for Cellular Endocytosis of Transporter-Targeting Nanoparticles: A Case Study of High-Efficiency SLC22A5 (OCTN2)-Mediated Carnitine Conjugated Nanoparticles for Oral Delivery of Therapeutic Drugs. AB - OCTN2 (SLC22A5) is a Na+ -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+ . Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+ -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles. PMID- 28661033 TI - Engineered Heart Repair. AB - There is a pressing need for the development of advanced heart failure therapeutics. Current state-of-the-art is protection from neurohumoral overstimulation, which fails to address the underlying cause of heart failure, namely loss of cardiomyocytes. Implantation of stem cell-derived cardiomyocytes via tissue-engineered myocardium is being advanced to realize the remuscularization of the failing heart. Here, we discuss pharmacological challenges pertaining to the clinical translation of tissue-engineered heart repair with a focus on engineered heart muscle (EHM). PMID- 28661034 TI - Context-induced relapse to cocaine seeking after punishment-imposed abstinence is associated with activation of cortical and subcortical brain regions. AB - We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. In exp. 1, we trained rats to self-administer cocaine (0.75 mg/kg/infusion, 6 hours/day, 12 days) in context A. Next, we transferred them to context B where for the paired group, but not unpaired group, 50 percent of cocaine-reinforced lever presses caused aversive footshock. We then tested the rats for cocaine seeking under extinction conditions in contexts A and B. We also retested them for relapse after retraining in context A and repunishment in context B. In exp. 2, we used Fos immunoreactivity to determine relapse-associated neuronal activation in brain regions of rats exposed to context A, context B or neither context. Results showed the selective shock induced suppression of cocaine self-administration and context-induced relapse after punishment-imposed abstinence in rats exposed to paired, but not unpaired, footshock. Additionally, context-induced relapse was associated with selective activation of dorsal and ventral medial prefrontal cortex, anterior insula, dorsal striatum, basolateral amygdala, paraventricular nucleus of the thalamus, lateral habenula, substantia nigra, ventral subiculum, and dorsal raphe, but not nucleus accumbens, central amygdala, lateral hypothalamus, ventral tegmental area and other brain regions. Together, context-induced relapse after punishment imposed abstinence generalizes to rats with a history of cocaine self administration and is associated with selective activation of cortical and subcortical regions. PMID- 28661035 TI - Up-regulated basigin-2 in microglia induced by hypoxia promotes retinal angiogenesis. AB - Retinal microglia cells contribute to vascular angiogenesis and vasculopathy induced by relative hypoxia. However, its concrete molecular mechanisms in shaping retinal angiogenesis have not been elucidated. Basigin, being involved in tumour neovasculogenesis, is explored to exert positive effects on retinal angiogenesis induced by microglia. Therefore, we set out to investigate the expression of basigin using a well-characterized mouse model of oxygen-induced retinopathy, which recapitulated hypoxia-induced aberrant neovessel growth. Our results elucidate that basigin is overexpressed in microglia, which accumulating in retinal angiogenic sprouts. In vitro, conditioned media from microglia BV2 under hypoxia treatment increase migration and tube formation of retinal capillary endothelia cells, compared with media from normoxic condition. The angiogenic capacity of BV2 is inhibited after basigin knockdown by small interfering RNAs. A new molecular mechanism for high angiogenic capacity, whereby microglia cells release basigin via up-regulation of PI3K-AKT and IGF-1 pathway to induce angiogenesis is unveiled. Collectively, our results demonstrate that basigin from hypoxic microglia plays a pivotal pro-angiogenic role, providing new insights into microglia-promoting retinal angiogenesis. PMID- 28661036 TI - Intracavitary vaginal brachytherapy using a custom balloon applicator. AB - A custom balloon applicator was created to deliver intracavitary high-dose-rate brachytherapy to a patient with a superficial vaginal cancer. The patient was unable to be treated conventionally due to an extremely narrow introitus that prevented the introduction of a conventional cylinder applicator. The custom applicator was constructed by inserting a straight titanium tandem applicator through the drainage lumen of a Foley catheter. The applicator was inserted and the catheter balloon was inflated when positioned at the vaginal apex. Three brachytherapy treatments were performed using this technique. Individual balloon eccentricities resulted in small radial tandem offsets within the balloon. This phenomenon was exploited by orientating the tandem offset in the direction of the target volume. Acceptable dosimetry was achieved for all fractions and the procedure was very well tolerated. The custom applicator was a viable solution that was safely developed in a short time frame using equipment readily available in our department. PMID- 28661038 TI - Trimethylphosphate and Dimethylphosphate Hydrolysis by Binuclear CdII , MnII , and ZnII -FeII Promiscuous Organophosphate-Degrading Enzyme: Reaction Mechanisms. AB - Organophosphate-degrading enzyme from Agrobacterium radiobacter P230 exhibits promiscuity, not only in the reactions it catalyzes, but also in the metals it uses to catalyze those reactions. Here, three different binuclear metal centers were studied: di-CdII , di-MnII and ZnII -FeII . This enzyme uses these metal centers for hydrolyzing trimethyl- and dimethyl-phosphates. Both mechanisms were studied at DFT level of theory using a cluster model approach. The ground spin state was determined for each enzyme. The outcomes confirmed that the hydrolysis of phosphotriester is faster than that of phosphodiester and in some case the phosphodiesterase reaction does not occur. The computed activation energies are in agreement with previous experimental results for phosphotriesterase enzymes. PMID- 28661037 TI - AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression. AB - Gastric cancer is the third leading cause of cancer-related deaths worldwide, and patients with lymph node, peritoneal and distant metastasis have a poor prognosis. Overexpression of Astrocyte-elevated gene-1 (AEG-1) has been reported to be correlated with the progression and metastasis of gastric cancer. However, its mechanisms are quite unclear. In this study, we found that elevated expression of AEG-1 was correlated with metastasis in human gastric cancer tissues. Moreover, gain- or loss-of-function of AEG-1, respectively, promoted or suppressed epithelial-mesenchymal transition (EMT), migration and invasion of gastric cancer cells. AEG-1 positively regulated eIF4E, MMP-9 and Twist expression. Manipulating eIF4E expression by transfection of overexpression constructs or siRNAs partially eliminated AEG-1-regulated EMT, cell migration and invasion. In addition, overexpression or knockdown of eIF4E promoted or suppressed EMT, cell migration and invasion in parallel with upregulation of MMP 9 and Twist expression, while manipulating eIF4E expression partially abrogated AEG-1-induced MMP-9 and Twist. Finally, silencing of AEG-1 expression not only inhibited tumour growth in parallel with downregulation of eIF4E, MMP-9 and Twist expression in a xenograft nude mouse model, but also suppressed lymph node and peritoneal metastasis of gastric cancer in an orthotopic nude mouse model. These findings suggest that AEG-1 promotes gastric cancer metastasis through upregulation of eIF4E-mediated MMP-9 and Twist, which provides new diagnostic markers and therapeutic targets for cancer metastasis. PMID- 28661039 TI - Rho-kinase inhibitor Y-27632 facilitates the proliferation, migration and pluripotency of human periodontal ligament stem cells. AB - The selective in vitro expansion and differentiation of multipotent stem cells are critical steps in cell-based regenerative therapies, while technical challenges have limited cell yield and thus affected the success of these potential treatments. The Rho GTPases and downstream Rho kinases are central regulators of cytoskeletal dynamics during cell cycle and determine the balance between stem cells self-renewal, lineage commitment and apoptosis. Trans-4-[(1R) aminoethyl]-N-(4-pyridinyl)cylohexanecarboxamidedihydrochloride (Y-27632), Rho associated kinase (ROCK) inhibitor, involves various cellular functions that include actin cytoskeleton organization, cell adhesion, cell motility and anti apoptosis. Here, human periodontal ligament stem cells (PDLSCs) were isolated by limiting dilution method. Cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) labelling assay, cell apoptosis assay, cell migration assay, wound-healing assay, alkaline phosphatase (ALP) activity assay, Alizarin Red S staining, Oil Red O staining, quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the effects of Y-27632 on the proliferation, apoptosis, migration, stemness, osteogenic and adipogenic differentiation of PDLSCs. Afterwards, Western blot analysis was performed to elucidate the mechanism of cell proliferation. The results indicated that Y-27632 significantly promoted cell proliferation, chemotaxis, wound healing, fat droplets formation and pluripotency, while inhibited ALP activity and mineral deposition. Furthermore, Y 27632 induced PDLSCs proliferation through extracellular-signal-regulated kinase (ERK) signalling cascade. Therefore, control of Rho-kinase activity may enhance the efficiency of stem cell-based treatments for periodontal diseases and the strategy may have the potential to promote periodontal tissue regeneration by facilitating the chemotaxis of PDLSCs to the injured site, and then enhancing the proliferation of these cells and maintaining their pluripotency. PMID- 28661040 TI - Effects of white light-emitting diode (LED) exposure on retinal pigment epithelium in vivo. AB - Ageing and alteration of the functions of the retinal pigment epithelium (RPE) are at the origin of lost of vision seen in age-related macular degeneration (AMD). The RPE is known to be vulnerable to high-energy blue light. The white light-emitting diodes (LED) commercially available have relatively high content of blue light, a feature that suggest that they could be deleterious for this retinal cell layer. The aim of our study was to investigate the effects of "white LED" exposure on RPE. For this, commercially available white LEDs were used for exposure experiments on Wistar rats. Immunohistochemical stain on RPE flat mount, transmission electron microscopy and Western blot were used to exam the RPE. LED induced RPE damage was evaluated by studying oxidative stress, stress response pathways and cell death pathways as well as the integrity of the outer blood retinal barrier (BRB). We show that white LED light caused structural alterations leading to the disruption of the outer blood-retinal barrier. We observed an increase in oxidized molecules, disturbance of basal autophagy and cell death by necrosis. We conclude that white LEDs induced strong damages in rat RPE characterized by the breakdown of the BRB and the induction of necrotic cell death. PMID- 28661041 TI - Metabolic control of type 2 immunity. AB - Type 2 immune responses play key roles in protection against parasitic worm infections, whole-body metabolic homeostasis, wound healing, and the development of allergies. As a result, there is considerable interest in understanding the pathways that regulate type 2 immunity in order to identify strategies of targeting and controlling these responses. In recent years, it has become increasingly clear that the functional properties of immune cells, including those involved in type 2 immune responses, are dependent on the engagement of specific metabolic pathways such as aerobic glycolysis and fatty acid oxidation (FAO). We here discuss the latest insights in the metabolic regulation of immune cells that initiate type 2 immune responses, such as dendritic cells and innate lymphoid cells, as well as immune cells involved in the effector phase, like T helper 2 (Th2) cells, B cells and alternatively activated macrophages (M2 macrophages). Finally, we consider whether these findings may provide new prospects for the treatment of type 2 immune response-associated diseases. PMID- 28661042 TI - CD11b promotes the differentiation of osteoclasts induced by RANKL through the spleen tyrosine kinase signalling pathway. AB - Macrophage surface antigen-1 (Mac-1, CD11b/CD18) has been implicated in the regulation of osteoclastogenesis. In the synovial tissues of patients with aseptic loosening after total hip replacement, CD11b was up-regulated, which indicated that CD11b is closely involved in osteolysis around the prosthesis. We found that CD11b, but not CD18, promoted osteoclast (OC) maturation. Here, we show CD11b up-regulated the levels of spleen tyrosine kinase (Syk), c-Fos and nuclear factor of activated T cells, cytoplasmic-1 (NFATc1), as well as the activity of extracellular-regulated kinase (Erk), and as a result, osteoclast precursors (OCPs) differentiated and became tartrate-resistant acid phosphatase (TRAP)-positive. In addition, increased tumour necrosis factor-alpha (TNF-alpha) induced by ultra-high molecular weight polyethylene (UHMWPE) particles up regulated the level of CD11b. Taken together, these findings suggest that CD11b is a positive regulator of osteoclastogenesis and that it functions by activating the Syk signalling pathway, while CD18 does not have the same effect. PMID- 28661043 TI - 3D Near-Field Electrospinning of Biomaterial Microfibers with Potential for Blended Microfiber-Cell-Loaded Gel Composite Structures. AB - This paper describes the development of a novel low-cost and efficient method, 3D near-field electrospinning, to fabricate high-resolution, and repeatable 3D polymeric fiber patterns on nonconductive materials with potential use in tissue engineering. This technology is based on readily available hobbyist grade 3D printers. The result is exquisite control of the deposition of single fibers in an automated manner. Additionally, the fabrication of various fiber patterns, which are subsequently translated to unique cellular patterns, is demonstrated. Finally, poly(methyl methacrylate) fibers are printed within 3D collagen gels loaded with cells to introduce anisotropic properties of polymeric fibers within the cell-loaded gels. PMID- 28661044 TI - The influence of familiar characters and other appealing images on young children's preference for low-quality objects. AB - This study examines the factors underlying young children's preference for products bearing a familiar character's image. Three-year-olds (N = 92) chose between low-quality objects with images on or near the objects and high-quality objects without images. Children showed stronger preferences for damaged objects bearing images of a preferred familiar character than for objects bearing images of a preferred colour star, and they showed weak preferences for damaged objects with the character near, but not on, the object. The results suggest that children's preference for low-quality products bearing character images is driven by prior exposure to characters, and not only by the act of identifying a favourite. Statement of contribution What is already known on this subject? Children are exposed to characters in the media and on products such as clothing and school supplies. Products featuring familiar characters appeal to preschool children, even if they are of low quality. What does this study add? Three-year olds prefer damaged objects with an image of a favourite character over plain undamaged objects. Children's preference is not solely a function of having identified a favourite image or of attentional cues. PMID- 28661045 TI - Sodium salicylate modulates inflammatory responses through AMP-activated protein kinase activation in LPS-stimulated THP-1 cells. AB - Sodium salicylate (NaSal) is a nonsteroidal anti-inflammatory drug. The putative mechanisms for NaSal's pharmacologic actions include the inhibition of cyclooxygenases, platelet-derived thromboxane A2, and NF-kappaB signaling. Recent studies demonstrated that salicylate could activate AMP-activated protein kinase (AMPK), an energy sensor that maintains the balance between ATP production and consumption. The anti-inflammatory action of AMPK has been reported to be mediated by promoting mitochondrial biogenesis and fatty acid oxidation. However, the exact signals responsible for salicylate-mediated inflammation through AMPK are not well-understood. In the current study, we examined the potential effects of NaSal on inflammation-like responses of THP-1 monocytes to lipopolysaccharide (LPS) challenge. THP-1 cells were stimulated with or without 10 ug/mL LPS for 24 h in the presence or absence of 5 mM NaSal. Apoptosis was measured by flow cytometry using Annexin V/PI staining and by Western blotting for the Bcl-2 anti apoptotic protein. Cell proliferation was detected by EdU incorporation and by Western blot analysis for proliferating cell nuclear antigen (PCNA). Secretion of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) was determined by enzyme linked immunosorbent assay (ELISA). We observed that the activation of AMPK by NaSal was accompanied by induction of apoptosis, inhibition of cell proliferation, and increasing secretion of TNF-alpha and IL-1beta. These effects were reversed by Compound C, an inhibitor of AMPK. In addition, NaSal/AMPK activation inhibited LPS-induced STAT3 phosphorylation, which was reversed by Compound C treatment. We conclude that AMPK activation is important for NaSal mediated inflammation by inducing apoptosis, reducing cell proliferation, inhibiting STAT3 activity, and producing TNF-alpha and IL-1beta. PMID- 28661046 TI - Activation of CaMKKbeta/AMPKalpha pathway by 2-AG in human platelets. AB - The objective of this study was to determine whether AMPK is activated by 2 arachidonoylglycerol (2-AG) and participates to the cytoskeleton control in human platelets. We found that 2-AG stimulates the AMPKalpha activation through a Ca2+ /Calmodulin-dependent pathway as the specific inhibition of the CaMKKbeta by STO 609 inhibits the AMPKalpha phosphorylation/activation. Moreover, the CaMKKbeta/AMPKalpha pathway activated by 2-AG is involved in the phosphorylation of cofilin, vasodilator stimulated phosphoprotein (VASP), and myosin light chain (MLCs). These proteins participate to actin cytoskeletal remodelling during aggregation. We found that the phosphorylation/activation inhibition of these proteins is associated with a significant reduction in actin polymerization, aggregation, ATP, and alpha-granule secretion. Finally, AMPKalpha activation, Cofilin, VASP, and MLCs phosphorylation are significantly reduced by SR141716, the specific inhibitor of type 1 cannabinoid (CB1) receptor, suggesting that the CB1 receptor is involved in the 2-AG effect. In conclusion, we have shown that the CaMKKbeta/AMPKalpha pathway is activated by 2-AG in human platelets and controls the phosphorylation of key proteins involved in actin polymerization and aggregation. PMID- 28661047 TI - Efficient Skin Temperature Sensor and Stable Gel-Less Sticky ECG Sensor for a Wearable Flexible Healthcare Patch. AB - Wearable, flexible healthcare devices, which can monitor health data to predict and diagnose disease in advance, benefit society. Toward this future, various flexible and stretchable sensors as well as other components are demonstrated by arranging materials, structures, and processes. Although there are many sensor demonstrations, the fundamental characteristics such as the dependence of a temperature sensor on film thickness and the impact of adhesive for an electrocardiogram (ECG) sensor are yet to be explored in detail. In this study, the effect of film thickness for skin temperature measurements, adhesive force, and reliability of gel-less ECG sensors as well as an integrated real-time demonstration is reported. Depending on the ambient conditions, film thickness strongly affects the precision of skin temperature measurements, resulting in a thin flexible film suitable for a temperature sensor in wearable device applications. Furthermore, by arranging the material composition, stable gel-less sticky ECG electrodes are realized. Finally, real-time simultaneous skin temperature and ECG signal recordings are demonstrated by attaching an optimized device onto a volunteer's chest. PMID- 28661048 TI - Prevalence of human papillomavirus infection in women in the Autonomous Region of Inner Mongolia: A population-based study of a Chinese ethnic minority. AB - Human papillomavirus (HPV) is one of the most common sexually transmitted infectious pathogens. Persistent infection has been linked to cancer development, in particular to cervical cancer. This study aims to investigate the epidemiology of HPV infection in women in Inner Mongolia of China and to dissect the disparities between the Han and Mongolian ethnic populations. Cervical cell samples from 5655 women (17-68 years old) were collected during routine gynecologic examination. HPV infection was established using the HPV GenoArray kit detecting 21 HPV genotypes. The overall HPV prevalence was 14.5%. HPV16 (5.0%), HPV58 (2.2%), and HPV52 (1.5%) are the most common genotypes. Of the 21 genotypes investigated, high-risk HPV genotypes dominate in all age groups. HPV16 and HPV58 are the most common genotypes in patients with cervical lesions. HPV prevalence among Han women is 11.5% and the most common genotypes are HPV16 (4%) and HPV58 (2.1%). HPV prevalence is significantly higher in Mongolian women (32.6%), with the most common genotypes being HPV16 (10.7%), HPV31 (7.1%), and HPV52 (4.3%). The multiple infection rate in Mongolian participants (14.9%) is also higher than that of Han participants (4.3%). Urbanization, the number of sex partners, and PAP history appear as risk factors for HPV infection in Han, but not in Mongolian participants. HPV infection is highly prevalent in women in Inner Mongolia, China. HPV16 remains the most common genotype in this area. However, there are clear ethnical disparities in respect to the HPV epidemiology between the Han and Mongolian population. PMID- 28661049 TI - Which priority indicators to use to evaluate nursing care performance? A discussion paper. AB - AIMS: A discussion of an optimal set of indicators that can be used on a priority basis to assess the performance of nursing care. BACKGROUND: Recent advances in conceptualization of nursing care performance, exemplified by the Nursing Care Performance Framework, have revealed a broad universe of potentially nursing sensitive indicators. Organizations now face the challenge of selecting, from this universe, a realistic subset of indicators that can form a balanced and common scorecard. DESIGN: Discussion paper drawing on a systematic assessment of selected performance indicators. DATA SOURCES: Previous works, based on systematic reviews of the literature published between 1990 - 2014, have contributed to the development of the Nursing Care Performance Framework. These works confirmed a robust set of indicators that capture the universe of content currently supported by the scientific literature and cover all major areas of nursing care performance. Building on these previous works, this study consisted in gathering the specific evidence supporting 25 selected indicators, focusing on systematic syntheses, meta-analyses and integrative reviews. IMPLICATIONS FOR NURSING: This study has identified a set of 12 indicators that have sufficient breadth and depth to capture the whole spectrum of nursing care and that could be implemented on a priority basis. CONCLUSIONS: This study sets the stage for new initiatives aiming at filling current gaps in operationalization of nursing care performance. The next milestone is to set up the infrastructure required to collect data on these indicators and make effective use of them. PMID- 28661050 TI - Liposomes with Silk Fibroin Hydrogel Core to Stabilize bFGF and Promote the Wound Healing of Mice with Deep Second-Degree Scald. AB - How to maintain the stability of basic fibroblast growth factor (bFGF) in wounds with massive wound fluids is important to accelerate wound healing. Here, a novel liposome with hydrogel core of silk fibroin (SF-LIP) is successfully developed by the common liposomal template, followed by gelation of liquid SF inside vesicle under sonication. SF-LIP is capable of encapsulating bFGF (SF-bFGF-LIP) with high efficiency, having a diameter of 99.8 +/- 0.5 nm and zeta potential of -9.41 +/- 0.10 mV. SF-LIP effectively improves the stability of bFGF in wound fluids. After 8 h of incubation with wound fluids at 37 degrees C, more than 50% of free bFGF are degraded, while only 18.6% of the encapsulated bFGF in SF-LIP are destroyed. Even after 3 d of preincubation with wound fluids, the cell proliferation activity and wound healing ability of SF-bFGF-LIP are still preserved but these are severely compromised for the conventional bFGF-liposome (bFGF-LIP). In vivo experiments reveal that SF-bFGF-LIP accelerates the wound closure of mice with deep second-degree scald. Moreover, due to the protective effect and enhanced penetration ability, SF-bFGF-LIP is very helpful to induce regeneration of vascular vessel in comparison with free bFGF or bFGF-LIP. The liposome with SF hydrogel core may be a potential carrier as growth factors for wound healing. PMID- 28661051 TI - N-linked glycosylation of a subunit isoforms is critical for vertebrate vacuolar H+ -ATPase (V-ATPase) biosynthesis. AB - The a subunit of the V0 membrane-integrated sector of human V-ATPase has four isoforms, a1-a4, with diverse and crucial functions in health and disease. They are encoded by four conserved paralogous genes, and their vertebrate orthologs have positionally conserved N-glycosylation sequons within the second extracellular loop, EL2, of the a subunit membrane domain. Previously, we have shown directly that the predicted sequon for the a4 isoform is indeed N glycosylated. Here we extend our investigation to the other isoforms by transiently transfecting HEK 293 cells to express cDNA constructs of epitope tagged human a1-a3 subunits, with or without mutations that convert Asn to Gln at putative N-glycosylation sites. Expression and N-glycosylation were characterized by immunoblotting and mobility shifts after enzymatic deglycosylation, and intracellular localization was determined using immunofluorescence microscopy. All unglycosylated mutants, where predicted N-glycosylation sites had been eliminated by sequon mutagenesis, showed increased relative mobility on immunoblots, identical to what was seen for wild-type a subunits after enzymatic deglycosylation. Cycloheximide-chase experiments showed that unglycosylated subunits were turned over at a higher rate than N-glycosylated forms by degradation in the proteasomal pathway. Immunofluorescence colocalization analysis showed that unglycosylated a subunits were retained in the ER, and co immunoprecipitation studies showed that they were unable to associate with the V ATPase assembly chaperone, VMA21. Taken together with our previous a4 subunit studies, these observations show that N-glycosylation is crucial in all four human V-ATPase a subunit isoforms for protein stability and ultimately for functional incorporation into V-ATPase complexes. PMID- 28661052 TI - Luminescence Resonance Energy Transfer in a Multiple-Component, Self-Assembled Supramolecular Hydrogel. AB - Cascade energy transfer from a sensitizer to TbIII then to fluorescent dyes was studied for the first time in a supramolecular hydrogel. Efficient energy transfer from TbIII to the dyes was observed, as established by time-delayed emission and excitation spectral analysis, lifetime data, and microscopic studies. PMID- 28661053 TI - Examining the scope and patterns of deliberate self-injurious cutting content in popular social media. AB - BACKGROUND: Social networking services (SNS) have rapidly become a central platform for adolescents' social interactions and media consumption patterns. The present study examined a representative sample of publicly accessible content related to deliberate self-injurious cutting across three SNS platforms: Twitter, Tumblr, and Instagram. METHODS: Data collection simulated searches for publicly available deliberate self-injury content on Twitter, Tumblr, and Instagram. Over a six-month period at randomly generated time points, data were obtained by searching "#cutting" on each SNS platform and collecting the first 10 posts generated. Independent evaluators coded posts for presence of the following: (a) graphic content, (b) negative self-evaluations, (c) references to mental health terms, (d) discouragement of deliberate self-injury, and (e) recovery-oriented resources. Differences across platforms were examined. RESULTS: Data collection yielded a sample of 1,155 public posts (770 of which were related to mental health). Roughly 60% of sampled posts depicted graphic content, almost half included negative self-evaluations, only 9.5% discouraged self-injury, and <1% included formal recovery resources. Instagram posts displayed the greatest proportion of graphic content and negative self-evaluations, whereas Twitter exhibited the smallest proportion of each. CONCLUSIONS: Findings characterize the graphic nature of online SNS deliberate self-injury content and the relative absence of SNS-posted resources for populations seeking out deliberate self injurious cutting content. Mental health professionals must recognize the rapidly changing landscape of adolescent media consumption, influences, and social interaction as they may pertain to self-harm patterns. PMID- 28661054 TI - Platelet-derived growth factor regulates YAP transcriptional activity via Src family kinase dependent tyrosine phosphorylation. AB - The Hippo pathway effector YAP is implicated in the pathogenesis of cholangiocarcinoma (CCA). The Hippo pathway relies on signaling cross talk for its regulation. Given the importance of platelet derived growth factor receptor (PDGFR) signaling in CCA biology, our aim was to examine potential YAP regulation by PDGFR. We employed human and mouse CCA specimens and cell lines for these studies. Initially, we confirmed upregulation of PDGFRbeta and PDGFR ligands in human and mouse CCA specimens and cell lines. YAP, a transcriptional co activator, was localized to the nucleus in human CCA specimens and a cell line, as well as patient derived xenografts (PDX). PDGFR pharmacologic inhibition led to a redistribution of YAP from the nucleus to cytosol and downregulation of YAP target genes in a human CCA cell line. siRNA silencing of PDGFR-beta similarly downregulated YAP target genes. YAP activation (nuclear localization and target gene expression) was regulated by Src family kinases (SFKs) downstream of PDGFR. SFK activity resulted in phosphorylation of YAP on tyrosine357 (YAPY357 ). The importance of YAPY357 phosphorylation in regulating YAP activation was confirmed utilizing the SB-1 cell line, a mouse cell line expressing YAP S127A precluding canonical serine phosphorylation. PDGFR inhibition decreased cellular abundance of the survival protein Mcl-1, a known YAP target gene, and accordingly increased cell death in CCA cells in vitro and in vivo. These preclinical data demonstrate that a PDGFR-SFK cascade regulates YAP activation via tyrosine phosphorylation in CCA. Inhibiting this cascade may provide a viable therapeutic strategy for this human malignancy. PMID- 28661055 TI - Evaluation the Architect EBV VCA IgM, VCA IgG, and EBNA-1 IgG chemiluminescent immunoassays to assess EBV serostatus prior transplantation. AB - Prior to transplantation of hematopoietic stem cells or solid organ, donor and recipient EBV serostatus has to be determined to assess risks of post-transplant lymphoproliferative disorders. Sensitivity of EBV Viral capsid antigens (VCA) IgG and EBV nuclear antigen-1 (EBNA-1) is critical to define past infection and a good specificity of VCA IgM is required to avoid any disqualification of cord blood (CB) units. ArchitectTM EBV antibody panel (Architect assay) providing a high throughput was compared to a semi-automated ELISA (Etimax assays Diasorin) to assess sensitivities and specificities of VCA and EBNA-1 IgG and VCA IgM on 419 sera collected from immunocompromised patients (n = 184) and from pregnant women who agreed to give CB cells (n = 235). Intra and inter-assay coefficient of variations ranged from 1.63% to 4.8% for VCA IgM, VCA IgG, and EBNA-1 IgG. Index of VCA IgG and IgM and EBNA IgG of the two assays were highly correlated. The concordance in the interpretation between the two assays was moderate for VCA IgM (kappa = 0.5), substantial for VCA IgG (kappa = 0.60) and good for EBNA-1 IgG (kappa = 0.75). Using serial dilutions of positive controls and in accordance with clinical results VCA IgG and EBNA IgG were detected at lower dilutions with Architect than Etimax. Conversely, 96.1% (74/77) of samples negative with Architect and positive with Etimax for VCA IgM did not have any heterophile antibodies and had VCA IgG and EBNA IgG antibodies supporting past infections. ArchitectTM EBV serology panel provided good sensitivities and specificities for EBV serostatus determination prior to transplantation. PMID- 28661056 TI - Multiple sub-solid nodules: Different or just more? PMID- 28661057 TI - A fast autofocus sharpness function of microvision system based on the Robert function and Gauss fitting. AB - For the microvision system, a new autofocus evaluation function based on the Robert function is proposed by increasing the threshold value. Compared with the traditional evaluation function, the new focus function reduces the local extreme value and increases the steepness of the focusing curve. According to the characteristics of the focusing evaluation function, the focus curve can be divided into two stages: the gentle area and the steep area. In the gentle area, there will be set a large step-length to realize the fast search. In the steep area, the data will be fitted by Gauss method, and on the basis of the fitting results, the motor of microvision system was directly driven to achieve the focal plane and this method has been improved in real-time and accuracy. PMID- 28661058 TI - Providing Limited Local Electric Service During a Major Grid Outage: A First Assessment Based on Customer Willingness to Pay. AB - While they are rare, widespread blackouts of the bulk power system can result in large costs to individuals and society. If local distribution circuits remain intact, it is possible to use new technologies including smart meters, intelligent switches that can change the topology of distribution circuits, and distributed generation owned by customers and the power company, to provide limited local electric power service. Many utilities are already making investments that would make this possible. We use customers' measured willingness to pay to explore when the incremental investments needed to implement these capabilities would be justified. Under many circumstances, upgrades in advanced distribution systems could be justified for a customer charge of less than a dollar a month (plus the cost of electricity used during outages), and would be less expensive and safer than the proliferation of small portable backup generators. We also discuss issues of social equity, extreme events, and various sources of underlying uncertainty. PMID- 28661059 TI - Rhodium-Catalyzed Denitrogenative [3+2] Cycloaddition: Access to Functionalized Hydroindolones and the Framework of Montanine-Type Amaryllidaceae Alkaloids. AB - Rhodium-catalyzed denitrogenative [3+2] cycloaddition of 1-sulfonyl-1,2,3 triazoles with cyclic silyl dienol ethers has been developed for the synthesis of functionalized hydroindolones or their corresponding silyl ethers. The present method has been employed to construct synthetically valuable bicyclo[3.3.1]alkenone derivatives and pyrrolidine-ring-containing bicyclic indole compounds. As a further synthetic application, a stereoselective synthesis of 5,11-methanomorphanthridin-3-one, which shares a key skeleton with montanine type Amaryllidaceae alkaloids has been achieved by using this chemistry. PMID- 28661061 TI - Maternal help-seeking for child developmental concerns: Associations with socio demographic factors. AB - AIM: To examine socio-demographic factors associated with maternal help-seeking for child developmental concerns in a longitudinal birth cohort study. An understanding of these factors is critical to improving uptake of services to maximise early identification and intervention for developmental concerns. METHODS: A birth cohort was recruited from the post-natal wards of two teaching hospitals and through community nurses in South Western Sydney, Australia, between November 2011 and April 2013. Of the 4047 mothers approached, 2025 consented to participate (response rate = 50%). Socio-demographic and service use information was collected after the child's birth and when the child was 18 months of age. Sources of help were divided into three categories (formal health services, other formal services and informal supports) and compound variables were created by summing the number of different sources identified by mothers. RESULTS: Significantly more sources of help were intended to be used and/or actually accessed by mothers born in Australia, whose primary language was English, with higher levels of education and annual household income, and among mothers of first-born children. CONCLUSIONS: Developmental concerns are known to increase with increased psychosocial adversity. Our findings of reduced intent to access and use of services by socio-economically disadvantaged families and those from culturally and linguistically diverse backgrounds suggests that an inverse care effect is in operation whereby those children with the greatest health needs may have the least access to services. Possible explanations for this, and recommendations for improving service accessibility for these populations through targeted and culturally appropriate services, are discussed. PMID- 28661060 TI - Decreased Glutamate Levels in Patients with Amnestic Mild Cognitive Impairment: An sLASER Proton MR Spectroscopy and PiB-PET Study. AB - BACKGROUND AND PURPOSE: Glutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1 H-MRS) protocol composed of semi-localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment. METHODS: Participants with amnestic mild cognitive impairment (n = 14; median age = 80) and age- and sex-matched clinically normal controls (n = 32; median age = 79) from the population-based Mayo Clinic Study of Aging were recruited prospectively to the 3T single-voxel 1 H-MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low beta-amyloid load on [11 C] Pittsburgh Compound B (PiB)-PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high beta-amyloid load (SUVr >= 1.42). RESULTS: Glutamate concentration and the glutamate/myo-inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P < .05). Higher global cortical PiB-PET SUVr correlated with lower glutamate/myo-inositol (r = -.3, P = .04). CONCLUSIONS: The advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced 1 H-MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment. PMID- 28661063 TI - Flourishing follicles: Overview of ovarioles. PMID- 28661062 TI - Randomised feasibility study of a more liberal haemoglobin trigger for red blood cell transfusion compared to standard practice in anaemic cancer patients treated with chemotherapy. AB - OBJECTIVES: The primary objective of this feasibility study was to identify quality of life (QoL) scores and symptom scales as tools for measuring patient reported outcomes (PRO) associated with haemoglobin level in chemotherapy-treated cancer patients. Secondary objectives included comparing QoL and symptoms between randomisation arms. BACKGROUND: Anaemia in cancer patients undergoing chemotherapy is associated with decreased QoL. One treatment option is red blood cell transfusion (RBCT). However, the optimal haemoglobin trigger for transfusion is unknown. METHODS: Patients were randomised to a haemoglobin trigger for RBCT of either < 9.7 g dL-1 (arm A) or < lower normal level, female: 11.5 g dL-1 , male: 13.1 g dL-1 (arm B). Four PROs were used: Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anaemia (FACT-An), a Numeric Rating Scale on symptoms of anaemia and self-reported Performance Status (PS). The association between haemoglobin and PRO variables was assessed using a linear mixed model with random effects. RESULTS: A total of 133 patients were enrolled, of which 86 patients received RBCT (28 in arm A, 58 in arm B). Baseline questionnaires were filled out in 79.7% of cases. Haemoglobin levels were significantly correlated with FACT-An, FACT-An Total Outcome Index (TOI), Functional Well-Being, fatigue and PS. Improvement on several PRO variables was observed in both arms after RBCT, with clinically minimal important differences observed in FACT-G, Physical Well-Being, FACT-An, FACT-An TOI, fatigue and dyspnoea. CONCLUSIONS: QoL scores of physical and functional domains as well as self-reported anaemia-related symptoms correlated well with haemoglobin level in chemotherapy-treated cancer patients. PMID- 28661064 TI - Multifunctional Polymeric Micelles for Combining Chelation and Detection of Iron in Living Cells. AB - Multifunctional self-assembled micelles composed of Pluronics F127 polymer chains are developed and investigated for chelation and selective detection of iron(III) in vitro and in iron-overloaded cells. Tetraphenylethene (TPE) is encapsulated into the micelle core and the iron chelate drug deferoxamine (DFO) is conjugated to micelles to generate a fluorescence quenching detection system termed DFO-TFM for short, where T stands for TPE, F for F127, and M for micelle. The key to the successful formation of this fluorescence quenching system is due to the near ideal overlap between the absorption spectrum of the DFO:iron(III) complex and fluorescence spectrum of TPE. DFO-TFM can retain the iron-chelation properties of DFO and exhibits negligible cytotoxicity compared to free DFO. Furthermore, this fluorescence "turn-off" system can be utilized to detect the presence of iron and to monitor the chelation process in an iron overload cell model. This study serves as an effective proof-of-concept model for designing future in vivo systems capable of combining the features of iron chelation with iron detection and efforts toward the development of such detection systems are currently underway. PMID- 28661065 TI - Prevalence and associations of epiretinal membranes in the Australian National Eye Health Survey. PMID- 28661066 TI - Sexual dimorphism in hepatic lipids is associated with the evolution of metabolic status in mice. AB - Ectopic lipid accumulation in the liver is implicated in metabolic disease in an age- and sex-dependent manner. The role of hepatic lipids has been well established within the scope of metabolic insults in mice, but has been insufficiently characterized under standard housing conditions, where age-related metabolic alterations are known to occur. We studied a total of 10 male and 10 female mice longitudinally. At 3, 7 and 11 months of age, non-invasive 1 H magnetic resonance spectroscopy (1 H-MRS) was used to monitor hepatic lipid content (HLC) and fatty acid composition in vivo, and glucose homeostasis was assessed with glucose and insulin challenges. At the end of the study, hepatic lipids were comprehensively characterized by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometric analyses of liver tissue samples. In males, HLC increased from 1.4 +/- 0.1% at 3 months to 2.9 +/- 0.3% at 7 months (p < 0.01) and 2.7 +/- 0.3% at 11 months (p < 0.05), in correlation with fasting insulin levels (p < 0.01, r = 0.51) and parameters from the insulin tolerance test (ITT; p < 0.001, r = -0.69 versus area under the curve; p < 0.01, r = -0.57 versus blood glucose drop at 1 h post-ITT; p < 0.01, r = 0.55 versus blood glucose at 3 h post-ITT). The metabolic performance of females remained the same throughout the study, and HLC was higher than that of males at 3 months (2.7 +/- 0.2%, p < 0.01), but comparable at 7 months (2.2 +/- 0.2%) and 11 months (2.2 +/- 0.1%). Strong sexual dimorphism in bioactive lipid species, including diacylglycerols (higher in males, p < 0.0001), phosphatidylinositols (higher in females, p < 0.001) and omega-3 polyunsaturated fatty acids (higher in females, p < 0.01), was found to be in good correlation with metabolic scores at 11 months. Therefore, in mice housed under standard conditions, sex-specific composition of bioactive lipids is associated with metabolic protection in females, whose metabolic performance was independent of hepatic cytosolic lipid content. PMID- 28661067 TI - Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome. AB - Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 +/ 10.1 years old) and 14 normal controls (NCs) (34.7 +/- 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE < 0.05) and between PSQI and T1w intensities (PFWE < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted. PMID- 28661069 TI - The posterior thigh flap for defect coverage of ischial pressure sores - a critical single-centre analysis. AB - The development of pressure sores is still not only an enormous economical but also a medical burden. Especially in the ischial region, the local defect coverage remains demanding as it is the main weight-bearing area in wheelchair mobilised patients and is prone to high mobility. The purpose of our study was to report our long-time experience with the reconstruction of ischial pressure ulcers with the medially based posterior thigh flap. A retrospective analysis of all primary pressure sores grade III-IV in the ischial area, which were covered with a medially based posterior thigh flap between January 2008 and December 2014, at our department was conducted. A total of 28 patients underwent defect coverage of an ischial pressure sore with the aforementioned flap. The subgroup with complications showed a statistically significant longer hospital stay. A statistically significant correlation between age and the coincidence of comorbidities could be seen. Older patients showed significantly higher grades of pressure sores. The medially based posterior thigh flap is a safe and reliable flap design. Complication rates are comparable to other flaps. Nevertheless, in case of complications, a significantly longer duration of hospitalisation has to be taken into account. PMID- 28661068 TI - Expression of miR-18a and miR-34c in circulating monocytes associated with vulnerability to type 2 diabetes mellitus and insulin resistance. AB - Chronic stress may facilitate the development of metabolic disorders including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). MiR-18a and miR-34c modulate central cell responsiveness to stress by targeting glucocorticoid receptor (GR) and corticotropin-releasing factor receptor type 1 (CRFR1) mRNA, which are important regulators of the hypothalamus-pituitary-adrenal (HPA) axis. This study explored the relationship between T2DM/IR and expression of miR-18a and miR-34c in peripheral blood mononuclear cells (PBMCs) in an occupational sample. Three groups of study subjects were involved, including T2DM patients, impaired fasting glucose (IFG) individuals and healthy controls. The degree of IR was determined using the homoeostasis model assessment of insulin resistance (HOMA-IR). The expression of miR-18a and miR-34c in PBMCs was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Expression levels of miR-18a and miR-34c were significantly correlated with cortisol, corticotropin-releasing factor (CRF) and interleukin 6 (IL-6) (P < 0.05). The increased levels of miR-18a were associated with risk of T2DM (adjusted OR = 1.48, 95% CI: 1.25-1.75, P < 0.001) and IFG (adjusted OR = 1.33, 95% CI: 1.09-1.63, P = 0.005). By contrast, the decreased levels of miR-34c were associated with risk of T2DM (adjusted OR = 0.81, 95% CI: 0.75-0.88, P < 0.001) and IFG (adjusted OR = 0.87, 95% CI: 0.81-0.94, P < 0.001). After adjusting for potential confounders, miR-18a and miR-34c were independent positive and negative predictors of HOMA-IR, respectively (P < 0.001). The miRNA panel with the two miRNAs demonstrated high accuracy in the diagnosis of T2DM (AUC = 0.851, 95% CI: 0.786-0.800, P < 0.001). MiR-18a and miR-34c in PBMCs may be important marker of stress reaction and may play a role in vulnerability to T2DM as well as IR. PMID- 28661070 TI - microRNA-145-3p inhibits non-small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway. AB - The mammalian target of rapamycin (mTOR) pathway is dysregulated in more than 50% of all human malignancies and is a major target in cancer treatment. In this study, we explored the underlying mechanism involving microRNA-145-3p (miR-145 3p) in the development and progression of non-small cell lung cancer (NSCLC) by targeting PDK1 via the mTOR signaling pathway. NSCLC tissues and adjacent normal tissues were obtained from 83 NSCLC patients. miR-145-3p, PDK1, and mTOR levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Human NSCLC cell lines A549 and H1299 were transfected with miR-145-3p and siPDK1 to confirm the effect of miR-145-3p and PDK1 on NSCLC cells in vitro. Cell growth was evaluated by a CCK8 assay. Cell motility and chemotaxis analysis were determined by the scratch test and chemotaxis assay, respectively. The protein levels of PDK1 and mTOR were measured using the western blotting. Results showed lower level of miR-145-3p and higher levels of PDK1 and mTOR in NSCLC tissues compared to the adjacent normal tissues. In vitro results showed that cell growth, cell motility, and chemotaxis were all inhibited in cells transfected with miR-145-3p and those transfected with siPDK. Additionally, dual luciferase reporter gene assay helped confirmed that PDK1 is a target of miR-145. Finally, levels of PDK1, mTOR, and phosphorylated-mTOR were lower in cells transfected with miR-145-3p as well as those with siPDK1. These findings indicate that miR-145-3p may inhibit cell growth, motility, and chemotaxis in NSCLC by targeting PDK1 through suppressing the mTOR pathway. PMID- 28661071 TI - Scheduled meal accelerates entrainment to a 6-h phase advance by shifting central and peripheral oscillations in rats. AB - Travelling across several time zones requires a fast adjustment of the circadian system and the differential adjustment speeds of organs and systems results in what is commonly referred as jet lag. During this transitory state of circadian disruption, individuals feel discomfort, appetite loss, fatigue, disturbed sleep and deficient performance of multiple tasks. We have demonstrated that after a 6 h phase advance of the light-dark cycle (LD) scheduled food in phase with the new night onset can speed up re-entrainment. In this study, we explored the possible mechanisms underlying the fast re-entrainment due to the feeding schedule. We focused on first- and second-order structures that provide metabolic information to the suprachiasmatic nucleus (SCN). We compared (i) control rats without change in LD cycle; (ii) rats exposed to a 6-h phase advance of the LD cycle with food ad libitum; and (iii) rats exposed to the 6-h phase advance combined with food access in phase with the new night. We found an immediate synchronizing effect of food on stomach distention and on c-Fos expression in the nucleus of the solitary tract, arcuate nucleus of the hypothalamus, dorsomedial hypothalamic nucleus and paraventricular nucleus. These observations indicate that in a model of jet lag, scheduled feeding can favour an immediate shift in first- and second-order relays to the SCN and that by keeping feeding schedules coupled to the new night, a fast re-entrainment may be achieved by shifting peripheral and extra-SCN oscillations. PMID- 28661072 TI - Sensing behavioral symptoms of mental health and delivering personalized interventions using mobile technologies. AB - Unlike most other health conditions, the treatment of mental illness relies on subjective measurement. In addition, the criteria for diagnosing mental illnesses are based on broad categories of symptoms that do not account for individual deviations from these criteria. The increasing availability of personal digital devices, such as smartphones that are equipped with sensors, offers a new opportunity to continuously and passively measure human behavior in situ. This promises to lead to more precise assessment of human behavior and ultimately individual mental health. More refined modeling of individual mental health and a consideration of individual context, assessed through continuous monitoring, opens the way for more precise and personalized digital interventions that may help increase the number of positive clinical outcomes in mental healthcare. In this paper, we provide a conceptual review of such techniques for measuring, modeling, and treating mental illness and maintaining mental health. PMID- 28661073 TI - Squamous neoplasms arising within tattoos: clinical presentation, histopathology and management. AB - Tattooing, which involves the placement of ink into the skin, is an ancient decorative technique that has remained popular in modern society. Tattoos have long been known to cause cutaneous reactions, which include the emergence of neoplasms such as keratoacanthoma (KA) and squamous cell carcinoma (SCC) in tattooed areas of the skin. We review the clinical presentations, histology and treatment options for squamous neoplasms, primarily KA and SCC, arising in tattoos. PMID- 28661074 TI - A Review of Recent Developments of Mesoporous Materials. AB - This personal account concerns novel recent discoveries in the area of mesoporous materials. Most of the papers discussed have been published within the last two to three years. A major emphasis of most of these papers is the synthesis of unique mesoporous materials by a variety of synthetic methods. Many of these articles focus on the control of the pore sizes and shapes of mesoporous materials. Synthetic methods of various types have been used for such control of porosity including soft templating, hard templating, nano-casting, electrochemical methods, surface functionalization, and trapping of species in pores. The types of mesoporous materials range from carbon materials, metal oxides, metal sulfides, metal nitrides, carbonitriles, metal organic frameworks (MOFs), and composite materials. The vast majority of recent publications have centered around biological applications with a majority dealing with drug delivery systems. Several other bio-based articles on mesoporous systems concern biomass conversion and biofuels, magnetic resonance imaging (MRI) studies, ultrasound therapy, enzyme immobilization, antigen targeting, biodegradation of inorganic materials, applications for improved digestion, and antitumor activity. Numerous nonbiological applications of mesoporous materials have been pursued recently. Some specific examples are photocatalysis, photo-electrocatalysis, lithium ion batteries, heterogeneous catalysis, extraction of metals, extraction of lanthanide and actinide species, chiral separations and catalysis, capturing and the mode of binding of carbon dioxide (CO2 ), optical devices, and magneto optical devices. Of this latter class of applications, heterogeneous catalysis is predominant. Some of the types of catalytic reactions being pursued include hydrogen generation, selective oxidations, aminolysis, Suzuki coupling and other coupling reactions, oxygen reduction reactions (ORR), oxygen evolution reactions (OER), and bifunctional catalysis. For perspective, there have been over 40,000 articles on mesoporous materials published in the last 4 years and about 1388 reviews. By no means is this personal account thorough or all inclusive. One objective has been to choose a variety of articles of different types to obtain a flavor of the breadth of diversity involved in the area of mesoporous materials. PMID- 28661076 TI - Identification of lateralized compensatory neural activities within the social brain due to autism spectrum disorder in adolescent males. AB - Socio-behavioral impairments are important characteristics of autism spectrum disorders (ASD) and MRI-based studies are pursued to identify a neurobiological basis behind these conditions. This paper presents an MRI-based study undertaken to (i) identify the differences in brain activities due to ASD, (ii) verify whether such differences exist within the 'social brain' circuit which is hypothesized to be responsible for social functions, and (iii) uncover potential compensatory mechanisms within the identified differences in brain activities. In this study, a whole-brain voxel-wise analysis is performed using resting-state fMRI data from 598 adolescent males, that is openly available from the ABIDE consortium. A new method is developed, which can (i) extract the discriminative brain activities, that provide high separability between the blood oxygenation time-series signals from ASD and neurotypical populations, (ii) select the activities that are relevant to ASD by evaluating the correlation between the separability and traditional severity scores, and (iii) map the spatial pattern of regions responsible for generating the discriminative activities. The results show that the most discriminative brain activities occur within a subset of the social brain that is involved with affective aspects of social processing, thereby supporting the idea of the social brain and also its fractionalization in ASD. Further, it has also been found that the diminished activities in the posterior cingulate area are potentially compensated by enhanced activities in the ventromedial prefrontal and anterior temporal areas within the social brain. Hemispherical lateralization is also observed on such compensatory activities. PMID- 28661075 TI - MRI reveals increased tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer. AB - High animal fat consumption is associated with an increase in triple-negative breast cancer (TNBC) risk. Based on previous MRI studies demonstrating the feasibility of detecting very early non-palpable mammary cancers in simian virus 40 large T antigen (SV40TAg) mice, we examined the effect of dietary fat fed from weaning to young adulthood in this model of TNBC. Virgin female C3(1)SV40TAg mice (n = 16) were weaned at 3-4 weeks of age and then fed either a low fat diet (LFD) (n = 8, 3.7 kcal/g; 17.2% kcal from vegetable oil) or a high animal fat diet (HAFD) (n = 8, 5.3 kcal/g; 60% kcal from lard). After 8 weeks on the diet (12 weeks of age), fast spin echo MR images of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed and inguinal mammary glands were excised and formalin fixed for ex vivo MRI. 3D volume-rendered MR images were then correlated with mammary gland histology to assess the glandular parenchyma and tumor burden. Using in vivo MRI, an average of 3.88 +/- 1.03 tumors were detected per HAFD-fed mouse compared with an average of 1.25 +/- 1.16 per LFD-fed mouse (p < 0.007). Additionally, the average tumor volume was significantly higher following HAFD feeding (0.53 +/- 0.45 mm3 ) compared with LFD feeding (0.20 +/- 0.08 mm3 , p < 0.02). Analysis of ex vivo MR and histology images demonstrated that HAFD mouse mammary glands had denser parenchyma, irregular and enlarged ducts, dilated blood vessels, increased white adipose tissue, and increased tumor invasion. MRI and histological studies of the SV40TAg mice demonstrated that HAFD feeding also resulted in higher cancer incidence and larger mammary tumors. Unlike other imaging methods for assessing environmental effects on mammary cancer growth, MRI allows routine serial measurements and reliable detection of small cancers as well as accurate tumor volume measurements and assessment of the three-dimensional distribution of tumors over time. PMID- 28661077 TI - Blood wastage management in a regional blood transfusion centre. AB - OBJECTIVES: The aim of this study was to determine the rate of blood component wastage before and after interventions at Yazd Blood Transfusion Center. BACKGROUND: The growing need for blood components along with blood safety issues and rising costs constantly pressurise blood centres to improve their efficiency. Reducing the quantity of discarded blood at all stages of the supply chain can decrease the total costs. METHODS: Data on discarded blood components were extracted from the database of Yazd Blood Transfusion Center. Multiple interventions, including implementation of wastage management standard operating procedures and reduction of red blood cells (RBCs) inventory level, were implemented. Discard rates of blood components in the 3 years after intervention (2013-2015) were compared with the discard rates in the 3 years before interventions. RESULTS: The total wastage rate of blood components decreased by almost 60%. Discard rates of RBCs, platelets and plasma decreased from 9.7%, 18.5% and 5.4% to 2.9%, 10.5% and 2.3%, (P < 0.001) after intervention, respectively. The most prevalent reason for discarding units was expiration of RBCs and platelets. Plasma units were discarded mostly due to technical faults during processing. The cost saving of reduction in blood wastage was estimated to be 1,500,000 dollars. CONCLUSION: Interventions had a significant impact on the reduction of blood wastage with respect to both cost and blood supply saving. PMID- 28661078 TI - Centre-level variation in speech outcome and interventions, and factors associated with poor speech outcomes in 5-year-old children with non-syndromic unilateral cleft lip and palate: The Cleft Care UK study. Part 4. AB - OBJECTIVES: To investigate centre-level variation in speech intervention and outcome and factors associated with a speech disorder in children in Cleft Care UK (CCUK). SETTING AND SAMPLE POPULATION: Two hundred and sixty-eight 5-year-old British children with non-syndromic unilateral cleft lip and palate recruited to CCUK. MATERIALS AND METHODS: Centre-based therapists undertook audio-video recordings. Perceptual analysis was undertaken using the CAPS-A tool. Speech outcomes were based on structural and articulation scores, and intelligibility/distinctiveness. Between-centre variation in treatment and outcomes were examined using multilevel models. These models were extended to estimate the association between a range of factors (hearing loss, speech intervention, fistula, secondary speech surgery for velopharyngeal insufficiency, socio-economic status, gender, and parental happiness with speech) and speech outcomes. RESULTS: There was centre-level variation in secondary speech surgery, speech intervention, structure and intelligibility outcomes. Children with a history of speech intervention had a lower odds of poor intelligibility/distinctiveness, 0.1 (95% CI: 0.0-0.4). Parental concern was associated with a higher odds of poor intelligibility/distinctiveness, 13.2 (95% CI: 4.9-35.1). Poor speech outcomes were associated with a fistula, secondary speech surgery and history of hearing loss. CONCLUSIONS: Within the centralized service there is centre-level variation in secondary speech surgery, intervention and speech outcomes. These findings support the importance of early management of fistulae, effective management of velopharyngeal insufficiency and hearing impairment, and most importantly speech intervention in the preschool years. Parental concern about speech is a good indicator of speech status. PMID- 28661079 TI - Centre-level variation in dental treatment and oral health and individual- and area-level predictors of oral health in 5-year-old children with non-syndromic unilateral cleft lip and palate: the Cleft Care UK study. Part 3. AB - OBJECTIVES: To explore centre-level variation in fluoride treatment and oral health outcomes and to examine the association of individual- and area-level risk factors with dental decay in Cleft Care UK (CCUK). SETTING: Two hundred and sixty eight 5-year-old British children with non-syndromic unilateral cleft lip and palate (UCLP). MATERIALS AND METHODS: Data on caries and developmental defects of enamel (DDE) were collected. The child's history of fluoride ingestion and postcode was used to assess exposure to fluoridated water. Centre-level variation in fluoride exposure and caries was examined using hierarchical regression. Poisson regression was used to estimate the association between individual- and area-level fluoride exposures and outcome. RESULTS: Children had high levels of caries, rampant caries and DDE. There was no evidence of variation between centres in the number of children with caries or rampant decay. There was evidence of variation in prescription of fluoride tablets and varnish and the type of toothpaste used. Area level of deprivation was associated with a higher risk of dental caries-risk ratio (RR) in the lowest quartile versus the rest was 1.43 (95% CI 1.13 to 1.81). Use of fluoride tablets and varnish was associated with higher risk of caries-RR 1.73 (95% CI 1.29 to 2.32) and RR 1.33 (95% CI 1.04 to 1.70), respectively, adjusted for age, sex and deprivation. CONCLUSION: The association with use of fluoride tablets and varnish probably reflects reverse causality but indicates the need for early preventative interventions in children with UCLP. PMID- 28661080 TI - Centre-level variation in outcomes and treatment for otitis media with effusion and hearing loss and the association of hearing loss with developmental outcomes at ages 5 and 7 years in children with non-syndromic unilateral cleft lip and palate: The Cleft Care UK study. Part 2. AB - OBJECTIVES: To explore centre-level variation in otitis media with effusion (OME), hearing loss and treatments in children in Cleft Care UK (CCUK) and to examine the association between OME, hearing loss and developmental outcomes at 5 and 7 years. SETTING AND SAMPLE POPULATION: Two hundred and sixty-eight 5-year old British children with non-syndromic unilateral cleft lip and palate (UCLP) recruited to CCUK. MATERIALS AND METHODS: Children had air and bone conduction audiometry at age 5. Information on grommet and hearing aid treatment was obtained from parental questionnaire and medical notes. Hearing loss at age 5 was defined as >20 dB in the better ear and history of OME and hearing loss was determined from past treatment. Children with sensorineural hearing loss were excluded. Associations were examined with speech, behaviour and self-confidence at age 5 and educational attainment at age 7. Centre variation was examined using hierarchical models and associations between hearing variables and developmental outcomes were examined using logistic regression. RESULTS: There was centre-level variation in early grommet placement (variance partition coefficient (VPC) 18%, P=.001) and fitting of hearing aids (VPC 8%, P=.03). A history of OME and hearing loss was associated with poor intelligibility of speech (adjusted odds ratio=2.87, 95% CI 1.42-5.77) and aspects of educational attainment. CONCLUSIONS: Hearing loss is an important determinant of poor speech and treatment variation across centres suggest management of OME and hearing loss could be improved. PMID- 28661081 TI - Centre-level variation in treatment and outcomes and predictors of outcomes in 5 year-old children with non-syndromic unilateral cleft lip treated within a centralized service: the Cleft Care UK study. Part 6: summary and implications. AB - OBJECTIVES: To summarize and discuss centre-level variation across a range of treatment and outcome measures and examine individual and ecological determinants of outcome in children in Cleft Care UK (CCUK). SETTING AND SAMPLE POPULATION: Two hundred and sixty-eight 5-year-old British children with non-syndromic unilateral cleft lip and palate (UCLP) recruited to CCUK and treated within a centralized service. MATERIALS AND METHODS: Children had a range of treatment and outcome measures collected at a 5-year audit clinic. These outcomes included dento-alveolar arch relationships from study models, measures of facial appearance from cropped photographs, hearing loss from audiological assessment, speech from speech recordings, self-confidence and strengths and difficulties from parental self-report. Data were collected on educational attainment at age 7 using record linkage. Centre variation was examined using hierarchical regression and associations between variables were examined using logistic or poisson regression. RESULTS: There was centre-level variation for some treatments (early grommet placement, fitting of hearing aids, fluoride treatment, secondary speech surgery and treatment for cleft speech characteristics) and for some outcomes (intelligibility of speech). Hearing loss was associated with a higher risk of poor speech while speech therapy was associated with a lower risk of poor speech. Children had high levels of caries but levels of preventative treatment (fluoride varnish and tablets) were low. CONCLUSIONS: Further improvements to and monitoring of the current centralized model of care are required to ensure the best outcomes for all children with cleft lip and palate. PMID- 28661082 TI - Centre-level variation of treatment and outcome in 5-year-old children with non syndromic unilateral cleft lip and palate: The Cleft Care UK study. Part 1: Methodology and results for dento-facial outcomes. AB - OBJECTIVES: Outline methods used to describe centre-level variation in treatment and outcome in children in the Cleft Care UK (CCUK) study. Report centre-level variation in dento-facial outcomes. SETTING AND SAMPLE POPULATION: Two hundred and sixty-eight five-year-old British children with non-syndromic unilateral cleft lip and palate (UCLP). MATERIALS AND METHODS: Between January 2011 and December 2012, data were collected on a comprehensive range of outcomes. Child facial appearance and symmetry were assessed using photographic pictures. Dental arch relationships were assessed from standardized dental study models. Hierarchical statistical models were used to predict overall means and the variance partition coefficient (VPC)-a measure of amount of variation in treatment or outcome explained by the centre. RESULTS: Data on dento-alveolar arch relationships and facial appearance were available on 197 and 252 children, respectively. The median age of the children was 5.5 years, and 68% were boys. Variation was described across 13 centres. There was no evidence of centre-level variation in good or poor dento-alveolar arch relationships with a VPC of 4% and 3%, respectively. Similarly, there was no evidence of centre-level variation in good or poor facial appearance with a VPC of 2% and 5%, respectively. CONCLUSIONS: There was no evidence of centre-level variation for dento-facial outcomes although this study only had the power to detect large variation between sites. PMID- 28661083 TI - Centre-level variation in behaviour and the predictors of behaviour in 5-year-old children with non-syndromic unilateral cleft lip: The Cleft Care UK study. Part 5. AB - OBJECTIVES: The aims of this study were to describe child behavioural and psychosocial outcomes associated with appearance and speech in the Cleft Care UK (CCUK) study. We also wanted to explore centre-level variation in child outcomes and investigate individual predictors of such outcomes. SETTING AND SAMPLE POPULATION: Two hundred and sixty-eight five-year-old children with non-syndromic unilateral cleft lip and palate (UCLP) recruited to CCUK. MATERIALS AND METHODS: Parents completed the Strengths and Difficulties questionnaire (SDQ) and reported their own perceptions of the child's self-confidence. Child facial appearance and symmetry were assessed using photographs, and intelligibility of speech was derived from audio-visual speech recordings. Centre-level variation in behavioural and psychosocial outcomes was examined using hierarchical models, and associations with clinical outcomes were examined using logit regression models. RESULTS: Children with UCLP had a higher hyperactive difficulty score than the general population. For boys, the average score was 4.5 vs 4.1 (P=.03), and for girls, the average score was 3.8 vs 3.1 (P=.008). There was no evidence of centre level variation for behaviour or parental perceptions of the child's self confidence. There is no evidence of associations between self-confidence and SDQ scores and either facial appearance or behaviour. CONCLUSIONS: Children born with UCLP have higher levels of behaviour problems than the general population. PMID- 28661084 TI - Assessing the Cost of Large-Scale Power Outages to Residential Customers. AB - Residents in developed economies depend heavily on electric services. While distributed resources and a variety of new smart technologies can increase the reliability of that service, adopting them involves costs, necessitating tradeoffs between cost and reliability. An important input to making such tradeoffs is an estimate of the value customers place on reliable electric services. We develop an elicitation framework that helps individuals think systematically about the value they attach to reliable electric service. Our approach employs a detailed and realistic blackout scenario, full or partial (20 A) backup service, questions about willingness to pay (WTP) using a multiple bounded discrete choice method, information regarding inconveniences and economic losses, and checks for bias and consistency. We applied this method to a convenience sample of residents in Allegheny County, Pennsylvania, finding that respondents valued a kWh for backup services they assessed to be high priority more than services that were seen as low priority ($0.75/kWh vs. $0.51/kWh). As more information about the consequences of a blackout was provided, this difference increased ($1.2/kWh vs. $0.35/kWh), and respondents' uncertainty about the backup services decreased (Full: $11 to $9.0, Partial: $13 to $11). There was no evidence that the respondents were anchored by their previous WTP statements, but they demonstrated only weak scope sensitivity. In sum, the consumer surplus associated with providing a partial electric backup service during a blackout may justify the costs of such service, but measurement of that surplus depends on the public having accurate information about blackouts and their consequences. PMID- 28661085 TI - Cyclic AMP-regulated opposing and parallel effects of serotonin and dopamine on phototaxis in the Marmorkrebs (marbled crayfish). AB - Phototactic behaviours are observed from prokaryotes to amphibians and are a basic form of orientation. We showed that the marbled crayfish displays phototaxis in which the behavioural response reversed from negative to positive depending on external light conditions. Animals reared in a 12-L/12-D light cycle showed negative phototaxis during daytime and positive phototaxis during night time. Animals reared under constant light conditioning showed negative phototaxis during day- and night-time, while animals reared under constant dark conditioning showed positive phototaxis during day- and night-time. Injection of serotonin leads to a reversal of negative to positive phototaxis in both light/dark-reared and light/light-reared animals while injection of dopamine induced reversed negative phototaxis in dark/dark-reared animals. Four hours of dark adaptation were enough for light/dark-reared animals to reverse phototaxis from negative to positive. Injection of a serotonin 5HT1 receptor antagonist blocked the reverse phototaxis while serotonin 5HT2 receptor antagonists had no effects. Similarly, dark/dark-reared animals reversed to showing negative phototaxis after 4 h of light adaptation. Injection of a dopamine DA1 receptor antagonist blocked this reverse phototaxis, while dopamine DA2 receptor antagonists had no effects. Injection of a cAMP analogue into light/dark-reared animals blocked reverse phototaxis after dark adaptation, while adenylate cyclase inhibitor in dark/dark reared animals blocked reverse phototaxis after light adaptation. These results strongly suggest that serotonin mediates positive phototaxis owing to decreased cAMP levels, while dopamine-mediated negative phototaxis occurs due to increased cAMP levels. Supporting this, the ratio of serotonin to dopamine in the brain was much higher in dark/dark-reared than light/dark-reared animals. PMID- 28661086 TI - Selective Plasma Exchange for the Removal of Pemphigus Autoantibodies, Fibrinogen, and Factor XIII in Pemphigus Vulgaris. AB - Pemphigus vulgaris is a serious autoimmune skin disorder associated with desmoglein 1 and 3. Selective plasma exchange (SePE) for pemphigus vulgaris remains unknown. We investigated the removal characteristics of pemphigus autoantibodies, immunoglobulins, and fibrinogen in three cases. When the mean processed volume for SePE was 1.2 plasma volumes, the mean percent reduction was 50.7% for desmoglein 1, 48.9% for desmoglein 3, 50.3% for IgG, 29.8% for IgA, 1.9% for IgM, and 17.6% for fibrinogen. In one case, the percent reduction after four sessions of SePE within eight days was 87.0% for desmoglein 1, 85.1% for desmoglein 3, 76.6% for IgG, 53.5% for IgA, 7.9% for IgM, 41.6% for fibrinogen, and 31.4% for factor XIII. SePE can effectively remove pemphigus autoantibodies and retain coagulation factors, e.g. factor XIII and fibrinogen. In severe cases, SePE can be useful and safe for induction therapy. PMID- 28661087 TI - Efficacy of Substance Removal by Immunoadsorption With a Selective Plasma Separator. AB - Immunoadsorption with a tryptophan-conjugated column has a limited capacity and reduces fibrinogen. We speculated that immunoadsorption with a selective plasma separator has higher efficiency in removing immunoglobulins than ordinary immunoadsorption without affecting coagulation factors. This study investigated the efficacy of immunoadsorption with a selective plasma separator in vitro. The sieving coefficients, the pool concentration, and the adsorbed amount were investigated serially with up to 5 L of processed plasma. The sieving coefficients of the selective plasma separator were 0.8, 0.5, and 0.1 for albumin, immunoglobulin G (IgG), and factor 13, respectively. The trend of concentrations for the ordinary plasma separator in the pool reached its nadir at 1.5 L and 3.5 L of plasma processed for IgG, IgG1, or IgG2, and IgG3, respectively. However, the volume was doubled for the selective plasma separator. The trends of fibrinogen and factor 13 concentrations differed significantly between two plasma separators. The trends of the absorbed amount were mirror images of the concentration in the pool. Comparison of the peak amount absorbed indicated that the amounts were almost identical between the two separators for IgG, IgG1, and IgG2. On the other hand, the peak amounts were less for albumin, fibrinogen, and IgG3 with the selective plasma separator than with the ordinary separator. Although further investigations about bradykinin are required, immunoadsorption with the selective plasma separator supports the administration of more frequent and intensive treatments to remove IgG1 or IgG2 without affecting coagulation factors. PMID- 28661089 TI - Immunological Analysis and Generation of Dendritic Cells From Lavage Fluid Obtained by Cell-Free and Concentrated Ascites Reinfusion Therapy. AB - Cell-free and concentrated ascites reinfusion therapy (CART) is an effective treatment for patients with refractory ascites. Cellular components such as cancer cells and blood cells are removed and discarded. The aim of this study was to investigate the alteration of immune cells in lavage fluid and the generation of dendritic cells (DCs) from lavage fluid obtained by CART. Flow cytometry analysis showed a trend toward immunosuppression and impairment in innate immunity in lavage fluid. Immature DCs with downregulation of CD14 and increased antigen-uptake were generated by culturing monocytes obtained from lavage fluid with GM-CSF and IL4. Following the culture with proinflammatory mediators, mature DCs with upregulation of CD83 and potent ability of T cell activation were induced. There were no significant phenotypical or functional differences between these DCs and DCs derived from peripheral blood, indicating lavage fluid might be employed for an alternative cellular source for the generation of DCs. PMID- 28661090 TI - Rituximab-Resistant Nephrotic Syndrome With Successful Induction of Remission by Low-Density Lipoprotein Apheresis. PMID- 28661093 TI - Severe Glyphosate-Surfactant Intoxication Successfully Treated With Continuous Hemodiafiltration and Direct Hemoperfusion: Case Report. PMID- 28661094 TI - Effect of Temperature on Granulocyte and Monocyte Adsorption to Cellulose Acetate Beads. AB - Granulocyte and monocyte (GM) adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including inflammatory bowel disease (IBD). During GMA, the blood of a patient with IBD passes through a column to contact cellulose acetate (CA) beads at a temperature below body temperature, likely close to room temperature. Here we investigated the effect of temperature on GM adsorption to CA beads in vitro. We incubated peripheral blood with and without CA beads at 5 degrees C, 25 degrees C, 37 degrees C, and 43 degrees C and calculated the ratios of adsorbed GMs. The ratios of adsorbed GMs increased as the temperature was raised. Additionally, we measured complement activation fragment concentrations. C3a and C5a concentrations also increased as the temperature was raised, and C5a concentrations had a positive correlation with the ratios of adsorbed GMs. These results suggest that warming the column during GMA might increase GM adsorption to CA beads, thereby enhancing the clinical efficacy of GMA. PMID- 28661095 TI - Protein Concentration of Refractory Ascites in Cancer Patients is Reflected by the Presence and Severity of Peritoneal and Liver Metastasis. AB - Ascites total protein concentration (A-TP) affects the performance of cell-free and concentrated ascites reinfusion therapy (CART). As the factors determining A TP remain unclear, we examined peritoneal and liver metastasis. Among 98 patients who received CART, 68 with cancer, ascites from no other apparent cause, and complete CT and A-TP data were recruited. Sixty-six patients (97%) with peritoneal and/or liver metastasis on CT were divided into the peritoneal metastasis group (PM group), peritoneal and liver metastasis group (PM + LM group), and liver metastasis group (LM group). A-TP was highest in the PM group (3.9 g/dL [3.4-4.4]), lowest in the LM group (1.0 g/dL [0.9-2.0]), and broadly dispersed in the PM + LM group (3.3 g/dL [2.0-3.8]). All differences were statistically significant. The percentage of metastasis volume occupying the liver was negatively and significantly related to A-TP in the PM + LM group. Taken together, the presence and severity of peritoneal and liver metastasis may influence A-TP. PMID- 28661096 TI - Fibrinogen Reduction During Selective Plasma Exchange due to Membrane Fouling. AB - Fibrinogen is substantially reduced by most plasmapheresis modalities but retained in selective plasma exchange using Evacure EC-4A10 (EC-4A). Although EC 4A's fibrinogen sieving coefficient is 0, a session of selective plasma exchange reduced fibrinogen by approximately 19%. Here, we investigated sieving coefficient in five patients. When the mean processed plasma volume was 1.15 * plasma volume, the mean reduction of fibrinogen during selective plasma exchange was approximately 15%. Fibrinogen sieving coefficient was 0 when the processed plasma volume was 1.0 L, increasing to 0.07 when the processed plasma volume was 3.0 L, with a mean of 0.03 during selective plasma exchange. When fibrinogen sieving coefficient was 0, selective plasma exchange reduced fibrinogen by approximately 10%. Scanning electron microscopy images revealed internal fouling of EC-4A's hollow fiber membrane by substances such as fibrinogen fibrils. Thus, fibrinogen reduction by selective plasma exchange may be predominantly caused by membrane fouling rather than filtration. PMID- 28661097 TI - Evaluating the Efficacy of Double-Filtration Plasmapheresis in Treating Five Patients With Drug-Resistant Pemphigus. AB - Double-filtration plasmapheresis is an effective and safe treatment for pemphigus. We retrospectively evaluated the decrease in autoantibody titer and pemphigus disease area index following double-filtration plasmapheresis in five patients with moderate to severe pemphigus, who were physically and/or serologically unresponsive to 1.0 mg/kg per day of prednisolone and other supportive drugs and ointments. The percentage reduction in autoantibodies 85.6 +/- 14.4% (P = 0.00014), and that in pemphigus disease area index was 75.4 +/- 24.3% (P = 0.0023). No side-effects were observed. All patients exhibited clinical improvement after undergoing double-filtration plasmapheresis, and the prednisolone dose was reduced by 41 +/- 8.9 mg (P = 0.0005) approximately 3 months after double-filtration plasmapheresis. To our knowledge, this is the first report evaluating the efficacy of double-filtration plasmapheresis with pemphigus disease area index, and it demonstrated that double-filtration plasmapheresis is a safe "subtracting" treatment for patients with drug-resistant pemphigus. PMID- 28661098 TI - Efficacy of Cryofiltration for Treatment of Mixed Cryoglobulinemia: A Report of Four Cases. AB - Cryoglobulinemia can induce systemic vasculitis affecting various organs such as skin, peripheral nerves, and kidney. The disease can induce chronic organ failure and even be life-threatening. Cryofiltration has been applied for the treatment of cryoglobulinemic vasculitis. We have experienced four cases with mixed cryoglobulinemia showing severe and progressive clinical manifestations, including skin purpura, nephrotic syndrome, acute kidney injury, and peripheral neuropathy. Cryofiltration in conjunction with conventional pharmacological therapies appeared to be safe and effective. After the treatments, plasma cryoglobulins were markedly reduced and the disease was well controlled. Although its efficacy has not yet been well established, this report can be another evidence showing efficacy of cryofiltration for treatment of mixed cryoglobulinemia. PMID- 28661100 TI - Estimation of lung tumor position from multiple anatomical features on 4D-CT using multiple regression analysis. AB - To estimate the lung tumor position from multiple anatomical features on four dimensional computed tomography (4D-CT) data sets using single regression analysis (SRA) and multiple regression analysis (MRA) approach and evaluate an impact of the approach on internal target volume (ITV) for stereotactic body radiotherapy (SBRT) of the lung. Eleven consecutive lung cancer patients (12 cases) underwent 4D-CT scanning. The three-dimensional (3D) lung tumor motion exceeded 5 mm. The 3D tumor position and anatomical features, including lung volume, diaphragm, abdominal wall, and chest wall positions, were measured on 4D CT images. The tumor position was estimated by SRA using each anatomical feature and MRA using all anatomical features. The difference between the actual and estimated tumor positions was defined as the root-mean-square error (RMSE). A standard partial regression coefficient for the MRA was evaluated. The 3D lung tumor position showed a high correlation with the lung volume (R = 0.92 +/- 0.10). Additionally, ITVs derived from SRA and MRA approaches were compared with ITV derived from contouring gross tumor volumes on all 10 phases of the 4D-CT (conventional ITV). The RMSE of the SRA was within 3.7 mm in all directions. Also, the RMSE of the MRA was within 1.6 mm in all directions. The standard partial regression coefficient for the lung volume was the largest and had the most influence on the estimated tumor position. Compared with conventional ITV, average percentage decrease of ITV were 31.9% and 38.3% using SRA and MRA approaches, respectively. The estimation accuracy of lung tumor position was improved by the MRA approach, which provided smaller ITV than conventional ITV. PMID- 28661099 TI - Self-administration of methamphetamine alters gut biomarkers of toxicity. AB - Methamphetamine (METH) is a highly abused psychostimulant that is associated with an increased risk for developing Parkinson's disease (PD). This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of alpha-synuclein and parkin. In PD, peripheral factors are thought to contribute to central nervous system (CNS) degeneration. For example, alpha-synuclein levels in the enteric nervous system (ENS) are elevated, and this precedes the onset of motor symptoms. It remains unclear whether neurons of the ENS, particularly catecholaminergic neurons, exhibit signs of METH-induced toxicity as seen in the CNS. The aim of this study was to determine whether self-administered METH altered the levels of alpha synuclein, parkin, tyrosine hydroxylase (TH), and dopamine-beta-hydroxylase (DbetaH) in the myenteric plexus of the distal colon ENS. Young adult male Sprague-Dawley rats self-administered METH for 3 h per day for 14 days and controls were saline-yoked. Distal colon tissue was collected at 1, 14, or 56 days after the last operant session. Levels of alpha-synuclein were increased, while levels of parkin, TH, and DbetaH were decreased in the myenteric plexus in the METH-exposed rats at 1 day following the last operant session and returned to the control levels after 14 or 56 days of forced abstinence. The changes were not confined to neurofilament-positive neurons. These results suggest that colon biomarkers may provide early indications of METH-induced neurotoxicity, particularly in young chronic METH users who may be more susceptible to progression to PD later in life. PMID- 28661101 TI - [SEX DIFFERENCES IN PHYSIOLOGICAL RESPONSES TO PAIN THROUGHOUT SURGICAL PROCEDURES]. AB - BACKGROUND: Recent research has shown that women and men respond differently to pain, and that biological mechanisms partially moderate sex-related differences in pain sensitivity. Previous pain studies regarding the relationship between pain and physiological aspects, such as brain function and hormone levels, have demonstrated gender differences. In this study we examined whether male and female autonomic reactivity patterns to pain, defined as increases in heart rate and blood pressure, differ throughout anesthetized abdominal surgical procedures. METHODS: We retrospectively reviewed 50 patients: 25 male and 25 female patients who underwent exploratory laparotomy surgeries and had intraoperative sympathetic response to surgical stimulation and were defined as patients who had an increase of 20% in heart rate or blood pressure at surgical incision. Baseline blood pressure and heart rate data, as well as blood pressure and heart rate measurements following surgical incision were gathered. Baseline data was compared to post surgical incision data, in order to evaluate whether blood pressure and heart rate change patterns differ amongst men and women. RESULTS: Demographic data between groups was analyzed according to the T - Test. Significant difference in demographic data was observed in weight. Average changes in mean, systolic diastolic blood pressure and heart rate, were analyzed according to Wilcoxon Rank Scores. No significant differences in any variable were found between the groups. CONCLUSIONS: In order to confirm our hypothesis as to whether the autonomic nerve system, such as heart rate and blood pressure reactivity, may partially moderate sexrelated differences to pain, a large prospective study with a standardized anesthesia protocol is needed. PMID- 28661102 TI - [AUTHORSHIP - A GREAT HONOR OR AN ONEROUS RESPONSIBILITY?] AB - INTRODUCTION: Over the years ethical issues have been raised regarding authorship of scientific literature. Research is mainly accomplished through teamwork, and publishing articles has a significant impact upon academic promotion and career path. Thus, concepts such as honorary authors, ghost authors, and equally contributing authors have been established. In order to maintain better regulation, authorship recommendation and policies have been developed such as the International Committee of Medical Journal Editors (ICMJE) guidelines. The senior researcher plays an important role in the process of publishing an article. While they may be eager to announce their findings, the senior researcher must first ensure that no falsification, fabrication or plagiarism has been committed, as well as address the sensitive subject of the correct order of authors on the paper. The senior researcher, along with the rest of the authors appearing on the paper, must also be accountable for the data reported in the article. In this editorial, we will review the topic of authorship and explore famous international incidents as well as our own experiences. PMID- 28661103 TI - [SCIENTIFIC PUBLICATIONS: ON HONORS AND GHOSTS]. AB - INTRODUCTION: The ethics committee at the Sackler Faculty of Medicine, Tel Aviv University deals with complaints which are not necessarily related to teaching or to issues in the realm of the Institutional Review Board (Helsinki Commission). Virtually all complaints reaching the committee are based on disputed authorship of scientific publications. Researchers and clinicians are interested in publishing their research in order to share knowledge but also in order to comply with the dictum "Publish or Perish". They are publishing to enhance their reputation, to improve chances for funding and to increase the likelihood for clinical and academic promotion. Yet, lack of appropriate planning and agreements on authorship ahead of time may lead to frictions, misunderstandings and outright belligerence between authors. The issue of authorship is being addressed by scientific journals, academic institutions and committees of editors. All of them have published appropriate guidelines which form the basis for the work of the ethics committee. We deal with "honorary authorship", that is individuals who are listed as authors, although they have not contributed sufficiently to the research in order to merit authorship and we deal with "Ghost Authorship" that is when contributing researchers are not listed, as they should be among authors of a scientific publication. Specific case studies are presented. PMID- 28661105 TI - [RECOMMENDATION FOR EVALUATION AND TREATMENT OF CHRONIC URTICARIA - THE ISRAELI ASSOCIATION FOR ALLERGY AND CLINICAL IMMUNOLOGY]. AB - INTRODUCTION: Chronic urticaria is a disease manifested by a pruritic rash lasting longer than 6 weeks that may severely affect quality of life and daily function. Chronic urticaria can be further divided into chronic spontaneous urticaria which appears without a trigger and chronic inducible urticaria which evolves following distinct physical triggers. These two clinical manifestations could coexist in the same patient. The pathogenesis of chronic urticaria is not fully elucidated, although it is considered an autoimmune disease in at least 50% patients that produce auto- IgG antibodies targeted against the high affinity Fc receptor and to a lesser extent against IgE itself. Auto-antibodies associated with different autoimmune diseases can be detected such as those directed at thyroid proteins. Urticaria tends to spontaneously resolve in 50% of patients within the first year while others will suffer from it for a much longer period of time. The treatment of chronic urticaria has dramatically progressed in the last decade, enabling reduction of systemic corticosteroid use which has been the cornerstone of treatment in the past. The recommended treatment for chronic urticaria is currently based on a stepwise approach that enables achieving disease control with a reasonably good quality of life. The first step of the treatment ladder consists of selective, new generation, anti-H1 histamine blockers, which do not cross the blood brain barrier, starting from the recommended dose (first line) and increasing up to four-fold (second line). The third line of treatment is the addition of immune modulators such as leukotriene receptor blockers (Singulair), anti-IgE biological therapy (Xolair), or cyclosporine. In this review we present the updates and considerations arising during evaluation and treatment of chronic urticaria. The need for specific tests, immunologist/allergologist evaluation, as well as treatment modalities taking into consideration the large body of evidence that has accumulated in the last few years, the new international guidelines as well as their application in Israel have been addressed. PMID- 28661106 TI - [43 YEARS TO THE ESTABLISHMENT OF THE FACULTY OF MEDICINE IN THE NEGEV]. AB - INTRODUCTION: On March 21, 1973, Israel's Council of Higher Education (CHE) was convened by Yigal Alon, the Council's chair and the Minister of Education, to vote on whether to approve a proposal to establish a school of medicine in the Negev. In the preliminary discussion, Avraham Harman, the president of the Hebrew University in Jerusalem turned to Professor Moshe Prywes, the president of Ben Gurion University in the Negev and commented: "Be assured, a school of medicine in Beer Sheva won't pass." At the close of the discussion, the twenty members of the CHE were asked to vote. The vote was a tie - 8 in favor, 8 against and 3 refrained. According to the CHE charter, the chairperson was required to break the tie. The minister - Yigal Alon, raised his hand in favor. Thus, by a bare voice, it was decided to establish a medical school in the Negev. This paper describes the processes that culminated in the approval of a school of medicine by the Council of Higher Education in March 1973. It presents the various personalities, agents, bodies and institutions that played a role in this process and their relative weights in the ultimate decision to establish a school of medicine in the Negev. PMID- 28661104 TI - [LAPAROSCOPIC SLEEVE GASTRECTOMY IN THE ELDERLY]. AB - INTRODUCTION: Obesity is an independent predictor of mortality, especially among patients suffering from chronic illnesses. Basically, obesity occurs as a result of an imbalance between the amount of food consumed and the energy expenditure of a person. Obesity treatment is aimed at creating a new imbalance of reduced food intake and increased energy expenditure. However, diet consultation and physical exercise have failed in the treatment of the majority of obese individuals. Surgical treatment (i.e. bariatric surgery) is aimed at reducing the amount of calories a patient can consume, and is the best treatment for weight reduction to date, and the only proven treatment for morbidly obese individuals. Despite the fact that bariatric surgery is covered by the medical insurer in Israel, individuals over the age of 65 cannot undergo bariatric surgery only on the basis of their obesity, and it requires the approval of the exceptions committee to enable coverage of the procedure. This review will focus on the prevalence of obesity in the elderly population, and will elaborate on the effect of such treatments in patients over 65 years of age compared to younger counterparts. PMID- 28661107 TI - [WHEN ULTRASOUND MEETS THE INTERNIST]. AB - INTRODUCTION: Point-of-care ultrasound (POCUS) is an important modality with many advantages. At the Shaare Zedek Medical Centre, we developed a case-based course to teach POCUS to internal medicine residents and attendings. The topics include: "Introduction to Point-of-Care Ultrasound", "Focused Assessment with Sonography of Trauma", "Basic Cardiac, Pulmonary and Vascular Ultrasound", "Rapid Ultrasound in Shock" and "Ultrasound Guided Central Lines". The use of POCUS should aid in rapid diagnosis, decrease complications associated with bed-side procedures, and ultimately improve patient care. PMID- 28661108 TI - [ENDOSCOPIC RESECTION OF ZENKER DIVERTICULUM - A SINGLE CENTER EXPERIENCE]. AB - BACKGROUND: Zenker diverticulum (ZD) is a pseudodiverticulum and usually affects males in the 6th-9th decade of life, symptoms include dysphagia, regurgitation, chronic cough, aspiration, halitosis and weight loss. Surgery has been the mainstay treatment of symptomatic ZD and can be divided into external and intraluminal (endoscopic) techniques. METHODS: Charts of all patients who had endoscopic correction of ZD in a tertiary referral center in the last 5 years were retrieved. RESULTS: Twenty patients, 90% were male, with ZD were reviewed with mean age of 68 +/- 9.5 years. The pre-operative mean pouch size was 3.43 +/- 0.9cm. Intraoperative pouch length was 2.55 +/- 1.5 cm. No major complications such as emphysema and mediastinitis were reported. The recurrence rate was 20%; 3 patients had revision endoscopic procedure and 1 had open surgery. CONCLUSIONS: Intraoperative length measure of Zenker diverticulum provides a good estimation of its size, with a more discreet and accurate dissection seeming to decrease the rate of major complications. Recurrence rate seems higher in small diverticulum. However, endoscopic treatment of these small diverticulum is safe with a tremendous impact on the patient's quality of life. PMID- 28661109 TI - [THE MULTIDISCIPLINARY MUSCLE INVASIVE BLADDER CANCER CLINIC AT THE RABIN MEDICAL CENTER]. PMID- 28661110 TI - [SINGLE FETAL DEMISE IN MONOCHORIONIC TWINS]. AB - INTRODUCTION: Single fetal death in a monochorionic twin pregnancy is more frequent than in a dichorionic twin gestation. Due to inter-twin vascular anastomosis in the monochorionic common placenta, the death of one twin causes a drop in blood pressure due to a shift of blood from the survivor to the dead fetus. If the drop of blood pressure is abrupt and serious, the survivor will die soon after (as occurs in 15% of cases). If the drop is less serious, the survivor may sustain ischemic injury (in about 26% of the cases) and if the drop in blood pressure is subtle, the survivor will be intact. Thus, 30% of survivors will sustain serious, mainly brain, injury - a significantly higher incidence than was previously reported. The diagnosis of single fetal demise in a monochorionic twin pregnancy is usually reached at an unknown interval from the co-twin's death and hence, damage has already occurred and there is no need for an untimely delivery of the survivor. PMID- 28661111 TI - [AT THE CROSSROADS: THE ROLE OF LABORATORY MEDICINE IN THE PATIENT CARE PROCESS]. AB - INTRODUCTION: In recent decades, the laboratory medicine profession has undergone significant changes due to both technological developments and economic constraints. Technological innovations support automation, provide faster and more accurate equipment, and allow increased efficiency through the use of commercial test kits. These changes, combined with budgetary constraints, have led to mergers and centralization of medical laboratories to optimize work and cut costs. While this centralization may be a business necessity, it leads to a disconnection between the laboratory and the clinical context. In addition, laboratory tests are treated as a commodity, which places emphasis on price only, rather than quality. In this article, we review the developments and changes that medical laboratories and the laboratory medicine profession have undergone in recent decades. We focus on technological and structural challenges affecting the functioning of medical laboratories and the relations between laboratory workers and medical teams. We then introduce vocational education changes required for the laboratory medicine profession. We propose defining the role of medical laboratory directors in terms of their basic training as medical doctors or doctors of science. We suggest that laboratory employees should become a reliable source of information regarding selection of appropriate test methods, processing data and presenting the results to the medical staff. Laboratory workers must deepen their clinical knowledge and become an integral part of the patient care process, along with medical and nursing staff. Special training programs for medical laboratory workers and directors must be developed in order to match the complex activities currently being conducted in laboratories. PMID- 28661112 TI - [TRENDS IN THE RATE OF OCCUPATIONAL PHYSICIANS VERSUS MANPOWER IN ISRAEL - STATUS AND SOLUTIONS]. AB - BACKGROUND: The specialization in occupational health was recognized in Israel in 1990. The number of specialists grew gradually over the years, yet a systematic analysis of occupational health physicians (OHP)/workers' ratio was never conducted. OBJECTIVES: To determine the trends of OHP/workers' ratio in Israel and the future activities needed in order to achieve the standards of developed countries. METHODS: The socio-demographic data was obtained by personal communication, from the Israeli Association of Occupational Medicine and Maccabi Health Services. The remaining data was obtained from publications of the Ministry of Health and the National Insurance Institute. RESULTS: By March 2014, 157 OHPs were registered in Israel, 104 active specialists and 25 residents. Among the specialists, 78 worked in the Health Maintenance Organizations (HMO), 18 in the public sector (other than HMOs) and 8 in the private sector. Even though the number of workers rises every year, the number of OHP has remained stable in the last 10 years, around 90-100 physicians. The ratio of occupational health physicians/workers in the HMOs is 1:48,000. CONCLUSIONS: The ratio of OHP/workers in Israel is comparable to the ratio in developing countries and 8-10 times less in comparison to the developed countries with a Gross Domestic Product (GDP) similar to Israel. The rate has decreased since 2007. The reason for the stable numbers is the lack of payments by the employers and the fact that the subject has been ignored by the regulatory authorities. DISCUSSION: The way to improve this situation is by doubling the number of residents every year by providing the required resources to support this new arrangement. The funds have to come from the employers, the Ministry of Economy and the Ministry of Health. PMID- 28661113 TI - [PREVALENCE OF IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA IN INFANTS AGED 9 TO 15 MONTHS IN A LOW INCOME POPULATION (2005-2010)]. AB - BACKGROUND: Iron deficiency (ID) is a common nutritional deficiency. OBJECTIVES: To estimate the prevalence and causes of ID and iron deficiency anemia (IDA) and to report the iron status in Israeli Arab infants. METHODS: Data on iron status was taken from 410 infants, aged 9 to 15 months, who were randomly selected from 2400 infants born between 2005-2010. Hemoglobin (Hb) <11 g/dL, ferritin <12 MUg/L and mean corpuscular volume (MCV) <70 fL were the criteria for establishing IDA, and ferritin<12 MUg/L and MCV <70 fL for establishing ID. RESULTS: Of the 410 infants, 116 (28%) had Hb <11 g/dL, and 68 (17%) had MCV<70 fL. We were able to analyze the samples of 368 infants for ferritin: 27 (7%) had ferritin <12 MUg/L. Iron deficiency anemia (Hb <11 g/dL and ferritin <12 MUg/L) was diagnosed in 15/368 infants (4%).The IDA rate was 2% (10/368 infants) when the criteria of three factors (Hb <11 g/dL and ferritin <12 MUg/L, MCV <70 fL) were used. Infants who were breastfed >6 months were significantly less prone to have anemia (P > 0.002) and infants who received >6 months of iron supplements were also less prone to have anemia (P < 0.05). CONCLUSIONS: Studies are needed for establishing valid cutoff points for diagnosing ID and IDA and for identifying the causes of the high rate of anemia in the absence of ID. Breastfeeding and iron preparation supplementation are recommended and the test of ferritin at one year of age could be considered. PMID- 28661116 TI - Dental Emergencies: Management Strategies That Improve Outcomes [Digest]. AB - Points & Pearls is a digest of Emergency Medicine Practice. Acute dental emergencies are a common chief complaint presenting to emergency departments, and they are increasing substantially in frequency. The diagnosis and management of dental emergencies is a core competency of the emergency clinician, and proper therapeutic strategies can significantly improve cosmetic and functional outcomes for patients. This issue provides a systematic review of the literature on common acute traumatic and atraumatic dental emergencies with a focus on the historical and physical examination findings that must be understood to identify life threatening infections, relieve pain, salvage natural teeth, and communicate with specialists in the further management of patients after emergency treatment. PMID- 28661118 TI - Nanostructured Phosphorus Doped Silicon/Graphite Composite as Anode for High Performance Lithium-Ion Batteries. AB - Silicon as the potential anode material for lithium-ion batteries suffers from huge volume change (up to 400%) during charging/discharging processes. Poor electrical conductivity of silicon also hinders its long-term cycling performance. Herein, we report a two-step ball milling method to prepare nanostructured P-doped Si/graphite composite. Both P-doped Si and coated graphite improved the conductivity by providing significant transport channels for lithium ions and electrons. The graphite skin is able to depress the volume expansion of Si by forming a stable SEI film. The as-prepared composite anode having 50% P doped Si and 50% graphite exhibits outstanding cyclability with a specific capacity of 883.4 mAh/g after 200 cycles at the current density of 200 mA/g. The cost-effective materials and scalable preparation method make it feasible for large-scale application of the P-doped Si/graphite composite as anode for Li-ion batteries. PMID- 28661119 TI - Versatile Dual Photoresponsive System for Precise Control of Chemical Reactions. AB - A versatile method for photoregulation of chemical reactions was developed through a combination of near-infrared (NIR) and ultraviolet (UV) light sensitive materials. This regulatory effect was achieved through photoresponsive modulation of reaction temperature and pH values, two prominent factors influencing reaction kinetics. Photothermal nanomaterial graphene oxide (GO) and photobase reagent malachite green carbinol base (MGCB) were selected for temperature and pH regulation, respectively. Using nanocatalyst- and enzyme-mediated chemical reactions as model systems, we demonstrated the feasibility and high efficiency of this method. In addition, a photoresponsive, multifunctional "Band-aid"-like hydrogel platform was presented for programmable wound healing. Overall, this simple, efficient, and reversible system was found to be effective for controlling a wide variety of chemical reactions. Our work may provide a method for remote and sustainable control over chemical reactions for industrial and biomedical applications. PMID- 28661120 TI - Analyzing the Folding and Binding Steps of an Intrinsically Disordered Protein by Protein Engineering. AB - Intrinsically disordered proteins (IDPs) are functionally active despite lacking a well-defined three-dimensional structure. Such proteins often undergo a disorder-to-order transition, or induced folding, when binding to their specific physiological partner. Because of cooperativity, the folding and binding steps typically appear as a single event, and therefore, induced folding is extremely difficult to characterize experimentally. In this perspective, the interaction between the disordered C-terminal domain of the measles virus nucleoprotein NTAIL and the folded X domain of the viral phosphoprotein (XD) is particularly interesting because the inherent complexity of the observed kinetics allows characterization of the binding and folding steps individually. Here we present a detailed structural description of the folding and binding events occurring in the recognition between NTAIL and XD. This result was achieved by measuring the effect of single-amino acid substitutions in NTAIL on the reaction mechanism. Analysis of the experimental data allowed us (i) to identify the key residues involved in the initial recognition between the two molecules and (ii) to depict the general features of the folding pathway of NTAIL. Furthermore, an analysis of the changes in stability obtained for the whole set of variants highlights how the sequence of this IDP has not been selected during evolution to fold efficiently. This feature might be a consequence of the weakly funneled nature of the energy landscape of IDPs in their unbound state and represents a plausible explanation of their highly dynamic nature even in the bound state, typically defined as "fuzziness". PMID- 28661121 TI - Dual-Mode Imaging-Guided Synergistic Chemo- and Magnetohyperthermia Therapy in a Versatile Nanoplatform To Eliminate Cancer Stem Cells. AB - Cancer stem cells (CSCs) have been identified as a new target for therapy in diverse cancers. Traditional therapies usually kill the bulk of cancer cells, but are often unable to effectively eliminate CSCs, which may lead to drug resistance and cancer relapse. Herein, we propose a novel strategy: fabricating multifunctional magnetic Fe3O4@PPr@HA hybrid nanoparticles and loading it with the Notch signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S phenylglycinet-butylester (DAPT) to eliminate CSCs. Hyaluronic acid ligands greatly enhance the accumulation of the hybrid nanoparticles in the tumor site and in the CSCs. Both hyaluronase in the tumor microenvironment and the magnetic hyperthermia effect of the inner magnetic core can accelerate the release of DAPT. This controlled release of DAPT in the tumor site further enhances the ability of the combination of chemo- and magnetohyperthermia therapy to eliminate cancer stem cells. With the help of polypyrrole-mediated photoacoustic and Fe3O4 mediated magnetic resonance imaging, the drug release can be precisely monitored in vivo. This versatile nanoplatform enables effective elimination of the cancer stem cells and monitoring of the drugs. PMID- 28661122 TI - pH-Responsive Dimeric Zinc(II) Phthalocyanine in Mesoporous Silica Nanoparticles as an Activatable Nanophotosensitizing System for Photodynamic Therapy. AB - An acid-cleavable acetal-linked zinc(II) phthalocyanine dimer with an azido terminal group (cPc) was prepared and conjugated to alkyne-modified mesoporous silica nanoparticles via copper(I)-catalyzed alkyne-azide cycloaddition reaction. For comparison, an amine-linked analogue (nPc) was also prepared as a non-acid cleavable counterpart. These dimeric phthalocyanines were significantly self quenched due to the close proximity of the phthalocyanine units inside the mesopores, resulting in much weaker fluorescence emission and singlet oxygen generation, both in N,N-dimethylformamide and in phosphate-buffered saline (PBS), compared with the free molecular counterparts. Under acidic conditions in PBS, the cPc-encapsulated nanosystem was activated in terms of fluorescence emission and singlet oxygen production. After internalization into human colon adenocarcinoma HT29 cells, it exhibited much higher intracellular fluorescence and photocytotoxicity compared to the nanosystem entrapped with nPc. The activation of this nanosystem was also demonstrated in tumor-bearing nude mice. The intratumoral fluorescence intensity increased gradually over 24 h, while for the nPc counterpart the fluorescence remained very weak. The results suggest that this nanosystem serves as a promising activatable nanophotosensitizing agent for photodynamic therapy. PMID- 28661123 TI - Mononuclear Lanthanide Complexes: Energy-Barrier Enhancement by Ligand Substitution in Field-Induced DyIII SIMs. AB - The sequential reaction of 2-((6-(hydroxymethyl)pyridin-2-yl) methyleneamino)phenol (LH2), LnCl3.6H2O, and 1,1,1-trifluoroacetylacetone (Htfa) in the presence of Et3N afforded [Ln(LH) (tfa)2] [Ln = Dy3+ (1), Ln = Tb3+ (2), and Ln = Gd3+ (3)], while under the same reaction conditions, but in the absence of the coligand, another series of mononuclear complexes, namely, [Ln(LH)2].Cl.2MeOH] [Ln = Dy3+ (4) and Tb3+ (5)] are obtained. Single-crystal X ray diffraction analysis revealed that the former set contains a mono deprotonated [LH]- and two tfa ligands, while the latter set comprises of two mono-deprotonated [LH]- ligands that are nearly perpendicular to each other at an angle of 86.9 degrees . Among these complexes, 2 exhibited a ligand-sensitized lanthanide-characteristic emission. Analyses of the alternating current susceptibility measurements reveal the presence of single-molecule magnet behavior for 1 and 4, in the presence of direct-current field, with effective energy barriers of 4.6 and 44.4 K, respectively. The enhancement of the effective energy barrier of the latter can be attributed to the presence of a large energy gap between the ground and first excited Kramers doublets, triggered by the change in coordination environments around the lanthanide centers. PMID- 28661124 TI - Stable Open-Shell Phosphorane Based on a Redox-Active Amidodiphenoxide Scaffold. AB - The synthesis and redox reactivity of pentacoordinate phosphorus compounds incorporating a redox-active ONO amidodiphenoxide scaffold [ONO = N,N-bis(3,5-di tert-butyl-2-phenoxide)amide] are described. Dichloro- and diphenylphosphoranes, 2.Cl2 and 2.Ph2, respectively, are synthesized and crystallographically characterized. Cyclic voltammograms of 2.Cl2 show only a single irreversible oxidation (Epa = +0.83 V vs Cp2Fe0/+), while the diphenyl analogue 2.Ph2 is reversibly oxidized at lower applied potential (E1/2 = +0.47 V vs Cp2Fe0/+). Chemical oxidation of 2.Ph2 with AgBF4 produces the corresponding radical cation [2.Ph2]*+, where electron paramagnetic resonance spectroscopy and density functional theory calculations reveal that the unpaired spin density is largely ligand-based and is highly delocalized throughout the ONO framework of the paramagnetic species. The solid-state structures indicate only minor geometrical changes between the neutral 2.Ph2 and oxidized [2.Ph2]*+ species, consistent with fast self-exchange electron transfer, as observed by NMR line-broadening experiments. PMID- 28661125 TI - Phasor-FLIM as a Screening Tool for the Differential Diagnosis of Actinic Keratosis, Bowen's Disease, and Basal Cell Carcinoma. AB - The aim of this study was to distinguish basal cell carcinoma (BCC) from actinic keratosis (AK) and Bowen's disease (BD) by fluorescence lifetimes of hematoxylin and eosin (H&E) and phasor analysis. Pseudocolor images of average fluorescence lifetime (taum) exhibited more contrast than conventional bright field and/or fluorescence images of H&E-stained sections. The mean values (MU) of taum distribution (taumMU) in three layers of skin were first explored for comparison with the corresponding layers of AK, BD, and BCC. Moreover, analysis of the H&E fluorescence lifetimes in the phasor space was performed by observing clusters in specific regions of the phasor plot. Various structures in the skin were distinguished. Comparisons of phase distributions from the corresponding layers of skin resulted in quantitative separation and calculation of distinctive parameters including coordinate values, diagonal slopes, and phasor areas. The combination of fluorescence lifetime imaging microscopy (FLIM) and phasor approach (phasor-FLIM) provides a simple method for histopathology analysis and can significantly improve the accuracy of bright field H&E diagnosis. We therefore believe that phasor-FLIM is an aided tool with the potential to provide rapid confirmation of diagnostic criteria and classification of histological types of skin neoplasms. PMID- 28661126 TI - Transition Metal Ions Enable the Transition from Electrospun Prolamin Protein Fibers to Nitrogen-Doped Freestanding Carbon Films for Flexible Supercapacitors. AB - Flexible carbon ultrafine fibers are highly desirable in energy storage and conversion devices. Our previous finding showed that electrospun hordein/zein fibers stabilized by Ca2+ were successfully transferred into nitrogen-doped carbon ultrafine fibers for supercapacitors. However, their relatively brittle nature needed to be improved. Inspired by this stabilizing effect of Ca2+, in this work, four transition metal divalent cations were used to assist the formation of flexible hordein/zein-derived carbon ultrafine fibers. Without alteration of the electrospinnability, adequate amounts of zinc acetate and cobalt acetate supported the fibrous structure during pyrolysis. This resulted in flexible freestanding carbon films consisting of well-defined fibers with nitrogen-doped graphitic layers and hierarchical pores. These carbon films were easily cut into small square pieces and directly applied as working electrode in the three-electrode testing system without the need for polymer binders or conducting agents. Notably, the hz-Zn0.3-p electrode, synthesized with 0.3 mol/L Zn2+ and post-acid treatment, exhibited a specific capacitance of 393 F/g (at 1 A/g), a large rate capability (72.3% remained at 20 A/g), and a capacitance retention of ~98% after 2000 charging-discharging cycles at 10 A/g. These superior electrochemical properties were attributed to the synergistic effects of the well-developed graphitic layers induced by Zn2+, the nitrogen-decorated carbon structure, and the interconnected channels generated by HCl treatment. This research advances potential applications for prolamin proteins as nitrogen containing raw materials in developing carbon structures for high-performance supercapacitors. PMID- 28661127 TI - Challenges in DNA Delivery and Recent Advances in Multifunctional Polymeric DNA Delivery Systems. AB - After more than 20 years of intensive investigations, gene therapy has become one of the most promising strategies for treating genetic diseases. However, the lack of ideal delivery systems has limited the clinical realization of gene therapy's tremendous potential, especially for DNA-based gene therapy. Over the past decade, considerable advances have been made in the application of polymer-based DNA delivery systems for gene therapy, especially through multifunctional systems. The core concept behind multifunctional polymeric DNA delivery systems is to endow one single DNA carrier, via materials engineering and surface modification, with several active functions, e.g., good cargo DNA protection, excellent colloidal stability, high cellular uptake efficiency, efficient endo/lysosome escape, effective import into the nucleus, and DNA unpacking. Such specially developed vectors would be capable of overcoming multiple barriers to the successful delivery of DNA. In this review, we first provide a comprehensive overview of the interactions between the protein corona and DNA vectors, the mechanisms and challenges of nonviral DNA vectors, and important concepts in the design of DNA carriers identified via past reports on DNA delivery systems. Finally, we highlight and discuss recent advances in multifunctional polymeric DNA delivery systems based on "off-the-shelf" polycations including polyethylenimine (PEI), poly-l-lysine (PLL), and chitosan and offer perspectives on future developments. PMID- 28661128 TI - High-Mobility InSe Transistors: The Role of Surface Oxides. AB - In search of high-performance field-effect transistors (FETs) made of atomic thin semiconductors, indium selenide (InSe) has held great promise because of its high intrinsic mobility and moderate electronic band gap (1.26 eV). Yet the performance of InSe FETs is decisively determined by the surface oxidation of InSe taking place spontaneously in ambient conditions, setting up a mobility ceiling and causing an uncontrollable current hysteresis. Encapsulation by hexagonal boron nitride (h-BN) has been currently used to cope with this deterioration. Here, we provide insights into the role of surface oxides played in device performance and introduce a dry-oxidation process that forms a dense capping layer on top, where InSe FETs exhibit a record-high two-probe mobility of 423 cm2/V.s at room temperature and 1006 cm2/V.s at liquid nitrogen temperature without the use of h-BN encapsulation or high-kappa dielectric screening. Ultrahigh on/off current ratio of >108 and current density of 365 MUA/MUm can be readily achieved without elaborate engineering of drain/source contacts or gating technique. Thickness-dependent device properties are also studied, with optimized performance shown in FETs comprising of 13 nm thick InSe. The high performance of InSe FETs with ultrathin dry oxide is attributed to the effective unpinning of the Fermi level at the metal contacts, resulting in a low Schottky barrier height of 40 meV in an optimized channel thickness. PMID- 28661129 TI - Supernormal Conversion Anode Consisting of High-Density MoS2 Bubbles Wrapped in Thin Carbon Network by Self-Sulfuration of Polyoxometalate Complex. AB - Large-capacity conversion electrodes are highly required to raise the energy density of batteries. However, their undesired phase segregation and volume expansion during cycling lead to the motivation for nanofabrication and nanochemistry of active species in order to decrease "dead mass" and promote better construction of conductive networks. However, the inactivity of the conductive skeleton and loose nanostructure would compromise the energy density of the electrode. The integration of large-sized (high-density) grains into an electroactive conductive network in a compact way is still a big challenge. Here we report a proof-of-concept prototype consisting of unusual MoS2 solid bubbles of hundreds of nanometers in size, which are conformally encapsulated by thin layer carbon. The seamless welding between this carbon coating and the surrounding broader carbon substrate can effectively avoid the peel-off of active species and breakage of the conductive network. This MoS2-C composite is achieved by simultaneous self-sulfuration and self-carbonization of a polyoxometalate (POM)-based chelate, and its Li-storage performance is superior to most MoS2 based anodes even with ultrathin 2D nanosheets. Partially benefiting from the electroactivity of a dithiooxamide (DTO)-derivate carbon network, the reversible capacity of MoS2-C by pyrolyzing the POM-DTO chelate can reach 1500-2000 mAh/g at 0.5-1 A/g even after 700 cycles and be maintained around 1000 mAh/g under as high as 10-20 A/g. PMID- 28661130 TI - Uncoordinated Amine Groups of Metal-Organic Frameworks to Anchor Single Ru Sites as Chemoselective Catalysts toward the Hydrogenation of Quinoline. AB - Here we report a precise control of isolated single ruthenium site supported on nitrogen-doped porous carbon (Ru SAs/N-C) through a coordination-assisted strategy. This synthesis is based on the utilization of strong coordination between Ru3+ and the free amine groups (-NH2) at the skeleton of a metal-organic framework, which plays a critical role to access the atomically isolated dispersion of Ru sites. Without the assistance of the amino groups, the Ru precursor is prone to aggregation during the pyrolysis process, resulting in the formation of Ru clusters. The atomic dispersion of Ru on N-doped carbon can be verified by the spherical aberration correction electron microscopy and X-ray absorption fine structure measurements. Most importantly, this single Ru sites with single-mind N coordination can serve as a semihomogeneous catalyst to catalyze effectively chemoselective hydrogenation of functionalized quinolones. PMID- 28661132 TI - Stability and Nature of Chemically Exfoliated MoS2 in Aqueous Suspensions. AB - We reveal that chemically exfoliated MoS2 nanosheets undergo lateral fracture and aggregation upon prolonged storage of the dispersion in ambient air, which was found to be associated with the reoxidation of the nanosheets. Such nanosheet degradation could be effectively prevented by storing the sample in an inert atmosphere to suppress the reoxidation process. PMID- 28661131 TI - Molecular Simulations Reveal an Unresolved Conformation of the Type IA Protein Kinase A Regulatory Subunit and Suggest Its Role in the cAMP Regulatory Mechanism. AB - We identify a previously unresolved, unrecognized, and highly stable conformation of the protein kinase A (PKA) regulatory subunit RIalpha. This conformation, which we term the "Flipback" structure, bridges conflicting characteristics in crystallographic structures and solution experiments of the PKA RIalpha heterotetramer. Our simulations reveal a hinge residue, G235, in the B/C helix that is conserved through all isoforms of RI. Brownian dynamics simulations suggest that the Flipback conformation plays a role in cAMP association to the A domain of the R subunit. PMID- 28661133 TI - Enantiospecific Synthesis of ortho-Substituted Benzylic Boronic Esters by a 1,2 Metalate Rearrangement/1,3-Borotropic Shift Sequence. AB - Coupling reactions between benzylamines and boronic esters have been investigated. ortho-Lithiated benzylamines react with boronic esters and a N activator to afford ortho-substituted benzylic boronic esters with formal 1,1' benzylidene insertion into the C-B bond. The reaction occurs by a SN2' elimination and 1,2-metalate rearrangement of the N-activated boronate complex to afford a dearomatized intermediate, which undergoes a Lewis-acid catalyzed 1,3 borotropic shift to afford the boronic ester products in high yield and with excellent enantiospecificity. The use of enantioenriched alpha-substituted benzylamines gave the corresponding secondary boronic esters with high ee. PMID- 28661134 TI - Magnetic Anisotropy from Main-Group Elements: Halides versus Group 14 Elements. AB - Precise modulation of the magnetic anisotropy of a transition-metal center would affect physical properties ranging from photoluminescence to magnetism. Over the past decade, exerting nuanced control over ligand fields enabled the incorporation of significant magnetic anisotropy in a number of mononuclear transition-metal complexes. An alternate approach to increasing spin-orbit coupling relies upon using heavy diamagnetic main-group elements as sources of magnetic anisotropy. Interacting first-row transition metals with main-group elements enables the transfer of magnetic anisotropy to the paramagnetic metal center without restricting coordination geometry. We sought to study the effect of covalency on this anisotropy transfer by probing the effect of halides in comparison to early main-group elements. Toward that end, we synthesized a series of four isostructural heterobimetallic complexes, with germanium or tin covalently bound to a triplet spin Fe(II) center. These complexes are ligated by a halide (Br- or I-) in the apical position to yield a series of complexes with variation in the mass of the main-group elements. This series enabled us to interrogate which electronic structure factors influence the heavy-atom effect. Using a suite of approaches including magnetometry, computation, and Mossbauer spectroscopy, we probed the electronic structure and the spin-orbit coupling, as parametrized by axial zero-field splitting across the series of complexes, and found an increase in zero-field splitting from -11.8 to -17.9 cm-1 by increasing the axial ligand mass. Through direct comparison between halides and group 14 elements, we observe a greater impact on magnetic anisotropy from the halide interaction. We attribute this counterintuitive effect to a larger spin population on the halide elements, despite greater covalency in the group 14 interactions. These results recommend modification of the intuitive design principle of increasing covalency toward a deeper focus on the interactions of the spin-bearing orbitals. PMID- 28661135 TI - Modeling CO2-Water-Mineral Wettability and Mineralization for Carbon Geosequestration. AB - Carbon dioxide (CO2) capture and storage (CCS) is an important climate change mitigation option along with improved energy efficiency, renewable energy, and nuclear energy. CO2 geosequestration, that is, to store CO2 under the subsurface of Earth, is feasible because the world's sedimentary basins have high capacity and are often located in the same region of the world as emission sources. How CO2 interacts with the connate water and minerals is the focus of this Account. There are four trapping mechanisms that keep CO2 in the pores of subsurface rocks: (1) structural trapping, (2) residual trapping, (3) dissolution trapping, and (4) mineral trapping. The first two are dominated by capillary action, where wettability controls CO2 and water two-phase flow in porous media. We review state-of-the-art studies on CO2/water/mineral wettability, which was found to depend on pressure and temperature conditions, salt concentration in aqueous solutions, mineral surface chemistry, and geometry. We then review some recent advances in mineral trapping. First, we show that it is possible to reproduce the CO2/water/mineral wettability at a wide range of pressures using molecular dynamics (MD) simulations. As the pressure increases, CO2 gas transforms into a supercritical fluid or liquid at ~7.4 MPa depending on the environmental temperature. This transition leads to a substantial decrease of the interfacial tension between CO2 and reservoir brine (or pure water). However, the wettability of CO2/water/rock systems depends on the type of rock surface. Recently, we investigated the contact angle of CO2/water/silica systems with two different silica surfaces using MD simulations. We found that contact angle increased with pressure for the hydrophobic (siloxane) surface while it was almost constant for the hydrophilic (silanol) surface, in excellent agreement with experimental observations. Furthermore, we found that the CO2 thin films at the CO2 hydrophilic silica and CO2-H2O interfaces displayed a linear correlation, which can in turn explain the constant contact angle on the hydrophilic silica surface. In view of the literature and our study results, a few recommendations seem necessary to construct a molecular system suitable to study wettability with MD simulations. Future work should be conducted to determine the influence of brine salinity on the wettability of minerals with high cation exchange capacity. Mineral trapping is believed to be an extremely slow process, likely taking thousands of years. However, a recent pilot study demonstrated that CO2 mineralization occurs within 2 years in highly reactive basalt reservoirs. A first-principles MD study has also shown that carbonation reactions occur rapidly at the surface oxygen sites of a reactive mineral. We observed carbonate ions on both a newly cleaved quartz surface (without hydrolysis), and a basalt andesine surface after hydrolysis in a CO2-rich environment. Future work should consider the influence of water, gas impurities, and mineral cation type on carbonation. PMID- 28661136 TI - Insertable NO/CO Microsensors Recording Gaseous Vasomodulators Reflecting Differential Neuronal Activation Level with Respect to Seizure Focus. AB - Nitric oxide (NO) and carbon monoxide (CO) are important signaling molecules shaping vasomodulation. This paper reports simultaneous in vivo monitoring of NO, CO and dendritic summation of action potential at three different cortical regions: seizure focus and two additional places, vertically and horizontally separated by 1.2 mm from the seizure focus, during epileptic seizure induced by 4 aminopyrindine injection. An amperometric dual microsensor having a high spatiotemporal resolution monitored fast and dynamic changes of NO and CO, and neural changes were recorded with a glass pipet electrode for local field potential (LFP). At all three locations, onsets and offsets of NO and CO changes well synchronized with fast LFP changes, while the patterns and concentrations of NO and CO changes were varied depending on the sensing locations. The insertable NO/CO dual microsensor was successful to measure intimately linked NO and CO in acute seizure events with high sensitivity, selectivity, and spatiotemporal resolution. PMID- 28661137 TI - Fabrication and Structural Characterization of an Ultrathin Film of a Two Dimensional-Layered Metal-Organic Framework, {Fe(py)2[Ni(CN)4]} (py = pyridine). AB - We report the fabrication and characterization of the first example of a tetracyanonickelate-based two-dimensional-layered metal-organic framework, {Fe(py)2Ni(CN)4} (py = pyridine), thin film. To fabricate a nanometer-sized thin film, we utilized the layer-by-layer method, whereby a substrate was alternately soaked in solutions of the structural components. Surface X-ray studies revealed that the fabricated film was crystalline with well-controlled growth directions both parallel and perpendicular to the substrate. In addition, lattice parameter analysis indicated that the crystal system is found to be close to higher symmetry by being downsized to a thin film. PMID- 28661138 TI - Three-Dimensional Scaffold Chip with Thermosensitive Coating for Capture and Reversible Release of Individual and Cluster of Circulating Tumor Cells. AB - Tumor metastasis is attributed to circulating tumor cells (CTC) or CTC clusters. Many strategies have hitherto been designed to isolate CTCs, but there are few methods that can capture and gently release CTC clusters as efficient as single CTCs. Herein, we developed a three-dimensional (3D) scaffold chip with thermosensitive coating for high-efficiency capture and release of individual and cluster CTCs. The 3D scaffold chip successfully combines the specific recognition and physically obstructed effect of 3D scaffold structure to significantly improve cell clusters capture efficiency. Thermosensitive gelatin hydrogel uniformly coated on the scaffold dissolves at 37 degrees C quickly, and the captured cells are gently released from chip with high viability. Notably, this platform was applied to isolate CTCs from cancer patients' blood samples. This allows global DNA and RNA methylation analysis of collected single CTC and CTC clusters, indicating the great potential of this platform in cancer diagnosis and downstream analysis at the molecular level. PMID- 28661139 TI - Achieving Mainstream Nitrogen Removal through Coupling Anammox with Denitratation. AB - Achieving maintream anammox is critical for energy-neutral sewage treatment. This study presents a new way to achieve mainstream anammox, which couples anammox with denitratation (nitrate reduction to nitrite) instead of nitritation (ammonium oxidation to nitrite). An anoxic/oxic (A/O) biofilm system treating systhetic domestic wastewater was used to demonstrate this concept for over 400 days. This A/O biofilm system achieved a total nitrogen (TN) removal efficiency of 80 +/- 4% from the influent with a low C/N ratio of 2.6 and a TN concentration of 60.5 mg/L. Nitrogen removal via anammox was found to account for 70% of dinitrogen production in the anoxic reactor. Batch tests confirmed that the anoxic biofilm could oxidize ammonium using nitrite as electron acceptor, and that it had a higher nitrate reduction rate than the nitrite reduction rate, thus producing nitrite for the anammox reaction. Metagenomic analysis showed that Candidatus Jettenia caeni and Candidatus Kuenenia stuttgartiensis were the top two dominant species in anoxic biofilm. Genes involved in the metabolism of the anammox process were detected in anoxic biofilm. The abundance of nitrate reductase (73360 hits) was much higher than nitrite reductase (13114 hits) in anoxic biofilm. This system can be easily integrated with the high-rate activated sludge technology, which produces an effluent with a low C/N ratio. While this new design consumes 21% more oxygen in comparison to the currently studied nitritation/anammox process, the nitrite-producing process appears to be more stable. PMID- 28661140 TI - Exploring the Dynamics of the Photoinduced Ring-Opening of Heterocyclic Molecules. AB - Excited states formed by electron promotion to an antibonding sigma* orbital are now recognized as key to understanding the photofragmentation dynamics of a broad range of heteroatom containing small molecules: alcohols, thiols, amines, and many of their aromatic analogues. Such excited states may be populated by direct photoexcitation, or indirectly by nonadiabatic transfer of population from some other optically excited state (e.g., a pipi* state). This Perspective explores the extent to which the fast-growing literature pertaining to such (n/pi)sigma* state mediated bond fissions can inform and enhance our mechanistic understanding of photoinduced ring-opening in heterocyclic molecules. PMID- 28661141 TI - Stretching Temperature Dependency of Fibrillation Process in Isotactic Polypropylene. AB - Isotactic polypropylene samples annealed at three temperatures were used to explore their fibrillation behaviors during tensile deformation at elevated temperatures via in situ synchrotron small and wide-angle X-ray scattering techniques. Fibrillation denotes the transition of the isotropic spherulitic morphology into a highly oriented one during tensile stretching of a semicrystalline polymer. It was found that the fibrillation was accomplished by a stress-induced melting and recrystallization process. Three regions, identified as fibrillation with the formation of only mesophase, fibrillation with the formation of both mesophase and alpha crystallites, and fibrillation with the formation of complete alpha modification, were identified in a map of deformation and annealing temperature. Such results are tightly linked to the different molecular mobilities of the samples prepared at different annealing temperatures and deformed at different temperatures. Lower annealing temperature and higher deformation temperature facilitate formation of alpha modification after stress induced mechanical melting of the original crystallites. However, thicker lamellar crystallite deformed at lower temperatures presenting limited chain mobility ends up with a large amount of oriented mesophase structure. PMID- 28661142 TI - Room-Temperature Coherent Optical Phonon in 2D Electronic Spectra of CH3NH3PbI3 Perovskite as a Possible Cooling Bottleneck. AB - A hot phonon bottleneck may be responsible for slow hot carrier cooling in methylammonium lead iodide hybrid perovskite, creating the potential for more efficient hot carrier photovoltaics. In room-temperature 2D electronic spectra near the band edge, we observe amplitude oscillations due to a remarkably long lived 0.9 THz coherent phonon population at room temperature. This phonon (or set of phonons) is assigned to angular distortions of the Pb-I lattice, not coupled to cation rotations. The strong coupling between the electronic transition and the 0.9 THz mode(s), together with relative isolation from other phonon modes, makes it likely to cause a phonon bottleneck. The pump frequency resolution of the 2D spectra also enables independent observation of photoinduced absorptions and bleaches independently and confirms that features due to band gap renormalization are longer-lived than in transient absorption spectra. PMID- 28661143 TI - IFPTarget: A Customized Virtual Target Identification Method Based on Protein Ligand Interaction Fingerprinting Analyses. AB - Small-molecule target identification is an important and challenging task for chemical biology and drug discovery. Structure-based virtual target identification has been widely used, which infers and prioritizes potential protein targets for the molecule of interest (MOI) principally via a scoring function. However, current "universal" scoring functions may not always accurately identify targets to which the MOI binds from the retrieved target database, in part due to a lack of consideration of the important binding features for an individual target. Here, we present IFPTarget, a customized virtual target identification method, which uses an interaction fingerprinting (IFP) method for target-specific interaction analyses and a comprehensive index (Cvalue) for target ranking. Evaluation results indicate that the IFP method enables substantially improved binding pose prediction, and Cvalue has an excellent performance in target ranking for the test set. When applied to screen against our established target library that contains 11,863 protein structures covering 2842 unique targets, IFPTarget could retrieve known targets within the top-ranked list and identified new potential targets for chemically diverse drugs. IFPTarget prediction led to the identification of the metallo-beta lactamase VIM-2 as a target for quercetin as validated by enzymatic inhibition assays. This study provides a new in silico target identification tool and will aid future efforts to develop new target-customized methods for target identification. PMID- 28661144 TI - Redfield Treatment of Multipathway Electron Transfer in Artificial Photosynthetic Systems. AB - Coherence effects on electron transfer in a series of symmetric and asymmetric two-, three-, four-, and five-site molecular model systems for photosystem I in cyanobacteria and green plants were studied. The total site energies of the electronic Hamiltonian were calculated using the density functional theory (DFT) formalism and included the zero point vibrational energies of the electron donors and acceptors. Site energies and couplings were calculated using a polarizable continuum model to represent various solvent environments, and the site-to-site couplings were calculated using fragment charge difference methods at the DFT level of theory. The Redfield formalism was used to propagate the electron density from the donors to the acceptors, incorporating relaxation and dephasing effects to describe the electron transfer processes. Changing the relative energies of the donor, intermediate acceptor, and final acceptor molecules in these assemblies has profound effects on the electron transfer rates as well as on the amplitude of the quantum oscillations observed. Increasing the ratio of a particular energy gap to the electronic coupling for a given pair of states leads to weaker quantum oscillations between sites. Biasing the intermediate acceptor energies to slightly favor one pathway leads to a general decrease in electron transfer yield. PMID- 28661145 TI - Role of Core-Shell Formation in Exciton Confinement Relaxation in Dithiocarbamate Capped CdSe QDs. AB - The possibility of exciton delocalization in alkyldithiocarbamate (ATC)-capped CdSe has been investigated for several alkyl groups and compared with phenyldithiocarbamates (PTCs). We find a bathochromic shift for ATC similar to the one obtained for PTC. Our computational studies show reduction in HOMO-LUMO gaps in both PTC and ATC, albeit with a lower shift. However, TDDFT studies revealed that ATC-capped CdSe is more of a localized HOMO state as compared with partly delocalized HOMO in PTC-capped CdSe, hinting at a difference in electronic interaction between the two binding groups. We hypothesized the formation of sulfide layer over the CdSe QDs as the possible reason for the observed bathochromic shift, as verified by absorption spectra of S2- ligand exchange samples. The formation of CdS shell leads to substantial electron delocalization because CdSe CB is in close resonance with CdS, which is exactly the opposite of what was previously concluded in the literature. PMID- 28661146 TI - Thermoresponsive Segments Retard the Formation of Equilibrium Micellar Interpolyelectrolyte Complexes by Detouring to Various Intermediate Structures. AB - The kinetics of interpolyelectrolyte complexation involving architecturally complex (star-like) polymeric components is addressed. Specifically, the spontaneous coupling of branched cationic star-shaped miktoarm polymers, i.e., quaternized poly(ethylene oxide)114-(poly(2-(dimethylamino)ethyl methacrylate)17)4 (PEO114-(qPDMAEMA17)4), and temperature-sensitive linear anionic diblock copolymers poly(vinyl sulfonate)31-b-poly(N isopropylacrylamide)27 (PVS31-b-PNIPAM27) and further rearrangements of the formed complexes were investigated by means of stopped-flow small-angle X-ray scattering (SAXS). Colloidally stable micelles were obtained upon mixing both polymers at a 1:1 charge molar ratio in saline solutions. The description of the time-resolved SAXS data with appropriate form factor models yielded dimensions for each micellar domain and detailed the picture of the time-dependent size changes and restructuring processes. A fast interpolyelectrolyte coupling and structural equilibration were observed when mixing occurs below the lower critical solution temperature (LCST) of PNIPAM, resulting in small spherical-like assemblies with hydrated PNIPAM coronal blocks. Above the LCST, the collapsed PNIPAM decelerates equilibration, though temperature as such is expected to boost the kinetics of complex formation: after a fast initial interpolyelectrolyte coupling, different nonequilibrium structures of spherical and worm-like shape are observed on different time scales. This study illustrates how a thermoresponsive component can modulate the influence of temperature on kinetics, particularly for rearrangement processes toward equilibrium structures during interpolyelectrolyte complexation. PMID- 28661147 TI - Exciton Dynamics, Transport, and Annihilation in Atomically Thin Two-Dimensional Semiconductors. AB - Large binding energy and unique exciton fine structure make the transition metal dichalcogenides (TMDCs) an ideal platform to study exciton behaviors in two dimensional (2D) systems. While excitons in these systems have been extensively researched, there currently lacks a consensus on mechanisms that control dynamics. In this Perspective, we discuss extrinsic and intrinsic factors in exciton dynamics, transport, and annihilation in 2D TMDCs. Intrinsically, dark and bright exciton energy splitting is likely to play a key role in modulating the dynamics. Extrinsically, defect scattering is prevalent in single-layer TMDCs, which leads to rapid picosecond decay and limits exciton transport. The exciton-exciton annihilation process in single-layer TMDCs is highly efficient, playing an important role in the nonradiative recombination rate in the high exciton density regime. Future challenges and opportunities to control exciton dynamics are discussed. PMID- 28661148 TI - Density Functional Physicality in Electronic Coupling Estimation: Benchmarks and Error Analysis. AB - Electronic coupling estimates from constrained density functional theory configuration interaction (CDFT-CI) depend critically on choice of density functional. In this Letter, the orbital multielectron self-interaction error (OMSIE), vertical electron affinity (VEA), and vertical ionization potential (VIP) are shown to be the key indicators inherited from the density functional that determine the accuracy of electronic coupling estimates. An error metric eta is derived to connect the three properties, based on the linear proportionality between electronic coupling and overlap integral, and the hypothesis that the slope of this line is a function of VEA/VIP, eta = (1/Ntestset)Sigmaitestset| VERef * OMSIE + DeltaVE - DeltaVE * OMSIE|i. Based on eta, BH&HLYP and LRC omegaPBEh are suggested as the best functionals for electron and hole transfer, respectively. Error metric eta is therefore a useful predictor of errors in CDFT CI electronic coupling, showing that the physical correctness of the density functional has a direct effect on the accuracy of the electronic coupling. PMID- 28661149 TI - Stereoselective Coupling of N-tert-Butanesulfinyl Aldimines and beta-Keto Acids: Access to beta-Amino Ketones. AB - The reaction of chiral N-tert-butanesulfinyl aldimines with beta-keto acids under basic conditions at room temperature proceeds with high levels of diastereocontrol, leading to beta-amino ketones in high yields. Based on DFT calculations, an eight-membered cyclic transition state involving coordination of the lithium atom to the oxygens of carboxylate and sulfinyl units was proposed, being in agreement with the observed experimental diastereomeric ratios. The synthesis of the piperidine alkaloid (-)-pelletierine was successfully undertaken in order to demonstrate the utility of this methodology. PMID- 28661150 TI - Rashba and Dresselhaus Couplings in Halide Perovskites: Accomplishments and Opportunities for Spintronics and Spin-Orbitronics. AB - In halide hybrid organic-inorganic perovskites (HOPs), spin-orbit coupling (SOC) presents a well-documented large influence on band structure. However, SOC may also present more exotic effects, such as Rashba and Dresselhaus couplings. In this Perspective, we start by recalling the main features of this effect and what makes HOP materials ideal candidates for the generation and tuning of spin states. Then, we detail the main spectroscopy techniques able to characterize these effects and their application to HOPs. Finally, we discuss potential applications in spintronics and in spin-orbitronics in those nonmagnetic systems, which would complete the skill set of HOPs and perpetuate their ride on the crest of the wave of popularity started with optoelectronics and photovoltaics. PMID- 28661151 TI - Total Synthesis of TAN1251C via Diastereoselective Construction of the Azaspiro Skeleton. AB - An efficient total synthesis of TAN1251C was accomplished by employing a Ugi four component accumulation reaction and a Dieckmann condensation to construct the spiro-fused cyclohexanone and gamma-lactam ring. Diastereoselective reduction by side-chain-controlled hydrogenation of enamide 15 or Zn reduction of oxime 23 enabled construction of the amino group with the desired stereochemistry. PMID- 28661153 TI - Synthesis of Methylenebicyclo[3.2.1]octanol by a Sm(II)-Induced 1,2-Rearrangement Reaction with Ring Expansion of Methylenebicyclo[4.2.0]octanone. AB - Direct conversion of methylenebicyclo[4.2.0]octanone to methylenebicyclo[3.2.1]octanol by a Sm(II)-induced 1,2-rearrangement with ring expansion of the methylenecyclobutane is described. Three conditions were optimized to allow the adaptation of this approach to various substrates. A rearrangement mechanism is proposed involving the generation of a ketyl radical and cyclopentanation by ketyl-olefin cyclization, followed by radical fragmentation and subsequent protonation. PMID- 28661152 TI - Profiles and Gender-Specifics of UDP-Glucuronosyltransferases and Sulfotransferases Expressions in the Major Metabolic Organs of Wild-Type and Efflux Transporter Knockout FVB Mice. AB - Hepatic and extrahepatic tissues participate in xenobiotic detoxication, carcinogen activation, prodrug processing, and estrogen regulation through UDP glucuronosyltransferases (UGTs/Ugts) and sulfotransferases (SULTs/Sults). Wild type (WT) and efflux transporter knockout (KO) FVB mice have been commonly used to perform the studies of pharmacokinetics, metabolism, and toxicity. We employed the developed UHPLC-MS/MS approach to gain systematic insight on gender-specific of Ugts and Sults in major metabolic organs. Results showed that the liver was the most abundant with Ugts/Sults, followed by the small intestine and the kidney. In the liver, Ugt2b5, Ugt2b1, Ugt1a6a, Ugt1a1, Sult1a1, and Sult1d1 were the major isoforms. The protein amounts of Ugt1a9 were significantly higher in male efflux transporter KO mice than in WT mice, whereas Ugt1a5 and Sult1a1 severely decreased in female efflux transporter KO mice. In WT and efflux transporter KO mice, the expression levels of Ugt1a1, Ugt1a5, Sult1a1, Sult1d1, and Sult3a1 were female-specific, whereas those of Ugt2b1, Ugt2b5, and Ugt2b36 were male-specific. In the small intestine, Ugt1a1, Sult1b1, and Sult2b1 were the major isoforms. The protein levels and gender differences of Ugts/Sults were obviously affected when KO of Mdr1a, and Bcrp1, Mrp1, Mrp2, and Mdr1a, respectively. The KO of efflux transporter affected the protein amounts of Ugts/Sults in the kidney, heart, and spleen. Therefore, a better understanding of the expression profiles and gender-specific of Ugts and Sults in major metabolic organs of WT and efflux transporter KO mice is useful for the evaluation of potential efficacy, and toxicity of corresponding substrates. PMID- 28661154 TI - Chiral Cyclic Ligand-Enabled Iridium-Catalyzed Asymmetric Arylation of Unactivated Racemic Allylic Alcohols with Anilines. AB - A highly enantioselective arylation of unactivated racemic secondary allylic alcohols with aniline derivatives has been developed. The transformation was enabled by an iridium-chiral cyclic phosphoramidite complex in the presence of boron trifluoride diethyl etherate as the promoter, and the reactivity and enantioselectivity of the substrates were tuned by the variation of our newly developed chiral cyclic phosphoramidite ligands together with temperature and solvents. The method shows advantages including use of the readily available starting materials, an operationally convenient protocol, full regioselectivity and excellent enantioselectivity, and tolerance of many functional groups with water as the only byproduct. PMID- 28661155 TI - Transition-Metal-Free N-O Reduction of Oximes: A Modular Synthesis of Fluorinated Pyridines. AB - An NH4I-based reductive system has been explored to promote the oxime N-O bond cleavage and thereby enable a modular synthesis of a broad range of pharmacologically significant fluorinated pyridines. Compared with traditional condensation methods for pyridine assembly, this protocol was found to be highly regio- and chemoselective and presented broad functional group tolerance. PMID- 28661156 TI - Freezing Directed Construction of Bio/Nano Interfaces: Reagentless Conjugation, Denser Spherical Nucleic Acids, and Better Nanoflares. AB - While nanoparticle solutions cannot freeze in general, they may remain stable in the presence of polymer stabilizers. We herein communicate that gold nanoparticles (AuNPs) are stable in the presence of thiolated DNA after a freeze thaw cycle. The DNA is conjugated to AuNPs during freezing without additional reagents and the conjugation can be completed in a few minutes. More importantly, the DNA density is 20-30% higher than that prepared by the typical salt-aging method. By lowering temperature, DNA hybridization is also promoted, allowing the construction of better nanoflares with doubled probe density and signaling sensitivity. This freezing method works for AuNPs from 5 to 100 nm and all tested DNA sequences. The mechanism was studied by separating the effect of temperature, freezing and thawing, where the exclusion of salt and AuNPs by the growing ice crystals is deemed critical. In addition to developing a simple method, this study articulates unique physical processes during freezing with important fundamental surface science implications, and it could be extended to other systems. PMID- 28661157 TI - Iron(III)-Catalyzed Chlorination of Activated Arenes. AB - A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide, and phenol derivatives. The reaction was utilized for the late-stage mono- and dichlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol, and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot, tandem, iron catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets. PMID- 28661158 TI - Tailoring the Structure of 58-Electron Gold Nanoclusters: Au103S2(S-Nap)41 and Its Implications. AB - We report the synthesis and crystal structure determination of a gold nanocluster with 103 gold atoms protected by 2 sulfidos and 41 thiolates (i.e., 2 naphthalenethiolates, S-Nap), denoted as Au103S2(S-Nap)41. The crystallographic analysis reveals that the thiolate ligands on the nanocluster form local tetramers by intracluster interactions of C-H...pi and pi...pi stacking. The herringbone pattern formation via intercluster interactions is also observed, which leads to a linearly connected zigzag pattern in the single crystal. The kernel of the nanocluster is a Marks decahedron of Au79, which is the same as the kernel of the previously reported Au102(pMBA)44 (pMBA = -SPh-p-COOH); this is a surprise given the much bulkier naphthalene-based ligand than pMBA, indicating the robustness of the decahedral structure as well as the 58-electron configuration. Despite the same kernel, the surface structure of Au103 is quite different from that of Au102, indicating the major role of ligands in constructing the surface structure. Other implications from Au103 and Au102 include (i) both nanoclusters show similar HOMO-LUMO gap energy (i.e., Eg ~ 0.45 eV), indicating the kernel is decisive for Eg while the surface is less critical; and (ii) significant differences are observed in the excited-state lifetimes by transient absorption spectroscopy analysis, revealing the kernel-to-surface relaxation pathway of electron dynamics. Overall, this work demonstrates the ligand-effected modification of the gold-thiolate interface independent of the kernel structure, which in turn allows one to map out the respective roles of kernel and surface in determining the electronic and optical properties of the 58e nanoclusters. PMID- 28661159 TI - Tunable Permeability of Cross-Linked Microcapsules from pH-Responsive Amphiphilic Diblock Copolymers: A Dissipative Particle Dynamics Study. AB - Using dissipative particle dynamics simulation, we probe the tunable permeability of cross-linked microcapsules made from pH-sensitive diblock copolymers poly(ethylene oxide)-b-poly(N,N-diethylamino-2-ethyl methacrylate) (PEO-b PDEAEMA). We first examine the self-assembly of non-cross-linked microcapsules and their pH-responsive collapse and then explore the effects of cross-linking and block interaction on the swelling or deswelling of cross-linked microcapsules. Our results reveal a preferential loading of hydrophobic dicyclopentadiene (DCPD) molecules in PEO-b-PDEAEMA copolymers. Upon reduction of pH, non-cross-linked microcapsules fully decompose into small wormlike clusters as a result of large self-repulsions of protonated copolymers. With increasing degree of cross-linking, the morphology of the microcapsule becomes more stable to pH change. The highly cross-linked microcapsule shell undergoes significant local polymer rearrangement in acidic solution, which eliminates the amphiphilicility and therefore enlarges the permeability of the shell. The responsive cross-linked shell experiences a disperse-to-buckle configurational transition upon reduction of pH, which is effective for the steady or pulsatile regulation of shell permeability. The swelling rate of the cross-linked shell is dependent on both electrostatic and nonelectrostatic interactions between the pH sensitive groups as well as the other groups. Our study highlights the combination of cross-linking structure and block interactions in stabilizing microcapsules and tuning their selective permeability. PMID- 28661160 TI - Styrylmalonates as an Alternative to Donor-Acceptor Cyclopropanes in the Reactions with Aldehydes: A Route to 5,6-Dihydropyran-2-ones. AB - A new strategy for modifying the reactivity of donor-acceptor cyclopropanes (DAC) has been suggested. It involves the use of isomeric styrylmalonates as alternative sources of reactive intermediates. The efficiency of the approach has been demonstrated in reactions with aromatic aldehydes. As a result, a new process for construction of the 5,6-dihydropyran-2-one skeleton has been developed. It efficiently occurs with high diastereoselectivity in the presence of BF3.Et2O; the products can be easily isolated by crystallization. The subsequent use of the resulting dihydropyranones in syntheses providing convenient access to various classes of compounds with broad molecular diversity has been demonstrated. PMID- 28661162 TI - "Why is Toma late to school again?" Preschoolers identify the most informative questions. AB - The current study investigates whether preschoolers are able to successfully identify the most effective among given questions, adapting their reliance on different types of questions (constraint-seeking vs. hypothesis-scanning) based on the quantitative measure of expected information gain. Children were presented with storybooks describing the reasons why a fictional character, Toma, was late to school over several days. In 3 experiments with 5-year-old children, we manipulated the frequency and likelihoods of the reasons presented. Children were asked to identify which of 2 given questions would be more effective in finding out why Toma was late to school again. In a fourth experiment, we investigated whether preschoolers are adaptive learners, that is, whether they can identify the most effective question iteratively, and we extended our investigation to younger preschoolers (3- and 4-year-olds). We find that children assessed the effectiveness of different types of questions based on the hypothesis space currently under consideration, and this adaptation may be guided by expected information gain. Overall, our results suggest that over the preschool years, children begin to develop the computational foundations that support successful question-asking strategies. (PsycINFO Database Record PMID- 28661161 TI - Activity level in the lab: Overlap with shyness indicates it is more than pure motoric activity. AB - The observation that children's activity level (AL) differs between novel and familiar situations is well established. What influences individual differences in how AL is different across these situations is less well understood. Drawing on animal literature, which links rats' AL when 1st placed in a novel setting with novelty seeking phenotypes, and child temperament literature, which links AL, novelty response, and shyness, we hypothesized that shyness would be an important component of children's AL in a novel situation. We examined this using mechanically assessed AL from 2 situations (the home and the lab) and 2 measures of shyness (1 parent-rated and 1 observer-rated) on up to 313 twin pairs (145 monozygotic and 168 dizygotic), at 2 and 3 years of age. Biometric genetic models removed from lab AL the variance shared with home AL, representing what was different in AL when the child entered the lab compared to the home. We report that almost half (43%) of the genetic component of AL in the lab was independent of AL in the home, and this unique genetic component shared genetic covariance with shyness. Shyness influences AL in a novel situation such as the lab, indicating that mechanically assessed AL represents more than global motoric activity and provides information on a child's temperamental response to novelty. (PsycINFO Database Record PMID- 28661163 TI - The feasibility of a culturally informed group therapy for patients with schizophrenia and their family members. AB - Research suggests that group-based psychosocial treatments for schizophrenia provide benefits to patients and family members alike. However, few existing treatments consider cultural factors that may enhance their efficacy with diverse populations. The current study examined the feasibility of a culturally informed group therapy for schizophrenia (CIGT-S), which incorporates collectivistic principles and spiritual coping into the treatment protocol. The feasibility of the group protocol was tested by examining differences in patient symptom severity and patient and family member depression, anxiety, and stress after completion of the group program. Within-groups analyses were conducted comparing baseline data to group termination data from 12 patients and 11 family members. Additionally, between-groups analyses were conducted comparing waitlist termination data from 20 patients and 13 family members to group termination data from 12 patients and 11 family members. Finally, we examined participant satisfaction with the group protocol, including qualitative reports on components of the protocol that participants deemed most valuable. Results indicated that patients demonstrated lower levels of symptom severity upon completion of the CIGT-S program; however, no other significant effects were found. Results examining overall patient and family member satisfaction with the treatment protocol indicated that patients and family members both reported being highly satisfied by the treatment program. This was also represented in participant's open-ended responses to our satisfaction questionnaire. These findings indicate that CIGT-S may represent a feasible, cost-effective approach that can be flexibly used with patients and family members of diverse racial and ethnic backgrounds. (PsycINFO Database Record PMID- 28661164 TI - Adaptation of behavioral activation in the treatment of chronic pain. AB - Chronic pain is a common problem that can be challenging to treat because of its complex history, unclear etiology, and poor response to traditional treatment approaches. A growing body of research suggests that behavioral activation (BA), which was originally developed as a treatment for depression, may be a promising treatment for chronic pain. BA involves the identification and enactment of activities that are reinforcing to the individual and consistent with his or her long-term goals. The application of BA for the treatment of chronic pain is fully consistent with models of chronic pain which post that fear and avoidance leads to a cycle of physical deconditioning, increased pain as a result of deconditioning, lack of positive reinforcement, and low mood, and further reduced motivation to physically engage. The present paper will detail the assessment and use of BA to treat "Veteran," a patient with low back and bilateral foot pain. This case study highlights how gradually increasing engagement in previously avoided activities can help disrupt the harmful cycle among pain, fear and avoidance, and mood. The implication of the outcomes from this case study for future psychotherapy research on chronic pain is also discussed. (PsycINFO Database Record PMID- 28661165 TI - Economic costs of bias-based bullying. AB - Because many school districts receive funding based on student attendance, absenteeism results in a high cost for the public education system. This study shows the direct links between bias-based bullying, school absenteeism because of feeling unsafe at school, and loss of funds for school districts in California. Data from the 2011-2013 California Healthy Kids Survey and the California Department of Education were utilized. Results indicate that annually, California school districts lose an estimated $276 million of unallocated funds because of student absences resulting from feeling unsafe at school. Experiences of bias based bullying were significantly associated with student absenteeism, and the combination of these experiences resulted in a loss of funds to school districts. For example, the absence of students who experienced bullying based on their race or ethnicity resulted in a projected loss of $78 million in unallocated funds. These data indicate that in addition to fostering student safety and well-being, schools have the societal obligation and economic responsibility to prevent bias based bullying and related absenteeism. (PsycINFO Database Record PMID- 28661166 TI - Predictors and academic outcomes associated with in-school suspension. AB - The negative consequences associated with out-of-school suspension (OSS) are widely recognized, yet its commonly utilized counterpart, in-school suspension (ISS), has received little attention. This study examined school and student characteristics that predicted ISS and its links to academic outcomes, using the nationally representative High School Longitudinal Study of 2009. The sample included 11,860 public high school students, equating to a nationally representative sample of 2,993,918 students upon the application of primary sampling weights for each student and balanced repeated replicate weights to account for students nested in schools. Students who were Black, male, of lower socioeconomic status (SES), or placed in special education were significantly more likely to receive ISS. Further, ISS was associated with lower grade point averages and increased likelihood of high school dropout. These findings raise caution about the use of ISS, particularly as schools consider using ISS as an alternative to OSS. (PsycINFO Database Record PMID- 28661167 TI - The devil's in the detail: Accessibility of specific personal memories supports rose-tinted self-generalizations in mental health and toxic self-generalizations in clinical depression. AB - Models of memory propose that separate systems underpin the storage and recollection of specific events from our past (e.g., the first day at school), and of the generic structure of our experiences (e.g., how lonely I am), and that interplay between these systems serves to optimize everyday cognition. Specifically, it is proposed that memories of discrete events help define the circumstances (boundary conditions) in which our generalized knowledge applies, thereby enhancing accuracy of memory-dependent cognitive processes. However, in the domain of self-judgment, cognition is systematically biased, with a robust self-enhancement bias characterizing healthy individuals and a negativity bias characterizing the clinically depressed. We hypothesized that self-enhancement effects in the mentally healthy may partly rest on an impaired ability for specific memories to set appropriate boundary conditions on positive self generalizations, while the opposite may be true for self-referred negative traits in the depressed. To assess this, we asked healthy and depressed individuals to think about the applicability of a trait to themselves, then to recall a specific memory that was inconsistent with that trait which would therefore index a boundary condition for its applicability. Healthy individuals showed faster recall only for specific positive memories following negative trait evaluations, while depressed individuals demonstrated faster recall only of specific negative memories following positive trait evaluations-the pattern expected given the respective self-enhancement and negativity biases. Results suggest that specific memories may serve to delimit self-generalizations in biased ways, and thus support systemic biases in trait judgments characteristic of healthy and depressed individuals. (PsycINFO Database Record PMID- 28661168 TI - Forgotten evidence: A mixed methods study of why sexual assault kits (SAKs) are not submitted for DNA forensic testing. AB - Throughout the United States, hundreds of thousands of sexual assault kits (SAKs) (also termed "rape kits") have not been submitted by the police for forensic DNA testing. DNA evidence can help sexual assault investigations and prosecutions by identifying offenders, revealing serial offenders through DNA matches across cases, and exonerating those who have been wrongly accused. In this article, we describe a 5-year action research project conducted with 1 city that had large numbers of untested SAKs-Detroit, Michigan-and our examination into why thousands of rape kits in this city were never submitted for forensic DNA testing. This mixed methods study combined ethnographic observations and qualitative interviews to identify stakeholders' perspectives as to why rape kits were not routinely submitted for testing. Then, we quantitatively examined whether these factors may have affected police practices regarding SAK testing, as evidenced by predictable changes in SAK submission rates over time. Chronic resource scarcity only partially explained why the organizations that serve rape victims-the police, crime lab, prosecution, and victim advocacy-could not test all rape kits, investigate all reported sexual assaults, and support all rape survivors. SAK submission rates significantly increased once criminal justice professionals in this city had full access to the FBI DNA forensic database Combined DNA Index System (CODIS), but even then, most SAKs were still not submitted for DNA testing. Building crime laboratories' capacities for DNA testing and training police on the utility of forensic evidence and best practices in sexual assault investigations can help remedy, and possibly prevent, the problem of untested rape kits. (PsycINFO Database Record PMID- 28661169 TI - Assessing law enforcement performance in behavior-based threat detection tasks involving a concealed weapon or device. AB - Across 3 experiments, we assessed the ability of law enforcement officers and naive controls to detect the concealment of a weapon or device. Study 1 used a classic signal detection paradigm in which participants were asked to assess whether a target was concealing a neutered 9-mm handgun. Study 2 involved a compound signal detection paradigm in which participants assessed whether or not 1 of several individuals was concealing an unstable device in their backpack. Study 3 moved to a 2-alternative forced choice paradigm in which participants evaluated which of 2 targets was concealing an unstable device in his backpack. Across all 3 experiments we consistently found no significant differences in detection performance between law enforcement and naive controls, although participants did perform above chance levels when response bias was free to vary. Furthermore, officers' years of experience was associated with a bias toward perceiving concealment. Given the frequency with which officers are asked to assess the concealment of weapons or devices, and therein to identify threats, our findings suggest the need for additional research to explore various factors (e.g., context, race of target, operational experience, etc.) likely related to performance on such tasks. (PsycINFO Database Record PMID- 28661171 TI - Utility of the MMPI-2 Restructured Form (MMPI-2-RF) in a sample of Lithuanian male offenders. AB - The aim of the current study was to examine the construct validity of the Multiphasic Personality Inventory-2 Restructured Form (Minnesota Multiphasic Personality Inventory [MMPI]-2-RF; Ben-Porath & Tellegen, 2008/2011) in a correctional setting. More specifically, we examined the associations between MMPI-2-RF scales with external variables relevant for sentence planning as well as the relationship with risk of reconviction assessed with the Offender Assessment System (OASys; Home Office, 2002). A random sample of 228 male offenders from Lithuanian custodial institutions was selected for the study. The results revealed that MMPI-2-RF scale scores differentiated offender groups classified on the basis of external variables, such as history of suicide attempts, violent offending, use of drugs, violence under the influence of alcohol, and early criminal onset, in a manner consistent with conceptual expectations. Moreover, Behavior/Externalizing Dysfunction (BXD), Antisocial Behavior (RC4), Juvenile Conduct Problems (JCP), Substance Abuse (SUB), and Disconstraint-Revised (DISC-r) scale scores evinced correlations with OASys scores that were moderate in magnitude. Results from regression analyses showed that MMPI-2-RF scale scores accounted for approximately 21% of variance of OASys risk of reconviction scores. Overall, the findings provide support for the utility of the MMPI-2-RF in Lithuanian correctional institutions. (PsycINFO Database Record PMID- 28661170 TI - Tablet computers and forensic and correctional psychological assessment: A randomized controlled study. AB - Mobile computing technology presents various possibilities and challenges for psychological assessment. Within forensic and correctional psychology, assessment of justice-involved persons facilitated by such technology has not been empirically examined. Accordingly, this randomized controlled experiment involved administering questionnaires about risk-needs, treatment readiness, and computerized technology opinions to a large (N = 212) and diverse sample of individuals under custodial correctional supervision using either a tablet computer or traditional paper-and-pencil materials. Results revealed that participants in the paper-and-pencil condition completed the packet of questionnaires faster but omitted items more frequently. Older participants and those with lower levels of education tended to take longer to complete the tablet administrated measures. The tablet format was rated as more usable irrespective of demographic and personal characteristics, and most participants across the 2 conditions indicated that they would prefer to use computerized technology to complete psychological testing. Administration format did not have a clear effect on attitudes toward correctional rehabilitation services. Noteworthy for researchers is the substantial time saved and absence of practical problems with the tablet condition. Implications for practitioners include the general usability of the devices, their appeal to incarcerated persons, and the potential for tablets to facilitate clinical and administrative tasks with corrections clients. Considering the novel nature of this study, its promising results, and its limitations, future research in this area is warranted. (PsycINFO Database Record PMID- 28661172 TI - Visual complexity accentuates picture-description deficit in amnesia. AB - OBJECTIVE: A recent study indicated that amnesic patients have difficulties not only in describing past and imagined scenarios, but also in describing pictures that are in full view. This finding suggests that impaired memory hampers descriptions of scenarios more broadly. However, no such impairment in picture description in amnesic patients was observed in a related study. One key methodological difference between these studies was the complexity of the pictures to be described, hinting that group differences might be marked only if pictures are sufficiently complex to tax aspects of memory. METHOD: To test this complexity hypothesis, we examined whether differences in picture description between amnesic patients and controls increase with increasing picture complexity. As in previous studies, we also assessed our participants' ability to describe imagined scenarios. RESULTS: Amnesic patients reported significantly fewer elements than did controls when describing pictures and imagined scenarios. The group difference in picture description was significantly larger for complex than for simple pictures. CONCLUSION: Although variations in lesion sites might have accounted for the aforementioned cross-study differences in picture description in amnesic patients, our results suggest that, at least in amnesic patients with extramedial temporal lobe lesions, the complexity of pictures can determine whether or not a (substantial) picture-description deficit is observed. We interpret these findings in terms of a narrative-construction deficit. We hypothesize that, whereas brief narrative can be constructed via nonmemory cognitive processes, the construction of more detailed narrative depends upon intact functioning of a temporary memory system, such as the episodic buffer. (PsycINFO Database Record PMID- 28661173 TI - Reduced parahippocampal theta activity during spatial navigation in low, but not in high elderly performers. AB - OBJECTIVE: Cognitive aging varies widely among individuals. Whereas optimal cognitive agers show highly preserved cognitive functions throughout life, other subjects experience cognitive deficits in various cognitive domains. Among them, elderly individuals frequently report difficulties in spatial navigation. In this study, we aimed to determine whether elderly participants with different cognitive profiles would perform differently at a navigation task, and explore underlying medial hippocampal activity. METHOD: Two groups of elderly subjects were selected, high- and low-performing (HP and LP, respectively), based on their performance on a detailed neuropsychological examination. A group of young adults was recruited as controls. Cerebral activity was recorded by electroencephalography (EEG) during a virtual navigation task in which participants had 3 trials to find their way in mazes. We analyzed theta activity during navigation in the mazes and performed source reconstruction analyses. RESULTS: The LP group was less accurate than the HP group during the navigation task. Theta activity during navigation was greater in HP subjects compared with controls, whereas that theta activity was reduced in LP subjects. Moreover, theta activity in the left parahippocampal gyrus increased across trials in HP, but not in LP, subjects. CONCLUSION: Elderly participants performed differently at a navigation task according to their cognitive profile: elderly with cognitive deficits seem to have greater difficulties in spatial navigation than HP elderly. Navigational difficulties in elderly with cognitive deficits might be related to functional alteration of the parahippocampal gyrus. (PsycINFO Database Record PMID- 28661175 TI - Primacy and recency effects for taste. AB - Historically, much of what we know about human memory has been discovered in experiments using visual and verbal stimuli. In two experiments, participants demonstrated reliably high recognition for nonverbal liquids. In Experiment 1, participants showed high accuracy for recognizing tastes (bitter, salty, sour, sweet) over a 30-s delay in a recognition task, even when the probe stimulus was only a different concentration within the same taste. In Experiment 2, participants tasted three liquids and showed both primacy and recency effects in a serial-position recognition task with varying delay lengths (15, 30, 45, 60 s). Recognition for liquids at the end of a list was most evident with shorter delay lengths (i.e., recency). Recognition for liquids at the start of the list was most evident with longer delay lengths (i.e., primacy). These data show that not only is gustatory information stored and maintained in working memory, but that memory for these liquids follow a recency-to-primacy shift in recognition memory. (PsycINFO Database Record PMID- 28661174 TI - Profiles of cognitive impairments in an older age community sample: A latent class analysis. AB - OBJECTIVE: Person-centered studies that could describe the different patterns of cognitive impairments among older people are lacking. To this end, the current study utilized a person-centered approach to examine the different profiles of cognitive impairment in an older age Chinese community sample. Additionally, the current study also examined whether functional impairments differ across the different profiles. METHOD: A total of 220 older people (Mage = 70.9 years) who were assessed to have an objective impairment in any of 7 domains (immediate memory, delayed memory, attention, inhibition, verbal fluency, working memory, and processing speed) were entered in a latent class analysis. Subsequently, functional impairment (both self-reported and clinician-rated) between the different profiles of cognitive impairments that emerged from the analyses were compared. RESULTS: A 4-class solution was chosen based on fit statistics and interpretability. Three profiles were characterized by impairments in cognitive rigidity, memory, and other executive functions, and the 4th with impairments in both executive functions and memory. Furthermore, relative to the non-memory impaired groups, the memory-impaired groups were significantly more likely to report a higher level of clinician-rated functional impairments even though these groups did not differ significantly in self-reported functional impairments. CONCLUSIONS: The observed cognitive impairments in the current sample can be classified into 4 distinct profiles along the lines of memory and/or executive functions impairment. The memory-impaired groups were significantly impaired relative to the non-memory-impaired groups, at least in terms of clinician-rated functional outcomes. These findings present some important implications. (PsycINFO Database Record PMID- 28661176 TI - Can the first letter advantage be shaped by script-specific characteristics? AB - We examined whether the first letter advantage that has been reported in the Roman script disappears, or even reverses, depending on the characteristics of the orthography. We chose Thai because it has several "nonaligned" vowels that are written prior to the consonant but phonologically follow it in speech (e.g., ??? is spoken as /fE:n/) whereas other "aligned" vowels are written and spoken in a corresponding order, as occurs in English (e.g., ??? is spoken as /fa:k/). We employed the forced choice decision paradigm of Adelman, Marquis, and Sabatos-DeVito (2010) to examine letter identification across letter positions in 3- and 4-letter Thai legal nonword pairs. Results showed an advantage of the initial letter position for the aligned legal nonwords, as occurs in Roman script (e.g., Scaltritti & Balota, 2013). However, for the nonaligned legal nonwords, an advantage of second letter position was found which is in line with the characteristics of these types of stimuli: the critical initial consonant occurs in the second letter position. These results highlight the importance of the initial phonological letter in Thai, which is crucial for mapping orthography to phonology and for lexical access. In conclusion, these results illustrate that initial letter advantage can be shaped by the characteristics of the orthography. (PsycINFO Database Record PMID- 28661177 TI - Attending globally or locally: Incidental learning of optimal visual attention allocation. AB - Attention allocation determines the information that is encoded into memory. Can participants learn to optimally allocate attention based on what types of information are most likely to change? The current study examined whether participants could incidentally learn that changes to either high spatial frequency (HSF) or low spatial frequency (LSF) Gabor patches were more probable and to use this incidentally learned probability information to bias attention during encoding. Participants detected changes in orientation in arrays of 6 Gabor patches: 3 HSF and 3 LSF. For half of the participants, an HSF patch changed orientation on 75% of the trials, and for the other half, an LSF patch changed orientation on 75% of the trials. Experiment 1 demonstrated a change probability effect and an attention allocation effect. Specifically, change detection performance was highest for the probable-change type, and participants learned to use a global spread of attention (fixating between Gabor patches) when LSF patches were most likely to change and to use a local allocation of attention (fixating directly on Gabor patches) when HSF patches were most likely to change. Experiments 2 and 3 replicated these effects and demonstrated that an internal monitoring system is sufficient for these effects. That is, the effects do not require explicit feedback or point rewards. This study demonstrates that incidental learning of probability information can affect the allocation of attention during encoding and can therefore affect what information is stored in visual working memory. (PsycINFO Database Record PMID- 28661178 TI - Retrieval practice makes procedure from remembering: An automatization account of the testing effect. AB - The "testing effect" refers to the striking phenomenon that repeated retrieval practice is one of the most effective learning strategies, and certainly more advantageous for long-term learning, than additional restudying of the same information. How retrieval can boost the retention of memories is still without unanimous explanation. In 3 experiments, focusing on the reaction time (RT) of retrieval, we showed that RT of retrieval during retrieval practice followed a power function speed up that typically characterizes automaticity and skill learning. More important, it was found that the measure of goodness of fit to this power function was associated with long-term recall success. Here we suggest that the automatization of retrieval is an explanatory component of the testing effect. As a consequence, retrieval-based learning has the properties characteristic of skill learning: diminishing involvement of attentional processes, faster processing, resistance to interference effects, and lower forgetting rate. (PsycINFO Database Record PMID- 28661179 TI - What are the costs of degraded parafoveal previews during silent reading? AB - It has been suggested that the preview benefit effect is actually a combination of preview benefit and preview costs. Marx et al. (2015) proposed that visually degrading the parafoveal preview reduces the costs associated with traditional parafoveal letter masks used in the boundary paradigm (Rayner, 1975), thus leading to a more neutral baseline. We report 2 experiments of skilled adults reading silently. In Experiment 1, we found no compelling evidence that degraded previews reduced processing costs associated with traditional letter masks. Moreover, participants were highly sensitive to detecting degraded display changes. Experiment 2 used the boundary detection paradigm (Slattery, Angele, & Rayner, 2011) to explore whether participants were capable of detecting actual letter changes or if they were responding purely to changes in degradation. Half of the participants were instructed to respond to any noticed display changes; the other half were instructed to respond only to changes in letter identities. Participants were highly sensitive to degraded changes. In fact, these changes were so apparent that they reduced the sensitivity to letter masks. In the context of the model proposed by Angele, Slattery, and Rayner (2016), we suggest that degraded previews interfere with the attentional stage, as evidenced by the general lack of foveal load effects. In summary, we found that increasingly degrading parafoveal letter masks does not reduce their processing costs in adults, but that both degraded valid and invalid previews introduce additional costs in terms of greater display change awareness. (PsycINFO Database Record PMID- 28661180 TI - Tension Pneumoperitoneum Associated with Nasopharyngeal Catheter Oxygen Delivery during Bronchoscopy. PMID- 28661181 TI - Coexistence of Mediastinal Castleman Disease with Spindle Cell Carcinoma of the Lung. PMID- 28661184 TI - Redox-Dependent Regulation of Sulfur Metabolism in Biomolecules: Implications for Cardiovascular Health. AB - SIGNIFICANCE: Sulfur-containing amino acids are integral to the molecular mechanisms that underlie many aspects of cellular function and homeostasis, facilitated by reversible changes in the oxidation states of sulfur atoms. Sulfur containing amino acids are metabolically linked by interacting pathways that impact the one-carbon metabolic cycle and generation of methyl groups, the folate cycle, and maintenance of the major cellular redox buffer; glutathione. Dysregulation of these pathways is associated with diverse pathologies, notably of the cardiovascular (CV) system, which are typically characterized by inappropriate plasma levels of sulfur-containing amino acids. Recent Advances: Perhaps not surprisingly, the cellular redox state has emerged as a major regulator of many enzymatic processes within these metabolic cycles. The metabolism of cysteine can also result in the production of hydrogen sulfide (H2S), a signaling molecule whose activity is potentially linked to intracellular levels of both reactive oxygen species (ROS) and molecular oxygen. CRITICAL ISSUES: In most cases, the endogenous physiological sources of ROS that might mediate the interlinked metabolic pathways of sulfur-containing biomolecules remain unknown. However, the family of NADPH oxidases, and Nox4 in particular, is emerging as a likely candidate. FUTURE DIRECTIONS: This review focuses on the current knowledge of key aspects of sulfur metabolism, which are regulated by redox-based chemical reactions, and the likely intracellular oxidant sources that might mediate this regulation. This knowledge will be important to guide future targeted therapeutic interventions in diverse CV disorders. Antioxid. Redox Signal. 00, 000-000. PMID- 28661182 TI - Prenatal Nitrate Exposure and Childhood Asthma. Influence of Maternal Prenatal Stress and Fetal Sex. AB - RATIONALE: Impact of ambient pollution upon children's asthma may differ by sex, and exposure dose and timing. Psychosocial stress can also modify pollutant effects. These associations have not been examined for in utero ambient nitrate exposure. OBJECTIVES: We implemented Bayesian-distributed lag interaction models to identify sensitive prenatal windows for the influence of nitrate (NO3-) on child asthma, accounting for effect modification by sex and stress. METHODS: Analyses included 752 mother-child dyads. Daily ambient NO3- exposure during pregnancy was derived using a hybrid chemical transport (Geos-Chem)/land-use regression model and natural log transformed. Prenatal maternal stress was indexed by a negative life events score (high [>2] vs. low [<=2]). The outcome was clinician-diagnosed asthma by age 6 years. MEASUREMENTS AND MAIN RESULTS: Most mothers were Hispanic (54%) or black (29%), had a high school education or less (66%), never smoked (80%), and reported low prenatal stress (58%); 15% of children developed asthma. BDILMs adjusted for maternal age, race, education, prepregnancy obesity, atopy, and smoking status identified two sensitive windows (7-19 and 33-40 wk gestation), during which increased NO3- was associated with greater odds of asthma, specifically among boys born to mothers reporting high prenatal stress. Cumulative effects of NO3- across pregnancy were also significant in this subgroup (odds ratio = 2.64, 95% confidence interval = 1.27 5.39; per interquartile range increase in ln NO3-). CONCLUSIONS: Prenatal NO3- exposure during distinct sensitive windows was associated with incident asthma in boys concurrently exposed to high prenatal stress. PMID- 28661185 TI - The value of serum antibodies in differentiating inflammatory bowel disease, predicting disease activity and disease course in the newly diagnosed patient. AB - BACKGROUND: Data on serum antibodies in untreated adult inflammatory bowel disease (IBD) patients at diagnosis are scarcely available, and results on the stability of antibody presence over time are inconsistent. Our aim was to investigate antibodies in newly diagnosed, untreated IBD patients in relation to disease phenotype and course. Furthermore, we analyzed antibody presence over time. METHODS: Baseline anti-Saccharomyces cerevisiae antibodies (ASCA), anti chitobioside carbohydrate antibodies (ACCA), anti-laminaribioside carbohydrate antibodies (ALCA) and anti-mannobioside carbohydrate antibodies (AMCA) were measured with enzyme-linked immunosorbent assays and perinuclear anti neutrophilic cytoplasmic antibodies (pANCA) was measured by indirect immunofluorescence in serum of 120 untreated IBD patients at diagnosis and 19 healthy controls. Antibodies were related to disease outcomes. Serial measurements were available in 71 patients. RESULTS: The combination of pANCA and ASCA enabled good discrimination between UC and CD (p = .004). Antibody presence was relatively stable over time, even though there were significant changes in concentrations. There was a trend towards larger fluctuations in concentration with immunosuppressive medication. Baseline pANCA in UC patients correlated with calprotectin values (rho = .545, p = .019) and change in pANCA status over time was associated with disease activity at that moment. No associations were found with antibodies at diagnosis and disease outcomes. CONCLUSION: Antibody profiles at diagnosis support the distinction between CD and UC. Anti-glycan antibodies are reasonably stable over time, but may fluctuate under the influence of immunosuppressive treatment which may explain the inconsistency in findings hitherto. The appearance or disappearance of pANCA antibodies during follow-up correlated with disease activity in UC and may be used in disease monitoring. PMID- 28661183 TI - Differential Expression of VEGF-Axxx Isoforms Is Critical for Development of Pulmonary Fibrosis. AB - RATIONALE: Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A165a and VEGF-A165b, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. OBJECTIVES: To establish VEGF-A isoform expression and functional effects in IPF. METHODS: We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTA+/-TetoCre+/-LoxP-VEGF-A+/+ to conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. MEASUREMENTS AND MAIN RESULTS: IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A165a and VEGF-A165b in terms of proliferation and matrix expression. Increased VEGF-A165b was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-A165b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A165b to wild-type mice. CONCLUSIONS: These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Axxxa to VEGF-Axxxb, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair. PMID- 28661186 TI - Syntheses and evaluation of multicaulin and miltirone-like compounds as antituberculosis agents. AB - Four multicaulin and miltirone-like phenanthrene derivatives were synthesised and evaluated as antituberculosis agents. The crucial step of the synthesis was Pschorr coupling of 4-(3-isopropyl-4-methoxyphenyl)-2-(2-aminophenyl)ethane (13) to give 2-isopropyl-3-methoxy-9,10-dihydrophenanthrene (9) and 4-isopropyl-3 methoxy-9,10-dihydrophenanthrene (9a). Compound 9 was converted to multicaulin and miltirone-like phenanthrene derivatives by further reactions. The best antituberculosis activity was exhibited by 2-isopropylphenanthrene-3-ol (11). PMID- 28661187 TI - Burnout and occupational stress in the medical residents of Oncology, Haematology and Radiotherapy: a prevalence and predictors study in Portugal. AB - Burnout is a professional syndrome associated with stress caused by overwork. Our aim was to calculate the prevalence of burnout and stress on medical residents of Oncology, Haematology and Radiotherapy in Portugal, as well as to determine predictors of burnout and stress. An anonymous questionnaire was applied (n = 118). Statistical analysis consisted of a descriptive and inferential analysis. The prevalence of burnout and stress was calculated to be 45.2 and 50%, respectively. The dimensions that generated higher levels of stress were 'dealing with patients' and 'overwork'. Burnout was directly related with stress dimension 'overwork'. The prevalence of burnout in Portuguese oncological residents is high as in other European countries and in the U.S. Therefore, interventional strategies can be designed. PMID- 28661188 TI - Bruton's tyrosine kinase inhibitors in B-cell lymphoma: current experience and future perspectives. AB - INTRODUCTION: The Bruton tyrosine kinase (BTK) is a central hub in the B cell receptor (BCR) pathway and strongly influences B cell maturation, differentiation and proliferation. Not surprisingly, BTK plays an essential role in the pathogenesis of various B cell lymphomas. Inhibitors of BTK have broadened our therapeutic options in several B cell lymphomas and already are an integral element in the treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenstrom's marcoglobulinemia. Several second generation BTK inhibitors are in clinical development and might further improve tolerability and efficacy of therapy in advanced stage CLL and MCL. Areas covered: This review illustrates the mechanism of action of BTK inhibitors and provides a comprehensive summary of key clinical trials in the development of BTK inhibitors. Characteristics of second generation BTK-inhibitors are described. Expert opinion: With accumulation of clinical experience after drug approval, longer patient follow-up and larger numbers of treated patients, future development will focus on the identification of intelligent treatment combinations. Individual selection of patients with distinct biologically properties might guide treatment decisions. While BTK inhibitors are moving to earlier treatment lines, the incorporation of these drugs into a comprehensive therapeutic strategy is still difficult to date. PMID- 28661189 TI - Transdiagnostic group-based occupational rehabilitation for participants with chronic pain, chronic fatigue and common mental disorders. A feasibility study. AB - PURPOSE: The aim was to investigate the feasibility of introducing a novel transdiagnostic occupational rehabilitation program delivered in groups mixing participants with chronic pain, chronic fatigue and common mental disorders. MATERIALS AND METHODS: Observational data on group climate and individual participation were triangulated with qualitative data from focus group interviews on the participants' experiences with transdiagnostic groups. RESULTS: The study included 222 participants receiving a temporary work disability benefit. Self reported chronic pain (75%), chronic fatigue (79%), and mental distress (62%) were prevalent and the majority reported overlapping conditions (78%). Program completion among participants was high (96%). Those completing participated actively (95%) in the program. Overall group climate was stable with moderately high engagement. Participants with clinically confirmed mental disorders (22%) showed similar outcomes. Self-reported problems with "working in a group" prior to rehabilitation were not associated with how participants experienced group climate. Qualitative data supported the findings of positive participant experiences with transdiagnostic group settings. CONCLUSIONS: Transdiagnostic groups showed high participation rates, moderately high group engagement across symptom profiles and positive participant experiences. Implementing transdiagnostic occupational rehabilitation in groups mixing participants with chronic pain, chronic fatigue and common mental disorders was feasible and acceptable to participants. Implications for rehabilitation Most research has been done on disorder-specific occupational rehabilitation programs, but emerging evidence supports a more generic approach. Transdiagnostic therapies, such as Acceptance and Commitment Therapy (ACT), have shown promising results for both somatic and mental disorders. The feasibility of implementing transdiagnostic rehabilitation groups, their acceptability to participants and the demand for such groups has not been established. This study indicates that it is feasible to introduce a novel transdiagnostic group-based occupational rehabilitation program for mixed groups of sick-listed participants with chronic pain, chronic fatigue and/or common mental disorders. PMID- 28661190 TI - Current clinical evidence for nucleos(t)ide analogues in patients with HBV related hepatocellular carcinoma. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of death globally and is frequently seen following Hepatitis B virus (HBV) or Hepatitis C virus infection. Areas with high HBV infection rates, such as Asia and sub-Saharan Africa, are therefore also high-risk areas for HCC. Areas covered: This review identifies and discusses the current evidence from robust clinical trials which have investigated the benefits of Nucleos(t)ide analogue (NA) antiviral therapy in HBV-related HCC patients, including HCC patients that underwent liver transplantation and HCC patients with or without curative treatment. In addition, we assess how this evidence has influenced current clinical practice, with a particular focus on those areas of high HBV infection rates. Expert commentary: A number of studies have assessed whether NA antiviral treatment can improve the prognosis of HBV-related HCC patients. In this review we evaluate the current evidence, including that from trials in Asia, for antiviral NA treatments in HBV related HCC patients. We also focus on those NAs with a high genetic barrier to resistance (i.e. ETV or TDF), on different therapeutic approaches, and on the future evidence that is required in this field. PMID- 28661191 TI - Assessment of an irritant gas plume model for epidemiologic study. AB - Previously, we reported the development of a Hazard Prediction and Assessment Capability plume dispersion model of the 2005 Graniteville, South Carolina, USA accidental release of chlorine. Here, we assess this model by spatial and statistical comparison with post-incident observed environmental indicators of exposure and other types of observations. Spatial agreement was found when the model was compared to phytotoxic bleaching and corrosion events observed in 2 km radius around the release site. When spatially compared to locations of injured or killed animals, model predictions of the plume footprint were in relatively good agreement. Model-predicted human casualties differed from observed casualty counts primarily due to the shielding effect of buildings. A statistical comparison of observed dog health outcome-derived exposure vs. model predicted exposure showed relatively good agreement, particularly when a subcohort of indoor dogs was excluded. Evaluation and assessment of the building infiltration effect would further improve the model prior to application in epidemiologic study. PMID- 28661192 TI - Shedding light on biosafety of platelet rich plasma. PMID- 28661193 TI - 'You want to show you're a valuable employee': A critical discourse analysis of multi-perspective portrayals of employed women with fibromyalgia. AB - Background Advice on fibromyalgia, a chronic illness primarily affecting women, often presents it as incompatible with work and rarely covers how to remain employed. Yet many women do. Objectives We aimed to understand how these women, their family members, and workmates portrayed employees with fibromyalgia, and how these portrayals helped women retain employment. Methods We interviewed 22 participants, comprising five triads and three dyads of people who knew each other. Using the methodology of critical discourse analysis, we analysed the interview data within and across the triads/dyads through coding, narrative summaries, and relational mapping. Results Participants reported stereotypes that employees with fibromyalgia are lazy, malingering, and less productive than healthy workers. Countering these assumptions, participants portrayed the women as normal, valuable employees who did not 'give in' to their illness. The portrayals drew on two discourses, normalcy and mind-controlling-the-body, and a related narrative, overcoming disability. We propose that participants' portrayals helped women manage their identities in competitive workplaces and thereby remain employed. Discussion Our findings augment the very sparse literature on employment with fibromyalgia. Using a new approach, critical discourse analysis, we expand on known job-retention strategies and add the perspectives of two key stakeholders: family members and workmates. PMID- 28661194 TI - Critical moments in long-term condition management: A longitudinal qualitative social network study. AB - Objectives Recent literature has demonstrated the nature and importance of social networks. This study aimed to understand how support needs of people with long term conditions change over time and how this influences their ability to self manage. Methods A longitudinal qualitative design was used to explore changes in individual's social networks over a period of year. Thirty participants were recruited and completed initial in-depth face-to-face interviews, telephone follow-ups, and final face-to-face interviews. Results Findings illuminated that changes in health and changes in social networks can influence each other. The social networks implicated in the management of long-term conditions change over time at critical moments and can range between positive and negative reciprocal influences with self-management. Network changes, such as the breaking or reconnecting of ties influenced the context of health management and the degree of engagement with self-management activities. Discussion By examining the specific processes of support and resource provision, this study highlights how overtime the variety of relationships and support available implicated in long term condition management changes. This has implications for the provision of formal support services and the need for a wider range of support to be identified that recognises change in support requirements as self-management strategies evolve. PMID- 28661195 TI - Optimising mindfulness-based stress reduction for people with multiple sclerosis. AB - Objectives To gather views from patients with multiple sclerosis after completing a standard eight-week mindfulness-based stress reduction course and optimise and test a modified version as required. Methods Two successive groups of 25 multiple sclerosis patients received mindfulness-based stress reduction in a wait-list randomised controlled trial. Seventeen participants and two mindfulness-based stress reduction instructors were individually interviewed after the first (standard) course and 16 participants and the same two instructors were interviewed following the second (optimised) course. Interviews were analysed using a thematic approach. Results Mindfulness-based stress reduction was well received in both groups, with participants describing a beneficial shift in awareness. An initial (at times unpleasant) increase in awareness of disability was generally followed by greater acceptance and self-compassion. Other benefits reported included improved relationships, walking and sleep, with less stress and pain. Mindful-movement and mindful walking were problematic in group 1. This component of mindfulness-based stress reduction was simplified in group 2. A pre course orientation session was introduced, and some organisational changes made based on feedback from group 1. Feedback from group 2 was positive in all these areas. Discussion Mindfulness-based stress reduction appears beneficial to people with multiple sclerosis, albeit mindful-movement required some modification. Contextual and organisational issues also appear important in this population. PMID- 28661196 TI - Design, synthesis and evaluation of 2-aryl benzoxazoles as promising hit for the A2A receptor. AB - The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 MUm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 MUm) without being cytotoxic at 100 MUm. This compound, along with low-molecular weight compound D1 (Ki = 10 MUm), can be easily modulated and thus considered as relevant starting points for further hit to-lead optimisation. PMID- 28661197 TI - VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo[g]quinazolin bearing benzenesulfonamide moiety. PMID- 28661199 TI - Respiratory microbiota and lower respiratory tract disease. AB - INTRODUCTION: The respiratory airways harbor a complex succession of ecological niches with distinct but related bacterial communities. Particular challenges of respiratory microbiome research have led to limited scientific output compared to other human microbiomes. Areas covered: In this review, we summarize the current state of knowledge of the bacterial respiratory microbiome, with a particular focus on associations between the respiratory microbiome and lower respiratory tract conditions. Expert commentary: There is growing evidence that the respiratory microbiome is associated with lower respiratory infectious diseases and related conditions. Most respiratory microbiome reports are metataxonomic cross-sectional or case-control studies with relatively small sample sizes. Large, prospective projects with metatranscriptomics or metabolomics approach are needed to unravel the effect of the respiratory microbiome on health-related conditions. Moreover, standardization in sampling, library preparation, sequencing techniques and data analysis should be encouraged. PMID- 28661198 TI - Metabolic Regulation of Adipose Tissue Macrophage Function in Obesity and Diabetes. AB - SIGNIFICANCE: Obesity and diabetes are associated with chronic activation of inflammatory pathways that are important mechanistic links between insulin resistance (IR), type 2 diabetes (T2D), and cardiovascular disease pathogenesis. The development of these metabolic diseases is associated with changes in both the number and phenotype of adipose tissue macrophages (ATMs). Emerging lines of evidence have shown that ATMs release proinflammatory cytokines similar to classically activated M1 macrophages, which directly contribute to IR or T2D. In contrast, adipose tissue (AT) from lean healthy individuals contains macrophages with a less inflammatory M2 phenotype. Recent Advances: Recent research has shown that macrophage phenotype is linked to profound changes in macrophage cellular metabolism. CRITICAL ISSUES: This review focuses on the role of macrophages in AT inflammation and obesity, and the metabolic changes in macrophage function that occur with activation that underpin their role in the pathogenesis of IR and T2D. We highlight current targets for altering macrophage metabolism from both within the field of metabolic disease and AT biology and more widely within inflammatory biology. FUTURE DIRECTIONS: As our knowledge of macrophage metabolic programming in AT builds, there will be increasing scope for targeting this aspect of macrophage biology as a therapeutic strategy in metabolic diseases. Antioxid. Redox Signal. 29, 297-312. PMID- 28661200 TI - Decreased serum glicentin concentration in patients with severe and morbid obesity. AB - Background Proglucagon-derived hormones represent a family of peptides mainly produced in the pancreas and the intestine. While several proglucagon-derived peptides play key roles in metabolic diseases, little is known about glicentin. The aim of the present study was to investigate serum glicentin concentrations in individuals with adult obesity and to study its potential link with various metabolic parameters. Methods Fifty-two individuals with normal body mass index (BMI < 25 kg/m2) and 39 patients with severe or morbid obesity (BMI > 35 kg/m2) were prospectively included at the University Hospital of Nice between January 2014 and April 2016. Clinical data were recorded, and a fasting blood sample was collected to measure glicentin, glucose, insulin, C-peptide, total cholesterol, triglyceride, LDL and HDL-cholesterol. In addition, a homeostasis model assessment for insulin resistance (HOMA2-IR) was also calculated. Results Patients with severe and morbid obesity had significantly higher plasma glucose, together with higher serum concentrations of insulin, C-peptide, HOMA2-IR, triglyceride, LDL-cholesterol and lower serum concentrations of HDL-cholesterol compared with individuals with a normal body mass index. The obese patients displayed significantly lower fasting serum concentrations of glicentin compared with subjects with a normal body mass index (12 pmol/L vs. 24 pmol/L, P < 0.0001). In the total population, fasting glicentin concentrations did not correlate with BMI, glycaemic parameters (glucose, insulin, C-peptide, HOMA-IR) or lipid parameters (total cholesterol, triglyceride, LDL and HDL-cholesterol). Conclusion To the best of our knowledge, this is the first study reporting serum glicentin concentrations in healthy lean and obese adult subjects. We found that fasting serum glicentin concentrations are decreased in patients with severe or morbid obesity suggesting the potential interest of this peptide in obesity and metabolic-related disorders. PMID- 28661201 TI - Diagnostic accuracy of the Coopscore(c) to predict liver fibrosis in human immunodeficiency virus/hepatitis B virus co-infection. AB - Background Non-invasive methods for assessing liver fibrosis are increasingly used as an alternative to liver biopsy. Recently, a score-based biochemical blood test (Coopscore(c)) was developed in a cohort of patients chronically infected with hepatitis C virus, showing higher diagnostic performances than Fibrometer(r), Fibrotest(r), Hepascore(r) and FibroscanTM. Here, we assess its performance in patients co-infected with the human immunodeficiency virus and hepatitis B virus. Methods Ninety-seven human immunodeficiency virus/hepatitis B virus co-infected patients with liver biopsies were included from a previously described cohort. Histological fibrosis staging using METAVIR criteria was used as the reference. Coopscore(c), Fibrotest(r), Fibrometer(r), Hepascore(r) and Zeng score were computed and compared with the Coopscore(c) using the Obuchowski index and area under the receiving operator characteristic curves. Results The distribution of liver fibrosis levels was as follows: F0-F1 ( n = 42), F2 ( n = 25), F3 ( n = 15) and F4 ( n = 15). The Obuchowski index was higher for Coopscore(c) (0.774) than Fibrometer(r) (0.668), Hepascore(r) (0.690) and Zeng scores (0.704) ( P < 0.05), reflecting a better ability to discriminate between fibrosis stages. Similarly, when predicting significant fibrosis (>=F2), the AUROC was significantly greater for the Coopscore(c) (0.836) than the Hepascore(r) (0.727) and Zeng scores (0.746), but not for the Fibrotest(r) (0.778, P = 0.14) or Fibrometer(r) (0.790, P = 0.19). The Coopscore(c) did not show a higher capacity than other scores to predict advanced fibrosis (>=F3) or cirrhosis (F4). Conclusions This study supports the diagnostic value of the Coospcore(c) in fibrosis staging among human immunodeficiency virus/hepatitis B virus co-infected patients, especially to predict significant fibrosis. PMID- 28661202 TI - Demand management by electronic gatekeeping of test requests does not influence requesting behaviour or save costs dramatically. AB - Background Healthcare budgets face constraints, and laboratories have developed strategies to adapt to the concomitant increase in workload. Some of the tests (7.4%) may be attributed to unnecessary repeat testing. Electronic gatekeeping has been implemented at selected laboratories in South Africa to limit unnecessary repeat testing. We performed a study of chemistry tests subjected to electronic gatekeeping to determine its effectiveness as a sustainable demand management tool. Methods A 22-month retrospective study of chemistry test requests at a Pretoria hospital was performed. Tests violating electronic gatekeeping rules were rejected upon registration before analysis, and cost savings were estimated from electronic gatekeeping-held tests. The impact of electronic gatekeeping on the test requesting pattern of clinicians was derived from the percentage cost of electronic gatekeeping-held tests. Results The total savings generated from electronic gatekeeping test rejections amounted to $84,380. Greatest savings were generated from high-cost tests: glycated haemoglobin ($14,139), urea ($8661) and thyroid-stimulating hormone ($7514). The average number of electronic gatekeeping-held tests as a percentage of their total requested number over 22 months was 3.18%. Discussion The savings from electronic gatekeeping-held tests were not as dramatic as anticipated, but were modest and may have some impact in a cost-constrained setting. Electronic gatekeeping was concluded not to have a substantial effect on the clinician test requesting pattern, demonstrated by the largely unchanged monthly percentage of electronic gatekeeping-held tests. As a solitary demand management strategy, electronic gatekeeping does not appear to be as effective as anticipated or as demonstrated in other studies. PMID- 28661203 TI - Application of NICE guideline NG12 to the initial assessment of patients with lower gastrointestinal symptoms: not FIT for purpose? AB - Background The National Institute for Health and Care Excellence (NICE) published NG12 in 2015. The referral criteria for suspected colorectal cancer (CRC) caused controversy, because tests for occult blood in faeces were recommended. Faecal immunochemical tests for haemoglobin (FIT), which estimate faecal haemoglobin concentrations (f-Hb), might more than fulfil the intentions. Our aim was to compare the utility of f-Hb as the initial investigation with the NICE NG12 symptom-based guidelines. Methods Data from three studies were included. Patients had sex, age, symptoms, f-Hb and colonoscopy and histology data recorded. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of f Hb and NG12 were calculated for all significant colorectal disease (SCD: CRC, higher risk adenoma and inflammatory bowel disease). Overall diagnostic accuracy was also estimated by the area under the receiver operating characteristic curve (AUC). Results A total of 1514 patients were included. At a cut-off of >=10 ug Hb/g faeces, the sensitivity of f-Hb for CRC was 93.3% (95% confidence interval (CI): 80.7-98.3) with NPV of 99.7% (95%CI: 99.2-99.9). The sensitivity and NPV for SCD were 63.2% (95%CI: 56.6-69.4) and 96.0% (95%CI: 91.4-94.4), respectively. The NG12 sensitivity and NPV for SCD were 58.4% (95%CI: 51.8-64.8) and 87.6% (95%CI: 85.0-89.8), respectively. The AUC for CRC was 0.85 (95% CI: 0.87-0.90) for f-Hb versus 0.65 (95%CI: 0.58-0.73) for NG12 ( P < 0.005). For SCD, the AUC was 0.73 (95%CI: 0.69-0.77) for f-Hb versus 0.56 (95%CI: 0.52-0.60) for NG12 ( P < 0.0005). Conclusion f-Hb provides a good rule-out test for SCD and has significantly higher overall diagnostic accuracy than NG12. PMID- 28661204 TI - User Survey of 3 Ankle Braces in Soccer, Volleyball, and Running: Which Brace Fits Best? AB - CONTEXT: Recurrence rates for ankle sprains are high. Therefore, preventive measures such as ankle bracing during sports are recommended. OBJECTIVE: To systematically evaluate the perceived ease of use, quality, comfort, stability, and hindrance of and the overall satisfaction with 3 contemporary brace types in 3 types of sports. DESIGN: Randomized comparative user survey. SETTING: Recreational sports: soccer, volleyball, and running. PATIENTS OR OTHER PARTICIPANTS: Young adult recreational athletes (29 soccer players, 26 volleyball players, and 31 runners). INTERVENTION(S): Compression brace (CB), lace-up brace (LB), and semirigid brace (SB). MAIN OUTCOME MEASURE(S): Rating of perceived ease of use, quality, comfort, stability, and hindrance of and overall satisfaction with the brace types during sports on a 5-point Likert scale. The secondary outcome measure was participants' willingness to buy the tested brace. RESULTS: Overall, the 3 brace types received high mean scores for ease of use and quality. Soccer players preferred the CB over both alternatives, considering the higher scores for comfort (CB = 4.0, LB = 3.5, SB = 2.8), hindrance (CB = 3.7, LB = 2.9, SB = 2.8), overall satisfaction (CB = 3.6, LB = 3.0, SB = 2.5), and greatest willingness to buy this brace. Volleyball players preferred the LB over both alternatives, considering the higher scores for stability (LB = 4.2, CB = 3.2, SB = 3.3), overall satisfaction (LB = 3.8, CB = 3.0, SB = 3.0), and greatest willingness to buy this brace. Runners preferred the CB over both alternatives considering the better score for hindrance (CB = 3.6, LB = 2.8, SB = 2.9) and greatest willingness to buy this brace. CONCLUSIONS: All 3 ankle-brace types scored high on perceived ease of use and quality. Regarding the brace types, soccer players, volleyball players, and runners differed in their assessments of subjective evaluation of comfort, stability, hindrance, overall satisfaction, and willingness to buy the brace. Soccer players and runners preferred the CB, whereas volleyball players preferred the LB. PMID- 28661205 TI - Preliminary profiling of blood transcriptome in a rat model of hemorrhagic shock. AB - Hemorrhagic shock is a leading cause of morbidity and mortality worldwide. Significant blood loss may lead to decreased blood pressure and inadequate tissue perfusion with resultant organ failure and death, even after replacement of lost blood volume. One reason for this high acuity is that the fundamental mechanisms of shock are poorly understood. Proteomic and metabolomic approaches have been used to investigate the molecular events occurring in hemorrhagic shock but, to our knowledge, a systematic analysis of the transcriptomic profile is missing. Therefore, a pilot analysis using paired-end RNA sequencing was used to identify changes that occur in the blood transcriptome of rats subjected to hemorrhagic shock after blood reinfusion. Hemorrhagic shock was induced using a Wigger's shock model. The transcriptome of whole blood from shocked animals shows modulation of genes related to inflammation and immune response (Tlr13, Il1b, Ccl6, Lgals3), antioxidant functions (Mt2A, Mt1), tissue injury and repair pathways (Gpnmb, Trim72) and lipid mediators (Alox5ap, Ltb4r, Ptger2) compared with control animals. These findings are congruent with results obtained in hemorrhagic shock analysis by other authors using metabolomics and proteomics. The analysis of blood transcriptome may be a valuable tool to understand the biological changes occurring in hemorrhagic shock and a promising approach for the identification of novel biomarkers and therapeutic targets. Impact statement This study provides the first pilot analysis of the changes occurring in transcriptome expression of whole blood in hemorrhagic shock (HS) rats. We showed that the analysis of blood transcriptome is a useful approach to investigate pathways and functional alterations in this disease condition. This pilot study encourages the possible application of transcriptome analysis in the clinical setting, for the molecular profiling of whole blood in HS patients. PMID- 28661207 TI - Thyroid Function in Aging: A Discerning Approach. AB - Thyroid disease, increasingly common among the general population, is also rising among the elderly, which, given that the global population is aging, constitutes a serious public health issue that needs to be urgently addressed. The most common thyroid disease in younger and older individuals alike is hypothyroidism, including subclinical (SCH) and overt disease. Since TSH tends to increase with age due to intrinsic changes of thyroid metabolism and the gradual resetting of the hypothalamic-pituitary-thyroid axis, the diagnosis of "true" hypothyroidism is challenging, another difficulty being distinguishing disease-specific from aging-associated clinical symptoms. Hypothyroidism in the elderly may cause or exacerbate macrocytic anemia, hypercholesterolemia and kidney dysfunction, therefore careful clinical and biochemical control is necessary. Meanwhile, as an increase of TSH in the old and very old has been associated with longevity, a resetting of the TSH normal range according to age is strongly required before any diagnosis is made and treatment is implemented. Levothyroxine, which remains the treatment of choice, should be initiated in the old at TSH>10 mIU/l, starting with 25 MUg/daily followed by cautious upward titration. Recent data (the TRUST study) revealed that treatment of SCH in the elderly does not improve hypothyroid symptoms and the tiredness score when compared with a placebo group. Hyperthyroidism is associated with increased mortality in the aged, this dependent upon type and adequacy of treatment. Treatment should be seriously considered in older patients who have endogenous subclinical hyperthyroidism with a TSH between 0.1 and 0.4 mIU/L, with regular monitoring being strongly advised. PMID- 28661206 TI - Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men. AB - Data from animal experiments and clinical investigations suggest that components of the renin-angiotensin system are markedly affected by sex hormones. However, whether estrogen affects human atrial myocardium has not been investigated yet. In this study, we determined the effects of estrogen on key components of atrial renin-angiotensin system: angiotensin-converting enzyme, responsible for generation of angiotensin II and angiotensin-converting enzyme 2, counteracting majority of AngII effects, and different renin-angiotensin system receptors, AT1R, AT2R, and MAS. First, the expression levels of estrogen receptors mRNA were determined in right atrial appendages obtained from patients undergoing heart surgery. The amounts of estrogen receptor alpha and estrogen receptor beta mRNA were similar between women ( n = 14) and men ( n = 10). Atrial tissue slices (350 um) were prepared from male donors which were exposed to estrogen (1-100 nM; n = 21) or stimulated at 4 Hz for 24 h in the presence or absence of 100 nM estrogen ( n = 16), respectively. The administration of estrogen did not change mRNA levels of estrogen receptors, but activated MAP kinases, Erk1/2. Furthermore, estrogen increased the amounts of angiotensin-converting enzyme 2-mRNA (1.89 +/- 0.23; P < 0.05) but reduced that of angiotensin-converting enzyme-mRNA (0.78 +/- 0.07, P < 0.05). In addition, the transcript levels of AT2R and MAS were upregulated by estrogen. Pacing of tissue slices significantly increased the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at both the mRNA and protein level. During pacing, administration of estrogen substantially lowered the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at the transcript (0.92 +/- 0.21 vs. 2.12 +/- 0.27 at 4 Hz) and protein level (0.94 +/- 0.20 vs. 2.14 +/- 0.3 at 4 Hz). Moreover, estrogen elicited anti inflammatory and anti-oxidative effects on renin-angiotensin system-associated downstream effectors such as pro-oxidative LOX-1 and pro-inflammatory ICAM-1. An antagonist of estrogen receptor alpha reversed these anti-inflammatory and anti oxidative effects of estrogen significantly. Overall, our results demonstrated that estrogen modifies the local renin-angiotensin system homeostasis and achieves protective effects in atrial myocardium from elderly men. Impact statement The present study demonstrates that estrogen affects the human atrial myocardium and mediates protective actions through estrogen receptors-(ER) dependent signaling. Estrogen substantially modulates the local RAS via downregulation of ACE and simultaneous upregulation of ACE2, AT2R and MAS expression levels. This is indicative of a shift of the classical RAS/ACE axis to the alternative, protective RAS/ACE2 axis. In support of this view, estrogen attenuated the expression of RAS-associated downstream effectors, LOX-1, and ICAM 1. A specific antagonist of ERalpha reversed the anti-inflammatory and anti oxidative effects of estrogen in paced and non-paced atrial tissue slices. In summary, our data demonstrate the existence of protective effects of estrogen in atrial tissue from elderly men which are at least in part, mediated by the regulation of local RAS homeostasis. PMID- 28661209 TI - Frontiers in Thoracic Pathology. PMID- 28661208 TI - Natural Substances for Prevention of Skin Photoaging: Screening Systems in the Development of Sunscreen and Rejuvenation Cosmetics. AB - Solar broadband UV irradiation is commonly regarded as a major causative reason for cutaneous photoaging. The pro-aging molecular pathways and cellular targets affected by UVA+UVB light in human skin have been extensively investigated. Notwithstanding growing knowledge in mechanisms of photoaging, research and development of clinically efficient, nontoxic, and sustainable topical preparations providing full physical, chemical, and biological photoprotection still remain a great challenge for pharmaceutical and cosmetic industries. In this study, we are proposing a panel of the in vitro methods for preselection of natural photoprotective substances with high photostability and low phototoxicity able of absorbing a broadband UVA+UVB irradiation (physical sunscreen), reducing UV-related overproduction of free radicals and loss of endogenous antioxidants (chemical protection), and attenuating UV-induced cytotoxicity and immune and metabolic responses (biological protection) in primary human epidermal keratinocytes and immortalized human keratinocyte cultures. Our data showed that secondary metabolites biosynthesized in plant cells in response to UV irradiation, such as phenylpropanoids and their glycosylated metabolites, aglycons and glycosylated flavonoids, and leontopodic acids, hold the best promise for complete natural topical prevention of photoaging and rejuvenation of photoaged skin. Meristem plant cell cultures elicited by solar simulating UV could be the most environmentally sustainable biotechnological source of polyphenols with combined photoprotective and antiaging properties. PMID- 28661211 TI - Errata. PMID- 28661210 TI - Solid Pseudopapillary Neoplasm of the Pancreas: A Rare Entity With Unique Features. AB - Solid pseudopapillary neoplasm of the pancreas is a rare entity with low malignant potential and excellent overall prognosis. It has nonspecific clinical presentations such as abdominal pain and nausea, with vague radiologic features. Histologic features of this neoplasm are usually specific. The tumor shows minimally cohesive, uniform, monotonous cells lining delicate capillary-sized blood vessels, described as pseudopapillary architecture. Other features including hyaline globules, cytoplasmic vacuoles, and nuclear grooving are frequently present. Use of a select panel of immunostains always helps pathologists to differentiate this tumor from other circumscribed tumors of the pancreas. Recently, beta-catenin, CD10, and E-cadherin have been shown to be very important in the diagnosis of solid pseudopapillary neoplasm. Nuclear staining of tumor cells by beta-catenin and membranous presentation of CD10 is seen in almost 100% of cases. Tumor cells can be partially positive for synaptophysin and chromogranin. This tumor has a low malignant potential, and definite treatment is surgical resection. PMID- 28661212 TI - A New Kind of Autopsy for 21st Century Medicine. PMID- 28661214 TI - Nitrogen losses and chemical parameters during co-composting of solid wastes and liquid pig manure. AB - The aim of this research was to study nitrogen losses during the treatment of the liquid fraction (LF) of pig manure by co-composting and to establish the best conditions for compost production with higher nitrogen and low heavy metal contents. Windrows were constituted with the solid fraction (SF) of pig manure, different organic waste (SF of pig manure, sawdust and grape bagasse) as co substrate and Populus spp. wood chips as bulking material and watered intensely with the LF. Results show that nitrogen losses ranged from 30% to 66% of initial nitrogen and were mainly governed by substrate to bulking mass ratio and liquid fraction to substrate (LF/S) ratio, and only secondarily by operational parameters. Nitrogen losses decreased from 55-65% at low LF/S ratios (1.7-1.9 m3/t total solids (TS)) to 30-39% at high LF/S ratios (4.4-4.7 m3/t TS). Therefore, integrating the LF in the composting process at high LF/S ratios favoured nitrogen recovery and conservation. Nitrogen in the fine fraction (ranging from 27% to 48% of initial nitrogen) was governed by operational parameters, namely pH and temperature. Final compost showed low content in most heavy metals, but Zn was higher than the limits for compost use in agriculture. Zn content in the obtained compost varied from 1863 to 3269 mg/kg dm, depending on several factors. The options for obtaining better quality composts from the LF of pig manure are selecting co-substrates with low heavy metal content and using them instead of the SF of pig manure. PMID- 28661213 TI - Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor outcome. Resistance to treatment is associated with impaired vascularity, extensive hypoxia, and interstitial hypertension. In this study, the potential of dynamic contrast-enhanced (DCE)-MRI as a method for assessing the microvascular density (MVD), the fraction of hypoxic tissue, and the interstitial fluid pressure (IFP) of PDACs was investigated. MATERIAL AND METHODS: Intramuscular BxPC-3, Capan-2, MIAPaCa-2, and Panc-1 PDAC xenografts were used as preclinical models of human PDACs. DCE-MRI with Gd-DOTA as contrast agent was conducted with a 7.05-T scanner, and the DCE-MRI series were analyzed voxelwise by using the Tofts pharmacokinetic model. Tumor MVD and hypoxia were measured in histological preparations by using pimonidazole as a hypoxia marker and CD31 as a marker of endothelial cells. IFP was measured with a Millar catheter. RESULTS: Ktrans (the volume transfer constant of Gd-DOTA) increased with increasing MVD and decreased with increasing hypoxic fraction, but was not associated with IFP. Any association between ve (the fractional distribution volume of Gd-DOTA) and MVD, hypoxic fraction, or IFP could not be detected. CONCLUSIONS: This study shows that DCE-MRI is a useful modality for assessing important features of the microenvironment of PDAC xenografts and thus provides the basis for future preclinical and clinical DCE-MRI investigations of PDAC. PMID- 28661215 TI - Anastomotic leak after surgical repair of type A aortic dissection - prevalence and consequences in midterm follow-up. AB - BACKGROUND: This study reports the mid-term prevalence and therapeutic consequences of anastomotic leaks after surgery for Stanford type A aortic dissections. PATIENTS AND METHODS: From July 2007 to July 2013, 93 patients survived surgery for acute type A dissections at our center and underwent a standardized follow-up. The pre-, peri-, and postoperative as well as the midterm results were collected prospectively. Follow-up computed tomography (CT) imaging was performed 7 days, 3, and 12 months after surgery, and yearly thereafter, to assess the presence or progression of anastomotic leaks at the aorto-prosthesis anastomotic sites. RESULTS: The mean follow-up was 4 years (1534 +/- 724 days). Follow-up CT revealed anastomotic leaks in 4 patients (4.3 %). All leaks developed during midterm follow-up and half of them did not increase with time. Two patients required redo surgery for an increase in periaortic extravasation and compression of neighboring structures. Further analysis was not able to reveal independent risk factors for development or deterioration of leaks. CONCLUSIONS: Anastomotic leaks after surgery for Stanford Type A aortic dissection can develop in midterm follow-up, even after initially excellent results. Meticulous follow-up is mandatory to detect possible deterioration and a need for redo surgery. PMID- 28661216 TI - Luteal-phase protocol in poor ovarian response: a comparative study with an antagonist protocol. AB - Objective This retrospective study compared the effect of the luteal phase ovarian stimulation protocol (LP group) with the gonadotrophin-releasing hormone (GnRH) antagonist protocol (AN group) in women with poor ovarian responses. Methods Ovarian stimulation was initiated with 225 IU of human gonadotrophin (hMG) daily. When the dominant follicle diameter exceeded 13 mm, 0.25 mg of a GnRH antagonist was used daily until human chorionic gonadotrophin (HCG) administration in the AN group. A GnRH antagonist was not used in the LP group. Ovulation was induced with HCG for all patients when at least one follicle reached a diameter of 16 mm or one dominant follicle reached 18 mm. The highest quality embryos were transferred or cryopreserved for later transfer. Results From January 2013 to December 2015, 274 women with poor ovarian response were included. A total of 108 patients underwent the luteal phase ovarian stimulation protocol while 166 patients underwent the GnRH antagonist protocol. hMG was used for more total days in the LP group was than in the AN group. Oestradiol levels on the day of HCG administration in the LP group were significantly lower than those in the AN group. The mean number of oocytes retrieved in the LP and AN groups was 3.5 +/- 2.5 and 3.5 +/- 2.9, respectively. The mean number of embryos of the highest quality was 1.7 +/- 1.2 and 1.7 +/- 1.5, respectively. The clinical pregnancy and implantation rates in the LP and AN groups were 26.2% (22/84) and 25% (29/116), and 15.5% (24/155) and 16.3% (35/215), respectively. Conclusions The luteal phase ovarian stimulation protocol can be applied in women with poor ovarian response and attain comparable clinical pregnancy and implantation rates to those of the GnRH antagonist protocol. PMID- 28661218 TI - On Human Nature. PMID- 28661217 TI - A comprehensive framework for evaluating the environmental health and safety implications of engineered nanomaterials. AB - Engineered nanomaterials (ENM) are a growing aspect of the global economy, and their safe and sustainable development, use, and eventual disposal requires the capability to forecast and avoid potential problems. This review provides a framework to evaluate the health and safety implications of ENM releases into the environment, including purposeful releases such as for antimicrobial sprays or nano-enabled pesticides, and inadvertent releases as a consequence of other intended applications. Considerations encompass product life cycles, environmental media, exposed populations, and possible adverse outcomes. This framework is presented as a series of compartmental flow diagrams that serve as a basis to help derive future quantitative predictive models, guide research, and support development of tools for making risk-based decisions. After use, ENM are not expected to remain in their original form due to reactivity and/or propensity for hetero-agglomeration in environmental media. Therefore, emphasis is placed on characterizing ENM as they occur in environmental or biological matrices. In addition, predicting the activity of ENM in the environment is difficult due to the multiple dynamic interactions between the physical/chemical aspects of ENM and similarly complex environmental conditions. Others have proposed the use of simple predictive functional assays as an intermediate step to address the challenge of using physical/chemical properties to predict environmental fate and behavior of ENM. The nodes and interactions of the framework presented here reflect phase transitions that could be targets for development of such assays to estimate kinetic reaction rates and simplify model predictions. Application, refinement, and demonstration of this framework, along with an associated knowledgebase that includes targeted functional assay data, will allow better de novo predictions of potential exposures and adverse outcomes. PMID- 28661219 TI - Feeding of the water extract from Ganoderma lingzhi to rats modulates secondary bile acids, intestinal microflora, mucins, and propionate important to colon cancer. AB - Consumption of reishi mushroom has been reported to prevent colon carcinogenesis in rodents, although the underlying mechanisms remain unclear. To investigate this effect, rats were fed a high-fat diet supplemented with 5% water extract from either the reishi mushroom (Ganoderma lingzhi) (WGL) or the auto-digested reishi G. lingzhi (AWGL) for three weeks. Both extracts markedly reduced fecal secondary bile acids, such as lithocholic acid and deoxycholic acid (colon carcinogens). These extracts reduced the numbers of Clostridium coccoides and Clostridium leptum (secondary bile acids-producing bacteria) in a per g of cecal digesta. Fecal mucins and cecal propionate were significantly elevated by both extracts, and fecal IgA was significantly elevated by WGL, but not by AWGL. These results suggest that the reishi extracts have an impact on colon luminal health by modulating secondary bile acids, microflora, mucins, and propionate that related to colon cancer. PMID- 28661220 TI - Immediate thrombocytopenia at time of alemtuzumab infusion for multiple sclerosis - Not always self-limiting, fully reversible or predictable. PMID- 28661221 TI - Thrombocytopenia at the time of alemtuzumab infusion in relapsing-remitting multiple sclerosis. PMID- 28661222 TI - Expression of Caspase Signaling Components in the Outer Membranes of Chronic Subdural Hematomas. AB - Chronic subdural hematoma (CSDH) is fundamentally treatable through surgery, although CSDH recurs in some cases. We have observed several cases of spontaneous resolution of CSDH outer membranes, including in trabecular CSDH, after trepanation surgery. In this study, we examined the expression of molecules involved in caspase signaling in CSDH outer membranes. Eight patients whose outer membranes were obtained successfully during trepanation surgery were included in this study. The expression of Fas; Fas-associated death domain (FADD); tumor necrosis factor receptor type 1-associated death domain (TRADD); receptor interacting protein (RIP); caspases 3, 7, 8, and 9; poly-(ADP-ribose) polymerase (PARP); DNA fragmentation factor 45 (DFF45) and beta-actin was examined by Western blot analysis. The expression levels of PARP, caspase-3, and cleaved caspase-3 were also examined by immunohistochemistry. Fas; FADD; TRADD; RIP; caspases 3, 7, 8, and 9; PARP, and DFF45 were detected in nearly all samples. Caspase-3 and PARP were localized in the endothelial cells of vessels and in fibroblasts in CSDH outer membranes. In addition, cleaved caspase-3 was detected in fibroblasts. We detected molecules of the caspase signaling pathway in CSDH outer membranes. In particular, cleaved caspase-3 was detected, which suggests that apoptosis may occur within these membranes. Thus, during the growth of CSDH outer membranes, the caspase signaling pathway may be restrained. Once the pathway is activated, gradual resolution of CSDH outer membranes may occur. Therefore, these molecules may be novel therapeutic targets for intractable CSDH. PMID- 28661223 TI - When lying changes memory for the truth. AB - In the legal field, victims and offenders frequently lie to avoid talking about serious incidents, such as past experiences of sexual abuse or criminal involvement. Although these individuals may initially lie about an experienced event, oftentimes these same people eventually abandon their lies and are forthcoming with what truly happened. To date, it is unclear whether such lying affects later statements about one's memory for the experienced event. The impetus of the present review is to compile the current state of knowledge on the effects of lying on memory. Based on existing literature, we will describe how deceptive strategies (e.g., false denials) regarding what is remembered may affect memory in consequential ways, such as forgetting of details, falsely remembering features that were not present, or a combination of both. It will be argued that the current literature suggests that mnemonic outcome is contingent on the type of lie and we will propose a theoretical framework outlining which forms of lying likely result in certain memory outcomes. Potential avenues of future research also will be discussed. PMID- 28661224 TI - Experimental study on the magnetic characteristics of coal fly ash at different combustion temperatures. AB - Two different coals containing iron minerals were combusted in a drop tube furnace at different temperatures. The ash samples collected were analyzed in detail to investigate the transformation behaviors of iron-bearing minerals and the magnetic characteristics of coal fly ash (FA). The vibrating sample magnetometer (VSM) was used to analyze the magnetic characteristics of the ash samples and Mossbauer spectroscopy was used to analyze the iron-bearing components in FA. The results indicate that combustion temperature does not significantly affect the crystals phases formed in FA, but does change the relative content of crystals. With an increase in temperature, the relative content of maghemite (gamma-Fe2O3) and magnetite (Fe3O4) decreases, while the relative content of hematite (alpha-Fe2O3) increases. The rising combustion temperature also results in a decreasing trend on saturation magnetization of FA. Furthermore, there is a significant positive correlation between the equivalent content of iron-bearing minerals and the saturation magnetization of FA, which can be applied to remove the particulates from flue gas more efficiently. PMID- 28661225 TI - Different amyloid aggregation of smooth muscles titin in vitro. AB - A comparative study of amyloid properties of the aggregates of smooth muscle titin (SMT) from chicken gizzard was carried out. These aggregates were formed in two solutions: 0.15 M glycine-KOH, pH 7.2-7.4 (SMT(Gly)) and 0.2 M KCl, 10 mM imidazole, pH 7.0 (SMT(KCl)). Electron microscopy data showed that SMT aggregates has an amorphous structure in both cases. The results of atomic-force microscopy demonstrated slight differences in morphology in two types of aggregates. The SMT(Gly) aggregates were represented as branching chains, composed of spherical aggregates approximately 300-500 nm in diameter and up to 35 nm in height. The SMT(KCl) aggregates formed sponge-like structures with strands of 8-10 nm in height. Structural analysis of SMT aggregates by X-ray diffraction revealed the presence of cross-beta-sheet structure in the samples under study. In the presence of SMT(Gly) aggregates, thioflavine T fluorescence intensity was higher (~3-fold times) compared with that in the presence of SMT(KCl) aggregates. Congo red-stained SMT(Gly) aggregates had yellow to apple-green birefringence under polarized light, which was not observed for SMT(KCl) aggregates. Dynamic light scattering data showed the similar rate of aggregation for both types of aggregates, though SMT(KCl) aggregates were able to partially disaggregate under increased ionic strength of the solution. The ability of SMT to aggregation followed by disaggregation may be functionally significant in the cell. PMID- 28661226 TI - MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3. AB - Oxidative stress-induced myocardial apoptosis and necrosis are involved in ischemia/reperfusion (I/R) injury. This study was performed to investigate microRNA (miR)-210's role in oxidative stress-related myocardial damage. The expression of miR-210 was upregulated in myocardial tissues of I/R rats, while that of Bcl-2 adenovirus E1B 19kDa-interacting protein 3 (BNIP3) was downregulated. To simulate in vivo oxidative stress, H9c2 cells were treated with H2O2 for 48 h. MiR-210 level was increased upon H2O2 stimulation, peaked at 8 h, and then decreased. An opposite expression pattern of BNIP3 was observed. BNIP3 was demonstrated as a direct target of miR-210 via luciferase reporter assay. H2O2-induced cell apoptosis was attenuated by miR-210 mimics, whereas aggravated by miR-210 inhibitor. MiR-210 knockdown-induced cell apoptosis in presence of H2O2 was attenuated by BNIP3 siRNA. Our work demonstrates that miR-210 plays a protective role in H2O2-induced cardiomyocyte apoptosis at least by regulating the pro-apoptotic BNIP3. PMID- 28661227 TI - A preliminary study of patient-specific mechanical properties of diabetic and healthy plantar soft tissue from gated magnetic resonance imaging. AB - Foot loading rate, load magnitude, and the presence of diseases such as diabetes can all affect the mechanical properties of the plantar soft tissues of the human foot. The hydraulic plantar soft tissue reducer instrument was designed to gain insight into which variables are the most significant in determining these properties. It was used with gated magnetic resonance imaging to capture three dimensional images of feet under dynamic loading conditions. Custom electronics controlled by LabVIEW software simultaneously recorded system pressure, which was then translated to applied force values based on calibration curves. Data were collected for two subjects, one without diabetes (Subject A) and one with diabetes (Subject B). For a 0.2-Hz loading rate, and strains 0.16, 0.18, 0.20, and 0.22, Subject A's average tangential heel pad stiffness was 10 N/mm and Subject B's was 24 N/mm. Maximum test loads were approximately 200 N. Loading rate and load magnitude limitations (both were lower than physiologic values) will continue to be addressed in the next version of the instrument. However, the current hydraulic plantar soft tissue reducer did produce a data set for healthy versus diabetic tissue stiffness that agrees with previous trends. These data are also being used to improve finite element analysis models of the foot as part of a related project. PMID- 28661228 TI - A comparison between electromechanical and pneumatic-controlled knee simulators for the investigation of wear of total knee replacements. AB - More robust preclinical experimental wear simulation methods are required in order to simulate a wider range of activities, observed in different patient populations such as younger more active patients, as well as to fully meet and be capable of going well beyond the existing requirements of the relevant international standards. A new six-station electromechanically driven simulator (Simulation Solutions, UK) with five fully independently controlled axes of articulation for each station, capable of replicating deep knee bending as well as other adverse conditions, which can be operated in either force or displacement control with improved input kinematic following, has been developed to meet these requirements. This study investigated the wear of a fixed-bearing total knee replacement using this electromechanically driven fully independent knee simulator and compared it to previous data from a predominantly pneumatically controlled simulator in which each station was not fully independently controlled. In addition, the kinematic performance and the repeatability of the simulators have been investigated and compared to the international standard requirements. The wear rates from the electromechanical and pneumatic knee simulators were not significantly different, with wear rates of 2.6 +/- 0.9 and 2.7 +/- 0.9 mm3/million cycles (MC; mean +/- 95% confidence interval, p = 0.99) and 5.4 +/- 1.4 and 6.7 +/- 1.5 mm3/MC (mean +/- 95 confidence interval, p = 0.54) from the electromechanical and pneumatic simulators under intermediate levels (maximum 5 mm) and high levels (maximum 10 mm) of anterior-posterior displacements, respectively. However, the output kinematic profiles of the control system, which drive the motion of the simulator, followed the input kinematic profiles more closely on the electromechanical simulator than the pneumatic simulator. In addition, the electromechanical simulator was capable of following kinematic and loading input cycles within the tolerances of the international standard requirements (ISO 14243-3). The new-generation electromechanical knee simulator with fully independent control has the potential to be used for a much wider range of kinematic conditions, including high-flexion and other severe conditions, due to its improved capability and performance in comparison to the previously used pneumatic-controlled simulators. PMID- 28661229 TI - The influence of malalignment and ageing following sterilisation by gamma irradiation in an inert atmosphere on the wear of ultra-high-molecular-weight polyethylene in patellofemoral replacements. AB - Complications of patellofemoral arthroplasty often occur soon after implantation and, as well as other factors, can be due to the design of the implant or its surgical positioning. A number of studies have previously considered the wear of ultra-high-molecular-weight polyethylene patellae following suboptimal implantation; however, studies have primarily been carried out under a limited number of degrees of freedom. The aim of this study was to develop a protocol to assess the wear of patellae under a malaligned condition in a six-axis patellofemoral joint simulator. The malalignment protocol hindered the tracking of the patella centrally in the trochlear groove and imparted a constant 5 degrees external rotation (tilt) on the patella button. Following 3 million cycles of wear simulation, this condition had no influence on the wear of ultra high-molecular-weight polyethylene patellae aged for 4 years compared to well positioned non-aged implants (p > 0.05). However, under the malaligned condition, ultra-high-molecular-weight polyethylene patellae aged 8-10 years after unpacking (following sterilisation by gamma irradiation in an inert atmosphere) and worn ultra-high-molecular-weight polyethylene components also aged 4 years after unpacking (following the same sterilisation process) exhibited a high rate of wear. Fatigue failure due to elevated contact stress led to delamination of the ultra-high-molecular-weight polyethylene and in some cases complete failure of the patellae. The results suggest that suboptimal tracking of the patella in the trochlear groove and tilt of the patella button could have a significant effect on the wear of ultra-high-molecular-weight polyethylene and could lead to implant failure. PMID- 28661230 TI - Circle (CO2 reabsorbing) breathing systems: Human applications. AB - Artificial breathing systems to help humans survive extreme environments are used over a range of ambient pressures, using various gases of different volumetric concentrations. These activities include anaesthesia and intensive care activity, high-altitude mountaineering, firefighting, aerospace extravehicular space activity and underwater diving operations. A circle breathing system is one in which the exhaled carbon dioxide is absorbed by an alkali substance and the remaining unused gases are recirculated, usually for the sake of economy and environment. This allows the flow of the fresh gas to be considerably reduced, thereby saving on fresh-gas supply. Circle systems are often used in the circumstances cited above, although not always at low fresh-gas flows. The circle system used in anaesthesia and intensive care has the least engineering demands made on it, although it is used on patients who are highly vulnerable; it usually provides a mixture of air and oxygen, and perhaps a breathable anaesthetic gas, all at sea-level pressure. Mountaineering and firefighting applications involve an extreme earthbound environment, with the user undergoing extreme physical work. The astronaut's spacesuit and life support system contains a high-flow circle system, the breathing gases themselves pressurising the suit as well as providing respiratory life support and thermal comfort; the gas provided is pure oxygen at about a third of sea-level atmosphere. There are numerous varieties of breathing systems for diving, including a circle system, often for clandestine naval activity; the gases used are a combination of oxygen, nitrogen and helium, to minimise the possibility of decompression sickness, nitrogen narcosis and oxygen toxicity and must be provided at a varying pressure and concentration appropriate to depth. PMID- 28661231 TI - Characteristics of hospital admissions for pneumonia in HIV-positive individuals in Winnipeg, Manitoba: a cross-sectional retrospective analysis. AB - Lung infection in human immunodeficiency virus (HIV)-positive individuals remains an important cause of morbidity and mortality, even in the current antiretroviral therapy era. Pneumonia is the most common cause of admission in HIV-positive individuals in our centre as reported in a previously published study. The objective of this retrospective observational study was to further characterize these admissions, with respect to index of disease severity at presentation, organisms identified, and investigations pursued including bronchoalveolar lavage (BAL). There were 123 unique patients accounting for a total of 209 admissions from 2005 to 2015. An organism was isolated in only 33% of all admissions (68/209). The most common organism was Pneumocystis jirovecii with a frequency of 29% of all admissions. Eighty-seven percent of presentations were mild, and 13% were moderate by CURB-65 criteria. A total of 39 BALs were performed, of which 27 yielded an organism (69%). Considering the burden of disease, low diagnostic yield of the current diagnostic strategy and increased morbidity and mortality caused by pneumonia in HIV-positive individuals, further methods are needed to more accurately target therapy. The preponderance of mild disease in this study suggests that better diagnostic tests may identify individuals that can be candidates for outpatient therapy. PMID- 28661232 TI - Pulmonary involvement of secondary syphilis. AB - Pulmonary involvement in secondary syphilis is considered a rare occurrence; however, the number of cases has increased in the 2000s. This is likely due to the increased use of computed tomography scans and molecular diagnostic testing. We report a case of an HIV-positive man with pleural chest pain and bilateral subpleural nodules on chest computed tomography. His rapid plasma reagin and Treponema pallidum hemagglutination tests were positive, and the specimen of one of the pulmonary nodules obtained by transthoracic biopsy was positive for the polA gene of Treponema pallidum. Since clinical manifestations of syphilis are highly variable, clinicians should bear in mind that pleural chest pain with bilateral subpleural nodules can be caused by pulmonary syphilis. PMID- 28661233 TI - The impact of diabetes on CD4 recovery in persons with HIV in an urban clinic in the United States. AB - The purpose of this study was to exam the impact of type 2 diabetes mellitus (T2DM) on CD4 cell count trends in adults with HIV. In a longitudinal retrospective study in an urban primary care HIV clinic in the southeastern United States from 2010 to 2012, patients with HIV medical charts were audited to obtain their CD4 cell count, diabetes status, weight, and demographic information. Rates of increase of CD4 T cell count (i.e. slopes) were obtained using a linear mixed-effects model. Most of the HIV-T2DM cohort (n = 262) and HIV only cohort (n = 2399) were African American (76%) and male (77%). The CD4 T cell counts were consistently higher in the HIV-T2DM cohort ( p < .0001). The mean rate of CD4 T cell count increase (mean +/- SE) was 63 +/- 9 cells/ul/year in HIV T2DM African American women and 28 +/- 7 cells/ul/year in HIV-T2DM African American men ( p = 0.003). In the multivariable slope analysis, the CD4 T cell count increase was significantly faster for HIV-T2DM African American women than for all other patients (mean difference = 30/cells/ul/year, 95% CI: 13-47; p < 0.001). Gender, race/ethnicity, and the diagnosis of diabetes influenced the recovery of CD4 cell counts. PMID- 28661234 TI - An evaluation of the SD Bioline HIV/syphilis duo test. AB - Many health agencies now recommend routine HIV and syphilis testing for pregnant women and most-at-risk populations such as men who have sex with men. With the increased availability of highly sensitive, low cost rapid point-of-care tests, the ability to meet those recommendations has increased, granting wider access to quick and accurate diagnoses. Using blood specimens collected from a Baltimore City Health Department (BCHD) sexually transmitted infection clinic, we evaluated the SD Bioline HIV/Syphilis Duo, a rapid test that simultaneously detects antibodies to HIV and syphilis and has the potential to further benefit clinics and patients by reducing costs, testing complexity, and patient wait times. SD DUO HIV sensitivity and specificity, when compared to BCHD results, were 91.7 and 99.5%, respectively. SD DUO syphilis sensitivity and specificity, when compared to rapid plasma reagin, were 85.7 and 96.8%, respectively, and 69.7 and 99.7%, respectively, when compared to Treponema pallidum particle agglutination (TPPA). SD DUO syphilis sensitivity and specificity, when compared to a traditional screening algorithm, improved to 92.3 and 100%, respectively, and improved to 72.9 and 99.7%, respectively, when compared to a reverse screening algorithm. The HIV component of the SD DUO performed moderately well. However, results for the SD DUO syphilis component, when compared to TPPA, support the need for further testing and assessment. PMID- 28661235 TI - President's message: The disaster within. PMID- 28661238 TI - Minding Ps and Qs: The Political and Policy Questions Framing Health Care Spending. AB - Tracing the evolution of political conversations about health care spending and their relationship to the formation of policy is a valuable exercise. Health care spending is about science and ethics, markets and government, freedom and community. By the late 1980s the unique upward trajectory of post-Medicare U.S. health care spending had been established, recessions and tax cuts were eroding federal and state budgets, and efforts to harness market forces to serve policy goals were accelerating. From the initial writings on "managed competition," through the failed Clinton health reform effort in the early 1990s, to the passage of the Affordable Care Act in 2010, the policy narrative of health spending acquired a superficial consistency. On closer examination, however, it becomes apparent that the cost problem has been repeatedly reframed in political discourse even during this relatively brief period. The clearest transition has been from a narrative centered on rationing necessary care to one committed to reducing wasteful care - although the role of accumulated law and regulation in perpetuating waste remains largely unrecognized and the recently articulated commitment to population health seems an imperfect proxy for explicitly developing social solidarity with respect to health and health care in the United States. PMID- 28661236 TI - Forty years of research concerning children and youth in Greenland: a mapping review. AB - OBJECTIVE: This study undertakes a mapping review of mainly concerning children and youth in Greenland in the period 1976-2016 and reflects on how the research has been conducted and knowledge thereby created about children and youth in Greenland, as well as how the research has been developed over time. DESIGN: 16 online databases; five journals; publication lists originating from seven organisations and ten prominent researchers; and local network and references were used in the search and subsequently screened through the scoping criteria. 342 publications were included, encompassing knowledge based on empirical research on children and youth in Greenland within the broader field of psychology. RESULTS: The majority of studies, 71%, were conducted through quantitative methods. The qualitative research is represented in 22% of the studies and participatory and action-orientated research is represented in 7% of the studies. The most prominent themes in research concerning children and youth in Greenland were physical problems, which were found in 38% of the studies. CONCLUSIONS: The result reflects a consistent objectivity and quantitative methodology in health research in Greenland since 1991.The health research thus represents a united research community with a shared methodological research approach, while the local participatory action research projects all appear differentiated. While health research covers a spectrum of psychology related objectives, the methodology traditions reveal a specific kind of knowledge, which has come to determine how the mental health of the Greenlandic children is perceived. We believe that more qualitative and locally grounded approaches need to be organised in order to produce a more nuanced knowledge of the Greenlandic children and youth. PMID- 28661239 TI - Health Reform in a New Presidency: The Challenge of Finding Common Ground. AB - Finding "common ground" to fix some of the policy problems with the ACA was never expected to be easy. How challenging depends on the election outcome. With split government or even same party control of the Congress and White House but without a supermajority in the Senate, fixing identifiable problems requires remedies that might garner bipartisan cooperation. Some potential strategies that might meet this requirement are described. PMID- 28661240 TI - It's the Prices, Advanced Capitalism, and the Need for Rate Setting - Stupid. AB - Competition cannot stem the rise of health care expenditures because it leaves agency diffuse and transferred in part to the institutions of advanced capitalism, which excel in generating demand for their services. The United States should turn to state rate setting to concentrate purchasing power. PMID- 28661241 TI - Who Do You Trust? AB - The ability of patients to trust physicians to act in their best interests is a critical aspect of a welfare-maximizing relationship. This commentary discusses physician trustworthiness within the framework of the Affordable Care Act and considers steps to reinforce trustworthy behavior. PMID- 28661242 TI - The Affordable Care Act's Day(s) in Court. AB - This article reviews the primary avenues of judicial challenge to the ACA, focusing on those that have reached, or have the potential to reach, the Supreme Court. The review demonstrates how deep-seated public policy opposition can be expressed through litigation. PMID- 28661243 TI - HIPAA Compliance and Training: A Perfect Storm for Professionalism Education? AB - The HIPAA Rules continue to support and bolster the importance of protecting the privacy and security of patients' protected health information. The HIPAA training requirements are at the cornerstone of meaningful implementation and provide a ripe opportunity for critical education. PMID- 28661244 TI - Mitigating Risks to Pregnant Teens from Zika Virus. AB - Zika infection in pregnant women is associated with an elevated probability of giving birth to a child with microcephaly and multiple other disabilities. Public health messaging on Zika prevention has predominantly targeted women who know they are pregnant or intend to become pregnant, but not teenage females for whom unintended pregnancy is more likely. Vulnerabilities among this population to reproductive risks associated with Zika are further amplified by restrictive abortion laws in several Zika-impacted states. Key to prevention is enhanced, targeted public health messaging centered on teens nationally and particularly in certain high-risk regions. PMID- 28661245 TI - Medicaid's Role in Health Reform and Closing the Coverage Gap. AB - Medicaid coverage matters for millions of low-income Americans, and especially for those with ongoing and serious health challenges. A source of comprehensive and affordable coverage, Medicaid has long been a cornerstone of federal and state efforts to improve access and health outcomes for very poor and medically vulnerable populations. The Affordable Care Act (ACA) leveraged Medicaid's role in serving the poor to broaden the program's reach to millions of low-income uninsured adults, and positioned the program as a fundamental component of the newly established continuum of public and private coverage. Looking ahead, if more states embrace the Medicaid expansion, there is the potential to build on this progress to significantly reduce the number of uninsured Americans. PMID- 28661246 TI - After the Affordable Care Act: Health Reform and the Safety Net. AB - Two major safety net providers - community health centers and public hospitals - continue to play a key role in the health care system even in the wake of coverage reform. This article examines the gains and threats they face under the Affordable Care Act. PMID- 28661247 TI - Show Us the Data: The Critical Role Health Information Plays in Health System Transformation. AB - Truly transforming the healthcare delivery and payment system turns on the ability to engage in the interoperable electronic exchange of patient health information across and beyond the care continuum. Achieving transformation requires a legal framework that supports information sharing with appropriate privacy and security protections and a trusted governance structure. PMID- 28661248 TI - Moving to the Next Phase of Reform. AB - Better health requires sectors like housing and education, and healthcare, to collaborate. That needs three strategies. Make full use of waivers to foster experimentation. Use techniques to encourage agencies at all levels to work together. And use new incentives to foster local partnerships. PMID- 28661249 TI - Regulating Information or Allowing Deception? Pharmaceutical Sales Visits in Canada, France, and the United States. AB - Diverse legal and regulatory measures are used internationally to control the information provided during pharmaceutical sales visits. Little is known about the comparative effectiveness of these measures however. We analyzed the perceptions of regulators, pharmaceutical industry officials, health professionals, and consumer respondents concerning these approaches in Canada, France, and the United States using an empirical realist interests-based approach. Interviews focused on the aims and effectiveness of regulation, barriers and enablers to regulation and suggestions for improvement. An alignment was found in North America regulator and industry respondents' satisfaction with the status quo and their view that further intervention is unfeasible and unnecessary. Health professionals generally expressed a lack of confidence in the impact of regulations on sales visit information while consumer advocates voiced their disappointment in both regulators and health professionals for their failure to counteract the influence of pharmaceutical marketing. Regulator and industry respondents in France differed from their North American counterparts in their willingness to increase and diversify the scope of regulatory interventions. As the first international comparison of regulatory experiences in this sector, the findings highlight the universal need for more focused and inclusive discussions among groups about how to tailor regulations to achieve public health goals. PMID- 28661250 TI - Letter from the Editor. PMID- 28661251 TI - Making Health Care Truly Affordable after Health Care Reform. AB - The Affordable Care Act (ACA) is an essential first step toward making health insurance more affordable for lower and moderate income Americans. It has accomplished historic reductions in the proportion of Americans who are uninsured. The number of Americans reporting delaying medical care for financial reasons has declined by approximately one-third since 2010. Medicaid expansions, in particular, have significantly reduced financial burdens and accompanying anxieties experienced by low-income Americans in states that have embraced this opportunity. 4 Consistent with these finding, one recent analysis of credit report data finds that Medicaid expansion was associated with between a $600 and $1000 decline in collection balances among individuals who gained coverage. Notwithstanding these gains, premiums and cost-sharing are still too high for many Americans. And cost-sharing has continued to edge higher for the majority of Americans who have coverage through employer-based plans. Measures to address these challenges must build on the ACA to provide greater protection to millions of Americans and to address continued dissatisfaction with our health care financing system among middle-income Americans. PMID- 28661252 TI - The Affordable Care Act at Six: Reaching for a New Normal. PMID- 28661253 TI - Are Military and Medical Ethics Necessarily Incompatible? A Canadian Case Study. AB - Military physicians are often perceived to be in a position of 'dual loyalty' because they have responsibilities towards their patients but also towards their employer, the military institution. Further, they have to ascribe to and are bound by two distinct codes of ethics (i.e., medical and military), each with its own set of values and duties, that could at first glance be considered to be very different or even incompatible. How, then, can military physicians reconcile these two codes of ethics and their distinct professional/institutional values, and assume their responsibilities towards both their patients and the military institution? To clarify this situation, and to show how such a reconciliation might be possible, we compared the history and content of two national professional codes of ethics: the Defence Ethics of the Canadian Armed Forces and the Code of Ethics of the Canadian Medical Association. Interestingly, even if the medical code is more focused on duties and responsibility while the military code is more focused on core values and is supported by a comprehensive ethical training program, they also have many elements in common. Further, both are based on the same core values of loyalty and integrity, and they are broad in scope but are relatively flexible in application. While there are still important sources of tension between and limits within these two codes of ethics, there are fewer differences than may appear at first glance because the core values and principles of military and medical ethics are not so different. PMID- 28661254 TI - Early Experience with the ACA: Coverage Gains, Pooling of Risk, and Medicaid Expansion. AB - We provide an overview of the characteristics of those who have gained insurance coverage due to the ACA as well as the characteristics of the remaining uninsured. We also describe the implications for the broader sharing of health care risks required under the law, and how they vary by individuals' health status. Finally, we assess the implications of state decisions to expand or not expand Medicaid eligibility under the law, how those decisions affect state finances, health care providers, residents, and how the effects may vary for those states using waivers to expand eligibility using strategies designed to be more broadly politically acceptable. PMID- 28661255 TI - Struggles in Defining and Addressing Requests for "Family Balancing": Ethical Issues Faced by Providers and Patients. AB - This study - the first to explore how infertility providers confront several critical dilemmas concerning sex selection of embryos for nonmedical, social reasons - highlights key challenges and questions. Clinicians struggle, for instance, with how to define "family balalancing", when to offer it, and how to decide. PMID- 28661256 TI - Food Labeling and Consumer Associations with Health, Safety, and Environment. AB - The food supply is complicated and consumers are increasingly calling for labeling on food to be more informative. In particular, consumers are asking for the labeling of food derived from genetically modified organisms (GMO) based on health, safety, and environmental concerns. At issue is whether the labels that are sought would accurately provide the information desired. The present study examined consumer (n = 181) perceptions of health, safety and the environment for foods labeled organic, natural, fat free or low fat, GMO, or non-GMO. Findings indicated that respondents consistently believed that foods labeled GMO are less healthy, safe and environmentally-friendly compared to all other labels (ps < .05). These results suggest that labels mean something to consumers, but that a disconnect may exist between the meaning associated with the label and the scientific consensus for GMO food. These findings may provide insight for the development of labels that provide information that consumers seek. PMID- 28661257 TI - Recreational 3,4-methylenedioxymethamphetamine or 'ecstasy': Current perspective and future research prospects. AB - AIMS: The purpose of this article is to debate current understandings about the psychobiological effects of recreational 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'), and recommend theoretically-driven topics for future research. METHODS: Recent empirical findings, especially those from novel topic areas were reviewed. Potential causes for the high variance often found in group findings were also examined. RESULTS AND CONCLUSIONS: The first empirical reports into psychobiological and psychiatric aspects from the early 1990s concluded that regular users demonstrated some selective psychobiological deficits, for instance worse declarative memory, or heightened depression. More recent research has covered a far wider range of psychobiological functions, and deficits have emerged in aspects of vision, higher cognitive skill, neurohormonal functioning, and foetal developmental outcomes. However, variance levels are often high, indicating that while some recreational users develop problems, others are less affected. Potential reasons for this high variance are debated. An explanatory model based on multi-factorial causation is then proposed. FUTURE DIRECTIONS: A number of theoretically driven research topics are suggested, in order to empirically investigate the potential causes for these diverse psychobiological deficits. Future neuroimaging studies should study the practical implications of any serotonergic and/or neurohormonal changes, using a wide range of functional measures. PMID- 28661258 TI - Antidepressant-like effect of a new selenium-containing compound is accompanied by a reduction of neuroinflammation and oxidative stress in lipopolysaccharide challenged mice. AB - Organoselenium compounds and indoles have gained attention due to their wide range of pharmacological properties. Depression is a recurrent and disabling psychiatric illness and current evidences support that oxidative stress and neuroinflammation are mechanisms underlying the pathophysiology of this psychiatric condition. Here, we evaluated the effect of 3-((4 chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) in lipopolysaccharide (LPS) induced depressive-like behaviour, neuroinflammation and oxidative stress in male mice. CMI pre-treatment (20 and 50 mg/kg, intragastrically) significantly attenuated LPS (0.83 mg/kg, intraperitoneally)-induced depressive-like behaviour in mice by reducing the immobility time in the tail suspension test (TST) and forced swimming test (FST). CMI pre-treatment ameliorated LPS-induced neuroinflammation by reducing the levels of interleukin (IL)-1beta, IL-4 and IL-6 in the hippocampus and prefrontal cortex, as well as markers of oxidative damage. Additionally, we investigated the toxicological effects of CMI (200 mg/kg, i.g.) in the liver, kidney and brain through determination of the activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), delta-aminolevulinate dehydratase (delta-ALA-D) and creatinine levels. These biomarkers were not modified, indicating the possible absence of neuro-, hepato- and nephrotoxic effects. Our results suggest that CMI could be a therapeutic approach for the treatment of depression and other neuropsychiatric disorders associated with inflammation and oxidative stress. PMID- 28661259 TI - Gonadotrophin-releasing hormone agonist treatment for sexual offenders: A systematic review. AB - BACKGROUND: Sexual offending is a significant international issue causing long term consequences for victims, perpetrators and society. AIMS: The purpose of this study was to review the existing research data assessing the efficacy of gonadotrophin-releasing hormone agonists for treating adult, male, sexual offenders. METHOD: The method of this review involved the examination of studies involving participants prescribed at least one month of a gonadotrophin-releasing hormone agonist for the purposes of reducing sexual drive related to offending. The primary outcome measures were recidivism rates and sexual functioning. Secondary outcome measures included assessment of side effects and effects on interpersonal/psychiatric functioning. Studies in the English language that were dated 1969-2015 were included. RESULTS: Twelve eligible studies (323 participants) were identified. A reduction in a variety of measures of sexual functioning and/or risk was found in all studies. Robust recidivism data was limited. Medication was rarely described as ineffectual. All studies reported side effects. Reduction in bone density and potential long-term reduction in fertility in some subjects were issues of concern. CONCLUSION: Whilst identified studies showed promising results with respect to sexual functioning, challenges in performing randomised control trials in this subject group meant that included studies were methodologically limited. This review recommends that future research must be performed before the effectiveness and tolerability of gonadotrophin-releasing hormone agonists in this population can be confirmed. PMID- 28661260 TI - Effect of team training on efficiency of trauma care in a Chinese hospital. AB - Objective Multidisciplinary trauma teams are the standard of care in the USA, but staffing differences and lack of advanced trauma life support training hinder replication of this system in Chinese hospitals. We investigated the effect of simulation team training on initial trauma care. Methods Over 15 months, we compared grade I trauma patients cared for by the trained team and those cared for using traditional practice on times from emergency room arrival to tests/procedures. Propensity-score analysis was performed to improve between group comparisons. Results During the study, 144 grade I trauma patients were treated. Trained team patients showed shorter times from emergency room arrival to initiation of hemostasis (31.0 [13.5-58.5] vs. 113.5 [77-150.50] min), blood routine report (8 [5-10.25] vs. 13 [10-21] min), other blood tests (21 [14.75 25.75] vs. 31 [25-37] min), computed tomography scan (29.5 [20.25-65] vs. 58.5 [30.25-71.25] min) and tranexamic acid administration (31 [13-65] vs. 90 [65-200] min). Similar results were obtained for the propensity-score matched cohort. Conclusion Simulation team training could help reduce time to blood routine reports, scans and hemostasis. Assessment of available resources and development of targeted team training could improve care in resource-limited hospitals. PMID- 28661261 TI - Changes in pulmonary function and functional capacity in adolescents with mild idiopathic scoliosis: observational cohort study. AB - Objective This observational cohort study aimed to evaluate ventilatory function (VF) and functional exercise capacity (FEC) in mild adolescent idiopathic scoliosis (AIS). Methods Seventy-three adolescents with idiopathic scoliosis, aged approximately 10 to 17 years (mean age: 13.43 +/- 1.27 years), with a Cobb angle less than 20 degrees (mean: 16.44 degrees +/- 1.59 degrees ), met the inclusion criteria and were assigned to group A. Another 34 healthy adolescents with normal VF and FEC served as controls (group B). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum voluntary ventilation (MVV), and FEC (by the 6-minute walk test [6MWT]) were the main outcome measures. Results Post-study mean values of FVC, FEV1, FEV1/FVC, MVV, and the 6MWT were 2.42 +/- 0.36 L and 3.26 +/- 0.59 L, 2.14 +/- 0.31 L and 3.03 +/- 0.43 L, 88.13% +/- 3.89% and 91.14% +/- 4.67%, 76.96 +/- 6.85 L/m and 107.61 +/- 11.44 L/m, and 581.12 +/- 12.25 m and 627.74 +/- 15.27 m in groups A and B, respectively. Between-group comparisons showed significant differences in FVC, FEV1, FEV1/FVC, MVV, and the 6MWT. Conclusion Mild pulmonary and functional restrictions start early in mild AIS. This issue requires immediate intervention to prevent further deterioration. PMID- 28661262 TI - Memantine improves semantic memory in patients with amnestic mild cognitive impairment: A single-photon emission computed tomography study. AB - Objective This study was performed to assess the efficacy of memantine in patients with amnestic mild cognitive impairment (aMCI). Methods Thirty healthy controls and 45 patients diagnosed with aMCI based on the Petersen criteria were classified into 3 groups. Group 1 comprised patients who received a single memantine dose following examination (n = 25), Group 2 comprised patients who did not receive memantine treatment following examination (n = 20), and Group 3 comprised healthy age-matched volunteers (n = 30). Neuropsychological testing was performed, and the response to memantine was examined at baseline and at 12, 24, and 48 weeks. Single-photon emission computed tomography was performed at baseline and at 48 weeks in patients who received memantine treatment. Results Memantine treatment significantly improved the symptoms of aMCI according to the Wechsler Adult Intelligence Scale-Revised vocabulary subtest, backward digit span, and Blessed Dementia Rating Scale, all of which were recorded for the duration of the study. Conclusion These data indicate that patients with aMCI receiving memantine develop an improved semantic memory compared with no treatment. Further studies including larger patient cohorts are necessary to validate these findings. PMID- 28661263 TI - Minimally invasive treatment of unstable pelvic ring injuries with modified pedicle screw-rod fixator. AB - Objective To evaluate the clinical application of the minimally invasive modified pedicle screw-rod fixator for unstable pelvic ring injuries, including its feasibility, merits, and limitations. Methods Twenty-three patients (13 males, 10 females; average age, 36.3 years) with unstable pelvic ring injuries underwent anterior fixation using a modified pedicle screw-rod fixator with or without posterior fixation using a transiliac internal fixator. The clinical findings were assessed using Majeed scores. The quality of reduction was evaluated using the Matta criteria. Results Clinical results at 1 year postoperatively were excellent in 14 patients, good in 7, and fair in 2. The two patients with fair results had intermittent pain at the sacroiliac joint because of the posterior implant. One woman complained of persistent pain at the pubic tubercle during sexual intercourse. Iatrogenic neuropraxia of the unilateral lateral femoral cutaneous nerve occurred in three patients. Unilateral femoral nerve palsy occurred in one patient. The quality of fracture reduction was excellent in 12 patients, good in 8, and fair in 3. Heterotopic ossification occurred in eight patients; all were asymptomatic. Conclusions Minimally invasive modified pedicle screw-rod fixation is an effective alternative treatment for pelvic ring injuries. PMID- 28661264 TI - Efficacy of solifenacin in the prevention of short-term complications after laparoscopic radical prostatectomy. AB - Objective To evaluate the efficacy of solifenacin in the prevention of short-term complications after laparoscopic radical prostatectomy (LRP). Methods This randomized placebo-controlled study enrolled patients with histologically proven prostate cancer who underwent LRP. The patients were randomized to receive either solifenacin (5 mg once daily; study group) or placebo (control group) for the 15 day period beginning on the first day after surgery. The mean duration of detrusor overactivity (DO), the frequency of DO, the duration of macroscopic haematuria, and the days before catheter removal were recorded. The International Continence Society Short Form Male questionnaire, bladder neck stenosis episodes, and maximum urinary flow rate were evaluated at 1 month after surgery. The side effects after using solifenacin were also recorded. Results A total of 120 patients were randomly assigned to the study group ( n = 62) or the control group ( n = 58). There were significantly lower rates of DO episodes during the daytime and night-time, haematuria and transient incontinence in the study group compared with the control group. Conclusion Solifenacin was a well-tolerated and effective treatment for the prevention of complications after LRP, with the main advantage compared with placebo being the decreased frequency of DO episodes during the daytime and night-time. PMID- 28661265 TI - Medium-term effects of Dynesys dynamic stabilization versus posterior lumbar interbody fusion for treatment of multisegmental lumbar degenerative disease. AB - Objective To compare the medium-term clinical and radiographic outcomes of Dynesys dynamic stabilization and posterior lumbar interbody fusion (PLIF) for treatment of multisegmental lumbar degenerative disease. Methods Fifty-seven patients with multisegmental lumbar degenerative disease underwent Dynesys stabilization (n = 26) or PLIF (n = 31) from December 2008 to February 2010. The mean follow-up period was 50.3 (range, 46-65) months. Clinical outcomes were evaluated using a visual analogue scale (VAS) and the Oswestry disability index (ODI). Radiographic evaluations included disc height and range of motion (ROM) of the operative segments and proximal adjacent segment on lumbar flexion-extension X-rays. The intervertebral disc signal change was defined by magnetic resonance imaging, and disc degeneration was classified by the Pfirrmann grade. Results The clinical outcomes including the VAS score and ODI were significantly improved in both groups at 3 months and the final follow-up, but the difference between the two was not significant. At the final follow-up, the disc height of stabilized segments in both groups was significantly increased; the increase was more notable in the Dynesys than PLIF group. The ROM of stabilized segments at the final follow-up decreased from 6.20 degrees to 2.76 degrees and 6.56 degrees to 0.00 degrees in the Dynesys and PLIF groups, respectively. There was no distinct change in the height of the proximal adjacent segment in the two groups. The ROM of the proximal adjacent segment in both groups increased significantly at the final follow-up; the change was significantly greater in the PLIF than Dynesys group. Only one case of adjacent segment degeneration occurred in the PLIF group, and this patient underwent a second operation. Conclusions Both Dynesys stabilization and PLIF can improve the clinical and radiographic outcomes of multisegmental lumbar degenerative disease. Compared with PLIF, Dynesys stabilization can maintain the mobility of the stabilized segments with less influence on the proximal adjacent segment and may help to prevent the occurrence of adjacent segment degeneration. Dynesys is reliable for the treatment of multisegmental lumbar degenerative disease at the medium-term follow-up. PMID- 28661266 TI - Argon and helium plasma coagulation of porcine liver tissue. AB - Objective Argon plasma coagulation (APC) and helium plasma coagulation (HPC) are electrosurgical techniques that provide noncontact monopolar electrothermal haemostasis. Although these techniques have been widely used clinically during the last three decades, their in vivo effects on liver tissue remain unclear. Methods We investigated the effects of different power levels (10-100 W) of APC and HPC on liver coagulation in 11 Landrace pigs. Capillary blood flow and capillary blood flow velocity were recorded with a combined laser Doppler flowmeter and spectrophotometer. The temperature, clinical biochemical parameters, blood gas parameters, bile duct-sealing effect, and coagulation depth were measured. Results APC and HPC significantly reduced the capillary blood flow and capillary blood flow velocity compared with baseline flow. No significant temperature change was measured on the liver surface immediately after coagulation. The clinical biochemical and blood gas parameters were not different before and after coagulation. The coagulation depth was positively correlated with the device power setting. Conclusions These results prove that APC and HPC provide sufficient superficial haemostasis. No significant systemic effects occurred following coagulation. The depth of the coagulation effect can be controlled through selection of the output power level. PMID- 28661267 TI - Clinical evidence of efficacy of simvastatin for aneurysmal subarachnoid hemorrhage. AB - Objective The present study was performed to explore the therapeutic potential of simvastatin in subarachnoid hemorrhage (SAH) in the context of the Simvastatin in Aneurysmal Subarachnoid Hemorrhage (STASH) trial. Methods MEDLINE, EMBASE, and the Cochrane Library were searched for all randomized controlled trials (RCTs) investigating the therapeutic effect of simvastatin on aneurysmal SAH. We applied a random-effects model to calculate the data. Results Five RCTs involving 951 patients met the eligibility criteria. We found no statistically significant effects on vasospasm detected by transcranial cerebral Doppler (relative risk [RR], 0.91; 95% confidence interval [CI], 0.55-1.49), delayed cerebral ischemia (DCI) (RR, 0.85; 95% CI, 0.63-1.14), or all-cause mortality (RR, 1.02; 95% CI, 0.67-1.54). Subgroup analysis showed that these consolidated results were stable at different doses, different times to start of treatment, and different courses of treatment in all included RCTs. Sensitivity analysis showed that the STASH trial, which had a large population, did not influence the consolidated results of all three outcomes. Conclusions Simvastatin showed no benefits in decreasing the incidence of vasospasm, DCI, or all-cause mortality after aneurysmal SAH. We conclude that patients with SAH should not be treated routinely with simvastatin during the acute stage. PMID- 28661270 TI - Letter from the Editor. PMID- 28661269 TI - Clinical characteristics and risk factors of severe infections in hospitalized adult patients with primary nephrotic syndrome. AB - Objective Infection is a common condition in patients with nephrotic syndrome. The objective of the present study is to investigate the clinical characteristics and risk factors of infections in adult patients with primary nephrotic syndrome (PNS). Methods Medical charts of 138 consecutive patients with PNS and infections who were admitted to hospital from April 2013 to April 2016 were systematically reviewed. Results Patients were divided into three groups according to the degree of infections: mild infection group (n = 45), moderate infection group (n = 60), and severe infection group (n = 33). In the severe infection group, most patients (96.9%) had pulmonary infections with opportunistic pathogens. There were significant differences in cumulative prednisone dose, immunosuppressor use, and CD4+ T cell count among the three groups. A lower CD4+ T cell count (<300 cells/mm3) (odds ratio = 4.25 [95% confidence interval 1.680-10.98]) and higher cumulative dose of prednisone (odds ratio = 1.38 [95% confidence interval 1.05 3.26]) were risk factors for severe infections in adult patients with PNS. Conclusions CD4+ T cell count (<300 cells/mm3) and a higher cumulative dose of prednisone are important risk factors for severe infections in adult patients with PNS. PMID- 28661268 TI - Attentional bias scores in patients with depression and effects of age: a controlled, eye-tracking study. AB - Objective To compare the attentional bias of depressed patients and non-depressed control subjects and examine the effects of age using eye-tracking technology in a free-viewing set of tasks. Methods Patients with major depressive disorder (MDD) and non-depressed control subjects completed an eye-tracking task to assess attention of processing negative, positive and neutral facial expressions. In this cross-sectional study, the tasks were separated in two types (neutral versus happy faces and neutral versus sad faces) and assessed in two age groups ('young' [18-30 years] and 'middle-aged' [31-55 years]). Results Compared with non depressed control subjects ( n = 75), patients with MDD ( n = 90) had a significant reduced positive attentional bias and enhanced negative attentional bias irrespective of age. The positive attentional bias in 'middle-aged' patients with MDD was significantly lower than in 'young' patients, although there was no difference between the two age groups in negative attentional bias. Conclusions These results confirm that there are emotional attentional biases in patients with MDD and that positive attentional biases are influenced by age. PMID- 28661272 TI - Informed Consent: Charade or Choice? AB - Informed consent has historically been described as critical in theory, but incapable of realization in practice, a superficial charade rather than an autonomous choice. This observation should help inspire us to reform our practice to make sure that informed choice actually upholds patient dignity, promotes rational decisionmaking, and protects self-determination. PMID- 28661273 TI - Flying Too Close to the Sun: Lessons Learned from the Judicial Expansion of the Objective Patient Standard for Informed Consent in Wisconsin. AB - The Wisconsin Supreme Court, after adopting the doctrine of the objective (reasonable) patient standard, expanded it in bold and innovative ways over nearly four decades, until the Wisconsin legislative and executive branches drastically reversed this course. The saga has implications for other jurisdictions considering adoption or expansion of the objective patient standard doctrine. PMID- 28661274 TI - Under Attack: Reconceptualizing Informed Consent. PMID- 28661275 TI - Informed Consent as Societal Stewardship. AB - When individual patients' medical decisions contribute to population-level trends, physicians may struggle with how to promote justice while maintaining respect for patient autonomy. This article argues that this tension might be resolved by using the informed consent conversation as an opportunity to position patients as societal stewards. PMID- 28661276 TI - Certified Patient Decision Aids: Solving Persistent Problems with Informed Consent Law. AB - The legal doctrine of informed consent has overwhelmingly failed to assure that the medical treatment patients get is the treatment patients want. This Article describes and defends an ongoing shift toward shared decision making processes incorporating the use of certified patient decision aids. PMID- 28661277 TI - Public Health "Preemption Plus". PMID- 28661278 TI - Shouldn't Dead Be Dead?: The Search for a Uniform Definition of Death. AB - In 1968, the definition of death in the United States was expanded to include not just death by cardiopulmonary criteria, but also death by neurologic criteria. We explore the way the definition has been modified by the medical and legal communities over the past 50 years and address the medical, legal and ethical controversies associated with the definition at present, with a particular highlight on the Supreme Court of Nevada Case of Aden Hailu. PMID- 28661279 TI - Beyond Canterbury: Can Medicine and Law Agree about Informed Consent? And Does It Matter? AB - Informed consent is central to the law of the physicianpatient relationship, respecting patient autonomy. This paper addresses a conflict between law and medicine in defining informed consent. Additionally, it addresses the possibility that patients prefer not to be "informed" and would defer decision-making to their physicians. PMID- 28661280 TI - Negotiating Commercial Interests in Biospecimens. AB - Proposed changes to the Common Rule would require publicly funded researchers to disclose whether a subject's biospecimens could be used for commercial profit and whether the subject will share in those proceeds. Disclosing commercial interests will inform research participants that their tissue may have commercial value, a possibility that those individuals might not have previously considered. The proposed changes may then provide people with an opportunity to negotiate commercial rights in their biospecimens despite the well-accepted legal precedent that individuals maintain no interests in their excised tissue. PMID- 28661281 TI - Informed Consent Is the Essence of Capacity Assessment. AB - Informed consent is the single most important concept for understanding decision making capacity. There is a steady pull in the clinical world to transform capacity into a technical concept that can be tested objectively, usually by calling for a psychiatric consult. This is a classic example of medicalization. In this article I argue that is a mistake, not just unnecessary but wrong, and explain how to normalize capacity assessment. Returning the locus of capacity assessment to the attending, the primary care doctor, and even to ethics consultation in today's environment will require a substantial effort to undo a strong but illusory impression of capacity assessment. Hospital attorneys as well as clinical ethicists with a sophisticated understanding of health law can be in the vanguard of this reorientation. PMID- 28661282 TI - Informed Consent in Dentistry. AB - A review of literature regarding informed consent in dentistry reveals a paucity of information and minimal scholarship devoted to this subject. But this begs the question about informed consent somehow being different for dentistry than for medicine or other healthcare delivery. My account draws distinctions where appropriate but is rooted in the premise that informed consent is an ethical construct applicable to vulnerable people as patients independent of what type of treatment or body part being considered. This paper highlights the crucial importance of the process of informed consent and refusal in dentistry, underscoring its important place in oral healthcare. This paper will not address the unique circumstances involving consent in those without capacity or focus on informed consent in the research setting; our focus will be on those patients with full decisionmaking capacity in the clinical setting. I will emphasize the importance of disclosure of treatment options and highlight the benefits of shared-decision-making in the informed consent process. PMID- 28661283 TI - Is There a Particular Ethical Practice and Policy Space in North America for Uncontrolled Kidney Donation after Circulatory Death? AB - Despite successful transplantation outcomes in Europe, uncontrolled organ donation after circulatory determination of death (uDCDD) has essentially been a non-starter in North America. In this paper, I identify and explore a set of interesting, ethics-related considerations that are of relevance to this organ donation-transplantation practice. The analysis provides a theoretical platform for my development of a proposal for the creation of a particular ethical practice and policy space for kidney uDCDD in the U.S. and Canada that recognizes and aims to effectively address the various, identified challenges and constraints. PMID- 28661284 TI - A New Age of Patient Transparency: An Organizational Framework for Informed Consent. AB - With the many changes occurring in today's healthcare organizations, patients are increasingly equipped with a vast quantity of health care data and being more included in the healthcare decision-making process. The new approach we propose incorporates a new patient-organization framework that examines relevant historical, legal and ethical elements within the doctrine of informed consent in addition to examining the role of new healthcare organizations' obligations to include data to support addressing issues such as population health, health outcomes and health disparities within the informed consent. There is a growing consensus among healthcare professionals that using an evidencebased organizational informed consent framework to improve the informed consent process can lead to better comprehension, health outcomes, transparency and improved patient trust and retention overall. PMID- 28661285 TI - Living Organ Donation and Informed Consent in the United States: Strategies to Improve the Process. AB - About 6,000 individuals participate in the U.S. transplant system as a living organ donor each year. Organ donation (most commonly a kidney or part of liver) by living individuals is a unique procedure, where healthy patients undergo a major surgical operation without any direct functional benefit to themselves. In this article, the authors explore how the ideal of informed consent guides education and evaluation for living organ donation. The authors posit that informed consent for living organ donation is a process. Though the steps in this process are partially standardized through national health policy, they can be improved through institutional structures at the local, transplant center-level. Effective structures and practices aimed at supporting and promoting comprehensive informed consent provide more opportunities for candidates to ask questions about the risks and benefits of living donation and to opt out voluntarily Additionally, these practices could enable new ways of measuring knowledge and improving the consent process. PMID- 28661286 TI - Research Capacity Strengthening in Low- and Middle-Income Countries: Ethical Explorations. AB - With developed country governments and high resource institutions engaging in research in low- and middle-income countries (LMIC), we argue that these entities have a moral obligation to help build and strengthen research infrastructure and capacity so local scientists and institutions can adequately conduct studies to understand and resolve the health burdens in low and middle income countries. We explore the moral justifications and motivations behind engaging in research capacity strengthening in the health sector in LMIC at multiple levels. In highlighting these issues, this paper aims to initiate a global discourse around why capacity development in LMIC has a moral basis at the individual, institutional and system levels. PMID- 28661287 TI - Compelled Disclosures of Health Records: Updated Estimates. PMID- 28661288 TI - The Prescription Drug Pricing Moment: Using Public Health Analysis to Clarify the Fair Competition Debate on Prescription Drug Pricing and Consumer Welfare. AB - Fair competition law and public health law talk past each other when discussing pharmaceutical pricing and distribution. The former cannot agree on the relevant definition of consumer welfare. The latter does not fully comprehend the highly complex but inherently collective nature of pharmaceutical drug acquisition in the United States. This essay proposes to inject public health discourse into this debate to enrich it, focus it, and render it more accessible to those who must live by its outcome. PMID- 28661289 TI - Immigration and Health: Law, Policy, and Ethics. AB - Immigration poses numerous challenges for health professionals and public health lawyers. This article reviews these challenges. We begin by offering some background on immigration and health and then explain some of the reasons why immigrants are less likely than natives to have health insurance. Next we turn to a discussion of some of the particular challenges relating to the health care of refugees. We conclude by analyzing and rejecting some of the arguments that are made for discriminating against immigrants with respect to the provision of public health benefits and services. PMID- 28661290 TI - Employer Requirements to Work during Emergency Responses: Key Ethics Considerations. AB - Local health departments and their employees are at the forefront of emergency preparedness and response. Yet, recent studies have found that some local public health workers are unwilling to report to work in a variety of disaster scenarios. This can greatly compromise a response, as many local health departments need "all hands on deck" to effectively meet increased demands. To address these concerns, local health departments have employed varied policy strategies to ensure that employees do report to work. After describing different approaches taken by local health departments throughout the United States, we briefly identify and explore key ethics considerations that arise for local health departments when employees are required to report to work for emergency responses. We then discuss how these ethics considerations may inform local health department practices intended to promote a robust emergency response. PMID- 28661291 TI - Introduction. PMID- 28661292 TI - Action, Not Rhetoric, Needed to Reverse the Opioid Overdose Epidemic. AB - Despite shifts in rhetoric and some positive movement, Americans with the disease of addiction are still often stigmatized, criminalized, and denied access to evidencebased care. Dramatically reducing the number of lives unnecessarily lost to overdose requires an evidence-based, equity-focused, well-funded, and coordinated response. We present in this brief article evidence-based and promising practices for improving and refocusing the response to this simmering public health crisis. Topics covered include improving clinical decision-making, improving access to non-judgmental evidence-based treatment, investing in comprehensive public health approaches to problematic drug use, and changing the way law enforcement actors interact with people who use drugs. PMID- 28661293 TI - Motorcycle Policy and the Public Interest: A Recommendation for a New Type of Partial Motorcycle Helmet Law. AB - Motorcycle helmet laws are perceived to infringe upon individual rights even though they reduce mortality and health care costs. We describe proposed helmet legislation that protects individual rights and provides incentives for helmet use through a differential motorcycle registration fee that requires higher fees for those who wish to ride without a helmet. PMID- 28661294 TI - Climate Change and Public Health Policy. AB - Climate change poses real and immediate impacts to the public health of populations around the globe. Adverse impacts are expected to continue throughout the century. Emphasizing co-benefits of climate action for health, combining adaptation and mitigation efforts, and increasing interagency coordination can effectively address both public health and climate change challenges. PMID- 28661295 TI - Reducing Hospital Readmissions: Addressing the Impact of Food Security and Nutrition. AB - Food insecurity in the United States is a profound public health challenge that hospitals are uniquely situated to address. Through the enactment of the Hospital Readmission Reduction Program, the Affordable Care Act provides a strong economic incentive for hospitals to actively confront food insecurity within the communities they serve. While there is a spectrum of nutrition interventions that hospitals can look to when engaging in these efforts, healthy food prescriptions and medically tailored meals are two particularly innovative and promising approaches that could help hospitals reduce readmissions by addressing the nutritional needs of vulnerable patients. PMID- 28661296 TI - Applying an Equity Lens to the Child Care Setting. AB - In the current landscape, child care is increasingly being seen as a place for early education, and systems are largely bundling child care in the Early Care and Education sphere through funding and quality measures. As states define school readiness and quality, they often miss critical elements, such as equitable access to quality and cultural traditions. This article provides a summary of the various definitions and structures of child care. It also discusses how the current child care policy conversation can and ought to be infused with a framework grounded in the context of institutional racism and trauma. Models and examples will explore the differences between state government regulations, and how those differ than the regulation and structure of child care in Indian Country. PMID- 28661297 TI - Letter from the Editor. PMID- 28661298 TI - Collaborating for Health: Health in All Policies and the Law. AB - This article introduces and defines the Health in All Policies (HiAP) concept and examines existing state legislation, with a focus on California. The article starts with an overview of HiAP and then analyzes the status of HiAP legislation, specifically addressing variations across states. Finally, the article describes California's HiAP approach and discusses how communities can apply a HiAP framework not only to improve health outcomes and advance health equity, but also to counteract existing laws and policies that contribute to health inequities. PMID- 28661299 TI - Legal Epidemiology: The Science of Law. AB - The importance of legal epidemiology in public health law research has undoubtedly grown over the last five years. Scholars and practitioners together have developed guidance on best practices for the field, including: placing emphasis on transdisciplinary collaborations; creating valid, reliable, and repeatable research; and publishing timely products for use in decision-making and change. Despite the energy and expertise researchers have brought to this important work, they name significant challenges in marshalling the diverse skill sets, quality controls, and funding to implement legal epidemiology activities. The Centers for Disease Control and Prevention (CDC) has worked to develop cross cutting research and translation on issues of national priority in legal epidemiology, and has explored ways to overcome some of these challenges. As such, this article describes a case study of the use of law to characterize states' prior authorization policies regarding medication used to treat attention deficit/hyperactivity disorder (ADHD), a central component of a broader effort to improve behavior therapy options for young children with ADHD. This article highlights the types of legal epidemiology work we have undertaken, the application of this work to an emerging public health problem, and the lessons learned in creating impactful research for the field. PMID- 28661300 TI - Maximizing Community Voices to Address Health Inequities: How the Law Hinders and Helps. AB - This paper highlights the need to apply an equity lens when assessing the impact of preemption and related legal doctrines on community health. Community autonomy to set and pursue public health priorities is an essential part of achieving health equity. Unfortunately, the priorities of organized industry interest groups often conflict with health equity goals. These groups have a history of successfully using law to limit community autonomy to pursue public health measures, most notably through preemption and related legal doctrines. We examine this phenomenon using two examples. First, we look at dental association efforts to block the spread of dental therapists in Indian Country. Native dental therapists have been improving the oral health of native people in Alaska for over a decade; yet the national and state dental associations have sought with mixed success to leverage state and federal laws to hinder other tribal governments from utilizing these providers. We compare these efforts with a restaurant association-led movement to limit what municipal governments can do to address food-based health inequities, focusing on a "model" ALEC bill that started in Ohio. Finally, we discuss how municipalities and Tribes are fighting back and continuing to pursue health equity for their communities. PMID- 28661301 TI - Finished with Menthol: An Evidence-Based Policy Option That Will Save Lives. AB - Smoking remains the leading cause of preventable disease and death in the United States, killing approximately 480,000 people each year. This crushing health burden falls disproportionately, and recent CDC data shows that large disparities in adult cigarette smoking remain. One factor in these disparities is the use of flavors. Menthol cigarettes and other flavored tobacco products are used at higher rates by vulnerable populations including youth and young adults, African Americans, women, Hispanics and Asian Americans. This is no accident; the tobacco industry has long targeted these same groups. Given FDA's failure to act to ban flavored tobacco products, states and municipalities are considering taking matters into their own hands to protect their communities from these dangerous products. The authors will explore state and local authority to restrict the sales of these products and review the evidence base indicating that removing flavored tobacco products - and menthol combustible products in particular - from the market would significantly reduce the toll of illness and death caused by these products. PMID- 28661302 TI - The Latest in Vaccine Policies: Selected Issues in School Vaccinations, Healthcare Worker Vaccinations, and Pharmacist Vaccination Authority Laws. AB - This paper discusses recent changes to state legal frameworks for mandatory vaccination in the context of school and healthcare worker vaccination. It then discusses state laws that allow pharmacists the authority to vaccinate. PMID- 28661303 TI - EPSDT's Role in Improving Child Vision, Hearing, and Oral Health. AB - The Medicaid Early and Periodic Screening, Diagnostic and Treatment (EPSDT) benefit offers health care coverage specifically targeted to meet the needs to low-income children and children with disabilities. This article provides a brief overview of EPSDT and then discusses how states are working to bring vision, hearing, and oral health services to children through EPSDT. PMID- 28661304 TI - Expanding Access to Care: Scope of Practice Laws. AB - Allied health professionals play an integral role in providing safe, affordable care to communities in need. Laws that define the permissible scope of practice for these professionals may take full advantage of these providers and may unnecessarily restrict safe and effective care. Nurse practitioners in many states may provide care independent of a physician; research reveals that this care is safe, affordable and accessible. Yet hurdles exist that prevent communities from securing the full benefit of NPs in independent practice. The scope of independent practice for allied dental providers varies greatly across the country, often including stringent supervision requirements. Emerging approaches to allowing allied dental providers to practice independently in certain settings or with dentist supervision via telemedicine and creating the intermediate provider, the dental therapist, may increase access to safe, affordable dental care. Research on the impact of laws that allow broader independent practice by NPs to ferret out the hurdles to full implementation of the spirit of such laws is needed. That research could support expanded independent scope for allied dental providers and other allied health care providers. PMID- 28661305 TI - Public Health and Politics: Using the Tax Code to Expand Advocacy. AB - Protecting the public's health has always been an inherently political endeavor. The field of public health, however, is conspicuously and persistently absent from sustained, sophisticated engagement in political processes, particularly elections, that determine policy outcomes. This results, in large part, from widespread misunderstanding of rules governing how, and how much, public advocates working in tax-exempt organizations can participate in public policy development. This article briefly summarizes the rules governing public policy engagement by exempt organizations. It then describes different types of exempt organizations, and how they can work together to expand engagement. Next, it identifies several key mechanisms of policy development that public health advocates could influence. Finally, it suggests some methods of applying the tax rules to increase participation in these arenas. PMID- 28661306 TI - Health Care System Transformation and Integration: A Call to Action for Public Health. AB - Restructured health care reimbursement systems and new requirements for nonprofit hospitals are transforming the U.S. health system, creating opportunities for enhanced integration of public health and health care goals. This article explores the role of public health practitioners and lawyers in this moment of transformation. We argue that the population perspective and structural strategies that characterize public health can add value to the health care system but could get lost in translation as changes to tax requirements and payment systems are rapidly implemented. We urge public health leaders to take a more active role in hospital assessments of community health needs and evaluation of the patient outcomes for which providers are accountable. PMID- 28661307 TI - Policy Approaches to Improving Housing and Health. AB - Safe and healthy housing conditions are critical to improving population health, particularly for the most vulnerable - young children, senior citizens, and individuals with chronic illnesses and disabilities - who spend more time at home and are more susceptible to illness and injury. Across the country, millions of Americans are exposed to lead, radon, asbestos, volatile organic compounds, pests, mold, carbon monoxide, and tobacco smoke in the home, affecting the air they breathe and the water they drink. These household hazards are also associated with a wide range of illnesses and injuries, including asthma, cancer, falls, respiratory infections, and mental health issues. Legal and policy interventions can assist communities grappling with the adverse impacts of poor housing conditions and improve the health and safety of all residents, including vulnerable populations. PMID- 28661308 TI - Homelessness and the Public's Health: Legal Responses. AB - This commentary addresses public health issues underlying homelessness and related law, policy, and advocacy options. After framing public health issues for affected individuals and the community, legal and policy approaches and related barriers are assessed. Major topics include deficits in housing availability, the role of state-based Medicaid programs, criminalization of homelessness, and the use of emergency declarations seeking to address particular issues related to homelessness in select states and localities. PMID- 28661310 TI - Promoting Mental Health and Well-Being in Public Health Law and Practice. AB - This article discusses the relationship between stress, physical health, and well being in cultural context, offers examples of laws, policies, and programs to promote mental health and well-being, and examines how collective impact supports mental health and well-being. PMID- 28661309 TI - Background Checks for all Gun Buyers and Gun Violence Restraining Orders: State Efforts to Keep Guns from High-Risk Persons. AB - There were more than 36,000 firearm-related deaths in the U.S. in 2015. Under federal law, a background check is required only for gun purchases from licensed dealers. Research suggests that some persons prohibited from owning a gun turn to private sellers, including those identified online, to attempt to obtain a firearm. State-level approaches to make it more difficult for high-risk persons to purchase or possess firearms include universal background check (UBC) and gun violence restraining order (GVRO) laws. UBC laws, on the books in 18 states as of the end of 2016, can reduce both homicide and suicide rates. After Colorado adopted a UBC law in 2013, the number of background checks conducted by private sellers for sales occurring at places other than gun shows steadily increased. GVRO laws give law enforcement and families the authority to petition a court to temporarily remove firearms from an individual who presents a danger to himself or others during times of crisis, regardless of whether that person has been diagnosed with a mental illness. California enacted a GVRO law in 2014. Data are emerging to suggest the effectiveness of GVRO-type laws at averting suicides and providing an entryway to services. PMID- 28661311 TI - A 3-Year Program From the Turkish Ministry of Health for Standardization and Service Quality Improvement of Transplant and Tissue Typing Laboratories in Turkey. PMID- 28661312 TI - Mixed Donor Chimerism Following Simultaneous Pancreas-Kidney Transplant. AB - OBJECTIVES: Graft-versus-host disease after solid-organ transplant is exceedingly rare. Although the precise pathogenetic mechanisms are unknown, a progressive increase in donor chimerism is a requirement for its development. The incidence of mixed donor chimerism and its timeline after simultaneous pancreas-kidney transplant is unknown. MATERIALS AND METHODS: After encountering 2 cases of graft versus-host disease after simultaneous pancreas-kidney transplant at our institution over a period of < 2 years, a collaborative pilot study was conducted by the bone marrow transplant, nephrology, and abdominal transplant surgery teams. We enrolled all consecutive patients undergoing sex-mismatched simultaneous pancreas-kidney transplant over 1 year and longitudinally monitored donor chimerism using fluorescence in situ hybridization for sex chromosomes. RESULTS: We found no evidence for chimerism in our 7 patients. In a comprehensive literature review, we found a total of 25 previously reported cases of graft versus-host disease after kidney, pancreas, and simultaneous pancreas-kidney transplants. The median onset of graft-versus-host disease was approximately 5 weeks after transplant, with a median of about 2 weeks of delay between first presentation and diagnosis. Skin, gut, and bone marrow were almost equally affected at initial presentation, and fever of unknown origin occurred in more than half of patients. The median survival measured from the first manifestation of graft-versus-host disease was only 48 days. CONCLUSIONS: Within the limitations related to small sample size, our results argue against an unusually high risk of graft-versus-host disease after simultaneous pancreas-kidney transplant. Collaboration between solid-organ and stem cell transplant investigators can be fruitful and can improve our understanding of the complications that are shared between the 2 fields. PMID- 28661313 TI - Acute Appendicitis After Kidney Transplantation: Experience at a Tertiary Care Hospital in Mexico City. AB - OBJECTIVES: Here, we describe the presentation, treatment, and outcomes of acute appendicitis in kidney transplant recipients at a tertiary care hospital in Mexico City. MATERIALS AND METHODS: We conducted a retrospective case series study at a tertiary care hospital in Mexico City from January 2000 to January 2015. RESULTS: During our study period, 1186 patients received a kidney transplant; among these patients, we identified 10 cases of acute appendicitis (0.008%). Four patients (40%) were diagnosed on day 5 of symptom onset. Nine patients (90%) showed abdominal pain, 2 patients (20%) presented with a typical migratory pattern, and 2 patients (20%) showed symptoms of small bowel intestinal obstruction. Thirty percent of patients (3/10) presented a rule-out Alvarado score (<= 3 points). A computed tomography scan was performed in all but one patient; among these 9 patients, 1 (11.1%) had a false-negative result. Among all patients with acute appendicitis, 50% (5/10) presented with a periappendiceal abscess and 40% (4/10) showed localized peritonitis. An open and laparoscopic appendectomy was performed in 7 of 10 patients (70%) and 3 of 10 patients (30%), respectively. All patients received ceftriaxone plus metronidazole or ertapenem for 5 to 7 days. There were no reported treatment failures or recurrence of symptoms. CONCLUSIONS: The diagnosis of acute appendicitis in kidney transplant recipients requires a high index of suspicion. Kidney transplant recipients with acute appendicitis had good outcomes with a therapeutic approach similar to that used in the general population. PMID- 28661314 TI - Effect of Single Sensitization Event on Human Leukocyte Antigen Alloimmunization in Kidney Transplant Candidates: A Single-Center Experience. AB - OBJECTIVES: Human leukocyte antigen alloimmunization is caused by exposure to HLA antigens through transfusion, pregnancy, or transplant. Our study objective was to present the rate of positivity of anti-HLA antibody considering the effects of a single sensitization event in kidney transplant candidates at our center. MATERIALS AND METHODS: Our study reviewed 606 kidney transplant candidates. Patient sera were analyzed using Luminex xMAP technology. Panel reactive antibody positivity rates and antibody strengths in patients were analyzed according to a single sensitization event. RESULTS: Our findings showed 246 patients (40.6%) with a panel reactive antibody > 0, of which 97 (39.4%) were sensitized from a single event, 119 (48.4%) were sensitized by multiple events, and 30 (12.2%) had no known sensitizing event. Considering patients sensitized by a single event with a panel reactive antibody > 0, we found that 25.8% had received transplant only, 49.5% had previous pregnancy only, and 24.7% had received transfusion only. The strength of antibodies was significantly higher in patients with previous transplant procedures than in those with transfusion for HLA-A (P < .01), HLA-B (P < .05), HLA-C (P < .05), HLA-DR (P < .001), HLA-DQ (P < .05), and HLA-DP (P < .05). Similarly, we observed significantly higher median fluorescence intensity values for HLA-A, -DR, -DQ, and -DP loci in patients with a previous transplant procedure versus pregnancy. The strength of antibodies against HLA-DR was significantly higher in patients with a previous pregnancy compared with those with transfusion (P < .01). CONCLUSIONS: This study documents the profile of HLA alloimmunization in kidney transplant candidates. In particular, transplant procedures appear to have a greater immunologic impact, followed by pregnancy and transfusion. Our data confirm and are in accordance with those of several studies in which the sensitization events were associated with higher prevalence of anti HLA antibodies. PMID- 28661315 TI - New-Onset Diabetes After Transplant in a Sudanese Renal Transplant Population: Prevalence and Risk Factors. AB - OBJECTIVES: New-onset diabetes after transplant is a well-recognized complication of solid-organ transplant. The true incidence of this complication in Sudan is not known. The aim of this study was to define the prevalence of new-onset diabetes after transplant in a Sudanese renal transplant population and to identify the contributing risk factors. MATERIALS AND METHODS: Fifty-nine patients who underwent living-donor related kidney transplant and who were followed for 2 years were included in this pilot study. Only patients who were not diabetic before transplant were included. Patients who developed new-onset diabetes after transplant were compared with those who did not develop type 2 diabetes mellitus. The variables analyzed were age, sex, body mass index, family history of type 2 diabetes mellitus, and interval between time of transplant and onset of diabetes. RESULTS: Five patients (5/58) developed diabetes after transplant (8.62%). There was no association between new-onset diabetes after transplant and age, sex, and body mass index. However, there was a strong association between family history of diabetes and new-onset diabetes after transplant. The mean duration for developing new-onset diabetes after transplant was 10 months posttransplant. Patients in the new-onset diabetes after transplant group had no graft loss or deterioration in graft function compared with those who did not develop diabetes. CONCLUSIONS: The prevalence of new-onset diabetes after transplant in our studied Sudanese population was found to be < 10%. There was no association between new-onset diabetes after transplant and age, sex, and body mass index. However, there was a significant association with family history of diabetes mellitus. PMID- 28661316 TI - Effects of isoflavone-containing soya protein on ex vivo cholesterol efflux, vascular function and blood markers of CVD risk in adults with moderately elevated blood pressure: a dose-response randomised controlled trial. AB - Emerging CVD risk factors (e.g. HDL function and central haemodynamics) may account for residual CVD risk experienced by individuals who meet LDL-cholesterol and blood pressure (BP) targets. Recent evidence suggests that these emerging risk factors can be modified by polyphenol-rich interventions such as soya, but additional research is needed. This study was designed to investigate the effects of an isoflavone-containing soya protein isolate (delivering 25 and 50 g/d soya protein) on HDL function (i.e. ex vivo cholesterol efflux), macrovascular function and blood markers of CVD risk. Middle-aged adults (n 20; mean age=51.6 (sem 6.6) years) with moderately elevated brachial BP (mean systolic BP=129 (sem 9) mmHg; mean diastolic BP=82.5 (sem 8.4) mmHg) consumed 0 (control), 25 and 50 g/d soya protein in a randomised cross-over design. Soya and control powders were consumed for 6 weeks each with a 2-week compliance break between treatment periods. Blood samples and vascular function measures were obtained at baseline and following each supplementation period. Supplementation with 50 g/d soya protein significantly reduced brachial diastolic BP (-2.3 mmHg) compared with 25 g/d soya protein (Tukey-adjusted P=0.03) but not the control. Soya supplementation did not improve ex vivo cholesterol efflux, macrovascular function or other blood markers of CVD risk compared with the carbohydrate matched control. Additional research is needed to clarify whether effects on these CVD risk factors depend on the relative health of participants and/or equol producing capacity. PMID- 28661317 TI - Minimizing Energy Use and GHG Emissions of Lift Stations Utilizing Real-Time Pump Control Strategies. AB - Wastewater collection system lift station operations require a substantial amount of energy, and can be as a major source of greenhouse gas (GHG) emissions for wastewater utilities. Many lift stations operate with local or basic controls that have no hydraulic relationship with other collection system lift stations. This study demonstrated a unique energy-efficient control method of lift station operation that utilizes hydraulic modeling results generated from site-specific conditions to optimize the pumping units and reduce simultaneous running cycles on a real time basis. The pilot tests conducted at two pilot areas of the wastewater collection system of a utility in Florida demonstrated that the energy savings obtained through such operational optimization was 14 to 17% for the two pilot areas investigated. The study demonstrated that substantial annual energy costs and GHG emissions reduction could be achieved utilizing this method, particularly for utilities located in flat geographic locations where hundreds of lift stations are required to transfer wastewater. PMID- 28661318 TI - Investigation on the Effect of Poly(butylmethacrylate)/attapulgite Nanocomposites for Oil Absorption. AB - In this work, a series of novel polybutylmethacrylate (PBMA)/attapulgite (APT) were synthesized by suspended emulsion polymerization, using ethylene glycol dimethacrylate (EGDMA) as crosslinker. The nanocomposites were characterized by means of Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). The effects of polymerization variables including amount of initiator, amount of crosslinker, and APT content on oil absorbency were investigated, and the swelling kinetics in toluene and chloroform was also systematically evaluated. The results indicated that incorporating 7 wt% APT into PBMA polymeric network could enhance the oil absorbency and oil absorption rate of the oil-absorbing resin. Furthermore, the developed nanocomposites also exhibited good reusability and oil-retention capabilities. The nanocomposites are expected to find practical applications in the recovery of spilled oils and the treatment of wastewater. PMID- 28661319 TI - Enhanced Photocatalytic Activity of Ag Doped ZnO Nanorods for Degradation of an Azo Dye. AB - In this study, Ag-ZnO nanophotocatalyst has been synthesized through microemulsion technique and the effect of silver modification on ZnO nanorods has been evaluated. The photocatalytic activity of nanocatalyst was examined by degradation of Acid Yellow 23 (AY23) as a model of mono azo dye under UV illumination. Ag-ZnO catalyst was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDXS) and diffuse reflectance spectroscopy (DRS) analysis. The degradation of AY23 was studied under different operational parameters. Results show that the photocatalytic reaction followed the pseudo first-order kinetic. The highest photocatalytic degradation of 20 mg/L AY23 dye solution under UV irradiation (light intensity = 50 W/m2 , [Ag-ZnO]0 = 400 mg/L with 2 wt% Ag doped ZnO, calcined at 450 degrees C) was about 93.3% during 30 minutes of reaction that shows an enhancement in comparison to pure ZnO which was 65.48%. PMID- 28661320 TI - Destabilization and Treatment of Emulsified Oils in Wastewaters by Electrocoagulation. AB - In this study, the optimum operating conditions for the treatment of emulsified oils by electrocoagulation were determined depending on droplet stability analysis. Zeta potential measurements were used as the indication of oil droplet charges. In addition, the effects of pH and ionic conductivity on the droplet sizes and surface charges were investigated. The studied emulsified oil droplet sizes were more sensitive to changes in pH rather than salt concentration. The droplets became larger and unstable in alkaline conditions. As the initial pH of wastewaters increased, the oil removal efficiency increased during the electrocoagulation experiments as well. The use of iron or aluminum electrodes resulted in higher removal efficiencies in comparison to stainless steel electrodes. In addition, the energy consumption for aluminum electrodes was much lower than iron electrodes. To obtain 98% oil removal efficiency, distance between the electrodes was recommended to be less than or equal to 1 cm. PMID- 28661321 TI - Data-driven Nutrient-landscape Relationships across Regions and Scales. AB - Previous studies have identified relationships between nutrient exports and upstream conditions, but have often disconnected interpretations from hydrological flows and changes. Here, we investigated basic relationships between largely flow-independent nutrient concentrations and two key descriptors of upstream landscape and human activity: population density and arable land cover. Consistent data were gathered from previous studies of the Baltic Sea and Mississippi River basins. These data span wide ranges of subcatchment scales, hydroclimatic conditions, and landscape characteristics. In general, investigated relationships were stronger in the Baltic than in the Mississippi region and stronger for total nitrogen (TN) than total phosphorous (TP) concentrations. However, TN concentration was both highly and consistently correlated to arable land cover across all scales and both regions. These findings support that TN export from catchments is dictated principally by retention and slow release from subsurface legacy stores while export TP concentrations appear to be dictated more by faster particulate surface transport. PMID- 28661322 TI - Pretreatment of Wastewater from Licorice Processing-A Preliminary Evaluation. AB - This study was performed as a preliminary investigation of anaerobic digestion and the activated sludge process as pretreatment options for highly loaded wastewater from licorice processing (approximately 8000 mg COD/L). Only 15% reduction of initial chemical oxygen demand (COD) was achieved by anaerobic digestion, whereas up to 80% reduction was attained with activated sludge process. Adsorption using powdered activated carbon (PAC) was studied for the removal of color and residual organics from the effluent of aerobic treatment. The combination of aerobic biological treatment with activated carbon adsorption offers a high-quality effluent, however only at very high carbon dosage (>2 kg PAC/m3). PMID- 28661323 TI - Advanced Oxidation Processes: Process Mechanisms, Affecting Parameters and Landfill Leachate Treatment. AB - Advanced oxidation processes (AOPs) are of special interest in treating landfill leachate as they are the most promising procedures to degrade recalcitrant compounds and improve the biodegradability of wastewater. This paper aims to refresh the information base of AOPs and to discover the research gaps of AOPs in landfill leachate treatment. A brief overview of mechanisms involving in AOPs including ozone-based AOPs, hydrogen peroxide-based AOPs and persulfate based AOPs are presented, and the parameters affecting AOPs are elaborated. Particularly, the advancement of AOPs in landfill leachate treatment is compared and discussed. Landfill leachate characterization prior to method selection and method optimization prior to treatment are necessary, as the performance and practicability of AOPs are influenced by leachate matrixes and treatment cost. More studies concerning the scavenging effects of leachate matrixes towards AOPs, as well as the persulfate-based AOPs in landfill leachate treatment, are necessary in the future. PMID- 28661324 TI - Anaerobic Codigestion of Grass and Sewage Sludge: Laboratory Experiments and Feasibility Analysis. AB - Grass is drawing attention for its high potential for biogas production. Anaerobic digesters in wastewater treatment plants can be used for producing biogas by processing grass without having to invest in the construction of new treatment facilities. Batch and continuous digestion experiments were conducted to assess the feasibility of codigestion of sewage sludge and grass. The focus was on a thermophilic condition, starting-up from existing mesophilic anaerobic digestion of sewage sludge only. The batch and continuous experiments used two different sewage sludges. Results demonstrated a methane generation of approximately 0.2 normal liter-methane/g volatile solids-grass. The addition of grass did not affect the ammonia concentration and improved the dewaterability of the digested sludge. The start-up performance from mesophilic digested sewage sludge to thermophilic codigestion with grass was confirmed. A feasibility analysis demonstrated that codigestion is applicable in terms of energy recovery and greenhouse gas emission, depending on the transport distance of grass. PMID- 28661325 TI - Upflow Anaerobic Sludge Blanket Reactor Codigestion of Algae and Acetate to Produce Methane. AB - Algae grown in wastewater treatment lagoons are a potentially important substrate for biofuel production. The feasibility of using upflow anaerobic sludge blanket (UASB) reactors in anaerobic digestion of algae to produce methane was investigated. A favorable carbon to nitrogen (C/N) weight ratio of 21/1 was determined in batch reactor experiments in which the ratio was adjusted by blending algal biomass with sodium acetate as a carbon source. This blend of algae and acetate was used in the feedstock applied to the UASB reactors. Duplicate, 34-L, UASB reactors initially received an organic loading rate (OLR) of 0.9 g chemical oxygen demand (COD)/L.d at a 7.2-day hydraulic retention time (HRT). The OLR was gradually increased to 5.4 g/L.d and the HRT was decreased to 5.5 days resulting in a methane production increase from 247 to 298 mL/g COD biodegraded. The COD removal efficiency was 80% with a biogas methane composition of 90%. PMID- 28661326 TI - The Effect of Solids Residence Time on Chemical Phosphorus Removal in Low Concentration Applications. AB - The effect of solids residence time (SRT) on steady state phosphorus (P) removal when striving for ultralow concentrations through metal salt addition was studied. Lab-scale continuous flow sequencing batch reactors (SBRs) were operated under high (6.4 mg P/L; 1.4 mol Fe/mol P) and low (3.4 mg P/L; 2.6 mol Fe/mol P) influent phosphate concentrations to characterize P removal. Residual P concentrations, particle size distribution, and microscopy analyses were determined over a range of SRTs. A majority of P removal (94% with 3.4 mg P/L; 83% with 6.4 mg P/L) occurred immediately after iron (Fe) addition with additional removal in the SBRs (3.3-4.8% with 3.4 mg P/L; 5.5-8.8% with 6.4 mg P/L). Soluble P uptake was higher for SRTs <= 7.4 days with 3.4 mg P/L and <= 14.3 days with 6.4 mg P/L. Normalized P uptake (MUg P/mg total suspended solids [TSS]) decreased with SRT providing evidence that aging changed floc properties relevant to P removal. Floc size was found to have no distinguishable influence on P removal. However, changes in floc morphology were consistent with P removal trends. PMID- 28661327 TI - Cr(VI) Adsorption to Magnetic Iron Oxide Nanoparticle-Multi-Walled Carbon Nanotube Adsorbents. AB - The aim of this study was to investigate the Cr(VI) adsorption to magnetic iron oxide(MIO) nanoparticle- multi-walled carbon nanotubes (MWCNTs) in aqueous solutions using batch experiments. Results show that the maximum adsorption capacity of Cr(VI) to MIO-MWCNTs was 11.256 mg/g. Kinetic model analysis demonstrates that the pseudo-second-order model and Elovich model are suitable for describing the kinetic data. Thermodynamic analysis indicates that Cr(VI) adsorption to MIO-MWCNTs decreased with increasing temperature from 5-60 degrees C, indicating the spontaneous and exothermic nature of the sorption process. Equilibrium isotherm analysis demonstrates that the Redlich-Peterson model suitably describes the equilibrium data. In the pH experiments, Cr(VI) adsorption to MIO-MWCNTs decreased gradually from 5.70-2.13 mg/g with increasing pH from 3.0 7.3. Sequential extraction indicates that, among the five binding forms of Cr(VI) associated with MIO-MWCNTs, the predominant contributions are the fraction bound to Fe-Mn oxides (57.82%) and the residual (23.38%). PMID- 28661328 TI - Reduction of non-Betalactam Antibiotics COD by Combined Coagulation and Advanced Oxidation Processes. AB - The present study evaluates the reduction of antibiotic COD from wastewater by combined coagulation and advanced oxidation processes (AOPS). The reduction of Azithromycin COD by combined coagulation and Fenton-like processes reached a maximum 96.9% at a reaction time of 30 min, dosage of ferric chloride 120 mg/L, dosages of Fe0 and H2O2of 0.36mM/L and 0.38 mM/L, respectively. Also, 97.9% of Clarithromycin COD reduction, was achieved at a reaction time of 30 min, dosage of ferric chloride 120 mg/L, dosages of Fe0 and H2O2 of 0.3 mM/L and 0.3mM/L, respectively. The results of kinetic studies were best fitted to the pseudo first order equation. The results showed a higher rate constant value for combined coagulation and Fenton-like processes [(kap = 0.022 min-1 and half-life time of 31.5 min for Azithromycin) and (kap = 0.023 min-1 and half-life time of 30.1 min for Clarithromycin)]. PMID- 28661329 TI - Insights on Flow Behavior of Foam in Unsaturated Porous Media during Soil Flushing. AB - One-dimensional column and two-dimensional tank experiments were carried out to determine (1) the physics of foam flow and propagation of foaming gas, foaming liquid, and foam; (2) the pressure distribution along foam flow and the effect of media permeability, foam flow rate and foam quality on foam injection pressure; and (3) the migration and distribution property of foam flow in homogeneous and heterogeneous sediments. The results demonstrated that: (1) gas and liquid front were formed ahead of the foam flow front, the transport speed order is foaming gas > foaming liquid > foam flowing; (2) injection pressure mainly comes from the resistance to bubble migration. Effect of media permeability on foam injection pressure mainly depends on the physics and behavior of foam flow; (3) foam has a stronger capacity of lateral spreading, besides, foam flow was uniformly distributed across the foam-occupied region, regardless of the heterogeneity of porous media. PMID- 28661330 TI - Spatial and Temporal Variations in Pollution Indicator Bacteria in the Lower Vaal River, South Africa. AB - The aim of this study was to evaluate the spatial and temporal variation of microbiological parameters of the Lower Vaal River, with emphasis on the Staphylococci population. River water concentrations of Staphylococci, heterotrophic, total coliforms, fecal coliforms and Streptococci groups of sanitary indicator bacteria were monitored. Results indicated significant contamination from agricultural land use inputs and municipal waste applications. Significant temporal and spatial variation was observed in response to the varying river discharge. Higher microbial concentrations were detected during high river discharge whereas during low river discharge both low and high microbial concentrations were detected. The varying responses associated with river discharge helped to identify the importance of different sources of contamination in the catchment and the mechanisms transferring them. The overall impact of contamination on the water quality of the Vaal River could have potentially serious public health risks but also provide valuable data for integrated water resource management. PMID- 28661331 TI - Enhancement of Cr(VI) Ion Removal Using Nanochitosan Coated on Bituminous Activated Carbon. AB - Bituminous activated carbon (AC) has been widely used as a sorbent for adsorption of non-polar species, but its performance for removal of ionic species such as heavy metals has not been as efficient. In this study, AC was modified with chitosan nanoparticles (CN) using facile methods of dip coating and wet impregnation. The CN-coated AC demonstrated an increase in Cr(VI) removal efficiency in both kinetics and adsorption capacity. The adsorption capacity of the CN-coated AC (mg/g) was more than twice that of the uncoated AC (36.36 mg/g), or pure chitosan (32.57 mg/g). The sizes of the synthesized CN (160-2,000 nm) can be controlled by varying the concentration of the chitosan/reagents used. The adsorption isotherms are better described using the Freundlich rather than the Langmuir model and are in agreement with the heterogeneity of the surfaces. Adsorption kinetics followed that of the pseudo-second-order kinetics, suggesting chemisorption as a rate limiting step. PMID- 28661332 TI - Biodegradability of Nonionic Surfactant Used in the Remediation of Groundwaters Polluted with PCE. AB - The objective of this work was to evaluate the degradation of the nonionic surfactant Tween 80 by a PCE-degrading consortium anchored in bioparticles of fluidized bed bioreactors used in onsite remediation. Batch lab-scale bioreactors were set with dominant denitrifying (DN), methanogenic (M), and aerobic (Ab) metabolisms. Tween 80 at 100 mg/L was the sole source of carbon and energy. Denitrifying bioreactors had the highest surfactant removal (70%). Tween removals in M and Ab bioreactors were 53 and 37%, respectively. Removals of organic matter (COD) closely followed the efficiencies reported for Tween. This strongly suggested that degradation of Tween 80 occurred. Positive consequences of Tween degradation in remediation are first, the surfactant will not become an environmental/health liability by remaining as a recalcitrant or toxic substance in aquifers or in treated effluents; and second, savings on aeration could be achieved by conducting Tween 80 degradation in anaerobic conditions, either DN or M. PMID- 28661333 TI - Acidogenesis and Two-Phase Codigestion of Fats, Oils, and Greases and Municipal Biosolids. AB - Acidogenic codigestion of fats, oils, and greases (FOG) was studied using suspended growth sludge digesters operated as batch fed reactors that were fed twice daily. The digesters were maintained at a 2-day retention time and at 37 degrees C to mimic the acid phase of an acid-gas digestion system. As FOG loading rates increased, volatile fatty acid (VFA) production was found to increase, although the percentage of VFA production compared to theoretical values decreased exponentially to just 20% at the highest loading rates. FOG matter was found to have accumulated in the reactor vessel in semi-solid balls that floated near the liquid surface. Two-phase codigestion of FOG was studied at 37 degrees C using Continuously Stirred Tank Reactors (CSTRs) as acid phase digesters (APD) operated with 2-day retention times, followed by gas phase digesters (GPD) with 15-day retention times. The two-phase systems were compared by FOG addition to the APD versus GPD. FOG addition to the APD resulted in 88% destruction of LCFAs, whereas FOG addition to the GPD resulted in 95% destruction of LCFAs. Accumulated LCFAs were found in the APD receiving FOG and were primarily composed palmitic acid (16:0), followed by oleic acid (18:1) and stearic acid (18:0). PMID- 28661334 TI - Editorial. PMID- 28661335 TI - Cysteine-specific Chemical Proteomics: From Target Identification to Drug Discovery. AB - Our laboratory focuses on chemical proteomics-enabled discovery of new cysteine reactive small molecules with intriguing biomedical activities as well as identification and detailed characterization of their proteomic targets. In this overview article, we summarize our progress since 2013 in this research field. We have developed a novel mass spectrometry-based chemoproteomic method that allows detection and monitoring of up to ~3000 reactive cysteines in any cellular proteome. This is achieved via strategic use of two clickable, cysteine-reactive chemical probes with complementary substrate selectivity profiles, iodoacetamide and ethynyl benziodoxolone. Using this method, we have been able to identify the direct biological targets of curcumin, a diarylheptanoid natural product with anticancer activity, and deoxyelephantopin, a highly cytotoxic natural sesquiterpene lactone. Furthermore, we have developed chloromethyl triazoles (CMTs) as a novel chemical scaffold for cysteine-reactive inhibitors that can be accessed from commercially available substrates in only two chemical steps. From a small collection of chloromethyl triazoles, we have identified compound AA CW236 as the first non-pseudosubstrate inhibitor of MGMT, a DNA repair protein that renders several devastating cancer forms resistant to chemotherapy. PMID- 28661336 TI - Selectivity Control in the Palladium-catalyzed Cross-coupling of Alkyl Nucleophiles. AB - Site-selectivity remains a major challenge in metal-catalyzed C-H bond functionalization. Most existing strategies rely on the introduction of a directing group or on the intrinsic reactivity of the substrate. In this account article, we describe the development of an alternative strategy based on the migration of an organopalladium species along an alkyl chain, wherein the phosphine ligand controls the cross-coupling site. This concept was first implemented with lithium enolates, and then extended to alpha-zincated alkylamines obtained by directed lithiation and transmetalation. Both the direct and the migrative cross-couplings, which are controlled by simply switching the ligand, furnish synthetically useful organic intermediates. PMID- 28661337 TI - Living on the Edge: Re-shaping the Interface of Synthetic Biology and Nanotechnology. AB - A new team of researchers at EPFL is taking an 'anti-disciplinary' approach to creating optical devices. These devices take advantage of the synergy in tuning both nano- and bio-material properties, coupling the advantages of two growing, albeit traditionally distinct, fields. With applications spanning from biosensing and microarray assays to living photovoltaics, the Laboratory of NanoBiotechnology (LNB) is uncovering an unexplored space for the next generation of chemical analytics and light-harvesting technologies. PMID- 28661338 TI - Colloidal Chemistry to Advance Studies in Artificial Photosynthesis. AB - This article presents an overview of our research in the field of colloidal nanocrystal synthesis and their implementation into water splitting and CO2 reduction electrochemical cells. We discuss our approaches to tailor-made novel material platforms to advance our knowledge in energy storage in chemical bonds, namely artificial photosynthesis. Herein, we focus on complex metal oxides as light absorbers to drive water splitting, nanocrystal hybrids and metals as electrocatalysts for carbon dioxide conversion. Our approach to solve the synthetic challenges so to achieve very precise control on size, shape and composition of such materials is highlighted. PMID- 28661339 TI - The Role of Molecular Imaging in Personalised Healthcare. AB - Functional molecular imaging provides a unique perspective on a disease. Methods including positron-emission tomography and magnetic resonance imaging allow us to interrogate spatial and temporal changes in biomarkers as well as probe the underlying biochemistry. When imaging is combined with molecular diagnostic tools, opportunities arise for measuring aberrant cellular signalling pathways with unprecedented detail. This brief commentary illustrates how radiotracers and nuclear imaging methods are being developed to monitor drug efficacy and simultaneously support the goal of personalised healthcare. PMID- 28661340 TI - Intracellular Photoactivation and Quantification Using Fluorescence Microscopy: Chemical Tools and Imaging Approaches. AB - Recent advances in optical microscopy enable the visualization and quantification of biological processes within live cells. To a great extent, these imaging techniques remain limited by the physical properties of the chemical probes that are used as fluorescent tags, detectors and actuators. At the same time, the quantification of concentrations in the intracellular medium is not trivial, but a few approaches that employ optical microscopy have been developed. Herein, we highlight a few examples of how a combination of novel chemical probes and microscopy methods could be used to bring a much-needed quantitative dimension to the field of biological imaging. PMID- 28661341 TI - Engineering Two-dimensional Materials Surface Chemistry. AB - This account reviews our recent research activities and achievements in the field of two-dimensional (2D) materials surface chemistry. 2D materials are atomically thin, so that carriers are less-restricted to move in the in-plane direction, whereas the out-of-plain motion is quantum-confined. Semiconductor quantum wells and graphene are two well-known examples. Applications of 2D materials in optoelectronics, surface modification, and complex materials must overcome engineering challenges associated with understanding and engineering surface chemistry of 2D materials, which essentially bridge multiscale physical phenomena. In my research group, we understand and engineer broad aspects of chemistry and physics at nanomaterials surfaces for advancing nanomaterials-based technologies. The three main topics covered in this account are as follows: i) colloidal synthesis of stacking-controlled 2D materials, ii) wetting properties of 2D materials, and iii) engineering electronic transport at 2D materials semiconductor interfaces. PMID- 28661342 TI - Self-assembled Lipid Structures as Model Systems for Studying Electrical and Mechanical Properties of Cell Membranes. AB - This mini review summarizes our recent works in the development of electrical and mechanical characterization tools for cell membranes. These research topics require the application of physical and chemical characterization tools to biological systems, thus are very interdisciplinary. PMID- 28661343 TI - Exploring Catalysis inside Self-assembled Supramolecular Containers. AB - Our group is interested in applying supramolecular host systems as catalysts for challenging transformations. Although a variety of supramolecular containers has been described in literature, their use as reaction chambers is still underexplored. We herein describe our first steps in this exciting interdisciplinary field of research. PMID- 28661345 TI - Fast Survey of Radiostrontium after an Emergency Incident involving Ionizing Radiation. PMID- 28661346 TI - Mesoporous, Colloidal 3D Materials - Trends and Opportunities in Silica Aerogel. PMID- 28661347 TI - The Innovation from Innsbruck: Plant-based Allergen Recombinantly Produced in Green Alga. AB - An innovation in biotechnology: for the first time, researchers from MCI Innsbruck and the University of Salzburg have manufactured and purified a plant based allergen in a green alga and opened the door to a specific immunotherapy against allergies. Their vision: to replace the unpleasant injection with oral administration, as its production is both simple and cost-effective. PMID- 28661348 TI - "Chemical Landmark" 2016. PMID- 28661350 TI - Editorial. PMID- 28661351 TI - (Life) Science Funding in Switzerland (1)S. AB - The Swiss National Science Foundation (SNSF), under mandate from the federal government, supports the high level of science research in Switzerland by funding scientific projects and scientists' careers across all disciplines. PMID- 28661352 TI - (Life) Science Funding in Switzerland (2)S. AB - In comparison with other European countries, Switzerland is very well positioned in terms of research funding and output thanks to a large part to the approx. 7 billion CHF annually with which the Swiss Federal Government funds education, research and innovation. PMID- 28661353 TI - SystemsX.ch. AB - SystemsX. ch has the objective of supporting and promoting the paradigm shift in life sciences research, moving from qualitative to quantitative and predictive biology. The Swiss government has invested CHF 220 million in around 250 interdisciplinary projects involving more than 400 research groups since 2008. Almost half of the projects are designed for PhD students and postdocs to train the next generation of systems biologists. The initiative will conclude in 2018; different measures will ensure its sustainable impact. PMID- 28661354 TI - Switzerland and the Digital Health Revolution. AB - New technologies in life sciences are helping to revolutionize health management with the objective to move towards personalized healthcare. The Swiss Federal government is investing in multidisciplinary, countrywide initiatives such as Health 2030 to meet this challenge. PMID- 28661355 TI - Inflammasomes in Host Defense and Autoimmunity. AB - Inflammasomes are large multi-protein complexes that control host defense and inflammation during infections with pathogens. Their clinical importance however reaches beyond infectious disease, since dysregulated inflammasome activity has also been linked to many auto-inflammatory disorders. This article gives a short overview on the basics of inflammasome signaling, their activation mechanisms and their role in autoimmunity. PMID- 28661356 TI - Chemokines: Chemistry, Biochemistry and Biological Function. AB - The in vitro synthesis of correctly folded functional proteins remains challenging. Chemokines, which consist of only 70-100 amino acids, are accessible through solid-phase synthesis and easily fold into a thermally stable tertiary structure. From the time of their discovery in the late 1980s chemokines could therefore be synthesized using biochemical and chemical protocols for structure function analyses and for exploring the chemokine system in vitro and in vivo. In this short overview aimed at a chemistry-oriented readership we will introduce chemokines in general, and then discuss their structure, their isolation from biological materials, as well as the different methods to produce chemokines in the laboratory and finally we will present some examples of their functions in vivo. PMID- 28661357 TI - Next-generation Proteomics from an Industrial Perspective. AB - Proteomics is the large-scale study of proteins. The field began with protein purification and analysis by various techniques but today is largely understood to be mass spectrometry-based highly multiplexed protein quantification. This article focusses on protein expression profiling, i.e. how much of each protein is in my sample or how much does the level of each protein change upon a change in the environment? PMID- 28661358 TI - The Swiss Society of Experimental Pharmacology in Times of Change. AB - Experimental pharmacology is undergoing fundamental changes. This article describes the challenges and opportunities associated with these changes from the perspective of the Swiss Society of Pharmacology (SSEP), the society which aims to advance experimental pharmacology in Switzerland and abroad. PMID- 28661359 TI - Medicinal Chemists Don't Just Make Drugs - The Art of Developing Low Molecular Weight Imaging Agents in Switzerland. AB - Radiolabeled molecular imaging agents are useful to study drug distribution, target engagement and disease progression in human patients. Medicinal chemists often develop them in parallel to drug discovery programs, to facilitate clinical development or to better understand physiological and pathological processes. While the properties required for imaging agents differ from those of drug candidates, their optimization follows similar principles. Developing them for clinical use also requires a multidisciplinary approach, and is best conducted in a close partnership between pharmaceutical and academic research centers. This article reviews recent scientific advances towards the identification and development of low molecular weight imaging agents in Switzerland. PMID- 28661360 TI - The Swiss Society of Microbiology: Small Bugs, Big Questions and Cool Answers. AB - The Swiss Society for Microbiology (SSM) represents around 700 scientists working in the fields of medical (human and veterinary), microbial biotechnology as well as fundamental, environmental, and food microbiology. Five sections: Clinical Microbiology, Environmental Microbiology, Mycology, Prokaryotic Biology, and Virology reflects the main interests of the membership. PMID- 28661361 TI - Automated Microscopy and High Content Screens (Phenotypic Screens) in Academia Labs. AB - Imaged-based screening has been developing extremely quickly in the past 10 years. Academic institutes quickly realized that the discovery capacity of this technology was huge, allowing the automatic detection and quantification of complex cell phenotypes. Associated with chemical or genetic perturbations, high content screening is the method of choice for a deep system biology analysis. The evolution of high-content screening is mainly due to the recent progress in the development of fast and high quality automated imagers and of a plethora of new very bright fluorescent markers, so that almost any cellular element can be seen and imaged. In this paper we review and summarize the major steps in the development of an image-based screening project. PMID- 28661362 TI - Landscape of Genomics Technology Platforms in Switzerland. AB - This review describes the innovative technological developments that have brought genomics from its beginnings in the late 1980s to the present day and then discusses the ways in which genomics platforms are deployed across Switzerland to play a key role in supporting basic and applied research in both academia and industry. PMID- 28661363 TI - Swiss Light Microscopy Facilities: A Success Story for the last Fifteen Years. AB - Core light microscopy facilities have been established at most major Swiss universities and research institutes. Their modern and technically diverse equipment is primarily dedicated to in-house users, but opens increasingly to externals from other academic institutions as well as from the private sector. A recent survey of Swiss light microscopy facility managers enabled an analysis of the challenges involved in the running of such facilities and highlighted their scientific and economic impact within thier home institutions and beyond. PMID- 28661364 TI - Recombinant Antibodies for Academia: A Practical Approach. AB - After several decades of optimization, phage display technology enables the routine isolation and production of recombinant monoclonal antibodies in vitro. As such it has the potential to provide the academic community with a vast, inexpensive and renewable supply of well-characterized reagents, reducing bottlenecks in basic science, helping increase reproducibility of experiments, and phasing out the use of animals for production and discovery of antibodies. Yet the overwhelming majority of fundamental research laboratories still use incompletely characterized antibodies developed in animals. In order to promote increased use of recombinant antibodies in academia, we have recently initiated an open source recombinant antibody facility in Geneva (http://www.unige.ch/antibodies). Here we describe our experience at the Geneva Antibody Facility: the various techniques involved in isolation and production of antibodies, the strategic choices that we have made, and what we hope will be a bright future for this project as part of a growing movement in the scientific community to replace all animal-derived antibodies with recombinant antibodies. PMID- 28661366 TI - Soil Contamination with Trace Metals: Quantification, Speciation, and Source Identification. PMID- 28661367 TI - On-line Monitoring and Control of Fed-batch Fermentations in Winemaking. AB - The fermentation of yeast in fed-batch mode shows great potential in winemaking because it allows the concentration of sugars to be kept low and constant throughout the process which, in turn, reduces cell stress and leads to a significant decrease in the production of unwanted secondary metabolites. The implementation of this technique requires reliable on-line analysis of sugar and a robust control strategy to maintain sugar concentrations at defined levels over the course of the fermentation. In this study, a laboratory-scale setup was used to implement and assess a fully automated fed-batch fermentation of Saccharomyces cerevisiae in grape must. Total sugar levels were monitored in-line by FT-MIR ATR spectroscopy and kept constant at 50 g/kg by a modified PI controller regulating the must feed flow rate. Good setpoint tracking and disturbance rejection were achieved in fermentations of up to four days despite occasional yeast sedimentation on the ATR crystal. The controller parameter adaptation strategy needs to be optimized for longer fermentations. PMID- 28661368 TI - Conference Report: The 2016 Olten Meeting at the Basel Life Science Week. AB - "This 'telephone' has too many shortcomings to be seriously considered as a means of communication. The device is inherently of no value to us." This was an internal memo written by Western Union in 1876. That's right. Without efficient knowledge sharing and technology transfer, even the best scientific development may prove to be a damp squib for a long time. The Basel Life Science Week was created in order to promote scientific and economic exchange and pave the way for innovative ideas. That's why NTN Swiss Biotech has moved its traditional 'Olten Meeting' to the Basel Life Science Week. It is the ideal setting for NTN Swiss Biotech and the School of Life Sciences FHNW to present innovative developments within its network of academic and industrial partners in the future-oriented disciplines of Molecular Diagnostics and Medicinal Chemistry. Short summaries of the key lectures are reported below. PMID- 28661369 TI - ECM-30 - European Crystallographic Meeting 2016. PMID- 28661370 TI - CLARIANT Chemistry Day 2016. PMID- 28661371 TI - The Swiss Summer School in Chemical Biology 2016 in brief. PMID- 28661372 TI - One Bronze Medal for Switzerland at the 48th International Chemistry Olympiad in Tbilisi, Georgia. AB - Four Swiss high school students participated in the 48th International Chemistry Olympiad (IChO), which took place from July 23 to August 1 in Tbilisi, Georgia. Dominic Egger, Nicola Gantenbein, Simone Heimgartner and Diego Zenhausern competed against 260 other students from 71 countries. Dominic Egger brought home a well-deserved bronze medal. PMID- 28661374 TI - Bullying Victimization, Social Network Usage, and Delinquent Coping in a Sample of Urban Youth: Examining the Predictions of General Strain Theory. AB - Guided by the propositions of general strain theory, this study examines the impact of experienced and anticipated strains on the delinquent coping of adolescents while accounting for the usage of social networking sites. Specifically, this study uses self-report survey data collected from 3,195 middle and high school students in a single Midwest city in the United States to explore the effect of experiencing the strains of traditional bullying victimization and cyberbullying victimization on adolescents self-reported soft drug use, hard drug use, and weapon carrying behavior. These relationships are explored among both frequent and infrequent users of social networking sites. Results indicate that cyberbullying victimization and the anticipated strain of feeling unsafe at or on the way to or from school are significantly and positively associated with all three mechanisms of delinquent coping among both frequent and infrequent social network users. PMID- 28661375 TI - Barriers to and facilitators of smoking cessation in pregnancy and following childbirth: literature review and qualitative study. AB - BACKGROUND: Although many women stop smoking in pregnancy, others continue, causing harm to maternal and child health. Smoking behaviour is influenced by many factors, including the role of women's significant others (SOs) and support from health-care professionals (HPs). OBJECTIVES: To enhance understanding of the barriers to, and facilitators of, smoking cessation and the feasibility and acceptability of interventions to reach and support pregnant women to stop smoking. DESIGN: Four parts: (1) a description of interventions in the UK for smoking cessation in pregnancy; (2) three systematic reviews (syntheses) of qualitative research of women's, SOs' and HPs' views of smoking in pregnancy using meta-ethnography (interpretative approach for combining findings); (3) semistructured interviews with pregnant women, SOs and HPs, guided by the social ecological framework (conceptualises behaviour as an outcome of individuals' interactions with environment); and (4) identification of new/improved interventions for future testing. SETTING: Studies in reviews conducted in high income countries. Qualitative research was conducted from October 2013 to December 2014 in two mixed urban/rural study sites: area A (Scotland) and area B (England). PARTICIPANTS: Thirty-eight studies (1100 pregnant women) in 42 papers, nine studies (150 partners) in 14 papers and eight studies described in nine papers (190 HPs) included in reviews. Forty-one interviews with pregnant women, 32 interviews with pregnant women's SOs and 28 individual/group interviews with 48 HPs were conducted. MAIN OUTCOME MEASURES: The perceived barriers to, and facilitators of, smoking cessation in pregnancy and the identification of potential new/modified interventions. RESULTS: Syntheses identified smoking related perceptions and experiences for pregnant women and SOs that were fluid and context dependent with the capacity to help or hinder smoking cessation. Themes were analysed in accordance with the social-ecological framework levels. From the analysis of the interviews, the themes that were central to cessation in pregnancy at an individual level, and that reflected the findings from the reviews, were perception of risk to baby, self-efficacy, influence of close relationships and smoking as a way of coping with stress. Overall, pregnant smokers were faced with more barriers than facilitators. At an interpersonal level, partners' emotional and practical support, willingness to change smoking behaviour and role of smoking within relationships were important. Across the review and interviews of HPs, education to enhance knowledge and confidence in delivering information about smoking in pregnancy and the centrality of the client relationship, protection of which could be a factor in downplaying risks, were important. HPs acknowledged that they could best assist by providing support and understanding, and access to effective interventions, including an opt-out referral pathway to Stop Smoking Services, routine carbon monoxide screening, behavioural support and access to pharmacotherapy. Additional themes at community, organisational and societal levels were also identified. LIMITATIONS: Limitations include a design grounded in qualitative studies, difficulties recruiting SOs, and local service configurations and recruitment processes that potentially skewed the sample. CONCLUSIONS: Perceptions and experiences of barriers to and facilitators of smoking cessation in pregnancy are fluid and context dependent. Effective interventions for smoking cessation in pregnancy should take account of the interplay between the individual, interpersonal and environmental aspects of women's lives. FUTURE WORK: Research focus: removing barriers to support, improving HPs' capacity to offer accurate advice, and exploration of weight concerns and relapse prevention. Interventions focus: financial incentives, self-help and social network interventions. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004170. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28661376 TI - Expanding the Implementation of the Americans With Disabilities Act for Populations With Intellectual and Developmental Disabilities: The Role of Organization-Level Occupational Therapy Consultation. AB - The Americans With Disabilities Act (ADA) provides standards and guidance for accessibility and accommodations that remove barriers to facilitate community social participation for individuals with disabilities. However, ADA implementation does not yet fully address the diverse access needs of people with intellectual and developmental disabilities (IDD), who continue to face barriers to community social participation. This article explores the potential for occupational therapy practitioners to provide organization-level consultation as a means of maximizing community social participation among people with IDD. Case examples of occupational therapy practitioners working with community organizations are presented to illustrate organization-level consultation that addresses access needs across diverse community contexts. The relevance of supporting community social participation within the context of health equity is discussed, and key next steps, including developing population-based outcome measures, addressing reimbursement considerations, and developing best practices for organization-level consultation, are outlined. PMID- 28661377 TI - Supporting Participation for Children With Sensory Processing Needs and Their Families: Community-Based Action Research. AB - OBJECTIVE: This qualitative study was part of efforts to develop and analyze specialized sensory-friendly, community-based programming at a local museum for families with children or young adults with sensory processing issues. METHOD: A qualitative, descriptive framework was used, aimed at uncovering the experience of families in attendance. Using convenience sampling, 46 participants were recruited from six separate cohorts of parents across a 1.5-yr period, using a community-based action research approach. RESULTS: Survey and interview data suggest that specialized programs with appropriate modifications in place improved the quality and the duration of museum visits for families with children or young adults with sensory processing needs, promoting both participation and well-being. CONCLUSION: Adapted community events that increase participation in context may be a promising intervention to support well-being for people with disabilities and their families. PMID- 28661378 TI - Effects of a One-to-One Fatigue Management Course for People With Chronic Conditions and Fatigue. AB - OBJECTIVE: We assessed the impact of a one-to-one fatigue management course on participants' fatigue, self-efficacy, quality of life, and energy conservation behaviors. METHOD: This observational study used a one-group, pretest-posttest, follow-up design. Forty-nine people with chronic conditions and fatigue participated in the one-to-one fatigue management course in outpatient and community-based settings. The Functional Assessment of Chronic Illness Therapy Fatigue Scale was used to measure fatigue; the Functional Assessment of Cancer Therapy-General measured quality of life; and the Self-Efficacy for Performing Energy Conservation Strategies Assessment was used to measure self-efficacy. RESULTS: Participants showed significant reductions in fatigue and significant increases in self-efficacy and quality of life at posttest. These beneficial effects were maintained at follow-up. The Social Well-Being subscale was the only measure on which outcomes did not change significantly. CONCLUSION: The one-to one fatigue management course is a beneficial intervention for people with chronic conditions and fatigue. PMID- 28661379 TI - Promoting Health, Well-Being, and Quality of Life in Occupational Therapy: A Commitment to a Paradigm Shift for the Next 100 Years. AB - Since the inception of the profession of occupational therapy a century ago, a clarion call to link health with occupation and occupational engagement has been heard. For decades, leaders in the profession have emphasized the need for prevention and health promotion as well as for development of assessments and models linking health with occupation. This article addresses the need for an increased presence of occupational therapy in health and wellness, emphasizing participation over performance, to optimize the health, well-being, and quality of life of individuals, communities, and populations. PMID- 28661380 TI - Intrarater Reliability and Other Psychometrics of the Health Promoting Activities Scale (HPAS). AB - OBJECTIVE: The Health Promoting Activities Scale (HPAS) measures the self-rated frequency with which adults participate in activities that promote health. We evaluated the internal consistency, construct validity, and intrarater reliability of the HPAS with a cohort of mothers (N = 56) of school-age children. METHOD: We used an online survey that included the HPAS and measures of mental and physical health. Statistical analysis included intraclass correlation coefficients (ICCs), measurement error, error range, limits of agreement, and minimum detectable change (MDC). RESULTS: The HPAS showed good internal consistency (Cronbach's alpha = .73). Construct validity was supported by a significant difference in HPAS scores among participants grouped by physical activity level; no other differences were significant. Results included a high aggregate ICC of .90 and an MDC of 5 points. CONCLUSION: Our evaluation of the HPAS revealed good reliability and stability, suggesting suitability for ongoing evaluation as an outcome measure. PMID- 28661381 TI - In-Home Medication Management Performance Evaluation (HOME-Rx): A Validity Study. AB - OBJECTIVE: This study assessed the initial psychometric properties of a novel in home, performance-based instrument for older adults called the In-Home Medication Management Performance Evaluation (HOME-Rx). METHOD: Content validity of the HOME Rx was determined through the multistep content validity index (CVI) process. Content experts provided qualitative and quantitative judgment of the instrument's ability to measure medication management. The assessment's target population provided qualitative feedback. CVI outcomes informed instrument revisions. RESULTS: Content experts (n = 7) were in agreement that the overall instrument was valid for measuring medication management (scale-level CVI = .95). Six items were deleted because of low agreement (item-level CVI <.80). Twenty nine minor edits were made to the order of questions and language. Older adult participants (n = 5) reported the instrument was relevant, acceptable, and easy to understand. CONCLUSION: The HOME-Rx appears to be a relevant and valid method to assess performance barriers to medication management in the home. PMID- 28661382 TI - Facilitating Wellness in Urban-Dwelling, Low-Income Older Adults Through Community Mobility: A Mixed-Methods Study. AB - OBJECTIVE: Community participation is integral to wellness. This study examined the outcomes of Let's Go, a program designed to facilitate community participation of urban-dwelling, low-income older adults. METHOD: Fifty-two older adults participated in a mixed-methods, single-group pretest-posttest study. The Impact on Participation and Autonomy Questionnaire, participant surveys, and semistructured interviews were used to evaluate self-reported participation in community-based occupations, confidence, isolation, frequency of community trips, autonomy outdoors, and satisfaction with social life and relationships. RESULTS: Significant improvement was found in participation, confidence, frequency of community trips, autonomy outdoors, and satisfaction with social life and relationships at 4 wk and 6 mo. Qualitative themes were decreased isolation, importance of peer and community support, increased knowledge of mobility options, and a shift from fear to confidence. CONCLUSION: Community mobility programming can facilitate the participation of marginalized older adults in community-based occupations. PMID- 28661383 TI - Lifestyle Redesign(r) for Chronic Pain Management: A Retrospective Clinical Efficacy Study. AB - OBJECTIVE: Our objective was to determine the efficacy of a Lifestyle Redesign(r) intervention for people living with chronic pain on quality of life (QOL), function, self-efficacy, and pain levels. METHOD: Clinical outcomes were collected from 45 patients who completed an individual outpatient Lifestyle Redesign occupational therapy program for chronic pain as part of their usual plan of medical care. Outcome measures included the Canadian Occupational Performance Measure, the 36-Item Short-Form Survey, the Brief Pain Inventory, and the Pain Self-Efficacy Questionnaire. We analyzed scores using paired-samples t tests. RESULTS: Significant changes were observed in occupational performance and satisfaction scores, physical and social functioning, role limitations due to physical and emotional problems, energy and fatigue, general health, and pain self-efficacy. CONCLUSION: Lifestyle Redesign interventions, when integrated into a patient's medical plan of care, can improve patient functioning, self-efficacy, and QOL. PMID- 28661384 TI - Child's Challenging Behaviour Scale, Version 2 (CCBS-2): Psychometric Evaluation With Young Children. AB - OBJECTIVE: In this article, we evaluate psychometric properties of the Child's Challenging Behaviour Scale, Version 2 (CCBS-2) with mothers of young, typically developing children. METHOD: A cross-sectional mail survey with Australian mothers (N = 337) included the CCBS-2, the Depression Anxiety Stress Scales, and the Parents' Evaluation of Developmental Status scale. RESULTS: Internal consistency was good, and no gender differences in CCBS-2 scores were significant. Significant results included differences between CCBS-2 scores: among children grouped according to age, among children grouped according to pre- and post-school entry, among mothers grouped according to extent of any symptom type, and between this sample and a previously collected age-matched sample of children with disabilities. CONCLUSION: Of the properties tested, results support sound psychometrics. The CCBS-2 can be used to differentiate children according to age, school entry, and disability as well as to identify families for potential services in behavior management and mental health. PMID- 28661385 TI - Caregivers' Perspectives on the Sensory Environment and Participation in Daily Activities of Children With Autism Spectrum Disorder. AB - The purpose of this phenomenological study was to obtain caregivers' perspectives on the impact of the sensory environment on participation in daily activities of their young children with autism spectrum disorders (ASD). Interviews were completed with 34 caregivers of children with ASD ages 3-7 yr. Results strongly suggest that parents and caregivers were pivotal in enabling participation for their children through the implementation of specific strategies and a parental decision-making process. The decision-making process considered amount of effort necessary to support participation and whether participation in a given activity was perceived as essential or nonessential. Strategies enabled participation and reduced the effort required to support the child's participation. Strategies either directly related to the sensory factors of the environment or focused on reducing behavioral responses associated with sensory factors. In this study, we identified important considerations to enhance participation in the home and community environments for children with ASD. PMID- 28661386 TI - A Way of Seeing: How Occupation Is Portrayed to Students When Taught as a Concept Beyond Its Use in Therapy. AB - OBJECTIVE: The concept of occupation is core to learning occupational therapy, yet how occupation is taught has not been widely studied. We explored how occupation is addressed in 25 U.S. occupational therapist and occupational therapy assistant programs. METHOD: We used a basic qualitative research design, collecting data through interviews, artifacts, and video recordings of teaching. We secondarily analyzed 8 programs in which occupation was taught beyond its application in practice. RESULTS: Educators portrayed occupation as (1) a way of seeing self (students learn about themselves as occupational beings), (2) a way of seeing others (students learn about others as occupational beings), and (3) a way of seeing the profession (students learn occupation as the central focus of occupational therapy). Varied learning experiences promoted these perspectives. CONCLUSION: Three concepts-subject-centered learning, threshold concepts, and transformative learning-formed the theoretical foundation for teaching occupation as a way of seeing. PMID- 28661387 TI - Caregiver Perceptions of a Telehealth Wellness Program. AB - OBJECTIVE: We sought to understand caregivers' experience of an education-based wellness program delivered using telehealth. METHOD: In this qualitative pilot study, 4 caregivers participated in a focus group after completing a 6-wk telehealth program. Data analysis involved open coding, thematic analysis, and coding triangulation. RESULTS: Two major themes emerged. The first, "I feel like I am now prepared," included the subthemes of strategies for caregiver self maintenance, the understanding that caregiving is a normal process, and the value of a group experience. The second theme, "It was just a good interaction," included the subthemes of benefits of telehealth, challenges of telehealth, and process of learning the technology. CONCLUSION: Participant discussion of the content learned and the value of group support indicated that telehealth was effective in both promoting learning and facilitating relationships. Even with challenges, participants reported an overall positive experience. Telehealth holds promise for increasing access to health promotion programs. PMID- 28661388 TI - Integration of Medication Management Into Occupational Therapy Practice. AB - Occupational therapy practitioners enable clients to improve performance in everyday occupations. As health care reform precipitates changes across health care service organizations, occupational therapy professionals must seize the opportunity to apply their unique skills and perspective to meet the changing needs of clients and other stakeholders. In this article, we explore the role and distinct value of occupational therapy practitioners in one area of changing need: medication management. We find that occupational therapy practitioners have unique skills that complement the factors affecting medication nonadherence and evidence-based interventions. With reforms to research, teaching, and practice, occupational therapy practitioners can better integrate medication management into regular evaluation and treatment, thereby contributing to broader patient outcomes defined by the Affordable Care Act. PMID- 28661389 TI - Whole genome sequencing (WGS) for food-borne pathogen surveillance and control - taking the pulse. PMID- 28661390 TI - Determinants of success and sustainability of the WHO multimodal hand hygiene promotion campaign, Italy, 2007-2008 and 2014. AB - A national hand hygiene promotion campaign based on the World Health Organization (WHO) multimodal, Clean Care is Safer Care campaign was launched in Italy in 2007. One hundred seventy-five hospitals from 14 of 20 Italian regions participated. Data were collected using methods and tools provided by the WHO campaign, translated into Italian. Hand hygiene compliance, ward infrastructure, and healthcare workers' knowledge and perception of healthcare-associated infections and hand hygiene were evaluated before and after campaign implementation. Compliance data from the 65 hospitals returning complete data for all implementation tools were analysed using a multilevel approach. Overall, hand hygiene compliance increased in the 65 hospitals from 40% to 63% (absolute increase: 23%, 95% confidence interval: 22-24%). A wide variation in hand hygiene compliance among wards was observed; inter-ward variability significantly decreased after campaign implementation and the level of perception was the only item associated with this. Long-term sustainability in 48 of these 65 hospitals was assessed in 2014 using the WHO Hand Hygiene Self-Assessment Framework tool. Of the 48 hospitals, 44 scored in the advanced/intermediate categories of hand hygiene implementation progress. The median hand hygiene compliance achieved at the end of the 2007-2008 campaign appeared to be sustained in 2014. PMID- 28661391 TI - Clinical and laboratory evidence of Haff disease - case series from an outbreak in Salvador, Brazil, December 2016 to April 2017. AB - We describe a series of 15 Haff disease cases from an outbreak in Salvador, Brazil, starting early December 2016. Eleven cases were grouped in four family clusters of two to four individuals, four were isolated cases. All but one patient consumed cooked fish; 11 within 24h before symptoms onset. Cases consumed 'Olho de Boi' (Seriola spp.) and 'Badejo' (Mycteroperca spp.). A total of 67 cases were detected, the last case was reported on 5 April 2017. PMID- 28661392 TI - Measles outbreak after 12 years without endemic transmission, Portugal, February to May 2017. AB - We report a measles outbreak in two Portuguese health regions (Algarve and Lisbon and the Tagus Valley) since February 2017, and which by 31 May resulted in 28 confirmed cases, of which 16 were unvaccinated. Thirteen cases were healthcare workers. One unvaccinated teenager died. Genotype B3 was identified in 14 cases from both regions. This outbreak occurs after 12 years without endemic measles transmission, and in a context of high measles vaccination coverage and immunity. PMID- 28661393 TI - Botulism in Italy, 1986 to 2015. AB - Botulism is a rare but severe neuroparalytic disease caused by botulinum toxins. Because of its high potential impact on public health, botulism is a closely monitored communicable disease in Europe. In Italy, which has one of the highest incidence rates in Europe (0.03 cases per 100,000 population), botulism is monitored through a case-based passive surveillance system: the front-line physician who diagnoses a suspected case must notify the Local Health Units immediately, and the Ministry of Health's office within 12 hours. From 1986 to 2015, 466 confirmed cases of botulism were recorded in Italy (of 1,257 suspected cases). Of these, 421 were food-borne (the most frequently seen form of botulism due to the consumption of improperly home-canned foods), 36 were infant botulism, which accounts for ca 50% of all these types of cases registered in Europe, six were wound-related and three were due to adult intestinal colonisation. This scenario suggests that stronger efforts should be made towards raising public awareness of the risk of food-borne botulism, especially with respect to home preserved foods, as well as improving the training of front-line medical personnel, to ensure that a quick and accurate diagnosis of botulism can be made. PMID- 28661394 TI - The Maritime Declaration of Health (MDH) as a tool to detect maritime traffic related health risks: analysis of MDH forms submitted to Spanish ports, October 2014 to March 2015. AB - The international maritime traffic of people and goods has often contributed to the spread of pathogens affecting public health. The Maritime Declaration of Health (MDH), according to the International Health Regulations (IHR) (2005), is a document containing data related to the state of health on board a ship during passage and on arrival at port. It is a useful tool for early detection of public health risks. The main objective of our study was to evaluate compliance with the model provided in the IHR, focusing on the format and degree of completion of MDH forms received at Spanish ports. We reviewed the content of 802 MDH forms submitted to nine Spanish ports between October 2014 and March 2015. Study results show that 22% of MDH forms presented did not comply with the recommended model and 39% were incomplete. The proportion of cargo ships with correct and complete MDH forms was lower than passenger ships; thus, the nine health questions were answered less frequently by cargo ships than passenger ships (63% vs 90%, p value < 0.001). The appropriate demand and usage of MDH forms by competent authorities should improve the quality of the document as a tool and improve risk assessment. PMID- 28661395 TI - Necrotising fasciitis as atypical presentation of infection with emerging Neisseria meningitidis serogroup W (MenW) clonal complex 11, the Netherlands, March 2017. AB - In March 2017, a patient with necrotising fasciitis caused by Neisseria meningitidis serogroup W (MenW) clonal complex 11 was diagnosed in the Netherlands. Unusual and severe presentations of MenW infections are common in the current European epidemic. In the Netherlands, the incidence of MenW infections increased 10-fold, from an average of 0.03 per 100,000 population in 2002-2014 to 0.29 in 2016. Awareness of atypical presentations enables timely adequate treatment and public health action. PMID- 28661396 TI - Non-Canonical G-quadruplexes cause the hCEB1 minisatellite instability in Saccharomyces cerevisiae. AB - G-quadruplexes (G4) are polymorphic four-stranded structures formed by certain G rich nucleic acids in vitro, but the sequence and structural features dictating their formation and function in vivo remains uncertain. Here we report a structure-function analysis of the complex hCEB1 G4-forming sequence. We isolated four G4 conformations in vitro, all of which bear unusual structural features: Form 1 bears a V-shaped loop and a snapback guanine; Form 2 contains a terminal G triad; Form 3 bears a zero-nucleotide loop; and Form 4 is a zero-nucleotide loop monomer or an interlocked dimer. In vivo, Form 1 and Form 2 differently account for 2/3rd of the genomic instability of hCEB1 in two G4-stabilizing conditions. Form 3 and an unidentified form contribute to the remaining instability, while Form 4 has no detectable effect. This work underscores the structural polymorphisms originated from a single highly G-rich sequence and demonstrates the existence of non-canonical G4s in cells, thus broadening the definition of G4 forming sequences. PMID- 28661397 TI - ESCRTs function directly on the lysosome membrane to downregulate ubiquitinated lysosomal membrane proteins. AB - The lysosome plays an important role in maintaining cellular nutrient homeostasis. Regulation of nutrient storage can occur by the ubiquitination of certain transporters that are then sorted into the lysosome lumen for degradation. To better understand the underlying mechanism of this process, we performed genetic screens to identify components of the sorting machinery required for vacuole membrane protein degradation. These screens uncovered genes that encode a ubiquitin ligase complex, components of the PtdIns 3-kinase complex, and the ESCRT machinery. We developed a novel ubiquitination system, Rapamycin-Induced Degradation (RapiDeg), to test the sorting defects caused by these mutants. These tests revealed that ubiquitinated vacuole membrane proteins recruit ESCRTs to the vacuole surface, where they mediate cargo sorting and direct cargo delivery into the vacuole lumen. Our findings demonstrate that the ESCRTs can function at both the late endosome and the vacuole membrane to mediate cargo sorting and intra-luminal vesicle formation. PMID- 28661398 TI - Unbridle biomedical research from the laboratory cage. AB - Many biomedical research studies use captive animals to model human health and disease. However, a surprising number of studies show that the biological systems of animals living in standard laboratory housing are abnormal. To make animal studies more relevant to human health, research animals should live in the wild or be able to roam free in captive environments that offer a natural range of both positive and negative experiences. Recent technological advances now allow us to study freely roaming animals and we should make use of them. PMID- 28661399 TI - Systematic bacterialization of yeast genes identifies a near-universally swappable pathway. AB - Eukaryotes and prokaryotes last shared a common ancestor ~2 billion years ago, and while many present-day genes in these lineages predate this divergence, the extent to which these genes still perform their ancestral functions is largely unknown. To test principles governing retention of ancient function, we asked if prokaryotic genes could replace their essential eukaryotic orthologs. We systematically replaced essential genes in yeast by their 1:1 orthologs from Escherichia coli. After accounting for mitochondrial localization and alternative start codons, 31 out of 51 bacterial genes tested (61%) could complement a lethal growth defect and replace their yeast orthologs with minimal effects on growth rate. Replaceability was determined on a pathway-by-pathway basis; codon usage, abundance, and sequence similarity contributed predictive power. The heme biosynthesis pathway was particularly amenable to inter-kingdom exchange, with each yeast enzyme replaceable by its bacterial, human, or plant ortholog, suggesting it as a near-universally swappable pathway. PMID- 28661402 TI - CIOMS guidelines remain conservative about vulnerability and social justice. AB - This paper begins by considering how the revised CIOMS guidelines have progressed beyond a mere labelling approach in the handling of vulnerability.. However, progress is limited as the guidelines remain fixated on voluntariness and harm reduction or prevention. Although these are important considerations, vulnerability could also serve as a robust analytic for the evaluation of situational and pathogenic (or structural) contributions to susceptibilities to harm. They could also provide better guidance on how to differentiate among varying types and degrees of harm, rather than merely noting their presence. The paper concludes by considering vulnerability in relation to especially vulnerable children in health research. PMID- 28661403 TI - Accelerated approval of drugs: ethics versus efficacy. AB - OBJECTIVE: To analyse the post-marketing status of molecules approved through the expedited review process in the last quintile. METHODS: This observational study was carried out between January 2016 and June 2016. The details of the time taken to approve drugs were collected from the official website of United States Food and Drug Administration (FDA). The average time taken to review drugs and take a decision following the review were ascertained from the FDA's annual release of novel drugs from 2011 to 2015. Information on adverse drug reactions noted after approval was gathered from the FDA Drug Safety Communication and FDA Adverse Event Reporting System (FAERS). RESULTS: In the last five years, 166 products were approved by expedited review. Of these, 45 (27.1%) did not meet the stringent criteria framed for expedited review. Reports of serious adverse event alerts were submitted for 79 (47.5%) of the 166 molecules. Fourteen (8.4%) drugs were associated with inducing severe autoimmune disorders. It can be observed that a lower average time of review is positively correlated with a greater number of adverse events (p<0.05). Thirty-seven (45.7%) of the molecules failed to be of any benefit in the treatment scenario. CONCLUSION: Drug approval by accelerated review should be stringent. Beneficence and non-maleficence are applicable to the global population, and should apply equally to subjects involved in trials. Approving drugs on the basis of trivial evidence is non scientific and absolutely unethical, since it can lead to clinical failure and produce serious adverse events. PMID- 28661400 TI - Cortex-dependent recovery of unassisted hindlimb locomotion after complete spinal cord injury in adult rats. AB - After paralyzing spinal cord injury the adult nervous system has little ability to 'heal' spinal connections, and it is assumed to be unable to develop extra spinal recovery strategies to bypass the lesion. We challenge this assumption, showing that completely spinalized adult rats can recover unassisted hindlimb weight support and locomotion without explicit spinal transmission of motor commands through the lesion. This is achieved with combinations of pharmacological and physical therapies that maximize cortical reorganization, inducing an expansion of trunk motor cortex and forepaw sensory cortex into the deafferented hindlimb cortex, associated with sprouting of corticospinal axons. Lesioning the reorganized cortex reverses the recovery. Adult rats can thus develop a novel cortical sensorimotor circuit that bypasses the lesion, probably through biomechanical coupling, to partly recover unassisted hindlimb locomotion after complete spinal cord injury. PMID- 28661404 TI - Theory and computer simulation of hard-core Yukawa mixtures: thermodynamical, structural and phase coexistence properties. AB - We report extensive calculations, based on the modified hypernetted chain (MHNC) theory, on the hierarchical reference theory (HRT), and on Monte Carlo simulations, of thermodynamical, structural and phase coexistence properties of symmetric binary hard-core Yukawa mixtures (HCYM) with attractive interactions at equal species concentration. The obtained results are throughout compared with those available in the literature for the same systems. It turns out that the MHNC predictions for thermodynamic and structural quantities are quite accurate in comparison with the MC data. The HRT is equally accurate for thermodynamics, and slightly less accurate for structure. Liquid-vapor (LV) and liquid-liquid (LL) consolute coexistence conditions as emerging from simulations, are also highly satisfactorily reproduced by both the MHNC and HRT for relatively long ranged potentials. When the potential range reduces, the MHNC faces problems in determining the LV binodal line; however, the LL consolute line and the critical end point (CEP) temperature and density turn out to be still satisfactorily predicted within this theory. The HRT also predicts with good accuracy the CEP position. The possibility of employing liquid state theories HCYM for the purpose of reliably determining phase equilibria in multicomponent colloidal fluids of current technological interest, is discussed. PMID- 28661401 TI - Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells. AB - Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here, we set up two assays to specifically identify the pharmacological properties of rat mGlu heterodimers composed of mGlu2 and 4 subunits. We used either a heterodimer-specific conformational LRET-based biosensor or a system that guarantees the cell surface targeting of the heterodimer only. We identified mGlu2-4 specific pharmacological fingerprints that were also observed in a neuronal cell line and in lateral perforant path terminals naturally expressing mGlu2 and mGlu4. These results bring strong evidence for the existence of mGlu2-4 heterodimers in native cells. In addition to reporting a general approach to characterize heterodimeric mGluRs, our study opens new avenues to understanding the pathophysiological roles of mGlu heterodimers. PMID- 28661405 TI - Crystal structures, magnetic properties, and DFT calculation of B-site defected 12L-perovskites Ba2La2MW2O12 (M = Mn, Co, Ni, Zn). AB - The synthesis, crystal structures and magnetic properties of Ba2La2MW2O12 (M = Mn, Co, Ni, Zn) were investigated. They crystallize in the 12-layer polytype of the perovskite structure with a regular cation defect in the B-site. The results of neutron diffraction measurements reveal that they adopt a rhombohedral structure with a space group R - 3 and have a cation ordering between Ba and La ions in the A-site. In these compounds, the magnetic M ions form the 2D triangular lattice. From the results of magnetic measurements, the ferromagnetic ordering of M2+ ions for M = Co (T C = 1.3 K) and Ni (6.2 K) and the paramagnetic behavior (T > 1.8 K) with an antiferromagnetic interaction for M = Mn are observed. From the DFT calculation, their band structures and magnetic interactions are discussed. PMID- 28661406 TI - Excitonic Aharonov-Bohm effect in QD-on-ring nanostructures. AB - We show by the first-order perturbation theory and the configuration interaction method that the Coulomb interaction in quantum rings mixes electron-hole pair states with the same total angular momentum, which makes it difficult to observe a clear excitonic Aharonov-Bohm (A-B) effect. To avoid this situation, we propose the use of a combined structure of a quantum dot on the top of a quantum ring with an applied static electric field. Under moderate experimental conditions with respect to the applied electric and magnetic fields, we show that we can observe the excitonic A-B effect due to the reduction of the Coulomb interaction and an increase in the difference between the average radii of the electron and hole trajectories. PMID- 28661408 TI - A Note from the Editor: Duchenne Muscular Dystrophy, Genetics, the FDA and Drug Pricing. AB - DMD is a muscle-wasting disease. It is caused by mutations in the dystrophin gene which is found on the X chromosome. It has an X-linked recessive inheritance pattern and is passed on by the mother (carrier). It is a progressive disease that usually causes death in early adulthood-often in the 20s, although there have been improvements in treatment, so some patients make it into their 30s and occasionally 40s. In addition to the muscle wasting aspects, serious complications include heart or respiratory-related problems. It mostly affects boys, about 1 in every 3,500 or 5,000 male children. On September 19, 2016, the FDA approved Sarepta Therapeutics (SRPT)'s eteplirsen, which now goes by the trade name Exondys 51, to treat DMD. It is the first drug to be approved to treat the underlying causes of the disease. [http://www.biospace.com/News/victory-at last-sarepta-stock-doublesas-the-fda/432777]. PMID- 28661409 TI - Cytogenetic Characterization of Myeloid Neoplasms with t(2;3)(p13-25;q25-29): An Analysis of 60 Cases. AB - Chromosomal translocations involving the short arm of chromosome 2 (p13-25) and the distal part of the long arm of chromosome 3 (q25-29) are rare and still poorly studied to date. These abnormalities are common in myeloid neoplasms and are associated with a poor prognosis. Chromosomal abnormalities within the involved range of bands may contribute to the ectopic expression or formation of fusion genes involving the EVI1 gene, but the exact mechanism by which EVI1 affects leukemogenesis remains unclear. Herein, we report an analysis of 60 patient cases presenting various myeloid malignancies with t(2;3)(p13-25;q25-29) compiled from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. In these studies, this translocation has been reported as a sole abnormality or within the context of a complex karyotype. Among the analysis in which molecular cytogenetic analysis was performed in order to assess the involvement of the EVI1 (ecotropic virus integration site 1 proton homolog) locus (n=19), 16 (84%) confirmed its rearrangement. In 37% of studies, the t(2;3) was seen as a sole abnormality (n=22). The t(2;3) was secondary in 11% of cases (n=4), and in 63% of the cases the t(2;3) had additional chromosomal abnormalities (n=38). Monosomy 7, deletion of the 5q arm, and translocations involving (9;22) were most common abnormalities in order of prevalence, occurring in 29% (n=11), 26% (n=10), and 13% (n=5) of case studies, respectively. These observations in the results of the literature on t(2;3), an anomaly not otherwise molecularly characterized, adds to the discussion of this translocation's approximate incidence in myeloid disease, and specifically in acute myeloid leukemia (AML). The data highlights its nonrandom nature and suggests that it is a part of the myeloid spectrum of disorders. Considering the severe clinical outcome associated with this translocation, this data provides information about a cytogenetic biomarker as well as an understanding of the significance of this set of chromosomal anomalies in the development of myeloid disease. PMID- 28661410 TI - Approach to adenovirus infections in the setting of hematopoietic cell transplantation. AB - PURPOSE OF REVIEW: To review risk-based pre-emptive treatment for adenovirus (ADV) based on quantitative PCR (qPCR) and to provide an update on clinical trials of brincidofovir (BCV) and ADV-specific cytotoxic T lymphocytes (ADV CTLs). RECENT FINDINGS: ADV qPCR in various body compartments enables distinction of clinically significant infection and assessment of treatment responses. Plasma ADV qPCR monitoring and aggressive pre-emptive treatment is recommended for high risk patients. Pre-emptive therapy at low viral load is associated with faster virologic response and improved outcomes. BCV has demonstrated virologic responses against all clinically significant ADV serotypes. Prolonged administration of oral BCV may be limited by gastrointestinal toxicity; an intravenous BCV formulation does not show gastrointestinal toxicity in early studies. ADV-CTLs can be generated from ADV-seropositive individuals using a variety of systems. Banked ADV-CTLs can achieve durable responses in patients for whom no donor-derived cell therapy product is available. SUMMARY: Disseminated ADV disease is associated with substantial mortality in hematopoietic cell transplant recipients. Routine monitoring by plasma ADV qPCR and pre-emptive therapy at low viral load are associated with improved outcomes in high-risk patients. BCV and ADV-CTLs are promising modalities currently undergoing clinical trials. PMID- 28661411 TI - Healthcare-associated infections in the elderly: what's new: Erratum. PMID- 28661412 TI - Risk of new-onset diabetes mellitus in primary aldosteronism: a population study over 5 years. AB - OBJECTIVE: Abnormal glucose metabolism due to insulin resistance has been linked to aldosterone overproduction. However, the long-term incidence of new-onset diabetes mellitus (NODM) among patients with primary aldosteronism after targeted treatment has not been well documented. METHODS: The diagnosis of primary aldosteronism and essential hypertension were identified, and then the occurrence of NODM, all-cause mortality among these patients, was ascertained by a validated algorithm from a 23-million population insurance registry. RESULTS: From 1999 to 2007, 2367 primary aldosteronism patients without previously diabetes mellitus were identified and propensity score-matched with 9468 patients with essential hypertension. Among those primary aldosteronism patients, 754 aldosterone producing adenomas patients were identified and matched with 3016 essential hypertension controls. After a mean 5.2 years of follow-up, primary aldosteronism patients who underwent adrenalectomy had an attenuated NODM incidence (hazard ratio = 0.60, P < 0.01, versus essential hypertension); whereas those treated with mineralocorticoid receptor antagonist had augmented risk of NODM (hazard ratio = 1.16, P < 0.001, versus essential hypertension). Among the aldosterone producing adenoma patients, adrenalectomy is also protective from developing NODM (hazard ratio = 0.61, P < 0.001, versus essential hypertension), however, mineralocorticoid receptor antagonist treatment did not alter the risk of NODM (P = 0.10, versus essential hypertension). Adjusted hazard ratios for long-term risk of mortality from this analysis revealed that adrenalectomy is protective, but NODM and major cardiovascular disease are deleterious. CONCLUSION: The primary aldosteronism patients who underwent adrenalectomy had reduced risk for incident NODM and all-cause of mortality, compared with matched hypertensive controls. This observation adds more evidence on the association of primary aldosteronism with a higher risk of metabolic syndrome and long-term mortality. PMID- 28661413 TI - Oxidative lipidomics: applications in critical care. AB - PURPOSE OF REVIEW: Lipid peroxidation has long been established as a key player in the pathophysiology of critical illness. Recent developments in oxidative lipidomics have aided in deciphering the molecular mechanisms of lipid oxidation in health and disease. This review discusses recent achievements and recent developments in oxidative lipidomics and its contribution to the understanding of critical illness. RECENT FINDINGS: Most studies involving acute injury focus on identifying the end products of lipid peroxidation. This misses the early events and targets of peroxidation mechanisms. Recent developments in liquid chromatography tandem mass spectrometry-based oxidative lipidomics have enabled the identification of a wide variety of enzymatically generated lipid oxidation products. Such lipid mediators have been found to play an important role in injury, inflammation, and recovery in disease states such as sepsis or head trauma. SUMMARY: Multiple lipid oxidation products are formed either through enzymatic pathways or through random chemical reactions. These products are often biologically active and can contribute to the regulation of cellular signaling. Oxidative lipidomics has contributed to the identification and quantification of lipid peroxidation products, the mechanism and time course of their production after injury, and synergistic functioning with other regulatory processes in the body. These advances in knowledge will help guide the future development of interventions in critical illness. PMID- 28661415 TI - More hemodynamic monitoring for personalized treatment in circulatory failure. PMID- 28661414 TI - Muscle mass and physical recovery in ICU: innovations for targeting of nutrition and exercise. AB - PURPOSE OF REVIEW: We have significantly improved hospital mortality from sepsis and critical illness in last 10 years; however, over this same period we have tripled the number of 'ICU survivors' going to rehabilitation. Furthermore, as up to half the deaths in the first year following ICU admission occur post-ICU discharge, it is unclear how many of these patients ever returned home or a meaningful quality of life. For those who do survive, recent data reveals many 'ICU survivors' will suffer significant functional impairment or post-ICU syndrome (PICS). Thus, new innovative metabolic and exercise interventions to address PICS are urgently needed. These should focus on optimal nutrition and lean body mass (LBM) assessment, targeted nutrition delivery, anabolic/anticatabolic strategies, and utilization of personalized exercise intervention techniques, such as utilized by elite athletes to optimize preparation and recovery from critical care. RECENT FINDINGS: New data for novel LBM analysis technique such as computerized tomography scan and ultrasound analysis of LBM are available showing objective measures of LBM now becoming more practical for predicting metabolic reserve and effectiveness of nutrition/exercise interventions. 13C-Breath testing is a novel technique under study to predict infection earlier and predict over-feeding and under-feeding to target nutrition delivery. New technologies utilized routinely by athletes such as muscle glycogen ultrasound also show promise. Finally, the role of personalized cardiopulmonary exercise testing to target preoperative exercise optimization and post-ICU recovery are becoming reality. SUMMARY: New innovative techniques are demonstrating promise to target recovery from PICS utilizing a combination of objective LBM and metabolic assessment, targeted nutrition interventions, personalized exercise interventions for prehabilitation and post ICU recovery. These interventions should provide hope that we will soon begin to create more 'survivors' and fewer victim's post-ICU care. PMID- 28661416 TI - Assessment of residual exposure to PCBs in metallurgy. AB - OBJECTIVE: To evaluate the occupational exposure to polychlorinated biphenyls (PCBs) in 56 workers employed in 6 electric arc furnace steelmaking plants and 2 secondary aluminum smelting plants located in the highly industrialized area of Brescia, Northern Italy. METHODS: Thirty-four PCB congeners were found in both environmental and biological samples from workers engaged in scrap yards, electric arc furnaces, casting and maintenance departments. RESULTS: The highest airborne PCB levels were found in the aluminum plant, even 100 times those detected in the steelwork plants. Dioxin-like PCB congeners (DL-PCBs) were poorly represented in all biological samples, whereas non Dioxin-Like PCB congeners (noDL-PCBs), in particular environmentally widespread congeners (PCB 153, 138, 180), could be detected in almost all samples. The mean total PCB serum level was 3.9 ng/ml, with a range of 1.3-10.3 ng/ml, while the geometric mean for airborne PCBs levels was 9305 pg/m3, with a range of 1138-217806 pg/m3. CONCLUSIONS: Despite the higher PCB values recorded in some metallurgical plant workplaces, we failed to find any significant difference between serum concentrations in workers from steel or aluminum production, even in consideration of different tasks or different job seniority, while positive association was found only according to the age of the workers. A possible explanation may be identified in the effectiveness of the individual and collective preventive measures adopted in the workplace. Assessment of the occupational exposure to such compounds, in consideration of the recent classifications as carcinogenic to humans, should be encouraged. PMID- 28661417 TI - Contrasting Eutrophication Risks and Countermeasures in Different Water Bodies: Assessments to Support Targeted Watershed Management. AB - Eutrophication is a major problem in China. To combat this issue, the country needs to establish water quality targets, monitoring systems, and intelligent watershed management. This study explores a new watershed management method. Water quality is first assessed using a single factor index method. Then, changes in total nitrogen/total phosphorus (TN/TP) are analyzed to determine the limiting factor. Next, the study compares the eutrophication status of two water function districts, using a comprehensive nutritional state index method and geographic information system (GIS) visualization. Finally, nutrient sources are qualitatively analyzed. Two functional water areas in Tianjin, China were selected and analyzed: Qilihai National Wetland Nature Reserve and Yuqiao Reservoir. The reservoir is a drinking water source. Results indicate that total nitrogen (TN) and total phosphorus (TP) pollution are the main factors driving eutrophication in the Qilihai Wetland and Yuqiao Reservoir. Phosphorus was the limiting factor in the Yuqiao Reservoir; nitrogen was the limiting factor in the Qilihai Wetland. Pollution in Qilihai Wetland is more serious than in Yuqiao Reservoir. The study found that external sources are the main source of pollution. These two functional water areas are vital for Tianjin; as such, the study proposes targeted management measures. PMID- 28661418 TI - Data Aggregation Based on Overlapping Rate of Sensing Area in Wireless Sensor Networks. AB - Wireless sensor networks are required in smart applications to provide accurate control, where the high density of sensors brings in a large quantity of redundant data. In order to reduce the waste of limited network resources, data aggregation is utilized to avoid redundancy forwarding. However, most of aggregation schemes reduce information accuracy and prolong end-to-end delay when eliminating transmission overhead. In this paper, we propose a data aggregation scheme based on overlapping rate of sensing area, namely AggOR, aiming for energy efficient data collection in wireless sensor networks with high information accuracy. According to aggregation rules, gathering nodes are selected from candidate parent nodes and appropriate neighbor nodes considering a preset threshold of overlapping rate of sensing area. Therefore, the collected data in a gathering area are highly correlated, and a large amount of redundant data could be cleaned. Meanwhile, AggOR keeps the original entropy by only deleting the duplicated data. Experiment results show that compared with others, AggOR has a high data accuracy and a short end-to-end delay with a similar network lifetime. PMID- 28661419 TI - Design, Synthesis, and Antifouling Activity of Glucosamine-Based Isocyanides. AB - Biofouling, an undesirable accumulation of organisms on sea-immersed structures such as ship hulls and fishing nets, is a serious economic issue whose effects include oil wastage and clogged nets. Organotin compounds were utilized since the 1960s as an antifouling material; however, the use of such compounds was later banned by the International Maritime Organization (IMO) due to their high toxicity toward marine organisms, resulting in masculinization and imposex. Since the ban, there have been extensive efforts to develop environmentally benign antifoulants. Natural antifouling products obtained from marine creatures have been the subject of considerable attention due to their potent antifouling activity and low toxicity. These antifouling compounds often contain isocyano groups, which are well known to have natural antifouling properties. On the basis of our previous total synthesis of natural isocyanoterpenoids, we envisaged the installation of an isocyano functional group onto glucosamine to produce an environmentally friendly antifouling material. This paper describes an effective synthetic method for various glucosamine-based isocyanides and evaluation of their antifouling activity and toxicity against cypris larvae of the barnacle Amphibalanus amphitrite. Glucosamine isocyanides with an ether functionality at the anomeric position exhibited potent antifouling activity, with EC50 values below 1 MUg/mL, without detectable toxicity even at a high concentration of 10 MUg/mL. Two isocyanides had EC50 values of 0.23 and 0.25 MUg/mL, comparable to that of CuSO4, which is used as a fouling inhibitor (EC50 = 0.27 MUg/mL). PMID- 28661420 TI - Induction of miR-3648 Upon ER Stress and Its Regulatory Role in Cell Proliferation. AB - MicroRNAs (miRNAs) play important roles under multiple cellular conditions including endoplasmic reticulum (ER) stress. We found that miR-3648, a human specific microRNA, was induced under ER stress. Moreover, Adenomatous polyposis coli 2 (APC2), a tumor suppressor and a negative regulator of Wnt signaling, was found to be the direct target of miR-3648. Levels of APC2 were downregulated when cells were under ER stress or after overexpressing miR-3648. Inhibition of miR 3648 by antagomir increased APC2 levels and decreased cell proliferation. Conversely, when miR-3648 was overexpressed, APC2 levels were decreased and the cell growth increased. Our data demonstrated that ER stress mediated induction of miR-3648 in human cells, which then downregulated APC2 to increase cell proliferation. PMID- 28661422 TI - Silicate-Promoted Phosphorylation of Glycerol in Non-Aqueous Solvents: A Prebiotically Plausible Route to Organophosphates. AB - Phosphorylation reactions of glycerol were studied using different inorganic phosphates such as sodium phosphate, trimetaphosphate (a condensed phosphate), and struvite. The reactions were carried out in two non-aqueous solvents: formamide and a eutectic solvent consisting of choline-chloride and glycerol in a ratio of 1:2.5. The glycerol reacted in formamide and in the eutectic solvent with phosphate to yield its phosphorylated derivatives in the presence of silicates such as quartz sand and kaolinite clay. The reactions were carried out by heating glycerol with a phosphate source at 85 degrees C for one week and were analyzed by 31P-nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). The yield of the phosphorylated glycerol was improved by the presence of silicates, and reached 90% in some experiments. Our findings further support the proposal that non-aqueous solvents are advantageous for the prebiotic synthesis of biomolecules, and suggest that silicates may have aided in the formation of organophosphates on the prebiotic earth. PMID- 28661421 TI - Oral Supplementation of Melatonin Protects against Fibromyalgia-Related Skeletal Muscle Alterations in Reserpine-Induced Myalgia Rats. AB - Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain and an extensive array of other symptoms including disordered sleep, fatigue, depression and anxiety. Important factors involved in the pathogenic process of fibromyalgia are inflammation and oxidative stress, suggesting that ant-inflammatory and/or antioxidant supplementation might be effective in the management and modulation of this syndrome. Recent evidence suggests that melatonin may be suitable for this purpose due to its well known ant inflammatory, antioxidant and analgesic effects. Thus, in the current study, the effects of the oral supplementation of melatonin against fibromyalgia-related skeletal muscle alterations were evaluated. In detail, 90 Sprague Dawley rats were randomly treated with reserpine, to reproduce the pathogenic process of fibromyalgia and thereafter they received melatonin. The animals treated with reserpine showed moderate alterations at hind limb skeletal muscles level and had difficulty in moving, together with significant morphological and ultrastructural alterations and expression of inflammatory and oxidative stress markers in the gastrocnemius muscle. Interestingly, melatonin, dose and/or time dependently, reduced the difficulties in spontaneous motor activity and the musculoskeletal morphostructural, inflammatory, and oxidative stress alterations. This study suggests that melatonin in vivo may be an effective tool in the management of fibromyalgia-related musculoskeletal morphofunctional damage. PMID- 28661423 TI - Polydopamine Nanoparticles for Combined Chemo- and Photothermal Cancer Therapy. AB - Cancer therapy with two different modalities can enhance treatment efficacy and reduce side effects. This paper describes a new method for combined chemo- and photothermal therapy of cancer using poly dopamine nanoparticles (PDA-NPs), where PDA-NPs serve not only as a photothermal agent with strong near infrared absorbance and high energy conversion efficiency, but also as a carrier to deliver cisplatin via interaction between cisplatin and catechol groups on PDA NPs. Polyethylene glycol (PEG) was introduced through Michael addition reaction to improve the stability of PDA-NPs in physiological condition. A remarkable synergistic therapeutic effect has been achieved compared with respective single treatments. This work suggests that the PDA-based nanoplatform can be a universal scaffold for combined chemo- and photothermal therapy of cancer. PMID- 28661424 TI - Vitamin C and Microvascular Dysfunction in Systemic Inflammation. AB - Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and, among others, the microvascular function. This review examines our recent work addressing ascorbate's ability to inhibit arteriolar dysfunction and capillary plugging in sepsis. Arteriolar dysfunction includes impaired vasoconstriction/dilation (previously reviewed) and impaired conduction of vasoconstriction/dilation along the arteriole. We showed that ascorbate injected into septic mice prevents impaired conducted vasoconstriction by inhibiting neuronal nitric oxide synthase-derived NO, leading to restored inter-endothelial electrical coupling through connexin 37-containing gap junctions. Hypoxia/reoxygenation (confounding factor in sepsis) also impairs electrical coupling by protein kinase A (PKA)-dependent connexin 40 dephosphorylation; ascorbate restores PKA activation required for this coupling. Both effects of ascorbate could explain its ability to protect against hypotension in sepsis. Capillary plugging in sepsis involves P-selectin mediated platelet-endothelial adhesion and microthrombi formation. Early injection of ascorbate prevents capillary plugging by inhibiting platelet-endothelial adhesion and endothelial surface P-selectin expression. Ascorbate also prevents thrombin-induced platelet aggregation and platelet surface P-selectin expression, thus preventing microthrombi formation. Delayed ascorbate injection reverses capillary plugging and platelet-endothelial adhesion; it also attenuates sepsis-induced drop in platelet count in systemic blood. Thrombin-induced release of plasminogen activator-inhibitor-1 from platelets (anti-fibrinolytic event in sepsis) is inhibited by ascorbate pH-dependently. Thus, under acidotic conditions in sepsis, ascorbate promotes dissolving of microthrombi in capillaries. We propose that protected/restored arteriolar conduction and capillary bed perfusion by ascorbate contributes to reduced organ injury and improved survival in sepsis. PMID- 28661425 TI - Characterizing Computer Access Using a One-Channel EEG Wireless Sensor. AB - This work studies the feasibility of using mental attention to access a computer. Brain activity was measured with an electrode placed at the Fp1 position and the reference on the left ear; seven normally developed people and three subjects with cerebral palsy (CP) took part in the experimentation. They were asked to keep their attention high and low for as long as possible during several trials. We recorded attention levels and power bands conveyed by the sensor, but only the first was used for feedback purposes. All of the information was statistically analyzed to find the most significant parameters and a classifier based on linear discriminant analysis (LDA) was also set up. In addition, 60% of the participants were potential users of this technology with an accuracy of over 70%. Including power bands in the classifier did not improve the accuracy in discriminating between the two attentional states. For most people, the best results were obtained by using only the attention indicator in classification. Tiredness was higher in the group with disabilities (2.7 in a scale of 3) than in the other (1.5 in the same scale); and modulating the attention to access a communication board requires that it does not contain many pictograms (between 4 and 7) on screen and has a scanning period of a relatively high t s c a n ~ 10 s. The information transfer rate (ITR) is similar to the one obtained by other brain computer interfaces (BCI), like those based on sensorimotor rhythms (SMR) or slow cortical potentials (SCP), and makes it suitable as an eye-gaze independent BCI. PMID- 28661426 TI - Rational Design of Recombinant Papain-Like Cysteine Protease: Optimal Domain Structure and Expression Conditions for Wheat-Derived Enzyme Triticain-alpha. AB - Triticain-alpha is a papain-like cysteine protease from wheat (Triticumaestivum L.) that possesses activity towards toxic gluten-derived peptides, and was thus proposed as a novel therapeutic tool for celiac disease. We report an original approach employing rational design of domain architecture of Triticain-alpha and selection of the appropriate expression system for development of cheap and efficient protocol yielding active recombinant enzyme. The segregated catalytic domain of Triticain-alpha did not adopt native structure in bacteria, neither being expressed as a single protein nor upon conjugation or co-expression with extrinsic chaperones. Meanwhile, its attachment to prodomain of the enzyme resulted in generation of insoluble (inclusion bodies) product that can be transformed into active protease upon refolding in vitro. The estimated yield of the product was affected by affinity six-histidine tag required for its single step purification with the preferable N-terminal position of the tag. Expression of the two-domain Triticain-alpha construct in yeast (Pichiapastoris) strain GS115 and bacterial (Escherichia coli) strain Rosetta gami B (DE3) led to the accumulation of a soluble protein, which underwent autocatalytic maturation during expression (in yeast)/purification (in bacteria) procedures and exhibited pronounced protease activity. Furthermore, expression and solubility of such construct in Rosetta gami B (DE3) cells was improved by reducing the temperature of the bacterial growth yielding more active enzyme than yeast counterpart presumably due to facilitated formation of a characteristic disulfide bond critical for maintaining the catalytic site. We suggest that these findings are helpful for obtaining active Triticain-alpha preparations for scientific or medical applications, and can be employed for the design and production of beneficial recombinant products based on other papain-like cysteine proteases. PMID- 28661427 TI - Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia. AB - BACKGROUND: Previous work demonstrated that high-fat diet (HFD) triggered thioredoxin-interacting protein (TXNIP) and that silencing TXNIP prevents diabetes-impaired vascular recovery. Here, we examine the impact of genetic deletion of TXNIP on HFD-impaired vascular recovery using hind limb ischemia model. METHODS: Wild type mice (WT, C57Bl/6) and TXNIP knockout mice (TKO) were fed either normal chow diet (WT-ND and TKO-ND) or 60% high-fat diet (WT-HFD and TKO-HFD). After four weeks of HFD, unilateral hind limb ischemia was performed and blood flow was measured using Laser doppler scanner at baseline and then weekly for an additional three weeks. Vascular density, nitrative stress, infiltration of CD68+ macrophages, and expression of inflammasome, vascular endothelial growth factor (VEGF), VEGF receptor-2 were examined by slot blot, Western blot and immunohistochemistry. RESULTS: By week 8, HFD caused similar increases in weight, cholesterol and triglycerides in both WT and TKO. At week 4 and week 8, HFD significantly impaired glucose tolerance in WT and to a lesser extent in TKO. HFD significantly impaired blood flow and vascular density (CD31 labeled) in skeletal muscle of WT mice compared to ND but not in TKO. HFD and ischemia significantly induced tyrosine nitration, and systemic IL-1beta and infiltration of CD68+ cells in skeletal muscle from WT but not from TKO. HFD significantly increased cleaved-caspase-1 and IL-1 beta compared to ND. Under both ND, ischemia tended to increase VEGF expression and increased VEGFR2 activation in WT only but not TKO. CONCLUSION: Similar to prior observation in diabetes, HFD-induced obesity can compromise vascular recovery in response to ischemic insult. The mechanism involves increased TXNIP-NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome activation, nitrative stress and impaired VEGFR2 activation. Deletion of TXNIP restored blood flow, reduced nitrative stress and blunted inflammasome-mediated inflammation; however, it did not impact VEGF/VEGFR2 in HFD. Targeting TXNIP-NLRP3 inflammasome can provide potential therapeutic target in obesity-induced vascular complication. PMID- 28661428 TI - Association between Excessive Use of Mobile Phone and Insomnia and Depression among Japanese Adolescents. AB - The aim of this study was to investigate the relationship between mobile phone use and insomnia and depression in adolescents. A cross-sectional study was conducted on 295 high school students aged 15-19 in Japan. Insomnia and depression were assessed using Athene Insomnia Scales (AIS) and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. Mobile phones were owned by 98.6% of students; 58.6% used mobile phones for over 2 h per day and 10.5% used them for over 5 h per day. Overall mobile phone use of over 5 h per day was associated with shorter sleep duration and insomnia (OR: 3.89 [[95% CI: 1.21-12.49]), but not with depression. Mobile phone use of 2 h or more per day for social network services (OR: 3.63 [[1.20-10.98]) and online chats (OR: 3.14 [[1.42-6.95]), respectively, was associated with a higher risk of depression. Mobile phone overuse can be linked to unhealthy sleep habits and insomnia. Moreover, mobile phone overuse for social network services and online chats may contribute more to depression than the use for internet searching, playing games or viewing videos. PMID- 28661429 TI - Effective Suckling C57BL/6, Kunming, and BALB/c Mouse Models with Remarkable Neurological Manifestation for Zika Virus Infection. AB - Since 2015, 84 countries and territories reported evidence of vector-borne Zika Virus (ZIKV) transmission. The World Health Organization (WHO) declared that ZIKV and associated consequences especially the neurological autoimmune disorder Guillain-Barre syndrome (GBS) and microcephaly will remain a significant enduring public health challenge requiring intense action. We apply a standardization of the multi-subcutaneous dorsal inoculation method to systematically summarize clinical neurological manifestation, viral distribution, and tissue damage during the progress of viremia and systemic spread in suckling mouse models. We found that C57BL/6 and Kunming mice (KM) both showed remarkable and uniform neurologic manifestations. C57BL/6 owned the highest susceptibility and pathogenicity to the nervous system, referred to as movement disorders, with 100% incidence, while KM was an economic model for a Chinese study characterized by lower limb weakness with 62% morbidity. Slight yellow extraocular exudates were observed in BALB/c, suggesting the association with similar ocular findings to those of clinical cases. The virus distribution and pathological changes in the sera, brains, livers, kidneys, spleens, and testes during disease progression had strong regularity and uniformity, demonstrating the effectiveness and plasticity of the animal models. The successful establishment of these animal models will be conducive to expound the pathogenic mechanism of GBS. PMID- 28661430 TI - Analysis of Hypericin-Mediated Effects and Implications for Targeted Photodynamic Therapy. AB - The phototoxic effect of hypericin can be utilized for Photodynamic Therapy (PDT) of cancer. After intravenous application and systemic distribution of the drug in the patient's body, the tumor site is exposed to light. Subsequently, toxic reactive oxygen species (ROS) are generated, inducing tumor cell death. To prevent unwanted activation of the drug in other regions of the body, patients have to avoid light during and after the treatment cycles, consequently impairing quality of life. Here, we characterize toxicity and hypericin-mediated effects on cancer cells in vitro and confirm that its effect clearly depends on concentration and illumination time. To reduce side effects and to increase therapy success, selective accumulation of hypericin in the tumor region is a promising solution. Loading hypericin on superparamagnetic iron oxide nanoparticles (SPIONs) and guiding them to the desired place using an external magnetic field might accomplish this task (referred to as Magnetic Drug Targeting (MDT)). Thus, using a double targeting strategy, namely magnetic accumulation and laser induced photoactivation, might improve treatment effectivity as well as specificity and reduce toxic side effects in future clinical applications. PMID- 28661431 TI - Colonization and Maize Growth Promotion Induced by Phosphate Solubilizing Bacterial Isolates. AB - Phosphorus (P) limits the production of maize, one of the major food crops in China. Phosphate-solubilizing bacteria (PSB) have the capacity to solubilize phosphate complexes into plant absorbable and utilizable forms by the process of acidification, chelation, and exchange reactions. In this study, six bacteria, including one Paenibacillus sp. B1 strain, four Pseudomonas sp. strains (B10, B14, SX1, and SX2) and one Sphingobium sp. SX14 strain, were those isolated from the maize rhizosphere and identified based on their 16S rRNA sequences. All strains could solubilize inorganic P (Ca3(PO4)2, FePO4 and AlPO4), and only B1 and B10 organic P (lecithin). All strains, except of SX1, produced IAA, and SX14 and B1 showed the highest level. B1 incited the highest increase in root length and the second increase in shoot and total dry weight, shoot length, and total P and nitrogen (N), along with increased root length. In addition, by confocal laser scanning microscopy (CLSM), we found that green fluorescent protein (GFP) labeled B1 mainly colonized root surfaces and in epidermal and cortical tissue. Importantly, B1 can survive through forming spores under adverse conditions and prolong quality guarantee period of bio-fertilizer. Therefore, it can act as a good substitute for bio-fertilizer to promote agricultural sustainability. PMID- 28661432 TI - Determination of Trace Metal Levels in the General Population of Korea. AB - The purpose of this study was to determine the levels of trace metals in the blood of the general Korean population. A total of 258 healthy individuals, according to their regular medical check-ups, (119 males and 139 females, age ranging from 12 to 78 years old) were enrolled from December 2014 to December 2016. Levels of 10 trace elements were determined using inductively coupled plasma mass spectrometry (ICP-MS). The geometric mean (GM) levels for lead, arsenic, cesium, mercury, aluminum, cadmium, copper, manganese, selenium, and zinc were 15.97 MUg/L, 7.19 MUg/L, 2.39 MUg/L, 3.41 MUg/L, 10.57 MUg/L, 0.78 MUg/L, 979.8 MUg/L, 11.06 MUg/L, 111.37 MUg/L, and 872.7 MUg/L, respectively. There were significant gender-related differences in the levels of several metals; male individuals had higher Pb, As, Cs, Hg, and Se than females, while females had higher Cd, Cu, and Mn than males. We noticed remarkably high blood levels of Hg, As and Al in the Korean population. The element concentrations reported represent a new contribution to the knowledge of the blood chemistry for the Korea population. The data can be used to assess the clinical health of this population. PMID- 28661433 TI - Health-Promoting Nature Access for People with Mobility Impairments: A Systematic Review. AB - This study systematically evaluated the scientific evidence for health benefits of natural environments for people with mobility impairments. Literature searches based on five categories of terms-target group, nature type, health-related impacts, nature-related activities and accessibility issues-were conducted in four databases (Web of Science, Scopus, CAB ABSTRACT and Medline). Twenty-seven articles from 4196 hits were included in the systematic reviews. We concluded that people with mobility disabilities could gain different health benefits, including physical health benefits, mental health benefits and social health benefits from nature in different kinds of nature contacts ranging from passive contact, active involvement to rehabilitative interventions. Several issues related to the accessibility and use of nature for people with mobility impairments need attention from professionals such as landscape architects, rehabilitative therapists, caregivers and policy makers. The overall quality of methodology of the included studies is not high based on assessment of the Mixed Methods Appraisal Tool (MMAT). Moreover, more randomized controlled trials and longitudinal studies that focus specifically on evidence-based health design of nature for people with mobility impairments in the future are needed. PMID- 28661434 TI - Ferulic Acid on Glucose Dysregulation, Dyslipidemia, and Inflammation in Diet Induced Obese Rats: An Integrated Study. AB - Obesity is considered to be a low-grade chronic inflammatory process, which is associated with cardiovascular and metabolic diseases. An integral evaluation of the effects of ferulic acid on biomarkers of glucose dysregulation, dyslipidemia, inflammation, and antioxidant potential induced by a high-fat diet (HFD) in rats was carried out. Three groups of male Wistar rats (six per group) consumed a basal diet (BD), which was supplemented with either lard at 310 g/kg (HFD) or lard and ferulic acid at 2 g/kg (HFD + FA), ad libitum for eight weeks. Body weight gain, hyperplasia, and hypertrophy in abdominal fat tissues were higher in the HFD group than in the HFD+FA group. The rats fed a HFD + FA significantly inhibited the increase in plasma lipids and glucose, compared with the HFD group. Biomarkers associated with inflammation were found at higher concentrations in the serum of rats fed a HFD than the HFD + FA group. Plasma antioxidant levels were lower in HFD rats compared to rats fed the HFD + FA. These results suggest that ferulic acid improves the obesogenic status induced by HFD, and we elucidated the integral effects of ferulic acid on a biological system. PMID- 28661435 TI - Comparable Performance Characteristics of Plasma Thiamine and Erythrocyte Thiamine Diphosphate in Response to Thiamine Fortification in Rural Cambodian Women. AB - Background: Traditionally, vitamin B1 status is assessed by a functional test measuring erythrocyte transketolase (ETK) activity or direct measurement of erythrocyte thiamine diphosphate (eThDP) concentration. However, such analyses are logistically challenging, and do not allow assessment of vitamin B1 status in plasma/serum samples stored in biobanks. Using a multiplex assay, we evaluated plasma concentrations of thiamine and thiamine monophosphate (TMP), as alternative, convenient measures of vitamin B1 status. Methods: We investigated the relationships between the established biomarker eThDP and plasma concentrations of thiamine and TMP, and compared the response of these thiamine forms to thiamine fortification using samples from 196 healthy Cambodian women (aged 18-45 years.). eThDP was measured by high performance liquid chromatography with fluorescence detection (HPLC-FLD) and plasma thiamine and TMP by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Plasma thiamine and TMP correlated significantly with eThDP at baseline and study end (p < 0.05). Among the fortification groups, the strongest response was observed for plasma thiamine (increased by 266%), while increases in plasma TMP (60%) and eThDP (53%) were comparable. Conclusions: Plasma thiamine and TMP correlated positively with eThDP, and all thiamine forms responded significantly to thiamine intervention. Measuring plasma concentrations of thiamine forms is advantageous due to convenient sample handling and capacity to develop low volume, high-throughput, multiplex assays. PMID- 28661436 TI - Occurrence of Regulated Mycotoxins and Other Microbial Metabolites in Dried Cassava Products from Nigeria. AB - Dried cassava products are perceived as one of the potential sources of mycotoxin ingestion in human foods. Processing either contributes to the reduction of toxins or further exposes products to contamination by microorganisms that release metabolic toxins into the products. Thus, the prevalence of microbial metabolites in 373 processed cassava products was investigated in Nigeria. With the use of liquid chromatography tandem-mass spectrometry (LC-MS/MS) for the constituent analysis, a few major mycotoxins (aflatoxin B1 and G1, fumonisin B1 and B2, and zearalenone) regulated in food crops by the Commission of the European Union were found at concentrations which are toxicologically acceptable in many other crops. Some bioactive compounds were detected at low concentrations in the cassava products. Therefore, the exposure of cassava consumers in Nigeria to regulated mycotoxins was estimated to be minimal. The results provide useful information regarding the probable safety of cassava products in Nigeria. PMID- 28661437 TI - A Simple and Fast Procedure to Determine 3-Nitropropanoic Acid and 3 Nitropropanol in Freeze Dried Canadian Milkvetch (Astragalus canadensis). AB - Canadian milkvetch (Astragalus canadensis) is a North American plant species in the legume family and some of this plant is fatally poisonous to livestock. The poisoning is attributed to the natural occurrence of notrotoxins, i.e., 3 nitropropanoic acid and 3-nitropropanol, present as aglycones and conjugated forms in the plant. Those compounds cause nitrite oxidization of hemoglobin and inhibition of cellular metabolism. To determine the toxicity of the plant, it is very important to develop an analytical method for the contents of the compounds in the plant. In this study, we have successfully developed an extraction procedure followed by HPLC-UV analysis to simultaneously analyze notrotoxins. The aglycones could be released from its conjugated forms in the freeze dried plant and extracted by water at room temperature. An HPLC-UV method using a Phenomenex Kinetex 2.6 MU F5 100 A 100 * 4.6 mm column with pH 3.5 phosphonate buffer as mobile phase have been developed and validated for the detection of the two compounds at 210 nm. This developed procedure for the analysis of 3 nitropropanoic acid and 3-nitropropanol has proven simple and efficient and it has been successfully applied for batch sample analysis. PMID- 28661438 TI - Macular Carotenoid Supplementation Improves Visual Performance, Sleep Quality, and Adverse Physical Symptoms in Those with High Screen Time Exposure. AB - The dramatic rise in the use of smartphones, tablets, and laptop computers over the past decade has raised concerns about potentially deleterious health effects of increased "screen time" (ST) and associated short-wavelength (blue) light exposure. We determined baseline associations and effects of 6 months' supplementation with the macular carotenoids (MC) lutein, zeaxanthin, and mesozeaxanthin on the blue-absorbing macular pigment (MP) and measures of sleep quality, visual performance, and physical indicators of excessive ST. Forty-eight healthy young adults with at least 6 h of daily near-field ST exposure participated in this placebo-controlled trial. Visual performance measures included contrast sensitivity, critical flicker fusion, disability glare, and photostress recovery. Physical indicators of excessive screen time and sleep quality were assessed via questionnaire. MP optical density (MPOD) was assessed via heterochromatic flicker photometry. At baseline, MPOD was correlated significantly with all visual performance measures (p < 0.05 for all). MC supplementation (24 mg daily) yielded significant improvement in MPOD, overall sleep quality, headache frequency, eye strain, eye fatigue, and all visual performance measures, versus placebo (p < 0.05 for all). Increased MPOD significantly improves visual performance and, in turn, improves several undesirable physical outcomes associated with excessive ST. The improvement in sleep quality was not directly related to increases in MPOD, and may be due to systemic reduction in oxidative stress and inflammation. PMID- 28661439 TI - Surface Acoustic Wave Sensor with Pd/ZnO Bilayer Structure for Room Temperature Hydrogen Detection. AB - A Surface Acoustic Wave (SAW) hydrogen sensor with a Pd/ZnO bilayer structure for room temperature sensing operation has been obtained by Pulsed Laser Deposition (PLD). The sensor structure combines a Pd layer with optimized porosity for maximizing mass effects, with the large acoustoelectric effect at the Pd/ZnO interface. The large acoustoelectric effect is due to the fact that ZnO has a surface conductivity which is highly sensitive to chemisorbed gases. The sensitivity of the sensor was determined for hydrogen concentrations between 0.2% and 2%. The limit of detection (LOD) of the bilayer sensor was about 4.5 times better than the single ZnO films and almost twice better than single Pd films. PMID- 28661440 TI - Online Recognition of Daily Activities by Color-Depth Sensing and Knowledge Models. AB - Visual activity recognition plays a fundamental role in several research fields as a way to extract semantic meaning of images and videos. Prior work has mostly focused on classification tasks, where a label is given for a video clip. However, real life scenarios require a method to browse a continuous video flow, automatically identify relevant temporal segments and classify them accordingly to target activities. This paper proposes a knowledge-driven event recognition framework to address this problem. The novelty of the method lies in the combination of a constraint-based ontology language for event modeling with robust algorithms to detect, track and re-identify people using color-depth sensing (Kinect(r) sensor). This combination enables to model and recognize longer and more complex events and to incorporate domain knowledge and 3D information into the same models. Moreover, the ontology-driven approach enables human understanding of system decisions and facilitates knowledge transfer across different scenes. The proposed framework is evaluated with real-world recordings of seniors carrying out unscripted, daily activities at hospital observation rooms and nursing homes. Results demonstrated that the proposed framework outperforms state-of-the-art methods in a variety of activities and datasets, and it is robust to variable and low-frame rate recordings. Further work will investigate how to extend the proposed framework with uncertainty management techniques to handle strong occlusion and ambiguous semantics, and how to exploit it to further support medicine on the timely diagnosis of cognitive disorders, such as Alzheimer's disease. PMID- 28661442 TI - Multisensor Parallel Largest Ellipsoid Distributed Data Fusion with Unknown Cross Covariances. AB - As the largest ellipsoid (LE) data fusion algorithm can only be applied to two sensor system, in this contribution, parallel fusion structure is proposed to introduce the LE algorithm into a multisensor system with unknown cross covariances, and three parallel fusion structures based on different estimate pairing methods are presented and analyzed. In order to assess the influence of fusion structure on fusion performance, two fusion performance assessment parameters are defined as Fusion Distance and Fusion Index. Moreover, the formula for calculating the upper bounds of actual fused error covariances of the presented multisensor LE fusers is also provided. Demonstrated with simulation examples, the Fusion Index indicates fuser's actual fused accuracy and its sensitivity to the sensor orders, as well as its robustness to the accuracy of newly added sensors. Compared to the LE fuser with sequential structure, the LE fusers with proposed parallel structures not only significantly improve their properties in these aspects, but also embrace better performances in consistency and computation efficiency. The presented multisensor LE fusers generally have better accuracies than that of covariance intersection (CI) fusion algorithm and are consistent when the local estimates are weakly correlated. PMID- 28661441 TI - Loss of Bone Mineral Density Associated with Age in Male Rats Fed on Sunflower Oil Is Avoided by Virgin Olive Oil Intake or Coenzyme Q Supplementation. AB - The role of dietary fat unsaturation and the supplementation of coenzyme Q have been evaluated in relation to bone health. Male Wistar rats were maintained for 6 or 24 months on two diets varying in the fat source, namely virgin olive oil, rich in monounsaturated fatty acids, or sunflower oil, rich in n-6 polyunsaturated fatty acids. Both dietary fats were supplemented or not with coenzyme Q10 (CoQ10). Bone mineral density (BMD) was evaluated in the femur. Serum levels of osteocalcin, osteopontin, receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), adrenocorticotropin (ACTH) and parathyroid hormone (PTH), as well as urinary F2-isoprostanes were measured. Aged animals fed on virgin olive oil showed higher BMD than those fed on sunflower oil. In addition, CoQ10 prevented the age-related decline in BMD in animals fed on sunflower oil. Urinary F2-isoprostanes analysis showed that sunflower oil led to the highest oxidative status in old animals, which was avoided by supplementation with CoQ10. In conclusion, lifelong feeding on virgin olive oil or the supplementation of sunflower oil on CoQ10 prevented, at least in part mediated by a low oxidative stress status, the age-related decrease in BMD found in sunflower oil fed animals. PMID- 28661443 TI - Effect of Cytomegalovirus (CMV) and Ageing on T-Bet and Eomes Expression on T Cell Subsets. AB - The differential impact of ageing and cytomegalovirus (CMV) latent infection on human T-cell subsets remains to some extent controversial. The purpose of this study was to analyse the expression of the transcription factors T-bet and Eomes and CD57 on CD4+, CD4hiCD8lo and CD8+ T-cell subsets in healthy individuals, stratified by age and CMV serostatus. The percentage of CD4+ T-cells expressing T bet or Eomes was very low, in particular in CD4+ T-cells from young CMV seronegative individuals, and were higher in CMV-seropositive older individuals, in both CD57- and CD57+ CD4+ T-cells. The study of the minor peripheral blood double-positive CD4hiCD8lo T-cells showed that the percentage of these T-cells expressing both Eomes and T-bet was higher compared to CD4+ T-cells. The percentage of CD4hiCD8lo T-cells expressing T-bet was also associated with CMV seropositivity and the coexpression of Eomes, T-bet and CD57 on CD4hiCD8lo T cells was only observed in CMV-seropositive donors, supporting the hypothesis that these cells are mature effector memory cells. The percentage of T-cells expressing Eomes and T-bet was higher in CD8+ T-cells than in CD4+ T-cells. The percentages of CD8+ T-cells expressing Eomes and T-bet increased with age in CMV seronegative and -seropositive individuals and the percentages of CD57- CD8+ and CD57+ CD8+ T-cells coexpressing both transcription factors were similar in the different groups studied. These results support that CMV chronic infection and/or ageing are associated to the expansion of highly differentiated CD4+, CD4hiCD8lo and CD8+ T-cells that differentially express T-bet and Eomes suggesting that the expression of these transcription factors is essential for the generation and development of an effector-memory and effector T lymphocytes involved in conferring protection against chronic CMV infection. PMID- 28661444 TI - Glycosylation of Recombinant Antigenic Proteins from Mycobacterium tuberculosis: In Silico Prediction of Protein Epitopes and Ex Vivo Biological Evaluation of New Semi-Synthetic Glycoconjugates. AB - Tuberculosis is still one of the most deadly infectious diseases worldwide, and the use of conjugated antigens, obtained by combining antigenic oligosaccharides, such as the lipoarabinomannane (LAM), with antigenic proteins from Mycobacterium tuberculosis (MTB), has been proposed as a new strategy for developing efficient vaccines. In this work, we investigated the effect of the chemical glycosylation on two recombinant MTB proteins produced in E. coli with an additional seven amino acid tag (recombinant Ag85B and TB10.4). Different semi-synthetic glycoconjugated derivatives were prepared, starting from mannose and two disaccharide analogs. The glycans were activated at the anomeric position with a thiocyanomethyl group, as required for protein glycosylation by selective reaction with lysines. The glycosylation sites and the ex vivo evaluation of the immunogenic activity of the different neo-glycoproteins were investigated. Glycosylation does not modify the immunological activity of the TB10.4 protein. Similarly, Ag85B maintains its B-cell activity after glycosylation while showing a significant reduction in the T-cell response. The results were correlated with the putative B- and T-cell epitopes, predicted using a combination of in silico systems. In the recombinant TB10.4, the unique lysine is not included in any T cell epitope. Lys30 of Ag85B, identified as the main glycosylation site, proved to be the most important site involved in the formation of T-cell epitopes, reasonably explaining why its glycosylation strongly influenced the T-cell activity. Furthermore, additional lysines included in different epitopes (Lys103, -123 and -282) are also glycosylated. In contrast, B-cell epitopic lysines of Ag85B were found to be poorly glycosylated and, thus, the antibody interaction of Ag85B was only marginally affected after coupling with mono- or disaccharides. PMID- 28661445 TI - Thermal Stability of Phase-Separated Domains in Multicomponent Lipid Membranes with Local Anesthetics. AB - The functional mechanisms of local anesthetics (LAs) have not yet been fully explained, despite their importance in modern medicine. Recently, an indirect interaction between channel proteins and LAs was proposed as follows: LAs alter the physical properties of lipid membranes, thus affecting the channel proteins. To examine this hypothesis, we investigated changes in thermal stability in lipid membranes consisting of dioleoylphosphocholine, dipalmitoylphosphocholine, and cholesterol by adding the LAs, lidocaine and tetracaine. The miscibility temperature of liquid-ordered (Lo) and liquid-disordered (Ld) phase separation was lowered, whereas that of phase separation between solid-ordered (So) and Ld phases was unchanged by LAs. Furthermore, we measured the line tension at the Lo/Ld interface from domain boundary fluctuation and found that it was significantly decreased by LAs. Finally, differential scanning calorimetry (DSC) revealed a change in the lipid main transition temperature on the addition of LAs. Based on the DSC measurements, we considered that LAs are partitioned into two coexisting phases. PMID- 28661446 TI - Olive Polyphenols and the Metabolic Syndrome. AB - Here, the effects of consuming polyphenol-rich olive products, including olive leaves, their crude extract, and extra virgin olive oil, on aspects of the metabolic syndrome are reviewed. We have sought to summarize the available scientific evidence from dietary intervention trials demonstrating a role for these phytochemicals in ameliorating aberrant glucose metabolism, high blood pressure and elevated blood lipids, and we discuss the potential mechanisms underpinning these observations. Searches for relevant literature published in English were conducted via PubMed and Science Direct. Based on published dietary intervention studies, there is convincing evidence to show that olive polyphenols, independently of olive lipids, reduce risk factors for metabolic syndrome, in particular by improving blood sugar and blood pressure control, and in reducing low density lipoprotein oxidation. There is more limited evidence to suggest that the consumption of olive polyphenols or related products can reduce body weight and visceral fat or impede weight gain, and similarly there are some limited data suggesting improved lipid profiles. There is some mechanistic data to support observations made in human volunteers, but further work is needed in this area. The consumption of olive polyphenols within the context of a healthy pattern of food intake may, in part, explain the reduced risk of metabolic disease associated with adherence to the Mediterranean diet. PMID- 28661447 TI - Biooxidation of Ciguatoxins Leads to Species-Specific Toxin Profiles. AB - Ciguatoxins (CTXs) contaminate fish worldwide and cause the foodborne illness ciguatera. In the Pacific, these toxins are produced by the dinoflagellate Gambierdiscus toxicus, which accumulates in fish through the food chain and undergoes oxidative modification, giving rise to numerous analogs. In this study, we examined the oxidation of CTXs in vitro with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using reference toxins, and found that CTX4A, CTX4B, and CTX3C, which are produced by the alga, are oxidized to the analogs found in fish, namely CTX1B, 52-epi-54-deoxyCTX1B, 54-deoxyCTX1B, 2-hydroxyCTX3C, and 2,3-dihydroxyCTX3C. This oxidation was catalyzed by human CYP3A4, fish liver S9 fractions, and microsomal fractions prepared from representative ciguateric fishes (Lutjanus bohar, L. monostigumus, and Oplegnathus punctatus). In addition, fish liver S9 fractions prepared from non-ciguateric fishes (L. gibbus and L. fulviflamma) in Okinawa also converted CTX4A and CTX4B to CTX1B, 54-deoxyCTX1B, and 52-epi-54-deoxyCTX1B in vitro. This is the first study to demonstrate the enzymatic oxidation of these toxins, and provides insight into the mechanism underlying the development of species-specific toxin profiles and the fate of these toxins in humans and fish. PMID- 28661448 TI - The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment. AB - Humans with the C5 genetic variant of butyrylcholinesterase (BChE) have 30-200% higher plasma BChE activity, low body weight, and shorter duration of action of the muscle relaxant succinylcholine. The C5 variant has an extra, slow-moving band of BChE activity on native polyacrylamide gel electrophoresis. This band is about 60 kDa larger than wild-type BChE. Umbilical cord BChE in 100% of newborn babies has a C5-like band. Our goal was to identify the unknown, 60 kDa protein in C5. Both wild-type and C5 BChE are under the genetic control of two independent loci, the BCHE gene on Chr 3q26.1 and the RAPH1 (lamellipodin) gene on Chr 2q33. Wild-type BChE tetramers are assembled around a 3 kDa polyproline peptide from lamellipodin. Western blot of boiled C5 and cord BChE showed a positive response with an antibody to the C-terminus of lamellipodin. The C terminal exon of lamellipodin is about 60 kDa including an N-terminal polyproline. We propose that the unknown protein in C5 and cord BChE is encoded by the last exon of the RAPH1 gene. In 90% of the population, the 60 kDa fragment is shortened to 3 kDa during maturation to adulthood, leaving only 10% of adults with C5 BChE. PMID- 28661449 TI - Comparative Analysis of Saponins from Different Phytolaccaceae Species and Their Antiproliferative Activities. AB - The quality and the efficacy of herbal medicine are of great concern especially with the increase in their global use. Medicinal plants of different species or collected from different geographical regions have shown variations in both their contents and pharmacological activities due to the differences in the environmental conditions of the collected sites. In this study, roots of Phytolacca acinosa found in different provinces in south China (Sichuan and Shandong) and a species of Phytolacca americana were investigated. To ensure a maximum yield of the major compounds, the extraction method and conditions were optimized. The preeminent method of extraction in this analysis was determined to be the ultrasound-assisted method with specific conditions as follows: ethanol H2O (1:1, v/v), with a solvent: sample ratio of 1:8, and extraction was performed 3 times, each for 30 min. Under these conditions, samples from the different regions varied both in quantity and quality via the LC-MS analysis. A total of 60 triterpenoid saponins were detected within the three samples, among which 22 were identified as common in the three samples. The amounts of these common triterpenoid saponin identified varied across the samples. Moreover, the analysis led to the detection of some novel compounds that have not yet been reported in this family, while other compounds differ in their fragmentation pathways compared to previous literature. To further divulge the correlations between the bioactivities in these three samples and the quantity and quality of their bioactive components, a cytotoxic analysis was thus carried out with two cancer cell lines, and SGC-7901 and Hep G2, which evidently showed remarkable differences in their anti-proliferative activities with respect to the IC50 value. Samples of P. acinosa from Sichuan showed higher values in both cell lines (27.20 +/- 1.60 and 25.59 +/- 1.63 ug/mL) compared to those of Shandong and P. americana. For the first time, analysis and comparison of both interspecies and of different species in this family were carried out. This study will significantly contribute to the quality insurance of herbal medicine, especially in the Phytolaccaceae family. PMID- 28661451 TI - Isobenzofuranones and Isochromenones from the Deep-Sea Derived Fungus Leptosphaeria sp. SCSIO 41005. AB - Four new isobenzofuranones, leptosphaerins J-M (1-4), including an unusual naturally-occurring centrosymmetric dimer skeleton (1), and two new isochromenones, clearanols I-J (9-10), were obtained from a culture of a deep-sea sediment-derived fungus Leptosphaeria sp. SCSIO 41005, together with four known isobenzofuranones (5-8) and six known isochromenones (11-16). These structures were elucidated by extensive spectroscopic analyses, and absolute configurations were assigned on the basis of electronic circular dichroism and optical rotations data comparison. Additionally, the absolute configurations of the new compounds 1 and 9, together with the known one 7 with stereochemistry undetermined, were further confirmed by single crystal X-ray diffraction experiments. A plausible biosynthetic pathway of these isobenzofuranones and isochromenones was also proposed. PMID- 28661450 TI - Functional Amyloids in Reproduction. AB - Amyloids are traditionally considered pathological protein aggregates that play causative roles in neurodegenerative disease, diabetes and prionopathies. However, increasing evidence indicates that in many biological systems nonpathological amyloids are formed for functional purposes. In this review, we will specifically describe amyloids that carry out biological roles in sexual reproduction including the processes of gametogenesis, germline specification, sperm maturation and fertilization. Several of these functional amyloids are evolutionarily conserved across several taxa, including human, emphasizing the critical role amyloids perform in reproduction. Evidence will also be presented suggesting that, if altered, some functional amyloids may become pathological. PMID- 28661452 TI - Synthesis and In Vitro Anticancer Activity of Novel Dehydroabietic Acid-Based Acylhydrazones. AB - In order to develop novel chemotherapeutic agents with potent anticancer activities, a series of dehydroabietic acid (DHA) derivatives bearing an acylhydrazone moiety were designed and synthesized by the condensation between dehydroabietic acylhydrazide (3) and a variety of substituted arylaldehydes. The inhibitory activities of these compounds against CNE-2 (nasopharynx), HepG2 (liver), HeLa (epithelial cervical), and BEL-7402 (liver) human carcinoma cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The screening results revealed that many of the compounds showed moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed similar potent inhibitory activities to the commercial anticancer drug cisplatin, while they exhibited lower cytotoxicity against normal human liver cell (HL-7702). Particularly, compound 4w, N'-(3,5-difluorobenzylidene)-2-(dehydroabietyloxy)acetohydrazide, with an IC50 (50% inhibitory concentration) value of 2.21 MUM against HeLa cell, was about 17-fold more active than that of the parent compound, and showed remarkable cytotoxicity with an IC50 value of 14.46 MUM against BEL-7402 cell. These results provide an encouraging framework that could lead to the development of potent novel anticancer agents. PMID- 28661453 TI - LXRalpha Regulates Hepatic ChREBPalpha Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice. AB - Liver X receptors (LXRalpha/beta) and carbohydrate response element-binding proteins (ChREBPalpha/beta) are key players in the transcriptional control of hepatic de novo lipogenesis. LXRalpha/beta double knockout (LXRalpha-/-/beta-/-) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBPalpha activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthesis. However, the role of LXRs in fructose-induced ChREBP activation and lipogenesis is currently unknown. In this study, we studied the effects of high fructose or high glucose feeding on hepatic carbohydrate metabolism and lipogenic gene expression in livers from fasted (24 h) and fasted-refed (12 h) wild type and LXRalpha knockout (LXRalpha-/-) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXRalpha-/- mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebpbeta, indicating reduced ChREBPalpha activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXRalpha-/- mice, concomitant with increased glucose-6 phosphatase (G6pc) expression and O-GlcNAc modified LXRbeta, suggesting a role for LXRbeta in regulating ChREBPalpha activity upon fructose feeding. In conclusion, we propose that LXRalpha is an important regulator of hepatic lipogenesis and ChREBPalpha activity upon glucose, but not fructose feeding in mice. PMID- 28661454 TI - Chlorogenic Acid Ameliorates Experimental Colitis by Promoting Growth of Akkermansia in Mice. AB - Chlorogenic acid (ChA)-one of the most abundant polyphenol compounds in the human diet-exerts anti-inflammatory activities. The aim of this study was to investigate the effect of ChA on gut microbiota in ulcerative colitis (UC). Colitis was induced by 2.5% dextran sulfate sodium (DSS) in C57BL/6 mice, which were on a control diet or diet with ChA (1 mM). The histopathological changes and inflammation were evaluated. Fecal samples were analyzed by 16S rRNA gene sequencing. ChA attenuated several effects of DSS-induced colitis, including weight loss, increased disease activity index, and improved mucosal damage. Moreover, ChA could significantly suppress the secretion of IFNgamma, TNFalpha, and IL-6 and the colonic infiltration of F4/80+ macrophages, CD3+ T cells, and CD177+ neutrophils via inhibition of the active NF-kappaB signaling pathway. In addition, ChA decreased the proportion of Firmicutes and Bacteroidetes. ChA also enhanced a reduction in fecal microbiota diversity in DSS treated mice. Interestingly, ChA treatment markedly increased the proportion of the mucin degrading bacterium Akkermansia in colitis mice. ChA acted as the intestine modifying gut microbial community structure, resulting in a lower intestinal and systemic inflammation and also improving the course of the DSS-induced colitis, which is associated with a proportional increase in Akkermansia. PMID- 28661455 TI - Water-soluble Manganese and Iron Mesotetrakis(carboxyl)porphyrin: DNA Binding, Oxidative Cleavage, and Cytotoxic Activities. AB - Two new water-soluble metal carboxyl porphyrins, manganese (III) meso-tetrakis (carboxyl) porphyrin and iron (III) meso-tetrakis (carboxyl) porphyrin, were synthesized and characterized. Their interactions with ct-DNA were investigated by UV-Vis titration, fluorescence spectra, viscosity measurement and CD spectra. The results showed they can strongly bind to ct-DNA via outside binding mode. Electrophoresis experiments revealed that both complexes can cleave pBR322 DNA efficiently in the presence of hydrogen peroxide, albeit 2-Mn exhibited a little higher efficiency. The inhibitor tests suggest the oxidative DNA cleavage by these two complexes may involve hydroxyl radical active intermediates. Notably, 2 Mn exhibited considerable photocytotoxicity against Hep G2 cell via triggering a significant generation of ROS and causing disruption of MMP after irradiation. PMID- 28661457 TI - Antibacterial Activity of AI-Hemocidin 2, a Novel N-Terminal Peptide of Hemoglobin Purified from Arca inflata. AB - The continued emergence of antibiotic resistant bacteria in recent years is of great concern. The search for new classes of antibacterial agents has expanded to non-traditional sources such as shellfish. An antibacterial subunit of hemoglobin (Hb-I) was purified from the mantle of Arcainflata by phosphate extraction and ion exchange chromatography. A novel antibacterial peptide, AI-hemocidin 2, derived from Hb-I, was discovered using bioinformatics analysis. It displayed antibacterial activity across a broad spectrum of microorganisms, including several Gram-positive and Gram-negative bacteria, with minimal inhibitory concentration (MIC) values ranging from 37.5 to 300 MUg/mL, and it exhibited minimal hemolytic or cytotoxic activities. The antibacterial activity of AI hemocidin 2 was thermostable (25-100 degrees C) and pH resistant (pH 3-10). The cellular integrity was determined by flow cytometry. AI-hemocidin 2 was capable of permeating the cellular membrane. Changes in the cell morphology were observed with a scanning electron microscope. Circular dichroism spectra suggested that AI hemocidin 2 formed an alpha-helix structure in the membrane mimetic environment. The results indicated that the anti-bacterial mechanism for AI-hemocidin 2 occurred through disrupting the cell membrane. AI-hemocidin 2 might be a potential candidate for tackling antibiotic resistant bacteria. PMID- 28661456 TI - Dry Eye Management: Targeting the Ocular Surface Microenvironment. AB - Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment. PMID- 28661458 TI - Adipokines in Liver Cirrhosis. AB - Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively. PMID- 28661459 TI - Macrophages and Phospholipases at the Intersection between Inflammation and the Pathogenesis of HIV-1 Infection. AB - Persistent low grade immune activation and chronic inflammation are nowadays considered main driving forces of the progressive immunologic failure in effective antiretroviral therapy treated HIV-1 infected individuals. Among the factors contributing to this phenomenon, microbial translocation has emerged as a key driver of persistent immune activation. Indeed, the rapid depletion of gastrointestinal CD4+ T lymphocytes occurring during the early phases of infection leads to a deterioration of the gut epithelium followed by the translocation of microbial products into the systemic circulation and the subsequent activation of innate immunity. In this context, monocytes/macrophages are increasingly recognized as an important source of inflammation, linked to HIV 1 disease progression and to non-AIDS complications, such as cardiovascular disease and neurocognitive decline, which are currently main challenges in treated patients. Lipid signaling plays a central role in modulating monocyte/macrophage activation, immune functions and inflammatory responses. Phospholipase-mediated phospholipid hydrolysis leads to the production of lipid mediators or second messengers that affect signal transduction, thus regulating a variety of physiologic and pathophysiologic processes. In this review, we discuss the contribution of phospholipases to monocyte/macrophage activation in the context of HIV-1 infection, focusing on their involvement in virus-associated chronic inflammation and co-morbidities. PMID- 28661460 TI - The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo. AB - Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4 yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP 1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-kappaB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-alpha and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis. PMID- 28661461 TI - Validity and Reproducibility of the Iodine Dietary Intake Questionnaire Assessment Conducted for Young Polish Women. AB - The aim of this study was to analyse a designed brief iodine dietary intake questionnaire based on a food frequency assessment (IOdine Dietary INtake Evaluation-Food Frequency Questionnaire-IODINE-FFQ), including the assessment of validity and reproducibility in a group of 90 Polish women aged 20-35 years. Participants collected 3-day dietary records and filled in the IODINE-FFQ twice (FFQ1-directly after the dietary record and FFQ2-6 weeks later). The analysis included an assessment of validity (comparison with the results of the 3-day dietary record) and of reproducibility (comparison of the results obtained twice FFQ1 and FFQ2). In the analysis of validity, a Bland-Altman index of 5.5% and 4.4% was recorded, respectively for FFQ1 and FFQ2. In the analysis of reproducibility it was 6.7%, but the share of individuals correctly classified into tertiles was over 70% (weighted kappa of 0.675). It was stated, that assessment of IODINE-FFQ revealed a satisfactory level of validity and reproducibility in the analysis of Bland-Alman plot. The IODINE-FFQ may be indicated as a tool for the assessment of iodine intake in the young women in Poland, however further studies should be considered in order to obtain the practical tool for public health specialists. Due to the lack of validated iodine specific food frequency questionnaires for countries of Eastern Europe, the IODINE-FFQ may be adjusted for courtiers other than Poland including iodine fortified products. PMID- 28661462 TI - Alcohol Marketing during the UEFA EURO 2016 Football Tournament: A Frequency Analysis. AB - This study examined the frequency and nature of alcohol marketing references in broadcasts of the 2016 UEFA (Union of European Football Associations) European Championships football tournament in the United Kingdom (UK). Eighteen matches from across the tournament were recorded in full as broadcast in the UK, including all four matches featuring the English national team and all seven featuring the French national team. All visual and verbal references to alcohol marketing were recorded using a tool with high inter-rater reliability. A total of 2213 alcohol marketing references were recorded, an average of 122.94 per broadcast and 0.65 per broadcast minute (0.52 per minute in-play and 0.80 per minute out-of-play). Almost all references were visual (97.5%), with 77.9% occurring around the pitch border. Almost all (90.6%) were indirect references to alcohol brands (e.g., references to well-known slogans), compared to only 9.4% direct references to brands (e.g., brand names). The frequency of references to alcohol marketing was high. Although the overall proportion of direct brand references was low, the high proportion of indirect references demonstrates that alcohol producers were able to circumvent the French national law governing alcohol marketing (the Loi Evin) using indirect "alibi marketing". To ensure the spirit of the Loi Evin regulations are achieved, stricter enforcement may be required to limit exposure to alcohol marketing, particularly for young people. PMID- 28661464 TI - Road Environments: Impact of Metals on Human Health in Heavily Congested Cities of Poland. AB - Road dust as a by-product of exhaust and non-exhaust emissions can be a major cause of systemic oxidative stress and multiple disorders. Substantial amounts of road dust are repeatedly resuspended, in particular at traffic lights and junctions where more braking is involved, causing potential threat to pedestrians, especially children. In order to determine the degree of contamination in the heavily traffic-congested cities of Poland, a total of 148 samples of road dust (RD), sludge from storm drains (SL) and roadside soil (RS) were collected. Sixteen metals were analysed using inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma atomic emission spectroscopy (ICP-OES) and atomic absorption spectroscopy (AAS) in all samples. Chemical evaluation followed by Principal Component Analysis (PCA) revealed that road environments have been severely contaminated with traffic-related elements. Concentration of copper in all road-environment samples is even higher, exceeding even up to 15 times its average concentrations established for the surrounding soils. Non-carcinogenic health risk assessment revealed that the hazard index (HI) for children in all road-environment samples exceeds the safe level of 1. Therefore, greater attention should be paid to potential health risks caused by the ingestion of traffic-related particles during outdoor activities. PMID- 28661463 TI - Nutrition Transition and Biocultural Determinants of Obesity among Cameroonian Migrants in Urban Cameroon and France. AB - Native of rural West Cameroon, the Bamileke population is traditionally predisposed to obesity. Bamileke who migrated to urban areas additionally experience the nutrition transition. We investigated the biocultural determinants of obesity in Bamileke who migrated to urban Cameroon (Yaounde), or urban France (Paris). We conducted qualitative interviews (n = 36; 18 men) and a quantitative survey (n = 627; 266 men) of adults using two-stage sampling strategy, to determine the association of dietary intake, physical activity and body weight norms with obesity of Bamileke populations in these three socio-ecological areas (rural Cameroon: n = 258; urban Cameroon: n = 319; urban France: n = 50). The Bamileke valued overweight and traditional energy-dense diets in rural and urban Cameroon. Physical activity levels were lower, consumption of processed energy dense food was frequent and obesity levels higher in new migrants living in urban Cameroon and France. Female sex, age, duration of residence in urban areas, lower physical activity and valorisation of overweight were independently associated with obesity status. This work argues in favour of local and global health policies that account for the origin and the migration trajectories to prevent obesity in migrants. PMID- 28661465 TI - Antibiotic Resistance and Antibiotic Resistance Genes in Escherichia coli Isolates from Hospital Wastewater in Vietnam. AB - The environmental spread of antibiotic-resistant bacteria has been recognised as a growing public health threat for which hospitals play a significant role. The aims of this study were to investigate the prevalence of antibiotic resistance and antibiotic resistance genes (ARGs) in Escherichia coli isolates from hospital wastewater in Vietnam. Wastewater samples before and after treatment were collected using continuous sampling every month over a year. Standard disk diffusion and E-test were used for antibiotic susceptibility testing. Extended spectrum beta-lactamase (ESBL) production was tested using combined disk diffusion. ARGs were detected by polymerase chain reactions. Resistance to at least one antibiotic was detected in 83% of isolates; multidrug resistance was found in 32%. The highest resistance prevalence was found for co-trimoxazole (70%) and the lowest for imipenem (1%). Forty-three percent of isolates were ESBL producing, with the blaTEM gene being more common than blaCTX-M. Co-harbouring of the blaCTX-M, blaTEM and qepA genes was found in 46% of isolates resistant to ciprofloxacin. The large presence of antibiotic-resistant E. coli isolates combined with ARGs in hospital wastewater, even post-treatment, poses a threat to public health. It highlights the need to develop effective processes for hospital wastewater treatment plants to eliminate antibiotic resistant bacteria and ARGs. PMID- 28661466 TI - An All-Nanocrystal Biosensing System for In Vitro Detection of STAT3 Oligonucleotides. AB - Lanthanide-doped nanocrystals have shown great promise in bio-detection due to their outstanding luminescent properties, including large Stokes shift and sharp emission bands. Herein, we describe an in vitro detection of STAT3 by using an all-nanocrystal biosensing system that takes advantage of inter-particle energy transfer between two types of lanthanide-doped nanocrystals. We investigate the effect of nanocrystal size on the sensing performance and find that smaller nanocrystals offer a lower detection limit and larger dynamic range. As STAT3 is identified as an oncogene aberrantly activated and expressed in malignant transformation and tumorigenesis, our study thus holds promise for cancer diagnosis and therapy. PMID- 28661467 TI - Early and Late Induction of KRAS and HRAS Proto-Oncogenes by Reactive Oxygen Species in Primary Astrocytes. AB - Astrocytes, one of the predominant types of glial cells, function as both supportive and metabolic cells for the brain. Among mammalian tissues, the highest levels of p21Ras protein are detected in the brain. Here, we investigated the expression of KRAS and HRAS proto-oncogenes in primary astrocytes following acute oxidative stimulation. Reactive oxygen species (ROS) changed the expression of proto-oncogenes at both transcriptional and translational levels. De novo protein synthesis analysis measured approximate values of proteins half-life, ranging from 1-4 h, of the different H- and K- isoforms by western blot analysis. Quantitative gene expression analysis of KRAS and HRAS revealed an unexpected short-term induction of KRAS mRNA in primary astrocytes in response to acute stimulation. Indeed, cultured astrocytes responded to proteasomal inhibition by preventing the reduction of c-K-Ras. A fraction of K-Ras protein accumulated in the presence of ROS and cycloheximide, while a substantial proportion was continuously synthesized. These data indicate that ROS regulate in a complementary fashion p21Ras isoforms in primary astrocytes: K-Ras is rapidly and transiently induced by post-translational and post-transcriptional mechanisms, while H-Ras is stably induced by mRNA accumulation. We suggest that K-Ras and H Ras are ROS sensors that adapt cells to metabolic needs and oxidative stress. PMID- 28661468 TI - Study on the Association among Mycotoxins and other Variables in Children with Autism. AB - Environmental factors and genetic susceptibility are implicated in the increased risk of autism spectrum disorder (ASD). Mycotoxins are agricultural contaminants of fungal origin that represent real risk factors for human health and especially for children. Thus, the main hypothesis of this work is that the deterioration of the clinical manifestation of autism in children may result from the exposure to mycotoxins through the consumption of contaminated food. Within a cross-sectional study, a group of autistic children (n = 172) and a group of controls (n = 61) (siblings and non-parental) were recruited in North and South Italy. All children had blood and urine samples taken, for testing some mycotoxins by a LC-MS/MS validated method. Blood samples were also tested for assessing specific IgG against food and fungal antigens and cytokines. The analyses outputs highlighted statistically significant differences comparing mycotoxins levels between (i) children groups both in urine (deoxynivalenol and de-epoxydeoxynivalenol, p = 0.0141 and p = 0.0259, respectively) and serum (aflatoxin M1, ochratoxin A and fumonisin B1, p = 0.0072, p = 0.0141 and p = 0.0061, respectively); (ii) a group of selected fungal IgGs, and IgGs against wheat and gluten and (iii) cytokines. These results suggest the need for a deeper examination of the role that mycotoxins may have on the etiology of ASD. PMID- 28661469 TI - Systemic Propagation of a Fluorescent Infectious Clone of a Polerovirus Following Inoculation by Agrobacteria and Aphids. AB - A fluorescent viral clone of the polerovirus Turnip yellows virus (TuYV) was engineered by introducing the Enhanced Green Fluorescent Protein (EGFP) sequence into the non-structural domain sequence of the readthrough protein, a minor capsid protein. The resulting recombinant virus, referred to as TuYV-RTGFP, was infectious in several plant species when delivered by agroinoculation and invaded efficiently non-inoculated leaves. As expected for poleroviruses, which infect only phloem cells, the fluorescence emitted by TuYV-RTGFP was restricted to the vasculature of infected plants. In addition, TuYV-RTGFP was aphid transmissible and enabled the observation of the initial sites of infection in the phloem after aphid probing in epidermal cells. The aphid-transmitted virus moved efficiently to leaves distant from the inoculation sites and importantly retained the EGFP sequence in the viral genome. This work reports on the first engineered member in the Luteoviridae family that can be visualized by fluorescence emission in systemic leaves of different plant species after agroinoculation or aphid transmission. PMID- 28661470 TI - Rotavirus Genomic RNA Complex Forms via Specific RNA-RNA Interactions: Disruption of RNA Complex Inhibits Virus Infectivity. AB - Rotavirus (RV), a member of the Reoviridae family, causes infection in children and infants, with high morbidity and mortality. To be viable, the virus particle must package a set of eleven RNA segments. In order to understand the packaging mechanism, here, we co-synthesized sets of RNA segments in vitro in different combinations and detected by two alternate methods: the electrophoretic mobility shift assay (EMSA) and the RNA-bead pull-down assay. We showed that viral positive-sense RNA segments interact with each other in a specific manner, forming RNA complexes, and that the RNA-RNA interactions followed a sequential order initiated by small RV segments. Further, we demonstrated that RNA complexes were perturbed by targeted specific antisense oligoribonucleotides (ORNs) complementary to short RNA sequences, indicating that the RNA-RNA interactions between different segments were sequence-specific. The same inhibitory ORNs also had the capability to inhibit virus replication. The combined in vitro and in vivo data inferred that RNA-RNA interactions and specific complex formation are essential for sorting different segments, possibly prior to, or during, genome packaging. As genome assembly is a universal requirement in the Reoviridae family, this work offers an approach towards a further understanding of the sorting and packaging mechanisms of RV and related dsRNA (double-stranded RNA) viruses. PMID- 28661471 TI - Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry Method Coupled with Dispersive Solid-Phase Extraction for Simultaneous Quantification of Eight Paralytic Shellfish Poisoning Toxins in Shellfish. AB - In this study, a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for simultaneous determination of eight paralytic shellfish poisoning (PSP) toxins, including saxitoxin (STX), neosaxitoxin (NEO), gonyautoxins (GTX1-4) and the N-sulfo carbamoyl toxins C1 and C2, in sea shellfish. The samples were extracted by acetonitrile/water (80:20, v/v) with 0.1% formic and purified by dispersive solid-phase extraction (dSPE) with C18 silica and acidic alumina. Qualitative and quantitative detection for the target toxins were conducted under the multiple reaction monitoring (MRM) mode by using the positive electrospray ionization (ESI) mode after chromatographic separation on a TSK-gel Amide-80 HILIC column with water and acetonitrile. Matrix-matched calibration was used to compensate for matrix effects. The established method was further validated by determining the linearity (R2 >= 0.9900), average recovery (81.52-116.50%), sensitivity (limits of detection (LODs): 0.33-5.52 MUg.kg-1; limits of quantitation (LOQs): 1.32 11.29 MUg.kg-1) and precision (relative standard deviation (RSD) <= 19.10%). The application of this proposed approach to thirty shellfish samples proved its desirable performance and sufficient capability for simultaneous determination of multiclass PSP toxins in sea foods. PMID- 28661472 TI - Genes versus Environment: cytoplasmic BAP1 determines the toxic response to environmental stressors in mesothelioma. PMID- 28661473 TI - Autophagy fails to prevent glucose deprivation/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons. AB - Autophagy is triggered during nutrient and energy deprivation in a variety of cells as a homeostatic response to metabolic stress. In the CNS, deficient autophagy has been implicated in neurodegenerative diseases and ischemic brain injury. However, its role in hypoglycemic damage is poorly understood and the dynamics of autophagy during the hypoglycemic and the glucose reperfusion periods, has not been fully described. In the present study, we analyzed the changes in the content of the autophagy proteins BECN1, LC3-II and p62/SQSTM1 by western blot, and autophagosome formation was followed through time-lapse experiments, during glucose deprivation (GD) and glucose reintroduction (GR) in cortical cultures. According to the results, autophagosome formation rapidly increased during GD, and was followed by an active autophagic flux early after glucose replenishment. However, cells progressively died during GR and autophagy inhibition reduced neuronal death. Neurons undergoing apoptosis during GR did not form autophagosomes, while those surviving up to late GR showed autophagosomes. Calpain activity strongly increased during GR and remained elevated during progressive neuronal death. Its activation led to the cleavage of LAMP2 resulting in lysosome membrane permeabilization (LMP) and release of cathepsin B to the cytosol. Calpain inhibition prevented LMP and increased the number of neurons containing lysosomes and autophagosomes increasing cell viability. Taken together, the present results suggest that calpain-mediated lysosome dysfunction during GR turns an adaptive autophagy response to energy stress into a defective autophagy pathway, which contributes to neuronal death. In these conditions, autophagy inhibition results in the improvement of cell survival. PMID- 28661474 TI - Mutant p53 dictates the oncogenic activity of c-Abl in triple-negative breast cancers. AB - We recently established c-Abl as a potent suppressor of triple-negative breast cancer (TNBC) progression through its reactivation of a p53:p21 signaling axis coupled to senescence. Moreover, we observed co-expression of p53 and c-Abl to be essential for normal mammary epithelial cell physiology, as this relationship is lost upon breast cancer progression. Cytoplasmic c-Abl activity is markedly increased in some TNBCs and contributes to disease progression; however, the mechanisms underlying these events remain largely unknown. In addressing this question, we show here that c-Abl is predominantly restricted to the cytoplasm of human MDA-MB-231 TNBC cells, and to the nucleus of human MCF-7 luminal A cells. TTK is a mitotic protein kinase that phosphorylates c-Abl on Thr735, thereby creating a recognition binding motif for 14-3-3 adaptor proteins in response to oxidative stress. By interrogating the METABRIC database, we observed a significant correlation between p53 expression and that of c-Abl and TTK in basal like breast cancers. Moreover, heterologous expression of TTK in MCF-7 cells significantly stimulated their growth in part via a c-Abl-dependent mechanism. Conversely, depleting TTK expression in MDA-MB-231 cells not only inhibited their organoid growth in 3D-cultures, but also sensitized them to the tumor suppressing activities of c-Abl independent of its subcellular localization. Moreover, we show that mutant p53 forms cytoplasmic complexes with c-Abl, thereby dictating the subcellular localization of c-Abl and the sensitivity of MDA-MB-231 cells to Imatinib. In response to nutrient deprivation, c-Abl:p53 complexes readily accumulate in the nucleus, resulting in the hyperactivation of c-Abl and initiation of its anti-tumor activities. Collectively, we identified a novel mutant p53:c-Abl cytoplasmic signaling complex that promotes MDA-MB-231 cell growth and highlights the contextual cues that confer oncogenic activity to c-Abl in breast cancer. PMID- 28661476 TI - Ubiquitin-dependent regulation of Cdc42 by XIAP. AB - Rho GTPases control fundamental cellular processes and Cdc42 is a well-studied member of the family that controls filopodia formation and cell migration. Although the regulation of Cdc42 activity by nucleotide binding is well documented, the mechanisms driving its proteostasis are not clear. Here, we demonstrate that the highly conserved, RING domain containing E3 ubiquitin ligase XIAP controls the protein stability of Cdc42. XIAP binds to Cdc42 and directly conjugates poly ubiquitin chains to the Lysine 166 of Cdc42 targeting it for proteasomal degradation. Depletion of XIAP led to an increased protein stability and activity of Cdc42 in normal and tumor cells. Consistently, loss of XIAP enhances filopodia formation in a Cdc42-dependent manner and this phenomenon phenocopies EGF stimulation. Further, XIAP depletion promotes lung colonization of tumor cells in mice in a Cdc42-dependent manner. These observations shed molecular insights into ubiquitin-dependent regulation of Cdc42 and that of actin cytoskeleton. PMID- 28661475 TI - Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis. AB - Chemotherapy-induced thrombocytopenia is a common bleeding risk in cancer patients and limits chemotherapy dose and frequency. Recent data from mouse and human platelets revealed that activation of protein kinase A/G (PKA/PKG) not only inhibited thrombin/convulxin-induced platelet activation but also prevented the platelet pro-coagulant state. Here we investigated whether or not PKA/PKG activation could attenuate caspase-dependent apoptosis induced by the anti-cancer drugs ABT-737 (the precursor of navitoclax) and thymoquinone (TQ), thereby potentially limiting chemotherapy-induced thrombocytopenia. This is particularly relevant as activation of cyclic nucleotide signalling in combination chemotherapy is an emerging strategy in cancer treatment. However, PKA/PKG activation, as monitored by phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), did not block caspase-3-dependent platelet apoptosis induced by the compounds. In contrast, both substances induced PKA activation themselves and PKA activation correlated with platelet inhibition and apoptosis. Surprisingly, ABT-737- and TQ-induced VASP-phosphorylation was independent of cAMP levels and neither cyclases nor phosphatases were affected by the drugs. In contrast, however, ABT-737- and TQ-induced PKA activation was blocked by caspase 3 inhibitors. In conclusion, we show that ABT-737 and TQ activate PKA in a caspase-3-dependent manner, which correlates with platelet inhibition and apoptosis and therefore potentially contributes to the bleeding risk in chemotherapy patients. PMID- 28661477 TI - MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET-SOCS1-MMP9 signaling axis. AB - Ten eleven translocation (TET) enzymes convert 5-methylcytosine (5-mC) to 5 hydroxy-methylcytosine (5-hmC) and have crucial roles in biological and pathological processes by mediating DNA demethylation, however, the functional role of this epigenetic mark and the related enzymes in hepatocellular carcinoma (HCC) progression remains unknown. Here, we demonstrated that TET-family enzymes downregulation was one likely mechanism underlying 5-hmC loss in HCC. We found that miR-29a overexpression increased DNA methylation of suppressor of cytokine signaling 1 (SOCS1) promoter was associated with HCC metastasis in vitro and in vivo. Furthermore, miR-29a silenced anti-metastatic SOCS1 through direct TET family targeting, resulting in SOCS1 promoter demethylation inhibition. Chromatin immunoprecipitation analyses confirmed that TET1 regulated SOCS1 expression through binding to the promoter region of SOCS1. Finally, miR-29a overexpression correlated with poor clinical outcomes and TET-SOCS1-matrix metalloproteinase (MMP) 9 axis silencing in HCC patients. In conclusion, our findings demonstrate that 5-hmC loss is an epigenetic hallmark of HCC, and miR-29a is an important epigenetic modifier, promoting HCC metastasis through TET-SOCS1-MMP9 axis silencing. The results offer a new strategy for epigenetic cancer therapy. PMID- 28661478 TI - KDM2B, an H3K36-specific demethylase, regulates apoptotic response of GBM cells to TRAIL. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells. TRAIL resistance in cancers is associated with aberrant expression of the key components of the apoptotic program. However, how these components are regulated at the epigenetic level is not understood. In this study, we investigated novel epigenetic mechanisms regulating TRAIL response in glioblastoma multiforme (GBM) cells by a short-hairpin RNA loss-of-function screen. We interrogated 48 genes in DNA and histone modification pathways and identified KDM2B, an H3K36-specific demethylase, as a novel regulator of TRAIL response. Accordingly, silencing of KDM2B significantly enhanced TRAIL sensitivity, the activation of caspase-8, -3 and -7 and PARP cleavage. KDM2B knockdown also accelerated the apoptosis, as revealed by live-cell imaging experiments. To decipher the downstream molecular pathways regulated by KDM2B, levels of apoptosis-related genes were examined by RNA-sequencing upon KDM2B loss, which revealed derepression of proapoptotic genes Harakiri (HRK), caspase-7 and death receptor 4 (DR4) and repression of antiapoptotic genes. The apoptosis phenotype was partly dependent on HRK upregulation, as HRK knockdown significantly abrogated the sensitization. KDM2B-silenced tumors exhibited slower growth in vivo. Taken together, our findings suggest a novel mechanism, where the key apoptosis components are under epigenetic control of KDM2B in GBM cells. PMID- 28661479 TI - Ochratoxin A-induced autophagy in vitro and in vivo promotes porcine circovirus type 2 replication. AB - Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium. Porcine circovirus type 2 (PCV2) is recognized as the causative agent of porcine circovirus-associated diseases. Recently, we reported that low doses of OTA promoted PCV2 replication in vitro and in vivo, but the underlying mechanism needed further investigation. The present studies further confirmed OTA-induced PCV2 replication promotion as measured by cap protein expression, viral titer, viral DNA copies and the number of infected cells. Our studies also showed that OTA induced autophagy in PK-15 cells, as assessed by the markedly increased expression of microtubule-associated protein 1 light chain 3 (LC3)-II, autophagy related protein 5 (ATG5), and Beclin-1 and the accumulation of green fluorescent protein (GFP)-LC3 dots. OTA induced complete autophagic flux, which was detected by monitoring p62 degradation and LC3-II turnover using immunoblotting. Inhibition of autophagy by 3-methylademine (3-MA) and chloroquine (CQ) significantly attenuated OTA-induced PCV2 replication promotion. The observed phenomenon was further confirmed by the knock-down of ATG5 or Beclin-1 by specific siRNA. Further studies showed that N-acetyl-L-cysteine (NAC), an ROS scavenger could block autophagy induced by OTA, indicating that ROS may be involved in the regulation of OTA-induced autophagy. Furthermore, we observed significant increases in OTA concentrations in lung, spleen, kidney, liver and inguinal lymph nodes (ILN) and bronchial lymph nodes (BLN) of pigs fed 75 and 150 MUg/kg OTA compared with controls in vivo. Administration of 75 MUg/kg OTA significantly increased PCV2 replication and autophagy in the lung, spleen, kidney and BLN of pigs. Taken together, it could be concluded that OTA-induced autophagy in vitro and in vivo promotes PCV2 replication. PMID- 28661480 TI - Role of peroxiredoxin2 downregulation in recurrent miscarriage through regulation of trophoblast proliferation and apoptosis. AB - Peroxiredoxin (Prdx) 2 is an antioxidant protein that utilizes its redox sensitive cysteine groups to reduce hydrogen peroxide molecules and protect cells against oxidative damage from reactive oxygen species (ROS). However, its function in trophoblasts at the maternal-fetal interface has not been clarified yet. In this study, significantly lower Prdx2 expression was found in the first trimester villous cytotrophoblasts of patients with recurrent miscarriage (RM) than in cytotrophoblasts from healthy controls. Further, Prdx2 knockdown inhibited proliferation and increased apoptosis of trophoblast cells. The reason for this may be an increase in the level of cellular ROS after knockdown of Prdx2, which may subsequently lead to an increase in the expression of phosphorylated p53 (p-p53) and p38-MAPK/p21. Prdx2 knockdown also impaired the fusion of BeWo cells induced by forskolin. Bioinformatics analysis identified a c Myc-binding site in the Prdx2 promoter region, and chromatin immunoprecipitation verified that c-Myc directly bound to a site in this locus. Suppression and overexpression of c-Myc resulted in reduction and increase of Prdx2 expression respectively. Furthermore, we demonstrated that c-Myc was downregulated in the first-trimester cytotrophoblasts of patients with RM, and its downregulation is also related with inhibited cell proliferation, increased apoptosis, as well as upregulated p21 expression and p-p53/p53 ratio. Our findings indicate that Prdx2 might have an important role in the regulation of trophoblast proliferation and apoptosis during early pregnancy, and that its expression is mediated by c-Myc. Thus, these two proteins may be involved in the pathogenesis of RM and may represent potential therapeutic targets. PMID- 28661481 TI - Inefficient differentiation response to cell cycle stress leads to genomic instability and malignant progression of squamous carcinoma cells. AB - Squamous cell carcinoma (SCC) or epidermoid cancer is a frequent and aggressive malignancy. However in apparent paradox it retains the squamous differentiation phenotype except for very dysplastic lesions. We have shown that cell cycle stress in normal epidermal keratinocytes triggers a squamous differentiation response involving irreversible mitosis block and polyploidisation. Here we show that cutaneous SCC cells conserve a partial squamous DNA damage-induced differentiation response that allows them to overcome the cell division block. The capacity to divide in spite of drug-induced mitotic stress and DNA damage made well-differentiated SCC cells more genomically instable and more malignant in vivo. Consistently, in a series of human biopsies, non-metastatic SCCs displayed a higher degree of chromosomal alterations and higher expression of the S phase regulator Cyclin E and the DNA damage signal gammaH2AX than the less aggressive, non-squamous, basal cell carcinomas. However, metastatic SCCs lost the gammaH2AX signal and Cyclin E, or accumulated cytoplasmic Cyclin E. Conversely, inhibition of endogenous Cyclin E in well-differentiated SCC cells interfered with the squamous phenotype. The results suggest a dual role of cell cycle stress-induced differentiation in squamous cancer: the resulting mitotic blocks would impose, when irreversible, a proliferative barrier, when reversible, a source of genomic instability, thus contributing to malignancy. PMID- 28661482 TI - Necroptosis in neurodegenerative diseases: a potential therapeutic target. AB - Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases. PMID- 28661483 TI - Gene knockout of Zmym3 in mice arrests spermatogenesis at meiotic metaphase with defects in spindle assembly checkpoint. AB - ZMYM3, a member of the MYM-type zinc finger protein family and a component of a LSD1-containing transcription repressor complex, is predominantly expressed in the mouse brain and testis. Here, we show that ZMYM3 in the mouse testis is expressed in somatic cells and germ cells until pachytene spermatocytes. Knockout (KO) of Zmym3 in mice using the CRISPR-Cas9 system resulted in adult male infertility. Spermatogenesis of the KO mice was arrested at the metaphase of the first meiotic division (MI). ZMYM3 co-immunoprecipitated with LSD1 in spermatogonial stem cells, but its KO did not change the levels of LSD1 or H3K4me1/2 or H3K9me2. However, Zmym3 KO resulted in elevated numbers of apoptotic germ cells and of MI spermatocytes that are positive for BUB3, which is a key player in spindle assembly checkpoint. Zmym3 KO also resulted in up-regulated expression of meiotic genes in spermatogonia. These results show that ZMYM3 has an essential role in metaphase to anaphase transition during mouse spermatogenesis by regulating the expression of diverse families of genes. PMID- 28661484 TI - Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury. AB - Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-kappaB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia-reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology. PMID- 28661485 TI - Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells. AB - Stimulating bone formation is an important challenge for bone anabolism in osteoporotic patients or to repair bone defects. The osteogenic properties of matrix glycosaminoglycans (GAGs) have been explored; however, the functions of GAGs at the surface of bone-forming cells are less documented. Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation. We used a transgenic mouse model with high syndecan-2 expression in osteoblasts to enrich the bone surface with cellular GAGs. Bone mass was increased in these transgenic mice. Syndecan-2 overexpression reduced the expression of receptor activator of NF-kB ligand (RANKL) in bone marrow cells and strongly inhibited bone resorption. Osteoblast activity was not modified in the transgenic mice, but bone formation was decreased in 4-month-old transgenic mice because of reduced osteoblast number. Increased proteoglycan expression at the bone surface resulted in decreased osteoblastic and osteoclastic precursors in bone marrow. Indeed, syndecan-2 overexpression increased apoptosis of mesenchymal precursors within the bone marrow. However, syndecan-2 specifically promoted the vasculature characterized by high expression of CD31 and Endomucin in 6-week-old transgenic mice, but this was reduced in 12-week-old transgenic mice. Finally, syndecan-2 functions as an inhibitor of Wnt-beta-catenin-T-cell factor signaling pathway, activating glycogen synthase kinase 3 and then decreasing the Wnt dependent production of Wnt ligands and R-spondin. In conclusion, our results show that GAG supply may improve osteogenesis, but also interfere with the crosstalk between the bone surface and marrow cells, altering the supporting function of osteoblasts. PMID- 28661486 TI - The role of MAP2 kinases and p38 kinase in acute murine liver injury models. AB - c-Jun N-terminal kinase (JNK) mediates hepatotoxicity through interaction of its phospho-activated form with a mitochondrial outer membrane protein, Sh3bp5 or Sab, leading to dephosphorylation of intermembrane Src and consequent impaired mitochondrial respiration and enhanced ROS release. ROS production from mitochondria activates MAP3 kinases, such as MLK3 and ASK1, which continue to activate a pathway to sustain JNK activation, and amplifies the toxic effect of acetaminophen (APAP) and TNF/galactosamine (TNF/GalN). Downstream of MAP3K, in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK. The relative role of MKK4 versus 7 in liver injury is largely unexplored, as is the potential role of p38 kinase, which might be a key mediator of toxicity in addition to JNK. Antisense oligonucleotides (ASO) to MKK4, MKK7 and p38 (versus scrambled control) were used for in vivo knockdown, and in some experiments PMH were used after in vivo knockdown. Mice were treated with APAP or TNF/GalN and injury assessed. MKK4 and MKK7 were expressed in liver and each was efficiently knocked down with two different ASOs. Massive liver injury and ALT elevation were abrogated by MKK4 but not MKK7 ASO pretreatment in both injury models. The protection was confirmed in PMH. Knockdown of MKK4 completely inhibited basal P p38 in both cytoplasm and mitochondria. However, ALT levels and histologic injury in APAP-treated mice were not altered with p38 knockdown versus scrambled control. p38 knockdown significantly increased P-JNK levels in cytoplasm but not mitochondria after APAP treatment. In conclusion, MKK4 is the major MAP2K, which activates JNK in acute liver injury. p38, the other downstream target of MKK4, does not contribute to liver injury from APAP or TNF/galactosamine. PMID- 28661487 TI - CAP/ACMG proficiency testing for biochemical genetics laboratories: a summary of performance. AB - PurposeTesting for inborn errors of metabolism is performed by clinical laboratories worldwide, each utilizing laboratory-developed procedures. We sought to summarize performance in the College of American Pathologists' (CAP) proficiency testing (PT) program and identify opportunities for improving laboratory quality. When evaluating PT data, we focused on a subset of laboratories that have participated in at least one survey since 2010.MethodsAn analysis of laboratory performance (2004 to 2014) on the Biochemical Genetics PT Surveys, a program administered by CAP and the American College of Medical Genetics and Genomics. Analytical and interpretive performance was evaluated for four tests: amino acids, organic acids, acylcarnitines, and mucopolysaccharides.ResultsSince 2010, 150 laboratories have participated in at least one of four PT surveys. Analytic sensitivities ranged from 88.2 to 93.4%, while clinical sensitivities ranged from 82.4 to 91.0%. Performance was higher for US participants and for more recent challenges. Performance was lower for challenges with subtle findings or complex analytical patterns.ConclusionUS clinical biochemical genetics laboratory proficiency is satisfactory, with a minority of laboratories accounting for the majority of errors. Our findings underscore the complex nature of clinical biochemical genetics testing and highlight the necessity of continuous quality management. PMID- 28661488 TI - Response to Herbert et al. PMID- 28661489 TI - FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants. AB - PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling. PMID- 28661490 TI - Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. AB - PurposeC-type natriuretic peptide (CNP) and its principal receptor, natriuretic peptide receptor B (NPR-B), have been shown to be important in skeletal development. CNP and NPR-B are encoded by natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor 2 (NPR2) genes, respectively. While NPR2 mutations have been described in patients with skeletal dysplasias and idiopathic short stature (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, no mutations in NPPC have been described in patients to date.MethodsNPPC was screened in 668 patients (357 with disproportionate short stature and 311 with autosomal dominant ISS) and 29 additional ISS families in an ongoing whole exome sequencing study.ResultsTwo heterozygous NPPC mutations, located in the highly conserved CNP ring, were identified. Both showed significant reductions in cyclic guanosine monophosphate synthesis, confirming their pathogenicity. Interestingly, one has been previously linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant.ConclusionsOur results demonstrate, for the first time, that NPPC mutations cause autosomal dominant short stature in humans. The NPPC mutations cosegregated with a short stature and small hands phenotype. A CNP analog, which is currently in clinical trials for the treatment of achondroplasia, seems a promising therapeutic approach, since it directly replaces the defective protein. PMID- 28661492 TI - Quantifying survival in patients with Proteus syndrome. AB - PurposeProteus syndrome is a rare mosaic overgrowth disorder that is associated with severe complications. While anecdotal data have suggested that the life span of affected patients is reduced, this has not been measured. Mortality data on rare diseases is critical for assessing treatments and other interventions.MethodsTo address this we used the clinical research records of 64 patients in a longitudinal natural history cohort at the National Institutes of Health to ascertain the data in an organized manner and estimate survival using a Kaplan-Meier approach.ResultsThe median age of diagnosis was 19 months. Based on this analysis, there was 25% probability of death by 22 years of age. Ten of the 11 patients who died were younger than 22 years of age, and there was only a single death after this age.ConclusionThese data quantify the risk of premature death in Proteus syndrome, which can be used to support interventions and trials. Although the risk of death is substantial, the fact that only one patient died after 22 years of age supports anecdotal evidence that the disease process moderates after the end of adolescence. Interventions to reduce mortality should be targeted to the pediatric age range. PMID- 28661493 TI - Mass spectrometrists should search for all peptides, but assess only the ones they care about. PMID- 28661491 TI - Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening. AB - PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (chi2=16.98, P<0.001). Overall, informed choice was high in both nonpregnant (77.4%) and pregnant (72.9%) women (chi2=0.21, P=0.644), and more tested (76.0%) than not tested (66.7%) women (chi2=6.35, P=0.012) made an informed choice. Measures of depression, stress, and anxiety were similar to population norms for ~85% of women. Decisional conflict and regret were generally low; however, decisional uncertainty and regret were greater in pregnant than nonpregnant women, and not tested than tested women (uncertainty: chi2=18.51, P<0.001 and chi2=43.11, P<0.001, respectively; regret: chi2=6.61, P<0.037 and chi2=35.54, P<0.001, respectively).ConclusionWe provide evidence to inform guidelines that population FXS carrier screening can be implemented with minimal psychosocial harms following appropriate information and prescreening genetic counseling. PMID- 28661494 TI - Assessing phototoxicity in live fluorescence imaging. AB - Are the answers to biological questions obtained via live fluorescence microscopy substantially affected by phototoxicity? Although a single set of standards for assessing phototoxicity cannot exist owing to the breadth of samples and experimental questions associated with biological imaging, we need quantitative, practical assessments and reporting standards to ensure that imaging has a minimal impact on observed biological processes and sample health. Here we discuss the problem of phototoxicity in biology and suggest guidelines to improve its reporting and assessment. PMID- 28661495 TI - Towards a perceptive understanding of size in cellular biology. AB - Cells are minute-typically too small to be seen by the human eye. Even so, the cellular world encompasses a range of scales, from roughly a tenth of a nanometer (10-10 m) to a millimeter (10-3 m) or larger, spanning seven orders of magnitude or more. Because they are so far from our experience, it is difficult for us to envision such scales. To help our imagination grasp such dimensions, I propose the adoption of a 'perceptive scale' that can facilitate a more direct experience of cellular sizes. From this, as I argue below, will stem a new perception also of biological shape, cellular space and dynamic processes. PMID- 28661496 TI - Response to "Mass spectrometrists should search for all peptides, but assess only the ones they care about". PMID- 28661497 TI - Illuminating redox biology using NADH- and NADPH-specific sensors. PMID- 28661498 TI - Metabolism: sweeter paths in glycoscience. PMID- 28661499 TI - ProHits-viz: a suite of web tools for visualizing interaction proteomics data. PMID- 28661500 TI - PIQED: automated identification and quantification of protein modifications from DIA-MS data. PMID- 28661501 TI - Image doctoring must be halted. PMID- 28661502 TI - Success of gravity-wave satellite paves way for three-craft mission. PMID- 28661503 TI - Overlooked water loss in plants could throw off climate models. PMID- 28661504 TI - Air guns used in offshore oil exploration can kill tiny marine life. PMID- 28661505 TI - How quantum trickery can scramble cause and effect. PMID- 28661506 TI - Let science be a springboard for politics. PMID- 28661507 TI - Three years to safeguard our climate. PMID- 28661508 TI - Modified viruses deliver death to antibiotic-resistant bacteria. PMID- 28661509 TI - Intuition harnessed in the name of particle packing. PMID- 28661510 TI - Pirate sites, grizzly bears and a cholera outbreak. PMID- 28661511 TI - Scientists in limbo as US Supreme Court allows modified travel ban. PMID- 28661512 TI - The secrets of a top salary in science. PMID- 28661513 TI - Mid-childhood outcomes after pre-viable preterm premature rupture of membranes. AB - OBJECTIVES: Investigate cardiorespiratory outcomes in children surviving previable preterm premature rupture of membranes (PV-PPROM) before 22 weeks' gestational age (GA) with minimum 2 weeks latency. STUDY DESIGN: Single institution, follow-up of retrospectively identified children who were born after PV-PPROM during 2000-2004, and individually matched preterm-born controls. RESULTS: Eleven PV-PPROM and matched control children were included at mean age of 10.5 and 10.7 years. Rupture of membranes occurred at mean GA 182 and 276 weeks and birth at 283 and 286 weeks, respectively. Compared to controls, the PV PPROM group had significantly poorer lung function, findings on echocardiography indicating mild pulmonary hypertension, and lower peak oxygen consumption. Chart reviews suggested more motor difficulties and a tendency towards more problems with learning and attention. CONCLUSION: The findings highlight a preterm-born sub-group in need of targeted long-term monitoring and possibly interventions regarding future cardiorespiratory and neurodevelopmental function. PMID- 28661514 TI - Delivery room resuscitation and adverse outcomes among very low birth weight preterm infants. AB - OBJECTIVE: To evaluate risk factors and impact of delivery room cardiopulmonary resuscitation (DR-CPR) on very low birth weight (VLBW) preterm infants. STUDY DESIGN: A national, population-based, observational study evaluating risk factors and short-term neonatal outcomes associated with DR-CPR among VLBW, extremely preterm infants (EPIs, 24 to 27 weeks' gestation) and very preterm infants (VPI, 28 to 31 weeks' gestation) born in 1995 to 2010. RESULTS: Among 17 564 VLBW infants, 636 (3.6%) required DR-CPR. In the group of 6478 EPI, 412 (6.4%) received DR-CPR compared with 224 of 11 086 infants (2.0%) in the VPI group. EPI who underwent DR-CPR had higher odds ratios (ORs (95% confidence interval)) for mortality compared to EPI not requiring DR-CPR (OR 3.32 (2.58, 4.29)), grades 3 to 4 intraventricular hemorrhage (IVH) (OR 1.59 (1.20, 2.10)) and periventricular leukomalacia (OR 1.81 (1.17, 2.82)). DR-CPR among VPI was associated with higher ORs for mortality (OR 4.99 (3.59, 6.94)), early sepsis (OR 2.07 (1.05, 4.09)), grades 3 to 4 IVH (OR 3.74 (2.55, 5.50)) and grades 3 to 4 retinopathy of prematurity (ROP) (OR 2.53 (1.18, 5.41)) compared to VPI not requiring DR-CPR. Only 11% of infants in the EPI DR-CPR group had favorable outcomes compared with 44% in the VPI DR-CPR group. Significantly higher ORs for mortality, IVH and ROP were found in the VPI compared to the EPI group. CONCLUSION: Preterm VLBW infants requiring DR-CPR were at increased risk of adverse outcomes compared to those not requiring CPR. This effect was more pronounced in the VPI group. PMID- 28661516 TI - Knowledge, attitudes, beliefs and practices of occupational physicians towards vaccinations of health care workers: A cross sectional pilot study in North Eastern Italy. AB - OBJECTIVES: This study aims to characterize personal attitudes and knowledge of a sample of Italian occupational physicians (OPhs) towards immunization practice in the case of healthcare workers (HCWs). MATERIAL AND METHODS: A total of 90 OPhs (42.2% of males, 57.8% of females, mean age of 50.1+/-8.3 years old) compiled a structured questionnaire through a telephonic interview. They were asked about the official Italian recommendations for HCWs, their general knowledge of vaccine practice, their propensity towards vaccines (both in general and about specific immunizations), their risk perception about the vaccine-preventable infectious diseases. Eventually, a regression analysis was performed in order to identify factors predictive for vaccine propensity. RESULTS: Only 12 out of 90 subjects correctly identified all the 7 recommended immunizations. The hepatitis B virus (HBV) vaccine was correctly identified by 95.6% of the sample, and was also associated with the more positive attitude and the more accurate risk perception. Influenza vaccine had the lowest acceptance (75.9%). Eventually, pertussis, measles, parotitis and varicella vaccines were insufficiently recognized as recommended ones (all cases < 50% of the sample). General knowledge of vaccine and knowledge of official recommendations were significantly correlated with the attitude towards immunization practice (r = 0.259, p = 0.014 and r = 0.438, p < 0.0001). In the regression analysis general knowledge (unstandardized coefficient (B) = 0.300, 95% confidence interval (CI): 0.090-0.510, p = 0.006) and risk perception (B = 0.579, 95% CI: 0.155-1.003, p = 0.008) were significant predictors of the propensity to vaccinate. CONCLUSIONS: Vaccinations gaps in HCWs may found their roots in OPhs incomplete knowledge of evidence-based recommendations. Specific training programs and formations courses should then be planned. Int J Occup Med Environ Health 2017;30(5):775-790. PMID- 28661515 TI - Surfactant utilization and short-term outcomes in an era of non-invasive respiratory support in Canadian neonatal intensive care units. AB - OBJECTIVE: Increased use of non-invasive respiratory support (NRS) in the delivery room management of preterm neonates has resulted in delayed surfactant treatment, yet the short-term effects of this change are unknown. The aim of this study was to comparatively evaluate the use of surfactant and the short-term outcomes prior to and after the implementation of early routine use of NRS. STUDY DESIGN: Eligible infants of <29 weeks gestational age (GA) admitted to a Canadian tertiary neonatal center during two time periods (2005 to 2008 and 2010 to 2013) were included in this retrospective cohort study. Timing of surfactant (prophylactic vs therapeutic) and short-term outcomes were compared between the two groups. Univariate and multivariate regression analysis was performed to determine the adjusted odds ratio (AOR) along with 95% confidence interval (CI) of receiving exogenous surfactant and developing bronchopulmonary dysplasia (BPD) using the later cohort as the reference group. Subgroup analyses were also performed for infants <26 and 26 to 286/7 weeks GA, respectively. RESULTS: A total of 3980 and 5137 infants were included in the first and second time periods, respectively. There was no significant difference in overall surfactant utilization between the two time periods (AOR 1.00, 95% CI 0.89, 1.13). However, between 2005 and 2008, a lower proportion of neonates received therapeutic surfactant compared with the later cohort (47.1% vs 56.9%, P<0.01) but were more likely to receive prophylactic surfactant (52.9% vs 43.1%, P<0.01). BPD overall was significantly higher in the earlier cohort (AOR 1.19, 95% CI 1.07, 1.33), particularly among the <26 weeks gestation subgroup (AOR 1.34, 95% CI 1.08, 1.66). CONCLUSION: Early routine use of NRS did not impact overall surfactant utilization rate, although therapeutic surfactant administration rates were higher with a concomitant decrease in BPD rates. PMID- 28661518 TI - Challenges in the development of bio-based solvents: a case study on methyl(2,2 dimethyl-1,3-dioxolan-4-yl)methyl carbonate as an alternative aprotic solvent. AB - Many traditional solvents have drawbacks including sustainability and toxicity issues. Legislation, such as REACH, is driving the move towards less hazardous chemicals and production processes. Therefore, safer bio-based solvents need to be developed. Herein, a 10 step method has been proposed for the development of new bio-based solvents, which utilises a combination of in silico modelling of Hansen solubility parameters (HSPs), experimental Kamlet-Abboud-Taft parameters, a selection of green synthetic routes followed by application testing and toxicity measurements. The challenges that the chemical industry face in the development of new bio-based solvents are highlighted through a case study on methyl(2,2-dimethyl-1,3-dioxolan-4-yl)methyl carbonate (MMC), which can be synthesised from glycerol. Although MMC is an attractive candidate as a replacement solvent, simply being bio-derived is not enough for a molecule to be regarded as green. The methodology of solvent development described here is a broadly applicable protocol that will indicate if a new bio-based solvent is functionally proficient, and will also highlight the importance of early stage Kamlet-Abboud-Taft parameters determination and toxicity testing in the development of a green solvent. PMID- 28661517 TI - Integrative self-sorting of coordination cages based on 'naked' metal ions. AB - Coordination-driven self-assembly of metal ions and organic ligands has been extensively utilised over the past four decades to access a variety of nano-sized cage assemblies, with functions ranging from sensing and catalysis to drug delivery. Many of the reported examples, however, are highly symmetric architectures that contain one type of organic ligand carrying not more than a single functionality. This contrasts significantly with the level of structural and functional complexity encountered in biological macromolecular hosts, which are able to bind and chemically convert smaller molecules in their highly decorated internal cavities. To address this disparity, rational approaches that facilitate heteroleptic assembly by regulating integrative self-sorting of metal ions and multiple ligand components have emerged. Among these, routes to access coordination cages from 'naked' metal cations that offer more than two coordination sites are still in early development, as the complexity of the self sorted products in terms of composition and stereochemistry presents an entropic challenge. This feature article highlights recent progress in controlling integrative self-sorting of multi-component cage systems with a focus on structures composed of 'naked' metal cations and two different ligands. Once heteroleptic self-assembly strategies find a wider implementation in supramolecular design, the resultant interplay between tailored combinations of precisely positioned substituents promises enhanced functionality in nanoscale structures. PMID- 28661519 TI - Recent advances using [Cp*Co(CO)I2] catalysts as a powerful tool for C-H functionalisation. AB - Expansion of the synthetic chemists' toolbox is currently a topic of great interest, with successes providing access to novel compounds and more efficient routes towards new and known pharmaceuticals and agrochemicals. In this context, the development and application of first-row transition metal-catalysed C-H functionalisation protocols is seen as a key opportunity. This perspective provides a brief background of the discovery and application of high-valent cobalt-catalysis in C-H functionalisation, before detailing examples of recent advances in this field using the powerful [Cp*Co(CO)I2] catalysts for both terminal couplings and heterocycle formation. Finally, a discussion on the detection and isolation of elusive reactive intermediates in high-valent cobalt catalysed C-H functionalisation, shedding light on how these catalyst systems operate, will be provided. PMID- 28661520 TI - Graphene chemistry. PMID- 28661521 TI - Expression of concern: Enantio- and diastereocontrolled conversion of chiral epoxides to trans-cyclopropane carboxylates: application to the synthesis of cascarillic acid, grenadamide and l-(-)-CCG-II. AB - Expression of concern for 'Enantio- and diastereocontrolled conversion of chiral epoxides to trans-cyclopropane carboxylates: application to the synthesis of cascarillic acid, grenadamide and l-(-)-CCG-II' by Pradeep Kumar et al., Org. Biomol. Chem., 2012, 10, 6987-6994. PMID- 28661522 TI - Tubulogenesis of co-cultured human iPS-derived endothelial cells and human mesenchymal stem cells in fibrin and gelatin methacrylate gels. AB - Here, we investigate the tubulogenic potential of commercially-sourced iPS-ECs with and without supporting commercially-sourced hMSCs within 3D natural fibrin or semi-synthetic gelatin methacrylate (GelMA) hydrogels. We developed a selectable dual color third generation lentiviral reporter (hEF1alpha-H2B mOrange2-IRES-EGFP PGK-Puro) to differentially label the nucleus and cytoplasm of iPS-ECs which allowed real-time tracking of key steps of vascular morphogenesis such as vacuole formation and coalescence to form shared multicellular lumens. We implement 3D quantification of the network character and validate that transduced and untransduced iPS-ECs can form tubules in fibrin with or without supporting hMSCs. In addition to natural fibrin gels, we also investigated tubulogenesis in GelMA, a semi-synthetic material that has received increased interest due to its ability to be photopatterned and 3D printed, and which may thus boost development of complex 3D models for regenerative medicine studies. We find that iPS-ECs alone have a muted tubulogenic response within GelMA, but that their tubulogenic response is enhanced when they are co-cultured with a small fraction of hMSCs (2% of total cells). Our work bolsters previous findings by validating established tubulogenic mechanisms with commercially available iPS-ECs, and we expect our findings will benefit biologic studies of vasculogenesis and will have applications in tissue engineering to pre-vascularize tissue constructs which are fabricated with advanced photopatterning and three-dimensional printing. PMID- 28661523 TI - Bimetallic core-based cuboctahedral core-shell nanoclusters for the formation of hydrogen peroxide (2e- reduction) over water (4e- reduction): role of core metals. AB - The design of an efficient and selective catalyst for hydrogen peroxide (H2O2) formation is highly sought due to its industrial importance. As alternatives to a conventional Pd-Au alloy-based catalyst, three cuboctahedral core-shell nanoclusters (Au19@Pt60, Co19@Pt60 and Au10Co9@Pt60 NCs) have been investigated. Their catalytic activities toward H2O2 formation have been compared with that of pure Pt cuboctahedral NC (Pt79). Much attention has been devoted to thermodynamic and kinetic parameters to find out the feasibility of the two-electron (2e-) over the four-electron (4e-) oxygen reduction reaction (ORR) to improve the product selectivity (H2O vs. H2O2). Elementary steps corresponding to H2O2 formation are significantly improved over the Au10Co9@Pt60 NC catalyst compared with the pure core-shell NCs and periodic surface based catalysts. Furthermore, the Au10Co9@Pt60 NC favours H2O2 formation via the much desired Langmuir-Hinshelwood mechanism. The potential-dependent study shows that the H2O2 formation is thermodynamically favourable up to 0.43 V on the Au10Co9@Pt60 NC and thus the overpotential for the 2e- ORR process is significantly lowered. Besides, the Au10Co9@Pt60 NC is highly selective for H2O2 formation over H2O formation. PMID- 28661524 TI - Correction: Zn2+ and Cd2+ cationized serine complexes: infrared multiple photon dissociation spectroscopy and density functional theory investigations. AB - Correction for 'Zn2+ and Cd2+ cationized serine complexes: infrared multiple photon dissociation spectroscopy and density functional theory investigations' by Rebecca A. Coates et al., Phys. Chem. Chem. Phys., 2016, 18, 22434-22445. PMID- 28661525 TI - Expression of concern: Organocatalytic stereoselective synthesis of passifloricin A. AB - Expression of concern for 'Organocatalytic stereoselective synthesis of passifloricin A' by Pradeep Kumar et al., Org. Biomol. Chem., 2012, 10, 1820 1825. PMID- 28661526 TI - Correction: Influence of particle size and dielectric environment on the dispersion behaviour and surface plasmon in nickel nanoparticles. AB - Correction for 'Influence of particle size and dielectric environment on the dispersion behaviour and surface plasmon in nickel nanoparticles' by Vikash Sharma et al., Phys. Chem. Chem. Phys., 2017, 19, 14096-14106. PMID- 28661527 TI - Rotating 1-D magnetic photonic crystal balls with a tunable lattice constant. AB - The responsive photonic crystal (RPC) balls with adjustable lattice constant and controllable rotation developed to date are all based on Janus particles of three dimensional (3-D) periodical structures, which suffer from color uneveness and asymmetric volume change, limiting the applications in the fields of encoding, sensing and displays. In this study, we have developed the first 1-D magnetic photonic crystal balls with tunable lattice constants by fixing collectively oriented periodical 1-D magnetic nanochain-like structures in responsive polymer poly(N-isopropylacrylamide) hydrogel balls under magnetic field (H) and UV irradiation. The structural colors of the balls are uniform on the entire ball and can be regulated by temperature (T) and solvents. The as-prepared RPC balls always retain a perfectly spherical shape even when the hydrogel volume changes with stimuli because of the low content of the included 1-D magnetic nanochain like structures. This endows smooth rotation in the H direction to switch "on/off" their structural colors at various stimuli, as demonstrated by a colorful display application at temperature ranging from 10 to 35 degrees C. The as-developed RPC balls are expected to have promising potential applications in color display, rewritable signage, biological and chemical sensors owing to their excellent multi-response properties. PMID- 28661529 TI - Nanoporous IrO2 catalyst with enhanced activity and durability for water oxidation owing to its micro/mesoporous structure. AB - Herein, we report a nanoporous IrO2 catalyst with a surface area of 363.3 m2 g-1, the highest ever reported. The IrO2 catalysts were prepared by a facile ammonia induced pore-forming method, and efficiently scaled up to several kilograms. Bimodal micro/mesopores were created at once without using a template. For the IrO2 (1 : 100)-450 degrees C (H2IrCl6 : NH3.H2O of 1 : 100) catalyst, the overpotential to attain a current density of 10 mA cm-2 for water oxidation was only 282 mV, and furthermore, its excellent durability was confirmed by accelerated durability tests. Moreover, the overall voltage to achieve a current density of 1000 mA cm-2 in a water electrolysis cell was only 1.649 V, making IrO2 (1 : 100)-450 degrees C a highly attractive catalyst for water electrolysis applications. PMID- 28661531 TI - Synthesis of 3-(2-thiopyridyl)indoles via the ruthenium catalyzed [2 + 2 + 2] cycloaddition of diynes and 3-thiocyanatoindoles. AB - A highly efficient protocol for the synthesis of 3-(2-thiopyridyl)indoles via the ruthenium(ii) catalyzed [2 + 2 + 2] cycloaddition reaction of alpha,omega-diynes with 3-thiocyanatoindoles under mild reaction conditions has been developed. A variety of 3-(2-thiopyridyl)indole derivatives were prepared by the reaction of the aforesaid substrates in the presence of a readily available chloro(pentamethylcyclopentadienyl)(cyclooctadiyne)ruthenium(ii) catalyst in ethanol with good to excellent yields. This atom economical methodology provides us efficient access to 3-(2-thiopyridyl)indole skeletons with close structural similarity to other pyridyl indole thioethers that have potential medicinal value. PMID- 28661532 TI - Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials. AB - Molecular self-assembly is a multi-disciplinary field of research, with potential chemical and biological applications. One of the main driving forces of self assembly is molecular amphiphilicity, which can drive formation of complex and stable nanostructures. Self-assembling peptide and peptide conjugates have attracted great attention due to their biocompatibility, biodegradability and biofunctionality. Understanding assembly enables the better design of peptide amphiphiles which may form useful and functional nanostructures. This review covers self-assembly of amphiphilic peptides and peptide mimetic materials, as well as their potential applications. PMID- 28661533 TI - Synthesis of disulfides tethered pyrroles from beta-ketothioamides via a bicyclization/ring-opening/oxidative coupling reaction. AB - A DABCO-promoted three-component reaction of beta-ketothioamides (KTAs), arylglyoxals and 2-cyanoacetates to construct disulfides tethered pyrroles by using air as an oxidant has been disclosed. Importantly, this protocol involves a tandem sequence that includes Knoevenagel condensation, Michael addition, N cyclization, O-cyclization, ring-opening and oxidative coupling. PMID- 28661534 TI - FOXO3 promoted mitophagy via nuclear retention induced by manganese chloride in SH-SY5Y cells. AB - OBJECTIVES: To evaluate the role of FOXO3 during the process of mitophagy induced by manganese chloride (MnCl2), mitochondrial dysfunction and mitophagy were detected before and after FOXO3 was knocked down in SH-SY5Y cells. METHOD: Transmission electron microscopy (TEM), flow cytometry, confocal microscopy and a western blot were used to detect mitochondrial ultrastructure and autophagy, Ca2+ levels, mitochondrial reactive oxygen species (ROS) and the mitochondrial membrane potential (MMP), autophagosomes and mitophagy marker proteins (p62, LC3 II/LC3-I, Beclin-1, PINK1 and P-parkin), respectively. RESULTS: After SH-SY5Y cells were exposed to MnCl2, the levels of cytoplasmic Ca2+ and mitochondrial ROS increased but the mitochondrial MMP decreased significantly compared to the control in a dose- and time-dependent manner (p < 0.05), which indicated that MnCl2 can lead to mitochondrial dysfunction. Under TEM, mitophagy and autolysosomes were observed. The WB results also showed that mitophagy marker proteins including LC3-II/LC3-I, Beclin-1, PINK1 and P-parkin except for p62 increased in a dose- and time-dependent manner, accompanied by FOXO3 nuclear retention, which indicated that MnCl2 can lead to mitophagy and FOXO3 nuclear translocation may be involved in this process. After FOXO3 was knocked down, the inverse results of mitophagy and the levels of mitochondrial ROS decreasing were observed, which showed that FOXO3 silencing could inhibit mitophagy and mitochondrial dysfunction induced by MnCl2. CONCLUSIONS: Our results indicated that Mn could induce mitophagy by enhancing FOXO3 nuclear retention, which might promote mitophagy induced by MnCl2. PMID- 28661538 TI - Enzymatic biomineralization of biocompatible CuInS2, (CuInZn)S2 and CuInS2/ZnS core/shell nanocrystals for bioimaging. AB - This work demonstrates a bioenabled fully aqueous phase and room temperature route to the synthesis of CuInS2/ZnS core/shell quantum confined nanocrystals conjugated to IgG antibodies and used for fluorescent tagging of THP-1 leukemia cells. This elegant, straightforward and green approach avoids the use of solvents, high temperatures and the necessity to phase transfer the nanocrystals prior to application. Non-toxic CuInS2, (CuInZn)S2, and CuInS2/ZnS core/shell quantum confined nanocrystals are synthesized via a biomineralization process based on a single recombinant cystathionine gamma-lyase (CSE) enzyme. First, soluble In-S complexes are formed from indium acetate and H2S generated by CSE, which are then stabilized by l-cysteine in solution. The subsequent addition of copper, or both copper and zinc, precursors then results in the immediate formation of CuInS2 or (CuInZn)S2 quantum dots. Shell growth is realized through subsequent introduction of Zn acetate to the preformed core nanocrystals. The size and optical properties of the nanocrystals are tuned by adjusting the indium precursor concentration and initial incubation period. CuInS2/ZnS core/shell particles are conjugated to IgG antibodies using EDC/NHS cross-linkers and then applied in the bioimaging of THP-1 cells. Cytotoxicity tests confirm that CuInS2/ZnS core/shell quantum dots do not cause cell death during bioimaging. Thus, this biomineralization enabled approach provides a facile, low temperature route for the fully aqueous synthesis of non-toxic CuInS2/ZnS quantum dots, which are ideal for use in bioimaging applications. PMID- 28661539 TI - Expression of concern: A general and concise asymmetric synthesis of sphingosine, safingol and phytosphingosines via tethered aminohydroxylation. AB - Expression of concern for 'A general and concise asymmetric synthesis of sphingosine, safingol and phytosphingosines via tethered aminohydroxylation' by Pradeep Kumar et al., Org. Biomol. Chem., 2010, 8, 5074-5086. PMID- 28661540 TI - Highly productive CO2 hydrogenation to methanol - a tandem catalytic approach via amide intermediates. AB - A new system for CO2 reduction to methanol has been demonstrated using homogeneous ruthenium catalysts with a range of amine auxiliaries. Modification of this amine has a profound effect on the yield and selectivity of the reaction. A TON of 8900 and TOF of 4500 h-1 is achieved using a [RuCl2(Ph2PCH2CH2NHMe)2] catalyst with a diisopropylamine auxiliary. PMID- 28661541 TI - Women 50 and Older and HIV: Prevention and Implications for Health Care Providers. AB - The current article discusses the importance of implementing HIV and AIDS education, prevention, and intervention programs that are tailored to women 50 and older and to determine HIV risk factors for this population. A literature search was performed, resulting in 41 relevant articles. The literature underscored the significance of increasing awareness of HIV/AIDS, particularly among older women. HIV risk behaviors and the effect that these behaviors have on HIV transmission and prevention among women 50 and older are described. Prior research findings identified risk categories of older women that may contribute to the transmission of HIV among this particular population, including heterosexual relations, perceived HIV risk, ageism and HIV transmission, biological factors, transfusions, sexual enhancement aids, and health care providers and prevention messages. In addition, previous findings indicate that health care providers have not traditionally targeted women 50 and older for HIV prevention. Health care providers should incorporate discussion of HIV risk and transmission during clinic visits and implement prevention programs that target this population. [Journal of Gerontological Nursing, 43(12), 29-34.]. PMID- 28661542 TI - Effects of Uncertainty on Perceived and Physiological Stress in Caregivers of Stroke Survivors: A 6-Week Longitudinal Study. AB - Caregivers' stress following a family member's stroke is likely accentuated by its associated uncertainty. The purpose of the current study was to examine the effect of uncertainty on caregivers' perceived and physiological stress (i.e., salivary cortisol). A prospective, longitudinal observational study was conducted with a convenience sample of 40 caregivers and stroke survivors recruited from acute care settings. Linear mixed models were used. Greater uncertainty was associated with higher perceived stress (p < 0.001), but not with physiological stress (p = 0.32 on waking, p = 0.06 evening), over the first 6 weeks post stroke. A significant association between uncertainty and evening salivary cortisol level was found at 6 weeks post-stroke (p = 0.009). Recognition of uncertainty early in the caregiving period and targeted interventions may be useful in reducing perceived stress for this group. [Journal of Gerontological Nursing, 43(11), 30-40.]. PMID- 28661543 TI - Implementing Nurse-Facilitated Person-Centered Care Approaches for Patients With Delirium Superimposed on Dementia in the Acute Care Setting. AB - Little is understood about the use of person-centered care (PCC) for individuals with delirium superimposed on dementia (DSD), especially in the acute care setting. As part of a larger clinical trial, the purpose of the current exploratory study was to describe examples and qualitatively derived themes of nurse-facilitated PCC for hospitalized older adults with dementia and delirium. A total of 750 delirium rounds were analyzed across three diverse acute care sites. Qualitative derived themes of PCC included: (a) Knowing the Patient's Baseline; (b) Knowing the Patient's Interests and Values; (c) Enhancing Sensory Abilities to Communicate; (d) Individualizing Cognitive Stimulation; and (e) Enhancing Behavioral Approaches to Comfort and Sleep. Barriers included failure to see the patient as an individual and lack of time. Principles of PCC were effectively used, demonstrating the potential for PCC to ease the burden of DSD for all members of the health care team. [Journal of Gerontological Nursing, 43(12), 21 28.]. PMID- 28661544 TI - Efficacy of a Daily Protective Moisturizer with High UVB and UVA Photoprotection in Decreasing Ultraviolet Damage: Evaluation by Reflectance Confocal Microscopy. AB - Patients with photodermatoses or actinic keratosis benefit from very high ultraviolet B-ultraviolet A (UVB-UVA) photoprotection. However, poor compliance is an issue that jeopardizes adequate protection, leading to disease recurrence. This study evaluated the efficacy of a daily protective moisturizer with high UVB and UVA photoprotection applied 8 h before irradiation. A monocentric, open label, prospective, control pilot study was performed including 10 patients. Patients were irradiated with UVB and UVA before and 8 h after topical application of the product. Reflectance confocal microscopy (RCM) assessment was performed 24 h later. Clinical assessment showed a statistically significant increase in minimal erythema dose (MED) after application of the product (p <0.001). Signs of UV damage according to RCM were not observed on photoprotected skin (p <0.05). Skin irradiated 8 h after applying a daily protective moisturizer presented an increase in MED and RCM findings that equal the findings for non irradiated skin. PMID- 28661546 TI - Skeletal muscle metabolism after stroke: A comparative study using treadmill and overground walking test. AB - OBJECTIVE: The primary aim of this study was to investigate muscle metabolism in stroke survivors through measurements of the respiratory exchange ratio and rates of fat and carbohydrate oxidation in relation to total energy expenditure at preferred walking speed during treadmill and overground walking. The secondary objective was to investigate whether the energy source used during walking influences the daily physical activity pattern and fatigue of post-stroke individuals. METHODS: The sample comprised 28 stroke participants and 10 non disabled, healthy controls. Measurements of oxygen consumption and carbon dioxide production were recorded. Participants wore a uniaxial accelerometer (activPALTM) over 4 days as an estimate of daily physical activity. Measurements of Human Activity Profile and Neurological Fatigue Index for stroke were documented. RESULTS: Carbohydrate oxidation accounted for the majority of fuel oxidation at preferred walking speed in the stroke group (55.86% vs 47.29% during tread-mill walking and 66.13% vs 50.15% during overground walking). Stroke patients who had higher levels of carbohydrate oxidation reached a lower score in the Human Activity Profile survey, had fewer steps screened by activPAL data (4,422 vs 6,692 steps/day) and higher fatigue index. CONCLUSION: Carbohydrate oxidation accounted for the majority of fuel oxidation at the preferred walking speed in post-stroke individuals. The increased carbohydrate utilization recorded at preferred walking speed may have influenced the physical activity profile. PMID- 28661545 TI - Nonlinear relationship between isokinetic muscle strength and activity limitations in patients with knee osteoarthritis: Results of the Amsterdam Osteoarthritis cohort. AB - OBJECTIVE: To investigate whether relationships between upper leg muscle strength and activity limitations are non-linear in patients with knee osteoarthritis, and, if so, to determine muscle strength thresholds for limitations in daily activities. DESIGN: Baseline data were used for 562 patients with knee osteoarthritis in the Amsterdam-Osteoarthritis cohort. Upper leg muscle strength (Nm/kg) was measured isokinetically. Activity limitations were measured with the timed Get Up and Go test and timed Stair Climb Test, subdivided into stair-ascent and stair-descent. Linear and non-linear relationships between muscle strength and activity limitations were evaluated, and thresholds were determined. RESULTS: Non-linear models improved model fit compared with linear models. The improvement in percentage variance accounted for was 5.9, 8.2 and 5.2 percentage points for the timed Get Up and Go, stair-ascent and stair-descent times, respectively. Muscle strength thresholds were 0.93 Nm/kg (95% confidence interval (95% CI) 0.82 1.04), 0.89 Nm/kg (95% CI 0.77-1.02) and 0.97 Nm/kg (95% CI 0.85-1.11) for relationships with timed Get Up and Go, stair-ascent and stair-descent times, respectively. CONCLUSION: In patients with knee osteoarthritis, relationships between muscle strength and activity limitations are non-linear. Patients with muscle strength below the described thresholds might benefit more from muscle strength training to reduce limitations in daily activities than would patients with muscle strength above the thresholds. Further research is needed to assess the clinical value of the thresholds determined. PMID- 28661547 TI - Being a person with disabilities or experiencing disability: Two perspectives on the social response to disability. AB - Disability has a profound impact, both on those who live with it and on society that responds to the needs of people experiencing disability. Society has a primary obligation to respond to the impact of disability. Rehabilitation has an essential role to play here; but its relationship to disability embodies a broader social ambiguity about what it means to experience disability. On the one hand, disability is a mark of a minority group persons with disabilities, which has, historically, been socially disadvantaged. On the other, disability is a matter of how health conditions and associated impairments interact with the physical and social world to create limits on what people can do or become. However, just as health problems are universal over the life course, so too is disability. Everyone experiences disability. This paper explores the historical underpinnings of these two perspectives on disability, in particular how they impact on rehabilitation practice and policy. After surveying the social consequences of these perspectives, the paper attempts to reconcile them in order to enhance the overall effectiveness and relevance of the social response to disability. PMID- 28661548 TI - Efficacy of workplace interventions for shoulder pain: A systematic review and meta-analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials on the efficacy of workplace-based interventions to prevent or treat shoulder pain. DATA SOURCES: A systematic review of 4 databases was performed up to January 2016. STUDY SELECTION: Randomized controlled trials were included if the intervention under study was a workplace-based intervention performed to prevent or reduce shoulder pain and disability in workers. DATA EXTRACTION: The methodological quality of the studies was evaluated and meta analyses were conducted. Pooled mean differences and risk ratios were calculated. DATA SYNTHESIS: Data from 4 studies on strengthening exercises performed in the workplace for workers with shoulder pain (n = 368) were pooled. A statistically significant reduction in pain intensity was observed compared with different control interventions (mean differences (scale out of 10) 1.31 (95% confidence interval (95% CI) 0.86-1.76)). Pooled data from 5 studies on the efficacy of workstation modifications (n = 2,148) showed a statistically significant reduction in the prevalence of shoulder pain with a risk ratio of 1.88 (95% CI 1.20-2.96) compared with different control interventions. CONCLUSION: Low-grade evidence exists that a workplace exercise programme may reduce the intensity of shoulder pain, and that workstation modifications may reduce the prevalence of shoulder pain. PMID- 28661549 TI - Hepatitis C in Pregnancy: Review of Current Knowledge and Updated Recommendations for Management. AB - Importance: An estimated 1% to 2.5% of pregnant women in the United States are infected with hepatitis C virus (HCV), which carries approximately a 6% risk of mother-to-infant transmission. Objectives: The aims of this article are to review the current evidence on HCV in pregnancy and to provide updated recommendations for management. Evidence Acquisition: Original research articles, review articles, and guidelines on HCV in general and specifically in pregnancy were reviewed, as were drug safety profiles from the Food and Drug Administration. Results: Pregnancy appears to have a beneficial effect on the course of maternal chronic HCV infection. However, it is associated with an increased risk of adverse fetal outcomes, including fetal growth restriction and low birth weight, and can be transmitted to the infant in utero or during the peripartum period. No perinatal intervention has been shown to reduce the risk of vertical transmission, but some may increase this risk. To date, no treatment regimens for HCV have been approved for use in pregnancy, but the new ribavirin-free, direct acting antiviral regimens are being used with high efficacy outside pregnancy. Conclusions and Relevance: Hepatitis C virus infection in pregnancy generally does not adversely affect maternal well-being but is associated with adverse effects on the fetus because of pregnancy complications and vertical transmission. There are currently no approved treatment regimens for HCV in pregnancy; this should be an active area of research in obstetrics. PMID- 28661551 TI - Uterine Malformations: An Update of Diagnosis, Management, and Outcomes. AB - Importance: The prevalence of uterine malformations has been reported in up to 7% of the general population and 18% of those with recurrent pregnancy loss. The diagnosis, classification, management, and outcome of the management have been subject to debate for decades. Objective: The aim of this article is to summarize the current knowledge regarding the genetics of mullerian anomalies, the varied classification schemes, the appropriate diagnostic modalities, the surgical methods, and the obstetric outcomes related to these surgical methods. Evidence Acquisition: An extensive literature review using the key words uterine anomaly, classification, mullerian, agenesis, unicornuate, didelphys, bicornuate, septate, arcuate, DES, and diethyl stilbestrol was conducted using PubMed. Only English language publications were reviewed. Relevant references within these publications were also obtained and reviewed in preparing this article. Conclusions: Current evidence favors continued use of the American Society of Reproductive Medicine classification. Three-dimensional sonography, especially when combined with saline infusion, can be very helpful in accurately classifying mullerian anomalies. Relevance: Mullerian anomalies are relatively common. Accurate knowledge of the advantages and limitations of various diagnostic modalities, the limitations of the classification systems, the surgical options available where appropriate, and the obstetric outcomes after these surgeries will help in the optimal management of these patients. PMID- 28661550 TI - Menstrual Hygiene Management in Resource-Poor Countries. AB - Importance: Adequate management of menstrual hygiene is taken for granted in affluent countries; however, inadequate menstrual hygiene is a major problem for girls and women in resource-poor countries, which adversely affects the health and development of adolescent girls. Objective: The aim of this article is to review the current evidence concerning menstrual hygiene management in these settings. Evidence Acquisition: A PubMed search using MeSH terms was conducted in English, supplemented by hand searching for additional references. Retrieved articles were reviewed, synthesized, and summarized. Results: Most research to date has described menstrual hygiene knowledge, attitudes, and practices, mainly in sub-Saharan Africa and South Asia. Many school-based studies indicate poorer menstrual hygiene among girls in rural areas and those attending public schools. The few studies that have tried to improve or change menstrual hygiene practices provide moderate to strong evidence that targeted interventions do improve menstrual hygiene knowledge and awareness. Conclusion and Relevance: Challenges to improving menstrual hygiene management include lack of support from teachers (who are frequently male); teasing by peers when accidental menstrual soiling of clothes occurs; poor familial support; lack of cultural acceptance of alternative menstrual products; limited economic resources to purchase supplies; inadequate water and sanitation facilities at school; menstrual cramps, pain, and discomfort; and lengthy travel to and from school, which increases the likelihood of leaks/stains. Areas for future research include the relationship between menarche and school dropout, the relationship between menstrual hygiene management and other health outcomes, and how to increase awareness of menstrual hygiene management among household decision makers including husbands/fathers and in-laws. PMID- 28661552 TI - Asthma treatment patterns in Dutch children using medication dispensing data. PMID- 28661553 TI - Spectroscopic investigation of the effects of aqueous-phase prepared CdTe quantum dots on protein hemoglobin at the molecular level. AB - 3-Mercaptopropionic Acid-modified CdTe quantum dots (QDs) were synthesized and characterized by infrared, fluorescence, and ultraviolet-visible absorption spectra and Nano-ZetaSizer measurements. Then the interaction between QDs and hemoglobin was studied to investigate the effects of QDs on the structure and function of hemoglobin by using a variety of spectroscopy methods and isothermal titration calorimetry. The results showed van der Waals forces and hydrogen bonding predominantly played major roles in the binding. The intrinsic fluorescence of hemoglobin was quenched with changes to the microenvironment of tyrosine and tryptophan residues and complex conformational changes of hemoglobin were induced with the loosening and unfolding skeleton. However, the heme in hemoglobin was still stable, indicating that the main physiological function of hemoglobin might not be significantly inhibited. This study will provide a new strategy to study the biological toxicity of QDs at the molecular level. PMID- 28661554 TI - Differentiation of olfactory neuroblastomas from nasal squamous cell carcinomas using MR diffusion kurtosis imaging and dynamic contrast-enhanced MRI. AB - PURPOSE: To evaluate the use of magnetic resonance (MR) diffusion kurtosis imaging (DKI) and dynamic contrast-enhanced MR imaging (DCE-MRI) in the differentiation of olfactory neuroblastomas (ONBs) from squamous cell carcinomas (SCCs). MATERIALS AND METHODS: DKI and DCE-MRI were performed in 17 patients with ONBs and 23 patients with SCCs on a 3T MR scanner. Parameters derived from DKI and DCE-MRI were measured and compared between ONBs and SCCs using an independent samples t-test. The sensitivity, specificity, accuracy, positive predictive values (PPV), negative predictive values (NPV), and the area under the receiver operating characteristic (ROC) curve were determined. RESULTS: The mean kurtosis (K) value of ONBs was significantly higher than that of SCCs (P < 0.001), and the mean fractional volume in the extravascular extracellular space (Ve ) value of ONBs was lower than that of SCCs (P < 0.001). The ROC curve analyses yielded a cutoff K value of 0.953, with a sensitivity of 94.1%, a specificity of 69.6%, and an accuracy of 80.0%; the cutoff Ve value was 0.493, with a sensitivity of 70.6%, a specificity of 95.7%, and an accuracy of 85.0%. A parallel test with K value >0.953 or Ve value <=0.493 achieved a sensitivity of 94.1%, a specificity of 100.0%, and an accuracy of 97.5% for differentiating ONBs from SCCs. CONCLUSION: The K value of DKI and Ve value of DCE-MRI have potential use in the differentiation of ONBs and SCCs. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:354-361. PMID- 28661555 TI - Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting. AB - Cryptophycins are a class of 16-membered highly cytotoxic macrocyclic depsipeptides isolated from cyanobacteria. The biological activity is based on their ability to interact with tubulin. They interfere with microtubule dynamics and prevent microtubules from forming correct mitotic spindles, which causes cell cycle arrest and apoptosis. Their strong antiproliferative activities with 100 fold to 1000-fold potency compared with those of paclitaxel and vinblastine have been observed. Cryptophycins are highly promising drug candidates, as their biological activity is not negatively affected by P-glycoprotein, a drug efflux system commonly found in multidrug-resistant cancer cell lines and solid tumors. Cryptophycin-52 had been investigated in phase II clinical trials but failed because of its high neurotoxicity. Recently, cryptophycin conjugates with peptides and antibodies have been developed for targeted delivery in tumor therapy. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28661556 TI - Synopsis of transoral endoscopic laryngopharyngeal surgery for superficial pharyngeal cancers. AB - BACKGROUND: Endoscopic laryngopharyngeal surgery (ELPS) was developed for superficial pharyngeal cancers in Japan. In this study, we present our results of ELPS for superficial pharyngeal cancers. METHODS: From November 2009 to December 2015, 258 patients with superficial pharyngeal cancers underwent ELPS. Results, including survival rates, postoperative complications, and vocal function, are reviewed. RESULTS: The median follow-up period of 258 patients was 31 months. The overall and cause-specific survival rates over 3 years were 85.7% and 100%, respectively. Only 3 patients incurred local recurrences and were successfully salvaged by re-ELPS. Regarding postoperative complications, 4 patients required reoperation because of postoperative bleeding. As for the postoperative quality of life, no patients developed vocal fold paralysis. Every patient was able to consume meals at preoperative levels. CONCLUSION: ELPS is a feasible and minimally invasive treatment for superficial pharyngeal cancers with impressive quality of life results. PMID- 28661557 TI - Indeterminate cell histiocytosis: A case treated with ultraviolet B narrow band phototherapy (NB UVB). PMID- 28661558 TI - Crystal structure of the tricellulin C-terminal coiled-coil domain reveals a unique mode of dimerization. AB - Tricellulin is a tight junction protein localized to tricellular contacts in many epithelial tissues, where it is required for full barrier control. Here, we present crystal structures of the tricellulin C-terminal coiled-coil domain, revealing a potential dimeric arrangement. By combining structural, biochemical, functional, and mutation analyses, we gain insight into the mode of tricellulin oligomerization and suggest a model where dimerization of its cytoplasmic C terminus may play an auxiliary role in stabilizing homophilic and potentially also heterophilic cis-interactions within tight junctions. PMID- 28661559 TI - Use of a midline mandibular osteotomy to improve surgical access for transoral robotic resection of the base of tongue in a patient with trismus. AB - BACKGROUND: The utilization of transoral robotic surgery (TORS) in patients with trismus is limited because of poor surgical exposure. METHODS: This report is about a 46-year-old man with a recurrent right base of tongue cancer who had severe postradiation trismus. We performed a midline mandibular osteotomy without a lip split and this resulted in a markedly improved surgical exposure. He underwent a TORS resection of the right base of the tongue with no significant complications. RESULTS: The midline mandibular osteotomy significantly improved the surgical exposure and facilitated exposure for TORS in a patient who otherwise would not be able to undergo TORS. CONCLUSION: Utilization of a midline mandibular osteotomy allowed for increased exposure for TORS in a patient with limited mouth opening from postradiation trismus. Postoperative hemorrhage remains a significant concern and appropriate measures to mitigate the catastrophic consequences of this should be considered. PMID- 28661560 TI - Pregnancy and spontaneous fetal loss: A pig perspective. AB - Pigs have a unique, non-invasive epitheliochorial placenta where maternal and fetal layers lay in apposition. Indentation of fetal capillaries into the trophoblasts and maternal capillaries into the uterine epithelium reduce the distance between the fetal and maternal blood, ensuring nutrient transfer for proper conceptus development. Another unique feature of pig pregnancy is conceptus-mediated immune cell enrichment during the early stages of conceptus attachment (around gestation Day 15). This period coincides with the development of vasculature networks at the maternal-fetal interface, which is critical for successful conceptus growth. Specific chemokines, their receptors, and chemokine decoy receptor networks coordinate this immune cell enrichment and the positioning at the maternal-fetal interface. The recruited immune cells, in turn, adopt a specialized phenotype to support key processes of maternal-fetal adaptations, including tolerance to the semi-allogeneic fetus and supporting vascularization. Disturbance in coordinated cross talk between the conceptus and maternal endometrium is an important mechanism associated with spontaneous fetal loss. The exact mechanism of fetal loss is still not yet identified, although research in the last two decades point to various factors including genetics, nutrition, uterine capacity, placental efficiency, and imbalanced immune factors at the maternal-fetal interface. In this review, we summarize some of the recent advances in endometrial immune cell functions and their regulation. We also provide insights into endometrial/placental transcriptome, microRNA biology, and extravesicular transport across the maternal-fetal interface, as well as their potential implications in porcine pregnancy success or failure. PMID- 28661561 TI - Comparative safety of pioglitazone versus clinically meaningful treatment alternatives concerning the risk of bladder cancer in older US adults with type 2 diabetes. AB - AIMS: To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl peptidase-4 inhibitors [DPP-4s] or sulfonylureas. METHODS: We identified Medicare beneficiaries aged >65 years who initiated treatment with pioglitazone (N = 38 700), DPP-4s (N = 82 552) or sulfonylureas (N = 126 104) between 2007 and 2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6-month induction/latency period, censoring for treatment change, death or end of 2014. We used propensity score-weighted Cox proportional hazards models to obtain adjusted hazard ratios (aHR) and their 95% confidence intervals. RESULTS: Overall mean age of participants was 75 years and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased incidence of bladder cancer (308 vs 204 [DPP-4s] or 231 [sulfonylureas] per 100 000 person-years; aHR, 1.57 [1.23 2.00] vs DPP-4s and 1.32 [1.02-1.70] vs sulfonylureas). The increased risk emerged within the first 2 years of treatment (aHR, 1.63 [1.22-2.17] vs DPP-4s and 1.32 [0.98-1.78] vs sulfonylureas). If treatment was discontinued within the first 2 years, the risk after 2 years post initiation was attenuated (aHR, 0.89 [0.61-1.28]) compared with patients treated for more than 2 years (aHR, 1.45 [0.93-2.26]) both vs DPP-4s. Findings were consistent across secondary and sensitivity analyses. CONCLUSIONS: Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP-4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in risk of bladder cancer. PMID- 28661563 TI - Evaluation of a new methodology to simulate damage and wear of polyethylene hip replacements subjected to edge loading in hip simulator testing. AB - Wear and fatigue of polyethylene acetabular cups have been reported to play a role in the failure of total hip replacements. Hip simulator testing under a wide range of clinically relevant loading conditions is important. Edge loading of hip replacements can occur following impingement under extreme activities and can also occur during normal gait, where there is an offset deficiency and/or joint laxity. This study evaluated a hip simulator method that assessed wear and damage in polyethylene acetabular liners that were subjected to edge loading. The liners tested to evaluate the method were a currently manufactured crosslinked polyethylene acetabular liner and an aged conventional polyethylene acetabular liner. The acetabular liners were tested for 5 million standard walking cycles and following this 5 million walking cycles with edge loading. Edge loading conditions represented a separation of the centers of rotation of the femoral head and the acetabular liner during the swing phase, leading to loading of the liner rim on heel strike. Rim damage and cracking was observed in the aged conventional polyethylene liner. Steady-state wear rates assessed gravimetrically were lower under edge loading compared to standard loading. This study supports previous clinical findings that edge loading may cause rim cracking in liners, where component positioning is suboptimal or where material degradation is present. The simulation method developed has the potential to be used in the future to test the effect of aging and different levels of severity of edge loading on a range of cross-linked polyethylene materials. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1456-1462, 2018. PMID- 28661562 TI - Predictors of visual outcome in patients operated for craniopharyngioma - a Danish national study. AB - PURPOSE: Craniopharyngioma often causes visual loss due to the close relation to the anterior visual pathways. This study investigates the incidence and predictors of visual outcomes in patients with craniopharyngioma. METHODS: Data from sixty-six patients who underwent surgery for craniopharyngioma from 2009 to 2013 in Denmark were reviewed. Primary outcomes were visual acuity (VA) and visual field (VF) defects from pre-and postoperative visits. Secondary outcomes were optic nerve atrophy (OA) and papilledema. RESULTS: Fifty-eight patients were included. The VA of the patients 1-year after surgery improved by -0.16 log(MAR) (95%CI: -0.30 to -0.02; p = 0.0266). Visual field (VF) defects worsened in 17 eyes (30%), remained stable in 21 eyes (37%) and improved in 19 eyes (33%). The presence of papilledema and the absence of OA were significantly correlated with an improvement in VA postoperatively (p = 0.011 and p = 0.011, respectively). Patients undergoing surgery within a week or less after their first ophthalmological examination had a significant improvement in VA (-0.36; 95%CI: 0.62 to -0.09; p = 0.0099). Patients undergoing surgery using a subfrontal approach also showed improvement in VA (p = 0.048). Tumour recurrence had a significantly worse VA outcome (p = 0.0074). CONCLUSION: Patients show a slight improvement in VA 1-year after operation for craniopharyngioma. The presence of papilledema and early surgical intervention is associated with a significant improvement in VA. Early involvement of a dedicated ophthalmologist is recommended to secure an early detection of a visual decline and potential tumour recurrence. PMID- 28661564 TI - Short-term intensive insulin therapy could be the preferred option for new onset Type 2 diabetes mellitus patients with HbA1c > 9. AB - Type 2 diabetes mellitus (T2DM) is a heterogeneous disease. Currently, the typical clinical therapeutic pathway for the disease consists of the stepwise addition of antihyperglycemic preparations over time, followed lastly by insulin therapy when functional beta-cell capacity is severely deteriorated. Recognizing the complexity of disease management, personalized (precision) medicine approaches may enable the physician to tailor diabetes treatment based on HbA1c levels, body mass index (BMI), efficacy, risk of hypoglycemia, risk of weight gain, age, safety, cost, and even genetic characteristics. Although insulin therapy has traditionally been recommended as the last option in the sequential treatment algorithm of T2DM, it is notable that several guidelines and consensus statements suggest consideration of insulin as part of a first-line regimen. In the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive T2DM 2017 management algorithm, insulin is recommended for T2DM patients presenting with symptoms and an HbA1c >9.0%. In addition, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus statement recommends initial insulin therapy as an option when HbA1c >=9%, and definite consideration with HbA1c >=10-12%, and mentions that it may be possible to taper off insulin once initial glucotoxicity is reversed and to consider transfer to other types of non-insulin therapies. Based on accumulating evidence, an expert group has endorsed the concept of short term intensive insulin (STII) therapy as an option for some patients with T2DM at the time of diagnosis. Notably, the latest Israeli guidelines suggest considering immediate, sometimes short-term, insulin treatment for patients with HbA1c >9% or with symptoms. It has been reported that nearly one-quarter (23%) of newly diagnosed T2DM patients in the US had an HbA1c >=9.0% prior to initiation of treatment. For such patients, initiating insulin is difficult, although it has been almost 10 years since the ACE/AACE Diabetes Road Map suggested insulin therapy for treatment-naive patients with high HbA1c. Lack of patient education resources in primary care and of provider knowledge as to approaches to insulin treatment (insulin initiation dosage, multiple daily injection or basal insulin supplement, insulin treatment duration) are major obstacles to selecting appropriately intensive but also timely therapy for newly diagnosed T2DM patients in clinical practice so as to minimize avoidable glycemic exposure. Treatment with STII early in the course of T2DM is of considerable interest. There is a wide range of evidence currently available supporting the use of STII therapy in newly diagnosed T2DM. For example, STII can quickly normalize glycemic control, improve beta-cell function, restore first-phase insulin secretion, and even reduce glucagonemia in newly diagnosed T2DM, suggesting that it may provide unique capacity for modification of the natural process of diabetes. The largest and most robust clinical trial of STII therapy enrolled 382 newly diagnosed people with T2DM at nine centers in China and randomized them to either insulin (short-term continuous subcutaneous insulin infusion [CSII] or multiple daily injections [MDI]) or oral anti-hyperglycemic therapy. First-phase insulin secretion was increased in all three groups after 2 weeks of normoglycemia. Remission rates at 1 year were higher in the two insulin-treated groups (51.1% in the CSII group, 44.9% in the MDI group) than in the oral therapy group (26.7%). Furthermore, the increase in first-phase insulin response was maintained at 1 year in the two insulin-treated groups, but declined in the group allocated to oral medication (Fig. ). A beneficial effect of insulin therapy over oral anti diabetic agents was also observed by Chen et al. [Figure: see text] A meta analysis, including seven studies and 839 participants, further underscored the robustness of the evidence supporting STII therapy by showing that the proportion of patients in drug-free remission was 66.2% at 3 months, 58.9% at 6 months, 46.3% at 12 months, and 42.1% at 24 months. All but one study showed an improvement in beta-cell function, as assessed by homeostatic model assessment of beta-cell function (HOMA-B), and all but one study showed a decrease in insulin resistance, as assessed by homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, STII has beneficial effects on both the fundamental pathophysiological mechanisms of T2DM (beta-cell dysfunction and insulin resistance). Recent animal studies suggest a potential mechanism for such clinical benefits: beta-cells dedifferentiate to endocrine progenitor-like cells during stress-induced hyperglycemia, and strictly normalizing blood glucose by insulin therapy could induce dedifferentiated cell redifferentiation to mature beta-cells, and hence restoration of drug responsivity. In addition to its glucose-lowering activity, insulin may contribute to improved beta-cell function by its antilipolytic, anti-inflammatory, and antiapoptotic effects. We recognized that not all newly diagnosed people with T2DM would experience improved beta-cell function or achieve long-term remission following cessation of STII. It would be worthwhile to precisely identify the subpopulation more likely to benefit from this strategy. Previous studies have suggested that lower baseline fasting glucose, higher BMI, better early phase insulin secretion, and lower exogenous insulin requirements may be predictors of diabetes remission in newly diagnosed patients treated with STII therapy. A recent study demonstrated that a shorter duration of diabetes supplanted baseline HbA1c and beta-cell function as an independent predictor of remission. In particular, diabetes duration <2 years predicted sustained remission, suggesting that the key determinant of inducing persistent drug-free diabetes remission with STII is early intervention. Although reluctance to initiate insulin treatment in T2DM is well described, it is interesting to see that when introduced early in the course of the disease as a short-term treatment, STII resulted in significant improvement in patient reported quality of life and treatment satisfaction, demonstrating the patient acceptability of early insulin therapy. In our clinical experience, patients often request insulin resumption after a trial has ended because of the good clinical outcomes and the recognition that such treatment is much easier and better tolerated than expected. The pros and cons of STII therapy for new-onset T2DM patients with HbA1c >9%, based on current evidence and our understanding, are listed in Table . It is important that STII be considered an option at this early stage of the disease. Existing studies and clinical experience do indicate that this concept is very well received by patients and clinicians alike, especially when they realize that insulin only needs to be used for a few weeks, and that STII at that point in time does not necessarily require continuing long term insulin therapy. Numerous public health, clinical efficacy and effectiveness, and cost-effectiveness questions need to be better understood before widespread adoption of this novel treatment regimen can be more endorsed. [Table: see text]. PMID- 28661566 TI - Rational Engineering of Photoconvertible Fluorescent Proteins for Dual-Color Fluorescence Nanoscopy Enabled by a Triplet-State Mechanism of Primed Conversion. AB - Green-to-red photoconvertible fluorescent proteins (pcFPs) are powerful tools for super-resolution localization microscopy and protein tagging. Recently, they have been found to undergo efficient photoconversion not only by the traditional 400 nm illumination but also by an alternative method termed primed conversion, employing dual wavelength illumination with blue and far-red/near-infrared light. Primed conversion has been reported only for Dendra2 and its mechanism has remained elusive. Here, we uncover the molecular mechanism of primed conversion by reporting the intermediate "primed" state to be a triplet dark state formed by intersystem crossing. We show that formation of this state can be influenced by the introduction of serine or threonine at sequence position 69 (Eos notation) and use this knowledge to create "pr"- (for primed convertible) variants of most known green-to-red pcFPs. PMID- 28661567 TI - Flocculation of Clay Colloids Induced by Model Polyelectrolytes: Effects of Relative Charge Density and Size. AB - Flocculation and its tuning are of utmost importance in the optimization of several industrial protocols in areas such as purification of waste water and civil engineering. Herein, we studied the polyelectrolyte-induced flocculation of clay colloids on a model system consisting of purified clay colloids of well defined size fractions and ionene polyelectrolytes presenting regular and tunable chain charge density. To characterize ionene-induced clay flocculation, we turned to the combination of light absorbance (turbidity) and zeta-potential measurements, as well as adsorption isotherms. Our model system allowed us to identify the exact ratio of positive and negative charges in clay-ionene mixtures, the (c+/c-) ratio. For all samples studied, the onset of efficient flocculation occurred consistently at c+/c- ratios significantly below 1, which indicated the formation of highly ionene-deficient aggregates. At the same time, the zeta-potential measurements indicated an apparent zero charge on such aggregates. Thus, the zeta-potential values could not provide the stoichiometry inside the clay-ionene aggregates. The early onset of flocculation in clay-ionene mixtures is reminiscent of the behavior of multivalent salts and contrasts that of monovalent salts, for which a large excess amount of ions is necessary to achieve flocculation. Clear differences in the flocculation behavior are visible as a function of the ionene charge density, which governs the conformation of the ionene chains on the clay surface. PMID- 28661565 TI - A brief review of intradialytic hypotension with a focus on survival. AB - Intradialytic hypotension (IDH), a common complication of ultrafiltration during hemodialysis therapy, is associated with high mortality and morbidity. IDH, defined as a nadir systolic blood pressure of less than 90 mm Hg on more than 30% of treatments, is a relevant definition and is correlated with mortality. Risk factors for IDH include patient demographics, anti-hypertensive medication use, larger interdialytic weight gain, and dialysis prescription features as dialysate sodium, high ultrafiltration rate, and dialysate temperature. A high frequency of IDH events carries a substantial death risk. An ultrafiltration rate >10 mL/h/kg, and even more so >13 mL/h/kg, is highly predictive of cardiovascular and all cause mortality. Evidence suggests that IDH causes acute reversible segmental myocardial hypoperfusion and contractile dysfunction (myocardial stunning), which can result in long-term loss of myocardial contractility, leading to premature death. IDH also has negative end-organ effects on the brain and gut, contributing to mortality through stroke, and endotoxin translocation with associated inflammation and protein-energy wasting. Given strong association of IDH and dialysis mortality, a paradigm shift to its approach is urgently needed. Randomized controlled trials are required to prospectively test drugs and monitoring devices which may reduce IDH. PMID- 28661568 TI - Everolimus-induced nephrotic syndrome precipitated by interaction with voriconazole in a patient with Hodgkin's lymphoma. AB - WHAT IS KNOWN AND OBJECTIVES: Everolimus is a small molecule that inhibits the mammalian target of rapamycin (mTOR) and is used for treatment of various solid tumours and renal transplant rejection prophylaxis. Whereas everolimus-induced proteinuria was previously observed in 3%-36% renal transplant recipients, nephrotic syndrome was not reported in cancer patients taking everolimus. However, nephrotic syndrome was reported in patients taking sirolimus. CASE SUMMARY: We report the case of a 32-year-old female with relapsed Hodgkin's lymphoma who was on everolimus for 5 years and developed nephrotic syndrome about 2 months after initiation of voriconazole. She was on 10 mg everolimus once a day and 200 mg voriconazole twice a day orally. Renal biopsy revealed thrombotic microangiopathic vasculopathy and thin basement membrane nephropathy. Discontinuation of everolimus and voriconazole rapidly improved her nephrotic syndrome. WHAT IS NEW AND CONCLUSION: We provide in-depth analysis of the underlying mechanisms of everolimus-induced nephrotic syndrome and hypothesize that voriconazole likely decreased everolimus metabolism. In the era of targeted therapy for cancer, healthcare providers should be aware of the drug-drug interaction between everolimus (as well as tyrosine kinase inhibitors) and cytochrome P450 CYP3A4 inhibitors (ie voriconazole). PMID- 28661569 TI - Effect of active evaluation on the detection of negative dysphotopsia after sequential cataract surgery: discrepancy between incidences of unsolicited and solicited complaints. AB - PURPOSE: To evaluate the incidence of negative dysphotopsia after sequential cataract surgery. METHODS: Retrospective cohort study. The incidence of negative dysphotopsia was assessed by retrospective reviewing of medical records and interviews with patients between 2 and 4 months after sequential cataract surgery. Inclusion criteria were uncomplicated surgery, postoperative corrected distance visual acuity (CDVA) >=20/25 Snellen and the absence of ocular comorbidity. The majority of intra-ocular lens (IOL) implants were one-piece AcrySof SN60WF (161 eyes). Other IOLs (29 eyes) were toric (SN6AT3-6), spherical (SN60AT), three-piece (MN60MA) and multifocal (ReSTOR SN6AD1, PanOptix TFNT00 and Finevision Micro F trifocal). RESULTS: The study population was comprised of 95 patients with a mean age of 72 +/- 10 years. Unsolicited complaints of negative dysphotopsia were reported by eight patients (8%), and two of them had a resolution of symptoms within 1 month of follow-up. Eighteen patients (19%) reported negative dysphotopsia at the time of the interview. Two patients reported bothersome negative dysphotopsia, and one of them was successfully treated with implantation of a supplementary IOL in the ciliary sulcus. Patients with negative dysphotopsia were younger than patients without dysphotopsia (p = 0.045) and had shorter axial eye length (p = 0.04), a tendency for higher IOL power (p = 0.09) and a higher CDVA (p = 0.001). CONCLUSION: The incidence of unsolicited negative dysphotopsia after sequential cataract surgery appears to be a substantial underestimation of complaints identified in active interviewing. Although symptoms are not bothersome in the majority of cases, some patients with undiagnosed severe negative dysphotopsia may benefit from reassurance or secondary treatment. PMID- 28661570 TI - One gene-one name: the AvrLmJ1 avirulence gene of Leptosphaeria maculans is AvrLm5. AB - Leptosphaeria maculans, the causal agent of blackleg disease, interacts with Brassica napus (oilseed rape, canola) and other Brassica hosts in a gene-for-gene manner. The avirulence gene AvrLmJ1 has been cloned previously and shown to interact with an unidentified Brassica juncea resistance gene. In this study, we show that the AvrLmJ1 gene maps to the same position as the AvrLm5 locus. Furthermore, isolates complemented with the AvrLmJ1 locus confer avirulence towards B. juncea genotypes harbouring Rlm5. These findings demonstrate that AvrLmJ1 is AvrLm5 and highlight the need for shared resources to characterize accurately avirulence and/or resistance genes. PMID- 28661571 TI - Polyglycerol Surfmers and Surfactants for Direct and Inverse Miniemulsion. AB - Poly(ethylene glycol)-based surfactants are a prominent example for nonionic surfactants. Poly(glycerol) (PG) is discussed as a polyfunctional alternative, however, it is not yet used to stabilize miniemulsions. The anionic polymerization of glycidyl ethers is used to prepare surfactants for direct or inverse emulsions and ambident surfactants by adjusting the copolymer composition. Orthogonal-protected poly(glycerol) block copolymers, using ethoxyethyl glycidyl ether and allyl glycidyl ether (AGE) or tert-butyl glycidyl ether (tBuGE), are synthesized. After cleavage of the acetal groups, these all polyglycerol surfactants (PG-b-PtBuGE) or multifunctional surfmers (PG-b-PAGE), are used in direct and inverse miniemulsion polymerizations. Polystyrene nanoparticles are obtained by free-radical miniemulsion polymerization, in which the allyl-functionalized copolymers act as surfmer. In inverse miniemulsion, hydroxyethyl starch nanocarriers are synthesized with PG-b-PAGE as surfmer, transferred into aqueous PG-b-PtBuGE solution, and functionalized by thiol-ene addition. The PG-b-PtBuGE with equal block length ratio is used as a surfactant for direct and inverse miniemulsions. With the PG being covalently bound to the nanocarriers, a desorption during protein adsorption does not occur. It is believed that these surfactants are promising alternatives to conventional surfactants with additional functionality. PMID- 28661572 TI - Delays in the diagnosis and initial treatment of bladder cancer in Western Australia. AB - OBJECTIVES: To quantify and examine the causes of delays in the diagnosis and initial treatment of patients with bladder cancer in Western Australia. SUBJECTS AND METHODS: All attendances at a one-stop haematuria clinic at a public tertiary level hospital in Western Australia between May 2008 and April 2014 were reviewed retrospectively. All patients diagnosed with a bladder tumour over this period were identified. These patients and their general practitioners were contacted retrospectively and invited to participate in telephone interviews, with additional data collected from clinical records as required. Waiting times to presentation, referral, assessment, and initial treatment were established for patients who presented with visible haematuria. RESULTS: Of 1 365 attendances, 151 patients were diagnosed with a bladder tumour and 100 of these were both suitable and agreed to participate in the study. For patients with visible haematuria the median (range) waiting time from initial bleeding to surgery was 69.5 (9-1 165) days. This was comprised of a median (range) pre-referral waiting time of 12 (0-1 137) days, assessment waiting time of 23.5 (0-207) days, and treatment waiting time of 20 (1-69) days. Reasons for prolonged waiting times included poor public awareness, patient fear and anxiety, delayed and non referral from primary care, administrative delays, and resource limitations. CONCLUSION: Many patients experience significant delays in the diagnosis and treatment of their bladder cancer in Western Australia, and this probably reflects national trends. These concerning data warrant consideration of how delays can be reduced to improve outcomes for these patients. PMID- 28661574 TI - Hyperthermia effect and antibacterial efficacy of Fe3+ /Co2+ co-substitutions in beta-Ca3 (PO4 )2 for bone cancer and defect therapy. AB - The combined effect of cobalt and iron substitutions in beta-Ca3 (PO4 )2 as a potent material for application in hyperthermia and as a bone substitute is presented. Structural analysis reveals the preferential accommodation of Co2+ and Fe3+ at the Ca2+ (5) sites of beta-Ca3 (PO4 )2 until the limit of ~10 mol % and, thereafter, prefer Ca2+ (4) lattice sites. Occupancy of both the Co2+ and Fe3+ ions induces a significant contraction of the beta-Ca3 (PO4 )2 unit cell. The Co2+ /Fe3+ co-substitutions in beta-Ca3 (PO4 )2 display magnetic characteristics that enhances hyperthermia effect. In addition, the presence of Co2+ in beta-Ca3 (PO4 )2 enunciates pronounced antibacterial efficacy against tested microorganisms. Nevertheless, the enhanced level of Co2+ in beta-Ca3 (PO4 )2 results to induce significant toxicity. The biocompatibility of the synthesized thermoseeds is verified from the hemolytic tests and cytotoxicity test performed on human sarcoma cell line MG-63. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1317-1328, 2018. PMID- 28661573 TI - Depressive symptoms predict cancer caregivers' physical health decline. AB - BACKGROUND: Cancer caregiving has been associated with worsening health among caregivers themselves, yet demographic and psychosocial predictors of their long term health decline are less known. This study examines changes in caregivers' physical health 2 to 8 years after their family members' cancer diagnosis and prospective predictors of that change. METHODS: Caregivers (n = 664; mean age, 53.2 years) participated in a nationwide study at 2 (T1), 5 (T2), and 8 (T3) years after their family members' cancer diagnosis. Physical health (12-item Medical Outcomes Study Short Form Health Survey Physical Component Scale) was assessed T1 through T3 as outcome. Predictors were self-reported at T1, including caregiver demographics (age, sex, education, income, relationship to patient, and employment status), patient cancer severity (from medical records), and caregiver psychosocial factors (caregiving stress, caregiving esteem, social support, and depressive symptoms). Latent growth modeling tested predictors of caregivers' initial physical health and their physical health change across time. RESULTS: At T1, caregivers reported slightly better physical health than the US population (M = 51.22, P = .002), which declined over the following 6 years (Mslope = -0.27, P < .001). All demographic factors, patient cancer severity, and T1 caregiving stress were related to caregivers' initial physical health (P <= .03). Higher depressive symptoms were unrelated to caregivers' initial physical health, but were the only significant predictor of caregivers' more rapid physical health decline (B = -0.02, P = .004). CONCLUSION: Findings highlight the unique contribution of caregivers' depressive symptoms to their physical health decline. Assessing and addressing depressive symptoms among caregivers early in the cancer survivorship trajectory may help to prevent premature health decline among this important yet vulnerable population. Cancer 2017;123:4277-4285. (c) 2017 American Cancer Society. PMID- 28661575 TI - Next generation phenotyping in Emanuel and Pallister-Killian syndrome using computer-aided facial dysmorphology analysis of 2D photos. AB - High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of next generation phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely consideration of (molecular) cytogenetics during the diagnostic quest. As NGP we used in this study the facial dysmorphology novel analysis (FDNA) technology to automatically identify facial phenotypes associated with Emanuel (ES) and Pallister-Killian Syndrome (PKS) from 2D facial photos. The comparison between ES or PKS and normal individuals expressed a full separation between the cohorts. Our results show that NPG is able to help in the clinic, and could reduce the time patients spend in diagnostic odyssey. It also helps to differentiate ES or PKS from each other and other patients with small supernumerary marker chromosomes, especially in countries with no access to more sophisticated genetic approaches apart from banding cytogenetics. Inclusion of more facial pictures of patient with sSMC, like isochromosome-18p-, cat-eye-syndrome or others may contribute to higher detection rates in future. PMID- 28661576 TI - Physiological alterations associated with intrauterine growth restriction in fetal pigs: Causes and insights for nutritional optimization. AB - Intrauterine growth restriction (IUGR) remains a major problem in swine production since the associated low birth weight leads to high rates of pre weaning morbidity and mortality plus permanent retardation of growth and development. Complex biological events-including genetics, epigenetics, maternal maturity, maternal nutrition, placenta efficiency, uterine capacity, and other environmental factors-can affect fetal growth and development during late gestation, as well as maturity of oocytes, duration of estrus, and both implantation and placentation of conceptuses in uteri of sows. Understanding the physiological changes related to initiation and progress of IUGR are, therefore, of great importance to formulate nutritional strategies that can mitigate IUGR in gilts and sows. Altering the nutritional status of sows prior to mating and during early-, mid-, and late-gestation may be effective at increasing the uniformity of oocytes and conceptuses, decreasing variation among conceptuses during elongation and implantation, and preventing increases in within-litter variation in fetal weights during late gestation. This review summarizes current progress on physiological alterations responsible for IUGR fetuses, as well as possible nutritional interventions to prevent the initiation and continuation of IUGR in gilts and sows. PMID- 28661577 TI - Atypical uterine cervix metastases from invasive lobular carcinoma of the breast. PMID- 28661578 TI - Fluoro-Carba-Sugars are Glycomimetic Activators of the glmS Ribozyme. AB - The glmS ribozyme is a bacterial gene-regulating riboswitch that controls cell wall synthesis, depending on glucosamine-6-phosphate as a cofactor. Due to the presence of this ribozyme in several human pathogen bacteria (e.g., MRSA, VRSA), the glmS ribozyme represents an attractive target for the development of artificial cofactors. The substitution of the ring oxygen in carbohydrates by functionalized methylene groups leads to a new generation of glycomimetics that exploits distinct interaction possibilities with their target structure in biological systems. Herein, we describe the synthesis of mono-fluoro-modified carba variants of alpha-d-glucosamine and beta-l-idosamine. (5aR)-Fluoro-carba alpha-d-glucosamine-6-phosphate is a synthetic mimic of the natural ligand of the glmS ribozyme and is capable of effectively addressing its unique self-cleavage mechanism. However, in contrast to what was expected, the activity is significantly decreased compared to its non-fluorinated analog. By combining self cleavage assays with the Bacillus subtilis and Staphylococcus aureus glmS ribozyme and molecular docking studies, we provide a structure-activity relationship for fluorinated carba-sugars. PMID- 28661579 TI - Investigation of perioperative complications associated with use of uterine compression sutures. AB - OBJECTIVE: To assess the association between use of uterine compression sutures (UCSs) and postoperative complications. METHODS: In a retrospective analysis, data were reviewed from cesarean deliveries at a medical center in Osaka, Japan, between January 2011 and March 2016. The deliveries were divided into elective and emergency cesarean groups. For each group, data on postoperative complications were compared between patients with UCSs and those without UCSs but at least 1500 mL of blood loss. RESULTS: Data from 158 patients were included in the study. No severe complications were observed. Among the patients who underwent elective cesarean, no differences were observed between the UCS and non UCS groups in the frequency of postoperative endometritis (3/28 [10.7%] vs 6/54 [11.1%]; P=0.957) or ileus (2/28 [7.1%] vs 3/54 [5.6%]; P=0.776). After emergency cesarean, postoperative endometritis was significantly more common in the UCS than in the non-UCS group (8/39 [20.5%] vs 4/37 [10.8%]; P=0.021), but the frequency of ileus did not differ (1/39 [2.6%] vs 2/37 [5.4%]; P=0.61). CONCLUSION: Use of UCSs during emergency cesarean delivery might increase the risk of postoperative endometritis. PMID- 28661580 TI - A review of endophenotypes in schizophrenia and autism: The next phase for understanding genetic etiologies. AB - Many psychiatric disorders are caused by multiple genes and multiple environmental factors, making the identification of specific genetic risk factors for these disorders difficult. Endophenotypes are behaviors or characteristics that are intermediate between the genotype and a phenotype of interest. Because they are more directly related to the gene action than is the endpoint disorder, they may be useful in the identification of specific genes related to psychiatric disorders and the classification of disorders or traits that share an underlying genetic etiology. We discuss genetic and endophenotype research on schizophrenia and autism spectrum disorder (ASD) in this review. Some of the psychophysiological endophenotypes that have been studied for schizophrenia include prepulse inhibition of the startle response, the antisaccadic task assessing frontal lobe function, inhibition of the P50 event-related potential (ERP), and other auditory ERP measures. Potential ASD endophenotypes include theory of mind, language skills (specifically, age at first spoken word and first spoken phrase), social skills, and certain brain functions, such as asynchronization of neural activity and brain responses to emotional faces. Because the link between genes and specific psychiatric disorders is difficult to determine, identification of endophenotypes is useful for beginning the search to identify specific genes that affect these disorders. PMID- 28661581 TI - Benzoyl Peroxide as an Efficient Dopant for Spiro-OMeTAD in Perovskite Solar Cells. AB - Although organic small molecule spiro-OMeTAD is widely used as a hole-transport material in perovskite solar cells, its limited electric conductivity poses a bottleneck in the efficiency improvement of perovskite solar cells. Here, a low cost and easy-fabrication technique is developed to enhance the conductivity and hole-extraction ability of spiro-OMeTAD by doping it with commercially available benzoyl peroxide (BPO). The experimental results show that the conductivity increases several orders of magnitude, from 6.2*10-6 S cm-1 for the pristine spiro-OMeTAD to 1.1*10-3 S cm-1 at 5 % BPO doping and to 2.4*10-2 S cm-1 at 15 % BPO doping, which considerably outperform the conductivity of 4.62*10-4 S cm-1 for the currently used oxygen-doped spiro-OMeTAD. The fluorescence spectra suggest that the BPO-doped spiro-OMeTAD-OMeTAD layer is able to efficiently extract holes from CH3 NH3 PbI3 and thus greatly enhances the charge transfer. The BPO-doped spiro-OMeTAD is used in the fabrication of perovskite solar cells, which exhibit enhancement in the power conversion efficiency. PMID- 28661582 TI - Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis. AB - Tyrosinase-related protein 1 (TYRP1) is one of three tyrosinase-like glycoenzymes in human melanocytes that are key to the production of melanin, the compound responsible for the pigmentation of skin, eye, and hair. Difficulties with producing these enzymes in pure form have hampered the understanding of their activity and the effect of mutations that cause albinism and pigmentation disorders. Herein we show that the typical tyrosinase-like subdomain of TYRP1 contains two zinc ions in the active site instead of copper ions as found in tyrosinases, which explains why TYRP1 does not exhibit tyrosinase redox activity. In addition, the structures reveal for the first time that the Cys-rich subdomain, which is unique to vertebrate melanogenic proteins, has an epidermal growth factor-like fold and is tightly associated with the tyrosinase subdomain. Our structures suggest that most albinism-related mutations of TYRP1 affect its stability or activity. PMID- 28661583 TI - MnO2 -Promoted Oxidative Radical Sulfonylation of Haloalkynes with Sulfonyl Hydrazides: C(sp)-S Bond Formation towards Alkynyl Sulfones. AB - A catalyst-free oxidative radical sulfonylation of haloalkynes with sulfonyl hydrazides is reported. It represents an example of C(sp)-S bond formation using sulfonyl hydrazides as sulfonyl radical sources. Various alkynyl sulfones were synthesized in moderate to good yields. Having MnO2 as the oxidant is very critical for this transformation. Remarkably, the self-coupling reaction of haloalkynes through C(sp)-C(sp) bond formation is significantly inhibited under the standard reaction conditions. PMID- 28661584 TI - Clinical and palliative care outcomes for patients of poor performance status treated with antiprogrammed death-1 monoclonal antibodies for advanced melanoma. AB - BACKGROUND: Antiprogrammed death-1 antibodies (anti-PD1) have response rates of 40% in metastatic melanoma. Patients with poor performance status (PS) were excluded from clinical trials, yet use of anti-PD1 is widespread in clinical practice. Literature regarding clinical and palliative care outcomes in patients with poor PS treated with anti-PD1 is lacking. METHODS: Retrospective review of outcomes for all patients with advanced melanoma treated with anti-PD1 between 2012 and June 2015 at Peter MacCallum Cancer Centre, a tertiary specialist cancer center in Australia. RESULTS: Between 2012 and 2015, 91 patients received anti PD1: median age 63, 65% males, 77% elevated LDH>1xULN (37/48 patients). Fifty eight patients had baseline ECOG PS of 0-1 (64%), 24 patients ECOG PS 2-3 (26%) and ECOG PS was not recorded in nine patients (10%). Median overall survival (OS) for the ECOG PS 0-1 group was 19.5 months and 1.8 months for ECOG PS 2-3 (HR 5.5; 95% CI, 9.1-50.3; P = 0.0001). Tumor response was 23/58 (39%) in ECOG PS 0-1, 2/16 (12%) in ECOG PS 2 and 0/8 in ECOG PS 3. Toxicity did not differ between different groups. ECOG PS 2-3 patients were more likely to be treated and hospitalized within the last month of life compared to ECOG PS 0-1 patients, RR 1.75 (95% CI, 1.04-2.56, P = 0.019) and RR 1.73 (95% CI, 1.10-2.16, P = 0.009), respectively. ECOG PS 2-3 patients were more likely to die in an acute hospital RR 2.68 (95% CI, 1.17-6.51, P = 0.016). CONCLUSIONS: Patients with poor baseline PS have a significantly lower OS and reduced response to anti-PD1. Further quality of life and palliative care research is needed. PMID- 28661586 TI - In vivo Optical Imaging / Intravital Microscopy. PMID- 28661585 TI - Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4). AB - AIMS: Insulin glargine 300 U/mL (Gla-300) offers a flatter pharmacodynamic profile than insulin glargine 100 U/mL (Gla-100). We have compared these insulins over 1 year in people with type 1 diabetes (T1DM). METHODS: EDITION 4 was a 6 month, multicentre, randomized, open-label phase 3 study. People with T1DM who completed the 6 months continued randomized Gla-300 or Gla-100 once daily, morning or evening, for a further 6 months. RESULTS: Among 549 participants randomized, 444 completed the 12-month study period (Gla-300, 80%; Gla-100, 82%). Mean HbA1c decreased similarly from baseline to month 12 in the 2 treatment groups (difference, 0.02 [95% CI, -0.13 to 0.17]) %-units [0.2 (-1.5 to 1.9) mmol/mol]), to a mean of 7.86 %-units (62.4 mmol/mol) in both groups. For morning vs evening injection, there was no difference in HbA1c change over 12 months for Gla-100, but a significantly larger decrease in HbA1c was observed in the Gla-300 morning group than in the Gla-300 evening group (difference, -0.25 [-0.47 to 0.04] %-units [-2.7 (-5.2 to -0.4) mmol/mol]). Mean glucose from the 8-point SMPG profiles decreased from baseline, and was similar between the 2 treatment groups. Basal insulin dose was 20% higher with Gla-300 than with Gla-100, while hypoglycaemia event rates, analysed at night, over 24 hours, or according to different glycaemic thresholds, did not differ between treatment groups, regardless of injection time. Adverse event profiles did not differ between groups. CONCLUSIONS: In T1DM, Gla-300 provides glucose control comparable to that of Gla-100, and can be given at any time of day. PMID- 28661588 TI - [[Influence of Nutrition Nature on Acid-Base Balance in the Mouth and the Risk of Dental Diseases].] AB - : The aim was to investigate the acid-base balance in the mouth and assess the risk of dental disease in practically healthy persons depending on the habitual diet. MATERIALS AND METHODS: The study involved 162 people, divided into three groups: with a mixed diet, with protein foods of animal origin and vegetarians. There were studied the pH value of oral fluid, dental, lingual plaque at stimulation with sucrose and urea. RESULTS: In individuals, characterized by the habitual diet, there are statistically significant persistent changes in acid base balance in the mouth, which provoke an increased risk of developing dental diseases. At normal mixed diet there is moving the acid-base balance towards weak acidosis that in the presence of other predisposing factors can lead to the risk of devel- opment of dental caries. There is a displacement of acid-base balance in the oral cavity to the alkaline side in case the long predominant consumption of protein foods of animal origin, that is dangerous in terms of formation of hard dental deposits and consequently of the development of inflammatory periodontal diseases. In vegetarians, there is a persistent shift of acid alkaline balance in the mouth in the direction of acidosis, which is a risk factor for development of dental caries. PMID- 28661587 TI - Endochondral Ossification in Critical-Sized Bone Defects via Readily Implantable Scaffold-Free Stem Cell Constructs. AB - The growing socioeconomic burden of musculoskeletal injuries and limitations of current therapies have motivated tissue engineering approaches to generate functional tissues to aid in defect healing. A readily implantable scaffold-free system comprised of human bone marrow-derived mesenchymal stem cells embedded with bioactive microparticles capable of controlled delivery of transforming growth factor-beta 1 (TGF-beta1) and bone morphogenetic protein-2 (BMP-2) was engineered to guide endochondral bone formation. The microparticles were formulated to release TGF-beta1 early to induce cartilage formation and BMP-2 in a more sustained manner to promote remodeling into bone. Cell constructs containing microparticles, empty or loaded with one or both growth factors, were implanted into rat critical-sized calvarial defects. Micro-computed tomography and histological analyses after 4 weeks showed that microparticle-incorporated constructs with or without growth factor promoted greater bone formation compared to sham controls, with the greatest degree of healing with bony bridging resulting from constructs loaded with BMP-2 and TGF-beta1. Importantly, bone volume fraction increased significantly from 4 to 8 weeks in defects treated with both growth factors. Immunohistochemistry revealed the presence of types I, II, and X collagen, suggesting defect healing via endochondral ossification in all experimental groups. The presence of vascularized red bone marrow provided strong evidence for the ability of these constructs to stimulate angiogenesis. This system has great translational potential as a readily implantable combination therapy that can initiate and accelerate endochondral ossification in vivo. Importantly, construct implantation does not require prior lengthy in vitro culture for chondrogenic cell priming with growth factors that is necessary for current scaffold-free combination therapies. Stem Cells Translational Medicine 2017;6:1644-1659. PMID- 28661589 TI - [CLINICAL INVESTIGATION OF TUBERCULOSIS PATIENTS IN A GENERAL HOSPITAL LACKING A TUBERCULOSIS WARD IN WESTERN AICHI PREFECTURE.] AB - With the recent decrease in the number of tuberculosis wards and increase in elderly tuber- culosis patients with comorbidities, the role of regional refer- ral hospitals has become more important in tuberculosis management. [Objective]. This study aimed to assess the current state of tuberculosis management and related issues in a general hospital lacking a tuberculosis ward. [Methods] We retrospectively evaluated the clinical char- acteristics and course of patients diagnosed with tuberculosis by culture testing from April 2008 to March 2015 at Kainan Hospital. [Results] A total of 146 patients (83 males and 63 females; mean age 76, range 18-94 years) were diagnosed with active tuberculosis. Of these, 129 were diagnosed with pulmonary tuberculosis (23 had pulmonary tuberculosis with pleurisy), and 17 patients were diagnosed with extrapulmonary tuber- culosis. The chief complains were cough/sputum in 40 cases, fever in 24, and no symptoms in 36. Associated major comorbidities included diabetes mellitus, chronic kidney disease, and malignancy. In 33 patients, over 30 days were required to diagnose tuberculosis after initial evaluation. Drug-resistant strains were detected in 14 patients. 57 were diagnosed with smear-positive pulmonary tuberculosis, and 66 were transferred to a tuberculosis hospital. Modify in anti- tuberculosis therapy due to adverse reactions were reported in 27 patients. [Conclusion] This study evaluated the current state of tuberculosis management in our hospital. Further educational guidance regarding tuberculosis is needed for the hospital staff, and is important for improvement of tuberculosis management in our hospital. PMID- 28661590 TI - [[COMPLIANCE RATE OF STANDARD TREATMENT REGIMEN AND OPTIMAL DOSE OF ANTI TUBERCULOSIS DRUGS IN LATE ELDERLY PATIENTS WITH PULMONARY TUBERCULOSIS].] AB - The proportion of the elderly in patients with pulmonary tuberculosis is increasing, and failure to complete the standard treatment regimen is not uncommon in these patients. We examined the compliance rate and prob- lems of the standard regimen in the late elderly pulmonary tuberculosis patients. [Methods] We reviewed the medical records of late elderly patients with pulmonary tuberculosis aged 75 or above who were smear-positive and treated in Kanagawa Cardiovascular and Respiratory Center between January 2011 and December 2014. Our retrospective study examined patient characteris- tics, imaging findings, laboratory results, and outcomes. The compliance rate of standard regimen during the hospitaliza- tion period was calculated. We compared the discontinua- tion rate and the incidence of adverse drug reactions by body weight equivalent doses of anti-tuberculosis drugs. [Results] A total of 298 patients were included in this study, and 76% of those patients were aged 80 or above. Anti-tuberculosis therapy was not able to be initiated for 3 patients (1%), and treatment other than standard regimen was inevitably introduced at initiation in 21 patients. The remaining 274 patients (92%) were administered the stan- dard regimen. Among them, at least one medication was subsequently discontinued for 85 patients (29%), and the medication was changed due to drug resistance in 6 patients . (2%). The remaining 183 patients (61%) complied with the standard regimen during hospitalization. In the comparison by body weight equivalent dose, significantly more patients discontinued their medication in the group using ethambutol with a higher standard dose per weight (37% vs. 21%, p=0.02). [Conclusion] Nearly 40% of the late elderly patients could not comply with the standard regimen. We may need to be more careful when calculating ethambutol equivalent dose. PMID- 28661591 TI - [[TUBERCULOSIS DIAGNOSIS FOLLOWING A VISIT TO THE EMERGENCY ROOM].] AB - We aimed to evaluate the clinical char- acteristics of patients admitted to the emergency room (ER) and diagnosed with tuberculosis. [Method] We conducted a retrospective study of patients aged ; 16 years admitted to the hospital between April 1980 and March 2015 and diagnosed with tuberculosis. We com- pared patient clinical characteristics and type of tuberculosis between ER and non-ER patients. We also compared the incidence of delayed diagnosis of tuberculosis between ER patients with and without respiratory symptoms. We compared the tuberculosis encounter rate and the time to diagnosis of tuberculosis in ER and non-ER patients. [Results] A total of 255 patients, including 54 ER and 201 non-ER patients were enrolled in this study. The average age J was higher in ER patients than in non-ER patients (71.7? 16.3 vs. 63.3 ?20.3 years, p=0.006). The reasons for visiting the ER included acute conditions such as fracture of the lumbar spine, acute myocardial infarction, hemorrhagic gastric ulcer, brain infarction, and carbon monoxide intoxication, requiring immediate treatment. The time to diagnosis of tuberculosis in ER patients without respiratory symptoms (n=21) was approximately three times longer than that in patients with respiratory symptoms (n=33) as urgent treatment is priori- tized. The tuberculosis encounter rate was 1/1,800 for pa- tients transported by ambulance and 1/22,000 for emergency outpatients. The time to diagnosis of tuberculosis for patients transported by ambulance was approximately 4-6 days lon- ger than that for emergency outpatients or non-ER patients. [Conclusion] Physicians should seek to rule out the possi- bility of tuberculosis in all patients admitted to the ER, even where more urgent clinical conditions are prioritized. PMID- 28661592 TI - [[LIVER TOXICITY DUE TO RIFAMPICIN MONOTHERAPY IN LATENT TUBERCULOSIS INFECTION].] AB - To investigate the outcome of rifam- picin (RFP) monotherapy for latent tuberculosis infection (LTBI) and the incidence of RFP-induced liver toxicity. [Method] We conducted a retrospective chart review of patients who received RFP monotherapy as LTBI treatment at the Daiichi Dispensary Clinic. [Result] Of 61 patients who received RFP monotherapy, the treatment completion rate was 88.5%, self-termination rate was 3.3%, abandonment rate due to adverse drug effects was 8.2% (5 cases: 3 cases of skin eruption and 2 cases of liver dysfunction). Among the 2 cases of liver dysfunction, I was not associated with abnormal alkaline phosphatase (ALP) or gamma-glutamyl transferase (y GTP) levels. Among patients with liver dysfunction who did not discontinue RFP mono- therapy, no cases-of severely abnormal ALP and/or y GTP levels were reported. [Conclusion] The incidence of liver toxicity due to RFP is lower than that observed with isoniazid, and liver dysfunction due to RFP was not always associated with abnormal of ALP and/or yGTP levels. PMID- 28661593 TI - [[CASE OF TUBERCULOSIS COMPLICATIONS DURING PREGNANCY LEADING TO AN INFECTION OUTBREAK].] AB - A 31-year-old woman developed a constant cough during the 8th week of pregnancy and was diagnosed with bronchial asthma. She was prescribed prednisolone and inhaled corticosteroids. At 28 weeks of pregnancy, she showed worsening weight loss, fever, night sweats, hoarseness, and coughs. At 31 weeks of pregnancy, a scatter shadow and cavitary lesions were detected on the chest radiograph. Acid- fast bacilli smear test and tuberculosis (TB) polymerase chain reaction tests yielded positive results (G-8), and she was diagnosed with TB. Contact tracing and screening indicated 3 patients with TB onset and 18 patients with latent TB infec- tion attributed to the initial patient, who infected a total of 36 people. In the present case, physicians were reluctant to order a chest radiograph for fear of harming the fetus and did not order sputum or interferon gamma release (IGRA) assay tests either. The diagnosis was delayed by 152 days, which was considered as a factor that caused the outbreak. The diag- nosis of TB in a pregnant patient may be very challenging because symptoms may initially be ascribed to the pregnan- cy, and delayed diagnosis and treatment of military TB can lead to the death of the mother and fetus. Consequently, to ensure early diagnosis and treatment, chest radiography and sputum and IGRA tests are recommended for pregnant women who have TB symptoms or are at high risk for TB. PMID- 28661594 TI - [[TUBERCULOSIS ANNUAL REPORT 2014 - (3) Case Finding and Condition of Tuberculosis Patients on Diagnosis].] AB - Tuberculosis (TB) surveillance data from 2014 was reviewed, with respect to modes of detection, symptoms at diagnosis, diagnostic delay, radiographic findings, comor- bidity, and drug susceptibility test (DST) results. Of the 19,615 newly registered TB cases, 82.8% were diagnosed while seeking care for, or during treatment of, other illnesses. Of the 15,149 patients with pulmonary TB (PTB), 55.9% presented with respiratory symptoms, while 18.0% presented with non respiratory symptoms, and 25.5% were asympto- matic. Considerable delay to the initiation of treatment following the appearance of symptoms was observed among the younger symptomatic smear-positive TB patients. Over 35% of patients aged 35 59 years did not seek care for more than 2 months after the initial appearance of symptoms. The proportion of PTB patients with advanced or far- advanced cavitation peaked at 49.9% among males aged 60- 64 years, while it remained constant at around 25% among females in all age groups. Positive HIV test results were obtained in 0.2% (n- 45) of the newly registered TB patients, among which 86.7% were male and 22.2% were foreign-born. In addition, 16.3% of male and 10.5% of female newly diagnosed patients had diabetes mellitus. Of the 10,259 culture positive PTB patients, DST results were available for 74.5% of patients. In previously untreated patients, the proportions of multi-drug resistant TB, any isoniazid resistance, and any rifampicin resistance were 0.6 %, 4.1 %, and 0.8%, respectively; among previously treated patients, these proportions were 3.3%, 12.7%, and 3.8%, respectively. PMID- 28661595 TI - [Possibilities of laparoscopic gastric resection for gastrointestinal stromal tumors]. AB - Possibilities of laparoscopic technologies application while surgical excision of gas- trointestinal stromal tumors (GIST) were analyzed. In 2000 - 2015 yrs in the clinic 28 patients were operated on for gastric GIST. In 10 of them laparoscopic gastric resec- tion with tumor (in 3 - the tumor excision in borders of nonaffected tissues, in 4 - gas- tric fundus resection or stapler resection of a great curvature together with tumor, in 3 - transgastric excision of the tumor, using staplers) surgery was done. The disease recurrence in 2-5 yrs follow-up was absent. Laparoscopic operations has advantage over open interventions while preserving oncological radicalism. PMID- 28661596 TI - [Diagnosis and surgical treatment of mirizzi syndrome]. AB - Retrospective analysis of the surgical treatment results in 34 patients, operated for intraoperatively diagnosed Mirizzi syndrome (MS), was done. Analysis of intraoperative changes have witnessed, that while transition occurrence of MS from the first to the fifth type a severity of morphological changes in a gallbladder-biliary ducts-duodenum system enhanced with duodenal integrity loss and development of cholecystobiliary or cholecystodigestive fistula. Surgical correction of MS have envisaged cholecystectomy performance or subtotal resection of gallbladder, plastic closure of biliary fistula, using various procedures, external biliary draining and formation of hepaticojejunostomy in accordance to Roux method. PMID- 28661597 TI - [[Substantiation of choisce of the kind, localization and method of the implant fixing in alloplasty of the abdominal wall complex defects].] AB - The method of the implant fixation for prophylaxis of complications after alloplasty of complex abdominal wall defects was proposed. Taking into account physico-mechan- ical parameters of implant, degree of anisotropy, in accordance to mechanical and morphological characteristics of the abdominal wall musculo aponeurotic structures, it is possible to individualize the choice maximally, to plan the alloplasty kind, and to determine the method of optimal surgical treatment objectively. PMID- 28661598 TI - [[Results of simultant prepertional plasty of inguinal hernia with a one-stage retropubical prostatectomy].] AB - Immediate and late follow-up results of simultant preperitoneal plasty of inguinal her- nia, performed in 10 patients with a one-stage retropubical prostatectomy, performed for benigr prostatic hyperplasia, were presented. In 2 patients a bilateral preperitoneal hernioplasty was performed. In early postoperative period the inguinal hernia recur- rence did not occur, and in a late follow-up period - in 2 (20%) patients the inguinal hernia recurrence have occurred. PMID- 28661599 TI - [[Efficacy of abdominal sanation, using superoxyodysmutase in the treatment of peritonitis for restoration of the kioneys functional activity].] AB - Results of treatment of 40 patients, suffering diffuse peritonitis in a terminal stage, were analyzed. In 20 patients (main group) the abdominal cavity sanation was done, using superoxyddysmutase solution. Concentration of uric acid, urea, creatinine, general bilirubin, C-reactive protein in the blood serum have had normalized more rapidly, than in a control group, witnessing satisfactory renal function present. PMID- 28661600 TI - [[Criteria and clinical significance of echographic patterns of the left ventriculus anomalous deformity].] AB - With the aim of the clinical significance studying of the abnormal myocardial deforma- tion (MD) patterns in left ventricle (LV) there were examined 45 patients, in whom oper- ative myocardial revascularization was performed for an ischemic heart disease. Also 31 volunteers were examined. Postsystolic myocardial contruction (PMC) of the LV, depending on its mechanism, was classified: in absence of the affection - PMC-0, in presence of myocardial ischemia - PMC-1, in loss of contractility - PMC-2a, in loss of elasticity - PMC-2b. There were depicted PMC, occurring due to overloading by pressure, delay in a free LV wall activation, protosystolic and intrasystolic delay of myocardial contruction of obscure origin. PMC-1 in the ischemic heart disease was revealed in the LV segments affected only, PMC-2 - in presence of LV aneurysm only. Appearance of PMC-1 constitutes a criterion of the myocardial function restoration. The PMC-2 severity lowering had witnessed improvement of the patients clinical state. The contraction delay of obscure origin may not be considered a criterion of the LV myocardium state. PMID- 28661601 TI - [[Impact of plestazol preparation on hyperplasia of inter vascular layer in the patients, suffering obliterating atherosclerosis of the lower extremities arteries after reconstructive operations].] AB - In the clinic 60 patients were examined, in whom reconstructive operations on the main arteries were performed for obliterating atherosclerosis (OA) of the lower extremities vessels. Efficacy of impact of Plestazol (in a 200 mg/day dose) on neointima hyperpla- sia was studied. Clopidogrel (75 mg/day) was administered to patients of comparative group. Effective criteria for estimation of the migration proliferation disorders state in endothelial dysfunction are concentration of the intercellular adhesion molecules (ICAM) and the basic factor of the fibroblasts growth (FGFb); morphological disorders in hyperplastic reactions of neointima - determination of thickness of "intima-media" complex in accordance to the ultrasound duplex scanning data. There was established, that Plestazol constitutes an effective disaggregate preparation, positively impacting decelerating reaction of neointima hyperplasia, including, deceleration of the smooth- muscle cells migration into subendotelial layer in the formation zone of the femoro- popliteal shunt distal anastomosis. PMID- 28661602 TI - [[Treatment and prophylaxis of complications of the sternotomy access in thoracic operations].] AB - Literature data and own experience of the treatment complications, occurring after tho- racic operations, using sternotomy access, were presented. Special attention was drawn to postoperative sternomediastinitis - most frequent infectious complication. Measures for the sternomediastinitis prophylaxis, methods of its diagnosis and treat- ment were presented. PMID- 28661603 TI - [[Video-assisted pulmonary resection application for pulmonary tuberculosis].] AB - Results of application of video-assisted (video-assisted thoracic surgery VATS) pulmonary resection for pulmonary tuberculosis in 63 patients in 2008 - 2016 yrs were analyzed. Typical lobectomy was done in 28 (44.4%) patients, pulmonectomy - in 1 (1.6%), lower bilobectomy - in 1 (1.6%), combined resection of upper lobe and the Cv segment - in 1 (1.6%), typical segmentectomy - in 23 (36.5%), atypical one - in 9 (14.3%). Intraoperative complications have occurred in 4,(6.3%) patients, and postop- erative - in 8 (12.7%). Total efficacy of performance of pulmonary VATS-resection have constituted 98.4%. VATS-pulmonary resection is a miniinvasive and perspective treatment procedure. Meticulous selection of patients is needed for such intervention be applied. PMID- 28661604 TI - [[Is it necessary to perform a central lymphodissection in highly differentiated iviicrocarcinoiva of thyroid gland?].] AB - The rate of the highly differentiated thyroid microcarcinoma methastasizing in central (6th) group of cervical lymph nodes was studied. In the clinic in 2013 - 2015 yrs 62 patients were operated for primary thyroid microcarcinoma. In accordance to TNM (UICC, AJCC, 2009) classification, papillary cancer in stage TlaNOMO was diagnosed in 35 (56.5%) patients, T1aN1MO - in 22 (35.5%); follicular cancer stage T1aNOMO - in 2 (3.2%); papillary cancer, follicular variant in stage T1aN1 MO - in 2 (3.2%); follicu- lar cancer, papillary variant in stage T1aNOMO - in 1 (1.6%). In 8 (12.9%) patients intraorgan multifocal metastasizing into contralateral thyroid lobe was revealed. In accordance to morphological investigation date of the excised samples, in 24 (38.7%) patients the metastases into the 6th group lymph nodes were revealed. In 4 (16.7%) patients, to whom lateral cervical lymphodissection was done, metastases in 2 - 5th groups of lymph nodes on the thyroid affection side were revealed. PMID- 28661605 TI - [[Peculiarities of operative treatment of recurrent goiter].] AB - Results of 20 patients with a recurrent goiter (RG) surgery were analyzed. All patients were from 37 to 73 years old. One-sided RG was in 6 patients, bilateral RG - in 14. With the purpose of specific intraoperation complications prevention the original method of final hemi- or thyroidectomy was developed. The observance of algorithm of actions during an operation concerning RG allows to prevent the damage of recur- rent laryngeal nerve and parathyroid glands. PMID- 28661606 TI - [[Peculiarities of transcutaneous nephrolithotripsy in the patient's position lying on the back].] AB - In 2014 - 2016 yrs transcutaneous nephrolithotripsy was performed in 245 patients for nephrolithiasis, of them in 228 (93.1%) - in position of patient lying on the abdomen (1st group), in 17 (6.9%) - lying on the back (2nd group) because of various concur- rent cardio-vascular and respiratory diseases present. Mini- transcutaneous nephro- lithotripsy was performed under regional epidural anesthesia in 224 (91.4%) patients, and under endotracheal narcosis - in 21 (8.6%). While conduction of mini- transcu- taneous nephrolithotripsy in position of patient lying on the back the operation duration is reducing, and it is possible to perform simultant endoscopic interventions (trans- ureteric, transcutaneous). Position of patient lying on the back while performing tran- scutaneous nephrolithotripsy in a complex with regional (epidural) anesthesia consti- tutes a relatively secure procedure. Hemodynamical and respiratory parameters are simply intraoperatively controlled, what is important for the patients, urologists and anesthesiologists. The complications rate and results of treatment are comparable with such while performing transcutaneous nephrolithotripsy in accordance to standard in position of patient lying on the abdomen. PMID- 28661607 TI - [[Morpho-functional peculiarities of course of purulent-septic wound process while impact of a low-dosed vacuum].] AB - Morpho-functional peculiarities of course of the purulent-septic wound process, while vacuum-therapy method application for local treatment of the wounds, were studied. High reparative effect of vacuum-therapy, caused by activation of the wound proliferative processes, was noted, It had permitted to improve the patients treatment results for purulent surgical diseases of soft tissues, to lower the rate of complications and reoperations and to improve their quality of life. PMID- 28661608 TI - [[Spongy microporous tampon for mechanical clearance of a gun-shot wounos].] AB - Application of a spongy microporous tampon in accordance to technology elaborated was proposed for enhancement of the mechanical clearance efficacy of the gun-shot soft tissues wounds. A procedure of manufacturing and application of spongy microp- orous tampon for the mechanical clearance of a gun-shot wounds was depicted. The clearance efficacy was improved due to application of the method elaborated, wit- nessing possibility of its usage on all stages of the surgical aid delivery. PMID- 28661609 TI - [[Estimation of bilio-oigestive and interintestinal anastomoses, formed in accordance to method of a high-frequency electric welding of tissues, in experiment].] AB - In the experiment on 50 rabbits cholecysto-entero and entero-entero anastomoses were formed on intestinal Roux loop. In 35 animals (the main group) a single layer evert- ing anastomoses by using high frequence (HF) electric welding method were formed, in 15 (the comparison group) single row suture anastomoses has been done. The anas- tomosis sufficiency were performed by using hydropressure, pneumopressure meth- ods and breakload test. It was established that all anastomoses formed by HF-electric welding method were passable and hermetic, also had strong sufficiency. Strength of weld joint in the postoperative period increased in a linear progression and after 3 weeks almost reached strength intact intestine (240-250 mm Hg). PMID- 28661611 TI - [[The ambulatory surgery state in environment of reformation in ukrainian health protection branch].] PMID- 28661612 TI - [[Total pancreatectomy].] PMID- 28661610 TI - [[Durable persistence of a biocompatible foreign body in a vertebral channel in open penetrating trauma of a spinal cord: clinico-experimental and pathomorphological peculiarities].] AB - Simulation model of open penetrating wound of a spinal cord (SC) with its durable com- pression by biocompatible foreign body, was tasted. Experimental animals - mature male rats (inbred line, descendent from a Wistar breed); the trauma simulation model - a left- sided transsection of the SC half on the Txi level; experimental groups: the main (a SC trau- ma + homotopic implantation of microporous hydrogel fragment - foreign body [n=10]), groups of comparison (the SC trauma [n=16]; the SC trauma + homotopic implantation of chemically identical analogue of hydrogel - NeuroGelTM [n=20]). A SC compression by a foreign body worsens the regeneration process course essentially: during first 2 mo the function index of a hind ipsilateral extremity in experimental animals of the main group was the lowest in the experiment - (1.30 ? 0.94) points in accordance to BBB scale, during 3 - 4 mo - the function index had enhanced trustworthy - up to (2.35 ? 0.95) points in accor- dance to BBB scale, what is connected with lowering of a local pressure on a SC tissue due to change of the foreign body form and volume. In 24 weeks the function index of hind ipsi- lateral extremity had constituted (8.45 ? 0.92) points - while application of NeuroGeTM and (2.35 ? 0.95) points - of the foreign body; the tissue processes in the implants localization zone had differed essentially. The tasted simulation model reproduces satisfactory a mechanical component of the foreign body impact on a SC tissue. The SC compression reduction, even in a late follow-up period, had improved the conditions and results of recenerative process essentially. PMID- 28661613 TI - [[Observation of recurrent biliary ileus].] PMID- 28661614 TI - Ambient and Controlled Particle Exposures as Triggers for Acute ECG Changes. AB - INTRODUCTION: Previous studies have examined changes in heart rate variability (HRV*) and repolarization associated with increased particulate matter (PM) concentrations on the same and previous few days. However, few studies have examined whether these health responses to PM occur within a few hours or even less. Moreover, it is not clear whether exposure of subjects to ambient or controlled PM concentrations both lead to similar health effects or whether any of the subjects' individual characteristics modify any of their responses to PM. The aims of the cur- rent study were to investigate whether exposure to PM was associated with rapid changes (< 60 minutes or con- current hour up to a delay of 6 hours) in markers of car- diac rhythni or changes in total antioxidant capacity (a marker of protection against oxidative stress) and whether any PM effects on cardiac rhythm markers were modified by total antioxidant capacity, age, obesity, smoking, hypertension, exertion, prior myocardial infarction (MI), or medication. METHODS: We obtained data from a completed study in Augsburg, Germany (a panel study in N= 109 subjects, including a group with type 2 diabetes or impaired glucose tolerance [IGT; also known as prediabetes]) and a group of other- wise healthy subjects with a potential genetic susceptibil- ity to detoxifying and inflammatory pathways (Hampel et al. 2012b), as well as three completed studies in Rochester, New York (the REHAB panel study of N= 76 postinfarction patients in a cardiac rehabilitation pro- gram [Rich et al. 2012b]; the UPDIABETES study of con- trolled exposure to ultrafine particles [UFPs, particles with an aerodynamic diameter < 100 nm] of N = 19 patients with type 2 diabetes [Stewart et al. 2010; Vora et al. 2014j; and the UPCON controlled-exposure study of concentrated UFP exposure in N = 20 young, healthy, life- time nonsmokers). Data included 5-minute and 1-hour values for HRV and repolarization parameters from elec- trocardiogram (ECG) recordings and total antioxidant capacity measured in stored blood samples. Ambient con- centrations of UFPs, accumulation-mode particles (AMP, particles with an aerodynamic diameter of 100-500 nm), fine PM (PM2.5, particles with an aerodynamic diameter 2.5 pm), and black carbon (BC) were also available. We first conducted factor analyses in each study to find subgroups of correlated ECG outcomes and to reduce the number of outcomes examined in our statistical models. We then restricted the statistical analyses to the factors and representative.outcomes that were common to all four studies, including total HRV (measured as the standard deviation of normal-to-normal [NN] beat intervals [SDNNj), parasympathetic modulation (measured as the root mean square of the successive differences [RMSSD between adjacent NN beat intervals), and T-wave morphol- ogy (measured as T-wave complexity). Next, we used addi- tive mixed models to estimate the change in each outcome associated with increased pollutant concentrations in the . concurrent and previous 6 hours and with 5-minute inter- vals up to the previous 60 minutes, accounting for the correlation of repeated outcome measures for each subject and adjusting for time trend, hour of the day, temperature, relative humidity, day of the week, month, and visit number. Because multiple comparisons were an issue in our. analyses, we used a discovery-and replication approach to draw conclusions across studies for each research question. RESULTS: In the Augsburg study, interquartile range (IQR) increases in UFP concentrations lagged 2 to 5 hours were associated with 1%-3% decreases in SDNN (e.g., lagged 3 hours in the group with a genetic susceptibility: -2.26%; 95% confidence interval [CI], -3.98% to -0.53%). In the REHAB study, similarly, IQR increases in UFP concentra- tions in the previous 5 hours were associated with < 3% decreases in SDNN (e.g., lagged 1 hour: -2.69%; 95% CI, -5.13% to 0.26%). We also found decreases in SDNN associated with IQR increases in total particle count-(a surrogate for UFP) in the UPDIABETES study (lagged 1 hour: 13.22%; 95% CI, -24.11% to -2.33%) but not in the UPCON study. In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and lagged 1-5 hours, AMP concentrations lagged 1 and 3 hours, and BC con- centrations lagged 1-5 hours were associated with -1%-5% decreases in SDNN (e.g., PM2.5 lagged 2 hours in the group with diabetes or IGT: -4.59%; 95% CI, -7.44% to 1.75%). In the REHAB study, IQR increases in PM2.5 concentrations lagged 5 and 6 hours and AMP concentra- tions in the concurrent hour and lagged up to 5 hours were associated with 1%-2% decreases in SDNN (e.g., PM2.5 lagged 4 hours: -2.13%; 95% CI, -3.91% to -0.35%). In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and BC lagged 1 and 6 hours were associated with 3%-7% decreases in RMSSD (e.g., PM2.5 concurrent hour in the group with diabetes or IGT: -7.20%; 95% CI, -12.11% to -2.02%). In the REHAB study, similarly, increases in PM2.5 concen- trations lagged 4 to 6 hours-though not AMP or BC con- centrations at any lag hour-were associated with -2.5%-3.5% decreases in RMSSD (e.g., PM2.5 lagged 5 hours: -3.49%; 95% CI, -6.13% to -0.84%). We did not find consistent evidence of any pollutant effects on T-wave complexity in 1-hour recordings. For 5-minute record- ings, there was no consistent evidence of UFP effects on SDNN, RMSSD, or T-wave complexity at any 5-minute interval within 60 minutes. We further concluded that these replicated hourly effects of UFP and PM2.5 on short-term measures of SDNN and RMSSD generally did not differ between the groups in the studies (i.e., type 2 diabetes, pre-diabetes/IGT, post- infarction, and healthy subjects). Last, we found no con- sistent evidence of effects of any pollutant on total anti- oxidant capacity and no consistent evidence of modification of our PM2.5-outcome associations by any of the potential effect modifiers. ONCLUSIONS: Increased UFP concentrations were associated with decreased SDNN in both of the panel studies and one of the two controlled-exposure studies. We also found that decreased SDNN was associated with both increased PM2.5 and AMP concentrations in the previous 6 hours in the panel studies and that decreased RMSSD was associ- ated with increased PM2.5 concentrations in the previous 6 hours in the panel studies. We therefore concluded that the research questions were replicated. Our findings suggest that both UFPs and PM2.5 are associated with autonomic dysfunction within hours of exposure, which may in part. explain the previously reported risk of acute cardiovascular events associated with increased PM in the previous few hours. Despite the heterogeneity of the study populations,and protocols, our findings provided consistent evidence for the induction of rapid pathophysiological responses by UFPs and PM2.5- The absence of consistent associations between UFPs, PM2.5, and these outcomes when examining shorter time intervals indicates that the 5- to 60-minute responses may be less pronounced than the responses occurring within hours. However, the findings from the 5-minute intervals may have been affected by the variety of proto- cols and conditions from study to study as well as by the potential effects of underlying diseases (e.g., healthy indi- viduals versus individuals with diabetes or a recent cor- onary artery. event), physical activity, circadian rhythms, stress, and/or medications. PMID- 28661648 TI - Graphene-Fiber-Based Supercapacitors Favor N-Methyl-2-pyrrolidone/Ethyl Acetate as the Spinning Solvent/Coagulant Combination. AB - One-dimensional flexible fiber supercapacitors (FSCs) have attracted great interest as promising energy-storage units that can be seamlessly incorporated into textiles via weaving, knitting, or braiding. The major challenges in this field are to develop tougher and more efficient FSCs with a relatively easy and scalable process. Here, we demonstrate a wet-spinning process to produce graphene oxide (GO) fibers from GO dispersions in N-methyl-2-pyrrolidone (NMP), with ethyl acetate as the coagulant. Upon chemical reduction of GO, the resulting NMP-based reduced GO (rGO) fibers (rGO@NMP-Fs) are twice as high in the surface area and toughness but comparable in tensile strength and conductivity as that of the water-based rGO fibers (rGO@H2O-Fs). When assembled into parallel FSCs, rGO@NMP-F based supercapacitors (rGO@NMP-FSCs) offered a specific capacitance of 196.7 F cm 3 (147.5 mF cm-2), five times higher than that of rGO@H2O-F-based supercapacitors (rGO@H2O-FSCs) and also higher than most existing wet-spun rGO-FSCs, as well as those FSCs built with metal wires, graphene/carbon nanotube (CNT) fibers, or even pseudocapacitive materials. In addition, our rGO@NMP-FSCs can provide good bending and cycling stability. The energy density of our rGO@NMP-FSCs reaches ca. 6.8 mWh cm-3, comparable to that of a Li thin-film battery (4 V/500 MUAh). PMID- 28661647 TI - Multiplex Aptamer Discovery through Apta-Seq and Its Application to ATP Aptamers Derived from Human-Genomic SELEX. AB - Laboratory-evolved RNAs bind a wide variety of targets and serve highly diverse functions, including as diagnostic and therapeutic aptamers. The majority of aptamers have been identified using in vitro selection (SELEX), a molecular evolution technique based on selecting target-binding RNAs from highly diverse pools through serial rounds of enrichment and amplification. In vitro selection typically yields multiple distinct motifs of highly variable abundance and target binding affinities. The discovery of new aptamers is often limited by the difficulty of characterizing the selected motifs, because testing of individual sequences tends to be a tedious process. To facilitate the discovery of new aptamers within in vitro selected pools, we developed Apta-Seq, a multiplex analysis based on quantitative, ligand-dependent 2' acylation of solvent accessible regions of the selected RNA pools, followed by reverse transcription (SHAPE) and deep sequencing. The method reveals, in a single sequencing experiment, the identity, structural features, and target dissociation constants for aptamers present in the selected pool. Application of Apta-Seq to a human genomic pool enriched for ATP-binding RNAs yielded three new aptamers, which together with previously identified human aptamers suggest that ligand-binding RNAs may be common in mammals. PMID- 28661649 TI - Subfilamentary Networks Cause Cycle-to-Cycle Variability in Memristive Devices. AB - A major obstacle for the implementation of redox-based memristive memory or logic technology is the large cycle-to-cycle and device-to-device variability. Here, we use spectromicroscopic photoemission threshold analysis and operando XAS analysis to experimentally investigate the microscopic origin of the variability. We find that some devices exhibit variations in the shape of the conductive filament or in the oxygen vacancy distribution at and around the filament. In other cases, even the location of the active filament changes from one cycle to the next. We propose that both effects originate from the coexistence of multiple (sub)filaments and that the active, current-carrying filament may change from cycle to cycle. These findings account for the observed variability in device performance and represent the scientific basis, rather than prior purely empirical engineering approaches, for developing stable memristive devices. PMID- 28661650 TI - Superflexible Wood. AB - Flexible porous membranes have attracted increasing scientific interest due to their wide applications in flexible electronics, energy storage devices, sensors, and bioscaffolds. Here, inspired by nature, we develop a facile and scalable top down approach for fabricating a superflexible, biocompatible, biodegradable three dimensional (3D) porous membrane directly from natural wood (coded as flexible wood membrane) via a one-step chemical treatment. The superflexibility is attributed to both physical and chemical changes of the natural wood, particularly formation of the wavy structure formed by simple delignification induced by partial removal of lignin/hemicellulose. The flexible wood membrane, which inherits its unique 3D porous structure with aligned cellulose nanofibers, biodegradability, and biocompatibility from natural wood, combined with the superflexibility imparted by a simple chemical treatment, holds great potential for a range of applications. As an example, we demonstrate the application of the flexible, breathable wood membrane as a 3D bioscaffold for cell growth. PMID- 28661651 TI - Nanochannel Arrays for Molecular Sieving and Electrochemical Analysis by Nanosphere Lithography Templated Graphoepitaxy of Block Copolymers. AB - The ability to design, fabricate, and manipulate materials at the nanoscale is fundamental to the quest to develop technologies to assemble nanometer-scale pieces into larger-scale components and materials, thereby transferring unique nanometer-scale properties to macroscopic objects. In this work, we describe a new approach to the fabrication of highly ordered, ultrahigh density nanochannel arrays that employs nanosphere lithography to template the graphoepitaxy of polystyrene-polydimethylsiloxane, diblock copolymers. By optimizing the well controlled solvent vapor annealing, overcoating conditions, and the subsequent reactive ion etching processes, silica nanochannel (SNC) arrays with areal densities, rhoA, approaching 1000 elements MUm-2, are obtained over macroscopic scales. The integrity and functionality of the SNC arrays was tested by using them as permselective ion barriers to nanopore-confined disk electrodes. The nanochannels allow cations to pass to the disk electrode but reject anions, as demonstrated by cyclic voltammetry. This ion gating behavior can be reversed from cation-permselective to anion-permselective by chemically inverting the surface charge from negative to positive. Furthermore, the conformal SNC array structures obtained could easily be lifted, detached, and transferred to another substrate, preserving the hierarchical organization while transferring the nanostructure derived properties to a different substrate. These results demonstrate how nanoscale behavior can be replicated over macroscale distances, using electrochemical analysis as a model. PMID- 28661652 TI - Human Concentrative Nucleoside Transporter 3 (hCNT3, SLC28A3) Forms a Cyclic Homotrimer. AB - Many anticancer and antiviral drugs are purine or pyrimidine analogues, which use membrane transporters to cross cellular membranes. Concentrative nucleoside transporters (CNTs) mediate the salvage of nucleosides and the transport of therapeutic nucleoside analogues across plasma membranes by coupling the transport of ligands to the sodium gradient. Of the three members of the human CNT family, CNT3 has the broadest selectivity and the widest expression profile. However, the molecular mechanisms of the transporter, including how it interacts with and translocates structurally diverse nucleosides and nucleoside analogues, are unclear. Recently, the crystal structure of vcCNT showed that the prokaryotic homologue of CNT3 forms a homotrimer. In this study, we successfully expressed and purified the wild type human homologue, hCNT3, demonstrating the homotrimer by size exclusion profiles and glutaraldehyde cross-linking. Further, by creating a series of cysteine mutants at highly conserved positions guided by comparative structure models, we cross-linked hCNT3 protomers in a cell-based assay, thus showing the existence of hCNT3 homotrimers in human cells. The presence and absence of cross-links at specific locations along TM9 informs us of important structural differences between vcCNT and hCNT3. Comparative modeling of the trimerization domain and sequence coevolution analysis both indicate that oligomerization is critical to the stability and function of hCNT3. In particular, trimerization appears to shorten the translocation path for nucleosides across the plasma membrane and may allow modulation of the transport function via allostery. PMID- 28661653 TI - Polydopamine-Based 3D Colloidal Photonic Materials: Structural Color Balls and Fibers from Melanin-Like Particles with Polydopamine Shell Layers. AB - Nature creates beautiful structural colors, and some of these colors are produced by nanostructural arrays of melanin. Polydopamine (PDA), an artificial black polymer produced by self-oxidative polymerization of dopamine, has attracted extensive attention because of its unique properties. PDA is a melanin-like material, and recent studies have reported that photonic materials based on PDA particles showed structural colors by enhancing color saturation through the absorption of scattered light. Herein, we describe the preparation of three dimensional (3D) colloidal photonic materials, such as structural color balls and fibers, from biomimetic core-shell particles with melanin-like PDA shell layers. Structural color balls were prepared through the combined use of membrane emulsion and heating. We also demonstrated the use of microfluidic emulsification and solvent diffusion for the fabrication of structural color fibers. The obtained 3D colloidal materials, i.e., balls and fibers, exhibited angle independent structural colors due to the amorphous assembly of PDA-containing particles. These findings provide new insight for the development of dye-free technology for the coloration of various 3D colloidal architectures. PMID- 28661654 TI - Matrix Metalloproteinase-Responsive Multifunctional Peptide-Linked Amphiphilic Block Copolymers for Intelligent Systemic Anticancer Drug Delivery. AB - The amphiphilic block copolymer anticancer drug nanocarriers clinically used or in the progress of clinical trials frequently suffer from modest final therapeutic efficacy due to a lack of intelligent features. For example, the biodegradable amphiphilic block copolymer, poly(ethylene glycol)-b-poly(d,l lactide) (PEG-PDLLA) has been approved for clinical applications as a paclitaxel (PTX) nanocarrier (Genexol-PM) due to the optimized pharmacokinetics and biodistribution; however, a lack of intelligent features limits the intracellular delivery in tumor tissue. To endow the mediocre polymer with smart properties via a safe and facile method, we introduced a matrix metalloproteinase (MMP) responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG-GPLGVRGDG-PDLLA (P1). P1 was further self-assembled into micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered dePEGylation due to cleavage of the peptide linkage. Moreover, the residual VRGDG sequences are retained on the surface of the NPs after dePEGylation, which can serve as ligands to facilitate the cellular uptake. The cytotoxicity of PTX loaded in P1 NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG-GPLGVRG-PDLLA (P2) and PEG PDLLA (P3) NPs. In vivo studies confirmed that PTX-loaded P1 NPs show prolonged blood circulation, which are similar to P2 and P3 NPs but exhibit more-efficient accumulation in the tumor site. Ultimately, PTX-loaded P1 NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration. Therefore, the strategy by facile incorporation of a responsive peptide linkage between PEG and PDLLA is a promising approach to improving the therapeutic efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles. PMID- 28661655 TI - Enhancing the Efficiency of Polymer Solar Cells by Incorporation of 2,5 Difluorobenzene Units into the Polymer Backbone via Random Copolymerization. AB - A series of conjugated polymers P0, P5, and P7 containing 0, 5, and 7 mol % 2,5 difluorobenzene units, respectively, were prepared and utilized as electron donors in polymer solar cells. Incorporation of a small amount of 2,5 difluorobenzene unit into the backbone of donor polymers can significantly increase their planarity and crystallinity as well as decrease their solubility. The improved molecular conformation can markedly affect the morphology of polymer:PC71BM blend films. After incorporation of 5 mol % 2,5-difluorobenzene unit into the backbone of donor polymers, the domain size of blend films became smaller and the hole mobility increased. Increasing the content of 2,5 difluorobenzene to 7 mol % can further decrease the solubility of resulting polymers and resulted in poor solution processability. As a result, P5-based devices achieved a power conversion efficiency (PCE) of 8.5%, whereas P0 based devices gave a PCE of 7.8%. PMID- 28661656 TI - Synthesis, Structure, and Reactivity of Low-Spin Cobalt(II) Imido Complexes [(Me3P)3Co(NAr)]. AB - The reactions of [Co(PMe3)4] with the bulky organic azides, DippN3 and DmpN3 [Dipp, 2,6-diisopropylphenyl; Dmp, 2,6-di(2',4',6'-trimethylphenyl)phenyl], afforded the cobalt(II) terminal imido complexes [(Me3P)3Co(NAr)] (Ar = Dipp, 1; Dmp, 2). The cobalt imido complexes in their solid states show trigonal pyramidal coordination geometry and long Co-N(imido) separations (ca. 1.71 A). Spectroscopic characterization and theoretical studies indicated their low-spin cobalt(II) nature. Reactivity studies on 1 revealed its nitrene-transfer reactions with PMe3 and CO, the imido/oxo and imido/sulfido exchange reactions with PhCHO and CS2, and the single-electron oxidation reaction by ferrocenium cation to form cobalt(III) imide. PMID- 28661657 TI - Environmental Applications of 2D Molybdenum Disulfide (MoS2) Nanosheets. AB - In an era of graphene-based nanomaterials as the most widely studied two dimensional (2D) materials for enhanced performance of devices and systems in numerous environmental applications, molybdenum disulfide (MoS2) nanosheets stand out as a promising alternative 2D material with many excellent physicochemical, biological, and mechanical properties that differ significantly from those of graphene-based nanomaterials, potentially leading to new environmental phenomena and novel applications. This Critical Review presents the latest advances in the use of MoS2 nanosheets for important water-related environmental applications such as contaminant adsorption, photocatalysis, membrane-based separation, sensing, and disinfection. Various methods for MoS2 nanosheet synthesis are examined, and their suitability for different environmental applications is discussed. The unique structure and properties of MoS2 nanosheets enabling exceptional environmental capabilities are compared with those of graphene-based nanomaterials. The environmental implications of MoS2 nanosheets are emphasized, and research needs for future environmental applications of MoS2 nanosheets are identified. PMID- 28661658 TI - Correction to "Intrinsic Instability of Cs2In(I)M(III)X6 (M = Bi, Sb; X = Halogen) Double Perovskites: A Combined Density Functional Theory and Experimental Study". PMID- 28661659 TI - Human Exposure to Legacy and Emerging Halogenated Flame Retardants via Inhalation and Dust Ingestion in a Norwegian Cohort. AB - In this study, we estimated human exposure to polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDDs), and several emerging flame retardants (EFRs) via inhalation and dust ingestion. Sixty indoor stationary air samples, 13 personal air samples, and 60 settled dust samples were collected from a Norwegian cohort during winter 2013. PBDEs showed the highest median concentration in dust (1200 ng/g), followed by EFRs (730 ng/g) and HBCDDs (190 ng/g). The PBDE concentrations in dust were mainly driven by BDE-209 and those of EFRs by bis(2 ethylhexyl) tetrabromophthalate. EFRs predominated in stationary air samples, with 2-ethylhexyl 2,3,4,5-tetrabromobenzoate and 4-(1,2-dibromoethyl)-1,2 dibromocyclohexane having the highest median concentrations (150 and 25 pg/m3 (sum of alpha- and beta-isomers), respectively). Different profiles and concentrations were observed in personal air samples compared to the corresponding stationary air samples. In relation to inhalation exposure, dust ingestion appears to be the major exposure pathway to FRs (median total exposure 230 pg/kg bw/d, accounting for more than 65% of the total exposure) for the Norwegian cohort. The calculated exposure due to air inhalation was substantially lower when the stationary air concentrations were used rather than personal air concentrations (43 pg/kg bw/d versus 130 pg/kg bw/d). This suggests that other exposure situations (such as outdoors or in offices) contributed significantly to the overall personal exposure, which cannot be included by using only a stationary air sampling technique. The median and 95th percentile exposures for all target FRs did not exceed the reference dose. PMID- 28661660 TI - Real-Time Monitoring the Dynamics of Coordination-Driven Self-Assembly by Fluorescence-Resonance Energy Transfer. AB - It is quite challenging to investigate the dynamics of coordination-driven self assembly due to the existence of multiple intermediates and many possible processes. By taking advantage of the high sensitivity and efficiency of fluorescence-resonance energy transfer (FRET), FRET was successfully employed to real-time monitor the dynamic behavior of coordination-driven self-assembly. The Forster energy transfer efficiencies and kinetic aspects of a series of discrete, well-defined metallacycles have been determined. Moreover, the dynamic characteristics of these supramolecular assemblies, such as the dynamic ligand exchange, anion-induced disassembly and reassembly, and stability in different solvents, have been investigated by using FRET. PMID- 28661662 TI - Effects of Deepwater Horizon Oil on the Movement and Survival of Marsh Periwinkle Snails (Littoraria irrorata). AB - The Deepwater Horizon (DWH) oil spill resulted in the release of millions of barrels of oil into the Gulf of Mexico, and some marsh shorelines experienced heavy oiling including vegetation laid over under the weight of oil. Periwinkle snails (Littoraria irrorata) are a critical component of these impacted habitats, and population declines following oil spills, including DWH, have been documented. This study determined the effects of oil on marsh periwinkle movement and survivorship following exposure to oil. Snails were placed in chambers containing either unoiled or oiled laid over vegetation to represent a heavily impacted marsh habitat, with unoiled vertical structure at one end. In the first movement assay, snail movement to standing unoiled vegetation was significantly lower in oiled chambers (oil thickness ~ 1 cm) compared to unoiled chambers, as the majority (~75%) of snails in oiled habitats never reached standing unoiled vegetation after 72 h. In a second movement assay, there was no snail movement standing unoiled structure in chambers with oil thicknesses of 0.1 and 0.5 cm, while 73% of snails moved in unoiled chambers after 4h. A toxicity assay was then conducted by exposing snails to oil coated Spartina stems in chambers for periods up to 72 h, and mortality was monitored for 7 days post exposure. Snail survival decreased with increasing exposure time, and significant mortality (~35%) was observed following an oil exposure of less than 24 h. Here, we have shown that oil impeded snail movement to clean habitat over a short distance and resulted in oil-exposure times that decreased survival. Taken together, along with declines documented by others in field surveys, these results suggest that marsh periwinkle snails may have been adversely affected following exposure to DWH oil. PMID- 28661661 TI - Caulobacter crescentus Cell Cycle-Regulated DNA Methyltransferase Uses a Novel Mechanism for Substrate Recognition. AB - Caulobacter crescentus relies on DNA methylation by the cell cycle-regulated methyltransferase (CcrM) in addition to key transcription factors to control the cell cycle and direct cellular differentiation. CcrM is shown here to efficiently methylate its cognate recognition site 5'-GANTC-3' in single-stranded and hemimethylated double-stranded DNA. We report the Km, kcat, kmethylation, and Kd for single-stranded and hemimethylated substrates, revealing discrimination of 107-fold for noncognate sequences. The enzyme also shows a similar discrimination against single-stranded RNA. Two independent assays clearly show that CcrM is highly processive with single-stranded and hemimethylated DNA. Collectively, the data provide evidence that CcrM and other DNA-modifying enzymes may use a new mechanism to recognize DNA in a key epigenetic process. PMID- 28661663 TI - Relationship between Coating-Induced Soot Aggregate Restructuring and Primary Particle Number. AB - The restructuring of monodisperse soot aggregates due to coatings of secondary organic aerosol (SOA) was investigated in a series of photo-oxidation chamber experiments. Soot aggregates were generated by one of three sources (an ethylene premixed burner, a methane inverted diffusion burner, or a diesel generator), treated by denuding, size-selected by a differential mobility analyzer, and injected into a smog chamber, where they were exposed to the photo-oxidation products of p-xylene, which partitioned to form SOA coatings. The evolution of aggregates from their initial to final morphologies was investigated in situ by mobility and mass measurements and ex situ by transmission electron microscopy. At a given initial aggregate mobility diameter, diesel aggregates are less dense and composed of smaller primary particles than those generated by the two burners, and they restructure to a smaller final mobility diameter. Remarkably, the final degrees of restructuring of aggregates from all three sources exhibit the same linear dependence on the number of primary particles per aggregate. The observed linear relationship, valid for the atmospherically relevant SOA coating investigated here, could allow modelers to predict the evolution of aggregate morphology based on a single property of the aggregates. PMID- 28661664 TI - Tetracationic and Tetraanionic Manganese Porphyrins: Electrochemical and Spectroelectrochemical Characterization. AB - The electrochemistry and spectroelectrochemistry of four tetrapositively charged and two tetranegatively charged porphyrins were characterized in two nonaqueous solvents (dimethyl sulfoxide and N,N-dimethylformamide) containing 0.1 M tetra-n butylammonium perchlorate. The tetrapositively charged compounds are represented by the tetrapyridylporphyrins [TRPyPM]4+(X-)4, where R is a methyl or [2-[2-(2 methoxy)ethoxy]ethoxy]ethyl group, M = MnIIII, MnIIICl, CuII, or PdII, and X = I- or Cl-. The tetranegatively charged porphyrins are represented by the tetrasulfonato derivatives [TPPSMn(OAc)]4-(NH4+)4 and [TArPSMn(OAc)]4-(NH4+)4, where Ar = 4-O-[2-[2-(2-methoxy)ethoxy]ethoxy]ethylphenyl. Up to seven electrons can be added to the tetrapyridyl porphyrins in three to five reversible reductions, while up to four electrons can be added to the tetrasulfonato derivatives in four reversible processes. Three types of electrochemical behaviors are observed for reduction of the pyridinium groups on the tetrapyridyl porphyrins. One is for the manganese(II) complexes where the four equivalent pyridinium groups are reduced in a single overlapping four-electron-transfer step. Another is for the free-base porphyrin, where four well-separated one electron reductions occur, while the third is for copper(II) and palladium(II) derivatives, where reduction of the four pyridinium groups proceeds in two well separated two-electron-transfer steps. The electrochemical and spectroelectrochemical properties were also characterized for a 1:1 mixture of the tetrapositively and tetranegatively charged manganese porphyrins to investigate possible interactions between these two species. An interaction between the two porphyrins was indeed observed in both solvents after electroreduction of the four pyridinium groups, which led to a substantial change in the mechanism for reduction of the pyridinium groups from an initial single overlapping four-electron-reduction process to two well-separated two-electron transfer processes. PMID- 28661665 TI - Ferroelectric Polarization and Second Harmonic Generation in Supramolecular Cocrystals with Two Axes of Charge-Transfer. AB - Ferroelectricity in organic materials remains a subject of great interest, given its potential impact as lightweight information storage media. Here we report supramolecular charge-transfer cocrystals formed by electron acceptor and donor molecules that exhibit ferroelectric behavior along two distinct crystallographic axes. The solid-state superstructure of the cocrystals reveals that a 2:1 ratio of acceptor to donor molecules assemble into nearly orthogonal mixed stacks in which the molecules are positioned for charge-transfer in face-to-face and edge to-face orientations, held together by an extended hydrogen-bonding network. Polarization hysteresis was observed along the face-to-face and edge-to-face axes at room temperature. The noncentrosymmetric nature of the cocrystals, required to observe ferroelectric behavior, is demonstrated using second harmonic generation measurements. This finding suggests the possibility of designing supramolecular arrays in which organic molecules support multidimensional information storage. PMID- 28661666 TI - A Fine-Tuned Metal-Organic Framework for Autonomous Indoor Moisture Control. AB - Conventional adsorbents, namely zeolites and silica gel, are often used to control humidity by adsorbing water; however, adsorbents capable of the dual functionality of humidification and dehumidification, offering the desired control of the moisture level at room temperature, have yet to be explored. Here we report Y-shp-MOF-5, a hybrid microporous highly connected rare-earth-based metal-organic framework (MOF), with dual functionality for moisture control within the recommended range of relative humidity (45%-65% RH) set by the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE). Y-shp-MOF-5 exhibits exceptional structural integrity, robustness, and unique humidity-control performance, as confirmed by the large number (thousand) of conducted water vapor adsorption-desorption cycles. The retained structural integrity and the mechanism of water sorption were corroborated using in situ single-crystal X-ray diffraction (SCXRD) studies. The resultant working water uptake of 0.45 g.g-1 is solely regulated by a simple adjustment of the relative humidity, positioning this hydrolytically stable MOF as a prospective adsorbent for humidity control in confined spaces, such as space shuttles, aircraft cabins, and air-conditioned buildings. PMID- 28661667 TI - Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes. AB - Kinetics and thermodynamics in supramolecular systems are intimately linked, yet both are independently important for application in sensing assays and stimuli responsive switching/self-healing of materials. Host-guest interactions are of particular interest in many water-based materials, sensing, and drug delivery applications. Herein we investigate the binding dynamics of a variety of electron rich aromatic moieties forming hetero-ternary complexes with the macrocycle cucurbit[8]uril (CB[8]) and an auxiliary guest, dimethyl viologen, with high selectivity and equilibrium binding constants (Keq up to 1014 M-2). Using stopped flow spectrofluorimetry, association rate constants were observed to approach the diffusion limit and were found to be insensitive to the structure of the guest. Conversely, the dissociation rate constants of the ternary complexes varied dramatically with the guest structure and were correlated with the thermodynamic binding selectivity. Hence differing molecular features were found to contribute to the associative and dissociative processes, mimicking naturally occurring reactions and giving rise to a decoupling of these kinetic parameters. Moreover, we demonstrate the ability to exploit these phenomena and selectively perturb the associative process with external stimuli (e.g., viscosity and pressure). Significantly, these complexes exhibit increased binding equilibria with increasing pressure, with important implications for the application of the CB[8] ternary complex for the formation of hydrogels, as these gels exhibit unprecedented pressure-insensitive rheological properties. A high degree of flexibility therefore exists in the design of host-guest systems with tunable kinetic and thermodynamic parameters for tailor-made applications across a broad range of fields. PMID- 28661668 TI - Effect of Corrosion Inhibitors on In Situ Leak Repair by Precipitation of Calcium Carbonate in Potable Water Pipelines. AB - Corrosion inhibitors can affect calcium carbonate precipitation and associated in situ and in-service water distribution pipeline leak repair via clogging. Clogging of 150 MUm diameter leak holes represented by glass capillary tubes, in recirculating solutions that are supersaturated with calcite (Omegacalcite = 13), demonstrated that Zn, orthophosphate, tripolyphosphate, and hexametaphosphate corrosion/scaling inhibitors hinder clogging but natural organic matter (NOM) has relatively little impact. Critical concentrations of phosphates that could inhibit leak repair over the short-term in one water tested were: tripolyphophate (0.05 mg/L as P) < hexametaphosphate (0.1 mg/L) < orthophosphate (0.3 mg/L). Inhibitor blends (Zn+orthophosphate and Zn+NOM+orthophosphate) had stronger inhibitory effects compared to each inhibitor (Zn, orthophosphate or NOM) alone, whereas Zn+NOM showed a lesser inhibitory effect than its individual component (NOM) alone due to formation of smaller CaCO3 particles with a much more negative zeta-potential. Overall, increased dosing of corrosion inhibitors is probably reducing the likelihood of scaling and in-service leak repair via clogging with calcium carbonate solids in potable water systems. PMID- 28661669 TI - Orthoborates LiCdRE5(BO3)6 (RE = Sm-Lu and Y) with Rare-Earth Ions on a Triangular Lattice: Synthesis, Crystal Structure, and Optical and Magnetic Properties. AB - Single crystals of LiCdY5(BO3)6 were successfully grown from a Li2O-B2O3 flux, and its lanthanide homotypic compounds, LiCdRE5(BO3)6 (RE = Sm-Lu), have been prepared by solid-state reaction. They crystallize in the noncentrosymmetric space group P6522 with cell parameters in the ranges of a = 7.0989(2)-6.9337(1) A and c = 25.9375(1)-24.8960(6) A. As a representative example, LiCdY5(BO3)6 features a triangular lattice in the ab plane composed of three distinct crystallographic Y sites. The triangular lattices spaced with the same distance of [Formula: see text]c are further stacked to build three-dimensional frameworks by reinforcement of the isolated planar BO3 groups and distorted LiO4 tetrahedra. Magnetic measurements show that Eu and Sm compounds exhibit typical Van Vleck type paramagnetism and other rare-earth borates show weak antiferromagnetic behavior. In addition, UV-vis-near-IR diffuse-reflectance and photoluminescence spectra were performed to understand the transition energy levels of active rare earth ions and their relationships to magnetism. PMID- 28661670 TI - psi-Graphene: A New Metallic Allotrope of Planar Carbon with Potential Applications as Anode Materials for Lithium-Ion Batteries. AB - Using state-of-the-art first-principles calculations, we propose a new two dimensional (2D) carbon allotrope constructed by polymerizing the carbon skeletons of s-indacenes, named PSI (psi)-graphene. We show that psi-graphene has the lowest energy among all hitherto reported 2D allotropes of carbon composed of 5-6-7 carbon rings and is dynamically and thermally stable. This structure is metallic with robust metallicity against external strain. In addition, we find that the adsorption of Li atoms on psi-graphene is exothermic, and the diffusion energy barrier is low and comparable to that of graphene. Furthermore, psi graphene can achieve a maximum Li storage capacity equivalent to that of LiC6, suggesting its potential as an anode material for Li-ion batteries (LIBs). In addition, we show that increasing the number of hexagons in this structure can enhance the thermodynamic stability of the sheet while maintaining its metallicity. This study provides new insights into the design of new metallic carbon for nanostructured anode materials in the next generation of LIBs. PMID- 28661671 TI - Bimetallic Ions Codoped Nanocrystals: Doping Mechanism, Defect Formation, and Associated Structural Transition. AB - Ionic codoping offers a powerful approach for modifying material properties by extending the selection of potential dopant ions. However, it has been a major challenge to introduce certain ions that have hitherto proved difficult to use as dopants (called "difficult-dopants") into crystal structures at high concentrations, especially through wet chemical synthesis. Furthermore, the lack of a fundamental understanding of how codopants are incorporated into host materials, which types of defect structures they form in the equilibrium state, and what roles they play in material performance, has seriously hindered the rational design and development of promising codoped materials. Here we take In3+ (difficult-dopants) and Nb5+ (easy-dopants) codoped anatase TiO2 nanocrystals as an example and investigate the doping mechanism of these two different types of metal ions, the defect formation, and their associated impacts on high-pressure induced structural transition behaviors. It is experimentally demonstrated that the dual mechanisms of nucleation and diffusion doping are responsible for the synergic incorporation of these two dopants and theoretically evidenced that the defect structures created by the introduced In3+, Nb5+ codopants, their resultant Ti3+, and oxygen vacancies are locally composed of both defect clusters and equivalent defect pairs. These formed local defect structures then act as nucleation centers of baddeleyite- and alpha-PbO2-like metastable polymorphic phases and induce the abnormal trans-regime structural transition of codoped anatase TiO2 nanocrystals under high pressure. This work thus suggests an effective strategy to design and synthesize codoped nanocrystals with highly concentrated difficult-dopants. It also unveils the significance of local defect structures on material properties. PMID- 28661672 TI - Flexible Force Field Parameterization through Fitting on the Ab Initio-Derived Elastic Tensor. AB - Constructing functional forms and their corresponding force field parameters for the metal-linker interface of metal-organic frameworks is challenging. We propose fitting these parameters on the elastic tensor, computed from ab initio density functional theory calculations. The advantage of this top-down approach is that it becomes evident if functional forms are missing when components of the elastic tensor are off. As a proof-of-concept, a new flexible force field for MIL-47(V) is derived. Negative thermal expansion is observed and framework flexibility has a negligible effect on adsorption and transport properties for small guest molecules. We believe that this force field parametrization approach can serve as a useful tool for developing accurate flexible force field models that capture the correct mechanical behavior of the full periodic structure. PMID- 28661673 TI - Scalable Electron Correlation Methods. 3. Efficient and Accurate Parallel Local Coupled Cluster with Pair Natural Orbitals (PNO-LCCSD). AB - A well-parallelized local singles and doubles coupled-cluster (LCCSD) method using pair natural virtual orbitals (PNOs) is presented. The PNOs are constructed using large domains of projected atomic orbitals (PAOs) and orbital specific virtual orbitals (OSVs). We introduce a hierarchy of close, weak, and distant pairs, based on pair energies evaluated by local Moller-Plesset perturbation theory (LMP2). In contrast to most previous implementations of LCCSD methods, the close and weak pairs are not approximated by LMP2 but treated by higher-order methods. This leads to greatly improved accuracy for large systems, in particular when long-range dispersion interactions are important. Close pair amplitudes are optimized using approximate LCCSD equations, in which slowly decaying terms that mutually cancel at long-range are neglected. For weak pairs, the same approximations are used, but in addition, the nonlinear terms are neglected (coupled electron pair approximation). Distant pairs are treated by spin component scaled (SCS)-LMP2 using multipole approximations. For efficiency reasons, various projection approximations are also introduced. The impact of these approximations on absolute and relative energies depends on the PNO domain sizes. The errors are found to be negligible, provided that sufficiently large PNO domains are used for close and weak pairs. For the selection of these domains the usual natural orbital occupation number criterion is found to be insufficient, and an additional energy criterion is used. For extended one dimensional systems, the computational effort of the method scales nearly linearly with the number of correlated electrons, but the linear scaling regime is usually not reached in real-life applications for three-dimensional systems. Nevertheless, due to the parallelization that is efficient up to about 100-200 CPU cores (dependent on the molecular size), accurate calculations for three dimensional molecules with about 100 atoms and augmented triple-zeta basis sets (e.g., cc-pVTZ-F12) can be carried out in 1-3 h of elapsed time (depending on the molecular structure and the number of CPU cores, excluding the time for Hartree Fock). The convergence of the results with respect to the thresholds and options that control the domain, pair, and projection approximations is extensively tested. Benchmark examples for several difficult and large cases are presented, which demonstrate that the errors of relative energies (e.g., reaction energies, barrier heights) caused by the pair and projection approximations can be reduced to below 1 kJ mol-1. The remaining errors are mainly caused by the finite PAO domains. The larger these are made, the more intramolecular or intermolecular basis set superposition errors are introduced, and the canonical results are approached only very slowly. This problem is eliminated in the explicitly correlated variant of our method (PNO-LCCSD-F12), which will be described in a separate paper, along with a larger set of benchmark calculations. PMID- 28661674 TI - Exploring the Origin of the Generalized Anomeric Effects in the Acyclic Nonplanar Systems. AB - Contrary to the published conclusions in the literature concerning the origin of the generalized anomeric relationships in open-chain nonplanar systems, its origin has remained an open question. In order to explore the origin of the generalized anomeric relationships in open-chain nonplanar systems, we assessed the roles and contributions of the effective factors on the conformational properties of methyl propargyl ether (1), methyl propargyl sulfide (2), and methyl propargyl selenide (3) by means of the G3MP2, CCSD(T), MP2, LC-omegaPBE, and B3LYP methods and natural bond orbital (NBO) interpretations. We examined the contributions of the hyperconjugative interactions on the conformational preferences of compounds 1-3 by the deletions of the orbitals overlapping from the Fock matrices of the gauche- and anti-conformations. The trend observed for energy changes in the Fock matrices justify the variations of the gauche conformations preferences going from compound 1 to compound 3, revealing that the hyperconjugative interactions are solely responsible for the generalized anomeric relationships in compounds 1-3. Accordingly, the conclusions published in the literature concerning the origin of the generalized anomeric effect in the acyclic nonplanar compounds should be revised by these findings. The Pauli exchange type repulsions (PETR) are in favors of the gauche-conformations and the variations of the PETR differences between the gauche- and anti-conformations of compounds 1-3 correlate well with their gauche-conformations preferences, revealing that the generalized anomeric relationships in compounds 1-3 have also the Pauli exchange-type repulsions origin. The resemblance between the preorthogonal natural bond orbitals (that are involved in the hyperconjugative interactions) and their corresponding molecular orbitals have been investigated. PMID- 28661675 TI - Hot-Carrier-Mediated Photon Upconversion in Metal-Decorated Quantum Wells. AB - Manipulating the frequency of electromagnetic waves forms the core of many modern technologies, ranging from imaging and spectroscopy to radio and optical communication. The process of converting photons from higher to lower energy is easily accomplished and technologically widespread. However, upconversion, which is the process of converting lower-energy photons into higher-energy photons, is still a growing field of study with nascent applications and burgeoning interest. Here, we experimentally demonstrate a new photon upconversion technique mediated by hot carriers in plasmonic nanostructures. Hot holes and hot electrons generated via plasmon decay in illuminated metal nanoparticles are injected into an adjacent semiconductor quantum well where they radiatively recombine to emit higher-energy photons. Using GaN/InGaN quantum wells decorated with gold and silver nanoparticles, we show photon upconversion from 2.4 to 2.8 eV. The process scales linearly with illumination power and enables both geometry- and polarization-based tunability. The conversion of plasmonic losses into upconverted optical emission has the potential to impact bioimaging, on-chip wavelength conversion, and high-efficiency photovoltaics. PMID- 28661676 TI - Meta-Lens Doublet in the Visible Region. AB - Recently, developments in meta-surfaces have allowed for the possibility of a fundamental shift in lens manufacturing-from the century-old grinding technology to nanofabrication-opening a way toward mass producible high-end meta-lenses. Inspired by early camera lenses and to overcome the aberrations of planar single layered meta-lenses, we demonstrate a compact meta-lens doublet by patterning two metasurfaces on both sides of a substrate. This meta-lens doublet has a numerical aperture of 0.44, a focal length of 342.5 MUm, and a field of view of 50 degrees that enables diffraction-limited monochromatic imaging along the focal plane at a wavelength of 532 nm. The compact design has various imaging applications in microscopy, machine vision, and computer vision. PMID- 28661677 TI - Deoxycyanamidation of Alcohols with N-Cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS). AB - The first one-pot deoxycyanamidation of alcohols has been developed using N-cyano N-phenyl-p-methylbenzenesulfonamide (NCTS) as both a sulfonyl transfer reagent and a cyanamide source, accessing a diverse range of tertiary cyanamides in excellent isolated yields. This approach exploits the underdeveloped desulfonylative (N-S bond cleavage) reactivity pathway of NCTS, which is more commonly employed for electrophilic C- and N-cyanation processes. PMID- 28661678 TI - Combining Eosin Y with Selectfluor: A Regioselective Brominating System for Para Bromination of Aniline Derivatives. AB - A mild, metal-free, and absolutely para-selective bromination of aniline derivatives has been developed in excellent yields, wherein the organic dye Eosin Y is employed as the bromine source in company with Selectfluor. Neither air nor moisture sensitive, this facile reaction proceeds smoothly at room temperature and completes within a short time. Mechanistic studies indicate a radical pathway; therefore, the existence of an in situ generated brominating reagent, "Selectbrom", is postulated, which may reasonably account for the unique regioselectivity for the para-bromination of N-acyl- as well as N sulfonylanilines. PMID- 28661679 TI - Viewing Molecular and Interface Interactions of Curcumin Amorphous Solid Dispersions for Comprehending Dissolution Mechanisms. AB - Tautomeric curcumin amorphous solid dispersions (Cur ASDs) formulated with various typical polymers (polyethylene glycol 6000 (PEG), polyvinylpyrrolidone K30 (PVP), Eudragit EPO (EuD), EuD/hydroxypropylmethyl cellulose E50 (HPMC), and PVP/EuD) were probed using in situ Raman imaging plus spectroscopy and molecular modeling techniques, and dissolution mechanism of Cur ASDs were revealed mainly through molecular and interfacial interactions formed between Cur and polymer. The results demonstrated that Cur of keto form existed in Cur-PEG, Cur of enol form was shown in Cur-PVP, while Cur-EuD or Cur ASDs formulated with EuD as component had Cur of keto form and enol form. Hydrogen bond interactions were formed between OH group (PEG, HPMC) with C?O (Cur), and C?O (PVP or EuD) with the OH group (Cur). For Cur ASDs formulated with single polymer, the existed form of Cur was possibly related with the molecular interactions formed between drug and polymer. The wetting effect of excipient and Cur ASDs as well as their fitting equations of contact angle profiles should be seriously considered when analyzing the dissolution mechanism of Cur ASDs. Furthermore, dissolution of Cur-EuD with erosion dissolution pattern was higher than Cur-PVP with diffusion mechanism, and their crystallization pathway can ascribe to solution pathway and solid matrix pathway, respectively. Last but not least, turbidimetry method was effective in determining which excipient was superior and evaluating the function of polymers, including their abilities to improve amorphous Cur loading, drug dissolution, and supersaturation levels. Therefore, both the probing of tautomeric Cur in ASDs at intermolecular level and elucidation of its dissolution mechanism has tremendous value. PMID- 28661680 TI - Dynamic Electronic Junctions in Organic-Inorganic Hybrid Perovskites. AB - Organic-inorganic hybrid perovskites have shown great potential as building blocks for low-cost optoelectronics for their exceptional optical and electrical properties. Despite the remarkable progress in device demonstration, fundamental understanding of the physical processes in halide perovskites remains limited, especially the unusual electronic behaviors such as the current-voltage hysteresis and the switchable photovoltaic effect. These phenomena are of particular interests for being closely related to device functionalities and performance. In this work, a microscopic picture of electric fields in halide perovskite thin films was obtained using scanning laser microscopy. Unlike conventional semiconductors, distribution of the built-in electric fields in the halide perovskite evolves dynamically under the stimulation of external biases. The observations can be well explained using a model based on field-assisted ion migration, indicating that the mechanism responsible for the evolving charge transport observed in this material is not purely electronic. The anomalous dynamic responses to the applied bias are found to be effectively suppressed by operating the devices at reduced temperature or processing the materials at elevated temperature, which provide potential strategies for designing and creating halide perovskites with more stable charge transport properties in the development of viable perovskite-based optoelectronics. PMID- 28661681 TI - A Fluorescence Lifetime Imaging Microscopy Supported Investigation on Temperature Dependent Penetration of Dopamine in a 1,2-Ditetradecanoyl-sn-glycero-3-phospho (1'-rac-glycerol) Lipid Bilayer. AB - Distribution of dopamine, an essential neurotransmitter in mammalian central and peripheral nervous systems, in a lipid bilayer and at the surface of 1,2 ditetradecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) vesicles has been studied herein. To track the progress of dopamine through different regions of the lipid vesicle, these were synthesized using 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) labeled phospholipid molecules tagged to either the headgroup (NBDPE) or the acyl chain (NBDPG). Dopamine-induced quenching of NBD fluorescence in the lipid vesicles demonstrates that dopamine has a preference to diffuse into the lipid bilayer. The change in the excited state lifetime obtained for NBDPG clearly indicates the preference in dopamine binding. The propositions were supported by fluorescence lifetime imaging microscopy. PMID- 28661682 TI - Calix[4, 5]tetrolarenes: A New Family of Macrocycles. AB - The facile and efficient one-step synthesis and the full characterization of novel pi-electron rich macrocycles, calix-[n]tetrolarenes (n = 4, 5), are described. The tetramer and the much rarer sized pentamer were easily prepared by reaction of the commercially available, partially methylated 1,2,3,5 benzenetetrol with paraformaldehyde under TFA catalysis, with a total isolated yield of 73%. The reaction is solvent sensitive, and the number of methylated oxygens also affects the tetramer/pentamer distribution. The compounds formed may be considered as "chimeric" macrocycles of calixarene and pyrogallol[n]arene that may serve as new building blocks in host-guest and supramolecular chemistry. PMID- 28661683 TI - Identification of Chemicals that Cause Oxidative Stress in Oil Sands Process Affected Water. AB - Oil sands process-affected water (OSPW) has been reported to cause oxidative stress in organisms, yet the causative agents remain unknown. In this study, a high-throughput in vitro Nrf2 reporter system was used, to determine chemicals in OSPW that cause oxidative stress. Five fractions, with increasing polarity, of the dissolved organic phase of OSPW were generated by use of solid phase extraction cartridges. The greatest response of Nrf2 was elicited by F2 (2.7 +/- 0.1-fold), consistent with greater hydroperoxidation of lipids in embryos of Japanese medaka (Oryzias latipes) exposed to F2. Classic naphthenic acids were mainly eluted in F1, and should not be causative chemicals. When F2 was fractionated into 60 subfractions by use of HPLC, significant activation of Nrf2 was observed in three grouped fractions: F2.8 (1.30 +/- 0.01-fold), F2.16 (1.34 +/- 0.05-fold), and F2.25 (1.28 +/- 0.15-fold). 54 compounds were predicted to be potential chemicals causing Nrf2 response, predominated by SO3+ and O3+ species. By use of high-resolution MS2 spectra, these SO3+ and O3+ species were identified as hydroxylated aldehydes. This study demonstrated that polyoxygenated chemicals, rather than classic NAs, were the major chemicals responsible for oxidative stress in the aqueous phase of OSPW. PMID- 28661685 TI - Kinetics of the Autoreduction of Hexavalent Americium in Aqueous Nitric Acid. AB - The rate of reduction of hexavalent 243Am due to self-radiolysis was measured across a range of total americium and nitric acid concentrations. These so-called autoreduction rates exhibited zero-order kinetics with respect to the concentration of hexavalent americium, and pseudo-first-order kinetics with respect to the total concentration of americium. However, the rate constants did vary with nitric acid concentration, resulting in values of 0.0048 +/- 0.0003, 0.0075 +/- 0.0005, and 0.0054 +/- 0.0003 h-1 for 1.0, 3.0, and 6.5 M HNO3, respectively. This indicates that reduction is due to reaction of hexavalent americium with the radiolysis products of total americium decay. The concentration changes of Am(III), Am(V), and Am(VI) were determined by UV-vis spectroscopy. The Am(III) molar extinction coefficients are known; however, the unknown values for the Am(V) and Am(VI) absorbances across the studied range of nitric acid concentrations were determined by sensitivity analysis in which a mass balance with the known total americium concentration was obtained. The new extinction coefficients and reduction rate constants have been tabulated here. Multiscale radiation chemical modeling using a reaction set with both known and optimized rate coefficients was employed to achieve excellent agreement with the experimental results, and indicates that radiolytically produced nitrous acid from nitric acid radiolysis and hydrogen peroxide from water radiolysis are the important reducing agents. Since these species also react with each other, modeling indicated that the highest concentrations of these species available for Am(VI) reduction occurred at 3.0 M HNO3. This is in agreement with the empirical finding that the highest rate constant for autoreduction occurred at the intermediate acid concentration. PMID- 28661684 TI - RutA-Catalyzed Oxidative Cleavage of the Uracil Amide Involves Formation of a Flavin-N5-oxide. AB - RutA is a novel flavoenzyme on the uracil catabolic pathway that catalyzes uracil ring opening by a unique amide oxidation reaction. Here we provide evidence that this reaction also involves the formation of a flavin-N5-oxide. PMID- 28661686 TI - A Tetramer Derived from Islet Amyloid Polypeptide. AB - Aggregation of the islet amyloid polypeptide (IAPP) to form fibrils and oligomers is important in the progression of type 2 diabetes. This article describes X-ray crystallographic and solution-state NMR studies of peptides derived from residues 11-17 of IAPP that assemble to form tetramers. Incorporation of residues 11-17 of IAPP (RLANFLV) into a macrocyclic beta-sheet peptide results in a monomeric peptide that does not self-assemble to form oligomers. Mutation of Arg11 to the uncharged isostere citrulline gives peptide homologues that assemble to form tetramers in both the crystal state and in aqueous solution. The tetramers consist of hydrogen-bonded dimers that sandwich together through hydrophobic interactions. The tetramers share several features with structures reported for IAPP fibrils and demonstrate the importance of hydrogen bonding and hydrophobic interactions in the oligomerization of IAPP-derived peptides. PMID- 28661688 TI - Solution Synthesis of Nonequilibrium Zincblende MnS Nanowires. AB - Uniform four-coordinate nonequilibrium MnS nanowires mainly in zincblende structure, other than the stable rock-salt phase, are reported for the first time. The MnS nanowires are grown via a solution-solid-solid model from the reaction of a Mn(II) source with dibenzyl disulfide in oleylamine at 180-200 degrees C catalyzed by Ag2S nanocrystals in a body-centered cubic (bcc) fast ionic phase transformed from their low-temperature monoclinic form. Investigations show that most of the zincblende MnS nanowires are grown along the ?112? zone axis but a small proportion grow along the ?111?ZB/?0001?Wur axis with zincblende/defect-section and/or wurtzite/defect-section superlattices connected with the stems along the ?112? direction. The nanowires have a tendency to grow straight at relatively low reaction temperature for short reaction times but twist at high temperature for long reaction times. Meanwhile, relatively high temperatures and long times favor the transition of the MnS nanowires in the zincblende phase to the corresponding thermodynamic ones in rock-salt form. Interestingly, even small increases in reaction pressure (1-2 atm) sensitively influence the growth of the MnS nanowires from zincblende to wurtzite form in the present catalytic system although low-pressure changes commonly do not have an obvious effect on condensed matter. In addition, the optical and magnetic properties of the zincblende MnS nanowires were studied, and they are varied largely from the bulk. PMID- 28661687 TI - Curcumin Acrylation for Biological and Environmental Applications. AB - Curcumin has recently gained interest for use in drug delivery, chemical sensing, and environmental applications. As a result, the development of synthesis strategies for the incorporation of curcumin into novel materials has become a priority. One such strategy, curcumin acrylation, involves the introduction of acrylate functional groups to the curcumin scaffold, with the potential generation of mono-, di-, and triacrylate curcumin species. The relative populations of these species in the resulting multiacrylate mixture can be controlled by the ratio of curcumin to acryloyl chloride in the initial reaction formulation. Characterization of the acrylation reaction and the resulting curcumin multiacrylate product is essential for the effective preparation of new curcumin-containing materials. In this work, a synthesis method for curcumin acrylation is presented and the resulting curcumin multiacrylate product is characterized via various techniques, i.e., HPLC, LCMS, and NMR, as a basis to establish the relationship between synthesis conditions and the extent of acrylation that is achieved. PMID- 28661689 TI - Grape Metabolic Response to Postveraison Water Deficit Is Affected by Interseason Weather Variability. AB - Postveraison water deficit is a common strategy implemented to improve fruit composition in many wine-growing regions. However, contrasting results are often reported on fruit size and composition, a challenge for generalizing the positive impact of this technique. Our research investigated the effect of water deficit (WD) imposed at veraison on Merlot grapevines, during two experimental seasons (2014-2015). In both years WD resulted in reduced carbon assimilation rates and leaf shedding. However, the treatment effect on the analyzed berry parameters varied between seasons. Modification of skin metabolites was more evident in 2015 than in 2014, despite the similar soil water content and water stress physiological parameters (gas exchange, water potential) recorded in the two experimental years. Higher solar radiation and air temperature in 2015 than in 2014 hint for the involvement of atmospheric parameters in fulfilling the potential effect of WD. Our results suggest that the interaction between water availability and weather conditions plays a crucial role in modulating the grape berry composition. PMID- 28661690 TI - Hydrophobically Modified Polymer/alpha-Cyclodextrin Thermoresponsive Hydrogels for Use in Ocular Drug Delivery. AB - We report herein on the preparation of thermoresponsive hydrogels by taking advantage of the interaction of cyclodextrins (CDs) and a hydrophobically modified polymer. A hydrophobically modified hydroxypropyl methylcellulose (HM HPMC) gel formed thermoresponsive hydrogels when small amounts of alpha-CD were added to the solution. The HM-HPMC/alpha-CD showed reversible sol-gel transition in the physiological temperature range that was completely opposite to the temperature dependency shown by the original HM-HPMC. The thermoresponsive gelation was attributed to the temperature dependency of the interaction between alpha-CD and the hydrophobic moiety of HM-HPMC. The potency of the HM-HPMC/alpha CD sol-gel transition system in ophthalmic formulation was tested on the eyes of a rabbit. The use of HM-HPMC/alpha-CD significantly improved the ocular absorption of a drug, diclofenac sodium, by virtue of the rapid formation of a gel on the ocular surface. That is, the HM-HPMC/alpha-CD was in a low viscous sol state at room temperature, which made administration easy, but it rapidly formed a viscous hydrogel on the ocular surface at physiological temperature. The thermoresponsive hydrogel based on the hydrophobically modified polymer and CD promises to have widespread applications in drug delivery. PMID- 28661691 TI - Submillimeter-Sized Bubble Entrapment and a High-Speed Jet Emission during Droplet Impact on Solid Surfaces. AB - When a droplet impacts a solid surface, the entrapment of a submillimeter-sized bubble and the emission of a high speed jet can be observed at low impact velocities. In this work, we show that bubble entrapment occurs only on sufficiently hydrophobic surfaces within a narrow range of impact velocities. The bubble is entrapped on hydrophobic surfaces, whereas it is trapped into the top of the droplet on superhydrophobic surfaces. The collapse of the air cavity formed during droplet impact, which is dominated by inertia and influenced by surface wettability, is the cause of the bubble entrapment. The velocity of liquid jets emitted after cavity collapse for drop impact with and without bubble entrapment scales with their sizes according to different power laws, which is explained by simple scaling analyses. PMID- 28661692 TI - Tabletop Femtosecond VUV Photoionization and PEPICO Detection of Microreactor Pyrolysis Products. AB - We report the combination of tabletop vacuum ultraviolet photoionization with photoion-photoelectron coincidence spectroscopy for sensitive, isomer-specific detection of nascent products from a pyrolysis microreactor. Results on several molecules demonstrate two essential capabilities that are very straightforward to implement: the ability to differentiate isomers and the ability to distinguish thermal products from dissociative ionization. Here, vacuum ultraviolet light is derived from a commercial tabletop femtosecond laser system, allowing data to be collected at 10 kHz; this high repetition rate is critical for coincidence techniques. The photoion-photoelectron coincidence spectrometer uses the momentum of the ion to identify dissociative ionization events and coincidence techniques to provide a photoelectron spectrum specific to each mass, which is used to distinguish different isomers. We have used this spectrometer to detect the pyrolysis products that result from the thermal cracking of acetaldehyde, cyclohexene, and 2-butanol. The photoion-photoelectron spectrometer can detect and identify organic radicals and reactive intermediates that result from pyrolysis. Direct comparison of laboratory and synchrotron data illustrates the advantages and potential of this approach. PMID- 28661693 TI - Hybrid Colloidal Stabilization Mechanism toward Improved Photoluminescence and Stability of CdSe/CdS Core/Shell Quantum Dots. AB - Colloidal quantum dots can be stabilized in either a polar solvent or a nonpolar solvent depending on their surface chemistry. The former is typically achieved by charge stabilization while the latter by steric hindrance. This allows reversible tuning of their surface polarity for targeted application by engineering their ligand profile. Here we developed a hybrid stabilization approach that leveraged a combination of steric hindrance and charge stabilization simultaneously. We demonstrated this mechanism in a phase transfer process where hexane dispersed and hydrophobic CdSe/CdS core/shell quantum dots were exchanged into the hydrophilic dimethylformamide (DMF) phase. This was achieved by employing both Z type cadmium acetate and X-type halide ligands. The results suggested only by using this hybrid stabilization strategy were we able to achieve good colloidal stability while preserving their photoluminescence quantum yield. This hybrid ligand strategy may promise new opportunities for the application of QDs in optoelectronic areas. PMID- 28661694 TI - Boltzmann Transport in Nanostructures as a Friction Effect. AB - Surface scattering is the key limiting factor to thermal transport in dielectric crystals as the length scales are reduced or when temperature is lowered. To explain this phenomenon, it is commonly assumed that the mean free paths of heat carriers are bound by the crystal size and that thermal conductivity is reduced in a manner proportional to such mean free paths. We show here that these conclusions rely on simplifying assumptions and approximated transport models. Instead, starting from the linearized Boltzmann transport equation in the relaxon basis, we show how the problem can be reduced to a set of decoupled linear differential equations. Then, the heat flow can be interpreted as a hydrodynamic phenomenon with the relaxon gas being slowed down in proximity of a surface by friction effects, similar to the flux of a viscous fluid in a pipe. As an example, we study a ribbon and a trench of monolayer molybdenum disulfide, describing the procedure to reconstruct the temperature and thermal conductivity profile in the sample interior and showing how to estimate the effect of nanostructuring. The approach is general and could be extended to other transport carriers, such as electrons, or extended to materials of higher dimensionality and to different geometries, such as thin films. PMID- 28661695 TI - Treatment of Chemotherapy-Induced Peripheral Neuropathy in Integrative Oncology: A Survey of Acupuncture and Oriental Medicine Practitioners. AB - OBJECTIVES: Complementary and alternative medicine is increasingly integrated into cancer care. We sought detail on the treatment of chemotherapy-induced peripheral neuropathy (CIPN) with acupuncture and oriental medicine (AOM) by surveying practitioners at integrative oncology (IO) sites across the United States. DESIGN: Online survey of licensed acupuncturists. SETTING/LOCATION: IO sites in the United States. SUBJECTS: Fifteen licensed acupuncturists who completed the survey between February 2014 and June 2014. OUTCOME MEASURES: Demographics, IO setting characteristics, AOM treatment characteristics, and practitioner-reported outcomes. RESULTS: Respondents reported an average of 31.3 +/- 17.2 patients per week, and one-third (10.1 mean; 7.2 standard deviation [SD]) were treated for CIPN. Medical doctors (86.7%) were the most common providers with whom respondents worked. Traditional Chinese medicine style acupuncture was utilized by a majority of respondents (86.7%), and the most commonly used points were local, typically in the hands and feet, such as Ba Feng, Ba Xie, LV3, and LI4. In addition to acupuncture, nutritional advice was the most frequent auxiliary modality provided by respondents (85.7%). On average, respondents provided 12.75 +/- 4.17 treatments for CIPN patients, and a majority (53%) reported treating patients once per week. Timing of the treatments relative to chemotherapy infusion was evenly distributed between "1-2 days after infusion" (60%), "at time of infusion" (53.3%), and "1-2 days before infusion" (46.7%). Sixty percent of respondents rated outcomes as "moderately successful with moderate improvement seen." CONCLUSION: This survey provides detail regarding IO sites using acupuncture for CIPN as well as real-world treatment patterns, including common point combinations, visit characteristics, and practitioner reported outcomes. This information contributes to the emerging evidence on the use of acupuncture to address unmet needs of CIPN patients, and supports the development of best practice guidelines for the treatment of CIPN with acupuncture in the IO setting. PMID- 28661696 TI - Double-Bundle Versus Single-Bundle Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Study With 10-Year Results. AB - BACKGROUND: A long-term follow-up comparing double-bundle and single-bundle techniques for anterior cruciate ligament (ACL) reconstruction has not been reported before. HYPOTHESIS: Double-bundle ACL reconstruction may have fewer graft ruptures, lower rates of osteoarthritis (OA), and better stability than single-bundle reconstruction. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Ninety patients were randomized for double-bundle ACL reconstruction with bioabsorbable screw fixation (DB group; n = 30), single bundle ACL reconstruction with bioabsorbable screw fixation (SBB group; n = 30), and single-bundle ACL reconstruction with metallic screw fixation (SBM group; n = 30). Evaluation methods consisted of a clinical examination, KT-1000 arthrometer measurements, International Knee Documentation Committee (IKDC) and Lysholm knee scores, and a radiographic examination of both the operated and contralateral knees. RESULTS: Eighty-one patients (90%) were available at the 10-year follow up. Eleven patients (1 in the DB group, 7 in the SBB group, and 3 in the SBM group) had a graft failure during the follow-up and went on to undergo revision ACL surgery ( P = .043). In the remaining 70 patients at 10 years, no significant group differences were found in the pivot-shift test findings, KT-1000 arthrometer measurements, or knee scores. The most OA findings were found in the medial compartment of the knee, with 38% of the patients in the operated knee and 28% of the patients in the contralateral nonoperated knee. However, no significant group difference was found. The most severe OA changes were in the patients who had the longest delay from the primary injury to ACL reconstruction ( P = .047) and in the patients who underwent partial meniscal resection at the time of ACL reconstruction ( P = .024). CONCLUSION: Double-bundle ACL reconstruction resulted in significantly fewer graft failures than single-bundle ACL reconstruction during the follow-up. Knee stability and OA rates were similar at 10 years. The most severe OA changes were found in the patients who had the longest delay from the primary injury to ACL reconstruction and in the patients who underwent partial meniscal resection at the time of ACL reconstruction. PMID- 28661697 TI - Improvement in Right Ventricular Strain with Ambrisentan and Tadalafil Upfront Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. PMID- 28661699 TI - Longitudinal Assessment of Children with Mild Cystic Fibrosis Using Hyperpolarized Gas Lung Magnetic Resonance Imaging and Lung Clearance Index. PMID- 28661700 TI - The Debate Should Now Be Over: Simplified Cardiorespiratory Sleep Tests Are a Reliable, Cost-Saving Option for Diagnosing Obstructive Sleep Apnea. PMID- 28661698 TI - The Role of Chest Computed Tomography in the Evaluation and Management of the Patient with Chronic Obstructive Pulmonary Disease. PMID- 28661701 TI - Bringing Lung Function Prediction Equations to Diverse Populations. PMID- 28661702 TI - Maternal Gaze Behaviors During Latching-On for Breastfeeding. AB - BACKGROUND: Studies in various fields have demonstrated that experts use specific gaze strategies to achieve better performance. Therefore, we hypothesized that mothers familiar with breastfeeding would use a specific gaze strategy to achieve better latching-on. METHODS: A head-mounted eye tracker was used to record pupil positions from 14 breastfeeding mothers with 1-month-old infants. Eye gazes were analyzed during the latching-on and assessment phases. RESULTS: During the latching-on phase, participants tended to fixate on their breast, the infant's lower face, an intermediate region between the infant's face and the breast, and the region of contact between the infant's mouth and the breast. Once the infant latched onto the breast, mothers typically assessed the latch by fixating on their breast or the region of contact between the infant's mouth and the breast. The gaze patterns were generally maintained without being influenced by the subtask properties of each phase. CONCLUSION: Similar to previous studies, we found that mothers fixated on specific locations that were relevant to the current breastfeeding subtask, suggesting that the gaze behavior contributes to the execution of latching-on. Therefore, it is important to consider that successful latching-on is influenced by maternal physical movements and efficient gazing behaviors. PMID- 28661703 TI - The Insidious Effects of Sexual Stereotypes in Clinical Practice. AB - The present study investigated the influence of sexual stereotyping on the diagnostic impressions and treatment expectations of gay and straight male patients. Italian male, straight, licensed psychotherapists (N = 152) were presented with clinical vignettes that described a gay (versus straight) male patient reporting either a straight-stereotypical disorder (i.e., rage dyscontrol) or a gay-stereotypical disorder (i.e., sexual compulsivity). Results revealed that treatment efficacy expectations were influenced by the patient's sexual orientation and the stereotypicality of the disorder. Specifically, psychotherapists anticipated fewer benefits from psychotherapy when gay patients reported a sexual disorder rather than a rage disorder. Furthermore, explicit and implicit levels of sexual prejudice did not play any role in driving such results. Taken together, these findings reveal that sexual stereotyping might exert its subtle effects among clinicians by influencing their clinical evaluations. PMID- 28661704 TI - The UK breast screening program - what you need to know. AB - Breast cancer is the most commonly diagnosed cancer in women with a lifetime risk of 1 in 8 in the UK. The disease is associated with considerable morbidity and mortality. The UK breast screening program has been in place for almost 30 years and has evolved with improved diagnostic imaging. The overall benefits of the screening program are subject to continued heated debate with multiple potential harms. The aim of this review is to provide the non-breast specialist health-care professional an overview of the evolution of the breast screening program, a summary of the evidence of the benefits, and a description of the harms. In addition, the diagnostic methods currently employed as well as potential future changes to the screening program and imaging techniques will be covered. PMID- 28661705 TI - Lichen sclerosus in women: a review. AB - Female lichen sclerosus is a chronic inflammatory dermatitis, with a predilection for the anogenital area, which in some cases can become seriously distorted (atrophy of the labia minora, phimosis, introital stenosis, etc.). Most cases are diagnosed in postmenopausal women, but it can affect women of any age. Lichen sclerosus is usually a pruriginous condition, although it can also be asymptomatic. It is associated with an increased risk of vulvar cancer, even though it is not a premalignant condition itself. The true precursor of cancer associated with lichen sclerosus is vulvar intraepithelial neoplasia, differentiated type. The diagnosis is usually clinical, but in some cases a biopsy can be performed, especially to exclude vulvar intraepithelial neoplasia or cancer. The treatment of lichen sclerosus aims at controlling the symptoms, stopping further scarring and distortion and reducing the risk of cancer. The gold standard in treatment is ultra-potent topical steroids (clobetasol propionate). Second-line treatments include calcineurin inhibitors, retinoids, and immunosuppressors. Surgery is used only for the treatment of complications associated with lichen sclerosus. Follow-up must be kept indefinitely. PMID- 28661706 TI - Designing a Health-Game Intervention Supporting Health Literacy and a Tobacco Free Life in Early Adolescence. AB - OBJECTIVE: The purpose of this study was to explore the design of a health game that aims to both support tobacco-related health literacy and a tobacco-free life in early adolescence and to meet adolescents' expectations. MATERIALS AND METHODS: Data were collected from adolescents using an open-ended questionnaire (n = 83) and focus groups (n = 39) to obtain their view of a health game used for tobacco-related health education. The data were analyzed using thematic analysis. A group of experts combined the adolescents' views with theoretical information on health literacy and designed and produced the first version of the game. Adolescents (session 1, n = 16; session 3, n = 10; and session 4, n = 44) and health promotion professionals (session 2, n = 3) participated in testing the game. Feedback from testing sessions 3 and 4 was analyzed using descriptive statistics. RESULTS: Adolescents pointed out that the health game needs to approach the topic of tobacco delicately and focus on the adolescents' perspective and on the positive sides of a tobacco-free life rather than only on the negative consequences of tobacco. The adolescents expected the game to be of high quality, stimulating, and intellectually challenging and to offer possibilities for individualization. Elements from the adolescents' view and theoretical modelling were embedded into the design of a game called Fume. Feedback on the game was promising, but some points were highlighted for further development. CONCLUSION: Investing especially in high-quality design features, such as graphics and versatile content, using humoristic or otherwise stimulating elements, and maintaining sufficiently challenging gameplay would promote the acceptability of theory-based health games among adolescents. PMID- 28661707 TI - Using Hadoop MapReduce for Parallel Genetic Algorithms: A Comparison of the Global, Grid and Island Models. AB - The need to improve the scalability of Genetic Algorithms (GAs) has motivated the research on Parallel Genetic Algorithms (PGAs), and different technologies and approaches have been used. Hadoop MapReduce represents one of the most mature technologies to develop parallel algorithms. Based on the fact that parallel algorithms introduce communication overhead, the aim of the present work is to understand if, and possibly when, the parallel GAs solutions using Hadoop MapReduce show better performance than sequential versions in terms of execution time. Moreover, we are interested in understanding which PGA model can be most effective among the global, grid, and island models. We empirically assessed the performance of these three parallel models with respect to a sequential GA on a software engineering problem, evaluating the execution time and the achieved speedup. We also analysed the behaviour of the parallel models in relation to the overhead produced by the use of Hadoop MapReduce and the GAs' computational effort, which gives a more machine-independent measure of these algorithms. We exploited three problem instances to differentiate the computation load and three cluster configurations based on 2, 4, and 8 parallel nodes. Moreover, we estimated the costs of the execution of the experimentation on a potential cloud infrastructure, based on the pricing of the major commercial cloud providers. The empirical study revealed that the use of PGA based on the island model outperforms the other parallel models and the sequential GA for all the considered instances and clusters. Using 2, 4, and 8 nodes, the island model achieves an average speedup over the three datasets of 1.8, 3.4, and 7.0 times, respectively. Hadoop MapReduce has a set of different constraints that need to be considered during the design and the implementation of parallel algorithms. The overhead of data store (i.e., HDFS) accesses, communication, and latency requires solutions that reduce data store operations. For this reason, the island model is more suitable for PGAs than the global and grid model, also in terms of costs when executed on a commercial cloud provider. PMID- 28661708 TI - Pilot Data Supporting Omega-3 Fatty Acids Supplementation in Medicated Children with Attention-Deficit/Hyperactivity Disorder and Deficits in Emotional Self Regulation. PMID- 28661710 TI - Use of Hemostatic Nasal Plugs in Emergency Medical Services in the Netherlands: A Prospective Study of 33 Cases. AB - BACKGROUND: Epistaxis is a common medical emergency with possible life threatening complications. In the prehospital setting, epistaxis can be treated with nasal tampons. HemCon(r) Nasal Plug is a nasal tampon impregnated with oxidized cellulose, which has hemostatic properties. OBJECTIVE: The objective of this study was to determine the effectiveness and usability of HemCon Nasal Plugs in the treatment of severe epistaxis in the prehospital setting. METHODS: From June 2012 to December 2014, all ambulances of two emergency medical services in the Netherlands were equipped with HemCon Nasal Plugs. The plug was used according to protocol; if conventional treatment failed to control severe epistaxis or if conventional treatment was unlikely to achieve hemostasis. The ambulance personnel filled in an evaluation form after each use. RESULTS: A total of 33 patients were treated with HemCon Nasal Plugs. Twenty-four patients were taking anticoagulants or suffered from a clotting disorder. The cause of epistaxis was idiopathic in the majority of the patients. Inserting HemCon Nasal Plugs resulted in cessation of epistaxis in 25/33 patients and resulted in reduction of epistaxis in 4/33 patients. HemCon Nasal Plugs failed to control epistaxis in 4/33 patients, possible due to an unreachable site of bleeding. CONCLUSION: This study demonstrated that HemCon Nasal Plug is an effective adjunct in the prehospital treatment of severe and uncontrolled epistaxis. PMID- 28661711 TI - Safety of ixazomib for the treatment of multiple myeloma. AB - INTRODUCTION: Despite a major positive impact of proteasome inhibitors (PI), such as bortezomib and carfilzomib, on the survival of patients with multiple myeloma (MM) over the last few years, their use in clinical practice is limited by the development of drug resistance, significant side-effects or constraining administration schedules. Ixazomib is the first, and for now the only, oral PI, which was approved by the US Food and Drug Administration in 2015 and by the European Medicines Agency in 2016. Areas covered: In this review, we provide an overview of the preclinical and early-phase studies of ixazomib used as single agent and in combination. Furthermore, we discuss the results of a recently published pivotal trial, which evaluated the safety profile and clinical benefit of the combination of ixazomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in 722 patients with relapsed/refractory MM. Expert opinion: Ixazomib combines the comfort of oral administration, substantial clinical efficacy and a good safety profile with manageable side-effects, which mainly comprise low-grade hematological, digestive or cutaneous events, and the agent will therefore play an active part in long-term treatment strategies, both as single agent and as part of combination regimens. Ongoing phase III trials are currently defining its place in first-line, maintenance and relapse settings. PMID- 28661713 TI - Publications on Palliative Care Development Can Be Used as an Indicator of Palliative Care Development in Africa. AB - BACKGROUND: Palliative care (PC) research in Africa has been proposed as a fifth dimension of the World Health Organization PC Public Health Strategy. We conducted a scoping review of published articles (2005-2016) on palliative care development (PCD) in African countries. Forty-seven articles were found across 26 countries. OBJECTIVE: To study whether the number of published articles on PCD in countries in Africa can be used as an indicator of PCD. DESIGN: This is a secondary analysis of a completed scoping review. MEASUREMENTS: Spearman correlations were applied to the number of published articles ("published articles") and the number of published articles with a coauthor from a high income country (HIC) ("HIC published articles") with level of PCD using Lynch et al's updated world map (PC World Map) as a proxy. A subanalysis was undertaken for Anglophone versus non-Anglophone countries. RESULTS: There were positive Spearman correlations (r) between the PC World Map's levels and published articles (r = 0.73; p < 0.001), and with HIC published articles (r = 0.68; p < 0.001). For Anglophone countries, the r was statistically significant (p < 0.001) at 0.69 and 0.70, versus 0.58 and 0.45 for non-Anglophone countries for published articles and HIC published articles, respectively. Kruskal-Wallis test showed a statistically significant difference between Anglophone and non-Anglophone countries for both published articles and HIC published articles (p < 0.01). CONCLUSION: Published articles and HIC published articles on PCD in Africa had strong positive r's with the PC World Map. These measures may be considered as two indicators of PCD for countries in Africa, particularly for Anglophone countries. PMID- 28661712 TI - Out-of-hospital and Inter-hospital Under-triage to Designated Tertiary Trauma Centers among Injured Older Adults: A 10-year Statewide Geospatial-Adjusted Analysis. AB - OBJECTIVE: While out-of-hospital under-triage of seriously injured older adults to tertiary trauma centers has long been acknowledged, no study has adjusted for place of injury or evaluated the extent of inter-facility under-triage. We sought to determine distance and confounder adjusted odds of treatment at a tertiary trauma center (TTC) for older adult trauma patients compared to younger trauma patients, for patients transported from the scene of injury and those transferred from a non-tertiary trauma (NTTC) center. METHODS: This was a retrospective cohort study utilizing data from a statewide trauma registry reported over a 10 year period (2005-14). The outcome of interest was treatment at an American College of Surgeons or state-designated Level I/II trauma center (TTC). The predictor variable of interest was age group (> = 55 years vs. < 55 years). Covariates of interest included patient demographics, clinical characteristics and various distance measures calculated based on the patient's injury location. RESULTS: 84 930 patients met study criteria. Of these 42% (35659) were 55 years and older with an average age of 74 years (SD, 11.6). Older adult patients were on average, injured slightly farther away from a TTC (median distance, 34 vs. 29 miles, p < 0.001). Among patients initially presenting to NTTCs, older adults were significantly more likely to be transferred to another NTTC (53% vs. 34%). After adjusting for confounders and distance measures, older adults were less likely to be treated at TTCs overall (OR = 0.54, 95% CI: 0.52-0.56), whether transported by EMS from the scene of injury (OR = 0.47, 95% CI: 0.44-0.50) or via inter-facility transfer (OR = 0.63, 95%CI: 0.59-0.68). CONCLUSIONS: Injured older adults face significant under-triage to TTCs whether by EMS from the scene of injury or via transfer from NTTCs. Adjusting for proximity of injury to a TTC does not alter these findings. PMID- 28661714 TI - Early Initiation of Amphetamine-Type Stimulants (ATS) Use Associated with Lowered Cognitive Performance among Individuals with Co-Occurring Opioid and ATS Use Disorders in Malaysia. AB - Amphetamine-type stimulants (ATS) use is increasingly prevalent in Malaysia, including among individuals who also use opioids. We evaluated cognitive functioning profiles among individuals with co-occurring opioid and ATS dependence and their lifetime patterns of drug use. Participants (N = 50) enrolling in a clinical trial of buprenorphine/naloxone treatment with or without atomoxetine completed the Raven's Standard Progressive Matrices, Rey-Osterrieth Complex Figure Test, Digit Span, Trail Making and Symbol Digit Substitution tasks. Multidimensional scaling and a K-means cluster analyses were conducted to classify participants into lower versus higher cognitive performance groups. Subsequently, analyses of variance procedures were conducted to evaluate between group differences on drug use history and demographics. Two clusters of individuals with distinct profiles of cognitive performance were identified. The age of ATS use initiation, controlling for the overall duration of drug use, was significantly earlier in the lower than in the higher cognitive performance cluster: 20.9 (95% CI: 18.0-23.8) versus 25.2 (95% CI: 22.4-28.0, p = 0.038). While adverse effects of ATS use on cognitive functioning can be particularly pronounced with younger age, potentially related to greater vulnerability of the developing brain to stimulant and/or neurotoxic effects of these drugs, the current study findings cannot preclude lowered cognitive performance before initiation of ATS use. PMID- 28661715 TI - Patient Characteristics and Temporal Trends in Police Transport of Blunt Trauma Patients: A Multicenter Retrospective Cohort Study. AB - BACKGROUND: Police transport (PT) of penetrating trauma patients has the potential to decrease prehospital times for patients with life-threatening hemorrhage and is part of official policy in Philadelphia, Pennsylvania. We hypothesized that rates of PT of bluntly injured patients have increased over the past decade. METHODS: We used Pennsylvania Trauma Outcomes Study registry data from 2006-15 to identify bluntly injured adult patients transported to all 8 trauma centers in Philadelphia. PT was compared to ambulance transport, excluding transfers, burn patients, and private transport. We compared demographics, mechanism, and injury outcomes between PT and ambulance transport patients and used multivariable logistic regression to identify independent predictors of PT. We also identified physiological indicators and injury patterns that might have benefitted from prehospital intervention by EMS. RESULTS: Of 28 897 bluntly injured patients, 339 (1.2%) were transported by police and 28 558 (98.8%) by ambulance. Blunt trauma accounted for 11% of PT and penetrating trauma for 89%. PT patients were younger, more likely to be male, and more likely to be African American or Asian and were more often injured by assault or motor vehicle crash. There were no significant differences presenting physiology between PT and EMS patients. In multivariable logistic regression analysis, male sex (OR 1.89, 95%CI 1.40-2.55), African American race (OR 1.71 95%CI 1.34-2.18), and Asian race (OR 2.25, 95%CI 1.22-4.14) were independently associated with PT. Controlling for injury severity and physiology, there was no significant difference in mortality between PT and EMS. Overall, 64% of PT patients had a condition that might have benefited from prehospital intervention such as supplemental oxygen for brain injury or spine stabilization for vertebral fractures. CONCLUSIONS: PT affects a small minority of blunt trauma patients, and did not appear associated with higher mortality. However, PT patients included many who might have benefited from proven, prehospital intervention. Clinicians, EMS providers, and law enforcement should collaborate to optimize use of PT within the trauma system. PMID- 28661716 TI - Gene-by-Activity Interactions on Obesity Traits of 6-Year-Old New Zealand European Children: A Children of SCOPE Study. AB - PURPOSE: The decline of physical activity in children is considered an important determinant to explain the rising rates of obesity. However, this risk may be augmented in children who are genetically susceptible to increased weight gain. We hypothesized that a sedentary lifestyle and moderate activity will interact with genetic loci, resulting in differential effects in relation to obesity risk. METHODS: We recruited 643 European children born to participants in the New Zealand-based Screening for Pregnancy Endpoints (SCOPE) study. Seventy gene variants were evaluated by the Sequenom assay. Interaction analyses were performed between the genetic variants and the activity type derived from actigraphy, in relation to percentage body fat. RESULTS: We found a statistically significant association between increased proportions of sedentary activity with increased percentage body fat scores (P = .012). The OLFM4-9568856 (P = .01) and GNPDA2-rs10938397 (P = .044) gene variants showed genotype differences with proportions of sedentary activity. Similarly, the OLFM4-9568856 (P = .021), CLOCK rs4864548 (P = .029), and LEPR-1045895 (P = .047) showed genotype differences with proportions of moderate activity. We found evidence for unadjusted gene-by activity interactions of SPACA3/SPRASA-rs16967845, PFKP-rs6602024, and SH2B1 rs7498665 on percentage body fat scores. CONCLUSIONS: These findings indicate a differential effect of physical activity in relation to obesity risk, suggesting that children genetically predisposed to increased weight gain may benefit from higher levels of moderate activity. PMID- 28661717 TI - Structural Strength Benefits Observed at the Hip of Premenarcheal Gymnasts Are Maintained Into Young Adulthood 10 Years After Retirement From the Sport. AB - PURPOSE: Premenarcheal female gymnasts have been consistently found to have greater bone mass and structural advantages. However, little is known about whether these structural advantages are maintained after the loading stimulus is removed. Therefore, the purpose of this study was to investigate the structural properties at the hip after long-term retirement from gymnastics. METHODS: Structural properties were derived from dual-energy X-ray absorptiometry scans using the hip structural analysis program for the same 24 gymnasts and 21 nongymnasts both in adolescence (8-15 y) and adulthood (22-30 y). Structural measures were obtained at the narrow neck, intertrochanter, and femoral shaft and included cross-sectional area, section modulus, and buckling ratio. Multivariate analysis of covariance was used to assess differences between groups in bone measures while controlling for size, age, maturity, and physical activity. RESULTS: Gymnasts were found to have structural advantages at the narrow neck in adolescence (16% greater cross-sectional area, 17% greater section modulus, and 25% lower buckling ratio) and 14 years later (13% greater cross-sectional area and 26% lower buckling ratio). Benefits were also found at the intertrochanter and femoral shaft sites in adolescence and adulthood. CONCLUSION: Ten years after retirement from gymnastics, former gymnasts' maintained significantly better hip bone structure than females who did not participate in gymnastics during growth. PMID- 28661718 TI - Three-Year Study of Students' Attitudes Toward Physical Education: Grades 4-8. AB - PURPOSE: A relationship exists between attitudes toward physical education and future physical activity. The purpose of this study was to examine changes in attitude toward physical education as students progressed from upper elementary school (Grade 4) through middle school (Grade 8). METHOD: Three cohorts of students (Cohort 1, Grades 4-6, n = 96; Cohort 2, Grades 5-7, n = 71; and Cohort 3, Grades 6-8, n = 73) were each followed for 3 years to examine changes in attitudes toward physical education. RESULTS: After an initial increase from Grade 4 to Grade 5, a significant decrease was observed from Grades 5 to 8 in students' positive attitudes toward physical education, with a faster rate of change for girls than boys. CONCLUSION: This longitudinal study provides further insights regarding the attitudes of students as they progress from Grade 4 to Grade 8 and expands on previous findings identifying decreasing positive attitudes toward physical education as students age, particularly for girls. The results provide evidence to support targeted interventions. PMID- 28661719 TI - Supporting Best Practice for Attending a Child's Funeral as Part of Our Professional Role: Guidelines for Developing Service Policy. PMID- 28661720 TI - Adaptive B Cell Responses to Influenza Virus Infection in the Lung. AB - Adaptive B cell response is a key arm of protective immunity against influenza viruses. Owing to the acutely infectious and cytopathic nature of these viruses, efficient containment of viral spread relies on the prompt provision of protective antibodies to the site of virus infection, the respiratory tract (RT). To accelerate the protective antibody response, B cell responses can be ectopically induced, maintained, and reactivated in the lungs after primary and secondary infection, thereby providing an anatomical advantage in supplying neutralizing antibodies against reinfecting viruses with faster kinetics. However, the prompt supply of protective antibodies may be insufficient to protect against reinfection because influenza viruses can easily change their antigenic profiles to escape antibody surveillance. B cell responses have multiple strategies for adjusting antibody repertoires according to viral fitness, one of which is the formation of local germinal centers capable of selecting B cell repertoires for antigenically subdominant, but conserved, epitopes. In this review, we discuss several unique aspects of B cell responses that take place at local sites to combat acutely infectious and rapidly mutating influenza viruses. PMID- 28661721 TI - Assessing the efficacy and external validity of interventions promoting calcium or dairy intake in young adults: A systematic review with meta-analysis. AB - Calcium and dairy products have a role in the prevention of chronic diseases and attainment of peak bone mass, during adolescence to young adulthood. However, intakes are often suboptimal and interventions to improve consumption of food sources are needed. This systematic review aimed to investigate the efficacy and external validity of interventions promoting calcium or dairy foods among young adults. Eight databases were searched from inception to identify relevant studies. Inclusion criteria included those aged 18 to 35 years in an intervention promoting calcium or dairy food intake. The mean age of the participants was 19.9 +/- 1.4 years. Of the 16 studies that met the selection criteria, five studies were included in the meta-analyses for calcium (pooled effect size 0.35, 95% CI 0.04 to 0.67) and three studies for dairy (pooled effect size 0.31, 95% CI 0.11 to 0.50). The quality of the body of evidence was determined using the GRADE system, and was of overall low quality with high risk of bias. Our review suggests young adults respond favorably to interventions but the effect size is small. PMID- 28661722 TI - Unconventional or Preset alphabeta T Cells: Evolutionarily Conserved Tissue Resident T Cells Recognizing Nonpeptidic Ligands. AB - A majority of T cells bearing the alphabeta T cell receptor (TCR) are specific for peptides bound to polymorphic classical major histocompatibility complex (MHC) molecules. Smaller subsets of T cells are reactive toward various nonpeptidic ligands associated with nonpolymorphic MHC class-Ib (MHC-Ib) molecules. These cells have been termed unconventional for decades, even though only the composite antigen is different from the one seen by classical T cells. Herein, we discuss the identity of these particular T cells in light of the coevolution of their TCR and MHC-Ib restricting elements. We examine their original thymic development: selection on hematopoietic cells leading to the acquisition of an original differentiation program. Most of these cells acquire memory cell features during thymic maturation and exhibit unique patterns of migration into peripheral nonlymphoid tissues to become tissue resident. Thus, these cells are termed preset T cells, as they also display a variety of effector functions. They may act as microbial or danger sentinels, fight microbes, or regulate tissue homeostasis. PMID- 28661723 TI - Differences of RNA Expression in the Tendon According to Anatomic Outcomes in Rotator Cuff Repair. AB - BACKGROUND: Despite increased understanding of the pathophysiology of rotator cuff tears and the evolution of rotator cuff repair, healing failure remains a substantial problem. The critical roles played by biological factors have been emphasized, but little is known of the implications of gene expression profile differences at the time of repair. PURPOSE: To document the relationship between the perioperative gene expression of healed and unhealed rotator cuffs by RNA microarray analysis. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Superior (supraspinatus involvement) and posterosuperior (supraspinatus and infraspinatus involvement) tears were included in the study. Samples of rotator cuff tendons were prospectively collected during rotator cuff surgery. Three samples were harvested at the tendon ends of tears from the anterior, middle (apex), and posterior parts using an arthroscopic punch. Seven patients with an unhealed rotator cuff were matched one-to-one with patients with a healed rotator cuff by sex, age, tear size, and fatty degeneration of rotator cuff muscles. mRNA microarray analysis was used to identify genetic differences between healed and unhealed rotator cuff tendons. Gene ontology and gene association files were obtained from the Gene Ontology Consortium, and the Gene Ontology system in DAVID was used to identify enhanced biological processes. RESULTS: Microarray analyses identified 262 genes that were differentially expressed by at least 1.5-fold between the healed and unhealed groups. Overall, in the healed group, 103 genes were significantly downregulated, and 159 were significantly upregulated. DAVID Functional Annotation Cluster analysis showed that in the healed group, the genes most upregulated were related to the G protein-coupled receptor protein signaling pathway and to the neurological system. On the other hand, the genes most downregulated were related to immune and inflammatory responses. BMP5 was the gene most upregulated in the healed group, and the majority of downregulated genes were involved in the immune/inflammatory response. CONCLUSION: The downregulation of inflammatory response genes and the upregulation of cell differentiation genes in torn rotator cuffs at the time of surgery are related to rotator cuff healing. These results provide useful baseline information for future biological studies on rotator cuff healing. PMID- 28661725 TI - "I Wanna Be the Very Best!" Agreeableness and Perseverance Predict Sustained Playing to Pokemon Go: A Longitudinal Study. AB - OBJECTIVE: The smartphone game Pokemon GoTM has attracted much scientific attention regarding its potential health-related outcomes. Most studies, however, limited their investigation to short-term outcomes. The aim of the present study is to investigate the role of personality traits in predicting sustained playing to the game on a 6-month period as well as related health outcomes in terms of distance walked per day. MATERIALS AND METHODS: Pokemon Go players from 10 countries were recruited through social media and answered an online questionnaire. At Phase I (August 2016), 402 participants provided their game statistics and filled an extensive personality inventory (six main personality traits, impulsivity, need for cognition, need for closure, competitiveness, and self-efficacy). At Phase II (December 2016), 151 participants indicated whether they were still playing or not and provided updated game statistics. RESULTS: No personality traits predicted the distance walked by the players. However, the probability of still being playing the game at Phase II was positively predicted by three personality traits: agreeableness, perseverance, and premeditation. Distance walked per day significantly decreased between Phases I and II but remained substantial. CONCLUSION: This study identified three personality traits that predicted sustained playing and thus potentially higher game-related physical activity in the long run. In comparison with prior work, this study goes a step forward by (i) investigating personality traits underlying use of the game and related health outcomes, and (ii) providing longitudinal data concerning the use of the game. Findings open new perspectives for the development of other exergames. PMID- 28661726 TI - Laparoscopic Findings Associated with Bladder Endometriosis Are Correlated with Disease Severity. AB - STUDY OBJECTIVE: Bladder involvement is rare in endometriosis. The prevalence is estimated to be ~1% in patients with endometriosis. However, this figure seems to be an underestimation. The diagnosis of bladder endometriosis might be missed during laparoscopy. The aim of this study was to determine an intraoperative visual score of pelvic lesions that help the surgeon suspect bladder endometriosis. Design, Design Classification: A retrospective analysis was performed on the intraoperative photographs and videos of 69 patients with histological confirmation of bladder endometriosis. SETTING: A tertiary referral center. PATIENTS: Sixty-nine patients with bladder endometriosis were operated on in our center over a 9-year period. INTERVENTIONS: Evaluation and analysis of intraoperative laparoscopic findings. MAIN RESULTS: We found three subtypes of laparoscopic findings that can assist with diagnosing bladder endometriosis. The most prominent sign was named "kissing round ligaments" (Type K), in which the right and left round ligaments appear closer to each other than usual or even touching one another. This sign is strongly associated with full-thickness invasion of the bladder. Other laparoscopic findings that indicated bladder endometriosis were anatomical distortion (Type A) and proximal occlusion of the tubes (Type B). We further define a scoring system for the lesion that correlates with the severity of the bladder endometriosis from superficial lesions to full thickness. CONCLUSION: Bladder endometriosis is a rare condition and often remains undiagnosed. Indeed, even during surgery, bladder endometriosis can be missed if the operator is not aware of the suggestive signs. Operative laparoscopic findings may help the surgeon to diagnose bladder endometriosis, and these signs correlate with the severity of the disease. PMID- 28661727 TI - Transcriptomic Perspectives on Neocortical Structure, Development, Evolution, and Disease. AB - The cerebral cortex is the source of our most complex cognitive capabilities and a vulnerable target of many neurological and neuropsychiatric disorders. Transcriptomics offers a new approach to understanding the cortex at the level of its underlying genetic code, and rapid technological advances have propelled this field to the high-throughput study of the complete set of transcribed genes at increasingly fine resolution to the level of individual cells. These tools have revealed features of the genetic architecture of adult cortical areas, layers, and cell types, as well as spatiotemporal patterning during development. This has allowed a fresh look at comparative anatomy as well, illustrating surprisingly large differences between mammals while at the same time revealing conservation of some features from avians to mammals. Finally, transcriptomics is fueling progress in understanding the causes of neurodevelopmental diseases such as autism, linking genetic association studies to specific molecular pathways and affected brain regions. PMID- 28661728 TI - May We Take Our Baby With Hypoplastic Left Heart Syndrome Home? PMID- 28661729 TI - EPR and uDCDD: A Response to Commentaries. PMID- 28661724 TI - SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection. AB - SIGNIFICANCE: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD+) binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. CRITICAL ISSUES: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. FUTURE DIRECTIONS: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple "omic" technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732. PMID- 28661730 TI - A Proposed Process for Reliably Updating the Common Rule. AB - The recent Common Rule revision process took almost a decade and the resulting changes are fairly modest, particularly when compared to the ambitious ideas proposed in the advance notice of proposed rulemaking (ANPRM) and notice of proposed rulemaking (NPRM). Furthermore, the revision process did not even attempt to tackle any of the Common Rule subparts pertaining to vulnerable populations (i.e., pregnant women and fetuses, prisoners, children) where commentators think the rules unduly restrict important research. We believe that this was a missed opportunity to make desirable changes, and that given the usual process the next opportunity to revisit the Common Rule is unacceptably remote. In this article, we argue that the Common Rule should be regularly reassessed, with a mechanism for making substantive (and expeditious) changes. Drawing on lessons learned from the recent revision process, we make recommendations about ways to structure future attempts to maximize the ability to make timely and necessary changes. PMID- 28661731 TI - At Last! Aye, and There's the Rub. AB - Mea culpa. In 1981 the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, of which I was the Executive Director, recommended to the President and Congress that all federal departments and agencies that conduct or support human subjects research adopt "as a common core" the HHS regulations, "while permitting additions needed by any department or agency that are not inconsistent with these core provisions." The commission believed-rightly, I still think-that having uniformity would ease administration, reduce regulatory burdens, simplify oversight, and make research more efficient. Yet our naive expectation the task could be accomplished in 180 days meant that we failed to anticipate that if it took much longer-namely, the 10 years that passed before the Common Rule was issued-federal officials would thereafter be reluctant to change the regulations and that when they tried to do so twenty years later, with the issuance of the ANPRM in 2011, they would propose comprehensive revisions. I argue that was the wrong conclusion to draw from the difficulties in issuing the first Common Rule, and that the process of producing the new "final rule" on January 19, 2017-during which many of the proposed changes were either dumped or promulgated without being adequately vetted reinforces the conclusion that a more incremental process, with ongoing involvement of the public through an advisory body like the President's Commission, would be a much better way to proceed. PMID- 28661732 TI - The "Reasonable Person" Standard for Research Informed Consent. PMID- 28661734 TI - Opportunities Missed and Created by the New Common Rule. PMID- 28661733 TI - The Ethics of Treatment for Hypoplastic Left Heart Syndrome (HLHS). PMID- 28661735 TI - Withdrawing Life Support in Pregnancy: State Laws and Implications for Ethics. PMID- 28661736 TI - Single-Minded Research Review: The Common Rule and Single IRB Policy. PMID- 28661737 TI - Respect for Patient Through Clinical Ethics and Standard of Best Interest. PMID- 28661738 TI - Nonmaleficence, Nondisclosure, and Nocebo: Response to Open Peer Commentaries. PMID- 28661739 TI - Growing Discomfort With Comfort Care for Hypoplastic Left Heart Syndrome: Why We Should Still Defer to Parental Wishes. PMID- 28661740 TI - Ethics and Law: The Many Tensions. PMID- 28661742 TI - Death Before Birth: The Ethicaland Legal Landscape. PMID- 28661741 TI - Hypoplastic Left Heart Syndrome: The Case Against Palliative Surgery. PMID- 28661743 TI - Law Is Not Enough: The Importance of Ethics Consultation in Complex Cases. PMID- 28661744 TI - Informed Consent and the Disclosure of Clinical Results to Research Participants. PMID- 28661745 TI - Dollars and Deadlines: Rule Reforms in Short Time Frames. PMID- 28661746 TI - The Indefinite "Stay" on Regulatory Reforms for Research With Prisoners. PMID- 28661747 TI - Comprehension and Choice Under the Revised Common Rule: Improving Informed Consent by Offering Reasons Why Some Enroll in Research and Others Do Not. PMID- 28661748 TI - Modernizing Research Regulations Is Not Enough: It's Time to Think Outside the Regulatory Box. PMID- 28661749 TI - The Challenges of Other Legal and Regulatory Standards on Informed Consent. PMID- 28661750 TI - A Measure of Effectiveness Is Key to the Success of sIRB Policy. PMID- 28661751 TI - Common Rule Revised: Opportunities Lost. PMID- 28661752 TI - Modernizing the Common Rule: Public Trust and Investigator Accountability. PMID- 28661753 TI - Rethinking the Belmont Report? AB - This article reflects on the relevance and applicability of the Belmont Report nearly four decades after its original publication. In an exploration of criticisms that have been raised in response to the report and of significant changes that have occurred within the context of biomedical research, five primary themes arise. These themes include the increasingly vague boundary between research and practice, unique harms to communities that are not addressed by the principle of respect for persons, and how growing complexity and commodification in research have shed light on the importance of transparency. The repercussions of Belmont's emphasis on the protection of vulnerable populations is also explored, as is the relationship between the report's ethical principles and their applications. It is concluded that while the Belmont Report was an impressive response to the ethical issues of its day, the field of research ethics involving human subjects may have outgrown it. PMID- 28661754 TI - Examining Provisions Related to Consent in the Revised Common Rule. AB - The long-standing overarching policy governing research with human subjects conducted and supported by most federal agencies and departments in the United States, known as the Common Rule, has recently been revised, with most requirements slated to become effective in 2018. Although there are multiple alterations to the current regulations, some of the most significant changes aim to enhance consent for research. While some of the particular provisions in this regard will be easy to apply and promise to help meet this goal, others may be more challenging to implement despite their intuitive appeal. In this article, I examine some of the provisions in the revised Common Rule that relate to consent: (1) new required consent elements; (2) the goal of comprehension in the consent process; (3) consent forms; and (4) broad consent. By raising issues about these provisions now and suggesting possible ways to overcome their potential shortfalls, the hope is that future efforts can be taken to help clarify and appropriately implement them. PMID- 28661755 TI - The Final Rule: When the Rubber Meets the Road. AB - The Common Rule originally issued in 1991 and last amended in 2005 is scheduled to be replaced on January 19, 2018 by a revised Common Rule (the final rule). The goal of the revisions is to modernize and improve applicability of the rule to a research landscape that has dramatically changed since 1991. Translating these changes into action will require comprehensive understanding of the final rule and detailed implementation planning by Human Research Protection Programs. This paper presents select changes that require substantial attention; including for example: expansion of the exempt category, changes to continuing review requirements, changes to the informed consent form and the use of single IRBs for domestic multi-site research. In addition, myriad policies, procedures and workflows will have to be developed, drastically rewritten, or just mildly tweaked. PMID- 28661756 TI - The sIRB System: A Single Beacon of Progress in the Revised Common Rule? PMID- 28661757 TI - Beyond Belmont: Ensuring Respect for AI/AN Communities Through Tribal IRBs, Laws, and Policies. PMID- 28661758 TI - Participant-Reported Symptoms and Their Effect on Long-Term Adherence in the International Breast Cancer Intervention Study I (IBIS I). AB - Purpose To assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I). IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the disease. Participants and Methods Women were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279). After 456 exclusions, 3,823 women were included in this analysis. Adherence (< 4.5 years or >= 4.5 years) was calculated using data from six monthly clinical visits. Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatment. Results Overall, 69.7% of women were adherent for at least 4.5 years (tamoxifen: 65.2% v placebo: 74.0%; P < .001). Differences in adherence between treatment arms were observed from 12 months onward (all P < .01) and were largest at 54 months. Dropout rates were highest in the first 12 to 18 months and decreased thereafter. Women reporting nausea/vomiting were less likely to be adherent in both the tamoxifen (odds ratio [OR], 0.57; 95% CI, 0.37 to 0.86; P = .007) and placebo (OR, 0.58; 95% CI, 0.37 to 0.93; P = .023) arms. Headaches were associated with adherence only in the placebo arm (OR, 0.62; 95% CI, 0.42 to 0.91; P = .016), whereas gynecologic symptoms were significant only in the tamoxifen arm (OR, 0.77; 95% CI, 0.62 to 0.97; P = .024). Effect sizes for each symptom on adherence were not significantly different between the treatment groups ( P > .05). In both treatment arms, we observed significant trends for lower adherence with increasing severity for all symptoms ( P < .01) except headaches ( P = .054). Conclusion In the IBIS-I trial, experiencing predefined symptoms in the first 6 months reduced long-term adherence. Effects were similar between treatment arms, suggesting that women were attributing age-related symptoms to preventive therapy. Interventions were required to support symptom management. PMID- 28661760 TI - Maximizing the Clinical Benefit of Anthracyclines in Addition to Taxanes in the Adjuvant Treatment of Early Breast Cancer. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A healthy 56-year-old postmenopausal woman discovered a palpable mass at the one o'clock position of the left breast. After an initial biopsy confirmed breast cancer, she underwent mastectomy and axillary node dissection for a left-sided breast cancer that measured 3.5 cm. There was extensive lymphovascular invasion. Pathology review indicated a poorly differentiated, grade 3 invasive ductal carcinoma and ductal carcinoma in situ (largest focus, 3.5 cm). The margins were negative. Two of the 11 axillary lymph nodes contained metastatic carcinoma. Immunohistochemical studies previously obtained on the core biopsy indicated that the tumor was positive for estrogen receptor expression (50%), negative for progesterone receptor expression, and had a Ki-67 score of 60%. There was no amplification of the human epidermal growth factor receptor 2/ neu gene. Staging scans were negative for metastatic disease. Our multidisciplinary tumor board recommended adjuvant chemotherapy, postmastectomy radiation therapy, and endocrine therapy. A 52-year-old postmenopausal woman presented with a palpable mass of the right breast. An initial core biopsy confirmed carcinoma in the breast. She underwent quadrantectomy and axillary node dissection. The final pathology report disclosed a moderately differentiated invasive ductal carcinoma (diameter, 2.5 cm). The margins were negative. None of the three sentinel lymph nodes contained metastatic carcinoma. Immunohistochemical studies showed that the tumor was positive for estrogen receptor expression (90%) and for progesterone receptor expression (40%) and had a Ki-67 score of 20%. There was no amplification of the human epidermal growth factor receptor 2/ neu gene. Staging scans were negative for metastatic disease. A genomic assay was obtained and suggested an intermediate to high risk of recurrence. Her past medical history was notable for hypertension and moderately overweight status (body mass index, 39 kg/m2). Our multidisciplinary tumor board recommended adjuvant chemotherapy, postsurgical radiation therapy, and endocrine therapy. PMID- 28661759 TI - Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial. AB - Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A normal breast cancer. PMID- 28661762 TI - Fostering Medical Sociology's Bridges and Bonds: A Note from the New Editors. PMID- 28661761 TI - Lack of Free Choice Reveals the Cost of Having to Search for More Than One Object. AB - It is debated whether people can actively search for more than one object or whether this results in switch costs. Using a gaze-contingent eye-tracking paradigm, we revealed a crucial role for cognitive control in multiple-target search. We instructed participants to simultaneously search for two target objects presented among distractors. In one condition, both targets were available, which gave the observer free choice of what to search for and allowed for proactive control. In the other condition, only one of the two targets was available, so that the choice was imposed, and a reactive mechanism would be required. No switch costs emerged when target choice was free, but switch costs emerged reliably when targets were imposed. Bridging contradictory findings, the results are consistent with models of visual selection in which only one attentional template actively drives selection and in which the efficiency of switching targets depends on the type of cognitive control allowed for by the environment. PMID- 28661763 TI - Resisting Throughput Pressures: Physicians' and Patients' Strategies to Manage Hospital Discharge. AB - In recent years, quickly discharging patients has become a collective goal at hospitals, as excessive medical workups and extended hospital stays have been associated with unnecessary healthcare spending. Physicians, however, frequently encounter numerous barriers when trying to discharge patients. Presenting ethnographic and interview data collected from September 2010 to September 2013, this paper examines one of the most difficult discharge cases physicians encounter on the internal medicine service at a U.S. teaching hospital: resistant patients-patients and families who refuse to leave the hospital. As physicians try to discharge resistant patients, they are met with conflicting financial and professional incentives. Drawing from the sociological literature on professions, managerialism, and consumerism, I analyze the strategies physicians develop to manage these difficult discharge cases. PMID- 28661764 TI - Policy Brief. PMID- 28661765 TI - Children's Education and Parents' Trajectories of Depressive Symptoms. AB - Using five waves of the Taiwanese Longitudinal Study of Aging (1996-2011), we investigate (1) the association between family members' education and the age trajectories of individuals' depressive symptoms and (2) gender differences in those relationships. Our examination is guided by several theoretical frameworks, including social capital, social control, age as leveler, and resource substitution. Nested models show that having a more educated father is associated with lower depressive symptoms, but the relationship disappears after controlling for respondent's education. Including spouse's education attenuates the coefficient for respondent's education. A similar pattern appears when children's education is added to the model. Among all the family members, children's education has the strongest association with depressive symptoms, with a similar magnitude for both genders, although its strength gradually weakens as respondents age. Our findings suggest the importance of the transfer of resources from children to parents and how it may affect mental health at older ages. PMID- 28661766 TI - Are You Still Bringing Me Down?: Romantic Involvement and Depressive Symptoms from Adolescence to Young Adulthood. AB - Romantic involvement and mental health are dynamically linked, but this interplay can vary across the life course in ways that speak to the social and psychological underpinnings of healthy development. To explore this variation, this study examined how romantic involvement was associated with trajectories of depressive symptomatology across the transition between adolescence and young adulthood. Growth mixture modeling of data from the National Longitudinal Study of Adolescent to Adult Health identified trajectories of depressive symptomatology as teens grew into their late 20s and early 30s ( N = 8,712). Multinomial logistic techniques regressed these trajectories on adolescent and young adult romantic experiences. Adolescent dating was associated with increased depressive symptoms early on, particularly for girls, but this risk faded over time. For both boys and girls, trajectories of decreasing symptoms were associated with young adult unions but also the coupling of adolescent dating with young adult singlehood. PMID- 28661767 TI - Crisis or Chronic Strain?: Gender and Age Differences in Sickness Absence following Early Spousal Loss. AB - This population-based study ( N = 908,468) examines the effects of spousal loss on being absent from work due to illness or injury (sickness absence) among employed individuals in Norway. Fixed-effects models capturing antecedent and short- and long-term effects of spousal loss over a 15-year period were estimated to explore gender and age differences in the impact of widowhood. The crisis model, the social-role model, and the life course perspective are discussed. Furthermore, the study calls into question whether parenthood explains the gendered age gradient of the widowhood effect. The results show that the theoretical relevance of the crisis and social-role models is best understood in dialogue with a gendered life course approach. The results show that the crisis response is especially high among young widowers, whereas the recovery period is markedly prolonged among young widows. Parenthood at the time of widowhood explains much of the age difference among widowers and widows. PMID- 28661768 TI - The Association between Education and Mortality for Adults with Intellectual Disability. AB - Although the relationship between education and mortality is well documented in the general population, it has not been examined for adults with intellectual disability. Informed by fundamental cause theory, I explore the association between education and mortality in a sample of 4,241 adults with intellectual disability from the 1986-2009 National Health Interview Survey with Linked Mortality Files through 2011. Cox regression models were utilized to analyze the predictive effect of education on mortality risk while taking into account birth cohort differences. Increased education was associated with lower mortality risk for adults with intellectual disability, and this relationship strengthened in later birth cohorts who had greater access to the public education system. Comparison with a sample of 21,205 adults without intellectual disability demonstrates that the association between education and mortality risk was not as robust for adults with intellectual disability and highlights the ongoing socioeconomic challenges faced by this population. PMID- 28661769 TI - Race, Socioeconomic Position, and Physical Health: A Descriptive Analysis. AB - A substantial and long-standing body of research supports the widely held conclusion that socioeconomic position (SEP) is a primary determinant of physical health risk. However, supporting evidence derives almost entirely from studies of dominantly white populations, and more recent research suggests that this relationship may vary across race-ethnicity. This article considers the extent to which such evidence applies to African Americans. It does so by examining the within-race relationships between SEP and physical health utilizing alternative research definitions of health and a nearly exhaustive array of measures of SEP. The results offer minimal support for SEP as a fundamental cause of disease among African Americans. They do not challenge the widely held view that health differences are rooted in the fundamental conditions of social context and experience. Rather, they indicate that these conditions tend to be defined more by being black than by being of lower SEP. PMID- 28661770 TI - Beyond Health Effects?: Examining the Social Consequences of Community Levels of Uninsurance Pre-ACA. AB - The lack of health insurance is traditionally considered a problem faced by individuals and their families. However, because of the geographically bounded organization and funding of healthcare in the United States, levels of uninsurance in a community may affect everyone living there. Health economists have examined how the effects of uninsurance spillover from the uninsured to the insured, negatively affecting healthcare access and quality for the insured. We extend research on uninsurance into the domain of sociologists by theorizing how uninsurance might exacerbate social inequalities and undermine social cohesion within communities. Using data from the Los Angeles Family and Neighborhood Survey, we show that individuals living in communities with higher levels of uninsurance report lower social cohesion net of other individual and neighborhood factors and discuss implications for implementation of the Affordable Care Act. PMID- 28661772 TI - Phenolic Compounds in Antimicrobial Therapy. AB - Long-term treatment with several conventional antibiotics can cause harmful side effects that can be alleviated by antioxidant therapy. Phenolic compounds (PCs) are the best source of antioxidants, and to identify the most suitable polyphenols for use as a supportive supplement during antibiotic therapy, this study screened a series of PCs to establish their antibacterial potential, including their biofilm and beta-lactamase inhibition activity. Several PCs were tested for antibacterial activity against Staphylococcus epidermidis and Pseudomonas aeruginosa. Among them, tannic acid, epigallocatechin gallate, rutin, and eugenol showed the highest antibacterial activity. Epigallocatechin gallate, tannic acid, quercetin, and epicatechin inhibited a significant level of beta lactamase activity. Tannic acid and epigallocatechin gallate presented the highest beta-lactamase inhibition potential in both in vitro and in silico analysis. In the present work, these two PCs were the most active agents, presenting both antibacterial activity and beta-lactamase and biofilm inhibition ability. PMID- 28661773 TI - In-Water Resisted Swim Training for Age-Group Swimmers: An Evaluation of Training Effects. AB - PURPOSE: The purpose of this study is to compare the efficacy of resisted sprint swim training with that of nonresisted sprint swim training on 50-m freestyle competition time (Vmax50) in age-group swimmers. METHODS: Twenty-four age-group swimmers (age 10.6-14.9 y) were divided into resisted or nonresisted sprint swim training groups and completed a sprint swim training intervention 2 times per week for 10 weeks. Repeated 10-m sprints with progressively increasing resistance were used to determine measures of swim power. Skeletal muscle mass was estimated using B-mode ultrasound. Maturity status was estimated using predicted adult height (%Htadult) and maturity offset. RESULTS: A 2-way repeated-measures analysis of variance revealed no group * time interaction for measured variables. Vmax50 was correlated with skeletal muscle mass and swim power variables, but no significant relationship was found between relative changes in these variables. Estimated maturity status (%Htadult) appeared to be associated with initial measures of swim power and performance variables. CONCLUSIONS: Ten weeks of resisted sprint swim training was not any more effective than nonresisted sprint swim training at improving sprint swim performance in age-group swimmers. PMID- 28661771 TI - A Twin Study on Perceived Stress, Depressive Symptoms, and Marriage. AB - Marriage is associated with reductions in both perceived stress and depressive symptoms, two constructs found to be influenced by common genetic effects. A study of sibling twins was used to test whether marriage decreases the proportion of variance in depressive symptoms accounted for by genetic and environmental effects underlying perceived stress. The sample consisted of 1,612 male and female twin pairs from the University of Washington Twin Registry. The stress buffering role of marriage was tested relative to two unmarried groups: the never married and the divorced. Multivariate twin models showed that marriage reduced genetic effects of perceived stress on depressive symptoms but did not reduce environmental effects. The findings suggest a potential marital trade-off for women: access to a spouse may decrease genetic effects of perceived stress on depressive symptoms, although marital and family demands may increase environmental effects of perceived stress on depressive symptoms. PMID- 28661775 TI - The Spillover of Genomic Testing Results in Families: Same Variant, Different Logics. AB - Due to heritability, next-generation genetic tests have the potential to affect family members beyond the patient being tested. Geneticists and genetic counselors, in dialogue with patients and their relatives, will need to establish for whom and in what way genomic testing results matter during the communication of testing results, indicating the spillover of presumed pathological variants. On the basis of video-recorded consultations of the return of exome results in a genetics clinic, we distinguish three different logics deployed to explain the relevance of the findings for the patient, extended family members, and unborn relatives. While geneticists tend to be cautious in interpreting findings for the patient and living relatives, the findings become more deterministic in the context of reproductive decision making. The presentation of results then establishes the causal role of variants and reflects back on disability as a state to be prevented, in the process establishing genetic ties between kin. PMID- 28661776 TI - Social Context, Biology, and the Definition of Disorder. AB - In recent years, medical sociologists have increasingly paid attention to a variety of interactions between social and biological factors. These include how social stressors impact the functioning of physiological systems, how sociocultural contexts trigger genetic propensities or mitigate genetic defects, and how brains are attuned to social, cultural, and interactional factors. This paper focuses on how both sociocultural and biological forces influence what conditions are contextually appropriate responses or disorders. It also suggests that some of the most obdurate health problems result from mismatches between natural genes and current social circumstances rather than from genetic defects. Finally, it examines how social environments have profound impacts on how much harm disorders create. It shows how sociological insights can help establish valid criteria for illnesses and indicates the complexities involved in defining what genuine disorders are. PMID- 28661774 TI - The Impact of Physical Disability on Pregnancy and Childbirth. AB - BACKGROUND: Women with physical disabilities increasingly aspire to become pregnant and bear children. Limited information about the potential interaction of their disabling conditions with pregnancy and childbirth exists to guide these women and their clinicians. MATERIALS AND METHODS: The interview guide was created with questions on topics such as pregnancy complications and secondary conditions, the impact of prior surgeries, experiences with pain relief during labor, and the impact on women's independence and participation in life activities. Interviews were conducted by telephone with 25 women with physical disabilities. They were subsequently transcribed verbatim and analyzed by using Atlas TI. RESULTS: Women generally reported a relatively modest impact of disabling conditions on their pregnancies. Most women were satisfied with the mode of delivery, but they experienced challenges during the labor and delivery process. The women found that careful advanced planning was helpful in managing the impact of their disabling conditions. The involvement of clinicians with disability-related expertise was, in some cases, another factor that contributed to a positive outcome. CONCLUSIONS: The importance of advanced planning and the utility of involving clinicians with disability-related expertise suggest that the use of integrated, interdisciplinary team approaches could promote quality care by facilitating improved planning and management. Additional clinical research is needed to provide women and their clinicians with more information on potential complications and options for labor and delivery. PMID- 28661777 TI - Policy Brief. PMID- 28661778 TI - Culture, Styles of Institutional Interactions, and Inequalities in Healthcare Experiences. AB - In this study, I examine how parents' cultural knowledge shapes experiences navigating the healthcare system after a child is diagnosed with cancer and the extent to which differential styles of health-related advocacy contribute to inequalities in healthcare experiences. I combine data from parents' perspectives, physicians' perspectives, and direct observation of clinical interactions and find three overarching styles of health-related advocacy. Findings show that cultural dispositions and competencies shape parents' abilities to effectively navigate the healthcare system, and physicians differentially reward each style of health-related advocacy. Parents' styles of advocacy shape relationships with clinicians, physicians' perceptions of families, and physicians' strategies for interacting with families. These findings refine understanding of the mechanisms through which social class manifests in clinical interactions, shapes patient-physician relationships, and contributes to unequal healthcare experiences. PMID- 28661780 TI - Working Hours Mismatch, Macroeconomic Changes, and Mental Well-being in Europe. AB - This study explores the association between involuntarily working less or more than the standard workweek and poor mental well-being, and whether this relationship is dependent upon (changing) national-level unemployment and gross domestic product growth rates. Data from the European Social Survey Round 2 (2004 2005) and Round 5 (2010) were analyzed. The sample included 16,224 male and 16,184 female employees. Mental well-being was assessed by the World Health Organization Well-being Index. Three-level linear multilevel modeling was used to account for clustering of employees within research years and countries. Working involuntary long hours was positively associated with poor mental well-being for men. For women, working voluntary long, involuntary long, and involuntary short hours were positively associated with poor mental well-being. The mental well being of women working voluntary and involuntary long hours was negatively influenced by deteriorating economic conditions. This study suggests women are more vulnerable to the effects of long working hours and working hours mismatch on mental well-being, especially during difficult economic periods. PMID- 28661779 TI - Emerging Adulthood, Emergent Health Lifestyles: Sociodemographic Determinants of Trajectories of Smoking, Binge Drinking, Obesity, and Sedentary Behavior. AB - During the transition to adulthood, many unhealthy behaviors are developed that in turn shape behaviors, health, and mortality in later life. However, research on unhealthy behaviors and risky transitions has mostly focused on one health problem at a time. In this article, we examine variation in health behavior trajectories, how trajectories cluster together, and how the likelihood of experiencing different behavior trajectories varies by sociodemographic characteristics. We use the National Longitudinal Study of Adolescent Health (Add Health) Waves I to IV to chart the most common health behavior trajectories over the transition to adulthood for cigarette smoking, alcohol consumption, obesity, and sedentary behavior. We find that health behavior trajectories cluster together in seven joint classes and that sociodemographic factors (including gender, parental education, and race-ethnicity) significantly predict membership in these joint trajectories. PMID- 28661781 TI - Children's Sense of Control as a Determinant of Adult Health: Causation, Mediation, and Spuriousness. AB - Previous research suggests higher levels of education instill a greater sense of internal control that promotes health in adulthood. We propose that the sense of control has its origins in early childhood and that prior research has possibly misattributed a mediational role to sense of control in adulthood. Using a conceptual framework that includes these early influences, we employ data from the 1970 British Cohort Study ( N = 9,855), examining the extent to which the association between education and adult health is spurious due to these early childhood factors. We find that the internal sense of control as assessed in childhood and adolescence has profound influences on both education and health in early adulthood and that a substantial portion of the latter association is spurious. We conclude that the sense of control is an important health-related factor originating early in life, influencing both health and education later in adulthood. PMID- 28661782 TI - College-going and Trajectories of Drinking from Adolescence into Adulthood. AB - To explore an exception to the association between educational attainment and health, this study unpacked variability in the drinking of U.S. college students by applying life course concepts to analyses of the National Longitudinal Study of Adolescent Health (Add Health). Growth curve models showed that youth who graduated from four-year colleges before turning 25 without later reentering higher education had the highest peaks in drinking after adolescence and the shallowest declines into their 30s. Deviations from this pathway in terms of type, timing, and order of college transitions flattened out drinking trajectories from adolescence into adulthood. Expectations that more alignment between precollege and college social contexts (defined by family backgrounds, high school academic performance, and peer norms) would predict the most problematic drinking trajectories among young four-year college-goers were not supported. Instead, youth who appeared headed for the early four-year college pathway but did not make it there had problematic drinking trajectories. PMID- 28661783 TI - Insecure People in Insecure Places: The Influence of Regional Unemployment on Workers' Reactions to the Threat of Job Loss. AB - Social comparison theory predicts that unemployment should be less distressing when the experience is widely shared, but does this prediction extend beyond the unemployed to those who are at risk of job loss? Research demonstrates a link between aggregate unemployment and employed individuals' perceptions of job insecurity; however, less is known about whether the stress associated with these perceptions is shaped by others' unemployment experiences. We analyze a nationally representative sample of Canadian workers (Canadian Work, Stress, and Health study; N = 3,900) linked to census data and test whether regional unemployment influences the mental health consequences of job insecurity. Multilevel analyses provide more support for the social norm of insecurity hypothesis over the amplified threat hypothesis: the health penalties of job insecurity are weaker for individuals in high-unemployment regions. This contingency is partially explained by the ability of insecure workers in poor labor market contexts to retain psychological resources important for protecting mental health. PMID- 28661785 TI - Effect of Pulsed Magnetic Stimulation on Sexual Function in Couples With Female Stress Urinary Incontinence Partners. AB - We prospectively evaluated the effects of pulsed magnetic stimulation (PMS) on sexual function of couples with stress urinary incontinence (SUI) partners. Female SUI subjects received 16 or 32 biweekly PMS sessions, depending on treatment response. Prior to, immediately after, and at 6-months posttreatment, couples completed the Golombok Rust Inventory of Sexual Satisfaction (GRISS) questionnaire. Fifty-three (80.3%) of 66 couples completed reassessments. Based on the overall GRISS score, there were significant improvements in sexual function in both female subjects (Mdiff -5.05, SE 1.34, p = 0.001) and their partners (Mdiff -3.42, SE 1.24, p = 0.026). Our findings suggest that PMS improved sexual function of SUI patients and their partners. PMID- 28661784 TI - Identifying Key Words in 9-1-1 Calls for Stroke: A Mixed Methods Approach. AB - OBJECTIVES: Identifying stroke during a 9-1-1 call is critical to timely prehospital care. However, emergency medical dispatchers (EMDs) recognize stroke in less than half of 9-1-1 calls, potentially due to the words used by callers to communicate stroke signs and symptoms. We hypothesized that callers do not typically use words and phrases considered to be classical descriptors of stroke, such as focal neurologic deficits, but that a mixed-methods approach can identify words and phrases commonly used by 9-1-1 callers to describe acute stroke victims. METHODS: We performed a mixed-method, retrospective study of 9-1-1 call audio recordings for adult patients with confirmed stroke who were transported by ambulance in a large urban city. Content analysis, a qualitative methodology, and computational linguistics, a quantitative methodology, were used to identify key words and phrases used by 9-1-1 callers to describe acute stroke victims. Because a caller's level of emotional distress contributes to the communication during a 9-1-1 call, the Emotional Content and Cooperation Score was scored by a multidisciplinary team. RESULTS: A total of 110 9-1-1 calls, received between June and September 2013, were analyzed. EMDs recognized stroke in 48% of calls, and the emotional state of most callers (95%) was calm. In 77% of calls in which EMDs recognized stroke, callers specifically used the word "stroke"; however, the word "stroke" was used in only 38% of calls. Vague, non-specific words and phrases were used to describe stroke victims' symptoms in 55% of calls, and 45% of callers used distractor words and phrases suggestive of non-stroke emergencies. Focal neurologic symptoms were described in 39% of calls. Computational linguistics identified 9 key words that were more commonly used in calls where the EMD identified stroke. These words were concordant with terms identified through qualitative content analysis. CONCLUSIONS: Most 9-1-1 callers used vague, non-specific, or distractor words and phrases and infrequently provide classic stroke descriptions during 9-1-1 calls for stroke. Both qualitative and quantitative methodologies identified similar key words and phrases associated with accurate EMD stroke recognition. This study suggests that tools incorporating commonly used words and phrases could potentially improve EMD stroke recognition. PMID- 28661786 TI - Impact of a Soccer Game on Cardiac Biomarkers in Adolescent Players. AB - PURPOSE: Biochemical markers such as cardiac troponin I (cTnI) and N-terminal pro B-type natriuretic peptide (NT-proBNP) have become indispensable tools for the diagnosis of myocardial injury, providing highly sensitive and specific information about cardiac cell damage and wall stress. The purpose of the present research was to examine the response of cardiac biomarkers to a soccer game in adolescent male soccer players. METHODS: Twenty-two trained adolescent male soccer players (14-16 y) were selected in a purposive manner. Blood samples were taken before, immediately after, and 2 and 24 hours after the game for the determination of cTnI and NT-proBNP. RESULTS: Serum concentration of cTnI and NT proBNP increased immediately and 2 hours after the soccer game (P < .001). After 24 hours, the levels of cTnI dropped but remained above baseline (P = .002), whereas serum NT-proBNP levels returned to baseline. At no time point did any of the values exceed the upper reference value. CONCLUSIONS: This is the first study to investigate the acute responses of cardiac biomarkers to a soccer game in adolescent male players. The postgame elevation of cardiac biomarkers and their rapid recovery are indicative of a physiological rather than a pathological response. PMID- 28661788 TI - Abstracts from The 35th Annual National Neurotrauma Symposium July 7-12, 2017 Snowbird, Utah. PMID- 28661787 TI - Goals of Care Ambulatory Resident Education: Training Residents in Advance Care Planning Conversations in the Outpatient Setting. AB - BACKGROUND: Advance care planning (ACP) discussions often occur in the inpatient setting when patients are too ill to participate in decision making. Although the outpatient setting is the preferred time to begin these discussions, few physicians do so in practice. Many internal medicine (IM) residents report inadequate training as a barrier to having outpatient ACP discussions. OBJECTIVE: To assess whether a novel curriculum entitled Goals of Care Ambulatory Resident Education (GOCARE) improved resident physicians' understanding of and preparedness for conducting ACP discussions in the outpatient setting. DESIGN: The curriculum was delivered over four weekly three-hour small group sessions to IM residents. Each session included didactics, a demonstration of skills, and a simulated patient communication laboratory that emphasized deliberate practice. SETTING/SUBJECTS: IM residents from an urban, academic ambulatory care practice. MEASUREMENTS: Impact of the intervention was evaluated using a retrospective pre post design. Residents completed surveys immediately after the course and six months later. RESULTS: Forty-two residents participated in the curriculum and 95% completed the postcourse survey. Residents' self-rated level of preparedness increased for ACP discussions overall (4.0 pre vs. 5.2 post on 7-point Likert scale) and for communication steps involved in ACP (p < 0.001). Fifty-nine percent of participants completed the six-month follow-up survey. Residents' self rated preparedness to engage in outpatient ACP discussions remained high (4.5 pre vs. 5.5 post at six months p < 0.001). Residents also reported increased use of ACP communication skills (p < 0.001) six months later. CONCLUSIONS: The GOCARE curriculum provides an alternative model of communication training that can be integrated into residency training and improve residents' skills in outpatient ACP discussions. PMID- 28661790 TI - Selected Use of Telemedicine in Intensive Care Units Based on Severity of Illness Improves Cost-Effectiveness. AB - BACKGROUND: Telemedicine in the intensive care unit (tele-ICU) is expected to address geographic health disparities through more efficient resource allocation. Our previous economic evaluation demonstrated tele-ICU to be cost-effective in most cases and cost saving in some cases, compared to conventional intensive care unit (ICU) care without adequate intensivist coverage. INTRODUCTION: This study's objective is to examine how to optimize the cost-effectiveness of tele-ICU use by selecting highest risk (i.e., both highest mortality and highest cost) subpopulations. We also explore potential cost savings. MATERIALS AND METHODS: We conducted simulation analyses among a hypothetical adult ICU patient cohort defined by the literature, distinguishing four types of hospitals: urban tertiary (primary analysis), urban community, rural tertiary, and rural community. The selected tele-ICU use was assumed to affect per-patient ICU cost and hospital mortality among highest risk subpopulations (10-100% of all ICU patients), defined by an established illness-severity measure. RESULTS: We found a U-shaped relationship between the economic efficiency and selected tele-ICU use among all 4 hospital types. Optimal cost-effectiveness was achieved when tele-ICU was applied to the 30-40% highest risk patients among all ICU patients (incremental cost-effectiveness ratio = $25,392 [2014 U.S. dollars] per extending a quality adjusted life year) in urban tertiary hospitals (primary analysis). Our break even analyses indicated that cost saving seems more feasible when reducing ICU medical care cost, rather than lowering the cost to operate telemedicine alone. DISCUSSION AND CONCLUSIONS: A selected use of tele-ICU based on severity of illness is likely to improve tele-ICU cost-effectiveness. To achieve cost saving, tele-ICU must reduce more than just telemedicine-related cost. PMID- 28661791 TI - Improving Access to Oral Health Services Among Uninsured and Underserved Populations: FirstHealth Dental Care Centers. PMID- 28661792 TI - Dental Therapy Education in Minnesota. PMID- 28661793 TI - Dental Student-Delivered Care at a Student-Faculty Collaborative Clinic in a Correctional Facility. PMID- 28661794 TI - The Oral Health Needs of the Incarcerated Population: Steps Toward Equal Access. PMID- 28661795 TI - Oral Health: Basic Tenets for a Healthy, Productive Life. PMID- 28661796 TI - The Nation's Oral Health Inequities: Who Cares.... PMID- 28661797 TI - Oral Health and Aging. PMID- 28661798 TI - Getting the Incentives Right: Improving Oral Health Equity With Universal School Based Caries Prevention. AB - Despite significant financial, training, and program investments, US children's caries experience and inequities continued to increase over the last 20 years. We posit that (1) dental insurance payment systems are not aligned with the current best evidence, exacerbating inequities, and (2) system redesign could meet health care's triple aim and reduce children's caries by 80%. On the basis of 2013 to 2016 Medicaid and private payment rates and the caries prevention literature, we find that effective preventive interventions are either (1) consistently compensated less than ineffective interventions or (2) not compensated at all. This economic and clinical misalignment may account for underuse of effective caries prevention and subsequent overuse of restorative care. We propose universal school-based comprehensive caries prevention to address this misalignment. Preliminary modeling suggests that universal caries prevention could eliminate 80% of children's caries and cost less than one fifth of current Medicaid children's oral health spending. If implemented with bundled payments based on cycle of care and measurable outcomes, there would be an alignment of incentives, best evidence, care, and outcomes. Such a program would meet the Healthy People Oral Health goals for children, as well as health care's triple aim. PMID- 28661800 TI - Expanding the Dental Workforce to Improve Access and Reduce Disparities in Oral Health. PMID- 28661799 TI - Accountable Care Organizations and Oral Health Accountability. AB - Accountable care organizations agree to be accountable for the cost and outcomes of an attributed population. However, in many, no provisions have been made to account for oral health. There are several social, medical, and financial implications for health care provider and payer systems and health care outcomes when oral health is not accounted for in patient management. How can an organization strive to improve population health without including the oral health system? Total systemic health for a population must include oral health. Accountable care organizations are positioned to change the course of oral health in the United States and close the disparities that exist among vulnerable populations, including seniors. Such efforts will reduce health care costs. Opportunities abound to expand points of entry into the health care system via dental or medical care. Closing the great divide between 2 historically isolated professions will position the United States to make gains in true population health. I provide evidence of the need to mandate access to oral health care services for all Americans-specifically adults, because legislation currently exists for pediatric dental coverage. PMID- 28661801 TI - The Dental Health Aide Therapist Program in Alaska: An Example for the 21st Century. PMID- 28661803 TI - Oral Health Inequities: An AJPH Supplement to Help Close the Gap. PMID- 28661802 TI - Effectiveness on Early Childhood Caries of an Oral Health Promotion Program for Medical Providers. AB - OBJECTIVES: To assess an oral health promotion (OHP) intervention for medical providers' impact on early childhood caries (ECC). METHODS: We implemented a quasiexperimental OHP intervention in 8 federally qualified health centers that trained medical providers on ECC risk assessment, oral examination and instruction, dental referral, and fluoride varnish applications (FVAs). We measured OHP delivery by FVA count at medical visits. We measured the intervention's impact on ECC in 3 unique cohorts of children aged 3 to 4 years in 2009 (preintervention; n = 202), 2011 (midintervention; n = 420), and 2015 (>= 4 FVAs; n = 153). We compared numbers of decayed, missing, and filled tooth surfaces using adjusted zero-inflated negative binomial models. RESULTS: Across 3 unique cohorts, the FVA mean (range) count was 0.0 (0), 1.1 (0-7), and 4.5 (4-7) in 2009, 2011, and 2015, respectively. In adjusted zero-inflated negative binomial models analyses, children in the 2015 cohort had significantly fewer decayed, missing, and filled tooth surfaces than did children in previous cohorts. CONCLUSIONS: An OHP intervention targeting medical providers reduced ECC when children received 4 or more FVAs at a medical visit by age 3 years. PMID- 28661804 TI - Oral Health Disparities and Inequities in Asian Americans and Pacific Islanders. PMID- 28661805 TI - How Dental Therapists Can Address the Social and Racial Disparities in Access to Care. PMID- 28661806 TI - Dental Therapy: Communities Lead the Way for Improved Oral Health. PMID- 28661807 TI - Indian Country Leads National Movement to Knock Down Barriers to Oral Health Equity. AB - Tribal and other underserved communities are struggling under the weight of devastating oral health disparities. Tribes as sovereign nations are searching for innovative solutions to address their unique barriers to oral health care. Dental therapists are primary oral health providers who work as part of the dental team to provide a limited scope of services to patients. They were first brought to tribal communities by the Alaska Native Tribal Health Consortium. Despite strong opposition from the American Dental Association aimed at protecting its monopoly on oral health care, dental therapists are sweeping the nation. Evidence shows that they are effective and provide high-quality care, particularly in underserved communities. A community's ability to develop public health policy solutions tailored to its needs and priorities is essential in eliminating health disparities and achieving health equity. The Swinomish Indian Tribal Community is leading the way to more effective and efficient dental teams and working hard to lay the groundwork for the elimination of oral health disparities. PMID- 28661808 TI - Using Registered Dental Hygienists to Promote a School-Based Approach to Dental Public Health. AB - We examine a strategy for improving oral health in the United States by focusing on low-income children in school-based settings. Vulnerable children often experience cultural, social, economic, structural, and geographic barriers when trying to access dental services in traditional dental office settings. These disparities have been discussed for more than a decade in multiple US Department of Health and Human Services publications. One solution is to revise dental practice acts to allow registered dental hygienists increased scope of services, expanded public health delivery opportunities, and decreased dentist supervision. We provide examples of how federally qualified health centers have implemented successful school-based dental models within the parameters of two state policies that allow registered dental hygienists varying levels of dentist supervision. Changes to dental practice acts at the state level allowing registered dental hygienists to practice with limited supervision in community settings, such as schools, may provide vulnerable populations greater access to screening and preventive services. We derive our recommendations from expert opinion. PMID- 28661809 TI - Oral Health and Medicine Integration: Overcoming Historical Artifact to Relieve Suffering. PMID- 28661810 TI - Oral Health Care Receipt and Self-Rated Oral Health for Diverse Asian American Subgroups in New York City. AB - OBJECTIVES: To identify determinants of receipt of annual oral health examinations and self-rated oral health among diverse Asian American subgroups. METHODS: We used data from the Community Health Resources and Needs Assessment, a community-based survey of Asian American immigrant adults conducted in the New York City metropolitan region from 2013 to 2016 (n = 1288). We used multivariable logistic regression models to assess determinants of oral health care receipt and self-rated oral health. RESULTS: Failure to receive an annual oral health examination was common in this sample (41.5%) and was more frequent for participants who were younger and male and those who had poorer English fluency and lower educational attainment. Not having dental insurance versus having private dental insurance resulted in 2 to 3 times the odds of nonreceipt of oral health care and poor self-rated oral health. CONCLUSIONS: Nonreceipt of annual oral health examinations and poor self-rated oral health were common across Asian American subgroups. Facilitating dental insurance sign-up and providing in language services may improve oral health care access and ultimately oral health among Asian American immigrants. PMID- 28661812 TI - The Dental Professional. PMID- 28661811 TI - Oral Health Intervention for Low-Income African American Men in Atlanta, Georgia. AB - OBJECTIVES: To describe the Minority Men's Oral Health Dental Access Program (MOHDAP) intervention and report participants' outcomes and satisfaction. METHODS: MOHDAP was designed to increase the oral health knowledge of low-income, African American men in Atlanta, GA, in 2013. A community-based participatory approach and needs assessment guided the intervention development, which consisted of 3 educational modules delivered over a 2-day period. All participants (n = 45; mean age = 50 years) were African American men. We assessed changes in oral health knowledge and attitudes at baseline and postintervention via survey. RESULTS: After the intervention, the percentage of correct responses to questions about gingivitis increased by 24.2% (P = .01), about use of a hard (instead of a soft) toothbrush increased by 42.2% (P < .01), and knowledge of ways to prevent gum diseases increased by 16.0% (P = .03). The percentage agreeing with erroneous statements decreased 11.3% (P = .02) regarding oral health-related fatalism and oral health self-care and 17.4% (P = .05) regarding saving front versus back teeth. CONCLUSIONS: Community-based oral health educational interventions designed for African American men may reduce oral health disparities among this population. PMID- 28661813 TI - A Workforce Strategy for Reducing Oral Health Disparities: Dental Therapists. AB - This article seeks to chronicle how dental therapists are being used to bolster the supply of providers for the underserved and explore their potential to diversify the field of dentistry and improve public health. Of the factors that contribute to persistent oral health disparities in the United States, an insufficient oral health workforce figures prominently. A growing number of states are authorizing a midlevel dental provider (often called a dental therapist) to address this problem. Dental therapists work under the supervision of dentists to deliver routine preventive and restorative care, including preparing and filling cavities and performing extractions. They can serve all populations in 3 states, are caring for Native Americans in an additional 3 states under federal or state authority, and are being considered in about a dozen state houses. PMID- 28661814 TI - The Aetna-NDA Partnership for Achieving Racial and Ethnic Health Equity. PMID- 28661815 TI - The 2014 Mid-Maryland Mission of Mercy Dental Clinic: Building Community Capacity and Complementing Public Policy. PMID- 28661816 TI - Effect of Outreach Messages on Medicaid Enrollment. AB - OBJECTIVES: To measure the impact of different outreach messages on health insurance enrollment among Medicaid-eligible adults. METHODS: Between March 2015 and April 2016, we conducted a series of experiments using mail-based outreach that encouraged individuals to enroll in Pennsylvania's expanded Medicaid program. Recipients were randomized to receive 1 of 4 different messages describing the benefits of health insurance. The primary outcome was the response rate to each letter. RESULTS: We mailed outreach letters to 32 993 adults in Philadelphia. Messages that emphasized the dental benefits of insurance were significantly more likely to result in a response than messages emphasizing the health benefits (odds ratio = 1.33; 95% confidence interval = 1.10, 1.61). CONCLUSIONS: Medicaid enrollment outreach messages that emphasized the dental benefits of insurance were more effective than those that emphasized the health related benefits. Public Health Implications. Although the structure and eligibility of the Medicaid program are likely to change, testing and identifying successful outreach and enrollment strategies remains important. Outreach messages that emphasize dental benefits may be more effective at motivating enrollment among individuals of low socioeconomic status. PMID- 28661818 TI - Oral Health Disparities: A Perspective From the National Institute of Dental and Craniofacial Research. PMID- 28661817 TI - Dental-Related Use of Hospital Emergency Departments by Hispanics and Non Hispanics in Florida. AB - OBJECTIVES: To examine differences between Hispanics and non-Hispanics in Florida in the dental-related use of hospital emergency departments (EDs). METHODS: We used ambulatory ED discharge records from 2013 to 2015 to compute rates of ED visits for dental complaints per 10 000 population, by region, age, gender, and the percentage distribution visits by primary payer, day of the week, and hour of arrival. RESULTS: There were 64 100 ED visits for dental complaints by Hispanics and 425 162 by non-Hispanics. Medicaid was the most common primary payer for Hispanics (42.2%) and for non-Hispanics (38.1%). Rates of ED utilization for dental problems per 10 000 population were 45.5 for Hispanics and 95.2 for non Hispanics. CONCLUSIONS: Rates of ED utilization for dental problems were different between Hispanics and non-Hispanics. Public Health Implications. Effective interventions need to be developed in the context of a social ecological model to better understand factors such as health, economics, and education, among others. Understanding and intervening with the individual, communities, and policy could help to modify behaviors and improve access to dental care. PMID- 28661819 TI - Dental Homes for Older Americans: The Santa Fe Group Call for Removal of the Dental Exclusion in Medicare. PMID- 28661821 TI - Revisiting Oral Health in America: A Report of the Surgeon General. PMID- 28661820 TI - Addressing Oral Health Disparities Via Educational Foci on Cultural Competence. AB - An ever-present challenge for the oral health profession is to reduce the extent of oral disease among racial and ethnic minority populations. Adding to this complex dilemma is the linkage between oral health and systemic health. We describe enhanced cultural competency, in the context of individual cultural beliefs, values, language, practice, and health behaviors, among dental professionals, as one approach to meeting the dental care needs of the underserved. An overview and examples of teaching methods used by University of Florida dental educators to enhance student cultural competency is provided. Evidence-based evaluation results provide evidence of methodology efficacy. We conclude by describing actions that can be implemented by academic dental institutions to facilitate development of culturally competent practitioners. PMID- 28661822 TI - The Comorbidity of Psychiatric and Substance Use Disorders Among Hispanic Adolescents. AB - OBJECTIVE: The comorbidity of psychiatric disorders and substance abuse disorders among adolescents and adults is well-documented in the literature. The current study investigates the relationship between psychiatric and substance use disorders in a sample of treatment-seeking Hispanic adolescents. METHODS: The study uses baseline data (N = 190) from a randomized control trial testing the effectiveness of a family-based treatment for Hispanic adolescents with substance abuse disorder to examine the relationship between psychiatric disorders and substance use patterns at baseline, including types of substances used (both lifetime use and past-month use) and age at onset of substance use, controlling for age and gender. RESULTS: Linear regression models were used to examine predictors of age at onset, while logistic regression models examined predictors of lifetime substance use. Significant findings predicting age at onset for marijuana and alcohol are discussed. In addition, psychiatric profiles were differentially associated with lifetime use of sedatives, stimulants, and hallucinogens, but not alcohol or marijuana. CONCLUSIONS: Findings from this study can be used to help inform the treatment of adolescents seeking mental health and substance use services. PMID- 28661824 TI - Sexual Abuse Prevention Mobile Application (SAP_MobAPP) for Primary School Children in Korea. AB - This study aimed to develop and evaluate the effects of a sexual abuse prevention mobile application, SAP_MobAPP, for primary school children. Forty-five subjects were trained for 40 minutes once a week. The experimental group received education that utilized the SAP_MobAPP. Control group A received Web based sexual abuse prevention education, while control group B received textbook based sexual abuse prevention education. Effectiveness was verified through a survey on child sexual abuse recognition and avoidance skills administered before and after training. The SAP_MobAPP program improved recognition (awareness) and the child's skills to avoid child sexual abuse situations, and the effects were long-lasting. However, differences between groups were not statistically significant. This study developed a sexual abuse prevention application and verified its effectiveness. Awareness and skills to avoid child sexual abuse after app education increased immediately after training and four weeks later. The SAP_MobAPP could be used for sexual abuse prevention education in schools. PMID- 28661823 TI - Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT). MATERIAL AND METHODS: We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30-33 Gy) or IMRT (25-28 fractions, 45-56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis. RESULTS: SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively). CONCLUSIONS: In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity. PMID- 28661825 TI - Concussions in Community-Level Rugby: Risk, Knowledge, and Attitudes. AB - BACKGROUND: Rugby is a popular collision sport where participants are at risk of sustaining concussions. Most research focuses on elite-level or youth divisions. Comparatively, little is known about adult community rugby. The aim of this research was to estimate the risk of sustaining a concussion during participation in community-level rugby and summarize the collective knowledge and attitudes toward concussions. HYPOTHESIS: Concussion symptoms will be reported frequently among community-level rugby players and a substantial proportion will report a willingness to continue participation despite the risk. STUDY DESIGN: Cross sectional analysis. LEVEL OF EVIDENCE: Level 3. METHODS: An anonymous, voluntary survey was administered to all 464 senior rugby players registered in the province of Manitoba in 2015. Two primary domains were assessed: (1) concussion history from the preceding season including occurrence, symptomatology, and impact on daily activities and (2) knowledge and attitudes toward concussion risks and management. RESULTS: In total, 284 (61.2%) rugby players responded. Concussive symptoms were reported by 106 (37.3%). Of those, 87% were formally diagnosed with a concussion and 27% missed school and/or work as a result. The danger of playing while symptomatic was recognized by 93.7% of participants, yet 29% indicated they would continue while symptomatic. Furthermore, 39% felt they were letting others down if they stopped playing due to a concussion. CONCLUSION: Concussive symptoms were common among the study cohort and had a notable impact on daily activities. A high proportion of players were willing to continue while experiencing symptoms despite recognizing the danger. The observed discord between knowledge and attitudes implicates a culture of "playing injured." CLINICAL RELEVANCE: Understanding the risk of injury may affect an individual's decision to participate in community-level rugby. Moreover, evidence of discord between the knowledge and attitudes of players may direct future research initiatives and league governance. PMID- 28661826 TI - Ultrasound Diagnosis of Calf Injuries. AB - CONTEXT: The medial head of the gastrocnemius is the third most commonly strained muscle in elite athletes after the biceps femoris and rectus femoris. The differential diagnosis of posterior calf injury includes musculoskeletal and nonmusculoskeletal causes. Classically, delineation of these injuries from one another relied primarily on historical features and physical examination findings. The utilization of musculoskeletal ultrasound (sonography) has augmented the diagnosis of these injuries by providing dynamic, real-time confirmation. EVIDENCE ACQUISITION: A review of PubMed, OVID, and MD Consult prior to January 2016 was performed using search terms, including s oleus ultrasound, gastrocnemius ultrasound, and tennis leg. The references of the pertinent articles were further reviewed for other relevant sources. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: There have been few reviews to date of calf injuries and the use of sonography in their diagnosis. Prompt diagnosis utilizing ultrasound allows the clinician to focus management on gastrocnemius injury if present. Two-thirds of calf injuries occur at the junction of the fascia between the medial head of the gastrocnemius and the soleus. Injuries to the lateral head of the gastrocnemius occur in up to 14% of patients in some case series, but injury may occur anywhere from the proximal origin to the mid-belly to the fascial junction with the soleus. Numerous injuries to the posterior compartment can mimic gastrocnemius strain, and musculoskeletal ultrasound can aide in their diagnosis by incorporating real-time imaging into the grading of the injury and visual confirmation of physical examination findings. CONCLUSION: Acute injury to the posterior compartment of the lower extremity can represent a diagnostic challenge. Medial gastrocnemius strain represents the most common injury of the posterior compartment of the lower extremity. Ultrasound is a useful tool to assist the clinician in determining the specific cause of calf injury, estimate the severity of the injury, and monitor progress of healing. The vast majority of calf injuries can be diagnosed and managed without any additional imaging. Serial diagnostic ultrasound of an injured area allows for direct monitoring of tissue healing and may allow the clinician to more confidently assess response to treatment and help guide return-to-play decisions. PMID- 28661829 TI - Return to Sports After Concussion. PMID- 28661827 TI - Cumulative Effects of Concussion History on Baseline Computerized Neurocognitive Test Scores: Systematic Review and Meta-analysis. AB - CONTEXT: It is unclear whether individuals with a history of single or multiple clinically recovered concussions exhibit worse cognitive performance on baseline testing compared with individuals with no concussion history. OBJECTIVE: To analyze the effects of concussion history on baseline neurocognitive performance using a computerized neurocognitive test. DATA SOURCES: PubMed, CINAHL, and psycINFO were searched in November 2015. The search was supplemented by a hand search of references. STUDY SELECTION: Studies were included if participants completed the Immediate Post-concussion Assessment and Cognitive Test (ImPACT) at baseline (ie, preseason) and if performance was stratified by previous history of single or multiple concussions. STUDY DESIGN: Systematic review and meta analysis. LEVEL OF EVIDENCE: Level 2. DATA EXTRACTION: Sample size, demographic characteristics of participants, as well as performance of participants on verbal memory, visual memory, visual-motor processing speed, and reaction time were extracted from each study. RESULTS: A random-effects pooled meta-analysis revealed that, with the exception of worsened visual memory for those with 1 previous concussion (Hedges g = 0.10), no differences were observed between participants with 1 or multiple concussions compared with participants without previous concussions. CONCLUSION: With the exception of decreased visual memory based on history of 1 concussion, history of 1 or multiple concussions was not associated with worse baseline cognitive performance. PMID- 28661830 TI - The Diagnostic Utility of Computer-Assisted Auscultation for the Early Detection of Cardiac Murmurs of Structural Origin in the Periodic Health Evaluation. AB - BACKGROUND: Identification of the nature of cardiac murmurs during the periodic health evaluation (PHE) of athletes is challenging due to the difficulty in distinguishing between murmurs of physiological or structural origin. Previously, computer-assisted auscultation (CAA) has shown promise to support appropriate referrals in the nonathlete pediatric population. HYPOTHESIS: CAA has the ability to accurately detect cardiac murmurs of structural origin during a PHE in collegiate athletes. STUDY DESIGN: Cross-sectional, descriptive study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 131 collegiate athletes (104 men, 28 women; mean age, 20 +/- 2 years) completed a sports physician (SP)-driven PHE consisting of a cardiac history questionnaire and a physical examination. An independent CAA assessment was performed by a technician who was blinded to the SP findings. Athletes with suspected structural murmurs or other clinical reasons for concern were referred to a cardiologist for confirmatory echocardiography (EC). RESULTS: Twenty-five athletes were referred for further investigation (17 murmurs, 6 abnormal electrocardiographs, 1 displaced apex, and 1 possible case of Marfan syndrome). EC confirmed 3 structural and 22 physiological murmurs. The SP flagged 5 individuals with possible underlying structural pathology; 2 of these murmurs were confirmed as structural in nature. Fourteen murmurs were referred by CAA; 3 of these were confirmed as structural in origin by EC. One such murmur was not detected by the SP, however, and detected by CAA. The sensitivity of CAA was 100% compared with 66.7% shown by the SP, while specificity was 50% and 66.7%, respectively. CONCLUSION: CAA shows potential to be a feasible adjunct for improving the identification of structural murmurs in the athlete population. Over-referral by CAA for EC requires further investigation and possible refinements to the current algorithm. Further studies are needed to determine the true sensitivity, specificity, and cost efficacy of the device among the athletic population. CLINICAL RELEVANCE: CAA may be a useful cardiac screening adjunct during the PHE of athletes, particularly as it may guide appropriate referral of suspected structural murmurs for further investigation. PMID- 28661832 TI - The Heavy Hitters as Repeal-and-Replace Moves to the Senate. AB - Now it's the Senate's turn and there's a good chance that much of what the House put in the American Health Care Act will be left by the wayside. Keep an eye on some key players such as Sen. John Cornyn of Texas, who heads the Senate Health Care Working Group. PMID- 28661833 TI - Drugs for Diabetes: It's No Longer Just About Controlling Blood Sugar. AB - The link between diabetes and cardiovascular disease has been clear for decades, but until 2015 no clinical trial had convincingly demonstrated a link between medications that lower blood glucose and cardiovascular risks. Enter SGKT2 inhibitors and GLP-1 agonists. PMID- 28661831 TI - Genetic Diversity of Highly Pathogenic Avian Influenza A(H5N8/H5N5) Viruses in Italy, 2016-17. AB - In winter 2016-17, highly pathogenic avian influenza A(H5N8) and A(H5N5) viruses of clade 2.3.4.4 were identified in wild and domestic birds in Italy. We report the occurrence of multiple introductions and describe the identification in Europe of 2 novel genotypes, generated through multiple reassortment events. PMID- 28661834 TI - Orphan Drugs: Way Too Many, Way Too Expensive. AB - Sales hit the billion dollar mark as pharmaceutical companies apply creative approaches to increase earnings. For instance, "salami slicing": Dividing diseases into smaller and smaller categories based on genetic and biomarker differences so that the product can achieve the coveted orphan drug status. PMID- 28661836 TI - No Price Pressure On Orphan Drugs (Yet). AB - Sales of orphan drugs are forecast to grow 11% over the next five years, to $209 billion. That growth rate is twice as fast as the expected increase in sales of all other prescription medicines. They may account for more than 21% of brand name prescription drug sales by 2022. PMID- 28661835 TI - Orphan Drug Debate: A Cheat Sheet. AB - In some respects, the 1983 Orphan Drug Act is a success story. But high prices and allegations that some drug companies have twisted the law to their advantage have made it controversial. Here are some of the main points in the debate. PMID- 28661837 TI - Readers Want Reforms of Orphan Drug Act. AB - More than half (53%) of the 111 respondents to an online survey rated orphan drugs as having a major impact on rising drug costs, although there was also fairly wide (if mild) agreement that the 1983 Orphan Drug Act has been successful in creating incentives to develop remedies for rare diseases. PMID- 28661838 TI - Venture Philanthropy Straddles Two Worlds. AB - Venture philanthropy and the move toward investment of not-for-profit dollars in for-profit companies started about 10 years ago. One expert argues that it's a little like calling someone an amateur-pro athlete. You can't be both. Proponents, however, point to some initially impressive results especially for niche diseases. PMID- 28661839 TI - 7 Strategies for Improving Drug Utilization. AB - When new pharmaceutical products enter the market, the lack of real-world experience with these drugs creates quandaries for payers and providers alike. Often, all there is to go on is the minimum required for FDA approval-non inferiority to a comparator product in terms of efficacy and safety. Here are a few promising strategies to end this ambiguity. PMID- 28661840 TI - Care Coordination: More Keystone Kops Than Coordinated. AB - Someone should check up on high-risk patients, make sure they are healing, taking their medications, and getting to their follow-up medical appointments. The question is, who? Health plans, hospitals, drug companies all have their methods. The result is too often confusion. PMID- 28661841 TI - Parsabiv Could Be Pricey Addition In Care for CKD, ESRD Patients. AB - Because it is given intravenously at the end of dialysis, Parsabiv could be the answer to the adherence problems posed by cinacalcet. Most patients are pretty adherent to dialysis. One study found that people missed only 7.1 episodes of dialysis per patient-year, which isn't perfect but it's certainly better than adherence to self-administered drugs. PMID- 28661842 TI - Innovative Care Model to Improve Clinical Quality and Safety of Transitional Care: Early Outcomes. AB - One in five elderly patients returns to the hospital within 30 days of leaving. These rehospitalizations are a common and costly occurrence. A program developed to address problems in post-acute transitional care seems to be effective in reducing 30-day readmission rates for some Medicare fee-for-service beneficiaries. PMID- 28661843 TI - Managing Cost of Niche Diseases Depends Innovative Approaches. AB - And health plans can't be caught flat-footed. They need to keep pace with the introduction of new treatments and be ready with strategies that address patient needs and manage costs. Using objective clinical data to guide dosing and working to redirect care to a patient's home is a place to start. PMID- 28661844 TI - GOP Jumps Back Into High-Risk Pools. But Will the Money Run Dry Again? AB - High-risk pools are not new. Before the ACA, 35 states had them. Today, only a handful still function. But in March, HHS Secretary Tom Price encouraged a comeback, sending letters to governors inviting them to apply for ACA innovation waivers to implement state-by-state high-risk pools and reinsurance programs. PMID- 28661845 TI - Now Might Be the Right Time To Kill Hospital Value-based Purchasing Program. AB - No real trends in quality improvement or cost savings have emerged, while mortality outcomes have remained flat. The program withholds 2% of hospitals' Medicare pay and redistributes most of it to high-performing hospitals. With so little money at risk, the program simply may not turn enough heads. PMID- 28661846 TI - Some Builders' Remorse: The Rise and Fall of the Oncology Medical Home. AB - Insurers pay for extra services that oncologists deliver in the hope that the investment will save them money down the road. That's the idea, anyway. In practice, payers and providers in general see the concept as another example of how vexing payment reform for cancer care is turning out to be. PMID- 28661847 TI - Keytruda Crosses First-Line Finish Line First. AB - Approval of Merck's checkpoint inhibitor is further evidence that cancer treatment decisions are increasingly dependent on the PD-L1 biomarker and other molecular-level differences in tumor cells. But testing for PD-L1 is tricky, and variations in the concentration of PD-L1 cells in different regions of the sample can produce different test results. PMID- 28661848 TI - Many Health Plans Avoid Paying For Prostate Cancer Genetic Tests. AB - One reason is that they figure that CMS will foot the bill because many of their beneficiaries age into Medicare. Also, for every insurer: churn, churn, churn. PMID- 28661849 TI - Affirmative: Cuts Cancer Mortality Negative: There's No Hard Proof. AB - The debate on screening continues. Critics say it has been oversold and most tests have yet to show lifesaving benefit. Others are skeptical of the skeptics. PMID- 28661850 TI - Cancer Screening Gets Thumbs-up From Readers. AB - Cancer screening may have its skeptics, but respondents to a Managed Care reader poll are not among them. Colorectal, cervical, breast, prostate, and lung care cancer screening were rated as highly beneficial by the 168 respondents to the online survey, although prostate and lung cancer screening were viewed somewhat less favorably than the other three. PMID- 28661851 TI - Staying the Course on Cancer Care. AB - The election upended a lot of expectations in health care. But the advantages of building integrated cancer care programs are still there. PMID- 28661852 TI - Real-World Evidence Faces Some Real-World Challenges. AB - RWE is a relatively new kid on the block. How exactly it will fit into the complicated world of cancer drug testing, approval, regulation, and marketing is uncertain. The randomized clinical trial has been the gold standard in oncology research for decades and will remain so for the foreseeable future. PMID- 28661853 TI - Chimeric Antigen Receptor T-Cell Therapy: The Next Big Thing Faces Challenges. AB - Some are using the word "cure" for chimeric antigen receptor T cells. The modular nature of CAR T cells could provide novel strategies to combat resistance and convert more initial complete responses into lasting complete responses. Problems include: cytokine release syndrome, resistance, and finding ways to produce them more efficiently. PMID- 28661854 TI - Oncology Care Model Headed for Shades of Gray. AB - Regardless of your politics, the motivation behind a program designed to curtail cancer costs is clear. Cancer epidemiology (the old are disproportionately affected), coupled with 21st century demography (longer life expectancy, aging boomers), means cancer costs are going up. PMID- 28661855 TI - Red blood cell transfusion policy: a critical literature review. AB - The issue of the most appropriate red blood cell transfusion policy has been addressed by a number of randomised controlled trials, conducted over the last decades, comparing the effects on patients' outcome of restrictive blood transfusion strategies (transfusing when the haemoglobin concentration is less than 7 g/dL to 8 g/dL) vs more liberal ones (transfusing when the haemoglobin concentration is less than 9 g/dL to 10 g/dL) in a variety of clinical settings. In parallel, various systematic reviews and meta-analyses have tried to perform pooled analyses of the data from these randomised controlled trials and their results have been utilised by scientific societies to provide recommendations and guidelines on red blood cell transfusion thresholds. All these aspects will be critically discussed in this narrative review. PMID- 28661856 TI - The use of fibrinogen concentrate for the management of trauma-related bleeding: a systematic review and meta-analysis. AB - Haemorrhage following injury is associated with significant morbidity and mortality. The role of fibrinogen concentrate in trauma-induced coagulopathy has been the object of intense research in the last 10 years and has been systematically analysed in this review. A systematic search of the literature identified six retrospective studies and one prospective one, involving 1,650 trauma patients. There were no randomised trials. Meta-analysis showed that fibrinogen concentrate has no effect on overall mortality (risk ratio: 1.07, 95% confidence interval: 0.83-1.38). Although the meta-analytic pooling of the current literature evidence suggests no beneficial effect of fibrinogen concentrate in the setting of severe trauma, the quality of data retrieved was poor and the final results of ongoing randomised trials will help to further elucidate the role of fibrinogen concentrate in traumatic bleeding. PMID- 28661858 TI - ? PMID- 28661857 TI - Awards season. PMID- 28661859 TI - Legislating away the future of family practice: Dangerous transition from continuity of care to continuous access. PMID- 28661860 TI - Why primary care guidelines are not prepared by family physicians. PMID- 28661861 TI - Response. PMID- 28661863 TI - Correction. PMID- 28661862 TI - Response. PMID- 28661865 TI - Health benefits of tai chi: What is the evidence? AB - OBJECTIVE: To summarize the evidence on the health benefits of tai chi. SOURCES OF INFORMATION: A literature review was conducted on the benefits of tai chi for 25 specific conditions, as well as for general health and fitness, to update a 2014 review of systematic reviews. Systematic reviews and recent clinical trials were assessed and organized into 5 different groups: evidence of benefit as excellent, good, fair, or preliminary, or evidence of no direct benefit. MAIN MESSAGE: During the past 45 years more than 500 trials and 120 systematic reviews have been published on the health benefits of tai chi. Systematic reviews of tai chi for specific conditions indicate excellent evidence of benefit for preventing falls, osteoarthritis, Parkinson disease, rehabilitation for chronic obstructive pulmonary disease, and improving cognitive capacity in older adults. There is good evidence of benefit for depression, cardiac and stroke rehabilitation, and dementia. There is fair evidence of benefit for improving quality of life for cancer patients, fibromyalgia, hypertension, and osteoporosis. Current evidence indicates no direct benefit for diabetes, rheumatoid arthritis, or chronic heart failure. Systematic reviews of general health and fitness benefits show excellent evidence of benefit for improving balance and aerobic capacity in those with poor fitness. There is good evidence for increased strength in the lower limbs. There is fair evidence for increased well-being and improved sleep. There were no studies that found tai chi worsened a condition. A recent systematic review on the safety of tai chi found adverse events were typically minor and primarily musculoskeletal; no intervention-related serious adverse events have been reported. CONCLUSION: There is abundant evidence on the health and fitness effects of tai chi. Based on this, physicians can now offer evidence-based recommendations to their patients, noting that tai chi is still an area of active research, and patients should continue to receive medical follow-up for any clinical conditions. PMID- 28661866 TI - Approaching a global definition of family medicine: The Besrour Papers: a series on the state of family medicine in the world. AB - OBJECTIVE: To find a common global definition of family medicine. COMPOSITION OF THE COMMITTEE: Since 2012, the College of Family Physicians of Canada has hosted the Besrour Conferences to reflect on its role in advancing the discipline of family medicine globally. The Besrour Papers Working Group, which was struck at the 2013 conference, was tasked with developing a series of papers to highlight the key issues, lessons learned, and outcomes emerging from the various activities of the Besrour collaboration. The working group comprised members of various academic departments of family medicine in Canada and abroad who attended the conferences. METHODS: Searching both definition of family medicine and history of family medicine yields a variety of defining features. Visiting family medicine training programs worldwide highlights this discrepancy. REPORT: It is not an easy task to define family medicine-one of its key attributes is its adaptability to a local context, but this makes aggregation of data challenging. There is a lack of clarity regarding whether family medicine is the same discipline globally and what the core features are that define it. Unifying components of the definition have always included comprehensive care at all life stages and the management of the common illnesses of a particular community. The emerging global emphasis on competency and social accountability demonstrates commitment to the principle that family doctors provide health care for all in the context of the community. Although the competencies are not universal, the fact that family physicians fill in primary care "gaps" and tailor learning strategies to community priorities is a unifying distinction. We argue for a focus on the core competencies that bind us as a discipline. CONCLUSION: Family medicine can be practised in various forms. The unifying elements are the socially accountable responsiveness to local need, the adaptation of existing health infrastructure, and the ongoing development of the skills required to succeed in that role-always grounded in relationships of care. In this way, family medicine will continue to evolve to suit the health needs of communities and health systems. PMID- 28661867 TI - Electronic cigarettes and adolescents. AB - Question I see in my office an increased number of adolescents who use electronic cigarettes (e-cigarettes). Should I encourage adolescents to choose e-cigarettes over regular cigarettes if they decide to smoke? Are e-cigarettes less harmful and a potential smoking cessation method for adolescents? Answer While e cigarettes do not have carcinogenic tobacco, most contain nicotine, which not only leads to addiction, but can also impair brain development and cognitive function in youth. Recent studies have also shown that adolescents who use e cigarettes are more likely to begin smoking tobacco cigarettes. It is therefore essential that physicians explain to adolescents the risks and health concerns e cigarettes present, and implement measures to prevent or cease e-cigarette use. PMID- 28661868 TI - Challenge of alpha1-antitrypsin deficiency diagnosis in primary care. PMID- 28661870 TI - Antimicrobial resistance: international health threat. PMID- 28661869 TI - Choosing Wisely Canada recommendations. PMID- 28661871 TI - Three drugs and still hypertensive: what's left? PMID- 28661872 TI - Duration of dual antiplatelet therapy after coronary stent insertion: Does the benefit of extended therapy outweigh the risk? PMID- 28661873 TI - [Not Available]. PMID- 28661874 TI - Pretty mighty good. PMID- 28661875 TI - A fine, fine balancing act: Circus creativity and medicine. PMID- 28661877 TI - Learning from our neighbours. PMID- 28661876 TI - Pathways to subspecialization in family practice. PMID- 28661878 TI - ? PMID- 28661879 TI - ? PMID- 28661880 TI - Role modeling. PMID- 28661881 TI - ? PMID- 28661882 TI - ? PMID- 28661883 TI - ? PMID- 28661884 TI - ? PMID- 28661885 TI - ? PMID- 28661886 TI - Family physician access to specialist advice by telephone: Reduction in unnecessary specialist consultations and emergency department visits. AB - PROBLEM ADDRESSED: Timely access to specialist care is an important issue for patients with mild to moderate symptoms, and wait times for referrals are currently quite long. OBJECTIVE OF PROGRAM: To provide FPs with quick telephone access to other specialists for treatment advice for patients with nonserious conditions that they would otherwise refer to specialist care. PROGRAM DESCRIPTION: The RACE (Rapid Access to Consultative Expertise) program is a telephone hot-line providing FPs and nurse practitioners in the Vancouver, BC, area with timely access to specialist consultations. An evaluation of data from RACE found 60% of RACE calls prevented patients from visiting a specialist and 32% of calls prevented FP referrals to hospital emergency departments. CONCLUSION: Supported by RACE, FPs can more effectively remain the locus of patient care, calling on other specialist expertise when appropriate and providing better coordination of care for their patients. Evaluations to date suggest RACE helps reduce system costs by reducing unnecessary emergency department visits and face-to-face specialist consultations. PMID- 28661887 TI - Getting by with a little help from friends and colleagues: Testing how residents' social support networks affect loneliness and burnout. AB - OBJECTIVE: To determine how residents' relationships with their sources of social support (ie, family, friends, and colleagues) affect levels of burnout and loneliness. DESIGN: Cross-sectional survey. SETTING: Faculty of Medicine at the University of British Columbia in Vancouver. PARTICIPANTS: A total of 198 physician-trainees in the university's postgraduate medical education program. MAIN OUTCOME MEASURES: Residents' personal and work-related burnout scores (measured using items from the Copenhagen Burnout Inventory); loneliness (measured using a 3-item loneliness scale); and social support (assessed with the Lubben Social Network Scale, version 6). RESULTS: Of the 234 respondents who completed the Internet-based survey (a 22% response rate), 198 provided complete information on all study variables and thus constituted the analytic sample. Seemingly unrelated regression analyses indicated that loneliness was significantly (P < .01) and positively associated with both personal and work related burnout scores. Greater friend-based and colleague-based social support were both indirectly associated with lower personal and work-related burnout scores through their negative associations with loneliness. CONCLUSION: Social relationships might help residents mitigate the deleterious effects of burnout. By promoting interventions that stabilize and nurture social relationships, hospitals and universities can potentially help promote resident resilience and well-being and, in turn, improve patient care. PMID- 28661888 TI - Health workers who ask about social determinants of health are more likely to report helping patients: Mixed-methods study. AB - OBJECTIVE: To assess the feasibility of implementing a clinical decision aid called the CLEAR Toolkit that helps front-line health workers ask their patients about social determinants of health, refer to local support resources, and advocate for wider social change. DESIGN: A mixed-methods study using quantitative (online self-completed questionnaires) and qualitative (in-depth interviews, focus groups, and key informant interviews) methods. SETTING: A large, university-affiliated family medicine teaching centre in Montreal, Que, serving one of the most ethnically diverse populations in Canada. PARTICIPANTS: Fifty family doctors and allied health workers responded to the online survey (response rate of 50.0%), 15 completed in-depth interviews, 14 joined 1 of 2 focus groups, and 3 senior administrators participated in key informant interviews. METHODS: Our multimethod approach included an online survey of front line health workers to assess current practices and collect feedback on the tool kit; in-depth interviews to understand why they consider certain patients to be more vulnerable and how to help such patients; focus groups to explore barriers to asking about social determinants of health; and key informant interviews with high-level administrators to identify organizational levers for changing practice. MAIN FINDINGS: Senior administrators consider asking about social determinants to be part of the mandate of health workers. However, barriers perceived by front-line clinicians include insufficient training in social history taking, uncertainty about how to address these issues in clinical practice, and a lack of knowledge of local referral resources. Health workers with specific ways of asking patients about their social challenges were more likely to report having helped their patients as compared with those who did not know how to ask (93.8% vs 52.9%; P = .003). CONCLUSION: While health workers recognize the importance of social determinants, many are unsure how to ask about these often sensitive issues or where to refer patients. The CLEAR Toolkit can be easily adapted to local contexts to help front-line health workers initiate dialogue around social challenges and better support patients in clinical practice. PMID- 28661889 TI - Voices in the wilderness: Co-location meeting the needs of children in protective care. AB - OBJECTIVE: To explore how access to a family medicine clinic co-locating with the Children's Aid Society (CAS) of Hamilton in Ontario helped meet the unique needs of children in care. DESIGN: Qualitative research using semistructured face-to face and telephone interviews. SETTING: The CAS of Hamilton. PARTICIPANTS: Nineteen foster parents. METHODS: Stakeholders were invited to participate with flyers posted in the clinic, notices that were mailed to foster parents, personal invitations that were distributed during clinic visits, and an internal memo that was distributed to the CAS staff. Informed consent and assent where appropriate was obtained before an interview was started. Interviews were audiorecorded when and where feasible, transcribed, and subsequently underwent inductive, thematic analysis. Common themes evolved by consensus. MAIN FINDINGS: Foster parents valued the family medicine clinic co-locating with the CAS. The co-location helped children in care to know that there were others in similar circumstances. Foster parents learned from and shared parenting skills with one another, which resulted in developing confidence in the care they provided. The clinic became a neutral place for children in care, foster parents, and birth parents. The clinic team gathered the children's complete health records and was responsible for sharing this information when appropriate. CONCLUSION: Access to a family medicine clinic designed specifically for children in care that co-located with the CAS enhanced not only the planning, management, and evaluation of care, but also provided a consistency that was not found in other parts of the children's lives; this helped generate trusting relationships over time. The co-location provided a strong spoke in the circle of care. PMID- 28661891 TI - ? PMID- 28661890 TI - Reflective practice and social responsibility in family medicine: Effect of performing an international rotation in a developing country. AB - OBJECTIVE: To explore the perceived effect of an elective international health rotation on family medicine resident learning. DESIGN: Qualitative, collaborative study based on semistructured interviews. SETTING: Quebec. PARTICIPANTS: A sample of 12 family medicine residents and 9 rotation supervisors (N = 21). METHODS: Semistructured interviews of residents and rotation supervisors. MAIN FINDINGS: Residents and supervisors alike reported that their technical skills and relationship skills had benefited. All increased their knowledge of tropical pathologies and learned to expand their clinical examinations. They benefited from having very rich interactions in other care settings, working with vulnerable populations. The rotations had their greatest effect on relationship skills (communication, empathy, etc) and the ability to work with vulnerable patients. All of the participants were exposed to local therapies and local interpretations of disease symptoms and pathogenesis. CONCLUSION: The findings of this study will have a considerable effect on pedagogy. The residents' experiences of their international health rotations and what they learned in terms of medical skills and pedagogic approaches in working with patients are described. Using a collaborative approach with the rotation supervisors, the data were triangulated and the benefits of an international rotation on academic training were more accurately defined. The findings can now be used to enrich academic programs in social and preventive medicine and more adequately prepare future family physicians for work in various social and cultural settings. PMID- 28661892 TI - ? PMID- 28661893 TI - Exact lower and upper bounds on stationary moments in stochastic biochemical systems. AB - In the stochastic description of biochemical reaction systems, the time evolution of statistical moments for species population counts is described by a linear dynamical system. However, except for some ideal cases (such as zero- and first order reaction kinetics), the moment dynamics is underdetermined as lower-order moments depend upon higher-order moments. Here, we propose a novel method to find exact lower and upper bounds on stationary moments for a given arbitrary system of biochemical reactions. The method exploits the fact that statistical moments of any positive-valued random variable must satisfy some constraints that are compactly represented through the positive semidefiniteness of moment matrices. Our analysis shows that solving moment equations at steady state in conjunction with constraints on moment matrices provides exact lower and upper bounds on the moments. These results are illustrated by three different examples-the commonly used logistic growth model, stochastic gene expression with auto-regulation and an activator-repressor gene network motif. Interestingly, in all cases the accuracy of the bounds is shown to improve as moment equations are expanded to include higher-order moments. Our results provide avenues for development of approximation methods that provide explicit bounds on moments for nonlinear stochastic systems that are otherwise analytically intractable. PMID- 28661894 TI - Exploring Explanatory Models of Risk in Breast Cancer Risk Counseling Discussions: NSABP/NRG Oncology Decision-Making Project 1. AB - BACKGROUND: Explanatory models represent patient understanding of etiology, pathophysiology, illness, symptoms, and treatments, but little attention has been paid to how they are used by patients "at risk" for future disease. OBJECTIVE: The aims of this study were to elucidate what constitutes an explanatory model of risk and to describe explanatory models of risk related to developing breast cancer. METHODS: Thirty qualitative interviews with women identified as at an increased risk for breast cancer were conducted. Interviews were coded to identify domains of explanatory models of risk using a priori codes derived from the explanatory model of illness framework. Within each domain, a grounded thematic analysis described participants' explanatory models related to breast cancer risk. RESULTS: The domains of treatment and etiology remained similar in a risk context compared with illness, whereas course of illness, symptoms, and pathophysiology differed. We identified a new, integrative concept relative to other domains within explanatory models of risk: social comparisons, which was dominant in risk perhaps due to the lack of physical experiences associated with being "at risk." CONCLUSIONS: Developing inclusive understandings of risk and its treatment is key to developing a framework for the care of high-risk patients that is both evidence based and sensitive to patient preferences. IMPLICATIONS FOR PRACTICE: The concept of "social comparisons" can assist healthcare providers in understanding women's decision making under conditions of risk. Ensuring that healthcare providers understand patient perceptions of risk is important because it relates to patient decision making, particularly due to an increasing focus on risk assessment in cancer. PMID- 28661895 TI - Validation of a Questionnaire to Delineate the Clinical Trial Nursing Roles in Korea. AB - BACKGROUND: In clinical trials, research nurses play a particularly important role in promoting cancer care best practices. However, no Korean questionnaire has been developed to define the clinical trial nursing roles based on Good Clinical Practice standards. OBJECTIVE: The aim of this study was to cross culturally evaluate the reliability and validity of a Korean version of the Clinical Trials Nursing Questionnaire (CTNQ) among Korean clinical research nurses. METHODS: Cross-cultural adaptation was performed, with forward and backward translation, a pilot test (linguistic validation), and a field test. Validation was performed by questioning 53 clinical research nurses who were working in clinical cancer centers at 5 tertiary university hospitals. The distribution of the item responses and internal consistency reliability were assessed using the ceiling and floor effects, Cronbach's alpha, and the item total correlation. Construct validity was assessed using Spearman correlation analysis and principal-component factor analysis. RESULTS: The distributions of the item responses and the item-total correlation were generally appropriate. The Cronbach's alpha values for the frequency scale and the importance scale were 0.852 and 0.899, respectively. Eight sections of the Korean CTNQ were generally correlated with each other. The frequency subscale loaded on 1 factor, and the importance subscale loaded on 2 factors, with broadly similar factor loadings. CONCLUSION: The Korean version of the CTNQ is reliable, valid, and interchangeable with the original CTNQ. IMPLICATIONS FOR PRACTICE: The Korean version of the CTNQ can be used to validly and reliably assess the clinical trial nursing roles in Korea. PMID- 28661896 TI - Vitamin K Antagonists Versus Novel Oral Anticoagulants for Elective Electrical Cardioversion of Atrial Fibrillation. AB - BACKGROUND: The management strategy for patients with atrial fibrillation (AF) is often very complex, electrical cardioversion (EC) being often used to restore sinus rhythm in those patients. The increased risk of thromboembolic complications was lowered using anticoagulation therapy. Usually, the anticoagulation was achieved using vitamin K antagonists (VKAs), but over the last years we witnessed a wide implementation of the novel oral anticoagulants (NOACs). STUDY QUESTION: Study question was to compare the efficacy of NOACs versus VKAs in patients undergoing elective EC for persistent AF, by assessing the presence of left atrial spontaneous contrast and left atrial thrombi (LACS), as well as the occurrence of the thromboembolic events in the first month after the procedure. STUDY DESIGN: A prospective study, including patients with persistent AF enrolled between January 1, 2015 and December 31, 2016, was conducted in 2 tertiary cardiology clinics. In all these patients, a management strategy based on EC was considered for the treatment of the disease. All patients received anticoagulant therapy for at least 3 weeks before cardioversion. The data of 103 patients were analyzed. RESULTS: The patients were divided into 2 groups: group A-VKAs treated-included 45 patients (43.68%), mean age 65.3 +/- 12.47, 36% women; group B-NOACs treated-included 58 patients (56.31%), mean age 66.4 +/- 9.79, 46% women. There was a trend toward higher incidence of left atrial thrombi in group B (16.28%) versus group A (7.69%), but the difference was not statistically significant (P = 0.5). The incidence of LACS was 40% in group A and 29% in group B, (P = 0.54). CONCLUSION: There are no statistically significant differences between the transesophageal echocardiography characteristics of left atrium and left atrial appendage examinations in the patients who received anticoagulation with VKAs as compared to patients who received anticoagulation with NOACs. PMID- 28661897 TI - Obesity and male infertility. AB - PURPOSE OF REVIEW: The prevalence of obesity has risen steadily for the past 35 years and presently affects more than a third of the US population. A concurrent decline in semen parameters has been described, and a growing body of literature suggests that obesity contributes to the male infertility. The purpose of this review is to examine the effects of obesity on male fertility, the mechanisms by which impaired reproductive health arise, and the outcomes of treatment. RECENT FINDINGS: Obesity alters the hypothalamic-pituitary-gonadal axis both centrally and peripherally, resulting in hypogonadotropic, hyperestrogenic hypogonadism. Adipose tissue-derived factors, like leptin and adipokines, regulate testosterone production and inflammation, respectively. Increased systemic inflammation results in increased reactive oxygen species and sperm DNA fragmentation. Increased testicular temperature because of body habitus and inactivity impairs spermatogenesis. The degree to which obesity affects hormone levels, semen parameters, sperm DNA integrity, and pregnancy rates is variable, which may be the result of other comorbid conditions. Treatment in the form of weight loss has also had inconsistent results. SUMMARY: Multiple interdependent mechanisms contribute to the detrimental effect of obesity on male fertility. Large, randomized control trials are needed to better characterize the therapeutic benefits of weight loss to restore male reproductive potential. PMID- 28661898 TI - Genomic testing for localized prostate cancer: where do we go from here? AB - PURPOSE OF REVIEW: The goal of this article is to discuss current genomic testing options in localized prostate cancer. RECENT FINDINGS: There are multiple genomic tests currently available for men with localized prostate cancer. Prolaris, OncotypeDx, and Decipher can all be tested using biopsy tissue. Prolaris and Decipher are also available for men undergoing radical prostatectomy to predict subsequent disease progression. SUMMARY: The Prolaris cell cycle progression score measured on biopsy predicts the risk of prostate cancer death in 10 years with conservative management, whereas, the primary endpoint for the OncotypeDx genomic prostate score is the risk of adverse disease at radical prostatectomy. Decipher measures genome-wide RNA expression, and its Genomic Classifier signature was initially designed to predict the risk of metastasis for men with adverse disease at radical prostatectomy, and more recently, a biopsy version was released. Recently, Decipher signatures predicting prostate cancer cell lineage and postoperative radiation sensitivity have also been described. Any of these tests can be used by men with localized prostate cancer to provide additional prognostic risk stratification to aid in treatment decisions. PMID- 28661899 TI - Genomes of early onset prostate cancer. AB - PURPOSE OF REVIEW: Prostate cancer is a disease of the elderly but a clinically relevant subset occurs early in life. In the current review, we discuss recent findings and the current understanding of the molecular underpinnings associated with early-onset prostate cancer (PCa) and the evidence supporting age-specific differences in the cancer genomes. RECENT FINDINGS: Recent surveys of PCa patient cohorts have provided novel age-dependent links between germline and somatic aberrations which points to differences in the molecular cause and treatment options. SUMMARY: Identifying the earliest molecular alterations in PCa can provide insight into the cause of the disease and biomarkers for patient risk stratification. Genomic aberrations of early-onset PCas display several patterns distinct from late-onset PCa genomes, suggesting age-dependent pathomechanisms involving alterations in the androgen receptor pathway. PMID- 28661900 TI - Palliative care and interstitial lung disease. AB - PURPOSE OF REVIEW: The palliative care needs of people with interstitial lung disease (ILD) have recently been highlighted by the National Institute for Health and Care Excellence. All people with progressive ILD should receive best supportive care to improve symptom control and quality of life and where possible this should be evidence based. RECENT FINDINGS: Deaths from ILD are increasing and deaths in hospital are more common compared to home. People with ILD experience a wide range of symptoms including breathlessness and cough. People living with ILD often suffer unmet physical and psychological needs throughout the disease journey. Few appropriately validated outcome measures exist for ILD which has hampered research on the longitudinal experience of symptoms and quality of life and the evaluation of interventions. Recent recommendations from the National Institute of Clinical Excellence promote the use of a new palliative care needs assessment tool. Use of a tool in busy respiratory clinics may help to highlight those requiring specialist input. SUMMARY: Further research into the role of opioids, oxygen and neuromodulatory agents in symptom management are needed. In addition, exploration of breathlessness and case conference interventions in transitioning patients from the hospital to community settings is a priority. Further work is needed to identify a core set of validated ILD specific patient-reported outcome measures for the robust evaluation of interventions. PMID- 28661901 TI - Long-term and late treatment consequences: endocrine and metabolic effects. AB - PURPOSE OF REVIEW: Cancer therapies often result in the 'late effect of cancer treatment' whereby secondary health complications emerge years after radiotherapy and chemotherapy. This review focuses on endocrine and metabolic consequences in adult cancer survivors as late treatment effects. RECENT FINDINGS: Endocrine and metabolic disorders are among the most common late effects. Endocrine disorders include hypopituitarism, which leads to growth hormone deficiency, hypogonadism, adrenal insufficiency and hypothyroidism and related clinical manifestations. Hypogonadism in particular is associated with a wide range of health complications requiring input from the like of endocrine and fertility specialists. Immune checkpoint inhibitors are novel anticancer agents, some of which are uniquely associated with hypophysitis which requires early recognition and management, including steroid replacement. Metabolic syndrome, a significant risk for cardiovascular disease, is highly prevalent. Although the effects of cranial irradiation on the hypothalamic-pituitary system are more apparent, the relationship between chemotherapy and endocrine/metabolic disorders remains to be elucidated. There exist published guidelines for monitoring endocrine and cardiometabolic risk in cancer survivors, but the extent of monitoring appears insufficient. SUMMARY: Regular monitoring and early management of endocrine/metabolic disorders is required to prevent the elevated rates of health complications after cancer treatment, and thereby improve cancer survivorship. PMID- 28661902 TI - Unmasking chronic breathlessness. PMID- 28661903 TI - P2Y12 receptor inhibitor resistance and coronary artery disease: a bench to bedside primer for cardiovascular specialists. AB - PURPOSE OF REVIEW: Platelet P2Y12 receptor inhibitors are routinely prescribed for patients after acute coronary syndromes and percutaneous coronary interventions. Patients may have underresponsiveness (or resistance) to these drugs and in particular to clopidogrel, the most often used type. This review aims to focus on the concept of P2Y12 receptor inhibitor resistance and discuss incidence, mechanisms, novel diagnostic techniques and past and future clinical trials on the topic. RECENT FINDINGS: Patients treated with P2Y12 receptor inhibitors may develop high on-treatment platelet reactivity (HPR), a phenomenon of impaired response toward the drug, which has been associated with ischemic complications. Although potent P2Y12 inhibitors provide better ischemic protection, this must be balanced with increased bleeding risk. Several clinical factors, including common genetic variants such as Cytochrome P450 2C19 loss-of function alleles, have been shown to predispose to HPR among patients on clopidogrel. Platelet function tests and genotyping platforms have enabled identification of patients at-risk for HPR. Past studies using platelet testing and tailoring therapy among patients with HPR have failed to provide conclusive data to support its routine use. SUMMARY: Ongoing studies using genotyping and novel antiplatelet regimens may identify potential strategies to minimize ischemic and bleeding risks concurrently. Until definitive studies demonstrate clear benefit of a personalized approach to P2Y12 inhibitor prescription, the choice of P2Y12 inhibitors should continue to be based on best evidence from previous large clinical trials. PMID- 28661904 TI - Cardiac sarcoidosis: challenges in clinical practice. AB - PURPOSE OF REVIEW: To address the current recommendations for screening, diagnosis, and treatment of cardiac sarcoidosis and the difficulties to put these recommendations into clinical practice. RECENT FINDINGS: The incidence of cardiac sarcoidosis appears to be higher than earlier reported, probably because of improved imaging techniques. Late gadolinium enhancement with cardiac MRI (LGE CMR) and fluorodeoxyglucose positron emission tomography obtained a central role in the diagnostic algorithm and monitoring of disease activity. New techniques are being investigated: T1 and T2 mapping for early detection in CMR, a sarcoid specific tracer in PET, integrated positron emission tomography/MRI scanners, and assessment of scar with LGE in cardiac computed tomography. Isolated cardiac sarcoidosis is an increasingly recognized phenotype, but still an enormous challenge in clinical practice. The prognostic value of (and extent of) LGE-CMR should be taken into account for risk assessment and internal cardiac defbrillator therapy, even in patients with preserved left ventricular function. Unfortunately, randomized controlled trials to guide immunosuppressive therapy are still lacking. A multidisciplinary approach to diagnose and treat cardiac sarcoidosis patients in specialized centers is strongly recommendable. SUMMARY: Cardiac sarcoidosis is increasingly recognized because of improved imaging techniques; however, treatment of cardiac sarcoidosis is still mainly based on expert opinion. PMID- 28661905 TI - Genetics of pulmonary hypertension in the clinic. AB - PURPOSE OF REVIEW: Heritable pulmonary arterial hypertension (PAH) is an autosomal dominant disease with incomplete penetrance because of mutations in bone morphogenetic protein receptor-II (BMPR2), activin A receptor type II-like kinase 1, endoglin, caveolin-1, potassium channel subfamily K, member 3, and T box gene 4 genes. Heritable pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH) is an autosomal recessive disease because of biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene. The 2015 european society of cardiology (ESC) and european respiratory society (ERS) pulmonary hypertension guidelines recommend genetic counselling and testing to adults and children with PAH or PVOD/PCH as well as in adult relatives at risk of carrying a predisposing mutation. RECENT FINDINGS: In France, genetic counseling and testing are offered to all patients displaying sporadic or familial form of PAH or PVOD/PCH and to their relatives at high risk of carrying a predisposing mutation. Patients with a heritable form of PAH are younger at diagnosis with a worse hemodynamic and a dismal prognosis. Patients with a heritable form of PVOD/PCH are younger at diagnosis with a worse response to specific PAH therapies. A program to detect PAH in an early phase was offered to all asymptomatic BMPR2 mutation carriers, according to the 2015 ESC/ERS guidelines. Finally, preimplantation genetic diagnosis has been performed in families with a history of BMPR2 mutations. SUMMARY: Genetic counseling and testing has to be implemented in pulmonary hypertension centers. PMID- 28661906 TI - Mental health promotion: a narrative review of emerging trends. AB - PURPOSE OF REVIEW: The current review aims to provide an update on the recent work in mental health promotion with a special emphasis on emerging evidence and innovations in the field. RECENT FINDINGS: Studies reviewed across settings like the home, school, workplace, communities, and internet-based platforms, have indicated a growing evidence base for effective mental health promotion strategies that are holistic, multicomponent, and targeted at both, specific vulnerable groups and whole populations. Innovative approaches involving online delivery platforms, sports and exercise, positive psychology and lifestyle interventions, mobilizing community networks, and mental health first aid, are some exciting and upcoming areas for future research. SUMMARY: Mental health promotion interventions are applicable to individuals, groups, and whole populations and can be delivered in many ways, including media and communication technology. They can be applied in low-resource settings by mobilizing existing community resources like opinion leaders, health workers, and peer educators, thereby increasing cost-efficiency, cultural acceptability, and local capacity. There needs to be a greater focus on study designs and variable measures that examine process-factors affecting well being outcomes. Early interventions through intersectorial collaborations may result in improved long-term positive mental health outcomes for individuals, families, and communities. PMID- 28661907 TI - Behavioural interventions for life style diseases: where are we now? PMID- 28661909 TI - Increased Risk of Bleeding in Left Ventricular Assist Device Patients Treated with Enoxaparin as Bridge to Therapeutic International Normalized Ratio. AB - Anticoagulation therapy is used to prevent thromboembolic events in patients with left ventricular assist devices (LVADs). This study aims to determine the safety of low molecular weight heparin (enoxaparin) for bridging subtherapeutic international normalized ratio (INR) in LVAD patients. In this retrospective single-center study, all patients who underwent LVAD implantation were examined between January 1, 2013, and December 31, 2014. Patients were divided into two groups: enoxaparin bridge and no bridge, with identification of major bleeding episodes (MBEs) and thrombotic events (TEs). Major bleeding episode and TE incidence was compared between the two groups, with subanalysis of incidence in the enoxaparin group between the periods on and off treatment. One hundred eighteen patients were included in this analysis. Fifty-five patients received enoxaparin, whereas 63 patients did not receive enoxaparin, with no significant difference between groups in all baseline characteristics. For the study period, enoxaparin patients had no increased incidence of MBEs (0.53 vs. 0.35 MBE per year; p = 0.12). However, there was a fourfold increase in MBEs during the bridged period in the enoxaparin group (2.02 vs. 0.45 MBE per year; p = 0.03). Major bleeding episodes on versus off enoxaparin had no major difference in transfusion requirements (2.7 +/- 2.9 vs. 2.5 +/- 3.4 units; p = 0.57) or mortality (p = 0.11). The enoxaparin group trended to a higher incidence of TEs (0.20 vs. 0.11 events per year; p = 0.08). Enoxaparin bridging in patients with subtherapeutic INR is associated with a significantly increased risk of MBEs. Prospective studies are needed to confirm these findings; however, until then, caution should be used with enoxaparin for bridging in LVAD patients. PMID- 28661908 TI - Associations Between Hormonal Biomarkers and Cognitive, Motor, and Language Developmental Status in Very Low Birth Weight Infants. AB - BACKGROUND: Male infants are more prone to health problems and developmental delays than female infants. OBJECTIVES: On the basis of theories of gender differences in brain development and social relationships, we explored associations between testosterone and cortisol levels with infant cognitive, motor, and language development ("infant development") in very low birth weight (VLBW) infants, controlling for mother-infant interactions, characteristics of mothers and infants, and days of saliva collection after birth. METHODS: A total of 62 mother-VLBW infant pairs were recruited from the newborn intensive care unit of a tertiary medical center in the Southeast United States. Data were collected through infant medical record review, biochemical measurement, observation of mother-infant interactions, and standard questionnaires. Infant development was assessed at 6 months corrected age (CA), and mother-infant interactions were observed at 3 and 6 months CA. RESULTS: General linear regression with separate analyses for each infant gender showed that high testosterone levels were positively associated with language development of male infants after controlling for mother-infant interactions and other covariates, whereas high cortisol levels were negatively associated with motor development of female infants after controlling for mother-infant interactions. CONCLUSIONS: Steroid hormonal levels may well be more fundamental factors for assessing infant development than infant gender or mother-infant interactions at 6 months CA. PMID- 28661911 TI - Pump in Parallel-Mechanical Assistance of Partial Cavopulmonary Circulation Using a Conventional Ventricular Assist Device. AB - Mechanical assistance of systemic single ventricle is effective in pulling blood through a cavopulmonary circuit. In patients with superior cavopulmonary connection, this strategy can lead to arterial desaturation secondary to increased inferior caval flow. We hypothesized that overall augmentation in cardiac output with mechanical assistance compensates for the drop in oxygen saturation thereby maintaining tissue oxygen delivery (DO2). Bidirectional Glenn (BDG) was established in seven swine (25 kg) after a common atrium had been established by balloon septostomy. Mechanical circulatory assistance of the single ventricle was achieved using an axial flow pump with ventricular inflow and aortic outflow. Cardiac output, mean pulmonary artery pressure (PAP), common atrial pressure (left atrial pressure [LAP]), arterial oxygen saturation (SaO2), partial pressure of arterial oxygen (PaO2), and DO2 were compared between assisted and nonassisted circulation. Significant augmentation of cardiac output was achieved with mechanical assistance in BDG circulation (BDG: median [interquartile range {IQR}], 0.8 [0.9-1.15] L/min versus assisted BDG: median [IQR], 1.5 [1.15-1.7] L/min; p = 0.05). Although oxygen saturations and PaO2 trended to be lower with assistance (SaO2; BDG: median [IQR], 43% [32-57%]; assisted BDG: median [IQR], 32% [24-35%]; p = 0.07) (PaO2; BDG: median [IQR], 24 [20-30] mm Hg; assisted BDG: median [IQR], 20 [17-21] mm Hg; p = 0.08), DO2 was unchanged with mechanical assistance (BDG: median [IQR], 94 [35-99] ml/min; assisted BDG: median [IQR], 79 [63-85] ml/min; p = 0.81). No significant change in the LAP or PAP was observed. In the setting of superior cavopulmonary connection/single ventricle, the systemic ventricular assistance with a ventricular assist device (VAD) leads to increase in cardiac output. Arterial oxygen saturations however may be lower with mechanical assistance, without any change in DO2. PMID- 28661910 TI - Determination of Reynolds Shear Stress Level for Hemolysis. AB - Reynolds shear stress (RSS) has served as a metric for the effect of turbulence on hemolysis. Forstrom (1969) and Sallam and Hwang (1984) determined the RSS threshold for hemolysis to be 50,000 and 4,000 dyne/cm, respectively, using a turbulent jet. Despite the order of magnitude discrepancy, the threshold by Sallam and Hwang has been frequently cited for hemolytic potential in blood pumps. We recreated a Sallam apparatus (SA) to resolve this discrepancy and provide additional data to be used in developing a more accurate hemolysis model. Hemolysis was measured over a large range of Reynolds numbers (Re) (Re = 1,000 80,000). Washed bovine red blood cells (RBCs) were injected into the free jet of phosphate buffered saline, and hemolysis was quantified using a percent hemolysis, Hp = h (100 - hematocrit [HCT])/Hb, where h (mg/dl) is free hemoglobin and Hb (mg/dl) is total hemoglobin. Reynolds shear stress was calculated using two-dimensional laser Doppler velocimetry. Reynolds shear stress of >=30,000 dyne/cm corresponding to Re of >=60,000 appeared to cause hemolysis (p < 0.05). This RSS is an order of magnitude greater than the RSS threshold that Sallam and Hwang suggested, and it is similar to Forstrom's RSS threshold. This study resolved a long-standing uncertainty regarding the critical values of RSS for hemolysis and may provide a foundation for a more accurate hemolysis model. PMID- 28661913 TI - Soluble endothelial cell molecules and circulating endothelial cells in patients with venous thromboembolism. AB - : To evaluate the plasma levels of soluble endothelial cell molecules in patients with venous thromboembolism (VTE) out of the acute phase as compared with healthy individuals. We also investigated the possible associations of the soluble endothelial cell molecules among them, as well as with other clinical and laboratory data, including the numbers of circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP), and CEC expressing activation related [cluster of differentiation (CD)54 and CD62E] and procoagulant (CD142) markers. In total, 15 patients with VTE and 20 normal individuals were studied. The CEC and CEP were quantified and characterized by flow cytometry. The soluble molecules studied included P-selectin, E-selectin, intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1 and tissue factor (ELISA), and von Willebrand factor antigen (immunoturbidimetry). VTE patients had significantly higher levels of vascular cell adhesion molecule 1 and von Willebrand factor antigen and lower levels of soluble E-selectin than controls. They also showed significantly higher numbers of CEC, as of activated/procoagulant CEC and lower numbers of CEP, compared with controls. We did not find any correlation between the levels of soluble molecules and the numbers of endothelial cell in circulation, but there was with several clinical and laboratory data in VTE patients. Our results would suggest that in VTE patients, the endothelium remains activated and in some hypercoagulable state. The levels of soluble endothelial cell molecules did not seem to be directly related to the numbers of CEC and CEP neither reflected the number of activated CEC, which may be because of the different function that surface and soluble molecules may have. PMID- 28661912 TI - Favorable Effects on Pulmonary Vascular Hemodynamics with Continuous-Flow Left Ventricular Assist Devices Are Sustained 5 Years After Heart Transplantation. AB - It is unclear whether pulmonary hemodynamics improvement with left ventricle unloading with left ventricular assist devices (LVADs) is sustained long term after heart transplant (HT). We sought to assess the effects on pulmonary vascular hemodynamics during continuous-flow (CF-LVAD) and pulsatile flow (PF LVAD) support up to 5 years after HT. Invasive hemodynamics were evaluated before LVAD, before HT, and at 3 months, 1, and 3-5 years posttransplant. Thirty-eight patients were included in the study and divided into two groups according to the type of LVAD support. The two groups were well matched in age and gender. Mean pulmonary artery pressure (PAPm) and systolic PAP (PAPs) improved significantly in the PF-LVAD group (40 +/- 10.6 to 19.8 +/- 4.4 mm Hg and 62.7 +/- 14.9 to 31.8 +/- 5.9 mm Hg, respectively) and in the CF-LVAD group (37.4 +/- 11.6 to 22.4 +/- 7.7 mm Hg and 53.7 +/- 18.0 to 34.6 +/- 11.8 mm Hg, respectively). Reductions in PAPm and PAPs were more pronounced in PF-LVAD group than in CF-LVAD group (p = 0.005 and p = 0.03, respectively). After HT, the improvement in PAPm and PAPs was sustained after 3-5 years in patients who received PF-LVAD (22.6 +/- 6.5 and 32.2 +/- 9.2 mm Hg, respectively) and in patients who received CF-LVAD (22.2 +/- 8.4 and 33.8 +/- 9.6 mm Hg, respectively). In conclusion, long-term LVAD support resulted in significant improvement in PAPm and PAPs regardless of the pump generation. The improvement in hemodynamics observed during LVAD support was sustained 3-5 years posttransplant. PMID- 28661914 TI - Exploration of Two Training Paradigms Using Forced Induced Weight Shifting With the Tethered Pelvic Assist Device to Reduce Asymmetry in Individuals After Stroke: Case Reports. AB - Many robotic devices in rehabilitation incorporate an assist-as-needed haptic guidance paradigm to promote training. This error reduction model, while beneficial for skill acquisition, could be detrimental for long-term retention. Error augmentation (EA) models have been explored as alternatives. A robotic Tethered Pelvic Assist Device has been developed to study force application to the pelvis on gait and was used here to induce weight shift onto the paretic (error reduction) or nonparetic (error augmentation) limb during treadmill training. The purpose of these case reports is to examine effects of training with these two paradigms to reduce load force asymmetry during gait in two individuals after stroke (>6 mos). Participants presented with baseline gait asymmetry, although independent community ambulators. Participants underwent 1-hr trainings for 3 days using either the error reduction or error augmentation model. Outcomes included the Borg rating of perceived exertion scale for treatment tolerance and measures of force and stance symmetry. Both participants tolerated training. Force symmetry (measured on treadmill) improved from pretraining to posttraining (36.58% and 14.64% gains), however, with limited transfer to overground gait measures (stance symmetry gains of 9.74% and 16.21%). Training with the Tethered Pelvic Assist Device device proved feasible to improve force symmetry on the treadmill irrespective of training model. Future work should consider methods to increase transfer to overground gait. PMID- 28661915 TI - Endocrine dysfunction following immune checkpoint inhibitor therapy. AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) represent an important milestone in the modern era of antineoplastic therapy and have ushered optimism amongst oncologists and patients alike. These agents, however, are associated with significant potential toxicities, the importance of which cannot be overstated. The clinical presentation, diagnosis, and management strategies of immune-related endocrinopathies associated with ICI use are described in this case-based review. RECENT FINDINGS: An increasing number of ICI have shown promise in the management of various malignancies in the recent years. These include cytotoxic T lymphocyte antigen-4 inhibitors, programmed cell death 1 (PD 1) antibodies, and PD-ligand 1 (PD-L1) antibodies. Several endocrinopathies, including hypophysitis, thyroid dysfunction, hyperglycemia, and primary adrenal insufficiency, have been associated with the use of these agents. Toxicities may range from mild transient laboratory abnormalities to potentially life threatening ones, warranting immediate therapeutic intervention. Combination ICI therapies may be associated with a greater risk of endocrine dysfunction when compared with monotherapy. The clinical presentation and laboratory assessment of these patients often pose a diagnostic challenge as they may be confused by the symptoms related to their underlying malignancy or potential associated acute illnesses. SUMMARY: ICI use is associated with serious endocrinopathies that may have a nonspecific initial presentation. A constant eye for these symptoms and a systematic approach to diagnosis are essential for prompt initiation of therapy and prevention of significant complications. PMID- 28661916 TI - In Response. PMID- 28661917 TI - In Response. PMID- 28661918 TI - Continuous Versus Bolus Local Anesthetic Administration in Peripheral Nerve Blocks: Time to Relook. PMID- 28661919 TI - In Response. PMID- 28661920 TI - Is Etomidate Sedation Associated With Excess Mortality in Intensive Care Unit Patients? What Is the Evidence? PMID- 28661921 TI - Fragmented Sleep Enhances Postoperative Neuroinflammation but Not Cognitive Dysfunction: Really? PMID- 28661922 TI - Predicting Difficult Laryngoscopy: Truly Complicated! PMID- 28661924 TI - Dryness at Fingertips: Is It a Premonitory Sign of Skin Peeling in Kawasaki Disease? PMID- 28661923 TI - In Response. PMID- 28661925 TI - Without Headache: Fever of Unknown Cause Due to Giant Cell Arteritis. PMID- 28661926 TI - The Discriminative Values of the Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity Score, C-Reactive Protein, and Erythrocyte Sedimentation Rate in Spondyloarthritis-Related Axial Arthritis. AB - OBJECTIVES: The aims of this study were to determine the effectiveness of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP), Ankylosing Spondylitis Disease Activity Score-Erythrocyte Sedimentation Rate (ASDAS-ESR), and inflammatory markers in screening for axial-joint inflammation as detected by magnetic resonance imaging (MRI) and to find out factors that could affect scoring of the indices. METHODS: One hundred fifty-three Chinese spondyloarthritis patients were recruited. Clinical data and BASDAI were collected, and Bath Ankylosing Spondylitis Metrology Index was measured. Serum ESR and CRP were checked, and ASDAS-ESR and ASDAS-CRP were calculated. Radiographs of cervical and lumbar spine were performed for modified Stoke Ankylosing Spondylitis Spinal Score. All patients underwent MRI of the spine and sacroiliac joints. Axial-joint inflammation was evaluated by Spondyloarthritis Research Consortium of Canada MRI indices. Multivariate linear regressions were used to determine potential factors that could affect disease activity indices. Receiver operating characteristic curve was used to determine the effectiveness in screening for axial-joint inflammation. RESULTS: BASDAI was associated with current back pain (B = 0.89, P = 0.01), ASDAS-CRP with current back pain (B = 0.74, P = 0.04), and current dactylitis (B = 0.70, P = 0.03) ASDAS-ESR with current back pain (B = 0.95, P = 0.01), and current dactylitis (B = 0.99, 0.002). The ROC curve revealed that CRP was the only variable that successfully discriminated spondyloarthritis patients with and without axial-joint inflammation by MRI, although it had poor accuracy (area under the curve, 0.63; 95% confident interval, 0.53-0.72; P = 0.01). CONCLUSIONS: Based on our results, MRI could be used to supplement traditional disease assessment tools for more accurate disease evaluation. PMID- 28661927 TI - Koebner Phenomenon in a Young Boy With Henoch-Schonlein Purpura. PMID- 28661928 TI - Ergotism Masquerading Systemic Vasculitis. PMID- 28661929 TI - In Response to: Hamstring-and-Lower-Back Flexibility in Male Amateur Soccer Players. PMID- 28661930 TI - Simultaneous Versus Sequential Ptosis and Strabismus Surgery in Children. AB - PURPOSE: The authors sought to compare the clinical outcomes of simultaneous versus sequential ptosis and strabismus surgery in children. METHODS: Retrospective, single-center cohort study of children requiring both ptosis and strabismus surgery on the same eye. Simultaneous surgeries were performed during a single anesthetic event; sequential surgeries were performed at least 7 weeks apart. Outcomes were ptosis surgery success (margin reflex distance 1 >= 2 mm, good eyelid contour, and good eyelid crease); strabismus surgery success (ocular alignment within 10 prism diopters of orthophoria and/or improved head position); surgical complications; and reoperations. RESULTS: Fifty-six children were studied, 38 had simultaneous surgery and 18 sequential. Strabismus surgery was performed first in 38/38 simultaneous and 6/18 sequential cases. Mean age at first surgery was 64 months, with mean follow up 27 months. A total of 75% of children had congenital ptosis; 64% had comitant strabismus. A majority of ptosis surgeries were frontalis sling (59%) or Fasanella-Servat (30%) procedures. There were no significant differences between simultaneous and sequential groups with regards to surgical success rates, complications, or reoperations (all p > 0.28). CONCLUSIONS: In the first comparative study of simultaneous versus sequential ptosis and strabismus surgery, no advantage for sequential surgery was seen. Despite a theoretical risk of postoperative eyelid malposition or complications when surgeries were performed in a combined manner, the rate of such outcomes was not increased with simultaneous surgeries. Performing ptosis and strabismus surgery together appears to be clinically effective and safe, and reduces anesthesia exposure during childhood. PMID- 28661931 TI - Splicing regulators in endothelial cell differentiation. AB - AIMS: Alternative splicing represents a key mechanism of gene regulation. Despite its role in regulating cell pluripotency and differentiation being well known, the underlining mechanisms are still poorly studied. Here, we investigated the possible involvement of splicing regulators during the different steps of endothelial cell differentiation through expression studies on human circulating progenitors. METHODS: Total RNAs were extracted from all cells and reverse transcribed. Semiquantitative and real-time RT-PCR was performed using selective oligonucleotides. Differences between group means were considered significant at P value less than 0.05 and more significant at P value less than 0.01. Protein extracts were incubated with an antibody directed against MED23. Immunoprecipitation of supernatants and pellets was probed with both anti Muscleblind-like splicing regulator (MBNL)1 and anti-MBNL2 antibodies. RESULTS: Several clinical trials demonstrated the safety and efficacy of progenitor cells in regenerative therapy of the cardiovascular system. Particularly, we analyzed the expression of genes belonging to muscleblind family members and MED complex subunits, which are known to be involved during differentiation in other models. This study shows that MED23, MBNL1 and MBNL2 were all expressed at high levels only in differentiated cells. Moreover, immunoprecipitation assays indicated that MED23 is able to bind MBNLs in endothelial cells. CONCLUSION: Our data suggest that MED23, MBNL1 and MBNL2 could regulate alternative splicing events activated during differentiation through a common mechanism. Hence, these observations corroborate previous evidence that splicing regulators may have an essential role in the basic apparatus required for cell pluripotency and reprogramming, allowing identification of novel biomarkers to use for early diagnosis in cardiovascular diseases. PMID- 28661932 TI - The role of echocardiography in the assessment of an iatrogenic coronary fistula. PMID- 28661933 TI - PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. AB - During sepsis, systemic inflammation is observed and is associated with multiple organ failure. Activation of NF-kappaB is crucial for inducing inflammation, which is controlled by degradation of inhibitor molecules (IkappaB). The ubiquitination proteasome pathway is responsible for the regulation of protein turnover. In this study, we hypothesized that administration of 4[4-(5-nitro furan-2-ylmethylene)-3, -dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR 41), an inhibitor of ubiquitination, could reduce inflammation and organ injury in septic mice. PYR-41 prevented the reduction of IkappaB protein levels and inhibited release of tumor necrosis factor (TNF)-alpha in mouse macrophage RAW264.7 cells at 4 h after lipopolysaccharide stimulation dose-dependently. Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. PYR-41 (5 mg/kg) or dimethyl sulfoxide in saline (vehicle) was injected intravenously immediately after CLP. At 20 h after CLP, PYR-41 treatment significantly decreased serum levels of proinflammatory cytokines (TNF-alpha, interleukin [IL]-1beta, and IL-6) and organ injury markers (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). PYR-41 significantly improved microscopic structure, and reduced myeloperoxidase activity, number of apoptotic cells and caspase-3 degradation in the lungs of septic mice. The reduced protein levels of IkappaB in the lungs after CLP were restored by PYR-41 treatment. PYR-41 inhibited the expression of cytokines (IL 1beta and IL-6), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and inflammatory mediators (cyclooxygenase-2 and inducible nitric oxide synthase) in the lungs of septic mice. Importantly, PYR-41 significantly increased 10-day survival in septic mice from 42% to 83%. Therefore, targeting ubiquitination by PYR-41 to inhibit NF-kappaB activation may represent a potential strategy of sepsis therapeutics. PMID- 28661934 TI - Associations Among Posttraumatic Stress Disorder Symptoms, Substance Use, and Affective Attentional Processing in OEF/OIF/OND Veterans. AB - The majority of research examining affective attentional bias in posttraumatic stress disorder (PTSD) has not examined the influence of co-occurring psychiatric disorders. This study examined the individual and interactive effects of PTSD symptoms and substance use disorders (SUDs) on affective attentional processing among 323 veterans deployed to Iraq or Afghanistan. Participants were divided into those with SUD (SUD+, n = 46) and those without (SUD-, n = 277). Substance use disorder was determined using the Structured Clinical Interview for DSM-IV. Posttraumatic stress disorder was measured using the Clinician Administered PTSD Scale. A computerized go/no-go task (Robbins et al., 1994, Robbins et al.,1998) assessed affective attentional processing. Relative to those without SUD, those with SUD showed a significant association between PTSD symptoms and increased omission and commission accuracy rates and decreased d prime. No effects of valence were found. Findings suggest the need to consider co-occurring SUD when investigating the effects of PTSD on attentional control. PMID- 28661935 TI - Musculoskeletal manifestations of systemic lupus erythmatosus. AB - PURPOSE OF REVIEW: Imaging studies suggest potential changes to the classification and assessment of inflammatory musculoskeletal lupus. This is important because of the burden of disease but the potential for new targeted therapies. RECENT FINDINGS: Using our current classification and treatment, musculoskeletal symptoms continue to impact significantly on quality of life and work disability. Ultrasound and MRI studies suggested that new approaches to the diagnosis, classification, and evaluation of these symptoms are needed. Many patients with pain but no synovitis have ultrasound-proven joint and tendon inflammation but would not qualify for clinical trials or score highly on disease activity instruments. MRI studies show that erosions are more common than previously thought and may have a different pathogenesis than RA. Immunology studies suggest differences from other autoimmune synovitis, with a complex role for type I interferons. A wide range of biologic therapies appear more consistently effective for arthritis than some other manifestations. SUMMARY: Changes to the selection of patients for therapy and stratification using musculoskeletal imaging may offer new approaches to clinical trials and the routine care of systemic lupus erythematosus patients with inflammatory musculoskeletal symptoms. Outcomes may thereby be improved using existing therapies. There are significant knowledge gaps that must be addressed to achieve these potential improved outcomes. PMID- 28661936 TI - Revisiting the role of steroids and aspirin in the management of acute Kawasaki disease. AB - PURPOSE OF REVIEW: Kawasaki disease is an acute multisystem childhood vasculitis with a predilection for the coronary arteries. The role of corticosteroids and acetyl salicylic acid (ASA) in the treatment of acute Kawasaki disease are matters of ongoing debate and changing attitudes from one extreme to the other. Recent work has provided new evidence to guide our thinking about these two therapeutic agents, which will be the focus of this review. RECENT FINDINGS: Corticosteroids are effective and well tolerated in Kawasaki disease, both as initial adjunctive treatment in those at high-risk for poor outcome, and as rescue therapy after failed intravenous immunoglobulin (IVIG).Higher doses of ASA (> 30 mg/kg/day) in the acute phase of Kawasaki disease, have no clear benefit over antiplatelet doses in improving coronary outcome. SUMMARY: Corticosteroids should be used in patients at high-risk for poor coronary outcome, and in patients who fail IVIG. The absence of widely applicable and validated risk scoring systems in Kawasaki disease outside of Japan remains a limiting factor to identify high-risk children. Current evidence does not demonstrate any advantage of high-dose over low-dose ASA in the acute phase of Kawasaki disease, in preventing coronary artery aneurysms. PMID- 28661937 TI - Ambient Temperature and Sudden Infant Death Syndrome in the United States. AB - BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear. METHODS: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time stratified case-crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate. RESULTS: There were a total of 60,364 SIDS cases during our study period. A 5.6 degrees C (10 degrees F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6% (95% confidence interval [CI] = 3.6%, 13.8%) in the summer, compared with a 3.1% decrease (95% CI = -5.0%, 1.3%) in the winter. Summer risks were greater among black infants (18.5%; 95% CI = 9.3%, 28.5%) than white infants (3.6%; 95% CI = -2.3%, 9.9%), and among infants 3-11 months old (16.9%; 95% CI = 8.9%, 25.5%) than infants 0-2 months old (2.7%; 95% CI = -3.5%, 9.2%). The temperature-SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions. CONCLUSIONS: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions. PMID- 28661938 TI - Age at Pubertal Onset in Girls and Tobacco Smoke Exposure During Pre- and Postnatal Susceptibility Windows. AB - BACKGROUND: Tobacco smoke contains known hormonally active chemicals and reproductive toxicants. Several studies have examined prenatal maternal smoking and offspring age at menarche, but few examined earlier pubertal markers, nor accounted for exposure during childhood. Our objective was to examine pre- and postnatal smoke exposure in relation to timing of early pubertal events. METHODS: An ethnically diverse cohort of 1239 girls was enrolled at age 6-8 years old for a longitudinal study of puberty at three US sites. Girls participated in annual or semi-annual exams to measure anthropometry and Tanner breast and pubic hair stages. Prenatal and current tobacco smoke exposures, as well as covariates, were obtained from parent questionnaire. Cotinine was measured in urine collected at enrollment. Using accelerated failure time models, we calculated adjusted time ratios for age at pubertal onset (maturation stages 2 or higher) and smoke exposure. RESULTS: Girls with higher prenatal (>=5 cigarettes per day) or secondhand smoke exposure had earlier pubic hair development than unexposed (adjusted time ratio: 0.92 [95% CI = 0.87, 0.97] and 0.94 [95% CI = 0.90, 0.97], respectively). Including both exposures in the same model yielded similar associations. Higher urinary cotinine quartiles were associated with younger age at breast and pubic hair onset in unadjusted models, but not after adjustment. CONCLUSIONS: Greater prenatal and childhood secondhand smoke exposure were associated with earlier onset of pubic hair, but not breast, development. These exposures represent modifiable risk factors for early pubertal development that should be considered for addition to the extensive list of adverse effects from tobacco smoke. PMID- 28661939 TI - Interactions of beta-amyloid peptide with fibrinogen and coagulation factor XII may contribute to Alzheimer's disease. AB - PURPOSE OF REVIEW: To review the evidence that the Alzheimer peptide beta-amyloid interacts with the blood coagulation system and influences the pathophysiology of the disease. RECENT FINDINGS: beta-amyloid can interact with fibrinogen and blood coagulation factor XII and trigger ischemia and inflammation. SUMMARY: beta amyloid interacts with fibrinogen and factor XII. These interactions can lead to increased clotting, abnormal clot formation, persistent fibrin deposition, and generation of proinflammatory molecules. These events can damage neurons and could contribute to the cognitive decline in Alzheimer's disease patients. PMID- 28661941 TI - What Will You Do When Your Turn Comes? PMID- 28661940 TI - Brain Structure and Response to Emotional Stimuli as Related to Gut Microbial Profiles in Healthy Women. AB - OBJECTIVE: Brain-gut-microbiota interactions may play an important role in human health and behavior. Although rodent models have demonstrated effects of the gut microbiota on emotional, nociceptive, and social behaviors, there is little translational human evidence to date. In this study, we identify brain and behavioral characteristics of healthy women clustered by gut microbiota profiles. METHODS: Forty women supplied fecal samples for 16S rRNA profiling. Microbial clusters were identified using Partitioning Around Medoids. Functional magnetic resonance imaging was acquired. Microbiota-based group differences were analyzed in response to affective images. Structural and diffusion tensor imaging provided gray matter metrics (volume, cortical thickness, mean curvature, surface area) as well as fiber density between regions. A sparse Partial Least Square Discrimination Analysis was applied to discriminate microbiota clusters using white and gray matter metrics. RESULTS: Two bacterial genus-based clusters were identified, one with greater Bacteroides abundance (n = 33) and one with greater Prevotella abundance (n = 7). The Prevotella group showed less hippocampal activity viewing negative valences images. White and gray matter imaging discriminated the two clusters, with accuracy of 66.7% and 87.2%, respectively. The Prevotella cluster was associated with differences in emotional, attentional, and sensory processing regions. For gray matter, the Bacteroides cluster showed greater prominence in the cerebellum, frontal regions, and the hippocampus. CONCLUSIONS: These results support the concept of brain-gut-microbiota interactions in healthy humans. Further examination of the interaction between gut microbes, brain, and affect in humans is needed to inform preclinical reports that microbial modulation may affect mood and behavior. PMID- 28661942 TI - Nursing Management of Lumbar Drainage in Cryptococcal Meningitis: A Case Report. AB - Raised intracranial pressure is a hallmark of cryptococcal meningitis and is associated with increased mortality. Continuous drainage of lumbar cerebrospinal fluid is suggested to control intracranial pressure. The complications induced by this treatment have been described. However, nursing care associated with identification and management of complications is less well known. We encountered a patient with human immunodeficiency virus-negative cryptococcal meningitis who developed increasing cerebrospinal fluid pressure, hearing impairment, and limb weakness. The patient's symptoms improved significantly by antifungal therapy and continuous lumbar drainage. Nurses play a vital role in monitoring patients with lumbar drainage for complications and to maintain integrity of the system. The nursing role in this approach is discussed with particular emphasis on recognition of complications and responses toward immediate emergent intervention. PMID- 28661944 TI - Internet Stroke Preparedness for African American Women. PMID- 28661943 TI - Internet Stroke Preparedness for African American Women. AB - BACKGROUND: African American women exhibit low stroke awareness and may benefit from experiential and lay language description of stroke symptoms. OBJECTIVES: The purpose of this pilot study was to examine the effect of an online stroke preparedness intervention for identification of stroke symptoms and appropriate action in response to suspected stroke and estimate effect sizes for a larger study. METHODS: A quasi-experimental nonequivalent comparison group design was used to randomized 44 women to intervention (n = 23) or wait-list control group (n = 21). Data were analyzed with Friedman and Wilcoxon signed rank tests and Cochran-Mantel-Haenszel statistics to examine intervention effect on (1) self efficacy to recognize stroke and know what to do in the event of stroke, (2) awareness of stroke symptoms, and (3) behavioral intent to call 911 for suspected stroke. Effect size estimates were calculated by converting z scores to r. RESULTS: Significant intervention effect was found for self-efficacy to know what to do in the event of stroke, ability to identify stroke symptoms presented in written vignettes, and ability to identify correct action in response to symptoms presented in written vignettes. Small to medium effect sizes were obtained. No improvement was found for ability to name stroke symptoms. Behavioral intent to call 911 for stroke in someone else was high, but significantly fewer women would call 911 for themselves. CONCLUSIONS: Experiential depictions of stroke symptoms in an online format showed preliminary effectiveness to improve stroke awareness among African American women. PMID- 28661945 TI - Effect of Visual Art School-Based Stroke Intervention for Middle School Students. AB - BACKGROUND: Community stroke awareness initiatives have traditionally been used to expand knowledge of stroke signs and risk factors to high-risk adult populations. Here, we use a novel unfettered, visual art-based approach for an elementary school initiative to raise stroke awareness. METHODS: Seventh graders in a middle school art class received stroke awareness training during the course of the 2015 to 2016 school year through their teacher in the visual arts class. In turn, they used this training to develop their own artistic interpretations of key stroke awareness concepts via project-based learning and then present their projects to raise awareness about stroke. We evaluated our predata and postdata to determine whether the visual art school-based stroke intervention was effective in both educating students about stroke and enabling them to effectively disseminate this information to parents and other adults in their community. RESULTS: The pretest evaluation indicates a fair or good knowledge about stroke, and no student indicated an "outstanding" or "excellent" knowledge. The posttest evaluation indicated a higher degree of stroke awareness because students were rated as having an "outstanding," "excellent," or "very good" performance especially in the ability to translate knowledge of stroke awareness lessons learned in their art class into a well-articulated stroke-related project and presentation. Pearson chi test reveals significant difference (P < .001) between the pretest and posttest evaluations. CONCLUSIONS: Our results indicate that our school-based stroke intervention was effective in both educating students about stroke and enabling them to effectively disseminate this information to parents and other adults in their community. The use of a visual art teacher to lead the educational component in the intervention indicates that expertise in neurology or stroke is not necessary to facilitate understanding of stroke and highlights the importance of creativeness in stroke education for children. PMID- 28661946 TI - Correlations Between Hourly Pupillometer Readings and Intracranial Pressure Values. AB - INTRODUCTION: Automated pupillometry is emerging as a mainstay in neurocritical care primarily because it overcomes limitations of manual pupillary examinations. Although several recent studies show improved assessment accuracy with a pupillometer, few investigate clinical use, specifically how well parameters correlate with multimodality monitoring and outcomes. The primary aim of this study was to examine correlations between serial pupillometer readings and intracranial pressure (ICP) values among neurocritically ill patients. DESIGN: Prospective cohort, repeated measures. SAMPLE: The study sample was composed of adult patients with neurological injury who were admitted to intensive care unit, requiring hourly neurological assessment and pupillary checks within a level I trauma, urban, academic medical center. PROCEDURES: Hourly pupillometer readings and corresponding ICP values were consecutively recorded for 72 hours after intensive care unit admission. RESULTS: Serial assessments resulted in more than 2100 pupillometer readings from 76 subjects. Mean age of the study sample was 55.4 years, with a mean Glasgow Coma Scale score of 8.9. The mean pupillometer values for the enrolled subjects included left constriction velocity of 1.22, left neurological pupil index of 4.21, left pupil size of 2.69, right constriction velocity of 1.18, right neurological pupil index of 4.18, and right pupil size of 2.57. The mean ICP of the study sample was 12, with mean cerebral perfusion pressure of 77. Pupillometer values significantly correlated with ICP values in bivariate (P < .001, r = 0.13-0.23) and multivariate regression models (F(6) = 17.63, P < .001). CONCLUSIONS: Automated pupillometry in neurocritical care is a valuable adjunct to traditional invasive monitoring. Integration of routine pupillometer assessments not only improves accuracy of examinations but also correlates with ICP values. PMID- 28661947 TI - Computer-Based Cognitive Rehabilitation Interventions for Traumatic Brain Injury: A Critical Review of the Literature. AB - BACKGROUND: Computer-based interventions have been developed to improve cognitive performance after mild traumatic brain injury; however, a thorough evaluation of this body of research has not been addressed in the literature. OBJECTIVES: The aim of this study was to provide a synthesis and critical review of current research studies that have tested the efficacy of computer-based interventions on cognitive performance after mild traumatic brain injury. METHODS: A critical review was conducted by identifying relevant studies in the electronic databases PubMed/MEDLINE, PsycInfo, and CINAHL from 2011 to the present. Because of the limited number of publications focused exclusively on mild traumatic brain injury, research studies that assessed the impact of computer-based interventions on cognitive outcomes in populations with acquired brain injury were included. RESULTS: Of the 58 studies identified, only 10 publications included participants with mild traumatic brain injury. Overall, the identified studies did not use a standard method for assessing the severity of traumatic brain injury, and many studies included participants with a wide variety of etiologies for acquired brain injury and used multiple measures of cognitive performance, which made comparisons difficult across studies. In addition to small sample sizes, the study samples were heterogeneous in regard to the number of previous traumatic brain injuries, time elapsed since injury, and age and gender distributions. Preinjury comorbidities that may affect cognitive performance, such as depression, anxiety, or learning disabilities, were often not assessed. DISCUSSION: There is weak evidence that computer-based interventions can improve working memory and cognitive function in individuals after mild traumatic brain injury. Because of the low-quality evidence, seminal questions remain regarding the optimal format, dosage, timing, and duration of computer-based intervention for improving cognitive performance. Future studies should focus on using a strong research design, such as a prospective, longitudinal, repeated-measures study, with an adequate number of participants who meet mild traumatic brain injury criteria. Preinjury comorbidities, cognitive reserve, time since injury, age, and gender should be addressed in the design because there may be differences in recovery time and mechanisms of cognitive plasticity among populations. CONCLUSIONS: Overall, computer-based interventions seem promising as an approach to improve working memory in individuals with acquired brain injury. There is no evidence that currently available interventions are specific to mild traumatic brain injury. Well-designed research studies with adequate sample sizes are needed to assess the effect of computer-based interventions on cognitive performance after mild traumatic brain injury. PMID- 28661948 TI - Continuous In-Home Symptom and Mobility Measures for Individuals With Multiple Sclerosis: A Case Presentation. AB - Gait impairment represents one of the most common and disabling symptoms of multiple sclerosis (MS). To identify which temporal or spatial parameters of gait could be used as outcome measures in interventional studies of individuals with MS with different levels of disability, we evaluated characteristics of these parameters in a case study of 3 participants with MS, using 1 case as an exemplar and the other participants as validation. A case study of an exemplar participant was conducted with a 67-year-old woman with secondary progressive MS served as exemplar, with 2 other participants (52 and 55 years old) as validation. The primary outcome measures we used were stride time, stride length, gait velocity, and daily symptoms. Stride length and velocity of gait decreased with increasing pain and fatigue. The step time was significantly longer later in the day, whereas the step length remained the same. Stride length and velocity are associated with the level of fatigue and pain, as well as the time of day. These characteristics and parameters of gait need to be considered in future studies of gait in MS, with particular attention to temporality of occurrence in persons with MS. PMID- 28661949 TI - An Overview of Stroke Infrastructure, Network, and Nursing Services in Contemporary Greece. AB - This article describes the provision of stroke services in Greece and addresses the possible effects of the hospital rotation system. Unique to Greece is a centrally administered rotation system for hospital 24-hour on-call systems in the major cities. This means that a hospital may admit new patients only during specific 24-hour periods every 3 to 5 days. All Greek city hospitals must conform to this rotation basis for emergency and scheduled admissions. Patients with stroke arrive to designated rotation on-call hospital via ambulance or taxi or by private means and are first seen in the accident and emergency department where they are given priority attention accordingly and allocated to a neurology ward, medical ward, or stroke bay if the hospital has one. Occasionally, a neurosurgical consultation is sought; the patient may be admitted directly to a neurosurgery ward. Some attempts have been made to reach a degree of specialization in stroke bays, but with only a few of these, situated only in major cities, the vast majority of patients are still admitted to neurology or medical wards. Nurses and physicians in Greece continue to strive to improve outcomes for their patients with stroke despite adverse circumstances. PMID- 28661951 TI - Correlations Between Hourly Pupillometer Readings and Intracranial Pressure Values. PMID- 28661950 TI - Establishing Normative Data for Pupillometer Assessment in Neuroscience Intensive Care: The "END-PANIC" Registry. AB - BACKGROUND: Trained medical practitioners have been assessing the pupillary light reflex for more than 2 millennia. However, the interrater reliability of the pupillary light reflex remains low. To overcome the drawbacks of a subjective interpretation of pupillary size and reactivity, automated pupillometers are becoming increasingly commonplace, but practitioners do not have adequate data from which to judge whether the numerical values provided by the pupillometer are "within reference limits." METHODS: This article details the methods used to create an extensive database of automated pupillometer readings and associated patient data (eg, intracranial pressure). DISCUSSION/CONCLUSIONS: The "Establishing Normative Data for Pupillometer Assessments in Neuroscience Intensive Care" Registry will provide a large data set of pupillary size, reactivity, and speed of contraction in a cohort of patients admitted to a neuroscience intensive care unit with a variety of conditions. Analysis of this data set will help establish normative data for pupillometer readings for neurologically impaired patients. Exploratory analysis of this data set may also provide preliminary hypothesis generating data for future prospective studies on pupillary findings and trends in acute neurological conditions. PMID- 28661952 TI - Victimization by Siblings in Children with Disability or Weight Problems. AB - OBJECTIVE: Children with a physical disability, psychological disorder, or of nonnormative weight are often targets of peer victimization. Sibling victimization, however, is more common than peer victimization, but rarely explored. We investigated linkages between sibling victimization and whether children had a physical disability, psychological disorder (i.e., internalizing disorder, attention deficit disorder/attention-deficit hyperactivity disorder), and were perceived by parents as being thinner than average or overweight. Also, we explored how the extent and kinds of sibling victimization experiences were related to these characteristics in childhood. METHODS: A US probability sample of adult caregivers of a child aged 0 to 9 (N = 780; 50% women; mean age 4.58) in 2-child households who completed a telephone interview. RESULTS: Controlling for other forms of maltreatment and individual and family characteristics, children with a physical disability and parent-perceived children who are thinner than average and children who are overweight experienced more sibling victimization. Children with an internalizing disorder experienced less sibling victimization. Sibling victimization did not differ for children with and without ADHD. Children perceived to be overweight by parents and children with a physical disability were at increased risk of experiencing more types of sibling victimization. Children with a physical disability had greater odds of being victims of property victimization by a sibling. CONCLUSION: Children with a physical disability or perceived as different from average weight are at risk for sibling victimization. Using a nationally representative sample, this is the first study to highlight the importance of screening for sibling victimization in families of children with a disability and/or nonnormative weight status. PMID- 28661953 TI - A Novel Approach to Increasing Access to Developmental-Behavioral Pediatrics Subspecialty Care. PMID- 28661954 TI - Association Between Parenting Style and Social Outcomes in Children with and Without Attention-Deficit/Hyperactivity Disorder: An 18-Month Longitudinal Study. AB - OBJECTIVE: In a community-based sample of children with attention deficit/hyperactivity disorder (ADHD) (n = 179) and non-ADHD controls (n = 212), this longitudinal study explored changes in parenting style over time; and whether parenting style prospectively predicts child functional outcomes. METHODS: Attention-deficit/hyperactivity disorder diagnosis was assessed using the Conners ADHD index and Diagnostic Interview Schedule for Children IV. Children (70.3% boys) were assessed at baseline (mean age: 7.3 yr) and after 18 months (mean age: 8.9 yr) using a range of parent- and teacher-reported measures of child socioemotional and academic functioning. Parenting style was assessed through parent-reported measures of warmth, consistency, and anger. RESULTS: At 18-month follow-up, there was a small significant decline in parenting warmth and parenting anger, and an increase in parenting consistency across groups. In the ADHD group, parenting warmth at baseline was positively related to 18-month prosocial behavior and responsibility by parent report, whereas parenting consistency predicted these child outcomes by teacher report. Parenting anger was positively associated with peer problems and negatively associated with prosocial behavior, self-control, and responsibility by parent report. Associations were similar for non-ADHD controls and all associations held after adjusting for a range of family, child, and parent factors. After additional adjustment of baseline levels of child functioning, parenting warmth and consistency continued to be associated with 18-month child outcomes. Parenting style was unrelated to emotional problems and academic competence over time. CONCLUSION: Parenting style is independently related to aspects of future social outcomes of children with ADHD. Results hold implications for parenting interventions aimed at managing ADHD-related social impairments over time. PMID- 28661955 TI - Tablet-Based Intervention for Reducing Children's Preoperative Anxiety: A Pilot Study. AB - OBJECTIVES: To examine the feasibility, acceptability, and effects of a novel tablet-based application, Story-Telling Medicine (STM), in reducing children's preoperative anxiety. METHODS: Children (N = 100) aged 7 to 13 years who were undergoing outpatient surgery were recruited from a local children's hospital. This study comprised 3 waves: Waves 1 (n = 30) and 2 (n = 30) examined feasibility, and Wave 3 (n = 40) examined the acceptability of STM and compared its effect on preoperative anxiety to Usual Care (UC). In Wave 3, children were randomly allocated to receive STM+UC or UC. A change in preoperative anxiety was measured using the Children's Perioperative Multidimensional Anxiety Scale (CPMAS) 7 to 14 days before surgery (T1), on the day of surgery (T2), and 1 month postoperatively (T3). RESULTS: Wave 1 demonstrated the feasibility of participant recruitment and data collection procedures but identified challenges with attrition at T2 and T3. Wave 2 piloted a modified protocol that addressed attrition and increased the feasibility of follow-up. In Wave 3, children in the STM+UC demonstrated greater reductions in CPMAS compared with the UC group (DeltaM = 119.90, SE = 46.36, t(27) = 2.59, p = .015; 95% confidence interval = 24.78-215.02). CONCLUSION: This pilot study provides preliminary evidence that STM is a feasible and acceptable intervention for reducing children's preoperative anxiety in a busy pediatric operative setting and supports the investigation of a full-scale randomized controlled trial. PMID- 28661956 TI - Emergent Literacy in Thai Preschoolers: A Preliminary Study. AB - OBJECTIVE: To investigate emergent literacy skills, including phonological awareness when presented with an initial phoneme-matching task and letter knowledge when presented with a letter-naming task in Thai preschoolers, and to identify key factors associated with those skills. METHODS: Four hundred twelve typically developing children in their final kindergarten year were enrolled in this study. Their emergent reading skills were measured by initial phoneme matching and letter-naming tasks. Determinant variables, such as parents' education and teachers' perception, were collected by self-report questionnaires. RESULTS: The mean score of the initial phoneme-matching task was 4.5 (45% of a total of 10 scores). The mean score of the letter-naming task without a picture representing the target letter name was 30.2 (68.6% of a total of 44 scores), which increased to 38.8 (88.2% of a total of 44 scores) in the letter-naming task when a picture representing the target letter name was provided. Both initial phoneme-matching and letter-naming abilities were associated with the mother's education and household income. Letter-naming ability was also influenced by home reading activities and gender. CONCLUSION: This was a preliminary study into emergent literacy skills of Thai preschoolers. The findings supported the importance of focusing on phonological awareness and phonics, especially in the socioeconomic disadvantaged group. PMID- 28661958 TI - Conferring Disadvantage: Behavioral and Developmental Implications for Children Growing up in the Shadow of Undocumented Immigration Status. PMID- 28661957 TI - Substance Use Among Adolescents with Attention-Deficit/Hyperactivity Disorder: Reasons for Use, Knowledge of Risks, and Provider Messaging/Education. AB - OBJECTIVE: Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for alcohol and marijuana use. This study's objective is to describe adolescents' ADHD-specific reasons for marijuana use, knowledge of ADHD specific alcohol risks, and reported subspecialty provider messaging/education regarding alcohol use among adolescents with ADHD. METHODS: Youths with ADHD aged 12 to 18 years completed a survey about alcohol and marijuana use, ADHD-specific reasons for marijuana use, knowledge of ADHD-specific alcohol risks, and reported provider messaging/education regarding alcohol use. We assessed knowledge toward substance use using descriptive statistics. We used chi and t tests to determine whether knowledge or provider messaging/education differed by sociodemographic characteristics. RESULTS: Of the 96 participants, 61.5% were male, average age was 15.7 years; 31.3% reported past-year alcohol use and 20.8% reported past-year marijuana use. The majority (65.2%) said "no/don't know" to both "Can alcohol make ADHD symptoms worse?" and "Can alcohol interfere or get in the way of the medications you take?" Older participants were more likely to correctly answer the medication question "yes." Despite most (74%) participants reporting that their provider asked about alcohol use, few youth reported that their providers gave specific messages/education that alcohol could make ADHD symptoms worse (9.4%) or interfere with ADHD medications (14.6%); older participants and past year alcohol users were more likely to have received these alcohol-specific messages. CONCLUSION: Many youth with ADHD are unaware of the risks of alcohol use in relation to ADHD and providers are not consistently discussing these risks in the context of clinical ADHD care. PMID- 28661959 TI - Family history of cardiometabolic diseases and its association with arterial stiffness in the Malmo Diet Cancer cohort. AB - OBJECTIVE: Arterial stiffening increases with age and is associated with increased cardiovascular risk. Several risk factors have been shown to predict the development of arterial stiffening; however, a positive family history (FH+) of cardiometabolic disease (CMD) and hypertension has not been extensively studied. We hypothesize that FH+ of CMD plays a significant role in the development of arterial stiffening in offspring. METHODS: We used data from the population-based Malmo Diet Cancer study (n = 3056) examined in 1992-1996 and again in 2007-2012. Several variables were analysed, including anthropometrics, carotid-femoral pulse wave velocity and FH+. The association between FH+ of CMD and arterial stiffening in the offspring was analysed with analysis of covariance in SPSS. FH+ was subdivided into three categories: family history for cardiovascular events (FH-CVEs), family history for diabetes mellitus type 2 (FH DM2) and family history for hypertension (FH-HT). The first analysis of covariance-model was adjusted for age, sex, mean arterial pressure and heart rate; the second model additionally adjusted for self-reported medical history in the offspring. RESULTS: Data indicated that FH-CVE (F = 14.64, P < 0.001), FH-DM2 (F = 18.57, P < 0.001) and FH-HT (F = 13.92, P < 0.001) all significantly increased carotid-femoral pulse wave velocity levels. The results remained when additional adjustment was made for confounders and for self-reported CMD in the index participants, respectively, for FH-CVE (F = 12.47, P < 0.001), FH-DM2 (F = 7.62, P = 0.006) as well as for FH-HT (F = 7.30, P = 0.007). CONCLUSION: These findings indicate that a FH+ of cardiometabolic conditions and hypertension affects arterial stiffness in offspring independently of haemodynamic factors and self-reported CMD in the offspring without sex differences. PMID- 28661960 TI - Longitudinal study of the influence of lung function on vascular health from adolescence to early adulthood in a British multiethnic cohort. AB - BACKGROUND: Vascular and lung function develop and decline over the life course; both predict cardiovascular events and mortality but little is known of how they develop over time. We analysed their relationship in a multiethnic cohort study to test whether lung function from early adolescence to young adulthood affected vascular indices. METHODS: 'DASH' (http://dash.sphsu.mrc.ac.uk) included 6643 children aged 11-13 years in 2003; a representative 10% sample (n = 665) participated in a pilot follow-up in 2013. Psychosocial, anthropometric, blood pressure (BP), and lung function measures were collected in both surveys; aortic pulse wave velocity (PWV) and augmentation index (AIx) were measured at aged 21 23 years. Relationships between forced expiratory volume Z-scores in 1 s (zFEV1), after global initiative-ethnic adjustments and BP, PWV, and AIx were tested in linear regression and general estimating statistical models. RESULTS: In total, 488 people with complete data were included. At 11-13 years, SBP was positively associated with zFEV1 (coefficient = 1.90, 95% confidence interval 1.11-2.68, P < 0.001); but not at 21-23 years. The 10-year increase in zFEV1 was associated with rise in SBP (1.38, 0.25-1.51, P < 0.05) in mixed effect models adjusted for age, sex, ethnicity, waist to height ratio, employment, reported racism, smoking, and alcohol use but DBP change was unrelated. In fully adjusted models, neither PWV nor central AIx were associated with zFEV1 at 11-13 years or 21-23 years (P > 0.05). CONCLUSION: Forced expiratory volume change is positively and independently associated with SBP change from adolescence to young adulthood, suggesting earlier lung function plays important roles in SBP development. Vascular indices were unrelated to lung function or its change. PMID- 28661962 TI - Brain changes associated with age-related hearing loss. AB - PURPOSE OF REVIEW: To discuss brain changes associated with age-related hearing loss (ARHL), including cognitive abilities and neuroimaging findings. This information will be helpful to hypothesize and ultimately understand how ARHL may be mechanistically related to changes in brain structure and function. It will also be helpful to guide the strength of treatment recommendations. RECENT FINDINGS: ARHL has recently been associated with cognitive impairment and dementia. This observation is present in both cross-sectional and longitudinal analyses, in diverse patient populations, and after controlling for a variety of potential confounders. Preliminary brain imaging studies show smaller brain volumes as well as white matter tract dysfunction in adults with hearing loss. SUMMARY: ARHL is related to cognitive impairment and dementia. More study is needed to determine if the association is causal, and if treatment efforts could reduce the risk of cognitive impairment and dementia. Given the low risk of treating ARHL and the potential health benefit for the aging brain, it is recommended to proactively discuss ARHL and treatment with patients. PMID- 28661961 TI - In-utero exposure to antihypertensive medication and neonatal and child health outcomes: a systematic review. AB - BACKGROUND: Although medication is generally avoided wherever possible during pregnancy, pharmacotherapy is required for the treatment of pregnancy associated hypertension, which remains a leading cause of maternal and fetal morbidity and mortality. The long-term effects to the child of in-utero exposure to antihypertensive agents remains largely unknown. OBJECTIVE: The aim of this study was to systematically review published studies on adverse outcomes to the child associated with in-utero exposure to antihypertensive medications. METHODS: OVID, Scopus, EBSCO Collections, the Cochrane Library, and Web of Science databases were searched for relevant publications published between January 1950 and October 2016 and a total of 688 potentially eligible studies were identified. RESULTS: Following review, 47 primary studies were eligible for inclusion. The Critical Appraisal Skills Programme checklist was used to assess study quality. Five studies were of excellent quality; the remainder were either mediocre or poor. Increased risk of low birth weight, low size for gestational age, preterm birth, and congenital defects following in-utero exposure to all antihypertensive agents were identified. Two studies reported an increased risk of attention deficit hyperactivity disorder following exposure to labetalol, and an increased risk of sleep disorders following exposure to methyldopa and clonidine. CONCLUSION: The current systematic review demonstrates a paucity of relevant published high-quality studies. A small number of studies suggest possible increased risk of adverse child health outcomes; however, most published studies have methodological weaknesses and/or lacked statistical power thus preventing any firm conclusions being drawn. PMID- 28661963 TI - First Cases of Severe Flaccid Paralysis Associated With Enterovirus D68 Infection in Spain, 2015-2016. AB - Enterovirus D68 was known to be the cause of mild to severe respiratory infections, but in the last few years, it has also been associated with myelitis and paralysis. This report describes the first Enterovirus D68 detections in acute flaccid paralysis cases occurring between December 2015 and March 2016 in Spain. PMID- 28661964 TI - Cerebrospinal Fluid B-lymphocyte Chemoattractant CXCL13 in the Diagnosis of Acute Lyme Neuroborreliosis in Children. AB - BACKGROUND: Current markers of Lyme neuroborreliosis (LNB) in children have insufficient sensitivity in the early stage of disease. The B-lymphocyte chemoattractant CXCL13 in the cerebrospinal fluid (CSF) may be useful in diagnosing LNB, but its specificity has not been evaluated in studies including children with clinically relevant differential diagnoses. The aim of this study was to elucidate the diagnostic value of CSF CXCL13 in children with symptoms suggestive of LNB. METHODS: Children with symptoms suggestive of LNB were included prospectively into predefined groups with a high or low likelihood of LNB based on CSF pleocytosis and the detection of Borrelia antibodies or other causative agents. CSF CXCL13 levels were compared between the groups, and receiver-operating characteristic analyses were performed to indicate optimal cutoff levels to discriminate LNB from non-LNB conditions. RESULTS: Two hundred and ten children were included. Children with confirmed LNB (n=59) and probable LNB (n=18) had higher CSF CXCL13 levels than children with possible LNB (n=7), possible peripheral LNB (n=7), non-Lyme aseptic meningitis (n=12), non-meningitis (n=91) and negative controls (n=16). Using 18 pg/mL as a cutoff level, both the sensitivity and specificity of CSF CXCL13 for LNB (confirmed and probable) were 97%. Comparing only children with LNB and non-Lyme aseptic meningitis, the sensitivity and specificity with the same cutoff level were 97% and 83%, respectively. CONCLUSION: CSF CXCL13 is a sensitive marker of LNB in children. The specificity to discriminate LNB from non-Lyme aseptic meningitis may be more moderate, suggesting that CSF CXCL13 should be used together with other variables in diagnosing LNB in children. PMID- 28661965 TI - Pyogenic Tenosynovitis in Infants: A Case Series. AB - Pyogenic tenosynovitis is an uncommon condition in children, and there are few published case reports. We present a series of 11 cases who were treated in the Geneva Children Hospital in the last 10 years. Kingella kingae was the main pathogen, and the characteristics of infection (inflammatory indices, clinical findings and severity) are similar to other osteoarticular K. kingae infections in infants. PMID- 28661966 TI - Pneumococcal Meningitis Before and After Universal Vaccination With Pneumococcal Conjugate Vaccines 7/13, Impact on Pediatric Hospitalization in Public and Nonpublic Institutions, in Uruguay. AB - This is the first study showing the impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in Latin America; a significant (63.5%) reduction in hospitalization was observed during the first 6 years after starting vaccination. A 90% reduction of pneumococcal conjugate vaccines 7/13 serotypes was observed (P < 0.0001). After vaccination, all strains were penicillin susceptible. Mortality had a reduction of 71%. PMID- 28661967 TI - Predictors of Virologic Failure on First-line Antiretroviral Therapy Among Children in a Referral Pediatric Center in Cameroon. AB - BACKGROUND: Suboptimal response to antiretroviral therapy (ART) is common among children living with HIV (CLHIV) in resource-limited settings. We sought to assess virologic failure (VF), time for switching to second-line regimens and factors associated with VF in CLHIV receiving first-line ART in Cameroon. METHODS: An observational cohort study was conducted in 375 CLHIV initiating a first-line ART and treated for >=6 months at the National Social Insurance Fund Hospital in Yaounde-Cameroon from 2009 to 2013. Using logistic regression, predictors of VF and delayed switch were assessed by univariate and multivariate analysis. P < 0.05 was considered statistically significant. RESULTS: Overall, 17% (64/375) CLHIV experienced VF on first-line ART after a median time of 28 (interquartile range: 22-38) months. After VF, median time to switching from first- to second-line ART was 20 (interquartile range: 8-24) months. In multivariate analysis, VF was associated with male gender (adjusted odds ratio: 0.36; 95% confidence interval: 0.19-0.71; P = 0.003), motherless children (adjusted odds ratio: 2.9; 95% confidence interval: 1.3-6.06; P = 0.005) and treatment with stavudine-containing compared with zidovudine-containing regimens (P = 0.022). Overall, male gender, orphanhood (motherless) and treatment with stavudine-containing regimens predicted VF at a rate of 70% (area under curve =0.70). CONCLUSION: VF on first-line pediatric ART is common, and switching children failing first-line to second-line ART is considerably delayed. These results suggest performance of pediatric ART program can be improved by targeting orphans, adapting counseling for male children, complete phasing-out of stavudine and ensuring timely switch to second-line regimens. PMID- 28661968 TI - Diagnostic and Therapeutic Challenges. PMID- 28661970 TI - Efficacy and Safety of Combination Therapy of Shenfu Injection and Postresuscitation Bundle in Patients With Return of Spontaneous Circulation After In-Hospital Cardiac Arrest: A Randomized, Assessor-Blinded, Controlled Trial. AB - OBJECTIVES: Postresuscitation care bundle treatment after return of spontaneous circulation in patients experiencing in-hospital cardiac arrest can improve patients' survival and quality of life. The aim of the study was to evaluate the efficacy and safety of combined therapy of Shenfu injection and postresuscitation care bundle in these patients. DESIGN: Prospective, randomized, controlled clinical study. SETTING: Fifty hospitals in China. PATIENTS: Adult patients had experienced in-hospital cardiac arrest between 2012 and 2015. INTERVENTIONS: Based on the standardized postresuscitation care bundle treatment, patients were randomized to a Shenfu injection group (Shenfu injection + postresuscitation care bundle) or control group (postresuscitation care bundle) for 14 days or until hospital discharge. In the Shenfu injection group, 100 mL Shenfu injection was additionally administered via continuous IV infusion, bid. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day survival after randomization. The secondary outcomes included 90-day survival as well as the duration of mechanical ventilation and the hospital stay and the total cost of hospitalization. Of 1,022 patients enrolled, a total of 978 patients were allocated to the two groups: the control (n = 486) and Shenfu injection (n = 492) groups. The Shenfu injection group had a significantly greater 28-day survival rate (42.7%) than the control group (30.1%). Also, the Shenfu injection group had a significantly higher survival rate at 90 days (39.6%) than the control group (25.9%). Compared with patients in the control group, patients in the Shenfu injection group had lower risks of 28-day mortality (hazard ratio, 0.61; 95% CI, 0.43-0.89; p = 0.009) and 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79; p = 0.002). In the Shenfu injection group, the duration of mechanical ventilation (8.6 +/- 3.2 vs 12.7 +/- 7.9 d; p < 0.001) and the hospital stay (8.7 +/- 5.9 vs 13.2 +/- 8.1 d; p < 0.001) were significantly less than in the control group. Irreversible brain damage was the main cause of death in both groups. No serious drug-related adverse event was recorded. CONCLUSIONS: This study demonstrates that Shenfu injection in combination with conventional postresuscitation care bundle treatment is effective at improving clinical outcomes in patients with return of spontaneous circulation after in-hospital cardiac arrest. PMID- 28661969 TI - Structural, Nursing, and Physician Characteristics and 30-Day Mortality for Patients Undergoing Cardiac Surgery in Pennsylvania. AB - OBJECTIVE: Cardiac surgery ICU characteristics and clinician staffing patterns have not been well characterized. We sought to describe Pennsylvania cardiac ICUs and to determine whether ICU characteristics are associated with mortality in the 30 days after cardiac surgery. DESIGN: From 2012 to 2013, we conducted a survey of cardiac surgery ICUs in Pennsylvania to assess ICU structure, care practices, and clinician staffing patterns. ICU data were linked to an administrative database of cardiac surgery patient discharges. We used logistic regression to measure the association between ICU variables and death in 30 days. SETTING: Cardiac surgery ICUs in Pennsylvania. PATIENTS: Patients having coronary artery bypass grafting and/or cardiac valve repair or replacement from 2009 to 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 57 cardiac surgical ICUs in Pennsylvania, 43 (75.4%) responded to the facility survey. Rounds included respiratory therapists in 26 of 43 (60.5%) and pharmacists in 23 of 43 (53.5%). Eleven of 41 (26.8%) reported that at least 2/3 of their nurses had a bachelor's degree in nursing. Advanced practice providers were present in most of the ICUs (37/43; 86.0%) but residents (8/42; 18.6%) and fellows (7/43; 16.3%) were not. Daytime intensivists were present in 21 of 43 (48.8%) responding ICUs; eight of 43 (18.6%) had nighttime intensivists. Among 29,449 patients, there was no relationship between mortality and nurse ICU experience, presence of any intensivist, or absence of residents after risk adjustment. To exclude patients who may have undergone transcatheter aortic valve replacement, we conducted a subgroup analysis of patients undergoing only coronary artery bypass grafting, and results were similar. CONCLUSIONS: Pennsylvania cardiac surgery ICUs have variable structures, care practices, and clinician staffing, although none of these are statistically significantly associated with mortality in the 30 days following surgery after adjustment. PMID- 28661971 TI - The Effects of Muscle Strength Responsiveness to Periodized Resistance Training on Resistin, Leptin, and Cytokine in Elderly Postmenopausal Women. AB - Prestes, J, Nascimento, DdC, Neto, IVS, Tibana, RA, Shiguemoto, GE, Perez, SEA, Botero, JP, Schoenfeld, BJ, and Pereira, GB. The effects of muscle strength responsiveness to periodized resistance training on resistin, leptin, and cytokine in elderly postmenopausal women. J Strength Cond Res 32(1): 113-120, 2018-The aim of this study was to evaluate muscle strength responsiveness and to determine whether interleukin 4 (IL-4), leptin, and resistin would be affected by the individual pattern of response to a resistance training (RT) periodization program. Twenty-six elderly postmenopausal women participated in the present study (mean age = 62.57 +/- 6.69 years and body mass index = 28.09 +/- 4.83 kg.m). Four-month longitudinal training program was performed consisting of 2 whole-body sessions per week with increasing intensity and decreasing volume by using 6-14 repetitions maximum (RM). Two acute whole-body RT sessions (before and after chronic training) were also performed comprising 3 sets of 12-14RM. The responsiveness was determined based on their relative muscle strength gains in 45 degrees leg press. High responders were defined as relative muscle strength gains >=32% and low responders <32% (n = 13 in each group). Muscle strength increased by a higher amount in the high-responsive group as compared with the low-responsive group in the 45 degrees leg press and bench press, whereas muscle strength increased for both groups when compared with pretraining evaluation (p = 0.001). Low responders displayed higher plasma leptin levels when compared with high responders at baseline (p = 0.001), and after 16 weeks of training, leptin levels were significantly lower when compared with baseline (pretraining period). Both groups displayed a decrease in baseline resistin values after 16 weeks of RT, but only a statistically simple main effect was observed for low responders. In addition, there were no effect of time and no significant interaction between the responsiveness and time on IL-4 concentration. In conclusion, RT is effective in improving upper and lower limb muscle strength in elderly women, with higher magnitudes of increase seen for those classified as high responders. Resistin and leptin displayed a decrease over time, regardless of responsiveness classification. PMID- 28661973 TI - Determinants of Antibiotic Tailoring in Pediatric Intensive Care: A National Survey. AB - OBJECTIVES: To describe the criteria that currently guide empiric antibiotic treatment in children admitted to Canadian PICUs. DESIGN: Cross-sectional survey. SETTING: Canadian PICUs. SUBJECTS: Pediatric intensivists and pediatric infectious diseases specialists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used focus groups and literature review to design the survey questions and its four clinical scenarios (sepsis, pneumonia, meningitis, and intra-abdominal infections). We analyzed our results using descriptive statistics and multivariate linear regression. Our response rate was 60% for pediatric intensivists (62/103) and 36% for pediatric infectious diseases specialists (37/103). Variables related to patient characteristics, disease severity, pathogens, and clinical, laboratory, and radiologic infection markers were associated with longer courses of antibiotics, with median increment ranging from 1.75 to 7.75 days. The presence of positive viral polymerase chain reaction result was the only variable constantly associated with a reduction in antibiotic use (median decrease from, -3.25 to -8.25 d). Importantly, 67-92% of respondents would still use a full course of antibiotics despite positive viral polymerase chain reaction result and marked clinical improvement for patients with suspected sepsis, pneumonia, and intra-abdominal infection. Clinical experience was associated with shorter courses of antibiotics for meningitis and sepsis (-1.3 d [95% CI, -2.4 to -0.2] and -1.8 d [95% CI, -2.8 to -0.7] per 10 extra years of clinical experience, respectively). Finally, site and specialty also influenced antibiotic practices. CONCLUSIONS: Decisions about antibiotic management for PICU patients are complex and involve the assessment of several different variables. With the exception of a positive viral polymerase chain reaction, our findings suggest that physicians rarely consider reducing the duration of antibiotics despite clinical improvement. In contrast, they will prolong the duration when faced with a nonreassuring characteristic. The development of objective and evidence-based criteria to guide antibiotic therapy in critically ill children is crucial to ensure the rational use of these agents in PICUs. PMID- 28661974 TI - Silver Sulfadiazine Encapsulated in Lipid-Based Nanocarriers for Burn Treatment. AB - Burn injuries are at risk of bacterial infection because of the damaged skin and reduced immune responses. Silver sulfadiazine, a potent antibacterial agent, is considered as a standard therapy for burn treatment. Recent advances in nanotechnology have had an immense impact on drug delivery systems particularly in burn healing. Lipid-based nanocarriers have been considered as efficient drug delivery systems for burn treatment. This review presents a comprehensive overview of silver sulfadiazine-based nanocarriers and their application in the conservative healing of burn wounds. PMID- 28661975 TI - Interleukin-6 Serum Levels Correlate With Severity of Burn Injury but Not With Gender. AB - Gender-specific differences in the outcome of patients with burn injury have been recognized in the past with female patients being at a higher risk of mortality. We hypothesized that early post-burn interleukin-6 (IL-6) cytokine levels may contribute to the different gender-specific outcome. We retrospectively examined 94 burned patients who were treated in the Burn Intensive Care Unit at the University Hospital Aachen. Age, gender, presence of inhalation injury, depth, TBSA, and clinical outcome were documented. Serum samples for IL-6 analysis were collected within 24 hours posttrauma. The relationship between IL-6 levels, gender, survival, and abbreviated burn severity index score was investigated. Male patients (64.9%; n = 61) presented a higher median TBSA (26%) than female patients (20%). The mortality rate of male patients (27.9%; n = 17) and female patients (21.2%; n = 7) was similar. Deceased patients had significant higher TBSA (P = 0.0005) and IL-6 levels (P = 0.0007) than burn survivors. A moderate correlation between IL-6 levels and abbreviated burn severity index score was observed (r = 0.554; P < 0.0001). While TBSA showed a significant influence on IL 6 levels (P = 0.0003), gender did not (P = 0.7395) and inhalation injury indicated a minor influence (P = 0.0780). Only TBSA and age presented a significant influence on mortality (P = 0.0028 and P = 0.0031, respectively). All patients with burn trauma were characterized by elevated IL-6 levels with higher TBSA values resulting in more pronounced levels. Deceased patients had higher initial IL-6 serum levels reflecting higher TBSA and severity. In contrast to other defined trauma mechanisms, gender had no significant influence on postburn IL-6 serum levels and mortality in our patient population. PMID- 28661972 TI - Continuous Chest Compressions During Sustained Inflations in a Perinatal Asphyxial Cardiac Arrest Lamb Model. AB - OBJECTIVE: Continuous chest compressions are more effective during resuscitation in adults. Sustained inflation rapidly establishes functional residual capacity in fluid-filled lungs at birth. We sought to compare the hemodynamics and success in achieving return of spontaneous circulation in an asphyxial cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs between subjects receiving continuous chest compressions during sustained inflation and those receiving conventional 3:1 compression-to-ventilation resuscitation. DESIGN: Prospective, randomized, animal model study. SETTING: An experimental laboratory. SUBJECTS: Fourteen newborn term gestation lambs. INTERVENTIONS: Lambs were randomized into two groups: 3:1 compression-to-ventilation (control) and continuous chest compressions during sustained inflation. The umbilical cord was occluded to induce asphyxia and asystole. The control group was resuscitated per NRP guidelines. In the sustained inflation + continuous chest compressions group, sustained inflation at 35 cm H2O was provided for 30 seconds with 1-second interruptions before another sustained inflation was provided. One hundred twenty chest compressions/min started after the initial sustained inflation. The first dose of IV epinephrine was given at 6 minutes if return of spontaneous circulation was not achieved and then every 3 minutes until return of spontaneous circulation or for a total of four doses. MEASUREMENT AND RESULTS: All lambs achieved return of spontaneous circulation in a comparable median time (interquartile range) of 390 seconds (225-405 s) and 345 seconds (204-465 s) in the sustained inflation + continuous chest compressions and control groups, respectively. Four of seven (sustained inflation + continuous chest compressions) and three of six (control) lambs required epinephrine to achieve return of spontaneous circulation. Diastolic blood pressures were lower in the sustained inflation + continuous chest compressions (4 +/- 2 mm Hg) compared to the control group (7 +/- 2 mm Hg), p < 0.05. PaCO2, PaO2, and lactate were similar between the groups during the study period. CONCLUSION: In this perinatal cardiac arrest lamb model with transitioning fetal circulation and fluid-filled lungs, sustained inflation + continuous chest compressions is as effective as 3:1 compression-to ventilation resuscitation in achieving return of spontaneous circulation. Half the lambs achieved return of spontaneous circulation without epinephrine. continuous chest compressions during sustained inflation reduced diastolic pressures but did not alter gas exchange or carotid blood flow compared to 3:1 compression-to-ventilation resuscitation. PMID- 28661976 TI - Enteral Nutrition Delivery Is Overestimated in Provider Documentation. AB - Burn-injured patients have the highest metabolic demand of all critically ill patients and are vulnerable to complications of malnutrition. Many burn centers have challenges in achieving prescribed rates of nutrition, despite aggressive algorithms. One possible reason for the discrepancy is inaccurate documentation of volumes. This is a retrospective review of patients requiring tube feeding admitted to a regional burn center between June and August 2015. Demographics were abstracted including gender, type of injury, TBSA, and age. The total feeding volume was recorded from the feeding pump every 24 hours. The values were compared with the enteral nutrition volume charted by the nursing staff and rate prescribed by the physician team. Repeated measures analysis of variance was used to compare continuous variables. Twenty-five patients were observed during the study period providing a total of 105 patient days. The average age was 44 years with 42% TBSA mean burn size. The average volume prescribed by providers was 1,598 ml/d. According to documentation, the average volume given was 1,448 ml/d, a significant difference (P = <.001). The average volume delivered as recorded on the feeding pump was less at 1,287 ml/d. The nourishment provided was significantly less than documented and even more so when compared with the prescribed rate (P < .001 and P < .001, respectively). Overall, 19% of ordered enteral nutrition was not provided. There was a significant discrepancy between ordered, recorded, and delivered volume of enteral nutrition. Potential reasons for the discrepancy may be frequent interruption for repositioning, wound care, linen changes, or other nursing workflow. Burn providers should be aware of the potential for underfeeding patients. PMID- 28661977 TI - Vitamin D Status May Explain Some of the Effects of Race on Burn Outcomes. PMID- 28661978 TI - Prone Positioning of the Burn Patient With Acute Respiratory Distress Syndrome: A Review of the Evidence and Practical Considerations. AB - Acute respiratory distress syndrome (ARDS) is a common sequela of severe burns and inhalation injury. The massive inflammatory reaction that follows deep burn injury, compounded by episodes of sepsis and organ dysfunction, predisposes patients to the development of ARDS. Prone positioning as a means of improving gas exchange has shown benefit in refractory cases of ARDS, but it is not well described in the burn population. We present a case report of a patient with severe ARDS who underwent prone positioning, review the relevant literature, and provide a discussion of practical concerns. PMID- 28661979 TI - A Hidden Danger of Vomiting: Gastric Acid Burns. AB - This case report describes a gastric acid burn. Gastric acid burns secondary to vomiting in an elderly patient who has fallen and experienced a so called "long lie" have not been reported. The patient was admitted under the physicians and referred to the burns team once the wounds were recognized as burns. The patient was treated nonsurgically with dressings and healed well with conservative treatment. Here, the authors highlight the importance of recognizing and treating burns of this nature in our ageing population. PMID- 28661980 TI - Assessment of Plasma Neutrophil Gelatinase-Associated Lipocalin for Early Detection of Acute Kidney Injury and Prediction of Mortality in Severely Burned Patients. AB - The purpose of this study was to assess the plasma neutrophil gelatinase associated lipocalin (NGAL) for early detection of acute kidney injury (AKI) and prediction of mortality in severely burned patients. From January 2014 to September 2015, 76 consecutive patients with more than 20% of TBSA burned were enrolled. Blood samples for plasma NGAL were collected at 0, 7, 14, 21, and 28 days after admission and analyzed with injury severity, clinical outcome, and AKI development. Plasma NGAL was significantly affected by the TBSA burned, AKI, and mortality, and it was significantly increased after operation and septic shock. Plasma NGAL was significantly increased within 7 days before AKI development in total patients (P < .001) and septic shock patients (P < .001) but not significantly increased in patients without septic shock (P = .167). Though, in a receiver operating characteristic curve analysis for predicting AKI, continuous renal replacement therapy application, and mortality, plasma NGAL was statistically significant; plasma NGAL was not independently associated with mortality in a multivariate logistic regression analysis. Plasma NGAL should be interpreted carefully in the major burn patients because it can reflect both inflammatory condition and AKI. PMID- 28661981 TI - An External Wire Frame Fixation Method of Skin Grafting for Burn Reconstruction. AB - The skin graft is a prevalent reconstructive method for burn injuries. We have been applying external wire frame fixation methods in combination with skin grafts since 1986 and have experienced better outcomes in percentage of successful graft take. The overall purpose of this method was to further secure skin graft adherence to wound beds in hard to stabilize areas. There are also location-specific benefits to this technique such as eliminating the need of tarsorrhaphy in periorbital area,1 allowing immediate food intake after surgery in perioral area,2 and performing less invasive fixing methods in digits,3 and so on. The purpose of this study was to clarify its benefits and applicable locations. We reviewed 22 postburn patients with skin graft reconstructions using the external wire frame method at our institution from December 2012 through September 2016. Details of the surgical technique and individual reports are also discussed. Of the 22 cases, 15 (68%) were split-thickness skin grafts and 7 (32%) were full-thickness skin grafts. Five cases (23%) involved periorbital reconstruction, 5 (23%) involved perioral reconstruction, 2 (9%) involved lower limb reconstruction, and 10 (45%) involved digital reconstruction. Complete (100%) survival of the skin graft was attained in all cases. No signs of complication were observed. With 30 years of experiences all combined, we have summarized fail-proof recommendations to a successful graft survival with an emphasis on the locations of its application. PMID- 28661982 TI - Extra-Articular Soft-Tissue Calcification After Burn Injury: A Case Study. AB - Soft-tissue calcifications after burn injury commonly develop in periarticular regions, especially in the elbow joint. They can be easily recognized in patients because calcification in the joint limits range of motion and brings about tingling sensation due to compression of ulnar nerve. However, the incidence of extra-articular soft-tissue calcification after burn injury has rarely been reported. We present a patient with massive soft-tissue calcification in extra articular burn scar with nonhealing ulcer after a long latency period of 40 years. We recommended wide excision and skin grafting, for prevention of recalcification and recurrence of ulceration, which could transform into a malignant case, if left untreated. Furthermore, we propose that such patients with burn injury should undergo follow-up in outpatient clinic and x-ray evaluation. PMID- 28661983 TI - U.S. Pediatric Burn Patient 30-Day Readmissions. AB - The objectives of the study were to determine unscheduled 30-day readmission rates for pediatric burn patients and to identify readmission reasons. We used the 2013-2014 National Readmission Database to produce 30-day all-cause unscheduled readmission rates by patient and hospital characteristics. Readmission risk factors were evaluated with multivariable logistic regression. An estimated 11,940 U.S. pediatric burn patients were discharged in January through November 2013 and 2014, and 325 had unscheduled readmissions within 30 days (2.7%; 95% confidence interval [CI], 1.5-3.9). This rate is higher than that seen in pediatric trauma patients (1.7%; P = 0.04]. Higher rates were seen in children with TBSA burned >= 10% (4.1%; 95% CI, 2.3-6.0) and patients with third degree burns (5.5%; 95% CI, 1.4-9.6). The majority (86%) had index admissions in hospitals treating 100 or more burn patients annually, and 98% returned to the same hospital. Over two-thirds had an operating room procedure during their readmission; 15% had infections. The highest adjusted odds of readmission (AOR = 2.7; 95% CI, 1.7-4.2) was for patients with third-degree burns. When compared with patients with lengths of stay (LOS) of 1 day, those with LOS of 2 to 3 days had a higher odds (AOR = 1.7; 95% CI, 1.03-2.9), but the AOR was not different for those with LOS > 3 days. TBSA, index operating room procedure, and patient residence were associated with readmission. This national dataset enhances our ability to predict patients at risk for unscheduled readmission and to plan for appropriate patient discharge, potentially reducing readmissions. PMID- 28661985 TI - A Novel Approach To Sealing The Denuded Dermis of the Abdominal Wall With A Negative Pressure Wound Device After A Decompressive Laparotomy. AB - The open abdomen is a well-known technique that is applied in a wide variety of clinical situations, including treatment of abdominal compartment syndrome, damage control laparotomy, and severe intraabdominal sepsis. Disease states such as Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis or extensive deep partial and/or full-thickness torso burns involving the abdomen often result in a complete epidermal and partial dermal loss. When ABThera Open Abdomen Negative Pressure Wound Therapy is attempted in these patients, the exposed subcutaneous tissue rarely allows for an adequate seal between the adhesive barrier and the denuded skin. This is because successful placement of negative pressure wound therapy device necessitates having a dry epidermal surface allowing the adhesive tape to actually adhere. The ABThera Open Abdomen Negative Pressure Wound Therapy visceral protective layer was placed over the exposed bowel, followed by the blue perforated foam interface and then the adhesive barrier drape. Over the top of the "less-than-air-tight" adhesive barrier drape was placed a standard isolation transport bowel bag, which was stapled to the dermis, but outside of the previously placed adhesive barrier drape's diameter to "bolster" the adhesive barrier drape, only allowing the suction tube to extend inferiorly. This ABThera Open Abdomen Negative Pressure Wound Therapy ABNPWT held suction, even during multiple adjacent dressing changes, despite the exposed dermis. This case report reveals a unique approach that solves the issue of inadequate seal due to extensive burns to the torso and has significant benefit in burn and wound care practices. PMID- 28661984 TI - Resting beta-Adrenergic Blockade Does Not Alter Exercise Thermoregulation in Children With Burn Injury: A Randomized Control Trial. AB - The objective of this study was to test the hypothesis that propranolol, a commonly prescribed beta-blocker to burned children, in combination with exercise heat stress, increases the risk of heat illness and exercise intolerance. In a randomized double-blind study, propranolol was given to 10 burned children, and placebo was given to 10 additional burned children (matched for TBSA burned; mean +/- SD, 62 +/- 13%), while nonburned children served as healthy controls. All groups were matched for age and body morphology (11.2 +/- 3.0 years; 146 +/- 19 cm; 45 +/- 18 kg; 1.3 +/- 0.4 m2). All children exercised in hot conditions (34.3 +/- 1.0 degrees C; 26 +/- 2% relative humidity) at 75% of their peak aerobic capacity. At the end of exercise, none of the groups differed for final or change from baseline intestinal temperature (38.0 +/- 0.5 degrees C; 0.02 +/- 0.01Delta degrees C.min-1), unburned (37.0 +/- 0.6 degrees C) and burned skin temperatures (36.9 +/- 0.7 degrees C; nonburn group excluded), heat loss (21 +/- 18 W m-2), whole-body thermal conductance (118 +/- 113 W m-2), or physiological strain index (5.6 +/- 1). However, burn children exercised less than nonburn group (21.2 +/- 8.6 vs 30 +/- 0.0 min; P < .001) and had a lower calculated exercise tolerance index (1.0 +/- 0.0 vs 6.7 +/- 4.3; P < .01). Burned children had lower peak heart rates than nonburned children (173 +/- 13 vs 189 +/- 7 bpm; P < .01), with greater relative cardiac work rates at the end of exercise (97 +/- 10 vs 85 +/- 11% peak heart rate; P < .01). Resting beta-adrenergic blockade does not affect internal body temperature of burned children exercising at similar relative intensities as nonburn children in the heat. Independent of propranolol, a suppressed cardiac function may be associated to exercise intolerance in children with severe burn injury. PMID- 28661986 TI - Comparison of Pain Severity and Management in Burn and Nonburn Trauma Patients. AB - Burn injuries are generally considered to be among the most painful. However, there is little evidence to support this. It is also unknown if pain management in burn patients differs from patients with other sources of pain. We compared pain severity among patients presenting to emergency departments (EDs) across the United States with burn and nonburn injuries using data generated from the National Hospital Ambulatory Care Survey. Multivariate analyses was performed to determine the association between predictor variables and pain severity as well as pain management in the ED. Of the estimated 527 million ED visits between 2010 and 2013, 2.1 million were due to burns and 128 million were due to nonburn trauma. Mean (SE) initial pain scores by patient group were burns 6.3 (0.27), nonburn trauma 5.4 (0.04), and nontrauma 4.8 (0.04), P < .001. Mean (95% confidence interval) pain scores by specific type of injury were burns 6.4 (5.9 6.9), fractures 6.7 (6.6-6.9), dislocations 6.7(6.3-7.1), and sprains/strains 6.8 (6.7-6.9), P < .001. Pain scores were higher for males and increased with age. Adjusted for age and gender, burns had the smallest effect of all types of injuries on pain score except for open wounds, contusions, and crush injuries. Patients with fractures and dislocations were more likely to receive an opioid than burn patients after adjusting for pain severity. We conclude that pain severity due to burns is no greater than due to dislocations, fractures, and sprains/strains and that burn patients are less likely to receive opioid and nonopioid analgesics than fractures and dislocations. PMID- 28661987 TI - Upper Gastrointestinal Endoscopic Evaluation Following Household Sodium Hypochlorite Ingestion. AB - Endoscopy is generally speculated to be unnecessary in sodium hypochlorite (NaClO) ingestions; however, a significant number of endoscopic evaluations are still being performed when this chemical is ingested. Therefore, the aim of the current study was to compare the outcome and endoscopic findings between patients who had ingested household NaClO and those who had ingested other types of corrosives. This retrospective cohort study enrolled 137 patients with a history of corrosive substance ingestion admitted to a tertiary hospital. Data were extracted from hospital records, and interviews were performed on follow-up. Demographic characteristics, endoscopic findings, and patient outcome were compared between those who had ingested household NaClO and those who ingested other corrosives (NaClO and control cohorts, respectively). Most patients (73%) had attempted suicide. Dysphonia (P <= .001), dysphagia (P = .04), and mouth burns (P = .047) were significantly different between the NaClO and control cohorts. Furthermore, patients who had dysphonia, dysphagia, skin burns, drooling, hematemesis, retrosternal pain, and abnormal abdominal examination were prone to death or severe complications. None of the NaClO cohort patients had severe endoscopic complications. All patients in the NaClO cohort survived without any sequelae (Odds Ratio (OR) [95% Confidence Interval (CI)] = 0.87 [0.80 0.94]) while 6 and 5 patients died and developed severe complications in the control cohort, respectively. Studies on endoscopic evaluations in patients who ingested household NaClO are scarce. Our results show that if there are no major clinical manifestations, urgent endoscopic evaluations are unnecessary in such patients. PMID- 28661988 TI - Bowel Necrosis and 3 Limb Amputation From High-Voltage Electrical Injury. AB - The objective of this study was to report the case and multidisciplinary management of a 44-year-old man with 40% TBSA third- and fourth-degree burns sustained during high-voltage electrical injury including 3 limb amputation and bowel necrosis requiring small bowel resection. This study is a case report and review of the literature. A 44-year-old man was brought to the Emergency Department with 40% TBSA third- and fourth-degree burns sustained during accidental contact with high-voltage electric current. He had multisystem injury including injuries to 3 of his extremities ultimately requiring a forequarter amputation of the left upper extremity and guillotine amputations of his bilateral lower extremities. He also sustained a visceral injury and underwent small bowel resection. While amputations are very common in electrical burn injuries, visceral electrical injuries are not. High-voltage electrical injuries are devastating multisystem insults that require multidisciplinary critical and operative care. PMID- 28661989 TI - Meditation: A Strategy With Promise in Chronic Disease. PMID- 28661990 TI - The Influence of Comorbidities, Risk Factors, and Medications on Sexual Activity in Individuals Aged 40 to 59 Years With and Without Cardiac Conditions: US National Health and Nutrition Examination Survey, 2011 to 2012. AB - BACKGROUND: Sexual activity is increasingly recognized as an important aspect of quality of life for many individuals with cardiovascular disease, although less is known about the factors contributing to sexual functioning in younger adults. OBJECTIVE: This study examined factors influencing sexual activity in individuals aged 40 to 59 years, comparing those reporting a cardiac condition with those without a cardiac condition, in a national population-based sample. METHODS: The data were derived from the 2011 to 2012 National Health and Nutrition Examination Survey, a publicly available data set with a noninstitutionalized nationally representative sample. The sample included individuals between the ages of 40 and 59 years (N = 1741) who completed relevant items related to cardiovascular disease, cardiovascular risk factors, comorbidities, cardiac symptoms, sexual activity, and medication use. Recommended weighting was applied, and the data were analyzed using chi and logistic regression. RESULTS: Overall, 94% of the sample reported sexual activity, although those with coronary artery disease, angina, and myocardial infarction engaged in significantly less sexual activity. Individuals who smoked; had a weight problem, depression, or lung problems; or experienced symptoms of shortness of breath or chest pain with exertion reported less sexual activity. Medications negatively affecting sexual function were central alpha agonists, potassium sparing diuretics, and antilipidemic agents. Predictors of less sexual activity were smoking, chest pain walking uphill, and weight problems. Unexpectedly more reported, sexual activity was predicted by one or more cardiac conditions. CONCLUSION: In men and women ages 40 to 59 years, certain cardiac conditions, risk factors, comorbidities, symptoms, and medications negatively affected sexual activity, illustrating the need for sexual assessment and counseling to support sexual quality of life. PMID- 28661991 TI - Testing a Holistic Meditation Intervention to Address Psychosocial Distress in Patients With Heart Failure: A Pilot Study. AB - BACKGROUND: Many patients with heart failure (HF) experience persistent symptoms and poor health-related quality of life (HRQOL). Psychosocial distress is common and adversely affects HF symptoms and HRQOL. A holistic meditation (HOME) intervention that combines mindfulness, compassionate meditation, and self management may reduce psychosocial distress. PURPOSE: The aims of this study were to examine the feasibility and acceptability of the HOME intervention in patients with HF and to obtain preliminary data about its effects on psychosocial factors (depressive symptoms, perceived control, and social support), HF symptoms, and HRQOL. METHODS: Weekly 90-minute intervention sessions were delivered to 11 patients with HF for 12 weeks. Data on feasibility and acceptability were collected for 12 weeks, and data on psychosocial factors, HF symptoms, and HRQOL were collected at baseline and after the intervention. RESULTS: Eleven of 13 enrolled patients completed all intervention sessions; 2 withdrew because of family health issues. Mean acceptability scores for all sessions ranged from 98% to 100%. In paired t test analyses, perceived control (P = .02, Cohen d = 0.82) and social support (P = .008, Cohen d = 1.00) increased, severity of depressive symptoms (P < .001, Cohen d = 1.54) and HF symptoms (P < .001, Cohen d = 1.91) decreased, and HRQOL was improved (P < .001, Cohen d = 1.82). CONCLUSIONS: The HOME intervention was feasible and acceptable and had positive effects on psychosocial variables, HF symptoms, and HRQOL for patients with HF. Our results indicate that treatment effects should be tested in a larger, controlled clinical trial. PMID- 28661992 TI - Treatment Patterns, Outcomes, and Patient Satisfaction of Primary Epidermally Limited Nonmelanoma Skin Cancer. AB - BACKGROUND: Epidermally limited nonmelanoma skin cancer (ELNMSC) (superficial basal cell carcinoma [SBCC] and squamous cell carcinoma in situ [SCCIS]) is common. Data on outcomes and patient satisfaction are lacking. OBJECTIVE: To examine treatment efficacy and satisfaction in ELNMSC patients. PATIENTS AND METHODS: Retrospective cohort study of adults with primary SBCC or SCCIS. A 25% random subset completed a satisfaction questionnaire. RESULTS: Five hundred and fifty patients with 227 SBCC and 451 SCCIS were included; 329 tumors (49%) were treated with Mohs micrographic surgery (MMS) and 349 (51%) with non-MMS (imiquimod [n = 26], 5% 5-fluorouracil [n = 234], ingenol mebutate [n = 32], or cryotherapy [n = 57]). Five-year recurrence-free survival was high in both groups, with MMS having a small but statistically significant advantage (99% vs 95%, p = .004). More MMS patients were willing to undergo treatment again (97% vs 86%, p = .024). Dissatisfaction was mostly due to prolonged treatment course and pain associated with non-MMS treatments. CONCLUSION: Surgical and nonsurgical treatments for primary ELNMSC have low recurrence rates, though cure rate and patient satisfaction are higher with MMS. Treatment choice for epidermal NMSC may be guided through patient preferences regarding ability to comply with topical treatment, out-of-pocket costs, desire to treat surrounding field disease, and desire to avoid a surgical scar. PMID- 28661993 TI - Commentary on The Clinical and Histological Effect of a Low-Fluence Q-Switched 1,064-nm Neodymium: Yttrium-Aluminum-Garnet Laser for the Treatment of Melasma and Solar Lentigenes in Asians. PMID- 28661994 TI - Commentary on The Facial Platysma and Its Underappreciated Role in Lower Face Dynamics and Contour. PMID- 28661995 TI - A Multicenter Pivotal Study to Evaluate Tissue Stabilized-Guided Subcision Using the Cellfina Device for the Treatment of Cellulite With 3-Year Follow-Up. AB - BACKGROUND: Cellulite is a common female cosmetic concern for which no single treatment option had been proven effective over the long term. A novel tissue stabilized-guided subsicion system (TS-GS system) has demonstrated significant reduction in the appearance of cellulite after treatment. OBJECTIVE: The objective of this extended follow-up period was to assess the effectiveness of TS GS out to 3 years after initial treatment. PATIENTS AND METHODS: After completing an open-label, multicenter, pivotal study, 45 subjects were followed for an extended period of up to 3 years after receiving a single treatment using the TS GS system. Treatment areas were photographed prior to the procedure and at multiple time points post-treatment throughout the 3 years. In this open-label study, subjects served as their own controls. Effectiveness was assessed based on blinded independent physician panel assessments of improvement from baseline using a cellulite severity scale. Subject aesthetic improvement and patient reported satisfaction were also collected. RESULTS: The results of this trial supported Food and Drug Administration clearance of the device for the long-term reduction in the appearance of cellulite following TS-GS. CONCLUSION: These data further demonstrate the safety and efficacy of this treatment with no reduction in treatment benefits out to 3 years. PMID- 28661996 TI - Pulsed-Dye Laser Treatment of a Nonhealing Chronic Wound That Developed After Incision and Drainage of a Hidradenitis Suppurativa Abscess. PMID- 28661997 TI - In a Pinch? Rocker-Slide Punch Biopsy Technique. PMID- 28661998 TI - Description and Yield of Current Quality and Safety Review in Selected US Academic Emergency Departments. AB - OBJECTIVES: Quality and safety review for performance improvement is important for systems of care and is required for US academic emergency departments (EDs). Assessment of the impact of patient safety initiatives in the context of increasing burdens of quality measurement compels standardized, meaningful, high yield approaches for performance review. Limited data describe how quality and safety reviews are currently conducted and how well they perform in detecting patient harm and areas for improvement. We hypothesized that decades-old approaches used in many academic EDs are inefficient and low yield for identifying patient harm. METHODS: We conducted a prospective observational study to evaluate the efficiency and yield of current quality review processes at five academic EDs for a 12-month period. Sites provided descriptions of their current practice and collected summary data on the number and severity of events identified in their reviews and the referral sources that led to their capture. Categories of common referral sources were established at the beginning of the study. Sites used the Institute for Healthcare Improvement's definition in defining an adverse event and a modified National Coordinating Council for Medication Error Reporting and Prevention (MERP) Index for grading severity of events. RESULTS: Participating sites had similar processes for quality review, including a two-level review process, monthly reviews and conferences, similar screening criteria, and a grading system for evaluating cases. In 60 months of data collection, we reviewed a total of 4735 cases and identified 381 events. This included 287 near-misses, errors/events (MERP A-I) and 94 adverse events (AEs) (MERP E-I). The overall AE rate (event rate with harm) was 1.99 (95% confidence interval = 1.62%-2.43%), ranging from 1.24% to 3.47% across sites. The overall rate of quality concerns (events without harm) was 6.06% (5.42%-6.78%), ranging from 2.96% to 10.95% across sites. Seventy-two-hour returns were the most frequent referral source used, accounting for 47% of the cases reviewed but with a yield of only 0.81% in identifying harm. Other referral sources similarly had very low yields. External referrals were the highest yield referral source, with 14.34% (10.64%-19.03%) identifying AEs. As a percentage of the 94 AEs identified, external referrals also accounted for 41.49% of cases. CONCLUSIONS: With an overall adverse event rate of 1.99%, commonly used referral sources seem to be low yield and inefficient for detecting patient harm. Approximately 6% of the cases identified by these criteria yielded a near miss or quality concern. New approaches to quality and safety review in the ED are needed to optimize their yield and efficiency for identifying harm and areas for improvement. PMID- 28661999 TI - Preoperative Site Marking: Are We Adhering to Good Surgical Practice? AB - OBJECTIVES: Wrong-site surgery is a never event and a serious, preventable patient safety incident. Within the United Kingdom, national guidance has been issued to minimize the risk of such events. The mandate includes preoperative marking of all surgical patients. This study aimed to quantify regional variation in practice within general surgery and opinions of the surgeons, to help guide the formulation and implementation of a regional general surgery preoperative marking protocol. METHODS: A SurveyMonkey questionnaire was designed and distributed to 120 surgeons within the Mersey region, United Kingdom. This included all surgical trainees in Mersey (47 registrars, 56 core trainees), 15 consultants, and 2 surgical care practitioners. This sought to ascertain their routine practice and how they would choose to mark for 12 index procedures in general surgery, if mandated to do so. RESULTS: A total of 72 responses (60%) were obtained to the SurveyMonkey questionnaire. Only 26 (36.1%) said that they routinely marked all of their patients preoperatively. The operating surgeon marked the patient in 69% of responses, with the remainder delegating this task. Markings were visible after draping in only 55.6% of marked cases. CONCLUSIONS: Based on our findings, surgeons may not be adhering to "Good Surgical Practice"; practice is widely variable and surgeons are largely opposed and resistant to marking patients unless laterality is involved. We suggest that all surgeons need to be actively engaged in the design of local marking protocols to gain support, change practice, and reduce errors. PMID- 28662000 TI - Using Prospective Risk Analysis Tools to Improve Safety in Pharmacy Settings: A Systematic Review and Critical Appraisal. AB - OBJECTIVES: This study aimed to review and critically appraise the published literature on 2 selected prospective risk analysis tools, Failure Mode and Effects Analysis and Socio-Technical Probabilistic Risk Assessment, as applied to the dispensing of medicines in both inpatient and outpatient pharmacy settings. METHODS: A comprehensive search of electronic databases (PubMed and Scopus) was conducted (January 1990-March 2016), supplemented by hand search of reference lists. Eligible articles were assessed for data sources used for the risk analysis, uniformity of the risk quantification framework, and whether the analysis teams assembled were multidisciplinary. RESULTS: Of 1011 records identified, 11 articles met our inclusion criteria. These studies were mainly focused on dispensing of high-alert medications, and most were conducted in inpatient settings. The main risks identified were transcription, preparation, and selection errors, whereas the most common corrective actions included electronic transmission of prescriptions to the pharmacy, use of barcode, and medication safety training. Significant risk reduction was demonstrated by implementing corrective measures in both inpatient and outpatient pharmacy settings. The main Failure Mode and Effects Analysis limitations were its subjectivity and the lack of common risk quantification criteria. CONCLUSIONS: The prospective risk analysis methods included in this review revealed relevant safety issues and hold significant potential for risk reduction. They were deemed suitable for application in both inpatient and outpatient pharmacy settings and should form an integral part of any patient safety improvement strategy. PMID- 28662001 TI - Drug-Related Problems Identified at Patients' Home: A Prospective Observational Study in a Rural Area of Thailand. AB - OBJECTIVE: The aim of the study was to examine the prevalence rates, nature, and predictors of drug-related problems (DRPs) experienced in participants living at home in a rural Thailand. METHOD: A cross-sectional observational study was undertaken during December 2015 to January 2016. Drug-related problems were identified within a rural township having a population of 5256 by means of home visits by pharmacists. All suspected cases were then assessed for severity and preventability by clinical specialists. Drug-related problems were categorized according to Pharmaceutical Care Network Europe classification (revised 2010).v.6.2 RESULTS: From a systematically recruited cohort of 359 participants, suspected DRPs were identified in 160 participants. After detailed reviews by clinical specialists, 141 cases (39.3%) were deemed to have DRPs. Types of DRPs with prevalence rates were the following: problems of treatment effectiveness (3.7% of DPRs), adverse reactions (15.3%), treatment cost (28.4%), nonadherence to drugs (42.1%), and poor drug storage (10.5%). The most common drug to involve DRPs was those treating cardiovascular disease, especially simvastatin. CONCLUSIONS: Nearly half of community living participants experienced DRPs, especially nonadherence to drugs, and has implications for other rural elderly persons of low education attainment for similar rural economies around the globe. Appropriate interventions should focus on reducing polypharmacy, providing outreach programs, and rigorous pharmacovigilance. PMID- 28662002 TI - Urrets-Zavalia Syndrome After Diode Laser Transscleral Cyclophotocoagulation. AB - OBJECTIVE: To report the occurrence of 5 cases of Urrets-Zavalia syndrome after transscleral diode laser cyclophotocoagulation (TSCPC). DESIGN: Retrospective cases series. METHODS: A review of the charts of 5 patients treated with TSCPC as primary glaucoma surgery who developed Urrets-Zavalia syndrome. RESULTS: A total of 8 eyes of 5 patients developed a fixed and dilated pupil after TSCPC, unresponsive to light. A mydriatic pupil could still be observed at least 6 months after treatment in 7 of 8 eyes; however, it was asymptomatic. CONCLUSIONS: Urrets-Zavalia syndrome is a possible complication of TSCPC, as well as of other 360-degree thermal laser procedures. PMID- 28662003 TI - In Reply. PMID- 28662004 TI - In Reply. PMID- 28662005 TI - CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions. AB - BACKGROUND: Obesity/hyperlipidemia is closely related to both atrial and ventricular arrhythmias. CaMKII, a multifunctional serine/threonine kinase, has been involved in cardiac arrhythmias of different etiologies. However, its role in obesity/hyperlipidemia-related cardiac arrhythmia is unexplored. The aim of this was to determine the involvement of CaMKII in the process. METHODS: Adult male APOE mice were fed a high-fat diet (HFD), administrated with KN93 (10 mg.kg.2d), a specific inhibitor of CaMKII. Serum lipid and glucose profile, cardiac function, and surface electrocardiogram were determined. Electrophysiological study and epicardial activation mapping were performed in Langendorff-perfused heart. Expression of cardiac ion channels, gap junction proteins, Ca handling proteins, and CaMKII were evaluated, coupled with histological analysis. RESULTS: A hyperlipidemia condition was induced by HFD in the APOE mice, which was associated with increased expression and activity of CaMKII in the hearts. In Langendorff-perfused hearts, HFD-induced heart showed increased arrhythmia inducibility, prolonged action potential duration, and decreased action potential duration alternans thresholds, coupled with slow ventricular conduction, connexin-43 upregulation, and interstitial fibrosis. Downregulation of ion channels including Cav1.2 and Kv4.2/Kv4.3 and disturbed Ca handling proteins were also observed in HFD-induced heart. Interestingly, all these alterations were significantly inhibited by KN93 treatment. CONCLUSION: Our results demonstrated an adverse effect of metabolic components on cardiac electrophysiology and implicated an important role of CaMKII underlying this process. PMID- 28662006 TI - [Turmeric - not only spice]. AB - The purpose of this article is to introduce the role of turmeric in medicine and summarize the current state of research on its applications. Turmeric (Curcuma longa) has had a wide range of uses in middle eastern and orietnal traditional medicine. Currently, however, its use has been truncated to a common cooking spice, despite numerous studies pointing to its healing properties and possible use in the treatment of many diseases. The main focus is on curcumin, a polyphenol which serves as the biologically active component of turmeric. Curcumin's anti-inflammatory effects have been well documented in medical studies, with wide ranging applications from the treatment of rheumatologic diseases such as arthritis to dermatology, with significant effects in the treatment of psoriasis, acne and in relieving of itching. In addition to the effect of pro-inflammatory cytokines, curcumin can also accelerate healing of skin wounds. Apart from controlling the body's inflammatory response, curcumin has a bacteriostatic effect, which has been shown to be an important factor in the treatment of diseases with complex etiology. Additionally, studies show that curcumin's effects on oncogenesis, the process of metastasis, angiogenesis, apoptosis or response to cytostatic drugs have yielded promising results. It has been confirmed that its antioxidant effect correlates with a decrease in LDL levels in blood and to a reduced risk of atherosclerosis. Curcumin consumption has also been shown to have a vasodilating effect through its indirect impact on prostacyclins and directly on vascular endothelium. Many of the mention medicinal properties of turmeric are still the subject of research and debate; as such, only some of them have entered the phase of clinical trials. PMID- 28662007 TI - [Evaluation of sleep apnea, detected by 24-hour ECG Holter monitoring analysis in patients with stable coronary artery disease and ischemic heart failure - correlations with clinical data]. AB - : Obstructive sleep apnoea (OSA) is frequently undiagnosed in patients with heart failure (HF) and coronary artery disease (CAD). Simple and widely available screening tests are needed to diagnose patients with SA. Measurements of thoracic impedance and heart rate variability during 24-hour ECG Holter (H-EKG) monitoring allows to calculate estimated apnoea-hypopnoea index (eAHI). AIM: The aim of the research was to assess prevalence of OSA evaluated with the use of H-EKG and determination of its clinical relevance in patients with CAD and ischeamic HF. MATERIALS AND METHODS: The study groups comprised of: 30 consecutive patients with ischeamic HF with reduced LVEF (HFrEF) (group A) and 30 patients with CAD (group B). Control group (C) comprised of 30 patients with arterial hypertension but no CAD nor HF. H-ECG monitoring was performed and eAHI was calculated. On the basis of AHI result group A was subdivided to subgroups A1 (eAHI <15) and A2 (eAHI >=15). RESULTS: Study groups differed with eAHI values (27,9+/-19,9 vs. 21,8+/-17,3 vs. 15,7+/-12,2; p=0,022). Post hoc analysis revealed that eAHI in group A was higher in comparison to group C (27,9+/-19,9 vs. 15,7+/-12,2; p=0,006). SA prevalence was higher in group A compared to group C (70,0% vs. 40,0%; p=0,019). Significant but weak correlation between eAHI and LVEDD was found (r=0,282; p<0,05). Subgroups A1 and A2 did not differ in terms of clinical and demographical parameters, HF symptoms, LVEF and NT-proBNP levels. CONCLUSIONS: OSA coexists more frequently with HF than with arterial hypertension Significant but weak correlation between eAHI and LVEDD was demonstrated. However, in patients with symptomatic ischeamic heart failure eAHI >=15 was not related to NYHA class, lower LVEF and higher NT-proBNP levels. PMID- 28662008 TI - [Evaluation of oxidative-reduction markers of blood in patients with acute coronary syndromes (ACS) subjected to cardiac rehabilitation]. AB - : Role in the pathogenesis of atherosclerosis play a reactive oxygen species. In the case of disturbance of dynamic balance between their production and antioxidant defense mechanisms comes to undesirable consequences - oxidative stress. Excessive exercise can, among others, disrupting the balance. AIM: The aim of the study was to evaluate the exponents of the processes of oxidation - reduction of blood in patients with ACS undergoing rehabilitation in a hospital setting. MATERIALS AND METHODS: The study included 25 patients after ACS STEMI, including 19 men and 6 women, aged 51.5+/-6.5 years, underwent rehabilitation in the Department of Internal Medicine and Cardiac Rehabilitation, University Hospital im. WAM in Lodz. Blood samples were taken after an initial exercise test (I) and after the final exercise test (IV). Marked: SOD-1, CAT, GPX- in red blood cells, plasma antioxidant activity (TAS) and the concentration of MDA in the red blood cells. Cardiac rehabilitation program included 15 interval training, each lasting 40-45 minutes. RESULTS: The results were statistically analyzed. For the statistically significant level of p<0.05. No significant effect of cardiac rehabilitation on the activity of GPX, SOD-1, MDA and antioxidant activity of plasma. There was only a significant impact on the rehabilitation of CAT activity (p=0.002). CONCLUSIONS: Properly conducted cardiac rehabilitation does not disturb the balance of oxidation - reduction of blood in patients with ACS. Exercise should be selected in such a way that this balance is maintained. PMID- 28662009 TI - [The assessment of risk factors for glucose metabolism disorders]. AB - AIM: The aim of the study was to assess risk factors for glucose metabolism disorders. MATERIALS AND METHODS: The study involved 197 people, 92 women and 105 men aged 63.21+/-8.74 years. In order to assess glucose metabolism disorders, patients were divided into three groups. The first group (DM) consisted of 60 people (16 women and 44 men aged 61.92+/-8.46 years). These were people with type 2 diabetes. Second group (IFG IGT) consisted of 67 people (35 women and 32 men aged 65+/-8.5 years). These were people who were diagnosed with impaired fasting glucose or impaired glucose tolerance. The third group, the control one (K) consisted of 70 people (41 women and 29 men aged 62.6+/-9.06 years). They were healthy individuals. Age, BMI, blood pressure, heart rate, pulse pressure, lipids in the blood serum, serum creatinine, glomerular filtration rate (GFR), the number of pack-years were assessed. Each patient responded to diabetes risk questionnaire. RESULTS: Univariate analyzes showed statistically significant differences between groups due to: systolic blood pressure, heart rate, pulse pressure, total cholesterol, LDL cholesterol, HDL cholesterol, the number of points obtained in diabetes risk questionnaire, serum creatinine and GFR. Multivariate analyzes demonstrated that in IFG IGT group independent risk factors that increased the risk of prediabetes were elevated levels of total cholesterol (OR 1,945, 95%CI [1,195-3,166], p=0,007) and the result of the diabetes risk questionnaire (OR 1,191, 95%CI [1,061-1,337], p=0,003). In diabetes mellitus (DM) group independent risk factors that increased the risk of diabetes were pulse pressure (OR 1,123, 95%CI [1,063-1,188], p<0,001) and the result of the diabetes risk questionnaire. Independent risk factor that lowered the risk of diabetes (OR 0,068, 95%CI [0,018-0,251], p<0,001) and prediabetes (OR 0,324, 95%CI [0,109 0,969], p=0,044) was higher serum HDL cholesterol. CONCLUSIONS: Elevated level of total cholesterol and the result of the diabetes risk questionnaire are independent risk factors that increase the risk of prediabetes. Puls pressure and the result of the diabetes risk questionnaire are independent risk factors that increase the risk of diabetes. Independent risk factor that lowers the risk of glucose metabolism disorders is higher serum HDL cholesterol. PMID- 28662010 TI - [The impact of dynamic platform exercises on knee joint muscle strength in patients with gonarthrosis treated with microfracture method]. AB - : Osteoarthritis is the most common joint disease. Gonarthrosis is one of the most serious diseases the highly developed modern medicine must face. The number of patients suffering from joint pain and progressive disability is growing, especially in economically developed countries. Over the years, the disease has been considered merely as a symptom of aging and the effect of "wear and tear" of the cartilage. At present it is known that the degenerative joint disease is of chronic and progressive nature and its pathogenesis is complex. AIM: The aim of the study was to determine the impact of dynamic platform exercises on knee joint muscle strength in patients with gonarthrosis treated with microfracture method. MATERIALS AND METHODS: The study included 120 patients of both sexes, aged 40 to 65 years, height range1.60-1.90 m., weight 50- 100 kg. Patients were divided into two groups. Group I of 60 patients after knee arthroscopy (with performed microfractures on the articular cartilage) who were subjected to physiotherapy with the use of dynamometric platform and to isometric and dynamic exercises of muscles surrounding the knee joint. Group II (control) of 60 patients after knee arthroscopy (with performed microfractures on the articular cartilage), who were subjected only to isometric and dynamic exercises of muscles surrounding the knee joint. The patients underwent rehabilitation according to the same rehabilitation program suggested by the Medical Magnus Clinic in Lodz, which consisted in performing daily exercises in open and closed kinetic chains. All Group I and II patients were examined three times: before the start of the rehabilitation, after 4th week of rehabilitation (on the average 20 days of the procedures) and 3 months afterwards. The clinical examination included the measurement of muscle strength using Lovett test. RESULTS: It has been demonstrated that the introduction of modern highly specialized physiotherapy contributes to the improvement of the outcome and to the shortening of the treatment duration. A significant improvement was observed in all the examined patients at all stages of rehabilitation in relation to the baseline values. CONCLUSIONS: The conducted modern physiotherapy has a significant effect on the condition of patients after surgery. Different exercises on dynamometric platform combined with static and dynamic exercises exert a positive impact on the strengthening of muscles surrounding the knee joint, which in time perspective results in better quality of life of the patients. PMID- 28662012 TI - Fatal course of takotsubo cardiomyopathy in a female with recurrent Clostridium difficile infection. AB - : Among diverse triggering factors of stress-induced takotsubo cardiomyopathy (TC), a viral or bacterial infection is rarely observed. Sepsis is an exception, regardless of the etiologic pathogen, in which case an excess of catecholamines may result in acute left ventricular dysfunction. TC precipitated by Clostridium difficile infection (CDI) has been reported only in two patients so far. A CASE REPORT: The authors describe another case of TC triggered this time by recurrent C. difficile colitis which occurred in a 72-yearold female. Severe heart failure developed on the second day of a new episode of diarrhea. Echocardiography revealed apical ballooning, a typical form of TC, while the coronary arteries in coronary angiography were normal. Despite proper treatment of CDI, the course of the disease was fatal due to heart failure progression. In considerations of TC pathogenesis in the case presented, the impact of C. difficile toxins should be taken into account. One should remember about the potential extraintestinal complications of CDI, including sudden myocardial depression. PMID- 28662011 TI - [The assessment of the impact of rehabilitation on the pain intensity level in patients with herniated nucleus pulposus of the intervertebral disc]. AB - : Back disorders are very common phenomena in modern society. One of the methods of spinal pain treatment is performing surgery. Unfortunately, this method is not one hundred percent effective. Some patients show no improvement after surgery, the pain persists and even increases. In these cases, it is reasonable to use the term Failed Back Surgery Syndrome (FBSS), i.e. back pain syndrome after unsuccessful spine surgery. AIM: The aim of the study is to assess the impact of rehabilitation on the pain intensity level in patients with FBSS. MATERIALS AND METHODS: The study was conducted in a group of 38 patients aged from 32 to 87 (mean age 61 years), including 20 women and 18 men. All patients were operated for spinal pain syndrome. Afterwards, they underwent rehabilitation because of persisting pain after the surgery. For the pain assessment was used The Visual- Analogue Scale and The Laitinen Modified Questionnaire Indicators of Pain. The results were statistically analyzed. RESULTS: The study showed the high efficacy of specialized rehabilitation in patients with FBSS. CONCLUSIONS: The rehabilitation in patients with FBSS has a significant analgesic effect. Rehabilitation should be a gold standard in patients with FBSS. PMID- 28662013 TI - [The long-term results of the treatment of renal hypercalciuria - a report of two cases]. AB - : In recent years there can be observed a growing number of cases of urolithialis, both in children and in adults. Many pathogenic mechanisms of forming stones have been recognized and there is possible profounder diagnostics. Facing increasing problem of urolithialis in children, it is necessary to seek all possible causes of the disease to prevent forming stones, relapses and its further consequences. In most cases it is possible to diagnose metabolic abnormalities, of which the most frequent is hypercalciuria (excessive excretion of calcium in urine). In children, idiopathic hypercalciuria occurs the most frequently. It is possible to diagnose different types of hypercalciuria (absorptive, renal or resorptive) and apply appropriate treatment. A CASE REPORT: We present two cases of patients with urolithialis and diagnosed renal hypercalciuria. Time of observation of the first patient was more than 6 years, of the second one - 9 years. In both cases there has been applied appropriate treatment, however it was the proper realization of the recommendations that influenced long-term results of the treatment. Even the most detailed examination cannot assure effectiveness if the patient and the parents do not have positive approach to the treatment. PMID- 28662014 TI - Perceptions and Attitudes of Patients About Adult Vaccination and Their Vaccination Status: Still a Long Way to Go? AB - BACKGROUND Immunization is one of the most effective public health measures to prevent disease, but vaccination rates in adult populations still remain below the targets. Patient and physician attitudes about vaccination are important for adult vaccination. In this study, we aimed to determine patient attitudes and perceptions about vaccination and the vaccination coverage rates of adult patients in a university hospital in Turkey. MATERIAL AND METHODS A survey was conducted between October 2014 and May 2015 at the Internal Medicine Outpatient Clinics of a university hospital. Adult patients were asked to fill out a questionnaire on their perceptions and attitudes about vaccination and their vaccination status. RESULTS We interviewed 512 patients ages 19-64 years. Eighty percent of the study population thought that adults should be vaccinated, while only 36.1% of the patients stated that vaccination was ever recommended to them in their adult life. Forty-eight percent of the patients stated that they were vaccinated at least once in their adulthood. The most commonly received vaccine was tetanus vaccine in general, while influenza vaccine was the leading vaccine among patients with chronic medical conditions. While 71.4% of the patients to whom vaccination was recommended received the vaccine, 34.9% of the patients received a vaccine without any recommendation. CONCLUSIONS Although the vaccine coverage rates among adults in this survey were low, the perceptions of patients about adult vaccination were mainly positive and of many of them positively reacted when their physician recommended a vaccine. PMID- 28662015 TI - Multistate Outbreak of Salmonella Anatum Infections Linked to Imported Hot Peppers - United States, May-July 2016. AB - Foodborne salmonellosis causes an estimated 1 million illnesses and 400 deaths annually in the United States (1). Salmonella Anatum is one of the top 20 Salmonella serotypes in the United States. During 2013-2015 there were approximately 300-350 annual illnesses reported to PulseNet, the national molecular subtyping network for foodborne disease surveillance. In June 2016, PulseNet identified a cluster of 16 Salmonella Anatum infections with an indistinguishable pulsed-field gel electrophoresis (PFGE) pattern from four states.* In April 2016, the same PFGE pattern had been uploaded to PulseNet from an isolate obtained from an Anaheim pepper, a mild to medium hot pepper. Hot peppers include many pepper varieties, such as Anaheim, jalapeno, poblano, and serrano, which can vary in heat level from mild to very hot depending on the variety and preparation. This rare PFGE pattern had been seen only 24 times previously in the PulseNet database, compared with common PFGE patterns for this serotype which have been seen in the database hundreds of times. Local and state health departments, CDC, and the Food and Drug Administration (FDA) investigated to determine the cause of the outbreak. Thirty-two patients in nine states were identified with illness onsets from May 6-July 9, 2016. Whole-genome sequencing (WGS) was performed to characterize clinical isolates and the Anaheim pepper isolate further. The combined evidence indicated that fresh hot peppers were the likely source of infection; however, a single pepper type or source farm was not identified. This outbreak highlights challenges in reconciling epidemiologic and WGS data, and the difficulties of identifying ingredient-level exposures through epidemiologic investigations alone. PMID- 28662016 TI - Notes from the Field: Late-Onset Infant Group B Streptococcus Infection Associated with Maternal Consumption of Capsules Containing Dehydrated Placenta - Oregon, 2016. PMID- 28662017 TI - QuickStats: Percentage* of Adults Aged >=45 Years Who Reduced or Delayed Medication to Save Money? in the Past 12 Months Among Those Who Were Prescribed Medication, by Diagnosed Diabetes Status and AgeS - National Health Interview Survey, 2015. AB - In 2015, among adults aged 45-64 years who were prescribed any medication, those with diabetes were more likely than those without diabetes to have reduced or delayed medication (18.8% compared with 9.6%) to save money in the past 12 months, with measures that included skipping medication doses (13.2% compared with 6.4%), taking less medication (14.4% compared with 6.9%), and delaying filling a prescription (16.3% compared with 7.9%). Among adults >=65, those with diabetes were more likely than those without diabetes to reduce or delay medication (6.8% compared with 4.7%) and to have used each of the specific cost saving measures. Regardless of diabetes status, among adults who were prescribed medication, those aged 45-64 years were more likely than those aged >=65 years to reduce or delay taking medication to save money. PMID- 28662018 TI - Walking for Transportation or Leisure Among U.S. Women and Men - National Health Interview Survey, 2005-2015. AB - Physical activity confers considerable health benefits, but only half of U.S. adults report participating in levels of aerobic physical activity consistent with guidelines (1,2). Step It Up! The Surgeon General's Call to Action to Promote Walking and Walkable Communities identified walking as an important public health strategy to increase physical activity levels (3). A previous report showed that the self-reported prevalence of walking for transportation or leisure increased by 6 percentage points from 2005 to 2010 (4), but it is unknown whether this increase has been sustained. CDC analyzed National Health Interview Survey (NHIS) data from 2005 (26,551 respondents), 2010 (23,313), and 2015 (28,877) to evaluate trends in the age-adjusted prevalence of self-reported walking among adults aged >=18 years. The prevalence of walking increased steadily among women, from 57.3% in 2005, to 62.5% in 2010, and to 65.1% in 2015 (significant linear trend). Among men, a significant linear increase in reported walking was observed, from 54.3% in 2005, to 61.8% in 2010, and to 62.8% in 2015, although the increase stalled between 2010 and 2015 (significant linear and quadratic trends). Community design policies and practices that encourage pedestrian activity and programs tailored to the needs of specific population subgroups remain important strategies for promoting walking (3). PMID- 28662020 TI - Hormonal Management of Small Bowel Failure. PMID- 28662019 TI - Update: Influenza Activity in the United States During the 2016-17 Season and Composition of the 2017-18 Influenza Vaccine. AB - During the 2016-17 influenza season (October 2, 2016-May 20, 2017) in the United States, influenza activity* was moderate. Activity remained low through November, increased during December, and peaked in February nationally, although there were regional differences in the timing of influenza activity. Influenza A(H3N2) viruses predominated through mid-March and were predominant overall for the season, but influenza B viruses were most commonly reported from late March through May. This report summarizes influenza activity in the United States during October 2, 2016-May 20, 2017? and updates the previous summary (1). PMID- 28662021 TI - The Role of Vitamin D and Vitamin D Receptors in Colon Cancer. PMID- 28662023 TI - A Randomized Controlled Trial of Glycyrrhizin Plus Tenofovir vs. Tenofovir in Chronic Hepatitis B with Severe Acute Exacerbation. AB - OBJECTIVES: Severe acute exacerbation (SAE) of chronic hepatitis B (CHB) may progress to liver failure with high potential mortality despite the prompt treatment with nucleos(t)ide analogs. This study aimed to evaluate the efficacy and safety of glycyrrhizin in the treatment of CHB with SAE. METHODS: Sixty patients with SAE of CHB were randomly treated with tenofovir plus intravenous glycyrrhizin (group A, n=30) or with tenofovir alone (group B, n=30). Primary end points were the improvement of serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and model for end-stage liver disease (MELD) score. Secondary end point was overall mortality or receipt of liver transplantation by week 24. RESULTS: Patients in group A had significant reductions of serum AST and ALT levels from baseline at days 3, 5, 8, and 15 than those in group B (all P<0.05). The MELD score significantly decreased since week 1 in the group A patients, whereas there were no changes relative to baseline in group B patients at weeks 1 and 2. By week 24, one (3.3%) of group A patients and four (13.3%) of group B patients died (n=3) or received liver transplantation (n=1) (P=0.177). Multivariate analysis identified baseline MELD score (P=0.021) as an independent factor for mortality or receipt of liver transplantation. There were no differences in the rates of grade 3 hypertension, hypokalemia and ascites between two groups. CONCLUSIONS: Early introduction of glycyrrhizin can be safe and helpful for patients with SAE of CHB. PMID- 28662022 TI - Impaired Esophageal Motility and Clearance Post-Lung Transplant: Risk For Chronic Allograft Failure. AB - OBJECTIVES: Gastroesophageal reflux is common in patients post-lung transplantation (LTx) and thus considered a risk factor for aspiration and consequently allograft rejection and the development of chronic allograft failure. However, evidence supporting this remains unclear and often contradictory. Our aim was to examine the role played by esophageal motility on gastroesophageal reflux exposure, along with its clearance and that of boluses swallowed, and the relationship to development of obstructive chronic lung allograft dysfunction (o-CLAD). METHODS: Patients post-LTx (n=50, 26 female; mean age 55 years (range, 20-73 years)) completed high-resolution impedance manometry and 24-h pH/impedance. Esophageal motility abnormalities were classified based upon the Chicago Classification version 3.0. RESULTS: Esophagogastric junction outflow obstruction alone (EGJOOa) (P=0.01), incomplete bolus transit (IBT) (P=0.006) and proximal reflux (P=0.042) increased the risk for o-CLAD. Patients with EGJOOa were most likely to present with o-CLAD (77%); despite being less likely to exhibit abnormal numbers of reflux events (10%) compared with those with normal motility (o-CLAD: 29%, P<0.05; abnormal reflux events: 64%, P<0.05). Patients with EGJOOa had lower total reflux bolus exposure time than those with normal motility (0.6 vs. 1.5%; P<0.05). In addition, poor esophageal clearance documented by abnormal post-reflux swallow-induced peristaltic wave index associated with o-CLAD; inversely correlating with the proportion of reflux events reaching the proximal esophagus (r=-0.251; P=0.052). CONCLUSIONS: These observations support esophageal dysmotility, especially EGJOOa, and impaired clearance of swallowed bolus or refluxed contents, more so than just the presence of gastroesophageal reflux alone, as important risk factors in the development of o-CLAD. PMID- 28662024 TI - Fungemia associated with Schizophyllum commune in Brazil. PMID- 28662025 TI - Biomolecular changes that occur in the antennal gland of the giant freshwater prawn (Machrobrachium rosenbergii). AB - In decapod crustaceans, the antennal gland (AnG) is a major primary source of externally secreted biomolecules, and some may act as pheromones that play a major role in aquatic animal communication. In aquatic crustaceans, sex pheromones regulate reproductive behaviours, yet they remain largely unidentified besides the N-acetylglucosamine-1,5-lactone (NAGL) that stimulates male to female attraction. In this study, we used an AnG transcriptome of the female giant freshwater prawn (Macrobrachium rosenbergii) to predict the secretion of 226 proteins, including the most abundantly expressed transcripts encoding the Spaetzle protein, a serine protease inhibitor, and an arthropodial cuticle protein AMP 8.1. A quantitative proteome analysis of the female AnG at intermolt, premolt and postmolt, identified numerous proteins of different abundances, such as the hemocyanin subunit 1 that is most abundant at intermolt. We also show that hemocyanin subunit 1 is present within water surrounding females. Of those metabolites identified, we demonstrate that the NAGL and N-acetylglucosamine (NAG) can bind with high affinity to hemocyanin subunit 1. In summary, this study has revealed components of the female giant freshwater prawn AnG that are released and contribute to further research towards understanding crustacean conspecific signalling. PMID- 28662026 TI - Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions. AB - Parasitic diseases caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania are an urgent public health crisis in the developing world. These closely related species possess a number of multimeric enzymes in highly conserved pathways involved in vital functions, such as redox homeostasis and nucleotide synthesis. Computational alanine scanning of these protein-protein interfaces has revealed a host of potentially ligandable sites on several established and emerging anti-parasitic drug targets. Analysis of interfaces with multiple clustered hotspots has suggested several potentially inhibitable protein protein interactions that may have been overlooked by previous large-scale analyses focusing solely on secondary structure. These protein-protein interactions provide a promising lead for the development of new peptide and macrocycle inhibitors of these enzymes. PMID- 28662027 TI - The different expressed serum proteins in rhCygb treated rat model of liver fibrosis by the optimized two-dimensional gel electrophoresis. AB - Liver fibrosis, a common pathological process of chronic liver diseases, is the final stage of liver dysfunction that has severely deleterious impact on human health. Cytoglobin was first discovered in 2001 by proteomic analysis in rat stellate cells and was reported to play an important role in controlling tissue fibrosis. However, the mechanism by which cytoglobin inhibits or reverses the progression of fibrosis remains unclear. The present study examines the effect of recombinant human cytoblobin (rhCygb) in a rat model of liver fibrosis. Proteomic approaches were employed to identify differentially expressed proteins in the fibrosis model. Optimized conditions for two-dimensional gel electrophoresis were developed to provide improved protein detection and separation. A total of 43 spots were obtained and, through the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry, 30 differentially expressed proteins were identified. Gene ontology term annotation and KEGG pathway analysis allowed us to explore the function of the represented proteins. Based on these results, we provide a theory of the molecular mechanism related to rhCygb reversion of fibrosis and which will assist in the identification of biomarkers in patient serum to improve early diagnosis of liver fibrosis. PMID- 28662028 TI - Cryptococcal meningitis: A neglected NTD? PMID- 28662029 TI - A genetic framework controlling the differentiation of intestinal stem cells during regeneration in Drosophila. AB - The speed of stem cell differentiation has to be properly coupled with self renewal, both under basal conditions for tissue maintenance and during regeneration for tissue repair. Using the Drosophila midgut model, we analyze at the cellular and molecular levels the differentiation program required for robust regeneration. We observe that the intestinal stem cell (ISC) and its differentiating daughter, the enteroblast (EB), form extended cell-cell contacts in regenerating intestines. The contact between progenitors is stabilized by cell adhesion molecules, and can be dynamically remodeled to elicit optimal juxtacrine Notch signaling to determine the speed of progenitor differentiation. Notably, increasing the adhesion property of progenitors by expressing Connectin is sufficient to induce rapid progenitor differentiation. We further demonstrate that JAK/STAT signaling, Sox21a and GATAe form a functional relay to orchestrate EB differentiation. Thus, our study provides new insights into the complex and sequential events that are required for rapid differentiation following stem cell division during tissue replenishment. PMID- 28662031 TI - High risk for chikungunya virus to initiate an enzootic sylvatic cycle in the tropical Americas. AB - BACKGROUND: Chikungunya virus (CHIKV) has dispersed in the Americas since 2013, and its range of distribution has overlapped large forested areas. Herein, we assess vector competence of two sylvatic Neotropical mosquito species, Haemagogus leucocelaenus and Aedes terrens, to evaluate the risk of CHIKV to initiate a sylvatic cycle in the continent. METHODOLOGY/PRINCIPAL FINDINGS: Haemagogus leucocelaenus and Ae. terrens from the state of Rio de Janeiro, Brazil were orally challenged with the two CHIKV lineages circulating in the Americas. Fully engorged females were kept in incubators at 28+/-1 degrees C and 70+/-10% humidity and examined at 3 and 7 days after virus exposure. Body (thorax plus abdomen), head and saliva samples were analyzed for respectively determining infection, dissemination and transmission. Both Hg. leucocelaenus and Ae. terrens exhibited high infection and dissemination rates with both CHIKV isolates at 7 dpi, demonstrating that they are susceptible to CHIKV, regardless of the lineage. Remarkably, Hg. leucocelaenus expectorated infectious viral particles as rapidly as 3 days after the infectious blood meal, displaying higher values of transmission rate and efficiency than Ae. terrens. Nevertheless, both species were competent to experimentally transmit both CHIKV genotypes, exhibiting vector competence similar to several American Aedes aegypti. CONCLUSIONS/SIGNIFICANCE: These results point out the high risk for CHIKV to establish a sylvatic transmission cycle in the Americas, which could be a serious health issue as CHIKV would become another zoonotic infection difficult to control in the continent. PMID- 28662030 TI - Chemosensory and hyperoxia circuits in C. elegans males influence sperm navigational capacity. AB - The sperm's crucial function is to locate and fuse with a mature oocyte. Under laboratory conditions, Caenorhabditis elegans sperm are very efficient at navigating the hermaphrodite reproductive tract and locating oocytes. Here, we identify chemosensory and oxygen-sensing circuits that affect the sperm's navigational capacity. Multiple Serpentine Receptor B (SRB) chemosensory receptors regulate Galpha pathways in gustatory sensory neurons that extend cilia through the male nose. SRB signaling is necessary and sufficient in these sensory neurons to influence sperm motility parameters. The neuropeptide Y pathway acts together with SRB-13 to antagonize negative effects of the GCY-35 hyperoxia sensor on spermatogenesis. SRB chemoreceptors are not essential for sperm navigation under low oxygen conditions that C. elegans prefers. In ambient oxygen environments, SRB-13 signaling impacts gene expression during spermatogenesis and the sperm's mitochondria, thereby increasing migration velocity and inhibiting reversals within the hermaphrodite uterus. The SRB-13 transcriptome is highly enriched in genes implicated in pathogen defense, many of which are expressed in diverse tissues. We show that the critical time period for SRB-13 signaling is prior to spermatocyte differentiation. Our results support the model that young C. elegans males sense external environment and oxygen tension, triggering long lasting downstream signaling events with effects on the sperm's mitochondria and navigational capacity. Environmental exposures early in male life may alter sperm function and fertility. PMID- 28662032 TI - Renal localization and regulation by dietary phosphate of the MCT14 orphan transporter. AB - MCT14 is an orphan transporter belonging to the SLC16 transporter family mediating the transport of monocarboxylates, aromatic amino acids, creatine, and thyroid hormones. The expression, tissue localization, regulation, and function of MCT14 are unknown. In mouse MCT14 mRNA abundance is highest in kidney. Using a newly developed and validated antibody, MCT14 was localized to the luminal membrane of the thick ascending limb of the loop of Henle colocalizing in the same cells with uromodulin and NKCC2. MCT14 mRNA and protein was found to be highly regulated by dietary phosphate intake in mice being increased by high dietary phosphate intake at both mRNA and protein level. In order to identify the transport substrate(s), we expressed MCT14 in Xenopus laevis oocytes where MCT14 was integrated into the plasma membrane. However, no transport was discovered for the classic substrates of the SLC16 family nor for phosphate. In summary, MCT14 is an orphan transporter regulated by phosphate and highly enriched in kidney localizing to the luminal membrane of one specific nephron segment. PMID- 28662033 TI - A phase I study of pazopanib in combination with escalating doses of 131I in patients with well-differentiated thyroid carcinoma borderline refractory to radioiodine. AB - OBJECTIVE: This trial was conducted to evaluate the ability of pazopanib to overcome therapeutic 131I resistance. MATERIALS, METHODS AND PATIENTS: This phase 1 trial assesses the combination of pazopanib and escalating doses of radioiodine (131I) in patients with recurrent or metastatic thyroid cancer that are borderline or relatively iodine refractory. Radioiodine uptake scans were assessed post therapy and compared to historical pre-treatment scans. Patients underwent FDG PET/CT before and after the initial pazopanib treatment to identify the impact of pazopanib on the cancer prior to 131I therapy. RESULTS: A dose limiting toxicity (cardiac arrhythmia and grade 3 fatigue) in the first patient in the first cohort prompted expansion to a total of 6 patients. Additional grade 3-4 hematologic toxicity and low accrual in the expanded cohort led to the decision not to pursue further study of the regimen. In patients with measurable disease 4/5 (80%) achieved stable disease. Median progression free survival was 6.7 months. At 3 years of follow up, one patient died due to progressive disease, two are being treated with systemic therapy and 3 continue without requiring subsequent therapy at 15, 27 and 35 months from the last dose of pazopanib. There was no convincing impact of pazopanib on iodine uptake in scans performed pre- and post-therapy compared to scans from historical 131I treatments without pazopanib. CONCLUSION: Despite a suggestion of therapeutic efficacy, combined pazopanib and 131I resulted in increased toxicity. There was no convincing evidence that the administration of pazopanib improved iodine uptake or retention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01413113. PMID- 28662035 TI - The emerging GII.P16-GII.4 Sydney 2012 norovirus lineage is circulating worldwide, arose by late-2014 and contains polymerase changes that may increase virus transmission. AB - Noroviruses are a leading cause of human gastroenteritis worldwide. The norovirus genotype GII.4 is the most prevalent genotype in the human population and has caused six pandemics since 1995. A novel norovirus lineage containing the GII.P16 polymerase and pandemic GII.4 Sydney 2012 capsid was recently detected in Asia and Germany. We demonstrate that this lineage is also circulating within the UK and USA and has been circulating since October 2014 or earlier. While the lineage does not contain unique substitutions in the capsid, it does contain polymerase substitutions close to positions known to influence polymerase function and virus transmission. These polymerase substitutions are shared with a GII.P16-GII.2 virus that dominated outbreaks in Germany in Winter 2016. We suggest that the substitutions in the polymerase may have resulted in a more transmissible virus and the combination of this polymerase and the pandemic GII.4 capsid may result in a highly transmissible virus. Further surveillance efforts will be required to determine whether the GII.P16-GII.4 Sydney 2012 lineage increases in frequency over the coming months. PMID- 28662034 TI - Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial. AB - BACKGROUND: There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option. METHODS: A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption. RESULTS: 378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003). CONCLUSIONS: Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738. TRIAL REGISTRATION: ClinicalTrials.gov NCT01310738. PMID- 28662036 TI - Prevention of mother-to-child transmission of HIV: Postpartum adherence to Option B+ until 18 months in Western Uganda. AB - Since 2012, the WHO recommends Option B+ for the prevention of mother-to-child transmission of HIV. This approach entails the initiation of lifelong antiretroviral therapy in all HIV-positive pregnant women, also implying protection during breastfeeding for 12 months or longer. Research on long-term adherence to Option B+ throughout breastfeeding is scarce to date. Therefore, we conducted a prospective observational cohort study in Fort Portal, Western Uganda, to assess adherence to Option B+ until 18 months postpartum. In 2013, we recruited 67 HIV-positive, Option B+ enrolled women six weeks after giving birth and scheduled them for follow-up study visits after six, twelve and 18 months. Two adherence measures, self-reported drug intake and amount of drug refill visits, were combined to define adherence, and were assessed together with feeding information at all study visits. At six months postpartum, 51% of the enrolled women were considered to be adherent. Until twelve and 18 months postpartum, adherence for the respective follow-up interval decreased to 19% and 20.5% respectively. No woman was completely adherent until 18 months. At the same time, 76.5% of the women breastfed for >=12 months. Drug adherence was associated with younger age (p<0.01), lower travel costs (p = 0.02), and lower number of previous deliveries (p = 0.04). Long-term adherence to Option B+ seems to be challenging. Considering that in our cohort, prolonged breastfeeding until >=12 months was widely applied while postpartum adherence until the end of breastfeeding was poor, a potential risk of postpartum vertical transmission needs to be taken seriously into account for Option B+ implementation. PMID- 28662038 TI - Venezuela and its rising vector-borne neglected diseases. PMID- 28662039 TI - Expression of Rickettsia Adr2 protein in E. coli is sufficient to promote resistance to complement-mediated killing, but not adherence to mammalian cells. AB - Bacteria exposed to host serum are subject to the antibacterial effects to the complement system. However, pathogenic microorganisms have evolved mechanisms of evading this immune attack. We have previously demonstrated that at least two R. conorii antigens, RC1281/Adr1 and OmpB beta-peptide, contribute to the evasion of complement-mediated killing by binding the complement regulatory proteins vitronectin and factor H. RC1282/Adr2, a protein related to Adr1, is predicted to share similar structural features, suggesting that this protein may also contribute to evasion of complement-mediated killing. Interestingly, the R. prowazekii Adr1 and Adr2(RP828) proteins were originally found to interact with host cell surface proteins, suggesting their putative roles as adhesins in this pathogenic rickettsial species. In this study, we expressed both R. conorii and R. prowazekii Adr2 on the surface of a non-adherent, serum-sensitive strain of E. coli to examine the potential role of this protein to mediate evasion of complement-mediated killing and adherence to host cells. We demonstrate that, similar to R. conorii Adr1, R. conorii and R. prowazekii Adr2 are sufficient to mediate serum resistance and to promote interaction with the host complement regulator vitronectin. Furthermore, we demonstrate that expression of Adr2 in a non-adherent strain of E. coli is insufficient to mediate adherence to cultured mammalian endothelial cells. Together, our data demonstrate that the R. conorii and R. prowazekii Adr2 protein does not participate in the interactions with mammalian cells, but rather, participates in the evasion of killing by complement. PMID- 28662037 TI - Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury. AB - The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in fB-/- mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB-/- mice, 20 +/- 4%; WT mice, 45 +/- 3%; P < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB /- mice, 0 +/- 0%; WT mice, 31 +/- 6%; P<0.05). Reconstitution of fB-/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological amplifier of I/R induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury. PMID- 28662040 TI - Tuning the transcription and translation of L-amino acid deaminase in Escherichia coli improves alpha-ketoisocaproate production from L-leucine. AB - alpha-Ketoisocaproate (KIC) is used widely in the pharmaceutical and nutraceutical industries. In previous studies, we achieved a one-step biosynthesis of KIC from l-leucine, using an Escherichia coli whole-cell biocatalyst expressing an l-amino acid deaminase (l-AAD) from Proteus vulgaris. Herein, we report the fine-tuning of l-AAD gene expression in E. coli BL21 (DE3) at the transcriptional and translational levels to improve the KIC titer. By optimizing the plasmid origin with different copy numbers, modulating messenger RNA structure downstream of the initiation codon, and designing the sequences at the ribosome binding site, we increased biocatalyst activity to 31.77%, 24.89%, and 30.20%, respectively, above that achieved with BL21/pet28a-lad. The highest KIC titers reached 76.47 g.L-1, 80.29 g.L-1, and 81.41 g.L-1, respectively. Additionally, the integration of these three engineering strategies achieved an even higher KIC production of 86.55 g.L-1 and a higher l-leucine conversion rate of 94.25%. The enzyme-engineering strategies proposed herein may be generally applicable to the construction of other biocatalysts. PMID- 28662041 TI - Effect of national wealth on BMI: An analysis of 206,266 individuals in 70 low-, middle- and high-income countries. AB - BACKGROUND: This study explores the relationship between BMI and national-wealth and the cross-level interaction effect of national-wealth and individual household-wealth using multilevel analysis. METHODS: Data from the World Health Survey conducted in 2002-2004, across 70 low-, middle- and high-income countries was used. Participants aged 18 years and over were selected using multistage, stratified cluster sampling. BMI was used as outcome variable. The potential determinants of individual-level BMI were participants' sex, age, marital-status, education, occupation, household-wealth and location(rural/urban) at the individual-level. The country-level factors used were average national income (GNI-PPP) and income inequality (Gini-index). A two-level random-intercepts and fixed-slopes model structure with individuals nested within countries was fitted, treating BMI as a continuous outcome. RESULTS: The weighted mean BMI and standard error of the 206,266 people from 70-countries was 23.90 (4.84). All the low income countries were below the 25.0 mean BMI level and most of the high-income countries were above. All wealthier quintiles of household-wealth had higher scores in BMI than lowest quintile. Each USD10000 increase in GNI-PPP was associated with a 0.4 unit increase in BMI. The Gini-index was not associated with BMI. All these variables explained 28.1% of country-level, 4.9% of individual-level and 7.7% of total variance in BMI. The cross-level interaction effect between GNI-PPP and household-wealth was significant. BMI increased as the GNI-PPP increased in first four quintiles of household-wealth. However, the BMI of the wealthiest people decreased as the GNI-PPP increased. CONCLUSION: Both individual-level and country-level factors made an independent contribution to the BMI of the people. Household-wealth and national-income had significant interaction effects. PMID- 28662042 TI - Response of adult dragonflies to artificial prey of different size and colour. AB - Aposematism is an evolved, cross-species association between a preys' unprofitability and the presence of conspicuous signals. Avian predators have been widely employed to understand the evolution of these warning signals However, insect predators are abundant, diverse, and highly visual foragers that have been shown to be capable of learned aversion. Therefore, it is likely that their behaviour also shapes the nature of anti-predator traits. In this study, we evaluated the rates of attack of a community (13 species) of mature adult dragonflies (Odonata) on artificial prey of varying size (2.5-31 mm lengthwise) and colour pattern (black, black/yellow striped). The relative attack rates of dragonflies on prey increased as prey size decreased, but there was no evidence that the attack rates by dragonflies were affected by prey colour pattern and no evidence for an interaction between colour pattern and size. To investigate prey selection by specific predator species under field conditions, we compared the time to attack distributions of black-painted prey presented to two common dragonflies: Leucorrhinia intacta and the larger, Libellula pulchella. We found that the two dragonfly species, as well as the two sexes, had different foraging responses. L. pulchella was more likely to attack larger prey, and females of both species more likely to attack prey than males. Collectively, our results indicate that dragonflies are highly size selective. However, while the nature of this selectivity varies among dragonfly species, there is little evidence that classic black/yellow warning signals deter attack by these aerial invertebrate predators. PMID- 28662043 TI - Treating village newcomers and travelers for trachoma: Results from ASANTE cluster randomized trial. AB - TRIAL DESIGN: Trachoma is targeted for global elimination. Infection rates with Chlamydia trachomatis are higher in new arrivals to a community and in travelers who leave for extended periods, suggesting they are sources of re-infection. This community-randomized, clinical trial was designed to determine if a surveillance program that targeted newcomers and travelers, identified weekly, would result in more communities achieving levels of infection of <=1%. METHODS: 52 communities were randomly allocated 1:1 to the control (annual MDA alone if warranted) or intervention arm (annual MDA if warranted, plus a surveillance program to identify and treat newcomers and travelers). In each community, surveys were completed every six months on a random sample of 100 children ages 1-9 years for trachoma and infection. The primary outcome was the proportion of communities in the intervention arm, compared to the control arm, which had a prevalence of infection at <=1% by 24 months. Registered: clinicaltrials.gov(NCT01767506). RESULTS: Intervention communities experienced an average of 110 surveillance events per month. At 24 months, 7 (27%) of 26 intervention communities achieved a prevalence of infection <=1% compared to 4 (15%) of the 26 control communities (odds ratio = 2.6, 95%CI = 0.56-11.9). At 24 months, the average infection prevalence in the intervention communities was 4.8, compared to 6.9 in the control communities (p = .06). CONCLUSION: Despite surveillance programs for community newcomers and travelers, the proportion of intervention communities with a level of infection <=1% was lower than expected and not significantly different from control communities. PMID- 28662044 TI - Whole genome structural analysis of Caribbean hair sheep reveals quantitative link to West African ancestry. AB - Hair sheep of Caribbean origin have become an important part of the U.S. sheep industry. Their lack of wool eliminates a number of health concerns and drastically reduces the cost of production. More importantly, Caribbean hair sheep demonstrate robust production performance even in the presence of drug resistant gastrointestinal nematodes, a rising concern to the industry. Despite the growing importance of hair sheep in the Americas their genetic origins have remained speculative. Prior to this report no genetic studies were able to identify a unique geographical origin of hair sheep in the New World. Our study clarifies the African and European ancestry of Caribbean hair sheep. Whole-genome structural analysis was conducted on four established breeds of hair sheep from the Caribbean region. Using breeds representing Africa and Europe we establish an objective measure indicating Caribbean hair sheep are derived from Iberian and West African origins. Caribbean hair sheep result from West African introgression into established ecotypes of Iberian descent. Genotypes from 47,750 autosomal single nucleotide polymorphism markers scored in 290 animals were used to characterize the population structure of the St. Croix, Barbados Blackbelly, Morada Nova, and Santa Ines. Principal components, admixture, and phylogenetic analyses results correlate with historical patterns of colonization and trade. These patterns support co-migration of these sheep with humans. PMID- 28662045 TI - Describing the performance of U.S. hospitals by applying big data analytics. AB - Public reporting of measures of hospital performance is an important component of quality improvement efforts in many countries. However, it can be challenging to provide an overall characterization of hospital performance because there are many measures of quality. In the United States, the Centers for Medicare and Medicaid Services reports over 100 measures that describe various domains of hospital quality, such as outcomes, the patient experience and whether established processes of care are followed. Although individual quality measures provide important insight, it is challenging to understand hospital performance as characterized by multiple quality measures. Accordingly, we developed a novel approach for characterizing hospital performance that highlights the similarities and differences between hospitals and identifies common patterns of hospital performance. Specifically, we built a semi-supervised machine learning algorithm and applied it to the publicly-available quality measures for 1,614 U.S. hospitals to graphically and quantitatively characterize hospital performance. In the resulting visualization, the varying density of hospitals demonstrates that there are key clusters of hospitals that share specific performance profiles, while there are other performance profiles that are rare. Several popular hospital rating systems aggregate some of the quality measures included in our study to produce a composite score; however, hospitals that were top-ranked by such systems were scattered across our visualization, indicating that these top ranked hospitals actually excel in many different ways. Our application of a novel graph analytics method to data describing U.S. hospitals revealed nuanced differences in performance that are obscured in existing hospital rating systems. PMID- 28662046 TI - A prospective study on an innovative online forum for peer reviewing of surgical science. AB - BACKGROUND: Peer review is important to the scientific process. However, the present system has been criticised and accused of bias, lack of transparency, failure to detect significant breakthrough and error. At the British Journal of Surgery (BJS), after surveying authors' and reviewers' opinions on peer review, we piloted an open online forum with the aim of improving the peer review process. METHODS: In December 2014, a web-based survey assessing attitudes towards open online review was sent to reviewers with a BJS account in Scholar One. From April to June 2015, authors were invited to allow their manuscripts to undergo online peer review in addition to the standard peer review process. The quality of each review was evaluated by editors and editorial assistants using a validated instrument based on a Likert scale. RESULTS: The survey was sent to 6635 reviewers. In all, 1454 (21.9%) responded. Support for online peer review was strong, with only 10% stating that they would not subject their manuscripts to online peer review. The most prevalent concern was about intellectual property, being highlighted in 118 of 284 comments (41.5%). Out of 265 eligible manuscripts, 110 were included in the online peer review trial. Around 7000 potential reviewers were invited to review each manuscript. In all, 44 of 110 manuscripts (40%) received 100 reviews from 59 reviewers, alongside 115 conventional reviews. The quality of the open forum reviews was lower than for conventional reviews (2.13 (+/- 0.75) versus 2.84 (+/- 0.71), P<0.001). CONCLUSION: Open online peer review is feasible in this setting, but it attracts few reviews, of lower quality than conventional peer reviews. PMID- 28662047 TI - MDD-Palm: Identification of protein S-palmitoylation sites with substrate motifs based on maximal dependence decomposition. AB - S-palmitoylation, the covalent attachment of 16-carbon palmitic acids to a cysteine residue via a thioester linkage, is an important reversible lipid modification that plays a regulatory role in a variety of physiological and biological processes. As the number of experimentally identified S-palmitoylated peptides increases, it is imperative to investigate substrate motifs to facilitate the study of protein S-palmitoylation. Based on 710 non-homologous S palmitoylation sites obtained from published databases and the literature, we carried out a bioinformatics investigation of S-palmitoylation sites based on amino acid composition. Two Sample Logo indicates that positively charged and polar amino acids surrounding S-palmitoylated sites may be associated with the substrate site specificity of protein S-palmitoylation. Additionally, maximal dependence decomposition (MDD) was applied to explore the motif signatures of S palmitoylation sites by categorizing a large-scale dataset into subgroups with statistically significant conservation of amino acids. Single features such as amino acid composition (AAC), amino acid pair composition (AAPC), position specific scoring matrix (PSSM), position weight matrix (PWM), amino acid substitution matrix (BLOSUM62), and accessible surface area (ASA) were considered, along with the effectiveness of incorporating MDD-identified substrate motifs into a two-layered prediction model. Evaluation by five-fold cross-validation showed that a hybrid of AAC and PSSM performs best at discriminating between S-palmitoylation and non-S-palmitoylation sites, according to the support vector machine (SVM). The two-layered SVM model integrating MDD identified substrate motifs performed well, with a sensitivity of 0.79, specificity of 0.80, accuracy of 0.80, and Matthews Correlation Coefficient (MCC) value of 0.45. Using an independent testing dataset (613 S-palmitoylated and 5412 non-S-palmitoylated sites) obtained from the literature, we demonstrated that the two-layered SVM model could outperform other prediction tools, yielding a balanced sensitivity and specificity of 0.690 and 0.694, respectively. This two layered SVM model has been implemented as a web-based system (MDD-Palm), which is now freely available at http://csb.cse.yzu.edu.tw/MDDPalm/. PMID- 28662048 TI - Capacity of blood plasma is higher in birds breeding in radioactively contaminated areas. AB - BACKGROUND: Environmental pollution in general, and radioactive contamination in particular, may deeply affect host-parasite relationships and their consequences for the evolution of organisms. The nuclear accident that occurred more than 30 years ago in Chernobyl resulted in significant changes in diversity and richness of microbial communities that could influence characteristics of animal-bacteria interactions, including host immune responses and competitive interference by bacteria. Given the high mortality rate of birds breeding in radioactively contaminated zones, those with stronger defences against infections should experience significant fitness advantages. METHODOLOGY/PRINCIPAL FINDINGS: Here we characterized antimicrobial capacity of barn swallows (Hirundo rustica) from different Ukrainian populations (subject to a gradient of ionizing radiation) against 12 bacterial species. We also quantified constitutive innate immunity, which is the non-specific first barrier of protection of hosts against microbial parasites. We found a positive association between specific antimicrobial capacity of individual hosts and radiation levels in breeding habitats even after controlling for other confounding variables such as sex and age. However, no significant relationship was found between immunocompetence (non-specific response) and background radiation. CONCLUSIONS/SIGNIFICANCE: These results suggest that radiation selects for broad antimicrobial spectra of barn swallows, although not for all bacterial strains. We discuss these results in the framework of host-parasite evolution under extreme environmental conditions. PMID- 28662049 TI - One year results of a randomized controlled clinical study evaluating the effects of non-surgical periodontal therapy of chronic periodontitis in conjunction with three or seven days systemic administration of amoxicillin/metronidazole. AB - BACKGROUND: To evaluate the clinical outcomes 12 months after systemic administration of amoxicillin (AMX) and metronidazole (MET) adjunctive to subgingival debridement (SD) in patients with severe chronic periodontitis (sChP). MATERIAL AND METHODS: 102 patients with sChP were treated randomly as follows: SD within 2 consecutive days and placebo for 7 days (group A), SD+AMX+MET (both 500mg x3 times daily TID) for 3 days (group B), SD+AMX+MET (both 500mg x 3 TID) for 7 days (group C). At baseline, at 3-, 6-, and 12-months post treatment probing pocket depth (PD), clinical attachment level (CAL), furcation involvement, bleeding on probing (BOP), full-mouth plaque score (FMPS) were determined. The reduction in the number of sites with PD>=6mm was defined as main outcome variable. RESULTS: 75 patients completed the study. At 12 months, all three treatment groups showed statistically significant improvements (p<0.001) of mean PD, CAL, BOP and number of sites with PD>=6mm compared to baseline. Mean residual PD were statistically significantly lower and CAL gain statistically significantly greater in the two antibiotic groups as compared to placebo. While PD reductions (p = 0.012) and CAL gain (p = 0.017) were statistically significantly higher in group C compared to group A, only the 3-day AB group showed statistically significantly fewer sites with PD>=6mm at 12 m (p = 0.003). The reduction in the number of sites with PD>=6 mm (primary outcome) showed no statistical significant differences between the 3 treatment groups. However, in both antibiotic groups significantly more patients compared to the placebo group reached a low risk for disease progression at 12 months (<=4 sites with PD>=5mm). CONCLUSION: At 12 months, both adjunctive antibiotic protocols resulted in statistically significantly greater clinical improvements compared to placebo. PMID- 28662050 TI - Cord blood T cell subpopulations and associations with maternal cadmium and arsenic exposures. AB - BACKGROUND: Arsenic and cadmium are environmental pollutants, and although the evidence for adverse immune effects after prenatal arsenic and cadmium exposures is increasing, little is known about the underlying immunological mechanisms. METHODS: We investigated the relationship between prenatal arsenic and cadmium exposures and a variety of T cell subpopulations measured in cord blood for 63 participants in the New Hampshire Birth Cohort Study. Post-partum toenail concentrations of arsenic and cadmium were used as an estimate of maternal exposure during pregnancy. The characteristics of cord blood proportions of T lymphocytes and subpopulations (expression of markers for Th1, Th2, Th17, Th1Th17, induced and natural regulatory T cells and NKTs) are presented. RESULTS: In regression analyses, maternal arsenic exposure levels were inversely associated with cord blood T helper memory cells (-21%, 95% CI: -36%, -3%) and the association was found to be stronger in females. They were also inversely associated with activated T helper memory cells, particularly in males (-26%, 95% CI: -43%, -3%). Similarly, inverse associations were observed between cadmium exposure levels and activated T helper memory cells (-16%, 95% CI: -30%, -1%) and also for T helper memory cells in females (-20%, 95% CI: -35%, -3%). CONCLUSION: The results suggest that prenatal exposures to relatively low levels of arsenic and cadmium may contribute to altered distribution of T cell populations at birth. These changes in theory, could have contributed to the previously reported immunosuppressive effects observed later in infancy/childhood. PMID- 28662051 TI - RRmix: A method for simultaneous batch effect correction and analysis of metabolomics data in the absence of internal standards. AB - With the surge of interest in metabolism and the appreciation of its diverse roles in numerous biomedical contexts, the number of metabolomics studies using liquid chromatography coupled to mass spectrometry (LC-MS) approaches has increased dramatically in recent years. However, variation that occurs independently of biological signal and noise (i.e. batch effects) in metabolomics data can be substantial. Standard protocols for data normalization that allow for cross-study comparisons are lacking. Here, we investigate a number of algorithms for batch effect correction and differential abundance analysis, and compare their performance. We show that linear mixed effects models, which account for latent (i.e. not directly measurable) factors, produce satisfactory results in the presence of batch effects without the need for internal controls or prior knowledge about the nature and sources of unwanted variation in metabolomics data. We further introduce an algorithm-RRmix-within the family of latent factor models and illustrate its suitability for differential abundance analysis in the presence of strong batch effects. Together this analysis provides a framework for systematically standardizing metabolomics data. PMID- 28662053 TI - Tire-road friction estimation and traction control strategy for motorized electric vehicle. AB - In this paper, an optimal longitudinal slip ratio system for real-time identification of electric vehicle (EV) with motored wheels is proposed based on the adhesion between tire and road surface. First and foremost, the optimal longitudinal slip rate torque control can be identified in real time by calculating the derivative and slip rate of the adhesion coefficient. Secondly, the vehicle speed estimation method is also brought. Thirdly, an ideal vehicle simulation model is proposed to verify the algorithm with simulation, and we find that the slip ratio corresponds to the detection of the adhesion limit in real time. Finally, the proposed strategy is applied to traction control system (TCS). The results showed that the method can effectively identify the state of wheel and calculate the optimal slip ratio without wheel speed sensor; in the meantime, it can improve the accelerated stability of electric vehicle with traction control system (TCS). PMID- 28662052 TI - Can cancer researchers accurately judge whether preclinical reports will reproduce? AB - There is vigorous debate about the reproducibility of research findings in cancer biology. Whether scientists can accurately assess which experiments will reproduce original findings is important to determining the pace at which science self-corrects. We collected forecasts from basic and preclinical cancer researchers on the first 6 replication studies conducted by the Reproducibility Project: Cancer Biology (RP:CB) to assess the accuracy of expert judgments on specific replication outcomes. On average, researchers forecasted a 75% probability of replicating the statistical significance and a 50% probability of replicating the effect size, yet none of these studies successfully replicated on either criterion (for the 5 studies with results reported). Accuracy was related to expertise: experts with higher h-indices were more accurate, whereas experts with more topic-specific expertise were less accurate. Our findings suggest that experts, especially those with specialized knowledge, were overconfident about the RP:CB replicating individual experiments within published reports; researcher optimism likely reflects a combination of overestimating the validity of original studies and underestimating the difficulties of repeating their methodologies. PMID- 28662054 TI - First evidence of lymphatic filariasis transmission interruption in Cameroon: Progress towards elimination. AB - BACKGROUND: Lymphatic filariasis (LF) is among the 10 neglected tropical diseases targeted for control or elimination by 2020. For LF elimination, the World Health Organization (WHO) has proposed a comprehensive strategy including (i) interruption of LF transmission through large-scale annual treatment (or mass drug administration (MDA)) of all eligible individuals in endemic areas, and (ii) alleviation of LF-associated suffering through morbidity management and disability prevention. In Cameroon, once-yearly mass administration of ivermectin and albendazole has been implemented since 2008. The aim of this study was to assess progress towards the elimination goal, looking specifically at the impact of six rounds of MDA on LF transmission in northern Cameroon. METHODOLOGY: The study was conducted in the North and Far North Regions of Cameroon. Five health districts that successfully completed six rounds of MDA (defined as achieving a treatment coverage >= 65% each year) and reported no positive results for Wuchereria bancrofti microfilariaemia during routine surveys following the fifth MDA were grouped into three evaluation units (EU) according to WHO criteria. LF transmission was assessed through a community-based transmission assessment survey (TAS) using an immunochromatographic test (ICT) for the detection of circulating filarial antigen (CFA) in children aged 5-8 years old. PRINCIPAL FINDINGS: A total of 5292 children (male/female ratio 1.04) aged 5-8 years old were examined in 97 communities. Positive CFA results were observed in 2, 8 and 11 cases, with a CFA prevalence of 0.13% (95% CI: 0.04-0.46) in EU#1, 0.57% (95% CI: 0.32-1.02) in EU#2, and 0.45% (95% CI: 0.23-0.89) in EU#3. CONCLUSION/SIGNIFICANCE: The positive CFA cases were below WHO defined critical cut-off thresholds for stopping treatment and suggest that transmission can no longer be sustained. Post-MDA surveillance activities should be organized to evaluate whether recrudescence can occur. PMID- 28662055 TI - Downregulation of adaptor protein MyD88 compromises the angiogenic potential of B16 murine melanoma. AB - The mechanisms that link inflammatory responses to cancer development remain a subject of intense investigation, emphasizing the need to better understand the cellular and molecular pathways that create a tumor promoting microenvironment. The myeloid differentiation primary response protein MyD88 acts as a main adaptor molecule for the signaling cascades initiated from Toll-like receptors (TLRs) and the interleukin 1 receptor (IL-1R). MyD88 has been shown to contribute to tumorigenesis in many inflammation-associated cancer models. In this study, we sought to better define the role of MyD88 in neoplastic cells using a murine melanoma model. Herein, we have demonstrated that MyD88 expression is required to maintain the angiogenic switch that supports B16 melanoma growth. By knocking down MyD88 we reduced TLR-mediated NF-kappaB activation with no evident effects over cell proliferation and survival. In addition, MyD88 downregulation was associated with a decrease of HIF1alpha levels and its target gene VEGF, in correlation with an impaired capability to induce capillary sprouting and tube formation of endothelial cells. Melanomas developed from cells lacking MyD88 showed an enhanced secretion of chemoattractant ligands such as CCL2, CXCL10 and CXCL1 and have an improved infiltration of macrophages to the tumor site. Our results imply that cell-autonomous signaling through MyD88 is required to sustain tumor growth and underscore its function as an important positive modulator of tumor angiogenesis. PMID- 28662056 TI - Development and validation of a Social Images Evaluation Questionnaire for youth in residential care. AB - Social images are defined as prevailing shared ideas about specific groups or societies without concrete or objective evidence of their accuracy or truthfulness. These images frequently have a negative impact on individuals and groups. Although of outmost importance, the study of the social images of youth in residential care is still scarce. In this article we present two studies for the development and validation of the Social Images Evaluation Questionnaire (SIEQ). In study 1, participants were asked to freely generate words that could be associated to youth in residential care in order to obtain a list of attributes to be used in the SIEQ. In study 2, the main psychometric characteristics of the SIEQ were tested with samples of laypeople and professionals. The main results support the proposal of a new and psychometrically sound measurement-the SIEQ-to analyze the social images of youth in residential care. PMID- 28662057 TI - Transcription coactivator and lncRNA duet evoke Hox genes. PMID- 28662058 TI - Psychometric assessment of a scale to measure bonding workplace social capital. AB - OBJECTIVES: Workplace social capital (WSC) has attracted increasing attention as an organizational and psychosocial factor related to worker health. This study aimed to assess the psychometric properties of a newly developed WSC scale for use in work environments, where bonding social capital is important. METHODS: We assessed the psychometric properties of a newly developed 6-item scale to measure bonding WSC using two data sources. Participants were 1,650 randomly selected workers who completed an online survey. Exploratory factor analyses were conducted. We examined the item-item and item-total correlations, internal consistency, and associations between scale scores and a previous 8-item measure of WSC. We evaluated test-retest reliability by repeating the survey with 900 of the respondents 2 weeks later. The overall scale reliability was quantified by an intraclass coefficient and the standard error of measurement. We evaluated convergent validity by examining the association with several relevant workplace psychosocial factors using a dataset from workers employed by an electrical components company (n = 2,975). RESULTS: The scale was unidimensional. The item item and item-total correlations ranged from 0.52 to 0.78 (p < 0.01) and from 0.79 to 0.89 (p < 0.01), respectively. Internal consistency was good (Cronbach's alpha coefficient: 0.93). The correlation with the 8-item scale indicated high criterion validity (r = 0.81) and the scale showed high test-retest reliability (r = 0.74, p < 0.01). The intraclass coefficient and standard error of measurement were 0.74 (95% confidence intervals: 0.71-0.77) and 4.04 (95% confidence intervals: 1.86-6.20), respectively. Correlations with relevant workplace psychosocial factors showed convergent validity. CONCLUSIONS: The results confirmed that the newly developed WSC scale has adequate psychometric properties. PMID- 28662059 TI - Analogue of electromagnetically induced absorption with double absorption windows in a plasmonic system. AB - We report the observation of an analog of double electromagnetically induced absorption (EIA) in a plasmonic system consisting of two disk resonators side coupled to a discrete metal-insulator-metal (MIM) waveguide. The finite difference time-domain (FDTD) simulation calculations show that two absorption windows are obtained and can be easily tuned by adjusting the parameters of the two resonance cavities. The consistence between the coupled-model theory and FDTD simulation results verify the feasibility of the proposed system. Since the scheme is easy to be fabricated, our proposed configuration may thus be applied to narrow-band filtering, absorptive switching, and absorber applications. PMID- 28662060 TI - A conserved mitochondrial surveillance pathway is required for defense against Pseudomonas aeruginosa. AB - All living organisms exist in a precarious state of homeostasis that requires constant maintenance. A wide variety of stresses, including hypoxia, heat, and infection by pathogens perpetually threaten to imbalance this state. Organisms use a battery of defenses to mitigate damage and restore normal function. Previously, we described a Caenorhabditis elegans-Pseudomonas aeruginosa assay (Liquid Killing) in which toxicity to the host is dependent upon the secreted bacterial siderophore pyoverdine. Although pyoverdine is also indispensable for virulence in mammals, its cytological effects are unclear. We used genetics, transcriptomics, and a variety of pathogen and chemical exposure assays to study the interactions between P. aeruginosa and C. elegans. Although P. aeruginosa can kill C. elegans through at least 5 different mechanisms, the defense responses activated by Liquid Killing are specific and selective and have little in common with innate defense mechanisms against intestinal colonization. Intriguingly, the defense response utilizes the phylogenetically-conserved ESRE (Ethanol and Stress Response Element) network, which we and others have previously shown to mitigate damage from a variety of abiotic stresses. This is the first report of this networks involvement in innate immunity, and indicates that host innate immune responses overlap with responses to abiotic stresses. The upregulation of the ESRE network in C. elegans is mediated in part by a family of bZIP proteins (including ZIP-2, ZIP-4, CEBP-1, and CEBP-2) that have overlapping and unique functions. Our data convincingly show that, following exposure to P. aeruginosa, the ESRE defense network is activated by mitochondrial damage, and that mitochondrial damage also leads to ESRE activation in mammals. This establishes a role for ESRE in a phylogenetically-conserved mitochondrial surveillance system important for stress response and innate immunity. PMID- 28662061 TI - Ultra-high field upper extremity peripheral nerve and non-contrast enhanced vascular imaging. AB - OBJECTIVE: The purpose of this study was to explore the efficacy of Ultra-high field [UHF] 7 Tesla [T] MRI as compared to 3T MRI in non-contrast enhanced [nCE] imaging of structural anatomy in the elbow, forearm, and hand [upper extremity]. MATERIALS AND METHOD: A wide range of sequences including T1 weighted [T1] volumetric interpolate breath-hold exam [VIBE], T2 weighted [T2] double-echo steady state [DESS], susceptibility weighted imaging [SWI], time-of-flight [TOF], diffusion tensor imaging [DTI], and diffusion spectrum imaging [DSI] were optimized and incorporated with a radiofrequency [RF] coil system composed of a transverse electromagnetic [TEM] transmit coil combined with an 8-channel receive only array for 7T upper extremity [UE] imaging. In addition, Siemens optimized protocol/sequences were used on a 3T scanner and the resulting images from T1 VIBE and T2 DESS were compared to that obtained at 7T qualitatively and quantitatively [SWI was only qualitatively compared]. DSI studio was utilized to identify nerves based on analysis of diffusion weighted derived fractional anisotropy images. Images of forearm vasculature were extracted using a paint grow manual segmentation method based on MIPAV [Medical Image Processing, Analysis, and Visualization]. RESULTS: High resolution and high quality signal-to noise ratio [SNR] and contrast-to-noise ratio [CNR]-images of the hand, forearm, and elbow were acquired with nearly homogeneous 7T excitation. Measured [performed on the T1 VIBE and T2 DESS sequences] SNR and CNR values were almost doubled at 7T vs. 3T. Cartilage, synovial fluid and tendon structures could be seen with higher clarity in the 7T T1 and T2 weighted images. SWI allowed high resolution and better quality imaging of large and medium sized arteries and veins, capillary networks and arteriovenous anastomoses at 7T when compared to 3T. 7T diffusion weighted sequence [not performed at 3T] demonstrates that the forearm nerves are clearly delineated by fiber tractography. The proper digital palmar arteries and superficial palmar arch could also be clearly visualized using TOF nCE 7T MRI. CONCLUSION: Ultra-high resolution neurovascular imaging in upper extremities is possible at 7T without use of renal toxic intravenous contrast. 7T MRI can provide superior peripheral nerve [based on fiber anisotropy and diffusion coefficient parameters derived from diffusion tensor/spectrum imaging] and vascular [nCE MRA and vessel segmentation] imaging. PMID- 28662062 TI - Reflectance confocal microscopy features of BRAF V600E mutated thin melanomas detected by immunohistochemistry. AB - The classification of melanoma into four histological subtypes has been questioned regarding its clinical validity in providing relevant information for treatment for metastatic tumors. Specific genetic alterations are associated with particular clinical and histopathological features, suggesting that these could be helpful in refining existing melanoma classification schemes. We analyzed BRAF V600E mutated melanomas to explore the Reflectance confocal microscopy (RCM) utility as a screening aid in the evaluation of the most appropriate patients for genetic testing. Thus, 32 melanomas were assessed regarding their BRAF V600E mutational status. Experts blinded to dermoscopic images and V600E immunohistochemistry results evaluated RCM images regarding previously described melanoma features. BRAF positive melanomas were related to younger age (p = 0.035), invasive melanomas (p = 0.03) and to the presence of hiporreflective cells (p = 0.02), epidermal nests (p = 0.02), dermal-epidermal junction nests (p = 0.05), edged papillae (p = 0.05), and bright dots (p = 0.05), and to absence of junctional thickening due to isolated cells (p = 0.01) and meshwork (p = 0.02). This study can not characterize other mutations in the BRAF, because the immunohistochemistry is specific to the type V600E. The findings should encourage the genetic evaluation of BRAF mutation. This study highlights the potential of RCM as a supplementary tool in the screening of BRAF-mutated melanomas. PMID- 28662063 TI - RNA-Seq and CyTOF immuno-profiling of regenerating lacrimal glands identifies a novel subset of cells expressing muscle-related proteins. AB - The purpose of the present studies was to use CyTOF and RNA-Seq technologies to identify cells and genes involved in lacrimal gland repair that could be targeted to treat diseases of lacrimal gland dysfunction. Lacrimal glands of female BALB/c mice were experimentally injured by intra-glandular injection of interleukin 1 alpha (IL-1alpha). The lacrimal glands were harvested at various time points following injury (1 to 14 days) and used to either prepare single cell suspensions for CyTOF immuno-phenotyping analyses or to extract RNA for gene expression studies using RNA-Seq. CyTOF immuno-phenotyping identified monocytes and neutrophils as the major infiltrating populations 1 and 2 days post injury. Clustering of significantly differentially expressed genes identified 13 distinct molecular signatures: 3 associated with immune/inflammatory processes included genes up-regulated at days 1-2 and 3 associated with reparative processes with genes up-regulated primarily between days 4 and 5. Finally, clustering identified 65 genes which were specifically up-regulated 2 days post injury which was enriched for muscle specific genes. The expression of select muscle-related proteins was confirmed by immunohistochemistry which identified a subset of cells expressing these proteins. Double staining experiments showed that these cells are distinct from the myoepithelial cells. We conclude that experimentally induced injury to the lacrimal gland leads to massive infiltration by neutrophils and monocytes which resolved after 3 days. RNAseq and immunohistochemistry identified a group of cells, other than myoepithelial cells, that express muscle related proteins that could play an important role in lacrimal gland repair. PMID- 28662064 TI - Identifiers for the 21st century: How to design, provision, and reuse persistent identifiers to maximize utility and impact of life science data. AB - In many disciplines, data are highly decentralized across thousands of online databases (repositories, registries, and knowledgebases). Wringing value from such databases depends on the discipline of data science and on the humble bricks and mortar that make integration possible; identifiers are a core component of this integration infrastructure. Drawing on our experience and on work by other groups, we outline 10 lessons we have learned about the identifier qualities and best practices that facilitate large-scale data integration. Specifically, we propose actions that identifier practitioners (database providers) should take in the design, provision and reuse of identifiers. We also outline the important considerations for those referencing identifiers in various circumstances, including by authors and data generators. While the importance and relevance of each lesson will vary by context, there is a need for increased awareness about how to avoid and manage common identifier problems, especially those related to persistence and web-accessibility/resolvability. We focus strongly on web-based identifiers in the life sciences; however, the principles are broadly relevant to other disciplines. PMID- 28662065 TI - Monoclonal antibodies expression improvement in CHO cells by PiggyBac transposition regarding vectors ratios and design. AB - Establishing stable Chinese Hamster Ovary (CHO) cells producing monoclonal antibodies (mAbs) usually pass through the random integration of vectors to the cell genome, which is sensitive to gene silencing. One approach to overcome this issue is to target a highly transcribed region in the genome. Transposons are useful devices to target active parts of genomes, and PiggyBac (PB) transposon can be considered as a good option. In the present study, three PB transposon donor vectors containing both heavy and light chains were constructed, one contained independent expression cassettes while the others utilized either an Internal Ribosome Entry Site (IRES) or 2A element to express mAb. Conventional cell pools were created by transferring donor vectors into the CHO cells, whereas transposon-based cells were generated by transfecting the cells with donor vectors with a companion of a transposase-encoding helper vector, with 1:2.5 helper/donor vectors ratio. To evaluate the influence of helper/donor vectors ratio on expression, the second transposon-based cell pools were generated with 1:5 helper/donor ratio. Expression levels in the transposon-based cells were two to five -folds more than those created by conventional method except for the IRES mediated ones, in which the observed difference increased more than 100-fold. The results were dependent on both donor vector design and vectors ratios. PMID- 28662066 TI - Mitochondrial DNA markers reveal high genetic diversity and strong genetic differentiation in populations of Dendrolimus kikuchii Matsumura (Lepidoptera: Lasiocampidae). AB - Dendrolimus kikuchii Matsumura, 1927 is a serious forest pest causing great damage to coniferous trees in China. Despite its economic importance, the population genetics of this pest are poorly known. We used three mitochondrial genes (COI, COII and Cytb) to investigate the genetic diversity and genetic differentiation of 15 populations collected from the main distribution regions of D. kikuchii in China. Populations show high haplotype and nucleotide diversity. Haplotype network and phylogenetic analysis divides the populations into three major clades, the central and southeastern China (CC+SEC) clade, the eastern China (EC) clade, and the southwestern China (SWC) clade. Populations collected from adjacent localities share the same clade, which is consistent with the strong relationship of isolation by distance (r = 0.74824, P = 0.00001). AMOVA analysis indicated that the major portion of this molecular genetic variation is found among the three groups of CC+SEC, EC and SWC (61.26%). Of 105 pairwise FST comparisons, 93 show high genetic differentiation. Populations of Puer (PE), Yangshuo (YS) and Leishan (LS) are separated from other populations by a larger genetic distance. Distributions of pairwise differences obtained with single and combined gene data from the overall populations are multimodal, suggesting these populations had no prior population expansion in southern China. The nonsignificant neutral test on the basis of Tajima' D and Fu's Fs, and the lack of a star-shaped haplotype network together with the multiple haplotypes support this hypothesis. Pleistocene climatic fluctuations, combined with the host specificity to Pinus species, made these regions of south China into a refuge for D. kikuchii. The high level of population genetic structuring is related to their weak flight capacity, their variations of life history and the geographic distance among populations. PMID- 28662067 TI - Sharing extended summary data from contemporary genetics studies is unlikely to threaten subject privacy. AB - BACKGROUND: Starting from a forensic problem, Homer et al. showed that it was possible to detect if an individual contributes only 0.5% of the DNA in a pool. The finding was extended to prove the possibility of detecting whether a subject participated in a small homogeneous GWAS. We denote this as the detection of a subject belonging to a certain cohort (SBCC). Subsequently, Visscher and Hill showed that the power to detect SBCC signal for an ethnically homogeneous cohort depends roughly on the ratio of the number of independent markers and total sample size. However, it is not clear if the same holds for more ethnically diverse cohorts. Later, Masca et al. propose running as SBCC test a regression of departure from assumed population frequency of i) subject genotype on ii) cohort of interest frequency. They use simulations to show that the approach has better SBCC detection power than the original Homer method but is impeded by population stratification. APPROACH: To investigate the possibility of SBCC detection in multi-ethnic cohorts, we generalize the Masca et al. approach by theoretically deriving the correlation between a subject genotype and the cohort reference allele frequencies (RAFs) for stratified cohorts. Based on the derived formula, we theoretically show that, due to background stratification noise, SBCC detection is unlikely even for mildly stratified cohorts of size greater than around a thousand subjects. Thus, for the vast majority of contemporary cohorts, the fear of compromising privacy via SBCC detection is unfounded. PMID- 28662068 TI - Effects of anabolic and catabolic nutrients on woody plant encroachment after long-term experimental fertilization in a South African savanna. AB - The causes of the worldwide problem of encroachment of woody plants into grassy vegetation are elusive. The effects of soil nutrients on competition between herbaceous and woody plants in various landscapes are particularly poorly understood. A long-term experiment of 60 plots in a South African savanna, comprising annual applications of ammonium sulphate (146-1166 kg ha-1 yr-1) and superphosphate (233-466 kg ha-1 yr-1) over three decades, and subsequent passive protection over another three decades, during which indigenous trees encroached on different plots to extremely variable degrees, provided an opportunity to investigate relationships between soil properties and woody encroachment. All topsoils were analysed for pH, acidity, EC, water-dispersible clay, Na, Mg, K, Ca, P, S, C, N, NH4, NO3, B, Mn, Cu and Zn. Applications of ammonium sulphate (AS), but not superphosphate (SP), greatly constrained tree abundance relative to control plots. Differences between control plots and plots that had received maximal AS application were particularly marked (16.3 +/- 5.7 versus 1.2 +/- 0.8 trees per plot). Soil properties most affected by AS applications included pH (H2O) (control to maximal AS application: 6.4 +/- 0.1 to 5.1 +/- 0.2), pH (KCl) (5.5 +/- 0.2 to 4.0 +/- 0.1), acidity (0.7 +/- 0.1 to 2.6 +/- 0.3 cmol kg-1), acid saturation (8 +/- 2 to 40 +/- 5%), Mg (386 +/- 25 to 143 +/- 15 mg kg-1), Ca (1022 +/- 180 to 322 +/- 14 mg kg-1), Mn (314 +/- 11 to 118 +/- 9 mg kg-1), Cu (3.6 +/- 0.3 to 2.3 +/- 0.2 mg kg-1) and Zn (6.6 +/- 0.4 to 3.7 +/- 0.4 mg kg-1). Magnesium, B, Mn and Cu were identified using principal component analysis, boundary line analysis and Kruskal-Wallis rank sum tests as the nutrients most likely to be affecting tree abundance. The ratio Mn/Cu was most related to tree abundance across the experiment, supporting the hypothesis that competition between herbaceous and woody plants depends on the availability of anabolic relative to catabolic nutrients. These findings, based on more than six decades of experimentation, may have global significance for the theoretical understanding of changes in vegetation structure and thus the practical control of invasive woody plants. PMID- 28662069 TI - Dog ownership and all-cause mortality in a population cohort in Norway: The HUNT study. AB - OBJECTIVE: There has been increased interest in human-animal interactions and their possible effects on human health. Some of this research has focused on human physical activity levels, mediated through increased dog walking. Much of the reported research has been cross sectional, and very few epidemiological studies have examined the association between dog ownership and mortality in populations. METHODS: We used data from the Norwegian county population-based Nord-Trondelag HUNT Study (HUNT2, 1995-1997). Cox proportional hazards models were fitted to analyse the relationship between dog ownership and all-cause mortality. The median follow-up time was 18.5 years and the maximum follow-up time was 19.7 years. RESULTS: In this population, dog owners were no more physically active than non-dog owners, both groups reporting a total of just over 3 hours/week of light and vigorous activity. Dog owners (n = 25,031, with 1,587 deaths during follow-up; 504,017 person-years of time at risk) had virtually the same hazard of dying as non-dog owners (Hazard ratio 1.00, 95% CI 0.91-1.09). CONCLUSIONS: We found no evidence for an association between the presence of a dog in the household and all-cause mortality or physical activity levels in this Norwegian population. Further epidemiological research is needed to clarify this relationship, as methodological limitations and an active Norwegian population sample means that generalizable evidence is not yet clear on dog ownership and mortality. PMID- 28662070 TI - Machine learning and microsimulation techniques on the prognosis of dementia: A systematic literature review. AB - BACKGROUND: Dementia is a complex disorder characterized by poor outcomes for the patients and high costs of care. After decades of research little is known about its mechanisms. Having prognostic estimates about dementia can help researchers, patients and public entities in dealing with this disorder. Thus, health data, machine learning and microsimulation techniques could be employed in developing prognostic estimates for dementia. OBJECTIVE: The goal of this paper is to present evidence on the state of the art of studies investigating and the prognosis of dementia using machine learning and microsimulation techniques. METHOD: To achieve our goal we carried out a systematic literature review, in which three large databases-Pubmed, Socups and Web of Science were searched to select studies that employed machine learning or microsimulation techniques for the prognosis of dementia. A single backward snowballing was done to identify further studies. A quality checklist was also employed to assess the quality of the evidence presented by the selected studies, and low quality studies were removed. Finally, data from the final set of studies were extracted in summary tables. RESULTS: In total 37 papers were included. The data summary results showed that the current research is focused on the investigation of the patients with mild cognitive impairment that will evolve to Alzheimer's disease, using machine learning techniques. Microsimulation studies were concerned with cost estimation and had a populational focus. Neuroimaging was the most commonly used variable. CONCLUSIONS: Prediction of conversion from MCI to AD is the dominant theme in the selected studies. Most studies used ML techniques on Neuroimaging data. Only a few data sources have been recruited by most studies and the ADNI database is the one most commonly used. Only two studies have investigated the prediction of epidemiological aspects of Dementia using either ML or MS techniques. Finally, care should be taken when interpreting the reported accuracy of ML techniques, given studies' different contexts. PMID- 28662071 TI - The developmental transcriptome of the bamboo snout beetle Cyrtotrachelus buqueti and insights into candidate pheromone-binding proteins. AB - Cyrtotrachelus buqueti is an extremely harmful bamboo borer, and the larvae of this pest attack clumping bamboo shoots. Pheromone-binding proteins (PBPs) play an important role in identifying insect sex pheromones, but the C. buqueti genome is not readily available for PBP analysis. Developmental transcriptomes of eggs, larvae from the first instar to the prepupal stage, pupae, and adults (females and males) from emergence to mating were built by RNA sequencing (RNA-Seq) in the present study to establish a sequence background of C. buqueti to help understand PBPs. Approximately 164.8 million clean reads were obtained and annotated into 108,854 transcripts. These were assembled into 24,338, 21,597, 24,798, 21,886, 24,642, and 83,115 unigenes for eggs, larvae, pupae, females, males, and the combined datasets, respectively. Unigenes were annotated against NCBI non redundant protein sequences, NCBI non-redundant nucleotide sequences, Gene Ontology (GO), Protein family, Clusters of Orthologous Groups of Proteins/ Clusters of Eukaryotic Orthologous Groups (KOG), Swiss-Prot, and KEGG Orthology databases. A total of 17,213 unigenes were annotated into 55 sub-categories belonging to three main GO categories; 10,672 unigenes were classified into 26 functional categories by KOG classification, and 8,063 unigenes were classified into five functional KEGG categories. RSEM software for RNA sequencing showed that 4,816, 3,176, 3,661, 2,898, 4,316, 8,019, 7,273, 5,922, 5,844, and 4,570 genes were differentially expressed between larvae and males, larvae and eggs, larvae and pupae, larvae and females, males and females, males and eggs, males and pupae, females and eggs, females and pupae, and eggs and pupae, respectively. Of these, three were confirmed to be significantly differentially expressed between larvae, females, and males. Furthermore, PBP Cbuq7577_g1 was highly expressed in the antenna of males. A comprehensive sequence resource of a desirable quality was constructed from developmental transcriptomes of C. buqueti eggs, larvae, pupae, and adults. This work enriches the genomic data of C. buqueti, and facilitates our understanding of its metamorphosis, development, and response to environmental change. The identified candidate PBP Cbuq7577_g1 might play a crucial role in identifying sex pheromones, and could be used as a targeted gene to control C. buqueti numbers by disrupting sex pheromone communication. PMID- 28662072 TI - Backfilling behavior of a mixed aggregate based on construction waste and ultrafine tailings. AB - To study the possibility of utilizing mixed construction waste and ultrafine tailings (CW&UT) as a backfilling aggregate that can be placed underground in a mine, physicochemical evaluation, proportioning strength tests, and pumpability experiments were conducted. It was revealed that mixed CW&UT can be used as a backfilling aggregate due to the complementarities of their physicochemical properties. In addition, as the results of the proportioning strength tests show, the compressive strength of a cemented CW&UT backfilling specimen cured for 28 days, with a mass fraction of 72-74%, a cement-sand ratio of 1:12, and a CW proportion of 30%, is higher than 1.0 MPa, which meets the safety requirements and economic consideration of backfilling technology in many underground metal mines, and can also be enhanced with an increase in the cement-sand ratio. The results of the pumpability experiments show that cemented backfilling slurry based on CW&UT can be transported to the stope underground with a common filling pump, with a 16.6 MPa maximum pressure, with the condition that the time of emergency shut-down is less than approximately 20 min. All in all, the research to utilize mixed CW&UT as a backfilling aggregate can not only provide a way to dispose of CW&UT but also will bring large economic benefits and can provide constructive guidance for environmental protection. PMID- 28662073 TI - APNG as a prognostic marker in patients with glioblastoma. AB - AIM: Expression of the base excision repair enzyme alkylpurine-DNA-N-glycosylase (APNG) has been correlated to temozolomide resistance. Our aim was to evaluate the prognostic value of APNG in a population-based cohort with 242 gliomas including 185 glioblastomas (GBMs). Cellular heterogeneity of GBMs was taken into account by excluding APNG expression in non-tumor cells from the analysis. METHODS: APNG expression was evaluated using automated image analysis and a novel quantitative immunohistochemical (IHC) assay (qIHC), where APNG protein expression was evaluated through countable dots. Non-tumor cells were excluded using an IHC/qIHC double-staining. For verification, APNG was measured by a quantitative double-immunofluorescence (IF) assay. As validation APNG mRNA expression was evaluated using independent TCGA data. RESULTS: Using qIHC, high levels of APNG were associated with better overall survival (OS) in univariate (HR = 0.50; P < 0.001) and multivariate analysis (HR = 0.53; P = 0.001). Patients with methylated MGMT promoters and high APNG expression demonstrated better OS, than patients with methylated MGMT promoters and low APNG expression (HR = 0.59; P = 0.08). Retesting the cohort using IF showed similar results in both univariate (HR = 0.61; P = 0.002) and multivariate analysis (HR = 0.81; P = 0.2). The results were supported by data from the TCGA database. CONCLUSIONS: Using two different assays combined with quantitative image analysis excluding non-tumour cells, APNG was an independent prognostic factor among patients with a methylated MGMT promoter. We expect that APNG qIHC can potentially identify GBM patients who will not benefit from treatment with temozolomide. PMID- 28662074 TI - Fiber-rich diet with brown rice improves endothelial function in type 2 diabetes mellitus: A randomized controlled trial. AB - BACKGROUND & AIMS: A fiber-rich diet has a cardioprotective effect, but the mechanism for this remains unclear. We hypothesized that a fiber-rich diet with brown rice improves endothelial function in patients with type 2 diabetes mellitus. METHODS: Twenty-eight patients with type 2 diabetes mellitus at a single general hospital in Japan were randomly assigned to a brown rice (n = 14) or white rice (n = 14) diet and were followed for 8 weeks. The primary outcome was changes in endothelial function determined from flow debt repayment by reactive hyperemia using strain-gauge plethysmography in the fasting state. Secondary outcomes were changes in HbA1c, postprandial glucose excursions, and markers of oxidative stress and inflammation. The area under the curve for glucose after ingesting 250 kcal of assigned rice was compared between baseline (T0) and at the end of the intervention (T1) to estimate glucose excursions in each group. RESULTS: Improvement in endothelial function, assessed by fasting flow debt repayment (20.4% vs. -5.8%, p = 0.004), was significantly greater in the brown rice diet group than the white rice diet group, although the between group difference in change of fiber intake was small (5.6 g/day vs. -1.2 g/day, p<0.0001). Changes in total, HDL-, and LDL-cholesterol, and urine 8-isoprostane levels did not differ between the two groups. The high-sensitivity C-reactive protein level tended to improve in the brown rice diet group compared with the white rice diet group (0.01 MUg/L vs. -0.04 MUg/L, p = 0.063). The area under the curve for glucose was subtly but consistently lower in the brown rice diet group (T0: 21.4 mmol/L*h vs. 24.0 mmol/L*h, p = 0.043, T1: 20.4 mmol/L*h vs. 23.3 mmol/L*h, p = 0.046) without changes in HbA1c. CONCLUSIONS: Intervention with a fiber-rich diet with brown rice effectively improved endothelial function, without changes in HbA1c levels, possibly through reducing glucose excursions. PMID- 28662075 TI - Microarray analyses of otospheres derived from the cochlea in the inner ear identify putative transcription factors that regulate the characteristics of otospheres. AB - Various tissues possess tissue-specific stem/progenitor cells, including the inner ears. Stem/progenitor cells of the inner ear can be isolated as so-called otospheres from differentiated cells using a sphere forming assay. Although recent studies have demonstrated the characteristics of otospheres to some extent, most of the features of these cells are unknown. In this report, we describe the findings of transcriptome analyses with a cDNA microarray of otospheres derived from the cochleae of the inner ears of neonatal mice in order to clarify the gene expression profile of otic stem/progenitor cells. There were common transcription factors between otospheres and embryonic stem cells, which were supposed to be due to the stemness of otospheres. In comparison with the cochlear sensory epithelium, the otospheres shared characteristics with the cochlea, although several transcription factors specific for otospheres were identified. These transcription factors are expected to be essential for maintaining the characteristics of otospheres, and appear to be candidate genes that promote the direct conversion of cells into otic stem/progenitor cells. PMID- 28662077 TI - Network analysis of pig movements: Loyalty patterns and contact chains of different holding types in Denmark. AB - Understanding animal movements is an important factor for the development of meaningful surveillance and control programs, but also for the development of disease spread models. We analysed the Danish pig movement network using static and temporal network analysis tools to provide deeper insight in the connection between holdings dealing with pigs, such as breeding and multiplier herds, production herds, slaughterhouses or traders. Pig movements, which occurred between 1st January 2006 and 31st December 2015 in Denmark, were summarized to investigate temporal trends such as the number of active holdings, the number of registered movements and the number of pigs moved. To identify holdings and holding types with potentially higher risk for introduction or spread of diseases via pig movements, we determined loyalty patterns, annual network components and contact chains for the 24 registered holding types. The total number of active holdings as well as the number of pig movements decreased during the study period while the holding sizes increased. Around 60-90% of connections between two pig holdings were present in two consecutive years and around one third of the connections persisted within the considered time period. Weaner herds showed the highest level of in-loyalty, whereas we observed an intermediate level of in loyalty for all breeding sites and for production herds. Boar stations, production herds and trade herds showed a high level of out-loyalty. Production herds constituted the highest proportion of holdings in the largest strongly connected component. All production sites showed low levels of in-going contact chains and we observed a high level of out-going contact chain for breeding and multiplier herds. Except for livestock auctions, all transit sites also showed low levels of out-going contact chains. Our results reflect the pyramidal structure of the underlying network. Based on the considered disease, the time frame for the calculation of network measurements needs to be adapted. Using these adapted values for loyalty and contact chains might help to identify holdings with high potential of spreading diseases and thus limit the outbreak size or support control or eradication of the considered pathogen. PMID- 28662076 TI - Landscape and variation of novel retroduplications in 26 human populations. AB - Retroduplications come from reverse transcription of mRNAs and their insertion back into the genome. Here, we performed comprehensive discovery and analysis of retroduplications in a large cohort of 2,535 individuals from 26 human populations, as part of 1000 Genomes Phase 3. We developed an integrated approach to discover novel retroduplications combining high-coverage exome and low coverage whole-genome sequencing data, utilizing information from both exon-exon junctions and discordant paired-end reads. We found 503 parent genes having novel retroduplications absent from the reference genome. Based solely on retroduplication variation, we built phylogenetic trees of human populations; these represent superpopulation structure well and indicate that variable retroduplications are effective population markers. We further identified 43 retroduplication parent genes differentiating superpopulations. This group contains several interesting insertion events, including a SLMO2 retroduplication and insertion into CAV3, which has a potential disease association. We also found retroduplications to be associated with a variety of genomic features: (1) Insertion sites were correlated with regular nucleosome positioning. (2) They, predictably, tend to avoid conserved functional regions, such as exons, but, somewhat surprisingly, also avoid introns. (3) Retroduplications tend to be co inserted with young L1 elements, indicating recent retrotranspositional activity, and (4) they have a weak tendency to originate from highly expressed parent genes. Our investigation provides insight into the functional impact and association with genomic elements of retroduplications. We anticipate our approach and analytical methodology to have application in a more clinical context, where exome sequencing data is abundant and the discovery of retroduplications can potentially improve the accuracy of SNP calling. PMID- 28662078 TI - DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress. AB - Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb girdle congenital myasthenic syndrome (CMS) with tubular aggregates. UDP-N acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway. The aim of the present study was to examine the effect of six variants in DPAGT1 detected in patients with DPAGT1-CDG, and the role of endoplasmic reticulum stress, as part of the search for therapeutic strategies to use against DPAGT1-CDG. The effect of the six mutations, i.e., c.358C>A (p.Leu120Met), c.791T>G (p.Val264Gly), c.901C>T (p.Arg301Cys), c.902G>A (p.Arg301His), c.1154T>G (p.Leu385Arg), and of the novel mutation c.329T>C (p.Phe110Ser), were examined via the analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. In addition, the transient expression of different mutations was analysed in COS-7 cells. The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane. The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG. Even so, the fibroblasts of patients with DPAGT1-CDG seemed to be more sensitive to the stressor tunicamycin. The present work improves our knowledge of DPAGT1-CDG and provides bases for developing tailored splicing and folding therapies. PMID- 28662079 TI - Diminished physical function in older HIV-infected adults in the Southeastern U.S. despite successful antiretroviral therapy. AB - BACKGROUND: As antiretroviral therapy efficacy improves, HIV is gradually being recognized more as a chronic disease within the aging HIV-infected population. While these individuals are surviving into old age, they may, however, be experiencing "accelerated aging" with greater declines in physical function than that observed among comparably matched individuals free of HIV. This decline is not well understood and it remains unclear if physical decline correlates with the degree of immunosuppression based on CD4 lymphocyte nadir. METHODS: In a cross-sectional study of accelerated aging in the older HIV-infected population on antiretroviral therapy (ART), physical performance evaluations were completed on a cohort of 107 HIV-infected subjects, age 50 years or older (with no HIV-1 RNA >200 copies/mL in the prior 12 months), and compared to reference ranges for age- and gender-matched HIV-uninfected persons. Physical performance testing consisted of four validated assessments: the 2.4-meter walk, 30-second chair stand, grip strength and 6-minute walk test. RESULTS: When compared to age- and gender-matched HIV-uninfected reference controls, older HIV-infected persons had diminished physical function. No correlation was found between physical function and degree of immunosuppression as determined by pre-ART CD4 nadir. CONCLUSIONS: Despite improved survival, HIV-infected adults on suppressive ART have diminished physical function compared to HIV-uninfected persons. The degree of HIV associated immunosuppression does not correlate with the observed degree of physical function decline in older HIV-infected persons, suggesting the decline is mediated by other mechanisms. PMID- 28662080 TI - Quantitative determination of free D-Asp, L-Asp and N-methyl-D-aspartate in mouse brain tissues by chiral separation and Multiple Reaction Monitoring tandem mass spectrometry. AB - Several studies have suggested that free d-Asp has a crucial role in N-methyl d Asp receptor-mediated neurotransmission playing very important functions in physiological and pathological processes. This paper describes the development of an analytical procedure for the direct and simultaneous determination of free d Asp, l-Asp and N-methyl d-Asp in specimens of different mouse brain tissues using chiral LC-MS/MS in Multiple Reaction Monitoring scan mode. After comparing three procedures and different buffers and extraction solvents, a simple preparation procedure was selected the analytes of extraction. The method was validated by analyzing l-Asp, d-Asp and N-methyl d-Asp recovery at different spiked concentrations (50, 100 and 200 pg/MUl) yielding satisfactory recoveries (75 110%), and good repeatability. Limits of detection (LOD) resulted to be 0.52 pg/MUl for d-Asp, 0.46 pg/MUl for l-Asp and 0.54 pg/MUl for NMDA, respectively. Limits of quantification (LOQ) were 1.57 pg/MUl for d-Asp, 1.41 pg/MUl for l-Asp and 1.64 pg/MUl for NMDA, respectively. Different concentration levels were used for constructing the calibration curves which showed good linearity. The validated method was then successfully applied to the simultaneous detection of d Asp, l-Asp and NMDA in mouse brain tissues. The concurrent, sensitive, fast, and reproducible measurement of these metabolites in brain tissues will be useful to correlate the amount of free d-Asp with relevant neurological processes, making the LC-MS/MS MRM method well suited, not only for research work but also for clinical analyses. PMID- 28662081 TI - Particulate matter and heavy metal deposition on the leaves of Euonymus japonicus during the East Asian monsoon in Beijing, China. AB - Plants can be effectively used as bio-monitors of environmental pollution. However, how the particulate matter (PM) and heavy metal retention ability of plants changes in different areas with human disturbance along with monsoon has not yet been investigated in urban ecosystems. In this study, we measured the amount of PM and heavy metals such as Ni, Cr, Cu, Pb, and Zn accumulated by the leaves of Euonymus japonicus during the East Asian monsoon from different functional units in Beijing, China. A rinse-and-weigh method developed in our laboratory was used to determine the mass of the PM, and electro-thermal atomic absorption spectrometry was used for heavy metal analysis. We found that the types of functional units had little influence, whereas the monsoon had a significant effect on the deposition of PM: northwest areas during the monsoon had the lowest effect (with 0.005, 0.453, 0.643, and 1.569 g/m2 fine, coarse, large, and total PM, respectively), and the southeast areas during the monsoon had the highest effect (0.015, 2.687, 1.941, and 4.228 g/m2 for fine, coarse, large, and total PM, respectively). Notable, we found considerable variations in heavy metal accumulation across the functional units analyzed, that is, the accumulation level was higher in communities than in parks (P < 0.0001 for all heavy metals). Moreover, a positive relationship was found between PM retention and heavy metal accumulation by the leaves of E. japonicus. Taken together, our results suggested that the PM and heavy metal retention ability of E. japonicus was sensitive to human disturbance and monsoon in Beijing. Since E. japonicus is a widely distributed tree and has the ability of to purify the atmosphere, it is an ideal plant for mitigating urban environmental pollution. PMID- 28662082 TI - Combination of poly I:C and Pam3CSK4 enhances activation of B cells in vitro and boosts antibody responses to protein vaccines in vivo. AB - Vaccines that can rapidly induce strong and robust antibody-mediated immunity could improve protection from certain infectious diseases for which current vaccine formulations are inefficient. For indications such as anthrax and influenza, antibody production in vivo is a correlate of efficacy. Toll-like receptor (TLR) agonists are frequently studied for their role as vaccine adjuvants, largely because of their ability to enhance initiation of immune responses to antigens by activating dendritic cells. However, TLRs are also expressed on B cells and may contribute to effective B cell activation and promote differentiation into antigen-specific antibody producing plasma cells in vivo. We sought to discover an adjuvant system that could be used to augment antibody responses to influenza and anthrax vaccines. We first characterized an adjuvant system in vitro which consisted of two TLR ligands, poly I:C (TLR3) and Pam3CSK4 (TLR2), by evaluating its effects on B cell activation. Each agonist enhanced B cell activation through increased expression of surface receptors, cytokine secretion and proliferation. However, when B cells were stimulated with poly I:C and Pam3CSK4 in combination, further enhancement to cell activation was observed. Using B cells isolated from knockout mice we confirmed that poly I:C and Pam3CSK4 were signaling through TLR3 and TLR2, respectively. B cells activated with Poly I:C and Pam3CSK4 displayed enhanced capacity to stimulate allogeneic CD4+ T cell activation and differentiate into antibody-producing plasma cells in vitro. Mice vaccinated with influenza or anthrax antigens formulated with poly I:C and Pam3CSK4 in DepoVaxTM vaccine platform developed a rapid and strong antigen-specific serum antibody titer that persisted for at least 12 weeks after a single immunization. These results demonstrate that combinations of TLR adjuvants promote more effective B cell activation in vitro and can be used to augment antibody responses to vaccines in vivo. PMID- 28662083 TI - Report about term infants with severe hyperbilirubinemia undergoing exchange transfusion in Southwestern China during an 11-year period, from 2001 to 2011. AB - OBJECTIVES: This study was intended to explore the etiology and risk factors of severe neonatal hyperbilirubinemia and to analyze the adverse events associated with ECT (Exchange Transfusion), as well as to identify the factors related to the poor prognosis. METHODS: All of the full-term neonates who had undergone ECT for hyperbilirubinemia at Children's Hospital of Chongqing Medical University from January 2001 to December 2011 were enrolled in this study. General demographic characteristics, comorbidities, pre- and post-exchange TSB(Total Serum Bilirubin) levels, duration and frequency of ECT, and clinical outcomes were recorded and analyzed anonymously. RESULTS: Of 614 total infants, 368 patients (59.9%) with ABO incompatibility were identified, of whom 197 (53.5%) developed acute bilirubin encephalopathy (ABE) and 16 (4.3%) suffered a poor prognosis. The etiology was unidentified in 103 patients (16.8%), of whom 62 (60.1%) developed ABE and 9 (8.7%) had a poor prognosis. Identified adverse events secondary to ECT included thrombocytopenia (54.6%), hyperglycemia (42.8%), apnea (3.3%) and necrotizing enterocolitis (NEC) (1.3%). No ECT-related mortality was documented in this study. CONCLUSIONS: The etiology, peak TSB level before ECT, and time of ECT had a significant impact on the outcome of severe neonatal hyperbilirubinemia. ABO incompatibility was the most common cause of extreme neonatal hyperbilirubinemia. Pathological weight loss could be involved in the development of extreme hyperbilirubinemia with an unidentified cause. PMID- 28662084 TI - Validation of an instrumented dummy to assess mechanical aspects of discomfort during load carriage. AB - Due to the increasing load in backpacks and other load carriage systems over the last decades, load carriage system designs have to be adapted accordingly to minimize discomfort and to reduce the risk of injury. As subject studies are labor-intensive and include further challenges such as intra-subject and inter subject variability, we aimed to validate an instrumented dummy as an objective laboratory tool to assess the mechanical aspects of discomfort. The validation of the instrumented dummy was conducted by comparison with a recent subject study. The mechanical parameters that characterize the static and dynamic interaction between backpack and body during different backpack settings were compared. The second aim was to investigate whether high predictive power (coefficient of determination R2>0.5) in assessing the discomfort of load carriage systems could be reached using the instrumented dummy. Measurements were conducted under static conditions, simulating upright standing, and dynamic conditions, simulating level walking. Twelve different configurations of a typical load carriage system, a commercially available backpack with a hip belt, were assessed. The mechanical parameters were measured in the shoulder and the hip region of the dummy and consisted of average pressure, peak pressure, strap force and relative motion between the system and the body. The twelve configurations consisted of three different weights (15kg, 20kg, and 25kg), combined with four different hip belt tensions (30N, 60N, 90N, and 120N). Through the significant (p<0.05) correlation of the mechanical parameters measured on the dummy with the corresponding values of the subject study, the dummy was validated for all static measurements and for dynamic measurements in the hip region to accurately simulate the interaction between the human body and the load carriage system. Multiple linear regressions with the mechanical parameters measured on the dummy as independent variables and the corresponding subjective discomfort scores from the subject study as the dependent variable revealed a high predictive power of the instrumented dummy. The dummy can explain 75% or more of the variance in discomfort using average pressures as predictors and even 79% or more of the variance in discomfort using strap forces as predictors. Use of the dummy enables objective, fast, and iterative assessments of load carriage systems and therefore reduces the need for labor-intensive subject studies in order to decrease the mechanical aspects of discomfort during load carriage. PMID- 28662085 TI - Metabolomic profiling to characterize acute intestinal ischemia/reperfusion injury. AB - Sepsis and septic shock are the leading causes of death in critically ill patients. Acute intestinal ischemia/reperfusion (AII/R) is an adaptive response to shock. The high mortality rate from AII/R is due to the severity of the disease and, more importantly, the failure of timely diagnosis. The objective of this investigation is to use nuclear magnetic resonance (NMR) analysis to characterize urine metabolomic profile of AII/R injury in a mouse model. Animals were exposed to sham, early (30 min) or late (60 min) acute intestinal ischemia by complete occlusion of the superior mesenteric artery, followed by 2 hrs of reperfusion. Urine was collected and analyzed by NMR spectroscopy. Urinary metabolite concentrations demonstrated that different profiles could be delineated based on the duration of the intestinal ischemia. Metabolites such as allantoin, creatinine, proline, and methylamine could be predictive of AII/R injury. Lactate, currently used for clinical diagnosis, was found not to significantly contribute to the classification model for either early or late ischemia. This study demonstrates that patterns of changes in urinary metabolites are effective at distinguishing AII/R progression in an animal model. This is a proof-of-concept study to further support examination of metabolites in the clinical diagnosis of intestinal ischemia reperfusion injury in patients. The discovery of a fingerprint metabolite profile of AII/R will be a major advancement in the diagnosis, treatment, and prevention of systemic injury in critically ill patients. PMID- 28662086 TI - Abscisic acid pathway involved in the regulation of watermelon fruit ripening and quality trait evolution. AB - Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai) is a non-climacteric fruit. The modern sweet-dessert watermelon is the result of years of cultivation and selection for fruits with desirable qualities. To date, the mechanisms of watermelon fruit ripening, and the role of abscisic acid (ABA) in this process, has not been well understood. We quantified levels of free and conjugated ABA contents in the fruits of cultivated watermelon (97103; C. lanatus subsp. vulgaris), semi-wild germplasm (PI179878; C. lanatus subsp. mucosospermus), and wild germplasm (PI296341-FR; C. lanatus subsp. lanatus). Results showed that ABA content in the fruits of 97103 and PI179878 increased during fruit development and ripening, but maintained a low steady state in the center flesh of PI296341 FR fruits. ABA levels in fruits were highest in 97103 and lowest in PI296341-FR, but no obvious differences in ABA levels were observed in seeds of these lines. Examination of 31 representative watermelon accessions, including different C. lanatus subspecies and ancestral species, showed a correlation between soluble solids content (SSC) and ABA levels in ripening fruits. Furthermore, injection of exogenous ABA or nordihydroguaiaretic acid (NDGA) into 97103 fruits promoted or inhibited ripening, respectively. Transcriptomic analyses showed that the expression levels of several genes involved in ABA metabolism and signaling, including Cla009779 (NCED), Cla005404 (NCED), Cla020673 (CYP707A), Cla006655 (UGT) and Cla020180 (SnRK2), varied significantly in cultivated and wild watermelon center flesh. Three SNPs (-738, C/A; -1681, C/T; -1832, G/T) in the promoter region of Cla020673 (CYP707A) and one single SNP (-701, G/A) in the promoter of Cla020180 (SnRK2) exhibited a high level of correlation with SSC variation in the 100 tested accessions. Our results not only demonstrate for the first time that ABA is involved in the regulation of watermelon fruit ripening, but also provide insights into the evolutionary mechanisms of this phenomenon. PMID- 28662087 TI - Unique intrahepatic transcriptomics profiles discriminate the clinical phases of a chronic HBV infection. AB - Chronic hepatitis B is a highly heterogeneous liver disease characterized by phases with fluctuations in viral replication and progressive liver damage in some, but not all infected individuals. Despite four decades of research, insight into host determinants underlying these distinct clinical phases-immunotolerant, immune active, inactive carrier, and HBeAg-negative hepatitis-remains elusive. We performed an in-depth transcriptome analysis of archived FFPE liver biopsies of each clinical phase to address host determinants associated with the natural history. Therefore, we determined, for the first time, intrahepatic global expression profiles of well-characterized chronic HBV patients at different clinical phases. Our data, obtained by microarray, demonstrate that B cells and NK/cytotoxic-related genes in the liver, including CD19, TNFRSF13C, GZMH, and KIR2DS3, were differentially expressed across the clinical HBV phases, which was confirmed by modular analysis and also Nanostring arrays in an independent cohort. Compared to the immunotolerant phase, 92 genes were differentially expressed in the liver during the immune active phase, 46 in the inactive carrier phase, and 71 in the HBeAg-negative phase. Furthermore, our study also revealed distinctive transcription of genes associated with cell cycle activity, NF-kappaB signaling, cytotoxic function and mitochondrial respiration between clinical phases. Our data define for the first time using microarray unique transcriptomes in the HBV-infected liver during consecutive clinical phases. We demonstrate that fluctuations of viral loads and liver damage coincide with fluctuations in the liver transcriptome and point to functional- immune and non-immune- components contributing to the clinical phenotype in patients. PMID- 28662088 TI - Automated interpretation of influenza hemagglutination inhibition (HAI) assays: Is plate tilting necessary? AB - The hemagglutination inhibition assay (HAI) is widely used to evaluate vaccine induced antibody responses as well as to antigenically characterize influenza viruses. The results of an HAI assay are based on an endpoint titration where the titers are generally manually interpreted and recorded by a well-trained expert. For serological applications, the lack of standardization in endpoint interpretation and interference from non-specific inhibitors in clinical samples can translate into a high degree of variability in the results. For example, tilting HAI plates at 45-60 degrees to look for a "tear drop pattern" with avian red blood cells is a common practice by many, but not all, research laboratories. In this work, we tested the hypothesis that an automated image analysis algorithm can be used to achieve an accurate and non-subjective interpretation of HAI assays-specifically without the need to tilt plates. In a side-by-side comparison study performed during FDA's biannual serological screening process for influenza viruses, titer calls for more than 2200 serum samples were made by the Cypher One automated hemagglutination analyzer without tilting and by an expert human with tilting. The comparison yielded 95.6% agreement between the expert reader and automated interpretation method (within +/- 1 dilution) for the complete dataset. Performance was also evaluated relative to the type of red blood cell (turkey and guinea pig) and influenza strain (12 different viruses). For the subset that utilized guinea pig red blood cells (~44% of the samples), for which no plate tilting was required, the agreement with an expert reader was 97.2%. For the subset that utilized turkey red blood cells (~56% of the samples), for which plate tilting was necessary by the expert reader, the agreement was 94.3%. Overall these results support the postulate that algorithm-based interpretation of a digital record with no plate tilting could replace manual reading for greater consistency in HAI assays. PMID- 28662089 TI - Mitogenome sequence accuracy using different elucidation methods. AB - Mitogenome sequences are highly desired because they are used in several biological disciplines. Their elucidation has been facilitated through the development of massive parallel sequencing, accelerating their deposition in public databases. However, sequencing, assembly and annotation methods might induce variability in their quality, raising concerns about the accuracy of the sequences that have been deposited in public databases. In this work we show that different sequencing methods (number of species pooled in a library, insert size and platform) and assembly and annotation methods generated variable completeness and similarity of the resulting mitogenome sequences, using three species of predaceous ladybird beetles as models. The identity of the sequences varied considerably depending on the method used and ranged from 38.19 to 90.1% for Cycloneda sanguinea, 72.85 to 91.06% for Harmonia axyridis and 41.15 to 93.60% for Hippodamia convergens. Dissimilarities were frequently found in the non coding A+T rich region, but were also common in coding regions, and were not associated with low coverage. Mitogenome completeness and sequence identity were affected by the sequencing and assembly/annotation methods, and high within species variation was also found for other mitogenome depositions in GenBank. This indicates a need for methods to confirm sequence accuracy, and guidelines for verifying mitogenomes should be discussed and developed by the scientific community. PMID- 28662090 TI - Center of pressure based segment inertial parameters validation. AB - By proposing efficient methods for estimating Body Segment Inertial Parameters' (BSIP) estimation and validating them with a force plate, it is possible to improve the inverse dynamic computations that are necessary in multiple research areas. Until today a variety of studies have been conducted to improve BSIP estimation but to our knowledge a real validation has never been completely successful. In this paper, we propose a validation method using both kinematic and kinetic parameters (contact forces) gathered from optical motion capture system and a force plate respectively. To compare BSIPs, we used the measured contact forces (Force plate) as the ground truth, and reconstructed the displacements of the Center of Pressure (COP) using inverse dynamics from two different estimation techniques. Only minor differences were seen when comparing the estimated segment masses. Their influence on the COP computation however is large and the results show very distinguishable patterns of the COP movements. Improving BSIP techniques is crucial and deviation from the estimations can actually result in large errors. This method could be used as a tool to validate BSIP estimation techniques. An advantage of this approach is that it facilitates the comparison between BSIP estimation methods and more specifically it shows the accuracy of those parameters. PMID- 28662091 TI - Revisiting the vulnerability of juvenile bigeye (Thunnus obesus) and yellowfin (T. albacares) tuna caught by purse-seine fisheries while associating with surface waters and floating objects. AB - Tuna fisheries catch over three million tonnes of skipjack tuna (Katsuwonus pelamis) each year, the majority of which come from purse-seine vessels targeting fish associated with man-made fish aggregating devices (FADs). A significant challenge for fisheries management is to maximize the efficiency of skipjack tuna catches whilst minimizing the bycatch of small and immature bigeye (Thunnus obesus) and yellowfin (T. albacares) tuna, for which long-term sustainability is uncertain in 75% of the world's stocks. To better manage the issues common with this fishing method, an improved understanding of tuna behaviour around FADs is necessary. We probabilistically classified the vertical behavioural patterns of 50 bigeye and 35 yellowfin tuna (mean fork length 72cm and 70cm, respectively) electronically tagged throughout the western and central Pacific Ocean into shallow and deep states, using a state-space modelling approach. The occurrence of surface-association behaviours, defined as an individual remaining in a shallow state for 24-hours, was examined in relation to known capture events and FAD density. In general, surface-association events for both species were short and lasted on average less than three days, although events as long as 28 days were observed, and were more common in yellowfin when in archipelagic waters. Events were longest immediately following tagging in 62% and 17% of bigeye and yellowfin, respectively. Surface-association behaviour was not generally estimated just prior to recapture, being either non-existent or shorter than two days for 85% of bigeye and 74% of yellowfin. Current management measures in purse seine tuna fisheries involve periodic or spatial closures for FAD use. If the chief benefit to purse-seine fishers of surface-association around floating objects is in locating schools in horizontal space at short-term time-scales, rather than holding fish near the surface for extended periods, controlling the number of sets made on FADs should be explored further as an additional management tool. PMID- 28662092 TI - Estimated collective effective dose to the population from nuclear medicine diagnostic procedures in Croatia: A comparison of 2010 and 2015. AB - OBJECTIVE: This study presents national surveys of patient exposure from nuclear medicine (NM) diagnostic procedures in 2010 and 2015 in the Republic of Croatia. METHODS: The survey was performed according to the European Commission Dose DataMed (DDM) project methodology. 28 most frequent NM diagnostic procedures were identified. Data about frequencies of procedures and average administered activities of radioisotopes used in those procedures were collected. Average administered activities were converted to effective doses according to the dose conversion coefficients. Then the collective effective dose to the population and an effective dose per capita were calculated based on the number of the most frequent NM diagnostic procedures and the average effective dose per procedure. RESULTS: In 2010, 41200 NM diagnostic procedures led to 146.7 manSv collective effective dose to the population and in 2015, 42000 NM diagnostic procedures led to 146.8 manSv collective effective dose to the population. The frequencies of NM diagnostic procedures were 9.7 and 9.8 annually per 1000 population with 34.1 MUSv and 34.2 MUSv effective dose per capita for 2010 and 2015, respectively. The main contributors to the annual collective dose from NM in Croatia are examinations of the bone, heart, thyroid and PET/CT tumour diagnostic. Average administered activities have not changed considerably from 2010 to 2015. Nevertheless, within the frequency of some of the procedures, significant changes were found in five-year period. CONCLUSIONS: Frequencies, average administered activities and collective effective dose to the population from NM diagnostic procedures in Croatia are comparable to the values reported by other European surveys. Changes were found between 2010 and 2015 and we intend to perform this study periodically to identify possible trends, but also to raise awareness about the potential dose optimization. PMID- 28662093 TI - Diversity of inland valleys and opportunities for agricultural development in Sierra Leone. AB - Inland valleys are becoming increasingly important agricultural production areas for rural households in sub-Saharan Africa due to their relative high and secure water availability and soil fertility. In addition, inland valleys are important as water buffer and biodiversity hot spots and they provide local communities with forest, forage, and fishing resources. As different inland-valley ecosystem functions may conflict with agricultural objectives, indiscriminate development should be avoided. This study aims to analyze the diversity of inland valleys in Sierra Leone and to develop guidelines for more precise interventions. Land use, biophysical and socio-economic data were analyzed on 257 inland valleys using spatial and multivariate techniques. Five cluster groups of inland valleys were identified: (i) semi-permanently flooded with high soil organic carbon (4.2%) and moderate available phosphorus (10.2 ppm), mostly under natural vegetation; (ii) semi-permanently flooded with low soil organic carbon (1.5%) and very low available phosphorus (3.1 ppm), abandoned by farmers; (iii) seasonally flooded with moderate soil organic carbon (3.1%) and low available phosphorus (8.3 ppm), used for rainfed rice and off-season vegetables produced without fertilizer application for household consumption and market; (iv) well drained with moderate soil organic carbon (3.8%) and moderate available phosphorus (10.0 ppm), used for rainfed rice and off-season vegetables produced with fertilizer application for household consumption and market; and (v) well drained with moderate soil organic carbon (3.6%) and moderate available phosphorus (11 ppm), used for household consumption without fertilizer application. Soil organic carbon, available phosphorus, hydrological regime, physical accessibility and market opportunity were the major factors affecting agricultural intensification of inland valleys. Opening up the areas in which inland valleys occur through improved roads and markets, and better water control through drainage infrastructures along with an integrated nutrient management would promote the sustainable agricultural use of inland valleys. PMID- 28662094 TI - Low-dose, non-supervised, health insurance initiated exercise for the treatment and prevention of chronic low back pain in employees. Results from a randomized controlled trial. AB - OBJECTIVE: Back pain is a major problem requiring pragmatic interventions, low in costs for health care providers and feasible for individuals to perform. Our objective was to test the effectiveness of a low-dose 5-month exercise intervention with small personnel investment on low back strength and self perceived pain. METHODS: Two hundred twenty-six employees (age: 42.7+/-10.2 years) from three mid-size companies were randomized to 5-month non-supervised training at home (3 times/week for 20 minutes) or wait-list-control. Health insurance professionals instructed the participants on trunk exercises at the start and then supervised participants once a month. RESULTS: Muscle strength for back extension increased after the 5-month intervention with a significant between-group difference (mean 27.4 Newton [95%CI 2.2; 60.3]) favoring the exercise group (p = 0.035). Low back pain was reduced more in subjects after exercise than control (mean difference -0.74 cm [95%CI -1.17; -0.27], p = 0.002). No between-group differences were observed for back pain related disability and work ability. After stratified analysis only subjects with preexisting chronic low back pain showed a between-group difference (exercise versus controls) after the intervention in their strength for back extension (mean 55.7 Newton [95%CI 2.8; 108.5], p = 0.039), self-perceived pain (mean -1.42 cm [95%CI -2.32; -0.51], p = 0.003) and work ability (mean 2.1 points [95%CI 0.2; 4.0], p = 0.032). Significant between-group differences were not observed in subjects without low back pain: strength for back extension (mean 23.4 Newton [95%CI -11.2; 58.1], p = 0.184), self-perceived pain (mean -0.48 cm [95%CI -0.99; 0.04], p = 0.067) and work ability (mean -0.1 points [95%CI -0.9; 0.9], p = 0.999). An interaction between low back pain subgroups and the study intervention (exercise versus control) was exclusively observed for the work ability index (p = 0.016). CONCLUSION: In middle-aged employees a low-dose, non-supervised exercise program implemented over 20 weeks improved trunk muscle strength and low back pain, and in those with preexisting chronic low back pain improved work ability. PMID- 28662095 TI - Population growth is limited by nutritional impacts on pregnancy success in endangered Southern Resident killer whales (Orcinus orca). AB - The Southern Resident killer whale population (Orcinus orca) was listed as endangered in 2005 and shows little sign of recovery. These fish eating whales feed primarily on endangered Chinook salmon. Population growth is constrained by low offspring production for the number of reproductive females in the population. Lack of prey, increased toxins and vessel disturbance have been listed as potential causes of the whale's decline, but partitioning these pressures has been difficult. We validated and applied temporal measures of progesterone and testosterone metabolites to assess occurrence, stage and health of pregnancy from genotyped killer whale feces collected using detection dogs. Thyroid and glucocorticoid hormone metabolites were measured from these same samples to assess physiological stress. These methods enabled us to assess pregnancy occurrence and failure as well as how pregnancy success was temporally impacted by nutritional and other stressors, between 2008 and 2014. Up to 69% of all detectable pregnancies were unsuccessful; of these, up to 33% failed relatively late in gestation or immediately post-partum, when the cost is especially high. Low availability of Chinook salmon appears to be an important stressor among these fish-eating whales as well as a significant cause of late pregnancy failure, including unobserved perinatal loss. However, release of lipophilic toxicants during fat metabolism in the nutritionally deprived animals may also provide a contributor to these cumulative effects. Results point to the importance of promoting Chinook salmon recovery to enhance population growth of Southern Resident killer whales. The physiological measures used in this study can also be used to monitor the success of actions aimed at promoting adaptive management of this important apex predator to the Pacific Northwest. PMID- 28662096 TI - Ultrasensitivity in signaling cascades revisited: Linking local and global ultrasensitivity estimations. AB - Ultrasensitive response motifs, capable of converting graded stimuli into binary responses, are well-conserved in signal transduction networks. Although it has been shown that a cascade arrangement of multiple ultrasensitive modules can enhance the system's ultrasensitivity, how a given combination of layers affects a cascade's ultrasensitivity remains an open question for the general case. Here, we introduce a methodology that allows us to determine the presence of sequestration effects and to quantify the relative contribution of each module to the overall cascade's ultrasensitivity. The proposed analysis framework provides a natural link between global and local ultrasensitivity descriptors and it is particularly well-suited to characterize and understand mathematical models used to study real biological systems. As a case study, we have considered three mathematical models introduced by O'Shaughnessy et al. to study a tunable synthetic MAPK cascade, and we show how our methodology can help modelers better understand alternative models. PMID- 28662097 TI - Reconstructive endovascular treatment of vertebral artery dissecting aneurysms with the Low-profile Visualized Intraluminal Support (LVIS) device. AB - INTRODUCTION: The Low-profile Visualized Intraluminal Support (LVIS) device is a new generation of self-expanding braided stent recently introduced in China for stent assisted coiling of intracranial aneurysms. The aim of our study is to evaluate the feasibility, safety, and efficacy of the LVIS device in reconstructive treatment of vertebral artery dissecting aneurysms (VADAs). METHODS: We retrospectively reviewed the neurointerventional database of our institution from June 2014 to May 2016. Patients who underwent endovascular treatment of VADAs with LVIS stents were included in this study. Clinical presentation, aneurysmal characteristics, technical feasibility, procedural complications, and angiographic and clinical follow-up results were evaluated. RESULTS: 38 patients with VADAs who underwent treatment with LVIS stent were identified, including 3 ruptured VADAs. All VADAs were successfully treated with reconstructive techniques including the stent-assisted coiling (n = 34) and stenting only (n = 4). Post-procedural complications developed in 3 patients (7.9%) including two small brainstem infarctions and one delayed thromboembolic event. Complications resulted in one case of minor permanent morbidity (2.6%). There was no procedure-related mortality. The follow-up angiogram was available in 30 patients at an average of 8.3 months (range, 2 to 30 months), which revealed complete occlusion in 23 patients (76.7%), residual neck in five patients (16.7%), and residual sac in two patients (6.7%). The follow-up of 25 aneurysms with incomplete immediate occlusion revealed 22 aneurysms (88%) with improvement in the Raymond class. One aneurysm (3.3%) showed recanalization and required retreatment. Clinical followed-up at 5-28 months (mean 14.1 months) was achieved in 36 patients because two patients died of pancreatic cancer and basal ganglia hemorrhage, respectively. No new neurologic deterioration or aneurysm (re)bleeding was observed. CONCLUSIONS: Our preliminary experience with reconstruction of VADAs with the LVIS device demonstrates that this treatment approach is feasible with good short-term angiographic and clinical outcomes. Long-term and larger cohort studies are necessary to determine long-term outcomes of this therapy. PMID- 28662098 TI - Molecular cloning and biochemical characterization of two cation chloride cotransporter subfamily members of Hydra vulgaris. AB - Cation Chloride Cotransporters (CCCs) comprise secondary active membrane proteins mainly mediating the symport of cations (Na+, K+) coupled with chloride (Cl-). They are divided into K+-Cl- outward transporters (KCCs), the Na+-K+-Cl- (NKCCs) and Na+-Cl- (NCCs) inward transporters, the cation chloride cotransporter interacting protein CIP1, and the polyamine transporter CCC9. KCCs and N(K)CCs are established in the genome since eukaryotes and metazoans, respectively. Most of the physiological and functional data were obtained from vertebrate species. To get insights into the basal functional properties of KCCs and N(K)CCs in the metazoan lineage, we cloned and characterized KCC and N(K)CC from the cnidarian Hydra vulgaris. HvKCC is composed of 1,032 amino-acid residues. Functional analyses revealed that hvKCC mediates a Na+-independent, Cl- and K+ (Tl+) dependent cotransport. The classification of hvKCC as a functional K-Cl cotransporter is furthermore supported by phylogenetic analyses and a similar structural organization. Interestingly, recently obtained physiological analyses indicate a role of cnidarian KCCs in hyposmotic volume regulation of nematocytes. HvN(K)CC is composed of 965 amino-acid residues. Phylogenetic analyses and structural organization suggest that hvN(K)CC is a member of the N(K)CC subfamily. However, no inorganic ion cotransport function could be detected using different buffer conditions. Thus, hvN(K)CC is a N(K)CC subfamily member without a detectable inorganic ion cotransporter function. Taken together, the data identify two non-bilaterian solute carrier 12 (SLC12) gene family members, thereby paving the way for a better understanding of the evolutionary paths of this important cotransporter family. PMID- 28662099 TI - Intratumoural production of TNFalpha by bacteria mediates cancer therapy. AB - : Systemic administration of the highly potent anticancer therapeutic, tumour necrosis factor alpha (TNFalpha) induces high levels of toxicity and is responsible for serious side effects. Consequently, tumour targeting is required in order to confine this toxicity within the locality of the tumour. Bacteria have a natural capacity to grow within tumours and deliver therapeutic molecules in a controlled fashion. The non-pathogenic E. coli strain MG1655 was investigated as a tumour targeting system in order to produce TNFalpha specifically within murine tumours. In vivo bioluminescence imaging studies and ex vivo immunofluorescence analysis demonstrated rapid targeting dynamics and prolonged survival, replication and spread of this bacterial platform within tumours. An engineered TNFalpha producing construct deployed in mouse models via either intra-tumoural (i.t.) or intravenous (i.v.) administration facilitated robust TNFalpha production, as evidenced by ELISA of tumour extracts. Tumour growth was impeded in three subcutaneous murine tumour models (CT26 colon, RENCA renal, and TRAMP prostate) as evidenced by tumour volume and survival analyses. A pattern of pro-inflammatory cytokine induction was observed in tumours of treated mice vs. CONTROLS: Mice remained healthy throughout experiments. This study indicates the therapeutic efficacy and safety of TNFalpha expressing bacteria in vivo, highlighting the potential of non-pathogenic bacteria as a platform for restricting the activity of highly potent cancer agents to tumours. PMID- 28662100 TI - miR-146a, miR-146b, and miR-155 increase expression of IL-6 and IL-8 and support HSP10 in an In vitro sepsis model. AB - microRNAs (miRNAs) play an essential role in inflammation processes including sepsis. This study aimed to identify miRNAs as candidates for therapies that are involved in the innate immune response and to assess their potential functions in the activation of the endothelium. We stimulated THP-1 monocytes with 10 ng/ml LPS for 4 h and used the supernatant for the stimulation of human umbilical vein endothelial cells (HUVEC) or human pulmonary microvascular endothelial cells (HPMEC) for 16 h. miRNA array analysis (of 1,891 miRNAs) identified a 1.5-fold upregulation of miR-146a, miR-146b, and miR-155 in stimulated endothelial cells. HUVEC were transfected with miRNA inhibitors for miR-146a, miR-146b, and miR-155 to investigate the function of these miRNAs in endothelial inflammatory pathways. Inhibition of miR-146a resulted in a diminished release of interleukin (IL)-6 and IL-8 by respective 68% and 55% (P<0.001). Inhibition of miR-146b reduced the expression of IL-6 by 49% (P<0.001). Inhibition of miR-155 reduced the expression of IL-6 and IL-8 by respective 31% (P<0.001) and 14%. The inhibition of miR-146a, miR-146b, and miR-155 reduced the release of HSP10 by 50%, 35%, and 69% (P<0.05), respectively, but did not influence the expression of HSP27 or TXA2. In conclusion, miR-146a, miR-146b, and miR-155 are exerting anti-inflammatory properties by down-regulating IL-6 and IL-8, and influencing the expression of HSP10 in the activated endothelium. We provide evidence for the central role of selected miRNAs in sepsis and their use in the development of small interfering RNA therapeutics to target immune cells and sepsis pathways. PMID- 28662102 TI - A novel monoclonal antibody against the N-terminus of Abeta1-42 reduces plaques and improves cognition in a mouse model of Alzheimer's disease. AB - Senile plaques consisting of Amyloid-beta (Abeta) peptides, in particular Abeta1 42, are the hallmark of Alzheimer's disease (AD) and have been the primary therapeutic targets. Passive immunotherapy with monoclonal antibodies (mAbs) has shown initial success in mouse models of AD. However, the existing Abeta-directed mAbs mostly were tested on animal models or patients with advanced disease. The effects and mechanisms of mAbs on animals or human trial participants in the prodromal phase of AD are not fully clarified. In the current study, a novel mAb (3F5) directed against the 1-11 amino acids of Abeta1-42 was generated by immunizing mice with an emulsion of full length human Abeta1-42. The mAb (3F5) showed the ability to disrupt Abeta1-42 aggregation and prevent Abeta-mediated neurotoxicity in vitro. In a mouse model of AD, administration with 3F5 for 3 months in 6 months-old mice demonstrated that the mAb specifically bound with Abeta1-42 to promote the depolymerization of Abeta fibrils, facilitated endocytosis of Abeta1-42 by microglia, and attenuated the death and apoptosis of neuronal cells, accompanied by neurite outgrowth. APP/PS1 double-transgenic mice treated with 3F5 mAb showed reduced memory loss, cognitive decline, and decreased levels of amyloid deposits in the brain. Abeta1-42 levels in cerebral tissues were also significantly reduced, whereas serum Abeta1-42 was markedly increased. Interestingly, the concentration of 3F5 in peripheral circulation is much higher than that in the brain. These results indicate that 3F5 is able to cross the blood-brain barrier (BBB) to bind Abeta and initiates the phagocytosis of antibody/Abeta complexes by microglia in the amyloid depositing mice. 3F5 also promotes Abeta efflux from the brain. As a consequence, the antibody reduces plaques in the AD mouse brain, in association with reduction in the pathology of AD. PMID- 28662101 TI - Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer. AB - Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. We found that, altogether, aberrant PI3K/AKT signalling in lung epithelial cells regulated the expression of 1,960/20,436 genes (9%), though only 30 differentially expressed genes (DEGs) (15 up-regulated, 12 down-regulated and 3 discordant) out of 20,436 that were common among BEAS-AKT1-E17K, BEAS-PIK3CA E545K and BEAS-shPTEN cells (0.1%). Conversely, DEGs specific for mutant AKT1 were 133 (85 up-regulated; 48 down-regulated), DEGs specific for mutant PIK3CA were 502 (280 up-regulated; 222 down-regulated) and DEGs specific for PTEN loss were 1549 (799 up-regulated, 750 down-regulated). The results obtained from array analysis were confirmed by quantitative RT-PCR on selected up- and down-regulated genes (n = 10). Treatment of BEAS-C cells and the corresponding derivatives with pharmacological inhibitors of AKT (MK2206) or PI3K (LY294002) further validated the significance of our findings. Moreover, mRNA expression of selected DEGs (SGK1, IGFBP3, PEG10, GDF15, PTGES, S100P, respectively) correlated with the activation status of the PI3K/AKT pathway assessed by S473 phosphorylation in NSCLC cell lines (n = 6). Finally, we made use of Ingenuity Pathway Analysis (IPA) to investigate the relevant BioFunctions enriched by the costitutive activation of AKT1-, PI3K- or PTEN-dependent signalling in lung epithelial cells. Expectedly, the analysis of the DEGs common to all three alterations highlighted a group of BioFunctions that included Cell Proliferation of tumor cell lines (14 DEGs), Invasion of cells (10 DEGs) and Migration of tumour cell lines (10 DEGs), with a common core of 5 genes (ATF3, CDKN1A, GDF15, HBEGF and LCN2) that likely represent downstream effectors of the pro-oncogenic activities of PI3K/AKT signalling. Conversely, IPA analysis of exclusive DEGs led to the identification of different downstream effectors that are modulated by mutant AKT1 (TGFBR2, CTSZ, EMP1), mutant PIK3CA (CCND2, CDK2, IGFBP2, TRIB1) and PTEN loss (ASNS, FHL2). These findings not only shed light on the molecular mechanisms that are activated by aberrant signalling through the PI3K/AKT pathway in lung epithelial cells, but also contribute to the identification of previously unrecognised molecules whose regulation takes part in the development of lung cancer. PMID- 28662103 TI - High prevalence of GII norovirus in hospitalized children with acute diarrhea, in Beijing. AB - : This study was addressed to the relationship between norovirus and acute diarrhea in hospitalized children, including hospital-acquired infection (HAI) and community-acquired infection (CAI) in a children's hospital in Beijing. RT PCR was used to detect norovirus in stool specimen, followed by sequence analysis for PCR products. From 2010 to 2013, a total of 1248 specimens, including 661 from the HAI group and 587 from the CAI group were tested for norovirus. Norovirus were detected in 380 of 1248 (30.4%) diarrheal specimens. The positive rate for norovirus detection was higher in children within HAI group than CAI group (35.3%, 232/661 vs. 25.6%, 148/587), and the difference was significant (X2 = 14.35, P<0.05). For age distribution, the highest positivity rates of norovirus were in age of 0-5 months for HAI group and 12-23 months for CAI group. In the study, 262 amplicons of the VP1 region from norovirus-positive specimens were sequenced, which showed GII.3 and GII.4 norovirus were the most common genotypes detected in 50.0% (n = 131) and 48.9% (n = 128) of the positive specimens, respectively. Regarding the wards distribution, GII.3 norovirus was mainly detected in ward for neonatal diseases (36/85 in HAI group; 19/46 in CAI group), GII.4 norovirus was mainly detected in ward for respiratory and digestive diseases (21/85 in HAI group; 15/33 in CAI group). CONCLUSION: The data elaborated the importance of norovirus in hospital associated infectious diarrhea. The prevalence of norovirus is higher from HAI group than CAI group, and the norovirus from the patients in CAI group could be the source of infection in HAI group. PMID- 28662104 TI - Vibrio aphrogenes sp. nov., in the Rumoiensis clade isolated from a seaweed. AB - A novel strain Vibrio aphrogenes sp. nov. strain CA-1004T isolated from the surface of seaweed collected on the coast of Mie Prefecture in 1994 [1] was characterized using polyphasic taxonomy including multilocus sequence analysis (MLSA) and a genome based comparison. Both phylogenetic analyses on the basis of 16S rRNA gene sequences and MLSA based on eight protein-coding genes (gapA, gyrB, ftsZ, mreB, pyrH, recA, rpoA, and topA) showed the strain could be placed in the Rumoiensis clade in the genus Vibrio. Sequence similarities of the 16S rRNA gene and the multilocus genes against the Rumoiensis clade members, V. rumoiensis, V. algivorus, V. casei, and V. litoralis, were low enough to propose V. aphrogenes sp. nov. strain CA-1004T as a separate species. The experimental DNA-DNA hybridization data also revealed that the strain CA-1004T was separate from four known Rumoiensis clade species. The G+C content of the V. aphrogenes strain was determined as 42.1% based on the genome sequence. Major traits of the strain were non-motile, halophilic, fermentative, alginolytic, and gas production. A total of 27 traits (motility, growth temperature range, amylase, alginase and lipase productions, and assimilation of 19 carbon compounds) distinguished the strain from the other species in the Rumoiensis clade. The name V. aphrogenes sp. nov. is proposed for this species in the Rumoiensis clade, with CA-1004T as the type strain (JCM 31643T = DSM 103759T). PMID- 28662105 TI - Discrepancies in prevalence trends for HIV, hepatitis B virus, and hepatitis C virus in Haiphong, Vietnam from 2007 to 2012. AB - We previously reported a significant reduction in the prevalence of human immunodeficiency virus type 1 (HIV) from 2007 to 2012 in people who inject drugs (PWID; 35.9% to 18.5%, p < 0.001) and female sex workers (FSW; 23.1% to 9.8%, p < 0.05), but not in blood donors (BD) or pregnant women, in Haiphong, Vietnam. Our aim in the present study was to assess trends in the prevalence of infection with hepatitis B and C viruses (HBV and HCV, respectively). We also investigated the coinfection rates of HBV and HCV with HIV in the same groups. Between 2007 and 2012, HBV prevalence was significantly decreased in BD (18.1% vs. 9.0%, p = 0.007) and slightly decreased in FSW (11.0% vs. 3.9%, p = 0.21), but not in PWID (10.7% vs. 11.1%, p = 0.84). HCV prevalence was significantly decreased in PWID (62.1% in 2007 vs. 42.7% in 2008, p < 0.0001), but it had rebounded to 58.4% in 2012 (2008 vs. 2012, p < 0.0001). HCV prevalence also increased in FSW: 28.6% in 2007 and 2009 vs. 35.3% in 2012; however, this difference was not significant (2007 vs. 2012, p = 0.41). Rates of coinfection with HBV and HCV among HIV infected PWID and FSW did not change significantly during the study period. Our findings suggest that the current harm reduction programs designed to prevent HIV transmission in PWID and FSW may be insufficient to prevent the transmission of hepatitis viruses, particularly HCV, in Haiphong, Vietnam. New approaches, such as the introduction of catch-up HBV vaccination to vulnerable adult populations and the introduction of HCV treatment as prevention, should be considered to reduce morbidity and mortality due to HIV and hepatitis virus coinfection in Vietnam. PMID- 28662106 TI - Variation between the oral and faecal microbiota in a free-living passerine bird, the great tit (Parus major). AB - The gastrointestinal tract of vertebrates is inhabited by diverse bacterial communities that induce marked effects on the host physiology and health status. The composition of the gastrointestinal microbiota is characterized by pronounced taxonomic and functional variability among different regions of the vertebrate gastrointestinal tract. Despite the relatively solid knowledge on the among region variations of the gastrointestinal microbiota in model mammalian species, there are only a few studies concerning among-region variations of the gastrointestinal microbiota in free-living non-mammalian vertebrate taxa. We used Illumina MiSeq sequencing of bacterial 16S rRNA amplicons to compare the diversity as well as taxonomic composition of bacterial communities in proximal vs. distal parts of the gastrointestinal tract (represented by oral swabs and faecal samples, respectively) in a wild passerine bird, the great tit (Parus major). The diversity of the oral microbiota was significantly higher compared to the faecal microbiota, whereas interindividual variation was higher in faecal than in oral samples. We also observed a pronounced difference in taxonomic content between the oral and faecal microbiota. Bacteria belonging to the phyla Proteobacteria, Firmicutes and Actinobacteria typically dominated in both oral and faecal samples. A high abundance of bacteria belonging to Tenericutes was observed only in faecal samples. Surprisingly, we found only a slight correlation between the faecal and oral microbiota at the within-individual level, suggesting that the microbial composition in these body sites is shaped by independent regulatory processes. Given the independence of these two communities at the individual level, we propose that simultaneous sampling of the faecal and oral microbiota will extend our understanding of host vs. microbiota interactions in wild populations. PMID- 28662107 TI - Highly mutable tandem DNA repeats generate a cell wall protein variant more frequent in disease-causing Candida albicans isolates than in commensal isolates. AB - During adaptation to host environments, many microorganisms alter their cell surface. One mechanism for doing so is variation in the number of amino acid repeats in cell surface proteins encoded by hypermutable DNA tandem repeats. In the yeast Candida albicans, an opportunistic human pathogen, the gene SSR1 encodes a GPI-anchored cell wall protein with a structural role. It contains two regions consisting of tandem repeats, almost exclusively encoding the amino acid pair Ser-Ala. As expected, the repeat regions make SSR1 highly mutable. New SSR1 alleles arose with a frequency of 1.11*10-4 per cell division in serially propagated cells. We also observed a large number (25) of SSR1 alleles with different repeat lengths in a survey of 131 isolates from a global strain collection. C. albicans is diploid, and combinations of these allele generated 41 different SSR1 genotypes. In both repeat regions, nonsynonymous mutations were largely restricted to one particular repeat unit. Two very similar allele combinations were largely restricted to one clade, clade 1. Each combination was present in ~30% of 49 infection-causing clade 1 strains, but one was rare (2%), the other absent in 46 infection-causing strains representing the remainder of the species (P < 0.00018 and 0.00004; Fisher's exact test). These results indicate that both repeat regions are under selection and that amino acid repeat length polymorphisms generate Ssr1 protein variants most suitable for specific genetic backgrounds. One of these two allele combinations was 5.51 times more frequent, the other 1.75 times less frequent in 49 clade 1 strains that caused disease than in 36 commensal clade 1 strains (P = 0.0105; Chi2 test). This indicates that insertion and deletion of repeats not only generates clade optimized Ssr1p variants, but may also assist in short-term adaptation when C. albicans makes the transition from commensal to pathogen. PMID- 28662108 TI - Short-term adaptations following Complex Training in team-sports: A meta analysis. AB - OBJECTIVE: The purpose of this meta-analysis was to study the short-term adaptations on sprint and vertical jump (VJ) performance following Complex Training (CT) in team-sports. CT is a resistance training method aimed at developing both strength and power, which has a direct effect on sprint and VJ. It consists on alternating heavy resistance training exercises with plyometric/power ones, set for set, on the same workout. METHODS: A search of electronic databases up to July 2016 (PubMed-MEDLINE, SPORTDiscus, Web of Knowledge) was conducted. Inclusion criteria: 1) at least one CT intervention group; 2) training protocols >=4-wks; 3) sample of team-sport players; 4) sprint or VJ as an outcome variable. Effect sizes (ES) of each intervention were calculated and subgroup analyses were performed. RESULTS: A total of 9 studies (13 CT groups) met the inclusion criteria. Medium effect sizes (ES) (ES = 0.73) were obtained for pre-post improvements in sprint, and small (ES = 0.41) in VJ, following CT. Experimental-groups presented better post-intervention sprint (ES = 1.01) and VJ (ES = 0.63) performance than control-groups. SPRINT: large ESs were exhibited in younger athletes (<20 years old; ES = 1.13); longer CT interventions (>=6 weeks; ES = 0.95); conditioning activities with intensities <=85% 1RM (ES = 0.96) and protocols with frequencies of <3 sessions/week (ES = 0.84). Medium ESs were obtained in Division I players (ES = 0.76); training programs >12 total sessions (ES = 0.74). VJ: Large ESs in programs with >12 total sessions (ES = 0.81). Medium ESs obtained for under-Division I individuals (ES = 0.56); protocols with intracomplex rest intervals >=2 min (ES = 0.55); conditioning activities with intensities <=85% 1RM (ES = 0.64); basketball/volleyball players (ES = 0.55). Small ESs were found for younger athletes (ES = 0.42); interventions >=6 weeks (ES = 0.45). CONCLUSIONS: CT interventions have positive medium effects on sprint performance and small effects on VJ in team-sport athletes. This training method is a suitable option to include in the season planning. PMID- 28662110 TI - Back pain in elite sports: A cross-sectional study on 1114 athletes. AB - OBJECTIVES: To establish the prevalence of back pain in German elite athletes; examine the influence of age, sex, sports discipline and training volume; and compare elite athletes with a physically active control group. METHODS: A standardized and validated online back pain questionnaire was sent by the German Olympic Sports Confederation to approximately 4,000 German national and international elite athletes, and a control group of 253 physically active but non-elite sports students. RESULTS: We received responses from 1,114 elite athletes (46.5% male and 53.1% female, mean age 20.9 years +/- 4.8 years, mean height 176.5 +/- 11.5 cm, mean weight 71.0 +/- 10.3 kg) and 166 physically active sports students (74.7% male and 24.1 female, mean age 21.2 +/- 2.0 years, mean height 180.0 +/- 8.0 cm, mean weight 74.0 +/- 14.5 kg). In elite athletes, the lifetime prevalence of back pain was 88.5%, the 12-month prevalence was 81.1%, the 3-month prevalence was 68.3% and the point prevalence was 49.0%, compared with 80.7%, 69.9%, 59.0% and 42.8%, respectively in the control group. The lifetime, 12-month and 3-month prevalences in elite athletes were significantly higher than in the control group. Regarding the individual sports disciplines, the prevalence of back pain was significantly higher in elite rowers, dancers, fencers, gymnasts, track and field athletes, figure skaters and marksmen, and those who play underwater rugby, water polo, basketball, hockey and ice hockey compared with the control group. The prevalence of back pain was significantly lower in elite triathletes. CONCLUSIONS: Back pain is a common complaint in German elite athletes. Low back pain seems to be a problem in both elite athletes and physically active controls. A high training volume in elite athletes and a low training volume in physically active individuals might increase prevalence rates. Our findings indicate the necessity for specific prevention programs, especially in high-risk sports. Further research should investigate the optimal dose-effect relationship of sporting activity for the general population to prevent back pain. PMID- 28662109 TI - Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation. AB - The ubiquitin proteasome system (UPS) is a highly conserved and tightly regulated biochemical pathway that degrades the majority of proteins in eukaryotic cells. Importantly, the UPS is responsible for counteracting altered protein homeostasis induced by a variety of proteotoxic stresses. We previously reported that Rpt6, the ATPase subunit of the 19S regulatory particle (RP) of the 26S proteasome, is phosphorylated in mammalian neurons at serine 120 in response to neuronal activity. Furthermore, we found that Rpt6 S120 phosphorylation, which regulates the activity and distribution of proteasomes in neurons, is relevant for proteasome-dependent synaptic remodeling and function. To better understand the role of proteasome phosphorylation, we have constructed models of altered Rpt6 phosphorylation in S. cerevisiae by introducing chromosomal point mutations that prevent or mimic phosphorylation at the conserved serine (S119). We find that mutants which prevent Rpt6 phosphorylation at this site (rpt6-S119A), had increased susceptibility to proteotoxic stress, displayed abnormal morphology and had reduced proteasome activity. Since impaired proteasome function has been linked to the aggregation of toxic proteins including the Huntington's disease (HD) related huntingtin (Htt) protein with expanded polyglutamine repeats, we evaluated the extent of Htt aggregation in our phospho-dead (rpt6-S119A) and phospho-mimetic (rpt6-S119D) mutants. We showed Htt103Q aggregate size to be significantly larger in rpt6-S119A mutants compared to wild-type or rpt6-S119D strains. Furthermore, we observed that phosphorylation of endogenous Rpt6 at S119 is increased in response to various stress conditions. Together, these data suggest that Rpt6 phosphorylation at S119 may play an important function in proteasome-dependent relief of proteotoxic stress that can be critical in protein aggregation pathologies. PMID- 28662111 TI - Mechanism of resistance to mesotrione in an Amaranthus tuberculatus population from Nebraska, USA. AB - Amaranthus tuberculatus is a troublesome weed in corn and soybean production systems in Midwestern USA, due in part to its ability to evolve multiple resistance to key herbicides including 4-hydroxyphenylpyruvate dioxygenase (HPPD). Here we have investigated the mechanism of resistance to mesotrione, an important chemical for managing broadleaf weeds in corn, in a multiple herbicide resistant population (NEB) from Nebraska. NEB showed a 2.4-fold and 45-fold resistance increase to mesotrione compared to a standard sensitive population (SEN) in pre-emergence and post-emergence dose-response pot tests, respectively. Sequencing of the whole HPPD gene from 12 each of sensitive and resistant plants did not detect any target-site mutations that could be associated with post emergence resistance to mesotrione in NEB. Resistance was not due to HPPD gene duplication or over-expression before or after herbicide treatment, as revealed by qPCR. Additionally, no difference in mesotrione uptake was detected between NEB and SEN. In contrast, higher levels of mesotrione metabolism via 4 hydroxylation of the dione ring were observed in NEB compared to the sensitive population. Overall, the NEB population was characterised by lower levels of parent mesotrione exported to other parts of the plant, either as a consequence of metabolism in the treated leaves and/or impaired translocation of the herbicide. This study demonstrates another case of non-target-site based resistance to an important class of herbicides in an A. tuberculatus population. The knowledge generated here will help design strategies for managing multiple herbicide resistance in this problematic weed species. PMID- 28662113 TI - Physiological mechanisms contributing to increased water-use efficiency in winter wheat under organic fertilization. AB - Improving the efficiency of resource utilization has received increasing research attention in recent years. In this study, we explored the potential physiological mechanisms underlying improved grain yield and water-use efficiency of winter wheat (Triticum aestivum L.) following organic fertilizer application. Two wheat cultivars, ChangHan58 (CH58) and XiNong9871 (XN9871), were grown under the same nitrogen (N) fertilizer rate (urea-N, CK; and manure plus urea-N, M) and under two watering regimes (WW, well-watered; and WS, water stress) imposed after anthesis. The M fertilizer treatment had a higher Pn and lower gs and Tr than CK under both water conditions, in particular, it significantly increased WRC and Psiw, and decreased EWLR and MDA under WS. Also, the M treatment increased post anthesis N uptake by 81.4 and 16.4% under WS and WW, thus increasing post anthesis photosynthetic capacity and delaying leaf senescence. Consequently, the M treatment increased post-anthesis DM accumulation under WS and WW by 51.5 and 29.6%, WUEB by 44.5 and 50.9%, grain number per plant by 11.5 and 12.2% and 1000 grain weight by 7.3 and 3.6%, respectively, compared with CK. The grain yield under M treatment increased by 23 and 15%, and water use efficiency (WUEg) by 25 and 23%, respectively. The increased WUE under organic fertilizer treatment was due to elevated photosynthesis and decreased Tr and gs. Our results suggest that the organic fertilizer treatment enabled plants to use water more efficiently under drought stress. PMID- 28662114 TI - Novel glycopolymer sensitizes Burkholderia cepacia complex isolates from cystic fibrosis patients to tobramycin and meropenem. AB - Burkholderia cepacia complex (Bcc) infection, associated with cystic fibrosis (CF) is intrinsically multidrug resistant to antibiotic treatment making eradication from the CF lung virtually impossible. Infection with Bcc leads to a rapid decline in lung function and is often a contraindication for lung transplant, significantly influencing morbidity and mortality associated with CF disease. Standard treatment frequently involves antibiotic combination therapy. However, no formal strategy has been adopted in clinical practice to guide successful eradication. A new class of direct-acting, large molecule polycationic glycopolymers, derivatives of a natural polysaccharide poly-N-acetyl-glucosamine (PAAG), are in development as an alternative to traditional antibiotic strategies. During treatment, PAAG rapidly targets the anionic structural composition of bacterial outer membranes. PAAG was observed to permeabilize bacterial membranes upon contact to facilitate potentiation of antibiotic activity. Three-dimensional checkerboard synergy analyses were used to test the susceptibility of eight Bcc strains (seven CF clinical isolates) to antibiotic combinations with PAAG or ceftazidime. Potentiation of tobramycin and meropenem activity was observed in combination with 8-128 MUg/mL PAAG. Treatment with PAAG reduced the minimum inhibitory concentration (MIC) of tobramycin and meropenem below their clinical sensitivity breakpoints (<=4 MUg/mL), demonstrating the ability of PAAG to sensitize antibiotic resistant Bcc clinical isolates. Fractional inhibitory concentration (FIC) calculations showed PAAG was able to significantly potentiate antibacterial synergy with these antibiotics toward all Bcc species tested. These preliminary studies suggest PAAG facilitates a broad synergistic activity that may result in more positive therapeutic outcomes and supports further development of safe, polycationic glycopolymers for inhaled combination antibiotic therapy, particularly for CF-associated Bcc infections. PMID- 28662112 TI - Strand specific RNA-sequencing and membrane lipid profiling reveals growth phase dependent cold stress response mechanisms in Listeria monocytogenes. AB - The human pathogen Listeria monocytogenes continues to pose a challenge in the food industry, where it is known to contaminate ready-to-eat foods and grow during refrigerated storage. Increased knowledge of the cold-stress response of this pathogen will enhance the ability to control it in the food-supply-chain. This study utilized strand-specific RNA sequencing and whole cell fatty acid (FA) profiling to characterize the bacterium's cold stress response. RNA and FAs were extracted from a cold-tolerant strain at five time points between early lag phase and late stationary-phase, both at 4 degrees C and 20 degrees C. Overall, more genes (1.3*) were suppressed than induced at 4 degrees C. Late stationary-phase cells exhibited the greatest number (n = 1,431) and magnitude (>1,000-fold) of differentially expressed genes (>2-fold, p<0.05) in response to cold. A core set of 22 genes was upregulated at all growth phases, including nine genes required for branched-chain fatty acid (BCFA) synthesis, the osmolyte transporter genes opuCBCD, and the internalin A and D genes. Genes suppressed at 4 degrees C were largely associated with cobalamin (B12) biosynthesis or the production/export of cell wall components. Antisense transcription accounted for up to 1.6% of total mapped reads with higher levels (2.5*) observed at 4 degrees C than 20 degrees C. The greatest number of upregulated antisense transcripts at 4 degrees C occurred in early lag phase, however, at both temperatures, antisense expression levels were highest in late stationary-phase cells. Cold-induced FA membrane changes included a 15% increase in the proportion of BCFAs and a 15% transient increase in unsaturated FAs between lag and exponential phase. These increases probably reduced the membrane phase transition temperature until optimal levels of BCFAs could be produced. Collectively, this research provides new information regarding cold-induced membrane composition changes in L. monocytogenes, the growth-phase dependency of its cold-stress regulon, and the active roles of antisense transcripts in regulating its cold stress response. PMID- 28662115 TI - A two-step approach for fluidized bed granulation in pharmaceutical processing: Assessing different models for design and control. AB - Various modeling techniques were used to understand fluidized bed granulation using a two-step approach. First, Plackett-Burman design (PBD) was used to identify the high-risk factors. Then, Box-Behnken design (BBD) was used to analyze and optimize those high-risk factors. The relationship between the high risk input variables (inlet air temperature X1, binder solution rate X3, and binder-to-powder ratio X5) and quality attributes (flowability Y1, temperature Y2, moisture content Y3, aggregation index Y4, and compactability Y5) of the process was investigated using response surface model (RSM), partial least squares method (PLS) and artificial neural network of multilayer perceptron (MLP). The morphological study of the granules was also investigated using a scanning electron microscope. The results showed that X1, X3, and X5 significantly affected the properties of granule. The RSM, PLS and MLP models were found to be useful statistical analysis tools for a better mechanistic understanding of granulation. The statistical analysis results showed that the RSM model had a better ability to fit the quality attributes of granules compared to the PLS and MLP models. Understanding the effect of process parameters on granule properties provides the basis for modulating the granulation parameters and optimizing the product performance at the early development stage of pharmaceutical products. PMID- 28662116 TI - Actinic keratosis modelling in mice: A translational study. AB - BACKGROUND: Actinic keratoses (AK) are pre-malignant cutaneous lesions caused by prolonged exposure to ultraviolet radiation. As AKs lesions are generally accepted to be the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC), AK lesions have to be treated. They are also the second most common reason for visits to the dermatologist. Several treatments are available but their efficacy still needs to be improved. The UV-B-induced KA lesion mouse model is used in preclinical studies to assess the efficacy of novel molecules, even though it is often more representative of advanced AK or SCC. OBJECTIVES: Here we report on a translational study, comparing the various stages of AK development in humans and in the UV-B irradiated mouse model, as well as the optimization of photograph acquisition of AK lesions on mouse skin. METHODS: Human and mouse skin lesions were analysed by histology and immunohistochemistry. Mouse lesions were also assessed using a digital dermatoscope. RESULTS: An histological and phenotypic analysis, including p53, Ki67 and CD3 expression detection, performed on human and mouse AK lesions, shows that overall AK modelling in mice is relevant in the clinical situation. Some differences are observed, such as disorganization of keratinocytes of the basal layer and a number of atypical nuclei which are more numerous in human AK, whereas much more pronounced acanthosis is observed in skin lesion in mice. Thanks to this translational study, we are able to select appropriate experimental conditions for establishing either early or advanced stage AK or an SCC model. Furthermore, we optimized photograph acquisition of AK lesions on mouse skin by using a digital dermatoscope which is also used in clinics and allows reproducible photograph acquisition for further reliable assessment of mouse lesions. Use of this camera is illustrated through a pharmacological study assessing the activity of CARAC(r). CONCLUSION: These data demonstrate that this mouse model of UV-B induced skin lesions is predictive for the identification of novel therapeutic treatments for both early and advanced stages of the disease. PMID- 28662117 TI - Detecting similar binding pockets to enable systems polypharmacology. AB - In the era of systems biology, multi-target pharmacological strategies hold promise for tackling disease-related networks. In this regard, drug promiscuity may be leveraged to interfere with multiple receptors: the so-called polypharmacology of drugs can be anticipated by analyzing the similarity of binding sites across the proteome. Here, we perform a pairwise comparison of 90,000 putative binding pockets detected in 3,700 proteins, and find that 23,000 pairs of proteins have at least one similar cavity that could, in principle, accommodate similar ligands. By inspecting these pairs, we demonstrate how the detection of similar binding sites expands the space of opportunities for the rational design of drug polypharmacology. Finally, we illustrate how to leverage these opportunities in protein-protein interaction networks related to several therapeutic classes and tumor types, and in a genome-scale metabolic model of leukemia. PMID- 28662118 TI - Low levels of serum ferritin and moderate transferrin saturation lead to adequate hemoglobin levels in hemodialysis patients, retrospective observational study. AB - BACKGROUND: Optimal iron levels in patients on hemodialysis are currently unknown, and a higher level than that for the healthy population is usually set for such patients considering the use of erythropoiesis-stimulating agents or the occurrence of chronic inflammation. However, excessive iron causes oxidative stress and impairment of its utilization by cells. Therefore we investigated the relationship between hemoglobin (Hb) level and iron status in hemodialysis patients to identify the optimal iron levels for patients undergoing hemodialysis. METHODS: A total of 208 outpatients on maintenance hemodialysis were followed up between July 2006 and June 2007. Men accounted for 64.9% cases [mean age, 59.3 +/- 13.1 years and median dialysis history, 7.7 (3.6-13.2) years], and diabetic nephropathy accounted for 25.0% cases. Hemoglobin level was measured twice a month and serum ferritin, serum iron, and total iron-binding capacity were measured once a month. The doses of recombinant human erythropoietin and low-dose iron supplement were adjusted to maintain a hemoglobin level of 10-11 g/dL, according to the guidelines of the Japanese Society for Dialysis Therapy. Hepcidin was measured at baseline. Using the mean values for 1-year period, the relationships among hemoglobin, serum ferritin levels, and transferrin saturation levels were investigated based on a receiver operating characteristic curve and a logistic regression model. In addition, the correlations among serum ferritin, transferrin saturation, and hepcidin levels were analyzed by Pearson product-moment correlation coefficient and linear regression model. RESULTS: By receiver operating characteristic curve, the cutoff point of serum ferritin and transferrin saturation levels with a hemoglobin >=10 g/dL showed <90 ng/mL (sensitivity: 69.1%, specificity: 72.1%, p < 0.001) and >=20% (sensitivity: 77.6%, specificity: 48.8%, p = 0.302). Upon logistic regression model analysis with a hemoglobin >=10 g/dL as the endpoint, the analysis of odds ratios relative to a group with serum ferritin >=90 ng/mL and transferrin saturation <20% revealed that the group with serum ferritin <90 ng/mL and transferrin saturation >=20% had the highest ratio: 46.75 (95% confidence interval: 10.89-200.70, p < 0.001). In Pearson product-moment correlation coefficient, hepcidin showed a strong positive correlation with serum ferritin [r = 0.78 (95% confidence interval: 0.72-0.83, p < 0.001)] and a weak positive correlation with transferrin saturation [r = 0.18 (95% confidence interval: 0.04 0.31, p = 0.010)]. In the multivariable analyses of the linear regression model, a positive relationship was shown between hepcidin and serum ferritin [beta coefficient of 0.30 (95% confidence interval: 0.27-0.34, p < 0.001)]; however, no relationship was shown with transferrin saturation [beta-coefficient of 0.09 (95% confidence interval: -0.31-0.49, p = 0.660)]. CONCLUSIONS: In this study, the iron status of serum ferritin <90 ng/mL and transferrin saturation >=20% was optimal in hemodialysis patients receiving recombinant human erythropoietin for anemia therapy. This result indicates that the threshold values for the optimal iron status may be lower than those currently recommended in iron-level management guideline. PMID- 28662119 TI - Combined poor diabetes control indicators are associated with higher risks of diabetic retinopathy and macular edema than poor glycemic control alone. AB - PURPOSE: To examine the association of individual and combined indicators of diabetes control with diabetic retinopathy and diabetic macular edema. MATERIALS AND METHODS: In this clinical, cross-sectional study, 613 adults with type 2 diabetes (372 any diabetic retinopathy; 183 any diabetic macular edema) were examined. Diabetic retinopathy was assessed from fundus photographs; diabetic macular edema from Ocular Coherence Tomography scans; and HbA1c and serum lipid values from fasting blood samples. Poor glucose control was defined as HbA1c>=7%; poor blood pressure control as SBP>=130/DBP>=80; and poor lipid control as total cholesterol:HDL ratio>=4.0. The association of poor glucose control, poor blood pressure control and poor lipid control alone and in combination (poor glucose & blood pressure control; poor glucose & lipid control; poor blood pressure & lipid control; and poor glucose, blood pressure & lipid control) with diabetic retinopathy/diabetic macular edema was examined using multiple logistic regression models. RESULTS: Patients' mean+/-standard deviation age was 64.9+/ 11.6 years (57% male). In adjusted models, compared to those with good control of all indicators (n = 99, 18.3%), the odds ratio (95% Confidence Interval) of having any diabetic retinopathy was 2.44 (1.34-4.46), 3.75 (1.75-8.07), 4.64 (2.13-10.12) and 2.28 (1.01-5.16) for poor glucose control only; poor glucose & blood pressure control; poor glucose & lipid control; and poor glucose, blood pressure & lipid control, respectively. Correspondingly for diabetic macular edema, they were 3.19 (1.55-6.59); 3.60 (1.58-8.22); 2.76 (1.18-6.44); and 3.01 (1.18-7.67), respectively. Odds were not significantly increased for other indicators. DISCUSSION: Compared to individual indicators of poor diabetes control, risk of diabetic retinopathy and diabetic macular edema increased three to fourfold with a combination of these indicators. Targeting combined diabetes control indicators is important to reduce risk of diabetic retinopathy/diabetic macular edema. PMID- 28662120 TI - Milieu matters: Evidence that ongoing lifestyle activities influence health behaviors. AB - Health behaviors occur within a milieu of lifestyle activities that could conflict with health actions. We examined whether cognitions about, and performance of, other lifestyle activities augment the prediction of health behaviors, and whether these lifestyle factors are especially influential among individuals with low health behavior engagement. Participants (N = 211) completed measures of past behavior and cognitions relating to five health behaviors (e.g., smoking, getting drunk) and 23 lifestyle activities (e.g., reading, socializing), as well as personality variables. All behaviors were measured again at two weeks. Data were analyzed using neural network and cluster analyses. The neural network accurately predicted health behaviors at follow-up (R2 = .71). As hypothesized, lifestyle cognitions and activities independently predicted health behaviors over and above behavior-specific cognitions and previous behavior. Additionally, lifestyle activities and poor self-regulatory capability were more influential among people exhibiting unhealthy behaviors. Considering ongoing lifestyle activities can enhance prediction and understanding of health behaviors and offer new targets for health behavior interventions. PMID- 28662121 TI - Cascades of emotional support in friendship networks and adolescent smoking. AB - Social support from peers and parents provides a key socialization function during adolescence. We examine adolescent friendship networks using a Stochastic Actor-Based modeling approach to observe the flow of emotional support provision to peers and the effect of support from parents, while simultaneously modeling smoking behavior. We utilized one school (n = 976) from The National Longitudinal Study of Adolescent to Adult Health (AddHealth) Study. Our findings suggest that emotional support is transacted through an interdependent contextual system, comprised of both peer and parental effects, with the latter also having distal indirect effects from youths' friends' parents. PMID- 28662122 TI - Genetic diversity and stock identification of small abalone (Haliotis diversicolor) in Taiwan and Japan. AB - Small abalone (Haliotis diversicolor) is a commercially valuable species for both fisheries and aquaculture. The production of annual farmed small abalone in Taiwan, once the highest in the world, has dramatically decreased in the past 15 years, and currently, the industry is close to collapse. Understanding the genetic diversity of small abalone and developing stock identification methods will be useful for genetic breeding, restoring collapsed stocks, managing stocks, and preventing illegal trade. We investigated 307 cultured and wild individuals from Taiwan, Japan, and Bali Island (Indonesia) by using the mitochondrial cytochrome c oxidase subunit I (COI) gene. Network analysis of mtDNA COI gene sequences revealed that the individuals collected from Taiwan, Japan, and Indonesia could be identified, and showed significant genetic divergence. In addition, the Indonesian population (Haliotis diversicolor squamata) was significantly different from the other populations and might need to be considered a separate species. We discovered a single nucleotide polymorphism marker in the mtDNA COI gene that can be used to distinguish the Taiwan population from the Japan population. We also developed a polymerase chain reaction-restriction fragment length polymorphism method for rapid detection. Furthermore, we could identify the cultured stocks, wild population, and hybrid stocks by using 6 microsatellites and amplified fragment length polymorphism. This study contributes useful tools for stock identification and the production of high-disease resistant small abalone strains (Japan * Taiwan or Taiwan * Japan). Efforts should be made to avoid unintentional random genetic mixing of the Taiwan population with the Japan population and subsequent breakdown of population differentiation, which impair local adaptation of the Taiwan wild population. Molecular markers revealed a split between the Taiwan and Japan populations, and the existence of a possible barrier to the free dispersal of small abalone is discussed. PMID- 28662123 TI - Effects of different re-warm up activities in football players' performance. AB - Warm up routines are commonly used to optimize football performance and prevent injuries. Yet, official pre-match protocols may require players to passively rest for approximately 10 to 15 minutes between the warm up and the beginning of the match. Therefore, the aim of this study was to explore the effect of different re warm up activities on the physical performance of football players. Twenty-Two Portuguese elite under-19 football players participated in the study conducted during the competitive season. Different re-warm up protocols were performed 6 minutes after the same standardized warm up in 4 consecutive days in a crossover controlled approach: without, eccentric, plyometric and repeated changes of direction. Vertical jump and Sprint performances were tested immediately after warm up and 12 minutes after warm up. Results showed that repeated changes of direction and plyometrics presented beneficial effects to jump and sprint. Different practical implications may be taken from the eccentric protocol since a vertical jump impairment was observed, suggesting a possibly harmful effect. The absence of re-warm up activities may be detrimental to players' physical performance. However, the inclusion of re-warm up prior to match is a complex issue, since the manipulation of volume, intensity and recovery may positively or negatively affect the subsequent performance. In fact, this exploratory study shows that eccentric exercise may be harmful for physical performance when performed prior a football match. However, plyometric and repeated changes of direction exercises seem to be simple, quick and efficient activities to attenuate losses in vertical jump and sprint capacity after warm up. Coaches should aim to develop individual optimal exercise modes in order to optimize physical performance after re warm activities. PMID- 28662124 TI - Individual perception of bees: Between perceived danger and willingness to protect. AB - The current loss of biodiversity has found its way into the media. Especially the loss of bees as pollinators has recently received much attention aiming to increase public awareness about the consequence of pollinator loss and strategies for protection. However, pollinating insects like bees often prompt considerable anxiety. Negative emotions such as fear and disgust often lead to lack of support for conservation and appropriate initiatives for protection. Our study monitored perceptions of bees in the contexts of conservation and danger bees possibly represent by applying a semantic differential using contrasting adjectives under the heading "I think bees are...". Additionally, open questions were applied to examine individual perceptions of danger and conservation of bees. Respondents were students from primary school, secondary school and university. We compared these novices (n = 499) to experts (beekeepers, n = 153). An exploratory factor analysis of the semantic differential responses yielded three major oblique factors: Interest, Danger and Conservation & Usefulness. The inter-correlations of these factors were significant. Although all subgroups showed an overall high willingness to protect bees, the perception of danger scored medium. The individual experience of bee stings was the most prevalent reason for expressing fear. Educational programs focusing on pollinator conservation may reduce the perceived danger through removing misinformation, and supporting interest in the species. Based on the overall positive attitude toward bees, we suggest introducing bees (e.g., Apis mellifera) as a flagship species for pollinator conservation. PMID- 28662125 TI - Digital divide among people with disabilities: Analysis of data from a nationwide study for determinants of Internet use and activities performed online. AB - INTRODUCTION: The Internet is both an opportunity as well as a challenge for people with disabilities. However, this segment of the population is usually indicated among social groups experiencing digital divide. The study is focused on the analysis of factors determining Internet usage and undertaking specific activities online among people with disabilities based on a nationwide study performed in 2013 in Poland. METHODS: Secondary analysis was performed on the data of persons who declared disability status in 2013 "Social Diagnosis" study. Multivariate logistic regression models were developed for the use of the Internet and performing three types of activities online. RESULTS: Among 3,556 respondents with disability 51.02% were females, 25.19% 65 years of age and over and 33.05% were Internet users. The predictors of Internet usage included the degree of disability, place of residence, level of education, marital status, occupational status, net income, use of health care service and the use of mobile phone. The odds ratio that a person with disability belonging to the oldest category will use the Internet was only 0.04 (95% CI 0.02-0.09), when compared to the youngest category. The odds that a person with disability from the highest category of education will use the Internet were 18 times higher than in the case of persons with only basic education (OR 18.17, 95% CI 11.70-28.21). Common predictors of online activities (accessing websites of public institutions, checking and sending emails, publishing own content on the Internet) included age category and net income. CONCLUSIONS: People with disabilities in Poland are facing a significant digital divide. The factors determining the use of the Internet in this group are similar to those of the general population. On the other hand, people with disabilities who are active online, access diversified types of services including presentation of their own content online. PMID- 28662126 TI - Relation between choice-induced preference change and depression. AB - Most experimental studies of depressive symptom effects on decision-making have examined situations in which a single correct answer exists based on external circumstances (externally guided decision-making, e.g., gambling task). In addition to such decision-making, for decision-making of other types, no correct answer exists based on external circumstances (internally guided decision-making, e.g., preference judgment). For internally guided decision-making, a phenomenon is known by which preference for the chosen item increases and preference for the rejected item is decreased after choosing between two equally preferred items which is designated as choice-induced preference change. Recent reports suggest that this phenomenon is explainable by reinforcement learning theory just as it is with externally guided decision-making. Although many earlier studies have revealed the effects of depression in externally guided decision-making, the relation between depressive symptoms and choice-induced preference change remains unclear. This study investigated the relation between depressive symptoms and choice-induced preference change using the blind choice paradigm. Results show that depressive symptoms are correlated with change in preference of rejected items (Spearman's r = .28, p = .04): depressed individuals tend to show less decreased preference of rejected items. These results indicate that individual differences of depressive symptoms affect choice-induced preference change. We discuss the mechanisms underlying the relation between depression and choice induced preference change. PMID- 28662127 TI - Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations. AB - BACKGROUND: There are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia. METHODS AND FINDINGS: We defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer's disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer's society focus groups. Attendees at a consensus conference (experts in dementia research, disease modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification. LIMITATIONS: Most trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties. INTERPRETATION: This is the first review to identify the 81 outcome measures the research community uses for disease-modifying trials in mild-to-moderate dementia. Our recommendations will facilitate designing, comparing and meta-analysing disease modification trials in mild-to-moderate dementia, increasing their value. TRIAL REGISTRATION: PROSPERO no. CRD42015027346. PMID- 28662128 TI - Molecular and functional characterization of two isoforms of chalcone synthase and their expression analysis in relation to flavonoid constituents in Grewia asiatica L. AB - Chalcone synthase constitutes a functionally diverse gene family producing wide range of flavonoids by catalyzing the initial step of the phenylpropanoid pathway. There is a pivotal role of flavonoids in pollen function as they are imperative for pollen maturation and pollen tube growth during sexual reproduction in flowering plants. Here we focused on medicinally important fruit bearing shrub Grewia asiatica. It is a rich repository of flavonoids. The fruits are highly acclaimed for various putative health benefits. Despite its importance, full commercial exploitation is hampered due to two drawbacks which include short shelf life of its fruits and larger seed volume. To circumvent these constraints, seed abortion is one of the viable options. Molecular interventions tested in a number of economic crops have been to impair male reproductive function by disrupting the chalcone synthase (CHS) gene activity. Against this backdrop the aim of the present study included cloning and characterization of two full-length cDNA clones of GaCHS isoforms from the CHS multigene family. These included GaCHS1 (NCBI acc. KX129910) and GaCHS2 (NCBI acc. KX129911) with an ORF of 1176 and 1170 bp, respectively. GaCHSs were heterologously expressed and purified in E. coli to validate their functionality. Functionality of CHS isoforms was also characterized via enzyme kinetic studies using five different substrates. We observed differential substrate specificities in terms of their Km and Vmax values. Accumulation of flavonoid constituents naringenin and quercetin were also quantified and their relative concentrations corroborated well with the expression levels of GaCHSs. Further, our results demonstrate that GaCHS isoforms show differential expression patterns at different reproductive phenological stages. Transcript levels of GaCHS2 were more than its isoform GaCHS1 at the anthesis stage of flower development pointing towards its probable role in male reproductive maturity. PMID- 28662129 TI - Maternal gestational weight gain and objectively measured physical activity among offspring. AB - OBJECTIVE: Animal studies have suggested that maternal weight-related factors during pregnancy can program offspring physical activity in a sex-dependent manner. However, there is limited evidence in humans. The purpose of this study was to investigate the association between maternal gestational weight gain (GWG) and offspring total physical activity (TPA) level and to determine whether these associations are moderated by sex of offspring or maternal pre-pregnancy weight status. METHOD: We studied 56 boys (mean age = 3.7 years, standard deviation (SD) 0.5) and 57 girls (mean age = 3.5+/-0.5 years) enrolled in licensed childcare centers. TPA was objectively measured using Actical(r) accelerometers. Information on pre-pregnancy body mass index (BMI), GWG, and other maternal factors were collected with a maternal health questionnaire. Associations between GWG, as a continuous variable or categorically (inadequate, adequate, and excessive), and offspring TPA were analysed using linear mixed models to take into account the intraclass correlation between the clusters (childcare centers). Models were adjusted for gestational age, accelerometer weartime, socioeconomic status, and pre-pregnancy BMI status. RESULTS: We found a significant sex interaction (P-value = 0.009). In boys, greater GWG was associated with decreased offspring TPA (beta = -3.2 counts?1000-1/d, 95% confidence intervals (CI) = -6.4 0.02, P-value = 0.049). In girls born to mothers categorized as overweight or obese, the association between the GWG and TPA followed an inverted U-shape curve (beta for GWG squared = -0.1 counts?1000-1/d, 95% CI = (-0.2 --0.04), P-value = 0.005). In contrast, a U-shaped curve was found in girls born to mothers classified as lean (pre-pregnancy BMI<25 kg/m2) (beta for GWG squared = 0.7 counts?1000-1/d, 95% CI = 0.2-1.2, P-value = 0.011). In boys, TPA in offspring was higher among women with inadequate GWG compared to adequate GWG (P-value = 0.0137), whereas no significant differences were found in girls (P-value = 0.107). CONCLUSION: Maternal GWG can be an important biological marker of offspring TPA. These findings support the sex-dependent early developmental programming influence of GWG on TPA. PMID- 28662130 TI - Circulating tumor cells detected by lab-on-a-disc: Role in early diagnosis of gastric cancer. AB - BACKGROUND: The use of circulating tumor cells (CTCs) as an early diagnostic biomarker and prognostic indicator after surgery or chemotherapy has been suggested for various cancers. This study aimed to evaluate CTCs in patients who underwent gastrectomy for gastric cancer and to explore their clinical usefulness in the early diagnosis of gastric cancer. METHODS: A total of 116 patients with gastric cancer who underwent gastrectomy and 31 healthy volunteers were prospectively included between 2014 and 2015. Peripheral blood samples were collected before gastrectomy, and CTCs were examined using a centrifugal microfluidic system with a new fluid-assisted separation technique. RESULTS: After creating a receiver operating characteristic curve to identify the discriminative CTC value needed differentiate patients with gastric cancer from healthy volunteers, sensitivity and specificity were nearly optimized at a CTC threshold of 2 per 7.5 mL of blood. Of the 102 persons with a CTC level >=2 per 7.5 mL of blood, 99 (97.1%) had gastric cancer, and of the 45 persons with a CTC level <2 per 7.5 mL of blood, 28 (62.2%) were healthy controls. Accordingly, the sensitivity and specificity for the differentiation of patients with gastric cancer from healthy controls were 85.3% and 90.3%, respectively. However, the presence of CTCs was not associated with any clinicopathologic features such as staging, histologic type, or mucin phenotype. CONCLUSION: Although we could not prove the clinical feasibility of CTCs for gastric cancer staging, our results suggest a potential role of CTCs as an early diagnostic biomarker of gastric cancer. PMID- 28662131 TI - The association between gout and cataract risk: A meta-analysis. AB - PURPOSE: To evaluate the relationship between gout and age-related cataracts (ARCs). METHODS: A comprehensive literature search of the PubMed and Web of Science databases was conducted to identify papers on the association between gout and cataract risk that had been published between February 1991 and January 2017. Pooled relative risks (RRs) or odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated. The random-effects model was used instead of the fixed-effects model when heterogeneity was identified, as indicated by a Cochran's Q statistic P-value <0.10 or I2 index score >50%. RESULTS: A total of 3 cross-sectional studies and 3 case-control studies were included in the meta-analysis. Gout was significantly associated with increased odds of ARCs (OR 1.53, 95% CI 1.27-1.84). In the subgroup analysis, gout exhibited positive associations with the odds of posterior subcapsular cataracts (PSCs, OR 1.69, 95% CI: 1.06-2.70) and cortical cataracts (CCs, OR 1.39, 95% CI: 1.06-1.81). However, no association was identified between gout and the odds of nuclear cataracts. CONCLUSIONS: The current literature suggested that gout may be associated with increased odds of ARCs, especially PSCs and CCs. Further efforts should be made to confirm these findings and clarify the effect of gout and gout medications on the development of cataracts. PMID- 28662132 TI - Time to tighten the belts? Exploring the relationship between savings and obesity. AB - BACKGROUND: Literature suggests that the higher the rate of time preference people have, the less likely they are to save for the future. Likewise, it has been hypothesised that rising rates of being overweight/obesity are associated with an increase in peoples' marginal rate of time preference. AIM: To investigate the relationship between being overweight/ obese and the rate of time preference in an older English population, using savings as a proxy for time preference. METHODS: Three different econometric methods-Random-effects Probit Estimation, Fixed-effects Estimation, and Generalised Method of Moments Estimation-were used to explore the link between being overweight/ obese and rate of time preference in the English Longitudinal Study of Ageing dataset. Six waves of panel data spanning eleven years provided the data to test whether savings variables are related to being overweight/ obese. RESULTS: The decision to save was shown to hold a statistically significant negative relationship with body mass index but only in the Generalised Method of Moments model. Placing savings in safe, low risk investments was significantly related to a lower probability of being obese but only in the random-effects Probit model. The proportion that people saved relative to their income was not found to be significantly associated with the probability of being overweight/ obese in any of the models. CONCLUSION: There is an unclear relationship between saving behaviour and being overweight/ obese in an older English population. A financial variable such as savings is a potentially appropriate but imperfect proxy for the rate of time preference of the population. Further research is required to clarify the relationship in order to help develop strategies for obesity prevention. The inconsistency in the results between methods highlights the importance of using a wide range of alternative techniques before implementing important policy decisions. PMID- 28662133 TI - Diet-induced impulsivity: Effects of a high-fat and a high-sugar diet on impulsive choice in rats. AB - Impulsive choice is a common charactertistic among individuals with gambling problems, obesity, and substance abuse issues. Impulsive choice has been classified as a trans-disease process, and understanding the etiology of trait impulsivity could help to understand how diseases and disorders related to impulsive choice are manifested. The Western diet is a possible catalyst of impulsive choice as individuals who are obese and who eat diets high in fat and sugar are typically more impulsive. However, such correlational evidence is unable to discern the direction and causal nature of the relationship. The present study sought to determine how diet may directly contribute to impulsive choice. After 8 weeks of dietary exposure (high-fat, high-sugar, chow), the rats were tested on an impulsive choice task, which presented choices between a smaller-sooner reward (SS) and a larger-later reward (LL). Then, the rats were transferred to a chow diet and retested on the impulsive choice task. The high sugar and high-fat groups made significantly more impulsive choices than the chow group. Both groups became more self-controlled when they were off the diet, but there were some residual effects of the diet on choice behavior. These results suggest that diet, specifically one high in processed fat or sugar, induces impulsive choice. This diet-induced impulsivity could be a precursor to other disorders that are characterized by impulsivity, such as diet-induced obesity, and could offer potential understanding of the trans-disease nature of impulsive choice. PMID- 28662134 TI - Generation of monoclonal pan-hemagglutinin antibodies for the quantification of multiple strains of influenza. AB - Vaccination is the most effective course of action to prevent influenza. About 150 million doses of influenza vaccines were distributed for the 2015-2016 season in the USA alone according to the Centers for Disease Control and Prevention. Vaccine dosage is calculated based on the concentration of hemagglutinin (HA), the main surface glycoprotein expressed by influenza which varies from strain to strain. Therefore yearly-updated strain-specific antibodies and calibrating antigens are required. Preparing these quantification reagents can take up to three months and significantly slows down the release of new vaccine lots. Therefore, to circumvent the need for strain-specific sera, two anti-HA monoclonal antibodies (mAbs) against a highly conserved sequence have been produced by immunizing mice with a novel peptide-conjugate. Immunoblots demonstrate that 40 strains of influenza encompassing HA subtypes H1 to H13, as well as B strains from the Yamagata and Victoria lineage were detected when the two mAbs are combined to from a pan-HA mAb cocktail. Quantification using this pan-HA mAbs cocktail was achieved in a dot blot assay and results correlated with concentrations measured in a hemagglutination assay with a coefficient of correlation of 0.80. A competitive ELISA was also optimised with purified viral like particles. Regardless of the quantification method used, pan-HA antibodies can be employed to accelerate process development when strain-specific antibodies are not available, and represent a valuable tool in case of pandemics. These antibodies were also expressed in CHO cells to facilitate large-scale production using bioreactor technologies which might be required to meet industrial needs for quantification reagents. Finally, a simulation model was created to predict the binding affinity of the two anti-HA antibodies to the amino acids composing the highly conserved epitope; different probabilities of interaction between a given amino acid and the antibodies might explain the affinity of each antibody against different influenza strains. PMID- 28662135 TI - Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy. AB - Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 +/- 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 +/- 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting. PMID- 28662136 TI - Influence of nicotine on choline-deficient, L-amino acid-defined diet-induced non alcoholic steatohepatitis in rats. AB - Nicotine, a major compound in cigarette smoke, decreases food intake and body weight gain in mammals; however, the influence of nicotine on the progression of non-alcoholic steatohepatitis (NASH) remains controversial. This study aimed to investigate the effect of nicotine on NASH in rat models. Male Wistar rats were fed choline-deficient, l-amino acid-defined (CDAA) diet and treated with nicotine or saline. Food intake, body weight gain, presence of hepatic steatosis, inflammation, and fibrosis were assessed 6 weeks after the rats were fed CDAA diet. Hepatic branch vagotomy was performed to elucidate the mechanism through which nicotine affected steatohepatitis. CDAA diet induced hepatic steatosis, inflammation, and fibrosis, as well as increased the expression of inflammation related genes. Conversely, nicotine significantly attenuated food intake, body weight gain, and inhibited the CDAA-diet-induced hepatic steatosis, inflammation, and fibrosis, together with increased expression of inflammation-related genes. Hepatic branch vagotomy by itself decreased food intake, body weight gain, and attenuated the CDAA-diet-induced hepatic steatosis, but not inflammation. However, nicotine did not change the food intake, body weight gain, and CDAA diet induced hepatic steatosis and inflammation in vagotomized rats. These results suggest that nicotine attenuates the CDAA-diet-induced hepatic steatosis and inflammation through the hepatic branch of the vagus nerve in rats. PMID- 28662137 TI - Associations between quality of life and duration and frequency of physical activity and sedentary behaviour: Baseline findings from the WALK 2.0 randomised controlled trial. AB - While physical and mental health benefits of regular physical activity are well known, increasing evidence suggests that limiting sedentary behaviour is also important for health. Evidence shows associations of physical activity and sedentary behaviour with health-related quality of life (HRQoL), however, these findings are based predominantly on duration measures of physical activity and sedentary behaviour (e.g., minutes/week), with less attention on frequency measures (e.g., number of bouts). We examined the association of HRQoL with physical activity and sedentary behaviour, using both continuous duration (average daily minutes) and frequency (average daily bouts>=10 min) measures. Baseline data from the WALK 2.0 trial were analysed. WALK 2.0 is a randomised controlled trial investigating the effects of Web 2.0 applications on engagement, retention, and subsequent physical activity change. Daily physical activity and sedentary behaviour (duration = average minutes, frequency = average number of bouts >=10 minutes) were measured (ActiGraph GT3X) across one week, and HRQoL was assessed with the 'general health' subscale of the RAND 36-Item Health Survey. Structural equation modelling was used to evaluate associations. Participants (N = 504) were 50.8+/-13.1 (mean+/-SD) years old with a BMI of 29.3+/-6.0. The 465 participants with valid accelerometer data engaged in an average of 24.0+/-18.3 minutes and 0.64+/-0.74 bouts of moderate-vigorous physical activity per day, 535.2+/-83.8 minutes and 17.0+/-3.4 bouts of sedentary behaviour per day, and reported moderate-high general HRQoL (64.5+/-20.0). After adjusting for covariates, the duration measures of physical activity (path correlation = 0.294, p<0.05) and sedentary behaviour were related to general HRQoL (path coefficient = -0.217, p<0.05). The frequency measure of physical activity was also significant (path coefficient = -0.226, p<0.05) but the frequency of sedentary behaviour was not significantly associated with general HRQoL. Higher duration levels of physical activity in fewer bouts, and lower duration of sedentary behaviour are associated with better general HRQoL. Further prospective studies are required to investigate these associations in different population groups over time. PMID- 28662138 TI - Longitudinal changes in macular retinal layer thickness in pediatric populations: Myopic vs non-myopic eyes. AB - Knowledge of the normal in vivo thickness of the retina, and its individual layers in pediatric populations is important for diagnosing and monitoring retinal disorders, and for understanding the eye's normal development and the impact of eye growth and refractive error such as myopia (short-sightedness) upon retinal morphology. In this prospective, observational longitudinal study, total retinal thickness (and individual retinal layer thickness) and the changes in retinal morphology occurring over an 18-month period were examined in 101 children with a range of refractive errors. In childhood, the presence of myopia was associated with subtle but statistically significant (p<0.05) changes in the topographical thickness distribution of macular retinal thickness (and retinal layer thickness), characterised by a thinning of the parafoveal retina (and parafoveal or perifoveal thinning in most outer and inner retinal layers). The parafoveal retina was on average 6 MUm thinner in myopic children. However, over 18 months, longitudinal changes in retinal thickness and individual layers were of small magnitude (average changes of less than 2 MUm over 18 months), indicative of a high degree of stability in retinal morphology in healthy adolescent eyes, despite significant eye growth over this same period of time. This provides the first detailed longitudinal assessment of macula retinal layer morphology in adolescence, and delivers new normative data on expected changes in retinal structure over time and associated with myopia during this period of childhood development. PMID- 28662140 TI - Biological interactions and cooperative management of multiple species. AB - Coordinated decision making and actions have become the primary solution for the overexploitation of interacting resources within ecosystems. However, the success of coordinated management is highly sensitive to biological, economic, and social conditions. Here, using a game theoretic framework and a 2-species model that considers various biological relationships (competition, predation, and mutualism), we compute cooperative (or joint) and non-cooperative (or separate) management equilibrium outcomes of the model and investigate the effects of the type and strength of the relationships. We find that cooperation does not always show superiority to non-cooperation in all biological interactions: (1) if and only if resources are involved in high-intensity predation relationships, cooperation can achieve a win-win scenario for ecosystem services and resource diversity; (2) for competitive resources, cooperation realizes higher ecosystem services by sacrificing resource diversity; and (3) for mutual resources, cooperation has no obvious advantage for either ecosystem services or resource evenness but can slightly improve resource abundance. Furthermore, by using a fishery model of the North California Current Marine Ecosystem with 63 species and seven fleets, we demonstrate that the theoretical results can be reproduced in real ecosystems. Therefore, effective ecosystem management should consider the interconnection between stakeholders' social relationship and resources' biological relationships. PMID- 28662139 TI - Bacterial microbiome in the nose of healthy cats and in cats with nasal disease. AB - BACKGROUND: Traditionally, changes in the microbial population of the nose have been assessed using conventional culture techniques. Sequencing of bacterial 16S rRNA genes demonstrated that the human nose is inhabited by a rich and diverse bacterial microbiome that cannot be detected using culture-based methods. The goal of this study was to describe the nasal microbiome of healthy cats, cats with nasal neoplasia, and cats with feline upper respiratory tract disease (FURTD). METHODOLOGY/PRINCIPAL FINDINGS: DNA was extracted from nasal swabs of healthy cats (n = 28), cats with nasal neoplasia (n = 16), and cats with FURTD (n = 15), and 16S rRNA genes were sequenced. High species richness was observed in all samples. Rarefaction analysis revealed that healthy cats living indoors had greater species richness (observed species p = 0.042) and Shannon diversity (p = 0.003) compared with healthy cats living outdoors. Higher species richness (observed species p = 0.001) and Shannon diversity (p<0.001) were found in middle aged cats in comparison to healthy cats in different age groups. Principal coordinate analysis revealed separate clustering based on similarities in bacterial molecular phylogenetic trees of 16S rRNA genes for indoor and outdoor cats. In all groups examined, the most abundant phyla identified were Proteobacteria, Firmicutes, and Bacteroidetes. At the genus level, 375 operational taxonomic units (OTUs) were identified. In healthy cats and cats with FURTD, Moraxella spp. was the most common genus, while it was unclassified Bradyrhizobiaceae in cats with nasal neoplasia. High individual variability was observed. CONCLUSION: This study demonstrates that the nose of cats is inhabited by much more variable and diverse microbial communities than previously shown. Future research in this field might help to develop new diagnostic tools to easily identify nasal microbial changes, relate them to certain disease processes, and help clinicians in the decision process of antibiotic selection for individual patients. PMID- 28662141 TI - SDHD promoter mutations are rare events in cutaneous melanomas but SDHD protein expression is downregulated in advanced cutaneous melanoma. AB - BACKGROUND: SDHD promoter mutations were reported in 4-10% of cutaneous melanomas. The advanced clinico-pathological and patient survival association with SDHD mutation and/or expression in cutaneous melanoma remains controversial. OBJECTIVES: To evaluate the presence of SDHD promoter mutations and SDHD protein expression in a melanoma series and its possible association with prognosis and survival of the patients. METHODS: We assessed SDHD promoter status in cutaneous melanomas (CM), ocular melanomas (OM) and melanoma cell lines, and the expression of SDHD protein by immunohistochemistry in CM and OM, and by western blot in melanoma cell lines. We explored the putative association between SDHD protein expression and clinico-pathological and prognostic parameters of melanoma. RESULTS: We detected 2% of SDHD promoter mutations in CM, but none in OM and cell lines. SDHD protein expression was present in all CM, in OM and in all CM and OM derived cell lines analysed. A significant association between lower SDHD mean protein expression and presence of ulceration and higher pT stage was found. CONCLUSIONS: SDHD promoter mutation seems to be a rare event in CM but SDHD lower expression might associate with worst prognostic features in CM. PMID- 28662142 TI - Effects of the probiotic Bifidobacterium animalis subsp. lactis on the non surgical treatment of periodontitis. A histomorphometric, microtomographic and immunohistochemical study in rats. AB - Lactobacillus probiotics have been investigated in periodontitis. However, the effects of the genus Bifidobacterium on periodontitis are hardly known. This study evaluated the effects of the probiotic (PROB) Bifidobacterium animalis subsp. lactis (B. lactis) HN019 as an adjunct to scaling and root planing (SRP) in rats with experimental periodontitis (EP). At baseline, 32 rats were assigned to 4 groups: C (control), PROB, EP-SRP and EP-SRP-PROB. In groups EP-SRP and EP SRP-PROB, the mandibular first molars of the animals received a ligature. At day 14, the ligatures were removed and SRP was performed. Animals of groups PROB and EP-SRP-PROB were orally administered with 10 mL/day of 109 colony forming units of B. lactis HN019 for 15 days, starting at day 14. Animals were euthanized at day 29. Histomorphometric, microtomographic and immunohistochemical analyses were performed. Microbiological effects of B. lactis on biofilm were also evaluated. Data were statistically analyzed (ANOVA, Tukey; Kruskal-Wallis, Dunn's; Two tailed t-test; p<0.05). Group EP-SRP-PROB presented reduced alveolar bone resorption and attachment loss when compared with Group EP-SRP (p<0.05). Group EP SRP-PROB showed significantly fewer osteoclasts, increased expression of anti inflammatory cytokines and reduced expression of proinflammatory cytokines compared with Group EP-SRP (p<0.05). B. lactis promoted a higher ratio between aerobic and anaerobic bacteria in biofilm samples (p<0.05). B. lactis HN019 may have a role in the treatment of EP in rats, as an adjunct to SRP. PMID- 28662143 TI - Activin/follistatin system in grass carp pituitary cells: - Regulation by local release of growth hormone and luteinizing hormone and its functional role in growth hormone synthesis and secretion. AB - Gonadotrophin regulation by activin/follistatin system is well-documented, but the corresponding effect on growth hormone (GH) has not been fully characterized and with little information available in lower vertebrates, especially in fish models. In grass carp, local interactions of GH and luteinizing hormone (LH) can induce GH release and gene expression at pituitary level via autocrine/paracrine mechanisms. To shed light on the role of activin/follistatin system in GH regulation by local actions of GH and LH, grass carp activin betaA and betaB were cloned, shown to be single-copy genes expressed in the pituitary, and confirmed to encode activin proteins capable of transactivating promoter with activin responsive elements. In grass carp pituitary cells, activin A and B were effective in reducing GH secretion and GH cell content with concurrent drop in GH mRNA level whereas the opposite was true for follistatin, the activin-binding protein known to neutralize the effects of endogenous activin. Treatment with activin A and B not only could suppress basal but also inhibit GH mRNA expression induced by GH and human chorionic gonadotropin (hCG), a functional analogue of LH in fish model. Apparently, down-regulation of GH mRNA by activin was mediated by reducing GH transcript stability with concurrent inhibition on GH promoter activity via the SMAD pathway. In reciprocal experiments, GH treatment was found to up-regulate activin betaA, activin betaB and follistatin mRNA levels in carp pituitary cells but the opposite was noted by removing endogenous GH with GH antiserum. Interestingly, parallel treatment with hCG could also inhibit basal as well as GH-induced activin betaA, activin betaB and follistatin gene expression. These results, as a whole, indicate that the pituitary activin/follistatin system can serve as a regulatory target for local interactions of GH and LH and contribute to GH regulation by autocrine/paracrine mechanisms in the carp pituitary. PMID- 28662144 TI - Seroprevalence of antibodies to dengue and chikungunya viruses in Thailand. AB - The abundance of Aedes mosquito species enabled widespread transmission of mosquito-borne chikungunya virus (CHIKV) and dengue virus (DENV) in Southeast Asia. Periodic seroprevalence surveys are therefore necessary to assess the viral burden in the population and the effectiveness of public health interventions. Since the current seroprevalence for CHIKV and DENV in Thailand are unknown, we evaluated evidence of past infection among Thais. Eight-hundred and thirty-five serum samples obtained from individuals living in central and southern Thailand were assessed for anti-CHIKV and anti-DENV IgG antibodies using commercial enzyme linked immunosorbent assays. Overall, 26.8% (224/835) of individuals were seropositive for CHIKV, the majority of whom were also DENV-seropositive (91.1%, 204/224). Approximately half of all adults in their fifth decade of life had attained CHIKV seropositivity. Children under 15 years of age in southern Thailand were significantly more likely to be CHIKV-seropositive compared to those residing in central Thailand. In contrast, 79.2% (661/835) of Thais were DENV-seropositive, 30.9% (204/661) of whom also had antibodies to CHIKV. CHIKV/DENV dual seropositivity among Thais was 24.4% (204/835). The age standardized seroprevalence for DENV was three times that of CHIKV (80.5% vs. 27.2%). Relatively high CHIKV seroprevalence among adults living in central Thailand revealed an under-recognized CHIKV burden in the region, while the low to-moderate transmission intensity of DENV (seroprevalence <50% at 9 years) is expected to reduce the impact of DENV vaccination in Thailand. This most recent seroprevalence data provide serological baselines for two of the most common mosquito-borne viruses in this region. PMID- 28662145 TI - Prevalence and antibiotic resistance profiles of cerebrospinal fluid pathogens in children with acute bacterial meningitis in Yunnan province, China, 2012-2015. AB - Acute bacterial meningitis is still considered one of the most dangerous infectious diseases in children. To investigate the prevalence and antibiotic resistance profiles of cerebrospinal fluid (CSF) pathogens in children with acute bacterial meningitis in Southwest China, CSF samples from 179 meningitis patients (3 days to 12 years old) with positive culture results were collected from 2012 to 2015. Isolated pathogens were identified using the Vitek-32 system. Gram stain results were used to guide subcultures and susceptibility testing. The antimicrobial susceptibility of isolates was determined using the disc diffusion method. Of the isolates, 50.8% were Gram-positive bacteria, and 49.2% were Gram negative bacteria. The most prevalent pathogens were E. coli (28.5%), Streptococcus pneumoniae (17.8%), Staphylococcus epidermidis (10.0%), Haemophilus influenzae type b (9.5%), and group B streptococcus (7.2%). In young infants aged <=3 months, E. coli was the organism most frequently isolated from CSF (39/76; 51.3%), followed by group B streptococcus (13/76; 17.1%) and Streptococcus pneumoniae (8/76; 10.5%). However, in young infants aged >3 months, the most frequently isolated organism was Streptococcus pneumoniae (24/103; 23.3%), followed by Staphylococcus epidermidis (18/103; 17.5%) and Haemophilus influenzae type b (16/103; 15.5%). Antimicrobial susceptibility tests indicated that for E. coli isolates, the susceptibility rates to aminoglycosides ranged from 56.8% to 100.0%, among them, amikacin was identified as the most effective against E. coli. As for cephalosporins, the susceptibility rates ranged from 29.4% to 78.4%, and cefoxitin was identified as the most effective cephalosporin. In addition, the susceptibility rates of piperacillin/tazobactam and imipenem against E. coli were 86.3% and 100%. Meanwhile, the susceptibility rates of Streptococcus pneumoniae isolates to penicillin G, erythromycin, chloramphenicol, ceftriaxone and tetracycline were 68.8%, 0.0%, 87.5%, 81.3% and 0.0%, respectively. Gentamycin, ofloxacin, linezolid and vancomycin were identified as the most effective antibiotics for Streptococcus pneumoniae, each with susceptibility rates of 100%. It was notable that other emerging pathogens, such as Listeria monocytogenes and group D streptococcus, cannot be underestimated in meningitis. PMID- 28662146 TI - NtrC-dependent control of exopolysaccharide synthesis and motility in Burkholderia cenocepacia H111. AB - Burkholderia cenocepacia is a versatile opportunistic pathogen that survives in a wide variety of environments, which can be limited in nutrients such as nitrogen. We have previously shown that the sigma factor sigma54 is involved in the control of nitrogen assimilation and virulence in B. cenocepacia H111. In this work, we investigated the role of the sigma54 enhancer binding protein NtrC in response to nitrogen limitation and in the pathogenicity of H111. Of 95 alternative nitrogen sources tested the ntrC showed defects in the utilisation of nitrate, urea, L citrulline, acetamide, DL-lactamide, allantoin and parabanic acid. RNA-Seq and phenotypic analyses of an ntrC mutant strain showed that NtrC positively regulates two important phenotypic traits: exopolysaccharide (EPS) production and motility. However, the ntrC mutant was not attenuated in C. elegans virulence. PMID- 28662147 TI - Development and evaluation of an up-converting phosphor technology-based lateral flow assay for the rapid, simultaneous detection of Vibrio cholerae serogroups O1 and O139. AB - Vibrio cholerae serogroups O1 and O139 are etiological agents of cholera, a serious and acute diarrheal disease, and rapid detection of V. cholerae is a key method for preventing and controlling cholera epidemics. Here, a point of care testing (POCT) method called Vch-UPT-LF, which is an up-converting phosphor technology-based lateral flow (UPT-LF) assay with a dual-target detection mode, was developed to detect V. cholerae O1 and O139 simultaneously from one sample loading. Although applying an independent reaction pair made both detection results for the two Vch-UPT-LF detection channels more stable, the sensitivity slightly declined from 104 to 105 colony-forming units (CFU) mL-1 compared with that of the single-target assay, while the quantification ranges covering four orders of magnitude were maintained. The strip showed excellent specificity for seven Vibrio species that are highly related genetically, and nine food-borne species whose transmission routes are similar to those of V. cholerae. The legitimate arrangement of the two adjacent test lines lessened the mutual impact of the quantitation results between the two targets, and the quantification values did not differ by more than one order of magnitude when the samples contained high concentrations of both V. cholerae O1 and O139. Under pre incubation conditions, 1*101 CFU mL-1 of V. cholerae O1 or O139 could be detected in fewer than 7 h, while the Vch-UPT-LF assay exhibited sensitivity as high as a real-time fluorescent polymerase chain reaction with fewer false-positive results. Therefore, successful development of Vch-UPT-LF as a dual-target assay for quantitative detection makes this assay a good candidate POCT method for the detection and surveillance of epidemic cholera. PMID- 28662148 TI - Zoospore exudates from Phytophthora nicotianae affect immune responses in Arabidopsis. AB - Zoospore exudates play important roles in promoting zoospore communication, homing and germination during plant infection by Phytophthora. However, it is not clear whether exudates affect plant immunity. Zoospore-free fluid (ZFF) and zoospores of P. nicotianae were investigated comparatively for effects on resistance of Arabidopsis thaliana Col-0 and mutants that affect signaling mediated by salicylic acid (SA) and jasmonic acid (JA): eds16 (enhanced disease susceptibility16), pad4 (phytoalexin deficient4), and npr1 (nonexpressor of pathogenesis-related genes1). Col-0 attracted more zoospores and had severe tissue damage when flooded with a zoospore suspension in ZFF. Mutants treated with ZFF alone developed disease symptoms similar to those inoculated with zoospores and requirements of EDS16 and PAD4 for plant responses to zoospores and the exudates was apparent. Zoospore and ZFFs also induced expression of the PR1 and PDF1.2 marker genes for defense regulated by SA and JA, respectively. However, ZFF affected more JA defense signaling, down regulating PR1 when SA signaling or synthesis is deficient, which may be responsible for Arabidopsis mutant plants more susceptible to infection by high concentration of P. nicotianae zoospores. These results suggest that zoospore exudates can function as virulence factors and inducers of plant immune responses during plant infection by Phytophthora. PMID- 28662149 TI - In vitro additive interaction between ketoconazole and antimony against intramacrophage Leishmania (Leishmania) amazonensis amastigotes. AB - Leishmaniasis is a group of diseases caused by protozoa of Leishmania genus. The currently available treatments for this disease are expensive, present high toxicity and are associated to difficulties of healing and parasite resistance. Therefore, the development of strategies for leishmaniasis treatment is indispensable and includes reposition of existing drugs, as well as drug combination therapy. The aim of this study was to assess the nature of ketoconazole and antimony association on the cytotoxic effect against Leishmania (Leishmania) amazonensis amastigotes. The calculated mean sum of fractional 50% inhibitory concentration ([Formula: see text]SigmaFIC50) was 2.54 and 1.43 for free and intracellular amastigotes, respectively, values that suggest an additive interaction between ketoconazole and antimony concerning to Leishmania toxicity only in the intramacrophage parasite form. Despite the clinical efficacy of ketoconazole-antimony combination has been shown in the literature, our study is the first to describe the nature of ketoconazole-antimony interaction against L. (L.) amazonensis amastigotes. Moreover, our results point out the need for future in vivo studies to confirm the nature of ketoconazole-antimony interaction and also to determine possible effective dosage regimens related to ketoconazole administration in association with the optimal lower dose of antimony. PMID- 28662150 TI - A viral metagenomic approach on a non-metagenomic experiment: Mining next generation sequencing datasets from pig DNA identified several porcine parvoviruses for a retrospective evaluation of viral infections. AB - Shot-gun next generation sequencing (NGS) on whole DNA extracted from specimens collected from mammals often produces reads that are not mapped (i.e. unmapped reads) on the host reference genome and that are usually discarded as by-products of the experiments. In this study, we mined Ion Torrent reads obtained by sequencing DNA isolated from archived blood samples collected from 100 performance tested Italian Large White pigs. Two reduced representation libraries were prepared from two DNA pools constructed each from 50 equimolar DNA samples. Bioinformatic analyses were carried out to mine unmapped reads on the reference pig genome that were obtained from the two NGS datasets. In silico analyses included read mapping and sequence assembly approaches for a viral metagenomic analysis using the NCBI Viral Genome Resource. Our approach identified sequences matching several viruses of the Parvoviridae family: porcine parvovirus 2 (PPV2), PPV4, PPV5 and PPV6 and porcine bocavirus 1-H18 isolate (PBoV1-H18). The presence of these viruses was confirmed by PCR and Sanger sequencing of individual DNA samples. PPV2, PPV4, PPV5, PPV6 and PBoV1-H18 were all identified in samples collected in 1998-2007, 1998-2000, 1997-2000, 1998-2004 and 2003, respectively. For most of these viruses (PPV4, PPV5, PPV6 and PBoV1-H18) previous studies reported their first occurrence much later (from 5 to more than 10 years) than our identification period and in different geographic areas. Our study provided a retrospective evaluation of apparently asymptomatic parvovirus infected pigs providing information that could be important to define occurrence and prevalence of different parvoviruses in South Europe. This study demonstrated the potential of mining NGS datasets non-originally derived by metagenomics experiments for viral metagenomics analyses in a livestock species. PMID- 28662151 TI - Bone marrow mesenchymal stem cell-derived vascular endothelial growth factor attenuates cardiac apoptosis via regulation of cardiac miRNA-23a and miRNA-92a in a rat model of myocardial infarction. AB - Bone marrow-mesenchymal stem cell (BM-MSC) therapy improves the recovery of cardiac function after myocardial infarction (MI); however, the underlying molecular mechanisms are not completely understood. Recent studies have shown that microRNAs (miRNAs) modulate the pathophysiology of cardiovascular diseases. Here, we investigated the mechanisms underlying the effects of BM-MSC-derived paracrine factors and cardiac miRNAs on myocardial regeneration after MI. In our study, MI was induced by permanent ligation of the left anterior descending (LAD) coronary artery. BM-MSCs transplanted in infarcted rats significantly downregulated the expression of miRNA-23a and miRNA-92a and inhibited apoptosis in the myocardium. An in vitro experiment showed that supernatant from BM-MSCs cultured under hypoxia contained higher levels of vascular endothelial growth factor (VEGF) than that from BM-MSCs under normoxia. In addition, inhibition of miRNA-23a and miRNA-92a reduced cardiac apoptosis. Moreover, the VEGF-containing BM-MSC supernatant inhibited miRNA-23a and miRNA-92a expression and reduced apoptotic signaling in cardiomyocytes under hypoxia. These effects were inhibited when the supernatant was treated with neutralizing antibodies against VEGF. Our results indicate that the paracrine factor, VEGF, derived from transplanted BM MSCs, regulated the expression of miRNAs such as miRNA-23a and miRNA-92a and exerted anti-apoptotic effects in cardiomyocytes after MI. PMID- 28662152 TI - Does external pneumatic compression treatment between bouts of overreaching resistance training sessions exert differential effects on molecular signaling and performance-related variables compared to passive recovery? An exploratory study. AB - PURPOSE: We sought to compare the effects of external pneumatic compression (EPC) and sham when used concurrently with resistance training on performance-related outcomes and molecular measures related to recovery. METHODS: Twenty (N = 20) resistance-trained male participants (aged 21.6+/-2.4 years) were randomized to balanced sham or EPC intervention groups. The protocol consisted of 3 consecutive days of heavy, voluminous back squat exercise followed by EPC/sham treatment (Days2-4) and 3 consecutive days of recovery (Days5-7) with EPC/sham only on Days5-6. On Day1 (PRE), and Days3-7, venipuncture, flexibility and pressure-to pain threshold (PPT) measures were performed. Vastsus lateralis muscle tissue was biopsied at PRE, 1-h post-EPC/sham treatment on Day2 (POST1) and 24-h post EPC/sham treatment on Day7 (POST2). Isokinetic peak torque was assessed at PRE and POST2. RESULTS: Peak isokinetic strength did not change from PRE to POST2 in either group. The PPT was significantly lower on Days3-6 with sham, indicating greater muscle soreness, though this was largely abolished in the EPC group. A significant decrease in flexibility with sham was observed on Day3 (+16.2+/-4.6% knee joint angle; P<0.01) whereas there was no change with EPC (+2.8+/-3.8%; P>0.01). Vastus lateralis poly-ubiquitinated proteins significantly increased at the POST2 time point relative to PRE with sham (+66.6+/-24.6%; P<0.025) and were significantly greater (P<0.025) than those observed with EPC at the same time point (-18.6+/-8.5%). 4-hydroxynonenal values were significantly lower at POST2 relative to PRE with EPC (-16.2+/-5.6%; P<0.025) and were significantly lower (P<0.025) than those observed with sham at the same time point (+11.8+/-5.9%). CONCLUSION: EPC mitigated a reduction in flexibility and PPT that occurred with sham. Moreover, EPC reduced select skeletal muscle oxidative stress and proteolysis markers during recovery from heavy resistance exercise. PMID- 28662153 TI - Effectiveness of acute in-hospital physiotherapy with knee-extension strength training in reducing strength deficits in patients with a hip fracture: A randomised controlled trial. AB - QUESTION: Is acute in-hospital physiotherapy with additional progressive knee extension strength training (ST) of the fractured limb more effective in reducing knee-extension strength deficit at follow-up compared to physiotherapy without strength training in patients with a hip fracture? DESIGN: Assessor blinded, randomised controlled trial with intention-to-treat analysis. PARTICIPANTS: 90 patients with a hip fracture admitted to an acute orthopaedic Hip Fracture Unit at a university hospital between October 2013 and May 2015. INTERVENTION: Daily physiotherapy with or without progressive knee-extension strength training (10RM), 3 x 10 repetitions, of the fractured limb using ankle weight cuffs conducted by ward physical therapists during hospital stay. OUTCOME MEASURES: Primary outcome was the change in maximal isometric knee-extension strength in the fractured limb in percentage of the non-fractured limb from inclusion to postoperative day 10 or discharge (follow-up). Secondary outcome was Timed Up and Go test measured early after surgery and at follow-up. RESULTS: In the intention to-treat analysis of between-group differences, the primary outcome improved 8.1% (95% CI -2.3; 18.4) by additional strength training from baseline to follow-up. In the per-protocol analysis of non-missing data, significant between-group improvements by 10.5% (95% CI 0.3; 20.7) were found in favour of additional ST. No significant between-group differences were found in any secondary outcome. CONCLUSION: Physiotherapy with addition of 5 sessions of ST yielded no additional improvements compared to physiotherapy without strength training in reducing the knee-extension strength deficit at follow-up in patients with a hip fracture. It is debatable whether larger improvements than the observed 8-10% can be expected given that only five exercise sessions, on average, were completed. In fragile patients with a hip fracture in the acute phase, where the ability to participate in functional exercise is compromised, we still consider early strength training a possibility to improve outcomes of clinical importance, given the results of the per-protocol analysis. The present data provides an important basis and call for future investigations including longer term interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT00848913. PMID- 28662154 TI - How minimal executive feedback influences creative idea generation. AB - The fixation effect is known as one of the most dominant of the cognitive biases against creativity and limits individuals' creative capacities in contexts of idea generation. Numerous techniques and tools have been established to help overcome these cognitive biases in various disciplines ranging from neuroscience to design sciences. Several works in the developmental cognitive sciences have discussed the importance of inhibitory control and have argued that individuals must first inhibit the spontaneous ideas that come to their mind so that they can generate creative solutions to problems. In line with the above discussions, in the present study, we performed an experiment on one hundred undergraduates from the Faculty of Psychology at Paris Descartes University, in which we investigated a minimal executive feedback-based learning process that helps individuals inhibit intuitive paths to solutions and then gradually drive their ideation paths toward creativity. Our results provide new insights into novel forms of creative leadership for idea generation. PMID- 28662155 TI - A three-microRNA signature as a diagnostic and prognostic marker in clear cell renal cancer: An In Silico analysis. AB - Accumulating evidence has demonstrated that some specific miRNAs were aberrantly expressed in renal clear cell carcinoma and participated in many biological processes. The aim of this study was to investigate a panel of miRNA signature for diagnosis and prognosis of renal clear cell carcinoma (KIRC). Here, we performed a comprehensive analysis for miRNA expression profiles and corresponding clinical information of 516 KIRC patients from The Cancer Genome Atlas (TCGA). In the study, a total of 63 differentially expressed miRNAs were identified, of which 34 were up-regulated and 29 were down-regulated. We constructed a panel of three-miRNA that were significantly associated with KIRC diagnosis and KIRC patients' prognosis. The three-miRNA signature reached a sensitivity of 98.3% and a specificity of 97.2% in the diagnosis of KIRC. Using the three-miRNA signature, we classified the KIRC patients into high-risk group and low-risk group. The Kaplan- Meier curves showed that KIRC patients with high risk scores had significantly worsen overall survival (OS) and disease free survival (DFS) than KIRC patients with low risk scores. In the univariate and multivariate Cox regression analysis, three-miRNA signature was an independent prognostic factor in OS. In conclusion, the three-miRNA signature could be used as a diagnostic and prognostic biomarker in KIRC, and therefore, may help to provide significant clinical implication for the treatment of KIRC. PMID- 28662156 TI - Hydrogen sulfide alleviates postharvest ripening and senescence of banana by antagonizing the effect of ethylene. AB - Accumulating evidence shows that hydrogen sulfide (H2S) acts as a multifunctional signaling molecule in plants, whereas the interaction between H2S and ethylene is still unclear. In the present study we investigated the role of H2S in ethylene promoted banana ripening and senescence by the application of ethylene released from 1.0 g.L-1 ethephon solution or H2S with 1 mM sodium hydrosulfide (NaHS) as the donor or in combination. Fumigation with ethylene was found to accelerate banana ripening and H2S treatment effectively alleviated ethylene-induced banana peel yellowing and fruit softening in parallel with decreased activity of polygalacturonase (PG). Ethylene+H2S treatment also delayed the decreases in chlorophyll and total phenolics, and increased the accumulation of flavonoid, whereas decreased the contents of carotenoid, soluble protein in banana peel and reducing sugar in pulp compared with ethylene treatment alone. Besides, ethylene+H2S treatment suppressed the accumulation of superoxide radicals (.O2-), hydrogen peroxide (H2O2) and malondialdehyde (MDA) which accumulated highly in ethylene-treated banana peels. Furthermore H2S enhanced total antioxidant capacity in ethylene-treated banana peels with the 2,2'-azobis(3-ethylbenz thiazoline-6-sulfonic acid (ABTS) assay. The result of quantitative real-time PCR showed that the combined treatment of ethylene with H2S down-regulated the expression of ethylene synthesis genes MaACS1, MaACS2 and MaACO1 and pectate lyase MaPL compared with ethylene treatment, while the expression of ethylene receptor genes MaETR, MaERS1 and MaERS2 was enhanced in combination treatment compared with ethylene alone. In all, it can be concluded that H2S alleviates banana fruit ripening and senescence by antagonizing the effect of ethylene through reduction of oxidative stress and inhibition of ethylene signaling pathway. PMID- 28662158 TI - A spatial predictive model for malaria resurgence in central Greece integrating entomological, environmental and social data. AB - Malaria constitutes an important cause of human mortality. After 2009 Greece experienced a resurgence of malaria. Here, we develop a model-based framework that integrates entomological, geographical, social and environmental evidence in order to guide the mosquito control efforts and apply this framework to data from an entomological survey study conducted in Central Greece. Our results indicate that malaria transmission risk in Greece is potentially substantial. In addition, specific districts such as seaside, lakeside and rice field regions appear to represent potential malaria hotspots in Central Greece. We found that appropriate maps depicting the basic reproduction number, R0, are useful tools for informing policy makers on the risk of malaria resurgence and can serve as a guide to inform recommendations regarding control measures. PMID- 28662157 TI - Sex-dependent aortic valve pathology in patients with rheumatic heart disease. AB - BACKGROUND: Rheumatic heart disease is an autoimmune disease caused by group A streptococci infection and frequently affects the aortic valve. Sex differences are common in the disease progression, treatment, and outcome. However, little is known about the sex differences in the pathology of aortic valves in rheumatic heart disease. DESIGN: We studied the end-stage calcific aortic valves from male versus female patients to reveal the sex-dependent pathology differences and molecular changes associated with requiring valve replacement. METHODS: Aortic valves from 39 patients with rheumatic heart disease (19 males and 20 females) were collected at the time of aortic valve replacement for comparative pathology, immunohistochemistry, and gene expression analyses. Clinical characteristics were also analyzed and compared between the two groups. RESULTS: Aortic valves from female patients exhibited increased expression of collagens, infiltration of monocytes/macrophages and neovascularization. Aortic valves from female patients also had increased expression of inflammatory genes involved in the NFKB pathway (phosphorylated NFKB p65 subunit, IL8, and NOS3) and Th1 cytokine genes (IFNA and IL12B). The severe valve pathology in female patients was correlated with a higher serum level of anti-streptolysin O antibodies. CONCLUSION: Inflammation is more prominent in aortic valves of female patients with rheumatic heart disease. This sex difference may contribute to the severe valve pathology and worse outcome of female patients. PMID- 28662159 TI - Pre-clinical carotid atherosclerosis and sCD163 among virally suppressed HIV patients in Botswana compared with uninfected controls. AB - OBJECTIVES: Human immune deficiency virus (HIV) is associated with increased cardiovascular disease (CVD) risk, yet the relationship between HIV and carotid atherosclerosis / monocyte activation among virally suppressed HIV-infected patients in sub-Saharan Africa is not well understood. METHODS: We measured traditional CVD risk factors, bilateral distal common carotid intima media thickness (cIMT), presence of carotid plaque and plasma sCD163 levels among virally suppressed HIV-infected adults and HIV-uninfected controls, in a cross sectional study in Gaborone, Botswana. The associations between HIV status, traditional CVD risk factors, sCD163 and outcome of cIMT were assessed in univariate and multivariate linear regression models. RESULTS: We enrolled 208 HIV-infected adults (55% Female, mean age 39 years) who had undetectable HIV-1 RNA on antiretroviral therapy and 224 HIV-uninfected controls (47% Female, mean age 37 years). There was no difference in cIMT between study groups, with mean cIMT 0.607mm and 0.599mm in HIV-infected and HIV-uninfected, respectively (p = 0.37). Plasma sCD163 was significantly higher in HIV-infected versus HIV uninfected persons (1917ng/ml vs 1593ng/ml, p = 0.003), but was not associated with cIMT (p = 0.43 among all, p = 0.72 for HIV-infected only). In the final multivariate model, increased cIMT was associated with older age, being treated for hypertension, and higher non-HDL cholesterol among all (p<0.001, p = 0.03, p<0.001 respectively), and with older age and waist-hip ratio in HIV-infected participants (p = 0.02 & p = 0.02 respectively). Carotid plaque was present in a significantly higher proportion of HIV-infected adults (RR 2.15, 95% CI 1.22, 3.81). CONCLUSIONS: HIV-infected participants aged 30-50 years who have achieved viral suppression did not have increased cIMT when compared to HIV-uninfected controls in Botswana. However, well-controlled HIV was associated with excess monocyte activation. Future work should explore the impact of subclinical atherosclerosis on CVD events among HIV-infected and -uninfected adults in Botswana. PMID- 28662160 TI - Previous cervical cytology and high-risk human papillomavirus testing in a cohort of patients with invasive cervical carcinoma in Shandong Province, China. AB - BACKGROUND: Currently, available data regarding previous cervical cytology and high-risk human papillomavirus (hrHPV) test results to detect invasive cervical cancer are limited and controversial in China. Therefore, this retrospective study in a population of Chinese women with invasive cervical carcinoma aimed to gain further insight into the roles of cytology and hrHPV testing in cervical cancer screening. METHODS: A total of 1214 cases with a histological diagnosis of invasive cervical cancer were retrieved from the Pathology Database of Jinan KingMed Diagnostics (JKD) over a 5-year period. Previous cytology and hrHPV test results of 469 patients carried out within the year before cancer diagnosis were documented. RESULTS: A higher percentage of patients who had undergone prior screening had micro-invasive cervical carcinoma than patients who had no prior screening (25.4% vs. 12.1%, P < 0.001). Of the 469 patients with available prior screening results, 170 had cytology alone, 161 had hrHPV testing alone, and 138 had both cytology and hrHPV testing. There was a significantly lower percentage of hrHPV-positive cases with adenocarcinoma than with squamous cell carcinoma (77.8% vs. 96.4%, P = 0.001). The hrHPV test showed a significantly higher sensitivity than cytology alone (94.4% vs. 85.3%, P = 0.006). The overall sensitivity of the combination of cytology and hrHPV testing (98.6%) was much higher than that of cytology alone (P < 0.001) but only marginally higher than that of hrHPV testing alone (P = 0.058). CONCLUSIONS: The results revealed that prior cervical screening can detect a significantly larger number of micro invasive cervical cancers. The hrHPV test can provide a more sensitive and efficient strategy than cytology alone. As the addition of cytology to hrHPV testing can only marginally increase the efficiency of the hrHPV test, hrHPV testing should be used as the primary screening approach, especially in the low resource settings of China. PMID- 28662161 TI - Absence of EEG correlates of self-referential processing depth in ALS. AB - Self-referential processing is a key cognitive process, associated with the serotonergic system and the default mode network (DMN). Decreased levels of serotonin and reduced activations of the DMN observed in amyotrophic lateral sclerosis (ALS) suggest that self-referential processing might be altered in patients with ALS. Here, we investigate the effects of ALS on the electroencephalography correlates of self-referential thinking. We find that electroencephalography (EEG) correlates of self-referential thinking are present in healthy individuals, but not in those with ALS. In particular, thinking about themselves or others significantly modulates the bandpower in the medial prefrontal cortex in healthy individuals, but not in ALS patients. This finding supports the view of ALS as a complex multisystem disorder which, as shown here, includes dysfunctional processing of the medial prefrontal cortex. It points towards possible alterations of self-consciousness in ALS patients, which might have important consequences for patients' self-conceptions, personal relations, and decision-making. PMID- 28662162 TI - BKM120 induces apoptosis and inhibits tumor growth in medulloblastoma. AB - Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20 percent of all childhood brain tumors. New treatment strategies are needed to improve patient survival outcomes and to reduce adverse effects of current therapy. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway plays a key role in cellular metabolism, proliferation, survival and angiogenesis, and is often constitutively activated in human cancers, providing unique opportunities for anticancer therapeutic intervention. The aim of this study was to evaluate the pre-clinical activity of BKM120, a selective pan-class I PI3K inhibitor, on MB cell lines and primary samples. IC50 values of BKM120 in the twelve MB cell lines tested ranged from 0.279 to 4.38 MUM as determined by cell viability assay. IncuCyte ZOOM Live-Cell Imaging system was used for kinetic monitoring of cytotoxicity of BKM120 and apoptosis in MB cells. BKM120 exhibited cytotoxicity in MB cells in a dose and time-dependent manner by inhibiting activation of downstream signaling molecules AKT and mTOR, and activating caspase mediated apoptotic pathways. Furthermore, BKM120 decreased cellular glycolytic metabolic activity in MB cell lines in a dose-dependent manner demonstrated by ATP level per cell. In MB xenograft mouse study, DAOY cells were implanted in the flank of nude mice and treated with vehicle, BKM120 at 30 mg/kg and 60 mg/kg via oral gavage daily. BKM120 significantly suppressed tumor growth and prolonged mouse survival. These findings help to establish a basis for clinical trials of BKM120, which could be a novel therapy for the treatment of medulloblastoma patients. PMID- 28662163 TI - Association between laboratory capacities and world-cup performance in Nordic combined. AB - BACKGROUND: Nordic combined (NC) is an Olympic winter-sport performed as a ski jumping (SJ) event followed by a cross-country (XC) pursuit race employing the skating style. PURPOSE: To elucidate the associations between sport-specific laboratory capacities and SJ, XC skiing, and overall NC performance in a world cup NC event. METHODS: Twelve international world-cup NC athletes from 8 nations performed laboratory testing one day prior to participating in a world-cup NC event. Squat jumps and SJ imitations (IMIT) were performed on a three-dimensional force plate, whereas XC skiing-specific physiological characteristics were obtained from roller ski skating tests on a treadmill and an all-out double poling (DP) test. Finally, body composition was measured. Laboratory capacities were correlated against performance in SJ, 10-km XC skiing, and overall NC in the world-cup event. Multiple regression analysis was used to determine the best suited laboratory variables for predicting performance. RESULTS: Vertical IMIT velocity together with body-mass provided the best prediction for SJ performance (r2 = 0.70, p<0.01), while body-mass-normalized [Formula: see text] and DP power provided the best prediction for XC performance (r2 = 0.68, p<0.05). Body-mass normalized [Formula: see text] was the only significant correlate with overall NC performance (r2 = 0.43, p<0.05) in this competition. CONCLUSION: Overall, the concurrent development of [Formula: see text], upper-body power, and SJ-specific vertical jump capacity while minimizing body-mass within the BMI limit set by FIS should be considered in the seasonal training of NC athletes. PMID- 28662164 TI - Associations of sitting accumulation patterns with cardio-metabolic risk biomarkers in Australian adults. AB - BACKGROUND: High amounts of time spent sitting can increase cardiovascular disease risk and are deleteriously associated cardio-metabolic risk biomarkers. Though evidence suggests that accruing sitting time in prolonged periods may convey additional risk, verification using high-quality measures is needed. We examined this issue in adults from the Australian Diabetes, Obesity and Lifestyle Study, using accurate measures of sitting accumulation. METHODS: In 2011/12, 739 adults aged 36 to 89 years (mean+/-SD 58+/-10 years) wore activPAL3TM monitors (which provide accurate objective measures of sitting); 678 provided >=4 valid days of monitor data and complete cardio-metabolic biomarker and confounder data. Multivariable linear regression models examined associations of sitting time, sitting time accrued in >=30 minute bouts (prolonged sitting time), and three measures of sitting accumulation patterns with cardio-metabolic risk markers: body mass index (BMI), waist circumference, blood pressure, high- and low- density lipoprotein (HDL and LDL) cholesterol, triglycerides, glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and 2-hour post-load glucose (PLG). Interactions tests examined whether associations of sitting time with biomarkers varied by usual sitting bout duration. RESULTS: Adjusted for potential confounders, greater amounts of sitting time and prolonged sitting time were significantly (p<0.05) deleteriously associated with BMI, waist circumference, HDL cholesterol, and triglycerides. Total sitting time was also significantly associated with higher PLG. Sitting accumulation patterns of frequently interrupted sitting (compared to patterns with relatively more prolonged sitting) were significantly beneficially associated with BMI, waist circumference, HDL cholesterol, triglycerides, PLG, and with FPG. Effect sizes were typically larger for accumulation patterns than for sitting time. Significant interactions (p<0.05) showed that associations of sitting time with HDL, triglycerides and PLG became more deleterious the longer at a time sitting was usually accumulated. CONCLUSIONS: Adding to previous evidence reliant on low-quality measures, our study showed that accumulating sitting in patterns where sitting was most frequently interrupted had significant beneficial associations with several cardio-metabolic biomarkers and that sitting for prolonged periods at a time may exacerbate some of the effects of sitting time. The findings support sedentary behavior guidelines that promote reducing and regularly interrupting sitting. PMID- 28662165 TI - The microbiome in hematopoietic stem cell transplant recipients and cancer patients: Opportunities for clinical advances that reduce infection. PMID- 28662166 TI - Reliability of temperature signal in various climate indicators from northern Europe. AB - We collected relevant observational and measured annual-resolution time series dealing with climate in northern Europe, focusing in Finland. We analysed these series for the reliability of their temperature signal at annual and seasonal resolutions. Importantly, we analysed all of the indicators within the same statistical framework, which allows for their meaningful comparison. In this framework, we employed a cross-validation procedure designed to reduce the adverse effects of estimation bias that may inflate the reliability of various temperature indicators, especially when several indicators are used in a multiple regression model. In our data sets, timing of phenological observations and ice break-up were connected with spring, tree ring characteristics (width, density, carbon isotopic composition) with summer and ice formation with autumn temperatures. Baltic Sea ice extent and the duration of ice cover in different watercourses were good indicators of winter temperatures. Using combinations of various temperature indicator series resulted in reliable temperature signals for each of the four seasons, as well as a reliable annual temperature signal. The results hence demonstrated that we can obtain reliable temperature information over different seasons, using a careful selection of indicators, combining the results with regression analysis, and by determining the reliability of the obtained indicator. PMID- 28662167 TI - Prediction of pneumonia hospitalization in adults using health checkup data. AB - OBJECTIVES: Community-acquired pneumonia is a common cause of hospitalization, and pneumococcal vaccinations are recommended for high-risk individuals. Although risk factors for pneumonia have been identified, there are currently no pneumonia hospitalization prediction models based on the risk profiles of healthy subjects. This study aimed to develop a predictive model for pneumonia hospitalization in adults to accurately identify high-risk individuals to facilitate the efficient prevention of pneumonia. METHODS: We conducted a retrospective database analysis using health checkup data and health insurance claims data for residents of Kyoto prefecture, Japan, between April 2010 and March 2015. We chose adults who had undergone health checkups in the first year of the study period, and tracked pneumonia hospitalizations over the next 5 years. Subjects were randomly divided into training and test sets. The outcome measure was pneumonia hospitalization, and candidate predictors were obtained from the health checkup data. The prediction model was developed and internally validated using a LASSO logistic regression analysis. Lastly, we compared the new model with comparative models. RESULTS: The study sample comprised 54,907 people who had undergone health checkups. Among these, 921 were hospitalized for pneumonia during the study period. The c-statistic for the prediction model in the test set was 0.71 (95% confidence interval: 0.69-0.73). In contrast, a comparative model with only age and comorbidities as predictors had a lower c-statistic of 0.55 (95% confidence interval: 0.54-0.56). CONCLUSIONS: Our predictive model for pneumonia hospitalization performed better than comparative models, and may be useful for supporting the development of pneumonia prevention measures. PMID- 28662168 TI - Do placebo expectations influence perceived exertion during physical exercise? AB - This study investigates the role of placebo expectations in individuals' perception of exertion during acute physical exercise. Building upon findings from placebo and marketing research, we examined how perceived exertion is affected by expectations regarding a) the effects of exercise and b) the effects of the exercise product worn during the exercise. We also investigated whether these effects are moderated by physical self-concept. Seventy-eight participants conducted a moderate 30 min cycling exercise on an ergometer, with perceived exertion (RPE) measured every 5 minutes. Beforehand, each participant was randomly assigned to 1 of 4 conditions and watched a corresponding film clip presenting "scientific evidence" that the exercise would or would not result in health benefits and that the exercise product they were wearing (compression garment) would additionally enhance exercise benefits or would only be worn for control purposes. Participants' physical self-concept was assessed via questionnaire. Results partially demonstrated that participants with more positive expectations experienced reduced perceived exertion during the exercise. Furthermore, our results indicate a moderator effect of physical self-concept: Individuals with a high physical self-concept benefited (in terms of reduced perceived exertion levels) in particular from an induction of generally positive expectations. In contrast, individuals with a low physical self-concept benefited when positive expectations were related to the exercise product they were wearing. In sum, these results suggest that placebo expectations may be a further, previously neglected class of psychological factors that influence the perception of exertion. PMID- 28662169 TI - Antidiabetic activities of polysaccharides separated from Inonotus obliquus via the modulation of oxidative stress in mice with streptozotocin-induced diabetes. AB - This study evaluated the effects of Inonotus obliquus polysaccharides (IOs) on diabetes and other underlying mechanisms related to inflammatory factors and oxidative stress in a mouse model of streptozotocin (STZ)-induced diabetes. Four weeks administration of metformin (120 mg/kg) and IO1-4 (50%-80% alcohol precipitation), or IO5 (total 80% alcohol precipitation) at doses of 50 mg/kg reverses the abnormal changes of bodyweights and fasting blood glucose levels of diabetic mice. IOs significantly increased the insulin and pyruvate kinase levels in serum, and improved the synthesis of glycogen, especially for IO5. IOs restored the disturbed serum levels of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde. The down-regulation of interleukin-2 receptor, matrix metalloproteinase-9, and the enhancement of interleukin-2 in serum of diabetic mice were significantly attenuated by IOs. Histologic and morphology examinations showed that IOs repaired the damage on kidney tissues, inhibited inflammatory infiltrate and extracellular matrix deposit injuries in diabetic mice. Compared with untreated diabetic mice, IOs decreased the expression of phosphor-NF-kappaB in the kidneys. These results show that IOs treatment attenuated diabetic and renal injure in STZ-induced diabetic mice, possibly through the modulation of oxidative stress and inflammatory factors. These results provide valuable evidences to support the use of I. obliquus as a hypoglycemic functional food and/or medicine. PMID- 28662170 TI - Exploring the HIV continuum of care among young black MSM. AB - BACKGROUND: HIV disproportionately impacts young, black men who have sex with men (YBMSM) who experience disparities across the HIV care continuum. A more nuanced understanding of facilitators and barriers to engagement in care, missed visits, antiretroviral uptake, adherence and viral suppression could improve care and intervention design. METHODS: A randomized controlled trial of an online intervention, healthMpowerment, enrolled 465 YBMSM (18-30 years); 193 identified as HIV-positive. Bivariable and multivariable analyses of baseline data explored predictors of: engagement in care, missed visits, antiretroviral uptake, self reported adherence, and viral suppression. RESULTS: Mean age was 24.9 years; most identified as gay (71.0%) and were receiving HIV care (89.1%). Among those in care, 52.1% reported no missed visits in the past 12 months, 41 (24.6%) reported one missed visit, and 39 (23.4%) reported two or more. Having insurance (prevalence odds ratio [POR] 4.5; 95% CI: 1.3, 15.8) and provider self-efficacy (POR 20.1; 95% CI: 6.1, 64.1) were associated with being in care. Those with a college degree (POR 9.1; 95% CI: 1.9, 45.2) and no recent marijuana (POR 2.6; 95% CI: 1.2, 5.6) or methamphetamine use (POR 5.4; 95% CI: 1.0, 28.5) were less likely to miss visits. Most (n = 153, 84.1%) had been prescribed antiretroviral therapy. A majority of participants (70.8%) reported >=90% adherence; those with depressive symptoms had 4.7 times the odds of reporting adherence <90% (95% CI: 1.65, 13.37). Of participants who reported viral load testing in the past six months, 65% (n = 102) reported an undetectable viral load. Disclosure to sex partners was associated with viral suppression (POR 6.0; 95% CI: 1.6, 22.4). CONCLUSIONS: Multi-level facilitators and barriers to engagement across the continuum of care were identified in this sample of YBMSM. Understanding the distinct needs of YBMSM at each stage of the continuum and addressing them through tailored approaches is critical for long term success in care. PMID- 28662171 TI - Innate immunity restricts Citrobacter rodentium A/E pathogenesis initiation to an early window of opportunity. AB - Citrobacter rodentium infection is a mouse model for the important human diarrheal infection caused by enteropathogenic E. coli (EPEC). The pathogenesis of both species is very similar and depends on their unique ability to form intimately epithelium-adherent microcolonies, also known as "attachment/effacement" (A/E) lesions. These microcolonies must be dynamic and able to self-renew by continuous re-infection of the rapidly regenerating epithelium. It is unknown whether sustained epithelial A/E lesion pathogenesis is achieved through re-infection by planktonic bacteria from the luminal compartment or local spread of sessile bacteria without a planktonic phase. Focusing on the earliest events as C. rodentium becomes established, we show here that all colonic epithelial A/E microcolonies are clonal bacterial populations, and thus depend on local clonal growth to persist. In wild-type mice, microcolonies are established exclusively within the first 18 hours of infection. These early events shape the ongoing intestinal geography and severity of infection despite the continuous presence of phenotypically virulent luminal bacteria. Mechanistically, induced resistance to A/E lesion de-novo formation is mediated by TLR-MyD88/Trif-dependent signaling and is induced specifically by virulent C. rodentium in a virulence gene-dependent manner. Our data demonstrate that the establishment phase of C. rodentium pathogenesis in vivo is restricted to a very short window of opportunity that determines both disease geography and severity. PMID- 28662173 TI - Robust stability of fractional order polynomials with complicated uncertainty structure. AB - The main aim of this article is to present a graphical approach to robust stability analysis for families of fractional order (quasi-)polynomials with complicated uncertainty structure. More specifically, the work emphasizes the multilinear, polynomial and general structures of uncertainty and, moreover, the retarded quasi-polynomials with parametric uncertainty are studied. Since the families with these complex uncertainty structures suffer from the lack of analytical tools, their robust stability is investigated by numerical calculation and depiction of the value sets and subsequent application of the zero exclusion condition. PMID- 28662172 TI - Quantitative proteomics analysis of proteins involved in alkane uptake comparing the profiling of Pseudomonas aeruginosa SJTD-1 in response to n-octadecane and n hexadecane. AB - While many data are available on genes encoding proteins for degradation of hydrocarbons in bacteria, the impact of alkane on transporter protein expression is unclear. Pseudomonas aeruginosa SJTD-1 is a strain that can consume medium- and long-chain n-alkanes. In order to study the proteins involved in n-octadecane uptake, we use iTRAQ and label free comparative proteomics analysis to identify the proteins of alkane uptake in response to n-octadecane (C18) comparing with n hexadecane (C16) in P. aeruginosa SJTD-1. A total of 1102 and 1249 proteins were identified by iTRAQ-based and label free quantitative methodologies, respectively. By application of 1.5 (iTRAQ) or 2-fold (label free) for upregulated and 0.65 (iTRAQ) or 0.5-fold (label free) for downregulated cutoff values, 91 and 99 proteins were found to be differentially expressed comparing SJTD-1 cultivated on C18 with C16 respectively. There are six proteins with the common differential expression by iTRAQ and label free-based methods. Results of bioinformational analysis suggested the involvement of bacterial chemotaxis in responds to C18. Additionally, quantitative reverse transcriptase PCR (qRT-PCR) results confirmed C18-induced change in levels of FleQ, FliC, NirS, FadL and FadD proteins and the role of the proteins in n-octadecane uptake was further discussed in P. aeruginosa. In conclusion, results of the present study provided information about possible target-related proteins of bacterial chemotaxis, swimming performance, alkane transport to stimulus of n-ctadecane rather than n hexadecane in P. aeruginosa SJTD-1. PMID- 28662174 TI - A synthetic multi-cellular network of coupled self-sustained oscillators. AB - Engineering artificial networks from modular components is a major challenge in synthetic biology. In the past years, single units, such as switches and oscillators, were successfully constructed and implemented. The effective integration of these parts into functional artificial self-regulated networks is currently on the verge of breakthrough. Here, we describe the design of a modular higher-order synthetic genetic network assembled from two independent self sustained synthetic units: repressilators coupled via a modified quorum-sensing circuit. The isolated communication circuit and the network of coupled oscillators were analysed in mathematical modelling and experimental approaches. We monitored clustering of cells in groups of various sizes. Within each cluster of cells, cells oscillate synchronously, whereas the theoretical modelling predicts complete synchronization of the whole cellular population to be obtained approximately after 30 days. Our data suggest that self-regulated synchronization in biological systems can occur through an intermediate, long term clustering phase. The proposed artificial multicellular network provides a system framework for exploring how a given network generates a specific behaviour. PMID- 28662175 TI - GABAB receptor-dependent bidirectional regulation of critical period ocular dominance plasticity in cats. AB - Gama amino butyric acid (GABA) inhibition plays an important role in the onset and offset of the critical period for ocular dominance (OD) plasticity in the primary visual cortex. Previous studies have focused on the involvement of GABAA receptors, while the potential contribution of GABAB receptors to OD plasticity has been neglected. In this study, the GABAB receptor antagonist SCH50911 or agonist baclofen was infused into the primary visual cortex of cats concurrently with a period of monocular deprivation (MD). Using single-unit recordings we found that the OD shift induced by four days of MD during the critical period was impaired by infusion of the antagonist SCH50911, but enhanced by infusion of the agonist baclofen. In contrast, seven days of MD in adult cats did not induce any significant OD shift, even when combined with the infusion of SCH50911 or baclofen. Together, these findings indicate that an endogenous GABAB receptor mediated inhibition contributes to juvenile, but not adult, OD plasticity. PMID- 28662176 TI - A new perspective on the interplay between self-control and cognitive performance: Modeling progressive depletion patterns. AB - Exerting self-control in a first task weakens self-control performance in a subsequent unrelated task (ego depletion). In self-control research new strategies are required to investigate the ego-depletion effect, which has recently been shown to be more fragile than previously assumed. Moreover, the relation between ego depletion and trait self-control is still unclear, as various studies have reported heterogeneous findings concerning the interplay of both variables. We addressed these lacunas by drawing on a sample of N = 120 students, who participated in two test sessions. In the first test session, we assessed trait self-control and several control variables. The second test session followed an experimental design and tested the effects of ego depletion on invested effort and cognitive performance trajectories in an ecologically valid computer-based assessment setting (i.e., a 30-minute mathematical problem solving and reasoning test). Trait self-control was then used as a moderator of the ego-depletion effect. Combining an established ego-depletion paradigm (i.e., the sequential-task paradigm) with multilevel modeling of time-on-task and performance changes, our results indicate (1) that trait self-control predicted the motivation to solve cognitive tasks, (2) that ego depletion led to a progressive performance decrease, and (3) that the negative effect of ego depletion on performance was stronger for students with high trait self-control. Additional analyses revealed that our results could not be alternatively explained by fatigue effects. All effects were robust even after controlling for the students' cognitive abilities, which are known to be closely related to mathematical performance. Our results provide evidence that the self-control invested in order to keep performance at a consistently high level wanes over time. By modeling progressive ego-depletion effects while considering trait self control, we provide an alternative approach that may help future researchers to investigate the underlying mechanisms of self-control. PMID- 28662177 TI - A new approach for the assessment of the toxicity of polyphenol-rich compounds with the use of high content screening analysis. AB - The toxicity of in vitro tested compounds is usually evaluated based on AC50 values calculated from dose-response curves. However, there is a large group of compounds for which a standard four-parametric sigmoid curve fitting may be inappropriate for estimating AC50. In the present study, 22 polyphenol-rich compounds were prioritized from the least to the most toxic based on the total area under and over the dose-response curves (AUOC) in relation to baselines. The studied compounds were ranked across three key cell indicators (mitochondrial membrane potential, cell membrane integrity and nuclear size) in a panel of five cell lines (HepG2, Caco-2, A549, HMEC-1, and 3T3), using a high-content screening (HCS) assay. Regarding AUOC score values, naringin (negative control) was the least toxic phenolic compound. Aronox, spent hop extract and kale leaf extract had very low cytotoxicity with regard to mitochondrial membrane potential and cell membrane integrity, as well as nuclear morphology (nuclear area). Kaempferol (positive control) exerted strong cytotoxic effects on the mitochondrial and nuclear compartments. Extracts from buckthorn bark, walnut husk and hollyhock flower were highly cytotoxic with regard to the mitochondrion and cell membrane, but not the nucleus. We propose an alternative algorithm for the screening of a large number of agents and for identifying those with adverse cellular effects at an early stage of drug discovery, using high content screening analysis. This approach should be recommended for series of compounds producing a non-sigmoidal cell response, and for agents with unknown toxicity or mechanisms of action. PMID- 28662178 TI - Genetic association of FTO/IRX region with obesity and overweight in the Polish population. AB - BACKGROUND/OBJECTIVES: Genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI) in many different populations. Variants in the FTO locus are reported to be one of the strongest genetic predictors of obesity. Recent publications pointed also to a topologically associated domain (TAD) which is identified as a novel region affecting BMI. The TAD area encompasses the IRXB cluster (IRX3, IRX5, IRX6), FTO and RPGRIP1L genes. SUBJECTS/METHODS: In this study, we investigated the relationship between variation of the FTO and IRX genes and obesity in Poles. We presented a case control association analysis (normal versus overweight and/or obesity group) of Polish adult individuals (N = 5418). We determined whether or not the chromosomal region 16:53 500 000-55 500 000 contains polymorphic variants which are correlated with BMI in Polish population, including sex and age stratified analysis. RESULTS: The obtained results showed that the problem of weight-height abnormalities differently affects populations of Polish women and men (chi2 = 187.1; p<0.0001). From 353 SNPs enrolled to this study, 86 were statistically significant (highest chi2 = 15.72; p = 7.35E-05 observed for rs1558902). Linkage disequilibrium (LD) analysis revealed 61 blocks in the tested region of chromosome 16, with 24 SNPs located within the same block (block 8) of approximately 40 kb, in almost complete LD (|D'|>0.98, r2>0.80). We confirmed presence of the genetic susceptibility loci located in intron 1 of the FTO gene, which were correlated with BMI in our study group. For the first time, our analyses revealed strong association of FTO intronic variants (block 8) with overweight in group of men only. We have also identified association of the IRX region with overweight and/or obesity in Polish individuals. CONCLUSION: Our study demonstrated how tested SNPs make differential contributions to obesity and overweight risk. We revealed sex dependent differences in the distribution of tested loci which are associated with BMI in the population of Poles. PMID- 28662179 TI - Small leucine zipper protein functions as a negative regulator of estrogen receptor alpha in breast cancer. AB - The nuclear transcription factor estrogen receptor alpha (ERalpha) plays a critical role in breast cancer progression. ERalpha acts as an important growth stimulatory protein in breast cancer and the expression level of ERalpha is tightly related to the prognosis and treatment of patients. Small leucine zipper protein (sLZIP) functions as a transcriptional cofactor by binding to various nuclear receptors, including glucocorticoid receptor, androgen receptor, and peroxisome proliferator-activated receptor gamma. However, the role of sLZIP in the regulation of ERalpha and its involvement in breast cancer progression is unknown. We found that sLZIP binds to ERalpha and represses the transcriptional activity of ERalpha in ERalpha-positive breast cancer cells. sLZIP also suppressed the expression of ERalpha target genes. sLZIP disrupted the binding of ERalpha to the estrogen response element of the target gene promoter, resulting in suppression of cell proliferation. sLZIP is a novel co-repressor of ERalpha, and plays a negative role in ERalpha-mediated cell proliferation in breast cancer. PMID- 28662180 TI - Kai 1 and Kai 2: Characterization of these dog erythrocyte antigens by monoclonal antibodies. AB - Dog Erythrocyte Antigens (DEA) have thus far been found by sensitizing dogs with canine allogeneic blood and are clinically important regarding blood transfusion incompatibilities, but remain poorly defined. The goals of this study were to discover and characterize two DEAs, named as Kai 1 and Kai 2. The monoclonal antibodies were produced by mouse hybridoma techniques and examined by ELISA isotyping, immunoblotting, and affinity chromatography. Canine blood samples were typed and the development of alloantibodies was examined in transfused dogs. The monoclonal Kai 1 and Kai 2 antibodies were isotyped as IgM kappa and IgG3 lamda, respectively, and identified two different erythrocyte membrane proteins of 200 kDa and 80 kDa in molecular weights, respectively. Either Kai 1 or Kai 2 can be expressed but not both in an individual dog. There were no naturally occurring anti-Kai 1 or Kai 2 alloantibodies. In addition, Kai 1- and/or Kai 2- dogs developed Kai 1 and Kai 2 alloantibodies, respectively, when transfused with mismatched blood. This is the first discovery of canine blood types by screening monoclonal antibodies. Kai 1 and Kai 2 are novel blood types which can induce anti-Kai 1 or anti-Kai 2 alloantibodies when Kai 1- and/or Kai 2- dogs are transfused with Kai 1+ or Kai 2+ blood. These canine blood types may explain some of the blood incompatibilities and transfusion reactions observed in dogs in clinical practice. PMID- 28662181 TI - Structure of the Neisseria Adhesin Complex Protein (ACP) and its role as a novel lysozyme inhibitor. AB - Pathogenic and commensal Neisseria species produce an Adhesin Complex Protein, which was first characterised in Neisseria meningitidis (Nm) as a novel surface exposed adhesin with vaccine potential. In the current study, the crystal structure of a recombinant (r)Nm-ACP Type I protein was determined to 1.4 A resolution: the fold resembles an eight-stranded beta-barrel, stabilized by a disulphide bond between the first (Cys38) and last (Cys121) beta-strands. There are few main-chain hydrogen bonds linking beta4-beta5 and beta8-beta1, so the structure divides into two four-stranded anti-parallel beta-sheets (beta1-beta4 and beta5-beta8). The computed surface electrostatic charge distribution showed that the beta1-beta4 sheet face is predominantly basic, whereas the beta5-beta8 sheet is apolar, apart from the loop between beta4 and beta5. Concentrations of rNm-ACP and rNeisseria gonorrhoeae-ACP proteins >=0.25 MUg/ml significantly inhibited by ~80-100% (P<0.05) the in vitro activity of human lysozyme (HL) over 24 h. Specificity was demonstrated by the ability of murine anti-Neisseria ACP sera to block ACP inhibition and restore HL activity. ACP expression conferred tolerance to HL activity, as demonstrated by significant 3-9 fold reductions (P<0.05) in the growth of meningococcal and gonococcal acp gene knock-out mutants in the presence of lysozyme. In addition, wild-type Neisseria lactamica treated with purified ACP-specific rabbit IgG antibodies showed similar fold reductions in bacterial growth, compared with untreated bacteria (P<0.05). Nm-ACPI is structurally similar to the MliC/PliC protein family of lysozyme inhibitors. However, Neisseria ACP proteins show <20% primary sequence similarity with these inhibitors and do not share any conserved MliC/PliC sequence motifs associated with lysozyme recognition. These observations suggest that Neisseria ACP adopts a different mode of lysozyme inhibition and that the ability of ACP to inhibit lysozyme activity could be important for host colonization by both pathogenic and commensal Neisseria organisms. Thus, ACP represents a dual target for developing Neisseria vaccines and drugs to inhibit host-pathogen interactions. PMID- 28662182 TI - Extreme low dose of 5-fluorouracil reverses MDR in cancer by sensitizing cancer associated fibroblasts and down-regulating P-gp. AB - We conducted a prospective, meaningful study of extreme low dose of 5 fluorouracil (5FU) as a metronomic agent targeting cancer associated fibroblasts (CAFs) to reverse Multidrug resistance (MDR) by sensitizing cancer associated fibroblasts and down-regulating P-glycoprotein (P-gp). The combination of 5FU and Taxol inhibited resistant KB-8-5 tumor growth by 79% and H460/Tax-R tumor growth by 55%. The inhibition was significant for both tumor types compared with Taxol treatment alone (p<0.001 and p = 0.0067, respectively). Nevertheless, the low dose 5FU (2.2 mg/kg compared to the therapeutic dose of 50-150 mg/kg) showed negligible tumor inhibitory effect. The tumor growth inhibition study on resistant tumors demonstrated that the continuous administration of low dose 5FU with Taxol significantly inhibited the tumor growth. The treatment overcomes drug resistance in tumors by down-regulating multi-drug resistance transporter protein (P-gp), and more importantly, by eliminating CAFs recruited by resistant tumors. Compared with traditional metronomic chemotherapy, 5FU as metronomic agent targeting CAFs can avoid the disadvantages resulted from the concomitant administration of antiangiogenetic drug. The approach has good translational potential for clinical trials when treating stroma-rich drug resistant tumors. PMID- 28662183 TI - RpoS role in virulence and fitness in enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli (EPEC) is a diarrheagenic pathogen that afflicts infants in developing countries. The most important virulence trait of EPEC is its ability to intimately adhere to cells in the small intestine, and to elicit diarrhea. The alternative sigma factor RpoS is involved in the virulence of several bacterial species. RpoS coordinates the general stress response and accumulates in cells under stress or in the stationary phase. RpoS levels differ across E. coli strains. High-RpoS strains are highly resistant to environmental stresses, but usually display low nutritional competence, while low-RpoS strains show the opposite phenotype. Here we investigated whether RpoS plays a role in the virulence and fitness of two different EPEC strains, E2348/69 and LRT9. A rpoS null mutation had a small positive effect on LRT9 adherence to epithelial cells, but the expression of the EPEC adhesins BfpA and intimin was not significantly affected by the mutation. E2348/69 adherence was not significantly affected by the rpoS mutation. The intrinsic level of RpoS was higher in LRT9 than in E2348/69 while the latter adhered more strongly and expressed higher levels of the adhesin BfpA than the former. Knockout of rpoS strongly impaired resistance to oxidative, osmotic and acid stress in both E2348/69 and LRT9. However, strain E2348/69 was significantly more sensitive to oxidative stress than LRT9. Finally, competition assays showed that the rpoS mutant of LRT9 displayed higher fitness under continuous culture than its isogenic wild-type strain, while E2348/69 outcompeted its rpoS mutant. In conclusion, RpoS plays mostly a positive role in EPEC biology and at least in the case of strain E2348/69 it is not constrained by the trade-off between vegetative growth and stress resistance. PMID- 28662184 TI - Corneal epithelial cells exposed to shear stress show altered cytoskeleton and migratory behaviour. AB - Cells that form the corneal epithelium, the outermost layer of the cornea, are exposed to shear stress through blinking during waking hours. In this in vitro study, the effect of fluid shear stress on human corneal epithelial cells (HCECs) was investigated. Following exposure to shear stresses of 4 and 8 dyn/cm2, HCECs showed cytoskeletal rearrangement with more prominent, organized and elongated filamentous actin. Cytoskeletal changes were time-dependent, and were most significant after 24 hours of shear stress. Higher rates of migration and proliferation, as evaluated by a scratch assay, were also observed following 24 hours of low shear stress exposure (4 dyn/cm2). This result contrasted the poor migration observed in samples scratched before shear exposure, indicating that shear-induced cytoskeletal changes played a key role in improved wound healing and must therefore precede any damage to the cell layer. HCEC cytoskeletal changes were accompanied by an upregulation in integrin beta1 and downregulation of ICAM-1. These results demonstrate that HCECs respond favourably to flow induced shear stress, impacting their proliferation and migration properties as well as phenotype. PMID- 28662185 TI - PD1 is highly expressed in diffuse large B-cell lymphoma with hepatitis B virus infection. AB - OBJECTIVE: The purpose of this study was to determine the association between PD1 expression and the clinical prognosis of diffuse large B-cell lymphoma (DLBCL) co occurring with hepatitis B virus (HBV) infection. METHODS: A total of 165 patients presented with newly diagnosed and untreated DLBCL at the First Hospital of Jilin University, Changchun, China, between 2011.01 and 2014.12. Complete clinical information was available for 152 of these 165 patients. We retrospectively reviewed the results of HBV serum marker assays and the clinical information of these 152 DLBCL patients from our hospital database; eventually, only 51 patients were enrolled in this study, and these 51 patients received the PD1 test item. RESULTS: 1 The incidence of HBsAg prevalence was 13.2% (20/152) in this study; 2 The incidence of PD1 expression in the HBsAg+ group was 4.3-fold higher than that in the HBsAg-group (40.0% vs 9.4%; P = 0.010); 3 The clinical information, including sex, age, clinical stage, IPI, molecular subtype and chemotherapy status, was analyzed between the HBsAg+ and HBsAg-groups, but there were no significant differences between the two groups; 4 The median OS and PFS of the patients in the HBsAg+ group were 36.5 months and 12 months, respectively; however, the median OS and PFS of patients in the HBsAg-group were not reached (P = 0.033) and 32 months (P = 0.049), respectively; and 5 The median OS and PFS of PD1-positive patients in the HBsAg+ group were the worst (24 months and 9 months, respectively), whereas the median OS and PFS of PD1-negative patients in the HBsAg-group were the best (not reached and 32 months, respectively). CONCLUSIONS: Compared with patients in the HBsAg-group, the incidence of PD1 expression was significantly higher in the HBsAg+ group, and the median OS and PFS times were the worst in PD1-positive patients in the HBsAg+ group. These results indicated that the dismal prognosis of patients with HBsAg+ may be related to the high rate of PD1 expression. Thus, a targeted PD1 treatment strategy may improve the prognosis of HBsAg+ DLBCL patients. PMID- 28662186 TI - Normal range of myocardial layer-specific strain using two-dimensional speckle tracking echocardiography. AB - BACKGROUND: Newer 2D strain software has a potential to assess layer-specific strain. However, normal reference values for layer-specific strain have not been established. We aimed to establish the normal ranges of layer-specific longitudinal and circumferential strain (endocardial global longitudinal strain (GLS), transmural GLS, epicardial GLS, endocardial global circumferential strain (GCS), transmural GCS, and epicardial GCS). METHODS AND RESULTS: We retrospectively analyzed longitudinal and circumferential strain parameters in 235 healthy subjects, with use of layer-specific 2D speckle tracking software (GE). The endocardial strain/epicardial strain (Endo/Epi) ratio was also measured to assess the strain gradient across the myocardium. The endocardial, transmural, and epicardial GLS values and the Endo/Epi ratio in the normal subjects were 23.1+/-2.3, -20.0+/-2.0, -17.6+/-1.9, and 1.31+/-0.07, respectively. The corresponding values of GCS were -28.5+/-3.0, -20.8+/-2.3, -15.3+/-2.0, and 1.88+/-0.17, respectively. The layer-specific global strain parameters exhibited no age dependency but did exhibit gender dependency except for endocardial GCS. A subgroup analysis revealed that basal and middle levels of endocardial LS was decreased in the middle and elderly aged group. However, apical endocardial LS was preserved even in the elderly subjects. CONCLUSIONS: We proposed normal reference values for layer-specific strain based on both age and gender. This detailed strain analysis provides layer-oriented information with the potential to characterize abnormal findings in various cardiovascular diseases. PMID- 28662187 TI - Scientometric and patentometric analyses to determine the knowledge landscape in innovative technologies: The case of 3D bioprinting. AB - This research proposes an innovative data model to determine the landscape of emerging technologies. It is based on a competitive technology intelligence methodology that incorporates the assessment of scientific publications and patent analysis production, and is further supported by experts' feedback. It enables the definition of the growth rate of scientific and technological output in terms of the top countries, institutions and journals producing knowledge within the field as well as the identification of main areas of research and development by analyzing the International Patent Classification codes including keyword clusterization and co-occurrence of patent assignees and patent codes. This model was applied to the evolving domain of 3D bioprinting. Scientific documents from the Scopus and Web of Science databases, along with patents from 27 authorities and 140 countries, were retrieved. In total, 4782 scientific publications and 706 patents were identified from 2000 to mid-2016. The number of scientific documents published and patents in the last five years showed an annual average growth of 20% and 40%, respectively. Results indicate that the most prolific nations and institutions publishing on 3D bioprinting are the USA and China, including the Massachusetts Institute of Technology (USA), Nanyang Technological University (Singapore) and Tsinghua University (China), respectively. Biomaterials and Biofabrication are the predominant journals. The most prolific patenting countries are China and the USA; while Organovo Holdings Inc. (USA) and Tsinghua University (China) are the institutions leading. International Patent Classification codes reveal that most 3D bioprinting inventions intended for medical purposes apply porous or cellular materials or biologically active materials. Knowledge clusters and expert drivers indicate that there is a research focus on tissue engineering including the fabrication of organs, bioinks and new 3D bioprinting systems. Our model offers a guide to researchers to understand the knowledge production of pioneering technologies, in this case 3D bioprinting. PMID- 28662188 TI - Genetic dissection of the Arabidopsis spaceflight transcriptome: Are some responses dispensable for the physiological adaptation of plants to spaceflight? AB - Experimentation on the International Space Station has reached the stage where repeated and nuanced transcriptome studies are beginning to illuminate the structural and metabolic differences between plants grown in space compared to plants on the Earth. Genes that are important in establishing the spaceflight responses are being identified, their roles in spaceflight physiological adaptation are increasingly understood, and the fact that different genotypes adapt differently is recognized. However, the basic question of whether these spaceflight responses are actually required for survival has yet to be posed, and the fundamental notion that spaceflight responses may be non-adaptive has yet to be explored. Therefore the experiments presented here were designed to ask if portions of the plant spaceflight response can be genetically removed without causing loss of spaceflight survival and without causing increased stress responses. The CARA experiment compared the spaceflight transcriptome responses in the root tips of two Arabidopsis ecotypes, Col-0 and WS, as well as that of a PhyD mutant of Col-0. When grown with the ambient light of the ISS, phyD plants displayed a significantly reduced spaceflight transcriptome response compared to Col-0, suggesting that altering the activity of a single gene can actually improve spaceflight adaptation by reducing the transcriptome cost of physiological adaptation. The WS genotype showed an even simpler spaceflight transcriptome response in the ambient light of the ISS, more broadly indicating that the plant genotype can be manipulated to reduce the cost of spaceflight adaptation, as measured by transcriptional response. These differential genotypic responses suggest that genetic manipulation could further reduce, or perhaps eliminate the metabolic cost of spaceflight adaptation. When plants were germinated and then left in the dark on the ISS, the WS genotype actually mounted a larger transcriptome response than Col-0, suggesting that the in-space light environment affects physiological adaptation, which implies that manipulating the local habitat can also substantially impact the metabolic cost of spaceflight adaptation. PMID- 28662189 TI - Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease. AB - Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to alpha galactosidase A (alpha-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with alpha-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (>= 18 months) mice were tested in the naive state and after i.pl. injection of complete Freund's adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety like behavior in naive young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naive young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors. PMID- 28662190 TI - Bone tissue, blood lipids and inflammatory profiles in adolescent male athletes from sports contrasting in mechanical load. AB - Exploring the effect of non-impact and impact sports is particular relevant to understand the interaction between skeletal muscle and bone health during growth. The current study aimed to compare total and regional bone and soft-tissue composition, in parallel to measurements of blood lipid and inflammatory profiles between adolescent athletes and non-athletes. Anthropometry, biological maturity, dual energy X-ray absorptiometry (DXA) scans, training load and lipid and inflammatory profiles were assessed in a cross-sectional sample of 53 male adolescents (20 non-athletes, 15 swimmers and 18 basketball players) aged 12-19 years. Multiple comparisons between groups were performed using analysis of variance, covariance and magnitude effects (ES-r and Cohen's d). The comparisons of controls with other groups were very large for high-sensitivity C-reactive protein (d range: 2.17-2.92). The differences between sports disciplines, regarding tissue outputs obtained from DXA scan were moderate for all variables except fat tissue (d = 0.4). It was possible to determine small differences (ES-r = 0.17) between controls and swimmers for bone area at the lower limbs (13.0%). In parallel, between swimmers and basketball players, the gradient of the differences was small (ES-r range: 0.15-0.23) for bone mineral content (24.6%), bone area (11.3%) and bone mineral density (11.1%) at the lower limbs, favoring the basketball players. These observations highlight that youth male athletes presented better blood and soft tissues profiles with respect to controls. Furthermore, sport-specific differences emerged for the lower limbs, with basketball players presenting higher bone mineral content, area and density than swimmers. PMID- 28662191 TI - Relationship between bone mineral density and alcohol intake: A nationwide health survey analysis of postmenopausal women. AB - OBJECTIVES: Among a variety of relevant factors of osteoporosis, the association between alcohol intake and postmenopausal women's bone mineral density (BMD) by using data from the Korean National Health and Nutrition Examination Survey was evaluated in this study. MATERIALS AND METHODS: Among a total of 31,596 subjects, males, premenopausal women, participants without BMD data were excluded. Finally, a total number of subjects in the study was 3,312. The frequency and amount of alcohol intake were determined by self-reported questionnaires, and BMD was measured by dual-energy x-ray absorptiometry. RESULTS: Mean femoral BMD for light drinkers was statistically significantly greater than that for heavy drinkers and non-drinkers. We observed the characteristic trends for BMD by drinking frequency; the mean BMD gradually increased from non-drinkers to the participants who drank 2-3 times per week; these participants exhibited the highest BMD. Participants who drank alcohol greater than 4 times per week showed a lower BMD. In the risk factor analysis, the adjusted odds ratio for osteoporosis (at femoral neck) was 1.68 in non-drinkers and 1.70 in heavy drinkers compared with light drinkers. CONCLUSIONS: Light alcohol intake (2-3 times per week and 1-2 or 5-6 glasses per occasion) in South Korean postmenopausal women was related to high femoral BMD. Non-drinkers and heavy drinkers had approximately a 1.7-times greater risk for osteoporosis than light drinkers. PMID- 28662192 TI - The risk of intravenous thrombolysis-induced intracranial hemorrhage in Taiwanese patients with unruptured intracranial aneurysm. AB - BACKGROUND: The presence of an intracranial aneurysm is contraindicated to recombinant tissue plasminogen activator (r-tPA) treatment for acute ischemic stroke. However, it is difficult to exclude asymptomatic intracranial aneurysms by using conventional, noncontrast head computed tomography (CT), which is the only neuroimaging suggested before r-tPA. Recent case reports and series have shown that administering r-tPA to patients with a pre-existing aneurysm does not increase the bleeding risk. However, Asians are known to have a relatively higher bleeding risk, and little evidence is available regarding the risk of using r-tPA on Asian patients with intracranial aneurysms. METHODS: Medical records from the Shuang Ho hospital stroke registration between July 2010 and December 2014 were retrospectively reviewed, and 144 patients received r-tPA. Unruptured intracranial aneurysms were detected using CT, or magnetic resonance or conventional angiography after r-tPA. The primary and secondary outcomes were the difference in overall intracranial hemorrhage (ICH) and symptomatic ICH after r tPA. The differences were analyzed using Fisher's exact or Mann-Whitney U tests, and p < 0.05 was defined as the statistical significance. RESULTS: A total of 144 patients were reviewed, and incidental unruptured intracranial aneurysms were found in 11 of them (7.6%). No significant difference was observed in baseline demographic data between the aneurysm and nonaneurysm groups. Among patients with an unruptured aneurysm, two had giant aneurysms (7.7 and 7.4 mm, respectively). The bleeding risk was not significant different between aneurysm group (2 out of 11, 18%) with nonaneurysm group (7 out of 133, 5.3%) (p = 0.14). None of the patients with an unruptured aneurysm had symptomatic ICH, whereas one patient without an aneurysm exhibited symptomatic ICH. CONCLUSIONS: The presence of an unruptured intracranial aneurysm did not significantly increase the risk of overall and symptomatic ICH in Taiwanese patients after they received r-tPA. PMID- 28662193 TI - Prescription of oral short-acting beta 2-agonist for asthma in non-resource poor settings: A national study in Malaysia. AB - OBJECTIVE: Use of oral short-acting beta 2-agonist (SABA) persists in non resource poor countries despite concerns for its lower efficacy and safety. Utilisation and reasons for such use is needed to support the effort to discourage the use of oral SABA in asthma. This study examined the frequency of oral short-acting Beta 2-agonist (SABA) usage in the management of asthma in primary care and determined correlates of its usage. METHODS: Data used were from the 2014 National Medical Care Survey in Malaysia, a nationally representative survey of primary care encounters (weighted n = 325818). Using methods of analysis of data for complex surveys, we determined the frequency of asthma diagnosis in primary care and the rate of asthma medication prescription, which includes oral SABA. Multivariate logistic regression models were built to assess associations with the prescription of oral SABA. RESULTS: A weighted estimate of 9241 encounters presented to primary care with asthma in 2014. The mean age of the patients was 39.1 years. The rate of oral SABA, oral steroids, inhaled SABA and inhaled corticosteroids prescriptions were 33, 33, 50 and 23 per 100 asthma encounters, respectively. It was most commonly used in patients with the age ranged between 20 to less than 40 years. Logistic regression models showed that there was a higher odds of oral SABA usage in the presence of respiratory infection, prescription of oral corticosteroids and in the private sector. CONCLUSION: Oral SABA use in asthma is found to be common in a non- resource poor setting and its use could be attributed to a preference for oral medicines along undesirable clinical practices within a fragmented health system. PMID- 28662194 TI - Diagnostic value of potassium level in a spot urine sample as an index of 24-hour urinary potassium excretion in unselected patients hospitalized in a hypertension unit. AB - BACKGROUND: Primary hyperaldosteronism may be associated with elevated 24-hour urinary potassium excretion. We evaluated the diagnostic value of spot urine (SU) potassium as an index of 24-hour urinary potassium excretion. METHODS: We measured SU and 24-hour urinary collection potassium and creatinine in 382 patients. Correlations between SU and 24-hour collections were assessed for potassium levels and potassium/creatinine ratios. We used the PAHO formula to estimate 24-hour urinary potassium excretion based on SU potassium level. The agreement between estimated and measured 24-hour urinary potassium excretion was evaluated using the Bland-Altman method. To evaluate diagnostic performance of SU potassium, we calculated areas under the curve (AUC) for SU potassium/creatinine ratio and 24-hour urinary potassium excretion estimated using the PAHO formula. RESULTS: Strongest correlation between SU and 24-hour collection was found for potassium/creatinine ratio (r = 0.69, P<0.001). The PAHO formula underestimated 24-hour urinary potassium excretion by mean 8.3+/-18 mmol/d (95% limits of agreement -28 to +44 mmol/d). Diagnostic performance of SU potassium/creatinine ratio was borderline good only if 24-hour urinary potassium excretion was largely elevated (AUC 0.802 for 120 mmol K+/24 h) but poor with lower values (AUC 0.696 for 100 mmol K+/24 h, 0.636 for 80 mmol K+/24 h, 0.675 for 40 mmol K+/24 h). Diagnostic performance of 24-hour urinary potassium excretion estimated by the PAHO formula was excellent with values above 120 mmol/d and good with lower values (AUC 0.941 for 120 mmol K+/24 h, 0.819 for 100 mmol K+/24 h, 0.823 for 80 mmol K+/24 h, 0.836 for 40 mmol K+/24 h). CONCLUSIONS: Spot urine potassium/creatinine ratio might be a marker of increased 24-hour urinary potassium excretion and a potentially useful screening test when reliable 24-hour urine collection is not available. The PAHO formula allowed estimation of the 24 hour urinary potassium excretion based on SU measurements with reasonable clinical accuracy. PMID- 28662195 TI - The relationship between minute ventilation and end tidal CO2 in intubated and spontaneously breathing patients undergoing procedural sedation. AB - BACKGROUND: Monitoring respiratory status using end tidal CO2 (EtCO2), which reliably reflects arterial PaCO2 in intubated patients under general anesthesia, has often proven both inaccurate and inadequate when monitoring non-intubated and spontaneously breathing patients. This is particularly important in patients undergoing procedural sedation (e.g., endoscopy, colonoscopy). This can be undertaken in the operating theater, but is also often delivered outside the operating room by non-anesthesia providers. In this study we evaluated the ability for conventional EtCO2 monitoring to reflect changes in ventilation in non-intubated surgical patients undergoing monitored anesthesia care and compared and contrasted these findings to both intubated patients under general anesthesia and spontaneously breathing volunteers. METHODS: Minute Ventilation (MV), tidal volume (TV), and respiratory rate (RR) were continuously collected from an impedance-based Respiratory Volume Monitor (RVM) simultaneously with capnography data in 160 patients from three patient groups: non-intubated surgical patients managed using spinal anesthesia and Procedural Sedation (n = 58); intubated surgical patients under General Anesthesia (n = 54); and spontaneously breathing Awake Volunteers (n = 48). EtCO2 instrument sensitivity was calculated for each patient as the slope of a Deming regression between corresponding measurements of EtCO2 and MV and expressed as angle from the x-axis (theta). All data are presented as mean +/- SD unless otherwise indicated. RESULTS: While, as expected, EtCO2 and MV measurements were negatively correlated in most patients, we found gross systematic differences across the three cohorts. In the General Anesthesia patients, small changes in MV resulted in large changes in EtCO2 (high sensitivity, theta = -83.6 +/- 9.9 degrees ). In contrast, in the Awake Volunteers patients, large changes in MV resulted in insignificant changes in EtCO2 (low sensitivity, theta = -24.7 +/- 19.7 degrees , p < 0.0001 vs General Anesthesia). In the Procedural Sedation patients, EtCO2 sensitivity showed a bimodal distribution, with an approximately even split between patients showing high EtCO2 instrument sensitivity, similar to those under General Anesthesia, and patients with low EtCO2 instrument sensitivity, similar to the Awake Volunteers. CONCLUSIONS: When monitoring non-intubated patients undergoing procedural sedation, EtCO2 often provides inadequate instrument sensitivity when detecting changes in ventilation. This suggests that augmenting standard patient care with EtCO2 monitoring is a less than optimal solution for detecting changes in respiratory status in non-intubated patients. Instead, adding direct monitoring of MV with an RVM may be preferable for continuous assessment of adequacy of ventilation in non-intubated patients. PMID- 28662196 TI - A feasible, low-cost, reproducible lamb's head model for endoscopic sinus surgery training. AB - OBJECTIVE: To describe and standardize a reproducible, viable, low-cost lamb's head model for endoscopic sinus surgery training. METHODS: Otorhinolaryngology residents performed the following three endoscopic sinus surgeries using the lamb's head model: inferior turbinectomy, bullectomy, and maxillary antrostomy. Each student dissected 10 specimens before training these procedures on human patients, and the benefit of the animal model training was evaluated. RESULTS: Nineteen resident physicians of comparable academic level participated in training. All participants agreed that the lamb's head model dissections improved their skills in using surgical and videoendoscopic instruments, 90% agreed that the dissections improved their confidence with respect to training in human patients, and all stated they would recommend the same training to future residents. DISCUSSION: Lamb's heads have been used for training in endoscopic sinus surgery. However, no standardization of this training had been performed to ensure that it is a valuable tool for learning and skill-building. The standardized method described in this study increased resident physicians' skills and confidence before beginning their training on human patients. Moreover, our results demonstrate the feasibility of the model, considering its low cost and reproducibility. CONCLUSION: Future studies with this model should be conducted to assess whether the resulting increase in skills prevents and reduces medical errors, increases patient safety, reduces surgical costs, and improves the quality of otorhinolaryngological care. PMID- 28662197 TI - Effects of iron supplementation on growth, gut microbiota, metabolomics and cognitive development of rat pups. AB - BACKGROUND: Iron deficiency is common during infancy and therefore iron supplementation is recommended. Recent reports suggest that iron supplementation in already iron replete infants may adversely affect growth, cognitive development, and morbidity. METHODS: Normal and growth restricted rat pups were given iron daily (30 or 150 MUg/d) from birth to postnatal day (PD) 20, and followed to PD56. At PD20, hematology, tissue iron, and the hepatic metabolome were measured. The plasma metabolome and colonic microbial ecology were assessed at PD20 and PD56. T-maze (PD35) and passive avoidance (PD40) tests were used to evaluate cognitive development. RESULTS: Iron supplementation increased iron status in a dose-dependent manner in both groups, but no significant effect of iron on growth was observed. Passive avoidance was significantly lower only in normal rats given high iron compared with controls. In plasma and liver of normal and growth-restricted rats, excess iron increased 3-hydroxybutyrate and decreased several amino acids, urea and myo-inositol. While a profound difference in gut microbiota of normal and growth-restricted rats was observed, with iron supplementation differences in the abundance of strict anaerobes were observed. CONCLUSION: Excess iron adversely affects cognitive development, which may be a consequence of altered metabolism and/or shifts in gut microbiota. PMID- 28662198 TI - Genetic background and embryonic temperature affect DNA methylation and expression of myogenin and muscle development in Atlantic salmon (Salmo salar). AB - The development of ectothermic embryos is strongly affected by incubation temperature, and thermal imprinting of body growth and muscle phenotype has been reported in various teleost fishes. The complex epigenetic regulation of muscle development in vertebrates involves DNA methylation of the myogenin promoter. Body growth is a heritable and highly variable trait among fish populations that allows for local adaptations, but also for selective breeding. Here we studied the epigenetic effects of embryonic temperature and genetic background on body growth, muscle cellularity and myogenin expression in farmed Atlantic salmon (Salmo salar). Eggs from salmon families with either high or low estimated breeding values for body growth, referred to as Fast and Slow genotypes, were incubated at 8 degrees C or 4 degrees C until the embryonic 'eyed-stage' followed by rearing at the production temperature of 8 degrees C. Rearing temperature strongly affected the growth rates, and the 8 degrees C fish were about twice as heavy as the 4 degrees C fish in the order Fast8>Slow8>Fast4>Slow4 prior to seawater transfer. Fast8 was the largest fish also at harvest despite strong growth compensation in the low temperature groups. Larval myogenin expression was approximately 4-6 fold higher in the Fast8 group than in the other groups and was associated with relative low DNA methylation levels, but was positively correlated with the expression levels of the DNA methyltransferase genes dnmt1, dnmt3a and dnmt3b. Juvenile Fast8 fish displayed thicker white muscle fibres than Fast4 fish, while Slow 8 and Slow 4 showed no difference in muscle cellularity. The impact of genetic background on the thermal imprinting of body growth and muscle development in Atlantic salmon suggests that epigenetic variation might play a significant role in the local adaptation to fluctuating temperatures over short evolutionary time. PMID- 28662199 TI - Genomic fossils reveal adaptation of non-autonomous pararetroviruses driven by concerted evolution of noncoding regulatory sequences. AB - The interplay of different virus species in a host cell after infection can affect the adaptation of each virus. Endogenous viral elements, such as endogenous pararetroviruses (PRVs), have arisen from vertical inheritance of viral sequences integrated into host germline genomes. As viral genomic fossils, these sequences can thus serve as valuable paleogenomic data to study the long term evolutionary dynamics of virus-virus interactions, but they have rarely been applied for this purpose. All extant PRVs have been considered autonomous species in their parasitic life cycle in host cells. Here, we provide evidence for multiple non-autonomous PRV species with structural defects in viral activity that have frequently infected ancient grass hosts and adapted through interplay between viruses. Our paleogenomic analyses using endogenous PRVs in grass genomes revealed that these non-autonomous PRV species have participated in interplay with autonomous PRVs in a possible commensal partnership, or, alternatively, with one another in a possible mutualistic partnership. These partnerships, which have been established by the sharing of noncoding regulatory sequences (NRSs) in intergenic regions between two partner viruses, have been further maintained and altered by the sequence homogenization of NRSs between partners. Strikingly, we found that frequent region-specific recombination, rather than mutation selection, is the main causative mechanism of NRS homogenization. Our results, obtained from ancient DNA records of viruses, suggest that adaptation of PRVs has occurred by concerted evolution of NRSs between different virus species in the same host. Our findings further imply that evaluation of within-host NRS interactions within and between populations of viral pathogens may be important. PMID- 28662200 TI - Long chain fatty acids alter the interactive binding of ligands to the two principal drug binding sites of human serum albumin. AB - A wide variety of drugs bind to human serum albumin (HSA) at its two principal sites, namely site I and site II. A number of reports indicate that drug binding to these two binding sites are not completely independent, and that interactions between ligands of these two discrete sites can play a role. In this study, the effect of the binding of long-chain fatty acids on the interactive binding between dansyl-L-asparagine (DNSA; site I ligand) and ibuprofen (site II ligand) at pH6.5 was examined. Binding experiments showed that the binding of sodium oleate (Ole) to HSA induces conformational changes in the molecule, which, in turn, changes the individual binding of DNSA and ibuprofen, as well as the mode of interaction between these two ligands from a 'competitive-like' allosteric interaction in the case of the defatted HSA conformer to a 'nearly independent' binding in the case of non-defatted HSA conformer. Circular dichroism measurements indicated that ibuprofen and Ole are likely to modify the spatial orientation of DNSA at its binding site. Docking simulations suggest that the long-distance electric repulsion between DNSA and ibuprofen on defatted HSA contributes to a 'competitive-like' allosteric interaction, whereas extending the distance between ligands and/or increasing the flexibility or size of the DNSA binding site in fatted HSA evokes a change in the interaction mode to 'nearly independent' binding. The present findings provide further insights into the structural dynamics of HSA upon the binding of fatty acids, and its effects on drug binding and drug-drug interactions that occur on HSA. PMID- 28662201 TI - Neural effects of muscle stretching on the spinal reflexes in multiple lower-limb muscles. AB - While previous studies have shown that muscle stretching suppresses monosynaptic spinal reflex excitability in stretched muscles, its effects on non-stretched muscles is still largely unknown. The purpose of this study was to examine the effects of muscle stretching on monosynaptic spinal reflex in non-stretched muscles. Ten healthy male subjects participated in this study. Muscle stretching of the right triceps surae muscle was performed using a motor torque device for 1 minute. Three different dorsiflexion torques (at approximately 5, 10, and 15 Nm) were applied during muscle stretching. Spinal reflexes evoked by transcutaneous spinal cord stimulation were recorded in both the lower-limb muscles before, during, and at 0 and 5 min following muscle stretching. The amplitudes of the spinal reflexes in both the stretched and non-stretched muscles in the right (ipsilateral) leg were smaller during stretching compared to before, and at 0 and 5 min after stretching. Furthermore, the degree of reduction in the amplitude of the spinal reflexes in the right (ipsilateral) leg muscles increased significantly as the dorsiflexion torque (i.e., stretching of the right triceps surae muscles) increased. In contrast, reduction in the amplitude of the spinal reflexes with increasing dorsiflexion torque was not seen in the left (contralateral) leg muscles. Our results clearly indicate that muscle stretching has inhibitory effects on monosynaptic spinal reflexes, not only in stretched muscles, but also in non-stretched muscles of the ipsilateral leg. PMID- 28662202 TI - Innovative non-thermal plasma disinfection process inside sealed bags: Assessment of bactericidal and sporicidal effectiveness in regard to current sterilization norms. AB - In this work, we developed a device capable to generate a non-thermal plasma discharge inside a sealed bag. The aim of this study was to assess the effectiveness of the oxygen, nitrogen and argon plasma sterilization on Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis spores according to the NF EN 556 Norm. Moreover the bag integrity which is a critical key to maintain the sterile state of items after the end of the process was verified by Fourier Transform Infrared (FTIR) and X-ray Photoelectron Spectrometry (XPS) analyses. After plasma treatments, the bacterial counting showed a 6 log reduction of P. aeruginosa and S. aureus in 45 min and 120 min respectively whatever the gas used and a 4 log reduction of B. subtilis spores in 120 min with only oxygen plasma. These results were confirmed by Scanning Electron Microscopy (SEM) observations showing altered bacteria or spores and numerous debris. Taking into account the studied microorganisms, the oxygen plasma treatment showed the highest efficiency. FTIR and XPS analyses showed that this treatment induced no significant modification of the bags. To conclude this non-thermal plasma sterilization technique could be an opportunity to sterilize heat and chemical-sensitive medical devices and to preserve their sterile state after the end of the process. PMID- 28662203 TI - Detection of bacterial-reactive natural IgM antibodies in desert bighorn sheep populations. AB - Ecoimmunology is a burgeoning field of ecology which studies immune responses in wildlife by utilizing general immune assays such as the detection of natural antibody. Unlike adaptive antibodies, natural antibodies are important in innate immune responses and often recognized conserved epitopes present in pathogens. Here, we describe a procedure for measuring natural antibodies reactive to bacterial antigens that may be applicable to a variety of organisms. IgM from desert bighorn sheep plasma samples was tested for reactivity to outer membrane proteins from Vibrio coralliilyticus, a marine bacterium to which sheep would have not been exposed. Immunoblotting demonstrated bighorn sheep IgM could bind to a variety of bacterial cell envelope proteins while ELISA analysis allowed for rapid determination of natural antibody levels in hundreds of individual animals. Natural antibody levels were correlated with the ability of plasma to kill laboratory strains of E. coli bacteria. Finally, we demonstrate that natural antibody levels varied in two distinct populations of desert bighorn sheep. These data demonstrate a novel and specific measure of natural antibody function and show that this varies in ecologically relevant ways. PMID- 28662204 TI - Validation of an algorithm to identify children with biopsy-proven celiac disease from within health administrative data: An assessment of health services utilization patterns in Ontario, Canada. AB - IMPORTANCE: Celiac disease (CD) is a common pediatric illness, and awareness of gluten-related disorders including CD is growing. Health administrative data represents a unique opportunity to conduct population-based surveillance of this chronic condition and assess the impact of caring for children with CD on the health system. OBJECTIVE: The objective of the study was to validate an algorithm based on health administrative data diagnostic codes to accurately identify children with biopsy-proven CD. We also evaluated trends over time in the use of health services related to CD by children in Ontario, Canada. STUDY DESIGN AND SETTING: We conducted a retrospective cohort study and validation study of population-based health administrative data in Ontario, Canada. All cases of biopsy-proven CD diagnosed 2005-2011 in Ottawa were identified through chart review from a large pediatric health care center, and linked to the Ontario health administrative data to serve as positive reference standard. All other children living within Ottawa served as the negative reference standard. Case identifying algorithms based on outpatient physician visits with associated ICD-9 code for CD plus endoscopy billing code were constructed and tested. Sensitivity, specificity, PPV and NPV were tested for each algorithm (with 95% CI). Poisson regression, adjusting for sex and age at diagnosis, was used to explore the trend in outpatient visits associated with a CD diagnostic code from 1995-2011. RESULTS: The best algorithm to identify CD consisted of an endoscopy billing claim follow by 1 or more adult or pediatric gastroenterologist encounters after the endoscopic procedure. The sensitivity, specificity, PPV, and NPV for the algorithm were: 70.4% (95% CI 61.1-78.4%), >99.9% (95% CI >99.9->99.9%), 53.3% (95% CI 45.1-61.4%) and >99.9% (95% CI >99.9->99.9%) respectively. It identified 1289 suspected CD cases from Ontario-wide administrative data. There was a 9% annual increase in the use of this combination of CD-associated diagnostic codes in physician billing data (RR 1.09, 95% CI 1.07-1.10, P<0.001). CONCLUSIONS: With its current structure and variables Ontario health administrative data is not suitable in identifying incident pediatric CD cases. The tested algorithms suffer from poor sensitivity and/or poor PPV, which increase the risk of case misclassification that could lead to biased estimation of CD incidence rate. This study reinforced the importance of validating the codes used to identify cohorts or outcomes when conducting research using health administrative data. PMID- 28662205 TI - Correction: Saccharomyces Boulardii and Bacillus Subtilis B10 modulate TLRs and cytokines expression patterns in jejunum and ileum of broilers. AB - [This corrects the article DOI: 10.1371/journal.pone.0173917.]. PMID- 28662206 TI - Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. AB - Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a "safe dose" of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs) which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration. PMID- 28662207 TI - The urine metabolome differs between lean and overweight Labrador Retriever dogs during a feed-challenge. AB - Obesity in dogs is an increasing problem and better knowledge of the metabolism of overweight dogs is needed. Identification of molecular changes related to overweight may lead to new methods to improve obesity prevention and treatment. The aim of the study was firstly to investigate whether Nuclear Magnetic Resonance (NMR) based metabolomics could be used to differentiate postprandial from fasting urine in dogs, and secondly to investigate whether metabolite profiles differ between lean and overweight dogs in fasting and postprandial urine, respectively. Twenty-eight healthy intact male Labrador Retrievers were included, 12 of which were classified as lean (body condition score (BCS) 4-5 on a 9-point scale) and 16 as overweight (BCS 6-8). After overnight fasting, a voided morning urine sample was collected. Dogs were then fed a high-fat mixed meal and postprandial urine was collected after 3 hours. Metabolic profiles were generated using NMR and 45 metabolites identified from the spectral data were evaluated using multivariate data analysis. The results revealed that fasting and postprandial urine differed in relative metabolite concentration (partial least squares discriminant analysis (PLS-DA) 1 comp: R2Y = 0.4, Q2Y = 0.32; cross validated ANOVA: P = 0.00006). Univariate analyses of discriminant metabolites showed that taurine and citrate concentrations were elevated in postprandial urine, while allantoin concentration had decreased. Interestingly, lean and overweight dogs differed in terms of relative metabolite concentrations in postprandial urine (PLS-DA 1 comp: R2Y = 0.5, Q2Y = 0.36, cross-validated ANOVA: P = 0.005) but not in fasting urine. Overweight dogs had lower postprandial taurine and a trend of higher allantoin concentrations compared with lean dogs. These findings demonstrate that metabolomics can differentiate 3-hour postprandial urine from fasting urine in dogs, and that postprandial urine metabolites may be more useful than fasting metabolites for identification of metabolic alterations linked to overweight. The lowered urinary taurine concentration in overweight dogs could indicate alterations in lipid metabolism and merits further investigation. PMID- 28662208 TI - What works best for whom? Cognitive Behavior Therapy and Mindfulness-Based Cognitive Therapy for depressive symptoms in patients with diabetes. AB - OBJECTIVE: Cognitive Behavior Therapy (CBT) and Mindfulness-Based Cognitive Therapy (MBCT) have shown to be effective interventions for treating depressive symptoms in patients with diabetes. However, little is known about which intervention works best for whom (i.e., moderators of efficacy). The aim of this study was to identify variables that differentially predicted response to either CBT or MBCT (i.e., prescriptive predictors). METHODS: The sample consisted of 91 adult outpatients with type 1 or type 2 diabetes and comorbid depressive symptoms (i.e., BDI-II >= 14) who were randomized to either individual 8-week CBT (n = 45) or individual 8-week MBCT (n = 46). Patients were followed for a year and depressive symptoms were measured at pre-treatment, post-treatment, and at 9 months follow-up. The predictive effect of demographics, depression related characteristics, and disease specific characteristics on change in depressive symptoms was assessed by means of hierarchical regression analyses. RESULTS: Analyses showed that education was the only factor that differentially predicted a decrease in depressive symptoms directly after the interventions. At post treatment, individuals with higher educational attainment responded better to MBCT, as compared to CBT. Yet, this effect was not apparent at 9-months follow up. CONCLUSIONS: This study did not identify variables that robustly differentially predicted treatment effectiveness of CBT and MBCT, indicating that both CBT and MBCT are accessible interventions that are effective for treating depressive symptoms in broad populations with diabetes. More research is needed to guide patient-treatment matching in clinical practice. PMID- 28662209 TI - Narrow-band imaging (NBI) for improving the assessment of vocal fold leukoplakia and overcoming the umbrella effect. AB - BACKGROUND: It is crucial to find a balance between functional and oncological outcome when choosing an adequate method for the management of vocal fold leukoplakia. Therefore, a detailed examination is a milestone in the decision making process. AIM: To examine whether narrow-band imaging (NBI) can be helpful in vocal fold assessment in the case of leukoplakia and how to overcome the "umbrella effect"- understood as the submucosal vascular pattern hidden under the plaque. MATERIAL AND METHODS: Prospective cohort of 41 consecutive patients. Inclusion criteria: vocal fold leukoplakia, no previous procedures (surgery, radiotherapy), and preoperative endoscopy with an optical filter for NBI. Two groups: "suspicious" and "normal", according to the submucosal microvascular pattern of peripheral regions of the mucosa surrounding the plaque, were distinguished. Patients were qualified for a full-thickness or partial-thickness biopsy, respectively. Criteria defining suspected characters were well-demarcated brownish areas with scattered brown spots corresponding to type IV, Va, Vb, and Vc NI classifications. RESULTS: In 22/41 (53.7%) patients with "suspected" microvascular pattern, full-thickness biopsy was performed. Moderate and severe dysplasia was revealed in 15 type IV and 7 type Va NI patients. In 19/41 (46.3%) patients with proper NBI vessel pattern treated by partial-thickness biopsy, hyperkeratosis was diagnosed. There was a strong correlation between the NBI pattern and final histology: Chi2 (2) = 41.0 (p = 0.0000). CONCLUSION: The results demonstrate that NBI endoscopic assessment of the submucosal microvascular pattern of mucosa surrounding the plaque can be an effective method to categorise the risk in vocal fold leukoplakia prior to treatment. PMID- 28662210 TI - Three-dimensional spatial modeling of spines along dendritic networks in human cortical pyramidal neurons. AB - We modeled spine distribution along the dendritic networks of pyramidal neurons in both basal and apical dendrites. To do this, we applied network spatial analysis because spines can only lie on the dendritic shaft. We expanded the existing 2D computational techniques for spatial analysis along networks to perform a 3D network spatial analysis. We analyzed five detailed reconstructions of adult human pyramidal neurons of the temporal cortex with a total of more than 32,000 spines. We confirmed that there is a spatial variation in spine density that is dependent on the distance to the cell body in all dendrites. Considering the dendritic arborizations of each pyramidal cell as a group of instances of the same observation (the neuron), we used replicated point patterns together with network spatial analysis for the first time to search for significant differences in the spine distribution of basal dendrites between different cells and between all the basal and apical dendrites. To do this, we used a recent variant of Ripley's K function defined to work along networks. The results showed that there were no significant differences in spine distribution along basal arbors of the same neuron and along basal arbors of different pyramidal neurons. This suggests that dendritic spine distribution in basal dendritic arbors adheres to common rules. However, we did find significant differences in spine distribution along basal versus apical networks. Therefore, not only do apical and basal dendritic arborizations have distinct morphologies but they also obey different rules of spine distribution. Specifically, the results suggested that spines are more clustered along apical than in basal dendrites. Collectively, the results further highlighted that synaptic input information processing is different between these two dendritic domains. PMID- 28662212 TI - qPCR analysis of bivalve larvae feeding preferences when grazing on mixed microalgal diets. AB - Characterization of the feeding preferences of bivalve larvae would help improving the bivalve aquaculture and hatchery by providing appropriate microalgal diets. However, inaccurate and laborious identification and counting of microalgal species have challenged the selective feeding of bivalves. In the present study, we developed a highly specific and sensitive assay using quantitative polymerase chain reaction (qPCR) to assess the selective feeding of bivalve larvae based on species-specific primers targeting to microalgal 18S rDNA sequences. The assay exhibited good specificity. The detection limits of the qPCR assay were 769, 71, 781 and 21 18S rDNA copies for Chaetoceros calcitrans, Isochrysis galbana, Platymonas helgolandica and Nannochloropsis oculata, respectively. Using such assay, we found that C. calcitrans and I. galbana were preferentially ingested, whereas N. oculata was preferentially rejected in biodeposits of four bivalve species, Tegillarca gransa, Cyclina sinensis, Scapharca subcrenata and Sinonovacula constricta. Furthermore, our growth experiments revealed that C. calcitrans and I. galbana could significantly promote the shell growth, whereas feeding of N. oculata resulted in poorer growth of four bivalve species. These data indicated that qPCR might be useful in screening of efficient and reliable microalgal species for each bivalve species, leading to improved bivalve aquaculture and hatchery. PMID- 28662211 TI - Identification of Interactions between Sindbis Virus Capsid Protein and Cytoplasmic vRNA as Novel Virulence Determinants. AB - Alphaviruses are arthropod-borne viruses that represent a significant threat to public health at a global level. While the formation of alphaviral nucleocapsid cores, consisting of cargo nucleic acid and the viral capsid protein, is an essential molecular process of infection, the precise interactions between the two partners are ill-defined. A CLIP-seq approach was used to screen for candidate sites of interaction between the viral Capsid protein and genomic RNA of Sindbis virus (SINV), a model alphavirus. The data presented in this report indicates that the SINV capsid protein binds to specific viral RNA sequences in the cytoplasm of infected cells, but its interaction with genomic RNA in mature extracellular viral particles is largely non-specific in terms of nucleotide sequence. Mutational analyses of the cytoplasmic viral RNA-capsid interaction sites revealed a functional role for capsid binding early in infection. Interaction site mutants exhibited decreased viral growth kinetics; however, this defect was not a function of decreased particle production. Rather mutation of the cytoplasmic capsid-RNA interaction sites negatively affected the functional capacity of the incoming viral genomic RNAs leading to decreased infectivity. Furthermore, cytoplasmic capsid interaction site mutants are attenuated in a murine model of neurotropic alphavirus infection. Collectively, the findings of this study indicate that the identified cytoplasmic interactions of the viral capsid protein and genomic RNA, while not essential for particle formation, are necessary for genomic RNA function early during infection. This previously unappreciated role of capsid protein during the alphaviral replication cycle also constitutes a novel virulence determinant. PMID- 28662213 TI - Verification and characterization of an alternative low density lipoprotein receptor-related protein 1 splice variant. AB - BACKGROUND: Low density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a ubiquitously expressed multi-ligand endocytosis receptor implicated in a wide range of signalling, among others in tumour biology. Tumour-associated genomic mutations of the LRP1 gene are described, but nothing is known about cancer associated expression of LRP1 splice variants Therefore, the focus of this study was on an annotated truncated LRP1 splice variant (BC072015.1; NCBI GenBank), referred to as smLRP1, which was initially identified in prostate and lung carcinoma. METHODS: Using PCR and quantitative PCR, the expression of LRP1 and smLRP1 in different human tissues and tumour cell lines was screened and compared on tumour biopsies of head and neck squamous cell carcinoma (HNSCC). Using a recently developed anti-smLRP1 antibody, the expression of the putative LRP1 protein isoform in tumour cell lines in Western blot and immunofluorescence staining was further investigated. RESULTS: The alternative transcript smLRP1 is ubiquitously expressed in 12 human cell lines of different origin and 22 tissues which is similar to LRP1. A shift in expression of smLRP1 relative to LRP1 towards smLRP1 was observed in most tumour cell lines compared to healthy tissue. The expression of LRP1 as well as smLRP1 is decreased in HNSCC cell lines in comparison to healthy mucosa. In vitro results were checked using primary HNSCC. Furthermore, the expression of the protein isoform smLRP1 (32 kDa) was confirmed in human tumour cell lines. CONCLUSIONS: Similar to LRP1, the truncated splice variant smLRP1 is ubiquitously expressed in healthy human tissues, but altered in tumours pointing to a potential role of smLRP1 in cancer. Comparative results suggest a shift in expression in favour of smLRP1 in tumour cells that warrant further evaluation. The protein isoform is suggested to be secreted. PMID- 28662215 TI - Litterfall production and fine root dynamics in cool-temperate forests. AB - Current understanding of litterfall and fine root dynamics in temperate forests is limited, even though these are the major contributors to carbon and nutrient cycling in the ecosystems. In this study, we investigated litterfall and fine root biomass and production in five deciduous and four coniferous forests at the Gwangneung Experimental Forest in Korea. We used ingrowth cores to measure fine root production and root turnover rate. The litterfall was separated into leaves, twigs, and others, and then leaves were further separated according to species. Annual litterfall mass was not significantly different between the years, 360 to 651 g m-2 in 2011 and 300 to 656 g m-2 in 2012. Annual fine root (<5 mm) production was significantly higher in 2012 (421 to 1342 g m-2) than in 2011 (99 to 872 g m-2). Annual litterfall mass was significantly different among the stands, while fine root production did not statistically differ among the stands. The average fine root turnover rate, calculated by dividing the annual fine root production by the maximum standing fine root biomass, was 1.65 for deciduous forests and 1.97 for coniferous forests. Fine root production constituted 18-44% of NPP, where NPP was the sum of woody biomass production, litterfall production, and fine root production. Belowground production was a greater fraction of NPP in more productive forests suggesting their greater carbon allocation belowground. PMID- 28662214 TI - RBM10 promotes transformation-associated processes in small cell lung cancer and is directly regulated by RBM5. AB - Lung cancers are the leading cause of cancer-related deaths worldwide, with small cell lung cancer (SCLC) being the most aggressive type. At the time of diagnosis, SCLC has usually already metastasized, and an astonishing 95% of patients eventually succumb to the disease. This highlights the need for more effective SCLC screening and treatment options. Interestingly, the earliest and most frequent genetic alteration associated with lung cancers involves a lesion in the region to which the RNA binding protein RBM5 maps. We have recently shown that a decrease in RBM5 expression may be a key step in SCLC development, as RBM5 regulated many transformation-associated processes in SCLC cells. RBM5 is structurally and functionally similar to another RNA binding protein, RBM10. Both proteins have tumor-suppressor properties in a variety of cancer cell lines, and it has been suggested that RBM5 expression can influence RBM10. Due to their similarities, and the recent evidence that RBM10 is mutated in up to 21% of lung cancers, we hypothesized that RBM10 would share RBM5's tumor-suppressor properties in SCLC. Using transcriptome analysis and functional assays, we show, however, that RBM10's function was opposite to what we hypothesized; in the endogenously RBM5-null GLC20 SCLC cell line, RBM10 actually promoted cell proliferation and other transformation-associated processes. Using RNA immunoprecipitation followed by next generation sequencing (RIP-Seq) and Western blotting, we demonstrate that RBM5 post-transcriptionally regulated RBM10 expression via direct interaction with specific RBM10 splice variants. We propose a working model describing the impact of this interaction on cellular processes. Our results provide evidence that RBM10 expression, in RBM5-null tumors, may contribute to tumor growth and metastasis. Measurement of both RBM10 and RBM5 expression in clinical samples may therefore hold prognostic and/or potentially predictive value. PMID- 28662216 TI - Increased dermal collagen bundle alignment in systemic sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs. AB - Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention. PMID- 28662217 TI - Mistakes in translation: Reflections on mechanism. AB - Mistakes in translation of messenger RNA into protein are clearly a detriment to the recombinant production of pure proteins for biophysical study or the biopharmaceutical market. However, they may also provide insight into mechanistic details of the translation process. Mistakes often involve the substitution of an amino acid having an abundant codon for one having a rare codon, differing by substitution of a G base by an A base, as in the case of substitution of a lysine (AAA) for arginine (AGA). In these cases one expects the substitution frequency to depend on the relative abundances of the respective tRNAs, and thus, one might expect frequencies to be similar for all sites having the same rare codon. Here we demonstrate that, for the ADP-ribosylation factor from yeast expressed in E. coli, lysine for arginine substitutions frequencies are not the same at the 9 sites containing a rare arginine codon; mis-incorporation frequencies instead vary from less than 1 to 16%. We suggest that the context in which the codons occur (clustering of rare sites) may be responsible for the variation. The method employed to determine the frequency of mis-incorporation involves a novel mass spectrometric analysis of the products from the parallel expression of wild type and codon-optimized genes in 15N and 14N enriched media, respectively. The high sensitivity and low material requirements of the method make this a promising technology for the collection of data relevant to other mis-incorporations. The additional data could be of value in refining models for the ribosomal translation elongation process. PMID- 28662218 TI - Robust colour constancy in red-green dichromats. AB - Colour discrimination has been widely studied in red-green (R-G) dichromats but the extent to which their colour constancy is affected remains unclear. This work estimated the extent of colour constancy for four normal trichromatic observers and seven R-G dichromats when viewing natural scenes under simulated daylight illuminants. Hyperspectral imaging data from natural scenes were used to generate the stimuli on a calibrated CRT display. In experiment 1, observers viewed a reference scene illuminated by daylight with a correlated colour temperature (CCT) of 6700K; observers then viewed sequentially two versions of the same scene, one illuminated by either a higher or lower CCT (condition 1, pure CCT change with constant luminance) or a higher or lower average luminance (condition 2, pure luminance change with a constant CCT). The observers' task was to identify the version of the scene that looked different from the reference scene. Thresholds for detecting a pure CCT change or a pure luminance change were estimated, and it was found that those for R-G dichromats were marginally higher than for normal trichromats regarding CCT. In experiment 2, observers viewed sequentially a reference scene and a comparison scene with a CCT change or a luminance change above threshold for each observer. The observers' task was to identify whether or not the change was an intensity change. No significant differences were found between the responses of normal trichromats and dichromats. These data suggest robust colour constancy mechanisms along daylight locus in R-G dichromacy. PMID- 28662220 TI - Optimizing Injection Technique to Minimize Ecchymosis in Upper Blepharoplasty. PMID- 28662221 TI - Exclusion of Kaposi Sarcoma From Analysis of Cancer Burden. PMID- 28662219 TI - The effects of C5-substituted 2,4-diaminoquinazolines on selected transcript expression in spinal muscular atrophy cells. AB - C5-substituted 2,4-diaminoquinazolines (2,4-DAQs) ameliorate disease severity in SMA mice. It is uncertain, however, that these compounds increase SMN protein levels in vivo even though they were identified as activators of the SMN2 promoter. These compounds also regulate the expression of other transcripts in neuroblastoma cells. In this study, we investigate the mechanism by which the 2,4 DAQs regulate the expression of SMN2 as well as other targets. D156844, D158872, D157161 and D157495 (RG3039) increased SMN2 promoter-driven reporter gene activity by at least 3-fold in NSC-34 cells. These compounds, however, did not significantly increase SMN2 mRNA levels in type II SMA fibroblasts nor in NSC-34 cells, although there was a trend for these compounds increasing SMN protein in SMA fibroblasts. The number of SMN-containing gems was increased in SMA fibroblasts in response to 2,4-DAQ treatment in a dose-dependent manner. ATOH7 mRNA levels were significantly lower in type II SMA fibroblasts. 2,4-DAQs significantly increased ATOH7, DRNT1 and DRTN2 transcript levels in type II SMA fibroblasts and restored ATOH7 levels to those observed in healthy fibroblasts. These compounds also increase Atoh7 mRNA expression in NSC-34 cells. In conclusion, 2,4-DAQs regulate SMN2 by increasing protein levels and gem localization. They also increase ATOH7, DRNT1 and DRNT2 transcript levels. This study reveals that the protective effects of 2,4-DAQs in SMA may be independent of SMN2 gene regulation. These compounds could be used in concert with a proven SMN2 inducer to develop a multi-faceted approach to treating SMA. PMID- 28662223 TI - Exclusion of Kaposi Sarcoma From Analysis of Cancer Burden-Reply. PMID- 28662224 TI - Unilateral Nasal Congestion in an Elderly Man. PMID- 28662222 TI - Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades. AB - Importance: The frequency of cancers with indolent behavior has increased with screening. Better tools to identify indolent tumors are needed to avoid overtreatment. Objective: To determine if a multigene classifier is associated with indolent behavior of invasive breast cancers in women followed for 2 decades. Design, Setting, and Participants: This is a secondary analysis of a randomized clinical trial of tamoxifen vs no systemic therapy, with more than 20 year follow-up. An indolent threshold (ultralow risk) of the US Food and Drug Administration-cleared MammaPrint 70-gene expression score was established above which no breast cancer deaths occurred after 15 years in the absence of systemic therapy. Immunohistochemical markers (n = 727 women) and Agilent microarrays, for MammaPrint risk scoring (n = 652 women), were performed from formalin-fixed paraffin-embedded primary tumor blocks. Participants were postmenopausal women with clinically detected node-negative breast cancers treated with mastectomy or lumpectomy and radiation enrolled in the Stockholm tamoxifen (STO-3) trial, 1976 to 1990. Exposures: After 2 years of tamoxifen vs no systemic therapy, regardless of hormone receptor status, patients without relapse who reconsented were further randomized to 3 additional years or none. Main Outcomes and Measures: Breast cancer-specific survival assessed by Kaplan-Meier analyses and multivariate Cox proportional hazard modeling, adjusted for treatment, patient age, year of diagnosis, tumor size, grade, hormone receptors, and ERBB2/HER2 and Ki67 status. Results: In this secondary analysis of node-negative postmenopausal women, conducted in the era before mammography screening, among the 652 women with MammaPrint scoring available (median age, 62.8 years of age), 377 (58%) and 275 (42%) were MammaPrint low and high risk, respectively, while 98 (15%) were ultralow risk. At 20 years, women with 70-gene high and low tumors but not ultralow tumors had a significantly higher risk of disease-specific death compared with ultralow-risk patients by Cox analysis (hazard ratios, 4.73 [95% CI, 1.38-16.22] and 4.54 [95% CI, 1.40-14.80], respectively). There were no deaths in the ultralow-risk tamoxifen-treated arm at 15 years, and these patients had a 20-year disease-specific survival rate of 97%, whereas for untreated patients the survival rate was 94%. Recursive partitioning identified ultralow risk as the most significant predictor of good outcome. In tumors "not ultralow risk," tumor size greater than 2 cm was the most predictive of outcome. Conclusions and Relevance: The ultralow-risk threshold of the 70-gene MammaPrint assay can identify patients whose long-term systemic risk of death from breast cancer after surgery alone is exceedingly low. PMID- 28662225 TI - Complete Philtrum Reconstruction on the Partial-Thickness Cross-Lip Flap by Nasolabial Muscle Tension Line Group Reconstruction in the Same Stage of Flap Transfer. AB - Importance: The blood supply pattern of the partial-thickness musculomucosal pedicle flaps is different from the traditional Abbe flap. The arterial blood supply and venous drainage are highly reliable during clinical practice. Objective: To describe the reconstruction of the philtrum in the cross-lip flap transfer using nasolabial muscle tension line group reconstruction. Design, Setting, and Participants: From January 1, 2014, through June 31, 2015, a total of 6 patients with upper lip defect were treated with philtrum reconstruction in the same stage of the split cross-lip flap transfer at the Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. These patients underwent reconstruction of the philtrum by nasolabial muscle tension line group reconstruction. The patients were compared with a randomly chosen group of 5 individuals without upper lip defects by measuring the 3-dimensional scans. Interventions: In the patient group, the split flap was elevated from the posterior portion of the oris orbicularis muscle after the inferior labial arteries were divided. Then the partial-thickness flap was rotated 180 degrees horizontally and inverted 180 degrees upward to the upper lip defect. The philtrum was reconstructed using the nasolabial muscle tension line group reconstruction. Main Outcomes and Measures: Three-dimensional scans were performed from the 2-month to 28-month revisits. Results: A total of 11 individuals were included in the study: 6 in the patient group (mean [SD] age, 17.0 [4.8] years; 2 [33.3%] female and 4 [66.7%] male) and 5 in the control group (mean [SD] age, 15.2 [6.0] years; 2 [40.0%] female and 3 [60.0%] male). In the patient group, 5 of 6 musculomucosal pedicle flaps were viable. A stable philtrum with philtral ridge and philtral dimple was reconstructed on the 5 flaps. The shape of the philtrum was natural according to the 3-dimensional scan measurement. One flap partially necrosed, and the scar retraction was severe postoperatively. Conclusions and Relevance: The blood supply of the partial thickness cross-lip flap was from the small vascular network of the lower lip. It is reliable to reconstruct a philtrum in this stage of flap transfer. A complete philtrum structure can be reconstructed by applying muscle tension on the flap. Level of Evidence: 4. PMID- 28662226 TI - Optimizing Injection Technique to Minimize Ecchymosis in Blepharoplasty-Reply. PMID- 28662227 TI - Power Morcellators, Postmarketing Surveillance, and the US Food and Drug Administration. PMID- 28662228 TI - Treatment Beyond Progression With Immune Checkpoint Inhibitors-Known Unknowns. PMID- 28662229 TI - Electroretinographic Responses in the Smallest Eyes. PMID- 28662230 TI - Vascular Adhesion Protein-1 Blockade Suppresses Ocular Inflammation After Retinal Laser Photocoagulation in Mice. AB - Purpose: To investigate the effect of the vascular adhesion protein-1 (VAP-1) inhibitor RTU-1096 on retinal morphologic changes and ocular inflammation after retinal laser photocoagulation in mice. Methods: C57BL/6JJcl mice were fed a diet containing RTU-1096, a specific inhibitor for VAP-1, or a control diet ad libitum for 7 days. Laser photocoagulation was performed on the peripheral retina of the animals. The semicarbazide sensitive amine oxidase (SSAO) activities in plasma and chorioretinal tissues were measured. Optical coherence tomography (OCT) images were acquired before and at 1, 3, and 7 days after laser photocoagulation, and thickness of the individual retinal layers was measured. Intravitreal leukocyte infiltration was assessed by histologic analysis. The expression level of intercellular adhesion molecule-1 (ICAM-1) in retinal tissues were examined by quantitative real-time PCR. Results: One day after laser photocoagulation, the thickness of the outer nuclear layer (ONL) increased in the laser group compared with in the control group, and RTU-1096 administration abrogated the ONL thickening. Histologic analysis and OCT observation revealed that laser photocoagulation caused infiltration of inflammatory cells and the appearance of hyperreflective foci at the vitreoretinal surface, both of which were suppressed by RTU-1096 administration. In addition, systemic administration of RTU-1096 reduced upregulation of the leukocyte adhesion molecules ICAM-1 in the retina. Conclusions: The current data indicate that VAP-1/SSAO inhibition may be a potential therapeutic strategy for the prevention of macular edema secondary to scatter laser photocoagulation in patients with ischemic retinal diseases such as diabetic retinopathy. PMID- 28662231 TI - Early-Onset Progressive Degeneration of the Area Centralis in RPE65-Deficient Dogs. AB - Purpose: Retinal epithelium-specific protein 65 kDa (RPE65)-deficient dogs are a valuable large animal model species that have been used to refine gene augmentation therapy for Leber congenital amaurosis type-2 (LCA2). Previous studies have suggested that retinal degeneration in the dog model is slower than that observed in humans. However, the area centralis of the dog retina is a cone and rod photoreceptor rich region comparable to the human macula, and the effect of RPE65 deficiency specifically on this retinal region, important for high acuity vision, has not previously been reported. Methods: Spectral-domain optical coherence tomography, fundus photography, and immunohistochemistry of retinal wholemounts and sagittal frozen sections were used to define the time-course and cell-types affected in degeneration of the area centralis in affected dogs. Results: Area centralis photoreceptor degeneration was evident from 6 weeks of age, and progressed to involve the inner retina. Immunohistochemistry showed that RPE65-deficient dogs developed early loss of S-cone outer segments, with slower loss of L/M-cone outer segments and rods. Conclusions: Early-onset severe photoreceptor degeneration in the area centralis of dogs with RPE65-deficiency offers a model of the early foveal/perifoveal degeneration in some patients with LCA2. This model could be used to refine interventions aiming to improve function and halt the progression of foveal/perifoveal photoreceptor degeneration. PMID- 28662233 TI - Control of Pain After Tonsillectomy in Children: A Review. AB - Importance: The relief of pain after tonsillectomy in children remains challenging and even controversial. While the need for pain control after this surgery is understood, recent debate has centered around the risks of opioids in children with obstructive sleep apnea syndrome (OSAS) and the possible increases in posttonsillectomy hemorrhage with the use of alternative nonsteroidal anti inflammatory drugs (NSAIDs). Observations: We discuss the multiple facets of posttonsillectomy pain control in children. A variety of pharmacologic and nonpharmacologic interventions used before, during, and after surgery are reviewed, presenting the evidence for efficacy and possible adverse effects. We also review the various surgical techniques used in tonsillectomy with a focus on reducing postoperative pain. Conclusions and Relevance: Clinicians should understand effective methods of analgesia after tonsillectomy in children, and know the potential consequences of each option. Caution should be employed when using opioids, particularly in young children with severe OSAS. Although large studies of NSAID use have shown effective pain management without an increase in posttonsillectomy bleeding frequency, the potential for more severe bleeding events has been debated. Cold dissection techniques lead to less pain, but hot techniques remain popular, with less intraoperative blood loss and shorter operative time. Partial (intracapsular) tonsillectomy seems to reduce pain as well. PMID- 28662232 TI - Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. AB - Importance: Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression. Objective: To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 defined progression. Design, Setting, and Participants: Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017. Interventions: Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion. Main Outcomes and Measures: Tumor response and safety in TBP and non-TBP patients. Results: Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2 7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively). Conclusions and Relevance: A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression. Trial Registration: clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067). PMID- 28662234 TI - A Diver With Double Vision. PMID- 28662235 TI - Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial. AB - Importance: There is a strong rationale for treating sarcomas with immunotherapy. Objective: To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. Design, Setting, and Participants: This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks. Intervention or Exposure: Pembrolizumab in combination with metronomic cyclophosphamide. Main Outcomes and Measures: There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples. Results: Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1-positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment. Conclusions and Relevance: We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. Trial Registration: clinicaltrials.gov Identifier: NCT02406781. PMID- 28662236 TI - Earlier saccades to task-relevant targets irrespective of relative gain between peripheral and foveal information. AB - Saccades bring objects of interest onto the fovea for high-acuity processing. Saccades to rewarded targets show shorter latencies that correlate negatively with expected motivational value. Shorter latencies are also observed when the saccade target is relevant for a perceptual discrimination task. Here we tested whether saccade preparation is equally influenced by informational value as it is by motivational value. We defined informational value as the probability that information is task-relevant times the ratio between postsaccadic foveal and presaccadic peripheral discriminability. Using a gaze-contingent display, we independently manipulated peripheral and foveal discriminability of the saccade target. Latencies of saccades with perceptual task were reduced by 36 ms in general, but they were not modulated by the information saccades provide (Experiments 1 and 2). However, latencies showed a clear negative linear correlation with the probability that the target is task-relevant (Experiment 3). We replicated that the facilitation by a perceptual task is spatially specific and not due to generally heightened arousal (Experiment 4). Finally, the facilitation only emerged when the perceptual task is in the visual but not in the auditory modality (Experiment 5). Taken together, these results suggest that saccade latencies are not equally modulated by informational value as by motivational value. The facilitation by a perceptual task only arises when task relevant visual information is foveated, irrespective of whether the foveation is useful or not. PMID- 28662237 TI - Oxidative Stress Measures of Lipid and DNA Damage in Human Tears. AB - Purpose: We evaluate feasibility and repeatability of measures for lipid peroxidation and DNA oxidation in human tears, as well as relationships between outcome variables, and compared our findings to previously reported methods of evaluation for ocular sun exposure. Methods: A total of 50 volunteers were seen for 2 visits 14 +/- 2 days apart. Tear samples were collected from the inferior tear meniscus using a glass microcapillary tube. Oxidative stress biomarkers were quantified using enzyme-linked immunosorbent assay (ELISA): lipid peroxidation by measurement of hexanoyl-lysine (HEL) expression; DNA oxidation by measurement of 8-oxo-2'-deoxyguinosone (8OHdG) expression. Descriptive statistics were generated. Repeatability estimates were made using Bland-Altman plots with mean differences and 95% limits of agreement were calculated. Linear regression was conducted to evaluate relationships between measures. Results: Mean (+/-SD) values for tear HEL and 8OHdG expression were 17368.02 (+/-9878.42) nmol/L and 66.13 (+/-19.99) ng/mL, respectively. Repeatability was found to be acceptable for both HEL and 8OHdG expression. Univariate linear regression supported tear 8OHdG expression and spring season of collection to be predictors of higher tear HEL expression; tear HEL expression was confirmed as a predictor of higher tear 8OHdG expression. Conclusions: We demonstrate feasibility and repeatability of estimating previously unreported tear 8OHdG expression. Seasonal temperature variation and other factors may influence tear lipid peroxidation. Support is demonstrated to suggest lipid damage and DNA damage occur concurrently on the human ocular surface. PMID- 28662238 TI - Use of Audiometric Measurement for Assessment of Vocal-Fold Function in Postextubation Infants. AB - Importance: Infants with vocal-fold motion impairment (VFMI) have an increased risk of aspiration and pulmonary complications. Flexible nasolaryngoscopy (FNL) is the gold standard for evaluation of vocal-fold mobility. Although safe, FNL causes measurable physiologic changes. Noxious stimuli, especially in neonates in the cardiovascular intensive care unit, may cause imbalance between the pulmonary and systemic circulations and potentially circulatory collapse. Objective: To examine whether bedside measurement of infant cry volume using a smartphone application can be a screening tool for vocal-fold movement in FNL. Design, Study, and Participants: This case-control study performed from December 1, 2013, through January 31, 2015, included 42 infants in the intensive care unit at Texas Children's Hospital, Houston. Main Outcomes and Measures: Patient cry volume in decibels was recorded using a smartphone application placed 12 in from their mouth. Results: Forty-two infants were identified at the intensive care unit (median age, 33 days; 20 [48%] female and 22 [52%] male), 21 with VFMI and 21 without, based on FNL findings. A statistically significant difference was found in the mean cry volume of infants with (76.60 dB) and without (85.72 dB) VFMI. The absolute difference in the mean cry volume was 9.12 dB (95% CI, 2.74-15.50 dB). A cry volume of 90 dB or greater had a sensitivity of 90.4% (95% CI, 71% 97%) for identification of normal vocal-fold mobility. A cry volume of 75 dB or less had a specificity of 90.5% (95% CI, 71%-97%) for the identification of VFMI. The mean (SE) area under the receiver operating characteristic curve was 0.721 (0.080) (95% CI, 0.565-0.877). The cry volume, however, was not a good screen for aspiration. Conclusions and Relevance: Bedside measurement of the cry volume with a smartphone application can be used by untrained health care professionals to screen patients for further evaluation of vocal-fold mobility using FNL. PMID- 28662239 TI - Eye Health Knowledge and Eye Health Information Exposure Among Hispanic/Latino Individuals: Results From the Hispanic Community Health Study/Study of Latinos. AB - Importance: Routine eye care is important to maintaining eye health and preventing visual impairment. However, poor knowledge of ocular risk factors and disease as well as minimal exposure to eye health information may compromise adherence to eye care recommendations. Studies have shown that Hispanic/Latino people have poor eye care utilization, but little is known about their knowledge of eye health and exposure to eye health information. Objective: To examine factors associated with more eye health knowledge and greater exposure to eye health information among Hispanic/Latino people. Design, Setting, and Participants: This was a cross-sectional ocular study of 1235 participants living in the Miami, Florida, site of the Hispanic Community Health Study/Study of Latinos, a multisite epidemiologic study of disease prevalence and development among Hispanic/Latino people. Data were collected from October 1, 2011, through September 30, 2013, and data analyses were conducted between May 28, 2014, and March 18, 2015. Descriptive and multivariable regression analyses were performed for 3 ocular health care outcomes. Regression models were built sequentially, with variables conceptually grouped according to Andersen's Behavioral Model of Health Services Use and Behavioral Model for Vulnerable Populations. Main Outcomes and Measures: Ability to identify 8 factors on a general eye health knowledge scale and number of eye health information sources seen or heard about in the past 12 months. Results: Of the 1235 participants, 748 (73.4%) self identified as being of Cuban descent and 407 (19.2%) self-identified as being from Central or South America, 478 (46.7%) were women and 757 (53.3%) were men, and the mean (SD) age was 53.6 (8.1) years. Participants with at least a high school degree or general educational development certificate had greater eye health knowledge (incidence rate ratio [IRR], 1.08; 95% CI, 1.01-1.15 and IRR, 1.11; 95% CI, 1.04-1.17, respectively) as did those with a higher mental health score on the Short Form 12-Item, version 2, Health Survey (IRR, 1.03; 95% CI, 1.01-1.04). Those with educational attainment beyond a high school degree or a general educational development certificate (IRR, 1.29; 95% CI, 1.07-1.54), those who were 60 years or older (IRR, 1.32; 95% CI, 1.06-1.63), and those with a household income in US dollars of $20 001 to $40 000 (IRR, 1.23; 95% CI, 1.05 1.44) or greater than $40 000 (IRR, 1.25; 95% CI, 0.98-1.59) were more likely to be exposed to at least 5 sources of eye health information in the past 12 months. Conclusions and Relevance: Among Hispanic/Latino people, age, educational level, income, and mental health may be important correlates of eye disease knowledge and eye health information exposure. These findings might be used to support the development of targeted interventions designed to improve eye health in this population. PMID- 28662240 TI - Consideration of Dental, Vision, and Hearing Services to Be Covered Under Medicare. PMID- 28662241 TI - Ultrafast laser-assisted spatially targeted optoporation into cortical axons and retinal cells in the eye. AB - Visualization and assessment of the cellular structure and function require localized delivery of the molecules into specific cells in restricted spatial regions of the tissue and may necessitate subcellular delivery and localization. Earlier, we have shown ultrafast near-infrared laser beam-assisted optoporation of actin-staining molecules into cortical neurons with single-cell resolution and high efficiency. However, diffusion of optoporated molecules in soma degrades toward the growth cone, leading to difficulties in visualization of the actin network in the growth cone in cases of long axons. Here, we demonstrate optoporation of impermeable molecules to functional cortical neurons by precise laser subaxotomy near the growth cone, leading to visualization of the actin network in the growth cone. Further, we demonstrate patterned delivery of impermeable molecules into targeted retinal cells in the rat eye. The development of optoporation as a minimally invasive approach to reliably deliver exogenous molecules into targeted axons and soma of retinal neurons in vivo will enable enhanced visualization of the structure and function of the retina. PMID- 28662242 TI - Multispectral imaging system based on light-emitting diodes for the detection of melanomas and basal cell carcinomas: a pilot study. AB - This article proposes a multispectral system that uses the analysis of the spatial distribution of color and spectral features to improve the detection of skin cancer lesions, specifically melanomas and basal cell carcinomas. The system consists of a digital camera and light-emitting diodes of eight different wavelengths (414 to 995 nm). The parameters based on spectral features of the lesions such as reflectance and color, as well as others empirically computed using reflectance values, were calculated pixel-by-pixel from the images obtained. Statistical descriptors were calculated for every segmented lesion [mean ( x ~ ), standard deviation ( sigma ), minimum, and maximum]; descriptors based on the first-order statistics of the histogram [entropy ( E p ), energy ( E n ), and third central moment ( MU 3 )] were also obtained. The study analyzed 429 pigmented and nonpigmented lesions: 290 nevi and 139 malignant (95 melanomas and 44 basal cell carcinomas), which were split into training and validation sets. Fifteen parameters were found to provide the best sensitivity (87.2% melanomas and 100% basal cell carcinomas) and specificity (54.5%). The results suggest that the extraction of textural information can contribute to the diagnosis of melanomas and basal cell carcinomas as a supporting tool to dermoscopy and confocal microscopy. PMID- 28662243 TI - Hyperspectral imaging acousto-optic system with spatial filtering for optical phase visualization. AB - We report a method for phase visualization in the images of transparent specimens using analog image processing in incoherent light. The experimental technique is based on adaptive bandpass spatial filtering with an amplitude mask matched with an acousto-optic tunable filter in a telecentric optical system. We demonstrate the processing of microscopic images of unstained and stained histological sections of human thyroid tumor with improved contrast. PMID- 28662244 TI - Association of Insurance and Community-Level Socioeconomic Status With Treatment and Outcome of Squamous Cell Carcinoma of the Pharynx. AB - Importance: Community-level socioeconomic status, particularly insurance status, is increasingly becoming important as a possible determinant in patient outcomes. Objective: To determine the association of insurance and community-level socioeconomic status with outcome for patients with pharyngeal squamous cell carcinoma (SCC). Design, Setting, and Participants: This study extracted data from more than 1500 Commission on Cancer-accredited facilities collected in the National Cancer Database. A total of 35 559 patients diagnosed with SCC of the pharynx from 2004 through 2013 were identified. The chi2 test, Kaplan-Meier method, and Cox regression models were used to analyze data from April 1, 2016, through April 16, 2017. Main Outcomes and Measures: Overall survival was defined as time to death from the date of diagnosis. Results: Among the 35 559 patients identified (75.6% men and 24.4% women; median age, 61 years [range, 18-90 years]), 15 146 (42.6%) had Medicare coverage; 13 061 (36.7%), private insurance; 4881 (13.7%), Medicaid coverage; and 2471 (6.9%), no insurance. Uninsured patients and Medicaid recipients were more likely to be younger, black, or Hispanic; to have lower median household income and lower educational attainment; to present with higher TNM stages of disease; and to start primary treatment at a later time from diagnosis. Those with private insurance (reference group) had significantly better overall survival than uninsured patients (hazard ratio [HR], 1.72; 95% CI, 1.59-1.87), Medicaid recipients (HR, 1.99; 95% CI, 1.88-2.12), or Medicare recipients (HR, 2.07; 95% CI, 1.99-2.16), as did those with median household income of at least $63 000 (reference) vs $48 000 to $62 999 (HR, 1.19; 95% CI, 1.13-1.26), $38 000 to $47 999 (HR, 1.31; 95% CI, 1.24-1.38), and less than $38 000 (HR, 1.51; 95% CI, 1.43-1.59). On multivariable analysis, insurance status and median household income remained independent prognostic factors for overall survival even after accounting for educational attainment, race, Charlson/Deyo comorbidity score, disease site, and TNM stage of disease. Conclusions and Relevance: Insurance status and household income level are associated with outcome in patients with SCC of the pharynx. Those without insurance and with lower household income may significantly benefit from improving access to adequate, timely medical care. Additional investigations are necessary to develop targeted interventions to optimize access to standard medical treatments, adherence to physician management recommendations, and subsequently, prognosis in these patients at risk. PMID- 28662246 TI - Factors Influencing Orthopedic Surgery Residents' Choice of Subspecialty Fellowship. AB - In the setting of increasing student debt, a rapidly changing health care system, and growing transparency in the age of outcome reporting, residents have many factors to consider when determining which fellowship to pursue. An institutional review board-approved link to an online survey was emailed to orthopedic surgery trainees across the United States. Demographics were collected, and 14 fellowship influences were assessed using a Likert scale. A total of 360 responses were received. Of the respondents, 85.5% (n=308) were male and 14.5% (n=52) were female. Responses were received from every region of the United States and from every postgraduate year. Respondents represented the gamut of relationship status and indebtedness. Respondents were interested in all of the current major subspecialties. Pursuit of an intellectually stimulating subspecialty had the highest average Likert score (3.38), followed by variety of cases (3.26). The lowest scores were for residency program with a strong tradition of placing into a particular subspecialty (2.08) and potential to conduct research in that subspecialty (2.09). Marital status, number of children, and level of debt did not significantly affect the importance of factors in selecting a fellowship. Choice of subspecialty did influence the level of importance of various factors. Intellectual stimulation and a strong mentor were the most influential factors in the decision to pursue a given fellowship. Because fellowship is now the norm, it is important to understand the motives behind young orthopedic surgeons' career aspirations. [Orthopedics. 2017; 40(5):e820-e824.]. PMID- 28662245 TI - Reduction of Rod and Cone Function in 6.5-Year-Old Children Born Extremely Preterm. AB - Importance: The function of rods and cones in children born extremely preterm has not yet been fully investigated. Objective: To compare retinal function via full field electroretinographic (ffERG) recordings in 6.5-year-old children born extremely preterm with children born at term. Design, Setting, and Participants: A subcohort study was conducted from July 1, 2010, to January 15, 2014, of the national Extremely Preterm Infants in Sweden Study, including preterm children (<27 weeks' gestational age) and children born at term, at 6.5 years of age and living in the Uppsala health care region in Sweden. Full-field electroretinography was performed binocularly, using DTL electrodes and electroretinographic (ERG) protocols with flash strengths of 0.009, 0.17, 3.0, and 12.0 candelas (cd)/s/m2, together with 30-Hz flicker and 3.0 cd/s/m2 single cone flash. Main Outcomes and Measures: The ffERG recordings were analyzed, and their associations with gestational age and retinopathy of prematurity were examined. Results: Adequate ffERG recordings were obtained from 52 preterm children (19 girls and 33 boys; mean [SD] age at examination, 6.6 [0.1] years) and 45 children born at term (22 girls and 23 boys; mean [SD] age at examination, 6.6 [0.1] years). Lower amplitudes of the combined rod and cone responses (the a wave of the dark-adapted ERG protocol of 3.0 cd/s/m2: mean difference, -48.9 MUV [95% CI, -80.0 to -17.9 MUV]; P=.003; the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2: mean difference, -55.7 MUV [95% CI, -92.5 to -18.8 MUV]; P = .004), as well as of the isolated cone response (30-Hz flicker ERG: mean difference, -12.1 MUV [95% CI, -22.5 to -1.6 MUV]; P = .03), were found in the preterm group in comparison with the group born at term. The implicit time of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2) was longer (mean difference, 1.2 milliseconds [95% CI, 0.3-2.0 milliseconds]; P = .01) in the preterm group, as were the isolated cone responses (30-Hz flicker ERG: mean difference, 1.2 milliseconds [95% CI, 0.5-1.8 milliseconds]; P < .001), than in the group born at term. No association was found between the ffERG recordings and gestational age or retinopathy of prematurity in the preterm group. Conclusions and Relevance: Both rod function and cone function were reduced in children born extremely preterm when compared with children born at term. There was no association with retinopathy of prematurity in the preterm group, which suggests that being born extremely preterm may be one of the main reasons for a general retinal dysfunction. PMID- 28662247 TI - Effectiveness of Reoperations for Adjacent Segment Disease Following Lumbar Spinal Fusion. AB - Although several options are available to address adjacent segment disease (ASD), the most effective surgical treatment has not been determined. In addition, it is important to subdivide ASD into stenosis with or without instability to determine if a decompression alone vs an extension of fusion is necessary. A systematic search of multiple medical reference databases was conducted for studies on surgical treatment of ASD. The primary outcome measures used were radiographic and clinical success rates. Meta-analysis was completed to determine effect summary values, 95% confidence intervals, and Q statistic and I2 values, using the random effects model for heterogeneity. The search yielded 662 studies, of which 657 were excluded. A total of 5 (level IV) studies with a total of 118 patients were included in this review. In 2 studies (46 patients), stenosis without instability was the indication for reoperation for ASD. However, extension of fusion was the modality of choice for the treatment of ASD in all studies. Overall clinical improvement (in back and/or leg pain scores) was noted in 71.3% of patients (95% confidence interval, 37.4-100), while radiographic fusion was noted in 89.3% of patients (95% confidence interval, 51.2-100). Following reoperation for ASD, revision surgery rates ranged from 4.5% to 23.1% at last clinical follow-up. There is variability in the clinical improvement following lumbar fusion for ASD. In addition, little literature exists regarding the optimal treatment options for patients with ASD for stenosis with or without instability. [Orthopedics. 2018; 41(2):e161-e167.]. PMID- 28662248 TI - Surgical Efficiency of Anterior Cruciate Ligament Reconstruction in Outpatient Surgical Center Versus Hospital Operating Room. AB - Anterior cruciate ligament (ACL) reconstructions are complex orthopedic procedures in which a proficient team is of vital importance. Outpatient surgical centers (OSCs) often provide orthopedic-specific teams; however, hospital operating rooms (ORs) commonly rotate staff. The purpose of this study was to compare the efficiency of pediatric ACL reconstructions between a surgical center and a hospital OR owned and directed by a single institution. Cases examined involved pediatric patients, aged 12 to 18 years (mean age, 15.9+/-1.5 years), who underwent ACL reconstructions by a single orthopedic surgeon from 2009 to 2014. Procedural efficiency was defined as shorter total OR time, less total staff, and fewer support staff changes. Total OR time was also broken into 3 distinct time periods: in-room to incision time, total procedure time, and stop time to out-of-room time. A total of 49 ACL reconstructions were performed in healthy athletes, with 28 surgeries at the OSC (mean age, 15.7+/-1.3 years) and 21 surgeries in the hospital OR (mean age, 16.1+/-1.8 years). Overall efficiency was higher at the OSC, with total OR time improved by 30 minutes on average (P=.0001) with less total staff (P=.0002). Surgical technician and nursing changes occurred 6 and 2.5 times more often in the hospital OR, respectively. Procedural efficiency was greater at the OSC. The provision of consistent and experienced orthopedicspecific teams allows for improvement in OR efficiency, cost, and value. [Orthopedics. 2017; 40(5):297-302.]. PMID- 28662249 TI - Hemophilic Arthropathy. AB - The musculoskeletal manifestations of hemophilia A and B are some of the most common presenting symptoms and continue to be challenging to practitioners. Hemophilic arthropathy, if not initially adequately treated and managed, may lead to debilitating disease and eventually require the consideration of major surgery, including total joint arthroplasty. Thorough comprehension of the pathophysiology, diagnosis, and both medical and surgical interventions is critical in establishing an appropriate treatment regimen for these patients. Furthermore, a true multidisciplinary approach involving hematology, orthopedics, and physical therapy is essential for a patient with hemophilic arthropathy. The authors present a comprehensive review of hemophilic arthropathy from an orthopedist's perspective. [Orthopedics. 2017; 40(6):e940-e946.]. PMID- 28662250 TI - Surgeons' Perspectives on Premium Implants in Total Joint Arthroplasty. AB - Declining total joint arthroplasty reimbursement and rising implant prices have led many hospitals to restrict access to newer, more expensive total joint arthroplasty implants. The authors sought to understand arthroplasty surgeons' perspectives on implants regarding innovation, product launch, costs, and cost containment strategies including surgeon gain-sharing and patient cost-sharing. Members of the International Congress for Joint Reconstruction were surveyed regarding attitudes about implant technology and costs. Descriptive and univariate analyses were performed. A total of 126 surgeons responded from all 5 regions of the United States. Although 76.9% believed new products advance technology in orthopedics, most (66.7%) supported informing patients that new implants lack long-term clinical data and restricting new implants to a small number of investigators prior to widespread market launch. The survey revealed that 66.7% would forgo gain-sharing incentives in exchange for more freedom to choose implants. Further, 76.9% believed that patients should be allowed to pay incremental costs for "premium" implants. Surgeons who believed that premium products advance orthopedic technology were more willing to forgo gain-sharing (P=.040). Surgeons with higher surgical volume (P=.007), those who believed implant companies should be allowed to charge more for new technology (P<.001), and those who supported discussing costs with patients (P=.004) were more supportive of patient cost-sharing. Most arthroplasty surgeons believe technological innovation advances the field but support discussing the "unproven" nature of new implants with patients. Many surgeons support alternative payment models permitting surgeons and patients to retain implant selection autonomy. Most respondents prioritized patient beneficence and surgeon autonomy above personal financial gain. [Orthopedics. 2017; 40(5):e825-e830.]. PMID- 28662251 TI - The Intra-articular "Wave Sign" as a Landmark for Suture Anchor Placement in Arthroscopic Remplissage. AB - In arthroscopic remplissage, surgeons may inadvertently pass sutures through the teres minor rather than the infraspinatus tendon. This misplacement of the sutures may lead to poor outcomes. The authors describe the novel use of the posterior band of the inferior glenohumeral ligament, known as the "wave sign," as a reliable intra-articular landmark for suture anchor placement to improve suture passage accuracy. Twelve cadaveric shoulders underwent arthroscopic remplissage by a fellowship-trained surgeon. During the first phase of the study, remplissage was performed on 6 specimens with standard technique. The intra articular wave sign was visualized on all specimens. Specimens were dissected to the level of the joint, and the location of each suture anchor and suture pass was noted. Using the results from the first set of specimens, the surgeon performed remplissage in the second set of 6 specimens using specific measurements from intra-articular landmarks. On dissection of the initial 6 specimens, 75% of sutures were passed through the infraspinatus and 25% were passed through the teres minor. For the remaining 6 specimens, care was taken to place 1 suture anchor at the superior edge of the wave sign and 1 suture anchor 1 cm superior to the wave sign. When suture anchors were successfully passed above the superior tip of the wave sign, the likelihood of infraspinatus tendon penetration was 17 times greater. Placement of the suture anchors at or above the superior tip of the intra-articular wave sign most reliably produced capsulotenodesis of the infraspinatus muscle. [Orthopedics. 2017; 40(5):e831 e835.]. PMID- 28662253 TI - Rethinking First-Time Pass Rates as an Academic Quality Metric. PMID- 28662252 TI - Chronic Expanding Hematoma After Metal-on-Metal Total Hip Arthroplasty. AB - A 76-year-old woman who underwent bilateral metal-on-metal total hip arthroplasty fell 3 years after this procedure and subsequently incurred continuous pain in her buttock. Plain radiographs showed no fracture and no loosening of the hip prosthesis. Magnetic resonance imaging revealed an abnormal, large, thick-walled mass with heterogeneous signal intensity at the right buttock. The prerevision diagnosis was adverse reaction to metal debris. The mass was surgically resected, and the metal femoral head was replaced by a dual-mobility prosthesis. The intraoperative and histological analyses indicated an expanding hematoma. Cobalt ion concentrations of whole blood and effusion around the hematoma-1.9 ug/L and 1.3 ug/L, respectively-were not indicative of adverse reaction to metal debris. Transcatheter arterial embolization was performed 2 days postoperatively. The hematoma was reduced and was not present after 9 months. The diagnosis of a periprosthetic soft tissue mass after metal-on-metal total hip arthroplasty should be carefully reached with magnetic resonance imaging and assessment of blood metal ion concentrations. Expanding hematoma should be considered a potential diagnosis if metal ion concentrations are not increasing and magnetic resonance imaging shows a periprosthetic mass with a heterogeneous lesion. Embolization is useful for the management of an expanding hematoma. [Orthopedics. 2017; 40(6):e1103-e1106.]. PMID- 28662254 TI - Issues Influencing Success: Comparing the Perspectives of Nurse Educators and Diverse Nursing Students. AB - BACKGROUND: Research has shown that diverse nursing students report experiencing numerous issues that affect their progression through nursing programs. At the same time, research has also shown that nurse educators find it challenging to meet the needs of these students. What is missing is an analysis of how these two perspectives intersect. METHOD: A mixed-methods parallel study compared the perceptions of diverse nursing students (n =13) and nurse educators (n = 22) regarding the learning environment in a baccalaureate nursing program. RESULTS: Important differences existed between the students' and nurse educators' perspectives on hindrances to the students' success. Nurse educators saw the biggest hindrance as language proficiency, whereas students saw it as lack of relationships with faculty and classmates. CONCLUSION: Nursing programs should encourage faculty to build relationships with diverse nursing students not only because students appreciate them, but also because such relationships play a role in helping students overcome hindrances to success. [J Nurs Educ. 2017;56(7):389 396.]. PMID- 28662255 TI - Influence of Intimate Partner Violence and Depression on Undergraduate Nursing Students: A Literature Review. AB - BACKGROUND: Intimate partner violence (IPV) and dating violence is a significant problem among college-age students. IPV has an associative outcome of depression and lower academic performance, but it is unknown how it relates to undergraduate nursing students. METHOD: Two literature searches were performed for IPV and depression from a combination of 87 databases including EBSCO, Proquest, Nursing at OVID, Medline, PubMed, CINAHL, PsycARTICLES, JSTOR, SAGE journals, and Google Scholar. RESULTS: Initial results yielded 24,675 research studies on IPV, dating violence, and depression. Forty-eight level-three studies were identified using the John Hopkins School of Nursing evidence-based practice model, including 42 nonexperimental studies, three meta-syntheses, and three governmental studies. CONCLUSION: Relevant data on the prevalence rates of IPV and depression among nursing students are lacking. IPV and dating violence among college students places them at a higher risk for failure and poor academic performance. [J Nurs Educ. 2017;56(7):397-403.]. PMID- 28662256 TI - Nursing Students' Perceived Faculty Support, Stress, and Substance Misuse. AB - BACKGROUND: Nursing school can be an extremely stressful experience. Many nurses with substance misuse issues developed the problem when they were students. The authors, guided by Peplau's interpersonal theory in nursing, examined whether stress and perceived faculty support were related to substance misuse. METHOD: A quantitative, cross-sectional, correlational design was used. Data were collected from members of the National Student Nurses Association using an Internet questionnaire. RESULTS: Students with higher stress scores had a higher incidence of substance use. Most students who had higher perceptions of faculty support tended to use fewer nonprescribed stimulants for academic enhancement. CONCLUSION: Nursing students reported a moderate level of stress and used non prescribed prescription drugs more frequently as the stress scores increased. Perceived faculty support was inversely related to the use of nonprescribed stimulants and does not appear to moderate the effects of stress on substance misuse. [J Nurs Educ. 2017;56(7):404-411.]. PMID- 28662257 TI - Assessing the Construct Congruence of the RN Comprehensive Predictor and NCLEX-RN Test Plan. AB - BACKGROUND: The 2013 NCLEX-RN(r) test plans specified an underlying general entry level nursing ability encompassing all the tested specific categories and subcategories, as indicated by a second-order factor structure. This study attempted to verify this hierarchical factor structure in real data. METHOD: Data from the RN Comprehensive Predictor(r) 2013 assessment, developed by Assessment Technologies Institute using the 2013 NCLEX-RN test plans, were used to test the entry-level nursing ability second-order factor structure by a confirmatory factor analysis technique. RESULTS: The results indicated a good fit of the proposed factor model to the RN Comprehensive Predictor 2013 assessment data. CONCLUSION: The verified second-order factor structure provides evidence for the existence of the general entry-level nursing ability, which has important theoretical implications to the development and testing of a nursing instrument or theory in nursing science research. In addition, the verified congruent factor structure provides strong evidence for the construct validity of the RN Comprehensive Predictor 2013 assessment. [J Nurs Educ. 2017;56(7):412-419.]. PMID- 28662258 TI - Collaborative Baccalaureate Programs: Preliminary Data on Canadian Undergraduate Nursing Students' Satisfaction. AB - BACKGROUND: Ten years ago, nursing education in Ontario, Canada, changed when entry to practice and licensure became a bachelor's of science in nursing (BScN) for RNs. This article presents the initial results of an ongoing 5-year longitudinal study on undergraduate students' satisfaction within a collaborative BScN program and predictors of satisfaction with their nursing education. METHOD: BScN nursing students from one group of collaborative sites participated in a survey pertaining to satisfaction with their program. Data were collected via paper and pen or online. RESULTS: Initial data found that students were satisfied or strongly satisfied with their collaborative nursing education (M +/- SD = 183.9 +/- 32.7). However, any type of conflict had a significant negative relationship with satisfaction in all domains. No other significant predictors of satisfaction were uncovered. CONCLUSION: Overall, students were very satisfied with a collaborative model of baccalaureate nursing education. Conflict of any type decreases satisfaction within all domains of nursing education. [J Nurs Educ. 2017;56(7):420-424.]. PMID- 28662259 TI - Team-Based Learning in a Community Health Nursing Course: Improving Academic Outcomes. AB - BACKGROUND: Population health concepts, such as upstream thinking, present challenging ideas to undergraduate nursing students grounded in an acute care orientation. The purpose of this study was to describe how team-based learning (TBL) influenced academic outcomes in a community health nursing course. METHOD: A descriptive correlational design examined the relationship among student scores on individual readiness assurance tests (iRATs), team readiness assurance tests (tRATs), and the final examination. The sample included 221 nursing students who had completed the course. RESULTS: A large positive correlation was found between iRAT and final examination scores. For all students, the mean tRAT score was higher than the mean iRAT score. A moderate positive correlation existed between tRAT and final examination scores. CONCLUSION: The study contributes to understanding the effects of TBL pedagogy on student academic outcomes in nursing education. TBL is a valuable teaching method in a course requiring the application of challenging concepts. [J Nurs Educ. 2017;56(7):425-429.]. PMID- 28662261 TI - Assessing Student Perceptions of Quality and Safety Education for Nurses Competencies in a Baccalaureate Curriculum. AB - BACKGROUND: Nursing programs must ensure that graduate competencies in quality and patient safety are sufficient to meet practice needs. Student perceptions of the extent to which they acquired the knowledge, skills, and attitudes, as well as the importance and levels of preparedness associated with the Quality and Safety Education for Nurses (QSEN) competencies, were measured. METHOD: Using a descriptive cross-sectional design, a convenience sample of 73 nursing students was surveyed using the QSEN Student Evaluation Survey tool. RESULTS: Students perceived being the least knowledgeable about, and least prepared to, engage in quality improvement (QI) activities. This competency was perceived as being the least important. Students reported they were somewhat prepared to perform all other skills related to QSEN competencies. CONCLUSION: Redesign of curricula emphasizing QI competencies is needed. A gap analysis identifying where in the curricula QI teaching is conducted and where it can be added may help ensure that students enter the workforce prepared to provide safe, quality care. [J Nurs Educ. 2017;56(7):435-438.]. PMID- 28662260 TI - Meditation's Effect on Attentional Efficiency, Stress, and Mindfulness Characteristics of Nursing Students. AB - BACKGROUND: Strengthening attention-regulation efficiency of nurse graduates is important to the quality and safety of nursing practice in increasingly complex and cognitively distracting workplaces. Neuroscientific evidence suggests that regular practice of focused meditation can enhance attentional skills. This study explored meditation as an educational strategy for enhancing nursing students' attentional efficiency. METHOD: A randomized-control trial with 52 prelicensure nursing students examined differences between those who meditated and those who did not on measurements of alerting, orienting, and executive attention. Stress and mindfulness were also explored. RESULTS: Meditation demonstrated moderate strength for enhancing executive attention, F = 4.26 (1, 49), n2 = .080, p = .044. Additional outcomes specific to the meditation group were reduced stress and increased mindfulness, F = 7.16 (2, 47), n2 = .234, p = .002. CONCLUSION: Results support the consideration of meditation training as a strategy for enhancing nursing students' attentional efficiency and other self-regulatory skills necessary for safe nursing practice. [J Nurs Educ. 2017;56(7):430-434.]. PMID- 28662262 TI - Integrating Spiritual Bereavement Skills Into an Advanced Practice Curriculum. AB - BACKGROUND: When advanced practice nurses (APNs) encounter the need to address a bereaved individual's spirituality, gaps in educational preparation may prevent effective intervention. In addition, past and current research studies have not provided clear guidance for spiritually based bereavement care curricula within the graduate APN program. METHOD: Graduate advanced practice faculty successfully introduced classroom-based spiritual bereavement care education modules for APN students. RESULTS: Course evaluations indicated student appreciation for the new content and practicum experiences provided. Students felt the new content to be essential in their development as expert practitioners. CONCLUSION: Through this innovation, the authors found that a variety of learning activities that addressed spiritual needs during the bereavement process was perceived as highly satisfactory by APNs. Within an ever increasingly diverse society, APNs have a significant role in performing responsibilities for bereaved individuals. [J Nurs Educ. 2017;56(7):439-442.]. PMID- 28662264 TI - Teach 100: Teaching Aggregate Education in Public Health Curriculum. PMID- 28662263 TI - The Evolution of a Writing Program. AB - BACKGROUND: Scholarly writing is required in nursing, and some students are unable to communicate effectively through writing. Faculty members may struggle with the grading of written assignments. A writing team, consisting of a nursing faculty member, the school of nursing library liaison, and members from academic support services, implemented strategies including workshops, handouts, and use of exemplars to improve student writing and to provide support to faculty. Few students sought help from the writing team. METHOD: An online writing center within the existing learning management system was developed to address nursing students' and faculty's scholarly writing needs. The writing center includes guides, tutorials, and exemplars. RESULTS: Anecdotal evidence indicates the use of the writing center during afternoons and evenings and prior to due dates of written assignments. CONCLUSION: Online writing resources were used more frequently than face-to-face support. Further research is needed to evaluate the effectiveness of the program. [J Nurs Educ. 2017;56(7):443-445.]. PMID- 28662265 TI - Pseudo-Twitter Format: Health Literacy Learning Activity. PMID- 28662266 TI - Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Regorafenib, a multikinase inhibitor, has demonstrated prolonged survival by 2.8 months as a second-line agent in patients with hepatocellular carcinoma (HCC) who progress on sorafenib therapy. The objective of the current study was to examine the cost effectiveness of regorafenib for the treatment of HCC. METHODS: The authors constructed a Markov simulation model of patients with unresectable HCC and Child-Pugh A cirrhosis who received treatment with regorafenib versus best supportive care. Model inputs for regorafenib effectiveness and rates of adverse events in patients with HCC were based on published clinical trial data and literature review. Quality-adjusted life years (QALYs) were calculated along with the incremental cost-effectiveness ratio (ICER) of regorafenib therapy. One-way sensitivity analyses also were conducted simultaneously on all model parameters and on various Monte-Carlo simulation parameters, and the regorafenib cost threshold at which cost effectiveness would be achieved was determined. RESULTS: Regorafenib provided an increase of 0.18 QALYs at a cost of $47,112. The ICER for regorafenib, compared with best supportive care, was $224,362. In 1-way sensitivity analyses, there were no scenarios in which regorafenib was cost effective. In cost threshold analysis, regorafenib would have to be priced at or below $67 per pill to be cost effective at an ICER of $100,000. CONCLUSIONS: Regorafenib is not cost effective as a second-line agent in the treatment of HCC, with a marginal increase in QALYs at a high cost. Lowering the cost of regorafenib or improving the selection of patients who can achieve maximal survival benefit would improve its value as a second-line treatment option for patients with HCC. Cancer 2017;123:3725-3731. (c) 2017 American Cancer Society. PMID- 28662267 TI - Impact of extending screening mammography to older women: Information to support informed choices. AB - From 2013 through 2017, the Australian national breast cancer screening programme is gradually inviting women aged 70-74 years to attend screening, following a policy decision to extend invitations to older women. We estimate the benefits and harms of the new package of biennial screening from age 50-74 compared with the previous programme of screening from age 50-69. Using a Markov model, we applied estimates of the relative risk reduction for breast cancer mortality and the risk of overdiagnosis from the Independent UK Panel on Breast Cancer Screening review to Australian breast cancer incidence and mortality data. We estimated screening specific outcomes (recalls for further imaging, biopsies, false positives, and interval cancer rates) from data published by BreastScreen Australia. When compared with stopping at age 69, screening 1,000 women to age 74 is likely to avert one more breast cancer death, with an additional 78 women receiving a false positive result and another 28 women diagnosed with breast cancer, of whom eight will be overdiagnosed and overtreated. The extra 5 years of screening results in approximately 7 more overdiagnosed cancers to avert one more breast cancer death. Thus extending screening mammography in Australia to older women results in a less favourable harm to benefit ratio than stopping at age 69. Supporting informed decision making for this age group should be a public health priority. PMID- 28662268 TI - Pembrolizumab as first-line therapy in programmed death ligand 1-positive advanced lung cancer: Is it as effective as we think it is? PMID- 28662269 TI - At least, do no harm. PMID- 28662270 TI - The Case of Abel: Religion as Boon and Bane for a Catholic Gay Man. AB - Conservative religions that condemn homosexual sexual orientation and acts as unnatural and sinful pose significant challenges for gay persons whose faith is a core part of their identity. The condemnation presents a serious barrier to the acceptance and integration of their sexuality, a primary task of psychosexual development. As a result, they can manifest depression, anxiety, suicidal ideation, and even suicide attempts. The ecclesiastical censure also imposes an untenable dilemma for homosexuals in that they feel pressed to reject their sexual identity or renounce their spiritual identity and heritage. Psychotherapists who treat gay persons caught in this quandary can find themselves facing a similar problem: how to help their homosexual client reconcile their proscribed sexuality with their spiritual commitments. The case presented here recounts the treatment over many years of a gay man suffering from such a conflict and his eventual accommodation of both his homosexuality and his faith. Recommendations are offered for constructive treatment with those torn between two conflicting core identities. PMID- 28662271 TI - Introduction: Science, Sexuality, and Psychotherapy: Shifting Paradigms. AB - This introduction presents an overview of the current issue (73, 8) of Journal of Clinical Psychology: In Session. This issue features a series of articles, with clinical cases, each presented to illustrate the challenges faced by individuals and couples whose sexual and gender identities and expressions do not comport with traditional and cultural norms. These articles also document the challenges to the therapists who treat them. Considered individually, each article underscores the need to recognize the importance of evidence in guiding psychotherapy in cases involving sexuality. The discussions in each article offer recommendations meant to help and guide psychotherapists. Considered collectively, they raise important questions and considerations about shifting paradigms of human sexuality. Implications for assessment and treatment of cases involving sexuality and gender identity are discussed and recommended. PMID- 28662272 TI - Campylobacter fetus impairs barrier function in HT-29/B6 cells through focal tight junction alterations and leaks. AB - Infections by Campylobacter species are the most common foodborne zoonotic disease worldwide. Campylobacter jejuni and C. coli are isolated most frequently from human stool samples, but severe infections by C. fetus (Cf), which can cause gastroenteritis, septicemia, and abortion, are also found. This study aims at the characterization of pathological changes in Cf infection using an intestinal epithelial cell model. The Cf-induced epithelial barrier defects appeared earlier than those of avian Campylobacter species like C. jejuni/C. coli. Two-path impedance spectroscopy (2PI) distinguished transcellular and paracellular resistance contributions to the overall epithelial barrier impairment. Both transcellular and paracellular resistance of Cf-infected HT-29/B6 monolayers were reduced. The latter was attributed to activation of active anion secretion. Western blot analysis showed no decrease in tight junction (TJ) protein expression (claudin-1, -2, -3, and -4) but showed redistribution of claudin-1 off the TJ domain. In addition, Cf induced epithelial cell death, cell detachment, and lesions (focal leaks), as the result of which macromolecule flux (10-kDa dextran) was increased in Cf-invaded cell monolayers. In conclusion, barrier dysfunction from Cf infection was due to TJ protein redistribution, cell death induction, and leak formation, resulting in bacterial translocation, ion leak flux, and antigen uptake (leaky gut). PMID- 28662273 TI - Sex-Positive Assessment and Treatment Among Female Trauma Survivors. AB - Sexuality and intimacy difficulties are often a part of the aftermath of sexual trauma. We argue that combining techniques from evidence-based, trauma-focused treatment with sex-positive techniques used in sex therapy can best help survivors reduce trauma-related symptoms and develop or regain comfort with their sexuality. In this article, we illustrate this approach by describing the case of a survivor of sexual assault, who completed 20 sessions of treatment that combined modules of trauma-focused therapies, Cognitive Processing Therapy (CPT), and Prolonged Exposure (PE) with sensate focus therapy, a technique often used in sex therapy. The outcome of this case suggests that clinicians who work with sexual trauma survivors may want to consider a sex-positive approach to conceptualizing and planning the course of treatment, to achieve optimal results. PMID- 28662275 TI - Childhood cancer chemotherapy-induced bone damage: pathobiology and protective effects of resveratrol and other nutraceuticals. AB - Intensive cancer chemotherapy causes significant bone loss, for which the mechanisms remain unclear and effective treatments are lacking. This is a significant issue particularly for childhood cancers, as the most common ones have a >75% cure rate following chemotherapy; there is an increasing population of survivors who live with chronic bone defects. Studies suggest that these defects are the result of reduced bone from increased marrow fat formation and increased bone resorption following chemotherapy. These changes probably result from altered expression/activation of regulatory molecules or pathways regulating skeletal cell formation and activity. Treatment with methotrexate, an antimetabolite commonly used in childhood oncology, has been shown to increase levels of proinflammatory/pro-osteoclastogenic cytokines (e.g., enhanced NF kappaB activation), leading to increased osteoclast formation and bone resorption, as well as to attenuate Wnt signaling, leading to both decreased bone and increased marrow fat formation. In recent years, understanding the mechanisms of action and potential health benefits of selected nutraceuticals, including resveratrol, genistein, icariin, and inflammatory fatty acids, has led to preclinical studies that, in some cases, indicate efficacy in reducing chemotherapy-induced bone defects. We summarize the supporting evidence. PMID- 28662276 TI - Nerve ultrasound shows subclinical peripheral nerve involvement in neurofibromatosis type 2. AB - INTRODUCTION: Neurofibromatosis type 2 (NF2) is mainly associated with central nervous system (CNS) tumors. Peripheral nerve involvement is described in symptomatic patients, but evidence of subclinical peripheral nerve involvement is scarce. METHODS: We conducted a cross-sectional pilot study in 2 asymptomatic and 3 minimally symptomatic patients with NF2 to detect subclinical peripheral nerve involvement. Patients underwent clinical examination, nerve conduction studies (NCS), and high-resolution ultrasonography (HRUS). RESULTS: A total of 30 schwannomas were found, divided over 20 nerve segments (33.9% of all investigated nerve segments). All patients had at least 1 schwannoma. Schwannomas were identified with HRUS in 37% of clinically unaffected nerve segments and 50% of nerve segments with normal NCS findings. DISCUSSION: HRUS shows frequent subclinical peripheral nerve involvement in NF2. Clinicians should consider peripheral nerve involvement as a cause of weakness and sensory loss in the extremities in patients with this disease. Muscle Nerve 57: 312-316, 2018. PMID- 28662274 TI - Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. AB - BACKGROUND: Patients with recurrent and/or metastatic, radioactive iodine refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results. METHODS: In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. RESULTS: The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. CONCLUSIONS: Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. (c) 2017 American Cancer Society. PMID- 28662278 TI - Topical brimonidine gel for extended-duration local anaesthesia. PMID- 28662277 TI - Thyroid neoplasia risk is increased nearly 30 years after the Chernobyl accident. AB - To evaluate risk of thyroid neoplasia nearly 30 years following exposure to radioactive iodine (I-131) from the 1986 Chernobyl nuclear accident, we conducted a fifth cycle of thyroid screening of the Ukrainian-American cohort during 2012 2015, following four previous screening cycles started in 1998. We identified 47 thyroid cancers (TC) and 33 follicular adenomas (FA) among 10,073 individuals who were <18 years at the time of the accident and had a mean I-131 dose of 0.62 Gy. We found a significant I-131 dose response for both TC and FA, with an excess odd ratio per Gy of 1.36 (95% CI: 0.39-4.15) and 2.03 (95% CI: 0.55-6.69), respectively. The excess risk of malignant and benign thyroid neoplasia persists nearly three decades after exposure and underscores the importance of continued follow-up of this cohort to characterize long-term pattern of I-131 risk. PMID- 28662279 TI - Impact of early conversion from cyclosporin to everolimus on left ventricular mass index: A randomized controlled trial. AB - This is an 18-month prospective, randomized controlled trial (RCT) designed to compare the effect of early conversion from cyclosporin to everolimus/mycophenolic acid (E-MPA) between 3 and 4 months post-transplant to cyclosporin/mycophenolic acid (CsA-MPA) on left ventricular mass index (LVMI) at 3 and 18 months post-transplant (primary outcome). Secondary outcomes included estimated glomerular filtration rate (eGFR), viral infection, and adverse events. Twenty-four patients were randomized in a 1:1 ratio to E-MPA or CsA-MPA groups. There were no significant differences in mean (SD) LVMI at 3 (51.6+/-18.5 vs 53.7+/-15.7 g/m2.7 ) and 18 months (52.7+/-16.3 vs 51.7+/-16.8 g/m2.7 ) between CsA-MPA and E-MPA groups. The incidence of viral infections was reduced in E-MPA compared to CsA-MPA treatment groups (8% vs 50%, P=.02), but the incidences of acute rejection, adverse events, and drug discontinuation were similar between groups. There was an overall increase in eGFR with time (0.04 log- mL/min/1.73 m2 per 6 months, P=.012) but no significant difference between the two groups across time (0.11 log- mL/min/1.73 m2 , P=.311). Immunosuppressive regimen comprising early conversion from cyclosporine to everolimus was not associated with a regression of LVMI, but a lower risk of viral infections was observed. PMID- 28662280 TI - A Direct Synthesis of Highly Substituted pi-Rich Aromatic Heterocycles from Oxetanes. AB - The ubiquitous use of pi-rich five-membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis-acid-catalyzed oxetane rearrangement. Notably, this methodology employs a keto-oxetane motif as a 1,4 dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4-dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo-fused versions thereof. PMID- 28662281 TI - Using Press Ganey Provider Feedback to Improve Patient Satisfaction: A Pilot Randomized Controlled Trial. AB - OBJECTIVE: The objective was to conduct a pilot randomized controlled trial to assess the feasibility, logistics, and potential effect of monthly provider funnel plot feedback reports from Press Ganey data and semiannual face-to-face coaching sessions to improve patient satisfaction scores. METHODS: This was a pilot randomized controlled trial of 25 emergency medicine faculty providers in one urban academic emergency department. We enrolled full-time clinical faculty with at least 12 months of baseline Press Ganey data, who anticipated working in the ED for at least 12 additional months. Providers were randomized into intervention or control groups in a 1:1 ratio. The intervention group had an initial 20-minute meeting to introduce the funnel plot feedback tool and standardized feedback based on their baseline Press Ganey scores and then received a monthly e-mail with their individualized funnel plot depicting cumulative Press Ganey scores (compared to their baseline score and the mean score of all providers) for 12 months. The primary outcome was the difference in Press Ganey "doctor-overall" scores between treatment groups at 12 months. We used a weighted analysis of covariance model to analyze the study groups, accounting for variation in the number of surveys by provider and baseline scores. RESULTS: Of 36 eligible faculty, we enrolled 25 providers, 13 of whom were randomized to the intervention group and 12 to the control group. During the study period, there were 815 Press Ganey surveys returned, ranging from four to 71 surveys per provider. For the standardized overall doctor score over 12 months (primary outcome), there was no difference between the intervention and control groups (difference = 1.3 points, 95% confidence interval = -2.4 to 5.9, p = 0.47). Similarly, there was no difference between groups when evaluating the four categories of doctor-specific patient satisfaction scores from the Press Ganey survey (all p > 0.05). CONCLUSIONS: In this pilot trial of monthly provider funnel plot Press Ganey feedback reports, there was no difference in patient satisfaction scores between the intervention and control groups after 12 months. While this study was not powered to detect outcome differences, we demonstrate the feasibility, logistics, and effect sizes that could be used to inform future definitive trials. PMID- 28662282 TI - The association between the clinical diversity of psoriasis and depressive symptoms: the HUNT Study, Norway. AB - BACKGROUND: While a number of observational hospital-based studies have reported an association between psoriasis and depression, less is known about the clinical diversity of psoriasis and depressive symptoms. OBJECTIVE: To investigate the associations of inverse psoriasis, psoriasis severity and psoriasis duration with depressive symptoms in a general population. METHODS: We linked data from the population-based third Nord-Trondelag Health Study (HUNT3) to the Norwegian Prescription Database (NorPD) and Statistics Norway. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Associations between psoriasis and depressive symptoms (HADS >= 8) were estimated using logistic regression. RESULTS: Among 37 833 participants in HUNT3, we found a weak association between any psoriasis and the prevalence of depressive symptoms [fully adjusted odds ratio (OR) 1.12, 95% confidence interval (CI) 0.97-1.28]. The association with depressive symptoms was stronger when psoriasis was characterized by inverse anatomical distribution (OR 1.32, 95% CI 1.02-1.70), requirement of systemic psoriasis medication (OR 1.47, 95% CI 1.00-2.17) or long disease duration (OR 1.33, 95% CI 1.09-1.64). Conversely, when there was no inverse psoriasis distribution, no requirement of systemic medication, or shorter disease duration, psoriasis was not meaningfully associated with depressive symptoms. CONCLUSION: Overall, depressive symptoms do not seem to be a major concern among subjects with psoriasis in a general Norwegian population. However, among subjects with inverse anatomical distribution, requirement of systemic psoriasis medication or long disease duration, depressive symptoms may be particularly important to address when evaluating the burden of psoriasis. PMID- 28662283 TI - Treatment of a patient with HIV and metastatic melanoma with consequitive ipilimumab and nivolumab. PMID- 28662284 TI - Estimate of vertical transmission of Hepatitis C virus in Pakistan in 2007 and 2012 birth cohorts. AB - : Despite a combination of high Hepatitis C virus (HCV) prevalence, a large adult population and high fertility, no published estimates of the scale and contribution of vertical transmission to HCV incidence in Pakistan exist. The objective of this study was to estimate the number of new HCV infections occurring in Pakistan as a result of vertical transmission. We adapted a published mathematical model based on HCV antibody and viraemia prevalence, fertility rates, risk of HCV vertical transmission and children mortality rates to estimate the number of infections in the 2007 and 2012 birth cohorts nationally and in four subnational regions. We estimated that 19 708 (95% uncertainty interval [UI]: 15 941-23 819) children were vertically infected by HCV in 2007 and 21 676 (95% UI: 17 498-26 126) in 2012. The majority of these cases (72.9% and 72.5% in 2007 and 2012, respectively) occurred in Punjab. We estimated that vertical transmission as a mode of exposure accounted for a quarter of HCV infections among children under 5 years of age (25.2% in 2007 and 24.0% in 2012). CONCLUSION: Our results showed that one in 260 children born in Pakistan in 2007 and 2012 acquired HCV vertically. While currently no interventions during pregnancy and childbirth are recommended to reduce this risk, prevention, testing and treatment strategies should be considered to reduce the burden of vertical HCV infections among young children. Other routes of transmission appear to contribute the majority of HCV infections among children and must also be clarified and urgently addressed. PMID- 28662286 TI - Various Current Responses of Single Silver Nanoparticle Collisions on a Gold Ultramicroelectrode Depending on the Collision Conditions. AB - Collisions of silver nanoparticles (NPs) with a more electrocatalytic gold or platinum ultramicroelectrode (UME) surface have been observed by using an electrochemical method. Depending on the applied potential to the UME, the current response to the collision of Ag NPs on the UME resulted in various shape changes. A staircase decrease, a blip decrease, and a blip increase of the hydrazine oxidation current were obtained at an applied potential of 0.33, 0.80, and 1.3 V, respectively. Different collision behaviors of Ag NPs on the UME surface were suggested for each shape of current response. Ag NP attachment, which hindered the diffusion flux to the UME, caused a staircase decrease of the electrocatalytic current. Instantaneous blocking of the hydrazine oxidation by Ag NP collision and, following recovery of the current by means of oxidation of Ag NP, caused a blip decrease of the electrocatalytic current. The formation of a higher oxidation state of Ag on the Ag NP and its electrocatalytic hydrazine oxidation resulted in a blip increase of the electrocatalytic current. The analysis of the current response of a single NP collision experiment can be a useful tool to understand the various behaviors of NPs on the electrode surface. PMID- 28662285 TI - Genetic predisposition for chronic venous insufficiency in several genes for matrix metalloproteinases (MMP-2, MMP-9, MMP-12) and their inhibitor TIMP-2. AB - OBJECTIVE: The project was scheduled as a case-control study to investigate the correlation between MMP-2 (rs243864), MMP-9 (3918242), MMP-12 (rs7123600) and TIMP-2 (rs8176329) polymorphisms and chronic venous disease (CVD) risk. The genotype and phenotype research envisages the testing of possible associations between MMP and TIMP-2 genotypes and phenotypes of CVD. MATERIAL AND METHODS: 150 patients with CVD and 227 controls were enrolled into the study. The MMPs and TIMP-2 genotypes were identified by the PCR method and restriction analysis according to standard protocols. RESULTS: The G allele of MMP-2 -790 T/G was 1.85 times more frequent in men with CVD than in the control group (P = 0.008). The T allele of MMP-9 -1562 C/T was observed 2.571 times more frequently in patients with CVD than in the control individuals (both in men and women) with clinically significant specificity (P = 0.0000009). The G allele of MMP-12 rs7123600 was determined 2.082 times more frequently in female patients with CVD than in the control group with clinically significant specificity (P = 0.02). No significant result in TIMP-2 rs8176329 polymorphism in the case-control study was observed. CVD women with G allele in MMP-2 -790 T/G in the genotype-phenotype study are seen to develop ulceration 2.539 times more frequently (P = 0.003). The G allele of MMP-12 rs7123600 was detected 3.167 times more frequently in CVD women with ulceration compared with CVD women without ulceration (P = 0.007). In CVD men in C6 stage, the incidence of AG genotype in rs7123600 MMP-12 polymorphism was found to be 4.675 times higher compared to CVD women with C6 staging (P = 0.005). The AG genotype in TIMP 2 rs8176329 polymorphism was found to be associated with higher risk of tumour (P = 0.01). CONCLUSION: Studying these polymorphisms can contribute to better identification of patients at higher risk of developing CVD, while providing the most appropriate prevention and treatment strategies for limiting the progression and complications of CVD. PMID- 28662287 TI - Weight management: A concept analysis. AB - AIM: There is a need to develop sound healthcare practices where patients and providers are able to succeed in meeting weight management goals. The aim of this analysis is to develop a better understanding the concept of weight management. BACKGROUND: Obesity is a rapidly growing healthcare issue, reaching epidemic levels around the world. According to the World Health Organization, the current incident rate of obesity makes it the leading risk for death across the globe. DESIGN: Walker and Avant's model for concept analysis. DATA SOURCE: A literature search was accomplished using Cumulative Index to Nursing and Allied Health, Health Source: Nursing Academic Edition, Medline, and ProQuest Health and Medical Complete. REVIEW METHODS: Keywords included weight management, weight control, weight loss, obesity, weight, and management. RESULTS: Weight management is complex concept. Strategies to develop successful weight management programs need to be multifaceted to have impact on this healthcare crisis. CONCLUSION: The critical attributes for weight management are dietary measures, physical activity, behavior modification, motivation, education, and lifelong changes. Unsuccessful weight management results in metabolic disorders and increased risk of mortality. Successful weight management practices include the prevention of weight gain, weight loss, and maintenance of ideal body weight. PMID- 28662288 TI - Deep Eutectic Solvents as Reaction Media for the Palladium-Catalysed C-S Bond Formation: Scope and Mechanistic Studies. AB - A unique jigsaw catalytic system based on deep eutectic solvents and palladium nanoparticles where C-S bonds are formed from aryl boronic acids and sodium metabisulfite, is introduced. The functionalization step is compatible with a broad spectrum of reagents such as nucleophiles, electrophiles or radical scavengers. This versatile approach allows the formation of different types of products in an environmentally friendly medium by selecting the components of the reaction, which engage one with another as pieces in a jigsaw. This simple procedure avoids the use of toxic volatile organic solvents allowing the formation of complex molecules in a one-pot reaction under mild conditions. Despite the fact that only 1 mol % of metal loading is used, the recyclability of the catalytic system is possible. Kinetic experiments were performed and the reaction order for all reagents, catalyst and ligand was determined. The obtained results were compared to palladium nanocrystals of different known shapes in order to shed some light on the properties of the catalyst. PMID- 28662289 TI - Genome-wide association analysis identifies a GLUL haplotype for familial hepatitis B virus-related hepatocellular carcinoma. AB - BACKGROUND: A family history of liver cancer increases the risk of developing hepatocellular carcinoma (HCC) by 2-fold to 10-fold among patients with chronic hepatitis B virus (HBV). Previous genome-wide association studies have identified many possible susceptible loci associated with sporadic HBV-related HCC. However, despite family history being a well-known risk factor for HBV-related HCC, to the authors' knowledge its genetic mechanisms and associating loci remain largely unknown or unexplored, most likely due to the relative rarity of familial HCC and the difficulty of sample collection. METHODS: The authors conducted a genome-wide association study with 139 male cases with familial HBV-related HCC and 139 non HCC male controls with chronic HBV. The results were corroborated further with an independent cohort of 101 patients with familial HBV-related HCC and comparison with both the 1000 Genomes Project and the Taiwan Biobank. RESULTS: A total of 51 risk single-nucleotide polymorphisms (P<=1E-04) were identified in the association analyses, which included 2 clusters of associated single-nucleotide polymorphisms and haplotypes at 1q25.3 (glutamate-ammonia ligase [GLUL]/transmembrane epididymal protein 1 [TEDDM1]/long intergenic non-protein coding RNA 272 [LINC00272]/regulator of G-protein signaling-like 1 [RGSL1]) and 17q11.2 (solute carrier family 13 member 2 [SLC13A2]/forkhead box N1 [FOXN1]). Both the GLUL and SLC13A2/FOXN1 haplotypes have large effect sizes and were found to be different from those found from genome-wide association studies of sporadic HCCs. CONCLUSIONS: To the authors' knowledge, the current study is the first genome-wide association study to identify genetic factors for familial HBV related HCC. The results identified 2 large effect susceptible haplotypes located at GLUL and SLC13A2/FOXN1. The current study findings also suggest different genetic susceptibility between familial and sporadic HBV-related HCC. Cancer 2017;123:3966-76. (c) 2017 American Cancer Society. PMID- 28662290 TI - Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer. AB - Growing evidence indicates that deregulation of the epigenetic machinery comprising the microRNA (miRNA) network is a critical factor in the progression of various diseases, including cancer. Concurrently, dietary phytochemicals are being intensively studied for their miRNA-mediated health-beneficial properties, such as anti-inflammatory, cardioprotective, antioxidative, and anticancer properties. Available experimental data have suggested that dietary polyphenols may be effective miRNA-modulating chemopreventive and therapeutic agents. Moreover, noninvasive detection of changes in miRNA expression in liquid biopsies opens enormous possibilities for their clinical utilization as novel prognostic and predictive biomarkers. In our published studies, we identified resveratrol regulated miRNA profiles in prostate cancer. Resveratrol downregulated the phosphatase and tensin homolog (PTEN)-targeting members of the oncogenic miR-17 family of miRNAs, which are overexpressed in prostate cancer. We have functionally validated the miRNA-mediated ability of resveratrol and its potent analog pterostilbene to rescue the tumor suppressor activity of PTEN in vitro and in vivo. Taken together, our findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development. PMID- 28662291 TI - Validation of the 2015 prostate cancer grade groups for predicting long-term oncologic outcomes in a shared equal-access health system. AB - BACKGROUND: A 5-tier prognostic grade group (GG) system was enacted to simplify the risk stratification of patients with prostate cancer in which Gleason scores of <=6, 3 + 4, 4 + 3, 8, and 9 or 10 are considered GG 1 through 5, respectively. The authors investigated the utility of biopsy GG for predicting long-term oncologic outcomes after radical prostatectomy in an equal-access health system. METHODS: Men who underwent prostatectomy at 1 of 6 Veterans Affairs hospitals in the Shared Equal Access Regional Cancer Hospital database between 2005 and 2015 were reviewed. The prognostic ability of biopsy GG was examined using Cox models. Interactions between GG and race also were tested. RESULTS: In total, 2509 men were identified who had data available on biopsy Gleason scores, covariates, and follow-up. The cohort included men with GG 1 (909 patients; 36.2%), GG 2 (813 patients; 32.4%), GG 3 (398 patients; 15.9%), GG 4 (279 patients; 11.1%), and GG 5 (110 patients; 4.4%) prostate cancer. The cohort included 1002 African American men (41%). The median follow-up was 60 months (interquartile range, 33-90 months). Higher GG was associated with higher clinical stage, older age, more recent surgery, and surgical center (P < .001) as well as increased biochemical recurrence, secondary therapy, castration-resistant prostate cancer, metastases, and prostate cancer-specific mortality (all P < .001). There were no significant interactions with race in predicting measured outcomes. CONCLUSIONS: The 5-tier GG system predicted multiple long-term endpoints after radical prostatectomy in an equal-access health system. The predictive value was consistent across races. Cancer 2017;123:4122-4129. (c) 2017 American Cancer Society. PMID- 28662292 TI - Benign and malignant tumors in the UK myotonic dystrophy patient registry. AB - INTRODUCTION: In light of recent evidence indicating that cancer is part of the myotonic dystrophy (DM) phenotype, we assessed the prevalence of benign and malignant tumors among 220 patients enrolled in the UK Myotonic Dystrophy Patient Registry and evaluated factors associated with their development. METHODS: A survey was distributed to collect tumor history and lifestyle information. We used multinomial logistic regression for the analysis. RESULTS: Thirty-nine benign (30 patients), and 16 malignant (15 patients) tumors were reported. Increasing age (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.05-1.21, P = 0.001) and earlier age at DM diagnosis (OR = 1.06, 95% CI = 1.00-1.13, P = 0.04) were associated with benign and malignant tumors (OR = 1.20, 95% CI = 1.10 1.30, P < 0.001 and OR = 1.08, 95% CI = 1.01-1.15, P = 0.02, respectively). Female gender was associated with benign tumors only (OR = 6.43, 95% CI = 1.79 23.04, P = 0.004). No associations were observed between tumors and smoking (P = 0.24), alcohol consumption (P = 0.50), or body mass index (P = 0.21). DISCUSSION: Our results confirm previous findings suggesting a limited role for common lifestyle factors and a potential genetic contribution in DM tumor predisposition. Muscle Nerve 57: 316-320, 2018. PMID- 28662293 TI - Retrospective evaluation of the efficacy and safety of belatacept with thymoglobulin induction and maintenance everolimus: A single-center clinical experience. AB - Belatacept use has been constrained by higher rates of acute rejection. We hypothesized that belatacept with low-dose rATG and initial mycophenolate maintenance with conversion to everolimus at 1 month post-transplant +/- corticosteroids would improve efficacy and maintain safety. Retrospective single center analysis of the first 44 low immunologic risk kidney transplant recipients treated with this regimen. The cohort was 59% male, mean age at transplant of 57 years. Diabetes was the most common cause of ESRD (39%). The mean 1-year eGFR was 61.4 (SD 18.4) mL/min/1.73 m2 . There were five acute cellular rejections (11.4%) that occurred in patients who had changed from everolimus to mycophenolate mofetil due to side effects. Thirty-two percent developed BK viremia and 12% developed CMV viremia. There were no cases of PTLD. A novel belatacept regimen with rATG induction and maintenance everolimus demonstrated a low acute rejection rate and maintained an excellent 1-year eGFR. PMID- 28662294 TI - Reliability of sonographic muscle thickness measurements of the thenar and hypothenar muscles. AB - : Introduction This study was undertaken to assess the intra- and interrater reliability of sonographic thickness measurements of the thenar and hypothenar muscles. METHODS: The thickness of the thenar and hypothenar muscles of both hands of 15 volunteers (7 male, 8 female) were evaluated with a 4-13-MHz linear probe by 2 examiners who were blinded to each other's measurements. Interrater reliability was then evaluated. To assess intrarater reliability, the first examiner also performed a second measurement after an interval of at least 1 day. RESULTS: Mean age of the subjects was 31.1 +/- 9.0 years. Test-retest reliability showed excellent intrarater reliability (intraclass correlation coefficient range: 0.889-0.963) and substantial to excellent results for interrater reliability (intraclass correlation coefficient range: 0.692-0.937). DISCUSSION: We found that ultrasound is a reliable method for thickness measurements of the thenar and hypothenar muscles. Muscle Nerve 57: E14-E17, 2018. PMID- 28662295 TI - alpha9-containing nicotinic acetylcholine receptors and the modulation of pain. AB - : Neuropathic pain is a complex and debilitating syndrome for which there are few effective pharmacological treatments. Opioid-based medications are initially effective for acute pain, but tolerance to their analgesic effects quickly develops, and long-term use often leads to physical dependence and addiction. Furthermore, neuropathic pain is generally resistant to non-steroidal anti inflammatory drugs. Other classes of medications including antidepressants, antiepileptics and voltage-gated calcium channel inhibitors are only partially effective in most patients, may be associated with significant side effects and have few disease-modifying effects on the underlying pathology. Medications that act through new mechanisms of action, and particularly ones that have disease modifying properties, would be highly desirable. In the last decade, a potential new target for the treatment of neuropathic pain has emerged: the alpha9 containing nicotinic acetylcholine receptor (nAChR). Recent studies indicate that antagonists of alpha9-containing nAChRs are analgesic in animal models of neuropathic pain. These nerve injury models include chronic constriction injury, partial sciatic nerve ligation, streptozotocin-induced diabetic neuropathy and chemotherapeutic-induced neuropathy. This review details the history and state of the field regarding the role that alpha9-containing nAChRs may play in neuropathic pain. An alternative hypothesis that alpha-conotoxins exert their therapeutic effect through blocking N-type calcium channels via activation of GABAB receptors is also reviewed. Understanding how antagonists of alpha9 containing nAChRs exert their therapeutic effects may ultimately result in the development of medications that not only treat but also prevent the development of neuropathic pain states. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 28662296 TI - Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. AB - INTRODUCTION: Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short term safety, tolerability, and target engagement of fingolimod in ALS. METHODS: Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression. RESULTS: Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1 ) and FEV1 /slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003). DISCUSSION: Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077-1084, 2017. PMID- 28662297 TI - Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials. AB - BACKGROUND: The objective of this study was to evaluate the safety and efficacy of carbon-ion radiotherapy (CIRT) in patients with hepatocellular carcinoma (HCC) with stepwise dose escalation and hypofractionation in 2 combined prospective trials. METHODS: Sequential phase 1/2 (protocol 9603) and phase 2 (protocol 0004) trials were conducted for patients with histologically proven HCC. The phase 1 component of protocol 9603 was a dose-escalation study; CIRT was delivered in 12, 8, or 4 fractions. After determination of the recommended dose, 2 phase 2 trials were performed in an expanded cohort, and the data were pooled to analyze toxicity, local control, and overall survival. RESULTS: In the phase 1 component of protocol 9603, 69.6, 58.0, and 52.8 Gy (relative biological effectiveness [RBE]) in 12, 8, and 4 fractions, respectively, constituted the maximum tolerated doses, and 52.8 Gy (RBE) in 4 fractions was established as the recommended dose regimen for the 2 phase 2 studies. In 124 patients with a total of 133 lesions, few severe adverse effects occurred, and local-control and overall survival rates at 1, 3, and 5 years were 94.7% and 90.3%, 91.4% and 50.0%, and 90.0% and 25.0%, respectively; this included 1-, 3-, and 5-year local-control rates of 97.8%, 95.5%, and 91.6%, respectively, in the phase 2 study. In a multivariate analysis, Child-Pugh class B and the presence of a tumor thrombus were significant factors for mortality. CONCLUSIONS: The safety and efficacy of CIRT in 12, 8, and 4 fractions were confirmed, with 52.8 Gy (RBE) in 4 fractions established as the recommended treatment course for eligible HCC patients. Cancer 2017;123:3955-65. (c) 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. PMID- 28662298 TI - Advanced film-forming gel formula vs spring thermal water and white petrolatum as primary dressings after full-face ablative fractional CO2 laser resurfacing: a comparative split-face pilot study. AB - BACKGROUND: Aesthetically pleasing results and fast, uneventful recovery are highly desirable after rejuvenating ablative laser procedures. Wound dressings following ablative laser procedures should ideally improve and optimize the wound healing environment. OBJECTIVE: The purpose of this comparative split-face, single-blinded, prospective observational study was to assess the efficacy and acceptability of two primary wound dressings immediately after a full-face fractional CO2 laser resurfacing procedure. METHODS: The assessments of an innovative film-forming dressing called Stratacel (SC) vs spring thermal water + Vaseline (V+) were conducted after a standardized, single-pass, full-face ablative fractional CO2 laser skin resurfacing procedure. Clinical parameters, such as haemoglobin - HB; surface temperature - ST; micro-textural modifications MT; superficial melanin - M; intrafollicular porphyrins - P, were assessed at different phases of the healing process using standardized, non-invasive technologies. RESULTS: Five female volunteers were enrolled in this inpatient, controlled pilot study. Most of the clinical parameters considered, including 3D surface texture analysis, revealed a better performance of SC vs. V+ during the early, more delicate phases of the healing process. CONCLUSIONS: This preliminary study, even if performed on a small number of volunteers, confirmed a definite advantage of the tested semipermeable film-forming formula (SC) over a more conventional postoperative skin care regime (V+). Clinical results could be explained by a better uniformity of distribution of SC over the micro irregularities induced by ablative fractional CO2 laser resurfacing. Its thin, semipermeable film might, in fact, act as an efficient, perfectly biocompatible, full contact, temporary skin barrier, able to protect extremely delicate healing surfaces from potential environmental irritations. PMID- 28662299 TI - Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study. AB - : Essentials Thrombotic risk stratification is an unmet need in antiphospholipid antibody carriers. Platelet count and antiphospholipid score (aPL-S) were combined to predict thrombotic events. Patients with high aPL-S are at high thrombotic risk regardless of platelet count. If platelet count is low, patients with low aPL-S are also on high thrombotic risk. SUMMARY: Background Thrombocytopenia is a non-criteria clinical manifestation of antiphospholipid syndrome. However, it remains to be elucidated whether thrombocytopenia increases thrombotic risk in antiphospholipid antibody (aPL) carriers. Objectives To investigate the impact of platelet count in terms of predicting thrombotic events in aPL carriers, and to stratify the thrombotic risk by combining platelet count and antiphospholipid score (aPL-S), which represents a quantification of aPL varieties and titers. Patients/methods A single-center, retrospective, longitudinal study comprising 953 consecutive patients who were suspected of having autoimmune disease between January 2002 and December 2006 was performed. Low platelet count was defined as a count of < 150 * 103 MUL-1 at the time of aPL testing. Results A negative correlation was observed between aPL-S and platelet count (r = - 0.2477). Among aPL-positive patients, those with a low platelet count developed thrombosis more frequently than those without (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.11-7.88). Among aPL-negative patients, no difference was found in the predictive value of thrombosis regardless of platelet count. Patients with aPLs were further divided into two subgroups according to aPL-S. Among low-aPL-S patients, those with low platelet counts developed thrombosis more frequently than those without (HR 3.44, 95% CI 1.05-11.2). In contrast, high-aPL-S patients developed thrombosis frequently regardless of platelet count. Conclusions aPL carriers with low platelet counts are at high risk of developing thrombosis. In particular, 'low-aPL-S carriers' may be stratified by platelet count in terms of predicting future thrombotic events. PMID- 28662300 TI - Compassion satisfaction: A concept analysis in nursing. AB - BACKGROUND: Nurses experience an intrinsic sense of fulfillment derived from their work in caring for other people. There is a need to further investigate the concept of compassion satisfaction as it is experienced in the profession of nursing. AIM: The aim of this analysis is to provide clarity to the concept of compassion satisfaction in nursing. DESIGN/DATA SOURCE: A search of social work and nursing literature was completed. The search terms "compassion satisfaction," "nursing," "social workers," "teachers," and "educators" were entered in various combinations to the CINAHL, Journals@Ovid, ProQuest Nursing & Allied Health Source, ProQuest Psychology Journals, PsychINFO, ERIC, and Education Full Text databases. REVIEW METHODS: A comprehensive review of the literature was completed to identify features of compassion satisfaction. Utilizing the Walker and Avant method, assumptions, antecedents, characteristics, and consequences of compassion satisfaction were identified. RESULTS: A conceptual model of compassion satisfaction was developed encompassing 7 antecedents, 11 characteristics, and 8 consequences. Further, a theoretical definition of compassion satisfaction in nursing was derived. CONCLUSION: There is a need to focus on the positive effects of caring. This concept analysis provides the initial step to strengthening the science related to compassion satisfaction in nursing and other helping professions. PMID- 28662301 TI - Multiple miliary osteoma cutis: an overlooked dermatosis? PMID- 28662302 TI - Cost-of-illness of patients with lymphoedema. AB - BACKGROUND: Chronic lymphoedema is characterized by a continuous need for medical treatment, many comorbidities and impaired quality of life. In Germany, about 4.5 million patients are affected by lymphoedema. Thus, lymphoedema causes high direct and indirect costs, even more in case of complications such as erysipelas and ulcers. OBJECTIVE: The aim of this study was to determine the costs of illness of community lymphoedema patients living in the metropolitan area of Hamburg, Germany. METHODS: An observational cross-sectional study in patients with lymphoedema and combined lipolymphoedema of any origin was performed analysing direct and indirect costs for the patients, the statutory health insurance and society. RESULTS: In total, 348 patients (90.8% female) were examined and interviewed. The mean age of the patients was 57.3 +/- 14.5 years. On average, the total costs per patient and year were ? 5784, of which ? 4445 (76.9%) were direct costs and ? 1338 indirect costs. Within the direct medical costs, ? 3796 were accounted for the statutory health insurances and ? 649 for the patient. The main cost drivers were costs for manual decongestive therapy and disability costs. CONCLUSION: Chronic lymphoedema is associated with high direct and indirect costs. This community-based study is the first cost analysis of chronic lymphoedema and combined lipolymphoedema giving insights to economic impact of lymphoedema treatment. There is a high need for structured disease management programs in order to diagnose and treat lymphoedema early and to avoid complications, thus limiting socio-economic burden. PMID- 28662303 TI - Measuring birth outcomes in New York State using a multidimensional approach. AB - OBJECTIVE: Poorer birth outcomes in the United States and New York State (NYS) remain a significant public health concern. The objectives of this study were to assess the effect of common and unique demographic, socioeconomic, and health services predictors on low birth weight (LBW), moderately LBW, very low birth weight (VLBW), and extremely low birth weight (ELBW) in NYS counties and to recommend policies that address unique differences at the county level. METHODS: Secondary data were collected for each of the 62 counties in NYS. Using a multidimensional approach, common and unique factors for LBW, moderately LBW, VLBW, and ELBW among NYS counties were evaluated. Correlations and multiple regression analyses were conducted for each of the outcome variables. RESULTS: Late prenatal care was the only significant predictor across all measures of poorer birth outcomes in NYS counties. Out-of-wedlock births, Medicaid Obstetrical Maternal Service providers, rural location, early prenatal care, advanced maternal age, and teen pregnancy rate were significant predictors, but not for all measures. CONCLUSIONS: Findings highlight the need to move beyond the number of providers when analyzing birth outcomes at the county level. Programs that support teens and women of all ages and marital status need to be expanded to curb poorer birth outcomes that take a heavy human and financial toll in NYS. PMID- 28662304 TI - Prevalence of hidradenitis suppurativa among patients with Down syndrome: a population-based cross-sectional analysis. AB - BACKGROUND: Hidradenitis suppurativa (HS) has been linked to Down syndrome (DS). OBJECTIVES: To determine whether patients with DS have a higher prevalence of HS, and whether the diagnosis of HS occurs at an earlier age for these patients. METHODS: A cross-sectional analysis was performed for a population sample of 11 936 patients with DS and 16 813 290 patients without DS. The primary outcome was the diagnosis of HS. Systemized Nomenclature of Medicine-Clinical Terms were used to identify patients with DS and HS. We used logistic regression models and significant interaction terms to evaluate the relationship between DS and HS. We also compared the proportion of incident HS cases within 5-year age groups to determine whether patients with DS had received an earlier diagnosis of HS. RESULTS: Prevalence of HS among patients with DS was 2.1%, compared with 0.3% for patients without DS (P < 0.001). HS prevalence was greatest among patients with DS who were aged 18-29 years. After controlling for age, sex and obesity, there was no difference in the prevalence of HS between female and male patients with DS or between white and nonwhite patients with DS. Compared with patients without DS, patients with DS had increased odds of HS in unadjusted [odds ratio (OR) 7.84, 95% confidence interval (CI) 6.93-8.88] and adjusted (OR 5.24, 95% CI 4.62 5.94) analyses. HS was diagnosed by the age of 29 years in 81.8% of patients with DS, compared with 34.0% of patients without DS (P < 0.001). CONCLUSIONS: HS is strongly associated with DS across demographic subgroups and may present earlier in life for these patients. PMID- 28662305 TI - Degranulation and shrinkage of dark cells in eccrine glands and elevated serum carcinoembryonic antigen in patients with acquired idiopathic generalized anhidrosis. AB - BACKGROUND: Acquired idiopathic generalized anhidrosis (AIGA) is characterized by anhidrosis/hypohidrosis without other autonomic and neurological dysfunctions. Pathologically, AIGA is considered to usually present no significant morphological alterations in eccrine glands, the secretory portion which consists of clear cells, dark cells, and myoepithelial cells. AIGA patients recently have been reported to show high serum concentrations of carcinoembryonic antigen (CEA). OBJECTIVE: Our aim is to reveal morphological abnormalities of dark cells and investigate their relationship with serum CEA. METHODS: We performed comparative analysis of eccrine glands between sweat-preserved and non-sweating skin in four AIGA patients. Serum CEA concentrations in 22 cases with AIGA were measured with healthy volunteers. Furthermore, we semiquantitatively investigated dermcidin, FoxA1 and CEA expression in eccrine glands of 12 cases with AIGA and 5 cases with non-AIGA. RESULTS: Marked degranulation and shrinkage of dark cells consistently occurred in AIGA. Furthermore, high serum CEA concentrations were found in 14 of 22 AIGA patients (over 60%), but serum CEA levels were not correlated with CEA expression in eccrine glands. Dermcidin expression in dark cells apparently decreased in AIGA patients, severely in those with high serum CEA and moderately in those with low serum CEA, while well-preserved expression was found in non-AIGA subjects. CONCLUSION: Our study suggests morphological damage and molecular dysregulation of dark cells, leading to impairment of their functions in AIGA patients. Severely damaged dark cells correspond to high serum CEA. Accordingly, these pathological changes in eccrine dark cells may be involved in anhidrosis/hypohidrosis of AIGA. PMID- 28662307 TI - Differential disease burden and treatment patterns among adults with psoriasis and atopic dermatitis seen in hospital vs. private clinics. PMID- 28662306 TI - Oxidative stress and chronic inflammation in osteoarthritis: can NRF2 counteract these partners in crime? AB - Osteoarthritis (OA) is an age-related joint degenerative disease associated with pain, joint deformity, and disability. The disease starts with cartilage damage but then progressively involves subchondral bone, causing an imbalance between osteoclast-driven bone resorption and osteoblast-driven remodeling. Here, we summarize the data for the role of oxidative stress and inflammation in OA pathology and discuss how these two processes are integrated during OA progression, as well as their contribution to abnormalities in cartilage/bone metabolism and integrity. At the cellular level, oxidative stress and inflammation are counteracted by transcription factor nuclear factor erythroid p45-related factor 2 (NRF2), and we describe the regulation of NRF2, highlighting its role in OA pathology. We also discuss the beneficial effect of some phytonutrients, including the therapeutic potential of NRF2 activation, in OA. PMID- 28662308 TI - Gender disparity in fistula use at initiation of hemodialysis varies markedly across ESRD networks-Analysis of USRDS data. AB - BACKGROUND: Gender disparities had been noted in the care of women with end stage renal disease (ESRD) in the early 2000's, including less frequent initiation of hemodialysis utilizing a fistula but more recent data have not been examined and underlying factors have not been extensively studied. STUDY DESIGN: Data from the United States Renal Data System (USRDS) were examined, including 202,999 hemodialysis patients. Only those who had received prior nephrology care were included. Multiple logistic regression was used, adjusted for possible confounders, including age, race, cause of ESRD, BMI, height, history of alcohol or drug abuse, medical comorbidities, ability to ambulate, time of nephrology care, type of insurance, and ESRD network. RESULTS: The odds of arteriovenous fistula (AVF) use at initiation of hemodialysis were significantly lower in women compared to men (OR = 0.69, 95% CI 0.67-0.71, P < 0.0001). The gender gap in AVF use at initiation was highest in New York and the upper Midwest (networks 2 and12) and smallest for Southern California and the Pacific Northwest and Alaska (18 and 16). Gender disparity was more pronounced for black women, with odds ratios for AVF use at initiation of dialysis (OR = 0.66, 95% CI 0.62-0.69), P < 0.0001 as compared to non-black (OR 0.70, 95% CI 0.68-0.73), P <= 0.0001. LIMITATIONS: Limitations include use of USRDS data. Data misclassification or errors in data reporting may exist and certain comorbid conditions may be underreported. Data regarding rate of primary fistula non-function are also not available. CONCLUSION: Adjusted odds ratio for AVF use was significantly lower in women compared to men, independent of time of nephrology care and other predictors. The gender disparity was most pronounced for black women and also varied from 20% to 46% lower odds for AVF use in women for different ESRD networks, after controlling for possible confounding variables, suggesting that practice based factors may be of importance in explaining this important finding. PMID- 28662309 TI - Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy and safety observations. AB - BACKGROUND: Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited. OBJECTIVE: To assess the efficacy and safety of omalizumab in SM. METHODS: In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality of life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored. RESULTS: A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient-reported quality of life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded. CONCLUSIONS: Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings. PMID- 28662311 TI - Complex Suicide by Self-stabbing and Drowning: A Case Report and a Review of Literature. AB - Sharp force injuries and drowning are methods exceptionally combined in complex suicides. We report a challenging case of complex suicide by self-stabbing and drowning that illustrates the difficulty in discriminating between homicide and suicide in such circumstances of death. The corpse of a young man was found submerged in a river, stabbed nine times with two wounds that had penetrated the thorax and had caused lung injuries and a hemopneumothorax. The postmortem and histological examinations were consistent with a death caused by drowning, but the manner of death still remained undetermined. Police investigation finally concluded to a suicide, although no suicide note had been left and the victim had no underlying diagnosed mental disorder. The parameters that may help distinguish suicide from homicide at the autopsy should be interpreted in light of a thorough forensic investigation to determine the exact manner of death in such a case. PMID- 28662312 TI - Accuracy of Computed Tomography Imaging Criteria in the Diagnosis of Adult Open Globe Injuries by Neuroradiology and Ophthalmology. AB - OBJECTIVE: The objective was to evaluate the sensitivity and specificity of computed tomography (CT) diagnosis of open globes, determine which imaging factors are most predictive of open globe injuries, and evaluate the agreement between neuroradiologist and ophthalmologist readers for diagnosis of open and closed globes. METHODS: This study was a retrospective cohort study. Patients who presented to Memorial Hermann-Texas Medical Center with suspicion for open globes were reviewed. One neuroradiologist and two ophthalmologists masked to clinical information reviewed CT images for signs concerning for open globe including change in globe contour, anterior chamber deformation, intraocular air, vitreous hemorrhage, subretinal fluid indicating retinal or choroidal detachment, dislocated or absent lens, intraocular foreign body, and orbital fracture. Using the clinically or surgically confirmed globe status as the true globe status, sensitivity, specificity, and agreement (kappa) were calculated and used to investigate which imaging factors are most predictive of open globe injuries. RESULTS: A total of 114 patients were included: 35 patients with open globes and 79 patients with closed globes. Specificity was greater than 97% for each reader, and sensitivity ranged from 51% to 77% among readers. The imaging characteristics most consistently used to predict an open globe injury were change in globe contour and vitreous hemorrhage (sensitivity = 43% to 57%, specificity > 98%). The agreement of impression of open globe between the neuroradiologist and ophthalmologists was good and excellent between ophthalmologists. CONCLUSIONS: Computed tomography imaging is not absolute, and the sensitivity is still inadequate to be fully relied upon. The CT imaging findings most predictive of an open globe injury were change in globe contour and vitreous hemorrhage. Clinical examination or surgical exploration remains the most important component in evaluating for a suspected open globe, with CT imaging as an adjunct. PMID- 28662310 TI - Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics. AB - Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF) cleaving metalloprotease ADAMTS-13. In general, severe deficiency of plasma ADAMTS-13 activity (< 10 IU dL-1 ) with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP. A patient usually presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS-13 activity (> 10 IU dL-1 ) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. Although plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS-13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with demonstrable autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide and splenectomy, etc., should be considered to eliminate autoantibodies for a sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS-13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS-13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis and diagnosis of, and current and potential novel therapies for, hereditary and acquired TTP. PMID- 28662313 TI - A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity. AB - BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. (c) 2017 American Cancer Society. PMID- 28662314 TI - LiTMP Trans-Metal-Trapping of Fluorinated Aromatic Molecules: A Comparative Study of Aluminum and Gallium Carbanion Traps. AB - Fluoroaromatic scaffolds pose a challenge to lithiation due to low stability of lithiated intermediates. Here we apply trans-metal-trapping (TMT) to a series of key fluorinated aromatics. In TMT, LiTMP performs the metalation, while an organometallic trap intercepts the emergent carbanion. This study contrasts the trapping abilities of iBu2 AlTMP and Ga(CH2 SiMe3 )3 , structurally mapping their TMT reactions and probing relative stabilities of metalated fluoroaromatic intermediates by NMR studies. Results show the installed Al-C(aryl) bonds are more prone to decomposition by benzyne formation and Li-F liberation, than the Ga C(aryl) species. The latter are thus better for onward reactivity as demonstrated in cross-coupling reactions with benzoyl chloride that produce ketones. PMID- 28662315 TI - Anaphylaxis to vanilla ice cream: a near fatal cross-reactivity phenomenon. PMID- 28662316 TI - Therapeutic potential of Rhizoma Alismatis: a review on ethnomedicinal application, phytochemistry, pharmacology, and toxicology. AB - Rhizoma Alismatis (RA), the dried rhizome of Alisma orientale (Sam.) Juzep, is a common traditional herbal medicine named Ze Xie in Chinese. RA is an important herbal component of a number of well-known Chinese medicinal preparations. It has been used to treat various ailments, such as dysuria, edema, nephropathy, hyperlipidemia, and diabetes. A wide range of chemical compounds, mainly triterpenoids, sesquiterpenoids, and diterpenoids, have been isolated from RA; among which the protostane-type triterpenoids, termed alisols, have attracted the most attention owing to their unique chemical structures and various biological activities. The extract and active compounds of RA possess a wide spectrum of pharmacological effects (e.g., diuretic, antimetabolic disorder, hepatoprotective, immunomodulatory, antiosteoporotic, anti-inflammatory, antitumor, antibacterial, and antiviral activities). Previous toxicological evaluations indicated that the RA extracts are relatively safe and have no serious side effects within certain dose ranges. This paper reviews the up-to date information on the ethnomedicinal application, phytochemistry, pharmacology, and toxicology of RA. This information will be useful for a better understanding of the therapeutic potential of RA. PMID- 28662317 TI - ClonEstiMate, a Bayesian method for quantifying rates of clonality of populations genotyped at two-time steps. AB - Partial clonality is commonly used in eukaryotes and has large consequences for their evolution and ecology. Assessing accurately the relative importance of clonal vs. sexual reproduction matters for studying and managing such species. Here, we proposed a Bayesian approach, ClonEstiMate, to infer rates of clonality c from populations sampled twice over a short time interval, ideally one generation time. The method relies on the likelihood of the transitions between genotype frequencies of ancestral and descendent populations, using an extended Wright-Fisher model explicitly integrating reproductive modes. Our model provides posterior probability distribution of inferred c, given the assumed rates of mutation, as well as inbreeding and selfing when occurring. Tested under various conditions, this model provided accurate inferences of c, especially when the amount of information was modest, that is low sample sizes, few loci, low polymorphism and strong linkage disequilibrium. Inferences remained robust when mutation models and rates were misinformed. However, the method was sensitive to moderate frequencies of null alleles and when the time interval between required samplings exceeding two generations. Misinformed rates on mating modes (inbreeding and selfing) also resulted in biased inferences. Our method was tested on eleven data sets covering five partially clonal species, for which the extent of clonality was formerly deciphered. It delivered highly consistent results with previous information on the biology of those species. ClonEstiMate represents a powerful tool for detecting and inferring clonality in finite populations, genotyped with SNPs or microsatellites. It is freely available at https://www6.rennes.inra.fr/igepp_eng/Productions/Software. PMID- 28662318 TI - Correlates of Achieving the Guidelines of Four Forms of Physical Activity, and the Relationship between Guidelines Achievement and Academic Performance: Undergraduate Students in Finland. AB - OBJECTIVES: We surveyed and compared, by gender, the levels and correlates of achieving the international guidelines of four forms of physical activity (PA): moderate PA (MPA), vigorous PA (VPA), moderate or vigorous PA (MVPA), and muscle strengthening PA (MSPA). The study assessed the associations between achieving the guidelines of the four PA forms and a range of socio-demographic, health and academic performance variables. METHODS: Data was collected across the seven faculties of the University of Turku (2013-2014 from a representative sample of 1,189 undergraduates). An English language online self-administered questionnaire assessed frequency and duration of PA/week for each form of PA. We employed cut offs for the guidelines in accordance with the American Heart Association. Chi square statistic tested the differences in PA, socio-demographic variables and academic performance between males and females. Binary logistic regression examined the factors associated with achieving the four PA guidelines and linear regression examined the association between the frequency of PA and academic performance. RESULTS: Achievement of PA guidelines was relatively low across the sample. Female students were less likely to achieve the VPA or MSPA guidelines, but were more health conscious and in generally exhibited better academic performace than males. High health awareness and excellent/very good self-rated health were the strongest predictors of achieving all forms of PA. Parents' education level was positively related to likelihood of achieving the VPA, MVPA and MSPA guidelines. Achieving the MPA guidelines (but not VPA or MSPA) was positively associated with subjective perceptions of better academic performance. CONCLUSIONS: Achievement of PA guidelines was generally low for this sample of Finnish students, and was associated with positive health status and high health awareness. Universities need a holistic approach to improve awareness of health and promote PA in students' lifestyles. PMID- 28662320 TI - An Approach to Determine the Prevalence of Poor Mental Health among Urban and Rural Population in Serbia Using Propensity Score Matching. AB - OBJECTIVE: Studies about mental health among urban and rural residents are scarce. A limited number of studies report somewhat better mental health in rural settings, despite higher rates of suicides. The main objective of this study was to describe social conditions of the population of Serbia in rural and urban settlements and to assess the differences in the prevalence of mental health disorders. METHODS: Propensity score matching of urban and rural persons (2 * 3,569 persons) has eliminated confounding effects from social variables (age, gender, wealth index, education level, employment, family status) and self-rated health. Thus, any statistical differences concerning mental health variables (five-item Mental Health Inventory and clinically diagnosed chronic anxiety or depression) between the two populations were not a result of differences in the matching variables. RESULTS: After matching all variables, the estimated prevalence rate of poor mental health was significantly higher among residents of urban (52.2%) than rural (49.1%) settlements (p=0.012). CONCLUSIONS: Almost half of the Serbian population suffers from poor mental health, therefore, there is a need to increase efforts on mental health promotion, prevention and treatment. Our study findings also support the importance of promoting benefits of rural settings for people with mental distress. PMID- 28662319 TI - Effect of Primary Preventive Examination with Cardiorespiratory Fitness Test. AB - OBJECTIVE: The aim of this study was to explore the potential of free comprehensive primary preventive examination (CPPE) combined with cardiorespiratory fitness (CRF) test in terms of its attractiveness for general population and moreover to evaluate the induced behavioural changes. The main focus was on physical activity behaviour (PA). METHODS: In 2009-2013, 250 people (100 men, 150 women) aged 18-65 years were examined. CPPE included assessment of health status and lifestyle, CRF test and individualized counselling. Expectations, reasons and motivations for participating were recorded. The sample was evaluated in terms of age, gender, lifestyle, body mass index, body fat percentage, CRF, and health characteristics. Evaluation according to subjective benefits, perceived effects on health and lifestyle was performed after six months using electronic feedback questionnaires (FQ). Comparison was made within groups formed according to the reported increase in PA. RESULTS: People aged 18 39 years accounted for 72.8% of the sample; mean age 34.4+/-11.0 years; 40.0% were men. Behavioural and health risks were lower in comparison with the general Czech population, but at least 1 of 5 assessed risk factors was present in 88.8% (low fruit and vegetable consumption 74.8%, low physical activity level (PAL) 45.6%, smoking 19.6%, risky alcohol use 18.8%, and stress load 10.4%). The most represented category of CRF was "endurance-trained" (both genders). CPPE was perceived as a source of information concerning health, CRF and lifestyle. 40.0% of men and 30.7% of women were focused on improvement in CRF. The response rate of FQ was 75.6%. Individuals with low PAL and low CRF provided feedback less often (p<0.05). In terms of perceived effect, 84.1% of the respondents implemented some kind of behavioural change; 60.9% reported increase in PA, but only 38.1% reported maintaining improvement in PA after 6 months. A higher proportion of reported lasting changes in PA occurred in subjects who were overweight/obese and in those with low CRF. Participants with low PAL and higher number of lifestyle risks more likely increased their PA only temporarily. Improvement in PA was associated with reported changes in diet (p<0.001). In the group of respondents there was an increase in self-perceived PA (SPA) compared to the baseline (p=0.001). Moreover, individuals who reported increase in PA showed improvement in subjectively perceived health. CONCLUSION: The testing of CRF appears to be a promising motivating factor for going through the intervention, especially for younger people and men. CPPE is effective at the individual level in terms of providing information and initiating behavioural changes in PA. However, this type of intervention is less attractive and less effective for individuals with a higher behavioural risk profile. PMID- 28662321 TI - A 12-year Trend of Psychological Distress: National Study of Finnish University Students. AB - OBJECTIVE: The study aimed to explore changes in the prevalence of psychological distress and co-occurring psychological symptoms among 19-34 years old Finnish university students between the years 2000 and 2012. METHODS: The prevalence of perceived frequent psychological symptoms was compared in four nationwide cross sectional student health surveys with random samples (N=11,502) in the following years: 2000 (N=3,174), 2004 (N=3,153), 2008 (N=2,750), and 2012 (N=2,425). RESULTS: In the time phase from 2000 to 2012, the overall psychological distress (12-item General Health Questionnaire, GHQ-12) increased from 22% to 28%, while there was also an increase in the frequently experienced psychological symptoms (depressiveness from 13% to 15%, anxiety from 8% to 13%, concentration problems from 12% to 18%, and psychological tension from 13% to 18% with a peak prevalence observed in 2008). The co-occurrence of different psychological symptoms increased as well. Psychological distress was more common in females and in older students. CONCLUSIONS: The findings suggest an increasing trend of frequent psychological distress among Finnish university students over the years from 2000 to 2012, with the peak prevalence occurring in 2008, which may reflect the growing multifaceted environmental demands. PMID- 28662322 TI - Child Safety Reference Frameworks: a Policy Tool for Child Injury Prevention at the Sub-national Level. AB - OBJECTIVES: The aim of this paper is to present the Child Safety Reference Frameworks (CSRF), a policy advice tool that places evidence-based child safety interventions, applicable at the sub-national level, into a framework resembling the Haddon Matrix. METHOD: The CSRF is based on work done in previous EU funded projects, which we have adapted to the field of child safety. The CSRF were populated following a literature review. RESULTS: Four CSRF were developed for four domains of child safety: road, water and home safety, and intentional injury prevention. CONCLUSION: The CSRF can be used as a reference, assessment and comparative tool by child safety practitioners and policy makers working at the sub-national level. PMID- 28662323 TI - Levels and Health Risk Assessment of PM10 Aerosol in Brno, Czech Republic. AB - OBJECTIVE: The main effort of this work was to evaluate the situation of the atmosphere in selected regions of Brno during the years 2009-2013 and to estimate health risks which might come up due to the increased concentrations of airborne particulate matter. METHODS: PM10 samples were collected in four areas varying in degree of automobile traffic using automatic and gravimetric sampling methods. PM10 concentrations were assessed using Spearman's rank correlation coefficient. Health risks were estimated based on calculation of relative risks and population for four health endpoints. The selected health outcomes were premature mortality, cardiovascular disease, respiratory disease, and chronic bronchitis. RESULTS: The highest PM10 concentrations were measured in two regions with high traffic loads T1, T2 and background region B2. The values were 34.33 +/- 11.52 ug.m-3 in 2010, 34.87 +/- 12.03 ug.m-3 in 2013 and 34.52 +/- 8.81 ug.m-3 in 2009, respectively. The highest correlation was between T1 and T2 having Spearman's correlation coefficient 0.888 followed by T1-B1 pair with coefficient 0.886. For all health outcomes, the highest health effect of PM (E) was determined for T2 site in 2010 which was 48 +/- 14, 49 +/- 21, 44 +/- 19 and 24 +/- 10 for premature mortality, cardiovascular disease, respiratory disease, and chronic bronchitis, respectively. CONCLUSION: The concentrations are highly correlated, especially in traffic regions. The annual concentrations did not exceed the legislation limit but 24-hours limit was exceeded more than two times in several cases. The highest number of cases with a given health outcome was estimated in traffic regions especially for cardiovascular disease and premature mortality. PMID- 28662324 TI - Psychosocial Risk Factors for Low Back Pain and Absenteeism among Slovenian Professional Drivers. AB - OBJECTIVE: The aim of this study was to determine the most common psychosocial risk factors for absenteeism and the extent to which low back pain occurs among Slovenian professional drivers as result of various psychosocial risk factors. METHOD: The study involved 275 professional drivers, mostly men (mean age 41.6 years). Statistical data analysis was conducted using SPSS package version 21, MS Excel version 2007 and Pajek, version 3. The main method for data processing was regression analysis. RESULTS: The results of the quantitative survey showed that lower back pain is mostly caused by lifting and carrying heavy loads, inadequate working conditions, poor physical fitness, regular nights out, shift work, and stress. Dissatisfaction with work, shift work and unsuitable working conditions significantly affect the incidence of low back pain. Absenteeism is influenced by factors such as dissatisfaction at work, disrespectful attitude of managers, unsuitable working conditions, personal dissatisfaction, lack of understanding of the partner, and enjoying nightlife on a regular basis. CONCLUSIONS: The study clarifies the unexplained holistic psychosocial risk factors and treatment effects on health in the population of professional drivers. Such factors can lead to absenteeism. The study also provides initial demonstration research in the Slovenian practice. Furthermore, it provides solutions in a holistic approach to solve the problem of risk factors management. PMID- 28662325 TI - Treatment of Tobacco Dependence, a Critical Gap in Czech Clinical Practice Guidelines. AB - OBJECTIVE: Tobacco related comorbidities and treatment of dependence are relevant to clinicians of all disciplines. Clinicians should provide a brief intervention about tobacco use with smokers at each clinical contact (success rate of 5-10 %). Intensive treatment (success rate >30%) should be available to those who need it. Brief intervention is not yet standard clinical practice. Our aim was to assess clinical practice guidelines (CPG) of selected medical professional societies to determine whether or not tobacco dependence treatment recommendations were included. METHODS: Between October and December 2013, we conducted a keyword search of CPG for 20 medical professional societies in the Czech Republic. We searched for the keywords "smoking", "tobacco" and "nicotine addiction" in 91 CPG documents, which were freely available on the websites of selected professional societies. We focused specifically on CPG relating to cardiovascular and respiratory diseases as well as cancer. We excluded any CPG focused on acute conditions, diagnostics only, laboratory methods, or administration. RESULTS: There was no mention of smoking in 27.7% (26/94) of CPG documents. Only 16% (15/94) of CPG documents listed smoking as a risk factor. 42.5% (40/94) mentioned smoking related phrases (e.g. "smoking ban"). Only 13.8% (13/94) of CPG included a section on tobacco dependence, referenced tobacco dependence treatment guidelines or mentioned specialized treatment centres where smokers can be referred. CONCLUSION: Nearly one third of CPG related to cardiovascular and respiratory diseases as well as cancer made no mention of smoking. Despite the clinical significance of smoking, the majority of CPG did not adequately address tobacco dependence and its treatment. PMID- 28662326 TI - Comparison of Alcohol Consumption and Alcohol Policies in the Czech Republic and Norway. AB - OBJECTIVE: The Czech Republic is characterized by high alcohol consumption and is well known as the world's biggest consumer of beer. In contrast, the alcohol consumption in Norway is relatively low. In this article, we describe and discuss alcohol policy development in the Czech Republic since the mid-1980s to the present and its impact on the alcohol consumption and compare our findings, including the dynamics of the total alcohol consumption and the development of drinking patterns among young people, with the situation in Norway. METHODS: The study uses the methodology of "process tracing". Selected national statistics, research outcomes and related policy documents were analyzed to identify possible relations between the alcohol consumption and the alcohol policy in two different environments and institutional/policy settings. RESULTS: There was a clear difference in alcohol consumption trends in both countries in the last three decades. Norway was characterized by low alcohol consumption with tendency to decline in the last years. In contrast, the Czech Republic showed an upward trend. In addition, alcohol consumption among Czech youth has been continuously increasing since 1995, whereas the opposite trend has occurred in Norway since the late 1990s. The results revealed that the alcohol-control policies of the Czech Republic and Norway were significantly different during the study period. Norway had a very restrictive alcohol policy, in contrast to the liberal alcohol policy adopted in the Czech Republic, in particular after political transition in 1990. Liberalization of social life together with considerable decline of alcohol price due to complete privatization of alcohol production and sale contributed to an increase of the alcohol consumption in the Czech Republic. CONCLUSIONS: Persistently high alcohol consumption among general population and its growth among young people in the Czech Republic pose social, economic and health threats. Norway could provide the inspiration to Czech politicians about effective options in combating these threats. PMID- 28662327 TI - Mumps in the Eastern Bohemia Region of the Czech Republic - a Serological Survey 2008-2012. AB - BACKGROUND: The incidence of mumps has decreased in many countries since the introduction of vaccination programmes, however, in the past decade a rapid increase in the disease occurrence has been reported worldwide. The reason for this situation is still not clear. We present the results of a serological survey carried out in the Eastern Bohemia Region of the Czech Republic during the years 2008-2012. METHODS: In total, 2,536 samples of 2,034 patients were examined during the study period. The study cohort was divided into two groups, one consisted of individuals born before the introduction of mandatory vaccination and the other one comprised individuals born after mandatory vaccination started. For the serology analyses the ELISA kits RIDASCREEN Mumpsvirus IgM and IgG (R Biopharm(r), Germany) were used. RESULTS: Out of 2,536 samples (including paired sera), 23.9% (n=606) were positive and 12% (n=304) had equivocal results. Most of the positive samples were obtained from patients aged 17-20 years. Significantly more (p<0.05) positive patients were born after the start of the national vaccination programme (patient group 2) (22.8%) compared to those born before its start (patient group 1) (13.7%). Interestingly, the analysis of data showed that 75.3% of patients falling into group 1 had anti-mumps IgG antibodies, which means that they had contracted mumps, whilst 23.5% of patients of group 2 had undetectable IgG antibodies, even though they should have been vaccinated. CONCLUSION: The data from our study, with a low number of positive samples in the first years of the study and an increase in the last two years, could suggest the occurrence of outbreaks every 4-6 years. PMID- 28662328 TI - Analysis of IL-6, IL-10 and NF-kappaB Gene Polymorphisms in Aggressive and Chronic Periodontitis. AB - OBJECTIVE: Pro-inflammatory cytokines, interleukin-6 (IL-6), demonstrated to be suppressed by interleukin-10 (IL-10) are known to be regulated by the transcription factor nuclear factor-kappaB(NF-kappaB). The aim of this study was to ascertain the association between genetic polymorphism of these genes (IL-6( 174), IL-10(-597) and NF-kappaB1-94ins/del)) and chronic/aggressive periodontitis. METHODS: Forty-five patients with chronic periodontitis (CP), 58 patients with aggressive periodontitis (AP) and 38 periodontally healthy subjects were included in this study. Genomic DNA was isolated from whole blood samples. The NF-kappaB, IL-6, and IL-10 polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Among subjects for the ins/ins genotypes of NF-kappaB1 gene, the AA genotypes of IL-10 presented a higher frequency in chronic periodontitis group than in healthy controls (p=0.023). A statistically significant difference in genotyping frequencies between AP group and healthy controls was observed for the IL-6 gene. The AA genotype of IL-10 was overrepresented in CP and AP groups compared to healthy controls (OR=9.93, 95% CI: 2.11-46.7, OR=5.7, 95% CI: 1.22 26.89, respectively). CONCLUSIONS: Within the limits of this study, it can be concluded that the IL-10 (-597) AA genotype is associated with susceptibility to chronic/aggressive periodontitis and IL-6 (-174) GG genotypes and G allele seems to be associated with aggressive periodontitis. Clinical relevance: The results of the current study indicate that IL-6 and IL-10 genotypes seem to be associated with aggressive periodontitis. Also, the AA genotypes of IL-10 presented a higher frequency in chronic periodontitis subjects with carrying NF-kappaB1 ins/ins genotypes. PMID- 28662329 TI - Quinolone-resistant Escherichia coli in Poultry Farming. AB - Increasing bacterial resistance to quinolone antibiotics is apparent in both humans and animals. For humans, a potential source of resistant bacteria may be animals or their products entering the human food chain, for example poultry. Between July 2013 and September 2014, samples were collected and analyzed in the Moravian regions of the Czech Republic to isolate the bacterium Escherichia coli. As a result, 212 E. coli isolates were obtained comprising 126 environmental isolates from poultry houses and 86 isolates from cloacal swabs from market weight turkeys. Subsequently, the E. coli isolates were tested for susceptibility to selected antibiotics. Resistance of the poultry isolates to quinolones ranged from 53% to 73%. Additionally, the presence of plasmid-mediated resistance genes was studied. The genes were confirmed in 58% of the tested strains. The data on resistance of isolates from poultry were compared with results of resistance tests in human isolates obtained in the same regions. The high levels of resistance determined by both phenotyping and genotyping methods and reported in the present study confirm the fact that the use of fluoroquinolones in poultry should be closely monitored. PMID- 28662330 TI - Gaseous Heterogeneous Catalytic Reactions over Mn-Based Oxides for Environmental Applications: A Critical Review. AB - Manganese oxide has been recognized as one of the most promising gaseous heterogeneous catalysts due to its low cost, environmental friendliness, and high catalytic oxidation performance. Mn-based oxides can be classified into four types: (1) single manganese oxide (MnOx), (2) supported manganese oxide (MnOx/support), (3) composite manganese oxides (MnOx-X), and (4) special crystalline manganese oxides (S-MnOx). These Mn-based oxides have been widely used as catalysts for the elimination of gaseous pollutants. This review aims to describe the environmental applications of these manganese oxides and provide perspectives. It gives detailed descriptions of environmental applications of the selective catalytic reduction of NOx with NH3, the catalytic combustion of volatile organic compounds, Hg0 oxidation and adsorption, and soot oxidation, in addition to some other environmental applications. Furthermore, this review mainly focuses on the effects of structure, morphology, and modified elements and on the role of catalyst supports in gaseous heterogeneous catalytic reactions. Finally, future research directions for developing manganese oxide catalysts are proposed. PMID- 28662332 TI - Magnetic Propulsion of Recyclable Catalytic Nanocleaners for Pollutant Degradation. AB - Electrochemically fabricated magnetic mesoporous CoNi@Pt nanorods are excellent nanomotors with controlled magnetic propulsion and excellent catalytic properties. The core-shell structure allows a double functionality: (i) controlled motion of the nanorods by applying rotating magnetic fields at different frequencies and field strengths and (ii) effective catalytic activity of the platinum shell for reactions involving sodium borohydride. The structure and magnetic properties of the CoNi core are not modified by the presence of the Pt shell. Nanorods were propelled via a tumbling-like dynamic by a rotating magnetic field. While in absence of NaBH4, nanorods move at constant speed showing a linear path; in the presence of NaBH4, they showed an intermittent trajectory. These catalytic nanorods can be used as nanocleaners with controlled directionality for pollutants degradation in the presence of borohydride. Their magnetic character allows control of the velocity and the direction throughout the contaminated solution by degrading the different pollutants in their path. The magnetic character of nanorods also allows their easy recycling. PMID- 28662331 TI - Ultraperformance Liquid Chromatography Tandem Mass Spectrometry Method To Determine Formaldehyde Hemoglobin Adducts in Humans as Biomarker for Formaldehyde Exposure. AB - Formaldehyde (FA) is an environmental chemical classified as a human carcinogen. It is highly reactive and can bind covalently with hemoglobin (Hb) to produce Hb adducts. Measurement of these Hb adducts provides valuable information about exposure to this chemical. We developed a robust, ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantifying FA-Hb adducts in red blood cells. The method measures the FA-VHLTPEEK peptide after trypic digestion. The peptide is a FA adduct at the N-terminus of the beta chain of human Hb. Method mean (+/-SD) accuracy, determined by recovery in quality control and blank material was 103.2% +/- 8.11. The mean among-day and within-day coefficients of variation determined at three concentration levels (%CV) were 9.2% (range: 7.2-10.2%) and 4.9% (range 3.1-7.3%), respectively. The limit of detection was 3.4 nmol/g Hb. This method was applied to the analysis of 135 human blood samples, and FA-VHLTPEEK was detected in all study samples. FA-VHLTPEEK concentrations were not significantly different between smokers and nonsmokers. This work is the first validated UPLC-MS/MS method in which a FA peptide derived from a FA-Hb adduct could be used to monitor exposure to FA in population studies. PMID- 28662333 TI - La0.8Sr0.2MnO3-Based Perovskite Nanoparticles with the A-Site Deficiency as High Performance Bifunctional Oxygen Catalyst in Alkaline Solution. AB - Perovskite (La0.8Sr0.2)1-xMn1-xIrxO3 (x = 0 (LSM) and 0.05 (LSMI)) nanoparticles with particle size of 20-50 nm are prepared by the polymer-assisted chemical solution method and demonstrated as high performance bifunctional oxygen catalyst in alkaline solution. As compared with LSM, LSMI with the A-site deficiency and the B-site iridium (Ir)-doping has a larger lattice, lower valence state of transition metal, and weaker metal-OH bonding; therefore, it increases the concentration of oxygen vacancy and enhances both oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). LSMI exhibits superior ORR performance with only 30 mV onset potential difference from the commercial Pt/C catalyst and significant enhancement in electrocatalytic activity in the OER process, resulting in the best oxygen electrode material among all the reported perovskite oxides. LSMI also exhibits high durability for both ORR (only 18 mV negative shift for the half-wave potential compared with the initial ORR) and OER process with 10% decay. The electrochemical results indicate that the A-site deficiency and Ir-doping in perovskite oxides could be promising catalysts for the applications in fuel cells, metal-air batteries, and solar fuel synthesis. PMID- 28662334 TI - Protease-Cleavable Linkers Modulate the Anticancer Activity of Noninternalizing Antibody-Drug Conjugates. AB - Antibody-drug conjugates (ADCs) represent an attractive class of biopharmaceutical agents, with the potential to selectively deliver potent cytotoxic agents to tumors. It is generally assumed that ADC products should preferably bind and internalize into cancer cells in order to liberate their toxic payload, but a growing body of evidence indicates that also ADCs based on noninternalizing antibodies may be potently active. In this Communication, we investigated dipeptide-based linkers (frequently used for internalizing ADC products) in the context of the noninternalizing F16 antibody, specific to a splice isoform of tenascin-C. Using monomethyl auristatin E (MMAE) as potent cytotoxic drug, we observed that a single amino acid substitution of the Val-Cit dipeptide linker can substantially modulate the in vivo stability of the corresponding ADC products, as well as the anticancer activity in mice bearing the human epidermoid A431 carcinoma. In these settings, the linker based on the Val-Ala dipeptide exhibited better performances, compared to Val-Cit, Val-Lys, and Val-Arg analogues. Mass spectrometric analysis revealed that the four linkers displayed not only different stability in vivo but also differences in cleavage sites. Moreover, the absence of anticancer activity for a F16-MMAE conjugate featuring a noncleavable linker indicated that drug release modalities, based on proteolytic degradation of the immunoglobulin moiety, cannot be exploited with noninternalizing antibodies. ADC products based on the noninternalizing F16 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed in the extracellular matrix of several tumors, while being virtually undetectable in most normal adult tissues. PMID- 28662335 TI - Modulus- and Surface-Energy-Tunable Thiol-ene for UV Micromolding of Coatings. AB - Micromolding of UV-curable materials is a patterning method to fabricate microstructured surfaces that is an additive manufacturing process fully compatible with roll-to-roll systems. The development of micromolding for mass production remains a challenge because of the multifaceted demands of UV curable materials and the risk of demolding-related defects, particularly when patterning high-aspect-ratio features. In this research, a robust micromolding approach is demonstrated that integrates thiol-ene polymerization and UV LED curing. The moduli of cured thiol-ene coatings were tuned over 2 orders of magnitude by simply adjusting the acrylate concentration of a coating formulation, the curing completed in all cases within 10 s of LED exposure. Densely packed 50-MUm-wide gratings were faithfully replicated in coatings ranging from soft materials to stiff highly cross-linked networks. Further, surface energy was modified with a fluorinated polymer, achieving a surface energy reduction of more than a half at a loading of 1 wt %, and enabling tall (100 MUm) defect-free patterns to be attained. The demolding strengths of microstructured coatings were compared using quantitative peel testing, showing its decrease with decreasing surface energy, coating modulus, and grating height. This micromolding process, combining tunability in thermomechanical and surface properties, makes thiol-ene microstructured coatings attractive candidates for roll-to-roll manufacture. As a demonstration of the utility of the process, superhydrophobic surfaces are prepared using the system modified by the fluorinated polymer. PMID- 28662336 TI - Surface-Enhanced, Spatially Offset Raman Spectroscopy (SESORS) in Tissue Analogues. AB - Surface-enhanced, spatially offset Raman spectroscopy (SESORS) combines the remarkable enhancements in sensitivity afforded by surface-enhanced Raman spectroscopy (SERS) with the non-invasive, subsurface sampling capabilities of spatially offset Raman spectroscopy. Taken together, these techniques show great promise for in vivo Raman measurements. Herein, we present a step forward for this technique, demonstrating SESORS through tissue analogues of six known and varied thicknesses, with a large number of distinct spatial offsets, in a backscattering optical geometry. This is accomplished by spin-coating SERS-active nanoparticles (NPs) on glass slides and monitoring the relative spectral contribution from the NPs and tissue sections, respectively, as a function of both the tissue thickness and the spatial offset of the collection probe. The results show that SESORS outperforms SERS alone for this purpose, the NP signal can be attained at tissue thicknesses of >6.75 mm, and greater tissue thicknesses require greater spatial offsets to maximize the NP signal, all with an optical geometry optimized for utility. This demonstration represents a step forward toward the implementation of SESORS for non-invasive, in vivo analysis. PMID- 28662337 TI - Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of NF-kappaB signaling pathway in vivo and in vitro. AB - Danshen (Salvia miltiorrhiza) is a traditional Chinese medicine herb that can alleviate the symptoms of osteoarthritis (OA) (Soder et al. 2006) in animals. However, the underlying mechanisms remain poorly understood and require further investigation. In this study, rabbits with experimentally induced OA were given an intra-articular injection of danshen (0.7 mL/day) for 5 weeks. In addition to attenuating the cartilage degeneration of OA in the rabbits, danshen decreased the expression and activity of matrix metalloproteinase 9 (MMP-9) and MMP-13, and increased the expression of their natural inhibitors: tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and TIMP-2. Apoptosis in osteoarthritic cartilage tissues was attenuated by danshen, accompanied with increased expression of B cell lymphoma 2 (Bcl-2) and decreased levels of Bcl-2-associated X protein (Bax). Further, danshen inhibited the nuclear accumulation of nuclear factor kappa-B (NF kappaB) p65 in osteoarthritic cartilage. The therapeutic effects of danshen in vivo were comparable to that of sodium hyaluronate, which is a drug used clinically for the treatment OA. In vitro, sodium nitroprusside (SNP) was used to stimulate apoptosis in primary rabbit chondrocytes. We found that the SNP-induced apoptosis was mitigated by danshen. BAY11-7028, an inhibitor of the NF-kappaB pathway, augmented danshen's anti-apoptotic effects in cells exposed to SNP. When these results are considered together, they indicate that danshen alleviates the cartilage injury in rabbit OA through inhibition of the NF-kappaB signaling pathway. PMID- 28662338 TI - Effect of a Couples' Relationship Enrichment Program on the Quality of Marital Relationships from the Perspective of Spouses of Patients with Multiple Sclerosis. AB - A relationship enrichment program involves family therapy with psychosocial training to improve relationship skills. This study was conducted to determine the effect of a couples' relationship enrichment program on marital relationship quality. This quasi-experimental study was conducted in 2016 with 80 spouses of patients, all members of the Multiple Sclerosis (MS) Center in Zahedan, Iran. The participants were randomly assigned to two groups: an intervention and a control group, each of which comprised 40 participants. The Perceived Relationship Quality Components questionnaire was used to collect the required data. After five-session couples' relationship enrichment program, the mean total marital relationship quality score and all the subscale scores except the love subscale score in the intervention group were significantly greater than those in the control group. Application of the program is recommended to increase the quality of marital relationships for spouses of patients with MS, as they are the most important sources of support for patients with MS. PMID- 28662339 TI - Grain and sweet sorghum (Sorghum bicolor L. Moench) serves as a novel source of bioactive compounds for human health. AB - Grain sorghum is an important staple food crop grown globally while sweet sorghum is increasingly considered as a promising biofuel feedstock. Biofuels are the major economic products from the processing of large quantities of biomass, which is currently being utilized to make value-added products in the biorefinery approach. To date, these value-added products are typically commodity chemicals and waste materials used in agriculture. However, there are opportunities to generate high-value bioactive compounds from sorghum grain and biomass. Chronic diseases, such as cancers, are the top causes for morbidity and mortality in developed nations and are promoted by inflammation and oxidative stress. Globally, colorectal cancer results in approximately one-half million deaths annually. It is estimated that as much as 80% of colorectal cancer cases can be attributed to environmental and dietary factors. The sorghum grain and ligno cellulosic biomass generated for biofuel production has been reported to be high in bioactive compounds, including phenolic acids and flavonoids, with antioxidant and anti-inflammatory properties. This review focuses on the bioactive compounds of grain and sweet sorghum (Sorghum bicolor L. Moench), for their anti inflammatory, antioxidant, anti-colon cancer, and immune modulator functions. The review summarizes previous efforts to identify and quantify bioactive compounds in sorghum and documents their anti-cancer biological activities. Finally, this review discusses bioactive compound extraction methodologies and technologies as well as considerations for incorporating these technologies into current biorefining practices. PMID- 28662340 TI - General Beliefs and Stigma Regarding Illicit Drug Use: Perspectives of Family Members and Significant Others of Drug Users in an Inner City in Brazil. AB - People who use drugs are continuously subjected to harsh stigmatization through a process of relational and social degradation, which limits their possibility for recovery. This quantitative study explores the perspectives of family members or significant others of illicit drug users, regarding general beliefs about illicit drug use and their stigma. Respondents agree that most people do not trust people who use drugs, disregard individuals who have been hospitalized due to drug problems and do not think people who use drugs are as intelligent as the general population. These findings reveal a high level of public stigma regarding illicit drug use. PMID- 28662342 TI - Use of phenolic compounds from olive mill wastewater as valuable ingredients for functional foods. AB - Olive mill wastewater (OMW) is a pollutant by-product from the virgin olive oil production. Its high content in phenolic compounds makes them play an important role for their use in foods, for their high antioxidant significance. The present paper gives an overview on the techniques for OMW valuable ingredient separation, focusing on the most effective ones for their use in food products as functional ingredients. We report on effective methods to recover OMW phenolics, and give several examples on the use these extracts in foods. When added into vegetable oils, their effect on retarding lipid oxidation improves the oxidative status of the product, whilst several challenges need to be faced. OMW phenolic extracts were also used in food emulsions, milk products or other model systems, showing promising results and little or no negative impact on the sensory characteristics or other properties. Their possible use as antimicrobial agents is also another promising approach, as positive results were obtained when applied in meat products. Other examples of using natural phenolic extracts from other sources are suggested also for OMW extracts, to expand their use and thus to improve the nutritional and technological quality of foods. PMID- 28662341 TI - A Phase II Study of the c-Met Inhibitor Tivantinib in Combination with FOLFOX for the Treatment of Patients with Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction, or Stomach. AB - BACKGROUND: This phase I/II study was designed to determine the maximum tolerated dose of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors and to evaluate the safety and efficacy of this combination for patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. METHODS: Patients with advanced solid tumors for which FOLFOX would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design in phase I. In phase II, patients with advanced GE cancer received standard FOLFOX day 1 and tivantinib (360 mg PO BID) days 1-14 of each 2 week cycle. Restaging occurred every four cycles. The primary phase II endpoint was response rate (RR). RESULTS: Forty-nine patients were enrolled (15 on phase I and 34 on phase II). The expansion dose was established as tivantinib 360 mg BID in combination with FOLFOX. Thirty-two phase II patients were treated for a median of eight cycles (range, 1-38), with an overall RR of 38%. Treatment related toxicities included neutropenia, fatigue, diarrhea, nausea, and peripheral neuropathy. Median progression-free survival (PFS) was 6.1 hmonths with a median time to progression of 7.0 months. Median overall survival was 9.6 months. Two patients remain on study at the time of this analysis. CONCLUSIONS: The combination treatment of tivantinib plus FOLFOX in patients with advanced GE cancer showed a response and PFS in the range of historical controls for first line FOLFOX therapy. However, two patients had extended time on study treatment (36 and 45 cycles) at the time of data cutoff. PMID- 28662343 TI - Effect of chronic gamma-hydroxybutyrate (GHB) administration on GHB toxicokinetics and GHB-induced respiratory depression. AB - BACKGROUND: gamma-hydroxybutyrate (GHB) has a high potential for illicit use; overdose of this compound results in sedation, respiratory depression and death. Tolerance to the hypnotic/sedative and electroencephalogram effects of GHB occurs with chronic GHB administration; however, tolerance to respiratory depression has not been evaluated. GHB toxicodynamic effects are mediated predominantly by GABAB receptors. Chronic treatment may affect monocarboxylate transporters (MCTs) and alter the absorption, renal clearance and brain uptake of GHB. OBJECTIVES: To determine effects of chronic GHB dosing on GHB toxicokinetics, GHB-induced respiratory depression, and MCT expression. METHODS: Rats were administered GHB 600 mg/kg intravenously daily for 5 days. Plasma, urine and tissue samples and respiratory measurements were obtained on days 1 and 5. Plasma and urine were analyzed for GHB by LC/MS/MS and tissue samples for expression of MCT1, 2 and 4 and their accessory proteins by QRT-PCR. RESULTS: No differences in GHB pharmacokinetics or respiratory depression were observed between days 1 and 5. Opposing changes in MCT1 and MCT4 mRNA expression were observed in kidney samples on day 5 compared to GHB-naive animals, and MCT4 expression was increased in the intestine. CONCLUSIONS: The lack of tolerance observed with GHB-induced respiratory depression, in contrast to the tolerance reported for the sedative/hypnotic and electroencephalogram effects, suggests that different GABAB receptor subtypes may be involved in different GABAB-mediated toxicodynamic effects of GHB. Chronic or binge users of GHB may be at no less risk for fatality from respiratory arrest with a GHB overdose than with a single dose of GHB. PMID- 28662345 TI - Comprehension of presuppositions in school-age Cantonese-speaking children with and without autism spectrum disorders. AB - While an enormous amount of research has been done on the deficient conversation skills in individuals with autism spectrum disorders (ASD), little is known about their performance on presuppositions, a domain of knowledge that is crucial for successful communication. This study investigated the comprehension of four types of presupposition, namely existential, factive, lexical and structural presuppositions, in school-age Cantonese-speaking children with and without ASD. A group of children with ASD (n = 21), mean age 8.8, was compared with a group of typically developing children (n = 106). Knowledge of presuppositions was evaluated based on children's ability to judge whether a given utterance was a correct presupposition of a preceding utterance. Children with ASD were found to show a deficit in the comprehension of presuppositions, even after controlling for differences in general language ability and non-verbal intelligence. The relative difficulty of the four types of presupposition did not differ between the two groups of children. The present findings provide new empirical evidence that children with ASD have a deficit in the comprehension of presuppositions. Future research should explore whether the deficit in the comprehension of presuppositions is related to the development of theory of mind skills in children with ASD. PMID- 28662344 TI - Oral and Craniofacial Anomalies of Bardet-Biedl Syndrome: Dental Management in the Context of a Rare Disease. AB - Standardized guidelines for the oral health management of patients with rare diseases exhibiting morphologic anomalies are currently lacking. This review considers Bardet-Biedl syndrome (BBS), a monogenic autosomal recessive nonmotile ciliopathy, as an archetypal condition. Dental anomalies are present in a majority of individuals affected by BBS due to abnormal embryonic orofacial and tooth development. Genetically encoded intrinsic oral structural anomalies and heterogeneous BBS clinical phenotypes and consequent oral comorbidities confound oral health management. Since the comorbid spectrum of BBS phenotypes spans diabetes, renal disease, obesity, sleep apnea, cardiovascular disease, and cognitive disorders, a broad spectrum of collateral oral disease may be encountered. The genetic impact of BBS on the anatomic development of oral components and oral pathology encountered in the context of various BBS phenotypes and their associated comorbidities are reviewed herein. Challenges encountered in managing patients with BBS are highlighted, emphasizing the spectrum of oral pathology associated with heterogeneous clinical phenotypic expression. Guidelines for provision of care across the spectrum of BBS clinical phenotypes are considered. Establishment of integrated medical-dental delivery models of oral care in the context of rare diseases is emphasized, including involvement of caregivers in the context of managing these patients with special needs. PMID- 28662346 TI - Lipomatous hypertrophy of the interatrial septum, an unusual tachycardia etiology in a hematopoietic stem cell transplanted patient. PMID- 28662347 TI - Nutritional chemistry of the peanut (Arachis hypogaea). AB - Peanuts, Arachis hypogaea, are one of the most widely consumed legumes globally due to its nutrition, taste, and affordability. Peanuts are protein and energy rich and have been utilized worldwide to address the nutritional needs in developing countries. Currently, its role in a heart-healthy diet has warranted tremendous attention among consumer groups and within the scientific community. Additionally, current studies have identified the value in the phytonutrient composition of peanuts, such as resveratrol, isoflavonoids, phenolic acids, and phytosterols, which may enhance overall health and wellness. This article presents a comprehensive review of the nutritional chemistry of peanut components (macronutrients-proteins, lipids, carbohydrates; micronutrients-vitamins, minerals, phytonutrients) as related to health and use within the body. An improved comprehensive knowledge and better understanding of the nutritional chemistry of peanuts enables us to better harness the power of these nutrients in improved peanut products within the food and feed industry. PMID- 28662348 TI - Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. AB - The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis. We used chicken embryo to express wild-type or 2 mutant versions of human WNT5A in the mandible and then examined the morphologic, cellular, and molecular effects. The 3 experimental viruses-wt WNT5A, WNT5AC83S, or WNT5AC182R-all caused shortening of the mandible on the injected side as compared with GFP controls. Although the phenotypes initially appeared similar, we uncovered specific disruption of chondrocyte polarity and shape, inhibition of cell migration, differences in target gene expression, and absence of JNK signaling only in the presence of mutant viruses. In addition, the missense mutations do not appear to block receptor binding, since in paracrine experiments, the mutant protein inhibits cell migration. In this study, we ruled out a straightforward gain or loss of function caused by the WNT5A missense mutations. Instead, the mutations are likely redirecting WNT signaling away from JNK-PCP toward other noncanonical pathways. We conclude that in RS, WNT5A missense mutations have dominant neomorphic effects that interfere with the function of the wild-type protein. PMID- 28662350 TI - LITMUS-CLT: A new way to assess bilingual lexicons. PMID- 28662349 TI - Injury Surveillance of Head, Neck, and Facial Injuries in Collegiate Ice Hockey Players, 2009-2010 Through 2013-2014 Academic Years. AB - CONTEXT: Ice hockey is a high-speed, full-contact sport with a high risk of head/face/neck (HFN) injuries. However, men's and women's ice hockey differ; checking is allowed only among men. OBJECTIVES: To describe the epidemiology of HFN injuries in collegiate men's and women's ice hockey during the 2009-2010 through 2013-2014 academic years. DESIGN: Descriptive epidemiology study. SETTING: Ice hockey data from the National Collegiate Athletic Association (NCAA) Injury Surveillance Program during the 2009-2010 through 2013-2014 academic years. PATIENTS OR OTHER PARTICIPANTS: Fifty-seven men's and 26 women's collegiate ice hockey programs from all NCAA divisions provided 106 and 51 team-seasons of data, respectively. MAIN OUTCOME MEASURE(S): Injury rates per 1000 athlete-exposures and rate ratios with 95% confidence intervals (CIs). RESULTS: The NCAA Injury Surveillance Program reported 496 and 131 HFN injuries in men's and women's ice hockey, respectively. The HFN injury rate was higher in men than in women (1.75 versus 1.16/1000 athlete-exposures; incidence rate ratio = 1.51; 95% CI = 1.25, 1.84). The proportion of HFN injuries from checking was higher in men than in women for competitions (38.5% versus 13.6%; injury proportion ratio = 2.82; 95% CI = 1.64, 4.85) and practices (21.9% versus 2.3%; injury proportion ratio = 9.41; 95% CI = 1.31, 67.69). The most common HFN injury diagnosis was concussion; most concussions occurred in men's competitions from player contact while checking (25.9%). Player contact during general play comprised the largest proportion of concussions in men's practices (25.9%), women's competitions (25.0%), and women's practices (24.0%). While 166 lacerations were reported in men, none were reported in women. In men, most lacerations occurred from player contact during checking in competitions (41.8%) and player contact during general play in practices (15.0%). CONCLUSIONS: A larger proportion of HFN injuries in ice hockey occurred during checking in men versus women. Concussion was the most common HFN injury and was most often due to player contact. Lacerations were reported only among men and were mostly due to checking. Injury-prevention programs should aim to reduce checking-related injuries. PMID- 28662351 TI - The emerging role of curcumin for improving vascular dysfunction: A review. AB - Curcumin, when administered in a bioavailable form, has potential to influence vascular health of various populations, leading to decreases in cardiovascular disease risk. Clinical intervention studies with curcumin have demonstrated significant improvements in endothelial function, arterial compliance, arterial stiffness, and other measures of vascular hemodynamics in young, middle-aged, old, post-menopausal, healthy, diabetic, and obese individuals. Mechanistically, curcumin is believed to improve vascular function through its effects on inflammation, oxidative stress, nitric oxide bioavailability, and structural proteins of the artery. Current data give support for curcumin to be administered for improvements in vascular health to individuals that may or may not be at risk for cardiovascular disease. This review briefly summarizes the techniques used for the establishment of vascular health and overviews the literature investigating the role of curcumin in the improvement of vascular health. PMID- 28662352 TI - Longitudinal associations between outpatient medical care use and substance use among rural stimulant users. AB - BACKGROUND: Negative views toward substance use treatment among some rural substance users and limited treatment resources in rural areas likely affect substance use utilization. It is therefore important to determine whether accessing healthcare options other than substance use treatment, specifically outpatient medical care (OMC), is associated with reductions in substance use. OBJECTIVES: We examined whether use of OMC was associated with reductions in substance use among rural substance users over a three-year period. We also explored whether substance user characteristics, including substance-use severity and related-problems, moderated this potential relationship. METHODS: Data were collected from an observational study of 710 (61% male) stimulant users using respondent-driven sampling. Participants were recruited from rural counties of Arkansas, Kentucky, and Ohio. RESULTS: We found a significant main effect of having at least one OMC visit (relative to none) on fewer days of alcohol, crack cocaine, and methamphetamine use over time. Fewer days of alcohol, crack cocaine, and methamphetamine use were reported in participants with at least one OMC visit (relative to those with none) among those reporting higher Addiction Severity Index employment and psychiatric severity scores, and low education, respectively. CONCLUSION: Our findings extend the results from prior studies with urban substance users to show that contact with an outpatient medical care clinic is associated with reductions in substance use over time among rural substance users with especially poorer functioning. These findings highlight the potential importance of OMCs in addressing unhealthy substance use in rural communities. PMID- 28662353 TI - Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors. AB - Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management. PMID- 28662354 TI - Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering. AB - INTRODUCTION: Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer. Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering. Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached. PMID- 28662355 TI - Metabolic engineering pathways for rare sugars biosynthesis, physiological functionalities, and applications-a review. AB - Biomolecules like rare sugars and their derivatives are referred to as monosaccharides particularly uncommon in nature. Remarkably, many of them have various known physiological functions and biotechnological applications in cosmetics, nutrition, and pharmaceutical industries. Also, they can be exploited as starting materials for synthesizing fascinating natural bioproducts with significant biological activities. Regrettably, most of the rare sugars are quite expensive, and their synthetic chemical routes are both limited and economically unfeasible due to expensive raw materials. On the other hand, their production by enzymatic means often suffers from low space-time yields and high catalyst costs due to hasty enzyme denaturation/degradation. In this context, biosynthesis of rare sugars with industrial importance is receiving renowned scientific attention, across the globe. Moreover, the utilization of renewable resources as energy sources via microbial fermentation or microbial metabolic engineering has appeared a new tool. This article presents a comprehensive review of physiological functions and biotechnological applications of rare ketohexoses and aldohexoses, including D-psicose, D-tagatose, L-tagatose, D-sorbose, L-fructose, D-allose, L-glucose, D-gulose, L-talose, L-galactose, and L-fucose. Novel in-vivo recombination pathways based on aldolase and phosphatase for the biosynthesis of rare sugars, particularly D-psicose and D-sorbose using robust microbial strains are also deliberated. PMID- 28662356 TI - A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts. AB - Prior genome-wide association studies for oral clefts have focused on clinic based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4 ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent. PMID- 28662357 TI - Potential applications of luminescent molecular rotors in food science and engineering. AB - Fluorescent molecular rotors (MRs) are compounds whose emission is modulated by segmental mobility; photoexcitation generates a locally excited (LE), planar state that can relax either by radiative decay (emission of a photon) or by formation of a twisted intramolecular charge transfer (TICT) state that can relax nonradiatively due to internal rotation. If the local environment around the probe allows for rapid internal rotation in the excited state, fast non-radiative decay can either effectively quench the fluorescence or generate a second, red shifted emission band. Conversely, any environmental restriction to twisting in the excited state due to free volume, crowding or viscosity, slows rotational relaxation and promotes fluorescence emission from the LE state. The environmental sensitivity of MRs has been exploited extensively in biological applications to sense microviscosity in biofluids, the stability and physical state of biomembranes, and conformational changes in macromolecules. The application of MRs in food research, however, has been only marginally explored. In this review, we summarize the main characteristics of fluorescent MRs, their current applications in biological research and their current and potential applications as sensors of physical properties in food science and engineering. PMID- 28662359 TI - Distinctions between seeking- and non-seeking-treatment research participants: implications for clinical trials effectiveness. PMID- 28662358 TI - Interaction between the ADH1B*3 allele and drinking motives on alcohol use among Black college students. AB - BACKGROUND: Black young adults have lower rates of alcohol use than other racial groups. Genetic factors may protect against drinking. Specifically, the ADH1B*3 allele is present almost exclusively in Black populations and has been protective against alcohol use and alcohol use disorder. The protective effects of the ADH1B*3 allele, however, may differ as a function of alcohol-promoting cognitions. OBJECTIVES: The current study examined whether ADH1B*3 moderated relations of drinking motives with alcohol consumption among Black college drinkers. METHODS: Participants were 241 undergraduate students of self identified Black race (mean age = 20 years; 66% female) who reported consuming alcohol at least once in the past 30 days. RESULTS: ADH1B*3 was not significantly associated with drinking motives or drinking behaviors. However, significant, albeit small, interaction effects of ADH1B*3 with drinking motives on drinking behavior were found; the presence of an ADH1B*3 allele protected against greater drinking quantity among students with high social motives (incidence rate ratio [IRR] = 0.95, 95% CI [0.92, 0.99]) and against frequent drinking among students with low coping motives (IRR = 1.06, 95% CI [1.01, 1.11]). CONCLUSION: These findings represent a novel demonstration of genetic modulation of alcohol-related cognitions within Black college drinkers, although replication is needed. Results represent an initial step toward better characterizing individual differences in associations of drinking motives with drinking behavior, with potential implications for interventions aimed at motivational processes in alcohol use. PMID- 28662360 TI - Adsorption kinetics, isotherm, and thermodynamics studies of acetyl-11-keto-beta boswellic acids (AKBA) from Boswellia serrata extract using macroporous resin. AB - An acetyl-11-keto-beta-boswellic acid (AKBA) is potent anti-inflammatory agent found in Boswellia serrata oleogum resin. Adsorption characteristics of AKBA from B. serrata were studied using macroporous adsorbent resin to understand separation and adsorption mechanism of targeted molecules. Different macroporous resins were screened for adsorption and desorption of AKBA and Indion 830 was screened as it showed higher adsorption capacity. The kinetic equations were studied and results showed that the adsorption of AKBA on Indion 830 was well fitted to the pseudo first-order kinetic model. The influence of two parameters such as temperature (298, 303, and 308 K) and pH (5-8) on the adsorption process was also studied. The experimental data was further investigated using Langmuir, Freundlich, and Temkin isotherm models. It was observed that Langmuir isotherm model was found to be the best fit for AKBA adsorption by Indion 830 and highest adsorption capacity (50.34 mg/g) was obtained at temperature of 303 K. The values of thermodynamic parameters such as the change of Gibbs free energy (DeltaG*), entropy (DeltaS*), and enthalpy (DeltaH*), indicated that the process of adsorption was spontaneous, favourable, and exothermic. PMID- 28662361 TI - Your genes decide what you are listening to. PMID- 28662362 TI - Sirt3-dependent deacetylation of SOD2 plays a protective role against oxidative stress in oocytes from diabetic mice. AB - Maternal diabetes has been demonstrated to adversely affect oocyte quality in mouse oocytes. However, the potential molecular mechanisms are poorly understood. Here, we established a type I diabetic mouse model and detected the increased reactive oxygen species (ROS) levels and decreased Sirt3 expression in oocytes from diabetic mice. Furthermore, we found that forced expression of Sirt3 in diabetic oocytes significantly attenuates such an excessive production of ROS. The acetylation status of lysine 68 of superoxide dismutase (SOD2K68) is dependent on Sirt3 in oocytes. In line with this, SOD2K68 acetylation levels were markedly increased in diabetic oocytes, and Sirt3 overexpression could effectively suppress this tendency. Importantly, the deacetylation-mimetic mutant SOD2K68R is capable of partly preventing the oxidative stress in oocytes from diabetic mice. In conclusion, our findings support a model where Sirt3 plays a protective role against oxidative stress in oocytes exposed to maternal diabetes through deacetylating SOD2K68. PMID- 28662363 TI - Polyvinylsulfonic acid: A Low-cost RNase inhibitor for enhanced RNA preservation and cell-free protein translation. AB - The effectiveness and economics of polyvinyl sulfonic acid (PVSA) as a ribonuclease inhibitor for in vitro systems is reported. PVSA was shown to inhibit RNA cleavage in the presence of RNase A as well as in the presence of Escherichia coli lysate, suggesting that PVSA can act as a broader ribonuclease inhibitor. In addition, PVSA was shown to improve the integrity of mRNA transcripts by up to 5-fold in vitro as measured by their translational viability. Improved preservation of mRNA transcripts in the presence of PVSA under common RNA storage conditions is also reported. A cost comparison with commercially available RNAse inhibitors indicates the economic practicality of PVSA which is approximately 1,700 times less expensive than commonly used ribonuclease inhibitors. PVSA can also be separated from RNA by alcohol precipitation for applications that may be sensitive to the presence of PVSA. PMID- 28662364 TI - Data Logger Technologies for Powered Wheelchairs: A Scoping Review. AB - In recent years, studies increasingly employed data loggers to record the objective behaviors of powered wheelchair users. Of the data logging work reported in the literature, the technologies used offer marked differences in characteristics. In order to identify and describe the extent of published research activity that relies on data logger technologies for powered wheelchairs, we performed a scoping review of the scientific and grey literature. This scoping review, complementary to a previous one related to manual wheelchairs, is part of a process aiming to help further the development and increase the functionality of data loggers with wheelchairs. Five databases were searched: Medline, Compendex, CINAHL, EMBASE, Google Scholar. Sixty papers were retained for analysis. The most frequently used technologies were all installed on the wheelchair: 19.0% were accelerometers, 14.6% were pressure sensors or switches, 13.9% were odometers, 10.9% were global positioning systems, 9.5% were tilt sensors, and 7.3% were force-sensing technologies. The most reported outcomes were pressure-relief activities (17.3%), distance traveled (9.3%), mobility events (8.9%), acceleration (8.5%), and sitting time (6.9%). Future research may be needed to assess the usefulness of different outcomes and to develop methods more appropriate to optimize the practicality of wheelchair data loggers. PMID- 28662365 TI - A compensatory mutagenesis study of a conserved hairpin in the M gene segment of influenza A virus shows its role in virus replication. AB - RNA structures are increasingly recognized to be of importance during influenza A virus replication. Here, we investigated a predicted conserved hairpin in the M gene segment (nt 967-994) within the region of the vRNA 5' packaging signal. The existence of this RNA structure and its possible role in virus replication was investigated using a compensatory mutagenesis approach. Mutations were introduced in the hairpin stem, based on natural variation. Virus replication properties were studied for the mutant viruses with disrupted and restored RNA structures. Viruses with structure-disrupting mutations had lower virus titers and a significantly reduced median plaque size when compared with the wild-type (WT) virus, while viruses with structure restoring-mutations replicated comparable to WT. Moreover, virus replication was also reduced when mutations were introduced in the hairpin loop, suggesting its involvement in RNA interactions. Northern blot and FACS experiments were performed to study differences in RNA levels as well as production of M1 and M2 proteins, expressed via alternative splicing. Stem-disruptive mutants caused lower vRNA and M2 mRNA levels and reduced M2 protein production at early time-points. When the RNA structure was restored, vRNA, M2 mRNA and M2 protein levels were increased, demonstrating a compensatory effect. Thus, this study provides evidence for functional importance of the predicted M RNA structure and suggests its role in splicing regulation. PMID- 28662367 TI - Inhibition of the miR-17-92 Cluster Separates Stages of Palatogenesis. AB - The role that noncoding regions of the genome play in the etiology of cleft palate is not well studied. A novel method of microRNA (miR) inhibition that allows for specific miR knockdown in vivo has been developed by our laboratory. To further understand the role of miRs in palatogenesis, we used a new mouse model to inhibit specific miRs within the miR-17-92 cluster. Transgenic mice expressing inhibitory complexes for miR-17 and miR-18 manifested a clefting phenotype that was distinct from that observed in mice carrying inhibitory complexes for miR-17, miR-18, miR-19, and miR-92. An in silico candidate gene analysis and bioinformatics review led us to identify TGFBR2 as a likely target of miR-17 and miR-19 family members. Reverse transcription polymerase chain reaction (RT-PCR) experiments showed that TGFBR1 and TGFBR2 expression levels were elevated in the palates of these miR transgenic embryos at embryonic day 15.5. RT-PCR data also showed that the expression of mature miRs from the miR-17 92 cluster was significantly decreased in the transgenic embryos. Decreased expression of TGFB pathway signaling ligands was also observed. Experiments in cells showed that inhibition of miR-17 and miR-18 was sufficient to induce increases in expression of TGFB receptors, while a concomitant decrease in TGFB signaling ligands was not observed. RT-PCR of mature miR-17-92 in cells demonstrated the selectivity and specificity of inhibitory complexes. While this study builds on previous studies that have implicated miR-17-92 in the regulation of important molecular components of the TGFB signaling pathway, it is likely that interactions remain to be elucidated between miR-17-92 and as-of-yet unidentified molecules important for the control of palatogenesis. The differential regulation of palatogenesis by members of the miR-17-92 cluster indicates that several gene combinations regulate palate elevation and extension during development. PMID- 28662369 TI - Generation of Genomic Deletions (of Rig-I GENE) in Goat Primary Cell Culture Using CRISPR/CAS9 Method. AB - CRISPR/Cas9 system is a natural immune system in prokaryotes protecting them from infectious viral or plasmid DNA invading the cells. This RNA-guided system can act as powerful tool for introducing genomic alterations in eukaryotic cells with high efficiency. In the present study, Rig-Igene is taken as model gene to study the efficiency of CRISPR/Cas9 system induced gene deletion in primary fibroblast cell culture. Rig-I(retinoic acid-inducible gene-1) is involved in regulating immune response in mammals. In this study, we optimized the CRISPR/Cas9 method for knocking out Rig-Igene in Goat primary fibroblasts by using a NHEJ pathway. Cells were screened for inactivation of the Rig-Igene and two positive clones were found out of thirty colonies screened. Thus, cells containing Rig-Igene inactivation could be achieved by CRISPR/Cas9 in goat fibroblast cells. PMID- 28662370 TI - Early Exposure to Recommended Calorie Delivery in the Intensive Care Unit Is Associated With Increased Mortality in Patients With Acute Respiratory Distress Syndrome. AB - BACKGROUND: The Intensive Nutrition in Acute Lung Injury: Clinical Trial (INTACT), designed to evaluate outcomes of calorie delivery from acute respiratory distress syndrome (ARDS) diagnosis through hospital discharge, was stopped due to higher mortality in the intervention group. Post hoc analysis found timing and dose of calorie delivery influenced mortality. The objective of this retrospective cohort study was to determine if early vs late calorie exposure changed the hazard of death among a larger sample of patients with ARDS. METHODS: Adult patients who met the eligibility criteria for INTACT but did not participate were included. Daily calorie delivery was collected from the date INTACT eligibility was determined to extubation or death. Cox proportional hazards regression was used to model the relationship between hazard of hospital death with average calorie exposure received over increasing study days and after day 7. RESULTS: A total of 298 patients were included; overall mortality was 33%. Among patients who remained intubated at 1 week (n = 202), higher kcal/kg received from intensive care unit (ICU) days 1-6 increased hazards of subsequent death on days 7+ (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01 1.06); kcal/kg received after ICU day 7 decreased the hazards of death on day 7+ (HR, 0.53; 95% CI, 0.33-0.84). CONCLUSIONS: Higher calorie exposure between ICU days 1 and 7 was associated with higher subsequent hazard of mortality, and provision of high-calorie exposure after day 8 decreased the hazards of death. PMID- 28662366 TI - The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse beta cells and their translational relevance. AB - In beta cells, stimulation by metabolic, hormonal, neuronal, and pharmacological factors is coupled to secretion of insulin through different intracellular signaling pathways. Our knowledge about the molecular machinery supporting these pathways and the patterns of signals it generates comes mostly from rodent models, especially the laboratory mouse. The increased availability of human islets for research during the last few decades has yielded new insights into the specifics in signaling pathways leading to insulin secretion in humans. In this review, we follow the most central triggering pathway to insulin secretion from its very beginning when glucose enters the beta cell to the calcium oscillations it produces to trigger fusion of insulin containing granules with the plasma membrane. Along the way, we describe the crucial building blocks that contribute to the flow of information and focus on their functional role in mice and humans and on their translational implications. PMID- 28662368 TI - Integration of mesenchymal stem cells into islet cell spheroids improves long term viability, but not islet function. AB - Pancreatic islets, especially the large islets (> 150um in diameter) have poor survival rates in culture. Co-culturing with mesenchymal stem cells (MSCs) has been shown to improve islet survival and function. However, most co-culture studies have been comprised of MSC surrounding islets in the media. The purpose of this study was to determine whether islet survival and function was improved when the 2 populations of cells were intermingled with each other in a defined geometry. Hybrid spheroids containing 25, 50 or 75 or 90% islets cells with appropriate numbers of MSCs were created along with spheroids comprised of only islet cells or only MSCs. Spheroids were tested for yield, viability, diameter, cellular composition, and glucose-stimulated insulin secretion. The 25% islet/75% MSC group created the fewest spheroids, with the poorest survival and insulin secretion and the largest diameter. The remaining groups were highly viable with average diameters under 80um at formation. However, the hybrid spheroid groups preferred to cluster in islet-only spheroids. The 50, 75 and 90% islet cell groups had excellent long-term survival with 90-95% viability at 2 weeks in culture, compared with the islet only group that were below 80% viability. The glucose-stimulated insulin secretion was not statistically different for the 50, 75, or 90 groups when exposed to 2.4, 16.8, or 22.4 mM glucose. Only the spheroids with 25% islet cells had a statistically lower levels of insulin release, and the 100% had statistically higher levels at 22.4 mM glucose and in response to secretagogue. Thus, imbedded co-culture improved long-term viability, but failed to enhance glucose-stimulated insulin secretion in vitro. PMID- 28662371 TI - Modeling food matrix effects on chemical reactivity: Challenges and perspectives. AB - The same chemical reaction may be different in terms of its position of the equilibrium (i.e., thermodynamics) and its kinetics when studied in different foods. The diversity in the chemical composition of food and in its structural organization at macro-, meso-, and microscopic levels, that is, the food matrix, is responsible for this difference. In this viewpoint paper, the multiple, and interconnected ways the food matrix can affect chemical reactivity are summarized. Moreover, mechanistic and empirical approaches to explain and predict the effect of food matrix on chemical reactivity are described. Mechanistic models aim to quantify the effect of food matrix based on a detailed understanding of the chemical and physical phenomena occurring in food. Their applicability is limited at the moment to very simple food systems. Empirical modeling based on machine learning combined with data-mining techniques may represent an alternative, useful option to predict the effect of the food matrix on chemical reactivity and to identify chemical and physical properties to be further tested. In such a way the mechanistic understanding of the effect of the food matrix on chemical reactions can be improved. PMID- 28662372 TI - Parenteral Nutrition Errors and Potential Errors Reported Over the Past 10 Years. AB - Parenteral nutrition (PN) is a complex, high-alert medication, and errors associated with the use of this therapy may lead to significant harm to patients. This document reviews error reports from the Institute for Safe Medication Practices' Medication Errors Reporting Program that are associated with the PN use process over the past 10 years. Actual PN-related errors are outlined, with most occurring in the PN-compounding/dispensing and PN administration steps. Clinicians involved in any phase of the PN use process should review their institutional or homecare company's processes for reporting of PN errors and collaborate with their medical safety officer and/or committees involved with medication error reporting. PMID- 28662373 TI - Anastomotic patterns of the facial parotid plexus (PP): A human cadaver study. AB - Details of the human facial parotid plexus (PP) are not readily accessible during ordinary anatomical teaching because of insufficient time and difficulties encountered in the preparation. For parotid and facial nerve surgery however, precise knowledge of PP is of crucial importance. The aim of this study was therefore to provide more details of PP in anatomic specimens. Following anatomical dissection, its location, syntopy and morphology were analyzed in 158 cervico-facial halves of 95 cadavers. The facial nerve (FN) divides into a larger temporo-facial and a smaller cervico-facial trunk. Both trunks branch, form PP, and thus form connections along six distinctive anastomotic types. These anastomoses may explain why accidental or essential severance of a supposed terminal facial branch fails to result in the expected muscle weakness. However, whereas earlier anatomical and clinical studies report connections between both trunks in 67-90% of the cases, our data indicate the presence of anastomoses only in 44%. One reason for this difference may be found in our microscope-assisted dissection in infratemporal regions from which the parotid gland has been removed. Thereby we tracked both FN-trunks in both directions - distally and proximally - and determined the exact origin of all terminal FN branches. This lower rate of occurrence of connections between both trunks reduces the chances of luckily preserved muscle innervation and enhances the risk of facial palsy after transection of a terminal branch. Accordingly, precise anatomical knowledge on PP should be renewed and transection of facial nerve branches avoided. PMID- 28662374 TI - Multiple Oral Deep Penetrating Nevi Extending to the Masseter and Buccal Fat Pad. AB - The deep penetrating nevus (DPN) is a rare benign melanocytic tumor often clinically and histopathologically mistaken for malignant melanoma (MM) and other nevus types. This report describes an extremely rare case of multiple lesions of a large DPN in the oral cavity with extensive infiltration to the minor salivary gland, buccal fat pad, buccinators, and masseter muscles, yet with preservation of the normal anatomic architecture. After receiving a diagnosis of MM in another hospital, the patient was at risk for receiving a wide excision that included the masticatory muscles, facial nerve, and overlying skin. Histopathologically, distinct cellular properties were completely masked with heavy pigmentation, thus precluding a proper distinction of benignity versus malignancy. The proliferative capacity of the tumor was analyzed further by immunohistochemistry of bleached tissue sections and tumor behavior was indirectly evaluated by insufficient tumor stromal interaction, with the conclusion that the specimen was benign. Conservative surgery was limited to the oral cavity. Multiple DPNs in the oral cavity merit attention because of the high risk of being mistaken for MM, which would require a wider surgical excision of the head and neck region. PMID- 28662375 TI - The impact of chronic mild stress on long-term depressive behavior in rats which have survived sepsis. AB - The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis. PMID- 28662376 TI - Proteases, actinidin, papain and trypsin reduce oral biofilm on the tongue in elderly subjects and in vitro. AB - OBJECTIVE: Dental plaque is a causative factor for oral disease and a potential reservoir for respiratory infection in the elderly. Therefore, there is a critical need for the development of effective methods to remove oral biofilm. The objective of this study was to investigate the effect of proteases on oral biofilm formation andremoval. DESIGN: The in vivo effect of actinidin, a cysteine protease, on the removal of tongue coating was assessed after orally taking a protease tablet. Effects of the proteases trypsin, papain and actinidin on Actinomyces monospecies biofilm and multispecies biofilm that was reconstructed using a plaque sample from the tongue coating were investigated using the microtiter plate method. Antimicrobial tests and limited proteolysis of fimbrial shaft proteins were also performed to clarify underlying mechanisms of oral biofilm removal. RESULTS: Tablets containing actinidin removed tongue coating in elderly subjects. Oral Actinomyces biofilm was significantly reduced by the proteases papain, actinidin and trypsin. Papain and trypsin effectively digested the major fimbrial proteins, FimP and FimA, from Actinomyces. Actinidin, papain and trypsin reduced multispecies biofilm that was reconstructed in vitro. Papain and trypsin inhibited formation of multispecies biofilm in vitro. CONCLUSIONS: This study shows that proteases reduced oral biofilm in vivo in elderly subjects and in vitro, and suggests that protease digests fimbriae and inhibits biofilm formation. PMID- 28662377 TI - A multifactor model for predicting mortality in critically ill patients: A multicenter prospective cohort study. AB - PURPOSE: The objective of this study was to develop a model using a combination of routine clinical variables to predict mortality in critically ill patients. METHODS: A cohort of 500 patients recruited from eight university hospital intensive care units (ICUs) was used to develop a model via logistic regression analyses. Discrimination and calibration analyses were performed to assess the model. RESULTS: The model included the lactate level (odds ratio [OR]=1.11, 95% confidence interval [CI] 1.01 to 1.22, P=0.029), neutrophil-to-lymphocyte ratio (OR=1.03, 95% CI 1.01 to 1.04, P=0.002), acute physiology score (OR=1.11, 95% CI 1.06 to 1.15, P<0.001), Charlson comorbidity index (OR=1.36, 95% CI 1.15 to 1.60, P<0.001) and surgery type (OR: selective=Ref, no surgery=8.04, 95% CI 3.74 to 17.30, P<0.001, emergency=3.66, 95% CI 1.60 to 8.36, P=0.002). The model showed good discrimination (area under receiver operating characteristic curve: 0.84, 95% CI: 0.80 to 0.87) and calibration (Hosmer-Lemeshow test P=0.137) for predicting in-hospital mortality. CONCLUSION: The developed multifactor model can be used to effectively predict mortality in critically ill patients at ICU admission. PMID- 28662379 TI - In Search of Metrics that Matter. PMID- 28662380 TI - Principles of Systems Biology, No. 18. AB - This month: imaging the organelle interactome (Lippincott-Schwartz), big data immunology (Pulendran, Ginhoux), protein interactomes expand (Barna, Harper, Marcotte), and computation/engineering insights (Milinkovitch, Silver, and Sastry). PMID- 28662378 TI - Application of a flexible lightwand in percutaneous dilatational tracheotomy. AB - PURPOSE: By comparing flexible lightwand-assisted and conventional endotracheal tube (ETT) withdrawal in percutaneous dilatational tracheotomy (PDT), this paper aims to provide guidance for precise ETT withdrawal by anesthesiologists and accurate determination of the incision site by surgeons. METHODS: Sixty patients who underwent PDT in our hospital were randomly divided into the lightwand group (Group L, n=30) and the withdrawal group (Group W, n=30) using the envelope method. For Group L patients, a flexible lightwand was inserted into an ETT (based on the patient's size), the light source was positioned at the root of the cuff, and the depth from the root of the cuff to the end of the ETT was marked. The flexible lightwand was inserted into the patient's ETT to the marked depth. The ETT along with the flexible lightwand was withdrawn until the highlighted spot was located at the level of the thyroid cartilage. The incision site was approximately 3 finger widths (approximately 4.8cm) below the highlighted spot. For Group W patients, the ETT was withdrawn to a tube depth of 17cm at the upper incisors in males and 15cm in females, and surgeons determined incision sites without assistance. The following metrics were recorded for the two groups: occurrences of inadvertent extubation, ETT puncture and cuff rupture; success rate of first puncture; hypoxia rate; SpO2 at the time of tracheostomy cannula intubation (T1); and postoperative hemorrhage rate. RESULTS: Inadvertent extubation, ETT puncture and cuff rupture occurred significantly less frequently in Group L than in Group W, and the success rate of first puncture and SpO2 at T1 were markedly higher in Group L than in Group W. Moreover, significant between group differences in hypoxia rate and postoperative hemorrhage rate were observed. CONCLUSIONS: The use of a flexible lightwand in PDT is a safe and effective approach. This approach can effectively and directly guide precise ETT repositioning and provide incision site confirmation with few intra- and postoperative anesthesia-related or operative complications compared with the traditional technique of ETT withdrawal to a pre-determined depth. PMID- 28662381 TI - What Is the Role of Circuit Design in the Advancement of Synthetic Biology? Part 3. AB - Different biological substrates dictate design rules and enable new functions. PMID- 28662382 TI - New Apex in Proteome Analysis. AB - Improved sample processing workflows enable rapid, deep analysis of human cellular and tissue proteomes. PMID- 28662383 TI - Tracking the Missing Footprints of Idle Ribosomes. AB - Once inactive ribosomes are accounted for, ribosome footprint profiling data and pulse-labeled proteomics provide similar, accurate measurements of protein synthesis. PMID- 28662384 TI - Kinetochores: Importance of Being Fashionably Late. AB - A model explains how a critical delay before microtubules detach from kinetochores during cell division might be achieved. PMID- 28662385 TI - Hepatic fat quantification using automated six-point Dixon: Comparison with conventional chemical shift based sequences and computed tomography. AB - PURPOSE: To compare automated six-point Dixon (6-p-Dixon) MRI comparing with dual echo chemical-shift-imaging (CSI) and CT for hepatic fat fraction in phantoms and clinical study. MATERIALS AND METHODS: Phantoms and fifty-nine patients were examined both MRI and CT for quantitative fat measurements. RESULTS: In phantom study, linear regression between fat concentration and 6-p-Dixon showed good agreement. In clinical study, linear regression between 6-p-Dixon and dual-echo CSI showed good agreement. CT attenuation value was strongly correlated with 6-p Dixon (R2=0.852; P<0.001) and dual-echo CSI (R2=0.812; P<0.001). CONCLUSION: Automated 6-p-Dixon and dual-echo CSI were accurate correlation with CT attenuation value of liver parenchyma. 6-p-Dixon has the potential for automated hepatic fat quantification. PMID- 28662386 TI - Phenols recovery after steam explosion of Olive Mill Solid Waste and its influence on a subsequent biomethanization process. AB - A promising source of high added value compounds is the Olive Mill Solid Waste (OMSW). The aim of this research was to evaluate the viability of a biorefinery approach to valorize OMSW through the combination of steam explosion, phenols extraction, and anaerobic digestion. Steam explosion treatment increased the total phenol content in the steam exploited OMSW, which was twice than that the total phenol content in raw OMSW, although some undesirable compounds were also formed. Phenol extraction allowed the recovery of 2098mg hydroxytyrosol per kg of OMSW. Anaerobic digestion allowed the partial stabilization of the different substrates, although it was not improved by the steam explosion treatment. The economic suitability of the proposed biorefinery approach is favorable up to a phenol extract price 90.7% lower than the referenced actual price of 520?/kg. PMID- 28662387 TI - alpha, omega-Dodecanedioic acid production by Candida viswanathii ipe-1 with co utilization of wheat straw hydrolysates and n-dodecane. AB - Candida viswanathii ipe-1 was used to produce alpha, omega-dodecanedioic acid (DC12), which showed capability to ferment xylose and glucose simultaneously, while arabinose utilization was less efficient. A low concentration of furfural enhanced cell growth, and the addition of 4.0g/L sodium acetate largely increased DC12 production. It indicated that detoxification of the wheat straw hydrolysates was not necessary for the biosynthesis of DC12. Based on the promising features of our strain, an efficient process was developed to produce DC12 from co utilization of wheat straw hydrolysates and n-dodecane. Using this process, 129.7g/L DC12 with a corresponding productivity of 1.13g.L-1.h-1 could be produced, which was increased by 40.0% compared with a sole carbon of glucose. The improved DC12 yield by the co-utilization of wheat straw hydrolysates and n dodecane using C. viswanathii ipe-1 demonstrates the great potential of using biomass as a feedstock in the production of DC12. PMID- 28662388 TI - White-rot fungi pretreatment combined with alkaline/oxidative pretreatment to improve enzymatic saccharification of industrial hemp. AB - White-rot fungi combined with alkaline/oxidative (A/O) pretreatments of industrial hemp woody core were proposed to improve enzymatic saccharification. In this study, hemp woody core were treated with only white rot fungi, only A/O and combined with the two methods. The results showed that Pleurotus eryngii (P. eryngii) was the most effective fungus for pretreatment. Reducing sugars yield was 329mg/g with 30 Filter Paper Unit (FPU)/g cellulase loading when treated 21day. In the A/O groups, the results showed that when treated with 3% NaOH and 3% H2O2, the yield of reducing sugars was 288mg/g with 30FPU/g cellulase loading. After combination pretreatment with P. eryngii and A/O pretreatment, the reducing sugar yield from enzymatic hydrolysis of combined sample increased 1.10-1.29-fold than that of bio-treated or A/O pretreatment sample at the same conditions, suggesting that P. eryngii combined with A/O pretreatment was an effective method to improve enzyme hydrolysis. PMID- 28662390 TI - Targeting property and toxicity of a novel ultrasound contrast agent microbubble carrying the targeting and drug-loaded complex FA-CNTs-PTX on MCF7 cells. AB - The application of ultrasound contrast agents not only is confined to the enhancement of ultrasound imaging but also has started to be used as a drug system for diagnosis and treatment. In this paper, Span60 and PEG1500 were used as membrane materials, and a new targeting and drug-loading multifunctional ultrasound contrast agent microbubble enveloping the FA-CNTs-PTX complex was successfully prepared by acoustic cavitation. With the breast cancer cell line MCF7 as the research target, the effects of the microbubble with FA-CNTs-PTX on the proliferation and toxicity of MCF7 cells were studied using a CCK-8 and AO/EB double-staining method. The influences of the microbubbles with FA-CNTs-PTX on the cellular morphology and apoptosis period of the MCF7 cells were detected using an inverted fluorescence microscope. The apoptosis of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was investigated with flow cytometry and an annexin and PI double staining fluorescence quantitative analysis. The results indicated that the ultrasound contrast agent microbubble with FA-CNTs-PTX remarkably inhibited the proliferation of MCF7 cells, which was mainly controlled by the drug loading rate and the nanometer size of the microbubbles. Moreover, the proliferative inhibition rate of the microbubbles with FA-CNTs-PTX was related to the cell apoptosis period of MCF7 cells. Its inhibition degree on the proliferation of MCF7 cells was higher than that of the hepatoma HepG2 cells. The apoptosis rate of MCF7 cells induced by the microbubbles with FA-CNTs-PTX was higher than that of normal human umbilical vein endothelial cells (HUVECs), and the microbubbles with FA-CNTs-PTX could target the MCF7 cells. PMID- 28662389 TI - Recent progress in developing selective inhibitors of protein methyltransferases. AB - Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histones as well as non-histone proteins, play a crucial role in diverse biological pathways and human diseases. In particular, PMTs have been recognized as major players in regulating gene expression and chromatin state. There has been an increasingly growing interest in these enzymes as potential therapeutic targets and over the past two years tremendous progress has been made in the discovery of selective, small molecule inhibitors of protein lysine and arginine methyltransferases. Inhibitors of PMTs have been used extensively in oncology studies as tool compounds, and inhibitors of EZH2, DOT1L and PRMT5 are currently in clinical trials. PMID- 28662391 TI - Gold nanoparticles as an efficient drug delivery system for GLP-1 peptides. AB - In this work, the potential application of gold nanoparticles for GLP-1 analogues delivery was studied. For this purpose, the original sequence of the incretin GLP 1 was slightly modified in the C-terminal region by adding a cysteine residue to facilitate conjugation to the gold surface. The interaction between peptides and gold nanoparticles and also the colloid stability of the conjugates were studied by UV-vis spectrophotometry, TEM, IR and XPS spectroscopy. Moreover, the permeability of these conjugates was assayed using a Caco-2/goblet monolayer model. On the basis of the stability and permeability results, one of the conjugates was chosen to be administered intraperitoneally to normoglycemic rats. The intraperitoneal delivery of the GLP-1 analogue using gold nanoparticles led to decrease levels of blood glucose in the same way as native GLP-1, thereby demonstrating that the formulation of the analogue is stable in physiological conditions and maintains the activity of this incretin. PMID- 28662392 TI - MC3T3-E1 pre-osteoblast response and differentiation after graphene oxide nanosheet uptake. AB - Nano-graphene oxide (GO) and its functionalized derivatives have aroused a great interest for drug delivery, tissue engineering and photothermal cancer therapy, but their biocompatibility has not yet been fully assessed. The aim of the present study was to evaluate the proliferation and differentiation of MC3T3-E1 pre-osteoblasts after the uptake of GO nanosheets (c.a. 400nm), functionalized with poly(ethylene glycol-amine) (PEG) and labelled with fluorescein isothiocyanate (FITC). Significant proliferation decrease and apoptosis increase were observed 3days after incorporation of FITC-PEG-GO by MC3T3-E1 cells. However, alterations on healthy pre-osteoblast differentiation into cells exhibiting osteoblast phenotype were not observed, as they showed normal alkaline phosphatase levels and matrix mineralization 12days after nanosheet uptake. The results suggest that 40MUg/mL concentrations of these nanosheets would not affect the differentiation of healthy pre-osteoblasts, thus these PEG-GO nanosheets have potential to be used for biomedical applications after their internalization, as the induction of local hyperthermia on bone cancer. PMID- 28662393 TI - Ionic strength-controlled hybridization and stability of hybrids of KRAS DNA single-nucleotides: A surface plasmon resonance study. AB - The discrimination of a fully matched, unlabeled KRAS wild-type (WT) (C-G) target sample with respect to three of the most frequent KRAS codon mutations (G12 S (C A), G12 R (C-C), G12C (C-T)) was investigated using an optimized detection strategy involving surface plasmon resonance (SPR), based on optimized probe surface density and ionic strength control. The changes observed in the SPR signal were always larger for WT compared with the single-mismatch target DNA oligonucleotides, and were aligned with the theoretical energy differences between the base pair C-G, C-T, C-A, C-C. Hybridization rates of ~106M-1s-1 were detected without the introduction of high temperature and labels, usually needed in conventional hybridization methods. One hundred percent mutation discrimination of the matched KRAS wild-type (C-G) sequence with respect to three mismatched G12C (C-T), G12 S (C-A), G12 R (C-C) target sequences was achieved. PMID- 28662394 TI - Omega-3 polyunsaturated fatty acids improve the antioxidative defense in rat astrocytes via an Nrf2-dependent mechanism. AB - BACKGROUND: Neuronal tolerance to hypoxia and nutrient defficiency highly depends on GSH levels and antioxidant enzyme activity in astrocytes. Omega-3 polyunsaturated fatty acids (omega-3PUFA) enhance antioxidant defence in different cells. The aim of present study was to investigate if omega-3PUFA improve antioxidant status in astrocytes. METHODS: Rat primary astrocytes were incubated for 24h with DHA and EPA (30MUM), then lysed, fractioned and fatty acids were determined by gas chromatography. GSH and protein thiols were assayed by enzymatic methods. Glutamate cysteine ligase (GCL), glutathione synthetase (GS), glutathione peroxidase 4 (GPx4) and Nrf2 protein expression was validated by Western blot. Intracellular ROS level using H2DCF-DA, and Nrf2 activation by ELISA were measured. RESULTS: Incubation of cells with DHA doubled DHA, not EPA content in the membranes, and incubation with EPA increased both fatty acids content compared to control. However, both omega-3PUFAs reduced ROS generation in dose-dependent manner in basal condition and in H2O2-treated cells, and significantly increased GSH, GCL and GPx4 levels. The thiols level was higher only in DHA-treated cells. DHA and EPA activated Nrf2 in a dose-dependent manner but p38MAPK-Nrf2 activation was found only in DHA-enriched astrocytes. CONCLUSION: Both omega-3PUFA improved the antioxidant defense in astrocytes via an Nrf2-dependent mechanism, however, upstream pathways of Nrf2 activation may depend on proportion of DHA to EPA incorporated into membrane phospholipids. These results suggest that enrichment of astrocytes with omega-3PUFA may better protect neurons during harmful conditions. PMID- 28662395 TI - Temperature regulates deterministic processes and the succession of microbial interactions in anaerobic digestion process. AB - Temperature plays crucial roles in microbial interactions that affect the stability and performance of anaerobic digestion. In this study, the microbial interactions and their succession in the anaerobic digestion process were investigated at three levels, represented by (1) present and (2) active micro organisms, and (3) gene expressions under a temperature gradient from 25 to 55 degrees C. Network topological features indicated a global variation in microbial interactions at different temperatures. The variations of microbial interactions in terms of network modularity and deterministic processes based on topological features, corresponded well with the variations of methane productions, but not with temperatures. A common successional pattern of microbial interactions was observed at different temperatures, which showed that both deterministic processes and network modularity increased over time during the digestion process. It was concluded that the increase in temperature-mediated network modularity and deterministic processes on shaping the microbial interactions improved the stability and efficiency of anaerobic digestion process. PMID- 28662396 TI - Stormwater loadings of antibiotic resistance genes in an urban stream. AB - Antibiotic resistance presents a critical public health challenge and the transmission of antibiotic resistance via environmental pathways continues to gain attention. Factors driving the spread of antibiotic resistance genes (ARGs) in surface water and sources of ARGs in urban stormwater have not been well characterized. In this study, five ARGs (sul1, sul2, tet(O), tet(W), and erm(F)) were quantified throughout the duration of three storm runoff events in an urban inland stream. Storm loads of all five ARGs were significantly greater than during equivalent background periods. Neither fecal indicator bacteria measured (E. coli or enterococci) was significantly correlated with sul1, sul2, or erm(F), regardless of whether ARG concentration was absolute or normalized to 16S rRNA levels. Both E. coli and enterococci were correlated with the tetracycline resistance genes, tet(O) and tet(W). Next-generation shotgun metagenomic sequencing was conducted to more thoroughly characterize the resistome (i.e., full complement of ARGs) and profile the occurrence of all ARGs described in current databases in storm runoff in order to inform future watershed monitoring and management. Between 37 and 121 different ARGs were detected in each stream sample, though the ARG profiles differed among storms. This study establishes that storm-driven transport of ARGs comprises a considerable fraction of overall downstream loadings and broadly characterizes the urban stormwater resistome to identify potential marker ARGs indicative of impact. PMID- 28662397 TI - Oxidation of beta-lactam antibiotics by peracetic acid: Reaction kinetics, product and pathway evaluation. AB - Peracetic acid (PAA) is a disinfection oxidant used in many industries including wastewater treatment. beta-Lactams, a group of widely prescribed antibiotics, are frequently detected in wastewater effluents and surface waters. The reaction kinetics and transformation of seven beta-lactams (cefalexin (CFX), cefadroxil (CFR), cefapirin (CFP), cephalothin (CFT), ampicillin (AMP), amoxicillin (AMX) and penicillin G (PG)) toward PAA were investigated to elucidate the behavior of beta-lactams during PAA oxidation processes. The reaction follows second-order kinetics and is much faster at pH 5 and 7 than at pH 9 due to speciation of PAA. Reactivity to PAA follows the order of CFR ~ CFX > AMP ~ AMX > CFT ~ CFP ~ PG and is related to beta-lactam's nucleophilicity. The thioether sulfur of beta-lactams is attacked by PAA to generate sulfoxide products. Presence of the phenylglycinyl amino group on beta-lactams can significantly influence electron distribution and the highest occupied molecular orbital (HOMO) location and energy in ways that enhance the reactivity to PAA. Reaction rate constants obtained in clean water matrix can be used to accurately model the decay of beta-lactams by PAA in surface water matrix and only slightly overestimate the decay in wastewater matrix. Results of this study indicate that the oxidative transformation of beta lactams by PAA can be expected under appropriate wastewater treatment conditions. PMID- 28662398 TI - Evaluation of ultrasmall superparamagnetic iron-oxide (USPIO) enhanced MRI with ferumoxytol to quantify arterial wall inflammation. AB - BACKGROUND AND AIMS: Inflammation in atherosclerotic plaques is an important determinant of plaque vulnerability, and can be detected non-invasively using ultra-small superparamagnetic iron-oxide (USPIO) enhanced MRI. The aims of the current study were: 1) to determine whether ferumoxytol can be used for USPIO-MRI of atherosclerotic plaques, 2) to establish a protocol for quantitative USPIO-MRI of carotid artery plaques using ferumoxytol, and 3) to study the relation between USPIO uptake and plaque burden and 18F-fluorodeoxyglucose (FDG) uptake (measured by 18F-FDG PET/CT scan) in atherosclerotic plaques. METHODS: In 9 patients with carotid artery stenosis >30% and 4 healthy controls, quantitative R2* MRI scans of the carotid arteries were performed before and 72 h after USPIO administration (4 mg/kg ferumoxytol). USPIO uptake was assessed by quantifying the difference in R2* (DeltaR2*) between baseline and post-USPIO scans. In addition to MRI, 18F-FDG PET/CT was performed on both carotid arteries. MR and PET/CT images were co registered, and 18F-FDG uptake was quantified in all slices containing atherosclerotic plaque. RESULTS: Infusion of ferumoxytol resulted in higher R2* values after 72 h in atherosclerotic plaques (DeltaR2* 24.6 +/- 19.8 s-1; p = 0.0003), but not in the healthy control vessel wall (DeltaR2* 2.6 +/- 5.6 s-1, p = 0.23). USPIO uptake in patients was higher in atherosclerotic plaques compared to the patient non-plaque vessel wall (DeltaR2* of 24.6 +/- 19.8 vs. 7.5 +/- 9.3 s-1, p = 0.004). No correlation was found between USPIO uptake and 18F-FDG uptake in atherosclerotic plaques (R2 = 0.03, p = 0.55). CONCLUSIONS: Ferumoxytol is selectively taken up by atherosclerotic plaques and can thus be used for carotid USPIO-MRI. As USPIO and 18F-FDG uptake in atherosclerotic plaque do not correlate in this cohort, these agents may visualize different pathophysiological aspects of plaque inflammation. PMID- 28662399 TI - Obesogens in the aquatic environment: an evolutionary and toxicological perspective. AB - The rise of obesity in humans is a major health concern of our times, affecting an increasing proportion of the population worldwide. It is now evident that this phenomenon is not only associated with the lack of exercise and a balanced diet, but also due to environmental factors, such as exposure to environmental chemicals that interfere with lipid homeostasis. These chemicals, also known as obesogens, are present in a wide range of products of our daily life, such as cosmetics, paints, plastics, food cans and pesticide-treated food, among others. A growing body of evidences indicates that their action is not limited to mammals. Obesogens also end up in the aquatic environment, potentially affecting its ecosystems. In fact, reports show that some environmental chemicals are able to alter lipid homeostasis, impacting weight, lipid profile, signaling pathways and/or protein activity, of several taxa of aquatic animals. Such perturbations may give rise to physiological disorders and disease. Although largely unexplored from a comparative perspective, the key molecular components implicated in lipid homeostasis have likely appeared early in animal evolution. Therefore, it is not surprising that the obesogen effects are found in other animal groups beyond mammals. Collectively, data indicates that suspected obesogens impact lipid metabolism across phyla that have diverged over 600 million years ago. Thus, a consistent link between environmental chemical exposure and the obesity epidemic has emerged. This review aims to summarize the available information on the effects of putative obesogens in aquatic organisms, considering the similarities and differences of lipid homeostasis pathways among metazoans, thus contributing to a better understanding of the etiology of obesity in human populations. Finally, we identify the knowledge gaps in this field and we set future research priorities. PMID- 28662400 TI - Linker-free covalent immobilization of heparin, SDF-1alpha, and CD47 on PTFE surface for antithrombogenicity, endothelialization and anti-inflammation. AB - Small-diameter vascular grafts made of biomedical polytetrafluoroethylene (PTFE) suffer from the poor long-term patency rate originating from thrombosis and intimal hyperplasia, which can be ascribed to the insufficient endothelialization and chronic inflammation of the materials. Hence, bio-functionalization of PTFE grafts is highly desirable to circumvent these disadvantages. In this study, a versatile "implantation-incubation" approach in which the biomedical PTFE is initially modified by plasma immersion ion implantation (PIII) is described. After the N2 PIII treatment, the surface of biomedical PTFE is roughened with nanostructures and more importantly, the abundant free radicals generated underneath the surface continuously migrate to the surface and react with environmental molecules. Taking advantage of this mechanism, various biomolecules with different functions can be steadily immobilized on the surface of PTFE by simple solution immersion. As examples, three typical biomolecules, heparin, SDF 1alpha, and CD47, are covalently grafted onto the PTFE. In addition to retaining the bioactivity, the surface-functionalized PTFE exhibits reduced thrombogenicity, facilitates the recruitment of endothelial progenitor cells, and even alleviates the inflammatory immune responses of monocytes-macrophages and is thus promising to the development of small-diameter prosthetic vascular grafts with good long-term patency. PMID- 28662401 TI - Fibrillin-2 and Tenascin-C bridge the age gap in lung epithelial regeneration. AB - Organ engineering based on native matrix scaffolds involves combining regenerative cell populations with corresponding biological matrices to form functional grafts on-demand. The extracellular matrix (ECM) that is retained following lung decellularization provides essential structure and biophysical cues for whole organ regeneration after recellularization. The unique ECM composition in the early post-natal lung, during active alveologenesis, may possess distinct signals that aid in driving cell adhesion, survival, and proliferation. We evaluated the behavior of basal epithelial stem cells (BESCs) isolated from adult human lung tissue, when cultured on acellular ECM derived from neonatal (aged < 1 week) or adult lung donors (n = 3 donors per group). A significant difference in cell proliferation and survival was found. We next performed in-depth proteomic analysis of the lung scaffolds to quantify proteins significantly enriched in the neonatal ECM, and identified the glycoproteins Fibrillin-2 (FBN-2) and Tenascin-C (TN-C) as potential mediators of the observed effect. BESCs cultured on Collagen Type IV coated plates, supplemented with FBN-2 and TN-C demonstrated significantly increased proliferation and decreased cellular senescence. No significant increase in epithelial-to-mesenchymal transition was observed. In vitro migration was also increased by FBN-2 and TN-C treatment. Decellularized lung scaffolds treated with FBN-2 and TN-C prior to re epithelialization supported greater epithelial proliferation and tissue remodeling. BESC distribution, matrix alignment, and overall tissue morphology was improved on treated lung scaffolds, after 3 and 7 days of ex vivo lung culture. These results demonstrate that scaffold re-epithelialization is enhanced on neonatal lung ECM, and that supplementation of FBN-2 and TN-C to the native scaffold may be a valuable tool in lung tissue regeneration. PMID- 28662403 TI - Iron oxide-mediated semiconductor photocatalysis vs. heterogeneous photo-Fenton treatment of viruses in wastewater. Impact of the oxide particle size. AB - The photo-Fenton process is recognized as a promising technique towards microorganism disinfection in wastewater, but its efficiency is hampered at near neutral pH operating values. In this work, we overcome these obstacles by using the heterogeneous photo-Fenton process as the default disinfecting technique, targeting MS2 coliphage in wastewater. The use of low concentrations of iron oxides in wastewater without H2O2 (wustite, maghemite, magnetite) has demonstrated limited semiconductor-mediated MS2 inactivation. Changing the operational pH and the size of the oxide particles indicated that the isoelectric point of the iron oxides and the active surface area are crucial in the success of the process, and the possible underlying mechanisms are investigated. Furthermore, the addition of low amounts of Fe-oxides (1mgL-1) and H2O2 in the system (1, 5 and 10mgL-1) greatly enhanced the inactivation process, leading to heterogeneous photo-Fenton processes on the surface of the magnetically separable oxides used. Additionally, photo-dissolution of iron in the bulk, lead to homogeneous photo-Fenton, further aided by the complexation by the dissolved organic matter in the solution. Finally, we assess the impact of the presence of the bacterial host and the difference caused by the different iron sources (salts, oxides) and the Fe-oxide size (normal, nano-sized). PMID- 28662404 TI - Novel laser induced photoacoustic spectroscopy for instantaneous trace detection of explosive materials. AB - Laser photoacoustic spectroscopy (LPAS) is an attractive technology in terms of simplicity, ruggedness, and overall sensitivity; it detects the time dependent heat generated (thermo-elastic effect) in the target via interaction with pulsed optical radiation. This study reports on novel LPAS technique that offers instant and standoff detection capabilities of trace explosives. Over the current study, light is generated using pulsed Q-switched Nd:YAG laser; the generated photoacoustic response in stimulated explosive material offers signature values that depend on the optical, thermal, and acoustical properties. The generated acoustic waves were captured using piezoelectric transducer as well as novel customized optical sensor with remotely laser interferometer probe. A digital signal processing algorithm was employed to identify explosive material signatures via calculation of characteristic optical properties (absorption coefficient), sound velocity, and frequency response of the generated photoacoustic signal. Customized LPAS technique was employed for instantaneous trace detection of three main different high explosive materials including TNT, RDX, and HMX. The main outcome of this study is that the novel customized optical sensor signals were validated with traditional piezoelectric transducer. Furthermore, the customized optical sensor offered standoff detection capabilities (10cm), fast response, high sensitivity, and enhanced signal to noise ratio. This manuscript shaded the light on the instant detection of trace explosive materials from significant standoffs using novel customized LPAS technique. PMID- 28662402 TI - Construction of an alkaline phosphatase-specific two-photon probe and its imaging application in living cells and tissues. AB - Alkaline phosphatase (ALP) is a family of enzymes involved in the regulation of important biological processes such as cell differentiation and bone mineralization. Monitoring the activity of ALP in serum can help diagnose a variety of diseases including bone and liver diseases. There has been growing interest in developing new chemical tools for monitoring ALP activity in living systems. Such tools will help further delineate the roles of ALP in biological and pathological processes. Previously reported fluorescent probes has a number of disadvantages that limit their application, such as poor selectivity and short wavelength excitation. In this work, we report a new two-photon fluorescent probe (TP-Phos) to selectively detect ALP activity. The probe is composed of a two photon fluorophore, a phosphate recognition moiety, and a self-cleavable adaptor. It offers a number of advantages over previously reported probes, such as fast reaction kinetics, high sensitivity and low cytotoxicity. Experimental results also showed that TP-Phos displayed improved selectivity over DIFMUP, a commonly utilized ALP probe. The selectivity is attributed to the utilization of an ortho functionalised phenyl phosphate group, which increases the steric hindrance of the probe and the active site of phosphatases. Moreover, the two-photon nature of the probe confers enhanced imaging properties such as increased penetration depth and lower tissue autofluorescence. TP-Phos was successfully used to image the endogenous ALP activity of hippocampus, kidney and liver tissues from rat. PMID- 28662405 TI - Effect of electronic and steric properties of 8-substituted quinolines in gold(III) complexes: Synthesis, electrochemistry, stability, interactions and antiproliferative studies. AB - In this work the synthesis and characterization of new gold(III) complexes with quinoline ligands are described. These complexes contain different steric and electronic properties of the donor atom at 8-position of the quinoline in order to modulate their stability and their biological activity. Their redox potential, stability in organic and aqueous solvents, and their biological activity in a panel of six different human tumor cell lines are also presented. In addition, interaction studies of the complexes with model biological molecules (pBR322 and L-acetyl-N-cysteine) were carried out, suggesting that their main target are proteins. From these studies, we have found that the gold(III) complex with an N tosyl-8-aminoquinoline ligand is the most active complex in all the tumor cell lines, including the cisplatin resistant T-47D and WiDr cell lines. Moreover, this complex showed to be the most stable compound in DMSO and saline solution, even after several hours. PMID- 28662406 TI - First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer. AB - BACKGROUND: The efficacy and safety of continuing multiple anti-HER2 therapies in advanced breast cancer (ABC) patients remains unclear. This study investigated eribulin in combination with pertuzumab and trastuzumab for both taxane- and trastuzumab-pretreated HER2-positive ABC patients. METHODS: In a single institute, single-arm, open-label, phase II trial, HER2-positive ABC patients who had previously received taxanes and trastuzumab were treated with eribulin in combination with pertuzumab and trastuzumab. The pharmacokinetics of eribulin in this combination were assessed in 6 patients. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was objective response rate (ORR). RESULTS: A total of 30 patients (median age, 58 years; range, 31-76) were enrolled, with a median number of previous chemotherapy regimens of 3.5 (range: 1-9) in the metastatic setting. Pharmacokinetic parameters of eribulin in this combination were similar to previous reports of eribulin monotherapy. ORR was 34.8% (95% CI: 16.4-57.3, n = 23), and median progression-free survival was 42.6 weeks (95% CI: 20.3-51.9, n = 30). Clinical benefit rate was 60.9% (95% CI: 16.4-57.3). The most common grade 3/4 adverse event was neutropenia in 20 patients (66.7%). A dose reduction of eribulin was required in 27 patients due to adverse events, particularly grade 3 neutropenia. CONCLUSIONS: Eribulin in combination with pertuzumab and trastuzumab was well tolerated in heavily pretreated patients. Eribulin may be a viable treatment option when used in combination with pertuzumab and trastuzumab for HER2-positive ABC patients (UMIN Clinical Trial Registry identification number, UMIN000012375). PMID- 28662407 TI - Role of the triple solute/ion/water interactions on the saccharide hydration: A volumetric approach. AB - The aim of this study is to further the understanding of the mechanisms that govern the hydration behavior of neutral solutes, with respect to the ions' properties that are present in a solution. For that, a systematic volumetric study of saccharides (xylose, glucose and sucrose), in the presence of various electrolytes (LiCl, NaCl, KCl, Na2SO4, K2SO4, CaCl2, MgCl2, MgSO4) has been carried out with density measurements at 298.15 K. From this data, the standard transfer molar volume of the saccharide DeltaVphi,S0, which characterizes the hydration state of the solute, has been determined. Positive and increasing values of DeltaVphi,S0 with increasing electrolyte concentrations were obtained. This indicated the dehydration of the saccharide in the presence of the electrolyte, due to the predominance of saccharide/cation interactions. Concerning the influence of the cation, it was shown that saccharides are more dehydrated in the presence of divalent cations than in the presence of monovalent ones. This is because the interactions are stronger between saccharides and divalent cations, in comparison to those with monovalent cations. For a specific cation valence and molality, regardless of the anion, saccharide dehydration increases according to the following sequences: Li+< Na+< K+ and Mg2+< Ca2+. These saccharide dehydration sequences have been explained by the Gibbs free energy of hydration of the cations, reflecting the cation/water interactions. For a specific cation valence, it was concluded that decreasing cation/water interactions induce the increase of saccharide dehydration. Concerning the influence of the anion, it was also observed that saccharides are more dehydrated in the presence of divalent anions than in the presence of monovalent ones. It was stated that saccharide/cation interactions are modulated by the nature of the anion. The anion impact was again attributed to its capacity to interact with water molecules. It was pointed out that anions with increasing values of Gibbs free energy of hydration cause an increase in saccharide/cation interactions or a decrease in saccharide/anion interactions. Therefore, saccharide dehydration increases. PMID- 28662408 TI - A quantitative method for analyzing glycome profiles of plant cell walls. AB - Glycome profiling allows for the characterization of plant cell wall ultrastructure via sequential extractions and subsequent detection of specific epitopes with a suite of glycan-specific monoclonal antibodies (mAbs). The data are often viewed as the amount of materials recovered and coinciding colored heatmaps of mAb binding are generated. Interpretation of these data can be considered qualitative in nature as it depends on detecting subtle visual differences in antibody binding strength. Here, we report a mixed model-based quantitative approach for glycome profile analyses, which accounts for the amount of materials recovered and displays the normalized values in revised heatmaps and statistical heatmaps depicting significant differences. The utility of this methodology was demonstrated on a previously published dataset investigating the effects of moisture stress on the roots and needles of Pinus taeda. An annotated R script for the quantitative methodology is included to allow future studies to utilize the same approach. PMID- 28662409 TI - Human placental mesenchymal stem cells of fetal origins-alleviated inflammation and fibrosis by attenuating MyD88 signaling in bleomycin-induced pulmonary fibrosis mice. AB - Pulmonary fibrosis is a progressive lung disease that its pathogenic mechanism currently is incompletely understood. Toll-like receptor (TLR) signaling has recently been identified as a regulator of inflammation and pulmonary fibrosis. In addition, mesenchymal stem cells (MSCs) of different origins offer a great promise in treatment of idiopathic pulmonary fibrosis (IPF). However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins (hfPMSCs). The results showed an alleviated pulmonary inflammation and fibrosis in myeloid differentiation primary response gene 88 (MyD88)-deficient mice treated with bleomycin (BLM), accompanied with a reduced TGF-beta signaling and production of pro-fibrotic cytokines, including TNF-alpha, IL-1beta. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-beta signaling cascades. Of interest, enforced expression and inhibition of MyD88 protein resulted in an enhanced and a reduced TGF-beta signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-beta1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary fibrosis in mice, along with a reduced hydroxyproline (HYP) deposition, MyD88 and TGF-beta signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of MyD88/TGF-beta signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary fibrosis. PMID- 28662410 TI - LEI0258 microsatellite variability and its association with humoral and cell mediated immune responses in broiler chickens. AB - Major histocompatibility complex (MHC) has a profound influence on disease resistance or susceptibility, productivity and important economic traits in chicken. Association of the MHC with a wide range of immune responses makes it a valuable predictive factor for the disease pathogenesis and outcome. The tandem repeat LEI0258 is a genetic marker which is located within the B locus of chicken MHC and strongly associated with serologically defined haplotypes. LEI0258 microsatellite marker was applied to investigate the MHC polymorphism in Ross 308 broiler chicken (N=104). Association of LEI0258 alleles with humoral and cell mediated immune responses to Newcastle disease (ND), Infectious bursal disease (IBD) and Avian influenza (AI) vaccines were also examined. LEI0258 polymorphism was determined by PCR-based fragment analysis, and association of LEI0258 alleles with immune responses were evaluated using multivariate regression analysis and GLM procedures. A total of seven alleles ranging from 195 to 448bp were found, including two novel alleles (263 and 362bp) that were unique in Ross 308 broiler population. Association study revealed a significant influence of MHC alleles on humoral and cellular immune responses in Ross population (P<0.05). Alleles 385 and 448bp were associated with increased peripheral blood lymphocyte proliferation response. Alleles 300, 362 and 448bp had a positive effect on immune responses to Infectious bursal disease vaccine, and allele 263bp was significantly correlated with elevated antibody titer against Newcastle disease vaccine. Results obtained from this study confirmed the important role of MHC as a candidate gene marker for immune responses that could be used in genetic improvement of disease-resistant traits and resource conservation in broiler population. PMID- 28662412 TI - Correlation between deposition parameters of periodic titanium metal/oxide nanometric multilayers and their chemical and structural properties investigated by STEM-EELS. AB - We analyze structure and composition of titanium-based metal/oxide periodic multilayers prepared by reactive sputtering. The reactive gas pulsing process is involved to periodically inject the oxygen gas during the multilayers deposition. This approach allows the growth of regular and tunable nanometric TiO2/Ti periods with thicknesses ranging from 14 to 50nm. The interfacial layer between oxide and metallic layers is mainly the fcc-TiO phase as clearly pointed out by transmission electron microscopy and associated electron spectroscopies. In addition, sharp transitions are produced at Ti/TiO2 interfaces (with a high density of defects) whereas the smoothest ones are obtained at TiO2/Ti interfaces. Similarly, the real-time measurements of the target voltage vs. time correlate with periodic alternations formed by a mixture of amorphous+rutile TiO2 compound, the fcc-TiO phase and the hcp metallic Ti phase through the films thickness. An abrupt transition from metallic to oxidized sputtering mode takes place when oxygen is injected and correlates with the sharp Ti/TiO2 interface. On the other hand, when oxygen is stopped, the restoration to the metallic sputtering mode is longer and corresponds to the occurrence of the fcc-TiO phase at the smooth TiO2/Ti interfaces. PMID- 28662411 TI - Activating transcription factor 3 protects mice against pseudomonas aeruginosa induced acute lung injury by interacting with lipopolysaccharide binding protein. AB - Excessive inflammatory response is critical event in the pathogenesis of acute lung injury (ALI). Previous study has shown that activating transcription factor 3 (ATF3) plays a role in downregulate inflammatory responses including ventilation-induced ALI. We hypothesized that ATF3 have a protective effect in ALI induced by pseudomonas aeruginosa. PA was intra-tracheally administrated to ATF3 knock-out (KO) mice to establish ALI model. Inflammatory factors, BALF protein, lung wet to dry ratio, lung injury score and mortality were determined. The activation of NF-kappaB was detected by western blot and Co immunoprecipitation (Co-ip) was used to determinate the binding of ATF3 to LBP. Peritoneal macrophages were isolated from ATF3 KO mice and stimulated by PA. PA increased the expression of ATF3 in the lung tissues in ATF3 wild type (WT) mice. ATF3 deficiency significantly increased the concentration of TNFalpha, IL-6 and IL-1beta in the supernatant of peritoneal macrophages, lung tissue and BALF after PA stimulation and also enhanced the activity of NF-kappaB. ATF3 deficiency also enhanced the BALF protein concentration and increased the lung wet to dry ratio. The lung injury score and mortality were higher in ATF3 KO mice treated with PA. Moreover, ATF3 was demonstrated to bind to LBP These finding suggest ATF3 protect mice against ALI induced by PA partly due to the binding to LBP. PMID- 28662413 TI - Effects of annealing on the microstructural evolution and phase transition in an AlCrCuFeNi2 high-entropy alloy. AB - An AlCrCuFeNi2 high entropy alloy (HEA) was prepared by arc melting, followed by annealing at different temperatures. The elemental distributions, phase formation, morphology and microstructural evolution of the HEA in both the as cast state and annealed state were investigated. The results indicate that the HEA undergoes elements segregation, precipitation and spinodal decomposition. The as-cast alloy consists of Cr-Fe-Ni rich FCC dendritic (DR) phase and BCC interdendritic (ID) phase. Spherical Fe-Cr rich BCC precipitates were found to disperse in Al-Ni rich B2 (ordered BCC) matrix. After heat treatments, the distribution of elements clearly changes, along with changes of the constituent phase and morphology. After annealing at 600 degrees C, the DR region remains Cr Fe-Ni rich phase, while some spherical precipitates transform into the needle like structure within the ID region. The L12 (ordered FCC) nanorod-shaped phase ((Ni,Cu)3Al) and plate-like Al-Ni rich phase form within the DR region when annealing up to 900 degrees C. The L12 phase almost dissolves in the FCC matrix due to the order-disorder transition and an obvious coarsening of the Fe-Cr rich phase occurs after annealing at 1100 degrees C. The segregation of Cu atoms at the interface between DR and ID regions is found at the as-cast state, while a uniform distribution of Cu atoms in DR and ID regions was observed after annealing at 1100 degrees C. PMID- 28662414 TI - Effects of freezing, fixation and dehydration on surface roughness properties of porcine left anterior descending coronary arteries. AB - BACKGROUND: To allow measurements of surface roughness to be made of coronary arteries using various imaging techniques, chemical processing, such as fixation and dehydration, is commonly used. Standard protocols suggest storing fresh biological tissue at -40 degrees C. The aim of this study was to quantify the changes caused by freezing and chemical processing to the surface roughness measurements of coronary arteries, and to determine whether correction factors are needed for surface roughness measurements of coronary arteries following chemical processes typically used before imaging these arteries. METHODS: Porcine left anterior descending coronary arteries were dissected ex vivo. Surface roughness was then calculated following three-dimensional reconstruction of surface images obtained using an optical microscope. Surface roughness was measured before and after a freeze cycle to assess changes during freezing, after chemical fixation, and again after dehydration, to determine changes during these steps of chemical processing. RESULTS: No significant difference was caused due to the freeze cycle (p>0.05). There was no significant difference in the longitudinally measured surface roughness (RaL=0.99+/-0.39MUm; p>0.05) of coronary arteries following fixation and dehydration either. However, the circumferentially measured surface roughness increased significantly following a combined method of processing (RaC=1.36+/-0.40, compared 1.98+/-0.27MUm, respectively; p<0.05). A correction factor can compensate for the change RaCbeta=RaC1+0.46in RaC due to processing of tissue, Where RaCbeta, the corrected RaC, had a mean of 1.31+/-0.21MUm. CONCLUSIONS: Independently, freezing, fixation and dehydration do not alter the surface roughness of coronary arteries. Combined, however, fixation and dehydration significantly increase the circumferential, but not longitudinal, surface roughness of coronary arteries. PMID- 28662415 TI - Medico legal aspects of self-injection of metallic mercury in cases of suicide or self-harming. AB - Metallic mercury may be self-injected for suicidal or self-harm purposes or sometimes for superstitious or other inadvisable reasons. Local tissue or systemic consequences such as mercurialism can frequently occur in cases of subcutaneous or deep injection, while death due to pulmonary embolism and cardiac, brain, hepatic or renal toxicity may occur in cases of high dosage intravenous administration. The aim of this review is to focus on the diagnostic difficulties facing coroners and forensic pathologists when the courts require confirmation that evidence of self-injection of metallic mercury is the result of suicide or self-harming. Forensic examination performed on the corpses of victims who died in or out of hospital or on surviving injured or intoxicated victims showing signs of mercurialism, demands the careful evaluation of the death scene, of all related circumstances and of the clinical and autopsy data. Close interaction between forensic pathologists and toxicologists is also needed to identify and quantify mercury levels in blood, urine and tissue. PMID- 28662417 TI - Mortality and histopathological effects in harbour-transplanted snails with different exposure histories. AB - Contaminants are important stressors in the aquatic environment and may exert selective pressures on organisms. We hypothesized that snails originating from a metal-contaminated habitat (B) would have increased tolerance to harbour contaminants (e.g. metals from antifouling paints), compared to snails originating from a relatively clean habitat (A). We assessed tolerance to metals in terms of survival and histopathological alterations after 2, 4 and 8 weeks of in situ exposure in three Baltic Sea boat harbours and three reference sites. We also hypothesized that any potential tolerance to contaminants would be associated with differences in genetic diversity between the two snail populations (evaluated as mitochondrial cytochrome c oxidase subunit I, COI). The results show that snails from population A survived to a higher extent compared to population B, possibly indicating either a lack of adaptation to metals in snails B or impaired health condition due to contaminant pre-exposure or a higher resilience of snails A. Moreover, the genetic diversity of COI was low within each population and did not differ between populations. In general, 83% of all the types of histopathological alterations (e.g. lysis and necrosis of gonads and digestive gland or granulocytoma and phagocytosis in the storage tissue, among others) had a higher probability of occurrence among harbour-exposed snails compared to reference-exposed snails, regardless of snail population origin. The only significant difference in histological effects between the two populations was in the frequency of parasite infestations and shell fouling, both being larger for population A than B. Interestingly, the rate of parasite infestations was higher for males than females from population A, whereas no sexual dichotomy was observed for population B. Our results show that exposure to harbour contaminants causes both lethal and sublethal toxicity to snails, and the association between many of the toxic responses and metals substantiates that antifouling substances contribute to the observed effects, although there is a large proportion of variation in our data that remains unexplained. PMID- 28662416 TI - A multi-tiered, in vivo, quantitative assay suite for environmental disruptors of thyroid hormone signaling. AB - The essential role of thyroid hormone (TH) signaling in mammalian development warrants the examination of man-made chemicals for its disruption. Among vertebrate species, the molecular components of TH signaling are highly conserved, including the thyroid hormone receptors (TRs), their heterodimer binding partners the retinoid-X receptors (RXRs), and their DNA recognition sequences (TREs). This molecular conservation allows examination of potential TH disruption in the tractable, in vivo model system of amphibian metamorphosis. Metamorphosis requires TH signaling for both instigation and progression, and it provides dramatic and well-characterized phenotypes involving different cell fates. Here we describe a quantitative, precocious-metamorphosis assay suite we developed using one-week post-fertilization (PF) Xenopus laevis tadpoles in order to assess disruption of TH signaling. Tadpoles at this developmental stage (Nieuwkoop-Faber (NF)-48) are competent to respond to TH hormone, although not yet producing TH, along many metamorphic pathways, and they are uniform in size. This allowed us to quantify changes in morphology associated with natural metamorphosis (e.g. gill and tail resorption, brain expansion, and craniofacial remodeling) after five days of treatment. Using the same tadpoles from morphological measurements, we quantified a 20-fold increase in TH-induced cellular proliferation in the rostral head region by whole-mount immunocytochemistry. At the molecular level, we used F3-generation tadpoles from a transgenic X. laevis line, which expresses luciferase under the control of a native TRE, to assess the ability of compounds to disrupt TR function. The luciferase reporter showed over 10-fold activation by physiologic concentrations of TH. We used the synthetic TR antagonist NH-3 to demonstrate the feasibility of our assay suite to measure inhibition of TH activity at the level of the receptor. Finally, we assessed the capabilities of suspected TH-disrupting chemicals tetrabrominated diphenyl ether 47 (BDE-47) and tetrabromobisphenol A (TBBPA). We found that BDE-47 displays general toxicity rather than TH disruption, as it did not increase brain width nor affect the TRE-luciferase reporter. However, TBBPA, a suspected TR antagonist, although not effective in antagonizing cell proliferation, significantly inhibited the TRE-luciferase reporter, suggesting that it bears closer scrutiny as a TH disruptor. Overall the assay suite has important advantages over the classical tadpole metamorphosis assays with respect to the uniformity of animal size, small test volume, reproducibility, and short test period. The assays are performed before endogenous TH production and free feeding start, which further reduces complexity and variability. PMID- 28662418 TI - Assessing the "social brain" in dementia: Applying TASIT-S. AB - : The ability to recognise how other people are feeling and make judgements based on their inferred thoughts is essential for successful social interactions, and is thought to depend on a complex network of brain regions, commonly referred to as the "social brain". These abilities, together referred to as social cognition, are increasingly recognised as being compromised in some dementia syndromes, particularly in behavioural-variant frontotemporal dementia (bvFTD), which is characterised by changes in personality and social conduct. Whether social cognition is impaired in other dementia syndromes, such as Alzheimer's disease (AD), or whether lower performance reflects general cognitive impairment, is less well established. Furthermore, ecologically valid tests with known neurobiological correlates are currently lacking. Here, we investigated performance on a newly devised short version of The Awareness of Social Inference Test (TASIT-S) and associated neural correlates in 25 bvFTD patients, 23 AD patients and 25 healthy controls. On Part 1-Emotion Evaluation, only bvFTD were impaired (p = .033) (AD vs. CONTROLS: p = .475) after controlling for cognitive impairment and education. On Part 2-Social Inference, both bvFTD and AD showed intact ability to interpret sincere exchanges (p values > .05). Importantly, however, bvFTD patients were impaired in interpreting sarcasm (p = .008), whereas AD performed within normal limits (p = .477). Voxel-based morphometry analyses demonstrated correlations between TASIT-S Part 1 performance and integrity of emotion processing brain regions (amygdala, insula, fusiform) and Part 2 performance with theory of mind brain regions (precuneus, temporal pole). These results demonstrate the utility of TASIT-S in identifying social cognition impairment in dementia and reveal that TASIT-S taps into integrity of key regions within the "social brain". PMID- 28662419 TI - Perceptual statistical learning over one week in child speech production. AB - What cognitive mechanisms account for the trajectory of speech sound development, in particular, gradually increasing accuracy during childhood? An intriguing potential contributor is statistical learning, a type of learning that has been studied frequently in infant perception but less often in child speech production. To assess the relevance of statistical learning to developing speech accuracy, we carried out a statistical learning experiment with four- and five year-olds in which statistical learning was examined over one week. Children were familiarized with and tested on word-medial consonant sequences in novel words. There was only modest evidence for statistical learning, primarily in the first few productions of the first session. This initial learning effect nevertheless aligns with previous statistical learning research. Furthermore, the overall learning effect was similar to an estimate of weekly accuracy growth based on normative studies. The results implicate other important factors in speech sound development, particularly learning via production. PMID- 28662420 TI - Speech-language pathologists' preferences for patient-centeredness. AB - PURPOSE: Preferences for patient-centeredness is an important indicator in healthcare service delivery. However, it remains largely unexplored in the field of communication science and disorders. This study investigated speech-language pathologists' (SLPs) preferences for patient-centeredness METHOD: The study involved a cross-sectional survey design. SLPs (n = 102) fully completed the modified Patient-Practitioner Orientation Scale (PPOS; Krupat et al, 2000) and also provided demographic details. Data were analyzed using descriptive statistics, correlation, and linear regression methods. RESULTS: Mean PPOS scores indicated that SLPs value patient-centeredness. There was a strong positive correlation among sharing and caring subscales with the full-scale. Results from the linear regression modeling suggested no relationship between demographic factors and preferences for patient-centeredness. CONCLUSIONS: SLPs value patient centeredness, although there may be regional and cultural variations. Qualitative investigations may help uncover dimensions of patient-centeredness that were not captured in the PPOS scale. In addition, further research should explore congruence in preferences for patient-centeredness among SLPs and patients. PMID- 28662421 TI - Preparation of hydrolytic liquid from dried distiller's grains with solubles and fumaric acid fermentation by Rhizopus arrhizus RH 7-13. AB - Fumaric acid production from lignocellulosic materials is an alternative chemicals production system. This work investigated the suitable conditions for hydrolysis of dried distiller's grains with solubles (DDGS). The hydrolytic liquid was subsequently used for the production of fumaric acid. After optimizing the hydrolysis conditions, the most suitable concentration of H2SO4 (2%), hydrolysis temperature (120 degrees C), hydrolysis time (100min) and solid/liquid ratio (1:10) were obtained. The yield of monosaccharides reached 258 mg/g DDGS and 15.88 g/L glucose, 7.53 g/L xylose and 2.35 g/L arabinose were obtained in unprocessed hydrolytic liquid. The furfural inhibitor in the hydrolytic liquid was also detected and the yield of it was reducing progressively in the pretreatment process. The ferment ability of the hydrolytic liquid from DDGS was tested through the process of fumaric acid production by Rhizopus arrhizus RH 7-13. The unprocessed hydrolytic liquid was not appropriate for the fermentation process. The yield of fumaric acid from the concentrated processed hydrolytic liquid reached 18.93 g/L, which was close to the yield of fermenting 80 g/L glucose. This result indicated that the commonly used carbon resource glucose could to some extent be replaced by processed hydrolytic liquid. PMID- 28662422 TI - Evaluation of the treatability of a winery distillery (vinasse) wastewater by UASB, anoxic-aerobic UF-MBR and chemical precipitation/adsorption. AB - A multi-stage pilot-scale treatment cycle consisting of an Upflow Anaerobic Sludge Blanket reactor (UASB) followed by an anoxic-aerobic Ultra Filtration Membrane Bio Reactor (UF-MBR) and a post treatment based on chemical precipitation with lime or adsorption on Granular Activated Carbons (GAC), was applied in order to evaluate the treatment feasibility of a real winery distillery wastewater at laboratory and bench scale. The wastewater was classified as high strength with acidic pH (3.8), and concentrations of 44,600, 254, 604 and 660 mg/l for CODtot, total nitrogen, total phosphorous and phenols, respectively. The UASB reactor was operated at Organic Loading Rates (OLR) in the range 3.0-11.5 kgCODtot/m3/d achieving treatment efficiency up to 97%, with an observed methane production of 340 L of CH4/kgCOD. The MBR system was operated with an organic load in the range 0.070-0.185 kgCOD/kgVSS/d, achieving a removal up to 48%, 67% and 65% of the influent COD, total nitrogen and phenols, respectively. The combination of UASB and UF-MBR treatment units was not effective in phosphate and colour removal assigning to further chemical precipitation and adsorption processes, respectively, their complete removal in order to comply with legal standards for wastewater discharge. Subsequently, the optimization of the investigated treatment chain was assessed by applying a chemical precipitation step upstream and downstream the UASB reactor, and a related treatment unit cost assessment is presented in view of a further technological scale-up. PMID- 28662423 TI - Biomechanical research on contour cage with transacetabular screws fixation in revision total hip arthroplasty. AB - BACKGROUND: Use biomechanical technique to access the strain distribution and stability of Contour anti-protrusion cage with or without the whole circumference acetabular cup fixation by the transacetabular screws. METHODS: Pelvic specimens from 10 male cadavers were used for the biomechanical test. The models of type C bone defect were copied according to the AAOS classification. Group 1: the contour reconstruction ring was fixed only by flange screws; Group 2: the contour reconstruction ring was fixed both by flange screws and transacetabular screws in dome. Under load in Heel Strike, Midstance, and Toe off phase, the transverse and longitudinal strains were measured in both the superior measure site near the root of the iliac wing and the inferior measure site near the root of the ischium. The relative displacement between the anterior inferior spine and the root of ischium below acetabular component was also measured. FINDINGS: Compared with Group 1, the transverse and longitudinal pressure strain of Group 2 on the superior measure site decreased, and measure sites also showed reductions on the inferior under load under three different gait phases. The result of mean relative displacement showed transacetabular screws fixation couldn't provide significant improvement of displacement prevention. INTERPRETATION: Biomechanical test showed that under the premise of a satisfied bone allograft and well-fixed flange screws in iliac and ischium, the satisfactory initial stability of the reconstruction cup can be achieved, but could not be improved by transacetabular screw technique. However, the max strain in root part of the flange will be reduced using transacetabular screws in ilium, pubis and ischium together, and the strain distribution will also be improved. PMID- 28662424 TI - Appraisement, source apportionment and health risk of polycyclic aromatic hydrocarbons (PAHs) in vehicle-wash wastewater, Pakistan. AB - Vehicle-wash wastewater (VWW) contains elevated concentrations of different petrochemicals including polycyclic aromatic hydrocarbons (PAHs), a carcinogenic group of organic compounds. This study investigates the discharge of PAHs present in the untreated wastewater of vehicle-wash stations (VWS) located in district Peshawar, Pakistan. The data obtained was being novel with the detection of 16 USEPA PAHs (both individuals and total) and compared with earlier studies and international standards. The ?16PAHs in wastewater from light vehicle-wash stations (LVWS) and heavy vehicle-wash stations (HVWS) ranged from 245-429MUg/l and 957-1582MUg/l, respectively. A significant difference (p<0.01) was observed in PAHs discharged from LVWS and HVWS. The projected ?16PAHs discharge from both HVWS (92% of total generated PAHs) and LVWS (8%) was about 5109.9 g per annum. According to PAH diagnostic ratios, PAHs were both petrogenic (chrysene/benz(a)anthracene, low molecular weight/high molecular weight) and pyrogenic (phenanthrene/anthracene, fluoranthene/pyrene, fluoranthene/fluoranthene+pyrene) in origin. The highest toxic equivalent quotient (TEQ) value was shown by benzo(a)pyrene (21.6MUg/l) followed by dibenz(ah)anthracene (9.81MUg/l) in wastewater from HVWS. However, in LVWS the case was reversed with highest value (7.54MUg/l) for dibenz(ah)anthracene followed by benzo(a)pyrene (3.54MUg/l). The lowest TEQ value was indicated for phenanthrene (0.007MUg/l) in wastewater of LVWS, while pyrene showed the lowest value (0.007MUg/l) in wastewater of HVWS. The results indicated that VWS contribute significant amount of PAHs each year, which is of great concern regarding water quality, ecological and human health risk. This is the first systematic and comprehensive research related with generation of PAHs load per day, week, month and annum from VWS, their source apportionment and health effects in Pakistan. PMID- 28662425 TI - Herbivory-induced maternal effects on growth and defense traits in the clonal species Alternanthera philoxeroides. AB - Plants have evolved a variety of defense traits against foliar herbivory, including the production of primary and secondary metabolites, the allocation of chemical compounds, and morphological plasticity. Using two vegetative generations of the invasive clonal species Alternanthera philoxeroides, we investigated the effects of maternal and offspring herbivory by Planococcus minor on the integrative defense strategy of plants. Herbivory severely inhibited leaf, stolon and root growth, as well as the production of primary metabolites (soluble sugars, starch, and total non-structural carbohydrates in stolons), and decreased average leaf area and specific leaf area of the second-generation A. philoxeroides. The changes in growth measures of the first-generation A. philoxeroides with herbivory were consistent with that of the second generation. By contrast, herbivory basically did not affect the concentration of non structural carbohydrate compounds in the roots, and even increased the concentrations of N and total phenols in taproots. Furthermore, herbivory-induced maternal effects also reduced the growth of the second-generation plants. The results suggest that A. philoxeroides is capable of adapting to herbivory by P. minor, mainly via the allocation of available resources in belowground organs, and that the herbivory effect can persist across vegetative generations. These features may potentially improve the regeneration and tolerance of A. philoxeroides after a short-term herbivory. PMID- 28662426 TI - First results from light scattering enhancement factor over central Indian Himalayas during GVAX campaign. AB - The present work examines the influence of relative humidity (RH), physical and optical aerosol properties on the light-scattering enhancement factor [f(RH=85%)] over central Indian Himalayas during the Ganges Valley Aerosol Experiment (GVAX). The aerosol hygroscopic properties were measured by means of DoE/ARM (US Department of Energy, Atmospheric Radiation Measurement) mobile facility focusing on periods with the regular instrumental operation (November-December 2011). The measured optical properties include aerosol light-scattering (sigmasp) and absorption (sigmaap) coefficients and the intensive parameters i.e., single scattering albedo (SSA), scattering Angstrom exponent (SAE), absorption Angstrom exponent (AAE) and light scattering enhancement factor (f(RH)=sigmasp(RH, lambda)/sigmasp(RHdry, lambda)). The measurements were separated for sub-micron (<1MUm, D1MUm) and particles with diameter<10MUm (D10MUm) in order to examine the influence of particle size on f(RH) and enhancement rate (gamma). The particle size affects the aerosol hygroscopicity since mean f(RH=85%) of 1.27+/-0.12 and 1.32+/-0.14 are found for D10MUm and D1MUm, respectively. These f(RH) values are relatively low suggesting the enhanced presence of soot and carbonaceous particles from biomass burning activities, which is verified via backward air mass trajectories. Similarly, the light-scattering enhancement rates are ~0.20 and 0.17 for the D1MUm and D10MUm particles, respectively. However, a general tendency for increasing f(RH) and gamma is shown for higher sigmasp and sigmaap values indicating the presence of rather aged smoke plumes, coated with industrial aerosols over northern India, with mean SSA, SAE and AAE values of 0.92, 1.00 and 1.15 respectively. On the other hand, a moderate-to-small dependence of f(RH) and gamma on SAE, AAE, and SSA was observed for both particle sizes. Furthermore, f(RH) exhibits an increasing tendency with the number of cloud condensation nuclei (NCCN) indicating larger particle hygroscopicity but without significant dependence on the activation ratio. PMID- 28662427 TI - Oral mycoses in avian scavengers exposed to antibiotics from livestock farming. AB - The exposure to antimicrobial pharmaceuticals as environmental contaminants can exert direct and indirect detrimental effects on health of wildlife. Fungal infections pose a major threat to domestic, captive-housed wild and free-ranging wild animals worldwide. However, little is known about their role in disease in birds in the wild. Here, we evaluated the incidence of thrush-like lesions in the oral cavity of wild nestling cinereous vultures (Aegypius monachus), griffon vultures (Gyps fulvus), Egyptian vultures (Neophron percnopterus) and golden eagles (Aquila chrysaetos) exposed to veterinary antibiotics via the consumption of medicated livestock carcasses. Lesions, which varied in number, size and location, were more frequent in the cinereous (77.8%, n=9) and griffon vultures (66.7%, n=48) than in the Egyptian vultures (28.6%, n=21) and golden eagles (28.6%, n=7). In all individuals (100%, n=24) of a subsample of the affected nestlings, yeast species were isolated from thrush-like oral lesions and identified using a well-established system based on their carbohydrate assimilation profiles and other complementary tests. Fourteen yeast species from seven genera (Candida, Meyerozyma, Pichia, Yarrowia, Cryptococcus, Rhodotorula and Trichosporon) were isolated from the lesions of the four host species. We found differential infections and effects depending on host age-related exposure or susceptibility to different yeast species across the development of nestling griffon vultures. This unprecedented outbreak of oral mycoses is alarming because of the delicate conservation status of several of the affected species. The role of livestock antibiotics in the transition of yeast species from commensal to opportunistic pathogens should be evaluated in an attempt to avoid the detrimental effects of contamination and disease on host health, as well as on the transmission of fungal emerging pathogens among wildlife populations and species, and their dissemination across livestock and human populations. PMID- 28662428 TI - Bacterial communities and chemical parameters in soils and coastal sediments in response to diesel spills at Carlini Station, Antarctica. AB - A diesel spill occurring at Carlini Station (King George Island (Isla 25 de Mayo), South Shetland Islands) in 2009 started the study of the fate of the hydrocarbons and their effect on the bacterial communities of the Potter Cove ecosystem. Soils and sediments were sampled across the 200-meter long diesel plume towards Potter Cove four and 15months after the spill. The sampling revealed a second fuel leakage from an underground pipeline at the spill site. The hydrocarbon fraction spilt over frozen and snow-covered ground reached the sea and dispersed with the currents. Contrary, diesel that infiltrated unfrozen soil remained detectable for years, and was seeping with ground water towards coastal marine sediments. Structural changes of the bacterial communities as well as hydrocarbon, carbon and nitrogen contents were investigated in sediments in front of the station, two affected terrestrial sites, and a terrestrial non contaminated reference site. Bacterial communities (16S rRNA gene clone libraries) changed over time in contaminated soils and sediments. At the underground seepage site of highest contamination (5812 to 366MUgg-1dw hydrocarbons from surface to 90-cm depth), communities were dominated by Actinobacteria (18%) and a betaproteobacterium closely related to Polaromonas naphthalenivorans (40%). At one of the spill sites, affected exclusively at the surface, contamination disappeared within one year. The same bacterial groups were enriched at both contaminated sites. This response at community level suggests that the cold-adapted indigenous microbiota in soils of the West Antarctic Peninsula have a high potential for bioremediation and can support soil cleaning actions in the ecosystem. Intensive monitoring of pollution and site assessment after episodic fuel spills is required for decision-making towards remediation strategies. PMID- 28662429 TI - The diatom-inferred pH reconstructions for a naturally neutralized pit lake in south-west Poland using the Mining and the Combined pH training sets. AB - Many artificial lakes in various parts of the world were formed as a result of the exploitation of lignite and other mineral deposits. Usually, lakes created after the end of lignite mine activity have extremely acidic or very acidic water, with pH<3.0, caused by the oxidation of pyrite and marcasite and other sulfide compounds. After the closure of mines, the lakes undergo natural neutralization. However, this process is long-term and depends on many different factors, such as the amount of carbonates, the geological structure of bedrock, hydrology and hydrobiology, climate and the method of lignite exploitation. In some types of anthropogenic lakes (i.e., clay pits), water pH is almost neutral or alkaline due to the adsorption properties of clay minerals. Along the Polish German border in the Luk Muzakowa Geopark, over 100 post-mining lakes were formed as a result of lignite and clay exploitation. The Mining pH training set of modern diatom samples and water chemistry was created from 69 lakes to quantify the relationship between the diatom assemblages living in these water bodies and the lakes' chemical composition. Then, this database was applied to the reconstruction of diatom-inferred pH in the sediments of a post-mining lake TR 33. The results of reconstruction was compared to similar analysis based on the Combined pH training set containing more variety of diatom taxa from a higher number of lakes. Although the second dataset was larger and gave a smaller root mean square error, the Mining pH training set has a longer gradient of pH including lakes with extremely acidic water and gives more reliable results. The reconstruction of DI-pH in TR-33 which had very acidic water in the past and currently neutralized from acidification was more precise and reliable using the database sensu stricto, which consists of only the post-mining lakes. PMID- 28662430 TI - Trends of two decadal precipitation chemistry in a subtropical rainforest in East Asia. AB - Long-term monitoring of precipitation chemistry provides a great opportunity to examine the evolution of air pollutant emissions and effectiveness of air pollution control measures. We evaluated the characteristics and trends of precipitation chemistry at both annual and seasonal scales based on the records of 1994-2013 at Fushan Experimental Forest (FEF) of northeastern Taiwan. The results showed that 77% of the weekly precipitation had pH<5.0. The two-decadal average annual pH was 4.62, without a significant inter-annual trend, possibly due to the concurrent declines of both acidic pollutants and base cations. There was a significant positive relationship between [SO42-+NO3-] and [Ca2++NH4+] indicating that their deposition was likely dominated by NH4NO3, (NH4)2SO4, Ca(NO3)2, and CaSO4. There was a significant negative relationship between precipitation pH and the difference between [SO42-+NO3-] and [Ca2++NH4+], not just [SO42-+NO3-], suggesting that precipitation acidity was not solely determined by acidic pollutants but by the balance between acidic pollutants and base cations. We also found temporal decreases of Ca2+ and NH4+ concentrations in precipitation which contributed to the low acid neutralization capacity of precipitation. Annual deposition of NO3- and SO42- was 23 and 55kgha-1yr-1, which is much higher than most forest sites in the industrialized countries suggesting that acid deposition is still a major environmental issue in Taiwan. Annual deposition of NH4+, Ca2+ and NO3- showed significant decreasing trends during the 20-year period, which was mostly due to the decreases in the summer deposition associated with air pollution mitigation strategies. Winter deposition showed no decreasing patterns for the same period. The high contribution to annual acid deposition from autumn-winter and spring rains (50%) associated with northeast monsoon implies that long-range transport of anthropogenic emissions from East Asia played a key role on acid depositions at FEF and possibly many areas in the region. Therefore, intergovernmental cooperation is urgently needed to effectively mitigate the threat of acid deposition in East Asia. PMID- 28662431 TI - Branched pathways in the degradation of cDCE by cytochrome P450 in Polaromonas sp. JS666. AB - Compound specific isotope analysis (CSIA) is widely used to monitor contaminant remediation in groundwater. CSIA-based approaches that use enrichment (epsilon) values to assess degradative processes rely on the assumption that the contaminant being investigated will have an epsilon value that is constant and specific to a catalytic pathway of a microorganism. Distinct epsilon values have been reported for aerobic degradation of cis-dichloroethene (cDCE), which has led to a number of proposed degradation mechanisms; however, cytochrome P450 catalyzed oxidation is the only biochemical mechanism that has been established in Polaromonas sp. JS666. Using CSIA we measured the epsilon values for microbial oxidation of cDCE (-18.80/00+/-1.50/00) and 1,2-dichloroethane (1,2-DCA) ( 16.60/00+/-0.90/00) in wild-type JS666 and the oxidation of cDCE (-13.50/00+/ 2.30/00) from a recombinant E. coli strain expressing the cytochrome P450 enzyme from JS666. This study supports the hypothesis that cytochrome P450 catalyzes the initial step in the degradation pathway of both cDCE and 1,2-DCA and provides evidence that a single enzyme can catalyze multiple pathways with different products and distinct epsilon values for a single substrate. Therefore, in cases where the products of the reaction cannot, or have not been characterized, caution must be used when employing epsilon values to interpret mechanisms, pathways, and their applications to environmental contaminant remediation. PMID- 28662432 TI - Cathelicidin augments VDR-dependent anti-leishmanial immune response in Indian Post-Kala-Azar Dermal Leishmaniasis. AB - OBJECTIVES: Indian Post kala-azar dermal leishmaniasis (PKDL) is the cutaneous aftermath of visceral leishmaniasis (VL) caused by L. donovani. Vitamin D regulated cationic antimicrobial peptide cathelicidin (hCAP-18/LL-37) has microbicidal and immunomodulatory role against cutaneous infections, but its role in PKDL remains elusive. METHODS: Skin snips and blood-derived monocytes of PKDL patients (n=46), before (BT) and after (AT) chemotherapy, were used for this study. Serum vitamin D3 level was evaluated by ELISA. Cathelicidin and vitamin D receptor (VDR) levels were analyzed by real-time PCR and flowcytometry in PKDL patients. The mechanistic effect of cathelicidin on macrophage differentiation and anti-leishmanial activity was assessed through RNA interference techniques followed by subsequent microscopic evaluation of in vitro parasite killing and Th1/Th2 counter-regulation by ELISA/RT-PCR. RESULTS: Low vitamin D3 levels were accompanied with decreased expression of cathelicidin and VDR in PKDL-BT patients. Results suggested positive induction of VDR-dependent cathelicidin in PKDL macrophages by Amphotericin B treatment, which could be due to indirect effect of drug-induced IL12 upregulation. 1,25-Vitamin D3 stimulation induced cathelicidin in PKDL-BT patients through involvement of TLR2/IL-1beta, but not TLR4. Cathelicidin also augmented the anti-leishmanial effect and macrophage activating potential of Amphotericin B, attributable to regulation of VDR dependent enhancement of CD40, p-STAT-I and MHC-II expression leading to regulation of IL10/IL12 balance in PKDL-BT patient macrophages. CONCLUSIONS: This study indicates that cathelicidin augments anti-leishmanial macrophage activating property of Amphotericin B in a TLR2/VDR dependent mechanism, and advocate the development of novel adjunct treatment modality of cathelicidin with conventional Amphotericin B in PKDL patients. PMID- 28662433 TI - CXCR5+CD8+ T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8+ T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5+CD8+ T cell is a novel cell subtype and share CXCR5 expression with CD19+ tumor cells. In this study, we investigated the frequency and function of existing CXCR5+CD8+ T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5+CD8+ T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CD8+ T cells as effector (E) cells and autologous CD19+ tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5+CD8+ T cell- and CXCR5-CD8+ T cell mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5+CD8+ T cells presented stronger cytotoxicity than CXCR5-CD8+ T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5+CD8+ T cells than in CXCR5-CD8+ T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/IL-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5+CD8+ T cells were significantly elevated. Together, these results suggest that CXCR5+CD8+ T cells are potential candidates of CD8+ T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression. PMID- 28662434 TI - A model to describe the inhomogeneous broadening of NQR lines in chlorohalobenzenes with orientational or substitutional disorder. AB - A simple model to explain the NQR lineshape in solids with orientational disorder or substitutional disorder is presented. The particular case of m chlorobromobenzene is studied. It is based on the assumption that Bromine atoms, of m-chlorobromobenzene molecules, behave as point defects in the m dichlorobenzene lattice that modify the crystalline Electric Field Gradient. The model is also tested successfully in solid solutions of p-dichlorobenzene-p dibromobenzene, where Bromine atoms of p-dibromobenzene molecules are assumed to be homogeneously distributed in the p-dichlorobenzene lattice. The lineshape, of others disordered chlorohalobenzenes, are also analyzed. Also, a characterization of m-chlorobromobenzene dynamics is included. In particular, there is no evidence of molecular reorientations as it is observed in the disordered phases of o chlorobromobenzene. PMID- 28662435 TI - Comparison of internet and mailing methods to recruit couples into research on unaided smoking cessation. AB - In smoking cessation studies with restrictive criteria (e.g., single-smoker couples), thousands of potential participants might need to be screened to obtain a reasonable sample size. Consideration of recruitment methodology is critical because recruitment methods influence both the success and cost effectiveness of recruitment. Although traditional recruitment methods are often used to recruit participants into smoking cessation research, newer technologies, such as paid Facebook advertising, might offer more cost-effective alternatives for recruitment. The current analysis compares two versions of paid Facebook advertising and a specialized mass mailing method used to recruit single-smoker couples into an intensive three-week study of unaided smoking cessation. The three methods are compared in terms of demographic characteristics, eligibility, and cost-effectiveness. Although Facebook's "Promote Your Page" mechanism achieved the fastest recruitment rate (2.75 couples per month; 498 USD per couple), Facebook's "Send People to Your Website" mechanism was the least expensive and provided the most demographically diverse sample (1.64 couples per month; 181 USD per couple). The specialized mailing method was not productive or cost-effective (0.80 couples per month; 454 USD per couple). Paid Facebook advertising fared better as a recruitment method than a specialized mailing method often used in survey research. Studies that have less restrictive eligibility criteria, that draw from a larger local population, or that recruit for a less intense study might find paid Facebook advertising to be quite feasible. PMID- 28662436 TI - Internet gaming disorder: Trends in prevalence 1998-2016. PMID- 28662437 TI - Parental monitoring protects against the effects of parent and adolescent depressed mood on adolescent drinking. AB - OBJECTIVE: Parental monitoring is a well-established protective factor for adolescent drinking. This study examined whether parental monitoring protected against three common risk factors for alcohol use in a sample of high-risk adolescents: parental depressed mood, adolescent depressed mood, and parental alcohol use. METHODS: Participants included 117 adolescents (mean age=15.5; 52% female) who presented to the hospital emergency department due to an alcohol related event and their primary parent/guardian. Adolescents completed self report measures of alcohol use frequency, depressed mood, and parental monitoring, while parents completed self-report measures of problematic alcohol use and depressed mood. RESULTS: Hierarchical regression confirmed that parental monitoring was associated with lower frequency of adolescent alcohol use, even after controlling for the three risk factors. Significant interactions were found between parental monitoring and both adolescent and parental depressed mood. Parental monitoring had significant protective effects against drinking frequency among adolescents with higher levels of depressed mood, but not among adolescents with lower levels of depressed mood. By contrast, parental monitoring only had protective effects among those parents with lower levels of depressed mood. Parental problematic alcohol use did not affect the relationship between parental monitoring and adolescent alcohol use. CONCLUSIONS: Our results suggest that adolescents with high levels of depressed mood may be more likely to benefit from parental monitoring, whereas parents with high levels of depressed mood may be less likely to monitor effectively. Interventions targeting parental monitoring in high-risk adolescents should take into account the influence of both adolescent and parental depressed mood. PMID- 28662438 TI - Foot-and-mouth disease virus induces lysosomal degradation of host protein kinase PKR by 3C proteinase to facilitate virus replication. AB - The interferon-induced double-strand RNA activated protein kinase (PKR) plays important roles in host defense against viral infection. Here we demonstrate the significant antiviral role of PKR against foot-and-mouth disease virus (FMDV) and report that FMDV infection inhibits PKR expression and activation in porcine kidney (PK-15) cells. The viral nonstructural protein 3C proteinase (3Cpro) is identified to be responsible for this inhibition. However, it is independent of the well-known proteinase activity of 3Cpro or 3Cpro-induced shutoff of host protein synthesis. We show that 3Cpro induces PKR degradation by lysosomal pathway and no interaction is determined between 3Cpro and PKR. Together, our results indicate that PKR acts an important antiviral factor during FMDV infection, and FMDV has evolved a strategy to overcome PKR-mediated antiviral role by downregulation of PKR protein. PMID- 28662439 TI - Interleukin-20 is triggered by TLR ligands and associates with disease activity in patients with rheumatoid arthritis. AB - BACKGROUND: Interleukin (IL)-20 is a pro-inflammatory cytokine that may be implicated in the pathogenesis of rheumatoid arthritis (RA). This study aimed to determine the association between IL-20 and disease activity in patients with RA. METHODS: The levels of serum and synovial fluid IL-20 were measured in patients with RA and OA. The disease activity was assessed based on the Disease Activity Score of 28 joints (DAS28). The expression of IL-20 in synovial tissue samples from patients with RA and OA were determined by immunohistochemistry. Immunofluorescence staining was used to co-localize IL-20 with selected cells. The secretion of IL-20 was analysed in human peripheral blood mononuclear cells (PBMCs) of patients with RA. RESULTS: Synovial fluid and synovial tissue IL-20 were significantly increased in patients with RA compared with patients with OA. The expression of IL-20 in RA synovial tissue was particularly associated with macrophages and neutrophil granulocytes, but also with synovial fibroblasts and lymphocytes. The IL-20 levels in synovial fluid correlated with DAS28 (r=0.434; p=0.015) and were significantly elevated in anti-CCP positive RA compared with anti-CCP negative RA (122.3+/-104.1pg/ml and 45.9+/-35.8pg/ml; p=0.008). IL-20 production from PBMCs was induced by Poly I:C and LPS but not with pro inflammatory cytokines, such as TNF-alpha or IL-1. CONCLUSION: Our data showed that IL-20 is independently associated with RA disease activity and may be triggered by TLR ligands at local sites of inflammation. PMID- 28662440 TI - Review of serious events in cases of (suspected) child abuse and/or neglect: A RoSE by any other name? AB - Child abuse and neglect (CAN) cases presenting to health-services may be complex; when things go seriously wrong such as a child death or near miss, cases are reviewed and health-services and professionals subject to intense scrutiny. While there are a variety of mechanisms to review critical incidents in health-services no formal process for the review of cases where child protection is the primary concern exists in Australia. We aimed to develop a systematic process to review serious events in cases of suspected CAN across two health districts in Sydney, so that shared learnings could fuel system change. Drawing upon mapping, case review, literature findings and using quality improvement methodology, we developed a model named Review of Serious Events (RoSE), in suspected cases of CAN. The RoSE model has the key features of: being child focused; seeking to examine care over a period of time; using child protection staff as lead reviewers; involving health professionals/services in the review who have been involved with the child; and actioning systems change at local levels. The RoSE model was trialled through 2014-2015. Eight cases were reviewed using RoSE; cases were similar to those reviewed prior to having a model. Participant feedback from RoSE group processes was overwhelmingly positive; outputs were transparent and accessible to key stakeholders, there was mixed progress with implementation. The RoSE model is a serious case review process that is strongly child-focused, is both investigative and reflective, led by child protection experts; and can be adapted to other settings and systems. PMID- 28662441 TI - An automated synthesizer for electrochemical 18F-fluorination of organic compounds. AB - Electrochemical 18F-fluorination of organic compounds provides a means to synthesize Positron-Emission-Tomography (PET) tracers difficult to obtain otherwise. Here, the first automated synthesizer that enables radiolabeling through carrier-added electrochemical 18F-fluorination is described. The system provides capabilities for all necessary operations such as drying of cyclotron derived [18F]fluoride, electrochemical incorporation of the radioisotope into a precursor molecule, subsequent reactions such as protecting group removals, HPLC purification and formulation of the final tracer. Demonstrated is the aliphatic electrochemical 18F-fluorination of methyl 2-(phenylthio)acetate. PMID- 28662442 TI - Synthetic biology-inspired therapies for metabolic diseases. AB - Our ability to engineer mammalian cells with effective therapeutic behaviors has brought new hope for treating metabolic diseases. Synthetic gene networks have been customized to interface with the host metabolism, discriminate between healthy and diseased states, and respond by producing an adjusted dose of the therapeutic molecule. Such devices have the potential to treat a range of dysfunctions that are simply not addressable using conventional therapies. Recently, the repurposing of native signaling pathways has formed the basis of autonomous therapeutic programs genetically installed in mammalian cells and has greatly expanded the possibilities to effectively tackle metabolic disorders. Here, we outline network topologies that have been successfully validated in animal models of metabolic diseases and discuss future developments that will be important for bringing this technology closer to clinical application. PMID- 28662443 TI - Fracture strength of lithium disilicate crowns compared to polymer-infiltrated ceramic-network and zirconia reinforced lithium silicate crowns. AB - OBJECTIVES: The aim of this study was to evaluate the fracture strength of crowns made from current CAD/CAM materials. In addition the influence of crown thickness and chewing simulation on the fracture strength was evaluated. METHODS: Crowns were fabricated from lithium disilicate, zirconia reinforced lithium silicate (ZLS-ceramic) and a polymer-infiltrated ceramic-network (PICN) with an occlusal thickness of 1.0mm or 1.5mm, respectively (n=16). Crowns were cemented on composite dies. Subgroups of eight specimens were loaded with 5kg in a chewing simulator for 1,200,000 cycles with thermal cycling. Finally, all specimens were loaded until fracture in a universal testing machine. Three-way ANOVA was used to detect statistical interaction. Differences regarding the materials were tested with two-way ANOVA, following one-way ANOVA and a post-hoc Tukey's-Test. RESULTS: All crowns survived the chewing simulation. The material had a significant influence on the fracture resistance (p<=0.05). Lithium disilicate achieved the highest values of fracture strength in almost all groups followed by ZLS-ceramic. PICN achieved the lowest values of fracture strength. Chewing simulation increased the fracture strength of thick lithium disilicate crown significantly. Greater occlusal thickness of all crown materials resulted in higher crown fracture strength before chewing simulation. After chewing simulation occlusal thickness of lithium disilicate and PICN crowns had no significant influence on the fracture strength. CONCLUSIONS: All crowns revealed fracture strength above the clinically expected loading forces. Therefore the durability of the tested CAD/CAM materials seems promising also in an occlusal thickness of 1.0mm. PMID- 28662444 TI - Neighborhood disorder, peer network health, and substance use among young urban adolescents. AB - BACKGROUND: The current study investigated the moderating effect of peer networks on neighborhood disorder's association with substance use in a sample of primarily African American urban adolescents. METHODS: A convenience sample of 248 adolescents was recruited from urban health care settings and followed for two years, assessing psychological, social, and geographic risk and protective characteristics. A subset of 106 substance using participants were used for the analyses. A moderation model was tested to determine if the influence of neighborhood disorder (percent vacant housing, assault index, percent single parent headed households, percent home owner occupied, percent below poverty line) on substance use was moderated by peer network health (sum of peer risk and protective behaviors). RESULTS: Evidence for hypothesized peer network moderation was supported. A latent growth model found that peer network health is most strongly associated with lower baseline substance use for young adolescents residing in more disordered neighborhoods. Over the course of two years (ages approximately 14-16) this protective effect declines, and the decline is stronger for more disordered neighborhoods. CONCLUSIONS: Understanding the longitudinal moderating effects of peer networks within high-risk urban settings is important to the development and testing of contextually sensitive peer-based interventions. RESULTS: suggest that targeting the potential protective qualities of peer networks may be a promising approach for interventions seeking to reduce substance use, particularly among younger urban adolescents living in high-risk neighborhoods. PMID- 28662445 TI - Direct reprogramming with SOX factors: masters of cell fate. AB - Over the last decade significant advances have been made toward reprogramming the fate of somatic cells, typically by overexpression of cell lineage-determinant transcription factors. As key regulators of cell fate, the SOX family of transcription factors has emerged as potent drivers of direct somatic cell reprogramming into multiple lineages, in some cases as the sole overexpressed factor. The vast capacity of SOX factors, especially those of the SOXB1, E and F subclasses, to reprogram cell fate is enlightening our understanding of organismal development, cancer and disease, and offers tremendous potential for regenerative medicine and cell-based therapies. Understanding the molecular mechanisms through which SOX factors reprogram cell fate is essential to optimize the development of novel somatic cell transdifferentiation strategies. PMID- 28662446 TI - Acquisition of the pluripotent and trophectoderm states in the embryo and during somatic nuclear reprogramming. AB - How the first cell fate decision of an embryo occurs is one of the most fascinating biological questions examined over the last few decades, with numerous in vivo models proposed and many factors tested for their role in the process. In this review, we will primarily focus on the mouse model and discuss the role that transcription factors play during establishment and maintenance of the first lineage segregation in the embryo, towards inner cell mass or trophectoderm. We will also overview recent developments in somatic nuclear reprogramming into induced pluripotent stem cells, the inner cell mass (epiblast) equivalent, and into induced trophoblast stem cells, the trophectoderm equivalent, and discuss potential correspondences between the in vivo and in vitro models. PMID- 28662447 TI - Metabolic switching and cell fate decisions: implications for pluripotency, reprogramming and development. AB - Cell fate decisions are closely linked to changes in metabolic activity. Over recent years this connection has been implicated in mechanisms underpinning embryonic development, reprogramming and disease pathogenesis. In addition to being important for supporting the energy demands of different cell types, metabolic switching from aerobic glycolysis to oxidative phosphorylation plays a critical role in controlling biosynthetic processes, intracellular redox state, epigenetic status and reactive oxygen species levels. These processes extend beyond ATP synthesis by impacting cell proliferation, differentiation, enzymatic activity, ageing and genomic integrity. This review will focus on how metabolic switching impacts decisions made by multipotent cells and discusses mechanisms by which this occurs. PMID- 28662448 TI - Arterial blood pressure responses to short-term exposure to fine and ultrafine particles from indoor sources - A randomized sham-controlled exposure study of healthy volunteers. AB - OBJECTIVES: Particulate air pollution is linked to adverse cardiovascular effects. The aim of the study was to investigate the effect of short-term exposure to indoor particles on blood pressure (BP). METHODS: We analyzed the association of particle emissions from indoor sources (candle burning, toasting bread, frying sausages) with BP changes in 54 healthy volunteers in a randomized cross-over controlled exposure study. Particle mass concentration (PMC), size specific particle number concentration (PNC) and lung-deposited particle surface area concentration (PSC) were measured during the 2h exposure. Systolic and diastolic blood pressure were measured before, during, directly, 2, 4 and 24h after exposure. We performed multiple mixed linear regression analyses of different particle metrics and BP. RESULTS: BP significantly increased with increasing PMC, PSC and PNC resulting from toasting bread. For example, an increase per 10ug/m3 PM10 and PM2.5, systolic BP increased at all time points with largest changes 1h after exposure initiation of 1.5mmHg (95%-CI: 1.1; 1.9) and of 2.2mmHg (95%-CI: 1.3; 3.1), respectively. CONCLUSIONS: Our study suggests an association of short-term exposure to fine and ultrafine particles emitted from toasting bread with increases in BP. Particles emitted from frying sausages and candle burning did not consistently affect BP. PMID- 28662450 TI - Dynamics and ecological risk assessment of chromophoric dissolved organic matter in the Yinma River Watershed: Rivers, reservoirs, and urban waters. AB - The extensive use of a geographic information system (GIS) and remote sensing in ecological risk assessment from a spatiotemporal perspective complements ecological environment management. Chromophoric dissolved organic matter (CDOM), which is a complex mixture of organic matter that can be estimated via remote sensing, carries and produces carcinogenic disinfection by-products and organic pollutants in various aquatic environments. This paper reports the first ecological risk assessment, which was conducted in 2016, of CDOM in the Yinma River watershed including riverine waters, reservoir waters, and urban waters. Referring to the risk formation theory of natural disaster, the entropy evaluation method and DPSIR (driving force-pressure-state-impact-response) framework were coupled to establish a hazard and vulnerability index with multisource data, i.e., meteorological, remote sensing, experimental, and socioeconomic data, of this watershed. This ecological vulnerability assessment indicator system contains 23 indicators with respect to ecological sensitivity, ecological pressure, and self-resilience. The characteristics of CDOM absorption parameters from different waters showed higher aromatic content and molecular weights in May because of increased terrestrial inputs. The assessment results indicated that the overall ecosystem risk in the study area was focused in the extremely, heavily, and moderately vulnerable regions. The ecological risk assessment results objectively reflect the regional ecological environment and demonstrate the potential of ecological risk assessment of pollutants over traditional chemical measurements. PMID- 28662451 TI - A spatial framework for targeting urban planning for pollinators and people with local stakeholders: A route to healthy, blossoming communities? AB - Pollinators such as bees and hoverflies are essential components of an urban ecosystem, supporting and contributing to the biodiversity, functioning, resilience and visual amenity of green infrastructure. Their urban habitats also deliver health and well-being benefits to society, by providing important opportunities for accessing nature nearby to the homes of a growing majority of people living in towns and cities. However, many pollinator species are in decline, and the loss, degradation and fragmentation of natural habitats are some of the key drivers of this change. Urban planners and other practitioners need evidence to carefully prioritise where they focus their resources to provide and maintain a high quality, multifunctional green infrastructure network that supports pollinators and people. We provide a modelling framework to inform green infrastructure planning as a nature based solution with social and ecological benefits. We show how habitat suitability models (HSM) incorporating remote sensed vegetation data can provide important information on the influence of urban landcover composition and spatial configuration on species distributions across cities. Using Edinburgh, Scotland, as a case study city, we demonstrate this approach for bumble bees and hoverflies, providing high resolution predictive maps that identify pollinator habitat hotspots and pinch points across the city. By combining this spatial HSM output with health deprivation data, we highlight 'win-win' opportunity areas in most need of improved green infrastructure to support pollinator habitat quality and connectivity, as well as societal health and well-being. In addition, in collaboration with municipal planners, local stakeholders, and partners from a local greenspace learning alliance, we identified opportunities for citizen engagement activities to encourage interest in wildlife gardening as part of a 'pollinator pledge'. We conclude that this quantitative, spatially explicit and transferable approach provides a useful decision-making tool for targeting nature-based solutions to improve biodiversity and increase environmental stewardship, with the aim of providing a more attractive city to live, work and invest in. PMID- 28662449 TI - Maternal exposure to selenium and cadmium, fetal growth, and placental expression of steroidogenic and apoptotic genes. AB - BACKGROUND: Cadmium (Cd) and selenium (Se) antagonistically influence redox balance and apoptotic signaling, with Cd potentially promoting and Se inhibiting oxidative stress and apoptosis. Alterations to placental redox and apoptotic functions by maternal exposure to Cd and Se during pregnancy may explain some of the Cd and Se associations with fetal development. OBJECTIVES: Investigate associations between Cd and Se concentrations in maternal toenails with placental expression patterns of tumor necrosis factor (TNF) and steroidogenic genes involved in redox reactions and test associations with fetal growth. METHODS: In a sub-sample from the Rhode Island Child Health Study (n = 173), we investigated the relationships between: (1) maternal toenail Cd and Se concentrations and fetal growth using logistic regression, (2) Cd and Se interactions with factor scores from placental TNF and steroidogenic expression patterns (RNAseq) using linear models, and (3) TNF and steroidogenic expression factors with fetal growth via analysis of covariance. RESULTS: Se was associated with decreased odds of intrauterine growth restriction (IUGR) (OR = 0.27, p-value = 0.045). Cd was associated with increased odds of IUGR (OR = 1.95, p-value = 0.13) and small for gestational age (SGA) births (OR = 1.46, p-value = 0.11), though not statistically significant. Cd and Se concentrations were antagonistically associated with placental TNF and steroidogenic expression patterns, which also differed by birth size. CONCLUSIONS: Se may act as an antagonist to Cd and as a modifiable protective factor in fetal growth restriction, and these data suggest these effects may be due to associated variations in the regulation of genes involved in placental redox balance and/or apoptotic signaling. PMID- 28662452 TI - Estimating human exposure to perfluoroalkyl acids via solid food and drinks: Implementation and comparison of different dietary assessment methods. AB - BACKGROUND: Diet is a major source of human exposure to hazardous environmental chemicals, including many perfluoroalkyl acids (PFAAs). Several assessment methods of dietary exposure to PFAAs have been used previously, but there is a lack of comparisons between methods. AIM: To assess human exposure to PFAAs through diet by different methods and compare the results. METHODS: We studied the dietary exposure to PFAAs in 61 Norwegian adults (74% women, average age: 42 years) using three methods: i) by measuring daily PFAA intakes through a 1-day duplicate diet study (separately in solid and liquid foods), ii) by estimating intake after combining food contamination with food consumption data, as assessed by 2-day weighted food diaries and iii) by a Food Frequency Questionnaire (FFQ). We used existing food contamination data mainly from samples purchased in Norway and if not available, data from food purchased in other European countries were used. Duplicate diet samples (n=122) were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify 15 PFAAs (11 perfluoroalkyl carboxylates and 4 perfluoroalkyl sulfonates). Differences and correlations between measured and estimated intakes were assessed. RESULTS: The most abundant PFAAs in the duplicate diet samples were PFOA, PFOS and PFHxS and the median total intakes were 5.6ng/day, 11ng/day and 0.78ng/day, respectively. PFOS and PFOA concentrations were higher in solid than liquid samples. PFOS was the main contributor to the contamination in the solid samples (median concentration 14pg/g food), while it was PFOA in the liquid samples (median concentrations: 0.72pg/g food). High intakes of fats, oils, and eggs were statistically significantly related to high intakes of PFOS and PFOA from solid foods. High intake of milk and consumption of alcoholic beverages, as well as food in paper container were related to high PFOA intakes from liquid foods. PFOA intakes derived from food diary and FFQ were significantly higher than those derived from duplicate diet, but intakes of PFOS derived from food diary and FFQ were significantly lower than those derived from duplicate diet. We found a positive and statistically significant correlation between the PFOS intakes derived from duplicate diet with those using the food diary (rho=0.26, p value=0.041), but not with the FFQ. Additionally, PFOA intakes derived by duplicate diet were significantly correlated with estimated intakes from liquid food derived from the food diary (rho=0.34, p=0.008) and estimated intakes from the FFQ (rho=0.25, p-value=0.055). CONCLUSIONS: We provide evidence that a food diary or a FFQ-based method can provide comparable intake estimates to PFOS and PFOA intakes derived from a duplicate diet study. These less burdensome methods are valuable and reliable tools to assess dietary exposure to PFASs in human studies. PMID- 28662453 TI - Per- and polyfluoroalkyl substances in plasma and feathers of nestling birds of prey from northern Norway. AB - Plasma samples from nestlings of two top predators, White-tailed eagle (Haliaeetus albicilla) and Northern goshawk (Accipiter gentilis) from northern Norway were analysed for a wide range of per- and polyfluoroalkyl substances (PFASs). Body feathers from the White-tailed eagles were also analysed and significant associations between specific PFASs in blood plasma and body feathers were found (0.36 = 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power >= 30% compared with placebo. RESULTS: No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. LIMITATIONS: A low rate of relapse events precluded detection of any statistically significant difference between groups. CONCLUSIONS: The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions. PMID- 28662461 TI - Standing on wedges modifies side-specific postural control in the presence of lateral external perturbations. AB - Standing on wedges changes the position in the ankle joints and affects postural stability in the medial-lateral direction. The objective of the study was to investigate the role of wedges and external lateral perturbations on anticipatory (APA) and compensatory postural adjustments (CPA). Ten healthy young participants were exposed to perturbations applied to the lateral part of their right shoulder when standing on a planar surface, on a medial or lateral wedges. Bilateral electromyographic activity of dorsal and ventral postural muscles and the center of pressure (COP) displacement were recorded and analyzed during the APA and CPA phases. When exposed to the lateral perturbation, reciprocal activation of shank muscles was seen on the side of the perturbation while co-contraction of shank muscles was seen on the contralateral side during the APA and CPA phases. Standing on a wedge was associated with decreased magnitudes of co-contraction and reciprocal activation of shank muscles. The COP displacements were smaller in the APA phase and larger in the CPA phase while standing on wedges compared to standing on the planar surface. The outcome of the study provides a basis for future investigations of incorporating wedges in balance re-training paradigms for the elderly or individuals with neurological impairment. PMID- 28662462 TI - Alterations of growth, antioxidant system and gene expression in Stylosanthes guianensis during Colletotrichum gloeosporioides infection. AB - Anthracnose caused by Colletotrichum gloeosporioides is one of the most destructive fungal diseases of many plants, including stylo (Stylosanthes spp.), which is an important tropical forage legume. Although C. gloeosporioides-caused anthracnose is the major constraint limiting the growth and yield of stylo, little information is available regarding the responses of stylo during the infection process of this pathogen. This study investigated the changes in growth, the antioxidant system and gene expression in stylo in response to C. gloeosporioides treatment. Negative effects of C. gloeosporioides were observed in inoculated stylo plants, as reflected by the formation of necrotic disease lesions and the decrease in shoot fresh weight. Reactive oxygen species (ROS) accumulation increased in stylo leaves during the C. gloeosporioides infection process. The activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase (GPX) and glutathione reductase (GR), as well as the concentrations of the antioxidant compounds ascorbate (AsA) and glutathione (GSH), increased in leaves under C. gloeosporioides treatment. Furthermore, transcriptional analysis showed that the expression of stress response genes, including NADPH oxidase (Nox), thioredoxin (Thi), pathogenesis related genes (PR1 and PR5), phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), chalcone synthase (CHS) and chitinase (Cht), was differentially enhanced in stylo leaves by C. gloeosporioides. Taken together, this study provides novel information regarding the alterations during the infection process of C. gloeosporioides in stylo at the levels of antioxidant system and gene expression. PMID- 28662463 TI - MEG language lateralization in partial epilepsy using dSPM of auditory event related fields. AB - OBJECTIVE: Methods employed to determine hemispheric language dominance using magnetoencephalography (MEG) have differed significantly across studies in the choice of language-task, the nature of the physiological response studied, recording hardware, and source modeling methods. Our goal was to determine whether an analysis based on distributed source modeling can replicate the results of prior studies that have used dipole-modeling of event-related fields (ERFs) generated by an auditory word-recognition task to determine language dominance in patients with epilepsy. METHODS: We analyzed data from 45 adult patients with drug-resistant partial epilepsy who performed an auditory word recognition task during MEG recording and also completed a language fMRI study as part of their evaluation for epilepsy surgery. Source imaging of auditory ERFs was performed using dynamic statistical parametric mapping (dSPM). Language laterality indices (LIs) were calculated for four regions of interest (ROIs) by counting above-threshold activations within a 300-600ms time window after stimulus onset. Language laterality (LL) classifications based on these LIs were compared to the results from fMRI. RESULTS: The most lateralized MEG responses to language stimuli were observed in a parietal region that included the angular and supramarginal gyri (AngSmg). In this region, using a half-maximal threshold, source activations were left dominant in 32 (71%) patients, right dominant in 8 (18%), and symmetric in 5 patients (11%). The best agreement between MEG and fMRI on the ternary classification of regional language dominance into left, right, or symmetric groups was also found at the AngSmg ROI (69%). This was followed by the whole-hemisphere and temporal ROIs (both 62%). The frontal ROI showed the least agreement with fMRI (51%). Gross discordances between MEG and FMRI findings were disproportionately of the type where MEG favored atypical right-hemispheric language in a patient with right-hemispheric seizure origin (p<0.05 at three of the four ROIs). SIGNIFICANCE: In a parietal region that includes the angular and supramarginal gyri, language laterality estimates based on dSPM of ERFs during auditory word-recognition shows a degree of MEG-fMRI concordance that is comparable to previously published estimates for MEG-Wada concordance using dipole counting methods and the same task. Our data also suggest that MEG language laterality estimates based on this task may be influenced by the laterality of epileptic networks in some patients. This has not been reported previously and deserves further study. PMID- 28662464 TI - Knowledge and practices of diabetes care providers in oral health care and their potential role in oral health promotion: A scoping review. AB - AIM: Oral health complications are common in people with diabetes yet very little is reported about the oral health care provided in diabetes care setting. This study reviewed global evidence on the oral health care knowledge and practices of diabetes care providers and the role of non-dental health professionals in oral health promotion. METHODS: A systematic search of five databases was undertaken with key search terms using a scoping review framework. Relevant studies published till October 2016 in the English language were included (n=30) and no restrictions were placed on the study design, quality or setting. RESULTS: Most diabetes care providers are not addressing oral health care with the main barriers being time constraints and limited oral health knowledge. Diabetes educators (DEs) could engage in oral health promotion with few studies showing this model of care can translate into improved patient outcomes. However, no appropriate oral health training programs and assessment tools exist for DEs. With proper training, non-dental professionals like nurses have successfully incorporated oral healthcare in other settings. CONCLUSIONS: DEs are well placed to promote oral health in diabetes care setting. Further research is needed to identify barriers and oral health resources to support DEs in this role. PMID- 28662465 TI - Neuroimaging of an attention demanding dual-task during dynamic postural control. AB - Cognitive tasks impact postural control when performed concurrently as dual tasks. This is presumed to result from capacity limitations in relevant brain regions. We used functional near-infrared spectroscopy (fNIRS) to measure brain activation of the left motor, temporal, and dorsal-lateral prefrontal brain regions of younger (n=6) and older (n=10) adults. Brain activation was measured during an auditory choice reaction task (CRT) and standing on a dynamic posturography platform, both as single-tasks and concurrently as dual-task. Body sway was assessed by median absolute deviation (MAD) of anterior-posterior translation of the center of mass (COM). Brain activation was measured as changes in oxy-hemoglobin by fNIRS. During both single- and dual-task conditions, we found that older adults had greater brain activation relative to younger adults. During dual task performance, the total activation was less than expected from the sum of individual conditions for both age groups, indicating a dual-task interference (reduction in younger adults=53% [p=0.02]; in older adults=53%; [p=0.008]). This reduction was greater for the activation attributable to the postural task (reduction younger adults=75% [p=0.03]; older adults=59% [p=0.005]) compared to the CRT task (reduction younger adults=10%, [p=0.6]; older adults=7.3%, [p=0.5]) in both age groups. Activation reduction was not accompanied by any significant changes in body sway in either group (older adults: single-task MAD=0.94cm, dual-task MAD=1.10cm, p=0.20; younger adults: single-task RMS=0.95cm, dual-task MAD=1.08cm, p=0.14). Our results indicate that neural resources devoted to postural control are reduced under dual-task conditions that engage attention. PMID- 28662466 TI - Informationally administered reward enhances intrinsic motivation in schizophrenia. AB - Even when individuals with schizophrenia have an intact ability to enjoy rewarding moments, the means to assist them to translate rewarding experiences into goal-directed behaviors is unclear. The present study sought to determine whether informationally administered rewards enhance intrinsic motivation to foster goal-directed behaviors in individuals with schizophrenia (SZ) and healthy controls (HCs). Eighty-four participants (SZ=43, HCs=41) were randomly assigned to conditions involving either a performance-contingent reward with an informationally administered reward or a task-contingent reward with no feedback. Participants were asked to play two cognitive games of equalized difficulty. Accuracy, self-reported intrinsic motivation, free-choice intrinsic motivation (i.e., game play during a free-choice observation period), and perceived competency were measured. Intrinsic motivation and perceived competency in the cognitive games were similar between the two participant groups. The informationally administered reward significantly enhanced self-reported intrinsic motivation and perceived competency in both the groups. The likelihood that individuals with schizophrenia would play the game during the free-choice observation period was four times greater in the informationally administered reward condition than that in the no-feedback condition. Our findings suggest that, in the context of cognitive remediation, individuals with schizophrenia would benefit from informationally administered rewards. PMID- 28662467 TI - Locus-specific DNA methylation changes and phenotypic variability in children with attention-deficit hyperactivity disorder. AB - Maternal smoking during pregnancy is the most commonly cited risk factor for ADHD. While the causal relation between this factor and ADHD is debated, several lines of evidence suggest that it modulates the severity of ADHD, particularly through higher association with conduct disorder (CD). We hypothesized that maternal smoking during pregnancy may be associated with differential methylation in selected genes in children with ADHD. DNA extracted from peripheral blood was used to examine methylation between 25 children exposed, and 22 children not exposed to maternal smoking during pregnancy. Three genes (AHRR, CYP1A1, GFI1) were selected based on previous results observed in the general population. Regression analysis was conducted between methylation levels in these candidate genes and: (a) total number of ADHD and CD symptoms; (b) birth weight. Significant differences in methylation were observed in each of the candidate genes between children exposed and not exposed to maternal smoking during pregnancy. Methylation at the selected sites showed significant association with specific phenotypes. Significant correlations were observed between methylation within AHRR and number of CD symptoms; GFI1 and number of ADHD symptoms and GFI1 and birth weight. These initial results may have important clinical implications if confirmed in a larger independent sample. PMID- 28662469 TI - Molecular, cellular and pharmacological effects of platinum(II) diiodido complexes containing 9-deazahypoxanthine derivatives: A group of broad-spectrum anticancer active agents. AB - The platinum(II) iodido complexes 1-5 of the general formula cis-[PtI2(Ln)2], where Ln stands for O-substituted 9-deazahypoxanthine derivatives, were prepared and thoroughly characterized by various techniques, including multinuclear 1D and 2D NMR spectroscopy. The complexes were screened for their anticancer potential in vitro on ten human cancer cell lines, concretely breast adenocarcinoma (MCF7), osteosarcoma (HOS), lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), malignant melanoma (G-361), prostate carcinoma (22Rv1, PC-3), hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780) and cisplatin-resistant ovarian carcinoma (A2780R). The complexes exhibited significant wide-spectrum anticancer activity in vitro against all the employed cell lines, with IC50~0.5-24.0MUM. Very good correlation between the lipophilicity parameter log P and IC50 values of anticancer activity in vitro were obtained by simple QSAR analysis. The most lipophilic complexes 2, 4 and 5 showed the best results, as they reached the sub micromolar IC50 values against the A2780 and A2780R sub-lines, with the best result equal 0.5+/-0.1MUM on A2780 for complex 5. The in vivo testing of the representative complexes 1, 4 and 5 (applied at the same dose of Pt as 2mg/kg dose of cisplatin) on a L1210 leukaemia model revealed their positive effect on the prolongation of the mean survival time, even if it was lower than that of cisplatin. The 1H NMR interaction study revealed the ability of complexes to interact with glutathione (GSH) and 5'-guanosine monophosphate (GMP) and overall higher stability of the complexes 1-5 as compared to cisplatin. The electrospray ionization mass spectrometry experiments with complex 1 identified the formation of a rich collection of hydrolytic species in water-containing media after 24h and the interaction intermediates with sulfur-containing biomolecule l-cysteine, but not with the reduced glutathione at physiologically relevant concentration levels. PMID- 28662468 TI - Novel carbohydrate-substituted metallo-porphyrazine comparison for cancer tissue type specificity during PDT. AB - A longstanding obstacle to cancer eradication centers on the heterogeneous nature of the tissue that manifests it. Variations between cancer cell resistance profiles often result in a survival percentage following classic therapeutics. As an alternative, photodynamic therapys' (PDT) unique non-specific cell damage mechanism and high degree of application control enables it to potentially deliver an efficient treatment regime to a broad range of heterogeneous tissue types thereby overcoming individual resistance profiles. This study follows on from previous design, characterization and solubility analyses of three novel carbohydrate-ligated zinc-porphyrazine (Zn(II)Pz) derivatives. Here we report on their PDT application potential in the treatment of five common cancer tissue types in vitro. Following analyses of metabolic homeostasis, toxicity and cell death induction, overall Zn(II)Pz-PDT proved comparably efficient between all cancer tissue populations. Differential localization patterns of Zn(II)Pz derivatives between cell types did not appear to influence the overall PDT effect. All cell types exhibited significant disruptions to mitochondrial activity and associated ATP production levels. Toxicity and chromatin structure profiles revealed indiscernible patterns of damage between Zn(II)Pz derivatives and cell type. The subtle differences observed between individual Zn(II)Pz derivatives is most likely due to a combination of carbohydrate moiety characteristics on energy transfer processes and associated dosage optimization requirements per tissue type. Collectively, this indicates that resistance profiles are negated to a significant extent by Zn(II)Pz-PDT making these derivatives attractive candidates for PDT applications across multiple tissue types and subtypes. PMID- 28662470 TI - Multiple functional strategies for amplifying sensitivity of amperometric immunoassay for tumor markers: A review. AB - Multiple functional strategies have shown great potential in ultrasensitive amperometric immunoassays for tumor markers, which promote conductivity and signal multiple amplification. The sensitivity of amperometric immunoassays is significantly affected by the conductivity and specific area of the sensing interface as well as the electrochemical activity of redox species. Thus, these strategies are generally based on integrating various materials together and endowing immunosensing systems with many advantages, such as large specific area, high electrochemical activity, good conductivity, biocompatibility, and catalytic performance. Owing to the rapid development of functional materials (such as conductive hybrids, catalytic hybrids, enzyme-like materials, highly electrochemical active species, redox nanocomposites, porous materials, hydrogels, and metal-organic framework) and new bioactive substances (including new blocking agents and receptors like peptides and oligonucleotide chains), the sensitivity of related biosensors is usually higher than that of traditional ones, indicating that multiple functional strategies are promising in amperometric immunoassays. Herein, we provide an overview of recent advances in multiple functional strategies that have proven to dramatically enhance the sensitivity of amperometric immunoassays, which incorporate the following materials: (1) conductive nanomaterials hybrids; (2) catalytic nanomaterials hybrids; (3) new redox materials; (4) three-dimensional porous materials; (5) new receptors and blocking agents. PMID- 28662471 TI - In situ grown DNA nanotail-templated silver nanoclusters enabling label-free electrochemical sensing of terminal deoxynucleotidyl transferase activity. AB - A novel label-free electrochemical strategy was established based on the unique electro-catalytic activity of graphene oxide (GO)-supported terminal deoxynucleotidyl transferase (TdT)-generated C-rich DNA nanotail-templated silver nanoclusters (DNA-AgNCs). TdT can catalyze the deoxycytidine triphosphate (dCTP) to the 3'-OH terminus of single-stranded DNA (ssDNA) with no template; then, in the presence of Ag(I), TdT-generated C-rich DNA sequence was employed for the synthetic template of AgNCs because of the formed complexes of nitrogen atoms of cytosine based with silver atoms. We proved that in situ grown DNA nanotail templated AgNCs can be adsorbed on GO-modified electrode and possess high electro catalytic activity to H2O2 reduction, presenting a good electrochemical indicator for signal readout. Under optimal conditions, the proposed biosensor could be employed for quantitatively monitoring TdT activity and within a dynamic range from 0.4 to 90U/mL and a low limit of detection is 0.08U/mL. With high sensitivity and excellent selectivity, this strategy offers a facile, convenient and specific electrochemical method for TdT activity detection and its relevant inhibitors screening. It holds a promising potential in the practical application of TdT-based biochemical research, disease diagnosis and drug discovery. PMID- 28662472 TI - Stepwise unfolding of Ribonuclease A by a biosurfactant. AB - The interaction of Ribonuclease A (RNase A) with the bile salt, sodium deoxycholate (NaDC) is meticulously investigated using various spectroscopic techniques. The binding isotherm constructed from the modulation of intrinsic tyrosine fluorescence of the protein following interaction with NaDC conspicuously reveals an intrinsically complex stepwise interaction process which proceeds through the formation of distinct conformational states of the protein. The conformational transitions are found to occur at c1=2.2mM, and c2=7.2mM of NaDC. These results are subsequently corroborated from the studies of excited state relaxation dynamics of the intrinsic tyrosine residues of RNase A, and the modulations in fluorescence behavior of an extrinsic probe (ANS) bound to the protein. The far-UV circular dichroism spectral analyses unveil only nominal influence on the secondary structural element of the protein up to [NaDC]=c1=2.2mM, which is then followed by marked disruption of the secondary structure of RNase A following further addition of NaDC. This clearly accounts for differential interaction behaviors of RNase A with the monomeric and micellar forms of NaDC (CMC of NaDC in aqueous buffer is estimated to be ~3.0mM). In Region-I (up to c1=2.2mM), the protein:surfactant interaction is argued to be predominantly governed by electrostatic/ionic interaction force. Subsequently, in Region-II (up to c2=7.2mM) the RNase A:NaDC interaction accompanies major denaturation of the protein (~17% loss of the secondary structure of RNase A at c2=7.2mM) resulting in significant exposure of hydrophobic surfaces of the protein. However, the tertiary structure of the protein remains essentially unperturbed within the concentration regime of NaDC under study. PMID- 28662473 TI - Graphene-supported mesoporous titania nanosheets for efficient photodegradation. AB - Graphene-supported mesoporous titania nanosheets (G-TiO2) were synthesized successfully by employing liquid-phase exfoliated few-layers graphene as a template and sandwich-like graphene-silica as intermediates. The as-prepared G TiO2 not only inherited the two-dimensional structure of directly exfoliated few layers graphene, high specific surface areas and large aspect ratio, but also possessed a mesoporous structure with nano-sized crystalline titania being anchored on the graphene nanosheets. Such unique features could enhance significantly the photocatalytic activities of TiO2 for degradating of hazardous organic compounds such as methyl orange (MO), rhodamine B (RhB) and methylene blue (MB). PMID- 28662474 TI - Polypyrrole decorated BiOI nanosheets: Efficient photocatalytic activity for treating diverse contaminants and the critical role of bifunctional polypyrrole. AB - A conducting polymer polypyrrole (Ppy) was first employed to decorate BiOI for fabricating an organic-inorganic hybridized Ppy-BiOI nanocomposite photocatalyst via a facile in situ precipitation strategy at room temperature. The composite and intimate interface was confirmed by FTIR, XPS, SEM, HRTEM and TEM-mapping. In comparison with pristine BiOI, the Ppy-BiOI hybrids present significantly enhanced photocatalytic activity for degradation of Rhodamine B (RhB) under visible light (lambda>420nm). Particularly, the Ppy-BiOI composite exhibits an universal photocatalytic performance for removing diverse industrial pollutants and antibiotics, including bisphenol A, 2,4-dichlorophenol, tetracycline hydrochloride and chlortetracycline hydrochloride. The enhanced photocatalytic activity of Ppy-BiOI composite is found attributable to the bifunctional role that Ppy takes. Ppy-BiOI composite has an enhanced specific surface area, which benefits adsorption and generation of more active sites. Notably, high separation and transfer of the photogenerated charge carriers was achieved on the interface between Ppy and BiOI, and the photogenerated hole transfer action of Ppy is demonstrated. Therefore, synergistic effect of adsorption-enrichment and photocatalytic degradation is realized. Our work may offer a guideline to manipulate high-performance Bi-based composite photocatalyst by coupling conducting polymers. PMID- 28662475 TI - Electrospun magnetic cobalt-embedded carbon nanofiber as a heterogeneous catalyst for activation of oxone for degradation of Amaranth dye. AB - A cobalt-embedded carbon nanofiber (CoCNF) is developed in this study by electrospinning techniques. Through one-step carbonization, the electrospun Co polyacrylonitrile nanofiber is converted to CoCNF. The resulting CoCNF consists of cobalt nanoparticles quite evenly distributed over CNF and also exhibits magnetically controllability, making it a suitable heterogeneous catalyst for activating Oxone (OX) to degrade organic contaminants. As degradation of Acid Red 27 (AR) is employed as a model reaction, CoCNF is validated to activate OX for generating sulfate radicals and then degrading AR. While a higher dosage of CoCNF and OX enhances AR degradation, CoCNF plays a more influential role in CoCNF-OX. AR degradation by CoCNF-OX is much enhanced at elevated temperature, and also favorable under the neutral condition. CoCNF-OX still remains quite effective for AR degradation even in the presence of salts and surfactants. The mechanism of AR degradation is elucidated by evaluating the effects of radical scavengers and the degradation is attributed to sulfate and derivative hydroxyl radicals. CoCNF is shown to activate OX for multiple times to degrade AR even without regeneration treatments. These results and findings validate that CoCNF can be a promising and advantageous heterogeneous for activating OX in advanced oxidation processes. The preparation method shown here can be also employed for fabricating other functional metal-embedded CNF for various applications. PMID- 28662476 TI - Effect of crosslinking on the physical and chemical properties of beta lactoglobulin (Blg) microgels. AB - HYPOTHESIS: Microgels assembled from the protein beta-lactoglobulin are colloidal structures with potential applications in food materials. Modifying the internal crosslinking within these microgels using enzymatic or chemical treatments should affect dissolution, swelling, and viscous attributes under strongly solvating conditions. EXPERIMENTS: Microgels were treated with citric acid, glutaraldehyde and transglutaminase to induce cross-linking or with tris(2 carboxyethyl)phosphine to reduce disulfide linkages. Change in hydrodynamic particle size due to acidic pH, alkaline pH, ionic strength, osmolyte concentration, ethanol, urea, sodium dodecyl sulfate, and reducing agents was evaluated by light scattering measurements. Changes in microgel nanomechanical properties were evaluated via force spectroscopic measurements in water. FINDINGS: Average microgel size increased ~20% in alkaline pH and with ethanol contents above 10%, and decreased ~20% with sucrose contents above 10%. Cross linking by glutaraldehyde and transglutaminase prevented size increases in alkaline pH. Microgel plasticity and elastic modulus were unaffected by treatments. Microgels treated with glutaraldehyde were found to have much greater stability to urea, sodium dodecyl sulfate, and reducing agents when compared to other samples. Even without cross-linking, microgels remained stable against precipitation and dissolution over a wide range conditions, indicating their broad utility as colloidal stabilizers, texture modifiers or controlled release agents in food or other applications. PMID- 28662477 TI - Synthesis and characterization of Silica/polyvinyl imidazole/H2PO4-core-shell nanoparticles as recyclable adsorbent for efficient scavenging of Sm(III) and Dy(III) from water. AB - In this study, we used Silica/polyvinyl imidazole core-shell nanoparticles impregnated with sodium dihydrogen phosphate (SiO2/PVI/H2PO4- NPs) for adsorption of samarium and dysprosium ions from aqueous solutions. The effects of the pH, adsorbent dose, contact time, and initial concentration of the adsorbate on the Core-shell nanoparticles adsorption capacity have been studied. The pH value for maximum removal of Sm (III) and Dy (III) on the core-shell nanoparticles surface were found to be 4. The saturated capacity of SiO2/PVI/H2PO4- NPs was up to 160mg.g-1 and 150mg.g-1at 25 degrees C for Sm (III) and Dy (III) ions respectively. The obtained uptake data were analyzed by the Langmuir and Freundlich equations using a linearized correlation coefficient at room temperature. The Freundlich isotherm was found to fit well with the equilibrium data. The adsorption kinetics could be modeled by a pseudo-second-order rate expression. Thermodynamic investigation revealed the adsorption process of the studied ions is entropy driven. Furthermore, the performance of regeneration and reutilization were studied. The adsorbed Sm (III) and Dy (III) can be desorbed by 0.5mol/L HCl, with the desorption percentage of 90% for Sm (III) and Dy (III). After five adsorption-desorption cycles, the adsorption capacity shows a slight decrease (about 15%), implying that the SiO2/PVI/H2PO4- NPs can be used as an effective adsorbent for the removal and recovery of Sm(III) and Dy(III) from aqueous solution. The colloid stability of the SiO2/PVI/H2PO4- NPs was investigated by dynamic light scattering measurements. The SiO2/PVI/H2PO4- NPs are stable in adsorption media after five adsorption - desorption cycles. The high stability of SiO2/PVI/H2PO4- NPs can be attributed to steric stabilization by polyvinyl imidazole adsorbed on SiO2 nanoparticle surfaces. PMID- 28662478 TI - Disassociation of cognitive and affective aspects of theory of mind in obsessive compulsive disorder. AB - Impairment in social functioning has been widely described in obsessive compulsive disorder (OCD). However, several aspects of social cognition, such as theory of mind (ToM), have not been substantially investigated in this context. This study examined cognitive and affective ToM in 40 OCD patients and 38 age-, sex-, and education-matched healthy controls (HCs) with the computerized Yoni task and a battery of neurocognitive tests. OCD symptom severity was assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Depressive and anxiety symptoms were also assessed. Compared to HCs, OCD patients performed worse on second-order affective condition trials, but not cognitive or physical condition trials, of the Yoni task; there were not group differences in any of the first order condition domains. Second-order ToM performance of OCD patients was associated with estimated intelligence and working memory performance. After controlling for neurocognitive variables, the group difference in second-order affective condition performance remained significant. These findings indicate that the affective component of ToM may be selectively impaired in OCD patients and that the observed deficit is largely independent of other neurocognitive impairments and clinical characteristics. PMID- 28662479 TI - Intact implicit statistical learning in borderline personality disorder. AB - Wide-spread neuropsychological deficits have been identified in borderline personality disorder (BPD). Previous research found impairments in decision making, declarative memory, working memory and executive functions; however, no studies have focused on implicit learning in BPD yet. The aim of our study was to investigate implicit statistical learning by comparing learning performance of 19 BPD patients and 19 healthy, age-, education- and gender-matched controls on a probabilistic sequence learning task. Moreover, we also tested whether participants retain the acquired knowledge after a delay period. To this end, participants were retested on a shorter version of the same task 24h after the learning phase. We found intact implicit statistical learning as well as retention of the acquired knowledge in this personality disorder. BPD patients seem to be able to extract and represent regularities implicitly, which is in line with the notion that implicit learning is less susceptible to illness compared to the more explicit processes. PMID- 28662480 TI - Adduct ion-targeted qualitative and quantitative analysis of polyoxypregnanes by ultra-high pressure liquid chromatography coupled with triple quadrupole mass spectrometry. AB - Polyoxypregnane and its glycosides (POPs) are frequently present in plants of Asclepiadaceae family, and have a variety of biological activities. There is a great need to comprehensively profile these phytochemicals and to quantify them for monitoring their contents in the herbs and the biological samples. However, POPs undergo extensive adduct ion formation in ESI-MS, which has posed a challenge for qualitative and quantitative analysis of POPs. In the present study, we took the advantage of such extensive adduct ion formation to investigate the suitability of adduct ion-targeted analysis of POPs. For the qualitative analysis, we firstly demonstrated that the sodium and ammonium adduct ion-targeted product ion scans (PIS) provided adequate MS/MS fragmentations for structural characterization of POPs. Aided with precursor ion (PI) scans, which showed high selectivity and sensitivity and improved peak assignment confidence in conjunction with full scan (FS), the informative adduct ion-targeted PIS enabled rapid POPs profiling. For the quantification, we used formic acid rather than ammonium acetate as an additive in the mobile phase to avoid simultaneous formation of sodium and ammonium adduct ions, and greatly improved reproducibility of MS response of POPs. By monitoring the solely formed sodium adduct ions [M+Na]+, a method for simultaneous quantification of 25 POPs in the dynamic multiple reaction monitoring mode was then developed and validated. Finally, the aforementioned methods were applied to qualitative and quantitative analysis of POPs in the extract of a traditional Chinses medicinal herb, Marsdenia tenacissima (Roxb.) Wight et Arn., and in the plasma obtained from the rats treated with this herb. The results demonstrated that adduct ion formation could be optimized for the qualitative and quantitative analysis of POPs, and our developed PI/FS-PIS scanning and sole [M+Na]+ ion monitoring significantly improved the analysis of POPs in both herbal and biological samples. This study also provides implications for the analysis of other compounds which undergo extensive adduct ion formation in ESI-MS. PMID- 28662481 TI - Liquid chromatography-tandem mass spectrometry assay to quantify plitidepsin in human plasma, whole blood and urine. AB - Plitidepsin is an anti-cancer drug currently evaluated in phase I/II/III clinical trials. This article describes the development and validation of a bioanalytical assay to quantify plitidepsin in human plasma, urine and whole blood using HPLC MS/MS. The analyte was extracted from the matrix by liquid-liquid extraction using tert-butyl methyl ether. Final extracts were injected onto a C18 column, gradient elution was applied for chromatographic separation and detection was performed on a triple quadrupole mass spectrometer operating in the positive ion mode. The assay was linear over the range 0.1-100ng/mL, with acceptable accuracy and precision values. This is the first reported bioanalytical assay quantifying plitidepsin using a stable isotopically labelled standard, achieving a lower limit of quantification of 0.1ng/mL in all three matrices, allowing the quantification of trace levels of plitidepsin, and accomplishing this in an analysis time of two minutes only. The presented method was successfully applied in a mass balance study with plitidepsin in patients with advanced cancer. PMID- 28662482 TI - Phonological experience modulates voice discrimination: Evidence from functional brain networks analysis. AB - Numerous behavioral studies have found a modulation effect of phonological experience on voice discrimination. However, the neural substrates underpinning this phenomenon are poorly understood. Here we manipulated language familiarity to test the hypothesis that phonological experience affects voice discrimination via mediating the engagement of multiple perceptual and cognitive resources. The results showed that during voice discrimination, the activation of several prefrontal regions was modulated by language familiarity. More importantly, the same effect was observed concerning the functional connectivity from the fronto parietal network to the voice-identity network (VIN), and from the default mode network to the VIN. Our findings indicate that phonological experience could bias the recruitment of cognitive control and information retrieval/comparison processes during voice discrimination. Therefore, the study unravels the neural substrates subserving the modulation effect of phonological experience on voice discrimination, and provides new insights into studying voice discrimination from the perspective of network interactions. PMID- 28662483 TI - Intensity of anticoagulation and risk of thromboembolism after elective cardioversion of atrial fibrillation. AB - BACKGROUND: Elective cardioversion (ECV) for atrial fibrillation (AF) is associated with a relatively low risk of thromboembolic complications. However, the optimal intensity of anticoagulation for ECV is unknown. We sought to assess the risk of thromboembolism in low (INR 2.0-2.4) vs. high (INR>=2.5) therapeutic range in a large retrospective cohort study. METHODS: This multi-centre "real world" study included 1424 ECVs in 1021 patients. The primary outcome was a stroke or a transient ischaemic attack (TIA) or a systemic embolus during the 30 day follow-up after ECV. RESULTS: Altogether 4 (0.3%) strokes, 2 (0.1%) TIAs and 2 (0.1%) bleeds were detected during the 30-day follow-up after ECV. No systemic emboli were detected. There were 2 deaths (0.1%), one associated with a stroke. Median time to stroke/TIA was 4 (IQR 9.5) days and the median CHA2DS2-VASc-score was 2 (IQR 1.25) among patients with thromboembolic events. Mean INR at ECV was 2.7 (SD 0.54) in the study cohort. Patients with INR 2.0-2.4 at ECV had more thromboembolic events compared with patients with INR>=2.5 (5/529 (0.9%) vs. 1/895 (0.1%), p=0.03). Comprehensive postprocedural INR data was available for 733 (71.8%) patients and 1007 cardioversions. At least one subtherapeutic (<2.0) INR value was detected within 21days after 230 (22.8%) ECVs and this drop in INR level was associated with a higher risk for thromboembolic events compared with continuous therapeutic post-cardioversion anticoagulation (1.7% vs 0.3%, p=0.03). CONCLUSIONS: Our results suggest that the intensity of periprocedural anticoagulation is associated with the risk of thromboembolic events after ECV. PMID- 28662484 TI - High platelet count at diagnosis is a protective factor for thrombosis in patients with essential thrombocythemia. AB - To assess the role of platelet (PLT) count for thrombotic complications in Essential Thrombocythemia (ET), 1201 patients followed in 11 Hematological centers in the Latium region were retrospectively evaluated. At multivariate analysis, the following factors at diagnosis were predictive for a worse Thrombosis-free Survival (TFS): the occurrence of previous thrombotic events (p=0.0004), age>60years (p=0.0044), spleen enlargement (p=0.042) and a lower PLT count (p=0.03). Receiver Operating Characteristic (ROC) analyses based on thrombotic events during follow-up identified a baseline platelet count of 944*109/l as the best predictive threshold: thrombotic events were 40/384 (10.4%) in patients with PLT count >944*109/l and 109/817 (13.3%) in patients with PLT count <944*109/l, respectively (p=0.04). Patients with PLT count <944*109/l were older (median age 60.4years. vs 57.1years., p=0.016), had a lower median WBC count (8.8*109/l vs 10.6*109/l, p<0.0001), a higher median Hb level (14.1g/dl vs 13.6g/dl, p<0.0001) and a higher rate of JAK-2-V617F positivity (67.2% vs 41.6%, p<0.0001); no difference was observed as to thrombotic events before diagnosis, spleen enlargement and concomitant Cardiovascular Risk Factors. In conclusion, our results confirm the protective role for thrombosis of an high PLT count at diagnosis. The older age and the higher rate of JAK-2 V617F positivity in the group of patients with a baseline lower PLT count could in part be responsible of this counterintuitive finding. PMID- 28662486 TI - Sensitivity enhancement by multiple-contact cross-polarization under magic-angle spinning. AB - Multiple-contact cross-polarization (MC-CP) is applied to powder samples of ferrocene and l-alanine under magic-angle spinning (MAS) conditions. The method is described analytically through the density matrix formalism. The combination of a two-step memory function approach and the Anderson-Weiss approximation is found to be particularly useful to derive approximate analytical solutions for single-contact Hartmann-Hahn CP (HHCP) and MC-CP dynamics under MAS. We show that the MC-CP sequence requiring no pulse-shape optimization yields higher polarizations at short contact times than optimized adiabatic passage through the HH condition CP (APHH-CP) when the MAS frequency is comparable to the heteronuclear dipolar coupling, i.e., when APHH-CP through a single sideband matching condition is impossible or difficult to perform. It is also shown that the MC-CP sideband HH conditions are generally much broader than for single contact HHCP and that efficient polarization transfer at the centerband HH condition can be reintroduced by rotor-asynchronous multiple equilibrations-re equilibrations with the proton spin bath. Boundary conditions for the successful use of the MC-CP experiment when relying on spin-lattice relaxation for repolarization are also examined. PMID- 28662485 TI - People learn other people's preferences through inverse decision-making. AB - People are capable of learning other people's preferences by observing the choices they make. We propose that this learning relies on inverse decision making-inverting a decision-making model to infer the preferences that led to an observed choice. In Experiment 1, participants observed 47 choices made by others and ranked them by how strongly each choice suggested that the decision maker had a preference for a specific item. An inverse decision-making model generated predictions that were in accordance with participants' inferences. Experiment 2 replicated and extended a previous study by Newtson (1974) in which participants observed pairs of choices and made judgments about which choice provided stronger evidence for a preference. Inverse decision-making again predicted the results, including a result that previous accounts could not explain. Experiment 3 used the same method as Experiment 2 and found that participants did not expect decision makers to be perfect utility-maximizers. PMID- 28662487 TI - Study on the interaction between typical phthalic acid esters (PAEs) and human haemoglobin (hHb) by molecular docking. AB - This work has evaluated the binding force between hHb and typcial PAEs (DMP, DEP, DPRP, DBP, DIBP, DHP and DPHP) using molecule docking technique. The DPHP with 3 aromatic rings has the strongest binding (-DeltaGbinding: 6.0kcalmol-1) than other PAEs (-DeltaGbinding: 2.91~4.48kcalmol-1). The DMP with the lowest molecular weight has a high binding force (-DeltaGbinding: 4.48kcalmol-1), while the DHP with the highest molecular weight has the lowest binding force ( DeltaGbinding: 2.91kcalmol-1). When the length of side chain increases, the binding force trend to decrease, regarding the VDW forces and H-bonding. The lgKow-DeltaGbinding plotting figure shows that a higher Kow value is accompanied by a lower binding force. The aromatic ring existed in PAEs largely increases the binding force between the hHb and the PAEs. On the other hand, the PAEs with higher number of carbon, meaning a higher hydrophobicity, can enter into the hydrophobic space of hHb centre deeper and bond to different position. The aromatic ring decreases the depth of binding position in the hydrophobic space. This work provides basic data and a theoretical method to assess the transport and accumulation of PAEs in human body, and the cytotoxicity of PAEs to hBRCs. PMID- 28662488 TI - Transcriptional response in rainbow trout (Oncorhynchus mykiss) B cells and thrombocytes following in vivo exposure to benzo[a]pyrene. AB - Immune toxicity of polycyclic aromatic hydrocarbons (PAHs) in fishes has been frequently reported but the reasons for differential cell toxicity remains unclear. Rainbow trout were exposed in vivo with a single intraperitoneal injection of corn oil or 100mg/kg of the immunotoxic PAH benzo[a]pyrene (B[a]P) in corn oil. Leukocytes were harvested from head kidney, spleen and blood after 14days, the optimal time for B cell depletion found in a previous study. The mRNA expression of five cytochrome P450 (CYP) enzymes, the aryl hydrocarbon receptor (AhR), and an intrinsic pathway apoptosis checkpoint (p53) in B cells and thrombocytes were examined. Transcript levels were measured in immunomagnetically isolated B cells and thrombocytes from those tissues as well as in liver as B cells had been previously shown to be responsive the BaP whereas thrombocytes were not. There was induction of CYP1A1 in liver, blood B cells, and blood and spleen thrombocytes; CYP1B1 in blood B cells, blood and spleen thrombocytes; CYP1A3 in liver, blood and spleen B cells, and blood thrombocytes; CYP1C1 in liver; and AhR in liver and spleen thrombocytes. There was no change in CYP1C2, or p53 mRNA levels across tissues or cell type. Induction in mRNA was observed 14 d after exposure, indicating a prolonged physiological effect of a single B[a]P injection. CYP1A1 and CYP1A3 were the most abundantly expressed CYP genes and CYP1B1 was generally least abundant. B[a]P-induced thrombocytes had a significantly different pattern of CYP expression than either liver or B cells. Given the importance of metabolites in the toxicity of PAHs, differences in CYP expression between tissues may explain differences in toxicity previously observed between B cells and thrombocytes. PMID- 28662489 TI - Viable but non-culturable E. coli induced by low level chlorination have higher persistence to antibiotics than their culturable counterparts. AB - Disinfectant used in drinking water treatment and distribution system can induce culturable bacteria, including various kinds of pathogenic bacteria, into viable but non-culturable (VBNC) state. The loss of cultural state, resuscitation and environmental persistence of VBNC bacteria will severely damage drinking water microbiological safety and thus pose a risk to public health. The manner in which chlorination treatment induced a VBNC state in Escherichia coli and the antibiotic persistence of VBNC bacteria was investigated. It was found that low dosage of chlorine (0.5 mg L-1) disinfection effectively reduced the culturability of E. coli and induced a VBNC state, after which metabolic activity was reduced and persistence to 9 typical antibiotics was enhanced. Furthermore, RT-qPCR results showed that stress resistance genes (rpoS, marA, ygfA, relE) and ARGs, especially efflux genes were up-regulated compared with culturable cells. The intracellular concentration was tested and found to be lower in VBNC cells than in actively growing E. coli, which suggested a higher efflux rate. The data presented indicate that VBNC E. coli are more persistent than culturable counterparts to a wide variety of antibiotics. VBNC E. coli constitute a potential source of contamination and should be considered during monitoring of drinking water networks. PMID- 28662490 TI - Transformation and bioavailability of metal oxide nanoparticles in aquatic and terrestrial environments. A review. AB - Metal oxide nanoparticles (MeO-NPs) are among the most consumed NPs and also have wide applications in various areas which increased their release into the environmental system. Aquatic (water and sediments) and terrestrial compartments are predicted to be the destination of the released MeO-NPs. In these compartments, the particles are subjected to various dynamic processes such as physical, chemical and biological processes, and undergo transformations which drive them away from their pristine state. These transformation pathways can have strong implications for the fate, transport, persistence, bioavailability and toxic-effects of the NPs. In this critical review, we provide the state-of-the knowledge on the transformation processes and bioavailability of MeO-NPs in the environment, which is the topic of interest to researchers. We also recommend future research directions in the area which will support future risk assessments by enhancing our knowledge of the transformation and bioavailability of MeO-NPs. PMID- 28662491 TI - First freshwater member ever reported for the family Bathycoccaceae (Chlorophyta; Archaeplastida) from Argentinean Patagonia revealed by environmental DNA survey. AB - We characterized molecularly the first freshwater member ever reported for the family Bathycoccaceae in Lake Musters (Argentinean Patagonia). Members of this family are extremely numerous and play a key ecological role in marine systems as primary producers. We cloned a fragment comprising the SSU rRNA gene+ITS region from environmental DNA using specific mamiellophyte primers. The unique SSU rRNA gene sequence obtained clustered robustly with Bathycoccus prasinos. Analysis of the two-dimensional structure of the ITS region showed the presence of a typical supplementary helix in the ITS-2 region, a synapomorphy of Bathycoccaceae, which confirmed further its phylogenetic placement. We finally discuss the possible causes for the presence of this organism in Lake Musters. PMID- 28662492 TI - New data of two trichodinid ectoparasites (Ciliophora: Trichodinidae) from farmed freshwater fishes in Hubei, China. AB - Trichodinids are ciliated protozoan parasites or symbionts of marine and freshwater organisms. During a parasitic ciliate survey in Hubei, China, two Trichodina species, T. acutaLom, 1961 and T. hyperparasitis Chen & Hsish, 1984, were isolated from body surface of loach Misgurnus anguillicaudatus and gills of yellow catfish Pelteobagrus fulvidraco, respectively. The two species were investigated morphologically, based on silver-strained specimens, and their small subunit ribosomal RNA gene (SSU rDNA) sequences were sequenced. Morphologically, T. acuta is distinguished mainly by the acute sickle-shaped blade with well developed sharp blade apophysis, the irregular circular granule, and the robust ray. Trichodina hyperparasitis is mainly characterized by the broad blade and the inconspicuous round ray apophysis. Phylogenetic analyses revealed that the two Trichodina species investigated were nested within a clade including several freshwater Trichodina species. This indicates that the central granule is a useful taxonomic feature, but it may not be an important phylogenetic characteristic. Histopathological analysis revealed that T. hyperparasitis firmly colonized gills, which resulted in discrete hyperplasia and injuries of the gill filaments. PMID- 28662493 TI - Gregarines (Apicomplexa, Gregarinasina) in psocids (Insecta, Psocoptera) including a new species description and their potential use as pest control agents. AB - Gregarine apicomplexans are unicellular organisms that infect invertebrate hosts in marine, freshwater and terrestrial habitats. The largest group of invertebrates infested on land is the insects. The insect order Psocoptera (booklice) has recently gained wider interest due to specimens occurring in stored food products and therefore being considered pest organisms. Biological control agents are often used to eliminate pest organisms. In this study we examined the psocid Dorypteryx domestica, an invasive psocid species that is spreading all over the world. We were able to isolate and describe a new gregarine species (Enterocystis dorypterygis sp. n.) infecting D. domestica. The trophozoites are panduri- or pyriform and their association/syzygy is caudo frontal. The surface is inscribed by longitudinal epicytic folds covering the complete cell. Phylogenetic analyses of the SSU rDNA gene revealed an only weakly supported relationship with two Gregarina species G. ormieri and G. basiconstrictonea, both from tenebrionid beetles. Gregarines have been proposed to have some potential as biological control agents for several insects. Identifying the gregarine species infecting pest organisms like psocids is a first step and prerequisite for the probable utilization of these parasites as biological control agents in the future. PMID- 28662494 TI - Gorilloflasca africana n.g., n.sp., (Entodiniomorphida) from wild habituated Virunga mountain gorillas (Gorilla beringei beringei) in Rwanda. AB - A new entodiniomorphid ciliate species, Gorilloflasca africana n. g., n. sp. was described from the Virunga mountain gorillas, Gorilla beringei beringei, in Rwanda. It is characterized by a flask-shaped body, a long tubular vestibulum, a round frontal lobe, a large posterior cavity, an ellipsoidal or peanut-shaped macronucleus and a single contractile vacuole. G. africana has the adoral and the vestibular ciliary zones in the buccal area. The adoral ciliary zone is non retractable, encircling the vestibular opening. The vestibular ciliary zone extends posteriorly in the vestibulum. The somatic ciliary zones are the cavity ciliary zone in the posterior cavity along the ventral side of its opening and two longitudinal ciliary zones on the dorsal body surface. The buccal infraciliary bands of G. africana are a C-shaped adoral polybrachykinety, a stick shaped vestibular kinety band, and paralabial kineties. The anterior region of the vestibular kinety band is composed of short kineties whereas, kineties in the remaining region are longitudinal. The somatic infraciliary bands are a cavity polybrachykinety and two longitudinal polybrachykineties. Gorilloflasca is a member of the family Blepharocorythidae based on the non-retractable adoral ciliary zone, the frontal lobe, the large posterior cavity and the vestibular longitudinal kineties. PMID- 28662495 TI - Rhogostomidae (Cercozoa) from soils, roots and plant leaves (Arabidopsis thaliana): Description of Rhogostoma epiphylla sp. nov. and R. cylindrica sp. nov. AB - Cercozoa are a highly diverse protist phylum in soils and in the phyllosphere of plants. Many families are still poorly described and the vast majority of species are still unknown. Although testate amoebae are among the better-studied protists, only little quantitative information exists on the morphology, phylogeny and ecology of cercozoan Rhogostomidae. We cultured four different strains of Rhogostoma spp. isolated from Arabidopsis leaves, agricultural soil and rhizosphere soil of Ocimum basilicum and Nicotiana sp. We describe Rhogostoma epiphylla sp. nov. and R. cylindrica sp. nov. and present their morphology, studied their food spectra in food range experiments and obtained two SSU rDNA gene sequences resulting in an updated thecofilosean phylogeny. Short generation times, desiccation resistance and the ability to prey on a wide range of algae and yeasts from the phyllosphere were seen as crucial traits for the phyllosphere colonization by Rhogostoma. In contrast, the soil-dwelling R. cylindrica did not feed on eukaryotes in our experiment. PMID- 28662496 TI - Macrophage Inflammatory Protein-2 in High Mobility Group Box 1 Secretion of Macrophage Cells Exposed to Lipopolysaccharide. AB - BACKGROUND/AIMS: Macrophage inflammatory protein-2 (MIP-2), a type of leukocyte chemokine, is primarily produced by macrophages, and levels increase significantly in early inflammation. However, the precise biological functions and mechanisms of MIP-2 in the development of inflammation remain unclear. The purposes of the present study were to investigate the role of MIP-2 in inflammation induced by lipopolysaccharide (LPS) in vitro and to determine the possibility of blocking the high mobility group box 1 (HMGB1) signalling pathway via MIP-2 inhibition. METHODS: Macrophage cells (RAW264.7, U937 and THP-1 cells) were divided into control and treatments groups. Expression levels of interleukin 6 (IL-6), interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), HMGB1, chemokine (C-C motif) ligand-2 (Ccl-2), Toll-like receptor-4 (TLR-4), inducible nitric oxide synthase (iNOS), phosphorylated MAPKs (p38, ERKs, JNKs), PI3K/Akts, JAKs/STAT3, IkappaB, and cytoplasmic and nuclear NF-kappaB p65 in RAW264.7 cells were detected by qRT-PCR, enzyme-linked immunosorbent assay (ELISA) or western blot assays. RESULTS: mip-2 siRNA and an anti-MIP-2 antibody significantly reduced the expression levels of Ccl-2, TLR-4, iNOS, IL-6, IL 1beta, HMGB1, and TNF-alpha in RAW264.7 cells exposed to LPS (P<0.01). Additionally, mRNA expression levels of HMGB1 and TLR-4 in cells treated with LPS+mip-2 siRNA were significantly lower than those in cells treated with LPS alone (P<0.01 or P<0.05). The MIP-2 antibody significantly suppressed activation of p38-MAPK, p-STAT3, and p-Akts and translocation of NF-kappaB p65 from the cytoplasm to the nucleus in RAW264.7 exposed to LPS (P<0.01 or P<0.05). CONCLUSION: mip-2 siRNA and the MIP-2 antibody can reduce the inflammatory effects induced by LPS in macrophage cells. The mechanisms may occur through down regulation of p38-MAPK, STAT3 and Akts phosphorylation and translocation of NF kappaB p65. MIP-2 plays an important role in inflammation induced by LPS. PMID- 28662497 TI - Identification and Characterization of Long Non-Coding RNAs in Osteogenic Differentiation of Human Adipose-Derived Stem Cells. AB - BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) play important roles in stem cell differentiation. However, their role in osteogenesis of human adipose-derived stem cells (ASCs), a promising cell source for bone regeneration, remains unknown. Here, we investigated the expression profile and potential roles of lncRNAs in osteogenic differentiation of human ASCs. METHODS: Human ASCs were induced to differentiate into osteoblasts in vitro, and the expression profiles of lncRNAs and mRNAs in undifferentiated and osteogenic differentiated ASCs were obtained by microarray. Bioinformatics analyses including subgroup analysis, gene ontology analysis, pathway analysis and co-expression network analysis were performed. The function of lncRNA H19 was determined by in vitro knockdown and overexpression. Quantitative reverse transcription polymerase chain reaction was utilized to examine the expression of selected genes. RESULTS: We identified 1,460 upregulated and 1,112 downregulated lncRNAs in osteogenic differentiated human ASCs as compared with those of undifferentiated cells (Fold change >= 2.0, P < 0.05). Among these, 94 antisense lncRNAs, 85 enhancer-like lncRNAs and 160 lincRNAs were further recognized. We used 12 lncRNAs and 157 mRNAs to comprise a coding-non-coding gene expression network. Additionally, silencing of H19 caused a significantly increase in expression of osteogenesis-related genes, including ALPL and RUNX2, while a decrease was observed after H19 overexpression. CONCLUSION: This study revealed for the first time the global expression profile of lncRNAs involved in osteogenic differentiation of human ASCs and provided a foundation for future investigations of lncRNA regulation of human ASC osteogenesis. PMID- 28662498 TI - Modulation of Oxidative Stress by 17 beta-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro. AB - BACKGROUND/AIMS: estrogens and phytoestrogens exert hepatoprotection through mechanisms not clearly examined yet. Here, we investigated the protective effects exerted by 17beta-estradiol and genistein against oxidative stress in hepatocytes and hepatic stellate cells (HSCs) and the involvement of specific receptors and the intracellular signalling. METHODS: Huh7.5 and LX-2, alone or in co-culture with Huh7.5, were treated with 17beta-estradiol and genistein alone or in the presence of menadione and of estrogen receptors (ERs) and G protein-coupled estrogenic-receptors (GPER) blockers. Cell viability, mitochondrial membrane potential and oxidant/antioxidant system were measured by specific kits. Western Blot was used for the analysis of Akt and p38-mitogen-activated-protein kinases (MAPK) activation and alpha-smooth-muscle actin expression. RESULTS: In Huh7.5, 17beta-estradiol and genistein prevented the effects of peroxidation by modulating Akt and p38MAPK activation. Similar antioxidant and protective findings were obtained in LX-2 of co-culture experiments, only. ERs and GPER blockers were able to prevent the effects of 17beta-estradiol and genistein. CONCLUSION: In Huh7.5 and LX-2, 17beta-estradiol and genistein counteract the effects of peroxidation through the involvement of ERs and GPER and by an intracellular signalling related to Akt and p38MAPK. As concerning LX-2, paracrine factors released by Huh7.5 play a key role in protection against oxidative stress. PMID- 28662499 TI - Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer. AB - BACKGROUND/AIMS: Gastric cancer (GC) is a common and lethal malignancy, and AMP activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. METHODS: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. RESULTS: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. CONCLUSION: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC. PMID- 28662500 TI - Overview of Chromosome Abnormalities in First Trimester Miscarriages: A Series of 1,011 Consecutive Chorionic Villi Sample Karyotypes. AB - In order to contribute to the knowledge of type and frequency of chromosome abnormalities in early pregnancy losses, we analyzed the cytogenetic results from a large series of first trimester miscarriages, using a diagnostic approach with a high success rate and no maternal contamination. A total of 1,119 consecutive chorionic villi samples were obtained before evacuation, and karyotypes were prepared after short-term culture (STC). In 603 samples, a long-term culture (LTC) was also performed. The overall and individual frequencies of the different types of chromosome abnormalities were established, including placental mosaicisms, and their relationship with maternal age and gestational weeks was assessed. An abnormal karyotype was detected in 70.3% of the samples. Single autosomal trisomy was the most frequent abnormality (64.6% of the abnormal cases), followed by triploidy (13.1%) and monosomy X (10.4%). Chromosome rearrangements were found in 5.2%, combined abnormalities in 8.9%, and placental mosaicism in 3.5% of the cases with STC and LTC performed. Individual trisomies behaved differently with respect to maternal age and intrauterine survival. Due to the combination of STC and LTC, our study offers reliable information on the incidence and type of chromosome abnormalities and placental mosaicism in miscarriages and contributes to define the cytogenetic implication in their etiology. PMID- 28662502 TI - MicroRNA-133b Ameliorates Allergic Inflammation and Symptom in Murine Model of Allergic Rhinitis by Targeting Nlrp3. AB - BACKGROUND: Emerging evidences indicate that post-transcriptional regulation by microRNAs is critical in allergic rhinitis (AR) pathogenesis. MircroRNA-133b (miR 133b) was recently suggested as a potential predictor of AR. However, the in vivo effect of miR-133b on AR is unclear. METHODS: AR model was established in BALB/c mice by intraperitoneal sensitization and intranasal challenge with ovalbumin (OVA). MiR-133b agomir was then intranasally administrated to mice after OVA challenge for another 7 days. The symptom of nasal rubbing and sneezing were recorded after the last OVA challenge. Nasal mucosa tissues and serum were collected. MiR-133b expression, serum OVA-specific immunoglobulin E (IgE) concentration, proinflammatory cytokines (TNF-alpha, IL-4, IL-5, IL-10 and IFN gamma) levels, and Nlrp3 inflammasome activation were measured by RT-PCR, ELISA, western blotting or immunohistochemistry, respectively. Histopathologic changes were evaluated using hematoxylin and eosin and Sirius red staining. The luciferase activity and protein expression of Nlrp3 were also determined. RESULTS: MiR-133b expression was significantly decreased in nasal mucosa of AR mice, which was restored by nasal administration with miR-133b agomir. Upregulation of miR-133b markedly reduced the concentration of OVA-specific IgE, the frequencies of nasal rubbing and sneezing, and the levels of cytokines (TNF alpha, IL-4, IL-5 and IFN-gamma). Levels of IL-4, IL-5, IL-10 and IFN-gamma produced by cervical lymph node cells were significantly lowered in miR-133b agomir-treated mice. Moreover, miR-133b also appeared to strongly attenuate pathological alterations and eosinophils and mast cells infiltration in nasal mucosa. Notably, we demonstrated for the first time that miR-133b negatively regulated Nlrp3 expression through binding with the 3' untranslated region of Nlrp3. Consequently, infection of miR-133b in nasal mucosa remarkably suppressed the Nlrp3 inflammasome activation, as evidenced by reduced Nlrp3, Caspase-1, ASC, IL-18 and IL-1 expressions. CONCLUSION: MiR-133b alleviates allergic symptom in AR mice by inhibition of Nlrp3 inflammasome-meditated inflammation. These findings provide us an insight into the potential role of miR-133b in relation to AR treatment. PMID- 28662501 TI - Cold Exposure Differentially Stimulates Angiogenesis in BAT and WAT of Mice: Implication in Adrenergic Activation. AB - BACKGROUND/AIMS: To characterize the temporal profile of cold-induced angiogenesis in brown and white adipose tissues of mice in vivo and the temporal changes of angiogenic factors in primary mice brown (BA) and white adipocytes (WA) treated with beta3-adrenoceptor agonist (CL316,243) in vitro. METHODS: 8 week old male C57BL/6J mice were individually housed in conventional cages under cold exposure (4 degrees C) for 1, 2, 3, 4 and 5 days. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous (sWAT) and epididymal white adipose tissues (eWAT) were harvested for immunohistochemical and gene expression analysis. In vitro, primary mice BA and WA treated with or without CL316,243 were harvested for gene expression and protein secretion analysis. RESULTS: A combination of morphological and genetic (Vegfa, Vegfr2, Hif-1alpha, Pai1 and Pedf) analyses demonstrated depot-specific angiogenesis in response to cold exposure. Upon CL316,243 treatment, angiogenic factors (Vegfa, Vegfr2, Hif 1alpha, Pai1 and Pedf) and secreted protein VEGFA were transiently increased in both BA and WA. CONCLUSION: Our results show that iBAT is highly responsive to cold-induced angiogenesis that is mainly supported by sWAT with a lesser extent by eWAT. Moreover, the angiogenesis is a transient process with the angiogenic factors may work in an autocrine/paracrine manner. PMID- 28662503 TI - The Effects of Switching to Vonoprazan, a Novel Potassium-Competitive Acid Blocker, on Gastric Acidity and Reflux Patterns in Patients with Erosive Esophagitis Refractory to Proton Pump Inhibitors. AB - BACKGROUND/AIM: The effects of vonoprazan and proton pump inhibitors (PPIs) in patients with reflux esophagitis (RE) have not yet been compared using multichannel intraluminal impedance-pH (MII-pH). METHODS: A total of 8 patients with persistent gastric mucosal injury, despite completing an 8-week standard PPI therapy, were enrolled in the study. While they were on standard PPI therapy, the baseline values of reflux parameters, holding time ratio (HTR) of gastric pH >4, and esophageal pH <4 were obtained by using 24 h MII-pH monitoring. They were re evaluated after discontinuation of the therapy and 4 weeks of subsequent treatment with vonoprazan 20 mg/day. RESULTS: The patients were found to be CYP2C19 extensive metabolizers and negative for Helicobacter pylori infection. In 7 patients (87.5%), the mucosal lesions had healed completely after vonoprazan therapy. A significant increase in gastric pH >4 HTR was observed, from 26.5 to 78.0% (p = 0.029). A reduction in esophageal pH <4 HTR was also observed but it was not statistically significant. Furthermore, acid clearance time and the total number of reflux events, including acid and proximal reflux events, were significantly reduced. CONCLUSION: Vonoprazan may be a better therapy for the treatment of patients with PPI-refractory RE. PMID- 28662504 TI - Anti-Diabetic Effects of the Ethyl-Acetate Fraction of Trichilia catigua in Streptozo-tocin-Induced Type 1 Diabetic Rats. AB - BACKGROUND/AIMS: Trichilia catigua A. Juss., known as "catuaba" in Brazil, has been popularly used as a tonic for fatigue, impotence and memory deficits. Previously, our group demonstrated that the ethyl-acetate fraction (EAF) of T. catigua has antioxidant and anti-inflammatory effects. The present study evaluated the anti-diabetic activity of EAF in type 1 diabetic rats. METHODS: Male Wistar rats were divided into four groups (N: non-diabetic group, D: type 1 diabetic group, NC: non-diabetic + EAF group and DC: type 1 diabetic + EAF group). The latter two groups were treated with 200 mg/kg EAF. Type 1 diabetes was induced by intravenous streptozotocin (STZ) injection (35 mg/kg). Starting two days after STZ injection, EAF was administered daily by gavage for 8 weeks. RESULTS: EAF attenuated body mass loss and reduced food and water intake. EAF improved hyperglycaemia and other biochemical parameters, such as alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Furthermore, the number of pancreatic beta-cells and the size of the islets had increased by beta-cell proliferation in the DC group. EAF promoted reduction in kidney tissue damage in STZ-induced diabetic rats by reduction of renal fibrosis. CONCLUSION: The present study showed that EAF improves glucose homeostasis and endocrine pancreas morphology and inhibits the development of diabetic nephropathy in STZ-induced diabetic rats. PMID- 28662505 TI - Empirically Reduced Dosages of Tinzaparin in Patients with Moderate-to-Severe Renal Insufficiency Lead to Inadequate Anti-Xa Levels. AB - BACKGROUND: Due to the higher molecular weight of tinzaparin, the low molecular weight heparin (LMWH) is less dependent on renal excretion than other LMWH preparations. However, several international guidelines recommend the same preemptive dosage reduction for all therapeutic dose LMWHs prescribed in renal insufficient patients, to ensure that there is no accumulation of anticoagulant activity and increased risk of bleeding. This study is aimed at assessing whether a preemptive dosage reduction of tinzaparin in all renal insufficient patients (comprising 25% reduction in patients with Modification of Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR) 30-60 mL/min/1.73 m2 and 50% reduction in patients with MDRD-eGFR <30 mL/min/1.73 m2) leads to adequate anti Xa levels. METHODS: We selected the anti-Xa levels of in-hospital patients (>=18 years) with moderate-to-severe renal insufficiency (MDRD-eGFR <60 mL/min/1.73 m2), on therapeutic dosages of tinzaparin. Anti-Xa levels were measured using a chromogenic assay. RESULTS: Preemptive dosage reduction resulted in a median anti Xa activity of 0.50 IU/mL (interquartile range [IQR] 0.38-0.60). In 92.3% of patients the anti-Xa level was below the target anti-Xa level of >0.85 IU/mL for therapeutic indications. Unadjusted dosages led to a median anti-Xa activity of 0.74 IU/mL (IQR 0.56-0.92). The preemptive dosage reduction was significantly associated with anti-Xa activity below therapeutic range (p = 0.007). No difference in anti-Xa activity was observed between patients with moderate (0.71 IU/mL, IQR 0.61-0.95) versus severe (0.65 IU/mL, IQR 0.41-1.06) renal insufficiency in whom an unadjusted dose had been administered (p = 0.77). None of the anti-Xa levels were above the upper margin of the presumed therapeutic range of 2.0 IU/mL. CONCLUSION: In renal insufficient patients, the preemptive dosage reduction of tinzaparin leads to inadequate anti-Xa levels. PMID- 28662506 TI - Polymyxin B Attenuates LPS-Induced Death but Aggravates Radiation-Induced Death via TLR4-Myd88-IL-6 Pathway. AB - BACKGROUND/AIMS: Polymyxin B (PMB) is a cyclic cationic polypeptide antibiotic widely used to counteract the effects of endotoxin contamination, both in vitro and in vivo. Lipopolysaccharide (LPS) is an endotoxin that acts as a radiation protection factor. In this study, we focus on the role of PMB in LPS-induced and radiation-induced mortality in mice. METHODS: Mice received total-body radiation or were pretreated by LPS or PMB, and the survival of mice was recorded. Elisa were used to detect the cytokines levels. RESULTS: PMB decreased LPS-induced, but increased radiation-induced mortality in mice. Moreover, PMB could block the LPS induced radioprotective effect. The ELISA and gene knock-out experiments indicated that PMB reduces TNF-alpha level to block LPS-induced mortality in mice, and inhibits IL-6, G-CSF and IL-10 to increase radiation-induced mortality via the TLR4-Myd88-IL-6 pathway. CONCLUSIONS: Our study revealed a role of PMB in LPS-induced endotoxemia and radiation exposure. We infer that the TLR4-Myd88-IL-6 pathway may play a crucial role in the process. PMID- 28662507 TI - Levistolide A Induces Apoptosis via ROS-Mediated ER Stress Pathway in Colon Cancer Cells. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the leading causes of cancer related death worldwide. Levistolide A (LA), a natural compound isolated from the traditional Chinese herb Ligusticum chuanxiong Hort, is used for treating cancer. In this study, we investigated the anticancer effect of LA in HCT116 and its isogenic p53-/- colon cancer cells, as well as the underlying mechanisms. METHODS: MTT assay was used to evaluate the effect of LA on the viability of cancer cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined by flow cytometry. Protein expression was detected by western blotting. RESULTS: The results showed that LA inhibited viability and caused apoptosis of both wild-type and p53-/- HCT116 cells. LA was able to trigger production of ROS and endoplasmic reticulum (ER) stress. Inhibition of ROS using N-acetylcysteine abrogated LA-induced ER stress and apoptosis, as well as the reduction in cancer cell viability. CONCLUSION: Our results indicate that LA causes apoptosis of colon cancer cells via ROS-mediated ER stress pathway. It will be interesting to develop the natural compound for chemotherapy of cancers such as CRC. PMID- 28662508 TI - Jumping in the Night: An Investigation of the Leaping Activity of the Western Tarsier (Cephalopachus bancanus borneanus) Using Accelerometers. AB - Accelerometers enable scientists to quantify the activity of free-living animals whose direct observation is difficult or demanding due to their elusive nature or nocturnal habits. However, the deployment of accelerometers on small-bodied animals and, in particular, on primates has been little explored. Here we show the first application of accelerometers on the western tarsier (Cephalopachus bancanus borneanus), a nocturnal, small-bodied primate endemic to the forests of Borneo. The fieldwork was carried out in the Lower Kinabatangan Wildlife Sanctuary, Sabah, Malaysian Borneo. We provide guidelines for the deployment of accelerometers on tarsiers that might also be applied to other primate species. Our collected data on 2 females show levels of leaping activity comparable to those previously described using direct observation of wild or captive individuals. The 2 females showed different patterns of leaping activity, which calls for work to explore individual differences further. Our work demonstrates that accelerometers can be deployed on small primates to acquire body motion data that would otherwise be demanding to collect using classic field observations. Future work will be focused on using accelerometer data to discriminate in more detail the different behaviours tarsiers can display and to address the causes and consequences of individual variations in activity. PMID- 28662509 TI - Preventing Hereditary Angioedema Attacks in Children Using Cinryze(r): Interim Efficacy and Safety Phase 3 Findings. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease causing unpredictable and potentially life-threatening subcutaneous and submucosal edematous attacks. Cinryze(r) (Shire ViroPharma Inc., Lexington, MA, USA), a nanofiltered C1 inhibitor (C1-INH), is approved in Europe for the treatment, preprocedure prevention, and routine prophylaxis of HAE attacks, and for the routine prophylaxis of attacks in the USA. This phase 3 study assessed the safety and efficacy of 2 C1-INH doses in preventing attacks in children aged 6-11 years. METHODS: A randomized single-blind crossover study was initiated in March 2014. Results for the first 6 patients completing the study are reported here. After a 12-week qualifying observation period, patients were randomly assigned to 1 of 2 C1-INH doses, 500 or 1,000 U, every 3-4 days for 12 weeks and crossed over to the alternative dose for a second 12-week period. The primary efficacy endpoint was the number of angioedema attacks per month. RESULTS: Six females with HAE type I and a median age of 10.5 years received 2 doses of C1-INH (500 and 1,000 U). The mean (SD) difference in the number of monthly angioedema attacks between the baseline observation period and the treatment period was -1.89 (1.31) with 500 U and -1.89 (1.11) with 1,000 U. During the treatment periods, cumulative attack severity, cumulative daily severity, and the number of attacks needing acute treatment were lower. No serious adverse events or study drug discontinuations occurred. CONCLUSIONS: Interim findings from this study indicate that routine prevention with intravenous administration of C1-INH is efficacious, safe, and well tolerated in children >=6 years of age. PMID- 28662510 TI - The Deubiquitinating Enzyme USP14 Regulates Leukemic Chemotherapy Drugs-Induced Cell Apoptosis by Suppressing Ubiquitination of Aurora Kinase B. AB - BACKGROUND/AIMS: Aurora kinase B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Aurora B has been found to be amplified and overexpressed in several types of leukemia. The deubiquitinating enzyme USP14 is one of three proteasome-associated deubiquitinating enzymes and plays critical roles in diverse biological processes including cancer. However, whether USP14 has a role in leukemia cells remains elusive. METHODS: Leukemic U937, NB4 and Jurkat cells were treated with diverse apoptosis-inducing drugs. The interaction between USP14 and Aurora B were determined by Western blot. The effect of USP14 in the regulation of Aurora B was detected by cycloheximide (CHX) and deubiquitination assays. FACS assay was used to determine the apoptosis ratio of cells after treatments. RESULTS: We found that Aurora B was ubiquitinated and degraded during leukemic chemotherapy drugs-induced cell apoptosis. FBXW7 mediated Aurora B ubiquitination and degradation during chemotherapeutic drugs induced apoptosis. USP14 associated with Aurora B and prevented Aurora B degradation. Functionally, overexpression of USP14 inhibits chemotherapeutic drugs-induced apoptosis in leukemia cells. On the contrary, administration of b AP15, a specific inhibitor of USP14, significantly increased leukemia cells apoptosis in a dose-dependent manner. CONCLUSION: Thus, our data suggest that USP14 plays a novel critical role of in leukemia cells apoptosis through Aurora B stabilization and USP14 could be a potential therapeutic target for leukemia. PMID- 28662511 TI - Antimelanogenic Efficacy of Melasolv (3,4,5-Trimethoxycinnamate Thymol Ester) in Melanocytes and Three-Dimensional Human Skin Equivalent. AB - BACKGROUND/AIMS: Excessive melanogenesis often causes unaesthetic hyperpigmentation. In a previous report, our group introduced a newly synthesized depigmentary agent, MelasolvTM (3,4,5-trimethoxycinnamate thymol ester). In this study, we demonstrated the significant whitening efficacy of Melasolv using various melanocytes and human skin equivalents as in vitro experimental systems. METHODS: The depigmentary effect of Melasolv was tested in melan-a cells (immortalized normal murine melanocytes), alpha-melanocyte-stimulating hormone (alpha-MSH)-stimulated B16 murine melanoma cells, primary normal human melanocytes (NHMs), and human skin equivalent (MelanoDerm). The whitening efficacy of Melasolv was further demonstrated by photography, time-lapse microscopy, Fontana-Masson (F&M) staining, and 2-photon microscopy. RESULTS: Melasolv significantly inhibited melanogenesis in the melan-a and alpha-MSH stimulated B16 cells. In human systems, Melasolv also clearly showed a whitening effect in NHMs and human skin equivalent, reflecting a decrease in melanin content. F&M staining and 2-photon microscopy revealed that Melasolv suppressed melanin transfer into multiple epidermal layers from melanocytes as well as melanin synthesis in human skin equivalent. CONCLUSION: Our study showed that Melasolv clearly exerts a whitening effect on various melanocytes and human skin equivalent. These results suggest the possibility that Melasolv can be used as a depigmentary agent to treat pigmentary disorders as well as an active ingredient in cosmetics to increase whitening efficacy. PMID- 28662512 TI - RU486 Reverses Emotional Disorders by Influencing Astrocytes and Endoplasmic Reticulum Stress in Chronic Restraint Stress Challenged Rats. AB - AIMS: To investigate the effect of RU486 (mifepristone) on emotional disorders in chronic restraint stress-induced rats and to explore the mechanisms of that phenomenon. METHODS: For this purpose, 80 healthy male Sprague Dawley rats were randomly divided into four groups: the normal group (Con group, The Con group members received no treatment, eating and drinking freely), the chronic restraint stress group (CRS group, normal Sprague Dawley rats treated with chronic restraint stress, 6 h/day for 21days), the propylene glycol group (CRS+propylene glycol) and the RU486 group (CRS+RU486). RU486 or propylene glycol was administered 30 mins before each CRS procedure. Twenty-four hours after CRS exposure, we investigated the effects of CRS on the anxiety-like behavior using an elevated plus-maze (EPM). To explore the mechanisms of RU486 on anxiety, we measured the expression of glial fibrillary acid protein (GFAP) and beta-subunit of S100 (S100beta) via immunohistochemistry and western blot analysis. Apoptosis was demonstrated by flow cytometry. In addition, endoplasmic reticulum (ER) stress markers, glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and Cysteine aspartic acid specific protease-12 (Caspase-12), were detected by western blot analysis. RESULTS: Compared to the control group, rats in the CRS and propylene glycol group showed decreased exploratory behavior on the open arms during EPM testing, and these reductions were accompanied by significantly reduced GFAP and S100beta expression, increased apoptosis and GRP78, CHOP, and caspase-12 expression in the amygdala. However, RU486 increases the exploratory behavior and reverses the changes of GFAP, S100beta, GRP78, CHOP, and caspase-12 and protects cells against apoptosis. CONCLUSIONS: Taken together, these data suggest that exposure to chronic restraint stress decreases the number of astrocytes and induces apoptosis and ER stress in the amygdala, which are possible causes for psychiatric disorders. RU486 can significantly ameliorate abnormal behaviors in CRS-induced anxiety model rats. The protective effects of RU486 could be attributed to its anti-ER stress, anti-apoptosis and astrocyte increasing effects. PMID- 28662513 TI - Lymphocyte Function in Human Acute Kidney Injury. AB - Acute kidney injury (AKI) has been recognised as an inflammatory condition with serious short- and long-term complications. Animal studies primarily using models of ischaemia reperfusion injury or caecal ligation and perforation have clearly demonstrated that inflammatory cells contribute to the initiation, propagation and recovery phase of AKI and that lymphocytes have a key role in these processes. Less is known about their involvement in common types of human AKI. This paper summarises the key findings of experimental AKI studies and limited human data with particular focus on the role of T-lymphocytes. PMID- 28662514 TI - Emodin: One Main Ingredient of Shufeng Jiedu Capsule Reverses Chemoresistance of Lung Cancer Cells Through Inhibition of EMT. AB - BACKGROUND: Chemoresistance has become a an important worldwide problem to cancer treatment. Understanding the mechanism of drug resistance is the key to solve this problem and improve the survival of the patient. Doxorubicin and its analogues are widely used as antitumor drugs but many doxorubicin resistant cases have been identified in recent years. Doxorubicin (Dox) resistance is a very serious phenomenon in lung cancer treatment. As we could show previously, Shufeng Jiedu Capsule (SFJDC) can effectively reverse H69AR cells resistance to Dox, thus, the present study was designed to explore the mechanism underlying the effects of the main ingredient Emodin on chemosensitivity of H69AR cells to Dox. METHODS: First, the growth inhibition rate of lung cancer cells and normal bronchial epithelial cells (BECs) was determined by MTT. Then, the resistance induced epithelial-mesenchymal transition (EMT) of H69AR cells was examined by western blot and the effect of Emodin on Twist, Snail or Slug was assayed by Real time PCR and Western blot. The activation of NF-kappa B was assayed by Western blot. Proliferation, apoptosis, migration and invasion of H69AR cells induced by Twist, Snail and Slug were also assayed by flow cytometry and transwell chamber. RESULTS: The results showed that after administration of Dox (10uM) with different concentrations of Emodin, the cells exhibited a dose-dependent inhibition action to H69AR cells at 48 hours. H69AR induced the expression of Twist, Snail, and Slug when compared with Dox-sensitive H69 cells. The expression of Twist, Snail, and Slug can be effectively inhibited by combination of Dox and Emodin. The reversal of resistance was associated with the inhibition of NF-kappa B. Twist, Snail and Slug promoted proliferation, migration and invasion and inhibited apoptosis. CONCLUSION: Our data suggest that Emodin can effectively reverse the resistance of H69AR to Dox, an effect paralleled by inhibition of EMT, cell proliferation, apoptosis, migration and invasion. PMID- 28662515 TI - TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells. AB - BACKGROUND/AIMS: Cholangiocarcinoma (CCA), arising from varying locations within the biliary tree, is the second most common primary liver malignancy worldwide. Shikonin, an active compound extracted from the Chinese herb Zicao, holds anti bacterial, anti-inflammatory, and anti-tumor activities. However, the effect of shikonin on human cholangiocarcinoma and detailed mechanisms of TRAIL enhancement remains to be elucidated. The purpose of the study was to investigate the protective functions of TRAIL enhancement for shikonin induced apoptosis in cholangiocarcinoma cells. METHODS: We use MTT assay, apoptosis assay, caspase activity assay, flow cytometry assay, real time PCR and Western blot to observe the effects of TRAIL on shikonin induced cholangiocarcinoma cells apoptosis and its mechanism. RESULTS: Shikonin inhibited cell viability and induced apoptosis of CCA cells, effects enhanced by TRAIL treatment via activation of caspase-3, 8, -9. Furhermore, TRAIL enhanced anti-proliferation of shikonin and shikonin induced apoptosis through induction of ROS mediated JNK activation, while AKT activation had an effect on shikonin anti-proliferation activity, but not in the TRAIL enhanced counterparts. Finally, shikonin upregulated DR5 expression, an effect essential for TRAIL-enhanced activities of shikonin in RBE cells. CONCLUSIONS: Our results revealed that shikonin could inhibit cells viability and induce apoptosis of CCA cells, effects enhanced by TRAIL treatment via ROS mediated JNK signalling pathways, involving up-regulation of DR5 expression. Our results provide further insight into the mechanism underlying the anti-tumor effects of shikonin by TRAIL enhanced in CCA and a new therapeutic strategy to CCA treatment. PMID- 28662516 TI - Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells. AB - BACKGROUND/AIMS: p53 dysfunction is frequently observed in lung cancer. Although restoring the tumour suppressor function of p53 is recently approved as a putative strategy for combating cancers, the lack of understanding of the molecular mechanism underlying p53-mediated lung cancer suppression has limited the application of p53-based therapies in lung cancer. METHODS AND RESULTS: Using RNA sequencing, we determined the transcriptional profile of human non-small cell lung carcinoma A549 cells after treatment with two p53-activating chemical compounds, nutlin and RITA, which could induce A549 cell cycle arrest and apoptosis, respectively. Bioinformatics analysis of genome-wide gene expression data showed that distinct transcription profiles were induced by nutlin and RITA and 66 pathways were differentially regulated by these two compounds. However, only two of these pathways, 'Adherens junction' and 'Axon guidance', were found to be synthetic lethal with p53 re-activation, as determined via integrated analysis of genome-wide gene expression profile and short hairpin RNA (shRNA) screening. Further functional protein association analysis of significantly regulated genes associated with these two synthetic lethal pathways indicated that GSK3 played a key role in p53-mediated A549 cell apoptosis, and then gene function study was performed, which revealed that GSK3 inhibition promoted p53 mediated A549 cell apoptosis in a p53 post-translational activity-dependent manner. CONCLUSION: Our findings provide us with new insights regarding the mechanism by which p53 mediates A549 apoptosis and may cast light on the development of more efficient p53-based strategies for treating lung cancer. PMID- 28662517 TI - Caveolae Depletion Contributes to Vasorelaxant Effects of Chenodeoxycholic Acid. AB - BACKGROUND/AIMS: High concentration of bile acids (BAs) induces hydrophobicity dependent vasorelaxtant effects with hydrophobic BAs showing greater responses than hydrophilic BAs, of which the underlying mechanisms are still unclear. Caveolae are invaginations on membranes of endothelial cells (ECs) entraping endothelial nitric oxide synthase (eNOS) to prevent its activation, which plays a critical role in regulation of vascular function. The purpose of the present study was to investigate the role of caveolae in vasorelaxant effects of BAs. METHODS: Chenodeoxycholic acid (CDCA) and cholic acid (CA) were used to represent hydrophobic and hydrophilic BA, respectively. Vascular responses of abdominal aorta were measured by isometric force recording. Morphology of caveolae was examined by transmission electron microscopy. Protein expression of total eNOS (t eNOS) or phosphorylated eNOS (p-eNOS) was determined by Western blot. Nitric oxide (NO) content was observed by fluorometric assay. RESULTS: We demonstrated that CDCA as well as Methyl-beta-cyclodextrin (MCD), a commonly used reagent for cholesterol depletion, reduced potassium chloride (KCl)- or phenylephrine (PE) elicited vasoconstriction (P < 0.05), and enhanced acetylcholine (Ach)-elicited vasodilatation (P < 0.05) in endothelium-intact abdominal aorta but not in endothelium-denuded or CA-treated vessels. CDCA and MCD, but not CA significantly disrupted caveolae structure on ECs of abdominal aorta which was recovered by cholesterol incubation (P < 0.05). Protein expression of t-eNOS was significantly decreased (P < 0.05), and that of p-eNOS together with NO content was significantly increased in CDCA- and MCD- but not CA-treated vessels (P < 0.05) as compared with vehicle. The effect was reversed by either endothelium denudation or cholesterol replenishment. Moreover, with cholesterol incubation, no significant differences were found in vascular responses among CDCA-, CA- or vehicle-treated vessels. CONCLUSION: These results indicate that CDCA diminishes caveolae on ECs of abdominal aorta promoting eNOS phosphorylation and NO production which contributes to its vasorelaxtant effect. PMID- 28662519 TI - Neuroprotective Effects of Pycnogenol Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Primary Rat Astrocytes via NF-kappaB and ERK1/2 MAPK Pathways. AB - BACKGROUNDS/AIMS: Pycnogenol (PYC) is a patented mix of bioflavonoids with potent anti-oxidant and anti-inflammatory properties. In this study, we investigated the effects of PYC on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in primary rat astrocytes. METHODS: The primary rat astrocytes were randomly divided into 6 groups, blank control, OGD/R, OGD/R+PYC (10, 20, 40, and 60 ug/mL). The cell activity were detected by MTT and LDH assays, then the levels of oxidant products [malondialdehyde (MDA) and reactive oxygen species (ROS)] , antioxidants [superoxide dismutase (SOD)], mitochondrial membrane potential (MMP) and inflammatory cytokines were detected. In addition, the expression levels of apoptosis-related proteins (Bax, Bcl-2 and Cleaved caspase 3), proinflammatory factors (NF-kappaB p65), and p-ERK1/2 were measured by Western blot analysis. RESULTS: The results showed that PYC incubation dose-dependently attenuated cell viability loss, LDH leakage, oxidative stress, inflammatory cytokines accumulation and cell apoptosis caused by OGD/R. Furthermore, PYC pretreatment dose-dependently suppressed OGD/R-induced NF-kappaB p65 nuclear translocation, NF kappaB activity and ERK1/2 phosphorylation. Similarly to PYC, NF-kappaB inhibitor PDTC and ERK1/2 inhibitor PD098059 dramatically inhibited OGD/R-induced NF-kappaB activation, ERK1/2 phosphorylation, and ROS production, as well as TNF-alpha secretion. CONCLUSIONS: These findings revealed that PYC has neuroprotective effects against OGD/R-induced injury via NF-kappaB and ERK1/2 pathways in primary rat astrocytes. PMID- 28662518 TI - Effects of N-Nitrosodiethylamine, a Potent Carcinogen, on Sexual Development, Gametogenesis, and Oocyte Maturation. AB - N-Nitrosodiethylamine (DEN), a well-known hepatocarcinogen, is found in certain food products as such or as a metabolic byproduct. This study investigated the effects of DEN on sexual development, gametogenesis, and oocyte maturation in Japanese medaka (Oryzias latipes). DEN reduced the germ cell number dose dependently during early stages of sexual differentiation in XX larvae, resulting in underdeveloped ovaries in adulthood at low doses. This effect was sex-specific as no such changes were seen in XY larvae. Furthermore, XX and XY larvae that were exposed at a low dose during early life showed a significant reduction in body weight in adulthood. Gonads in sexually immature adult medaka males and females exposed to DEN were in advanced stages in comparison to that of the controls. Gonado-somatic indices were significantly high in treated males and females. DEN induced oocyte maturation in vitro, which was inhibited by cordycepin, demonstrating that it stimulated oocyte maturation through polyadenylation of cyclin B mRNA as in the case of the endogenous maturation inducing hormone. Altogether, our results have proven that DEN could disrupt or mimic the signaling pathways involved in germ cell development, proliferation, and maturation. PMID- 28662522 TI - 17th ESASO Retina Academy. June 29-July 1, 2017, Berlin, Germany: Abstracts. PMID- 28662520 TI - Regulation of AP-1 by MAPK Signaling in Metal-Stressed Sea Anemone. AB - BACKGROUND/AIMS: AP-1 transcription factor plays a conserved role in the immediate response to stress. Activation of AP-1 members jun and fos is mediated by complex signaling cascades to control cell proliferation and survival. To understand the evolution of this broadly-shared pathway, we studied AP-1 regulation by MAPK signaling in a basal metazoan. METHODS: Metal- stressed cnidarian Nematostella vectensis anemones were tested with kinase inhibitors and analyzed for gene expression levels and protein phosphorylation. RESULTS: We show that in cnidarian, AP-1 is regulated differently than in bilaterian models. ERK2 and ERK5, the main MAPK drivers of AP-1 activation in Bilateria, down-regulated fos1 and jun1 transcription in anemones exposed to metal stress, whereas p38 MAPK, triggered transcription of jun1 but not fos1. Furthermore, our results reveal that GSK3-beta is the main driver of the immediate stress response in Nematostella. GSK3-beta triggered transcription of AP-1 and two other stress related genes, egr1 and hsp70. Finally, phylogenetic analysis and protein characterization show that while MAPKs and GSK3-beta are evolutionarily conserved, Fos and Jun proteins in Nematostella and other cnidarians lack important regulatory and phosphorylation sites found in Bilateria. CONCLUSION: These findings reveal alternative network interactions of conserved signaling kinases, providing insight into the evolutionary plasticity of immediate stress response mechanisms. PMID- 28662523 TI - Insights from Systems Biology in Physiological Studies: Learning from Context. AB - Systems biology presents an integrated view of biological systems, focusing on the relations between elements, whether functional or evolutionary, and providing a rich framework for the comprehension of life. At the same time, many low throughput experimental studies are performed without influence from this integrated view, whilst high-throughput experiments use low-throughput results in their validation and interpretation. We propose an inversion in this logic, and ask which benefits could be obtained from a holistic view coming from high throughput studies-and systems biology in particular-in interpreting and designing low-throughput experiments. By exploring some key examples from the renal and adrenal physiology, we try to show that network and modularity theory, along with observed patterns of association between elements in a biological system, can have profound effects on our ability to draw meaningful conclusions from experiments. PMID- 28662524 TI - EVICR. net. European Network of Clinical Research in Ophthalmology. Information Update - June 2017. PMID- 28662525 TI - Colonic Histological Criteria Predict Development of Pouchitis after Ileal Pouch: Anal Anastomosis for Patients with Ulcerative Colitis. AB - BACKGROUND/AIMS: Pouchitis is one of the main complications after ileal pouch anal anastomosis in patients with ulcerative colitis. The aim of this study was to determine whether the use of colonic histological criteria can predict the development of pouchitis. METHODOLOGY: We retrospectively reviewed 147 patients' clinical data and performed a histological evaluation of the resected total colon using Tanaka's criteria, which comprise the following 6 factors: ulceration (H1), crypt abscesses (H2), degree of mononuclear cell infiltration (MNCI) (H3), segmental distribution of MNCI (H4), eosinophil infiltration (H5), and extent of disease of resected colon (H6). RESULTS: The development of pouchitis and chronic pouchitis within 3 years after restoration of gastrointestinal continuity was recognized in 52 (35.4%) and 26 (17.7%) of the 147 patients, respectively. Using various combinations of each score, the H3 + H4 - H5 scores of patients with pouchitis or chronic pouchitis were significantly higher than those of patients without. A H3 + H4 - H5 score of >0.4 was a statistically significant risk factor for the development of both pouchitis and chronic pouchitis. CONCLUSIONS: The combination of the degree of MNCI, segmental distribution of MNCI, and eosinophil infiltration from histological criteria has utility in predicting the future development of pouchitis, especially chronic pouchitis. PMID- 28662526 TI - [Psychosocial Working Conditions and Quality of Care: Results of a Qualitative Study Among Physician Assistants (MFAs)]. AB - Background Working conditions may not only impair the health of health care staff, but also the quality of delivered patient care. Evidence for this in relation to physician assistants remains limited despite the fact that they represent the largest professional group in German primary care and perform occupational tasks that are highly relevant to the quality of patient care. This study aimed to gain insights into the potential relationship of working conditions with the quality of care. Methods Participants were recruited from a randomized sample of medical practices in and around the city of Dusseldorf (Germany) and with support from the medical health care staff association (VMF e.V.). In total, 26 qualitative in-depth interviews were conducted (11/2015 02/2016), transcribed and content-analyzed using MaxQDA. Results The majority of participants expressed the view that working conditions impact on the quality of care. In particular, the quality of social interactions with patients and minor mistakes were alluded to in this regard. Conclusions Working conditions of physician assistants are characterized by high demands. Their potential impact on the quality of social interactions with patients and the rate of minor mistakes highlights the relevance of preventive actions. Our findings may represent the starting point for further research into preventive measures. PMID- 28662527 TI - Anti-inflammatory and Anti-HIV Compounds from Swertia bimaculata. AB - Three new compounds (1 - 3), including a sesterterpenoid, aspterpenacid C (1), with an unusual 5/3/7/6/5 pentacyclic skeleton, together with seven known ones (4 - 10), were isolated from the ethanol extract of the traditional Chinese medicinal plant Swertia bimaculata. Their structures were elucidated on the basis of the methods of spectroscopic NMR, MS, and computational chemistry. The structure of 1 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 - 10 were tested for activities on the inhibition of nitric oxide production and HIV-1 replication in vitro. Compound 1 exhibited moderate activity in inhibiting nitric oxide production (IC50 = 16.1 uM) and HIV-1 replication (EC50 = 1.35 uM). PMID- 28662529 TI - Bioactivity-Guided Investigation of the Anti-Inflammatory Activity of Hippophae rhamnoides Fruits. AB - According to modern ethnobotanical records, the fruit of Hippophae rhamnoides is effective in the treatment of different allergic symptoms. In order to obtain pharmacological evidence for this observation, the fruit was investigated for anti-inflammatory activity using in vivo animal models. Aqueous and 70% MeOH extracts were tested in 48/80-induced rat paw edema assay after oral administration, and it was found that the 70% MeOH extract (500 mg/kg) reduced significantly edema volume (0.660 +/- 0.082 mL vs. control 0.935 +/- 0.041 mL). Extracts of different parts of the fruit (pulp, peel, seed) were investigated in the same assay, and the peel extract was shown to exhibit maximum edema-reducing effect (0.470 +/- 0.124 mL vs. control 0.920 +/- 0.111 mL). This extract was used to elucidate the mode of action. Different inflammation inducers (serotonin, histamine, dextran, bradykinin, and carrageenan) were applied in the rat paw model, but the extract inhibited only the compound 48/80 elicited inflammation. The active extract was then fractionated by solvent-solvent partitioning and chromatographic methods with the guidance of the 48/80-induced anti-inflammatory assay, and the main compounds responsible for the activity were identified as ursolic acid and oleanolic acid. Our data suggest that the activity is most probably based on a membrane stabilizing effect caused by the inhibition of degranulation of mast cells. Moreover, previously unknown 2,5-bis-aryl-3,4 dimethyltetrahydrofuran lignans, nectandrin B, fragransin A2, and saucernetindiol were isolated and identified from H. rhamnoides for the first time. PMID- 28662528 TI - Three New Abietane-Type Diterpenoids from Plectranthus africanus and Their Antibacterial Activities. AB - Three new abietane-type diterpenoids, plectranthroyleanones A - C (1: - 3: ), together with five known compounds (4: - 8: ) were isolated from the methanol extract of the whole plant of Plectranthus africanus using column chromatography techniques. The structures of the new compounds were elucidated using a combination of 1D and 2D NMR and HRESIMS analyses. Compound 1: exhibited weak activities with minimal inhibitory concentration values of 75 ug/mL against gram positive bacteria, Bacillus subtilis and Staphylococcus aureus, and 150 ug/mL against two gram-negative bacteria, Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively, while 2: and 3: had moderate antibacterial activity against K. pneumoniae with a minimal inhibitory concentration value of 37.5 ug/mL. PMID- 28662530 TI - DNA Barcoding for Industrial Quality Assurance. AB - DNA barcoding methods originally developed for the identification of plant specimens have been applied to the authentication of herbal drug materials for industrial quality assurance. These methods are intended to be complementary to current morphological and chemical methods of identification. The adoption of these methods by industry will be accelerated by the introduction of DNA-based identification techniques into regulatory standards and monographs. The introduction of DNA methods into the British Pharmacopoeia is described, along with a reference standard for use as a positive control for DNA extraction and polymerase chain reaction (PCR). A general troubleshooting chart is provided to guide the user through the problems that may be encountered during this process. Nevertheless, the nature of the plant materials and the demands of industrial quality control procedures mean that conventional DNA barcoding is not the method of choice for industrial quality control. The design of DNA barcode-targeted quantitative PCR and high resolution melt curve tests is one strategy for developing rapid, robust, and reliable protocols for high-throughput screening of raw materials. The development of authentication tests for wild-harvested Rhodiola rosea L. is used as a case study to exemplify these relatively simple tests. By way of contrast, the application of next-generation sequencing to create a complete profile of all the biological entities in a mixed herbal drug is described and its potential for industrial quality assurance discussed. PMID- 28662531 TI - Effects of In-Season Explosive Strength Training on Maximal Leg Strength, Jumping, Sprinting, and Intermittent Aerobic Performance in Male Handball Athletes. AB - Background Team handball is an intense ball sport with specific requirements on technical skills, tactical understanding, and physical performance. The ability of handball players to develop explosive efforts (e. g. sprinting, jumping, changing direction) is crucial to success. Objective The purpose of this pilot study was to examine the effects of an in-season high-intensity strength training program on the physical performance of elite handball players. Materials and methods Twenty-two handball players (a single national-level Tunisian team) were randomly assigned to a control group (CG; n = 10) or a training group (TG; n = 12). At the beginning of the pilot study, all subjects performed a battery of motor tests: one repetition maximum (1-RM) half-squat test, a repeated sprint test [6 * (2 * 15 m) shuttle sprints], squat jumps, counter movement jumps (CMJ), and the Yo-Yo intermittent recovery test level 1. The TG additionally performed a maximal leg strength program twice a week for 10 weeks immediately before engaging in regular handball training. Each strength training session included half-squat exercises to strengthen the lower limbs (80 - 95 % of 1-RM, 1 - 3 repetitions, 3 - 6 sets, 3 - 4 min rest between sets). The control group underwent no additional strength training. The motor test battery was repeated at the end of the study interventions. Results In the TG, 3 parameters (maximal strength of lower limb: eta2 = 0.74; CMJ: eta2 = 0.70, and RSA best time: eta2 = 0.25) showed significant improvements, with large effect sizes (e. g. CMJ: d = 3.77). A reduction in performance for these same 3 parameters was observed in the CG (d = -0.24). Conclusions The results support our hypothesis that additional strength training twice a week enhances the maximal strength of the lower limbs and jumping or repeated sprinting performance. There was no evidence of shuttle sprints ahead of regular training compromising players' speed and endurance capacities. PMID- 28662532 TI - [Dancing with Pointe Shoes: Characteristics and Assessment Criteria for Pointe Readiness]. AB - Training with pointe shoes is an integral part of professional dance education and ambitious hobby dancing. Pointe shoes - developed more than hundred years ago and almost unaltered since then - are highly specific and strike a balance between aesthetics, function, protection, and health care. Therefore, pointe readiness should be tested prior to all dance training or career training. Medical specialists are often confronted with this issue. Specific anatomical dance technique-orientated general conditional and coordinative preconditions as well as dance-technical prerequisites must be met by pointe readiness tests in order to keep traumatic injuries or long-term damage at a minimum. In addition to a (training) history, medical counselling sessions have come to include various tests that enable a reliable decision for or against pointe work. This article suggests adequate testing procedures (STT TEST), taking account of professional dancing as well as hobby dancing. PMID- 28662533 TI - Parental Internet Use and Health Information Seeking Behavior Comparing Elective and Emergency Pediatric Surgical Situations. AB - INTRODUCTION: This study evaluates usage patterns of online health information in parents with children undergoing elective or emergency surgical procedures. MATERIALS AND METHODS: We prospectively surveyed parents of children admitted to our institution for common emergency (appendicectomy, abscess drainage, gonadal torsion) or elective (herniotomy, orchidopexy) operations between March and September 2016. Each completed an anonymized modification of a previously published survey comprising 19 questions on demographic data, Internet usage, and review of Internet resources. Chi-square tests were used for categorical data with p < 0.05 considered significant. RESULTS: Eighty-four parents were surveyed: 50(59.5%) elective and 34(40.5%) emergency procedures, with no refusals. Majority were mothers (n = 53; 63.1%). Despite high home Internet availability (n = 81; 96.4%) and high casual Internet usage rates (74 parents, 88.1%, reported daily use), just 38 (76%) parents from the elective group and 24 (70.6%) from the emergency group went online to access their child's admitting condition. Friends and family were more likely to be approached for information in elective (n = 27; 54%) and emergency groups (n = 24;70.6%) than general practitioners or other health care workers. When condition-specific online information was sought, more than 95% felt that the information concurred with the doctor's. Most common reasons were for more information on the condition (n = 56; 90.3%) and on medical treatment (n = 52; 83.9%). Eighteen (18/62; 29%) parents reported excessively technical information. No significant difference in behavior was found comparing elective and emergency groups. CONCLUSION: Approximately one quarter of parents do not access condition-specific online medical information despite high Internet penetration rates. More than half depend on friends and family for additional information, reflecting societal and cultural norms in our population. Surgeons must incorporate awareness of these behaviors during counselling. PMID- 28662534 TI - Successful ERCP through an endoscopic ultrasound-guided gastrojejunostomy. PMID- 28662535 TI - Endosonographically guided gallbladder drainage to treat neoplastic jaundice after Roux-en-Y gastric resection. PMID- 28662536 TI - Successful endoscopic closure of a refractory button-battery tracheoesophageal fistula in a 3-year child using endoscopic submucosal dissection of the surrounding mucosa. PMID- 28662537 TI - Funnel-shaped retrieval device for wrapping large colorectal resection specimens. PMID- 28662538 TI - An unusual case of impacted biliary stone. PMID- 28662539 TI - Salvage of a dislodged hepaticogastrostomy stent in the peritoneum with NOTES. PMID- 28662540 TI - Endoscopic ultrasonography-guided freestyle rendezvous recanalization of a complete postoperative rectosigmoid anastomotic obstruction with a lumen-apposing metal stent. PMID- 28662541 TI - Reproductive endocrine issues in men with sickle cell anemia. AB - In patients with sickle cell anemia, the sickling of red blood cells is known to cause end-organ damage by infarction. In some men who are affected by sickle cell anemia, the obstruction of venous outflow of the penis causes priapism, which could lead to erectile dysfunction. There is also evidence that the disease is linked to other reproductive issues in men-specifically delayed puberty, low testosterone, and sperm abnormalities-although the causes of these problems are less clear. Treatment of sickle cell anemia can have effects on the reproductive system as well. This review summarizes the findings from various publications pertaining to reproductive endocrinology, along with their conclusions and discrepancies. PMID- 28662542 TI - Quantitative disease progression model of alpha-1 proteinase inhibitor therapy on computed tomography lung density in patients with alpha-1 antitrypsin deficiency. AB - AIMS: Early-onset emphysema attributed to alpha-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human alpha-1 proteinase inhibitor (A1 -PI; 60 mg kg 1 week-1 ) therapy completed to date, demonstrated for the first time that A1 PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response. METHODS: A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response. Dose exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels. RESULTS: A dose of 60 mg kg-1 week-1 achieved trough serum levels >11 MUmol l-1 (putative 'protective threshold') in >=98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates >=0.5 g l-1 year-1 occurred more often in patients receiving A1 -PI: 63 vs. 12%. CONCLUSION: Weight-based A1 PI dosing reliably raises serum levels above the 11 MUmol l-1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects. PMID- 28662543 TI - The impact of serum potassium-influencing antihypertensive drugs on the risk of out-of-hospital cardiac arrest: A case-control study. AB - AIMS: Sudden cardiac arrest (SCA) is a complex multifactorial event and most commonly caused by ventricular tachycardia/ fibrillation (VT/ VF). Some antihypertensive drugs could induce hypokalaemia or hyperkalaemia, which may increase susceptibility to VT/VF and SCA. OBJECTIVE: To assess the association between different classes of antihypertensive drugs classified according to their potential impact on serum potassium levels and the occurrence of out-of-hospital cardiac arrest (OHCA) based on VT/VF. METHODS: A case-control study was performed among current users of antihypertensive drugs. Cases were OHCA victims with electrocardiogram documented VT/VF drawn from the AmsteRdam REsuscitation STudies (ARREST) registry, and controls were non-OHCA individuals from the PHARMO database. Antihypertensive drugs were classified into: (i) antihypertensives with neutral effect on serum potassium levels; (ii) hypokalaemia-inducing antihypertensives; (iii) hyperkalaemia-inducing antihypertensives; (iv) combination of antihypertensives with hypo- and hyperkalaemic effects. RESULTS: We included 1345 cases and 4145 controls. The risk of OHCA was significantly increased among users of hypokalaemia-inducing antihypertensives [adjusted odds ratio (OR) 1.39; 95% confidence interval (CI) 1.10-1.76] and among users of a combination of antihypertensives with hypo- and hyperkalaemic effects (adjusted OR 1.42; 95%CI 1.17-1.72) vs. users of antihypertensives with neutral effect. There was no difference in OHCA risk between users of hyperkalaemia-inducing antihypertensives vs. users of antihypertensive drugs with neutral effect (adjusted OR 1.15; 95%CI 0.95-1.40). CONCLUSION: The risk of OHCA is significantly increased in patients who were current users of hypokalaemia inducing antihypertensives and patients using a combination of antihypertensives with hypo- and hyperkalaemic effects. PMID- 28662544 TI - Host shift and cospeciation rate estimation from co-phylogenies. AB - Host shifts can cause novel infectious diseases, and is a key process in diversification. Disentangling the effects of host shift vs. those of cospeciation is non-trivial as both can result in phylogenic congruence. We develop a new framework based on network analysis and Approximate Bayesian Computation to quantify host shift and cospeciation rates in host-parasite systems. Our method enables estimation of the expected time to the next host shift or cospeciation event. We then apply it to avian haemosporidian parasite systems and to the pocket gophers-chewing lice system, and demonstrate that both host shift and cospeciation can be reliably estimated by our method. We confirm that host shifts have shaped the evolutionary history of avian haemosporidian parasites and have played a minor role in the gopher-chewing lice system. Our method is promising for predicting the rate of potential host shifts and thus the emergence of novel infectious diseases. PMID- 28662545 TI - Defective acid hydrolase secretion in RUNX1 haplodeficiency: Evidence for a global platelet secretory defect. AB - BACKGROUND: RUNX1 haplodeficiency is associated with thrombocytopenia, platelet dysfunction and a predisposition to acute leukaemia. Platelets possess three distinct types of granules and secretory processes involving dense granules (DG), alpha-granules and vesicles or lysosomes containing acid hydrolases (AH). Dense granules and granule deficiencies have been reported in patients with RUNX1 mutations. Little is known regarding the secretion from AH-containing vesicles. METHODS AND RESULTS: We studied two related patients with a RUNX1 mutation, easy bruising, and mild thrombocytopenia. Platelet aggregation and 14 C serotonin in platelet-rich plasma (PRP) were impaired in response to ADP, epinephrine, collagen and arachidonic acid. Contents of DG (ATP, ADP), alpha-granules (beta thromboglobulin) and AH-containing vesicles (beta-glucuronidase, beta hexosaminidase, alpha-mannosidase) were normal or minimally decreased. Dense granules secretion on stimulation of gel-filtered platelets with thrombin and divalent ionophore A23187 (4-12 MUmol L-1 ) were diminished. beta-thromboglobulin and AH secretion was impaired in response to thrombin or A23187. We studied thromboxane-related pathways. The incorporation of 14 C -arachidonic acid into phospholipids and subsequent arachidonic acid release on thrombin activation was normal. Platelet thromboxane A2 production in whole blood serum and on thrombin stimulation of PRP was normal, suggesting that the defective secretion was not due to impaired thromboxane production. CONCLUSIONS: These studies provide the first evidence in patients with a RUNX1 mutation for a defect in AH (lysosomal) secretion, and for a global defect in secretion involving all three types of platelet granules that is unrelated to a granule content deficiency. They highlight the pleiotropic effects and multiple platelet defects associated with RUNX1 mutations. PMID- 28662547 TI - Patient participation: causing moral stress in psychiatric nursing? PMID- 28662548 TI - Sustainable pyrolytic sludge-char preparation on improvement of closed-loop sewage sludge treatment: Characterization and combined in-situ application. AB - Aiming at closed-loop sustainable sewage sludge treatment, an optimal and economical pyrolytic temperature was found at 400-450 degrees C considering its pyrolysis efficiency of 65%, fast cracking of hydrocarbons, proteins and lipids and development of aromatized porous structure. Fourier-transform infrared (FTIR) and X-ray diffraction (XRD) tests demonstrated the development of adsorptive functional groups and crystallographic phases of adsorptive minerals. The optimal sludge-char, with a medium specific surface area of 39.6 m2 g-1 and an iodine number of 327 mgI2 g-1, performed low heavy metals lixiviation. The application of sludge-char in raw sewage could remove 30% of soluble chemical oxygen demand (SCOD), along with an acetic acid adsorption capacity of 18.0 mg g-1. The developed mesopore and/or macropore structures, containing rich acidic and basic functional groups, led to good biofilm matrices for enhanced microbial activities and improved autotrophic nitrification in anoxic stage of an A/O reactor through adsorbed extra carbon source, and hence achieved the total nitrogen (TN) removal up to 50.3%. It is demonstrated that the closed-loop sewage sludge treatment that incorporates pyrolytic sludge-char into in-situ biological sewage treatment can be a promising sustainable strategy by further optimization. PMID- 28662549 TI - Organic matters removal from landfill leachate by immobilized Phanerochaete chrysosporium loaded with graphitic carbon nitride under visible light irradiation. AB - This study investigated the technical applicability of a combination of Phanerochaete chrysosporium (P. chrysosporium) with photocatalyst graphitic carbon nitride (g-C3N4) for organic matters removal from landfill leachate under visible light irradiation. Photocatalyst g-C3N4 was well immobilized on the hyphae surface of P. chrysosporium by calcium alginate. The typical absorption edge in visible light region for g-C3N4 was at about 460 nm, and the optical absorption bandgap of g-C3N4 was estimated to be 2.70 eV, demonstrating the great photoresponsive ability of g-C3N4. An optimized g-C3N4 content of 0.10 g in immobilized P. chrysosporium and an optimized immobilized P. chrysosporium dosage of 1.0 g were suitable for organic matters removal. The removal efficiency of total organic carbon (TOC) reached 74.99% in 72 h with the initial TOC concentration of 100 mg L-1. In addition, the gas chromatography coupled with mass spectrometry (GC-MS) measurements showed that immobilized P. chrysosporium presented an outstanding removal performance for almost all organic compounds in landfill leachate, especially for the volatile fatty acids and long-chain hydrocarbons. The overall results indicate that the combination P. chrysosporium with photocatalyst g-C3N4 for organic matters removal from landfill leachate may provide a more comprehensive potential for the landfill leachate treatment. PMID- 28662550 TI - Financing Reform for Long-term Services and Supports. PMID- 28662551 TI - Reclassification of the Sacral Autonomic Outflow to Pelvic Organs as the Caudal Outpost of the Sympathetic System Is Misleading. PMID- 28662552 TI - Correction. PMID- 28662555 TI - Cardiovascular Disease Risk Factors After an Employer-Based Risk Reduction Program: An Observational Cohort Study. AB - Context: The burden of cardiovascular disease (CVD) continues to be a public health concern. Workplace interventions that focus on modifying lifestyle habits may reduce CVD risk factors in people at risk. Objective: To determine the effectiveness of a comprehensive lifestyle intervention program that integrated dietary modification, physical activity, stress management, and behavior modification counseling to reduce the risk of CVD in at-risk adults. Methods: Twelve 1-year cohorts who participated in a comprehensive employer-sponsored lifestyle intervention program targeting diet, exercise, behavior modification, and stress management between 2006 and 2010 at a rural university in Appalachian Ohio were studied. Body composition, fasting glucose and lipid levels, and maximal oxygen consumption were measured at baseline, after 100 days, and at 1 year. Repeated-measures analyses of variance were conducted to compare measures at baseline with measures at 100 days and at 1 year. Results: Seventy-four participants (57 women [77.1%], 17 men [22.9%]) of 97 completed the program (76.3% completion rate). Body weight (P<.001); percentage of body fat (P<.001); fat mass (P<.001); body mass index (P<.001); waist circumference (P<.001); blood levels of high-density lipoprotein (P=.035), low-density lipoprotein (P=.011), and glucose (P=.008); serum triglyceride levels (P=.019); blood pressure (systolic P=.028; diastolic, P=.001); and maximal oxygen consumption (P<.001) improved from baseline to 1 year after the intervention. Lean body mass (P=.111) and total cholesterol (P=.053) did not improve. Conclusions: This employer-based lifestyle intervention program was effective in reducing CVD risk factors after 1 year of treatment. Future studies should examine the effects of the intervention at 2 and 5 years to further assess long-term adoption of the lifestyle changes and maintenance of health promoted by this program. PMID- 28662556 TI - Effect of Latitude on Vitamin D Levels. AB - Context: Vitamin D levels have been linked to bone health and to numerous diseases; however, an element that lacks substantial direct data and limits the evidence basis regarding whom to screen for vitamin D deficiency is the effect of latitude on vitamin D levels. Objectives: To determine whether latitude influences vitamin D levels and to investigate the influence of other factors that may affect vitamin D levels, including sex, race, skin type, and body mass index. Methods: Osteopathic medical students were recruited from campuses in Bradenton, Florida, and Erie, Pennsylvania. Surveys were administered to obtain demographic information, and blood samples were drawn to measure total vitamin D levels. Two-sample t tests, Fisher exact test, and logistic regression was used to assess differences in total vitamin D levels between the 2 locations. Results: A total of 359 medical students (aged 22-57 years) were included in the study, 194 at the Bradenton campus and 214 at the Erie campus. The mean (SD) vitamin D level was 34.5 (11.8) ng/mL among participants in Bradenton and 28.1 (12.4) ng/mL among participants in Erie. Logistic regression models revealed an adjusted OR of 3.3 (95% CI, 1.73-6.4) for deficient total vitamin D among Erie students. Non white race, male sex, and high body mass index were also statistically significant risk factors for vitamin D deficiency in regression models (P<.05). Conclusion: Latitude was found to be a statistically significant risk factor for vitamin D deficiency. Additionally, the findings suggest that persons with darker skin tone and, to a lesser degree, men and persons who are overweight or obese are also at increased risk for vitamin D deficiency. Physicians should be cognizant of these risk factors when deciding whom to screen. PMID- 28662557 TI - Reducing Off-Label Antipsychotic Use in Older Community-Dwelling Adults With Dementia: A Narrative Review. AB - The off-label use of antipsychotics for the management of behavioral and psychologic symptoms of dementia (BPSD) in older adults (age >=65 years) is common, despite evidence of modest benefits and serious risks. Although national initiatives aimed at reducing antipsychotic use among older adults with BPSD in nursing homes have been successful, similar initiatives are lacking for community dwelling adults with dementia. As a result, older adults with BPSD residing in the community may be at an even greater risk of being negatively affected by antipsychotic use. Physicians should be knowledgeable of this issue and understand the alternatives to antipsychotics, as well as how to reduce antipsychotic use in patients with dementia who are already taking antipsychotics. PMID- 28662558 TI - Integrating Point-of-Care Ultrasonography Into the Osteopathic Medical School Curriculum. AB - Point-of-care ultrasonography has been shown to have pervasive clinical and educational utility in medicine. The need to provide medical students with training in point-of-care ultrasonography has been recognized by an increasing number of osteopathic and allopathic medical schools. A 4-year integrated ultrasonography curriculum was implemented at Rocky Vista University College of Osteopathic Medicine in 2015. A review of the curriculum design, content, educational methods, and student feedback are described. Barriers to curriculum implementation and lessons learned, unique to integrating point-of-care ultrasonography into the osteopathic curriculum, are also discussed. PMID- 28662559 TI - Highlights From the American Diabetes Association's 2017 Standards of Medical Care in Diabetes for Osteopathic Physicians. AB - The American Diabetes Association (ADA) updates its Standards of Medical Care (SOMC) in Diabetes annually. These ADA standards make up a comprehensive document that serves as an excellent resource for clinical care. The current article comes from the ADA's Primary Care Advisory Group. This article highlights key aspects of the SOMC that are relevant to the day-to-day practice of osteopathic primary care physicians. It is not intended to replace the full SOMC but will refer to the master document for further explanation and evidence-based support. PMID- 28662560 TI - Thrombocytopenia and Spontaneous Intracranial Hemorrhage After Olanzapine Therapy. AB - The use of atypical antipsychotics in the United States has increased over the past decade, since atypical antipsychotics such as olanzapine and clozapine were introduced. Of the adverse effects associated with olanzapine, bone marrow suppression is one of the most common, but spontaneous intracranial hemorrhage secondary to thrombocytopenia is rare. The present case report describes an 88 year-old man who presented with an intracranial hemorrhage after taking olanzapine for 2 weeks. This case emphasizes the importance of monitoring the potential adverse effects associated with olanzapine and other antipsychotics, especially in elderly patients. PMID- 28662561 TI - Heads Up on Headers: Effects of Soccer Ball Heading on Brain Function. PMID- 28662562 TI - Effects of Manual Therapy on Patients With Carpal Tunnel Syndrome. PMID- 28662564 TI - Osteopathic Manipulative Therapy for Foot-Pain: How Many Sessions? How Often? PMID- 28662563 TI - Manual Therapy to Manage Carpal Tunnel Syndrome. PMID- 28662565 TI - Hematemesis Caused by Forgotten Corrective Device. PMID- 28662566 TI - Ontogeny of Flight Capacity and Pectoralis Function in a Precocial Ground Bird (Alectoris chukar). AB - SYNOPSIS: Flight is the defining characteristic of birds, yet the mechanisms through which flight ability develops are only beginning to be understood. Wing assisted incline running (WAIR) and controlled flapping descent (CFD) are behaviors that may offer significant adaptive benefits to developing birds. Recent research into these forms of locomotion has focused on species with precocial development, with a particularly rich data set from chukar partridge (Alectoris chukar). Here we briefly review the kinematics and aerodynamics of flight development in this species. We then present novel measurements of the development of pectoralis contractile behavior during the ontogenetic transition toward powered flight. To obtain these new empirical data, we used indwelling electromyography (EMG) and sonomicrometry and tested WAIR and CFD in seven age classes of chukar (n = 2-4 birds per age) from 5 days post hatching (dph) to adult (300+ dph). For each age class, we measured muscle activity during maximal performance, which was WAIR at 65 degrees in birds 5 dph, CFD in birds 9 dph, WAIR at 80 degrees in birds 14 dph, level flight in birds 25-61 dph, and ascending flight in adults. We also measured muscle activity during sub-maximal performance in all age classes. Flapping chukar chicks use near-continuous activation of their pectoralis at relatively low electromyography amplitudes for the first 8 days and progress to stereotypic higher-amplitude activation bursts by Day 12. The pectoralis undergoes increasing strain at higher strain rates with age, and length trajectory becomes more asymmetrical with greater variation in contractile velocity within the shortening phase of individual contractions. At 20-25 days (12-15% adult chukar mass), pectoralis activity and locomotor performance approaches that of adults, although strain rate exhibits a temporary decrease at 61 dph concurrent with using newly-replaced primary feathers. To better understand how these patterns relate to the evolution of life-history strategy and locomotion, we encourage future efforts to explore these behaviors in altricial and semi-altricial bird species. PMID- 28662568 TI - Clinical implication of an impaired fasting glucose and prehypertension related to new onset atrial fibrillation in a healthy Asian population without underlying disease: a nationwide cohort study in Korea. AB - Aims: For healthy populations without comorbidities, whether prehypertension and impaired fasting glucose (IFG) are associated with new onset atrial fibrillation (AF) is not well known. Methods and results: We included 366 507 subjects (age >=20 years) not diagnosed with non-valvular AF from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2003 to 2008. In total, 139 306 subjects diagnosed with AF-related comorbidities were excluded, and a 227 102 healthy population was followed up until 2013. The body mass index (BMI), blood pressure (BP), and fasting blood glucose (BG) level were acquired during National health check-ups. Subjects with IFG [hazard ratio (HR) 1.16, P = 0.017] had a higher AF risk and the diastolic BP (HR 1.11, P = 0.045) was a stronger indicator for an AF incidence than the systolic BP. After dividing the subjects into two mutually exclusive groups, AF incidence was increased dramatically by the combination effect of both prehypertension and an IFG in BMI <25 kg/m2 group, but, in BMI ?25 kg/m2 group, did not show this tendency. An IFG related to AF risk was more prominent in the BMI <25 kg/m2 population (HR 1.18, P = 0.025) than those with a BMI >=25 kg/m2, and subjects with both an IFG and prehypertension had a greater AF risk (HR 1.27, P = 0.016) than those without. Conclusion: Even in a healthy Asian populations without comorbidities, prehypertension and IFG were important risk factors of AF. Specifically, when prehypertension, including systolic and diastolic BPs, was finally combined with the IFG, the risk of new onset AF was increased especially in the BMI <25 kg/m2 group. PMID- 28662569 TI - The Physiology of Exercise in Free-Living Vertebrates: What Can We Learn from Current Model Systems? AB - SYNOPSIS: Many behaviors crucial for survival and reproductive success in free living animals, including migration, foraging, and escaping from predators, involve elevated levels of physical activity. However, although there has been considerable interest in the physiological and biomechanical mechanisms that underpin individual variation in exercise performance, to date, much work on the physiology of exercise has been conducted in laboratory settings that are often quite removed from the animal's ecology. Here we review current, laboratory-based model systems for exercise (wind or swim tunnels for migration studies in birds and fishes, manipulation of exercise associated with non-migratory activity in birds, locomotion in lizards, and wheel running in rodents) to identify common physiological markers of individual variation in exercise capacity and/or costs of increased activity. Secondly, we consider how physiological responses to exercise might be influenced by (1) the nature of the activity (i.e., voluntary or involuntary, intensity, and duration), and (2) resource acquisition and food availability, in the context of routine activities in free-living animals. Finally, we consider evidence that the physiological effects of experimentally elevated activity directly affect components of fitness such as reproduction and survival. We suggest that developing more ecologically realistic laboratory systems, incorporating resource-acquisition, functional studies across multiple physiological systems, and a life-history framework, with reproduction and survival end-points, will help reveal the mechanisms underlying the consequences of exercise, and will complement studies in free-living animals taking advantage of new developments in wildlife-tracking. PMID- 28662567 TI - Electrical risk score beyond the left ventricular ejection fraction: prediction of sudden cardiac death in the Oregon Sudden Unexpected Death Study and the Atherosclerosis Risk in Communities Study. AB - Aims: There is an urgent need to extend sudden cardiac death (SCD) risk stratification beyond the left ventricular ejection fraction (LVEF). We evaluated whether a cumulative electrocardiogram (ECG) risk score would improve identification of individuals at high risk of SCD. Methods and results: In the community-based Oregon Sudden Unexpected Death Study (catchment population ~1 million), 522 SCD cases with archived 12-lead ECG available (65.3 +/- 14.5 years, 66% male) were compared with 736 geographical controls to assess the incremental value of multiple ECG parameters in SCD prediction. Heart rate, LV hypertrophy, QRS transition zone, QRS-T angle, QTc, and Tpeak-to-Tend interval remained significant in the final model, which was externally validated in the Atherosclerosis Risk in Communities (ARIC) Study. Sixteen percent of cases and 3% of controls had >=4 abnormal ECG markers. After adjusting for clinical factors and LVEF, increasing ECG risk score was associated with progressively greater odds of SCD. Overall, subjects with >=4 ECG abnormalities had an odds ratio (OR) of 21.2 for SCD [95% confidence interval (CI) 9.4-47.7; P < 0.001]. In the LVEF >35% subgroup, the OR was 26.1 (95% CI 9.9-68.5; P < 0.001). The ECG risk score increased the C-statistic from 0.625 to 0.753 (P < 0.001), with net reclassification improvement of 0.319 (P < 0.001). In the ARIC cohort validation, risk of SCD associated with >=4 ECG abnormalities remained significant after multivariable adjustment (hazard ratio 4.84; 95% CI 2.34-9.99; P < 0.001; C statistic improvement 0.759-0.774; P = 0.019). Conclusion: This novel cumulative ECG risk score was independently associated with SCD and was particularly effective for LVEF >35% where risk stratification is currently unavailable. These findings warrant further evaluation in prospective clinical investigations. PMID- 28662570 TI - Defining the Degree of Seasonality and its Significance for Future Research. AB - Seasonality describes cyclic and largely predictable fluctuations in the environment. Such variations in day length, temperature, rainfall, and resource availability are ubiquitous and can exert strong selection pressure on organisms to adapt to seasonal environments. However, seasonal variations exhibit large scale geographical divergences caused by a whole suite of factors such as solar radiation, ocean currents, extent of continents, and topography. Realizing these contributions in driving patterns of overall seasonality may help advance our understanding of the kinds of evolutionary adaptations we should expect at a global scale. Here, we introduce a new concept and provide the data describing the overall degree of seasonality, based on its two major components-amplitude and predictability. Using global terrestrial datasets on temperature, precipitation and primary productivity, we show that these important seasonal factors exhibit strong differences in their spatial patterns with notable asymmetries between the southern and the northern hemisphere. Furthermore, our analysis reveals that seasonality is highly diverse across latitudes as well as longitudinal gradients. This indicates that using a direct measure of seasonality and its components, amplitude and predictability, may yield a better understanding of how organisms are adapted to seasonal environments and provide support for predictions on the consequences of rapid environmental change. PMID- 28662571 TI - Scaling from Metabolism to Population Growth Rate to Understand How Acclimation Temperature Alters Thermal Performance. AB - SYNOPSIS: The mean and variance of environmental temperature are changing as a consequence of human activities. Ectotherms are sensitive to these temperature changes in the short term, typically displaying a unimodal response of most biological rates to temperature (thermal performance curves; TPCs). Many organisms, however, may acclimate or evolve in response to new temperature regimes. In particular, population growth rate TPCs (r TPCs) reflect the ability to maintain positive growth under a range of temperatures, and therefore shifts in r TPCs due to acclimation are fundamental to our understanding of how ectotherms will respond to changes in climate. Here, we derive a model for r TPCs rooted in temperature dependent metabolic rate (through enzyme kinetics and activity). We then use this model to interpret the effects of acclimation to different temperatures on r TPCs of the protist Paramecium bursaria. Intermediate acclimation temperatures generally resulted in higher upper critical thermal limits, thermal optima, maximum population growth rate, and the area under the TPC. Lower critical thermal limits increased linearly with acclimation temperature, causing a decrease in thermal breadth with increased acclimation temperature. Thus, rather than showing improved performance at the acclimation temperature, P. bursaria appeared to pay a price at all temperatures for acclimating to higher temperatures. The fits of our data to our model also suggest that changes in the structure and function of metabolic enzymes may underlie the changes in the TPCs. Specifically, our results suggest that both the delta heat capacity and delta enthalpy of formation of metabolic enzymes may have increased with acclimation. Since these two factors are correlated across acclimation temperatures, our data also suggest potential trade-offs that may constrain changes in TPCs. PMID- 28662572 TI - Beyond Fermentation: Other Important Services Provided to Endothermic Herbivores by their Gut Microbiota. AB - For decades, comparative biologists have recognized the importance of microbial partners in facilitating herbivory as a successful feeding strategy. Most of this success is attributed to the ability of gut microbes to digest recalcitrant dietary fiber and provides usable nutrients to their hosts. Gut microbes can also provide numerous other functions, such as vitamin synthesis, nitrogen recycling, and the detoxification of plant secondary compounds. Here, we review these microbial functions in herbivorous mammals and birds, highlighting studies that utilize recently developed metagenomic techniques. Several of these studies emphasize that microbial services are the product of interactions and exchanges within a complex microbial community, rather than the product of an individual member. Additionally, a number of these microbial functions are interdependent. For example, levels of dietary nitrogen or plant toxins can influence fiber digestibility. Further studies into the variety of microbial services provided to herbivorous hosts, and how these services might interact will broaden our understanding of host-microbe interactions. PMID- 28662574 TI - Microbiome Structural and Functional Interactions across Host Dietary Niche Space. AB - Host-associated microbiomes are integral components of host health, but microbiome community structure varies among and within hosts. Reconciling community variability with the apparent dependence of hosts on community function, and characterizing how functional divergence proceeds across niches, remains challenging. Here, through the study of gut microbiomes and diets of three insectivorous bat species we characterize how community structure is shaped by predicted functional properties of community members. We found that while host diet and microbiome community composition do not significantly relate to each other, host diet and metagenome function do, suggesting that diet directly selects metagenomic functions rather than communities. We use a novel inference framework to show how the discordance between community structure and functional variation derives from functional equivalence and is influenced by the continuum of shared and derived gene sets across microbial lineages. Our findings help clarify how metagenome community structure-function relationships contribute to deterministic processes in community assembly, and describe the basis for metagenomic differences across ecologically similar hosts. PMID- 28662573 TI - Early-Life Diet Affects Host Microbiota and Later-Life Defenses Against Parasites in Frogs. AB - Food resources can affect the health of organisms by altering their symbiotic microbiota and affecting energy reserves for host defenses against parasites. Different diets can vary in their macronutrient content and therefore they might favor certain bacterial communities of the host and affect the development and maintenance of the immune system, such as the inflammatory or antibody responses. Thus, testing the effect of diet, especially for animals with wide diet breadths, on host-associated microbiota and defenses against parasites might be important in determining infection and disease risk. Here, we test whether the early-life diet of Cuban tree frogs (Osteopilus septentrionalis) affects early- and later life microbiota as well as later-life defenses against skin-penetrating, gut worms (Aplectana hamatospicula). We fed tadpoles two ecologically common diets: a diet of conspecifics or a diet of algae (Arthrospira sp.). We then: (1) characterized the gut microbiota of tadpoles and adults; and (2) challenged adult frogs with parasitic worms and measured host resistance (including the antibody mediated immune response) and tolerance of infections. Tadpole diet affected bacterial communities in the guts of tadpoles but did not have enduring effects on the bacterial communities of adults. In contrast, tadpole diet had enduring effects on host resistance and tolerance of infections in adult frogs. Frogs that were fed a conspecific-based diet as tadpoles were more resistant to worm penetration compared with frogs that were fed an alga-based diet as tadpoles, but less resistant to worm establishment, which may be related to their suppressed antibody response during worm establishment. Furthermore, frogs that were fed a conspecific-based diet as tadpoles were more tolerant to the effect of parasite abundance on host mass during worm establishment. Overall, our study demonstrates that the diet of Cuban tree frog tadpoles affects the gut microbiota and defenses against parasitic gut worms of frogs, but these effects depend on the stage of the host and infection, respectively. PMID- 28662575 TI - Insect Development, Thermal Plasticity and Fitness Implications in Changing, Seasonal Environments. AB - Historical data show that recent climate change has caused advances in seasonal timing (phenology) in many animals and plants, particularly in temperate and higher latitude regions. The population and fitness consequences of these phenological shifts for insects and other ectotherms have been heterogeneous: warming can increase development rates and the number of generations per year (increasing fitness), but can also lead to seasonal mismatches between animals and their resources and increase exposure to environmental variability (decreasing fitness). Insect populations exhibit local adaptation in their developmental responses to temperature, including lower developmental thresholds and the thermal requirements to complete development, but climate change can potentially disrupt seasonal timing of juvenile and adult stages and alter population fitness. We investigate these issues using a global dataset describing how insect developmental responds to temperature via two traits: lower temperature thresholds for development (T0) and the cumulative degree-days required to complete development (G). As suggested by previous analyses, T0 decreases and G increases with increasing (absolute) latitude; however, these traits and the relationship between G and latitude varies significantly among taxonomic orders. The mean number of generations per year (a metric of fitness) increases with both decreasing T0 and G, but the effects of these traits on fitness vary strongly with latitude, with stronger selection on both traits at higher (absolute) latitudes. We then use the traits to predict developmental timing and temperatures for multiple generations within seasons and across years (1970-2010). Seasonality drives developmental temperatures to peak mid-season and for generation lengths to decline across seasons, particularly in temperate regions. We predict that climate warming has advanced phenology and increased the number of generations, particularly at high latitudes. The magnitude of increases in developmental temperature varies little across latitude. Increases in the number of seasonal generations have been greatest for populations experiencing the greatest phenological advancements and warming. Shifts in developmental rate and timing due to climate change will have complex implications for selection and fitness in seasonal environments. PMID- 28662576 TI - Social Aggression, Experience, and Brain Gene Expression in a Subsocial Bee. AB - The genetic mechanisms behind aggressive behaviors are important for understanding the formation of dominance hierarchies, and thus social systems in general. Studies into the effects of social experience and agonistic contest outcomes have shown significant changes in brain gene expression resulting from repeated winning and losing, as well as changing dominance rank, primarily in obligately social species. However, our knowledge of the genetic underpinnings of behavior in subsocial organisms is relatively poor, yet understanding the behavioral genetics of this simplest form of sociality provides the basis for understanding all other forms of social living. Here, we measured the effects of aggression on brain gene expression in the subsocial bee, Ceratina calcarata, in individuals that had experienced repeated winning, repeated losing, or a change in rank during repeated encounters. Consistent winning accounted for the majority of variation in brain gene expression, followed by changing rank over maintaining rank. Candidate genes for aggression are identified through comparative transcriptomics across 21 invertebrate and 6 vertebrate taxa. Lastly, we identified significantly over-represented cis-regulatory elements, namely transcription factor binding motifs deeply conserved across a wide range of taxa and broadly implicated in differential regulation of genes related to aggressive/dominant behavior. We present evidence for both genetic and cis regulatory mechanisms for aggression that may have broad importance to social evolution. PMID- 28662577 TI - Reversible Dendrite-Free Potassium Plating and Stripping Electrochemistry for Potassium Secondary Batteries. AB - Rechargeable potassium metal batteries have recently emerged as alternative energy storage devices beyond lithium-ion batteries. However, potassium metal anodes suffer from poor reversibility during plating and stripping processes due to their high reactivity and unstable solid electrolyte interphase (SEI). Herein, it is reported for the first time that a potassium bis(fluoroslufonyl)imide (KFSI)-dimethoxyethane (DME) electrolyte forms a uniform SEI on the surface of potassium enabling reversible potassium plating/stripping electrochemistry with high efficiency (~99%) at ambient temperature. Furthermore, the superconcentrated KFSI-DME electrolyte shows excellent electrochemical stability up to 5 V (vs K/K+) which enables good compatibility with high-voltage cathodes. Full cells with potassium Prussian blue cathodes are demonstrated. Our work contributes toward the understanding of potassium plating/stripping electrochemistry and paves the way for the development of potassium metal battery technologies. PMID- 28662578 TI - Tuning of Enthalpic/Entropic Parameters of a Protein Redox Center through Manipulation of the Electronic Partition Function. AB - Manipulation of the partition function (Q) of the redox center CuA from cytochrome c oxidase is attained by tuning the accessibility of a low lying alternative electronic ground state and by perturbation of the electrostatic potential through point mutations, loop engineering and pH variation. We report clear correlations of the entropic and enthalpic contributions to redox potentials with Q and with the identity and hydrophobicity of the weak axial ligand, respectively. PMID- 28662579 TI - Effect of Nitrogen Oxides on Elemental Mercury Removal by Nanosized Mineral Sulfide. AB - Because of its large surface area, nanosized zinc sulfide (Nano-ZnS) has been demonstrated in a previous study to be efficient for removal of elemental mercury (Hg0) from coal combustion flue gas. The excellent mercury adsorption performance of Nano-ZnS was found to be insusceptible to water vapor, sulfur dioxide, and hydrogen chloride. However, nitrogen oxides (NOX) apparently inhibited mercury removal by Nano-ZnS; this finding was unlike those of many studies on the promotional effect of NOX on Hg0 removal by other sorbents. The negative effect of NOX on Hg0 adsorption over Nano-ZnS was systematically investigated in this study. Two mechanisms were identified as primarily responsible for the inhibitive effect of NOX on Hg0 adsorption over Nano-ZnS: (1) active sulfur sites on Nano ZnS were oxidized to inactive sulfate by NOX; and (2) the chemisorbed mercury, i.e., HgS, was reduced to Hg0 by NOX. This new insight into the role of NOX in Hg0 adsorption over Nano-ZnS can help to optimize operating conditions, maximize Hg0 adsorption, and facilitate the application of Nano-ZnS as a superior alternative to activated carbon for Hg0 removal using existing particulate matter control devices in power plants. PMID- 28662580 TI - Proton Transfer Rates in Ionized Hydrogen Chloride-Water Clusters: A Direct Ab Initio Molecular Dynamics Study. AB - Reactions of the microhydrated hydrogen chloride radical cation, [HCl-(H2O)n]+ (n = 1-5), following the ionization of the parent neutral cluster were investigated by the direct ab initio molecular dynamics (AIMD) method to elucidate the cluster size dependence of the proton transfer (PT) rate in the ionized state. The ionization occurred from the HCl moiety of the clusters. The proton of HCl+ was transferred to the neighboring water molecule in the cluster. The time of PT was strongly dependent on the cluster size (n); the time of PT decreased with increasing n and reached a limiting value at n = 4-5 (the time of PT was ca. 7 fs). The acceleration of the PT rate was mainly caused by the shortness of the hydrogen bond between HCl+ and H2O in larger clusters, that is, a short hydrogen bond causes fast PT. The electrostatic effects of the water cluster further accelerated the rate of PT. After the first PT from HCl+ to H2O, the second PT (H3O+ + H2O ->H2O + H3O+) was detected for n = 3-5. The times of the first and second PTs were calculated as 7-15 and 30-40 fs, respectively. The reaction mechanism was discussed based on the theoretical results. PMID- 28662581 TI - Proteomics of Parma Dry-Cured Ham: Analysis of Salting Exudates. AB - The production of Parma dry-cured ham involves the steps of salting, drying, and ripening. Although sea salt is the only preserving agent, there are strategies being developed with the goal of reducing salt content in order to decrease its negative impact on consumer health. A 24 h pressure treatment was applied before salting to reduce thickness and inequalities in shape. To evaluate the potential impact of the pressure step on the process outcome, differential proteomic analyses by complementary 2D-PAGE and LC-MS/MS were carried out on exudates collected at day 1, 5, and 18 of the salting phase for hams treated or untreated with pressure. Specific proteins were found differentially abundant in exudates from pressed vs unpressed hams and as a function of time. These changes include glycolytic enzymes and several myofibrillar proteins. These findings indicate that pressure causes a faster loosening of the myofibrillar structure with the release of specific groups of proteins. PMID- 28662582 TI - Further New Gypenosides from Jiaogulan (Gynostemma pentaphyllum). AB - Jiaogulan (Gynostemma pentaphyllum) has been widely used as a herbal tea, dietary supplement, and vegetable in Asian countries. In this study, six new gypenosides (1-6) were isolated from the aerial parts of G. pentaphyllum. Their molecular structures were elucidated through spectroscopic analysis and acid hydrolysis. Gypenosides 1 and 2 represented the first example of a dammar-21-O- glucopyranoside without any unsaturated functional group and a dammar-3-O glucopyranosyl-25-O-glucopyranoside without any cyclization in the side chain, respectively. In addition, gypenosides 5 and 6 exhibited the first example of a 24-hydroperoxy-19-oxo-dammarane triterpenoid and 19-oxo-dammar-21-O glucopyranoside with a saturated side chain, respectively. Gypenoside 5 was found to possess protein tyrosine phosphatase 1B inhibitory activity, with an IC50 value of 8.2 +/- 0.9 MUM, and moderate cytotoxicity against human breast cancer cells MCF7, MCF7/ADR, and MDA-MB-231, with IC50 values ranging from 10.5 +/- 1.4 to 14.2 +/- 2.6 MUM. The outcome of the study provided crucial information regarding the structural diversity and health benefits of gypenosides. PMID- 28662583 TI - Acceleration and Reaction Mechanism of the N-Nitrosation Reaction of Dimethylamine with Nitrite in Ice. AB - Some reactions (e.g., oxidation of nitrite, denitrification of ammonium) are accelerated in freeze-concentrated solution (FCS) compared to those in aqueous solution. Ice is highly intolerant to impurities, and the ice excludes those that would accelerate reactions. Here we show the acceleration of the N-nitrosation reaction of dimethylamine (DMA) with nitrite to produce N-nitrosodimethylamine (NDMA) in FCS. NDMA is a carcinogenic compound, and this reaction is potentially accelerated in frozen fish/meat. The eaction rate of the N-nitrosation reaction becomes fastest at specific pH. This means that it is a third-order reaction. Theoretical pH values of the peak in the third-order reaction are higher than the experimental one. Freeze-concentration of acidic solution causes pH decrement; however, the freeze-concentration alone could not explain the difference of pH values. The theoretical value was obtained under the assumption that no solute took part in ice. However, solutes are incorporated in ice with a small distribution coefficient of solutes into ice. This small incorporation enhanced the decrement of pH values. Using the distribution coefficient of chloride and sodium ion and assuming those of nitrite and DMA to explain the enhancement, we succeeded in estimating the distribution coefficients of nitrite: 2 * 10-3 and DMA: 3 * 10-2. PMID- 28662584 TI - Necrolytic Migratory Erythema: A Forgotten Paraneoplastic Condition. AB - BACKGROUND: Necrolytic migratory erythema (NME) is most commonly a paraneoplastic condition. It is the dermatologic manifestation classically associated with glucagonoma pancreatic neuroendocrine tumour. Glucagonoma syndrome has been defined by the constellation of secreting tumour associated with overproduction by the alpha-cells in the pancreatic islets of Langerhans, abnormally elevated blood level of glucagon, and skin findings of NME. OBJECTIVE: Although rare, all dermatologists must know and recognise NME promptly to request useful investigations for the diagnosis of this characteristic neuroendocrine tumour. METHODS AND RESULTS: We report a case of a middle-aged woman seen in our dermatology clinic with longstanding skin findings suggestive of NME revealing a glucagonoma. Surgical removal was associated with complete resolution of the cutaneous and systemic features. CONCLUSION: NME is often the first clinical finding of an occult neuroendocrine pancreatic neoplasia. Dermatologists must be aware of this condition since they can be the first physician to suspect it and allow multidisciplinary management, which influences the prognostic value. Surgical removal is the first-line therapy if early diagnosis is done before liver metastases occur. PMID- 28662585 TI - Characteristics of school-based health services associated with students' mental health. AB - Objective School-based health services (SBHS) have been shown to improve access to mental health services but the evidence of their effectiveness on students' mental health is lacking. Our objective was to examine associations between variation in the provision of SBHS and students' mental health. Methods A cross sectional analysis of a nationally representative health and well-being survey of 8500 New Zealand high school students conducted in March-November 2012. Students' mental health is related to data on school health services obtained from clinic leaders and clinicians from 90 participating high schools. Results After adjustment for socio-demographic differences in students between schools, increasing levels of services were associated with progressively lower levels of student-reported depressive symptoms (p = 0.002), emotional and behavioural difficulties (p = 0.004) and suicidality (p = 0.008). Services with greater levels of nursing hours (p = 0.02) and those that performed routine, comprehensive psychosocial assessments (p = 0.01) were both associated with lower levels of student-reported depressive symptoms. Greater levels of nursing hours and doctor hours were associated with lower self-reported suicidality among students. Conclusions Although a causal association between school-based health services and students' mental health cannot be demonstrated, these findings support the benefit of such services and the need for a cluster randomized trial. PMID- 28662586 TI - Social anxiety and emotion regulation flexibility: considering emotion intensity and type as contextual factors. AB - BACKGROUND AND OBJECTIVES: Individuals with social anxiety disorder have often been considered inflexible in their emotion regulation. The aim of this study was to investigate emotion regulation flexibility in socially anxious individuals in response to two contextual factors, namely different levels of emotion intensity and emotion type. METHODS: A daily diary approach was employed, investigating emotion regulation (i.e., experiential avoidance, expressive suppression and cognitive reappraisal) in college students scoring high (N = 62; HSA) and low (N = 52; LSA) on social anxiety. RESULTS: Results revealed that HSAs were found to use more experiential avoidance than LSAs, especially at higher levels of negative intensity. The use of this emotion regulation strategy appeared to be driven by guilt, nervousness, and sadness. There were no between-group differences concerning the other strategies in response to varying levels of emotional intensity. CONCLUSIONS: Together, the results provide evidence for inflexible emotion regulation in HSAs, reflected in an unwillingness to experience negative emotions. PMID- 28662587 TI - Research participation, trust, and fair compensation among people living with and without HIV in Florida. AB - Florida has the second highest number of newly diagnosed cases of HIV in the United States. Sociodemographic representation that is reflective of the population is essential in developing evidence based interventions to improve HIV outcomes and reduce disparities. Understanding HIV research trial participation, preferences for types of research, and fair compensation for research will further our understanding of someone's decision to participate in research. The purpose of this analysis was to identify differences in prior research participation, trust, interests in types of research, and fair compensation between people living with HIV and without HIV in North Central Florida. In this sample of 8340 people interviewed in the community about their health concerns and research participation, 156 reported living with HIV. Only 20.5% of people with HIV reported past participation in research, however 94.2% said they were interested in future research participation. While people with HIV were slightly more interested in higher risk/low convenience research, there were no statistically significant differences in preferences for types of research between those with and without HIV. People with HIV reported no difference in the amount they would request for fair compensation ($78.4 USD) compared with those without HIV ($72.2 USD, p = 0.69). Community members are interested in participating in research, although few had previously participated. Improving our understanding of research study participation will help improve recruitment efforts and draw stronger conclusions regarding the effectiveness of interventions, as well as enhance implementation of these interventions. PMID- 28662588 TI - Utilization of multiple spinal cord stimulation (SCS) waveforms in chronic pain patients. AB - BACKGROUND: Advances in spinal cord stimulation (SCS) have improved patient outcomes, leading to its increased utilization for chronic pain. Chronic pain is dynamic showing exacerbations, variable severity, and evolving pain patterns. Given this complexity, SCS systems that provide a broad range of stimulation waveforms may be valuable. METHODS: The aim of this research was to characterize the usage pattern of stimulation waveforms and field shapes in chronic pain patients implanted with the Spectra System. A review of daily device usage in a cohort of 250 patients implanted for a minimum duration of one month was conducted. RESULTS: With follow-ups ranging between 1 month and 1 year post implant, 72.8% of patients used Standard Rate, 34.8% Anode Intensification, 23.2% Higher Rate, and 8.4% Burst stimulation waveforms. Collectively, 60% used 1 or more advanced waveforms, either exclusively or along with Standard Rate. A trend showed patients continuing to use up to 3 programs one year post-implant. CONCLUSION: When given a choice, SCS patients often utilize a variety of waveforms, suggesting that patients may benefit from a single system that provides multiple waveforms and field shapes to customize therapy and improve efficacy. PMID- 28662589 TI - Model Selection in Continuous Test Norming With GAMLSS. AB - To compute norms from reference group test scores, continuous norming is preferred over traditional norming. A suitable continuous norming approach for continuous data is the use of the Box-Cox Power Exponential model, which is found in the generalized additive models for location, scale, and shape. Applying the Box-Cox Power Exponential model for test norming requires model selection, but it is unknown how well this can be done with an automatic selection procedure. In a simulation study, we compared the performance of two stepwise model selection procedures combined with four model-fit criteria (Akaike information criterion, Bayesian information criterion, generalized Akaike information criterion (3), cross-validation), varying data complexity, sampling design, and sample size in a fully crossed design. The new procedure combined with one of the generalized Akaike information criterion was the most efficient model selection procedure (i.e., required the smallest sample size). The advocated model selection procedure is illustrated with norming data of an intelligence test. PMID- 28662590 TI - The True North Strong and Free? Opportunities for Improving Canadian Mental Health Care and Education by Adopting the WHO's ICD-11 Classification. PMID- 28662591 TI - Prevalence of vitamin D deficiency in pregnant mothers in Tehran and investigating its association with serum glucose and insulin. AB - PURPOSE: (1) To determine the prevalence of vitamin D deficiency in pregnant women. (2) To identify any correlations between maternal vitamin D levels and maternal and newborns' glucose and insulin levels. METHODS: This observational cohort study followed 149 healthy pregnant women visiting a hospital in Tehran, Iran in 2014 until the delivery of their term babies. Maternal serum vitamin D levels, and fasting blood glucose and insulin levels in both mothers and newborns were measured at delivery. Mothers' weight before pregnancy and right before delivery and babies' birth weight were measured. RESULTS: Of sample population, 27% had vitamin D deficiency, while 73% had insufficient vitamin D. No mother had sufficient vitamin D level. Maternal weight right before delivery negatively correlated with maternal serum vitamin D level (p = .04). Vitamin D deficiency is more prevalent in mothers who deliver a male infant (p = .03). Maternal serum vitamin D levels did not correlate with maternal or neonatal serum glucose or insulin levels or newborns' birth weight. Gestational age, maternal weight right before delivery, parity and maternal serum glucose predict infant's birth weight. CONCLUSION: Vitamin D deficiency/insufficiency is prevalent among pregnant women. Factors causing this epidemic need investigation. Promoting consumption of vitamin D-fortified foods and supplements among pregnant women is suggested. PMID- 28662592 TI - Structure-activity relationship of Triterpenes and derived Glycosides against cancer cells and mechanism of apoptosis induction. AB - Triterpenoids possess a wide range of biological effects. Here, the cytotoxic activities of 55 triterpenes and derived glycosides against BEL-7404 and SGC-7901 cells were assessed, and structure-activity relationships were analysed accordingly. Nine of them effectively inhibited the two cell lines. In particular, compounds 49 and 52 inhibited BEL-7404 cells as efficiently as 5' fluorouracil (IC50 values 0.46 and 1.48, respectively). Moreover, we found that compounds 49 and 52 induced apoptosis in BEL-7404 cells. Indeed, DNA fragmentation assay showed a time-dependent degradation of DNA after treatment of cells with compounds 49 and 52. In addition, Bax gene expression levels were increased after treatment with these compounds, in a concentration-dependent manner. Taken together, our findings suggested that compounds 49 and 52 induce apoptosis in BEL-7404 cells by upregulating the Bax gene without affecting Bcl-2 gene expression. PMID- 28662593 TI - Isolation and structure elucidation of halymeniaol, a new antimalarial sterol derivative from the red alga Halymenia floresii. AB - A new mono-hydroxy acetylated sterol derivative: 12beta-hydroxy-3beta, 15alpha, 16beta-triacetoxy-cholest-5-en-7-one (halymeniaol) (1), and cholesterol (2) were isolated from the marine red alga Halymenia floresii. The structure of the compound 1 (halymeniaol) was established from its spectral data, derived from HRMS/MS and 2D NMR. Compound 1 exhibited growth inhibitory activity against chloroquine-resistant Plasmodium falciparum 3D7 strain with an IC50 of 3.0 MUM. PMID- 28662594 TI - "This Is What Family Does": The Family Experience of Caring for Serious Illness. AB - BACKGROUND: As the demographics of caregiving in United States evolve toward multigenerational, distributed family structures, the ways in which individuals and their families experience serious illness are changing. As part of a project to create an innovative model of supportive care for serious illness, a series of user interviews were conducted, forming the basis for this article. OBJECTIVE: To understand the experience of caregiving for individuals with serious illness from an intergenerational family perspective. METHODS: Twelve semistructured group interviews were conducted with patients, families, and professionals. Transcript data were analyzed with descriptive coding, looking for major themes and subthemes related to family experiences. RESULTS: Seventy-three individuals participated in group interview sessions. While both families and individuals encountered caregiving challenges, the family unit experienced care in several unique ways. It accommodated differences in temperament and readiness, managed internal conflict, and strived to emerge as a cohesive unit. Individual struggles were often magnified or, more often, ameliorated by family context. Caregiving itself formed a legacy for future generations. Finally, care was seen as bidirectional, being tendered both by the family caregivers and in turn by the patient. CONCLUSIONS: When talking about care for serious illness, individuals report both rewards and challenges, often in a family context. The family enterprise manages a loved one's care, negotiates the health-care system, and adjusts its own internal dynamics. Integrating the family narrative provides a more balanced view of the family system that provides the day-to-day care for individuals with serious illness. PMID- 28662596 TI - Influence of drug colour on perceived drug effects and efficacy. AB - A drug's physical characteristics, such as colour, could be factors influencing its therapeutic effects. It is not well understood whether people's expectations on drug effects and efficacy are affected by colour, especially among Chinese population. This study was conducted to examine people's expectations on drug effects and efficacy on the basis of drug colour, and to reveal possible gender differences in colour-related drug expectations. Participants (n = 224) were asked to classify seven single-coloured and six two-coloured capsules into one of four categories of drug effects, and to indicate the strength of drug efficacy. It is found that all the coloured capsules yielded non-chance distributions in classifications of drug effects, with six single-coloured and four two-coloured capsules associated with specific drug effects. Colour also conveyed differential strengths of drug efficacy in general and in relation to specific drug effects. There were gender differences in drug expectations for some colours and colour combinations. Practitioner Summary: Drug colour was found to have impacts on perceived drug effects and efficacy. The findings from the present study can be used by ergonomics practitioners to design appropriate drug colours in support of drug differentiation, therapeutic effects and medication adherence. PMID- 28662595 TI - Fatigue and depression predict reduced health-related quality of life in childhood-onset lupus. AB - We aimed to identify risk factors for persistently reduced health-related quality of life in childhood-onset lupus and describe a risk profile for persistently reduced health-related quality of life. At a tertiary rheumatology clinic, 50 childhood onset lupus patients were assessed twice, approximately six months apart. Measures of disease activity and patient-reported measures of health related quality of life, pain, depressive symptoms, anxiety and disability were collected at each visit. At visits 1 and 2, respectively, clinically relevant fatigue was present in 66% and 56% of patients; clinically significant depressive symptoms in 26% and 24%; and clinically significant anxiety in 34% and 28%. Poorer health-related quality of life at follow-up was significantly predicted by higher fatigue and depressive symptoms at the initial visit. Using clinically relevant cut-offs for fatigue and depressive symptoms, patients were assigned to Low ( n = 27) or High Risk ( n = 23) groups. A profile of significantly greater pain, anxiety and coping difficulties was seen in the High Risk group. Routine assessment of fatigue and mood symptoms in youth with childhood-onset lupus could be helpful in identifying those at risk for persistently poor health-related quality of life. Integration of behavioral interventions to address fatigue and mood symptoms into medical care for such patients may be beneficial, but more research in this area is needed. PMID- 28662597 TI - Biochar application mode influences nitrogen leaching and NH3 volatilization losses in a rice paddy soil irrigated with N-rich wastewater. AB - Impacts of biochar application mode on nitrogen (N) leaching, ammonia (NH3) volatilization, rice grain yield and N use efficiency (NUE) are not well understood. Therefore, a field experiment was conducted to evaluate those impacts in a rice paddy soil received 225 kg N ha-1 from either urea or N-rich wastewater. One treatment received 10 t ha-1 biochar with the basal fertilization, and the other received same total amount of biochar but split applied with the three split N applications with same ratio as N fertilizer split ratio (40%, 30% and 30%). Results showed that N leaching loads were 4.20-6.22 kg ha-1. Biochar one-time application reduced N leaching by 23.1%, and biochar split application further reduced N leaching by 32.4%. Total NH3 volatilization loss was 15.5-24.5 kg ha-1. Biochar one-time application did not influence the NH3 volatilization, but biochar split application stimulated the cumulative NH3 volatilization by 57.7%. Both biochar treatments had no influence on NUE and rice grain yield. In conclusion, biochar application mode indeed influences the N leaching and NH3 volatilization in rice paddy soils, and biochar one-time application should be recommended for reducing N leaching without increasing NH3 volatilization. PMID- 28662598 TI - Comparing the effects of clinician and caregiver-administered lexical retrieval training for progressive anomia. AB - There is a growing body of literature indicating that lexical retrieval training can result in improved naming ability in individuals with neurodegenerative disease. Traditionally, treatment is administered by a speech-language pathologist, with little involvement of caregivers or carry-over of practice into the home. This study examined the effects of a lexical retrieval training programme that was implemented first by a clinician and, subsequently, by a trained caregiver. Two dyads, each consisting of one individual with anomia caused by neurodegenerative disease (one with mild cognitive impairment and one with logopenic primary progressive aphasia) and their caregiver, participated in the study. Results indicated medium and large effect sizes for both clinician- and caregiver-trained items, with generalisation to untrained stimuli. Participants reported improved confidence during communication as well as increased use of trained communication strategies after treatment. This study is the first to document that caregiver-administered speech and language intervention can have positive outcomes when paired with training by a clinician. Caregiver-administered treatment may be a viable means of increasing treatment dosage in the current climate of restricted reimbursement, particularly for patients with progressive conditions. PMID- 28662599 TI - Hair growth promoting activity of discarded biocomposite keratin extract. AB - Keratin biomaterial has been used in regenerative medicine owing to its in-vivo and in-vitro biocompatibility. The present study was aimed to investigate the hair growth promoting activity of keratin extract and its mechanism of action. Keratin extract was topically applied on the synchronized depilated dorsal skin of telogenic C57BL/6 mice and promoted hair growth by inducing the anagen phase. The histomorphometric observation indicated significantly increases the number, shaft of hair follicles and deep subcutis area in the keratin extract treated group in contrast to the control group, which was considered an indication of anagen phase induction. Subsequently, the quantitative real-time polymerase chain reaction analysis revealed that fibroblast growth factor-10, vascular endothelial growth factor, insulin-like growth factor-1, beta-catenin, and Shh were expressed earlier in the keratin extract-treated group than in the control group. Besides, keratin extract has been observed to be biocompatible when analyzed with 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 4',6-diamidino-2 phenylindole staining using immortalized human keratinocyte cells, showing more than 90% cell viability. Our study demonstrated that keratin extract stimulating hair follicle growth by inducing the growth phase; anagen in telogenic C57BL/6 mice and thus the topical application of keratin extract may represent a promising biomaterial for the management and applications of hair follicle disorder. PMID- 28662600 TI - Risk factors for vasovagal reaction associated with cerebral angiography via femoral catheterisation. AB - Objective To analyse the related risk factors for vasovagal reaction associated with cerebral angiography via femoral catheterisation and discuss treatment measures and prevention and control methods. Methods The data of 3107 patients on whom cerebral angiography was performed in two high-volume interventional neuroradiology centres within 8 years were retrospectively analysed. Patients were divided into the vasovagal reaction and non-vasovagal reaction groups according to whether vasovagal reaction developed. The two groups' clinical data were analysed using univariate and multivariate logistic regression analysis to examine vasovagal reaction-related factors. Results Of the 3107 patients included, 127 developed vasovagal reaction (4.09%). Of the 127 patients who developed vasovagal reaction, 123, three and one had vasovagal reaction after sheath removal, during cerebral angiography and upon femoral artery compression device removal, respectively. Differences in age, body mass index, sex ratios, proportions of patients with hypertension, diabetes and hyperlipemia, and adoption rate of femoral artery compression device were not statistically significant between the two groups ( P > 0.05). Compared with the control group, the vasovagal reaction group had a significantly longer preoperative fasting time ( P < 0.05). Multivariate logistic regression analysis revealed preoperative fasting time as the only risk factor for vasovagal reaction that was associated with cerebral angiography ( P < 0.001). Conclusion Excessive fasting time before cerebral angiography is the most important risk factor for vasovagal reaction associated with cerebral angiography. PMID- 28662602 TI - Racial/ethnic disparities in disability outcomes among post-acute home care patients. AB - OBJECTIVE: To examine activities of daily living (ADL) disability outcomes among racially/ethnically diverse elders receiving home care (HC) after hospitalization. METHOD: We conducted a retrospective cohort analysis of single agency, 2013-2014 Outcome and Assessment Information Set data from older adults who received post-hospitalization HC ( n = 20,674). We measured overall change in ADL disability by summing the difference of standardized admission and discharge scores from nine individual ADL. Associations between race/ethnicity and overall ADL change scores were modeled using general linear regression, adjusting for covariates consistent with the Disablement Model. RESULTS: Overall, patients experienced improvement in ADL disability from HC admission to discharge. However, Asian, African American, and Hispanic patients experienced significantly less improvement compared with non-Hispanic Whites (all p < .001), even after controlling for covariates. DISCUSSION: Racial/ethnic disparities exist in ADL disability improvement among HC patients. Research is needed to clarify mechanisms underlying these disparities. Disablement Model factors may be targets for clinical intervention. PMID- 28662601 TI - A Discrete Event Simulation Model of Patient Flow in a General Hospital Incorporating Infection Control Policy for Methicillin-Resistant Staphylococcus Aureus (MRSA) and Vancomycin-Resistant Enterococcus (VRE). AB - BACKGROUND: Hospitalized patients are assigned to available staffed beds based on patient acuity and services required. In hospitals with double-occupancy rooms, patients must be additionally matched by gender. Patients with methicillin resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) must be bedded in single-occupancy rooms or cohorted with other patients with similar MRSA/VRE flags. METHODS: We developed a discrete event simulation (DES) model of patient flow through an acute care hospital. Patients are matched to beds based on acuity, service, gender, and known MRSA/VRE colonization. Outcomes included time to bed arrival, length of stay, patient-bed acuity mismatches, occupancy, idle beds, acuity-related transfers, rooms with discordant MRSA/VRE colonization, and transmission due to discordant colonization. RESULTS: Observed outcomes were well-approximated by model-generated outcomes for time-to-bed arrival (6.7 v. 6.2 to 6.5 h) and length of stay (3.3 v. 2.9 to 3.0 days), with overlapping 90% coverage intervals. Patient-bed acuity mismatches, where patient acuity exceeded bed acuity and where patient acuity was lower than bed acuity, ranged from 0.6 to 0.9 and 8.6 to 11.1 mismatches per h, respectively. Values for observed occupancy, total idle beds, and acuity-related transfers compared favorably to model-predicted values (91% v. 86% to 87% occupancy, 15.1 v. 14.3 to 15.7 total idle beds, and 27.2 v. 22.6 to 23.7 transfers). Rooms with discordant colonization status and transmission due to discordance were modeled without an observed value for comparison. One-way and multi-way sensitivity analyses were performed for idle beds and rooms with discordant colonization. CONCLUSIONS: We developed and validated a DES model of patient flow incorporating MRSA/VRE flags. The model allowed for quantification of the substantial impact of MRSA/VRE flags on hospital efficiency and potentially avoidable nosocomial transmission. PMID- 28662603 TI - Carbon dioxide from geothermal gas converted to biomass by cultivating coccoid cyanobacteria. AB - The Blue Lagoon is a geothermal aquifer with a diverse ecosystem located within the Reykjanes UNESCO Global Geopark on Iceland's Reykjanes Peninsula. Blue Lagoon Ltd., which exploits the aquifer, isolated a strain of coccoid cyanobacteria Cyanobacterium aponinum (C. aponinum) from the geothermal fluid of the Blue Lagoon more than two decades ago. Since then Blue Lagoon Ltd. has cultivated it in a photobioreactor, for use as an active ingredient in its skin care products. Until recently, the cultivation of C. aponinum was achieved by feeding it on 99.99% (4N) bottled carbon dioxide (CO2). In this investigation, C. aponinum was cultivated using unmodified, non-condensable geothermal gas (geogas) emitted from a nearby geothermal powerplant as the feed-gas instead of the 4N-gas. The geogas contains roughly 90% vol CO2 and 2% vol hydrogen sulfide (H2S). A comparison of both CO2 sources was made. It was observed that the use of geogas did enhance the conversion efficiency. A 13 weeks' average CO2 conversion efficiency of C. aponinum was 43% and 31% when fed on geogas and 4N-gas, respectively. Despite the high H2S concentration in the geogas, sulfur accumulation in the cultivated biomass was similar for both gas sources. Our results provide a model of a CO2 sequestration by photosynthetic conversion of otherwise unused geothermal emission gas into biomass. PMID- 28662605 TI - Incidence and risk factors of biliary fistulation from a hepatic hydatid cyst in clinically asymptomatic patients. AB - Biliary fistulation from a hepatic hydatid cyst is its most frequent complication. If unrecognised, this may cause difficulties during and after surgical intervention. Our study looked into its incidence and also the possible risk factors in a retrospective investigation of 60 patients (34 women) who had undergone surgery or percutaneous treatment. Demographics and anatomical characteristics, such as cyst type, location, number, diameter and laboratory findings were examined. A full 50% had biliary fistulation, with increased risk if the cyst diameter was >=8.8 cm. PMID- 28662606 TI - Patients With Vasculitides Admitted to the Intensive Care Unit: Implications From a Single-Center Retrospective Study. AB - BACKGROUND: Vasculitides are a group of disorders characterized by inflammation of vessels. Vasculitides may have life-threatening complications with significant morbidity and mortality; however, information regarding the outcome and prognosis of patients with vasculitides requiring intensive care unit (ICU) is scarce. METHODS: Data of patients with vasculitides admitted to the ICU of the Sheba Medical Center between the years 2000 and 2014 were retrieved retrospectively. Continuous variables were computed as mean (standard deviation), whereas categorical variables were recorded as percentages. In order to investigate the impact of clinical variables on mortality, Student t test and chi2 analyses were performed. RESULTS: Twenty-five patients with vasculitides were admitted to the ICU during the study period with mean age of 52 +/- 14 years and sex ratio of male/female: 12/13. The mortality rate among these patients was 48%. Leading causes for ICU admission were infection (64%), disease exacerbation (34%), and hemorrhage (16%), while respiratory or cardiovascular involvement accounted for the majority of mortality during admission. An elevated Sequential Organ Failure Assessment (SOFA) score was significantly associated with mortality ( P = .041). CONCLUSION: Our study confirms the high mortality rate among patients with vasculitides who require ICU care as well as the roles of infection and disease flare-up as causes for admission. An elevated SOFA score was found to be predictive of mortality. PMID- 28662607 TI - Integrating Fat Embolism Syndrome Scoring Indices in Sickle Cell Disease: A Practice Management Review. AB - Fat embolism syndrome (FES) has been described in the literature as a rare complication of sickle cell disease (SCD). A review article published in 2005 reported 24 cases of FES associated with SCD. In many cases, a definitive diagnosis of FES in SCD is made on autopsy because of the lack of early recognition and the paucity of sensitive and specific testing for this syndrome. Patients with FES usually have a fulminant, rapidly deteriorating clinical course with mortality occurring within the first 24 hours. We postulate that FES is not well recognized in SCD and that FES scores are useful diagnostic tools in patients with SCD. We queried the electronic medical records with the diagnostic codes for SCD with acute chest syndrome (ACS), pulmonary embolism, or acute respiratory distress syndrome admitted to our hospital from 2008 to 2016 to identify patients suspected of having FES. In addition, we performed an extensive literature review to evaluate the management practice of pediatric patients with FES and SCD from 1966 to 2016. Six patients met our selection criteria from the hospital records, and 4 case reports from the literature search were also included. We applied the Gurd and Wilson criteria and the Schonfeld Fat Embolism Index to identify patients who met the criteria for FES. Nine patients fulfilled Gurd and Wilson criteria, and 9 patients who were evaluable met the Schonfeld criteria for FES. A rapidly deteriorating clinical course in a patient with SCD presenting with ACS or severe vaso-occlusive crisis should trigger a high index of suspicion for FES. Gurd and Wilson criteria or the Schonfeld Fat Embolism Index are useful diagnostic tools for FES in SCD. PMID- 28662608 TI - Scotland: a changing prescription for pharmacy. AB - Within primary care in Scotland, the community pharmacist is considered the first port of call for advice on minor ailments and public health issues, and providing care for people with long-term conditions. This leading article explores the educational pathway underpinning the training of these pharmacists and pharmacists working in GP practices, as they move from undergraduate through Foundation to undertake significant new patient-focused clinical roles. NHS Education for Scotland (NES) are working with these pharmacists to support these developments. In Scotland pharmacists and their teams are now very much part of the primary care team providing high quality pharmaceutical care to patients on the high street and in GP practices. PMID- 28662609 TI - Rapid degradation of FOG discharged from food industry wastewater by lipolytic fungi as a bioaugmentation application. AB - Fats, oils and grease (FOG) congregate in grease traps and are a slowly biodegradable particulate organic matter, which may require enzymatic or hydrolytic conversion to form readily biodegradable soluble organic matter. The existing treatment methods employ water-based hydrolysis of FOG to form long chain fatty acids (LCFAs). The LCFAs discharged into wastewater treatment system create functional difficulties, especially the inhibitory effect caused by accumulation of LCFAs. This study aims to find an effective treatment method for this persistent problem encountered in conventional wastewater treatment system. Solid-state degradation by lipolytic fungi was performed in a tray-type reactor as a novel approach of bioaugmentation. Grease trap waste samples were dried to have moisture content of 25-35% and mixed with coir fiber (1% w/v) for proper aeration. Each 10 mg/g dry weight of substrate was inoculated with 1 mL of spore suspension (1 * 107 spores/mL) of lipolytic fungi. Thereafter, moisture content in the reactor was increased to 65%, and incubated at 30 degrees C. Within 72 h of post incubation, degradation efficiency of about 50% was recorded by fungal isolates. The feasibility of using developed protocol for FOG degradation was tested with a laboratory-scale prototype reactor. PMID- 28662610 TI - 'Church hurt can be the worst hurt': community stakeholder perceptions of the role of Black churches in HIV prevention among young Black gay and bisexual men. AB - Black gay and bisexual men aged 15-29 are disproportionately represented among new cases of HIV in the USA. Researchers have argued that community-based prevention cannot succeed without the participation of faith-based organisations, particularly given the salience of religion and spirituality in the lives of young Black gay and bisexual men. Yet some Black churches may be hesitant to engage in HIV prevention efforts given their beliefs about same-sex behaviour. It is less clear, however, whether and how public health practitioners in the field of HIV prevention have approached church inclusion. We therefore explored how community stakeholders describe the involvement of Black churches with the HIV continuum of care. We draw on a qualitative dataset of 50 in-depth semi structured interviews conducted in Detroit, USA. Participants offered multiple perspectives on the response of Black churches to the HIV epidemic, from overt stigma to gradual acceptance and action. Nevertheless, participants agreed that when stigma was present in the pews and the pulpit, young Black gay and bisexual men were at potential risk of social isolation. Furthermore, tensions may exist between Black churches and secular community-based organisations that are attributable to histories of mistrust. These findings have important implications for future community-based intervention strategies among young Black gay and bisexual men. PMID- 28662611 TI - Cognition and anatomy of adult Niemann-Pick disease type C: Insights for the Alzheimer field. AB - Niemann-Pick disease type C (NPC) is a rare lysosomal storage disorder causing an intracellular lipid trafficking defect and varying damage to the spleen, liver, and central nervous system. The adult form, representing approximately 20% of the cases, is associated with progressive cognitive decline. Intriguingly, brains of adult NPC patients exhibit neurofibrillary tangles, a characteristic hallmark of Alzheimer's disease (AD). However, the cognitive, psychiatric, and neuropathological features of adult NPC and their relation to AD have yet to be explored. We systematically reviewed the literature on adult NPC with a particular focus on cognitive and neuroanatomical abnormalities. The careful study of cognition in adult NPC allows drawing critical insights in our understanding of the pathophysiology of AD as well as normal cognition. PMID- 28662612 TI - The Effect of Cognitive Control on Different Types of Auditory Distraction. AB - Deviant as well as changing auditory distractors interfere with short-term memory. According to the duplex model of auditory distraction, the deviation effect is caused by a shift of attention while the changing-state effect is due to obligatory order processing. This theory predicts that foreknowledge should reduce the deviation effect, but should have no effect on the changing-state effect. We compared the effect of foreknowledge on the two phenomena directly within the same experiment. In a pilot study, specific foreknowledge was impotent in reducing either the changing-state effect or the deviation effect, but it reduced disruption by sentential speech, suggesting that the effects of foreknowledge on auditory distraction may increase with the complexity of the stimulus material. Given the unexpected nature of this finding, we tested whether the same finding would be obtained in (a) a direct preregistered replication in Germany and (b) an additional replication with translated stimulus materials in Sweden. PMID- 28662613 TI - Pilot Study Comparing 2 Oral Rehydration Solutions in Patients With Short Bowel Syndrome Receiving Home Parenteral Nutrition: A Prospective Double-Blind Randomized Controlled Trial. AB - BACKGROUND: Short bowel syndrome (SBS) is a common indication for home parenteral nutrition (HPN). Oral rehydration solutions (ORSs) have the ability to supplement or reduce HPN dependence. However, ORSs have suffered from poor taste profiles, making long-term consumption and compliance unlikely. The goal of the current study was to assess the taste and compliance of 2 ORSs among patients with SBS requiring HPN. METHODS: All participants with SBS receiving HPN with anticipated duration >3 months were offered enrollment: 31 participants met inclusion criteria; 3 declined enrollment; and 28 were randomized to receive a modified World Health Organization ORS (group A) or a commercially available ORS (DripDrop; group B). RESULTS: Six participants dropped out shortly after randomization (3 in each group) due to poor taste or intolerance. An additional 3 (1 in group A and 2 in group B) discontinued the ORS before the end of the study at 6 months. At the end of the study, 19 remained. The mean taste rating given by the participants was, on a scale of 1-10, 7.3 +/- 1.9 for group A and 7.6 +/- 1.6 for group B ( P = .61). The mean number of days that ORSs were consumed each week was 6.0 +/- 1.3 for group A and 6.6 +/- 1 days for group B ( P = .06). CONCLUSION: Taste rating was not different for both ORSs; however, a significant number of participants did not complete the study. PMID- 28662614 TI - Thromboelastography in term neonates. AB - BACKGROUND: Thromboelastography (TEG) is utilized as a point-of-care test of coagulation function to improve evidence-based blood product replacement in adults. In contrast to standard indices of coagulation, TEG reflects the dynamic interactions among the elements involved in hemostasis, including fibrinolysis. Although normal adult values and various abnormalities have been characterized, normative values for term neonates have not been described. Studies of neonatal TEG remain limited and have small sample sizes with inconsistent methodology. The aim of this study is to provide normative data on healthy term neonates, and to assess the impact of mode of delivery on TEG parameters at term. METHODS: Venous umbilical blood was obtained from the placenta within 10 min of delivery. TEG analysis of citrated kaolin-activated samples was performed for 50 healthy term vaginal and 50 cesarean deliveries. Samples collected for cesarean sections were from scheduled cases or unscheduled ones due to failure of progression of labor. RESULTS: Healthy neonates with uncomplicated vaginal term deliveries resulted in the following TEG parameters: R: 5.41 +/- 1.34 (mean +/- SD) min; K: 1.62 +/- 0.75 min; alpha-angle: 65.39 +/- 8.77 degrees ; MA: 65.86 +/- 5.81 mm; and LY30: 1.40 +/- 1.18%. Results for the cesarean delivery neonatal TEG assays showed: R: 5.51 +/- 1.74 (mean +/- SD) min; K: 1.52 +/- 0.47 min; alpha-angle: 64.15 +/- 4.61 degrees ; MA: 64.15 +/- 4.61 mm; and LY30: 2.44 +/- 3.51%. Of note, no statistical differences were observed (p < .01) between the groups. CONCLUSION: TEG measurements from term neonates were no different when the neonates were delivered vaginally or by cesarean section. Labor had no effect on neonatal TEG levels. Neonatal TEG values may therefore serve as insight for fetal values at the appropriate postconceptional age. PMID- 28662615 TI - Editor's Presentation. PMID- 28662616 TI - Facilitation of creative performance by using blue and red accent lighting in work and learning areas. AB - Research has shown that colours influence motivation and cognitive performance. In achievement contexts, red evokes avoidance motivation that hinders creativity, while blue elicits an approach motivation that facilitates creativity. However, due to their position and mode of presentation, colours may convey a different message. Red accent lighting creates a cosy, friendly room atmosphere that may, even in an achievement context, elicit an approach rather than an avoidance motivation. Results (N = 146) showed that both blue and red accent light increased strategic approach motivation compared to white accent light. Moreover, through the heightened approach motivation, colourful accent light indirectly improved creative performance. Implications for future research on colour and practical implications for colour usage are discussed. Practitioner Summary: Designing work environments for creativity is a new topic in ergonomics research and practice. The present study demonstrates indirect effects of coloured accent light on creativity providing interesting possibilities for the design of workplaces for knowledge workers, classrooms and all other rooms in which people work on new ideas. PMID- 28662617 TI - Both sides of the story: Addiction is not a pastime activity. AB - The proposed inclusion of Internet gaming disorder (IGD) into the upcoming ICD-11 has caused mixed reactions. Having a sound diagnostic framework for defining this new phenomenon has been applauded but concerns have risen regarding overpathologizing a mere pastime activity. The review by Aarseth et al. (2016) provides a fine but one-sided impression on IGD. What has been totally left out in the argumentation is the clinical perspective. Although the concerns depicted must not be ignored, the conclusion provided by the authors is reflecting quite subjective speculations while objectivity would rather be needful. PMID- 28662618 TI - Efficacy of face-to-face versus self-guided treatments for disordered gambling: A meta-analysis. AB - Background and aims In the light of growing traditional and novel forms of gambling, the treatment of disordered gambling is gaining increasing importance and practical relevance. Most studies have examined face-to-face treatments. Although trials implementing self-guided treatments have recently been conducted, these options have not yet been systematically examined. The primary objective of this meta-analysis, therefore, was to analyze the efficacy of all types of psychological face-to-face and self-guided treatments. Methods A multilevel literature search yielded 27 randomized controlled studies totaling 3,879 participants to provide a comprehensive comparative evaluation of the short- and long-term efficacies of face-to-face and self-guided treatments for disordered gambling. Results As expected, the results revealed significantly higher effect sizes for face-to-face treatments (16 studies with Hedges's g ranging from 0.67 to 1.15) as compared with self-guided treatments (11 studies with Hedges's g ranging from 0.12 to 0.30) regarding the reduction of problematic gambling behavior. The intensity of treatment moderated the therapy effect, particularly for self-guided treatments. Discussion and Conclusions The results of this meta analysis favor face-to-face treatments over self-guided treatments for the reduction of disordered gambling. Although the findings broaden the scope of knowledge about psychological treatment modalities for disordered gambling, further research is needed to identify the reasons for these differences with the goal to optimize the treatment for this disabling condition. PMID- 28662619 TI - DSM-5 diagnosis of Internet Gaming Disorder: Some ways forward in overcoming issues and concerns in the gaming studies field. AB - Background and aims The current DSM-5 diagnosis of Internet Gaming Disorder (IGD; American Psychiatric Association [APA], 2013) has led to a number of issues and concerns that we highlighted in our recent paper (Kuss, Griffiths, & Pontes, 2017). Experts in the field responded to our evaluation of these issues resulting in six commentaries. Methods In this paper, we offer responses to the six commentaries to move the scientific field forward. All of the responses to our original paper highlighted many conceptual, theoretical, and/or methodological problems with the proposed IGD diagnosis as outlined in the DSM-5. We outline some ways forward in overcoming issues and concerns in the gaming studies field. Results We argue that rather than stigmatizing gaming per se, the role of scientists and practitioners is to establish a clear-cut distinction between someone who may use games excessively but non-problematically and someone who is experiencing significant impairment in their daily lives as a consequence of their excessive gaming. This responsibility needs to be shared by popular media who are often quick to build a moral panic around gaming behaviors, often based on cherry-picking specific case studies and pieces of research which support their headlines. Conclusion Researchers, practitioners, gaming developers, and the media need to work together and collaboratively to build a realistic and comprehensive understanding of gaming as a normal, enjoyable, and often beneficial sociocultural practice, which for a small minority of excessive users may be associated with the experience of addiction-related symptoms that may require professional support. PMID- 28662620 TI - Multisubstrate specific flavin containing monooxygenase from Chlorella pyrenoidosa with potential application for phenolic wastewater remediation and biosensor application. AB - Microbial degradation of phenolic pollutants in industrial wastewater is dependent on enzymatic pathway comprising a cascade of phenol metabolizing enzymes. Phenol hydroxylase is the first enzyme of the pathway catalysing the initial attack on phenol in green algae Chlorella pyrenoidosa. The present work reports cost-effective production of partially purified microalgal phenol hydroylase by single-step purification and characterization of its kinetic properties with the view of application for enzyme-based remediation of phenolic wastewater or in phenolic biosensor. The enzyme with a molecular weight of 25 kDa shows all characteristics of phenol hydroxylases, that is, hydroxylation of phenol to catechol (confirmed by HPLC), substrate-dependent NADPH oxidation, absorption spectrum typical of flavoproteins and peptide mass fingerprint corresponding to flavoprotein hydroxylase. The enzyme utilizes phenol with apparent Michealis constant (Km) of 1.71 uM, maximal velocity (Vmax) of 0.4 uM/min with optimal activity at pH 7 and 35 degrees C. Fe2+chelators (Phenanthroline and sodium arsenate), heavy metals, denaturants and oxidizing agents showed inhibitory effect on phenol hydroxylation activity of the enzyme. The enzyme has broad substrate specificity against isomeric diphenols, isomeric methylphenols, halogen-substituted phenols, amino-substituted phenols, nitrophenols, hydroxybenzaldehyde and hydroxylbenzoic acid. The enzyme shows remarkable storage stability at room temperature and at 4 degrees C. The multisubstrate specificity coupled to remarkable storage stability of the microalgal phenol hydroxylase opens up avenues for its application in remediation of a wide range of phenolics released in industrial wastewater or phenolic biosensor application. PMID- 28662621 TI - Diabetes Camp Counselors: An Exploration of Counselor Characteristics and Quality of Life Outcomes. AB - Purpose The purpose of this study is to investigate the effect of volunteering at a diabetes camp on emerging adults with and without type 1 diabetes mellitus (T1DM). Methods Thirty counselors with and 22 without T1DM (19.07 +/- 2.71 years old) volunteered at a 1-week T1DM camp in the northeastern United States. Counselors with T1DM had a range of self-reported A1C scores (5.8% or 39.9 mmol/mol to 14.0% or 129.5 mmol/mol). Self-report measures of quality of life, hope, and well-being were completed pre- and postcamp at 4 time points: 1 month before camp, arrival at camp, final day of camp, and 2 months postcamp. Open ended questions regarding counselor experiences were analyzed to understand camp effect. Results There were significant differences between counselors' levels of trait hope in comparison to published norms. There were few clear differences in psychosocial outcomes pre- and postcamp; however, some increases in well-being were revealed in anticipation of camp. Major reasons for volunteering included assisting others and reciprocating or continuing a perceived positive experience as a camper. Conclusion No changes in psychosocial outcomes pre- to postcamp were observed. However, measures used in this study may be poorly defined for a counselor population. Further research on the characteristics of emerging adults who choose to be camp counselors is needed. By understanding the demographics of this population, health professionals can help target individuals to become camp counselors as well as enhance the camp experience to fit their developmental needs. PMID- 28662622 TI - Determinants of Home Death in Patients With Cancer: A Population-Based Study in Ontario, Canada. AB - AIM: To determine factors associated with home death in patients with cancer in Ontario, particularly to assess the association between death at home and (1) patients' rural/urban residence and (2) neighborhood income in urban areas. MATERIALS AND METHODS: We conducted a retrospective cross-sectional study in Ontario (2003-2010) using linked administrative databases. In order to account for clustering phenomenon, multivariable generalized estimating equation model was used to evaluate factors associated with home death. Analysis was performed in both rural and urban areas. For urban areas, neighborhood income was tested as a determinant of the place of death. RESULTS: A total of 193 783 deaths were analyzed, 9.1% of which occurred at home. In urban areas, home death was more likely for patients living in richer neighborhoods (odds ratio 1.69 for the highest compared to lowest neighborhood income quintile, 95% confidence interval: 1.54-1.86). The odds of dying at home when living in a rural area were no different from those living in the poorest urban neighborhood. Other variables associated with lower odds of home death were comorbidity index, certain cancers, and year of death. CONCLUSION: The likelihood of dying at home significantly increases with living in higher-income urban neighborhoods and decreases with rural residence. Urban neighborhoods with lowest income have odds of home death similar to rural areas. These findings underline the importance of targeting proper populations for public support at the end of life. PMID- 28662623 TI - Engagement of Primary Care Physicians in Home Palliative Care. AB - PURPOSE: To describe prevalence and characteristics associated with family physician and general practitioner (FP/GP) provision of home palliative care (HPC). METHODS: We surveyed FP/GPs in an urban health region of Ontario, Canada, to determine their current involvement in HPC, the nature of services provided, and perceived barriers and enablers. RESULTS: A total of 1439 surveys were mailed. Of the 302 FP/GP respondents, 295 provided replies regarding engagement in HPC: 101 of 295 (33%) provided HPC, 76 (26%) were engageable with further support, and 118 (40%) were not engageable regardless of support. The most substantial barrier was time to provide home visits (81%). Engaged FP/GPs were most likely to be working with another physician providing HPC ( P < .0001). Engageable FP/GPs were younger ( P = .007) and placed greater value on improved remuneration ( P < .001) than the other groups. Nonengageable physicians were most likely to view time as a barrier ( P < .0001) and to lack interest in PC ( P = .03). CONCLUSION: One-third of FP/GPs provide HPC. A cohort of younger physicians could be engageable with adequate support. Integrated practices including collaboration with specialist PC colleagues should be encouraged and supported. PMID- 28662624 TI - Interference Between Family Caregivers' Mental Disorders and Their Estimates of Quality of Dying and Death (QODD) of Their Loved Ones. AB - BACKGROUND: In studies enrolling informal caregivers of patients in palliative care, it is necessary to ensure that findings are not influenced by factors such as mental disorders. AIM: This study aims to describe the influence of anxiety and depression on bereaved informal caregivers' retrospective ratings of the quality of dying and death (QoDD) of their loved ones. DESIGN: Informal caregivers of deceased patients from 2 German palliative care (PC) units took part in a validation study of the German version of the original QoDD-Deutsch Angehorige (QoDD-D-Ang) during the fourth week following the patient's death at the earliest. Depressive and panic disorders were assessed via the Patient Health Questionnaire (PHQ). Group comparisons (chi2, t test; significance level P < .05) analyzed whether informal caregivers with depression or panic disorders and those without such disorders differ in their estimates. RESULTS: A total of 226 informal caregivers participated between August 2012 and December 2013. The mean age of participants was 55.5 years; 61.1% were female. The PHQ of 221 participants resulted in 8.6% with major disorders, 13.6% with other depressive syndromes, and 77.8% without depressive disorders. In this secondary data analysis here, there was no difference between female and male participants concerning the incidence of depression ( P = .519, chi2). Two participants screened positive for both panic and major depressive disorders. Both groups presented no significant differences in the mean total QoDD-D-Ang scores ( P = .343). CONCLUSION: Informal caregivers' estimates on the QoDD-D-Ang of their significant others do not interfere with mental disorders. Therefore, bereaved informal caregivers are able to participate in the PC research after a few weeks following the loss of a loved one. PMID- 28662625 TI - Oxycodone in Palliative Care-Art and Empathy Still Have a Place. AB - A 47-year-old woman who was receiving palliative care for metastatic breast cancer, which included oxycodone, was found dead in bed. The femoral blood level of oxycodone at autopsy was 1200 ug/L, which is a value within the lethal range. Could the cause of death be attributed to misadventure or suicide? Would the coroner consider a recommendation of therapeutic drug monitoring in palliative care which could have a serious negative impact on pain relief practice? A narrative verdict was the outcome linking the primary cause of death with the drug cocktail found at autopsy. PMID- 28662626 TI - Expert Discussion on Taking a Spiritual History. AB - This article elaborates on the hazards of spiritual history taking. It provides expert insights to consider before entering the field. In summer 2012, a group of spiritual care experts were invited to discuss the complexity of taking spiritual histories in a manner of hermeneutic circle. Thematic analysis was applied to define the emerging themes. The results demonstrate that taking a spiritual history is a complex and challenging task, requiring a number of personal qualities of the interviewer, such as 'being present', 'not only hearing, but listening', 'understanding the message beyond the words uttered', and 'picking up the words to respond'. To 'establish a link of sharing', the interviewer is expected 'to go beyond the ethical stance of neutrality'. The latter may cause several dilemmas, such as 'fear of causing more problems', 'not daring to take it further', and above all, 'being ambivalent about one's role'. Interviewer has to be careful in terms of the 'patient's vulnerability'. To avoid causing harm, it is essential to propose 'a follow-up contract' that allows responding to 'patient's yearning for genuine care'. These findings combined with available literature suggest that the quality of spiritual history taking will remain poor unless the health-care professionals revise the meaning of spirituality and the art of caring on individual level. PMID- 28662627 TI - Continuous Palliative Sedation for Existential Distress? A Survey of Canadian Palliative Care Physicians' Views. AB - BACKGROUND: Palliative sedation can be used for refractory symptoms during end-of life care. However, continuous palliative sedation (CPS) for existential distress remains controversial due to difficulty determining when this distress is refractory. OBJECTIVES: The aim was to determine the opinions and practices of Canadian palliative care physicians regarding CPS for existential distress. METHODS: A survey focusing on experience and views regarding CPS for existential distress was sent to 322 members of the Canadian Society of Palliative Care Physicians. RESULTS: Eighty-one surveys returned (accessible target, 314), resulting in a response rate of 26%. One third (31%) of the respondents reported providing CPS for existential distress. On a 5-point Likert-type scale, 40% of participants disagreed, while 43% agreed that CPS could be used for existential distress alone. CONCLUSION: Differing opinions exist regarding this complex and potentially controversial issue, necessitating the education of health-care professionals and increased awareness within the general public. PMID- 28662628 TI - Diversity and evolution of mariner-like elements in aphid genomes. AB - BACKGROUND: Although transposons have been identified in almost all organisms, genome-wide information on mariner elements in Aphididae remains unknown. Genomes of Acyrthosiphon pisum, Diuraphis noxia and Myzus persicae belonging to the Macrosiphini tribe, actually available in databases, have been investigated. RESULTS: A total of 22 lineages were identified. Classification and phylogenetic analysis indicated that they were subdivided into three monophyletic groups, each of them containing at least one putative complete sequence, and several non autonomous sublineages corresponding to Miniature Inverted-Repeat Transposable Elements (MITE), probably generated by internal deletions. A high proportion of truncated and dead copies was also detected. The three clusters can be defined from their catalytic site: (i) mariner DD34D, including three subgroups of the irritans subfamily (Macrosiphinimar, Batmar-like elements and Dnomar-like elements); (ii) rosa DD41D, found in A. pisum and D. noxia; (iii) a new clade which differs from rosa through long TIRs and thus designated LTIR-like elements. Based on its catalytic domain, this new clade is subdivided into DD40D and DD41D subgroups. Compared to other Tc1/mariner superfamily sequences, rosa DD41D and LTIR DD40-41D seem more related to maT DD37D family. CONCLUSION: Overall, our results reveal three clades belonging to the irritans subfamily, rosa and new LTIR-like elements. Data on structure and specific distribution of these transposable elements in the Macrosiphini tribe contribute to the understanding of their evolutionary history and to that of their hosts. PMID- 28662629 TI - In vitro optical quality measurements of three intraocular lens models having identical platform. AB - BACKGROUND: With recent advances in technology and introduction of new intraocular lens (IOL) models, surgeons today have the opportunity to choose from various optical designs, which can influence the postoperative quality of vision. In our laboratory study, we compared the optical quality of three different IOLs that use the identical platform and are produced by the same manufacturer. The study included two diffractive multifocal IOLs, a bifocal and a trifocal one, as well as a monofocal IOL. METHODS: Three IOL models: monofocal CT ASPHINA 409 M, diffractive bifocal AT LISA 809 M, and diffractive trifocal AT LISA Tri 839MP (Carl Zeiss Meditec AG, Germany) were assessed for optical quality by measuring modulation transfer function (MTF) and Strehl Ratio (SR) values at pupil sizes of 3.0 and 4.5 mm on the OptiSpheric(r) IOL PRO (Trioptics GmbH, Germany). The United States Air Force (USAF) Target images were also recorded to comfirm the optical performance qualitatively. RESULTS: For far focus at 50 lp/mm and 3.0 mm pupil size, MTF value of the monofocal lens (MTF = 0.798) was 1.8-fold and 2.1 fold better than the bifocal (MTF = 0.446) and the trifocal (MTF = 0.382) IOLs, respectively. For near focus, bifocal IOL (MTF = 0.265) was 1.4-fold better than trifocal IOL (MTF = 0.187), while for intermediate focus, the trifocal IOL (MTF = 0.148) was 1.7-fold better than the bifocal IOL (MTF = 0.086). For the same pupil size, total sum of light loss amounted to 5.2% for the monofocal, 16.0% for the bifocal and 6.0% for the trifocal IOL. For a larger pupil, the amount of light loss increased significantly for the multifocal IOLs. CONCLUSIONS: The monofocal IOL performed the best for far, the bifocal IOL for near and the trifocal IOL for intermediate focus. While the monofocal IOL created the least amount of light loss for both pupil sizes, the trifocal IOL created less than half the amount of light loss than the bifocal IOL for small pupil. For large pupil, however, less light scatter was observed for the bifocal than the trifocal IOL. PMID- 28662630 TI - Sequence differences in the seed dormancy gene Qsd1 among various wheat genomes. AB - BACKGROUND: Pre-harvest sprouting frequently occurs in Triticum aestivum (wheat) and Hordeum vulgare (barley) at the end of the maturity period due to high rainfall, particularly in Asian monsoon areas. Seed dormancy is a major mechanism preventing pre-harvest sprouting in these crops. RESULTS: We identified orthologous sequences of the major Hordeum vulgare (barley) seed dormancy gene Qsd1 in hexaploid wheat cv. Chinese Spring by performing genomic clone sequencing, followed by transcript sequencing. We detected 13 non-synonymous amino acid substitutions among the three sub-genomes of wheat and found that the Qsd1 sequence in the B sub-genome is most similar to that in barley. The Qsd1 sequence in A genome diploid wheat is highly similar to that in the hexaploid A sub-genome. Wheat orthologs of Qsd1 showed closer similarities to barley Qsd1 than did those of other accessions in the DNA database. Like barley Qsd1, all three wheat Qsd1s showed embryo-specific gene expression patterns, indicating that barley and wheat Qsd1 share an orthologous origin. The alignment of four hexaploid wheat cultivars indicated that the amino acid sequences of three spring cultivars, Chinese Spring, Haruyo Koi, and Fielder, are exactly the same in each sub-genome. Only Kitahonami has three amino acid substitutions at the B sub genome. CONCLUSIONS: Kitahonami has a longer seed dormancy period than does Chinese Spring. Sequence polymorphisms between Chiniese Spring and Kitahonami in the B sub-genome may underlie the phenotypic differences in seed dormancy between these hexaploid wheat cultivars. PMID- 28662631 TI - A case of neuropsychiatric lupus Erythematosus characterized by the Owl's eye sign: a case report. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder characterized by multiple affected systems. More than half of SLE patients will suffer from neuropsychiatric lupus erythematosus (NPSLE) during the course of their disease. Although nearly half of the NPSLE patients have normal MRI manifestations, the abnormalities found in the remainder can be located anywhere in the brain, and especially in the subcortical white matter of the frontal and temporal lobe. However, NPSLE involving the medulla oblongata and spinal cord which presents as the "owl's eye" sign has to our best knowledge not been reported to date. CASE PRESENTATION: A 19-year-old girl presented at our hospital with a 7-day history of fever and headache since a one day's exertion, accompanied by 2 days of weakness. The patient had slurred speech. Neurological examination revealed the presence of horizontal nystagmus and a limitation of bilateral eye movement when looking up and down. At the same time, she showed difficulty in raising the jaw, accompanied by a weak pharyngeal reflex. Muscle strength was remarkably decreased in all four extremities: the MRCS grade of the upper limbs was 4/5, while in the lower limbs it was 0/5. Hypotonia was apparent in the lower extremities. Regarding subjective sensation, the patient appeared to be experiencing an increased sense of pain in the whole body, and especially in the cervical region, abdomen, and feet. An examination of shallow reflex documented the reinforcement of the abdominal reflex. Deep tendon reflexes were symmetric: absent in lower, normal in upper extremities. The patient also had a stiff neck with a positive Kernig's sign. The laboratory examination showed elevated C - reactive protein and rheumatoid factor, as well as complement components 3 and 4. Symptomatic treatments were applied, but she did not respond well, after which we did immunological laboratory examinations. The results showed the presence of anti-nRNP/Sm, anti-dsDNA and anti-AMA M2 antibodies. An MRI scan and enhancement of the cervical and thoracic regions displayed abnormal signs in the medulla and bilateral anterior horn of the lower thoracic spine. Following the exclusion of other possible diseases, neuropsychiatric lupus was diagnosed. High-dose intravenous gamma-globulin combined with methylprednisolone gradually improved her condition. CONCLUSION: We report the first case of NPSLE presenting with medulla oblongata and spinal cord involvement, manifesting as the "owl's eye" sign in MRI. PMID- 28662632 TI - Timing of delivery in a high-risk obstetric population: a clinical prediction model. AB - BACKGROUND: The efficacy of antenatal corticosteroid treatment for women with threatened preterm birth depends on timely administration within 7 days before delivery. We modelled the probability of delivery within 7 days of admission to hospital among women presenting with threatened preterm birth, using routinely collected clinical characteristics. METHODS: Data from the Canadian Perinatal Network (CPN) were used, 2005-11, including women admitted to hospital with preterm labour, preterm pre-labour rupture of membranes, short cervix without contractions, or dilated cervix or prolapsed membranes without contractions at preterm gestation. Women with fetal anomaly, intrauterine fetal demise, twin-to twin transfusion syndrome, and quadruplets were excluded. Logistic regression was undertaken to create a predictive model that was assessed for its calibration capacity, stratification ability, and classification accuracy (ROC curve). RESULTS: We included 3012 women admitted at 24-28 weeks gestation, or readmitted at up to 34 weeks gestation, to 16 tertiary-care CPN hospitals. Of these, 1473 (48.9%) delivered within 7 days of admission. Significant predictors of early delivery included maternal age, parity, gestational age at admission, smoking, preterm labour, prolapsed membranes, preterm pre-labour rupture of membranes, and antepartum haemorrhage. The area under the ROC curve was 0.724 (95% CI 0.706 0.742). CONCLUSION: We propose a useful tool to improve prediction of delivery within 7 days after admission among women with threatened preterm birth. This information is important for optimal corticosteroid treatment. PMID- 28662633 TI - RNA-Seq study reveals genetic responses of diverse wild soybean accessions to increased ozone levels. AB - BACKGROUND: Ozone is an air pollutant widely known to cause a decrease in productivity in many plant species, including soybean (Glycine max (L.) Merr). While the response of cultivated soybean to ozone has been studied, very little information is available regarding the ozone response of its wild relatives. RESULTS: Ozone-resistant wild soybean accessions were identified by measuring the response of a genetically diverse group of 66 wild soybean (Glycine soja Zucc. and Sieb.) accessions to elevated ozone levels. RNA-Seq analyses were performed on leaves of different ages from selected ozone-sensitive and ozone-resistant accessions that were subjected to treatment with an environmentally relevant level of ozone. Many more genes responded to elevated ozone in the two ozone sensitive accessions than in the ozone-resistant accessions. Analyses of the ozone response genes indicated that leaves of different ages responded differently to ozone. Older leaves displayed a consistent reduction in expression of genes involved in photosynthesis in response to ozone, while changes in expression of defense genes dominated younger leaf tissue in response to ozone. As expected, there is a substantial difference between the response of ozone sensitive and ozone-resistant accessions. Genes associated with photosystem 2 were substantially reduced in expression in response to ozone in the ozone resistant accessions. A decrease in peptidase inhibitors was one of several responses specific to one of the ozone resistant accessions. CONCLUSION: The decrease in expression in genes associated with photosynthesis confirms that the photosynthetic apparatus may be an early casualty in response to moderate levels of ozone. A compromise of photosynthesis would substantially impact plant growth and seed production. However, the resistant accessions may preserve their photosynthetic apparatus in response to the ozone levels used in this study. Older leaf tissue of the ozone-resistant accessions showed a unique down regulation of genes associated with endopeptidase inhibitor activity. This study demonstrates the existence of significant diversity in wild soybean for ozone response. Wild soybean accessions characterized in this study can be used by soybean breeders to enhance ozone tolerance of this important food crop. PMID- 28662634 TI - Healthy dietary patterns decrease the risk of colorectal cancer in the Mecca Region, Saudi Arabia: a case-control study. AB - BACKGROUND: Colorectal cancer (CRC) is the first most common cancer in males and the third most common cancer in females in Saudi Arabia. Dietary habits are strongly associated with the inhibition or proliferation of malignancy. Therefore, this study is aiming to investigate the risks and protective benefits of dietary factors affecting CRC in the Mecca region of Saudi Arabia. METHODS: A case-control study was conducted from June 2014 to March 2015. One hundred thirty seven patients with colon and/or rectal cancer were recruited in the case group, while 164 healthy participants were recruited in the control group. A questionnaire was completed with the help of trained dietitians to study the effects of several dietary patterns on the risk of CRC. RESULTS: Dairy product intake of 1-5 servings/day, legume intake of 3-5 servings/week, leafy vegetables intake of 1-5 servings/week, olive oil intake of 1-5 servings/week, black tea intake of three or more cups/day, and coffee intake of one or more cups/day was found to decrease the risk of CRC in participants. CONCLUSION: This study highlights the importance of changing dietary habits to decrease CRC incidence in the Mecca region. PMID- 28662635 TI - An alternative technique for Descemet's membrane detachment following phacoemulsification: case report and review of literature. AB - BACKGROUND: Descemet's membrane detachment (DMD) is one of the most serious complications of modern cataract surgery. We present an alternative technique for management of DMD with a review of the literature on current strategies for the treatment of DMD. CASE PRESENTATION: A 74-year-old woman developed DMD after phacoemulsification and failed the first descemetopexy with air tamponade. An alternative method was used to drain the pre-descematic fluid and reposition the detached Descemet's membrane in this rare case. This technique involved completely filling the anterior chamber with an intracameral air injection, followed by using a 23-gauge needle to puncture the peripheral cornea to drain the pre-descematic fluid. The Descemet's membrane was completely reattached to the stroma during the follow-up. CONCLUSIONS: Drainage of pre-descematic fluid combined with intracameral air tamponading was used as an alternative surgical option for the management of this severe case of DMD. PMID- 28662636 TI - Relating genomic characteristics to environmental preferences and ubiquity in different microbial taxa. AB - BACKGROUND: Despite the important role that microorganisms play in environmental processes, the low percentage of cultured microbes (5%) has limited, until now, our knowledge of their ecological strategies. However, the development of high throughput sequencing has generated a huge amount of genomic and metagenomic data without the need of culturing that can be used to study ecological questions. This study aims to estimate the functional capabilities, genomic sizes and 16S copy number of different taxa in relation to their ubiquity and their environmental preferences. RESULTS: To achieve this goal, we compiled data regarding the presence of each prokaryotic genera in diverse environments. Then, genomic characteristics such as genome size, 16S rRNA gene copy number, and functional content of the genomes were related to their ubiquity and different environmental preferences of the corresponding taxa. The results showed clear correlations between genomic characteristics and environmental conditions. CONCLUSIONS: Ubiquity and adaptation were linked to genome size, while 16S copy number was not directly related to ubiquity. We observed that different combinations of these two characteristics delineate the different environments. Besides, the analysis of functional classes showed some clear signatures linked to particular environments. PMID- 28662637 TI - The role of metacognition and obsessive-compulsive symptoms in psychosis: an analogue study. AB - BACKGROUND: Several studies have indicated that obsessive-compulsive disorder (OCD) is a common comorbidity in patients with psychotic disorders, but there is sparse knowledge about the relationship between symptoms of OCD and psychotic symptoms. Metacognitions which guides thinking and coping is theorized to be a transdiagnostic component central for development and maintenance of psychological disorders, OCD and psychosis included. The aim of the study was therefore to explore how symptoms of OCD and metacognitions relate to symptoms of psychosis. Our main hypotheses were that metacognitions would be significantly related to all symptoms of psychological distress, and that there is considerable overlap between symptoms of psychosis and OCD. METHODS: Community controls (N = 194) completed an internet survey measuring levels of paranoid ideation, predisposition to hallucinations, symptoms of OCD, depression, anxiety, and metacognitions. Correlations and hierarchical multiple linear regression analyses were used to unveil the relationship between symptoms and beliefs. RESULTS: Symptoms of OCD showed a strong positive correlation with symptoms of psychosis, and the relationships were still significant after controlling for symptoms of anxiety and depression. Metacognitions also showed strong positive correlations with all symptom measures. Metacognition and OCD-symptoms accounted for 53.8% of the variance in paranoid ideation and 43.8% of predisposition to hallucinations. There was a large overlap between symptoms of psychosis, OCD-symptoms, and metacognitions (30.2-37.3%). CONCLUSIONS: In general, the results suggest considerable overlap between paranoid ideation, predisposition to hallucinations, and OCD and metacognitive beliefs in a non-clinical sample. Further experimental- and clinical studies are needed in order to explore metacognitive models of OCD and psychosis. PMID- 28662638 TI - How life stressors influence modifiable lifestyle factors, depressive symptoms, and physical and mental health among Vietnamese older women? AB - BACKGROUND: Research has demonstrated that exposure to life stressors can influence health through a number of pathways. However, knowledge about the patterns of life stressors and their contributions to health in different populations is limited. Vietnamese older women have attracted little research to date in this area. METHODS: This cross-sectional study used an interview administered-questionnaire to collect data from 440 Vietnamese older women. Descriptive analysis was used to describe life stressors among Vietnamese older women. Binary analysis and Structural Equation Modelling statistical analysis were used to examine the influences of life stressors on modifiable lifestyle factors, depressive symptoms, physical and mental health among Vietnamese older women. RESULTS: Vietnamese older women in this study commonly reported the experience of losing a close person, including a baby/child, serious health or money problems, violence and disaster. Among the study participants, (1) exposure to more life stressors increased their depressive symptoms, and decreased their physical and mental health; (2) exposure to more life stressors also increased their physical health by increasing their physical activity levels. CONCLUSION: Life stressors influenced health among Vietnamese older women through different pathways. Interventions to manage stress and depressive symptoms are required for Vietnamese older women in the future. PMID- 28662639 TI - Equitable resourcing of primary health care in remote communities in Australia's Northern Territory: a pilot study. AB - BACKGROUND: Improved Primary Health Care (PHC) utilisation is central to reducing the unacceptable morbidity and mortality rates characterising populations living in remote communities. Despite poorer health, significant inequity characterises the funding of PHC services in Australia's most remote areas. This pilot study sought to ascertain what funding is required to ensure equitable access to sustainable, high quality primary health care irrespective of geographical remoteness of communities. METHODS: High performing remote Primary Health Care (PHC) services were selected using improvement measures from the Australian Primary Care Collaboratives Program and validated by health experts. Eleven PHC services provided data relating to the types of services provided, level of service utilisation, human resources, operating and capital expenses. A further four services that provide visiting PHC to remote communities provided information on the level and cost of these services. Demographic data for service catchment areas (including estimated resident population, age, Indigenous status, English spoken at home and workforce participation) were obtained from the Australian Bureau of Statistics 2011 census. Formal statistical inference (p values) were derived in the linear regression via the nonparametric bootstrap. RESULTS: A direct linear relationship was observed between the total cost of resident PHC services and population, while cost per capita decreased with increasing population. Services in smaller communities had a higher number of nursing staff per 1000 residents and provided more consultations per capita than those in larger communities. The number of days of visiting services received by a community each year also increased with population. A linear regression with bootstrapped statistical inference predicted a significant regression equation where the cost of resident services per annum is equal to $1,251,893.92 + ($1698.83 x population) and the cost of resident and visiting services is equal to $1,378,870.85 + ($2600.00 x population). CONCLUSIONS: The research findings provide empirical evidence based on real costs to guide funding for remote PHC services that takes into account the safety and equity requirements for a minimum viable service. This method can be used as a transparent, coordinated approach to ensure the equitable delivery of sustainable, high quality PHC in remote communities. This will in turn contribute to improved health outcomes. PMID- 28662640 TI - Community analysis of biofilms on flame-oxidized stainless steel anodes in microbial fuel cells fed with different substrates. AB - BACKGROUND: The flame-oxidized stainless steel anode (FO-SSA) is a newly developed electrode that enhances microbial fuel cell (MFC) power generation; however, substrate preference and community structure of the biofilm developed on FO-SSA have not been well characterized. Herein, we investigated the community on FO-SSA using high-throughput sequencing of the 16S rRNA gene fragment in acetate , starch-, glucose-, and livestock wastewater-fed MFCs. Furthermore, to analyze the effect of the anode material, the acetate-fed community formed on a common carbon-based electrode-carbon-cloth anode (CCA)-was examined for comparison. RESULTS: Substrate type influenced the power output of MFCs using FO-SSA; the highest electricity was generated using acetate as a substrate, followed by peptone, starch and glucose, and wastewater. Intensity of power generation using FO-SSA was related to the abundance of exoelectrogenic genera, namely Geobacter and Desulfuromonas, of the phylum Proteobacteria, which were detected at a higher frequency in acetate-fed communities than in communities fed with other substrates. Lactic acid bacteria (LAB)-Enterococcus and Carnobacterium-were predominant in starch- and glucose-fed communities, respectively. In the wastewater-fed community, members of phylum Planctomycetes were frequently detected (36.2%). Exoelectrogenic genera Geobacter and Desulfuromonas were also detected in glucose-, starch-, and wastewater-fed communities on FO-SSA, but with low frequency (0-3.2%); the lactate produced by Carnobacterium and Enterococcus in glucose- and starch-fed communities might affect exoelectrogenic bacterial growth, resulting in low power output by MFCs fed with these substrates. Furthermore, in the acetate-fed community on FO-SSA, Desulfuromonas was abundant (15.4%) and Geobacter had a minor proportion (0.7%), while in that on CCA, both Geobacter and Desulfuromonas were observed at similar frequencies (6.0-9.8%), indicating that anode material affects exoelectrogenic genus enrichment in anodic biofilm. CONCLUSIONS: Anodic community structure was dependent on both substrate and anode material. Although Desulfuromonas spp. are marine microorganisms, they were abundant in the acetate-fed community on FO-SSA, implying the presence of novel non-halophilic and exoelectrogenic species in this genus. Power generation using FO-SSA was positively related to the frequency of exoelectrogenic genera in the anodic community. Predominant LAB in saccharide-fed anodic biofilm caused low abundance of exoelectrogenic genera and consequent low power generation. PMID- 28662641 TI - Antenatal depressive symptoms and utilisation of delivery and postnatal care: a prospective study in rural Ethiopia. AB - BACKGROUND: Uptake of delivery and postnatal care remains low in Low and Middle Income Countries (LMICs), where 99% of global maternal deaths take place. However, the potential impact of antenatal depression on use of institutional delivery and postnatal care has seldom been examined. This study aimed to examine whether antenatal depressive symptoms are associated with use of maternal health care services. METHODS: A population-based prospective study was conducted in Sodo District, Southern Ethiopia. Depressive symptoms were assessed during pregnancy with a locally validated, Amharic version of the Patient Health Questionnaire (PHQ-9). A cut off score of five or more indicated possible depression. A total of 1251 women were interviewed at a median of 8 weeks (4-12 weeks) after delivery. Postnatal outcome variables were: institutional delivery care utilization, type of delivery, i.e. spontaneous or assisted, and postnatal care utilization. Multivariate logistic regression was used to examine the association between antenatal depressive symptoms and the outcome variables. RESULTS: High levels of antenatal depressive symptoms (PHQ score 5 or higher) were found in 28.7% of participating women. Nearly two-thirds, 783 women (62.6%), delivered in healthcare institutions. After adjusting for potential confounders, women with antenatal depressive symptoms had increased odds of reporting institutional birth [adjusted Odds Ratio (aOR) =1.42, 95% Confidence Interval (CI): 1.06, 1.92] and increased odds of reporting having had an assisted delivery (aOR = 1.72, 95% CI: 1.10, 2.69) as compared to women without these symptoms. However, the increased odds of institutional delivery among women with antenatal depressive symptoms was associated with unplanned delivery care use mainly due to emergency reasons (aOR = 1.62, 95% CI: 1.09, 2.42) rather than planning to deliver in healthcare institutions. CONCLUSION: Improved detection and treatment of antenatal depression has the potential to increase planned institutional delivery and reduce perinatal complications, thus contributing to a reduction in maternal morbidity and mortality. PMID- 28662642 TI - Integrated transcriptomics and metabolomics analysis to characterize cold stress responses in Nicotiana tabacum. AB - BACKGROUND: CB-1 and K326 are closely related tobacco cultivars; however, their cold tolerance capacities are different. K326 is much more cold tolerant than CB 1. RESULTS: We studied the transcriptomes and metabolomes of CB-1 and K326 leaf samples treated with cold stress. Totally, we have identified 14,590 differentially expressed genes (DEGs) in CB-1 and 14,605 DEGs in K326; there was also 200 differentially expressed metabolites in CB-1 and 194 in K326. Moreover, there were many overlapping genes (around 50%) that were cold-responsive in both plant cultivars, although there were also many differences in the cold responsive genes between the two cultivars. Importantly, for most of the overlapping cold responsive genes, the extent of the changes in expression were typically much more pronounced in K326 than in CB-1, which may help explain the superior cold tolerance of K326. Similar results were found in the metabolome analysis, particularly with the analysis of primary metabolites, including amino acids, organic acids, and sugars. The large number of specific responsive genes and metabolites highlight the complex regulatory mechanisms associated with cold stress in tobacco. In addition, our work implies that the energy metabolism and hormones may function distinctly between CB-1 and K326. CONCLUSIONS: Differences in gene expression and metabolite levels following cold stress treatment seem likely to have contributed to the observed difference in the cold tolerance phenotype of these two tobacco cultivars. PMID- 28662643 TI - E3 ubiquitin ligase, RNF139, inhibits the progression of tongue cancer. AB - BACKGROUND: Tongue cancer is still one of the leading causes of mortality around the world. Recently, the ubiquitin system has been established as a critical modulator of tumors. In order to find the oral cancer related E3 ubiquitin ligases, we screened the human E3 ubiquitin ligase library and found that RING finger protein 139 (RNF139) regulated the biological behavior of tongue cancer cells. METHODS: MTT assay was used to analyze the cell viability changes of tongue cancer SCC9 and SCC25 cells caused by RNF139. The invasion ability of SCC9 and SCC25 cells with or without the knockdown of RNF139 was evaluated through transwell assay. The immunoblotting was recruited to determine the expression level of RNF139 in human tongue cancer tissues and para-carcinoma tissues. The effect of RNF139 on tumorigenicity of tongue cancer cells was analyzed by xenograft model on immunodeficient Balb/c nude mice. RESULTS: Overexpression of RNF139 inhibits the viability of tongue cancer cells since day 2. The colony formation ability of SCC9 and SCC25 cells was also decreased with the overexpression of RNF139. Knockdown of RNF139 significantly promoted the invasion ability of SCC9 and SCC25 cells. Furthermore, knockdown of RNF139 also induced the activation of AKT signaling pathway. While human tongue cancer tissues had low expression of RNF139. In nude mice, knockdown of RNF139 promoted the tumorigenicity of the SCC25 cells. CONCLUSIONS: Our data establish a role for RNF139 in regulating the progression of tongue cancer. PMID- 28662644 TI - Robot-assisted radical prostatectomy significantly reduced biochemical recurrence compared to retro pubic radical prostatectomy. AB - BACKGROUND: The pathological and oncological outcomes of retro-pubic radical prostatectomy (RRP) and robot-assisted radical prostatectomy (RARP) have not been sufficiently investigated. METHODS: Treatment-naive patients with localized prostate cancer (PC) (n = 908; RRP, n = 490; and RARP, n = 418) were enrolled in the study. The clinicopathological outcomes, rate and localization of the positive surgical margin (PSM), localization of PSM, and biochemical recurrence (BCR)-free survival groups were compared between RRP and RARP. RESULTS: The median patient age and serum PSA level (ng/mL) at diagnosis were 67 years and 7.9 ng/ml, respectively, for RRP, and 67 years and 7.6 ng/ml, respectively, for RARP. The overall PSM rate with RARP was 21%, which was 11% for pT2a, 12% for pT2b, 9.8% for pT2c, 43% for pT3a, 55% for pT3b, and 0% for pT4. The overall PSM rate with RRP was 44%, which was 12% for pT2a, 18% for pT2b, 43% for pT2c, 78% for pT3a, 50% for pT3b, and 40% for pT4. The PSM rate was significantly lower for RARP in men with pT2c and pT3a (p < 0.0001 for both). Multivariate analysis showed that RARP reduced the risk of BCR (hazard ratio; 0.6, p = 0.009). CONCLUSIONS: RARP versus RRP is associated with an improved PSM rate and BCR. To examine the cancer-specific survival, further investigations are needed. PMID- 28662645 TI - Measuring women's childbirth experiences: a systematic review for identification and analysis of validated instruments. AB - BACKGROUND: Women's childbirth experience can have immediate as well as long-term positive or negative effects on their life, well-being and health. When evaluating and drawing conclusions from research results, women's experiences of childbirth should be one aspect to consider. Researchers and clinicians need help in finding and selecting the most suitable instrument for their purpose. The aim of this study was therefore to systematically identify and present validated instruments measuring women's childbirth experience. METHODS: A systematic review was conducted in January 2016 with a comprehensive search in the bibliographic databases PubMed, CINAHL, Scopus, The Cochrane Library and PsycINFO. Included instruments measured women's childbirth experiences. Papers were assessed independently by two reviewers for inclusion, and quality assessment of included instruments was made by two reviewers independently and in pairs using Terwee et al's criteria for evaluation of psychometric properties. RESULTS: In total 5189 citations were screened, of which 5106 were excluded by title and abstract. Eighty-three full-text papers were reviewed, and 37 papers were excluded, resulting in 46 included papers representing 36 instruments. These instruments demonstrated a wide range in purpose and content as well as in the quality of psychometric properties. CONCLUSIONS: This systematic review provides an overview of existing instruments measuring women's childbirth experiences and can support researchers to identify appropriate instruments to be used, and maybe adapted, in their specific contexts and research purpose. PMID- 28662646 TI - Effect of transmission intensity on hotspots and micro-epidemiology of malaria in sub-Saharan Africa. AB - BACKGROUND: Malaria transmission intensity is heterogeneous, complicating the implementation of malaria control interventions. We provide a description of the spatial micro-epidemiology of symptomatic malaria and asymptomatic parasitaemia in multiple sites. METHODS: We assembled data from 19 studies conducted between 1996 and 2015 in seven countries of sub-Saharan Africa with homestead-level geospatial data. Data from each site were used to quantify spatial autocorrelation and examine the temporal stability of hotspots. Parameters from these analyses were examined to identify trends over varying transmission intensity. RESULTS: Significant hotspots of malaria transmission were observed in most years and sites. The risk ratios of malaria within hotspots were highest at low malaria positive fractions (MPFs) and decreased with increasing MPF (p < 0.001). However, statistical significance of hotspots was lowest at extremely low and extremely high MPFs, with a peak in statistical significance at an MPF of ~0.3. In four sites with longitudinal data we noted temporal instability and variable negative correlations between MPF and average age of symptomatic malaria across all sites, suggesting varying degrees of temporal stability. CONCLUSIONS: We observed geographical micro-variation in malaria transmission at sites with a variety of transmission intensities across sub-Saharan Africa. Hotspots are marked at lower transmission intensity, but it becomes difficult to show statistical significance when cases are sparse at very low transmission intensity. Given the predictability with which hotspots occur as transmission intensity falls, malaria control programmes should have a low threshold for responding to apparent clustering of cases. PMID- 28662647 TI - A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE). AB - BACKGROUND: We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease. METHODS/DESIGN: Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory. DISCUSSION: The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016. PMID- 28662648 TI - Prevalence of high, medium and low-risk medical conditions for pneumococcal vaccination in Catalonian middle-aged and older adults: a population-based study. AB - BACKGROUND: Updated population-based data on the frequency and distribution of risk factors for pneumococcal disease is scarce. This study investigated the prevalence of distinct comorbidities and underlying risk conditions related to an increasing risk of pneumococcal disease among Catalonian middle-aged and older adults. METHODS: Cross-sectional population-based study including 2,033,465 individuals aged 50 years or older registered at 01/01/2015 in the Catalonian Health Institute (Catalonia, Spain). The clinical research database of the Information System for the Development of Research in Primary Care (SIDIAP database) was used to identify high-risk (asplenia and/or immunocompromising conditions) and other increased-risk conditions (chronic pulmonary, cardiac or liver disease, diabetes mellitus, alcoholism and/or smoking) among study subjects. RESULTS: Globally, 980,310 (48.2%) of the 2,033,465 study population had at least one risk condition of suffering pneumococcal disease (55.4% in men vs 42.0% in women, p < 0.001; 41.7% in people 50-64 years vs 54.7% in persons 65 years or older, p < 0.001). An amount of 176,600 individuals (8.7%) had high-risk conditions (basically immunocompromising conditions). On the other hand, 803,710 persons (39.5%) had one or more other risk conditions. In fact, 212,255 (10.4%) had chronic pulmonary diseases, 248,377 (12.2%) cardiac disease, 41,734 (2.1%) liver disease, 341,535 (16.8%) diabetes mellitus, 58,781 (2.9%) alcoholism and 317,558 (15.6%) were smokers. CONCLUSION: In our setting, approximately 50 % of overall persons 50 years or older may be considered at-risk population for pneumococcal disease (almost 10 % have high-risk conditions and 40 % have other risk conditions). PMID- 28662649 TI - Use of generic and essential medicines for prevention and treatment of cardiovascular diseases in Portugal. AB - BACKGROUND: The successful control of cardiovascular diseases at the lowest possible cost requires the use of the most effective and affordable medicines. We aimed to describe the trends in the ambulatory use of medicines for prevention and treatment of cardiovascular diseases [Anatomic Therapeutic Chemical classification system (ATC): C and B01A] in Portugal, between 2004 and 2012, and to estimate the potential for expenditure reduction through changes in patterns of use. METHODS: We analysed sell-out data, expressed as defined daily doses (DDD) and pharmacy retail price (?), from a nationwide database. We estimated potential reduction in expenditures through the increase, up to 90% of the volume of DDD, in the use of generic and essential medicines; the latter were defined according to guidelines from Portugal and another European country. RESULTS: Overall consumption increased by approximately 50% from 2004 to 2012, reaching nearly 2400 million DDD, whereas expenditure decreased to 753 million ? (-31.3% since 2006). Use of generics and essential medicines increased, representing 43.6 and 39.9% of DDD consumption in 2012, respectively. The 40 most used groups of medicines in 2012 accounted for just over 80% of overall consumption; among these, increase in use of generics and essential medicines would have contributed to a saving of 275 million ?. CONCLUSIONS: Changes in patterns of consumption of medicines towards a more frequent use of generics, a preferential use of essential medicines and a more rational use of fixed-dose combinations may contribute to a more efficient use of health resources. PMID- 28662650 TI - Non-imported malaria in non-endemic countries: a review of cases in Spain. AB - Spain declared the elimination of malaria in 1964. In non-endemic areas, the overwhelming majority of malaria cases are acquired abroad, and locally acquired infections are rare events. In Spain, malaria is a statutorily notifiable disease. During these fifty years more than ten thousand malaria cases have been reported, and about 0.8% of them did not have a history of recent travel. In this report, it was carried out a review of the ways in which malaria can be transmitted in non-endemic areas and a short description of the Spanish cases, aggregated by their transmission mechanisms. Four cases contracted malaria by mosquito bites; there were two autochthonous cases and two of "airport malaria". The other 28 cases were: congenital malaria cases, transfusion-transmitted malaria, post-transplant cases, nosocomial transmission and cases in intravenous drug users. In addition, in 1971 there was an outbreak of 54 cases due to exposure to blood or blood products. So, while malaria usually is an imported disease in non-endemic areas, it should not be excluded in the differential diagnosis of persons who have fever of unknown origin, regardless of their travel history. PMID- 28662651 TI - Erratum to: The refractive state of the eye in Icelandic horses with the Silver mutation. PMID- 28662653 TI - Motivations for participating in a non-interventional gender-based violence survey in a low-income setting in South Africa. AB - BACKGROUND: Qualitative study of motivations to participate in research into violence and other sensitive issues can help interpretation of findings from community based quantitative surveys. It is equally important to conduct research that may enable a deeper understanding on what motivates people to participate in GBV studies. To date, not much research has been conducted to investigate the factors that influence non-enrolment and enrolment in GBV studies from the viewpoint of the real participants. The present study sought to explore people's reasons for participating in a non-intervention GBV community-based survey in Gauteng province, South Africa. METHODS: Twenty-two qualitative in-depth interviews were conducted with adult black African men and women who had participated in a gender-based violence survey conducted in a low-income setting in South Africa. RESULTS: Some participants reported motives for survey participation which could be interpreted as altruistic. Their motives included a desire to contribute to advancement of knowledge and to share life experiences so that unknown others could learn from these experiences. Yet, some participants hoped their participation will result in personal benefit or that they may be helped with their socio-economic challenges. The analysis further revealed a complex relationship between altruism and self-interest motives for participating in the survey amongst some of the participants. CONCLUSION: We conclude that it is difficult to discern which motive was primary or preceded the other. This is because such motives are not fixed, probably multiple and owing to their fluidity, may shift in people's minds at different times and depending on the nature of the conversation. Moreover, there may be a shift in the weight given to different motives over time. PMID- 28662652 TI - The Korean Study of Women's Health-Related Issues (K-Stori): Rationale and Study Design. AB - BACKGROUND: Measures to address gender-specific health issues are essential due to fundamental, biological differences between the sexes. Studies have increasingly stressed the importance of customizing approaches directed at women's health issues according to stages in the female life cycle. In Korea, however, gender-specific studies on issues affecting Korean women in relation to stages in their life cycle are lacking. Accordingly, the Korean Study of Women's Health-Related Issues (K-Stori) was designed to investigate life cycle-specific health issues among women, covering health status, awareness, and risk perceptions. METHODS: K-Stori was conducted as a nationwide cross-sectional survey targeting Korean women aged 14-79 years. Per each stage in the female life cycle (adolescence, childbearing age, pregnancy & postpartum, menopause, and older adult stage), 3000 women (total 15,000) were recruited by stratified multistage random sampling for geographic area based on the 2010 Resident Registration Population in Korea. Specialized questionnaires per each stage (total of five) were developed in consultation with multidisciplinary experts and by reflecting upon current interests into health among the general population of women in Korea. This survey was conducted from April 1 to June 31, 2016, at which time investigators from a professional research agency went door-to-door to recruit residents and conducted in-person interviews. DISCUSSION: The study's findings may help with elucidating health issues and unmet needs specific to each stage in the life cycle of Korean women that have yet to be identified in present surveys. PMID- 28662654 TI - Monitoring and evaluation of disaster response efforts undertaken by local health departments: a rapid realist review. AB - BACKGROUND: Local health departments are often at the forefront of a disaster response, attending to the immediate trauma inflicted by the disaster and also the long term health consequences. As the frequency and severity of disasters are projected to rise, monitoring and evaluation (M&E) efforts are critical to help local health departments consolidate past experiences and improve future response efforts. Local health departments often conduct M&E work post disaster, however, many of these efforts fail to improve response procedures. METHODS: We undertook a rapid realist review (RRR) to examine why M&E efforts undertaken by local health departments do not always result in improved disaster response efforts. We aimed to complement existing frameworks by focusing on the most basic and pragmatic steps of a M&E cycle targeted towards continuous system improvements. For these purposes, we developed a theoretical framework that draws on the quality improvement literature to 'frame' the steps in the M&E cycle. This framework encompassed a M&E cycle involving three stages (i.e., document and assess, disseminate and implement) that must be sequentially completed to learn from past experiences and improve future disaster response efforts. We used this framework to guide our examination of the literature and to identify any context mechanism-outcome (CMO) configurations which describe how M&E may be constrained or enabled at each stage of the M&E cycle. RESULTS: This RRR found a number of explanatory CMO configurations that provide valuable insights into some of the considerations that should be made when using M&E to improve future disaster response efforts. Firstly, to support the accurate documentation and assessment of a disaster response, local health departments should consider how they can: establish a culture of learning within health departments; use embedded training methods; or facilitate external partnerships. Secondly, to enhance the widespread dissemination of lessons learned and facilitate inter-agency learning, evaluation reports should use standardised formats and terminology. Lastly, to increase commitment to improvement processes, local health department leaders should possess positive leadership attributes and encourage shared decision making. CONCLUSION: This study is among the first to conduct a synthesis of the CMO configurations which facilitate or hinder M&E efforts aimed at improving future disaster responses. It makes a significant contribution to the disaster literature and provides an evidence base that can be used to provide pragmatic guidance for improving M&E efforts of local health departments. TRIAL REGISTRATION: PROSPERO 2015: CRD42015023526 . PMID- 28662655 TI - Identification, characterization and purification of porcine Quiescin Q6 Sulfydryl Oxidase 2 protein. AB - BACKGROUND: Post-spermiogenesis membrane surface modifications rely on molecules present in the reproductive tracts. Two isoforms (isoform 1 and 2) from Quiescin Q6-Sulfydryl Oxidase protein family have been identified in the male reproductive tract of rodent species. However, unlike isoform 1, scarce information is available for isoform 2, likely due to its lower expression level and lack of proper purification methods to obtain sufficient protein quantity for further assays. RESULTS: This study demonstrated the presence of short and long forms of Quiescin Q6-Sulfydryl Oxidase 2 in boar, likely representing the secretory (short form) and transmembrane (long form) forms of Quiescin Q6-Sulfydryl Oxidase 2. Immunohistochemistry studies revealed the presence of Quiescin Q6-Sulfydryl Oxidase 2 in a broad range of porcine tissues; the pronounced vesicle-contained Quiescin Q6-Sulfydryl Oxidase 2 at the apical region of epididymis and seminal vesicles epithelium suggested its involvement in sperm physiology and its participation in semen formation. The majority of porcine Quiescin Q6-Sulfydryl Oxidase 2 could be purified via either antibody affinity column or be salted out using 10%-40% ammonium sulfate. Higher amount of low molecular weight Quiescin Q6 Sulfydryl Oxidase 2 observed in the seminal vesicle likely represents the secretory form of Quiescin Q6-Sulfydryl Oxidase 2 and reflects an exuberant secretory activity in this organ. CONCLUSIONS: We demonstrated for the first time, the presence of Quiescin Q6-Sulfydryl Oxidase 2 in porcine species; moreover, two forms of Quiescin Q6-Sulfydryl Oxidase 2 were identified and exhibited distinct molecular weights and properties during protein purification processes. This study also provided feasible Quiescin Q6-Sulfydryl Oxidase 2 purification methods from slaughterhouse materials that could potentially allow obtaining sufficient amount of Quiescin Q6-Sulfydryl Oxidase 2 for future functional investigations. PMID- 28662656 TI - Effect of vitamin E on oxidative stress level in blood, synovial fluid, and synovial tissue in severe knee osteoarthritis: a randomized controlled study. AB - BACKGROUND: This study was performed to evaluate the antioxidative and anti inflammatory effects of vitamin E on oxidative stress in the plasma, synovial fluid, and synovial tissue of patients with knee osteoarthritis. METHODS: Seventy two patients with late-stage knee osteoarthritis scheduled for total knee arthroplasty were randomized to take oral placebo (Group A) or 400 IU of vitamin E (Group B) once a day for 2 months before undergoing surgery. The blood levels of endpoints indicating oxidative stress or antioxidant capacity, Knee Society Score (KSS), Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC), and adverse effects were compared before and after the intervention between the two groups. At surgery, these redox endpoints and histological findings were compared between the synovial fluid and synovial tissue. RESULTS: In blood samples, the pre-intervention of oxidative stress and antioxidative capacity were not different between Group A and Group B. In post-intervention blood samples, the Malondialdehyde (Group A 1.34 +/- 0.10, Group B 1.00 +/- 0.09, p < 0.02), Alpha tocopherol (Group A 15.92 +/- 1.08, Group B 24.65 +/- 1.47, p < 0.01) and Trolox equivalent antioxidant capacity (Group A 4.22 +/- 0.10, Group B 5.04 +/- 0.10, 0 < 0.01) were significantly different between Group A and Group B. In synovial fluid samples, the Malondialdehyde (Group A 1.42 +/- 0.12, Group B 1.06 +/- 1.08, p 0.01), Alphatocopherol (Group A 4.51, Group B 7.03, p < 0.01), Trolox equivalent antioxidant capacity (Group A, 1.89 +/- 0.06, Group B 2.19 +/- 0.10) were significantly different between Group A and Group B. The pre intervention WOMAC score and KSS score were not different between Group A and Group B. The post-intervention WOMAC score was significantly improved in all categories in Group B (Pain: Group A 27.26 +/- 0.89, Group B 19.19 +/- 1.43, p < 0.01; Stiffness: Group A 8.23 +/- 0.79, Group B 5.45 +/- 0.73, p 0.01; Function: Group A 94.77 +/- 4.22, Group B 72.74 +/- 6.55, p < 0.01). The post-intervention KSS score was significantly improved in all categories in Group B (Clinical: Group A 25.31 +/- 14.33, Group B 33.52 +/- 16.96, p < 0.01; Functional: Group A 41.43 +/- 16.11, Group B 51.61 +/- 19.60, p 0.02). Significantly fewer synovial tissue cells were stained with nitrotyrosine and hematoxylin-eosin in Group B than in Group A. There were no differences in adverse effects or surgical complications between the groups. CONCLUSION: Vitamin E is an effective antioxidant that can improve clinical symptoms and reduce oxidative stress conditions in patients with late-stage knee osteoarthritis. TRIAL REGISTRATION: This research project had been approved for registration at Thai Clinical Trials Registry (TCTR) since 2016-08-28 11:26:32 (Retrospective registered). The TCTR identification number is TCTR20160828001 . PMID- 28662657 TI - Bacteraemia and fungaemia in cystic fibrosis patients with febrile pulmonary exacerbation: a prospective observational study. AB - BACKGROUND: Bloodstream pathogens can be identified by multiplex PCR (SeptiFast (SF)) or blood culture (BC); whether these pathogens are present in cystic fibrosis (CF) patients during febrile pulmonary exacerbations (FPE) has not been sufficiently studied. METHODS: In this prospective observational study, blood from CF patients experiencing FPE was tested with SF and BC before the initiation of antibiotic treatment. RESULTS: After contaminants had been excluded, 9 of 72 blood samples tested positive by BC or SF. SF exclusively detected four pathogens; BC, one. Pulmonary pathogen transmission was likely in all cases except for 2 cases of candidaemia, which were believed to be caused by catheter related infections. For three cases, test results caused us to change the antibiotic regimen. Sensitivity (85.7% vs. 42.9%) and negative predictive value (98.4% vs. 87.0%) tended to be higher for SF than for BC. CONCLUSIONS: The results of SF and BC show that bacteraemia and fungaemia are present in CF patients during FPE and may affect antibiotic therapy. SF can help rule out catheter-related bloodstream infections. PMID- 28662658 TI - Vertical transmission of avian leukosis virus subgroup J (ALV-J) from hens infected through artificial insemination with ALV-J infected semen. AB - BACKGROUND: Avian leukosis virus (ALV) is one of the main causes of tumour development within the poultry industry in China. The subgroup J avian leukosis viruses (ALV-J), which induce erythroblastosis and myelocytomatosis, have the greatest pathogenicity and transmission ability within this class of viruses. ALV can be transmitted both horizontally and vertically; however, the effects of ALV infection in chickens-especially roosters-during the propagation, on future generations is not clear. Knowing the role of the cock in the transmission of ALV from generation to generation might contribute to the eradication programs for ALV. RESULTS: The results showed that two hens inseminated with ALV-J-positive semen developed temporary antibody responses to ALV-J at 4-5 weeks post insemination. The p27 antigen was detected in cloacal swabs of six hens, and in 3 of 26 egg albumens at 1-6 weeks after insemination. Moreover, no viremia was detected at 6 weeks after insemination even when virus isolation had been conducted six times at weekly intervals for each of the 12 females. However, ALV J was isolated from 1 of their 34 progeny chicks at 1 week of age, and its gp85 had 98.4%-99.2% sequence identity with the gp85 of ALV-J isolated from semen samples of the six cocks. CONCLUSIONS: Our findings indicated that females that were late horizontally infected with ALV-J by artificial insemination might transmit the virus to progeny through eggs, which amounts to vertical transmission. PMID- 28662659 TI - The Start2Bike program is effective in increasing health-enhancing physical activity: a controlled study. AB - BACKGROUND: The sports club is seen as a new relevant setting to promote health enhancing physical activity (HEPA) among inactive population groups. Little is known about the effectiveness of strategies and activities implemented in the sports club setting on increasing HEPA levels. This study investigated the effects of Start2Bike, a six-week training program for inactive adults and adult novice cyclers, on HEPA levels of participants in the Netherlands. METHODS: To measure physical activity, the Short QUestionnaire to ASsess Health-enhancing physical activity was used (SQUASH). Start2Bike participants were measured at baseline, six weeks and six months. A matched control group was measured at baseline and six months. The main outcome measure was whether participants met the Dutch Norm for Health-enhancing Physical Activity (DNHPA: 30 min of moderate intensity activity on five days a week); Fit-norm (20 min of vigorous-intensity activity on three days a week); and Combi-norm (meeting the DNHPA and/or Fit norm). Other outcome measures included: total minutes of physical activity per week; and minutes of physical activity per week per domain and intensity category. Statistical analyses consisted of McNemar tests and paired t-tests (within-group changes); and multiple logistic and linear regression analyses (between-group changes). RESULTS: In the Start2Bike group, compliance with Dutch physical activity norms increased significantly, both after six weeks and six months. Control group members did not alter their physical activity behavior. Between-group analyses showed that participants in the Start2Bike group were more likely to meet the Fit-norm at the six-month measurement compared to the control group (odds ratio = 2.5; 95% confidence interval (CI) = 1.1-5.8, p = 0.03). This was due to the Start2Bike participants spending on average 193 min/week more in vigorous-intensity activities (b = 193; 95% CI = 94-293, p < 0.001) and 130 min/week more in sports activities (b = 130; 95% CI = 82-178, p < 0.001) than control group members. CONCLUSIONS: Start2Bike positively influences HEPA levels of participants by increasing participation in sport. A relatively short sporting program, offered by a sports club, can be used to encourage less active people to engage in and continue sport at HEPA levels. Overall, sport can contribute to health through increased HEPA and the sports club can serve as a setting to stimulate this. PMID- 28662660 TI - Primary pancreatic-type acinar cell carcinoma of the jejunum with tumor thrombus extending into the mesenteric venous system: a case report and literature review. AB - BACKGROUND: Although ectopic pancreatic tissue is common in the upper gastrointestinal tract, the incidence of ectopic pancreatic tissue in the jejunum is low, and malignant transformation in ectopic pancreatic tissue is rare. Furthermore, pancreatic-type acinar cell carcinoma (ACC) developing in the jejunum and ACC accompanied by tumor thrombus are extremely rare. CASE PRESENTATION: A 78-year-old-woman presented with melena. Abdominal computed tomography images and endoscopic examination revealed a submucosal jejunal mass with tumor thrombus extending into a jejunal vein. The patient underwent a curative resection combined with a partial jejunectomy and partial pancreatectomy. Histopathological examination of the resected tissue showed tumor cells with a homogeneous acinar architecture identical to pancreatic-type ACC and tumor thrombus. Postoperatively, she was followed for 10 months and had no recurrence. CONCLUSION: We present an extremely rare case of pancreatic-type ACC in the jejunum with extensive tumor thrombus invading into the mesenteric venous system. This type of cancer has not been reported previously but should be considered in the differential diagnosis of a jejunal mass. PMID- 28662662 TI - Tissue macrophages: heterogeneity and functions. AB - Macrophages are present in all vertebrate tissues, from mid-gestation throughout life, constituting a widely dispersed organ system. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes in defence against microbes and in clearance of dead and senescent cells, but also through trophic, regulatory and repair functions. In this review, we describe macrophage phenotypic heterogeneity in different tissue environments, drawing particular attention to organ-specific functions. PMID- 28662663 TI - Anti-diabetic effect of black ginseng extract by augmentation of AMPK protein activity and upregulation of GLUT2 and GLUT4 expression in db/db mice. AB - BACKGROUND: Black ginseng (Panax ginseng C. A. Meyer), three to nine times steamed and dried ginseng, has biological and pharmacological activities. In this study, the anti-diabetic effects of the black ginseng ethanol extract (GBG05-FF) in typical type 2 diabetic model db/db mice were investigated. METHODS: The effect of GBG05-FF in Type 2 diabetic mice was investigated by their blood analysis, biological mechanism analysis, and histological analysis. RESULTS: The mice group treated with GBG05-FF showed decreased fasting blood glucose and glucose tolerance compared to that of the nontreated GBG05-FF group. In the blood analysis, GBG05-FF decreased main plasma parameter such as HbA1c, triglyceride, and total-cholesterol levels related to diabetes and improved the expression of genes and protein related to glucose homeostasis and glucose uptake in the liver and muscle. The histological analysis result shows that GBG05-FF decreased lipid accumulation in the liver and damage in the muscle. Moreover, GBG05-FF increased the phosphorylation of the AMPK in the liver and upregulated the expression of GLUT2 in liver and GLUT4 in muscle. Therefore, the mechanisms of GBG05-FF may be related to suppressing gluconeogenesis by activating AMPK in the liver and affecting glucose uptake in surrounding tissues via the upregulation of GLUT2 and GLUT4 expression. CONCLUSION: These findings provided a new insight into the anti diabetic clinical applications of GBG05-FF and it might play an important role in the development of promising functional foods and drugs from the viewpoint of the chemical composition and biological activities. PMID- 28662664 TI - Dual role for p16 in the metastasis process of HPV positive head and neck cancers. AB - Several studies show that human papillomavirus (HPV) positive head and neck cancers (HNSCC) are typically characterized by low tumor and high regional node stages, intrinsically indicating high local metastatic potential. Despite this, the distant metastasis rates of HPV positive and negative HNSCC are similar. To date, majority of the studies focus on molecular characterization of HPV positive disease and on treatment outcome. Here we assessed the biological mechanisms of metastasis by combining in vitro and in vivo head and neck carcinoma xenograft models with patient data. We provide experimental evidence for a dual role of p16, a surrogate marker for HPV infections, in the metastasis process of HNSCC. We found that p16 regulates the invasiveness and metastatic potential of HNSCC cells by impairing angiogenesis. In parallel, we found that p16 is regulating the nodal spread by mediating lymphatic vessel formation through the upregulation of integrins. These findings not only provide understanding of the biology of the different dissemination patterns but also suggest that inhibition of lymphangiogenesis in HPV positive cancers and inhibition of angiogenesis in HPV negative cancers can form a treatment strategy against metastasis. PMID- 28662665 TI - Effect of modified compound calcium phosphate cement on the differentiation and osteogenesis of bone mesenchymal stem cells. AB - BACKGROUND: The aim of this study is to evaluate the effect of self-invented compound calcium phosphate cement upon the proliferation and osteogenesis of bone mesenchymal stem cells (BMSCs). METHODS: Four groups including traditional calcium phosphate cement, modified calcium phosphate cement, modified calcium phosphate cement plus bone morphogenetic protein (BMP), and control groups were established. The cell proliferation curve was delineated by MTT. The activity of BMSCs to synthesize alkaline phosphatase (AKP) was evaluated. The growth and invasion of BMSCs were observed. The expression levels of aggrecan, collagen I, collagen II, AKP, and OSX messenger RNA (mRNA) were measured by using RT-PCR. RESULTS: Compared with other groups, the BMSCs in the modified calcium phosphate cement group presented with loose microstructure and the BMSCs closely attached to the vector margin. At 7 days after co-culture, the expression of AKP in the modified calcium phosphate cement plus BMP group was significantly upregulated compared with those in other groups. In the modified calcium phosphate cement group, the BMSCs properly proliferated on the surface of bone cement and invaded into the cement space. At 10 days, the expression levels of aggrecan, collagen I, collagen II, AKP, and OSX mRNA in the modified calcium phosphate cement and modified calcium phosphate cement plus BMP groups were significantly upregulated than those in other groups. CONCLUSIONS: Modified compound calcium phosphate cement possesses excellent biocompatibility and osteogenic induction ability. Loose microstructure and large pore size create a favorable environment for BMSCs proliferation and vascular invasion, as an ideal vector for releasing BMP cytokines to mediate the differentiation and osteogenesis of BMSCs. PMID- 28662666 TI - Erratum to: Ethical standards for mental health and psychosocial support research in emergencies: review of literature and current debates. PMID- 28662661 TI - Non-model model organisms. AB - Model organisms are widely used in research as accessible and convenient systems to study a particular area or question in biology. Traditionally only a handful of organisms have been widely studied, but modern research tools are enabling researchers to extend the set of model organisms to include less-studied and more unusual systems. This Forum highlights a range of 'non-model model organisms' as emerging systems for tackling questions across the whole spectrum of biology (and beyond), the opportunities and challenges, and the outlook for the future. PMID- 28662667 TI - Evolution of strigolactone receptors by gradual neo-functionalization of KAI2 paralogues. AB - BACKGROUND: Strigolactones (SLs) are a class of plant hormones that control many aspects of plant growth. The SL signalling mechanism is homologous to that of karrikins (KARs), smoke-derived compounds that stimulate seed germination. In angiosperms, the SL receptor is an alpha/beta-hydrolase known as DWARF14 (D14); its close homologue, KARRIKIN INSENSITIVE2 (KAI2), functions as a KAR receptor and likely recognizes an uncharacterized, endogenous signal ('KL'). Previous phylogenetic analyses have suggested that the KAI2 lineage is ancestral in land plants, and that canonical D14-type SL receptors only arose in seed plants; this is paradoxical, however, as non-vascular plants synthesize and respond to SLs. RESULTS: We have used a combination of phylogenetic and structural approaches to re-assess the evolution of the D14/KAI2 family in land plants. We analysed 339 members of the D14/KAI2 family from land plants and charophyte algae. Our phylogenetic analyses show that the divergence between the eu-KAI2 lineage and the DDK (D14/DLK2/KAI2) lineage that includes D14 occurred very early in land plant evolution. We show that eu-KAI2 proteins are highly conserved, and have unique features not found in DDK proteins. Conversely, we show that DDK proteins show considerable sequence and structural variation to each other, and lack clearly definable characteristics. We use homology modelling to show that the earliest members of the DDK lineage structurally resemble KAI2 and that SL receptors in non-seed plants likely do not have D14-like structure. We also show that certain groups of DDK proteins lack the otherwise conserved MORE AXILLARY GROWTH2 (MAX2) interface, and may thus function independently of MAX2, which we show is highly conserved throughout land plant evolution. CONCLUSIONS: Our results suggest that D14-like structure is not required for SL perception, and that SL perception has relatively relaxed structural requirements compared to KAI2-mediated signalling. We suggest that SL perception gradually evolved by neo functionalization within the DDK lineage, and that the transition from KAI2-like to D14-like protein may have been driven by interactions with protein partners, rather than being required for SL perception per se. PMID- 28662668 TI - Experimentally confirmed toltrazuril resistance in a field isolate of Cystoisospora suis. AB - BACKGROUND: Constant treatment regimens with toltrazuril against Cystoisospora suis infection in piglets are being applied in the intensive production systems for the last two decades, but the possibility of resistance development has not been addressed so far despite limited availability of treatment alternatives. Recently, a pig producer in The Netherlands who routinely used toltrazuril complained about diarrhea in suckling piglets in the absence of bacterial and viral pathogens, and oocysts of C. suis could be isolated from feces of affected litters. METHODS: Piglets from two litters were infected with a field isolate of C. suis, Holland-I, and treated with 0 (Holl-Ctrl), 20 (Holl-20) or 30 (Holl-30) mg/kg of body weight (BW) of toltrazuril (Baycox(r)). The efficacy of toltrazuril was measured by assessment of oocyst excretion, fecal consistency and BW gain. A separate litter was infected with a toltrazuril-susceptible strain of C. suis, Wien-I, and treated with 0 (Wien-Ctrl) or 20 (Wien-20) mg/kg BW of toltrazuril for comparison. RESULTS: Treatment with the recommended (20 mg/kg) dose of toltrazuril completely suppressed oocyst shedding and diarrhea in group Wien-20. The prevalence of oocyst excretion was 100% in the groups infected with Holland-I and 80% in the group Wien-Ctrl. Most days with diarrhea were observed in group Holl-20 with an average of 6.40%, followed by 5.71% in Wien-Ctrl, while in Holl Ctrl and Holl-30 diarrhea was only seen in 1.79% of the samples (n = 14/piglet). Oocyst excretion, fecal consistency and BW gain did not differ significantly among groups infected with Holland-I, indicating loss of efficacy to toltrazuril. CONCLUSION: Experimental infections and treatment confirmed toltrazuril resistance against the field isolate even at increased dosage. Such isolates are a potential threat to pig production as no other effective and economically sustainable alternative treatment is currently available. In the absence of a standardized protocol for resistance testing in C. suis, regular parasitological examination and, if possible, experimental confirmation should be considered to evaluate the extent and consequences of toltrazuril resistance. PMID- 28662669 TI - Glial contributions to neurodegeneration in tauopathies. AB - Tauopathies are a broad set of neurodegenerative dementias characterized by aggregation of the tau protein into filamentous inclusions that can be found in neurons and glial cells. Activated microglia, astrocytes and elevated levels of proinflammatory molecules are also pathological hallmarks that are found in brain regions affected by tau pathology. There has been abundant research in recent years to understand the role of gliosis and neuroinflammation in neurodegenerative diseases, particularly in Alzheimer's disease (AD) which is the most common form of dementia. AD is a tauopathy characterized by both extracellular amyloid-beta plaques in addition to intracellular neurofibrillary tangles and neuropil threads containing aggregated tau protein. Accumulating evidence suggests that neuroinflammation offers a possible mechanistic link between these pathologies. Additionally, there appears to be a role for neuroinflammation in aggravating tau pathology and neurodegeneration in tauopathies featuring tau deposits as the predominant pathological signature. In this review, we survey the literature regarding inflammatory mechanisms that may impact neurodegeneration in AD and related tauopathies. We consider a physical role for microglia in the spread of tau pathology as well as the non-cell autonomous effects of secreted proinflammatory cytokines, specifically interleukin 1 beta, interleukin 6, tumor necrosis factor alpha and complement proteins. These molecules appear to have direct effects on tau pathophysiology and overall neuronal health. They also indirectly impact neuronal homeostasis by altering glial function. We conclude by proposing a complex role for gliosis and neuroinflammation in accelerating the progression of AD and other tauopathies. PMID- 28662671 TI - Plasma levels of MMP-7 and TIMP-1 in laboratory diagnostics and differentiation of selected histological types of epithelial ovarian cancers. AB - BACKGROUND: MMP-7 and TIMP-1 may play a role in the pathogenesis of cancer disease. In this study we investigated plasma levels of selected metalloproteinase and its tissue inhibitor in comparison to plasma levels of the commonly accepted tumor markers (CA 125 and HE4) in selected histological types of epithelial ovarian cancer patients as compared to control groups: patients with a benign ovarian tumor and healthy subjects. Plasma levels of MMP-7 and TIMP 1 were determined using ELISA, CA 125 and HE4 - by CMIA methods. RESULTS: Plasma levels of all biomarkers studied were significantly higher in ovarian cancer patients as compared to both control groups. MMP-7 demonstrated comparable to HE4 or CA125 values of diagnostic sensitivity (SE: 61%; 68%; 58%, respectively), specificity (SP: 95%; 95%; 98%, respectively), positive (PPV: 93%; 96%; 98%, respectively) and negative predictive values (NPV: 61%; 66%; 60%, respectively) in the groups tested. The combined use of the aforementioned biomarkers resulted in a further increase in diagnostic criteria and AUC, especially in the early stages of the disease. CONCLUSIONS: These findings suggest the usefulness of combining MMP-7 with CA 125 and HE4 in the diagnosis of epithelial ovarian cancer as a new tumor marker panel. PMID- 28662672 TI - Fibroblast growth factor 2 supports osteoblastic niche cells during hematopoietic homeostasis recovery after bone marrow suppression. AB - BACKGROUND: Hematopoietic stem cell (HSC) maintenance requires a specific microenvironment. HSC niches can be activated by tissue damaging chemotherapeutic drugs and various cell signaling molecules such as SDF-1 and FGF, which might also result in bone marrow stress. Recent research has insufficiently shown that endosteal osteolineage cells and other niche constituents recover after marrow injury. METHODS: We investigated the role of FGF2 in the osteoblastic niche cells during hematopoietic homeostasis recovery after bone marrow injury. Mice were treated with 5-fluorouracil (5FU) to eliminate actively cycling cells in the bone marrow. Primary osteoblasts were isolated and subjected to cell culture. Real time PCR, western blot and immunohistochemical staining were performed to study niche-related genes, osteoblast markers, and FGF2 signaling. Proliferation rate were analyzed by marker gene Ki67 and colony formation assay. Also, osterix positive osteoprogenitor cells were isolated by FACS from Osx-GFP-Cre mice after 5FU treatment, and subjected to RNA-sequencing and analyzed for Fgf receptors and niche markers. RESULTS: The endosteal osteolineage cells isolated from 5FU treated mice showed increased expression of the niche-related genes Sdf-1, Jagged 1, Scf, N-cad, Angpt1 and Vcam-1 and the osteoblast marker genes Osx, Opn, Runx2, and Alp, indicating that BM stress upon 5FU treatment activated the osteoblastic niche. Endosteal osteoblast expanded from a single layer to several layers 3 and 6 days after 5FU treatment. During the early recovery phase in 5FU-activated osteoblastic niches increased FGF2 expression and activated its downstream pERK. FGF2 treatment resulted in increased proliferation rate and the expression of niche marker genes in 5FU-activated osteoblastic niche cells. RNA-seq analysis in Osterix-positive osteoprogenitor cells isolated from 5FU-treated Osx-GFP mice showed significantly increased expression of Fgf receptors Fgfr1, 2 and 3. Although osteoblastic niche cells were damaged by 5FU treatment in the beginning, the increased number of OB layers in the recovery phase may be derived from resident osteoprogenitor cells by FGF2 activation under stress. CONCLUSIONS: Taken together, FGF2 signaling can regulate osteoblastic niche cells to support HSC homeostasis in response to bone marrow damage. PMID- 28662670 TI - Lipid Droplets in Health and Disease. AB - Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions. PMID- 28662673 TI - Patient-reported health state utilities in metastatic gastroenteropancreatic neuroendocrine tumours - an analysis based on the CLARINET study. AB - BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are rare cancers most often found in the gastrointestinal system or the pancreas. However, patient-reported health state utilities based on clinical trials have not been previously reported in this disease area. METHODS: The CLARINET study collected EORTC QLQ-C30 data from patients in both stable and progressive disease states, although data for the latter were only available during the early stage of progression due to trial design. Using published algorithms, data were mapped to EQ-5D utility values. Random-effects generalised least squares models were used to investigate the impacts of progression status, tumour site and other patient characteristics on mapped utility values. RESULTS: In total, 1053 observations from 204 patients were mapped to EQ-5D utilities using the McKenzie mapping algorithm. The final random-effects model included age, gender, baseline utility and progression status as covariates; it was not feasible to investigate time-to death utility due to a limit number of deaths in the CLARINET study. Tumour location (midgut vs pancreas) does not seem to affect utility. However, the difference in utilities based on progression status is statistically significant (p < 0.05) in the base case analysis, and the estimated utilities for stable and progressive disease are 0.776 and 0.726, respectively. Furthermore, scenario analyses showed that utility for progressive disease is numerically lower than for stable disease, but this may not be statistically significant in scenarios where alternative Longworth mapping algorithm was used. CONCLUSIONS: Patients with GEP-NETs experience worse utility values in the progressive disease state compared to the stable disease state, based on patient-reported health-related quality of life (HRQL) data from the CLARINET study. The decline of utility in the progressive disease state may be underestimated because progressive HRQL data were only collected shortly after the progression event in the trial. The estimated trial-based utilities can be used in future economic evaluations for GEP-NET treatments and to provide more insights to physicians on patient-reported quality of life outcomes in GEP-NETs. TRIAL REGISTRATION: CLARINET EU Clinical Trials Register Number, 2005-004904-35 . PMID- 28662674 TI - Evaluation of a knowledge transfer scheme to improve policy making and practices in health promotion and disease prevention setting in French regions: a realist study protocol. AB - BACKGROUND: Evidence-based decision-making and practice are pivotal in public health. However, barriers do persist and they relate to evidence properties, organisations and contexts. To address these major knowledge transfer (KT) issues, we need to rethink how knowledge is produced and used, to enhance our understanding of decision-making processes, logics and mechanisms and to examine the ability of public health services to integrate research findings into their decisions and operations. This article presents a realist evaluation protocol to assess a KT scheme in prevention policy and practice at local level in France. METHODS/DESIGN: This study is a comparative multiple case study, using a realist approach, to assess a KT scheme in regional health agencies (ARS) and regional non-profit organisations for health education and promotion (IREPS), by analysing the configurations contexts/mechanisms/outcomes of it. The KT scheme assessed is designed for the use of six reviews of systematic reviews concerning the following themes: nutrition, alcohol, tobacco smoking, physical activity, emotional and sexual life and psychosocial skills. It combines the following activities: supporting the access to and the adaptation of scientific and usable evidences; strengthening professionals' skills to analyse, adopt and use the evidences in the course of their practices and their decision-making process; facilitating the use of evidence in the organisations and processes. RAMESE II reporting standards for realist evaluations was used. DISCUSSION: The aims of this study are to experiment and characterise the factors related to the scheme's ability to enable public health stakeholders to address the challenges of KT and to integrate scientific knowledge into policy and practice. We will use the realist approach in order to document the parameters of successful KT strategies in the specific contexts of preventive health services in France, while seeking to determine the transferability of such strategies. PMID- 28662675 TI - New era towards advancing in girls' and women's health and rights? PMID- 28662676 TI - Effects of Bifidobacterium animalis subsp. lactis BB-12(r) on the lipid/lipoprotein profile and short chain fatty acids in healthy young adults: a randomized controlled trial. AB - BACKGROUND: Some probiotics have hypocholesterolemic effects in animal studies, which are mediated, in part, by increases in fecal short chain fatty acids (SCFAs). Clinical trials of probiotics on lipids/lipoproteins are inconsistent. OBJECTIVE: We examined the effects of Bifidobacterium animalis subsp. lactis BB 12(r) (BB-12(r)) (3.16 * 109 CFUs/day) on lipids and lipoproteins and fecal excretion of SCFAs in healthy adults. METHODS: In a randomized, partially blinded, 4-period, crossover study, 30 adults (11 men, 19 women) aged 18-40 years were randomly assigned to: 1) yogurt smoothie with no BB-12(r) (YS), 2) yogurt smoothie with BB-12(r) added pre-fermentation (PRE), 3) yogurt smoothie with BB 12(r) added post-fermentation (POST), 4) BB-12(r) containing capsule (CAP). We measured serum lipids/lipoproteins, glucose, insulin, C-reactive protein (CRP), and fecal SCFAs at baseline and after each treatment period. RESULTS: Total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides (TGs) did not differ after the PRE, POST, and CAP periods versus the YS or between treatments. Compared to baseline, fecal acetate was significantly increased after the YS (Delta = 211.89 +/- 75.87 MUg/g, P = 0.007) and PRE (Delta = 204.98 +/- 75.70 MUg/g, P = 0.009) periods. The percent increase in fecal acetate was significantly greater after the YS versus the POST period (52.2 +/- 13.2% vs. 24.5 +/- 13.2%, P = 0.023). Fecal total SCFAs, propionate and butyrate did not differ between treatment periods. Fecal total SCFAs were negatively associated with TC (r = -0.22, P = 0.01), LDL-C (r = -0.24, P = 0.004), age (r = -0.33, P < 0.001), and waist circumference (r = -0.25, P = 0.003). CONCLUSIONS: BB-12(r) supplementation did not improve lipids, lipoproteins and total and individual fecal SCFAs. Fecal SCFAs were negatively associated with TC, LDL-C, age, and waist circumference. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT01399996 . PMID- 28662677 TI - A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma: evaluation of safety and clinical and immunologic response. AB - BACKGROUND: Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. METHODS: The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon's two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. DISCUSSION: The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564). PMID- 28662678 TI - Risk factors associated with diarrhea in Danish commercial mink (Neovison vison) during the pre-weaning period. AB - BACKGROUND: Pre-weaning diarrhea in mink, also known as "sticky kits", is a syndrome and outbreaks occur every year on commercial mink farms in all mink producing countries. Morbidity and mortality can be considerable on a farm with huge economic consequences for the farmer as well as compromised welfare for the mink kits. Although efforts have been taken to identify etiologic agents involved in outbreaks, the syndrome is still regarded as multifactorial and recurring problems on the same farms draw attention to management and environmental risk factors. In the pre-weaning period from May to June 2015, a case control study was carried out on 30 Danish mink farms. Data concerning management, biosecurity, hygiene, feed consumption, antibacterial prescription and production efficiency were analyzed. RESULTS: The proportion of 1-year old females, farm size (total number of females), energy supply per female in the late gestation period, and dogs accessing the farm area were significantly associated with being a case farm. Case farms were prescribed almost twice the amount of antibacterials per gestational unit (female and litter) as in control farms. Farmers on case farms spent significantly more time nursing and treating the animals and experienced more females with mastitis compared to farmers on control farms. No significant differences in cleaning practices or hygienic measures between case and control farms were found and there were no differences in drinking water quality, bedding material, composition neither of color types nor in management regarding litter equalization. CONCLUSIONS: Results from this study showed an association between the occurrence of pre-weaning diarrhea on mink farms and parity profile, farm size and feeding intensity in the gestational period. The access of dogs to the farm area was a significant risk factor, but needs further clarification. PMID- 28662679 TI - Evaluating the accuracy of genomic prediction of growth and wood traits in two Eucalyptus species and their F1 hybrids. AB - BACKGROUND: Genomic prediction is a genomics assisted breeding methodology that can increase genetic gains by accelerating the breeding cycle and potentially improving the accuracy of breeding values. In this study, we use 41,304 informative SNPs genotyped in a Eucalyptus breeding population involving 90 E.grandis and 78 E.urophylla parents and their 949 F1 hybrids to develop genomic prediction models for eight phenotypic traits - basic density and pulp yield, circumference at breast height and height and tree volume scored at age three and six years. We assessed the impact of different genomic prediction methods, the composition and size of the training and validation set and the number and genomic location of SNPs on the predictive ability (PA). RESULTS: Heritabilities estimated using the realized genomic relationship matrix (GRM) were considerably higher than estimates based on the expected pedigree, mainly due to inconsistencies in the expected pedigree that were readily corrected by the GRM. Moreover, the GRM more precisely capture Mendelian sampling among related individuals, such that the genetic covariance was based on the true proportion of the genome shared between individuals. PA improved considerably when increasing the size of the training set and by enhancing relatedness to the validation set. Prediction models trained on pure species parents could not predict well in F1 hybrids, indicating that model training has to be carried out in hybrid populations if one is to predict in hybrid selection candidates. The different genomic prediction methods provided similar results for all traits, therefore either GBLUP or rrBLUP represents better compromises between computational time and prediction efficiency. Only slight improvement was observed in PA when more than 5000 SNPs were used for all traits. Using SNPs in intergenic regions provided slightly better PA than using SNPs sampled exclusively in genic regions. CONCLUSIONS: The size and composition of the training set and number of SNPs used are the two most important factors for model prediction, compared to the statistical methods and the genomic location of SNPs. Furthermore, training the prediction model based on pure parental species only provide limited ability to predict traits in interspecific hybrids. Our results provide additional promising perspectives for the implementation of genomic prediction in Eucalyptus breeding programs by the selection of interspecific hybrids. PMID- 28662680 TI - Systematic review of patient reported quality of life following stereotactic ablative radiotherapy for primary and metastatic liver cancer. AB - BACKGROUND: Stereotactic ablative radiotherapy (SABR) is a safe and effective modality in patients with liver cancer who are ineligible for other local therapies. However SABR is not current standard of practice and requires further validation. Patient reported quality of life (QOL) is key to this validation, yet no systematic reviews to date have been performed to analyse QOL following liver SABR. QOL is a critical part of therapy evaluation, particularly in disease states with short life expectancy. The purpose of this study was to conduct a systematic review of QOL outcomes for liver SABR. MATERIALS AND METHODS: MEDLINE and EMBASE databases from 1996 to October 2015 were queried to obtain English language studies analysing QOL following liver SABR. Included studies described patient-reported QOL as either a primary or secondary endpoint, and analysed QOL change over time. Studies were screened, and relevant data were abstracted and analysed. RESULTS: Of 2181 initially screened studies, 5 met all inclusion criteria. Extracted studies included a total of 392 eligible patients with hepatocellular carcinoma, liver metastases and intrahepatic cholangiocarcinoma. Four studies were prospective in design, and only one study was a conference abstract. Extracted studies were heterogeneous in dose prescription used (11-70 Gy in 3-30 fractions), in addition to reported QOL metrics (EORTC QLQ C-15 PAL,/C 30/LM-21, EuroQol 5D, FACT-Hep, FLIC) and final endpoints (range 6 weeks to 12 months). Despite this there were few statistically significant declines in QOL scores following SABR. Four studies demonstrated transient fatigue in the first 1 4 weeks, while 2 studies showed transient worsening of appetite at 1 month. In all but one instance (loss of appetite at 6 weeks), levels returned to insignificant difference baseline by the final endpoints. All studies showed no significant QOL decline in any domain at their respective endpoints. In studies with overlapping QOL tools, estimates of 3-month post SABR global QOL were similar. CONCLUSION: Results of this systematic review demonstrate well-preserved post liver SABR QOL. These findings strengthen the argument for liver SABR, and should aim to support future comparative effectiveness trials with other local modalities including surgery, chemoembolization and radiofrequency ablation, with a focus on QOL outcomes as an important endpoint. PMID- 28662681 TI - Comparison of two related lines of tauGFP transgenic mice designed for lineage tracing. AB - BACKGROUND: The tauGFP reporter fusion protein is produced nearly ubiquitously by the TgTP6.3 transgene in TP6.3 mice and its localisation to microtubules offers some advantages over soluble GFP as a lineage marker. However, TgTP6.3 Tg/Tg homozygotes are not viable and TgTP6.3 Tg/- hemizygotes are smaller than wild type. TP6.4 mice carry the TgTP6.4 transgene, which was produced with the same construct used to generate TgTP6.3, so we investigated whether TgTP6.4 had any advantages over TgTP6.3. RESULTS: Although TgTP6.4 Tg/Tg homozygotes died before weaning, TgTP6.4 Tg/- hemizygotes were viable and fertile and only males were significantly lighter than wild-type. The TgTP6.4 transgene produced the tauGFP fusion protein by the 2-cell stage and it was widely expressed in adults but tauGFP fluorescence was weak or absent in several tissues, including some neural tissues. The TgTP6.4 transgene expression pattern changed over several years of breeding and mosaic transgene expression became increasingly common in all expressing tissues. This mosaicism was used to visualise clonal lineages in the adrenal cortex of TgTP6.4 Tg/- hemizygotes and these were qualitatively and quantitatively comparable to lineages reported previously for other mosaic transgenic mice, X-inactivation mosaics and chimaeras. Mosaicism occurred less frequently in TP6.3 than TP6.4 mice and was only observed in the corneal epithelium and adrenal cortex. CONCLUSIONS: Mosaic expression makes the TgTP6.4 transgene unsuitable for use as a conventional cell lineage marker but such mosaicism provides a useful system for visualising clonal lineages that arise during development or maintenance of adult tissues. Differences in the occurrence of mosaicism between related transgenic lines, such as that described for lines TP6.3 and TP6.4, might provide a useful system for investigating the mechanism of transgene silencing. PMID- 28662682 TI - Pooled-DNA sequencing identifies genomic regions of selection in Nigerian isolates of Plasmodium falciparum. AB - BACKGROUND: The burden of falciparum malaria is especially high in sub-Saharan Africa. Differences in pressure from host immunity and antimalarial drugs lead to adaptive changes responsible for high level of genetic variations within and between the parasite populations. Population-specific genetic studies to survey for genes under positive or balancing selection resulting from drug pressure or host immunity will allow for refinement of interventions. METHODS: We performed a pooled sequencing (pool-seq) of the genomes of 100 Plasmodium falciparum isolates from Nigeria. We explored allele-frequency based neutrality test (Tajima's D) and integrated haplotype score (iHS) to identify genes under selection. RESULTS: Fourteen shared iHS regions that had at least 2 SNPs with a score > 2.5 were identified. These regions code for genes that were likely to have been under strong directional selection. Two of these genes were the chloroquine resistance transporter (CRT) on chromosome 7 and the multidrug resistance 1 (MDR1) on chromosome 5. There was a weak signature of selection in the dihydrofolate reductase (DHFR) gene on chromosome 4 and MDR5 genes on chromosome 13, with only 2 and 3 SNPs respectively identified within the iHS window. We observed strong selection pressure attributable to continued chloroquine and sulfadoxine pyrimethamine use despite their official proscription for the treatment of uncomplicated malaria. There was also a major selective sweep on chromosome 6 which had 32 SNPs within the shared iHS region. Tajima's D of circumsporozoite protein (CSP), erythrocyte-binding antigen (EBA-175), merozoite surface proteins MSP3 and MSP7, merozoite surface protein duffy binding-like (MSPDBL2) and serine repeat antigen (SERA-5) were 1.38, 1.29, 0.73, 0.84 and 0.21, respectively. CONCLUSION: We have demonstrated the use of pool-seq to understand genomic patterns of selection and variability in P. falciparum from Nigeria, which bears the highest burden of infections. This investigation identified known genomic signatures of selection from drug pressure and host immunity. This is evidence that P. falciparum populations explore common adaptive strategies that can be targeted for the development of new interventions. PMID- 28662683 TI - The Raine study had no evidence of significant perinatal selection bias after two decades of follow up: a longitudinal pregnancy cohort study. AB - BACKGROUND: Cohort studies may increase or decrease their selection bias as they progress through time. The Western Australian Pregnancy Cohort (Raine) Study has followed 2868 children for over two decades; from fetal into adult life. This paper analyses the cohort over time, assessing potential bias that may come and go with recruitment, retention and loss of participants. METHODS: Linked data from all births in Western Australian over the 3 years the Raine Cohort was recruited were obtained to compare perinatal characteristics and subsequent health outcomes between the Western Australian (WA) contemporaneous birth population and the Raine Cohort at five time points. Perinatal exposure-outcome comparisons were employed to assess bias due to non-participation in Raine Study subsets. RESULTS: There were demographic differences between the Raine Study cohort and its source population at recruitment with further changes across the period of follow up. Despite these differences, the pregnancy and infant data of those with continuing participation were not significantly different to the WA contemporaneous birth population. None of the exposure-outcome associations were significantly different to those in the WA general population at recruitment or at any cohort reviews suggesting no substantial recruitment or attrition bias. CONCLUSIONS: The Raine Study is valuable for association studies, even after 20 years of cohort reviews with increasing non-participation of cohort members. Non participation has resulted in greater attrition of socially disadvantaged participants, however, exposure-outcome association analyses suggest that there is no apparent resulting selection bias. PMID- 28662684 TI - Atypical blood glucose response to continuous and interval exercise in a person with type 1 diabetes: a case report. AB - BACKGROUND: Therapy must be adapted for people with type 1 diabetes to avoid exercise-induced hypoglycemia caused by increased exercise-related glucose uptake into muscles. Therefore, to avoid hypoglycemia, the preexercise short-acting insulin dose must be reduced for safety reasons. We report a case of a man with long-lasting type 1 diabetes in whom no blood glucose decrease during different types of exercise with varying exercise intensities and modes was found, despite physiological hormone responses. CASE PRESENTATION: A Caucasian man diagnosed with type 1 diabetes for 24 years performed three different continuous high intensity interval cycle ergometer exercises as part of a clinical trial (ClinicalTrials.gov identifier NCT02075567). Intensities for both modes of exercises were set at 5% below and 5% above the first lactate turn point and 5% below the second lactate turn point. Short-acting insulin doses were reduced by 25%, 50%, and 75%, respectively. Measurements taken included blood glucose, blood lactate, gas exchange, heart rate, adrenaline, noradrenaline, cortisol, glucagon, and insulin-like growth factor-1. Unexpectedly, no significant blood glucose decreases were observed during all exercise sessions (start versus end, 12.97 +/- 2.12 versus 12.61 +/- 2.66 mmol L-1, p = 0.259). All hormones showed the expected response, dependent on the different intensities and modes of exercises. CONCLUSIONS: People with type 1 diabetes typically experience a decrease in blood glucose levels, particularly during low- and moderate-intensity exercises. In our patient, we clearly found no decline in blood glucose, despite a normal hormone response and no history of any insulin insensitivity. This report indicates that there might be patients for whom the recommended preexercise therapy adaptation to avoid exercise-induced hypoglycemia needs to be questioned because this could increase the risk of severe hyperglycemia and ketosis. PMID- 28662686 TI - Type II Peter's anomaly with histopathological proof: a case report. AB - BACKGROUND: Peter's anomaly is a rare congenital anterior segment dysgenesis with poor visual results. This case report describes a case of bilateral Type II Peter's anomaly with notable clinical and histopathological features. CASE PRESENTATION: A 7-year-old boy was admitted to our center with complaints of bilateral central opacification, photophobia and severe reduced vision since birth. He underwent phacoemulsification, intraocular lens (IOL) implantation and anterior vitrectomy on the right eye in another medical institution two years ago. Slit lamp examination revealed bilateral central corneal opacity, few strands of peripheral iris, irregular pupils and cloudy lens with central adhesion to posterior corneal surface in the left eye. Additionally, a history of premature birth and mental retardation was also noted. The patient was diagnosed with Peter's anomaly in the left eye, pseudophakia in the right eye and bilateral amblyopia. Similar surgery to the right one was performed on the left eye. A vesicle-like structure was found in the anterior chamber intraoperatively, which was composed mainly of immature lens and some corneal stroma as revealed by postoperative histopathological examinations. CONCLUSIONS: The exact mechanism of Peter's anomaly is not completely understood, however, the notable histopathological features of tissue obtained from the present case may provide evidence to the hypothesis of developmental anomalies. PMID- 28662687 TI - 'Both parents should care for babies': A cross-sectional, cross-cultural comparison of adolescents' breastfeeding intentions, and the influence of shared parenting beliefs. AB - BACKGROUND: Many young men and women expect to co-parent their newborn infant. This may have a positive or negative impact on decisions to breastfeed, which is an important health behaviour, influenced by cultural and psycho-social norms. We investigated the relationship between shared parenting, infant feeding beliefs and intentions in male and female (non-parent) adolescents, comparing Nordic countries (Sweden, Norway, Finland) with high breastfeeding rates with others with low rates (Scotland, USA). METHODS: We utilised cross-sectional surveys of male and female adolescents (n = 1064, age 12-18) administered directly in schools or via the internet. We assessed attitudes to breast and formula feeding and shared parenting, using a Theory of Planned Behaviour framework, assessing beliefs, attitudes, norms and control as predictors of intention. RESULTS: Male and female adolescents' breastfeeding intentions varied in line with national cultural norms. Young people from Nordic countries (high breastfeeding rates) were significantly more likely to intend to breastfeed than those from Scotland or the USA (low breastfeeding rates). Positive beliefs about breastfeeding, norms and 'exposure' to breastfeeding and feeding confidence were consistently stronger in Nordic countries, whereas young people in Scotland had more positive beliefs, norms and 'exposure' to formula feeding. Differences in parenting beliefs, norms and confidence were less consistent. In logistic regression, cultural group, positive breastfeeding beliefs and exposure, norms, and shared parenting beliefs were significant predictors of breastfeeding feeding intention. CONCLUSIONS: Positive beliefs about shared parenting and equal gender norms were related to future breastfeeding intentions for female and male adolescents. Health education programmes for young people could encourage positive breastfeeding choices by considering how this would fit with young people's ideal parenting roles, and by emphasising benefits of complementary maternal and paternal roles in breastfeeding newborn infants. PMID- 28662688 TI - Ethnic differences in the +405 and -460 vascular endothelial growth factor polymorphisms and peripheral neuropathy in patients with diabetes residing in a North London, community in the United Kingdom. AB - BACKGROUND: There are marked ethnic differences in the susceptibility to the long term diabetic vascular complications including sensory neuropathy. The vascular endothelial growth factor (VEGF) +405 (C/G) and -460 (T/C) polymorphisms are associated with retinopathy and possibly with nephropathy, however no information is available on their relationship with peripheral neuropathy. Therefore, we examined the prevalence of these VEGF genotypes in a multi-ethnic cohort of patients with diabetes and their relationship with evident peripheral diabetic neuropathy. METHODS: In the current investigation, we studied 313 patients with diabetes mellitus of African-Caribbean, Indo-Asian and Caucasian ethnic origin residing in an inner-city community in London, United Kingdom attending a single secondary care centre. Genotyping was performed for the VEGF +405 and VEGF -460 polymorphisms using a pyrosequencing technique. RESULTS: Forty-nine patients (15.6%) had clinical evidence of peripheral neuropathy. Compared to Caucasian patients, African-Caribbean and Indo-Asian patients had lower incidence of neuropathy (24.6%, 14.28%, 6.7%, respectively; P = 0.04). The frequency of the VEGF +405 GG genotype was more common in Indo-Asian patients compared to African Caribbean and Caucasian patients (67.5%, 45.3%, 38.4%, respectively; p <= 0.02). The G allele was more common in patients with type 2 diabetes of Indo-Asian origin compared to African-Caribbean and Caucasian origin (p <= 0.02). There was no difference between the ethnic groups in VEGF -460 genotypes. The distributions of the VEGF +405 and VEGF -460 genotypes were similar between the diabetic patients with and without neuropathy. CONCLUSIONS: In this cohort of patients, VEGF +405 and VEGF -460 polymorphisms were not associated with evident diabetic peripheral neuropathy, however an association was found between VEGF +405 genotypes and Indo-Asian which might have relevance to their lower rates of ulceration and amputation. This finding highlights the need for further investigation of any possible relationship between VEGF genotype, circulating VEGF concentrations and differential vulnerability to peripheral neuropathy amongst diabetic patients of different ethnic backgrounds. PMID- 28662690 TI - Comparative efficacy of a new spot-on combination product containing selamectin and sarolaner (Stronghold(r)Plus) versus fluralaner (Bravecto(r)) against induced infestations with Ixodes ricinus ticks on cats. AB - BACKGROUND: Ticks are increasingly reported on cats worldwide, with Ixodes ricinus being a relevant species across Europe and in near by areas of North Africa and the Middle East. Yet there are few acaracidal products with proven efficacy approved for use in cats. The objective of this study was to compare the efficacy of a new spot-on formulation containing selamectin and sarolaner with a topical application of fluralaner (Bravecto(r)) against Ixodes ricinus ticks on cats. To that end, twenty-four (24) cats were randomly allocated to one of three treatment groups. The cats in the control group remained untreated. Cats in group 2 were treated with selamectin/sarolaner (Stronghold(r)Plus; Zoetis) at the minimum recommended dose of 1.0 mg/kg sarolaner and 6.0 mg/kg selamectin on Days 0, 30 and 60. The cats in group 3 received a fluralaner treatment (Bravecto(r)spot-on solution for cats, MSD) at the minimum recommended dose of 40.0 mg/kg on Day 0. Cats were infested with 50 (+/- 4) viable, adult, unfed I. ricinus ticks on Days 26, 54, 82 and 89 and ticks were removed for counting 48 h (+/- 2 h) later. RESULTS: Three monthly treatments with selamectin/sarolaner provided high and consistent efficacy against I. ricinus for the entire duration of the study period. In contrast, the efficacy of fluralaner declined in the second month after treatment and was below the efficacy threshold of 90% on Days 56, 84 and 91. The percentage efficacy against I. ricinus was numerically higher in the selemectin/sarolaner treated group than in the fluralaner-treated group on Days 56, 84 and 91. Furthermore, greasiness and spiking of the hair, as well as white deposits were frequently observed in the fluralaner-treated cats. CONCLUSION: The results of the present study confirm the high and consistent efficacy of a new spot-on combination product containing selamectin and sarolaner against I. ricinus in cats, and indicate a decline in fluralaner efficacy during the 91 day period after treatment. PMID- 28662691 TI - The wolf reference genome sequence (Canis lupus lupus) and its implications for Canis spp. population genomics. AB - BACKGROUND: An increasing number of studies are addressing the evolutionary genomics of dog domestication, principally through resequencing dog, wolf and related canid genomes. There is, however, only one de novo assembled canid genome currently available against which to map such data - that of a boxer dog (Canis lupus familiaris). We generated the first de novo wolf genome (Canis lupus lupus) as an additional choice of reference, and explored what implications may arise when previously published dog and wolf resequencing data are remapped to this reference. RESULTS: Reassuringly, we find that regardless of the reference genome choice, most evolutionary genomic analyses yield qualitatively similar results, including those exploring the structure between the wolves and dogs using admixture and principal component analysis. However, we do observe differences in the genomic coverage of re-mapped samples, the number of variants discovered, and heterozygosity estimates of the samples. CONCLUSION: In conclusion, the choice of reference is dictated by the aims of the study being undertaken; if the study focuses on the differences between the different dog breeds or the fine structure among dogs, then using the boxer reference genome is appropriate, but if the aim of the study is to look at the variation within wolves and their relationships to dogs, then there are clear benefits to using the de novo assembled wolf reference genome. PMID- 28662692 TI - Comparison of fixed and mobile-bearing total knee arthroplasty in terms of patellofemoral pain and function: a prospective, randomised, controlled trial. AB - BACKGROUND: Despite growing evidence in the literature, there is still a lack of consensus regarding the use of the mobile-bearing (MB) design total knee arthroplasty (TKA). METHODS: In a prospective, comparative, randomised, single centre trial, 106 patients with end-stage osteoarthritis of the knee were randomised to either an MB or fixed-bearing (FB) group to receive posterior stabilised (PS)-TKA using a standard medial parapatellar approach and patellar resurfacing with follow-up (FU) for 5 years. The primary outcome was anterior knee pain (AKP) during the chair rise test and the stair climb test 5 years after surgery. The secondary outcome was the ability to rise from a chair and to climb stairs, range of motion (ROM), Knee Society Score (KSS), RAND-36 scores and radiological analysis of the patellar tilt. RESULTS: No statistically significant difference was found between the two groups at 5 years FU in terms of median AKP during the chair rise test and the stair climb test (p = 0.5 and p = 0.8, respectively). There was no significant difference in any of the other secondary outcome parameters between the groups at 5 years FU. CONCLUSION: A mobile-bearing TKA does not decrease AKP compared to fixed bearings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02892838 . LEVEL OF EVIDENCE: II. PMID- 28662693 TI - Transesophageal vs. intracardiac echocardiographic screening in patients undergoing atrial fibrillation ablation with uninterrupted rivaroxaban. AB - BACKGROUND: Patients with atrial fibrillation (AF) routinely undergo different imaging modalities for the evaluation of the left atrial (LA) appendage to rule out thrombus prior to the AF ablation procedure. Recently, uninterrupted novel oral anticoagulants were introduced for patients undergoing atrial fibrillation (AF) ablation to minimize the peri-procedural thromboembolism risk. We performed a retrospective analysis to evaluate the safety of uninterrupted rivaroxaban and whether transesophageal (TEE) or intracardiac echocardiography (ICE) is necessary for patients undergoing AF ablation. METHODS: Data from 332 consecutive patients (42% females, aged 64 +/- 11 years) with AF undergoing either TEE (n = 115) prior to catheter ablation or ICE (n = 217) for the detection of LA thrombus were analyzed. All patients were on uninterrupted rivaroxaban during, and for at least, 4 weeks before the procedure. Heparin bolus was administered in all patients before transseptal puncture to maintain a target activated clotting time of >350 s. RESULTS: A total of 277 patients (80.4%) had paroxysmal AF. The average CHA2DS2-VASc score was 2.11 +/- 0.91 in the TEE group and 2.46 +/- 0.61 in the ICE group. The CHA2DS2-VASc score was >=2 in 64 (55.7%) and 214 (98.6%) patients in the TEE and ICE groups, respectively. The left atrial appendage was adequately visualized in all cases. None of the patients have an identifiable LA thrombus either in the TEE group or the ICE group. One (0.3%) thromboembolic periprocedural stroke occurred in a patient with long-standing persistent AF in the TEE group. CONCLUSIONS: This study illustrates that performing AF ablation with ICE guidance on uninterrupted rivaroxaban for at least 4 weeks even without TEE is feasible and safe. PMID- 28662694 TI - A cross-national study on gender differences in suicide intent. AB - BACKGROUND: Suicide accounts for over 58,000 deaths in Europe per annum, where suicide attempts are estimated to be 20 times higher. Males have been found to have a disproportionately lower rate of suicide attempts and an excessively higher rate of suicides compared to females. The gender difference in suicide intent is postulated to contribute towards this gender imbalance. The aim of this study is to explore gender differences in suicide intent in a cross-national study of suicide attempts. The secondary aims are to investigate the gender differences in suicide attempt across age and country. METHODS: Data on suicide attempts (acquired from the EU-funded OSPI-Europe project) was obtained from eight regions in Germany, Hungary, Ireland and Portugal. Suicide intent data was categorized into 'Non-habitual Deliberate Self-Harm' (DSH), 'Parasuicidal Pause' (SP), 'Parasuicidal Gesture' (SG), and 'Serious Suicide Attempt' (SSA), applying the Feuerlein scale. Gender differences in intent were explored for significance by using chi2-tests, odds ratios, and regression analyses. RESULTS: Suicide intent data from 5212 participants was included in the analysis. A significant association between suicide intent and gender was found, where 'Serious Suicide Attempts' (SSA) were rated significantly more frequently in males than females (p < .001). There was a statistically significant gender difference in intent and age groups (p < .001) and between countries (p < .001). Furthermore, within the most utilised method, intentional drug overdose, 'Serious Suicide Attempt' (SSA) was rated significantly more often for males than females (p < .005). CONCLUSIONS: Considering the differences in suicidal intent between males and females highlighted by the current study, gender targeted prevention and intervention strategies would be recommended. PMID- 28662695 TI - Determinants of contraceptive use among postpartum women in a county hospital in rural KENYA. AB - BACKGROUND: There is a high unmet need for limiting and spacing child births during the postpartum period. Given the consequences of closely spaced births, and the benefits of longer pregnancy intervals, targeted activities are needed to reach this population of postpartum women. Our objective was to establish the determinants of contraceptive uptake among postpartum women in a county referral hospital in rural Kenya. METHODS: Sample was taken based on a mixed method approach that included both quantitative and qualitative methods of data collection. Postpartum women who had brought their children for the second dose of measles vaccine between 18 and 24 months were sampled Participants were interviewed using structured questionnaires, data was collected about their socio demographic characteristics, fertility, knowledge, use, and access to contraceptives. Chi square tests were used to determine the relationship between uptake of postpartum family planning and: socio demographic characteristics, contraceptive knowledge, use access and fertility. Qualitative data collection included focus group discussions (FDGs) with mothers and in-depth interviews with service providers Information was obtained from mothers' regarding their perceptions on family planning methods, use, availability, access and barriers to uptake and key informants' views on family planning counseling practices and barriers to uptake of family planning RESULTS: More than three quarters (86.3%) of women used contraceptives within 1 year of delivery, with government facilities being the most common source. There was a significant association (p <= 0.05) between uptake of postpartum family planning and lower age, being married, higher education level, being employed and getting contraceptives at a health facility. One third of women expressing no intention of having additional children were not on contraceptives. In focus group discussions women perceived that the quality of services offered at the public facilities was relatively good because they felt that they were adequately counseled, as opposed to local chemist shops where they perceived the staff was not experienced. CONCLUSION: Contraceptive uptake was high among postpartum women, who desired to procure contraceptives at health facilities. However, there was unmet need for contraceptives among women who desired no more children. Government health facility stock outs represent a missed opportunity to get family planning methods, especially long acting reversible contraceptives, to postpartum women. PMID- 28662696 TI - Contribution of trans regulatory eQTL to cryptic genetic variation in C. elegans. AB - BACKGROUND: Cryptic genetic variation (CGV) is the hidden genetic variation that can be unlocked by perturbing normal conditions. CGV can drive the emergence of novel complex phenotypes through changes in gene expression. Although our theoretical understanding of CGV has thoroughly increased over the past decade, insight into polymorphic gene expression regulation underlying CGV is scarce. Here we investigated the transcriptional architecture of CGV in response to rapid temperature changes in the nematode Caenorhabditis elegans. We analyzed regulatory variation in gene expression (and mapped eQTL) across the course of a heat stress and recovery response in a recombinant inbred population. RESULTS: We measured gene expression over three temperature treatments: i) control, ii) heat stress, and iii) recovery from heat stress. Compared to control, exposure to heat stress affected the transcription of 3305 genes, whereas 942 were affected in recovering animals. These affected genes were mainly involved in metabolism and reproduction. The gene expression pattern in recovering animals resembled both the control and the heat-stress treatment. We mapped eQTL using the genetic variation of the recombinant inbred population and detected 2626 genes with an eQTL in the heat-stress treatment, 1797 in the control, and 1880 in the recovery. The cis-eQTL were highly shared across treatments. A considerable fraction of the trans-eQTL (40-57%) mapped to 19 treatment specific trans-bands. In contrast to cis-eQTL, trans-eQTL were highly environment specific and thus cryptic. Approximately 67% of the trans-eQTL were only induced in a single treatment, with heat-stress showing the most unique trans-eQTL. CONCLUSIONS: These results illustrate the highly dynamic pattern of CGV across three different environmental conditions that can be evoked by a stress response over a relatively short time span (2 h) and that CGV is mainly determined by response related trans regulatory eQTL. PMID- 28662697 TI - Regulation of apoptosis is impaired in atrophic gastritis associated with gastric cancer. AB - BACKGROUND: Gastric premalignant conditions, atrophic gastritis (AG) and intestinal metaplasia (IM) are characterized by an increase of proliferation and a reduction of apoptosis in epithelial cells. The epithelial cell kinetics in AG and IM in gastric mucosa adjacent to gastric cancer is still unclear. The aim of this study was to evaluate the epithelial cell turnover and expression of proliferation and apoptosis-related genes in gastric cancer (GC) and adjacent mucosa with atrophic gastritis or intestinal metaplasia (AG/IM GC+), as well as in atrophic gastritis or intestinal metaplasia mucosa of patients without GC (AG/IM GC-) and in control biopsy samples of non-transformed gastric mucosa (Control). METHODS: We selected 58 patients (M: F = 34:24; age range 20-84 years, median 61.06 years) with 4 well defined histological conditions: 20 controls with histological finding of non-transformed gastric mucosa, 20 patients with AG or IM (AG/IM GC-), and 18 patients with intestinal type gastric adenocarcinoma (GC) and AG or IM in the adjacent mucosa (3 cm from the macroscopic tumour margin, AG/IM GC+). We performed an immunohistochemical staining of Ki67 and TUNEL and quantitative RT-PCR to determine the expression of PCNA and Bax/Bcl-2. RESULTS: The immunohistochemical expression of Ki67 and TUNEL in AG/IM GC- was significantly increased compared to not transformed gastric mucosa (p < 0.0001) but not compared to AG/IM in gastric mucosa adjacent to GC. Levels of Bcl-2 were reduced in GC and AG/IM GC- compared to controls as well as in AG/IM GC- compared to AG/IM in mucosa adjacent to GC+ (p < 0.05). Proliferation and apoptosis markers did not correlate with H.pylori status in our study population. CONCLUSIONS: In AG/IM associated with GC, no significant changes in the epithelial cell turnover were detected. Decreased Bcl-2 gene expression signified atrophic gastritis and IM in presence of cancer, as well as intestinal type gastric adenocarcinoma. PMID- 28662698 TI - Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. AB - BACKGROUND: Moloney leukemia virus 10 (Mov10) is an RNA helicase that mediates access of the RNA-induced silencing complex to messenger RNAs (mRNAs). Until now, its role as an RNA helicase and as a regulator of retrotransposons has been characterized exclusively in cell lines. We investigated the role of Mov10 in the mouse brain by examining its expression over development and attempting to create a Mov10 knockout mouse. Loss of both Mov10 copies led to early embryonic lethality. RESULTS: Mov10 was significantly elevated in postnatal murine brain, where it bound retroelement RNAs and mRNAs. Mov10 suppressed retroelements in the nucleus by directly inhibiting complementary DNA synthesis, while cytosolic Mov10 regulated cytoskeletal mRNAs to influence neurite outgrowth. We verified this important function by observing reduced dendritic arborization in hippocampal neurons from the Mov10 heterozygote mouse and shortened neurites in the Mov10 knockout Neuro2A cells. Knockdown of Fmrp also resulted in shortened neurites. Mov10, Fmrp, and Ago2 bound a common set of mRNAs in the brain. Reduced Mov10 in murine brain resulted in anxiety and increased activity in a novel environment, supporting its important role in the development of normal brain circuitry. CONCLUSIONS: Mov10 is essential for normal neuronal development and brain function. Mov10 preferentially binds RNAs involved in actin binding, neuronal projection, and cytoskeleton. This is a completely new and critically important function for Mov10 in neuronal development and establishes a precedent for Mov10 being an important candidate in neurological disorders that have underlying cytoarchitectural causes like autism and Alzheimer's disease. PMID- 28662699 TI - Hypoglycaemic activity of Mathurameha, a Thai traditional herbal formula aqueous extract, and its effect on biochemical profiles of streptozotocin-nicotinamide induced diabetic rats. AB - BACKGROUND: The Thai traditional herbal formula-Mathurameha, consisting of 26 medicinal plants, has been used as an alternative and complementary medicine for diabetes treatment in Wangnamyen Hospital, Thailand. To provide scientific evidences on the efficacy and safety of this herbal formula, in vivo hypoglycaemic activity, effect on serum biochemical profiles and acute toxicity were investigated. METHODS: Experimental type 2 diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of nicotinamide 15 min prior to intravenous injection of streptozotocin. The most effective extract from the oral glucose tolerant test (OGTT) was administered daily via the oral route to diabetic rats for 2 weeks. Two-hour postprandial plasma glucose (2h-PPG) levels were measured on days 0, 7, and 14. Biochemical data were measured at the end of daily oral administration experiment. RESULTS: Aqueous extract of the herbal formula was the most potent extract for improving glucose tolerance of streptozotocin-nicotinamide-induced diabetic rats after single oral administration. After 2 weeks of daily oral administration, the aqueous extract showed a dose-dependent glucose lowering effect. At doses of 12.5, 25, and 50 mg/kg, the 2h-PPG level of diabetic rats decreased by 3.32%, 15.78%, and 17.94%, respectively. Most of the biochemical profiles of diabetic rats were improved, including the total cholesterol (TC), alkaline phosphatase (ALP), total protein, albumin, globulin, creatinine, and uric acid levels. The significantly increased triglyceride (TG) level observed in treated diabetic rats indicated a lack of a beneficial effect of the extract on lipid homeostasis. Nevertheless, there were no signs or symptoms of acute toxicity observed after oral administration of aqueous extract (5 g/kg) to both male and female rats. CONCLUSIONS: The results revealed that the herbal formula aqueous extract has hypoglycaemic activity, beneficial effects on biochemical profiles and a lack of acute toxicity. This study confirms the efficacy and safety of the Mathurameha herbal formula used for treating type 2 diabetes mellitus. PMID- 28662700 TI - Risk of unsafe abortion associated with long-term contraception behaviour: a case control study from Sri Lanka. AB - BACKGROUND: When faced with an unintended pregnancy, some women choose to undergo an unsafe abortion, while others do not. This choice may depend on long-term contraception that shapes the fertility goals of women, along with many other risk factors. We assessed the risk for unsafe abortion associated with contraceptive practices based on women's long-term behaviour, and its likely modification by the use of different types of contraceptives among women in Sri Lanka. METHODS: An unmatched case-control study was conducted in nine hospitals among 171 women admitted for care following an unsafe abortion (Cases) and 600 women admitted to same hospitals for delivery of an unintended term pregnancy (Controls). Interviewer-administered-questionnaires assessed their socio economic, reproductive and fertility (decisions on family size, family completion) characteristics, contraceptive method last used (traditional, modern), reasons for discontinuation/never-use, and contraceptive practices assessed at different time points. Using several regression models, the risk of abortion was assessed for 'non-use' of contraception against 'ineffective use' at conception; for non-use further categorised as 'never-use', 'early discontinuation' (discontinued before last birth interval) and 'late discontinuation' (discontinued during last birth interval); and for any interaction between the contraceptive practice and contraceptive method last used among the ever-users of contraception. RESULTS: At conception, 'non-use' of contraception imparted a two-fold risk for abortion against ineffective use (adjusted-OR = 2.0; 95% CI: 1.2-3.2). The abortion risk on 'non-use' varied further according to 'early' (adjusted-OR = 1.7; 95% CI: 1.1-3.1) and 'late' (adjusted-OR = 2.3; 95% CI: 1.5-3.6) discontinuation of contraception, but not with 'never-use' (crude-OR = 1.1; 95% CI: 0.6-2.3). Among the ever-users, the risk of abortion varied within each contraceptive practice by their last used contraceptive method and reasons for discontinuation. A significant interaction between modern contraceptives and early discontinuation (adjusted-OR = 1.4; 95% CI = 1.1-3.1) demonstrated a seven-fold abortion risk for early discontinuation of modern methods against its ineffective use. In particular, hormonal methods seemed to be responsible for this risk (51.1% cases versus 42.5% controls). CONCLUSIONS: Long-term contraceptive practices showed varying risk for abortion, and was further modified by early discontinuation of modern contraceptives. This knowledge should be applied during postnatal visits by public-health staff. PMID- 28662702 TI - Medical Advice for Sick-reported Students (MASS) in intermediate vocational education schools: design of a controlled before-and-after study. AB - BACKGROUND: School absenteeism, including medical absenteeism, is associated with early school dropout and may result in physical, mental, social and work-related problems in later life. Especially at intermediate vocational education schools, high rates of medical absenteeism are found. In 2012 the Dutch intervention 'Medical Advice for Sick-reported Students' (MASS), previously developed for pre vocational secondary education, was adjusted for intermediate vocational education schools. The aim of the study outlined in this paper is to evaluate the effectiveness of the MASS intervention at intermediate vocational education schools in terms of reducing students' medical absenteeism and early dropping out of school. Additionally, the extent to which biopsychosocial and other factors moderate the effectiveness of the intervention will be assessed. METHODS: A controlled before-and-after study will be conducted within Intermediate Vocational Education schools. Schools are allocated to be an intervention or control school based on whether the schools have implemented the MASS intervention (intervention schools) or not (control schools). Intervention schools apply the MASS intervention consisting of active support for students with medical absenteeism provided by the school including a consultation with the Youth Health Care (YHC) professional if needed. Control schools provide care as usual. Data will be collected by questionnaires among students in both groups meeting the criteria for extensive medical absenteeism (i.e. 'reported sick four times in 12 school weeks or for more than six consecutive school days' at baseline and at 6 months follow-up). Additionally, in the intervention group a questionnaire is completed after each consultation with a YHC professional, by both the student and the YHC professional. Primary outcome measures are duration and cumulative incidence of absenteeism and academic performances. Secondary outcome measures are biopsychosocial outcomes of the students. DISCUSSION: It is hypothesized that implementing the MASS intervention including a referral to a YHC professional on indication, will result in a lower level of medical absenteeism and a lower level of school drop outs among intermediate vocational education students compared to students receiving usual care. The study will provide insight in the effectiveness of the intervention as well as in factors moderating the intervention's effectiveness. TRIAL REGISTRATION: Nederlands Trial Register NTR5556. Date of clinical trial registration: 29-Oct-2015. PMID- 28662701 TI - Association of circulating leptin and adiponectin with periodontitis: a systematic review and meta-analysis. AB - BACKGROUND: This study aimed to assess the difference in serum levels of leptin and adiponectin in patients with periodontitis and in periodontally healthy individuals and evaluate the changes in circulating leptin and adiponectin after periodontal therapy. Leptin and adiponectin are the most generally studied adipokines that function as inflammatory cytokines. Although the association between periodontitis and serum levels of leptin and adiponectin has been studied extensively, the results were not consistent. METHODS: A systematic search of the Pubmed, Embase, Web of Science, and Cochrane Library up to September 2016 was conducted. The studies were screened and selected by two writers according to the specific eligibility criteria. The quality of included cross-sectional studies was assessed using the quality assessment form recommended by the Agency for Healthcare Research and Quality and Methodological Index for Nonrandomized Studies. The meta-analyses were conducted using the STATA 12.0 software. RESULTS: A total of 399 manuscripts were yielded and 25 studies were included in the present meta-analysis. Significantly elevated serum levels of leptin and decreased serum levels of adiponectin in patients with periodontitis were observed in the subgroup analysis of body mass index (BMI) <30. The overall and subgroup analyses showed no significant change in the serum levels of leptin in patients with periodontitis after periodontal treatment. The subgroup analysis of systemically healthy patients showed no significant change in serum levels of adiponectin in patients with periodontitis after periodontal treatment. CONCLUSIONS: The present meta-analysis supported elevated serum levels of leptin and decreased serum levels of adiponectin in patients with periodontitis compared with controls in the BMI <30 population. In systemically healthy patients with periodontitis, serum levels of leptin and adiponectin do not significantly change after periodontal treatment. PMID- 28662703 TI - The diagnosis of a metastatic breast tumor from ovarian cancer by the succession of a p53 mutation: a case report. AB - BACKGROUND: Metastatic breast tumors from other organs are very rare. We herein describe the case of a patient with a metastatic breast tumor due to ovarian cancer who was diagnosed by the succession of a p53 mutation. CASE PRESENTATION: The patient was a 59-year-old woman with sigmoid colon stenosis. Diagnostic imaging revealed a pelvic mass, multiple liver tumors, ascites, and multiple swollen para-aortic lymph nodes, suggesting an advanced ovarian tumor. Transverse loop colostomy and partial resection of the greater omentum was performed followed by six cycles of paclitaxel with carboplatin chemotherapy (TC therapy). Her cancer almost disappeared, with the exception of a small tumor in her pelvis. Simple hysterectomy with bilateral salpingo-oophorectomy was performed. Two years and 5 months after the second surgery, a mass was detected in her right breast and simple mastectomy was performed. A histological examination of the tumors from the first surgery revealed infiltrating papillary adenocarcinoma and the solid nest proliferation of atypical cells with comedo necrosis and psammoma bodies. The findings of an immunohistochemical analysis were as follows: cancer antigen 125 (CA125 (+)), cytokeratin 7 (CK7 (+)), cytokeratin 20 (CK20 (-)), p53 (+) and CDX2 (-), estrogen receptor (ER (slightly +)), progesterone receptor (PR (slightly +)), and human epidermal growth factor receptor 2 (HER2 (1+)). The breast tumors presented similar morphological features (ER (-), PR (-), HER2 (-), CA125 (+), CK7 (+), CK20 (-), p53 (+), mammaglobin (-), and GCDFP15 (-)), which were not characteristic of breast cancer. A direct sequencing analysis of p53 revealed a p.V173M mutation in exon 5 in both the breast tumor and the ovarian cancer. It was not detected in normal tissue, suggesting that the breast tumors were metastatic serous adenocarcinomas from ovarian cancer. CONCLUSIONS: A direct sequencing mutation analysis of p53 was useful for distinguishing the primary tumor from the metastatic tumor. We should resect metastatic breast tumors to the extent that is possible because the prognosis of such patients is relatively good. PMID- 28662704 TI - Thrombocytopenia induced by dabigatran: two case reports. AB - BACKGROUND: Vitamin K inhibitors (e.g. warfarin) and indirect thrombin inhibitors (e.g. heparin) are widely used to prevent thromboembolic disorders (e.g. myocardial infarction, venous thromboembolism, and stroke). These agents have been mainstays of anticoagulation for people older than 60 years. However, their administration is associated with a risk of bleeding and requires careful monitoring of patients. Novel oral anticoagulants (NOACs), such as dabigatran, are significantly safer in preventing thromboembolism than warfarin and heparin (sporadically causes thrombocytopenia) and are more specific for their target protein, thrombin. The major advantage of dabigatran, a direct thrombin inhibitor, is that it reversibly inhibits both free and clot-bound thrombin by tight binding affinity and the predictable pharmacodynamic effect. A few studies, however, reported that dabigatran can cause thrombocytopenia, although the underlying mechanism remains unclear. Thus, an antidote for dabigatran was developed to prevent thrombocytopenia. CASE PRESENTATION: In this report, we discuss two cases of thrombocytopenia and purpura after dabigatran treatment. A 73-year-old man showed hemorrhagic necrotic skin lesions on his neck and right hand. He was administered dabigatran (220 mg/day) for cerebral infarction for three days and his platelet count decreased abruptly (6000/MUL). This suggested that dabigatran had caused thrombocytopenia and purpura; therefore, dabigatran administration was discontinued. The results of a blood test, performed 14 days after stopping dabigatran treatment, showed that the platelet count had recovered to the normal range of more than 150,000/MUL. A 75-year-old woman had taken warfarin continuously for 8 years. However, she had a new cerebral infarction. Therefore, warfarin treatment was replaced with dabigatran (300 mg/day). Her platelet count decreased (41,000/MUL) significantly and dabigatran treatment was discontinued. The blood test results show that platelet counts gradually recovered to the normal range. CONCLUSIONS: Dabigatran application may cause bleeding; therefore, careful monitoring during dabigatran treatment is required to prevent thrombocytopenia. An explanation is that the interaction of dabigatran with thrombin, because of its strong binding affinity, may cause the observed thrombocytopenia. PMID- 28662705 TI - High intensity of Tunga penetrans infection causing severe disease among pigs in Busoga, South Eastern Uganda. AB - BACKGROUND: Towards the improvement of stakeholders' awareness of animal tungiasis, we report 10 unusual severe clinical cases of pig tungiasis which were associated with very high infection intensities of T. penetrans in an endemic area. RESULTS: Morbidity of ten pigs with high sand flea intensities detected during high transmission seasons in an endemic area in Busoga sub region, Uganda is described in detail. The cases of pigs presented with a very high number of embedded sand fleas (median = 276, range = 141-838). Acute manifestations due to severe tungiasis included ulcerations (n = 10), abscess formation (n = 6) and lameness (n = 9). Chronic morphopathological presentations were overgrowth of claws (n = 5), lateral deviation of dew claws (n = 6), detachment (n = 5) or loss of dew claws (n = 1). Treatment of severe cases with a topical insecticidal aerosol containing chlorfenvinphos, dichlorvos and gentian violet resolved acute morbidity and facilitated healing by re-epithelialisation. CONCLUSIONS: The presentations of tungiasis highlighted in this report show that high intensities of embedded T. penetrans can cause a severe clinical disease in pigs. Effective tungiasis preventive measures and early diagnosis for treatment could be crucial to minimize its effects on animal health. PMID- 28662706 TI - Prevalence and associated risk factors of chronic bronchitis in First Nations people. AB - BACKGROUND: Inadequate housing, low family income, household smoking, personal smoking status, and poor schooling are some of the conditions that have been significantly associated with the prevalence and incidence of chronic bronchitis. The aim of the current study was to determine the prevalence of chronic bronchitis (CB) and associated risk factors among First Nations people. METHODS: An interviewer-administered survey was conducted as part of the First Nations Lung Health Project in 2012 and 2013 with 874 individuals from 406 households in two First Nations communities located in the province of Saskatchewan, Canada. The questionnaire collected information on individual and contextual determinants of health and a history of ever diagnosed with CB (outcome variable) from the two communities participating in the First Nations Lung Health Project. Clustering effect within households was adjusted using Generalized Estimating Equations. RESULTS: The prevalence of CB was 8.9% and 6.8% among residents (18 years and older) of community A and community B respectively and was not significantly different. CB prevalence was positively associated with odour or musty smell of mildew/mould in the house [OR adj (95% CI) = 2.33 (1.21, 4.50)], allergy to house dust [3.49 (1.75, 6.97)], an air conditioner in home [2.33 (1.18, 4.24)], and increasing age [0.99 (0.33, 2.95), 4.26 (1.74, 10.41), 6.08 (2.58, 14.33)]. An interaction exposure to environmental tobacco smoke in the house*body mass index showed that exposure to household smoke increased the risk of CB for overweight and obese participants (borderline). Some of the variables of interest were not significantly associated with the prevalence of CB in multivariable analysis, possibly due to small numbers. CONCLUSIONS: Our results suggest that significant determinants of CB were: increasing age; odour or musty smell of mildew/mould in the house; allergy to house dust; and, body mass index. Modifiable risk factors identified were: (i) community level-housing conditions (such as mould or mildew in home, exposure to environmental tobacco smoke in house); and, (ii) policy level-remediation of mould, and obesity. TRIAL REGISTRATION: Not applicable. PMID- 28662707 TI - Oral symptoms and salivary findings in oral lichen planus, oral lichenoid lesions and stomatitis. AB - BACKGROUND: To examine if patients with oral lichen planus, oral lichenoid lesions and generalised stomatitis and concomitant contact allergy have more frequent and severe xerostomia, lower unstimulated and chewing-stimulated saliva and citric-acid-stimulated parotid saliva flow rates, and higher salivary concentration of total protein and sIgA than cases without contact allergy and healthy controls. METHODS: Forty-nine patients (42 women, aged 61.0 +/- 10.3 years) and 29 healthy age- and gender-matched subjects underwent a standardised questionnaire on general and oral health, assessment of xerostomia, clinical examination, sialometry, mucosal biopsy and contact allergy testing. RESULTS: Nineteen patients had oral lichen planus, 19 patients had oral lichenoid lesions and 11 patients had generalised stomatitis. 38.8% had contact allergy. Xerostomia was significantly more common and severe in patients (46.9%) than in healthy controls, whereas the saliva flow rates did not differ. The patients had higher sIgA levels in unstimulated and chewing-stimulated saliva than the healthy controls. The total protein concentration in saliva was lower in the unstimulated saliva samples whereas it was higher in the chewing stimulated saliva samples from patients when compared to healthy controls. The differences were not significant and they were irrespective of the presence of contact allergy. CONCLUSION: Xerostomia is prevalent in patients with oral lichen planus, lichenoid lesions and generalised stomatitis, but not associated with salivary gland hypofunction, numbers of systemic diseases or medications, contact allergy, age, or gender. Salivary sIgA levels were higher in patients than in healthy controls, but did not differ between patient groups. The total salivary protein concentration was lower in unstimulated saliva samples and higher in chewing stimulated saliva samples in patients than in healthy controls, but did not differ between patient groups. Our findings do not aid in the discrimination between OLP and OLL and these conditions with or without contact allergic reactions. PMID- 28662708 TI - Comparison of the efficacy and safety of URSL, RPLU, and MPCNL for treatment of large upper impacted ureteral stones: a randomized controlled trial. AB - BACKGROUND: There are three minimally invasive methods for the management of large upper impacted ureteral stones: mini-percutaneous nephrolithotomy (MPCNL), transurethral ureteroscope lithotripsy (URSL), and retroperitoneal laparoscopic ureterolithotomy (RPLU). This study aimed to compare MPCNL, URSL, and RPLU, and to evaluate which one is the best choice for large upper impacted ureteral stones. METHODS: Between January 2012 and December 2015, at the Department of Urology, Huai'an First People's Hospital, 150 consecutively enrolled patients with a large upper impacted ureteral stone (>15 mm) were included. The patients were randomly divided (1:1:1) into the MPCNL, URSL, and RPLU groups. The primary endpoint was success of stone removal measured 1 month postoperatively and the secondary endpoints were intraoperative and postoperative parameters and complications. RESULTS: Fifteen patients needed auxiliary ESWL after URSL, and 3 patients after MPCNL, but none after RPLU. The stone clearance rate was 96% (48/50) in the MPCNL group and 72% (33/46) in the URSL group. In the RPLU group the stones were completely removed and the stone clearance rate was 100% (48/48) (P = 0.021 vs. URSL; P = 0.083 vs. MPCNL). Operation-related complications were similar among the three groups (all P > 0.05). Hospital stay was shorter in the URSL group compared with MPCNL (P = 0.003). Operation time was the shortest with URSL and the longest with MPCNL (all P < 0.05). CONCLUSIONS: MPCNL and RPUL are more suitable for upper ureteral impacted stones of >15 mm. URSL could be considered if the patient is not suitable for general anesthesia, or the patient requests transurethral uretroscopic surgery. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR INR-17011507 ; Registration date: 2017-5-22). PMID- 28662709 TI - Interval follow up of a 4-day pilot program to implement the WHO surgical safety checklist at a Congolese hospital. AB - BACKGROUND: The World Health Organisation Surgical Safety Checklist (SSC) improves surgical outcomes and the research question is no longer 'does the SSC work?' but, 'how to make the SSC work?' Evidence for implementation strategies in low-income countries is sparse and existing strategies are heavily based on long term external support. Short but effective implementation programs are required if widespread scale up is to be achieved. We designed and delivered a four-day pilot SSC training course at a single hospital centre in the Republic of Congo, and evaluated the implementation after one year. We hypothesised that participants would still be using the checklist over 50% of the time. METHOD: We taught the four-day SSC training course at Dolisie hospital in February 2014, and undertook a mixed methods impact evaluation based on the Kirkpatrick model in May 2015. SSC implementation was evaluated using self-reported questionnaire with a 3 point Likert scale to assess six key process measures. Learning, behaviour, organisational change and facilitators and inhibitors to change were evaluated with questionnaires, interviews and focus group discussion. RESULTS: Seventeen individuals participated in the training and seven (40%) were available for impact evaluation at 15 months. No participant had used the SSC prior to training. Over half the participants were following the six processes measures always or most of the time: confirmation of patient identity and the surgical procedure (57%), assessment of difficult intubation risk (72%), assessment of the risk of major blood loss (86%), antibiotic prophylaxis given before skin incision (86%), use of a pulse oximeter (86%), and counting sponges and instruments (71%). All participants reported positive improvements in teamwork, organisation and safe anesthesia. Most participants reported they worked in helpful, supportive and respectful atmosphere; and could speak up if they saw something that might harm a patient. However, less than half felt able to challenge those in authority. CONCLUSION: Our study demonstrates that a 4-day pilot course for SSC implementation resulted in over 50% of participants using the SSC at 15 months, positive changes in learning, behaviour and organisational change, but less impact on hierarchical culture. The next step is to test our novel implementation strategy in a larger hospital setting. PMID- 28662710 TI - Healthcare provider's attitude towards disability and experience of women with disabilities in the use of maternal healthcare service in rural Nepal. AB - BACKGROUND: Women with disabilities are less likely to receive maternal healthcare services compared to women without disabilities. While few studies have reviewed healthcare experience of women with disabilities, no studies have been conducted to understand provider's attitude towards disability in Nepal, yet the attitude and behaviour of healthcare providers may have a significant influence on aspects of care and the use of service by women with disabilities. This study examines healthcare provider's attitudes towards disability and explores the experience of women with disabilities in maternal healthcare service utilization during pregnancy and childbirth. METHOD: The study used mixed method approach. An attitude survey was conducted among 396 healthcare providers currently working in public health facilities in Rupandehi district of Nepal. For additional insight, eighteen in-depth interviews with women with disabilities who used maternal healthcare services in a healthcare facility within the study district in their last pregnancy were undertaken. The Attitude Towards Disabled Persons (ATDP) scale score was used to measure the attitudes of healthcare providers. For quantitative data, univariate and multivariate analysis using ANOVA was used to understand the association between outcome and independent variables and qualitative analysis generated and described themes. RESULTS: Mean ATDP score among healthcare providers (78.52; SD = 14.75), was low compared to the normative score of 100 or higher. Nurses/auxiliary nurse midwives obtained the highest mean score (85.59, SD = 13.45), followed by general clinical health workers (Mean score = 82.64, SD 15.10). The lowest score was obtained by Female Community Health Volunteers (FCHV) (Score = 73.75, SD = 13.40) (P < 0.001). Younger providers were more positive compared to older age groups (P < 0.001). Similarly, providers working in urban health facilities compared to those working in rural health facilities, and non-Dalit providers compared to Dalit providers reported more positive attitudes towards disability (P < 0.05). However, there were no significant differences in ATDP mean scores between those who had or had not previously provided services for women with disabilities. The mean score difference between those who received disability training and who did not was also found statistically insignificant (P > 0.05). This may reflect the small number of individuals, who have had training on disability thus far, or the nature or quality of the training currently available. The majority of qualitative interview participants perceived providers to have the negative attitude with poor knowledge, skills and preparation for providing care to persons with disabilities. Few participants perceived the providers as kind, respectful, caring or helpful. CONCLUSION: Overall, provider's attitude towards disability was found to be negative with poor knowledge and skills about providing services. This may have adversely impact maternal healthcare service utilization by women with disabilities. More organized, effective training for healthcare providers is required through on-going mainstream efforts to develop favorable attitudes towards disability. Further research on this subject is also needed. PMID- 28662711 TI - Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease. AB - BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumours. Haemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma and pheochromocytomas are the most common tumours. The absence of treatment for VHL leads to the need of repeated surgeries as the only option for these patients. Targeting VHL-derived tumours with drugs with reduced side effects is urgent to avoid repeated CNS surgeries. Recent reports have demonstrated that propranolol, a beta-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control haemangioblastoma growth in VHL disease given its antiangiogenic effects that were recently demonstrated by us. The main objective of the present study was the assessment of the efficacy and safety of propranolol on retinal haemangioblastoma in von Hippel-Lindau disease (VHL). METHODS: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily. Patients were evaluated every 3 months for 12 months, at Virgen de la Salud Hospital (Toledo). The patients had juxtapapillary or peripheral haemangioblastomas but had refused standard treatments. RESULTS: Propranolol was initiated with a progressive increase up to a final dose of 120 mg daily. All tumours remained stable, and no new tumours appeared. The reabsorption of retinal exudation was noted in the two patients having exudates. No adverse effects were recorded. VEGF and miRNA 210 levels were monitored in the plasma of patients as possible biomarkers of VHL. These levels decreased in all cases from the first month of treatment. CONCLUSIONS: Although more studies are necessary, the results of this work suggest that propranolol is a drug to be considered in the treatment of VHL patients with retinal haemangioblastomas. VEGF and miRNA 210 could be used as biomarkers of the VHL disease activity. TRIAL REGISTRATION: The study has a clinical trial design and was registered at EU Clinical Trials Register and Spanish Clinical Studies Registry, EudraCT Number: 2014-003671-30 . Registered 2 September 2014. PMID- 28662713 TI - The neutrophil-to-lymphocyte ratio (NLR) predicts adrenocortical carcinoma and is correlated with the prognosis. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is reported as a biomarker for some solid malignant diseases. Thus far, however, no reports of the relationship between the NLR and adrenal tumors have been published. We analyzed the utility of the preoperative NLR as a biomarker for predicting the prognosis or diagnosis of malignant disease. METHODS: A total of 59 patients with adrenal tumors (13 cases of malignant disease and 46 with benign disease) were analyzed in this study from February 2004 to June 2015 at our institute. The NLR was obtained just before adrenalectomy. The diagnosis of adrenal tumor was confirmed by a pathological examination of surgical specimens. RESULTS: The NLR in malignant adrenal tumor specimens was significantly higher than in non-malignant specimens (p = 0.028). Adrenocortical carcinoma (ACC) showed the highest NLR among all adrenal tumors. In ACC, the higher NLR group (NLR >= 5) showed a significantly poorer overall survival than the lower NLR group (NLR < 5) (p = 0.032). CONCLUSIONS: In adrenal tumors, a higher NLR indicates a higher incidence of malignancy. The NLR might be a new biomarker for predicting the prognosis of adrenal tumor patients. PMID- 28662712 TI - 11q deletion in neuroblastoma: a review of biological and clinical implications. AB - Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma. PMID- 28662714 TI - Recall T cell responses to bluetongue virus produce a narrowing of the T cell repertoire. AB - In most viral infections, recall T cell responses are critical for protection. The magnitude of these secondary responses can also affect the CD8 and CD4 epitope repertoire diversity. Bluetongue virus (BTV) infection in sheep elicits a T cell response that contributes to viremia control and could be relevant for cross-protection between BTV serotypes. Here, we characterized CD4+ and CD8+ T cell responses during primary and recall responses. During primary immune responses, both CD4+ and CD8+ T cell populations expanded by 14 days post infection (dpi). CD4+ T cell populations showed a lower peak of expansion and prolonged contraction phase compared to CD8+ T cell populations. Recall responses to BTV challenge led to BTV-specific expansion and activation of CD8+ but not of CD4+ T cells. The evolution of the BTV-specific TCR repertoire was also characterized in response to VP7 peptide stimulation. Striking differences in repertoire development were noted over the time-course of infection. During primary responses, a broader repertoire was induced for MHC-I and MHC-II epitopes. However, during memory responses, a narrowed repertoire was activated towards a dominant motif in VP7 comprising amino acids 139-291. Monocytes were also examined, and expanded during acute infection resolution. In addition, pro inflammatory cytokine levels increased after BTV inoculation and persisted throughout the experiment, indicative of a prolonged inflammatory state during BTV infections. These findings could have implications for vaccine design as the narrowing memory T cell repertoire induced after BTV re-infection could lead to the development of protective immunodominant TCR repertoires that differs between individual sheep. PMID- 28662715 TI - Cognitive Bias Modification for paranoia (CBM-pa): study protocol for a randomised controlled trial. AB - BACKGROUND: Persecutory delusions are the most common type of delusions in psychosis and present in around 10-15% of the general population. Persecutory delusions are thought to be sustained by biased cognitive and emotional processes. Recent advances favour targeted interventions, focussing on specific symptoms or mechanisms. Our aim is to test the clinical feasibility of a novel psychological intervention, which manipulates biased interpretations toward more adaptive processing, in order to reduce paranoia in patients. METHODS: The 'Cognitive Bias Modification for paranoia' (CBM-pa) study is a feasibility, double-blind, randomised controlled trial (RCT) for 60 stabilised outpatients with persistent, distressing paranoid symptoms. Patients will be randomised at a 50:50 ratio, to computerised CBM-pa or a text-reading control intervention, receiving one 40-min session per week, for 6 weeks. CBM-pa involves participants reading stories on a computer screen, completing missing words and answering questions about each story in a way that encourages more helpful beliefs about themselves and others. Treatment as Usual will continue for patients in both groups. Patients will be assessed by a researcher blind to allocation, at baseline, each interim session, post treatment and 1- and 3-month follow-up post treatment. The primary outcome is the feasibility parameters (trial design, recruitment rate and acceptability) of the intervention. The secondary outcomes are clinical symptoms (including severity of paranoia) as assessed by a clinical psychologist, and 'on-line' measurement of interpretation bias and stress/distress. The trial is funded by the NHS National Institute for Health Research. DISCUSSION: This pilot study will test whether CBM-pa has the potential to be a cost-effective, accessible and flexible treatment. If the trial proves feasible and demonstrates preliminary evidence of efficacy, a fully powered RCT will be warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN: 90749868 . Retrospectively registered on 12 May 2016. PMID- 28662716 TI - Awareness of pre-exposure prophylaxis (PrEP) among women who inject drugs in NYC: the importance of networks and syringe exchange programs for HIV prevention. AB - BACKGROUND: Women who inject drugs (WWID) are at heightened risk for HIV due to biological, behavioral, and structural factors. Pre-exposure prophylaxis (PrEP) could aid in HIV prevention for WWID. However, little is known about WWID awareness of PrEP, which is a necessary step that must occur before PrEP uptake. We report factors associated with greater awareness among WWID to identify efficient means of awareness dissemination. METHODS: Data from the 2015 National HIV Behavioral Surveillance (NHBS) system cycle on injection drug use collected in New York City (NYC) were used. Bivariable analyses, using chi-squared statistics, were conducted to examine correlates of awareness of PrEP with socio demographic, behavioral, and health care variables. Multivariable logistic regression was used to estimate adjusted associations and determine differences in awareness of PrEP. RESULTS: The analysis consisted of 118 WWID. Awareness of PrEP was relatively low (31%), and risk factors were high. In the last 12 months, almost two thirds (65%) reported condomless sex, approximately one third (31%) reported transactional sex, and one third (32%) reported sharing injection equipment. In multivariable logistic regression, increased PrEP awareness was associated with reported transactional sex (AOR 3.32, 95% CI 1.22-9.00) and having a conversation about HIV prevention at a syringe exchange program (SEP) (AOR 7.61, 95% CI 2.65-21.84). We did not find race, education, household income, age, binge drinking, or sexual identity to be significantly associated with PrEP awareness. CONCLUSIONS: Large proportions of WWID were unaware of PrEP. These findings suggest that social networks (specifically sex work and SEP networks) are an efficient means for disseminating messaging about prevention materials such as PrEP. We recommend that SEP access increase, SEP processes be adopted in other health care settings, and WWID networks be utilized to increase PrEP awareness. PMID- 28662717 TI - Nonenhanced MR angiography of the pulmonary arteries using single-shot radial quiescent-interval slice-selective (QISS): a technical feasibility study. AB - BACKGROUND: For evaluation of the pulmonary arteries in patients suspected of pulmonary embolism, CT angiography (CTA) is the first-line imaging test with contrast-enhanced MR angiography (CEMRA) a potential alternative. Disadvantages of CTA include exposure to ionizing radiation and an iodinated contrast agent, while CEMRA is sensitive to respiratory motion and requires a gadolinium-based contrast agent. The primary goal of our technical feasibility study was to evaluate pulmonary arterial conspicuity using breath-hold and free-breathing implementations of a recently-developed nonenhanced approach, single-shot radial quiescent-interval slice-selective (QISS) MRA. METHODS: Breath-hold and free breathing, navigator-gated versions of radial QISS MRA were evaluated at 1.5 Tesla in three healthy subjects and 11 patients without pulmonary embolism or arterial occlusion by CTA. Images were scored by three readers for conspicuity of the pulmonary arteries through the level of the segmental branches. In addition, one patient with pulmonary embolism was imaged. RESULTS: Scan time for a 54-slice acquisition spanning the pulmonary arteries was less than 2 minutes for breath hold QISS, and less than 3.4 min using free-breathing QISS. Pulmonary artery branches through the segmental level were conspicuous with either approach. Free breathing scans showed only mild blurring compared with breath-hold scans. For both readers, less than 1% of pulmonary arterial segments were rated as "not seen" for breath-hold and navigator-gated QISS, respectively. In subjects with atrial fibrillation, single-shot radial QISS consistently depicted the pulmonary artery branches, whereas navigator-gated 3D balanced steady-state free precession showed motion artifacts. In one patient with pulmonary embolism, radial QISS demonstrated central pulmonary emboli comparably to CEMRA and CTA. The thrombi were highly conspicuous on radial QISS images, but appeared subtle and were not prospectively identified on scout images acquired using a single-shot bSSFP acquisition. CONCLUSIONS: In this technical feasibility study, both breath-hold and free-breathing single-shot radial QISS MRA enabled rapid, consistent demonstration of the pulmonary arteries through the level of the segmental branches, with only minimal artifacts from respiratory motion and cardiac arrhythmias. Based on these promising initial results, further evaluation in patients with suspected pulmonary embolism appears warranted. PMID- 28662719 TI - Erratum to: Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naive Parkinson's disease patients. PMID- 28662718 TI - Thrombin-induced, TNFR-dependent miR-181c downregulation promotes MLL1 and NF kappaB target gene expression in human microglia. AB - BACKGROUND: Controlling thrombin-driven microglial activation may serve as a therapeutic target for intracerebral hemorrhage (ICH). Here, we investigated microRNA (miRNA)-based regulation of thrombin-driven microglial activation using an in vitro thrombin toxicity model applied to primary human microglia. METHODS: A miRNA array identified 22 differential miRNA candidates. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) identified miR-181c as the most significantly downregulated miRNA. TargetScan analysis identified mixed lineage leukemia-1 (MLL1) as a putative gene target for miR-181c. qRT-PCR was applied to assess tumor necrosis factor-alpha (TNF-alpha), miR-181c, and MLL1 levels following thrombin or proteinase-activated receptor-4-specific activating peptide (PAR4AP) exposure. Anti-TNF-alpha antibodies and tumor necrosis factor receptor (TNFR) silencing were employed to test TNF-alpha/TNFR dependence. A dual luciferase reporter system and miR-181c mimic transfection assessed whether mir 181c directly binds to and negatively regulates MLL1. Nuclear factor kappa-B (NF kappaB)-dependent luciferase reporter assays and NF-kappaB target gene expression were assessed in wild-type (MLL1+) and MLL1-silenced cells. RESULTS: Thrombin or PAR4AP-induced miR-181c downregulation (p < 0.05) and MLL1 upregulation (p < 0.05) that were dependent upon TNF-alpha/TNFR. miR-181c decreased wild-type MLL1 3'-UTR luciferase reporter activity (p < 0.05), and a miR-181c mimic suppressed MLL1 expression (p < 0.05). Thrombin treatment increased, while miR-181c reduced, NF-kappaB activity and NF-kappaB target gene expression in both wild-type (MLL1+) and MLL1-silenced cells (p < 0.05). CONCLUSIONS: Thrombin-induced, TNF-alpha/TNFR dependent miR-181c downregulation promotes MLL1 expression, increases NF-kappaB activity, and upregulates NF-kappaB target gene expression. As miR-181c opposes thrombin's stimulation of pro-inflammatory NF-kappaB activity, miR-181c mimic therapy may show promise in controlling thrombin-driven microglial activation following ICH. PMID- 28662720 TI - A practical examination of RNA isolation methods for European pear (Pyrus communis). AB - OBJECTIVE: With the goal of identifying fast, reliable, and broadly applicable RNA isolation methods in European pear fruit for downstream transcriptome analysis, we evaluated several commercially available kit-based RNA isolation methods, plus our modified version of a published cetyl trimethyl ammonium bromide (CTAB)-based method. RESULTS: We confirmed previous work indicating chaotropic agent-based kits produced sufficient, high-quality RNA in freshly harvested, mature 'Bartlett' fruit. However, RNA isolation from 'd'Anjou' pear peel and especially cortical tissues of fruit stored for 11 months proved challenging to all but our modified CTAB-based method. Generally, more RNA was recovered from peel tissues than cortical tissues. Less toxic dithiothreitol was confirmed to be an acceptable reducing agent as its substitution for 2 mercaptoethanol often yielded high quality RNA. Finally, we present evidence that erroneous signals in the 5S region of Bioanalyzer RNA size plot histograms, that interfered with RNA integrity number calculation, were small RNA fragments that are reduced by simple cleanup procedures, not artifacts as previously reported. PMID- 28662721 TI - Rheopheresis in treatment of idiopathic sensorineural sudden hearing loss. AB - BACKROUND: Only few therapeutic options exist for patients with refractory sudden idiopathic sensorineural hearing loss (SISHL). Little is known about the efficacy of second-line therapies. Rheopheresis seems to be an effective therapeutic possibility. METHODS: Between 2012 and 2015, 106 patients with SISHL were enrolled in the study, of whom 52 were refractory to initial treatment. As salvage therapy, these patients were offered either 3 sessions of rheopheresis (33 pts) or intratympanic steroid treatment through MicroWick application (19 pts). Pure tone audiometry was performed at diagnosis, at the 1st month and the 1st year during the follow-up. RESULTS: Patients in the rheopheretic arm had higher hearing loss than in the MicroWick arm (81% vs. 52%, p = 0.04). In spite of this, there was a significant improvement for patients in the rheopheretic arm (27% of hearing loss reduction, p < 0.001) after the 1st month and this remained unchanged during the 1st year, while no improvement was seen in the MicroWick arm (0% of hearing loss reduction, p = 0.424). We found no predictive factor for steroid-failure in first-line therapy. Older age (p = 0.003), presence of vertigo (p = 0.006) and more profound initial hearing loss (p < 0.001) were identified as negative prognostic markers. CONCLUSION: Rheopheresis can be used as a potentially effective and safe salvage therapy for patients with cortico refractory SISHL. PMID- 28662722 TI - Yeast lysates carrying the nucleoprotein from measles virus vaccine as a novel subunit vaccine platform to deliver Plasmodium circumsporozoite antigen. AB - BACKGROUND: Yeast cells represent an established bioreactor to produce recombinant proteins for subunit vaccine development. In addition, delivery of vaccine antigens directly within heat-inactivated yeast cells is attractive due to the adjuvancy provided by the yeast cell. In this study, Pichia pastoris yeast lysates carrying the nucleoprotein (N) from the measles vaccine virus were evaluated as a novel subunit vaccine platform to deliver the circumsporozoite surface antigen (CS) of Plasmodium. When expressed in Pichia pastoris yeast, the N protein auto-assembles into highly multimeric ribonucleoparticles (RNPs). The CS antigen from Plasmodium berghei (PbCS) was expressed in Pichia pastoris yeast in fusion with N, generating recombinant PbCS-carrying RNPs in the cytoplasm of yeast cells. RESULTS: When evaluated in mice after 3-5 weekly subcutaneous injections, yeast lysates containing N-PbCS RNPs elicited strong anti-PbCS humoral responses, which were PbCS-dose dependent and reached a plateau by the pre-challenge time point. Protective efficacy of yeast lysates was dose dependent, although anti-PbCS antibody titers were not predictive of protection. Multimerization of PbCS on RNPs was essential for providing benefit against infection, as immunization with monomeric PbCS delivered in yeast lysates was not protective. Three weekly injections with N-PbCS yeast lysates in combination with alum adjuvant produced sterile protection in two out of six mice, and significantly reduced parasitaemia in the other individuals from the same group. This parasitaemia decrease was of the same extent as in mice immunized with non adjuvanted N-PbCS yeast lysates, providing evidence that the yeast lysate formulation did not require accessory adjuvants for eliciting efficient parasitaemia reduction. CONCLUSIONS: This study demonstrates that yeast lysates are an attractive auto-adjuvant and efficient platform for delivering multimeric PbCS on measles N-based RNPs. By combining yeast lysates that carry RNPs with a large panel of Plasmodium antigens, this technology could be applied to developing a multivalent vaccine against malaria. PMID- 28662723 TI - HLA B27 antigen in Middle Eastern and Arab countries: systematic review of the strength of association with axial spondyloarthritis and methodological gaps. AB - BACKGROUND: Axial spondyloarthritis (AxSpA) is a relatively frequent and debilitating disease, with a prevalence ranging from 0.1 to 2% in the Caucasian population. Current Assessment of Spondyloarthritis International Society (ASAS) classification criteria of AxSpA rely either on sacroiliitis on imaging plus one SpA feature or positive HLAB27 antigen plus two SpA features, in a patient with chronic low back pain and age at onset of less than 45 years. Therefore, HLA-B27 is a central feature in SpA classification and plays a pivotal role in referral strategies and early diagnosis. The primary objective of the study is to review the prevalence of HLA-B27 in normal and AxSpA populations in Middle Eastern and Arab Countries and to assess the strength of association between HLA-B27 antigen and AxSpA. The secondary objective is to identify the gaps in the methodology of the studies and suggest a framework for future research. METHODS: Studies were included in the analysis if they reported prevalence of HLA-B27 in AxSpA and/or general population and if they covered geographical location in the Middle East or Arab countries in the Mediterranean basin. Odds ratios (OR) were calculated for each country, as a measure of the strength of association between HLA-B27 and AxSpA, compared to the normal population, using the two-by-two frequency table. Available data from the literature were analyzed according to the following quality indicators: sample size, method of HLA-B27 testing, presence of control group and external validity. RESULTS: Twenty-seven studies were analyzed. HLAB27 prevalence in the normal population ranged from 0.3% (Oman) to 6.8% (Turkey). HLA B27 prevalence in AxSpA ranged from 26.2% (Lebanon) to 91% (Turkey). HLA-B27 prevalence in all SpA ranged from 13.87% (Lebanon) to 69.43% (Kuwait). Peripheral SpA was less associated with HLA-B27 than AxSpA, indicating the need of differentiating between the two entities when calculating prevalence. When available (8 studies), the OR ranged from 21.63 (Morocco) to 105.6 (Syria). The high heterogeneity between the results can be due to differences in methodology: study sample size, different classification criteria, absence of control groups, HLA-B27 testing method. CONCLUSIONS: The prevalence of HLA-B27 in the normal population is significantly lower in the Middle Eastern and Arab countries than in Western Countries. However, HLA-B27 testing can be useful for AxSpA positive diagnosis, given the high OR. Heterogeneity between countries may be due to methodological differences. PMID- 28662725 TI - In vitro induction of human embryonal carcinoma differentiation by a crude extract of Rhazya stricta. AB - BACKGROUND: Rhazya stricta Decne. is a medicinal plant that is widespread in Saudi Arabia and desert areas of the Arabian Peninsula. Its extract contains alkaloids, tannins, and flavonoids that are involved in different biological activities. The study aim was to evaluate the effects of Rhazya stricta plant extracts on the proliferation and differentiation of NTERA-2 (NT2) pluripotent embryonal carcinoma cells. METHODS: Soxhlet extraction was carried out using different solvents to extract stems, leaves and fruit parts of this plant. Cytotoxicity was evaluated by an MTS cell viability assay. The ability of the plant extract to induce cell differentiation was examined phenotypically using an inverted light microscope. The expression of pluripotency markers was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry. Phytochemical screening of chloroform stem extracts was carried out and a chromatographic fingerprint was generated using gas chromatography - mass spectrometry (GC-MS). RESULTS: Chloroform stem extract induced differentiation of NT2 cells at 5 MUg/ml, and the differentiated cells exhibited neurite formation. Following induction of differentiation, there was significant down-regulation of the pluripotency marker genes Oct4 and Sox2. In addition, the surface antigen pluripotency marker, TRA-1-60, was strongly down regulated. Phytochemical analysis of the extract showed the presence of alkaloids and saponins. The chromatogram revealed the presence of fifteen compounds with different retention times. CONCLUSION: Our results demonstrate for the first time that chloroform stem extract of R. stricta can induce neuronal differentiation of stem cells at an early stage and may contain potential therapeutic agent that can be used in neurodegenerative diseases. PMID- 28662724 TI - Insecticide resistance and resistance mechanisms in bed bugs, Cimex spp. (Hemiptera: Cimicidae). AB - The worldwide resurgence of bed bugs [both Cimex lectularius L. and Cimex hemipterus (F.)] over the past two decades is believed in large part to be due to the development of insecticide resistance. The transcriptomic and genomic studies since 2010, as well as morphological, biochemical and behavioral studies, have helped insecticide resistance research on bed bugs. Multiple resistance mechanisms, including penetration resistance through thickening or remodelling of the cuticle, metabolic resistance by increased activities of detoxification enzymes (e.g. cytochrome P450 monooxygenases and esterases), and knockdown resistance by kdr mutations, have been experimentally identified as conferring insecticide resistance in bed bugs. Other candidate resistance mechanisms, including behavioral resistance, some types of physiological resistance (e.g. increasing activities of esterases by point mutations, glutathione S-transferase, target site insensitivity including altered AChEs, GABA receptor insensitivity and altered nAChRs), symbiont-mediated resistance and other potential, yet undiscovered mechanisms may exist. This article reviews recent studies of resistance mechanisms and the genes governing insecticide resistance, potential candidate resistance mechanisms, and methods of monitoring insecticide resistance in bed bugs. This article provides an insight into the knowledge essential for the development of both insecticide resistance management (IRM) and integrated pest management (IPM) strategies for successful bed bug management. PMID- 28662726 TI - Identification of clear cell renal cell carcinoma and oncocytoma using a three gene promoter methylation panel. AB - BACKGROUND: Promoter methylation has emerged as a promising class of epigenetic biomarkers for diagnosis and prognosis of renal cell tumors (RCTs). Although differential gene promoter methylation patterns have been reported for the major subtypes (clear cell, papillary and chromophobe renal cell carcinoma, and oncocytoma), validation of diagnostic performance in independent series have been seldom performed. Herein, we aimed at assessing the diagnostic performance of genes previously shown to be hypermethylated in RCTs in different clinical settings. METHODS: Promoter methylation levels of HOXA9 and OXR1 were assessed by quantitative methylation specific PCR. ROC curves were generated for OXR1, OXR1 combined with MST1R and HOXA9. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were computed, maximizing specificity. Methylation levels were also correlated with clinical and pathological relevant parameters. RESULTS: HOXA9 and OXR1 promoter methylation was disclosed in 73 and 87% of RCTs, respectively. A two-gene methylation panel comprising OXR1 and MST1R identified malignancy with 98% sensitivity and 100% specificity, and clear cell renal cell carcinoma with 90% sensitivity and 98% specificity. HOXA9 promoter methylation allowed for discrimination between oncocytoma and both papillary and chromophobe renal cell carcinoma but only with 77% sensitivity and 73% specificity. Significantly higher OXR1 promoter methylation levels (p = 0.005) were associated with high nuclear grade in ccRCC. CONCLUSIONS: A panel including OXR1 and MST1R promoter methylation allows specific and sensitive identification of renal cell tumors, and, especially, of clear cell renal cell carcinoma. Moreover, higher OXR1 promoter methylation levels associate with clear cell renal cell carcinoma nuclear grade, a surrogate for tumor aggressiveness. Thus, gene promoter methylation analysis might a useful ancillary tool in diagnostic management of renal masses. PMID- 28662729 TI - The moving junction protein RON4, although not critical, facilitates host cell invasion and stabilizes MJ members. AB - Toxoplasma gondii is an obligate intracellular parasite of phylum Apicomplexa. To facilitate high-efficiency invasion of host cells, T. gondii secretes various proteins related to the moving junction (MJ) complex from rhoptries and micronemes into the interface between the parasite and host. AMA1/RON2/4/5/8 is an important MJ complex, but its mechanism of assembly remains unclear. In this study, we used the CRISPR-Cas9 system to generate a derivative of T. gondii strain RH with a null mutation in TgRON4, thought to be an essential MJ component. Deficiency of TgRON4 moderately decreased invasion ability relative to that of the wild-type parasite. In addition, expression of the endogenous N terminal fragment of RON5 decreased in the mutant. Together, the results improve our understanding of the assembly mechanism of the MJ complex of T. gondii and raise the possibility of developing new therapeutic drugs that target this complex. PMID- 28662728 TI - Actions of sesquiterpene lactones isolated from Moquiniastrum polymorphum subsp. floccosum in MCF7 cell line and their potentiating action on doxorubicin. AB - BACKGROUND: In order to obtain better clinical results in anticancer therapies, polychemotherapy or combination therapies are used. For this, the combinations are required to increase the efficacy and reduce the adverse reactions of the associated chemotherapies. The aim of this study was to evaluate the cytotoxic, apoptotic and (anti)proliferative potential of two sesquiterpene lactones isolated from Moquiniastrum polymorphum, 11,13-diidrozaluzanin C (1) and gochnatiolide C (2), and their associations with chemotherapeutic agents irinotecan, tamoxifen, cisplatin, 5-fluouracyl and doxorubicin in the tumoral lineage of MCF-7 breast adenocarcinoma. METHODS: The analyses were performed by MTT cytotoxicity assays, drug combination index (CI), apoptosis morphological assay and cell proliferation assay. Treatments were evaluated with short exposure times (4 h), followed or not by recovery in drug-free medium for 24 h. For the cell viability assay the statistical analysis was performed using software INSTAT, and the ANOVA/Tukey test was applied. Combination Indices (CI) was made using CompuSyn software and demonstrated through isoboles. The assays that evaluated cell death and proliferation used statistical analysis SAS 9.4 (Statistical Analysis System), and the procedure adopted was PROC NPAR1WAY. The Wilcoxon test at 5% level was applied for comparing statistical differences. RESULTS: The results demonstrated that the compounds decrease cell viability and increase their action when associated with irinotecan, tamoxifen and doxorubicin (CI < 1 and CI = 1). In periods of 4 h-exposure, the compounds cause cell death by apoptosis and after 24 h, they increase the mean number of cells in programmed cell death, especially when treated with 2. In addition, the association with doxorubicin increases the apoptotic potential induced by tested compounds. Both isolates had effect on the reduction of the number of mitoses, especially when 2 at its highest concentration is associated with doxorubicin. CONCLUSIONS: Finally, these compounds are presented as potential agents in chemotherapy combined with doxorubicin, since they trigger the mechanism of apoptosis, which, through the mechanism of action of sesquiterpene lactones, leads to a reduction in toxicity. In addition, the tested compounds have the ability to exert a synergistic action with doxorubicin, possibly by down-regulating the drug resistance mechanisms. PMID- 28662727 TI - Frontal brain activation changes due to dual-tasking under partial body weight support conditions in older adults with multiple sclerosis. AB - BACKGROUND: Gait impairments present while dual-tasking in older adults with multiple sclerosis (MS) have been associated with an increased risk of falls. Prior studies have examined prefrontal cortex (PFC) activity using functional near infrared spectroscopy (fNIRS) while dual-tasking in older adults with and without cognitive impairment. While the benefits of partial body weight support (PBWS) on gait have been clearly outlined in the literature, the potential use of PBWS to improve the ability to dual task in older adults with and without MS has not been examined. The aim of this study was to examine the effects of PBWS on the PFC activation while dual-tasking in older adults with and without MS. METHODS: Ten individuals with MS (mean 56.2 +/- 5.1 yrs., 8 females) and 12 healthy older adults (HOA) (mean 63.1 +/- 4.4 yrs., 9 females) participated in this study. PFC activation (i.e., oxygenated hemoglobin-HbO2) was measured using fNIRS. Assessments were done under two treadmill walking conditions: no body weight support (NBWS) and PBWS. Under each condition, participants were asked to walk at a comfortable speed (W) or walk and talk (WT). Linear mixed models were used to test for differences between cohorts, conditions, and tasks. RESULTS: HbO2 levels differed significantly between task (p < .001), cohort (p < .001), and BWS (p = .02). HbO2 levels increased under higher cognitive demands (i.e., W vs WT), in individuals with MS, and under different conditions (i.e., NBWS vs PBWS). Post-hoc analysis demonstrated a significant difference between cohorts during the WT and NBWS condition (p = .05). When examining the relative change in HbO2 levels during each task, a significant interaction between task, BWS, and cohort across time was observed (p < 0.01). While HOA increased PFC activation across time, MS exhibited a maintenance of PFC activation patterns during the WT under PBWS condition. CONCLUSIONS: This study establishes the potential impact of PBWS on PFC activation patterns under dual-tasking conditions and sheds light on the ability for PBWS to be used as a therapeutic tool in individuals with neurological conditions to decrease cognitive demands while dual-tasking and thus decrease the risk of falls. PMID- 28662730 TI - Effective nutrition education and communication for sustainable maternal and child health. AB - Maternal and child health (MCH) consists of an interdependent reproductive system that collectively determines the survival of the mother during childbirth, and determines the health and survival of the child. This interdependency underscores the importance of appropriate and timely interventions during pregnancy through the first 1000 d at the minimum. The Millennium Development Goals (MDG) recommended the use of the continuum of care for the development of interventions by addressing all the stages of MCH. The purpose of the present paper is to review the factors that contributed to the attainment of the MDG 4 and MDG 5 by analysing the interventions conducted by the countries that achieved at least 5.0 and 5.5 %, respectively, and determine the level of their intervention based on the MCH conceptual framework. Out of the eighteen selected countries discussed, fifteen countries achieved their target for either MDG 4 or MDG 5 or both, while three countries did not achieve their target. The countries that were more likely to achieve their targets addressed the societal, underlying and direct causes, and implemented country wide policies. In contrast, the countries that did not succeed were more likely to address the direct causes with poor policy implementation. Understanding the motivation and limitations of the target population, including nutrition education and targeting behaviour change has the potential to result in sustainable MCH. This information has the potential to enlighten the policymakers as we progress to the sustainable development goals, specifically goals 2 and 3. PMID- 28662731 TI - A 12-week intervention with protein-enriched foods and drinks improved protein intake but not physical performance of older patients during the first 6 months after hospital release: a randomised controlled trial. AB - During and after hospitalisation, older adults are recommended to consume 1.2-1.5 g of protein/kg body weight per d (g/kg per d) to improve recovery. This randomised controlled trial studied the effectiveness of a 12-week intervention with protein-enriched foods and drinks by following-up seventy-five older patients (mean age: 76.8 (sd 6.9) years) during their first 6 months after hospital discharge. Primary outcomes were protein intake and physical performance (measured with Short Physical Performance Battery (SPPB)). Secondary outcomes for physical recovery were gait speed, chair-rise time, leg-extension strength, hand grip strength, body weight, nutritional status (Mini Nutritional Assessment), independence in activities of daily living (ADL) and physical activity. The intervention group consumed more protein during the 12-week intervention period compared with the control group (P<0.01): 112 (sd 34) g/d (1.5 (sd 0.6) g/kg per d) v. 78 (sd 18) g/d (1.0 (sd 0.4) g/kg per d). SPPB total score, gait speed, chair-rise time, body weight and nutritional status improved at week 12 compared with baseline (time effect P<0.05), but were not different between groups. Leg extension strength, hand-grip strength and independence in ADL did not change. In conclusion, protein-enriched products enabled older adults to increase their protein intake to levels that are higher than their required intake. In these older adults with already adequate protein intakes and limited physical activity, protein enrichment did not enhance physical recovery in the first 6 months after hospital discharge. PMID- 28662733 TI - HEALTH TECHNOLOGY ASSESSMENT IN SERBIA. AB - OBJECTIVES: This study provides an overview of the Republic of Serbia healthcare system and describes the process of developing and conducting health technology assessment (HTA). METHODS: The authors performed pragmatic, nonsystematic literature review based on available statistical data, legislation, and studies. RESULTS: Healthcare law creates conditions that allow implementation of the principle "value for money." The institutions directly vested in the implementation of HTA are the National Health Insurance Fund (NHIF) and the Ministry of Health (MoH). There are some reflections of the efforts by NHIF and MoH toward achieving this goal. CONCLUSIONS: Despite the highly set objectives, there is still a lot of work to be done to build an adequate model to support decision-making processes to bridge the discrepancies between broadly defined rights to health care and limited resources in the country. PMID- 28662732 TI - Diet quality and attention capacity in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study. AB - Adolescence represents an important period for the development of executive functions, which are a set of important cognitive processes including attentional control. However, very little is known regarding the associations of nutrition with components of executive functions in adolescence. Thus, the aim of this study was to investigate associations of dietary patterns and macronutrient composition with attention capacity in European adolescents. This cross-sectional study included 384 (165 boys and 219 girls) adolescents, aged 12.5-17.5 years, from five European countries in the Healthy Lifestyle in Europe by Nutrition in Adolescence study. Attention capacity was examined using the d2 Test of Attention. Dietary intake was assessed through two non-consecutive 24 h recalls using a computer-based self-administered tool. Three dietary patterns (diet quality index, ideal diet score and Mediterranean diet score) and macronutrient/fibre intakes were calculated. Linear regression analysis was conducted adjusting for age, sex, BMI, maternal education, family affluence scale, study centre and energy intake (only for Mediterranean diet score). In these adjusted regression analyses, higher diet quality index for adolescents and ideal diet score were associated with a higher attention capacity (standardised beta=0.16, P=0.002 and beta=0.15, P=0.005, respectively). Conversely, Mediterranean diet score or macronutrient/fibre intake were not associated with attention capacity (P>0.05). Our results suggest that healthier dietary patterns, as indicated by higher diet quality index and ideal diet score, were associated with attention capacity in adolescence. Intervention studies investigating a causal relationship between diet quality and attention are warranted. PMID- 28662734 TI - Editorial. PMID- 28662735 TI - Microfluidics: A Tool to Control the Size and Composition of Particles. AB - Particles and capsules are used as containers for active ingredients to delay their degradation and control the location and kinetics of their release. Key to a successful application of these containers is a good control over their size, composition, and the release kinetics of encapsulants. These parameters can be tuned if containers are made from drops of a controlled size and composition; a method that enables formation of drops of a defined size is microfluidics. This review highlights some recent developments in the use of drops made with microfluidics to produce particles and capsules of controlled sizes, compositions, and structures. PMID- 28662736 TI - Programmable Control in Extracellular Matrix-mimicking Polymer Hydrogels. AB - The extracellular matrix (ECM) and cells have a reciprocal relationship, one shapes the other and vice versa. One of the main challenges of synthetic material systems for developmental cell culturing, organoid and stem cell work includes the implementation of this reciprocal nature. The largest hurdle to achieve true cell-instructive materials in biomaterials engineering is a lack of spatial and temporal control over material properties and the display of bioactive signals compared to the natural cell environment. ECM-mimicking hydrogels have been developed using a wide range of polymers, assembly and cross-linking strategies. While our synthetic toolbox is larger than nature, often our systems underperform when compared to ECM systems with natural components like Matrigel. Material properties and three-dimensional structure ill-represent the three-dimensional ECM reciprocal nature and ligand presentation is an oversimplified version of the complexity found in nature. We hypothesize that the lack of programmable control in properties and ligand presentation forms the basis of this mismatch in performance and analyze the presence of control in current state of the art ECM mimicking systems based on covalent, supramolecular and recombinant polymers. We conclude that through combining the dynamics of supramolecular materials, robustness from covalent systems and the programmable spatial control of bio activation in recombinant ECM materials, the optimal synthetic artificial ECM could be assembled. PMID- 28662737 TI - Hybrid Colloids Produced by Sequential Capillarity-assisted Particle Assembly: A New Path for Complex Microparticles. AB - Colloidal particles have long been under the spotlight of a very diverse research community, given their ubiquitous presence in a broad class of materials and processes, and their pivotal role as model systems. More recently, intense efforts have been devoted to the development of micro- and nanoparticles combining multiple materials in objects with a controlled architecture, hence introducing multiple functionalities and a prescribed symmetry for interactions. These particles are often called hybrid colloids or colloidal molecules, given the analogy with classical molecules presenting well defined structures and chemical compositions. Here, we review the recent progress made in our group to fabricate a broad library of hybrid colloids exploiting a novel assembly route, which uses capillary forces at the moving edge of an evaporating droplet for the sequential composition of colloidal clusters, whose geometry and chemistry can be independently programmed. PMID- 28662738 TI - The Art and Science of Polymer Brushes: Recent Developments in Patterning and Characterization Approaches. AB - Polymer brushes are dense arrays of macromolecular chains tethered by one end at a surface. They are at the cutting edge of polymer nanotechnology since the dawn of controlled surface-initiated polymerization techniques unlocked new prospects for the synthesis of polymer brushes with tailorable properties. More recently, thanks to the growing interest in the use of brushes for the generation of functional surfaces, the need for advanced patterning and characterization approaches rapidly increased. Meeting these needs requires the contribution of experts from different disciplines: polymer chemistry, surface science, electrochemistry and particle physics. The focus of this review is to highlight recent developments in the field of polymer brushes, specifically the application of photocatalytic lithography as a versatile patterning strategy, the study of grafted-from polymer brushes by electrochemical methods and, most importantly, the introduction of positron annihilation spectroscopy as a powerful technique for the investigation of the structure of polymer brushes and of their composites with nanoparticles. PMID- 28662739 TI - Challenges and Perspectives in the Macromolecular Flatland. AB - Polymer chemistry has recently welcomed a new addition to its field: the planar macromolecules known as two-dimensional polymers (2DPs). These topologically planar and crystalline monolayer covalent sheets are reminiscent of molecular fishermen's nets and apart from being conceptually very interesting for the field of macro-molecular chemistry, they also show some potential applications as novel 2D materials. This article reviews how the field has developed five years after the first 2DP was synthesised in 2012. After a brief historical introduction, the main synthetic approaches will be discussed providing concrete examples of 2DPs and highlighting the challenges associated with the synthesis and especially structural characterisation of these fascinating macro-molecules. Finally an overview on their potential applications such as membranes for gas separation, rewritable molecular paper and miniaturisation of optical devices will be presented. PMID- 28662740 TI - Molecular Strategies for Morphology Control in Semiconducting Polymers for Optoelectronics. AB - Solution-processable semiconducting polymers have been explored over the last decades for their potential applications in inexpensively fabricated transistors, diodes and photovoltaic cells. However, a remaining challenge in the field is to control the solid-state self-assembly of polymer chains in thin films devices, as the aspects of (semi)crystallinity, grain boundaries, and chain entanglement can drastically affect intra-and inter-molecular charge transport/transfer and thus device performance. In this short review we examine how the aspects of molecular weight and chain rigidity affect solid-state self-assembly and highlight molecular engineering strategies to tune thin film morphology. Side chain engineering, flexibly linking conjugation segments, and block co-polymer strategies are specifically discussed with respect to their effect on field effect charge carrier mobility in transistors and power conversion efficiency in solar cells. Example systems are taken from recent literature including work from our laboratories to illustrate the potential of molecular engineering semiconducting polymers. PMID- 28662741 TI - Cellulose Nanocrystals: Surface Modification, Applications and Opportunities at Interfaces. AB - Cellulose nanocrystals (CNCs) are rod-like nano-scale particles that are widely available in nature and have recently gained great interest in both research and industry, due to their high strength, high crystallinity, high surface area, low density, biodegradability and low toxicity. CNCs can be easily extracted from natural cellulose sources and are broadly useful, for example in polymer reinforcement, paper manufacturing, and rheology modification. The high density of functional groups on the surface of CNCs allows various chemical surface modifications, which permit tuning the properties of CNCs over a wide range. This review gives a brief overview of surface chemical modification of CNCs, focusing especially on those often utilized for our own research, which focuses on some of the most prominent areas of interests of CNCs, notably polymer reinforcement, healable polymers, stimuli-responsive nanohybrids, Pickering emulsion stabilizers, viral inhibitors, and cholesteric liquid crystal assemblies. PMID- 28662743 TI - Precision Diagnostics for Mobile Health Using Capillary-driven Microfluidics. PMID- 28662744 TI - Anionic Vesicles Can Control the Reaction Pathway of a Highly Reactive Intermediate. PMID- 28662745 TI - The 52nd EUCHEMS Conference on Stereochemistry: Burgenstock Conference 2017, Brunnen, April 30th-May 4th, 2017. PMID- 28662746 TI - 2017 Chemistry Travel Award by SCNAT and SCS. PMID- 28662747 TI - Special Issue: Infectious Disease Research: Animal Models and Risk Management. PMID- 28662748 TI - Institutional Oversight of Occupational Health and Safety for Research Programs Involving Biohazards. AB - Research with hazardous biologic materials (biohazards) is essential to the progress of medicine and science. The field of microbiology has rapidly advanced over the years, partially due to the development of new scientific methods such as recombinant DNA technology, synthetic biology, viral vectors, and the use of genetically modified animals. This research poses a potential risk to personnel as well as the public and the environment. Institutions must have appropriate oversight and take appropriate steps to mitigate the risks of working with these biologic hazards. This article will review responsibilities for institutional oversight of occupational health and safety for research involving biologic hazards. PMID- 28662749 TI - Personal Protective Equipment in Animal Research. AB - The occupational health and safety program is an integral component of a comprehensive animal care and use program. It is important to mitigate the risk of exposures of animal care and research personnel to allergens and physical, chemical, radiologic, and biologic hazards during the conduct of various tasks. This need is especially true in infectious disease and biocontainment research. One aspect of the program is the provision of personal protective equipment (PPE). Commercially available PPE should be carefully evaluated based on their material composition and performance according to manufacturer data. To help institutions and end users by providing them guidance on choosing appropriate PPE, we here discuss the regulatory framework, device standards, and materials engineering for various PPE, including gloves, shoe covers, head caps, gowns, aprons, masks, hearing and eye protection devices, and respirators. Ultimately, the choice of appropriate PPE is based on the risk assessment, which should include consideration for personnel comfort, correct device fitting, and the containment level for the hazard used. PMID- 28662750 TI - Viral Vector Biosafety in Laboratory Animal Research. AB - Viral vector research presents unique occupational health and safety challenges to institutions due to the rapid development of both in vivo and in vitro gene editing technologies. Risks to human and animal health make it incumbent on institutions to appropriately evaluate viral vector usage in research on the basis of available information and governmental regulations and guidelines. Here we review the factors related to risk assessment regarding viral vector usage in animals and the relevant regulatory documents associated with this research, and we highlight the most commonly used viral vectors in research today. This review is particularly focused on the background, use in research and associated health and environmental risks related to adenoviral, adeno-associated viral, lentiviral, and herpesviral vectors. PMID- 28662751 TI - Considerations for Infectious Disease Research Studies Using Animals. AB - Animal models are vital in understanding the transmission and pathogenesis of infectious organisms and the host immune response to infection. In addition, animal models are essential in vaccine and therapeutic drug development and testing. Prior to selecting an animal model to use when studying an infectious agent, the scientific team must determine that sufficient in vitro and ex vivo data are available to justify performing research in an animal model, that ethical considerations are addressed, and that the data generated from animal work will add useful information to the body of scientific knowledge. Once it is established that an animal should be used, the questions become 'Which animal model is most suitable?' and 'Which experimental design issues should be considered?' The answers to these questions take into account numerous factors, including scientific, practical, welfare, and regulatory considerations, which are the focus of this article. PMID- 28662752 TI - An Overview of Animal Models for Arthropod-Borne Viruses. AB - Arthropod-borne viruses (arboviruses) have continued to emerge in recent years, posing a significant health threat to millions of people worldwide. The majority of arboviruses that are pathogenic to humans are transmitted by mosquitoes and ticks, but other types of arthropod vectors can also be involved in the transmission of these viruses. To alleviate the health burdens associated with arbovirus infections, it is necessary to focus today's research on disease control and therapeutic strategies. Animal models for arboviruses are valuable experimental tools that can shed light on the pathophysiology of infection and will enable the evaluation of future treatments and vaccine candidates. Ideally an animal model will closely mimic the disease manifestations observed in humans. In this review, we outline the currently available animal models for several viruses vectored by mosquitoes, ticks, and midges, for which there are no standardly available vaccines or therapeutics. PMID- 28662753 TI - Animal Models of Zika Virus. AB - Zika virus has garnered great attention over the last several years, as outbreaks of the disease have emerged throughout the Western Hemisphere. Until quite recently Zika virus was considered a fairly benign virus, with limited clinical severity in both people and animals. The size and scope of the outbreak in the Western Hemisphere has allowed for the identification of severe clinical disease that is associated with Zika virus infection, most notably microcephaly among newborns, and an association with Guillian-Barre syndrome in adults. This recent association with severe clinical disease, of which further analysis strongly suggested causation by Zika virus, has resulted in a massive increase in the amount of both basic and applied research of this virus. Both small and large animal models are being used to uncover the pathogenesis of this emerging disease and to develop vaccine and therapeutic strategies. Here we review the animal model-based Zika virus research that has been performed to date. PMID- 28662754 TI - Animal Models of Ebolavirus Infection. AB - Ebola virus is a highly pathogenic member of the family Filoviridae that causes a severe hemorrhagic disease in humans and NHP. The 2013-2016 West African outbreak has increased interest in the development and refinement of animal models of Ebola virus disease. These models are used to test countermeasures and vaccines, gain scientific insights into the mechanisms of disease progression and transmission, and study key correlates of immunology. Ebola virus is classified as a BSL4 pathogen and Category A agent, for which the United States government requires preparedness in case of bioterrorism. Rodents, such as Syrian golden hamsters (Mesocricetus auratus), mice (Mus musculus), and guinea pigs (Cavia porcellus), are the most common research species. However, NHP, especially macaques, are favored for Ebola virus disease research due to similarities with humans regarding the pathogenesis, clinical presentation, laboratory findings, and causes of fatality. To satisfy the regulatory requirements for approval of countermeasures against high-consequence pathogens, the FDA instituted the Animal Rule, which permits efficacy studies in animal models in place of human clinical data when such studies are not feasible or ethical. This review provides a comprehensive summary of various animal models and their use in Ebola virus disease research. PMID- 28662755 TI - Stress Leukogram Induced by Acute and Chronic Stress in Zebrafish (Danio rerio). AB - The use of zebrafish (Danio rerio) as an animal model for experimental studies of stress has increased rapidly over the years. Although many physiologic and behavioral characteristics associated with stress have been defined in zebrafish, the effects of stress on hematologic parameters have not been described. The purpose of our study was to induce a rise in endogenous cortisol through various acute and chronic stressors and compare the effects of these stressors on peripheral WBC populations. Acutely stressed fish underwent dorsal or full-body exposure to air for 3 min, repeated every 30 min over the course of 90 min. Chronically stressed fish underwent exposure to stressors twice daily over a period of 5 d. After the last stressful event, fish were euthanized, and whole blood and plasma were obtained. A drop of whole blood was used to create a blood smear, which was subsequently stained with a modified Wright-Giemsa stain and a 50-WBC differential count determined. Plasma cortisol levels were determined by using a commercially available ELISA. Endogenous cortisol concentrations were significantly higher in both stressed groups as compared with control fish. Acutely stressed fish demonstrated significant lymphopenia, monocytosis, and neutrophilia, compared with unstressed, control fish. Chronic stress induced lymphopenia and monocytosis but no significant changes in relative neutrophil populations in zebrafish. The changes in both stressed groups most likely are due to increases in endogenous cortisol concentrations and represent the first description of a stress leukogram in zebrafish. PMID- 28662756 TI - Effect of Antibiotic Administration during Infancy on Growth Curves through Young Adulthood in Rhesus Macaques (Macaca mulatta). AB - Recent human studies indicate a possible correlation between the administration of antibiotics during early life and the risk of later obesity, potentially due to antibiotic-induced alteration of the gastrointestinal microbiome. In humans, the risk of obesity increases with multiple courses of antibiotics and when fetuses or infants are treated with broad-spectrum and macrolide antibiotics. In addition, the obesity risk in humans seems higher for males than females. We used a retrospective, case-control, matched-pair study design to evaluate health records for 99 control-matched pairs of rhesus macaques (Macaca mulatta) from an outdoor breeding colony. We hypothesized that NHP treated with antibiotics prior to 6 mo of age would have steeper growth curves than those who were not. However, in contrast to prior research with humans and mice, growth curves did not differ between antibiotic-treated and control animals. Differences between humans and NHP may have influenced this outcome, including the relative standardization of NHP environmental factors and diet compared with those of human populations, types of infections encountered in infancy and choice of antibiotic treatment, and the different relative maturity at 6 mo of age in the 2 species. The results provide support for current standard medical practice in NHP and highlight a difference between macaques and humans that may influence future obesity research using macaques. Determining the basis for this difference might improve our understanding of the risks of earlylife antibiotic treatment and suggest mitigation strategies for treating infant illnesses without risking obesity. PMID- 28662757 TI - Abdominal Wall Endometriosis in a Rhesus Macaque (Macaca mulatta). AB - Endometriosis is the presence of endometrium outside of the uterus. Although endometriosis occurs in both pelvic and extrapelvic locations, extrapelvic locations are less common. The development of abdominal wall or incisional endometriosis in women is associated with gynecologic surgeries and is often misdiagnosed. Because they naturally develop endometriosis similar to women, Old World NHP, including rhesus macaques, provide excellent opportunities for studying endometriosis. Here, we describe a case of abdominal wall endometriosis in a rhesus macaque that had undergone cesarean section. Microscopically, the tissue consisted of pseudocolumnar epithelium-lined glands within a decidualized stroma, which dissected through the abdominal wall musculature and into the adjacent subcutaneous tissue. The stroma was strongly positive for vimentin and CD10 but was rarely, weakly positive for estrogen receptors and negative for progesterone. Close examination of extrapelvic endometriosis in rhesus macaques and other NHP may promote increased understanding of endometriosis in women. PMID- 28662759 TI - A Project to Promote Adherence to Blood Pressure Medication Among People Who Use Community Pharmacies in Rural Montana, 2014-2016. AB - INTRODUCTION: Pharmacists can assist patients in managing their blood pressure levels. We assessed whether adherence to blood pressure medication improved among people who used community pharmacies in rural Montana after pharmacists initiated consultations and distributed educational materials developed for the Million Hearts Initiative's "Team Up. Pressure Down." (TUPD) program. METHODS: From 2014 to 2016, the Cardiovascular Health Program at the Montana Department of Public Health and Human Services conducted a statewide project to evaluate an intervention for adherence to blood pressure medication administered through community pharmacies. After the year 1 pilot, we redesigned the program for year 2 and year 3 and measured the percentage of participating patients who adhered to blood pressure medication. We also conducted a statewide survey to assess pharmacy characteristics, computer-system capabilities, and types of consulting services provided by pharmacists. RESULTS: Twenty-five community pharmacies completed Montana's TUPD program: 8 pharmacies in the pilot year, 11 pharmacies in year 2, and 6 pharmacies in year 3. For year 2 and year 3 combined, the percentage of participating patients who achieved blood pressure medication adherence improved preintervention to postintervention from 73% to 89%, and adherence improved in 15 of the 17 pharmacies. The pilot pharmacies identified 3 major barriers to project success: patient buy-in, staff burden in implementing the project, and funding. In the statewide assessment, TUPD-funded pharmacies were significantly more likely than non-TUPD-funded pharmacies to provide prescription synchronization and medication management with feedback to the patient's physician. CONCLUSION: Community pharmacies in rural areas can effectively use brief consultations and standard educational materials to improve adherence to blood pressure medication. PMID- 28662760 TI - A Feasibility Study of Supply and Demand for Diabetes Prevention Programs in North Carolina. AB - INTRODUCTION: Diabetes Prevention Programs (DPPs) have shown that healthy eating and moderate physical activity are effective ways of delaying and preventing type 2 diabetes in people with impaired glucose tolerance. We assessed willingness to pay for DPPs from the perspective of potential recipients and the cost of providing these programs from the perspective of community health centers and local health departments in North Carolina. METHODS: We used contingent valuation to determine how much potential recipients would be willing to pay to participate in DPPs under 3 different models: delivered by registered professionals (traditional model), by community health workers, or online. By using information on the minimum reimbursement rate at which public health agencies would be prepared to provide the 3 models, we estimated the marginal costs per person of supplying the programs. Matching supply and demand, we estimated the degree of cost sharing between recipients and providers. RESULTS: Potential program recipients (n = 99) were willing to pay more for programs led by registered professionals than by community health workers, and they preferred face-to-face contact to an online format. Socioeconomic status (measured by education and employment) and age played the biggest roles in determining willingness to pay. Leaders of public health agencies (n = 27) reported up to a 40% difference in the cost of providing the DPP, depending on the delivery model. CONCLUSION: By using willingness to pay to understand demand for DPPs and computing the provider's marginal cost of providing these services, we can estimate cost sharing and market coverage of these services and thus compare the viability of alternate approaches to scaling up and sustaining DPPs with available resources. PMID- 28662761 TI - Genomic investigation of a suspected outbreak of Legionella pneumophila ST82 reveals undetected heterogeneity by the present gold-standard methods, Denmark, July to November 2014. AB - Between July and November 2014, 15 community-acquired cases of Legionnaires' disease (LD), including four with Legionella pneumophila serogroup 1 sequence type (ST) 82, were diagnosed in Northern Zealand, Denmark. An outbreak was suspected. No ST82 isolates were found in environmental samples and no external source was established. Four putative-outbreak ST82 isolates were retrospectively subjected to whole genome sequencing (WGS) followed by phylogenetic analyses with epidemiologically unrelated ST82 sequences. The four putative-outbreak ST82 sequences fell into two clades, the two clades were separated by ca 1,700 single nt polymorphisms (SNP)s when recombination regions were included but only by 12 to 21 SNPs when these were removed. A single putative-outbreak ST82 isolate sequence segregated in the first clade. The other three clustered in the second clade, where all included sequences had < 5 SNP differences between them. Intriguingly, this clade also comprised epidemiologically unrelated isolate sequences from the UK and Denmark dating back as early as 2011. The study confirms that recombination plays a major role in L. pneumophila evolution. On the other hand, strains belonging to the same ST can have only few SNP differences despite being sampled over both large timespans and geographic distances. These are two important factors to consider in outbreak investigations. PMID- 28662762 TI - Fall in new HIV diagnoses among men who have sex with men (MSM) at selected London sexual health clinics since early 2015: testing or treatment or pre exposure prophylaxis (PrEP)? AB - Since October 2015 up to September 2016, HIV diagnoses fell by 32% compared with October 2014-September 2015 among men who have sex with men (MSM) attending selected London sexual health clinics. This coincided with high HIV testing volumes and rapid initiation of treatment on diagnosis. The fall was most apparent in new HIV testers. Intensified testing of high-risk populations, combined with immediately received anti-retroviral therapy and a pre-exposure prophylaxis (PrEP) programme, may make elimination of HIV achievable. PMID- 28662763 TI - Baseline incidence of intussusception in early childhood before rotavirus vaccine introduction, the Netherlands, January 2008 to December 2012. AB - Intussusception is a rare, potentially life-threatening condition in early childhood. It gained attention due to an unexpected association with the first rotavirus vaccine, RotaShield, which was subsequently withdrawn from the market. Across Europe, broad variations in intussusception incidence rates have been reported. This study provides a first estimate of intussusception incidence in young children in the Netherlands from 1 January 2008 to 31 December 2012, which could be used for future rotavirus safety monitoring. Our estimates are based on two different sources: electronic medical records from the primary healthcare database (IPCI), as well as administrative data from the Dutch hospital register (LBZ). The results from our study indicate a low rate of intussusception. Overall incidence rate in children < 36 months of age was 21.2 per 100,000 person-years (95% confidence interval (CI): 12.5-34.3) based on primary healthcare data and 22.6 per 100,000 person-years (95% CI: 20.9-24.4) based on hospital administrative data. The estimates suggest the upper and lower bound of the expected number of cases. PMID- 28662765 TI - Third Director of the European Centre for Disease Prevention and Control takes office. PMID- 28662766 TI - Electrokinetic transport in liquid foams. AB - Investigating electrokinetic transport in a liquid foam is at the confluence of two well developed research areas. On one hand, the study of electrokinetic flows (i.e. surface-driven flows generated close to a charged interface) is fairly well understood in regards the solid/liquid interface. On the other hand, the flow of liquid in a 3D deformable network, i.e a foam, under a volume force such as gravity has been thoroughly studied over the past decade. The overlapping zone of these two frameworks is of great interest for both communities as it gives rise to challenging new questions such as: what is the importance of the nature of the charged interface, created by mobile and soluble surfactants in the case of foam, on electrokinetic transport? How does a foam behave when submitted to a surface driven flow? Can we compensate a volume-driven flow, i.e. gravity, by a surface driven flow, i.e. electroosmosis? In this review, we will explore these questions on three different scales: a surfactant laden interface, a foam film and a macroscopic foam. PMID- 28662764 TI - PulseNet International: Vision for the implementation of whole genome sequencing (WGS) for global food-borne disease surveillance. AB - PulseNet International is a global network dedicated to laboratory-based surveillance for food-borne diseases. The network comprises the national and regional laboratory networks of Africa, Asia Pacific, Canada, Europe, Latin America and the Caribbean, the Middle East, and the United States. The PulseNet International vision is the standardised use of whole genome sequencing (WGS) to identify and subtype food-borne bacterial pathogens worldwide, replacing traditional methods to strengthen preparedness and response, reduce global social and economic disease burden, and save lives. To meet the needs of real-time surveillance, the PulseNet International network will standardise subtyping via WGS using whole genome multilocus sequence typing (wgMLST), which delivers sufficiently high resolution and epidemiological concordance, plus unambiguous nomenclature for the purposes of surveillance. Standardised protocols, validation studies, quality control programmes, database and nomenclature development, and training should support the implementation and decentralisation of WGS. Ideally, WGS data collected for surveillance purposes should be publicly available, in real time where possible, respecting data protection policies. WGS data are suitable for surveillance and outbreak purposes and for answering scientific questions pertaining to source attribution, antimicrobial resistance, transmission patterns, and virulence, which will further enable the protection and improvement of public health with respect to food-borne disease. PMID- 28662767 TI - Rituximab for the Treatment of Autoimmune Retinopathy. PMID- 28662768 TI - Total duodenectomy with panceratic preservation for duodenal polyposis. PMID- 28662769 TI - Post-traumatic rupture of a suprarenal metastasis of hepatocarcinoma. PMID- 28662770 TI - Monitoring intraoperative neuromuscular blockade and blood pressure with one device (TOF-Cuff): A comparative study with mechanomyography and invasive blood pressure. AB - OBJECTIVE: The overall objective of the study is to determine the ability of TOF Cuff device (blood-pressure modified cuff, including stimulation electrodes) to monitor with the same device the non-invasive blood pressure (NIBP) and the depth of a neuromuscular blockade (NMB) induced pharmacologically, by stimulation of the brachial plexus at the humeral level and recording evoked changes in arterial pressure. MATERIAL AND METHOD: Clinical, single-centre, open-controlled study with 32 adult patients ASA I-III for scheduled elective surgery under general anaesthesia in supine position, for the validation of neuromuscular monitoring, comparing the values obtained from neuromuscular relaxation TOF-Cuff with those obtained by mechanomyography (MMG) (control method) during the recovery phase of NMB, when a TOF ratio>0.7 and>0.9 (primary endpoint) were reached respectively. And an additional consecutive study of 17 patients for validation of NIBP monitoring with TOF-Cuff device vs invasive blood pressure measured by an intra arterial catheter. All data were analyzed using the Bland-Altman method. RESULTS: Recovery from NMB measured with the TOF-Cuff was earlier compared to MMG. Comparing TOF-ratio>0.9 measured with TOF-Cuff vs TOF-ratio>0.7 with MMG, a specificity of 91% and a positive predictive value of 84% were obtained. In NIBP measurement, the mean error and standard deviation of both systolic blood pressure (1.6+/-7mmHg) and diastolic blood pressure (-3.4+/-6.3) were within the European accuracy requirements for medical devices. CONCLUSIONS: The TOF-Cuff device has been shown to be valid and safe in the monitoring of NMB and in the measurement of NIBP, with no patient presenting any adverse events, skin-level lesions or residual pain. It is not interchangeable with MMG, having a TOF ratio>0.9 quantified by the TOF-Cuff device, a good correlation with a TOF ratio>0.7 on MMG. PMID- 28662772 TI - Management of hyperparathyroidism - Influence of patient and disease factors. PMID- 28662771 TI - Predicting delayed discharge in a multimodal Enhanced Recovery Pathway. AB - BACKGROUND: Despite advances with Enhanced Recovery Pathways(ERP), some patients have unexpected prolonged lengths of stay(LOS). Our goal was to identify the patient and procedural variables associated with delayed discharge despite an established ERP. METHODS: A divisional database was reviewed for minimally invasive colorectal resections with a multimodal ERP(8/1/13-7/31/15). Patients were stratified into ERP success or failure based on length of stay >=5 days. Logistic regression modeling identified variables predictive of ERP failure. RESULTS: 274 patients were included- 229 successes and 45 failures. Groups were similar in demographics. Failures had higher rates of preoperative anxiety(p = 0.0352), chronic pain(p = 0.0040), prior abdominal surgery(p = 0.0313), and chemoradiation(p = 0.0301). Intraoperatively, failures had higher conversion rates(13.3% vs. 1.7%, p = 0.0002), transfusions(p = 0.0032), and longer operative times(219.8 vs. 183.5min,p = 0.0099). Total costs for failures were higher than successes($22,127 vs. $13,030,p = 0.0182). Variables independently associated with failure were anxiety(OR 2.28, p = 0.0389), chronic pain(OR 10.03, p = 0.0045), and intraoperative conversion(OR 8.02, p = 0.0043). CONCLUSIONS: Identifiable factors are associated with delayed discharge in colorectal surgery. By prospectively preparing for patient factors and changing practice to address procedural factors and ERP adherence, postoperative outcomes could be improved. PMID- 28662774 TI - Current advances in endocrine therapy options for premenopausal women with hormone receptor positive breast cancer. PMID- 28662773 TI - Oral immunotherapy for food allergy: A Spanish guideline. Immunotherapy egg and milk Spanish guide (items guide). Part I: Cow milk and egg oral immunotherapy: Introduction, methodology, rationale, current state, indications contraindications and oral immunotherapy build-up phase. AB - INTRODUCTION: Cow's milk and egg are the most frequent causes of food allergy in the first years of life. Treatments such as oral immunotherapy (OIT) have been investigated as an alternative to avoidance diets. No clinical practice guides on the management of OIT with milk and egg are currently available. OBJECTIVES: To develop a clinical guide on OIT based on the available scientific evidence and the opinions of experts. METHODS: A review was made of studies published in the period between 1984 and June 2016, Doctoral Theses published in Spain, and summaries of communications at congresses (SEAIC, SEICAP, EAACI, AAAAI), with evaluation of the opinion consensus established by a group of experts pertaining to the scientific societies SEICAP and SEAIC. RESULTS: Recommendations have been established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of suffering adverse reactions. CONCLUSIONS: A clinical practice guide is presented for the management of OIT with milk and egg, based on the opinion consensus of Spanish experts. PMID- 28662775 TI - Improved survival with definitive chemoradiation compared to definitive radiation alone in squamous cell carcinoma of the vulva: A review of the National Cancer Database. AB - BACKGROUND: It is unclear whether definitive chemoradiation (CRT) results in improved overall survival compared to radiation therapy (RT) alone in patients with vulvar cancer who are not candidates for surgery. We compared these treatment strategies in the National Cancer Database (NCDB). METHODS: We identified 1352 patients with pathologically-confirmed squamous cell carcinoma of the vulva treated with definitive RT (n=353) or definitive CRT (n=999) between 2003 and 2014 in the NCDB. Exclusion criteria were metastatic disease at diagnosis, RT dose <4000cGy, follow-up <6months, and surgical treatment. Overall survival was compared using Kaplan-Meier method with log-rank test. Cox proportional hazard modeling, propensity score matching, and subgroup analyses were performed. RESULTS: The median age overall was 66 (23-90) years. The CRT group was younger (p<0.001) and had more advanced FIGO staging (p<0.001) compared to the RT group. Median radiation dose was 5940 (4000-7920) cGy. The median follow-up for living patients was longer in the CRT group (45.2months [6.0 131.6]) than RT (34.4months [6.1-127.6]) (p=0.004). The 5-year overall survival was higher in the CRT group compared to RT (49.9% vs. 27.4%, p<0.001). On multivariate analysis, CRT was associated with a reduced hazard of death compared to RT (HR: 0.76 [0.63-0.91], p=0.003). The effect remained significant after propensity score matching (HR: 0.78 [0.63-0.97], p=0.023). On subgroup analysis, patients with FIGO stage I only had a trend towards improved survival with CRT (p=0.058). CONCLUSIONS: In the NCDB, definitive chemoradiation was associated with higher overall survival compared to radiation alone in patients with squamous cell carcinoma of the vulva who did not receive surgery. These findings suggest that concurrent chemoradiation may be beneficial for select patients in the definitive setting. PMID- 28662776 TI - An atypical presentation of Paget's Disease of the breast without nipple involvement: Case report and review of the literature. AB - We present a case of a 63 year-old Caucasian female who developed a right breast skin lesion discrete from the nipple that was subsequently diagnosed as Paget's Disease of the breast (PDB). Imaging did not reveal an underlying breast cancer or involvement of the nipple. The patient underwent a segmental mastectomy preserving the nipple and final pathology demonstrated residual Paget's disease of the skin and did not reveal any additional underlying breast carcinoma. To our knowledge, this case represents the first reported diagnosed case of isolated PDB without nipple involvement. PMID- 28662777 TI - Wastewater treatment by membrane ultrafiltration enhanced with ultrasound: Effect of membrane flux and ultrasonic frequency. AB - Membrane ultrafiltration is increasingly applied for wastewater treatment and reuse, even though membrane fouling still represents one of the main drawbacks of this technology. In the last years, innovative strategies for membrane fouling control have been developed, such as the combination of membrane processes with ultrasound (US). In present work, the application of membrane ultrafiltration and its combination with US were studied, evaluating the influence on the performance of the treatment and membrane fouling formation of two membrane fluxes, 75 and 150L/m2h, along with two US frequencies, 35 and 150kHz. The results observed showed that the combination of membrane ultrafiltration with US, respect to the filtration process alone, reduced membrane fouling rates to a greater extent at the higher membrane flux and lower US frequency applied, reaching a reduction of 57.33% at 150L/m2h and 35kHz. Furthermore, higher organic matter and turbidity removals were observed at higher frequency (130kHz). The results obtained highlights the applicability of this combined process for the upgrading of membrane ultrafiltration and as an alternative option to conventional tertiary wastewater treatments. PMID- 28662778 TI - Prospective analysis of 231 elective neck dissections in oral squamous cell carcinoma with node negative neck-To decide the extent of neck dissection. AB - OBJECTIVE: To evaluate the incidence of level IIB and IV lymph node metastases in patients of oral carcinoma with N0 necks. This study will help to decide the extent and need of routine comprehensive removal of these specific lymph node groups in selective neck dissection. METHODS: Prospective analytical study of 231 patients of oral carcinoma with N0 necks undergoing neck dissections were prospectively analyzed. The incidence of metastases at level IIB and IV were then observed. RESULTS: 71 (30.73%) out of 231 cases had microscopic metastatic lymphadenopathy. Lymph node metastases from oral cancers were seen predominantly at levels IB and IIA. Metastases at levels IIB and IV were very rare (0.86% and 0%, respectively). Metastases at level IIB was associated with metastases at the level IIA in both cases (100%) and with level IB in 1 case (50%). 27 (11.68%) out of 231 cases had positive IIA nodes and conversely, only 7.4% (2/27) of all level IIA metastases had positive nodes at level IIB. CONCLUSION: Selective neck dissection from I-III may be adequate for majority of patients with oral cancers. Level IIB and IV need not be dissected in N0 patients. PMID- 28662780 TI - Embrace Action: Advocate for Perioperative Nursing. PMID- 28662779 TI - Ocular vestibular evoked myogenic potential in patients with myasthenia gravis: A prospective clinical study. AB - OBJECTIVE: Myasthenia gravis (MG) is an archetypic disorder of neuromuscular junctions (NMJs) and autoantibody-mediated disease causing fatigable weakness of skeletal muscles with an ocular onset in up to 85%. The aim of this study was to detect extra ocular muscles (EOMs) abnormalities in MG patients using ocular vestibular evoked myogenic potential (oVEMP) n10 response. METHODS: The oVEMP was performed on 40 myasthenia gravis patients that were divided into three groups: newly diagnosed (10 patients), uncontrolled on treatment (15 patients) and controlled on treatment (15 patients) groups in addition to a control group of 10 subjects. Also a comparison of oVEMP response was held between patients with generalized and ocular MG. RESULTS: The oVEMP n10 showed significant difference between the 3 study groups and the control. The n10 showed no significant difference between the newly diagnosed group and the other 2 groups. There was also significant difference between uncontrolled and controlled on treatment group and between generalized and ocular types of myasthenic patients. CONCLUSION: The oVEMP can be usefully used in diagnosis of new MG patients as regard n10 amplitude, threshold and AR except n10 latency with no therapeutic or monitoring value of oVEMP in MG. PMID- 28662781 TI - Do-Not-Resuscitate Orders in the Perioperative Environment: A Multidisciplinary Quality Improvement Project. AB - Do-not-resuscitate (DNR) orders in the perioperative environment must be managed according to national and institutional guidelines. Health care professionals, including perioperative nurses, may be unfamiliar with the guidelines and unsure of their role in reevaluating a DNR order. We conducted a multidisciplinary quality improvement project at a metropolitan community hospital that aimed to improve health care providers' compliance with the institutional policy, nursing involvement in DNR reevaluation, and communication between providers. The project intervention was an educational fair preceded and followed by a survey measuring knowledge about DNR orders, institutional policy, and national guidelines; attitude toward and comfort with the reevaluation process; and the effectiveness of the communication processes. Knowledge of DNR orders improved (P < .0001) for three of four survey questions. Attitude, comfort, and communication also improved (P < .01). A chart audit two months after the intervention showed that compliance with the institutional policy increased by 75%. PMID- 28662782 TI - Danish Perioperative Nurses' Documentation: A Complex, Multifaceted Practice Connected With Unit Culture and Nursing Leadership. AB - Researchers have described the documentation practices of perioperative nurses as flawed and characterized by subjectivity and poor quality, which is often related to both the documentation tool and the nurses' level of commitment. Studies suggest that documentation of nursing care in the OR places special demands on electronic health records (EHRs). The purpose of this study was to explore how the use of an EHR tailored to perioperative practice affects Danish perioperative nurses' documentation practices. This study was a follow-up to a baseline study from 2014. For three months in the winter of 2015 to 2016, six participants tested an EHR containing a Danish edition of a selected section of the Perioperative Nursing Data Set. This study relied on realistic evaluation and participant observations to generate data. We found that nursing leadership was essential for improving perioperative nurses' documentation practices and that a tailored EHR may improve documentation practices. PMID- 28662783 TI - Back to Basics: Radiation Safety. AB - Perioperative team members and patients are frequently exposed to radiation during operative and other invasive procedures. The use of equipment that emits radiation (eg, a fluoroscopy unit) is beneficial for diagnosing and treating patients but carries the risk of harm if team members do not follow radiation safety guidelines. Perioperative team members should implement safety precautions for themselves and their patients when radiation is used. This Back to Basics article addresses the basics of radiation safety and the precautions that perioperative team members should implement in the perioperative setting. PMID- 28662784 TI - There is Magic in Collaboration. PMID- 28662785 TI - Guideline Implementation: Minimally Invasive Surgery, Part 1. AB - Since its inception in the early 1990s, technological developments have made minimally invasive surgery the preferred approach for many operative procedures. However, perioperative personnel have had to develop new skills and techniques to manage this technology. The advent of robotic-assisted procedures in the early 2000s added another level of complexity to the perioperative arena. The updated AORN "Guideline for minimally invasive surgery" provides guidance for creating a safe environment for patients undergoing a wide range of procedures in which complex, advanced equipment and techniques are used. This article focuses on key points of the guideline that address OR configuration for minimally invasive surgery, safe practices for robotic-assisted procedures, and reducing risks associated with gas insufflation media. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 28662786 TI - Guideline Summary: Minimally Invasive Surgery, Part 1. PMID- 28662787 TI - Improving Patient Safety by Practicing in a Just Culture. PMID- 28662788 TI - Clinical Issues-July 2017. AB - Operation of fluoroscopy equipment Key words: fluoroscopy, mini C-arm, scope of practice, radiologic device. Patient education after radionuclide implantation Key words: radionuclides, brachytherapy, prostate cancer, radiation safety. Personal protective equipment Key words: clean, decontamination, instruments, PPE, tray assembly. Safe staffing patterns Key words: on-call staffing, schedules, safe staffing levels. Counting instruments when laparoscopy procedures convert to open procedures Key words: counts, instrument, laparoscopy, retained surgical items. PMID- 28662789 TI - Evidence appraisal of de Jonge SW, Atema JJ, Solomkin JS, Boermeester MA. Meta analysis and trial sequential analysis of triclosan-coated sutures for the prevention of surgical-site infection.: Br J Surg. 2017;104(2):e118-e133. PMID- 28662790 TI - Perioperative Nursing Management of Donor and Recipient Patients Undergoing Face Transplantation. AB - Individuals with debilitating facial injuries and deformities have achieved significant improvement of aesthetic form and function after undergoing a face transplantation. The involvement of surgical technologists and perioperative nurses in the care of the recipient and donor plays a critical role in the success of these procedures. There are unique challenges that staff members may be presented with when caring for a donor and recipient undergoing a face transplantation, including less comfort with and knowledge of the surgical procedure and instrumentation, an increased amount of equipment and personnel in the OR, donor and recipient admission and discharge care, and increased shift length. At New York University Langone Medical Center, New York, we have developed a comprehensive process to prepare staff members to care for patients undergoing face transplantation. PMID- 28662791 TI - Guideline at a Glance: Sharps Safety. PMID- 28662792 TI - An Obstructed View. PMID- 28662793 TI - Medical Error - the Perspective of the Clinician and the Director of a Department Involved in an Error. PMID- 28662794 TI - Lessons Learnt from Past Incidents and Accidents in Radiation Oncology. AB - The purpose of this report is to review and compile what have been and can be learnt from incidents and accidents in radiation oncology, especially in external beam and brachytherapy. Some major accidents from the last 20 years will be discussed. The relationship between major events and minor or so-called near misses is mentioned, leading to the next topic of exploring the knowledge hidden among them. The main lessons learnt from the discussion here and elsewhere are that a well-functioning and safe radiotherapy department should help staff to work with awareness and alertness and that documentation and procedures should be in place and known by everyone. It also requires that trained and educated staff with the required competences are in place and, finally, functions and responsibilities are defined and well known. PMID- 28662795 TI - Purple urine bag syndrome. PMID- 28662796 TI - The Cardiovascular Effects of Cocaine. AB - Cocaine is the leading cause for drug-abuse-related visits to emergency departments, most of which are due to cardiovascular complaints. Through its diverse pathophysiological mechanisms, cocaine exerts various adverse effects on the cardiovascular system, many times with grave results. Described here are the varied cardiovascular effects of cocaine, areas of controversy, and therapeutic options. PMID- 28662797 TI - Sudden Cardiac Death in Patients With Spontaneous Coronary Artery Dissection. PMID- 28662798 TI - Calmodulin Mutants Linked to Catecholaminergic Polymorphic Ventricular Tachycardia Fail to Inhibit Human RyR2 Channels. PMID- 28662799 TI - Differences Between Conditional and Marginal Propensity Score Estimates: A Real World Application. PMID- 28662801 TI - Adequate Control of Blood Pressure for the Elderly... in a Less Than Adequate Healthcare System. PMID- 28662800 TI - Inconsistent Dosing of Non-Vitamin K Oral Anticoagulants: Differences Between the United States and Japan. PMID- 28662802 TI - Outcomes of Intensive Blood Pressure Lowering in Older Hypertensive Patients: Should AKI Be Watched? PMID- 28662803 TI - Reply: Adequate Blood Pressure Control and Monitoring Acute Kidney Injury in Older Hypertensive Patients. PMID- 28662804 TI - Correction. PMID- 28662805 TI - Procedural Experience for Transcatheter Aortic Valve Replacement and Relation to Outcomes: The STS/ACC TVT Registry. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been introduced into U.S. clinical practice with efforts to optimize outcomes and minimize the learning curve. OBJECTIVES: The goal of this study was to assess the degree to which increasing experience during the introduction of this procedure, separated from other outcome determinants including patient and procedural characteristics, is associated with outcomes. METHODS: The authors evaluated the association of hospital TAVR volume and patient outcomes for TAVR by using data from 42,988 commercial procedures conducted at 395 hospitals submitting to the Transcatheter Valve Therapy Registry from 2011 through 2015. Outcomes assessed included adjusted and unadjusted in-hospital major adverse events. RESULTS: Increasing site volume was associated with lower in-hospital risk-adjusted outcomes, including mortality (p < 0.02), vascular complications (p < 0.003), and bleeding (p < 0.001) but was not associated with stroke (p = 0.14). From the first case to the 400th case in the volume-outcome model, risk-adjusted adverse outcomes declined, including mortality (3.57% to 2.15%), bleeding (9.56% to 5.08%), vascular complications (6.11% to 4.20%), and stroke (2.03% to 1.66%). Vascular and bleeding volume-outcome associations were nonlinear with a higher risk of adverse outcomes in the first 100 cases. An association of procedure volume with risk-adjusted outcomes was also seen in the subgroup having transfemoral access. CONCLUSIONS: The initial adoption of TAVR into practice in the United States showed that increasing experience was associated with better outcomes. This association, whether deemed a prolonged learning curve or a manifestation of a volume-outcome relationship, suggested that concentrating experience in higher volume heart valve centers might be a means of improving outcomes. (STS/ACC Transcatheter Valve Therapy Registry [TVT Registry]; NCT01737528). PMID- 28662807 TI - TAVR, 15 Years Down: Shooting for the Moon, Reaching the Stars. PMID- 28662809 TI - The Promise of Vascular Restoration Is Still Alive. PMID- 28662808 TI - Arterial Remodeling After Bioresorbable Scaffolds and Metallic Stents. AB - BACKGROUND: Although previous observational studies have documented late luminal enlargement and expansive remodeling following implantation of a bioresorbable vascular scaffold (BVS), no comparison with metallic stents has been conducted in a randomized fashion. OBJECTIVES: This study sought to compare vessel remodeling patterns after either Absorb BVS or Xience metallic drug-eluting stent (DES) implantation (Abbott Vascular, Santa Clara, California) and determine the independent predictors of remodeling. METHODS: In the ABSORB II randomized trial, 383 lesions (n = 359) were investigated by intravenous ultrasound both post procedure and at 3-year follow-up. According to vessel and lumen area changes over 3 years, we categorized 9 patterns of vessel remodeling that were beyond the reproducibility of lumen and vessel area measurements. RESULTS: The relative change in mean vessel area was significantly greater with the BVS compared to the DES (6.7 +/- 12.6% vs. 2.9 +/- 11.5%; p = 0.003); the relative change in mean lumen area was significantly different between the 2 arms (1.4 +/- 19.1% vs. -1.9 +/- 10.5%, respectively; p = 0.031). Multivariate analysis indicated that use of the BVS, female sex, balloon-artery ratio >1.25, expansion index >=0.8, previous percutaneous coronary intervention, and higher level of low-density lipoprotein cholesterol were independent predictors of expansive remodeling. Furthermore, in the BVS arm, necrotic core pre-procedure was an independent determinant of expansive remodeling. CONCLUSIONS: Expansive vessel wall remodeling was more frequent and intense with the BVS than the metallic DES and could be determined by patient baseline characteristics and periprocedural factors. The clinical effect of the observed lumen and vessel remodeling must be investigated in further large clinical studies to optimize the clinical outcome of patients and lesions treated by bioresorbable scaffolds. (ABSORB II Randomized Controlled Trial; NCT01425281). PMID- 28662811 TI - Opportunities to Improve Outcomes in Atrial Fibrillation: Provider Specialty and Beyond. PMID- 28662810 TI - Treating Specialty and Outcomes in Newly Diagnosed Atrial Fibrillation: From the TREAT-AF Study. AB - BACKGROUND: Atrial fibrillation (AF) occurs in many clinical contexts and is diagnosed and treated by clinicians across many specialties. This approach has resulted in treatment variations. OBJECTIVES: The goal of this study was to evaluate the association between treating specialty and AF outcomes among patients newly diagnosed with AF. METHODS: Using data from the TREAT-AF (Retrospective Evaluation and Assessment of Therapies in AF) study from the Veterans Health Administration, patients with newly diagnosed, nonvalvular AF between 2004 and 2012 were identified who had at least 1 outpatient encounter with primary care or cardiology within 90 days of the AF diagnosis. Cox proportional hazards regression was used to evaluate the association between treating specialty and AF outcomes. RESULTS: Among 184,161 patients with newly diagnosed AF (age 70 +/- 11 years; 1.7% women; CHA2DS2-VASc score 2.6 +/- 1.7), 40% received cardiology care and 60% received primary care only. After adjustment for covariates, cardiology care was associated with reductions in stroke (hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.86 to 0.96; p < 0.001) and death (HR: 0.89; 95% CI: 0.88 to 0.91; p < 0.0001) and increases in hospitalizations for AF/supraventricular tachycardia (HR: 1.38; 95% CI: 1.35 to 1.42; p < 0.0001) and myocardial infarction (HR: 1.03; 95% CI: 1.00 to 1.05; p < 0.04). The propensity-matched cohort had similar results. In mediation analysis, oral anticoagulation prescription within 90 days of diagnosis may have mediated reductions in stroke but did not mediate reductions in survival. CONCLUSIONS: In patients with newly diagnosed AF, cardiology care was associated with improved outcomes, potentially mediated by early prescription of oral anticoagulation therapy. Although hypothesis-generating, these data warrant serious consideration and study of health care system interventions at the time of new AF diagnosis. PMID- 28662812 TI - Vitamin D and Cardiovascular Disease: Controversy Unresolved. AB - Vitamin D deficiency is typically caused by inadequate cutaneous synthesis secondary to decreased exposure to sunlight. Serum levels of 25-hydroxyvitamin D l <20 ng/ml are diagnostic of vitamin D deficiency. Vitamin D has various cardiovascular pleiotropic effects by activating its nuclear receptor in cardiomyocytes and vascular endothelial cells and by regulating the renin angiotensin-aldosterone system, adiposity, energy expenditure, and pancreatic cell activity. In humans, vitamin D deficiency is associated with the following: vascular dysfunction; arterial stiffening; left ventricular hypertrophy; and worsened metrics of diabetes, hypertension, and hyperlipidemia. It is also linked with worse cardiovascular morbidity and mortality. However, meta-analyses of vitamin D supplementation trials have failed to show clear improvements in blood pressure, insulin sensitivity, or lipid parameters, thus suggesting that the link between vitamin D deficiency and cardiovascular disease may be an epiphenomenon. Ongoing larger randomized trials will clarify whether monitoring and supplementation of vitamin D play roles in cardiovascular protection. PMID- 28662813 TI - Discovery and development of a novel class of phenoxyacetyl amides as highly potent TRPM8 agonists for use as cooling agents. AB - The paper presents the activity trends for a novel series of phenoxyacetyl amides as human TRPM8 receptor agonists. This series encompasses in vitro activity values ranging from the micromolar to the picomolar levels. Sensory evaluation of these molecules highlights their relevance as cooling agents for oral applications. The positive outcome of the complete evaluation of N-(1H-pyrazol-3 yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide resulted in its approval for Generally Recognized As Safe (GRAS) status by the Flavor & Extract Manufacturer Association (FEMA) as FEMA 4809. PMID- 28662815 TI - Cardiovascular Risk Factors and Carotid Intima-Media Thickness in a Colombian Population With Psoriasis. AB - BACKGROUND AND OBJECTIVES: Psoriasis is now known to have a clear association with metabolic syndrome and its components. The aim of our study was to determine the prevalence of cardiovascular risk factors (CVRFs) and increased carotid intima-media thickness in psoriasis patients seen in the dermatology department of a quaternary hospital. MATERIAL AND METHODS: This was a descriptive cross sectional study of psoriasis patients aged over 18 years seen in the dermatology department of Hospital de San Jose in Bogota, Colombia, between March and August, 2015. Directed medical history and physical examination were performed to detect CVRFs, laboratory studies to exclude metabolic syndrome, and ultrasound examination to measure carotid intima-media thickness. RESULTS: Forty patients with psoriasis were included in the study. The prevalence of the distinct CVRFs was 35% for systemic hypertension, 17.5% for dyslipidemia, 17.5% for smoking, and 10% for type 2 diabetes mellitus. A history of acute myocardial infarction was detected in 12.5% of patients. Metabolic syndrome was found in 20 patients (50%), and blood biochemistry revealed dyslipidemia in 32 patients (80%). Based on the Framingham score, the cardiovascular risk was low in 11 patients (31.4%), intermediate in 22 (62.8%), and high in 2 (5.7%). Mean (SD) carotid intima-media thickness was 0.7 (0.12) mm, with thickening observed in 6 patients (15%). CONCLUSIONS: This study provides evidence of the high prevalence of CVRFs in psoriasis patients and indicates the need for strict clinical control to monitor cardiovascular risk in this population. PMID- 28662816 TI - Premature ventricular contraction detection combining deep neural networks and rules inference. AB - Premature ventricular contraction (PVC), which is a common form of cardiac arrhythmia caused by ectopic heartbeat, can lead to life-threatening cardiac conditions. Computer-aided PVC detection is of considerable importance in medical centers or outpatient ECG rooms. In this paper, we proposed a new approach that combined deep neural networks and rules inference for PVC detection. The detection performance and generalization were studied using publicly available databases: the MIT-BIH arrhythmia database (MIT-BIH-AR) and the Chinese Cardiovascular Disease Database (CCDD). The PVC detection accuracy on the MIT-BIH AR database was 99.41%, with a sensitivity and specificity of 97.59% and 99.54%, respectively, which were better than the results from other existing methods. To test the generalization capability, the detection performance was also evaluated on the CCDD. The effectiveness of the proposed method was confirmed by the accuracy (98.03%), sensitivity (96.42%) and specificity (98.06%) with the dataset over 140,000 ECG recordings of the CCDD. PMID- 28662817 TI - Acute and painful exacerbation of RLS and PLM induced by opioid interaction - withdrawal syndrome. PMID- 28662818 TI - Wiener-Hopf optimal control of a hydraulic canal prototype with fractional order dynamics. AB - This article addresses the control of a laboratory hydraulic canal prototype that has fractional order dynamics and a time delay. Controlling this prototype is relevant since its dynamics closely resembles the dynamics of real main irrigation canals. Moreover, the dynamics of hydraulic canals vary largely when the operation regime changes since they are strongly nonlinear systems. All this makes difficult to design adequate controllers. The controller proposed in this article looks for a good time response to step commands. The design criterium for this controller is minimizing the integral performance index ISE. Then a new methodology to control fractional order processes with a time delay, based on the Wiener-Hopf control and the Pade approximation of the time delay, is developed. Moreover, in order to improve the robustness of the control system, a gain scheduling fractional order controller is proposed. Experiments show the adequate performance of the proposed controller. PMID- 28662806 TI - Temporal Trends in Transcatheter Aortic Valve Replacement in France: FRANCE 2 to FRANCE TAVI. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is standard therapy for patients with severe aortic stenosis who are at high surgical risk. However, national data regarding procedural characteristics and clinical outcomes over time are limited. OBJECTIVES: The aim of this study was to assess nationwide performance trends and clinical outcomes of TAVR during a 6-year period. METHODS: TAVRs performed in 48 centers across France between January 2013 and December 2015 were prospectively included in the FRANCE TAVI (French Transcatheter Aortic Valve Implantation) registry. Findings were further compared with those reported from the FRANCE 2 (French Aortic National CoreValve and Edwards 2) registry, which captured all TAVRs performed from January 2010 to January 2012 across 34 centers. RESULTS: A total of 12,804 patients from FRANCE TAVI and 4,165 patients from FRANCE 2 were included in this analysis. The median age of patients was 84.6 years, and 49.7% were men. FRANCE TAVI participants were older but at lower surgical risk (median logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE]: 15.0% vs. 18.4%; p < 0.001). More than 80% of patients in FRANCE TAVI underwent transfemoral TAVR. Transesophageal echocardiography guidance decreased from 60.7% to 32.3% of cases, whereas more recent procedures were increasingly performed in hybrid operating rooms (15.8% vs. 35.7%). Rates of Valve Academic Research Consortium-defined device success increased from 95.3% in FRANCE 2 to 96.8% in FRANCE TAVI (p < 0.001). In-hospital and 30-day mortality rates were 4.4% and 5.4%, respectively, in FRANCE TAVI compared with 8.2% and 10.1%, respectively, in FRANCE 2 (p < 0.001 for both). Stroke and potentially life-threatening complications, such as annulus rupture or aortic dissection, remained stable over time, whereas rates of cardiac tamponade and pacemaker implantation significantly increased. CONCLUSIONS: The FRANCE TAVI registry provided reassuring data regarding trends in TAVR performance in an all-comers population on a national scale. Nonetheless, given that TAVR indications are likely to expand to patients at lower surgical risk, concerns remain regarding potentially life-threatening complications and pacemaker implantation. (Registry of Aortic Valve Bioprostheses Established by Catheter [FRANCE TAVI]; NCT01777828). PMID- 28662819 TI - Defining 'Ethnobotanical Convergence'. PMID- 28662820 TI - Survival in Parkinson's disease in relation to striatal dopamine transporter binding. AB - OBJECTIVE: To investigate whether dopamine transporter (DAT) binding, as measured with single photon emission computed tomography (SPECT), can be used to predict mortality in patients with Parkinson's disease (PD). METHODS: A total of 162 patients with PD and abnormal [I-123]FP-CIT SPECT were clinically followed for a median of 5.8 years. A multivariate Cox regression model was used to investigate survival with the independent predictors of age, gender, severity of motor impairment, levodopa-equivalent daily dose of medication, presence of cognitive defects, and putaminal specific binding ratio (SBR) of [I-123]FP-CIT. In addition, associations between striatal and extrastriatal SBRs and survival were investigated using voxel-based analyses. RESULTS: The overall mortality was 25.9%, and the Kaplan-Meier estimate for mortality was 36%. Older age (P < 0.001), presence of cognitive defects (P = 0.001), and more severe motor symptom severity (P = 0.002) were significantly associated with increased mortality. No associations were found between putaminal DAT binding and survival (P = 0.99). There were no significant differences in SBRs in any striatal or extrastriatal region between survivors and non-survivors, and no associations were found between SBRs and scan-to-death intervals among non-survivors. CONCLUSIONS: Unlike the severity of motor and cognitive symptoms, the level of striatal dopaminergic defect in DAT SPECT does not predict mortality in PD. Although presynaptic dopaminergic functional imaging may have value as a diagnostic tool, the clinical symptom-based characteristics are superior for predicting lifespan. PMID- 28662821 TI - The Role of Matrix Metalloproteinases in Development, Repair, and Destruction of the Lungs. AB - Normal gas exchange after birth requires functional lung alveolar units that are lined with epithelial cells, parts of which are intricately fused with microvascular capillaries. A significant phase of alveolar lung development occurs in the perinatal period, continues throughout early stages in life, and requires activation of matrix-remodeling enzymes. Failure to achieve an optimum number of alveoli during lung maturation can cause several untoward medical consequences including disabling obstructive and/or restrictive lung diseases that limit physiological endurance and increase mortality. Several members of the matrix metalloproteinase (MMP) family are critical in lung remodeling before and after birth; however, their resurgence in response to environmental factors, infection, and injury can also compromise lung function. Therefore, temporal expression, regulation, and function of MMPs play key roles in developing and maintaining adequate oxygenation under steady state, as well as in diseased conditions. Broadly, with the exception of MMP2 and MMP14, most deletional mutations of MMPs fail to perturb lung development; however, their individual absence can alter the pathophysiology of respiratory diseases. Specifically, under stressed conditions such as acute respiratory infection and allergic inflammation, MMP2 and MMP9 can play a protective role through bacterial clearance and production of chemotactic gradient, while loss of MMP12 can protect mice from smoke-induced lung disease. Therefore, better understanding of the expression and function of MMPs under normal lung development and their resurgence in response respiratory diseases could provide new therapeutic options in the future. PMID- 28662822 TI - Matrix Metalloproteinases, Neural Extracellular Matrix, and Central Nervous System Pathology. AB - The functionality and stability of the central nervous system (CNS) pabulum, called neural extracellular matrix (nECM), is paramount for the maintenance of a healthy network. The loosening or the damage of the scaffold disrupts synaptic transmission with the consequent imbalance of the neurotransmitters, reactive cells invasion, astrocytosis, new matrix deposition, digestion of the previous structure and ultimately, maladaptive plasticity with the loss of neuronal viability. nECM is constantly affected by CNS disorders, particularly in chronic modifying such as neurodegenerative disease, or in acute/subacute with chronic sequelae, like cerebrovascular and inflammatory pathology. Matrix metalloproteinases (MMPs) are the main interfering agent of nECM, guiding the balance of degradation and new deposition of proteins such as proteoglycans and glycoproteins, or glycosaminoglycans, such as hyaluronic acid. Activation of these enzymes is modulated by their physiologic inhibitors, the tissue inhibitors of MMPs or via other proteases inhibitors, as well as genetic or epigenetic up- or downregulation through molecular interaction or receptor activation. The appropriate understanding of the pathways underlying nECM modifications in CNS pathology is probably one of the pivotal future directions to identify the healthy brain network and subsequently design new therapies to interfere with the progression of the CNS disease and eventually find appropriate therapies. PMID- 28662823 TI - Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. AB - Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering. PMID- 28662824 TI - Matrix Metalloproteinases and Synovial Joint Pathology. AB - Matrix metalloproteinases (MMPs) are zinc-dependent enzymes. These enzymes play a critical role in the destruction of articular cartilage in rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and the spondyloarthropathies. MMP gene expression is upregulated in these synovial joint pathologies in response to elevated levels of proinflammatory cytokines and soluble mediators such as tumor necrosis factor-alpha, interleukin-1 (IL-1), IL 6, IL-17, and interferon-gamma. These molecules are capable of activating the mitogen-activated protein kinase and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways by binding the cytokine to their respective receptors on immune cells, macrophages, chondrocytes, synoviocytes, and osteocytes leading to increased synthesis of MMPs. Biologic drugs and/or small-molecule inhibitors designed to block cytokine to cytokine receptor interactions or to selectively inhibit JAKs have clinical efficacy in RA, PsA, and ankylosing spondylitis which correlated with a reduction in MMPs. Although there are currently no OA-selective drugs, it is likely that such a drug would have to reduce MMP gene expression to have clinical efficacy. PMID- 28662825 TI - Matrix Metalloproteinases in Kidney Disease: Role in Pathogenesis and Potential as a Therapeutic Target. AB - Matrix metalloproteinases (MMPs) are large family of proteinases. In addition to a fundamental role in the remodeling of the extracellular matrix, they also cleave a number of cell surface proteins and are involved in multiple cellular processes. MMP activity is regulated via numerous mechanisms, including inhibition by endogenous tissue inhibitors of metalloproteinases (TIMPs). Similar to MMPs, a role for TIMPs has been established in multiple cell signaling pathways. Aberrant expression of MMPs and TIMPS in renal pathophysiology has long been recognized, and with the generation of specific knockout mice, the mechanistic role of several MMPs and TIMPs is becoming more understood and has revealed both pathogenic and protective roles. This chapter will focus on the expression and localization of MMPs and TIMPs in the kidney, as well as summarizing the current information linking these proteins to acute kidney injury and chronic kidney disease. In addition, we will summarize studies suggesting that MMPs and TIMPs may be biomarkers of renal dysfunction and represent novel therapeutic targets to attenuate kidney disease. PMID- 28662826 TI - Metalloproteinases in Rheumatoid Arthritis: Potential Therapeutic Targets to Improve Current Therapies. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by the destruction of joint tissues including cartilage and bone. Cartilage degradation is attributed to metalloproteinases (MPs) that belong to matrix metalloproteinase family and a disintegrin and metalloprotease with thrombospondin type 1 motifs produced by inflamed joint tissues. In addition, an enzyme that belongs to a disintegrin and metalloprotease family is also involved in release of inflammatory cytokines. Several highly selective inhibitors have been developed for MPs thought to play a role in RA pathogenesis and examining these inhibitors as potential drugs is becoming realistic. This chapter discusses recent reports on MPs in RA and their potential as a therapeutic target. PMID- 28662827 TI - The Roles of Matrix Metalloproteinases in Pancreatic Cancer. AB - Matrix metalloproteinases (MMPs) have long been implicated for roles in cancer initiation, tumor growth, and metastasis. However, pancreatic cancer clinical trials using broad-based MMP inhibitors were discouraging. To better evaluate the use of MMP inhibitors in pancreatic cancer, (a) more precise roles of individual MMPs in pancreatic cancer needed to be determined and (b) animal models that more accurately represented human pancreatic cancer needed to be developed. The last decade has seen substantial progress in both areas. MT1-MMP has been recognized as a critical mediator of several steps in pancreatic cancer progression, while MMP-9 appears to be an antitarget when considering pancreatic cancer therapies. PMID- 28662829 TI - Regulation of Matrix Metalloproteinase in the Pathogenesis of Diabetic Retinopathy. AB - Diabetic retinopathy, a progressive disease, is the major cause of acquired blindness in the developed countries. Despite cutting-edge research in the field, the exact mechanism of this multifactorial disease remains elusive. Matrix metalloproteinases (MMPs) degrade extracellular matrix and play significant role in regulating intracellular homeostasis. In the pathogenesis of diabetic retinopathy, activation of gelatinase MMPs (MMP-2 and MMP-9) in the retina is an early event, and activated MMPs damage the mitochondria and augment retinal capillary cell apoptosis, a phenomenon which is observed before histopathology characteristic of diabetic retinopathy can be seen. MMPs are regulated by a number of different mechanisms including cleavage of their zymogens, regulation of their tissue inhibitors, and their gene expressions by transcriptional factors and epigenetic modifications. This chapter reviews the current literature about the role of MMPs in the development of diabetic retinopathy, and describes different mechanisms to regulate their activation. With evolving research implicating MMPs in both preneovascularization and neovascularization stages of diabetic retinopathy, they could be an attractive target to inhibit the development/progression of diabetic retinopathy, a disease which has potential to rob vision during the most productive years of a diabetic patient's life. PMID- 28662831 TI - Preface. PMID- 28662828 TI - Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders. AB - Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes that degrade various proteins in the extracellular matrix (ECM). MMPs may also regulate the activity of membrane receptors and postreceptor signaling mechanisms and thereby affect cell function. The MMP family includes collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs. Inactive proMMPs are cleaved by other MMPs or proteases into active MMPs, which interact with various protein substrates in ECM and cell surface. MMPs regulate important biological processes such as vascular remodeling and angiogenesis and may be involved in the pathogenesis of cardiovascular disorders such as hypertension, atherosclerosis, and aneurysm. The role of MMPs is often assessed by measuring their mRNA expression, protein levels, and proteolytic activity using gel zymography. MMP inhibitors are also used to assess the role of MMPs in different biological processes and pathological conditions. MMP activity is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP balance could determine the net MMP activity, ECM turnover, and tissue remodeling. Also, several synthetic MMP inhibitors have been developed. Synthetic MMP inhibitors include a large number of zinc-binding globulins (ZBGs), in addition to non-ZBGs and mechanism-based inhibitors. MMP inhibitors have been proposed as potential tools in the management of osteoarthritis, cancer, and cardiovascular disorders. However, most MMP inhibitors have broad-spectrum actions on multiple MMPs and could cause undesirable musculoskeletal side effects. Currently, doxycycline is the only MMP inhibitor approved by the Food and Drug Administration. New generation biological and synthetic MMP inhibitors may show greater MMP specificity and fewer side effects and could be useful in targeting specific MMPs, reducing unrestrained tissue remodeling, and the management of MMP-related pathological disorders. PMID- 28662832 TI - Vascular Causes of Syncope: An Emergency Medicine Review. AB - BACKGROUND: Syncope is a common emergency department (ED) complaint, accounting for 2% of visits annually. A wide variety of etiologies can result in syncope, and vascular causes may be deadly. OBJECTIVE: This review evaluates vascular causes of syncope and their evaluation and management in the ED. DISCUSSION: Syncope is defined by a brief loss of consciousness with loss of postural tone and complete, spontaneous recovery without medical intervention. Causes include cardiac, vasovagal, orthostatic, neurologic, medication-related, and idiopathic, and most cases of syncope will not receive a specific diagnosis pertaining to the cause. Emergency physicians are most concerned with life-threatening causes such as dysrhythmia and obstruction, and electrocardiogram is a primary means of evaluation. However, vascular etiologies can result in patient morbidity and mortality. These conditions include pulmonary embolism, subclavian steal, aortic dissection, cerebrovascular disease, intracerebral hemorrhage, carotid/vertebral dissection, and abdominal aortic aneurysm. A focused history and physical examination can assist emergency physicians in determining the need for further testing and management. CONCLUSIONS: Syncope is common and may be the result of a deadly condition. The emergency physician, through history and physical examination, can determine the need for further evaluation and resuscitation of these patients, with consideration of vascular etiologies of syncope. PMID- 28662834 TI - An app with remote support achieves better adherence to home exercise programs than paper handouts in people with musculoskeletal conditions: a randomised trial. AB - QUESTION: Do people with musculoskeletal conditions better adhere to their home exercise programs when these are provided to them on an app with remote support compared to paper handouts? DESIGN: Randomised, parallel-group trial with intention-to-treat analysis. PARTICIPANTS: Eighty participants with upper or lower limb musculoskeletal conditions were recruited to the trial. Each participant was prescribed a 4-week home exercise program by a physiotherapist at a tertiary teaching hospital in Australia. Participants were randomly assigned via a computer-generated concealed block randomisation procedure to either intervention (n=40) or control (n=40) groups. INTERVENTION: Participants in the intervention group received their home exercise programs on an app linked to the freely available website www.physiotherapyexercises.com. They also received supplementary phone calls and motivational text messages. Participants in the control group received their home exercise programs as a paper handout. OUTCOME MEASURES: Blinded assessors collected outcome measures at baseline and 4 weeks. The primary outcome was self-reported exercise adherence. There were five secondary outcomes, which captured functional performance, disability, patient satisfaction, perceptions of treatment effectiveness, and different aspects of adherence. RESULTS: Outcomes were available on 77 participants. The mean between group difference for self-reported exercise adherence at 4 weeks was 1.3/11 points (95% CI 0.2 to 2.3), favouring the intervention group. The mean between group difference for function was 0.9/11 points (95% CI 0.1 to 1.7) on the Patient-Specific Functional Scale, also favouring the intervention group. There were no significant between-group differences for the remaining outcomes. CONCLUSION: People with musculoskeletal conditions adhere better to their home exercise programs when the programs are provided on an app with remote support compared to paper handouts; however, the clinical importance of this added adherence is unclear. TRIAL REGISTRATION: ACTRN12616000066482. [Lambert TE, Harvey LA, Avdalis C, Chen LW, Jeyalingam S, Pratt CA, Tatum HJ, Bowden JL, Lucas BR (2017) An app with remote support achieves better adherence to home exercise programs than paper handouts in people with musculoskeletal conditions: a randomised trial. Journal of Physiotherapy 63: 161-167]. PMID- 28662833 TI - Additional vertebral augmentation with posterior instrumentation for unstable thoracolumbar burst fractures. AB - BACKGROUND: To investigate the role of vertebral augmentation in kyphosis reduction, vertebral fracture union, and correction loss after surgical management of thoracolumbar burst fracture. DESIGN: Retrospective chart and radiographic review. SETTING: Level 1 trauma center. METHODS: The analysis included patients treated between April 2007 and June 2015, who received pedicle screw-rod distraction and reduction within two days following acute traumatic thoracolumbar burst fracture with a load sharing score >6. Medical records were retrospectively reviewed for data regarding operative details, imaging and laboratory findings, neurological function, and functional outcomes. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Sagittal index, pain score, loss of correction, and implant failure rate. RESULTS: Nineteen patients were enrolled in this study (mean age, 37.2+/-13years; age range, 17-62 years; female/male ratio: 10/9). Of the five patients who received only reduction (no augmentation), one underwent revision surgery because of implant failure and pedicle screw backing out. Compared to patients who received only reduction, those who received both reduction and augmentation showed better sagittal alignment after the operation, with better sagittal index immediately postoperatively and during the follow-up (p<0.05). CONCLUSIONS: Transpedicular vertebral augmentation with calcium sulfate/phosphate-based bone cement may reinforce thoracolumbar burst fracture stability, partially restore vertebral body height, and reduce pedicle screw bending and movement, thereby preventing early implant failure and late loss of correction, especially in patients with excellent fracture reduction. LEVEL OF EVIDENCE: Therapeutic level III, retrospective chart review. PMID- 28662835 TI - CT angiography to evaluate coronary artery disease and revascularization requirement before trans-catheter aortic valve replacement. AB - BACKGROUND: Coronary artery disease (CAD) and aortic stenosis share pathophysiological mechanisms and risk factors. We evaluated the clinical utility of coronary computed tomography angiography (CTA) to identify CAD and revascularization requirement in patients with severe aortic stenosis considered for transcatheter aortic valve replacement (TAVR). METHODS: Consecutive patients without known CAD underwent calcium scoring, CTA and invasive coronary angiography (ICA). A second-generation dual-source CT scanner was used. ICA quantitative coronary angiography (QCA) served as reference standard. CAD was reported using a lenient threshold of >=50% and a stricter threshold of >=70% diameter reduction. Findings of >=70% diameter reduction and of high-risk CAD were used to predict revascularization. RESULTS: The study included 140 patients [68 males; 82.3 (7.7) years]. CAD defined by the 50% threshold on ICA was found in 58/140 (41%) patients. CAD by the 70% threshold was found in 23/140 (16%) patients. High-risk CAD was found in 16/140 (11%) patients. CTA and ICA had similar odd-ratios of 3.22 (1.26-8.23) and 4.62 (1.64-13.05), respectively, in predicting revascularization. Forty-two/140 (30%) patients had <400 Agatston calcium score, 98/140 (70%) patients had >=400 calcium score. The diagnostic performance of CTA in the low calcium score group was better than the high calcium score group (AUC 0.81 vs. 0.63). CONCLUSION: CTA remained questionable to rule-out CAD as gatekeeper to ICA in TAVR candidates who had severe coronary calcifications. In patients with less severe coronary calcifications, accounting for 30% of participants in this study, CTA may play a clinical role. PMID- 28662836 TI - Conceptions of pregnancy health and motivations for healthful behavior change among women in American Samoa. AB - BACKGROUND: American Samoan women are particularly at risk of obesity-related non communicable disease (NCD), requiring efficacious interventions to protect their health and that of their infants. Prior studies have identified pregnancy as an ideal time for behavior change interventions related to NCD. AIM: This study aimed to understand American Samoan women's conceptions of health during pregnancy, their motivations for pregnancy behavior change, and the role of their family in both enabling and preventing these changes. METHODS: Eighteen women (2 19 weeks post-partum) completed semi-structured interviews that explored their experiences of pregnancy-related behavior change and social support. A thematic analysis identified prominent themes. A stages of change framework was used to describe the sample's readiness for behavior change. FINDINGS: Participants expressed a Westernized conception of health during pregnancy that focused on eating a balanced diet and exercising regularly; behaviors that would usually be stigmatized outside of pregnancy. Many were in the contemplative/pre contemplative stages of change, although some reported initiating healthful behaviors in pregnancy. Participants overwhelmingly described external motivations for adopting healthy behaviors, most notably the perceived benefit to their baby. During pregnancy, women reported protective treatment from their families as a result of communal ownership over the baby that is potentially limiting for women's agency over their health. CONCLUSIONS: This study confirmed pregnancy as an opportune moment for health behavior intervention, especially within the context of Samoan culture. Future efforts should capitalize on external motivations for behavior change but also encourage the development of internal motivators to sustain changes initiated in pregnancy post-partum. PMID- 28662837 TI - A snapshot of novel psychoactive substances (legal highs) use in London. PMID- 28662838 TI - Can advanced musculoskeletal physiotherapy practitioners help to relieve some of the pressures on the emergency department? PMID- 28662839 TI - What Does Not Kill You Makes You Stronger. AB - Colicin production is an extreme form of labor division; cells lyse after making the toxin! Stochastic phenotype switching allows producers to outcompete sensitive strains since colicin release frees up vacancy. If patch dynamics does not kill you, it stimulates adaptation to a dynamic habitat landscape which selects for rapid dispersal. PMID- 28662840 TI - Bronchopleural Fistula Management with AmplatzerTM Insertion. PMID- 28662830 TI - Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia. AB - Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation, and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy. MMP expression/activity may be altered during complications of pregnancy. Decreased vascular MMP-2 and MMP-9 may lead to decreased vasodilation, increased vasoconstriction, hypertensive pregnancy, and preeclampsia. Abnormal expression of uteroplacental integrins, cytokines, and MMPs may lead to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate remodeling of spiral arteries, and reduced uterine perfusion pressure (RUPP). RUPP may cause imbalance between the antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the proangiogenic vascular endothelial growth factor and placental growth factor, or stimulate the release of inflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could target MMPs in the extracellular matrix as well as endothelial and vascular smooth muscle cells, causing generalized vascular dysfunction, increased vasoconstriction and hypertension in pregnancy. MMP activity can also be altered by endogenous tissue inhibitors of metalloproteinases (TIMPs) and changes in the MMP/TIMP ratio. In addition to their vascular effects, decreases in expression/activity of MMP-2 and MMP-9 in the uterus could impede uterine growth and expansion and lead to premature labor. Understanding the role of MMPs in uteroplacental and vascular remodeling and function could help design new approaches for prediction and management of preeclampsia and premature labor. PMID- 28662841 TI - Deferred Locoregional Recurrence of Pleural Mesothelioma. PMID- 28662843 TI - Environmental impacts and benefits of state-of-the-art technologies for E-waste management. AB - This study aims to evaluate the environmental impacts and benefits of state-of the-art technologies for proper e-waste handling using Jordan as a case study. Life Cycle Assessment (LCA) was employed to evaluate five advanced management systems represent state-of-the-art treatment technologies, including sanitary landfilling; proper recycling of metals, materials, and precious metals (PMs); and incineration of plastic and the hazardous portion of printed circuit boards (PCBs). Six e-waste products that contribute the most to the e-waste in Jordan were included in the assessment of each scenario, which resulted in 30 total cases of e-waste management. The findings indicated that landfills for the entire components of the e-waste stream are the worst option and should be avoided. The most promising e-waste management scenario features integrated e-waste processes based on the concept of Integrated Waste Management (IWM), including recycling materials such as non-PMs and PMs, incinerating plastic and the hazardous content of PCBs using the energy recovered from incineration, and using sanitary landfills of residues. For this scenario, the best environmental performance was obtained for the treatment of mobile phones. Incineration of the portion of hazardous waste using energy recovery is an option that deserves attention. Because scenario implementation depends on more than just the environmental benefits (e.g., economic cost and technical aspects), the study proposes a systematic approach founded on the IWM concept for e-waste management scenario selection. PMID- 28662844 TI - Contributions of nitrification and denitrification to N2O emissions from aged refuse bioreactor at different feeding loads of ammonia substrates. AB - Nitrous oxide (N2O) is a strong greenhouse gas, and its emissions from microbial nitrification (NF) and denitrification (DNF) are a threat to the environment. In the present study, a combined approach consisting of 15N stable isotope and molecular biology (qPCR) was used to determine the contributions of autotrophic nitrification (ANF), heterotrophic nitrification (HNF), and DNF to N2O emissions in laboratory incubations of aged refuse for different ammonia (NH4+-N) loads (200, 400, and 800mg.NH4+-N/kg.aged refuse) and incubation times (2-144h). Experimental results showed that the N2O emissions increased with the increase in applied amount of NH4+-N substrates. Simultaneous nitrification and denitrification (SND) were demonstrated to be present in the incubations of aged refuse. The results of 15N stable isotope labelling experiment indicated that NF (54.60%-68.8%) and DNF (83.38%-85.90%) contributed to majority of N2O emissions in the incubations of 24h and 72h, respectively. The results of functional genes (amoA and nosZ) quantification experiments indicated that the high gene copies of amoA and nosZ were present at 24h and 72h, respectively. The study also demonstrated the utility of a combined stable isotope and molecular biology approach. The approaches not only provide similar inferences about the N2O emissions, but also enable the determination of relative contributions of ANF, HNF, and DNF to N2O emissions. The results of the study are important in providing guidance to artificially optimize the operating conditions for alleviating N2O emissions in aged refuse bioreactors. PMID- 28662842 TI - Critical review of willingness to pay for clinical oral health interventions. AB - OBJECTIVES: This critical review aimed to identify, consolidate and evaluate the quality of Willingness to Pay (WTP) studies applied to clinical contexts in the field of dentistry. METHODS: PubMed and Web of Science databases were systematically searched for relevant publications. Screening and data extraction was then performed. Primary literature in English-language were included to assess the WTP for oral health interventions, when the valuations were applied to a clinical measure. Twenty-six publications met the inclusion criteria. RESULTS: WTP was elicited mainly via face-to-face interviews (13 publications) and questionnaires (12 publications). The majority (24) of publications selected an out-of-pocket payment vehicle. Eleven publications adopted a bidding method, nine publications adopted an open-ended format, and the remaining six studies adopted a payment card or choice method. Pre-testing was reported in only nine publications, and few studies accounted for starting point bias. Eight of 11 publications found that higher incomes were associated with higher WTP values. The female gender, a younger age and higher education levels were associated with a higher WTP in select studies. CONCLUSIONS: Only a small minority of the studies used strategies to avoid well documented biases related to WTP elicitation. Cost versus benefit of many clinical scenarios remain uninvestigated. CLINICAL SIGNIFICANCE: WTP studies in dentistry may benefit from pre-testing and the inclusion of a script to minimise hypothetical bias. They may also be better conducted face-to-face and via a shuffled payment card method. Income levels, and potentially education levels, gender and age, should be assessed for their influence on WTP values. PMID- 28662845 TI - Effects of pH buffering agents on the anaerobic hydrolysis acidification stage of kitchen waste. AB - This study investigated effects of initial pH buffering agents on the lab-scale anaerobic hydrolysis acidification stage of kitchen waste (KW). Different cheap, available and suitable buffering agents (NaOH(s), NaOH(l), CaO(s)-NaOH, KOH(l) NaOH, K2HPO4(s)-KOH, Na2CO3(s)-NaOH) were added under optimal adjusting mode (first two days: per 16h, after: one time per day) which was obtained in previous work. The effects of buffering agents were evaluated according to indexes of pH, VFAs, NH4+-N, TS, VS, VS/TS, TS and VS removal rate. The results showed treatment 5 with adding K2HPO4-KOH buffering agents had the most stable pH (6.7-7.0). Also treatment 5, 2, 4 and 6 provided stable pH ranging in 5-8. Among the treatments, treatment 6 with adding Na2CO3 as initial buffering agents and 10mol/L NaOH as regulator was chosen as the optimal mode for highest VFAs content (44.05g/L) with high acetic acid and butyrate acid proportion (42.64%), TS and VS removal rate (44.84% and 58.67%, respectively), low VS/TS ratio (58.55), fewer adding dosage and low adjusting frequency. The VFAs content of treatment 6 at the end of hydrolysis acidification stage could be used for methanogenic phase of anaerobic two-phase digestion. Thus, treatment 6 (adding Na2CO3 as initial buffering agents and 10mol/L NaOH as regulator) with highest VFAs content and TS and VS removal rate could be considered using in anaerobic hydrolysis acidification stage pH adjustment. PMID- 28662846 TI - Reply to: "Calreticulin mutations and their importance in Budd-Chiari syndrome". PMID- 28662847 TI - Calreticulin mutations and their importance in Budd-Chiari syndrome. PMID- 28662848 TI - Blood count values and ratios for predicting sleep apnea in obese children. PMID- 28662849 TI - Use of an in-house Monte Carlo platform to assess the clinical impact of algorithm-related dose differences on DVH constraints. AB - PURPOSE: The aim of the present work is to evaluate a semi-automatic prescription and validation system of treatment plans for complex delivery techniques, integrated in a Monte Carlo platform, and to investigate the clinical impact of dose differences due to the calculation algorithms, by assessing the changes in DVH constraints. METHODS: A new prescription module was implemented into the Moderato system, an in-house Monte Carlo platform, with corresponding dose constraints generated depending on the anatomical region and fractionation scheme considered. The platform was tested on 83 cases treated with Cyberknife and Tomotherapy machines, to assess whether dose variations between the re-calculated dose and the Treatment Planning System might impact the dose constraints on the sensitive structures. RESULTS: Dose differences were small (within 3%) between calculation algorithms in most of the thoracic, pelvic and abdominal cases, both for the Cyberknife and Tomotherapy machines. On the other hand, spinal and head and neck treatments presented a few significant dose deviations for constraints on small volumes, such as the optic pathways and the spinal cord. These differences range from -11% to +6%, inducing constraint violations of up to 8% over the dose limit. CONCLUSIONS: The Moderato platform offers an interesting tool for plan quality validation, with a prescription module highlighting crucial features in the structures list, and a Monte Carlo dose re-calculation for complex modern techniques. Due to the high number of warnings appearing in some situations, display optimization is required in practice. PMID- 28662850 TI - Patient dose monitoring systems: A new way of managing patient dose and quality in the radiology department. AB - PURPOSE: Due to the upcoming European Directive (2013/59/EURATOM) and the increased focus on patient safety in international guidelines and regulations, Patient Dose Monitoring Systems, also called Dose Management Systems (DMS), are introduced in medical imaging departments. This article focusses on the requirements for a DMS, its benefits and the necessary implementation steps. METHOD: The implementation of a DMS can be perceived as a lengthy, yet worthy, procedure: users have to select the appropriate system for their applications, prepare data collection, validate, perform configuration, and start using the results in quality improvement projects. RESULTS: A state of the art DMS improves the quality of service, ensures patient safety and optimizes the efficiency of the department. The gain is multifaceted: the initial goal is compliance monitoring against diagnostic reference levels. At a higher level, the user gets an overview of the performance of the devices or centers that are under his supervision. Error identification, generation of alerts and workflow analysis are additional benefits. It can also enable a more patient-centric approach with personalized dosimetry. Skin dose, size-specific dose estimates and organ doses can be calculated and evaluated per patient. CONCLUSION: A DMS is a powerful tool and essential for improved quality and patient care in a radiology department. It can be configured to the needs of medical physicists, radiologists, technologists, even for the management of the hospital. Collaboration between all health professionals and stakeholders, input-output validation and communication of findings are key points in the process of a DMS implementation. PMID- 28662851 TI - Dosimetric properties of a Solid Water High Equivalency (SW557) phantom for megavoltage photon beams. AB - The dosimetric properties of the recently developed SW557 phantom have been investigated by comparison with those of the existing SW457 phantom in megavoltage photon beams. The electron fluence ratio phiplw, and chamber ionization ratio kpl, of water to SW457 and water to SW557 for 4-15MV photons were calculated as a function of depth using Monte Carlo simulations, and compared with measured values. Values of phiplw for SW457 were in the range of 1.004-1.014 for 4MV, and 1.014-1.018 for 15MV photons. The phiplw for SW557 ranged from 1.005 to 1.008 for 4MV and from 1.010 to 1.015 for 15MV photons and the variation of phiplw with depth for each beam energy was within +/-0.5%. Values of kpl were obtained with a PTW 30013 Farmer-type ionization chamber. The kpl for SW457 ranged from 0.997 to 1.011 for 4-15MV photons. Values of kpl for SW557 were almost unity for 4 and 6MV photons, while in the case of 10 and 15MV photons they were less than 1.006, excepting the build-up region. The measured and calculated kpl values of water to SW557 were in the range of 0.997-1.002 and 1.000-1.006, respectively, for 4-15MV photons, at a depth of 10cm with a source to-axis distance of 100cm. The measured and calculated kpl values were in agreement within their uncertainty ranges. As a water-equivalent phantom, SW557 can be used with a dosimetric difference within+/-0.6%, for 4-15MV photons, and is more water-equivalent than SW457 in megavoltage photon beams. PMID- 28662852 TI - Ionic liquid functionalization of semi-packed columns for high-performance gas chromatographic separations. AB - Gas chromatography columns fabricated using microelectromechanical system (MEMS) technology provide a number of clear advantages. However, successful deposition of stationary phases having a wide application range remains an important technical challenge. In this paper, we report, for the first time, on the deposition of room temperature ionic liquids (RTILs)-a versatile class of stationary phases-inside the channels of semi-packed columns (SPCs) for high performance gas chromatographic separation of complex chemical mixtures. A 1m long, 240MUm deep, 190MUm wide column comprising an array circular micropillars of 20MUm in diameter and 40MUm post spacing was fabricated using MEMS processes. Two RTILs were immobilized inside these columns using a dynamic coating method, and the columns were tested for separation of three different mixtures: a 15 component mixture of hazardous chemical pollutants, an 8-component mixture of fatty acid methyl esters, and a sample of gasoline. These columns displayed sharp and symmetrical peaks, significant selectivity variation between the two columns, and rapid separation times. The columns yielded high separation efficiencies measured by approximately 2300 plates/m under isothermal conditions. This work highlights the potential of RTILs to be used as excellent stationary phases for SPCs, thereby dramatically expanding the range of complex mixtures that could be analyzed using a micro gas chromatograph. PMID- 28662853 TI - The high efficient separation of divinylbenzene and ethylvinylbenzene isomers using high performance liquid chromatography with Fe-based MILs packed columns. AB - The baseline separation of divinylbenzene (DVB) and ethylvinylbenzene (EVB) isomers was achieved using HPLC with MIL-53(Fe) and MIL-100(Fe) packed columns respectively when hexane/dichloromethane (100:0) used as mobile phase, at flow rate of 0.5mLmin-1, room temperature, and monitored with a UV detector at 254nm. The two Fe-based MILs packed columns showed different separated performances, analytes had short retention time on MIL-100(Fe) compared to MIL-53(Fe), but selectivity of DVB isomers (m-DVB and p-DVB) was lower, which was mainly due to the differences of the pore size and structure of MILs. Moreover, the results of calculated thermodynamic parameters showed that the separation of DVB and EVB isomers was not only controlled by enthalpy change (DeltaH), but also controlled by entropy change (DeltaS). The head-to-tail stacking was the main reason for the separation according to the mechanism of the DVB and EVB isomers on Fe-based MILs packed columns. PMID- 28662854 TI - Female Runner With Painful Left Thigh Swelling: A Case of May-Thurner Syndrome. AB - : We discuss a case of a female runner who presented with burning left groin and thigh pain and positional swelling after a long run. The workup revealed May Thurner syndrome. May-Thurner syndrome anatomy is a common anatomical variant present in approximately 20% of the population. Compression of the iliac vein may result in venous stasis in the lower limb with a predisposition to deep venous thrombosis. We identify 4 reported cases of May-Thurner syndrome in female runners and review the importance of diagnosis and appropriate treatment of this condition. LEVEL OF EVIDENCE: V. PMID- 28662855 TI - Measuring Physical and Cognitive Fatigue in People With Post-Polio Syndrome: Development of the Neurological Fatigue Index for Post-Polio Syndrome (NFI-PP). AB - BACKGROUND: Fatigue in post-polio syndrome (PPS) has been shown to affect quality of life adversely. There is currently no disease-specific measure of fatigue for PPS. OBJECTIVE: To develop a scale to measure fatigue in PPS that meets rigorous psychometric standards. DESIGN: Qualitative followed by validation and test retest studies. SETTING: Polio clinic followed by national questionnaire studies. PARTICIPANTS: A total of 45 participants from polio clinic for qualitative; 319 participants from clinic or self-referral for validation study, of whom 87 completed the retest questionnaire. METHODS: Draft questionnaire items on PPS fatigue were derived from transcripts of qualitative interviews. After cognitive debriefing, the draft measure was administered by mail along with comparator questionnaires to a new sample. MAIN OUTCOME MEASUREMENTS: Draft PPS fatigue measure, Fatigue Severity Scale, and visual analog scale for fatigue. RESULTS: Analysis of 271 of 319 (85%) questionnaires identified a 2-factor solution (RMSEA 0.058). For the physical subscale, a 20-item scale showed good fit (chi2P = .189), strict unidimensionality (t-test 5.17%), and reliability 0.91. For the cognitive subscale, a 7-item scale showed excellent fit (chi2P = .917), strict unidimensionality (t-test 5.2%), and reliability 0.89. Evidence of a "difficulty factor" emerged also supporting a total score that showed good fit (chi2P = .151), strict unidimensionality (t-test 0.4%), and reliability consistent with group use at 0.73. Test-retest correlations for all scales were greater than 0.85. Standard error of measurement on metric ranges was 5.4 for total, 2.9 for physical, and 1.69 for cognitive domains. With the latent estimate of the total score transformed to a 0-100 scale, the mean score was 49.5 (SD 6.9). Spearman correlations with the Fatigue Severity Scale and visual analog scale were 0.60 and 0.55, respectively. CONCLUSIONS: A patient-derived Neurological Fatigue Index for PPS, with physical and cognitive subscales and a total score, has demonstrated good reliability, appropriate concurrent validity, and satisfies the Rasch measurement model. A raw-score to interval scale transformation is available for parametric applications and the calculation of change scores. LEVEL OF EVIDENCE: III. PMID- 28662856 TI - Within- and between-person and group variance in behavior and beliefs in cross cultural longitudinal data. AB - This study grapples with what it means to be part of a cultural group, from a statistical modeling perspective. The method we present compares within- and between-cultural group variability, in behaviors in families. We demonstrate the method using a cross-cultural study of adolescent development and parenting, involving three biennial waves of longitudinal data from 1296 eight-year-olds and their parents (multiple cultures in nine countries). Family members completed surveys about parental negativity and positivity, child academic and social emotional adjustment, and attitudes about parenting and adolescent behavior. Variance estimates were computed at the cultural group, person, and within-person level using multilevel models. Of the longitudinally consistent variance, most was within and not between cultural groups-although there was a wide range of between-group differences. This approach to quantifying cultural group variability may prove valuable when applied to quantitative studies of acculturation. PMID- 28662857 TI - Glass-ceramic coating material for the CO2 laser based sintering of thin films as caries and erosion protection. AB - OBJECTIVES: The established method of fissure-sealing using polymeric coating materials exhibits limitations on the long-term. Here, we present a novel technique with the potential to protect susceptible teeth against caries and erosion. We hypothesized that a tailored glass-ceramic material could be sprayed onto enamel-like substrates to create superior adhesion properties after sintering by a CO2 laser beam. METHODS: A powdered dental glass-ceramic material from the system SiO2-Na2O-K2O-CaO-Al2O3-MgO was adjusted with individual properties suitable for a spray coating process. The material was characterized using X-ray fluorescence analysis (XRF), heating microscopy, dilatometry, scanning electron microscopy (SEM), grain size analysis, biaxial flexural strength measurements, fourier transform infrared spectroscopy (FTIR), and gas pycnometry. Three different groups of samples (each n=10) where prepared: Group A, powder pressed glass-ceramic coating material; Group B, sintered hydroxyapatite specimens; and Group C, enamel specimens (prepared from bovine teeth). Group B and C where spray coated with glass-ceramic powder. All specimens were heat treated using a CO2 laser beam process. Cross-sections of the laser sintered specimens were analyzed using laser scanning microscopy (LSM), energy dispersive X-ray analysis (EDX), and SEM. RESULTS: The developed glass-ceramic material (grain size d50=13.1mm, coefficient of thermal expansion (CTE)=13.310 6/K) could be spray coated on all tested substrates (mean thickness=160MUm). FTIR analysis confirmed an absorption of the laser energy up to 95%. The powdered glass-ceramic material was successfully densely sintered in all sample groups. The coating interface investigation by SEM and EDX proved atomic diffusion and adhesion of the glass-ceramic material to hydroxyapatite and to dental enamel. SIGNIFICANCE: A glass-ceramic material with suitable absorption properties was successfully sprayed and laser-sintered in thin films on hydroxyapatite as well as on bovine enamel. The presented novel technique of tooth coating with a dental glass-ceramic using a CO2-laser holds a great potential as a possible method to protect susceptible teeth against caries and erosion. PMID- 28662858 TI - Comparison of three and four point bending evaluation of two adhesive bonding systems for glass-ceramic zirconia bi-layered ceramics. AB - OBJECTIVES: To quantify the adhesion of two bonding approaches of zirconia to more aesthetic glass-ceramic materials using the Schwickerath (ISO 9693-2:2016) three point bend (3PB) [1] test to determine the fracture initiation strength and strain energy release rate associated with stable crack extension with this test and the Charalamabides et al. (1989) [2] four point bend (4PB) test. METHODS: Two glass-ceramic materials (VITABLOCS Triluxe forte, Vita Zahnfabrik, Germany and IPS.emax CAD, Ivoclar Vivadent, Liechtenstein) were bonded to sintered zirconia (VITA InCeram YZ). The former was resin bonded using a dual-cure composite resin (Panavia F 2.0, Kuraray Medical Inc., Osaka, Japan) following etching and silane conditioning, while the IPS.emax CAD was glass bonded (IPS e.max CAD Crystall/Connect) during crystallization of the IPS.emax CAD. Specimens (30) of the appropriate dimensions were fabricated for the Schwickerath 3PB and 4PB tests. Strength values were determined from crack initiation while strain energy release rate values were determined from the minima in the force-displacement curves with the 3PB test (Schneider and Swain, 2015) [3] and for 4PB test from the plateau region of stable crack extension. RESULTS: Strength values for the resin and glass bonded glass ceramics to zirconia were 22.20+/-6.72MPa and 27.02+/-3.49MPa respectively. The strain energy release rates for the two methods used were very similar and for the glass bonding, (4PB) 15.14+/-5.06N/m (or J/m2) and (3PB) 16.83+/-3.91N/m and resin bonding (4PB) 8.34+/-1.93N/m and (3PB) 8.44+/ 2.81N/m respectively. The differences in strength and strain energy release rate for the two bonding approaches were statistically significant (p<0.05). SEM observations showed fracture occurred adhesively for the resin bonding and cohesively for the glass bonding. SIGNIFICANCE: The present results indicate 3PB and 4PB tests have very similar values for the strain energy release rate determination. However while strength tests reveal minimal differences between resin and glass bonding, strain energy release rates for the latter are superior for bonding CAD/CAM milled glass-ceramics to zirconia. PMID- 28662859 TI - Monolithic zirconia dental crowns. Internal fit, margin quality, fracture mode and load at fracture. AB - OBJECTIVE: Dental all-ceramic restorations of zirconia, with and without an aesthetic veneering layer, have become a viable alternative to conventional metal ceramic restorations. The aim of this study was to evaluate whether factors of the production methods or the material compositions affect load at fracture, fracture modes, internal fit or crown margins of monolithic zirconia crowns. METHODS: Sixty crowns made from six different commercially available dental zirconias were produced to a model tooth with a shallow circumferential chamfer preparation. Internal fit was assessed by the replica method. The crown margin quality was assessed by light microscopy on an ordinal scale. The cemented crowns were loaded centrally in the occlusal fossa with a horizontal steel cylinder with a diameter of 13mm at 0.5mm/min until fracture. Fractographic analysis was performed on the fractured crowns. RESULTS: There were statistically significant differences among the groups regarding crown margins, internal fit and load at fracture (p<0.05, Kruskall Wallis). Fracture analyses revealed that all fractures started cervically and propagated to the occlusal surface similar to clinically observed fractures. There was statistically significant correlation between margin quality and load at fracture (Spearman's rank correlation, p<0,05). SIGNIFICANCE: Production method and material composition of monolithic zirconia crowns affect internal fit, crown margin quality and the load at fracture. The hard-machined Y-TZP zirconia crowns had the best margin quality and the highest load at fracture. Reduction of margin flaws will improve fracture strength of monolithic zirconia crowns and thereby increase clinical success. PMID- 28662860 TI - Different PEEK qualities irradiated with light of different wavelengths: Impact on Martens hardness. AB - OBJECTIVES: To assess the impact of irradiation on Martens hardness parameters of different PEEK qualities filled with titanium dioxide (TiO2), namely PEEK/0%, PEEK/20%, and PEEK/>30%. METHODS: For Martens hardness (HM) measurements, 40 specimens of each PEEK quality were fabricated and air-abraded with 50MUm Al2O3. HM parameters of PEEK specimens were measured initially and stepwise after irradiating for 5, 10, 20, 30, 40, 60, 80, 100, 180, 360 and 540s using light units with different wavelength: Elipar S10 (430-480nm), EyeVolutionMAX (385 390nm+465-470nm), Translux CL (380-500nm) and bre.Lux Power Unit (370-500nm). HM parameters of 10 human teeth were measured initially on enamel and dentin. Data was analysed using 3-way ANOVA with partial eta-squared (etaP2) and post-hoc Tuckey-HSD-test (p<0.05). RESULTS: PEEK qualities followed by the wavelength showed the highest effect on Martens hardness (p<0.013). PEEK/>30% (197.35+/ 19.9N/mm2), followed by PEEK/20% (191.45+/-15.49 N/mm2) showed significantly higher values for HM than PEEK/0% (189.55+/-16.89N/mm2). PEEK/>30% (5.49+/ 0.4kN/mm) and PEEK/20% (5.38+/-0.26kN/mm2) presented higher indentation modulus (EIT) than PEEK/0% (4.77+/-0.36kN/mm2). Irradiated with wavelength of 430-480nm (PEEK/0%: 193.28N/mm2, PEEK20%: 198.83N/mm2, PEEK/>30%: 200.5N/mm2) indicated higher HM compared to specimens irradiated with 380-500nm (PEEK/0%: 186.63N/mm2, PEEK20%: 191.05N/mm2, PEEK/>30%: 196.13N/mm2). Irradiation using 430-480nm (PEEK/0%: 4.95kN/mm2, PEEK20%: 5.52kN/mm2, PEEK/>30%: 5.59kN/mm2) and 370-500nm (PEEK/0%: 4.92kN/mm2, PEEK20%: 5.43kN/mm2, PEEK/>30%: 5.53kN/mm2) indicated higher EIT values compared to specimens irradiated with 380-500nm (PEEK/0%: 4.72kN/mm2, PEEK20%: 5.34kN/mm2, PEEK/>30%: 5.47kN/mm2). Duration of irradiation presented no impact on results. Enamel (HM: 2263.6+/-405.16, EIT: 63.16+/-19.24) and dentin (HM: 468.2+/-30.77N/mm2, EIT: 14.14+/-4.59kN/mm2) presented significantly higher HM and EIT than the tested PEEK qualities (p<0.001). SIGNIFICANCE: Irradiation with different wavelength impacted HM parameter. The increase of TiO2 percentage in PEEK matrix improved the HM parameter. However, PEEK showed significantly lower HM parameter than human teeth. PMID- 28662861 TI - The influence of Y-TZP surface treatment on topography and ceramic/resin cement interfacial fracture toughness. AB - OBJECTIVE: Consider the efficacy of glass infiltration etching (SIE) treatment as a procedure to modify the zirconia surface resulting in higher interfacial fracture toughness. METHODS: Y-TZP was subjected to 5 different surface treatments conditions consisting of no treatment (G1), SIE followed by hydrofluoric acid treatment (G2), heat treated at 750 degrees C (G3), hydrofluoric acid treated (G4) and airborne-particle abrasion with alumina particles (G5). The effect of surface treatment on roughness was evaluated by Atomic Force Microscopy providing three different parameters: Ra, Rsk and surface area variation. The ceramic/resin cement interface was analyzed by Fracture Mechanics KI test with failure mode determined by fractographic analysis. Weibull's analysis was also performed to evaluate the structural integrity of the adhesion zone. RESULTS: G2 and G4 specimens showed very similar, and high Ra values but different surface area variation (33% for G2 and 13% for G4) and they presented the highest fracture toughness (KIC). Weibull's analysis showed G2 (SIE) tendency to exhibit higher KIC values than the other groups but with more data scatter and a higher early failure probability than G4 specimens. SIGNIFICANCE: Selective glass infiltration etching surface treatment was effective in modifying the zirconia surface roughness, increasing the bonding area and hence the mechanical imbrications at the zirconia/resin cement interface resulting in higher fracture toughness (KIC) values with higher KIC values obtained when failure probability above 20% was expected (Weibull's distribution) among all the experimental groups. PMID- 28662862 TI - The use of rigid gas permeable contact lenses in children with myopic amblyopia: A case series. AB - PURPOSE: To explore the safety profile and overall visual improvement over the course of RGP contact lens wear on children with unilateral or bilateral amblyopia resulting from myopia. METHODS: This was a retrospective analysis case series study. Clinical records of 15 patients who were fitted with RGP contact lenses at the Shanghai Eye and EENT Hospital of Fudan University between the period of January 2009 to December 2014 were reviewed. The inclusion criteria for review included patients with myopia of -3.00DS or greater in one or both eyes and an initial best-corrected visual acuity (BCVA) of logMAR 0.4 or worse for 3year olds, and logMAR 0.3 or worse for 4 years old and above. One or both myopic eyes were fitted with RGP lenses. RESULTS: 15 subjects and 22 amblyopic eyes were included. The mean baseline BCVA was logMAR0.70+/-0.38, which improved to a VA of 0.23+/-0.28 at the time of review (p<0.05). Baseline myopia also increased from 8.18+/-2.93DS to -11.41+/-3.76DS (p<0.05). The final visual acuity at the time of this review was correlated with the initial refractive error (r=-0.695, p<0.05) as well as the initial BCVA (r=0.854, p<0.05). There was also a strong correlation between initial refractive error and initial BCVA (r=0.-801, p<0.05) CONCLUSION: RGP contact lens wear is a safe and effective refractive treatment option in young children with amblyopia due to myopia. PMID- 28662863 TI - Lung Adenocarcinoma Harboring EGFR T790M and In Trans C797S Responds to Combination Therapy of First- and Third-Generation EGFR TKIs and Shifts Allelic Configuration at Resistance. AB - INTRODUCTION: The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as EGFR C797S. In vitro study proved that cells harboring EGFR C797S in trans with T790M are sensitive to a combination of first- and third-generation EGFR tyrosine kinase inhibitors. However, this has not been reported clinically. METHODS: We performed capture-based sequencing on longitudinal plasma samples obtained at various treatment milestones from a patient with advanced lung adenocarcinoma who was undergoing targeted therapy. RESULTS: At the development of resistance to osimertinib, the patient's plasma sample revealed EGFR C797S located in trans with T790M. He achieved partial response accompanied by undetectable C797S after commencement of a combinatorial treatment consisting of erlotinib and osimertinib. After 3 months of progression free survival, he experienced progressive disease with emergence of EGFR C797S located in cis to T790M. CONCLUSION: We report the first clinical evidence of efficacy generated by combination therapy consisting of first- and third generation EGFR tyrosine kinase inhibitors targeting concomitant EGFR T790M and C797S in trans. We also reveal that the clonal progression of C797S from in trans to in cis at disease progression may serve as a potential resistance mechanism. PMID- 28662864 TI - Thermodynamic modelling of an onsite methanation reactor for upgrading producer gas from commercial small scale biomass gasifiers. AB - Small scale biomass gasifiers have the advantage of having higher electrical efficiency in comparison to other conventional small scale energy systems. Nonetheless, a major drawback of small scale biomass gasifiers is the relatively poor quality of the producer gas. In addition, several EU Member States are seeking ways to store the excess energy that is produced from renewables like wind power and hydropower. A recent development is the storage of energy by electrolysis of water and the production of hydrogen in a process that is commonly known as "power-to-gas". The present manuscript proposes an onsite secondary reactor for upgrading producer gas by mixing it with hydrogen in order to initiate methanation reactions. A thermodynamic model has been developed for assessing the potential of the proposed methanation process. The model utilized input parameters from a representative small scale biomass gasifier and molar ratios of hydrogen from 1:0 to 1:4.1. The Villar-Cruise-Smith algorithm was used for minimizing the Gibbs free energy. The model returned the molar fractions of the permanent gases, the heating values and the Wobbe Index. For mixtures of hydrogen and producer gas on a 1:0.9 ratio the increase of the heating value is maximized with an increase of 78%. For ratios higher than 1:3, the Wobbe index increases significantly and surpasses the value of 30 MJ/Nm3. PMID- 28662865 TI - Retraction notice to "Pierisformoside B exhibits neuroprotective and anti inflammatory effects in murine hippocampal and microglial cells via the HO-1/Nrf2 mediated pathway", [International Immunopharmacology 24 (2015) 353-360]. PMID- 28662866 TI - Refining the extended circumflex scapular flap for neck burn reconstruction: A 30 year experience. AB - INTRODUCTION: Neck burn sequelae remain a major challenge for the reconstructive surgeon. To achieve satisfactory functional and aesthetic results, the anterior neck aesthetic unit must be covered as a single unit. In cases where free flaps are required, harvesting a flap of sufficient size can cause major donor site morbidity. In 1994, we published our favorable 6-year experience of reconstructing neck burn sequelae with an extended circumflex scapular flap (ECSF). Since then, we have made several modifications to the technique, resulting in improved long-term functional and aesthetic results. Herein, we present our 30-year, 150-patient experience with the ECSF flap for the treatment of anterior neck burn sequelae. METHODS: We retrospectively reviewed the records of 150 consecutive patients who underwent ECSF procedure for neck resurfacing performed or supervised by the senior author from 1986 to 2015. All cases were assessed for function, aesthetics, satisfaction, and complications. RESULTS: A total of 160 ECSFs were used in 150 patients. Ninety-nine patients were available for updated follow-up [1-30 years (mean, 15.3)]. At the last follow-up, 92 patients regained full range of motion, and 90 patients had acceptable cervicomental angle (<110 degrees ). The mean patient satisfaction score was 4.8/5. Nine flaps (5.6%) failed completely and were successfully replaced. Twenty two patients (15%) had distal necrosis of the flap. Fifteen of these 22 patients underwent complementary flaps to replace the necrotic area, and all 15 patients regained full range of motion. CONCLUSIONS: For neck burn sequelae, the ECSF provides safe and effective long-term functional and aesthetic results with minimal donor site morbidity. PMID- 28662867 TI - Thoracic outlet syndrome after the Nuss procedure for pectus excavatum: Is it a rare complication? AB - OBJECTIVE: The present study aims to elucidate the frequency of thoracic outlet syndrome after the Nuss procedure for pectus excavatum and the conditions in which thoracic outlet syndrome is likely to develop. METHODS: A retrospective study including 85 pectus excavatum patients (58 males and 27 females) was conducted. Thoracic outlet syndrome was defined as a condition in which the patient has numbness, lassitude, or pain of the upper limbs at rest or during motion of the upper limbs. The frequency of the thus-defined thoracic outlet syndrome was evaluated in 85 patients. Age, sex, Haller indices, and the positions of the correction bars were compared between the patients who developed thoracic outlet syndrome and those who did not. RESULTS: Preadolescent patients (18 out of 85) did not develop postoperative thoracic outlet syndrome. In total, 15.2% of adult male patients (7 out of 46) and 33% of adult female patients (7 out of 21) developed postoperative thoracic outlet syndrome. For both male and female groups, Haller indices were significantly greater for patients who had postoperative thoracic outlet syndrome than for those who did not. Correction bars were generally placed at higher intercostal spaces in patients who developed postoperative thoracic outlet syndrome than in those who did not. CONCLUSION: A considerable percentage of adult patients develop thoracic outlet syndrome after the Nuss procedure for pectus excavatum. Maturity of the thoracic wall, femininity, severity of the deformity (represented by greater Haller indices), and placement of correction bars at superior intercostal spaces are risk factors for postoperative thoracic outlet syndrome. PMID- 28662868 TI - The incidence of symptomatic brain metastases from extra-pulmonary small cell carcinoma: Is there a role for prophylactic cranial irradiation in a clinically relevant population cohort? AB - BACKGROUND AND PURPOSE: To examine the incidence and outcomes of patients with brain metastases from extra-pulmonary small cell carcinoma (EPSCC) and assess the indication for prophylactic cranial irradiation (PCI). MATERIALS AND METHODS: A Provincial cancer registry was used to conduct a retrospective, population-based study of patients diagnosed with EPSCC between January 1997 and December 2011. The primary end point was the incidence of brain metastases. The secondary endpoint was overall survival. A "PCI Eligible" cohort was defined to provide an estimation of the incidence of brain metastases in clinically relevant patients. RESULTS: In 287 patients, the primary sites were 21% gastrointestinal, 34% genito urinary, 14% gynecologic, 5% head/neck and 25% unknown primary. Thirty-five (12.5%) patients had brain metastases: 12 (4.2%) at initial diagnosis and 23 (8%) later in the disease course. In PCI Eligible patients, the 3-year cumulative incidence of new brain metastases was 5.5% for M0 stage disease and 26.3% for M1 disease. There was no significant difference in the incidence of brain metastases between primary sites. CONCLUSIONS: The incidence of brain metastases in patients with EPSCC is comparatively low, even in a cohort of patients that were suitable for PCI. Based on our analysis, we cannot recommend PCI for patients with EPSCC. PMID- 28662869 TI - Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation. AB - BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune checkpoint blockade targeting the programed death (PD)-1 receptor, often with palliative radiation therapy. Outcome data are limited in this population. MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy at four centers. RESULTS: We identified 137 patients who received radiation and PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and 121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received radiation following the start of PD-1 blockade, 25 continued to receive PD-1 inhibition for a median of 179days and survived for a median of 238 additional days. Median survival following first course of radiation for brain metastases was 634days. Melanoma patients received brain directed radiation relatively less frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS: Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD 1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls. PMID- 28662870 TI - Survival and central photopenia detected by fluorine-18 fluoro-deoxy-glucose positron emission tomography (FDG-PET) in patients with locoregional non-small cell lung cancer treated with radiotherapy. AB - BACKGROUND: Primary non-small cell lung cancer cavitation and central photopenia, detected by radiology and FDG-PET scanning respectively, are thought to be the result of tumor necrosis. Such regions may contain hypoxic but viable carcinoma cells which may be relatively radioresistant compared with fully oxygenated regions. We hypothesized that photopenic tumors treated with radiotherapy with or without chemotherapy would be associated with worse survival compared with tumors not showing central photopenia. PATIENTS AND METHODS: The data were from a prospective trial (TROG 99-05) investigating the prognostic significance of primary tumor volume in patients receiving radical radiotherapy for locoregional non-small cell lung cancer (NSCLC). A subset of patients who had a pre-treatment FDG-PET scan formed the study population. The scans were evaluated by two observers for central photopenia in the primary tumor using a visual scoring system. The relationship of photopenia with survival was determined after adjusting for other prognostic factors. RESULTS: There were 172 eligible patients. The two observers agreed on the presence of photopenia in 90% of cases (Kappa=0.822, p<0.001). Seventy-three patients were scored as having photopenia. Photopenia was not associated with worse survival, either on univariate analysis, or after adjusting for sex, performance status and nodal status (HR=1.20, 95% CI 0.78-1.87, p=0.4) Photopenia was however significantly associated with larger tumor volume and weight loss. CONCLUSIONS: This study failed to demonstrate a significantly worse survival associated with central photopenia in patients treated with radiotherapy for NSCLC. PMID- 28662871 TI - External validation of leukocytosis and neutrophilia as a prognostic marker in anal carcinoma treated with definitive chemoradiation. AB - PURPOSE: To validate the prognostic value of leukocyte disorders in anal squamous cell carcinoma (SCC) patients receiving definitive concurrent chemoradiation. MATERIALS AND METHODS: Bi-institutional clinical records from consecutive patients treated between 2001 and 2015 with definitive chemoradiation for anal SCC were retrospectively reviewed. Prognostic value of pretreatment leukocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as leukocyte or neutrophil count exceeding 10G/L and 7G/L, respectively. RESULTS: We identified 133 patients, treated in two institutions. Eight% and 7% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year overall survival (OS) and progression-free survival (PFS) were 88% and 77%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS (p<0.01), locoregional control (LRC) and Distant Metastasis Control (DMC) (p<0.05), also after stratification by each institution. In multivariate analysis, leukocytosis and neutrophilia remained as independent risk factors associated with poorer OS, PFS, LRC and DMC (p<0.05). CONCLUSION: This study validates leukocytosis and neutrophilia as independent prognostic factors in anal SCC patients treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters are clinically relevant biomarkers to be considered for further clinical investigations. PMID- 28662872 TI - Feline Cardiogenic Arterial Thromboembolism: Prevention and Therapy. AB - Feline cardiogenic arterial thromboembolism (CATE) is a devastating disease whereby 33% of cats survive their initial event, although approximately 50% of mortality is from euthanasia. Short-term management focuses on inducing a hypocoagulable state, improving blood flow, and providing supportive care. Ideally, all cats should be given 72 hours of treatment to determine the acute clinical course. Preventive protocols include antiplatelet and/or anticoagulant drugs, with the only prospective clinical trial demonstrating that clopidogrel is superior to aspirin with a lower CATE recurrence rate and longer time to recurrent CATE. Newer anticoagulant drugs hold great promise in the future of managing this disease. PMID- 28662873 TI - Asymptomatic Hypertrophic Cardiomyopathy: Diagnosis and Therapy. AB - Hypertrophic cardiomyopathy (HCM) affects 15% of cats, and prevalence increases with age. Although many cats with HCM have normal life expectancy, some cats die suddenly, or develop congestive heart failure or arterial thromboembolism (ATE). High-risk cats can be recognized by left atrial enlargement on echocardiography, which can be missed on physical examination, as a heart murmur is often absent. Alternatively, plasma biomarkers can be measured as an initial screening test; echocardiography is indicated in cats with plasma NT-probrain natriuretic peptide concentrations exceeding 100 pmol/L. High-risk cats should be treated with clopidogrel to reduce the risk of ATE. PMID- 28662874 TI - E-coaching: New future for cardiac rehabilitation? A systematic review. AB - OBJECTIVE: To provide an evidence-based overview of the effectiveness of e coaching as a cardiac rehabilitation program (CRP). METHODS: Pubmed, Embase, PEDro and CINAHL were searched to identify relevant RCTs. The e-coaching programs were divided into basic or complex depending on their content. Two reviewers independently assessed the methodological quality and extracted the data. A best evidence synthesis was used to summarize the results. RESULTS: 19 RCTs were included. Detailed descriptions of the e-coaching programs were lacking. Complex e-coaching was more effective than usual-care for physical capacity (moderate evidence for short-, and mid-term; strong evidence for long-term), for clinical status (limited evidence for short- and mid-term; moderate evidence for the long term), and for psychosocial health (moderate evidence for short-term; strong evidence for mid-, and long-term). For basic e-coaching only limited or no evidence for effectiveness was found. CONCLUSION: Promising results were found for the effectiveness of complex e-coaching as a CRP to improve a patients' physical capacity, clinical status and psychosocial health. PRACTICE IMPLICATIONS: The content of the e-coaching programs were not clearly described. This makes it difficult to identify which components of e-coaching are most effective and should be further developed to deliver the most optimal care for cardiac rehabilitation patients. PMID- 28662875 TI - The Role of Varicella Zoster Virus in the Development of Periapical Pathoses and Root Resorption: A Systematic Review. AB - INTRODUCTION: Varicella zoster virus (VZV) and subsequent herpes zoster (HZ) infection have been proposed as a causative agent of periapical pathoses and root resorption. This review aimed to identify, synthesize, and present a critical analysis of the available data on the association among VZV, subsequent HZ infection, and the development of periapical pathoses and root resorption and to analyze the level of evidence of available studies. METHODS: The literature search covered MEDLINE, Science Citation Index Expanded, and Scopus. A qualitative critical appraisal of the included articles was performed. RESULTS: The electronic database search yielded 66 hits from PubMed, 73 hits from Web of Science, and 107 from Scopus. Seven case reports and 3 cross-sectional studies were included in the final review. When summarized, in 7 patients with a history of a previous HZ attack and with no other apparent cause, 23 teeth were diagnosed with apical periodontitis, 8 teeth with internal and 1 tooth with external root resorption. The cross-sectional studies investigated the presence of VZV DNA in samples of acute apical abscess. The VZV DNA was found only in 2 of 65 samples. CONCLUSIONS: All studies included in this systematic review had a low level of evidence (4 and 5). Still, the potential role of VZV in the etiopathogenesis of periapical pathoses and root resorption cannot be ruled out. Future investigations should be directed toward the analysis of VZV pathologic effects on pulp blood vessels, which might cause local ischemia and tissue necrosis. PMID- 28662876 TI - Herpes Zoster Involving the Second Division of the Trigeminal Nerve: Case Report and Literature Review. AB - Herpes zoster along the maxillary division of the trigeminal nerve is a rare condition that is caused by reactivation of the varicella zoster virus that resides within the trigeminal ganglion after the primary infection of chickenpox. The disease may be manifested as a toothache during its prodromal stage. The active stage of the disease is characterized by the appearance of a vesicular rash. Postherpetic neuralgia is a common complication of herpes zoster after resolution of the facial and intraoral symptoms. There is increasing evidence for herpes zoster patients to develop stroke later in life. The present case reports the development of herpes zoster maxillaris in a 71-year-old man whose maxillary right canine was diagnosed as pulpal necrosis and symptomatic apical periodontitis and was subsequently treated endodontically by cleaning and shaping and filling the canal space with gutta-percha and an epoxy resin-based sealer. The patient presented 3 days later with midfacial ulceration, desquamation, and crusting as well as intraoral ulceration along the course of the V2 dermatome. After successful treatment with antiviral medication, postherpetic neuralgia developed within the next 2 months. Complete resolution of the neuralgia occurred at the 4-month recall with negligible facial scarring. Herpes zoster may mimic odontogenic pain during the prodromal stage of the disease. Reactivation of the virus has also been implicated in the pathogenesis of pulpal pathoses. These paradoxical facets are of interest to the endodontist and should be considered in the differential diagnosis of the disease. PMID- 28662877 TI - Cyclic Fatigue Resistance of Reciproc Blue, Reciproc, and WaveOne Gold Reciprocating Instruments. AB - INTRODUCTION: The aim of the present study was to compare the cyclic fatigue resistance of Reciproc Blue R25 (VDW, Munich, Germany) with Reciproc R25 (VDW) and WaveOne Gold Primary (Denstply Maillefer, Ballaigues, Switzerland). METHODS: Fifteen Reciproc Blue R25, 15 Reciproc R25, and 15 WaveOne Gold Primary instruments were collected and tested in a dynamic cyclic fatigue test device, which has an artificial canal with a 60 degrees angle of curvature and a 5-mm radius of curvature. All instruments were operated until fracture occurred, and time to fracture (TF) and the lengths of the fractured fragments were recorded. The mean and standard deviations of TF and fragment length were calculated for each reciprocating system. TF data were subjected to Kruskal-Wallis 1-way analysis of variance and the Dunn test, whereas fractured fragment length data were subjected to 1-way analysis of variance (P < .05). RESULTS: Reciproc Blue R25 exhibited the highest cyclic fatigue resistance (P < .05). The cyclic fatigue resistance values of WaveOne Gold Primary were significantly higher than those of Reciproc R25 (P < .05). There was no significant difference in the mean length of the fractured fragments among the instruments (P > .05). CONCLUSIONS: Reciproc Blue R25 instruments had significantly higher cyclic fatigue resistance than WaveOne Gold and Reciproc R25 instruments. PMID- 28662878 TI - Bonding over Dentin Replacement Materials. AB - INTRODUCTION: Dentin replacement materials are necessary in large cavities to protect the pulp and reduce the bulk of filling material. These materials are layered with a composite resin restorative material. Microleakage caused by poor bonding of composite resin to underlying dentin replacement material will result in pulp damage. The aim of this study was to characterize the interface between dentin replacement materials and composite resin and to measure the shear bond strength after dynamic aging. METHODS: Biodentine (Septodont, Saint Maur-des Fosses, France), Theracal LC (Bisco, Schaumburg, IL), and Fuji IX (GC, Tokyo, Japan) were used as dentin replacement materials. They were then overlaid with a total-etch and bonding agent or a self-etch primer and composite resin or a glass ionomer cement. All combinations were thermocycled for 3000 cycles. The interface was characterized using scanning electron microscopy and elemental mapping. Furthermore, the shear bond strength was assessed. RESULTS: The Biodentine surface was modified by etching. The Theracal LC and Fuji IX microstructure was unchanged upon the application of acid etch. The Biodentine and glass ionomer interface showed an evident wide open space, and glass particles from the glass ionomer adhered to the Biodentine surface. Elemental migration was shown with aluminum, barium, fluorine, and ytterbium present in Biodentine from the overlying composite resin. Calcium was more stable. The bond strength between Theracal LC and composite using a total-etch technique followed by self-etch primer achieved the best bond strength values. Biodentine exhibited the weakest bond with complete failure of bonding shown after demolding and thermocycling. CONCLUSIONS: Dynamic aging is necessary to have clinically valid data. Bonding composite resin to water-based dentin replacement materials is still challenging, and further alternatives for restoration of teeth using such materials need to be developed. PMID- 28662879 TI - Use of Platelet-rich Plasma in Endodontic Procedures in Adults: Regeneration or Repair? A Report of 3 Cases with 5 Years of Follow-up. AB - INTRODUCTION: Regenerative endodontic procedures (REP) are a promising alternative for necrotic immature teeth in adolescents and children, but very little evidence is available on this alternative in long-lasting necrotic teeth with open apices in adults. REPs are designed to replace damaged structures of the pulp-dentin complex, but no regeneration has been obtained in any of the cases described in necrotic immature permanent teeth with apical periodontitis with histologic results. The results are limited to periapical tissue repair with increasing root length, thickening of the root walls, and apical closure in young patients. In this series of cases, we report on the outcomes of the adjuvant use of autologous platelet-rich plasma (PRP) in endodontic therapy in adults by monitoring periapical tissue healing with periodic periapical radiographs and cone-beam computed tomographic scanning. METHODS: Three teeth with apical periodontitis and open apices in 3 different patients from 21 to 35 years-old were evaluated. An REP was performed with the adjuvant use of PRP. RESULTS: At controls, complete disappearance of the radiolucent lesions and the presence of calcified structures forming bridges occupying the pulp lumen were observed but not an ostensible thickening of root walls with a regeneration of pulp-dentin complex. CONCLUSIONS: The repair of periapical tissues with REPs of open apex teeth with apical periodontitis and in nonsurgical endodontic retreatment appears to be feasible in adults, but no regeneration was obtained in any of the present cases. The use of PRP may be a good choice as an autologous matrix because of its stability and induction; it contains growth factors and bioactive molecules like transforming growth factor beta, bone morphogenic proteins, insulinlike growth factors, and angiogenetic growth factors, which stimulate collagen production, angiogenesis, and cell differentiation. Anti-inflammatory and antibacterial properties have also been reported for this preparation, which are involved in all processes of repair. PMID- 28662880 TI - 3-Rooted Maxillary First Premolars: An Ex Vivo Study of External and Internal Morphologies. AB - INTRODUCTION: This study aimed to analyze the external and internal morphologies of 3-rooted maxillary first premolars using cone-beam computed tomographic (CBCT) imaging. METHODS: Fifty-six three-rooted maxillary first premolars were imaged by CBCT imaging and classified into 4 groups on the basis of external root morphology. Internal morphologic features, including the shapes of the buccal and palatal orifices and distances of bifurcation of the buccal-palatal and mesiobuccal-distobuccal root canals from the cementoenamel junction (CEJ), were measured. RESULTS: The teeth were classified into 4 groups on the basis of external morphology: group A, separation of the buccal and palatal roots with bifurcation of the former into the mesiobuccal and distobuccal roots (n = 22); group B, fusion of 2 buccal roots with the palatal root being separate (n = 19); group C, complete or partial fusion of the distobuccal and palatal roots (n = 9); and group D, fusion of all 3 roots (n = 6). The buccal orifice was mainly triangular/heart shaped. The distance of bifurcation of the buccal-palatal root canals from the CEJ in group A differed significantly from those in groups B and C (P < .05). There were significant differences in the distance of bifurcation of the mesiobuccal-distobuccal root canals from the CEJ among groups A, B, and C (P < .05). Four teeth exhibited C-shaped root canal systems of different configurations. CONCLUSIONS: The external and internal morphologies of 3-rooted maxillary first premolars vary considerably. PMID- 28662881 TI - Sperm membrane proteins associated with the boar semen cryopreservation. AB - This study aimed to define sperm membrane protein markers of semen freezability of boars with the aid of a proteomic approach. Semen from fourteen adult boars were subjected to slow freezing and rapid thawing. After thawing, sperm vigor and motility were analyzed, and based on these results, animals were separated into two groups: good (GFEs) and poor freezability (PFEs). Sperm membrane proteins were extracted and subjected to two-dimensional electrophoresis. Stained gels were analyzed by computerized resources to indicate differentially expressed protein spots, that were identified by mass spectrometry. Six animals showed good freezability with average sperm vigor and motility of 2.2+/-0.8 and 41.8+/-22.9, respectively, whereas eight boars showed poor freezability, with 1.9+/-0.6 and 26.8+/-17.5 of sperm vigor sperm motility, respectively. An average of 263+/-62.2 spots per gel and 234.2+/-54.6 of spots consistently present in all gels were detected. The intensities of five spots were significantly different between groups. Fc fragment of IgG binding protein and lactadherin were more intense in the PFE group, while Arylsulfatase A and F-actin capping protein subunit alpha 1 were more expressed in the GEF group. Based on their functions and interactions with other proteins, we conclude that these four sperm membrane proteins may act as potential markers of boar semen freezability. PMID- 28662882 TI - Ovum pick-up interval in buffalo (Bubalus bubalis) managed under wetland conditions in Argentina: Effect on follicular population, oocyte recovery, and in vitro embryo development. AB - The excellent adaptation of water buffalo (Bubalis bubalis) to swampy environments means that animals are frequently managed in areas with restricted access for reproductive procedures. The objective of this study was to evaluate the effect of the ovum pick-up (OPU) interval on follicular population, oocyte recovery, oocyte quality and in vitro embryo production. Twelve Murrah buffaloes were subjected to two consecutive dominant follicle reductions, and randomly assigned to either 7-day (n=6) or 14-day (n=6) OPU interval groups. Although there was no significant difference in the average number of small (<3mm) and large (>8mm) diameter follicles available per OPU, a higher proportion of medium sized follicles (3-8mm) were observed in the 14-day interval group (5.129 vs 3.267; p<0.05). The number of recovered oocytes per donor was also significantly higher (4.51 vs. 2.8; p<0.05) in the 14-day interval group, although this was attributed to an increase in the proportion of lower quality oocytes (grades III and IV). After in vitro fertilization, embryo developmental competence from grade I and II oocytes was superior to that from grade III and IV oocytes, irrespective of OPU interval group. There was no significant difference in the proportion of grade I and II oocytes cleaved after sperm co-incubation; however, there was a higher proportion of blastocysts produced in 14-day interval group (28 vs. 6%, p<0.05). No blastocysts were produced from grade III and IV oocytes. This study indicates it is possible to use a 14-day interval for oocyte collection in water buffalo; this approach could be considered as an alternative when access to animals is restricted. PMID- 28662883 TI - Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for treatment of recurrent chronic hepatitis C genotype 1 infection after liver transplantation: Real-world experience. AB - BACKGROUND/AIMS: The registered trial has demonstrated that paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD) with ribavirin was effective for recurrent hepatitis C virus genotype 1 (HCV-1) infection after liver transplantation in patients with mild fibrosis; however, the real-world efficacy and safety of this regimen have not been determined. METHODS: The efficacy (sustained virological response, SVR12, undetectable HCV RNA 12 weeks post-treatment) and safety were evaluated in 12 patients with recurrent HCV-1 infection after liver transplantation. RESULTS: Nine patients were treated for 24 weeks, and three patients (two treatment-naive patients and one interferon intolerant patient) were treated for 12 weeks. HCV RNA was undetectable at treatment day 1, week 1, week 4, week 12, and at the end of treatment in 8.3% (n = 1), 25% (n = 3), 83.3% (n = 10), 100% (n = 12), and 100% (n = 12) of patients, respectively. All twelve patients achieved SVR12. Treatment was temporarily stopped in one patient because of leucopenia. The other patient with minimal fibrosis experienced an elevation in alanine aminotransferase concentration, which returned to normal levels after dose reduction. Seven (58.3%) patients required RBV dose reduction and two (16.7%) required transient RBV discontinuation during treatment. There were no serious adverse events, and most adverse events were related to ribavirin. No patient developed graft rejection or deterioration in hepatic or renal function during treatment. Treatment efficacy and safety were comparable between patients with and without advanced liver fibrosis. CONCLUSION: PrOD plus ribavirin had a highly satisfactory real-world efficacy and safety profile in the treatment of recurrent HCV-1 infection after liver transplantation in Asian patients. PMID- 28662885 TI - Use of intravenous iron in the current clinical practice. PMID- 28662884 TI - Factors associated with month 2 smear non-conversion among Category 1 tuberculosis patients in Karachi, Pakistan. AB - Predictors of smear non-conversion at baseline can help identify cases at risk for failure of tuberculosis treatment. Retrospective data for smear-positive Category 1 patients in Karachi, Pakistan, was analyzed. Predictors of sputum conversion were determined using multiple logistic regression with sputum conversion as outcome variable and patient demographics, baseline weight, baseline sputum smear grade, case-finding approach as explanatory variables. Age >=35 years, baseline sputum grade of 3+ were significantly associated with predicting sputum smear positivity at month 2 of treatment. Monitoring compliance to TB treatment should be considered amongst older patients and those with a high sputum grade at baseline. PMID- 28662886 TI - Dress syndrome and bilateral panuveitis caused by strontium ranelate. PMID- 28662887 TI - Blood sweat! PMID- 28662888 TI - Parechovirus infection in a neonate. PMID- 28662889 TI - Metachronous bilateral adrenal hemorrhage in primary antiphospholipid syndrome. PMID- 28662890 TI - Diabetic ketoacidosis in patients under treatment with sodium-glucose cotransporter type 2 inhibitors. PMID- 28662891 TI - Reply. PMID- 28662892 TI - Glibenclamide pretreatment protects against chronic memory dysfunction and glial activation in rat cranial blast traumatic brain injury. AB - Blast traumatic brain injury (bTBI) affects both military and civilian populations, and often results in chronic deficits in cognition and memory. Chronic glial activation after bTBI has been linked with cognitive decline. Pharmacological inhibition of sulfonylurea receptor 1 (SUR1) with glibenclamide was shown previously to reduce glial activation and improve cognition in contusive models of CNS trauma, but has not been examined in bTBI. We postulated that glibenclamide would reduce chronic glial activation and improve long-term memory function after bTBI. Using a rat direct cranial model of bTBI (dc-bTBI), we evaluated the efficacy of two glibenclamide treatment paradigms: glibenclamide prophylaxis (pre-treatment), and treatment with glibenclamide starting after dc bTBI (post-treatment). Our results show that dc-bTBI caused hippocampal astrocyte and microglial/macrophage activation that was associated with hippocampal memory dysfunction (rapid place learning paradigm) at 28days, and that glibenclamide pre treatment, but not post-treatment, effectively protected against glial activation and memory dysfunction. We also report that a brief transient time-window of blood-brain barrier (BBB) disruption occurs after dc-bTBI, and we speculate that glibenclamide, which is mostly protein bound and does not normally traverse the intact BBB, can undergo CNS delivery only during this brief transient opening of the BBB. Together, our findings indicate that prophylactic glibenclamide treatment may help to protect against chronic cognitive sequelae of bTBI in warfighters and other at-risk populations. PMID- 28662893 TI - Both serotonergic and noradrenergic systems modulate the development of tolerance to chronic stress in rats with lesions of the serotonergic neurons of the median raphe nucleus. AB - Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2 h) or chronic restraint (2 h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10 mg/kg) or saline was performed twice daily (12-12 h interval), for 7 consecutive days. EPM test was conducted 24 h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs. PMID- 28662894 TI - Medial Patellofemoral Ligament, Medial Patellotibial Ligament, and Medial Patellomeniscal Ligament: Anatomic, Histologic, Radiographic, and Biomechanical Study. AB - PURPOSE: To describe the anatomy (quantitative macroscopic and histologic), radiographic parameters of the insertions, and biomechanical characteristics of the medial ligamentous restrictors of the patella (medial patellofemoral ligament [MPFL], medial patellotibial ligament [MPTL], and medial patellomeniscal ligament [MPML]) in cadaveric knees. Because the MPTL and the MPML are not as well known as the MPFL, they were the focus of this study. METHODS: MPFLs, MPTLs, and MPMLs from 9 knees were dissected. Histologic evaluations were conducted. Length, width, and insertion relations with anatomic references were determined. Metallic spheres were introduced into the insertion points of each ligament, and anteroposterior and lateral radiographs were taken. The distances of the insertions from the baselines were measured on radiographs. Tensile tests of the ligaments were performed. RESULTS: All the samples showed dense connective tissue characteristic of ligaments. The MPTL was inserted into the proximal tibia (13.7 mm distal to the joint line) and in the distal end of the patella (3.6 mm proximal to the distal border). The MPTL had a length of 36.4 mm and a width of 7.1 mm. The MPML was inserted into the medial meniscus and distally in the patella (5.7 mm proximal to the distal border). Per radiography, on the anteroposterior view, the tibial insertion of the MPTL was 9.4 mm distal to the joint line and in line with the medial border of the medial spine. On the lateral view, the patellar insertions of the MPTL and MPML were 4.8 and 6.6 mm proximal to its distal border, respectively. The MPTL was stiffer than the MPFL (17.0 N/mm vs 8.0 N/mm, P = .024) and showed less deformation in the maximum tensile strength (8.6 mm vs 19.3 mm, P = .005). CONCLUSIONS: The MPTL inserts into the proximal tibia and into the distal pole of the patella. The MPML inserts into the medial meniscus and into the distal pole of the patella. They present with identifiable anatomic and radiographic parameters. Grafts commonly used for ligament reconstructions should be adequate for reconstruction of the MPTL. CLINICAL RELEVANCE: The study contributes to the anatomic, radiographic, and biomechanical knowledge of the MPTL to improve the outcomes of its reconstruction. PMID- 28662895 TI - Does Study Design Affect Redislocation Rates After Primary Shoulder Dislocations? A Systematic Review Comparing Prospective and Retrospective Studies. AB - PURPOSE: To compare recurrence rates between prospectively collected and retrospectively collected data on primary anterior shoulder dislocations, as this could influence the timing of surgical decision making. METHODS: A comprehensive literature search of Medline, Embase, CINAHL, and hand searches was performed. Recurrence rates of anterior shoulder dislocations were collected from relevant articles, along with follow-up length, age, and gender. An independent sample t test was conducted to evaluate our hypothesis. A multiple linear regression model was used to examine the variance in recurrence rates while controlling for covariates. RESULTS: A total of 1,379 articles were identified, of which 25 were relevant to our study-16 prospective and 9 retrospective. The average rate of recurrence of anterior shoulder dislocations in retrospective studies (mean [M] = 45.2, standard deviation [SD] = 31.67) was not significantly different from that in prospective studies (M = 56.7, SD = 22.55). The 95% confidence interval for the difference of the means ranged from -34.05 to 10.91. After controlling for covariates with the multiple linear regression, only 1.9% of the variance in recurrence rates was due to study type and was not significant (P = .42). The t test performed to evaluate our hypothesis was also not significant t(23) = -1.07, P = .298. CONCLUSIONS: When comparing prospective and retrospective studies, there was no significant difference in recurrence rates of primary anterior shoulder dislocations treated nonoperatively. The average redislocation rate was 56.7% in prospective studies and 45.2% in retrospective studies. Furthermore, the majority of this difference was accounted for by varying rates between age groups. Further research is needed to determine the risk of redislocation in specific age groups, to guide treatment decisions based on varying risk. LEVEL OF EVIDENCE: Systematic review of Level II and III studies. PMID- 28662896 TI - Response to: Mild to moderate clozapine-induced gastrointestinal hypomotility should not require cessation of clozapine. PMID- 28662897 TI - Effects of a randomized exercise trial on physical activity, psychological distress and quality of life in older adults. AB - OBJECTIVE: Evidence suggests improvements in positive psychological health indices (e.g., self-esteem) may explain the relationship between physical activity and quality of life (QoL) in older adults. Less is known about the role of reductions in negative psychological health indices (e.g., depression). The present study examined the effects of changes in moderate-to-vigorous physical activity (MVPA) and psychological distress on change in QoL in older adults enrolled in an exercise program. METHODS: Older adults (N=247, Mage=65.68+/-4.59) participated in a six-month randomized exercise trial. Participants wore accelerometers and completed questionnaires to measure MVPA, psychological health, and QoL at baseline and post-intervention. Psychological distress was modeled as a latent factor comprised of anxiety, depression, sleep dysfunction, and stress. Structural models were used to examine the effects of changes in MVPA and distress on change in QoL. RESULTS: Increases in MVPA predicted reductions in distress from baseline to post-intervention (B=-0.10, p=0.05). In turn, reductions in distress predicted increases in QoL (B=-0.51, p=0.001). The indirect effect of MVPA on QoL through distress was also significant (p=0.05; 90% CI=0.005, 0.125). CONCLUSIONS: Findings extend previous research on the mediators of the MVPA-QoL relationship in older adults, suggesting reductions in negative psychological health outcomes may also mediate this pathway. PMID- 28662898 TI - Insomnia as an additional clinical correlate of suicidal ideation after stroke. PMID- 28662899 TI - L-type amino acid transporter 1 utilizing prodrugs: How to achieve effective brain delivery and low systemic exposure of drugs. AB - L-type amino acid transporter 1 (LAT1) is selectively expressed in the blood brain barrier (BBB) and brain parenchyma. This transporter can facilitate brain delivery of neuroprotective agents and additionally give opportunity to minimize systemic exposure. Here, we investigated structure-pharmacokinetics relationship of five newly synthesized LAT1-utilizing prodrugs of the cyclooxygenase inhibitor, ketoprofen, in order to identify beneficial structural features of prodrugs to achieve both targeted brain delivery and low peripheral distribution of the parent drug. Besides, we studied whether pharmacokinetics and bioconversion of LAT1-utilizing prodrugs in vivo can be predicted in early stage experiments. To achieve these goals, we compared the in vitro brain uptake mechanism of prodrugs, rate of BBB permeation of compounds using in situ perfusion technique, their systemic pharmacokinetics and release of parent drug in brain, plasma and liver of mice. The results revealed that both excellent LAT1 binding ability and transporter utilization in vitro can be achieved by conjugating the parent drug to aromatic amino acids such as phenylalanine in comparison to prodrugs with an aliphatic promoiety. The presence of an aromatic promoiety directly conjugated in meta- or para-position to ketoprofen led to LAT1 utilizing prodrugs capable of delivering the parent drug into the brain with higher unbound brain to plasma ratio and reduced liver exposure than with ketoprofen itself. In contrast, the prodrugs with aliphatic promoieties and with an additional carbon attached between the parent drug and phenylalanine aromatic ring did not enhance brain delivery of ketoprofen. Furthermore, we have devised a screening strategy to pinpoint successful candidates at an early stage of development of LAT1-utilizing prodrugs. The screening approach demonstrated that early stage experiments could not replace pharmacokinetic studies in vivo due to the lack of prediction of the intra-brain/systemic distribution of the prodrugs as well as the release of the parent drug. Overall, this study provides essential knowledge required for improvement of targeted brain delivery and reduction of systemic exposure of drugs via the LAT1-mediated prodrug approach. PMID- 28662900 TI - Revisiting the use of sPLA2-sensitive liposomes in cancer therapy. AB - The first developed secretory phospholipase A2 (sPLA2) sensitive liposomal cisplatin formulation (LiPlaCis(r)) is currently undergoing clinical evaluation. In the present study we revisit and evaluate critical preclinical parameters important for the therapeutic potential and safety of platinum drugs, here oxaliplatin (L-OHP), formulated in sPLA2 sensitive liposomes. We show the mole percentage of negatively charged phospholipid needed to obtain enzyme-sensitivity for saturated systems is >=25% for 16-carbon chain lipid membranes, and >40% for 18-chain lipid membranes, which was surprising as 25% is used clinically in LiPlaCis(r). Efficient sPLA2-dependent growth inhibition of colorectal cancer cells was demonstrated in vitro, where cell membrane degradation and cytolysis depends on the sensitivity of the formulation towards the enzyme and is governed by the amount of lysolipids generated and the presence of serum proteins. We found that serum proteins did not affect the lipase activity of the enzyme towards the membranes but instead sequester the lysolipid byproducts consequently inhibiting their detergent-like cytotoxic properties. In vivo therapeutic potential and safety of the liposomes was investigated in nude mice bearing sPLA2 deficient FaDu squamous carcinoma and sPLA2-expressing Colo205 colorectal adenocarcinoma. After intravenous injections, the tumor growth was suppressed for liposomal L-OHP relative to free drug, but only a weak response was observed for both slow- and fast-releasing sPLA2-sensitive formulations compared to non sensitive liposomes. Also, the mice did not show longer survival. In turn, for the highly sPLA2-sensitive liposomes, multiple high doses caused petechial cutaneous hemorrhages, along with multifocal hepatonecrotic lesions, suggestive of premature activation in skin and liver irrespective of sPLA2-status of the tumor engraft. These results indicate that although liposomal carriers can improve the antitumor efficacy of platinum drugs, sPLA2-triggered release suffers from a narrow therapeutic index and has safety concerns. PMID- 28662901 TI - Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. AB - Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory. In this study, we employed vismodegib to inhibit the sonic-hedgehog pathway with the aim to i) elucidate the mechanism of how CAFs depletion improves drug delivery, ii) extent and evaluate the potential use of sonic-hedgehog inhibitors to breast cancers, and iii) investigate whether sonic-hedgehog inhibition improves not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely Abraxane(r) and Doxil(r). We found that treatment with vismodegib normalizes the tumor microenvironment by reducing the proliferative CAFs and in cases the levels of collagen and hyaluronan. These modulations re-engineered the solid and fluid stresses in the tumors, improving blood vessel functionality. As a result, the delivery and efficacy of chemotherapy was improved in two models of pancreatic cancer. Additionally, vismodegib treatment significantly improved the efficacy of both Abraxane and Doxil in xenograft breast tumors. Our results suggest the use of vismodegib, and sonic hedgehog inhibitors in general, to enhance cancer chemo- and nanotherapy. PMID- 28662902 TI - The use of electronic-neutral penetrating peptides cyclosporin A to deliver pro apoptotic peptide: A possibly better choice than positively charged TAT. AB - Cell-penetrating peptides (CPPs) are increasingly important in transporting macromolecules across cell membranes, but their use remains confined to narrow clinical applications due to the systemic toxicity induced by their positive charges. Several newly discovered electronic neutral penetrating peptides are not attracting much attention because their penetrating capacity is normally far less powerful than cationic or amphiphilic CPPs. In this study, we found the electronic neutral cyclic peptide cyclosporin A (CsA) exhibited 5.6-fold and 19.1 fold stronger penetrating capacity, respectively, than two reported electronic neutral peptides PFVYLI (PFV) and pentapeptide VPTLQ (VPT) in MCF-7 human breast cancer cells. To systematically evaluate the efficiency and toxicity of CsA, we utilized CsA to deliver a membrane-impenetrable pro-apoptotic peptide (PAD) and compared this to the well-established cationic penetrating peptide TAT (RKKRRQRRR). By conjugating CsA to PAD, the internalization of PAD increased 2.2- to 4.7-fold in four different tumor cell lines, and that of CsA-PAD conjugate was significantly higher than TAT-PAD conjugate in MCF-7 and HeLa human cervical cancer cells. Cytotoxicity studies demonstrated that CsA-PAD exhibited a large increase in cell cytotoxicity compared to PAD in four different tumor cell lines, with the effect being similar or greater than the effect of TAT-PAD, depending upon the cell type. The mechanistic studies demonstrated that modifying CsA or TAT did not change the cytotoxicity mechanism of PAD, which occurred via mitochondrial membrane damage related to apoptosis. In vivo studies showed that CsA-PAD could achieve similar anti-tumor efficacy to TAT-PAD but with much lower systemic toxicity, especially to the heart and liver. In conclusion, our study demonstrates for the first time that the electronic-neutral penetrating peptide CsA can be used as a powerful tool to deliver peptide drugs with similar efficiency and less toxicity than the positively charged TAT peptide. PMID- 28662903 TI - Trends in food waste valorization for the production of chemicals, materials and fuels: Case study South and Southeast Asia. AB - Staggering amounts of food waste are being generated in Asia by means of agricultural processing, food transportation and storage, and human food consumption activities. This along with the recent sustainable development goals of food security, environmental protection, and energy efficiency are the key drivers for food waste valorization. The aim of this review is to provide an insight on the latest trends in food waste valorization in Asian countries such as India, Thailand, Singapore, Malaysia and Indonesia. Landfilling, incineration, and composting are the first-generation food waste processing technologies. The advancement of valorisation alternatives to tackle the food waste issue is the focus of this review. Furthermore, a series of examples of key food waste valorization schemes in this Asian region as case studies to demonstrate the advancement in bioconversions in these countries are described. Finally, important legislation aspects for food waste disposal in these Asian countries are also reported. PMID- 28662904 TI - Corrigendum to "Cost-effectiveness analysis in melanoma detection: A transition model applied to dermoscopy" [Eur J Cancer 67 (2016) 38-45]. PMID- 28662905 TI - Letter to the Editor regarding the paper by F. Cardoso et al. 'European Breast Cancer Conference manifesto on breast centres/units'. PMID- 28662906 TI - Reducing consumption of confectionery foods: A post-hoc segmentation analysis using a social cognition approach. AB - Considering confectionary consumption behaviour this cross-sectional study used social cognition variables to identify distinct segments in terms of their motivation and efforts to decrease their consumption of such foods with the aim of informing targeted social marketing campaigns. Using Latent Class analysis on a sample of 500 adults four segments were identified: unmotivated, triers, successful actors, and thrivers. The unmotivated and triers segments reported low levels of perceived need and perceived behavioural control (PBC) in addition to high levels of habit and hedonic hunger with regards their consumption of confectionery foods. Being a younger adult was associated with higher odds of being in the unmotivated and triers segments and being female was associated with higher odds of being in the triers and successful actors segments. The findings indicate that in the absence of strong commitment to eating low amounts of confectionery foods (i.e. perceived need) people will continue to overconsume free sugars regardless of motivation to change. It is therefore necessary to identify relevant messages or 'triggers' related to sugar consumption that resonate with young adults in particular. For those motivated to change, counteracting unhealthy eating habits and the effects of hedonic hunger may necessitate changes to food environments in order to make the healthy choice more appealing and accessible. PMID- 28662907 TI - Sensory properties of chile pepper heat - and its importance to food quality and cultural preference. AB - Chile peppers are one of the most important vegetable and spice crops in the world. They contain capsaicinoids that are responsible for the characteristic burning (pungency) sensation. Currently, there are 22 known naturally occurring capsaicinoids that can cause the heat sensation when consumed. Each produces a different heat sensation effect in the mouth. A need exists for a standard and new terminology to describe the complex heat sensation one feels when eating a chile pepper. A comprehensive set of descriptors to describe the sensory characteristics of chile pepper heat was developed. It was validated with trained panelists tasting samples representing the five domesticated species and 14 pod types within these species. Five key attributes that define and reference a lexicon for describing the heat sensation of chile peppers were determined to describe the heat sensation in any product, and importantly, can be used in the food industry worldwide. PMID- 28662908 TI - Arrhythmic storm solved with ExtraCorporeal Membrane Oxygenation and consecutive percutaneous coronary intervention and ventricular tachycardia ablation. PMID- 28662909 TI - Emergency Department Escalation in Theory and Practice: A Mixed-Methods Study Using a Model of Organizational Resilience. AB - STUDY OBJECTIVE: Escalation policies are used by emergency departments (EDs) when responding to an increase in demand (eg, a sudden inflow of patients) or a reduction in capacity (eg, a lack of beds to admit patients). The policies aim to maintain the ability to deliver patient care, without compromising safety, by modifying "normal" processes. The study objective is to examine escalation policies in theory and practice. METHODS: This was a mixed-method study involving a conceptual analysis of National Health Service escalation policies (n=12) and associated escalation actions (n=92), as well as a detailed ethnographic study of escalation in situ during a 16-month period in a large UK ED (n=30 observations). RESULTS: The conceptual analysis of National Health Service escalation policies found that their use requires the ability to dynamically reconfigure resources (staff and equipment), change work flow, and relocate patients. In practice, it was discovered that when the ED is under pressure, these prerequisites cannot always be attained. Instead, escalation processes were adapted to manage pressures informally. This adaptive need ("work as done") was found to be incompletely specified in policies ("work as imagined"). CONCLUSION: Formal escalation actions and their implementation in practice differed and varied in their effectiveness. Monitoring how escalation works in practice is essential in understanding whether and how escalation policies help to manage workload. PMID- 28662910 TI - Capacity? Informed Consent; Informed Discharge? Uncertainty! PMID- 28662911 TI - What Is the Efficacy of Droperidol for the Management of Acute Psychosis-Induced Agitation? PMID- 28662912 TI - Does Antipyresis Improve Mortality in Critically Ill Septic Patients? PMID- 28662913 TI - What Elements of the History, Examination, Laboratory Testing, or Point-of-Care Ultrasonography Are Most Useful in the Diagnosis of Acute Appendicitis in Children? PMID- 28662914 TI - Development of single-step multiplex real-time RT-PCR assays for rapid diagnosis of enterovirus 71, coxsackievirus A6, and A16 in patients with hand, foot, and mouth disease. AB - Real-time reverse-transcription polymerase chain reaction (rRT-PCR) to detect enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) has facilitated the rapid and accurate identification of the two most common etiological agents underlying hand, foot, and mouth disease (HFMD). However, the worldwide emergence of CV-A6 infection in HFMD necessitates development of an improved multiplex rRT-PCR method. To rapidly determine the etiology of HFMD, two rRT-PCR assays using TaqMan probes were developed to differentiate among three selected common enteroviruses (EV-A71, CV-A16 and CV-A6) and to enable broad detection of enteroviruses (pan-enterovirus assay). No cross-reactions were observed with other RNA viruses examined. The detection limits of both assays were 10 copies per microliter for EV-A71, CV-A6 and CV-A16, and pan-enterovirus. The methods showed high accuracy (EV-A71, 90.6%; CV-A6, 92.0%; CV-A16, 100%), sensitivity (EV A71, 96.5%; CV-A6, 95.8%; CV-A16, 99.0%), and specificity (EV-A71, 100%; CV-A6, 99.9%; CV-A16, 99.9%) in testing clinical specimens (n=1049) during 2014-2016, superior to those of conventional RT-PCR. Overall, the multiplex rRT-PCR assays enabled highly sensitive detection and rapid simultaneous typing of EV-A71, CV-A6 and CV-A16, and enteroviruses, rendering them feasible and attractive methods for large-scale surveillance of enteroviruses associated with HFMD outbreaks. PMID- 28662915 TI - A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease. AB - BACKGROUND: Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity. PATIENT DESCRIPTION: This five-year-old girl presented with infantile-onset severe global developmental delay, truncal hypotonia, and generalized dystonia following normal development during her first six months of life. Brain magnetic resonance imaging showed marked hypomyelination and a thin corpus callosum at age 19 months, both unchanged on follow-up at age 28 months. Urine free sialic acid was moderately elevated. Cerebrospinal fluid free sialic acid was marginally elevated. Sequencing of SLC17A5 revealed compound heterozygous likely pathogenic variants, namely, a known missense (c.291G>A) variant and a novel truncating (c.819+1G>A) variant, confirming the diagnosis of Salla disease at age 3.5 years. CONCLUSION: We report a new patient with intermediate severe Salla disease. Normal or marginally elevated urine or cerebrospinal fluid free sialic acid levels cannot exclude Salla disease. In patients with progressive global developmental delay and hypomyelination on brain magnetic resonance imaging, Salla disease should be included into the differential diagnosis. PMID- 28662916 TI - Patterns of Head Computed Tomography Abnormalities During Pediatric Extracorporeal Membrane Oxygenation and Association With Outcomes. AB - BACKGROUND: We sought to classify type and distribution of acute infarction and hemorrhage on head computed tomography (CT) during pediatric extracorporeal membrane oxygenation (ECMO). We also analyzed the occurrence of seizures on electroencephalography and outcomes between those with and without CT abnormalities. METHODS: We conducted a single center observational study in pediatric intensive care units. The medical records of 179 children who underwent ECMO between 2009 and 2013 were reviewed. No interventions were done. RESULTS: A total of 46% (82/179) of children underwent CT. Of these, 60% (49/82) had acute pathology. Cerebral infarction occurred in 55% (27/49) and hemorrhage in 41% (20/49). Infarction was arterial in 67% (18/27) with a preponderance in the middle cerebral artery territory (17 patients). Infarction was bilateral in 41% (11/27) and not specific to the side of cannulation in the rest. Sensitivity and specificity for head ultrasound in predicting infarction on CT were 100% and 53%, respectively. A total of 36% (65/179) underwent continuous encephalography monitoring; 22% (14/65) of these had electrographic seizures. Electrographic seizures were increased in those with infarction (odds ratio [OR], 6.81; 95% confidence interval [CI], 1.98 to 23.43). Survival was reduced with both infarction (OR, 0.22; 95% CI, 0.09 to 0.54) and hemorrhage (OR, 0.31; 95% CI, 0.13 to 0.72). Children with CT abnormalities had more unfavorable outcomes (P = 0.01). CONCLUSIONS: Head ultrasound is insufficient to rule out infarction. Infarction is middle cerebral artery predominant and associated with an increased risk of electrographic seizures. PMID- 28662917 TI - Accumulative scFv-Fc antibody gene integration into the hprt chromosomal locus of Chinese hamster ovary cells. AB - We have previously developed an accumulative site-specific gene integration system (AGIS) using Cre-recombinase and mutated loxP sites. AGIS enables repeated transgene integration into a predetermined chromosomal site in mammalian cells. However, the process of establishing cells with multiple integrated copies of the transgene is still time-consuming. In the present study, we describe an improved version of AGIS that facilitates and accelerates the establishment of high producer Chinese hamster ovary (CHO) cells. Two donor vectors were simultaneously introduced into the cells in a single transfection. Cells with successfully targeted transgene integration were screened based on a change in the color of the reporter fluorescent protein that they express. Repeated rounds of integration allowed the transgene copy number to be increased. As a model, an scFv-Fc antibody gene was integrated into the hprt locus of the CHO cell genome. After three rounds of integration, a high-producer CHO cell clone with six copies of the scFv-Fc gene was successfully established. scFv-Fc productivity was approximately four-fold greater than a control cell line harboring a single copy of the transgene. This newly designed AGIS procedure should facilitate the development of producer cells suitable for biopharmaceutical protein production. PMID- 28662918 TI - Reproducibility of Cardiac Magnetic Resonance Imaging (CMRI)-Derived Right Ventricular Parameters in Repaired Tetralogy of Fallot (ToF). AB - BACKGROUND: Quantification of right ventricular (RV) volumes is challenging owing to variable reproducibility and is especially so in congenital heart disease. Cardiac magnetic resonance (CMR) has the ability to more comprehensively survey the entire right ventricle and is currently considered the gold standard. AIMS: We aimed to determine the inter-observer reproducibility of CMR-derived RV volumes generated by two independent and experienced (SCMR Level III) observers in Tetralogy of Fallot (ToF) patients with varying degrees of RV dilatation. METHODS: We performed a retrospective analysis of 120 consecutive patients with repaired ToF who underwent CMR. Two blinded observers calculated RV volumes in each oblique short axis slice independently. Bland-Altman analysis and inter observer correlation coefficients (ICC) were assessed. RESULTS: The coefficients of variation for RV parameters were: 2.9%, 8% and 3.4% for right ventricular end diastolic volume (RVEDV), right ventricular end systolic volume (RVESV) and right ventricular ejection fraction (RVEF) respectively. For RVEDV the interobserver correlation was 0.992 demonstrating excellent volumetric correlation between observers. The mean difference between the observers for right ventricular end diastolic volume index (RVEDVi) was 2.5ml/m2 (95% limits of agreement -7.3 to 12.2ml/m2). For patients with mild-moderate RV dilatation (RVEDVi <150ml/m2) the mean difference of RVEDVi was 1.8ml/m2 (95% limits of agreement -5.7 to 9.3ml/m2). For patients with severe RV dilatation (RVEDVi>=150ml/m2) the mean difference was -3.4ml/m2 (95% limits of agreement -8.6 to 15.4ml/m2). CONCLUSIONS: In patients with repaired ToF and variable degrees of RV dilatation, CMR assessment of RV volumes and function has high inter-observer reproducibility. This allows for optimal timing of pulmonary valve replacement, based on progression of RV dilatation over time. PMID- 28662919 TI - Risk Factor Management and Atrial Fibrillation Clinics: Saving the Best for Last? AB - Atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality worldwide. Management of AF is a complex process involving: 1) the prevention of thromboembolic complications with anticoagulation; 2) rhythm control; and 3) the detection and treatment of underlying heart disease. However, cardiometabolic risk factors, such as obesity, hypertension, diabetes mellitus, and obstructive sleep apnoea, have been proposed as contributors to the expanding epidemic of atrial fibrillation (AF). Thus, a fourth pillar of AF care would include aggressive targeting of interdependent, modifiable cardiovascular risk factors as part of an integrated care model. Such risk factor management could retard and reverse the pathological processes underlying AF and reduce AF burden. PMID- 28662920 TI - Seven-year review of dental foundation year 2/senior house officer training at the Oral and Maxillofacial Surgery Unit in Oxford. AB - The dental senior house officer (SHO)/dental foundation year 2 (DF2) posts in Oxford have provided hospital-based training for dentists, but in 2013 the Oral and Maxillofacial Surgery (OMFS) Unit withdrew from DF2 training because persistent negative feedback from the dental deanery varied from that obtained internally. We sent questionnaires to a consecutive group of 62 dentists who had worked at the John Radcliffe Hospital, Oxford, between 2006 and 2013 to find out about their experience of the posts. Forty responded (65% response rate). We analysed their expectations, the support provided, their experience of teaching and training, the opportunities available, and free-text feedback about the post and their current posts. They had all found the job helpful, and had gained generic, dental, medical, and surgical skills. The overall mean (SD) score for the post was 8 (2) on a Likert scale of 1-10 (with 10 being excellent). When they completed the questionnaire between December 2013 and July 2014, 18 respondents were working as general dental practitioners and four were training for a career in OMFS. The study showed that work as a dental SHO or DF2 has multiple benefits. We hope that our findings will help to improve OMFS training posts for dental core trainees in Oxford. PMID- 28662921 TI - Panton-Valentine leukocidin-producing Staphylococcus aureus infection of the neck that mimicked disseminated malignancy. PMID- 28662922 TI - Descendens vagohypoglossi: rare variant of the superior root of ansa cervicalis. AB - Knowledge of variants in the formation and position of the ansa cervicalis is important in head and neck surgery, specifically in reconstructions of the tongue that use the infrahyoid muscles, and in the anastomosis of the ansa cervicalis to the recurrent laryngeal nerve when the laryngeal muscles have been paralysed. We describe a rare variant of the superior root of the ansa cervicalis, which had a contribution from the vagus and hypoglossal nerves. The inferior root was formed by the C2 and C3 ventral rami, but it passed medial to the internal jugular vein before it joined the superior root to form the loop. PMID- 28662923 TI - The influence of experimental conditions on the final result of photoinhibition of Staphylococcus aureus. AB - BACKGROUND: By and large, phototherapies are a promising approach to promote inactivation of microorganisms using light exposure, providing an effective alternative to control multidrug-resistant bacterial infections. Considering this, intercomparison between experiments is vitally important. Most experiments are performed using multiwell plates in which the volume of the culture medium is not standardized. In such cases, light attenuation and the distance it travels, which also depends on the volume and vessel geometry, can lead to different results. This study investigated how the different volumes imply different depths that light will have to travel through in this volume and the relation of this parameter with the result that will be obtained. METHODS: Staphylococcus aureus was exposed to 460nm light with 50, 100 and 200J/cm2, in 100, 200, 500 and 1000MUL of inocula in a 24-well plate to investigate pure light inactivation. RESULTS: The literature suggests that fluence is the most important light parameter to obtain a high eradication of microbial cells in phototherapies. Our results show evidence that different geometrical configurations, taking into account the volume of the vessels, clearly affect the in vitro results, risking misinterpretation of dosimetry studies. Effects, such as dose distribution and decantation, are discussed throughout the paper. CONCLUSION: The outcome strongly depends on the volume and vessel geometry used. This study aims to encourage the standardization of phototherapies in vitro in general. PMID- 28662924 TI - Anticancer effects elicited by combination of Rubus extract with phthalocyanine photosensitiser on MCF-7 human breast cancer cells. AB - BACKGROUND: Photodynamic therapy (PDT) is a novel approach for the treatment of cancer and other related diseases. Breast cancer remains the most common cause of cancer-related death in women. This study was carried out to investigate the photosensitizing capacity of Rubus fairholmianus root acetone extract (RFRA) in vitro. METHODS: RFRA was coupled with phthalocyanine photosensitizer to enhance the therapeutic properties on MCF-7 breast cancer cells. Comparatively low dose photosensitizer (PS) and Rubus extract have been used for the conjugation as it induces cell death at low doses. The diode laser of wavelength 680 nm and 5, 10 and 15 J/cm2 fluencies have been used for PDT experiments/laser irradiation. MCF 7 cells were exposed to Rubus extract and conjugated Rubus-PS for 24 h and analysed the alterations in cell morphology, proliferation, cytotoxicity and apoptosis induction. RESULTS: The PDT-treated cells displayed substantial features of apoptotic cell death by changes in morphology with a reduction in cell number, development of apoptotic bodies and cell detachment from culture plates. Cellular viability (51.25% for RFRA-PS at 15 J/cm2) and Adenosine 5' triphosphate (ATP) proliferation of treated cells reduced significantly and the cytotoxicity increased in lactate dehydrogenase (LDH) assay. The Annexin V/PI double staining supports the caspase 3/7 activities by the increased apoptotic cells population and the increased levels of cytochrome c. CONCLUSION: Our results show that the phototoxic properties of RFRA and photosensitizer may be through the caspase-mediated apoptosis and it can be summarised that Rubus may be a potent anticancer plant with phototoxic effects on breast cancer cells. PMID- 28662925 TI - The best in vitro conditions for two and three parallel stenting during endovascular aneurysm repair. AB - OBJECTIVE: The aim of this study is to identify which endograft-parallel stent combinations and which degree of oversizing result in the most adequate fit in a juxtarenal abdominal aneurysmal neck, when using a double or triple parallel stent (chimney) technique. METHODS: In vitro silicon, juxtarenal, abdominal aortic aneurysmal neck models of different diameters, with two and three side branches (simulating both the renal and superior mesenteric arteries), were constructed. Two different endografts of three diameters each, with two or three parallel stents (of 6 mm and 6 mm; or 6 mm, 6 mm, and 8 mm) were tested (Endurant II endograft [Medtronic Inc, Santa Rosa, Calif] with balloon-expandable BeGraft stent [Bentley InnoMed, Hechingen, Germany] and an Excluder endograft [W. L. Gore and Associates, Flagstaff, Ariz] with self-expanding Viabahn stent [W. L. Gore and Associates]), applying three endograft-oversizing degrees: recommended (15%), excessive (30%), and over-excessive (40%). After remodeling, using the kissing balloon technique at 37 degrees C (98.6 degrees F), 36 endograft-stent-oversizing models were scanned by computed tomography. The area of the gutters, parallel stent compression, and main endograft infolding were recorded. RESULTS: Increasing oversizing (15%, 30%, and 40%) revealed a nonsignificant propensity toward smaller gutters and similar parallel-stent compression, but it significantly augmented infolding, more in three parallel-stent models (0%, 0%, 67% and 0%, 33%, 83% of cases; P = .015 and .018, for two and three parallel stent models; n = 36) and mainly for the Excluder-Viabahn combination. The Excluder-Viabahn showed significantly smaller gutters, but with higher stent compression, than Endurant-BeGraft combinations for both two and three parallel stents (8.2 mm2, 22.6 mm2; P = .002 and 14.4 mm2, 23.3 mm2; P = .009 gutter area; and 18%, 2%; P < .001 and 15%, 2%; P = .007 relative stent area compression, respectively). CONCLUSIONS: Better endograft stent apposition was usually attained when using 30% oversizing during two and three parallel-stent techniques. Higher oversizing was related to nonsignificant smaller gutters but higher rates of infolding. Smaller gutters, but higher stent compression and risk of infolding, were achieved with the Excluder-Viabahn than with the Endurant BeGraft combination. PMID- 28662926 TI - Defining the burden, scope, and future of vascular acute care surgery. AB - OBJECTIVE: The paradigm of acute care surgery has revolutionized nonelective general surgery. Similarly, nonelective vascular surgery may benefit from specific management and resource capabilities. To establish the burden and scope of vascular acute care surgery, we analyzed the characteristics and outcomes of patients hospitalized for vascular surgical procedures in Maryland. METHODS: A retrospective analysis of a statewide inpatient database was performed to identify patients undergoing noncardiac vascular procedures in Maryland from 2009 to 2013. Patients were stratified by admission acuity as elective, urgent, or emergent, with the last two groups defined as acute. The primary outcome was inpatient mortality, and secondary outcomes were critical care and hospital resource requirements. Groups were compared by univariate analyses, with multivariable analysis of mortality based on acuity level and other potential risk factors for death. RESULTS: Of 3,157,499 adult hospital admissions, 154,004 (5%) patients underwent a vascular procedure; most were acute (54% emergent, 13% urgent), whereas 33% were elective. Acute patients had higher rates of critical care morbidity and required more hospital resource utilization. Admission for acute vascular surgery was independently associated with mortality (urgent odds ratio, 2.1; emergent odds ratio, 3.0). CONCLUSIONS: The majority of inpatient vascular care in Maryland is for acute vascular surgery, which is an independent risk factor for mortality. Acute vascular surgical care entails greater critical care and hospital resource utilization and-similar to emergency general surgery may benefit from dedicated training and practice models. PMID- 28662927 TI - Endovascular treatment of abdominal aortic aneurysms with narrow aortic bifurcation using Excluder bifurcated stent grafts. AB - OBJECTIVE: This study investigated the influence of the aortic bifurcation anatomy on the endovascular treatment of abdominal aortic aneurysms using Excluder (W. L. Gore & Associates, Flagstaff, Ariz) bifurcated stent grafts. METHODS: This was a retrospective single-center study of patients treated with the Excluder stent graft. Analysis included anatomical factors of the aortic bifurcation (aortic bifurcation diameter [ABD], calcification, thrombus), characteristics of the stent graft limbs (sum of stent graft limbs diameters [SLD]), and the SLD/ABD ratio. Narrow bifurcation was defined as ABD <20 mm. Primary outcomes were intraoperative stenosis, need for additional intraoperative measures, limb stenosis, and occlusion during follow-up. RESULTS: The study included 232 patients. Mean ABD was 24.6 +/- 6 mm, with 53 patients (23%) presenting with narrow bifurcation (range, 12.5-19.5 mm). Median SLD in these patients was 28 mm, and the SLD/ABD ratio was 1.64. Calcification involving >50% of the bifurcation circumference was present in 32% of the patients, with 17% presenting thrombus in this area. Of 53 patients with narrow bifurcation, intraoperative stenosis >50% occurred in three (5.7%), which required adjunctive treatment. Computed tomography at 1 month showed limb stenosis >50% in nine patients (17%). No limb occlusions were recorded with a median follow-up of 34 months. Multivariate analysis of the overall series showed a higher risk of limb stenosis on the computed tomography at 1 month in patients with peripheral artery disease (hazard ratio [HR], 5.3; 95% confidence interval [CI], 1.2-24.4; P = .032), narrow bifurcation (HR, 5.7; 95% CI, 2-15.8; P = .001), higher SLD/ABD ratio (HR, 29.3; 95% CI, 4-215.2; P = .001), and calcium >50% (HR, 3; 95% CI, 1.1 8; P = .03), and lower in bifurcations with thrombus (HR, 0.3; 95% CI, 0.1-0.8; P = .017). CONCLUSIONS: Abdominal aortic aneurysms with narrow bifurcation can be treated with the bifurcated Excluder device without additional adjunctive measures. The presence of limb stenosis during follow-up is not associated with occlusion. Long-term follow-up studies are needed to confirm these results. PMID- 28662928 TI - A systematic review of surveillance after endovascular aortic repair. AB - OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the optimal modality and frequency of surveillance after endovascular aortic repair (EVAR) in adult patients with abdominal aortic aneurysms. METHODS: We searched for studies of post-EVAR surveillance in MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Scopus through May 10, 2016. The outcomes of interest were endoleaks, mortality, limb ischemia, renal complications, late rupture, and aneurysm-related mortality. Outcomes were pooled using a random-effects model and were reported as incidence rate and 95% confidence interval. RESULTS: Of 1099 candidate references, we included 6 meta-analyses and 52 observational studies. Complication rates were common after EVAR, particularly in the first year. Magnetic resonance imaging had a higher detection rate of endoleaks than computed tomography angiography. Doppler ultrasound had lower diagnostic accuracy, whereas contrast-enhanced ultrasound was likely to be as sensitive as computed tomography angiography. The highest endoleak detection rates were in surveillance approaches that used combined tests. There were no studies that compared different surveillance intervals to determine optimal intervals; however, most studies reported detection rates of patient-important outcomes at 1, 6, 12, 24, 36, 48, and 60 months. Data were insufficient to provide comparative inferences about the best strategy to reduce the risk of patient-important outcomes, such as mortality, limb ischemia, rupture, and renal complications. CONCLUSIONS: Several tests with reasonable diagnostic accuracy are available for surveillance after EVAR. The available evidence suggests a high complication rate, particularly in the first year, and provides a rationale for surveillance. PMID- 28662929 TI - Isolation and characterization of a novel cervid adenovirus from white-tailed deer (Odocoileus virginianus) fawns in a captive herd. AB - A novel adenovirus, CeAdV1, was isolated from buffy coat and nasal swab samples collected from two captive white-tailed deer (Odocoileus virginianus) fawns. The isolation was an incidental finding in the course of screening animals for use in a research study on an unrelated pathogen. In the screening process, virus isolation was performed on both nasal swabs and buffy coat samples and cytopathic effect was observed. Electron microscopy revealed viral particles with the shape and morphology of an adenovirus. Next generation sequencing followed by phylogenetic analysis classified this virus to the Mastadenovirus genus. Its sequence was genetically distinct from all other recognized species in this genus, with only 76% sequence identity to its closest genetic match, bovine adenovirus 3 (BAdV3). The virus could be propagated in bovine derived cells but grew to a higher titer in cervid derived cells. Inoculation of white-tailed deer fawns with the isolated virus resulted in pyrexia, depletion of thymus tissue and mild respiratory disease. Comparative serology performed using convalescent sera revealed distinct antigenic differences between the novel cervid adenovirus and BAdV3. A retrospective serological survey of the captive deer herd indicated that this virus had been circulating in the herd for at least 14 years with no report of clinical disease. A survey of serum collected from free ranging mule deer residing in Nevada revealed high serum titers against this novel adenovirus. PMID- 28662930 TI - New tests identify patterns of vestibular loss. PMID- 28662931 TI - Reply to "Need for updating safety recommendations on repetitive transcranial magnetic stimulation in stroke patients". PMID- 28662932 TI - Dynamic in vivo 3D atlantoaxial spine kinematics during upright rotation. AB - Diagnosing dysfunctional atlantoaxial motion is challenging given limitations of current diagnostic imaging techniques. Three-dimensional imaging during upright functional motion may be useful in identifying dynamic instability not apparent on static imaging. Abnormal atlantoaxial motion has been linked to numerous pathologies including whiplash, cervicogenic headaches, C2 fractures, and rheumatoid arthritis. However, normal C1/C2 rotational kinematics under dynamic physiologic loading have not been previously reported owing to imaging difficulties. The objective of this study was to determine dynamic three dimensional in vivo C1/C2 kinematics during upright axial rotation. Twenty young healthy adults performed full head rotation while seated within a biplane X-ray system while radiographs were collected at 30 images per second. Six degree-of freedom kinematics were determined for C1 and C2 via a validated volumetric model based tracking process. The maximum global head rotation (to one side) was 73.6+/ 8.3 degrees , whereas maximum C1 rotation relative to C2 was 36.8+/-6.7 degrees . The relationship between C1/C2 rotation and head rotation was linear through midrange motion (+/-20 degrees head rotation from neutral) in a nearly 1:1 ratio. Coupled rotation between C1 and C2 included 4.5+/-3.1 degrees of flexion and 6.4+/-8.2 degrees of extension, and 9.8+/-3.8 degrees of contralateral bending. Translational motion of C1 relative to C2 was 7.8+/-1.5mm ipsilaterally, 2.2+/-1.2mm inferiorly, and 3.3+/-1.0mm posteriorly. We believe this is the first study describing 3D dynamic atlantoaxial kinematics under true physiologic conditions in healthy subjects. C1/C2 rotation accounts for approximately half of total head axial rotation. Additionally, C1 undergoes coupled flexion/extension and contralateral bending, in addition to inferior, lateral and posterior translation. PMID- 28662933 TI - Sedentary behavior: Is it time to break up with your chair? PMID- 28662934 TI - High triglycerides and low high-density lipoprotein cholesterol lipid profile in rheumatoid arthritis: A potential link among inflammation, oxidative status, and dysfunctional high-density lipoprotein. AB - BACKGROUND: The interactions between inflammation and lipid profile in rheumatoid arthritis (RA) are poorly understood. The lipid profile study in RA has been biased toward lipoprotein levels, whereas those of triglycerides (TGs) and lipoprotein functionality have been underestimated. OBJECTIVES: Since recent findings suggest a role for TG and TG-rich lipoproteins (TRL) on inflammation, we aimed to evaluate a combined lipid profile characterized by high TG and low high density lipoprotein cholesterol levels (TGhighHDLlow) in RA. METHODS: Lipid profiles were analyzed in 113 RA patients, 113 healthy controls, and 27 dyslipemic subjects. Levels of inflammatory mediators, paraoxonase-1 (PON1) activity, and total antioxidant capacity were quantified in serum. PON1-rs662 status was evaluated by real-time polymerase chain reaction. RESULTS: The TGhighHDLlow profile was detected in 29/113 RA patients. Although no differences in prevalence compared with healthy controls or dyslipemic subjects were observed, this profile was associated with increased tumor necrosis factor alpha (P = .004), monocyte chemotactic protein (P = .004), interferon-gamma-inducible protein-10 (P = .018), and leptin (P < .001) serum levels in RA, where decreased PON1 activity and total antioxidant capacity were found. TGhighHDLlow prevalence was lower among anti-TNFalpha-treated patients (P = .004). When RA patients were stratified by PON1-rs662 status, these associations remained in the low-activity genotype (QQ). Finally, a poor clinical response on TNFalpha blockade was related to an increasing prevalence of the TGhighHDLlow profile over treatment (P = .021) and higher TRL levels at baseline (P = .042). CONCLUSIONS: The TGhighHDLlow profile is associated with systemic inflammation, decreased PON1 activity, and poor clinical outcome on TNFalpha blockade in RA, suggesting a role of TRL and HDL dysfunction as the missing link between inflammation and lipid profile. PMID- 28662935 TI - Prevalence and Predictors of Prenatal and Postpartum Contraceptive Counseling in Two Texas Cities. AB - OBJECTIVES: We investigated the prevalence of and sociodemographic associations with receiving prenatal and postpartum contraceptive counseling, including counseling on intrauterine devices (IUDs) and implants. METHODS: We used data from a prospective cohort study of 803 postpartum women in El Paso and Austin, Texas. We examined the prevalence of prenatal and postpartum counseling, provider discouragement of IUDs and implants, and associated sociodemographic characteristics using chi2 tests and logistic regression. RESULTS: One-half of participants had received any prenatal contraceptive counseling, and 13% and 37% received counseling on both IUDs and implants prenatally and postpartum, respectively. Women with more children were more likely to receive any contraceptive counseling prenatally (odds ratio [OR], 1.99; p < .01). Privately insured women (OR, 0.53; p < .05) had a lower odds of receiving prenatal counseling on IUDs and implants than publicly insured women. Higher education (OR, 2.16; p < .05) and attending a private practice (OR, 2.16; p < .05) were associated with receiving any postpartum counseling. Older age (OR, 0.61; p < .05) was negatively associated with receiving postpartum counseling about IUDs and implants and a family income of $10,000 to $19,000 (OR, 2.21; p < .01) was positively associated. Approximately 20% of women receiving prenatal counseling and 10% receiving postpartum counseling on IUDs and implants were discouraged from using them. The most common reason providers restricted use of these methods was inaccurate medical advice. CONCLUSIONS: Prenatal and postpartum counseling, particularly about IUDs and implants, was infrequent and varied by sociodemographics. Providers should implement evidence-based prenatal and postpartum contraceptive counseling to ensure women can make informed choices and access their preferred method of postpartum contraception. PMID- 28662936 TI - Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial. AB - OBJECTIVES: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). BACKGROUND: HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. METHODS: The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction >=45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. CONCLUSIONS: PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). PMID- 28662938 TI - Intersection of 2 Epidemics: Asthma and Cardiovascular Disease. PMID- 28662937 TI - A History of Asthma From Childhood and Left Ventricular Mass in Asymptomatic Young Adults: The Bogalusa Heart Study. AB - OBJECTIVES: This study aimed to examine whether a history of asthma from childhood is associated with left ventricular (LV) mass in adulthood. BACKGROUND: Asthma has been related to various cardiovascular risk factors affecting LV hypertrophy. The authors saw a need for a prospective study to analyze the relationship between a history of asthma from childhood and markers of LV mass among asymptomatic young adults. METHODS: Prospective analyses were performed among 1,118 Bogalusa Heart Study participants (average age at follow-up 36.7 +/- 5.1 years), with a baseline history of self-reported asthma collected since childhood (average age at baseline 26.8 +/- 10.1 years). LV mass (g) was assessed using 2-dimensional guided M-mode echocardiography and was indexed for body height (m2.7) as LV mass index (LVMI; g/m2.7). A multivariate linear mixed model was fitted for the repeated measures. RESULTS: After an average of 10.4 +/- 7.5 years of follow-up, participants with a history of asthma from childhood had a greater LV mass (167.6 vs. 156.9; p = 0.01) and LVMI (40.7 vs. 37.7; p < 0.01) with adjustment for age, sex, race, smoking status, antihypertensive medication, heart rate, and systolic blood pressure (SBP). The difference of LVMI between group with asthma and the group without asthma remained significant after additional adjustment for body mass index (39.0 vs. 37.1; p = 0.03) and high sensitivity C-reactive protein (38.4 vs. 36.6; p = 0.04). In addition, the authors found significant interactions between SBP and asthma on LV mass and LVMI (p for interaction <0.01, respectively). The associations between asthma and LV measures appeared to be stronger among pre-hypertensive and hypertensive participants (SBP >=130 mm Hg) compared with participants with normal SBP (<130 mm Hg) (regression coefficient: 39.5 vs. 2.3 for LV mass and 9.0 vs. 0.9 for LVMI). CONCLUSIONS: The findings of this study indicate that a history of asthma is associated with higher LVMI, and this association is stronger among participants with pre-hypertension and hypertension. PMID- 28662939 TI - A Decade With Editorial Mentors: The Day They Dropped the Mic. PMID- 28662940 TI - Impacts of Implantable Collamer Lens V4c Placement on Angle Measurements Made by Optical Coherence Tomography: Two-Year Follow-up. AB - PURPOSE: To determine iridocorneal angle changes produced after 2 years of implantable collamer lens (ICL) V4c (STAAR Surgical AG, Nidau, Switzerland) placement by Fourier-domain optical coherence tomography (FD-OCT). DESIGN: Prospective interventional case series. METHODS: In 54 eyes of 27 myopic subjects FD-OCT iridocorneal angle measurements were made before and 1 month, 3 months, 1 year, and 2 years after ICL implant. Trabecular-iris angle (TIA), angle opening distance 500 MUm from the scleral spur (AOD500), and iridotrabecular contact length (TICL) were compared among these time points and the nasal, temporal, and inferior quadrants. RESULTS: Preoperative TIAs were 49.5 +/- 8.7, 48.3 +/- 9.6, and 49.1 +/-8.6 degrees for the nasal, temporal and inferior quadrants (P < .001). Corresponding values were 29.9 +/- 10.4, 28.4 +/- 10.8, and 28.8 +/- 9.7 degrees at 1 month and 27.3 +/- 8.8, 26.8 +/- 8.1, and 28.9 +/- 7 degrees at 2 years of follow-up, indicating angle narrowing of 39%-45% and no further narrowing beyond 1 month in the nasal (P = .133), temporal (P = .376), and inferior (P = 1.000) quadrants. Trabecular-iris contact (TIC) was observed in 8 eyes of 8 subjects, mostly only in the temporal quadrant. Mean TICL failed to vary during follow-up (307 +/- 288 MUm at 3 months and 225 +/- 142 MUm at 2 years, P = .159). CONCLUSIONS: In response to ICL V4c implant, considerable angle narrowing was detected at 1 month but this narrowing remained stable at 2 years. In the 8 cases of TIC, no progression of contact was observed beyond 3 months postimplant. PMID- 28662941 TI - No Light Perception Outcomes Following Boston Keratoprosthesis Type 1 Surgery. AB - PURPOSE: To determine the incidence rate, principal causes, and clinical course of eyes developing no light perception (NLP) visual acuity (VA) following Boston Keratoprosthesis (B-KPro) type 1 surgery. Secondary objectives include determining the incidence rate, relative risk (RR), and survival probability with respect to NLP outcomes among eyes with congenital aniridia. DESIGN: Retrospective, interventional case series. SUBJECTS: All patients undergoing B KPro type 1 surgery between October 2008 and June 2016 by a single surgeon at CHUM - Hopital Notre-Dame. METHODS: Records of patients having undergone B-KPro implantation were reviewed. Eyes with a final outcome of NLP were further reviewed to determine best recorded postoperative VA, time to NLP onset, clinical course, and principal cause. Descriptive statistics, incidence rates, Kaplan Meier survival curves, and the RR of NLP outcomes among eyes with aniridia were determined. Statistical significance was defined as P < .05. RESULTS: Records of 119 patients were included, with an average follow-up of 49.1 +/- 26.8 months postoperatively. Nineteen eyes had a final outcome of NLP, representing 16.0%. The incidence rate of NLP was 0.04 cases per eye-year of follow-up. The most common principal causes were inoperable retinal detachment (n = 7, 36.8%), terminal glaucoma (n = 6, 31.6%), and carrier graft melt-related complications (n = 5, 26.3%). The RR of developing NLP among eyes with aniridia was 3.04 (P = .01). CONCLUSIONS: No light perception is a devastating but uncommon outcome of B KPro surgery. Patients with aniridia seem to be at increased risk. In spite of all available medical and surgical interventions, some eyes may still suffer this outcome. PMID- 28662942 TI - Secretion clearance strategies in Australian and New Zealand Intensive Care Units. AB - INTRODUCTION/AIMS: To describe the processes of care for secretion clearance in adult, intubated and mechanically ventilated patients in Australian and New Zealand Intensive Care Units (ICUs). METHODS/RESULTS: A prospective, cross sectional study was conducted through the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) Point Prevalence Program. Forty seven ICUs collected data from 230 patients intubated and ventilated on the study day. Secretion clearance techniques beyond standard suctioning were used in 84/230 (37%) of patients during the study period. Chest wall vibration 34/84 (40%), manual lung hyperinflation 24/84 (29%), chest wall percussion 20/84 (24%), postural drainage/patient positioning 17/84 (20%) and other techniques including mobilisation 15/84 (18%), were the most common secretion clearance techniques employed. On average (SD), patients received airway suctioning 8.8 (5.0) times during the 24-h study period. Mucus plugging events were infrequent (2.7%). The additional secretion clearance techniques were provided by physiotherapy staff in 24/47 (51%) ICUs and by both nursing and physiotherapy staff in the remaining 23/47 (49%) ICUs. CONCLUSION: One-third of intubated and ventilated patients received additional secretion clearance techniques. Mucus plugging events were infrequent with these additional secretion clearance approaches. Prospective studies must examine additional secretion clearance practices, prevalence of mucus plugging episodes and impact on patient outcomes. PMID- 28662943 TI - Discovery of novel antimycobacterial drug therapy in biofilm of pathogenic nontuberculous mycobacterial keratitis. AB - PURPOSE: The potential of slow-growing mycobacteria to form biofilms in human tissues contributes to the problem of establishing an effective treatment strategy. The purpose of this study was to examine new antibiotic strategies to enhance current treatment options for these infections. METHODS: Sensitivities of Mycobacterium fortuitum ATCC 49404 and Mycobacterium chelonae ATCC 35752 were evaluated for different antimicrobials singly and in combination using broth microdilution and FICI (Fractional Inhibitory Concentration Index) synergy screening. Anti-biofilm effects were evaluated in an 8-well chamber slide biofilm model. The efficacy of a new treatment strategy was validated using the novel neutropenic mouse keratitis model and monitored by slit-lamp microscopy, confocal microscopy, and colony forming unit measurements. RESULTS: We reported the very first evidence that these organisms develop corneal biofilms by the accumulation of extracellular DNA (eDNA) and the presence of microcolonies using a novel mycobacterial neutropenic mouse keratitis model. The combination of amikacin and gatifloxacin or besifloxacin was more effective than the current gold-standard drug, amikacin, and we developed a novel treatment strategy (amikacin + gatifloxacin + DNase), the destruction of biofilm matrix component, eDNA, which increased the efficacy of the new antibiotic combination for treating mycobacterial infection in in vitro (P = 0.002) and in vivo (P = 0.001) compared to its respective control. CONCLUSION: Biofilms have a role in mycobacterial keratitis leading to poor treatment outcomes in clinical practice and the use of combination therapy (amikacin + gatifloxacin + DNase) could be a useful new treatment option. PMID- 28662944 TI - Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms. AB - OBJECTIVE: To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment. STUDY DESIGN: Retrospective case review of 38 children with a skeletal muscle channelopathy attending the specialist pediatric neuromuscular service at Great Ormond Street Hospital over a 15-year period. RESULTS: Gait disorder and leg cramps are a frequent presentation of myotonic disorders (19 of 29). Strabismus or extraocular myotonia (9 of 19) and respiratory and/or bulbar symptoms (11 of 19) are common among those with sodium channelopathy. Neonatal hypotonia was observed in periodic paralysis. Scoliosis and/or contractures were demonstrated in 6 of 38 children. School attendance or ability to engage fully in all activities was often limited (25 of 38). CONCLUSIONS: Children with skeletal muscle channelopathies frequently display symptoms that are uncommon in adult disease. Any child presenting with abnormal gait, leg cramps, or strabismus, especially if intermittent, should prompt examination for myotonia. Those with sodium channel disease should be monitored for respiratory or bulbar complications. Neonatal hypotonia can herald periodic paralysis. Early diagnosis is essential for children to reach their full educational potential. PMID- 28662945 TI - Nonalcoholic Fatty Liver Disease in Italian Children with Down Syndrome: Prevalence and Correlation with Obesity-Related Features. AB - OBJECTIVE: To assess the prevalence of overweight/obesity in a cohort of Italian children with Down syndrome (DS) and to investigate the correlation of both obesity and DS with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: We enrolled 280 children with DS (age range 5-18 years), who were referred to the DS outpatient clinic of the Bambino Gesu Children's Hospital in Rome. For all children, we collected the clinical history and measured anthropometric variables. Eighty-four of 280 children with DS were selected to undergo liver ultrasound scanning to evaluate the presence of NAFLD. RESULTS: Italian children with DS exhibited a prevalence of 19.64% for overweight and 12.14% for obesity. The prevalence of NAFLD in nonobese (45%) and overweight/obese (82%) children with DS is greater than in the European pediatric nonobese (5.7%) or obese population (33%). Moreover, the severity of liver brightness on ultrasound scan correlated positively with body mass index, triglycerides, low-density lipoprotein-cholesterol, and leptin levels and negatively with adiponectin. CONCLUSIONS: We demonstrated that, independently from the obese phenotype, children with DS display a greater risk to develop NAFLD than the general pediatric population. PMID- 28662946 TI - Cardiac Morphology and Function in Preterm Growth Restricted Infants: Relevance for Clinical Sequelae. AB - OBJECTIVES: To assess cardiac morphology and function in preterm infants with fetal growth restriction (FGR) compared with an appropriate for gestational age cohort, and to ascertain clinical correlation with neonatal sequelae. STUDY DESIGN: With informed consent, 20 infants born between 28 and 32 weeks of gestational age and birthweight (BW) <10th percentile were compared using conventional and tissue Doppler echocardiography with 20 preterm appropriate for gestational age infants. Total duration of respiratory support was recorded. RESULTS: The gestational age and BW of the infants with FGR and appropriate for gestational age infants were 29.8 +/- 1.3 weeks vs 30 +/- 0.9 weeks (P = .78) and 923.4 +/- 168 g vs 1403 +/- 237 g (P < .001), respectively. Preterm infants with FGR had significantly greater interventricular septal hypertrophy, greater free wall thickening, and lower sphericity indices (1.53 +/- 0.15 vs 1.88 +/- 0.2; P < .001), signifying globular and hypertrophied hearts. The transmitral E/A ratio and isovolumic relaxation time, markers of diastolic function, were significantly increased in the FGR cohort (0.84 +/- 0.05 vs 0.78 +/- 0.03 [P < .001] and 61.4 +/- 4.1 ms vs 53.2 +/- 3.2 ms [P < .001], respectively). Ejection fraction, as measured by the rate corrected mean velocity of circumferential fiber shortening was reduced (1.93 +/- 0.4 circ/second vs 2.77 +/- 0.5 circ/second; P < .001) in the FGR cohort. On follow-up, the total duration of respiratory support was significantly longer in the FGR cohort, and correlated with tissue Doppler E/E' (r = 0.65; P = .001), mean velocity of circumferential fiber shortening (r = 0.64; P = .001) and mitral annular peak systolic excursion (r = -0.57; P = .008). CONCLUSIONS: Preterm infants with FGR have altered cardiac function evident within days after birth, which is associated with respiratory sequelae. PMID- 28662947 TI - Rehospitalization Through Childhood and Adolescence: Association with Neonatal Morbidities in Infants of Very Low Birth Weight. AB - OBJECTIVE: To evaluate the impact of major neonatal morbidities on the risks for rehospitalization in children and adolescents born of very low birth weight. STUDY DESIGN: An observational study was performed on data of the Israel Neonatal Network linked together with the Maccabi Healthcare Services medical records. After discharge from the neonatal intensive care unit, 6385 infants of very low birth weight born from 1995 to 2012 were registered with Maccabi Healthcare Services and formed the study cohort. Multivariable negative binomial regression models were calculated to estimate the adjusted relative risk (aRR) and 95% CI for hospitalization. RESULTS: Up to 18 years following discharge, 3956 infants were hospitalized at least once. The median age of follow-up was 10.7 years with total of follow-up of 67 454 patient years and 10 895 hospitalizations. The risks for rehospitalization were increased significantly for each of the neonatal morbidities: surgical necrotizing enterocolitis (NEC), aRR 2.71 (95% CI 2.08 3.53), intraventricular hemorrhage grades 3-4, 2.13 (1.85-2.46), periventricular leukomalacia (PVL), 1.83 (1.58-2.13), bronchopulmonary dysplasia, 1.94 (1.72 2.17), and retinopathy of prematurity stages 3-4, 1.59 (1.36-1.85). During the first 4 years, children with surgically treated NEC, intraventricular hemorrhage, PVL, or bronchopulmonary dysplasia had 1.5- to 2.5-fold greater risks for hospitalization compared with those without the specific morbidity. In the 11th 14th and 15th-18th years, respectively, surgically treated NEC was associated with a 3.05 (1.32-7.04) and 3.26 (0.99-10.7) aRR for hospitalization, and PVL was associated with a 2.67 (1.79-3.97) and 3.47 (2.03-5.92) aRR for hospitalization. CONCLUSIONS: Specific major neonatal morbidities as well as the number of morbidities were associated with excess risks of rehospitalization through childhood and adolescence. PMID- 28662948 TI - Cardiac Events and the Maximum Diameter of Coronary Artery Aneurysms in Kawasaki Disease. AB - OBJECTIVES: To clarify the occurrence of cardiac events based on the maximal diameter of the maximal coronary artery aneurysm (CAA) in Kawasaki disease (KD). STUDY DESIGN: Two hundred fourteen patients (160 male and 54 female) who had had at least 1 CAA in the selective coronary angiogram less than 100 days after the onset of KD were studied. We measured the maximal CAA diameters in the major branches of the initial coronary angiograms. Death, myocardial infarction and coronary artery revascularization were included as cardiac events in this study. We divided the patients into three groups based on the maximal CAA diameter (large >=8.0 mm; medium >=6.0 mm and <8.0 mm; small <6.0 mm). Further, we also analyzed the cardiac events based on laterality of maximal CAA (bilateral, unilateral) and body surface area (BSA). RESULTS: Cardiac events occurred in 44 patients (21%). For BSA < 0.50 m2, the 30-year cardiac event-free survival in the large and medium groups was 66% (n = 38, 95% CI, 49-80) and 62% (n = 27, 95% CI, 38-81), respectively. For BSA >= 0.50 m2, that in large group was 54% (n = 58, 95% CI, 40-67). There were no cardiac events in the medium group for BSA >=0.50 m2 (n = 36) and the small group (n = 56). In the large analyzed group, the 30 year cardiac event-free survival in the bilateral and unilateral groups was 40% (n = 48, 95% CI, 27-55) and 78% (n = 48, 95% CI, 63-89), respectively (P < .0001). CONCLUSIONS: The group with the highest risk of cardiac events was the patient group with the maximal CAA diameter >=6.0 mm with BSA < 0.50 m2 and the maximal CAA diameter >=8.0 mm with BSA >= 0.50 m2. At 30 years after the onset of KD, cardiac event-free survival was about 60%. Given the high rate of cardiac events in this patient population, life-long cardiovascular surveillance is advised. PMID- 28662949 TI - Patched Skin Bilirubin Assay to Monitor Neonates Born Extremely Preterm Undergoing Phototherapy. AB - OBJECTIVE: To verify the reliability and safety of transcutaneous bilirubin (TcB) measurements in patched skin areas in neonates born extremely preterm under phototherapy. STUDY DESIGN: Sixty neonates (<30 weeks' gestation) receiving phototherapy were enrolled and TcB was measured via a second-generation transcutaneous bilirubinometer in patched skin areas (of at least 2.5 cm diameter). Total serum bilirubin (TSB), lactate, pH, hemoglobin, and skin temperature were measured within 10 minutes of the TcB assay. Clinicians were blinded to TcB values, and clinical decisions about phototherapy were made with the TSB measurement only. RESULTS: TcB and TSB significantly were correlated (r = 0.84; P <.001), even after adjustment for hemoglobin, pH, lactate, gestational and postnatal age (standardized beta = 0.8; P <.001; adjusted R2 = 0.75), or treatment duration (standardized beta = 0.8; P <.001; adjusted R2 = 0.7). When the Bland-Altman analysis was used, TcB overestimated TSB at high values (mean difference TSB - TcB: -2.8 [2.4] mg/dL). If clinicians used the TcB only, no neonate would have had phototherapy stopped prematurely, and 21 (35%) would have continued phototherapy when it could have been stopped. CONCLUSIONS: The correlation between TSB and TcB (measured in patched skin areas) was comparable with that obtained in more mature neonates, and it was not influenced by clinical variables or factors affecting skin bilirubin passage. TcB overestimated TSB, and this may expose infants born preterm to unnecessary phototherapy, although it could spare approximately 65% of TSB assays. PMID- 28662950 TI - A Newborn with No Bones: Neonatal Hypophosphatasia with Respiratory Distress. PMID- 28662951 TI - CD11a and CD49d enhance the detection of antigen-specific T cells following human vaccination. AB - BACKGROUND: Determining the efficacy of human vaccines that induce antigen specific protective CD4 T cell responses against pathogens can be particularly challenging to evaluate. Surface expression of CD11a and CD49d has been shown to identify antigen-specific CD4 T cells against viral pathogens in mice. We hypothesized that CD11a and CD49d would also serve as markers of human antigen specific T cells responding to vaccination. METHODS: A phase I vaccine trial enabled us to evaluate a novel gating strategy based on surface expression of CD11a and CD49d as a means of detecting antigen-specific, cytokine producing CD4 and CD8 T cells induced after vaccination of naive individuals against leishmaniasis. Three study groups received LEISH-F3 recombinant protein combined with either squalene oil-in-water emulsion (SE) alone, SE with the synthetic TLR 4 ligand glucopyranosyl lipid adjuvant (GLA-SE), or SE with Salmonella minnesota derived monophosphoryl lipid A (MPL-SE). Individuals were given 3 vaccine doses, on days 0, 28 and 168. RESULTS: Starting after the first vaccine dose, the frequency of both CD11ahiCD49d+ CD4 and CD11ahiCD49d+ CD8 T cells significantly increased over time throughout the 24-week trial. To confirm the role of CD11ahiCD49d+ expression in the identification of the antigen-specific T cells, cytokine production was measured following LEISH-F3 stimulation. All of the IFN gamma, TNF-alpha, and IL-2 producing cells were found within the CD11ahiCD49d+ population. CONCLUSIONS: Our results suggest that the change in the frequency of CD11ahiCD49d+ T cells can be used to track antigen-specific CD4 and CD8 T cell responses following T cell-targeted vaccination. PMID- 28662953 TI - Corrigendum to "Fertilisers production from ashes after sewage sludge combustion strategy towards sustainable development" [Environ. Res. 154 (2017) 171-180]. PMID- 28662952 TI - Vaccination against histomonosis limits pronounced changes of B cells and T-cell subsets in turkeys and chickens. AB - The protozoan parasite Histomonas meleagridis is the causative agent of histomonosis in gallinaceous birds. In turkeys, the disease can result in high mortality due to severe inflammation and necrosis in caecum and liver, whereas in chickens the disease is less severe. Recently, experimental vaccination was shown to protect chickens and turkeys against histomonosis but dynamics in the cellular immune response are not yet demonstrated. In the present work, different groups of birds of both species were vaccinated with attenuated, and/or infected with virulent histomonads. Flow cytometry was applied at different days post inoculation to analyse the absolute number of T-cell subsets and B cells in caecum, liver, spleen and blood, in order to monitor changes in these major lymphocyte subsets. In addition, in chicken samples total white blood cells were investigated. Infected turkeys showed a significant decrease of T cells in the caecum within one week post infection compared to control birds, whereas vaccination showed delayed changes. The challenge of vaccinated turkeys led to a significant increase of all investigated lymphocytes in the blood already at 4 DPI, indicating an effective and fast recall response of the primed immune system. In the caecum of chickens, changes of B cells, CD4+ and CD8alpha+ T cells were much less pronounced than in turkeys, however, mostly caused by virulent histomonads. Analyses of whole blood in non-vaccinated but infected chickens revealed increasing numbers of monocytes/macrophages on all sampling days, whereas a decrease of heterophils was observed directly after challenge, suggesting recruitment of this cell population to the local site of infection. Our results showed that virulent histomonads caused more severe changes in the distribution of lymphocyte subsets in turkeys compared to chickens. Moreover, vaccination with attenuated histomonads resulted in less pronounced alterations in both species, even after challenge. PMID- 28662954 TI - Structural Allograft Supporting a Trabecular Metal Cup Provides Durable Results in Complex Revision Arthroplasty. AB - BACKGROUND: Revision total hip arthroplasty (THA) is challenging specially in the presence of severe acetabular bone deficiency. We report the use of a highly porous revision shell augmented by structural allograft to provide structural support and coverage to the acetabular component. METHODS: We identified 56 patients (58 hips) undergoing revision THA, where a trabecular metal revision cup was supported by structural allograft. Mean follow-up was 5.4 years (range 2-12 years). Preoperatively acetabular bone defects were classified as Paprosky 2A in 6 hips (10%), 2B in 12 hips (21%), 2C in 12 hips (21%), 3A in 11 hips (19%), and 3B in 17 hips (29%). Structural allograft configuration was classified as type 1 (flying buttress) in 13 hips, type 2 (dome support) in 23 hips, and type 3 (footings) in 17 hips, with 5 hips having combined configurations. RESULTS: All hips showed evidence of union between the allograft and host bone at latest follow-up, 14 hips had partial resorption of the allograft that did not affect cup stability. Three acetabular components demonstrated failure of ingrowth. Survivorship-free from radiographic acetabular loosening as end point was 94% at 5 years. The 5-year survivorship with revision for any reason as end point was 90%. CONCLUSION: Trabecular metal shells combined with structural bone allograft in revision THA demonstrate excellent midterm survival, with 94% of acetabular components obtaining stable union onto host bone at 5 years. Allograft restored bone stock with minimal resorption, and when it occurred did not alter the survivorship of the acetabular component. PMID- 28662955 TI - Determining the Threshold for HbA1c as a Predictor for Adverse Outcomes After Total Joint Arthroplasty: A Multicenter, Retrospective Study. AB - BACKGROUND: Although HbA1c is commonly used for assessing glycemic control before surgery, there is no consensus regarding its role and the appropriate threshold in predicting adverse outcomes. This study was designed to evaluate the potential link between HbA1c and subsequent periprosthetic joint infection (PJI), with the intention of determining the optimal threshold for HbA1c. METHODS: This is a multicenter retrospective study, which identified 1645 diabetic patients who underwent primary total joint arthroplasty (1004 knees and 641 hips) between 2001 and 2015. All patients had an HbA1c measured within 3 months of surgery. The primary outcome of interest was a PJI at 1 year based on the Musculoskeletal Infection Society criteria. Secondary outcomes included orthopedic (wound and mechanical complications) and nonorthopedic complications (sepsis, thromboembolism, genitourinary, and cardiovascular complications). A regression analysis was performed to determine the independent influence of HbA1c for predicting PJI. RESULTS: Overall 22 cases of PJI occurred at 1 year (1.3%). HbA1c at a threshold of 7.7 was distinct for predicting PJI (area under the curve, 0.65; 95% confidence interval, 0.51-0.78). Using this threshold, PJI rates increased from 0.8% (11 of 1441) to 5.4% (11 of 204). In the stepwise logistic regression analysis, PJI remained the only variable associated with higher HbA1c (odds ratio, 1.5; confidence interval, 1.2-2.0; P = .0001). There was no association between high HbA1c levels and other complications assessed. CONCLUSION: High HbA1c levels are associated with an increased risk for PJI. A threshold of 7.7% seems to be more indicative of infection than the commonly used 7% and should perhaps be the goal in preoperative patient optimization. PMID- 28662956 TI - Tranexamic Acid in Knee Surgery Study-A Multicentered, Randomized, Controlled Trial. AB - BACKGROUND: Postoperative anemia following elective arthroplasty can lead to prolonged hospital stay and delays in rehabilitation and is often poorly tolerated in patients with cardiovascular disease. Tranexamic acid (TXA) has been shown to reduce perioperative blood loss in total knee arthroplasty (TKA). However, questions over its optimal route of administration remain. METHODS: A double-blinded, placebo, multicentered, randomized, controlled trial investigating the efficacy of topical and systemic routes of a single intraoperative dose (1.5 g) of TXA was conducted. Patients undergoing primary, unilateral TKA were screened for eligibility. Eligible patients were consecutively enrolled from 5 New Zealand centers between July 2014 and November 2015. Three prospective groups running in parallel (topical TXA [tTXA], systemic TXA [sTXA], and placebo) were investigated for a primary outcome of estimated perioperative blood loss. An intention-to-treat analysis was used to compare outcomes between the study groups (P value <.05). RESULTS: One hundred and thirty four patients across the 5 hospitals were recruited into the study. Estimated blood loss was equivalent in the 2 treatment groups, sTXA (749 mL [95% confidence interval, 637-860]) and tTXA (723 mL [620-826]). Compared to the placebo group (1090 mL [923-1257]), blood loss was significantly lower in both treatment groups (P = .001 and P = .0003, respectively). There were no significant differences in secondary outcomes, including rates of symptomatic deep vein thrombosis and pulmonary embolism (P = .759). CONCLUSION: In the setting of elective TKA, a single 1.5-g dose of tTXA given intraoperatively either systemically or topically effectively reduces blood loss without an increase in complications. PMID- 28662957 TI - Comparison of Early Functional Recovery After Total Hip Arthroplasty Using a Direct Anterior or Posterolateral Approach: A Randomized Controlled Trial. AB - BACKGROUND: Controversy exists as to whether early functional outcomes differ after total hip arthroplasty performed using the direct anterior approach (DAA) or the posterolateral approach (PLA). METHODS: One hundred twenty patients were enrolled in this study and were divided into 2 groups based on surgical approach. Group A included patients who had a total hip arthroplasty with a DAA, whereas group B included those with a PLA. Patients were randomized into the DAA or PLA groups (n = 60), and perioperative and postoperative outcomes were recorded. RESULTS: When compared with the PLA, the DAA had a shorter incision length (9.1 vs 13.1 cm; P < .01), shorter hospital stay (2.8 vs 3.3 days, P = .04), and lower self-reported pain. Both serum inflammatory and muscle damage markers were lower in the DAA group. However, the PLA had shorter operative times (65.5 vs 83.3 min, P = .03) and less intraoperative blood loss (123.8 vs 165.9 mL, P = .04). The DAA had significantly lower variance in cup inclination and anteversion. Similar rates of intraoperative complications were identified in the 2 groups. The DAA was associated with better functional recovery at 3 months based on the Harris hip score, University of California Los Angeles activity score, and gait analysis; however, functional recovery at 6 months was similar between the 2 groups. CONCLUSION: We found functional advantages in early recovery after the DAA compared with the PLA. The DAA can offer rapid functional recovery with less muscle damage, greater pain relief, and lower variance in cup inclination and anteversion. However, no functional difference was found at 6 months follow-up. PMID- 28662958 TI - Targeting ATR in cancer medicine. AB - DNA damage occurs continually through various intrinsic and extrinsic mechanisms such as ultraviolet radiation, smoking, reactive oxygen species, and errors during replication. The cellular DNA damage response (DDR) comprises signaling networks that regulate a spectrum of processes, including cell cycle progression, which enable DNA repair to occur. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and rad3-related (ATR) kinase are 2 key regulators of the DDR cell cycle checkpoints. ATR plays an essential role in the repair of replication-associated DNA damage, while ATM is activated by DNA double-strand breaks. The investigation of cell cycle checkpoint signaling through ATR and ATM, as well as the relevant pathways involved in oncogenesis and cancer progression, has led to the discovery and development of potent and selective ATR inhibitors (ATRi). Preclinical data have demonstrated that ATR inhibition leads to tumor synthetic lethality in specific molecular contexts, and it exhibits synergy in combination with different antitumor therapies, including chemotherapy, radiotherapy, and poly(ADP-ribose) polymerase inhibitors. ATRi are now being assessed in early-phase clinical trials as single agents and in combinatorial regimens, including platinum and other chemotherapies, radiotherapy, poly(ADP ribose) polymerase inhibitors, and immune checkpoint inhibitors. This article details the preclinical biology leading to the discovery and development of novel ATRi and discusses the rationale for monotherapy and combination antitumor strategies. We focus on the clinical development of ATRi and discuss the progress made in identifying putative predictive biomarkers of response for patient selection, such as p53, ATM, ARID1A, and other DDR aberrations. PMID- 28662959 TI - Novel 3H-[1,2,3]triazolo[4,5-c]pyridine derivatives as GPR119 agonists: Synthesis and structure-activity/solubility relationships. AB - We previously reported a novel series of 1H-pyrazolo[3,4-c]pyridine derivatives and the identification of compound 4b as a highly potent GPR119 agonist. However, the advancement of preclinical evaluations of compound 4b is expected to be difficult because of the compound's significantly poor aqueous solubility (0.71MUM at pH6.8). In this article, we describe the further optimization of compound 4b focusing on the improvement of its aqueous solubility. Optimization of the central spacer, left-hand aryl group and right-hand piperidine N-capping group led to the identification of a potent GPR119 agonist, 3H [1,2,3]triazolo[4,5-c]pyridine derivative 32o, with improved solubility (15.9MUM at pH6.8). PMID- 28662960 TI - Improved synthesis of (S)-N-Boc-5-oxaproline for protein synthesis with the alpha ketoacid-hydroxylamine (KAHA) ligation. AB - We describe a new route for the synthesis of (S)-N-Boc-5-oxaproline. This building block is a key element for the chemical synthesis of proteins with the alpha-ketoacid-hydroxylamine (KAHA) ligation. The new synthetic pathway to the enantiopure oxaproline is based on a chiral amine mediated enantioselective conjugate addition of a hydroxylamine to trans-4-oxo-2-butenoate. This route is practical, scalable and economical and provides decagram amounts of material for protein synthesis and conversion to other protected forms of (S)-oxaproline. PMID- 28662961 TI - Stereospecific inhibition of nitric oxide production in macrophage cells by flavanonols: Synthesis and the structure-activity relationship. Part 2. AB - To explore the structure-activity relationships of flavanonols on the inhibition of nitric oxide (NO) production in RAW 264.7 cells, we have prepared a series of synthetic flavanonols. In our previous study, the 2',3'-dihydroxyphenyl substructure was found to be the most potent B ring substructure among the flavanonols having 3,5,7-trihydroxychroman-4-one as the A/C ring. In this study, we examined the effect of diverse substitutions on the A ring of the 2-(2,3 dihydroxyphenyl)-3-hydroxychroman-4-one scaffold, i.e., by fixing the B ring to the 2',3'-dihydroxyphenyl substructure. Eighteen stereoisomers and 4 racemic mixtures were prepared, and their inhibitory potency on NO production in RAW 264.7 cells was tested. We observed higher inhibitory activity in the (2R,3R) stereoisomers than in the (2S,3S) stereoisomers. The presence of a hydroxy or a methoxy group at the 7-postiion enhanced the inhibitory potency, and the additional substitutions at the 6- or 8-position in the A ring increased potency and stereospecificity. A representative compound, (2R,3R)-2',3',7,8 tetrahydroxyflavanonol 5e, had an IC50 value of 17uM, whereas its (2S,3S) stereoisomer did not inhibit NO production at all at a concentration of 100uM. In this study, it was necessary to determine the absolute configuration of the stereoisomers of the synthesized flavanonols that carry methoxy substitutions in the A ring. The procedure to determine their absolute configuration by the CD excitation chirality method is also discussed. PMID- 28662963 TI - Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen. AB - We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure-activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC50 values were 100-1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC50 values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond. PMID- 28662962 TI - Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. AB - Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core. PMID- 28662964 TI - Synthesis and biological activity of cyclolinopeptide A analogues modified with gamma4-bis(homo-phenylalanine). AB - Cyclolinopeptide A (CLA), an immunosuppressive nonapeptide derived from linen seeds, was modified with S or R-gamma4-bis(homo-phenylalanine) in positions 3 or 4, or both 3 and 4. These modifications changed the flexibility of new analogues and distribution of intramolecular hydrogen bonds. Analogues 11 c(Pro1-Pro2-Phe3 S-gamma4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9), 13 c(Pro1-Pro2-S-gamma4-hhPhe3-R gamma4-hhPhe4-Leu5-Ile6-Ile7-Leu8-Val9) and 15 c(Pro1-Pro2-R-gamma4-hhPhe3-Phe4 Leu5-Ile6-Ile7-Leu8-Val9) existed as a mixture of stable cis/trans isomers of Pro Pro peptide bond. The comparison of the relative spatial orientations in crystal state of the two carbonyl groups, neighboring gamma-amino acids, revealed conformational similarities to alpha-peptides. The addition of two -CH2- groups in gamma-amino acids led to a more rigid conformation, although a more flexible one was expected. A significant difference in the relative orientation of the carbonyl groups was found for cyclic gamma-peptides with a dominance of an antiparallel arrangement. As carbonyl groups may be engaged in the interactions with plausible receptors through hydrogen bonds, a similar biological activity of the modified peptides was expected. Our biological studies showed that certain cyclic, but not the corresponding linear peptides, lowered the viability of peripheral blood mononuclear cells (PBMC) at 100MUg/mL concentration. The proliferation of PBMC induced by phytohemagglutinin A (PHA) was strongly inhibited by cyclic peptides only, in a dose-dependant manner. On the other hand, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production in whole blood cell cultures was inhibited by both linear and cyclic peptides. Peptide 15 c(Pro1-Pro2-R-gamma4-hhPhe3-Phe4-Leu5-Ile6-Ile7-Leu8-Val9) blocked the expression of caspase-3, inhibited the expression of caspases-8 and 9 in 24h culture of Jurkat cells, and caused DNA fragmentation in these cells, as an indicator of apoptosis. Thus, we revealed a new mechanism of immunosuppressive action of a nonapeptide. PMID- 28662965 TI - Gerontoxanthone B from Maclura cochinchinensis var. gerontogea exhibits anti inflammatory potential as an aryl hydrocarbon receptor agonist. AB - The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptional factor belonging to the basic helix-loop-helix-Per-Ahr/Arnt-Sim family. In this study, we evaluated the AhR agonistic activities of 12 xanthones isolated from the roots of M. cochinchinensis var. gerontogea using HepG2 cells transfected with pX4TK Luc reporter plasmids. Gerontoxanthone B (GXB) showed the most potent activity at a concentration of 10MUM, and the activity was inhibited by AhR antagonists such as GNF-351. GXB also increased cytochrome P450 1A1 mRNA and protein levels in HepG2 cells. Similar to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin, however, GXB suppressed the IL-1beta-induced mRNA level of SAA1, an acute-phase response gene that is up-regulated AhR-dependently but XRE-independently. Thus, GXB shows XRE-dependent transcriptional activity and XRE-independent activity involving AhR. PMID- 28662966 TI - Antitrichomonal activity of delta opioid receptor antagonists, 7 benzylidenenaltrexone derivatives. AB - The 7-benzylidenenaltrexone (BNTX) derivatives 2a-v, 3a-c, 13a-c, and 14a were synthesized from naltrexone (1) and evaluated for their antitrichomonal activity. The structure-activity-relationship studies found that 4-iodo-BNTX (2g) showed the highest activity (IC50=10.5uM) and the affinity for the opioid receptor was less important for antitrichomonal activity against Trichomonas vaginalis. The morphinan skeleton bearing both the double bond for a Michael acceptor and the phenolic hydroxy group would be a specific template for development of antitrichomonal agents. In addition, the mechanism of the antitrichomonal activity of the BNTX derivatives may differ from that of the standard drug, metronidazole. PMID- 28662967 TI - Low Hepcidin in Type 2 Diabetes Mellitus: Examining the Molecular Links and Their Clinical Implications. AB - The relationship between iron and glucose metabolism has been evidenced strongly, but the molecular mediation of this connection is just being revealed. The discovery of hepcidin as the prime controller of iron metabolism has paved the way for understanding the main actors behind this mediation. Recent data suggest that insulin therapy and probably other diabetes drugs can influence hepcidin production, thus influencing the iron load in cells. Correcting iron load through hepcidin expression could be a novel and important mechanism of action of antidiabetes drugs. This effect would further establish the protective role of antidiabetes therapy and might even affect prevention strategies in diabetes. In this review, we summarize the recent data about iron-glucose links through hepcidin expression, the molecular mediation of this interplay and the clinical implications of these findings. PMID- 28662968 TI - Adherence to Guidelines for Inpatient Pharmacologic Management of Type 2 Diabetes in Adults and Glycemic Outcomes. AB - OBJECTIVES: Diabetes is often poorly managed in hospitals. This study assessed the level of adherence to current Canadian practice guidelines for inpatient pharmacologic management of type 2 diabetes and whether it affected the frequency of hyperglycemia or hypoglycemia. METHODS: Retrospectively, we assessed the first 3 days of routine inpatient capillary blood glucose measurement (CBGM) records for hyperglycemia (>8 mmol/L fasting, >10 mmol/L nonfasting) and hypoglycemia (<4 mmol/L) in adults with drug-treated type 2 diabetes admitted to internal medicine without metabolic decompensation or nil per os (NPO) status at 2 hospitals during October through December 2014. Patients, divided according to their admission orders into guideline-adherent versus guideline-nonadherent groups were compared for frequency of hyperglycemia and hypoglycemia. Factors predicting guideline adherence were assessed. RESULTS: Of 150 patients with diabetes who were admitted, 108 met entry criteria. A total of 89 patients received guideline-based care (82%), whereas 19 patients did not (18%). Charlson index and preadmission medications did not predict guideline-based care, but admitting physicians' seniority did (junior, senior resident, attending physician; p=0.05). In the adherent group, 43% of CBGMs were hyperglycemic, versus 64% in the nonadherent group (p=0.01). For hypoglycemia, proportions were 2% versus 1%, respectively (p=0.21). CONCLUSIONS: Adherence to guidelines for inpatient type 2 diabetes management is good and may be greater with more training. Hyperglycemia was more common in patients who did not receive guideline-based care. Hypoglycemia was uncommon and did not appear to be more common in the guideline-adherent group, although numbers were small. These results may alleviate physicians' fear that providing adequate insulin to hospitalized patients may cause hypoglycemia. PMID- 28662969 TI - Pathway to better patient care and nurse workforce outcomes in home care. AB - BACKGROUND: Unlike the Magnet Recognition Program, the newer Pathway to Excellence Program designed to improve work environments in a broader range of organizations has not yet been the focus of substantial research. PURPOSE: The purpose of the study was to examine the association of Pathway to Excellence Program Standards with better patient care quality and workforce outcomes in home care. METHOD: Cross-sectional survey of registered nurses yielded informants from 871 home care agencies in the United States. Variables representing each of the 12 Pathway Standards were entered into logistic regression models to determine associations with better patient care and nurse workforce outcomes. DISCUSSION: All Pathway Standards are strongly and significantly associated with better patient care and better workforce outcomes. Home care agencies with better-rated professional work environments consistently had better patient care and nurse workforce outcomes. CONCLUSIONS: This study validates the Pathway to Excellence Standards as important to patient care quality and nursing workforce outcomes in home care. PMID- 28662971 TI - Head and neck desmoplastic melanoma: Utility of sentinel node biopsy. AB - PURPOSE: The utility of sentinel lymph node biopsy in desmoplastic melanoma has been questioned due to multiple reports of a low rate of occult nodal metastasis in this variant of melanoma. We describe a single institution experience with management of desmoplastic melanoma of the head and neck and discuss the utility of sentinel lymph node biopsy. MATERIALS AND METHODS: A retrospective review was performed of 49 patients with desmoplastic melanoma of the head and neck at a tertiary care center from 1994 to 2014. RESULTS: Sentinel lymph node biopsy was performed in 15 patients. Only 1 (6.7%) of these patients was found to have a positive sentinel node. Of the 46 patients without evidence of neck disease at presentation, 3 (6.5%) were found to have occult nodal disease or developed neck recurrences. When looking at the entire cohort, there were a total of 16 recurrences in 14 patients (28.6%). The majority (85.7%) of recurrences were either local or distant metastasis with only 2 (14.3%) recurrences being in regional lymph node basins. The overall rates of local, regional, and distant recurrences were 14.2%, 4.1%, and 10.2% respectively. The mixed pathologic subtype was not associated with a higher rate of nodal metastasis. CONCLUSIONS: Desmoplastic melanoma has a low rate of occult nodal metastasis and a high propensity to recur locally or as a distant metastasis, regardless of regional node status. Our experience combined with the uncertain impact that sentinel node status has on survival raises the question of the utility of routine sentinel node biopsy in this specific variant of melanoma. PMID- 28662970 TI - Molecular Dissection of CD8+ T-Cell Dysfunction. AB - Chronic viral infections and cancer often lead to the emergence of dysfunctional or 'exhausted' CD8+ T cells, and the restoration of their functions is currently the focus of therapeutic interventions. In this review, we detail recent advances in the annotation of the gene modules and the epigenetic landscape associated with T-cell dysfunction. Together with analysis of single-cell transcriptomes, these findings have enabled a deeper and more precise understanding of the transcriptional mechanisms that induce and maintain the dysfunctional state and highlight the heterogeneity of CD8+ T-cell phenotypes present in chronically inflamed tissue. We discuss the relevance of these findings for understanding the transcriptional and spatial regulation of dysfunctional T cells and for the design of therapeutics. PMID- 28662972 TI - Utilization of sinus stents as a novel approach for benign cystic lesions of the sella. AB - Steroid-releasing sinus stents have emerged as a safe and effective tool in endoscopic sinus surgery. In this case report, we present two patients with recurrent cystic sellar masses. Transsphenoidal approach was used to access the sella. Following resection and drainage of the cystic pathology, a Propel (Menlo Park, CA) stent was placed through the corridor of the resection site to stent the cavity open. This is the first report where a steroid-releasing sinus stent was used in the treatment of a sellar lesion. It supports that this technology is safe and effective for use in skull base surgery. PMID- 28662973 TI - Assessment of Bone Mineral Density at the Distal Femur and the Proximal Tibia by Dual-Energy X-ray Absorptiometry in Individuals With Spinal Cord Injury: Precision of Protocol and Relation to Injury Duration. AB - Spinal cord injury (SCI) is characterized by marked bone loss at the knee, and there is a need for established dual-energy X-ray absorptiometry (DXA) protocols to examine bone mineral density (BMD) at this location to track therapeutic progress and to monitor fracture risk. The purpose of this study was to quantify the precision and reliability of a DXA protocol for BMD assessment at the distal femur and the proximal tibia in individuals with SCI. The protocol was subsequently used to investigate the relationship between BMD and duration of SCI. Nine individuals with complete SCI and 9 able-bodied controls underwent 3 repeat DXA scans in accordance with the short-term precision methodology recommended by the International Society of Clinical Densitometry. The DXA protocol demonstrated a high degree of precision with the root-mean-square standard deviation ranging from 0.004 to 0.052 g/cm2 and the root-mean-square coefficient of variation ranging from 0.6% to 4.4%, depending on the bone, the region of interest, and the rater. All measurements of intra- and inter-rater reliability were excellent with an intraclass correlation of >=0.950. The relationship between the BMD and the duration of SCI was well described by a logarithmic trend (r2 = 0.68-0.92). Depending on the region of interest, the logarithmic trends would predict that, after 3 yr of SCI, BMD at the knee would be 43%-19% lower than that in the able-bodied reference group. We believe the DXA protocol has the level of precision and reliability required for short-term assessments of BMD at the distal femur and the proximal tibia in people with SCI. However, further work is required to determine the degree to which this protocol may be used to assess longitudinal changes in BMD after SCI to examine clinical interventions and to monitor fracture risk. PMID- 28662974 TI - U.S. cannabis legalization and use of vaping and edible products among youth. AB - BACKGROUND: Alternative methods for consuming cannabis (e.g., vaping and edibles) have become more popular in the wake of U.S. cannabis legalization. Specific provisions of legal cannabis laws (LCL) (e.g., dispensary regulations) may impact the likelihood that youth will use alternative methods and the age at which they first try the method - potentially magnifying or mitigating the developmental harms of cannabis use. METHODS: This study examined associations between LCL provisions and how youth consume cannabis. An online cannabis use survey was distributed using Facebook advertising, and data were collected from 2630 cannabis-using youth (ages 14-18). U.S. states were coded for LCL status and various LCL provisions. Regression analyses tested associations among lifetime use and age of onset of cannabis vaping and edibles and LCL provisions. RESULTS: Longer LCL duration (ORvaping: 2.82, 95% CI: 2.24, 3.55; ORedibles: 3.82, 95% CI: 2.96, 4.94), and higher dispensary density (ORvaping: 2.68, 95% CI: 2.12, 3.38; ORedibles: 3.31, 95% CI: 2.56, 4.26), were related to higher likelihood of trying vaping and edibles. Permitting home cultivation was related to higher likelihood (OR: 1.93, 95% CI: 1.50, 2.48) and younger age of onset (beta: -0.30, 95% CI: 0.45, -0.15) of edibles. CONCLUSION: Specific provisions of LCL appear to impact the likelihood, and age at which, youth use alternative methods to consume cannabis. These methods may carry differential risks for initiation and escalation of cannabis use. Understanding associations between LCL provisions and methods of administration can inform the design of effective cannabis regulatory strategies. PMID- 28662976 TI - Selective isolation of gonyautoxins 1,4 from the dinoflagellate Alexandrium minutum based on molecularly imprinted solid-phase extraction. AB - Gonyautoxins 1,4 (GTX1,4) from Alexandrium minutum samples were isolated selectively and recognized specifically by an innovative and effective extraction procedure based on molecular imprinting technology. Novel molecularly imprinted polymer microspheres (MIPMs) were prepared by double-templated imprinting strategy using caffeine and pentoxifylline as dummy templates. The synthesized polymers displayed good affinity to GTX1,4 and were applied as sorbents. Further, an off-line molecularly imprinted solid-phase extraction (MISPE) protocol was optimized and an effective approach based on the MISPE coupled with HPLC-FLD was developed for selective isolation of GTX1,4 from the cultured A. minutum samples. The separation method showed good extraction efficiency (73.2-81.5%) for GTX1,4 and efficient removal of interferences matrices was also achieved after the MISPE process for the microalgal samples. The outcome demonstrated the superiority and great potential of the MISPE procedure for direct separation of GTX1,4 from marine microalgal extracts. PMID- 28662975 TI - Association between process measures and mortality in individuals with opioid use disorders. AB - BACKGROUND: Individuals with opioid use disorders have high rates of mortality relative to the general population. The relationship between treatment process and mortality is unknown. AIM: To examine the association between 7 process measures and 12- and 24-month mortality. METHODS: Retrospective cohort study of patients with opioid use disorders who received care from the Veterans Administration between October 2006 and September 2007. Logistic regression models were used to examine the association between 12 and 24-month mortality and 7 patient-level process measures, while risk-adjusting for patient characteristics. Process measures included quarterly physician visits, any opioid use disorder pharmacotherapy, continuous pharmacotherapy, psychosocial treatment, Hepatitis B/C and HIV screening, and no prescriptions for benzodiazepines or opioids. We conducted sensitivity analyses to examine the robustness of our findings to an unobserved confounder. RESULTS: Among individuals with opioid use disorders, not being prescribed opioids or benzodiazepines, receipt of any psychosocial treatment and quarterly physician visits were significantly associated with lower mortality at both 12 and 24 months, but Hepatitis and HIV screening, and measures related to opioid use disorder pharmacotherapy were not. Sensitivity analyses indicated that the difference in the prevalence of an unobserved confounder would have to be unrealistically large given the observed data, or there would need to be a large effect of the confounder, to render these findings non-significant. CONCLUSIONS AND RELEVANCE: This is the first study to show an association between process measures and mortality in patients with opioid use disorders and provides initial evidence for their use as quality measures. PMID- 28662977 TI - Anthropogenic noise compromises the anti-predator behaviour of the European seabass, Dicentrarchus labrax (L.). AB - Anthropogenic noise is a significant pollutant of the world's oceans, affecting behavioural and physiological traits in a range of species, including anti predator behaviours. Using the open field test, we investigated the effects of recordings of piling and drilling noise on the anti-predator behaviour of captive juvenile European seabass in response to a visual stimulus (a predatory mimic). The impulsive nature of piling noise triggered a reflexive startle response, which contrasted the behaviour elicited by the continuous drilling noise. When presented with the predatory mimic, fish exposed to both piling and drilling noise explored the experimental arena more extensively than control fish exposed to ambient noise. Fish under drilling and piling conditions also exhibited reduced predator inspection behaviour. Piling and drilling noise induced stress as measured by ventilation rate. This study provides further evidence that the behaviour and physiology of European seabass is significantly affected by exposure to elevated noise levels. PMID- 28662978 TI - Concentrations of metallic elements in kidney, liver, and lung tissue of Indo Pacific bottlenose dolphin Tursiops aduncus from coastal waters of Zanzibar, Tanzania. AB - Concentrations of metallic elements in kidney, liver and lung tissues of Indo Pacific bottlenose dolphins Tursiops aduncus from coastal waters of Zanzibar were determined using inductively coupled plasma - optical emission spectroscopy. Cadmium, chromium, copper, and zinc were quantifiable in all tissues at concentration ranges of 0.10-150, 0.08-3.2, 1.1-88 and 14-210MUg/g dry mass, respectively. Copper and zinc was significantly higher in liver, and females had significantly higher Cd in liver, and chromium in lung. Generally, T. aduncus dolphins from coastal waters around Zanzibar carry low concentrations of metals compared with dolphins from other areas. Cadmium increased significantly with age in kidney and lung. Copper decreased significantly with age in liver, probably due to foetal metallothionein. This study supplied baseline data against which future trends in marine mammals in the Indian Ocean, the world's third largest, can be assessed. PMID- 28662979 TI - Assessment of metal concentrations (Cu, Zn, and Pb) in seawater, sediment and biota samples in the coastal area of Eastern Black Sea, Turkey. AB - This study investigated the contents of Cu, Zn and Pb in seawater, sediment, different shell sizes of mussel (Mytilus galloprovincialis) and sea snail (Rapana venosa) samples collected from four different provinces of the Eastern Black Sea Region. With the exception of Zn, all the metal concentration values measured in the sea snail were observed to be higher than those of mussels in all stations. While the correlation between mussels and sea snail according to metal concentrations was found to be positive (p?0.05), this relation was not observed between the other parameters, such as the shell sizes, salinity and pH (p?0.05). Although the mean concentration values of Cu, Zn, and Pb for mussel and sea snail are significantly above the tolerable levels, the estimated daily intake values for mussel were below the daily intake recommended. PMID- 28662980 TI - Storms do not alter long-term watershed development influences on coastal water quality. AB - A twelve year (2000-2011) study of three coastal lagoons in the Gulf of Mexico was conducted to assess the impacts of local watershed development and tropical storms on water quality. The lagoons have similar physical and hydrological characteristics, but differ substantially in the degree of watershed urban development and nutrient loading rates. In total the lagoons experienced 22 storm events during the period studied. Specifically, we examine (1) whether there are influences on water quality in the lagoons from watershed development, (2) whether there are influences on water quality in the lagoons from storm activity, and (3) whether water quality is affected to a greater degree by watershed development versus storm activity. The two urbanized lagoons typically showed higher water-column nitrate, dissolved organic nitrogen, and phosphate compared with the non-urbanized lagoon. One of the urbanized lagoons had higher water column chlorophyll a concentrations than the other two lagoons on most sampling dates, and higher light extinction coefficients on some sampling dates. The non urbanized lagoon had higher water-column dissolved oxygen concentrations than other lagoons on many sampling dates. Our results suggest long-term influences of watershed development on coastal water quality. We also found some evidence of significant storm effects on water quality, such as increased nitrate, phosphate, and dissolved oxygen, and decreased salinity and water temperature. However, the influences of watershed development on water quality were greater. These results suggest that changes in water quality induced by human watershed development pervade despite the storm effects. These findings may be useful for environmental management since they suggest that storms do not profoundly alter long-term changes in water quality that resulted from human development of watersheds. PMID- 28662981 TI - Linking fish species traits to environmental conditions in the Jakarta Bay-Pulau Seribu coral reef system. AB - Coral reefs around the globe have been subjected to a wide range of stressors. In the present study, fish species were recorded across a pronounced in-to-offshore gradient in the Jakarta Bay-Pulau Seribu reef system. In addition to this, fish species traits were obtained from FishBase. RLQ analysis revealed a significant association between fish species traits and environmental variables. Fish species associated with perturbed, inshore waters were resilient to disturbance, had higher mortality rates, higher growth rates and mainly consumed animals. In contrast, fish species associated with less perturbed, mid- and offshore waters had greater life expectancy, higher age at maturity, greater life span, greater generation time and mainly fed on plants or plants and animals. Eutrophication, pollution and physical destruction of coral substrate in inshore waters has thus selected for a low biomass and depauperate fish community characterised by fast growing and short lived species. PMID- 28662982 TI - Extended oil spill spreading with Langmuir circulation. AB - When spilled in the ocean, most crude oils quickly spread into a thin film that ruptures into smaller slicks distributed over a larger area. Observers have also reported the film tearing apart into streaks that eventually merge forming fewer but longer bands of floating oil. Understanding this process is important to model oil spill transport. First, slick area is calculated using a spreading model. Next, Langmuir circulation models are used to approximate the merging of oiled bands. Calculations are performed on Troll blended and Alaska North Slope crude oils and results compared with measurements from the 1990s North Sea field experiments. Langmuir circulation increases the oil area but decreases the surface coverage of oil. This work modifies existing oil spreading formulas by providing a surface area correction due to the effects of Langmuir circulation. The model's simplicity is advantageous in situations with limited data, such as emergency oil spill response. PMID- 28662983 TI - Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: A phase I/II study. AB - BACKGROUND AIMS: Despite the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the procedure is still associated with high toxicity in patients with refractory graft-versus-host disease (GvHD). Mesenchymal stromal cells (MSCs) are a new mode of therapy in the context of allo-HSCT. The objective of this study was to evaluate the safety and feasibility of the use of adipose tissue-derived MSCs (AT-MSCs) in patients with chronic GvHD. METHODS: Fourteen patients with moderate (n = 7) or severe (n = 7) chronic GvHD received 1 * 106/kg (group A, n = 9) or 3 * 106/kg (group B, n = 5) AT-MSCs with cyclosporine and prednisone as first-line therapy. RESULTS: Ten of the 14 patients were able to continue under the protocol: 80% were in complete remission, and 100% were off of steroids at week 56. The remaining 4 patients either worsened from chronic GvHD (n = 3) or abandoned the study (n = 1). At the end of the study, 11 of 14 patients are alive (overall survival 71.4%, median survival of 45.3 weeks). No suspected unexpected serious adverse reactions occurred during the trial. Neither relapse of underlying disease nor mortality due to infection was observed in this cohort. Biological studies showed increased CD19, CD4 and tumor necrosis factor alpha with a temporary decrease in natural killer cells. DISCUSSION: AT-MSCs, in combination with immunosuppressive therapy, may be considered feasible and safe and likely would have an impact on the course of chronic GvHD. More studies are warranted to understand the potential benefits of AT-MSCs in these patients. PMID- 28662984 TI - MR Enterography in Crohn's disease complicated with enteroenteric fistula. AB - OBJECTIVE: In this retrospective study, we aimed to evaluate MR enterography (MRE) findings, MR index of activity (MaRIA) and laboratory markers in Crohn patients with enteroenteric fistula. METHODS: Institution's electronic medical records (laboratory, pathology, ileocolonoscopy results and discharge summary) were reviewed and MR images retrieved from the PACS were reanalyzed in Crohn patients assessed at Gastroenterology Clinic of our university between July 2011 and July 2016. MR enterography and clinic parameters of 38 Crohn patients with enteroenteric fistula and 48 Crohn patients without enteroenteric fistula were compared. RESULTS: Of the findings, perienteric inflammation was seen only in fistula group. The mean wall thickness was significantly greater; perienteric fluid, mural hyperenhancement, cecal contraction, thickening of ileocecal valve, and colonic involvement were significantly more common in fistula patients. There was no significant difference between groups with regards to MaRIA index and perianal disease. In patients with enteroenteric fistula, there was significant association between the presence of hypoalbuminemia and presence of ileitis at ileocolonoscopy. In the overall study population, there was a positive correlation between the MaRIA and CRP values at the time of the MRE. CONCLUSIONS: Perienteric mesenteric inflammation and fluid collection are common in enteroenteric fistulization. MaRIA indices and laboratory findings of patients with enteroenteric fistula are not significantly different from those without fistulas. PMID- 28662985 TI - Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System. AB - BACKGROUND: The emergence of molecular systems offers opportunities for improving the assessment of rejection in heart transplant biopsy specimens. The present study developed a microarray-based system for assessing heart transplant endomyocardial biopsy (EMB) specimens. METHODS: We analyzed 331 protocol or for cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris). Unsupervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both. To compare EMB specimens to kidney biopsy specimens, rejection status in both was simplified to TCMR, ABMR, or no rejection. RESULTS: The pattern of RAT expression was similar in EMB and kidney specimens, permitting use of RATs to assign scores and group ("cluster") membership to each EMB, independent of histology. Three clusters emerged in EMB specimens, similar to kidney specimens: TCMR, ABMR, and no rejection. This permitted each EMB specimen to be given 3 scores and assigned to 1 cluster by its highest score. There was significant agreement between molecular phenotype-archetype scores or clusters and both histologic diagnoses and donor-specific antibody. Area under curve estimates for predicting histologic TCMR, ABMR, and no rejection by molecular assessment were lower in EMB specimens than in kidney specimens, reflecting more uncertainty in EMB specimens, particularly in histologic diagnosis of TCMR. CONCLUSIONS: Rejection-associated transcripts can be used to estimate the probability of TCMR and ABMR in heart transplant specimens, providing a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. PMID- 28662986 TI - Therapy options for chronic lung allograft dysfunction-bronchiolitis obliterans syndrome following first-line immunosuppressive strategies: A systematic review. AB - BACKGROUND: Long-term success of lung transplantation is limited by the development of chronic lung allograft dysfunction (CLAD), of which bronchiolitis obliterans syndrome (BOS) is the most common form. This systematic review sought to identify the current evidence base for CLAD-BOS therapies after initial immunosuppressive treatment strategies. METHODS: The MEDLINE, Embase, and Cochrane Library databases from inception to May 3, 2016, were searched using keywords relating to CLAD-BOS, study designs, and treatments of interest, including extracorporeal photopheresis (ECP), aerosolized cyclosporine, total lymphoid irradiation (TLI), alemtuzumab, and montelukast. Titles, abstracts, and full texts were screened by 2 independent reviewers to identify studies of CLAD BOS second-line therapy in adult lung transplant patients. Quality was assessed according to the Downs and Black checklist. RESULTS: Of the 936 individual citations identified, 47 reports of 40 studies met inclusion criteria, including 17 full publications, 11 recent (2015-2016), and 12 older (pre-2015) congress proceedings. Most of the full publications and recent abstracts investigated ECP (n = 11), TLI (n = 5), alemtuzumab (n = 4), and montelukast (n = 2). Most studies were uncontrolled and retrospective. Compared with standard therapy alone, improved lung function and survival was reported for ECP in 2 studies without randomization, with lower-quality evidence for improved lung function for TLI, montelukast, and aerosolized cyclosporine. CONCLUSIONS: Because most identified studies were of retrospective and uncontrolled design, comparison of treatment effects was limited. Available evidence suggests stabilized lung function after ECP in combination with established immunosuppressive regimens in late-line CLAD BOS treatment, with fewer data for TLI, montelukast, and aerosolized cyclosporine. PMID- 28662987 TI - Changes in disease-specific versus generic health status measures after left ventricular assist device implantation: Insights from INTERMACS. AB - BACKGROUND: Quantifying quality of life (QoL) after left ventricular assist device (LVAD) remains challenging. Heart failure (HF)-specific health status measures are ideal for assessing symptoms of HF; however, if patients' QoL is limited by other factors, they may experience improved HF-specific QoL but no concurrent improvement in generic QoL. We sought to examine and predict discrepancies between disease-specific and generic QoL measures after LVAD. METHODS: We examined HF-specific and generic QoL with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol-5D Visual Analog Scale (VAS), respectively, among 1,888 patients with advanced heart failure who underwent LVAD implantation from 2012 to 2014 as part of the INTERMACS registry. RESULTS: Both measures showed substantial improvement, on average, at 6 months after LVAD, with mean changes of 32.7 +/- 25.0 and 27.6 +/- 27.4, respectively. Among the 1,539 patients (81.5%) with moderate/large improvement in KCCQ, 334 (21.7%) had discordant changes in generic QoL (i.e., VAS did not substantially increase despite improvement in KCCQ). In a multivariable logistic regression model, baseline VAS score was the strongest predictor of KCCQ-VAS discordance, whereas post-LVAD complications were not significant predictors of discordance. CONCLUSIONS: Most patients have major improvements in both HF-specific and generic QoL after LVAD implantation, and discordance in these measures after LVAD is uncommon. When it did occur, discordance was primarily observed in patients who reported good generic QoL on the VAS before LVAD (despite substantial impairment due to congestive HF). These results support the continued use of HF specific health status measures to monitor QoL before and after LVAD implantation. PMID- 28662988 TI - The Rare Extragonadal Omental Teratoma: A Case Report. AB - Teratomas of extragonadal origin are extremely rare, and the most common extragonadal site to find teratomas is the omentum. Teratomas are typically found in women of reproductive age, but they are also seen in young girls and postmenopausal women. Generally, teratomas arise from germ cells that may induce different cells to originate from the 3 primitive embryonic layers. Three main theories have been proposed to explain their location. The present report summarizes these theories as well as describes a case of a mature cystic teratoma of the omentum that was managed by laparoscopic resection. PMID- 28662989 TI - Radiofrequency Thermal Ablation for Uterine Myomas: Long-term Clinical Outcomes and Reinterventions. AB - STUDY OBJECTIVE: To assess the long-term efficacy and rate of reintervention after ultrasound-guided radiofrequency thermal ablation (RFA) for uterine myomas. DESIGN: A retrospective follow-up, cohort study (Canadian Task Force classification II-2). SETTING: University hospitals and private clinics. PATIENTS: Between November 1, 2007, and February 26, 2010, 66 consecutive women underwent ultrasound-guided RFA. INTERVENTIONS: Patients underwent abdominal or vaginal ultrasound-guided RFA and were contacted for a long-term follow-up to complete the Uterine Fibroid Symptom and Quality of Life Score (UFS-QOL) questionnaire and optional ultrasound and examination. MEASUREMENTS AND MAIN RESULTS: Sixty-six consecutive patients (mean age 45 +/- 7 years) with type 2 to 5 symptomatic myomas per the International Federation of Gynecology and Obstetrics (median size = 122.5 cm3 [range, 24-675]) were included. Forty of 62 patients recruited for follow-up underwent no/minor hysteroscopic reinterventions; 35 patients from this group completed the UFS-QOL questionnaire and showed sustained and improved symptom severity scores (100-point scale) from baseline (57.2 +/- 16.6) to long-term follow-up (23.8 +/- 20.8, p < .001). Twenty two patients (35%) had major reinterventions (15 hysterectomies and 7 myomectomies). Six of the 22 patients underwent major reinterventions for reasons other than myoma-related complaints. The estimated major reintervention rate because of myoma-related symptoms determined by the Kaplan-Meier method was 13.5% (95% confidence interval [CI], 7%-25%) after 2 years and 29.1% (95% CI, 19%-43%) after 5 years. Women >=45 years of age had a major reintervention rate of 12% (95% CI, 5%-26%) after 2 years and 19% (95% CI, 10%-35%) after 5 years, and women <45 years had a major reintervention rate of 35.0% (95% CI, 19%-60%) and 73.8% (95% CI, 52%-92%) after 2 and 5 years, respectively. Fewer major reinterventions occurred in women with only 1 RFA-treated myoma (volume <=180 cm3, diameter <7 cm) than women with more than 1 RFA-treated myoma (>180 cm3, p < .01). The Kaplan Meier estimates for reintervention in women with only 1 RFA-treated myoma with a volume <=180 cm3 were 13% (95% CI, 6-28%) and 26% (95% CI, 14%-45%) after 2 and 5 years, respectively. No patients with morphologic myoma characteristics underwent reinterventions. CONCLUSION: Ultrasound-guided RFA for uterine myomas is an alternative treatment option especially for women >=45 years of age with only 1 myoma (volume <=180 cm3) and warrants further evaluation. PMID- 28662990 TI - The Adoption of Single-port Laparoscopy for Full Staging of Endometrial Cancer: Surgical and Oncology Outcomes and Evaluation of the Learning Curve. AB - STUDY OBJECTIVE: To study the safety, feasibility, learning curve, and surgical outcome for single-port laparoscopic full staging of endometrial cancer. DESIGN: A retrospective study (Canadian Task Force classification II-3). SETTING: A university academic hospital. PATIENTS: Women with endometrial cancer undergoing single-port laparoscopic full surgical staging. INTERVENTIONS: This was a single center, retrospective consecutive study of patients undergoing single-port laparoscopic full staging of endometrial cancer from March 2012 to December 2015. MEASUREMENTS AND MAIN RESULTS: One hundred ten consecutive cases were included in the study. The mean age was 63 years (standard deviation = 14), and the mean body mass index was 34 kg/m2 (standard deviation = 7). Medical comorbidity was noted in 62% (68/110) of patients, and 55% (61/110) of patients had previous abdominal surgery. Preoperative histology included grade 1 (63%), grade 2 (23%), grade 3 (4%), papillary serous (6%), clear cell (3%), and mixed (1%). Postoperatively, 73% of patients were stage I, 2% were stage II, 21% were stage III, and 4% were stage IV. The conversion rate to multiple ports or to laparotomy was 6.3%. The average total surgical time was 186 minutes. Comparing the last 30 cases of our cohort with the first 20, there was a significant improvement in the reduction of the total operative time (191 vs 152 minutes, p = .036), estimated blood loss (389 vs 121 mL, p = .002), conversion rate (20 % vs 0%, p = .02), and rate of surgical complication (10% vs. 0%, p = .03). The readmission rate was 11% (12/110) with 75% of those patients being readmitted for surgical indications and 25% for medical indications. The rate of ventral hernia was 1.8% (2/110) with an average follow-up of 298 days (31-1085 days). CONCLUSION: Single-port laparoscopic staging of endometrial cancer is a safe and feasible technique to introduce into a gynecologic oncology practice that is compatible with other minimally invasive modalities with similar complication rates, discharge timing, and operative times. Drastic improvement in surgical time can be seen after approximately the first 20 cases. PMID- 28662991 TI - Inpatient and 90-day post-discharge outcomes in elective Medicare spine fusion surgery. AB - BACKGROUND CONTEXT: Elective spine surgery is a commonly performed operative procedure, that requires knowledge of risk-adjusted results to improve outcomes and reduce costs. PURPOSE: To develop risk-adjusted models to predict the adverse outcomes (AOs) of care during the inpatient and 90-day post-discharge period for spine fusion surgery. STUDY DESIGN/SETTING: To identify the significant risk factors associated with AOs and to develop risk models that measure performance. PATIENT SAMPLE: Hospitals that met minimum criteria of both 20 elective cervical and 20 elective non-cervical spine fusion operations in the 2012-2014 Medicare limited dataset. OUTCOME MEASURES: The risk-adjusted AOs of inpatient deaths, prolonged length-of-stay for the index hospitalization, 90-day post-discharge deaths, and 90-day post-discharge readmissions were dependent variables in predictive risk models. METHODS: Over 500 candidate risk factors were used for logistic regression models to predict the AOs. Models were then used to predicted risk-adjusted AO rates by hospitals. RESULTS: There were 874 hospitals with a minimum of both 20 cervical and 20 non-cervical spine fusion patients. There were 167,395 total cases. A total of 7,981 (15.9%) of cervical fusion patients and 17,481 (14.9%) of non-cervical fusion patients had one or more AOs for an overall AO rate of 15.2%. A total of 54 hospitals (6.2%) had z-scores that were 2.0 better than predicted with a median risk adjusted AO rate of 9.2%, and 75 hospitals (8.6%) were 2.0 z-scores poorer than predicted with a median risk adjusted AO rate of 23.2%. CONCLUSIONS: Differences among hospitals defines opportunities for care improvement. PMID- 28662992 TI - Candidate gene investigation of spinal degenerative osteoarthritis in Greek population. AB - BACKGROUND CONTEXT: Few data exist concerning the natural history of degenerative osteoarthritis (OA) of the spine and its associated gene investigation. Degenerative spinal OA demonstrates an international prevalence of 15% in the general population. PURPOSE: The aim of this Greek case-control study is to examine gene polymorphisms that have been previously shown or hypothesized to be correlated to degenerative OA. Gene polymorphisms, especially for OA, have never been previously studied in the Greek population. STUDY DESIGN/SETTING: The study was conducted from May 2009 to December 2012. Eligible subjects who agreed to take part in the study were Greek adults from all of Greece, referred for consultation to the Palliative Care and Pain Relief Unit of Aretaieion University Hospital, in Athens, Greece. PATIENT SAMPLE: A total of 601 matched pairs (cases and controls) participated in the study, 258 patients (188 women and 70 men) with clinically and radiologically confirmed degenerative OA and 243 control subjects (138 women and 105 men). OUTCOME MEASURES: All patients presented with chronic pain at the spine (cervical, thoracic or lumbar) caused by sympomatic osteophytes or disc narrowing, whereas clinical diagnosis of OA was based on the presence of both joint symptoms and evidence of structural changes seen on plain conventional X-rays. METHODS: We investigated genetic variation across candidate OA gene GDF5, CDMP1, CDMP2, Asporin, SMAD3, and chromosomal region 7q22, in a sample of 258 patients with clinically and radiologically confirmed degenerative OA, and 243 control subjects from the Greek population. All subjects (patients and controls) were subsequently matched for the epidemiologic, demographic, and clinical risk factors, to prevent selection biases. A tagging single nucleotide polymorphism (SNP) approach was pursued to cover variation across all targeted loci. Single marker tests as well as haplotypic tests of association were performed. There is no conflict of interest, and also, there are no study funding sources. RESULTS: We found significant association of spine OA with SNPs and haplotypes along the 7q22 chromosomal region and the SMAD3 gene. At 7q22, single marker association tests showed SNPs rs3801954 and rs2023685 to be associated with the disorder (p value .0312 and .0041, respectively), but only SNP rs2023685 retained a significant p-value (.046) after performing 1,000 permutation tests. At the SMAD3 gene, SNP rs422342 was also found to be statistically associated (p-value .0282) to intervertebral disc degeneration (permutation p-value .042). CONCLUSIONS: This is the first study to investigate genetic variation in relation to spine OA in the Greek population. Our results indicate that the genetic basis of the disease may differ in the Greek population in relation to populations of Asian origin, although larger sample sizes are required to underpin the full extent of the involvement of analyzed loci. PMID- 28662994 TI - Re: Gaskill CS, Awan JA, Watts CR, Awan SN. Acoustic and perceptual classification of within-sample normal, intermittently dysphonic, and consistently dysphonic voice types. J Voice. 2016;31:218-228. PMID- 28662993 TI - The pathologic mechanisms underlying lumbar distraction spinal cord injury in rabbits. AB - BACKGROUND CONTEXT: A reliable experimental rabbit model of distraction spinal cord injury (SCI) was established to successfully simulate gradable and replicable distraction SCI. However, further research is needed to elucidate the pathologic mechanisms underlying distraction SCI. PURPOSE: The aim of this study was to investigate the pathologic mechanisms underlying lumbar distraction SCI in rabbits. STUDY DESIGN: This is an animal laboratory study. METHODS: Using a self designed spine distractor, the experimental animals were divided into a control group and 10%, 20%, and 30% distraction groups. Pathologic changes to the spinal cord microvessels in the early stage of distraction SCI were identified by perfusion of the spinal cord vasculature with ink, production of transparent specimens, observation by light microscopy, and observation of corrosion casts of the spinal cord microvascular architecture by scanning electron microscopy. Malondialdehyde (MDA) and superoxide dismutase (SOD) concentrations in the injured spinal cord tissue were measured after 8 hours. RESULTS: With an increasing degree and duration of distraction, the spinal cord microvessels were only partially filled and had the appearance of spasm until rupture and hemorrhage were observed. The MDA concentration increased and the SOD concentration decreased in the spinal cord tissue. CONCLUSIONS: Changes to the internal and external spinal cord vessels led to spinal cord ischemia, which is a primary pathologic mechanism of distraction SCI. Lipid peroxidation mediated by free radicals took part in secondary pathologic damage of distraction SCI. PMID- 28662995 TI - Simplifying the human serum proteome for discriminating patients with bipolar disorder of other psychiatry conditions. AB - PURPOSE: An exploratory analysis using proteomic strategies in blood serum of patients with bipolar disorder (BD), and with other psychiatric conditions such as Schizophrenia (SCZ), can provide a better understanding of this disorder, as well as their discrimination based on their proteomic profile. METHODS: The proteomic profile of blood serum samples obtained from patients with BD using lithium or other drugs (N=14), healthy controls, including non-family (HCNF; N=3) and family (HCF; N=9), patients with schizophrenia (SCZ; N=23), and patients using lithium for other psychiatric conditions (OD; N=4) were compared. Four methods for simplifying the serum samples proteome were evaluated for both removing the most abundant proteins and for enriching those of lower-abundance: protein depletion with acetonitrile (ACN), dithiothreitol (DTT), sequential depletion using DTT and ACN, and protein equalization using commercial ProteoMiner(r) kit (PM). For proteomic evaluation, 2-D DIGE and nanoLC-MS/MS analysis were employed. RESULTS: PM method was the best strategy for removing proteins of high abundance. Through 2-D DIGE gel image comparison, 37 protein spots were found differentially abundant (p<0.05, Student's t-test), which exhibited >=2.0-fold change of the average value of normalized spot intensities in the serum of SCZ, BD and OD patients compared to subject controls (HCF and HCNF). From these spots detected, 13 different proteins were identified: ApoA1, ApoE, ApoC3, ApoA4, Samp, SerpinA1, TTR, IgK, Alb, VTN, TR, C4A and C4B. CONCLUSIONS: Proteomic analysis allowed the discrimination of patients with BD from patients with other mental disorders, such as SCZ. The findings in this exploratory study may also contribute for better understanding the pathophysiology of these disorders and finding potential serum biomarkers for these conditions. PMID- 28662996 TI - Cutaneous/subcutaneous mesenchymal proliferations of the breast. AB - Cutaneous mesenchymal "spindle cell" lesions arising in the vicinity of the breast represent a complex clinical and diagnostic scenario which may overlap histopathologically and immunohistochemically with mammary spindle cell proliferations, potentially impacting management and overall prognostication. In this review, we suggest a pattern-based approach to assist in the evaluation of these lesions. A comprehensive description of each entity is accompanied by a cutaneous and mammary differential diagnosis. PMID- 28662997 TI - Next generation immunohistochemistry: Emerging substitutes to genetic testing? AB - The identification of at-risk kindreds facilitates screening and risk reduction strategies for patients with hereditary cancer predisposition syndromes. Recently, immunohistochemistry (IHC) has emerged as a cost-effective strategy for detecting or inferring the presence of mutations in both tumors and the germline of patients presenting with tumors associated with hereditary cancer predisposition syndromes. In this review we discuss the use of novel IHC markers, including PRKAR1A, beta-catenin, SDHB, fumarate hydratase and 2SC, HRASQ61R, BAP1, parafibromin and glucagon, which have either established applications or show promise for surgical pathologists to complement morphological or clinical suspicion of hereditary cancer predisposition syndromes. Specifically, we focus on Carney complex, familial adenomatous polyposis (FAP)-associated cribriform morular variant of papillary thyroid carcinoma, familial succinate dehydrogenase related pheochromocytoma/paraganglioma syndromes, hereditary leiomyomatosis and renal cell cancer (HLRCC), medullary thyroid cancer and Multiple Endocrine Neoplasia 2 (MEN2), BAP1 hereditary cancer predisposition syndrome, Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT), and Pancreatic Neuroendocrine Tumor Syndrome (Mahvash disease). PMID- 28662998 TI - Hematolymphoid lesions of the breast. AB - Hematolymphoid malignancies of the breast are most commonly neoplasms of mature B lymphocytes, and may arise as a primary disease or by secondary involvement of a systemic disease. Primary breast lymphomas (PBL) account for 0.04-0.5% of breast malignancies, less than 1% of all non-Hodgkin's lymphomas (NHL), and less than 5% of extranodal lymphomas (Lakhani et al., 2012; Swerdlow et al., 2008; Joks et al., 2011; Barista et al., 2000; Giardini et al., 1992; Brogi and Harris, 1999; Topalovski et al., 1999).1-7 Secondary breast lymphomas (SBL) are also rare, with an estimated annual incidence of 0.07% (Domchek et al., 2002; Talwalkar et al., 2008).8,9 Recognition of breast lesions as hematolymphoid is critical to distinguish them from other entities that can occur in the breast. PMID- 28662999 TI - Lipomatous tumors of the breast: A contemporary review. AB - Breast tumors with lipomatous or liposarcomatous components are infrequently encountered, but can be a source of diagnostic difficulty if the context of the fatty differentiation is not recognized. Among the true adipocytic tumors, lipoma is the most common lipomatous tumor arising in the breast. Several mammary spindle cell tumors may show adipocytic differentiation, including fibroepithelial tumors and myofibroblastoma. Liposarcomatous components most often arise in malignant phyllodes tumors, as opposed to primary liposarcomas of the breast which are believed to be uncommon. This article will review the spectrum fat-containing tumors of the breast with an emphasis on differential diagnosis and insights from recent molecular studies. PMID- 28663000 TI - Skewed X-chromosome inactivation and XIST locus methylation levels do not contribute to the lower prevalence of Parkinson's disease in females. AB - Parkinson's disease (PD) is a degenerative disorder of the nervous system and the cause of the majority of sporadic cases is unknown. Females are relatively protected from PD as compared with males and linkage studies suggested a PD susceptibility locus on the X chromosome. To determine a putative association of skewed X-chromosome inactivation (XCI) and PD, we examined XCI patterns using a human androgen receptor gene-based assay (HUMARA) and did not identify any association of skewed or random X inactivation with clinical heterogeneity among female PD patients. In addition, we sought to determine methylation-specific changes at the X-inactive specific transcript (XIST) locus, which is known to be responsible for initiating X inactivation. We observed a trend towards hypomethylation in the gene body region of the XIST locus in PD females which did not reach significance. Furthermore, we extended our analysis of DNA methylation across the entire X-chromosome which revealed no methylation-specific differences between PD females and healthy controls. Thus, we propose that skewed XCI and methylation levels on the entire X chromosome did not reveal changes which could account for the decreased PD susceptibility in females or suitable to use as a biomarker. PMID- 28663001 TI - A plate-based histo-blood group antigen binding assay for evaluation of human norovirus receptor binding ability. AB - Human norovirus is a leading cause of gastroenteritis worldwide. Although two in vitro cultivation methods have been reported, they cannot provide mechanistic insights into viral inactivation. Receptor-binding assays supplement these assays and give insight into capsid integrity. We present a streamlined version of a receptor-binding assay with minimal time-to-result while maintaining accuracy and high throughput. We validate assay performance for physical and chemical inactivation treatments of a norovirus GII.4 capsid. The assay produces a high positive/negative ratio (25.3 +/- 4.9) in <2.5 h and has a limit of detection of 0.1 MUg/ml capsid. This method is a valuable additional tool for understanding human norovirus inactivation. PMID- 28663003 TI - Postoperative radiotherapy after DCIS: Useful for whom? AB - The number of patients with ductal carcinoma in situ (DCIS) increases with more widely used screening mammography programs. DCIS accounts for approximately 20% of all new breast cancer diagnoses in these programs and the natural course of this heterogeneous group of pre-invasive lesions is not fully known. Better definition of subgroups benefitting from radiotherapy and knowledge on the natural course of DCIS are important issues for the future management of DCIS. Four large randomized trials have studied the effects of postoperative radiotherapy after breast conserving surgery in patients with wider spectrum of DCIS and all of them have shown radiotherapy to halve the risk of ipsilateral events, however, without any significant effect on breast cancer mortality. SweDCIS is one of these four randomized trials (n = 1046) and with 20 years follow-up the relative risk reduction for an ipsilateral event was 37.5% and the absolute reduction was 12%. For an in-situ ipsilateral event the absolute reduction was 10% and for an invasive ipsilateral event the reduction was 2%. The reduction of new events in the SweDCIS was most evident during the first decade after treatment. In RTOG 9804 patients in a good-risk subset of DCIS were randomized to radiotherapy or not and with seven years of follow-up the ipsilateral local failure rate was 0.9% and 6.7% in the two arms, respectively. Radiotherapy to the conserved breast may also give long-term side effects in a small proportion of the patients, in which experience of breast pain is the most common, reported in about 10% of the patients. With modern radiotherapy techniques the dose to the heart can be restricted to low levels and meta analyses from the randomized DCIS trials showed no difference in non-breast cancer mortality. Several factors in different trials have shown to influence the risk for an ipsilateral event: age, size, grade, necrosis, clear margin, and detected on mammography or not. But identification of subgroups without relative efficacy of radiotherapy has been challenging to find. The Van Nuys prognostic index and the nomogram from the Memorial Sloan-Kettering take several of these factors into account. These and genomic assays may help to optimize the treatments of patients with DCIS. Still, radiotherapy after breast conserving surgery is the standard of care for a majority of DCIS patients. For some low risk DCIS patients accepting a slight increased risk of an ipsilateral event it is reasonable to omit radiotherapy after close communication with the patient about pros and cons of radiotherapy. PMID- 28663002 TI - Autoantibodies in juvenile-onset myositis: Their diagnostic value and associated clinical phenotype in a large UK cohort. AB - OBJECTIVES: Juvenile myositis is a rare and heterogeneous disease. Diagnosis is often difficult but early treatment is important in reducing the risk of associated morbidity and poor outcomes. Myositis specific autoantibodies have been described in both juvenile and adult patients with myositis and can be helpful in dividing patients into clinically homogenous groups. We aimed to explore the utility of myositis specific autoantibodies as diagnostic and prognostic biomarkers in patients with juvenile-onset disease. METHODS: Using radio-labelled immunoprecipitation and previously validated ELISAs we examined the presence of myositis specific autoantibodies in 380 patients with juvenile onset myositis in addition to, 318 patients with juvenile idiopathic arthritis, 21 patients with juvenile-onset SLE, 27 patients with muscular dystrophies, and 48 healthy children. RESULTS: An autoantibody was identified in 60% of juvenile onset myositis patients. Myositis specific autoantibodies (49% patients) were exclusively found in patients with myositis and with the exception of one case were mutually exclusive and not found in conjunction with another autoantibody. Autoantibody subtypes were associated with age at disease onset, key clinical disease features and treatment received. CONCLUSIONS: In juvenile patients the identification of a myositis specific autoantibody is highly suggestive of myositis. Autoantibodies can be identified in the majority of affected children and provide useful prognostic information. There is evidence of a differential treatment approach and patients with anti-TIF1gamma autoantibodies are significantly more likely to receive aggressive treatment with IV cyclophosphamide and/or biologic drugs, clear trends are also visible in other autoantibody subgroups. PMID- 28663004 TI - Evaluation of margins in invasive carcinoma and ductal carcinoma in situ: The pathologist's perspective. PMID- 28663005 TI - Music-based interventions in neurological rehabilitation. AB - During the past ten years, an increasing number of controlled studies have assessed the potential rehabilitative effects of music-based interventions, such as music listening, singing, or playing an instrument, in several neurological diseases. Although the number of studies and extent of available evidence is greatest in stroke and dementia, there is also evidence for the effects of music based interventions on supporting cognition, motor function, or emotional wellbeing in people with Parkinson's disease, epilepsy, or multiple sclerosis. Music-based interventions can affect divergent functions such as motor performance, speech, or cognition in these patient groups. However, the psychological effects and neurobiological mechanisms underlying the effects of music interventions are likely to share common neural systems for reward, arousal, affect regulation, learning, and activity-driven plasticity. Although further controlled studies are needed to establish the efficacy of music in neurological recovery, music-based interventions are emerging as promising rehabilitation strategies. PMID- 28663007 TI - Ventral concavity and musculature arrangement in notocotylid maritae (Digenea: Notocotylidae). AB - Maritae of family Notocotylidae have no ventral sucker, an organ that serves for attachment in many other digeneans. Instead, attachment is accomplished through the ventral concavity which is formed by the whole body. Musculature providing such an attachment was previously described only in part, and specific patterns of body-wall and internal muscle arrangement in notocotylids have never been studied before. In this paper we describe muscle system organization in maritae of three notocotylid species by means of fluorescent actin staining and confocal microscopy. A very special U-shaped pattern of body-wall longitudinal muscle fibres is found to support the ventral concavity. Together with very prominent dorsoventral musculature this pattern must play a key role in actions of ventral concavity. Other details concerning the muscle system are provided, including the musculature of ventral protrusions, oral sucker, walls of digestive tract and reproductive organs. We discuss functionality of the musculature and also make comparisons with cercariae of this family. PMID- 28663006 TI - Effect of an emergency department opioid prescription policy on prescribing patterns. AB - BACKGROUND: Staten Island University Hospital is located in NYC, where the opioid epidemic has resulted in significant mortalities from unintentional overdoses. In 2013 as a response to the rising threat to our community, our Emergency Department (ED) administration adopted a clinical practice policy focused on decreasing the prescription of controlled substances. The effects of this policy on our provider prescription patterns are presented here. METHODS: A retrospective chart review of patients prescribed opioids from the ED before and after policy implementation was performed. Dates chosen for analysis was November 1, 2012 through January 31, 2013 and November 1, 2013 through January 31, 2014; these time periods were used to serve as a seasonally comparative group pre and post clinical practice policy implementation. Opioids written for the treatment of cough, and for children under eighteen were excluded from analysis. Patient age, sex, diagnoses, and prescription formulation, strength, and pill number was recorded for each patient receiving an opioid prescription. RESULTS: There was a drop in the total prescriptions from 1756 to 1128 without a change in the average number of pills (12.78 vs 12.44) or average total dose prescribed (69.39 vs 68.98) mg of morphine equivalent per prescription. Additionally, there were sizable reductions in opioid prescriptions written for arthralgias/myalgias, dental pain, soft tissue injuries, and headaches. CONCLUSION: The opioid clinical policy had a clear effect in decreasing the number of patients prescribed opioids. Such policies may be the key to reducing the epidemic and saving lives from unintentional opioid overdoses. PMID- 28663008 TI - A new species of Eimeria (Apicomplexa: Eimeriidae) from Californian rabbits in Hebei Province, China. AB - Rabbit coccidiosis is caused by infection with one or usually several Eimeria species, parasitizing in hepatobiliary ducts or intestinal epithelium of rabbits. To date, 11 species of rabbit coccidia have been well documented. Here we report a new species of Eimeria from rabbits. Sporulated oocysts were ellipsoidal to slightly ovoidal, 37.4 (32.6-41.2) MUm in length, 23.5 (20.9-25.5) MUm in width, with a shape index (length/width) 1.6 (1.43-1.91) and smooth, bilayered, homogeneously thick wall. The micropyle was obvious and with an inner diameter of 6.2 (5.0-7.5) MUm. Both oocyst residuum and polar granule were absent. Sporocysts were ellipsoidal to elongate, 17.2 (13.2-20.0) MUm long and 8.4 (7.5-9.1) MUm wide, with a shape index (length/width) of 2.1 (1.74-2.21) and the presence of Stieda body and sporocyst residuum. The prepatent period was 132h. Phylogenetic analysis showed that 18S rDNA sequence of the new species clustered together with the 11 rabbit Eimeria species into a clade. However, ITS-1 sequence of the new species shared low similarities (27.1%-30%) with those of 11 rabbit Eimeria species. As the data above supported the erection of a new species, we named it as Eimeria kongi n. sp., in honor of Fanyao Kong, a Chinese parasitologist. The finding of the new species has important implications for the diagnosis and prevention of rabbit coccidiosis. PMID- 28663009 TI - The potent cell permeable calpain inhibitor MDL28170 affects the interaction of Leishmania amazonensis with macrophages and shows anti-amastigote activity. AB - Since the discovery of the28 first drugs used in leishmaniasis treatment up to now, the search for compounds with anti-Leishmania activity without toxic effects and able to overcome the emergency of resistant strains remains a major goal to combat this neglected disease. With this in mind, in the present work, we evaluated the effects of the calpain inhibitor MDL28170 on the interaction process of Leishmania amazonensis promastigote forms with murine peritoneal macrophages and on the intracellular amastigotes. Our results showed that the calpain inhibitor MDL28170 at 15 and 30MUM significantly reduced the interaction process of promastigotes with macrophages by 16% and 41%, respectively. The inhibitor was also able to drastically reduce the number of infected macrophages in a time- and dose-dependent manner: after only 24h, MDL28170 was able to significantly diminish the infection rate, presenting an IC50 value of 18.2MUM for amastigotes. The treatment with MDL28170 did not alter the nitric oxide production, but the production of TNF-alpha was significantly raised. Altogether, the results presented here contribute to the search of new proteolytic inhibitors able to act in a selective and effective manner against the diseases caused by trypanosomatids. PMID- 28663010 TI - Intravenous Fibrinolysis in Ischemic Stroke of Large Vessel after Reversing Effect of Dabigatran with Idarucizumab. AB - Currently the use of idarucizumab to reverse the effect of dabigatran emerges as a possibility of treatment for those patients who present with an ischemic stroke despite taking this anticoagulant. We present our experience regarding the use of intravenous tissue plasminogen activator in a patient with ischemic stroke due to complete occlusion of the left middle cerebral artery after blocking the effect of dabigatran with idarucizumab and whose result was an almost total improvement of the neurologic deficit. The use of this monoclonal antibody without a prothrombotic effect seems safe to be an intravenous fibrinolytic treatment option for patients taking dabigatran and having an ischemic stroke; however, more extensive studies are needed to determine its safety and efficacy. PMID- 28663011 TI - Evoked and event-related potentials in disorders of consciousness: A quantitative review. AB - Sixty-one publications about evoked and event-related potentials (EP and ERP, respectively) in patients with severe Disorders of Consciousness (DoC) were found and analyzed from a quantitative point of view. Most studies are strongly underpowered, resulting in very broad confidence intervals (CI). Results of such studies cannot be correctly interpreted, because, for example, CI>1 (in terms of Cohen's d) indicate that the real effect may be very strong, very weak, or even opposite to the reported effect. Furthermore, strong negative correlations were obtained between sample size and effect size, indicating a possible publication bias. These correlations characterized not only the total data set, but also each thematically selected subset. The minimal criteria of a strong study to EP/ERP in DoC are proposed: at least 25 patients in each patient group; as reliable diagnosis as possible; the complete report of all methodological details and all details of results (including negative results); and the use of appropriate methods of data analysis. Only three of the detected 60 studies (5%) satisfy these criteria. The limitations of the current approach are also discussed. PMID- 28663012 TI - Planned experiments and corpus based research play a complementary role: Comment on "Dependency distance: A new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28663013 TI - Dependency distance: A new perspective on the syntactic development in second language acquisition: Comment on "Dependency distance: A new perspective on syntactic patterns in natural language" by Haitao Liu et al. PMID- 28663014 TI - Generalizing dependency distance: Comment on "Dependency distance: A new perspective on syntactic patterns in natural languages" by Haitao Liu et al. AB - With the support of the comprehensive review in Liu et al. [14], we consider dependency distance minimization to be firmly established as a quantitative property of syntactic trees. In this comment, we consider future empirical and theoretical directions for this concept, including a recent information-theoretic reinterpretation of dependency locality effects as proposed by Futrell and Levy [4]. PMID- 28663015 TI - Parent oriented teacher selection causes language diversity. AB - An evolutionary model for emergence of diversity in language is developed. We investigated the effects of two real life observations, namely, people prefer people that they communicate with well, and people interact with people that are physically close to each other. Clearly these groups are relatively small compared to the entire population. We restrict selection of the teachers from such small groups, called imitation sets, around parents. Then the child learns language from a teacher selected within the imitation set of her parent. As a result, there are subcommunities with their own languages developed. Within subcommunity comprehension is found to be high. The number of languages is related to the relative size of imitation set by a power law. PMID- 28663016 TI - Activity determination of 68Ge/68Ga by means of 4pibeta(C)-gamma coincidence counting. AB - Germanium-68 is an important radionuclide since it is used to generate its daughter 68Ga which is frequently used for positron emission tomography (PET). In addition, 68Ge/68Ga sources are often used as surrogates for short-lived PET isotopes when calibrating instruments. In this work, 4pibeta(C)-gamma coincidence counting was used to determine the activity concentration of a 68Ge/68Ga solution. The presented measurements were made by means of a new PTB-custom-built 4pi(LS)beta-gamma coincidence counting system, where a liquid scintillation detector in the beta channel can also be used as a Cerenkov counter, and a NaI(Tl) crystal detects annihilation radiation. The arithmetic mean of two results (from double ND and triple NT coincidences in the beta channel) was adopted as the final result for the activity concentration of the solution under study. The overall relative uncertainty was estimated to be 0.82% and the uncertainty consideration as well as details about the measurement and the analysis are discussed. The measurements were carried out within the scope of the international CCRI(II)-K2.Ge-68 comparison. PMID- 28663017 TI - The application of a delayed expansion technique for horizontal alveolar ridge augmentation in dental implantation. AB - The aim of this study was to evaluate the application of delayed expansion of the alveolar ridge in dental implantation. This method avoids the need to harvest autogenous bone and the requirement to fix a block with screws, and could help prevent the uncontrolled fracture and avascular necrosis that may result from the traditional alveolar split. Eighteen patients and 43 implants were included in this retrospective study. The width of the alveolar ridge was measured before implantation, immediately after implantation, and after the final restoration. The width increased significantly after the insertion of implants and decreased slightly after bone remodelling. Overall, the width of the alveolar ridge increased by 2.37+/-1.44mm on average, ranging from -0.20mm to 5.75mm. The results suggest the use of delayed expansion for horizontal alveolar bone augmentation; however, the maxillary premolar area may not be a suitable site. PMID- 28663018 TI - Intraoral vertico-sagittal ramus osteotomy: modification of the L-shaped osteotomy. AB - The sagittal split ramus osteotomy and intraoral vertical ramus osteotomy carry the potential risk of postoperative nerve paralysis, bleeding, and fracture and dislocation of the condyle. In 1992, Choung first described the intraoral vertico sagittal ramus osteotomy for the purpose of avoiding postoperative dislocation of the condyle. However, there is still potential for damaging the inferior alveolar nerve and maxillary artery with this technique. The authors have developed a modified technique to minimize these risks. An evaluation of surgical experience and patient outcomes with the use of this technique is presented herein. One hundred twenty-two sides in 97 Japanese patients diagnosed with a jaw deformity were analyzed. This technique includes a horizontal osteotomy that is performed at a higher position than in the original Choung procedure. Intraoperatively, there was no unexpected bleeding from the operative site. Proximal segment dislocation from the glenoid fossa was observed on one side (0.82%). Non-union of the osteotomy was not observed in any patient. Intraoperative fracture of the coronoid process occurred in 2.46%, but none necessitated treatment of the fracture. Nerve dysfunction was found in 2.46% at the 12-month postoperative follow-up. The modified technique presented herein was developed to reduce postoperative nerve dysfunction and intraoperative hemorrhage. PMID- 28663019 TI - Do antiplatelet drugs increase the risk of bleeding after tooth extraction? A case-crossover study. AB - The aim of this study was to assess the risk of bleeding after tooth extraction in patients taking aspirin or clopidogrel. This case-crossover study evaluated patients taking aspirin (80mg/day) or clopidogrel (75mg/day) and undergoing tooth extraction. In the first session, extraction was performed without discontinuing aspirin (group 1) or clopidogrel (group 2). In the second session, patients ceased using antiplatelet drugs 5days prior to tooth extraction. Bleeding was evaluated using a visual analogue scale (VAS) for 72h after tooth extraction. The platelet function assay (PFA) was performed for group 1 and flow cytometry assessment of vasodilator-stimulated phosphoprotein (VASP) was performed for group 2, in both sessions. Thirty-eight patients were studied: 20 in group 1 and 18 in group 2. Analysis of the data did not demonstrate any difference in bleeding severity between sessions 1 and 2 in either group (P>0.05). There was a significant difference between sessions 1 and 2 in group 1 for the mean collagen/epinephrine membrane closure time (PFA) (P=0.001). A significant difference in platelet reactivity index (flow cytometry for VASP) was noted between sessions 1 and 2 in group 2 (P=0.001). According to this case-crossover study, dental extraction can be performed safely without withdrawal of aspirin or clopidogrel. PMID- 28663020 TI - Treatment of End-Stage Hallux Rigidus Using Total Joint Arthroplasty: A Short Term Clinical Study. AB - The treatment of advanced hallux rigidus remains controversial. Only a few studies have analyzed the short- and mid-term results of metatarsophalangeal (MTP) joint arthroplasty to treat patients with advanced hallux rigidus. We present the short-term follow-up results of patients who underwent MTP joint arthroplasty. We reviewed the medical records of 15 consecutive patients (3 males and 12 females) who had had grade 3 or 4 hallux rigidus diagnosed according to the Coughlin and Shurnas classification. The age range at surgery was 44 to 74 (mean 61.6) years. The mean follow-up period was 21.7 (range 18 to 28) months. The mean change in the overall American Orthopaedic Foot and Ankle Society Hallux First Ray scale score was from 26.9 +/- 2.3 preoperatively to 78.7 +/- 8.8 postoperatively (p < .005). The mean change in the overall visual analog scale score was from 8.3 +/- 0.8 preoperatively to 1.7 +/- 0.7 postoperatively (p < .005). The mean preoperative first MTP joint range of motion was 22.3 degrees +/ 7.7 degrees (range 15 degrees to 45 degrees ), which had increased to 77 degrees (range 65 degrees to 90 degrees ) at the final follow-up visit. No patient required revision surgery or removal. These results indicate that for patients with advanced-stage hallux rigidus refractory to conservative treatment, total joint arthroplasty can lead to good satisfaction and good functional results in the short term. PMID- 28663021 TI - Comparative analysis of diabetes self-management education programs in the European Union Member States. AB - Diabetes self-management education (DSME) is generally considered as an integral part of diabetes care. The availability of different types of self-management in the European Union Member States (EUMS) remains uncertain. The aim of this study is to perform a comparative analysis of existing DSME programs (DSMEP) implemented in EUMS. Unpublished data regarding DSME in the EUMS was assessed with Diabetes Literacy Survey using wiki tool (WT) targeting patients and different stakeholders. An additional literature review (LR) was performed in PubMed to identify published studies regarding DSMEP in the EUMS from 2004 to 2014. A total of 102 DSMEP implemented in EUMS were reported in the WT and 154 programs were identified from the LR. Comparative analysis of the data indicated that a majority of programs are aimed at adults and only a minority at children and elderly. Only a small percentage of the programs utilize information technology for teaching and learning, and only one out of five programs pay attention to depression. The identified DSMEP aimed primarily to empower patients through increasing knowledge and changing attitudes and beliefs towards diabetes. This study provides an overview of the present state-of-the-art on diabetes self management education programs in the 28 EUMS. To increase participation, existing DSMEP should be made more accessible to the patients as well as tailored to specific patient groups. PMID- 28663022 TI - The impact of an intervention to improve diabetes management in primary healthcare professionals' practices in Brazil. AB - AIMS: To evaluate the results of a structured intervention in primary healthcare to improve type 2 diabetes management. METHODS: The intervention was implemented in 2011-2012 in two cities in the State of Pernambuco, Brazil, and evaluated in 2013 by interviewing healthcare professionals about their practices in all primary care facilities of these two cities (intervention group), and of two paired control cities (control group). Comparisons between the intervention and control groups were made using standard parametric tests. RESULTS: The percentage of professionals who measured adherence to treatment, developed educational actions to control high-risk situations or prevent complications, or declared that they "explained" the disease to the patients, was higher in the control group (p<0.05). Multidisciplinary involvement, requests for electrocardiograms and referrals to specialists were also more frequent in the control group (p<0.01). The only differences favoring the intervention group were the higher proportion of nurses (p<0.05) and community health workers (p<0.01) trained for diabetes management and a greater frequency of discussing the cases of diabetic patients at team meetings (p<0.01). CONCLUSIONS: These negative results raise questions about the effectiveness of actions aiming to improve diabetes management in primary care, and reinforce the need for careful evaluation of their impact. PMID- 28663023 TI - Epidemiological trends and direct costs of diabetes in a Northern Italy area: 2012 health administrative records analysis LHT n. 20 Verona. AB - OBJECTIVE: This analysis estimates type 1 and type 2 diabetes direct costs in 2012, in terms of hospital care, outpatient visits, diagnostics and medications, in a local healthcare trust in Northern Italy (ULSS n.20 Verona). METHODS: The Johns Hopkins Adjusted Clinical Group (ACG(r)) System was used to analyze data, including hospital discharges, emergency room admissions, medical encounter records, disease registries, copayment exemptions, home care services, psychiatric services, rehabilitation services, and medications. Data from general practitioners and nursing homes were not directly available. Patients obtained from the first analysis were subsequently divided in two groups (type 1 and type 2 diabetes) according to ATC drug classification system and age. Costs were estimated from inpatient and outpatients fees and drugs costs. RESULTS: ULSS n. 20 takes care of about 480.000 people. We identified 974 people affected by type 1 diabetes (prevalence 0,2%) and 24.087 people affected by type 2 diabetes (prevalence 5,0%) among the residents in 2012. Hospitalization mean annual cost was 4.753,50? (SD 9.330,19?) for type 1 diabetes and 1.718,08? (SD 5.087,34?) for type 2 diabetes. Outpatient care mean annual cost was 1.401,76? (SD 4.394,88?) for type 1 diabetes and 669,15? (SD 2.121,24?) for type 2 diabetes. Medications mean annual cost was 1,369,35? (SD1.781,18?) for type 1 diabetes and 874,07? (SD 2.832,2?) for type 2 diabetes. CONCLUSIONS: ACG(r) diabetes data analysis agrees with data obtained by more expensive methods and seems to be a comprehensive and applicable tool to analyze chronic diseases dynamics in the Italian setting in order to prioritize future research and analyze the effects of interventions aimed to ensure the sustainability of public health services. Because of the combination between prevalence data and epidemiological trends, we could be at the eve of a dramatic increase of diabetes costs with major concerns for the Italian NHS ability to withstand. PMID- 28663024 TI - Comparison and evaluation of marginal and internal gaps in cobalt-chromium alloy copings fabricated using subtractive and additive manufacturing. AB - PURPOSE: To evaluate the marginal and internal gaps of cobalt-chromium (Co-Cr) alloy copings fabricated using subtractive and additive manufacturing. METHODS: A study model of an abutment tooth 46 was prepared by a 2-step silicone impression with dental stone. Fifteen stereolithography files for Co-Cr alloy copings were compiled using a model scanner and dental CAD software. Using the lost wax (LW), wax block (WB), soft metal block (SMB), microstereolithography (MU-SLA), and selected laser melting (SLM) techniques, 15 Co-Cr alloy copings were fabricated per group. The marginal and internal gaps of these Co-Cr alloy copings were measured using a digital microscope (160*), and the data obtained were analyzed using the non-parametric Kruskal-Wallis H-test and post-hoc Mann-Whitney U-test with Bonferroni correction. RESULTS: The mean values of the marginal, axial wall, and occlusal gaps were 91.8, 83.4, and 163MUm in the LW group; 94.2, 77.5, and 122MUm in the WB group; 60.0, 79.4, and 90.8MUm in the SMB group; 154, 72.4, and 258MUm in the MU-SLA group; and 239, 73.6, and 384MUm in the SLM group, respectively. The differences in the marginal and occlusal gaps between the 5 groups were statistically significant (P<.05). CONCLUSIONS: The marginal gaps of the LW, WB, and SMB groups were within the clinically acceptable limit, but further improvements in the MU-SLA and SLM approaches may be required prior to clinical implementation. PMID- 28663025 TI - What rodent models of deep brain stimulation can teach us about the neural circuit regulation of prepulse inhibition in neuropsychiatric disorders. AB - Deep brain stimulation (DBS) is routinely used for treatment of movement disorders and it is also under investigation for neuropsychiatric disorders with deficient sensorimotor gating, such as schizophrenia, Tourette's syndrome and obsessive compulsive disorder. Electrical stimulation induces excitation and inhibition both at the stimulation site and at projection sites, thus modulating synchrony and oscillatory behavior of neuronal networks. We first provide background information on DBS in neuropsychiatric disorders accompanied by deficient sensorimotor gating. We then introduce prepulse inhibition (PPI) as a measure for sensorimotor gating in these disorders. Thereafter, we report on the use of DBS in rat models with deficient PPI induced by pharmacologic, genetic and neurodevelopmental manipulation. These models offer the opportunity to define the neuronal circuit regulation that is of relevance to PPI and its deficits in neuropsychiatric disorders with disturbed sensorimotor gating. Finally, we report on the use of the PPI paradigm in human patients operated for DBS on/off stimulation, which may further elucidate the neuronal network involved in regulation of PPI. PMID- 28663026 TI - Evolution of metabolic risk factors over a two-year period in a cohort of first episodes of psychosis. AB - Patients with a first episode of psychosis (FEP) display a broad range of metabolic risk factors related to the development of diverse medical comorbidities. Initial stages of these disorders are essential in understanding the increased vulnerability of developing cardiometabolic disturbances, associated with a reduced life expectancy. This study aimed to evaluate the metabolic profile of a cohort of patients with a FEP and its evolution during a two year follow-up, as well as the factors that influence the changes in their metabolic status. 16 participating centers from the PEPs Project recruited 335 subjects with a FEP and 253 matched healthy controls, aged 9-35years. We investigated a set of anthropometric measures, vital signs and laboratory data obtained from each participant over two years in a prospective, naturalistic study. From the beginning of the study the FEP group showed differences in the metabolic profile compared to the control group, together with a progressive worsening in the major part of the analyzed variables during the follow-up period, with higher rates of obesity and metabolic syndrome. Certain risk factors were related to determinate clinical variables such as male gender, the presence of affective symptoms or an early onset or to treatment variables such as the use of antipsychotic polypharmacy, antidepressants or mood stabilizers. Our results highlight the extremely high risk of patients at early phases of schizophrenia and other psychotic disorders of developing cardiovascular comorbidity and the fast worsening of the metabolic profile during the first two years. PMID- 28663027 TI - Evaluation of adherence patterns in schizophrenia using electronic monitoring (MEMS(r)): A six-month post-discharge prospective study. AB - BACKGROUND: Medication Event Monitoring System (MEMS(r)) is considered the gold standard for the evaluation of medication adherence, yet few studies have applied this method, especially over long periods of time. OBJECTIVE: To investigate medication adherence patterns in a sample of post-discharge patients with schizophrenia monitored with MEMS caps during a six-month period. METHOD: Adherence to antipsychotics was prospectively investigated using MEMS among 68 patients with schizophrenia. Treatment initiation, implementation or whether or not the patient takes his dosing regimen as prescribed, persistence or the length of time between initiation and discontinuation, and treatment discontinuation were used to describe adherence. Persistence over time was described using Kaplan Meier curves. RESULTS: After discharge 16% of the patients never initiated treatment. On average 37.3% of patients adhered to treatment in the first 6months. However, a strong decrease in adherence was observed over time (p<0.0001), primarily due by treatment non-persistence. Only half of the patients were persistent at 6weeks, persistence further dropped to 19.0% after 6months. Among persistent patients, implementation was consistent over time with 87.8% of patients taking their medication as prescribed on any given day. CONCLUSIONS: Dosing profile analysis provides further evidence for the magnitude of non adherence with antipsychotic prescriptions among post-discharge patients with schizophrenia. Using the high precision of MEMS(r), dosing profiles may provide a better understanding of non-adherence patterns and help clinicians determine optimal individualized strategies. PMID- 28663028 TI - Dust exposure in workers from grain storage facilities in Costa Rica. AB - BACKGROUND: About 12 million workers are involved in the production of basic grains in Central America. However, few studies in the region have examined the occupational factors associated with inhalable dust exposure. OBJECTIVES: (i) To assess the exposure to inhalable dust in workers from rice, maize, and wheat storage facilities in Costa Rica; (ii) to examine the occupational factors associated with this exposure; and (iii) to measure concentrations of respirable and thoracic particles in different areas of the storage facilities. METHODS: We measured inhalable (<100MUm) dust concentrations in 176 personal samples collected from 136 workers of eight grain storage facilities in Costa Rica. We also measured respirable (<4MUm) and thoracic (<10MUm) dust particles in several areas of the storage facilities. RESULTS: Geometric mean (GM) and geometric standard deviation (GSD) inhalable dust concentrations were 2.0mg/m3 and 7.8 (range=<0.2-275.4mg/m3). Personal inhalable dust concentrations were associated with job category [GM for category/GM for administrative staff and other workers (95% CI)=4.4 (2.6, 7.2) for packing; 20.4 (12.3, 34.7) for dehulling; 109.6 (50.1, 234.4) for unloading in flat bed sheds; 24.0 (14.5, 39.8) for unloading in pits; and 31.6 (18.6, 52.5) for drying], and cleaning task [15.8 (95% CI: 10.0, 26.3) in workers who cleaned in addition to their regular tasks]. Higher area concentrations of thoracic dust particles were found in wheat (GM and GSD=4.3mg/m3 and 4.5) and maize (3.0mg/m3 and 3.9) storage facilities, and in grain drying (2.3mg/m3 and 3.1) and unloading (1.5mg/m3 and 4.8) areas. CONCLUSIONS: Operators of grain storage facilities showed elevated inhalable dust concentrations, mostly above international exposure limits. Better engineering and administrative controls are needed. PMID- 28663029 TI - Names and phenotypes of CD163 positive macrophages in oral precancerous lesions. PMID- 28663031 TI - Mutational analysis in BCR-ABL1 positive leukemia by deep sequencing based on nanopore MinION technology. AB - We report a third-generation sequencing assay on nanopore technology (MinION) for detecting BCR-ABL1 KD mutations and compare the results to a Sanger sequencing(SS)-based test in 24 Philadelphia-positive (Ph+) leukemia cases. Our data indicates that MinION is markedly superior to SS in terms of sensitivity, costs and timesaving, and has the added advantage of determining the clonal configuration of multiple mutations. We demonstrate that MinION is suitable for employment in the hematology laboratory for detecting BCR-ABL1 KD mutation in Ph+ leukemias. PMID- 28663030 TI - Early experience with formalin-fixed paraffin-embedded (FFPE) based commercial clinical genomic profiling of gliomas-robust and informative with caveats. AB - BACKGROUND: Commercial targeted genomic profiling with next generation sequencing using formalin-fixed paraffin embedded (FFPE) tissue has recently entered into clinical use for diagnosis and for the guiding of therapy. However, there is limited independent data regarding the accuracy or robustness of commercial genomic profiling in gliomas. METHODS: As part of patient care, FFPE samples of gliomas from 71 patients were submitted for targeted genomic profiling to one commonly used commercial vendor, Foundation Medicine. Genomic alterations were determined for the following grades or groups of gliomas; Grade I/II, Grade III, primary glioblastomas (GBMs), recurrent primary GBMs, and secondary GBMs. In addition, FFPE samples from the same patients were independently assessed with conventional methods such as immunohistochemistry (IHC), Quantitative real-time PCR (qRT-PCR), or Fluorescence in situ hybridization (FISH) for three genetic alterations: IDH1 mutations, EGFR amplification, and EGFRvIII expression. RESULTS: A total of 100 altered genes were detected by the aforementioned targeted genomic profiling assay. The number of different genomic alterations was significantly different between the five groups of gliomas and consistent with the literature. CDKN2A/B, TP53, and TERT were the most common genomic alterations seen in primary GBMs, whereas IDH1, TP53, and PIK3CA were the most common in secondary GBMs. Targeted genomic profiling demonstrated 92.3%-100% concordance with conventional methods. The targeted genomic profiling report provided an average of 5.5 drugs, and listed an average of 8.4 clinical trials for the 71 glioma patients studied but only a third of the trials were appropriate for glioma patients. CONCLUSIONS: In this limited comparison study, this commercial next generation sequencing based-targeted genomic profiling showed a high concordance rate with conventional methods for the 3 genetic alterations and identified mutations expected for the type of glioma. While it may not be feasible to exhaustively independently validate a commercial genomic profiling assay, examination of a few markers provides some reassurance of its robustness. While potential targeted drugs are recommended based on genetic alterations, to date most targeted therapies have failed in glioblasomas so the usefulness of such recommendations will increase with development of novel and efficacious drugs. PMID- 28663032 TI - A 90-day oral toxicity study of glycolipids from Dacryopinax spathularia in CD(r) rats. AB - The subchronic toxicity of jelly mushroom glycolipids from Dacryopinax spathularia (herein referred to as "AM-1") was studied in Crl:CD(SD) rats. The test item was administered via the drinking water at concentrations of 1.5, 5.0 or 15 mg/mL for 90 days with an additional 4-week recovery period. No test article-related deaths, clinical observations or neurological effects were noted. Decreased drinking water consumption for mid- and high-dose groups was attributable to the reduced palatability of drinking water containing higher test article concentrations. Mean body weights of high-dose males were slightly reduced beginning study week 1 due to decreased food and drinking water intake, but were not statistically significant by week 7. No test article-related adverse effects were noted for hematological or clinical chemistry, or urinalysis parameters. Statistically significant changes in select parameters were within historical control data ranges, lacked histopathological correlates, and did not occur in a consistent pattern that would suggest biological significance. Microscopic examination did not reveal any test article-related morphological changes. The no-observed-adverse-effect level (NOAEL) was considered to be 15 mg/mL (1201 and 1423 mg AM-1/kg bw/day for male and female rats, respectively). These results support the safety assessment of jelly mushroom glycolipids for potential use in food. PMID- 28663033 TI - Letter to the editor regarding "GRAS from the ground up: Review of the Interim Pilot Program for GRAS notification" by. AB - Present letter is aimed at clarifying some critical points highlighted by Hanlon et al. regarding the common knowledge element of the safety of food enzymes in support of their GRAS designation. Particularly, we outline the development of peer-reviewed, generally recognized safety evaluation methodology for microbial enzymes and its adoption by the enzyme industry, which provides the US FDA with a review framework for enzyme GRAS Notices. This approach may serve as a model to other food ingredient categories for a scientifically sound, rigorous, and transparent application of the GRAS concept. PMID- 28663034 TI - Interference of ursolic acid treatment with glioma growth: An in vitro and in vivo study. AB - Glioblastoma multiforme is the most devastating tumor in the brain. Ursolic acid (UA) is found in a variety of plants, and exhibits several pharmacological activities. In this study, we investigated the effects of UA in vitro, clarifying the mechanisms that mediate its toxicity and the long-lasting actions of UA in C6 glioma cells. We also evaluated the antitumor activity of UA in an in vivo orthotopic glioma model. Cell numbers were assessed using the Trypan blue exclusion test, and the cell cycle was characterized by flow cytometry using propidium iodide staining. Apoptosis was analyzed using an Annexin V kit and by examining caspase-3. Akt immunocontent was verified by Western blot and the long lasting actions of UA were measured by cumulative population doubling (CPD). In vivo experiments were performed in rats to measure the effects on tumor size, malignant features and toxicological parameters. In vitro results showed that UA decreased glioma cell numbers, increased the sub-G1 fraction and induced apoptotic death, accompanied by increased active caspase-3 protein levels. Akt phosphorylation/activation in cells was also diminished by UA. With regard to CPD, cell proliferation was almost completely restored upon single UA treatments, but when the UA was added again, the majority of cells died, demonstrating the importance of re-treatment cycles with chemotherapeutic agents for abolishing tumor growth. In vivo, ursolic acid slightly reduced glioma tumor size but did not decrease malignant features. Ursolic acid may be a potential candidate as an adjuvant for glioblastoma therapy. PMID- 28663035 TI - Inhibition of interleukin-6 function attenuates the central sensitization and pain behavior induced by osteoarthritis. AB - Chronic pain is the most prominent and disabling symptom in the patients with osteoarthritis (OA), and the underlying mechanism largely remains unclear. Interleukin-6 (IL-6), a proinflammatory cytokine, is critically involved in the development and maintenance of central sensitization in several rodent models of chronic pain. The present study aims to elucidate the IL-6 mediated neurological adaptation in dorsal horn in the rat with monosodium iodoacetate (MIA) - induced OA. Significant upregulation of IL-6 expression was detected in the dorsal horn in the modeled rats. Blockade of IL-6 function by tocilizumab markedly suppressed the activation of astrocytes and microglia in the ipsilateral dorsal horn, reduced c-Fos immunoreactivity in dorsal horn neurons, and attenuated the upregulation of glutamate receptor subunits GluR1 and NR2B in dorsal horn in the rats with MIA-induced OA. It was further reported that administration of tocilizumab significantly improved the performance in weight-bearing test and mitigated the mechanical allodynia in the modeled rats. These data illustrated spinal IL-6 mediated mechanism underlying the chronic pain, and proposed the potential therapeutic effect of tocilizumab on the chronic pain in the setting of OA. PMID- 28663036 TI - Population-based Semen Analysis Results and Fertility Among Patients With Inflammatory Bowel Disease: Results From Subfertility Health Assisted Reproduction and the Environment (SHARE) Study. AB - OBJECTIVE: To evaluate male fertility in Crohn disease (CD) and ulcerative colitis (UC) by examining semen analysis results and paternity from the SHARE study (Subfertility Health Assisted Reproduction and the Environment), a population-based cohort of semen analysis results from Utah men. METHODS: A population-based cohort of men with CD or UC was identified using the Utah Population Database (contains person-level linked demographic, genealogical, and medical record information for 85% of Utahans) from 1996 to 2014, and validated by clinical chart review. This cohort was then cross-linked (n = 55) to the SHARE population dataset of semen analysis results. Men with CD or UC were compared with population-based, age-matched, paired (1:1) controls (n = 47). Paternity was evaluated though presence and number of linked offspring and inter-birth interval. RESULTS: Offspring were identified in 71% of UC patients (mean of 1.8 children) and 61% of CD patients (mean of 1.2 children). Compared with matched controls, there were no differences in number of offspring, mean inter-birth interval, or any of the evaluated semen analysis parameters among either men with CD or UC. CONCLUSION: Fertility and semen analysis values among men with UC or CD are not significantly impacted compared with population-based, age-matched controls. PMID- 28663037 TI - Freeze dried solid dispersion of exemestane: A way to negate an aqueous solubility and oral bioavailability problems. AB - This study was envisaged to demonstrate the potential of exemestane loaded phospholipid/sodium deoxycholate solid dispersions (EXE-PL/SDC-SDs) on the solubility and oral bioavailability of EXE. Initial studies were performed to screen the best suitable phospholipid among lysophosphatidylcholine, Phospholipon(r) P80H and Lipoid(r) E80S for solid dispersion preparation. Further studies were carried out to optimize the molar concentration of phospholipid and sodium deoxycholate (SDC) for EXE-PL/SDC-SDs preparation. Optimized EXE-PL/SDC SDs was prepared using Lipoid(r) E80S and SDC in 1:4M concentration, respectively and lyophilized using 10% w/w 2-hydroxypropyl-beta-cyclodextrin (2-HPCD). The physical state of EXE in lyophilized formulation was confirmed by DSC and PXRD. Lyophilized formulation exhibits a significant increase in solubility and dissolution rate as compared to free drug EXE. Apparent permeability study was performed on Caco-2 cell line for 2h. The lyophilized EXE-PL/SDC-SDs exhibits 4.6 fold increase in absorptive transport as compared to EXE. Pharmacokinetic study in fasted female Sprague-Dawley rats revealed a 2.3-fold increase in AUC0-72h. Thus, the results suggest that PL/SDC-SDs is a promising carrier for EXE delivery. PMID- 28663038 TI - Measuring fatigue with multiple instruments in a Brazilian cohort of early rheumatoid arthritis patients. AB - OBJECTIVE: To assess the prevalence of fatigue in a Brazilian population with early rheumatoid arthritis using multiple instruments, and the predictors of these instruments by differents independent variables. METHODS: Cross-sectional study with direct interview and medical records review. Fatigue, dependent variable, was assessed using eight instruments: Profile of Mood States (POMS), Multidimensional Assessment of Fatigue scale (MAF), Fatigue Severity Scale (FSS), Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ), Numerical Rating Scales (BRAF-NRS), Short-form Survey 36 (SF-36), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F) and Visual Analogic Scale for Fatigue (VASf). INDEPENDENT VARIABLES: sociodemographic, clinical and serological, were measured using medical records and direct interview. Disability and disease activity were assessed using the Health Assessment Questionnaire (HAQ) and disease activity assessed using the Disease Activity Score 28 joints (DAS28). The scores of scales demonstrated the level of fatigue and multiple linear regression method used in statistical analysis to demonstrate prediction models. RESULTS: A total of 80 patients was assessed, and 57 reported clinically relevant fatigue (VASf>2), representing 71.25% prevalence point (51 women [89.5%], mean age 48.35+/-15 years, and mean disease duration of 4.92+/-3.8 years). Eight predictive models showed statistical significance, one for each fatigue instrument. The highest coefficient of determination (R2) was 56% for SF 36 and the lowest (R2=21%) for FSS. The HAQ was the only independent variable to predict fatigue on all instruments. CONCLUSION: Clinically relevant fatigue is a highly prevalent symptom and is mostly predicted by disability and age in the population assessed. PMID- 28663039 TI - The Relationship Between CRP and MACE: Controversial and Confounded. PMID- 28663041 TI - Maternal intake of cashew nuts accelerates reflex maturation and facilitates memory in the offspring. AB - Essential fatty acids, being indispensable during the stages of pregnancy, lactation and infancy influence the transmission of nerve impulses and brain function, and cashew nuts are a good source of these fatty acids. The objective of this study was to evaluate the effects of cashew nut consumption on reflex development, memory and profile of fatty acids of rat offspring treated during pregnancy and lactation. The animals were divided into three groups: Control (CONT), treated with 7% lipid derived from soybean oil; Normolipidic (NL) treated with 7% lipids derived from cashew nuts; and Hyperlipidic (HL) treated with 20% lipids derived from cashew nuts. Reflex ontogeny, Open-field habituation test and the Object Recognition Test (ORT) were assessed. The profile of fatty acids in the brain was carried out when the animals were zero, 21 and 60days old. Accelerated reflex maturation was observed in animals treated with cashew nuts (p<0.05). NL presented better memory in the Open-field habituation test; the NL and HL showed improvement of short-term memory in the ORT, but long term damage in HL (p<0.05). The results of the lipid profile of the brain at the end of the experiment showed an increase in levels of saturated fatty acids and less Docosahexaenoic acid (DHA) in animals of the HL. The data showed that maternal consumption of cashew nuts can accelerate reflex maturation and facilitate memory in offspring when offered in adequate quantities. PMID- 28663040 TI - Aortic Elongation and Stanford B Dissection: The Tubingen Aortic Pathoanatomy (TAIPAN) Project. AB - OBJECTIVE/BACKGROUND: Aortic elongation has not yet been considered as a potential risk factor for Stanford type B dissection (TBD). The role of both aortic elongation and dilatation in patients with TBD was evaluated. METHODS: The aortic morphology of a healthy control group (n = 236) and patients with TBD (n = 96) was retrospectively examined using three dimensional computed tomography imaging. Curved multiplanar reformats were used to examine aortic diameters at defined landmarks and aortic segment lengths. RESULTS: Diameters at all landmarks were significantly larger in the TBD group. The greatest diameter difference (56%) was measured in dissected descending aortas (p < .001). The segment with the most considerable difference between the study groups with regard to elongation was the non-dissected aortic arch of patients with TBD (36%; p < .001). Elongation in the aortic arch was accompanied by a diameter increase of 21% (p < .001). In receiver-operating curve analysis, the area under the curve was .85 for the diameter and .86 for the length of the aortic arch. CONCLUSIONS: In addition to dilatation, aortic arch elongation is associated with the development of TBD. The diameter and length of the non-dissected aortic arch may be predictive for TBD and may possibly be used for risk assessment in the future. This study provides the basis for further prospective evaluation of these parameters. PMID- 28663042 TI - Pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular administration in male cats. AB - OBJECTIVE: To characterize the pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular (IM) administration to cats. STUDY DESIGN: Prospective randomized crossover experimental study. ANIMALS: A total of eight healthy adult male castrated cats aged 1-2 years. METHODS: Cats were administered dexmedetomidine (25 MUg kg-1) IM (treatment D25IM) or intravenously (IV; treatment D25IV); MK-467 (600 MUg kg-1) IM (treatment MK600IM) or IV (treatment MK600IV); or dexmedetomidine (25 MUg kg-1) IM with 300, 600 or 1200 MUg kg-1 MK-467 IM (treatments D25MK300IM, D25MK600IM and D25MK1200IM). D25MK600IM was the only combination treatment analyzed. Blood samples were obtained prior to drug administration and at various times for 5 hours (D25IV) or 8 hours (all other treatments) thereafter. Plasma dexmedetomidine and MK-467 concentrations were measured using liquid chromatography/mass spectrometry. Compartment models were fitted to the time-concentration data. RESULTS: A one compartment model best fitted the time-plasma dexmedetomidine concentration data in cats administered D25IM, and the time-plasma MK-467 concentration data in cats administered MK600IM and D25MK600IM. A two-compartment model best fitted the time plasma dexmedetomidine concentration data in cats administered D25IV and D25MK600IM, and the time-plasma MK-467 concentration data in cats administered MK600IV. Median (range) area under the time-concentration curve, absorption rate half-life, maximum concentration, time to maximum concentration and terminal half life for dexmedetomidine in D25IM and D25MK600IM were 1129 (792-1890) and 924 (596-1649) ng minute mL-1, 4.4 (0.4-15.7) and 2.3 (0.2-8.0) minutes, 10.2 (4.8 16.9) and 17.8 (15.8-73.5) ng mL-1, 17.8 (2.6-44.9) and 5.2 (1.2-15.1) minutes and 62 (52-139) and 50 (31-125) minutes, respectively. Rate of absorption but not systemic exposure was significantly influenced by treatment. No significant differences were observed in MK-467 pharmacokinetic parameters in MK600IM and D25MK600IM. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 significantly influenced the disposition of dexmedetomidine, whereas dexmedetomidine did not significantly affect the disposition of MK-467 when the drugs were coadministered IM. PMID- 28663043 TI - Patients' and procedural characteristics of AV-block during slow pathway modulation for AVNRT-single center 10year experience. AB - BACKGROUND: Permanent AV-block is a recognized and feared complication of slow pathway modulation for AVNRT. We aimed to assess incidence of transient and permanent AV-block as well as consequences of transient AV-block in a large contemporary AVNRT ablation cohort. METHODS: We searched our single center prospective ablation database for occurrence of transient and permanent AV-block during slow pathway modulation between January 2004 and October 2015. We analyzed patients' and procedural characteristics as well as outcome of patients in whom transient or permanent AV-block occurred. RESULTS: Of 9170 patients who underwent a catheter ablation at our institution between January 2004 and October 2015, 2101 patients (64% women, mean age 50+/-18years) underwent slow pathway modulation. In three patients, permanent AV-block occurred during RF application. Additional two patients had transient AV-block that recovered (after a few minutes and 25min), but recurred within two days of the procedure. All five patients underwent dual chamber pacemaker implantation (0.2%). Transient AV-block related to RF delivery occurred in 44 patients (2%). Transient mechanical AV block occurred in additional 17 patients (0.8%). In 12 patients, ablation was continued despite transient AV-block. One of these patients developed permanent AV-block. CONCLUSION: Permanent AV-block following slow pathway modulation is a rare event, occurring in 0.2% of patients in a large contemporary single center cohort. Transient AV-block is more frequent (2%). PMID- 28663044 TI - Carotid artery plaques - Are risk factors the same in men and women with familial hypercholesterolemia? AB - BACKGROUND AND AIMS: High low-density lipoprotein (LDL)-cholesterol levels are a major cause of premature coronary heart disease (CHD) and death in patients with familial hypercholesterolemia (FH). It is uncertain whether these risk factors affect men and women equally. We aimed to compare the risk factors of carotid plaques, which are reliable surrogates of coronary atherosclerosis, in men and women with FH. METHODS: 154 patients with FH (40.9% men) were included, diagnosed according to Simon Broome criteria. Carotid plaques were assessed by ultrasound. RESULTS: In women multiple logistic regression analysis revealed that systolic blood pressure, high-density lipoprotein-cholesterol (HDL-C), apolipoprotein (apo) A1, and alanine aminotransferase (ALT) were associated with the presence of carotid plaques. In this female cohort, the age adjusted odds ratio for the increase of HDL-C by 1 standard deviation was related to a 55% decrease in the odds of having carotid plaques (p=0.01) and the age adjusted odds ratio for the increase of ALT by 1U/L was related to a 7% in the increase odds of having carotid plaques (p=0.02). In men, in multiple logistic regression analysis only apo B concentration was significantly related to carotid plaque presence. The odds ratio for the increase of apo B by 1mg/dl corresponded to a 4% increase in the odds of having carotid plaques (p=0.01) and, interestingly, in men not treated with statin, this ratio reached 8% (p=0.04). CONCLUSIONS: In summary, our study suggests a difference in risk factors of carotid artery plaques between men and women with FH. PMID- 28663045 TI - APpropriateness Assessment in Antiplatelet THerapY (APATHY) registry: Insight from current clinical practice. AB - BACKGROUND: In clinical practice there is a gap between guidelines recommendation and antiplatelet strategies used for acute coronary syndrome (ACS). We sought to evaluate appropriateness of antiplatelet strategies employed in a tertiary center. METHODS AND RESULTS: From January to June 2014, 430 ACS were treated with percutaneous coronary intervention by 3 groups of interventional cardiologists. Aspirin and clopidogrel (52%) were the most commonly used antiplatelet therapies, being prasugrel associated with aspirin in 110 (25.5%) and ticagrelor in 97 (22.5%) ACS. Inappropriate use of prasugrel (Tia/Ictus) was found in 2 (1.8%) patients and not recommended use (>75years, without diabetes or previous myocardial infarction) in 11 (10%). Not recommended use of ticagrelor (plus warfarin) was found in 4 (4.4%). Switching from clopidogrel to prasugrel occurred in 29% [28 showing high residual platelet reactivity (HRPR: ADP 10MUmol>70%), and 4 left main stenting], while from clopidogrel to ticagrelor occurred in 13.4% (all showing HRPR, but 1). The most powerful predictor for prescription of 3rd generation P2Y12 inhibitors was the HRPR (OR 5.473, 95%CI 2.41-12.43, p<0.0001), whereas the behavior of attending cardiologist (HR 0.674, 95%CI 0.573-0.847, p=0.001) and the older age reduced the probability of receiving it (OR0.963, 95%CI 0.943-0.984, p=0.001). CONCLUSIONS: Clopidogrel remained the most common P2Y12 inhibitor employed for ACS. Third generation P2Y12 inhibitor prescription was lower than the one expected by guidelines recommendations, and the switching was largely based on clopidogrel HRPR. These findings suggest the need for a greater effort to improve adherence of cardiology community to current guidelines. PMID- 28663046 TI - Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. AB - BACKGROUND: The NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six month randomized phase of the study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS. METHODS: Ninety-six patients were randomized 2:1 to active or inactive VNS for 6months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all cause mortality. RESULTS: Ninety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion). Left ventricular systolic volume decreased in the crossover group (VNS OFF->ON; 144+/-37 to 139+/-40, p<0.05) after VNS activation; LVESD (5.02+/ 0.77 to 4.96+/-0.82, p>0.05) and LVEF (33.2+/-4.9 to 33.3+/-6.5, p>0.05) did not change. A new technique to detect subtle heart rate changes during Holter recordings, i.e. "heat maps", revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12months with active VNS. CONCLUSIONS: Although a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models. PMID- 28663047 TI - Diagnostic and prognostic value of miR-1 and miR-29b on adverse ventricular remodeling after acute myocardial infarction - The SITAGRAMI-miR analysis. AB - BACKGROUND: MicroRNAs (miRs) have shown to exert fibrotic and anti-fibrotic effects in preclinical models of acute myocardial infarction (AMI). The aim of this study was to evaluate miR-1, miR-21, miR-29b and miR-92a as circulating biomarkers for adverse ventricular remodeling (AVR) in post-AMI patients. METHODS: Plasma levels of miR-1, miR-21, miR-29b and miR-92a were measured in 44 patients of the SITAGRAMI trial population at day 4, day 9 and 6month after AMI and in 18 matched controls (CTL). MiR expression patterns were correlated with magnetic resonance imaging (MRI) parameters for AVR (absolute change (Delta) in infarct volume (IV), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) between day 4 and 6months after AMI) and a combined cardiovascular endpoint. RESULTS: Expression of miR-1, miR-21 and miR 29b but not miR-92a was increased in AMI vs. CTL cohort showing highest miR levels at d9. However, only miR-1 and miR-29b levels significantly correlated with DeltaIV and showed a trend for correlation with DeltaLVEF. Only miR-29b levels at day 9 correlated with DeltaLVEDV at 6-month follow-up. There was no correlation of miR levels with an adverse outcome. CONCLUSION: Mir-1 and miR-29b plasma levels post-AMI correlate with IV changes. In addition, miR-29b levels are associated with changes of LVEDV over time. These results provide insights into the role of miRs as diagnostic AVR surrogate markers. Further large scale clinical trials will be needed to evaluate the real prognostic relevance of these miRs with respect to a clinical implication in the future. PMID- 28663048 TI - Evaluation of Continuous Irrigation and Drainage with a Double-Cavity Sleeve Tube to Treat Brain Abscess. AB - BACKGROUND: Brain abscesses carries a high morbidity and mortality, and despite medical advances, it continues to pose diagnostic and therapeutic challenges worldwide. The traditional surgical approaches to treating brain abscess (burr hole aspiration and craniotomy) have both advantages and disadvantages and remain controversial. Here we report a single institution's experience with a new surgical approach for brain abscess. METHODS: We retrospectively analyzed 46 patients with intracranial abscess who underwent continuous irrigation and drainage through a double-cavity sleeve tube placed surgically in conjunction with a 4-week course of intravenous cefotaxime and metronidazole at Renmin Hospital of Wuhan University between January 2008 and December 2016. The patients' medical records were analyzed for demographic data, clinical presentation, predisposing factors, imaging findings, microbiological test results, treatments, surgical techniques, and outcomes. RESULTS: The 46 patients included 29 males and 17 females, ranging in age from 22 to 74 years. A single abscess was detected in 34 patients, whereas 12 patients had multiple abscesses. The average duration of hospitalization was 12.6 days. After treatment, 38 of the 46 patients resumed a normal life despite minor deficits (Glasgow Outcome Score [GOS] 5), 6 patients exhibited slight neurologic deficits (GOS 4), and 2 patients died of severe systemic infection and multiorgan failure. In particular, a patient with a brain abscess broken into the ventricle recovered well (GOS 5). No patient required repeat aspiration or surgical excision. CONCLUSIONS: Continuous brain abscess cavity irrigation and drainage with a double-cavity sleeve tube is an effective treatment for brain abscess and produces excellent results, especially for an abscess broken into the ventricle. It combines the advantages of burr hole aspiration and open craniotomy excision. It is easy to perform and reduces costs and damage to the patient, and also shortens hospitalization time and antibiotic treatment time, greatly reducing the likelihood of reoperation. This approach may be the optimal choice to treat brain abscess. PMID- 28663049 TI - Challenges and perspectives of metaproteomic data analysis. AB - In nature microorganisms live in complex microbial communities. Comprehensive taxonomic and functional knowledge about microbial communities supports medical and technical application such as fecal diagnostics as well as operation of biogas plants or waste water treatment plants. Furthermore, microbial communities are crucial for the global carbon and nitrogen cycle in soil and in the ocean. Among the methods available for investigation of microbial communities, metaproteomics can approximate the activity of microorganisms by investigating the protein content of a sample. Although metaproteomics is a very powerful method, issues within the bioinformatic evaluation impede its success. In particular, construction of databases for protein identification, grouping of redundant proteins as well as taxonomic and functional annotation pose big challenges. Furthermore, growing amounts of data within a metaproteomics study require dedicated algorithms and software. This review summarizes recent metaproteomics software and addresses the introduced issues in detail. PMID- 28663050 TI - MicroRNA-144 modulates oxidative stress tolerance in SH-SY5Y cells by regulating nuclear factor erythroid 2-related factor 2-glutathione axis. AB - Genome-wide analysis of miRNA expression has revealed increased levels of miR-144 in the brains of Alzheimer's disease (AD) patients. Nuclear factor erythroid 2 related factor 2 (NRF2), a potential target of miR-144, is a central regulator of antioxidant response, and plays an important role in glutathione (GSH) biosynthesis and recycling. In this study, miR-144 mimic was used to over express miR-144. Abeta (1-42) was used to induce oxidative stress in SH-SY5Y cells. Cell viability and intracellular reactive oxygen species (ROS) were assessed to identify the effects of miR-144 on oxidative stress status. GSH and glutathion peroxidase (GPX) activities were detected to reveal the effect of miR-144 on GSH accumulation. To understand the effects of miR-144 on GSH biosynthesis and recycling, intracellular GPX1, glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), glutathione reductase (GR), and NRF2 expression were detected by western blot and Real-time PCR. In oxidative stress conditions, miR-144 increased the intracellular accumulation of ROS, reduced cell viability, reduced the activities of GSH and antioxidant enzymes, GPX1, and decreased the expression of GCLC, GCLM, GR and NRF2. In conclusion, miR-144 modulates oxidative stress tolerance by regulating NRF2 expression and GSH generation, which may contribute to the pathogenesis of AD. PMID- 28663051 TI - Electroencephalographic theta oscillatory dynamics reveal attentional bias to angry faces. AB - Although previous studies have reported the temporal neural dynamics (e.g., N2pc component) of threat-detection orientation for face-processing (e.g., the "anger superiority effect"), little is known about the neural oscillatory features of this phenomenon. Here, we extracted the event-related potentials and event related oscillatory power dynamics from electroencephalographic data when participants performed a visual search task consisting of realistic angry, happy, and neutral facial expressions. We observed a shorter response time and a larger N2pc for angry faces than for happy faces, suggesting the existence of preferential processing for angry faces. Similarly, elevated theta synchronization was observed for angry faces compared to happy faces, while both angry and happy faces elicited heightened theta oscillatory activity on contralateral location of target face compared to ipsilateral location. Moreover, the theta oscillation difference negatively correlated with the amplitude of the N2pc difference. Our findings suggest that the occipital theta oscillation is engaged in the search advantage of angry facial expressions. Further, our results provide evidence that the theta oscillation may reflect the processing dynamics of threat-stimuli orientation in an ever-changing environment. PMID- 28663052 TI - Application of a common spatial pattern-based algorithm for an fNIRS-based motor imagery brain-computer interface. AB - Motor imagery is one of the most investigated paradigms in the field of brain computer interfaces (BCIs). The present study explored the feasibility of applying a common spatial pattern (CSP)-based algorithm for a functional near infrared spectroscopy (fNIRS)-based motor imagery BCI. Ten participants performed kinesthetic imagery of their left- and right-hand movements while 20-channel fNIRS signals were recorded over the motor cortex. The CSP method was implemented to obtain the spatial filters specific for both imagery tasks. The mean, slope, and variance of the CSP filtered signals were taken as features for BCI classification. Results showed that the CSP-based algorithm outperformed two representative channel-wise methods for classifying the two imagery statuses using either data from all channels or averaged data from imagery responsive channels only (oxygenated hemoglobin: CSP-based: 75.3+/-13.1%; all-channel: 52.3+/-5.3%; averaged: 64.8+/-13.2%; deoxygenated hemoglobin: CSP-based: 72.3+/ 13.0%; all-channel: 48.8+/-8.2%; averaged: 63.3+/-13.3%). Furthermore, the effectiveness of the CSP method was also observed for the motor execution data to a lesser extent. A partial correlation analysis revealed significant independent contributions from all three types of features, including the often-ignored variance feature. To our knowledge, this is the first study demonstrating the effectiveness of the CSP method for fNIRS-based motor imagery BCIs. PMID- 28663053 TI - Protective effect of electroacupuncture on neurons autophagy in perfusion period of cerebral ischemia. AB - Electroacupuncture (EA) is an important treatment method in Chinese traditional medicine. The main purpose of the investigation was to explore whether EA could improve cerebral ischemia/reperfusion (CI/R) via neurons' autophagy. 4-vessel occlusion (4-VO) was applied to establish cerebral ischemia model and reperfusion 12h, 24h and 48h respectively were conduct 3h later. TTC staining was applied to assess cerebral infarction area and the concentrations of IL-6, TNF-alpha, IL 1beta, SOD and MDA were detected by commercial kits. The expressions of autophagy related protein LC3, mammalian target of rapamycin (mTOR) and Beclin1 were measured by Western blot. EA treatment was given at "BaiHui", "MingMen" and "ZuSanLiXue". The obtained results from TTC showed that the severity of cerebral ischemia-reperfusion was improved with EA treatment. Oxidative and inflammatory damages were also alleviated with EA intervention. Meanwhile, western blot analysis revealed the decreased levels of LC3 and Beclin1 in EA rats, as well as the elevated level of mTOR. Besides, our previous study found that EA can enhance mitochondrial respiratory chain enzyme activity, reduce mitochondrial damage and inhibit neuronal apoptosis further. Thus, it is assumed that 4-VO-induced cerebral ischemia/reperfusion might be alleviated by EA through inhibiting neurons' excessive autophagy in reperfusion period. PMID- 28663054 TI - Early detection of cerebral microbleeds following traumatic brain injury using MRI in the hyper-acute phase. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in people under 45. Advanced imaging techniques to identify injury and classify severity in the first few hours and days following trauma could improve patient stratification and aid clinical decision making. Traumatic cerebral microbleeds (TCMBs), detectable on magnetic resonance susceptibility weighted imaging (SWI), can be used as markers of long-term clinical outcome. However, the relationship between TCMBs and injury severity in the first few hours after injury, and their natural evolution, is unknown. METHODS: We obtained SWI scans in 10 healthy controls, and 13 patients scanned 3-24h following TBI and again at 7-15days. TCMBs were identified and total volume quantified for every lesion in each scan. RESULTS: TCMBs were present in 6 patients, all with more severe injury classified by GCS. No lesions were identified in patients with an initial GCS of 15. Improvement in GCS in the first 15days following injury was significantly associated with a reduction in microbleed volume over the same time-period. CONCLUSION: MRI is feasible in severely injured patients in the first 24h after trauma. Detection of TCMBs using SWI provides an objective early marker of injury severity following trauma. TCMBs revealed in this time frame, offer the potential to help determine the degree of injury, improving stratification, in order to identify patients who require admission to hospital, transfer to a specialist center, or an extended period of intubation on intensive care. PMID- 28663055 TI - Propofol inhibits invasion and proliferation of C6 glioma cells by regulating the Ca2+ permeable AMPA receptor-system xc- pathway. AB - Anesthetics are documented to affect tumors; therefore, we studied the antiglioma effect of propofol on proliferation and invasiveness of glioma cells and explored the underlying mechanism. C6 glioma cells were cultured and treated with propofol, and cell viability, invasiveness, and migration were measured. Glutamate release was measured using an enzyme-catalyzed kinetic reaction. xCT protein and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR2 subunit protein expression was assessed with Western blot analysis and immunofluorescent staining. We observed that propofol significantly inhibited C6 glioma cell viability, invasiveness, and migration and decreased glutamate release. An agonist of the cystine/glutamate antiporter system (system xc-), N acetylcysteine (NAC), reversed propofol's effects, and propofol could inhibit C6 glioma cell proliferation by adding excess exogenous glutamate (100MUM). Finally, propofol increased the surface expression of GluR2, but decreased surface expression of xCT. The effects of propofol on surface expression of GluR2 and xCT could be rescued by (R, S)-AMPA, an agonist of Ca2+ permeable AMPA receptor (CPAR). Thus, propofol can inhibit cell viability, invasiveness, and migration of C6 glioma cells, and the CPAR-system xc- pathway contributes to these events. PMID- 28663056 TI - From in vitro to in vivo: Integration of the virtual cell based assay with physiologically based kinetic modelling. AB - Physiologically based kinetic (PBK) models and the virtual cell based assay can be linked to form so called physiologically based dynamic (PBD) models. This study illustrates the development and application of a PBK model for prediction of estragole-induced DNA adduct formation and hepatotoxicity in humans. To address the hepatotoxicity, HepaRG cells were used as a surrogate for liver cells, with cell viability being used as the in vitro toxicological endpoint. Information on DNA adduct formation was taken from the literature. Since estragole induced cell damage is not directly caused by the parent compound, but by a reactive metabolite, information on the metabolic pathway was incorporated into the model. In addition, a user-friendly tool was developed by implementing the PBK/D model into a KNIME workflow. This workflow can be used to perform in vitro to in vivo extrapolation and forward as backward dosimetry in support of chemical risk assessment. PMID- 28663057 TI - Inhibition of Mcl-1 enhances Pevonedistat-triggered apoptosis in osteosarcoma cells. AB - Neddylation inhibitor Pevonedistat (MLN4924) is a novel anticancer drug and has demonstrated broad-spectrum anticancer activity. Nevertheless, we found that Pevonedistat had only a modest apoptotic effect in osteosarcoma (OS) cells. Moreover, we noted that inhibition of neddylation by Pevonedistat led to accumulation of Mcl-1 protein in OS cells. Because Mcl-1 is an important anti apoptotic protein and also because apoptosis has been shown to be a major cell death pathway, we hypothesized that Mcl-1 accumulation negatively impacted Pevonedistat-mediated anticancer activity in OS cells. In this regard, we employed genetic or pharmacological approaches to inhibit Mcl-1 expression and to examine the effect on Pevonedistat-induced apoptosis in OS cells. We found that inhibition of Mcl-1 expression by siRNA considerably enhanced Pevonedistat triggered the activation of caspase-3, PARP cleavage and apoptosis, and also dramatically promoted the ability of Pevonedistat to inhibit colony formation of OS cells. Moreover, we observed that flavopiridol, a FDA approved drug, inhibited Mcl-1 expression and substantially enhanced Pevonedistat-mediated activation of apoptosis signaling and significantly augmented cell killing effect in OS cells. Altogether, our study shows that Mcl-1 is a critical resistance factor to Pevonedistat monotherapy, and suggests that Pevonedistat in combinations with flavopiridol may achieve better anticancer therapy. PMID- 28663058 TI - The induction of tumour suppressor protein P53 limits the entry of cells into the pluripotent inner cell mass lineage in the mouse embryo. AB - The early preimplantation embryo is susceptible to a range of exogenous stresses which result in their reduced long-term developmental potential. The P53 tumour suppressor protein is normally held at low levels in the preimplantation embryo and we show that culture stress induces the expression of a range of canonical P53-response genes (Mdm2, Bax and Cdkn1a). Culture stress caused a P53-dependent loss of cells from resulting blastocysts, and this was most evident within the inner cell mass population. Culture stress increased the proportion of cells expressing active caspase-3 and undergoing apoptosis, while inhibition of caspase 3 increased the number of cells within the inner cell mass. The P53-dependent loss of cells from the inner cell mass was accompanied by a loss of NANOG positive epiblast progenitors. Pharmacological activation of P53 by the MDM2 inhibitor, Nutlin-3, also caused increased P53-dependent transcription and the loss of cells from the inner cell mass. This loss of cells could be ameliorated by simultaneous treatment with the P53 inhibitor, Pifithrin-alpha. Culture stress causes reduced signalling via the phosphatidylinositol-3-kinase signalling pathway, and blocking this pathway caused P53-dependent loss of cells from the inner cell mass. These results point to P53 acting to limit the accumulation and survival of cells within the pluripotent lineage of the blastocyst and provide a molecular framework for the further investigation of the factors determining the effects of stressors on the embryo's developmental potential. PMID- 28663059 TI - Human IGF-I Eb-peptide induces cell attachment and lamellipodia outspread of metastatic breast carcinoma cells (MDA-MB-231). AB - Although Insulin-like growth factor (IGF-I) has been intensively studied, the functions of E-domain peptides of pro-IGF-I, however, have been overlooked. In our laboratory, several anti-cancer activities of the E-peptide of pro-IGF-I have been identified for the longest isoforms of human and rainbow trout E-peptides. These activities include dose-dependent inhibition of colony formation, inhibition of cancer cell metastasis and invasion through matrigel, suppression of cancer-induced angiogenesis, and attenuation of expression of apoptotic genes in favor of cell death. In this study, we were able to produce two-tagged recombinant human Eb-peptide (hEb) of pro-IGF-I with a purity over 99%. With its antimicrobial peptide (AMP)-like characteristics such as binding to the cytoplasmic membrane, and the affinity to the substratum of culture plate, hEb forms a layer of interface rapidly which facilitates the attachment of breast carcinoma cells, MDA-MB-231. Furthermore, the likely conformational change of homo-dimerized hEb through a single disulfide bond, as well as the ability to trigger clathrin-mediated endocytosis may play important roles for inducing lamellipodia outspread in MDA-MB-231 cells. With the highly purified hEb-peptide, not only could we study its function(s) in detail but also the minimum requirement for cancerous cells to metastasize to a suitable environment and grow. PMID- 28663060 TI - Tg737 acts as a key driver of invasion and migration in liver cancer stem cells and correlates with poor prognosis in patients with hepatocellular carcinoma. AB - We previously demonstrated that the Tg737 gene plays a critical role in the carcinogenesis of hepatocellular carcinoma (HCC). However, few systematic investigations have focused on the biological function of Tg737 in the invasion and migration of liver cancer stem cells (LCSCs) and on its clinical significance. In this study, Tg737 overexpression was achieved via gene transfection in MHCC97-H side population (SP) cells, which are considered a model for LCSCs in scientific studies. Tg737 overexpression significantly inhibited the invasion and migration of SP cells in an extracellular signal-regulated kinase1/2 (ERK1/2)/matrix metalloproteinase-2 (MMP-2)-dependent manner. Furthermore, Tg737 expression was frequently decreased in HCC tissues relative to that in adjacent noncancerous liver tissues. This decreased expression was significantly associated with tumor differentiation, the American Joint Committee on Cancer (AJCC) stage, metastasis, tumor size, vascular invasion, alpha-fetoprotein (AFP) levels, and tumor number. Moreover, multivariate Cox regression analyses demonstrated that Tg737 expression was an independent factor for predicting the overall survival of HCC patients. Notably, Kaplan-Meier analysis further showed that overall survival was significantly worse among patients with low Tg737 expression. Collectively, our findings demonstrated that Tg737 is a poor prognostic marker in patients with HCC, which may be due to its ability to promote LCSCs invasion and migration. These results provide a basis for investigating of Tg737 as a novel prognostic biomarker and therapeutic target. PMID- 28663061 TI - Family Aggregation and Heritability of ESRD in Taiwan: A Population-Based Study. AB - BACKGROUND: Aggregation of end-stage renal disease (ESRD) has been observed in families of European origin, as well as those of African origin. However, it is not well documented if this disease aggregates in Asian families. Furthermore, the contribution of genetic factors and shared environmental factors to family aggregation remains unclear. STUDY DESIGN: Population-based cross-sectional cohort study. SETTING & PARTICIPANTS: All 23,422,955 individuals registered in the Taiwan National Health Insurance Research Database in 2013. Among these, 47.45%, 57.45%, 47.29%, and 1.51% had a known parent, child, sibling, or twin, respectively. We identified 87,849 patients who had a diagnosis of ESRD. PREDICTOR: Family history of ESRD. OUTCOMES & MEASUREMENTS: ESRD and heritability defined as the proportion of phenotypic variance attributable to genetic factors. RESULTS: Having an affected first-degree relative with ESRD was associated with an adjusted relative risk of 2.46 (95% CI, 2.32-2.62). Relative risks were 96.38 (95% CI, 48.3-192.34) for twins of patients with ESRD, 2.15 (95% CI, 2.02-2.29) for parents, 2.78 (95% CI, 2.53-3.05) for offspring, 4.96 (95% CI, 4.19-5.88) for siblings, and 1.66 (95% CI, 1.54-1.78) for spouses without genetic similarities. Heritability in this study was 31.1% to 11.4% for shared environmental factors and 57.5% for nonshared environmental factors. LIMITATIONS: This was a registry database study and we did not have detailed information about clinical findings or the definite causes of ESRD. CONCLUSIONS: This whole population-based family study in Asia confirmed, in a Taiwanese population, that a family history of ESRD is a strong risk factor for this disease. Moderate heritability was noted and environmental factors were related to disease. Family history of ESRD is an important piece of clinical information. PMID- 28663063 TI - Development of Focal Segmental Glomerulosclerosis Patient-Reported Outcome Measures: Symptom Diary and Symptom Impact Questionnaire. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a kidney disease that affects patients' functioning and well-being. This study aimed to develop patient reported outcome questionnaires to measure patient experiences related to FSGS. STUDY DESIGN: Qualitative patient interviews to identify important symptoms and concepts (concept elicitation) formed the basis for the development of 2 questionnaires, one on symptoms and one on their impact. Additional qualitative interviews were implemented to evaluate/refine the questionnaires (cognitive debriefing). Transcripts of concept elicitation and cognitive debriefing interviews, conducted by telephone, were analyzed for concepts of interest using qualitative text analysis. SETTING & PARTICIPANTS: Patients with FSGS (aged 18-65 years with estimated glomerular filtration rates >= 40mL/min/1.73m2) whose disease remained inadequately controlled after 2 or fewer courses of treatment. METHODOLOGY: Qualitative concept elicitation and cognitive debriefing interviews. ANALYTICAL APPROACH: Interview transcripts were analyzed using qualitative software, MAXQDA. RESULTS: 30 patients completed concept elicitation interviews; 9 patients completed cognitive debriefing interviews. Frequently mentioned symptoms included swelling from the waist down/legs/knees/feet/ankles (67%), fatigue (57%), stomach/abdomen swelling (43%), body pain/pressure (30%), and shortness of breath (20%), as well as impacts on physical (52%), emotional (68%), and social functioning (89%). Based on analyses of interview transcripts and clinical input, 2 questionnaires, one on symptoms and one on the impact of the symptom, were drafted. The 23-item FSGS Symptom Diary (assessing the frequency and severity of FSGS symptoms during the past 24 hours) and the FSGS Symptom Impact Questionnaire (17 items assessing interference with activities and emotions during the past 7 days) were iteratively revised based on cognitive debriefing interviews. LIMITATIONS: The study was restricted to English-speaking adults located in the United States, and the concept elicitation interview group had a low number of African Americans. CONCLUSIONS: The FSGS Symptom Diary and FSGS Symptom Impact Questionnaire are new FSGS-specific patient-reported outcomes measures designed to support a comprehensive assessment of symptoms and symptom impact in adults with FSGS. Future research is needed to evaluate their quantitative measurement properties. PMID- 28663062 TI - Community Pharmacist Training-and-Communication Network and Drug-Related Problems in Patients With CKD: A Multicenter, Cluster-Randomized, Controlled Trial. AB - BACKGROUND: Appropriate training for community pharmacists may improve the quality of medication use. Few studies have reported the impact of such programs on medication management for patients with chronic kidney disease (CKD). STUDY DESIGN: Multicenter, cluster-randomized, controlled trial. SETTING & PARTICIPANTS: Patients with CKD stage 3a, 3b, or 4 from 6 CKD clinics (Quebec, Canada) and their community pharmacies. INTERVENTION: Each cluster (a pharmacy and its patients) was randomly assigned to either ProFiL, a training-and communication network program, or the control group. ProFiL pharmacists completed a 90-minute interactive web-based training program on use of medications in CKD and received a clinical guide, patients' clinical summaries, and facilitated access to the CKD clinic. OUTCOMES: Drug-related problems (primary outcome), pharmacists' knowledge and clinical skills, and patients' clinical attributes (eg, blood pressure and glycated hemoglobin concentration). MEASUREMENTS: Drug related problems were evaluated the year before and after the recruitment of patients using a validated set of significant drug-related problems, the Pharmacotherapy Assessment in Chronic Renal Disease (PAIR) criteria. Pharmacists' questionnaires were completed at baseline and after 1 year. Clinical attributes were documented at baseline and after 1 year using available information in medical charts. RESULTS: 207 community pharmacies, 494 pharmacists, and 442 patients with CKD participated. After 1 year, the mean number of drug-related problems per patient decreased from 2.16 to 1.60 and from 1.70 to 1.62 in the ProFiL and control groups, respectively. The difference in reduction of drug related problems per patient between the ProFiL and control groups was -0.32 (95% CI, -0.63 to -0.01). Improvements in knowledge (difference, 4.5%; 95% CI, 1.6% 7.4%) and clinical competencies (difference, 7.4%; 95% CI, 3.5%-11.3%) were observed among ProFiL pharmacists. No significant differences in clinical attributes were observed across the groups. LIMITATIONS: High proportion of missing data on knowledge and clinical skills questionnaire (34.6%) and clinical attributes (11.1%). CONCLUSIONS: Providing community pharmacists with essential clinical data, appropriate training, and support from hospital pharmacists with expertise in nephrology increases pharmacists' knowledge and reduces drug-related problems in patients with CKD who are followed up in clinics incorporating a multidisciplinary health care team. PMID- 28663064 TI - Dialysis Payment Model Reform: Managing Conflicts Between Profits and Patient Goals of Care Decision Making. PMID- 28663065 TI - Potential therapeutic and protective effect of curcumin against stroke in the male albino stroke-induced model rats. AB - AIMS: The present study was carried out to understand the therapeutic effect of curcumin (CUR) against stroke in the experimental animal model. The study investigates the healing effect of CUR on mitochondrial dysfunction and inflammation. MATERIALS AND METHODS: Male albino, Wistar strain rats were used for the induction of middle cerebral artery occlusion (MCAO), and reperfusion. Enzyme-linked immunosorbent assay (ELISA) was used for the determination of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in the brain region. Western blot analysis was used to determine the protein expression levels of Bax, Bcl-2, p53, and Sirt1. KEY FINDINGS: The water level was determined in brain region by using standard method. Experimental results indicated that the use of CUR significantly reduced brain edema and water content. IL-6 and TNF alpha were significantly reduced in the brain region following use of CUR. Mitochondrial membrane potential (MMP) also reduced significantly after CUR treatment. Protein expression of p53 and Bax were significantly reduced, whereas Bcl-2 and Sirt1 were increased following CUR treatment. SIGNIFICANCE: Taking all these data together, it is suggested that the use of CUR may be a potential therapeutic agent for the treatment of stroke. PMID- 28663066 TI - Successful management of acute liver failure in Italian children: A 16-year experience at a referral centre for paediatric liver transplantation. AB - BACKGROUND: Identifying the causes of acute liver failure (ALF) and predictors of death or liver transplantation (LTX) is crucial to decide its management. We aimed to describe features and outcome of ALF in Italian children. METHODS: Retrospective review of cases presenting between 1996-2012. ALF was defined by high transaminases, INR >=2.0 regardless of hepatic encephalopathy (HE), no evidence of underlying chronic liver disease. RESULTS: 55 children (median age 2.6 years, range 0.1-15.1; M/F=31/24) had ALF due to autoimmune hepatitis (AIH) in 10 (18%), metabolic disorders in 9 (17%), paracetamol overdose in 6 (11%), mushroom poisoning in 3 (5%), viral infection in 1 (2%), indeterminate in 26 (47%); 25/55 recovered with supportive management (45%); 28/55 underwent LTX and 2 died on the waiting list (55%). On multivariate analysis severity of HE grade 3 4 and bilirubin >=12mg/dl were independent predictors of death or LTX (p<0.05). After a median follow up of 4 years (range 2-15.0 years) the overall survival rate was 93%. CONCLUSION: Children with ALF can be managed successfully with combined medical treatment and transplantation, warranting a survival rate similar to children transplanted because of chronic conditions. In our cohort of patients severe HE and high bilirubin on admission were independent predictors of the need of LTX. PMID- 28663067 TI - Economic burden of diverticular disease: An observational analysis based on real world data from an Italian region. AB - INTRODUCTION: Diverticular disease (DD), a herniation of the colonic mucosa through the muscle layer, covers a wide variety of conditions associated with the presence of diverticula in the colon. The most serious form is an acute episode of diverticulitis, which can lead to hospitalization and surgery with various types of consequences. The main aim of this study is to evaluate the economic burden of hospitalizations arising from acute episodes of diverticulitis using data from the administrative databases used in the Marche region in Italy and, as a secondary objective of this real-world data analysis, to study patient outcome variables following initial hospitalization for diverticulitis. METHOD: A deterministic linkage was performed at individual user level between the different administrative sources of the Marche region through anonymous ID number for a period of analysis between 1 January, 2008 and 31 December, 2014. We enrolled all patients with at least one hospitalization for "diverticulitis of the colon without mention of haemorrhage" (ICD-9-CM code 562.11) or "diverticulitis of the colon with haemorrhage" (ICD-9-CM code 562.13) as primary or secondary diagnosis. For each patient we assessed the cost of hospitalization, of medicines and of specialist services considering a time-scale of one year or cohort analysis 365days after first admission. RESULTS: The total number of residents in the Marche region who had at least one hospitalization for diverticulitis in the period 2008-2014 was 2987 (427 patients a year, corresponding to about 35 patients per 100,000 adult residents); the total number of admissions was 3453 (just over 490 a year). The direct healthcare costs incurred by the Marche region for episodes of diverticulitis in 2008-2014 amounted to approximately ?11.4 million (?1.6 million a year), of which ?10.9 million (95.5%) for the hospitalizations, ? 246,000 (2.1%) for pharmaceutical treatment and ?270,000 (2.4%) for specialist outpatient services. The average annual cost per patient was ?3826, of which ?3653 was for hospitalization, while pharmaceutical expenditure and specialist services accounted for ?83 and ?90, respectively. The cohort of patients undergoing a first admission for diverticulitis between 2010 and 2013 was made up of 1729 people (54.4% women, mean age 68.9 years), of whom 1500 (86.8%) did not undergo surgery while in hospital. Hospital mortality, recorded only for the over-65 age class, averaged 1.2%; for patients not receiving surgery during the initial hospitalization it was 0.5%, reaching 5.2% in patients undergoing surgery. The percentage of patients with one or more readmissions for diverticulitis within a year of the first was on average 7.8% and in 48% of cases this resulted in surgery. CONCLUSIONS: Our study is the first analysis in Italy to use real-world data to measure the financial impact of diverticular disease. Assuming that the diagnostic and therapeutic behaviour identified in the Marche region could be representative of the situation nationwide, the estimated annual number of hospitalizations in Italy for acute episodes of diverticulitis is 19,000. The total amount of economic resources needed to treat patients suffering from acute episodes of diverticulitis is estimated at ?63.5 million a year. PMID- 28663068 TI - Interpreting the dimensions of neural feature representations revealed by dimensionality reduction. AB - Recent progress in understanding the structure of neural representations in the cerebral cortex has centred around the application of multivariate classification analyses to measurements of brain activity. These analyses have proved a sensitive test of whether given brain regions provide information about specific perceptual or cognitive processes. An exciting extension of this approach is to infer the structure of this information, thereby drawing conclusions about the underlying neural representational space. These approaches rely on exploratory data-driven dimensionality reduction to extract the natural dimensions of neural spaces, including natural visual object and scene representations, semantic and conceptual knowledge, and working memory. However, the efficacy of these exploratory methods is unknown, because they have only been applied to representations in brain areas for which we have little or no secondary knowledge. One of the best-understood areas of the cerebral cortex is area MT of primate visual cortex, which is known to be important in motion analysis. To assess the effectiveness of dimensionality reduction for recovering neural representational space we applied several dimensionality reduction methods to multielectrode measurements of spiking activity obtained from area MT of marmoset monkeys, made while systematically varying the motion direction and speed of moving stimuli. Despite robust tuning at individual electrodes, and high classifier performance, dimensionality reduction rarely revealed dimensions for direction and speed. We use this example to illustrate important limitations of these analyses, and suggest a framework for how to best apply such methods to data where the structure of the neural representation is unknown. PMID- 28663069 TI - Meditation is associated with increased brain network integration. AB - INTRODUCTION: This study aims to identify novel quantitative EEG measures associated with mindfulness meditation. As there is some evidence that meditation is associated with higher integration of brain networks, we focused on EEG measures of network integration. METHODS: Sixteen novice meditators and sixteen experienced meditators participated in the study. Novice meditators performed a basic meditation practice that supported effortless awareness, which is an important quality of experience related to mindfulness practices, while their EEG was recorded. Experienced meditators performed a self-selected meditation practice that supported effortless awareness. Network integration was analyzed with maximum betweenness centrality and leaf fraction (which both correlate positively with network integration) as well as with diameter and average eccentricity (which both correlate negatively with network integration), based on a phase-lag index (PLI) and minimum spanning tree (MST) approach. Differences between groups were assessed using repeated-measures ANOVA for the theta (4-8 Hz), alpha (8-13 Hz) and lower beta (13-20 Hz) frequency bands. RESULTS: Maximum betweenness centrality was significantly higher in experienced meditators than in novices (P = 0.012) in the alpha band. In the same frequency band, leaf fraction showed a trend toward being significantly higher in experienced meditators than in novices (P = 0.056), while diameter and average eccentricity were significantly lower in experienced meditators than in novices (P = 0.016 and P = 0.028 respectively). No significant differences between groups were observed for the theta and beta frequency bands. CONCLUSION: These results show that alpha band functional network topology is better integrated in experienced meditators than in novice meditators during meditation. This novel finding provides the rationale to investigate the temporal relation between measures of functional connectivity network integration and meditation quality, for example using neurophenomenology experiments. PMID- 28663071 TI - Outside-in, inside-out: Proteomic analysis of endothelial stress mediated by 7 ketocholesterol. AB - Oxysterols are cholesterol oxidation products formed through enzymatic or autoxidation mechanisms. 7-ketocholeterol (7KC) is one of most abundant oxysterols found in atherosclerotic lesions. Its role in atherosclerosis pathogenesis has been broadly studied in a variety of models. The arterial microenvironment is a multicellular dynamic compartment that, among other systemic factors, is continuously stimulated by 7KC. Endothelial cells have a key role on that environment, being in intimate contact with both the blood stream and the vessel wall, the site of disease origin. 7KC has been shown to promote endothelial cell death and/or dysfunction, depending on its concentration. However, its contribution to the cell microenvironment through cell stimulation has not received much attention. Here we applied mass spectrometry-based proteomics followed by bioinformatics workflow to analyze the effect of a non toxic 7KC concentration on endothelial cell protein expression and secretion in vitro. Trypsin digests were prepared from the secretome of the endothelial cells and from the total cell pellet after 24h exposure to 7KC. All samples were analyzed by high resolution and accurate mass nano-LC MS/MS. After database search and statistical analysis, differentially expressed proteins were selected for further studies. Our workflow identified 1805 secreted proteins and 2203 intracellular proteins, and of these, 48 and 53, respectively, were regulated. Regulated proteins upon 7KC exposure are involved in unfolded protein response, vascular homeostasis, and reduced control of angiogenesis. Moreover, blood coagulation was another main pathway regulated through Tissue Factor Pathway Inhibitor (TFPI), an antithrombotic agent associated with coronary disease that we found to be more than 2 times downregulated. Taken together, these data show differential endothelial protein regulation and secretion upon 7KC exposure for short time periods under non-toxic conditions. Herewith, these data support the role of 7KC in atherosclerosis pathophysiology and thus reinforce the deleterious effect of endothelial cells stress in the arterial microenvironment. PMID- 28663070 TI - Poetry in motion: Increased chromosomal mobility after DNA damage. AB - Double-strand breaks (DSBs) are among the most lethal DNA lesions, and a variety of pathways have evolved to manage their repair in a timely fashion. One such pathway is homologous recombination (HR), in which information from an undamaged donor site is used as a template for repair. Although many of the biochemical steps of HR are known, the physical movements of chromosomes that must underlie the pairing of homologous sequence during mitotic DSB repair have remained mysterious. Recently, several groups have begun to use a variety of genetic and cell biological tools to study this important question. These studies reveal that both damaged and undamaged loci increase the volume of the nuclear space that they explore after the formation of DSBs. This DSB-induced increase in chromosomal mobility is regulated by many of the same factors that are important during HR, such as ATR-dependent checkpoint activation and the recombinase Rad51, suggesting that this phenomenon may facilitate the search for homology. In this perspective, we review current research into the mobility of chromosomal loci during HR, as well as possible underlying mechanisms, and discuss the critical questions that remain to be answered. Although we focus primarily on recent studies in the budding yeast, Saccharomyces cerevisiae, examples of experiments performed in higher eukaryotes are also included, which reveal that increased mobility of damaged loci is a process conserved throughout evolution. PMID- 28663072 TI - Automatic prediction of coronary artery disease from clinical narratives. AB - Coronary Artery Disease (CAD) is not only the most common form of heart disease, but also the leading cause of death in both men and women (Coronary Artery Disease: MedlinePlus, 2015). We present a system that is able to automatically predict whether patients develop coronary artery disease based on their narrative medical histories, i.e., clinical free text. Although the free text in medical records has been used in several studies for identifying risk factors of coronary artery disease, to the best of our knowledge our work marks the first attempt at automatically predicting development of CAD. We tackle this task on a small corpus of diabetic patients. The size of this corpus makes it important to limit the number of features in order to avoid overfitting. We propose an ontology guided approach to feature extraction, and compare it with two classic feature selection techniques. Our system achieves state-of-the-art performance of 77.4% F1 score. PMID- 28663073 TI - A study of the suitability of autoencoders for preprocessing data in breast cancer experimentation. AB - Breast cancer is the most common cause of cancer death in women. Today, post transcriptional protein products of the genes involved in breast cancer can be identified by immunohistochemistry. However, this method has problems arising from the intra-observer and inter-observer variability in the assessment of pathologic variables, which may result in misleading conclusions. Using an optimal selection of preprocessing techniques may help to reduce observer variability. Deep learning has emerged as a powerful technique for any tasks related to machine learning such as classification and regression. The aim of this work is to use autoencoders (neural networks commonly used to feed deep learning architectures) to improve the quality of the data for developing immunohistochemistry signatures with prognostic value in breast cancer. Our testing on data from 222 patients with invasive non-special type breast carcinoma shows that an automatic binarization of experimental data after autoencoding could outperform other classical preprocessing techniques (such as human dependent or automatic binarization only) when applied to the prognosis of breast cancer by immunohistochemical signatures. PMID- 28663074 TI - Impact of preoperative wait time due to insurance-mandated medically supervised diets on weight loss after sleeve gastrectomy. Are patients losing momentum? AB - BACKGROUND: Few studies have examined whether preoperative period length, as defined by the amount of time from enrollment in a surgical weight loss program to the day of surgery, affects postoperative weight loss. OBJECTIVES: To identify associations between preoperative period length and postoperative weight loss. SETTING: Single surgeon at an academic medical center in the United States. METHODS: Retrospective chart review in 109 consecutive patients undergoing sleeve gastrectomy from 2014-2015. RESULTS: When patients were grouped based on postoperative percentage of total weight loss, greater weight loss was associated with shorter preoperative wait time. During the preoperative period, 72.2% of our patients achieved a net weight loss, but 34.6% had gained net weight until they started the preoperative "liver-shrinking" diet; 71.4+/-8.3% of the total preoperative weight loss occurred after initiating the preoperative diet, which accounted for approximately 15% of the whole preoperative period length. There was no correlation between the length of the preoperative diet and preoperative weight loss. CONCLUSIONS: Shorter preoperative periods and earlier initiation of liver reduction diets may increase postoperative weight loss, although ultimately there may be a limit to the weight loss that patients can achieve while adhering to highly restrictive lifestyle modifications. PMID- 28663075 TI - A comparison of perceived and calculated weight status classification congruence between pre- and post-bariatric surgery patients. AB - BACKGROUND: One prominent reason patients undergo bariatric surgery is to reduce their excess weight and body mass index. Weight status classifications (WSCs), based on calculated body mass index, organize patients into distinct groups (underweight, healthy weight, overweight, class I obesity, class II obesity, and class III obesity) for treatment recommendations, including surgery for patients with obesity. Bariatric patients' perceptions of their WSC is important to consider, because patients who accurately perceive their WSC presurgery have greater motivation for health behavior changes; alternatively, incongruence between perceived and calculated WSC could deter motivation and ultimately their health changes postsurgery. OBJECTIVES: This study seeks to understand the congruence between patients' perceived and calculated WSC, and to determine if there are differences in congruence between groups of pre- or postsurgery, male and female, and emerging/early adulthood and middle/late adulthood patients. SETTING: University Hospital. METHODS: Self-report measures. RESULTS: Results indicate the presurgery patients were more congruent in their perceptions of WSC compared with their postsurgery peers and emerging/early adulthood patients were more congruent in their perceptions of WSC compared with middle/late adulthood patients. No gender differences emerged in the full sample, but when divided by surgical status, presurgery females reported more congruent perceptions of WSC compared with their postsurgery peers. Males did not differ in their rates of congruence. CONCLUSION: These rates of incongruence may suggest a need for assessment of patients' perceived WSC, particularly postsurgery. PMID- 28663076 TI - Family functioning and parents' dispositions moderate the affective, attentional and physiological consequences of rumination in children. AB - In adults, rumination has been associated with costs at affective, cognitive, and physiological levels. We examined if rumination in children is characterized by the same dysfunctional consequences and the possible moderating role of family functioning (cohesion and flexibility) and parents' trait rumination and depression. After induction of rumination, forty children (20 girls; 9.6 years) performed a tracking task with thought probes while their mood, reaction times (RT), heart rate (HR), and variability (HRV) were assessed. Self-reported episodes of rumination were associated with higher HR, lower HRV, mood worsening, and slower RT compared to being on task. Moderation analysis suggested that children's slower RT during ruminative thinking were associated with greater trait rumination in mothers and less flexibility in the family, whereas higher HR and lower HRV during rumination in children were associated with less family cohesion. Findings help our understanding of the person-environment interaction in modulating the costs of rumination. PMID- 28663077 TI - Antioxidants reduce reactive oxygen species but not embryotoxicity in the metabolic Danio rerio test (mDarT). AB - Mammalian liver microsomes are occasionally used as a metabolic activation system (MAS) to compensate for the low CYP-mediated bioactivation of drugs in zebrafish embryos, in the so-called mDarT. However, this MAS is embryotoxic and consequently zebrafish embryos are only exposed during a very limited developmental window. The main aim of this study was to try to reduce the embryotoxic properties of MAS in order to extend the exposure window in the mDarT. Removing the microsomes from the incubation medium prior to exposure of the zebrafish embryos did not reduce embryotoxicity. Free radicals (ROS) in the incubation medium were successfully reduced by antioxidants, but the medium remained embryotoxic. Single dosing of NADPH or omitting toxic components from the MAS preparation did also not reduce embryotoxicity. In conclusion, the exposure window in the mDarT could not be extended by reducing ROS levels, single dosing of NADPH or modifications of the MAS preparation. PMID- 28663078 TI - Living with Multiple Myeloma: A Continuum-Based Approach to Cancer Survivorship. AB - OBJECTIVES: To describe a tailored approach to survivorship care for health care providers (HCPs) involved in the care of patients and caregivers living with multiple myeloma (MM) and identify key transition points within the continuum of care with recommended adaptation to the survivorship care plan (SCP). DATA SOURCES: Review of the literature, web-based resources. CONCLUSION: The health care needs of cancer survivors will vary throughout the continuum of care. Effective patient self-management requires several key elements: consistent and clear communication that allows the patient to make informed decisions, reinforcement of key messages at each visit, adjustment of visit frequency to the specific phase of survivorship and health care needs, integration of community programs and resources, and development of mutually determined goals. The goal is to focus on living, maintaining or improving quality of life (QOL) in the MM survivor with consideration of the needs of caregivers. IMPLICATIONS FOR NURSING PRACTICE: Implementation of a tailored survivorship care plan (SCP) based on individual disease- and treatment-related factors, personal preferences, and available resources, setting expectations, and continuing to communicate openly with the MM patients and their caregivers promotes health-self-management, reduces symptom burden, and improves QOL. Innovative strategies for survivorship care that promote communicative health literacy, engage the patient and their caregivers in health self-management, involve the survivor in developing the SCP, and clearly designate the roles of HCPs are needed. PMID- 28663079 TI - Male sex and poverty predict abrupt health decline: Deficit accumulation patterns and trajectories in the KORA-Age cohort study. AB - Ageing individuals differ both in their deficit accumulation (DA) trajectories and resulting DA patterns (improvement, stability, gradual or abrupt decline). This heterogeneity is still incompletely understood. The objectives of this study were thus to identify determinants of DA trajectories and DA patterns in people aged 65 and older. Data originates from the 2009 baseline assessment and 2012 follow-up of the KORA (Cooperative Health Research in the Region of Augsburg)-Age study from Southern Germany. DA was measured with a Frailty Index (FI). The effects of socio-demographic, socio-economic and lifestyle factors were analyzed using generalized linear mixed models and multinomial regressions. FI scores were available for 1076 participants at baseline (mean age 76years, 50% female) and 808 participants at follow-up. Higher baseline FI levels were significantly associated with higher age, female sex, lower physical activity, moderate alcohol consumption and obesity. Longitudinal increase in FI levels over 3years was 31% (CL: [-3%; 77%]) independent of all examined predictors. The most frequent DA patterns were stability (59%) and gradual decline (30%). Compared to stability, higher age, male sex and low income predicted (mostly fatal) abrupt decline. In conclusion, several factors are associated with FI levels at baseline whereas the change in FI levels over time seems hardly modifiable. Thus, future research should investigate if the same factors predicting older-age FI levels constitute predictors of DA onset earlier in life. Towards the end of life, being male with low income may increase the risk for abrupt decline, indicating need for early detection. PMID- 28663080 TI - Free will in Bayesian and inverse Bayesian inference-driven endo-consciousness. AB - How can we link challenging issues related to consciousness and/or qualia with natural science? The introduction of endo-perspective, instead of exo perspective, as proposed by Matsuno, Rossler, and Gunji, is considered one of the most promising candidate approaches. Here, we distinguish the endo-from the exo perspective in terms of whether the external is or is not directly operated. In the endo-perspective, the external can be neither perceived nor recognized directly; rather, one can only indirectly summon something outside of the perspective, which can be illustrated by a causation-reversal pair. On one hand, causation logically proceeds from the cause to the effect. On the other hand, a reversal from the effect to the cause is non-logical and is equipped with a metaphorical structure. We argue that the differences in exo- and endo perspectives result not from the difference between Western and Eastern cultures, but from differences between modernism and animism. Here, a causation-reversal pair described using a pair of upward (from premise to consequence) and downward (from consequence to premise) causation and a pair of Bayesian and inverse Bayesian inference (BIB inference). Accordingly, the notion of endo-consciousness is proposed as an agent equipped with BIB inference. We also argue that BIB inference can yield both highly efficient computations through Bayesian interference and robust computations through inverse Bayesian inference. By adapting a logical model of the free will theorem to the BIB inference, we show that endo-consciousness can explain free will as a regression of the controllability of voluntary action. PMID- 28663081 TI - Cytotoxic aspidofractinine alkaloids from Kopsia hainanensis. AB - Five new aspidofractinine-type alkaloids, kopsiahainins A-E (1-5), were isolated from a 80% EtOH extract of the leaves and stems of Kopsia hainanensis. Structural elucidation of all the compounds were performed by spectral methods such as 1D- and 2D-NMR, IR, UV, and HR-ESI-MS. Alkaloids 3 and 4 exhibited some cytotoxic activity against all of six tested tumor cell lines (BGC-823, HepG2, MCF-7, SGC 7901, SK-MEL-2, and SK-OV-3) with IC50 values of 7.3-9.5MUM and 9.2-10.6MUM, respectively. PMID- 28663082 TI - p16 expression in cutaneous squamous cell carcinoma of the head and neck is not associated with integration of high risk HPV DNA or prognosis. AB - Head and neck cutaneous squamous cell carcinoma (HNcSCC) can present with cervical metastases without an obvious primary. Immunohistochemistry for p16 is established as a surrogate marker of human papillomavirus (HPV) in oropharyngeal cancer. p16 expression in HNcSCC needs to be elucidated to determine its utility in predicting the primary site. The aim of this study was to evaluate the rate of p16 expression in HNcSCC and its association with prognostic factors and survival. p16 immunohistochemistry was performed on 166 patients with high risk HNcSCC (2000-2013) following histopathology review. Chromogenic in situ hybridisation (CISH) for HPV was performed. Fifty-three (31.9%) cases showed strong, diffuse nuclear and cytoplasmic p16 expression including 14 (41%) non metastatic and 39 (29.5%) metastatic tumours (p=0.21). HPV CISH was negative in all cases. p16 expression significantly increased with poorer differentiation (p=0.033), but was not associated with size (p=0.30), depth of invasion (p=0.94), lymphovascular invasion (p=0.31), perineural invasion (p=0.69), keratinisation (p=0.99), number of involved nodes (p=0.64), extranodal extension (p=0.59) or survival. Nearly 32% of HNcSCCs, particularly poorly differentiated HNcSCCs, show p16 expression. A primary HNcSCC should be considered in p16 positive neck node metastases in regions with high prevalence of HNcSCC. p16 expression is not associated with improved survival in HNcSCC. PMID- 28663083 TI - Brunner's gland cyst: a clinicopathological study of 25 cases highlighting an underappreciated lesion. AB - Brunner's gland cysts are rare, benign lesions of the duodenum usually seen as incidental, polypoid or cystic lesions of the duodenum. We present a series of 25 cases of Brunner's gland cyst, the largest case series to date. All the cases were identified during endoscopic assessment for unrelated causes. The mean age of the patients was 66.2 years and the sex ratio was approximately equal. Most were detected as a small (3-10 mm) polypoid lesion in the second part of the duodenum, away from the ampulla. Most of the cysts were unilocular and all were lined by undulating, cytologically bland cuboidal to columnar cells with clear cytoplasm and small, basal nuclei. No mitotic activity or proliferative activity was seen. No recurrence was noted, despite incomplete removal in many cases. We agree with the hypothesis that Brunner's gland cysts are likely to be caused by local obstruction to the draining duct of Brunner's glands. PMID- 28663084 TI - Crystallographic and theoretical studies of an inclusion complex of beta cyclodextrin with fentanyl. AB - The crystal structure of an inclusion complex of beta-cyclodextrin (beta-CD) with fentanyl was determined by single crystal X-ray diffraction analysis. The crystal belongs to the triclinic space group P1 and the complex comprises one fentanyl, two beta-CD, and several water molecules. beta-CD and fentanyl form a host-guest inclusion complex at a ratio of 2:1 and the asymmetric unit of the complex contains two host molecules (beta-CDs) in a head-to-head arrangement that form dimers through hydrogen bonds between the secondary hydroxyl groups of beta-CD and one guest molecule. Fentanyl is totally contained within the beta-CD cavity and the structure of the phenylethyl part of fentanyl inside the dimeric cavity of the complex is disordered. Furthermore, theoretical molecular conformational calculations were conducted to clarify the mobility of the guest molecule in the beta-CD cavity using CONFLEX software. Crystal optimization and crystal energy calculations were also conducted. The results of the theoretical calculations confirmed that the conformation of disorder part 1, which was high in occupancy by crystal structure analysis, was more stable. The phenylethyl part of fentanyl existed in several stable conformations. PMID- 28663085 TI - Spectroscopic and structural studies of the diosmin monohydrate and anhydrous diosmin. AB - Diosmin, a flavone glycoside frequently used in therapy of various veins diseases in monohydrate form, exhibits poor solubility in water and low bioavailability. Due to the fact that the anhydrous forms of drugs generally have better bioavailability than the corresponding hydrates, the aim of this study was to analyze the conversion of diosmin monohydrate (DSNM) to anhydrous diosmin (DSNA) that occurs upon heating. The mechanism of this transformation was examined as well as advanced structural studies of each form were performed using 13C CP/MAS SSNMR, DSC, FT-IR and PXRD techniques. Spectroscopic findings were supported by CASTEP-DFT calculations of NMR and IR parameters. The pathway of reversible transformation was specified as follows: DSNM upon heating for 24h at temperature up to 110 degrees C losses non-crystalline water and converts into metastable form (DSNM*) that turns into DSNA during heating at temperature 140 degrees C for next 24h. Under room temperature DSNA spontaneously absorbs moisture from air and turns into a DSNM within 72h. The detailed analysis of CP kinetic parameters (T1rhoI) revealed presence of metastable, intermediate form of diosmin (DSNM*) and allowed its characterization. The results are essential for further studies comparing dissolution and bioavailability of DSNM and DSNA. The study provided an understanding of the conversion pathway of the diosmin monohydrate into its anhydrate form when it is exposed to increased temperature. PMID- 28663086 TI - Chitosan centered bionanocomposites for medical specialty and curative applications: A review. AB - The polyfunctional nature of chitosan enables its application not only in polymer technology but also shows their importance in the field of nanotechnology for the fabrication of the wide spectrum of functional nanomaterials in biomedical field. Chitosan is a poly aminosaccharide with appealing structure composed of beta-(1 >4)-linked D-glucosamine (deacetylated unit) and N-acetyl-d-glucosamine (acetylated unit). It has various functional groups that enriches for various properties such as antibacterial, mucoadhasive, nontoxic, biodegradable, biocompatible. With the advancement of material technologies, chitosan is being chemically modified into self-assembled nanocomposites for advanced biomedical applications. This review article demonstrate the various schemes for the preparation of chitosan nanocomposites from different functional material, focusing on their application specifically in tissue engineering, drug and gene delivery, wound healing and bioimaging. PMID- 28663087 TI - Superiority of aromatase inhibitor and cyclooxygenase-2 inhibitor combined delivery: Hyaluronate-targeted versus PEGylated protamine nanocapsules for breast cancer therapy. AB - Despite several reports have revealed the beneficial effect of co-administration of COX-2 inhibitors with aromatase inhibitors in managing postmenopausal breast cancer; no nanocarriers for such combined delivery have been developed till now. Therefore, protamine nanocapsules (PMN-NCs) have been developed to co-deliver letrozole (LTZ) that inhibits aromatase-mediated estrogen biosynthesis and celecoxib (CXB) that synergistically inhibits aromatase expression. Inspired by the CD44-mediated tumor targeting ability of hyaluronate (HA), we developed HA coated PMN-NCs (HA-NCs) via electrostatic layer-by-layer assembly. Moreover, multi-compartmental PEGylated phospholipid-CXB complex bilayer enveloping PMN-NCs (PEG-NCs) were designed for conferring biphasic CXB release from the phospholipid corona and oily core as well as enabling passive-targeting. The NCs demonstrated excellent stability, prolonged circulation and could be scaled up with the aid of spray-drying technology. Hemolysis, serum stability and cytotoxicity studies confirmed the superiority of combined LTZ-CXB nano-delivery. Mechanistically, the NCs especially HA-NCs and PEG-NCs demonstrated precious anti-tumor effects in vivo revealed as reduction in the tumor volume and aromatase level, increased apoptosis, as well as inhibition of VEGF, NF-kappaB and TNF-alpha augmented by histopathological and immunohistochemical studies. Overall, our approach provided for the first time a potential strategy for targeted LTZ-CXB combined therapy of hormone-dependent breast cancer via singular nanocapsule delivery system. PMID- 28663088 TI - Thermoplastic polyurethane-based intravaginal rings for prophylaxis and treatment of (recurrent) bacterial vaginosis. AB - The aim of the present study was to develop thermoplastic polyurethane (TPU) based intravaginal rings (IVRs) for prophylaxis and treatment of bacterial vaginosis via hot melt extrusion/injection molding. Therefore, different TPU grades were processed in combination with lactic acid or metronidazole, targeting a sustained lactic acid release over a 28day-period and sustained metronidazole release over 4-7days. Hot melt extrusion of lactic acid/TPU combinations required a lower extrusion temperature due to the plasticizing properties of lactic acid, evidenced by the lower glass transition temperature (Tg) and cross-over point (Ttandelta=1) values. NIR-chemical imaging data showed a homogenous distribution of lactic acid in TPU matrices at drug loads up to 30% (w/w). The addition of metronidazole did not lower processing temperatures, as the active pharmaceutical ingredient remained crystalline in the TPU matrix. Hydrophobic TPUs with a low ratio between the soft and hard segments (SS/HS ratio) in the polymer structure were suitable carriers for the lactic acid-eluting device over a 28-day period, while hydrophilic TPUs were needed to achieve the required release rate of metronidazole-eluting IVRs. IVRs manufactured with a TPU grade having a higher SS/HS ratio and lactic acid/TPU ratio exhibited a more elastic behavior. The addition of 25% (w/w) metronidazole did not affect the mechanical properties of the IVRs. Hydrophilic TPUs were most prone to biofilm formation by Candida albicans and Staphylococcus aureus, but the incorporation of metronidazole in the device prevented biofilm formation. Based on the drug eluting performance and mechanical tests, a mixture of lactic acid and TecoflexTM EG-93A (20/80, w/w) and a combination of metronidazole and TecophilicTM SP-93A-100 (25/75, w/w) were selected to design IVRs for the prophylaxis and treatment of bacterial vaginosis, respectively. Slug mucosal irritation tests predicted low irritation potency for both devices. PMID- 28663089 TI - Sinomenine produces peripheral analgesic effects via inhibition of voltage-gated sodium currents. AB - Sinomenium acutum has been used in traditional medicine to treat a painful disease such as rheumatic arthritis and neuralgia. Sinomenine, which is a main bioactive ingredient in Sinomenium acutum, has been reported to have an analgesic effect in diverse pain animal models. However little is known about the detailed mechanisms underlying peripheral analgesic effect of sinomenine. In the present study, we aimed to elucidate its cellular mechanism by using formalin-induced acute inflammatory pain model in mice. We found that intraperitoneal (i.p.) administration of sinomenine (50mg/kg) suppressed formalin-induced paw licking behavior in both the first and the second phase. Formalin-induced c-Fos protein expression was also suppressed by sinomenine (50mg/kg i.p.) in the superficial dorsal horn of spinal cord. Whole-cell patch-clamp recordings from small-sized dorsal root ganglion (DRG) neurons revealed that sinomenine reversibly increased the spike threshold and the threshold current intensity for evoking a single spike and decreased firing frequency of action potentials evoked in response to a long current pulse. Voltage-gated sodium currents (INa) were also significantly reduced by sinomenine in a dose-dependent manner (IC50=2.3+/-0.2mM). Finally, we confirmed that intraplantar application of sinomenine suppressed formalin-induced pain behavior only in the first phase, but not the second phase. Taken together, our results suggest that sinomenine has a peripheral analgesic effect by inhibiting INa. PMID- 28663090 TI - Patterns of activation and de-activation associated with cue-guided spatial navigation: A whole-brain, voxel-based study. AB - Functional imaging studies have implicated the hippocampus and parahippocampal gyrus in cue-guided spatial navigation, but also many other regions. Furthermore, little is known about de-activations that take place during performance of navigation tasks, something that is of interest given that the hippocampus is a component of the default mode network, which de-activates during attention demanding tasks. In this study 22 healthy subjects underwent whole-brain functional Magnetic Resonance Imaging (fMRI) while they navigated toward a previously learned goal in a virtual reality environment. At a threshold of p<0.05 corrected, the subjects showed a pattern of widespread cortical activations, including the parahippocampal and retrosplenial cortex and also parts of the frontal, temporal and occipital cortex. Hippocampal activation, however, was restricted to the posterior portion of the structure bilaterally. De activations were seen in the medial frontal cortex and other regions of the default mode network, but not in the posterior cingulate cortex/precuneus. The findings support the involvement of the hippocampus in cue-guided navigation, but suggest that its posterior regions are particularly important. Cue-guided spatial navigation is associated with de-activation in some but not all parts of the default mode network. PMID- 28663091 TI - Locomotion in intact and in brain cortex-ablated cats. AB - The current decerebration procedures discard the role of the thalamus in the motor control and decortication only rules out the brain cortex part, leaving a gap between the brain cortex and the subthalamic motor regions. In here we define a new preparation denominated Brain Cortex-Ablated Cat (BCAC), in which the frontal and parietal brain cortices as well as the central white matter beneath them were removed, this decerebration process may be considered as suprathalamic, since the thalamus remained intact. To characterize this preparation cat hindlimb electromyograms (EMG), kinematics and cutaneous reflexes (CR) produced by electrical stimulation of sural (SU) or saphenous (SAPH) nerves were analyzed during locomotion in intact and in BCAC. In cortex-ablated cats compared to intact cats, the hindlimb EMG amplitude was increased in the flexors, whereas in most extensors the amplitude was decreased. Bifunctional muscle EMGs presented complex and speed-dependent amplitude changes. In intact cats CR produced an inhibition of extensors, as well as excitation and inhibition of flexors, and a complex pattern of withdrawal responses in bifunctional muscles. The same stimuli applied to BCAC produced no detectable responses, but in some cats cutaneous reflexes produced by electrical stimulation of saphenous nerve reappeared when the locomotion speed increased. In BCAC, EMG and kinematic changes, as well as the absence of CR, imply that for this cat preparation there is a partial compensation due to the subcortical locomotor apparatus generating close to normal locomotion. PMID- 28663092 TI - Nicotinic activity depresses synaptic potentiation in layer V pyramidal neurons of mouse insular cortex. AB - The insular cortex is a critical brain region involved in nicotine addiction. However, its specific cellular and synaptic mechanisms underlying nicotine addiction remains largely unknown. In the present study, we examined how nicotine modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex. We also examined which type of neurons express functional nicotinic acetylcholine receptors (nAChRs) in layer V of the insular cortex. We found that nicotine suppresses synaptic potentiation induced by combination of presynaptic stimulation with postsynaptic depolarization (paired training). An application of nicotine significantly enhanced both spontaneous excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs): the former effect was mediated by activation of beta2-containing nAChRs while the latter one was mediated largely by activation of beta2-containing nAChRs and to a minor extent by activation of alpha7-containing nAChRs. The application of nicotine significantly enhanced evoked IPSCs but had no effect on evoked EPSCs. We also found that in layer V of the mouse insular cortex, majority of non-fast-spiking (non-FS) interneurons have beta2-containing nAChRs while about half of pyramidal neurons and FS interneurons have functional nAChRs. Blockade of GABAA receptors or beta2-containing nAChRs prevented the effects of nicotine on synaptic potentiation. Taken together, these results suggest that in layer V pyramidal neurons of the insular cortex, activation of beta2-containing nAChRs expressed in non-FS interneurons suppresses synaptic potentiation through enhancing GABAergic synaptic transmission. These findings provide important insights into the cellular and synaptic mechanisms of insular cortical changes in nicotine addiction. PMID- 28663093 TI - Heat stress-induced neuroinflammation and aberration in monoamine levels in hypothalamus are associated with temperature dysregulation. AB - Heat Stress (HS) induces diverse pathophysiological changes, which include brain ischemia, oxidative stress and neuronal damage. The present study was undertaken with the objective to ascertain whether neuroinflammation in Hypothalamus (HTH) caused under HS affects monoamine levels and hence, its physiological role in thermoregulation. Rats were exposed to HS in a heat simulation environmental chamber (Ambient temperature, Ta=45+/-0.5 degrees C and Relative Humidity, RH=30+/-10%) with real-time measurement of core temperature (Tc) and skin temperature (Ts). Animals were divided into two subgroups: Moderate HS (MHS) (Tc=40 degrees C) and Severe HS (SHS)/Heat stroke (Tc=42 degrees C). Rats with MHS showed an increase in Mean Arterial Pressure (MAP) and Heart Rate (HR) while fall in MAP and rise in HR was observed in rats with SHS. In addition, oxidative stress and an increase in pyknotic neurons were observed in HTH. High levels of Adrenocorticotropic-hormone (ACTH), Epinephrine (EPI), Norepinephrine (NE) and Dopamine (DA) in the systemic circulation and progressive increase in EPI and DA levels in HTH were recorded after the thermal insult. Moreover, a substantial increase in Glutamate (Glu) level was observed in HTH as well as in systemic circulation of heat stroke rats. We found a rise in NE whereas a fall in Serotonin (5-HT) level in HTH at MHS, without perturbing inflammatory mediators. However, rats with SHS exhibited significant elevations in NF-kB, IL-1beta, COX2, GFAP and Iba1 protein expression in HTH. In conclusion, the data suggest that SHS induces neuroinflammation in HTH, which is associated with monoamines and Glu imbalances, leading to thermoregulatory disruption. PMID- 28663094 TI - Homeostatic interplay between electrical activity and neuronal apoptosis in the developing neocortex. AB - An intriguing feature of nervous system development in most animal species is that the initial number of generated neurons is higher than the number of neurons incorporated into mature circuits. A substantial portion of neurons is indeed eliminated via apoptosis during a short time window - in rodents the first two postnatal weeks. While it is well established that neurotrophic factors play a central role in controlling neuronal survival and apoptosis in the peripheral nervous system (PNS), the situation is less clear in the central nervous system (CNS). In postnatal rodent neocortex, the peak of apoptosis coincides with the occurrence of spontaneous, synchronous activity patterns. In this article, we review recent results that demonstrate the important role of electrical activity for neuronal survival in the neocortex, describe the role of Ca2+ and neurotrophic factors in translating electrical activity into pro-survival signals, and finally discuss the clinical impact of the tight relation between electrical activity and neuronal survival versus apoptosis. PMID- 28663095 TI - Meta-analysis of stem cell transplantation for reflex hypersensitivity after spinal cord injury. AB - Stem cells have been used in novel therapeutic strategies for spinal cord injury (SCI), but the effect of stem cell transplantation on neuropathic pain after SCI is unclear. The current meta-analysis evaluates the effects of stem cell transplantation on neuropathic pain after SCI. We first conducted online searches of PubMed, Web of Science, China Academic Journals Full-text Database, and Wanfang Data for randomized controlled trials that compared stem cell transplantation and vehicle treatments in rodent models of neuropathic pain after SCI. Quality assessment was performed using Cochrane Reviewer's Handbook 5.1.0, and meta-analysis was conducted with RevMan 5.3. Then, we developed a rat model of SCI and transplanted bone marrow mesenchymal stem cells to verify meta analysis results. Twelve randomized, controlled trials (n=354 total animals) were included in our meta-analysis and divided by subgroups, including species, timing of behavioral measurements, and transplantation time after SCI. Subgroup analysis of these 12 studies indicated that stem cell-treated animals had a higher mechanical reflex threshold than vehicle groups, with a significant difference in both rats and mice. The thermal withdrawal latency showed the same results in mouse subgroups, but not in rat subgroups. In addition, mesenchymal stem cell transplantation was an effective treatment for mechanical, but not thermal reflex hypersensitivity relief in rats. Transplantation showed a positive effect when carried out at 3 or 7days post-SCI. Stem cell transplantation alleviates mechanical reflex hypersensitivity in rats and mice and thermal reflex hypersensitivity in mice after SCI. PMID- 28663097 TI - Interleukin 17A in atherosclerosis - Regulation and pathophysiologic effector function. AB - This review summarizes the current data on the interleukin (IL)-17A pathway in experimental atherosclerosis and clinical data. IL-17A is a prominent cytokine for early T cell response produced by both innate and adaptive leukocytes. In atherosclerosis, increased total IL-17A levels and expression in CD4+ T helper and gammadelta T cells have been demonstrated. Cytokines including IL-6 and TGFbeta that increase IL-17A expression are elevated. Many other factors such as lipids, glucose and sodium chloride concentrations as well as vitamins and arylhydrocarbon receptor agonists that promote IL-17A expression are closely associated with cardiovascular risk in the human population. In acute inflammation models, IL-17A mediates innate leukocyte recruitment of both neutrophils and monocytes. In atherosclerosis, IL-17A increased aortic macrophage and T cell infiltration in most models. Secondary recruitment effects via the endothelium and according to recent data also pericytes have been demonstrated. IL-17 receptor A is highly expressed on monocytes and direct effects have been reported as well. Beyond leukocyte accumulation, IL-17A may affect other factors of plaque formation such as endothelial function, and according to some reports, fibrous cap formation and vascular relaxation with an increase in blood pressure. Anti-IL-17A agents are now available for clinical use. Cardiovascular side effect profiles are benign at this point. IL-17A appears to be a differential regulator of atherosclerosis and its effects in mouse models suggest that its modulation may have contradictory effects on plaque size and possibly stability in different patient populations. PMID- 28663096 TI - Genotype-phenotype correlation and identification of two novel SRD5A2 mutations in 33 Chinese patients with hypospadias. AB - Hypospadias, a common congenital malformation of male external genitalia, is characterized mainly by an aberrant opening of the urethra on the ventral side of the penis. Depending on the severity of the disease, it can be classified into three types: anterior, middle, and posterior. In our study, 33 patients with hypospadias were recruited, including eight with anterior hypospadias and 25 with posterior hypospadias. We performed mutation analysis of the SRD5A2, AR and HSD17B3 genes in these patients. Eight different SRD5A2 mutations were detected in 15 patients with posterior hypospadias (60%, 15/25), including six previously described mutations (p.Q6X, Q71X, p.L20P, p.G203S, p.R227Q, and p.R246Q) and two novel mutations (p.G196R and p.L73Pfs*17). One AR gene mutation (p.A597T) was found in a patient and no HSD17B3 mutations were detected. Additionally, we carried out routine semen analyses in all adult patients. Combing mutation analysis with semen examination results, showed that whole five adult patients who carried SRD5A2 mutations had abnormal semen quality. In summary, all the detected mutations were responsible for the clinical features observed in these 16 patients. Our data suggest that mutations of the SRD5A2 gene are the main causes of posterior hypospadias and seem to affect the semen quality of adult patients, whereas mutations in AR and HSD17B3 gene were rare in these hypospadias patients. Our study expanded the SRD5A2 mutation spectrum in the Han Chinese population and provided useful information for genetic and reproductive counselling for patients with hypospadias. PMID- 28663098 TI - Impact Factor Revisited. PMID- 28663099 TI - Microsporidia: An Emerging Threat to Bumblebees? AB - Microsporidia may cause emerging infectious diseases (EIDs) in bumblebees. Two drivers - commercial bumblebees and managed honey bees - have been identified as possible sources of pathogen spillover. In addition, declines in bumblebee populations may have led to lower genetic diversity and subsequent higher susceptibility to infection, enabling microsporidia to increase in prevalence. There is strong evidence for relatively recent increases in the prevalence of Nosema bombi in North America. However, the lack of definitive data on spillover by microsporidia, in North America or elsewhere, makes it difficult to identify the causes of such increases. Phylogenomic studies are urgently needed to identify the global population structure of microsporidia in bumblebees, and thus identify the source of current and future epidemics. PMID- 28663100 TI - A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model. AB - One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1G93A mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD). Skipping of hSOD1 exon 2 led to the generation of a premature termination codon, inducing production of a deleted transcript that was subsequently degraded by the activation of nonsense-mediated decay. Combined intravenous and intracerebroventricular delivery of AAV10-U7-hSOD increased the survival of SOD1G93A mice injected either at birth or at 50 days of age (by 92% and 58%, respectively) and prevented weight loss and the decline of neuromuscular function. This study reports the effectiveness of an exon-skipping approach in SOD1-ALS mice, supporting the translation of this technology to the treatment of this as yet incurable disease. PMID- 28663101 TI - Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells. AB - Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 * 108 to 1 * 109 CD34+ cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34+ cells uses LV inefficiently, because the majority of CD34+ cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34+CD38- cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34+CD38- cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34+ purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34+CD38- cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38+ cells. Importantly, LV modification and transplantation of IB-purified CD34+CD38- cells/non-modified CD38+ cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34+ cells, while utilizing ~7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases. PMID- 28663102 TI - RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus. AB - RNase H1-dependent antisense oligonucleotides (ASOs) are active in reducing levels of both cytoplasmic mRNAs and nuclear retained RNAs. Although ASO activity in the nucleus has been well demonstrated, the cytoplasmic activity of ASOs is less clear. Using kinetic and subcellular fractionation studies, we evaluated ASO activity in the cytoplasm. Upon transfection, ASOs targeting exonic regions rapidly reduced cytoplasmically enriched mRNAs, whereas an intron-targeting ASO that only degrades the nuclear pre-mRNA reduced mRNA levels at a slower rate, similar to normal mRNA decay. Importantly, some exon-targeting ASOs can rapidly and vigorously reduce mRNA levels without decreasing pre-mRNA levels, suggesting that pre-existing cytoplasmic mRNAs can be cleaved by RNase H1-ASO treatment. In addition, we expressed a cytoplasm-localized mutant 7SL RNA that contains a partial U16 small nucleolar RNA (snoRNA) sequence. Treatment with an ASO simultaneously reduced both the nuclear U16 snoRNA and the cytoplasmic 7SL mutant RNA as early as 30 min after transfection in an RNase H1-dependent manner. Both the 5' and 3' cleavage products of the 7SL mutant RNA were accumulated in the cytoplasm. Together, these results demonstrate that RNase H1-dependent ASOs are robustly active in both the cytoplasm and nucleus. PMID- 28663105 TI - Does good critical thinking equal effective decision-making among critical care nurses? A cross-sectional survey. AB - BACKGROUND: A critical thinker may not necessarily be a good decision-maker, but critical care nurses are expected to utilise outstanding critical thinking skills in making complex clinical judgements. Studies have shown that critical care nurses' decisions focus mainly on doing rather than reflecting. To date, the link between critical care nurses' critical thinking and decision-making has not been examined closely in Malaysia. AIM: To understand whether critical care nurses' critical thinking disposition affects their clinical decision-making skills. METHOD: This was a cross-sectional study in which Malay and English translations of the Short Form-Critical Thinking Disposition Inventory-Chinese Version (SF CTDI-CV) and the Clinical Decision-making Nursing Scale (CDMNS) were used to collect data from 113 nurses working in seven critical care units of a tertiary hospital on the east coast of Malaysia. Participants were recruited through purposive sampling in October 2015. RESULTS: Critical care nurses perceived both their critical thinking disposition and decision-making skills to be high, with a total score of 71.5 and a mean of 48.55 for the SF-CTDI-CV, and a total score of 161 and a mean of 119.77 for the CDMNS. One-way ANOVA test results showed that while age, gender, ethnicity, education level and working experience factors significantly impacted critical thinking (p<0.05), only age and working experience significantly impacted clinical decision-making (p<0.05). Pearson's correlation analysis showed a strong and positive relationship between critical care nurses' critical thinking and clinical decision-making (r=0.637, p=0.001). CONCLUSION: While this small-scale study has shown a relationship exists between critical care nurses' critical thinking disposition and clinical decision-making in one hospital, further investigation using the same measurement tools is needed into this relationship in diverse clinical contexts and with greater numbers of participants. Critical care nurses' perceived high level of critical thinking and decision-making also needs further investigation. PMID- 28663104 TI - Causal effects of transitions to adult roles on early adult smoking and drinking: Evidence from three cohorts. AB - Transitions into work and family roles have become increasingly delayed as participation in tertiary education widens. Such transitions may have adverse or beneficial effects on health behaviours such as smoking and drinking (alcohol). Role socialisation effects may reduce smoking or drinking, but clustering of transitions may lead to role overload, weakening or reversing any role socialisation effects. Effects of transitions were examined in three UK cohorts: the 1958 National Child Development Study, the 1970 British Birth Cohort Study, and the West of Scotland: Twenty-07 Youth Cohort (from around Glasgow, growing up in the same time period as the 1970 cohort). Latent class analysis was employed to identify heterogeneous patterns of transition timing for leaving education, entering employment, starting cohabitation, having a first child, and leaving the parental home. Propensity weighting was then used to estimate causal effects of transition patterns (relative to tertiary education) on smoking and heavy drinking in early adulthood (ages 22-26), adjusting for background confounders (gender, parental socioeconomic position, family structure, parental and adolescent health behaviours, adolescent distress and school performance). Three groups made early (age 16) transitions from education to employment and then either delayed other transitions, made other transitions quickly, or staggered transitions with cohabitation beginning around ages 19-21; a fourth group transitioned from education to employment around ages 17-18. Compared to those in tertiary education with similar background characteristics, those in these groups generally had higher levels of smoking, especially where transitions were more clustered, but less heavy drinking (except those who delayed other transitions after moving into employment). Results partially supported role socialisation effects for drinking, and role overload effects for smoking. Wider participation in tertiary education could have helped reduce smoking levels in these cohorts, but might also have increased risk for heavy drinking. PMID- 28663106 TI - Parents' experiences and the effect on the family two years after their child was admitted to a PICU-An interview study. AB - BACKGROUND: For parents, having a child admitted to a paediatric intensive care unit (PICU) is a very stressful experience filled with anxiety. Parents are often scared and traumatised. This stress can lead to PTSD. AIM: The aim was to describe parents' experiences and the effect on the family two years after their child was admitted to a paediatric intensive care unit. MATERIAL AND METHODS: Ten parents were interviewed according to a semi-structured interview guide. An inductive approach was applied for the study and qualitative content analysis was used to analyse the data. FINDINGS: The parents carried vivid memories and they were still strongly affected by the experience of having their child admitted to a paediatric intensive care unit. They could clearly recall the environment, feelings that affected them and how they felt powerless. The relationship between the parents had been strengthened. CONCLUSION: Parents, siblings and the ill child could all show symptoms of anxiety, stress and sleeping disorders. The parents valued life differently. PMID- 28663107 TI - Prevention of central venous line associated bloodstream infections in adult intensive care units: A systematic review. AB - BACKGROUND: In adult Intensive Care Units, the complexity of patient treatment requirements make the use of central venous lines essential. Despite the potential benefits central venous lines can have for patients, there is a high risk of bloodstream infection associated with these catheters. AIM: Identify and critique the best available evidence regarding interventions to prevent central venous line associated bloodstream infections in adult intensive care unit patients other than anti-microbial catheters. METHODS: A systematic review of studies published from January 2007 to February 2016 was undertaken. A systematic search of seven databases was carried out: MEDLINE; CINAHL Plus; EMBASE; PubMed; Cochrane Library; Scopus and Google Scholar. Studies were critically appraised by three independent reviewers prior to inclusion. RESULTS: Nineteen studies were included. A range of interventions were found to be used for the prevention or reduction of central venous line associated bloodstream infections. These interventions included dressings, closed infusion systems, aseptic skin preparation, central venous line bundles, quality improvement initiatives, education, an extra staff in the Intensive Care Unit and the participation in the 'On the CUSP: Stop Blood Stream Infections' national programme. CONCLUSIONS: Central venous line associated bloodstream infections can be reduced by a range of interventions including closed infusion systems, aseptic technique during insertion and management of the central venous line, early removal of central venous lines and appropriate site selection. PMID- 28663103 TI - Quantitative Imaging Approaches to Study the CAR Immunological Synapse. AB - The lytic immunological synapse (IS) is a discrete structural entity formed after the ligation of specific activating receptors that leads to the destruction of a cancerous cell. The formation of an effector cell IS in cytotoxic T lymphocytes or natural killer cells is a hierarchical and stepwise rearrangement of structural and signaling components and targeted release of the contents of lytic granules. While recent advances in the generation and testing of cytotoxic lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated their efficacy in the targeted lysis of tumor targets, the contribution and dynamics of IS components have not yet been extensively investigated in the context of engineered CAR cells. Understanding the biology of the CAR IS will be a powerful approach to efficiently guide the engineering of new CARs and help identify mechanistic problems in existing CARs. Here, we review the formation of the lytic IS and describe quantitative imaging-based measurements using multiple microscopy techniques at a single cell level that can be used in conjunction with established population-based assays to provide insight into the important cytotoxic function of CAR cells. The inclusion of this approach in the pipeline of CAR product design could be a novel and valuable innovation for the field. PMID- 28663108 TI - Expression patterns of sex differentiation-related genes during gonadal sex change in the protogynous wrasse, Halichoeres trimaculatus. AB - The three-spot wrasse, Halichoeres trimaculatus, can change sex from female to male (i.e. protogyny) due to sharp decrease in endogenous estrogen. During the sex change, ovarian tissue degenerates and testicular tissue arises newly. Finally, ovarian tissue disappears completely and replaces into mature testis. In order to predict the molecular mechanisms controlling the processes of sex change, we investigated the expression patterns of four genes (rspo1, figla, sox9b and amh), which have been thought to be associated with ovarian/testicular differentiation in vertebrates. Expression levels of rspo1 and figla, which play important roles for ovarian differentiation in vertebrates, were stable until the middle stage of the sex change, and subsequently down-regulated. Therefore, it was indicated that decrease in rspo1 and figla could result from ovarian degeneration. On the other hand, basis on the expression pattern, it was indicated that sox9b and amh, which are involved in testicular differentiation in vertebrates, were implicated in testicular formation and spermatogenesis during the sex change as well. The present results could be fundamental information for investigating the relationship between these factors and E2 depletion, which is crucial trigger for sex change. PMID- 28663109 TI - The reinforcing value and liking of resistance training and aerobic exercise as predictors of adult's physical activity. AB - OBJECTIVE: Reinforcing value (motivating value) is a stronger predictor than hedonic value (liking) for engaging in drug use, gambling, and eating. The associations of reinforcing value and liking with physical activity of adults have not yet been studied and may depend on the modes of exercise (e.g., aerobic/cardiovascular exercise, resistance training) under consideration. The purpose of this study was to test associations of the reinforcing value and liking of aerobic exercise training (AT) and resistance exercise training (RT) modes of exercise with usual participation in aerobic and resistance exercise in adults. METHODS: Men (n=38) and women (n=50) were measured for their liking and relative reinforcing value (RRV) of AT and RT, for their usual vigorous physical activity (VPA) participation, and for usual resistance exercise behavior (Yale physical activity questionnaire). RESULTS: The RRV of AT (RRVAT) and liking of AT were correlated, (r=0.22, p<0.04), as were the RRV of RT (RRVRT) and liking of RT (r=0.42, p?0.01). The reinforcing value for, but not the liking of, a mode of exercise predicted how much an individual engaged in that mode of exercise. RRVAT (p?0.01) was positively associated with usual VPA. RRVRT (p?0.01) was positively associated with RT behavior. The hedonic value of AT and of RT were not associated (p>0.30) with VPA or RT behavior. CONCLUSION: Reinforcing value of a mode of exercise is a stronger predictor than the liking of that mode of exercise for usual amount of participation in the exercise. PMID- 28663110 TI - Sucrose and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: Role of BDNF and beta endorphin. AB - Pain in neonates is associated with short and long-term adverse outcomes. Data demonstrated that long-term consequences of untreated pain are linked to the plasticity of the neonate's brain. Sucrose is effective and safe for reducing painful procedures from single events. However, the mechanism of sucrose-induced analgesia is not fully understood. The role of the opioid system in this analgesia using the opioid receptor antagonist Naltrexone was investigated, plus the long-term effects on learning and memory formation during adulthood. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution and/or naltrexone were administered before the pricks. All treatments started on day one of birth and continued for two weeks. At the end of 8weeks, behavioral studies were conducted to test spatial learning and memory using radial arm water maze (RAWM), and pain threshold via foot-withdrawal response to a hot plate. The hippocampus was dissected; levels of brain derived neurotrophic factor (BDNF) and endorphins were assessed using ELISA. Acute repetitive neonatal pain increased pain sensitivity later in life, while naltrexone with sucrose decreased pain sensitivity. Naltrexone and/or sucrose prevented neonatal pain induced impairment of long-term memory, while neonatal pain decreased levels of BDNF in the hippocampus; this decrease was averted by sucrose and naltrexone. Sucrose with naltrexone significantly increased beta-endorphin levels in noxiously stimulated rats. In conclusion, naltrexone and sucrose can reverse increased pain sensitivity and impaired long-term memory induced by acute repetitive neonatal pain probably by normalizing BDNF expression and increasing beta-endorphin levels. PMID- 28663111 TI - Seasonal behavioral responses of an arid-zone passerine in a hot environment. AB - Many arid-zone animals have to forage under extremely hot conditions to maintain water and energy balance. The effect of high air temperatures (Tair) on the behavioral patterns of small endothermic animals-characterized by their high energy and water demands-will provide a valuable framework for understanding species vulnerability to climate warming. We determined the seasonal behavioral responses to changes in Tair in a~10-g arid-zone passerine, the rufous-eared warbler (Malcorus pectoralis), in the Karoo semi-desert, South Africa. Rufous eared warblers showed significant temperature-dependence in their behavior in summer, but not in winter. During summer, the warblers frequently experienced Tair exceeding 40 degrees C in the shade. For all observations <26 degrees C compared to >36 degrees C, the warblers showed reductions in preening (40% decrease), foraging effort (56% decrease), and foraging success (15% decrease), as well as a significant increase in time spent engaged in evaporative cooling behavior. Moreover, as Tair increased the warblers shifted increasingly off the ground and out of the full sun, into microsites in the shade (131% increase) and in shrubs (23% increase). In this regard, behavior varied seasonally, with the time spent in the shade 23% higher, and foraging effort 28% higher, in summer compared to winter across a range of moderate Tair (15-30 degrees C). Our findings emphasize the link between behavior and temperature in small birds inhabiting hot, arid environments, as well as the importance of understanding these responses for predicting biologically meaningful responses (and hence, vulnerability) of arid-zone avian communities to climactic shifts. PMID- 28663113 TI - Pregnancy exposure to citalopram - Therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. AB - RATIONALE: Aim of the study was to measure and correlate citalopram concentrations in maternal blood, amniotic fluid and umbilical cord blood to account for the distribution of the drug between these three compartments. METHODS: Concentrations of citalopram were measured in twelve mother infant pairs at the time of delivery. Data are provided as median values, first (Q1) and third (Q3) quartiles as well as ranges. To account for the penetration ratio into amniotic fluid and cord blood, the concentration of citalopram in was divided by the concentration in maternal serum. Correlations between daily dosage, maternal serum concentrations and umbilical cord blood concentrations were computed for twelve patients. As amniotic fluid was only available for nine mother infant pairs, appropriate calculations are provided for these mother-infant pairs. RESULTS: The median daily dosage of citalopram was 20mg (Q1: 10mg, Q3: 20mg; range 10-40mg). The relation between the daily dosage of citalopram and its concentrations in maternal serum was highly significant (r=0.667, p=0.018). Maternal serum concentrations and cord blood concentrations were positively correlated (r=0.790, p=0.002) with a median penetration ratio into the fetal circulation of 0.78 (Q1: 0.52, Q3: 1.16, range 0.46-1.66). The median penetration ratio into amniotic fluid was 1.8 (Q1: 1.07, Q3: 2.64; range 0.52-6.97). CONCLUSIONS: Citalopram concentrations in amniotic fluid and cord blood give evidence that maternally administered citalopram is constantly accessible to the fetus via amniotic fluid. A high correlation between maternal serum concentrations of citalopram and umbilical cord blood concentrations highlights a predictive role of quantifying drug concentrations in maternal serum for assessing drug concentrations in the fetal circulation. Findings support the important role of therapeutic drug monitoring in maintaining the safety of pregnant women and exposed infants. PMID- 28663114 TI - Palatable food self-administration and reinstatement are not affected by dual orexin receptor antagonism. AB - The orexins are widely regarded potential therapeutic targets for a range of disorders of appetitive motivation, including obesity. The motivational activator theory, the first coherent account of the orexin system's role in appetitive motivation, predicts that orexin release motivates appetitive behaviour when the reinforcer is highly salient, available under a high unit-cost or when reward seeking is cue-driven. The present study tested the effect of intracerebroventricular (i.c.v.) administration of the highly potent and commercially available dual orexin receptor antagonist, TCS 1102, on self administration and reinstatement of palatable food seeking in hungry and sated rats. TCS 1102 was also tested on FR1, FR5, FR10 and PR schedules. Orexin neuron activation was measured by c-Fos/orexin-A immunohistochemistry after cue-induced reinstatement, an extinction test, or a home-cage control. No effect of i.c.v. TCS 1102 was observed on self-administration at any fixed or progressive ratio schedule of reinforcement or reinstatement in hungry or sated rats. Although there was robust recruitment of orexin neurons during behavioural testing conditions, there was no specific activation of these neurons during cue-induced reinstatement when compared to extinction testing conditions. These results suggest that orexin antagonism may not be a useful therapeutic target for obesity as it does not appear to regulate food-seeking, and that the conditions determining orexin involvement as a motivational activator may be less clear than currently understood. PMID- 28663112 TI - Defining the place of habit in substance use disorders. AB - It has long been suggested that alcohol or substance use disorders could emerge from the progressive development and dominance of drug habits. Like habits, drug related behaviors are often triggered by drug-associated cues. Like habits, addictive behaviors are strong, rigid and "hard to break". Like habits, these behaviors are insensitive to their outcome and persist despite negative consequences. "Pathological habit" thus appears as a good candidate to explain the transition to compulsive drug use. However, drug use could also be considered as a goal-directed choice, driven by the expectation of drug outcomes. For example, drug addicts may engage in drug-seeking behaviors because they view the drug as more valuable than available alternatives. Substance use disorders therefore may not be all about habit, nor fully intentional, and could be considered as resulting from an imbalance between goal-directed and habitual control. The main objective of this review is to disentangle the relative contribution of habit formation and impairment of goal-directed behavior in this unbalanced control of addictive behaviors. Although deficits in goal-directed behavior have been demonstrated in alcohol and substance use disorders, reliable demonstration of abnormal habit formation has been curtailed by the paucity of paradigms designed to assess habit as a positive result. Refining our animal and human model of habit is therefore required to precisely define the place of habit in substance use disorders and develop appropriate and adapted neurobehavioral treatments. PMID- 28663116 TI - Short-term selection for high and low ethanol intake yields differential sensitivity to ethanol's motivational effects and anxiety-like responses in adolescent Wistar rats. AB - Alcohol use disorders are modulated by genetic factors, but the identification of specific genes and their concomitant biological changes that are associated with a higher risk for these disorders has proven difficult. Alterations in the sensitivity to the motivational effects of ethanol may be one way by which genes modulate the initiation and escalation of ethanol intake. Rats and mice have been selectively bred for high and low ethanol consumption during adulthood. However, selective breeding programs for ethanol intake have not focused on adolescence. This phase of development is associated with the initiation and escalation of ethanol intake and characterized by an increase in the sensitivity to ethanol's appetitive effects and a decrease in the sensitivity to ethanol's aversive effects compared with adulthood. The present study performed short-term behavioral selection to select rat lines that diverge in the expression of ethanol drinking during adolescence. A progenitor nucleus of Wistar rats (F0) and filial generation 1 (F1), F2, and F3 adolescent rats were derived from parents that were selected for high (STDRHI) and low (STDRLO) ethanol consumption during adolescence and were tested for ethanol intake and responsivity to ethanol's motivational effects. STDRHI rats exhibited significantly greater ethanol intake and preference than STDRLO rats. Compared with STDRLO rats, STDRHI F2 and F3 rats exhibited a blunted response to ethanol in the conditioned taste aversion test. F2 and F3 STDRHI rats but not STDRLO rats exhibited ethanol-induced motor stimulation. STDRHI rats exhibited avoidance of the white compartment of the light-dark box, a reduction of locomotion, and a reduction of saccharin consumption, suggesting an anxiety-prone phenotype. The results suggest that the genetic risk for enhanced ethanol intake during adolescence is associated with lower sensitivity to the aversive effects of ethanol, heightened reactivity to ethanol's stimulating effects, and enhanced innate anxiety. PMID- 28663115 TI - Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort. AB - BACKGROUND: Tobacco use is common in patients with schizophrenia (SZ) but little is known on the role of tobacco in the physiopathology or on the course of the disease. Only few studies embrace an extensive examination of clinical and therapeutic characteristics in stabilized patients. The objective of the present study was to determine the prevalence of tobacco smoking in stabilized SZ outpatients and the clinical and treatment characteristics associated with daily tobacco use in a large community-dwelling sample of patients. METHODS: Three hundred-and-sixty-one patients were included in the network of the FondaMental Expert Centers for Schizophrenia. Current tobacco status was self-declared. RESULTS: 53.7% were smokers. Mean age at tobacco onset was 17.2years old. In multivariate analyses, after adjustment for confounding factors, positive symptoms and mean daily antipsychotic dose were associated with a higher frequency of tobacco use (OR=1.06 95%IC[1.02-1.12], for positive symptoms, OR=1.1, 95%IC[1.02-1.18] for daily antipsychotic dose). Education level, negative symptoms, anticholinergic agents, clozapine or aripiprazole administration were independently associated with a lower frequency of tobacco use (respectively OR=0.87, 95%IC [0.79, 0.95], OR=0.95, 95%IC[0.91-0.98], OR=0.41, 95%IC[0.22 0.76], OR=0.56, 95%IC=[0.32, 0.99] and OR=0.49, 95%IC [0.26-0.91]). CONCLUSION: The prevalence of current tobacco smoking in a French community-dwelling SZ patients is higher that observed in the general population. Patients with tobacco use present clinical and therapeutic specificities that may involve interaction between cholinergic-nicotinic and dopaminergic systems. The present study suggests that some therapeutics may improve daily smoking behavior in smokers. These results should be confirmed in longitudinal studies. PMID- 28663118 TI - A cfr-like gene cfr(C) conferring linezolid resistance is common in Clostridium difficile. AB - Clostridium difficile T10 and Clostridium bolteae 90B3 were co-resistant to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A (PhLOPSA) and harbored an unreported cfr-like determinant that may alter the 23S rRNA by m8A2503 methylation. The cfr-like cfr(C) gene was cloned in C. difficile 630Deltaerm in which it conferred PhLOPSA resistance. In C. bolteae 90B3: (i) qRT PCR analysis indicated that cfr(C) was similarly expressed in the absence or presence of either chloramphenicol or clindamycin or linezolid; and (ii) cfr(C) was part of a putative 24 kb-transposon, which generated a detectable circular intermediate. An element differing by a single nucleotide was found in C. difficile DA00203 from GenBank data, consistent with a recent horizontal transfer. In silico analysis showed cfr(C) in 19 out of 274 C. difficile genomes. This gene was also detected by PCR analysis in 9 out of 80 C. difficile from our laboratory strain collection according to resistance to linezolid and florfenicol. The fact that cfr(C) was mainly confined in C. difficile within polymorphic environments indicates this microorganism is a reservoir for PhLOPSA resistance. PMID- 28663117 TI - Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord. AB - Chemotherapeutic drugs, including bortezomib, often cause painful peripheral neuropathy, which is a severe dose-limiting adverse effect experienced by many cancer patients. The glutamate N-methyl-d-aspartate receptors (NMDARs) at the spinal cord level are critically involved in the synaptic plasticity associated with neuropathic pain. In this study, we determined whether treatment with bortezomib, a proteasome inhibitor, affects the NMDAR activity of spinal dorsal horn neurons. Systemic treatment with bortezomib in rats did not significantly affect postsynaptic NMDAR currents elicited by puff application of NMDA directly to dorsal horn neurons. Bortezomib treatment markedly increased the baseline frequency of miniature excitatory postsynaptic currents (EPSCs), which was completely normalized by the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5). AP5 also reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation in bortezomib-treated, but not vehicle-treated, rats. Furthermore, inhibition of protein kinase C (PKC) with chelerythrine fully reversed the increased frequency of miniature EPSCs and the amplitude of evoked EPSCs in bortezomib-treated rats. Intrathecal injection of AP5 and chelerythrine both profoundly attenuated mechanical allodynia and hyperalgesia induced by systemic treatment with bortezomib. In addition, treatment with bortezomib induced striking membrane translocation of PKC-betaII, PKC-delta, and PKC-epsilon in the dorsal root ganglion. Our findings indicate that bortezomib treatment potentiates nociceptive input from primary afferent nerves via PKC-mediated tonic activation of presynaptic NMDARs. Targeting presynaptic NMDARs and PKC at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain. PMID- 28663119 TI - Minimal traumatic brain injury causes persistent changes in DNA methylation at BDNF gene promoters in rat amygdala: A possible role in anxiety-like behaviors. AB - Minimal traumatic brain injury (MTBI) often transforms into chronic neuropsychiatric conditions including anxiety, the underlying mechanisms of which are largely unknown. In the present study, we employed the closed-head injury paradigm to induce MTBI in rats and examined whether DNA methylation can explain long-term changes in the expression of the brain-derived neurotrophic factor (BDNF) in the amygdala as well as trauma-induced anxiety-like behaviors. The MTBI caused anxiety-like behaviors and altered the expression of DNA methyltransferase (DNMT) isoforms (DNMT1, DNMT3a, and DNMT3b) and factors involved in DNA demethylation such as the growth arrest and DNA damage 45 (GADD45a and GADD45b). After 30days of MTBI, the over-expression of DNMT3a and DNMT3b corresponded to heightened DNMT activity, whereas the mRNA levels of GADD45a and GADD45b were declined. The methylated cytosine levels at the BDNF promoters (Ip, IVp and IXp) were increased in the amygdala of the trauma-induced animals; these coincided negatively with the mRNA levels of exon IV and IXa, but not of exon I. Interestingly, treatment with 5-azacytidine, a pan DNMT inhibitor, normalized the MTBI-induced DNMT activity and DNA hypermethylation at exon IVp and IXp. Furthermore, 5-azacytidine also corrected the deficits in the expression of exons IV and IXa and reduced the anxiety-like behaviors. These results suggest that the DNMT-mediated DNA methylation at the BDNF IVp and IXp might be involved in the regulation of BDNF gene expression in the amygdala. Further, it could also be related to MTBI-induced anxiety-like behaviors via the regulation of synaptic plasticity. PMID- 28663120 TI - Biotechnology and the bioeconomy-Towards inclusive and sustainable industrial development. AB - To transform developing and least developing countries into industrialised ones, biotechnology could be deployed along the value chain, to provide support to the development of the bio-based industries in such a way to ensure sustainability of the sector and to reduce negative environmental impacts that might otherwise occur. In agribusiness development, for instance, interventions could start from inputs and agricultural mechanization, modern processing technologies, packaging of perishable products, the promotion of food safety in the processing and regulatory environment; and interventions to improve competitiveness and productivity. Worth over USD 300 billion in revenue, the role of the biotechnology goes beyond industrial growth, since it provides opportunities for progress towards many of the UN sustainable development goals (SDGs). This paper reviews the status of industrial biotechnology as it relates to inclusive and sustainable industrial development. PMID- 28663121 TI - The effects of enhancing endocannabinoid signaling and blocking corticotrophin releasing factor receptor in the amygdala and hippocampus on the consolidation of a stressful event. AB - Current clinical and pre-clinical data suggest that both cannabinoid agents and blockage of CRF through corticotrophin releasing factor receptor type 1 (CRFr1) may offer therapeutic benefits for post-traumatic stress disorder (PTSD). Here we aim to determine whether they are more effective when combined when microinjected into the basolateral amygdala (BLA) or CA1 area of the hippocampus after exposure to a stressful event in the shock/reminders rat model for PTSD. Injection of the fatty acid amide hydrolase (FAAH) inhibitor URB597 after the shock into either the BLA or CA1 facilitated extinction, and attenuated startle response and anxiety-like behavior. These preventive effects of URB597 were found to be mediated by the CB1 receptor. Intra-BLA and intra-CA1 microinjection of the CRFr1 antagonist, CP-154,526 attenuated startle response. When microinjected into the BLA, CP-154,526 also attenuated freezing behavior during exposure to the first reminder and decreased anxiety-like behavior. The combined treatment of URB597 and CP-154,526 was not more effective than the separate treatments. Finally, mRNA levels of CRF, CRFr1 and CB1r were significantly higher in the BLA of rats exposed to shock and reminders compared to non-shocked rats almost one month after the shock. Taken together, the results show that enhancing endocannabinoid signaling in the amygdala and hippocampus produced a more favorable spectrum of effects than those caused by the CRFr1 antagonist. The findings suggest that FAAH inhibitors may be used as a novel treatment for stress-related anxiety disorders. PMID- 28663122 TI - DSM-5 cannabis use disorder, substance use and DSM-5 specific substance-use disorders: Evaluating comorbidity in a population-based sample. AB - Cannabis use disorder (CUD) is frequently associated with concurrent substance use and/or comorbid substance use disorders (SUDs); however there is little specificity with regard to commonly abused individual drug types/classes. This study therefore aimed to provide insight into the degree of these co-occurring relationships across several specific newer and older generation illicit and prescription drugs. 36,309 adults aged 18+ from wave 3 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III) were assessed. Weighted cross-tabulations and multivariable logistic regression analyses were used to evaluate comorbidity between current DSM-5 CUD, substance use and DSM-5 SUD. Current DSM-5 CUD is associated with greater lifetime use of all examined drug classes, and previous 12-month use of several newer-class illicit and prescription stimulant-based substances (all p< 0.05). Current DSM-5 CUD was similarly associated with increased incidence of a range of DSM-5 SUDs and was independently associated with concurrently reporting current DSM-5; sedative (Adjusted OR= 5.1, 95%CI 2.9-9.0), cocaine (AOR= 9.3, 95%CI 5.6-15.5), stimulant (AOR= 4.3, 95%CI 2.3-7.9), club drug (AOR= 16.1, 95%CI 6.3-40.8), opioid (AOR= 4.6, 95%CI 3.0-6.8) and alcohol-use disorder (AOR= 3.0, 95%CI 2.5 3.7); but not heroin or 'other' drug use disorder (both p>0.05). High comorbidity exists between DSM-5 CUD and many specific DSM-5 SUDs. Newer-class illicit and prescription stimulant-based drug use disorders are overrepresented among those with DSM-5 CUD. These findings underscore the need for tailored treatment programs for those presenting with DSM-5 CUD, and for greater treatment specification where poly-drug use is evident. PMID- 28663123 TI - Association between high sensitivity CRP and suicidal ideation in the Korean general population. AB - Inflammation has been linked with a potential critical role in suicide. The purpose of this study is to examine the relation of CRP with suicidal behavior in the Korean population. We conducted a cross-sectional study in 4693 Korean adults aged 20-81 years who participated in the 2015 Korea National Health and Nutrition Examination Survey. High sensitivity CRP levels were measured by immunoturbidimetric method. Suicidal ideation and suicide attempt were assessed by using a questionnaire. Data were analyzed in 2017. Multiple logistic regression analysis was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). The prevalence of suicidal ideation was 4.9% and that of suicide attempt was 0.4%. Suicidal ideation was more prevalent in the highest compared with the lowest serum CRP quartile (OR, 1.79; 95% CI, 1.11-2.89) after adjustment for age, sex, household income, educational level, marital status, employment status, alcohol dependency, current smoking, physical activity, BMI, sleep duration, number of chronic diseases, restriction on activity, subjective health status, perceived stress, depression and depressive mood (p for trend<0.05). In conclusion, elevated levels of CRP were associated with an increased risk of suicidal ideation among South Korean adults. PMID- 28663124 TI - Comparative evaluation of vortioxetine as a switch therapy in patients with major depressive disorder. AB - Switching antidepressant therapy is a recommended strategy for depressed patients who neither respond to nor tolerate an initial pharmacotherapy course. This paper reviews the efficacy and tolerability of switching to vortioxetine. All three published studies of patients with major depressive disorder (MDD) switched from SSRI/SNRI therapy to vortioxetine due to lack of efficacy or tolerability were selected. Vortioxetine was evaluated versus agomelatine directly (REVIVE) and versus sertraline, venlafaxine, bupropion, and citalopram in an indirect treatment comparison (ITC) from switch studies retrieved in a literature review. Vortioxetine's impact on SSRI-induced treatment-emergent sexual dysfunction (TESD) was assessed directly versus escitalopram (NCT01364649) in stable patients with MDD. Vortioxetine's tolerability in the switch population was compared to the overall MDD population. Vortioxetine showed significant benefits over agomelatine on efficacy, functioning, and quality-of-life outcomes, with fewer withdrawals due to adverse events (AEs) (REVIVE). Vortioxetine had numerically higher remission rates versus all therapies included (ITC). Withdrawal rates due to AEs were significantly lower for vortioxetine versus sertraline, venlafaxine, and bupropion, and numerically lower versus citalopram. Switching to vortioxetine was statistically superior to escitalopram in improving TESD (NCT01364649). Tolerability was similar in the switch and overall MDD populations. These findings suggest that vortioxetine is an effective switch therapy for patients with MDD whose response to SSRI/SNRI therapy is inadequate. Vortioxetine was well tolerated and, for patients with a history of TESD, showed significant advantages versus escitalopram. Vortioxetine appears to be a valid option for patients with MDD who have not been effectively treated with first-line pharmacotherapies. PMID- 28663125 TI - Characterization of three serotonin receptors from the small white butterfly, Pieris rapae. AB - Serotonin (5-hydroxytryptamine, 5-HT) plays a key role in modulating diverse physiological processes and behaviors in both protostomes and deuterostomes. These functions are mediated through the binding of serotonin to its receptors, which are recognized as potential insecticide targets. We investigated the sequence, pharmacology and tissue distribution of three 5-HT receptors (Piera5 HT1A, Piera5-HT1B, Piera5-HT7) from the small white butterfly Pieris rapae, an important pest of cultivated cabbages and other mustard family crops. Activation of Piera5-HT1A or Piera5-HT1B by 5-HT inhibited the production of cAMP in a dose dependent manner. Stimulation of Piera5-HT7 with 5-HT increased cAMP level significantly. Surprisingly, with the exception of 5-methoxytryptamine, agonists including alpha-methylserotonin, 8-Hydroxy-DPAT and 5-carboxamidotryptamine activated these receptors poorly. The results are consistent with previous findings in Manduca sexta. All three receptors were blocked by methiothepin, but ketanserin and yohimbine were not effective. The selective mammalian 5-HT receptor antagonists SB 216641 and SB 269970 displayed potent inhibition effects on Piera5-HT1B and Piera5-HT7 respectively. The results we achieved here indicate that the pharmacological properties of Lepidoptera 5-HT receptors are quite different from those in other insects and vertebrates and may contribute to development of new selective pesticides. This study offers important information on three 5-HT receptors from P. rapae that will facilitate further analysis of the functions of 5-HT receptors in insects. PMID- 28663126 TI - Ameliorative effect of vitamin E on hepatic oxidative stress and hypoimmunity induced by high-fat diet in turbot (Scophthalmus maximus). AB - This study was conducted to examine the effects of vitamin E on growth performance, oxidative stress and non-specific immunity of turbot (Scophthalmus maximus) fed with high-fat diet. Results showed that high-fat diet significantly increased hepatosomatic index, viscerosomatic index, hepatic malondialdehyde level and decreased catalase and superoxide dismutase activities, whereas final weight, specific growth rate and survival rate remained unchanged. Meanwhile, nitro blue tetrazolium positive leucocytes of head kidney, respiratory burst activity in head-kidney macrophage, phagocytic index and serum lysozyme activity were significantly reduced after feeding with high-fat diet. Furthermore, fish fed with high-fat diet promoted higher expression of heat shock protein (hsp70, hsp90), and inhibited expression of complement component 3 (c3) in the liver and tumor necrosis factor-alpha (tnf-alpha), interleukine 1beta (il-1beta), toll like receptor 22 (tlr-22) in the spleen and head-kidney, respectively. However, simultaneous supplementation with 480 mg kg-1 vitamin E protected turbot against high-fat diet-induced hepatic oxidative stress, hypoimmunity through attenuating lipid peroxidation, renewing antioxidant enzymes activities and nonspecific immune responses, and modulating the expression of stress protein (hsp70, hsp90) and immune-related genes (c3, tnf-alpha, il-1beta, tlr-22). In conclusion, the obtained results indicate the vitamin E as a wildly used functional feed additive contributes potentially to alleviate high-fat diet-induced hepatic oxidative stress and hypoimmunity, maintain the health, and improve the broodstock management for turbot. PMID- 28663127 TI - Antimicrobial effect of the 60S ribosomal protein L29 (cgRPL29), purified from the gill of pacific oyster, Crassostrea gigas. AB - We purified an ~6.4-kDa antimicrobial peptide from an acidified gill extract of the Pacific oyster, Crassostrea gigas, by cation-exchange and C18 reversed-phase high performance liquid chromatography (HPLC). The identified peptide was composed of 54 amino acids and had a molecular weight of 6484.6 Da. Comparison of the amino acid sequence and molecular weight with those of other known proteins or peptides revealed that the peptide had high identity with the 60S ribosomal protein L29, and so was named cgRPL29. The full-length cgRPL29 cDNA of the Pacific oyster comprised 325-bp, including a 5'-untranslated region (UTR) of 100 bp, a 3'-UTR of 57-bp, and an open reading frame of 168-bp encoding 55 amino acids, with a Met residue at the N-terminus. The cgRPL29 mRNA tissue distribution suggested that it is constitutively expressed in a non-tissue-specific manner. Secondary structural prediction and homology modeling indicated cgRPL29 have an unordered structure containing two partial alpha-helical regions. This is to our knowledge the first report of the antimicrobial effect of the 60S ribosomal protein L29 from marine invertebrates. PMID- 28663128 TI - Infectious spleen and kidney necrosis disease (ISKND) outbreaks in farmed barramundi (Lates calcarifer) in Vietnam. AB - Emergence of a disease with clinical signs resembling megalocytivirus infection seriously affected large-scale barramundi farms in Vietnam in 2012-2014 with estimated losses reaching $435,810 per year. An oil-based, inactivated vaccine against red sea bream iridovirus (RSIV) was applied in one farm for disease prevention without analysis of the causative agent, and the farmer reported inadequate protection. Here we describe histological and molecular analysis of the diseased fish. PCR targeting the major capsid protein (MCP) of megalocytiviruses yielded an amplicon with high sequence identity to infectious spleen and kidney necrosis virus (ISKNV) genotype II previously reported from other marine fish but not barramundi. Detection of the virus was confirmed by positive in situ hybridization results with fish tissue lesions of the kidney, liver, pancreas, and brain of the PCR-positive samples. Based on the complete sequence of the MCP gene, the isolate showed 95.2% nucleotide sequence identity and 98.7% amino acid sequence identity (6 residue differences) with the MCP of RSIV. Prediction of antigenic determinants for MCP antigens indicated that the 6 residue differences would result in a significant difference in antigenicity of the two proteins. This was confirmed by automated homology modeling in which structure superimpositioning revealed several unique epitopes in the barramundi isolate. This probably accounted for the low efficiency of the RSIV vaccine when tested by the farmer. PMID- 28663129 TI - Molecular characterization and expression pattern of X box-binding protein-1 (XBP1) in common carp (Cyprinus carpio L.): Indications for a role of XBP1 in antibacterial and antiviral immunity. AB - X box-binding protein-1 (XBP1) is a transcription factor that is essential for the unfolded protein response (UPR) and the differentiation of plasma cells, and some findings have also uncovered its function in innate immunity. XBP1 typically has two different transcripts, un-spliced (XBP1u) and spliced forms (XBP1s), but XBP1s is an active transcription factor in the regulation of target genes. To date, there is no evidence about the identification and function of XBP1 in common carp. Moreover, no data are currently available regarding the role of fish XBP1 in innate immunity. Thus, to determine whether XBP1 is involved in innate immune response in common carp, we cloned CcXBP1s and examined the expression of XBP1s and a XBP1s stimulated gene (IL-6) after Aeromonas hydrophila (A. hydrophila) and polyinosinic-polycytidylic acid (polyI:C) challenges. The results imply that CcXBP1s, as an active transcription factor, might play regulation roles in the antibacterial and antiviral innate immune responses of common carp. This allows us to gain new insights into the immunological function of XBP1 in fish innate immunity and the evolution of this important class of genes across vertebrates. PMID- 28663130 TI - Zebrafish (Danio rerio) as a model to visualize infection dynamics of Vibrio anguillarum following intraperitoneal injection and bath exposure. AB - Vaccine development is important for sustainable fish farming and novel vaccines need to be efficacy tested before release to the market. Challenge of fish with the pathogen towards which the vaccine has been produced can be conducted either by external exposure though bathing or cohabitation, or by bypassing the mucosa through injection. The latter approach is often preferred since it is easier to control than the former. However, injection is not a very natural route of infection, and the bypass of the mucosa may result in a different efficacy profile of experimental fish compared to farmed fish, for which the vaccines are targeted. The zebrafish is by now a well established practical vertebrate model species due in part to its size and ease of maintenance and genetic manipulation. Here we use zebrafish as a model to visualize and compare the development of infection of Vibrio anguillarum on and in the fish following injection or bathing. Injection of 103 bacteria per fish resulted in approximately 50% mortality by day 4 post-injection. Similar mortality levels were reached in the other group by bathing in 1.25 * 109 bacteria for 1 min. The spreading of bacteria was followed for the first 24 h after injection/bathing by immunohistochemistry and optical projection tomography. The tissues and organs where bacteria were detected differed significantly as a result of time as well as treatment. In the bath group, bacteria were initially found on external surfaces including gut. After 24 h V. anguillarum still persisted in gut but had now also spread to the blood. In the injection group bacteria were found in the blood throughout all sampling times, as well as in the hypodermis and body cavity at most sampling times. PMID- 28663131 TI - Correlation of Lyso-Gb3 levels in dried blood spots and sera from patients with classic and Later-Onset Fabry disease. AB - BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder, results from the deficient activity of alpha-galactosidase A (alpha-Gal A) and the accumulation of its substrates, globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Here, we compared the levels of Lyso-Gb3 in dried blood spots (DBS) and sera in affected males and heterozygotes with the "Classic" and "Later-Onset" phenotypes. METHODS: The Lyso-Gb3 concentrations in DBS and sera from 56 FD patients were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. RESULTS: The serum Lyso-Gb3 levels in 18 and 5 affected males with the Classic and Later-Onset phenotypes, were 61+/-38 and 14+/-12ng/mL, respectively. Lyso-Gb3 levels in 30 females from Classic families and three females from Later-Onset families were 10+/-5.4 and 2.4+/-1.0ng/mL, respectively. The linear regression model with serum Lyso-Gb3 as the dependent variable and DBS Lyso-Gb3 an independent variable was described by the function y=-1.83+1.68*x and showed a high coefficient of determination, R2=0.976. The overall correlation between the Lyso-Gb3 levels in DBS and sera was high (R=0.99; p<0.001). CONCLUSION: DBS provides a convenient, sensitive, and reproducible source to measure Lyso-Gb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with Fabry disease. PMID- 28663132 TI - Developmental neurogenesis in mouse and Xenopus is impaired in the absence of Nosip. AB - BACKGROUND: Genetic deletion of Nosip in mice causes holoprosencephaly, however, the function of Nosip in neurogenesis is currently unknown. RESULTS: We combined two vertebrate model organisms, the mouse and the South African clawed frog, Xenopus laevis, to study the function of Nosip in neurogenesis. We found, that size and cortical thickness of the developing brain of Nosip knockout mice were reduced. Accordingly, the formation of postmitotic neurons was greatly diminished, concomitant with a reduced number of apical and basal neural progenitor cells in vivo. Neurospheres derived from Nosip knockout embryos exhibited reduced growth and the differentiation capability into neurons in vitro was almost completely abolished. Mass spectrometry analysis of the neurospheres proteome revealed a reduced expression of Rbp1, a regulator of retinoic acid synthesis, when Nosip was absent. We identified the homologous nosip gene to be expressed in differentiated neurons in the developing brain of Xenopus embryos. Knockdown of Nosip in Xenopus resulted in a reduction of brain size that could be rescued by reintroducing human NOSIP mRNA. Furthermore, the expression of pro neurogenic transcription factors was reduced and the differentiation of neuronal cells was impaired upon Nosip knockdown. In Xenopus as well as in mouse we identified reduced proliferation and increased apoptosis as underlying cause of microcephaly upon Nosip depletion. In Xenopus Nosip and Rbp1 are similarly expressed and knockdown of Nosip resulted in down regulation of Rbp1. Knockdown of Rbp1 caused a similar microcephaly phenotype as the depletion of Nosip and synergy experiments indicated that both proteins act in the same signalling pathway. CONCLUSIONS: Nosip is a novel factor critical for neural stem cell/progenitor self-renewal and neurogenesis during mouse and Xenopus development and functions upstream of Rbp1 during early neurogenesis. PMID- 28663134 TI - Analysis of IgD CSR junctions by high-throughput sequencing. PMID- 28663135 TI - Use of a tibial accelerometer to measure ground reaction force in running: A reliability and validity comparison with force plates. AB - OBJECTIVES: The use of microsensor technologies to conduct research and implement interventions in sports and exercise medicine has increased recently. The objective of this paper was to determine the validity and reliability of the ViPerform as a measure of load compared to vertical ground reaction force (GRF) as measured by force plates. DESIGN: Absolute reliability assessment, with concurrent validity. METHODS: 10 professional triathletes ran 10 trials over force plates with the ViPerform mounted on the mid portion of the medial tibia. Calculated vertical ground reaction force data from the ViPerform was matched to the same stride on the force plate. Bland-Altman (BA) plot of comparative measure of agreement was used to assess the relationship between the calculated load from the accelerometer and the force plates. Reliability was calculated by intra-class correlation coefficients (ICC) with 95% confidence intervals. RESULTS: BA plot indicates minimal agreement between the measures derived from the force plate and ViPerform, with variation at an individual participant plot level. Reliability was excellent (ICC=0.877; 95% CI=0.825-0.917) in calculating the same vertical GRF in a repeated trial. Standard error of measure (SEM) equalled 99.83 units (95% CI=82.10-119.09), which, in turn, gave a minimum detectable change (MDC) value of 276.72 units (95% CI=227.32-330.07). CONCLUSIONS: The ViPerform does not calculate absolute values of vertical GRF similar to those measured by a force plate. It does provide a valid and reliable calculation of an athlete's lower limb load at constant velocity. PMID- 28663133 TI - Wbp2nl has a developmental role in establishing neural and non-neural ectodermal fates. AB - In many animals, maternally synthesized mRNAs are critical for primary germ layer formation. In Xenopus, several maternal mRNAs are enriched in the animal blastomere progenitors of the embryonic ectoderm. We previously identified one of these, WW-domain binding protein 2 N-terminal like (wbp2nl), that others previously characterized as a sperm protein (PAWP) that promotes meiotic resumption. Herein we demonstrate that it has an additional developmental role in regionalizing the embryonic ectoderm. Knock-down of Wbp2nl in the dorsal ectoderm reduced cranial placode and neural crest gene expression domains and expanded neural plate domains; knock-down in ventral ectoderm reduced epidermal gene expression. Conversely, increasing levels of Wbp2nl in the neural plate induced ectopic epidermal and neural crest gene expression and repressed many neural plate and cranial placode genes. The effects in the neural plate appear to be mediated, at least in part, by down-regulating chd, a BMP antagonist. Because the cellular function of Wbp2nl is not known, we mutated several predicted motifs. Expressing mutated proteins in embryos showed that a putative phosphorylation site at Thr45 and an alpha-helix in the PH-G domain are required to ectopically induce epidermal and neural crest genes in the neural plate. An intact YAP binding motif also is required for ectopic epidermal gene expression as well as for down-regulating chd. This work reveals novel developmental roles for a cytoplasmic protein that promotes epidermal and neural crest formation at the expense of neural ectoderm. PMID- 28663136 TI - Can salivary testosterone and cortisol reactivity to a mid-week stress test discriminate a match outcome during international rugby union competition? AB - OBJECTIVES: Evidence suggests that stress-induced changes in testosterone and cortisol are related to future competitive behaviours and team-sport outcomes. Therefore, we examined whether salivary testosterone and cortisol reactivity to a mid-week stress test can discriminate a match outcome in international rugby union competition. DESIGN: Single group, quasi-experimental design with repeated measures. METHOD: Thirty-three male rugby players completed a standardised stress test three or four days before seven international matches. Stress testing involved seven minutes of shuttle runs (2*20m), dispersed across one-minute stages with increasing speeds. Salivary testosterone and cortisol were measured in the morning, along with delta changes from morning to pre-test (Morn-PreDelta) and pre-test to post-test (Pre-PostDelta). Data were compared across wins (n=3) and losses (n=4). RESULTS: The Morn-PreDelta in cortisol increased before winning and decreased prior to losing (p<0.001), with a large effect size difference (d=1.6, 90% CI 1.3-1.9). Testosterone decreased significantly across the same period, irrespective of the match outcome. The Morn-PreDelta in testosterone and cortisol, plus the Pre-PostDelta in testosterone, all predicted a match outcome (p<=0.01). The final model showed good diagnostic accuracy (72%) with cortisol as the main contributor. CONCLUSIONS: The salivary testosterone and cortisol responses to mid-week testing showed an ability to discriminate a rugby match outcome over a limited number of games. The Morn-PreDelta in cortisol was the strongest diagnostic biomarker. This model may provide a unique format to assess team readiness or recovery between competitions, especially with the emergence of rapid hormonal testing. PMID- 28663137 TI - Online news media reporting of football-related fatalities in Australia: A matter of life and death. AB - OBJECTIVES: While deaths in sports settings are rare, they do occur. To develop an understanding of the sports and people most at risk, and to identify opportunities for prevention, routine and systematic data detailing the occurrence of these fatalities is required. There is currently no routine reporting of data of this nature in Australia. As there is often strong community interest in these incidents, the media offers an opportunity for surveillance. However before this can occur, understanding of the terminology used by the media is required. The aim of this study was to identify the terminology most frequently used in online Australian news media coverage of football-related deaths. DESIGN: Retrospective review of online news media. METHODS: Three databases were searched for online news media reports of people who died while participating in football (all football codes) in Australia. A descriptive analysis of terminology was undertaken to identify the common language applied. RESULTS: Thirty-four football-related fatalities in Australia were identified between 2010-2016, via 149 separate articles. The most frequent terms identified in the media items were: Family; Club; Rugby; Football; Player; League; Died; Game; Death; Life; Loved; Hospital; Match; Young; Community; Playing; Friends; Sport; Heart; AFL [Australian Football League]. CONCLUSIONS: This study identified terminology used in reporting football-related fatalities in Australia, identifying common reference to terms relating to 'death' as metaphors and the frequent celebration of 'life.' The findings suggest that a reliance on researcher-generated terminology will be insufficient to reflect media discourse in prospective monitoring of sports deaths for surveillance. PMID- 28663138 TI - The ethanol pathway from Thermoanaerobacterium saccharolyticum improves ethanol production in Clostridium thermocellum. AB - Clostridium thermocellum ferments cellulose, is a promising candidate for ethanol production from cellulosic biomass, and has been the focus of studies aimed at improving ethanol yield. Thermoanaerobacterium saccharolyticum ferments hemicellulose, but not cellulose, and has been engineered to produce ethanol at high yield and titer. Recent research has led to the identification of four genes in T. saccharolyticum involved in ethanol production: adhE, nfnA, nfnB and adhA. We introduced these genes into C. thermocellum and observed significant improvements to ethanol yield, titer, and productivity. The four genes alone, however, were insufficient to achieve in C. thermocellum the ethanol yields and titers observed in engineered T. saccharolyticum strains, even when combined with gene deletions targeting hydrogen production. This suggests that other parts of T. saccharolyticum metabolism may also be necessary to reproduce the high ethanol yield and titer phenotype in C. thermocellum. PMID- 28663139 TI - [Cardiac arrest resuscitation protocols in hospitals: A pending task]. PMID- 28663140 TI - [Collagenous gastritis: An unusual atypical form in a male infant]. PMID- 28663141 TI - Electrospun conductive nanofibrous scaffolds for engineering cardiac tissue and 3D bioactuators. AB - : Mimicking the nanofibrous structure similar to extracellular matrix and conductivity for electrical propagation of native myocardium would be highly beneficial for cardiac tissue engineering and cardiomyocytes-based bioactuators. Herein, we developed conductive nanofibrous sheets with electrical conductivity and nanofibrous structure composed of poly(l-lactic acid) (PLA) blending with polyaniline (PANI) for cardiac tissue engineering and cardiomyocytes-based 3D bioactuators. Incorporating of varying contents of PANI from 0wt% to 3wt% into the PLA polymer, the electrospun nanofibrous sheets showed enhanced conductivity while maintaining the same fiber diameter. These PLA/PANI conductive nanofibrous sheets exhibited good cell viability and promoting effect on differentiation of H9c2 cardiomyoblasts in terms of maturation index and fusion index. Moreover, PLA/PANI nanofibrous sheets enhanced the cell-cell interaction, maturation and spontaneous beating of primary cardiomyocytes. Furthermore, the cardiomyocytes laden PLA/PANI conductive nanofibrous sheets can form 3D bioactuators with tubular and folding shapes, and spontaneously beat with much higher frequency and displacement than that on cardiomyocytes-laden PLA nanofibrous sheets. Therefore, these PLA/PANI conductive nanofibrous sheets with conductivity and extracellular matrix like nanostructure demonstrated promising potential in cardiac tissue engineering and cardiomyocytes-based 3D bioactuators. STATEMENT OF SIGNIFICANCE: Cardiomyocytes-based bioactuators have been paid more attention due to their spontaneous motion by integrating cardiomyocytes into polymer structures, but developing suitable scaffolds for bioactuators remains challenging. Electrospun nanofibrous scaffolds have been widely used in cardiac tissue engineering because they can mimic the extracellular matrix of myocardium. Developing conductive nanofibrous scaffolds by electrospinning would be beneficial for cardiomyocytes based bioactuators, but such scaffolds have been rarely reported. This work presented a conductive nanofibrous sheet based on polylactide and polyaniline via electrospinning with tunable conductivity. These conductive nanofibrous sheets performed the ability to enhance cardiomyocytes maturation and spontaneous beating, and further formed cardiomyocytes-based 3D bioactuators with tubular and folding shapes, which indicated their great potential in cardiac tissue engineering and bioactuators applications. PMID- 28663142 TI - In situ dual-crosslinked nanoparticles for tumor targeting gene delivery. AB - : The instability of gene delivery systems and their "off-target" features are among the major hurdles in gene therapy. In this study, a facile fabrication platform is constructed to endow the gene delivery system with high stability in the circulation system and achieve targeted delivery of plasmid DNA (pDNA) into cancer cells. Aldehyde groups-bearing hyaluronic acid (HA-CHO) is initially synthesized through oxidation, and is then shielded on polyethylenimine/DNA (PEI/DNA) complex particles to form dual-crosslinked nanoparticles in situ. These nanoparticles simultaneously possess electrostatic and chemical crosslinks between outer layers and cores. The dual-crosslinking system further offers the following advantages when used for gene delivery. First, the two different in situ crosslinking routes strengthen nanoparticle stability. Second, targeting ligands on HA layers mediate specific recognition toward cancer cells. Cell and animal experiments demonstrate that the as-prepared complex particles exhibit enhanced stability in serum and excellent long circulation behavior in vivo. Third, the dual-crosslinked nanoparticles present good accumulation ability in tumors after intravenous injection into nude mice bearing HeLa tumors. Overall, the dual-crosslinking strategy is a promising solution for constructing an efficient gene delivery system. STATEMENT OF SIGNIFICANCE: This manuscript focused on the in situ dual-crosslinked nanoparticles for tumor targeting pDNA delivery. The novel system is prepared by in situ shielding HA-CHO on PEI/DNA complexes. The electrostatic crosslink formed between carboxyl groups on HA-CHO and amine groups on PEI as well as the reaction between aldehyde groups on HA-CHO and amine groups on PEI contributes to the chemical crosslink. By introduction of HA-CHO on PEI/DNA complexes, they show promoting colloidal stability, enhanced cellular uptake and tumor targeting ability. The in vivo experiments further confirm the excellent ability of long circulation and tumor accumulation. Accordingly, HA-CHO2/PEI/DNA has great potential for tumor targeting antitumor therapy. PMID- 28663143 TI - Oxygen self-enriched nanoparticles functionalized with erythrocyte membranes for long circulation and enhanced phototherapy. AB - : In recent years, indocyanine green (ICG) encapsulated in different kinds of nano-carriers have been developed to overcome its short lifetime in vivo and non selectivity in cancer cells. However, these nanoparticles are still easily recognized and captured by the reticuloendothelial system (RES) and the low singlet oxygen quantum (0.08) of ICG inevitably leads to a limited efficacy of phototherapy. To overcome these limitations, a novel oxygen self-enriched biomimetic red blood cell (RBC) was developed by cloaking albumin nanoparticles which contained ICG and perfluorocarbon (PFC) with RBC membranes. Due to the high oxygen capacity of PFC, the oxygen self-enriched nanoparticles can enhance photodynamic therapy (PDT) by generating more singlet oxygen (1O2). After successfully coated RBC membranes onto nanoparticles, the novel oxygen self enriched biomimetic RBCs remained the characteristics of photothermal therapy (PTT) and enhanced PDT in vitro. Importantly, it can effectively reduce immune clearance in macrophage cells (RAW264.7) and significantly prolong blood circulation time, achieving high accumulation in tumor. In addition, the tumor growth was effectively inhibited after intravenous injection to tumor-bearing mice. Altogether, this oxygen self-enriched RBCs with long circulation time and high oxygen capacity as natural RBCs provide a new strategy to design biomimetic nano-system for clinical cancer phototherapy treatment. STATEMENT OF SIGNIFICANCE: Near-infrared (NIR) dyes encapsulated in nanocarriers have been achieved great interest in cancer phototherapy treatment. However, the low singlet oxygen (1O2) quantum of NIR dyes and short circulation time of nanoparticles lead to unsatisfactory efficacy, limiting their applications. In this study, a novel oxygen self-enriched biomimetic red blood cell (bio-RBC) was developed to produce fluorescence, imaging-guided for photothermal therapy (PTT) and enhanced photodynamic therapy (PDT). It was composed of RBC membranes and albumin nanoparticles (IPH) which contained indocyanine green (ICG) and perfluorocarbon (PFC). After RBC membranes successfully being coated on nanoparticles, bio-RBC can effectively reduce immune clearance in macrophage cells and achieve longer circulation time in vivo, due to the protein retention in RBC membranes. In addition, PFC with high oxygen capacity can provide more oxygen to generate more 1O2 and dissolve 1O2 to enhance its life-time, enhancing PDT cancer treatment. In summary, the novel bio-RBC with longer lifetime and higher oxygen capacity as natural RBCs can significantly accumulate on tumor and effectively enhance phototherapy. It could serve as a novel strategy to overcome the problems of NIR dyes encapsulated nanoparticles, promising for future clinical application. PMID- 28663144 TI - Quantitative fabrication, performance optimization and comparison of PEG and zwitterionic polymer antifouling coatings. AB - : A versatile fabrication and performance optimization strategy of PEG and zwitterionic polymer coatings is developed on the sensor chip of surface plasma resonance (SPR) instrument. A random copolymer bearing phosphorylcholine zwitterion and active ester side chains (PMEN) and carboxylic PEG coatings with comparable thicknesses were deposited on SPR sensor chips via amidation coupling on the precoated polydopamine (PDA) intermediate layer. The PMEN coating showed much stronger resistance to bovine serum albumin (BSA) adsorption than PEG coating at very thin thickness (~1nm). However, the BSA resistant efficacy of PEG coating could exceed that of PMEN due to stronger steric repelling effect when the thickness increased to 1.5~3.3nm. Interestingly, both the PEG and PMEN thick coatings (~3.6nm) showed ultralow fouling by BSA and bovine plasma fibrinogen (Fg). Moreover, changes in the PEG end group from -OH to -COOH, protein adsorption amount could increase by 10-fold. Importantly, the optimized PMEN and PEG-OH coatings were easily duplicated on other substrates due to universal adhesion of the PDA layer, showed excellent resistance to platelet, bacteria and proteins, and no significant difference in the antifouling performances was observed. These detailed results can explain the reported discrepancy in performances between PEG and zwitterionic polymer coatings by thickness. This facile and substrate-independent coating strategy may benefit the design and manufacture of advanced antifouling biomedical devices and long circulating nanocarriers. STATEMENT OF SIGNIFICANCE: Prevention of biofouling is one of the biggest challenges for all biomedical applications. However, it is very difficult to fabricate a highly hydrophilic antifouling coating on inert materials or large devices. In this study, PEG and zwitterion polymers, the most widely investigated polymers with best antifouling performance, are conveniently immobilized on different kinds of substrates from their aqueous solutions by precoating a polydopamine intermediate layer as the universal adhesive and readily re modifiable surface. Importantly, the coating fabrication and antifouling performance can be monitored and optimized quantitatively by a surface plasma resonance (SPR) system. More significantly, the SPR on-line optimized coatings were successfully duplicated off-line on other substrates, and supported by their excellent antifouling properties. PMID- 28663145 TI - Type 1 Diabetes and Type 1 Interferonopathies: Localization of a Type 1 Common Thread of Virus Infection in the Pancreas. AB - Type 1 diabetes (T1D) has been associated with both genetic and environmental factors. Increasing incidence of T1D worldwide is prompting researchers to adopt different approaches to explain the biology of T1D, beyond the presence and activity of autoreactive lymphocytes. In this review, we propose inflammatory pathways as triggers for T1D. Within the scope of those inflammatory pathways and in understanding the pathogenesis of disease, we suggest that viruses, in particular Coxsackieviruses, act by causing a type 1 interferonopathy within the pancreas and the microenvironment of the islet. As such, this connection and common thread represents an exciting platform for the development of new diagnostic, treatment and/or prevention options. PMID- 28663146 TI - Human nonsense-mediated RNA decay regulates EMT by targeting the TGF-beta signaling pathway in lung adenocarcinoma. AB - Nonsense-mediated mRNA decay (NMD) is a highly conserved pathway that selectively degrades aberrant RNA transcripts. In this study, we proved that NMD regulates the epithelial-mesenchymal transition (EMT) of lung adenocarcinoma (ADC). Moreover, we found that NMD core factor UP-frameshift 1 tends to be expressed at lower levels in human ADC tissues than in normal lung tissues, thereby raising the possibility that NMD may be downregulated to permit ADC oncogenesis. Our experiments in human ADC cell lines showed that downregulating NMD can promote EMT. Moreover, EMT can be inhibited by upregulating NMD. We tested the role of TGF-beta signaling and found that NMD influences EMT by targeting the TGF-beta signaling pathway. Our findings reveal that NMD is a potential tumor regulatory mechanism and may be a potential therapeutic target for ADC. PMID- 28663147 TI - Acute, sub-acute toxicity and antioxidant activities (in vitro and in vivo) of Reichardia picroide crude extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Reichardia picroide is a species mainly used for alimentary purposes, but it is traditionally known to be used as hypoglycemiant, diuretic, depurative, galactagogue and tonic. AIM OF THE STUDY: To date, there are no studies corroborating both its safety and antioxidant activities. The objective of the present study, thus, was to assess the safety profile of Reichardia picroide methanolic extract (RPE) and as well as on its antioxidant and antihemolytic activities. MATERIALS AND METHODS: The acute toxicity of RPE was carried out based on OECD guidelines 425. Signs accompanying toxicity and possible death of animals were monitored for two weeks to ascertain the median lethal dose (LD50) of the RPE. In sub-acute toxicity study, the extract was administered by gavage at the doses of 250, 500 and 1000mg/kg/day for 21 consecutive days. The antioxidant activity of RPE was investigated through various methods both in vitro and in vivo. RESULTS: The admistrated doses did not produce mortality or changes in general behaviors of the tested males and females mice. The LD50 was found to be superior to 5000mg/kg DW. Moreover, daily administration of RPE at doses ranged from 500 to 1000mg/kg could result in alteration of liver and kidney histology. Significant decrease in liver enzymes (ALT and AST), urea and creatinine levels in female plasma was recorded. The RPE was, in vitro, strong in DPPH scavenging and hemolytic inhibition, benificial in lipid peroxidation inhibition and reducing power. In addition, it exhibited, in vivo, a strong effect on GSH level increasing and lipid peroxidation inhibition in liver and kidney. CONCLUSIONS: It can be suggested, based on the results of this study, that the crude extract of Reichardia picroide was non-toxic in acute administration and the use of this extract is safe at doses <= 250mg/kg. This study supports the application of Reichardia picroides in alimentary and traditional medicine purposes. Moreover, antioxidant activity results suggested that Reichardia picroide had potent antioxidant activities and could be utilized as new natural antioxidant in food and therapeutics. PMID- 28663148 TI - Oral reproductive and developmental toxicity of Lignosus rhinocerotis mycelium in rat. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lignosus rhinocerotis (L. rhinocerotis), also known as the tiger milk mushroom, is widely used as traditional medicine and as soup ingredient in Malaysia and Hong Kong. It is edible and is used traditionally for the treatment of fever, cough, asthma, wounds, chronic hepatitis, gastric ulcers and cancers. In view of its safety profile, little information is found in scientific literature. The objective of this study is to investigate developmental toxicity of L. rhinocerotis in pregnant Sprague-Dawley (SD) rats. MATERIALS AND METHODS: Eighty pregnant SD female rats were used in this study for three treatment groups and a control group, each consisting of 20 pregnant female rats. Three doses of 850mg/kg/day (Low-dose), 1700mg/kg/day (Mid-dose) and 3400mg/kg/day (High-dose) were selected for the study, whereas 10mL/kg distilled water was served as the control. Examinations were conducted on pregnant rats and fetuses respects to mortality, body weight, body weights gains, food consumption and clinical observations. The pregnant females were gross necropsied on G20, followed by maternal and fetus examination, to evaluate the teratogenicity, reproductive and developmental performance of L. rhinocerotis mycelium. RESULTS: Results showed that no L. rhinocerotis mycelium-related animal death and abnormal clinical sign were noted. No statistical differences were noted in maternal mean body weight and maternal mean body weight gains. Some animals in the high-dose group appeared audible respiration due to dosing accident, it resulted in lower food consumption but not relevant to L. rhinocerotis mycelium treatment. In maternal gross necropsy, no L. rhinocerotis mycelium-related gross lesion was noted. In maternal examination, parameters of gravid uterus weight, implantation number, corpora lutea number, litter size, live or dead fetal number, male or female fetus number, resorption number, fetal sex ratio (M/F), pre-implantation loss and post-implantation loss were all within the normal reference ranges and showed no significant difference when compared to the control group. In fetus examination, including external, visceral and skeletal evaluations, there were no significant changes between any of the L. rhinocerotis mycelium treated groups and the control group. CONCLUSIONS: Based on the study results, the no-observable adverse-effect level (NOAEL) for pregnant female rats under the conditions of this study was 3400mg/kg/day. PMID- 28663149 TI - Uranium and neodymium biosorption using novel chelating polysaccharide. AB - A direct reaction is described to prepare hydrophobic alpha-aminomethylphosphonic acid as a novel chitosan-based material. It exhibits chelating properties for polyvalent metal ions such as U(VI) and Nd(III) ions. The new sorbent was fully characterized using Elemental analysis, scanning electron microscope (SEM) and FTIR spectra. Different parameters were examined in order to evaluate the optimum conditions for U(VI) and Nd(III) ions biosorption. Sorption mechanisms of metal ions were investigated using kinetic and isotherm models. In addition, the sorbent selectivity was tested for both metal ions together in a binary solution. PMID- 28663150 TI - Synthesis, structural characterization, QSAR and docking studies of a new binuclear nickel (II) complex based on the flexible tetradentate N-donor ligand as a potent antibacterial and anticancer agent. AB - A new nickel (II)complex namely [Ni2(Lt)Cl4] derived from the NiCl2.6H2O and 1,1,3,3-tetrakis(3,5-dimethyl-1-pyrazolyl)propane (Lt) has been synthesized and fully characterized by the single crystal X-ray diffraction, elemental analysis, FT-IR, UV-vis, density functional theory (DFT) calculations, antibacterial and anticancer activities. In the title complex, each of the Ni(II) atoms is tetrahedrally coordinated by two N atoms from one of the chelating bidentate bis(3,5-dimethylpyrazolyl)methane units of the Lt ligand and two Cl as terminal ligands. The neighboring [Ni2(Lt)Cl4] molecules are linked together by the intermolecular CH?Cl hydrogen bonds to generate a 1D chain structure. The chains are further stabilized by the intermolecular CH?pi interactions to form a two dimensional non-covalent bonded structure. The antibacterial activity of the free Lt ligand and its Ni (II) complex shows that the ability of these compounds to inhibit growth of the tested bacteria increase from the Lt to binuclear nickel (II) complex. Scanning probe microscopy (SPM) study of the treated B. subtilis and E. coli bacteria was implemented to understand the structural changes caused by the interactions between the nickel (II) complex and the target bacteria. The cytotoxicity test of the Lt ligand and its complex was evaluated against the human carcinoma cell line (Caco-2) using the MTT assay. The results indicate that the Lt ligand and its complex display cytotoxicity against Caco-2 with the IC50 values of 36.29MUM and 12.97MUM, respectively. Therefore, the complex can be nominated as a potential anticancer agent. Molecular docking investigations on the five standard antibiotic, five standard anticancer drugs, free Lt ligand, title complex and twelve receptors were performed by Autodock vina function. The results of docking and DFT calculations are in line with the in vitro data obtained via the antibacterial and anticancer activity of Lt ligand and its made complex. PMID- 28663151 TI - A comparison of chemical, structural and functional properties of fenugreek (Trigonella foenum graecum) protein isolates produced using different defatting solvents. AB - This study showed defatting solvents including hexane, diethyl ether, chloroform, ethanol and acetone, due to their influence on protein denaturation and structure, have considerable effect on the amino acid composition, thermal characterizations, surface and functional properties of fenugreek protein isolate. FTIR analysis while confirmed the presence of secondary structures in all fenugreek protein isolates, showed differences in these structures. Hexane and diethyl ether resulted in comparable coagulated protein percentage, interfacial tension, emulsifying properties, surface hydrophobicity, Td and SDS PAGE profile in fenugreek protein isolates. The lowest surface tension in fenugreek protein isolate produced from ethanol defatted flour was in accordance with its considerable foaming properties. Maximum Td and DeltaH were observed in fenugreek protein isolate obtained from acetone defatted fenugreek flour. The highest amounts of hydrophobic and charged hydrophilic amino acids in fenugreek protein isolate produced from hexane and acetone defatted fenugreek flours respectively, were in accordance with the polarity of the applied defatting solvents. Thermograph and coagulated protein percentage confirmed that chloroform caused the lowest thermal stability in fenugreek protein isolate. PMID- 28663152 TI - Catalase inhibition an anti cancer property of flavonoids: A kinetic and structural evaluation. AB - Flavonoids are dietary polyphenols that present abundantly in fruits and vegetables. Flavonoids have inhibitory effects on enzymes and catalase is one among them. Catalase is a common enzyme ubiquitously found in all living organisms exposed to oxygen. It catalyzes the decomposition of hydrogen peroxide to water and oxygen (2H2O2->2H2O+O2). Inhibition of pure and cellular catalase from K562 cells by flavonoids was similar and exhibited the following efficacy; Myrecetin>Quercetin>Kaempferol and Quercetin>Luteolin>Apigenin demonstrating structure activity relationship. Circular Dichroism (CD) spectra have shown distinct loss in alpha-helical structure of the catalase on interaction with the flavonoids. All flavonoids inhibited the catalase activity by uncompetitive mechanism. The Km and Vmax values of pure catalase were observed to be 294mM-1 and 0.222mM-1s-1 respectively and on inhibition with myrecetin the values decreased to a minimum of 23mM-1 and 0.014mM-1s-1 respectively. Inhibition of catalase will directly results in increased production of Reactive Oxygen Species (ROS) and pro-oxidant property of flavonoids. This inhibition was reversed in presence of Cu2+ ions because of the chelating affect of flavonoids. PMID- 28663153 TI - Bioconversion of shrimp waste Penaeus merguiensis using lactic acid fermentation: An alternative procedure for chemical extraction of chitin and chitosan. AB - Chitin extraction from shrimp wastes by biological treatment, using the Pseudomonas aeruginosa was a positive and simple method. In order to look for the optimal conditions, the wastes were incubated at 30 degrees C and 100rpm in different glucose (0%, 10%, 15% and 20%) and inoculation (10%, 15% and 20%) concentrations for 4 and 6days. At the end of fermentation, Protease activity was investigated at different temperatures and temperature 50 degrees C was considered as the optimum. The results obtained also showed a direct relationship between the concentration of different parameters and deproteinization and demineralization rates, so that the optimal conditions were 20% glucose, 20% inoculation and 6days fermentation. These conditions led to 82% demineralization, 92% deproteinization and chitin yield of 47%. Then, chitin was converted to chitosan using microwave, autoclave and traditional methods. The highest yield (87%) was obtained with autoclave method. At the end, the chitin and chitosan were characterized by elemental analysis and FTIR. PMID- 28663154 TI - Comment on: Factors Associated with Increased Pain in Primary Dysmenorrhea: Analysis through a Multivariate Ordered Logistic Regression Model. PMID- 28663155 TI - Multivariate Ordered Logistic Regression Models: Dealing with the Model-Building Strategy. PMID- 28663156 TI - Clinical and Genetic Findings of Turkish Hypophosphatasia Cases. AB - OBJECTIVE: Hypophosphatasia (HPP) is a rare, commonly unrecognized hereditary mineralization defect with a dramatically poor prognosis in severe cases. This study is the first to examine the detailed clinical and laboratory characteristics of patients with HPP and healthy carriers in Turkey. METHODS: The study data were obtained retrospectively from the files of 10 healthy carriers and of 16 cases with HPP (12 children and 4 adults) who were followed in our center from 2012 to 2016. RESULTS: The annual incidence of perinatal lethal hypophosphatasia (PLH) was estimated to be approximately 1 case per 435,517 live births,, which is the first report from Turkey. The clinical courses of the cases differed depending on the type of HPP. All of the seven cases (58.3% of all cases) with perinatal lethal form of HPP died. A need for respiratory support (p=0.001), a history of pyridoxine-dependent seizures (p=0.001), a low chest circumference measurement (p=0.017), younger age at diagnosis (p=0.029), a small head circumference at the time of presentation (p=0.042), a low arm span to height ratio (p=0.048), and a low serum alkaline phosphatase (ALP) level (p=0.042) seemed to be predicting factors for mortality. The mean height standard deviation score of the patients and those of the healthy carriers did not differ significantly (p=0.173). Different mutations were detected in nine of 14 cases (64.2%) in whom an ALPL gene mutation analysis could be performed, and five of these cases (35.7%) had novel mutations. The most common mutations were c746G>T (five alleles), c346G>A (three alleles), and c.140C>T (three alleles). In addition, the most frequently observed genotype in Turkish HPP cases was autosomal-dominant c.346G>A (p.A116T) mutations which were detected in three cases in two different families. CONCLUSION: Because of the respiratory problems, especially the lung hypoplasia, the clinical course is poor in cases with the perinatal lethal form of HPP. Some minor abnormalities such as mild short stature and osteopenia could be observed in asymptomatic heterozygote carriers. Laboratory findings were normal in these cases. PMID- 28663157 TI - Phenotype Heterogeneity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK MODY) Patients. AB - OBJECTIVE: The aim of the study was to evaluate the clinical phenotypes of glucokinase-maturity-onset diabetes of the young (GCK-MODY) pediatric patients from Southwest Poland and to search for phenotype-genotype correlations. METHODS: We conducted a retrospective analysis of data on 37 CGK-MODY patients consisting of 21 girls and 16 boys of ages 1.9-20.1 (mean 12.5+/-5.2) years, treated in our centre in the time period between 2002 and 2013. RESULTS: GCK-MODY carriers were found in a frequency of 3% among 1043 diabetes mellitus (DM) patients and constituted the second most numerous group of DM patients, following type 1 DM, in our centre. The mean age of GCK-MODY diagnosis was 10.4+/-4.5 years. The findings leading to the diagnosis were impaired fasting glucose (IFG) (15/37), symptoms of hyperglycemia (4/37), and a GCK-MODY family history (18/37). Mean fasting blood glucose level was 6.67+/-1.64 mmol/L. In the sample, there were patients with normal values (4/37), those with DM (10/37), and IFG (23/37). In OGTT, 120 min glucose level was normal in 8, diabetic in 2, and characteristic for glucose intolerance in 27 of the 37 cases. Twelve of the 37 cases (32%) were identified as GCK-MODY carriers. In the total group, mean C-peptide level was 2.13+/-0.65 ng/mL and HbA1c was 6.26+/-0.45% (44.9+/--18 mmol/mol). Thirty-two patients had a family history of DM. DM autoantibodies were detected in two patients. The most common mutations were p.Gly318Arg (11/37) and p.Val302Leu (8/37). There was no correlation between type of mutations and plasma glucose levels. CONCLUSION: The phenotype of GCK-MODY patients may vary from those characteristic for other DM types to an asymptomatic state with normal FG with no correlation with genotype. PMID- 28663158 TI - An ABCC8 Nonsense Mutation Causing Neonatal Diabetes Through Altered Transcript Expression. AB - The pancreatic ATP-sensitive K+ (K-ATP) channel is a key regulator of insulin secretion. Gain-of-function mutations in the genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the channel cause neonatal diabetes, whilst loss-of function mutations in these genes result in congenital hyperinsulinism. We report two patients with neonatal diabetes in whom we unexpectedly identified recessively inherited loss-of-function mutations. The aim of this study was to investigate how a homozygous nonsense mutation in ABCC8 could result in neonatal diabetes. The ABCC8 p.Glu747* was identified in two unrelated Vietnamese patients. This mutation is located within the in-frame exon 17 and RNA studies confirmed (a) the absence of full length SUR1 mRNA and (b) the presence of the alternatively spliced transcript lacking exon 17. Successful transfer of both patients to sulphonylurea treatment suggests that the altered transcript expression enhances the sensitivity of the K-ATP channel to Mg-ADP/ATP. This is the first report of an ABCC8 nonsense mutation causing a gain-of-channel function and these findings extend the spectrum of K-ATP channel mutations observed in patients with neonatal diabetes. PMID- 28663159 TI - Synchronous Solid Pseudopapillary Tumor and Insulinoma in an Adolescent MEN1 Patient Presenting with Diagnostic Dilemmas. AB - Multiple endocrine neoplasia (MEN1) is a rare autosomal dominant disorder characterized by primary hyperparathyroidism, enteropancreatic neuroendocrine tumors, and anterior pituitary adenomas. A 16-year-old male presented to the emergency outpatient clinic with tonic convulsions. Physical examination in the postconvulsive period was unremarkable and revealed a muscular, postpubertal adolescent. Biochemical tests at admission were consistent with hyperinsulinemic hypoglycemia and remarkable for elevated levels of liver transaminases and creatine kinase. Work-up for a potential inborn error of metabolism and Doppler ultrasound for congenital portal-hepatic shunt were negative. When the patient was questioned, he reported using the anabolic steroid stanozolol to strengthen his muscles. His enzyme levels normalized after cessation of stanozolol. Hypoglycemia did not recur on diazoxide therapy. Magnetic resonance imaging showed two discrete lesions in the pancreas. Distal pancreatectomy revealed two masses 1.1 and 1.4 cm in diameter: a solid pseudopapillary tumor and an insulinoma. The patient also had asymptomatic primary hyperparathyroidism. DNA sequence analysis of the MEN1 gene in the index patient and his father and brother revealed a previously reported "pW183S" heterozygous mutation. This case further adds to the "pancreatic tumor" phenotype of MEN1 with the presence of a solid pseudopapillary tumor. This case report also confirms the need to meticulously question drug abuse in adolescents presenting to clinics with diagnostic challenges. PMID- 28663160 TI - A Mutation in INSR in a Child Presenting with Severe Acanthosis Nigricans. AB - Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized by acanthosis nigricans, generalized lanugo, tooth and nail dysplasia, high nasal bridge, and growth retardation. A 5-year-old female patient was referred due to acanthosis nigricans and generalized lanugo. On her physical examination, severe acanthosis nigricans of the neck, axillae, the external genitalia and antecubital regions, generalized lanugo, mildly decreased subcutaneous fat, dysmorphic facial features, and polydactyly on her left hand were noted. Insulin resistance and impaired glucose tolerance were found. Sequence analysis of the INSR in the patient revealed c.3529+5G>A mutation in homozygous state. RMS should be suspected in a patient with characteristic physical features and insulin resistance. PMID- 28663161 TI - Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene. AB - Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis. PMID- 28663163 TI - Validation of an Improved Computer-Assisted Technique for Mining Free-Text Electronic Medical Records. AB - BACKGROUND: The use of electronic medical records (EMRs) offers opportunity for clinical epidemiological research. With large EMR databases, automated analysis processes are necessary but require thorough validation before they can be routinely used. OBJECTIVE: The aim of this study was to validate a computer assisted technique using commercially available content analysis software (SimStat-WordStat v.6 (SS/WS), Provalis Research) for mining free-text EMRs. METHODS: The dataset used for the validation process included life-long EMRs from 335 patients (17,563 rows of data), selected at random from a larger dataset (141,543 patients, ~2.6 million rows of data) and obtained from 10 equine veterinary practices in the United Kingdom. The ability of the computer-assisted technique to detect rows of data (cases) of colic, renal failure, right dorsal colitis, and non-steroidal anti-inflammatory drug (NSAID) use in the population was compared with manual classification. The first step of the computer-assisted analysis process was the definition of inclusion dictionaries to identify cases, including terms identifying a condition of interest. Words in inclusion dictionaries were selected from the list of all words in the dataset obtained in SS/WS. The second step consisted of defining an exclusion dictionary, including combinations of words to remove cases erroneously classified by the inclusion dictionary alone. The third step was the definition of a reinclusion dictionary to reinclude cases that had been erroneously classified by the exclusion dictionary. Finally, cases obtained by the exclusion dictionary were removed from cases obtained by the inclusion dictionary, and cases from the reinclusion dictionary were subsequently reincluded using Rv3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Manual analysis was performed as a separate process by a single experienced clinician reading through the dataset once and classifying each row of data based on the interpretation of the free text notes. Validation was performed by comparison of the computer-assisted method with manual analysis, which was used as the gold standard. Sensitivity, specificity, negative predictive values (NPVs), positive predictive values (PPVs), and F values of the computer-assisted process were calculated by comparing them with the manual classification. RESULTS: Lowest sensitivity, specificity, PPVs, NPVs, and F values were 99.82% (1128/1130), 99.88% (16410/16429), 94.6% (223/239), 100.00% (16410/16412), and 99.0% (100*2*0.983*0.998/[0.983+0.998]), respectively. The computer-assisted process required few seconds to run, although an estimated 30 h were required for dictionary creation. Manual classification required approximately 80 man-hours. CONCLUSIONS: The critical step in this work is the creation of accurate and inclusive dictionaries to ensure that no potential cases are missed. It is significantly easier to remove false positive terms from a SS/WS selected subset of a large database than search that original database for potential false negatives. The benefits of using this method are proportional to the size of the dataset to be analyzed. PMID- 28663162 TI - Developing and Evaluating Digital Interventions to Promote Behavior Change in Health and Health Care: Recommendations Resulting From an International Workshop. AB - Devices and programs using digital technology to foster or support behavior change (digital interventions) are increasingly ubiquitous, being adopted for use in patient diagnosis and treatment, self-management of chronic diseases, and in primary prevention. They have been heralded as potentially revolutionizing the ways in which individuals can monitor and improve their health behaviors and health care by improving outcomes, reducing costs, and improving the patient experience. However, we are still mainly in the age of promise rather than delivery. Developing and evaluating these digital interventions presents new challenges and new versions of old challenges that require use of improved and perhaps entirely new methods for research and evaluation. This article discusses these challenges and provides recommendations aimed at accelerating the rate of progress in digital behavior intervention research and practice. Areas addressed include intervention development in a rapidly changing technological landscape, promoting user engagement, advancing the underpinning science and theory, evaluating effectiveness and cost-effectiveness, and addressing issues of regulatory, ethical, and information governance. This article is the result of a two-day international workshop on how to create, evaluate, and implement effective digital interventions in relation to health behaviors. It was held in London in September 2015 and was supported by the United Kingdom's Medical Research Council (MRC), the National Institute for Health Research (NIHR), the Methodology Research Programme (PI Susan Michie), and the Robert Wood Johnson Foundation of the United States (PI Kevin Patrick). Important recommendations to manage the rapid pace of change include considering using emerging techniques from data science, machine learning, and Bayesian approaches and learning from other disciplines including computer science and engineering. With regard to assessing and promoting engagement, a key conclusion was that sustained engagement is not always required and that for each intervention it is useful to establish what constitutes "effective engagement," that is, sufficient engagement to achieve the intended outcomes. The potential of digital interventions for testing and advancing theories of behavior change by generating ecologically valid, real-time objective data was recognized. Evaluations should include all phases of the development cycle, designed for generalizability, and consider new experimental designs to make the best use of rich data streams. Future health economics analyses need to recognize and model the complex and potentially far reaching costs and benefits of digital interventions. In terms of governance, developers of digital behavior interventions should comply with existing regulatory frameworks, but with consideration for emerging standards around information governance, ethics, and interoperability. PMID- 28663164 TI - Assessing User Engagement of an mHealth Intervention: Development and Implementation of the Growing Healthy App Engagement Index. AB - BACKGROUND: Childhood obesity is an ongoing problem in developed countries that needs targeted prevention in the youngest age groups. Children in socioeconomically disadvantaged families are most at risk. Mobile health (mHealth) interventions offer a potential route to target these families because of its relatively low cost and high reach. The Growing healthy program was developed to provide evidence-based information on infant feeding from birth to 9 months via app or website. Understanding user engagement with these media is vital to developing successful interventions. Engagement is a complex, multifactorial concept that needs to move beyond simple metrics. OBJECTIVE: The aim of our study was to describe the development of an engagement index (EI) to monitor participant interaction with the Growing healthy app. The index included a number of subindices and cut-points to categorize engagement. METHODS: The Growing program was a feasibility study in which 300 mother-infant dyads were provided with an app which included 3 push notifications that was sent each week. Growing healthy participants completed surveys at 3 time points: baseline (T1) (infant age <=3 months), infant aged 6 months (T2), and infant aged 9 months (T3). In addition, app usage data were captured from the app. The EI was adapted from the Web Analytics Demystified visitor EI. Our EI included 5 subindices: (1) click depth, (2) loyalty, (3) interaction, (4) recency, and (5) feedback. The overall EI summarized the subindices from date of registration through to 39 weeks (9 months) from the infant's date of birth. Basic descriptive data analysis was performed on the metrics and components of the EI as well as the final EI score. Group comparisons used t tests, analysis of variance (ANOVA), Mann Whitney, Kruskal-Wallis, and Spearman correlation tests as appropriate. Consideration of independent variables associated with the EI score were modeled using linear regression models. RESULTS: The overall EI mean score was 30.0% (SD 11.5%) with a range of 1.8% - 57.6%. The cut-points used for high engagement were scores greater than 37.1% and for poor engagement were scores less than 21.1%. Significant explanatory variables of the EI score included: parity (P=.005), system type including "app only" users or "both" app and email users (P<.001), recruitment method (P=.02), and baby age at recruitment (P=.005). CONCLUSIONS: The EI provided a comprehensive understanding of participant behavior with the app over the 9-month period of the Growing healthy program. The use of the EI in this study demonstrates that rich and useful data can be collected and used to inform assessments of the strengths and weaknesses of the app and in turn inform future interventions. PMID- 28663165 TI - Early Interventions Following the Death of a Parent: Protocol of a Mixed Methods Systematic Review. AB - BACKGROUND: Previous meta-analyses examined the effectiveness of interventions for bereaved children showing small to moderate effect sizes. However, no mixed methods systematic review was conducted on bereavement interventions following the loss of a parent focusing on the time since death in regard to the prevention of grief complications. OBJECTIVE: The overall purpose of the review is to provide a rigorous synthesis of early intervention after parental death in childhood. Specifically, the aims are twofold: (1) to determine the rationales, contents, timeframes, and outcomes of early bereavement care interventions for children and/or their parents and (2) to assess the quality of current early intervention studies. METHODS: Quantitative, qualitative, and mixed methods intervention studies that start intervention with parentally bereaved children (and/or their parents) up to 6 months postloss will be included in the review. The search strategy was based on the Population, Interventions, Comparator, Outcomes, and Study Designs (PICOS) approach, and it was devised together with a university librarian. The literature searches will be carried out in the Medical Literature Analysis and Retrieval System Online (MEDLINE), PsycINFO, Excerpta Medica Database (EMBASE), and Cumulative Index to Nursing and Allied Health Literature (CINAHL). The Mixed Methods Appraisal Tool will be used to appraise the quality of eligible studies. All data will be narratively synthetized following the Guidance on the Conduct of Narrative Synthesis in Systematic Reviews. RESULTS: The systematic review is ongoing and the data search has started. The review is expected to be completed by the end of 2017. Findings will be submitted to leading journals for publication. CONCLUSIONS: In accordance with the current diagnostic criteria for prolonged grief as well as the users' perspectives literature, this systematic review outlines a possible sensitive period for early intervention following the death of a parent. The hereby presented protocol ensures the groundwork and transparency for the process of conducting the systematic review. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) CRD42017064077; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017064077 (Archived by WebCite at http://www.webcitation.org/6rMq6F0fv). PMID- 28663167 TI - Successive governments have failed to tackle gaps in social mobility. PMID- 28663166 TI - Researching Mental Health Disorders in the Era of Social Media: Systematic Review. AB - BACKGROUND: Mental illness is quickly becoming one of the most prevalent public health problems worldwide. Social network platforms, where users can express their emotions, feelings, and thoughts, are a valuable source of data for researching mental health, and techniques based on machine learning are increasingly used for this purpose. OBJECTIVE: The objective of this review was to explore the scope and limits of cutting-edge techniques that researchers are using for predictive analytics in mental health and to review associated issues, such as ethical concerns, in this area of research. METHODS: We performed a systematic literature review in March 2017, using keywords to search articles on data mining of social network data in the context of common mental health disorders, published between 2010 and March 8, 2017 in medical and computer science journals. RESULTS: The initial search returned a total of 5386 articles. Following a careful analysis of the titles, abstracts, and main texts, we selected 48 articles for review. We coded the articles according to key characteristics, techniques used for data collection, data preprocessing, feature extraction, feature selection, model construction, and model verification. The most common analytical method was text analysis, with several studies using different flavors of image analysis and social interaction graph analysis. CONCLUSIONS: Despite an increasing number of studies investigating mental health issues using social network data, some common problems persist. Assembling large, high-quality datasets of social media users with mental disorder is problematic, not only due to biases associated with the collection methods, but also with regard to managing consent and selecting appropriate analytics techniques. PMID- 28663168 TI - Healthcare for the many. PMID- 28663169 TI - Childhood comorbidity and parental mental health problems appear to be associated with ADHD persistence. PMID- 28663170 TI - Spoken language shows some improvement following intervention for children with autism: but for which children and why? PMID- 28663171 TI - Increased serotonin 1A receptor availability in the raphe nuclei predicts future suicidal behaviour. PMID- 28663173 TI - Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings. PMID- 28663175 TI - Cancer and Race: What They Tell Us about the Emerging Focus of Health Equity. AB - This article examines the history of concepts and frames (such as "equity" or "disparities") and how these frames have guided public policies and explanations about differences in health across the population. Considering the emblematic case of cancer, which has stimulated long and heated debate over social, economic, and biological causes, the article argues that the vocabularies of health reform are both semantic and also deeply political-framing different reform agendas. The article describes the evolving US debate over the biological, social, or environmental origins of differential cancer mortality along lines of social difference and race, tracing important shifts and reversal over time. Through this analysis, the article explains how and why equity concerns have figured (sometimes implicitly, sometimes explicitly) in health reform discussions, often in tension with other frames. It examines how Americans have used these frameworks to justify different kinds of action and inaction, concluding with a discussion of how these frameworks of "disparities" and "equity" should be understood today in scientific, political, and policy discourse.1. PMID- 28663176 TI - People, Places, Power: Medicaid Concentration and Local Political Participation. AB - The geographic concentration of disadvantage is a key mechanism of inequity. In the United States, the spatial patterning of disadvantage renders it more than the sum of its individual parts and disproportionately harms economically and racially marginalized Americans. This article focuses specifically on the political effects of Medicaid beneficiaries being concentrated in particular locales. After offering a framework for conceptualizing the community-wide consequences of such policy concentration, I analyze aggregate multiyear data to examine the effect of Medicaid density on county-level voter turnout and local organizational strength. I find that, as the proportion of county residents enrolled in Medicaid increases, the prevalence of civic and political membership associations declines and aggregate rates of voting decrease. These results suggest that, if grassroots political action is to be part of a strategy to achieve health equity, policy makers and local organizations must make efforts to counteract the sometimes demobilizing "place-based" political effects of "people based" policies such as Medicaid. PMID- 28663172 TI - METTL21B Is a Novel Human Lysine Methyltransferase of Translation Elongation Factor 1A: Discovery by CRISPR/Cas9 Knockout. AB - Lysine methylation is widespread on human proteins, however the enzymes that catalyze its addition remain largely unknown. This limits our capacity to study the function and regulation of this modification. Here we used the CRISPR/Cas9 system to knockout putative protein methyltransferases METTL21B and METTL23 in K562 cells, to determine if they methylate elongation factor eEF1A. The known eEF1A methyltransferase EEF1AKMT1 was also knocked out as a control. Targeted mass spectrometry revealed the loss of lysine 165 methylation upon knockout of METTL21B, and the expected loss of lysine 79 methylation on knockout of EEF1AKMT1 No loss of eEF1A methylation was seen in the METTL23 knockout. Recombinant METTL21B was shown in vitro to catalyze methylation on lysine 165 in eEF1A1 and eEF1A2, confirming it as the methyltransferase responsible for this methylation site. Proteomic analysis by SILAC revealed specific upregulation of large ribosomal subunit proteins in the METTL21B knockout, and changes to further processes related to eEF1A function in knockouts of both METTL21B and EEF1AKMT1 This indicates that the methylation of lysine 165 in human eEF1A has a very specific role. METTL21B exists only in vertebrates, with its target lysine showing similar evolutionary conservation. We suggest METTL21B be renamed eEF1A KMT3. This is the first study to specifically generate CRISPR/Cas9 knockouts of putative protein methyltransferase genes, for substrate discovery and site mapping. Our approach should prove useful for the discovery of further novel methyltransferases, and more generally for the discovery of sites for other protein-modifying enzymes. PMID- 28663177 TI - The Many Roads toward Achieving Health Equity. AB - This special issue of the Journal is devoted to understanding the many roads that lead toward achieving health equity. The eleven articles in the issue portray an America that is struggling with the clash between its historical ideal of pursuing equality for all and its ambivalence toward achieving equity in all social domains, especially health. Organized in five sections, the issue contains articles that examine and analyze: the role of civil rights law and the courts in shaping health equity; the political discourse that has framed our understanding of health equity; health policies that affect health equity, such as the Medicaid program, as well as related strategies that might help to improve equity, such as the use of mobile technologies to empower individuals; immigration policies and practices that impact health equity in marginalized populations; and commentaries in the final section that explore how the Affordable Care Act has addressed health equity, how repeal of the law would jeopardize equity gains, and how the political discourse and culture of the Trump administration could adversely affect health equity. PMID- 28663178 TI - Falling through the Coverage Cracks: How Documentation Status Minimizes Immigrants' Access to Health Care. AB - Recent policy debates have centered on health reform and who should benefit from such policy. Most immigrants are excluded from the 2010 Affordable Care Act (ACA) due to federal restrictions on public benefits for certain immigrants. But, some subnational jurisdictions have extended coverage options to federally ineligible immigrants. Yet, less is known about the effectiveness of such inclusive reforms for providing coverage and care to immigrants in those jurisdictions. This article examines the relationship between coverage and health care access for immigrants under comprehensive health reform in the Boston metropolitan area. The article uses data from interviews conducted with a total of 153 immigrants, health care professionals, and immigrant and health advocacy organization employees under the Massachusetts and ACA health reforms. Findings indicate that respondents across the various stakeholder groups perceive that immigrants' documentation status minimizes their ability to access health care even when they have health coverage. Specifically, respondents expressed that intersecting public policies, concerns that using health services would jeopardize future legalization proceedings, and immigrants' increased likelihood of deportation en route to medical appointments negatively influenced immigrants' health care access. Thus, restrictive federal policies and national-level anti-immigrant sentiment can undermine inclusive subnational policies in socially progressive places. PMID- 28663179 TI - Cautious Citizenship: The Deterring Effect of Immigration Issue Salience on Health Care Use and Bureaucratic Interactions among Latino US Citizens. AB - Research shows that health care use among Latino immigrants is adversely affected by restrictive immigration policy. A core concern is that immigrants shy away from sharing personal information in response to policies that expand bureaucratic monitoring of citizenship status across service-providing organizations. This investigation addresses the concern that immigration politics also negatively influences health care utilization among Latino US citizens. One implication is that health insurance expansions may not reduce health care inequities among Latinos due to concern about exposure to immigration law enforcement authorities. Using data from the 2015 Latino National Health and Immigration Survey, we examine the extent to which the politics of immigration deters individuals from going to health care providers and service-providing institutions. Results indicate that Latino US citizens are less likely to make an appointment to see a health care provider when the issue of immigration is mentioned. Additionally, Latino US citizens who know someone who has been deported are more inclined to perceive that information shared with health care providers is not secure. We discuss how cautious citizenship, or risk-avoidance behaviors toward public institutions in order to avoid scrutiny of citizenship status, informs debates about reducing health care inequities. PMID- 28663180 TI - Framing Health Equity: US Health Disparities in Comparative Perspective. AB - In this article we explore systematically the different conceptions of health equity in key national health policy documents in the United States, the United Kingdom, and France. We find substantial differences across the three countries in the characterization of group differences (by SES, race/ethnicity, or territory), and the theorized causes of health inequalities (socioeconomic structures versus health care system features). In all three countries, reports throughout the period alluded at least minimally to inequalities in social determinants as the underlying cause of health inequalities. However, even in the reports with the strongest attachment to this causal model, the authors stop well short of advocating the redistribution of power and resources that would likely be necessary to redress these inequalities. PMID- 28663181 TI - Viewing Health Equity through a Legal Lens: Title VI of the 1964 Civil Rights Act. AB - Enacted as part of the watershed Civil Rights Act of 1964, Title VI prohibits discrimination by federally assisted entities on the basis of race, color, or national origin. Indeed, the law is as broad as federal funding across the full range of programs and services that affect health. Over the years, governmental enforcement efforts have waxed and waned, and private litigants have confronted barriers to directly invoking its protections. But Title VI endures as the formal mechanism by which the nation rejects discrimination within federally funded programs and services. Enforcement efforts confront problems of proof, remedies whose effectiveness may be blunted by underlying residential segregation patterns, and a judiciary closed to legal challenges focusing on discriminatory impact rather than intentional discrimination. But Title VI enforcement has experienced a resurgence, with strategies that seek to use the law as a basic compliance tool across the range of federally assisted programs. This resurgence reflects an enduring commitment to more equitable outcomes in federally funded programs that bear directly on community health, and it stands as a testament to the vital importance of a legal framework designed to move the nation toward greater health equity. PMID- 28663182 TI - Missed Opportunity? Leveraging Mobile Technology to Reduce Racial Health Disparities. AB - Blacks and Latinos are less likely than whites to access health insurance and utilize health care. One way to overcome some of these racial barriers to health equity may be through advances in technology that allow people to access and utilize health care in innovative ways. Yet, little research has focused on whether the racial gap that exists for health care utilization also exists for accessing health information online and through mobile technologies. Using data from the Health Information National Trends Survey (HINTS), we examine racial differences in obtaining health information online via mobile devices. We find that blacks and Latinos are more likely to trust online newspapers to get health information than whites. Minorities who have access to a mobile device are more likely to rely on the Internet for health information in a time of strong need. Federally insured individuals who are connected to mobile devices have the highest probability of reliance on the Internet as a go-to source of health information. We conclude by discussing the importance of mobile technologies for health policy, particularly related to developing health literacy, improving health outcomes, and contributing to reducing health disparities by race and health insurance status. PMID- 28663183 TI - Health Equity in a Trump Administration. AB - Donald Trump's rhetoric and leadership are destroying the "culture of community" necessary for progress on health equity. His one-line promises to provide "quality health care at a fraction of the cost" smack of neoliberal nostrums that shifted ever more costs onto patients, thereby preventing many people from getting care. The dangers of Trump go far beyond health policy, however; Trump's presidency threatens the political and cultural institutions that make any good policy possible. PMID- 28663184 TI - How the ACA Addressed Health Equity and What Repeal Would Mean. AB - This commentary reviews the many different ways the Affordable Care Act (ACA) explicitly and implicitly attempted to improve health equity, and then assesses how the Republican proposal to repeal and replace the ACA (the proposed American Health Care Act) would impact efforts to improve health equity. Although the American health care system still had a long way to go to achieve health equity, it may be argued that the ACA was a major step forward in creating new programs and regulations that had the potential to improve health equity. In stark contrast, Trumpcare makes no mention of health equity as a goal and-if passed would result in an increase in health inequity. It would shamefully represent the first time in modern US history that a major federal health reform bill would actually move us further away from creating more equal access to health care coverage and toward reduced health equity. PMID- 28663185 TI - Words and Deeds: Presidential Discussion of Minority Health, Public Policies, and Minority Perceptions. AB - What are the different rhetorical approaches presidents used to address minority health inequality? More importantly, how have the efforts of presidents impacted minorities' perceptions of health? I offer a historical perspective that describes the three major periods of presidential engagement in discussions of minority health since the 1960s. I couple this historical overview with an empirical assessment that introduces a novel and extensive dataset of every presidential discussion of minority health spanning five decades (1960-2016). This study finds that, since the early 1990s, presidents have transported their discussion of minority health beyond the confines of Washington, DC, traveling to speak to local communities throughout the nation that have a disproportionate number of blacks and Latinos. Moreover, a presidential discussion of minority health leads to greater salience on this issue and thus increases public health awareness. This work suggests that presidential messaging on minority health provides a framework for minority groups to understand and discuss the health disparities that may plague their communities. PMID- 28663186 TI - The Role of Courts in Shaping Health Equity. AB - United States' courts have played a limited, yet key, role in shaping health equity in three areas of law: racial discrimination, disability discrimination, and constitutional rights. Executive and administrative action has been much more instrumental than judicial decisions in advancing racial equality in health care. Courts have been reluctant to intervene on racial justice because overt discrimination has largely disappeared, and the Supreme Court has interpreted civil rights laws in a fashion that restricts judicial authority to address more subtle or diffused forms of disparate impact. In contrast, courts have been more active in limiting disability discrimination by expanding the conditions that are considered disabling and by articulating and applying the operative concepts "reasonable accommodation" and "other qualified" in the context of both treatment and insurance coverage decisions. Finally, regarding constitutional rights, courts have had limited opportunity to intervene because, outside of specially protected arenas such as reproduction, constitutional law gives government wide discretion to define health and safety goals and methods. Thus, courts have had only a limited role in shaping health equity in the United States. It remains to be seen whether this will change under the Affordable Care Act or whatever health reform measure might replace it. PMID- 28663187 TI - Lung cancer incidence attributable to residential radon exposure in Alberta in 2012. AB - BACKGROUND: Radon is carcinogenic, and exposure to radon has been shown to increase the risk of lung cancer. The objective of this study was to quantify the proportion and number of lung cancer cases in Alberta in 2012 that could be attributed to residential radon exposure. METHODS: We estimated the population attributable risk of lung cancer for residential radon using radon exposure data from the Cross-Canada Survey of Radon Concentrations in Homes from 2009-2011 and data on all-cause and lung cancer mortality from Statistics Canada from 2008 2012. We used cancer incidence data from the Alberta Cancer Registry for 2012 to estimate the total number of lung cancers attributable to residential radon exposure. Estimates were also stratified by sex and smoking status. RESULTS: The mean geometric residential radon level in Alberta in 2011 was 71.0 Bq/m3 (geometric standard deviation 2.14). Overall, an estimated 16.6% (95% confidence interval 9.4%-29.8%) of lung cancers were attributable to radon exposure, corresponding to 324 excess attributable cancer cases. The estimated population attributable risk of lung cancer due to radon exposure was higher among those who had never smoked (24.8%) than among ever smokers (15.6%). However, since only about 10% of cases of lung cancer occur in nonsmokers, the estimated total number of excess cases was higher for ever smokers (274) than for never smokers (48). INTERPRETATION: With about 17% of lung cancer cases in Alberta in 2012 attributable to residential radon exposure, exposure reduction has the potential to substantially reduce Alberta's lung cancer burden. As such, home radon testing and remediation techniques represent important cancer prevention strategies. PMID- 28663188 TI - BMA annual meeting: STPs should be abandoned, says BMA. PMID- 28663189 TI - Erratum. National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. Diabetes 2016;65:3418-3428. PMID- 28663190 TI - Functional and Structural Findings of Neurodegeneration in Early Stages of Diabetic Retinopathy: Cross-sectional Analyses of Baseline Data of the EUROCONDOR Project. AB - This cross-sectional study evaluated the relationship between 1) functional and structural measurements of neurodegeneration in the initial stages of diabetic retinopathy (DR) and 2) the presence of neurodegeneration and early microvascular impairment. We analyzed baseline data of 449 patients with type 2 diabetes enrolled in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) study (NCT01726075). Functional studies by multifocal electroretinography (mfERG) evaluated neurodysfunction, and structural measurements using spectral domain optical coherence tomography (SD-OCT) evaluated neurodegeneration. The mfERG P1 amplitude was more sensitive than the P1 implicit time and was lower in patients with Early Treatment of Diabetic Retinopathy Study (ETDRS) level 20-35 than in patients with ETDRS level <20 (P = 0.005). In 58% of patients, mfERG abnormalities were present in the absence of visible retinopathy. Correspondence between SD-OCT thinning and mfERG abnormalities was shown in 67% of the eyes with ETDRS <20 and in 83% of the eyes with ETDRS level 20-35. Notably, 32% of patients with ETDRS 20-35 presented no abnormalities in mfERG or SD-OCT. We conclude that there is a link between mfERG and SD-OCT measurements that increases with the presence of microvascular impairment. However, a significant proportion of patients in our particular study population (ETDRS <=35) had normal ganglion cell-inner plexiform layer thickness and normal mfERG findings. We raise the hypothesis that neurodegeneration may play a role in the pathogenesis of DR in many but not in all patients with type 2 diabetes. PMID- 28663192 TI - PSMA Ligands for Imaging Prostate Cancer: Alternative Labeling by Complex Formation with Al18F2. PMID- 28663193 TI - Improving Tools and Options for the Management of Patients with Neuroendocrine Tumors: A Patient Perspective. PMID- 28663191 TI - The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes. AB - Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-kappaB (NF-kappaB) mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid specific Mll1 knockout (Mll1f/fLyz2Cre+ ) to determine the function of MLL1 in wound healing. Mll1f/fLyz2Cre+ mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from Mll1f/fLyz2Cre+ mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-kappaB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased Mll1 compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds. PMID- 28663194 TI - Using and Interpreting 18F-FDG PET/CT Images in Patients Referred for Assessment of Cardiac Sarcoidosis: The Devil Is in the Details. PMID- 28663195 TI - 177Lu-PSMA Radioligand Therapy for Prostate Cancer. AB - 177Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) using inhibitors of PSMA is a novel therapeutic option in patients with metastatic castration-resistant prostate cancer. The current literature suggests that this therapy is well tolerated and effective. On the basis of clinical need and current evidence, the therapy is being implemented in a growing number of centers worldwide. Here, we review important aspects of 177Lu-PSMA RLT, including patient stratification, the therapy protocol, concomitant medication, and follow-up, to inform medical staff involved in the RLT and care of patients with metastatic castration-resistant prostate cancer. PMID- 28663196 TI - The Triple-Flash Illusion Reveals a Driving Role of Alpha-Band Reverberations in Visual Perception. AB - The modulatory role of spontaneous brain oscillations on perception of threshold level stimuli is well established. Here, we provide evidence that alpha-band (~10 Hz) oscillations not only modulate perception of threshold-level sensory inputs but also can drive perception and generate percepts without a physical stimulus being present. We used the "triple-flash" illusion: Occasional perception of three flashes when only two spatially coincident veridical ones, separated by ~100 ms, are presented. The illusion was proposed to result from superposition of two hypothetical oscillatory impulse response functions generated in response to each flash: When the delay between flashes matches the period of the oscillation, the superposition enhances a later part of the oscillation that is normally damped; when this enhancement crosses perceptual threshold, a third flash is erroneously perceived (Bowen, 1989). In Experiment 1, we varied stimulus onset asynchrony and validated Bowen's theory: The optimal stimulus onset asynchrony for illusion to occur was correlated, across human subjects (both genders), with the subject-specific impulse response function period determined from a separate EEG experiment. Experiment 2 revealed that prestimulus parietal, but no occipital, alpha EEG phase and power, as well as poststimulus alpha phase locking, together determine the occurrence of the illusion on a trial-by-trial basis. Thus, oscillatory reverberations create something out of nothing: A third flash where there are only two.SIGNIFICANCE STATEMENT We highlight a novel property of alpha-band (~10 Hz) oscillations based on three experiments (two EEG and one psychophysics) by demonstrating that alpha-band oscillations do not merely modulate perception, but can also drive perception. We show that human participants report seeing a third flash when only two are presented (the "triple flash" illusion) most often when the interflash delay matches the period of participant's oscillatory impulse response function reverberating in alpha. Within-subject, the phase and power of ongoing parietal, but not occipital, alpha band oscillations at the time of the first flash determine illusory percept on a trial-by-trial basis. We revealed a physiologically plausible mechanism that validates and extends the original theoretical account of the triple-flash illusion proposed by Bowen in 1989. PMID- 28663197 TI - Subcellular Distribution of HDAC1 in Neurotoxic Conditions Is Dependent on Serine Phosphorylation. AB - Calcium-dependent nuclear export of histone deacetylase 1 (HDAC1) was shown previously to precede axonal damage in culture, but the in vivo relevance of these findings and the potential posttranslational modifications of HDAC1 remained elusive. Using acute hippocampal slices from mice of either sex with genetic conditional ablation of Hdac1 in CA1 hippocampal neurons (i.e., Camk2a cre;Hdac1fl/fl), we show significantly diminished axonal damage in response to neurotoxic stimuli. The protective effect of Hdac1 ablation was detected also in CA3 neurons in Grik4-cre;Hdac1fl/f mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid. The amino acid residues modulating HDAC1 subcellular localization were identified by site-directed mutagenesis, which identified serine residues 421 and 423 as critical for its nuclear localization. The physiological phosphorylation of HDAC1 was decreased by neurotoxic stimuli, which stimulated the phosphatase enzymatic activity of calcineurin. Treatment of neurons with the calcineurin inhibitors FK506 or cyclosporin A resulted in nuclear accumulation of phospho-HDAC1 and was neuroprotective. Together, our data identify HDAC1 and the phosphorylation of specific serine residues in the molecule as potential targets for neuroprotection.SIGNIFICANCE STATEMENT The importance of histone deacetylation in normal brain functions and pathological conditions is unquestionable, yet the molecular mechanisms responsible for the neurotoxic potential of histone deacetylase 1 (HDAC1) and its subcellular localization are not fully understood. Here, we use transgenic lines to define the in vivo relevance of HDAC1 and identify calcineurin-dependent serine dephosphorylation as the signal modulating the neurotoxic role of HDAC1 in response to neurotoxic stimuli. PMID- 28663199 TI - Behavioral Consequences of a Bifacial Map in the Mouse Somatosensory Cortex. AB - The whisker system is an important sensory organ with extensive neural representations in the brain of the mouse. Patterned neural modules (barrelettes) in the ipsilateral principal sensory nucleus of the trigeminal nerve (PrV) correspond to the whiskers. Axons of the PrV barrelette neurons cross the midline and confer the whisker-related patterning to the contralateral ventroposteromedial nucleus of the thalamus, and subsequently to the cortex. In this way, specific neural modules called barreloids and barrels in the contralateral thalamus and cortex represent each whisker. Partial midline crossing of the PrV axons, in a conditional Robo3 mutant (Robo3R3-5cKO) mouse line, leads to the formation of bilateral whisker maps in the ventroposteromedial, as well as the barrel cortex. We used voltage-sensitive dye optical imaging and somatosensory and motor behavioral tests to characterize the consequences of bifacial maps in the thalamocortical system. Voltage-sensitive dye optical imaging verified functional, bilateral whisker representation in the barrel cortex and activation of distinct cortical loci following ipsilateral and contralateral stimulation of the specific whiskers. The mutant animals were comparable with the control animals in sensorimotor tests. However, they showed noticeable deficits in all of the whisker-dependent or -related tests, including Y-maze exploration, horizontal surface approach, bridge crossing, gap crossing, texture discrimination, floating in water, and whisking laterality. Our results indicate that bifacial maps along the thalamocortical system do not offer a functional advantage. Instead, they lead to impairments, possibly due to the smaller size of the whisker-related modules and interference between the ipsilateral and contralateral whisker representations in the same thalamus and cortex.SIGNIFICANCE STATEMENT The whisker sensory system plays a quintessentially important role in exploratory behavior of mice and other nocturnal rodents. Here, we studied a novel mutant mouse line, in which the projections from the brainstem to the thalamus are disrupted. This led to formation of bilateral whisker maps in both the thalamus and the cortex. The two whisker maps crowd in a space normally devoted to the contralateral map alone and in a nonoverlapping fashion. Stimulation of the whiskers on either side activates the corresponding region of the map. Mice with bilateral whisker maps perform well in general sensorimotor tasks but show poor performance in specific tests that require whisker-dependent tactile discrimination. These observations indicate that contralateral, instead of bilateral, representation of the sensory space plays a critical role in acuity and fine discrimination during somesthesis. PMID- 28663200 TI - Bilateral Discrimination of Tactile Patterns without Whisking in Freely Running Rats. AB - A majority of whisker discrimination tasks in rodents are performed on head-fixed animals to facilitate tracking or control of the sensory inputs. However, head fixation critically restrains the behavior and thus the incoming stimuli compared with those occurring in natural conditions. In this study, we investigated whether freely behaving rats can discriminate fine tactile patterns while running, in particular when stimuli are presented simultaneously on both sides of the snout. We developed a two-alternative forced-choice task in an automated modified T-maze. Stimuli were either a surface with no bars (smooth) or with vertical bars spaced irregularly or regularly. While running at full speed, rats encountered simultaneously the two discriminanda placed on the two sides of the central aisle. Rats learned to recognize regular bars versus a smooth surface in 8 weeks. They solved the task while running at an average speed of 1 m/s, so that the contact with the stimulus lasted <1 typical whisking cycle, precluding the use of active whisking. Whisker-tracking analysis revealed an asymmetry in the position of the whiskers: they oriented toward the rewarded stimulus during successful trials as early as 60 ms after the first possible contact. We showed that the whiskers and activity in the primary somatosensory cortex are involved during the discrimination process. Finally, we identified irregular patterns of bars that the rats can discriminate from the regular one. This novel task shows that freely moving rodents can make simultaneous bilateral tactile discrimination without whisking.SIGNIFICANCE STATEMENT The whisker system of rodents is a widely used model to study tactile processing. Rats show remarkable abilities in discriminating surfaces by actively moving their whiskers (whisking) against stimuli, typically sampling them several times. This motor strategy affects considerably the way that tactile information is acquired and thus the way that neuronal networks process the information. However, when rats run at high speed, they protract their whiskers in front of the snout without large movements. Here, we investigated whether rats are able to discriminate regular and irregular patterns of vertical bars while running without whisking. We found that the animals can perform a bilateral simultaneous discrimination without whisking and that this involves both whiskers and barrel cortex activity. PMID- 28663198 TI - Representation of Multidimensional Stimuli: Quantifying the Most Informative Stimulus Dimension from Neural Responses. AB - A common way to assess the function of sensory neurons is to measure the number of spikes produced by individual neurons while systematically varying a given dimension of the stimulus. Such measured tuning curves can then be used to quantify the accuracy of the neural representation of the stimulus dimension under study, which can in turn be related to behavioral performance. However, tuning curves often change shape when other dimensions of the stimulus are varied, reflecting the simultaneous sensitivity of neurons to multiple stimulus features. Here we illustrate how one-dimensional information analyses are misleading in this context, and propose a framework derived from Fisher information that allows the quantification of information carried by neurons in multidimensional stimulus spaces. We use this method to probe the representation of sound localization in auditory neurons of chinchillas and guinea pigs of both sexes, and show how heterogeneous tuning properties contribute to a representation of sound source position that is robust to changes in sound level.SIGNIFICANCE STATEMENT Sensory neurons' responses are typically modulated simultaneously by numerous stimulus properties, which can result in an overestimation of neural acuity with existing one-dimensional neural information transmission measures. To overcome this limitation, we develop new, compact expressions of Fisher information-derived measures that bound the robust encoding of separate stimulus dimensions in the context of multidimensional stimuli. We apply this method to the problem of the representation of sound source location in the face of changes in sound source level by neurons of the auditory midbrain. PMID- 28663202 TI - Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. PMID- 28663206 TI - BMA annual meeting: One in 10 doctors have European colleagues who have left the UK because of Brexit, says BMA. PMID- 28663203 TI - Use of the M-CHAT follow-up interview (M-CHAT/F) by paediatricians during well child care visits is feasible, valid and reliable. PMID- 28663201 TI - Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice. AB - Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder.SIGNIFICANCE STATEMENT People who maternally inherit a deletion or nonfunctional copy of the UBE3A gene develop Angelman syndrome (AS), a severe neurodevelopmental disorder. To better understand how loss of maternal UBE3A function derails brain development, we analyzed brain structure in a maternal Ube3a knock-out mouse model of AS. We report that the volume of white matter (WM) is disproportionately reduced in AS mice, indicating that deficits in WM development are a major factor underlying impaired brain growth and microcephaly in the disorder. Notably, we find that axons within the WM pathways of AS model mice are abnormally small in caliber. This defect is associated with slowed nerve conduction, which could contribute to behavioral deficits in AS, including motor dysfunction. PMID- 28663207 TI - Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Immunogenetic Considerations Underlying B-Cell Biology in the Development of a Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem. AB - Current influenza vaccines preferentially generate B-cell responses to the variable hemagglutinin (HA) head. Focusing vaccine-induced antibody responses on epitopes in the conserved HA stem may provide better protection against future drifted and pandemic strains. Understanding the basis for the dominant HA head and subdominant HA stem-specific responses at the level of B-cell activation and differentiation will be critical for designing vaccines that induce sustained stem-specific responses. Identifying antibody lineages with broad neutralizing activity against influenza A viruses and defining the structural mode of recognition for germline precursors of those antibodies will also guide future immunogen design. PMID- 28663208 TI - Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Potential for a Universal Influenza Vaccine. AB - Development of optimal vaccines for influenza is challenging, in part as a result of the high antigenic variability in field strains associated with genetic shift from reassortment and genetic drift from point mutations. Discovery of conserved antigenic sites on the hemagglutinin (HA) protein for neutralizing antibodies suggested the possibility that influenza vaccines could be developed that induce focused antibody responses to the conserved neutralizing determinants, especially the HA stem region. Recent studies have focused on the antigenicity and immunogenicity of such domains, using monoclonal antibodies and candidate engineered HA stem-based vaccines. Much progress has been made, but we still do not fully understand the biology of the immune response to this unique antigenic region. PMID- 28663209 TI - Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Potential Target Antigens and Critical Aspects for a Universal Influenza Vaccine. AB - Influenza viruses cause seasonal epidemics as well as pandemics and are a significant concern for human health. Current influenza virus vaccines show efficacy when they are antigenically well matched to circulating strains. Seasonal influenza viruses undergo antigenic drift at a high rate and, therefore, current vaccines have to be reformulated and readministered on an annual basis. Mismatches between vaccine strains and circulating strains frequently occur, significantly decreasing vaccine efficacy. In addition, current seasonal influenza virus vaccines have limited efficacy against newly emerging pandemic viruses. A universal influenza virus vaccine that induces long-term protection against all influenza virus strains would abolish the need for annual readministration of seasonal influenza virus vaccines and would significantly enhance our pandemic preparedness. Here we discuss the characteristics of universal influenza virus vaccines, their potential target antigens, and critical aspects to consider on the path to successfully developing such vaccines. PMID- 28663210 TI - Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Outflanking Antibody Immunodominance on the Road to Universal Influenza Vaccination. AB - Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome immunodominance and improve the breadth and efficacy of antibody responses. PMID- 28663211 TI - Launch of new series: bright spots, physical activity investments that work. PMID- 28663212 TI - The 'Goldilocks Principle': designing physical activity at work to be 'just right' for promoting health. PMID- 28663213 TI - Prevention forecast: cloudy with a chance of injury. PMID- 28663214 TI - Has reimbursement for knee osteoarthritis treatments now reached 'postfact' status? PMID- 28663215 TI - NICE low back pain guidelines: opportunities and obstacles to change practice. PMID- 28663216 TI - Bright spots, physical activity investments that work: Agita Mundo global network. PMID- 28663217 TI - A video analysis of head injuries satisfying the criteria for a head injury assessment in professional Rugby Union: a prospective cohort study. AB - OBJECTIVES: Concussion is the most common match injury in professional Rugby Union, accounting for 25% of match injuries. The primary prevention of head injuries requires that the injury mechanism be known so that interventions can be targeted to specifically overall incidence by focusing on characteristics with the greatest propensity to cause a head injury. METHODS: 611 head injury assessment (HIA) events in professional Rugby Union over a 3-year period were analysed, with specific reference to match events, position, time and nature of head contact. RESULTS: 464 (76%) of HIA events occur during tackles, with the tackler experiencing a significantly greater propensity for an HIA than the ball carrier (1.40 HIAs/1000 tackles for the tackler vs 0.54 HIAs/1000 tackles for the ball carrier, incidence rate ratio (IRR) 2.59). Propensity was significantly greater for backline players than forwards (IRR 1.54, 95% CI 1.28 to 1.84), but did not increase over the course of the match. Head to head contact accounted for the most tackler HIAs, with the greatest propensity. CONCLUSIONS: By virtue of its high propensity and frequency, the tackle should be the focus for interventions that may include law change and technique education. A specific investigation of the characteristics of the tackle is warranted to refine the approach to preventative strategies. PMID- 28663218 TI - Physical fitness training for stroke survivors (PEDro synthesis). PMID- 28663220 TI - Aural microsuction. PMID- 28663221 TI - A Richter transformation PD-1 block party. PMID- 28663222 TI - CD1d-dependent CLL progression? PMID- 28663223 TI - Singling out FLI1 in Paris-Trousseau syndrome. PMID- 28663224 TI - Cystic splenomegaly: ectopic adenocarcinoma of unknown primary. PMID- 28663225 TI - Targeted therapy-induced differentiation of acute myeloid leukemia blasts. PMID- 28663226 TI - Infection Monitoring in Dialysis Units: A Plea for "Cleaner" Data. PMID- 28663227 TI - National Healthcare Safety Network (NHSN) Dialysis Event Surveillance Report for 2014. AB - BACKGROUND AND OBJECTIVES: Persons receiving outpatient hemodialysis are at risk for bloodstream and vascular access infections. The Centers for Disease Control and Prevention conducts surveillance for these infections through the National Healthcare Safety Network. We summarize 2014 data submitted to National Healthcare Safety Network Dialysis Event Surveillance. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Dialysis facilities report three types of dialysis events (bloodstream infections; intravenous antimicrobial starts; and pus, redness, or increased swelling at the hemodialysis vascular access site). Denominator data consist of the number of hemodialysis outpatients treated at the facility during the first 2 working days of each month. We calculated dialysis event rates stratified by vascular access type (e.g., arteriovenous fistula, arteriovenous graft, or central venous catheter) and standardized infection ratios (comparing individual facility observed with predicted numbers of infections) for bloodstream infections. We described pathogens identified among bloodstream infections. RESULTS: A total of 6005 outpatient hemodialysis facilities reported dialysis event data for 2014 to the National Healthcare Safety Network. These facilities reported 160,971 dialysis events, including 29,516 bloodstream infections, 149,722 intravenous antimicrobial starts, and 38,310 pus, redness, or increased swelling at the hemodialysis vascular access site events; 22,576 (76.5%) bloodstream infections were considered vascular access related. Most bloodstream infections (63.0%) and access-related bloodstream infections (69.8%) occurred in patients with a central venous catheter. The rate of bloodstream infections per 100 patient-months was 0.64 (0.26 for arteriovenous fistula, 0.39 for arteriovenous graft, and 2.16 for central venous catheter). Other dialysis event rates were also highest among patients with a central venous catheter. Facility bloodstream infection standardized infection ratio distribution was positively skewed with a median of 0.84. Staphylococcus aureus was the most commonly isolated bloodstream infection pathogen (30.6%), and 39.5% of S. aureus isolates tested were resistant to methicillin. CONCLUSIONS: The 2014 National Healthcare Safety Network Dialysis Event data represent nearly all United States outpatient dialysis facilities. Rates of infection and other dialysis events were highest among patients with a central venous catheter compared with other vascular access types. Surveillance data can help define the epidemiology of important infections in this patient population. PMID- 28663229 TI - Government is in dark about scale of mental health problems in prisons, says NAO. PMID- 28663228 TI - Testicular vs adrenal sources of hydroxy-androgens in prostate cancer. AB - Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3beta,17beta-diol (5-adiol), 5alpha androstane-3alpha,17beta-diol (3alpha-adiol), 5alpha-androstane-3beta,17beta-diol (3beta-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3alpha-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5alpha-dihydrotestosterone (DHT), 3alpha-adiol and 3beta-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin. PMID- 28663232 TI - Are drug regulators really too slow? PMID- 28663230 TI - Tissue-Specific MicroRNA Expression Patterns in Four Types of Kidney Disease. AB - MicroRNAs contribute to the development of kidney disease. Previous analyses of microRNA expression in human kidneys, however, were limited by tissue heterogeneity or the inclusion of only one pathologic type. In this study, we used laser-capture microdissection to obtain glomeruli and proximal tubules from 98 human needle kidney biopsy specimens for microRNA expression analysis using deep sequencing. We analyzed specimens from patients with diabetic nephropathy (DN), FSGS, IgA nephropathy (IgAN), membranoproliferative GN (MPGN) (n=19-23 for each disease), and a control group (n=14). Compared with control glomeruli, DN, FSGS, IgAN, and MPGN glomeruli exhibited differential expression of 18, 12, two, and 17 known microRNAs, respectively. The expression of several microRNAs also differed between disease conditions. Specifically, compared with control or FSGS glomeruli, IgAN glomeruli exhibited downregulated expression of hsa-miR-3182. Furthermore, in combination, the expression levels of hsa-miR-146a-5p and hsa-miR 30a-5p distinguished DN from all other conditions except IgAN. Compared with control proximal tubules, DN, FSGS, IgAN, and MPGN proximal tubules had differential expression of 13, 14, eight, and eight microRNAs, respectively, but expression of microRNAs did not differ significantly between the disease conditions. The abundance of several microRNAs correlated with indexes of renal function. Finally, we validated the differential glomerular expression of select microRNAs in a second cohort of patients with DN (n=19) and FSGS (n=21). In conclusion, we identified tissue-specific microRNA expression patterns associated with several kidney pathologies. The identified microRNAs could be developed as biomarkers of kidney diseases and might be involved in disease mechanisms. PMID- 28663231 TI - Complement Recognition Pathways in Renal Transplantation. AB - The complement system, consisting of soluble and cell membrane-bound components of the innate immune system, has defined roles in the pathophysiology of renal allograft rejection. Notably, the unavoidable ischemia-reperfusion injury inherent to transplantation is mediated through the terminal complement activation products C5a and C5b-9. Furthermore, biologically active fragments C3a and C5a, produced during complement activation, can modulate both antigen presentation and T cell priming, ultimately leading to allograft rejection. Earlier work identified renal tubule cell synthesis of C3, rather than hepatic synthesis of C3, as the primary source of C3 driving these effects. Recent efforts have focused on identifying the local triggers of complement activation. Collectin-11, a soluble C-type lectin expressed in renal tissue, has been implicated as an important trigger of complement activation in renal tissue. In particular, collectin-11 has been shown to engage L-fucose at sites of ischemic stress, activating the lectin complement pathway and directing the innate immune response to the distressed renal tubule. The interface between collectin-11 and L fucose, in both the recipient and the allograft, is an attractive target for therapies intended to curtail renal inflammation in the acute phase. PMID- 28663233 TI - The focal facial dermal dysplasias: phenotypic spectrum and molecular genetic heterogeneity. AB - Focal facial dermal dysplasias (FFDDs) are rare genetic/developmental disorders characterised by bilateral 'scar-like' facial lesions. Four subtypes are classified by the bitemporal (FFDD1-3) or preauricular (FFDD4) lesion location. FFDD1-3 are differentiated by additional facial abnormalities and inheritance patterns. Although the genetic defects causing FFDD1 and FFDD2 remain unknown, recent studies identified defects causing FFDD3 and FFDD4. Here, the clinical phenotypes, genetic defects and inheritance of the four FFDD subtypes are described. In addition, the overlapping facial abnormalities in FFDD3 and two other genetic disorders, Ablepharon macrostomia syndrome and Barber-Say syndrome, are noted. Familiarity with the FFDDs by clinicians will further delineate the phenotypes and genetic/developmental defects of these dermal facial disorders. PMID- 28663234 TI - Pericarditis as a Marker of Occult Cancer and a Prognostic Factor for Cancer Mortality. AB - BACKGROUND: Pericarditis may be a serious complication of malignancy. Its significance as a first symptom of occult cancer and as a prognostic factor for cancer survival is unknown. METHODS: Using Danish medical databases, we conducted a nationwide cohort study of all patients with a first-time diagnosis of pericarditis during 1994 to 2013. We excluded patients with previous cancer and followed up the remaining patients for subsequent cancer diagnosis until November 30, 2013. We calculated risks and standardized incidence ratios of cancer for patients with pericarditis compared with the general population. We assessed whether pericarditis predicts cancer survival by the Kaplan-Meier method and Cox regression using a matched comparison cohort of cancer patients without pericarditis. RESULTS: Among 13 759 patients with acute pericarditis, 1550 subsequently were diagnosed with cancer during follow-up. The overall cancer standardized incidence ratio was 1.5 (95% confidence interval [CI], 1.4-1.5), driven predominantly by increased rates of lung, kidney, and bladder cancer, lymphoma, leukemia, and unspecified metastatic cancer. The <3-month cancer risk among patients with pericarditis was 2.7%, and the standardized incidence ratio was 12.4 (95% CI, 11.2-13.7). The 3- to <12-month standardized incidence ratio of cancer was 1.5 (95% CI, 1.2-1.7), subsequently decreasing to 1.1 (95% CI, 1.0 1.2). Three-month survival after the cancer diagnosis was 80% and 86% among those with and without pericarditis, respectively, and the hazard ratio was 1.5 (95% CI, 1.3-1.8). One-year survival was 65% and 70%, respectively, corresponding to a 3- to <12-month hazard ratio of 1.3 (95% CI, 1.1-1.5). CONCLUSIONS: Pericarditis may be a marker of occult cancer and augurs increased mortality after a cancer diagnosis. PMID- 28663235 TI - Immunotherapy of Prostate Cancer: Facts and Hopes. AB - In the last few years, immunotherapy has become an important cancer treatment modality, and although the principles of immunotherapy have evolved over many decades, the FDA approvals of sipuleucel-T and ipilimumab began a new wave in immuno-oncology. Despite the current enthusiasm, it is unlikely that any of the immunotherapeutics alone can dramatically change prostate cancer outcomes, but combination strategies are more promising and provide a reason for optimism. Several completed and ongoing studies have shown that the combination of cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents, hormonal therapy (enzalutamide), radiotherapy (radium 223), DNA-damaging agents (olaparib), or chemotherapy (docetaxel) can enhance immune responses and induce more dramatic, long-lasting clinical responses without significant toxicity. The goal of prostate cancer immunotherapy does not have to be complete eradication of advanced disease but rather the return to an immunologic equilibrium with an indolent disease state. In addition to determining the optimal combination of treatment regimens, efforts are also ongoing to discover biomarkers of immune response. With such concerted efforts, the future of immunotherapy in prostate cancer looks brighter than ever. Clin Cancer Res; 23(22); 6764-70. (c)2017 AACR. PMID- 28663236 TI - Manipulation and quantification of microtubule lattice integrity. AB - Microtubules are structural polymers that participate in a wide range of cellular functions. The addition and loss of tubulin subunits allows the microtubule to grow and shorten, as well as to develop and repair defects and gaps in its cylindrical lattice. These lattice defects act to modulate the interactions of microtubules with molecular motors and other microtubule-associated proteins. Therefore, tools to control and measure microtubule lattice structure will be invaluable for developing a quantitative understanding of how the structural state of the microtubule lattice may regulate its interactions with other proteins. In this work, we manipulated the lattice integrity of in vitro microtubules to create pools of microtubules with common nucleotide states, but with variations in structural states. We then developed a series of novel semi automated analysis tools for both fluorescence and electron microscopy experiments to quantify the type and severity of alterations in microtubule lattice integrity. These techniques will enable new investigations that explore the role of microtubule lattice structure in interactions with microtubule associated proteins. PMID- 28663238 TI - Remarkable Evolutionary Conservation of Antiobesity ADIPOSE/WDTC1 Homologs in Animals and Plants. AB - ASG2 (Altered Seed Germination 2) is a prenylated protein in Arabidopsis thaliana that participates to abscisic acid signaling and is proposed to act as a substrate adaptor for the DDB1 (DNA damage-binding protein 1)-CUL4 (Cullin 4) E3 ubiquitin ligase complex. ASG2 harbors WD40 and TetratricoPeptide Repeat (TPR) domains, and resembles the well-conserved animal gene called ADP (antiobesity factor ADIPOSE) in fly and WDTC1 (WD40 and TPR 1) in humans. Loss of function of WDTC1 results in an increase in adipocytes, fat accumulation, and obesity. Antiadipogenic functions of WDTC1 involve regulation of fat-related gene transcription, notably through its binding to histone deacetylases (HDACs). Our sequence and phylogenetic analysis reveals that ASG2 belongs to the ADP/WDTC1 cluster. ASG2 and WDTC1 share a highly conserved organization that encompasses structural and functional motifs: seven WD40 domains and WD40 hotspot-related residues, three TPR protein-protein interaction domains, DDB1-binding elements [H box and DWD (DDB1-binding WD40 protein)-box], and a prenylatable C-terminus. Furthermore, ASG2 involvement in fat metabolism was confirmed by reverse genetic approaches using asg2 knockout Arabidopsis plants. Under limited irradiance, asg2 mutants produce "obese" seeds characterized by increased weight, oil body density, and higher fatty acid contents. In addition, considering some ASG2- and WDTC1-peculiar properties, we show that the WDTC1 C-terminus is prenylated in vitro and HDAC-binding capability is conserved in ASG2, suggesting that the regulation mechanism and targets of ADP/WDTC1-like proteins may be conserved features. Our findings reveal the remarkable evolutionary conservation of the structure and the physiological role of ADIPOSE homologs in animals and plants. PMID- 28663240 TI - Interpreting Iron Studies. PMID- 28663239 TI - Secretory phospholipase A2 group IIA modulates insulin sensitivity and metabolism. AB - Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases that have been implicated in inflammation, atherogenesis, and antibacterial actions. Here, we evaluated the role of PLA2G2A in the metabolic response to a high fat diet. C57BL/6 (BL/6) mice do not express PLA2g2a due to a frameshift mutation. We fed BL/6 mice expressing the human PLA2G2A gene (IIA+ mice) a fat diet and assessed the physiologic response. After 10 weeks on the high fat diet, the BL/6 mice were obese, but the IIA+ mice did not gain weight or accumulate lipid. The lean mass in chow- and high fat-fed IIA+ mice was constant and similar to the BL/6 mice on a chow diet. Surprisingly, the IIA+ mice had an elevated metabolic rate, which was not due to differences in physical activity. The IIA+ mice were more insulin sensitive and glucose tolerant than the BL/6 mice, even when the IIA+ mice were provided the high fat diet. The IIA+ mice had increased expression of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), and PPARgamma coactivator 1alpha (PGC-1alpha) in brown adipose tissue (BAT), suggesting that PLA2G2A activates mitochondrial uncoupling in BAT. Our data indicate that PLA2G2A has a previously undiscovered impact on insulin sensitivity and metabolism. PMID- 28663242 TI - Stress at work. PMID- 28663241 TI - Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. AB - O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts. PMID- 28663245 TI - Large prostatic stones with staghorn renal calculus in a 61-year-old man: an unusual presentation of uncommon disease. AB - Prostatic parenchymal calculi are common in ageing men who are evaluated for benign prostatic hyperplasia or prostate cancer. Giant prostatic calculi are very rare, usually associated with local predisposing factors for urinary stasis and infections, and traditionally managed by open surgery. We present the first case of its kind to be associated with a concurrent staghorn nephrolithiasis, and removed successfully by endoscopic approach using an access sheath through the urethra. PMID- 28663246 TI - Cardiogenic shock from coronary vasculitis in granulomatosis with polyangiitis. AB - Granulomatosis with polyangiitis (GPA) is a systemic vasculitis characterised by necrotising inflammatory changes in small-sized and medium-sized vessels and granuloma formation. It most commonly involves the kidneys and respiratory tract, but it can present with widespread manifestations involving any organ system. Rarely, it causes coronary vasculitis which can precipitate a severe cardiomyopathy. Here, we report a patient who presented in cardiogenic shock requiring vasopressors and was found to have extensive myocardial ischaemia secondary to coronary vasculitis. Further investigation led to a diagnosis of GPA, and he responded to treatment with corticosteroids, cyclophosphamide and plasmapheresis. PMID- 28663244 TI - Frontline Science: c-Myc regulates P-selectin glycoprotein ligand-1 expression in monocytes during HIV-1 infection. AB - Leukocyte extravasation is a crucial feature of the normal immune response to disease and infection and is implicated in various pathologies during chronic inflammatory disease. P-Selectin glycoprotein ligand-1 (PSGL-1) is critical for leukocyte extravasation; however, despite extensive study, it remains unclear how its expression is regulated, which in turn, impedes a more precise understanding of how its expression level affects transmigration. To investigate the regulation of PSGL-1, 60 subjects, with or without HIV infection, were recruited and PSGL-1 expression in monocytes was measured. PSGL-1 was found to be up-regulated on leukocytes from HIV-infected individuals, and the physiologically relevant mediators soluble CD40 ligand (sCD40L) and glutamate were able to induce PSGL-1 transcription in human monocytes ex vivo. HIV-1 induced PSGL-1 induction, and its dependence on CD40L was validated further by use of the mouse-tropic HIV (EcoHIV) mouse model of HIV infection in C57BL/6 and CD40L knockout (KO) mice. To investigate crosstalk between the signaling cascades induced by CD40L and glutamate that lead to PSGL-1 induction, a network-based, discrete dynamic model was developed. The model reveals the MAPK pathway and oxidative stress as critical mediators of crosstalk between CD40L and glutamate-induced pathways. Importantly, the model predicted induction of the c-Myc transcription factor upon cotreatment, which was validated using transcriptomic data and pharmacologic inhibition of c-Myc. This study suggests a novel systems serology approach for translational research and reveals a mechanism for PSGL-1 transcriptional regulation, which might be leveraged to identify novel targets for therapeutic intervention. PMID- 28663247 TI - Gangrenous digital infarcts in a severe case of cutaneous polyarteritis nodosa. AB - Cutaneous polyarteritis nodosa (CPAN) is a rare diagnosis which is distinct from polyarteritis nodosa (PAN). PAN is a medium-vessel vasculitis which can affect multiple organs and classically produces microaneurysms in the vasculature. CPAN is limited to the skin mainly affecting small vessels. There is an absence of microaneurysms in CPAN and it does not affect internal organs. However, the histopathological findings on the skin are similar to PAN. CPAN rarely progresses to PAN but relapses more often. We will illustrate a challenging case of a patient with CPAN who developed gangrenous infarcts despite initial immunosuppressive treatment with high-dose steroids and azathioprine. His treatment had to be escalated to intravenous cyclophosphamide which induced disease remission. PMID- 28663248 TI - Anal herpes. PMID- 28663249 TI - Quick starting hormonal contraception after using oral emergency contraception: a systematic review. AB - INTRODUCTION: Unprotected intercourse after oral emergency contraception (EC) significantly increases pregnancy risk. This underlies the importance of promptly starting effective, ongoing contraception - known as 'quick starting'. However, theoretical concern exists that quick starting might interact with EC or hormonal contraception (HC) potentially causing adverse side effects. METHOD: A systematic review was conducted, evaluating quick starting HC after oral EC [levonorgestrel 1.5 mg (LNG) or ulipristal acetate 30 mg (UPA)]. PubMed, EMBASE, The Cochrane Library, ICTRP, ClinicalTrials.gov and relevant reference lists were searched in February 2016. A lack of comparable studies prevented meta-analysis. RESULTS: Three randomised controlled trials were identified. Two biomedical studies suggested HC action was unaffected by quick starting after UPA; one study examined ovarian quiescence (OR 1.27; 95% CI 0.51-3.18) while taking combined oral contraception (COC). Another assessed cervical mucus impenetrability (OR 0.76; 95% CI 0.27-2.13) while taking progestogen-only pills (POP). Quick starting POP reduced the ability of UPA to delay ovulation (OR 0.04; 95% CI 0.01-0.37). Side effects (OR 1.22; 95% CI 0.48-3.12) and unscheduled bleeding (OR 0.53; 95% CI 0.16-1.81) were unaffected by quick starting COC after UPA. Another study reported higher self-reported contraceptive use at 8 weeks among women quick starting POP after LNG, compared with women given LNG alone (OR 6.73; 95% CI 2.14 21.20). PMID- 28663250 TI - Association Between Elevated Pulse Pressure and High Resting Coronary Blood Flow Velocity in Patients With Angiographically Normal Epicardial Coronary Arteries. AB - BACKGROUND: The aim of our study was to evaluate the relationship of pulse pressure (PP), a raw index of arterial stiffness, with noninvasively determined coronary flow reserve (CFR) and its components, in patients with angiographically normal epicardial coronary arteries. METHODS AND RESULTS: The study population included 398 patients without angiographic evidence of coronary stenosis, who underwent high-dose dipyridamole stress echocardiography with transthoracic derived CFR evaluation on the left anterior descending artery. CFR was calculated as the ratio between high-dose dipyridamole and resting coronary diastolic peak velocities. Patients were divided into 2 groups: the first group included the first and second PP tertiles (n=298, PP <=60 mm Hg) and the second group included the highest PP tertile (n=100, PP >60 mm Hg). Mean blood pressure, systolic blood pressure (both P<0.0001), age (P<0.002), and left ventricular mass index (P=0.013) were higher in the highest PP tertile, which also showed higher resting coronary flow velocity (31.6+/-9.6 cm/s versus 27.7+/-6.4 cm/s, P<0.0001) and marginally lower CFR (2.5+/-0.6 versus 2.6+/-0.6, P=0.044). Hyperemic coronary flow velocity did not differ between the 2 groups. By separate multiple linear regression analyses, after adjusting for sex, age, the highest systolic blood pressure tertile (>=140 mm Hg), left ventricular mass index, and cardiovascular risk factors, the highest PP tertile was associated with resting coronary flow velocity (P=0.003) and only marginally with hyperemic coronary flow velocity (P<0.02), whereas its association with CFR was not significant. CONCLUSIONS: In patients without epicardial coronary artery stenosis, the highest PP tertile is associated with an increased coronary flow velocity at rest. PMID- 28663251 TI - Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta-Analysis of Prospective Studies. AB - BACKGROUND: Gut microbial metabolites have been implicated as novel risk factors for cardiovascular events and premature death. The strength and consistency of associations between blood concentrations of the gut microbial metabolites, trimethylamine-N-oxide (TMAO) and its precursors, with major adverse cardiovascular events (MACE) or death have not been comprehensively assessed. We quantified associations of blood concentrations of TMAO and its precursors with risks of MACE and mortality. METHODS AND RESULTS: PubMed and Embase databases were searched up, and a total of 19 prospective studies from 16 publications (n=19 256, including 3315 incident cases) with quantitative estimates of the associations of TMAO with the development of MACE or death were included in our main analysis. Multivariate-adjusted relative risks (RRs) were used when these were available. Elevated concentrations of TMAO were associated with a pooled RR of 1.62 (95% CI, 1.45, 1.80; Pheterogeneity=0.2; I2=23.5%) for MACE compared with low TMAO levels, and 1 study of black participants influenced the heterogeneity of the association. After excluding the data of blacks, the RRs were not different according to body mass index, prevalence of diabetes mellitus, history of cardiovascular diseases, and kidney dysfunction. Furthermore, elevated TMAO concentrations were associated with a pooled RR of 1.63 (1.36, 1.95) for all cause mortality. Individuals with elevated concentrations of TMAO precursors (l carnitine, choline, or betaine) had an approximately 1.3 to 1.4 times higher risk for MACE compared to those with low concentrations. CONCLUSIONS: Elevated concentrations of TMAO and its precursors were associated with increased risks of MACE and all-cause mortality independently of traditional risk factors. PMID- 28663252 TI - Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation. AB - OBJECTIVE: On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets. APPROACH AND RESULTS: Platelet-specific knockout of GLUT3 was generated by crossing mice harboring GLUT3 floxed allele to a PF4 (platelet factor 4)-driven Cre recombinase. In platelets, GLUT3 is localized primarily on alpha-granule membranes and under basal conditions facilitates glucose uptake into alpha-granules to be used for glycolysis. After activation, platelets degranulate and GLUT3 translocates to the plasma membrane, which is responsible for activation-mediated increased glucose uptake. In vivo, loss of GLUT3 in platelets increased survival in a collagen/epinephrine model of pulmonary embolism, and in a K/BxN model of autoimmune inflammatory disease, platelet-specific GLUT3 knockout mice display decreased disease progression. Mechanistically, loss of GLUT3 decreased platelet degranulation, spreading, and clot retraction. Decreased alpha-granule degranulation is due in part to an impaired ability of GLUT3 to potentiate exocytosis. CONCLUSIONS: GLUT3-mediated glucose utilization and glycogenolysis in platelets promotes alpha-granule release, platelet activation, and postactivation functions. PMID- 28663253 TI - Inner Mitochondrial Membrane Disruption Links Apoptotic and Agonist-Initiated Phosphatidylserine Externalization in Platelets. AB - OBJECTIVE: Phosphatidylserine exposure mediates platelet procoagulant function and regulates platelet life span. Apoptotic, necrotic, and integrin-mediated mechanisms have been implicated as intracellular determinants of platelet phosphatidylserine exposure. Here, we investigate (1) the role of mitochondrial events in platelet phosphatidylserine exposure initiated by these distinct stimuli and (2) the cellular interactions of the procoagulant platelet in vitro and in vivo. APPROACH AND RESULTS: Key mitochondrial events were examined, including cytochrome c release and inner mitochondrial membrane (IMM) disruption. In both ABT-737 (apoptotic) and agonist (necrotic)-treated platelets, phosphatidylserine externalization was temporally correlated with IMM disruption. Agonist stimulation resulted in rapid cyclophilin D-dependent IMM disruption that coincided with phosphatidylserine exposure. ABT-737 treatment caused rapid cytochrome c release, eventually followed by caspase-dependent IMM disruption that again closely coincided with phosphatidylserine exposure. A nonmitochondrial and integrin-mediated mechanism has been implicated in the formation of a novel phosphatidylserine-externalizing platelet subpopulation. Using image cytometry, this subpopulation is demonstrated to be the result of the interaction of an aggregatory platelet and a procoagulant platelet rather than indicative of a novel intracellular mechanism regulating platelet phosphatidylserine externalization. Using electron microscopy, similar interactions between aggregatory and procoagulant platelets are demonstrated in vitro and in vivo within a mesenteric vein hemostatic thrombus. CONCLUSIONS: Platelet phosphatidylserine externalization is closely associated with the mitochondrial event of IMM disruption identifying a common pathway in phosphatidylserine externalizing platelets. The limited interaction of procoagulant platelets and integrin-active aggregatory platelets identifies a potential mechanism for procoagulant platelet retention within the hemostatic thrombus. PMID- 28663254 TI - Blood Pressure and Heart Rate Measures Associated With Increased Risk of Covert Brain Infarction and Worsening Leukoaraiosis in Older Adults. AB - OBJECTIVE: In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings. APPROACH AND RESULTS: In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15% and worsening white matter grade in 27%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95% confidence interval, 1.12-1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95% confidence interval, 1.24-1.69). These findings persisted in secondary and sensitivity analyses. CONCLUSIONS: Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ. PMID- 28663255 TI - Subcutaneous Adipocyte Lipolysis Contributes to Circulating Lipid Levels. AB - OBJECTIVE: Fatty acids released via fat cell lipolysis can affect circulating lipid levels. However, the contribution of different lipolysis measures in adipose tissue is unknown and was presently examined in isolated subcutaneous adipocytes. APPROACH AND RESULTS: One thousand and sixty-six men and women were examined for lipolysis regulation in subcutaneous abdominal fat cells. Results were compared with fasting plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C) and triglycerides. Spontaneous (basal) lipolysis and the effects of the major hormones stimulating (catecholamines and natriuretic peptides) and inhibiting lipolysis (insulin) were examined. Several statistically significant (P<0.0001) correlations between the different lipolysis parameters and plasma lipids were observed. However, physiologically relevant correlations (adjusted r2>=0.05) were only evident between basal or insulin inhibited lipolysis and plasma triglycerides or HDL-C. Together, these lipolysis measures explained 14% of the variation in triglycerides or HDL-C, respectively. In comparison, a combination of established factors associated with variations in plasma lipids, that is, age; body mass index; waist circumference; waist-to-hip ratio; sex; nicotine use; fat cell volume; and pharmacotherapy against diabetes mellitus; hypertension; or hyperlipidemia explained 17% and 28%, respectively, of the variations in plasma triglycerides and HDL-C. CONCLUSIONS: Subcutaneous fat cell lipolysis is an important independent contributor to interindividual variations in plasma lipids. High spontaneous lipolysis activity and resistance to the antilipolytic effect of insulin associate with elevated triglyceride and low HDL-C concentrations. Thus, although several other factors also play a role, subcutaneous adipose tissue may have a causal influence on dyslipidemia. PMID- 28663256 TI - Magnesium Counteracts Vascular Calcification: Passive Interference or Active Modulation? AB - Over the last decade, an increasing number of studies report a close relationship between serum magnesium concentration and cardiovascular disease risk in the general population. In end-stage renal disease, an association was found between serum magnesium and survival. Hypomagnesemia was identified as a strong predictor for cardiovascular disease in these patients. A substantial body of in vitro and in vivo studies has identified a protective role for magnesium in vascular calcification. However, the precise mechanisms and its contribution to cardiovascular protection remain unclear. There are currently 2 leading hypotheses: first, magnesium may bind phosphate and delay calcium phosphate crystal growth in the circulation, thereby passively interfering with calcium phosphate deposition in the vessel wall. Second, magnesium may regulate vascular smooth muscle cell transdifferentiation toward an osteogenic phenotype by active cellular modulation of factors associated with calcification. Here, the data supporting these major hypotheses are reviewed. The literature supports both a passive inorganic phosphate-buffering role reducing hydroxyapatite formation and an active cell-mediated role, directly targeting vascular smooth muscle transdifferentiation. However, current evidence relies on basic experimental designs that are often insufficient to delineate the underlying mechanisms. The field requires more advanced experimental design, including determination of intracellular magnesium concentrations and the identification of the molecular players that regulate magnesium concentrations in vascular smooth muscle cells. PMID- 28663257 TI - Smooth Muscle Cells Derived From Second Heart Field and Cardiac Neural Crest Reside in Spatially Distinct Domains in the Media of the Ascending Aorta-Brief Report. AB - OBJECTIVE: Smooth muscle cells (SMCs) of the proximal thoracic aorta are embryonically derived from the second heart field (SHF) and cardiac neural crest (CNC). However, distributions of these embryonic origins are not fully defined. The regional distribution of SMCs of different origins is speculated to cause region-specific aortopathies. Therefore, the aim of this study was to determine the distribution of SMCs of SHF and CNC origins in the proximal thoracic aorta. APPROACH AND RESULTS: Mice with repressed LacZ in the ROSA26 locus were bred to those expressing Cre controlled by either the Wnt1 or Mef2c (myocyte-specific enhancer factor 2c) promoter to trace CNC- and SHF-derived SMCs, respectively. Thoracic aortas were harvested, and activity of beta-galactosidase was determined. Aortas from Wnt1-Cre mice had beta-galactosidase-positive areas throughout the region from the proximal ascending aorta to just distal of the subclavian arterial branch. Unexpectedly, beta-galactosidase-positive areas in Mef2c-Cre mice extended from the aortic root throughout the ascending aorta. This distribution occurred independent of sex and aging. Cross and sagittal aortic sections demonstrated that CNC-derived cells populated the inner medial aspect of the anterior region of the ascending aorta and transmurally in the media of the posterior region. Interestingly, outer medial cells throughout anterior and posterior ascending aortas were derived from the SHF. beta-Galactosidase-positive medial cells of both origins colocalized with an SMC marker, alpha-actin. CONCLUSIONS: Both CNC- and SHF-derived SMCs populate the media throughout the ascending aorta. The outer medial cells of the ascending aorta form a sleeve populated by SHF-derived SMCs. PMID- 28663258 TI - Ly6Chigh Monocytes Oscillate in the Heart During Homeostasis and After Myocardial Infarction-Brief Report. AB - OBJECTIVE: Circadian regulation of neutrophil homeostasis affects myocardial infarction (MI) healing. It is unknown whether diurnal variations of monocyte counts exist in the heart and whether this affects their cardiac infiltration in response to MI. APPROACH AND RESULTS: Murine blood and organs were harvested at distinct times of day and analyzed by flow cytometry. Ly6Chigh monocyte surface expression levels of chemokine receptors (CCR) were ~2-fold higher at the beginning of the active phase, Zeitgeber Time (ZT) 13 compared with ZT5. This was because of enhanced receptor surface expression at ZT13, whereas no significant changes in total cellular protein levels were found. Most blood Ly6Chigh monocytes were CCR2high, whereas only a minority was CCR1high and CCR5high. We also found diurnal changes of classical monocyte blood counts in humans, being higher in the evening, while exhibiting enhanced CCR2 surface expression in the morning. In support of monocyte oscillations between blood and tissue, murine cardiac Ly6Chigh monocyte counts were highest at ZT13, accompanied by an upregulation of cardiac CC chemokine ligand 2 mRNA. Mice subjected to MI at ZT13 had an even higher upregulation of CCR2 surface expression on circulating monocytes compared with noninfarcted mice and more elevated cardiac CC chemokine ligand 2 protein expression and more pronounced Ly6Chigh monocyte infiltration compared with ZT5-infarcted mice. Concomitantly, CCR2 antagonism only inhibited the excessive cardiac Ly6Chigh monocyte infiltration after ZT13 MI but not ZT5 MI. CONCLUSIONS: CCR2 surface expression on Ly6Chigh monocytes changes in a time of-day-dependent manner, which crucially affects cardiac monocyte recruitment after an acute ischemic event. PMID- 28663260 TI - Minor Stroke and Thrombolysis: What Is in the Pipeline? PMID- 28663259 TI - What trial participants need to be told about placebo effects to give informed consent: a survey to establish existing knowledge among patients with back pain. AB - INTRODUCTION: Patients require an accurate knowledge about placebos and their possible effects to ensure consent for placebo-controlled clinical trials is adequately informed. However, few previous studies have explored patients' baseline (ie, pretrial recruitment) levels of understanding and knowledge about placebos. The present online survey aimed to assess knowledge about placebos among patients with a history of back pain. DESIGN: A 15-item questionnaire was constructed to measure knowledge about placebos. Additional questions assessed sociodemographic characteristics, duration and severity of back pain, and previous experience of receiving placebos. SETTING: Participants recruited from community settings completed the study online. RESULTS: 210 participants completed the questionnaire. 86.7% had back pain in the past 6 months, 44.3% currently had back pain. 4.3% had received a placebo intervention as part of a clinical trial and 68.1% had previously read or heard information about placebos. Overall knowledge of placebos was high, with participants on average answering 12.07 of 15 questions about placebos correctly (SD=2.35). However, few participants correctly answered questions about the nocebo effect (31.9% correct) and the impact of the colour of a placebo pill (55.2% correct). CONCLUSIONS: The findings identified key gaps in knowledge about placebos. The lack of understanding of the nocebo effect in particular has implications for the informed consent of trial participants. Research ethics committees and investigators should prioritise amending informed consent procedures to incorporate the fact that participants in the placebo arm might experience adverse side effects. PMID- 28663261 TI - Reply. PMID- 28663262 TI - Ethanol Ablation of Ranulas: Short-Term Follow-Up Results and Clinicoradiologic Factors for Successful Outcome. AB - BACKGROUND AND PURPOSE: Surgical excision of an affected sublingual gland for treatment of a ranula can carry a potential of a nerve damage or postoperative complications. However, there have been little studies about effective minimally invasive therapeutic method, yet. Our aim was to evaluate the efficacy and safety of ethanol ablation of ranulas and the clinicoradiologic factors that can predict outcome. MATERIALS AND METHODS: This retrospective study evaluated 23 patients with ranulas treated by percutaneous ethanol ablation. Treatment outcome was assessed in 20 patients followed for at least 6 months. The duration of symptoms before ethanol ablation, pretreatment volume, and parapharyngeal extension on sonography and/or CT were correlated with the outcome. The Mann-Whitney U test and Fisher exact test were used for comparison of the factors according to the outcome. RESULTS: The study evaluated 14 males and 9 females with a median age of 26 years (range, 3-41 years). Among 20 patients who were followed for at least 6 months (median, 20 months; range, 6-73 months), 9 patients (45%) demonstrated complete disappearance of the ranulas and 11 (55%) showed an incomplete response. When the patients were divided according to the duration of symptoms before ethanol ablation, the complete response rate was significantly higher in patients with <=12 months of symptoms (73%, 8/11) than that in others (11%, 1/9) (P = .010). Pretreatment volume and parapharyngeal extension were not significantly different between the 2 groups. CONCLUSIONS: Ethanol ablation is a safe and noninvasive treatment technique for ranulas with a significantly better outcome in patients with <=12 months of symptoms. Therefore, it could be considered an alternative nonsurgical approach for ranulas with recent onset of symptoms. PMID- 28663263 TI - How Common Is Signal-Intensity Increase in Optic Nerve Segments on 3D Double Inversion Recovery Sequences in Visually Asymptomatic Patients with Multiple Sclerosis? AB - BACKGROUND AND PURPOSE: In postmortem studies, subclinical optic nerve demyelination is very common in patients with MS but radiologic demonstration is difficult and mainly based on STIR T2WI. Our aim was to evaluate 3D double inversion recovery MR imaging for the detection of subclinical demyelinating lesions within optic nerve segments. MATERIALS AND METHODS: The signal intensities in 4 different optic nerve segments (ie, retrobulbar, canalicular, prechiasmatic, and chiasm) were evaluated on 3D double inversion recovery MR imaging in 95 patients with MS without visual symptoms within the past 3 years and in 50 patients without optic nerve pathology. We compared the signal intensities with those of the adjacent lateral rectus muscle. The evaluation was performed by a student group and an expert neuroradiologist. Statistical evaluation (the Cohen kappa test) was performed. RESULTS: On the 3D double inversion recovery sequence, optic nerve segments in the comparison group were all hypointense, and an isointense nerve sheath surrounded the retrobulbar nerve segment. At least 1 optic nerve segment was isointense or hyperintense in 68 patients (72%) in the group with MS on the basis of the results of the expert neuroradiologist. Student raters were able to correctly identify optic nerve hypersignal in 97%. CONCLUSIONS: A hypersignal in at least 1 optic nerve segment on the 3D double inversion recovery sequence compared with hyposignal in optic nerve segments in the comparison group was very common in visually asymptomatic patients with MS. The signal-intensity rating of optic nerve segments could also be performed by inexperienced student readers. PMID- 28663264 TI - New Ultrasound Measurements to Bridge the Gap between Prenatal and Neonatal Brain Growth Assessment. AB - BACKGROUND AND PURPOSE: Most ultrasound markers for monitoring brain growth can only be used in either the prenatal or the postnatal period. We investigated whether corpus callosum length and corpus callosum-fastigium length could be used as markers for both prenatal and postnatal brain growth. MATERIALS AND METHODS: A 3D ultrasound study embedded in the prospective Rotterdam Periconception Cohort was performed at 22, 26 and 32 weeks' gestational age in fetuses with fetal growth restriction, congenital heart defects, and controls. Postnatally, cranial ultrasound was performed at 42 weeks' postmenstrual age. First, reliability was evaluated. Second, associations between prenatal and postnatal corpus callosum and corpus callosum-fastigium length were investigated. Third, we created reference curves and compared corpus callosum and corpus callosum-fastigium length growth trajectories of controls with growth trajectories of fetuses with fetal growth retardation and congenital heart defects. RESULTS: We included 199 fetuses; 22 with fetal growth retardation, 20 with congenital heart defects, and 157 controls. Reliability of both measurements was excellent (intraclass correlation coefficient >= 0.97). Corpus callosum growth trajectories were significantly decreased in fetuses with fetal growth restriction and congenital heart defects (beta = -2.295; 95% CI, -3.320-1.270; P < .01; beta = -1.267; 95% CI, -0.972-0.562; P < .01, respectively) compared with growth trajectories of controls. Corpus callosum-fastigium growth trajectories were decreased in fetuses with fetal growth restriction (beta = -1.295; 95% CI, -2.595-0.003; P = .05). CONCLUSIONS: Corpus callosum and corpus callosum-fastigium length may serve as reliable markers for monitoring brain growth from the prenatal into the postnatal period. The clinical applicability of these markers was established by the significantly different corpus callosum and corpus callosum-fastigium growth trajectories in fetuses at risk for abnormal brain growth compared with those of controls. PMID- 28663265 TI - Maximizing the Tweet Engagement Rate in Academia: Analysis of the AJNR Twitter Feed. AB - The use of social media by medical professionals and organizations is increasing, with Twitter receiving the most attention. User engagement is an important goal of social media activity, and engagement metrics represent a viable gauge of value in social media. No thorough analysis of tweet characteristics that increase academic user engagement has yet been published. In this study, the authors analyzed the American Journal of Neuroradiology Twitter feed to determine the tweet characteristics that were associated with higher engagement rates. PMID- 28663266 TI - Relationship between Glioblastoma Heterogeneity and Survival Time: An MR Imaging Texture Analysis. AB - BACKGROUND AND PURPOSE: The heterogeneity of glioblastoma contributes to the poor and variant prognosis. The aim of this retrospective study was to assess the glioblastoma heterogeneity with MR imaging textures and to evaluate its impact on survival time. MATERIALS AND METHODS: A total of 133 patients with primary glioblastoma who underwent postcontrast T1-weighted imaging (acquired before treatment) and whose data were filed with the survival times were selected from the Cancer Genome Atlas. On the basis of overall survival, the patients were divided into 2 groups: long-term (>=12 months, n = 67) and short-term (<12 months, n = 66) survival. To measure heterogeneity, we extracted 3 types of textures, co-occurrence matrix, run-length matrix, and histogram, reflecting local, regional, and global spatial variations, respectively. Then the support vector machine classification was used to determine how different texture types perform in differentiating the 2 groups, both alone and in combination. Finally, a recursive feature-elimination method was used to find an optimal feature subset with the best differentiation performance. RESULTS: When used alone, the co occurrence matrix performed best, while all the features combined obtained the best survival stratification. According to feature selection and ranking, 43 top ranked features were selected as the optimal subset. Among them, the top 10 features included 7 run-length matrix and 3 co-occurrence matrix features, in which all 6 regional run-length matrix features emphasizing high gray-levels ranked in the top 7. CONCLUSIONS: The results suggest that local and regional heterogeneity may play an important role in the survival stratification of patients with glioblastoma. PMID- 28663268 TI - Increased Curvature of the Tentorium Cerebelli in Idiopathic Intracranial Hypertension. AB - BACKGROUND AND PURPOSE: Transverse sinus effacement is detectable on MRV examinations in almost all patients with idiopathic intracranial hypertension. This effacement of the transverse sinus is presumed to be mediated by elevation of intracranial pressure, resulting in compression and inward collapse of the dural margins of the sinus. We sought to establish whether supratentorial broad based downward deformity of the tentorium might explain transverse sinus effacement in idiopathic intracranial hypertension. MATERIALS AND METHODS: MRV examinations of 53 adult patients with idiopathic intracranial hypertension were reviewed retrospectively and compared with 58 contemporaneously acquired controls. The curvature of the tentorium with reference to a line connecting the transverse sinus laterally with the confluence of the tentorial leaves medially was calculated as a segment of a circle. The height and area of the segment and the angle subtended by the midpoint of the tentorium from the falx were calculated. RESULTS: The height and area of the segment described by the chord connecting the transverse sinus with the apex of the tentorial confluence and subtended midtentorial angle were greater in the idiopathic intracranial hypertension group; this finding supports the hypothesis that increased tentorial bowing is present in idiopathic intracranial hypertension. CONCLUSIONS: Increased bowing of the tentorium in patients with idiopathic intracranial hypertension compared with controls is a new observation, lending itself to new hypotheses on the nature and localization of elevated intracranial pressure in idiopathic intracranial hypertension. Bowing of the tentorium may play a part in distorting the contour of the transverse sinuses, resulting, at least in part, in the effacement of the transverse sinuses in idiopathic intracranial hypertension. PMID- 28663267 TI - Comparison of Gadoterate Meglumine and Gadobutrol in the MRI Diagnosis of Primary Brain Tumors: A Double-Blind Randomized Controlled Intraindividual Crossover Study (the REMIND Study). AB - BACKGROUND AND PURPOSE: Effective management of patients with brain tumors depends on accurate detection and characterization of lesions. This study aimed to demonstrate the noninferiority of gadoterate meglumine versus gadobutrol for overall visualization and characterization of primary brain tumors. MATERIALS AND METHODS: This multicenter, double-blind, randomized, controlled intraindividual, crossover, noninferiority study included 279 patients. Both contrast agents (dose = 0.1 mmol/kg of body weight) were assessed with 2 identical MRIs at a time interval of 2-14 days. The primary end point was overall lesion visualization and characterization, scored independently by 3 off-site readers on a 4-point scale, ranging from "poor" to "excellent." Secondary end points were qualitative assessments (lesion border delineation, internal morphology, degree of contrast enhancement, diagnostic confidence), quantitative measurements (signal intensity), and safety (adverse events). All qualitative assessments were also performed on-site. RESULTS: For all 3 readers, images of most patients (>90%) were scored good or excellent for overall lesion visualization and characterization with either contrast agent; and the noninferiority of gadoterate meglumine versus gadobutrol was statistically demonstrated. No significant differences were observed between the 2 contrast agents regarding qualitative end points despite quantitative mean lesion percentage enhancement being higher with gadobutrol (P < .001). Diagnostic confidence was high/excellent for all readers in >81% of the patients with both contrast agents. Similar percentages of patients with adverse events related to the contrast agents were observed with gadoterate meglumine (7.8%) and gadobutrol (7.3%), mainly injection site pain. CONCLUSIONS: The noninferiority of gadoterate meglumine versus gadobutrol for overall visualization and characterization of primary brain tumors was demonstrated. PMID- 28663269 TI - Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2. AB - Cyclin-dependent kinase 10 (CDK10), a CDC2-related kinase, is highly expressed in colorectal cancer. Its role in the pathogenesis of colorectal cancer is unknown. This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections of lentivirus-mediated CDK10 siRNA in a patient-derived xenograft mouse model demonstrated its efficacy in suppressing tumor growth. Furthermore, using a tissue microarray of human colorectal cancer tissues, the potential for CDK10 to be a prognostic biomarker in colorectal cancer was explored. In tumors of individuals with colorectal cancer, high expression of CDK10 correlates with earlier relapse and shorter overall survival. The findings of this study indicate that CDK10 plays a role in the pathogenesis in colorectal cancer and may be a potential therapeutic target for treatment. Mol Cancer Ther; 16(10); 2292-303. (c)2017 AACR. PMID- 28663270 TI - Febrile headache and leg weakness as the initial symptoms of tickborne encephalitis. PMID- 28663271 TI - Correction for Fogal et al., "Mitochondrial p32 Protein Is a Critical Regulator of Tumor Metabolism via Maintenance of Oxidative Phosphorylation". PMID- 28663272 TI - Correction for Ezzeddine et al., "Evidence Providing New Insights into TOB Promoted Deadenylation and Supporting a Link between TOB's Deadenylation Enhancing and Antiproliferative Activities". PMID- 28663273 TI - Correction for Cassinat et al., "New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor alpha Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation". PMID- 28663274 TI - Correction for Vigneron et al., "Characterization of the Mechanisms Controlling Greatwall Activity". PMID- 28663277 TI - Correction for Sen et al., "Fine-Tuning of FACT by the Ubiquitin Proteasome System in Regulation of Transcriptional Elongation". PMID- 28663275 TI - Retraction for Zhang et al., "Role of MicroRNA 30a Targeting Insulin Receptor Substrate 2 in Colorectal Tumorigenesis". PMID- 28663278 TI - An unusual case of aphasia. PMID- 28663279 TI - Comparative Exploration of the Structure-Activity Space of Cloned alpha-Like Octopamine Receptors from a Marine and a Terrestrial Arthropod. AB - The alpha-like octopamine receptors (OctR) are believed to be the evolutionary precursor to the vertebrate alpha2-adrenergic receptors (alpha2-ARs) based upon sequence similarity and the ability to interact with norepinephrine and a number of compounds that bind with high affinity to alpha2-ARs. Barnacles and fruit flies are two prominent model marine and terrestrial representatives of the Arthropoda phylum, and although alpha-like OctRs have been cloned from Balanus improvisus (BiOctR) and Drosophila melanogaster (DmOctR), little is known about the structure-activity space for these important species. A diverse panel of 22 probes spanning different structural classes were employed to interrogate the structure-activity of the BiOctR and DmOctR. While BiOctR and DmOctR exhibited similar functional profiles for mammalian biogenic amine G protein-coupled receptor agonists and antagonists, some ligands had dramatically different mechanisms of action. For instance, significant differences in the efficacy for some agonists were observed, including that vertebrate biogenic amines structurally related to octopamine acted as superagonists at the DmOctR but partial agonists at the BiOctR, and the two species diverged in their sensitivities to the alpha2-AR antagonist [3H]rauwolscine. Furthermore, sodium enhanced [3H]rauwolscine's interactions with the BiOctR, but not at a vertebrate alpha2-AR. Molecular mechanistic studies indicate that rauwolscine interacts with the BiOctR, DmOctR, and alpha2C-adrenergic receptor at an allosteric site. In addition, compounds that acted as agonists at a cloned alpha-like BiOctR also induced a hyperactivity response in Balanus cyprids mediated by the alpha-like OctR, suggesting that the receptor may serve as a higher throughput proxy for discovering compounds with potential cyprid deterrent properties. PMID- 28663281 TI - BMA annual meeting: Pregabalin must be made a controlled drug, BMA says. PMID- 28663280 TI - Megakaryocytic Smad4 Regulates Platelet Function through Syk and ROCK2 Expression. AB - Smad4, a key transcription factor in the transforming growth factor-beta signaling pathway, is involved in a variety of cell physiologic and pathologic processes. Here, we characterized megakaryocyte/platelet-specific Smad4 deficiency in mice to elucidate its effect on platelet function. We found that megakaryocyte/platelet-specific loss of Smad4 caused mild thrombocytopenia and significantly extended first occlusion time and tail bleeding time in mice. Smad4 deficient platelets showed reduced agonist-induced platelet aggregation. Further studies showed that a severe defect was seen in integrin alphaIIbbeta3-mediated bidirectional (inside-out and outside-in) signaling in Smad4-deficient platelets, as evidenced by reduced fibrinogen binding and alpha-granule secretion, suppressed platelet spreading and clot retraction. Microarray analysis showed that the expression levels of multiple genes were altered in Smad4-deficient platelets. Among these genes, spleen tyrosine kinase (Syk) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) were downregulated several times as confirmed by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Further research showed that Smad4 directly regulates ROCK2 transcription but indirectly regulates Syk. Megakaryocyte/platelet-specific Smad4 deficiency caused decreased expression levels of Syk and ROCK2 in platelets. These results suggest potential links among Smad4 deficiency, attenuated Syk, and ROCK2 expression and defective platelet activation. PMID- 28663282 TI - Are postnatal ampicillin levels actually related to the duration of intrapartum antibiotic prophylaxis prior to delivery? A pharmacokinetic study in 120 neonates. AB - OBJECTIVE: To assess ampicillin levels according to the duration of intrapartum antibiotic prophylaxis (IAP). DESIGN: Prospective cohort single-centre study. SETTING: Tertiary care centre (Modena, Italy). PATIENTS: 120 neonates>=35 weeks' gestation exposed to IAP. INTERVENTIONS: Neonates were divided into four groups, according to the duration of IAP prior to delivery: group 1 (n=30; <1 hour), group 2 (n=30; >=1 and <2 hours), group 3 (n=30; >=2 and <4 hours) and group 4 (n=30; >=2 doses, >=4 hours). MAIN OUTCOME MEASURES: Blood samples were collected at delivery (from the umbilical cord) and at age 4 hours (from a peripheral vessel). RESULTS: Median duration of IAP was 121 min (range 7-2045 min). Median ampicillin levels in umbilical cord blood were 10.4 ug/mL (IQR 6.4-14.9) and in peripheral blood were 4.7 ug/mL (IQR 2.8-6.4ug/mL). Umbilical cord blood levels reached a peak approximately 30 min after IAP and then declined significantly (p<0.001). Peripheral blood levels did not differ among study groups. Neonates exposed to a full loading dose (n=115) had peripheral blood levels 2.5-70 times higher than the minimal inhibitory concentration for group B streptococcus. There was no relationship between neonatal ampicillin concentrations and the duration of IAP prior to delivery (beta=-0.0003, 95% CI -0.02 to 0.001, p=0.680). CONCLUSIONS: Ampicillin levels reach a peak in the umbilical cord blood within 30 min of intrapartum administration. After a full loading dose, bactericidal levels persist for at least 4 hours after birth and seem independent of the duration of IAP prior to delivery. PMID- 28663284 TI - A case of generalised papules. PMID- 28663283 TI - T-piece versus self-inflating bag ventilation in preterm neonates at birth. AB - OBJECTIVE: To verify whether the use of the T-piece resuscitator compared with the self-inflating bag in preterm infants ventilated at birth modifies survival to hospital discharge without major morbidities. DESIGN: Pragmatic prospective cohort study. SETTING: 20 Brazilian university hospitals of Brazilian Network on Neonatal Research. Patients were 1962 inborn infants in 2014-2015 ventilated at birth with 23-33' weeks gestation and birth weight 400-1499 g without malformations. Patients transferred until the 27th day after birth were excluded. INTERVENTIONS: Positive pressure ventilation at birth with T-piece resuscitator or self-inflating bag without positive end expiratory pressure valve. Intervention with ventilation followed the Brazilian Society of Pediatrics guidelines. The choice of the equipment was at the neonatologist's discretion in each delivery. The main outcome measures were survival to hospital discharge without bronchopulmonary dysplasia, severe peri-intraventricular haemorrhage and periventricular leucomalacia. Logistic regression adjusted for confounding variables was applied for main outcome. RESULTS: 1456 (74%) were only ventilated with T-piece resuscitator and 506 (26%) with the self-inflating bag. The characteristics of those ventilated with T-Piece resuscitator versus self inflating bag were birth weight 969 +/- 277 vs 941 +/- 279 g, gestational age 28.2+/-2.5 vs 27.8+/-2.7 weeks and survival to hospital discharge without major morbidities 47% vs 35%. Logistic regression adjusted for maternal characteristics, obstetric and neonatal morbidities showed that the T-piece resuscitator increased the chance of survival to hospital discharge without major morbidities (OR=1.38; 95% CI 1.06 to 1.80; Hosmer-Lemeshow goodness of fit: 0.695). CONCLUSION: This study is the first that highlights the effectiveness of T-piece resuscitator ventilation in improving relevant outcomes in preterm neonates. PMID- 28663285 TI - Inhibitory Effects of Selected Antituberculosis Drugs on Common Human Hepatic Cytochrome P450 and UDP-glucuronosyltransferase Enzymes. AB - The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs. Pyrazinamide, ethambutol, rifabutin and bedaquiline were also studied for their inhibitory effects on eight of the most common human CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Rifabutin inhibited multiple CYPs to varying degrees in vitro, but with all IC50 values exceeding 25 uM. Rifabutin and rifampicin also inhibited several human UGTs including UGT1A4. The Ki value for rifabutin on human hepatic UGT1A4 was 2 MUM. Finally, the six anti-TB drugs produced minimal inhibition of acetaminophen glucuronidation in vitro. Overall, the findings do not raise major concerns regarding metabolic inhibition of human hepatic CYPs and UGTs by the tested anti-TB drugs. PMID- 28663288 TI - What your PI forgot to tell you: why you actually might want a job running a research lab. AB - A PhD in biomedical science and the critical thinking skills that it provides can open the door to many different careers. The current popular scientific press and blogosphere too often portray the job of a research-intensive faculty member and principal investigator (PI) as both unattainable and undesirable. We want to make sure our trainees include our own career path among their options, as for each of us it has been a fantastic, family-friendly, and highly impactful career. PMID- 28663289 TI - Genome Sequence of a Novel HIV-1 Circulating Recombinant Form (CRF77_cpx) Identified among Blood Donors in Malaysia. AB - We report here the first HIV-1 circulating recombinant form (CRF) complex identified among the blood donors in Malaysia. The CRF77_cpx mosaic genome consists of parental subtypes B', C, and CRF01_AE and is structurally related to CRF07_BC. The identification of CRF77_cpx underlines the genetic complexity and mobility of HIV-1 among the blood donors. PMID- 28663287 TI - CARMIL family proteins as multidomain regulators of actin-based motility. AB - CARMILs are large multidomain proteins that regulate the actin-binding activity of capping protein (CP), a major capper of actin filament barbed ends in cells. CARMILs bind directly to CP and induce a conformational change that allosterically decreases but does not abolish its actin-capping activity. The CP binding domain of CARMIL consists of the CP-interaction (CPI) and CARMIL-specific interaction (CSI) motifs, which are arranged in tandem. Many cellular functions of CARMILs require the interaction with CP; however, a more surprising result is that the cellular function of CP in cells appears to require binding to a CARMIL or another protein with a CPI motif, suggesting that CPI-motif proteins target CP and modulate its actin-capping activity. Vertebrates have three highly conserved genes and expressed isoforms of CARMIL with distinct and overlapping localizations and functions in cells. Various domains of these CARMIL isoforms interact with plasma membranes, vimentin intermediate filaments, SH3-containing class I myosins, the dual-GEF Trio, and other adaptors and signaling molecules. These biochemical properties suggest that CARMILs play a variety of membrane associated functions related to actin assembly and signaling. CARMIL mutations and variants have been implicated in several human diseases. We focus on roles for CARMILs in signaling in addition to their function as regulators of CP and actin. PMID- 28663290 TI - Draft Genome Sequence of Pseudomonas graminis PDD-13b-3, a Model Strain Isolated from Cloud Water. AB - The whole genome of Pseudomonas graminis PDD-13b-3, a strain of bacteria isolated from cloud water, was sequenced. This showed that this microorganism is equipped with genes that could potentially be involved in its survival in the atmosphere and clouds: those for oxidative stress and carbon starvation responses, DNA repair, and iron uptake. PMID- 28663291 TI - Draft Genome Sequence of Anoxybacillusayderensis Strain MT-Cab (Firmicutes). AB - The draft genome of the Gram-positive spore-forming Anoxybacillus ayderensis strain MT-Cab (Firmicutes), isolated from an enrichment culture of Chloracidobacterium thermophilum, was sequenced and comprises 2,577,015 bp in 92 contigs. The draft genome is predicted to consist of 2,699 protein-coding genes, 73 tRNA-coding genes, and an estimated 8 rRNA operons. PMID- 28663292 TI - Identification of a Second Raccoon-Associated Polyomavirus. AB - Raccoon polyomavirus 1 (RacPyV1) is the suspected cause of an outbreak of fatal brain tumors among raccoons (Procyon lotor) in the western United States. Spleen samples from Georgia raccoons were screened for polyomaviruses. Although RacPyV1 was not detected, a previously unknown polyomavirus, which we designate RacPyV2, was identified and sequenced. PMID- 28663293 TI - Draft Genome Sequence of Pseudomonas koreensis CI12, a Bacillus cereus "Hitchhiker" from the Soybean Rhizosphere. AB - Pseudomonas koreensis CI12 was coisolated with Bacillus cereus from a root of a soybean plant grown in a field in Arlington, WI. Here, we report the draft genome sequence of P. koreensis CI12 obtained by Illumina sequencing. PMID- 28663294 TI - Draft Genome Sequence of Kingella negevensis SW7208426, the First European Strain of K. negevensis Isolated from a Healthy Child in Switzerland. AB - We report here the draft genome of Kingella negevensis strain SW7208426, isolated from the oropharynx of a healthy 6-year-old boy in Geneva, Switzerland. To our knowledge, this is the first genome report of the newly described K. negevensis species from Europe. PMID- 28663295 TI - Draft Genome Sequence of a Multidrug-Resistant Serratia marcescens Strain, Isolated from a Patient with Peritoneal Cancer in South Africa. AB - We report here the draft genome sequence of Serratia marcescens ML2637, isolated from a South African pediatric patient in the intensive care unit with peritoneal cancer. The genome comprised 5,718,350 bp, with a 59.1% G+C content. There were 5,594 predicted genes, including 5,301 protein-coding genes, 199 pseudogenes, and 94 RNA genes. PMID- 28663296 TI - Draft Genome Sequences of Alloscardovia macacae UMA81211 and UMA81212, Isolated from the Feces of a Rhesus Macaque (Macaca mulatta). AB - Here, we provide the draft genome sequences of two isolates identified as Alloscardovia macacae These bacteria originated from the feces of a rhesus macaque. The draft genomes of both Alloscardovia macacae isolates are ~1.8 Mb in length, with a G+C content of 56.1%. PMID- 28663297 TI - Draft Genome Sequences of Two Janthinobacteriumlividum Strains, Isolated from Pristine Groundwater Collected from the Oak Ridge Field Research Center. AB - We present here the draft genome sequences of two Janthinobacterium lividum strains, GW456P and GW458P, isolated from groundwater samples collected from a background site at the Oak Ridge Field Research Center. Production of a purple pigment by these two strains was observed when grown on diluted (1/10) LB agar plates. PMID- 28663298 TI - Draft Genome Sequence of Lactobacillus curvatus FLEC03, a Meat-Borne Isolate from Beef Carpaccio Packaged in a Modified Atmosphere. AB - In this study, we present the draft genome sequence for Lactobacillus curvatus FLEC03. This strain was isolated from beef carpaccio packaged in a modified atmosphere. The draft genome will contribute to understanding the role of L. curvatus strains in food products (fermentation, biopreservation, or spoilage) through comparative genomics with other strains. PMID- 28663299 TI - Multiple Genome Sequences of Exopolysaccharide-Producing, Brewery-Associated Lactobacillus brevis Strains. AB - Lactobacillus brevis represents one of the most relevant beer-spoiling bacteria. Besides strains causing turbidity and off flavors upon growth and metabolite formation, this species also comprises strains that produce exopolysaccharides (EPSs), which increase the viscosity of beer. Here, we report the complete genome sequences of three EPS-producing, brewery-associated L. brevis strains. PMID- 28663300 TI - Complete Genome of Chronic Bee Paralysis Virus Strain SLO/M92/2010, Detected from Apis mellifera carnica. AB - Chronic bee paralysis virus (CBPV) causes an infectious and contagious disease of adult honeybees. Here, we report the complete genome sequence of CBPV strain SLO/M92/2010. This is the first published complete genome of CBPV in Apis mellifera carnica, which provides important additional knowledge about the divergence of the CBPV genome. PMID- 28663301 TI - Draft Genome Sequence of Streptococcus pyogenes Strain M3KCL. AB - We present here the draft genome sequence of Streptococcus pyogenes strain M3KCL. The assembly contains 1,864,059 bp in 60 contigs. This strain is an M3 strain close to MGAS315 but produces SpeB. It was isolated from the blood of a human patient with an invasive infection in 2009. PMID- 28663302 TI - Complete Genome Sequences of Two Salmonella enterica subsp. enterica Serovar Enteritidis Strains Isolated from Egg Products in the United States. AB - Egg-associated salmonellosis is an important public health problem in many countries. Here, we report the genome sequences, including plasmids, of two strains of Salmonella enterica subsp. enterica serovar Enteritidis isolated from egg products in 2012 and 2013 in the United States. This will provide more information and insight into the research about egg-associated salmonellosis. PMID- 28663303 TI - Draft Genome Sequence of Phaeobacter leonis Type Strain 306, an Alphaproteobacterium Isolated from Mediterranean Sea Sediments. AB - Phaeobacter leonis strain 306T is an alphaproteobacterium isolated from Mediterranean Sea sediments. It belongs to the genus Phaeobacter, which was recently proposed and is still poorly characterized. In an effort to better understand the fundamental aspects of the microbiology of this genus, we present here the 4.82-Mb draft genome sequence of Phaeobacter leonis strain 306T. PMID- 28663304 TI - Determinants of postprandial plasma bile acid kinetics in human volunteers. AB - Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n = 72, 62 +/- 8 yr, mean +/- SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmenopausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota.NEW & NOTEWORTHY Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma bile acid (BA) profiles. Despite high interindividual variability, three main patterns in postprandial BA response were identified using multivariate analysis. A variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases in response to both the oral glucose tolerance test and the mixed-meal tolerance test. PMID- 28663305 TI - Application of linear mixed-effects model with LASSO to identify metal components associated with cardiac autonomic responses among welders: a repeated measures study. AB - BACKGROUND: Environmental and occupational exposure to metals is ubiquitous worldwide, and understanding the hazardous metal components in this complex mixture is essential for environmental and occupational regulations. OBJECTIVE: To identify hazardous components from metal mixtures that are associated with alterations in cardiac autonomic responses. METHODS: Urinary concentrations of 16 types of metals were examined and 'acceleration capacity' (AC) and 'deceleration capacity' (DC), indicators of cardiac autonomic effects, were quantified from ECG recordings among 54 welders. We fitted linear mixed-effects models with least absolute shrinkage and selection operator (LASSO) to identify metal components that are associated with AC and DC. The Bayesian Information Criterion was used as the criterion for model selection procedures. RESULTS: Mercury and chromium were selected for DC analysis, whereas mercury, chromium and manganese were selected for AC analysis through the LASSO approach. When we fitted the linear mixed-effects models with 'selected' metal components only, the effect of mercury remained significant. Every 1 ug/L increase in urinary mercury was associated with -0.58 ms (-1.03, -0.13) changes in DC and 0.67 ms (0.25, 1.10) changes in AC. CONCLUSION: Our study suggests that exposure to several metals is associated with impaired cardiac autonomic functions. Our findings should be replicated in future studies with larger sample sizes. PMID- 28663307 TI - Response to: 'Umbilical-cord messenchymal stem cells for the treatment of automimmune diseases: beware of cell to cell contact' by Alunno et al. PMID- 28663306 TI - The yield of a positive MRI of the spine as imaging criterion in the ASAS classification criteria for axial spondyloarthritis: results from the SPACE and DESIR cohorts. AB - OBJECTIVES: To assess the prevalence of spinal inflammation on MRI in patients with chronic back pain (CBP) of maximally 3 years duration and to evaluate the yield of adding a positive MRI-spine as imaging criterion to the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA). METHODS: Baseline imaging of the sacroiliac joints (X SI), MRI of the sacroiliac joints (MRI-SI) and MRI-spine were scored by >=2 experienced central readers per modality in the SPondyloArthritis Caught Early (SPACE) and DEvenir des Spondylarthropathies Indifferenciees Recentes (DESIR) cohorts. Inflammation suggestive of axSpA was assessed in the entire spine. A positive MRI-spine was defined by the presence of >=5 inflammatory lesions. Alternative less strict definitions were also tested. RESULTS: In this study, 541 and 650 patients with CBP from the SPACE and DESIR cohorts were included. Sacroiliitis on X-SI and MRI-SI was found in 40/541 (7%) and 76/541 (14%) patients in SPACE, and in DESIR in 134/650 (21%) and 231/650 (36%) patients, respectively. In SPACE and DESIR, a positive MRI-spine was seen in 4/541 (1%) and 48/650 (7%) patients. Of the patients without sacroiliitis on imaging, 3/447 (1%) (SPACE) and 8/382 (2%) (DESIR) patients had a positive MRI-spine. Adding positive MRI-spine as imaging criterion led to new classification in only one patient in each cohort, as the other patients already fulfilled the clinical arm. Other definitions of a positive MRI-spine yielded similar results. CONCLUSION: In two cohorts of patients with CBP with a maximum symptom duration of 3 years, a positive MRI-spine was rare in patients without sacroiliitis on MRI-SI and X-SI. Addition of MRI-spine as imaging criterion to the ASAS axSpA criteria had a low yield of newly classified patients and is therefore not recommended. PMID- 28663308 TI - Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib: a real-world study. PMID- 28663309 TI - Juvenile onset arthritis and pregnancy outcome: a population-based cohort study. AB - OBJECTIVES: Reports on pregnancy outcomes among women with juvenile onset arthritis (JIA) have been few and small. The aim of this study was to assess pregnancy outcomes in a large and contemporary cohort of women diagnosed with JIA. METHODS: In a nationwide Swedish population-based cohort study between 1992 and 2011, we identified 1807 births among women with JIA and 1 949 202 control births. Since JIA is a heterogenic condition, births to women with JIA was divided into JIA paediatric only (n=1169) and JIA persisting into adulthood (n=638). ORs and 95% CIs were estimated with generalised estimating equations. RESULTS: Women with JIA were at increased risk of preterm birth, especially medically indicated, in both subgroups: adjusted OR (aOR) 1.74 (1.35-2.67) for JIA paediatric and aOR 4.12 (2.76-6.15) for JIA persisting into adulthood. JIA persisting into adulthood was associated with very preterm birth (aOR 3.14, 1.58 6.24), spontaneous preterm birth (aOR 1.63, 1.11-2.39), small for gestational age birth (aOR 1.84, 1.19-2.85), early-onset pre-eclampsia (aOR 6.28, 2.68-13.81) and late-onset pre-eclampsia (aOR 1.96, 1.31-2.91). Women with JIA paediatric only were at increased risk of delivery by caesarean section (aOR 1.42, 1.66-1.73) and induction of labour (aOR 1.45, 1.18-1.77). CONCLUSIONS: We found increased risks of both maternal and infant complications among women with JIA confined to childhood and in women with JIA persistent into adulthood as compared with population controls. Pregnancies in women with JIA should thus be subject to increased surveillance during pregnancy and delivery. PMID- 28663310 TI - Chondroitin sulfate for knee osteoarthritis. PMID- 28663311 TI - The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468. AB - The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 and OX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met. PMID- 28663312 TI - Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers. AB - Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; P = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; P < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; P < 0.001) and glucuronidation partial clearance (by 23-48%; P < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein adduct concentrations than *1/*2 (by 42%; P = 0.003) and *1/*1 (by 41%; P = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; P = 0.041) and *1C/*1C (by 44%; P = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans. PMID- 28663313 TI - Colder temperature is associated with increased COPD morbidity. PMID- 28663314 TI - The asbestos fibre burden in human lungs: new insights into the chrysotile debate. AB - The traceability of asbestos fibres in human lungs is a matter of discussion especially for chrysotile. This issue is of high significance for differential diagnosis, risk assessment and occupational compensation. At present no intra individual longitudinal information is available. This study addresses the question whether the asbestos fibre burden in human lungs decreases with time after exposure cessation.The database of the German Mesothelioma Register was screened for patients with asbestos body counts of at least 500 fibres per gram of wet lung, which had been analysed twice from different tissue excisions at minimum intervals of 4 years.Twelve datasets with individual longitudinal information were discovered with a median interval of about 8 years (range 4-21 years). Both examinations were performed after exposure cessation (median: surgery, 9.5 years; autopsy, 22 years). Pulmonary asbestos fibre burden was stable between both examinations (median 1623/4269 asbestos bodies per gram wet lung). Electron microscopy demonstrated a preponderance of chrysotile (median 80%).This study is the first to present longitudinal intra-individual data about the asbestos fibre burden in living human lungs. The high biopersistence of amphiboles, but also of chrysotile, offers mechanistic explanations for fibre toxicity, especially the long latency period of asbestos-related diseases. PMID- 28663315 TI - Upfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension. AB - In pulmonary arterial hypertension (PAH), upfront combination therapy is associated with better clinical outcomes and a greater reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) than monotherapy. NT-proBNP levels reflect right ventricular (RV) wall stress, which increases when the right ventricle dilates. This study explored the impact of upfront combination therapy on RV volumes compared with monotherapy in PAH patients.This retrospective study involved 80 incident PAH patients (New York Heart Association class II and III) who were treated with upfront combination therapy (n=35) (i.e. endothelin receptor antagonists (ERAs) plus phosphodiesterase-5-inhibitors (PDE5Is)) or monotherapy (n=45) (i.e. either ERAs or PDE5Is). All patients underwent right sided heart catheterisation and cardiac magnetic resonance imaging at baseline and after 1-year follow-up.Combination therapy resulted in more significant reductions in pulmonary vascular resistance and pulmonary pressures than monotherapy. NT-proBNP was decreased by ~77% in the combination therapy group compared with a ~51% reduction after monotherapy (p<0.001). RV volumes and calculated RV wall stress improved after combination therapy (both p<0.001) but remained unchanged after monotherapy (both p=NS). RV ejection fraction improved more in the combination therapy group than in the monotherapy group (p<0.001).In PAH patients, upfront combination therapy was associated with improved RV volumes. PMID- 28663316 TI - Mortality and acute exacerbation of COPD: a pilot study on the influence of myocardial injury. PMID- 28663317 TI - A sputum gene expression signature predicts oral corticosteroid response in asthma. AB - Biomarkers that predict responses to oral corticosteroids (OCS) facilitate patient selection for asthma treatment. We hypothesised that asthma patients would respond differently to OCS therapy, with biomarkers and inflammometry predicting response.Adults with stable asthma underwent a randomised controlled cross-over trial of 50 mg prednisolone daily for 10 days (n=55). A six-gene expression biomarker signature (CLC, CPA3, DNASE1L3, IL1B, ALPL and CXCR2) in induced sputum, and eosinophils in blood and sputum were assessed and predictors of response were investigated (changes in forced expiratory volume in 1 s (DeltaFEV1), six-item Asthma Control Questionnaire score (DeltaACQ6) or exhaled nitric oxide fraction (DeltaFeNO)).At baseline, responders to OCS (n=25) had upregulated mast cell CPA3 gene expression, poorer lung function, and higher sputum and blood eosinophils. Following treatment, CLC and CPA3 gene expression was reduced, whereas DNASE1L3, IL1B, ALPL and CXCR2 expression remained unchanged. Receiver operating characteristic (ROC) analysis showed the six-gene expression biomarker signature as a better predictor of clinically significant responses to OCS than blood and sputum eosinophils.The six-gene expression signature including eosinophil and Th2 related mast cell biomarkers showed greater precision in predicting OCS response in stable asthma. Thus, a novel sputum gene expression signature highlights an additional role of mast cells in asthma, and could be a useful measurement to guide OCS therapy in asthma. PMID- 28663318 TI - Management of incidental pulmonary embolism. AB - Incidental pulmonary embolism (PE) is a frequent finding on routine computed tomography (CT) scans of the chest, occurring in 1.1% of coronary CT scans and 3.6% of oncological CT scans. Despite this high frequency, optimal management of incidental PE has not been addressed in clinical trials and remains the subject of debate. Although these CT scans have not been performed with a dedicated PE protocol and have suboptimal contrast enhancement, diagnosis of incidental PE has been shown to be accurate up to the segmental and subsegmental arteries. The embolic load in incidental PE is lower than that in symptomatic PE. Even so, observational studies suggest that the natural course of incidental PE is similar to that of symptomatic PE with regard to the risk of recurrent venous thrombotic disease and mortality. Interestingly, the increased use of more advanced CT technology has coincided with an increase in the rate of incidental subsegmental PE, as is the case for symptomatic subsegmental PE. Although clinical trials are lacking, and observational data are limited to cancer-associated incidental PE, the consensus is that the management of incidental PE is identical to that of symptomatic PE, including the choice of optimal drug class, outpatient treatment and total duration of treatment. PMID- 28663319 TI - Measuring the effects of treatment in patients with PAH: should we image the right ventricle? PMID- 28663320 TI - Quantifying asbestos in lung tissue: what debate? PMID- 28663321 TI - Time to move from prognostication to diagnosis and treatment of heart disease in acute exacerbation of COPD. PMID- 28663322 TI - Asthma and corticosteroids: time for a more precise approach to treatment. PMID- 28663323 TI - Workplace violence against physicians in Turkey's emergency departments: a cross sectional survey. AB - OBJECTIVE: We aimed to determine the prevalence of violence directed at emergency department (ED) physicians in Turkey and confirm the factors influencing such violence. DESIGN: Cross-sectional survey study. SETTING: Country of Turkey. PARTICIPANTS: Physicians currently practising in EDs in Turkey. MAIN OUTCOME MEASURES: The prevalence of violence directed at physicians and factors that may influence it, such as physicians' personal characteristics, ED characteristics and physicians' opinions regarding the causes of and suggested methods of preventing violence. RESULTS: A total of 713 physicians participated. Of these, 78.1% reported being subjected to violence in the past year and 65.9% reported more than one such incident. Being subjected to violence was related to age (p=0.008), working in an ED with a high patient admission rate (p=0.018), current position (p<0.001), working outside regular work hours (p<0.001), working in a state hospital (p<0.001) and level of experience (p<0.001). Gender, type of patient typically seen, region and patient waiting period did not influence subjection to violence. The present safety precautions against violence do not appear to influence the prevalence of violence. CONCLUSIONS: Our results indicated that ED physicians' experience of violence is related to personal characteristics such as age and level of expertise, and hospital and ED characteristics such as high patient admission rates. Presently, no measures taken to reduce this violence have been proven effective. PMID- 28663324 TI - New indices from microneurography to investigate the arterial baroreflex. AB - Baroreflex-mediated changes in heart rate and vascular resistance in response to variations in blood pressure are critical to maintain homeostasis. We aimed to develop time domain analysis methods to complement existing cross-spectral techniques in the investigation of the vascular resistance baroreflex response to orthostatic stress. A secondary goal was to apply these methods to distinguish between levels of orthostatic tolerance using baseline data. Eleven healthy, normotensive males participated in a graded lower body negative pressure protocol. Within individual neurogenic baroreflex cycles, the amount of muscle sympathetic nerve activity (MSNA), the diastolic pressure stimulus and response amplitudes, diastolic pressure to MSNA burst stimulus and response times, as well as the stimulus and response slopes between diastolic pressure and MSNA were computed. Coherence, gain, and frequency of highest coherence between systolic/diastolic arterial pressure (SAP/DAP) and RR-interval time series were also computed. The number of MSNA bursts per low-frequency cycle increased from 2.55 +/- 0.68 at baseline to 5.44 +/- 1.56 at -40 mmHg of LBNP Stimulus time decreased (3.21 +/- 1.48-1.46 +/- 0.43 sec), as did response time (3.47 +/- 0.86 2.37 +/- 0.27 sec). At baseline, DAP-RR coherence, DAP-RR gain, and the time delay between decreases in DAP and MSNA bursts were higher in participants who experienced symptoms of presyncope. Results clarified the role of different branches of the baroreflex loop, and suggested functional adaptation of neuronal pathways to orthostatic stress. PMID- 28663325 TI - Relationship between cerebral arterial inflow and venous outflow during dynamic supine exercise. AB - The regulation of cerebral venous outflow during exercise has not been studied systematically. To identify relations between cerebral arterial inflow and venous outflow, we assessed the blood flow (BF) of the cerebral arteries (internal carotid artery: ICA and vertebral artery: VA) and veins (internal jugular vein: IJV and vertebral vein: VV) during dynamic exercise using ultrasonography. Nine subjects performed a cycling exercise in supine position at a light and moderate workload. Similar to the ICA BF, the IJV BF increased from baseline during light exercise (P < 0.05). However, the IJV BF decreased below baseline levels during moderate exercise, whereas the ICA BF returned near resting levels. In contrast, BF of the VA and VV increased with the workload (P < 0.05). The change in the ICA or VA BF from baseline to exercise was significantly correlated with the change in the IJV (r = 0.73, P = 0.001) or VV BF (r = 0.52, P = 0.028), respectively. These findings suggest that dynamic supine exercise modifies the cerebral venous outflow, and there is coupling between regulations of arterial inflow and venous outflow in both anterior and posterior cerebral circulation. However, it remains unclear whether changes in cerebral venous outflow influence on the regulation of cerebral arterial inflow during exercise. PMID- 28663326 TI - Clinical associations of the positive anti Ro52 without Ro60 autoantibodies: undifferentiated connective tissue diseases. AB - AIMS: Autoantibodies targeting Ro52 and Ro60 antigens are historically reported as anti SSA/Ro. In general anti SSA/Ro results are either anti Ro52+Ro60+ or anti Ro52-Ro60+ antibodies. Anti Ro52 without anti Ro60 (Ro52+ Ro60-) antibodies are often not reported routinely. This study intends to review the potential significance of these autoantibodies in the management of connective tissue diseases. METHOD: A retrospective survey of Ro52+Ro60- was carried out as part of the service evaluation of extractable nuclear antigen antibodies (ENA) reporting from the immunology laboratory, the NHS Greater Glasgow and Clyde (GGC), UK. The clinical documents and laboratory results of 97 patients with Ro52+Ro60- and 100 patients with Ro52+Ro60+ were reviewed. RESULTS: Seventy-one patients (73%) with anti Ro52+Ro60- antibodies have been diagnosed with autoimmune conditions including undifferentiated connective tissue diseases (n=14, 14%), systemic lupus erythematosus (n=10, 10%), Sjogren's syndrome (n=10, 10%) and rheumatoid arthritis (n=13, 13%). Twenty-three patients (24%) with anti Ro52+Ro60- antibodies have no autoimmune features but were found to have significant clinical conditions including malignancies. In contrast, 87 patients (87%) with anti Ro52+Ro60+ antibodies have autoimmune conditions including Sjogren's syndrome (n=34, 34%), systemic lupus erythematosus (SLE; n=23, 23%), undifferentiated connective tissue diseases (n=12, 12%) and rheumatoid arthritis (n=6, 6%). CONCLUSION: Anti Ro52 without anti Ro60 (Ro52+Ro60-) antibodies should be reported. In the majority of patients these autoantibodies were associated with various autoimmune diseases. Anti Ro52+Ro60- antibodies were also found in patients with significant clinical conditions including malignancies even though there was no suggestion of autoimmunity at the time of testing. PMID- 28663327 TI - Prognostic value of vitamin D receptor and insulin-like growth factor receptor 1 expression in triple-negative breast cancer. AB - AIM: Triple-negative breast cancer (TNBC) is characterised by shorter overall survival and an early peak of distant recurrences with still no specific targeted treatment available. Vitamin D receptor (VDR) and insulin-like growth factor receptor 1 (IGFR) have recently been described as potential new targets for anticancer therapy, yet their roles in TNBCs are still to be explored. In this study we investigated VDR and IGFR expression in patients with TNBC and compared them with clinical and pathological parameters and survival to possibly demonstrate their prognostic and therapeutic relevance. METHODS: The study included 96 patients with TNBC. Clinical and pathological parameters were compared with the immunohistochemical expression of VDR and IGFR. RESULTS: Positive VDR immunostaining was present in 27% of tumours and inversely correlated with higher mitotic score, histological grade and higher proliferation index measured by Ki-67 and related to the increased overall survival (OS). Out of 96 patients with TNBC, 35.5% of tumours were IGFR positive and correlated with higher mitotic score and Ki-67, and strongly correlated with shorter disease-free survival (DFS). Patients with VDR-negative and IGF-positive tumours had significantly lower DFS and OS. CONCLUSION: Approximately one third of TNBCs express VDR and/or IGFR. Their expression is linked with the recurrence of the disease and survival, which make them possible targets for treatment and a prognostic tool for dividing TNBCs into more homogeneous subgroups. PMID- 28663328 TI - Comparative evaluation of six chromogenic media for presumptive yeast identification. AB - AIMS: The present study was undertaken to evaluate the discrimination ability of six chromogenic media in presumptive yeast identification. METHODS: We analysed 108 clinical isolates and reference strains belonging to eight different species: Candida albicans,Candida dubliniensis, Candida tropicalis, Candida krusei, Candida glabrata, Candida parapsilosis,Candida lusitaniae and Trichosporon mucoides. RESULTS: C. albicans, C. tropicalis and C. krusei could be distinguished from one another in all the tested chromogenic media, as predicted by the manufacturers. In addition, C. albicans could be distinguished from C. dubliniensis on BBL CHROMagar Candida, Kima CHROMagar Candida and Brilliance Candida, and C. parapsilosis could be identified on CHROMATIC Candida agar, CHROMOGENIC Candida agar, and Brilliance Candida agar. CONCLUSIONS: Brilliance Candida provided the widest discrimination ability, being able to discriminate five out of the seven Candida species tested. Interestingly, C. tropicalis and C. krusei could be already distinguished from each other after 24 hours of incubation. PMID- 28663329 TI - Long QT syndrome and sudden unexpected infant death. AB - Long QT syndrome (LQTS) is an inheritable primary electric disease of the heart characterised by abnormally long QT intervals and a propensity to develop atrial and ventricular tachyarrhythmias. It is caused by an inherited channelopathy responsible for sudden cardiac death in individuals with structurally normal hearts. Long QT syndrome can present early in life, and some studies suggest that it may be associated with up to 20% of sudden unexplained infant death (SUID), particularly when associated with external stressors such as asphyxia, which is commonly seen in many infant death scenes. With an understanding of the genetic defects, it has now been possible to retrospectively analyse samples from infants who have presented to forensic pathology services with a history of unexplained sudden death, which may, in turn, enable the implementation of preventative treatment for siblings previously not known to have pathogenic genetic variations. In this viewpoint article, we will discuss SUID, LQTS and postmortem genetic analysis. PMID- 28663330 TI - Gene of the month: PRPF31. AB - Pre-mRNA splicing is an essential process in eukaryotic cells where the transcribed intronic sequences are removed, prior to translation into protein. PRPF31 is a ubiquitously expressed splicing factor, which aids in the assembly of the macromolecular spliceosome. Mutations in PRPF31 cause autosomal dominant retinitis pigmentosa (adRP), a form of retinal degeneration that causes progressive visual impairment. Interestingly, mutations in PRPF31 are non penetrant, with some mutation carriers being phenotypically unaffected. In this review, the gene organisation, protein structure and biological function of PRPF31 are discussed, and the mechanisms of non-penetrance in PRPF31-associated adRP are discussed. PMID- 28663331 TI - Multiplexed Gene Editing and Protein Overexpression Using a Tobacco mosaic virus Viral Vector. AB - Development of CRISPR/Cas9 transient gene editing screening tools in plant biology has been hindered by difficulty of delivering high quantities of biologically active single guide RNAs (sgRNAs). Furthermore, it has been largely accepted that in vivo generated sgRNAs need to be devoid of extraneous nucleotides, which has limited sgRNA expression by delivery vectors. Here, we increased cellular concentrations of sgRNA by transiently delivering sgRNAs using a Tobacco mosaic virus-derived vector (TRBO) designed with 5' and 3' sgRNA proximal nucleotide-processing capabilities. To demonstrate proof-of-principle, we used the TRBO-sgRNA delivery platform to target GFP in Nicotiana benthamiana (16c) plants, and gene editing was accompanied by loss of GFP expression. Surprisingly, indel (insertions and deletions) percentages averaged nearly 70% within 7 d postinoculation using the TRBO-sgRNA constructs, which retained 5' nucleotide overhangs. In contrast, and in accordance with current models, in vitro Cas9 cleavage assays only edited DNA when 5' sgRNA nucleotide overhangs were removed, suggesting a novel processing mechanism is occurring in planta. Since the Cas9/TRBO-sgRNA platform demonstrated sgRNA flexibility, we targeted the N. benthamiana NbAGO1 paralogs with one sgRNA and also multiplexed two sgRNAs using a single TRBO construct, resulting in indels in three genes. TRBO-mediated expression of an RNA transcript consisting of an sgRNA adjoining a GFP protein coding region produced indels and viral-based GFP overexpression. In conclusion, multiplexed delivery of sgRNAs using the TRBO system offers flexibility for gene expression and editing and uncovered novel aspects of CRISPR/Cas9 biology. PMID- 28663332 TI - The MicroRNA390/TAS3 Pathway Mediates Symbiotic Nodulation and Lateral Root Growth. AB - Legume roots form two types of postembryonic organs, lateral roots and symbiotic nodules. Nodule formation is the result of the interaction of legumes with rhizobia and requires the mitotic activation and differentiation of root cells as well as an independent, but coordinated, program that allows infection by rhizobia. MicroRNA390 (miR390) is an evolutionarily conserved microRNA that targets the Trans-Acting Short Interference RNA3 (TAS3) transcript. Cleavage of TAS3 by ARGONAUTE7 results in the production of trans-acting small interference RNAs, which target mRNAs encoding AUXIN RESPONSE FACTOR2 (ARF2), ARF3, and ARF4. Here, we show that activation of the miR390/TAS3 regulatory module by overexpression of miR390 in Medicago truncatula promotes lateral root growth but prevents nodule organogenesis, rhizobial infection, and the induction of two key nodulation genes, Nodulation Signaling Pathway1 (NSP1) and NSP2 Accordingly, inactivation of the miR390/TAS3 module, either by expression of a miR390 target mimicry construct or mutations in ARGONAUTE7, enhances nodulation and rhizobial infection, alters the spatial distribution of the nodules, and increases the percentage of nodules with multiple meristems. Our results revealed a key role of the miR390/TAS3 pathway in legumes as a modulator of lateral root organs, playing opposite roles in lateral root and nodule development. PMID- 28663333 TI - Leaf Starch Turnover Occurs in Long Days and in Falling Light at the End of the Day. AB - We investigated whether starch degradation occurs at the same time as starch synthesis in Arabidopsis (Arabidopsis thaliana) leaves in the light. Starch accumulated in a linear fashion for about 12 h after dawn, then accumulation slowed and content plateaued. Following decreases in light intensity, the rate of accumulation of starch declined in proportion to the decline in photosynthesis if the decrease occurred <10 h after dawn, but accumulation ceased or loss of starch occurred if the same decrease in light intensity was imposed more than 10 h after dawn. These changes in starch accumulation patterns after prolonged periods in the light occurred at both high and low starch contents and were not related to time-dependent changes in either the rate of photosynthesis or the partitioning of assimilate between starch and Suc, as assessed from metabolite measurements and 14CO2 pulse experiments. Instead, measurements of incorporation of 13C from 13CO2 into starch and of levels of the starch degradation product maltose showed that substantial starch degradation occurred simultaneously with synthesis at time points >14 h after dawn and in response to decreases in light intensity that occurred >10 h after dawn. Starch measurements in circadian clock mutants suggested that the clock influences the timing of onset of degradation. We conclude that the propensity for leaf starch to be degraded increases with time after dawn. The importance of this phenomenon for efficient use of carbon for growth in long days and for prevention of starvation during twilight is discussed. PMID- 28663334 TI - Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression. AB - Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including cancer. Using a unique mouse model that contains nDNA from one mouse strain and homoplasmic mitochondrial haplotypes from different mouse strain(s)-designated Mitochondrial Nuclear Exchange (MNX)-we showed that mtDNA could alter mammary tumor metastasis. Because retrograde and anterograde communication exists between the nuclear and mitochondrial genomes, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation. Genome-wide nDNA methylation and gene expression were measured in harvested brain tissue from paired wild-type and MNX mice. Selective differential DNA methylation and gene expression were observed between strains having identical nDNA, but different mtDNA. These observations provide insights into how mtDNA could be altering epigenetic regulation and thereby contribute to the pathogenesis of metastasis. Cancer Res; 77(22); 6202-14. (c)2017 AACR. PMID- 28663335 TI - Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice. AB - Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung's physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell's mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho- mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) was present on day 1 Cell death in alveolar type I (AT1) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT2 cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT2 cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT2 cells. These findings imply that mitochondrial QC activation in pneumonia-damaged AT2 cells promotes cell survival in support of alveolar function. PMID- 28663337 TI - Tracking LINE1 retrotransposition in the germline. PMID- 28663336 TI - Effects of prostaglandin lipid mediators on agonist-induced lung endothelial permeability and inflammation. AB - Prostaglandins (PG), the products of cyclooxygenase-mediated conversion of arachidonic acid, become upregulated in many situations including allergic response, inflammation, and injury, and exhibit a variety of biological activities. Previous studies described barrier-enhancing and anti-inflammatory effects of PGE2 and PGI2 on vascular endothelial cells (EC). Yet, the effects of other PG members on EC barrier and inflammatory activation have not been systematically analyzed. This study compared effects of PGE2, PGI2, PGF2alpha, PGA2, PGJ2, and PGD2 on human pulmonary EC. EC permeability was assessed by measurements of transendothelial electrical resistance and cell monolayer permeability for FITC-labeled tracer. Anti-inflammatory effects of PGs were evaluated by analysis of expression of adhesion molecule ICAM1 and secretion of soluble ICAM1 and cytokines by EC. PGE2, PGI2, and PGA2 exhibited the most potent barrier-enhancing effects and most efficient attenuation of thrombin-induced EC permeability and contractile response, whereas PGI2 effectively suppressed thrombin-induced permeability but was less efficient in the attenuation of prolonged EC hyperpermeability caused by interleukin-6 or bacterial wall lipopolysaccharide, LPS. PGD2 showed a modest protective effect on the EC inflammatory response, whereas PGF2alpha and PGJ2 were without effect on agonist induced EC barrier dysfunction. In vivo, PGE2, PGI2, and PGA2 attenuated LPS induced lung inflammation, whereas PGF2alpha and PGJ2 were without effect. Interestingly, PGD2 exhibited a protective effect in the in vivo model of LPS induced lung injury. This study provides a comprehensive analysis of barrier protective and anti-inflammatory effects of different prostaglandins on lung EC in vitro and in vivo and identifies PGE2, PGI2, and PGA2 as prostaglandins with the most potent protective properties. PMID- 28663338 TI - Getting a charge out of hybrid perovskites. PMID- 28663339 TI - The influence of connective tissue growth factor on rabbit ligament injury repair. AB - OBJECTIVES: The injured anterior cruciate ligament (ACL) is thought to exhibit an impaired healing response, and attempts at surgical repair have not been successful. Connective tissue growth factor (CTGF) is reported to be associated with wound healing, probably through transforming growth factor beta 1 (TGF beta1). METHODS: A rabbit ACL injury model was used to study the effect of CTGF on ligament recovery. Quantitative real-time PCR (qRT-PCR) was performed for detection of changes in RNA levels of TGF-beta1, type 1 collagen (COL1), type 2 collagen (COL2), SRY-related high mobility group-box gene9 (SOX9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metallopeptidase 13 (MMP 13). Expression of related proteins was detected by Western blotting. RESULTS: The current study showed that CTGF could promote the recovery of an injured anterior cruciate ligament. It can upregulate mRNA and expression of TGF-beta1, COL1, COL2, SOX9, and tissue inhibitor of TIMP-1, and downregulate mRNA and expression of MMP-13, suggesting that the curative effect of CTGF on injured rabbit ligaments is through regulation of these cellular factors. CONCLUSIONS: This finding revealed the healing role of CTGF in injured tissues and provides new possibilities of treating injured tissues and wound healing by using CTGF.Cite this article: X. Sun, W. Liu, G. Cheng, X. Qu, H. Bi, Z. Cao, Q. Yu. The influence of connective tissue growth factor on rabbit ligament injury repair. Bone Joint Res 2017;6:399-404. DOI: 10.1302/2046-3758.67.BJR.2016 0255.R1. PMID- 28663340 TI - Safety of pulmonary function testing: data from 20 years. AB - BACKGROUND: Pulmonary function testing (PFT) is a key investigation in the evaluation of individuals with respiratory symptoms; however, the safety of routine and specialised PFT testing has not been reported in a large data set. Using patient safety incident (PSI) records, we aimed to assess risk of PFT and to characterise these events and any associated risk factors. METHODS: In this single-centre audit, demographics and PSI data were collected and categorised for PFT performed between 1996 and 2016 and subdivided into cardiopulmonary or non cardiopulmonary events. The severity of each PSI was rated using the NHS National Patient Safety Agency and any hospital admission reported. RESULTS: There were 119 PSIs reported from 186 000 PFT; that is, 0.6 PSIs per 1000 tests. Cardiopulmonary PSIs were 3.3 times more likely to occur than non-cardiopulmonary (95% CI 2.17 to 5.12). Syncope was the most frequently occurring cardiopulmonary PSI. Cardiopulmonary exercise testing was associated with 2 PSIs per 1000 tests. PSIs necessitating hospital admission and/or emergency department attendance occurred approximately once every 10 000 tests and there was no PFT-associated mortality. CONCLUSION: Routine and specialised PFT is safe for patients, in the context of established screening preparticipation guidelines. In the event of a PSI, these are likely to be low risk of harm. Our findings highlight the most common PSIs encountered during PFT to facilitate risk reduction. PMID- 28663341 TI - Determinants of hospital death in haematological cancers: findings from a qualitative study. AB - OBJECTIVES: Current UK health policy promotes enabling people to die in a place they choose, which for most is home. Despite this, patients with haematological malignancies (leukaemias, lymphomas and myeloma) are more likely to die in hospital than those with other cancers, and this is often considered a reflection of poor quality end-of-life care. This study aimed to explore the experiences of clinicians and relatives to determine why hospital deaths predominate in these diseases. METHODS: The study was set within the Haematological Malignancy Research Network (HMRN-www.hmrn.org), an ongoing population-based cohort that provides infrastructure for evidence-based research. Qualitative interviews were conducted with clinical staff in haematology, palliative care and general practice (n=45) and relatives of deceased HMRN patients (n=10). Data were analysed for thematic content and coding and classification was inductive. Interpretation involved seeking meaning, salience and connections within the data. RESULTS: Five themes were identified relating to: the characteristics and trajectory of haematological cancers, a mismatch between the expectations and reality of home death, preference for hospital death, barriers to home/hospice death and suggested changes to practice to support non-hospital death, when preferred. CONCLUSIONS: Hospital deaths were largely determined by the characteristics of haematological malignancies, which included uncertain trajectories, indistinct transitions and difficulties predicting prognosis and identifying if or when to withdraw treatment. Advance planning (where possible) and better communication between primary and secondary care may facilitate non hospital death. PMID- 28663342 TI - Comparative Genomics of Two Sequential Candida glabrata Clinical Isolates. AB - Candida glabrata is an important fungal pathogen which develops rapid antifungal resistance in treated patients. It is known that azole treatments lead to antifungal resistance in this fungal species and that multidrug efflux transporters are involved in this process. Specific mutations in the transcriptional regulator PDR1 result in upregulation of the transporters. In addition, we showed that the PDR1 mutations can contribute to enhance virulence in animal models. In this study, we were interested to compare genomes of two specific C. glabrata-related isolates, one of which was azole susceptible (DSY562) while the other was azole resistant (DSY565). DSY565 contained a PDR1 mutation (L280F) and was isolated after a time-lapse of 50 d of azole therapy. We expected that genome comparisons between both isolates could reveal additional mutations reflecting host adaptation or even additional resistance mechanisms. The PacBio technology used here yielded 14 major contigs (sizes 0.18-1.6 Mb) and mitochondrial genomes from both DSY562 and DSY565 isolates that were highly similar to each other. Comparisons of the clinical genomes with the published CBS138 genome indicated important genome rearrangements, but not between the clinical strains. Among the unique features, several retrotransposons were identified in the genomes of the investigated clinical isolates. DSY562 and DSY565 each contained a large set of adhesin-like genes (101 and 107, respectively), which exceed by far the number of reported adhesins (63) in the CBS138 genome. Comparison between DSY562 and DSY565 yielded 17 nonsynonymous SNPs (among which the was the expected PDR1 mutation) as well as small size indels in coding regions (11) but mainly in adhesin-like genes. The genomes contained a DNA mismatch repair allele of MSH2 known to be involved in the so-called hyper mutator phenotype of this yeast species and the number of accumulated mutations between both clinical isolates is consistent with the presence of a MSH2 defect. In conclusion, this study is the first to compare genomes of C. glabrata sequential clinical isolates using the PacBio technology as an approach. The genomes of these isolates taken in the same patient at two different time points exhibited limited variations, even if submitted to the host pressure. PMID- 28663343 TI - Fine Mapping, Transcriptome Analysis, and Marker Development for Y2 , the Gene That Conditions beta-Carotene Accumulation in Carrot (Daucus carota L.). AB - Domesticated carrots, Daucus carota subsp. sativus, are the richest source of beta-carotene in the US diet, which, when consumed, is converted into vitamin A, an essential component of eye health and immunity. The Y2 locus plays a significant role in beta-carotene accumulation in carrot roots, but a candidate gene has not been identified. To advance our understanding of this locus, the genetic basis of beta-carotene accumulation was explored by utilizing an advanced mapping population, transcriptome analysis, and nucleotide diversity in diverse carrot accessions with varying levels of beta-carotene. A single large effect Quantitative Trait Locus (QTL) on the distal arm of chromosome 7 overlapped with the previously identified beta-carotene accumulation QTL, Y2 Fine mapping efforts reduced the genomic region of interest to 650 kb including 72 genes. Transcriptome analysis within this fine mapped region identified four genes differentially expressed at two developmental time points, and 13 genes differentially expressed at one time point. These differentially expressed genes included transcription factors and genes involved in light signaling and carotenoid flux, including a member of the Di19 gene family involved in Arabidopsis photomorphogenesis, and a homolog of the bHLH36 transcription factor involved in maize carotenoid metabolism. Analysis of nucleotide diversity in 25 resequenced carrot accessions revealed a drastic decrease in diversity of this fine-mapped region in orange cultivated accessions as compared to white and yellow cultivated and to white wild samples. The results presented in this study provide a foundation to identify and characterize the gene underlying beta carotene accumulation in carrot. PMID- 28663344 TI - Gene2Function: An Integrated Online Resource for Gene Function Discovery. AB - One of the most powerful ways to develop hypotheses regarding the biological functions of conserved genes in a given species, such as humans, is to first look at what is known about their function in another species. Model organism databases and other resources are rich with functional information but difficult to mine. Gene2Function addresses a broad need by integrating information about conserved genes in a single online resource. PMID- 28663345 TI - Putting social care on the map. PMID- 28663347 TI - Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover. AB - Cell motility depends on tight coordination between the microtubule (MT) and actin cytoskeletons, but the mechanisms underlying this MT-actin cross talk have remained poorly understood. Here, we show that the tumor suppressor protein adenomatous polyposis coli (APC), which is a known MT-associated protein, directly nucleates actin assembly to promote directed cell migration. By changing only two residues in APC, we generated a separation-of-function mutant, APC (m4), that abolishes actin nucleation activity without affecting MT interactions. Expression of full-length APC carrying the m4 mutation (APC (m4)) rescued cellular defects in MT organization, MT dynamics, and mitochondrial distribution caused by depletion of endogenous APC but failed to restore cell migration. Wild type APC and APC (m4) localized to focal adhesions (FAs), and APC (m4) was defective in promoting actin assembly at FAs to facilitate MT-induced FA turnover. These results provide the first direct evidence for APC-mediated actin assembly in vivo and establish a role for APC in coordinating MTs and actin at FAs to direct cell migration. PMID- 28663349 TI - A nationwide cohort study of slipped capital femoral epiphysis. AB - OBJECTIVES: To describe the epidemiology of slipped capital femoral epiphysis (SCFE), to examine associations with childhood obesity and socioeconomic deprivation, and to explore factors associated with diagnostic delays. DESIGN: Historic cohort study using linked primary and secondary care data from the Clinical Practice Research Datalink and Hospital Episode Statistics. SETTING: All contacts with healthcare services, including emergency presentations, outpatient appointments, inpatient admissions and primary care visits, within the UK National Health Service. PATIENTS: All individuals <16 years old with a diagnosis of SCFE and whose electronic medical record was held by one of 650 primary care practices in the UK between 1990 and 2013. MAIN OUTCOME MEASURES: Annual incidence, missed opportunities for diagnosis and diagnostic delay. RESULTS: Over the 23-year period the incidence remained constant at 4.8 (95% CI 4.4 to 5.2) cases per 100,000 0-16-year-olds. There was a strong association with socioeconomic deprivation. Predisease obesity was also strongly associated with SCFE; mean predisease z-score of body mass index was 1.43 (95% CI 1.20 to 1.68) compared with the UK reference mean. Diagnostic delays were common, with most children (75.4%) having multiple primary care contacts with relevant symptomatology, and those who presented with knee pain having significantly longer diagnostic delay (median 161 (IQR 27-278) days) than those with hip pain (20 (5-126)) or gait abnormalities (21 (7-72)). CONCLUSIONS: SCFE has a strong association with both area-level socioeconomic deprivation and predisease obesity. The majority of patients with SCFE are initially misdiagnosed and those presenting with knee pain are particularly at risk. PMID- 28663346 TI - Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging. AB - Intestinal stem cells (ISCs) maintain the midgut epithelium in Drosophila melanogaster Proper cellular turnover and tissue function rely on tightly regulated rates of ISC division and appropriate differentiation of daughter cells. However, aging and epithelial injury cause elevated ISC proliferation and decreased capacity for terminal differentiation of daughter enteroblasts (EBs). The mechanisms causing functional decline of stem cells with age remain elusive; however, recent findings suggest that stem cell metabolism plays an important role in the regulation of stem cell activity. Here, we investigate how alterations in mitochondrial homeostasis modulate stem cell behavior in vivo via RNA interference-mediated knockdown of factors involved in mitochondrial dynamics. ISC/EB-specific knockdown of the mitophagy-related genes Pink1 or Parkin suppresses the age-related loss of tissue homeostasis, despite dramatic changes in mitochondrial ultrastructure and mitochondrial damage in ISCs/EBs. Maintenance of tissue homeostasis upon reduction of Pink1 or Parkin appears to result from reduction of age- and stress-induced ISC proliferation, in part, through induction of ISC senescence. Our results indicate an uncoupling of cellular, tissue, and organismal aging through inhibition of ISC proliferation and provide insight into strategies used by stem cells to maintain tissue homeostasis despite severe damage to organelles. PMID- 28663350 TI - Parental restriction reduces the harmful effects of in-bedroom electronic devices. AB - OBJECTIVE: To investigate whether school readiness could be affected by placing electronic devices (EDs) in children's bedroom and whether the relationship was moderated by parental restriction and family socioeconomic status (SES). DESIGN: This is a cross-sectional study with bedroom ED placement and parental restriction reported by parents. Multiple linear regressions were used to test the relationship between school readiness and ED placement. Multiple regression with interaction terms were used to test whether the effect was consistent with and without parental restriction. SETTING: Kindergartens randomly selected from two districts of different socioeconomic backgrounds in Hong Kong, China. PATIENTS: 556 young children attending the third year of kindergarten. MAIN OUTCOME MEASURES: Children's school readiness was rated by teachers using the Chinese Early Development Instrument. RESULTS: 556 preschoolers (mean age 5.46; 51.8% girls) from 20 kindergartens participated in this study. About 30% of parents placed at least one ED in their children's bedroom. After controlling for sex and SES, the placement of television in the bedroom was associated with lower overall school readiness (beta -1.11, 95% CI -1.80 to -0.42) and the placement of game console was associated with lower social competence (beta-0.94, 95% CI -1.74 to -0.15). Such harmful effect was more prominent among lower SES families and could be partially alleviated with parental restriction. CONCLUSION: ED placement in children's bedroom was associated with lower school readiness, particularly among lower SES families. Parental restriction might help to alleviate the harm. PMID- 28663351 TI - Dofetilide-induced torsade de pointes in high-grade atrioventricular node dysfunction. PMID- 28663353 TI - No lead is better than a little lead. PMID- 28663352 TI - A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback. AB - PURPOSE: Most residency programmes do not have a formal high value care curriculum. Our goal was to design and implement a multidisciplinary high value care curriculum specifically targeted at interns. DESIGN: Our curriculum was designed with multidisciplinary input from attendings, fellows and residents at Stanford. Curricular topics were inspired by the American Board of Internal Medicine's Choosing Wisely campaign, Alliance for Academic Internal Medicine, American College of Physicians and Society of Hospital Medicine. Our topics were as follows: introduction to value-based care; telemetry utilisation; lab ordering; optimal approach to thrombophilia work-ups and fresh frozen plasma use; optimal approach to palliative care referrals; antibiotic stewardship; and optimal approach to imaging for low back pain. Our curriculum was implemented at the Stanford Internal Medicine residency programme over the course of two academic years (2014 and 2015), during which 100 interns participated in our high value care curriculum. After each high value care session, interns were offered the opportunity to complete surveys regarding feedback on the curriculum, self reported improvements in knowledge, skills and attitudinal module objectives, and quiz-based knowledge assessments. RESULTS: The overall survey response rate was 67.1%. Overall, the material was rated as highly useful on a 5-point Likert scale (mean 4.4, SD 0.6). On average, interns reported a significant improvement in their self-rated knowledge, skills and attitudes after the six seminars (mean improvement 1.6 points, SD 0.4 (95% CI 1.5 to 1.7), p<0.001). CONCLUSIONS: We successfully implemented a novel high value care curriculum that specifically targets intern physicians. PMID- 28663354 TI - Feeding the microbiota: transducer of nutrient signals for the host. AB - Advances in microbiome science cast light on traditional concepts on nutritional science, and are poised for clinical translation. Epidemiologic observations which linked lifestyle factors to risk of disease are being re-interpreted with mechanistic insight based on improved understanding of the microbiota. Examples include the role of dietary fibre in disease prevention, the deleterious effects of highly restricted diets, and the contribution of the microbiota to over- and undernutrition. While the microbiota transduces nutrient signals for the host, food and habitual diet shape the composition of the gut microbiota at every stage of life. The composition and diversity of food intake determines which microbes will colonise, flourish, persist, or become extinct. Disruption of the developing microbiota in infancy contributes to the risk of immune and metabolic disease in later life, whereas loss of microbes in the elderly due to monotonous diets has been linked with unhealthy ageing and frailty. This should influence modern dietary advice regarding prevention and management of chronic non-communicable inflammatory and metabolic disorders, and will inform the design of infant and future food formula. The microbiota profile is also emerging as a biomarker to predict responsiveness to dietary interventions and promises to make personalised nutrition a reality. PMID- 28663355 TI - Persistent cough: A question for the gastroenterologist? PMID- 28663357 TI - Sustained enjoyment of life and mortality at older ages: analysis of the English Longitudinal Study of Ageing. PMID- 28663358 TI - Necrotising coronaritis with fatal outcome. AB - A 56-year-old woman presented with acute onset of typical chest pain. She was diagnosed with acute coronary syndrome with ST-segment elevation myocardial infarction. Although significant obstructive coronary artery disease was ruled out by coronary angiography, cardiac MRI showed transmural necrosis of the lateral free wall with extensive microvascular obstruction consistent with ischaemic heart disease. Within 48 hours after initial presentation, the patient suddenly arrested due to pulseless electrical activity with futile resuscitation efforts. Autopsy revealed myocardial perforation with extensive haematothorax due to pericardial laceration, caused by the mechanical chest compressions. Eventually, histology identified diffuse necrotising coronary vasculitis as a rare cause of ischaemic heart disease. PMID- 28663356 TI - Appendiceal Mucinous Neoplasms: Diagnosis and Management. AB - OBJECTIVE: Appendiceal mucinous neoplasms (AMNs) are a rare and heterogeneous disease for which clinical management is challenging. We aim to review the literature regarding modalities of treatment to guide the management of AMNs. METHODS AND REVIEW CRITERIA: We conducted a PubMed search in February 2016 for English-language publications, using the terms "appendiceal," "appendix," "carcinoma," "cancer," "mucinous," "treatment," "genes," "target," "genomic," and terms listed in the articles' subheadings. Published reports and abstracts from the American Society of Clinical Oncology meetings were also searched. RESULTS: In this review, we summarize current data and controversies in AMN classification, clinical presentation, molecular alterations, treatment outcomes with regard to cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and the role of systemic chemotherapy. CONCLUSION: Appendiceal mucinous neoplasms are a heterogeneous group of tumors with a rising incidence. Treatment is based on stage and histology. Low-grade tumors are treated surgically with resection of the primary site in early stage disease, or peritoneal debulking and HIPEC in patients with advanced stage disease. Treatment of high-grade tumors requires further prospective trials, and options include debulking surgery and HIPEC with or without preoperative chemotherapy. Trials evaluating novel therapies based on the molecular profiling of AMN tumors are needed to evaluate therapeutic options in patients who are not surgical candidates. IMPLICATIONS FOR PRACTICE: This review provides a reference to guide gastroenterologists, pathologists, surgeons, and oncologists in the management of appendiceal mucinous neoplasms (AMNs), a rare and heterogeneous disease with no consensus on histologic classification or guidelines for treatment algorithms. This review summarizes all AMN classifications and proposes a treatment algorithm based on stage and histology of disease. PMID- 28663360 TI - Public knowledge of cardiovascular disease and response to acute cardiac events in three cities in China and India. AB - OBJECTIVE: To inform interventions targeted towards reducing mortality from acute myocardial infarction (AMI) and sudden cardiac arrest in three megacities in China and India, a baseline assessment of public knowledge, attitudes and practices was performed. METHODS: A household survey, supplemented by focus group and individual interviews, was used to assess public understanding of cardiovascular disease (CVD) risk factors, AMI symptoms, cardiopulmonary resuscitation (CPR) and automated external defibrillators (AEDs). Additionally, information was collected on emergency service utilisation and associated barriers to care. RESULTS: 5456 household surveys were completed. Hypertension was most commonly recognised among CVD risk factors in Beijing and Shanghai (68% and 67%, respectively), while behavioural risk factors were most commonly identified in Bangalore (smoking 91%; excessive alcohol consumption 64%). Chest pain/discomfort was reported by at least 60% of respondents in all cities as a symptom of AMI, but 21% of individuals in Bangalore could not name a single symptom. In Beijing, Shanghai and Bangalore, 26%, 15% and 3% of respondents were trained in CPR, respectively. Less than one-quarter of participants in all cities recognised an AED. Finally, emergency service utilisation rates were low, and many individuals expressed concern about the quality of prehospital care. CONCLUSIONS: Overall, we found low to modest knowledge of CVD risk factors and AMI symptoms, infrequent CPR training and little understanding of AEDs. Interventions will need to focus on basic principles of CVD and its complications in order for patients to receive timely and appropriate care for acute cardiac events. PMID- 28663362 TI - Bicuspid aortic valves and intracranial aneurysms: more than an incidental coexistence? PMID- 28663361 TI - Hyperaemic microvascular resistance predicts clinical outcome and microvascular injury after myocardial infarction. AB - OBJECTIVES: Early detection of microvascular dysfunction after acute myocardial infarction (AMI) could identify patients at high risk of adverse clinical outcome, who may benefit from adjunctive treatment. Our objective was to compare invasively measured coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR) for their predictive power of long-term clinical outcome and cardiac magnetic resonance (CMR)-defined microvascular injury (MVI). METHODS: Simultaneous intracoronary Doppler flow velocity and pressure measurements acquired immediately after revascularisation for AMI from five centres were pooled. Clinical follow-up was completed for 176 patients (mean age 60+/-10 years; 140(80%) male; ST-elevation myocardial infarction (STEMI) 130(74%) and non ST-segment elevation myocardial infarction 46(26%)) with median follow-up time of 3.2 years. In 110 patients with STEMI, additional CMR was performed. RESULTS: The composite end point of death and hospitalisation for heart failure occurred in 17 patients (10%). Optimal cut-off values to predict the composite end point were 1.5 for CFR and 3.0 mm Hg cm-1*s for HMR. CFR <1.5 was predictive for the composite end point (HR 3.5;95% CI 1.1 to 10.8), but not for its individual components. HMR >=3.0 mm Hg cm-1 s was predictive for the composite end point (HR 7.0;95% CI 1.5 to 33.7) as well as both individual components. HMR had significantly greater area under the receiver operating characteristic curve for MVI than CFR. HMR remained an independent predictor of adverse clinical outcome and MVI, whereas CFR did not. CONCLUSIONS: HMR measured immediately following percutaneous coronary intervention for AMI with a cut-off value of 3.0 mm Hg cm-1 s, identifies patients with MVI who are at high risk of adverse clinical outcome. For this purpose, HMR is superior to CFR. PMID- 28663363 TI - First and recurrent ischaemic heart disease events continue to decline in New Zealand, 2005-2015. AB - OBJECTIVES: To examine recent trends in first and recurrent ischaemic heart disease (IHD) deaths and hospitalisations. METHODS: Using anonymous patient linkage of routinely collected data, all New Zealanders aged 35-84 years who experienced an International Statistical Classification of Diseases and Related Health Problems I(CD)-coded IHD hospitalisation and/or IHD death between 1 January 2005 and 31 December 2015 were identified. A 10-year look-back period was used to differentiate those experiencing first from recurrent events. Age standardised hospitalisation and mortality rates were calculated for each calendar year and trends compared by sex and age. RESULTS: 160 109 people experienced at least one IHD event (259 678 hospitalisations and 35 548 deaths) over the 11-year study period, and there was a steady decline in numbers (from almost 24 000 in 2005 to just over 16 000 in 2015) and in age-standardised rates each year. With the exception of deaths in younger (35-64 years) women with prior IHD, there was a significant decline in IHD events in men and women of all ages, with and without a history of IHD. The decline in IHD mortality was greater for those experiencing a first rather than recurrent IHD event (3.8%-5.2% vs 0%-3.7% annually on average). In contrast, the decline in IHD hospitalisations was greater for those experiencing a recurrent compared with a first IHD event (5.6% 7.3% vs 3.2%-5.7% annually on average). CONCLUSIONS: The substantial decline in IHD hospitalisations and mortality observed in New Zealanders with and without prior IHD between 2005 and 2015 suggests that primary and secondary prevention efforts have been effective in reducing the occurrence of IHD events. PMID- 28663364 TI - Platelet count and mean platelet volume predict outcome in adults with Eisenmenger syndrome. AB - OBJECTIVES: Although a significant proportion of patients with cyanotic congenital heart disease are thrombocytopaenic, its prevalence and clinical significance in adults with Eisenmenger syndrome (ES) is not well studied. Accordingly, we examined the relationship of thrombocytopaenia and mean platelet volume (MPV) to bleeding or thrombotic complications and survival in a contemporary cohort of patients with ES, including patients with Down syndrome. METHODS: Demographics, laboratory and clinical data were analysed from 226 patients with ES under active follow-up over 11 years. RESULTS: Age at baseline was 34.6+/-11.4 years and 34.1% were men. Mean platelet count and MPV were 152.6+/-73.3*109/L and 9.6+/-1.2 fL, respectively. A strong inverse correlation was found between platelet count and haemoglobin concentration and MPV. During the study, there were 39 deaths, and 21 thrombotic and 43 bleeding events. On univariate Cox regression analysis, patients with a platelet count <100*109/L had a twofold increased mortality (HR 2.10, 95% CI 1.10 to 4.01, p=0.024). Platelet count was not associated with an increased risk of thrombosis. However, there was a threefold increased thrombotic risk with MPV >9.5 fL (HR 3.50, 95% CI 1.28 to 9.54, p=0.015). Patients with either severe secondary erythrocytosis (>220g/L) or anaemia (<130g/L) were at higher risk of thrombotic events (HR 3.93, 95% CI 1.60 to 9.67, p=0.003; and HR 4.75, 95% CI 1.03 to 21.84, p=0.045, respectively). CONCLUSIONS: Thrombocytopaenia significantly increased the risk of mortality in ES. Furthermore, raised MPV, severe secondary erythrocytosis and anaemia, but not platelet count, were associated with an increased risk of thrombotic events in our adult cohort. PMID- 28663365 TI - Outcome after percutaneous edge-to-edge mitral repair for functional and degenerative mitral regurgitation: a systematic review and meta-analysis. AB - OBJECTIVES: Differences in terms of safety and efficacy of percutaneous edge-to edge mitral repair between patients with functional and degenerative mitral regurgitation (MR) are not well established. We performed a systematic review and meta-analysis to clarify these differences. METHODS: PubMed, EMBASE, Google scholar database and international meeting abstracts were searched for all studies about MitraClip. Studies with <25 patients or where 1-year results were not delineated between MR aetiology were excluded. This study is registered with PROSPERO. RESULTS: A total of nine studies investigating the mid-term outcome of percutaneous edge-to-edge repair in patients with functional versus degenerative MR were included in the meta-analysis (n=2615). At 1 year, there were not significant differences among groups in terms of patients with MR grade<=2 (719/1304 vs 295/504; 58% vs 54%; risk ratio (RR) 1.12; 95% CI: 0.86 to 1.47; p=0.40), while there was a significantly lower rate of mitral valve re intervention in patients with functional MR compared with those with degenerative MR (77/1770 vs 80/818; 4% vs 10%; RR 0.60; 95% CI: 0.38 to 0.97; p=0.04). One year mortality rate was 16% (408/2498) and similar among groups (RR 1.26; 95% CI: 0.90 to 1.77; p=0.18). Functional MR group showed significantly higher percentage of patients in New York Heart Association class III/IV (234/1480 vs 49/583; 16% vs 8%; p<0.01) and re-hospitalisation for heart failure (137/605 vs 31/220; 23% vs 14%; p=0.03). No differences were found in terms of single leaflet device attachment (25/969 vs 20/464; 3% vs 4%; p=0.81) and device embolisation (no events reported in both groups) at 1 year. CONCLUSIONS: This meta-analysis suggests that percutaneous edge-to-edge repair is likely to be an efficacious and safe option in patients with both functional and degenerative MR. Large, randomised studies are ongoing and awaited to fully assess the clinical impact of the procedure in these two different MR aetiologies. PMID- 28663366 TI - Diagnosis and management of resistant hypertension. PMID- 28663367 TI - Genome-Wide Temporal Profiling of Transcriptome and Open Chromatin of Early Cardiomyocyte Differentiation Derived From hiPSCs and hESCs. AB - RATIONALE: Recent advances have improved our ability to generate cardiomyocytes from human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). However, our understanding of the transcriptional regulatory networks underlying early stages (ie, from mesoderm to cardiac mesoderm) of cardiomyocyte differentiation remains limited. OBJECTIVE: To characterize transcriptome and chromatin accessibility during early cardiomyocyte differentiation from hiPSCs and hESCs. METHODS AND RESULTS: We profiled the temporal changes in transcriptome and chromatin accessibility at genome-wide levels during cardiomyocyte differentiation derived from 2 hiPSC lines and 2 hESC lines at 4 stages: pluripotent stem cells, mesoderm, cardiac mesoderm, and differentiated cardiomyocytes. Overall, RNA sequencing analysis revealed that transcriptomes during early cardiomyocyte differentiation were highly concordant between hiPSCs and hESCs, and clustering of 4 cell lines within each time point demonstrated that changes in genome-wide chromatin accessibility were similar across hiPSC and hESC cell lines. Weighted gene co-expression network analysis (WGCNA) identified several modules that were strongly correlated with different stages of cardiomyocyte differentiation. Several novel genes were identified with high weighted connectivity within modules and exhibited coexpression patterns with other genes, including noncoding RNA LINC01124 and uncharacterized RNA AK127400 in the module related to the mesoderm stage; E-box-binding homeobox 1 (ZEB1) in the module correlated with postcardiac mesoderm. We further demonstrated that ZEB1 is required for early cardiomyocyte differentiation. In addition, based on integrative analysis of both WGCNA and transcription factor motif enrichment analysis, we determined numerous transcription factors likely to play important roles at different stages during cardiomyocyte differentiation, such as T and eomesodermin (EOMES; mesoderm), lymphoid enhancer-binding factor 1 (LEF1) and mesoderm posterior BHLH transcription factor 1 (MESP1; from mesoderm to cardiac mesoderm), meis homeobox 1 (MEIS1) and GATA-binding protein 4 (GATA4) (postcardiac mesoderm), JUN and FOS families, and MEIS2 (cardiomyocyte). CONCLUSIONS: Both hiPSCs and hESCs share similar transcriptional regulatory mechanisms underlying early cardiac differentiation, and our results have revealed transcriptional regulatory networks and new factors (eg, ZEB1) controlling early stages of cardiomyocyte differentiation. PMID- 28663368 TI - Betaine is accumulated via transient choline dehydrogenase activation during mouse oocyte meiotic maturation. AB - Betaine (N,N,N-trimethylglycine) plays key roles in mouse eggs and preimplantation embryos first in a novel mechanism of cell volume regulation and second as a major methyl donor in blastocysts, but its origin is unknown. Here, we determined that endogenous betaine was present at low levels in germinal vesicle (GV) stage mouse oocytes before ovulation and reached high levels in the mature, ovulated egg. However, no betaine transport into oocytes was detected during meiotic maturation. Because betaine can be synthesized in mammalian cells via choline dehydrogenase (CHDH; EC 1.1.99.1), we assessed whether this enzyme was expressed and active. Chdh transcripts and CHDH protein were expressed in oocytes. No CHDH enzyme activity was detected in GV oocyte lysate, but CHDH became highly active during oocyte meiotic maturation. It was again inactive after fertilization. We then determined whether oocytes synthesized betaine and whether CHDH was required. Isolated maturing oocytes autonomously synthesized betaine in vitro in the presence of choline, whereas this failed to occur in Chdh /- oocytes, directly demonstrating a requirement for CHDH for betaine accumulation in oocytes. Overall, betaine accumulation is a previously unsuspected physiological process during mouse oocyte meiotic maturation whose underlying mechanism is the transient activation of CHDH. PMID- 28663369 TI - Structure-function analyses of a pertussis-like toxin from pathogenic Escherichia coli reveal a distinct mechanism of inhibition of trimeric G-proteins. AB - Pertussis-like toxins are secreted by several bacterial pathogens during infection. They belong to the AB5 virulence factors, which bind to glycans on host cell membranes for internalization. Host cell recognition and internalization are mediated by toxin B subunits sharing a unique pentameric ring like assembly. Although the role of pertussis toxin in whooping cough is well established, pertussis-like toxins produced by other bacteria are less studied, and their mechanisms of action are unclear. Here, we report that some extra intestinal Escherichia coli pathogens (i.e. those that reside in the gut but can spread to other bodily locations) encode a pertussis-like toxin that inhibits mammalian cell growth in vitro We found that this protein, EcPlt, is related to toxins produced by both nontyphoidal and typhoidal Salmonella serovars. Pertussis like toxins are secreted as disulfide-bonded heterohexamers in which the catalytic ADP-ribosyltransferase subunit is activated when exposed to the reducing environment in mammalian cells. We found here that the reduced EcPlt exhibits large structural rearrangements associated with its activation. We noted that inhibitory residues tethered within the NAD+-binding site by an intramolecular disulfide in the oxidized state dissociate upon the reduction and enable loop restructuring to form the nucleotide-binding site. Surprisingly, although pertussis toxin targets a cysteine residue within the alpha subunit of inhibitory trimeric G-proteins, we observed that activated EcPlt toxin modifies a proximal lysine/asparagine residue instead. In conclusion, our results reveal the molecular mechanism underpinning activation of pertussis-like toxins, and we also identified differences in host target specificity. PMID- 28663372 TI - Muscle hypertrophy in prediabetic men after 16 wk of resistance training. AB - Resistance training of healthy young men typically results in muscle hypertrophy and a shift in vastus lateralis composition away from type IIx fibers to an increase in IIa fiber content. Our previous studies of 8 wk of resistance training found that many metabolic syndrome men and women paradoxically increased IIx fibers with a decrease in IIa fibers. To confirm the hypothesis that obese subjects might have muscle remodeling after resistance training very different from healthy lean subjects, we subjected a group of nine obese male volunteers to progressive resistance training for a total of 16 wk. In these studies, weight loss was discouraged so that muscle changes would be attributed to the training alone. Detailed assessments included comparisons of histological examinations of needle biopsies of vastus lateralis muscle pretraining and at 8 and 16 wk. Prolonging the training from 8 to 16 wk resulted in increased strength, improved body composition, and more muscle fiber hypertrophy, but euglycemic clamp quantified insulin responsiveness did not improve. Similar to prior studies, muscle fiber composition shifted toward more fast-twitch type IIx fibers (23 to 42%). Eight weeks of resistance training increased the muscle expression of phosphorylated Akt2 and mTOR. Muscle GLUT4 expression increased, although insulin receptor and IRS-1 expression did not change. We conclude that resistance training of prediabetic obese subjects is effective at changing muscle, resulting in fiber hypertrophy and increased type IIx fiber content, and these changes continue up to 16 wk of training.NEW & NOTEWORTHY Obese, insulin-resistant men responded to 16 wk of progressive resistance training with muscle hypertrophy and increased strength and a shift in muscle fiber composition toward fast-twitch, type IIx fibers. Activation of muscle mTOR was increased by 8 wk but did not increase further at 16 wk despite continued augmentation of peak power and rate of force generation. PMID- 28663370 TI - Short-term starvation is a strategy to unravel the cellular capacity of oxidizing specific exogenous/endogenous substrates in mitochondria. AB - Mitochondrial oxidation of nutrients is tightly regulated in response to the cellular environment and changes in energy demands. In vitro studies evaluating the mitochondrial capacity of oxidizing different substrates are important for understanding metabolic shifts in physiological adaptations and pathological conditions, but may be influenced by the nutrients present in the culture medium or by the utilization of endogenous stores. One such influence is exemplified by the Crabtree effect (the glucose-mediated inhibition of mitochondrial respiration) as most in vitro experiments are performed in glucose-containing media. Here, using high-resolution respirometry, we evaluated the oxidation of endogenous or exogenous substrates by cell lines harboring different metabolic profiles. We found that a 1-h deprivation of the main energetic nutrients is an appropriate strategy to abolish interference of endogenous or undesirable exogenous substrates with the cellular capacity of oxidizing specific substrates, namely glutamine, pyruvate, glucose, or palmitate, in mitochondria. This approach primed mitochondria to immediately increase their oxygen consumption after the addition of the exogenous nutrients. All starved cells could oxidize exogenous glutamine, whereas the capacity for oxidizing palmitate was limited to human hepatocarcinoma Huh7 cells and to C2C12 mouse myoblasts that differentiated into myotubes. In the presence of exogenous glucose, starvation decreased the Crabtree effect in Huh7 and C2C12 cells and abrogated it in mouse neuroblastoma N2A cells. Interestingly, the fact that the Crabtree effect was observed only for mitochondrial basal respiration but not for the maximum respiratory capacity suggests it is not caused by a direct effect on the electron transport system. PMID- 28663373 TI - CORP: The assessment of total hemoglobin mass by carbon monoxide rebreathing. AB - In this Cores of Reproducibility in Physiology (CORP) article, we present the theory and practical aspects of the carbon monoxide (CO) rebreathing method for the determination of total hemoglobin mass in humans. With CO rebreathing, a small quantity of CO is diluted in O2 and rebreathed for a specified time period, during which most of the CO is absorbed and bound to circulating hemoglobin. The dilution principle then allows calculation of the total number of circulating hemoglobin molecules based on the number of absorbed CO molecules and the resulting changes in the fraction of carboxyhemoglobin in blood. Total hemoglobin mass is derived by multiplication with the molar weight of hemoglobin. CO rebreathing has been used for >100 yr and has undergone steady improvement so that today excellent values in terms of accuracy and precision can be achieved if the methodological precautions are carefully followed. PMID- 28663371 TI - Functional characterization of a constitutively active kinase variant of Arabidopsis phototropin 1. AB - Phototropins (phots) are plasma membrane-associated serine/threonine kinases that coordinate a range of processes linked to optimizing photosynthetic efficiency in plants. These photoreceptors contain two light-, oxygen-, or voltage-sensing (LOV) domains within their N terminus, with each binding one molecule of flavin mononucleotide as a UV/blue light-absorbing chromophore. Although phots contain two LOV domains, light-induced activation of the C-terminal kinase domain and subsequent receptor autophosphorylation is controlled primarily by the A'alpha LOV2-Jalpha photosensory module. Mutations that disrupt interactions between the LOV2 core and its flanking helical segments can uncouple this mode of light regulation. However, the impact of these mutations on phot function in Arabidopsis has not been explored. Here we report that histidine substitution of Arg-472 located within the A'alpha-helix of Arabidopsis phot1 constitutively activates phot1 kinase activity in vitro without affecting LOV2 photochemistry. Expression analysis of phot1 R472H in the phot-deficient mutant confirmed that it is autophosphorylated in darkness in vivo but unable to initiate phot1 signaling in the absence of light. Instead, we found that phot1 R472H is poorly functional under low-light conditions but can restore phototropism, chloroplast accumulation, stomatal opening, and leaf positioning and expansion at higher light intensities. Our findings suggest that Arabidopsis can adapt to the elevated phosphorylation status of the phot1 R472H mutant in part by reducing its stability, whereas the activity of the mutant under high-light conditions can be attributed to additional increases in LOV2-mediated photoreceptor autophosphorylation. PMID- 28663374 TI - Extra- and intracranial blood flow regulation during the cold pressor test: influence of age. AB - We determined how the extra- and intracranial circulations respond to generalized sympathetic activation evoked by a cold pressor test (CPT) and whether this is affected by healthy aging. Ten young [23 +/- 2 yr (means +/- SD)] and nine older (66 +/- 3 yr) individuals performed a 3-min CPT by immersing the left foot into 0.8 +/- 0.3 degrees C water. Common carotid artery (CCA) and internal carotid artery (ICA) diameter, velocity, and flow were simultaneously measured (duplex ultrasound) along with middle cerebral artery and posterior cerebral artery mean blood velocity (MCAvmean and PCAvmean) and cardiorespiratory variables. The increases in heart rate (~6 beats/min) and mean arterial blood pressure (~14 mmHg) were similar in young and older groups during the CPT (P < 0.01 vs. baseline). In the young group, the CPT elicited an ~5% increase in CCA diameter (P < 0.01 vs. baseline) and a tendency for an increase in CCA flow (~12%, P = 0.08); in contrast, both diameter and flow remained unchanged in the older group. Although ICA diameter was not changed during the CPT in either group, ICA flow increased (~8%, P = 0.02) during the first minute of the CPT in both groups. Whereas the CPT elicited an increase in MCAvmean and PCAvmean in the young group (by ~20 and ~10%, respectively, P < 0.01 vs. baseline), these intracranial velocities were unchanged in the older group. Collectively, during the CPT, these findings suggest a differential mechanism(s) of regulation between the ICA compared with the CCA in young individuals and a blunting of the CCA and intracranial responses in older individuals.NEW & NOTEWORTHY Sympathetic activation evoked by a cold pressor test elicits heterogeneous extra- and intracranial blood vessel responses in young individuals that may serve an important protective role. The extra- and intracranial responses to the cold pressor test are blunted in older individuals. PMID- 28663376 TI - Origin of the forward-going "backward" wave. PMID- 28663375 TI - Sexually dimorphic skeletal muscle and cardiac dysfunction in a mouse model of limb girdle muscular dystrophy 2i. AB - The fukutin-related protein P448L mutant mouse replicates many pathologies common to limb girdle muscular dystrophy 2i (LGMD2i) and is a potentially strong candidate for relevant drug screening studies. Because striated muscle function remains relatively uncharacterized in this mouse, we sought to identify metabolic, functional and histological metrics of exercise and cardiac performance. This was accomplished by quantifying voluntary exercise on running wheels, forced exercise on respiratory treadmills and cardiac output with echocardiography and isoproterenol stress tests. Voluntary exercise revealed few differences between wild-type and P448L mice. By contrast, peak oxygen consumption (VO2peak) was either lower in P448L mice or reduced with repeated low intensity treadmill exercise while it increased in wild-type mice. P448L mice fatigued quicker and ran shorter distances while expending 2-fold more calories/meter. They also received over 6-fold more motivational shocks with repeated exercise. Differences in VO2peak and resting metabolic rate were consistent with left ventricle dysfunction, which often develops in human LGMD2i patients and was more evident in female P448L mice, as indicated by lower fractional shortening and ejection fraction values and higher left ventricle systolic volumes. Several traditional markers of dystrophinopathies were expressed in P448L mice and were exacerbated by exercise, some in a muscle dependent manner. These include elevated serum creatine kinase and muscle central nucleation, smaller muscle fiber cross-sectional area and more striated muscle fibrosis. These studies together identified several markers of disease pathology that are shared between P448L mice and human subjects with LGMD2i. They also identified novel metrics of exercise and cardiac performance that could prove invaluable in preclinical drug trials.NEW & NOTEWORTHY Limb-girdle muscular dystrophy 2i is a rare dystroglycanopathy that until recently lacked an appropriate animal model. Studies with the FKRP P448L mutant mouse began assessing muscle structure and function as well as running gait. Our studies further characterize systemic muscle function using exercise and cardiac performance. They identified many markers of respiratory, cardiac and skeletal muscle function that could prove invaluable to better understanding the disease and more importantly, to preclinical drug trials. PMID- 28663377 TI - Rat supraspinatus tendon responds acutely and chronically to exercise. AB - The objective of this study was to identify acute responses and chronic adaptations of supraspinatus tendon to noninjurious exercise. We hypothesized that chronic exercise (EX) increases tendon mechanical properties, and a single exercise bout increases matrix metalloproteinase (MMP) activity acutely. Rats were divided into acute or chronic EX or cage activity groups. Animals in acute EX groups were euthanized, 3, 12, 24, 48, or 72 h upon completion of a single bout of exercise (10 m/min, 1 h) on a flat treadmill. Animals in chronic EX groups walked on a flat treadmill for 3 days or 1, 2, or 8 wk. Tendon histology, MMP activity, and mechanics were measured. A single bout of exercise trended toward reducing tendon mechanical properties, but 2 or 8 wk of chronic EX increased tendon mechanics. Cell density was not affected. Cells became rounder with chronic EX. All tendons were highly organized. MMP activity decreased after a single bout of exercise and returned to baseline by 72 h. MMP activity decreased after 8 wk of chronic EX. Decreased MMP activity may indicate an anabolic instead of catabolic response in contrast to injury. Results suggest that mild, acute decreases in MMP activity and tendon mechanics following a single exercise bout lead to enhanced tendon mechanical adaptations with repeated exercise bouts. This study defines acute and chronic changes of MMP activity, mechanical properties, and histology of the rat supraspinatus tendon in response to beneficial exercise and proposes a mechanism by which acute responses translate to chronic adaptations.NEW & NOTEWORTHY The line between beneficial exercise and overuse has not been elucidated. This study defines the acute and chronic temporal response to exercise of supraspinatus tendon in an in vivo model. We found that decreased matrix metalloproteinase activity and tendon mechanics after a single bout of exercise are followed by beneficial chronic adaptations of the tendon with repeated bouts. How the acute responses to exercise lead to chronic adaptations may distinguish beneficial exercise from overuse. PMID- 28663378 TI - Factors contributing to lower metabolic demand of eccentric compared with concentric cycling. AB - This study compared muscle-tendon behavior, muscle oxygenation, and muscle activity between eccentric and concentric cycling exercise at the same work output to investigate why metabolic demand is lower during eccentric cycling than with concentric cycling. Eleven untrained men (27.1 +/- 7.0 y) performed concentric cycling (CONC) and eccentric cycling (ECC) for 10 min (60 rpm) at 65% of the maximal concentric cycling power output (191 +/- 45 W) 4 wk apart. During cycling, oxygen consumption (Vo2), heart rate (HR), vastus lateralis (VL) tissue total hemoglobin (tHb), and oxygenation index (TOI) were recorded, and muscle tendon behavior was assessed using ultrasonography. The surface electromyogram (EMG) was recorded from VL, vastus medialis (VM), rectus femoris (RF), and biceps femoris (BF) muscles, and cycling torque and knee joint angle during each revolution were also recorded. Average Vo2 (-65 +/- 7%) and HR (-35 +/- 9%) were lower and average TOI was greater (16 +/- 1%) during ECC than CONC, but tHb was similar between bouts. Positive and negative cycling peak crank torques were greater (32 +/- 21 and 48 +/- 24%, respectively) during ECC than CONC, but muscle tendon unit and fascicle and tendinous tissue length changes during pedal revolutions were similar between CONC and ECC. VL, VM, RF, and BF peak EMG amplitudes were smaller (24 +/- 15, 22 +/- 18, 16 +/- 17, and 18 +/- 9%, respectively) during ECC than CONC. These results suggest that the lower metabolic cost of eccentric compared with concentric cycling was due mainly to a lower level of muscle activation per torque output.NEW & NOTEWORTHY This study shows that lower oxygen consumption of eccentric compared with concentric cycling at the same workload is explained by lower muscle activity of agonist and antagonist muscles during eccentric compared with during concentric cycling. PMID- 28663379 TI - In obese mice, exercise training increases 11beta-HSD1 expression, contributing to glucocorticoid activation and suppression of pulmonary inflammation. AB - Exercise training is advocated for treating chronic inflammation and obesity related metabolic syndromes. Glucocorticoids (GCs), the anti-inflammatory hormones, are synthesized or metabolized in extra-adrenal organs. This study aims to examine whether exercise training affects obesity-associated pulmonary inflammation by regulating local GC synthesis or metabolism. We found that sedentary obese (ob/ob) mice exhibited increased levels of interleukin (IL) 1beta, IL-18, monocyte chemotactic protein (MCP)-1, and leukocyte infiltration in lung tissues compared with lean mice, which was alleviated by 6 wk of exercise training. Pulmonary corticosterone levels were decreased in ob/ob mice. Exercise training increased pulmonary corticosterone levels in both lean and ob/ob mice. Pulmonary corticosterone levels were negatively correlated with IL-1beta, IL-18, and MCP-1. Immunohistochemical staining of the adult mouse lung sections revealed positive immunoreactivities for the steroidogenic acute regulatory protein, the cholesterol side-chain cleavage enzyme (CYP11A1), the steroid 21-hydroxylase (CYP21), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and type 1 and type 2 11beta-hydroxysteroid dehydrogenase (11beta-HSD) but not for 11beta-hydroxylase (CYP11B1). Exercise training significantly increased pulmonary 11beta-HSD1 expression in both lean and ob/ob mice. In contrast, exercise training per se had no effect on pulmonary 11beta-HSD2 expression, although pulmonary 11beta-HSD2 levels in ob/ob mice were significantly higher than in lean mice. RU486, a glucocorticoid receptor antagonist, blocked the anti-inflammatory effects of exercise training in lung tissues of obese mice and increased inflammatory cytokines in lean exercised mice. These findings indicate that exercise training increases pulmonary expression of 11beta-HSD1, thus contributing to local GC activation and suppression of pulmonary inflammation in obese mice.NEW & NOTEWORTHY Treadmill training leads to a significant increase in pulmonary corticosterone levels in ob/ob mice, which is in parallel with the favorable effects of exercise on obesity-associated pulmonary inflammation. Exercise training increases pulmonary 11beta-hydroxysteroid dehydrogenase type 1 (11beta HSD1) expression but has no significant effect on 11beta-HSD2 expression in both lean and ob/ob mice. These findings indicate that exercise training increases pulmonary expression of 11beta-HSD1, thus contributing to local glucocorticoid activation and suppression of pulmonary inflammation in obese mice. PMID- 28663380 TI - Bone microvascular flow differs from skin microvascular flow in response to head down tilt. AB - Loss of hydrostatic pressures in microgravity may alter skin and bone microvascular flows in the lower extremities and potentially reduce wound healing and bone fracture repair. The purpose of this study was to determine the rate at which skin and bone microvascular flows respond to head-down tilt (HDT). We hypothesized that microvascular flows in tibial bone and overlying skin would increase at different rates during HDT. Tibial bone and skin microvascular flows were measured simultaneously using photoplethysmography (PPG) in a total of 17 subjects during sitting (control posture), supine, 6 degrees HDT, 15 degrees HDT, and 30 degrees HDT postures in random order. With greater angles of HDT, bone microvascular flow increased significantly, but skin microvascular flow did not change. Tibial bone microvascular flow increased from the sitting control posture (0.77 +/- 0.41 V) to supine (1.95 +/- 1.01 V, P = 0.001) and from supine posture to 15 degrees HDT (3.74 +/- 2.43 V, P = 0.004) and 30 degrees HDT (3.91 +/- 2.68 V, P = 0.006). Skin microvascular flow increased from sitting (0.703 +/- 0.75 V) to supine (2.19 +/- 1.72 V, P = 0.02) but did not change from supine posture to HDT (P = 1.0). We show for the first time that microcirculatory flows in skin and bone of the leg respond to simulated microgravity at different rates. These altered levels of blood perfusion may affect rates of wound and bone fracture healing in spaceflight.NEW & NOTEWORTHY Our data show that bone microvascular flow increases more than cutaneous blood flow with greater degrees of head-down tilt. A higher level of perfusion in bone may give insight into the bone mineral density loss in lower extremities of astronauts and why similar tissue degradation is not observed in the skin of the same areas. PMID- 28663381 TI - A study of clinical and physiological relations of daily physical activity in precapillary pulmonary hypertension. AB - Daily physical activity is reduced in precapillary pulmonary hypertension (PH), but the underlying mechanisms are inadequately explored. We sought to investigate clinical and physiological relations of daily physical activity and profile differences between less and more active patients with precapillary PH. A prospective, cross-sectional study of 20 patients with precapillary PH who undertook 1) a comprehensive clinical assessment, 2) a preliminary treadmill test, 3) 7-day monitoring of daily walking intensity with triaxial accelerometry, and 4) a personalized treadmill test corresponding to the individual patient mean daily walking intensity with real-time physiological measurements. Significant clinical correlations with individual patient mean walking intensity [1.71 +/- 0.27 (SD) m/s2] were observed for log-transformed N-terminal probrain natriuretic peptide (log NT-proBNP; r = -0.75, P = <.001), age (r = -0.70, P = 0.001), transfer factor for carbon monoxide %predicted (r = 0.51, P = 0.022), and 6-min walk distance (r = 0.50, P = 0.026). Significant physiological correlations were obtained for heart rate reserve (r = 0.68, P = 0.001), quadriceps tissue oxygenation index (Q-[Formula: see text]; r = 0.58, P = 0.008), change in Q [Formula: see text] from rest (r = 0.60, P = 0.006), and ventilatory equivalent for oxygen uptake (r = -0.56, P = 0.013). Stepwise multiple regression analyses retained log NT-proBNP (R2 = 0.55), heart rate reserve (R2 = 0.44), and Q [Formula: see text] (R2 = 0.13) accounting for a significant variance in individual walking intensity. Less active patients had greater physical activity induced cardiopulmonary impairment, worse quadriceps oxygenation profile, and compromised health-related quality of life compared with more active patients. These preliminary findings suggest a significant relation between right ventricular and peripheral muscle oxygenation status and reduced daily physical activity in precapillary PH. Further research is warranted to unravel the physiological determinants, establish clinical predictors, and identify beneficial interventions.NEW & NOTEWORTHY Daily physical activity holds promise to be a meaningful, patient-related outcome measure in pulmonary hypertension. In this study, novel findings in a representative sample of patients with precapillary pulmonary hypertension link reduced daily walking activity, as measured by triaxial accelerometry, with compromised right ventricular and pulmonary vascular status, peripheral muscle oxygenation, and health-related quality of life, providing a preliminary insight into the physiological mechanisms and clinical predictors of daily physical activity in precapillary pulmonary hypertension. PMID- 28663382 TI - Sodium nitrate ingestion increases skeletal muscle nitrate content in humans. AB - Nitrate ([Formula: see text]) ingestion has been shown to have vasoactive and ergogenic effects that have been attributed to increased nitric oxide (NO) production. Recent observations in rodents suggest that skeletal muscle tissue serves as an endogenous [Formula: see text] "reservoir." The present study determined [Formula: see text] contents in human skeletal muscle tissue in a postabsorptive state and following ingestion of a sodium nitrate bolus (NaNO3). Seventeen male, type 2 diabetes patients (age 72 +/- 1 yr; body mass index 26.5 +/- 0.5 kg/m2; means +/- SE) were randomized to ingest a dose of NaNO3 (NIT; 9.3 mg [Formula: see text]/kg body wt) or placebo (PLA; 8.8 mg NaCl/kg body wt). Blood and muscle biopsy samples were taken before and up to 7 h following [Formula: see text] or placebo ingestion to assess [Formula: see text] [and plasma nitrite ([Formula: see text])] concentrations. Additionally, basal plasma and muscle [Formula: see text] concentrations were assessed in 10 healthy young (CON-Y; age 21 +/- 1 yr) and 10 healthy older (CON-O; age 75 +/- 1 yr) control subjects. In all groups, baseline [Formula: see text] concentrations were higher in muscle (NIT, 57 +/- 7; PLA, 61 +/- 7; CON-Y, 80 +/- 10; CON-O, 54 +/- 6 umol/l) than in plasma (NIT, 35 +/- 3; PLA, 32 +/- 3; CON-Y, 38 +/- 3; CON-O, 33 +/- 3 umol/l; P <= 0.011). Ingestion of NaNO3 resulted in a sustained increase in plasma [Formula: see text], plasma [Formula: see text], and muscle [Formula: see text] concentrations (up to 185 +/- 25 umol/l) in the NIT group (time effect P < 0.001) compared with PLA (treatment effect P < 0.05). In conclusion, basal [Formula: see text] concentrations are substantially higher in human skeletal muscle tissue compared with plasma. Ingestion of a bolus of dietary [Formula: see text] increases both plasma and muscle [Formula: see text] contents in humans.NEW & NOTEWORTHY Literature of the pharmacokinetics following dietary nitrate ingestion is usually limited to the changes observed in plasma nitrate and nitrite concentrations. The present investigation assessed the skeletal muscle nitrate content in humans during the postabsorptive state, as well as following dietary nitrate ingestion. We show that basal nitrate content is higher in skeletal muscle tissue than in plasma and that ingestion of a dietary nitrate bolus strongly increases both plasma and muscle nitrate concentrations. PMID- 28663383 TI - My Child Is Islet Autoantibody Positive: Impact on Parental Anxiety. AB - OBJECTIVE: To assess parent anxiety in response to genetic and islet autoantibody (IA) testing in children at increased genetic risk for type 1 diabetes followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS: Parent anxiety about TEDDY children's risk was assessed with the State Anxiety Inventory (SAI). Parents completed the SAI when the child was 3, 6, and 15 months old and annually thereafter. Children were tested for IA every 3 months for 4 years and every 6 months thereafter. Parent SAI scores of 6,799 children followed with IA testing for at least 1 and up to 6 years were examined. RESULTS: At study inception, parents showed high levels of anxiety in response to their child's increased genetic type 1 diabetes risk; mothers were more anxious than fathers, and parents with diabetes in the family were more anxious than parents with no family history. In response to repeated IA negative (IA-) test results, parent anxiety declined to normal levels. Anxiety increased in parents faced with an IA-positive (IA+) test result. Parents faced with two or more types of IA+ test results showed particularly high levels of anxiety (all P < 0.001). CONCLUSIONS: Infant genetic screening for type 1 diabetes raises parent anxiety when the child is at increased risk, but anxiety dissipates over time in cases of repeated IA- results. IA+ results heighten parent anxiety, and parents faced with two or more types of IA+ results may experience considerable anxiety for longer periods. PMID- 28663384 TI - Computed Tomography Angiography Images of Coronary Artery Stenosis Provide a Better Prediction of Risk Than Traditional Risk Factors in Asymptomatic Individuals With Type 2 Diabetes: A Long-term Study of Clinical Outcomes. AB - OBJECTIVE: We investigated the efficacy of coronary computed tomography angiography (CCTA) in predicting the long-term risks in asymptomatic patients with type 2 diabetes and compared it with traditional risk factors. RESEARCH DESIGN AND METHODS: We analyzed 933 patients with asymptomatic type 2 diabetes who underwent CCTA. Stenosis was considered obstructive (>=50%) in each coronary artery segment using CCTA. The extent and severity scores for coronary artery disease (CAD) were evaluated. The primary end point was major adverse cardiovascular events (MACE), including all-cause mortality, nonfatal myocardial infarction, and late coronary revascularization during a mean follow-up period of 5.5 +/- 2.1 years. RESULTS: Ninety-four patients with MACE exhibited obstructive CAD with a greater extent and higher severity scores (P < 0.001 for all). After adjusting for confounding risk factors, obstructive CAD remained an independent predictor of MACE (hazard ratio 3.11 [95% CI 2.00-4.86]; P < 0.001]). The performance of a risk prediction model based on C-statistics was significantly improved (C-index 0.788 [95% CI 0.747-0.829]; P = 0.0349) upon the addition of a finding of obstructive CAD using CCTA to traditional risk factors, including age, male, hypertension, hyperlipidemia, smoking, estimated glomerular filtration rate, and HbA1c. Both integrated discrimination improvement (IDI) and net reclassification improvement (NRI) analyses further supported this finding (IDI 0.046 [95% CI 0.020-0.072], P < 0.001, and NRI 0.55 [95% CI 0.343-0.757], P < 0.001). In contrast, the risk prediction power of the coronary artery calcium score remained unimproved (C-index 0.740, P = 0.547). CONCLUSIONS: Based on our data, the addition of CCTA-detected obstructive CAD to models that include traditional risk factors improves the predictions of MACE in asymptomatic patients with type 2 diabetes. PMID- 28663385 TI - Re-examining the role of Cdc14 phosphatase in reversal of Cdk phosphorylation during mitotic exit. AB - Inactivation of cyclin-dependent kinase (Cdk) and reversal of Cdk phosphorylation are universally required for mitotic exit. In budding yeast (Saccharomyces cerevisiae), Cdc14 is essential for both and thought to be the major Cdk counteracting phosphatase. However, Cdc14 is not required for mitotic exit in many eukaryotes, despite highly conserved biochemical properties. The question of how similar enzymes could have such disparate influences on mitotic exit prompted us to re-examine the contribution of budding yeast Cdc14. By using an auxin inducible degron, we show that severe Cdc14 depletion has no effect on the kinetics of mitotic exit and bulk Cdk substrate dephosphorylation, but causes a cell separation defect and is ultimately lethal. Phosphoproteomic analysis revealed that Cdc14 is highly selective for distinct Cdk sites in vivo and does not catalyze widespread Cdk substrate dephosphorylation. We conclude that additional phosphatases likely contribute substantially to Cdk substrate dephosphorylation and coordination of mitotic exit in budding yeast, similar to in other eukaryotes, and the critical mitotic exit functions of Cdc14 require trace amounts of enzyme. We propose that Cdc14 plays very specific, and often different, roles in counteracting Cdk phosphorylation in all species. PMID- 28663386 TI - An improved Akt reporter reveals intra- and inter-cellular heterogeneity and oscillations in signal transduction. AB - Akt is a key node in a range of signal transduction cascades and play a critical role in diseases such as cancer and diabetes. Fluorescently-tagged Akt reporters have been used to discern Akt localisation, yet it has not been clear how well these tools recapitulate the behaviour of endogenous Akt proteins. Here, we observed that fusion of eGFP to Akt2 impaired both its insulin-stimulated plasma membrane recruitment and its phosphorylation. Endogenous-like responses were restored by replacing eGFP with TagRFP-T. The improved response magnitude and sensitivity afforded by TagRFP-T-Akt2 over eGFP-Akt2 enabled monitoring of signalling outcomes in single cells at physiological doses of insulin with subcellular resolution and revealed two previously unreported features of Akt biology. In 3T3-L1 adipocytes, stimulation with insulin resulted in recruitment of Akt2 to the plasma membrane in a polarised fashion. Additionally, we observed oscillations in plasma membrane localised Akt2 in the presence of insulin with a consistent periodicity of 2 min. Our studies highlight the importance of fluorophore choice when generating reporter constructs and shed light on new Akt signalling responses that may encode complex signalling information.This article has an associated First Person interview with the first author of the paper. PMID- 28663387 TI - How much evidence does it take to change practice? PMID- 28663388 TI - When is a simple fracture of the lateral malleolus not so simple? how to assess stability, which ones to fix and the role of the deltoid ligament. AB - Stable fractures of the ankle can be safely treated non-operatively. It is also gradually being recognised that the integrity of the 'medial column' is essential for the stability of the fracture. It is generally thought that bi- and tri malleolar fractures are unstable, as are pronation external rotation injuries resulting in an isolated high fibular fracture (Weber type-C), where the deltoid ligament is damaged or the medial malleolus fractured. However, how best to identify unstable, isolated, trans-syndesmotic Weber type-B supination external rotation (SER) fractures of the lateral malleolus remains controversial. We provide a rationale as to how to classify SER distal fibular fractures using weight-bearing radiographs, and how this can help guide the management of these common injuries. Cite this article: Bone Joint J 2017;99-B:851-5. PMID- 28663389 TI - An epidemic of the use, misuse and overdose of opioids and deaths due to overdose, in the United States and Canada: is Europe next? AB - The United States and Canada are in the midst of an epidemic of the use, misuse and overdose of opioids, and deaths related to overdose. This is the direct result of overstatement of the benefits and understatement of the risks of using opioids by advocates and pharmaceutical companies. Massive amounts of prescription opioids entered the community and were often diverted and misused. Most other parts of the world achieve comparable pain relief using fewer opioids. The misconceptions about opioids that created this epidemic are finding their way around the world. There is particular evidence of the increased prescription of strong opioids in Europe. Opioids are addictive and dangerous. Evidence is mounting that the best pain relief is obtained through resilience. Opioids are often prescribed when treatments to increase resilience would be more effective. Cite this article: Bone Joint J 2017;99-B:856-64. PMID- 28663390 TI - Risk factors for wear-related failures after hip resurfacing in patients with a low contact patch to rim distance. AB - AIMS: A contact patch to rim (CPR) distance of < 10 mm has been associated with edge-loading and excessive wear. However, not all arthroplasties with a low CPR distance show problems with wear. Therefore, CPR distance may not be the only variable affecting the post-operative metal ion concentrations. PATIENTS AND METHODS: We used multiple logistic regression to determine what variables differed between the patients who had high and low cobalt (CoS) and chromium (CrS) serum ion concentrations within a cohort of patients with low (< 10 mm) CPR distances. A total of 56 patients treated with unilateral hip resurfacing arthroplasty (HRA) had CoS and CrS ion studies performed more than one year after surgery. The mean age of the patients at the time of surgery was 51.7 years (29 to 70), with 38 women (68%) and 18 men (32%). RESULTS: It was seen that 47 patients had low ion levels (< 7ug/L) and nine had high ion levels (>= 7ug/L). We found increased risks of high wear with decreasing CPR distance. CONCLUSION: The use of CPR distance measurements to predict hips at risk for elevated wear is needed for all patients with HRA. We recommend that patients with low CPR distances have at least one serum ion study performed while patients with CPR distance > 10 mm do not need routine ion studies. We believe that patients with low CPR distance and low ions do not need repeat ion studies unless the patient becomes symptomatic or has substantial radiographic changes. Cite this article: Bone Joint J 2017;99-B:865-71. PMID- 28663391 TI - Equalisation of leg lengths in total hip arthroplasty for patients with Crowe type-IV developmental dysplasia of the hip: classification and management. AB - AIMS: There is no consensus about the best method of achieving equal leg lengths at total hip arthroplasty (THA) in patients with Crowe type-IV developmental dysplasia of the hip (DDH). We reviewed our experience of a consecutive series of patients who underwent THA for this indication. PATIENTS AND METHODS: We retrospectively reviewed 78 patients (86 THAs) with Crowe type-IV DDH, including 64 women and 14 men, with a minimum follow-up of two years. The mean age at the time of surgery was 52.2 years (34 to 82). We subdivided Crowe type-IV DDH into two major types according to the number of dislocated hips, and further categorised them into three groups according to the occurrence of pelvic obliquity or spinal curvature. Leg length discrepancy (LLD) and functional scores were analysed. RESULTS: Type-I included 53 patients with unilateral dislocation, in which 25 (category A) had no pelvic obliquity or spinal deformity, 19 (category B) had pelvic obliquity with a compensated spinal curvature and nine (category C) had pelvic obliquity and decompensated spinal degenerative changes. Type-II included 25 patients with one dislocated and one dysplastic hip, in which there were eight of category A, 15 of category B and two of category C. Pre operatively, there were significant differences between the anatomical and functional LLD in type-IB (p = 0.005) and -IC (p < 0.001), but not in type-IA, IIA or -IIB. Post-operatively, bony LLD increased significantly in types-IB, -IC and -IIB, whereas functional LLD decreased significantly in each type except for IIA. The mean functional LLD decreased from 30.7 mm (standard deviation (sd) 18.5) pre-operatively to 6.2 mm (sd 4.4) post-operatively and the mean anatomical LLD improved from 35.8 mm (sd 19.7) pre-operatively to 12.4 mm (sd 8.3) post operatively. CONCLUSION: Pelvic and spinal changes are common in patients with Crowe type-IV DDH and need to be taken into consideration when planning THA, in order to obtain equal leg lengths post-operatively. The principal subdivisions of Crowe type-IV DDH which we describe proved effective in achieving equal leg lengths and satisfactory outcomes. Cite this article: Bone Joint J 2017;99-B:872 9. PMID- 28663392 TI - Promising early results for trabecular metal acetabular components used at revision total hip arthroplasty: 42 acetabular revisions followed with radiostereometry in a prospective randomised trial. AB - AIMS: The aim of this study was to compare the incidence of aseptic loosening after the use of a cemented acetabular component and a Trabecular Metal (TM) acetabular component (Zimmer Inc., Warsaw, Indiana) at acetabular revision with bone impaction grafting. PATIENTS AND METHODS: A total of 42 patients were included in the study. Patients were randomised to receive an all- polyethylene cemented acetabular component (n = 19) or a TM component (n = 23). Radiostereometric analysis and conventional radiographic examinations were performed regularly up to two years post-operatively or until further revision. RESULTS: The proximal migration was significantly higher in the cemented group. At two years, the median proximal migration was 1.45 mm and 0.25 mm in the cemented and TM groups, respectively (p = 0.02). One cemented component was revised due to dislocation. There were no revisions in the TM group. CONCLUSION: Lower proximal migration in the TM group suggests that this design might be associated with a lower risk of aseptic loosening in the long term compared with an all polyethylene cemented component. Longer follow-up is required to confirm the clinical advantages of using this component at acetabular revision. Cite this article: Bone Joint J 2017;99-B:880-6. PMID- 28663393 TI - The prevention of a lateral hinge fracture as a complication of a medial opening wedge high tibial osteotomy: a case control study. AB - AIMS: We aimed to investigate factors related to the technique of medial opening wedge high tibial osteotomy which might predispose to the development of a lateral hinge fracture. PATIENTS AND METHODS: A total of 71 patients with 82 osteotomies were included in the study. Their mean age was 62.9 years (37 to 80). The classification of the type of osteotomy was based on whether it extended beyond the fibular head. The level of the osteotomy was classified according to the height of its endpoint. RESULTS: At a mean follow-up of 20 months (6 to 52), a total of 15 lateral hinge fractures (18.3%) were identified. A sufficient osteotomy, in which both anterior and posterior tibial cortices were involved with extension into the lateral aspect of the plateau in relation to an anteroposterior line tangential to the medial edge of the fibular head in the CT axial plane, was seen in 48 knees (71.6%) in those without a lateral hinge fracture and in seven (46.7%) in those with a lateral hinge fracture. An osteotomy which ended above the level of the fibular head was seen in nine (13.4%) of the knees without a lateral hinge fracture and seven (46.7%) of the those with a lateral hinge fracture. There was a significant relationship between the absence of a lateral hinge fracture and both a sufficient osteotomy and one whose endpoint was at the level of the fibular head (p = 0.0451 and p = 0.0214, respectively). CONCLUSION: A sufficient osteotomy involving both the anterior and posterior cortices, whose endpoint is at the level of the fibular head, should be performed when undertaking a medial opening wedge high tibial osteotomy if a lateral hinge fracture is to be avoided as a complication. Cite this article: Bone Joint J 2017;99-B:887-93. PMID- 28663394 TI - External rotation of the femoral component increases asymmetry of the posterior condyles. AB - AIMS: The morphometry of the distal femur was largely studied to improve bone implant fit in total knee arthroplasty (TKA), but little is known about the asymmetry of the posterior condyles. This study aimed to investigate the dimensions of the posterior condyles and the influence of externally rotating the femoral component on potential prosthetic overhang or under-coverage. PATIENTS AND METHODS: We analysed the shape of 110 arthritic knees at the time of primary TKA using pre-operative CT scans. The height and width of each condyle were measured at the posterior femoral cut in neutral position, and in 3o and 5o of external rotation, using both central and medial referencing systems. We compared the morphological characteristics with those of 14 TKA models. RESULTS: In the neutral position, the dimensions of the condyles were nearly equal. Externally rotating the femoral cut by 3o and 5o with 'central referencing' induced width asymmetry > 3 mm in 23 (21%) and 33 (30%) knees respectively, while with 'medial referencing' it induced width asymmetry > 3 mm in 43 (39%) and 75 (68%) knees respectively. The asymmetries induced by rotations were not associated with gender, aetiology or varus-valgus alignment. CONCLUSION: External rotation may amplify the asymmetry between the medial and lateral condyles, and exacerbate prosthetic overhang, particularly in the superolateral zone. 'Central referencing' guides result in less potential prosthetic overhang than 'medial referencing' guides. Cite this article: Bone Joint J 2017;99-B:894-903. PMID- 28663396 TI - Proximalisation of the tibial tubercle gives a good outcome in patients undergoing revision total knee arthroplasty who have pseudo patella baja. AB - AIMS: The aim of this study was to compare the outcome of revision total knee arthroplasty (TKA) with and without proximalisation of the tibial tubercle in patients with a failed primary TKA who have pseudo patella baja. PATIENTS AND METHODS: All revision TKAs, performed between January 2008 and November 2013 at a tertiary referral University Orthopaedic Department were retrospectively reviewed. Pseudo patella baja was defined using the modified Insall-Salvati and the Blackburne-Peel ratios. A proximalisation of the tibial tubercle was performed in 13 patients with pseudo patella baja who were matched with a control group of 13 patients for gender, age, height, weight, body mass index, length of surgery and Blackburne-Peel ratio. Outcome was assessed two years post operatively using the Knee Society Score (KSS). RESULTS: The increase in KSS was significantly higher in the osteotomy group compared with the control group. The outcome was statistically better in patients in whom proximalisation of > 1 cm had been achieved compared with those in whom the proximalisation was < 1 cm. CONCLUSION: In this retrospective case-control study, a proximal transfer of the tibial tubercle at revision TKA in patients with pseudo patella baja gives good outcomes without major complications. Cite this article: Bone Joint J 2017;99 B:912-16. PMID- 28663395 TI - A pragmatic randomised controlled trial comparing the efficacy of a femoral nerve block and periarticular infiltration for early pain relief following total knee arthroplasty. AB - AIMS: The aim of this study was to compare the effectiveness of a femoral nerve block and a periarticular infiltration in the management of early post-operative pain after total knee arthroplasty (TKA). PATIENTS AND METHODS: A pragmatic, single centre, two arm parallel group, patient blinded, randomised controlled trial was undertaken. All patients due for TKA were eligible. Exclusion criteria included contraindications to the medications involved in the study and patients with a neurological abnormality of the lower limb. Patients received either a femoral nerve block with 75 mg of 0.25% levobupivacaine hydrochloride around the nerve, or periarticular infiltration with 150 mg of 0.25% levobupivacaine hydrochloride, 10 mg morphine sulphate, 30 mg ketorolac trometamol and 0.25 mg of adrenaline all diluted with 0.9% saline to make a volume of 150 ml. RESULTS: A total of 264 patients were recruited and data from 230 (88%) were available for the primary analysis. Intention-to-treat analysis of the primary outcome measure of a visual analogue score for pain on the first post-operative day, prior to physiotherapy, was similar in both groups. The mean difference was -0.7 (95% confidence interval (CI) -5.9 to 4.5; p = 0.834). The periarticular group used less morphine in the first post-operative day compared with the femoral nerve block group (74%, 95% CI 55 to 99). The femoral nerve block group reported 39 adverse events, of which 27 were serious, in 31 patients and the periarticular group reported 51 adverse events, of which 38 were serious, in 42 patients up to six weeks post-operatively. None of the adverse events were directly attributed to either of the interventions under investigation. CONCLUSION: Periarticular infiltration is a viable and safe alternative to femoral nerve block for the early post-operative relief of pain following TKA. Cite this article: Bone Joint J 2017;99-B:904-11. PMID- 28663397 TI - Primary hip and knee arthroplasty in a temporary operating theatre is associated with a significant increase in deep periprosthetic infection. AB - AIMS: Infection following total hip or knee arthroplasty is a serious complication. We noted an increase in post-operative infection in cases carried out in temporary operating theatres. We therefore compared those cases performed in standard and temporary operating theatres and examined the deep periprosthetic infection rates. PATIENTS AND METHODS: A total of 1223 primary hip and knee arthroplasties were performed between August 2012 and June 2013. A total of 539 (44%) were performed in temporary theatres. The two groups were matched for age, gender, body mass index and American Society of Anesthesiologists grade. RESULTS: The deep infection rate for standard operating theatres was 0 of 684 (0%); for temporary theatres it was eight of 539 (1.5%) (p = 0.001). CONCLUSION: Use of a temporary operating theatre for primary hip and knee arthroplasty was associated with an unacceptable increase in deep infection. We do not advocate the use of these theatres for primary joint arthroplasty. Cite this article: Bone Joint J 2017;99-B:917-20. PMID- 28663398 TI - Cardiac disease and advanced age increase the mortality risk following surgery for periprosthetic femoral fractures. AB - AIMS: Periprosthetic fracture is a significant complication of total hip and knee arthroplasty. This study aimed to describe the survival of patients sustaining periprosthetic femoral fractures and compare this with that of the general population, as well as to identify the factors that influence survival. PATIENTS AND METHODS: A total of 151 patients (women: men 116:35, mean age 74.6 years, standard deviation 11.5) that sustained a periprosthetic fracture between January 2005 and October 2012 were retrospectively analysed. Epidemiological data, comorbidities, type of surgical management, type of implant, and mortality data were studied. RESULTS: The mean survival time was 77 months (95% confidence interval 71 to 84; numbers at risk: 73) and was lower than that of the general population. The risk analyses showed that previous cardiac disease, particularly ischaemic heart disease, cardiac arrhythmias, and heart failure, age over 75 years and American Society of Anesthesiologists (ASA) scores above 3 were associated with a significantly higher mortality. CONCLUSIONS: Periprosthetic fractures carry a high risk of post-operative mortality. Our data demonstrate that advanced age (> 75 years) and previous cardiac disease are associated with a significantly higher risk of mortality. The ASA score is an appropriate instrument for risk stratification. Pre-operative cardiac status should be optimised before surgery. Cite this article: Bone Joint J 2017;99-B:921-6. PMID- 28663399 TI - Prediction of the pre-morbid 3D anatomy of the proximal humerus based on statistical shape modelling. AB - AIMS: Restoring the pre-morbid anatomy of the proximal humerus is a goal of anatomical shoulder arthroplasty, but reliance is placed on the surgeon's experience and on anatomical estimations. The purpose of this study was to present a novel method, 'Statistical Shape Modelling', which accurately predicts the pre-morbid proximal humeral anatomy and calculates the 3D geometric parameters needed to restore normal anatomy in patients with severe degenerative osteoarthritis or a fracture of the proximal humerus. MATERIALS AND METHODS: From a database of 57 humeral CT scans 3D humeral reconstructions were manually created. The reconstructions were used to construct a statistical shape model (SSM), which was then tested on a second set of 52 scans. For each humerus in the second set, 3D reconstructions of four diaphyseal segments of varying lengths were created. These reconstructions were chosen to mimic severe osteoarthritis, a fracture of the surgical neck of the humerus and a proximal humeral fracture with diaphyseal extension. The SSM was then applied to the diaphyseal segments to see how well it predicted proximal morphology, using the actual proximal humeral morphology for comparison. RESULTS: With the metaphysis included, mimicking osteoarthritis, the errors of prediction for retroversion, inclination, height, radius of curvature and posterior and medial offset of the head of the humerus were 2.9 degrees (+/- 2.3 degrees ), 4.0 degrees (+/- 3.3 degrees ), 1.0 mm (+/ 0.8 mm), 0.8 mm (+/- 0.6 mm), 0.7 mm (+/- 0.5 mm) and 1.0 mm (+/- 0.7 mm), respectively. With the metaphysis excluded, mimicking a fracture of the surgical neck, the errors of prediction for retroversion, inclination, height, radius of curvature and posterior and medial offset of the head of the humerus were 3.8 degrees (+/- 2.9 degrees ), 3.9 degrees (+/- 3.4 degrees ), 2.4 mm (+/- 1.9 mm), 1.3 mm (+/- 0.9 mm), 0.8 mm (+/- 0.5 mm) and 0.9 mm (+/- 0.6 mm), respectively. CONCLUSION: This study reports a novel, computerised method that accurately predicts the pre-morbid proximal humeral anatomy even in challenging situations. This information can be used in the surgical planning and operative reconstruction of patients with severe degenerative osteoarthritis or with a fracture of the proximal humerus. Cite this article: Bone Joint J 2017;99-B:927 33. PMID- 28663400 TI - Comparative outcomes of outpatient and inpatient total shoulder arthroplasty: an analysis of the Medicare dataset. AB - AIMS: The aim of the present study was to compare the 30- and 90-day re-admission rates and complication rates of outpatient and inpatient total shoulder arthroplasty (TSA). PATIENTS AND METHODS: The United States Medicare Standard Analytical Files database was questioned to identify patients who had undergone outpatient or inpatient TSA between 2005 and 2012. Patient characteristics were compared between the two groups using chi-squared analysis. Multivariate logistic regression analysis was used to control for differences in baseline patient characteristics and to compare the two groups in terms of post-operative complications within 90 days and re-admission within 30 days and 90 days. RESULTS: A total of 123 347 Medicare subscribers underwent TSA between 2005 and 2012; 3493 (2.8%) had the procedure performed as an outpatient. A significantly greater proportion of patients who underwent TSA as inpatients were women, had a history of smoking, and had a greater incidence of medical comorbidity including diabetes, coronary artery disease, congestive heart failure, and chronic kidney disease (p < 0.05 for all). Re-admission rates were significantly higher for inpatients at both 30 days (0.83% versus 0.60%, p = 0.016, odds ratio 1.8) and 90 days (2.87% versus 2.04%, p < 0.001, odds ratio 1.8). Complications, including thromboembolic events (p < 0.001) and surgical site infection (p = 0.002), were significantly higher in inpatients. CONCLUSION: Patients who underwent TSA on an outpatient basis were overall younger and healthier than those who had inpatient surgery, which suggests that patient selection was taking place. After controlling for age, gender, and medical conditions, patients who underwent TSA as outpatients had lower rates of 30- and 90-day re-admission and a lower rate of complications than inpatients. Cite this article: Bone Joint J 2017;99-B:934-8. PMID- 28663401 TI - The medium- and long-term outcome of total shoulder arthroplasty for primary glenohumeral osteoarthritis in middle-aged patients. AB - AIMS: Promising medium-term results from total shoulder arthroplasty (TSA) have been reported for the treatment of primary osteoarthritis in young and middle aged patients. The aim of this study was to evaluate the long-term functional and radiological outcome of TSA in the middle-aged patient. PATIENTS AND METHODS: The data of all patients from the previous medium-term study were available. At a mean follow-up of 13 years (8 to 17), we reviewed 21 patients (12 men, nine women, 21 shoulders) with a mean age of 55 years (37 to 60). The Constant-Murley score (CS) with its subgroups and subjective satisfaction were measured. Radiological signs of implant loosening were analysed. RESULTS: Two shoulders (two patients) were revised and in two shoulders of two different patients, revision surgery was recommended. The mean CS increased from 23.3 (10 to 45) pre operatively to 56.5 (26 to 81; p < 0.0001), but with a decrease in CS from 62.8 (38 to 93) to 56.5 (26 to 81) between medium- and long-term follow-up (p = 0.01). Without revision surgery, 18 patients (95%) rated their result as good or very good. The mean radiolucent line score for the glenoid components increased from 1.8 (0 to 6) to 8.2 (2 to 18) between medium- and long-term follow-up (p < 0.001). CONCLUSION: TSA in young and middle-aged patients leads to improvement in clinical function and a relatively high satisfaction rate. However, clinical or radiological glenoid loosening worsens in the long term. Further studies are needed to optimise the treatment options in this patient population. Cite this article: Bone Joint J 2017;99-B:939-43. PMID- 28663402 TI - Radiation reduction of minimally invasive transforaminal lumbar interbody fusion with localisation system in overweight patients: practical technique. AB - AIMS: Minimally invasive transforaminal lumbar interbody fusion (MITLIF) has been well validated in overweight and obese patients who are consequently subject to a higher radiation exposure. This prospective multicentre study aimed to investigate the efficacy of a novel lumbar localisation system for MITLIF in overweight patients. PATIENTS AND METHODS: The initial study group consisted of 175 patients. After excluding 49 patients for various reasons, 126 patients were divided into two groups. Those in Group A were treated using the localisation system while those in Group B were treated by conventional means. The primary outcomes were the effective radiation dosage to the surgeon and the exposure time. RESULTS: There were 62 patients in Group A and 64 in Group B. The mean effective dosage was 0.0217 mSv (standard deviation (sd) 0.0079) in Group A and 0.0383 mSv (sd 0.0104) in Group B (p < 0.001). The mean fluoroscopy exposure time was 26.42 seconds (sd 5.91) in Group A and 40.67 seconds (sd 8.18) in Group B (p < 0.001). The operating time was 175.56 minutes (sd 32.23) and 206.08 minutes (sd 30.15) (p < 0.001), respectively. The mean pre-operative localisation time was 4.73 minutes (sd 0.84) in Group A and 7.03 minutes (sd 1.51) in Group B (p < 0.001). The mean screw placement time was 47.37 minutes (sd 10.43) in Group A and 67.86 minutes (sd 14.15) in Group B (p < 0.001). The pedicle screw violation rate was 0.35% (one out of 283) in Group A and 2.79% (eight out of 287) in Group B (p = 0.020). CONCLUSION: The study shows that the localisation system can effectively reduce radiation exposure, exposure time, operating time, pre operative localisation time, and screw placement time in overweight patients undergoing MITLIF. Cite this article: Bone Joint J 2017;99-B:944-50. PMID- 28663403 TI - 'Modern' distal femoral locking plates allow safe, early weight-bearing with a high rate of union and low rate of failure: five-year experience from a United Kingdom major trauma centre. AB - AIMS: Fractures of the distal femur can be challenging to manage and are on the increase in the elderly osteoporotic population. Management with casting or bracing can unacceptably limit a patient's ability to bear weight, but historically, operative fixation has been associated with a high rate of re operation. In this study, we describe the outcomes of fixation using modern implants within a strategy of early return to function. PATIENTS AND METHODS: All patients treated at our centre with lateral distal femoral locking plates (LDFLP) between 2009 and 2014 were identified. Fracture classification and operative information including weight-bearing status, rates of union, re-operation, failure of implants and mortality rate, were recorded. RESULTS: A total of 127 fractures were identified in 122 patients. The mean age was 72.8 years (16 to 101) and 92 of the patients (75%) were female. A consultant performed the operation in 85 of the cases, (67%) with the remainder performed under direct consultant supervision. In total 107 patients (84%) were allowed to bear full weight immediately. The rate of clinical and radiological union was 81/85 (95%) and only four fractures of 127 (3%) fractures required re-operation for failure of surgery. The 30-day, three- and 12-month mortality rates were 6 (5%), 17 (15%) and 25 (22%), respectively. CONCLUSION: Our study suggests an exponential increase in the incidence of a fracture of the distal femur with age, analogous to the population suffering from a proximal femoral fracture. Allowing immediate unrestricted weight-bearing after LDFLP fixation in these elderly patients was not associated with failure of fixation. There was a high rate of union and low rate of re-operation. Cite this article: Bone Joint J 2017;99-B:951-7. PMID- 28663404 TI - Outcomes after early return to theatre following hip hemiarthroplasty for intracapsular fracture of the femoral neck. AB - AIMS: Hip hemiarthroplasty is a standard treatment for intracapsular proximal femoral fractures in the frail elderly. In this study we have explored the implications of early return to theatre, within 30 days, on patient outcome following hip hemiarthroplasty. PATIENTS AND METHODS: We retrospectively reviewed the hospital records of all hip hemiarthroplasties performed in our unit between January 2010 and January 2015. Demographic details, medical backround, details of the primary procedure, complications, subsequent procedures requiring return to theatre, re-admissions, discharge destination and death were collected. RESULTS: A total of 705 procedures were included; 428 Austin Moore and 277 Exeter Trauma Stems were used. A total of 34 fractures (in 33 patients) required early return to theatre within 30 days. Age, gender, laterality, time from admission to primary procedure, American Society of Anesthesiologists grade, and implant type were similar for those requiring early return to theatre and those who did not. Early return to theatre was associated with a significantly higher length of stay (mean 33.6 days (7 to 107) versus 18.6 days (0 to 152), p < 0.001), re-admission rate (38.2% versus 8.6%, p < 0.001), and subsequent revision rate (17.6% versus 1.3%, p < 0.001). We found no difference in level of care required on discharge or mortality. CONCLUSION: Proximal femoral fractures are common in the elderly population, with far-reaching medical and economic implications. Factors such as infection or dislocation may require early return to theatre, and this is associated with outcomes which may be both medically and economically detrimental. This illustrates the importance of avoiding early complications to improve longer term outcome. Return to theatre within 30 days is associated with longer length of stay, higher re-admission rate, and higher subsequent revision rate. It may be a useful short-term quality indicator for longer term outcome measures following hip hemiarthroplasty for intracapsular fractures of the proximal femur. Cite this article: Bone Joint J 2017;99-B:958-63. PMID- 28663405 TI - Prospective randomised trial of non-operative versus operative management of olecranon fractures in the elderly. AB - AIMS: The aim of this prospective randomised controlled trial was to compare non operative and operative management for acute isolated displaced fractures of the olecranon in patients aged >= 75 years. PATIENTS AND METHODS: Patients were randomised to either non-operative management or operative management with either tension-band wiring or fixation with a plate. They were reviewed at six weeks, three and six months and one year after the injury. The primary outcome measure was the Disabilities of the Arm, Shoulder and Hand (DASH) score at one year. RESULTS: A total of 19 patients were randomised to non-operative (n = 8) or operative (n = 11; tension-band wiring (n = 9), plate (n = 2)) management. The trial was stopped prematurely as the rate of complications (nine out of 11, 81.8%) in the operative group was considered to be unacceptable. There was, however, no difference in the mean DASH scores between the groups at all times. The mean score was 23 (0 to 59.6) in the non-operative group and 22 (2.5 to 57.8) in the operative group, one year after the injury (p = 0.763). There was no significant difference between groups in the secondary outcome measures of the Broberg and Morrey Score or the Mayo Elbow Score at any time during the one year following injury (all p >= 0.05). CONCLUSION: These data further support the role of primary non-operative management of isolated displaced fractures of the olecranon in the elderly. However, the non-inferiority of non-operative management cannot be proved as the trial was stopped prematurely. Cite this article: Bone Joint J 2017;99-B:964-72. PMID- 28663406 TI - Intercalary allograft augmented with intramedullary cement and plate fixation is a reliable solution after resection of a diaphyseal tumour. AB - AIMS: Intercalary allografts following resection of a primary diaphyseal tumour have high rates of complications and failures. At our institution intercalary allografts are augmented with intramedullary cement and fixed using compression plating. Our aim was to evaluate their long-term outcomes. PATIENTS AND METHODS: A total of 46 patients underwent reconstruction with an intercalary allograft between 1989 and 2014. The patients had a mean age of 32.8 years (14 to 77). The most common diagnoses were osteosarcoma (n = 16) and chondrosarcoma (n = 9). The location of the tumours was in the femur in 21, the tibia in 16 and the humerus in nine. Function was assessed using the Musculoskeletal Tumor Society (MSTS) scoring system and the Toronto Extremity Salvage Score (TESS). The survival of the graft and the overall survival were assessed using the Kaplan-Meier method. RESULTS: The median follow-up was 92 months (4 to 288). The mean MSTS 87 score was 29.1 (19 to 35), the mean MSTS 93 score was 82.2 (50 to 100) and the mean TESS score was 81.2 (43 to 100). Overall survival of the allograft was 84.8%. A total of 15 patients (33%) had a complication. Five allografts were revised for complications and one for local recurrence. CONCLUSION: Intercalary allografts augmented with intramedullary cement and compression plate fixation provide a reliable and durable method of reconstruction after the excision of a primary diaphyseal bone tumour, with high levels of function and satisfaction. Cite this article: Bone Joint J 2017;99-B:973-8. PMID- 28663407 TI - Quality of life after resection of a chordoma of the mobile spine. AB - AIMS: The aim of the study was to compare measures of the quality of life (QOL) after resection of a chordoma of the mobile spine with the national averages in the United States and to assess which factors influenced the QOL, symptoms of anxiety and depression, and coping with pain post-operatively in these patients. PATIENTS AND METHODS: A total of 48 consecutive patients who underwent resection of a primary or recurrent chordoma of the mobile spine between 2000 and 2015 were included. A total of 34 patients completed a survey at least 12 months post operatively. The primary outcome was the EuroQol-5 Dimensions (EQ-5D-3L) questionnaire. Secondary outcomes were the Patient-Reported Outcome Measurement Information System (PROMIS) anxiety, depression and pain interference questionnaires. Data which were recorded included the indication for surgery, the region of the tumour, the number of levels resected, the status of the surgical margins, re-operations, complications, neurological deficit, length of stay in hospital and rate of re-admission. RESULTS: The median EQ-5D-3L score was 0.71 (interquartile range (IQR) 0.44 to 0.79) which is worse than the national average in the United States of 0.85 (p < 0.001). Anxiety (median: 55 (IQR 49 to 61), p = 0.031) and pain (median: 61 (IQR 56 to 68), p < 0.001) were also worse than the national average in the United States (50), while depression was not (median: 52 (IQR 38 to 57), p = 0.513). Patients who underwent a primary resection had better QOL and less anxiety, depression and pain compared with those who underwent resection for recurrent or residual disease. The one- and five-year probabilities were 0.96 and 0.74 for survival, 0.07 and 0.25 for tumour recurrence, and 0.02 and 0.16 for developing distant metastasis. A total of 25 local complications occurred in 20 patients (42%), and there were 50 systemic and other complications in 25 patients (52%) within 90 days. CONCLUSION: These patient reported outcomes and oncological and surgical outcomes can be used when counselling patients and to aid decision-making when planning surgery. Cite this article: Bone Joint J 2017;99-B:979-86. PMID- 28663408 TI - A long-term follow-up study of the clinical and radiographic outcome of distal trochanteric transfer in Legg-Calve-Perthes' disease following varus derotational osteotomy. AB - AIMS: To assess the long-term effect of distal trochanteric transfer (DTT) on the clinical and radiographic outcomes of patients with Legg-Calve-Perthes' disease (LCPD) following a varus derotational osteotomy (VDRO). PATIENTS AND METHODS: For this single centre cross-sectional retrospective study we analysed the data of 22 patients (24 hips) with LCPD who had greater trochanteric overgrowth (GTO), following a VDRO performed in our institution between 1959 and 1983. GTO was defined as an articular trochanteric distance (ATD) of < 5 mm. We compared the radiographic and clinical outcomes of patients who underwent DTT for GTO (ten patients, ten hips) with those who did not (12 patients, 14 hips). Age at presentation was 6.9 years (4 to 10) and 8.0 years (3.2 to 12) respectively. Symptoms associated with the hip and general quality of life were assessed using the Harris hip score (HHS) and the Short Form (SF)-36 questionnaires. RESULTS: At long-term follow-up of the DTT group, the ATD was 21.7 mm (standard deviation (sd) 9.8) and the centro-trochanteric distance (CTD) was 13.8 mm (sd 8.3). In the control group the ATD was -0.6 mm (sd 7.8) and the CTD was 32.5 mm (sd 10.2). These differences were statistically significant (p < 0.001). The mean HHS and SF 36 scores were 68.4 (sd 25.0) and 62.0 (sd 27.7) for the DTT group and 73.2 (sd 24.2) and 73.3 (sd 21.5) for the control group, respectively. There was no statistically significant difference in the HHS (p = 0.63) or SF-36 score (p = 0.25). There were four patients who had undergone hip arthroplasty in the DTT group (40%) and one patient (7.1%) in the control group (p = 0.07). The mean age at the time of arthroplasty was 45.3 years (42.1 to 56.5) and 43.6 years respectively. Six patients in the DTT group suffered from moderate to severe osteoarthritis (Tonnis grade 2 or 3) compared with eight patients in the control group (60% versus 57.1%, p = 0.61). CONCLUSION: Although DTT improved the radiographic results in the long-term follow-up of patients with GTO following VDRO, there was no clinical benefit seen in the HHS, SF-36 or incidence of osteoarthritis compared with patients who had not undergone DTT. Cite this article: Bone Joint J 2017;99-B:987-92. PMID- 28663409 TI - Persistent vegetative state and minimally conscious state: ethical, legal and practical dilemmas. PMID- 28663410 TI - Procedure, practice and legal requirements: a commentary on 'Why I wrote my advance decision'. PMID- 28663411 TI - Random Access. PMID- 28663412 TI - Realising the full potential of primary care: uniting the 'two faces' of generalism. PMID- 28663413 TI - Improving together: a new quality framework for GP clusters in Scotland. PMID- 28663414 TI - Should we screen for atrial fibrillation? PMID- 28663415 TI - Non-invasive prenatal testing: use of cell-free fetal DNA in Down syndrome screening. PMID- 28663416 TI - Multimorbidity: what next? PMID- 28663417 TI - When the words 'handover' and 'prioritise' are overused. PMID- 28663418 TI - The NHS: have the rivets popped? PMID- 28663419 TI - Dangerous Ideas: GPs should stop prescribing opioid medication except for palliative care. PMID- 28663420 TI - Good enough is good enough! PMID- 28663421 TI - The Republicans go over the cliff: the losing case to replace Obamacare. PMID- 28663422 TI - What it's like to be a transgender patient and a GP. PMID- 28663423 TI - Bad Medicine: Good medicine - the GP paramedic. PMID- 28663424 TI - Yonder: Loneliness, breast cancer, medically unexplained symptoms, and delivering babies. PMID- 28663425 TI - Exhibition: David Hockney and the BJGP. PMID- 28663426 TI - Exhibition: Giacometti Reimagined. PMID- 28663427 TI - Books: Utopia for Realists: and How We Can Get There: A New Source of Hope. PMID- 28663428 TI - Books: Challenging Perspectives on Organizational Change in Health Care: Change in the Right Way. PMID- 28663429 TI - The unheralded. PMID- 28663430 TI - Identifying high-frequency attendees in general practice. PMID- 28663431 TI - HIV pre-exposure prophylaxis: the primary care implications of prescribing restrictions. PMID- 28663432 TI - Practical guidance on heart failure diagnosis and management in primary care: recent EPCCS recommendations. PMID- 28663433 TI - Why worry about bisphosphonate-related osteonecrosis of the jaw? A guide to diagnosis, initial management, and referral of patients. PMID- 28663434 TI - Practice that suspended GP who later died by suicide used "a sledgehammer to crack a nut," says coroner. PMID- 28663435 TI - Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity. AB - CD8+ T cells mediate antigen-specific immune responses that can induce rejection of solid tumors. In this process, dendritic cells (DCs) are thought to take up tumor antigens, which are processed into peptides and loaded onto MHC-I molecules, a process called "cross-presentation." Neither the actual contribution of cross-presentation to antitumor immune responses nor the intracellular pathways involved in vivo are clearly established because of the lack of experimental tools to manipulate this process. To develop such tools, we generated mice bearing a conditional DC-specific mutation in the sec22b gene, a critical regulator of endoplasmic reticulum-phagosome traffic required for cross presentation. DCs from these mice show impaired cross-presentation ex vivo and defective cross-priming of CD8+ T cell responses in vivo. These mice are also defective for antitumor immune responses and are resistant to treatment with anti PD-1. We conclude that Sec22b-dependent cross-presentation in DCs is required to initiate CD8+ T cell responses to dead cells and to induce effective antitumor immune responses during anti-PD-1 treatment in mice. PMID- 28663437 TI - 2017 ACC/AAP/AHA Health Policy Statement on Opportunities and Challenges in Pediatric Drug Development: Learning From Sildenafil. PMID- 28663436 TI - Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation. AB - Despite frequent herpes simplex virus (HSV) reactivation, peripheral nerve destruction and sensory anesthesia are rare. We discovered that skin biopsies obtained during asymptomatic human HSV-2 reactivation exhibit a higher density of nerve fibers relative to biopsies during virological and clinical quiescence. We evaluated the effects of HSV infection on keratinocytes, the initial target of HSV replication, to better understand this observation. Keratinocytes produced IL 17c during HSV-2 reactivation, and IL-17RE, an IL-17c-specific receptor, was expressed on nerve fibers in human skin and sensory neurons in dorsal root ganglia. In ex vivo experiments, exogenous human IL-17c provided directional guidance and promoted neurite growth and branching in microfluidic devices. Exogenous murine IL-17c pretreatment reduced apoptosis in HSV-2-infected primary neurons. These results suggest that IL-17c is a neurotrophic cytokine that protects peripheral nerve systems during HSV reactivation. This mechanism could explain the lack of nerve damage from recurrent HSV infection and may provide insight to understanding and treating sensory peripheral neuropathies. PMID- 28663438 TI - Bismuthene on a SiC substrate: A candidate for a high-temperature quantum spin Hall material. AB - Quantum spin Hall materials hold the promise of revolutionary devices with dissipationless spin currents but have required cryogenic temperatures owing to small energy gaps. Here we show theoretically that a room-temperature regime with a large energy gap may be achievable within a paradigm that exploits the atomic spin-orbit coupling. The concept is based on a substrate-supported monolayer of a high-atomic number element and is experimentally realized as a bismuth honeycomb lattice on top of the insulating silicon carbide substrate SiC(0001). Using scanning tunneling spectroscopy, we detect a gap of ~0.8 electron volt and conductive edge states consistent with theory. Our combined theoretical and experimental results demonstrate a concept for a quantum spin Hall wide-gap scenario, where the chemical potential resides in the global system gap, ensuring robust edge conductance. PMID- 28663439 TI - A cyclic oligonucleotide signaling pathway in type III CRISPR-Cas systems. AB - Type III CRISPR-Cas systems in prokaryotes provide immunity against invading nucleic acids through the coordinated degradation of transcriptionally active DNA and its transcripts by the Csm effector complex. The Cas10 subunit of the complex contains an HD nuclease domain that is responsible for DNA degradation and two Palm domains with elusive functions. In addition, Csm6, a ribonuclease that is not part of the complex, is also required to provide full immunity. We show here that target RNA binding by the Csm effector complex of Streptococcus thermophilus triggers Cas10 to synthesize cyclic oligoadenylates (cA n ; n = 2 to 6) by means of the Palm domains. Acting as signaling molecules, cyclic oligoadenylates bind Csm6 to activate its nonspecific RNA degradation. This cyclic oligoadenylate based signaling pathway coordinates different components of CRISPR-Cas to prevent phage infection and propagation. PMID- 28663441 TI - The influence of health concerns in scientific and policy debates on climate change. PMID- 28663440 TI - ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. AB - Preeclampsia (PE) is a gestational hypertensive syndrome affecting between 5 and 8% of all pregnancies. Although PE is the leading cause of fetal and maternal morbidity and mortality, its molecular etiology is still unclear. Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. Elabela but not Apelin knockout pregnant mice exhibit PE-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis. In mice, infusion of exogenous ELA normalizes hypertension, proteinuria, and birth weight. ELA, which is abundant in human placentas, increases the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent PE. The ELA-APLNR signaling axis may offer a new paradigm for the treatment of common pregnancy-related complications, including PE. PMID- 28663442 TI - The relationship between early childhood head injury and later life criminal behaviour: a longitudinal cohort study. AB - BACKGROUND: Childhood head injury has been associated with the development of behavioural and psychological problems. This study examined the relationship between head injury in young childhood and subsequent criminal behaviour. METHODS: Data were from the Providence cohort of the Collaborative Perinatal Project, a multicentre longitudinal study aimed at identifying the role of perinatal and prenatal factors on child health. History of head injury between ages 0 and 7 years was ascertained from health records of 2893 children. In total, 120 (4%) of children had a head injury. Propensity score matching was used to match each head injury case to five controls. Negative binomial regression was used to estimate the relationship between head injury and number of arrests, and log binomial regression was used to estimate risk of conduct problems. RESULTS: Those who suffered any head injury from ages 0 to 7 years had approximately 1.5 times the rate of arrests and risk of conduct problems compared with uninjured controls, though results did not meet the p<0.05 threshold for statistical significance. Severe head injury was associated with a twofold increased rate of juvenile arrests (incident rate ratio=2.44, 95% CI 0.93 to 6.46) and risk of conduct problems (risk ratio=2.47, 95% CI 0.90 to 6.74) that approached statistical significance. CONCLUSIONS: Head injury in childhood was associated with increased criminality and conduct problems. Future work should identify mechanisms of this association in order to develop interventions to prevent criminal behaviour resulting from head injury. PMID- 28663443 TI - Cellulosic biofuel contributions to a sustainable energy future: Choices and outcomes. AB - Cellulosic crops are projected to provide a large fraction of transportation energy needs by mid-century. However, the anticipated land requirements are substantial, which creates a potential for environmental harm if trade-offs are not sufficiently well understood to create appropriately prescriptive policy. Recent empirical findings show that cellulosic bioenergy concerns related to climate mitigation, biodiversity, reactive nitrogen loss, and crop water use can be addressed with appropriate crop, placement, and management choices. In particular, growing native perennial species on marginal lands not currently farmed provides substantial potential for climate mitigation and other benefits. PMID- 28663445 TI - Deja vu for U.S. nuclear waste. PMID- 28663446 TI - News at a glance. PMID- 28663444 TI - Atomic structure of the human cytomegalovirus capsid with its securing tegument layer of pp150. AB - Herpesviruses possess a genome-pressurized capsid. The 235-kilobase genome of human cytomegalovirus (HCMV) is by far the largest of any herpesvirus, yet it has been unclear how its capsid, which is similar in size to those of other herpesviruses, is stabilized. Here we report a HCMV atomic structure consisting of the herpesvirus-conserved capsid proteins MCP, Tri1, Tri2, and SCP and the HCMV-specific tegument protein pp150-totaling ~4000 molecules and 62 different conformers. MCPs manifest as a complex of insertions around a bacteriophage HK97 gp5-like domain, which gives rise to three classes of capsid floor-defining interactions; triplexes, composed of two "embracing" Tri2 conformers and a "third wheeling" Tri1, fasten the capsid floor. HCMV-specific strategies include using hexon channels to accommodate the genome and pp150 helix bundles to secure the capsid via cysteine tetrad-to-SCP interactions. Our structure should inform rational design of countermeasures against HCMV, other herpesviruses, and even HIV/AIDS. PMID- 28663447 TI - Cholera vaccine faces major test in Yemen. PMID- 28663448 TI - Predicting where victims of Mexico's violence are buried. PMID- 28663449 TI - Stem cell approach for cataracts challenged. PMID- 28663450 TI - Europe's top court alarms vaccine experts. PMID- 28663451 TI - European bee study fuels debate over pesticide ban. PMID- 28663452 TI - The unbearable lightness of neutrinos. PMID- 28663453 TI - How latitude affects biotic interactions. PMID- 28663454 TI - What's the damage from climate change? PMID- 28663455 TI - A cocktail of toxins. PMID- 28663456 TI - Taking six-dimensional spectra in finite time. PMID- 28663457 TI - Releasing plant volatiles, as simple as ABC. PMID- 28663458 TI - Rejuvenating brain plasticity. PMID- 28663459 TI - Plasmons that won't stick. PMID- 28663461 TI - What's next for the Ju/'hoansi? PMID- 28663460 TI - Help, hope, and hype: Ethical dimensions of neuroprosthetics. PMID- 28663463 TI - If I Understood You, Would I Have This Look on My Face? My Adventures in the Art and Science of Relating and Communicating. PMID- 28663462 TI - The enlightened empiricist. PMID- 28663464 TI - Quantify endangered species listings. PMID- 28663465 TI - Research cuts threaten public trust. PMID- 28663466 TI - Reform China's fisheries subsidies. PMID- 28663467 TI - AAAS Leshner fellow aligns science with public service. PMID- 28663468 TI - Burn less, baby, burn less. PMID- 28663470 TI - Maintaining tree diversity. PMID- 28663469 TI - Are better drugs just a click away? PMID- 28663472 TI - Building the neural tube. PMID- 28663471 TI - Carbon nanotubes on the roadmap. PMID- 28663473 TI - Get a grip. PMID- 28663474 TI - An early skull cult from Neolithic Turkey. PMID- 28663475 TI - Damage confirmed. PMID- 28663476 TI - The promise of cellulose. PMID- 28663478 TI - Reopening a critical period. PMID- 28663477 TI - Strong under pressure. PMID- 28663479 TI - Costing out the effects of climate change. PMID- 28663480 TI - To bunch or to antibunch. PMID- 28663481 TI - Specialization in brain neurogenic niche. PMID- 28663482 TI - Healing defects with triiodide ions. PMID- 28663483 TI - Active transport of aromas. PMID- 28663484 TI - Antiviral gets the jump on coronaviruses. PMID- 28663486 TI - Separating charges is a gas. PMID- 28663485 TI - Treating WNT-driven colorectal cancer. PMID- 28663487 TI - Genomics trace plant gene evolution. PMID- 28663488 TI - Characterizing a 12-hour biological clock. PMID- 28663489 TI - Social activity: A new dimension in STEM. PMID- 28663490 TI - Temperature signals in seed germination. PMID- 28663491 TI - Great American ozone loss. PMID- 28663492 TI - A vaccine for heroin addiction? PMID- 28663493 TI - Pairing up copper and tin to reduce CO2. PMID- 28663494 TI - Restoring auditory cortex plasticity in adult mice by restricting thalamic adenosine signaling. AB - Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. Here we show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5'-nucleotidase-dependent adenosine production or A1-adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement of tone-discrimination abilities. We conclude that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception. PMID- 28663495 TI - A human-driven decline in global burned area. AB - Fire is an essential Earth system process that alters ecosystem and atmospheric composition. Here we assessed long-term fire trends using multiple satellite data sets. We found that global burned area declined by 24.3 +/- 8.8% over the past 18 years. The estimated decrease in burned area remained robust after adjusting for precipitation variability and was largest in savannas. Agricultural expansion and intensification were primary drivers of declining fire activity. Fewer and smaller fires reduced aerosol concentrations, modified vegetation structure, and increased the magnitude of the terrestrial carbon sink. Fire models were unable to reproduce the pattern and magnitude of observed declines, suggesting that they may overestimate fire emissions in future projections. Using economic and demographic variables, we developed a conceptual model for predicting fire in human-dominated landscapes. PMID- 28663496 TI - Estimating economic damage from climate change in the United States. AB - Estimates of climate change damage are central to the design of climate policies. Here, we develop a flexible architecture for computing damages that integrates climate science, econometric analyses, and process models. We use this approach to construct spatially explicit, probabilistic, and empirically derived estimates of economic damage in the United States from climate change. The combined value of market and nonmarket damage across analyzed sectors-agriculture, crime, coastal storms, energy, human mortality, and labor-increases quadratically in global mean temperature, costing roughly 1.2% of gross domestic product per +1 degrees C on average. Importantly, risk is distributed unequally across locations, generating a large transfer of value northward and westward that increases economic inequality. By the late 21st century, the poorest third of counties are projected to experience damages between 2 and 20% of county income (90% chance) under business-as-usual emissions (Representative Concentration Pathway 8.5). PMID- 28663497 TI - Carbon nanotube transistors scaled to a 40-nanometer footprint. AB - The International Technology Roadmap for Semiconductors challenges the device research community to reduce the transistor footprint containing all components to 40 nanometers within the next decade. We report on a p-channel transistor scaled to such an extremely small dimension. Built on one semiconducting carbon nanotube, it occupies less than half the space of leading silicon technologies, while delivering a significantly higher pitch-normalized current density-above 0.9 milliampere per micrometer at a low supply voltage of 0.5 volts with a subthreshold swing of 85 millivolts per decade. Furthermore, we show transistors with the same small footprint built on actual high-density arrays of such nanotubes that deliver higher current than that of the best-competing silicon devices under the same overdrive, without any normalization. We achieve this using low-resistance end-bonded contacts, a high-purity semiconducting carbon nanotube source, and self-assembly to pack nanotubes into full surface-coverage aligned arrays. PMID- 28663498 TI - Iodide management in formamidinium-lead-halide-based perovskite layers for efficient solar cells. AB - The formation of a dense and uniform thin layer on the substrates is crucial for the fabrication of high-performance perovskite solar cells (PSCs) containing formamidinium with multiple cations and mixed halide anions. The concentration of defect states, which reduce a cell's performance by decreasing the open-circuit voltage and short-circuit current density, needs to be as low as possible. We show that the introduction of additional iodide ions into the organic cation solution, which are used to form the perovskite layers through an intramolecular exchanging process, decreases the concentration of deep-level defects. The defect engineered thin perovskite layers enable the fabrication of PSCs with a certified power conversion efficiency of 22.1% in small cells and 19.7% in 1-square centimeter cells. PMID- 28663499 TI - Decoding of position in the developing neural tube from antiparallel morphogen gradients. AB - Like many developing tissues, the vertebrate neural tube is patterned by antiparallel morphogen gradients. To understand how these inputs are interpreted, we measured morphogen signaling and target gene expression in mouse embryos and chick ex vivo assays. From these data, we derived and validated a characteristic decoding map that relates morphogen input to the positional identity of neural progenitors. Analysis of the observed responses indicates that the underlying interpretation strategy minimizes patterning errors in response to the joint input of noisy opposing gradients. We reverse-engineered a transcriptional network that provides a mechanistic basis for the observed cell fate decisions and accounts for the precision and dynamics of pattern formation. Together, our data link opposing gradient dynamics in a growing tissue to precise pattern formation. PMID- 28663500 TI - Emission of volatile organic compounds from petunia flowers is facilitated by an ABC transporter. AB - Plants synthesize a diversity of volatile molecules that are important for reproduction and defense, serve as practical products for humans, and influence atmospheric chemistry and climate. Despite progress in deciphering plant volatile biosynthesis, their release from the cell has been poorly understood. The default assumption has been that volatiles passively diffuse out of cells. By characterization of a Petunia hybrida adenosine triphosphate-binding cassette (ABC) transporter, PhABCG1, we demonstrate that passage of volatiles across the plasma membrane relies on active transport. PhABCG1 down-regulation by RNA interference results in decreased emission of volatiles, which accumulate to toxic levels in the plasma membrane. This study provides direct proof of a biologically mediated mechanism of volatile emission. PMID- 28663502 TI - Country-specific effects of neonicotinoid pesticides on honey bees and wild bees. AB - Neonicotinoid seed dressings have caused concern world-wide. We use large field experiments to assess the effects of neonicotinoid-treated crops on three bee species across three countries (Hungary, Germany, and the United Kingdom). Winter sown oilseed rape was grown commercially with either seed coatings containing neonicotinoids (clothianidin or thiamethoxam) or no seed treatment (control). For honey bees, we found both negative (Hungary and United Kingdom) and positive (Germany) effects during crop flowering. In Hungary, negative effects on honey bees (associated with clothianidin) persisted over winter and resulted in smaller colonies in the following spring (24% declines). In wild bees (Bombus terrestris and Osmia bicornis), reproduction was negatively correlated with neonicotinoid residues. These findings point to neonicotinoids causing a reduced capacity of bee species to establish new populations in the year following exposure. PMID- 28663501 TI - Plant diversity increases with the strength of negative density dependence at the global scale. AB - Theory predicts that higher biodiversity in the tropics is maintained by specialized interactions among plants and their natural enemies that result in conspecific negative density dependence (CNDD). By using more than 3000 species and nearly 2.4 million trees across 24 forest plots worldwide, we show that global patterns in tree species diversity reflect not only stronger CNDD at tropical versus temperate latitudes but also a latitudinal shift in the relationship between CNDD and species abundance. CNDD was stronger for rare species at tropical versus temperate latitudes, potentially causing the persistence of greater numbers of rare species in the tropics. Our study reveals fundamental differences in the nature of local-scale biotic interactions that contribute to the maintenance of species diversity across temperate and tropical communities. PMID- 28663503 TI - Chronic exposure to neonicotinoids reduces honey bee health near corn crops. AB - Experiments linking neonicotinoids and declining bee health have been criticized for not simulating realistic exposure. Here we quantified the duration and magnitude of neonicotinoid exposure in Canada's corn-growing regions and used these data to design realistic experiments to investigate the effect of such insecticides on honey bees. Colonies near corn were naturally exposed to neonicotinoids for up to 4 months-the majority of the honey bee's active season. Realistic experiments showed that neonicotinoids increased worker mortality and were associated with declines in social immunity and increased queenlessness over time. We also discovered that the acute toxicity of neonicotinoids to honey bees doubles in the presence of a commonly encountered fungicide. Our work demonstrates that field-realistic exposure to neonicotinoids can reduce honey bee health in corn-growing regions. PMID- 28663505 TI - Extraordinary and poor. PMID- 28663506 TI - Letter by Dorlo Regarding Article, "Acupuncture Therapy and Incidence of Depression After Stroke". PMID- 28663507 TI - Response by Mulder et al to Letter Regarding Article, "Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands)". PMID- 28663508 TI - Ambient Particulate Matter Concentrations and Hospitalization for Stroke in 26 Chinese Cities: A Case-Crossover Study. AB - BACKGROUND AND PURPOSE: Little is known about the short-term health impacts of particulate matter (PM) on stroke in China. We, therefore, conducted a time stratified case-crossover study to examine the association between ambient PM and hospital admissions for stroke in 26 Chinese cities. METHODS: We identified hospital admissions for stroke by using electronic hospitalization summary reports from January 1, 2014 through December, 31 2015. We applied conditional logistic regression to explore the association between PM and hospital admissions for stroke. We also assessed the effect modification of stroke risk by geographical region, sex, and age. RESULTS: Hospital admissions for ischemic (n=278 980) and hemorrhagic (69 399) strokes were examined separately. For ischemic stroke, both PM2.5 and PM10 had the strongest effect at lag 3 days, with an interquartile range increase in PM2.5 (47.5 MUg/m3) and PM10 (76.9 MUg/m3) significantly associated with a 1.0% (95% confidence interval, 0.7%-1.4%) and 0.8% (95% confidence interval, 0.3%-1.3%) increase in admissions for ischemic stroke, respectively. In northern China where PM pollution is more severe, the risk estimates for both PM2.5 and PM10 were larger than those in southern China in all lag structures. An interquartile range increase in PM2.5 and PM10 in northern China corresponded to a 1.0% (95% confidence interval, 0.7%-1.4%) and 0.7% (95% confidence interval, 0.3%-1.2%) increase in ischemic stroke admissions at lag 3 days, respectively. For hemorrhagic stroke, no significant association was observed with PM in the 26 cities. CONCLUSIONS: This study suggests that short-term elevations in PM may increase the risk of ischemic but not hemorrhagic stroke. The associations of PM with ischemic stroke are stronger in northern China than in the south. PMID- 28663509 TI - Physical Exercise Improves Cognitive Outcomes in 2 Models of Transient Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: Preclinical studies suggest that exercise can enhance cognition after cerebral ischemia but often use long training regiments and test cognition during or acutely after training. The cognitive changes may result from enhanced physical fitness and may only provide acute benefit. We sought to determine whether a short period of exercise after cerebral ischemia could improve cognitive outcomes when measured days after completion of exercise training in 2 cerebral ischemia models. METHODS: Focal or global cerebral ischemia was induced in Sprague-Dawley rats. Rats recovered (3-4 days) then were subject to no exercise (0 m/min), mild (6 m/min), moderate (10 m/min), or heavy (15-18 m/min) treadmill exercise (5-6 days). Cognition was tested 8 to 10 days after the last exercise session with hippocampal-dependent contextual fear conditioning. RESULTS: A short training period of moderate exercise enhanced cognitive function for a week after exercise completion in both models of cerebral ischemia. CONCLUSIONS: Utilization of this exercise paradigm can further the elucidation of exercise-mediated factors involved in cognitive recovery independent of changes in physical fitness. PMID- 28663510 TI - Use of Statins and Outcomes in Intracerebral Hemorrhage Patients. AB - BACKGROUND AND PURPOSE: Statin use may be associated with improved outcome in intracerebral hemorrhage patients. However, the topic remains controversial. Our analysis examined the effect of prior, continued, or new statin use on intracerebral hemorrhage outcomes using the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) data set. METHODS: We analyzed ERICH (a multicenter study designed to examine ethnic variations in the risk, presentation, and outcomes of intracerebral hemorrhage) to explore the association of statin use and hematoma growth, mortality, and 3-month disability. We computed subset analyses with respect to 3 statin categories (prior, continued, or new use). RESULTS: Two thousand four hundred and fifty-seven enrolled cases (mean age, 62 years; 42% females) had complete data on mortality and 3-month disability (modified Rankin Scale). Among those, 1093 cases were on statins (prior, n=268; continued, n=423; new, n=402). Overall, statin use was associated with reduced mortality and disability without any effect on hematoma growth. This association was primarily driven by continued/new statin use. A multivariate analysis adjusted for age and major predictors for poor outcome showed that continued/new statins users had good outcomes compared with prior users. However, statins may have been continued/started more frequently among less severe patients. When a propensity score was developed based on factors that could influence a physician's decision in prescribing statins and used as a covariate, continued/new statin use was no longer a significant predictor of good outcome. CONCLUSIONS: Although statin use, especially continued/new use, was associated with improved intracerebral hemorrhage outcomes, this effect may merely reflect the physician's view of a patient's prognosis rather than a predictor of survival. PMID- 28663513 TI - Letter by Freeman Regarding Article, "Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands)". PMID- 28663512 TI - Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Recent studies suggest that extracellular mitochondria may be involved in the pathophysiology of stroke. In this study, we assessed the functional relevance of endogenous extracellular mitochondria in cerebrospinal fluid (CSF) in rats and humans after subarachnoid hemorrhage (SAH). METHODS: A standard rat model of SAH was used, where an intraluminal suture was used to perforate a cerebral artery, thus leading to blood extravasation into subarachnoid space. At 24 and 72 hours after SAH, neurological outcomes were measured, and the standard JC1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl benzimidazolylcarbocyanineiodide) assay was used to quantify mitochondrial membrane potentials in the CSF. To further support the rat model experiments, CSF samples were obtained from 41 patients with SAH and 27 control subjects. Mitochondrial membrane potentials were measured with the JC1 assay, and correlations with clinical outcomes were assessed at 3 months. RESULTS: In the standard rat model of SAH, extracellular mitochondria was detected in CSF at 24 and 72 hours after injury. JC1 assays demonstrated that mitochondrial membrane potentials in CSF were decreased after SAH compared with sham-operated controls. In human CSF samples, extracellular mitochondria were also detected, and JC1 levels were also reduced after SAH. Furthermore, higher mitochondrial membrane potentials in the CSF were correlated with good clinical recovery at 3 months after SAH onset. CONCLUSIONS: This proof-of-concept study suggests that extracellular mitochondria may provide a biomarker-like glimpse into brain integrity and recovery after injury. PMID- 28663514 TI - Response by Lu and Chen to Letter Regarding Article, "Acupuncture Therapy and Incidence of Depression After Stroke". PMID- 28663516 TI - Locus and Focus (but Not Hocus Pocus) in Medicine. PMID- 28663515 TI - Noninvasive Assessment of Oxygen Extraction Fraction in Chronic Ischemia Using Quantitative Susceptibility Mapping at 7 Tesla. AB - BACKGROUND AND PURPOSE: The oxygen extraction fraction (OEF) is an effective metric to evaluate metabolic reserve in chronic ischemia. However, OEF is considered to be accurately measured only when using positron emission tomography (PET). Thus, we investigated whether OEF maps generated by magnetic resonance quantitative susceptibility mapping (QSM) at 7 Tesla enabled detection of OEF changes when compared with those obtained with PET. METHODS: Forty-one patients with chronic stenosis/occlusion of the unilateral internal carotid artery or middle cerebral artery were examined using 7 Tesla-MRI and PET scanners. QSM images were obtained from 3-dimensional T2*-weighted images, using a multiple dipole-inversion algorithm. OEF maps were generated based on susceptibility differences between venous structures and brain tissues on QSM images. OEF ratios of the ipsilateral middle cerebral artery territory against the contralateral side were calculated on the QSM-OEF and PET-OEF images, using an anatomic template. RESULTS: The OEF ratio in the middle cerebral artery territory showed significant correlations between QSM-OEF and PET-OEF maps (r=0.69; P<0.001), especially in patients with a substantial increase in the PET-OEF ratio of 1.09 (r=0.79; P=0.004), although showing significant systematic biases for the agreements. An increased QSM-OEF ratio of >1.09, as determined by receiver operating characteristic analysis, showed a sensitivity and specificity of 0.82 and 0.86, respectively, for the substantial increase in the PET-OEF ratio. Absolute QSM-OEF values were significantly correlated with PET-OEF values in the patients with increased PET-OEF. CONCLUSIONS: OEF ratios on QSM-OEF images at 7 Tesla showed a good correlation with those on PET-OEF images in patients with unilateral steno-occlusive internal carotid artery/middle cerebral artery lesions, suggesting that noninvasive OEF measurement by MRI can be a substitute for PET. PMID- 28663517 TI - Cholesterol: the debate should be terminated. AB - Here, I offer personal perspectives on cholesterol homeostasis that reflect my belief that certain aspects of the debate have been overstated.-Nathan, D. G. Cholesterol: the debate should be terminated. PMID- 28663520 TI - Erratum. PMID- 28663521 TI - Intra-arterial vasodilators for vasospasm following aneurysmal subarachnoid hemorrhage: a meta-analysis. AB - OBJECTIVE: The efficacy of intra-arterial vasodilators (IADs) for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) remains debatable. The objective of this meta-analysis was to pool estimates of angiographic and neurological response, clinical outcome, and mortality following treatment of vasospasm with IADs. METHODS: We searched PubMed, Embase, Scopus, Clinicaltrials.gov, Cochrane database, and CINAHL in December 2015 and August 2016. Studies reporting angiographic and neurological response, clinical outcome, and mortality following IAD treatment of vasospasm in 10 or more adults with aSAH were included. All established IADs were allowed. Two authors independently selected studies and abstracted the data. Mean weighted probabilities (MWP) were calculated using random effects model. RESULTS: Inclusion criteria were met by 55 studies (n=1571). MWP for immediate angiographic response to IAD treatment was 89% (95% CI 83% to 94%), post-IAD neurological improvement 57% (95% CI 49% to 65%), good outcome 66% (95% CI 60% to 71%), and mortality was 9% (95% CI 7% to 12%). After adjusting for publication bias, MWP for mortality was 5% (95% CI 4% to 7%). When transcranial Doppler (TCD) was used along with clinical deterioration for patient selection, rates of neurological response (64%) and good outcome (72%) were better. IADs were not superior to controls (balloon angioplasty or medical management). CONCLUSION: IAD treatment leads to a robust angiographic response and fair (but lower) rates of neurological response and good clinical outcome. Mortality was lower than the average reported in the literature. Rates of neurological response and good outcome were better when TCD was used for patient selection. Carefully designed studies are needed to compare IADs against medical management and balloon angioplasty. PMID- 28663522 TI - It's the 21st century: isn't it past time to ban menthol cigarette sales? PMID- 28663525 TI - Endoscopic ultrasonography and rectal duplication cyst in an adult. AB - Rectal duplication cysts account for 4% of all duplications of the alimentary tract. Presentation in adulthood is rare. An asymptomatic 54-year-old man was referred for endoscopic colorectal cancer screening. A bulging mass covered by normal mucosa was identified in the rectum. Endoscopic ultrasonography (EUS) with fine needle aspiration (FNA) was made for a diagnosis of rectal duplication cyst. The patient was operated and the diagnosis was confirmed. The diagnosis of the rectal duplication cyst is a challenge. EUS may have a singular role when identifying a muscular layer, because this is the only absolutely necessary criterion for the diagnosis. FNA by EUS may eventually identify colorectal and/or heterotypic epithelium that are the other diagnostic criteria of the duplication cyst. PMID- 28663526 TI - Seagulls of endoscopic ultrasound. PMID- 28663518 TI - Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease. AB - Abnormalities of the endosomal-lysosomal network (ELN) are a signature feature of Alzheimer's disease (AD). These include the earliest known cytopathology that is specific to AD and that affects endosomes and induces the progressive failure of lysosomes, each of which are directly linked by distinct mechanisms to neurodegeneration. The origins of ELN dysfunction and beta-amyloidogenesis closely overlap, which reflects their common genetic basis, the established early involvement of endosomes and lysosomes in amyloid precursor protein (APP) processing and clearance, and the pathologic effect of certain APP metabolites on ELN functions. Genes that promote beta-amyloidogenesis in AD (APP, PSEN1/2, and APOE4) have primary effects on ELN function. The importance of primary ELN dysfunction to pathogenesis is underscored by the mutations in more than 35 ELN related genes that, thus far, are known to cause familial neurodegenerative diseases even though different pathogenic proteins may be involved. In this article, I discuss growing evidence that implicates AD gene-driven ELN disruptions as not only the antecedent pathobiology that underlies beta amyloidogenesis but also as the essential partner with APP and its metabolites that drive the development of AD, including tauopathy, synaptic dysfunction, and neurodegeneration. The striking amelioration of diverse deficits in animal AD models by remediating ELN dysfunction further supports a need to integrate APP and ELN relationships, including the role of amyloid-beta, into a broader conceptual framework of how AD arises, progresses, and may be effectively therapeutically targeted.-Nixon, R. A. Amyloid precursor protein and endosomal lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease. PMID- 28663527 TI - Endoscopic ultrasound-guided fine needle aspiration and diagnosis of omental plasmacytoma. PMID- 28663528 TI - Colon carcinoma staging by endoscopic ultrasonography miniprobes. AB - BACKGROUND AND OBJECTIVES: Due to the increasing use of endoscopic techniques for colon cancer resection, pretreatment locoregional staging may gain critical interest. The use of endoscopic ultrasonography (EUS) miniprobes in this context has been seldom reported. Our aim was to determine the accuracy of EUS miniprobes for colon cancer staging. MATERIALS AND METHODS: Forty patients with colon cancer (2 in the cecum, 9 in the ascending colon, 5 in the transverse colon, 5 in the descending colon, and 19 in the sigmoid colon) were submitted to staging using 12 MHz EUS miniprobes. EUS and the anatomopathological results were compared with regard to the T and N stages. It was assessed if the location, longitudinal extension, or circumferential extension of the tumor had any influence on the accuracy in EUS staging. RESULTS: Tumor staging was feasible in 39 (98%) patients except in one case with a stenosing tumor (out of 6). Globally, T stage was accurately determined in 88% of the cases. In the assessment of the presence or absence of lymph node metastasis, miniprobes presented an accuracy of 82% with a sensitivity of 67%. These results were neither affected by the location nor by the longitudinal or circumferential extension of the tumor. CONCLUSIONS: EUS miniprobes may play an important role in assessing T and N stages in colon cancer and may represent an incentive to the research of new therapeutic areas for this disease. PMID- 28663529 TI - Impact of introduction of endoscopic ultrasound on volume, success, and complexity of endoscopic retrograde cholangiopancreatography in a tertiary referral center. AB - BACKGROUND AND OBJECTIVES: Endoscopic ultrasound (EUS) is commonly used to examine pancreaticobiliary disorders. We hypothesize that the introduction of EUS service may change the pattern and the complexity of endoscopic retrograde cholangiopancreatographies (ERCPs) performed. The aim of this study is to assess the impact of introducing EUS on the volume, success, and complexity of ERCP. MATERIALS AND METHODS: This is a single-center retrospective data review of ERCP procedures done "before" and "after" the introduction of EUS (before EUS and after EUS). Patients' demographics, ERCP indications, types of sedation, therapeutic interventions, outcomes, complications, and complexity of ERCP were collected. The categorical and continuous variables were compared using Fisher's exact test and the unpaired t-test, respectively. Multivariable logistic regression analysis was used to compare ERCP outcomes. RESULTS: A total of 945 ERCPs performed over a 3-year period between January 2010 and January 2013 (411 and 534 in the "before EUS" and "after EUS" time periods, respectively) were included in this study. There was a 30% relative increase in the volume of ERCPs after the introduction of EUS. ERCP success rate was higher after the introduction of EUS, even after adjusting the complexity grade [odds ratio (OR) = 4.54, P = 0.001]. Significant increase in the complexity of ERCP was observed after the introduction of EUS service. The OR of performing grade 4 ERCP was 4.44 (P = 0.0005) after the introduction of EUS. CONCLUSIONS: The introduction of a new EUS service in our tertiary referral university medical center is associated with an increase in the volume, success, and complexity of ERCP procedures. EUS expertise may be valuable for better ERCP outcomes. PMID- 28663530 TI - Extramedullary plasmacytoma mimicking pancreatic cancer: A case report and literature review. AB - Pancreatic adenocarcinoma may account for more than 80% of all pancreatic neoplasms. Occasionally, other rare tumors such as lymphoma, metastatic tumor, and solid pseudopapillary neoplasm can be considered in the differential diagnosis. We report the case of an 82-year-old man with a pancreatic solid mass. This case suggests that endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) with biopsy, that is, EUS-FNA is recommended in the differential diagnosis of the pancreatic solid mass apart from pancreatic adenocarcinoma. In particular, the histologic core obtained by EUS-guided biopsy is helpful for the immunostaining of molecular markers to confirm the final diagnosis. PMID- 28663531 TI - Impact of sedation technique on the diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND AND OBJECTIVES: There is a paucity of data concerning the impact of the sedation technique used for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) on diagnostic accuracy. The aim of this retrospective study was to compare the diagnostic accuracy of EBUS-TBNA in deep and moderate sedations, and to investigate other possible determinants of diagnostic accuracy in three lymph node locations (mediastinal, subcarinal, and hilar). MATERIALS AND METHODS: The first consecutive patients at our institution undergoing EBUS-TBNA for selective sampling in deep sedation were compared with the first consecutive patients in moderate sedation between 2006 and 2014. Diagnoses based on EBUS-TBNA were compared with those on surgical or radiological follow-up. RESULTS: In a total of 232 patients, the overall diagnostic accuracy for correct diagnosis at the mediastinal, subcarinal, and hilar locations irrespective of the sedation technique was 91%, 93%, and 92%, respectively. At the three mentioned lymph node locations, overall diagnostic accuracy of EBUS TBNA in deep sedation compared to moderate sedation was 88.5% and 95.5% (P = 0.3), 93.2 and 93.6% (P = 0.9), and 88.6 and 94.0% (P = 0.4), respectively. CONCLUSIONS: The sedation technique does not seem to influence the diagnostic accuracy of EBUS-TBNA. PMID- 28663532 TI - Endoscopic ultrasound for the diagnosis of an uncommon cause of obstructive jaundice masquerading as malignancy. PMID- 28663533 TI - Conversion to endoscopic ultrasound-guided biliary drainage by temporary nasobiliary drainage placement in patients with prior biliary stenting. AB - BACKGROUND AND OBJECTIVES: Endoscopic ultrasound-guided biliary drainage (EUS BD), first reported as an alternative to percutaneous transhepatic BD in failed endoscopic retrograde cholangiography, is sometimes performed as reintervention for transpapillary stent dysfunction such as in patients with new onset gastric outlet obstruction, but direct conversion to EUS-BD can potentially have a risk of leakage of infected bile. The aim of this study is to evaluate the safety and efficacy of conversion to EUS-BD using a temporary endoscopic nasobiliary drainage (ENBD) tube placement as a reintervention for prior BD. PATIENTS AND METHODS: Sixteen patients with prior BD for malignant biliary obstruction undergoing conversion to EUS-BD using a temporary ENBD tube placement were studied. Technical and clinical success rate and adverse events were evaluated. RESULTS: The major reason for conversion to EUS-BD was recurrent cholangitis due to duodenobiliary reflux (n = 13). In 14 patients with an indwelling covered metal or plastic stent, the stents were removed before temporary ENBD placement. After a median duration of 6 days, subsequent conversion to EUS-BD using a covered metal stent was performed, which was technically and clinically successful in all 16 patients (14 hepaticogastrostomy and 2 choledochoduodenostomy). Adverse events were observed in 3 patients (19%): one bleeding, one cholecystitis, and one cholangitis. No bile leak, peritonitis, or sepsis was observed. CONCLUSIONS: Conversion to EUS-BD using temporary ENBD tube placement in patients with prior BD was technically feasible and relatively safe without infectious complications related to bile leakage. PMID- 28663534 TI - Diagnostic dilemma in gastric varices: Endoscopic ultrasound resolves the issue (with videos). PMID- 28663535 TI - Chronic diarrhea and diffuse gastric wall thickening: What is the common link? PMID- 28663536 TI - Transbronchial cryobiopsy: a new way to assess lung disease in rheumatic disorders. PMID- 28663537 TI - Algorithm for Bosniak 2F Cyst in Kidney Donation. AB - BACKGROUND The Bosniak system for radiological classification of renal cysts offers a tool for surgical decision-making in clinical practice. Although 95% of Bosniak 2F cysts remain benign, a consensus on the management of Bosniak 2F cysts in kidney donation has not been developed. CASE REPORT We present a donor with a Bosniak 2F cyst, who successfully donated her kidney after partial resection of the Bosniak 2F cyst. Postoperative pathology examination of the partially resected cystic wall revealed a multilocular cystic renal cell carcinoma. Postoperative pathology examination revealed a multilocular cystic renal cell carcinoma. Resection of the Bosniak 2F cyst provides 2 advantages: the recipient receives a new donor kidney and will be free of dialysis, and the donor will be free of surveillance. CONCLUSIONS We present a practical guideline for kidney donors with Bosniak 2F cysts, balancing the risk of tumor transmission or recurrence with the benefit associated with organ transplantation, without compromising the risk of the donor and recipient. Further evaluation of this algorithm by longer follow-up and more studies is needed to prove its safety. PMID- 28663538 TI - Urinary Tract Infections After Kidney Transplantation: A Risk Factor Analysis of 417 Patients. AB - BACKGROUND The aim of this study was to evaluate the number of urinary tract infections (UTI) that occur after kidney transplantation (KT) and to identify possible risk factors for development of a UTI. MATERIAL AND METHODS We retrospectively analyzed all KTs performed between January 2012 and December 2013 in the Erasmus University Medical Center, Rotterdam. UTI was scored if: (1) a patient had a urine culture with no more than 2 species of microorganisms, (2) at least 1 of which was a bacterium of >=10^5 CFU/mL, (3) which was treated with antibiotics, and (4) which occurred within 3 months after KT. RESULTS A total of 417 patients were transplanted from January 2012 until December 2013. A UTI developed in 115 (28%), after a median of 13 days from transplantation (range: 3 82 days). The most common causative agent was Escherichia coli, followed by Enterococcus faecalis, Enterococcus faecium, and Klebsiella pneumoniae. The variables that were independently related to a UTI were female gender (OR 3.58, 95%CI 2.16-5.91), recipients age >60 y (OR 2.12, 95%CI 1.28-3.48), percutaneous nephrostomy placements (OR 6.29, 95%CI 3.35-11.85), and surgical re-interventions (OR 2.12, 95%CI 1.04-4.32). Mean glomerular filtration rate was significantly lower in the group of patients with a UTI at 3, 6, 9, and 12 months postoperatively compared to those patients who did not have a UTI. CONCLUSIONS We conclude that a UTI after KT is a common problem. We identified independent risk factors for the development of a UTI. UTI is associated with a GFR decrease postoperatively. PMID- 28663539 TI - Transcription Factor 21 (TCF21) rs12190287 Polymorphism is Associated with Osteosarcoma Risk and Outcomes in East Chinese Population. AB - BACKGROUND The transcription factor 21 (TCF21) gene is believed to be a tumor suppressor gene. TCF21 gene polymorphisms were found to play a role in the tumorigenesis of some solid malignancies. We raised a hypothesis that genetic polymorphisms of TCF21 were correlated with risk and prognosis of osteosarcoma. MATERIAL AND METHODS We recruited 225 young osteosarcoma individuals and 250 cancer-free controls. Five tagging SNPs (TCF21 rs2327429 T>C, rs2327433 A>G, rs2327433 A>G, rs12190287 C>G, and rs4896011 T>A) were genotyped. Preserved DNA samples from blood underwent PCR analysis for genotyping. RESULTS rs12190287 C>G is a good predictor of osteosarcoma risk and outcomes. The CG and GG genotypes of rs12190287 predict elevated risk of osteosarcoma. Besides, rs12190287 CG and GG genotypes are associated with Enneking stage and potential in forming metastasis of osteosarcoma. CONCLUSIONS Genetic polymorphisms of TCF21 are potentially predictive for osteosarcoma risk and outcomes. PMID- 28663540 TI - Self-assembly of ordered graphene nanodot arrays. AB - The ability to fabricate nanoscale domains of uniform size in two-dimensional materials could potentially enable new applications in nanoelectronics and the development of innovative metamaterials. However, achieving even minimal control over the growth of two-dimensional lateral heterostructures at such extreme dimensions has proven exceptionally challenging. Here we show the spontaneous formation of ordered arrays of graphene nano-domains (dots), epitaxially embedded in a two-dimensional boron-carbon-nitrogen alloy. These dots exhibit a strikingly uniform size of 1.6 +/- 0.2 nm and strong ordering, and the array periodicity can be tuned by adjusting the growth conditions. We explain this behaviour with a model incorporating dot-boundary energy, a moire-modulated substrate interaction and a long-range repulsion between dots. This new two-dimensional material, which theory predicts to be an ordered composite of uniform-size semiconducting graphene quantum dots laterally integrated within a larger-bandgap matrix, holds promise for novel electronic and optoelectronic properties, with a variety of potential device applications.The nanoscale patterning of two-dimensional materials offers the possibility of novel optoelectronic properties; however, it remains challenging. Here, Camilli et al. show the self-assembly of large arrays of highly-uniform graphene dots imbedded in a BCN matrix, enabling novel devices. PMID- 28663541 TI - The effect of trauma and PTSD on telomere length: An exploratory study in people exposed to combat trauma. AB - Telomere length has been suggested to be a cellular marker for age-related diseases as well as psychosocial stress. The present study investigated whether telomere length is associated with post-traumatic stress disorder (PTSD) among veterans exposed to combat trauma in the Vietnam War. The potentially associated factors on cellular aging were considered. Korean male veterans with (n = 122) and without (n = 120) PTSD were included and leukocyte telomere length was measured with a quantitative PCR-based technique. As a whole, no significant difference in telomere length was found between PTSD and non-PTSD groups. In linear regression analysis stratified by trauma levels, among veterans exposed to severe combat (n = 45), PTSD status (B = -1.176, t = -2.259, p = 0.029), antidepressant use (B = 0.168, t = 2.528, p = 0.015), and education level (B = 0.019, t = 2.369, p = 0.023) affected telomere length. However, among veterans with light-to-moderate combat exposure (n = 197), only age (B = -0.007, t = 2.434, p = 0.016) and education level (B = 0.010, t = 2.295, p = 0.023) were associated with telomere length. In the Post-hoc analysis, antidepressant use was associated with longer telomere length in subjects exposed to severe combat. Our exploratory results suggest that PTSD status in combination with severe trauma may be associated with accelerated telomere shortening, and that antidepressant use may have a protective effect on telomere dynamics. PMID- 28663542 TI - A green route to prepare fluorescent and absorbent nano-hybrid hydrogel for water detection. AB - An environment-friendly fluorescent nano-hybrid hydrogel has been synthesized successfully, from cellulose nanocrystal (CNC), acrylic acid (AA) and phosphorescent Eu2+/Dy3+ doped SrAl2O4 via free radical polymerization. The hydrogel network matrix fixed Eu2+/Dy3+ doped SrAl2O4 nanoparticles by polymer chains with coordinate bonds that prevented particles from aggregating and quenching in water. The fluorescent nano-hybrid hydrogel exhibited extremely high water absorption of which the swelling ratio in distilled water and NaCl salt solution were respectively of 323.35 g/g and 32.65 g/g. Furthermore, the hydrogel displayed excellent water retention property that can keep half of the moisture even exposed to 80 degrees C for 210 min. Besides, the hydrogel had bright green fluorescence under the sunlight or ultraviolet excitation, and the fluorescence intensity was up to 125477 after swelling 50 times in water. The time-resolved photoluminescence (TRPL) afterglow decay examination showed that the fluorescent emission persisted for 4 h after hydrogels excited at 368 nm wavelength UV-light for 10 min. The fluorescence intensity behaved significant linear relationship with the swelling ratio. As a result, these hydrogels were considered as promising candidates for the preparation of stable and sensitive sensor materials in green water detection. PMID- 28663543 TI - nr3c1 null mutant zebrafish are viable and reveal DNA-binding-independent activities of the glucocorticoid receptor. AB - Glucocorticoids (GCs) play important roles in developmental and physiological processes through the transcriptional activity of their cognate receptor (Gr). Using CRISPR/Cas9 technology, we established a zebrafish null Gr mutant line and compared its phenotypes with wild type and a zebrafish line with partially silenced gr (gr s357/s357 ). Homozygous gr -/- larvae are morphologically inconspicuous and, in contrast to GR -/- knockout mice, viable through adulthood, although with reduced fitness and early life survival. Mutants gr -/- are fertile, but their reproductive capabilities fall at around 10 months of age, when, together with cardiac and intestinal abnormalities already visible at earlier stages, increased fat deposits are also observed. Mutants show higher levels of whole-body cortisol associated with overstimulated basal levels of crh and pomca transcripts along the HPI axis, which is unresponsive to a mechanical stressor. Transcriptional activity linked to immune response is also hampered in the gr -/- line: after intestinal damage by dextran sodium sulphate exposure, there are neither inflammatory nor anti-inflammatory cytokine gene responses, substantiating the hypothesis of a dual-action of the GC-GR complex on the immune system. Hence, the zebrafish gr mutant line appears as a useful tool to investigate Gr functions in an integrated in vivo model. PMID- 28663544 TI - Plasma homocysteine and cerebral small vessel disease as possible mediators between kidney and cognitive functions in patients with diabetes mellitus. AB - Cognitive impairment is more prevalent in those with decreased kidney function. We tested a hypothesis that an increased homocysteine and/or cerebral small vessel diseases (SVDs) mediate the link between kidney and cognitive functions in a cross-sectional study in 143 type 2 diabetes patients without diagnosis of dementia or prior stroke. The exposure and outcome variables were estimated glomerular filtration rate (eGFR) and cognitive performance evaluated with Modified Mini-Mental State (3 MS) examination, respectively. The candidate mediators were plasma homocysteine concentration, and SVDs including silent cerebral infarction, cerebral microbleed, periventricular hyperintensity, and deep and subcortical white matter hyperintensity by magnetic resonance imaging. In multiple regression models adjusted for 12 potential confounders, eGFR was positively associated with 3 MS score, inversely with homocysteine, but not significantly with the presence of any type of SVD. The association of eGFR with 3 MS remained significant when each of the SVDs was added to the model, whereas it disappeared when homocysteine was included in place of SVD. Mediation analysis indicated nearly significant mediation of homocysteine (P = 0.062) but no meaningful mediations of SVDs (P = 0.842-0.930). Thus, homocysteine, not SVDs, was shown to be the possible mediator between kidney and cognitive functions in patients with type 2 diabetes mellitus. PMID- 28663545 TI - Towards an Understanding of Enhanced Biomass Digestibility by In Planta Expression of a Family 5 Glycoside Hydrolase. AB - In planta expression of a thermophilic endoglucanase (AcCel5A) reduces recalcitrance by creating voids and other irregularities in cell walls of Arabidopsis thaliana that increase enzyme accessibility without negative impacts on plant growth or cell wall composition. Our results suggest that cellulose beta 1-4 linkages can be cut sparingly in the assembling wall and that these minimal changes, made at the proper time, have an impact on plant cell wall recalcitrance without negative effects on overall plant development. PMID- 28663547 TI - Explicit instructions and consolidation promote rewiring of automatic behaviors in the human mind. AB - One major challenge in human behavior and brain sciences is to understand how we can rewire already existing perceptual, motor, cognitive, and social skills or habits. Here we aimed to characterize one aspect of rewiring, namely, how we can update our knowledge of sequential/statistical regularities when they change. The dynamics of rewiring was explored from learning to consolidation using a unique experimental design which is suitable to capture the effect of implicit and explicit processing and the proactive and retroactive interference. Our results indicate that humans can rewire their knowledge of such regularities incidentally, and consolidation has a critical role in this process. Moreover, old and new knowledge can coexist, leading to effective adaptivity of the human mind in the changing environment, although the execution of the recently acquired knowledge may be more fluent than the execution of the previously learned one. These findings can contribute to a better understanding of the cognitive processes underlying behavior change, and can provide insights into how we can boost behavior change in various contexts, such as sports, educational settings or psychotherapy. PMID- 28663546 TI - Inherited determinants of early recurrent somatic mutations in prostate cancer. AB - Prostate cancer is a highly heritable molecularly and clinically heterogeneous disease. To discover germline events involved in prostate cancer predisposition, we develop a computational approach to nominate heritable facilitators of somatic genomic events in the context of the androgen receptor signaling. Here, we use a ranking score and benign prostate transcriptomes to identify a non-coding polymorphic regulatory element at 7p14.3 that associates with DNA repair and hormone-regulated transcript levels and with an early recurrent prostate cancer specific somatic mutation in the Speckle-Type POZ protein (SPOP) gene. The locus shows allele-specific activity that is concomitantly modulated by androgen receptor and by CCAAT/enhancer-binding protein (C/EBP) beta (CEBPB). Deletion of this locus via CRISPR-Cas9 leads to deregulation of the genes predicted to interact with the 7p14.3 locus by Hi-C chromosome conformation capture data. This study suggests that a polymorphism at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone-dependent DNA damage response.Prostate cancer is a heterogeneous disease, and many cases show somatic mutations of SPOP. Here, the authors show that a non-coding polymorphic regulatory element at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone dependent DNA damage response. PMID- 28663548 TI - Hybrid soliton dynamics in liquid-core fibres. AB - The discovery of optical solitons being understood as temporally and spectrally stationary optical states has enabled numerous innovations among which, most notably, supercontinuum light sources have become widely used in both fundamental and applied sciences. Here, we report on experimental evidence for dynamics of hybrid solitons-a new type of solitary wave, which emerges as a result of a strong non-instantaneous nonlinear response in CS2-filled liquid-core optical fibres. Octave-spanning supercontinua in the mid-infrared region are observed when pumping the hybrid waveguide with a 460 fs laser (1.95 MUm) in the anomalous dispersion regime at nanojoule-level pulse energies. A detailed numerical analysis well correlated with the experiment uncovers clear indicators of emerging hybrid solitons, revealing their impact on the bandwidth, onset energy and noise characteristics of the supercontinua. Our study highlights liquid-core fibres as a promising platform for fundamental optics and applications towards novel coherent and reconfigurable light sources.Here, Chemnitz et al. report experimental evidence for hybrid solitons - a type of solitary wave, which emerges as a result of a strong non-instantaneous nonlinear response in CS2 filled liquid-core optical fibres, demonstrating efficient soliton-driven supercontinuum generation. PMID- 28663549 TI - Determinants of initial inhaled corticosteroid use in patients with GOLD A/B COPD: a retrospective study of UK general practice. AB - : Initial use of inhaled corticosteroid therapy is common in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A or B chronic obstructive pulmonary disease, contrary to GOLD guidelines. We investigated UK prescribing of inhaled corticosteroid therapy in these patients, to identify predictors of inhaled corticosteroid use in newly diagnosed chronic obstructive pulmonary disease patients. A cohort of newly diagnosed GOLD A/B chronic obstructive pulmonary disease patients was identified from the UK Clinical Practice Research Datalink (June 2005-June 2015). Patients were classified by prescribed treatment, with those receiving inhaled corticosteroid-containing therapy compared with those receiving long-acting bronchodilators without inhaled corticosteroid. In all, 29,815 patients with spirometry-confirmed chronic obstructive pulmonary disease were identified. Of those prescribed maintenance therapy within 3 months of diagnosis, 63% were prescribed inhaled corticosteroid-containing therapy vs. 37% prescribed non-inhaled corticosteroid therapy. FEV1% predicted, concurrent asthma diagnosis, region, and moderate exacerbation were the strongest predictors of inhaled corticosteroid use in the overall cohort. When concurrent asthma patients were excluded, all other co-variates remained significant predictors. Other significant predictors included general practitioner practice, younger age, and co-prescription with short-acting bronchodilators. Trends over time showed that initial inhaled corticosteroid prescriptions reduced throughout the study, but still accounted for 47% of initial prescriptions in 2015. These results suggest that inhaled corticosteroid prescribing in GOLD A/B patients is common, with significant regional variation that is independent of FEV1% predicted. EARLY STAGE CHRONIC LUNG DISEASE: OVERUSE OF INHALED STEROIDS IN THE UK: Inhaled steroids are often prescribed to early-stage chronic lung disease patients in the UK despite guidelines to the contrary. Patients newly diagnosed with early-stage chronic obstructive pulmonary disease (COPD) should not be prescribed inhaled corticosteroids (ICS), because they carry an increased risk of side effects such as pneumonia and osteoporosis. ICS should be reserved for patients with severe COPD and frequent exacerbations. James Chalmers at the Scottish Centre for Respiratory Research, Dundee, and co-workers examined prescribed medication data from the UK spanning 10 years, to determine key predictors of ICS prescription during early-stage COPD. Of 29,815 patients identified, an average of 63% were prescribed ICS upon diagnosis, regardless of disease severity. Younger patients were more likely to receive ICS, possibly due to co-morbidity with chronic asthma, and particular UK regions and medical practices prescribed ICS more readily than others. PMID- 28663551 TI - Spectral insights into the transformation and distribution of CdSe quantum dots in microorganisms during food-chain transport. AB - The discharge of engineered nanomaterials (ENMs) into environment is raising widespread concern not only due to their direction bio-toxicity but also their bio-concentration and bio-magnification through food web. However, the transformation and distribution of ENMs during food-chain transport are poorly understood, due to lack of accurate, reliable analytical methods. In this study, by using a suite of advanced spectrum techniques, we successfully tracked the distribution and biotransformation dynamics of CdSe quantum dots (QDs) during their transport from Shewanella onedensis to Caenorchabditis elegans in predation. Fluorescence microscopy and Raman mapping showed that the ingested QDs by C. elegans were located at the gut lumen and subcutaneous tissue, and were partially excreted from the nematode body over time. Micro-X-ray fluorescence (MU XRF) spectroscopy and Se K-edge X-ray absorption fine structure (XAFS) results further revealed the changed distribution of Se element over time, and a shift in the major Se species from CdSe to Se0 and Na2SeO3IV. This work demonstrates the utility of advanced spectral techniques for characterizing QDs in vivo, and may facilitate a better understanding on the environmental transformation and fates of ENMs. PMID- 28663550 TI - Photosynthesis-dependent H2O2 transfer from chloroplasts to nuclei provides a high-light signalling mechanism. AB - Chloroplasts communicate information by signalling to nuclei during acclimation to fluctuating light. Several potential operating signals originating from chloroplasts have been proposed, but none have been shown to move to nuclei to modulate gene expression. One proposed signal is hydrogen peroxide (H2O2) produced by chloroplasts in a light-dependent manner. Using HyPer2, a genetically encoded fluorescent H2O2 sensor, we show that in photosynthetic Nicotiana benthamiana epidermal cells, exposure to high light increases H2O2 production in chloroplast stroma, cytosol and nuclei. Critically, over-expression of stromal ascorbate peroxidase (H2O2 scavenger) or treatment with DCMU (photosynthesis inhibitor) attenuates nuclear H2O2 accumulation and high light-responsive gene expression. Cytosolic ascorbate peroxidase over-expression has little effect on nuclear H2O2 accumulation and high light-responsive gene expression. This is because the H2O2 derives from a sub-population of chloroplasts closely associated with nuclei. Therefore, direct H2O2 transfer from chloroplasts to nuclei, avoiding the cytosol, enables photosynthetic control over gene expression.Multiple plastid-derived signals have been proposed but not shown to move to the nucleus to promote plant acclimation to fluctuating light. Here the authors use a fluorescent hydrogen peroxide sensor to provide evidence that H2O2 is transferred directly from chloroplasts to nuclei to control nuclear gene expression. PMID- 28663552 TI - Using Attenuated Total Reflection-Fourier Transform Infra-Red (ATR-FTIR) spectroscopy to distinguish between melanoma cells with a different metastatic potential. AB - The vast majority of cancer related deaths are caused by metastatic tumors. Therefore, identifying the metastatic potential of cancer cells is of great importance both for prognosis and for determining the correct treatment. Infrared (IR) spectroscopy of biological cells is an evolving research area, whose main aim is to find the spectral differences between diseased and healthy cells. In the present study, we demonstrate that Attenuated Total Reflection Fourier Transform IR (ATR-FTIR) spectroscopy may be used to determine the metastatic potential of cancer cells. Using the ATR-FTIR spectroscopy, we can identify spectral alterations that are a result of hydration or molecular changes. We examined two murine melanoma cells with a common genetic background but a different metastatic level, and similarly, two human melanoma cells. Our findings revealed that higher metastatic potential correlates with membrane hydration level. Measuring the spectral properties of the cells allows us to determine the membrane hydration levels. Thus, ATR-FTIR spectroscopy has the potential to help in cancer metastasis prognosis. PMID- 28663554 TI - High-transmission acoustic self-focusing and directional cloaking in a graded perforated metal slab. AB - A design strategy and its modeling for high-transmission acoustic self-focusing and directional cloaking in a two-dimensional (2D) and an axisymmetric three dimensional (3D) gradient-index phononic crystal (GRIN-PC) are reported in this paper. A gradient perforated aluminum slab sandwiched by water is considered. A low-loss directional cloaking device is achieved by controlling the matching coefficient between the slab and the water. The anisotropy coefficient that affects the scattering properties is also introduced. Furthermore, the phase discontinuity for directional cloaking inside and outside the slab is overcome by introducing a non-gradient slab having a lower group velocity behind the GRIN slab as an acoustic delay device. In addition, an axisymmetric 3D directional cloaking structure is obtained by rotating the corresponding 2D structure around the slab axis. PMID- 28663553 TI - Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. AB - TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that physiological nuclear TDP-43 in mouse and human brain forms homo-oligomers that are resistant to cellular stress. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 A crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy. These head-to-tail TDP 43 oligomers are unique among known RNA-binding proteins and represent the functional form of the protein in vivo, since their destabilization results in loss of alternative splicing regulation of known neuronal RNA targets. Our findings indicate that N-terminal domain-driven oligomerization spatially separates the adjoining highly aggregation-prone, C-terminal low-complexity domains of consecutive TDP-43 monomers, thereby preventing low-complexity domain inter-molecular interactions and antagonizing the formation of pathologic aggregates.TDP-43 aggregation is observed in amyotrophic lateral sclerosis. Here the authors combine X-ray crystallography, nuclear magnetic resonance and electron microscopy studies and show that physiological oligomerization of TDP-43 is mediated through its N-terminal domain, which forms functional and dynamic oligomers antagonizing pathologic aggregation. PMID- 28663555 TI - Three-dimensional spheroid culture targeting versatile tissue bioassays using a PDMS-based hanging drop array. AB - Biomaterial-based tissue culture platforms have emerged as useful tools to mimic in vivo physiological microenvironments in experimental cell biology and clinical studies. We describe herein a three-dimensional (3D) tissue culture platform using a polydimethylsiloxane (PDMS)-based hanging drop array (PDMS-HDA) methodology. Multicellular spheroids can be achieved within 24 h and further boosted by incorporating collagen fibrils in PDMS-HDA. In addition, the spheroids generated from different human tumor cells exhibited distinct sensitivities toward drug chemotherapeutic agents and radiation as compared with two dimensional (2D) cultures that often lack in vivo-like biological insights. We also demonstrated that multicellular spheroids may enable key hallmarks of tissue based bioassays, including drug screening, tumor dissemination, cell co-culture, and tumor invasion. Taken together, these results offer new opportunities not only to achieve the active control of 3D multicellular spheroids on demand, but also to establish a rapid and cost-effective platform to study anti-cancer therapeutics and tumor microenvironments. PMID- 28663556 TI - Desensitized D2 autoreceptors are resistant to trafficking. AB - Dendritic release of dopamine activates dopamine D2 autoreceptors, which are inhibitory G protein-coupled receptors (GPCRs), to decrease the excitability of dopamine neurons. This study used tagged D2 receptors to identify the localization and distribution of these receptors in living midbrain dopamine neurons. GFP-tagged D2 receptors were found to be unevenly clustered on the soma and dendrites of dopamine neurons within the substantia nigra pars compacta (SNc). Physiological signaling and desensitization of the tagged receptors were not different from wild type receptors. Unexpectedly, upon desensitization the tagged D2 receptors were not internalized. When tagged D2 receptors were expressed in locus coeruleus neurons, a desensitizing protocol induced significant internalization. Likewise, when tagged u-opioid receptors were expressed in dopamine neurons they too were internalized. The distribution and lack of agonist-induced internalization of D2 receptors on dopamine neurons indicate a purposefully regulated localization of these receptors. PMID- 28663558 TI - The common cuckoo is an effective indicator of high bird species richness in Asia and Europe. AB - Common cuckoo Cuculus canorus is a charismatic bird species with a dominant presence in human culture: from folklore legends to nowadays there is evidence of cuckoos being a prime candidate as a surrogate of bird diversity. Recent studies demonstrated that the cuckoo can predict hotspots of taxonomic diversity and functional diversity of bird communities in European countries. In this study, we demonstrated that the cuckoo is an excellent bioindicator at multi-spatial scale, extending cuckoo surrogacy from Europe to Asia. Even using three different survey methods (transect, square, point counts), comparing the new findings with results of our research in Europe, sites where the cuckoo is present were characterized by greater species richness, while the cuckoo was absent from sites with low species richness. The goodness of fit of models based on point counts ranged between 71 and 92%. Furthermore, the cuckoo population trend mirrors the average population trend and climate suitability of overall bird communities in Europe. The common cuckoo is therefore a suitable intercontinental bioindicator of hotspots of bird richness, even under climate change scenarios or in areas where the species co-occurs with other cuckoo species, opening a new avenue for standardized citizen science on bird biodiversity surveys worldwide. PMID- 28663557 TI - Disruption of the C/EBPalpha-miR-182 balance impairs granulocytic differentiation. AB - Transcription factor C/EBPalpha is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPalpha by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPalpha. Moreover, we identify a regulatory loop between C/EBPalpha and miR-182. While C/EBPalpha blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPalpha protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPalpha blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPalpha and miR-182 for the maintenance of healthy granulopoiesis.C/EBPalpha is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPalpha and miR 182 and identify this miRNA as a marker of high-risk AML. PMID- 28663559 TI - Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study. AB - SIX1 and SIX6 are glaucoma susceptibility genes. Previous reports indicate that the single nucleotide polymorphism (SNP) rs33912345 in SIX6 is associated with inferior circumpapillary retinal nerve fibre layer (cpRNFL) thickness (cpRNFLT). Although the region of visual field defect in glaucoma patients is directly related to cpRNFL thinning, a detailed sector analysis has not been performed in genetic association studies. In the present study, we evaluated 26 tagging SNPs in the SIX1/SIX6 locus +/-50 kb region in a population of 2,306 Japanese subjects with 4- and 32-sector cpRNFLT analysis. While no SNPs showed a significant association with cpRNFLT in the 4-sectored analysis, the finer 32-sector assessment clearly showed a significant association between rs33912345 in the SIX1/SIX6 locus with inferior cpRNFL thinning at 292.5-303.8 degrees (beta = 4.55, P = 3.0 * 10-5). Furthermore, the fine-sectored cpRNFLT analysis indicated that SIX1/SIX6 polymorphisms would affect cpRNFL thinning at 281.3-303.8 degrees , which corresponds to parafoveal scotoma in a visual field test of glaucoma patients. PMID- 28663560 TI - Sewage outburst triggers Trichodesmium bloom and enhance N2 fixation rates. AB - The southeastern Mediterranean Sea (SEMS) is a warm and sunlit marine environment with low ambient N concentration, thus considered ideal for diazotrophy by autotrophic diazotrophs such as Trichodesmium. Despite the favorable conditions, N2 fixation rates are often low and Trichodesmium has hardly been spotted in the SEMS. This study reports on the occurrence of a Trichodesmium bloom in the SEMS which was ascribed to T. erythraeum according to DNA fingerprinting of the nifH gene. We found that this bloom (1407 +/- 983 cells L-1) was triggered by an intense outburst of raw sewage that supplied high concentrations of N, P and dissolved organic carbon (DOC), which resulted in low N:P (~12:1) and exceptionally high C:P (~1340:1) ratios. We surmise that these conditions provided favorable conditions for Trichodesmium bloom to form via mixotrophic metabolism. As a result, a fourfold increase in N2 fixation was recorded, which contributed ~70% to new primary production and spur a sharp increase in phytoplankton activity and biomass. The conclusions of this study point on a new paradigm for bloom-forming T. erythraeum which is tightly linked to anthropogenic sources and prompt microbial productivity in oligotrophic marine environments such as the SEMS. PMID- 28663561 TI - A Simple and Rapid Turn On ESIPT Fluorescent Probe for Colorimetric and Ratiometric Detection of Biothiols in Living Cells. AB - Biothiols, such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play a key role in an extensive range of physiological processes and biological functions. Therefore, the selective and sensitive detection of intracellular thiols is important for revealing cellular function. In this study, ethyl 2-(4 (acryloyloxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate (NL-AC) was designed and synthesized as a colorimetric and ratiometric fluorescent probe that can be utilized to rapidly, sensitively and selectively detect biothiols in physiological media. The fluorescence intensity of this probe using the three target biothiols at a concentration of 20 equiv. of the probe increased by approximately 6~10-fold in comparison to that without the biothiols in aqueous solution. The limits of detection (LOD) for Cys, Hcy and GSH were 0.156, 0.185, and 1.838 MUM, respectively. In addition, both 1H-NMR and MS analyses suggested the mechanism of fluorescence sensing to be excited-state intramolecular proton transfer (ESIPT). The novel colorimetric and ratiometric probe is structurally simple and offers detection within 20 min. Furthermore, this probe can be successfully applied in bioimaging. The results indicate high application potential in analytical chemistry and diagnostics. PMID- 28663562 TI - Expression analysis of inflammasome sensors and implication of NLRP12 inflammasome in prostate cancer. AB - Inflammasomes are multi-proteins complex regulating inflammation-associated signaling. While inflammation plays a critical role in cancer cell growth, studies remain uncharacterized on the role of inflammasomes in prostate cancer. Using Gene Expression Omnibus (GEO) public datasets, we screened the expression profiles of inflammasome sensors NLRP3, NLRC4, NLRP6, NRLP12, and AIM2 in prostate tumor tissues, and verified their mRNA level in a panel of prostate cancer cell lines. The selected expression of NLRP3 and NLRP12 inflammasomes was validated, and the clinical association was evaluated in human prostate archival tumor tissues. We observed that the expression of inflammasome sensors was dysregulated at the mRNA level except for the NLRP12. The intensity of NLRP12 immunostaining was significantly higher in malignant prostate as compared to their adjacent benign tissues. In contrast, the NLRP3 immunostaining in prostate tissues was heterogeneous. The inflammasome complex proteins ASC (apoptosis associated speck-like protein containing a CARD) and pro-caspase-1, as well as its downstream targets IL-1beta and IL-18 were confined to aggressive prostate cancer cells. These data suggest an increased expression of NLRP12 in association with prostate cancer and support the role of NLRP12 inflammasome complex regulating inflammatory cytokines in understanding the role of inflammation in the prostate cancer. PMID- 28663563 TI - A low-frequency chip-scale optomechanical oscillator with 58 kHz mechanical stiffening and more than 100th-order stable harmonics. AB - For the sensitive high-resolution force- and field-sensing applications, the large-mass microelectromechanical system (MEMS) and optomechanical cavity have been proposed to realize the sub-aN/Hz1/2 resolution levels. In view of the optomechanical cavity-based force- and field-sensors, the optomechanical coupling is the key parameter for achieving high sensitivity and resolution. Here we demonstrate a chip-scale optomechanical cavity with large mass which operates at ~77.7 kHz fundamental mode and intrinsically exhibiting large optomechanical coupling of 44 GHz/nm or more, for both optical resonance modes. The mechanical stiffening range of ~58 kHz and a more than 100th-order harmonics are obtained, with which the free-running frequency instability is lower than 10-6 at 100 ms integration time. Such results can be applied to further improve the sensing performance of the optomechanical inspired chip-scale sensors. PMID- 28663565 TI - Detachment and successive re-attachment of multiple, reversibly-binding tethers result in irreversible bacterial adhesion to surfaces. AB - Bacterial adhesion to surfaces occurs ubiquitously and is initially reversible, though becoming more irreversible within minutes after first contact with a surface. We here demonstrate for eight bacterial strains comprising four species, that bacteria adhere irreversibly to surfaces through multiple, reversibly binding tethers that detach and successively re-attach, but not collectively detach to cause detachment of an entire bacterium. Arguments build on combining analyses of confined Brownian-motion of bacteria adhering to glass and their AFM force-distance curves and include the following observations: (1) force-distance curves showed detachment events indicative of multiple binding tethers, (2) vibration amplitudes of adhering bacteria parallel to a surface decreased with increasing adhesion-forces acting perpendicular to the surface, (3) nanoscopic displacements of bacteria with relatively long autocorrelation times up to several seconds, in absence of microscopic displacement, (4) increases in Mean Squared-Displacement over prolonged time periods according to talpha with 0 < alpha ? 1, indicative of confined displacement. Analysis of simulated position maps of adhering particles using a new, in silico model confirmed that adhesion to surfaces is irreversible through detachment and successive re-attachment of reversibly-binding tethers. This makes bacterial adhesion mechanistically comparable with the irreversible adsorption of high-molecular-weight proteins to surfaces, mediated by multiple, reversibly-binding molecular segments. PMID- 28663564 TI - No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice. AB - Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. DNA glycosylases recognize and remove specific lesions in the first step of BER. The existence of a number of these enzymes with overlapping substrate specificities has been thought to be the reason why single knock-out models of individual DNA glycosylases are not cancer prone. In this work we have characterized DNA glycosylases NEIL1 and NEIL2 (Neil1 -/- /Neil2 -/-) double and NEIL1, NEIL2 and NEIL3 (Neil1 -/- /Neil2 -/- /Neil3 -/-) triple knock-out mouse models. Unexpectedly, our results show that these mice are not prone to cancer and have no elevated mutation frequencies under normal physiological conditions. Moreover, telomere length is not affected and there was no accumulation of oxidative DNA damage compared to wild-type mice. These results strengthen the hypothesis that the NEIL enzymes are not simply back-up enzymes for each other but enzymes that have distinct functions beyond canonical repair. PMID- 28663566 TI - Marsupial brood care in Cretaceous tanaidaceans. AB - Parental care in animal evolution has long fascinated biologists, but tracing this complex of behavioural repertoires is challenging, as these transitory states often leave no corporeal traces as fossils. Among modern invertebrates, the tanaidaceans (Malacostraca: Peracarida), a lineage of marsupial crustaceans, show an interesting variety of brooding strategies. Here we report on fossil tanaidaceans from the Cretaceous of Spain and France that provide conclusive evidence for marsupial care of brood-offspring. Two exceptionally preserved female specimens of Alavatanais carabe and A. margulisae from Late Albian Penacerrada I amber (Spain) possess four pairs of rudimentary oostegites, indicating formation of a marsupium. From Recent data, given the taxonomic distribution of a marsupium of four pairs of oostegites, we hypothesize that this may be plesiomorphic for the Tanaidomorpha. We also report on a peculiar tanaidacean specimen referable to the fossil family Alavatanaidae, Daenerytanais maieuticus gen. et sp. nov., from Early Cenomanian La Buzinie amber (France), preserved with its marsupial pouch and content. Our discoveries provide early evidence of the peracarid reproductive strategy, as seen in modern Tanaidacea, and argue that this form of parental care may have played a role in the diversification of the lineage during this period. PMID- 28663567 TI - Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption. AB - Sepsis, during which the intestinal epithelial barrier is frequently disrupted, remains a challenging and life-threatening problem in clinical practice. The P2X7 receptor (P2X7R) is a non-selective adenosine triphosphate-gated cation channel present in macrophages that is involved in inflammatory responses. However, little is known about the role of P2X7R in macrophages during sepsis-induced intestinal barrier disruption. In this study, mice were treated with the P2X7R antagonist A740003 or the agonist BzATP by intra-peritoneal injection after the induction of gut-origin sepsis. The survival rates, inflammatory responses, intestinal barrier integrity, macrophage marker expression, and ERK and NF-kappaB activities were evaluated. Intestinal macrophages were also isolated and studied after exposure to Brilliant Blue G or BzATP. We found that a systemic P2X7R blockade downregulated sepsis-induced inflammatory responses and attenuated intestinal barrier dysfunction based on the evidence that mice in the A740003 treated group exhibited alleviated pro-inflammatory cytokine synthesis, intestinal hyperpermeability, epithelial apoptosis rates and tight junction damage compared with the septic mice. These changes were partly mediated by the inhibition of M1 macrophages activation via ERK/NF-kappaB pathways. Our data presented herein show that a P2X7R blockade could be a potential therapeutic target for the treatment of sepsis-induced intestinal barrier dysfunction. PMID- 28663569 TI - Lower school performance in late chronotypes: underlying factors and mechanisms. AB - Success at school determines future career opportunities. We described a time-of day specific disparity in school performance between early and late chronotypes. Several studies showed that students with a late chronotype and short sleep duration obtain lower grades, suggesting that early school starting times handicap their performance. How chronotype, sleep duration, and time of day impact school performance is not clear. At a Dutch high school, we collected 40,890 grades obtained in a variety of school subjects over an entire school year. We found that the strength of the effect of chronotype on grades was similar to that of absenteeism, and that late chronotypes were more often absent. The difference in grades between the earliest 20% and the latest 20% of chronotypes corresponds to a drop from the 55th to 43rd percentile of grades. In academic subjects using mainly fluid cognition (scientific subjects), the correlation with grades and chronotype was significant while subjects relying on crystallised intelligence (humanistic/linguistic) showed no correlation with chronotype. Based on these and previous results, we can expand our earlier findings concerning exam times: students with a late chronotype are at a disadvantage in exams on scientific subjects, and when they are examined early in the day. PMID- 28663571 TI - Single ion fluorescence excited with a single mode of an UV frequency comb. AB - Optical frequency combs have revolutionized the measurement of optical frequencies and improved the precision of spectroscopic experiments. Besides their importance as a frequency-measuring ruler, the frequency combs themselves can excite target transitions (direct frequency comb spectroscopy). The direct frequency comb spectroscopy may extend the optical frequency metrology into spectral regions unreachable by continuous wave lasers. In high precision spectroscopy, atoms/ions/molecules trapped in place have been often used as a target to minimize systematic effects. Here, we demonstrate direct frequency comb spectroscopy of single 25Mg ions confined in a Paul trap, at deep-UV wavelengths. Only one mode out of about 20,000 can be resonant at a time. Even then we can detect the induced fluorescence with a spatially resolving single photon camera, allowing us to determine the absolute transition frequency. The demonstration shows that the direct frequency comb spectroscopy is an important tool for frequency metrology for shorter wavelengths where continuous wave lasers are unavailable.Frequency combs are useful tools in high precision measurement including atomic transitions and atomic clocks. Here the authors demonstrate direct frequency comb spectroscopy to shorter wavelengths by probing a transition frequency in a trapped Mg+ ion using a single mode of a UV frequency comb. PMID- 28663570 TI - Brain stimulation in obesity. AB - Obesity is taking up epidemic proportions worldwide with significant impacts on the health of both the affected individual and on society as a whole. Treatment approaches consist of behavioural and pharmacological approaches, however, these are often found to be ineffective. In severe obesity, bariatric surgery is frequently performed. Unfortunately, 40% of patients show substantial weight gain over the long term or display the associated metabolic syndrome, making the development of novel therapies necessary. This review summarizes some of the current conceptual models, in particularly the 'food addiction' model, and then discusses specific therapeutic targets of brain stimulation, both non-invasive (transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcutaneous vagus nerve stimulation (VNS)) and invasive (deep brain stimulation and invasive VNS). As we will show, neuromodulatory approaches represent a promising tool for targeting specific brain structures implicated in the pathophysiology of obesity. Non-invasive techniques such as TMS, tDCS and transcutaneous VNS need further investigation before they may become ready for clinical usage. The currently available study data suggest that deep brain stimulation may become an effective and acceptable therapy for otherwise treatment-resistant obese patients. The results of the currently undergoing clinical trials are eagerly awaited. PMID- 28663573 TI - Adipokines, C-reactive protein and Amyotrophic Lateral Sclerosis - results from a population- based ALS registry in Germany. AB - To investigate the associations of leptin, adiponectin and high-sensitive (hs) C reactive protein (CRP) with risk and prognosis of amyotrophic lateral sclerosis (ALS). Data from a population-based case-control study in Southern Germany (10/2010-6/2014) of 289 ALS patients (mean age of 65.7 (SD 10.5) years, 59.5% men) and 506 controls were included. During median follow-up of 14.5 months of 279 ALS patients 104 (53.9% men, 68.9 (10.3) years) died. Serum samples were measured for leptin, adiponectin and hs-CRP. Conditional logistic regression was used to estimate ALS risk. Survival models were used to appraise the prognostic value. ALS patients were characterized by lower levels of school education, BMI and smoking prevalence. Adjusted for covariates, leptin was inversely associated with ALS risk (top vs. bottom quartile: OR 0.49; 95% CI 0.29-0.80), while for adiponectin a positive association was found (OR 2.89; 95% CI 1.78-4.68). Among ALS patients increasing leptin concentrations were associated with longer survival (p for trend 0.002), while for adiponectin no association was found (p for trend 0.55). For hs-CRP no association was found. Leptin and adiponectin, two key hormones regulating energy metabolism, were strongly and independently related with ALS risk. Leptin levels were further negatively related with overall survival of ALS patients. PMID- 28663568 TI - Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity. AB - Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 * 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. PMID- 28663575 TI - New drugs in myeloma: beware of phase I trial results, beware of cost and demand for new trials. PMID- 28663574 TI - Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. AB - The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating ten-eleven translocation 2 (TET2) mutations and neomorphic isocitrate dehydrogenase (IDH) mutations are recurrent and mutually exclusive in acute myeloid leukaemia genomes. Ascorbic acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukaemic model expressing IDH1R132H. Vitamin C treatment induced an IDH1R132H-dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation. Vitamin C induced differentially methylated regions that displayed a significant overlap with enhancers implicated in myeloid differentiation and were enriched in sequence elements for the haematopoietic transcription factors CEBPbeta, HIF1alpha, RUNX1 and PU.1. Chromatin immunoprecipitation sequencing of PU.1 and RUNX1 revealed a significant loss of PU.1 and increase of RUNX1-bound DNA elements accompanied by their demethylation following vitamin C treatment. In addition, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. On the basis of these data we propose a model of vitamin C-induced epigenetic remodelling of transcription factor-binding sites driving differentiation in a leukaemic model. PMID- 28663577 TI - Preclinical modeling of myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematological clonal disorders. Here, we have tested the bone marrow (BM) cells from 38 MDS patients covering all risk groups in two immunodeficient mouse models: NSG and NSG-S. Our data show comparable level of engraftment in both models. The level of engraftment was patient specific with no correlation to any specific MDS risk group. Furthermore, the co-injection of mesenchymal stromal cells (MSCs) did not improve the level of engraftment. Finally, we have developed an in vitro two dimensional co-culture system as an alternative tool to in vivo. Using our in vitro system, we have been able to co-culture CD34+ cells from MDS patient BM on auto- and/or allogeneic MSCs over 4 weeks with a fold expansion of up to 600 times. More importantly, these expanded cells conserved their MDS clonal architecture as well as genomic integrity. PMID- 28663576 TI - SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. AB - The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM. PMID- 28663578 TI - Trends in pre- and post-transplant therapies with first autologous hematopoietic cell transplantation among patients with multiple myeloma in the United States, 2004-2014. PMID- 28663579 TI - Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. AB - The hematological malignancies classified as mixed lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis, and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia, here we show that genetic inactivation or small-molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein-driven transformation. Genome-wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small-molecule inhibitors in the treatment of leukemias harboring MLL rearrangements. PMID- 28663580 TI - An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia. AB - The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 beta2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-alpha-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML. PMID- 28663581 TI - Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients. AB - Novel anti-myeloma agents have improved patient response rates, which are historically based on reductions of the M-protein. These methods can be inaccurate for quantifying M-proteins at low concentrations. We compared the consistency and clinical impact of response assignment by electrophoretic and heavy+light chain (HLC) immunoassays post-consolidation in 463 newly diagnosed patients. The two methods gave similar assignments in patients with partial (PR; 79% agreement) or complete response (?CR; 92%). However, in patients achieving very good PR (VGPR) there was poor concordance between methods (45%). Median progression-free survival (PFS) for standard VGPR patients was 34.5 months; HLC responses stratified these patients further into PR, VGPR and ?CR, with median PFS of 21.3, 28.9 months and not reached, respectively; P<0.001. At this time, abnormal HLC ratios had better concordance with multiparametric flow cytometry (sensitivity 10-4) (37 and 34% positive, respectively), compared to immunofixation (62% positive). In addition, HLC-pair suppression was identified in 38% of patients and associated with shorter PFS (30.6 months vs not reached; P<0.001). We conclude that HLC monitoring could augment electrophoretic assessments in patients achieving VGPR. The prognostic significance of HLC responses might partly depend on the patients' ability to recover their immune system, as determined by normalisation of HLC measurements. PMID- 28663582 TI - BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. AB - Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-kappaB (NF-kappaB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-kappaB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL. PMID- 28663583 TI - Aminoglycoside-driven biosynthesis of selenium-deficient Selenoprotein P. AB - Selenoprotein biosynthesis relies on the co-translational insertion of selenocysteine in response to UGA codons. Aminoglycoside antibiotics interfere with ribosomal function and may cause codon misreading. We hypothesized that biosynthesis of the selenium (Se) transporter selenoprotein P (SELENOP) is particularly sensitive to antibiotics due to its ten in frame UGA codons. As liver regulates Se metabolism, we tested the aminoglycosides G418 and gentamicin in hepatoma cell lines (HepG2, Hep3B and Hepa1-6) and in experimental mice. In vitro, SELENOP levels increased strongly in response to G418, whereas expression of the glutathione peroxidases GPX1 and GPX2 was marginally affected. Se content of G418-induced SELENOP was dependent on Se availability, and was completely suppressed by G418 under Se-poor conditions. Selenocysteine residues were replaced mainly by cysteine, tryptophan and arginine in a codon-specific manner. Interestingly, in young healthy mice, antibiotic treatment failed to affect Selenop biosynthesis to a detectable degree. These findings suggest that the interfering activity of aminoglycosides on selenoprotein biosynthesis can be severe, but depend on the Se status, and other parameters likely including age and general health. Focused analyses with aminoglycoside-treated patients are needed next to evaluate a possible interference of selenoprotein biosynthesis by the antibiotics and elucidate potential side effects. PMID- 28663584 TI - Spatially Confined Spin Polarization and magnetic sublattice control in (La,Sr)MnO3-delta Thin Films by Oxygen Vacancy Ordering. AB - Perovskite oxides are known for their strong structure property coupling and functional properties such as ferromagntism, ferroelectricity and high temperature superconductivity. While the effect of ordered cation vacancies on functional properties have been much studied, the possibility of tuning the functionality through anion vacancy ordering has received much less attention. Oxygen vacancies in ferromagnetic La0.7Sr0.3MnO3-delta thin films have recently been shown to accumulate close to interfaces and form a brownmillerite structure (ABO2.5). This structure has alternating oxygen octahedral and tetrahedral layers along the stacking direction, making it a basis for a family of ordered anion defect controlled materials. We use density functional theory to study how structure and properties depend on oxygen stoichiometry, relying on a block-by block approach by including additional octahedral layers in-between each tetrahedral layer. It is found that the magnetic and electronic structures follow the layers enforced by the ordered oxygen vacancies. This results in spatially confined electronic conduction in the octahedral layers, and decoupling of the magnetic sub-lattices in the octahedral and tetrahedral layers. These results demonstrate that anion defect engineering is a promising tool to tune the properties of functional oxides, adding a new avenue for developing functional oxide device technology. PMID- 28663586 TI - Radiocarbon as a Novel Tracer of Extra-Antarctic Feeding in Southern Hemisphere Humpback Whales. AB - Bulk stable isotope analysis provides information regarding food web interactions, and has been applied to several cetacean species for the study of migration ecology. One limitation in bulk stable isotope analysis arises when a species, such as Southern hemisphere humpback whales, utilises geographically distinct food webs with differing isotopic baselines. Migrations to areas with different baselines can result in isotopic changes that mimic changes in feeding relations, leading to ambiguous food web interpretations. Here, we demonstrate the novel application of radiocarbon measurement for the resolution of such ambiguities. Radiocarbon was measured in baleen plates from humpback whales stranded in Australia between 2007 and 2013, and in skin samples collected in Australia and Antarctica from stranded and free-ranging animals. Radiocarbon measurements showed lower values for Southern Ocean feeding than for extra Antarctic feeding in Australian waters. While the whales mostly relied on Antarctic-derived energy stores during their annual migration, there was some evidence of feeding within temperate zone waters in some individuals. This work, to our knowledge, provides the first definitive biochemical evidence for supplementary feeding by southern hemisphere humpback whales within temperate waters during migration. Further, the work contributes a powerful new tool (radiocarbon) for tracing source regions and geographical feeding. PMID- 28663585 TI - CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. AB - Inner ear hair cells detect sound through deflection of stereocilia, the microvilli-like projections that are arranged in rows of graded heights. Calcium and integrin-binding protein 2 is essential for hearing and localizes to stereocilia, but its exact function is unknown. Here, we have characterized two mutant mouse lines, one lacking calcium and integrin-binding protein 2 and one carrying a human deafness-related Cib2 mutation, and show that both are deaf and exhibit no mechanotransduction in auditory hair cells, despite the presence of tip links that gate the mechanotransducer channels. In addition, mechanotransducing shorter row stereocilia overgrow in hair cell bundles of both Cib2 mutants. Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.Inner ear hair cells detect sound through deflection of stereocilia that harbor mechanically-gated channels. Here the authors show that protein responsible for Usher syndrome, CIB2, interacts with these channels and is essential for their function and hearing in mice. PMID- 28663587 TI - Challenge of Liquid Stressed Protective Materials and Environmental Persistence of Ebola Virus. AB - After the largest Ebola virus outbreak in history, experts have attempted to answer how the Zaire ebolavirus species emerged in West Africa and caused chains of human-to-human transmission. The widespread and untimely infection of Health Care Workers (HCW) in the affected countries accelerated spread of the virus within the community. Among the reasons attributed to this trend, it must be considered that HCW were exposed to the virus in their occupational environment. The contribution of environmental conditions to the spread of Ebola in West Africa was examined by investigating the effect of temperature/humidity on the virus's environmental persistence and by modeling if saturation (liquid stress) allows for penetration of Ebola virus through personal protective equipment (PPE). Ebola-Makona virus persisted on PPE and materials found in outbreak settings for less than 72 hours at 27 degrees C and 80% relative humidity (RH). A difference in virus penetration was observed between dry (5%, 1/21 tests) and saturated (33%, 7/21 tests) samples of PPE. Infectious virus particles penetrated through saturated coupons of Tyvek Micro Clean, Tychem QC, whole surgical masks and N95 respirators. These findings suggest inclusion of saturation or similar liquid stress simulation in protective equipment testing standards. PMID- 28663588 TI - The Nep1-like protein family of Magnaporthe oryzae is dispensable for the infection of rice plants. AB - The necrosis- and ethylene-inducing protein 1 (Nep1)-like proteins (NLPs) are a class of microbe-associated molecular patterns widely distributed across diverse groups of plant-associated microorganisms. In spite of the cytotoxic activity in dicot plants, the role of most NLPs in the virulence of plant pathogens is still largely unknown. We showed that the MoNLP family of rice blast fungus varied very little in amino acid sequence, transient expression of three MoNLPs induced cell death and the production of reactive oxygen species in Nicotiana benthamiana, and the expression of MoNLPs was induced during infection of susceptible rice plants. To further investigate the biological role of the MoNLP family, a marker-free gene replacement vector was developed and used to knock out the whole family in Magnaporthe oryzae. Results showed no significant difference in disease levels caused by wild type and the quadruple DeltaMoNLP mutant strains. Likewise, the sporulation and radial growth of the two strains were similar under various unfavorable cultural conditions including malnutrition and abiotic stresses. These observations demonstrated that the MoNLP family is dispensable for the fungal tolerance to the tested adverse cultural conditions, and more importantly, for the virulence of blast fungus on susceptible rice plants. PMID- 28663589 TI - Pancreatic cancer: iExosomes target the 'undruggable'. PMID- 28663590 TI - Carbon footprint of grain production in China. AB - Due to the increasing environmental impact of food production, carbon footprint as an indicator can guide farmland management. This study established a method and estimated the carbon footprint of grain production in China based on life cycle analysis (LCA). The results showed that grain production has a high carbon footprint in 2013, i.e., 4052 kg ce/ha or 0.48 kg ce/kg for maize, 5455 kg ce/ha or 0.75 kg ce/kg for wheat and 11881 kg ce/ha or 1.60 kg ce/kg for rice. These footprints are higher than that of other countries, such as the United States, Canada and India. The most important factors governing carbon emissions were the application of nitrogen fertiliser (8-49%), straw burning (0-70%), energy consumption by machinery (6-40%), energy consumption for irrigation (0-44%) and CH4 emissions from rice paddies (15-73%). The most important carbon sequestration factors included returning of crop straw (41-90%), chemical nitrogen fertiliser application (10-59%) and no-till farming practices (0-10%). Different factors dominated in different crop systems in different regions. To identity site specific key factors and take countermeasures could significantly lower carbon footprint, e.g., ban straw burning in northeast and south China, stopping continuous flooding irrigation in wheat and rice production system. PMID- 28663592 TI - No compelling need to reclassify. PMID- 28663593 TI - The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations. AB - This corrects the article DOI: 10.1038/modpathol.2016.182. PMID- 28663594 TI - Metabolite profiling in identifying metabolic biomarkers in older people with late-onset type 2 diabetes mellitus. AB - Regulation of blood glucose requires precise coordination between different endocrine systems and multiple organs. Type 2 diabetes mellitus (T2D) arises from a dysregulated response to elevated glucose levels in the circulation. Globally, the prevalence of T2D has increased dramatically in all age groups. T2D in older adults is associated with higher mortality and reduced functional status, leading to higher rate of institutionalization. Despite the potential healthcare challenges associated with the presence of T2D in the elderly, the pathogenesis and phenotype of late-onset T2D is not well studied. Here we applied untargeted metabolite profiling of urine samples from people with and without late-onset T2D using ultra-performance liquid-chromatography mass-spectrometry (UPLC-MS) to identify urinary biomarkers for late-onset T2D in the elderly. Statistical modeling of measurements and thorough validation of structural assignment using liquid chromatography tandem mass-spectrometry (LC-MS/MS) have led to the identification of metabolite biomarkers associated with late-onset T2D. Lower levels of phenylalanine, acetylhistidine, and cyclic adenosine monophosphate (cAMP) were found in urine samples of T2D subjects validated with commercial standards. Elevated levels of 5'-methylthioadenosine (MTA), which previously has only been implicated in animal model of diabetes, was found in urine of older people with T2D. PMID- 28663595 TI - Altered miRNA expression network in locus coeruleus of depressed suicide subjects. AB - Norepinephrine (NE) is produced primarily by neurons in the locus coeruleus (LC). Retrograde and ultrastructural examinations reveal that the core of the LC and its surrounding region receives afferent projections from several brain areas which provide multiple neurochemical inputs to the LC with changes in LC neuronal firing, making it a highly coordinated event. Although NE and mediated signaling systems have been studied in relation to suicide and psychiatric disorders that increase the risk of suicide including depression, less is known about the corresponding changes in molecular network within LC. In this study, we examined miRNA networks in the LC of depressed suicide completers and healthy controls. Expression array revealed differential regulation of 13 miRNAs. Interaction between altered miRNAs and target genes showed dense interconnected molecular network. Functional clustering of predicated target genes yielded stress induced disorders that collectively showed the complex nature of suicidal behavior. In addition, 25 miRNAs were pairwise correlated specifically in the depressed suicide group, but not in the control group. Altogether, our study revealed for the first time the involvement of LC based dysregulated miRNA network in disrupting cellular pathways associated with suicidal behavior. PMID- 28663596 TI - A novel programmable lysozyme-based lysis system in Pseudomonas putida for biopolymer production. AB - Cell lysis is crucial for the microbial production of industrial fatty acids, proteins, biofuels, and biopolymers. In this work, we developed a novel programmable lysis system based on the heterologous expression of lysozyme. The inducible lytic system was tested in two Gram-negative bacterial strains, namely Escherichia coli and Pseudomonas putida KT2440. Before induction, the lytic system did not significantly arrest essential physiological parameters in the recombinant E. coli (ECPi) and P. putida (JBOi) strain such as specific growth rate and biomass yield under standard growth conditions. A different scenario was observed in the recombinant JBOi strain when subjected to PHA-producing conditions, where biomass production was reduced by 25% but the mcl-PHA content was maintained at about 30% of the cell dry weight. Importantly, the genetic construct worked well under PHA-producing conditions (nitrogen-limiting phase), where more than 95% of the cell population presented membrane disruption 16 h post induction, with 75% of the total synthesized biopolymer recovered at the end of the fermentation period. In conclusion, this new lysis system circumvents traditional, costly mechanical and enzymatic cell-disrupting procedures. PMID- 28663597 TI - Prognostic factors in head and neck cancer: a 10-year retrospective analysis in a single-institution in Italy. AB - This study was undertaken to evaluate the association between demographics, lifestyle habits, and clinical data and overall survival (OS), recurrence and second primary cancer (SPC) in patients with first primary head and neck cancer (HNC). We retrospectively reviewed data from 482 patients treated at the "Agostino Gemelli" Teaching Hospital, Rome, between 2002-2012 for primary HNC. Individual parameters were evaluated for association with specific outcomes such as OS, cancer recurrence and second primary cancer (SPC) appearance using hazard ratios (HR) and 95% confidence intervals (CIs). Five-year OS was 60.6% for all HNC cases, 49.0% for oral cavity, 54.8% for oropharynx, 50.0% for hypopharynx and 63.4% for larynx. Predictors of OS were older age (HR = 1.04; 95% CI: 1.02-1.05) and advanced tumour stage (HR = 2.00; 95% CI: 1.41-2.84). The risk of recurrence was associated with drinking 8-14 drinks per week (HR = 1.73; 95% CI: 1.00-2.97). The risk of developing SPC increased with advanced tumour stage (HR = 2.75; 95% CI: 1.39-5.44) and with smoking for more than 40 years (HR = 3.68; 95% CI: 1.10 12.30). OS differed among HNC sites. Increasing age was an unfavourable predictor of HNC OS. Tumour stage was a prognostic factor both for OS and for risk of developing SPC. Alcohol and tobacco consumption were prognostic factors for recurrence and SPC, respectively. PMID- 28663599 TI - Palate perforation differentiates cocaine-induced midline destructive lesions from granulomatosis with polyangiitis. AB - Cocaine abuse occasionally causes extensive destruction of the osteocartilaginous structures of the nose, sinuses and palate, which mimics the clinical picture of other diseases associated with necrotising midfacial lesions. The differentiation of cocaine-induced midline destructive lesions (CIMDL) and limited granulomatosis with polyangiitis (GPA) may be difficult, particularly if patients do not readily admit substance abuse. We studied 10 patients with CIMDL and palate perforation referred to our Unit between 2002 and 2015. All cases underwent nasal endoscopy, sinus CT or MRI and ANCA test. In 8 patients, a nasal biopsy was performed. The PubMed database was searched to review all cases of palate perforation described in patients affected by CIMDL or GPA. All 10 cases presented with septal perforation and inferior turbinate destruction. We found hard palate perforation in 7 patients, soft palate perforation in 2 patients, and perforation of both in one patient. ANCA testing was negative in 8 patients and positive in 2, with C ANCA and P-ANCA specificity, respectively. A review of the English literature identified palate perforation in 5 patients with GPA and in 73 patients with CIMDL. The presence of palate perforation in patients with MDL may represent a clinical marker that strongly favors CIMDL over GPA. PMID- 28663598 TI - Cost-effectiveness strategies in OSAS management: a short review. AB - Obstructive sleep apnoea (OSAS) is an underdiagnosed chronic disease with a high prevalence in adults. It is becoming a significant social problem, since it is associated with a worsening in quality of life and increase in mortality. The cost-effectiveness ratio of diagnostic and therapeutic management of OSAS is a strategic issue to counteract the expected increasing demand of objective testing. OSAS patients with any clinical evidence of comorbidities must be studied using simplified and less expensive systems such as Home Sleep Testing (HST). On the other hand, Sleep Laboratory Polysomnography (PSG) is the gold standard to manage OSAS patients with comorbidities. It should be pointed out that the use of HST can lead to incorrect diagnosis in poorly selected OSAS subjects. This short review discusses various topics for the proper diagnosis and treatment of OSAS in view of epidemiological factors and results in terms of costs and social benefit of the disease. Whatever the strategy chosen and/or the organisational model adopted for managing OSAS, it cannot and should not take into account only cost-effectiveness. Long-term prospective studies evaluating cost-effectiveness ratios and outcomes of OSAS treatment of hospital management models versus home care models are needed. PMID- 28663600 TI - Enabling Interactive Measurements from Large Coverage Microscopy. AB - Microscopy could be an important tool for characterizing stem cell products if quantitative measurements could be collected over multiple spatial and temporal scales. With the cells changing states over time and being several orders of magnitude smaller than cell products, modern microscopes are already capable of imaging large spatial areas, repeat imaging over time, and acquiring images over several spectra. However, characterizing stem cell products from such large image collections is challenging because of data size, required computations, and lack of interactive quantitative measurements needed to determine release criteria. We present a measurement web system consisting of available algorithms, extensions to a client-server framework using Deep Zoom, and the configuration know-how to provide the information needed for inspecting the quality of a cell product. The cell and other data sets are accessible via the prototype web-based system at http://isg.nist.gov/deepzoomweb. PMID- 28663601 TI - A Mixed-Method Analysis of Reports on 100 Cases of Improper Prescribing of Controlled Substances. AB - Improper prescribing of controlled substances contributes to opioid addictions and deaths by overdose. Studies conducted to-date have largely lacked a theoretical framework and ignored the interaction of individual with environmental factors. We conducted a mixed-method analysis of published reports on 100 cases that occurred in the United States. An average of 17 reports (e.g., from medical boards) per case were coded for 38 dichotomous variables describing the physician, setting, patients, and investigation. A theory on how the case occurred was developed for each case. Explanatory typologies were developed and then validated through hierarchical cluster analysis. Most cases involved physicians who were male (88%), >40 years old (90%), non-board certified (63%), and in small private practices (97%); 54% of cases reported facts about the physician indicative of self-centered personality traits. Three explanatory typologies were validated. Increasing oversight provided by peers and trainees may help prevent improper prescribing of controlled substances. PMID- 28663603 TI - Stemphylium revisited. AB - In 2007 a new Stemphylium leaf spot disease of Beta vulgaris (sugar beet) spread through the Netherlands. Attempts to identify this destructive Stemphylium sp. in sugar beet led to a phylogenetic revision of the genus. The name Stemphylium has been recommended for use over that of its sexual morph, Pleospora, which is polyphyletic. Stemphylium forms a well-defined monophyletic genus in the Pleosporaceae, Pleosporales (Dothideomycetes), but lacks an up-to-date phylogeny. To address this issue, the internal transcribed spacer 1 and 2 and intervening 5.8S nr DNA (ITS) of all available Stemphylium and Pleospora isolates from the CBS culture collection of the Westerdijk Institute (N = 418), and from 23 freshly collected isolates obtained from sugar beet and related hosts, were sequenced to construct an overview phylogeny (N = 350). Based on their phylogenetic informativeness, parts of the protein-coding genes calmodulin and glyceraldehyde 3-phosphate dehydrogenase were also sequenced for a subset of isolates (N = 149). This resulted in a multi-gene phylogeny of the genus Stemphylium containing 28 species-clades, of which five were found to represent new species. The majority of the sugar beet isolates, including isolates from the Netherlands, Germany and the UK, clustered together in a species clade for which the name S. beticola was recently proposed. Morphological studies were performed to describe the new species. Twenty-two names were reduced to synonymy, and two new combinations proposed. Three epitypes, one lectotype and two neotypes were also designated in order to create a uniform taxonomy for Stemphylium. PMID- 28663604 TI - A rose by any other name is still a rose: A reinterpretation of Hantsch and Madebach. AB - The Response Exclusion Hypothesis localises the semantic interference effect as observed in the picture-word paradigm at a postlexical level of processing. An important aspect of this proposal is that the ease with which distractor words can be excluded from production at the response level is determined by the degree to which they satisfy criteria demanded of a correct response. This proposal predicts that naming a picture of a "rose" with the response "flower" will be slower with the distractor "rose" than a distractor word that would not be appropriate for the picture (e.g., "tulip"). Hantsch and Madebach report evidence consistent with this expectation; however, the authors argue that the results are problematic for the Response Exclusion Hypothesis. Here we unpack Hantsch and Madebach's arguments about why their finding is (putatively) problematic for the Response Exclusion Hypothesis. We conclude that the pattern of effects that the authors report are not only in line with what would be expected by the Response Exclusion Hypothesis, but are difficult to reconcile with Hantsch and Madebach's preferred theoretical position. PMID- 28663605 TI - Processing ser and estar to locate objects and events: An ERP study with L2 speakers of Spanish. AB - In Spanish locative constructions, a different form of the copula is selected in relation to the semantic properties of the grammatical subject: sentences that locate objects require estar while those that locate events require ser (both translated in English as 'to be'). In an ERP study, we examined whether second language (L2) speakers of Spanish are sensitive to the selectional restrictions that the different types of subjects impose on the choice of the two copulas. Twenty-four native speakers of Spanish and two groups of L2 Spanish speakers (24 beginners and 18 advanced speakers) were recruited to investigate the processing of 'object/event + estar/ser' permutations. Participants provided grammaticality judgments on correct (object + estar; event + ser) and incorrect (object + ser; event + estar) sentences while their brain activity was recorded. In line with previous studies (Leone-Fernandez, Molinaro, Carreiras, & Barber, 2012; Sera, Gathje, & Pintado, 1999), the results of the grammaticality judgment for the native speakers showed that participants correctly accepted object + estar and event + ser constructions. In addition, while 'object + ser' constructions were considered grossly ungrammatical, 'event + estar' combinations were perceived as unacceptable to a lesser degree. For these same participants, ERP recording time locked to the onset of the critical word 'en' showed a larger P600 for the ser predicates when the subject was an object than when it was an event (*La silla es en la cocina vs. La fiesta es en la cocina). This P600 effect is consistent with syntactic repair of the defining predicate when it does not fit with the adequate semantic properties of the subject. For estar predicates (La silla esta en la cocina vs. *La fiesta esta en la cocina), the findings showed a central-frontal negativity between 500-700 ms. Grammaticality judgment data for the L2 speakers of Spanish showed that beginners were significantly less accurate than native speakers in all conditions, while the advanced speakers only differed from the natives in the event+ser and event+estar conditions. For the ERPs, the beginning learners did not show any effects in the time-windows under analysis. The advanced speakers showed a pattern similar to that of native speakers: (1) a P600 response to 'object + ser' violation more central and frontally distributed, and (2) a central-frontal negativity between 500-700 ms for 'event + estar' violation. Findings for the advanced speakers suggest that behavioral methods commonly used to assess grammatical knowledge in the L2 may be underestimating what L2 speakers have actually learned. PMID- 28663606 TI - Conscious Sedation: Emerging Trends in Pediatric Dentistry. AB - Dental fear and anxiety is a common problem in pediatric patients. There is considerable variation in techniques used to manage them. Various sedation techniques using many different anesthetic agents have gained considerable popularity over the past few years. Children are not little adults; they differ physically, psychologically, and emotionally. The purpose of this review is to survey recent trends and concerning issues in the rapidly changing field of pediatric sedation. We will study the topic from the perspective of an anesthesiologist. It will also provide information to practitioners on the practice of conscious sedation in dentistry and will also outline the route of administration, pharmacokinetics, and pharmacodynamics of various drugs used. PMID- 28663607 TI - Effect of Single Compared to Repeated Doses of Intravenous S(+) Ketamine on the Release of Pro-inflammatory Cytokines in Patients Undergoing Radical Prostatectomy. AB - BACKGROUND: Radical prostatectomy is a major surgical procedure that is associated with marked inflammatory response and impairment of the immune system which may affect the postoperative outcome. The aim of this study was to evaluate the effect of preincision single or multiple doses of S(+) ketamine on the pro inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). PATIENTS AND METHODS: This is a randomized controlled trial including 60 American Society of Anesthesiologists Physical Status I and II patients scheduled for radical prostatectomy under combined general-epidural anesthesia in Cairo university Teaching Hospital. Patients were randomly divided into three groups each of twenty patients: Group I received no S(+) ketamine (control group), Group II received S(+) ketamine as a single preincision dose, and Group III received preincision and repeated doses of S(+) ketamine. S(+) ketamine was injected as a single intravenous dose of 0.5 mg/kg in Group II and III, repeated as 0.2 mg/kg at 20 min interval until 30 min before the end of surgery. RESULTS: The three groups were comparable in age, weight, and duration of the operation. The study also revealed that a single preincision dose of S(+) ketamine decreased TNF-alpha to reach 1027.04 +/- 50.13 MU/ml and IL-6 to reach 506.89 +/- 25.35 pg/ml whereas the repeated doses of S(+) ketamine decreased TNF alpha to reach 905.64 +/- 35065 MU/ml and IL-6 to reach 412.79 +/- 16.5 pg/ml (P < 0.05). CONCLUSION: S(+) ketamine suppresses pro-inflammatory cytokine production, especially when given in repeated doses. PMID- 28663608 TI - Comparison of Usefulness of Ketamine and Magnesium Sulfate Nebulizations for Attenuating Postoperative Sore Throat, Hoarseness of Voice, and Cough. AB - CONTEXT: Postoperative sore throat (POST) is a complication that is unresolved in patients undergoing endotracheal intubation. AIM: To compare the effects of ketamine and magnesium sulfate nebulizations in two strengths, on the incidence and severity of POST, hoarseness, and cough. SETTINGS AND DESIGN: Sixty surgical patients undergoing elective abdominal and lower limb surgeries under combined epidural and general anesthesia were included in this prospective, randomized, double-blinded study. SUBJECTS AND METHODS: Patients in each group were nebulized with the respective study drug 15 min prior to the surgery, i.e., ketamine in Group K, magnesium sulfate 250 mg, and 500 mg in Group M1 and Group M2, respectively, and normal saline as control in Group C. A standardized anesthesia protocol was followed for all patients. After extubation, the patients were asked to grade POST, hoarseness, and cough at 0, 2, 4, 12, and 24 h. STATISTICAL ANALYSIS USED: One-way analysis of variance, Chi-square test, Fisher's exact test, paired t-tests, and Wilcoxon's signed-rank test as applicable. RESULTS: Ketamine and magnesium sulfate 500 mg demonstrated a statistically significant decrease in POST at 0, 2, and 4 h, and postoperative hoarseness at 0 h. There was decrease in the incidence and severity of sore throat, hoarseness, and cough at all periods in the study groups as compared with control. CONCLUSION: Nebulization with ketamine 50 mg and magnesium sulfate 500 mg, 15 min before induction of general anesthesia and intubation, reduce the incidence and severity of POST and hoarseness of voice. PMID- 28663602 TI - Genera of phytopathogenic fungi: GOPHY 1. AB - Genera of Phytopathogenic Fungi (GOPHY) is introduced as a new series of publications in order to provide a stable platform for the taxonomy of phytopathogenic fungi. This first paper focuses on 21 genera of phytopathogenic fungi: Bipolaris, Boeremia, Calonectria, Ceratocystis, Cladosporium, Colletotrichum, Coniella, Curvularia, Monilinia, Neofabraea, Neofusicoccum, Pilidium, Pleiochaeta, Plenodomus, Protostegia, Pseudopyricularia, Puccinia, Saccharata, Thyrostroma, Venturia and Wilsonomyces. For each genus, a morphological description and information about its pathology, distribution, hosts and disease symptoms are provided. In addition, this information is linked to primary and secondary DNA barcodes of the presently accepted species, and relevant literature. Moreover, several novelties are introduced, i.e. new genera, species and combinations, and neo-, lecto- and epitypes designated to provide a stable taxonomy. This first paper includes one new genus, 26 new species, ten new combinations, and four typifications of older names. PMID- 28663609 TI - Efficacy of Dexmedetomidine Infusion for Procedural Comfort and Intraoperative Sedation in Patients Undergoing Surgeries with Subarachnoid Block: A Randomized Double-blind Clinical Trial. AB - INTRODUCTION: There is increasing evidence to include sedation as an integral part of regional anesthesia to ensure patient comfort. This may compromise patient cooperation, an important component of regional anesthesia. We decided to determine the efficacy of dexmedetomidine (0.3 MUg/kg/h and 0.5 MUg/kg/h) for allaying procedural discomfort and ensuring their cooperation in patients undergoing surgery with subarachnoid block. SETTING: Tertiary care center. MATERIALS AND METHODS: Sixty patients with the American Society of Anesthesiologists physical status Class I and II posted for surgeries under subarachnoid block were randomized into two groups of 30 each to receive dexmedetomidine in a loading dose of 1 MUg/kg in both groups followed by continuous infusion of 0.3 MUg/kg/h in Group D 0.3 and 0.5 MUg/kg/h in Group D 0.5. Observer assessment sedation score, ease of positioning score, response to spinal needle insertion, hemodynamic parameters, patient satisfaction (PS) score, and surgeon satisfaction (SS) score were evaluated. RESULTS: Median observer Assessment Sedation Score ranged between four and three at all times during dexmedetomidine infusion in Group D 0.3. In Group D 0.5, median Observer assessment of alertness/sedation scale ranged between three and two. Ease of positioning (P = 1.000) and response to spinal needle insertion (P = 0.521) were comparable in both groups. PS was higher in Group D 0.5 as compared to Group D 0.3. SS score was comparable in both the groups. CONCLUSION: Intravenous dexmedetomidine infusion 0.3 MUg/kg/h produces effective sedation in patients undergoing surgery with spinal anesthesia while ensuring patient cooperation for positioning and without any recall of the procedure in postoperative period. PMID- 28663610 TI - Lignocaine Versus Ropivacaine Infiltration for Postpartum Perineal Pain. AB - BACKGROUND: Millions of women worldwide undergo postpartum perineal repair under local infiltration. Inadequate postpartum pain management can negatively impact a mother's physical and psychological recovery. AIMS: To study and compare the analgesic effect and maternal satisfaction with lignocaine versus ropivacaine infiltration for postpartum perineal pain relief. MATERIALS AND METHODS: After clearance from the Institutional Ethics Committee, a double-blind prospective randomized study carried out on 100 parturients of aged 18-40 years who had spontaneous vaginal delivery, comparing 1% lignocaine and 0.75% ropivacaine infiltration for the repair of selective episiotomy or perineal injury. Time of the first analgesic (TFA) demand, maternal satisfaction at 24 h, and visual analog scale (VAS) pain score were studied. STATISTICAL ANALYSIS: Chi-square test and Student's t-test were used and P < 0.05 was considered as significant. RESULTS: VAS pain score was significantly lower at 2 and 4 h in ropivacaine group versus lignocaine group (P < 0.0001). Significantly, longer TFA (10.2 +/- 1.54 vs. 2.20 +/- 0.44 h, P < 0.0001) and higher percentage of maternal satisfaction (86% vs. 44%) were observed in ropivacaine as compared to lignocaine group (P < 0.0001). CONCLUSIONS: Prolonged analgesia and higher rate of maternal satisfaction were found when ropivacaine infiltration was used for perineal repair as compared to lignocaine. PMID- 28663611 TI - Financial Implications of Intravenous Anesthetic Drug Wastage in Operation Room. AB - BACKGROUND AND OBJECTIVES: Anesthetic drugs and material wastage are common in operation rooms (ORs). In this era of escalating health-care expenditure, cost reduction strategies are highly relevant. The aim of this study was to assess the amount of daily intravenous anesthetic drug wastage from major ORs and to estimate its financial burden. Any preventive measures to minimize drug wastage are also looked for. METHODS: It was a prospective study conducted at the major ORs of a tertiary care hospital after getting the Institutional Research Committee approval. The total amount of all drugs wasted at the end of a surgical day from each major OR was audited for five nonconsecutive weeks. Drug wasted includes the drugs leftover in the syringes unutilized and opened vials/ampoules. The total cost of the wasted drugs and average daily loss were estimated. RESULTS: The drugs wasted in large quantities included propofol, thiopentone sodium, vecuronium, mephentermine, lignocaine, midazolam, atropine, succinylcholine, and atracurium in that order. The total cost of the wasted drugs during the study period was Rs. 59,631.49, and the average daily loss was Rs. 1987.67. The average daily cost of wasted drug was maximum for vecuronium (Rs. 699.93) followed by propofol (Rs. 662.26). INTERPRETATION AND CONCLUSIONS: Financial implications of anesthetic drug wastage can be significant. Propofol and vecuronium contributed maximum to the financial burden. Suggestions for preventive measures to minimize the wastage include education of staff and residents about the cost of drugs, emphasizing on the judicial use of costly drugs. PMID- 28663612 TI - Dexmedetomidine as an Anesthetic Adjuvant in Intracranial Surgery. AB - BACKGROUND: The basic principle of neuroanesthesia is to provide hemodynamic stability, provision of optimal operative conditions, maintenance of cerebral perfusion pressure, and cerebral oxygenation. AIM: This study was undertaken to see the effect of dexmedetomidine infusion on hemodynamics and its ability to act as an anesthetic adjuvant in patients undergoing supratentorial tumor surgery. SETTING AND DESIGN: Prospective randomized control double blind study. SUBJECTS AND METHODS: In this study, we compared two groups with 25 patients in each group. Group C patients received saline infusion during surgery and 4 MUg/kg of fentanyl intravenously (i.v.) at the induction and at pin head application. Group D patients received dexmedetomidine infusion during surgery at the rate of 0.4 MUg/kg/h and 2 MUg/kg of fentanyl i.v. at the induction and at pin head application. STATISTICAL ANALYSES USED: Parametric data were analyzed using Student's t-test. The categorical data were studied using Chi-squared test or Fisher's test as appropriate. RESULTS: The vitals remained within 20% of baseline in both groups during the study period except at the time of extubation where the rise in heart rate was more than 20% in control group. The requirement of thiopentone for induction was significantly less in dexmedetomidine group. In dexmedetomidine group, less number of patients required intraoperative fentanyl (P < 0.05), and the time to rescue analgesic was also more in Group D (P < 0.05). CONCLUSION: Dexmedetomidine infusion started before surgery maintains hemodynamic stability intraoperatively and is effective in attenuating the cardiovascular responses to intubation, skull pin application, and extubation. It decreases the requirement of other anesthetic agents as well. PMID- 28663613 TI - Hemodynamic Responses at Intubation, Change of Position, and Skin Incision: A Comparison of Multimodal Analgesia with Conventional Analgesic Regime. AB - BACKGROUND: Lumbar spine surgery is associated with hemodynamic variations at intubation, change of position, and skin incision. A balanced anesthesia with multimodal analgesia (MMA) is necessary to attenuate these changes. AIM: To assess the relative effectiveness of preemptive MMA compared with the conventional analgesic regime in suppressing the hemodynamic response to endotracheal intubation, prone positioning, and skin incision. SETTINGS AND DESIGN: A randomized, prospective study involving 42 patients belonging to the American Society of Anesthesiologists Physical Status 1 and II scheduled to undergo elective lumbar spine surgery were allocated into two groups of 21 each. MATERIALS AND METHODS: Forty-two patients were randomly allocated into Groups A and B. Group A (study group) received diclofenac, paracetamol, clonidine, and bupivacaine with adrenaline skin infiltration and Group B (control group) injection paracetamol and saline with adrenaline skin infiltration. STATISTICAL ANALYSIS USED: Hemodynamic parameters (heart rate [HR], systolic blood pressure [SBP], diastolic blood pressure [DBP], and mean arterial pressure [MAP]) between the groups following intubation, prone position, and skin incision were noted and compared using repeated measure analysis of variance. One sample t-test was used to compare the standard mean concentration with the means of the study and control groups. P < 5% being considered statistically significant. RESULTS: In the study group, HR, SBP, DBP, and MAP were lower at intubation and change of position as compared to the control group and were statistically significant. CONCLUSION: Preemptive MMA with balanced anesthesia is effective in attenuating the hemodynamic responses to multiple noxious stimuli during lumbar spine surgery. PMID- 28663614 TI - To Study the Efficacy of Intravenous Dexamethasone in Prolonging the Duration of Spinal Anesthesia in Elective Cesarean Section. AB - BACKGROUND AND AIMS: Various additives have been evaluated for the purpose of enhancing quality of analgesia and prolonging duration of spinal anesthesia. This randomized, double-blind study was conducted to evaluate the efficacy of intravenous dexamethasone in spinal anesthesia. METHODS: A total of sixty patients scheduled for lower segment cesarean section under spinal anesthesia were randomly allocated into two groups, group SD and group SN, including thirty patients each. All the patients received injection bupivacaine 0.5% heavy 10 mg through spinal anesthesia. Group SD received injection dexamethasone 8 mg intravenously, and group SN received injection normal saline (NS) 2 cc immediately after spinal anesthesia. Duration of sensory block, motor block, postoperative analgesia, visual analog pain scale (VAS) score, time of rescue analgesia, total analgesic requirement in the first 24 h, intra- and post operative hemodynamics, and side effects if any were recorded. Whenever demanded rescue analgesia was given in the form of injection tramadol 100 mg. RESULTS: The mean duration of sensory block (min) in group SD and group SN was 162.50 and 106.17, respectively which was highly significant. Similarly, time to the requirement of first rescue analgesia was prolonged in group SD (8.67 h) as compared to group SN (4.40 h). Significant changes were also seen in VAS score in postoperative period after 1 h of surgery in group SD and group SN. Duration of motor block, intra- and post-operative hemodynamic parameters were comparable in both the groups. No side effects were recorded in both the groups. CONCLUSION: We concluded that administration of dexamethasone 8 mg intravenously prolongs the duration of postoperative analgesia and sensory block in patients undergoing lower segment cesarean section under spinal anesthesia. PMID- 28663615 TI - Randomized Controlled Trial for Evaluating the Analgesic Effect of Nalbuphine as an Adjuvant to Bupivacaine in Supraclavicular Block under Ultrasound Guidance. AB - INTRODUCTION: Benefits of regional anesthesia can be prolonged by adding adjuvants to local anesthetics. This study was designed to test the efficacy of adding nalbuphine to bupivacaine in supraclavicular brachial plexus blockade using ultrasound (US) guidance. METHODOLOGY: This was a prospective, randomized, double-blind study involving sixty patients of either sex undergoing elective orthopedic procedures of upper limb. In control Group C (n = 30), 30 mL of 0.375% bupivacaine + 1 mL normal saline and in study Group N (n = 30), 30 mL of 0.375% bupivacaine + 1 mL (10 mg) nalbuphine were used for giving supraclavicular block under US guidance. Parameters assessed were onset and duration of sensory and motor block, duration of analgesia (DOA), and any adverse events. Data between the groups were analyzed using independent t-test with SPSS 16.0 software. RESULTS: In Group N, there was a statistically significant shorter time to onset of sensory blockade (4.89 +/- 1.5 vs. 14.62 +/- 1.73 min, P = 0.000), longer duration of sensory block (373.17 +/- 15.56 min vs. 157.82 +/- 11.02 min, P = 0.000), shorter onset time to achieve motor block (8.83 +/- 1.9 min vs. 18.76 +/- 1.75 min, P = 0.000), longer duration of motor block (313.92 +/- 16.22 min vs. 121.87 +/- 16.62 min, P = 0.000), and prolonged analgesia (389.33 +/- 14.52 min vs. 171.65 +/- 19.79 min, P = 0.000). CONCLUSION: Nalbuphine when added to bupivacaine as an adjuvant in supraclavicular block significantly shortened the onset of sensory and motor block and enhanced the duration of sensory and motor block and DOA. PMID- 28663616 TI - Effect of Pregabalin Premedication on the Requirement of Anesthetic and Analgesic Drugs in Laparoscopic Cholecystectomy: Randomized Comparison of Two Doses. AB - BACKGROUND: Preoperative medication has a vital role in anesthesia. Pregabalin (PG) is a newer drug of gabapentinoid class and is six times more potent than gabapentin. Our study was designed to evaluate the effect of PG as premedication on the perioperative anesthetic requirement and analgesia. MATERIALS AND METHODS: The study was conducted on ninety patients of American Society of Anesthesiologists Grade I and II of age group 20-60 years, allocated to one of the three groups of thirty patients each. Group I received tablet diazepam 10 mg HS and 5 mg 1 h before surgery, Group II received capsule PG 75 mg HS and 150 mg 1 h before surgery, and Group III received capsule PG 75 mg HS and 300 mg 1 h before surgery. Patients were induced with injection fentanyl citrate, thiopentone sodium, and rocuronium bromide and maintained by 66% N2O + 33% O2 gas mixture with sevoflurane and intermittent boluses of fentanyl. RESULTS: Perioperative consumption of thiopentone sodium was 5.59 +/- 0.49 mg/kg in Group I, 4.29 +/- 0.53 mg/kg in Group II, and 4.06 +/- 0.59 mg/kg in Group III; fentanyl was 1.55 +/- 0.42 MUg/kg in Group I, 1.00 +/- 0.00 MUg/kg in Group II, and 1.05 +/- 0.20 MUg/kg in Group III; sevoflurane (%) was 1.20 +/- 0.31 in Group I, 0.933 +/- 0.25 in Group II, and 1.00 +/- 0.00 in Group III. Perioperative requirement of thiopentone sodium, opioid, and inhalational agent was significantly less in Group II and III when compared with Group I. Maximum number of patients required postoperative rescue analgesia within 0-2 h of surgery in Group I, 2-4 h of surgery in Group II, and 6-8 h after surgery in Group III. Patients were more comfortable and asleep with a longer pain-free postoperative period in PG groups. CONCLUSION: PG premedication effectively reduced the consumption of all anesthetic agents during induction and maintenance of anesthesia as compared to diazepam. Patient's postoperative comfort and pain-free duration were also greater with PG premedication; more so with PG 300 mg as compared to PG 150 mg. PMID- 28663617 TI - Comparison between Epidural Ropivacaine versus Ropivacaine with Clonidine in Patients Undergoing Abdominal Hysterectomy: A Randomized Study. AB - CONTEXT: Regional anesthesia has emerged as one of the preferred and convenient modes for intra- and post-operative management owing to its advantage of not interfering with the metabolic functions, better tolerability, and decrease in reflex activity. In recent years, ropivacaine has increasingly replaced bupivacaine as a preferred local anesthetic because of its similar analgesic properties, lesser motor blockade, and decreased propensity of cardiotoxicity. Neuraxial adjuvant such as clonidine used in epidural anesthesia offers advantage by augmenting the local anesthetic effect and reducing the anesthetic and analgesic requirement. AIMS AND OBJECTIVES: Comparison of onset, duration of sensory and motor block, and any adverse effects between 0.5% ropivacaine with normal saline versus 0.5% ropivacaine with clonidine (75 MUg/kg). MATERIALS AND METHODS: This prospective randomized study was carried out in 50 patients (25 in each group) of American Society of Anesthesiologist Grade 1 and 2 scheduled for abdominal hysterectomy under epidural block. Group-1 (ropivacaine-clonidine [RC]): Epidural ropivacaine 20 ml (0.5%) with 0.75 MUg/kg clonidine. Group-2 (ropivacaine [R]): Epidural ropivacaine 20 ml (0.5%) with normal saline. Onset, duration of sensory-motor block, heart rate, blood pressure, oxygen saturation, and respiratory rate were recorded. STATISTICAL ANALYSIS: The statistical analysis was done using Statistical Package for Social Sciences version 15.0. Chi square test, ANOVA, Student's t-test, and paired t-test were used. RESULTS: Groups were comparable with regard to demographic data and hemodynamic stability. Onset of sensory and motor blockade was faster in RC group as compared to R group. Duration of postoperative analgesia was significantly prolonged in RC group. No potential side effect was seen in either group. CONCLUSION: On account of faster onset, hemodynamic stability, and prolonged postoperative analgesia, ropivacaine with clonidine is a better option than ropivacaine alone. PMID- 28663618 TI - Postoperative Analgesia After Panhysterectomy, Addition of Clonidine to Bupivacaine: Boon for the Patients. AB - INTRODUCTION: Postoperative period after panhysterectomy is very painful as there is too much tissue handling. In the practice of regional anesthesia neuraxial, opioids have been used extensively as an adjuvant to bupivacaine to enhance the potency and duration of sensory and motor block produced by bupivacaine with satisfactory results. However, delayed respiratory depression by opioids has prompted further research to develop nonopioid analgesics. This study was undertaken to assess the degree of sensory and motor block and postoperative analgesia provided by low dose 50 MUg intrathecal clonidine admixed with 0.5% hyperbaric bupivacaine as compared to bupivacaine alone in patients undergoing a total abdominal hysterectomy. MATERIALS AND METHODS: Hundred adult patients of American Society of Anesthesiologist Class 1 and 2 were randomly allocated to Group A and Group B. Group A patients received 15 mg 0.5% hyperbaric bupivacaine with 50 MUg clonidine intrathecally. Group B patients received 15 mg 0.5% hyperbaric bupivacaine with normal saline. OBSERVATION AND RESULTS: The mean duration of motor block was significantly higher in Group A (270.80+/- 66.0 min) as compared to Group B (184.60 +/- 72.03 min), with statistically significant difference. There was also statistically significant difference in the duration of sensory block between Group A (290.20 +/- 80.27 min) and Group B (190.83 +/- 86.90 min). The duration of postoperative analgesia was significantly higher in Group A as compared to Group B (541.06 +/- 130.64 min and 252.80 +/- 84.10 min respectively). CONCLUSION: Addition of intrathecal clonidine 50 MUg to bupivacaine (15 mg, 0.5%) prolongs the duration of sensory and motor block and duration of analgesia, thus produces an effective spinal anesthesia and good postoperative analgesia for longer duration and reduced postoperative analgesic requirement. PMID- 28663619 TI - Comparison of the Effects of Four Subdoses of Dextroketamine to Reduce Pain during Posterior Brachial Plexus Block: A Randomized Double Blind Study. AB - BACKGROUND: The needle puncture produces discomfort during regional anesthesia. Sedation and local anesthesia are used to promote analgesia and amnesia. The main objective of this study was to compare the efficacy of four subanesthetic doses of dextroketamine for pain relief during brachial plexus block via the posterior approach. MATERIALS AND METHODS: Patients American Society of Anesthesiology I and II programed for elective surgery under brachial plexus block were distributed at randomized into four groups of twenty patients. Group A received dextroketamine 0.1 mg/kg, Group B received dextroketamine 0.15 mg/kg, Group C received dextroketamine 0.2 mg/kg, and Group D received dextroketamine 0.25 mg/kg. Sedation, facility to positioning, reaction to pinprick, nystagmus, hallucination, tachycardia, elevation of systolic blood pressure or cardiac rate, reduction in SpO2 (<96%), apnea, airway obstruction, collateral effects, and patient satisfaction were monitored. RESULTS: There is a positive correlation between increasing dose of ketamine and the degree of sedation and easiness to position the patient on the table. There exists a negative correlation associated between increasing the dose of ketamine and the response to pinprick, as also to the incidence of hallucination. CONCLUSION: Dextroketamine in doses of 0.1 mg/kg provide sufficient sedation to maintain the patient in position for brachial plexus block and for the relief of pain in 55% of them during the procedure, without hemodynamic variation. The pain relief and collateral effects are dose dependent. PMID- 28663620 TI - Pregabalin in Monitored Anesthesia Care for Ear-nose-throat Surgery. AB - AIM: The aim of this study was to determine intraoperative sedative and perioperative analgesic requirement and associated side effects of pregabalin (150 mg) for monitored anesthesia care during ear-nose-throat (ENT) surgeries. MATERIALS AND METHODS: The study design was randomized and single-blinded; fifty patients undergoing elective ambulatory ENT surgeries under monitored anesthesia care were randomly allocated to receive either placebo (Group P) or pregabalin (Group PG) 150 mg, orally 1 h before surgery. All patients were then given intravenous (i.v.) midazolam 2 mg and fentanyl 1 MUg/kg and local anesthesia at the site. Sedation was induced by administering an i.v. bolus of propofol 0.8 mg/kg and was maintained by continuous infusion of propofol. Level of sedation was assessed by Ramsay scale, and propofol infusion was titrated accordingly. Intraoperative pain was assessed by verbal rating scale (VRS) score. Patient having VRS >4 or complaint of pain was given fentanyl (0.5 MUg/kg) i.v. bolus. Intraoperative sedative and analgesic requirement were recorded. Postoperative visual analog scale scores and requirement of analgesics were recorded for the first 24 h after surgery. Diclofenac 75 mg intramuscular (i.m.) was administered as rescue analgesic. Side effects (nausea/vomiting, sedation, dizziness, blurred vision) were also recorded. RESULTS: Intraoperative propofol (212 +/- 11 mg vs. 174 +/- 9 mg; P = 0.013) and fentanyl (120 +/- 8 MUg vs. 94 +/- 6 MUg; P = 0.02) consumption was significantly lower in Group PG. Time to first analgesic request was longer (6.1 +/- 0.4 h vs. 9.5 +/- 1.2 h) with lesser requirement of analgesics (diclofenac) in the postoperative period. Incidence of side effects (sedation, nausea, vomiting) was found to be similar in both the groups. CONCLUSION: Premedication with pregabalin (150 mg) reduces intraoperative sedative and perioperative analgesic requirement in patients undergoing ENT surgeries under monitored anesthesia care with tolerable side effects. PMID- 28663621 TI - Effect of Premedication with Oral Clonidine on Hemodynamic Response during Electroconvulsive Therapy. AB - BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment available for the acute treatment of depression in patients who do not respond to medications. It is generally used as a second line treatment for many psychological disorders, mainly major depression and schizophrenia where medication is not effective. ECT is often associated with some complications such as hypertension, tachycardia arrhythmia and even myocardial infarction. Various methods have been used for prevention or control of these cardiovascular side effects. AIM: The aim of this study was evaluating the effect of oral clonidine (0.3 mg) with control group to know the effect of oral clonidine on hemodynamic response during ECT. METHODS AND MATERIAL: This prospective randomized crossover clinical trial was performed on 25 patients aged 20-50 years, weight 50-70 kg with ASA I and II who were candidates for ECT. Prior to ECT, each patient received oral doses of clonidine (0.3 mg) or a placebo 90 minutes before ECT. Baseline Heart rate, systolic, diastolic and mean arterial pressures were noted just before securing the intravenous cannula. The same parameters were noted after induction, immediately after seizure cessation following delivery of the electric shock and at 1 minute interval for 10 minutes. STATISTICAL ANALYSIS: Data was analyzed by ANOVA test (analysis of variance). P < 0.05 was considered statistically significant. RESULTS: Attenuation of maximum rise in the heart rate and mean arterial pressure by clonidine (0.3 mg) was evident and statistically significant when compared with control group. CONCLUSION: Oral clonidine (0.3 mg) decreases the acute hypertensive response after electroconvulsive therapy; however, this antihypertensive effect was achieved by decreasing the blood pressure before the electrical stimulus. PMID- 28663622 TI - Comparative Evaluation of Continuous Thoracic Paravertebral Block and Thoracic Epidural Analgesia Techniques for Post-operative Pain Relief in Patients Undergoing Open Nephrectomy: A Prospective, Randomized, Single-blind Study. AB - BACKGROUND: Open surgical procedures are associated with substantial postoperative pain; an alternative method providing adequate pain relief with minimal side effects is very much required. AIM: The aim of this study was a comparative evaluation of the efficacy of continuous thoracic paravertebral block (PVB) and thoracic epidural analgesia (EA) for postoperative pain relief in patients undergoing open nephrectomy. SETTINGS AND DESIGN: Prospective, randomized, and single-blind study. MATERIALS AND METHODS: Sixty adult patients undergoing open nephrectomy under general anesthesia were randomized to receive a continuous thoracic epidural infusion (Group E) or continuous thoracic paravertebral infusion (Group P) with bupivacaine 0.1% with 1 MUg/ml fentanyl at 7 ml/h; both infusions were started after induction of anesthesia. The primary outcome measures were postoperative pain during rest (static pain), deep inspiration, coughing, and movement (getting up from supine to sitting position); the secondary outcome measures were postoperative nausea and vomiting, requirement of rescue antiemetic, hypotension, sedation, pruritus, motor block, and respiratory depression. These were assessed till the morning of the third postoperative day. STATISTICAL ANALYSIS: Results were analyzed by the one-way ANOVA, Chi-square test, and Mann-Whitney U-test. P < 0.05 was considered significant. RESULTS: Both the groups were similar with regard to demographic factors (P > 0.05). The visual analog scale scores at rest, deep breathing, coughing and movement, and postoperative fentanyl consumption were similar in the two groups (P > 0.05); the incidence of side effects was also similar in the two groups (P > 0.05). CONCLUSIONS: Continuous thoracic PVB is as effective as continuous thoracic EA in providing pain relief in patients undergoing open nephrectomy in the postoperative period. The side effect profile of the two techniques was also similar. PMID- 28663624 TI - The Effect of Preemptive Ankle Block using Ropivacaine and Dexamethasone on Postoperative Analgesia in Foot Surgery. AB - BACKGROUND: Peripheral nerve blocks have become an increasingly popular form of anesthesia. Preemptive analgesia reduces central sensitization, postoperative pain, and analgesic consumption. Different additive has been used to prolong regional blockade and improve postoperative analgesia. AIM: This study was conducted to evaluate whether preemptive ankle block using combination of ropivacaine and dexamethasone would succeed in improving the postoperative analgesia after foot surgery in patients receiving general anesthesia. STUDY DESIGN: Randomized double-blind clinical trial. PATIENTS AND METHODS: The study was done on forty American Society of Anesthesiologists physical Status I and II, patients undergoing elective forefoot and midfoot surgery under general anesthesia after written informed consent and Ethical Committee approval, general anesthesia was induced as usual, the patients were breathing spontaneously, laryngeal mask airway was inserted, and anesthesia was maintained using inhalational anesthetic. Ankle block was performed before surgery using 20 ml containing 18 ml ropivacaine 0.75% and 2 ml containing 8 mg dexamethasone in Group I and 20 ml containing 18 ropivacaine 0.75% plus 2 ml normal saline in Group II. Evaluation of ankle block was performed by testing the motor response to electric nerve stimulation of both the posterior tibial nerve and the deep peroneal nerve. The absence of any motor responses indicated success of the block. Surgery was started in 30 min after the block. After recovery from anesthesia, the following was measured, visual analog score at 1, 4, 6, 12, and 24 h, the time to the first rescue analgesic, the analgesic requirements, and any side effects. STATISTICAL ANALYSIS: Data were presented as means (standard deviation). Mann-Whitney U-test were used for continuous data. Student's t-test was used for normal distributed data. RESULTS: Patients were similar as regard to demographic data, type, and duration of surgery. Pain intensity was significantly lower in dexamethasone group (P < 0.05). Time to first rescue analgesic was prolonged in dexamethasone group (110 +/- 3.3 min vs. 66 +/- 7.9 min; P = 0.001) The analgesic consumption was significantly lower in dexamethasone group. The complication was minor and self-controlled in both groups. CONCLUSION: The addition of dexamethasone to ropivacaine improved preemptive ankle block analgesia by decreasing postoperative pain intensity and analgesic consumption with minimal postoperative complication. PMID- 28663623 TI - Comparison of Epidural Butorphanol with Neostigmine and Epidural Sufentanyl with Neostigmine for First Stage of Labor Analgesia: A Randomized Controlled Trial. AB - BACKGROUND: Epidural administration of neostigmine appears to be safe in the obstetric population. Recently, few studies have concluded 10 MUg sufentanil to be an effective adjuvant with epidural neostigmine in providing labor analgesia. However, no study has evaluated the analgesic effect of epidural butorphanol with neostigmine for the same. MATERIALS AND METHODS: The parturients were randomly allocated to one of the three study groups - Group A (n = 30) received butorphanol 1 mg and neostigmine 7 MUg/kg. Group B (n = 30) received sufentanil 10 MUg and neostigmine 7 MUg/kg. Group C (n = 30) received neostigmine 7 MUg/kg and 0.9% normal saline. Maternal hemodynamic parameters and fetal heart rate (FHR) were continuously monitored. The level of sensory and motor block, and visual analog scale (VAS) pain score were recorded at designated time points. In addition, the total duration of analgesia, duration of labor, mode of delivery, and any maternal or fetal adverse effects were also recorded. STATISTICAL ANALYSIS USED: A one-way analysis of variance (ANOVA) with post hoc Tukey's test was used to compare mean value among the three groups for age, height, weight, gestational age, and cervical dilatation. Repeated measure ANOVA was used to compare mean difference among the time points and also the trend among the various time points for hemodynamic parameters, VAS pain score, and FHR. For inter-group comparison among the groups, post hoc Tukey test was used. RESULTS: There was a statistically significant longer effect of analgesic drug in Group B with respect to Group A and C (P < 0.001); however, the parturient in Group C had minimum duration of analgesia. Epidural neostigmine combined with sufentanil produces effective analgesia in early labor (VAS <30 within 10 min in 63.3% of parturient and within 15 min in 83.3% parturient) with average duration of 111.67 +/- 24.51 min without motor block or other side effect in mother and fetus. No significant effect was observed in the duration of labor and mode of delivery in between the two groups, and none of the patients in any group had any maternal or fetal side effects. CONCLUSION: Epidural combination of sufentanil with neostigmine provided better pain relief in terms of the total duration of analgesia and the reduction in VAS pain scores at various time points in the initial 30 min of epidural administration of drugs during the first stage of labor in parturient when compared to the epidural combination of butorphanol with neostigmine. PMID- 28663625 TI - A Comparative Study of Analgesic Efficacy of Intrathecal Buprenorphine with Ultrasound-Guided Transversus Abdominis Plane Block for Postcesarean Delivery Analgesia. AB - BACKGROUND: Women undergoing cesarean (CS) delivery present a unique set of challenges to the anesthetist in terms of postoperative pain management. This study was conducted to compare the analgesic efficacy of intrathecal buprenorphine (ITB) with ultrasound-guided transversus abdominis plane (TAP) block in post-CS delivery pain. METHODOLOGY: A prospective randomized comparative study of sixty American Society of Anesthesiologists physical status I and II pregnant patients divided into two groups of thirty each as ITB group and TAP block group after satisfying the inclusion criteria. RESULTS: In the present study, demographic data were comparable between both groups. The time to first analgesic request was significantly longer in ITB group (389.67 +/- 90.78 min) compared to TAP group (669.17 +/- 140.65 min) and was statistically significant, P < 0.001. The mean paracetamol consumption in the first 24 h was higher in the TAP group (3.5 g) compared to the ITB group (1.13 g) and was statistically significant, P < 0.0001, and the mean tramadol consumed in first 24 h was higher in the TAP (46.66 mg) group as compared to the ITB group (16.66 mg) and was statistically significant, P < 0.001. The mean visual analog scale scores assessed at 4, 6, 12, and 24 h was higher in the TAP group and was statistically significant, P < 0.001. CONCLUSIONS: Our study showed that patients receiving ITB for post-CS pain management reported longer duration of analgesia, lower pain scores, and lower analgesic consumption during the first 24 h. The benefits of neuraxial opiates are significant and far outweigh the side effects. PMID- 28663626 TI - ProSeal Laryngeal Mask Airway Placement: A Comparison of Blind versus Direct Laryngoscopic Insertion Techniques. AB - BACKGROUND AND OBJECTIVES: The laryngeal mask airway (LMA) ProSeal is most commonly used supraglottic airway device; it is routinely inserted by blind technique. Although blind insertion technique is most widely used, there are many techniques which are available such as priming the drain tube with a guiding instrument such as a suction catheter, a gum elastic bougie, a Flexi-Slip Stylet, direct laryngoscopy, and even a fiber-optic bronchoscope (FOB). The present study was undertaken to compare and assess the placement of LMA ProSeal using blind versus direct laryngoscopy techniques using FOB. MATERIALS AND METHODS: A prospective randomized comparative study of 110 patients divided into two groups of 55 each as Group I (blind insertion) and Group II (direct laryngoscopic insertion) after satisfying the inclusion criteria. The anatomical position was assessed by flexible FOB and evaluated based on fiber-optic scoring system. RESULTS: In the present study, demographic characteristics, vital parameters, Mallampati score, and Wilson's score were comparable in both the groups (P > 0.05). The fiber-optic score (FOS) 1 in Group II was 78.18% compared to 60% in Group I, but the difference was statistically not significant (P > 0.05). Furthermore, the mean FOS in Group II was slightly high (3.84 +/- 0.87) compared to Group II (1.62 +/- 0.87), but the difference was statistically not significant (P > 0.05). Further hemodynamic parameters (P > 0.05) and complications (P > 0.05) were comparable in both the groups. CONCLUSION: The LMA placement scoring was similar in both blind and direct laryngoscopic techniques. Blind insertion technique is a simpler, easier, and has stood the test of time. PMID- 28663627 TI - Efficacy of Low-dose Ketamine as Sole Analgesic Agent in Maintaining Analgesia and Intraoperative Hemodynamics During Laparoscopic Gynecological Surgeries. AB - BACKGROUND: Ketamine, in low doses, is known to possess intense analgesic properties. The available literature shows wide variation regarding the time and dose of administration of ketamine during surgery. AIM: The aim of this study was to evaluate the effect of intraoperative administration of ketamine when used as sole analgesic in low doses, on hemodynamics and postoperative analgesia in patients undergoing laparoscopic gynecological surgery and compared on the basis of duration of surgery. SETTINGS AND DESIGN: This prospective, observational study was conducted from July to December 2015, over a period of 6 months in a tertiary care medical college and hospital. MATERIALS AND METHODS: Seventy patients between 23 and 55 years planned for laparoscopic gynecological surgery were recruited. Ketamine was given in a dose of 0.5 mg/kg preoperatively and then repeated every 1/2 hourly in a dose of 0.25 mg/kg throughout the surgery. Hemodynamic parameters, time to the first rescue analgesia and complications were recorded for the first 8 h. Statistical evaluation was done and result expressed as percentage. Paired t-test was employed for the comparison of numerical variables within the group. RESULTS: Seventy percent of the patients did not require any postoperative rescue analgesia during the first 8 h after surgery. None of the patients complained of pain immediately after extubation, and 16% of the patients had minor postoperative complications. The intraoperative hemodynamic profile was significantly altered. Duration of surgery and dose of ketamine required did not affect the duration of analgesia. CONCLUSION: Ketamine in low dose proved to be an efficacious analgesic even in the long duration laparoscopic gynecological surgeries. It stabilizes intraoperative hemodynamics thereby reducing the requirement of other anesthetic and antihypertensive agents. PMID- 28663628 TI - Preoperative Anxiety before Spinal Anesthesia: Does Internet-based Visual Information/Multimedia Research Decrease Anxiety and Information Desire? A Prospective Multicentered Study. AB - BACKGROUND: Preoperative anxiety may lead to peroperative or postoperative problems when not overcome. AIMS: The aim of this study was to examine the effect of seeking information and other factors on the anxiety of patients preoperatively. SETTINGS AND DESIGN: This study was a prospective, multicentered survey. MATERIALS AND METHODS: Patients scheduled to undergo surgical procedures under spinal anesthesia, preoperatively evaluated as the American Society of Anesthesia 1-3 and where spinal anesthesia was agreed on beforehand, were included. Patients completed State-Trait Anxiety Inventory Scale-State (STAI-S) survey preoperatively. Patients who sought information were also asked to complete the Amsterdam Preoperative Anxiety and Information Scale survey. STATISTICAL ANALYSIS: Quantitative data were compared with one-way ANOVA with post hoc analysis or Kruskal-Wallis test. Comparison of two groups of parameters showing normal distribution was compared using Student's t-test. Comparison of groups versus anxiety was performed using Chi-square and Fisher's exact tests. RESULTS: A total of 330 patients were included. Average STAI-S scores were similar when evaluated for patients' demographic data, gender, marital status, place of residence, type of operation, preoperative fasting time, and comorbidities. University graduates were found to have lower anxiety when compared to other educational statuses. Seeking information from the internet caused a significant decrease in surgical anxiety (P < 0.05) although it had no effect on anesthesia-related anxiety. Interestingly, those seeking information had higher information desire levels compared to patients who had not sought other sources of information (P < 0.05). CONCLUSION: While patients seeking information regarding surgical procedure and/or spinal anesthesia have lower preoperative anxiety levels, their information desire remains high. Apart from detailed information given by the anesthesiologist or surgeon, having access to correct and validated information in multimedia form may decrease anxiety and information desire. PMID- 28663629 TI - The Effect of Multimodal Analgesia on Intraoperative Morphine Requirement in Lumbar Spine Surgeries. AB - BACKGROUND: Lumbar spine surgery demands intense analgesia. Preemptive multimodal analgesia (MMA) is a novel approach to attenuate the stress response to surgical stimulus. AIMS: The aim of the study was to assess the intraoperative morphine consumption in patients undergoing lumbar spine surgery. PATIENTS AND METHODS: A randomized, prospective, double-blind study involving 42 patients belonging to the American Society of Anesthesiologists Class I and II scheduled to undergo elective lumbar spine surgery were allocated into two groups of 21 each. Group A (study group) received injection diclofenac sodium, paracetamol, clonidine, and skin infiltration with bupivacaine adrenaline and Group B (control group) received paracetamol and skin infiltration with saline adrenaline. Preemptive analgesia was practiced in both the groups. Intraoperative morphine consumption was documented. STATISTICAL METHODS: Intraoperative morphine consumption between the two groups was compared using Mann-Whitney U-test. Postextubation sedation score between the two groups was compared using Chi-square test and presented as number and percentage. P < 5% was considered statistically significant. RESULTS: Intraoperative morphine consumption was significantly low in the study group (P < 0.001). Postextubation sedation score was comparable between the two groups. CONCLUSION: Preemptive MMA has demonstrated significant morphine sparing effect intraoperatively in patients undergoing lumbar spine surgeries. PMID- 28663630 TI - A Comparative Study of Clonidine and Lignocaine for Attenuating Pressor Responses to Laryngoscopy and Endotracheal Intubation in Neurosurgical Cases. AB - BACKGROUND AND AIMS: Laryngoscopy and endotracheal intubation are associated with reflex sympathetic stimulation, known as pressor response and can cause major complications. We compared the attenuating effect of time-tested lignocaine versus clonidine on the hemodynamic response to laryngoscopy and intubation in neurosurgical cases. DESIGN: A prospective, randomized, comparative, double-blind study with a sample size of sixty patients. METHODS: Sixty patients undergoing elective neurosurgery were randomly allocated into one of the two groups: Group L (n = 30) received lignocaine 1.5 mg/kg intravenous (i.v.) before induction and Group C (n = 30) received clonidine 2 MUg/kg i.v. before induction. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were recorded at baseline, after drug, after induction and 1, 2, 3,5,10, and 15 min after intubation. STATISTICAL ANALYSIS: Statistical software, namely, SPSS, version 15.0 by SPSS Inc., Chicago, USA was used for the analysis of data with Chi-square test to compare intergroup hemodynamic parameters. RESULTS: Mean HR remained above baseline at all times after intubation in lignocaine group but decreased at 2 min after intubation and remained below baseline at all times in the clonidine group. SBP, DBP, and MAP all increased above baseline at 1 min after intubation in lignocaine group, and decreased below baseline at 2 min after intubation, whereas in the clonidine group they all decreased below baseline after drug administration and remained below baseline at all times. Therefore, clonidine is very effective in attenuating pressor responses and this difference between the groups is statistically very significant with P < 0.001. CONCLUSION: Clonidine is more effective than lignocaine for attenuating the pressor responses to laryngoscopy and endotracheal intubation in neurosurgical cases. PMID- 28663631 TI - Influence of Difference in Timing of Perioperative Administration of Low-dose Ketamine on Postoperative Analgesia. AB - BACKGROUND: Preemptive analgesia is a part of multimodal regime for effective postoperative analgesia. Ketamine is said to possess preemptive effects, which has been simultaneously refuted by other studies. Hence, we designed this randomized, double-blinded trial to establish the influence of timing of perioperative ketamine administration for superior postoperative analgesia. METHODS: Ninety patients undergoing infraumbilical surgeries under spinal anesthesia were randomized to receive ketamine either preincision (Group KI), preincision and during skin closure (Group KII), or only during skin closure (Group KIII). Outcomes studied were postoperative pain, sedation, and incidence of side effects. RESULTS: Analysis of variance statistics for postoperative visual analog scales (VAS) for pain showed no significant difference in three groups. However, there was a significant difference between Groups KII and KIII in the immediate postoperative period (95% confidence interval [CI] of mean VAS for Group KI = 0.9249-1.4889; 95% CI for Group KII = 1.4406-1.8260; P = 0.043). Sedation scores in the immediate, 4 h and 8 h postoperative showed a significant difference between Group KI and Group KII (P = 0.007, 0.008, 0.001, respectively) and between Group KI and KIII (KI: KIII - P = 0.0008, 0.0006, 0.02, respectively). Although the incidence of psychotomimetic effect was more in Groups KIII, it was not statistically significant. CONCLUSION: Ketamine possesses postoperative analgesic effects in the immediate postoperative period only when its preemptive administration is supplemented with repeat administration during closure. Incidences of side effects were comparable in all groups. PMID- 28663632 TI - Obturator Nerve Block in Transurethral Resection of Bladder Tumor: A Comparison of Ultrasound-guided Technique versus Ultrasound with Nerve Stimulation Technique. AB - BACKGROUND: Obturator nerve (ON) stimulation during transurethral resection of lateral and posterolateral bladder wall tumor under spinal anesthesia may lead to obturator reflex, adductor contraction, and leg jerking with complications such as bleeding, bladder perforation, or incomplete tumor resection. Our study was carried out to obtain successful block of ON using ultrasound (US)-guided technique with or without nerve stimulation in patients undergoing transurethral resection of bladder tumor (TURBT) under spinal anesthesia. AIMS: The aim of the study was to compare the effectiveness of two different techniques in blocking ON and adductor spasm during TURBT. SETTINGS AND DESIGN: Prospective, randomized, double-blind study. SUBJECTS AND METHODS: Sixty patients with American Society of Anesthesiologists Status II and III scheduled to undergo TURBT for lateral and posterolateral bladder wall tumor were enrolled. Group I (US group, n = 30) patients received 5 ml of bupivacaine 0.5% each at anterior, and posterior division of ON under real-time US visualization and Group II (US-NS group, n = 30) received the same amount of bupivacaine 0.5% for each division using US guidance with nerve stimulation-assisted technique. Motor block onset time, block success and performance time, ease of performance of block, and complications were measured besides assessing patient and surgeon satisfaction into two groups. STATISTICAL METHODS USED: SPSS using two sample independent t-test and Pearson's Chi-square/Fisher's exact test. RESULTS: Motor block onset was significantly faster in Group II (6.67 +/- 2.40) than in Group I (12.39 +/- 2.55). A success rate of 90% was achieved in Group II as compared to 76.7% in Group I with increased block performance time in Group II (4.47 +/- 0.73 min) versus (2.10 +/- 0.51 min) in Group I. A better patient and surgeon satisfaction were seen in Group II with combination of US and nerve stimulation technique. No complications were encountered. CONCLUSION: We conclude that both techniques are safe and easy to perform; however, nerve stimulation as an adjunct to US results in a faster onset of block with a higher success rate. PMID- 28663633 TI - Comparing the Efficacy of Caudal with Intravenous Dexamethasone in the Management of Pain Following Lumbosacral Spine Surgeries: A Randomized Double Blinded Controlled Study. AB - BACKGROUND: The challenge in providing analgesia for spine surgeries is to provide extended postoperative pain relief and simultaneously allow early neurological assessment and mobilization. Our study aimed to evaluate the analgesic efficacy of intravenous versus caudal dexamethasone in lumbosacral spine surgeries. MATERIALS AND METHODS: In this prospective double-blind study, a total of 96 patients undergoing lumbosacral spine surgery were randomized into three groups to receive 25 ml of preemptive caudal epidural injection of either injection ropivacaine 0.2% (Group A, n = 32), a 25 ml of injection ropivacaine 0.2%, and intravenous injection dexamethasone 8 mg (Group B, n = 32) or 25 ml mixture of injection ropivacaine 0.2% with injection dexamethasone 8 mg (Group C, n = 32) under general anesthesia. Visual analog scale (VAS), heart rate, blood pressures, blood sugar levels, and time to rescue analgesia were recorded at regular intervals for the first 24 h. Time to discharge was noted. Analysis of variance has been used to find the significance of study parameters between the groups of patients. Statistical software, namely, SAS 9.2 and SPSS 15.0, have been used for the analysis of the data. RESULTS: The mean VAS was significantly lower in the Group C for up to 24 h following the caudal block. No significant hemodynamic changes were noted in any of the groups. The intravenous dexamethasone group showed higher blood glucose levels at 24 h but was not clinically relevant. CONCLUSION: These results suggest that injection dexamethasone is a safe adjunct to caudal ropivacaine in lumbosacral spine surgeries. PMID- 28663634 TI - Comparison of Effect of Ephedrine and Priming on the Onset Time of Vecuronium. AB - BACKGROUND: Succinylcholine has been the neuromuscular blocking drug of choice for laryngoscopy and intubation, but it has several adverse effects. Nondepolarizing neuromuscular blocking drugs are good alternative provided their onset of action is hastened. Priming technique and use of ephedrine or MgSO4 pretreatment is good options. AIMS: To compare the effects of priming and ephedrine pretreatment on the onset time of intubating dose of vecuronium. SETTINGS AND DESIGN: A prospective, randomized comparative study was done at a state-owned tertiary care teaching hospital. MATERIALS AND METHODS: After obtaining the Institutional Ethical Committee approval and written informed consent, sixty patients of either gender aged 18-60 years, the American Society of Anesthesiologists physical status Class I/II, weighing 40-70 kg, were randomly divided into two groups of thirty each. Group E received 70 MUg/kg ephedrine, and Group P received 0.01 mg/kg of vecuronium 3 min before intubating dose of vecuronium. Intubation was done after getting a train of four zero. Intubation time, clinical intubation grade using Cooper's scale, and hemodynamic parameters were noted. STATISTICAL ANALYSIS USED: Chi-square test and independent t-test were done with PASW statistics 18 to analyze data. RESULTS: The mean time for intubation in ephedrine group (E) was 104 +/- 23.282 s and in the priming group (P), it was 142 +/- 55.671 s (P = 0.001). All patients had clinically acceptable intubating conditions, and the grades were comparable among groups (P = 0.791). Hemodynamic parameters were comparable between groups at all time frames (P > 0.05). CONCLUSION: Pretreatment with ephedrine 70 MUg/kg shortens the onset time of vecuronium for intubation and is superior to the priming technique. Low-dose ephedrine, when used along with propofol induction, provides hemodynamic stability during induction and intubation. PMID- 28663635 TI - An Audit of Comparison of Perioperative Outcomes with the Introduction of Standardized Preoperative Evaluation form at a Tertiary Care Hospital in Rural India. AB - INTRODUCTION: Preoperative evaluation of a patient is the fundamental component of anaesthetic practice. Inadequate documentation and record keeping on the preoperative evaluation form (PEF) can be a major obstacle to attaining good practice and improving patient outcomes following operative procedures. AIM: The aim of the study was to conduct an audit to assess the quality of the preoperative anaesthetic information gathered and to observe the quality profile after the introduction of a standardized pre-operative evaluation form. STUDY DESIGN: This was a retrospective study, using a sample of 3000 files of patients who underwent elective surgery in a tertiary care hospital of rural India. We devised 11 quality indicators, looking at factors in the pre-operative, peri operative and post-operative period, and used them to audit 3000 patient records in our Hospital. RESULTS: We found several areas where quality could be significantly improved;last minute postponement/change of plan of planned surgeries has reduced from 134 (8.9%) to 23 (1.53%) cases after implementation of standardised PEF. 784 (52.26%) patients were not formally handed over to the theatre recovery staff before implementation of standardised PEF compared to 147(9.8%) after implementation of standardised PEF. CONCLUSION: This audit found several areas of practice that fall below expected standards before the introduction of standardised PEF, but after the introduction of standardised PEF there is a significant improvement in quality of pre anaesthetic evaluation and overall outcome of the patient. We therefore advocate the use of such standardised PEFs for performing preoperative and perioperative assessment of surgical patients. PMID- 28663636 TI - Comparison of a New Auto-controlled Injection System with Traditional Syringe for Mandibular Infiltrations in Children: A Randomized Clinical Trial. AB - BACKGROUND: Pain in the dental operatory can have a profound effect on the behavior of children. AIM: The aim of this study is to evaluate the pain perception while administering local infiltration, in children undergoing dental extractions, using a new auto-controlled injection system. MATERIALS AND METHODS: Children in the age range of 6-10 years with teeth indicated for extraction were recruited and allocated to either Group I, computer-controlled injection system (auto system with special cartridge and compatible disposable 30-gauge, 10 mm needles), or Group II, traditional system (30-gauge, 10 mm needle and disposable traditional syringe). Local infiltration was administered and extraction performed after 3 min. The time of administration (TOA) of infiltrate was noted whereas anxiety and pain in both groups were assessed using the Modified Child Dental Anxiety Faces Scale simplified (MCDAS(f)), pulse rate, Faces Pain Scale Revised (FPS-R), and Face, Legs, Activity, Cry, Consolability (FLACC) Scale. RESULTS: The TOA was high in computer group, compared to the traditional system (P < 0.001***); however, anxiety and pain were significantly less in computer group as reported in MCDAS(f), pulse rate, FPS-R, and FLACC (P < 0.001***). CONCLUSIONS: Computer system created a positive and comfortable experience for the child, as well as the practitioner. The possibility of using buccal infiltration instead of inferior alveolar nerve block in children below 10 years was also demonstrated. PMID- 28663637 TI - Evaluation of Leg Wrapping for the Prevention of Postspinal Hypotension in Cesarean Section under Spinal Anesthesia. AB - BACKGROUND: Spinal blockade provides excellent anesthesia for patients undergoing cesarean section. However, hypotension after spinal anesthesia is a common adverse effect that is commonly experienced in patients undergoing cesarean section. The aim of our study was to analyze if a simple technique like leg wrapping with elastic crepe bandage would be effective in controlling postspinal hypotension. MATERIALS AND METHODS: Sixty full-term pregnant patients who were posted for cesarean section belonging to American Society of Anesthesiologists I and II were divided into two groups. Patients in Group W had their legs wrapped with elastic crepe bandage and in the other Group N, leg wrapping was not done. All the patients were preloaded with Ringer lactate at 10 ml/kg before the spinal anesthesia. The hemodynamic parameters were monitored every 3 min until the delivery of the baby and every 5 min until the end of surgery. If hypotension occurred, then along with crystalloid loading a bolus dose of mephentermine 6 mg was given intravenously. STATISTICAL ANALYSIS: Statistical software "Numbers version 3.6.1 (2566)" was used for statistical calculations. RESULTS: Frequency of hypotension in Group W (10%) was significantly less compared to Group N (60%). Vasopressor requirement was significantly less in Group W (P = 0.009), which was highly significant. CONCLUSION: Wrapping of lower extremities was a simple, easy, and an effective method of decreasing episodes of hypotension and vasopressor requirement after spinal anesthesia in cesarean patients and needs to be practiced routinely. PMID- 28663638 TI - Comparative Evaluation of the Local Anesthetic Activity of Root Extract of Anacyclus pyrethrum and its Interaction at the Site of Injection in Guinea Pigs. AB - AIM: The aim of the study was to evaluate the local anesthetic activity of root extracts of the Anacyclus pyrethrum, and to check its effect of interaction at the site of injection in guinea pigs. MATERIALS AND METHODS: The study sample included thirty guinea pigs each weighing 450-500 g, maintained under standard conditions. The root extracts were prepared using three solvents, in 1% and 2% concentration and injected in guinea pigs. The animals were divided into five groups, six in each group based on the type of extract used along with a control and a standard drug. All the animals received 0.5 ml of intradermal injection of the prepared extract, with 1% concentration in the left and 2% in the right dorsal flank of the animal and were checked for local anesthetic activity by a pinprick test. After 72 h, biopsy was done from the injected site to check for drug interaction. RESULTS: The number of negative response obtained from 2% ethanol extract is more effective when compared to other extracts. Histological samples showed inflammatory changes in 1% aqueous extract in a single animal. CONCLUSION: Among the test compounds, 2% ethanol showed more significant effect; hence, it is suggested to synthesize more compounds in this series and evaluate their pharmacological actions. PMID- 28663639 TI - Anesthesiologist's Role in Relieving Patient's Anxiety. AB - INTRODUCTION: Anesthesia and surgery have proved to be highly anxiety provoking and with the rise of elective surgery, its aspect of patient's experience has become prominent in time. However, our fault as anesthesiologists is that we have not made people get versed with what we people as anesthesiologist do in the operating room. Hence, keeping in view all this, a study was carried out, in which video information/images regarding anesthesia and surgical procedure was shown to patients on PowerPoint Presentation. Different images showing previous patient's hospital journey were shown to educate patients. METHODS: Two hundred patients scheduled to undergo elective surgery were taken and were divided into two groups of 100 each. Patients (study group or Group I) were shown video clippings/images of other previously operated patients and their hospital journey including surgery and anesthesia for which patient came in hospital. The study was carried out on the patient in each group while Group II was treated in normal way and not shown any type of images/videos. Hamilton Anxiety Rating Scale was used as a criterion to measure the level of anxiety in Group I and II at four different intervals that are before pre anesthetic check up (PAC), after showing videos and images in Group I, 1 h before surgery and 8 h after surgery. STATISTICAL ANALYSIS: The results of observation of both the groups at different intervals time were statistically compared and analyzed. These characteristics were analyzed using the "Chi-square tests" and "unpaired t-test." RESULTS: Video and images information if done preoperatively have been shown to reduce patient's anxiety, although little is known regarding the effects of the method. CONCLUSION: Showing videos/images of hospital journey for educating the patients before the operation is beneficial to patients undergoing elective surgery. PMID- 28663640 TI - Sonographic Evaluation of Internal Jugular Vein Diameter and Cross-sectional Area Measurements in Correlation with Left Ventricular End Diastolic Area as a Tool for Perioperative Assessment of Volume Status in Pediatric Patients Undergoing Cardiac Surgery. AB - AIM: The aim of this study is to compare the ultrasound estimation of the cross sectional area (CSA) and diameter of internal jugular vein (IJV) with left ventricular end diastolic area (LVEDA) for the assessment of intravascular volume in pediatric patients during cardiac surgery. PATIENTS AND METHODS: The CSA and diameter of the left IJV were defined, using ultrasound machine, and compared with LVEDA, estimated by transesophageal echo, in four times intervals (immediately after induction [T1], before the start of cardiopulmonary bypass [CPB] [T2], immediately after weaning of CPB [T3], and at the end of surgery before transfer to the Intensive Care Unit [T4]) as a tool for intravascular volume assessment in 16 pediatric patients undergoing cardiac surgery. RESULTS: There was a poor correlation between IJV CSA and diameter with LVEDA. r values were 0.158, 0.265, 0.449, and 0.201 at the four time intervals (T1, T2, T3, and T4), respectively. CONCLUSION: Estimation of the CSA and diameter of the left IJV using ultrasound is not reliable and cannot be used alone to decide further management. PMID- 28663641 TI - The Postdural Puncture Headache and Back Pain: The Comparison of 26-gauge Atraucan and 26-gauge Quincke Spinal Needles in Obstetric Patients. AB - BACKGROUND: The postdural puncture headache (PDPH) and postdural puncture backache (PDPB) are well-known complications of spinal anesthesia. There are some attempts to reduce the frequency of complication such as different design of the spinal needles. AIMS: The primary outcome of this study is to compare the incidence of PDPH between 26-gauge Atraucan and 26-gauge Quincke spinal needles in elective cesarean operations. The severity of symptoms, the incidence of backache, technical issues, and comparison of cost of needles are secondary outcomes. MATERIALS AND METHODS: After Investigational Review Board approval, a randomized, prospective, double-blinded study was designed in 682 American Society of Anesthesiologists I-II women having elective cesarean operations under spinal anesthesia. Patients were divided into two groups as 26-gauge Atraucan Group A (n = 323) and 26-gauge Quincke spinal needles Group Q (n = 342). All patients were questioned about backache 1 week later. Differences between categorical variables were evaluated with Chi-square test. Continuous variables were compared by Student's t-test for two independent groups. A two-sided P < 0.05 was considered statistically significant for all analyses. RESULTS: There were no significant differences between groups in all demographic data. The one attempt success rate of the dural puncture in Group A (70,58%) and in Group Q (69.3%) was similar (P > 0.05). The incidence of PDPH was 6.5% in Group A and 4.9% in Group Q (P > 0.05). The epidural blood patch was performed to the three patients in Group A and five patients in Group Q who had severe headache (P > 0.05). The incidence of PDPB was 4.33% versus 2.04% in Group A and Group Q (P > 0.05). CONCLUSIONS: The incidence of complication rates and technical handling characteristics did not differ between two groups. Quincke needle is cheaper than Atracaun needle, so it can be a cost-effective choice in obstetric patients. PMID- 28663642 TI - Capnographic Analysis of Minimum Mandatory Flow Rate for Hudson Face Mask: A Randomized Double-blind Study. AB - BACKGROUND: Oxygen supplementation through Hudson type face mask is frequently used in perioperative settings. Hudson mask is a variable rate performance device with the risk of rebreathing. Studies using capnography to find out an actual fraction of rebreathing in spontaneously breathing patients are not available. AIMS: In this study, we analyzed the effects of different flow rates through Hudson mask with capnography on fractional inspired carbon dioxide (FiCO2). SETTING AND DESIGNS: Forty patients posted for minor surgeries under monitored anesthesia care were divided into four groups. They received oxygen flow rate of 3 L/min, 4 L/min, 5 L/min, and 6 L/min as per group division, through Hudson mask. MATERIALS AND METHODS: Parameters such as pulse rate, noninvasive blood pressure, oxygen saturation, respiratory rate (RR), end-tidal carbon dioxide (EtCO2), and FiCO2 were noted at baseline. After starting oxygen supplementation, these parameters were monitored every minute for ten minutes. Statistical analysis was done using analysis of variance and Kruskal-Wallis test. Pearson correlation was used to establish a relation between RR and FiCO2. RESULTS AND CONCLUSIONS: EtCO2 and FiCO2 were comparable in all four groups with no statistical significance. There was strong positive correlation seen between RR and FiCO2 at a flow rate of 3 L/min while negative correlation in other groups. We conclude that FiCO2 is similar at all flow rates while breathing through Hudson mask. Increase in RR can cause increase in FiCO2 at lower flow rate, which is within physiological tolerance limits. PMID- 28663643 TI - Comparison between Conventional and Ultrasound-Guided Supraclavicular Brachial Plexus Block in Upper Limb Surgeries. AB - INTRODUCTION: Brachial plexus blockade is a time-tested technique for upper limb surgeries. The classical approach using paresthesia technique is a blind technique and may be associated with a higher failure rate and injury to the nerves and surrounding structures. To avoid some of these problems, use of peripheral nerve stimulator and ultrasound techniques were started which allowed better localization of the nerve/plexus. Ultrasound for supraclavicular brachial plexus block has improved the success rate of the block with excellent localization as well as improved safety margin. Hence, this study was planned for comparing the efficacy of conventional supraclavicular brachial plexus block with ultrasound-guided technique. SUBJECTS AND METHODS: After obtaining the Institutional ethical committee approval and patient consent total of 60 patients were enrolled in this prospective randomized study and were randomly divided into two groups: US (Group US) and C (Group C). Both groups received 0.5% bupivacaine. The amount of local anesthetic injected calculated according to the body weight and was not crossing the toxic dosage (injection bupivacaine 2 mg/kg). The parameters compared between the two groups were lock execution time, time of onset of sensory and motor block, quality of sensory and motor block success rates were noted. The failed blocks were supplemented with general anesthesia. RESULTS: Demographic data were comparable in both groups. The mean time taken for the procedure to administer a block by eliciting paresthesia is less compared to ultrasound, and it was statistically significant. The mean time of onset of motor block, sensory blockade, the duration of sensory and motor blockade was not statistically significant. The success rate of the block is more in ultrasound group than conventional group which was not clinically significant. The incidence of complications was seen more in conventional method. CONCLUSION: Ultrasound guidance is the safe and effective method for the supraclavicular brachial plexus block. Incidence of complications are less as ultrasound provides real-time visulaization of underlying structures and the spread of local anaesthetic. PMID- 28663644 TI - Comparison of Intravenous Infusion of Tramadol Alone with Combination of Tramadol and Paracetamol for Postoperative Pain after Major Abdominal Surgery in Children. AB - BACKGROUND: Pain is a common complaint after surgery and seems to be difficult to manage in children because of fear of complications of pain treatment or misconception that infants and small children do not feel pain at all or feel less pain. A survey reported that 40% of pediatric surgical patients experienced moderate or severe postoperative pain and that more than 75% had insufficient analgesia. Our study was carried to provide continuous infusion of intravenous (i.v.) tramadol alone using a dedicated infusion device Graseby 2100 syringe pump and compared it to a combination of i.v. tramadol infusion and per rectal paracetamol. SUBJECTS AND METHODS: A total of 124 children aged 1-8 years selected for the study were randomized into two groups using a table of random numbers. Power calculation had suggested a sample size of 62 in each group with a power of 80% and significance level of 5%. Group A comprising 62 children, received i.v. infusion of tramadol in a dose of 0.25 mg/kg/h for 24 h postoperatively. Group B comprising 62 children, received i.v. infusion of tramadol in a dose of 0.25 mg/kg/h for 24 h postoperatively in addition to per rectal suppository of paracetamol in a dose of 90 mg/kg in 24 h (30 mg/kg as first dose followed by 20 mg/kg every 6 hourly for the next 18 h). Postoperatively, patients were observed for 24 h. RESULTS: A statistically significant difference (P <= 0.001) in Face, Legs, Activity, Cry, Consolability pain scores was seen between two groups at 4, 6, and 8 h. Pain scores being less in Group B patients who had received infusion of tramadol and per rectal suppositories of paracetamol compared to Group A patients who received only infusion of tramadol. A statistically significant difference (P < 0.05) was found in mean analgesic consumption during the first 24 h between the groups. Consumption was more in Group A as compared to Group B. In Group A, 13 patients (21%) required rescue analgesia as compared to only 4 patients (6.5%) in Group B. CONCLUSION: We recommend use of an infusion of tramadol in a dose of 0.25 mg/kg/h in the first 24 h after surgery, in combination with a regular per rectal paracetamol in a daily dose of 90 mg/kg/day in four divided doses for children after major abdominal surgery. However, a close nursing supervision is essential to increase the safety profile. PMID- 28663645 TI - Prophylactic Use of Intravenous Clonidine Compared to Tramadol in Prevention of Intraoperative Shivering under Regional Anesthesia. AB - OBJECTIVES: This study aimed to evaluate the relative efficacy of prophylactic intravenous (IV) clonidine and tramadol for control of intraoperative shivering following spinal anesthesia. MATERIALS AND METHODS: After institutional ethical clearance, 142 patients were chosen from either gender, aged 20-60 years, physical status American Society of Anesthesiology Class I and II scheduled for elective infraumbilical surgery under spinal anesthesia. Patients were randomized into two groups: Group C (n = 71) received injection clonidine 50 MUg) IV in 100 ml normal saline (NS) over 10 min and Group T (n = 71) received injection tramadol 50 mg IV. In 100 ml NS over 10 min after spinal anesthesia. RESULTS: Incidence of shivering was not significant when compared between the two groups (P > 0.05). The axillary temperatures fell significantly in Group C from the baseline and remained at a significantly lower level up to 60 min after rescue drug was administered in patients who shivered. There was a similar fall in axillary temperature in Group T in patients having shivering, but the difference was not significant. When compared between the two groups among patients who shivered, the difference in fall of temperature was not significant. Side effects such as hypotension, bradycardia, and sedation were significantly more common in clonidine group, whereas nausea was significantly more common patients of tramadol group. CONCLUSION: Prophylactic administration of both tramadol and clonidine is effective for controlling shivering under spinal anesthesia. However, tramadol is better because of higher response rate, less sedation, and lesser hemodynamic alterations. PMID- 28663646 TI - Fears and Perceptions Associated with Regional Anesthesia: A Study from a Tertiary Care Hospital in South India. AB - AIMS: To assess the patients' fears and their perception about regional anesthesia and to study the correlation between fears and perception and demographic profile. DESIGN: A prospective cross-sectional survey on 150 patients scheduled for surgery under regional anesthesia (RA). MATERIALS AND METHODS: The structured questionnaires composed of patients' demographic data and questions regarding patients' fears about RA. Questionnaires along with consent forms were sequentially distributed to patients. American Society of Anesthesiologists physical status Classes I and II patients aged between 18 and 80 years scheduled for surgery under RA at the preanesthesia clinics were included in the study. STATISTICAL ANALYSIS: Statistical analysis was done by calculating percentages using Chi-square test. RESULTS: One hundred and fifty participants were studied, and their responses were analyzed. Overall, 75.3% (n = 113) patients had preoperative fear. Fear of pain during surgery, i.e., 49.3% (n = 56) and fear of needles 48.7% (n = 55) were the most common fears that were observed in the study population. Patients had less fear regarding nausea, vomiting, and headache. Patients' demographic details did not have a significant correlation with their fears except for gender, with women being more afraid (86.3% vs. 67.7% of men, P = 0.01). Six patients (4%) revealed dissatisfaction and 10 patients were neutral with RA. Ten patients (6.7%) opted for GA in the future and one patient opted for RA with sedation. CONCLUSION: There is a significant prevalence of fear for RA and its procedures which can affect the patients' decision and postoperative anxiety. The study replicated the high prevalence of anxiety and fear and has clinical implication of improving the education and specifically targeting the fears and anxiety to help the patients' better cope during and after the surgical procedure. PMID- 28663647 TI - Incidence of Awareness with Recall under General Anesthesia in Rural India: An Observational Study. AB - CONTEXT: Awareness under anesthesia is a rare but extremely unpleasant phenomenon. There are very few studies in the developing world and none from rural areas where incidence of intraoperative awareness may be higher due to increased patient load, limited patient knowledge and lack of trained hospital staff, reliance on older, cheaper but less effective drugs, and lack of proper equipment both for providing anesthesia, as well as monitoring the patient. AIMS: To assess the incidence of intraoperative awareness during general anesthesia among patients in rural India and any factors associated with the same. SETTINGS AND DESIGN: Prospective, nonrandomized, observational study. SUBJECTS AND METHODS: Patients undergoing elective surgical procedures in various specialties under general anesthesia from over a period of 1 year were considered for this study. Approximately, after 1 h of arrival in postanaesthesia care unit, anesthesiologist (not involved in administering anesthesia) assessed intraoperative awareness using a modified form of Brice questionnaire. STATISTICAL ANALYSIS USED: Data were collected on a Microsoft Excel(r) sheet and analyzed using Statistical Package for the Social Sciences(r) version 23 (SPSS Inc., Chicago, IL, USA) for windows. RESULTS: A total of 896 patients completed the questionnaire. Postoperatively, in response to the questionnaire, seven patients reported to have remembered something under anesthesia. Out of these, three patients described events that were confirmed by operation theater staff to have occurred whereas they were under anesthesia. CONCLUSIONS: Incidence of definite awareness under anesthesia with postoperative recall was found to be 0.33% (three patients out of total 896) in our study. PMID- 28663648 TI - Comparison of Intrathecal Levobupivacaine and Levobupivacaine plus Fentanyl for Cesarean Section. AB - AIMS AND OBJECTIVES: The aim of this study is to compare the effects of intrathecal levobupivacaine with levobupivacaine and fentanyl in patients undergoing cesarean section. METHODS: Patients with American Society of Anesthesiologists Physical Status I and II scheduled for cesarean section under spinal anesthesia were randomly allocated with thirty patients each. Group L: levobupivacaine group - thirty patients (10 mg). Group F: levobupivacaine plus fentanyl group - thirty patients (7.5 mg + 12.5 MUg). Hemodynamic monitoring, sensory and motor levels, and neonatal Apgar score were noted intraoperatively. The total duration of motor and sensory block, time for rescue analgesia was noted postoperatively. RESULTS: Prolonged duration of postoperative sensory and rescue analgesia was found in Group F - 112.97 +/- 19.42, 231.26 +/- 10.92 min as compared to Group L - 100.37 +/- 10.64, 185.93 +/- 11.09 min and duration of motor blockade was prolonged in Group L - 87.83 +/- 15.04 min than Group F - 79.20 +/- 8.93 min and P < 0.05 was found statistically significant. Apgar scores in both groups were comparable. CONCLUSION: Intrathecal levobupivacaine plus fentanyl prolonged duration of sensory block and rescue analgesia without prolonging motor block which could help in early ambulation. PMID- 28663649 TI - The Analgesic Efficacy of Dexamethasone Added to Ropivacaine in Transversus Abdominis Plane Block for Transabdominal Hysterectomy under Subarachnoid Block. AB - BACKGROUND AND AIMS: Ultrasound-guided transversus abdominis plane (TAP) block has been proven as a safe and effective analgesic technique for several lower abdominal surgeries. Various adjuvants have been used to intensify the quality and prolong the local anesthetic effect. We evaluated the analgesic efficacy of dexamethasone addition to ropivacaine in TAP block following open abdominal hysterectomy. MATERIALS AND METHODS: After clearance from the Institutional Ethics Committee, a double-blind, prospective, randomized study was carried out on sixty patients aged 40-60 years posted for elective open abdominal hysterectomy comparing bilateral TAP block using 20 ml of 0.5% ropivacaine + 1 ml of 0.9% saline (control Group R) or 20 ml of 0.5% ropivacaine + 4 mg dexamethasone (Group RD). The aim of our study was to observe postoperative pain score (visual analog scale [VAS]), time for first analgesic (TFA) demand, total analgesic consumption, and incidence of nausea or vomiting. STATISTICAL ANALYSIS: Chi-square test and Student's t-test were used, and P < 0.05 was considered as statistically significant. RESULTS: Postoperative VAS pain scores were significantly lower at 4, 6, and 12 h in Group RD as compared to Group R (P < 0.05). Significantly longer TFA (13.2 +/- 7.6 vs. 7.1 +/- 4.6 h, P < 0.001) with lesser tramadol requirement in first 24 h (50.2 +/- 34 vs. 94 +/- 35 mg, P < 0.001) were observed in Group RD as compared to Group R. Incidence of nausea or vomiting was statistically insignificant between the groups (P > 0.05). CONCLUSIONS: Addition of dexamethasone to ropivacaine TAP block prolonged the postoperative analgesia and reduced analgesic requirement following abdominal hysterectomy. PMID- 28663650 TI - Comparison of Epidural Clonidine and Dexmedetomidine for Perioperative Analgesia in Combined Spinal Epidural Anesthesia with Intrathecal Levobupivacaine: A Randomized Controlled Double-blind Study. AB - BACKGROUND: Epidural administrations of alpha2 agonists are being used as adjuvants as they lead to anxiolysis, sedation, analgesia, and hypnosis. AIM: This study aims to evaluate the analgesic effects of epidural alpha2 agonists dexmedetomidine and clonidine in conjunction with intrathecal levobupivacaine in combined spinal epidural anesthesia (CSEA). METHODS: A prospective, randomized controlled study was done to assess and compare the efficacy and clinical profile of two alpha2 adrenergic agonists, clonidine, and dexmedetomidine administered epidurally in combination with intrathecal levobupivacaine in CSEA. The study was conducted for 1 year. Sixty adult patients physical status Class I and II undergoing below umbilical surgeries under CSEA were included in the study after a valid consent. Patients were randomly assigned into two groups, to receive either epidural dexmedetomidine (1.5 MUg/kg) or clonidine (2 MUg/kg) in 10 ml normal saline along with 0.5% isobaric levobupivacaine 15 mg (3 ml). Block characteristics, ability to provide sedation, duration, and quality of analgesia and side effects were studied and compared between the groups. RESULTS: The characteristics of intraoperative block were comparable among two groups. As compared to clonidine, dexmedetomidine provided a better sedation and prolonged analgesia, evidenced by the distribution of visual analog scale scores and requirement rescue analgesic among two groups. The side effect profile of the two drugs was comparable. CONCLUSION: Dexmedetomidine at 1.5 MUg/kg epidurally with intrathecal levobupivacaine is a better adjuvant compared to clonidine at 2 MUg/kg epidurally in CSEA because of better sedation, prolonged analgesia, and safe side-effect profile. PMID- 28663651 TI - Efficacy of Intravenous Ondansetron for Prevention of Postspinal Shivering during Lower Segment Cesarean Section: A Double-Blinded Randomized Trial. AB - BACKGROUND AND AIMS: Elective lower segment cesarean section under spinal anesthesia is frequently associated with shivering. Ondansetron has been shown to be effective for postspinal shivering. In the present study, we compare the efficacy of ondansetron to prevent postspinal shivering in parturients undergoing cesarean delivery under spinal anesthesia. MATERIALS AND METHODS: A total of eighty full-term parturients scheduled for elective lower segment cesarean section under spinal anesthesia were randomly allocated into two groups. Group O received 8 mg/4 ml ondansetron, and Group S received 4 ml normal saline intravenously immediately before induction of spinal anesthesia. The level of sensory block, core body temperature, shivering score, and presence or absence of nausea and vomiting during the perioperative period, 1st and 5th min neonates Apgar scores were recorded. The data analysis was carried out with Z-test and Chi square test. RESULTS: Ten percent (4/40) of patients in Group O and 42.5% (17/40) of patients in Group S had Grade III shivering during the perioperative period and that was treated with intravenous injection tramadol (P = 0.001). Two patients (5%) in ondansetron and 19 patients (47.5%) in control group had nausea and vomiting (P < 0.001) and was treated with intravenous 10 mg metoclopramide. 1st and 5th min Apgar scores of neonates were not statistically different in the groups. CONCLUSIONS: Ondansetron is an effective way to prevent shivering, nausea and vomiting during lower segment cesarean section under spinal anesthesia with no effect on Apgar score. PMID- 28663652 TI - Clonidine as an Adjuvant in Fluoroscopic-guided Transforaminal Epidural Steroid Injection in a Patient of Chronic Lumbosacral Radiculopathy. AB - Transforaminal epidural steroid injection (TFESI) is a minimally invasive modality used to treat patients with lumbosacral radiculopathy secondary to prolapsed intervertebral disc or spinal canal stenosis. In this case report, we describe the management of a patient with chronic lumbosacral radiculopathy secondary to intervertebral disc herniation which was seen as a right paracentral disc protrusion at levels L4-L5, L5-S1 causing thecal sac indentation, effacement of the right lateral recess and right exiting nerve root impingement as was seen on the magnetic resonance image. Diffuse disc bulge at levels L4-L5 and L5-S1 caused thecal sac indentation with right neural foraminal narrowing. There was no evidence of associated facet joint arthropathy. Owing to the persistence of symptoms for >6 weeks despite medicines and an ESI through the caudal route 4 weeks back, anticipation of efficacy of TFESI with methylprednisolone using clonidine as an adjuvant in our patient was justifiable. PMID- 28663653 TI - Anesthetic Management of a Parturient with Severe Pulmonary Restenosis Posted for Cesarean Section. AB - Adults with congenital heart disease are increasing due to improvement in infant heart surgery and availability of better cardiac care. Pregnancy in these patients requires multidisciplinary team approach due to circulatory changes. We describe an anesthetic management of the parturient undergoing cesarean section having severe pulmonary restenosis. PMID- 28663654 TI - Successful Management of above Knee Amputation with Combined and Modified Nerve Blocks. AB - We report a successful management of a case of methicillin-resistant Staphylococcus aureus positive right lower limb cellulitis for above knee amputation under combined nerve blocks. The ongoing sepsis, thrombocytopenia, and severe respiratory infection with wheeze made us avoid both neuraxial block and general anesthesia and plan for a nerve block. We instituted a modified high inguinal femoral block along with sciatic and lateral femoral nerve blocks separately to successfully conduct the case. We decided to report as there were not as many cases as ours in the literature. PMID- 28663655 TI - Extradural Hematoma Following Temporomandibular Joint Interposition Arthroplasty. AB - We describe a case of a 17-year-old male who remained drowsy following left temporomandibular joint (TMJ) interposition arthroplasty for TMJ ankylosis. Computed tomography of the head demonstrated an extradural hematoma. The possible cause of this unusual occurrence is discussed. PMID- 28663656 TI - Dilemmas in Anesthetic Management of a Patient with History of Anaphylaxis to Vecuronium. AB - Anaphylaxis during anesthesia is a life-threatening situation that occurs uncommonly. A 60-year-old woman with a history of anaphylaxis during previous anesthesia is scheduled to undergo elective open cholecystectomy. Her skin tests revealed sensitivity to vecuronium and nonsensitivity to injections of midazolam, fentanyl, and propofol. Due to high incidence of cross sensitivity among neuromuscular drugs, it was thought best to avoid general anesthesia. Spinal anesthesia was planned for the patient. The patient refused to give consent for spinal anesthesia, and she had to be taken up for surgery under general anesthesia. The only alternate neuromuscular blocking drug available to us was atracurium, which was tested for sensitivity by intradermal test. Atracurium was found to be not sensitive on intradermal test. We report here the dilemma and the challenges faced during management of general anesthesia in a patient with history of anaphylaxis to vecuronium. PMID- 28663657 TI - Continuous Positive Airway Pressure Prevents Hypoxia in Dental Patient with Obstructive Sleep Apnea Syndrome under Intravenous Sedation. AB - Use of sedation in patients with obstructive sleep apnea (OSA) in dentistry is limited. Hypoxia may develop during medication sleep in dental patients with OSA because of repetitive partial or complete obstruction of the upper airway. In this regard, anesthesiologists prefer not to give any sedative to surgical patients with OSA or support the use of general anesthesia due to good airway control. We report a case where we could successfully sedate a dental patient with OSA using intraoperative continuous positive airway pressure (CPAP) without hypoxia. Use of sedation and intraoperative CPAP in patients with OSA may be considered only if the effectiveness at home CPAP therapy is proven. PMID- 28663658 TI - Jet Nebulization of the Supine Patient: The Need for a Modified Front-loading Mask with a Swivel Adaptor and Curvilinear Connector. PMID- 28663659 TI - A Modified Insertion Technique of Ambu AuraGainTM Laryngeal Airway, a Third generation Supraglottic Airway to Reduce the Oral Mucosal Injury. PMID- 28663660 TI - Airway Management with Videolaryngoscope in a Morbidly Obese Patient in a Tertiary Care Centre: Are the Peripheral Hospitals Ready for Such a Scenario? PMID- 28663661 TI - A Simple Novel Technique to Make any Supraglottic Airway Device Magnetic Resonance Imaging Compatible: A Fusion of the Past with the Present. PMID- 28663662 TI - Implications of Pass-over Brachial Plexus. PMID- 28663663 TI - Design Optimization for Accurate Flow Simulations in 3D Printed Vascular Phantoms Derived from Computed Tomography Angiography. AB - 3D printing has been used to create complex arterial phantoms to advance device testing and physiological condition evaluation. Stereolithographic (STL) files of patient-specific cardiovascular anatomy are acquired to build cardiac vasculature through advanced mesh-manipulation techniques. Management of distal branches in the arterial tree is important to make such phantoms practicable. We investigated methods to manage the distal arterial flow resistance and pressure thus creating physiologically and geometrically accurate phantoms that can be used for simulations of image-guided interventional procedures with new devices. Patient specific CT data were imported into a Vital Imaging workstation, segmented, and exported as STL files. Using a mesh-manipulation program (Meshmixer) we created flow models of the coronary tree. Distal arteries were connected to a compliance chamber. The phantom was then printed using a Stratasys Connex3 multimaterial printer: the vessel in TangoPlus and the fluid flow simulation chamber in Vero. The model was connected to a programmable pump and pressure sensors measured flow characteristics through the phantoms. Physiological flow simulations for patient specific vasculature were done for six cardiac models (three different vasculatures comparing two new designs). For the coronary phantom we obtained physiologically relevant waves which oscillated between 80 and 120 mmHg and a flow rate of ~125 ml/min, within the literature reported values. The pressure wave was similar with those acquired in human patients. Thus we demonstrated that 3D printed phantoms can be used not only to reproduce the correct patient anatomy for device testing in image-guided interventions, but also for physiological simulations. This has great potential to advance treatment assessment and diagnosis. PMID- 28663664 TI - Nanomanufacturing Concerns about Measurements Made in the SEM Part IV: Charging and its Mitigation. AB - This is the fourth part of a series of tutorial papers discussing various causes of measurement uncertainty in scanned particle beam instruments, and some of the solutions researched and developed at NIST and other research institutions. Scanned particle beam instruments especially the scanning electron microscope (SEM) have gone through tremendous evolution to become indispensable tools for many and diverse scientific and industrial applications. These improvements have significantly enhanced their performance and made them far easier to operate. But, the ease of operation has also fostered operator complacency. In addition, the user-friendliness has reduced the apparent need for extensive operator training. Unfortunately, this has led to the idea that the SEM is just another expensive "digital camera" or another peripheral device connected to a computer and that all of the problems in obtaining good quality images and data have been solved. Hence, one using these instruments may be lulled into thinking that all of the potential pitfalls have been fully eliminated and believing that, everything one sees on the micrograph is always correct. But, as described in this and the earlier papers, this may not be the case. Care must always be taken when reliable quantitative data are being sought. The first paper in this series discussed some of the issues related to signal generation in the SEM, including instrument calibration, electron beam-sample interactions and the need for physics-based modeling to understand the actual image formation mechanisms to properly interpret SEM images. The second paper has discussed another major issue confronting the microscopist: specimen contamination and methods to eliminate it. The third paper discussed mechanical vibration and stage drift and some useful solutions to mitigate the problems caused by them, and here, in this the fourth contribution, the issues related to specimen "charging" and its mitigation are discussed relative to dimensional metrology. PMID- 28663665 TI - Does Your SEM Really Tell the Truth?-How Would You Know? Part 4: Charging and its Mitigation. AB - This is the fourth part of a series of tutorial papers discussing various causes of measurement uncertainty in scanned particle beam instruments, and some of the solutions researched and developed at NIST and other research institutions. Scanned particle beam instruments, especially the scanning electron microscope (SEM), have gone through tremendous evolution to become indispensable tools for many and diverse scientifc and industrial applications. These improvements have significantly enhanced their performance and made them far easier to operate. But, the ease of operation has also fostered operator complacency. In addition, the user-friendliness has reduced the apparent need for extensive operator training. Unfortunately, this has led to the idea that the SEM is just another expensive "digital camera" or another peripheral device connected to a computer and that all of the problems in obtaining good quality images and data have been solved. Hence, one using these instruments may be lulled into thinking that all of the potential pitfalls have been fully eliminated and believing that, everything one sees on the micrograph is always correct. But, as described in this and the earlier papers, this may not be the case. Care must always be taken when reliable quantitative data are being sought. The first paper in this series discussed some of the issues related to signal generation in the SEM, including instrument calibration, electron beam-sample interactions and the need for physics-based modeling to understand the actual image formation mechanisms to properly interpret SEM images. The second paper has discussed another major issue confronting the microscopist: specimen contamination and methods to eliminate it. The third paper discussed mechanical vibration and stage drift and some useful solutions to mitigate the problems caused by them, and here, in this the fourth contribution, the issues related to specimen "charging" and its mitigation are discussed relative to dimensional metrology. PMID- 28663666 TI - Optimizing noise for defect analysis with through-focus scanning optical microscopy. AB - Through-focus scanning optical microscopy (TSOM) shows promise for patterned defect analysis, but it is important to minimize total system noise. TSOM is a three-dimensional shape metrology method that can achieve sub-nanometer measurement sensitivity by analyzing sets of images acquired through-focus using a conventional optical microscope. Here we present a systematic noise-analysis study for optimizing data collection and data processing parameters for TSOM and then demonstrate how the optimized parameters affect defect analysis. We show that the best balance between signal-to-noise performance and acquisition time can be achieved by judicious spatial averaging. Correct background-signal subtraction of the imaging-system inhomogeneities is also critical, as well as careful alignment of the constituent images used in differential TSOM analysis. PMID- 28663667 TI - Practical Limitations of Aerosol Separation by a Tandem Differential Mobility Analyzer-Aerosol Particle Mass Analyzer. AB - A cavity ring-down spectrometer and condensation particle counter were used to investigate the limitations in the separation of singly and multiply charged aerosol particles by a tandem differential mobility analyzer (DMA) and aerosol particle mass analyzer (APM). The impact of particle polydispersity and morphology was investigated using three materials: nearly-monodisperse polystyrene latex nanospheres (PSL); polydisperse, nearly-spherical ammonium sulfate (AS) and polydisperse lacey fractal soot agglomerates. PSL and AS particles were easily resolved as a function of charge. For fresh soot, the presence of multiply charged particles severely affects the isolation of the singly charged particles. In cases where the DMA-APM was unable to fully resolve the singly charged particles of interest, the peak mass deviated by up to 13 % leading to errors in the mass specific extinction cross section of over 100 %. For measurements of non-spherical particles, non-symmetrical distributions of concentration as a function of mass were a sign of the presence of multiply charged particles. Under these conditions, the effects of multiply charged particles can be reduced by using a second charge neutralizer after the DMA and prior to the APM. Dilution of the aerosol stream serves to decrease the total number concentration of particles and does not remove the contributions of multiply charged particles. PMID- 28663668 TI - Testing a single regression coefficient in high dimensional linear models. AB - In linear regression models with high dimensional data, the classical z-test (or t-test) for testing the significance of each single regression coefficient is no longer applicable. This is mainly because the number of covariates exceeds the sample size. In this paper, we propose a simple and novel alternative by introducing the Correlated Predictors Screening (CPS) method to control for predictors that are highly correlated with the target covariate. Accordingly, the classical ordinary least squares approach can be employed to estimate the regression coefficient associated with the target covariate. In addition, we demonstrate that the resulting estimator is consistent and asymptotically normal even if the random errors are heteroscedastic. This enables us to apply the z test to assess the significance of each covariate. Based on the p-value obtained from testing the significance of each covariate, we further conduct multiple hypothesis testing by controlling the false discovery rate at the nominal level. Then, we show that the multiple hypothesis testing achieves consistent model selection. Simulation studies and empirical examples are presented to illustrate the finite sample performance and the usefulness of the proposed method, respectively. PMID- 28663669 TI - Youth migration, livelihood prospects and demographic dividend: A comparison of the Census 2011 and Agincourt Health and Demographic Surveillance System in the rural northeast of South Africa. AB - The 2011 South African national census shows a cohort of young adults comprising an increasing share of the population. This finding is borne out in longitudinal data from the Agincourt Health and Demographic Surveillance System (HDSS). This primarily descriptive paper uses the Agincourt HDSS to examine the migration, employment and unemployment patterns in young adults. The study reveals high levels of temporary labour migration linking rural areas to metropolitan areas and secondary urban places. The type of work conducted by young adults in the Agincourt population is predominantly unskilled labour for both sexes. However, there is some evidence of female employment increasing in more educated sectors. Across all working ages there is pronounced unemployment, but the main pressure is felt by the younger adult population. Education and skills development for both sexes should be strengthened to support the country's efforts to vastly improve labour force participation amongst the youth. PMID- 28663671 TI - Efficacy and Safety of Sofosbuvir-Based Direct Acting Antivirals for Hepatitis C in Septuagenarians and Octogenarians. AB - BACKGROUND/AIMS: Treatment of chronic hepatitis C (HCV) with newer direct acting antiviral (DAA) agents has been highly effective. Unfortunately, patients over 70 years old are underrepresented in studies. Given current recommendations to screen patients born between 1945 and 1965 for HCV, it is essential to determine the efficacy and safety of DAAs within the elderly population. This study aims to evaluate clinical outcomes of patients aged 70 years or older treated for HCV with DAAs at a single tertiary care center. METHODS: We identified 25 patients aged 70 years or older who were treated for HCV with a sofosbuvir-based regimen. Baseline demographics, prior HCV treatment history, HCV treatment regimen, adverse effects, and interruption or discontinuation of therapy were collected. The primary endpoint was sustained virologic response at 12 weeks after end of treatment (SVR12). Secondary outcomes were self-reported side effects, drug interactions, and changes in medical regimen of treated patients. RESULTS: All patients were genotype 1 (13 1a, 9 1b, 3 unspecified). Seventeen (68%) had cirrhosis including 1 Child's Pugh class B. Fifteen patients were treatment-naive and 10 previously failed treatment with interferon. Seventeen patients were on ledipasvir/sofosbuvir, 4 on simeprevir/sofosbuvir/ribavirin, and 4 on simeprevir/sofosbuvir. Of 25 patients included, 96% (24/25) patients achieved SVR12. Two patients had a greater than 2 g/dL drop in hemoglobin from baseline and both were on ribavirin. Ribavirin was discontinued in 1 patient. One patient required a change in proton pump inhibitor. No patients discontinued therapy due to side effects. CONCLUSIONS: Patients aged 70 years or older with genotype 1 achieved high rates of sustained virologic response with treatment with newer sofosbuvir-based DAAs without any undue adverse events. PMID- 28663670 TI - The Plasma and Serum Metabotyping of Hepatocellular Carcinoma in a Nigerian and Egyptian Cohort using Proton Nuclear Magnetic Resonance Spectroscopy. AB - BACKGROUND/AIMS: Previous studies have observed disturbances in the 1H nuclear magnetic resonance (NMR) blood spectral profiles in malignancy. No study has metabotyped serum or plasma of hepatocellular carcinoma (HCC) patients from two diverse populations. We aimed to delineate the HCC patient metabotype from Nigeria (mostly hepatitis B virus infected) and Egypt (mostly hepatitis C virus infected) to explore lipid and energy metabolite alterations that may be independent of disease aetiology, diet and environment. METHODS: Patients with HCC (53) and cirrhosis (26) and healthy volunteers (19) were recruited from Nigeria and Egypt. Participants provided serum or plasma samples, which were analysed using 600 MHz 1H NMR spectroscopy with nuclear Overhauser enhancement spectroscopy pulse sequences. Median group spectra comparison and multivariate analysis were performed to identify regions of difference. RESULTS: Significant differences between HCC patients and healthy volunteers were detected in levels of low density lipoprotein (P = 0.002), very low density lipoprotein (P < 0.001) and lactate (P = 0.03). N-acetylglycoproteins levels in HCC patients were significantly different from both healthy controls and cirrhosis patients (P < 0.001 and 0.001). CONCLUSION: Metabotype differences were present, pointing to disturbed lipid metabolism and a switch from glycolysis to alternative energy metabolites with malignancy, which supports the Warburg hypothesis of tumour metabolism. PMID- 28663672 TI - Gastric Varices in Cirrhosis vs. Extrahepatic Portal Venous Obstruction and Response to Endoscopic N-butyl-2-cyanoacrylate Injection. AB - BACKGROUND: Gastric varices (GV) are found in patients with portal hypertension. Incidence of bleeding from GV is relatively low, but is severe, and associated with higher mortality. AIMS AND OBJECTIVES: To compare the types of GV in cirrhosis vs. extrahepatic portal venous obstruction (EHPVO) and the results of endoscopic N-butyl-2-cyanoacrylate (NBC, glue) injection. METHODS: Four hundred and fifty-four patients undergone glue injection of GV for primary prophylaxis or control of bleeding for first episode of bleeding from GV between August 2010 and August 2015 were analyzed. RESULTS: Of 454 patients, 64% (n = 292) were cirrhotics and 36% (n = 162) had EHPVO. Types of GV were GOV1 in 16.4% (n = 48) of cirrhotics vs. 7.4% (n = 12) of EHPVO, GOV2 in 76.7% (n = 224) of cirrhotics vs. 53.1% (n = 86) of EHPVO, Isolated gastric Varices (IGV1) in 39.5% (n = 64) of patients with EHPVO vs. 6.8% (n = 20) cirrhotics. The patients were treated with NBC injections. The mean volume of glue injected was 2.89 +/- 1.59 ml over a median of 1 session (range: 1-7). The total volume of glue required was lower in cirrhotics (2.44 +/- 1.17 ml vs. 3.69 +/- 1.91 ml, P < 0.05) than in EHPVO patients. One hundred and seventeen (40.1%) of cirrhotics required >1 sessions of glue injection as compared to 102 (63%) of EHPVO patients. Over mean follow up of 14.7 +/- 6.46 months, rebleeding (10% vs. 13%) was similar in patients with cirrhosis and EHPVO and mortality (15.4% vs. 2.5%) was higher in cirrhotics than EHPVO. CONCLUSION: In patients with bleeding from GV, GOV2 are more common in cirrhotics and IGV1 in patients with EHPVO. Patients with EHPVO required higher total volume of glue and more glue sessions for GV obturation. PMID- 28663673 TI - Spontaneous Bacterial Peritonitis by Burkholderia cepacia Complex: A Rare, Difficult to Treat Infection in Decompensated Cirrhotic Patients. AB - INTRODUCTION: Burkholderia cepacia complex (Bcc) is non-fermenting Gram-negative bacillus and has been rarely reported to cause spontaneous bacterial peritonitis (SBP) in decompensated cirrhosis. OBJECTIVE: This study was done to evaluate the clinical presentation of cirrhotic patients with SBP due to Bcc and to determine its impact on clinical outcome. METHODS: This is a retrospective, observational study conducted during the period from 1st January 2013 through 31st March 2015. Medical records and microbiology laboratory files were reviewed to identify all cases of Bcc associated SBP among patients hospitalized at the liver intensive care unit and analyzed. RESULTS: During the study period, out of 252 SBP patients, 11 (4.3%) patients with a positive ascitic fluid culture for Bcc were identified. Pain abdomen was the predominant symptom present in 9 (81%) patients followed by hepatic encephalopathy in 7 (63%) patients. Acute kidney injury (AKI) was universally present, seen in 6 (54%) patients at the time of presentation and 4 (36%) patients developed AKI during hospital stay. The mean CTP score was 11.2 +/- 1.1 (10-13), and the mean MELD was 24.3 +/- 5.9 (14-35). The mean SOFA and APACHE II score at presentation were 11 +/- 4.2 (4-18) and 19.4 +/- 5.2 (11-28), respectively. A total of 8 (72%) patients (6-ACLF, 2-NASH) succumbed to the illness during hospitalization due to severe sepsis and multiorgan dysfunction and 3 (27%) patients are doing well on follow-up after 3 months. CONCLUSION: SBP caused by Bcc has been rarely reported in cirrhotic patients. This organism is intrinsically resistant to third generation cephalosporins, which are the initial antibiotic of choice for SBP patients, hence associated with multi organ failure and high mortality rates. PMID- 28663674 TI - Fas Receptor Activation by Endogenous Opioids Is A New Mechanism for Cardiomyopathy in Cirrhotic Rats. AB - BACKGROUND: Cirrhosis, a common consequence of chronic liver inflammation is associated with various cardiovascular dysfunctions which are called cirrhotic cardiomyopathy (CC). Among the various possible causes of CC, apoptosis is considered to have a pivotal role. OBJECTIVES: To explore the contribution of endogenous opioids in the apoptosis process in a rat model of CC. MATERIAL AND METHODS: Four genes were selected to cover both intrinsic and extrinsic pathways of apoptosis. Cardiac samples from 4 groups of rats were evaluated. Two groups were cirrhotic through bile duct ligation (BDL) receiving either naltrexone (BDL naltrexone) or saline (BDL-saline), two others were normal rats as sham groups receiving either naltrexone (sham-naltrexone) or saline (sham-saline). Expression level of BCL2, Caspase3, Fas and FasL was explored in all groups using reverse transcriptase real-time PCR. RESULTS: BDL-saline group showed significant over expression of BCL2, caspase3 and Fas. BCL2 expression was 1.44 (P < 0.001) and caspasse3 was 1.35 (P < 0.001) times higher than sham-saline group, Fas was also overexpressed 1.3 (P < 0.001) times higher than BDL-naltrexone group and 1.91 (P < 0.001) compared to sham-naltrexone group. Caspase3 expression was 1.35 (P < 0.001) folds higher than sham-naltrexone group. The expression pattern of FasL revealed no statistically significant change among study groups. CONCLUSION: Fas molecule enrollment during CC is a novel finding. Fas molecule is activated during cirrhosis through elevated levels of endogenous opioids. This pathway is one of the leading causes of CC. Our findings also demonstrated the protective role of naltrexone as opioids antagonist on cardiomyocytes in a rat model of CC. PMID- 28663675 TI - Synchronous Gall Bladder and Bile Duct Cancer: A Short Series of Seven Cases and a Brief Review of Literature. AB - BACKGROUND: Simultaneous presence of cancer in the gall bladder and in the biliary tree could be due to local spread, metastases, de novo multifocal origin, or as part of a field change. In the past, such an association has been described in patients with anomalous pancreatico-biliary ductal junction. AIMS: We studied seven consecutive patients with simultaneous gall bladder and bile duct malignancy with a view to identify the best way to treat them, and if possible to hypothesize the etiopathogenesis. METHODS: Over a period of 24 months, there were seven cases, with synchronous gall bladder and extra-hepatic bile duct cancer. RESULTS: None of our patients had anomalous pancreatico-biliary ductal junction. Three patients were found to have inoperable disease, three other underwent curative resection, and one patient had a complete response to chemotherapy. Herein, we describe these patients and our lessons learnt from these patients with synchronous bile duct and gall bladder cancer. Of the seven patients, we were able to complete a curative resection in three patients, and the three patients were found to have inoperable disease. One patient had an excellent response to chemotherapy. CONCLUSION: Thus aggressive therapy in such patients with gall bladder cancer may be warranted in select cases. Also, the gall bladder specimens in patients undergoing surgery for cholangiocarcinoma should be analyzed in detail to identify foci of dysplasia or change in the epithelium. The pathogenesis may be due to a common field change in the biliary epithelium. PMID- 28663676 TI - Can Alcoholic Liver Disease and Nonalcoholic Fatty Liver Disease Co-Exist? AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) by definition would require exclusion of significant alcohol intake. Present study was aimed to assess the prevalence of various components of metabolic syndrome (MS) in patients with alcoholic cirrhosis (AC) and to study the affect of its presence on the severity of liver disease, testing the hypothesis if alcoholic liver disease (ALD) and NAFLD could co-exist. METHODS: In a retrospective analysis of 16 months data, 81 patients with AC were analysed for the prevalence of MS. The diagnosis of AC was based on the history of alcohol intake, clinical examination, serum biochemistry, hematological parameters, exclusion of other causes of chronic liver disease, imaging and upper gastrointestinal endoscopy. Severity of liver disease was assessed by Child-Turcott-Pugh (CTP) score. MS was assessed as per the ATP III criteria and the affect of MS on CTP score was evaluated. RESULTS: All 81 patients with AC were male [mean age 50.9 +/- 9.5, mean CTP score 8.38 +/- 1.66]. But for three patients (3.7%) all other 78 patients (96.3%) with AC had at least one component of MS. Forty-three (53.0%) patients had full blown MS with three or more components of MS. Sixty-one (75.30%) patients were either overweight [22 (27.1%)] or obese [39 (48.1%)], with a mean BMI of 25.35 +/- 3.86 kg/m2. Type II DM was present in 40 (25%) and 28 (34.5%) patients were hypertensive. Twenty-two (27.2%) patients had hypertriglyceridemia and 52 (64.2%) had low HDL. Eleven (13.6%) patients had Child's A cirrhosis, 46 (56.8%) had Child's B and 24 (29.6%) patients had Child's C cirrhosis. Even though not significant statistically, patients with Child's C cirrhosis (17, 70.83%) had higher presence of MS in comparison to Child's A (7, 63.6%) and B (19, 41.3%) cirrhosis. CONCLUSION: MS is common in patients with AC. Presence of MS may be contributing towards severity of liver disease in these patients indirectly suggesting the co-existence of ALD and NAFLD. PMID- 28663677 TI - Patulin Induced Oxidative Stress Mediated Apoptotic Damage in Mice, and its Modulation by Green Tea Leaves. AB - BACKGROUND: The present study demonstrates the antioxidant and hepatic protective effects of Green tea leaves (GTL). METHODS: The serum level of aspartate aminotransferase and alanine aminotransferase was analyzed. The liver antioxidant enzymes such as SOD, CAT, GPx, GR, GSH, lipid peroxidation and protein carbonyls, ROS content were estimated. The histology of liver tissue was observed and the protein expression of SOD, CAT, Caspase-3 and p53 was investigated by Western blotting. RESULTS: Effectiveness of GTL extract in preventing patulin induced liver damage showed significant reduction in serum ALT and AST to 19% and 85% respectively, the increase in antioxidant levels and lipid peroxidation products with patulin treatment were also reduced with GTL supplementation. The patulin induced increase in hepatic protein carbonyls was significantly reduced by 141 111% with 100 and 200 mg/kg b.wt GTL and in ROS was significantly reduced by 171 140% with 100 and 200 mg/kg b.wt GTL administration respectively. Also showed protection against hepatic tissue damage and protein expression in mice. CONCLUSION: This study showed remarkable antioxidant and hepatic protective effects of GTL. PMID- 28663678 TI - A Dynamic Definition of Acute Kidney Injury Does not Improve Prognosis Assessment in Acutely Decompensated Patients with Cirrhosis. AB - BACKGROUND/OBJECTIVES: to compare the prognostic accuracy for 28 and 90-day transplant-free mortality of a modified CLIF-SOFA score (including a dynamic definition of acute kidney injury) with that of the classic CLIF-SOFA score and KDIGO score for acute kidney injury in patients with acute decompensation of cirrhosis. METHODS: A retrospective analysis of all admissions of acutely decompensated patients with cirrhosis was carried out from January 2012 to December 2014. Classic and modified CLIF-SOFA scores were analyzed, as well as acute kidney injury diagnosis using the KDIGO score regarding their accuracy for 28- and 90-day transplant free mortality prediction. RESULTS: 108 admissions were analyzed. Acute kidney injury diagnosis was met in 37 (34%) patients. Acute-on chronic liver failure was diagnosed in 59 (55%) patients using the classic CLIF SOFA score; and in 64 (59%) patients using the modified CLIF-SOFA score. Both CLIF-SOFA scores were highly effective in predicting 28-day transplant-free mortality (AUCROC 0.93 and 0.92, p = 0.34) as well as 90-day transplant-free mortality (AUCROC 0.79 and 0.78, p = 0.78). Acute kidney injury diagnosis had significantly lower accuracy in mortality assessment (28 and 90-day transplant free mortality AUCROC 0.67 [p = 0.002] and 0.63 [p = 0.02]). CONCLUSIONS: To our knowledge, this is the first evidence of the limited impact of modifying the fixed kidney injury definition currently used for acute-on-chronic liver failure. PMID- 28663680 TI - Hepatocellular Carcinoma: An Unusual Complication of Longstanding Wilson Disease. AB - Wilson disease is caused by the accumulation of copper in the liver, brain or other organs, due to the mutation in ATP7B gene, which encodes protein that helps in excretion of copper in the bile canaliculus. Clinical presentation varies from asymptomatic elevation of transaminases to cirrhosis with decompensation. Hepatocellular carcinoma is a known complication of cirrhosis, but a rare occurrence in Wilson disease. We present a case of neurological Wilson disease, who later developed decompensated cirrhosis and hepatocellular carcinoma. PMID- 28663679 TI - Cytomegalovirus Infection in Liver Transplant Recipients: Current Approach to Diagnosis and Management. AB - Cytomegalovirus (CMV) infection is the most common viral infection in liver transplant recipients, affecting post-transplant patients and graft survival. Recent advances in diagnosis and management of CMV have led to marked reduction in incidence, severity, and its associated morbidity and mortality. CMV DNA assay is the most commonly used laboratory parameter to diagnose and monitor CMV infection. Current evidence suggests that both pre-emptive and universal prophylaxis approaches are equally justified in liver transplant recipients. Intravenous ganciclovir and oral valganciclovir are the most commonly used drugs for treatment of CMV disease. Most of the centre use valganciclovir prophylaxis for prevention of CMV disease in liver trasplant recipient. The aim of this article is to review the current standard of care for diagnosis and management of CMV disease in liver transplant recipients. PMID- 28663681 TI - Living Donor Liver Transplantation for Acute Liver Failure With Fixed Pupils: Are We Fixed? AB - Living donor liver transplantation (LDLT) is fraught with the social and ethical dilemma of excising a part of the liver from a healthy first-degree relative. When LDLT is to be done for an acute liver failure (ALF), identification of a suitable donor is a race against time. Herein, we describe a unique challenge faced by the transplant team of whether to proceed with donor hepatectomy from a son, when the recipient (HBV-related ALF) developed non-reactive fully dilated pupils on the table, prior to beginning the surgery. The patient ultimately underwent a LDLT despite fixed dilated pupils by virtue of further workup, which suggested that cerebral blood flow was maintained despite clinical evidence of brainstem herniation. PMID- 28663682 TI - Hepatitis E Virus Induced Acute Liver Failure with Scrub Typhus Coinfection in a Pregnant Woman. AB - Coinfections contribute significantly to diagnostic challenges of acute febrile illnesses, especially in endemic areas. The confusion caused by overlapping clinical features impedes timely management. Herein, we report an unusual, previously unreported case of a pregnant woman suffering from a coinfection of scrub typhus and hepatitis E virus. A 25-year-old, 31-week pregnant woman presented with jaundice for 5 days and altered sensorium for 2 days. She had features of both viral acute liver failure (ALF) and tropical infections mimicking ALF, including hyperbilirubinemia, coagulopathy, anemia, thrombocytopenia, intravascular hemolysis, and hepatosplenomegaly. Etiological workup revealed rare coinfection of hepatitis E and scrub typhus. Despite all supportive measures, the patient succumbed to her illness (i.e., absent brainstem reflexes and intracranial bleed secondary to coagulopathy) and had poor fetal outcome, which resulted in stillbirth. ALF in a pregnant woman is a medical and obstetric emergency. It can result from varied etiologies that though differ in their incidence, mode of occurrence, and pregnancy outcome, can clinically masquerade as each other, causing diagnostic dilemma. This unusual case report highlights the significance of keeping all such possibilities in mind while managing a pregnant woman with ALF, especially in a country like India where maternal and perinatal mortality rates, the core indicators of national health, are still among the highest in the world. PMID- 28663683 TI - Epigastric Pain in a Patient with Cirrhosis. AB - *Classic images of Schistosomiasis.*Pathology proved case.*Impressive educational case. PMID- 28663684 TI - What is the Risk of Graft Reinfection in Case of Liver Transplantation for Patients With Acute HEV or HAV Infection? PMID- 28663685 TI - Variable Selection via Partial Correlation. AB - Partial correlation based variable selection method was proposed for normal linear regression models by Buhlmann, Kalisch and Maathuis (2010) as a comparable alternative method to regularization methods for variable selection. This paper addresses two important issues related to partial correlation based variable selection method: (a) whether this method is sensitive to normality assumption, and (b) whether this method is valid when the dimension of predictor increases in an exponential rate of the sample size. To address issue (a), we systematically study this method for elliptical linear regression models. Our finding indicates that the original proposal may lead to inferior performance when the marginal kurtosis of predictor is not close to that of normal distribution. Our simulation results further confirm this finding. To ensure the superior performance of partial correlation based variable selection procedure, we propose a thresholded partial correlation (TPC) approach to select significant variables in linear regression models. We establish the selection consistency of the TPC in the presence of ultrahigh dimensional predictors. Since the TPC procedure includes the original proposal as a special case, our theoretical results address the issue (b) directly. As a by-product, the sure screening property of the first step of TPC was obtained. The numerical examples also illustrate that the TPC is competitively comparable to the commonly-used regularization methods for variable selection. PMID- 28663686 TI - Complications of Laparoscopy in Connection with Entry Techniques. AB - The anatomy of the human being has not changed. However, technical developments in operating materials and methods call for improvements in surgical procedures as well as the management of complications. A fundamental distinction between any operating method and laparoscopy is that, in the latter, the initial entry is usually performed in blind fashion. Blind entry may result in vessel or organ damage, especially in patients who have undergone previous surgery. One of the difficulties associated with the entry is that the damage may not be identified immediately and then necessitate major abdominal repair. Furthermore, the improvement of surgical instruments and techniques enables the surgeon to perform even major operations by the laparoscopic approach. This is associated with renewed learning curves and a high rate of complications due to vascular, bowel, uterine, or bladder damage. The improvement of surgical techniques must be accompanied by advancements in the management of complications. The aim of this review is to address the risks of laparoscopy as well as their correct and professional management. (J GYNECOL SURG 33:81). PMID- 28663687 TI - Inference Based on the Best-Fitting Model can Contribute to the Replication Crisis: Assessing Model Selection Uncertainty Using a Bootstrap Approach. AB - Inference and conclusions drawn from model fitting analyses are commonly based on a single "best-fitting" model. If model selection and inference are carried out using the same data model selection uncertainty is ignored. We illustrate the Type I error inflation that can result from using the same data for model selection and inference, and we then propose a simple bootstrap based approach to quantify model selection uncertainty in terms of model selection rates. A selection rate can be interpreted as an estimate of the replication probability of a fitted model. The benefits of bootstrapping model selection uncertainty is demonstrated in a growth mixture analyses of data from the National Longitudinal Study of Youth, and a 2-group measurement invariance analysis of the Holzinger Swineford data. PMID- 28663688 TI - Editorial message: Special issue on current research in apiculture. PMID- 28663689 TI - Brief Biography of Guest Editors of SI of SJBS. PMID- 28663690 TI - Role of honey in modern medicine. AB - Use of honey has a very long history. Honey has been used since ancient time due to its nutritional and therapeutic values. There had been varied ways of consumption honey including its use as a sweetener and flavoring agent. Honey is produced all over the world. The most important nutriment of honey is carbohydrates present in the form of monosaccharides, fructose and glucose. Honey plays an important role as an antioxidant, anti-inflammatory, anti-bacterial agent and augments the adherence of skin grafts and wound healing process. The role of honey has been acknowledged in the scientific literature and there is convincing evidence in support of its antioxidant and antibacterial nature, cough prevention, fertility and wound healing properties. However, its use has been controversially discussed and has not been well accepted in the modern medicine. The aim of this review was explore and highlight the role of honey in modern medicine. PMID- 28663691 TI - Prevalence of the microsporidian Nosema ceranae in honeybee (Apis mellifera) apiaries in Central Italy. AB - Nosema ceranae and Nosema apis are microsporidia which play an important role in the epidemiology of honeybee microsporidiosis worldwide. Nosemiasis reduces honeybee population size and causes significant losses in honey production. To the best of our knowledge, limited information is available about the prevalence of nosemiasis in Italy. In this research, we determined the occurrence of Nosema infection in Central Italy. Thirty-eight seemingly healthy apiaries (2 to 4 hives each) were randomly selected and screened from April to September 2014 (n = 11) or from May to September 2015 (n = 27). The apiaries were located in six areas of Central Italy, including Lucca (n = 11), Massa Carrara (n = 9), Pisa (n = 9), Leghorn (n = 7), Florence (n = 1), and Prato (n = 1) provinces. Light microscopy was carried out according to current OIE recommendations to screen the presence of microsporidiosis in adult worker honeybees. Since the morphological characteristics of N. ceranae and N. apis spores are similar and can hardly be distinguished by optical microscopy, all samples were also screened by multiplex polymerase chain reaction (M-PCR) assay based on 16S rRNA-gene-targeted species specific primers to differentiate N. ceranae from N. apis. Furthermore, PCR positive samples were also sequenced to confirm the species of amplified Nosema DNA. Notably, Nosema spores were detected in samples from 24 out of 38 (63.2%, 95% CI: 47.8-78.5%) apiaries. Positivity rates in single provinces were 10/11, 8/9, 3/9, 1/7, or 1/1 (n = 2). A full agreement (Cohen's Kappa = 1) was assessed between microscopy and M-PCR. Based on M-PCR and DNA sequencing results, only N. ceranae was found. Overall, our results highlighted that N. ceranae infection occurs frequently in the cohort of honeybee populations that was examined despite the lack of clinical signs. These findings suggest that colony disease outbreaks might result from environmental factors that lead to higher susceptibility of honeybees to this microsporidian. PMID- 28663692 TI - Geographical distribution and molecular detection of Nosema ceranae from indigenous honey bees of Saudi Arabia. AB - The aim of the study was to detect the infection level of honey bees with Nosema apis and/or Nosema ceranae using microscopic and molecular analysis from indigenous honeybee race of eight Saudi Arabian geographical regions. A detailed survey was conducted and fifty apiaries were chosen at random from these locations. Infection level was determined both by microscope and Multiplex-PCR and data were analyzed using bioinformatics tools and phylogenetic analysis. Result showed that N. ceranae was the only species infecting indigenous honeybee colonies in Saudi Arabia. As determined by microscope, Nosema spores were found to be in 20.59% of total samples colonies, while 58% of the samples evaluated by PCR were found to be positive for N. ceranae, with the highest prevalence in Al Bahah, a tropical wet and dry climatic region, whereas low prevalence was found in the regions with hot arid climate. Honeybees from all eight locations surveyed were positive for N. ceranae. This is the first report about the N. ceranae detection, contamination level and distribution pattern in Saudi Arabia. PMID- 28663693 TI - Fertility and reproductive rate of Varroa mite, Varroa destructor, in native and exotic honeybee, Apis mellifera L., colonies under Saudi Arabia conditions. AB - Varroa mite is the most destructive pest to bee colonies worldwide. In Saudi Arabia, preliminary data indicated high infestation levels in the exotic honeybee colonies; such as Apis mellifera carnica and Apis mellifera ligustica, compared to native honeybee subspecies Apis mellifera jemenitica, which may imply higher tolerance to Varroasis. In this study, fertility and reproductive rate of Varroa mite, Varroa destructor, in capped brood cells of the native honeybee subspecies were investigated and compared with an exotic honeybee subspecies, A. m. carnica. Mite fertility was almost alike (87.5% and 89.4%) in the native and craniolan colonies respectively. Similarly, results did not show significant differences in reproduction rate between both subspecies (F = 0.66, Pr > F = 0.42). Number of adult Varroa daughters per fertile mother mite was 2.0 and 2.1 for native and craniolan honeybee subspecies respectively. This may indicate that mechanisms of keeping low infestation rates in the native honeybee colonies are not associated with Varroa reproduction. Therefore, potential factors of keeping lower Varroa infestation rates in native honey bee subspecies should be further investigated. PMID- 28663694 TI - The effects of clove oil on the enzyme activity of Varroa destructor Anderson and Trueman (Arachnida: Acari: Varroidae). AB - Varroa destructor, a key biotic threat to the Western honey bee, has played a major role in colony losses over the past few years worldwide. Overuse of traditional acaricides, such as tau-fluvalinate and flumethrin, on V. destructor has only increased its tolerance to them. Therefore, the application of essential oils in place of traditional pesticides is an attractive alternative, as demonstrated by its high efficiency, lack of residue and tolerance resistance. To study the acaricidal activity of essential oils, we used clove oil (Syzygium aromaticum L.), a typical essential oil with a wide range of field applications, and examined its effects on the enzyme activities of Ca2+-Mg2+-ATPase, glutathione-S-transferase (GST) and superoxide dismutase (SOD) and its effects on the water-soluble protein content of V. destructor body extracts after exposure to 0.1 MUl and 1.0 MUl of clove oil for 30 min. Our results showed that the water soluble protein content significantly decreased after the treatments, indicating that the metabolism of the mites was adversely affected. The bioactivity of GSTs increased significantly after a low dosage (0.1 MUl) exposure but decreased at a higher dosage (1.0 MUl), while the activities of SOD and Ca2+-Mg2+-ATPase were significantly elevated after treatments. These results suggest that the protective enzyme SOD and detoxifying enzymes Ca2+-Mg2+-ATPase and GST contributed to the stress reaction of V. destructor to the essential oils and that the detoxification ability of V. destructor via GST was inhibited at higher dosages. Our findings are conducive to understanding the physiological reactions of V. destructor to treatment with essential oils and the underlying mechanisms behind the acaricidal activities of these natural products. PMID- 28663695 TI - In vitro evaluation of the effects of some plant essential oils on Ascosphaera apis, the causative agent of Chalkbrood disease. AB - Ascosphaera apis is one of the major fungal pathogens of honey bee broods and the causative agent of Chalkbrood disease. The factors responsible for the pathogenesis of Chalkbrood disease are still not fully understood, and the increasing resistance of A. apis to commonly used antifungal agents necessitates a search for new agents to control this disease. The in vitro antifungal activities of 27 plant essential oils against two isolates of A. apis (Aksu-4 and Aksu-9) were evaluated. Out of the 27 plant essential oils tested, 21 were found to be effective in killing both isolates of A. apis. Based on their minimum fungicidal concentration (MFC) values, the effective oils were grouped into three categories: highly effective, moderately effective and minimally effective. Mountain pepper oil, Kala Bhangra oil, spearmint oil, babuna oil, betel leaf oil, carrot seed oil, cumin seed oil and clove bud oil were highly effective, with MBC values between 50.0 MUg/mL and 600.0 MUg/mL. Mountain pepper was the most effective essential oil, with an MBC value of 50.0 MUg/mL. Citral and caryophyllene containing oils were the most effective with MIC 50 ppm. The essential oils tested exhibited significant antimicrobial activities against both strains of A. apis, and they may contain compounds that could play an important role in the treatment or prevention of Chalkbrood disease of honeybee. PMID- 28663696 TI - Effects of abamectin and deltamethrin to the foragers honeybee workers of Apis mellifera jemenatica (Hymenoptera: Apidae) under laboratory conditions. AB - This study aimed at evaluating the toxicity of some insecticides (abamectin and deltamethrin) on the lethal time (LT50) and midgut of foragers honeybee workers of Apis mellifera jemenatica were studied under laboratory conditions. The bees were provided with water, food, natural protein and sugar solution with insecticide (concentration: 2.50 ppm deltamethrin and 0.1 ppm abamectin). The control group was not treated with any kind of insecticides. The mortality was assessed at 1, 2, 4, 6, 12, 24, 48, and 72 hour (h) after insecticides treatment and period to calculate the value of lethal time (LT50). But the samples the histology study of midgut collected after 24 h were conducted by Scanning Electron Microscope. The results showed the effects of insecticides on the current results show that abamectin has an adverse effect on honeybees, there is a clear impact on the lethal time (LT50) was the abamectin faster in the death of honeybee workers compared to deltamethrin. Where have reached to abamectin (LT50 = 21.026) h, deltamethrin (LT50 = 72.011) h. However, abamectin also effects on cytotoxic midgut cells that may cause digestive disorders in the midgut, epithelial tissue is formed during morphological alterations when digestive cells die. The extends into the internal cavity, and at the top, there is epithelial cell striated border that has many holes and curves, abamectin seems to have crushed the layers of muscle. Through the current results can say abamectin most toxicity on honeybees colony health and vitality, especially foragers honeybee workers. PMID- 28663697 TI - Toxicity of some insecticides to the haemocytes of giant honeybee, Apis dorsata F. under laboratory conditions. AB - Quantitative studies concerning total and differential haemocyte counts and abnormalities were performed under laboratory conditions for larvae, pupae and adults collected from a wild Apis dorsata colony. Haemolymph samples were observed immediately, thirty and sixty minutes after field recommended concentration exposure of five different insecticides. Total haemocyte counts were significantly higher for larvae and pupae but less for adult bees, however, differential haemocyte counts insignificantly different. Exposure of insecticides showed variable response for tested insecticides with immediate increased change with ethofenprox, diafenthiuron and imidacloprid but decreased for all tested insecticides after sixty minutes. For differential haemocyte counts, plasmatocytes and granulocytes increased with exposure of insecticides. Immune response of haemocytes against insecticides showed different degrees of abnormalities like agglutination, denucleation and cell shape distortion. Such studies may help in possible identification of insect defense mechanisms against their exposure to external hazards for instance insecticide exposure. PMID- 28663698 TI - Efficacy of Mastoparan-AF alone and in combination with clinically used antibiotics on nosocomial multidrug-resistant Acinetobacter baumannii. AB - Emergence of multidrug-resistant Acinetobacter baumannii (MDRAB) has become a critical clinical problem worldwide and limited therapeutic options for infectious diseases caused by MDRAB. Therefore, there is an urgent need for the development of new antimicrobial agents or alternative therapy to combat MDRAB infection. The aim of this study was to investigate effects of Mastoparan-AF (MP AF), an amphipathic peptide isolated from the hornet venom of Vespa affinis with broad-spectrum antimicrobial activity, on MDRAB. As compared with clinical used antibiotics, MP-AF exhibited potent antimicrobial activity at 2-16 MUg/ml against the reference strain A. baumannii ATCC 15151 and seven MDRAB clinical isolates, especially the colistin-resistant MDRAB, E0158. The synergistic antimicrobial combination study revealed that MP-AF acted synergistically with specific antibiotics, e.g., ciprofloxacin, trimethoprim/sulfamethoxazole (SXT) or colistin against some isolates of the MDRAB. It was noteworthy when MP-AF combined with SXT exhibited synergistic activity against all SXT-resistant MDRAB isolates. The synergistic combination of MP-AF and antibiotics could reduce the dosage recommended of each antimicrobial agent and improve the safety of medications with ignorable adverse effects, such as colistin with nephrotoxicity in therapeutic dose. Furthermore, MP-AF combined with antibiotics with different antimicrobial mechanisms could reduce selective pressure of antibiotics on bacteria and prevent the emergence of antimicrobial-resistant strains. Importantly, we are the first finding that MP-AF could make MDRAB from the original non-susceptibility to SXT become sensitivity. In conclusion, MP-AF alone or in combination with other antibiotics, especially SXT, is a potential candidate against MDRAB infection in clinical medicine. PMID- 28663699 TI - Honey and diabetes mellitus: Obstacles and challenges - Road to be repaired. AB - BACKGROUND AND OBJECTIVE: Since ancient times, honey has been used due to its nutritional and therapeutic value. The role of honey has been acknowledged in the scientific literature however, its use has been controversially discussed and has not been well accepted in modern medicine especially for diabetic patients. This study aimed to investigate the role of honey in diabetic patients. METHODS: In this study, we identified 107 research articles from data based search engines including "PubMed", "ISI-Web of Science", "Embase" and "Google Scholar". The research papers were selected by using the primary key-terms including "Honey", "Honey bee" and "Diabetes Mellitus". The research documents in which "Honey" and "Diabetes Mellitus" were debated are included. After screening, we reviewed 66 papers and finally we selected 35 studies which met the inclusion criteria and the remaining documents were excluded. RESULTS: This study investigated the preclinical, clinical, human and animal model studies on honey and diabetes mellitus and found that honey decreases the fasting serum glucose, increases the sting C-peptide and 2-h postprandial C-peptide. Although, there is a dearth of data and literature also contrary discussed the use of honey in diabetic patients. CONCLUSION: Honey decreases the fasting serum glucose, increases fasting C-peptide and 2-h postprandial C-peptide. Honey had low glycemic index and peak incremental index in diabetic patients. The use of honey in diabetic patients still has obstacles and challenges and needs more large sample sized, multi-center clinical controlled studies to reach better conclusions. PMID- 28663700 TI - Interleukin-6 expression on inflamed rat dental pulp tissue after capped with Trigona sp. propolis from south Sulawesi, Indonesia. AB - Background: Propolis is a natural product of plant resins collected by honeybees from various plant sources. It is used as a remedy in folk medicine since ancient times because of its several biological and pharmacological properties. Recently, propolis has been used by dentist to treat various oral diseases. It was always mentioned as an anti-inflammatory agent. Cytokines are proteins that provide communication between cells and play a critical role in a wide variety of processes. It released from cells in an inflammatory process that active, mediate or potential actions of other cells or tissues. When dental pulp has inflammation, several pro-inflammatory cytokines including Interleukin-6 (IL-6) was released by innate immune cells. Objective: To analyse the expression of IL-6 on inflamed rat dental pulp tissue following application of propolis. Material and methods: Trigona sp. propolis was obtained from Luwu Regency, south Sulawesi Province, Indonesia. Flavonoid and non-flavonoid extracts were purified from propolis using thin layer chromatography. The study was applied on 80 male Sprague Dawley rats, 10-12 weeks of age, divided randomly and equally into 5 groups. Group I, as negative control group was not conducted any treatment. At group II, III, IV and V. A Class I cavity (Black Classification) were made on the occlusal surface of right maxillary first molar. The dental pulp was perforated using dental explorer and allowed in the oral environment for 1 h, after that, Ethanolic Extract Propolis (EEP) (Group II), Extract Flavonoid-Propolis (EFP) (Group III), Extract Non-Flavonoid Propolis (ENFP) (Group IV), or Calcium Hydroxide (Ca(OH)2) (Group V) were applied on dental pulp. All cavities were then filled with Glass Ionomer Cement as permanent filling. The rats being sacrificed in 6 h, 2 days, 4 days and 7 days. Sample biopsy were obtained, IL-6 expression was detected by using immunohistochemistry method. Data was analyzed statistically using Freidman and Kruskal Wallis tests with significance level of P < 0.05. Results: All agent showed IL-6 expression in inflamed rat dental pulp tissue, and this expression was decreased with the longer of observation time periods. EEP more stronger to decreased IL-6 expression on inflamed rat dental pulp tissue than other agent. There is significant difference (P < 0.05) of IL-6 expression between group I and other groups in 6 h and 2 days but not in 4 and 7 days time periods. Conclusion: Trigona sp. propolis from south Sulawesi, Indonesia could suppressed the expression of IL-6 on inflamed rat dental pulp tissue. PMID- 28663701 TI - Determining spatio-temporal distribution of bee forage species of Al-Baha region based on ground inventorying supported with GIS applications and Remote Sensed Satellite Image analysis. AB - In arid zones, the shortage of bee forage is critical and usually compels beekeepers to move their colonies in search of better forages. Identifying and mapping the spatiotemporal distribution of the bee forages over given area is important for better management of bee colonies. In this study honey bee plants in the target areas were inventoried following, ground inventory work supported with GIS applications. The study was conducted on 85 large plots of 50 * 50 m each. At each plot, data on species name, height, base diameter, crown height, crown diameter has been taken for each plant with their respective geographical positions. The data were stored, and processed using Trimble GPS supported with ArcGIS10 software program. The data were used to estimate the relative frequency, density, abundance and species diversity, species important value index and apicultural value of the species. In addition, Remotely Sensed Satellite Image of the area was obtained and processed using Hopfield Artificial Neural Network techniques. During the study, 182 species from 49 plant families were identified as bee forages of the target area. From the total number of species; shrubs, herbs and trees were accounting for 61%, 27.67%, and 11.53% respectively. Of which Ziziphus spina-christi, Acacia tortilis, Acacia origina, Acacia asak, Lavandula dentata, and Hypoestes forskaolii were the major nectar source plants of the area in their degree of importance. The average vegetation cover values of the study areas were low (<30%) with low Shannon's species diversity indices (H') of 0.5-1.52 for different sites. Based on the eco-climatological factors and the variations in their flowering period, these major bee forage species were found to form eight distinct spatiotemporal categories which allow beekeepers to migrate their colonies to exploit the resources at different seasons and place. The Remote Sensed Satellite Image analysis confirmed the spatial distribution of the bee forage resources as determined by the ground inventory work. An integrated approach, combining the ground inventory work with GIS and satellite image processing techniques could be an important tool for characterizing and mapping the available bee forage resources leading to their efficient and sustainable utilization. PMID- 28663702 TI - A novel GIS-based approach to assess beekeeping suitability of Mediterranean lands. AB - Honeybees are critically important for the environment and to the economy. However, there are in substantial decline worldwide, leading to serious threat to the stability and yield of food crops. Beekeeping is of pivotal importance, combining the wide economical aspect of honey production and the important ecological services provided by honeybees. In this scenario, the prompt identification of beekeeping areas is strategic, since it maximised productivity and lowered the risks of colony losses. Fuzzy logic is an ideal approach for problem-solving tasks, as it is specifically designed to manage problems with a high degree of uncertainty. This research tested a novel GIS-based approach to assess beekeeping suitability of lands located in Calabria (Southern Italy), without relying to Analytic Hierarchy Process - Multiple Criteria Decision Making (AHP-MCDM), thus avoiding the constraints due to the technique and decision makers' influences. Furthermore, the data used here were completely retrieved from open access sources, highlighting that our approach is characterized by low costs and can be easily reproduced for a wide arrays of geographical contexts. Notably, the results obtained by our experiments were validated by the actual beekeeping reality. Besides beekeeping, the use of this system could not only be applied in beekeeping land suitability evaluations, but may be successfully extended to other types of land suitability evaluations. PMID- 28663703 TI - Alfalfa (Medicago sativa L.) seed yield in relation to phosphorus fertilization and honeybee pollination. AB - This investigation was conducted at the Agricultural and Veterinary Training and Research Station, King Faisal University, Al-Ahsa, Saudi Arabia, during the alfalfa growing season in 2014. The study aimed to evaluate the impact of phosphorus fertilization and honeybee pollination on alfalfa seed production. The experiment was divided into 9 treatments of open pollination, honeybee pollination, and non-pollination with three different levels (0, 300 or 600 kg P2O5/ha/year) of triple super phosphate. All vegetative growth attributes of Hassawi alfalfa were significantly higher in the non-insect pollination plots, while the yield and yield component traits were significantly higher with either open pollination or honeybee pollination in parallel with the increasing level of phosphorus fertilizer up to 600 kg P2O5/ha/year in light salt-affected loamy sand soils. There was no seed yield in Hassawi alfalfa without insect pollination. Therefore, placing honeybee colonies near the fields of Hassawi alfalfa and adding 600 kg P2O5/ha/year can increase seed production. PMID- 28663704 TI - Food for honeybees? Pollinators and seed set of Anthyllis barba-jovis L. (Fabaceae) in arid coastal areas of the Mediterranean basin. AB - Abundance and diversity of insect pollinators are declining in many ecosystems worldwide. The abundance and diversity of wild and managed bees are related to the availability of continuous floral resources. In particular, in Mediterranean basin countries, the presence of wildflower spots enhances the establishment of social Apoidea, since coastal regions are usually characterized by pollen and nectar shortage in early spring and late summer. Anthyllis barba-jovis produces both nectar and pollen as important food source for bees helping them to overcome early spring period food shortage. We investigated flowering, seed set, and pollinator diversity of A. barba-jovis in arid coastal environments of the Mediterranean basin. Pollinator abundance reached a maximum in early April. Honeybees were the most common pollinators followed by bumblebees and solitary bees. Plants prevented from entomophilous pollination showed inbreeding depression with a strong decrease in seed-set. To the best of our knowledge, this is the first report on pollination ecology of A. barba-jovis. PMID- 28663705 TI - Investigation of gut microbial communities associated with indigenous honey bee (Apis mellifera jemenitica) from two different eco-regions of Saudi Arabia. AB - The microbial communities associated with the alimentary tract of honey bees are very important as they help with food digestion, provide essential nutrients, protect the host from pathogens, detoxify harmful molecules, and increase host immunity. In this study, the structural diversity of the gut microbial communities of native honey bees, Apis mellifera jemenitica from two different geographical regions (Riyadh and Al-Baha) of Saudi Arabia was analyzed by culture dependent methods and 16S ribosomal RNA (rRNA) gene sequencing. In this study, 100 bacterial isolates were cultivated and phylogenetic analyses grouped them into three phyla: Proteobacteria, Firmicutes, and Actinobacteria. Bacteria in the phylum Proteobacteria were the most dominant (17 species), followed by Firmicutes (13 species) and Actinobacteria (4 species). Some of the identified bacteria (Citrobacter sp., Providencia vermicola, Exiguobacterium acetylicum, and Planomicrobium okeanokoites) were reported for the first time in the genus Apis, while others identified bacteria belonged to the genera Proteus, Enterobacter, Bacillus, Morganella, Lactobacillus, and Fructobacillus. To the best of our knowledge, this is the first study on the gut microbiota of the local honey bees in Saudi Arabia. PMID- 28663706 TI - PCR-RFLP of mitochondrial DNA reveals two origins of Apis mellifera in Taiwan. AB - Beekeeping has been a highly valued industry in Taiwan. As a result, many subspecies of Apis mellifera have been introduced to Taiwan since 1911, leading to the hybridization of different subspecies. In order to know the matrilineal origins of Taiwan A. mellifera, a total of 280 samples collected from 33 apiaries throughout the island were examined. Using PCR-RFLP of four mitochondrial gene fragments, i.e., the non-coding region between tRNAleu and cytochrome c oxidase subunit II (intergenic tRNAleu-COII), cytochrome b (Cyt b), large subunit rRNA (Ls rRNA) and cytochrome c oxidase subunit I (COI), we only found two haplotypes exist in 280 samples. Haplotypes ababa and bbbaa account for 87% of these Western bees belonged to the Eastern European (C) lineage and 13% belonged to the Middle East (Z) lineage, respectively, with the latter being totally absent in northern Taiwan. African (A) and Mellifera (M) lineages, officially imported once in 1990s and 1930s respectively, were not detected. The identification of subspecies of A. mellifera and survey of their distribution on the island are expected to facilitate efficient breeding programs and establish a more booming beekeeping industry. PMID- 28663707 TI - Comparative analysis of profitability of honey production using traditional and box hives. AB - Information on the profitability and productivity of box hives is important to encourage beekeepers to adopt the technology. However, comparative analysis of profitability and productivity of box and traditional hives is not adequately available. The study was carried out on 182 beekeepers using cross sectional survey and employing a random sampling technique. The data were analyzed using descriptive statistics, analysis of variance (ANOVA), the Cobb-Douglas (CD) production function and partial budgeting. The CD production function revealed that supplementary bee feeds, labor and medication were statistically significant for both box and traditional hives. Generally, labor for bee management, supplementary feeding, and medication led to productivity differences of approximately 42.83%, 7.52%, and 5.34%, respectively, between box and traditional hives. The study indicated that productivity of box hives were 72% higher than traditional hives. The average net incomes of beekeepers using box and traditional hives were 33,699.7 SR/annum and 16,461.4 SR/annum respectively. The incremental net benefit of box hives over traditional hives was nearly double. Our study results clearly showed the importance of adoption of box hives for better productivity of the beekeeping subsector. PMID- 28663708 TI - Osmotic concentration in three races of honey bee, Apis mellifera L. under environmental conditions of arid zone. AB - Hemolymph osmolarity has great effect on honey bee health, especially in arid and semi-arid zones. It regulates water and nutrients in stressed tissues. Osmotic concentration in three races (Apis mellifera ligustica, A. m. carnica and A. m. jemenitica) of Apis mellifera was tested in central Saudi Arabia during spring and summer seasons in 2015. Newly emerged bee workers were first marked and later their hemolymph was extracted after intervals of 1, 5, 10, 15, 20 and 25 days. A significant positive correlation between age and osmolarity was found in all three races during spring and summer seasons. The lowest combined osmotic concentration for all three races was found after 1 day interval, while the highest osmotic concentration was recorded after 25 days. Among all races, A. m. ligustica showed significantly high osmotic concentration after 25 days in spring and summer seasons as compared to the other two races. Only A. m. jemenitica showed similar osmotic concentration after 10 and 15 days in both spring and summer seasons compared to other two races. Mean osmotic concentration of all three races was significantly different after 20 and 25 days in spring and summer seasons. Overall mean recorded during summer was significantly higher than the mean of spring season. Combined osmotic concentration in young drones of all races was significantly lower than that of old drones during spring and summer seasons. PMID- 28663709 TI - Comparative study on the dynamics and performances of Apis mellifera jemenitica and imported hybrid honeybee colonies in southwestern Saudi Arabia. AB - The aims of this study were to assess the seasonal population dynamics and evaluate the performance of Apis mellifera jemenitica (local bee) and introduced hybrid honeybee colonies in the lowlands and highlands of southwestern Saudi Arabia. Data regarding the performance and population dynamics parameters such as brood and adult bee population, amounts of stored pollen and nectar were gathered from the two races (25 colonies of each) for one year (April 2013 through March 2014), and statistically tested. The results indicated that at low lands, local bee colonies maintained relatively high brood and adult bee populations (P < 0.05) than introduced honeybee colonies and produced more (P < 0.05) honey. The local bee colonies were able to hoard three times more (P < 0.05) pollen and built more (P < 0.05) queen cells than introduced bees in both the low and highland areas. The annual survival rate of local bee colonies was almost double (P < 0.05) than that of introduced honeybee colonies. Moreover, local bees had greater (P < 0.05) adult bee and brood populations than imported, throughout the year. The relatively good performance of local colonies could be due to their long year's adaptation to cope with resource scarcity and unpredictable environmental conditions of the regions. The possible reasons for the dwindling of the imported hybrid colonies could be due to continuing to exhibit adaptive characteristics of their original that might not fit well with the new environment. PMID- 28663710 TI - Chemical compositions and characteristics of organic compounds in propolis from Yemen. AB - Propolis is a gummy material made by honeybees for protecting their hives from bacteria and fungi. The main objective of this study is to determine the chemical compositions and concentrations of organic compounds in the extractable organic matter (EOM) of propolis samples collected from four different regions in Yemen. The propolis samples were extracted with a mixture of dichloromethane and methanol and analyzed by gas chromatography-mass spectrometry (GC-MS). The results showed that the total extract yields ranged from 34% to 67% (mean = 55.5 +/- 12.4%). The major compounds were triterpenoids (254 +/- 188 mg g-1, mainly alpha-, beta-amyryl and dammaradienyl acetates), n-alkenes (145 +/- 89 mg g-1), n alkanes (65 +/- 29 mg g-1), n-alkanoic acids (40 +/- 26 mg g-1), long chain wax esters (38 +/- 25 mg g-1), n-alkanols (8 +/- 3 mg g-1) and methyl n-alkanoates (6 +/- 4 mg g-1). The variation in the propolis chemical compositions is apparently related to the different plant sources. The compounds of these propolis samples indicate that they are potential sources of natural bio-active compounds for biological and pharmacological applications. PMID- 28663711 TI - GAP Peptide Synthesis via Design of New GAP Protecting Group: An Fmoc/tBu Synthesis of Thymopentin Free from Polymers, Chromatography and Recrystallization. AB - A novel method for Fmoc/tBu solution-phase peptide synthesis and the development of a new benzyl-type GAP protecting group is reported. This new GAP protecting group is utilized in place of a polymer support, facilitating C->N Fmoc peptide synthesis without chromatography, recrystallization, or polymer supports. The GAP group can be added and removed in high yield, and was used to synthesize over 1 gram of the immunostimulant, thymopentin, in high overall yield (83%) and purity (99%). PMID- 28663712 TI - The Great Recession and America's Geography of Unemployment. AB - BACKGROUND: The Great Recession of 2007-2009 was the most severe and lengthy economic crisis in the U.S. since the Great Depression. The impacts on the population were multi-dimensional, but operated largely through local labor markets. OBJECTIVE: To examine differences in recession-related changes in county unemployment rates and assess how population and place characteristics shaped these patterns. METHODS: We calculate and decompose Theil Indexes to describe recession-related changes in the distribution of unemployment rates between counties and states. We use exploratory spatial statistics to identify geographic clusters of counties that experienced similar changes in unemployment. We use spatial regression to evaluate associations between county-level recession impacts on unemployment and demographic composition, industrial structure, and state context. RESULTS: The recession was associated with increased inequality between county labor markets within states, but declining between-state differences. Counties that experienced disproportionate recession-related increases in unemployment were spatially clustered and characterized by large shares of historically disadvantaged racial and ethnic minority populations, low educational attainment, and heavy reliance on pro-cyclical industries. Associations between these sources of vulnerability were partially explained by unobserved state-level factors. CONCLUSIONS: The local consequences of macroeconomic trends are associated with county population characteristics, as well as the structural contexts and policy environments in which they are embedded. The recession placed upward pressure on within-state inequality between local labor market conditions. CONTRIBUTION: To present new estimates of the recession's impact on local labor markets, quantify how heterogeneous impacts affected the distribution of unemployment prevalence, and identify county characteristics associated with disproportionately large recession-related increases in unemployment. PMID- 28663713 TI - Amine dehydrogenases: efficient biocatalysts for the reductive amination of carbonyl compounds. AB - Amines constitute the major targets for the production of a plethora of chemical compounds that have applications in the pharmaceutical, agrochemical and bulk chemical industries. However, the asymmetric synthesis of alpha-chiral amines with elevated catalytic efficiency and atom economy is still a very challenging synthetic problem. Here, we investigated the biocatalytic reductive amination of carbonyl compounds employing a rising class of enzymes for amine synthesis: amine dehydrogenases (AmDHs). The three AmDHs from this study - operating in tandem with a formate dehydrogenase from Candida boidinii (Cb-FDH) for the recycling of the nicotinamide coenzyme - performed the efficient amination of a range of diverse aromatic and aliphatic ketones and aldehydes with up to quantitative conversion and elevated turnover numbers (TONs). Moreover, the reductive amination of prochiral ketones proceeded with perfect stereoselectivity, always affording the (R)-configured amines with more than 99% enantiomeric excess. The most suitable amine dehydrogenase, the optimised catalyst loading and the required reaction time were determined for each substrate. The biocatalytic reductive amination with this dual-enzyme system (AmDH-Cb-FDH) possesses elevated atom efficiency as it utilizes the ammonium formate buffer as the source of both nitrogen and reducing equivalents. Inorganic carbonate is the sole by-product. PMID- 28663714 TI - Biodegradable seeds of holmium don't change neurological function after implant in brain of rats. AB - AIM: To evaluate the surgical procedure and parenchymal abnormalities related to implantation of ceramic seeds with holmium-165 in rats' brain. BACKGROUND: An effective method of cancer treatment is brachytherapy in which radioactive seeds are implanted in the tumor, generating a high local dose of ionizing radiation that can eliminate tumor cells while protecting the surrounding healthy tissue. Biodegradable Ho166-ceramic-seeds have been addressed recently. METHODS AND MATERIALS: The experiments in this study were approved by the Ethics Committee on Animal Use at the Federal University of Ouro Preto, protocol number 2012/034. Twenty-one adult Fischer rats were divided into Naive Group, Sham Group and Group for seed implants (ISH). Surgical procedures for implantation of biodegradable seeds were done and 30 days after the implant radiographic examination and biopsy of the brain were performed. Neurological assays were also accomplished to exclude any injury resulting from either surgery or implantation of the seeds. RESULTS: Radiographic examination confirmed the location of the seeds in the brain. Neurological assays showed animals with regular spontaneous activity. The histological analysis showed an increase of inflammatory cells in the brain of the ISH group. Electron microscopy evidenced cytoplasmic organelles to be unchanged. Biochemical analyzes indicate there was neither oxidative stress nor oxidative damage in the ISH brain. CAT activity showed no difference between the groups as well as lipid peroxidation measured by TBARS. CONCLUSIONS: The analysis of the data pointed out that the performed procedure is safe as no animal showed alterations of the neurological parameters and the seeds did not promote histological architectural changes in the brain tissue. PMID- 28663715 TI - Personalized radiotherapy treatment planning based on functional imaging. AB - In recent years, a huge progress in the field of radiotherapy could be observed. From treating patients with kilo-voltage X-rays units to cutting edge technology that can deliver a certain dose with an extreme precision. Modern radiotherapy is characterized, among others, by an individualized approach to the patient. This can be provided by functional imaging which is another step toward a better tumor control. In this paper, we discuss the potential application of functional imaging modalities in personalized radiotherapy planning with emphasis on dose painting. Some limitations of this approach will also be evaluated. PMID- 28663716 TI - Reirradiation with IMRT for recurrent head and neck cancer: A single institutional report on disease control, survival, and toxicity. AB - AIM: To study and explores the feasibility and efficacy of re-irradiation (Re-RT) for locally recurrent head and neck cancer (HNC) and second primary (SP) malignancies. BACKGROUND: The most common form of treatment failure after radiotherapy (RT) for HNC is loco-regional recurrence (LRR), and around 20-50% of patients develop LRR. Re-irradiation (Re-RT) has been the primary standard of care in the last decade for unresectable locally recurrent/SP HNC. MATERIALS AND METHODS: It was a retrospective analysis in which we reviewed the medical records of 51 consecutive patients who had received Re-RT to the head and neck region at our institute between 2006 and 2015. RESULTS: Forty-eight patients were included for assessment of acute and late toxicities, response evaluation at 3 months post Re-RT, and analyses of locoregional control (LRC) and overall survival (OS). The median LRC was 11.2 months, and at 2 and 5 years the LRC rates were 41% and 21.2%, respectively. A multivariate analysis revealed two factors: initial surgical resection performed prior to Re-RT, and achievement of CR at 3 months after completion of Re-RT to be significantly associated with a better median LRC. The median OS was 28.2 months, and at 1, 2, and 5 years, OS were 71.1%, 55.9% and 18%, respectively. A multivariate analysis revealed initial surgical resection performed prior to Re-RT, and achievement of CR at 3 months post completion of Re-RT being only two factors significantly associated with a better median OS. Acute toxicity reports showed that no patients developed grade 5 toxicity, and 2 patients developed grade 4 acute toxicities. CONCLUSION: Re-RT for the treatment of recurrent/SP head and neck tumors is feasible and effective, with acceptable toxicity. However, appropriate patient selection criteria are highly important in determining survival and treatment outcomes. PMID- 28663717 TI - Computational and Experimental Characterization of Five Crystal Forms of Thymine: Packing Polymorphism, Polytypism/Disorder and Stoichiometric 0.8-Hydrate. AB - New polymorphs of thymine emerged in an experimental search for solid forms, which was guided by the computationally generated crystal energy landscape. Three of the four anhydrates (AH) are homeoenergetic (A degrees - C) and their packing modes differ only in the location of oxygen and hydrogen atoms. AHs A degrees and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Anhydrates AHs A degrees and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Analysis of the crystal energy landscape for alternative AH C hydrogen bonded ribbon motifs identified a number of different packing modes, whose 3D structures were calculated to deviate by less than 0.24 kJ mol-1 in lattice energy. These structures provide models for stacking faults. The three anhydrates A degrees - C show strong similarity in their powder X-ray diffraction, thermoanalytical and spectroscopic (IR and Raman) characteristics. The already known anhydrate AH A degrees was identified as the thermodynamically most stable form at ambient conditions; AH B and AH C are metastable but show high kinetic stability. The hydrate of thymine is stable only at water activities (aw) > 0.95 at temperatures <= 25 degrees C. It was found to be a stoichiometric hydrate despite being a channel hydrate with an unusual water:thymine ratio of 0.8:1. Depending on the dehydration conditions, either AH C or AH D is obtained. The hydrate is the only known precursor to AH D. This study highlights the value and complementarity of simultaneous explorations of computationally and experimentally generated solid form landscapes of a small molecule anhydrate <-> hydrate system. PMID- 28663718 TI - Temperament and Maternal Emotion Socialization Beliefs as Predictors of Early Childhood Social Behavior in the Laboratory and Classroom. AB - OBJECTIVE: We examined the roles of children's approach behavior and maternal emotion socialization practices in the development of social behavior in unfamiliar and familiar contexts from preschool to early childhood years. DESIGN: At 4.5 years of age, children were observed, and an assessment of approach behavior was obtained; at this time, mothers reported about their emotion socialization beliefs. Two years later, children returned to the laboratory to participate in a peer play paradigm. When children were 7 years of age, teachers completed a questionnaire about children's social behaviors in the classroom. RESULTS: Mothers' emotion socialization beliefs contribute to the developmental outcomes of approach behavior. For instance, observations of approach behaviors predicted a greater proportion of group play in the unfamiliar peer group when mothers reported highly supportive emotion socialization beliefs. CONCLUSION: Mothers' emotion socialization beliefs appear to play an important role in modifying the developmental course of approach behavior during early childhood. PMID- 28663719 TI - From Image Tiles to Web-Based Interactive Measurements in One Stop. AB - This article introduces readers to a web-based solution useful for interactive nanoscale measurements of centimeter-sized specimens. This solution is a client server system that promotes collaborative measurements and discovery. The system consists of multiple computational modules that enable uploading microscopy images, extracting metadata, assembling many nanometer-resolution images into an image covering a centimeter-sized area, and interactive viewing and measuring of objects of interest at multiple length scales over terabyte-sized images. We illustrate the use of the system on images of aerosolized nanoparticles and dye particles on printing paper. PMID- 28663720 TI - Label-Free Microfluidic Manipulation of Particles and Cells in Magnetic Liquids. AB - Manipulating particles and cells in magnetic liquids through so-called "negative magnetophoresis" is a new research field. It has resulted in label-free and low cost manipulation techniques in microfluidic systems and many exciting applications. It is the goal of this review to introduce the fundamental principles of negative magnetophoresis and its recent applications in microfluidic manipulation of particles and cells. We will first discuss the theoretical background of three commonly used specificities of manipulation in magnetic liquids, which include the size, density and magnetic property of particles and cells. We will then review and compare the media used in negative magnetophoresis, which include paramagnetic salt solutions and ferrofluids. Afterwards, we will focus on reviewing existing microfluidic applications of negative magnetophoresis, including separation, focusing, trapping and concentration of particles and cells, determination of cell density, measurement of particles' magnetic susceptibility, and others. We will also examine the need for developing biocompatible magnetic liquids for live cell manipulation and analysis, and its recent progress. Finally, we will conclude this review with a brief outlook for this exciting research field. PMID- 28663721 TI - A Refined Bead-Free Method to Identify Astrocytic Exosomes in Primary Glial Cultures and Blood Plasma. AB - Astrocytes are the most abundant glial cell type in the central nervous system (CNS) and are known to fulfill critical homeostatic functions. Dysfunction of activated astrocytes is also known to participate in the development of several neurological diseases. Astrocytes can be uniquely identified by expression of the intermediate filament protein glial acidic fibrillary protein (GFAP). Herein, we report on the development of a rigorous and sensitive methodology to identify GFAP+ exosomes in primary culture using flow cytometry. We then demonstrate that activated astrocytes release increased amounts of exosomes in response to treatment with interleukin-1beta. Using this methodology, we report the identification of GFAP+ exosomes in blood and then use a mouse model of inflammatory demyelination, experimental autoimmune encephalomyelitis (EAE), to examine whether the abundance of GFAP+ exosomes in blood circulation changes during clinical illness. We find a detectable increase in the presence of GFAP+ exosomes in EAE mice when compared with non-EAE, control mice. Our data provide a novel perspective on the presence of GFAP in blood as it identifies exosomes as potential astrocyte-derived signals within blood. These data are complementary to previous clinical studies that reported elevated GFAP protein in blood samples from multiple sclerosis (MS) patients during a clinical relapse. These data also reveal the existence of a potential systemic role for astrocyte-derived exosomes in CNS conditions involving inflammation such as multiple sclerosis. PMID- 28663722 TI - Bacoside A Induces Tumor Cell Death in Human Glioblastoma Cell Lines through Catastrophic Macropinocytosis. AB - Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumor with an extremely poor prognosis. Recent evidences have shown that the "biomechanical imbalances" induced in GBM patient-derived glioblastoma cells (GC) and in vivo via the administration of synthetic small molecules, may effectively inhibit disease progression and prolong survival of GBM animal models. This novel concept associated with de novo anti-GBM drug development has however suffered obstacles in adequate clinical utility due to the appearance of unrelated toxicity in the prolonged therapeutic windows. Here, we took a "drug repurposing approach" to trigger similar physico-chemical disturbances in the GBM tumor cells, wherein, the candidate therapeutic agent has been previously well established for its neuro-protective roles, safety, efficacy, prolonged tolerance and excellent brain bioavailability in human subjects and mouse models. In this study, we show that the extracts of an Indian traditional medicinal plant Bacopa monnieri (BM) and its bioactive component Bacoside A can generate dosage associated tumor specific disturbances in the hydrostatic pressure balance of the cell via a mechanism involving excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A) enzyme that is further involved in the release of calcium from the smooth endoplasmic reticular networks. High intracellular calcium stimulated massive macropinocytotic extracellular fluid intake causing cell hypertrophy in the initial stages, excessive macropinosome enlargement and fluid accumulation associated organellar congestion, cell swelling, cell rounding and membrane rupture of glioblastoma cells; with all these events culminating into a non-apoptotic, physical non-homeostasis associated glioblastoma tumor cell death. These results identify glioblastoma tumor cells to be a specific target of the tested herbal medicine and therefore can be exploited as a safe anti-GBM therapeutic. PMID- 28663723 TI - Huntingtin-Interacting Protein 1-Related Protein Plays a Critical Role in Dendritic Development and Excitatory Synapse Formation in Hippocampal Neurons. AB - Huntingtin-interacting protein 1-related (HIP1R) protein is considered to be an endocytic adaptor protein like the other two members of the Sla2 family, Sla2p and HIP1. They all contain homology domains responsible for the binding of clathrin, inositol lipids and F-actin. Previous studies have revealed that HIP1R is highly expressed in different regions of the mouse brain and localizes at synaptic structures. However, the function of HIP1R in the nervous system remains unknown. In this study, we investigated HIP1R function in cultured rat hippocampal neurons using an shRNA knockdown approach. We found that, after HIP1R knockdown, the dynamics and density of dendritic filopodia, and dendritic branching and complexity were significantly reduced in developing neurons, as well as the densities of dendritic spines and PSD95 clusters in mature neurons. Moreover, HIP1R deficiency led to significantly reduced expression of the ionotropic glutamate receptor GluA1, GluN2A and GluN2B subunits, but not the GABAA receptor alpha1 subunit. Similarly, HIP1R knockdown reduced the amplitude and frequency of the miniature excitatory postsynaptic current, but not of the miniature inhibitory postsynaptic current. In addition, the C-terminal proline rich region of HIP1R responsible for cortactin binding was found to confer a dominant-negative effect on dendritic branching in cultured developing neurons, implying a critical role of cortactin binding in HIP1R function. Taken together, the results of our study suggest that HIP1R plays important roles in dendritic development and excitatory synapse formation and function. PMID- 28663724 TI - Activation of Transient Receptor Potential Vanilloid 4 Impairs the Dendritic Arborization of Newborn Neurons in the Hippocampal Dentate Gyrus through the AMPK and Akt Signaling Pathways. AB - Neurite growth is an important process for the adult hippocampal neurogenesis which is regulated by a specific range of the intracellular free Ca2+ concentration ([Ca2+]i). Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable channel and activation of it causes an increase in [Ca2+]i. We recently reported that TRPV4 activation promotes the proliferation of stem cells in the adult hippocampal dentate gyrus (DG). The present study aimed to examine the effect of TRPV4 activation on the dendrite morphology of newborn neurons in the adult hippocampal DG. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days (GSK1016790A-injected mice) reduced the number of doublecortin immunopositive (DCX+) cells and DCX+ fibers in the hippocampal DG, showing the impaired dendritic arborization of newborn neurons. The phosphorylated AMP-activated protein kinase (p-AMPK) protein level increased from 30 min to 2 h, and then decreased from 1 to 5 days after GSK1016790A injection. The phosphorylated protein kinase B (p-Akt) protein level decreased from 30 min to 5 days after GSK1016790A injection; this decrease was markedly attenuated by the AMPK antagonist compound C (CC), but not by the AMPK agonist AICAR. Moreover, the phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6k) protein levels were decreased by GSK1016790A; these changes were sensitive to 740 Y-P and CC. The phosphorylation of glycogen synthase kinase 3beta (GSK3beta) at Y216 was increased by GSK1016790A, and this change was accompanied by increased phosphorylation of microtubule-associated protein 2 (MAP2) and collapsin response mediator protein-2 (CRMP-2). These changes were markedly blocked by 740 Y-P and CC. Finally, GSK1016790A-induced decrease of DCX+ cells and DCX+ fibers was markedly attenuated by 740 Y-P and CC, but was unaffected by AICAR. We conclude that TRPV4 activation impairs the dendritic arborization of newborn neurons through increasing AMPK and inhibiting Akt to inhibit the mTOR-p70S6k pathway, activate GSK3beta and thereby result in the inhibition of MAP2 and CRMP-2 function. PMID- 28663725 TI - Mice Lacking the Alpha9 Subunit of the Nicotinic Acetylcholine Receptor Exhibit Deficits in Frequency Difference Limens and Sound Localization. AB - Sound processing in the cochlea is modulated by cholinergic efferent axons arising from medial olivocochlear neurons in the brainstem. These axons contact outer hair cells in the mature cochlea and inner hair cells during development and activate nicotinic acetylcholine receptors composed of alpha9 and alpha10 subunits. The alpha9 subunit is necessary for mediating the effects of acetylcholine on hair cells as genetic deletion of the alpha9 subunit results in functional cholinergic de-efferentation of the cochlea. Cholinergic modulation of spontaneous cochlear activity before hearing onset is important for the maturation of central auditory circuits. In alpha9KO mice, the developmental refinement of inhibitory afferents to the lateral superior olive is disturbed, resulting in decreased tonotopic organization of this sound localization nucleus. In this study, we used behavioral tests to investigate whether the circuit anomalies in alpha9KO mice correlate with sound localization or sound frequency processing. Using a conditioned lick suppression task to measure sound localization, we found that three out of four alpha9KO mice showed impaired minimum audible angles. Using a prepulse inhibition of the acoustic startle response paradigm, we found that the ability of alpha9KO mice to detect sound frequency changes was impaired, whereas their ability to detect sound intensity changes was not. These results demonstrate that cholinergic, nicotinic alpha9 subunit mediated transmission in the developing cochlear plays an important role in the maturation of hearing. PMID- 28663726 TI - Neural Cross-Frequency Coupling Functions. AB - Although neural interactions are usually characterized only by their coupling strength and directionality, there is often a need to go beyond this by establishing the functional mechanisms of the interaction. We introduce the use of dynamical Bayesian inference for estimation of the coupling functions of neural oscillations in the presence of noise. By grouping the partial functional contributions, the coupling is decomposed into its functional components and its most important characteristics-strength and form-are quantified. The method is applied to characterize the delta-to-alpha phase-to-phase neural coupling functions from electroencephalographic (EEG) data of the human resting state, and the differences that arise when the eyes are either open (EO) or closed (EC) are evaluated. The delta-to-alpha phase-to-phase coupling functions were reconstructed, quantified, compared, and followed as they evolved in time. Using phase-shuffled surrogates to test for significance, we show how the strength of the direct coupling, and the similarity and variability of the coupling functions, characterize the EO and EC states for different regions of the brain. We confirm an earlier observation that the direct coupling is stronger during EC, and we show for the first time that the coupling function is significantly less variable. Given the current understanding of the effects of e.g., aging and dementia on delta-waves, as well as the effect of cognitive and emotional tasks on alpha-waves, one may expect that new insights into the neural mechanisms underlying certain diseases will be obtained from studies of coupling functions. In principle, any pair of coupled oscillations could be studied in the same way as those shown here. PMID- 28663728 TI - Object Localization Does Not Imply Awareness of Object Category at the Break of Continuous Flash Suppression. AB - In continuous flash suppression (CFS), a dynamic noise masker, presented to one eye, suppresses conscious perception of a test stimulus, presented to the other eye, until the suppressed stimulus comes to awareness after few seconds. But what do we see breaking the dominance of the masker in the transition period? We addressed this question with a dual-task in which observers indicated (i) whether the test object was left or right of the fixation mark (localization) and (ii) whether it was a face or a house (categorization). As done recently Stein et al. (2011a), we used two experimental varieties to rule out confounds with decisional strategy. In the terminated mode, stimulus and masker were presented for distinct durations, and the observers were asked to give both judgments at the end of the trial. In the self-paced mode, presentation lasted until the observers responded. In the self-paced mode, b-CFS durations for object categorization were about half a second longer than for object localization. In the terminated mode, correct categorization rates were consistently lower than correct detection rates, measured at five duration intervals ranging up to 2 s. In both experiments we observed an upright face advantage compared to inverted faces and houses, as concurrently reported in b-CFS studies. Our findings reveal that more time is necessary to enable observers judging the nature of the object, compared to judging that there is "something other" than the noise which can be localized, but not recognized. This suggests gradual transitions in the first break of CFS. Further, the results imply that suppression is such that no cues to object identity are conveyed in potential "leaks" of CFS (Gelbard-Sagiv et al., 2016). PMID- 28663727 TI - Who Deserves My Trust? Cue-Elicited Feedback Negativity Tracks Reputation Learning in Repeated Social Interactions. AB - Trust and trustworthiness contribute to reciprocal behavior and social relationship development. To make better decisions, people need to evaluate others' trustworthiness. They often assess this kind of reputation by learning through repeated social interactions. The present event-related potential (ERP) study explored the reputation learning process in a repeated trust game where subjects made multi-round decisions of investment to different partners. We found that subjects gradually learned to discriminate trustworthy partners from untrustworthy ones based on how often their partners reciprocated the investment, which was indicated by their own investment decisions. Besides, electrophysiological data showed that the faces of the untrustworthy partners induced larger feedback negativity (FN) amplitude than those of the trustworthy partners, but only in the late phase of the game. The ERP results corresponded with the behavioral pattern and revealed that the learned trustworthiness differentiation was coded by the cue-elicited FN component. Consistent with previous research, our findings suggest that the anterior cue-elicited FN reflects the reputation appraisal and tracks the reputation learning process in social interactions. PMID- 28663729 TI - Estimating the Information Extracted by a Single Spiking Neuron from a Continuous Input Time Series. AB - Understanding the relation between (sensory) stimuli and the activity of neurons (i.e., "the neural code") lies at heart of understanding the computational properties of the brain. However, quantifying the information between a stimulus and a spike train has proven to be challenging. We propose a new (in vitro) method to measure how much information a single neuron transfers from the input it receives to its output spike train. The input is generated by an artificial neural network that responds to a randomly appearing and disappearing "sensory stimulus": the hidden state. The sum of this network activity is injected as current input into the neuron under investigation. The mutual information between the hidden state on the one hand and spike trains of the artificial network or the recorded spike train on the other hand can easily be estimated due to the binary shape of the hidden state. The characteristics of the input current, such as the time constant as a result of the (dis)appearance rate of the hidden state or the amplitude of the input current (the firing frequency of the neurons in the artificial network), can independently be varied. As an example, we apply this method to pyramidal neurons in the CA1 of mouse hippocampi and compare the recorded spike trains to the optimal response of the "Bayesian neuron" (BN). We conclude that like in the BN, information transfer in hippocampal pyramidal cells is non-linear and amplifying: the information loss between the artificial input and the output spike train is high if the input to the neuron (the firing of the artificial network) is not very informative about the hidden state. If the input to the neuron does contain a lot of information about the hidden state, the information loss is low. Moreover, neurons increase their firing rates in case the (dis)appearance rate is high, so that the (relative) amount of transferred information stays constant. PMID- 28663730 TI - The Humanistic Burden of Small Cell Lung Cancer (SCLC): A Systematic Review of Health-Related Quality of Life (HRQoL) Literature. AB - Background: Little is known about the humanistic burden of small cell lung cancer (SCLC), specifically the impact on health-related quality of life (HRQoL). The aim of this systematic literature review was to explore the impact of SCLC on HRQoL and the patient reported outcomes (PROs) used to capture this impact. Methods: We conducted a systematic search of Medline(r), Embase, and PsycINFO, oncology organization websites and conference proceedings within the past 10 years. Articles reporting HRQoL outcomes of SCLC patients were selected. Results: Twenty-seven eligible publications were identified. Global or overall impact on HRQoL (n = 21) was reported most often, with considerably fewer reporting individual domains that comprise HRQoL. Results indicated that HRQoL was negatively impacted in SCLC patients in comparison to the normal population in most domains. Overall, the domains measuring physical functioning and activities of daily living were most impacted. However, results on cognitive and emotional functioning were inconclusive. The impact on HRQoL may be least in both limited disease and extensive disease (ED) SCLC patients who have responded to treatment, and greatest in ED patients who were treatment naive. The most frequently used PROs were the EORTC QLQ-C30 core cancer instruments, the lung cancer specific module the EORTC QLQ-LC13, LCSS, and EQ-5D. Conclusion: There exists a paucity of reporting on SCLC HRQoL outcomes. This extends to the reporting of domain level scores and by patient sub-group. Greater reporting at a granular level is recommended to allow for more robust conclusions to be made. PMID- 28663731 TI - Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress. AB - Psychological stress contributes to increased susceptibility to a number of diseases including cancer. The present study was designed to assess the effect of chronic unpredictable stress on N-nitrosodiethylamine induced liver toxicity in terms of in vivo antioxidant status and DNA damage in Swiss albino mice. The animals used in this study were randomized into different groups based on the treatment with N-nitrosodiethylamine or chronic unpredictable stress alone and post-stress administration of N-nitrosodiethylamine. The mice were sacrificed after 12 weeks of treatment, and the status of major enzymatic and non-enzymatic antioxidants, liver function markers, lipid peroxidation and the extent of DNA damage were determined in circulation and liver tissues of all the groups. The N nitrosodiethylamine treated group showed significantly compromised levels of the antioxidant enzymes, lipid peroxidation, and the liver function markers with enhanced DNA damage as compared to chronic unpredictable stress or control groups. A similar but less typical pattern observed in the chronic unpredictable stress treated mice. All the measured biochemical parameters were significantly altered in the group treated with the combination of chronic unpredictable stress and N-nitrosodiethylamine when compared to controls, or chronic unpredictable stress alone and/or N-nitrosodiethylamine alone treated groups. Thus, exposure to continuous, unpredictable stress conditions even in general life may significantly enhance the hepatotoxic potential of N-nitrosodiethylamine through an increase in the oxidative stress and DNA damage. PMID- 28663732 TI - Preserved Crossmodal Integration of Emotional Signals in Binge Drinking. AB - Binge drinking is an alcohol consumption pattern with various psychological and cognitive consequences. As binge drinking showed qualitatively comparable cognitive impairments to those reported in alcohol-dependence, a continuum hypothesis suggests that this habit would be a first step toward alcohol-related disorders. Besides these cognitive impairments, alcohol-dependence is also characterized by large-scale deficits in emotional processing, particularly in crossmodal contexts, and these abilities have scarcely been explored in binge drinking. Emotional decoding, most often based on multiple modalities (e.g., facial expression, prosody or gesture), yet represents a crucial ability for efficient interpersonal communication and social integration. The present study is the first exploration of crossmodal emotional processing in binge drinking, in order to test whether binge drinkers already present the emotional impairments described among alcohol-dependent patients, in line with the continuum hypothesis. Twenty binge drinkers and 20 matched controls performed an experimental task requiring the identification of two emotions (happiness or anger) presented in two modalities (visual or auditory) within three conditions (unimodal, crossmodal congruent or crossmodal incongruent). In accordance with previous research in binge drinking and alcohol-dependence, this study was based on two main hypotheses. First, binge drinkers would present a reduced facilitation effect (i.e., classically indexed in healthy populations by faster reaction times when two congruent modalities are presented simultaneously). Second, binge drinkers would have higher difficulties to inhibit interference in incongruent modalities. Results showed no significant difference between groups in emotional decoding ability, whatever the modality or condition. Control participants, however, appeared slower than binge drinkers in recognizing facial expressions, also leading to a stronger facilitation effect when the two modalities were presented simultaneously. However, findings did not show a disrupted facilitation effect in binge drinkers, whom also presented preserved performance to inhibit incongruence during emotional decoding. The current results thus suggest that binge drinkers do not demonstrate a deficit for emotional processing, both in unimodal and crossmodal contexts. These results imply that binge drinking might not be characterized by impairments for the identification of primary emotions, which could also indicate that these emotional processing abilities are well-preserved at early stages of excessive alcohol consumption. PMID- 28663733 TI - Student Engagement as a General Factor of Classroom Experience: Associations with Student Practices and Educational Outcomes in a University Gateway Course. AB - The purpose of this study was to evaluate a model for considering general and specific elements of student experience in a gateway course in undergraduate Financial Accounting in a large university on the East Coast, USA. Specifically, the study evaluated a bifactor analytic strategy including a general factor of student classroom experience, conceptualized as student engagement as rooted in flow theory, as well as factors representing specific dimensions of experience. The study further evaluated the association between these general and specific factors and both student classroom practices and educational outcomes. The sample of students (N = 407) in two cohorts of the undergraduate financial accounting course participated in the Experience Sampling Method (ESM) measuring students' classroom practices, perceptions, engagement, and perceived learning throughout the one-semester course. Course grade information was also collected. Results showed that a two-level bifactor model fit the data better than two traditional (i.e., non-bifactor) models and also avoided significant multicollinearity of the traditional models. In addition to student engagement (general factor), specific dimensions of classroom experience in the bifactor model at the within-student level included intrinsic motivation, academic intensity, salience, and classroom self-esteem. At the between-student level, specific aspects included work orientation, learning orientation, classroom self-esteem, and disengagement. Multilevel Structural Equation Modeling (MSEM) demonstrated that sitting in the front of the classroom (compared to the sitting in the back), taking notes, active listening, and working on problems during class had a positive effect on within-student variation in student engagement and attention. Engagement, in turn, predicted perceived learning. With respect to between-student effects, the tendency to sit in front seats had a significant effect on student engagement, which in turn had a significant effect on perceived learning and course grades. A significant indirect relationship of seating and active learning strategies on learning and course grade as mediated by student engagement was found. Support for the general aspect of student classroom experience was interpreted with flow theory and suggested the need for additional research. Findings also suggested that active learning strategies are associated with positive learning outcomes even in educational environments where possibilities for action are relatively constrained. PMID- 28663734 TI - The Contribution of Grammar, Vocabulary and Theory of Mind in Pragmatic Language Competence in Children with Autistic Spectrum Disorders. PMID- 28663735 TI - What Property of the Contour of a Deforming Region Biases Percepts toward Liquid? AB - Human observers can perceive the existence of a transparent surface from dynamic image deformation. They can also easily discriminate a transparent solid material such as plastic and glass from a transparent fluid one such as water and shampoo just by viewing them. However, the image information required for material discrimination of this sort is still unclear. A liquid changes its contour shape non-rigidly. We therefore examined whether additional properties of the contour of a deformation-defined region, which indicated contour non-rigidity, biased percepts of the region toward liquid materials. Our stimuli had a translating circular region wherein a natural texture image was deformed at the spatiotemporal deformation frequency that was optimal for the perception of a transparent layer. In Experiment 1, we dynamically deformed the contour of the circular region and found that large deformation of the contour biased the percept toward liquid. In Experiment 2, we manipulated the blurriness of the contour and observed that a strongly blurred contour biased percepts toward liquid. Taken together, the results suggest that a deforming region lacking a discrete contour biases percepts toward liquid. PMID- 28663737 TI - Functional Changes of the Perigenual Part of the Anterior Cingulate Cortex after External Trigeminal Neurostimulation in Migraine Patients. AB - OBJECTIVE: To explore the functional reorganization of the pain processing network during trigeminal heat stimulation (THS) after 60 days of external trigeminal neurostimulation (eTNS) in migraine without aura (MwoA) patients between attacks. METHODS: Using whole-brain BOLD-fMRI, functional response to THS at two different intensities (41 and 51 degrees C) was investigated interictally in 16 adults MwoA patients before and after eTNS with the Cefaly(r) device. We calculated the percentage of patients having at least a 50% reduction of monthly migraine attacks and migraine days between baseline and the last month of eTNS. Secondary analyses evaluated associations between BOLD signal changes and clinical features of migraine. RESULTS: Before eTNS treatment, there was no difference in BOLD response between MwoA patients and healthy controls (HC) during low-innocuous THS at 41 degrees C, whereas the perigenual part of the right anterior cingulate cortex (ACC) revealed a greater BOLD response to noxious THS at 51 degrees C in MwoA patients when compared to HC. The same area demonstrated a significant reduced BOLD response induced by the noxious THS in MwoA patients after eTNS (p = 0.008). Correlation analyses showed a significant positive correlation between ACC BOLD response to noxious THS before eTNS treatment and the decrease of ACC BOLD response to noxious THS after eTNS. Moreover, a significant negative correlation in the migraine group after eTNS treatment between ACC functional activity changes and both the perceived pain ratings during noxious THS and pre-treatment migraine attack frequency has been found. CONCLUSION: Our findings suggest that eTNS treatment with the Cefaly(r) device induces a functional antinociceptive modulation in the ACC that is involved in the mechanisms underlying its preventive anti-migraine efficacy. Nevertheless, further observations to confirm whether the observed fMRI effects of eTNS are both related to clinical improvement and specific to antinociceptive modulation in migraine patients are mandatory. PMID- 28663736 TI - A Mechanistic End-to-End Concussion Model That Translates Head Kinematics to Neurologic Injury. AB - Past concussion studies have focused on understanding the injury processes occurring on discrete length scales (e.g., tissue-level stresses and strains, cell-level stresses and strains, or injury-induced cellular pathology). A comprehensive approach that connects all length scales and relates measurable macroscopic parameters to neurological outcomes is the first step toward rationally unraveling the complexity of this multi-scale system, for better guidance of future research. This paper describes the development of the first quantitative end-to-end (E2E) multi-scale model that links gross head motion to neurological injury by integrating fundamental elements of tissue and cellular mechanical response with axonal dysfunction. The model quantifies axonal stretch (i.e., tension) injury in the corpus callosum, with axonal functionality parameterized in terms of axonal signaling. An internal injury correlate is obtained by calculating a neurological injury measure (the average reduction in the axonal signal amplitude) over the corpus callosum. By using a neurologically based quantity rather than externally measured head kinematics, the E2E model is able to unify concussion data across a range of exposure conditions and species with greater sensitivity and specificity than correlates based on external measures. In addition, this model quantitatively links injury of the corpus callosum to observed specific neurobehavioral outcomes that reflect clinical measures of mild traumatic brain injury. This comprehensive modeling framework provides a basis for the systematic improvement and expansion of this mechanistic based understanding, including widening the range of neurological injury estimation, improving concussion risk correlates, guiding the design of protective equipment, and setting safety standards. PMID- 28663738 TI - Cerebral Microstructural Alterations after Radiation Therapy in High-Grade Glioma: A Diffusion Tensor Imaging-Based Study. AB - OBJECTIVE: To investigate radiation therapy-induced microstructural damage of white matter in patients with high-grade glioma by diffusion tensor imaging (DTI). METHODS: DTI was performed in 18 patients with high-grade glioma (WHO grades III and IV) and 13 healthy controls. DTI images were cross-sectionally aligned for the calculation of baseline fractional anisotropy (FA). Interhemispheric FA values in patients with high-grade glioma before or without brain radiation therapy were compared with the interhemispheric FA values in patients after radiation therapy and in healthy controls. In a subgroup without any clinical or diagnostic evidence of tumor progression, serial DTI data (5-11 scans) before and after radiation therapy were collected and longitudinal interhemispheric FA changes were assessed and compared to longitudinal data from the control group.In addition, interhemispheric axial, mean, and radial diffusivity was assessed. RESULTS: Global interhemispheric FA reductions could be detected cross-sectionally in patients after radiation therapy; these were significantly different from global interhemispheric FA differences both in patients without radiation and in healthy controls. Longitudinal scans in patients with radiation therapy confirmed these findings and revealed progressive microstructural white matter damage after partial brain radiotherapy. The additional DTI metrics axial diffusion, mean diffusivity, and radial diffusion confirmed interhemispheric differences in patients without or before radiation therapy, which were lower than the differences in patients after radiation therapy, although not reaching significance. CONCLUSION: Interhemispheric global FA differences could potentially serve as a biological marker for irradiation induced microstructural white matter damage. PMID- 28663740 TI - Editorial: Phage Therapy: Past, Present and Future. PMID- 28663739 TI - Impact of Mid-Luteal Phase GnRH Agonist Administration on Reproductive Outcomes in GnRH Agonist-Triggered Cycles: A Randomized Controlled Trial. AB - OBJECTIVE: To explore whether the addition of a mid-luteal bolus of GnRH agonist (GnRHa) improves the implantation rate (IR) in in vitro fertilization (IVF) cycles. DESIGN: A randomized controlled trial. SETTING: Private IVF center. PATIENTS: 328 IVF/intracytoplasmic sperm injection patients were triggered with GnRHa and received 1,500 IU HCG on the day of oocyte pick-up (OPU) in addition to a standard luteal phase support (LPS). INTERVENTIONS: In addition, the study group received a bolus of GnRHa 6 days after OPU, whereas the control group did not. MAIN OUTCOME MEASURE: Implantation rate. SECONDARY OUTCOME MEASURES: Ongoing pregnancy (OP) and live birth (LB) rates. RESULTS: Although serum concentrations of FSH, LH, E2, and P on day OPU + 7 were significantly higher in the study group compared to the control group, the IR was not statistically different between the treatment group (27%) and the control group (23%) [odds ratio (OR) 1.2 (95% CI 0.9-1.7), P < 0.27]. Similarly, the OP rate was 37% in the treatment group and 31% in the control group [OR 1.3 (95% CI 0.8-2.0), P < 0.23]. The LB rate was 36% in the treatment group and 31% in the control group [OR: 1.3 (95% CI 0.8-2.0), P < 0.27]. CONCLUSION: Although a trend toward a higher IR and pregnancy rate was observed in the treatment group, this difference was not statistically significant. However, the absolute risk difference of 5% found for LB is clinically relevant, warranting further investigation. NCT: 02053779. PMID- 28663741 TI - Melatonin Reduces Oxidative Stress Damage Induced by Hydrogen Peroxide in Saccharomyces cerevisiae. AB - Melatonin (N-acetyl-5-methoxytryptamine), which is synthesized from tryptophan, is formed during alcoholic fermentation, though its role in yeast is unknown. This study employed Saccharomyces cerevisiae as an eukaryote model to evaluate the possible effects of melatonin supplementation on endogenous cellular defense systems by measuring its effects on various cellular targets. Cell viability, intracellular reduced and oxidized glutathione levels (GSH and GSSG, respectively), reactive oxygen species (ROS) production, and expression of genes related to antioxidant defense in yeast, such as the glutathione system, catalase, superoxide dismutase, glutaredoxin, and thioredoxin, were assessed. Melatonin alone decreased GSH, increased GSSG, and activated antioxidant defense system genes, which reached maximum levels in the stationary phase. These results indicate that melatonin supplementation enables cells to resist better the stress generated in the stationary phase. However, when cells were subjected to oxidative stress induced by H2O2, melatonin was able to partially mitigate cell damage by decreasing ROS accumulation and GSH and increasing GSSG; this was followed by enhanced cell viability after stress exposure, mostly when occurring in the early stationary phase. Additionally, under such conditions, most genes related to endogenous antioxidant defense continued to be up-regulated with melatonin supplementation. The findings demonstrate that melatonin can act as antioxidant in S. cerevisiae. PMID- 28663742 TI - HIV Progression Depends on Codon and Amino Acid Usage Profile of Envelope Protein and Associated Host-Genetic Influence. AB - Acquired immune deficiency syndrome (AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Two types of HIV have been characterized: HIV-1 and HIV-2. The present study investigated whether evolutionary selection pressure differs between rapid progressor (RP), slow progressor (SP), and long-term non-progressor (LTNP) of HIV-I infected individuals. An unexpected association between the evolutionary rate of substitution in envelope (env) gene and disease progression is observed. Our present study suggests that env genes of LTNP are subject to unusually strong functional constraint with respect to RP. We also observed that the three categories of env genes i.e., RP, SP, and LTNP, had their own characteristic pattern of amino acid usage and SP and LTNP sequences shared similar patterns of amino acid usage different from RP sequences and evolutionary rate significantly influenced the amino acid usage pattern of the three different types of env gene sequences. It was also noted that the evolutionary rate for the glycosylation sites of LTNP and SP sequences were even significantly less than the RP sequences. Comparative analysis on the influence of human host on the three categories of env genes are well correlated with the rates of disease progression suggesting the adaptive strategies of the viruses for successful residence and infection. Host associated selective constraints appeared most relaxed on the RP sequences and strongest in LTNP sequences. The present study clearly portrays how evolutionary selection pressure differs between three categories of env genes i.e., RP, SP, and LTNP. The env genes, coding for the env glycoproteins, experience severe selection constraints from the host due to their constant exposure to the host immune system. In this perspective it might be suggested that env gene evolution occurs mainly by negative selection with the occurrence of mutation that might not reach fixation in the viral population. This work also confers a deeper insight into the crucial effects of host factors that govern the overall progression of HIV infection. PMID- 28663743 TI - Viral Population Changes during Murine Norovirus Propagation in RAW 264.7 Cells. AB - Laboratory adaptation of viruses is an essential technique for basic virology research, including the generation of attenuated vaccine strains, although the principles of cell adaptation remain largely unknown. Deep sequencing of murine norovirus (MuNoV) S7 during serial passages in RAW264.7 cells showed that the frequencies of viral variants were altered more dynamically than previously reported. Serial passages of the virus following two different multiplicity of infections gave rise to distinct haplotypes, implying that multiple cell adaptable sequences were present in the founder population. Nucleotide variants lost during passage were assembled into a viral genome representative of that prior to cell adaptation, which was unable to generate viral particles upon infection in cultured cells. In addition, presence of the reconstructed genome interfered with production of infectious particles from viruses that were fully adapted to in vitro culture. Although the key nucleotide changes dictating cell adaptation of MuNoV S7 viral infection are yet to be elucidated, our results revealed the elaborate interplay among selected sequences of viral variants better adapted to propagation in cell culture. Such knowledge will be instrumental in understanding the processes necessary for the laboratory adaptation of viruses, especially to those without relevant cell culture systems. PMID- 28663744 TI - Genome-Wide Detection of Small Regulatory RNAs in Deep-Sea Bacterium Shewanella piezotolerans WP3. AB - Shewanella are one of the most abundant Proteobacteria in the deep-sea and are renowned for their versatile electron accepting capacities. The molecular mechanisms involved in their adaptation to diverse and extreme environments are not well understood. Small non-coding RNAs (sRNAs) are known for modulating the gene expression at transcriptional and posttranscriptional levels, subsequently playing a key role in microbial adaptation. To understand the potential roles of sRNAs in the adaptation of Shewanella toward deep-sea environments, here an in silico approach was utilized to detect the sRNAs in the genome of Shewanella piezotolerans WP3, a piezotolerant and psychrotolerant deep-sea iron reducing bacterium. After scanning 3673 sets of 5' and 3' UTRs of orthologous genes, 209 sRNA candidates were identified with high confidence in S. piezotolerans WP3. About 92% (193 out of 209) of these putative sRNAs belong to the class trans encoded RNAs, suggesting that trans-regulatory RNAs are the dominant class of sRNAs in S. piezotolerans WP3. The remaining 16 cis-regulatory RNAs were validated through quantitative polymerase chain reaction. Five cis-sRNAs were further shown to act as cold regulated sRNAs. Our study provided additional evidence at the transcriptional level to decipher the microbial adaptation mechanisms to extreme environmental conditions. PMID- 28663745 TI - Viromes As Genetic Reservoir for the Microbial Communities in Aquatic Environments: A Focus on Antimicrobial-Resistance Genes. AB - Despite studies of viromes isolated from aquatic environments are becoming increasingly frequent, most of them are limited to the characterization of viral taxonomy. Bacterial reads in viromes are abundant but the extent to which this genetic material is playing a role in the ecology of aquatic microbiology remains unclear. To this aim, we developed of a useful approach for the characterization of viral and microbial communities of aquatic environments with a particular focus on the identification of microbial genes harbored in the viromes. Virus like particles were isolated from water samples collected across the Lambro River, from the spring to the high urbanized Milan area. The derived viromes were analyzed by shotgun metagenomic sequencing looking for the presence, relative abundance of bacterial genes with particular focus on those genes involved in antimicrobial resistance mechanisms. Antibiotic and heavy metal resistance genes have been identified in all virome samples together with a high abundance of reads assigned to cellular processes and signaling. Virome data compared to those identified in the microbiome isolated from the same sample revealed differences in terms of functional categories and their relative abundance. To verify the role of aquatic viral population in bacterial gene transfer, water-based mesocosms were perturbed or not perturbed with a low dose of tetracycline. The results obtained by qPCR assays revealed variation in abundance of tet genes in the virome and microbiome highlighting a relevant role of viral populations in microbial gene mobilization. PMID- 28663746 TI - Marine Group II Dominates Planktonic Archaea in Water Column of the Northeastern South China Sea. AB - Temperature, nutrients, and salinity are among the important factors constraining the distribution and abundance of microorganisms in the ocean. Marine Group II (MGII) belonging to Euryarchaeota commonly dominates the planktonic archaeal community in shallow water and Marine Group I (MGI, now is called Thaumarchaeota) in deeper water in global oceans. Results of quantitative PCR (qPCR) and 454 sequencing in our study, however, showed the dominance of MGII in planktonic archaea throughout the water column of the northeastern South China Sea (SCS) that is characterized by strong water mixing. The abundance of ammonia-oxidizing archaea (AOA) representing the main group of Thaumarchaeota in deeper water in the northeastern SCS was significantly lower than in other oceanic regions. Phylogenetic analysis showed that the top operational taxonomic units (OTUs) of the MGII occurring predominantly below 200 m depth may be unique in the northeastern SCS based on the observation that they are distantly related to known sequences (identity ranging from 90-94%). The abundance of MGII was also significantly correlated with total bacteria in the whole column, which may indicate that MGII and bacteria may have similar physiological or biochemical properties or responses to environmental variation. This study provides valuable information about the dominance of MGII over AOA in both shallow and deep water in the northeastern SCS and highlights the need for comprehensive studies integrating physical, chemical, and microbial oceanography. PMID- 28663747 TI - Polychlorinated Biphenyl (PCB)-Degrading Potential of Microbes Present in a Cryoconite of Jamtalferner Glacier. AB - Aiming to comprehensively survey the potential pollution of an alpine cryoconite (Jamtalferner glacier, Austria), and its bacterial community structure along with its biodegrading potential, first chemical analyses of persistent organic pollutants, explicitly polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) as well as polycyclic aromatic hydrocarbons (PAHs), revealed a significant contamination. In total, 18 PCB congeners were detected by high resolution gas chromatography/mass spectrometry with a mean concentration of 0.8 ng/g dry weight; 16 PAHs with an average concentration of 1,400 ng/g; and 26 out of 29 OCPs with a mean concentration of 2.4 ng/g. Second, the microbial composition was studied using 16S amplicon sequencing. The analysis revealed high abundances of Proteobacteria (66%), the majority representing alpha Proteobacteria (87%); as well as Cyanobacteria (32%), however high diversity was due to 11 low abundant phyla comprising 75 genera. Biodegrading potential of cryoconite bacteria was further analyzed using enrichment cultures (microcosms) with PCB mixture Aroclor 1242. 16S rDNA analysis taxonomically classified 37 different biofilm-forming and PCB-degrading bacteria, represented by Pseudomonas, Shigella, Subtercola, Chitinophaga, and Janthinobacterium species. Overall, the combination of culture-dependent and culture-independent methods identified degrading bacteria that can be potential candidates to develop novel bioremediation strategies. PMID- 28663749 TI - Discovery of Several Novel Targets that Enhance beta-Carotene Production in Saccharomyces cerevisiae. AB - beta-Carotene is the precursor of vitamin A, and also exhibits multiple pharmaceutical functions by itself. In comparison to chemical synthesis, the production of beta-carotene in microbes by metabolic engineering strategy is relatively inexpensive. Identifying genes enhancing beta-carotene production in microbes is important for engineering a strain of producing higher yields of beta carotene. Most of previous efforts in identifying the gene targets have focused on the isoprenoid pathway where the beta-carotene biosynthesis belongs. However, due to the complex interactions between metabolic fluxes, seemingly irrelevant genes that are outside the isoprenoid pathway might also affect beta-carotene biosynthesis. To this end, here we provided an example that several novel gene targets, which are outside the isoprenoid pathway, have improving effects on beta carotene synthesis in yeast cells, when they were over-expressed. Among these targets, the class E protein of the vacuolar protein-sorting pathway (Did2) led to the highest improvement in beta-carotene yields, which was 2.1-fold to that of the corresponding control. This improvement was further explained by the observation that the overexpression of the DID2 gene generally boosted the transcriptions of beta-carotene pathway genes. The mechanism by which the other targets improve the production of beta-carotene is discussed. PMID- 28663748 TI - Marine Rare Actinobacteria: Isolation, Characterization, and Strategies for Harnessing Bioactive Compounds. AB - Actinobacteria are prolific producers of thousands of biologically active natural compounds with diverse activities. More than half of these bioactive compounds have been isolated from members belonging to actinobacteria. Recently, rare actinobacteria existing at different environmental settings such as high altitudes, volcanic areas, and marine environment have attracted attention. It has been speculated that physiological or biochemical pressures under such harsh environmental conditions can lead to the production of diversified natural compounds. Hence, marine environment has been focused for the discovery of novel natural products with biological potency. Many novel and promising bioactive compounds with versatile medicinal, industrial, or agricultural uses have been isolated and characterized. The natural compounds cannot be directly used as drug or other purposes, so they are structurally modified and diversified to ameliorate their biological or chemical properties. Versatile synthetic biological tools, metabolic engineering techniques, and chemical synthesis platform can be used to assist such structural modification. This review summarizes the latest studies on marine rare actinobacteria and their natural products with focus on recent approaches for structural and functional diversification of such microbial chemicals for attaining better applications. PMID- 28663750 TI - Anaphylatoxins Activate Ca2+, Akt/PI3-Kinase, and FOXO1/FoxP3 in the Retinal Pigment Epithelium. AB - PURPOSE: The retinal pigment epithelium (RPE) is a main target for complement activation in age-related macular degeneration (AMD). The anaphylatoxins C3a and C5a have been thought to mostly play a role as chemoattractants for macrophages and immune cells; here, we explore whether they trigger RPE alterations. Specifically, we investigated the RPE as a potential immunoregulatory gate, allowing for active changes in the RPE microenvironment in response to complement. DESIGN: In vitro and in vivo analysis of signaling pathways. METHODS: Individual activities of and interaction between the two anaphylatoxin receptors were tested in cultured RPE cells by fluorescence microscopy, western blot, and immunohistochemistry. MAIN OUTCOME MEASURES: Intracellular free calcium, protein phosphorylation, immunostaining of tissues/cells, and multiplex secretion assay. RESULTS: Similar to immune cells, anaphylatoxin exposure resulted in increases in free cytosolic Ca2+, PI3-kinase/Akt activation, FoxP3 and FOXO1 phosphorylation, and cytokine/chemokine secretion. Differential responses were elicited depending on whether C3a and C5a were co-administered or applied consecutively, and response amplitudes in co-administration experiments ranged from additive to driven by C5a (C3a + C5a = C5a) or being smaller than those elicited by C3a alone (C3a + C5a < C3a). CONCLUSION: We suggest that this combination of integrative signaling between C3aR and C5aR helps the RPE to precisely adopt its immune regulatory function. These data further contribute to our understanding of AMD pathophysiology. PMID- 28663751 TI - Lactoferrin Efficiently Counteracts the Inflammation-Induced Changes of the Iron Homeostasis System in Macrophages. AB - Human lactoferrin (hLf), an 80-kDa multifunctional iron-binding cationic glycoprotein, is constitutively secreted by exocrine glands and by neutrophils during inflammation. hLf is recognized as a key element in the host immune defense system. The in vitro and in vivo experiments are carried out with bovine Lf (bLf), which shares high sequence homology and identical functions with hLf, including anti-inflammatory activity. Here, in "pure" M1 human macrophages, obtained by stimulation with a mixture of 10 pg/ml LPS and 20 ng/ml IFN-gamma, as well as in a more heterogeneous macrophage population, challenged with high-dose of LPS (1 ug/ml), the effect of bLf on the expression of the main proteins involved in iron and inflammatory homeostasis, namely ferroportin (Fpn), membrane bound ceruloplasmin (Cp), cytosolic ferritin (Ftn), transferrin receptor 1, and cytokines has been investigated. The increase of IL-6 and IL-1beta cytokines, following the inflammatory treatments, is associated with both upregulation of cytosolic Ftn and downregulation of Fpn, membrane-bound Cp, and transferrin receptor 1. All these changes take part into intracellular iron overload, a very unsafe condition leading in vivo to higher host susceptibility to infections as well as iron deficiency in the blood and anemia of inflammation. It is, therefore, of utmost importance to counteract the persistence of the inflammatory status to rebalance iron levels between tissues/secretions and blood. Moreover, levels of the antiinflammatory cytokine IL-10 were increased in cells treated with high doses of LPS. Conversely, IL-10 decreased when the LPS/IFN-gamma mix was used, suggesting that only the inflammation triggered by LPS high doses can switch on an anti-inflammatory response in our macrophagic model. Here, we demonstrate that bLf, when included in the culture medium, significantly reduced IL-6 and IL-1beta production and efficiently prevented the changes of Fpn, membrane-bound Cp, cytosolic Ftn, and transferrin receptor 1 in "pure" M1 macrophages, as well as in the more heterogeneous macrophage population. In addition, the decrease of IL-10 induced by the LPS/IFN-gamma mix was counteracted by bovine lactoferrin. Several drugs capable of modulating macrophagic phenotypes are emerging as attractive molecules for treating inflammation, and in this sense, bovine lactoferrin is no exception. PMID- 28663753 TI - Dominant Groups of Potentially Active Bacteria Shared by Barley Seeds become Less Abundant in Root Associated Microbiome. AB - Endophytes are microorganisms colonizing plant internal tissues. They are ubiquitously associated with plants and play an important role in plant growth and health. In this work, we grew five modern cultivars of barley in axenic systems using sterile sand mixture as well as in greenhouse with natural soil. We characterized the potentially active microbial communities associated with seeds and roots using rRNA based amplicon sequencing. The seeds of the different cultivars share a great part of their microbiome, as we observed a predominance of a few bacterial OTUs assigned to Phyllobacterium, Paenibacillus, and Trabusiella. Seed endophytes, particularly members of the Enterobacteriacea and Paenibacillaceae, were important members of root endophytes in axenic systems, where there were no external microbes. However, when plants were grown in soil, seed endophytes became less abundant in root associated microbiome. We observed a clear enrichment of Actinobacteriacea and Rhizobiaceae, indicating a strong influence of the soil bacterial communities on the composition of the root microbiome. Two OTUs assigned to Phyllobacteriaceae were found in all seeds and root samples growing in soil, indicating a relationship between seed-borne and root associated microbiome in barley. Even though the role of endophytic bacteria remains to be clarified, it is known that many members of the genera detected in our study produce phytohormones, shape seedling exudate profile and may play an important role in germination and establishment of the seedlings. PMID- 28663752 TI - Identification and Characterization of miRNA Transcriptome in Asiatic Cotton (Gossypium arboreum) Using High Throughput Sequencing. AB - MicroRNAs (miRNAs) are small 20-24nt molecules that have been well studied over the past decade due to their important regulatory roles in different cellular processes. The mature sequences are more conserved across vast phylogenetic scales than their precursors and some are conserved within entire kingdoms, hence, their loci and function can be predicted by homology searches. Different studies have been performed to elucidate miRNAs using de novo prediction methods but due to complex regulatory mechanisms or false positive in silico predictions, not all of them express in reality and sometimes computationally predicted mature transcripts differ from the actual expressed ones. With the availability of a complete genome sequence of Gossypium arboreum, it is important to annotate the genome for both coding and non-coding regions using high confidence transcript evidence, for this cotton species that is highly resistant to various biotic and abiotic stresses. Here we have analyzed the small RNA transcriptome of G. arboreum leaves and provided genome annotation of miRNAs with evidence from miRNA/miRNA* transcripts. A total of 446 miRNAs clustered into 224 miRNA families were found, among which 48 families are conserved in other plants and 176 are novel. Four short RNA libraries were used to shortlist best predictions based on high reads per million. The size, origin, copy numbers and transcript depth of all miRNAs along with their isoforms and targets has been reported. The highest gene copy number was observed for gar-miR7504 followed by gar-miR166, gar miR8771, gar-miR156, and gar-miR7484. Altogether, 1274 target genes were found in G. arboreum that are enriched for 216 KEGG pathways. The resultant genomic annotations are provided in UCSC, BED format. PMID- 28663754 TI - A Highly Dense Genetic Map for Ginkgo biloba Constructed Using Sequence-Based Markers. AB - Ginkgo biloba L. is a well-known living gymnosperm fossil that has medicinal and ornamental value. In this study, a high density genetic map was constructed with megagametophytes of 94 seeds from a single Ginkgo tree by employing the specific locus amplified fragment (SLAF) sequencing technique. The average sequencing depth was 11.20*, which yielded 538,031 high-quality SLAFs. Among these SLAFs, 204,361 were heterozygous in the maternal tree and segregated in the progeny. The established map contained 12,263 SLAFs that were assigned to 12 linkage groups (LGs). The number of LGs on this map equaled the number of chromosomes in Ginkgo. The total map length was 1,671.77 cM, with an average distance of 0.89 cM between adjacent marker bins. Map evaluation based on the haplotype map and the heat map validated the high quality of the established map. Because Ginkgo is an economically and biologically important tree, strenuous efforts have been exerted to sequence its genome. This new map, built using sequence-based markers, will serve in the future as a fundamental platform for anchoring sequence assemblies along Ginkgo chromosomes. This map also provides a desirable platform for various genetic studies of Ginkgo, including gene/quantitative trait locus mapping and marker-aided selection. PMID- 28663755 TI - Drought Stress Causes a Reduction in the Biosynthesis of Ascorbic Acid in Soybean Plants. AB - Drought provokes a number of physiological changes in plants including oxidative damage. Ascorbic acid (AsA), also known as vitamin C, is one of the most abundant water-soluble antioxidant compound present in plant tissues. However, little is known on the regulation of AsA biosynthesis under drought stress conditions. In the current work we analyze the effects of water deficit on the biosynthesis of AsA by measuring its content, in vivo biosynthesis and the expression level of genes in the Smirnoff-Wheeler pathway in one of the major legume crop, soybean (Glycine max L. Merr). Since the pathway has not been described in legumes, we first searched for the putative orthologous genes in the soybean genome. We observed a significant genetic redundancy, with multiple genes encoding each step in the pathway. Based on RNA-seq analysis, expression of the complete pathway was detected not only in leaves but also in root tissue. Putative paralogous genes presented differential expression patterns in response to drought, suggesting the existence of functional specialization mechanisms. We found a correlation between the levels of AsA and GalLDH biosynthetic rates in leaves of drought-stressed soybean plants. However, the levels of GalLDH transcripts did not show significant differences under water deficit conditions. Among the other known regulators of the pathway, only the expression of VTC1 genes correlated with the observed decline in AsA in leaves. PMID- 28663756 TI - Transcriptional Network Analysis Reveals Drought Resistance Mechanisms of AP2/ERF Transgenic Rice. AB - This study was designed to investigate at the molecular level how a transgenic version of rice "Nipponbare" obtained a drought-resistant phenotype. Using multi omics sequencing data, we compared wild-type rice (WT) and a transgenic version (erf71) that had obtained a drought-resistant phenotype by overexpressing OsERF71, a member of the AP2/ERF transcription factor (TF) family. A comprehensive bioinformatics analysis pipeline, including TF networks and a cascade tree, was developed for the analysis of multi-omics data. The results of the analysis showed that the presence of OsERF71 at the source of the network controlled global gene expression levels in a specific manner to make erf71 survive longer than WT. Our analysis of the time-series transcriptome data suggests that erf71 diverted more energy to survival-critical mechanisms related to translation, oxidative response, and DNA replication, while further suppressing energy-consuming mechanisms, such as photosynthesis. To support this hypothesis further, we measured the net photosynthesis level under physiological conditions, which confirmed the further suppression of photosynthesis in erf71. In summary, our work presents a comprehensive snapshot of transcriptional modification in transgenic rice and shows how this induced the plants to acquire a drought-resistant phenotype. PMID- 28663757 TI - Genome-Wide Analysis Suggests the Relaxed Purifying Selection Affect the Evolution of WOX Genes in Pyrus bretschneideri, Prunus persica, Prunus mume, and Fragaria vesca. AB - WUSCHEL-related homeobox (WOX) family is one of the largest group of transcription factors (TFs) specifically found in plant kingdom. WOX TFs play an important role in plant development processes and evolutionary novelties. Although the roles of WOXs in Arabidopsis and rice have been well-studied, however, little are known about the relationships among the main clades in the molecular evolution of these genes in Rosaceae. Here, we carried out a genome wide analysis and identified 14, 10, 10, and 9 of WOX genes from four Rosaceae species (Fragaria vesca, Prunus persica, Prunus mume, and Pyrus bretschneideri, respectively). According to evolutionary analysis, as well as amino acid sequences of their homodomains, these genes were divided into three clades with nine subgroups. Furthermore, due to the conserved structural patterns among these WOX genes, it was proposed that there should exist some highly conserved regions of microsynteny in the four Rosaceae species. Moreover, most of WOX gene pairs were presented with the conserved orientation among syntenic genome regions. In addition, according to substitution models analysis using PMAL software, no significant positive selection was detected, but type I functional divergence was identified among certain amino acids in WOX protein. These results revealed that the relaxed purifying selection might be the main driving force during the evolution of WOX genes in the tested Rosaceae species. Our result will be useful for further precise research on evolution of the WOX genes in family Rosaceae. PMID- 28663758 TI - LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes. AB - Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases ('laminopathies') including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2), insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations ('variants') in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA). We identified 169 variants in the ExAC cohort, of which 37 (~22%) are disease associated including p.I299V (allele frequency 0.0402%), p.G602S (allele frequency 0.0262%) and p.R644C (allele frequency 0.124%), suggesting certain LMNA mutations are more common than previously recognized. Independent analysis of LMNA variants via the type 2 diabetes (T2D) Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (p = 0.02; odds ratio = 4.58), and was more frequent in African Americans (allele frequency 0.297%). The FPLD2-associated variant I299V was most prevalent in Latinos (allele frequency 0.347%). The ExAC cohort also revealed 132 novel LMNA missense variants including p.K108E (limited to individuals with psychiatric disease; predicted to perturb coil-1B), p.R397C and p.R427C (predicted to perturb filament biogenesis), p.G638R and p.N660D (predicted to perturb prelamin A processing), and numerous Ig-fold variants predicted to perturb phenotypically characteristic protein-protein interactions. Overall, this two-pronged strategy- mining a large database for missense variants in a single gene (LMNA), coupled to knowledge about the structure, biogenesis and functions of A-type lamins- revealed an unexpected number of LMNA variants, including novel variants predicted to perturb lamin assembly or function. Interestingly, this study also correlated novel variant p.K108E with psychiatric disease, identified known variant p.I299V as a potential risk factor for metabolic disease in Latinos, linked variant p.G602 with type 2 diabetes, and identified p.G602S as a predictor of diabetes risk in African Americans. PMID- 28663760 TI - Atrial fibrosis: an obligatory component of arrhythmia mechanisms in atrial fibrillation? AB - Atrial fibrosis is common in atrial fibrillation (AF). Experimental studies have provided convincing evidence that fibrotic transformation of atrial myocardium results in deterioration of atrial conduction, increasing anisotropy of impulse propagation and building of boundaries that promote re-entry in the atrial walls that maybe directly relevant for the mechanisms responsible for maintaining AF. Whether or not fibrosis is a result of structural remodelling caused by persistent AF or a manifestation of occult myocardial process that leads to development of arrhythmia is less clear. Human data indicate the presence of association between persistency of AF and the extent of structural changes in atrial myocardium. The role atrial fibrosis plays in the mechanisms of AF, however, may differ between patients with structurally normal hearts, such as lone AF, and those with advanced cardiovascular comorbidities. PMID- 28663759 TI - New challenges of geriatric cardiology: from clinical to preclinical research. AB - The field of geriatric cardiology reflects the evolving medical approaches tailored to address the needs of the growing population of oldest old with cardiovascular diseases (CVD). The burden of CVD is expected to increase particularly for the most common types of chronic heart disease of the elderly including coronary artery disease, heart failure and atrial fibrillation. In this context of dramatic demographic changes, geriatric cardiologists are facing important challenges. In this review, we outline the basic concepts of geriatric cardiology and describe these challenges as well as the unmet needs around this discipline with also a focus on the translation from basic research. PMID- 28663761 TI - Clinical outcome of cardiac resynchronization therapy in dilated-phase hypertrophic cardiomyopathy. AB - BACKGROUNDS: Clinical trials have demonstrated that cardiac resynchronization therapy (CRT) is effective in patients with "non-ischemic cardiomyopathy". However, patients with dilated-phase hypertrophic cardiomyopathy (DHCM) have been generally excluded from such trials. We aimed to compare the clinical outcome of CRT in patients with DHCM, idiopathic dilated cardiomyopathy (IDCM), or ischemic cardiomyopathy (ICM). METHODS: A total of 312 consecutive patients (DHCM: n = 16; IDCM: n = 231; ICM: n = 65) undergoing CRT in Fuwai hospital were studied respectively. Response to CRT was defined as reduction in left ventricular end systolic volume (LVESV) >= 15% at 6-month follow-up. RESULTS: Compared with DHCM, IDCM was associated with a lower total mortality (HR: 0.35, 95% CI: 0.13-0.90), cardiac mortality (HR: 0.29; 95% CI: 0.11-0.77), and total mortality or heart failure (HF) hospitalizations (HR: 0.34, 95% CI: 0.17-0.69), independent of known confounders. Compared with DHCM, the total mortality, cardiac mortality and total mortality or HF hospitalizations favored ICM but were not statistically significant (HR: 0.59, 95% CI: 0.22-1.61; HR: 0.59, 95% CI: 0.21-1.63; HR: 0.54, 95% CI: 0.26-1.15; respectively). Response rate to CRT was lower in the DHCM group than the other two groups although the differences didn't reach statistical significance. CONCLUSIONS: Compared with IDCM, DHCM was associated with a worse outcome after CRT. The clinical outcome of DHCM patients receiving CRT was similar to or even worse than that of ICM patients. These indicate that DHCM behaves very differently after CRT. PMID- 28663762 TI - Comparison of very-high-frequency ultrasound assessment of radial arterial wall layers after first and repeated transradial coronary procedures. AB - BACKGROUND: Transradial coronary procedure (TRP) traumatizes the radial artery (RA), especially resulting in changes to arterial wall morphology. This study explored the significance of the early onset of traumatic effects to wall layers of the RA following the first TRP (FTRP) and repeat TRP (RTRP) using very-high frequency ultrabiomicroscopy (VHFUBM). METHODS: A total of 1431 patients that received TRP were divided into the FTRP group that comprised 781 patients and the RTRP group that comprised 650 patients depending on the number of procedures. Two dimensional RA images were acquired by 30-55 MHz ultrasound one day before and one day after the procedure. RESULTS: After TRP, the incidence of intimal tears, medial dissections and external elastic lamina fracture were greater in the RTRP (P < 0.001). The RTRP group showed significantly thicker intimal thickness (IT), media thickness (MT), adventitia thickness and all complex layer thicknesses as compared with the FTRP group (P < 0.001). CONCLUSIONS: Multivariate linear regression analysis discovered that repeated TRP and other observations were independent predictors of increased IT in post-operative RA. VHFUBM provides an approach to study structural and histopathological injury in the wall layers of RA which showed increased trauma to the RA following RTRP. PMID- 28663763 TI - Long-term outcomes of PCI vs. CABG for ostial/midshaft lesions in unprotected left main coronary artery. AB - BACKGROUND: There are limited data on long-term (> 5 years) outcomes of drug eluting stent (DES) implantation compared with coronary artery bypass grafting (CABG) for ostial/midshaft left main coronary artery (LMCA) lesions. METHODS: Of the 259 consecutive patients in Beijing Anzhen Hospital with ostial/midshaft LMCA lesions, 149 were treated with percutaneous coronary intervention (PCI) with DES and 110 were with CABG. The endpoints of the study were death, repeat revascularization, myocardial infarction (MI), stroke, the composite of cardiac death, and major adverse cardiac and cerebrovascular events (MACCE, the composite of cardiac death, MI, stroke or repeat revascularization).The duration of follow up is 7.1 years (interquartile range 5.3 to 8.2 years). RESULTS: There is no significant difference between the PCI and CABG group during the median follow-up of 7.1 years (interquartile range: 5.3-8.2 years) in the occurrence of death (HR: 0.727, 95% CI: 0.335-1.578; P = 0.421), the composite endpoint of cardiac death, MI or stroke (HR: 0.730, 95% CI: 0.375-1.421; P = 0.354), MACCE (HR: 1.066, 95% CI: 0.648-1.753; P = 0.801), MI (HR: 1.112, 95% CI: 0.414-2.987; P = 0.833), stroke (HR: 1.875, 95% CI: 0.528-6.659; P = 0.331), and repeat revascularization (HR: 1.590, 95% CI: 0.800-3.161; P = 0.186). These results remained after multivariable adjusting. CONCLUSION: During a follow-up up to 8.2 years, we found that DES implantation had similar endpoint outcomes compared with CABG. PMID- 28663764 TI - Transvenous versus open chest lead placement for resynchronization therapy in patients with heart failure: comparison of ventricular electromechanical synchronicity. AB - BACKGROUND: Transvenous lead placement is the standard approach for left ventricular (LV) pacing in cardiac resynchronization therapy (CRT), while the open chest access epicardial lead placement is currently the most frequently used second choice. Our study aimed to compare the ventricular electromechanical synchronicity in patients with heart failure after CRT with these two different LV pacing techniques. METHODS: We enrolled 33 consecutive patients with refractory heart failure secondly to dilated cardiomyopathy who were eligible for CRT in this study. Nineteen patients received transvenous (TV group) while 14 received open chest (OP group) LV lead pacing. Intra- and inter-ventricular electromechanical synchronicity was assessed by tissue Doppler imaging (TDI) before and one year after CRT procedure. RESULTS: Before CRT procedure, the mean QRS-duration, maximum time difference to systolic peak velocity among 12 left ventricle segments (LV Ts-12), standard deviation of time difference to systolic peak velocity of 12 left ventricle segments (LV Ts-SD), and inter-ventricular mechanical delay (IVMD) in OP and TV group were 166 +/- 17 ms and 170 +/- 21 ms, 391 +/- 42 ms and 397 +/- 36 ms, 144 +/- 30 ms and 148 +/- 22 ms, 58 +/- 25 ms and 60 +/- 36 ms, respectively (all P > 0.05). At one year after the CRT, the mean QRS-duration, LV Ts-12, LV Ts-SD, and IVMD in TV and OP group were 128 +/- 14 ms and 141 +/- 22 ms (P = 0.031), 136 +/- 37 ms and 294 +/- 119 ms (P = 0.023), 50 +/- 22 ms and 96 +/- 34 ms (P = 0.015), 27 +/- 11 ms and 27 +/- 26 ms (P = 0.86), respectively. The LV lead implantation procedure time was 53.4 +/- 16.3 min for OP group and 136 +/- 35.1 min for TV group (P = 0.016). The mean LV pacing threshold increased significantly from 1.7 +/- 0.6 V/0.5 ms to 2.3 +/- 1.6 V/0.5 ms (P < 0.05) in TV group while it remained stable in the OP group. CONCLUSIONS: Compared to conventional endovascular approach, open chest access of LV pacing for CRT leads to better improvement of the intraventricular synchronization. PMID- 28663765 TI - Minimally invasive thalamic hematoma drainage can improve the six-month outcome of thalamic hemorrhage. AB - OBJECTIVE: To explore predictors of the 6-month clinical outcome of thalamic hemorrhage, and evaluate if minimally invasive thalamic hematoma drainage (THD) could improve its prognosis. METHODS: A total of 54 patients with spontaneous thalamic hemorrhage were evaluated retrospectively. Clinical data, including demographics, stroke risk factors, neuroimaging variables, Glasgow Coma Score (GCS) on admission, surgical strategy, and outcome, were collected. Clinical outcome was assessed using a modified Rankin Scale, six months after onset. Univariate analysis and multivariate logistic regression analysis were performed to determine predictors of a poor outcome. RESULTS: Conservative treatment was performed for five patients (9.3%), external ventricular drainage (EVD) for 20 patients (37.0%), THD for four patients (7.4%), and EVD combined with THD for 25 patients (46.3%). At six months after onset, 21 (38.9%) patients achieved a favorable outcome, while 33 (61.1%) had a poor outcome. In the univariate analysis, predictors of poor 6-month outcome were lower GCS on admission (P = 0.001), larger hematoma volume (P < 0.001), midline shift (P = 0.035), acute hydrocephalus (P = 0.039), and no THD (P = 0.037). The independent predictors of poor outcome, according to the multivariate logistic regression analysis, were no THD and larger hematoma volume. CONCLUSIONS: Minimally invasive THD, which removes most of the hematoma within a few days, with limited damage to perihematomal brain tissue, improved the 6-month outcome of thalamic hemorrhage. Thus, THD can be widely applied to treat patients with thalamic hemorrhage. PMID- 28663766 TI - Non-invasive ventilation improves hemorheology status in hypoxemic patients with acute myocardial infarction after PCI. AB - BACKGROUND: Hypoxemia sometimes occurs in the emergency room in the patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), even in those with administration of conventional high-flow oxygen inhalation. The objective of the present study was to evaluate the effectiveness of non invasive ventilation (NIV) in improving blood oxygen content and hemorheology in patients with AMI and hypoxemia. METHODS: This prospective study enrolled 50 consecutive eligible patients with AMI (aged 72.3 +/- 9.5 years), who had undergone PCI and been administered high-flow oxygen but still had hypoxemia. Blood was taken before NIV and at 0.5, 1, and 2 h after NIV. Blood gases, hemorheological variables including erythrocyte deformability, erythrocyte aggregation, erythrocyte osmotic fragility, membrane fluidity, and oxidative stress level were measured. RESULTS: Blood PaO2 increased to normal by 1 h after NIV. Assessed hemorheological variables had all improved and plasma malondialdehyde concentration decreased significantly after 2 h of NIV. CONCLUSIONS: Our data suggest that NIV can help to improve blood oxygen content, hemorheological status, and minimize plasma lipid peroxidation injury in hypoxemic patients with AMI who have undergone PCI. PMID- 28663767 TI - Changes in physical activity and cardiovascular mortality in older adults. PMID- 28663768 TI - Depression is associated with increased C-reactive protein levels in patients with heart failure and hyperuricemia. PMID- 28663769 TI - The role of CCK8 in the inhibition of glucose production. AB - A recent study suggested that a rise of cholecystokinin (CCK8) in the duodenum may bring about an inhibition of hepatic glucose production. The authors made use of the pancreatic clamp technique to characterize a gut-brain-liver signal generated by CCK8 that reduces glucose output by the liver. The pancreatic clamp conditions used created a situation in which the liver was markedly deficient in both insulin and glucagon. Although the data presented indicated that CCK8 can reduce glucose production, the authors do not establish a role for this inhibition in the reduction of glucose output seen in response to feeding. It must be remembered that in response to a meal the insulin level in the hepatic sinusoids rises markedly, as does the insulin level to which the brain is exposed. It therefore seems likely that either or both of these effects will drive the suppression of glucose production rather than any effect of CCK8. The importance of the CCK8 effect needs to be determined in the presence of elevated arterial and sinusoidal insulin before any conclusion can be drawn about its relevance. PMID- 28663770 TI - The Development of Body Structure Knowledge in Infancy. AB - Although we know much about the development of face processing, we know considerably less about the development of body knowledge-despite bodies also being significant sources of social information. One set of studies indicated that body structure knowledge is poor during the 1st year of life and spawned a model that posits that, unlike the development of face knowledge, which benefits from innate propensities and dedicated learning mechanisms, the development of body knowledge relies on general learning mechanisms and develops slowly. In this article, we review studies on infants' knowledge about the structure of bodies and their processing of gender and emotion that paint a different picture. Although questions remain, a general social cognition system likely engenders similar trajectories of development of knowledge about faces and bodies, and may equip developing infants with the capacity to obtain socially critical information from many sources. PMID- 28663771 TI - Experience with code-switching modulates the use of grammatical gender during sentence processing. AB - Using code-switching as a tool to illustrate how language experience modulates comprehension, the visual world paradigm was employed to examine the extent to which gender-marked Spanish determiners facilitate upcoming target nouns in a group of Spanish-English bilingual code-switchers. The first experiment tested target Spanish nouns embedded in a carrier phrase (Experiment 1b) and included a control Spanish monolingual group (Experiment 1a). The second set of experiments included critical trials in which participants heard code-switches from Spanish determiners into English nouns (e.g., la house) either in a fixed carrier phrase (Experiment 2a) or in variable and complex sentences (Experiment 2b). Across the experiments, bilinguals revealed an asymmetric gender effect in processing, showing facilitation only for feminine target items. These results reflect the asymmetric use of gender in the production of code-switched speech. The extension of the asymmetric effect into Spanish (Experiment 1b) underscores the permeability between language modes in bilingual code-switchers. PMID- 28663772 TI - Proton Environments in Biomimetic Calcium Phosphates Formed from Mesoporous Bioactive CaO-SiO2-P2O5 Glasses in Vitro: Insights from Solid-State NMR. AB - When exposed to body fluids, mesoporous bioactive glasses (MBGs) of the CaO-SiO2 P2O5 system develop a bone-bonding surface layer that initially consists of amorphous calcium phosphate (ACP), which transforms into hydroxy-carbonate apatite (HCA) with a very similar composition as bone/dentin mineral. Information from various 1H-based solid-state nuclear magnetic resonance (NMR) experiments was combined to elucidate the evolution of the proton speciations both at the MBG surface and within each ACP/HCA constituent of the biomimetic phosphate layer formed when each of three MBGs with distinct Ca, Si, and P contents was immersed in a simulated body fluid (SBF) for variable periods between 15 min and 30 days. Directly excited magic-angle-spinning (MAS) 1H NMR spectra mainly reflect the MBG component, whose surface is rich in water and silanol (SiOH) moieties. Double quantum-single-quantum correlation 1H NMR experimentation at fast MAS revealed their interatomic proximities. The comparatively minor H species of each ACP and HCA component were probed selectively by heteronuclear 1H-31P NMR experimentation. The initially prevailing ACP phase comprises H2O and "nonapatitic" HPO42-/PO43- groups, whereas for prolonged MBG soaking over days, a well-progressed ACP -> HCA transformation was evidenced by a dominating O1H resonance from HCA. We show that 1H-detected 1H -> 31P cross-polarization NMR is markedly more sensitive than utilizing powder X-ray diffraction or 31P NMR for detecting the onset of HCA formation, notably so for P-bearing (M)BGs. In relation to the long-standing controversy as to whether bone mineral comprises ACP and/or forms via an ACP precursor, we discuss a recently accepted structural core-shell picture of both synthetic and biological HCA, highlighting the close relationship between the disordered surface layer and ACP. PMID- 28663774 TI - Infection Prophylaxis for Breast Implant Surgery: Could We Do Better? AB - Objective: Infective complications following breast implant surgery may result in implant removal. This causes patient distress and is costly to treat. A range of precautions is undertaken at the time of surgery to reduce infection, with varying levels of supporting evidence. This study aimed to determine how frequently and consistently infection prevention precautions are used during breast implant surgery. Methods: Multicenter observational study of surgical practice with real-time data collection during breast implant surgery. Results: From 7 NHS breast units, 121 implant procedures were assessed in 94 patients under the care of 22 consultant surgeons. The commonest procedure was immediate reconstruction (58%; 70/121). All patients were methicillin-resistant Staphylococcus aureus (but not methicillin-sensitive Staphylococcus aureus) screened. Antibiotics were given at surgery in all cases; 92% (85/94) received postoperative antibiotics. Other precautions included closed glove technique (67%; 63/94), door signs to reduce theater traffic (72%; 68/94), glove changing prior to implant handling (98%; 119/121), laminar air flow theaters (55%; 52/94), disposable drapes (94%; 88/94) and gowns (74%; 70/94), and cavity washing (89%; 108/121). Among the 14 consultants evaluated on more than 1 procedure (range, 2 22; median = 5), only 1 consistently used exactly the same precautions when siting an implant. Conclusion: Despite national guidance, infection prevention measures are not applied consistently during breast implant surgery, with variability between surgeons and within individual surgeon's practice. The introduction of an infection prevention checklist for all breast implant procedures could improve the reliability with which these precautions are undertaken. PMID- 28663773 TI - Optimizing Outcomes of Postmastectomy Breast Reconstruction With Acellular Dermal Matrix: A Review of Recent Clinical Data. AB - Background: This article reports on the current use of acellular dermal matrix in breast reconstruction. Methods: A literature review of articles on acellular dermal matrix in breast reconstruction from January 1, 2010, through December 20, 2016, was performed and analyzed for trends in acellular dermal matrix use and differences between commonly used acellular dermal matrixes. Findings: Clinical findings varied but include improved cosmesis and more 1-stage reconstructions using acellular dermal matrix. Superiority of sterile versus aseptic acellular dermal matrixes was noted, and the increased incidence of red breast syndrome with AlloDerm was significant. The cost-effectiveness of acellular dermal matrix use despite increased upfront costs was also highlighted. Finally, the article emphasizes the importance of well-vascularized mastectomy flaps and the use of indocyanine green angiography as an adjunct in immediate reconstruction with acellular dermal matrix. PMID- 28663775 TI - A Single-Center Review of Palatal Fractures: Etiology, Patterns, Concomitant Injuries, and Management. AB - Introduction: Palatal fractures are frequently associated with facial trauma and Le Fort fractures. The complex anatomy of the midfacial skeleton makes diagnosing and treating these injuries a challenge. The goal of this study was to report our experience with the presentation, concomitant injuries, and management of palatal fractures at a level I trauma center in an urban environment. Methods: Data were collected for all palatal fractures diagnosed between January 2000 and December 2012 at the University Hospital in Newark, NJ. Data on patient demographics, Glasgow Coma Scale score on presentation, concomitant facial fractures, extrafacial injuries, and management strategies were collected from these records. Results: Of the 3147 facial fractures treated at our institution during this time period, 61 were associated with a palatal fracture following blunt trauma. There was a strong male predominance (87%) and a mean age of 35.6 years in this subset of patients. The most common causes of injury were assault and motor vehicle accident. The most common fracture patterns were alveolar, parasagittal, and para-alveolar, whereas sagittal and transverse fractures were rare. The most frequently encountered facial and extrafacial injuries were orbital fractures and intracranial hemorrhage, respectively. There was a significant association between type II sagittal fractures and traumatic brain injury (P < .05). Conclusions: Our study examines a single center's experience with palatal fractures in terms of presentation, concomitant injuries, and management strategies. Palatal fractures are most often associated with high energy mechanisms, and the severity of injury appears to correlate with the type of palatal fracture. PMID- 28663776 TI - Direct Perforator Anastomosis of Free ALT Flap in Massive Weight Loss Due to Increased Size of Vessels. PMID- 28663777 TI - Disseminated Mycobacterium Avium Complex in an Adolescent with Perinatally Acquired HIV Infection. AB - Mycobacterium avium complex (MAC) is the most frequent nontuberculous mycobacteria implicated in opportunistic infections that define acquired immunodeficiency syndrome. With highly active antiretroviral therapy, disseminated MAC (dMAC) has become a rare entity. This unique case of dMAC was diagnosed in an adolescent with newly diagnosed perinatally-acquired HIV infection whose initial CD4 cell count was severely depleted and viral load was extremely high. While maximized treatment regimen had not been able to control his dMAC, improvement was noted when granulocyte macrophage colony-stimulating factor (GM-CSF) was added. GM-CSF should be considered as an adjunctive therapy in patients with refractory dMAC. PMID- 28663778 TI - Epidemiology and Clinical Complication Patterns of Influenza A (H1N1 Virus) in Northern Saudi Arabia. AB - The aim of the present study is to describe epidemiologic and clinical presentation, clinical complications and outcomes of patients diagnosed with influenza A infection (H1N1) during a one-year period. We retrospectively investigated 300 patients with influenza-like clinical presentation during the period January 2015 - January 2016 in King Khalid Hospital, Saudi Arabia. Fifty four patients out of 300 (18%) were diagnosed with H1N1 virus infection; their age ranged from 7 months to 85 years, with a mean age of 25 years. Among them, 34 (63%) were males and 20 (37%) were females, with a M:F ratio of 1.70. The findings of this study show the great spread of influenza A outside the main holy cities of Saudi Arabia, and underline the absolute need for strict prevention strategies including vaccinations, public awareness and hygiene measures. PMID- 28663779 TI - Antiretroviral Therapy Containing Raltegravir to Prevent Mother-to-Child Transmission of HIV in Infected Pregnant Women. AB - We conducted a retrospective study in a general hospital in Buenos Aires, Argentina (2009-2015) aimed at evaluating outcomes in HIV-infected pregnant women (HIPW), who were prescribed raltegravir (RAL)-containing antiretroviral therapy (ART). A total of 239 HIPW were enrolled in our study; among them 31 received RAL (12.9%) at different clinical stages: i) intensification (INS): addition of RAL to current ART because of detectable antepartum viral load, 13 (41.9%); ii) late presenter (LP): standard ART + RAL as fourth drug, 15 (48.4%); iii) treatment of resistant-HIV: 3 (9.7%). Median gestational age at RAL initiation was 34 weeks and median exposure was 30 days. In INS-group, median viral load (VL) decrease was 1.48 log10. In LP-group, median VL decline was 2.15 log10. No clinical adverse events or maternal intolerance attributable to RAL were observed. Elective cesarean section was done in 51.7%; mild elevation of transaminases was observed in 35% of neonates. No vertical transmission was documented. PMID- 28663780 TI - New insights into the pathogenesis and prevention of tuberous sclerosis associated neuropsychiatric disorders (TAND). AB - Tuberous sclerosis complex (TSC) is a multi-system disorder resulting from mutations in either the TSC1 or TSC2 genes leading to hyperactivation of mechanistic target of rapamycin (mTOR) signaling. TSC is commonly associated with autism (61%), intellectual disability (45%), and behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties that are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). More than 90% of children with TSC have epilepsy, including infantile spasms, and early onset of seizures, especially infantile spasms, is associated with greater impairment in intellectual development compared with individuals with TSC without seizures. Development of the mTOR inhibitors everolimus and sirolimus has led to considerable progress in the treatment of renal angiomyolipomata, pulmonary lymphangioleiomyomatosis, and subependymal giant cell astrocytomas in the brain. However, similar therapeutic progress is needed in the treatment of TAND. PMID- 28663782 TI - Dose Titration Algorithm Tuning (DTAT) should supersede the Maximum Tolerated Dose (MTD) concept in oncology dose-finding trials. AB - Background. Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent 'confirmatory' Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational drug. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of 'the' maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived of, not as 'dose-finding', but as dosing algorithm-finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug's population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple dose titration algorithm targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace 'the' MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible dose titration algorithm capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. The individual-level linearization of myelosuppression dynamics demonstrated for the simulation model used here suggest that a titration algorithm specified in the more general terms of the linear Kalman filter will be worth exploring. PMID- 28663781 TI - Recent advances in understanding maternal perinatal mood disorders. AB - The study of perinatal mental health (mental health during pregnancy and postpartum) is a complex field of study that is of major importance both for the mental and physical health of new mothers and for the neurobehavioral development and long-term functioning of the children they bear. In this review, we cover the most recent additions to this rapidly evolving field. Notable advances include further illumination of the epidemiological patterns and clinical manifestations of perinatal mood disruption; new efficacy data on treatment and prevention; clarifications of the respective contributions of maternal mental illness and psychotropic medication to outcomes of pregnancy, birth, and child development; and updated expert guidelines for screening. PMID- 28663783 TI - Questions on unusual Mimivirus-like structures observed in human cells. AB - Background: Mimiviruses or giant viruses that infect amoebas have the ability to retain the Gram stain, which is usually used to colour bacteria. There is some evidence suggesting that Mimiviruses can also infect human cells. Guided by these premises, we performed a routine Gram stain on a variety of human specimens to see if we could detect the same Gram positive blue granules that identify Mimiviruses in the amoebas. Methods: We analysed 24 different human specimens (liver, brain, kidney, lymph node and ovary) using Gram stain histochemistry, electron microscopy immunogold, high resolution mass spectrometry and protein identification. Results: We detected in the human cells Gram positive granules that were distinct from bacteria. The fine blue granules displayed the same pattern of the Gram positive granules that diagnose Mimiviruses in the cytoplasm of the amoebas. Electron microscopy confirmed the presence of human Mimiviruses like structures and mass spectrometry identified histone H4 peptides, which had the same footprints as giant viruses. However, some differences were noted: the Mimivirus-like structures identified in the human cells were ubiquitous and manifested a distinct mammalian retroviral antigenicity. Conclusions: Our main hypotheses are that the structures could be either giant viruses having a retroviral antigenicity or ancestral cellular components having a viral origin. However, other possible alternatives have been proposed to explain the nature and function of the newly identified structures. PMID- 28663784 TI - The internet trade of counterfeit spirits in Russia - an emerging problem undermining alcohol, public health and youth protection policies? AB - Counterfeit alcohol belongs to the category of unrecorded alcohol not reflected in official statistics. The internet trade of alcoholic beverages has been prohibited by the Russian Federation since 2007, but various sellers still offer counterfeit spirits (i.e., forged brand spirits) over the internet to Russian consumers, mostly in a non-deceptive fashion at prices up to 15 times lower than in regular sale. The public health issues arising from this unregulated trade include potential harm to underage drinkers, hazards due to toxic ingredients such as methanol, but most importantly alcohol harms due to potentially increased drinking volumes due to low prices and high availability on the internet. The internet sale also undermines existing alcohol policies such as restrictions of sale locations, sale times and minimum pricing. The need to enforce measures against counterfeiting of spirits, but specifically their internet trade should be implemented as key elements of alcohol policies to reduce unrecorded alcohol consumption, which is currently about 33 % of total consumption in Russia. PMID- 28663785 TI - Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability. AB - Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37 year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband's mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy. PMID- 28663787 TI - CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets. AB - High dimensional mass and flow cytometry (HDCyto) experiments have become a method of choice for high throughput interrogation and characterization of cell populations.Here, we present an R-based pipeline for differential analyses of HDCyto data, largely based on Bioconductor packages. We computationally define cell populations using FlowSOM clustering, and facilitate an optional but reproducible strategy for manual merging of algorithm-generated clusters. Our workflow offers different analysis paths, including association of cell type abundance with a phenotype or changes in signaling markers within specific subpopulations, or differential analyses of aggregated signals. Importantly, the differential analyses we show are based on regression frameworks where the HDCyto data is the response; thus, we are able to model arbitrary experimental designs, such as those with batch effects, paired designs and so on. In particular, we apply generalized linear mixed models to analyses of cell population abundance or cell-population-specific analyses of signaling markers, allowing overdispersion in cell count or aggregated signals across samples to be appropriately modeled. To support the formal statistical analyses, we encourage exploratory data analysis at every step, including quality control (e.g. multi-dimensional scaling plots), reporting of clustering results (dimensionality reduction, heatmaps with dendrograms) and differential analyses (e.g. plots of aggregated signals). PMID- 28663788 TI - Using spectral decomposition of the signals from laurdan-derived probes to evaluate the physical state of membranes in live cells. AB - Background: We wanted to investigate the physical state of biological membranes in live cells under the most physiological conditions possible. Methods: For this we have been using laurdan, C-laurdan or M-laurdan to label a variety of cells, and a biphoton microscope equipped with both a thermostatic chamber and a spectral analyser. We also used a flow cytometer to quantify the 450/530 nm ratio of fluorescence emissions by whole cells. Results: We find that using all the information provided by spectral analysis to perform spectral decomposition dramatically improves the imaging resolution compared to using just two channels, as commonly used to calculate generalized polarisation (GP). Coupled to a new plugin called Fraction Mapper, developed to represent the fraction of light intensity in the first component in a stack of two images, we obtain very clear pictures of both the intra-cellular distribution of the probes, and the polarity of the cellular environments where the lipid probes are localised. Our results lead us to conclude that, in live cells kept at 37 degrees C, laurdan, and M laurdan to a lesser extent, have a strong tendency to accumulate in the very apolar environment of intra-cytoplasmic lipid droplets, but label the plasma membrane (PM) of mammalian cells ineffectively. On the other hand, C-laurdan labels the PM very quickly and effectively, and does not detectably accumulate in lipid droplets. Conclusions: From using these probes on a variety of mammalian cell lines, as well as on cells from Drosophila and Dictyostelium discoideum, we conclude that, apart from the lipid droplets, which are very apolar, probes in intracellular membranes reveal a relatively polar and hydrated environment, suggesting a very marked dominance of liquid disordered states. PMs, on the other hand, are much more apolar, suggesting a strong dominance of liquid ordered state, which fits with their high sterol contents. PMID- 28663786 TI - The advantage of channeling nucleotides for very processive functions. AB - Nucleoside triphosphate (NTP)s, like ATP (adenosine 5'-triphosphate) and GTP (guanosine 5'-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP- or GTP consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised 'microcompartments', where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, i.e. is very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases. PMID- 28663789 TI - Molecular and phenotypic biomarkers of aging. AB - Individuals of the same age may not age at the same rate. Quantitative biomarkers of aging are valuable tools to measure physiological age, assess the extent of 'healthy aging', and potentially predict health span and life span for an individual. Given the complex nature of the aging process, the biomarkers of aging are multilayered and multifaceted. Here, we review the phenotypic and molecular biomarkers of aging. Identifying and using biomarkers of aging to improve human health, prevent age-associated diseases, and extend healthy life span are now facilitated by the fast-growing capacity of multilevel cross sectional and longitudinal data acquisition, storage, and analysis, particularly for data related to general human populations. Combined with artificial intelligence and machine learning techniques, reliable panels of biomarkers of aging will have tremendous potential to improve human health in aging societies. PMID- 28663790 TI - Recent advances in the management of chronic obstructive pulmonary disease. AB - Novel pharmacotherapies introduce additional options to providers and patients in how to best treat chronic obstructive pulmonary disease (COPD). Emerging data question the role of inhaled corticosteroids in COPD treatment, particularly as combination dual bronchodilator pharmacotherapies demonstrate robust results. For those maximized on pharmacotherapy with continued dyspnea or exacerbations or both, emerging bronchoscopic procedures may offer additional therapy in select patients. This review focuses on data supporting the use of novel ultra bronchodilators, particularly in combination, and on the role for inhaled corticosteroid withdrawal and new bronchoscopic procedures. PMID- 28663791 TI - Human papillomavirus vaccination: the population impact. AB - We currently have the knowledge and experience to prevent much of human papillomavirus (HPV)-related disease burden globally. In many countries where prophylactic HPV vaccination programs have been adopted as highly effective public health programs with good vaccine coverage, we are already seeing, in real world settings, reduction of vaccine-related HPV-type infections, genital warts and cervical pre-cancers with potential reductions in vulvar, vaginal and anal pre-cancers. Moreover, we are seeing a change in cervical screening paradigms, as HPV-based screening programs now have strong evidence to support their use as more sensitive ways to detect underlying cervical abnormalities, as compared with conventional cervical cytology. This article describes the impact of prophylactic vaccination on these outcomes and in settings where these vaccines have been implemented in national immunisation programs. Given the successes seen to date and the availability of essential tools, there has been a global push to ensure that every woman has access to effective cervical screening and every girl has the opportunity for primary prevention through vaccination. A gender-neutral approach by offering vaccination to young boys has also been adopted by some countries and is worthy of consideration given that HPV-related cancers also affect males. Furthermore, vaccination of young boys has the advantage of reducing the risk of HPV transmission to sexual partners, lowering the infectious pool of HPV in the general population and ultimately HPV-related diseases for both genders. Therefore, it is appropriate that all countries consider and promote national guidelines and programs to prevent HPV-related diseases. PMID- 28663792 TI - Recent advances in congenital heart disease genomics. AB - Congenital heart disease is the most common congenital abnormality, and advances in medical care mean that this population of individuals is surviving for longer than ever before. It represents a significant healthcare challenge, as many patients require life-long care and individuals may ask about the likelihood of their children being affected. Whilst a number of genes have been identified previously from investigation of families with Mendelian inheritance patterns, sequencing the DNA from large cohorts of individuals with congenital heart disease is now providing fresh insights into the genetics of these conditions. This research has enabled novel gene discovery and uncovered the different genetic mechanisms underlying both isolated congenital heart disease and that which occurs in association with other medical problems. This article discusses the most recent advances in this field and the implications for patient care. In addition, we consider the challenges facing researchers in this field and emphasise the need for close working relationships between clinicians and researchers. PMID- 28663793 TI - Recent advances in hematopoietic stem cell transplantation. AB - Hematopoietic cell transplantation (HCT), once used as a last-resort therapy, is now considered a lifesaving procedure for thousands of patients with life threatening diseases worldwide and is frequently used early in the course of treatment for diseases destined to be uncontrollable by non-HCT therapies. Incremental advances leading to reduction of post-transplant morbidity and mortality by better control of graft versus host disease (GVHD), infections, and regimen-related toxicities, coupled with greater donor options, not only significantly increased the utilization and success of this procedure but also allowed many of these patients to enjoy healthy and productive lives after HCT. Emerging concepts in the field are now focused on the expansion of available donor options, further reduction of transplant-related toxicity, and decrease in post-transplant relapse. PMID- 28663795 TI - Temporal artery biopsy in the diagnosis of giant cell arteritis: Does the end justify the means? AB - BACKGROUND: Early temporal artery biopsy is recommended in all patients with suspected cranial GCA (Giant Cell Arteritis) by the BSR (British Society of Rheumatology) and BHPR (British Health Professionals in Rheumatology) guidelines. This should be performed within one week ideally. AIM: To assess ACR (American College of Rheumatology) score at presentation and whether temporal artery biopsy result affects clinical management of the clinically suspected GCA patient. METHOD: Case records of all temporal artery biopsies performed within January 2012 until December 2014 were analysed for size and result of biopsy and this was correlated to clinical management following result. RESULTS: 129 temporal arteries were biopsied with a total of 17 positive biopsy results. 10 biopsy samples were insufficient to confirm or refute GCA. 8 patients within the biopsies negative for GCA had their prednisolone therapy stopped. 5 patients had unknown follow up, with the remainder (89, 87.3%) of the patients continued prednisolone management for treatment of GCA for at least 6 weeks. CONCLUSION: Overall 13.2% of our biopsies were positive for GCA and 87.3% of biopsy negative patients continued prednisolone therapy on clinical grounds. In the face of new diagnostic tests (high resolution MRI (Magnetic Resonance Imaging), colour duplex USS (Ultra Sound Scan) and PET (Positive Emission Topography) can we justify invasive surgery to all patients on histological grounds when the results may not alter management? Further investigation is needed directly comparing newer imaging modalities to histology. PMID- 28663796 TI - Improving antibiotic prophylaxis in gastrointestinal surgery patients: A quality improvement project. AB - BACKGROUND: A surgical site infection (SSI) is a frequent complication following gastrointestinal surgery, but the careful selection and administration of prophylactic antibiotics can reduce the risk. The aim of this study was to develop a package of interventions that could be used to improve surgical antibiotic prophylaxis (SAP) at our institution. METHODS: A pre-post quality improvement project at a private hospital in Saudi Arabia was conducted between January 2014 until July 2016. A multidisciplinary team was assembled to identify and overcome barriers that were responsible for patients receiving suboptimal antibiotic prophylaxis. Patients were included if they had undergone surgery on their appendix, colon, rectum, or small intestine. Compliance with use of an adapted order form, as well as appropriate antibiotic selection, dosing, timing, and timing of re-dosing, were measured. Data on the rates of SSI before and after the intervention were also obtained. RESULTS: Of the 269 patients included in the study, 161 (61.5%) had appendix surgery, 86 (32.8%) had colorectal surgery, and 15 (5.7%) had small bowel surgery. The surgery was performed laparoscopically in 218 (83.5%) of patients. Utilization of the adapted order form increased from 1.8% to 92.0% following the intervention (p < 0.001). Compliance with a bundle of appropriate antibiotic selection, dosing and timing improved from 47.3% to 82.2% after the intervention (p < 0.001). Additionally, there was a non-statistically significant reduction in SSI rate (9.1% vs 5.1%; p = 0.27). CONCLUSIONS: Our quality improvement intervention was successful in improving SAP for patients undergoing gastrointestinal surgery at our institution. PMID- 28663794 TI - Recent advances in the understanding of renal inflammation and fibrosis in lupus nephritis. AB - Lupus nephritis is a potentially reversible cause of severe acute kidney injury and is an important cause of end-stage renal failure in Asians and patients of African or Hispanic descent. It is characterized by aberrant exaggerated innate and adaptive immune responses, autoantibody production and their deposition in the kidney parenchyma, triggering complement activation, activation and proliferation of resident renal cells, and expression of pro-inflammatory and chemotactic molecules leading to the influx of inflammatory cells, all of which culminate in destruction of normal nephrons and their replacement by fibrous tissue. Anti-double-stranded DNA (anti-dsDNA) antibody level correlates with disease activity in most patients. There is evidence that apart from mediating pathogenic processes through the formation of immune complexes, pathogenic anti dsDNA antibodies can bind to resident renal cells and induce downstream pro apoptotic, pro-inflammatory, or pro-fibrotic processes or a combination of these. Recent data also highlight the critical role of macrophages in acute and chronic kidney injury. Though clinically effective, current treatments for lupus nephritis encompass non-specific immunosuppression and the anti-inflammatory action of high-dose corticosteroids. The clinical and histological impact of novel biologics targeting pro-inflammatory molecules remains to be investigated. Insight into the underlying mechanisms that induce inflammatory and fibrotic processes in the kidney of lupus nephritis could present opportunities for more specific novel treatment options to improve clinical outcomes while minimizing off-target untoward effects. This review discusses recent advances in the understanding of pathogenic mechanisms leading to inflammation and fibrosis of the kidney in lupus nephritis in the context of established standard-of-care and emerging therapies. PMID- 28663798 TI - First chikungunya outbreak in Pakistan: a trail of viral attacks. AB - Despite explicit warning from the National Institute of Health, Pakistan experienced its first chikungunya outbreak in the metropolis of Karachi. We underscore the attention of health authorities and healthcare professionals towards contributing factors associated with this outbreak and the measures required to combat this viral disease. PMID- 28663797 TI - Identification of tigecycline- and vancomycin-resistant Staphylococcus aureus strains among patients with urinary tract infection in Iran. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital- and community-acquired infections worldwide. Although S. aureus rarely accounts for urinary tract infections (UTI), untreated UTI can lead to several complications. For decades vancomycin has been used for the treatment of MRSA infections. This study was performed to assess the in vitro activity of vancomycin, tigecycline, linezolid and quinupristin/dalfopristin against MRSA isolates from UTI patients. Thirty MRSA strains from 54 S. aureus isolates were isolated from patients with UTI. The antimicrobial susceptibility patterns of the strains were determined by the Kirby-Bauer disk diffusion and broth microdilution methods. PCR assays were used to detect the vanA gene. The MRSA isolates resistant to vancomycin were confirmed using the broth microdilution method. The results revealed that the MRSA isolates were 100% susceptible to linezolid and quinupristin/dalfopristin but 93.3% susceptible to vancomycin and tigecycline respectively. The broth microdilution method confirmed two MRSA strains (6.6%) to be resistant to vancomycin and tigecycline. The study identified vancomycin resistance among the MRSA isolates from UTI patients. This vancomycin resistance in MRSA isolates poses a challenge in managing S. aureus infections. Our study's results highlight the need to correctly identify patients in whom last-resort therapy such as linezolid and quinupristin/dalfopristin should be administered. PMID- 28663799 TI - First description of wound infection with Vibrio harveyi in Spain. PMID- 28663800 TI - Septic arthritis caused by an emerging ST121 methicillin-susceptible, PVL negative Staphylococcus aureus harbouring a variant of bone sialoprotein-binding protein gene. AB - ST121/agr-IV methicillin-susceptible Staphylococcus aureus was isolated from a patient of septic arthritis (synovial fluid, blood, skin and nasal cavity). Although the Panton-Valentine leukocidin (PVL) gene was negative, this isolate harboured a gene encoding a variant of bone sialoprotein-binding protein with a shortened SD-repeat region. PMID- 28663801 TI - Presence of Shiga toxin 2e-producing Escherichia coli and atypical enteropathogenic E. coli in an asymptomatic child. AB - INTRODUCTION: Escherichia coli causes gastroenteritis in humans and animals. CASE PRESENTATION: In this study, both Shiga toxin-producing E. coli (STEC) and atypical enteropathogenic E. coli (EPEC) strains were identified in a stool sample from a healthy child, and they were serotyped as Shiga toxin-producing E. coli (STEC) ONT : H19 and atypical enteropathogenic E. coli (EPEC) O37 : H45. CONCLUSION: This is the first report, to our knowledge, of a concomitant presence of diarrhoeagenic E. coli (DEC) strains in an asymptomatic child. None of the microorganisms was able to produce diarrhoea, maybe because they were transient bacteria or because of the good immune status of the child. Attention should be paid to this result and it could be of interest in vaccine prospects. PMID- 28663802 TI - Clinical spectrum of severe leptospirosis in the UK. AB - INTRODUCTION: Human leptospirosis is a global zoonotic infection with a characteristic biphasic illness and protean clinical manifestations. The majority are mild flu-like infections. The severe forms cause multiorgan damage with a greater predilection to hepatorenal failure. CASE PRESENTATION: We attempted to analyse the clinical presentation of severe leptospirosis and decipher the clinical spectrum within this group by reviewing a series of 15 patients with leptospirosis requiring intensive care support for their management. We noticed complications becoming apparent before antibodies became detectable in the blood in a significant number of patients. This appears to belie the biphasic nature of leptospirosis and raises the question of whether the complications occur during the leptospiraemic phase or the immune phase of the infection. The presence of leptospiral DNA in the blood at this time as detected by a molecular assay strengthened this suspicion. Among the 15 patients with severe leptospirosis, only 3 (20 %) had an overseas travel history and the remaining 12 patients acquired their infection within the UK. Fourteen of the 15 patients had hepatorenal dysfunction, with seven requiring dialysis. Eight of the 15 patients received intravenous ceftriaxone with very good outcomes. Three showed significant clinical improvement after the administration of steroids. CONCLUSION: Many patients with severe leptospirosis will have complications on presentation. Molecular testing is now available for early diagnosis, facilitating early interventions. Ceftriaxone has been effective in treating severe leptospirosis. This study reminds clinicians to consider leptospirosis in the differential diagnosis of similar clinical spectra and offers tools for appropriate management. PMID- 28663803 TI - Highly pathogenic avian influenza A/H7N3 in great-tailed grackles (Quiscalus mexicanus) in the Altos de Jalisco region of Mexico. AB - INTRODUCTION: In June 2012, the presence of a severe highly pathogenic avian influenza (HPAI) outbreak produced by an influenza type A, subtype H7N3 (A/H7N3) virus was reported in Mexico, which significantly affected the region of Los Altos de Jalisco, the most important table-egg production zone in Mexico. CASE PRESENTATION: To the best of our knowledge, this is the first report describing the occurrence of infection in wild endemic birds, and particularly in the great tailed grackle (Quiscalus mexicanus), by an HPAI A/H7N3 orthomyxovirus, during the avian influenza epizootic, which occurred in June-October 2012, in the Los Altos region of Jalisco, Mexico, a highly significant poultry area. The great tailed grackle population has increased significantly due to intense agricultural and livestock farming expansion throughout North and Central America and northern South America, in diverse ecological systems. The great-tailed grackle's infectious/epidemiological role is unknown, as is its role as the avian influenza virus reservoir and as disseminator of other infectious diseases. CONCLUSION: Because of the huge impact that avian influenza virus has on food production, on the economic activity of the affected areas and on the public health of animal and human populations, it is necessary to further investigate the significance of a wild population existing in the vicinity of industrial poultry farms and backyard poultry operations. PMID- 28663804 TI - A rare case of Streptococcus sanguinis mycotic popliteal aneurysm. AB - INTRODUCTION: Mycotic popliteal aneurysms are not a common phenomenon. They can initially be easily confused with other more trivial conditions such as a Baker's cyst. We present a case of a patient presenting with a progressively worsening leg swelling which was initially misdiagnosed. Only until symptoms rapidly progressed was a popliteal aneurysm diagnosed. To our knowledge this is the only identified case of a Streptococcus sanguinis mycotic popliteal aneurysm. CASE PRESENTATION: An 81-year-old gentleman presented to the surgical assessment unit with a six-week history of a painful, diffuse swelling in the left popliteal fossa. Initially, when symptoms developed a provisional diagnosis of a Baker's cyst was made. When the symptoms progressed to involve swelling of the entire lower limb, an ultrasound was arranged. Detailed Imaging revealed a popliteal aneurysm with signs of rupture. Urgent repair was performed, with high suspicion of a mycotic aneurysm intra-operatively. Cultures confirmed this, isolating Streptococcus sanguinis. Multiple investigations failed to isolate an acute infective source of this infection. The patient recovered promptly with a long course of intravenous antibiotics, being able to mobilize normally. CONCLUSION: Mycotic popliteal aneurysms are not very common and can easily be confused with other benign lesions. The key to diagnosis is the presence of a pulsatile mass and further detailed imaging. This case was unique in that Streptococcus sanguinis has not been isolated from such an aneurysm until now. The most likely explanation of this case was that the aneurysm was secondary to transient bacteraemia of this organism through the oral cavity, in the absence of any cardiac involvement. PMID- 28663805 TI - Cutaneous Mycobacterium haemophilum infections in immunocompromised patients in a tertiary hospital in Bangkok, Thailand: under-reported/under-recognized infection. AB - INTRODUCTION: Mycobacterium haemophilum is one of the non-tuberculous mycobacteria (NTM) that can cause cutaneous infection. As acid-fast staining cannot distinguish NTM from Mycobacterium tuberculosis, and as skin culture for M. haemophilum is not performed routinely, the diagnosis of M. haemophilum infection in Thailand is rarely made. CASE PRESENTATION: Between 2006 and 2009, five patients with M. haemophilum infection were diagnosed in Ramathibodi Hospital, a tertiary care centre in Bangkok, Thailand. The patients were aged 3, 29, 47, 75 and 76 years, and four were immunocompromised. Three patients received immunosuppressive medication. Most patients presented with subacute cutaneous infection. A suboptimal response to conventional antibiotics raised suspicions of M. haemophilum cutaneous infections, which can occur in immunocompromised patients. Diagnoses of these cases were made by skin culture for mycobacteria at an incubating temperature of around 30 degrees C with iron supplementation, DNA sequencing, or PCR/restriction enzyme analysis. Rifampicin, ofloxacin and clarithromycin were active against all isolates, whereas ethambutol and streptomycin were inactive. CONCLUSION: Skin culture should be performed under special conditions or molecular technique should be used to identify M. haemophilum in susceptible patients. PMID- 28663806 TI - First case of systemic phaeohyphomycosis due to Cladophialophora bantiana in Slovakia. AB - INTRODUCTION: Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Cladophialophora bantiana is one of the most common and dangerous neurotropic fungi, able to cause brain abscess and disseminated infection. CASE PRESENTATION: We report a new case of phaeohyphomycosis brain abscesses caused by C. bantiana in Slovakia. The patient was a 63-year-old man having undergone heart transplantation, with dyspnoea, left-sided bronchopneumonia and fevers. CT (computed tomography) and MRI (magnetic resonance imaging) of the brain revealed numerous abscesses. Bacterial infection was proven by neither the growth of bacteria in culture nor the presence of bacterial antigens. Direct microscopy of the pus from the brain abscess showed Gram positive hyphae. The isolate was finally identified as C. bantiana based on morphological and physiological features, and on DNA sequence analysis. CONCLUSION: In spite of appropriate therapy, neurological complications and accelerated respiratory insufficiency resulted in the patient's death. Concerning clinical manifestation of the brain phaeohyphomycosis that can sometimes be a problem to distinguish from malignancy, physicians should also assume infection caused by this serious pathogen. PMID- 28663807 TI - R77Q and Q3R HIV1-VPR mutations in an otherwise asymptomatic 5-year-old child with repeated ear infections. AB - INTRODUCTION: Viral protein R (Vpr) of human immunodeficiency virus type 1 (HIV 1) has been described as being involved in the progression of AIDS, and specific mutations are associated with long-term non-progressor patients. CASE PRESENTATION: We describe the case of a child with repeated ear infections who was otherwise healthy. The patient, a 5-year-old boy, was HIV-1 positive and the viral load at admission was 1 073 899 RNA copies ml-1 and 0 % CD4+ lymphocytes. A detailed study of the vpr gene sequence of the child revealed mutations leading to amino acid substitutions at positions 3 and 77. CONCLUSION: The case reported provides clinical support of previous findings that show that the R77Q and Q3R HIV-1 Vpr variants are associated with patients with delayed disease progression. PMID- 28663808 TI - Frequent respiratory viral infections in a young child in a 27-month follow-up study. AB - INTRODUCTION: Viruses are major aetiological agents of acute respiratory infection in young children. Although many studies have reported detection and analysis of respiratory viruses in sporadic cases, there have been few follow-up studies of individuals. The purpose of this study was to investigate the frequency of respiratory viral infections in a young child and to examine the duration of viral genome detection in clinical specimens. CASE PRESENTATION: A total of 284 nasal swabs were collected during symptomatic (196 specimens) and asymptomatic (88 specimens) periods of respiratory symptoms from a young female child (from 4 months to 31 months of age, who was admitted to a nursery school at 9 months). Multiplex real-time PCR for 19 respiratory viruses or subtypes was performed. One hundred and ninety-eight of the tested specimens were virus positive (69.7 %) (symptomatic periods, 149/196, 76.0 %; asymptomatic periods, 49/88, 55.7 %). Rhinovirus was the most frequently detected (26 times). Long durations of detection were observed for human coronavirus NL63 (30 days), rhinovirus (28 days) and human bocavirus 1 (22 days). CONCLUSION: Young children living in a group context have a high risk of respiratory virus infections, especially rhinovirus. In some instances, viral genomes were detectable for about 1 month by PCR. PMID- 28663809 TI - Community-acquired cutaneous ulcer in a child caused by Serratia marcescens. AB - INTRODUCTION: Serratia marcescens is a Gram-negative, aerobic, motile bacillus belonging to the family Enterobacteriaceae. S. marcescens has been implicated in different types of infections including urinary tract infection, septicaemia, meningitis and wound infections. Very few cases of skin infections caused by this organism have been reported in the medical literature. S. marcescens is an important nosocomial pathogen but has rarely been implicated as a cause of community-acquired soft-tissue infections. CASE PRESENTATION: We present a rare case of a community-acquired spontaneous cutaneous ulcer in an immunocompetent child from a sub-Himalayan region. Infections caused by S. marcescens may be difficult to treat because of its ability to produce a beta-lactamase, which confers resistance to broad-spectrum, beta-lactam antibiotics. CONCLUSION: In our patient, the treatment was modified to ceftazidime and amikacin after sensitivity testing and the patient's condition improved. This necessitated isolation by culture and antimicrobial susceptibility testing to ensure appropriate therapy. PMID- 28663810 TI - Gastrointestinal basidiobolomycosis with hepatic dissemination: a case report. AB - INTRODUCTION: Gastrointestinal basidiobolomycosis (GIB) is an emerging fungal infection with a few cases reported worldwide. It is caused by Basidiobolus ranarum, which does not usually invade blood vessels and rarely disseminates. CASE PRESENTATION: We present a rare case of GIB with hepatic dissemination in a 12-year-old Yemeni boy living in southwestern Saudi Arabia. The initial provisional diagnosis was intestinal lymphoma, and a right hemicolectomy was carried out, but histopathological assessment ruled out lymphoma and suggested intestinal tuberculosis. Two weeks after starting antituberculous medications, the patient was referred to our hospital because of fever and right upper abdominal discomfort. There was leukocytosis with marked eosinophilia, and a liver biopsy showed evidence of B. ranarum infection. A second opinion by histopathological examination of resected tissues diagnosed colonic basidiobolomycosis. The patient was treated successfully with itraconazole. CONCLUSION: GIB is an emerging disease in southwestern Saudi Arabia and should be considered in a patient with an abdominal mass and eosinophilia coming from this region. Persistent elevation of leukocytes and eosinophils after surgical resection of the affected tissue could be used as a predictor of fungal dissemination. Further research is needed for a better understanding of GIB. PMID- 28663811 TI - Isolation of Mycobacterium massiliense from a corneal biopsy in India. AB - INTRODUCTION: Rapidly growing mycobacteria (RGM) are ubiquitous and are usually considered as saprophytes, and have been recovered from the environment, particularly in dust, watery soil and water distribution systems. However, Mycobacterium massiliense is a rare causative agent of ocular infection. CASE PRESENTATION: We report a case of M. massiliense in a 44-year-old female with signs and symptoms of a corneal ulcer. We carried out PCR-based DNA sequencing targeting the hsp 65 gene for the identification of M. massiliense. To confirm the identification, we also performed PCR-based RFLP targeting the hsp65 gene and PCR-based DNA sequencing targeting the internal transcribed spacer region, which showed 97 % nucleotide identity with M. massiliense. CONCLUSION: To the best of our knowledge, this is the first study in India to report the detection of M. massiliense from a corneal biopsy. PMID- 28663812 TI - Relapsing Bacillus cereus peritonitis in a patient treated with continuous ambulatory peritoneal dialysis. AB - INTRODUCTION: Peritonitis is a severe complication of peritoneal dialysis (PD) due to associated morbidity and mortality. Although Bacillus cereus is mostly considered as a contaminant, its role as a causative agent in a few cases of PD peritonitis has been documented. Peritonitis due to B. cereus has been associated with high rates of catheter removal and resistance to beta-lactam antibiotics. CASE PRESENTATION: A case of relapsing peritonitis caused by B. cereus in a 69 year-old man with end-stage renal disease on continuous ambulatory PD for 3 years is described. B. cereus was recovered from the patient's peritoneal fluid and was identified by phenotypic and molecular methods. The patient was treated, according to the susceptibility test, with tobramycin for 14 days. Cultures became sterile and the patient was discharged from hospital. Three days after discharge, the patient reported recurrence of abdominal pain and a new antibiotic regimen based on the previous culture results was initiated consisting of vancomycin and ciprofloxacin. The presence of B. cereus in the peritoneal fluid was confirmed, whereas repeated cultures for the next 15 days were positive. All B. cereus isolates produced biofilm. On day 16, the PD catheter was removed and the patient was transferred to haemodialysis. A review of previously reported cases is also presented. CONCLUSION: Since peritonitis is the most common cause of transition to haemodialysis, isolation of B. cereus from PD patients, even though rare, should not be considered as a contaminant. An appropriate antibiotic regimen and, whenever necessary, catheter removal should be applied. PMID- 28663813 TI - Severe Pneumocystis jirovecii pneumonia in an idiopathic CD4+ lymphocytopenia patient: case report and review of the literature. AB - INTRODUCTION: When diagnosing Pneumocystis jirovecii pneumonia (PJP), the clinical suspicion must be confirmed by laboratory tests. PJP is rarely described in patients with idiopathic CD4+ lymphocytopenia (ICL), a rare T-cell deficiency of unknown origin with persistently low levels of CD4+ T-cells (<300 ul-1 or <20 % of total lymphocytes) but repeated negative human immunodeficiency virus (HIV) tests. We retrospectively analysed a case of an ICL patient with severe PJP associated with multiple opportunistic infections (OIs). We also reviewed the literature since 1986. CASE PRESENTATION: A laboratory-confirmed case of PJP associated with invasive candidiasis and cytomegalovirus infection was reported in an ICL patient. Despite early treatment, the patient died of respiratory failure under polymicrobial pneumonia. According to the literature, the mortality rate of ICL patients is 10.4 % (33/316). In ICL patients, the risk of OI is 83.2 % (263/316), with viral infections being the most prevalent (58.2 %, 184/316), followed by fungal infections (52.2 %, 165/316) and mycobacterial infections (15.5 %, 49/316). Dysimmunity is reported in 15.5 % (49/316) of ICL patients. Among the fungal infections, cryptococcal infections are the most prevalent (24.1 %, 76/316), followed by candidiasis (15.5 %, 49/316) and PJP (7.9 %, 25/316). CONCLUSIONS: The high risk of OIs underlines the importance of more vigorous preventative actions in hospitals. The response to therapy and the detection of early relapse of PJP may be monitored by several laboratory tests including quantitative PCR. It is essential to treat the ICL and to follow the guidelines concerning therapy and prophylaxis of OIs as given to HIV patients. PMID- 28663814 TI - Necrotizing fasciitis as the initial presentation of disseminated infection with fluconazole-resistant Cryptococcus neoformans. AB - INTRODUCTION: Cryptococcus neoformans is an encapsulated budding yeast that is a common cause of opportunistic infections, rarely giving rise to cellulitis, vasculitis or fasciitis. Necrotizing fasciitis caused by C. neoformans is a rare but serious problem in post-transplant immunosuppression. CASE PRESENTATION: We report a case of cryptococcal necrotizing fasciitis in the left adductor longus of a patient on immunosuppressive therapy. The patient's medical history was significant for orthotopic heart transplant secondary to cardiac and systemic amyloidosis (AL type) with subsequent cardiac biopsy demonstrating mild rejection (grade 1R). A thigh muscle biopsy demonstrated numerous encapsulated fungi in the fascia and no evidence of myositis. Cryptococcal antigen was subsequently identified in the patient's serum and cerebrospinal fluid. The patient progressed to involvement of the central nervous system, left biceps femoris and skin of the left lower leg by fluconazole-resistant C. neoformans. CONCLUSION: This case illustrates a rare initial presentation of disseminated fluconazole-resistant C. neoformans as an isolated necrotizing fasciitis of the thigh. Necrotizing fungal fasciitis should be considered in immunosuppressed patients with clinical findings of either myositis or cellulitis of a lower extremity. PMID- 28663815 TI - Rhizobium radiobacter peritonitis: the first case report from India and review. AB - BACKGROUND: Rhizobium radiobacter is an opportunistic human pathogen in debilitated patients with foreign plastic intravascular devices and peritoneal dialysis (PD) catheters. We performed a Medline search of the English-language literature on R. radiobacter continuous ambulatory peritoneal dialysis (CAPD) peritonitis in end-stage renal disease (ESRD) and reviewed 13 cases. CASE PRESENTATION: A 54-year-old male with ESRD secondary to chronic long-standing type II diabetes mellitus presented to the nephrology outpatient department with fever, abdominal pain and cloudy PD effluent. The patient was admitted to the hospital. PD fluid was sent for cell count, Gram stain and culture. The white blood cell (WBC) count in the PD fluid was 6400 mm-3 with 82 % neutrophils. Gram staining of the fluid showed plenty of Gram-negative bacilli. A presumptive diagnosis of CAPD peritonitis was made and empiric intraperitoneal cefazolin and tobramycin were started. The PD fluid culture grew non-fermenting, Gram-negative bacilli identified as R. radiobacter. Empiric antibiotic therapy was continued and the patient's abdominal pain subsided. The peritoneal fluid counts decreased to 50 WBCs mm-3 on day 4. However, his abdominal pain recurred on day 8 and his PD fluid count increased to 300 cells mm-3. The catheter was therefore surgically removed. CONCLUSION: Although R. radiobacter is considered a contaminant, it can cause relapsing symptomatic peritonitis peritoneal catheter removal. PMID- 28663816 TI - Unusual case presentation of intestinal Sarcocystis hominis infection in a healthy adult. AB - INTRODUCTION: Sarcocystosis is mainly a veterinary problem; however, humans can serve as the definitive host for at least two species (Sarcocystis hominis and Sarcocystis suihominis). Intestinal infections occur in the definitive host after ingesting the intramuscular cysts (sarcocysts) in the intermediate host, which initiate sexual stages in the intestine that terminate in oocysts excreted in the faeces. CASE PRESENTATION: A 19-year-old male presented with diffuse abdominal pain, watery non-bloody diarrhoea, nausea, vomiting and intermittent low-grade fever that lasted for more than 3 weeks. Multiple stool cultures on enriched and selective media gave negative results. Microscopic examination of wet mounts of stool prepared from formalin/ethyl acetate concentrates, together with permanent staining helped in making a definitive diagnosis and ruling out other coccidian parasites. Diagnosis of the parasite as S. hominis was made based on the size and morphology of the individual sporocysts that were observed in the wet-mount preparations. This severe case of intestinal sarcocystosis in a healthy adult after eating undercooked beef shawarma meat is described. CONCLUSION: The unusual presentation of intestinal sarcocystis described in this case is very rare. The clinical signs and size and morphology of both oocysts and sarcocysts observed in concentrated wet mounts of stool helped in the definitive diagnosis. The food ingested prior to the appearance of symptoms was important in making the definitive diagnosis of the parasite as S. hominis, as well as the incubation period and treatment. PMID- 28663817 TI - Peripheral eosinophilia and eosinophilic colitis during long-term azole therapy for pulmonary aspergillosis. AB - INTRODUCTION: Voriconazole and posaconazole are often used to treat invasive Aspergillus infections. We describe a patient with chronic pulmonary aspergillosis (CPA) who experienced peripheral eosinophilia and eosinophilic colitis while on voriconazole, and also experienced gastrointestinal symptoms and recurrent eosinophilia while on subsequent posaconazole therapy. CASE PRESENTATION: A 75-year-old female with recurrent pulmonary mucus plugs due to CPA was treated with long-term oral voriconazole. The patient had no clinical evidence of CPA exacerbations while on such antifungal treatment but developed peripheral eosinophilia, diarrhoea and eosinophilic colitis after >5 years of voriconazole therapy that resolved after cessation of azole therapy. Due to a CPA exacerbation after stopping voriconazole, the patient was started on posaconazole as an alternative CPA therapy. However, after 15 months, the patient developed a recurrence of peripheral eosinophilia and diarrhoea while on posaconazole. CONCLUSION: Long-term use of voriconazole and posaconazole can be used successfully to reduce the incidence of CPA exacerbations. However, such antifungal therapy may also lead to peripheral eosinophilia, diarrhoea and eosinophilic colitis. PMID- 28663818 TI - Case of Fonsecaea nubica chromoblastomycosis from the French territory of Mayotte. AB - INTRODUCTION: Fonsecaea nubica is a newly described species in the genus Fonsecaea. CASE PRESENTATION: We describe here a clinical case of chromoblastomycosis in a 66-year-old man who presented a 3-year history of leg lesions. F. nubica was identified by morphological and molecular methods. Four months of treatment with itraconazole (300 mg daily) significantly improved the lesions. CONCLUSION: To the best of our knowledge, this case represents the first clinical case of F. nubica described in France. Particular attention should be paid to microscopic examination for fungal cultures in order to avoid confusion with a contaminating fungus. Moreover, recurrent, wide and deep biopsies should be performed to monitor the evolution of the lesions. PMID- 28663819 TI - Legionella longbeachae infection in a persistent hand-wound after a gardening accident. AB - INTRODUCTION: Unlike other Legionella species, Legionella longbeachae has been associated with soil and potting composts instead of water systems, and it has caused pneumonia in gardeners. CASE PRESENTATION: We report, to our knowledge, the first case of prolonged localized L. longbeachae infection in an accidental wound on the back of a hand caused by a broken flowerpot. CONCLUSION: Identification of L. longbeachae requires awareness and expertise, since commercial tests are most often specific for L. pneumophila. PMID- 28663820 TI - A case of otitis media complicated by intracranial infection with Actinomyces turicensis. AB - INTRODUCTION: Actinomycosis is a granulomatous suppurative infection caused by filamentous Gram-positive anaerobic bacteria from the family Actinomycetaceae. To our knowledge, this is the first reported case of otogenic brain abscess associated with Actinomyces turicensis. CASE PRESENTATION: We report the case of an immunocompetent 5-year-old boy with recurrent otitis media who re-presented to the emergency department with a 3-week history of otorrhoea, progressive anorexia, vomiting and lethargy. He was admitted with a working diagnosis of otitis media and dehydration, and was treated with intravenous fluids and oral co trimoxazole. He subsequently developed abnormal posturing with a reduced Glasgow coma score and seizures. Urgent computed tomography revealed a cerebellar abscess with obstructive hydrocephalus for which he underwent urgent neurosurgical intervention. Tissue and aspirate cultures revealed a polymicrobial infection with A. turicensis. The patient has since undergone long-term antibiotic treatment and has made a good recovery. CONCLUSION: This case demonstrates the successful use of long-term antibiotic therapy and neurosurgical intervention to treat otogenic brain abscess associated with A. turicensis infection. To the best of our knowledge, this is the first such documented case. Our report also provides a timely reminder that, despite a reduced incidence in the developed world, intracranial complications of otitis media continue to occur and a high index of suspicion is required. PMID- 28663821 TI - Skin infection caused by a novel strain of Staphylococcus pseudintermedius in a Siberian husky dog owner. AB - Introduction.Staphylococcus pseudintermedius, an opportunistic pathogen of dogs and cats, is rarely reported to cause infection in humans. Here, we describe a case of severe skin infection caused by S. pseudintermedius, in a 47-year-old male, a dog owner; to the best of our knowledge, this is the first such case reported from Scotland. Case presentation. The patient presented with a short history of a severe ecthyma-like lesion on his forehead, with smaller lesions on his abdomen and legs. Bacterial culture revealed Clostridium perfringens, thought to be colonizing the wound, and a Staphylococcus species, identified as S. pseudintermedius by matrix-assisted laser desorption/ionization-time of flight MS and confirmed by molecular methods using a PCR-RFLP approach. The patient was treated with flucloxacillin, penicillin V and Fucibet cream, and recovered fully. Zoonotic infection was considered likely; however, screening swabs from his dogs grew S. pseudintermedius of a different clonal type. Both patient and dog strains carried Staphylococcus intermedius exfoliative toxin and leucocidin I, closely related to Panton-Valentine leucocidin, possibly contributing to the severity of the infection. S pseudintermedius, although coagulase positive, is normally negative by rapid slide clumping and latex agglutination tests routinely used to identify Staphylococcus aureus. Hence, S. pseudintermedius may easily be misidentified as a coagulase-negative staphylococcus and considered insignificant. Conclusion. This is, to the best of our knowledge, the first reported case of a human S. pseudintermedius infection in Scotland. Zoonotic transmission of S. pseudintermedius between pets and owners has been shown. However, in this case zoonosis could not be confirmed. PMID- 28663823 TI - Sequencing a piece of history: complete genome sequence of the original Escherichia coli strain. AB - In 1885, Theodor Escherich first described the Bacillus coli commune, which was subsequently renamed Escherichia coli. We report the complete genome sequence of this original strain (NCTC 86). The 5 144 392 bp circular chromosome encodes the genes for 4805 proteins, which include antigens, virulence factors, antimicrobial resistance factors and secretion systems, of a commensal organism from the pre antibiotic era. It is located in the E. coli A subgroup and is closely related to E. coli K-12 MG1655. E. coli strain NCTC 86 and the non-pathogenic K-12, C, B and HS strains share a common backbone that is largely co-linear. The exception is a large 2 803 932 bp inversion that spans the replication terminus from gmhB to clpB. Comparison with E. coli K-12 reveals 41 regions of difference (577 351 bp) distributed across the chromosome. For example, and contrary to current dogma, E. coli NCTC 86 includes a nine gene sil locus that encodes a silver-resistance efflux pump acquired before the current widespread use of silver nanoparticles as an antibacterial agent, possibly resulting from the widespread use of silver utensils and currency in Germany in the 1800s. In summary, phylogenetic comparisons with other E. coli strains confirmed that the original strain isolated by Escherich is most closely related to the non-pathogenic commensal strains. It is more distant from the root than the pathogenic organisms E. coli 042 and O157 : H7; therefore, it is not an ancestral state for the species. PMID- 28663822 TI - Pregnancy eating attributes study (PEAS): a cohort study examining behavioral and environmental influences on diet and weight change in pregnancy and postpartum. AB - BACKGROUND: The rising prevalence of maternal overweight/obesity and excessive gestational weight gain poses a serious public health concern due to the contribution of these factors to increased risk of negative health outcomes for both mother and child. Scant intervention research has indicated moderate short term improvement in maternal diet and gestational weight gain, with little evidence of long-term behavior change, in parallel with findings from interventions outside of pregnancy. Recent laboratory-based findings from neuroscience implicate aberrant reward processing of food at the brain level ("food reward sensitivity," the between-individual variation in the response to food stimuli) as a contributor to eating beyond energy needs. However, scant research has examined the influence of these processes on weight change in population-based settings, and the relevance of these processes to pregnancy related weight change has not been explored. The purpose of the Pregnancy Eating Attributes Study (PEAS) is to examine the role of food reward sensitivity in maternal diet and weight change during pregnancy and postpartum. The study examines the interplay of food reward sensitivity with behavioral control, home food environment, and related aspects of eating behavior in the context of weight related biomedical, psychosocial, genetic and behavioral factors including physical activity, stress, sleep and depression. METHODS: Women of varying baseline weight status (n = 450) are enrolled early in pregnancy and followed, along with their infants, until 1 year postpartum. Assessments occur during each trimester of pregnancy, and postpartum at approximately 2 months, 6 months, 9 months and 12 months. Maternal food reward, self-control, home food environment, eating behaviors, dietary intake, health behaviors, and anthropometrics are assessed along with maternal and infant clinical and biological data, infant anthropometrics, and feeding practices. Primary exposures of interest include food reward sensitivity, behavioral control, and home food environment. Primary outcomes include gestational weight gain, postpartum weight retention and maternal diet quality. DISCUSSION: With increasing evidence suggesting the relevance of food reward sensitivity for understanding eating behavior, PEAS aims to advance understanding of the determinants of eating behavior during pregnancy, informing future interventions for improving maternal diet and weight change, and leading to improved maternal and child health and weight trajectories. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02217462. Date of registration: August 13, 2014. PMID- 28663825 TI - Applications of CTAB modified magnetic nanoparticles for removal of chromium (VI) from contaminated water. AB - This study investigated the elimination of Cr(VI) from aqueous solution utilizing a composite from magnetic nanoparticles (Fe3O4) capped with cetyltrimethylammonium bromide (CTAB). The structure of the prepared composite system was examined by Fourier Transform Infra Red Spectroscopy (FTIR), X-ray Diffractometry (XRD), and Transmission Electron Microscopy (TEM). Separation of the Fe3O4/CTAB composite from the wastewater can be achieved by application of an external magnetic field. Factors affecting the Cr(VI) expulsion from wastewater such as pH, competing ions, the dosage level of the nanoparticles, and contact time were studied. The results indicated that the maximum efficiency of the present system for removal of Cr(VI) (95.77%) was in acidic conditions (pH 4), contact time 12 h, and composite dosage of 12 mg/mL. The used Cr(VI) concentration was 100 mg/L. Considering results, the Fe3O4/CTAB system showed a high capability and selectivity for the treatment of water sullied with Cr(VI). This can recede the mutagenic and carcinogenic health risk caused by Cr(VI) water tainting. PMID- 28663826 TI - A practical application of photogrammetry to performing rib characterization measurements in an underground coal mine using a DSLR camera. AB - Understanding coal mine rib behavior is important for inferring pillar loading conditions as well as ensuring the safety of miners who are regularly exposed to ribs. Due to the variability in the geometry of underground openings and ground behavior, point measurements often fail to capture the true movement of mine workings. Photogrammetry is a potentially fast, cheap, and precise supplemental measurement tool in comparison to extensometers, tape measures, or laser range meters, but its application in underground coal has been limited. The practical use of photogrammetry was tested at the Safety Research Coal Mine, National Institute for Occupational Safety and Health (NIOSH). A commercially available, digital single-lens reflex (DSLR) camera was used to perform the photogrammetric surveys for the experiment. Several experiments were performed using different lighting conditions, distances to subject, camera settings, and photograph overlaps, with results summarized as follows: the lighting method was found to be insignificant if the scene was appropriately illuminated. It was found that the distance to the subject has a minimal impact on result accuracy, and that camera settings have a significant impact on the photogrammetric quality of images. An increasing photograph resolution was preferable when measuring plane orientations; otherwise a high point cloud density would likely be excessive. Focal ratio (F-stop) changes affect the depth of field and image quality in situations where multiple angles are necessary to survey cleat orientations. Photograph overlap is very important to proper three-dimensional reconstruction, and at least 60% overlap between photograph pairs is ideal to avoid unnecessary post-processing. The suggestions and guidelines proposed are designed to increase the quality of photogrammetry inputs and outputs as well as minimize processing time, and serve as a starting point for an underground coal photogrammetry study. PMID- 28663824 TI - Towards the complete proteinaceous regulome of Acinetobacter baumannii. AB - The emergence of Acinetobacter baumannii strains, with broad multidrug-resistance phenotypes and novel virulence factors unique to hypervirulent strains, presents a major threat to human health worldwide. Although a number of studies have described virulence-affecting entities for this organism, very few have identified regulatory elements controlling their expression. Previously, our group has documented the global identification and curation of regulatory RNAs in A. baumannii. As such, in the present study, we detail an extension of this work, the performance of an extensive bioinformatic analysis to identify regulatory proteins in the recently annotated genome of the highly virulent AB5075 strain. In so doing, 243 transcription factors, 14 two-component systems (TCSs), 2 orphan response regulators, 1 hybrid TCS and 5 sigma factors were found. A comparison of these elements between AB5075 and other clinical isolates, as well as a laboratory strain, led to the identification of several conserved regulatory elements, whilst at the same time uncovering regulators unique to hypervirulent strains. Lastly, by comparing regulatory elements compiled in this study to genes shown to be essential for AB5075 infection, we were able to highlight elements with a specific importance for pathogenic behaviour. Collectively, our work offers a unique insight into the regulatory network of A. baumannii strains, and provides insight into the evolution of hypervirulent lineages. PMID- 28663827 TI - Heart structural remodeling in a mouse model of Duchenne cardiomyopathy revealed using optical polarization tractography [Invited]. AB - We investigated the heart structural remodeling in the mdx4cv mouse model of Duchenne cardiomyopathy using optical polarization tractography. Whole heart tractography was obtained in freshly dissected hearts from six mdx4cv mice. Six hearts from C57BL/6J mice were also imaged as the normal control. The mdx4cv hearts were significantly larger than the control hearts and had significantly higher between-subject variations in myofiber organization. While both strains showed classic cross-helical fiber organization in the left ventricle, the rate of the myocardial fiber orientation change across the heart wall was significantly altered in the right ventricle of the mdx4cv heart. PMID- 28663828 TI - Transcutical imaging with cellular and subcellular resolution. AB - We demonstrate transcutical structural and functional imaging of neurons labeled with genetically encoded red fluorescent proteins and calcium indicators in the living Drosophila brain with cellular and subcellular resolution. PMID- 28663829 TI - Three-dimensional multi-contrast imaging of in vivo human skin by Jones matrix optical coherence tomography. AB - A custom made dermatological Jones matrix optical coherence tomography (JM-OCT) is presented. It uses a passive-polarization-delay component based swept-source JM-OCT configuration, but is specially designed for in vivo human skin measurement. The center wavelength of its probe beam is 1310 nm and the A-line rate is 49.6 kHz. The JM-OCT is capable of simultaneously providing birefringence (local retardation) tomography, degree-of-polarization-uniformity tomography, complex-correlation-based optical coherence angiography, and conventional scattering OCT. To evaluate the performance of this JM-OCT, we measured in vivo human skin at several locations. Using the four kinds of OCT contrasts, the morphological characteristics and optical properties of different skin types were visualized. PMID- 28663830 TI - Automated boundary detection of the optic disc and layer segmentation of the peripapillary retina in volumetric structural and angiographic optical coherence tomography. AB - To improve optic disc boundary detection and peripapillary retinal layer segmentation, we propose an automated approach for structural and angiographic optical coherence tomography. The algorithm was performed on radial cross sectional B-scans. The disc boundary was detected by searching for the position of Bruch's membrane opening, and retinal layer boundaries were detected using a dynamic programming-based graph search algorithm on each B-scan without the disc region. A comparison of the disc boundary using our method with that determined by manual delineation showed good accuracy, with an average Dice similarity coefficient >=0.90 in healthy eyes and eyes with diabetic retinopathy and glaucoma. The layer segmentation accuracy in the same cases was on average less than one pixel (3.13 MUm). PMID- 28663831 TI - Lateral resolution improvement of oversampled OCT images using Capon estimation of weighted subvolume contribution. AB - A novel technique for lateral resolution improvement in optical coherence tomography (OCT) is presented. The proposed method is based on lateral oversampling of the image. The locations and weights of multiple high spatial resolution sub-volumes are calculated using a Capon estimator assuming each contributes a weighted portion to the detected signal. This technique is independent of the delivery optics and the depth of field. Experimental results demonstrate that it is possible to achieve ~4x lateral resolution improvement which can be diagnostically valuable, especially in cases where the delivery optics are constrained to low numerical aperture (NA). PMID- 28663832 TI - State space approach to single molecule localization in fluorescence microscopy. AB - Single molecule super-resolution microscopy enables imaging at sub-diffraction limit resolution by producing images of subsets of stochastically photoactivated fluorophores over a sequence of frames. In each frame of the sequence, the fluorophores are accurately localized, and the estimated locations are used to construct a high-resolution image of the cellular structures labeled by the fluorophores. Many methods have been developed for localizing fluorophores from the images. The majority of these methods comprise two separate steps: detection and estimation. In the detection step, fluorophores are identified. In the estimation step, the locations of the identified fluorophores are estimated through an iterative approach. Here, we propose a non-iterative state space-based localization method which combines the detection and estimation steps. We demonstrate that the estimated locations obtained from the proposed method can be used as initial conditions in an estimation routine to potentially obtain improved location estimates. The proposed method models the given image as the frequency response of a multi-order system obtained with a balanced state space realization algorithm based on the singular value decomposition of a Hankel matrix. The locations of the poles of the resulting system determine the peak locations in the frequency domain, and the locations of the most significant peaks correspond to the single molecule locations in the original image. The performance of the method is validated using both simulated and experimental data. PMID- 28663833 TI - In vivo pentamodal tomographic imaging for small animals. AB - Multimodality molecular imaging emerges as a powerful strategy for correlating multimodal information. We developed a pentamodal imaging system which can perform positron emission tomography, bioluminescence tomography, fluorescence molecular tomography, Cerenkov luminescence tomography and X-ray computed tomography successively. Performance of sub-systems corresponding to different modalities were characterized. In vivo multimodal imaging of an orthotopic hepatocellular carcinoma xenograft mouse model was performed, and acquired multimodal images were fused. The feasibility of pentamodal tomographic imaging system was successfully validated with the imaging application on the mouse model. The ability of integrating anatomical, metabolic, and pharmacokinetic information promises applications of multimodality molecular imaging in precise medicine. PMID- 28663834 TI - Dermoscopy guided dark-field multi-functional optical coherence tomography. AB - Dermoscopy is a skin surface microscopic technique allowing specular reflection free observation of the skin, and has been used to examine pigmented skin lesions. However, dermoscopy has limitations in providing depth information due to lack of 3D resolution. In order to overcome the limitations, we developed dermoscopy guided multi-functional optical coherence tomography (MF-OCT) providing both high-contrast superficial information and depth-resolved structural, birefringent, and vascular information of the skin simultaneously. Dermoscopy and MF-OCT were combined by using a dichroic mirror, and dark-field configuration was adapted for MF-OCT to reduce specular reflection. After characterization, dermoscopy guided MF-OCT was applied to several human skin lesions such as the scar, port-wine stain (PWS) as well as the normal skin for demonstration. Various features of the scar and PWS were elucidated by both dermoscopy and MF-OCT. Dermoscopy guided MF-OCT may be useful for evaluation and treatment monitoring of skin lesions in clinical applications. PMID- 28663835 TI - Performance of a differential contrast sensitivity method to measure intraocular scattering. AB - Increased intraocular scatter degrades quality of vision, especially in the presence of glare sources. Standard tests, such as visual acuity, are not well suited to capture this condition. There are specific methods to measure intraocular scatter, but require dedicated instruments. In this work, we propose a method to estimate the amount of scatter by combining to sequential measurements of the contrast sensitivity function for two conditions, with and without a glare source. We applied the approach in a group of young subjects with no know ocular pathology fitted with photographic diffusing filters. The straylight estimates were compared with those provided by two alternative techniques, one based on the compensation comparison method and the other the optical integration. The results obtained with the three approaches were in a good agreement, demonstrating the feasibility of the proposed method. PMID- 28663836 TI - Chemical basis for alteration of an intraocular lens using a femtosecond laser. AB - The chemical basis for the alteration of the refractive properties of an intraocular lens with a femtosecond laser was investigated. Three different microscope setups have been used for the study: Laser Induced Fluorescence (LIF) microscopy, Raman microscopy and coherent anti-Stokes Raman Scattering (CARS) microscopy. Photo-induced hydrolysis of polymeric material in aqueous media produces two hydrophilic functional groups: acid group and alcohol group. The spectral signatures identify two of the hydrophilic polar molecules as N-phenyl-4 (phenylazo)-benzenamine (C18H15N3) and phenazine-1-carboxylic acid (C13H8N2O2). The change in hydrophilicity results in a negative refractive index change in the laser-treated areas. PMID- 28663837 TI - Hyperopic Q-optimized algorithms: a theoretical study on factors influencing optical quality. AB - In this work, we analyze the way in which pupil size, optical zone, and initial hyperopic level influence optical quality for hyperopic Q-optimized corneal refractive surgery. Different Q-optimized algorithms and the Munnerlyn formula were tested to analyze the optical quality of the final retinal image for initial hyperopic errors from 1D to 5D. Three optical zones (5.5, 6, and 6.5 mm) and two pupil diameters (5 and 7 mm) were considered. To evaluate optical quality, we computed the modulation transfer function (MTF) and the area under MTF (MTFa). Q optimized values at around Q = -0.18 were found to provide the best optical quality for most of the conditions tested. This optimum final asphericity for hyperopic ablation was not depending on the degree of hyperopia corrected, the optical zone or the pupil size being this information important for clinical practice. PMID- 28663838 TI - Retinal oximetry in humans using visible-light optical coherence tomography [Invited]. AB - We measured hemoglobin oxygen saturation (sO2) in the retinal circulation in healthy humans using visible-light optical coherence tomography (vis-OCT). The measurements showed clear oxygenation differences between central retinal arteries and veins close to the optic nerve head. Spatial variations at different vascular branching levels were also revealed. In addition, we presented theoretical and experimental results to establish that noises in OCT intensity followed Rice distribution. We used this knowledge to retrieve unbiased estimation of true OCT intensity to improve the accuracy of vis-OCT oximetry, which had inherently lower signal-to-nose ratio from human eyes due to safety and comfort limitations. We demonstrated that the new statistical-fitting sampling strategy could reduce the estimation error in sO2 by three percentage points (pp). The presented work aims to provide a foundation for using vis-OCT to achieve accurate retinal oximetry in clinical settings. PMID- 28663839 TI - Optoacoustic response of gold nanorods in soft phantoms using high-power diode laser assemblies at 870 and 905 nm. AB - In the present paper we show the optoacoustic (OA) response of two solutions of gold nanorods dispersed in distilled water (0.8 mg/ml) and hosted in tissue-like phantoms by using small arrays of HPDLs at 870 and 905 nm as excitation sources. The HPDLs are coupled to a 7-to-1 optical fiber bundle with output diameter of 675 MUm. Each solution of gold nanorods exhibits an absorption peak close to the operating wavelength, i.e. ~860 nm and ~900 nm, respectively, to optimize the generation of OA signals. The phantoms are made of agar, intralipid and hemoglobin to simulate a soft biological tissue with reduced properties of scattering. Three 3-mm diameter tubes done in the phantoms at different depths (0.9 cm, 1.8 cm, and 2.7 cm) have been filled with gold nanorods. In this way, OA signals with appreciable SNR are generated at different depths in the phantoms. The high OA response exhibited by gold nanorods suggests their application in OA spectroscopy as exogenous contrast agents to detect and monitor emerging diseases like metastasis and arteriosclerotic plaques. PMID- 28663840 TI - Endoscope field of view measurement. AB - The current International Organization for Standardization (ISO) standard (ISO 8600-3: 1997 including Amendment 1: 2003) for determining endoscope field of view (FOV) does not accurately characterize some novel endoscopic technologies such as endoscopes with a close focus distance and capsule endoscopes. We evaluated the endoscope FOV measurement method (the FOVWS method) in the current ISO 8600-3 standard and proposed a new method (the FOVEP method). We compared the two methods by measuring the FOV of 18 models of endoscopes (one device for each model) from seven key international manufacturers. We also estimated the device to device variation of two models of colonoscopes by measuring several hundreds of devices. Our results showed that the FOVEP method was more accurate than the FOVWS method, and could be used for all endoscopes. We also found that the labelled FOV values of many commercial endoscopes are significantly overstated. Our study can help endoscope users understand endoscope FOV and identify a proper method for FOV measurement. This paper can be used as a reference to revise the current endoscope FOV measurement standard. PMID- 28663841 TI - Optically sectioned wide-field fluorescence lifetime imaging microscopy enabled by structured illumination. AB - In this paper, we demonstrate the ability of structured illumination microscopy to enhance the ability of fluorescence lifetime imaging to resolve fluorescence lifetimes in relatively thick samples that possess distinct but spectrally overlapping fluorescent layers. Structured illumination fluorescent lifetime imaging microscopy (SI-FLIM) is shown to be able to accurately reconstruct lifetime values in homogenous fluorophore samples (POPOP, NADH, and FAD) as well as accurately measure fluorescent lifetime in two layer models that are layered with NADH/FAD over POPOP, where NADH/FAD and POPOP have spectral overlap. Finally, the ability of SI-FLIM was demonstrated in a hamster cheek pouch ex vivo to show that more accurate lifetimes could be measured for each layer of interest in the oral mucosa (epithelium and submucosa). PMID- 28663842 TI - Persistent luminescence tomography for small animal imaging. AB - Fluorescence imaging is a widely used in vivo optical imaging technique for preclinical studies, but strong tissue autofluorescence and external excitation light make it suffer from a low signal-to-noise ratio (SNR). Recently, a new optical imaging method using persistent luminescence has become of interest due to its advantage of circumvention of autofluorescence and bleed-through of excitation light during signal acquisition. In this work, we proposed a tomographic imaging method based on persistent luminescence named persistent luminescence tomography (PLT), which can obtain three dimensional distributions of persistent luminescence probes deep inside small animals. Persistent luminescence signals can last several hours after excitation, which makes it possible for PLT to collect signals without interference by autofluorescence and bleed-through of excitation light, and then to reconstruct tomographic images of high quality. Phantom and mouse experiments are implemented to verify the feasiblity of PLT. PMID- 28663843 TI - TuebingenCSTest - a useful method to assess the contrast sensitivity function. AB - Since contrast sensitivity (CS) relies on the accuracy of stimulus presentation, the reliability of the psychophysical procedure and observer's attention, the measurement of the CS-function is critical and therefore, a useful threshold contrast measurement was developed. The Tuebingen Contrast Sensitivity Test (TueCST) includes an adaptive staircase procedure and a 16-bit gray-level resolution. In order to validate the CS measurements with the TueCST, measurements were compared with existing tests by inter-test repeatability, test retest reliability and time. The novel design enables an accurate presentation of the spatial frequency and higher precision, inter-test repeatability and test retest reliability compared to other existing tests. PMID- 28663844 TI - Fluorescence quenching of free and bound NADH in HeLa cells determined by hyperspectral imaging and unmixing of cell autofluorescence. AB - Carbonyl cyanide-p-trifluoro methoxyphenylhydrazone (FCCP) is a well-known mitochondrial uncoupling agent. We examined FCCP-induced fluorescence quenching of reduced nicotinamide adenine dinucleotide / nicotinamide adenine dinucleotide phosphate (NAD(P)H) in solution and in cultured HeLa cells in a wide range of FCCP concentrations from 50 to 1000uM. A non-invasive label-free method of hyperspectral imaging of cell autofluorescence combined with unsupervised unmixing was used to separately isolate the emissions of free and bound NAD(P)H from cell autofluorescence. Hyperspectral image analysis of FCCP-treated HeLa cells confirms that this agent selectively quenches fluorescence of free and bound NAD(P)H in a broad range of concentrations. This is confirmed by the measurements of average NAD/NADH and NADP/NADPH content in cells. FCCP quenching of free NAD(P)H in cells and in solution is found to be similar, but quenching of bound NAD(P)H in cells is attenuated compared to solution quenching possibly due to a contribution from the metabolic and/or antioxidant response in cells. Chemical quenching of NAD(P)H fluorescence by FCCP validates the results of unsupervised unmixing of cell autofluorescence. PMID- 28663845 TI - Reduction of frame rate in full-field swept-source optical coherence tomography by numerical motion correction [Invited]. AB - Full-field swept-source optical coherence tomography (FF-SS-OCT) was recently shown to allow new and exciting applications for imaging the human eye that were previously not possible using current scanning OCT systems. However, especially when using cameras that do not acquire data with hundreds of kHz frame rate, uncorrected phase errors due to axial motion of the eye lead to a drastic loss in image quality of the reconstructed volumes. Here we first give a short overview of recent advances in techniques and applications of parallelized OCT and finally present an iterative and statistical algorithm that estimates and corrects motion induced phase errors in the FF-SS-OCT data. The presented algorithm is in many aspects adopted from the phase gradient autofocus (PGA) method, which is frequently used in synthetic aperture radar (SAR). Following this approach, the available phase errors can be estimated based on the image information that remains in the data, and no parametrization with few degrees of freedom is required. Consequently, the algorithm is capable of compensating even strong motion artifacts. Efficacy of the algorithm was tested on simulated data with motion containing varying frequency components. We show that even in strongly blurred data, the actual image information remains intact, and the algorithm can identify the phase error and correct it. Furthermore, we use the algorithm to compensate real phase error in FF-SS-OCT imaging of the human retina. Acquisition rates can be reduced by a factor of three (from 60 to 20 kHz frame rate) with an image quality that is even higher compared to uncorrected volumes recorded at the maximum acquisition rate. The presented algorithm for axial motion correction decreases the high requirements on the camera frame rate and thus brings FF-SS OCT closer to clinical applications. PMID- 28663846 TI - Flexible silicon sensors for diffuse reflectance spectroscopy of tissue. AB - Diffuse reflectance spectroscopy (DRS) is being used in exploratory clinical applications such as cancer margin assessment on excised tissue. However, when interrogating nonplanar tissue anomalies can arise from non-uniform pressure. Herein is reported the design, fabrication, and test of flexible, thin film silicon photodetectors (PDs) bonded to a flexible substrate designed for use in conformal DRS. The PDs have dark currents and responsivities comparable to conventional Si PDs, and were characterized while flat and while flexed at multiple radii of curvature using liquid phantoms mimicking adipose and malignant breast tissue. The DRS and nearest neighbor crosstalk results were compared with Monte Carlo simulations, showing good agreement between simulation and experiment. PMID- 28663847 TI - Development of a multimodal foveated endomicroscope for the detection of oral cancer. AB - A multimodal endomicroscope was developed for cancer detection that combines hyperspectral and confocal imaging through a single foveated objective and a vibrating optical fiber bundle. Standard clinical examination has a limited ability to identify early stage oral cancer. Optical detection methods are typically restricted by either achievable resolution or a small field-of-view. By combining high resolution and widefield spectral imaging into a single probe, a device was developed that provides spectral and spatial information over a 5 mm field to locate suspicious lesions that can then be inspected in high resolution mode. The device was evaluated on ex vivo biopsies of human oral tumors. PMID- 28663848 TI - Reflectance-based projection-resolved optical coherence tomography angiography [Invited]. AB - Optical coherence tomography angiography (OCTA) is limited by projection artifacts from the superficial blood vessels onto deeper layers. We have recently described projection-resolved (PR) OCTA that solves the ambiguity between in situ flow and flow projection along each axial scan and suppresses the artifact on both en face and cross-sectional angiograms. While this method significantly improved the depth resolution of OCTA, the vascular integrity of the deeper layers was not fully preserved. In this study, we propose a novel reflectance based projection-resolved (rbPR) OCTA algorithm which uses OCT reflectance to enhance the flow signal and suppress the projection artifacts in 3-dimensional OCTA. We demonstrated quantitatively that rbPR improved the vascular connectivity and improved the discrimination of the deeper plexus angiograms in healthy eyes, compared to prior PR-OCTA method. We also demonstrated qualitatively that rbPR removes flow projection artifacts more completely from the outer retinal slab in the eyes with age-related macular degeneration, and preserves vascular integrity of the intermediate and deep capillary plexuses in the eyes with diabetic retinopathy. Additionally, this method improves the resolution of the choriocapillaris and demonstrates details comparable to scanning electron microscopy. PMID- 28663850 TI - Multimodal evaluation of ultra-short laser pulses treatment for skin burn injuries. AB - Thousands of people die every year from burn injuries. The aim of this study is to evaluate the feasibility of high intensity femtosecond lasers as an auxiliary treatment of skin burns. We used an in vivo animal model and monitored the healing process using 4 different imaging modalities: histology, Optical Coherence Tomography (OCT), Second Harmonic Generation (SHG), and Fourier Transform Infrared (FTIR) spectroscopy. 3 dorsal areas of 20 anesthetized Wistar rats were burned by water vapor exposure and subsequently treated either by classical surgical debridement, by laser ablation, or left without treatment. Skin burn tissues were non-invasively characterized by OCT images and biopsied for further histopathology analysis, SHG imaging and FTIR spectroscopy at 3, 5, 7 and 14 days after burn. The laser protocol was found as efficient as the classical treatment for promoting the healing process. The study concludes to the validation of femtosecond ultra-short pulses laser treatment for skinburns, with the advantage of minimizing operatory trauma. PMID- 28663849 TI - Computational optical coherence tomography [Invited]. AB - Optical coherence tomography (OCT) has become an important imaging modality with numerous biomedical applications. Challenges in high-speed, high-resolution, volumetric OCT imaging include managing dispersion, the trade-off between transverse resolution and depth-of-field, and correcting optical aberrations that are present in both the system and sample. Physics-based computational imaging techniques have proven to provide solutions to these limitations. This review aims to outline these computational imaging techniques within a general mathematical framework, summarize the historical progress, highlight the state-of the-art achievements, and discuss the present challenges. PMID- 28663851 TI - Scattering and absorption control in biocompatible fibers towards equalized photobiomodulation. AB - Transparent tissue scaffolds enable illumination of growing tissue to accelerate cell proliferation and improve other cell functions through photobiomodulation. The biphasic dose response of cells exposed to photobiomodulating light dictates that the illumination be evenly distributed across the scaffold such that the cells are neither under nor over exposed to light. However, equalized illumination has not been sufficiently addressed. Here we analyze and experimentally demonstrate spatially equalizing illumination by three methods, namely: engineered surface scattering, reflection by a gold mirror, and traveling waves in a ring mesh. Our results show that nearly equalized illumination is achievable by controlling the light scattering-to-loss ratio. This demonstration furthers opportunities for dose-optimized photobiomodulation in tissue regeneration. PMID- 28663852 TI - Correlation of the derivative as a robust estimator of scatterer size in optical coherence tomography (OCT). AB - The size-dependent spectral variations, predicted by Mie theory, have already been considered as a contrast enhancement mechanism in optical coherence tomography. In this work, a new spectroscopic metric, the bandwidth of the correlation of the derivative, was developed for estimating scatterer size which is more robust and accurate compared to existing methods. Its feasibility was demonstrated using phantoms containing polystyrene microspheres as well as images of normal and cancerous human colon. The results are very promising, suggesting that the proposed metric could be utilized for measuring nuclear size distribution, a diagnostically valuable marker, in human tissues. PMID- 28663854 TI - The ecosystem that powered the translation of OCT from fundamental research to clinical and commercial impact [Invited]. AB - 25 years is a relatively short period of time for a medical technology to become a standard of care impacting the treatment of millions of people every year. Yet 25 years ago there were no OCT companies, no OCT products, no OCT markets, and only one journal article published using the term OCT (optical coherence tomography). OCT has had a tremendous scientific, clinical, and economic impact on society. Today, it is estimated that there are ~30 Million OCT imaging procedures performed worldwide every year and the OCT system market is approaching $1B per year. OCT has helped diagnose patients with retinal disease at early treatable stages, preventing or greatly reducing irreversible vision loss. The technology has facilitated pharmaceutical development and contributed to fundamental understanding of disease mechanisms in multiple fields. The invention and translation of OCT from fundamental research to daily clinical practice would not have been possible without a complex ecosystem involving interaction among physics, engineering, and clinical medicine; government funding of fundamental and clinical research; collaborative and competitive research in the academic sector; entrepreneurship and industry; addressing real clinical needs; harnessing the innovation that occurs at the boundaries of disciplines; and economic and societal impact. This invited review paper discusses the translation of OCT from fundamental research to clinical practice and commercial impact, as well as describes the ecosystem that helped power OCT to where it is today and will continue to drive future advances. While OCT is an example of a technology that has had a powerful impact, there are many biomedical technologies which are poised for translation to clinical practice, and it is our hope that highlighting this ecosystem will help accelerate their translation and clinical impact. PMID- 28663855 TI - Simulation of nanoparticle-mediated near-infrared thermal therapy using GATE. AB - Application of nanotechnology for biomedicine in cancer therapy allows for direct delivery of anticancer agents to tumors. An example of such therapies is the nanoparticle-mediated near-infrared hyperthermia treatment. In order to investigate the influence of nanoparticle properties on the spatial distribution of heat in the tumor and healthy tissues, accurate simulations are required. The Geant4 Application for Emission Tomography (GATE) open-source simulation platform, based on the Geant4 toolkit, is widely used by the research community involved in molecular imaging, radiotherapy and optical imaging. We present an extension of GATE that can model nanoparticle-mediated hyperthermal therapy as well as simple heat diffusion in biological tissues. This new feature of GATE combined with optical imaging allows for the simulation of a theranostic scenario in which the patient is injected with theranostic nanosystems that can simultaneously deliver therapeutic (i.e. hyperthermia therapy) and imaging agents (i.e. fluorescence imaging). PMID- 28663853 TI - Review of intraoperative optical coherence tomography: technology and applications [Invited]. AB - During microsurgery, en face imaging of the surgical field through the operating microscope limits the surgeon's depth perception and visualization of instruments and sub-surface anatomy. Surgical procedures outside microsurgery, such as breast tumor resections, may also benefit from visualization of the sub-surface tissue structures. The widespread clinical adoption of optical coherence tomography (OCT) in ophthalmology and its growing prominence in other fields, such as cancer imaging, has motivated the development of intraoperative OCT for real-time tomographic visualization of surgical interventions. This article reviews key technological developments in intraoperative OCT and their applications in human surgery. We focus on handheld OCT probes, microscope-integrated OCT systems, and OCT-guided laser treatment platforms designed for intraoperative use. Moreover, we discuss intraoperative OCT adjuncts and processing techniques currently under development to optimize the surgical feedback derivable from OCT data. Lastly, we survey salient clinical studies of intraoperative OCT for human surgery. PMID- 28663856 TI - Early biomarker for radiation-induced wounds: day one post-irradiation assessment using hemoglobin concentration measured from diffuse optical reflectance spectroscopy. AB - Normal tissue radiation toxicities are evaluated subjectively and cannot predict the development of severe side-effects. Using a hand-held diffuse reflectance optical spectroscopy probe, we measured optical parameters in mouse skin 1-4 days after irradiation. Using a radiation toxicity model and a therapeutic mitigator described previously [BMC Cancer14, 614 (2014)], we found that hemoglobin (Hb) levels increased sharply 24 h after irradiation only in the irradiated group without the mitigator. This group also had the largest peak wound areas after 14 days. We conclude that increased Hb one day after skin irradiation predicts the severity of the subsequent irradiation-induced wound. PMID- 28663857 TI - Interstitial photoacoustic spectral analysis: instrumentation and validation. AB - Photoacoustic (PA) spectral analysis (PASA) is a recently developed approach for quantifying molecular components and microscopic architectures in tissue. The PASA relies on signals with sufficient temporal length and narrow dynamic range for statistics based analysis. However, the optical and acoustic attenuation within the biological tissue make it difficult to acquire desirable signals from deep locations in biological tissue for PASA. This study proposes an interstitial PASA approach. By combining a fiber optics diffuser and a small aperture needle hydrophone, a fine needle PA probe facilitates PASA in deep tissue. A prototype probe has been fabricated and tested in quantifying the prostate cancer cell concentrations in vitro and lipid infiltrated hepatocyte in liver ex vivo. Experiment results show that the needle probe could potentially provide pathologic information of the tissues. PMID- 28663858 TI - Infrared radiative properties and thermal modeling of ceramic-embedded textile fabrics. AB - The infrared optical properties of textiles are of great importance in numerous applications, including infrared therapy and body thermoregulation. Tuning the spectral response of fabrics by the engineering of composite textile materials can produce fabrics targeted for use in these applications. We present spectroscopic data for engineered polyester fabric containing varying amounts of ceramic microparticles within the fiber core and report a spectrally-dependent shift in infrared reflectance, transmittance and absorptance. A thermal transport model is subsequently implemented to study the effect of these modified properties on the spectral distribution of infrared radiation incident upon the wearer of a garment constructed of this fabric. PMID- 28663859 TI - Label-free protein sensing by employing blue phase liquid crystal. AB - Blue phases (BPs) are mesophases existing between the isotropic and chiral nematic phases of liquid crystals (LCs). In recent years, blue phase LCs (BPLCs) have been extensively studied in the field of LC science and display technology. However, the application of BPLCs in biosensing has not been explored. In this study, a BPLC-based biosensing technology was developed for the detection and quantitation of bovine serum albumin (BSA). The sensing platform was constructed by assembling an empty cell with two glass slides coated with homeotropic alignment layers and with immobilized BSA atop. The LC cells were heated to isotropic phase and then allowed to cool down to and maintained at distinct BP temperatures for spectral measurements and texture observations. At BSA concentrations below 10-6 g/ml, we observed that the Bragg reflection wavelength blue-shifted with increasing concentration of BSA, suggesting that the BP is a potentially sensitive medium in the detection and quantitation of biomolecules. By using the BPLC at 37 degrees C and the same polymorphic material in the smectic A phase at 20 degrees C, two linear correlations were established for logarithmic BSA concentrations ranging from 10-9 to 10-6 g/ml and from 10-6 to 10 3 g/ml. Our results demonstrate the potential of BPLCs in biosensing and quantitative analysis of biomolecules. PMID- 28663860 TI - Pixel-based speckle adjustment for noise reduction in Fourier-domain OCT images. AB - Speckle resides in OCT signals and inevitably effects OCT image quality. In this work, we present a novel method for speckle noise reduction in Fourier-domain OCT images, which utilizes the phase information of complex OCT data. In this method, speckle area is pre-delineated pixelwise based on a phase-domain processing method and then adjusted by the results of wavelet shrinkage of the original image. Coefficient shrinkage method such as wavelet or contourlet is applied afterwards for further suppressing the speckle noise. Compared with conventional methods without speckle adjustment, the proposed method demonstrates significant improvement of image quality. PMID- 28663861 TI - Autofocus method for automated microscopy using embedded GPUs. AB - In this paper we present a method for autofocusing images of sputum smears taken from a microscope which combines the finding of the optimal focus distance with an algorithm for extending the depth of field (EDoF). Our multifocus fusion method produces an unique image where all the relevant objects of the analyzed scene are well focused, independently to their distance to the sensor. This process is computationally expensive which makes unfeasible its automation using traditional embedded processors. For this purpose a low-cost optimized implementation is proposed using limited resources embedded GPU integrated on cutting-edge NVIDIA system on chip. The extensive tests performed on different sputum smear image sets show the real-time capabilities of our implementation maintaining the quality of the output image. PMID- 28663862 TI - Quantitative characteristics of sickle cell retinopathy in optical coherence tomography angiography. AB - Early detection is an essential step for effective intervention of sickle cell retinopathy (SCR). Emerging optical coherence tomography angiography (OCTA) provides excellent three-dimensional (3D) resolution to enable label-free, noninvasive visualization of retinal vascular structures, promising improved sensitivity in detecting SCR. However, quantitative analysis of SCR characteristics in OCTA images is yet to be established. In this study, we conducted comprehensive analysis of six OCTA parameters, including blood vessel tortuosity, vessel diameter, vessel perimeter index (VPI), area of foveal avascular zone (FAZ), contour irregularity of FAZ and parafoveal avascular density. Compared to traditional retinal thickness analysis, five of these six OCTA parameters show improved sensitivity for SCR detection than retinal thickness. It is observed that the most sensitive parameters were the contour irregularity of FAZ in the superficial layer and avascular density in temporal regions, while the area of FAZ, tortuosity and mean diameter of the vessel were moderately sensitive. PMID- 28663863 TI - Geometrically complex 3D-printed phantoms for diffuse optical imaging. AB - Tissue-equivalent phantoms that mimic the optical properties of human and animal tissues are commonly used in diffuse optical imaging research to characterize instrumentation or evaluate an image reconstruction method. Although many recipes have been produced for generating solid phantoms with specified absorption and transport scattering coefficients at visible and near-infrared wavelengths, the construction methods are generally time-consuming and are unable to create complex geometries. We present a method of generating phantoms using a standard 3D printer. A simple recipe was devised which enables printed phantoms to be produced with precisely known optical properties. To illustrate the capability of the method, we describe the creation of an anatomically accurate, tissue equivalent premature infant head optical phantom with a hollow brain space based on MRI atlas data. A diffuse optical image of the phantom is acquired when a high contrast target is inserted into the hollow space filled with an aqueous scattering solution. PMID- 28663864 TI - Measurement of multispectral scattering properties in mouse brain tissue. AB - We present the scattering properties of mouse brain using multispectral diffraction phase microscopy. Typical diffraction phase microscopy was incorporated with the broadband light source which offers the measurement of the scattering coefficient and anisotropy in the spectral range of 550-900 nm. The regional analysis was performed for both the myeloarchitecture and cytoarchitecture of the brain tissue. Our results clearly evaluate the multispectral scattering properties in the olfactory bulb and corpus callosum. The scattering coefficient measured in the corpus callosum is about four times higher than in the olfactory bulb. It also indicates that it is feasible to realize the quantitative phase microscope in near infrared region for thick brain tissue imaging. PMID- 28663865 TI - Multimodal nonlinear optical microscopy reveals critical role of kinesin-1 in cartilage development. AB - We developed a multimodal nonlinear optical (NLO) microscope system by integrating stimulated Raman scattering (SRS), second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging. The system was used to study the morphological and biochemical characteristics of tibial cartilage in a kinesin-1 (Kif5b) knockout mouse model. The detailed structure of fibrillar collagen in the extracellular matrix of cartilage was visualized by the forward and backward SHG signals, while high resolution imaging of chondrocytes was achieved by capturing endogenous TPEF and SRS signals of the cells. The results demonstrate that collagen fibrils in the superficial surface of the articular cartilage decreased significantly in the absence of Kif5b. The distorted morphology along with accumulated intracellular collagen was observed in the Kif5b-deficient chondrocytes, indicating the critical roles of kinesin-1 in the chondrocyte morphogenesis and collagen secretion. The study shows that multimodal NLO imaging method is an effective approach to investigate early development of cartilage. PMID- 28663866 TI - Three-dimensional eye motion correction by Lissajous scan optical coherence tomography. AB - A three-dimensional optical coherence tomography imaging method based on Lissajous scanning is presented. This method was designed to correct eye motion in OCT images. A Lissajous scanning pattern, which has a trajectory that frequently overlaps with itself, is adopted as the OCT scanning protocol to obtain measurement data. Eye motion artifacts are then corrected automatically by software. By comparing the images without and with motion correction, we show the effectiveness of our method. We performed an experiment and compared the results obtained by our method with the ground truths to verify its validity. The experimental results showed that our method effectively corrects eye motion artifacts. Furthermore, the sufficient repeatability of our method was confirmed. PMID- 28663867 TI - Adaptive optics optical coherence tomography angiography for morphometric analysis of choriocapillaris [Invited]. AB - Histological studies have shown that morphometric changes at the microscopic level of choriocapillaris (CC) occur with aging and disease onset, and therefore may be sensitive biomarkers of outer retinal health. However, visualizing CC at this level in the living human eye is challenging because its microvascular is tightly interconnected and weakly reflecting. In this study, we address these challenges by developing and validating a method based on adaptive optics optical coherence tomography with angiography (AO-OCTA) that provides the necessary 3D resolution and image contrast to visualize and quantify these microscopic details. The complex network of anastomotic CC capillaries was successfully imaged in nine healthy subjects (26 to 68 years of age) and at seven retinal eccentricities across the macula. Using these images, four fundamental morphometric parameters of CC were characterized: retinal pigment epithelium-to CC depth separation (17.5 +/- 2.1 um), capillary diameter (17.4 +/- 2.3 um), normalized capillary density (0.53 +/- 0.08), and capillary length per unit area (50.4 +/- 9.5 mm-1). AO-OCTA results were consistent with histologic studies and, unlike OCTA, showed clear delineation of CC capillaries, a requirement for measuring three of the four morphometric parameters. Success in younger and older eyes establishes a path for testing aging and disease effects in larger populations. To the best of our knowledge, this is the first quantitative morphometry of choriocapillaris at the level of individual capillaries in the living human retina. PMID- 28663868 TI - Embryonic aortic arch hemodynamics are a functional biomarker for ethanol-induced congenital heart defects [Invited]. AB - The great arteries develop from symmetrical aortic arch arteries which are extensively remodeled. These events are vulnerable to perturbations. Hemodynamic forces have a significant role in this remodeling. In this study, optical coherence tomography (OCT) visualized live avian embryos for staging and measuring pharyngeal arch morphology. Measurements acquired with our orientation independent, dual-angle Doppler OCT technique revealed that ethanol exposure leads to higher absolute blood flow, shear stress, and retrograde flow. Ethanol exposed embryos had smaller cardiac neural crest (CNC) derived pharyngeal arch mesenchyme and fewer migrating CNC-derived cells. These differences in forces and CNC cell numbers could explain the abnormal aortic arch remodeling. PMID- 28663870 TI - Joint retinal layer and fluid segmentation in OCT scans of eyes with severe macular edema using unsupervised representation and auto-context. AB - Modern optical coherence tomography (OCT) devices used in ophthalmology acquire steadily increasing amounts of imaging data. Thus, reliable automated quantitative analysis of OCT images is considered to be of utmost importance. Current automated retinal OCT layer segmentation methods work reliably on healthy or mildly diseased retinas, but struggle with the complex interaction of the layers with fluid accumulations in macular edema. In this work, we present a fully automated 3D method which is able to segment all the retinal layers and fluid-filled regions simultaneously, exploiting their mutual interaction to improve the overall segmentation results. The machine learning based method combines unsupervised feature representation and heterogeneous spatial context with a graph-theoretic surface segmentation. The method was extensively evaluated on manual annotations of 20,000 OCT B-scans from 100 scans of patients and on a publicly available data set consisting of 110 annotated B-scans from 10 patients, all with severe macular edema, yielding an overall mean Dice coefficient of 0.76 and 0.78, respectively. PMID- 28663871 TI - Validation of a spectral light scattering method to differentiate large from small particles in intraocular lenses. AB - A psychophysical approach has been designed to measure straylight from intraocular lenses (IOLs) in vitro. This approach uses a clinical straylight meter (C-Quant) and an observer's eye as optical detector. Based on this, we introduced a method for study of straylight-wavelength dependency for IOLs. This dependency can be used to distinguish between 2 types of scattering particles (small and large) as defined by Mie theory. Validation was performed using a turbidity standard and scattering filters. Several IOLs were analyzed to identify potential scattering sources. Large particles were found to predominate in scattering from the studied lenses. This was confirmed by straylight-angular dependency found in these IOLs. PMID- 28663872 TI - Lookup table-based sampling of the phase function for Monte Carlo simulations of light propagation in turbid media. AB - Analytical expressions for sampling the scattering angle from a phase function in Monte Carlo simulations of light propagation are available only for a limited number of phase functions. Consequently, numerical sampling methods based on tabulated values are often required instead. By using Monte Carlo simulated reflectance, we compare two existing and propose an improved numerical sampling method and show that both the number of the tabulated values and the numerical sampling method significantly influence the accuracy of the simulated reflectance. The provided results and guidelines should serve as a good starting point for conducting computationally efficient Monte Carlo simulations with numerical phase function sampling. PMID- 28663869 TI - Polarization sensitive optical coherence tomography - a review [Invited]. AB - Optical coherence tomography (OCT) is now a well-established modality for high resolution cross-sectional and three-dimensional imaging of transparent and translucent samples and tissues. Conventional, intensity based OCT, however, does not provide a tissue-specific contrast, causing an ambiguity with image interpretation in several cases. Polarization sensitive (PS) OCT draws advantage from the fact that several materials and tissues can change the light's polarization state, adding an additional contrast channel and providing quantitative information. In this paper, we review basic and advanced methods of PS-OCT and demonstrate its use in selected biomedical applications. PMID- 28663873 TI - Autofluorescence imaging captures heterogeneous drug response differences between 2D and 3D breast cancer cultures. AB - Two-photon microscopy of cellular autofluorescence intensity and lifetime (optical metabolic imaging, or OMI) is a promising tool for preclinical drug development. OMI, which exploits the endogenous fluorescence from the metabolic coenzymes NAD(P)H and FAD, is sensitive to changes in cell metabolism produced by drug treatment. Previous studies have shown that drug response, genetic expression, cell-cell communication, and cell signaling in 3D culture match those of the original in vivo tumor, but not those of 2D culture. The goal of this study is to use OMI to quantify dynamic cell-level metabolic differences in drug response in 2D cell lines vs. 3D organoids generated from xenograft tumors of the same cell origin. BT474 cells and Herceptin-resistant BT474 (HR6) cells were tested. Cells were treated with vehicle control, Herceptin, XL147 (PI3K inhibitor), and the combination. The OMI index was used to quantify response, and is a linear combination of the redox ratio (intensity of NAD(P)H divided by FAD), mean NADH lifetime, and mean FAD lifetime. The results confirm that the OMI index resolves significant differences (p<0.05) in drug response for 2D vs. 3D cultures, specifically for BT474 cells 24 hours after Herceptin treatment, for HR6 cells 24 and 72 hours after combination treatment, and for HR6 cells 72 hours after XL147 treatment. Cell-level analysis of the OMI index also reveals differences in the number of cell sub-populations in 2D vs. 3D culture at 24, 48, and 72 hours post-treatment in control and treated groups. Finally, significant increases (p<0.05) in the mean lifetime of NADH and FAD were measured in 2D vs. 3D for both cell lines at 72 hours post-treatment in control and all treatment groups. These whole-population differences in the mean NADH and FAD lifetimes are supported by differences in the number of cell sub-populations in 2D vs. 3D. Overall, these studies confirm that OMI is sensitive to differences in drug response in 2D vs. 3D, and provides further information on dynamic changes in the relative abundance of metabolic cell sub-populations that contribute to this difference. PMID- 28663874 TI - Automated intraretinal segmentation of SD-OCT images in normal and age-related macular degeneration eyes. AB - This work introduces and evaluates an automated intra-retinal segmentation method for spectral-domain optical coherence (SD-OCT) retinal images. While quantitative assessment of retinal features in SD-OCT data is important, manual segmentation is extremely time-consuming and subjective. We address challenges that have hindered prior automated methods, including poor performance with diseased retinas relative to healthy retinas, and data smoothing that obscures image features such as small retinal drusen. Our novel segmentation approach is based on the iterative adaptation of a weighted median process, wherein a three dimensional weighting function is defined according to image intensity and gradient properties, and a set of smoothness constraints and pre-defined rules are considered. We compared the segmentation results for 9 segmented outlines associated with intra-retinal boundaries to those drawn by hand by two retinal specialists and to those produced by an independent state-of-the-art automated software tool in a set of 42 clinical images (from 14 patients). These images were obtained with a Zeiss Cirrus SD-OCT system, including healthy, early or intermediate AMD, and advanced AMD eyes. As a qualitative evaluation of accuracy, a highly experienced third independent reader blindly rated the quality of the outlines produced by each method. The accuracy and image detail of our method was superior in healthy and early or intermediate AMD eyes (98.15% and 97.78% of results not needing substantial editing) to the automated method we compared against. While the performance was not as good in advanced AMD (68.89%), it was still better than the manual outlines or the comparison method (which failed in such cases). We also tested our method's performance on images acquired with a different SD-OCT manufacturer, collected from a large publicly available data set (114 healthy and 255 AMD eyes), and compared the data quantitatively to reference standard markings of the internal limiting membrane and inner boundary of retinal pigment epithelium, producing a mean unsigned positioning error of 6.04 +/- 7.83um (mean under 2 pixels). Our automated method should be applicable to data from different OCT manufacturers and offers detailed layer segmentations in healthy and AMD eyes. PMID- 28663875 TI - Lenslet array tunable snapshot imaging spectrometer (LATIS) for hyperspectral fluorescence microscopy. AB - Snapshot hyperspectral imaging augments pixel dwell time and acquisition speeds over existing scanning systems, making it a powerful tool for fluorescence microscopy. While most snapshot systems contain fixed datacube parameters (x,y,lambda), our novel snapshot system, called the lenslet array tunable snapshot imaging spectrometer (LATIS), demonstrates tuning its average spectral resolution from 22.66 nm (80x80x22) to 13.94 nm (88x88x46) over 485 to 660 nm. We also describe a fixed LATIS with a datacube of 200x200x27 for larger field-of view (FOV) imaging. We report <1 sec exposure times and high resolution fluorescence imaging with minimal artifacts. PMID- 28663876 TI - Amplitude-selective filtering for remote-PPG. AB - Biometric signatures of remote photoplethysmography (rPPG), including the pulse induced characteristic color absorptions and pulse frequency range, have been used to design robust algorithms for extracting the pulse-signal from a video. In this paper, we look into a new biometric signature, i.e., the relative pulsatile amplitude, and use it to design a very effective yet computationally low-cost filtering method for rPPG, namely "amplitude-selective filtering" (ASF). Based on the observation that the human relative pulsatile amplitude varies in a specific lower range as a function of RGB channels, our basic idea is using the spectral amplitude of, e.g., the R-channel, to select the RGB frequency components inside the assumed pulsatile amplitude-range for pulse extraction. Similar to band-pass filtering (BPF), the proposed ASF can be applied to a broad range of rPPG algorithms to pre-process the RGB-signals before extracting the pulse. The benchmark in challenging fitness use-cases shows that applying ASF (ASF+BPF) as a pre-processing step brings significant and consistent improvements to all multi channel pulse extraction methods. It improves different (multi-wavelength) rPPG algorithms to the extent where quality differences between the individual approaches almost disappear. The novelty of the proposed method is its simplicity and effectiveness in providing a solution for the extremely challenging application of rPPG to a fitness setting. The proposed method is easy to understand, simple to implement, and low-cost in running. It is the first time that the physiological property of pulsatile amplitude is used as a biometric signature for generic signal filtering. PMID- 28663877 TI - Subsampled phase retrieval for temporal resolution enhancement in lensless on chip holographic video. AB - On-chip holographic video is a convenient way to monitor biological samples simultaneously at high spatial resolution and over a wide field-of-view. However, due to the limited readout rate of digital detector arrays, one often faces a tradeoff between the per-frame pixel count and frame rate of the captured video. In this report, we propose a subsampled phase retrieval (SPR) algorithm to overcome the spatial-temporal trade-off in holographic video. Compared to traditional phase retrieval approaches, our SPR algorithm uses over an order of magnitude less pixel measurements while maintaining suitable reconstruction quality. We use an on-chip holographic video setup with pixel sub-sampling to experimentally demonstrate a factor of 5.5 increase in sensor frame rate while monitoring the in vivo movement of Peranema microorganisms. PMID- 28663878 TI - Measuring sickle cell morphology during blood flow. AB - During a sickle cell crisis in sickle cell anemia patients, deoxygenated red blood cells may change their mechanical properties and block small blood vessels, causing pain, local tissue damage, and possibly organ failure. Measuring the structural and morphological changes in sickle cells is important for understanding the factors contributing to vessel blockage and for developing an effective treatment. In this work, we image blood cells from sickle cell anemia patients using spectrally encoded flow cytometry, and analyze the interference patterns between reflections from the cell membranes. Using a numerical simulation for calculating the interference pattern obtained from a model of a red blood cell, we propose an analytical expression for the three-dimensional shape of characteristic sickle cells and compare our results to a previously suggested model. Our imaging approach offers new means for analyzing the morphology of sickle cells, and could be useful for studying their unique physiological and biomechanical properties. PMID- 28663879 TI - Fluorescence lifetime microscopy of NADH distinguishes alterations in cerebral metabolism in vivo. AB - Evaluating cerebral energy metabolism at microscopic resolution is important for comprehensively understanding healthy brain function and its pathological alterations. Here, we resolve specific alterations in cerebral metabolism in vivo in Sprague Dawley rats utilizing minimally-invasive 2-photon fluorescence lifetime imaging (2P-FLIM) measurements of reduced nicotinamide adenine dinucleotide (NADH) fluorescence. Time-resolved fluorescence lifetime measurements enable distinction of different components contributing to NADH autofluorescence. Ostensibly, these components indicate different enzyme-bound formulations of NADH. We observed distinct variations in the relative proportions of these components before and after pharmacological-induced impairments to several reactions involved in glycolytic and oxidative metabolism. Classification models were developed with the experimental data and used to predict the metabolic impairments induced during separate experiments involving bicuculline induced seizures. The models consistently predicted that prolonged focal seizure activity results in impaired activity in the electron transport chain, likely the consequence of inadequate oxygen supply. 2P-FLIM observations of cerebral NADH will help advance our understanding of cerebral energetics at a microscopic scale. Such knowledge will aid in our evaluation of healthy and diseased cerebral physiology and guide diagnostic and therapeutic strategies that target cerebral energetics. PMID- 28663880 TI - Three-dimensional MRI study of the relationship between eye dimensions, retinal shape and myopia. AB - We investigated changes in eye dimensions and retinal shape with degree of myopia, gender and race. There were 58 young adult emmetropes and myopes (range 1.25D to -8.25D), with 30 East-Asians (21 female/9 male), 23 Caucasians (16/7) and 5 South-Asians (1/4). Three-dimensional magnetic resonance imaging was undertaken with a 3.0 Tesla whole-body clinical MRI system using a 4.0 cm receive only surface coil positioned over the eye. Automated methods determined eye length, width and height, and curve fitting procedures determined asymmetric and symmetric ellipsoid shapes to 75%, 55% and 35% of the retina. With myopia increase, eye dimensions increased in all directions such that increase in length was considerably greater than increases in width and height. Emmetropic retinas were oblate (steepening away from the vertex) but oblateness decreased with the increase in myopia, so that retinas were approximately spherical at 7 to 8D myopia. Asymmetry of eyes about the best fit visual axis was generally small, with small differences between the vertex radii of curvature and between asphericities in the axial and sagittal planes. Females had smaller eyes than males, with overall dimensions being about 0.5mm less for the former. Race appeared not to have a systematic effect. PMID- 28663881 TI - Achromatic doublet intraocular lens for full aberration correction. AB - A doublet intraocular lens optimized for both chromatic and monochromatic aberration correction in pseudophakic eyes is presented. Ray-tracing techniques were applied to design the lens in white light within a chromatic eye model. Combinations of two materials, already commonly used in intraocular lenses, as acrylic and silicone, were used. Iterative optimization algorithms were employed to correct for longitudinal chromatic aberration, spherical aberration and off axis aberrations within 10 degrees of visual field. The performance of this lens was compared with a standard single-material aspheric intraocular lens. Near full aberration correction was achieved with the doublet intraocular lens. The modulation transfer function and Strehl ratio were superior for the doublet lens. Through-focus calculations were also conducted showing better optical quality for the doublet. Real higher-order aberrations from normal eyes were incorporated in the model to evaluate the effect on the doublet intraocular lens performance. Results showed that the doublet lens preserved its benefits under realistic conditions. This doublet intraocular lens should provide patients with a better quality of vision after it is further developed in terms of manufacturing and surgical limitations. PMID- 28663883 TI - Reconstruction of super-resolution STORM images using compressed sensing based on low-resolution raw images and interpolation. AB - Single-molecule-localization-based super-resolution microscopic technologies, such as stochastic optical reconstruction microscopy (STORM), require lengthy runtimes. Compressed sensing (CS) can partially overcome this inherent disadvantage, but its effect on super-resolution reconstruction has not been thoroughly examined. In CS, measurement matrices play more important roles than reconstruction algorithms. Larger measurement matrices have better restricted isometry properties (RIPs). This paper proposes, analyzes, and compares uses of higher resolution cameras and interpolation to achieve better outcomes. Statistical results demonstrate that super-resolution reconstructions is significantly improved by interpolating low-resolution STORM raw images and using point-spread-function-based measurement matrices with better RIPs. The analysis of publically accessible experimental data confirms this conclusion. PMID- 28663884 TI - In vivo volumetric quantitative micro-elastography of human skin. AB - In this paper, we demonstrate in vivo volumetric quantitative micro-elastography of human skin. Elasticity is estimated at each point in the captured volume by combining local axial strain measured in the skin with local axial stress estimated at the skin surface. This is achieved by utilizing phase-sensitive detection to measure axial displacements resulting from compressive loading of the skin and an overlying, compliant, transparent layer with known stress/strain behavior. We use an imaging probe head that provides optical coherence tomography imaging and compression from the same direction. We demonstrate our technique on a tissue phantom containing a rigid inclusion, and present in vivo elastograms acquired from locations on the hand, wrist, forearm and leg of human volunteers. PMID- 28663882 TI - Endoscopic optical coherence tomography: technologies and clinical applications [Invited]. AB - In this paper, we review the current state of technology development and clinical applications of endoscopic optical coherence tomography (OCT). Key design and engineering considerations are discussed for most OCT endoscopes, including side viewing and forward-viewing probes, along with different scanning mechanisms (proximal-scanning versus distal-scanning). Multi-modal endoscopes that integrate OCT with other imaging modalities are also discussed. The review of clinical applications of endoscopic OCT focuses heavily on diagnosis of diseases and guidance of interventions. Representative applications in several organ systems are presented, such as in the cardiovascular, digestive, respiratory, and reproductive systems. A brief outlook of the field of endoscopic OCT is also discussed. PMID- 28663885 TI - STED imaging performance estimation by means of Fourier transform analysis. AB - Due to relatively high powers used in STED, biological samples may be affected by the illumination in the process of image acquisition. Similarly, the performance of the system may be limited by the sample itself. Optimization of the STED parameters taking into account the sample itself is therefore a complex task as there is no clear methodology that can determine the image improvement in an objective and quantitative manner. In this work, a method based on Fourier transform formalism is presented to analyze the performance of a STED system. The spatial frequency distribution of pairs of confocal and STED images are compared to obtain an objective parameter, the Azimuth Averaged Spectral Content Spread (AASCS), that is related to the performance of the system in which the sample is also considered. The method has been first tested on samples of beads, and then applied to cell samples labeled with multiple fluorescent dyes. The results show that a single parameter, the AASCS, can be used to determine the optimal settings for STED image acquisition in an objective way, only by using the information provided by the images from the sample themselves. The AASCS also helps minimize the depletion power, for better preservation of the samples. PMID- 28663886 TI - Adaptive optics two-photon excited fluorescence lifetime imaging ophthalmoscopy of exogenous fluorophores in mice. AB - In vivo cellular scale fluorescence lifetime imaging of the mouse retina has the potential to be a sensitive marker of retinal cell health. In this study, we demonstrate fluorescence lifetime imaging of extrinsic fluorophores using adaptive optics fluorescence lifetime imaging ophthalmoscopy (AOFLIO). We recorded AOFLIO images of inner retinal cells labeled with enhanced green fluorescent protein (EGFP) and capillaries labeled with fluorescein. We demonstrate that AOFLIO can be used to differentiate spectrally overlapping fluorophores in the retina. With further refinements, AOFLIO could be used to assess retinal health in early stages of degeneration by utilizing lifetime-based sensors or even fluorophores native to the retina. PMID- 28663887 TI - Structured illumination multimodal 3D-resolved quantitative phase and fluorescence sub-diffraction microscopy. AB - Sub-diffraction resolution imaging has played a pivotal role in biological research by visualizing key, but previously unresolvable, sub-cellular structures. Unfortunately, applications of far-field sub-diffraction resolution are currently divided between fluorescent and coherent-diffraction regimes, and a multimodal sub-diffraction technique that bridges this gap has not yet been demonstrated. Here we report that structured illumination (SI) allows multimodal sub-diffraction imaging of both coherent quantitative-phase (QP) and fluorescence. Due to SI's conventionally fluorescent applications, we first demonstrate the principle of SI-enabled three-dimensional (3D) QP sub-diffraction imaging with calibration microspheres. Image analysis confirmed enhanced lateral and axial resolutions over diffraction-limited QP imaging, and established striking parallels between coherent SI and conventional optical diffraction tomography. We next introduce an optical system utilizing SI to achieve 3D sub diffraction, multimodal QP/fluorescent visualization of A549 biological cells fluorescently tagged for F-actin. Our results suggest that SI has a unique utility in studying biological phenomena with significant molecular, biophysical, and biochemical components. PMID- 28663888 TI - Focus scanning with feedback-control for fiber-optic nonlinear endomicroscopy. AB - Fiber-optic endomicroscopes open new avenues for the application of non-linear optics to novel in vivo applications. To achieve focus scanning in vivo, shape memory alloy (SMA) wires have been used to move optical elements in miniature endomicroscopes. However, this method has various limitations, making it difficult to achieve accurate and reliable depth scanning. Here we present a feedback-controlled SMA depth scanner. With a Hall effect sensor, contraction of the SMA wire can be tracked in real time, rendering accurate and robust control of motion. The SMA depth scanner can achieve up to 490 um travel and with open loop operation, it can move more than 350 um within one second. With the feedback loop engaged, submicron positioning accuracy was achieved along with superior positioning stability. The high-precision positioning capability of the SMA depth scanner was verified by depth-resolved nonlinear endomicroscopic imaging of mouse brain samples. PMID- 28663889 TI - Using speckle to measure tissue dispersion in optical coherence tomography. AB - Tissue dispersion could be used as a marker of early disease changes to further improve the diagnostic potential of optical coherence tomography (OCT). However, most methods to measure dispersion, described in the literature, rely on the presence of distinct and strong reflectors and are, therefore, rarely applicable in vivo. A novel technique has been developed which estimates the dispersion induced resolution degradation from the image speckle and, as such, is applicable in situ. This method was verified experimentally ex vivo and was applied to the classification of a set of normal and cancerous colon OCT images resulting in 96% correct classification. PMID- 28663890 TI - Review of adaptive optics OCT (AO-OCT): principles and applications for retinal imaging [Invited]. AB - In vivo imaging of the human retina with a resolution that allows visualization of cellular structures has proven to be essential to broaden our knowledge about the physiology of this precious and very complex neural tissue that enables the first steps in vision. Many pathologic changes originate from functional and structural alterations on a cellular scale, long before any degradation in vision can be noted. Therefore, it is important to investigate these tissues with a sufficient level of detail in order to better understand associated disease development or the effects of therapeutic intervention. Optical retinal imaging modalities rely on the optical elements of the eye itself (mainly the cornea and lens) to produce retinal images and are therefore affected by the specific arrangement of these elements and possible imperfections in curvature. Thus, aberrations are introduced to the imaging light and image quality is degraded. To compensate for these aberrations, adaptive optics (AO), a technology initially developed in astronomy, has been utilized. However, the axial sectioning provided by retinal AO-based fundus cameras and scanning laser ophthalmoscope instruments is limited to tens of micrometers because of the rather small available numerical aperture of the eye. To overcome this limitation and thus achieve much higher axial sectioning in the order of 2-5um, AO has been combined with optical coherence tomography (OCT) into AO-OCT. This enabled for the first time in vivo volumetric retinal imaging with high isotropic resolution. This article summarizes the technical aspects of AO-OCT and provides an overview on its various implementations and some of its clinical applications. In addition, latest developments in the field, such as computational AO-OCT and wavefront sensor less AO-OCT, are covered. PMID- 28663891 TI - Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics. AB - The longitudinal effect of an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (DC 101) therapy on a xenografted renal cell carcinoma (RCC) mouse model was monitored using hybrid diffuse optics. Two groups of immunosuppressed male nude mice (seven treated, seven controls) were measured. Tumor microvascular blood flow, total hemoglobin concentration and blood oxygenation were investigated as potential biomarkers for the monitoring of the therapy effect twice a week and were related to the final treatment outcome. These hemodynamic biomarkers have shown a clear differentiation between two groups by day four. Moreover, we have observed that pre-treatment values and early changes in hemodynamics are highly correlated with the therapeutic outcome demonstrating the potential of diffuse optics to predict the therapy response at an early time point. PMID- 28663892 TI - Assessment of mental stress effects on prefrontal cortical activities using canonical correlation analysis: an fNIRS-EEG study. AB - This paper presents an investigation about the effects of mental stress on prefrontal cortex (PFC) subregions using simultaneous measurement of functional Near-Infrared Spectroscopy (fNIRS) and Electroencephalography (EEG) signals. The aim is to explore canonical correlation analysis (CCA) technique to study the relationship among the bi-modality signals in mental stress assessment, and how we could fuse the signals for better accuracy in stress detection. Twenty-five male healthy subjects participated in the study while performing mental arithmetic task under control and stress (under time pressure with negative feedback) conditions. The fusion of brain signals acquired by fNIRS-EEG was performed at feature-level using CCA by maximizing the inter-subject covariance across modalities. The CCA result discovered the associations across the modalities and estimated the components responsible for these associations. The experiment results showed that mental stress experienced by this cohort of subjects is subregion specific and localized to the right ventrolateral PFC subregion. These suggest the right ventrolateral PFC as a suitable candidate region to extract biomarkers as performance indicators of neurofeedback training in stress coping. PMID- 28663893 TI - Functional imaging of neuronal activity of auditory cortex by using Cal-520 in anesthetized and awake mice. AB - The organization in the primary auditory cortex (Au1) is critical to the basic function of auditory information processing and integration. However, recent mapping experiments using in vivo two-photon imaging with different Ca2+ indicators have reached controversial conclusions on this topic, possibly because of the different sensitivities and properties of the indicators used. Therefore, it is essential to identify a reliable Ca2+ indicator for use in in vivo functional imaging of the Au1, to understand its functional organization. Here, we demonstrate that a previously reported indicator, Cal-520, performs well in both anesthetized and awake conditions. Cal-520 shows a sufficient sensitivity for the detection of single action potentials, and a high signal-to-noise ratio. Cal-520 reliably reported on both spontaneous and sound-evoked neuronal activity in anesthetized and awake mice. After testing with pure tones at a range of frequencies, we confirmed the local heterogeneity of the functional organization of the mouse Au1. Therefore, Cal-520 is a reliable and useful Ca2+ indicator for in vivo functional imaging of the Au1. PMID- 28663894 TI - Three-dimensional reconstruction and measurements of zebrafish larvae from high throughput axial-view in vivo imaging. AB - High-throughput imaging is applied to provide observations for accurate statements on phenomena in biology and this has been successfully applied in the domain of cells, i.e. cytomics. In the domain of whole organisms, we need to take the hurdles to ensure that the imaging can be accomplished with a sufficient throughput and reproducibility. For vertebrate biology, zebrafish is a popular model system for High-throughput applications. The development of the Vertebrate Automated Screening Technology (VAST BioImager), a microscope mounted system, enables the application of zebrafish high-throughput screening. The VAST BioImager contains a capillary that holds a zebrafish for imaging. Through the rotation of the capillary, multiple axial-views of a specimen can be acquired. For the VAST BioImager, fluorescence and/or confocal microscopes are used. Quantitation of a specific signal as derived from a label in one fluorescent channel requires insight in the zebrafish volume to be able to normalize quantitation to volume units. However, from the setup of the VAST BioImager, a specimen volume cannot be straightforwardly derived. We present a high-throughput axial-view imaging architecture based on the VAST BioImager. We propose profile based 3D reconstruction to produce 3D volumetric representations for zebrafish larvae using the axial-views. Volume and surface area can then be derived from the 3D reconstruction to obtain the shape characteristics in high-throughput measurements. In addition, we develop a calibration and a validation of our methodology. From our measurements we show that with a limited amount of views, accurate measurements of volume and surface area for zebrafish larvae can be obtained. We have applied the proposed method on a range of developmental stages in zebrafish and produced metrical references for the volume and surface area for each stage. PMID- 28663895 TI - Optimization of fluorescent imaging in the operating room through pulsed acquisition and gating to ambient background cycling. AB - The design of fluorescence imaging instruments for surgical guidance is rapidly evolving, and a key issue is to efficiently capture signals with high ambient room lighting. Here, we introduce a novel time-gated approach to fluorescence imaging synchronizing acquisition to the 120 Hz light of the room, with pulsed LED excitation and gated ICCD detection. It is shown that under bright ambient room light this technique allows for the detection of physiologically relevant nanomolar fluorophore concentrations, and in particular reduces the light fluctuations present from the room lights, making low concentration measurements more reliable. This is particularly relevant for the light bands near 700nm that are more dominated by ambient lights. PMID- 28663896 TI - Evaluation of non-thermal plasma-induced anticancer effects on human colon cancer cells. AB - Non-thermal atmospheric-pressure plasma has been introduced in various applications such as sterilization, wound healing, blood coagulation, and other biomedical applications. The most attractive application of non-thermal atmospheric-pressure plasma is in cancer treatment, where the plasma is used to produce reactive oxygen species (ROS) to facilitate cell apoptosis. We investigate the effects of different durations of exposure to dielectric-barrier discharge (DBD) plasma on colon cancer cells using measurement of cell viability and ROS levels, western blot, immunocytochemistry, and Raman spectroscopy. Our results suggest that different kinds of plasma-treated cells can be differentiated from control cells using the Raman data. PMID- 28663898 TI - Quadratic divergence regularized SVM for optic disc segmentation. AB - Machine learning has been used in many retinal image processing applications such as optic disc segmentation. It assumes that the training and testing data sets have the same feature distribution. However, retinal images are often collected under different conditions and may have different feature distributions. Therefore, the models trained from one data set may not work well for another data set. However, it is often too expensive and time consuming to label the needed training data and rebuild the models for all different data sets. In this paper, we propose a novel quadratic divergence regularized support vector machine (QDSVM) to transfer the knowledge from domains with sufficient training data to domains with limited or even no training data. The proposed method simultaneously minimizes the distribution difference between the source domain and target domain while training the classifier. Experimental results show that the proposed transfer learning based method reduces the classification error in superpixel level from 14.2% without transfer learning to 2.4% with transfer learning. The proposed method is effective to transfer the label knowledge from source to target domain, which enables it to be used for optic disc segmentation in data sets with different feature distributions. PMID- 28663897 TI - Intravascular optical coherence tomography [Invited]. AB - Shortly after the first demonstration of optical coherence tomography for imaging the microstructure of the human eye, work began on developing systems and catheters suitable for intravascular imaging in order to diagnose and investigate atherosclerosis and potentially to monitor therapy. This review covers the driving considerations of the clinical application and its constraints, the major engineering milestones that enabled the current, high-performance commercial imaging systems, the key studies that laid the groundwork for image interpretation, and the clinical research that traces intravascular optical coherence tomography (OCT) from early human pilot studies to current clinical trials. PMID- 28663899 TI - Automatic and robust segmentation of endoscopic OCT images and optical staining. AB - We report a generic method for automatic segmentation of endoscopic optical coherence tomography (OCT) images. In this method, OCT images are first processed with L1 -L0 norm minimization based de-noising and smoothing algorithms to increase the signal-to-noise ratio (SNR) and enhance the contrast between adjacent layers. The smoothed images are then formulated into cost graphs based on their vertical gradients. After that, tissue-layer segmentation is performed with the shortest path search algorithm. The efficacy and capability of this method are demonstrated by automatically and robustly identifying all five interested layers of guinea pig esophagus from in vivo endoscopic OCT images. Furthermore, thanks to the ultrahigh resolution, high SNR of endoscopic OCT images and the high segmentation accuracy, this method permits in vivo optical staining histology and facilitates quantitative analysis of tissue geometric properties, which can be very useful for studying tissue pathologies and potentially aiding clinical diagnosis in real time. PMID- 28663900 TI - Assessment of eye length changes in accommodation using dynamic extended-depth OCT. AB - It has been suggested that accommodation induces increases in axial eye length which could contribute to the development of myopia. However, it is debated whether changes in eye length occur during accommodation as the degree of change varies widely across literature. In this study, an extended-depth optical coherence tomography (OCT) system that provides dynamic whole eye biometry was utilized to assess changes in lens thickness (LT) and axial eye length (AEL) in young subjects responding to step disaccommodation stimuli of amplitude 2D, 4D, and 6D. The decrease in lens thickness with disaccommodation was strongly correlated with stimulus amplitude. No statistically significant changes in AEL during accommodation were observed. PMID- 28663901 TI - Noise adaptive wavelet thresholding for speckle noise removal in optical coherence tomography. AB - Optical coherence tomography (OCT) is based on coherence detection of interferometric signals and hence inevitably suffers from speckle noise. To remove speckle noise in OCT images, wavelet domain thresholding has demonstrated significant advantages in suppressing noise magnitude while preserving image sharpness. However, speckle noise in OCT images has different characteristics in different spatial scales, which has not been considered in previous applications of wavelet domain thresholding. In this study, we demonstrate a noise adaptive wavelet thresholding (NAWT) algorithm that exploits the difference of noise characteristics in different wavelet sub-bands. The algorithm is simple, fast, effective and is closely related to the physical origin of speckle noise in OCT image. Our results demonstrate that NAWT outperforms conventional wavelet thresholding. PMID- 28663902 TI - Automatic segmentation of nine retinal layer boundaries in OCT images of non exudative AMD patients using deep learning and graph search. AB - We present a novel framework combining convolutional neural networks (CNN) and graph search methods (termed as CNN-GS) for the automatic segmentation of nine layer boundaries on retinal optical coherence tomography (OCT) images. CNN-GS first utilizes a CNN to extract features of specific retinal layer boundaries and train a corresponding classifier to delineate a pilot estimate of the eight layers. Next, a graph search method uses the probability maps created from the CNN to find the final boundaries. We validated our proposed method on 60 volumes (2915 B-scans) from 20 human eyes with non-exudative age-related macular degeneration (AMD), which attested to effectiveness of our proposed technique. PMID- 28663903 TI - Ocular damage effects from 1338-nm pulsed laser radiation in a rabbit eye model. AB - The ocular damage effects induced by transitional near-infrared (NIR) lasers have been investigated for years. However, no retinal damage thresholds are determined in a wide interval between 0.65 ms and 80 ms, and a definite relationship between corneal damage threshold and spot size cannot be drawn from existing data points. In this paper, the in-vivo corneal damage thresholds (ED50s) were determined in New Zealand white rabbits for a single 5 ms pulse at the wavelength of 1338 nm for spot sizes from 0.28 mm to 3.55 mm. Meanwhile, the retinal damage threshold for this laser was determined in chinchilla grey rabbits under the condition that the beam was collimated, and the incident corneal spot diameter was 5.0 mm. The corneal ED50s given in terms of the corneal radiant exposure for spot diameters of 0.28, 0.94, 1.91, and 3.55 mm were 70.3, 35.6, 29.6 and 30.3 J/cm2, respectively. The retinal ED50 given in terms of total intraocular energy (TIE) was 0.904 J. The most sensitive ocular tissue to this laser changed from the cornea to retina with the increase of spot size. PMID- 28663904 TI - Design and evaluation of a compound acoustic lens for photoacoustic computed tomography. AB - In photoacoustic computed tomography, the limited directivity of the detectors may cause deformation of off-center targets and lead to an imbalanced resolution in the imaging area. To improve the directivity of the acoustic detectors, several negative acoustic lenses have been proposed. In this study, we develop a new compound acoustic lens fabricated by integrating a concave polydimethylsiloxane (PDMS) lens and a convex epoxy lens. Both theoretical simulations and experimental evaluations demonstrate that the compound lens provides a larger directivity compared to single lenses made of PDMS, epoxy, and liquid. The measured acceptance angles of a 6-mm piezoelectric acoustic transducer equipped with the compound, epoxy, liquid, and PDMS lenses are 55 degrees , 36 degrees , 25 degrees , and 20 degrees , respectively. No deformation is observed in the off-center targets by using compound lens. However, serious deformation appears in the cases using single lenses. PMID- 28663905 TI - Digital micromirror device based ophthalmoscope with concentric circle scanning. AB - Retinal imaging is demonstrated using a novel scanning light ophthalmoscope based on a digital micromirror device with 810 nm illumination. Concentric circles were used as scan patterns, which facilitated fixation by a human subject for imaging. An annular illumination was implemented in the system to reduce the background caused by corneal reflections and thereby to enhance the signal-to-noise ratio. A 1.9-fold increase in the signal-to-noise ratio was found by using an annular illumination aperture compared to a circular illumination aperture, resulting in a 5-fold increase in imaging speed and a better signal-to-noise ratio compared to our previous system. We tested the imaging performance of our system by performing non-mydriatic imaging on two subjects at a speed of 7 Hz with a maximum 20 degrees (diameter) field of view. The images were shot noise limited and clearly show various anatomical features of the retina with high contrast. PMID- 28663906 TI - Fiber bundle-based integrated platform for wide-field fluorescence imaging and patterned optical stimulation for modulation of vasoconstriction in the deep brain of a living animal. AB - We report a fiber optics-based intravital fluorescence imaging platform that includes epi-fluorescence microscopy and laser patterned-light stimulation system. The platform can perform real-time fluorescence imaging with a lateral resolution of ~4.9 MUm while directly inserted into the intact mouse brain, optically stimulate vasoconstriction during real-time imaging, and avoid vessel damage in the penetration path of imaging probe. Using 473-nm patterned-light stimulation, we successfully modulated the vasoconstriction of a single targeted 37-MUm-diameter blood vessel located more than 4.7 mm below the brain surface of a live SM22-ChR2 mouse. This platform may permit the hemodynamic studies associated with deeper brain neurovascular disorders. PMID- 28663907 TI - Temporal focusing microscopy using three-photon excitation fluorescence with a 92 fs Yb-fiber chirped pulse amplifier. AB - Temporal focusing (TF) microscopy is a wide-field two-photon excitation fluorescence (2PEF) microscopy technique, the optical sectioning capability of which is lower than that of point-scanning 2PEF microscopy. Here we demonstrate TF microscopy using three-photon excitation fluorescence (3PEF), which enhances the optical sectioning capability. As an excitation light source for the 3PEF, we developed an Yb-fiber chirped pulse amplifier, which produces 92-fs 9.0-MUJ 1060 nm pulses at a repetition rate of 200 kHz. The optical sectioning capability was improved by a factor of 1.3 compared with that of 2PEF-TF microscopy. We also demonstrate dual-color imaging with both 2PEF and 3PEF. PMID- 28663908 TI - Transient absorption imaging of hemes with 2-color, independently tunable visible wavelength ultrafast source. AB - Pump probe microscopy is a time-resolved multiphoton imaging technique capable of generating contrast between non-fluorescent pigments based on differences in excited-state lifetimes. Here we describe a fiber-based ultrafast system designed for imaging heme proteins with an independently-tunable pulse pair in the visible wavelength regime. Starting with a 1060 nm fiber amplifier (1.3 W at 63 MHz, 140 fs pulses), visible pulses were produced in the vicinity of 488 nm and 532 nm by doubling the output of a short photonic crystal fiber with a pair of periodically poled lithium niobate crystals, providing 5-20 mW power in each beam. This was sufficient for acquiring transient absorption images from unstained cryosectioned tissue. PMID- 28663909 TI - The value of polarization in camera-based photoplethysmography. AB - Camera-based photoplethysmography (cbPPG) is a novel measuring technique that permits the remote acquisition of cardiovascular signals using video cameras. Research still lacks in fundamental studies to reach a deeper technical and physiological understanding. This work analyzes the employment of polarization filtration to (i) assess the gain for the signal quality and (ii) draw conclusions about the cbPPG signal's origin. We evaluated various forehead regions of 18 recordings with different color and filter settings. Our results prove that for an optimal illumination, the perpendicular filter setting provides a significant benefit. The outcome supports the theory that signals arise from blood volume changes. For lateral illumination, ballistocardiographic effects dominate the signal as polarization's impact vanishes. PMID- 28663910 TI - Raman active components of skin cancer. AB - Raman spectroscopy (RS) has shown great potential in noninvasive cancer screening. Statistically based algorithms, such as principal component analysis, are commonly employed to provide tissue classification; however, they are difficult to relate to the chemical and morphological basis of the spectroscopic features and underlying disease. As a result, we propose the first Raman biophysical model applied to in vivo skin cancer screening data. We expand upon previous models by utilizing in situ skin constituents as the building blocks, and validate the model using previous clinical screening data collected from a Raman optical fiber probe. We built an 830nm confocal Raman microscope integrated with a confocal laser-scanning microscope. Raman imaging was performed on skin sections spanning various disease states, and multivariate curve resolution (MCR) analysis was used to resolve the Raman spectra of individual in situ skin constituents. The basis spectra of the most relevant skin constituents were combined linearly to fit in vivo human skin spectra. Our results suggest collagen, elastin, keratin, cell nucleus, triolein, ceramide, melanin and water are the most important model components. We make available for download (see supplemental information) a database of Raman spectra for these eight components for others to use as a reference. Our model reveals the biochemical and structural makeup of normal, nonmelanoma and melanoma skin cancers, and precancers and paves the way for future development of this approach to noninvasive skin cancer diagnosis. PMID- 28663911 TI - Quantifying melanin concentration in retinal pigment epithelium using broadband photoacoustic microscopy. AB - Melanin is the dominant light absorber in retinal pigment epithelium (RPE). The loss of RPE melanin is a sign of ocular senescence and is both a risk factor and a symptom of age-related macular degeneration (AMD). Quantifying the RPE melanin concentration provides insight into the pathological role of RPE in ocular aging and the onset and progression of AMD. The main challenge in accurate quantification of RPE melanin concentration is to distinguish this ten-micrometer thick cell monolayer from the underlying choroid, which also contains melanin but carries different pathognomonic information. In this work, we investigated a three-dimensional photoacoustic microscopic (PAM) method with high axial resolution, empowered by broad acoustic detection bandwidth, to distinguish RPE from choroid and quantify melanin concentrations in the RPE ex vivo. We first conducted numerical simulation on photoacoustic generation in the RPE, which suggested that a PAM system with at least 100-MHz detection bandwidth provided sufficient axial resolution to distinguish the melanin in RPE from that in choroid. Based on simulation results, we integrated a transparent broadband micro ring resonator (MRR) based detector in a homebuilt PAM system. We imaged ex vivo RPE-choroid complexes (RCCs) from both porcine and human eyes and quantified the absolute melanin concentrations in the RPE and choroid, respectively. In our study, the measured melanin concentrations were 14.7 mg/mL and 17.0 mg/mL in human and porcine RPE, and 12 mg/mL and 61 mg/mL in human and porcine choroid, respectively. This study suggests that broadband PAM is capable of quantifying the RPE melanin concentration from RCCs ex vivo. PMID- 28663912 TI - Digital micromirror based near-infrared illumination system for plasmonic photothermal neuromodulation. AB - Light-mediated neuromodulation techniques provide great advantages to investigate neuroscience due to its high spatial and temporal resolution. To generate a spatial pattern of neural activity, it is necessary to develop a system for patterned-light illumination to a specific area. Digital micromirror device (DMD) based patterned illumination system have been used for neuromodulation due to its simple configuration and design flexibility. In this paper, we developed a patterned near-infrared (NIR) illumination system for region specific photothermal manipulation of neural activity using NIR-sensitive plasmonic gold nanorods (GNRs). The proposed system had high power transmission efficiency for delivering power density up to 19 W/mm2. We used a GNR-coated microelectrode array (MEA) to perform biological experiments using E18 rat hippocampal neurons and showed that it was possible to inhibit neural spiking activity of specific area in neural circuits with the patterned NIR illumination. This patterned NIR illumination system can serve as a promising neuromodulation tool to investigate neuroscience in a wide range of physiological and clinical applications. PMID- 28663913 TI - Plum pudding random medium model of biological tissue toward remote microscopy from spectroscopic light scattering. AB - Biological tissue has a complex structure and exhibits rich spectroscopic behavior. There has been no tissue model until now that has been able to account for the observed spectroscopy of tissue light scattering and its anisotropy. Here we present, for the first time, a plum pudding random medium (PPRM) model for biological tissue which succinctly describes tissue as a superposition of distinctive scattering structures (plum) embedded inside a fractal continuous medium of background refractive index fluctuation (pudding). PPRM faithfully reproduces the wavelength dependence of tissue light scattering and attributes the "anomalous" trend in the anisotropy to the plum and the powerlaw dependence of the reduced scattering coefficient to the fractal scattering pudding. Most importantly, PPRM opens up a novel venue of quantifying the tissue architecture and microscopic structures on average from macroscopic probing of the bulk with scattered light alone without tissue excision. We demonstrate this potential by visualizing the fine microscopic structural alterations in breast tissue (adipose, glandular, fibrocystic, fibroadenoma, and ductal carcinoma) deduced from noncontact spectroscopic measurement. PMID- 28663914 TI - Multispectral oximetry of murine tendon microvasculature with inflammation. AB - We report a novel multispectral imaging technique for localised measurement of vascular oxygen saturation (SO2) in vivo. Annular back-illumination is generated using a Schwarzchild-design reflective objective. Analysis of multispectral data is performed using a calibration-free oximetry algorithm. This technique is applied to oximetry in mice to measure SO2 in microvasculature supplying inflamed tendon tissue in the hind leg. Average SO2 for controls was 94.8 +/- 7.0 % (N = 6), and 84.0 +/- 13.5 % for mice with inflamed tendon tissue (N = 6). We believe this to be the first localised measurement of hypoxia in tendon microvasculature due to inflammation. Quantification of localised SO2 is important for the study of inflammatory diseases such as rheumatoid arthritis, where hypoxia is thought to play a role in pathogenesis. PMID- 28663915 TI - Conical scan pattern for enhanced visualization of the human cornea using polarization-sensitive OCT. AB - Conventional imaging of the human cornea with optical coherence tomography (OCT) relies on telecentric scanning optics with sampling beams that are parallel to the optical axis of the eye. Because of the shape of the cornea, the beams have in some areas considerable inclination to the corneal surface which is accompanied by low signal intensities in these areas and thus an inhomogeneous appearance of corneal structures. In addition, alterations in the polarization state of the probing light depend on the angle between the imaging beam and the birefringent axis of the sample. Therefore, changes in the polarization state observed with polarization-sensitive (PS-) OCT originate mainly from the shape of the cornea. In order to minimize the effects of the corneal shape on intensity and polarization-sensitive based data, we developed a conical scanning optics design. This design provides imaging beams that are essentially orthogonal to the corneal surface. Thus, high signal intensity throughout the entire imaged volume is obtained and the influence of the corneal shape on polarization-sensitive data is greatly reduced. We demonstrate the benefit of the concept by comparing PS-OCT imaging results of the human cornea in healthy volunteers using both scanning schemes. PMID- 28663916 TI - Degradation of silicon photonic biosensors in cell culture media: analysis and prevention. AB - Silicon photonic biosensors are being widely researched as they combine high performance with the potential for low-cost mass-manufacturing. Sensing is typically performed in an aqueous environment and it is assumed that the sensor is chemically stable, as silicon is known to etch in strong alkaline solutions but not in liquids with a pH close to 7. Here, we show that silicon can be affected surprisingly strongly by typical cell culture media, and we observe etch rates of up to 2 nm/hour. We then demonstrate that a very thin (< 10 nm) layer of thermal oxide is sufficient to suppress the etching process and provide the long term stability required for monitoring cells and related biological processes over extended periods of time. We also show that employing an additional pH buffering compound in the culture medium can significantly reduce the etch rate. PMID- 28663917 TI - Use of a handheld terahertz pulsed imaging device to differentiate benign and malignant breast tissue. AB - Since nearly 20% of breast-conserving surgeries (BCS) require re-operation, there is a clear need for developing new techniques to more accurately assess tumor resection margins intraoperatively. This study evaluates the diagnostic accuracy of a handheld terahertz pulsed imaging (TPI) system to discriminate benign from malignant breast tissue ex vivo. Forty six freshly excised breast cancer samples were scanned with a TPI handheld probe system, and histology was obtained for comparison. The image pixels on TPI were classified using (1) parameters in combination with support vector machine (SVM) and (2) Gaussian wavelet deconvolution in combination with Bayesian classification. The results were an accuracy, sensitivity, specificity of 75%, 86%, 66% for method 1, and 69%, 87%, 54% for method 2 respectively. This demonstrates the probe can discriminate invasive breast cancer from benign breast tissue with an encouraging degree of accuracy, warranting further study. PMID- 28663918 TI - Optical detection and monitoring of pigmented skin lesions. AB - A method is presented for discriminating between malignant and benign pigmented skin lesions based on multispectral and multi-angle images. It is discussed how to retrieve maps of physiology properties and morphometric parameters from recorded images using a bio-optical model, radiative transfer calculations, and nonlinear inversion, and how to employ automated zooming to extract lesion and surrounding masks. Training and validation of a classification scheme for separation between benign and malignant tissue yielded sensitivity/specificity ranging from 97%/97% for application to a small dataset comprised of lesions not used for training and validation to 99%/93% for application to a larger dataset. PMID- 28663919 TI - Photothermal imaging of skeletal muscle mitochondria. AB - The morphology and topology of mitochondria provide useful information about the physiological function of skeletal muscle. Previous studies of skeletal muscle mitochondria are based on observation with transmission, scanning electron microscopy or fluorescence microscopy. In contrast, photothermal (PT) microscopy has advantages over the above commonly used microscopic techniques because of no requirement for complex sample preparation by fixation or fluorescent-dye staining. Here, we employed the PT technique using a simple diode laser to visualize skeletal muscle mitochondria in unstained and stained tissues. The fine mitochondrial network structures in muscle fibers could be imaged with the PT imaging system, even in unstained tissues. PT imaging of tissues stained with toluidine blue revealed the structures of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria and the swelling behavior of mitochondria in damaged muscle fibers with sufficient image quality. PT image analyses based on fast Fourier transform (FFT) and Grey-level co-occurrence matrix (GLCM) were performed to derive the characteristic size of mitochondria and to discriminate the image patterns of normal and damaged fibers. PMID- 28663920 TI - Quantitative interferometric reflectance imaging for the detection and measurement of biological nanoparticles. AB - The sensitive detection and quantitative measurement of biological nanoparticles such as viruses or exosomes is of growing importance in biology and medicine since these structures are implicated in many biological processes and diseases. Interferometric reflectance imaging is a label-free optical biosensing method which can directly detect individual biological nanoparticles when they are immobilized onto a protein microarray. Previous efforts to infer bio-nanoparticle size and shape have relied on empirical calibration using a 'ruler' of particle samples of known size, which was inconsistent and qualitative. Here, we present a mechanistic physical explanation and experimental approach by which interferometric reflectance imaging may be used to not only detect but also quantitatively measure bio-nanoparticle size and shape. We introduce a comprehensive optical model that can quantitatively simulate the scattering of arbitrarily-shaped nanoparticles such as rod-shaped or filamentous virions. Finally, we optimize the optical design for the detection and quantitative measurement of small and low-index bio-nanoparticles immersed in water. PMID- 28663921 TI - Depth sensitivity of frequency domain optical measurements in diffusive media. AB - The depth sensitivity functions for AC amplitude, phase (PH) and DC intensity signals have been obtained in the frequency domain (where the source amplitude is modulated at radio-frequencies) by making use of analytical solutions of the photon diffusion equation in an infinite slab geometry. Furthermore, solutions for the relative contrast of AC, PH and DC signals when a totally absorbing plane is placed at a fixed depth of the slab have also been obtained. The solutions have been validated by comparisons with gold standard Monte Carlo simulations. The obtained results show that the AC signal, for modulation frequencies < 200 MHz, has a depth sensitivity with similar characteristics to that of the continuous-wave (CW) domain (source modulation frequency of zero). Thus, the depth probed by such a signal can be estimated by using the formula of penetration depth for the CW domain (Sci. Rep.6, 27057 (2016)). However, the PH signal has a different behavior compared to the CW domain, showing a larger depth sensitivity at shallow depths and a less steep relative contrast as a function of depth. These results mark a clear difference in term of depth sensitivity between AC and PH signals, and highlight the complexity of the estimation of the actual depth probed in tissue spectroscopy. PMID- 28663922 TI - Line-scanning hyperspectral imaging based on structured illumination optical sectioning. AB - Line-scanning hyperspectral imaging (LHSI) is known to have a higher acquisition rate but lower sectioning capability than point-scanning hyperspectral imaging. To further increase the axial imaging contrast of LHSI, structured illumination was integrated into line excitation to remove the off-focus and scattered on focus fluorescence signals. In an unsectioned leaf, the imaging contrast can be enhanced by 8 times, while in sectioned mouse skin tissues, a 4.5-fold enhancement can be achieved. With a spectral resolution of 1.15 nm, the fluorophores with seriously-overlapped spectra was proved to be separated without cross-talk by applying linear unmixing to the recorded spectral information. PMID- 28663923 TI - Spectral-spatial feature-based neural network method for acute lymphoblastic leukemia cell identification via microscopic hyperspectral imaging technology. AB - Microscopic examination is one of the most common methods for acute lymphoblastic leukemia (ALL) diagnosis. Most traditional methods of automized blood cell identification are based on RGB color or gray images captured by light microscopes. This paper presents an identification method combining both spectral and spatial features to identify lymphoblasts from lymphocytes in hyperspectral images. Normalization and encoding method is applied for spectral feature extraction and the support vector machine-recursive feature elimination (SVM-RFE) algorithm is presented for spatial feature determination. A marker-based learning vector quantization (MLVQ) neural network is proposed to perform identification with the integrated features. Experimental results show that this algorithm yields identification accuracy, sensitivity, and specificity of 92.9%, 93.3%, and 92.5%, respectively. Hyperspectral microscopic blood imaging combined with neural network identification technique has the potential to provide a feasible tool for ALL pre-diagnosis. PMID- 28663924 TI - Simulation and analysis of light scattering by multilamellar bodies present in the human eye. AB - A modified computational model of the human eye was used to obtain and compare different probability density functions, radial profiles of light pattern distributions, and images of the point spread function formed in the human retina under the presence of different kinds of particles inside crystalline lenses suffering from cataracts. Specifically, this work uses simple particles without shells and multilamellar bodies (MLBs) with shells. The emergence of such particles alters the formation of images on the retina. Moreover, the MLBs change over time, which affects properties such as the refractive index of their shell. Hence, this work not only simulates the presence of such particles but also evaluates the incidence of particle parameters such as particle diameter, particle thickness, and shell refractive index, which are set based on reported experimental values. In addition, two wavelengths (400 nm and 700 nm) are used for light passing through the different layers of the computational model. The effects of these parameters on light scattering are analyzed using the simulation results. Further, in these results, the effects of light scattering on image formation can be seen when single particles, early-stage MLBs, or mature MLBs are incorporated in the model. Finally, it is found that particle diameter has the greatest impact on image formation. PMID- 28663925 TI - Noninvasive mesoscopic imaging of actinic skin damage using spatial frequency domain imaging. AB - For prevention and accurate intervention planning, it is crucial to predict if lesions will progress towards cancer. In this study, we investigated the change in optical properties and vascular parameters to characterize skin tissue from mild photodamage to actinic keratosis (AK). Multi-wavelength spatial frequency domain imaging (SFDI) measurements were performed on three patients with clinically normal skin, as well as pre-cancerous actinic keratosis lesions. Our results indicate that there exist significant differences in both optical and vascular parameters between these patients, and that these parameters can be early biomarkers of neoplasia. Ultimately, clinicians can use this noninvasive approach for frequent monitoring of high-risk population. PMID- 28663926 TI - Regression-based algorithm for bulk motion subtraction in optical coherence tomography angiography. AB - We developed an algorithm to remove decorrelation noise due to bulk motion in optical coherence tomography angiography (OCTA) of the posterior eye. In this algorithm, OCTA B-frames were divided into segments within which the bulk motion velocity could be assumed to be constant. This velocity was recovered using linear regression of decorrelation versus the logarithm of reflectance in axial lines (A-lines) identified as bulk tissue by percentile analysis. The fitting parameters were used to calculate a reflectance-adjusted upper bound threshold for bulk motion decorrelation. Below this threshold, voxels are identified as non flow tissue, their flow values are set to zeros. Above this threshold, the voxels are identified as flow voxels and bulk motion velocity is subtracted from each using a nonlinear decorrelation-velocity relationship previously established in laboratory flow phantoms. Compared to the simpler median-subtraction method, the regression-based bulk motion subtraction improved angiogram signal-to-noise ratio, contrast, vessel density repeatability, and bulk motion noise cleanup in the foveal avascular zone, while preserving the connectivity of the vascular networks in the angiogram. PMID- 28663927 TI - Detection of local tissue alteration during retinal laser photocoagulation of ex vivo porcine eyes using phase-resolved optical coherence tomography. AB - Retinal laser photocoagulation is used to treat several ophthalmic diseases. However, it is associated with damage to surrounding healthy tissue. Local tissue alteration during coagulation laser illumination was measured using phase resolved optical coherence tomography (OCT) M-mode scan as a change in the local optical path length (LOPL). A metric that represents global net tissue alteration was defined using the LOPL change. The visibility of a laser lesion was assessed by three-dimensional OCT volume measurement. Multiple logistic regression analysis was performed to investigate the association between the introduced metric and the laser lesion visibility. The metric was found to be a statistically significant predictor of the laser lesion visibility independent to laser condition. The proposed method based on an LOPL change is thus promising for retinal photocoagulation monitoring. PMID- 28663928 TI - Unsupervised identification of cone photoreceptors in non-confocal adaptive optics scanning light ophthalmoscope images. AB - Precise measurements of photoreceptor numerosity and spatial arrangement are promising biomarkers for the early detection of retinal pathologies and may be valuable in the evaluation of retinal therapies. Adaptive optics scanning light ophthalmoscopy (AOSLO) is a method of imaging that corrects for aberrations of the eye to acquire high-resolution images that reveal the photoreceptor mosaic. These images are typically graded manually by experienced observers, obviating the robust, large-scale use of the technology. This paper addresses unsupervised automated detection of cones in non-confocal, split-detection AOSLO images. Our algorithm leverages the appearance of split-detection images to create a cone model that is used for classification. Results show that it compares favorably to the state-of-the-art, both for images of healthy retinas and for images from patients affected by Stargardt disease. The algorithm presented also compares well to manual annotation while excelling in speed. PMID- 28663929 TI - Noninvasive depth estimation using tissue optical properties and a dual wavelength fluorescent molecular probe in vivo. AB - Translation of fluorescence imaging using molecularly targeted imaging agents for real-time assessment of surgical margins in the operating room requires a fast and reliable method to predict tumor depth from planar optical imaging. Here, we developed a dual-wavelength fluorescent molecular probe with distinct visible and near-infrared excitation and emission spectra for depth estimation in mice and a method to predict the optical properties of the imaging medium such that the technique is applicable to a range of medium types. Imaging was conducted at two wavelengths in a simulated blood vessel and an in vivo tumor model. Although the depth estimation method was insensitive to changes in the molecular probe concentration, it was responsive to the optical parameters of the medium. Results of the intra-tumor fluorescent probe injection showed that the average measured tumor sub-surface depths were 1.31 +/- 0.442 mm, 1.07 +/- 0.187 mm, and 1.42 +/- 0.182 mm, and the average estimated sub-surface depths were 0.97 +/- 0.308 mm, 1.11 +/- 0.428 mm, 1.21 +/- 0.492 mm, respectively. Intravenous injection of the molecular probe allowed for selective tumor accumulation, with measured tumor sub surface depths of 1.28 +/- 0.168 mm, and 1.50 +/- 0.394 mm, and the estimated depths were 1.46 +/- 0.314 mm, and 1.60 +/- 0.409 mm, respectively. Expansion of our technique by using material optical properties and mouse skin optical parameters to estimate the sub-surface depth of a tumor demonstrated an agreement between measured and estimated depth within 0.38 mm and 0.63 mm for intra-tumor and intravenous dye injections, respectively. Our results demonstrate the feasibility of dual-wavelength imaging for determining the depth of blood vessels and characterizing the sub-surface depth of tumors in vivo. PMID- 28663930 TI - Looking inside the heart: a see-through view of the vascular tree. AB - The ability to acquire 3D images of the heart and its vasculature at cellular resolution facilitates a more detailed study of many heart diseases. Here, we describe a novel technique to image in 3D the heart vasculature by combining the CUBIC clearing protocol combined with in vivo administration of fluorescent labeled lectin. The use of these techniques in combination with Selective Plane Illumination Microscopy (SPIM) made it possible to obtain high resolution 3D images of the cardiac vascular tree. This methodological approach may enhance the visualization of 3D images of the cardiac vasculature remodeling associated with coronary disease. PMID- 28663931 TI - Development of bimolecular fluorescence complementation using rsEGFP2 for detection and super-resolution imaging of protein-protein interactions in live cells. AB - Direct visualization of protein-protein interactions (PPIs) at high spatial and temporal resolution in live cells is crucial for understanding the intricate and dynamic behaviors of signaling protein complexes. Recently, bimolecular fluorescence complementation (BiFC) assays have been combined with super resolution imaging techniques including PALM and SOFI to visualize PPIs at the nanometer spatial resolution. RESOLFT nanoscopy has been proven as a powerful live-cell super-resolution imaging technique. With regard to the detection and visualization of PPIs in live cells with high temporal and spatial resolution, here we developed a BiFC assay using split rsEGFP2, a highly photostable and reversibly photoswitchable fluorescent protein previously developed for RESOLFT nanoscopy. Combined with parallelized RESOLFT microscopy, we demonstrated the high spatiotemporal resolving capability of a rsEGFP2-based BiFC assay by detecting and visualizing specifically the heterodimerization interactions between Bcl-xL and Bak as well as the dynamics of the complex on mitochondria membrane in live cells. PMID- 28663932 TI - ENHANCING COMMUNITY HEALTH BY IMPROVING PHYSICIAN PARTICIPATION. AB - Leading medical associations have called for renewed standards of medical professionalism, including stronger public advocacy, a commitment to social justice in health care, and greater community engagement. New strategies are needed to enhance community participation among physicians, which can improve public trust in the medical profession and contribute needed expertise and teamwork to matters of community health. One strategy is to incorporate community participation and leadership in medical training through community-based organization (CBO) placement of residents. We describe a model CBO placement program within a family medicine residency in Harlem, New York City. This program enables residents to partner with organizations that address social, political, economic, and environmental determinants of health in underserved populations, and to assume leadership roles in community health activities. Broader implementation of this model in other settings, both urban and rural, can enhance community participation by physicians within a sustainable framework, and promote medical professionalism and community health. PMID- 28663933 TI - Pathological game use in adults with and without Autism Spectrum Disorder. AB - This study tested whether adults with autism spectrum disorder (ASD) are at higher risk for pathological game use than typically developing (TD) adults. Participants included 119 adults with and without ASD. Participants completed measures assessing daily hours of video game use, percent of free time spent playing video games, and symptoms of pathological game use. The results indicated that adults with ASD endorsed more symptoms of video game pathology than did TD adults. This relationship was strong, enjoying 300,000-to-1 odds in Bayesian model comparison. Results also showed that adults with ASD spent more daily hours playing video games and spent a higher percent of their free time playing video games than did TD adults. Even after adjustment for these differences in daily video game hours and proportion of free time spent on games, model comparisons found evidence for a difference in game pathology scores associated with ASD status. Additionally, escapism motives for playing video games was associated with game pathology scores in both ASD and TD adults, replicating and extending a previous report. In conclusion, the risk for pathological game use appears larger in adults with ASD compared with TD adults. These findings point to pathological game use as a potentially important focus of clinical attention in adults with ASD. PMID- 28663934 TI - Effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta analysis. AB - AIM: To evaluate the effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes. METHODS: We conducted systematic searches of PubMed, Embase and Cochrane Central Register of Controlled Trials up to June 2016 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetic patients reporting estimated glomerular filtration rate (eGFR) and/or urine albumin/creatinine ratio (ACR) changes. Data were synthesized using the random-effects model. RESULTS: Forty seven studies with 22,843 participants were included. SGLT2 inhibition was not associated with a significant change in eGFR in general (weighted mean difference (WMD), -0.33 ml/min per 1.73 m2, 95% CI [-0.90 to 0.23]) or in patients with chronic kidney disease (CKD) (WMD -0.78 ml/min per 1.73 m2, 95% CI [-2.52 to 0.97]). SGLT2 inhibition was associated with eGFR reduction in short-term trials (WMD -0.98 ml/min per 1.73 m2, 95% CI [-1.42 to -0.54]), and with eGFR preservation in long-term trials (WMD 2.01 ml/min per 1.73 m2, 95% CI [0.86 to 3.16]). Urine ACR reduction after SGLT2 inhibition was not statistically significant in type 2 diabetic patients in general (WMD -7.24 mg/g, 95% CI [ 15.54 to 1.06]), but was significant in patients with CKD (WMD -107.35 mg/g, 95% CI [-192.53 to -22.18]). CONCLUSIONS: SGLT2 inhibition was not associated with significant changes in eGFR in patients with type 2 diabetes, likely resulting from a mixture of an initial reduction of eGFR and long-term renal function preservation. SGLT2 inhibition was associated with statistically significant albuminuria reduction in type 2 diabetic patients with CKD. PMID- 28663935 TI - Differential gene expression analysis by RNA-seq reveals the importance of actin cytoskeletal proteins in erythroleukemia cells. AB - Development of drug resistance limits the effectiveness of anticancer treatments. Understanding the molecular mechanisms triggering this event in tumor cells may lead to improved therapeutic strategies. Here we used RNA-seq to compare the transcriptomes of a murine erythroleukemia cell line (MEL) and a derived cell line with induced resistance to differentiation (MEL-R). RNA-seq analysis identified a total of 596 genes (Benjamini-Hochberg adjusted p-value < 0.05) that were differentially expressed by more than two-fold, of which 81.5% (486/596) of genes were up-regulated in MEL cells and 110 up-regulated in MEL-R cells. These observations revealed that for some genes the relative expression of mRNA amount in the MEL cell line has decreased as the cells acquired the resistant phenotype. Clustering analysis of a group of genes showing the highest differential expression allowed identification of a sub-group among genes up-regulated in MEL cells. These genes are related to the organization of the actin cytoskeleton network. Moreover, the majority of these genes are preferentially expressed in the hematopoietic lineage and at least three of them, Was (Wiskott Aldrich syndrome), Btk (Bruton's tyrosine kinase) and Rac2, when mutated in humans, give rise to severe hematopoietic deficiencies. Among the group of genes that were up regulated in MEL-R cells, 16% of genes code for histone proteins, both canonical and variants. A potential implication of these results on the blockade of differentiation in resistant cells is discussed. PMID- 28663936 TI - Revision of "Balaena" belgica reveals a new right whale species, the possible ancestry of the northern right whale, Eubalaena glacialis, and the ages of divergence for the living right whale species. AB - In 1941, Abel established Balaena belgica based on a series of fused cervical vertebrae and citing other cranial fragments from the late Neogene of the Antwerp harbor (northern Belgium). Later, Plisnier-Ladame & Quinet (1969) added a neurocranium and other skeletal remains from the same area to this species. Recently, the neurocranium was re-assigned to the genus Eubalaena thanks to newer phylogenetic analyses. Here, a new description is provided of materials previously assigned to "Balaena" belgica together with taxonomic revisions. Our work suggests that the cervical complex originally designated as the type of "Balaena" belgica is too poorly preserved to be used as such and is assigned to Balaenidae gen. et sp. indet., thus making "Balaena" belgica a nomen dubium. In addition to the neurocranium, the other remains consist in a fragment of maxilla assigned to Balaenidae gen. et sp. indet. and in a humerus assigned to Eubalaena sp. Discovered in the Kruisschans Sands Member of the Lillo Formation (3.2-2.8 Ma, Piacenzian, Late Pliocene), the neurocranium is designated as the holotype of the new species Eubalaena ianitrix. Our phylogenetic analysis supports a sister group relationship of Eubalaena ianitrix and Eubalaena glacialis, and helps constraining the ages of origin for balaenid clades. Ecological and phylogenetic data suggest that Eubalaena ianitrix may represent the direct ancestor of Eubalaena glacialis, the latter having evolved through phyletic transformation including body size increase during the temperature decline of the Late Pliocene. PMID- 28663937 TI - LuxS-dependent AI-2 production is not involved in global regulation of natural product biosynthesis in Photorhabdus and Xenorhabdus. AB - The Gram-negative bacteria Photorhabdus and Xenorhabdus are known to produce a variety of different natural products (NP). These compounds play different roles since the bacteria live in symbiosis with nematodes and are pathogenic to insect larvae in the soil. Thus, a fine tuned regulatory system controlling NP biosynthesis is indispensable. Global regulators such as Hfq, Lrp, LeuO and HexA have been shown to influence NP production of Photorhabdus and Xenorhabdus. Additionally, photopyrones as quorum sensing (QS) signals were demonstrated to be involved in the regulation of NP production in Photorhabdus. In this study, we investigated the role of another possible QS signal, autoinducer-2 (AI-2), in regulation of NP production. The AI-2 synthase (LuxS) is widely distributed within the bacterial kingdom and has a dual role as a part of the activated methyl cycle pathway, as well as being responsible for AI-2 precursor production. We deleted luxS in three different entomopathogenic bacteria and compared NP levels in the mutant strains to the wild type (WT) but observed no difference to the WT strains. Furthermore, the absence of the small regulatory RNA micA, which is encoded directly upstream of luxS, did not influence NP levels. Phenotypic differences between the P. luminescens luxS deletion mutant and an earlier described luxS deficient strain of P. luminescens suggested that two phenotypically different strains have evolved in different laboratories. PMID- 28663938 TI - Microplasma-assisted hydrogel fabrication: A novel method for gelatin-graphene oxide nano composite hydrogel synthesis for biomedical application. AB - Toxicity issues and biocompatibility concerns with traditional classical chemical cross-linking processes prevent them from being universal approaches for hydrogel fabrication for tissue engineering. Physical cross-linking methods are non-toxic and widely used to obtain cross-linked polymers in a tunable manner. Therefore, in the current study, argon micro-plasma was introduced as a neutral energy source for cross-linking in fabrication of the desired gelatin-graphene oxide (gel-GO) nanocomposite hydrogel scaffolds. Argon microplasma was used to treat purified gelatin (8% w/v) containing 0.1~1 wt% of high-functionality nano graphene oxide (GO). Optimized plasma conditions (2,500 V and 8.7 mA) for 15 min with a gas flow rate of 100 standard cm3/min was found to be most suitable for producing the gel-GO nanocomposite hydrogels. The developed hydrogel was characterized by the degree of cross-linking, FTIR spectroscopy, SEM, confocal microscopy, swelling behavior, contact angle measurement, and rheology. The cell viability was examined by an MTT assay and a live/dead assay. The pore size of the hydrogel was found to be 287 +/- 27 um with a contact angle of 78 degrees +/ 3.7 degrees . Rheological data revealed improved storage as well as a loss modulus of up to 50% with tunable viscoelasticity, gel strength, and mechanical properties at 37 degrees C temperature in the microplasma-treated groups. The swelling behavior demonstrated a better water-holding capacity of the gel-GO hydrogels for cell growth and proliferation. Results of the MTT assay, microscopy, and live/dead assay exhibited better cell viability at 1% (w/w) of high-functionality GO in gelatin. The highlight of the present study is the first successful attempt of microplasma-assisted gelatin-GO nano composite hydrogel fabrication that offers great promise and optimism for further biomedical tissue engineering applications. PMID- 28663939 TI - Penetrance of symbiont-mediated parthenogenesis is driven by reproductive rate in a parasitoid wasp. AB - Trichogramma wasps are tiny parasitoids of lepidopteran eggs, used extensively for biological control. They are often infected with the bacterial symbiont Wolbachia, which converts Trichogramma to an asexual mode of reproduction, whereby females develop from unfertilized eggs. However, this Wolbachia-induced parthenogenesis is not always complete, and previous studies have noted that infected females will produce occasional males in the lab. The conditions that reduce penetrance of the parthenogenesis phenotype are not well understood. We hypothesized that more ecologically relevant conditions of limited host access will sustain female-biased sex ratios. After restricting access to host eggs, we found a strong relationship between reproductive rate and sex ratio. By limiting reproduction to one hour a day, wasps could sustain up to 100% effective parthenogenesis for one week, with no significant impact on total fecundity. Reproductive output in the first 24-hours appears to be critical to the total sex ratio of the entire brood. Limiting oviposition in that period resulted in more effective parthenogenesis after one week, again without any significant impact on total fecundity. Our data suggest that this phenomenon may be due to the depletion of Wolbachia when oviposition occurs continuously, whereas Wolbachia titers may recover when offspring production is limited. In addition to the potential to improve mass rearing of Trichogramma for biological control, findings from this study help elucidate the context-dependent nature of a pervasive symbiotic relationship. PMID- 28663940 TI - Considerations for Use of Investigational Drugs in Public Health Emergencies. AB - The paradigm for the use of investigational drugs in public health emergencies has been recently tested to prevent and treat highly infectious and lethal diseases. Examples include the successful implementation of vaccine and therapeutic clinical trials during the recent Ebola outbreak in West Africa. On the other end of the spectrum was the Emergency Use Authorization (EUA) of peramivir in the treatment of H1N1 influenza virus that did not provide an opportunity to collect data or understand the effectiveness of the EUA program. Between the gold standard of a randomized controlled clinical trial and the problems associated with EUAs are the domain of expanded access protocols that may provide an avenue to make products available while awaiting licensure. This paper will examine the regulatory pathways in the United States (US) for the use of investigational drugs in a public health emergency as well as considerations when making these products available outside the US. Descriptions of the applications of the various approaches will be presented. Regardless of the pathway chosen, public health and clinical research planners need to work together to consider several factors associated with the respective options and maintain a goal of working toward the collection of data to support licensure before faced with future outbreaks. Finally, this paper will consider the lessons learned from public health response in the context of investigational drugs in other diseases where "right to try laws" may pose opportunities, as well as challenges. PMID- 28663941 TI - Small Bowel Volvulus: A Case Report. AB - Small bowel volvulus is a rare clinical entity which presents as recurrent intermittent abdominal pain after consumption of food. Although the entity is well described in the literature, diagnosis is often difficult due to its clinical presentation being similar to mesenteric ischemia. Herein we present the case of a 44-year-old male who presented to us with this condition. PMID- 28663942 TI - Recurrence of a Refractory Chronic Subdural Hematoma after Middle Meningeal Artery Embolization That Required Craniotomy. AB - Middle meningeal artery (MMA) embolization has been performed to treat refractory chronic subdural hematoma (CSDH) with good reported outcomes. We have treated three cases of CSDH with MMA embolization to date, but there was a postoperative recurrence in one patient, which required a craniotomy for hematoma removal and capsulectomy. MMA embolization blocks the blood supply from the dura to the hematoma outer membrane in order to prevent recurrences of refractory CSDH. Histopathologic examination of the outer membrane of the hematoma excised during craniotomy showed foreign-body giant cells and neovascular proliferation associated with embolization. Because part of the hematoma was organized in this case, the CSDH did not resolve when the MMA was occluded, and the development of new collateral pathways in the hematoma outer membrane probably contributed to the recurrence. Therefore, in CSDH with some organized hematoma, MMA embolization may not be effective. Magnetic resonance imaging (MRI) should be performed in these patients before embolization. PMID- 28663943 TI - Endovascular Repair of a Middle Meningeal Artery Aneurysm after Cranial Surgery. AB - This report describes a case of middle meningeal artery aneurysm caused after cranial surgery. A 55-year-old woman who experienced a ruptured internal carotid artery anterior wall aneurysm was treated by internal carotid artery trapping and high-flow bypass using a radial artery graft. Eight days after surgery, we performed cerebral angiography to confirm patency of the radial artery graft and discovered a middle meningeal artery aneurysm, which was not identified in preoperative angiography. The aneurysm was treated by endovascular embolization using n-butyl cyanoacrylate and complete obliteration was confirmed by angiography. This middle meningeal artery aneurysm was associated with prior surgical procedures, particularly craniotomy or dural tenting sutures. Our study suggests that middle meningeal artery aneurysms can be a rare complication associated with brain surgery. Endovascular embolization using a liquid material may provide an effective and safe treatment for such cases. PMID- 28663944 TI - Pathological Considerations for Unruptured Dissecting Aneurysm in the Posterior Inferior Cerebellar Artery: Case Report. AB - Because of the wide spread of magnetic resonance image (MRI), it may be increasing to find a dissecting aneurysm (DA) of the posterior inferior cerebellar artery (PICA) that causes headache without associated hemorrhage or infarction. Generally, surgical treatment might be considered in cases of DA with hemorrhage. However, the treatment of an unruptured DA with headache or infarction has not been well established. This is the first report regarding the pathology of an intact DA of the PICA that presents with headache only, and the pathological findings showed interesting figures. A 44-year-old man with an unruptured DA of the left PICA presented with sudden left occipital headache. MRI revealed no hemorrhage or infarction. Magnetic resonance angiography (MRA) showed growth of the DA 12 days after the onset of headache. Therefore, surgery was performed to prevent aneurysmal rupture. This DA aneurysm was trapped and removed after an occipital artery (OA)-PICA anastomosis was performed. The surgery was performed without complication. Pathological findings showed folding of the internal elastic lamina, and the true lumen was torn by the false lumen. The dissection reached the adventitia and the wall had numerous macrophages. Pathological findings might help understanding the etiology of DAs and inflammation might play an important role in DAs. PMID- 28663945 TI - Dissecting Aneurysm at the Proximal Segment of the Anterior Cerebral Artery Associated with Infraoptic Course Anterior Cerebral Artery. AB - A 48-year-old man presented a subarachnoid hemorrhage caused by a rupture of a dissecting aneurysm at the proximal segment (A1 segment) of the right anterior cerebral artery (ACA). He also had an anomalous artery named infraoptic course ACA and an agenesis of the contralateral ACA A1 segment. Balloon occlusion test at the bifurcation of the right internal carotid artery demonstrated that the distal segments of the bilateral ACAs were perfused through the infraoptic course ACA. Therefore, we surgically trapped the A1 segment including the aneurysm. The patient got discharged without any neurological deficit. Natural course of ACA dissecting aneurysms is unclear because of rarity of the disease and treatment strategy is still controversial. Most of the dissecting aneurysms in the A1 segment are surgically treated, because they often present with massive hemorrhage and poor prognosis. In the present case, the contralateral A1 segment was absent but trapping of the dissecting aneurysm could be achieved without vascular reconstruction (e.g., bypass surgery) because of the presence of the infraoptic course ACA. PMID- 28663946 TI - A Case Involving Needles in the Medulla Oblongata, Cervical Spinal Cord, and Abdomen. AB - It is extremely rare to encounter intracranial foreign bodies caused by penetrating injuries other than gunshot wounds or low-velocity wounds. We present a case describing a 5-year-old girl with metallic foreign bodies in the medulla oblongata, cervical spinal cord, and abdomen. The foreign bodies may have been there and remained silent for several years until the patient developed nausea and vomiting that persisted for 3 months. A craniotomy and a laparotomy were performed after a thorough discussion. Five pieces of metallic foreign bodies were removed, and the patient had a good outcome. Despite the precarious location of the needles in the medulla oblongata and cervical spinal cord, this rare case supports the use of surgery to remove the foreign bodies. PMID- 28663947 TI - Effect of the Intrathecal Baclofen Screening Test on the Spatiotemporal Gait Motion Parameters of Patients with Cervical Spinal Cord Injuries Who Exhibited Diffuse Spasticity: A Report of Three Cases. AB - We examine the quantitative changes in the gait motion of patients with cervical spinal cord injuries (CSCIs) before and after the intrathecal baclofen (ITB) screening test. The subjects were three patients with CSCI, who exhibited spasticity in the lower extremities. They could all walk 10 or more meters with/without aids. All patients were subjected to the ITB screening test, in which they had gabalon (50 MUg) injected into their spinal column via paramedian puncture at the L3-4 level. The subjects had their ankle clonus; patellar tendon reflex; and modified Ashworth scale, Berg balance scale, Spinal Cord Independence Measure, and 10 -meter walk test (10MWT) assessed before and 5 hours after the ITB screening test. At 5 hours after the ITB screening test, all of the patients exhibited decreased spasticity in static position, and improved balance. There were no differences in the abilities of any of the patients to perform ADL. One patient did not change the spatiotemporal gait motion parameters (walking time, step count, and step length in the 10MW T). Therefore, the pomp implantation for ITB therapy was not performed. Two patients who had suffered CSCI more than 20 years ago exhibited a reduced walking time, increased step count, and step length. Out of the two patients one received the pomp of implantation after ITB screening test, and the other was planned to operate. The spatiotemporal gait motion parameters might be one of the useful tests to decide the pomp implantation for CSCI patients who hope improvement of gait ability. PMID- 28663949 TI - Primary Central Nervous System Lymphoma of the Cerebellopontine Angle That Initially Occurred as Neurolymphomatosis of the Acoustic Nerve. AB - We report a rare case of a primary central nervous system lymphoma (PCNSL) of the cerebellopontine angle (CPA) with infiltration into the pyramidal tract that initially presented as neurolymphomatosis (NL) of the acoustic nerve. A 60-year old male suffered from right-side deafness and was referred to an otolaryngologist. Magnetic resonance imaging (MRI) showed fusiform enlargement of the right acoustic nerve with a hyperintense signal on a T2-weighted image (T2WI) and with gadolinium (Gd) enhancement, without an evidence of parenchymal CNS involvement. Although he was treated with steroids, his symptoms deteriorated. MRI was performed again and showed the mass lesion at the right CPA with enhancement. In addition to this, a lesion with slightly high intensity on a T2WI with Gd enhancement was observed along the right pyramidal tract. Despite steroid pulse therapy, the lesion rapidly progressed. We performed a tumor biopsy, and the histological diagnosis was diffuse large B-cell lymphoma. Pelvic, abdominal, and chest computed tomography scans, gallium cintigraphy, and bone marrow biopsy failed to detect any other evidence of lymphomatous involvement of other organs. We attempted high-dose methotrexate therapy (3.5 g/m2). We found a discrepancy in the therapeutic effect between the CPA lesion and the infiltrated lesion along the pyramidal tract; the lesions were chemo-resistant and chemo-sensitive, respectively. After completion of the second courses of chemotherapy, we began radiotherapy (total dose: 36 Gy). Four months after radiotherapy, the CPA tumor completely disappeared. Thirty-three months after the biopsy, he is doing well with a normal daily life and no signs of recurrence. PMID- 28663948 TI - Incidental Detection of Primary Spinal Malignant Melanoma before Central Nervous System Dissemination. AB - The present case illustrates the incidental detection of a primary malignant melanoma of the thoracic spinal cord before central nervous system dissemination. A 54-year-old female fell down and bruised the thoracolumbar region. The patient visited a local doctor and underwent magnetic resonance imaging (MRI) of the thoracic and lumbar spine to rule out vertebral fractures. MRI revealed no vertebral fracture, but an intradural extramedullary mass was observed at the T12 level. She was referred to our hospital in October 2008. MRI showed that the mass appeared hyperintense on T1-weighted images and hypointense on T2-weighted images. T1-weighted MRI with gadolinium showed a mild homogeneous enhancement of the lesion. The patient underwent laminectomy at T11-L1, along with the complete removal of the tumor, and she exhibited no remarkable symptoms after surgery. Histopathological examination confirmed the diagnosis of malignant melanoma. Malignant melanoma was not detected elsewhere in the body. Neither radiotherapy nor chemotherapy was performed after surgery. Her neurological examination was unremarkable 5 years after the surgery and no tumor recurrence was detected. The present case suggests that patients with primary spinal malignant melanoma may survive >5 years without recurrence after complete surgical removal of the tumor alone. Complete removal of the tumor before central nervous system dissemination may be critical for treatment in such cases. Precise diagnosis via MRI may increase the detection of primary spinal malignant melanoma before central nervous system dissemination, thus facilitating prompt surgical removal, improving the prognosis of patients. PMID- 28663950 TI - Isolated Pituitary Tuberculoma. AB - Pituitary tuberculomas are extremely rare, even in the developing countries where tuberculosis is endemic. We report a rare case of isolated pituitary tuberculoma mimicking a pituitary adenoma or a Rathke's cleft cyst in Japan, a developed country. The patient was a 69-year-old woman presented with visual disturbance. Head magnetic resonance imaging (MRI) with contrast enhancement revealed an isolated intrasellar mass showing central hypointensity with an irregularly enhancing rim. She was operated on via an endoscopic transsphenoidal approach. Histopathological findings and an interferon-gamma release assay were highly suspicious of an isolated tuberculous granuloma. After proper infection control management, she was treated with four-drug antituberculous therapy (ATT). Follow up MRI showed no recurrence 3 years after the discontinuation of ATT. An isolated pituitary tuberculoma has rarely been reported, especially in developed countries. In conclusion, neurosurgeons should consider an isolated pituitary tuberculoma as one of the differential diagnoses for pituitary tumors, because special management for infection control is required for tuberculosis. An interferon-gamma release assay is helpful for the difficult diagnosis of an isolated pituitary tuberculoma with inactive tuberculosis. PMID- 28663951 TI - Delayed Massive Traumatic Hematoma in the Corpus Callosum: Two Case Reports with Literature Review. AB - A delayed massive traumatic hematoma in the corpus callosum is extremely rare. We report two cases with a delayed massive callosal hematoma caused by blunt head trauma. A massive callosal hematoma was diagnosed by computed tomography (CT) 2 weeks after a minor head injury in a 29-year-old man. A similar but larger hematoma developed 12 hours post-trauma with acute onset of consciousness disturbance in a 39-year-old man. Emergency CT angiography revealed no vascular pathologies in either case. The first patient was managed conservatively and recovered, whereas the second patient was treated surgically and died. The literature was reviewed regarding the possible mechanism of production of these lesions following head injury and therapeutic considerations are discussed. PMID- 28663952 TI - A Case of the Internal Carotid Artery-Posterior Communicating Artery Aneurysm Mimicking Tolosa-Hunt Syndrome. AB - A 53-year-old woman experienced a right retrobulbar pain followed by ipsilateral extraocular palsies in all directions without dilated pupils or ptosis. Because a plain head computed tomography (CT) scan obtained on her initial visit showed no abnormal findings, such as subarachnoid hemorrhage or a giant cavernous aneurysm, her condition was provisionally diagnosed as Tolosa-Hunt syndrome and elective magnetic resonance (MR) imaging was scheduled. The day after her initial visit, however, she suddenly developed complete ptosis and a dilated pupil on the right side. Emergency MR imaging and angiography revealed a clover leaf-shaped aneurysm projecting to the cavernous sinus at the junction of the internal carotid artery and the posterior communicating artery. Her condition was diagnosed as impending rupture of the aneurysm, and she underwent emergency open surgery. Her symptoms completely resolved within the following 2 weeks. Our case demonstrated that a medium-sized internal carotid artery-posterior communicating artery aneurysm can cause simultaneous oculomotor and abducens nerve palsies with retrobulbar pain if the shape of the aneurysm is complicated. Although these symptoms are very similar to those of Tolosa-Hunt syndrome, we believe that prompt radiological examinations such as MR or 3D CT angiography should be performed to prevent subsequent rupture of the aneurysm. PMID- 28663953 TI - Dural Arteriovenous Fistula of the Transverse and Sigmoid Sinus Manifesting Ascending Dysesthesia: Case Report and Literature Review. AB - Cases involving intracranial dural arteriovenous fistulas (AVFs) with spinal perimedullary venous drainage exhibit variable presentations, which results in delayed diagnoses. We describe a case of a 66-year-old female with a transverse sigmoid sinus dural AVF with spinal perimedullary venous drainage who developed dysesthesia and hypalgesia that ascended from the peripheral lower extremities. Sixty cases of intracranial dural AVFs resulting in myelopathy have been reported, and an absence of brainstem signs significantly correlated with a delay in diagnosis (positive group: 3.4 months vs. negative group: 9.6 months, P < 0.05). Intracranial dural AVFs with brainstem signs should be diagnosed without delay because the myelopathy and bulbar symptoms could progress aggressively without alternative drainage routes besides the perimedullary veins. We emphasize that intracranial dural AVFs should be considered as a differential diagnosis in case presenting with symptoms, such as atypical dysesthesia and hypalgesia ascending from the toes, without brainstem signs. Moreover, we should perform cerebral angiography as early as possible because dural AVFs with slow-flow venous drainage can produce false negatives on magnetic resonance angiography. PMID- 28663954 TI - Bow Hunter's Stroke Due to Stretching of the Vertebral Artery Fenestration: A Case Report. AB - Bow Hunter's syndrome is an unusual symptomatic vertebrobasilar insufficiency resulting from intermittent mechanical compression of the vertebral artery, and is rarely a trigger for cerebral infarction following thrombus formation on the damaged endothelial vessels (Bow Hunter's stroke). The authors present an extremely rare case of a 45-year-old man showing Bow Hunter's stroke due to congenital vertebral artery fenestration stretching and sliding between C1 and C2 after head rotation to the right. Congenital vertebral artery anomaly rarely causes cerebral infarction, but could cause embolic strokes by mechanical stretching without bony abnormalities. PMID- 28663955 TI - Steroids and Immunosuppressant Agents Do Not Affect Indirect Revascularization in Quasi-Moyamoya Disease Associated with Pure Red Cell Aplasia: A Case Report. AB - A 31-year-old woman with pure red cell aplasia presented with motor aphasia and right homonymous hemianopia due to a left temporal and parietal lobe infarction. Magnetic resonance angiography revealed an occlusion of the left anterior and middle cerebral artery, with the development of moyamoya vessels. She was diagnosed with quasi-moyamoya disease and subsequently underwent direct and indirect anastomosis surgery, while continuing steroid and immunosuppressant therapy for pure red cell aplasia. The postoperative course was uneventful, and follow-up cerebral angiography 6 months after the surgery revealed the development of neovascularization through an indirect anastomosis. Neovascularization can be induced while the patient is receiving steroid and immunosuppressant therapy in quasi-moyamoya disease. PMID- 28663957 TI - Carotid Artery Dissection Caused by an Elongated Styloid Process: Three Case Reports and Review of the Literature. AB - Eagle syndrome is a set of symptoms associated with an elongated styloid process. Although it is an important cause of cerebrovascular complications such as carotid artery dissection (CAD) or thromboembolism, the condition may be underdiagnosed. We treated three patients with CAD caused by an elongated styloid process within a year. The first patient was a 55-year-old man who developed recurrent thromboembolism despite anticoagulation therapy. Computed tomography (CT) angiography showed bilateral CAD with tips of styloid processes attached to the dissected lesions. He underwent surgical resection of the styloid process followed by carotid artery stenting. The second patient was also a 55-year-old man who developed acute stroke due to carotid artery occlusion, and underwent thrombectomy and carotid artery stenting. Both these patients experienced resolution of their neurological symptoms and had no recurrence of stroke. The third patient was an 80-year-old man with an asymptomatic dissecting aneurysm of the cervical internal carotid artery. He had a history of odynophagia and underwent surgical resection of the styloid process, with resolution of his symptoms. These cases, taken together with recent evidences showing that CAD was associated with the styloid process length, suggest that Eagle syndrome may not be an uncommon cause of CAD. Examination by CT angiography is important to avoid misdiagnosis. A literature review indicates that some cases were refractory to anticoagulation and surgical resection of the elongated styloid process or carotid artery stenting could be a treatment option to prevent further stroke. PMID- 28663956 TI - Vascular Reconstruction for Radiation-induced Bilateral Internal Carotid Artery Occlusion and Unilateral External Carotid Artery Stenosis by a Combination of Surgical and Endovascular Method: Case Report. AB - We present a case of a 63-year-old male presenting with right hemiparesis and diagnosed as cerebral infarction. He had a previous history of left pharyngeal carcinoma, which was treated by radial dissection and radiation therapy 10 years before. Magnetic resonance imaging (MRI) showed multiple cerebral infarction in the bilateral cerebral hemisphere, predominantly on the left. Cerebral angiography showed occlusion of bilateral internal carotid arteries and severe stenosis at the orifice of the left external carotid artery (ECA). Single photon emission tomography (SPECT) showed reduced cerebral blood flow and decreased cerebral vascular reserve in the bilateral anterior cerebral artery and left middle cerebral artery territories. He was successfully treated by a combination of carotid stenting for the left ECA and left superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. He did not have further ischemic symptom for more than 2 years. Radiation-induced carotid vasculopathy often involves multiple arteries and treatment is often complex and difficult. Safer and less invasive treatment strategy should be considered using both endovascular and direct surgery. PMID- 28663958 TI - Thrombus Removal by Acute-phase Endovascular Reperfusion Therapy to Treat Cerebral Embolism Caused by Thrombus in the Pulmonary Vein Stump after Left Upper Pulmonary Lobectomy: Case Report. AB - Thrombus formation in a pulmonary vein stump after pulmonary lobectomy is extremely rare, but can trigger cerebral embolism of unknown cause. We encountered a case of cerebral embolism in a 58-year-old man 2 days after left upper lobectomy. Since intravenous administration of recombinant tissue plasminogen activator was contraindicated, thrombus removal by endovascular reperfusion therapy was performed. Cerebral angiography showed left internal carotid artery occlusion. Thrombus removal using a retrieval device was performed and complete recanalization of the left internal carotid artery was obtained. Although blood abnormalities or arrhythmia such as atrial fibrillation were not observed, thrombus in the left upper pulmonary vein stump was detected with contrast-enhanced computed tomography of the body trunk, which was therefore considered as the source of cerebral embolism. The patient is continuing on anticoagulant therapy to prevent embolism recurrence caused by thrombus formation in the pulmonary vein resection stump. To the best of our knowledge, this is the first report of thrombus removal by acute-phase endovascular reperfusion therapy to treat cerebral embolism likely caused by thrombus formation in the pulmonary vein stump after left upper lobectomy. When cerebral embolism of unknown cause develops after left upper lobectomy, thrombus formation in the pulmonary vein stump should be considered among the differential diagnoses. For acute-phase onset of cerebral embolism after pulmonary lobectomy, thrombus removal by endovascular reperfusion therapy may be considered as one of the therapies. PMID- 28663959 TI - Primary Intracerebral Alveolar Soft Part Sarcoma in an 11-Year-Old Girl: Case Report and Review of the Literature. AB - Alveolar soft part sarcoma (ASPS), a rarely observed tumor, is a soft tissue sarcoma with an unidentified cell origin. It constitutes 0.5-1.0% of all soft tissue sarcomas. It may appear in various parts of the body, but mostly observed in the trunk and the extremities. It has a high metastasis potential. To the best of our knowledge, only three cases of primary intracranial ASPS without a demonstrable lesion elsewhere is encountered. An 11-year-old girl was operated because of fronto-parietal mass lesion by craniotomy. Pathological examination revealed ASPS and no primary focus was detected. In spite of radiotherapy and chemotherapy as an adjuvant therapy, after 45 months she had a second operation for recurrence of the tumor. Since it is possible to observe metastases in late phases, up to 30 years, the patients must be followed up for a long period. Although radiotherapy and chemotherapy followed by surgery is the most accepted treatment strategy, the prognosis is still poor. PMID- 28663960 TI - Cerebral Infarction Related to Carmustine Wafers in Glioblastoma: A Case Report. AB - Implantation of carmustine-impregnated wafers (Gliadel(r)) into the tumor resection cavity has demonstrated a survival benefit for patients with malignant glioma. However, some precautions should be taken regarding Gliadel implantation. We report a case of a 63-year-old man with glioblastoma who was implanted with Gliadel after a left temporal lobe tumor had been removed, and who later developed vasospasm of the lenticulostriate artery close to the implanted Gliadel, leading to serious cerebral infarction. Therefore, the implantation of Gliadel in cases where important vessels run close to the resection cavity should be considered with great caution. PMID- 28663961 TI - Double-edged Sword in the Placement of Carmustine (BCNU) Wafers along the Eloquent Area: A Case Report. AB - Although direct Gliadel(r) wafer implantation into the resection cavity has been shown to significantly improve survival in patients with high-grade gliomas, several complications have been associated with the implantations of Gliadel wafers, including brain edema, healing delay, cerebral spinal fluid leak, intracranial infections, and cyst formation. The brain edema that is associated with Gliadel wafer implantation might result in neurological deficits and significant morbidities and mortalities. In particular, it is not clear if they should be placed in the eloquent areas, such as language areas, motor areas, and areas related to cognitive function, even if these areas contain a remnant tumor. Here, we present a case of profound brain edema along the pyramidal tract due to Gliadel wafer implantation, which resulted in severe neurological deficits. This treatment represents a double-edged sword due to the possibility of severe symptomatic brain edema along the eloquent area, even though Gliadel wafers might be effective in controlling local tumor growth. We should keep in mind that Gliadel wafer placement in eloquent areas may result in severe disadvantages to patients and a loss of their quality of life. PMID- 28663962 TI - Agenesis of the Left Internal Carotid Artery in the Right Aortic Arch with Isolation of the Left Innominate Artery Associated with Ruptured Cerebral Aneurysm: Case Report. AB - As we occasionally encounter congenital blood vessel abnormalities, their variety, embryology, and associated clinical problems must be understood. We report a case of a 50-year-old man with subarachnoid hemorrhage due to a ruptured cerebral aneurysm at the internal carotid-anterior choroidal artery bifurcation who manifested extremely rare congenital anomalies, i.e., a right aortic arch, isolated left innominate artery, agenesis of the left internal carotid artery, and dysplasia of the basilar artery to the posterior cerebral arteries. This complex anomaly, to the best of our knowledge, has not been previously reported. PMID- 28663963 TI - Spinal Subarachnoid Hemorrhage Caused by a Mycotic Aneurysm of the Radiculomedullary Artery: A Case Report and Review of Literature. AB - We report a case of spinal subarachnoid hemorrhage (SAH) caused by rupture of a mycotic anerurysm. A 59-year-old woman was admitted to our hospital with a sudden onset of headache and tetraparesis. Computed tomography (CT) scan of the brain revealed SAH, and magnetic resonance imaging (MRI) of the cervical spine showed an acute intradural hematoma. On angiogram, a saccular aneurysm was found on the C5 radiculomedullary artery, which arose from the left ascending cervical artery. Subsequently, her consciousness status deteriorated due to rebleeding, and she was brought to surgery. An aneurysm was found at the cephalad aspect of the left C5 root. On histological examination, it showed typical characteristics of mycotic aneurysms. Spinal mycotic aneurysm is a very rare entity with scant description in the literature. It can be extremely brittle and therefore warrants expeditious surgical treatment. When encountering spinal origin of subarachnoid hemorrhage, it should be included in the differential diagnosis. PMID- 28663964 TI - Mechanical Endovascular Recanalization in a Patient with Middle Cerebral Artery Occlusion by Tumorous Emboli Originating from Cardiac Myxoma. AB - Cardiac tumor is a rare cause of cerebral embolic infarction which has no established therapeutic strategies. Although some cases were successfully treated by recombinant tissue-plasminogen activator (rt-PA), this article indicates the effectiveness of emergency mechanical thrombectomy for tumorous type of emboli which do not respond to rt-PA. A 34-year-old man presented with ischemic stroke and right middle cerebral artery (MCA) occlusion by cardiac tumor originating emboli. Intravenous rt-PA therapy was ineffective, but mechanical endovascular thrombectomy using Merci Retriever was successful. His neurological deficit began to improve and good outcome was obtained at discharge. The embolus was histologically identical to a cardiac myxoma, confirmed and treated successfully by surgery later. We report the first successfully treated tumorous embolic stroke case with cardiac tumor by using Merci Retriever. Emergency mechanical thrombectomy would be an option for elastic hard myxoma emboli. PMID- 28663965 TI - Primary Sellar Neuroblastoma in an Elderly Patient: Case Report. AB - A 71-year-old male presented with an isolated well-enhanced sellar lesion accompanied by hypopituitarism, diagnosed preoperatively as a pituitary adenoma, meningioma, or metastatic brain tumor. However, histological examinations yielded a diagnosis of neuroblastoma. Primary sellar neuroblastoma in the elderly is very rare. We therefore describe this case of primary sellar neuroblastoma, mimicking common pituitary tumor, and review the literature. There have so far been only nine reported cases of primary sellar neuroblastoma in the English literature. All reports like the present case, demonstrated similar neuroimaging of a "dumbbell-shaped extension in the sellar region." Moreover, the tumors may exhibit characteristic features, such as rapid tumor growth, hypopituitarism, or oculomotor nerve palsy, and these findings may represent helpful signs for the diagnosis of primary sellar neuroblastoma. PMID- 28663966 TI - Candida Albicans Dural Granuloma: Case Report. AB - Candida albicans dissemination to the central nervous system (CNS) may occur in immunocompromised patients even without prior cranial surgery. In such cases, intracerebral lesions are most frequent, meningeal or cerebrospinal fluid involvement being rare. We, here, describe a case of Candida albicans granuloma developing exclusively inside the width of the dura mater, successfully treated by surgical excision followed by antimycotic therapy. A 75-year-old man, previously affected by urinary sepsis from Candida albicans, was admitted to the emergency department of our hospital because of the acute appearance of sensory obtundation, blurred speech, and right hemiparesis. Emergency computed tomography (CT) scan and magnetic resonance imaging (MRI) with and without contrast enhancement disclosed a huge, left fronto-parietal mass, causing severe brain compression. At surgery, the lesion appeared to develop exclusively inside the dural envelope, and was completely removed. At pathology, a totally intradural Candida albicans granuloma was observed and appropriate antimycotic treatment was started. After an uneventful postoperative course the patient was sent to rehabilitation. Five months later he was admitted again because of a bone flap infection, leading to bone removal and further cranioplasty, with full neurological recovery. At 2 years follow-up, no neuroradiological or clinical evidence of residual/relapsing intracranial infection was found. Isolated intradural granuloma from Candida albicans has never been described before. Even though surgical excision may lead to complete resolution of mass effect in these patients, prolonged observation should be maintained, to disclose further, potentially lethal, complications. PMID- 28663967 TI - Rosette-forming Glioneuronal Tumor: Rare Case Presented with Spontaneous Disappearance of Contrast Enhancement. AB - This report presents rosette-forming glioneuronal tumor (RGNT) of the tectum in a 24-year-old woman in whom spontaneous disappearance of contrast enhancement (CE) on magnetic resonance (MR) imaging was observed during 9-year follow-up period before therapeutic intervention. MR imaging obtained 9 years ago when she first visited local hospital with headaches showed a mass of the brain stem with CE. Follow-up MR imaging showed disappearance of CE without tumor growth. Nine years later, she was admitted to our hospital with headache and nausea, due to obstructive hydrocephalus. She underwent endoscopic third ventriculostomy (ETV) and tumor biopsy. Histological study revealed RGNT. To our knowledge, this is the first report presenting that the RGNT may show spontaneous disappearance of CE without tumor growth. It is unclear what this phenomenon means, however, knowledge of this phenomenon may be helpful for correct diagnosis and for follow up of RGNT. PMID- 28663969 TI - Fourth Ventriculostomy in Occlusion of the Foramen of Magendie Associated with Chiari Malformation and Syringomyelia. AB - We present four cases of hydrocephalus caused by occlusion of foramen of Magendie associated with Chiari Type I malformation and syringomyelia. The aim of this study is to evaluate the results of surgical treatment via fourth ventriculostomy with catheter from the fourth ventricle to the upper cervical subarachnoid space. Obstructive tetraventricular hydrocephalus due to occlusion of the foramina of Luschka and Magendie can be treated with cerebrospinal fluid shunting, opening the membranes with suboccipital craniotomy, placement of a catheter, endoscopic third ventriculostomy, and endoscopic fourth ventriculostomy. Our aim was to solve all the pathologies such as Chiari malformation, hydrocephalus, and syringomyelia in one approach. Thus, the treatment consisted of posterior fossa decompression and exploration. All the patients were treated with suboccipital craniectomy and C1 laminectomy with excision of the membrane obstructing the foramen of Magendie. Fourth ventriculostomy with cathetering from fourth ventricle to upper cervical subarachnoid space was performed. The postoperative period was uneventful in all the patients. Neurological status of all the patients improved. Tetraventricular hydrocephalus and syrinx were reduced in the control cranial magnetic resonance imaging. Complications such as infection and catheter migration were not observed during the follow-up period. Treatment with fourth ventriculostomy using a catheter from fourth ventricle to upper cervical subarachnoid space could be a treatment of choice in cases with hydrocephalus caused by occlusion of the foramina of Magendie, with associated Chiari Type I malformation and syringomyelia. PMID- 28663968 TI - Aspergillus Sphenoiditis Associated with an Artificial Bone Graft Used for Transsphenoidal Surgery. AB - Cerebrospinal fluid (CSF) leakage is a major complication during and after transsphenoidal surgery (TSS) for intra- and suprasellar tumors. To prevent postoperative CSF leakage, various surgical techniques have been used, including sellar floor reconstruction with artificial bone grafts. However, some authors have recently reported infections associated with artificial bone grafts. Most cases are associated with bacterial infection, and fungal infection is extremely rare. We present the case of a 53-year-old woman with sphenoiditis caused by Aspergillus infection that developed 8 years after TSS and following local radiation therapy for a non-functioning pituitary adenoma. An artificial bone graft prepared from polymethylmethacrylate was used for sellar floor reconstruction. The patient presented to our department with a complaint of bloody nasal discharge. Magnetic resonance imaging showed that a fungal lump had formed around the bone graft, which had broken into two pieces and dropped out into the sphenoid sinus, without tumor recurrence. Histological examination of an endoscopic biopsy specimen led to a diagnosis of aspergillosis. Subsequent complete removal of both the bone graft and fungal lump resulted in a good postoperative outcome. Although fungal infection is an extremely rare complication after TSS using artificial bone grafts, it should be diagnosed as early as possible, and removal of both the fungal lump and the bone graft should be performed in a timely manner after clinical and radiological confirmation. PMID- 28663970 TI - 3D-CT Epidurography Can Detect Cerebrospinal-Fluid Leakage in a Patient with Spontaneous Intracranial Hypotension: A Case Report. AB - Spontaneous intracranial hypotension presents with many symptoms including orthostatic headache, dizziness, and nausea due to cerebrospinal-fluid (CSF) leakage from the spinal dural sac. Although CSF leakage can be estimated by radioisotope (RI) cisternography or computed tomography/magnetic resonance imaging myelography, it is not easy to detect the leakage point using these modalities. Here, we describe a patient with spontaneous intracranial hypotension in whom three-dimensional computed tomography (3D-CT) performed just after an epidural blood patch (EBP) containing contrast medium detected leakage point. The contrast medium injected into the epidural space at the L3/4 level migrated into the intradural space at the lower cervical spine level. RI cisternography performed before EBP did not show the CSF leakage point or any intracranial extension of the tracer. The rostral extension of the RI may be blocked by the collapse of the CSF space due to a large amount of CSF leakage, and due to the compression of the intradural CSF space by epidural CSF. 3D-CT epidurography may be useful to detect the fistula of a CSF leakage even in patients where other modalities including MRI, CT, or RI cisternography cannot specify the leakage point. PMID- 28663971 TI - Surgical Treatment of Gorham's Disease with Massive Osteolysis of the Skull and Cervical Spine: A Case Report and Review of Literature. AB - Gorham's disease is a rare disorder of unknown etiology and variable clinical presentation and is characterized by the proliferation of lymphatic vessels associated with massive regional osteolysis. Although 10 cases involving the skull and cervical spine have been reported in the literature, little is available concerning the surgical treatment of either atlantoaxial dislocation or basilar impression. Most cases have experienced universally unsuccessful treatment with bone grafts, which have led to dissolution. This case report describes the clinical course, and radiotherapeutic, medical, and surgical treatment for Gorham's disease with basilar impression and massive osteolysis of the skull and upper cervical spine. The case of a 27-year-old man with progressive massive osteolysis of the skull and cervical spine is reported. Multiple surgical treatments to decompress the spinal cord and stabilize the skull and upper cervical spine with autologous fibular grafts were performed in order to prevent the progression of atlantoaxial dislocation and basilar impression. Pathologically, radiotherapy failed to show any effect. The efficacy of antiresorptive therapy with bisphosphonates could not be confirmed either clinically or radiologically. Although solid bone fusion was not obtained, the patient has achieved a satisfactory functional outcome and remains completely active after repeated surgeries. Surgical treatment is extremely difficult in cases of Gorham's disease involving the skull and upper cervical spine. Fibular bone grafts seem to show resistance to erosion to osteolytic tissue. PMID- 28663972 TI - Ruptured Posterior Communicating Artery Aneurysm Associated with Aarskog Syndrome. AB - A 44-year-old male with Aarskog syndrome (AS) presented with subarachnoid hemorrhage secondary to ruptured posterior communicating artery aneurysm. AS, also known as faciogenital dysplasia, is an X-linked, autosomal dominant or autosomal recessive congenital developmental disorder. This syndrome is characterized by short stature in association with a variety of multiple anomalies in musculoskeletal, neurological, and urogenital systems. Cerebrovascular abnormalities such as anomalous cerebral venous drainage, dysplastic internal carotid artery, and basilar artery malformation have been reported to be associated with AS. To our knowledge this represents the first case of a ruptured intracranial aneurysm in a patient with AS. PMID- 28663973 TI - Surgical Treatment of a Dural Arteriovenous Fistula in the Sphenoid Wing with a Unique Drainage Pattern through the Basal Vein of Rosenthal. AB - A 69-year-old man consulted our department regarding further examination because abnormal venous ectasia of the basal vein of Rosenthal (BVR) was accidentally found on magnetic resonance imaging. Angiography revealed a dural arteriovenous fistula (DAVF) in the left sphenoid wing; the fistula was supplied by the ophthalmic artery and the middle meningeal artery. Venous drainage from the fistula consisted of a large collector vein located in the temporal tip, which drained into the BVR. We selected open surgery because this lesion may be difficult to access and is associated with significant risks through an endovascular approach. After temporal clip ligation of the drainer, the superficial middle cerebral vein became the main drainage route directly in connection with the fistula. Therefore, both were ligated, after coagulation of feeding arterial networks on the dura around the sphenoid wing. The patient experienced no complications from the surgical procedure, and postoperative angiography demonstrated obliteration of the fistula. DAVF in the sphenoid wing with deep drainage is believed to carry a high risk of hemorrhage or venous infarction because of the presence of Galenic drainage, varix, and cortical venous reflux. Treatment is strongly recommended even if the symptoms are minimal. Open surgery appears to be safe and often the best therapeutic option. PMID- 28663974 TI - Overlapped Stenting for Treatment of an Extracranial Carotid Artery Aneurysm. AB - Extracranial carotid artery aneurysms (ECAAs) are rare, and their treatment is very difficult and challenging. The case of a 59-year-old woman who presented with a pulsatile mass on the left side of her neck, was diagnosed with a left sided giant thrombosed common carotid artery aneurysm, and underwent definitive treatment by overlapped stenting, is presented. Overlapped stenting is a safe and an effective treatment procedure for ECAA. A covered stent would theoretically be reasonable and immediately effective, but its long-term patency remains unknown. Therefore, in patients lacking ischemic tolerance and those not requiring urgent intervention, overlapped stenting using uncovered stents is preferable. PMID- 28663975 TI - Basilar Artery Dissection Presenting with Subarachnoid Hemorrhage: Report of Two Cases. AB - Basilar artery dissection (BAD) presenting with subarachnoid hemorrhage (SAH) is life-threatening, but its treatment has not been established yet. We treated two patients with ruptured BAD. They were 40-year-old and 41-year-old women. Both of them were treated conservatively during the acute stage. In one patient, radiological abnormality of BAD improved spontaneously. In another patient, reconstructive endovascular treatment (stent with coiling) was required in the chronic stage because the lesion deteriorated morphologically. Neither of them suffered from rebleeding and both had favorable outcome. We reported two patients with ruptured BAD treated conservatively during the acute stage and their outcomes were favorable. We reviewed the literature of BAD presenting with SAH and discussed the management for these lesions. PMID- 28663976 TI - A Purely Endoscopic and Simultaneous Transsphenoidal and Transcranial Keyhole Approach for Giant Pituitary Adenoma Resection: A Technical Case Report. AB - A combined transsphenoidal-transcranial approach for the resection of pituitary adenomas has previously been reported. While this approach is useful for specific types of pituitary adenomas, it is an invasive technique. To reduce the invasiveness of this approach, we adopted the keyhole concept for pituitary adenoma resection. A 23-year-old man presented at a local hospital with a 6-month history of bilateral hemianopia. Magnetic resonance imaging revealed a large pituitary adenoma extending from the sella turcica toward the right frontal lobe. Endoscopic transsphenoidal surgery was planned at a local hospital; however, the operation was abandoned at the start of the resection because of the firm and fibrous nature of the tumor. The patient was subsequently referred to our hospital for additional surgery. The tumor was removed purely endoscopically via a transsphenoidal and transcranial route. Keyhole craniotomy, 3 cm in diameter, was performed, and a tubular retractor was used to achieve a wider surgical corridor; this enabled better visualization and dissection from the surrounding brain and provided enough room for the use of surgical instruments under endoscopic view. The tumor was successfully removed without complication. This is the first case report to describe the resection of a giant pituitary adenoma using a purely endoscopic and simultaneous transsphenoidal and transcranial keyhole approach. PMID- 28663977 TI - Cardiopulmonary Resuscitation-induced Thoracic Vertebral Fracture: A Case Report. AB - Thoracic vertebral fractures are very unusual complications of cardiopulmonary resuscitation (CPR). A 78-year-old man developed cardiac arrest after aspirating and conventional CPR was performed. After recovery, the patient had complete paraplegia (Frankel grade A). Magnetic resonance image of spine showed a dislocation fracture with hematoma at T6 thoracic level. Computed tomography scan of chest revealed the fracture of sternum. After the patient's condition became stable with subsequent medical treatment, posterior decompression and pedicle screw fixation was performed. The patient had uneventful postoperative course with continued rehabilitation. Thus, this report emphasizes that care should be taken especially in elderly patients with fragile bone to recognize such rare complication of chest compression; however, adequate compressions to ensure circulation should be maintained. PMID- 28663978 TI - Three Case Reports of Donor Site Iliac Bone Fracture as a Complication of Anterior Cervical Fixation Surgery. AB - Although intervertebral implants have been advocated for cervical fixation surgery, classic Cloward's method or Smith-Robinson's methods using autologous iliac bone has been performed in our clinic for about 30 years. In most cases, the postoperative clinical course is uneventful with satisfactory result. However, the authors experienced three cases of donor site iliac bone fracture in the patients who performed anterior cervical fixation surgery. All three patients were female, elderly, short, and lean with low bone mineral density. Iliac bone fractures manifested with sudden pain in the vicinity of donor site. For the iliac bone fracture, two patients received invasive plate fixation surgery and the other was managed conservatively. As to the mechanism of donor site iliac bone fracture, the share stress during bone donation is speculated to cause iliac crest fragile. After beginning of walking after surgery, tractive force of the muscles attaching to the iliac crest play an important role in promoting the fracture cleft. Several clinical factors were analyzed to investigate the cause and prevention of this troublesome complication of cervical anterior fixation surgery. Age, female gender, lean, and small structure were risk factors for such iliac donor site fracture. PMID- 28663979 TI - Remote Cerebellar Hemorrhage after Supratentorial Burr-Hole Trepanation for Unilateral Chronic Subdural Hematoma: Case Report. AB - Remote cerebellar hemorrhage (RCH) after burr-hole evacuation for chronic subdural hematoma (cSDH) is a rare and uncommon complication of minor supratentorial surgery with very few reports in the literature and an uncertain etiology. We present the case of a 62-year-old male who underwent single burr hole trepanation for unilateral cSDH, revealing incidental RCH on routine postoperative computed tomography (CT) scan most likely resulting from overdrainage of cerebrospinal fluid (CSF) within the postoperative period. The patient recovered well without further neurosurgical intervention. Intra- and postoperative drainage of large volumes of CSF and the venous origin of the bleeding are accepted factors in the controversial concept of its pathophysiology. Alterations in transtentorial pressure and stretching of superficial cerebellar veins with consequent rupture seem to constitute a useful concept, although details on mechanical or hemodynamic changes still remain unknown. A multifactorial etiology with CSF-overdrainage as the major main factor seems reasonable. Neurosurgeons should be aware of the possibility of RCH even in minor supratentorial procedures such as simple burr-hole trepanation. There is a tendency towards more benign courses, but higher patient age and severity of RCH correlate with a poor outcome. Early diagnosis of RCH and close monitoring reduce unnecessary diagnostic and therapeutic interventions in these patients, probably affecting morbidity and mortality. PMID- 28663980 TI - Therapeutic Suggestions for Chronic Subdural Hematoma Associated with Idiopathic Thrombocytopenic Purpura: A Case Report and Literature Review. AB - A 66-year-old woman who was previously diagnosed with idiopathic thrombocytopenic purpura (ITP) presented with mild right-sided hemiparesis and drowsiness. Head computed tomography (CT) imaging demonstrated a massive left chronic subdural hematoma (CSDH) with a midline shift. Because initial laboratory data showed a significantly decreased blood platelet count (0.3 * 104/mm3), medical treatments such as platelet transfusion, intravenous immunoglobulin (IVIG), and high-dose corticosteroid therapy, were initiated. She clinically and radiologically responded well to these treatments without any surgical intervention. In addition to presenting our case, we searched the PubMed and Ichushi Web databases to comprehensively illustrate clinical characteristics and treatment outcomes of similar cases. Including the present case, we found 19 reports and 23 cases of CSDH associated with ITP in the literature, and assessed 17 reports and 21 cases that were written in English and Japanese. None or mild neurological symptom were seen in 13 cases, and severe, such as coma and hemiparesis, were described in the younger 8 cases with significant difference. All except one were first treated with medical therapies. Most cases of the former group responded well to conservative therapy. On the other hand, most in the latter eventually needed surgical treatment in addition except recent two cases including the present case. CSDH associated with ITP is rarely described, and its management remains controversial. However, this report highlights multiple continuous medical treatments under strict observation and general care might be a useful alternative to avoid surgery in cases presenting with severe neurological deficits and extremely low platelet counts. PMID- 28663981 TI - Malignant Transformation of a Neurenteric Cyst in the Posterior Fossa Presenting with Intracranial Metastasis: A Case Report and Literature Review. AB - Intracranial neurenteric cysts are relatively rare and almost exclusively benign. Here we present a case of an intracranial neurenteric cyst that was histologically benign in the first surgery and later demonstrated significant growth and intracranial metastasis with malignant transformation. A 47-year-old woman presented with a headache, which had gradually worsened over 1 year. Initial magnetic resonance (MR) images revealed a solitary cystic lesion in the left cerebellopontine angle with significant mass effect. Subtotal resection leaving a small mass strongly adhered to the brainstem was achieved. Histopathological diagnosis was neurenteric cyst with no malignant features. This lesion recurred 4 years after the first surgery in the form of a cystic mass adjacent to the brainstem. In addition, histopathological examination of a specimen from the second surgery revealed malignant transformation. The patient declined to undergo radiation therapy and was conservatively managed. Three years after the second surgery, MR imaging showed recurrence of the solid mass. Although the patient had been treated with subtotal resection and radiation therapy, she died with metastatic masses in the right frontal lobe and cervical cord. A specimen from the third surgery revealed diffuse malignant features similar to mucinous adenocarcinoma. Our case and literature review indicate that, although rare, malignant transformation can occur particularly among intracranial neurentreric cysts. This finding suggests the importance of long-term follow-up for subtotally or partially resected intracranial neurenteric cysts. PMID- 28663982 TI - Occipital Condyle Osteoid Osteoma with Severe Occipital Pain that Disappeared after Surgical Resection. AB - Osteoid osteoma is a benign bone tumor characterized by local pain that typically increases at night. The tumor commonly occurs in the long bones of the lower extremities, and in rare instances in cranial bones. Here we report the case of a 25-year-old man diagnosed with an osteoid osteoma of the right occipital condyle. The patient suffered from severe occipital pain in the 3 years leading up to surgery, and the pain disappeared after surgical resection of the tumor. Due caution must be taken to avoid vertebral artery injury in the surgical approach in this region. An intraoperative navigation guidance system and preoperative analysis using three-dimensional reconstructed computed tomography (CT) images improved the accuracy and safety of the resection. The typical pain in osteoid osteoma is presumed to be associated with prostaglandin E2 secretion. Plasma prostaglandin E2 of this patient was elevated preoperatively and normalized after the operation. This is the first report describing an elevation of plasma prostaglandin E2 before surgical resection followed by a normalization of serum prostaglandin E2 after surgical resection. PMID- 28663983 TI - Exposure of Titanium Mesh after Cranioplasty for Microvascular Decompression Surgery: Two Case Reports. AB - Two cases of exposed titanium mesh occurred after implantation for cranioplasty after repeated procedures for microvascular decompression (MVD). Case 1 was a 62 year-old female who underwent MVD for left hemifacial spasm followed by repair of cerebrospinal fluid leak after the surgery, and Case 2 was a 75-year-old female who underwent MVD twice for right trigeminal neuralgia. Both patients visited our hospital again with complaints of postauricular lesion. Titanium mesh was visible through the operative scar and was successfully removed with no complication in both cases. Both patients were underweight females, and combined with multistep surgery may have contributed to the pathology. The present cases suggest that use of titanium mesh should be avoided for cranioplasty of posterior fossa surgery, especially for repeated procedures. PMID- 28663984 TI - Neuroendoscopic Findings of Ventricular Wall in Adult Hemorrhagic Moyamoya Disease: Report of Two Cases. AB - Moyamoya disease usually manifests as ischemic events in childhood, and as more severe hemorrhagic events, including intraventricular hemorrhage, in adults. Recently, the indication for neuroendoscopic surgery has been extended to cast formation intraventricular hematomas. However, detailed information about the use of neuroendoscopic surgery for the treatment of intraventricular hemorrhage associated with moyamoya disease has not been reported. We describe two cases of intraventricular hemorrhage with moyamoya disease; one in a 62-year-old and another in a 33-year-old women who both presented with severe neurological symptoms. Cerebral angiography revealed unilateral moyamoya disease. Neuroendoscopic surgery to remove the intraventricular hematoma was performed via bilateral frontal burr holes in both cases. Abnormal findings in the ventricle were observed only in the affected side and the intact side was normal. Specific findings of neuroendoscopic observation were dilated and tortuous vessels, intersection vessels, black-brown macules in the subependyma, and rattan blind like (Japanese sudare) bleeding vessels. These characteristic neuroendoscopic findings may be useful for the exact diagnosis and treatment of intraventricular hemorrhage associated with moyamoya disease. Endoscopic evacuation of the ventricular hematoma may be important for intracranial pressure control in patients with intraventricular hemorrhage in adult moyamoya disease. PMID- 28663985 TI - Repetitive Plantar Flexion (Provocation) Test for the Diagnosis of Intermittent Claudication due to Peroneal Nerve Entrapment Neuropathy: Case Report. AB - The diagnosis of peroneal nerve (PN) entrapment neuropathy (PNEN) is based on clinical symptoms and nerve conduction studies. However, these studies do not always detect PNEN. Our 64-year-old patient suffered persistent left L5 numbness after two lumbar surgeries. Two years before admission to our institute his left leg pain gradually reappeared. When walking, his numbness in the left lower thigh to the dorsum of the foot increased. Electrophysiological testing revealed no conduction block on the PN. To identify the origin of his intermittent symptoms we performed loading of repetitive ankle plantar flexion in the at-rest posture to avoid the lumbar factor. We used this provocation test to check for PNEN because it occurs at a site where the PN passes the soleus- and the peroneus longus muscle (SM, PLM). The symptoms appeared reproducibly within 10 s of loading. PN neurolysis under local anesthesia showed that the PN was strongly compressed by the SM and PLM. This procedure eased his symptoms and he was able to walk without elicitation of numbness and pain upon repetitive ankle plantar flexion. In our case, repetitive plantar flexion elicited the symptoms and this provocation test may be useful to identify PN dynamic entrapment neuropathy as the origin of intermittent claudication. PMID- 28663986 TI - Postoperative Acute Submandibular Sialadenitis after Neurosurgery: Two Case Reports and a Review of the Literature. AB - This article details two case reports and reviews the extant literature concerning acute postoperative submandibular sialadenitis occurring in the side contralateral to the operated site after neurosurgery. Although its precise pathogenesis remains to be elucidated, it is likely related to intraoperative compression of the submandibular gland and surrounding tissues, caused by head positioning and the endotracheal tube. Submandibular swelling rapidly deteriorates after surgery, and emergent airway protection is required in most cases in order to avoid fatal airway obstruction. To avoid serious sequelae, we should be aware of acute submandibular sialadenitis that occurs contralateral to the surgical side, which, although rare, is more probable after posterior fossa surgery. When it occurs, early airway protection is crucial, and the following conservative treatment could provide a good prognosis. PMID- 28663987 TI - A Case of Lumbosacral Arachnoiditis Ossificans. AB - The patient was a 13-year-old boy who complained of pain in both buttocks. Plain and reconstructive computed tomography (CT) images showed an ossified lesion within the dura mater at the L5-S2 levels, and arachnoiditis ossificans in the lumbosacral area was suspected. In the operative findings obtained after cutting the dura, a bone fragment 4.5 * 0.5 * 0.5 cm in size was observed in the center of the strongly adhesive nerve bundle of the cauda equina, which was removed en bloc. The postoperative clinical course of the patient was excellent. The case, along with a review of literature is presented. PMID- 28663988 TI - Carotid Artery Stenting in Right-sided Aortic Arch: A Case Report. AB - The present report describes a patient with pseudo-occlusion of the left internal carotid artery accompanied by aortic anomalies consisting of right-sided aortic arch with aberrant left subclavian artery arising from Kommerell's diverticulum. Initial attempt of carotid artery stenting via the trans-femoral approach was unsuccessful because of low origin of the left common carotid artery. Therefore, carotid artery stenting (CAS) via the trans-brachial approach was successfully performed with distal balloon protection. Eight months later, the patient presented with restenosis of the left internal carotid artery, and CAS via the trans-brachial approach was performed again. CAS via the trans-brachial approach should be considered when standard femoral access is relatively contraindicated due to aortic anomalies consisting of a right-sided aortic arch. PMID- 28663989 TI - Remote Supratentorial Hemorrhage following Supratentorial Craniotomy: A Case Report. AB - Intracranial hemorrhage (ICH) in regions remote from the initial intracranial operation site is rare. The mechanism of ICH following cranial surgery remains unclear, although several theories have been proposed. Most of the reports describe cerebellar hemorrhages after supratentorial procedures or supratentorial hemorrhages after infratentorial procedures. Remote supratentorial hemorrhage (RSH) following supratentorial surgery is extremely rare. We report a case of postoperative RSH occurring away from the surgical site. A 62-year-old woman underwent a right occipital lobectomy to resect lung carcinoma metastases. The patient developed a postoperative consciousness disturbance, and a brain computed tomography (CT) scan revealed an ICH in the left frontal region. The patient underwent ICH evacuation, but remained severely disabled. It is necessary to be aware that this complication is possible after craniotomy. PMID- 28663990 TI - "Dynamic" Rotational Canal Stenosis Caused by Osteoma of the Atlas: A Case Report and Review of Literature. AB - The upper cervical canal stenosis is relatively rare compared to other cervical regions. We report a rare case of upper cervical canal stenosis caused by osteoma of C1 lamina related to dynamic factor of cervical rotation. A 43-year-old woman had a 2-year history of numbness and pain in the right hand. Because of aggravation of the numbness and loss of the fine movement and strength in the right hand, she visited our outpatient clinic. Computed tomographic (CT) scan revealed an ovoid bony lesion at the right side of the C1 lamina. And magnetic resonance (MR) imagings of the cervical spine showed intramedullary high intensity signals in T2-weighted imaging at a site slightly distant from the bony lesion. Rotational dynamic myelo-CT scan was performed because aggravation of the radiating pain was observed with neck rotation to the right. Dynamic CT scan of the craniocervical junction with neck rotation to the right revealed that the bony lesion was moved to the dorsal side and posteriorly compressed the spinal cord. The symptoms were relieved following surgical removal of this bony lesion. The histopathological examination was compatible for osteoma. The dynamic rotational factor for cervical canal stenosis should be taken in consideration, especially in dealing with upper cervical lesions. PMID- 28663991 TI - Modified Goel's Methods for Basilar Impression: A Case Report with Literature. AB - We report the case of a 57-year-old woman who had basilar impression manifesting as severe myelopathy and occipital neuralgia and was treated by distraction and fixation performed using a modification of Goel's method. Magnetic resonance imaging (MRI) and computed tomography (CT) scans showed severe myelocompression by the dens of the axis from the ventral side and occipitalization of the atlas. After traction using a Halo vest, C1-2 facet distraction and fixation was performed in one stage using a modified Goel's method. Although Goel et al. used a custom-made spacer to distract the facet joints, we used a threaded titanium cylindrical cage that was inserted into the joint to fix the C1-2 facet joint with posterior fixation from occipital bone to C5. Postoperatively, gradual symptomatic and neurological amelioration were observed. The atlantoaxial joints were bone-fused at 3 years post-operation. Distraction and fixation performed using this modified version of Goel's method was effective for treating basilar invagination. The threaded titanium cylindrical cage provided adequate C1-2 space and strong initial fixation. PMID- 28663992 TI - Cerebral and Intra-ventricular Abscess Caused by Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ). AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the major complications caused by prolonged bisphosphonate administration. We treated a case of BRONJ-related cerebral and intraventricular abscess. An 80-year-old woman was referred to our hospital for osteonecrosis of the maxilla. Removal of a decayed tooth followed by several oral antimicrobial administrations was performed, but the inflammation spread gradually into the orbit. Twenty-seven months after the initial treatment, she was referred to our hospital. A computed tomography (CT) scan revealed formation of an intraventricular abscess secondary to destruction of the maxillary and sphenoid sinuses. Reports of BRONJ associated with intracranial infection are rare. With prolonged life expectancy, BRONJ cases will increase with many comorbid diseases. Co-operation among physicians, dentists, and pharmacologists will be needed to treat these conditions appropriately. PMID- 28663993 TI - Adult Diffuse Astrocytoma in the Medulla Oblongata: Molecular Biological Analyses Including H3F3A Mutation of Histone H3.3. AB - Unlike in children, brain stem gliomas in adult are rare and still poorly understood. In addition, most adult brain stem gliomas result predominantly in the pons and are less often found in the medulla oblongata. Here, we report a case of an adult glioma in the medulla oblongata and its molecular biological features. A 46-year-old male presented with gait disturbance, paresthesia, and dysphagia. Magnetic resonance imaging (MRI) showed a diffuse hyper-intensive lesion in the medulla oblongata on a T2-weighted image without gadolinium contrast enhancement. We performed an open biopsy and the lesion was pathologically diagnosed as a diffuse astrocytoma. Molecular biological analyses revealed the absence of histone H3.3 mutation (H3F3A K27M), and presence of methylation of O-6-methylguanine-DNA methyltransferase (MGMT) promoter and a mutation in isocitrate dehydrogenase 1 (IDH-1). The patient received local radiotherapy and temozolomide chemotherapy. The patient's symptoms were ameliorated, and MRI showed no tumor growth at 6 months after the initial treatment. Biopsy for brain stem lesions is generally thought to have risk of complications, but if performed minimally, it is useful to diagnose and determine treatment strategy. Obtaining patient characteristics and molecular biological features will provide insight towards therapeutic treatment for adult brain stem gliomas. PMID- 28663994 TI - Brain Abscess in a Patient with Rendu-Osler-Weber Syndrome: Value of Proton Magnetic Resonance Spectroscopy. AB - The diagnosis of intracranial focal lesions based on imaging studies is a challenge. In brain abscess, proton magnetic resonance spectroscopy (1H-MRS) is useful to define etiology, differentiating anaerobic from aerobic pathogens and inclusive sterile abscess based on the behavior of certain metabolites. We report a patient with Rendu-Osler-Weber syndrome, pulmonary arteriovenous fistulas, and brain abscesses characterized by brain magnetic resonance imaging (MRI), with a spectroscopy pattern compatible with anaerobic infection. PMID- 28663995 TI - A Large Endodermal Cyst with Xanthogranuloma at the Frontal Skull Base, Slowly Recurring with Hemorrhage. AB - A 45-year-old man with a past history of the removal of a degenerated hematoma two times presented with general convulsion. Computed tomography (CT) showed a high-density lobular mass growing from the right frontal skull base and occupying the right frontal lobe. Magnetic resonance imaging (MRI) demonstrated a homogeneously hyperintense mass on T1-weighted imaging and a homogeneously hypointense mass on T2- and T2*-weighted imaging. We removed the lesion, which intraoperatively showed a blackish-brown and jellylike mass with machine oil-like fluid. There was a thin and elastic membrane at the boundary between the mass and degenerated brain tissue, and we removed as much of the membrane as possible. On light microscopy, most parts of the mass consisted of a degenerated hematoma with xanthogranuloma, while the thin and elastic membrane revealed one or two layers of non-ciliated columnar epithelial cells based on thin fibrous tissues with microvessels. Immunohistochemical staining showed that these epithelial cells contained periodic acid-Schiff (PAS)-positive granules, and were positive for cytokeratin (CAM5.2), carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA). Ultrastructual examination showed numerous microvilli at the surface of non-ciliated cells, and an interdigitation-like, dense adhesion structure. On the basis of pathological findings, the patient was considered to have a large endodermal cyst (EC) at the frontal skull base, probably derived from Seessel's pouch. We speculate that EC developed inflammatory changes with xanthogranuloma, which caused further damage to the blood vessels and continuous hemorrhage. PMID- 28663996 TI - Onion-skin Hemifacial Dysesthesia Successfully Treated with C2-4 Anterior Cervical Decompression and Fusion: A Case Report. AB - A 49-year-old man with cervical spondylosis at the C2-4 level presented with onion-skin hemifacial dysesthesia in addition to the right extremities. C2-4 anterior cervical decompression and fusion were performed. Onion-skin hemifacial pain disappeared after surgery. Although we cannot conclude the etiology of the pain was either referred pain or direct injury to the spinal trigeminal nucleus, cervical spondylosis at the middle cervical level has a possibility to present facial pain. PMID- 28663997 TI - Free Air in the Cavernous Sinus Secondary to Acute Isolated Sphenoid Sinusitis. AB - Pneumocephalus is a rare but important complication of acute isolated sphenoid sinusitis (ISS). If not adequately treated, it may cause serious neurological and life-threatening complications. We report the presence of free air in the cavernous sinus arising from intracranial extension of acute ISS. A 41-year-old healthy man presented to our department with a 7-day history of headache. Neurological examination revealed no meningitis, and cerebrospinal fluid culture was negative. A head computed tomography (CT) and magnetic resonance imaging on admission revealed sinusitis in the sphenoid sinus and presence of air in the cavernous sinus. We started an antibiotic treatment and the patient's fever immediately decreased and the inflammatory response improved. In addition, the bilateral retro-orbital headache diminished. A repeated head CT scan revealed that fluid retention in the sphenoid sinus and air in the cavernous sinus had disappeared. To our knowledge, this is the fifth case of pneumocephalus accompanied by acute ISS reported in the literature and the first case report of intracranial air located only in the cavernous sinus. Meningitis accompanied by pneumocephalus can be a warning sign for poor outcome in patients with ISS. PMID- 28663999 TI - Carotid Endarterectomy for Atherosclerotic Stenosis Associated with Non bifurcating Cervical Carotid Artery: A Case Report. AB - We report a case of a 79-year-old man presenting with left cervical carotid artery stenosis associated with non-bifurcating cervical carotid artery, a very rare congenital anatomical variation supplying different branches of the external carotid artery directly from a common trunk without a bifurcation. We performed carotid endarterectomy for this symptomatic carotid artery atherosclerotic stenosis. Here, we discuss the treatment strategy, arteriotomy, route for flush out, and usage of a shunt devise system for this characteristic morphology. In addition, the embryological mechanism for developing this rare anatomical variation is discussed. PMID- 28663998 TI - Lemierre Syndrome Associated with Ipsilateral Recurrent Laryngeal Nerve Palsy: A Case Report and Review. AB - Lemierre syndrome (LS) is a rare life-threatening disease that is often caused by an acute oropharyngeal infection with a secondary thrombophlebitis of the internal jugular vein. LS rarely manifests as cranial nerve palsy. To the best of our knowledge, this is the second case report of LS associated with recurrent laryngeal nerve palsy. A 66-year-old female presented to a dental clinic with gingivitis and sore throat. Due to moderate periodontitis, her left first upper molar was extracted. A few days later, she subsequently developed a coarse voice and occipital headaches, and was referred to an otolaryngologist. She was diagnosed with left recurrent laryngeal nerve palsy and subsequent left-sided otitis media, and was referred to us for persistent headaches. She intermittently presented with high-grade fever and complained of salty taste disturbance. Her head magnetic resonance imaging (MRI) revealed left mastoiditis, thrombosis in the left transverse and sigmoid sinus, and left internal jugular vein. Her laboratory tests revealed an elevated white blood cell count, levels of C reactive protein, and D-dimer. No endogenous coagulopathy was confirmed. Although, blood and cerebrospinal fluid culture grew no microorganisms, respectively, the empirically determined antibiotic therapy was initiated. In a week, the patient defervesced and had no headaches despite persistent thrombosis. Early diagnosis and an immediate antibiotic treatment are crucial for LS patients. Anticoagulation therapy was not needed for our patient and is still controversial for LS. PMID- 28664000 TI - Nontraumatic Pure Acute Subdural Hematoma Caused by a Ruptured Cortical Middle Cerebral Artery Aneurysm: Case Report and Literature Review. AB - Nontraumatic or "spontaneous" acute subdural hematoma (SDH) is rare, and "pure" acute SDH without subarachnoid hemorrhage (SAH) due to aneurysmal rupture is extremely rare. We report a case of nontraumatic pure acute SDH caused by the rupture of a cortical middle cerebral artery (MCA) aneurysm. A 43-year-old man with no antecedents, except hypertension, presented to the emergency department with acute-onset moderate headache and nausea after swimming. He reported neither preceding head trauma nor dental check-up. Neurological examinations and laboratory tests were unremarkable. Computed tomography (CT) showed an acute SDH on the left convexity without SAH, but both magnetic resonance (MR) angiography and three-dimensional CT (3D-CT) angiography disclosed no vascular abnormality. As he became drowsy, the patient emergently underwent an evacuation of the SDH. Unexpectedly, a small saccular aneurysm of a cortical branch of the left MCA was recognized at surgery. Although indocyanine green (ICG) angiography revealed this aneurysm was thrombosed, a clip was applied on the aneurysmal base. He was discharged home without any complications 21 days after admission. To seek the cause of nontraumatic acute SDH, supplementary examinations including 3D-CT, MR, and/or catheter angiography are necessary. Even if angiography reveals no vascular lesions, the present case warrants that the cortical surface should be meticulously inspected at surgery, because a thrombosed cortical artery aneurysm might be an underlying cause. PMID- 28664001 TI - A Case of Dural Arteriovenous Fistula in the Falx Cerebri: Case Report and Review of the Literature. AB - A 67-year-old man presented with consciousness disturbance and right hemiparesis. Computed tomography (CT) scan showed an intracerebral hematoma with two enhanced vascular lesions. Digital subtraction angiography revealed the dural arteriovenous fistula (dAVF) in the falx cerebri which was supplied by both bilateral middle meningeal arteries and left pericallosal artery and drained into both the superior sagittal sinus and the vein of Galen via the posterior callosal vein accompanied by two venous pouches. The dAVF was obliterated by a combination of the endovascular and the direct surgeries. A dAVF in a falx cerebri is very rare and only five cases were reported. Clinical characteristics of the dAVFs are uncertain. Before deciding the strategy of treatment, it is important to consider the pathological condition including embryology of the falx, the falcine sinus, and the falcine venous plexus. PMID- 28664002 TI - Central Retinal Artery Occlusion after the Endovascular Treatment of Unruptured Ophthalmic Artery Aneurysm: A Case Report and a Literature Review. AB - Endovascular coil embolization for ophthalmic artery (OphA) aneurysms has a risk of occlusion of the OphA, which can lead to loss of vision. The authors report a patient with unruptured OphA aneurysm which treated with endovascular coiling and were complicated by blindness due to OphA thromboembolic occlusion after the procedure. The OphA successfully recanalized using local intra-arterial fibrinolysis with complete regain of visual acuity. The risk of visual loss due to thromboembolic complications cannot be ignored during endovascular coiling of the OphA aneurysm despite of good retrograde flow during OphA occlusion test using a balloon catheter. Rapid intervention is required for recovering visual disturbance in such a situation. PMID- 28664003 TI - Prolonged Dysphagia due to a Combination of Cerebral Hemorrhage and Diffuse Idiopathic Skeletal Hyperostosis: A Case Report. AB - A 79-year-old man was diagnosed with left thalamic hemorrhage. On admission, the Functional Independence Measure (FIM) motor score was 13 points, and the Food Intake Level Scale (FILS) was Level 2, with the patient needing enteral nutrition. Six months after stroke onset, the FIM motor score had improved to 38 points and the dysphagia to FILS Level 7. The patient was able to ingest easy-to swallow food orally three times a day, but only after postural adjustment with rotation of the head. Seven months after stroke onset, the FIM motor score had reached 45 points but without further improvement in swallowing function. Videofluoroscopic swallowing evaluation (VF) revealed that the persistence of dysphagia was due to osteophytes on the cervical vertebrae caused by diffuse idiopathic skeletal hyperostosis. On surgical removal of the osteophytes, swallowing function improved to FILS Level 9; the patient was able to ingest normal food in a seated position without postural adjustment. One year after stroke onset, the patient was discharged with an FIM motor score of 59 points and FILS Level 9. At the 2-year follow-up, there was minimal recurrence of the osteophytes, and both motor and swallowing functions were maintained at the same level as at discharge. This case suggests that dysphagia in elderly patients may be due to multiple disorders, and that surgical intervention may occasionally be effective. PMID- 28664004 TI - Post-traumatic Unilateral Avulsion of the Abducens Nerve with Damage to Cranial Nerves VII and VIII: Case Report. AB - Traumatic injuries of the abducens nerve as a consequence of facial and/or head trauma occur with or without associated cervical or skull base fracture. This is the first report on unilateral avulsion of the abducens nerve in a 29-year-old man with severe right facial trauma. In addition, he exhibited mild left facial palsy, and moderate left hearing disturbance. Magnetic resonance imaging (MRI) using fast imaging employing steady-state acquisition (FIESTA) revealed avulsion of left sixth cranial nerve. We recommend thin-slice MR examination in patients with abducens palsy after severe facial and/or head trauma. PMID- 28664005 TI - Moyamoya Disease Emerged with Corpus Callosum Hemorrhage: A 3D Computer Graphic Analysis. AB - The authors present a rare case of moyamoya disease emerged with corpus callosum hemorrhage. A 31-year-old woman suddenly complained of severe headache followed by consciousness disturbance. Radiological examinations revealed the bleeding in the splenium of corpus callosum, which was associated with intraventricular hemorrhage. On cerebral angiography, the carotid fork was severely stenotic on both sides, and a marked dilatation was observed in the anterior/posterior choroidal arteries and posterior pericallosal artery as well as the lenticulostriate arteries. Therefore, she was diagnosed as moyamoya disease. She successfully underwent superficial temporal artery to middle cerebral artery (STA MCA) anastomosis and indirect bypass on both sides. Postoperative course was uneventful. Follow-up cerebral angiography performed 4 months after surgery showed well-developed surgical collaterals via the external carotid system and a marked decrease of the dilated moyamoya vessels. She has been free from any cerebrovascular events for 36 months after surgery. Radiological findings strongly suggest that splenial bleeding occurred due to the rupture of the dilated abnormal collateral vessels that originate from the medial posterior choroidal artery and penetrate the corpus callosum in this case. Three dimensional computer graphic analysis was useful to determine the complex collateral circulation in moyamoya disease. PMID- 28664006 TI - Spontaneous Hemorrhage of a Spinal Ependymoma in the Filum Terminale Presenting with Acute Cauda Equina Syndrome: Case Report. AB - We present a rare case of spontaneous hemorrhage of a spinal ependymoma in the filum terminale presenting with acute cauda equina syndrome. A 16-year-old male presented with a sudden onset of severe back pain that began 10 days before hospitalization. This symptom progressed, followed by development of decreased sensation in the lower extremities, bladder dysfunction, and motor weakness that advanced to an inability to walk. Spinal magnetic resonance imaging revealed a hemorrhagic mass from Th12 to L2 and L4 to L5, and clinical signs indicated acute cauda equina compression. One day after admission to the hospital, emergency surgery was performed. A spinal tumor in the conus portion with a spinal subarachnoid hemorrhage was seen. Gross total excision of the massive hematoma mixed with the underlying tumor was performed. Pathological findings of the excised tumor demonstrated a WHO Grade II cellular ependymoma of the non myxopapillary type. The patient made a significant recovery. The ability to walk was restored, and impaired bladder function improved at follow-up. Early diagnosis and suitable treatment are associated with a more favorable outcome. PMID- 28664007 TI - Ganglioglioma in the Third Ventricle: A Case Report and Literature Review. AB - Gangliogliomas typically arise in the cerebral hemispheres, but may occur rarely in the ventricles. Herein, we report a 38-year-old woman who was treated for hydrocephalus caused by a ganglioglioma of the third ventricle. Magnetic resonance imaging (MRI) revealed a heterogeneously enhanced tumor occupying the anterior part of the third ventricle. A left trans-lateral ventricular trans foramen of Monroi approach was effective in achieving subtotal resection of the tumor, which had arisen from the medial part of left thalamus to the hypothalamus. Follow-up MRI showed no recurrence of the tumor 5-years after surgery. On pathological examination, the tumor was composed of a glial component that presented features mimicking pilocytic astrocytoma with proliferations of large gangliocytic cells that stained positive for neuronal markers. A review of six similar cases in the literature, including our own, revealed hydrocephalus to be the main symptom of gangliogliomas, with pituitary insufficiencies and visual disturbances having also been reported. In conclusion, we highlight the importance of gangliogliomas in the differential diagnosis of third ventricular tumors presenting with hydrocephalus. PMID- 28664008 TI - Idiopathic Interdural Hematoma in Adult: A Case Report. AB - Interdural hematomas are primarily observed in infants, and adult interdural hematomas are rare. We describe a 54-year-old woman with a round, well-defined mass. The mass was an interdural hematoma that was misdiagnosed as an epidural hematoma. Unlike an epidural hematoma, interdural hematomas are located between the two layers of the dura mater, and the dural tail sign can be observed. PMID- 28664009 TI - Orbital Abducens Nerve Schwannoma: A Case Report and Review of the Literature. AB - Intraorbital schwannoma is a rare tumor which accounts for about 1-2% of all neoplasms of the orbit. Orbital schwannomas most commonly arise from the sensory branches of the trigeminal nerve. On the other hand, intraorbital abducens nerve schwannomas are extremely rare, with a search of the English literature identifying only four cases of intraorbital abducens nerve schwannoma. This is the 5th reported case of an orbital schwannoma arising from the terminal branch of the abducens nerve to the lateral rectus muscle. We report a case of an intraorbital abducens nerve schwannoma in a 51-year-old man with no signs of neurofibromatosis. The tumor was totally excised with functional preservation of the nerve by a zygomatic approach with lateral orbitotomy. With knowledge of these anatomic features, total removal of the tumor with preservation of the abducens nerve function might be possible. PMID- 28664010 TI - Spontaneous Regression of Inflammatory Pseudotumor in the Cauda Equina: A Case Report. AB - Spinal intradural extramedullary inflammatory pseudotumor (IPT) is an extremely rare entity. Spontaneous shrinking of a spinal IPT has never been reported. A case of an IPT of the cauda equina that regressed spontaneously is presented. A 78-year-old woman presented with hypoesthesia of both lower legs in the L4 nerve root distribution and motor weakness of the right leg. Preoperative CT myelography and MRI showed two tumor-like lesions located at T12-L1 and L2-3. The lesion at the T12-L1 level appeared to encase several nerve roots. The preoperative diagnosis was ependymoma, schwannoma, or malignant lymphoma. The tumors were biopsied. In the operation, the lesion turned out to consist of swollen and adherent nerve roots. On histopathological examination of the biopsied nerve roots, they were diagnosed as IPT. The patient's symptoms improved gradually without any treatment after the operation. The IPTs regressed on the postoperative MR images and disappeared at one year. This is the first report of spontaneous regression of an IPT in the spinal region. IPT should be considered in the differential diagnosis of a tumor that appears to involve several nerve roots on preoperative imaging, but surgery is necessary for diagnosis. Complete resection is not absolutely required if an intraoperative pathological diagnosis of the frozen section reveals IPT. PMID- 28664011 TI - Mechanical Thrombectomy in the Treatment of Distal Occlusions during Coil Embolization of Ruptured Intracranial Aneurysms. AB - The experience in the management of thromboembolic complications of distal vessels during coil embolization using stent-retrievers in the setting of subarachnoid hemorrhage (SAH) is still limited. We report a case of 58-year-old woman with a ruptured small anterior communicating aneurysm who experienced during coil embolization a thromboembolic occlusion of the upper post-bifurcation branch of the middle cerebral artery. Mechanical thrombectomy with a stent retriever (Solitaire, Covidien, Neurovascular) resulted in complete recanalization of the occluded branch with no ischemic complication. This case should encourage the use of the Solitaire device as an effective rescue strategy in the treatment of distal artery occlusions in the setting of SAH. PMID- 28664013 TI - Erdheim-Chester Disease Involving the Central Nervous System with the Unique Appearance of a Coated Vertebral Artery. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. It is characterized by multiple xanthogranulomatous masses throughout the body, predominantly in the tibia. One of the characteristic radiological findings of the lesions associated with ECD is a "coated artery," which is often observed in the aorta. Although approximately one-fourth of ECD cases involve the central nervous system (CNS), an intracranial-coated artery has only been reported in four cases. We report a case of ECD that involves the CNS and has the unique appearance of a coated vertebral artery (VA). These tumors entirely encase the bilateral VAs without stenosis and are attached to the dura. Cranial magnetic resonance imaging also showed multiple extra-axial tumors in the cavernous sinus, the frontal convexity, and the orbital cavity. Further investigation revealed additional extracranial lesions around the cervical carotid artery, at the bilateral tibia, and at the elbow joint. A biopsy of the cervical and tibial lesions confirmed ECD. Steroid therapy resulted in a month-long improvement of preoperative symptoms. However, the patient's condition gradually progressed and he died of pneumonia 1 year after ECD diagnosis. The encasement of the intracranial artery by the tumor without stenosis and the dural attachment suggest ECD, which requires whole body investigation. PMID- 28664012 TI - Cerebral Infarction Arising from Takotsubo Cardiomyopathy: Case Report and Literature Review. AB - Although most patients with takotsubo cardiomyopathy have a favorable outcome, complications are not uncommon. Recent studies have reported an increase in incidence of cardioembolic complications; however, the association between takotsubo cardiomyopathy and stroke, in particular thromboembolic cerebral infarction, remains unclear. We reported a 44-year-old woman who had a cerebral infarction resulting from takotsubo cardiomyopathy. She had felt chest discomfort a few days prior to infarction, and later developed left hemiparesis. Head magnetic resonance imaging (MRI) revealed acute infarction in the right insular cortex and occlusion of the right middle cerebral artery at the M2 segment. Echocardiogram revealed a takotsubo-like shape in the motion of the left ventricular wall, and coronary angiography showed neither coronary stenosis nor occlusion. Cerebral infarction resulting from takotsubo cardiomyopathy was diagnosed and treatment with anticoagulant was started. MRI on the eighth day after hospitalization showed recanalization of the right middle cerebral artery and no new ischemic lesions. The findings of the 19 previously published cases who had cerebral infarction resulting from takotsubo cardiomyopathy were also reviewed and showed the median interval between takotsubo cardiomyopathy and cerebral infarction was approximately 1 week and cardiac thrombus was detected in 9 of 19 patients. We revealed that thromboembolic events occurred later than other complications of takotsubo cardiomyopathy and longer observation might be required due to possible cardiogenic cerebral infarction. Anticoagulant therapy is recommended for patients with takotsubo cardiomyopathy with cardiac thrombus or a large area of akinetic left ventricle. PMID- 28664014 TI - Super-selective Balloon Test Occlusion of the Posterior Communicating Artery in the Treatment of a Posterior Cerebral Artery Fusiform Aneurysm: a Case Report. AB - We report the case of a 49-year-old man with underlying hypertension who developed diplopia lasting 2 months. Magnetic resonance imaging and digital subtraction angiography showed multi-lobular unruptured aneurysms in the P2 portion of the posterior cerebral artery (PCA) migrating into the interpeduncular cistern of the midbrain. Because the shapes of the aneurysms were serpentine fusiform and the posterior communicating artery (PCoA) was the fetal type, we planned anastomosis of the occipital artery to the P4 portion of the PCA followed by endovascular obliteration of the parent artery including the aneurysms. Endovascular treatment was performed via a femoral approach one week after the anastomosis. Super-selective balloon test occlusion (BTO) of the PCoA was performed by using an occlusion balloon microcatheter before endovascular treatment. Occlusion of the proximal segment of the PCoA induced disturbance of consciousness of the patient. Occlusion of the distal segment other than the first point of the PCoA did not induce any neurological symptoms. The information from this super-selective BTO helped us to perform precise endovascular obliteration. The aneurysm was successfully obliterated, and the diplopia almost disappeared in a few months. Super-selective BTO of the PCoA might be a useful method for preventing ischemic complications due to occlusion of invisible perforators. PMID- 28664015 TI - Central Hypoventilation Syndrome Complicated with Lateral Medullary Infarction after Endovascular Treatment of the Vertebral Artery Dissecting Aneurysm: A Case Report. AB - Lateral medullary infarction rarely leads to central hypoventilation syndrome (CHS). CHS is a life-threatening disorder characterized by hypoventilation during sleep. We report the first case of CHS as a complication of lateral medullary infarction after endovascular treatment. A 65-year-old man presented twice with severe headache. Computed tomography revealed subarachnoid hemorrhage and cerebral angiography showed a right vertebral dissecting aneurysm involving the posterior inferior cerebellar artery. After emergent endovascular patent artery occlusion, he developed Wallenberg syndrome and experienced apnea and a conscious disturbance episode due to CHS on postoperative days 6 and 16. Intensive respiratory care including intubation, tracheostomy, mechanical ventilation, and rehabilitation prevented subsequent recurrence of apnea and the CHS resolved completely. CHS after unilateral medullary infarction involving respiratory centers tends to occur in the acute and subacute phase and may be lethal without careful respiratory management. PMID- 28664016 TI - Delayed Onset Eye Opening Apraxia due to Progression of Brain Atrophy following Subthalamic Nucleus Deep Brain Stimulation: A Case Report. AB - Eye opening apraxia (EOA) has been described in literature as a complication of deep brain stimulation (DBS), especially after electrode implantation in the subthalamic nucleus (STN). EOA can be either worsened or alleviated by DBS depending on the etiology. Herein, we report a rare case where the progression of brain atrophy may have contributed to the delayed onset of EOA. The patient, a 73 year-old woman, had previously undergone bilateral STN-DBS for advanced Parkinson's disease (PD), which was performed by another DBS team, at the age of 68 years. She initially experienced a dramatic improvement in her motor symptoms, with no adverse events. However, she had difficulty in opening her right eye 3 years after the DBS surgery. Imaging studies showed that the brain atrophy had progressed over the past 5 years, and that the DBS electrodes were implanted through the far anterior entry points. We considered that the relative movement of the DBS might have been caused by the progression of the brain atrophy to the posterior limb of the internal capsule (IC) where the corticobulbar tract exists, and this was enhanced by the lower implantation angle. The present case illustrates the importance of the DBS insertion angle considering the a+ trophic effect and the follow-up imaging studies after DBS. PMID- 28664017 TI - Coexistence of Quasi-moyamoya Disease and POEMS Syndrome in a Patient with Intracranial Hemorrhage: A Case Report and Literature Review. AB - POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare paraneoplastic syndrome elicited by plasma cell dyscrasia. Its clinical manifestations are multiple and stroke is not a recognized feature. A 44-year-old woman with a 3-month history of bilateral lower extremity sensorimotor disturbance was admitted to our hospital. Examinations revealed polyneuropathy, organomegaly, hypothyroidism, monoclonal gammopathy, pelvic plasmacytoma, and elevated serum vascular endothelial growth factor (VEGF) levels. A diagnosis of POEMS was made. Her condition was improved by radiation therapy of her pelvic plasmacytoma and she continued to be seen on an outpatient basis. Five years after her first admission she was re-admitted with sudden-onset right hemiparesis. A brain computed tomography (CT) scan revealed a left intracranial hemorrhage and magnetic resonance (MR) angiography and cerebral angiography showed occlusion of the proximal portion of the bilateral middle cerebral artery and narrowing of the bilateral internal carotid artery at the terminal portion; moyamoya vessels were seen. This is the first report of a patient whose intracranial hemorrhage was attributable to quasi-moyamoya disease associated with POEMS syndrome. We suggest that the POEMS syndrome be ruled out in the differential diagnosis of patients presenting with atypical stroke, multivessel stenotic lesions (moyamoya vessels), and polyneuropathy. PMID- 28664018 TI - Embolization for Refractory Subacute Subdural Hematoma in a Child with Severe Hemophilia Type A. AB - Hemophilia is an X-linked hemorrhagic disease due to coagulation factor VIII or IX deficiency with approximately 5-10% incidence of central nervous system bleeding. We present an intriguing case of a refractory subacute subdural hematoma (SDH) controlled with endovascular embolization in a hemophilic patient. A 5-year-old severe hemophilic A boy presented with a life threatening left parietal subcortical hemorrhage, for which he underwent craniotomy and evacuation of the hematoma. Recurrent hemorrhage necessitated a repeat craniotomy. This was followed by three episodes of SDH development at the craniotomy site that were treated surgically, and finally controlled with embolization in the subacute period. This case presents a novel option for treating a refractory SDH in patients with coagulation disorders. PMID- 28664019 TI - Crowned Dens Syndrome Occurred in a Patient after Simple Drainage for Chronic Subdural Hematoma: A Case Report. AB - Crowned dens syndrome (CDS) is a rare disease which presents with neck pain and rigidity. A 74-year-old man with right chronic subdural hematoma (CSDH) underwent hematoma drainage. After the operation, he complained of neck pain and laboratory test revealed elevation of C-reactive protein (CRP) and white blood cell (WBC). Suspecting localized infection, wound irrigation was performed. Neck pain relieved after irrigation, but we could not find the source of infection. CDS was diagnosed by computed tomography (CT). CDS is frequently misdiagnosed as meningitis and localized infection. CT is useful for diagnosis. Neurosurgeons need to be aware of CDS after operation. PMID- 28664020 TI - Intradiploic Arachnoid Cyst with Meningothelial Hyperplasia: A Case Report. AB - We report the case of a 40-year-old man presenting with focal headache and a bulge at the right parietal bone, diagnosed as an intradiploic arachnoid cyst. The cyst wall included "meningothelial hyperplasia," which is a rare finding. While over 40 cases of intradiploic arachnoid cysts have been reported to date, meningothelial hyperplasia in an intradiploic arachnoid cyst does not appear to have been reported. We also discuss the pathological findings of arachnoid cysts with meningothelial hyperplasia and mechanisms of enlargement of the arachnoid cyst. PMID- 28664021 TI - Abdominal Flank Bulging after Lateral Retroperitoneal Approach: A Case Report. AB - The lateral transpsoas approach to access the vertebrae obviates the need for an approach surgeon and minimizes muscular disruption, thus allowing for quicker recovery. Several reports on the lateral transpsoas procedure have described few complications. However, the development of an unsightly and painful abdominal flank bulge is a largely under-recognized and very rare complication of the lateral transpsoas approach. A 59-year-old man suffered from back pain and bilateral posterior leg pain. Computed tomography (CT) scan and MRI showed retrolisthesis at L3-4, L2 wedge vertebrae with kyphosis, left L4 screw loosening, and L3-4 disc herniation with central canal stenosis. L2 corpectomy and L3-4 DLIF and posterior fusion to T12 for kyphosis correction were performed. For the lateral approach, resection of the T11 rib was performed. One month later, he developed left abdominal flank bulging below the lateral approach site, which was aggravated by walking, coughing, defecating, constipation, and eating. CT scan showed left abdominal flank bulging accompanied by abdominal muscle thinning. We believe that this complication is caused by denervation of the abdominal musculature after injury to the T11 intercostal nerves. PMID- 28664022 TI - Intracerebral Hemorrhage Caused by Cerebral Hyperperfusion after Superficial Temporal Artery to Middle Cerebral Artery Bypass for Atherosclerotic Occlusive Cerebrovascular Disease. AB - Few papers have reported detailed accounts of intracerebral hemorrhage caused by cerebral hyperperfusion after superficial temporal artery to middle cerebral artery bypass (STA-MCA) bypass for atherosclerotic occlusive cerebrovascular disease. We report a case of vasogenic edema and subsequent intracerebral hemorrhage caused by the cerebral hyperperfusion syndrome (CHS) after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease disease without intense postoperative blood pressure control. A 63-year-old man with repeating left hemiparesis underwent magnetic resonance angiography (MRA), which revealed right internal carotid artery (ICA) occlusion. We performed a double bypass superficial temporal artery (STA)-middle cerebral artery (MCA) bypass surgery for the M2 and M3 branches. While the patient's postoperative course was relatively uneventful, he suffered generalized convulsions, and computed tomography revealed a low area in the right frontal lobe on Day 4 after surgery. We considered this lesion to be pure vasogenic edema caused by cerebral hyperperfusion after revascularization. Intravenous drip infusion of a free radical scavenger (edaravone) and efforts to reduce systolic blood pressure to <120 mmHg were continued. The patient experienced severe left hemiparesis and disturbance of consciousness on Day 8 after surgery, due to intracerebral hemorrhage in the right frontal lobe at the site of the earlier vasogenic edema. Brain edema associated with cerebral hyperperfusion after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease should be recognized as a risk factor for intracerebral hemorrhage. The development of brain edema associated with CHS after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease requires not only intensive control of blood pressure, but also consideration of sedation therapy with propofol. PMID- 28664023 TI - Late-Onset Massive Epistaxis due to a Ruptured Traumatic Internal Carotid Artery Aneurysm: A Case Report. AB - A traumatic internal carotid artery (ICA) aneurysm is rare and difficult to treat. Trapping of ICA is commonly performed owing to the difficulty of directly approaching ICA aneurysms. Recently, coiling the aneurysm itself was recommended if possible. However, it is controversial which of methods are best to completely treat aneurysm. We present the case of a 74-year-old man, who had experienced a head injury 8 years previously, with recurrent severe epistaxis. An ICA aneurysm was detected on computed tomography. The trapping and bypass was planned. However, sudden epistaxis occurred, we performed trapping to stop the bleeding and save his life. After the operation, no right ICA or aneurysm was detected. However, severe epistaxis recurred two months after the operation. In the second operation, a ligation of the common -/- external carotid artery and a severance of an ICA portion between the ophthalmic artery and the aneurysm were insufficient to stop the bleeding. This case indicates ICA trapping, even if a trapping portion is below an ophthalmic artery, is insufficient to treat an ICA aneurysm. ICA aneurysms should be suspected when a patient present with recurrent -/- massive epistaxis, who has a head injury history, even if it is far past. PMID- 28664024 TI - Neuroendoscopy via an Extremely Narrow Foramen of Monro: A Case Report. AB - Herein, safe and reliable neuroendoscopic biopsy via an extremely narrow foramen of Monro (ENFM) for a non-hydrocephalic patient with hypothalamic and pineal region tumors was successfully applied. A 17-year-old boy presented with hypothalamic manifestations attributed to hypothalamic and pineal region tumors. Small ventricles were seen. Intraoperatively, to advance different diameter steerable fiberscopes via ENFM, the third ventricle was flushed to induce a moment increase in the intraventricular pressure with subsequent dilatation of FM. Postoperative course was uneventful. Histopathological studies revealed a yolk sac tumor. Adjuvant therapy was applied. Follow-up neuroimaging disclosed marvellous improvement of the condition. His symptoms gradually improved. PMID- 28664025 TI - Traumatic Carotid Cavernous Fistula with a Connection between the Supraclinoid Internal Carotid Artery and Cavernous Sinus via a Pseudoaneurysm Presenting with Delayed Life-threatening Epistaxis. AB - Traumatic carotid cavernous fistula (CCF) presents most commonly as a direct connection between the cavernous segment of internal carotid artery (ICA) and cavernous sinus (CS), and often accompanies basal skull fracture (BSF). The most frequently reported signs and symptoms are proptosis, chemosis, and bruit. Epistaxis is uncommon symptom of CCF. A 63-year-old man with a history of BSF due to blunt head trauma eight months previously was referred to our emergency room for massive epistaxis. Cerebral angiography demonstrated a high-flow CCF with a connection between the supraclinoid portion of left ICA and CS via a pseudoaneurysm, suggesting the life-threatening epistaxis had been caused by high flow shunting, through the gap created by the BSF. After the complete obliteration of the pseudoaneurysm arising from the supraclinoid ICA by stent assisted coil embolization, the CCF was no longer evident and epistaxis ceased. To the best of our knowledge, this is the first case of a traumatic CCF with a connection between the supraclinoid ICA and CS via a pseudoaneurysm, presenting with delayed life-threatening epistaxis. PMID- 28664027 TI - Chronic Encapsulated Intracerebral Hematoma: Endoscopic Removal as Minimally Invasive Surgery for a Patient with Alcoholic Cirrhosis. AB - Chronic encapsulated intracerebral hematoma (CEIH) is a rare cerebrovascular disease. Here, we describe a case of a patient with alcoholic cirrhosis and an abnormal coagulation state that was treated with minimally invasive endoscopic hematoma removal. A 54-year-old man presented with a 2-week history of incoherent speech, incontinence, and repeated stumbling. Laboratory analysis showed thrombocytopenia and the prolongation of prothrombin time due to alcoholic cirrhosis. Computed tomography and magnetic resonance imaging showed a large mass in the left parieto-occipital lobe suggesting a hematoma. Minimally invasive endoscopic hematoma removal was then performed. CEIH was diagnosed from the intraoperative findings of serous hematoma, a thin yellowish capsule, and old clots. The postoperative course was uneventful and there was no hematoma recurrence. In conclusion, endoscopic hematoma removal may be one of the options for the treatment of CEIH in patients with cirrhosis and an abnormal coagulation state. PMID- 28664026 TI - Transarterial Sinus Embolization for a Dural Arteriovenous Fistula in a Sinus of the Lesser Sphenoid Wing: A Case Report. AB - Dural arteriovenous fistula (DAVF) in a sinus of the lesser sphenoid wing (SLSW) is rarely reported. Here, we report a case of an isolated SLSW DAVF treated by coils placed into the sinus through the feeding artery. A 68-year-old man was admitted to our hospital with headache. Magnetic resonance images and an angiogram showed a varix in the right middle cranial fossa. A DAVF, consisting of three main feeders and the isolated SLSW, was diagnosed based on the angiogram findings. Retrograde leptomeningeal venous drainage to the deep middle cerebral vein was observed. Given the remarkable extent of cortical venous ectasia together with the presence of headache and right abducens nerve paralysis, endovascular treatment was initiated. A transvenous approach through the right inferior petrosal sinus was not feasible because of difficulty associated with inserting the microcatheter into the SLSW. Thus, we tried a transarterial approach and were able to advance the microcatheter beyond the fistula into the isolated SLSW, through the artery of the foramen rotundum. The isolated sinus and feeding arteries were embolized with coils. The postoperative angiogram showed the total occlusion of the SLSW DAVF. This case demonstrates the feasibility of transarterial sinus packing for an isolated SLSW DAVF. PMID- 28664028 TI - A Case of Acute Isolated Posterior Cerebral Artery Occlusion Successfully Treated with Endovascular Clot Aspiration. AB - Posterior cerebral artery (PCA) strokes produce various symptoms. Therefore, the diagnosis is often delayed and patients arrive late for thrombolytic therapy. We report a case of acute isolated PCA occlusion that was successfully treated with endovascular clot aspiration. A 63-year-old man presented with right complete homonymous hemianopia. Diffusion-weighted image (DWI) showed a high-intensity area (HIA) in the occipital lobe, and magnetic resonance angiography (MRA) showed PCA occlusion. Emergency endovascular clot aspiration was performed immediately after the diagnosis. Blood flow in PCA completely recovered 210 min after symptom onset. DWI after surgery showed partial disappearance of HIA, and the patient recovered from the symptom of right complete homonymous hemianopia. Endovascular recanalization is useful for acute PCA occlusion. This is the first reported case of acute isolated PCA occlusion successfully treated with endovascular clot aspiration. Prompt reperfusion results in a good clinical course in patients with PCA stroke. In this case, endovascular clot aspiration resulted in prompt recanalization in a patient with acute isolated PCA occlusion. PMID- 28664029 TI - Endovascular Therapy for a Post-irradiated Cervical Pseudoaneurysm at the Carotid Stump: A Case Report. AB - A nearly 80-year-old man with a history of radiotherapy (RT) and total laryngectomy for laryngeal cancer 25 years previously presented with a rapidly growing mass on the right side of his neck. A huge pseudoaneurysm (pseudoAN) was detected at the right carotid bifurcation, though angiography performed four years previously had shown total occlusion of the internal carotid artery. Stent assisted coil embolization enabled aneurysm sac shrinkage. Clinicians must be aware that the stump of an arterial occlusion associated with RT can change into a pseudoAN over the long term and must provide follow-up in such cases. PMID- 28664030 TI - Disseminated Nannizziopsis obscura infection in a renal transplant patient- The first reported case. AB - This is a presentation of a case of disseminated fungal infection in a renal transplant patient with Nannizziopsis obscura, a species not previously reported as having caused disseminated disease in humans and not previously reported in the UK. The fungus was isolated from a intramuscular collection and from a lymph node. The patient responded well to a course of posaconazole. PMID- 28664031 TI - Large-scale structural alteration of brain in epileptic children with SCN1A mutation. AB - OBJECTIVE: Mutations in SCN1A gene encoding the alpha 1 subunit of the voltage gated sodium channel are associated with several epilepsy syndromes including genetic epilepsy with febrile seizures plus (GEFS +) and severe myoclonic epilepsy of infancy (SMEI). However, in most patients with SCN1A mutation, brain imaging has reported normal or non-specific findings including cerebral or cerebellar atrophy. The aim of this study was to investigate differences in brain morphometry in epileptic children with SCN1A mutation compared to healthy control subjects. METHODS: We obtained cortical morphology (thickness, and surface area) and brain volume (global, subcortical, and regional) measurements using FreeSurfer (version 5.3.0, https://surfer.nmr.mgh.harvard.edu) and compared measurements of children with epilepsy and SCN1A gene mutation (n = 21) with those of age and gender matched healthy controls (n = 42). RESULTS: Compared to the healthy control group, children with epilepsy and SCN1A gene mutation exhibited smaller total brain, total gray matter and white matter, cerebellar white matter, and subcortical volumes, as well as mean surface area and mean cortical thickness. A regional analysis revealed significantly reduced gray matter volume in the patient group in the bilateral inferior parietal, left lateral orbitofrontal, left precentral, right postcentral, right isthmus cingulate, right middle temporal area with smaller surface area and white matter volume in some of these areas. However, the regional cortical thickness was not significantly different in two groups. SIGNIFICANCE: This study showed large scale developmental brain changes in patients with epilepsy and SCN1A gene mutation, which may be associated with the core symptoms of the patients. Further longitudinal MRI studies with larger cohorts are required to confirm the effect of SCN1A gene mutation on structural brain development. PMID- 28664032 TI - Five-class differential diagnostics of neurodegenerative diseases using random undersampling boosting. AB - Differentiating between different types of neurodegenerative diseases is not only crucial in clinical practice when treatment decisions have to be made, but also has a significant potential for the enrichment of clinical trials. The purpose of this study is to develop a classification framework for distinguishing the four most common neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobe degeneration, Dementia with Lewy bodies and vascular dementia, as well as patients with subjective memory complaints. Different biomarkers including features from images (volume features, region-wise grading features) and non-imaging features (CSF measures) were extracted for each subject. In clinical practice, the prevalence of different dementia types is imbalanced, posing challenges for learning an effective classification model. Therefore, we propose the use of the RUSBoost algorithm in order to train classifiers and to handle the class imbalance training problem. Furthermore, a multi-class feature selection method based on sparsity is integrated into the proposed framework to improve the classification performance. It also provides a way for investigating the importance of different features and regions. Using a dataset of 500 subjects, the proposed framework achieved a high accuracy of 75.2% with a balanced accuracy of 69.3% for the five-class classification using ten fold cross validation, which is significantly better than the results using support vector machine or random forest, demonstrating the feasibility of the proposed framework to support clinical decision making. PMID- 28664033 TI - Decreased susceptibility of major veins in mild traumatic brain injury is correlated with post-concussive symptoms: A quantitative susceptibility mapping study. AB - Cerebral venous oxygen saturation (SvO2) is an important biomarker of brain function. In this study, we aimed to explore the relative changes of regional cerebral SvO2 among axonal injury (AI) patients, non-AI patients and healthy controls (HCs) using quantitative susceptibility mapping (QSM). 48 patients and 32 HCs were enrolled. The patients were divided into two groups depending on the imaging based evidence of AI. QSM was used to measure the susceptibility of major cerebral veins. Nonparametric testing was performed for susceptibility differences among the non-AI patient group, AI patient group and healthy control group. Correlation was performed between the susceptibility of major cerebral veins, elapsed time post trauma (ETPT) and post-concussive symptom scores. The ROC analysis was performed for the diagnostic efficiency of susceptibility to discriminate mTBI patients from HCs. The susceptibility of the straight sinus in non-AI and AI patients was significantly lower than that in HCs (P < 0.001, P = 0.004, respectively, Bonferroni corrected), which may indicate an increased regional cerebral SvO2 in patients. The susceptibility of the straight sinus in non-AI patients positively correlated with ETPT (r = 0.573, P = 0.003, FDR corrected) while that in AI patients negatively correlated with the Rivermead Post Concussion Symptoms Questionnaire scores (r = - 0.582, P = 0.018, FDR corrected). The sensitivity, specificity and AUC values of susceptibility for the discrimination between mTBI patients and HCs were 88%, 69% and 0.84. In conclusion, the susceptibility of the straight sinus can be used as a biomarker to monitor the progress of mild TBI and to differentiate mTBI patients from healthy controls. PMID- 28664034 TI - Fully automatic acute ischemic lesion segmentation in DWI using convolutional neural networks. AB - Stroke is an acute cerebral vascular disease, which is likely to cause long-term disabilities and death. Acute ischemic lesions occur in most stroke patients. These lesions are treatable under accurate diagnosis and treatments. Although diffusion-weighted MR imaging (DWI) is sensitive to these lesions, localizing and quantifying them manually is costly and challenging for clinicians. In this paper, we propose a novel framework to automatically segment stroke lesions in DWI. Our framework consists of two convolutional neural networks (CNNs): one is an ensemble of two DeconvNets (Noh et al., 2015), which is the EDD Net; the second CNN is the multi-scale convolutional label evaluation net (MUSCLE Net), which aims to evaluate the lesions detected by the EDD Net in order to remove potential false positives. To the best of our knowledge, it is the first attempt to solve this problem and using both CNNs achieves very good results. Furthermore, we study the network architectures and key configurations in detail to ensure the best performance. It is validated on a large dataset comprising clinical acquired DW images from 741 subjects. A mean accuracy of Dice coefficient obtained is 0.67 in total. The mean Dice scores based on subjects with only small and large lesions are 0.61 and 0.83, respectively. The lesion detection rate achieved is 0.94. PMID- 28664036 TI - Virtual brain biopsies in amyotrophic lateral sclerosis: Diagnostic classification based on in vivo pathological patterns. AB - BACKGROUND: Diagnostic uncertainty in ALS has serious management implications and delays recruitment into clinical trials. Emerging evidence of presymptomatic disease-burden provides the rationale to develop diagnostic applications based on the evaluation of in-vivo pathological patterns early in the disease. OBJECTIVES: To outline and test a diagnostic classification approach based on an array of complementary imaging metrics in key disease-associated anatomical structures. METHODS: Data from 75 ALS patients and 75 healthy controls were randomly allocated in a 'training' and 'validation' cohort. Spatial masks were created for anatomical foci which best discriminate patients from controls in the 'training sample'. In a virtual 'brain biopsy', data was then retrieved from these key disease-associated brain regions. White matter diffusivity indices, grey matter T1-signal intensity values and basal ganglia volumes were evaluated as predictor variables in a canonical discriminant function. RESULTS: Following predictor variable selection, a classification specificity of 85.5% and sensitivity of 89.1% was achieved in the training sample and 90% specificity and 90% sensitivity in the validation sample. DISCUSSION: This study evaluates disease-associated imaging measures in a dummy diagnostic application. Although larger samples will be required for robust validation, the study confirms the potential of multimodal quantitative imaging in future clinical applications. PMID- 28664035 TI - Neurophysiological mechanisms of circadian cognitive control in RLS patients - an EEG source localization study. AB - The circadian variation of sensory and motor symptoms with increasing severity in the evening and at night is a key diagnostic feature/symptom of the restless legs syndrome (RLS). Even though many neurological diseases have shown a strong nexus between motor and cognitive symptoms, it has remained unclear whether cognitive performance of RLS patients declines in the evening and which neurophysiological mechanisms are affected by the circadian variation. In the current study, we examined daytime effects (morning vs. evening) on cognitive performance in RLS patients (n = 33) compared to healthy controls (n = 29) by analyzing flanker interference effects in combination with EEG and source localization techniques. RLS patients showed larger flanker interference effects in the evening than in the morning (p = .023), while healthy controls did not display a comparable circadian variation. In line with this, the neurophysiological data showed smaller N1 amplitudes in RLS patients compared to controls in the interfering task condition in the evening (p = .042), but not in the morning. The results demonstrate diurnal cognitive changes in RLS patients with intensified impairments in the evening. It seems that not all dopamine-regulated cognitive processes are altered in RLS and thus show daytime-dependent impairments. Instead, the daytime-related cognitive impairment emerges from attentional selection processes within the extra-striate visual cortex, but not from later cognitive processes such as conflict monitoring and response selection. PMID- 28664038 TI - Case report: Epilepsy surgical outcome for epileptic and non epileptic seizures with posttraumatic stress disorder and depression. AB - A 48-year-old male was diagnosed with both drug resistant epilepsy and psychogenic nonepileptic seizures. Both diagnoses were confirmed by video-EEG monitoring. His epileptic seizures were a consequence of right mesial temporal sclerosis. He was diagnosed by a psychiatrist to have depression and posttraumatic stress disorder (PTSD). Following a right anterior temporal resection he became seizure free (both epileptic and nonepileptic) with a remarkable improvement in his psychiatric comorbidities leading to significant reduction in his psychotropic medications. No reports have been identified in the literature of patients with epilepsy and PNES with coexisting PTSD having epilepsy surgery. PMID- 28664039 TI - Congratulations on the publication of the first issue of Integrative Medicine Research. PMID- 28664040 TI - Why integration? AB - The recent growth of the systems approach to biology provides a better conceptual framework within which to interpret holistic approaches to medicine. The reason is that systems biology respects the way in which the whole constrains the parts to behave in ways that are different from what they would do in isolation. Holistic treatments depend on the same insight and can therefore be successful in practice where reductionist approaches would fail. PMID- 28664041 TI - "Feeling lighter": Why the patient's treatment evaluation matters to the health scientist. AB - "Feeling lighter" is a cross-culturally found subjective patient experience, but it may well contain a comment on intersubjectively recognisable physical, neuro chemical and bio-electro-magnetic processes that natural scientific research can identify. The health scientist is advised to take the patient's experiences seriuosly, and regard them as a possible source of for future research topics. PMID- 28664037 TI - White matter tractography for neurosurgical planning: A topography-based review of the current state of the art. AB - We perform a review of the literature in the field of white matter tractography for neurosurgical planning, focusing on those works where tractography was correlated with clinical information such as patient outcome, clinical functional testing, or electro-cortical stimulation. We organize the review by anatomical location in the brain and by surgical procedure, including both supratentorial and infratentorial pathologies, and excluding spinal cord applications. Where possible, we discuss implications of tractography for clinical care, as well as clinically relevant technical considerations regarding the tractography methods. We find that tractography is a valuable tool in variable situations in modern neurosurgery. Our survey of recent reports demonstrates multiple potentially successful applications of white matter tractography in neurosurgery, with progress towards overcoming clinical challenges of standardization and interpretation. PMID- 28664042 TI - Review on the current trends in tongue diagnosis systems. AB - Tongue diagnosis is an essential process to noninvasively assess the condition of a patient's internal organs in traditional medicine. To obtain quantitative and objective diagnostic results, image acquisition and analysis devices called tongue diagnosis systems (TDSs) are required. These systems consist of hardware including cameras, light sources, and a ColorChecker, and software for color correction, segmentation of tongue region, and tongue classification. To improve the performance of TDSs, various types TDSs have been developed. Hyperspectral imaging TDSs have been suggested to acquire more information than a two dimensional (2D) image with visible light waves, as it allows collection of data from multiple bands. Three-dimensional (3D) imaging TDSs have been suggested to provide 3D geometry. In the near future, mobile devices like the smart phone will offer applications for assessment of health condition using tongue images. Various technologies for the TDS have respective unique advantages and specificities according to the application and diagnostic environment, but this variation may cause inconsistent diagnoses in practical clinical applications. In this manuscript, we reviewed the current trends in TDSs for the standardization of systems. In conclusion, the standardization of TDSs can supply the general public and oriental medical doctors with convenient, prompt, and accurate information with diagnostic results for assessing the health condition. PMID- 28664043 TI - Temperament profiles of Sasang typology in a child clinical sample. AB - BACKGROUND: Sasang typology is a personalized traditional medicine widely used in clinical diagnosis and treatment in Korea. The aim of this study was to examine the biopsychological personality profiles of traditional Korean Sasang typology in a clinical sample of Korean children. METHODS: A total of 150 children were classified as one of three traditional Korean Sasang types (19 So-Yang, 118 Tae Eum, and 13 So-Eum) by two clinical experts in Sasang typology. The childrens' mothers completed the Korean version of the Junior Temperament and Character Inventory (JTCI). The four temperament dimensions of JTCI were compared between the different Sasang types using analysis of variance (ANOVA) and profile analysis. RESULTS: There were no significant differences in age, gender, and parents' education levels across the Sasang types. The JTCI temperament profile for each of the child Sasang types was significantly different (profile analysis, df = 5.315, F = 2.508, p = 0.027). There were significant differences in novelty seeking (F = 3.850, p = 0.023) and novelty-seeking subscales, but not with other temperament dimensions. CONCLUSION: These results demonstrated distinct temperament traits associated with traditional Korean Sasang types in children using an objective biopsychological personality inventory. With further investigation into the biopsychological profiles of the children, the longitudinal stability of the Sasang typology can be examined. PMID- 28664044 TI - Analysis of Sasang constitutional types using facial features with compensation for photographic distance. AB - BACKGROUND: Facial features are regarded as representative and reliable characteristics for diagnosing a person's Sasang Constitution (SC). However, the description of these features tends to depend on the interpretation and the opinion of the doctor that follows the SC approach. In this paper, we performed a facial feature analysis of SC types in an objective and quantitative manner. Here, site-to-site variability can be an obstacle to properly analyzing facial features when images are taken from various sites, which may have different experimental environments. A compensation technique to reduce the site-to-site variability was proposed before performing the feature analysis. METHODS: The frontal and profile images of 1464 patients recruited from various oriental medical clinics (19 sites) were used. Candidate feature variables were created, which were inspired by the facial characteristics of the SC types described in the Sasang constitutional medicine literature. To resolve the problems involved in processing data collected from various sites with heterogeneous experimental environments, a compensation technique was proposed. Statistical analysis techniques were employed to observe the differences among the SC types and to demonstrate how effectively the site-to-site variability was reduced. RESULTS: The facial features that were significant for diagnosing the SC types were identified by a statistical analysis, and it was verified that the compensation technique reduced the site-to-site variability produced by the differences in photographic distance. CONCLUSION: It is noted that the significant facial features represent common characteristics of each SC type in the sense that we collected extensive opinions from many Sasang constitutional medicine doctors with various points of view. Additionally, a compensation method for the photographic distance is needed to find the significant facial features. We expect these findings and the related compensation technique to contribute to establishing a scientific basis for the precise diagnosis of SC types in clinical practice. PMID- 28664045 TI - Adjacent, distal, or combination of point-selective effects of acupuncture on temporomandibular joint disorders: A randomized, single-blind, assessor-blind controlled trial. AB - BACKGROUND: The objectives of this study were to compare the efficacy of acupuncture among different types and to evaluate point-selective pain relief effects between selected adjacent or distant points in participants with temporomandibular joint disorders (TMDs). METHODS: Forty-two participants were randomly allocated to three groups: an adjacent point selection group (Trt, n = 14), a distant point selection group (Con1, n = 14), or a combination group (Con2, n = 14). All three groups received a total of six acupuncture sessions (twice a week for 3 weeks), the outcomes being assessed pain intensity using a 10 cm visual analogue scale, and the palpation index of the muscle and temporomandibular joint every week of treatment and 4 weeks after the end of treatment. RESULTS: The pain intensity was reduced in the Trt (34%), Con1 (31%), and Con2 (36%) groups after 3 weeks compared with each group's baseline, with no significant difference among the three groups (p = 0.5867). Similarly, the palpation index was decreased by 52% (Trt), 62% (Con1), and 50% (Con2) after 3 weeks of treatment, but no significant differences between groups were shown (p = 0.3289). CONCLUSION: Our results suggest that point-selective effects among adjacent, distal, or a combination of acupoints are hardly associated with pain intensity or palpation index in participants with TMDs. Larger sample size trials are required to overcome the shortcomings of the study. PMID- 28664046 TI - Taeeum-type people in Sasang constitutional medicine have a reduced mitochondrial metabolism. AB - Sasang constitutional medicine (SCM) is a traditional form of medicine that is widely used in Korea to clinically diagnose and treat disease. The main characteristic of SCM is its classification of people according to physical constitution. The theory asserts that four different types of physical constitution exist: Taeyang, Soyang, Taeeum, and Soeum. One noticeable clinical observation in SCM is that Taeeum-type people are prone to obesity. Although extensive clinical investigations have shown this tendency in SCM, no scientific hypothesis has been proposed to delineate its mechanism. According to SCM theory, Taeeum-type people have a hypoactive lung system and a hyperactive liver system. In this paper, we propose a new hypothesis explaining this finding from a physiological viewpoint. A functional weakness in the lung system indicates intrinsic hypoactivity in the consumption of metabolic energy, therefore we deduced that the tendency can easily induce body weight gain via an increase in anabolism. PMID- 28664047 TI - Re-interpretation of traditional Asian medicine with constitutional perspective. AB - There has been a rapid increase in tailored medicine that emphasizes the complex inter-individual interactions, and this increase has paralleled recent significant achievements in genomics and Systems Biology. However, attempts to create a virtual human have been limited to low-levels of organization, such as gene-protein networks, due to the lack of systematic concepts at the higher levels of organisms (organ, individual, and environment). Constitutional perspective of various forms of traditional Asian medicine through the ancient, middle, and modern eras, particularly the holistic approach of Sasang constitutional medicine (SCM), may provide a novel framework for creating tailored medicine. This article aims to review the theoretical development of traditional Chinese medicine and the initiation of SCM in addition to summarizing current evidence on the genetic basis, bio-physiological features, and risk of disease of different SCM phenotypes. We also suggest that the patho-physiological principle and scientific evidence underlying SCM, particularly for the TaeEum type, can be effective in dealing with obesity-linked disease, which is a predominant disease in today's society. PMID- 28664048 TI - Development of pulse diagnostic devices in Korea. AB - In Korean medicine, pulse diagnosis is one of the important methods for determining the health status of a patient. For over 40 years, electromechanical pulse diagnostic devices have been developed to objectify and quantify pulse diagnoses. In this paper, we review previous research and development for pulse diagnostic devices according to various fields of study: demand analysis and current phase, literature studies, sensors, actuators, systems, physical quantity studies, clinical studies, and the U-health system. We point out some confusing issues that have been naively accepted without strict verification: original pressure pulse waveform and derivative pressure pulse waveform, pressure signals and other signal types, and minutely controlled pressure exertion issues. We then consider some technical and clinical issues to achieve the development of a pulse diagnostic device that is appropriate both technically and in terms of Korean medicine. We hope to show the history of pulse diagnostic device research in Korea and propose a proper method to research and develop these devices. PMID- 28664049 TI - Screening of aqueous extracts of medicinal herbs for antimicrobial activity against oral bacteria. AB - BACKGROUND: Dental caries is considered to be a preventable disease, and various antimicrobial agents have been developed for the prevention of dental diseases; however, many bacteria show resistance to existing agents. In this study, 14 medicinal herbs were evaluated for antimicrobial activity against five common oral bacteria as a screen for potential candidates for the development of natural antibiotics. METHODS: Aqueous extracts of medicinal herbs were tested for activity against Enterococcus faecalis, Actinomyces viscosus, Streptococcus salivarius, Streptococcus mutans, and Streptococcus sanguis grown in brain heart infusion (BHI) broth. A broth microdilution assay was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). A disk diffusion assay was performed by inoculating bacterial cultures on BHI agar plates with paper disks soaked in each of the medicinal herb extracts. Inhibition of the synthesis of water-insoluble glucans by S. mutans was also investigated. RESULTS: The aqueous extracts of many of the 14 medicinal herbs demonstrated antimicrobial activity against the five types of pathogenic oral bacteria. The extracts of Sappan Lignum, Coptidis Rhizoma, and Psoraleae Semen effectively inhibited the growth of oral bacteria and showed distinct bactericidal activity. The extracts of Notoginseng Radix, Perillae Herba, and Psoraleae Semen decreased the synthesis of water-insoluble glucans by the S. mutans enzyme glucosyltransferase (GTase). The present study is the first to confirm the antimicrobial activity of the extract of Sappan Lignum against all five species of oral bacteria strains. CONCLUSION: These results suggest that certain herbal medicines with proven antimicrobial effects, such as Sappan Lignum and Psoraleae Semen, may be useful for the treatment of dental diseases. PMID- 28664051 TI - A case of chronic fatigue syndrome improved by traditional Korean medicine. AB - The etiology of chronic fatigue syndrome (CFS) is unknown and no conventional medicine therapies are available. This report presents a clinical case of a patient suffering from CFS who was cured by traditional Korean medicine. A 33 year-old female patient had to take time off work because of terrible fatigue symptoms that did not respond to conventional treatments. Her disorder was significantly reduced by herbal medicine, acupuncture, and moxibustion. Changes in fatigue severity were evaluated using a visual analog scale (VAS) and a numerical rating scale (NRS). NRS and VAS scores decreased from 70 and 8.1 to 37 and 3.7, respectively, during 3 months. This case reveals the therapeutic potential of traditional Korean medicine for CFS and fatigue-associated disorders. PMID- 28664050 TI - Use of complementary and alternative medicine by self- or non-institutional therapists in South Korea: a community-based survey. AB - BACKGROUND: The purpose of this study is to investigate the prevalence and utilization pattern of complementary and alternative medicine (CAM) administered by oneself or by non-institutional practitioners in a general population in South Korea. METHODS: Nationwide, face-to-face surveys were conducted from September 1, 2011 to October 5, 2011. We conveniently selected the participants by using a proportional allocation method according to age, gender, and region. The use of CAM in the last year, the patterns of use, sources of information, and counseling objects were investigated in addition to respondents' demographic characteristics. RESULTS: Among the 1284 people approached, 915 respondents (71.3%) reported having had at least one CAM therapy during the past 12 months. Natural products were used the most frequently (58.8%). Unexpectedly, 82.6% out of 1740 therapies reported were self-administered CAM. Healthcare professionals were the source of information on CAM in only 5.6% of all instances of use, and only 17.7% of participants had consulted with doctors regarding CAM use. CONCLUSIONS: Owing to the widespread use of CAM in South Korea, researchers should focus on the safety and potential effectiveness of CAM therapy when self administered by users or by unauthorized CAM practitioners. PMID- 28664052 TI - Who has super-digestive system? PMID- 28664053 TI - Digestive system-related pathophysiological symptoms of Sasang typology: Systematic review. AB - The purpose of this study was to review clinical studies on digestive system related pathophysiological symptoms of each Sasang type to obtain the generalizable typespecific clinical features, which are important for the diagnosis of the Sasang type and subsequent disease treatment. Sasang typology and digestive system symptom-related keywords were used to search through eight domestic and foreign databases up to March 2012. The results were organized and analyzed based on four categories [digestive function, appetite, eating pattern, and body mass index (BMI)] to elucidate type-specific symptoms. Sasang type specific digestive system-related symptoms were identified by reviewing 30 related articles that were gathered by searching through the databases. The Tae Eum (TE) type had the highest digestive functions and the So-Eum (SE) type had the lowest. The TE type appeared to have larger volume with fast eating speed compared with the SE type and individuals in the TE category preferred fatty or salty food, which is responsible for the high occurrence rates of organic digestive diseases such as gastritis. Moreover, BMI was higher in the TE type and lower in the SE type. We systematically reviewed previously published clinical reports on digestive functions, which can be used to meet the objective of Sasang type differentiation and pathophysiological pattern identification. PMID- 28664055 TI - Comparative antioxidant potential of Withania somnifera based herbal formulation prepared by traditional and non-traditional fermentation processes. AB - BACKGROUND: Ashwagandharishtha is a liquid polyherbal formulation traditionally prepared by fermentation process using the flowers of Woodfordia fruticosa. It contains roots of Withania somnifera as a major crude drug. Alcohol generated during the fermentation causes the extraction of water insoluble phytoconstituents. Yeasts present on the flowers are responsible for this fermentation. METHODS: Total nine formulations of ashwagandharishtha were prepared by fermentation process using traditional Woodfordia fruticosa flowers (ASG-WFS) and using yeasts isolated from the same flowers. During fermentation, kinetic of alcohol generation, sugar consumption, changes in pH and withanolides extraction were studied. All the formulations were tested for in vitro antioxidant potential by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging, hydrogen peroxide scavenging and total reducing power assay. The results were compared with standard ascorbic acid. RESULTS: Traditional formulation (ASG-WFS) showed the highest activity (p < 0.001) relative to other formulations and standard ascorbic acid. ASG-WFS showed significant (DPPH) free radical scavenging (78.75%) and hydrogen peroxide scavenging (69.62%) at the concentration of 1000 MUg/mL and 100 MUg/mL, respectively. CONCLUSION: Traditional process is the best process for preparing ashwagandharishtha to obtain significant antioxidant activity. PMID- 28664054 TI - Exercise perspective on common cardiac medications. AB - Medicinal tablets have been used for a long time to treat cardiovascular disease. However, mortality rate is steadily increasing partly because of the patients' sedentary lifestyle and unhealthy diet. By contrast, exercise has been systematically shown to have multiple benefits. Regular exercise training can prevent various diseases in healthy individuals. Combined exercise and cardiac medications may lead to the improvement of heart disease. Numerous exercise training pathways still need further investigations. How exercise can prevent, treat, or attenuate diseases remains somewhat elusive. Thus, this review will discuss cardiac medications in parallel with the mechanism of action of exercise. PMID- 28664056 TI - Involvement of transient receptor potential melastatin type 7 channels on Poncirus fructus-induced depolarizations of pacemaking activity in interstitial cells of Cajal from murine small intestine. AB - BACKGROUND: Extracts of Poncirus trifoliata (L.) Raf. (Rutaceae; PT) are widely used as a traditional medicine in Eastern Asia, especially for the treatment of gastrointestinal (GI) disorders related to GI motility. Interstitial cells of Cajal (ICCs) are pacemakers in the GI tract, and transient receptor potential melastatin type 7 (TRPM7) channels and Ca2+ activated Cl- channels are candidate pacemaker channels. METHODS: In the present study, the effects of a methanolic extract of the dried roots of PT on ICC pacemaking activity were examined using the whole-cell patch-clamp technique. RESULTS: The methanolic extract of PT (PTE) was found to decrease the amplitudes of pacemaker potentials in ICC clusters and to depolarize the resting membrane potentials in a concentration-dependent manner. Intracellular GDP-beta-S suppressed PTE-induced depolarizations, and pretreatment with a U-73122 (a phospholipase C inhibitor) or with 2-APB (an 1,4,5 inositol triphosphate receptor inhibitor) abolished this generation of pacemaker potentials and suppressed PTE-induced effects. The applications of flufenamic acid, niflumic acid, waixenicin A, or 5-lipoxygenase inhibitors (NDGA or AA861) abolished this generation of pacemaker potentials and inhibited PTE-induced membrane depolarization. Furthermore, PTE inhibited TRPM7 channels but did not affect Ca2+-activated Cl- channels (both channels play important roles in the modulation of the pacemaking activity related to GI motility). CONCLUSION: These results suggest that the PTE-induced depolarization of pacemaking activity occurs in a G-protein-, phospholipase C-, and 1,4,5-inositol triphosphate-dependent manner via TRPM7 channels in cultured ICCs from murine small intestine, which indicates that ICCs are PTE targets and that their interactions affect intestinal motility. PMID- 28664058 TI - Korean medicine coverage in the National Health Insurance in Korea: present situation and critical issues. AB - National Health Insurance (NHI) in Korea has covered Korean medicine (KM) services including acupuncture, moxibustion, cupping, and herbal preparations since 1987, which represents the first time that an entire traditional medicine system was insured by an NHI scheme anywhere in the world. This nationwide insurance coverage led to a rapid increase in the use of KM, and the KM community became one of the main interest groups in the Korean healthcare system. However, due to the public's safety concern of and the stagnancy in demand for KM services, KM has been facing new challenges. This paper presents a brief history and the current structure of KM health insurance, and describes the critical issues related to KM insurance for in-depth understanding of the present situation. PMID- 28664057 TI - Antiplatelet and antithrombotic effect of Phyllostachys pubescens leaves and Mume Fructus combination. AB - BACKGROUND: Agents currently used for the treatment and prevention of thrombosis have a number of side effects. We conducted this study to develop antithrombotic agents from herbs that are used in food. METHODS: The 80% (v/v) ethanol extracts of Phyllostachys pubescens leaf (PL) and Mume Fructus (MF) and their combinations 2:1 (PM21), 1:1 (PM11), and 1:2 (PM12)-were evaluated on rat platelet aggregation induced by adenosine diphosphate (ADP) in vitro and on arteriovenous shunt thrombosis after 3 days of oral treatment in rats in vivo. RESULTS: At 100 MUg/mL, PM21 and PM11 inhibited in vitro ADP-induced aggregation by 44.0 +/- 4.3% and 30.0 +/- 3.2%, respectively, whereas PL, MF, and PM12 weakly or scarcely inhibited ADP-induced aggregation by 3.9 +/- 3.2%, 13.0 +/- 2.7%, and 5.2 +/- 1.3%, respectively. The IC50 values of PM21 on ADP-, collagen-, and thrombin induced platelet aggregations were 135.6 +/- 7.4 MUg/mL, 142.7 +/- 5.8 MUg/mL, and 186.5 +/- 9.7 MUg/mL, respectively. In an in vivo rat arteriovenous-shunt thrombosis model, thrombus weight was significantly decreased after the oral administration of 400 mg/kg PL (27.8 +/- 3.0%, p < 0.01) or MF (35.2 +/- 2.1%, p < 0.01), and with a good accord to the in vitro results, the combination of PL and MF in the ratio of 2:1, PM21 (60.9 +/- 1.2%, p < 0.001), showed a superior antithrombotic effect to those of individual extracts. At dosages of 200 mg/kg, 100 mg/kg, and 50 mg/kg, PM21 dose-dependently decreased thrombosis weight (ED50, 314 mg/kg). CONCLUSION: These results suggest that combination preparations of PL and MF, especially their 2:1 combination, can increase antiplatelet and antithromboticeffects more than PL and MF alone, offering evidence for a potential novel combination antithrombotic therapy. PMID- 28664059 TI - Intrarater and interrater reliability of pulse examination in traditional Indian Ayurvedic medicine. AB - BACKGROUND: In Ayurveda, pulse examination (nadipariksha) is an important tool to assess the status of three doshas: vata, pitta, and kapha. Long historical use has been seen as a documentation of its efficacy; however, there is a lack of a quantitative measure of the reliability of the pulse examination method. The objective of this study was to test the intrarater and interrater reliability of pulse examination in Ayurveda. METHODS: Fifteen registered Ayurvedic doctors with 3-15 years of experience examined the pulse of 20 healthy volunteers twice, for a total of 600 examinations. The examinations were performed blind and in a random order. Only the current status of dosha-specific methods of pulse examination were considered. Cohen's weighted kappa statistic was used as a measure of intrarater and interrater reliability, and a hypothesis of homogeneous diagnosis (random rating) was tested. Following this, we tested whether proportions of ratings were equal between doctors. RESULTS: According to the Landis and Koch scale, the level of reliability ranged from poor to moderate. It was observed that the doctors more frequently diagnosed a combination of two doshas than a single dosha. The kappa values were generally larger for experienced doctors (p = 0.04). CONCLUSION: Experience and proper training have important roles in pulse examination. PMID- 28664060 TI - Histological similarity of primo vascular systems derived from three internal organs of rats. AB - BACKGROUND: The primo vascular system has been suggested as the third circulatory system. Although primo tissues have been observed in various tissues isolated from a number of animal species, including mice, rats, and rabbits, very few reports on the histological characteristics of primo tissues from different body parts are available. This study was designed to compare the histological characteristics of primo tissues isolated from different body parts of rats. METHODS: Rats were anesthetized and operated on, to locate primo tissues. The primo tissues were searched at the all organs' surface and in lymphatic vessels using suitable finding methods. The tissues found were then separated and observed by histological test methods. RESULTS: This histological study revealed that there was no difference between the histological characteristics of the organ-surface primo tissues, the primo tissues inside lymphatic vessels, and the primo tissues on the falciform ligament. Moreover, primo tissues could be differentiated from those with a similar structure, such as lymphatic vessels and blood vessels, by immunostaining against a-LYVE-1 and a-CD31, and can be observed by specific immunostaining against the Von Willebrand factor (vWF). CONCLUSION: The results of this study support the fact that primo tissues could possibly constitute a third circulatory system in the whole-body network. PMID- 28664061 TI - Pu-18-N-butylimide-NMGA-GNP conjugate is effective against hepatocellular carcinoma. AB - BACKGROUND: Photodynamic therapy (PDT) is a new modality in the treatment of cancer. This study thus aims to examine whether the PDT is effective against in vivo hepatocellular carcinoma. METHODS: In vivo efficacy of PDT on hepatocellular carcinoma was tested in xenografted mice with human hepatocellular carcinoma cell lines (Huh7) by utilizing a gold nanoparticles (GNPs) conjugate of new photosensitizer (PS), purpurin-18-N-butylimide-N-methyl-D-glucamine (Pu-18-N butylimide-NMGA). The conjugate (PS-GNPs) was synthesized from the reaction between Pu-18-N-butylimide-NMGA and chloroauric acid (HAuCl4). Mice were arbitrarily assigned into one of three groups. First group received saline alone, second group received PS-GNPs alone, and the last group received both PS-GNPs and irradiation. PS-GNPs was injected directly into the tumor mass and irradiations were performed 24 hours after injection of PS-GNPs. RESULTS: Tumor volume was significantly smaller in the group which received both PS-GNPs and irradiation compared with other two groups. Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that the group which received both PS-GNPs and irradiation showed larger amount of apoptotic protein and DNA fragmentation compared with other two groups. CONCLUSION: This study suggests that Pu-18-N-butylimide-NMGA-GNP conjugate is an effective agent for PDT in the treatment of hepatocellular carcinoma. PMID- 28664062 TI - Activation of rat transient receptor potential cation channel subfamily V member 1 channels by 2-aminoethoxydiphenyl borate. AB - BACKGROUND: The transient receptor potential cation channel subfamily V member 1 (TRPV1) channel has been proved to be a molecular integrator of inflammatory pain sensation. 2-Aminoethoxydiphenyl borate (2-APB) and its analogs have been noticed as attractive candidates for the development of a selective TRPV1 agonist and/or antagonist. However, selectivity and effectiveness, species dependence, and the binding site(s) of 2-APB on TRPV1 channel protein remain controversial. METHODS: The present study aimed to characterize acting sites of 2-APB on heterologously expressed rat TRPV1 (rTRPV1) channels in HEK 293 cells. Rat TRPV1 currents were recorded by cell-free, excised patch clamp techniques. RESULTS: In inside-out and outside-out patch modes, 2-APB applied either side of the membrane dose dependently activated rTRPV1 channels. 2-APB dose-dependently potentiated rTRPV1 currents, that activated by capsaicin, protons, or noxious heat. 2-APB potentiated the capsaicin-activated rTRPV1 current from both side of the patch membrane. A structural analogue of 2-APB, diphenylboronic anhydride, showed the same potentiation effect on the capsaicin-activated rTRPV1 current. CONCLUSION: It is suggested that 2-APB directly opens rTRPV1 channels from both sides of the membrane and potentiates the opening of channels by inflammatory stimuli. PMID- 28664063 TI - Reminiscing on my visits to the Needham Research Institute. PMID- 28664064 TI - Exercise and obesity-induced insulin resistance in skeletal muscle. AB - The skeletal muscle in our body is a major site for bioenergetics and metabolism during exercise. Carbohydrates and fats are the primary nutrients that provide the necessary energy required to maintain cellular activities during exercise. The metabolic responses to exercise in glucose and lipid regulation depend on the intensity and duration of exercise. Because of the increasing prevalence of obesity, recent studies have focused on the cellular and molecular mechanisms of obesity-induced insulin resistance in skeletal muscle. Accumulation of intramyocellular lipid may lead to insulin resistance in skeletal muscle. In addition, lipid intermediates (e.g., fatty acyl-coenzyme A, diacylglycerol, and ceramide) impair insulin signaling in skeletal muscle. Recently, emerging evidence linking obesity-induced insulin resistance to excessive lipid oxidation, mitochondrial overload, and mitochondrial oxidative stress have been provided with mitochondrial function. This review will provide a brief comprehensive summary on exercise and skeletal muscle metabolism, and discuss the potential mechanisms of obesity-induced insulin resistance in skeletal muscle. PMID- 28664065 TI - Morning and evening exercise. AB - A growing body of evidence suggests that exercise may contribute to preventing pathological changes, treating multiple chronic diseases, and reducing mortality and morbidity ratios. Scientific evidence moreover shows that exercise plays a key role in improving health-related physical fitness components and hormone function. Regular exercise training is one of the few strategies that has been strictly adapted in healthy individuals and in athletes. However, time-dependent exercise has different outcomes, based on the exercise type, duration, and hormone adaptation. In the present review, we therefore briefly describe the type, duration, and adaptation of exercise performed in the morning and evening. In addition, we discuss the clinical considerations and indications for exercise training. PMID- 28664066 TI - The combined effects of physical exercise training and detraining on adiponectin in overweight and obese children. AB - BACKGROUND: The purpose of this study is to assess the combined exercise programs (12 weeks' physical exercise training, resistance and aerobic) and 6 weeks' detraining on the correlation of metabolic syndrome (MS) markers and plasma adiponectin level in two groups. METHODS: Participants were divided into two groups [physical exercise training group (EG, n = 8) and control group (CG, n = 7)]. The EG performed a 12-week training program (aerobic and resistance training twice/wk, more than 40 min/d). After 12 weeks' exercise training and 6 weeks' detraining, we also evaluated MS markers and plasma adiponectin at three time periods (baseline, EBP; 12 weeks' exercise program, 12 EP; 12 weeks' and 6 weeks' detraining, 12 + 6 EDP) in overweight and obese children. RESULTS: Compared with the CG, After the 12 weeks' exercise treatment, weight, body mass index (BMI), waist girth, percent body fat, lean body mass (LBM), percentage lean body, systolic blood pressure, and insulin and homeostatic model assessment (HOMA) indices were lowered in the EG, and plasma adiponectin levels were not altered in the EG. After 6 weeks' detraining, insulin, insulin resistance, and plasma adiponectin levels were significantly increased in the EG. In the adiponectin level, there were positive correlations with LBM and percent lean body and negative correlations with percent body fat, insulin, and insulin resistance after 12 weeks' physical exercise intervention and 6 weeks' detraining. CONCLUSION: These findings suggest that combined physical training is a useful tool in the management of MS markers in the training periods. Moreover, there was an additive effect even after the 6-weeks detraining period. PMID- 28664067 TI - Plaster body wrap: effects on abdominal fat. AB - BACKGROUND: Abdominal fat is associated with metabolic disorders, leading to cardiovascular risk factors and numerous diseases. This study aimed to analyze the effect of plaster body wrap in combination with aerobic exercise on abdominal fat. METHODS: Nineteen female volunteers were randomly divided into intervention group (IG; n = 10) performing aerobic exercise with plaster body wrap, and control group (CG; n = 9) performing only exercise. Subcutaneous and visceral fat were measured using ultrasound; subcutaneous fat was also estimated on analysis of skinfolds and abdominal perimeters. RESULTS: At the end of the 10-sessions protocol, the IG demonstrated a significant decrease (p <= 0.05) in subcutaneous fat at the left anterior superior iliac spine (ASIS) level and in iliac crest perimeter measurements. A large intervention effect size strength (0.80) was found in subcutaneous fat below the navel and a moderate effect size strength on the vertical abdominal skinfold (0.62) and the perimeter of the most prominent abdominal point (0.57). Comparing the initial and final data of each group, the IG showed a significant decrease in numerous variables including visceral and subcutaneous fat above and below the navel measured by ultrasound (p <= 0.05). CONCLUSION: Plaster body wrap in combination with aerobic exercise seems to be effective for abdominal fat reduction. PMID- 28664068 TI - Low-intensity treadmill exercise enhances fast recovery from bupivacaine-induced muscle injury in rats. AB - BACKGROUND: Although bupivacaine has been used to study muscle degeneration and regeneration, the potential enhancement of muscle injury by exercise has not been well examined. The purpose of this study was to determine whether low-intensity treadmill exercise enhances fast recovery from bupivacaine-induced muscle injury and to examine concomitant changes in heat-shock protein 70 (HSP70) expression during regeneration process. METHODS: In this study, Sprague-Dawley rats were randomly divided into the following four groups: the control group (CON), the sham group (SHAM), the injury group (INJ), and the injury and exercise group (EX) (n = 14 in each group). Expressions of HSP70, inducible nitric oxide synthase (iNOS), and caspase-3 were determined at 1 and 7 days after bupivacaine-induced muscle injury in gastrocnemius. RESULTS: Results showed that bupivacaine-induced muscle injury (1 day) significantly increased the expressions of HSP70 and iNOS. At 7 days after the muscle injury, HSP70 expression was higher in the EX group compared with that in the INJ group and elevated level of HSP70 by exercise is concomitant with downregulation of iNOS and the decreased number of caspase-3 positive cells as a marker of apoptosis. Fewer necrosis of myofibers were also found in the EX group compared with the INJ group. CONCLUSION: Our results suggest that low-intensity treadmill exercise may enhance fast recovery from bupivacaine-induced muscle injury in rat partly by HSP70 upregulation. PMID- 28664069 TI - The effects of exercise and conjugated linoleic acid intake on IGF-1 and pro inflammatory cytokines in atrophied skeletal muscle of rats. AB - BACKGROUND: Conjugated linoleic acid (CLA) can be proposed as an effective nutrient for skeletal muscle atrophy. However, the research related to this is still insufficient. This study was carried out to analyze the mRNA expression of IGF-1 and cytokines in atrophied skeletal muscle of rats. METHODS: Forty-two rats were randomly divided into seven groups, each group containing six rats. Sham-Pre and USN-Pre groups underwent a sham operation and a unilateral sciatic nerve (USN) cut, and were sacrificed 1 week later. Other groups had 4 weeks of treatment exercise and CLA intake, and then their blood, liver, and skeletal muscles were sampled after sacrifice. RESULTS: Among the treatment groups, the group treated with both exercise and CLA (USN-EC) showed the lowest body weight. Groups with the sciatic nerve cut showed significantly (p < 0.05) lower muscle weight than groups with the sham operation. However, exercise and CLA intake had no effect on muscle weight. Regarding IGF-1 mRNA, the USN-EC group showed significantly higher expressions in the red muscle of the gastrocnemius and liver than the Sham-Pre and USN-CLA groups. Regarding TNF-alpha pro-inflammatory cytokine, there was no particular trend; however, the expression of IL-1beta mRNA increased in the white muscle of the gastrocnemius muscle and tibialis anterior muscle after sciatic nerve cut, but showed a decrease with exercise and CLA treatment. Particularly in the gastrocnemius white muscle, the group treated with both exercise and CLA showed a significant decrease as compared to groups without treatment after sciatic nerve cut so that positive effects can be expected. CONCLUSION: It is thought that combining treadmill training with CLA partially influences pro-inflammatory cytokines, so that this can act positively on improving skeletal muscle atrophy caused by sciatic nerve cut. PMID- 28664070 TI - Study on time-based variation of blood circulation index, pulse wave energy, and RAI of healthy adult men after different eating times. AB - BACKGROUND: The purpose of this study is to examine the effects of different eating times on blood circulation index, pulse wave energy (E), and radial augmentation index (RAI) of healthy adult men. METHODS: Blood circulation index, E, and RAI were measured using a three-dimensional (3-D) pulse imaging system (3 D MAC) at before, right after, 30 minutes after, 1 hour after, and 2 hours after eating. RESULTS: In the blood circulation index, heart rate (HR), estimated cardiac output (ECO), and estimated cardiac output index (ECI) increased significantly right after eating compared to before eating. By contrast, estimated circulation resistance (ECR) and estimated circulation resistance index (ECRI) decreased significantly right after eating compared to before eating. E had a tendency to increase right after eating compared to before eating and decrease gradually at every experimental point (left and right Chon, Kwan, and Cheok). RAI had a tendency to decrease right after eating compared to before eating and increase gradually at every experimental point. CONCLUSIONS: Different eating times can bring about changes on blood circulation index, E, and RAI. These changes show a certain tendency and coincide with the physiological factors that eating causes a rise of HR, an increase of systolic cardiac pump performance, and a reduction of peripheral vascular resistance. PMID- 28664071 TI - Green tea: a tea or a remedy? PMID- 28664073 TI - Chemopreventive role of green tea in head and neck cancers. AB - In the era of personalized medicine, selecting the ideal treatment modality for head and neck cancer is becoming more complex. Also, despite the use of the newest agents, overall survival has not been improved notably over the past few decades. Currently, in accordance with the development of diagnostic tools, prevention and early detection of cancer are being emphasized more in obtaining better treatment outcomes. Among the various cancer preventative methods, the use of green tea is one of the most common approaches, and tea is known to be involved in multiple steps of carcinogenesis. Thus, in this short review, the protective roles of green tea components against the initiation, progression, and metastasis of head and neck malignancies will be discussed. PMID- 28664072 TI - Green tea and type 2 diabetes. AB - Green tea and coffee consumption have been widely popular worldwide. These beverages contain caffeine to activate the central nervous system by adenosine receptor blockade, and due to the caffeine, addiction or tolerance may occur. In addition to this caffeine effect, green tea and coffee consumption have always been at the center of discussions about human health, disease, and longevity. In particular, green tea catechins are involved in many biological activities such as antioxidation and modulation of various cellular lipid and proteins. Thus, they are beneficial against degenerative diseases, including obesity, cancer, cardiovascular diseases, and various inflammatory diseases. Some reports also suggest that daily consumption of tea catechins may help in controlling type 2 diabetes. However, other studies have reported that chronic consumption of green tea may result in hepatic failure, neuronal damage, and exacerbation of diabetes, suggesting that interindividual variations in the green tea effect are large. This review will focus on the effect of green tea catechins extracted from the Camellia sinensis plant on type 2 diabetes and obesity, and the possible mechanistic explanation for the experimental results mainly from our laboratory. It is hoped that green tea can be consumed in a suitable manner as a supplement to prevent the development of type 2 diabetes and obesity. PMID- 28664075 TI - Physiological effects of formulation containing tannase-converted green tea extract on skin care: physical stability, collagenase, elastase, and tyrosinase activities. AB - BACKGROUND: Green tea contains numerous polyphenols, which have health-promoting effects. The purpose of this study was to evaluate the effect of tannase converted green tea extract (TGE) formulation on the physical stability and activities of skin-related enzymes. METHODS: Physical stability was evaluated by measuring the pH, precipitation, and colors at 25 +/- 2 degrees C/ambient humidity and at 40 +/- 2 degrees C/70% +/- 5% relative humidity for 4 months. Activities of collagenase, elastase, and tyrosinase as skin-related enzymes were assessed on TGE formulation. RESULTS: The concentrations of epigallocatechin-3 gallate and epicatechin-3-gallate in green tea extract were greatly decreased to the extent of negligible level when treated with tannase. The formulation containing 5% tannase-converted green tea extract showed relatively stable pH, precipitation, and color features for 16 weeks. When TGE was added to the formulation, there was a significant increase in the inhibition of elastase and tyrosinase activities (p < 0.05) compared with the formulation containing 5% normal green tea extract. CONCLUSION: The TGE could be used in cosmetics as skin antiwrinkling or depigmenting agent. PMID- 28664074 TI - Anticancer effects and molecular mechanisms of epigallocatechin-3-gallate. AB - Epigallocatechin-3-gallate (EGCG) is a type of catechin found in green tea. EGCG exhibits a variety of activities, including anti-inflammatory, antidiabetes, antiobesity, and antitumor. In this review, we focus on the antitumor effects of EGCG. EGCG inhibits carcinogen activity, tumorigenesis, proliferation, and angiogenesis, and induces cell death. These effects are associated with modulation of reactive oxygen species (ROS) production. Although EGCG has a dual function of antioxidant and pro-oxidant potential, EGCG-mediated modulation of ROS production is reported to be responsible for its anticancer effects. The EGCG mediated inhibition of nuclear factor-kappaB signaling is also associated with inhibition of migration, angiogenesis, and cell viability. Activation of mitogen activated protein kinases activity upregulates the anticancer effect of EGCG on migration, invasion, and apoptosis. In addition, EGCG could also induce epigenetic modification by inhibition of DNA methyltransferase activity and regulation of acetylation on histone, leading to an upregulation of apoptosis. Although EGCG promotes strong anticancer effects by multiple mechanisms, further studies are needed to define the use of EGCG in clinical treatment. PMID- 28664076 TI - Effect of hydroxypropyl methyl cellulose phthalate coating on digestive stability and intestinal transport of green tea catechins. AB - BACKGROUND: The purpose of this study was to investigate the effect of hydroxypropyl methyl cellulose phthalate (HPMCP) coating on the digestive stability and intestinal transport of green tea catechins (GTCs). METHODS: Two types of HPMCP coating were prepared: one type with size smaller than 500 MUm (S HPMCP) and the other with size larger than 500 MUm (L-HPMCP). An in vitro gastrointestinal model system coupled with Caco-2 cells was used for estimating the bioavailability of GTCs. Ultraperformance liquid chromatography with a photodiode array detector was performed to analyze GTCs. RESULTS: The digestive stability of GTCs was enhanced up to 33.73% and 35.28% for S-HPMCP and L-HPMCP, respectively. Intestinal transport of the GTCs was increased to 22.98% and 23.23% for S-HPMCP and L-HPMCP, respectively. Overall, the bioavailability of GTCs increased by 4.08 and 11.71 times for S-HPMCP and L-HPMCP, respectively. CONCLUSION: The results of this study confirm that coating with HPMCP could be a way to improve the digestive stability and intestinal transport of GTCs. PMID- 28664077 TI - Research advances in treatment of neurological and psychological diseases by acupuncture at the Acupuncture Meridian Science Research Center. AB - Acupuncture is an ancient therapeutic intervention that can be traced back at least 2100 years and is emerging worldwide as one of the most widely used therapies in the field of complementary and alternative medicine. Due to limitations associated with Western medicine's focus on the treatment of diseases rather than on their causes, interests are shifting to complementary and alternative medicines. The Acupuncture and Meridian Science Research Center (AMSRC) was established in 2005 to elucidate the neurophysiological mechanisms of acupuncture for neurological diseases based on multidisciplinary research supported by the Korean Ministry of Science and Technology. In the AMSRC, resultant research articles have shown that acupuncture can improve neurological and psychological problems, including Parkinson's disease, pain, and depression, in animal models. Basic research studies suggest its effectiveness in treating various problems such as depression, drug addiction, epilepsy, ischemia, dementia, Parkinson's disease, and pain. We strongly believe that these effects, evident from the AMSRC research results, can play leading roles in the use of acupuncture for treating neurological diseases, based on collaboration among various academic fields such as neurophysiology, molecular genetics, and traditional Korean medicine. PMID- 28664078 TI - An introduction to Chuna manual medicine in Korea: History, insurance coverage, education, and clinical research in Korean literature. AB - The objectives of this study were to summarize the curriculum, history, and clinical researches of Chuna in Korea and to ultimately introduce Chuna to Western medicine. Information about the history and insurance coverage of Chuna was collected from Chuna-related institutions and papers. Data on Chuna education in all 12 Korean medicine (KM) colleges in Korea were reconstructed based on previously published papers. All available randomized controlled trials (RCTs) of Chuna in clinical research were searched using seven Korean databases and six KM journals. As a result, during the modern Chuna era, one of the three periods of Chuna, which also include the traditional Chuna era and the suppressed Chuna era, Chuna developed considerably because of a solid Korean academic system, partial insurance coverage, and the establishment of a Chuna association in Korea. All of the KM colleges offered courses on Chuna-related subjects (CRSs); however, the total number of hours dedicated to lectures on CRSs was insufficient to master Chuna completely. Overall, 17 RCTs were reviewed. Of the 14 RCTs of Chuna in musculoskeletal diseases, six reported Chuna was more effective than a control condition, and another six RCTs proposed Chuna had the same effect as a control condition. One of these 14 RCTs made the comparison impossible because of unreported statistical difference; the last RCT reported Chuna was less effective than a control condition. In addition, three RCTs of Chuna in neurological diseases reported Chuna was superior to a control condition. In conclusion, Chuna was not included in the regular curriculum in KM colleges until the modern Chuna era; Chuna became more popular as the result of it being covered by Korean insurance carriers and after the establishment of a Chuna association. Meanwhile, the currently available evidence is insufficient to characterize the effectiveness of Chuna in musculoskeletal and neurological diseases. PMID- 28664079 TI - Recognition of and interventions for Mibyeong (subhealth) in South Korea: a national web-based survey of Korean medicine practitioners. AB - BACKGROUND: Medically unexplained symptoms (MUSs) are common in primary care. At present, there are no proven, comprehensive treatments available in primary care for patients with MUSs. However, MUS has parallels with "subhealth" or Mibyeong from traditional East-Asian medicine, and thus, Mibyeong interventions could be effective in treating MUS. Unfortunately, studies on Mibyeong and its intervention methods are relatively rare. METHODS: We administered a web-based survey to 17,279 Korean medicine (KM) practitioners registered with the Association of Korean Medicine. The response rate was 4.9% (n = 849). Based on the responses received, we assessed how much they agreed with concepts related to Mibyeong on a 7-point scale from "do not agree" to "strongly agree." Respondents were also asked to indicate how frequently they encountered various subtypes and patterns of Mibyeong, and how frequently they use listed intervention methods. RESULTS: Data from 818 respondents were analyzed after excluding those with no clinical experience. On average, respondents were male general practitioners aged between 30 years and 49 years, working or living in metropolitan areas such as Seoul, Incheon, and Gyeonggi-do. Responses did not differ by demographics. Respondents generally thought that Mibyeong referred to subjective or borderline findings without certain disease, and that Mibyeong has various subtypes and patterns. Subtypes included fatigue, pain, and digestion problems; patterns were either deficiencies (e.g., qi, blood, and yin deficiency) or stagnations (e.g., liver qi depression and qi stagnation). Decoction was the most frequently used type of intervention for Mibyeong of all items listed, followed by acupuncture and moxibustion. Patient education was also recommended, suggesting healthy eating, promoting healthy environment, and exercise. CONCLUSION: We were able to provide preliminary results on KM practitioners' recognition of and interventions for Mibyeong, but further research is needed to develop a detailed definition of Mibyeong and its myriad subtypes and patterns, and evaluations of the efficacy of Mibyeong interventions. PMID- 28664080 TI - Screening of Stat3 inhibitory effects of Korean herbal medicines in the A549 human lung cancer cell line. AB - BACKGROUND: The transcription factor signal transducer and activator of transcription 3 (Stat3) is constitutively activated in many human cancers. It promotes tumor cell proliferation, inhibits apoptosis, induces angiogenesis and metastasis, and suppresses antitumor host immune responses. Therefore, Stat3 has emerged as a promising molecular target for cancer therapies. In this study, we evaluated the Stat3-suppressive activity of 38 herbal medicines traditionally used in Korea. METHODS: Medicinal herb extracts in 70% ethanol were screened for their ability to suppress Stat3 in the A549 human lung cancer cell line. A Stat3 responsive reporter assay system was used to detect intracellular Stat3 activity in extract-treated cells, and Western blot analyses were performed to measure the expression profiles of Stat3-regulated proteins. RESULTS: Fifty percent of the 38 extracts possessed at least mild Stat3-suppressive activities (i.e., activity less than 75% of the vehicle control). Ethanol extracts of Bupleurum falcatum L., Taraxacum officinale Weber, Solanum nigrum L., Ulmus macrocarpa Hance, Euonymus alatus Sieb., Artemisia capillaris Thunb., and Saururus chinensis (Lour.) Baill inhibited up to 75% of the vehicle control Stat3 activity level. A549 cells treated with these extracts also had reduced Bcl-xL, Survivin, c-Myc, and Mcl-1 expression. CONCLUSION: Many medicinal herbs traditionally used in Korea contain Stat3 activity-suppressing substances. Because of the therapeutic impact of Stat3 inhibition, these results could be useful when developing novel cancer therapeutics from medicinal herbs. PMID- 28664081 TI - Synergistic antioxidant action of Phikud Navakot ameliorates hydrogen peroxide induced stress in human endothelial cells. AB - BACKGROUND: Phikud Navakot (PN), a combination of nine herbs, has been used traditionally in Thai medicinal formulas to relieve circulatory disorder. The present study aimed to compare the synergistic antioxidant efficacy and toxicity of the hydroethanolic and water extracts of PN at cellular level. METHODS: PN and its nine herbs were extracted with either 50% ethanol or water. All extracts were tested for in vitro antioxidant potential using standard antioxidant assays. Evaluation of cytotoxicity, genotoxicity, and intracellular reactive oxygen species were performed using human endothelial ECV304 cells. RESULTS: Antioxidant assays in cell-free systems showed that the hydroethanolic extract of PN scavenged superoxide, hydroxyl, nitric oxide radicals, and hydrogen peroxide more effectively than its water extract. Combination indices were calculated to show that the ingredients of the hydroethanolic extract acted synergistically to exhibit antioxidant activities against all tested radicals, whereas, in the case of water extract, this effect was observed only against 2,2-diphenyl-1 picrylhydrazyl, superoxide, and hydroxyl radicals. A cell-based assay also revealed that the hydroethanolic extract concentration-dependently attenuated hydrogen peroxide-induced stress more effectively than the water extract. At the antioxidant and cytotoxic concentrations of both extracts, no genotoxicity was found. CONCLUSION: Our findings demonstrate that the synergistic antioxidant action of PN ameliorates endothelial stress, which may provide some clues for understanding the traditional use of PN for the treatment of circulatory disorder. Additionally, the selection of a suitable solvent for the extraction of PN herbal combination is essential for maximal efficacy and safety. PMID- 28664082 TI - The effect of extract of Punica granatum var. pleniflora for treatment of minor recurrent aphthous stomatitis. AB - BACKGROUND: Herbal drugs are considered alternative agents and have been used for several years around the world. Recurrent aphthous stomatitis (RAS) is one of the most common problems recognized by dentists and skin specialists. This problem is characterized by recurring, painful, small oral mucosal ulcers with a round or oval aspect that mostly appear in keratinized mucosa, cheeks, and on the surface of the mouth under the tongue. METHODS: In our experiment, the alcoholic and water extracts of Punica granatum var. pleniflora, P. granatum var. Sweet Alak, and P. granatum var. Saveh Black were tested on minor RAS. The study was carried out using the double-blind method. The study population consisted of 210 participants, of whom 69 were females (32%) and 141 were males (68%). In addition to checking several factors, the pain and the degree of the participant's satisfaction had been determined based on visual analog scale. Data analysis was done in the form of a nonparametric method using Kruskal-Wallis test and SPSS version 20 software. RESULTS: The results show that the alcoholic and water extracts of P. granatum var. pleniflora have a meaningful therapeutic effect on minor RAS. Results from the antioxidant activity and its relation to total phenolics show that P. granatum var. pleniflora and P. granatum var. Sweet Alak are rich in phenols. CONCLUSION: The water and alcoholic extracts of P. granatum varpleniflora decreased the entire time of complete treatment, and the treatment was meaningfully satisfactory for patients who participated in this experiment. PMID- 28664083 TI - Development and evaluation of orodispersible tablets using a natural polysaccharide isolated from Cassia tora seeds. AB - BACKGROUND: Orodispersible tablets or fast dissolving tablets dissolve or disintegrate immediately on the patients' tongue or buccal mucosa. This drug delivery system is suitable for drugs undergoing high first pass metabolism. It improves bioavailability, reduces dosing frequency, and thereby minimizes the side effects and also makes the dosage form more cost-effective. In this study, polysaccharide isolated from the seeds of Cassia tora was investigated as a superdisintegrant in the orodispersible tablets. The model drug chosen was valsartan, an antihypertensive drug. METHODS: Valsartan tablets were prepared separately using different concentrations (1%, 2.5%, 5%, and 7.5% w/w) of isolated C. tora seed polysaccharide (natural) and sodium starch glycolate (synthetic) as superdisintegrant by the direct compression method. Evaluation of tablets was done for various pre- and postcompression parameters. The stability studies were performed on optimized formulation F4. The disintegration time and in vitro drug release of the formulation F4 were compared with marketed formulations (conventional tablets). RESULTS: The drug excipient interactions were characterized by Fourier transform infrared studies. The formulation F4 containing 7.5% polysaccharide showed good wetting time and disintegration time as compared to a formulation prepared using a synthetic superdisintegrant at the same concentration level. Hence, batch F4 was considered optimized formulation. CONCLUSION: The present work revealed that C. tora seed polysaccharide has a good potential as a disintegrant in the formulation of orodispersible tablets. Because C. tora polysaccharide is inexpensive as compared to synthetic superdisintegrants, nontoxic, compatible, and easy to manufacture, it can be used in place of currently marketed superdisintegrants. PMID- 28664084 TI - Functional abdominal pain syndrome treated with Korean medication. AB - A 37-year-old female patient with chronic and stubborn abdominal pain had been hospitalized five times in three Western hospitals, but no effects were observed. No abnormalities were found in blood tests, gastrointestinal endoscopy, sonogram, and computed tomography of the abdomen, except mild paralytic ileus. The patient decided to rely on Korean medicine as an inpatient. She was diagnosed with functional abdominal pain syndrome, and her symptom differentiation was the "Yang deficiency of spleen and kidney." A herbal drug, Hwangikyeji-tang, along with moxibustion and acupuncture, was given to the patient. Abdominal pain and related symptoms were reduced radically within 16 days of treatment. This report shows a therapeutic potential of Korean medicine-based treatment for functional abdominal pain syndrome. PMID- 28664085 TI - Acupuncture in Australia: regulation, education, practice, and research. AB - Acupuncture was introduced to Australia as early as in the 1880s, and is a form of complementary and alternative medicine in this country. In the past 2 decades since the 1990s, acupuncture has experienced a rapid growth. Today, nearly 4000 acupuncturists are registered with the Chinese Medicine Board of Australia. "Acupuncturist," "Oriental medicine practitioner," and "Chinese medicine practitioners" are protected titles for registered acupuncturists. A bachelor's degree of 4 years in related fields is the minimal requirement for registration in Australia. Three public universities and three major private colleges offer nine undergraduate and three postgraduate programs that are approved by the Chinese Medicine Board of Australia. Those three universities also offer Master degree and Doctor of Philosophy programs. Acupuncture is well accepted by the Australians, with 10% having received this treatment and 80% general medical practitioners referring their patients to acupuncture service. All private health insurance schemes provide rebates to patients receiving acupuncture treatment, and third-party payment is also available in six of eight Australian states and territories. Research output in acupuncture has increased greatly since 2000. A majority of research focuses on acupuncture and Tai Chi as treatment modalities, and mainly investigates their mechanism of action, associated pain, and gynecological and respiratory conditions. The future direction of acupuncture in Australia is to introduce this medicine in hospitals and gain access to the medical benefit scheme so that acupuncture can be accessed by a wider community, in particular those who come from a disadvantaged background. In conclusion, improved education, regulation, and research of acupuncture in Australia put this country in a leading position among Western countries with respect to acupuncture services. PMID- 28664086 TI - Current knowledge on alleviating Helicobacter pylori infections through the use of some commonly known natural products: bench to bedside. AB - Helicobacter pylori, a spiral-shaped Gram-negative bacterium, has been classified as a class I carcinogen by the World Health Organization and recognized as the causative agent for peptic ulcers, duodenal ulcer, gastritis, mucosa-associated lymphoid tissue lymphomas, and gastric cancer. Owing to their alarming rate of drug resistance, eradication of H. pylori remains a global challenge. Triple therapy consisting of a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole, is generally the recommended standard for the treatment of H. pylori infection. Complementary and alternative medicines have a long history in the treatment of gastrointestinal ailments and various compounds has been tested for anti-H. pylori activity both in vitro and in vivo; however, their successful use in human clinical trials is sporadic. Hence, the aim of this review is to analyze the role of some well-known natural products that have been tested in clinical trials in preventing, altering, or treating H. pylori infections. Whereas some in vitro and in vivo studies in the literature have demonstrated the successful use of a few potential natural products for the treatment of H. pylori-related infections, others indicate a need to consider natural products, with or without triple therapy, as a useful alternative in treating H. pylori-related infections. Thus, the reported mechanisms include killing of H. pylori urease inhibition, induction of bacterial cell damage, and immunomodulatory effect on the host immune system. Furthermore, both in vitro and in vivo studies have demonstrated the successful use of some potential natural products for the treatment of H. pylori-related infections. Nevertheless, the routine prescription of potential complementary and alternative medicines continues to be restrained, and evidence on the safety and efficacy of the active compounds remains a subject of ongoing debate. PMID- 28664087 TI - Role of red grape polyphenols as antidiabetic agents. AB - The worldwide incidence of diabetes mellitus has reached alarming proportions. Persistent hyperglycemia due to impaired insulin activity and/or insulin resistance inversely affects the retina, cerebrovascular system, kidney, peripheral limbs, and other parts of the body, which leads to life-threatening complications. The causal role of oxidative stress in the development and progression of diabetic complications has been emphasized. Polyphenols present in natural products have gained much attention in recent decades in preventive studies against diabetes-associated pathologies. In the present review, we provide a comparative update on the role of quercetin, myricetin, and resveratrol the major polyphenols present in red grapes-in intervening with diabetic complications, and a brief highlight on the molecular mechanisms underlying oxidative stress mediated hyperglycemia. PMID- 28664088 TI - Adverse drug reactions in some African herbal medicine: literature review and stakeholders' interview. AB - BACKGROUND: In view of the large consumption of herbal medicine in Africa countries, it is likely that many adverse drugs reactions go unrecorded with either patients failing to present to health services, or no pharmacovigilance analysis being made, or the analysis not being reported centrally. This problem is of interest especially for those who are working in the general area of adverse drug reactions or stakeholders in the domain of herbal medicine for considering safety issues. METHODS: We are particularly interested in the way that the use of very well-known and highly valued plants is linked to the observation of adverse drug reactions in African countries. We investigated, through a literature review and using the Internet (with a semantic search strategy), some well-known or popular medicinal plants used in African herbal medicine (AHM). Other information on the properties related to use, and characteristics of medicinal plants was complemented by some interviews with stakeholders. RESULTS: Although substantial progress has been made in elucidating the mechanisms of action of many drugs, the pharmacological actions of many medicinal plants are generally not well understood. The results of a literature review suggest that the reported adverse drug reactions of herbal remedies are often due to a lack of understanding of their preparation and appropriate use. The results of stakeholders' interviews suggest that there is a growing need to provide patients with correct information about the herbal medicines they consume. CONCLUSION: An important aspect of herbal medicine is the correct, timely, and integrated communication of emerging data on risk as an essential part of pharmacovigilance, which could actually improve the health and safety of patients. This calls for improved collaboration between traditional practitioners and modern healthcare professionals, researchers, and drug regulatory authorities. In addition, there is a need for an adverse drug reaction reporting system to facilitate the collection, monitoring, and evaluation of adverse drug events. PMID- 28664090 TI - Antimicrobial and cytotoxic evaluation of some herbal essential oils in comparison with common antibiotics in bioassay condition. AB - BACKGROUND: Since ancient times, various infectious diseases have been treated using herbal drugs. Today, efforts regarding the discovery of the effectual components of plants possessing antimicrobial properties are advanced. Herbal essential oils are widely used for treatment of various diseases, and they play an important role in health care considerations. METHODS: The antibacterial activity of Artemisia kermanensis, Lavandula officinalis, and Zataria multiflora Boiss essential oils against Staphylococcus aureus (ATCC 25923), Pseudomonas aeruginosa (PTCC 1310), and Klebsiella pneumonia (PTCC 1053) was evaluated using the disk diffusion method as well as determination of the minimal inhibitory concentration and minimal bactericidal concentration. The composition of the three essential oils was determined with gas chromatography-mass spectrometry. Variable amounts of different components (such as oxygenated monoterpenes, thymol, carvacrol, and 1,8-cineol) were found in all three oils. Among the tested bacteria, S. aureus was the most sensitive to the three essential oils. RESULTS: The obtained results showed that each of the three essential oils has an inhibitory effect on pathogenic strains. Of these three oils, Z. multiflora Boiss essential oil showed the highest inhibitory effect on microbial strains. Furthermore, comparison of the antibacterial effects of these three essential oils with ampicillin and tetracycline revealed that these antibiotics have a better effect in controlling pathogenic strains. CONCLUSION: The essential oils used in the present study with different components showed antibacterial activity (especially Z. multiflora Boiss essential oil), and therefore they can be used as a new antibacterial substance. PMID- 28664089 TI - Monitoring in vitro antibacterial efficacy of 26 Indian spices against multidrug resistant urinary tract infecting bacteria. AB - BACKGROUND: To screen methanolic extracts of 26 commonly used Indian spices against nine species of uropathogenic bacteria (Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa), isolated from clinical samples of a tertiary care hospital for antibacterial activity. METHODS: Bacterial strains were subjected to antibiotic sensitivity testing by Kirby-Bauer's disc diffusion method. Monitoring antibacterial potentiality of spice extracts was done by the agar-well diffusion method with multidrug resistant (MDR) strains of nine uropathogens. RESULTS: The Gram-positive (GP) bacteria E. faecalis and S. aureus were resistant to 16 of the 21 antibiotics used. Among the Gram-negative (GN) bacteria, resistant patterns were A. baumannii and E. aerogenes to 12, C. freundii to 14, E. coli to 12, K. pneumoniae to 10, P. mirabilis to 11, and P. aeruginosa to 15 antibiotics of the 18 antibiotics used. The most effective 15 spices, having at least 25-29 mm as the size of the zone of inhibition, were Allium cepa, Brassica juncea, Cinnamomum tamala, Cinnamomum zeylanicum, Coriandrum sativum, Cuminum cyminum, Curcuma longa, Mentha spicata, Murraya koenigii, Nigella sativa, Papaver somniferum, Piper nigrum, S. aromaticum, Trachyspermum ammi, and Trigonella foenum for at least one of the GP or GN MDR bacterial strains used. Moderate control capacity was registered by nine spices, Curcuma amada, Foeniculum vulgare, Illicium verum, Mentha spicata, Papaver somniferum, Syzygium aromaticum, Trachyspermum ammi, Trigonella foenum, and Zingiber officinale. However, the best two spices for controlling all the pathogens used were C. zeylanicum and C. longa, with the highest value of 29 mm as the inhibition zone size. CONCLUSION: The most effective and unique 16 spice plants recorded for the in vitro control of MDR uropathogens could further be pursued for the development of complementary and supplementary medicine against MDR bacteria. PMID- 28664091 TI - Gathering, connecting, integrating. PMID- 28664092 TI - Exercise-induced PGC-1alpha transcriptional factors in skeletal muscle. AB - Skeletal muscle is adapting to the needs of the body by changes of various gene expression that control mitochondrial biogenesis, angiogenesis, and the composition of muscle fiber types. Recently, it was revealed that PGC-1alpha, which is an auxiliary transcription factor, plays a key role in the aforementioned adaptation phenomena. It means that various signal transduction systems within muscle directly affect the expression and activation of PGC-1alpha and also PGC-1s activates various programs for muscle adaptation. Therefore, this review assessed PGC-1alpha to understand the reaction and adaptation phenomena of muscle against the biological stimulus such as exercise and came to the conclusion that PGC-1alpha and PGC-1beta significantly affect skeletal muscle in various ways, and also have an affect on the increase of exercise capacity, inducing of angiogenesis and the prevention of muscle atrophy and degeneration. PMID- 28664094 TI - Exercise-induced myokines in health and metabolic diseases. AB - Skeletal muscle has been emerging as a research field since the past 2 decades. Contraction of a muscle, which acts as a secretory organ, stimulates production, secretion, and expression of cytokines or other muscle fiber-derived peptides, i.e., myokines. Exercise-induced myokines influence crosstalk between different organs in an autocrine, endocrine, or paracrine fashion. Myokines are recently recognized as potential candidates for treating metabolic diseases through their ability to stimulate AMP-activated protein kinase signaling, increase glucose uptake, and improve lipolysis. Myokines may have positive effects on metabolic disorders, type 2 diabetes, or obesity. Numerous studies on myokines suggested that myokines offer a potential treatment option for preventing metabolic diseases. This review summarizes the current understanding of the positive effects of exercise-induced myokines, such as interleukin-15, brain-derived neurotrophic factor, leukemia inhibitory factor, irisin, fibroblast growth factor 21, and secreted protein acidic and rich in cysteine, on metabolic diseases. PMID- 28664093 TI - Recent advances in mitochondrial turnover during chronic muscle disuse. AB - Chronic muscle disuse, such as that resulting from immobilization, denervation, or prolonged physical inactivity, produces atrophy and a loss of mitochondria, yet the molecular relationship between these events is not fully understood. In this review we attempt to identify the key regulatory steps mediating the loss of muscle mass and the decline in mitochondrial content and function. An understanding of common intracellular signaling pathways may provide much-needed insight into the possible therapeutic targets for treatments that will maintain aerobic energy metabolism and preserve muscle mass during disuse conditions. PMID- 28664095 TI - Integrative understanding of hypoxic pulmonary vasoconstriction using in vitro models: from ventilated/perfused lung to single arterial myocyte. AB - Contractile response of a pulmonary artery (PA) to hypoxia (hypoxic pulmonary vasoconstriction; HPV) is a unique physiological reaction. HPV is beneficial for the optimal distribution of blood flow to differentially ventilated alveolar regions in the lung, thereby preventing systemic hypoxemia. Numerous in vitro studies have been conducted to elucidate the mechanisms underlying HPV. These studies indicate that PA smooth muscle cells (PASMCs) sense lowers the oxygen partial pressure (PO2) and contract under hypoxia. As for the PO2-sensing molecules, a variety of ion channels in PASMCs had been suggested. Nonetheless, the modulator(s) of the ion channels alone cannot mimic HPV in the experiments using PA segments and/or isolated organs. We compared the hypoxic responses of PASMCs, PAs, lung slices, and total lungs using a variety of methods (e.g., patch clamp technique, isometric contraction measurement, video analysis of precision cut lung slices, and PA pressure measurement in ventilated/perfused lungs). In this review, the relevant results are compared to provide a comprehensive understanding of HPV. Integration of the influences from surrounding tissues including blood cells as well as the hypoxic regulation of ion channels in PASMCs are indispensable for insights into HPV and other related clinical conditions. PMID- 28664096 TI - Coffee and health. AB - Most people start their day with a cup of coffee. Many people would also finish their daily work with coffee. As such, coffee drinking is an important part of modern daily life. It has been told that coffee is a driving force for humans to develop science, because it has an alerting effect on the human brain. However, some people report experiencing irregular heartbeat or headaches and are thus reluctant to drink coffee, which suggests individual variation to coffee intolerance. The aim of this review is to briefly summarize the effects of coffee on human health. PMID- 28664097 TI - Practical approaches to the nutritional management of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and a serious health burden worldwide which increases risk of cirrhosis, type 2 diabetes mellitus (T2DM), and cardiovascular complications. Current epidemics of obesity, unhealthy dietary patterns, and sedentary lifestyles, all contribute to the high prevalence of NAFLD. Dietary patterns and nutrients are important contributors to the development, progression, and treatment of NAFLD. A healthy diet is beneficial for all NAFLD patients beyond weight reduction. Generally, hypercaloric diets, especially rich in trans/saturated fat and cholesterol, high consumption of red and processed meat, and fructose-sweetened beverages seem to increase the risk of progression toward nonalcoholic steatohepatitis (NASH), whereas reducing caloric intake and high glycemic index (GI) foods, increasing consumption of monounsaturated fatty acids, omega-3 fatty acids, fibers, and specific protein sources such as fish and poultry have preventive and therapeutic effects. Therefore, nutrition serves as a major route of prevention and treatment of NAFLD, and patients with NAFLD should have an individualized diet recommendation. In this review, the evidence linking macronutrients to NAFLD are discussed. PMID- 28664098 TI - Antagonistic crosstalk between SIRT1, PARP-1, and -2 in the regulation of chronic inflammation associated with aging and metabolic diseases. AB - Current studies have indicated the association of chronic sterile inflammation (inflammation in the absence of pathogens) with the pathogenesis of age-related and metabolic diseases. The inflammation is under the control of transcription factor NF-kappaB through an antagonistic crosstalk between SIRT1, PARP-1, and -2 signaling pathways. The transcriptional activity of NF-kappaB is increased in various tissues with aging and metabolic abnormalities and is related with various aging and metabolic diseases such as Alzheimer's disease, diabetes, and osteoporosis. Furthermore, NF-kappaB activation with chronic inflammation is connected with many known life span and metabolic regulators including DNA damage, obesity, SIRT, and PARP. Thus, the crossroads between PARP and SIRT signaling pathways represent efficient therapeutic targets for extending health span without metabolic diseases. PMID- 28664099 TI - Different effects of prolonged beta-adrenergic stimulation on heart and cerebral artery. AB - The aim of this review was to understand the effects of beta-adrenergic stimulation on oxidative stress, structural remodeling, and functional alterations in the heart and cerebral artery. Diverse stimuli activate the sympathetic nervous system, leading to increased levels of catecholamines. Long term overstimulation of the beta-adrenergic receptor (betaAR) in response to catecholamines causes cardiovascular diseases, including cardiac hypertrophy, stroke, coronary artery disease, and heart failure. Although catecholamines have identical sites of action in the heart and cerebral artery, the structural and functional modifications differentially activate intracellular signaling cascades. betaAR-stimulation can increase oxidative stress in the heart and cerebral artery, but has also been shown to induce different cytoskeletal and functional modifications by modulating various components of the betaAR signal transduction pathways. Stimulation of betaAR leads to cardiac dysfunction due to an overload of intracellular Ca2+ in cardiomyocytes. However, this stimulation induces vascular dysfunction through disruption of actin cytoskeleton in vascular smooth muscle cells. Many studies have shown that excessive concentrations of catecholamines during stressful conditions can produce coronary spasms or arrhythmias by inducing Ca2+-handling abnormalities and impairing energy production in mitochondria, In this article, we highlight the different fates caused by excessive oxidative stress and disruptions in the cytoskeletal proteome network in the heart and the cerebral artery in responsed to prolonged betaAR stimulation. PMID- 28664100 TI - Integrative approach in the era of failing drug discovery and development. AB - The productivity decline in drug discovery and development is mainly caused by two factors; higher regulatory hurdles and low-hanging fruits being all picked. In addition, the recent target-based approach is thought to be increasing the price of innovation. Although target-based approach had many successes, a postreductionism method, which is systems biology, is on the rise. In this review, we discuss the foundations of two distinct approaches in finding a new drug. PMID- 28664101 TI - Long-term effect of cupping for chronic neck pain. PMID- 28664102 TI - The multidisciplinary study on Sasang typology. PMID- 28664103 TI - Morality and longevity in the viewpoint of Sasang medicine. AB - The concepts of morality and health of humans are discussed from the viewpoint of Sasang medicine, as described by Je-Ma Lee in his books Donguisusebowon and Gyeokchigo. Sasang medicine suggests that human beings exist with qualities of "heavenly loom," "humanly affair," and "nature and conduct in following parts." In addition, Sasang medicine classifies people into the following four Sasang types: Tae-Yang, So-Yang, Tae-Eum, and So-Eum. This classification is based on the following traits: benevolence-righteousness-propriety-wisdom, manifestations of sorrow-anger-joy-pleasure (Seong and Jeong), and largeness and smallness of lung-spleen-liver-kidney. Human diseases are always caused by the excessive mind action of sorrow-anger-joy-pleasure. Mind action affects the body unilaterally and makes it ill. According to Sasang medicine, both good health and illness in human beings originate from morality. Therefore, realizing and acting in accordance with the right moral behavior are essential to lead a healthy life. PMID- 28664104 TI - Psychological typology of Sasang medicine. AB - This study briefly reviewed and summarized published studies related to the Sasang typology in order to investigate the common psychological characteristics in each type and suggest conceptual and methodological implications for future research. A total of 44 articles written in Korean between 1990 and 2014, and that used objective measures of personality, were selected from two Korean database for this study. The number of publications, type of scale used, and distribution of each Sasang type were reviewed and summarized. From these works, it was found that there was significant common ground between the classification of Sasang types, which is rooted in Eastern concepts, and the psychological features and types revealed by objective personality measures used in Western psychology. On the basis of these findings, the degree of overlap between Eastern and Western personality typologies was highlighted, and further considerations for developing a more valid and objective classification method, and the limitations of the existing searching method and scope were discussed. PMID- 28664105 TI - Best-fit index for describing physical perspectives in Sasang typology. AB - INTRODUCTION: We examined the best-fit index for describing the constitutional or physical characteristics of Sasang typology for its universal application. METHODS: Ponderal index (PI), body mass index (BMI), and basal metabolic rate (BMR) of the nationwide participants (n = 1663; age, 31-60 years) were calculated. We described and analyzed the usefulness of each index for maximizing the differences between Sasang types across age and sex using box plots, Pearson's correlation, and analysis of variance. RESULTS: We found that the So Eum, So-Yang, and Tae-Eum Sasang types were significantly (p < 0.001) different from each other in terms of PI, BMI, and BMR by the World Health Organization with weight (BMR-WHOw). The BMI was significantly correlated with PI (r = 0.933) and BMR-WHOw (r = 0.577). DISCUSSION AND CONCLUSION: These study results show that PI, BMR, and BMI have their own clinical values, and could contribute to the study of the pathophysiological mechanism underlying the Sasang typology as the hypothalamus hypothesis. PMID- 28664106 TI - Personality construct of Sasang Personality Questionnaire in an adolescent sample. AB - BACKGROUND: Sasang typology is a widely used personalized traditional medicine in clinical diagnosis and treatment in Korea. The aim of this study was to examine the personality construct of the Sasang Personality Questionnaire (SPQ) to replicate the previous findings in the adolescent sample. METHODS: A total of 543 high school students completed the SPQ and the Korean version of the Junior Temperament and Character Inventory (JTCI). The relationships between the subscales of JTCI and SPQ were examined using Pearson's correlation. The profile analysis and analysis of variance were used to investigate the difference among high, middle, and low SPQ total score groups. RESULTS: The SPQ and its subscales were significantly correlated with the JTCI subscales. SPQ total score was positively correlated with Novelty Seeking (r = 0.424) and negatively correlated with Harm Avoidance (r = -0.291). The high, middle, and low SPQ total score groups showed significantly different JTCI profile (flatness with Greenhouse Geisser correction, df = 3.424, F = 443.812, p < 0.001; parallelism with Greenhouse-Geisser correction, df = 6.848, F = 18.610, p < 0.001). CONCLUSION: The validity of the SPQ construct was confirmed with adolescents. Further investigation on its personality construct would extend the clinical application of SPQ to young age groups including children. PMID- 28664107 TI - Personal computer wallpaper user segmentation based on Sasang typology. AB - BACKGROUND: As human-computer interaction (HCI) is becoming a significant part of all human life, the user's emotional satisfaction is an important factor to consider. These changes have been pointed out by several researchers who claim that a user's personality may become the most important factor in the design. The objective of this study is to examine Sasang typology as a user segmentation method in the area of HCI design. To test HCI usage patterns in terms of the user's personality and temperament, this study focuses on personal computer (PC) or lap-top wallpaper settings. METHODS: One hundred and four Facebook friends completed a QSCC II survey assessing Sasang typology type and sent a captured image of their personal PC or lap-top wallpaper. To classify the computer usage pattern, folder organization and wallpaper setting were investigated. RESULTS: The research showed that So-Yang type organized folders and icons in an orderly manner, whereas So-Eum type did not organize folders and icons at all. With regard to wallpaper settings, So-Yang type used the default wallpaper provided by the PC but So-Eum type used landscape images. Because So-Yang type was reported to be emotionally stable and extrovert, they tended to be highly concerned with online privacy compared with So-Eum type. So-Eum type use a lot of images of landscapes as the background image, which demonstrates So-Eum's low emotional stability, anxiety, and the desire to obtain analogy throughout the computer screen. Also, So-Yang's wallpapers display family or peripheral figures and this is due to the sociability that extrovert So-Yang types possess. CONCLUSION: By proposing the Sasang typology as a factor in influencing an HCI usage pattern in this study, it can be used to predict the user's HCI experience, or suggest a native design methodology that can actively cope with the user's psychological environment. PMID- 28664108 TI - Comparisons of physical fitness and body composition among Sasang types with and without body mass index as a covariate. AB - BACKGROUND: The purpose of this study was to examine the difference of physical fitness and body composition among Sasang types with BMI as covariate, which is reported to have influence on physical fitness and body composition. METHODS: We measured the physical fitness and body composition of 930 korean female college students, and compared the differences among Sasang type groups with or without considering Body Mass Index (BMI). We evaluated muscle strength, agility, muscle endurance, power and flexibility for the physical fitness, and total body water, protein, muscle mass, mineral, lean body mass and fat mass for the body composition. RESULTS: We got 352 So-Yang (SY), 385 So-Eum (SE), and 193 Tae-Eum (TE) Sasang types, and there were significant differences among Sasang types in height, weight and BMI. The significant differences among TE and SY types were disappeared in muscle strength, total body water, protein when BMI is used as a covariate. In ANOVA, there were significant differences that TE was higher on the mineral and fat mass compared to the SY type and SE type. However it disappeared when we introduced BMI as covariate. CONCLUSION: The results demonstrated that the BMI should be considered as an important element for studying physical characteristics of Sasang typology. PMID- 28664109 TI - Effects of oriental medicine music therapy in an ovarian cancer patient with So Eum-type constitution: a case report. AB - The cancer incidence in Korea has been increasing, although there is a serious lack of supportive care for the treatment and management of the rapidly increasing number of cancer patients, and there is an immense need for therapeutic interventions to support cancer patients. A 47-year-old So-Eum-type Korean female patient, who was diagnosed with ovarian cancer, had been receiving chemotherapies. She was experiencing pain due to swelling of her hands and feet, and under extreme stress due to hardships of life. During the patient's fourth chemotherapy treatment, she received oriental medicine music therapy twice per week for 2 weeks, for 1 hour each time (4 sessions in total). A self-administered questionnaire and the visual analog scale were used to assess and determine the level of negative and positive feelings. After receiving the oriental medicine music therapy, her negative and positive feelings as well as the visual analog scale score that reflects subjective health conditions have improved and stabilized. This case report suggests the potential of oriental medicine music therapy as a complementary and alternative medical treatment method to promote and enhance quality of life and health conditions of cancer patients in postsurgical care and chemotherapy treatment. PMID- 28664110 TI - How do psychological factors influence autonomic responses to acupuncture? PMID- 28664111 TI - Quantification of the parameters of twisting-rotating acupuncture manipulation using a needle force measurement system. AB - BACKGROUND: To date, much research has been conducted to measure needle manipulation quantitatively and objectively. This study was performed to quantitatively measure the differences in the amount of stimulation caused by various rotation frequencies and angles in twisting-rotating acupuncture needle manipulation. METHODS: The torque Z force exerted on a tissue was measured at various rotation frequencies and angles by rotating a needle with a needle force measurement system attached to a needle insertion tissue model. RESULTS: The results show that with rotation frequency at 60 degrees , the torque Z force increased significantly from 0.023 N mm to 0.118 N mm as the rotation angle increased (p < 0.05). In addition, the torque Z force was significantly increased from 0.082 N mm to 0.292 N mm when the rotation angle increased from 60 degrees to 180 degrees at 0.15 Hz. (p < 0.05). A strong linear positive relationship between the torque Z force and rotation angle or frequency was obtained [Pearson correlation coefficient (r) > 0.88; p < 0.001]. CONCLUSION: The change in needle tissue interaction force by rotating angles showed a tendency to be higher than those by rotation frequency. Further quantitative research on various manipulations will be required for a standardized education on manipulation and stimulation as well as on needle model development to become possible. PMID- 28664112 TI - Mangiferin induces cell death against rhabdomyosarcoma through sustained oxidative stress. AB - BACKGROUND: Embryonic rhabdomyosarcoma (RD) is the most prevalent type of cancer among children. The present study aimed to investigate cell death induced by mangiferin in RD cells. METHODS: The Inhibitory concentration (IC50) value of mangiferin was determined by an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium Bromide) assay. Cell death induced by mangiferin against RD cells was determined through lactate dehydrogenase and nitric oxide release, intracellular calcium levels, reactive oxygen species generation, antioxidant status, mitochondrial calcium level, and mitochondrial membrane potential. Furthermore, acridine orange/ethidium bromide staining was performed to determine early/late apoptotic event. RESULTS: Mangiferin induced cell death in RD cells with an IC50 value of 70 MUM. The cytotoxic effect was reflected in a dose dependent increase in lactate dehydrogenase leakage and nitric oxide release during mangiferin treatment. Mangiferin caused dose dependent increase in reactive oxygen species generation, intracellular calcium levels with subsequent decrease in antioxidant status (catalase, superoxide dismutase, glutathione-S transferase, and glutathione) and loss of mitochondrial membrane potential in RD cells. Further data from fluorescence microscopy suggest that mangiferin caused cell shrinkage and nuclear condensation along with the occurrence of a late event of apoptosis. CONCLUSION: Results of the present study shows that mangiferin can act as a promising chemopreventive agent against RD by inducing sustained oxidative stress. PMID- 28664113 TI - Inhibitory effects of Taraxacum mongolicum with phreatic water on melanin synthesis. AB - BACKGROUND: Recently, people have begun showing heightened interest in skin whitening. Melanin is an important factor that determines skin color. The purpose of this study is to investigate the inhibitory effect of Taraxacum mongolicum (TAM) with phreatic water (PW) from Dogo Hot Springs on melanin synthesis. METHODS: We assessed the inhibitory effects of TAM on melanin synthesis in B16F10 mouse melanoma cells. The mRNA levels of tyrosinase related protein (TRP)-1, TRP 2, tyrosinase, MITF, ERK, and PKA protein were analyzed with reverse transcription polymerase chain reaction and Western blot analysis. We also assessed the inhibitory effects of TAM with PW on melanin synthesis in HRM-2 melanin-possessing hairless mice. After UVB irradiation, differences in melanin were analyzed with an image analysis software between the left dorsal skin (untreated part) and the right dorsal skin (treated part). The mRNA levels of TRP 1, TRP-2, and matrix metalloproteinase (MMP)-9 were analyzed with real-time quantitative polymerase chain reaction. The dorsal skins were analyzed with histological test by hematoxylin and eosin staining. RESULTS: TAM inhibited the TRP-1, TRP-2, tyrosinase, MITF mRNA gene expression, and PKA protein expression on the concentration-dependent B16F10 cell. Moreover, TAM increased the ERK mRNA gene expression in the B16F10 cell. After UVB irradiation, TAM with PW increased the differences in melanin between the left dorsal skin (untreated part) and the right dorsal skin (treated part) in HRM-2 mice. TAM with PW inhibited the TRP-1, TRP-2, and MMP-9 mRNA gene expression in HRM-2 mice. TAM with PW decreased the epidermal thickness, around the cell deformation, keratinization, and infiltration in HRM-2 mice. CONCLUSION: These results indicate that TAM with PW has the inhibitory effect of decreasing the melanin synthesis. PMID- 28664114 TI - Potentiating antimicrobial efficacy of propolis through niosomal-based system for administration. AB - BACKGROUND: Propolis is a multicomponent active, complex resinous substance collected by honeybees (Apis mellifera) from a variety of plant sources. This study was designed to improve the antimicrobial efficacy of propolis by engineering a niosomal-based system for topical application. METHODS: Propolis was extracted in ethanol and screened for total polyphenol content. Propolis loaded niosomes (PLNs) were prepared with varying concentrations of Span 60 and cholesterol. The PLNs were evaluated for physicochemical parameters, namely, vesicle size, entrapment efficiency, zeta potential, surface topography and shape, and stability, followed by screening for in vitro antimicrobial activity. The PLNs were formulated into propolis niosomal gel (PNG) using Carbopol P934 base and subjected to ex vivo skin deposition study. RESULTS: The ethanolic extract of propolis had high polyphenolic content (270 +/- 9.2 mg GAE/g). The prepared PLNs showed vesicle size between 294 nm and 427 nm, and the percent entrapment in the range of 50.62-71.29% with a significant enhancement in antimicrobial activity against Staphylococcus aureus and Candida albicans. Enhanced antimicrobial activity of PLNs was attributed to the ability of niosomes to directly interact with the bacterial cell envelop thereby facilitating the diffusion of propolis constituents across the cell wall. The formulated PNG exhibited a twofold better skin deposition due to improved retention of niosomes in the skin. CONCLUSION: The findings indicate that the engineering of a niosomal based system for propolis enhanced its antimicrobial potential through topical application. PMID- 28664115 TI - Water extract of Magnolia officinalis cortex inhibits osteoclastogenesis and bone resorption by downregulation of nuclear factor of activated T cells cytoplasmic 1. AB - BACKGROUND: Magnolia officinalis cortex has been traditionally used to treat stomach and intestine diseases in traditional Korean medicine. In this study, we investigated the effect of water extract of M. officinalis cortex (WEMC) on osteoclast differentiation and function. METHODS: Phytochemical characterization of WEMC was performed by high-performance liquid chromatography analysis. Osteoclast differentiation of bone marrow-derived macrophages was determined by tartrate-resistant acid phosphatase activity assay. Receptor activator of nuclear factor-kappaB ligand (RANKL) signaling factors and transcription factors regulating osteoclast differentiation were analyzed by Western blot and real-time polymerase chain reaction. Bone resorption function of mature osteoclasts was examined by using culture plate coated with inorganic crystalline calcium phosphate. Furthermore, the in vivo effect of WEMC on osteoporosis was examined using RANKL-induced bone loss model, characterized by micro-computed tomography and bone metabolism marker analysis. RESULTS: WEMC inhibited RANKL-induced osteoclast differentiation and the bone resorbing activity of mature osteoclasts. WEMC contains gallic acid and honokiol as active constituents contributing to the inhibitory effect of WEMC on osteoclast differentiation. Further, WEMC suppressed RANKL-induced activation of p38 and nuclear factor-kappaB pathways and expression of osteoclastogenic transcription factors such as c-Fos for AP-1 and nuclear factor of activated T cells cytoplasmic 1. Ectopic overexpression of a constitutive active form of nuclear factor of activated T cells cytoplasmic 1 rescued the antiosteoclastogenic effect of WEMC. Consistent with the in vitro results, WEMC suppressed RANKL-induced trabecular bone loss in mice. CONCLUSION: WEMC might have a therapeutic potential to treat pathological bone diseases due to increased osteoclast differentiation and function. PMID- 28664116 TI - Comparative efficacy of herbal essences with amphotricin B and ketoconazole on Candida albicans in the in vitro condition. AB - BACKGROUND: The Candida species are the most important factors of fungal infections in humans and animals. It is necessary to prepare antifungal or antimicrobial drugs because of increasing drug resistance. The natural treatment of diseases of bacterial origin using medicinal plants is important. In this study the effect of antimicrobial medicinal herbal essential oils and conventional antifungal drugs were evaluated on Candida albicans in vitro. METHODS: Disc diffusion assay and the microbroth dilution method were used to investigate the anticandidal effects of Foeniculum vulgare Mill, Satureja hortensis L, Cuminum cyminum, and Zataria multiflora Boiss essential oils. The anticandidal effect of these essential oils was compared with that of amphotricin B and ketoconazole in vitro. We then measured the chemical composition of the studied essential oils using gas chromatography-mass spectroscopy. RESULTS: Z. multiflora Boiss essential oil at the minimum inhibitory concentration (MIC) of 34 MUg/mL and minimal lethal concentration [i.e., minimal fungicidal concentration (MFC)] of 64 MUg/mL had more powerful anti-Candida activity than the other essential oils. C. cyminum essential oil showed the least effect on the tested fungus. A comparison of the effect of the studied essential oils and antifungal drugs showed that the antifungal effect on the C. albicans fungus was better with the fungicides than with the essential oils. CONCLUSION: In the present study, essential oils with different components showed antifungal activity (especially Z. multiflora Boiss essential oil). They can therefore be used as new antifungal substances. PMID- 28664117 TI - Does acupuncture increase the risk of bleeding in patients taking warfarin? PMID- 28664118 TI - Medicinal plants of the family Caryophyllaceae: a review of ethno-medicinal uses and pharmacological properties. AB - Several species of the family Caryophyllaceae are widely used by many ethnic communities as traditional medicine throughout the world. The highest number of plants of the family are used in Chinese traditional medicine. The ethnopharmacologial studies of this family indicate that plants of the family possess anticancer, antibacterial, antifungal, antiviral, antioxidant, and anti inflammatory properties. Other miscellaneous properties reported are ribosome inactivation properties, inhibition of prostatic enlargement in rats, and inhibition of intestinal enzyme carboxyelasterase in rats, cerebro-protective activity, and antiobesity in rats. Few reviews have been published yet, providing information regarding medicinal plants of the family and their biomedical properties. All published reviews have focused either on a particular taxa or a few species. The present review is focused on the traditional medicinal uses of the plants of the family Caryophyllaceae along with phytochemical and pharmacological studies of the family. A study of the literature revealed significant traditional medicinal importance of the family. Major chemical constituents of Caryophyllceae are saponins, Phytoecdysteroids, benzenoids, phenyl propanoids, and nitrogen containing compounds. The most important property of plants of the family is anticancer activity and is shown by the large number of plant species studied. This review of traditional medicinal and pharmacological uses of plants of the family, provide a ground for future research in the family. PMID- 28664119 TI - Omega-3 fatty acids and the treatment of depression: a review of scientific evidence. AB - Depression is a condition in which an individual feels lethargic, irritable, and guilty, has difficulty and trouble, no enjoyment in life, mood swings, sometimes suicidal ideation and thoughts, and loss of pleasure in activities. There are hundreds of millions of individuals suffering from major depression disorder all over the world. This leads to a considerable portion of the economy going for treatment as large amounts of money are spent on drugs every year. Pharmaceutical drugs are not very effective and they also have side effects that compound the problem. There are number of studies which shows that omega-3 fatty acids are proving to be very effective against the treatment of major depression disorder and other psychiatric disorders. However, the data regarding the efficacy of omega-3 fatty acids in depression treatment are conflicted. This article reviews the recent research showing the relation between omega-3 fatty acids and depression. The roles of the omega-3 fatty acids in the treatment of depression are being studied with increased pace in the last decade due to heightened prevalence of depression. It is emphasized that omega-3 fatty acids have no record of associated side effects, which deserves greater attention for further research. PMID- 28664120 TI - The direct modulatory activity of zinc toward ion channels. AB - The divalent zinc ion is a cation that plays an indispensable role as a structural constituent of numerous proteins, including enzymes and transcription factors. Recently, it has been suggested that zinc also plays a dynamic role in extracellular and intracellular signaling as well. Ion channels are pore-forming proteins that control the flow of specific ions across the membrane, which is important to maintain ion gradients. In this review, we outline the modulatory effect of zinc on the activities of several ion channels through direct binding of zinc into histidine, cysteine, aspartate, and glutamate moieties of channel proteins. The binding of zinc to ion channels results in the activation or inhibition of the channel due to conformational changes. These novel aspects of ion-channel activity modulation by zinc provide new insights into the physiological regulation of ion channels. PMID- 28664121 TI - Alleviating exercise-induced muscular stress using neat and processed bee pollen: oxidative markers, mitochondrial enzymes, and myostatin expression in rats. AB - BACKGROUND: The current study was designed to investigate the influence of monofloral Indian mustard bee pollen (MIMBP) and processed monofloral Indian mustard bee pollen (PMIMBP) supplementation on chronic swimming exercise-induced oxidative stress implications in the gastrocnemius muscle of Wistar rats. METHODS: MIMBP was processed with an edible lipid-surfactant mixture (Captex 355:Tween 80) to increase the extraction of polyphenols and flavonoid aglycones as analyzed by UV spectroscopy and high performance liquid chromatography-photo diode array. Wistar rats in different groups were fed with MIMBP or PMIMBP supplements at a dose of 100 mg/kg, 200 mg/kg and 300 mg/kg individually, while being subjected to chronic swimming exercise for 4 weeks (5 d/wk). Various biochemical [superoxide dismutase (SOD), glutathione (GSH), malonaldehyde (MDA), nitric oxide (NO), and total protein content], mitochondrial (Complex I, II, III, and IV enzyme activity), and molecular (myostatin mRNA expression) parameters were monitored in the gastrocnemius muscle of each group. RESULTS: Administration of both MIMBP (300 mg/kg) and PMIMBP (100 mg/kg, 200 mg/kg, and 300 mg/kg) wielded an antioxidant effect by significantly improving SOD, GSH, MDA, NO, and total protein levels. Further MIMBP (300 mg/kg) and PMIMBP (200 mg/kg and 300 mg/kg) significantly improved impaired mitochondrial Complex I, II, III, and IV enzyme activity. Significant down-regulation of myostatin mRNA expression by MIMBP (300 mg/kg) and PMIMBP (200 mg/kg and 300 mg/kg) indicates a muscle protectant role in oxidative stress conditions. CONCLUSION: The study establishes the antioxidant, mitochondrial upregulatory, and myostatin inhibitory effects of both MIMBP and PMIMBP in exercise-induced oxidative stress conditions, suggesting their usefulness in effective management of exercise-induced muscular stress. Further, processing of MIMBP with an edible lipid-surfactant mixture was found to improve the therapeutic efficiency of pollen. PMID- 28664122 TI - Numerical reproduction of hemodynamics change by acupuncture on Taichong (LR-3) based on the lumped-parameter approximation model of the systemic arteries. AB - BACKGROUND: The aim of this study was to develop a mathematical model of blood flow in the systemic circulation to emulate the change in hemodynamics by acupuncture therapy to elucidate the mechanism of the therapy. For this purpose, as a first step, a simple model of arterial blood flow was presented to reproduce previously reported change in the blood flow volume by the acupuncture needle stimulation of Taichong (LR-3). METHODS: This model was based on the lumped parameter approximation of arterial blood flow together with linear resistance of peripheral circulation. It has been reported that blood flow in the left arm was enhanced after the stimulation, yielding the peripheral vascular resistance regulated blood flow dominated by the sympathetic nervous system. In addition to the peripheral resistance, another parameter that possibly regulates the blood flow is the cross-sectional area of the vessel. These two factors were changed to numerically examine their contributions to the blood flow based on the hypothesis that they could be changed by the stimulation. The numerical result was compared with the experimental result to confirm the validity of the hypothesis that the blood flow in the arm is regulated by the peripheral resistance. RESULTS: This model is extremely simple and the physical parameters introduced for the simulation were gleaned from different reports in the literature. It was demonstrated, however, that regulation of the peripheral resistance rather than of the cross-sectional area could reproduce the experimentally observed change in the blood flow. Moreover, the relationship between the changes in the flow volume and the systemic vascular resistance quantitatively matched the experimental data. CONCLUSION: The present model has a potential to emulate hemodynamic change by acupuncture therapy by incorporating physiological correlation of stimulation of an acupoint and regulation of parameters that affect the hemodynamics. PMID- 28664123 TI - A comparison of volatile fractions obtained from Lonicera macranthoides via different extraction processes: ultrasound, microwave, Soxhlet extraction, hydrodistillation, and cold maceration. AB - BACKGROUND: Hydrodistillation has been traditionally used to extract volatile fraction in traditional Chinese medicine. However, with the development of Soxhlet extraction (SE), microwave (MW), ultrasound (US), and cold maceration (CM), hydrodistillation (HD) is being replaced to meet some practical requirements. In this study, we investigated the effect of the five methods on the volatile fraction extract of Lonicera macranthoides. METHODS: Volatile fraction from the flower buds of Lonicera macranthoides was obtained by using different extraction methods, HD, SE, MW, US, and CM. The compositions of volatile fraction were analyzed by gas chromatography-mass spectrometric and further compared among extraction methods. RESULTS: Extracts obtained by the five methods reveal the qualitative and quantitative diversity in their compositions, especially for the low-content compositions. According to the results, SE shows the great value in the research where the high molecular-mass compound is of primary interest, and MW offers a way for the isolation of specific compound like octadecadienoic acid and hexadecanoic acid. HD, US, and CM have the advantage over SE and MW for the integrity of the constituents, whereas the phenomenon of compound degradation seems not so serious in solvent extraction methods such as US or CM as HD. Additionally, US and CM show superiority over time or material saving and diversity of the constituent. CONCLUSION: HD is still the best choice for the pure volatile fraction without organic solvent pollution. However, when it comes to some specifically actual demands, it can be replaced by the four methods for the volatile fraction extraction process, especially for production of certain compound groups. PMID- 28664124 TI - Ethanol extract of Kilkyung-baeksan, a traditional herbal formula, induces G0/G1 cell cycle arrest in human lung cancer cell lines. AB - BACKGROUND: Despite current advances in diagnostics and medicines, the incidence of lung cancer is increasing and effective treatment is very challenging. Traditional herbal formulae as well as many herbal plant extracts have been recognized as attractive sources for novel multi-targeted therapy of cancer with minimal side effects. METHODS: The ethanol extract of Kilkyung-baeksan (EE-KKBS) and its component herbs were tested for their ability to inhibit cancer growth in several lung cancer cell lines. The effects of EE-KKBS and ethanol extract of Croton tiglium Linne seed (EE-CT) on cell cycle progression were measured by flow cytometric analysis using propidium iodide staining. Western blot analyses were performed to measure the expression profiles of proteins regulating cell cycle checkpoints. RESULTS: EE-KKBS inhibited the growth of lung cancer cells after 24 72 hours treatment. Lung cancer cells treated with either EE-KKBS or EE-CT showed strong G0/G1 cell cycle arrest. The expressions of p21 and p27, two key regulators of G1 cell cycle checkpoint, were significantly upregulated upon treatment with EE-KKBS and EE-CT. CONCLUSION: EE-KKBS exerted its cytostatic activity through regulating G1 cell cycle checkpoint in lung cancer cells, and this activity is mainly mediated by one of its component herbs, seeds of Croton tiglium. Collectively, our data suggest that EE-KKBS could be a novel candidate for adjuvant therapy for lung cancer. PMID- 28664125 TI - Is acupuncture effective for functional recovery in ischemic stroke? PMID- 28664126 TI - Body temperature regulation: Sasang typology-based perspective. AB - Global warming induces a dramatic elevation of heat-related morbidity and mortality worldwide. Individual variation of heat stress vulnerability depends on various factors such as age, gender, living area and conditions, health status, and individual innate characteristics. Sasang typology is a unique form of Korean traditional medicine, which is based on the hypothesis that constitution-specific traits of an individual determine the particular distinctive tendency in various aspects, including responses to the external environment. Recent scientific evidence shows that Sasang types differ in body composition, metabolic profile, susceptibility to certain disease patterns, and perspiration. This review aims to interpret these findings under the context of heat balance consisting of heat production (Hprod), heat loss (Hloss), and heat load (Hload). Based on the published data, at a given body mass, the TaeEum type tended to have a lower Hprod at rest and at the exhaustion state, which may indicate the lower metabolic efficiency of this type. Meanwhile, the surface-to-mass ratio and heat capacity of the TaeEum type appear to be lower, implying a lower heat dissipation capacity and heat storage tolerance. Thus, because of these characteristics, the TaeEum type seems to be more vulnerable to heat stress than the other constitutions. Differences in temperature regulation across constitutional types should be taken into account in daily physical activity, health management, and medical research. PMID- 28664128 TI - The value of Avicenna's heritage in development of modern integrative medicine in Uzbekistan. AB - The heritage of Abu Ali al-Husayn ibn Abd Allah ibn Sina (known in Europe as Avicenna, hereinafter referred to as Avicenna; around 980-1037 ce)has been used in the practice of doctors of various specialties in the treatment of various diseases for many centuries. Extensive clinical experience accumulated over a long time is actively used in modern medicine. Avicenna has had an invaluable contribution to world medicine. He is the largest representative of advanced sociohumanitarian ideas among the peoples of Central Asia. He was a philosopher and physician, scientist and mathematician, poet, and specialist in literature. The rich heritage of the scientist takes a worthy place in the history of medicine in particular, and world civilization in general. Avicenna introduced the main contribution to the treasury of the universal culture by his work in medicine. Avicenna brought together the achievements of Hippocrates (c. 460-370 bce),Galen (c. 130-200 ce),and healers of Egypt, Persia, and India, and he supplemented them with own research results, brilliant discoveries, and hypotheses. Avicenna left many works, among them the especially popular Canon of Medicine. He paid great attention to the prevention of diseases rather than their treatment, which is important today. In his works he gives advice on the use of herbal medicines and biologically active points for various diseases. This article highlights some topical issues of multifaceted heritage of Avicenna for modern medicine and identified promising areas for the development of integrative medicine in Uzbekistan. PMID- 28664129 TI - Developing an optimized cold/heat questionnaire. AB - BACKGROUND: The cold/heat questionnaire is one of the most actively developed patient diagnostic tools in traditional Korean medicine (hereafter abbreviated as TKM) because of its objectivity. Unfortunately, the existing questionnaires contain too many items to hold the respondent's attention. In the current study, we aimed to develop an optimized cold/heat questionnaire to be used as a complement to the existing questionnaires. METHODS: We developed a new cold/heat questionnaire based on a domain analysis of the existing questionnaires. The questionnaire's reliability was examined via two test-retest reliability analyses involving 1890 individuals in November 2013 and February 2014. Its validity was examined using a professional cold/heat diagnosis kappa value. RESULTS: The new cold/heat questionnaire consisted of a total of seven items, which were created based on an analysis of the existing questionnaires. A reliability analysis performed using the study participants revealed a correlation coefficient of 0.609, 74.5% agreement with professional cold/heat diagnoses by TKM practitioners, and a kappa value of 0.487. CONCLUSION: In the current study, we developed an optimized cold/heat questionnaire. The level of agreement between the questionnaire and professional cold/heat diagnoses by TKM practitioners was significant, which indicates great potential for its widespread use as a diagnostic tool in TKM. PMID- 28664130 TI - Neferine, a bisbenzylisoquinoline alkaloid, offers protection against cobalt chloride-mediated hypoxia-induced oxidative stress in muscle cells. AB - BACKGROUND: Neferine, a bisbenzylisoquinoline alkaloid, isolated from Nelumbo nucifera has a wide range of biological activities. Cobalt chloride (CoCl2) was known to mimic hypoxic condition. In the present study, we assessed the cytoprotective effect of neferine against CoCl2-induced oxidative stress in muscle cells. METHODS: Rhabdomyosarcoma cells were exposed to different concentrations of CoCl2, and the IC50 value was determined using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Lactate dehydrogenase and NO assays were performed in order to determine the cytotoxic effect of CoCl2. Reactive oxygen species generation and cellular antioxidant status were determined for evaluating oxidative stress. For analyzing the effect of neferine on CoCl2-induced apoptosis, propidium iodide staining was performed. RESULTS: The results of the present study indicate that CoCl2 induces cell death in a dose-dependent manner. Neferine pretreatment at 700 nM concentration offers better cytoprotection in the cells exposed to CoCl2. Lactate dehydrogenase and NO release in the culture medium were restored after neferine pretreatment. CoCl2 triggers time-dependent reactive oxygen species generation in muscle cells. Further, results of propidium iodide staining, mitochondrial membrane potential, and intracellular calcium accumulation confirm that neferine offers protection against CoCl2-induced hypoxic injury. Depleted activities of antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione S transferase due to CoCl2 exposure were also reinstated in the group that received neferine pretreatment. CONCLUSION: Our study suggests that neferine from N. nucifera offers protection to muscle cells by counteracting the oxidative stress induced by CoCl2. PMID- 28664127 TI - Modern acupuncture-like stimulation methods: a literature review. AB - Acupuncture therapy has been proved to be effective for diverse diseases, symptoms, and conditions in numerous clinical trials. The growing popularity of acupuncture therapy has triggered the development of modern acupuncture-like stimulation devices (ASDs), which are equivalent or superior to manual acupuncture with respect to safety, decreased risk of infection, and facilitation of clinical trials. Here, we aim to summarize the research on modern ASDs, with a focus on featured devices undergoing active research and their effectiveness and target symptoms, along with annual publication rates. We searched the popular electronic databases Medline, PubMed, the Cochrane Library, and Web of Science, and analyzed English-language studies on humans. Thereby, a total of 728 studies were identified, of which 195 studies met our inclusion criteria. Electrical stimulators were found to be the earliest and most widely studied devices (133 articles), followed by laser (44 articles), magnetic (16 articles), and ultrasound (2 articles) stimulators. A total of 114 studies used randomized controlled trials, and 109 studies reported therapeutic benefits. The majority of the studies (32%) focused on analgesia and pain-relief effects, followed by effects on brain activity (16%). All types of the reviewed ASDs were associated with increasing annual publication trends; specifically, the annual growth in publications regarding noninvasive stimulation methods was more rapid than that regarding invasive methods. Based on this observation, we anticipate that the noninvasive or minimally invasive ASDs will become more popular in acupuncture therapy. PMID- 28664131 TI - Stromal interaction molecule 2 regulates C2C12 myoblast differentiation. AB - BACKGROUND: Enhanced intracellular Ca2+ signaling by stromal interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) is required for skeletal muscle differentiation. However, the contribution of STIM2, STIM1's analogue protein, on muscle cell differentiation has not been clearly elucidated. The present study aimed to explore the contribution of STIM2-mediated SOCE on C2C12 myoblast differentiation. METHODS: Changes in STIM2 expression level (reverse transcription-polymerase chain reaction and Western blotting) and SOCE activity ([Ca2+]i measurement) were measured during 3 days of in vitro differentiation of C2C12 skeletal myoblast. Transcriptional regulation of STIM2 by nuclear factor of activated T cells, cytoplasmic (NFATc) overexpression was observed, and the effect of STIM2 knockdown on NFAT transcriptional activity (luciferase assay) and myoblast differentiation was quantified. RESULTS: Increase of STIM2 protein level and enhanced SOCE activity were observed in differentiating myoblasts. Treatment with a SOCE blocker (2-APB) inhibited the differentiation. Overexpression of NFATc1 increased STIM2 expression and SOCE activity. Knockdown of STIM2 decreased NFAT transcriptional activity, SOCE activity, and differentiation of C2C12 myoblast. CONCLUSION: It is suggested that STIM2-activated SOCE controls C2C12 myoblast differentiation. PMID- 28664132 TI - Protocol for the evaluation and validation of Qi Blood Yin Yang deficiency pattern questionnaire: prospective observational study. AB - BACKGROUND: The aim of this study is to validate the pattern identification standard of qi, blood, yin, and yang deficiency patterns diagnosis. The current study will investigate the usefulness of the Qi Blood Yin Yang deficiency pattern questionnaire as a diagnostic tool for qi, blood, yin, and yang deficiencies by assessing the agreement between the scores and a gold standard established by assessors. METHODS: This protocol is for a single center, prospective, observational study. A total of 248 eligible patients with unexplained chronic fatigue will be assigned to four groups in a 1:1:1:1 ratio as the qi deficiency group, blood deficiency group, yin deficiency group, and yang deficiency group. The primary outcome will be measured using the score of the Qi Blood Yin Yang deficiency pattern questionnaire and the secondary outcomes will be measured using the fatigue severity scale, Korean-translated chalder fatigue scale, computerized tongue image analysis system, and three types of pattern identification questionnaires (cold-heat, food accumulation, and seven emotions patterns). The safety of the clinical study will be assessed after measurements at every visit. All statistical analysis will be performed using the R Statistics program. Statistics experts will analyze the relationship between clinical data using the Pearson's Chi-squared test and independent t-test. DISCUSSION: This study will provide reference data and good evidence that are applicable to future studies. Furthermore, the results of the present study are useful to improve the care of patients with unexplained chronic fatigue and unexplained chronic fatigue related disorders. PMID- 28664133 TI - Is traditional Chinese herbal medicine effective in prolonging survival times in extensive-stage small-cell lung cancer patients? PMID- 28664134 TI - Traditional Indian medicine (TIM) and traditional Korean medicine (TKM): aconstitutional-based concept and comparison. AB - Traditional and complementary medicine (T&CM) plays an integral role in providing health care worldwide. It is based on sound fundamental principles and centuries of practices. This study compared traditional Indian medicine (TIM) and traditional Korean medicine (TKM) basing on data obtained from peer reviewed articles, respective government institutional reports and World Health Organization reports. Despite the fact that TIM and TKM have individual qualities that are unique from each other including different histories of origin, they share a lot in common. Apart from Homeopathy in TIM, both systems are hinged on similar principle of body constitutional-based concept and similar disease diagnosis methods of mainly auscultation, palpation, visual inspection, and interrogation. Similarly, the treatment methods of TIM and TKM follow similar patterns involving use of medicinal herbs, moxibustion, acupuncture, cupping, and manual therapy. Both T&CM are majorly practiced in well-established hospitals by T&CM doctors who have undergone an average of 6-7 years of specialized trainings. However, unlike TIM which has less insurance coverage, the popularity of TKM is majorly due to its wide national insurance coverage. These two medical traditions occupy increasingly greater portion of the global market. However, TIM especially Ayurveda has gained more global recognition than TKM although the emergence of Sasang Constitutional Medicine in TKM is beginning to become more popular. This comparative analysis between TIM and TKM may provide vital and insightful contribution towards constitutional-based concept for further development and future studies in T&CM. PMID- 28664135 TI - Ethnomedicinal plants used for snakebite in India: a brief overview. AB - The result of human interface and assortment of the most desirable, influential, and successful plant species found in the immediate environment at a precise circumstance is attributable to indigenous knowledge of plant species. India has a rich variety of medicinal plants growing under different geographical and ecological conditions; 1500 out of 15,000 privileged plant species have been reported to have medicinal uses. Snakebite is a severe medical, social, and economic problem in many parts of the world, chiefly in tropical and subtropical nations where majority of the world's dangerous snakes are found and where access to treatment is limited. In India, a range of medicinal plants are used as antidotes for snakebites, used either singly or in combination with other agents. The present study makes an effort to assemble information on medicinal plants that are grown and used for snakebite treatment in India. From a range of literature sources, data have been compiled with emphasis on the plants, family, parts used, etc., depending on the availability of information. This paper enumerates 523 plant species belonging to 122 families that act as antidotes against snakebites. We believe this study of herbal antidotes against snake venom is of substantial significance to society. PMID- 28664136 TI - Modulatory effect of dianthrone rich alcoholic flower extract of Cassia auriculata L. on experimental diabetes. AB - BACKGROUND: Diabetes is rapidly rising all over the world at an alarming rate and has changed from a mild disorder to major causes of mortality and morbidity in the youth and middle-aged people, and the prevalence is seen especially in six inhabited continents of the globe. The present study aims to explore the antidiabetic, lipid lowering effect of Cassia auriculata L. flowers in alloxan induced diabetes. METHODS: Diabetes was induced using alloxan monohydrate in experimental rats and subsequent therapeutic effects of C. auriculata extract and standard drug glibenclamide were monitored. Bioassay-directed fractionation using silica gel column chromatography was performed until pure fractions were isolated. The effect of the treatment was analyzed by hematological parameters and enzyme assays. The pure compounds were confirmed with thin layer chromatography and high performance liquid chromatography pattern and further subjected for characterization. RESULTS: The alterations in blood glucose were monitored throughout the study. There was a gradual fall in blood glucose and significant changes were observed in lipid profile and metabolic enzyme after treatment with C. auriculata. Bioassay fractionation represented that the C2 subfraction produced a dose-dependent fall in blood glucose and lipid profile and upon further purification yielded two pure compounds. The structure of the pure compound was elucidated using Fourier transform infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and mass spectral data. CONCLUSION: The present study clearly indicated the significant antidiabetic effect of C. auriculata and lends support for its traditional usage without evident toxic effects. PMID- 28664137 TI - Evaluation of cytotoxic activity of platinum nanoparticles against normal and cancer cells and its anticancer potential through induction of apoptosis. AB - BACKGROUND: Plant mediated green synthesis of nanoparticles is an eco-friendly and efficacious approach which finds immense application in the field of medicine. This study aimed to evaluate the cytotoxicity of platinum nanoparticles (ptNPs) synthesized through green technology against normal and different cancer cell lines. METHODS: Platinum nanoparticles were synthesized by green technology and characterized earlier. In this study we examined the cytotoxic effect of platinum nanoparticles (ptNPs) on human lung adenocarcinoma (A549), ovarian teratocarcinoma (PA-1), pancreatic cancer (Mia-Pa-Ca-2) cells and normal peripheral blood mononucleocyte (PBMC) cells and evaluate anticancer potential through induction of apoptosis on PA-1 cells if any. Cytotoxicity was evaluated using MTT assay, trypan blue dye exclusion assay and anticancer potential assessed through clonogenic assay, apoptosis assay, cell cycle analysis. RESULTS: We found that ptNPs exerted cytotoxic effect on cancer cell lines, whereas no cytotoxic effect was observed at highest dose on normal cells. The results showed that ptNPs had potent anticancer activities against PA-1 cell line via induction of apoptosis and cell cycle arrest. CONCLUSION: Overall, these findings have proved that biosynthesized ptNPs could be potent anti-ovarian cancer drugs. Further studies are required to elucidate the molecular mechanism of ptNPs induced anti-tumor effect in vivo. PMID- 28664138 TI - Naringenin inhibits pacemaking activity in interstitial cells of Cajal from murine small intestine. AB - BACKGROUND: Naringenin (NRG) is a common dietary polyphenolic constituent of fruits. NRG has diverse pharmacological activities, and is used in traditional medicine to treat various diseases including gastrointestinal (GI) disorders. Interstitial cells of Cajal (ICCs) are pacemaker cells of the GI tract. In this study, the authors investigated the effects of NRG on ICCs and on GI motility in vitro and in vivo. METHODS: ICCs were dissociated from mouse small intestines by enzymatic digestion. The whole-cell patch clamp configuration was used to record pacemaker potentials in cultured ICC clusters. The effects of NRG on GI motility were investigated by calculating percent intestinal transit rates (ITR) using Evans blue in normal mice. RESULTS: NRG inhibited ICC pacemaker potentials in a dose-dependent manner. In the presence of tetraethylammonium chloride or iberiotoxin, NRG had no effect on pacemaker potentials, but it continued to block pacemaker potentials in the presence of glibenclamide. Preincubation with SQ 22536 had no effect on pacemaker potentials or on their inhibition by NRG. However, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one blocked pacemaker potential inhibition by NRG. In addition, L-NG-nitroarginine methyl ester blocked pacemaker potential inhibition by NRG. Furthermore, NRG significantly suppressed murine ITR enhancement by neostigmine in vivo. CONCLUSION: This study shows NRG dose dependently inhibits ICC pacemaker potentials via a cyclic guanosine monophosphate/nitric oxide-dependent pathway and Ca2+-activated K+ channels in vitro. In addition, NRG suppressed neostigmine enhancement of ITR in vivo. PMID- 28664139 TI - Analysis of seven animation characters in Pororo the Little Penguin with Sasang typology. AB - BACKGROUND: Animation characters are created to embody distinctive personalities and body images; however, these features have not been analyzed with objective measures based on East Asian theory. The purpose of this study was to analyze the biopsychological features of seven animation characters in Pororo the Little Penguin, which scored unprecedented success in Korea, with clinically validated and standardized measures of Sasang typology. METHODS: Forty-one graduate students completed a survey examining body mass index (BMI) and Sasang Personality Questionnaire (SPQ) of seven characters in Pororo the Little Penguin after watching three selected episodes. The differences in physical appearance and psychological traits among animation characters were analyzed with analysis of variance. RESULTS: SPQ and BMI showed distinctive biopsychological features of seven animation characters. Pororo (28.29 +/- 6.38 and 36.61 +/- 3.09) was a typical So-Yang type boy, Petty (20.98 +/- 4.07 and 31.66 +/- 4.59) was a typical So-Yang type girl, and Loopy (28.05 +/- 6.60 and 22.78 +/- 4.78) was a typical So Eum type girl in terms of BMI and SPQ, respectively. The BMI and SPQ of Poby (41.10 +/- 4.26 and 22.32 +/- 3.48) and Harry (19.63 +/- 5.17 and 37.61 +/- 2.40) showed the most obvious contrast. CONCLUSION: This study showed that SPQ and BMI are useful objective measures for analyzing the biopsychosocial features of animation characters as well as patients. The interdisciplinary research methodology of Sasang typology suggested here would provide useful tools for educating healthcare professionals and the general public about Korean medicine, and also contribute to the development of animation characters. PMID- 28664140 TI - Energy metabolism and whole-exome sequencing-based analysis of Sasang constitution: a pilot study. AB - BACKGROUND: Traditional Korean Sasang constitutional (SC) medicine categorizes individuals into four constitutional types [Tae-eum (TE), So-eum (SE), Tae-yang (TY), or So-yang (SY)] based on biological and physiological characteristics. As these characteristics are closely related to the bioenergetics of the human body, we assessed the correlation between SC type and energy metabolism features. METHODS: Forty healthy, young (22.3 +/- 1.4 years) males volunteered to participate in this study. Participants answered an SC questionnaire, and their face shape, voice tone, and body shape were assessed using an SC analysis tool. Thirty-one participants (10 TE, 10 SE, 3 TY, and 8 SY) were selected for further analysis. Collected blood samples were subjected to blood composition analysis, mitochondrial function analysis, and whole-exome sequencing. RESULTS: The SY type showed significantly lower total cholesterol and high-density lipoprotein cholesterol levels than the SE type. Cellular and mitochondrial Adenosine triphosphate (ATP) levels were similar across types. All types showed similar basal mitochondrial oxygen consumption rates, whereas the TE type showed a significantly lower ATP-linked oxygen consumption rate than the other types. Whole-exome sequencing identified several genes variants that were exclusively detected in particular SC types, including 19 for SE, seven for SY, 11 for TE, and six for TY. CONCLUSION: SC type-specific differences in mitochondrial function and gene mutations were detected in a small group of healthy, young Korean males. These results are expected to greatly improve the accurate screening and utilization of SC medicine. PMID- 28664141 TI - Induction of apoptosis by Dae-Hwang-Mok-Dan-Tang in HCT-116 colon cancer cells through activation of caspases and inactivation of the phosphatidylinositol 3 kinase/Akt signaling. AB - BACKGROUND: Dae-Hwang-Mok-Dan-Tang (DHMDT), a traditional Korean medicine, contains five species of medicinal plants and has been used to treat patients with digestive tract cancer for hundreds of years; however, its anticancer mechanism is poorly understood. In the present study, we investigated the proapoptotic effects of DHMDT in human colon cancer HCT-116 cells. METHODS: Cytotoxicity was evaluated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assay. Apoptosis was detected using 4,6-diamidino-2 phenyllindile staining, agarose gel electrophoresis, and flow cytometry. The protein levels were determined using Western blot analysis. Caspase activity was measured using a colorimetric assay. RESULTS: Treatment with DHMDT resulted in a growth inhibition coupled with apoptosis induction, which was associated with the downregulation of members of IAP (inhibitor of apoptosis protein) family, including XIAP and survivin, and the activation of caspase-9 and -3 accompanied by proteolytic degradation of poly(ADP-ribose)-polymerase and phospholipase C gamma1. DHMDT treatment also showed a correlation with the translocation of proapoptotic Bax to mitochondria, the loss of mitochondrial membrane permeabilization, and the cytochrome c release from the mitochondria to the cytosol. Moreover, DHMDT increased the levels of death receptor-associated ligands and enhanced activation of caspase-8 and cleavage of its substrate, Bid. However, the pan-caspase inhibitor could reverse DHMDT-induced apoptosis. In addition, DHMDT suppressed the phosphoinositide 3-kinase (PI3K)/Akt pathway, and treatment with a potent inhibitor of PI3K further increased the apoptotic activity of DHMDT. CONCLUSION: Our data showed that DHMDT induces HCT-116 cell apoptosis by activating intrinsic and extrinsic apoptosis pathways and by suppressing the PI3K/Akt signal pathway; however, further studies are needed to identify the active compounds. PMID- 28664143 TI - The effects of personality traits on academic burnout in Korean medical students. AB - BACKGROUND: Previous studies suggest that personality traits play an important role in academic burnout. The aim of this study was to investigate how Cloninger's temperament and character traits explain academic burnout in a highly competitive environment of medical school. METHODS: A total of 184 Korean medical students participated in the survey. The Cloninger's Temperament and Character Inventory was measured around the beginning of the semester and Maslach Burnout Inventory-Student Survey at the end of the semester. The correlations and stepwise regression analysis were conducted to explain the association between personality traits and academic burnout. In addition, latent profile analysis and profile analysis were employed to distinguish and explain differences of personality traits among latent academic burnout subgroups. RESULTS: The higher harm avoidance of temperament and lower self-directedness and cooperativeness of character predicted the subscales of academic burnout in medical students. The Temperament and Character Inventory personality profile of high, middle, and low latent burnout subgroups were significantly different. CONCLUSION: This study showed that personality might account for the burnout level in medical education. The importance of character dimension for modulating the effects of temperament traits on academic burnout was discussed for future research. PMID- 28664142 TI - Molecular mechanisms of anticancer activity of deoxyelephantopin in cancer cells. AB - BACKGROUND: Deoxyelephantopin (DOE) is a natural bioactive sesquiterpene lactone from Elephantopus scaber, a traditionally relevant herb in Chinese and Indian medicine. It has shown promising anticancer effects against a broad spectrum of cancers. METHODS: We examined the effect of DOE on growth, autophagy, apoptosis, cell cycle progression, metastasis, and various molecular signaling pathways in cancer cells, and endeavored to decipher the molecular mechanisms underlying its effect. The cytotoxicity of DOE was examined by MTT (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide) and colony formation assays. The antimetastatic potential of DOE was identified by wound closure, as well as invasion and migration assays. The expression of mRNAs and proteins related to cytotoxicity in cancer cells induced by DOE was investigated using reverse transcription polymerase chain reaction, flow cytometry, and Western blot analysis. RESULTS: DOE showed significant cytotoxicity and induced apoptosis in cancer cells. DOE promoted the autophagy of HCT 116 and K562 cells. DOE arrested cell cycle progression in the G2/M phase. DOE treatment caused activation of caspase-8, -9, 3 and -7, reactive oxygen species production, and cleavage of cleavage of poly ADP-ribose polymerase (PARP), the markers of apoptosis. Moreover, apoptosis induction was associated with mitochondrial permeability and endoplasmic reticulum stress. Treatment of cancer cells with DOE inhibited mitogen-activated protein kinases, nuclear factor-kappa B, phosphatidylinositol 3-kinase (PI3K/Akt), and beta-catenin signaling. Furthermore, treatment of DOE increased the expression of p53, phospho-Jun amino-terminal kinases (p-JNK), and p-p38 and decreased the expression of phospho-signal transducer and activator of transcription 3 (p-STAT3) and phospho-mammalian target of rapamycin (p-mTOR) in cancer cells. DOE downregulated matrix metalloproteinase (MMP-2) and MMP-9, urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR) mRNA levels in cancer cells. CONCLUSION: These findings concluded that DOE may be useful as a chemotherapeutic agent against cancer. PMID- 28664144 TI - Acute toxicity and genotoxicity of fermented traditional medicine oyaksungi-san. AB - BACKGROUND: The traditional medicine oyaksungi-san (OY) has been prescribed in East Asia for hundreds of years for the treatment of stroke, paralysis, and ataxia. OY also has therapeutic effects on arthralgia, myalgia, and rheumatoid arthritis, and recent studies have shown its protective effects against apoptosis of hippocampal cells and its anti-inflammatory effects on the peripheral blood cells of patient with cerebral infarction. Many studies have explored the use of traditional medicine and herb materials in the development of safe, novel, and effective pharmaceuticals with fewer side effects. These efforts commonly adopt a bioconversion tool for fermentation with beneficial microbes. However, only pharmaceuticals with high levels of safety and low levels of toxicity can be used in healthcare system. METHODS: OY water extract was fermented with Lactobacillus and assayed for acute toxicity and genotoxicity. Single dose acute toxicity, bacterial reverse mutation, chromosome aberrations, and micronucleus were observed and assayed in rats, histidine/tryptophan auxotrophic bacteria, Chinese hamster ovary fibroblast cells, and mice bone marrow cells, respectively. RESULTS: All the experimental animals showed no abnormal behavior, clinical signs, body weight increases, or mortality. In the bacterial cultures, no revertant colonies were observed. Morphological and numerical chromosomal aberrations were not found in all metaphases examined. Frequency of induced micronuclei was not significantly increased in all doses applied. CONCLUSION: As a whole, no acute toxicity or genotoxicity were observed in all the assays examined. Therefore, fermented OY is considered to be a safe material that can be used for development of complementary and alternative medicine using bioconversion. PMID- 28664145 TI - Factors related to the parallel use of complementary and alternative medicine with conventional medicine among patients with chronic conditions in South Korea. AB - BACKGROUND: This study aims to examine the characteristics and behavioral patterns of patients with chronic conditions behind their parallel use of the conventional medicine (CM) and the complementary and alternative medicine (CAM) that includes traditional Korean Medicine (KM). METHODS: This cross-sectional study used the self-administered anonymous survey method to obtain the results from inpatients who were staying in three hospitals in Gyeongnam province in Korea. RESULTS: Of the 423 participants surveyed, 334 participants (79.0%) used some form of CAM among which KM therapies were the most common modalities. The results of a logistic regression analysis showed that the parallel use pattern was most apparent in the groups aged over 40. Patients with hypertension or joint diseases were seen to have higher propensity to show the parallel use patterns, whereas patients with diabetes were not. In addition, many sociodemographic and health-related characteristics are related to the patterns of the parallel use of CAM and CM. CONCLUSION: In the rural area of Korea, most inpatients who used CM for the management of chronic conditions used CAM in parallel. KM was the most common in CAM modalities, and the aspect of parallel use varied according to the disease conditions. PMID- 28664146 TI - Oviductal transcriptional profiling of a bovine fertility model by next generation sequencing. AB - In cattle, the oviduct plays a fundamental role in the reproductive process. Oviductal functions are controlled by the ovarian sex steroids: estradiol and progesterone. Here, we tested the hypothesis that the exposure to contrasting sex steroid milieus differentially impacts the oviductal transcriptional profile. We manipulated growth of the pre-ovulatory follicle to obtain cows that ovulated a larger (LF group) or a smaller (SF group) follicle. The LF group presented greater proestrus/estrus concentrations of estradiol and metaestrus concentrations of progesterone (Gonella-Diaza et al. 2015 [1], Mesquita et al. 2014 [2]). Also, the LF group was associated with greater fertility in timed artificial insemination programs (Pugliesi et al. 2016 [3]). Cows were slaughtered on day 4 of the estrous cycle and total RNA was extracted from ampulla and isthmus fragments and analyzed by RNAseq. The resulting reads were mapped to the bovine genome (Bos taurus UMD 3.1, NCBI). The differential expression analyses revealed that 325 and 367 genes in ampulla and 274 and 316 genes in the isthmus were up-regulated and down-regulated in LF samples, respectively. To validate the RNAseq results, transcript abundance of 23 genes was assessed by qPCR and expression patterns were consistent between the two techniques. A functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Processes enriched in the LF group included tissue morphology changes (extracellular matrix remodeling), cellular changes (proliferation), and secretion changes (growth factors, ions and metal transporters). An overview of the gene expression data was deposited in the NCBI's Gene Expression Omnibus (GEO) and is accessible through the accession number GSE65681. In conclusion, differences in the peri ovulatory sex steroid milieu modify the oviductal gene expression profiles. Such differences may be associated with the greater fertility of the LF cows. This dataset is useful for further investigations of the oviductal biology and the impact of sex-steroid on the female reproductive tract. PMID- 28664147 TI - Mineralisation of atmospheric aerosol particles and further analysis of trace elements by inductively coupled plasma-optical emission spectrometry. AB - Several protocols using different treatments (various mixtures of acids at different temperatures for mineralisation) or using several analysis instrumentations were tested with the aim to define the method allowing the analysis of some groups of elements. This study proposes a protocol of sample treatment and analysis permitting in a single batch the determination of 16 elements (Al, As, Ba, Cd, Co, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Ti, V and Zn) with different chemical features such as volatile or refractory trace elements. This method is specifically adapted to chemical matrices found in unpolluted to moderately polluted atmospheric aerosol samples. Aerosol samples were digested using a mixture aqua regia/hydrofluoric acid at 130 degrees C during 2 h, and were then analysed with specifically tuned inductively coupled plasma-optical emission spectrometry. *Reduction of costs: use of hot block, use of inductively coupled plasma-optical emission spectrometry (ICP-OES), easiness, reliability and adaptability to routine analysis*Digestion of up to 54 samples at the same time in 2 h and low amount of material required, only 10 mg is necessary.*Better accordance with Occupational Health and Safety requirements (reduced use of acids, in particular HF, no use of high-pressure Teflon bombs). PMID- 28664148 TI - Synthesis of silver nanoparticles using bacterial exopolysaccharide and its application for degradation of azo-dyes. AB - In this study, the synthesis and characterization of exopolysaccharide-stabilized sliver nanoparticles (AgNPs) was carried out for the degradation of industrial textile dyes. Characterization of AgNPs was done using surface plasmon spectra using UV-Vis spectroscopy, X-ray diffraction (XRD) and Raman spectroscopy. The morphological nature of AgNPs was determined through transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM), which indicated that the AgNPs were spherical in shape, with an average size of 35 nm. The thermal behaviour of AgNPs revealed that it is stable up to 437.1 degrees C and the required energy is 808.2J/g in TGA-DTA analysis. Ability of EPS stabilized AgNPs for degradation of azo dyes such as Methyl orange (MO) and Congo red (CR) showed that EPS stabilized AgNPs were found to be efficient in facilitating the degradation process of industrial textile dyes. The electron transfer takes place from reducing agent to dye molecule via nanoparticles, resulting in the destruction of the dye chromophore structure. This makes EPS AgNPs a suitable, cheap and environment friendly candidate for biodegradation of harmful textile dyes. PMID- 28664149 TI - Selecting an appropriate method for expressing S locus F-box-S2 recombinant protein. AB - A single locus (S locus) including at least two linked genes (female and male determinants) genetically controls the gametophytic self-incompatibility (GSI) in apple, which has evolved to avoid self-fertilization. There has been extensive work done on the female determinant of self-incompatibility, which has led to the determination of the tertiary structure of S-RNase. However, the tertiary structure of male determinant (S locus F-box, SLF/SFB) remains unresolved, which could mainly be due to difficulties associated with its expression in the recombinant expression systems. In addressing this, we have evaluated several in vivo (prokaryotic and eukaryotic) and in vitro expression systems for their efficiency in the expression of apple SLF2. The most successful expression of SLF2 (1 mg/ml) was achieved in E. coli using the synthesized gene in a high salt culture and applying heat shock before induction of culture. We therefore present an approach for the efficient expression of S locus F-box recombinant proteins for future functional and structural studies. PMID- 28664150 TI - Coexpression and expression quantitative trait loci analyses of the angiogenesis gene-gene interaction network in prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) shows a substantial clinical heterogeneity. The existing risk classification for PCa prognosis based on clinical factors is not sufficient. Although some biomarkers for PCa aggressiveness have been identified, their underlying functional mechanisms are still unclear. We previously reported a gene-gene interaction network associated with PCa aggressiveness based on single nucleotide polymorphism (SNP)-SNP interactions in the angiogenesis pathway. The goal of this study is to investigate potential functional evidence of the involvement of the genes in this gene-gene interaction network. METHODS: A total of 11 angiogenesis genes were evaluated. The crosstalks among genes were examined through coexpression and expression quantitative trait loci (eQTL) analyses. The study population is 352 Caucasian PCa patients in the Cancer Genome Atlas (TCGA) study. The pairwise coexpressions among the genes of interest were evaluated using the Spearman coefficient. The eQTL analyses were tested using the Kruskal-Wallis test. RESULTS: Among all within gene and 55 possible pairwise gene evaluations, 12 gene pairs and one gene (MMP16) showed strong coexpression or significant eQTL evidence. There are nine gene pairs with a strong correlation (Spearman correlation >=0.6, P<1*10-13). The top coexpressed gene pairs are EGFR SP1 (r=0.73), ITGB3-HSPG2 (r=0.71), ITGB3-CSF1 (r=0.70), MMP16-FBLN5 (r=0.68), ITGB3-MMP16 (r=0.65), ITGB3-ROBO1 (r=0.62), CSF1-HSPG2 (r=0.61), CSF1-FBLN5 (r=0.6), and CSF1-ROBO1 (r=0.60). One cis-eQTL in MMP16 and five trans-eQTLs (MMP16-ESR1, ESR1-ROBO1, CSF1-ROBO1, HSPG2-ROBO1, and FBLN5-CSF1) are significant with a false discovery rate q value less than 0.2. CONCLUSIONS: These findings provide potential biological evidence for the gene-gene interactions in this angiogenesis network. These identified interactions between the angiogenesis genes not only provide information for PCa etiology mechanism but also may serve as integrated biomarkers for building a risk prediction model for PCa aggressiveness. PMID- 28664151 TI - Type VI Secretion Effectors: Methodologies and Biology. AB - The type VI secretion system (T6SS) is a nanomachine deployed by many Gram negative bacteria as a weapon against eukaryotic hosts or prokaryotic competitors. It assembles into a bacteriophage tail-like structure that can transport effector proteins into the environment or target cells for competitive survival or pathogenesis. T6SS effectors have been identified by a variety of approaches, including knowledge/hypothesis-dependent and discovery-driven approaches. Here, we review and discuss the methods that have been used to identify T6SS effectors and the biological and biochemical functions of known effectors. On the basis of the nature and transport mechanisms of T6SS effectors, we further propose potential strategies that may be applicable to identify new T6SS effectors. PMID- 28664153 TI - SopB-Mediated Recruitment of SNX18 Facilitates Salmonella Typhimurium Internalization by the Host Cell. AB - To invade epithelial cells, Salmonella enterica serovar Typhimurium (S. Typhimurium) induces macropinocytosis through the action of virulence proteins delivered across the host cell membrane via a type III secretion system. We show that after docking at the plasma membrane S. Typhimurium triggers rapid recruitment of cytosolic SNX18, a SH3-PX-BAR domain sorting nexin protein, to the bacteria-induced membrane ruffles and to the nascent Salmonella-containing vacuole. SNX18 recruitment required the inositol-phosphatase activity of the Salmonella effector SopB and an intact phosphoinositide-binding site within the PX domain of SNX18, but occurred independently of Rho-GTPases Rac1 and Cdc42 activation. SNX18 promotes formation of the SCV from the plasma membrane by acting as a scaffold to recruit Dynamin-2 and N-WASP in a process dependent on the SH3 domain of SNX18. Quantification of bacteria uptake revealed that overexpression of SNX18 increased bacteria internalization, whereas a decrease was detected in cells overexpressing the phosphoinositide-binding mutant R303Q, the DeltaSH3 mutant, and in cells where endogenous levels of SNX18 were knocked down. This study identifies SNX18 as a novel target of SopB and suggests a mechanism where S. Typhimurium engages host factors via local manipulation of phosphoinositide composition at the site of invasion to orchestrate the internalization process. PMID- 28664155 TI - The Role of Dentists and Primary Care Physicians in the Care of Patients with Sleep-Related Breathing Disorders. PMID- 28664152 TI - Type III Secretion in the Melioidosis Pathogen Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a Gram-negative intracellular pathogen and the causative agent of melioidosis, a severe disease of both humans and animals. Melioidosis is an emerging disease which is predicted to be vastly under reported. Type III Secretion Systems (T3SSs) are critical virulence factors in Gram negative pathogens of plants and animals. The genome of B. pseudomallei encodes three T3SSs. T3SS-1 and -2, of which little is known, are homologous to Hrp2 secretion systems of the plant pathogens Ralstonia and Xanthomonas. T3SS-3 is better characterized and is homologous to the Inv/Mxi-Spa secretion systems of Salmonella spp. and Shigella flexneri, respectively. Upon entry into the host cell, B. pseudomallei requires T3SS-3 for efficient escape from the endosome. T3SS-3 is also required for full virulence in both hamster and murine models of infection. The regulatory cascade which controls T3SS-3 expression and the secretome of T3SS-3 have been described, as well as the effect of mutations of some of the structural proteins. Yet only a few effector proteins have been functionally characterized to date and very little work has been carried out to understand the hierarchy of assembly, secretion and temporal regulation of T3SS 3. This review aims to frame current knowledge of B. pseudomallei T3SSs in the context of other well characterized model T3SSs, particularly those of Salmonella and Shigella. PMID- 28664154 TI - Geldanamycin Reduces Acute Respiratory Distress Syndrome and Promotes the Survival of Mice Infected with the Highly Virulent H5N1 Influenza Virus. AB - Infections with lethal influenza viruses lead to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which may be related to the activation of the host's immune system. Here, in our study, male C57BL/6 mice were infected with 10 LD50 of the H5N1 influenza virus and treated with geldanamycin or oseltamivir 2 h after infection. Lung injury was assessed by histopathology on days 4 and 7. The viral load was quantified by measuring the NP gene expression level on days 2, 4, and 7. Levels of cytokines and chemokines in bronchoalveolar lavage fluids and inflammatory cells were analyzed at different time points. Geldanamycin administration prolonged survival in mice and dramatically reduced lung injury and pulmonary inflammatory compared with other mice. Viral loads in geldanamycin-treated mice also significantly reduced compared with non-treated mice, but not to the extent as the oseltamivir-treated mice. Furthermore, the geldanamycin treatment markedly reduced the production of major proinflammatory cytokines and chemokines and attenuated the infiltration and activation of immune cells, but it did not alter the generation of virus-neutralizing antibodies. In conclusion, geldanamycin plays an important role in attenuating virus infection induced ALI/ARDS by reducing the host's inflammatory responses and may provide an important reference for clinical treatments. PMID- 28664156 TI - LTRs of Endogenous Retroviruses as a Source of Tbx6 Binding Sites. AB - Retrotransposons are abundant in mammalian genomes and can modulate the gene expression of surrounding genes by disrupting endogenous binding sites for transcription factors (TFs) or providing novel TFs binding sites within retrotransposon sequences. Here, we show that a (C/T)CACACCT sequence motif in ORR1A, ORR1B, ORR1C, and ORR1D, Long Terminal Repeats (LTRs) of MaLR endogenous retrovirus (ERV), is the direct target of Tbx6, an evolutionary conserved family of T-box TFs. Moreover, by comparing gene expression between control mice (Tbx6 +/-) and Tbx6-deficient mice (Tbx6 -/-), we demonstrate that at least four genes, Twist2, Pitx2, Oscp1, and Nfxl1, are down-regulated with Tbx6 deficiency. These results suggest that ORR1A, ORR1B, ORR1C and ORR1D may contribute to the evolution of mammalian embryogenesis. PMID- 28664157 TI - Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents. AB - The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors. PMID- 28664161 TI - Adaptive Multi-scale PHM for Robotic Assembly Processes. AB - Adaptive multiscale prognostics and health management (AM-PHM) is a methodology designed to support PHM in smart manufacturing systems. As a rule, PHM information is not used in high-level decision-making in manufacturing systems. AM-PHM leverages and integrates component-level PHM information with hierarchical relationships across the component, machine, work cell, and production line levels in a manufacturing system. The AM-PHM methodology enables the creation of actionable prognostic and diagnostic intelligence up and down the manufacturing process hierarchy. Decisions are made with the knowledge of the current and projected health state of the system at decision points along the nodes of the hierarchical structure. A description of the AM-PHM methodology with a simulated canonical robotic assembly process is presented. PMID- 28664158 TI - Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases. AB - The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the Tripterygium wilfordii (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects. The most promising bioactive compound obtained from TW is celastrol. During the last decade, an increasing number of studies were published highlighting the medicinal usefulness of celastrol in diverse clinical areas. Here we systematically review the mechanism of action and the therapeutic properties of celastrol in inflammatory diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis and allergy, as well as in cancer, neurodegenerative disorders and other diseases, such as diabetes, obesity, atherosclerosis, and hearing loss. We will also focus in the toxicological profile and limitations of celastrol formulation, namely, solubility, bioavailability, and dosage issues that still limit its further clinical application and usefulness. PMID- 28664160 TI - New Techniques for Ancient Proteins: Direct Coupling Analysis Applied on Proteins Involved in Iron Sulfur Cluster Biogenesis. AB - Direct coupling analysis (DCA) is a powerful statistical inference tool used to study protein evolution. It was introduced to predict protein folds and protein protein interactions, and has also been applied to the prediction of entire interactomes. Here, we have used it to analyze three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that DCA can correctly reproduce structural features of the CyaY/frataxin family (a protein involved in the human disease Friedreich's ataxia) despite being based on the relatively small number of sequences allowed by its genomic distribution. This result gives us confidence in the method. Its application to the iron-sulfur cluster scaffold protein IscU, which has been suggested to function both as an ordered and a disordered form, allows us to distinguish evolutionary traces of the structured species, suggesting that, if present in the cell, the disordered form has not left evolutionary imprinting. We observe instead, for the first time, direct indications of how the protein can dimerize head-to-head and bind 4Fe4S clusters. Analysis of the alternative scaffold protein IscA provides strong support to a coordination of the cluster by a dimeric form rather than a tetramer, as previously suggested. Our analysis also suggests the presence in solution of a mixture of monomeric and dimeric species, and guides us to the prevalent one. Finally, we used DCA to analyze interactions between some of these proteins, and discuss the potentials and limitations of the method. PMID- 28664162 TI - System Interdependency Modeling in the Design of Prognostic and Health Management Systems in Smart Manufacturing. AB - The fields of risk analysis and prognostics and health management (PHM) have developed in a largely independent fashion. However, both fields share a common core goal. They aspire to manage future adverse consequences associated with prospective dysfunctions of the systems under consideration due to internal or external forces. This paper describes how two prominent risk analysis theories and methodologies - Hierarchical Holographic Modeling (HHM) and Risk Filtering, Ranking, and Management (RFRM) - can be adapted to support the design of PHM systems in the context of smart manufacturing processes. Specifically, the proposed methodologies will be used to identify targets - components, subsystems, or systems - that would most benefit from a PHM system in regards to achieving the following objectives: minimizing cost, minimizing production/maintenance time, maximizing system remaining usable life (RUL), maximizing product quality, and maximizing product output. HHM is a comprehensive modeling theory and methodology that is grounded on the premise that no system can be modeled effectively from a single perspective. It can also be used as an inductive method for scenario structuring to identify emergent forced changes (EFCs) in a system. EFCs connote trends in external or internal sources of risk to a system that may adversely affect specific states of the system. An important aspect of proactive risk management includes bolstering the resilience of the system for specific EFCs by appropriately controlling the states. Risk scenarios for specific EFCs can be the basis for the design of prognostic and diagnostic systems that provide real-time predictions and recognition of scenario changes. The HHM methodology includes visual modeling techniques that can enhance stakeholders' understanding of shared states, resources, objectives and constraints among the interdependent and interconnected subsystems of smart manufacturing systems. In risk analysis, HHM is often paired with Risk Filtering, Ranking, and Management (RFRM). The RFRM process provides the users, (e.g., technology developers, original equipment manufacturers (OEMs), technology integrators, manufacturers), with the most critical risks to the objectives, which can be used to identify the most critical components and subsystems that would most benefit from a PHM system. A case study is presented in which HHM and RFRM are adapted for PHM in the context of an active manufacturing facility located in the United States. The methodologies help to identify the critical risks to the manufacturing process, and the major components and subsystems that would most benefit from a developed PHM system. PMID- 28664163 TI - Measurement Science for Prognostics and Health Management for Smart Manufacturing Systems: Key Findings from a Roadmapping Workshop. AB - The National Institute of Standards and Technology (NIST) hosted the Roadmapping Workshop - Measurement Science for Prognostics and Health Management for Smart Manufacturing Systems (PHM4SMS) in Fall 2014 to discuss the needs and priorities of stakeholders in the PHM4SMS technology area. The workshop brought together over 70 members of the PHM community. The attendees included representatives from small, medium, and large manufacturers; technology developers and integrators; academic researchers; government organizations; trade associations; and standards bodies. The attendees discussed the current and anticipated measurement science challenges to advance PHM methods and techniques for smart manufacturing systems; the associated research and development needed to implement condition monitoring, diagnostic, and prognostic technologies within manufacturing environments; and the priorities to meet the needs of PHM in manufacturing. This paper will summarize the key findings of this workshop, and present some of the critical measurement science challenges and corresponding roadmaps, i.e., suggested courses of action, to advance PHM for manufacturing. Milestones and targeted capabilities will be presented for each roadmap across three areas: PHM Manufacturing Process Techniques; PHM Performance Assessment; and PHM Infrastructure - Hardware, Software, and Integration. An analysis of these roadmaps and crosscutting themes seen across the breakout sessions is also discussed. PMID- 28664164 TI - Public Attitudes toward Gene Therapy in China. PMID- 28664159 TI - Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases. AB - There is currently an unmet need for better biomarkers across the spectrum of renal diseases. In this paper, we revisit the role of beta-2 microglobulin (beta2M) as a biomarker in patients with chronic kidney disease and end-stage renal disease. Prior to reviewing the numerous clinical studies in the area, we describe the basic biology of beta2M, focusing in particular on its role in maintaining the serum albumin levels and reclaiming the albumin in tubular fluid through the actions of the neonatal Fc receptor. Disorders of abnormal beta2M function arise as a result of altered binding of beta2M to its protein cofactors and the clinical manifestations are exemplified by rare human genetic conditions and mice knockouts. We highlight the utility of beta2M as a predictor of renal function and clinical outcomes in recent large database studies against predictions made by recently developed whole body population kinetic models. Furthermore, we discuss recent animal data suggesting that contrary to textbook dogma urinary beta2M may be a marker for glomerular rather than tubular pathology. We review the existing literature about beta2M as a biomarker in patients receiving renal replacement therapy, with particular emphasis on large outcome trials. We note emerging proteomic data suggesting that beta2M is a promising marker of chronic allograft nephropathy. Finally, we present data about the role of beta2M as a biomarker in a number of non-renal diseases. The goal of this comprehensive review is to direct attention to the multifaceted role of beta2M as a biomarker, and its exciting biology in order to propose the next steps required to bring this recently rediscovered biomarker into the twenty first century. PMID- 28664165 TI - Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice. AB - Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of alpha-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu-/- mouse brain. To further evaluate regional, cell type-specific, and dose-dependent biodistribution of NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu-/- mice were treated with 1-100 MUg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 MUg doses) resulted in above-normal NAGLU activity levels, broad biodistribution, and uptake in all cell types, with NAGLU predominantly localized to neurons in the Naglu-/- mouse brain. This led to complete clearance of disease-specific HS and reduction of secondary lysosomal defects and neuropathology across various brain regions lasting for at least 28 days after the last dose. The substantial brain uptake of NAGLU attainable by this highest ICV dosage was required for nearly complete attenuation of disease-driven storage accumulations and neuropathology throughout the Naglu-/- mouse brain. PMID- 28664166 TI - Lentiviral Fluorescent Genetic Barcoding for Multiplex Fate Tracking of Leukemic Cells. AB - Tracking the behavior of leukemic samples both in vitro and in vivo plays an increasingly large role in efforts to better understand the leukemogenic processes and the effects of potential new therapies. Such work can be accelerated and made more efficient by methodologies enabling the characterization of leukemia samples in multiplex assays. We recently developed three sets of lentiviral fluorescent genetic barcoding (FGB) vectors that create 26, 14, and 6 unique immunophenotyping-compatible color codes from GFP-, yellow fluorescent protein (YFP)-, and monomeric kusabira orange 2 (mKO2)-derived fluorescent proteins. These vectors allow for labeling and tracking of individual color-coded cell populations in mixed samples by real-time flow cytometry. Using the prototypical Hoxa9/Meis1 murine model of acute myeloid leukemia, we describe the application of the 6xFGB vector system for assessing leukemic cell characteristics in multiplex assays. By transplanting color-coded cell mixes, we investigated the competitive growth behavior of individual color-coded populations, determined leukemia-initiating cell frequencies, and assessed the dose-dependent potential of cells exposed to the histone deacetylase inhibitor Entinostat for bone marrow homing. Thus, FGB provides a useful tool for the multiplex characterization of leukemia samples in a wide variety of applications with a concomitant reduction in workload, processing times, and mouse utilization. PMID- 28664167 TI - Enabling Smart Manufacturing Research and Development using a Product Lifecycle Test Bed. AB - Smart manufacturing technologies require a cyber-physical infrastructure to collect and analyze data and information across the manufacturing enterprise. This paper describes a concept for a product lifecycle test bed built on a cyber physical infrastructure that enables smart manufacturing research and development. The test bed consists of a Computer-Aided Technologies (CAx) Lab and a Manufacturing Lab that interface through the product model creating a "digital thread" of information across the product lifecycle. The proposed structure and architecture of the test bed is presented, which highlights the challenges and requirements of implementing a cyber-physical infrastructure for manufacturing. The novel integration of systems across the product lifecycle also helps identify the technologies and standards needed to enable interoperability between design, fabrication, and inspection. Potential research opportunities enabled by the test bed are also discussed, such as providing publicly accessible CAx and manufacturing reference data, virtual factory data, and a representative industrial environment for creating, prototyping, and validating smart manufacturing technologies. PMID- 28664168 TI - Data on analysis of coronary atherosclerosis on computed tomography and 18F sodium fluoride positron emission tomography. AB - This article contains the data showing illustrative examples of plaque classification on coronary computed tomography angiography (CCTA) and measurement of 18F-sodium fluoride (18F-NaF) uptake in coronary atherosclerotic lesions on positron emission tomography (PET). We divided the lesions into one of three plaque types on CCTA (calcified plaque, non-calcified plaque, partially calcified plaque). Focal 18F-NaF uptake of each lesion was quantified using maximum tissue to-background ratio. This article also provides a representative case with a non calcified coronary plaque detected on CCTA and identified on 18F-NaF PET/non contrast computed tomography based on a location of a vessel branch as a landmark. These complement the data reported by Kitagawa et al. (2017) [1]. PMID- 28664169 TI - Demonstration and validation of Kernel Density Estimation for spatial meta analyses in cognitive neuroscience using simulated data. AB - The data presented in this article are related to the research article entitled "Convergence of semantics and emotional expression within the IFG pars orbitalis" (Belyk et al., 2017) [1]. The research article reports a spatial meta-analysis of brain imaging experiments on the perception of semantic compared to emotional communicative signals in humans. This Data in Brief article demonstrates and validates the use of Kernel Density Estimation (KDE) as a novel statistical approach to neuroimaging data. First, we performed a side-by-side comparison of KDE with a previously published meta-analysis that applied activation likelihood estimation, which is the predominant approach to meta-analyses in cognitive neuroscience. Second, we analyzed data simulated with known spatial properties to test the sensitivity of KDE to varying degrees of spatial separation. KDE successfully detected true spatial differences in simulated data and displayed few false positives when no true differences were present. R code to simulate and analyze these data is made publicly available to facilitate the further evaluation of KDE for neuroimaging data and its dissemination to cognitive neuroscientists. PMID- 28664170 TI - Data on TOF-SIMS analysis of Cu2+, Co2+ and Cr3+ doped calcium phosphate cements. AB - This article contains data of time of flight secondary ion mass spectrometry (TOF SIMS) analysis of brushite-forming calcium phosphate cements doped with biologically active metal ions. This data are related to the research article "Cu2+, Co2+ and Cr3+ doping of a calcium phosphate cement influences materials properties and response of human mesenchymal stromal cells" (Schamel et al., 2017) [1]. Cu2+, Co2+ and Cr3+ doped beta-tricalcium phosphate precursor powders were used to prepare cement samples. The incorporation and distribution of the metal ions in the cement matrix was visualized by imaging mass spectrometry. PMID- 28664171 TI - Immunoglobulin characteristics and RNAseq data of FcRL4+ B cells sorted from synovial fluid and tissue of patients with rheumatoid arthritis. AB - This manuscript is a companion paper to Amara et al. [1]. Data shown here include detailed clinical characteristics from anonymized patients, the Ig subclass data generated from B cells sorted from four individual patients, tables detailing variable gene region sequences from sorted cells linked to the patient information and the sequence yields from individual patients. Furthermore a URL link to the RNAseq datasets submitted to GEO is included. PMID- 28664172 TI - Data for whole and mitochondrial proteome of human embryonic stem cells. AB - The data presented here pertain to the research article entitled "Proteome Analysis of Human Embryonic Stem Cell Organelles" (Shekariet al., 2017 [1]). In the present article we endeavour to locate new proteins and pathways in human embryonic stem cells (hESCs) by mass spectrometry and bioinformatics analysis. We have analyzed total and mitochondrial proteins extracted from three biological replicates of the hESC H9 cell line according to mass spectrometry proteomics and bioinformatics investigations. PMID- 28664173 TI - Dietary amino acid intakes associated with a low-phenylalanine diet combined with amino acid medical foods and glycomacropeptide medical foods and neuropsychological outcomes in subjects with phenylketonuria. AB - This article provides original data on median dietary intake of 18 amino acids from amino acid medical foods, glycomacropeptide medical foods, and natural foods based on 3-day food records obtained from subjects with phenylketonuria who consumed low-phenylalanine diets in combination with amino acid medical foods and glycomacropeptide medical foods for 3 weeks each in a crossover design. The sample size of 30 subjects included 20 subjects with classical phenylketonuria and 10 with a milder or variant form of phenylketonuria. Results are presented for the Delis-Kaplan Executive Function System and the Cambridge Neuropsychological Test Automated Battery; the tests were administered at the end of each 3-week dietary treatment with amino acid medical foods and glycomacropeptide medical foods. The data are supplemental to our clinical trial, entitled "Glycomacropetide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial, 2016 (1) and "Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria, 2017 (2). This data has been made public and has utility to clinicians and researchers due to the following: 1) This provides the first comprehensive report of typical intakes of 18 amino acids from natural foods, as well as amino acid and glycomacropeptide medical foods in adolescents and adults with phenylketonuria; and 2) This is the first evidence of similar standardized neuropsychological testing data in adolescents and adults with early-treated phenylketonuria who consumed amino acid and glycomacropeptide medical foods. PMID- 28664174 TI - Data on the surface morphology of additively manufactured Ti-6Al-4V implants during processing by plasma electrolytic oxidation. AB - Additively manufactured Ti-6Al-4V implants were biofunctionalized using plasma electrolytic oxidation. At various time points during this process scanning electron microscopy imaging was performed to analyze the surface morphology (van Hengel et al., 2017) [1]. This data shows the changes in surface morphology during plasma electrolytic oxidation. Data presented in this article are related to the research article "Selective laser melting porous metallic implants with immobilized silver nanoparticles kill and prevent biofilm formation by methicillin-resistant Staphylococcus aureus" (van Hengel et al., 2017) [1]. PMID- 28664175 TI - CT images and radiotherapy treatment planning of patients with breast cancer: A dataset. AB - The data presented here were originally collected for the research project "CT Scan processing and analysis in patient with breast cancer after radiotherapy". Also, it reported in our study "Prediction of Lung Tissue Damage by Evaluating Clinical and Dosimetric Parameters in Breast Cancer Patients" (Hasanabdali et al., 2016) [1]. This article describes and directly links to 52 subjects referred to Mahdieh Oncology and Radiotherapy Center from February to August 2015. Treatment planning was done for delivering 50 Gy dose to PTV in 25 fractions. the lungs and heart objects were extracted from CT images along with compliance Dose plan. Dose-volume histogram (DVH) and Dose-mass histogram (DMH) extracted using CT images and dose plan matrix. Moreover, the complete clinical and dosimetric specifications of subjects is attached. PMID- 28664176 TI - Data set on stability comparison of emulsions stabilized by cationic fluorosurfactant against conventional surfactants and high thermal performance of fluoropolymer foams. AB - This data article includes emulsion stability comparison of cationic fluorosurfactant (CFS) against conventional surfactants. Span 80, Hypermer, Tween 80 and CTAB were used as conventional emulsifiers and only after 30 minutes bilayer phase separation observed in emulsions prepared by Tween 80 while CTAB failed to give fluoroemulsion, as compared to the CFS stabilized fluoro-HIPE which demonstrated superb stabilization of more than 72 h without phase separation. Thermal stability of Poly(hexafluorobutyl acrylate)-Divinyl benzene (PHFBA-DVB) was compared with porous polymer prepared by the same concentration of CFS 9 wt% by using trifluoroethyl methacrylate (TFEMA) as monomer phase. Results of PFP prepared with HFBA showed remarkable stability performance at more than 340.69 degrees C while porous polymer synthesized by TFEMA started to decompose even at 237.36 degrees C. The main findings based on the data presented here are reported in the paper "A cationicfluorosurfactant for fabrication of high-performance fluoropolymer foams with controllable morphology" (Azhar et al., 2017) [1]. PMID- 28664177 TI - Data set for fabrication of conformal two-dimensional TiO2 by atomic layer deposition using tetrakis (dimethylamino) titanium (TDMAT) and H2O precursors. AB - The data and complementary information presented hare are related to the research article of "http://dx.doi.org/10.1016/j.matdes.2017.02.016; Materials and Design 120 (2017) 99-108" [1]. The article provides data and information on the case of atomic layer deposition (ALD) of ultra-thin two-dimensional TiO2 film. The chemical structure of precursors, and the fabrication process were illustrated. The data of spectral ellipsometric measurements and the methods of calculations were presented. Data of root mean square roughness and the average roughness of the ADL TiO2 film are presented. The method of bandgap measurements and the bandgap calculation are also explained in the present data article. PMID- 28664178 TI - Residual stress measurements via neutron diffraction of additive manufactured stainless steel 17-4 PH. AB - Neutron diffraction was employed to measure internal residual stresses at various locations along stainless steel (SS) 17-4 PH specimens additively manufactured via laser-powder bed fusion (L-PBF). Of these specimens, two were rods (diameter=8 mm, length=80 mm) built vertically upward and one a parallelepiped (8*80*9 mm3) built with its longest edge parallel to ground. One rod and the parallelepiped were left in their as-built condition, while the other rod was heat treated. Data presented provide insight into the microstructural characteristics of typical L-PBF SS 17-4 PH specimens and their dependence on build orientation and post-processing procedures such as heat treatment. Data have been deposited in the Data in Brief Dataverse repository (doi:10.7910/DVN/T41S3V). PMID- 28664179 TI - The tell-tale heart: A case of recurrent vulvar carcinoma with cardiac metastasis and review of literature. AB - A 50-year-old female was diagnosed with vulvar cancer treated with left partial vulvectomy and bilateral lymphadenectomy. Ten months after her surgery, she presented with increased labial swelling, pain and discharge. Biopsy confirmed recurrence of squamous cell vulvar carcinoma. Incidentally, on restaging radiographic scans, she was found to have a large right ventricular mass which, after surgical debulking, was shown to be a squamous cell cancer of vulvar origin. She was commenced on chemotherapy with carboplatin and paclitaxel along with concurrent radiation therapy. Restaging PET scan showed persistent metastatic disease. She was switched to Cisplatin/Taxol after having hypersensitivity reaction to Carboplatin. She received 5 cycles with progression of disease in the follow up scans. She then received Nivolumab for 2 cycles. The patient then opted for comfort directed care given worsening functional status and progression of disease on repeat imaging. Secondary cardiac tumors are very rare and not extensively studied in oncology. Therefore, optimal management is not entirely clear. It is extremely rare for vulvar cancer to metastasize to the heart and only two cases have been reported in the literature. However, vulvar cancer metastasizing to the right ventricular cavity and endocardium has not been described before. We believe that this is the first ever such reported case. PMID- 28664180 TI - Metastatic hepatoid carcinoma of ovarian origin - a case report from northern Pakistan. AB - *Hepatoid carcinoma of the ovary is rapidly progressing rare epithelial ovarian tumor.*The term 'hepatoid' refers to the morphological resemblance with hepatocellular carcinoma.*Final diagnosis is made via positive staining for alpha fetoprotein along with immunohistochemistry*Combination chemotherapy can be considered superior over the targeted agents while treating this tumor. PMID- 28664181 TI - Apparent ectopic pregnancy with unexpected finding of a germ cell tumor: A case report. AB - *Ovarian germ cell tumors can produce hCG and be confused with ectopic pregnancy.*Ovarian germ cell tumors can present with subacute pelvic pain.*Ectopic pregnancy should be the primary differential diagnosis due to its acuity. PMID- 28664182 TI - Abdominal radical trachelectomy for vaginal cancer - A case report. AB - *Vaginal cancer is most common in elderly woman and very rare in young woman.*Stage I vaginal cancer is treated with surgery and radiotherapy.*Vaginal cancer in a young patient was treated by intra-arterial chemotherapy followed by abdominal radical trachelectomy. PMID- 28664183 TI - The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics. AB - Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain's structure-function relationship, necessitating the close integration of diverse neuroinformatics fields. Here we extend the open-source simulation software The Virtual Brain (TVB) to whole mouse brain network modeling based on individual diffusion magnetic resonance imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain (TVMB) to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease. TVMB enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions. PMID- 28664184 TI - microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism. AB - The membrane-bound transcription factors, SREBPs (sterol regulatory element binding proteins), play a central role in regulating lipid metabolism. The transcriptional activation of SREBPs requires the key protein SCAP (SREBP cleavage activating protein) to translocate their precursors from the endoplasmic reticulum to the Golgi for subsequent proteolytic activation, a process tightly regulated by a cholesterol-mediated negative feedback loop. Our previous work showed that the SCAP/SREBP-1 pathway is significantly upregulated in human glioblastoma (GBM), the most deadly brain cancer, and that glucose-mediated N glycosylation of SCAP is a prerequisite step for SCAP/SREBP trafficking. More recently, we demonstrated that microRNA-29 (miR-29) mediates a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling to control lipid metabolism. We found that SREBP-1, functioning as a transcription factor, promotes the expression of the miR-29 family members, miR-29a, -29b and -29c. In turn, the miR-29 isoforms reversely repress the expression of SCAP and SREBP-1. Moreover, treatment with miR-29 mimics effectively suppressed GBM tumor growth by inhibiting SCAP/SREBP-1 and de novo lipid synthesis. These findings, recently published in Cell Reports, strongly suggest that delivery of miR-29 in vivo may be a promising approach to treat cancer and metabolic diseases by suppressing SCAP/SREBP-1-regulated lipid metabolism. PMID- 28664185 TI - The miR-125a and miR-320c are potential tumor suppressor microRNAs epigenetically silenced by the polycomb repressive complex 2 in multiple myeloma. AB - We have previously presented the histone methyltransferase enhancer of zeste homolog 2 (EZH2) of the polycomb repressive complex 2 (PRC2) as a potential therapeutic target in Multiple Myeloma (MM). In a recent article in Oncotarget by Alzrigat. et al. 2017, we have reported on the novel finding that EZH2 inhibition using the highly selective inhibitor of EZH2 enzymatic activity, UNC1999, reactivated the expression of microRNA genes previously reported to be underexpressed in MM. Among these, we have identified miR-125a-3p and miR-320c as potential tumor suppressor microRNAs as they were predicted to target MM associated oncogenes; IRF-4, XBP-1 and BLIMP-1. We also found EZH2 inhibition to reactivate the expression of miR-494, a previously reported regulator of the c MYC oncogene. In addition, we could report that EZH2 inhibition downregulated the expression of a few well described oncogenic microRNAs in MM. The data from our recent article are here highlighted as it shed a new light onto the oncogenic function of the PRC2 in MM. These data further strengthen the notion that the PRC2 complex may be of potential therapeutic interest. PMID- 28664186 TI - Highly Articulated Robotic Needle Achieves Distributed Ablation of Liver Tissue. AB - Robotic needle steering will improve percutaneous radio-frequency ablation (RFA) in the liver by performing distributed ablations without requiring multiple punctures of the liver capsule, thus enabling the treatment of large or multifocal tumors. However, state-of-the-art asymmetric-tip robotic needle steering systems do not yet achieve clinically relevant curvature. This work presents the design and development of a highly articulated needle that enables distributed RFA in liver tissue under ultrasound (US) image guidance. Our new needle design attains the target curvature required for liver procedures while meeting important clinical requirements, such as the use of fixed diameter needle introducers, presence of a free needle working channel, robustness for repeated insertions, and conductivity for the delivery of RF current for tissue ablation. The new needle tip includes two important design features: A tendon-actuated Nitinol asymmetric flexure joint, which allows for an active amplification of the needle steering force, and a steel back-bevel tip profile, which decreases the risk of needle jamming. The needle's resulting curvature was evaluated in both phantom and ex vivo liver tissues using segmented US images. The average radius of minimum curvature in ex vivo liver tissue was found to be 33.6 mm, the smallest reported to date. Furthermore, RFA in ex vivo porcine liver tissue tests were performed to demonstrate that distributedablation with a single puncture of the liver capsule is possible via robotic needle steering. PMID- 28664187 TI - Design of a Compact Actuation and Control System for Flexible Medical Robots. AB - Flexible medical robots can improve surgical procedures by decreasing invasiveness and increasing accessibility within the body. Using preoperative images, these robots can be designed to optimize a procedure for a particular patient. To minimize invasiveness and maximize biocompatibility, the actuation units of flexible medical robots should be placed fully outside the patient's body. In this letter, we present a novel, compact, lightweight, modular actuation, and control system for driving a class of these flexible robots, known as concentric tube robots. A key feature of the design is the use of three dimensional printed waffle gears to enable compact control of two degrees of freedom within each module. We measure the precision and accuracy of a single actuation module and demonstrate the ability of an integrated set of three actuation modules to control six degrees of freedom. The integrated system drives a three-tube concentric tube robot to reach a final tip position that is on average less than 2 mm from a given target. In addition, we show a handheld manifestation of the device and present its potential applications. PMID- 28664188 TI - Mammary epithelial polarity and macrophage infiltration. AB - Loss of epithelial cell polarity and inflammation are hallmarks of breast cancer development. Although the association between the disruption of tissue polarity and inflammation has been demonstrated, we know little about how these two events are coupled. Using the 3D co-culture model of mammary epithelial cells and monocytes, a recent study reveals a link between disruption of epithelial polarity and monocytes infiltration. PMID- 28664189 TI - Insertion into lipid bilayer of truncated pHLIP(r)peptide. AB - The investigation of pH-dependent membrane-associated folding has both fundamental interest and practical applications for targeting of acidic tumors and specific delivery of therapeutic molecules across membrane of cancer cells. We and others investigated molecular mechanism and medical uses of class of water soluble membrane peptides, pH (Low) Insertion Peptides (pHLIP(r) peptides). Here we employed optical spectroscopy methods to study interactions of the truncated pHLIP(r) peptide (Short pHLIP(r)) with lipid bilayer of membrane. Tryptophan fluorescence, CD and OCD data indicate on pH-triggered formation of transmembrane helical structure. Dual quenching and FRET assays demonstrated that Short pHLIP(r) peptide spans lipid bilayer of membrane similar to Long pHLIP(r) peptides. Truncated pHLIP(r) peptides with multiple charged and protonatable residues in their sequences potentially can make these peptides to be less hydrophobic compared to Long pHLIP(r) peptides, and might have utility in tumor imaging, and potentially, in pH-regulated cytoplasmic delivery of moderately hydrophobic drugs. PMID- 28664190 TI - Social interactions in different environments impacts and motivates reproductive displays in college students. AB - Social environments can have an impact on the interactions between the sexes, specifically pre-courtship behaviors. Sexual selection theory may explain social interactions of the sexes, where males display and attract mates more than females. These behaviors may intensify in a sexual environment. It was hypothesized that individuals would display more in a sexualized environment compared to a non-sexualized location. This research sampled N = 880 participants at a university in a southern state in North America and asked which unisex sunglasses they preferred. While the most popular non-showy sunglasses were selected the most, showy new arrival sunglasses were selected more often when the surveyor's behavior was flirty, compared to normal behavior and dressing sexy. Thus, social interactions such as flirting between the sexes impacted the behaviors of others and increased the intensity of reproductive displays. At the location with sexualized behaviors and dress, individuals selected the non-showy sunglasses, possibly to draw attention to their bodies in swimsuits, whereas at the non-sexy location, new arrivals were chosen at a higher frequency, possibly to stand out when wearing normal clothes. The sexes chose to stand out at equal frequencies as did single participants and people in a relationship, suggesting that all individuals are trying to display and attract mates equally. Social environments impacted display behaviors and the motivation to display is discussed. PMID- 28664191 TI - Knowledge, attitude, and practices about tsetse control among communities neighbouring Serengeti National Park, Tanzania. AB - Tsetse flies are vectors of blood parasite of the genus Trypanosoma, which causes African trypanosomiasis to both human beings and animals. Large losses due to nagana have been reported; and this indicates the importance of tsetse control to avoid estimated losses. This study assessed the knowledge of tsetse and control practices, attitude towards control practices against tsetse, and the actual control practices used by the local communities in Serengeti District near the Serengeti National Park (SENAPA). Data for this study were collected using various methods. An interview schedule was administered to 70 randomly selected households, 12 focus group discussions with men and women farmers, and four key informant interviews with technical staff were held. The data were analysed using largely descriptive statistics and content analysis method. The farmers had inadequate knowledge of tsetse such that they confused them with other similar flies. On the other hand, they demonstrated knowledge of tsetse control measures, and these included some, which were not among those recommended by the extension staff. While the attitude towards control methods was positive most of the farmers did not use the recommended methods largely due to the cost associated with them. This suggests that the positive attitude towards a recommendation by itself is not sufficient to influence its use. Besides, poor management of dipping facilities for tsetse control and inadequate supervision by district staff impacted on the quality of services offered. Thus enabling local community members to have clear knowledge of tsetse flies is an important starting point for mobilizing them to take appropriate control measures against tsetse. Also, district authorities need to take an active role in monitoring the performance of the dipping facilities in the district by taking up appropriate measures to ensure quality control of services offered. Moreover, there is need for the district authorities and the central government to address the challenges which privatization of veterinary services posed to animal health and the wellbeing of people who depend on livestock for their livelihood. PMID- 28664192 TI - Utilization of agro waste pectin for the production of industrially important polygalacturonase. AB - In the present study, a variety of agro-industrial wastes have been utilized for meaningful purpose to produce valuable biocatalyst. All wastes used were low cost and easily accessible while, some available throughout the year. A number of bacterial strains isolated from rotten fruits and vegetables were screened for the production of industrially important polygalacturonase (PGase) using pectin present in these agro-industrial wastes. The strain producing maximum PGase was identified as Bacillus licheniformis KIBE-IB3 on the basis of taxonomic studies and 16S rDNA analysis. Among different agro-industrial wastes studied, high yield of PGase was achieved from fermentation broth having wheat bran (1.0%) as a substrate in to the medium supplemented with nitrogen sources in combination of NaNO3 and yeast extract while KH2PO4 was selected as suitable micronutrient. After optimizing fermentation parameters it was noticed that Bacillus licheniformis KIBE-IB3 was capable of producing maximum PGase at 37 degrees C, pH 7.0 and after 48 h of incubation time. From the current research, wheat bran was proven as a cheap and easily available source throughout the year for hyper production of pectinase. The utilization of the waste will also help to minimize the concerned environmental issues. PMID- 28664193 TI - Knowledge, practice and approaches of health professionals to adverse events following immunization and their reporting in Albania. AB - In Albania, the reporting of an adverse events following immunization (AEFI) is done not only by immunization providers but also from clinicians providing clinical treatment of AEFI in health posts, health centers and private or public hospitals. The AEFI reporting system in Albania has started in 2001 with the establishment of National Regulatory Authority of Vaccines in the Institute of Public Health. The most important problems of passive surveillance systems include underreporting, deficiency and inaccuracy of information. A structured questionnaire containing 68 questions constructed from immunization experts constituted the study tool. The questionnaire addressed health professionals working at child consultant's facilities and primary health centers in the district of Tirana. There were a total of 102 health professional interviewed. The majority of the respondents working at health centers in the district of Tirana in general, had poor knowledge levels on AEFI surveillance. The lowest score were received in knowledge about the role of different stakeholders involved in AEFI surveillance. The number of years practicing the profession did not influence in the total score of "practice and attitude toward reporting and managing an AEFI". Although the majority of health care professionals have encountered an AEFI during their practice (72/102, 70,5%), only half of them have never reported an AEFI (37/102, 36,2%). Barriers to reporting included lack of interest, unclear definition of AEFI and lack of awareness of what to report. Nevertheless, the main reason for not reporting was because a respondent thought he or she had not observed an AEFI in the last years (44,1%). Majority of the respondents did not have any training about AEFI (68,6%, 70/102). From this study it is concluded that it is necessary to develop training and educational programs in order to increase awareness of all health professionals involved in child health toward reporting of adverse events following immunization. It is necessary to build feedback systems to give information on AEFI. This study shows the influence of knowledge, perceptions and practices of health care workers in the surveillance of adverse events following immunization. Thus, information generated from this study might be valuable for the public health regulators to generate new guidelines about AEFI surveillance and update existing information. PMID- 28664194 TI - Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines. AB - Chronic infections with HBV and HCV continue to be major public health problems, with hundreds of millions of people infected worldwide; this is despite the availability of both an effective prophylactic HBV vaccine for more than 3 decades and potent direct antivirals for HBV and, more recently, HCV infection. Consequently, development of HBV immunotherapies and prophylactic HCV vaccines remains extremely urgent, but limited funding and significant gaps in our understanding of the correlates of immune protection pose serious hurdles for the development of novel immune-based interventions. Here we discuss immunological questions related to HBV and HCV, some shared and some pertinent to only 1 of the viruses, that should be addressed for the rational design of HBV immunotherapies and HCV vaccines. PMID- 28664195 TI - Partial exhaustion of CD8 T cells and clinical response to teplizumab in new onset type 1 diabetes. AB - Biologic treatment of T1D typically results in transient stabilization of C peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. Here, we used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in subjects with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1. These cells expanded after treatment, with levels peaking after 3-6 months. To functionally characterize these exhausted-like T cells, we isolated memory CD8 TIGIT+KLRG1+ T cells from responders and showed that they exhibited expanded TCR clonotypes, indicative of prior in vivo expansion; recognized a broad-based spectrum expressed of environmental and auto-antigens; and were hypo-proliferative during polyclonal stimulation, increasing expression of IR genes and decreasing cell cycle genes. Triggering these cells with a recombinant ligand for TIGIT during polyclonal stimulation further downregulated their activation, demonstrating their exhausted phenotype was not terminal. These findings identify and functionally characterize a partially exhausted cell type associated with response to teplizumab therapy and suggest that pathways regulating T cell exhaustion may play a role in successful immune interventions for T1D. PMID- 28664196 TI - Postinflammatory hyperpigmentation after human cold pain testing. AB - Changes in cold temperature sensitivity are often associated with chronic pain conditions. Progress in understanding the neurobiological mechanism underlying these changes and resulting development of effective therapies has been slowed by the accessibility and affordability of devices used to measure thermal sensitivity in humans. To address this gap, we developed an inexpensive method to measure cold pain thresholds in healthy adult volunteers using dry ice and a thermode. However, early in preliminary testing, a subject presented with epidermal postinflammatory hyperpigmentation that lasted for >200 days. Although this response was unique among the small number of subjects in development of the assay, it raised questions as to the safety of the assay design. PMID- 28664197 TI - Shape Based Segmentation of Anatomical Structures in Magnetic Resonance Images. AB - Standard image based segmentation approaches perform poorly when there is little or no contrast along boundaries of different regions. In such cases, segmentation is largely performed manually using prior knowledge of the shape and relative location of the underlying structures combined with partially discernible boundaries. We present an automated approach guided by covariant shape deformations of neighboring structures, which is an additional source of prior information. Captured by a shape atlas, these deformations are transformed into a statistical model using the logistic function. Structure boundaries, anatomical labels, and image inhomogeneities are estimated simultaneously within an Expectation-Maximization formulation of the maximum a posteriori probability estimation problem. We demonstrate the approach on 20 brain magnetic resonance images showing superior performance, particularly in cases where purely image based methods fail. PMID- 28664198 TI - 3D Motion Modeling and Reconstruction of Left Ventricle Wall in Cardiac MRI. AB - The analysis of left ventricle (LV) wall motion is a critical step for understanding cardiac functioning mechanisms and clinical diagnosis of ventricular diseases. We present a novel approach for 3D motion modeling and analysis of LV wall in cardiac magnetic resonance imaging (MRI). First, a fully convolutional network (FCN) is deployed to initialize myocardium contours in 2D MR slices. Then, we propose an image registration algorithm to align MR slices in space and minimize the undesirable motion artifacts from inconsistent respiration. Finally, a 3D deformable model is applied to recover the shape and motion of myocardium wall. Utilizing the proposed approach, we can visually analyze 3D LV wall motion, evaluate cardiac global function, and diagnose ventricular diseases. PMID- 28664199 TI - Low-Dimensional Statistics of Anatomical Variability via Compact Representation of Image Deformations. AB - Using image-based descriptors to investigate clinical hypotheses and therapeutic implications is challenging due to the notorious "curse of dimensionality" coupled with a small sample size. In this paper, we present a low-dimensional analysis of anatomical shape variability in the space of diffeomorphisms and demonstrate its benefits for clinical studies. To combat the high dimensionality of the deformation descriptors, we develop a probabilistic model of principal geodesic analysis in a bandlimited low-dimensional space that still captures the underlying variability of image data. We demonstrate the performance of our model on a set of 3D brain MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our model yields a more compact representation of group variation at substantially lower computational cost than models based on the high-dimensional state-of-the-art approaches such as tangent space PCA (TPCA) and probabilistic principal geodesic analysis (PPGA). PMID- 28664200 TI - An Ontology-Enabled Natural Language Processing Pipeline for Provenance Metadata Extraction from Biomedical Text (Short Paper). AB - Extraction of structured information from biomedical literature is a complex and challenging problem due to the complexity of biomedical domain and lack of appropriate natural language processing (NLP) techniques. High quality domain ontologies model both data and metadata information at a fine level of granularity, which can be effectively used to accurately extract structured information from biomedical text. Extraction of provenance metadata, which describes the history or source of information, from published articles is an important task to support scientific reproducibility. Reproducibility of results reported by previous research studies is a foundational component of scientific advancement. This is highlighted by the recent initiative by the US National Institutes of Health called "Principles of Rigor and Reproducibility". In this paper, we describe an effective approach to extract provenance metadata from published biomedical research literature using an ontology-enabled NLP platform as part of the Provenance for Clinical and Healthcare Research (ProvCaRe). The ProvCaRe-NLP tool extends the clinical Text Analysis and Knowledge Extraction System (cTAKES) platform using both provenance and biomedical domain ontologies. We demonstrate the effectiveness of ProvCaRe-NLP tool using a corpus of 20 peer reviewed publications. The results of our evaluation demonstrate that the ProvCaRe-NLP tool has significantly higher recall in extracting provenance metadata as compared to existing NLP pipelines such as MetaMap. PMID- 28664201 TI - How do fluorescence spectroscopy and multimodal fluorescence imaging help to dissect the enhanced efficiency of the vancomycin-rifampin combination against Staphylococcus aureus infections? AB - Staphylococcus aureus is one of the most frequent pathogens responsible for biofilm-associated infections. Among current clinical antibiotics, very few enable long-term successful treatment. Thus, it becomes necessary to better understand antibiotic failures and successes in treating infections in order to master the use of proper antibiotic therapies. In this context, we took benefit from a set of fluorescence spectroscopy and imaging methods, with the support of conventional microbiological tools to better understand the vancomycin-rifampin combination (in)efficiency against S. aureus biofilms. It was shown that both antibiotics interacted by forming a complex. This latter allowed a faster penetration of the drugs before dissociating from each other to interact with their respective biological targets. However, sufficiently high concentrations of free vancomycin should be maintained, either by increasing the vancomycin concentration or by applying repetitive doses of the two drugs, in order to eradicate rifampin-resistant mutants. PMID- 28664202 TI - Bioaccessibility and bioavailability of phenolic compounds in bread: a review. AB - Cereal-based products, like breads, are a vehicle for bioactive compounds, including polyphenols. The health effects of polyphenols like phenolic acids (PAs) are dependent on their bioaccessibility and bioavailability. The present review summarizes the current understanding of potential strategies to improve phenolic bioaccessibility and bioavailability and the main findings of in vitro and in vivo studies investigating these strategies applied to breads, including the use of raw ingredients with greater phenolic content and different pre processing technologies, such as fermentation and enzymatic treatment of ingredients. There is considerable variability between in vitro studies, mainly resulting from the use of different methodologies, highlighting the need for standardization. Of the few in vivo bioavailability studies identified, acute, single-dose studies demonstrate that modifications to selected raw materials and bioprocessing of bran could increase the bioavailability, but not necessarily the net content, of bread phenolics. The two medium-term identified dietary interventions also demonstrated greater phenolic content, resulting from the modification of the raw materials used. Overall, the findings suggest that several strategies can be used to develop new bread products with greater phenolic bioaccessibility and bioavailability. However, due to the large variability and the few studies available, further investigations are required to determine better the usefulness of these innovative processes. PMID- 28664203 TI - Cobalt carbonate hydroxide superstructures for oxygen evolution reactions. AB - A novel three-dimensional (3D) superstructure of cobalt hydroxide carbonate assembled from nanoneedles has been synthesized via a facile hydrothermal method. Furthermore, we tested the electrocatalytic oxygen evolution reaction performance, which demonstrated that the superstructure exhibited high catalytic activity, achieving 10 mA cm-2 at a low overpotential of merely 240 mV. PMID- 28664204 TI - Photoredox-catalyzed procedure for carbamoyl radical generation: 3,4 dihydroquinolin-2-one and quinolin-2-one synthesis. AB - A reductive approach for carbamoyl radical generation from N-hydroxyphthalimido oxamides under photoredox catalysis is outlined. This strategy was applied to the synthesis of 3,4-dihydroquinolin-2-ones via the intermolecular addition/cyclization of carbamoyl radicals with electron deficient olefins in a mild, redox-neutral manner. Under a general set of reaction conditions, diversely substituted 3,4-dihydroquinolin-2-ones, including spirocyclic systems can be prepared. By using chlorine-substituted olefins, aromatic quinolin-2-ones can also be accessed. PMID- 28664205 TI - Synthesis of controlled, high-molecular weight poly(l-glutamic acid) brush polymers. AB - We report the synthesis and characterization of high-molecular weight poly(l glutamic acid) based brush polymers. Utilizing a combination of ring-opening metathesis polymerization of norbornene based monomers and ring-opening polymerization of gamma-benzyl-l-glutamate N-carboxyanhydride, high-molecular weight gamma-benzyl protected poly(l-glutamic acid) brush polymers are synthesized. Controlled and complete deprotection of the benzyl groups using trimethylsilyl iodide resulted in poly(l-glutamic acid) based brush polymers with molecular weights up to 3.6 MDa, which may potentially be used to prepare size controlled unimolecular polymeric nanomedicine for drug delivery applications. Camptothecin brush poly(l-glutamic acid) conjugates were prepared and their stability, drug release kinetics, and in vitro toxicity were studied. PMID- 28664206 TI - Boosting electrochemical water oxidation through replacement of Oh Co sites in cobalt oxide spinel with manganese. AB - The strikingly high catalytic performance and stability of manganese substituted cobalt oxide spinel (MnxCo3-xO4) over pristine cobalt oxide spinel (Co3O4) for the alkaline electrochemical water oxidation is reported. The different role of cations could be uncovered along with the detection of drastic surface-structural changes during the catalysis using spectroscopic and microscopic methods. PMID- 28664207 TI - Recent progress in nanomedicine-based combination cancer therapy using a site specific co-delivery strategy. AB - Combination cancer therapy possesses considerable appeal due to its many merits such as enhancing efficacy by synergistic effects and overcoming drug resistance as compared to monotherapy. Nanomedicine-mediated co-delivery of multiple anticancer agents is more effective than conventional cocktail-based physical mixture of free drugs. A strategy is required to differentiate their unique targets for maximizing the synergistic effects based on individual sites of action of different drugs. This review summarizes the recent progresses in nanomedicine-based combination cancer therapies using site-specific co-delivery strategies, which have been classified by different target sites at the anatomical scales such as tissue, cellular and subcellular levels. In particular, the design of materials and formulations functionalized with tumor-associated signal-responsive elements has been highlighted. The potential and perspective of future developments have also been discussed. PMID- 28664208 TI - Fast Mg2+ diffusion in Mo3(PO4)3O for Mg batteries. AB - In this work, we identify a new potential Mg battery cathode structure Mo3(PO4)3O, which is predicted to exhibit ultra-fast Mg2+ diffusion and relatively high voltage based on first-principles density functional theory calculations. Nudged elastic band calculations reveal that the migration barrier of the percolation channel is only ~80 meV, which is remarkably low, and comparable to the best Li-ion conductors. This low barrier is verified by ab initio molecular dynamics and kinetic Monte Carlo simulations. The voltage and specific energy are predicted to be ~1.98 V and ~173 W h kg-1, respectively. If confirmed by experiments, this material would have the highest known Mg mobility among inorganic compounds. PMID- 28664213 TI - Real-time activity monitoring of New Delhi metallo-beta-lactamase-1 in living bacterial cells by UV-Vis spectroscopy. AB - We report an UV-Vis method for monitoring the hydrolysis of the beta-lactam antibiotics inside living bacterial cells. Cell-based studies demonstrated that the hydrolysis of cefazolin was inhibited by three known NDM-1 inhibitors. This approach can be applied to the monitoring of reactions in a complex biological system, for instance in medical testing. PMID- 28664214 TI - Assessment of upper limb spasticity in stroke patients using the robotic device REAplan. AB - OBJECTIVE: To assess the capacity of the robotic device REAplan to measure overall upper limb peak resistance force, as a reflection of upper limb spasticity. METHODS: Twelve patients with chronic stroke presenting upper limb spasticity were recruited to the study. Patients underwent musculocutaneous motor nerve block to reduce the spasticity of elbow flexor muscles. Each patient was assessed before and after the motor nerve block. Overall the REAplan measured upper limb resistance force. The robot passively mobilized the patient's upper limb at various velocities (10, 20, 30, 40 and 50 cm/s) in a back-and-forth trajectory (30 cm). The peak resistance force was analysed for each forward movement. Ten movements were performed and averaged at each velocity condition. RESULTS: The overall upper limb resistance force increased proportionally to the mobilization velocity (p< 0.001). Resistance force decreased after the motor nerve block at 40 and 50 cm/s (p < 0.05). Overall upper limb resistance force results showed excellent correlation with the Modified Ashworth Scale for elbow flexor muscles, for each velocity condition equal or higher than 30 cm/s (rho >0.6). CONCLUSION: This study proposes a new, valid, reliable and sensitive protocol to quantify upper limb resistance force using the REAplan, as a reflection of upper limb spasticity. PMID- 28664216 TI - Rating scale item assessment of self-harm in postpartum women: a cross-sectional analysis. AB - We examined the utility of screening instruments to identify risk factors for suicidal ideation (SI) in a population of women with neuropsychiatric illnesses at high risk for postpartum depression. Pregnant women with neuropsychiatric illness enrolled prior to 20 weeks of gestation. Follow-up visits at 4-8-week intervals through 13 weeks postpartum included assessment of depressive symptoms with both clinician and self-rated scales. A total of 842 women were included in the study. Up to 22.3% of postpartum women admitted SI on rating scales, despite the majority (79%) receiving active pharmacological treatment for psychiatric illness. Postpartum women admitting self-harm/SI were more likely to meet criteria for current major depressive episode (MDE), less than college education, an unplanned pregnancy, a history of past suicide attempt, and a higher score on the Childhood Trauma Questionnaire. In women with a history of neuropsychiatric illness, over 20% admitted SI during the postpartum period despite ongoing psychiatric treatment. Patient-rated depression scales are more sensitive screening tools than a clinician-rated depression scale for +SI in the postpartum period. PMID- 28664215 TI - Anti-inflammatory effect of galectin-1 in a murine model of atopic dermatitis. AB - : Atopic dermatitis (AD) is caused by both dysregulated immune responses and an impaired skin barrier. Although beta-galactoside-binding protein galectin-1 (Gal 1) has immunomodulatory effects in several inflammatory disorders, therapeutic strategies based on its anti-inflammatory properties have not been explored in AD. Thus, we evaluate pharmacological treatment with Gal-1 in the progression of an ovalbumin (OVA)-induced AD-like skin lesions. The skin of OVA-immunized male BALB/c mice was challenged with drops containing OVA on days 11, 14-18 and 21-24. Additionally, in the last week, a subset of animals was treated intraperitoneally with recombinant Gal-1 (rGal-1) or dexamethasone (Dex). Treatment with rGal-1 decreased the clinical signs of dermatitis in BALB/c mice and diminished local eotaxin and IFN-gamma levels. The treatment also suppressed the infiltration of eosinophils and mast cells, which was verified by reduced expression of mouse mast cell protease 6 (mMCP6) and eosinophil peroxidase (EPX). These localized effects are associated with extracellular signal-regulated kinase (ERK) activation and downregulation of endogenous Gal-1. The inhibition of disease progression induced by rGal-1 was also correlated with reduced plasma IL-17 levels. Our results demonstrate that rGal-1 is an effective treatment for allergic skin inflammation in AD and may impact the development of novel strategies for skin inflammatory diseases. KEY MESSAGES: Pharmacological treatment with rGal-1 reduces clinical signs of atopic dermatitis. Systemic treatment with rGal-1 inhibits eosinophil and mast cell influx in the skin of AD animals. rGal-1 reduced local eotaxin levels and systemic IL-17 levels. The inhibition of disease progression induced by rGal-1 was correlated with upregulation of phosphorylated ERK. PMID- 28664217 TI - Impairment Experiences, Identity and Attitudes Towards Genetic Screening: the Views of People with Spinal Muscular Atrophy. AB - Developments in genetics are rapidly changing the capacity and scope of screening practices. However, people with genetic conditions have been under-represented in the literature exploring their implications. This mixed methods study explores the attitudes of people with Spinal Muscular Atrophy (SMA) towards three different population-level genetic screening programmes for SMA: pre-conception, prenatal and newborn screening. Drawing on qualitative interviews (n = 15) and a survey (n = 82), this study demonstrates that more severely affected individuals with early-onset symptoms (Type II SMA), are less likely to support screening and more likely to view SMA positively than those with milder, later onset and/or fluctuating symptoms (Types III/ IV SMA). Indeed, this clinically milder group were more likely to support all forms of screening and view SMA negatively. This paper highlights that screening is a complex issue for people with genetic conditions, and the nature of impairment experiences plays a critical role in shaping attitudes. PMID- 28664218 TI - Identification of Acinetobacter baumannii of Human and Animal Origins by a Gene Specific PCR. AB - Acinetobacter baumannii is a notorious nosocomial pathogen known for its ability to cause severe infections, especially in intensive care units. The identification of a conserved gene encoding a hypothetical protein in A. baumannii isolates but not in other Acinetobacter species during a comparative genomic analysis was reported. For the purpose of this study, we call this gene, A.b_hyp gene. The aim of this study was to report the results of screening for the presence of the A.b_hyp gene in a worldwide collection of well-characterized A. baumannii collected from clinical and animal specimens. A total of 83 clinical, animal, and type strains were used. These comprised 73 A. baumannii isolates of clinical (n = 60) and animal origin (n = 13), and ten type strains, including a positive control strain, A. baumannii ATCC 19606. All isolates were examined by PCR amplification of the A.b_hyp gene. The A.b_hyp gene was detected in 72 isolates (99%) of A. baumannii but one clinical isolate failed to produce an amplicon. The control strain, A. baumannii ATCC 19606, was also positive for this gene. No bands were detected in non-A. baumannii species and therefore the isolates are thought to be negative for the gene. No bands were detected in non A. baumannii isolates and therefore they are thought to be negative for the gene. The PCR A.b_ hyp method provides evidence that detection of this gene can be used as a reliable, easy, and low-cost biomarker for A. baumannii identification. PMID- 28664219 TI - Biological Characterization of the Biocontrol Agent Bacillus amyloliquefaciens CPA-8: The Effect of Temperature, pH and Water Activity on Growth, Susceptibility to Antibiotics and Detection of Enterotoxic Genes. AB - This work focuses on the biological understanding of the biocontrol agent Bacillus amyloliquefaciens CPA-8 in order to accomplish the characterization required in the registration process for the development of a microorganism-based product. The tolerance of CPA-8 to grow under different pH-temperature and water activity (a w)-temperature conditions was widely demonstrated. Regarding the pH results, optimum growth at the evaluated conditions was observed at 37 degrees C and pH between 7 and 5. On the contrary, the slowest growth was recorded at 20 degrees C and pH 4.5. Moreover, the type of solute used to reduce a w had a great influence on the minimum a w at which the bacterium was able to grow. The lowest a w values for CPA-8 growth in media modified with glycerol and glucose were 0.950 and 0.960, respectively. Besides, the lowest a w for CPA-8 growth increased when the temperature decreased to 20 degrees C, at which CPA-8 was not able to grow at less than 0.990 a w, regardless of the type of solute. Antibiotic susceptibility tests were carried out to determine which antibiotic could affect the behavior of the bacteria and revealed that CPA-8 was clearly resistant to hygromycin. Finally, a PCR amplification assay to detect the presence of enterotoxic genes from Bacillus cereus in CPA-8 was also performed. CPA-8 gave negative results for all the genes tested except for nheA gene, which is not enough for the toxicity expression, suggesting that fruit treated with this antagonist will not be a potential vehicle for foodborne illnesses. PMID- 28664220 TI - Minimal time spiking in various ChR2-controlled neuron models. AB - We use conductance based neuron models, and the mathematical modeling of optogenetics to define controlled neuron models and we address the minimal time control of these affine systems for the first spike from equilibrium. We apply tools of geometric optimal control theory to study singular extremals, and we implement a direct method to compute optimal controls. When the system is too large to theoretically investigate the existence of singular optimal controls, we observe numerically the optimal bang-bang controls. PMID- 28664221 TI - A stoichiometric organic matter decomposition model in a chemostat culture. AB - Biodegradation, the disintegration of organic matter by microorganism, is essential for the cycling of environmental organic matter. Understanding and predicting the dynamics of this biodegradation have increasingly gained attention from the industries and government regulators. Since changes in environmental organic matter are strenuous to measure, mathematical models are essential in understanding and predicting the dynamics of organic matters. Empirical evidence suggests that grazers' preying activity on microorganism helps to facilitate biodegradation. In this paper, we formulate and investigate a stoichiometry-based organic matter decomposition model in a chemostat culture that incorporates the dynamics of grazers. We determine the criteria for the uniform persistence and extinction of the species and chemicals. Our results show that (1) if at the unique internal steady state, the per capita growth rate of bacteria is greater than the sum of the bacteria's death and dilution rates, then the bacteria will persist uniformly; (2) if in addition to this, (a) the grazers' per capita growth rate is greater than the sum of the dilution rate and grazers' death rate, and (b) the death rate of bacteria is less than some threshold, then the grazers will persist uniformly. These conditions can be achieved simultaneously if there are sufficient resources in the feed bottle. As opposed to the microcosm decomposition models' results, in a chemostat culture, chemicals always persist. Besides the transcritical bifurcation observed in microcosm models, our chemostat model exhibits Hopf bifurcation and Rosenzweig's paradox of enrichment phenomenon. Our sensitivity analysis suggests that the most effective way to facilitate degradation is to decrease the dilution rate. PMID- 28664222 TI - On selection in finite populations. AB - Two major forces shaping evolution are drift and selection. The standard models of neutral drift-the Wright-Fisher (WF) and Moran processes-can be extended to include selection. However, these standard models are not always applicable in practice, and-even without selection-many other drift models make very different predictions. For example, "generalised Wright-Fisher" models (so-called because their first two conditional moments agree with those of the WF process) can yield wildly different absorption times from WF. Additionally, evolutionary stability in finite populations depends only on fixation probabilities, which can be evaluated under less restrictive assumptions than those required to estimate fixation times or more complex population-genetic quantities. We therefore distill the notion of a selection process into a broad class of finite population, mutationless models of drift and selection (including the WF and Moran processes). We characterize when selection favours fixation of one strategy over another, for any selection process, which allows us to derive finite population conditions for evolutionary stability independent of the selection process. In applications, the precise details of the selection process are seldom known, yet by exploiting these new theoretical results it is now possible to make rigorously justifiable inferences about fixation of traits. PMID- 28664223 TI - The influence of pregnancy on women with adolescent idiopathic scoliosis. AB - PURPOSE: The study's aim was to address three fundamental questions related to pregnancy and adolescent idiopathic scoliosis (AIS), and provide clinically applicable answers to spine specialists and general practitioners alike. METHODS: The authors performed a systematic literature review using MEDLINE, EMBASE, Google Scholar, and Cochrane Database of Systematic Reviews to identify articles published between 1980 and 2015 that described pregnancy-related characteristics and outcomes in AIS patients. The search was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and evidence was classified according to the Oxford CEBM (Centre for Evidence-Based Medicine) appraisal tool. RESULTS: Twenty-two articles incorporating more than 3125 AIS patients were included. All studies concluded level 2b evidence or lower. Nulliparity rates were slightly higher among AIS patients, and more frequent infertility treatment was required. Pregnancy-related back pain was common, and while non-disabling, may have been more severe than in healthy women. Minor curve progression often occurred during pregnancy, though its permanence was questioned and significance unknown. Back pain and curve progression occurred independent of AIS treatment modality. With modern technology, anesthetic and obstetric complications in the perinatal period were not elevated in AIS mothers. CONCLUSIONS: Women with AIS experience slightly elevated rates of nulliparity, infertility treatment, prepartum back pain, and peripartum curve progression. However, most women are able to have children and are not at increased risk of pregnancy-related complications. Higher quality evidence is needed to better define these relationships and allow more guided counseling and treatment. PMID- 28664224 TI - Complex surgery for locally advanced bone and soft tissue sarcomas of the shoulder girdle. AB - Surgical management of primary musculoskeletal tumors of the shoulder girdle is cognitively and technically demanding. Over the last decades, advances in the medical treatments, imaging and surgical techniques have fostered limb salvage surgery and reduced the need for amputation. Despite well-accepted general principles, an individualized approach is often necessary to accommodate tumor extension, anatomical challenges and patient characteristics. A combination of techniques is often required to achieve optimal oncologic and durable functional outcome. Goal of this article is to review approach and management of patients with locally advanced sarcomas of the shoulder girdle requiring major tumor surgery, to illustrate principles of surgical strategy, outcome and complications, and to provide useful guidelines for the treating physicians. PMID- 28664225 TI - Does "OPTINAB" strategy ("stop-and-go") work in treatment of advanced pancreatic cancer (APC) with nab-paclitaxel-gemcitabine? AB - BACKGROUND: MPACT demonstrated a survival benefit of nab-paclitaxel plus gemcitabine versus gemcitabine in advanced pancreatic cancer (APC). However, sensory peripheral neuropathy is a dose-limiting toxicity and neuromodulators have shown limited, if any activity in ameliorating neuropathy. In colorectal cancer, the OPTIMOX ("stop-and-go") approach offered a strategy to reduce neuropathy. No data exist to support this strategy for nab-paclitaxel in APC. METHODS: Retrospective study of APC patients who developed grade 3 neuropathy during nab-paclitaxel plus gemcitabine was done. Nab-paclitaxel was held and then reinstituted upon radiological or tumor marker progression. Duration of disease control (DCC) was measured. We named this strategy "OPTINAB". RESULTS: Seven patients out of 27 (25%) developed grade 3 neuropathy after an average of 4.2 months; nab-paclitaxel was suspended while gemcitabine was continued. Maintenance gemcitabine continued for a mean of 2.8 months. Upon progression (radiologic or CA19-9) nab-paclitaxel was re-instituted with gemcitabine. One patient could not tolerate nab-paclitaxel due to worsening of neuropathy while other six continued the combo with mean progression-free survival 2 (PFS2) of 2.2 months. The six patients continued nab-paclitaxel for a mean of PFS2 of 2.2 months (range 1-4 months). Nab-paclitaxel resulted in improvement of an average DDC with an average of (7.0 + 2.2 =) 8.2 months (range 8-13 months). Average overall survival for this group was 11.7 months (range 9.5-17 months). Reintroduction of nab paclitaxel resulted in an average DDC of 9.4 months. Average overall survival (OS) for this group was 11.7 months. CONCLUSIONS: "OPTINAB" approach improved PFS2 in these patients and was feasible as majority of the patient tolerated nab paclitaxel. Although it is a small study, it supports the need for a randomized, prospective study to test the concept of "OPTINAB". PMID- 28664226 TI - Eribulin shows high concentration and long retention in xenograft tumor tissues. AB - PURPOSE: Eribulin, a synthetic analog of the natural product halichondrin B, is a microtubule dynamics inhibitor. In this study, we report the pharmacokinetic profiles of eribulin in mice, rats, and dogs following intravenous administrations with optimized and validated bio-analytical methods. METHODS: Eribulin was administered at 0.5 and 2 mg/kg in mice, 0.5 and 1 mg/kg in rats, and 0.08 mg/kg in dogs. Tumor and brain penetration of eribulin was also evaluated in LOX human melanoma xenograft models. Concentrations in plasma, tumor, and brain were measured by the LC-MS/MS method. RESULTS: The profiles of eribulin were characterized by extensive distribution, moderate clearance, and slow elimination in the three species. The pharmacokinetics are linear in mice and rats. In xenograft mice, the penetration into the brain was low, as expected, since eribulin is a P-glycoprotein substrate. In contrast to disposition in brain, the exposure of eribulin was approximately 20-30 times higher in tumor than that in plasma and half-lives were 17.8-35.9 h after both single and multiple dose regimens. CONCLUSIONS: Eribulin was distributed rapidly and eliminated slowly in mice, rats, and dogs. The exposure of eribulin was approximately 20-30 times higher in tumor than in plasma in xenograft mice. These results might be caused by eribulin's mechanism of action including increased perfusion in tumor by vascular remodeling effect. PMID- 28664227 TI - Within-Family Effects of Smoking during Pregnancy on ADHD: the Importance of Phenotype. AB - We sought to test within- and between- family associations of smoking during pregnancy (SDP) and attention deficit-hyperactivity disorder (ADHD) symptoms using a structured interview based on the conventional Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) symptoms and the Strengths and Weaknesses of ADHD-Symptoms and Normal-Behavior (SWAN) scale, which is a population based measure that grew out of the notion that an ADHD diagnosis exists on the extreme end of a continuum of normative behaviors and includes both above- and below- average performance on attention and activity. We used a sibling-comparison approach in a sample of 173 families including siblings aged 7 16 years (52% male) drawn from the state of Missouri, USA, wherein mothers smoked during one pregnancy but not the other. There was a within-family effect of smoking during pregnancy on SWAN hyperactivity/impulsivity and SWAN total ADHD behaviors. The associations between SDP and DSM-IV-based ADHD symptom dimensions as well as SWAN inattention were explained by familial confounds. These findings suggest that SDP exerts a potentially causal effect on increased ADHD hyperactive/impulsive behaviors and that this SDP effect is best captured when hyperactivity/impulsivity is assessed more normatively across the population, rather than specifically assessing problematic behaviors via DSM symptoms. Thus, any potentially causal effect of SDP on ADHD symptom dimensions may be restricted to hyperactive/impulsive behaviors rather than inattention, and normative, non DSM-IV based behavioral measures may provide a more sensitive test of mechanisms of SDP-ADHD symptom associations, particularly in non-clinical samples. PMID- 28664228 TI - Serum microRNAs in male subfertility-biomarkers and a potential pathogenetic link to metabolic syndrome. AB - PURPOSE: The purpose of the study was to identify serum microRNAs providing a link between male subfertility and metabolic syndrome (MetS) and validate their diagnostic potential. METHODS: Sera were analyzed for fertility and MetS-related parameters in subfertile men (n = 79) and controls (n = 38). Literature review identified miR-155-5p, miR-122-5p, miR-200a-3p, and miR-200c-3p which previously were associated with parameters of fertility as well as metabolic disorders. They were measured in the sera using an absolute quantitation method (qPCR). In order to investigate the value of miRNAs in predicting subfertility, receiver operating characteristic analysis was done. RESULTS: Subfertile men had higher concentrations of miR-155-5p than controls (p = 0.003) and for miR-200c-3p, the difference was borderline statistically significant (p = 0.05). miR-155-5p and miR-200c-3p were also associated with subfertility in men with no metabolic disturbances (p = 0.008, p = 0.004, respectively). This association was abrogated if any component of MetS was present. The combination of miR-155-5p and miR-200c 3p with follicle-stimulating hormone, being a well-established subfertility parameter, resulted in an overall diagnostic power of AUC = 0.87, which was even higher when men without MetS components were analyzed (AUC = 0.93). Regarding MetS components, statistically significant correlations were found between miR 122-5p and fasting triglycerides, and waist circumference, but no association with subfertility was identified. CONCLUSIONS: Among the four miRNAs analyzed, none of them was associated both with male subfertility and MetS components. The ability of miR-155-5p and miR-200c-3p to identify subfertile men was partly overruled by the presence of metabolic disturbances. PMID- 28664229 TI - Response criteria of tolvaptan for the treatment of hepatic edema. AB - BACKGROUND: Although tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response. METHODS: The study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals. RESULTS: A cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961; sensitivity, 89.8%; specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated. CONCLUSIONS: The cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week; this value is expected to be an effective indicator of response to tolvaptan in clinical practice. PMID- 28664230 TI - Cortical thickness abnormalities in trichotillomania: international multi-site analysis. AB - Trichotillomania is a prevalent but often hidden psychiatric condition, characterized by repetitive hair pulling. The aim of this study was to confirm or refute structural brain abnormalities in trichotillomania by pooling all available global data. De-identified MRI scans were pooled by contacting authors of previous studies. Cortical thickness and sub-cortical volumes were compared between patients and controls. Patients (n = 76) and controls (n = 41) were well matched in terms of demographic characteristics. Trichotillomania patients showed excess cortical thickness in a cluster maximal at right inferior frontal gyrus, unrelated to symptom severity. No significant sub-cortical volume differences were detected in the regions of interest. Morphometric changes in the right inferior frontal gyrus appear to play a central role in the pathophysiology of trichotillomania, and to be trait in nature. The findings are distinct from other impulsive-compulsive disorders (OCD, ADHD, gambling disorder), which have typically been associated with reduced, rather than increased, cortical thickness. Future work should examine sub-cortical and cerebellar morphology using analytic approaches designed for this purpose, and should also characterize grey matter densities/volumes. PMID- 28664231 TI - Clinical relevance of microhemorrhagic lesions in subacute mild traumatic brain injury. AB - Magnetic resonance imaging (MRI) is often performed in patients with persistent complaints after mild traumatic brain injury (mTBI). However, the clinical relevance of detected microhemorrhagic lesions is still unclear. In the current study, 54 patients with uncomplicated mTBI and 20 matched healthy controls were included. Post-traumatic complaints were measured at two weeks post-injury. Susceptibility weighted imaging and T2*-gradient echo imaging (at 3 Tesla) were performed at four weeks post-injury. Microhemorrhagic lesions (1-10 mm) were subdivided based on depth (superficial or deep) and anatomical location (frontal, temporoparietal and other regions). Twenty-eight per cent of patients with mTBI had >=1 lesions compared to 0 % of the healthy controls. Lesions in patients with mTBI were predominantly located within the superficial frontal areas. Number, depth and anatomical location of lesions did not differ between patients with and without post-traumatic complaints. Within the group of patients with complaints, number of complaints was not correlated with number of lesions. In summary, microhemorrhages were found in one out of four patients with uncomplicated mTBI during follow-up at four weeks post-injury, but they were not related to early complaints. PMID- 28664232 TI - [Elbow dislocation fractures]. AB - The treatment of complex elbow dislocation fractures is a challenge to both the treating surgeon as well as to the patient due to the complex bony and soft tissue anatomy of the joint. In order to establish an expedient treatment algorithm, all osseous and ligamentous injuries need to be thoroughly assessed. Furthermore, a detailed knowledge of the joint-stabilizing structures, practicable surgical approaches as well as the possible techniques for fracture fixation and/or arthroplasty are essential to facilitate early rehabilitation of the elbow and avoid injury-related complications. Any unnecessary delay in treatment of this complex injury can result in posttraumatic functional disorders, recurrent instability and secondary arthrosis. In conclusion, the goals of surgical treatment must be the correct restoration of the joint anatomy and stability as the prerequisites for any successful treatment of elbow fracture dislocations in order to enable early motion of the joint. PMID- 28664233 TI - Endovascular Treatment of Wide-Necked Visceral Artery Aneurysms Using the Neurovascular Comaneci Neck-Bridging Device: A Technical Report. AB - INTRODUCTION: Visceral and renal artery aneurysms (VRAAs) are an uncommon clinical entity but carry a risk of rupture with associated morbidity and mortality. The rupture risk is particularly high when the aneurysms are large, of unfavourable morphology or in the setting of pregnancy and perioperative period. Endovascular approaches are now first line in the treatment of VRAA, but conventional techniques may be ineffective in excluding aneurysms with unfavourable anatomy such as those with wide necks or at arterial bifurcation points. The neurovascular Comaneci neck-bridging device is used to temporarily cover the neck of intracranial aneurysms without occluding forward arterial flow during endovascular coiling. We report the novel use of the Comaneci neck bridging device for the treatment of complex peripheral VRAAs. MATERIALS AND METHODS: We describe the treatment of two patients with renal and splenic artery aneurysms demonstrating unfavourable anatomic morphology for conventional endovascular approaches. RESULTS: In the first patient, the renal artery aneurysm was situated at the intrarenal bifurcation of the main renal artery in the setting of a solitary kidney. In the second patient, the splenic artery aneurysm was situated close to the splenic hilum at the distal splenic arterial bifurcation. The Comaneci neck-bridging device was successfully used in both cases to assist coil embolisation with visceral preservation. CONCLUSIONS: The Comaneci neck-bridging device is potentially safe and effective for the treatment of peripheral VRAA with unfavourable anatomic characteristics that would have been deemed unsuitable for treatment using conventional techniques. LEVEL OF EVIDENCE: Level 4, Technical Report. PMID- 28664234 TI - Regarding "Predicting Success in Percutaneous Transhepatic Biliary Drainage". PMID- 28664235 TI - Public-Private Partnerships Working Beyond Scale Challenges toward Water Quality Improvements from Private Lands. AB - In recognition that Iowa agriculture must maintain long-term production of food, fiber, clean water, healthy soil, and robust rural economies, Iowa recently devised a nutrient reduction strategy to set objectives for water quality improvements. To demonstrate how watershed programs and farmers can reduce nutrient and sediment pollution in Iowa waters, the Iowa Water Quality Initiative selected the Boone River Watershed Nutrient Management Initiative as one of eight demonstration projects. For over a decade, diverse public, private, and non profit partner organizations have worked in the Boone River Watershed to engage farmers in water quality management efforts. To evaluate social dynamics in the Boone River Watershed and provide partners with actionable recommendations, we conducted and analyzed semi-structured interviews with 33 program leaders, farmers, and local agronomists. We triangulated primary interview data with formal analysis of Boone River Watershed documents such as grant applications, progress reports, and outreach materials. Our evaluation suggests that while multi-stakeholder collaboration has enabled partners to overcome many of the traditional barriers to watershed programming, scale mismatches caused by external socio-economic and ecological forces still present substantial obstacles to programmatic resilience. Public funding restrictions and timeframes, for example, often cause interruptions to adaptive management of water quality monitoring and farmer engagement. We present our findings within a resilience framework to demonstrate how multi-stakeholder collaboration can help sustain adaptive watershed programs to improve socio-ecological function in agricultural watersheds such as the Boone River Watershed. PMID- 28664236 TI - Alterations in biomechanical properties of the cornea among patients with polycystic kidney disease. AB - PURPOSE: The aim of this study was to evaluate the corneal biomechanical features in polycystic kidney disease (PKD) patients and compare them with the healthy individuals. METHODS: Totally 81 patients with a mean age of 48.46 +/- 14.51 years and 60 control cases with a mean age of 44.68 +/- 12.69 years were included in the study. All of the subjects underwent a complete ophthalmological examination, including visual acuity testing, biomicroscopic anterior and posterior segment examinations. Corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg) and corneal compensated intraocular pressure (IOPcc) were evaluated with the ocular response analyzer, and the central corneal thickness was evaluated with Sirius(r) corneal topography. RESULTS: PKD patients had significantly increased CH values, without any alterations in IOP or CCT values, compared with the control cases (p:0.001). Among PKD patients, 23 were having liver cysts accompanying renal cysts. There was not any statistically significant difference between PKD patients with or without liver cysts regarding biomechanical properties of the cornea. However, both patient groups had statistically significantly increased CH values compared with the control cases. CONCLUSION: Patients with PKD present with higher CH values than age-matched controls. Larger studies are warranted to elucidate the alterations in corneal biomechanical properties and their clinical relevance in PKD patients. PMID- 28664237 TI - Surgical and Minimally Invasive Therapies for the Management of the Small Renal Mass. AB - PURPOSE OF REVIEW: This article aims to summarise recent developments in surgical and minimally invasive therapies in the management of small renal masses (SRMs). RECENT FINDINGS: The incidence of the small renal mass is increasing. Standard management of the SRM is partial nephrectomy. More recently, use of ablative techniques to manage the SRM has been increasing and an exciting array of technical advances is currently being made in the field. Nephron-sparing surgery looks set to become more financially viable with the advent of newer robotic platforms and, potentially, even less invasive with the evaluation of single-port access. Real-time imaging promises to improve tumour definition, nephron preservation and vascular management intraoperatively. Advances in surgical and minimally invasive therapies for the management of the SRM have the potential to improve cancer clearance and long-term renal function preservation. Patients will experience safer, more reliable and less invasive treatments for their small renal tumours. We describe the current advances underlying these changes. PMID- 28664238 TI - Intralabyrinthine schwannomas : Surgical management and hearing rehabilitation with cochlear implants. AB - Intralabyrinthine schwannomas (ILS) are a rare differential diagnosis of sudden hearing loss and vertigo. In an own case series of 12 patients, 6 tumors showed an intracochlear, 3 an intravestibular, 1 a transmodiolar including the cerebellopontine angle (CPA), 1a transotic including the CPA, and 1 a multilocular location. The tumors were removed surgically in 9 patients, whereas 3 patients decided for a "wait-and-test-and-scan" strategy. Of the surgical patients, 3 underwent labyrinthectomy and cochlear implant (CI) surgery in a single-stage procedure; 1 patient had extended cochleostomy with CI surgery; 3 underwent partial or subtotal cochleoectomy, with partial cochlear reconstruction and CI surgery (n = 1) or implantation of electrode dummies for possible later CI after repeated MRI follow-up (n = 2); and in 2 patients, the tumors of the internal auditory canal and cerebellopontine angle exhibiting transmodiolar or transmacular growth were removed by combined translabyrinthine-transotic resection. For the intracochlear tumors, vestibular function could mostly be preserved after surgery. In all cases with CI surgery, hearing rehabilitation was successful, although speech discrimination was limited for the case with subtotal cochleoectomy. Surgical removal of intracochlear schwannomas via partial or subtotal cochleoectomy is, in principle, possible with preservation of vestibular function. In the authors' opinion, radiotherapy of ILS is only indicated in isolated cases. Cochlear implantation during or after tumor resection (i. e., as synchronous or staged surgeries) is an option for hearing rehabilitation in cartain cases and represents a therapeutic approach in contrast to a "wait-and test-and-scan" strategy. PMID- 28664239 TI - Blood Flow in Idealized Vascular Access for Hemodialysis: A Review of Computational Studies. AB - Although our understanding of the failure mechanism of vascular access for hemodialysis has increased substantially, this knowledge has not translated into successful therapies. Despite advances in technology, it is recognized that vascular access is difficult to maintain, due to complications such as intimal hyperplasia. Computational studies have been used to estimate hemodynamic changes induced by vascular access creation. Due to the heterogeneity of patient-specific geometries, and difficulties with obtaining reliable models of access vessels, idealized models were often employed. In this review we analyze the knowledge gained with the use of computational such simplified models. A review of the literature was conducted, considering studies employing a computational fluid dynamics approach to gain insights into the flow field phenotype that develops in idealized models of vascular access. Several important discoveries have originated from idealized model studies, including the detrimental role of disturbed flow and turbulent flow, and the beneficial role of spiral flow in intimal hyperplasia. The general flow phenotype was consistent among studies, but findings were not treated homogeneously since they paralleled achievements in cardiovascular biomechanics which spanned over the last two decades. Computational studies in idealized models are important for studying local blood flow features and evaluating new concepts that may improve the patency of vascular access for hemodialysis. For future studies we strongly recommend numerical modelling targeted at accurately characterizing turbulent flows and multidirectional wall shear disturbances. PMID- 28664240 TI - Understanding patients' preferences for surgical management of urethral stricture disease. AB - OBJECTIVES: To understand how prioritization of treatment attributes and treatment choice varies by patient characteristics, we sought to specifically determine how demographic variables affect patient treatment preference. PATIENTS AND METHODS: Male patients with urethral stricture disease participated in a choice-based conjoint (CBC) analysis exercise evaluating six treatment attributes associated with internal urethrotomy and urethroplasty. Demographic and past symptom data were collected. Stratified analysis of demographic variables, including age, education, income, was conducted using a mixed effect logistic regression model to evaluate the coefficient size and confidence intervals between the treatments attribute preferences of each strata. RESULTS: 169 patients completed the CBC exercise and were included in our analysis. Overall success of the procedure is the most important treatment attribute to patients and this persists across strata. Older patients (>=65) express preferences for better success rates and fewer future procedures, whereas younger patients prefer a less invasive approach and are more willing to accept additional procedures if needed. Patients with lower levels of education preferred open reconstruction and had a stronger preference against multiple future procedures, whereas those with higher levels of education preferred endoscopic treatment and had a less strong preference against multiple future procedures. Low-income individuals express statistically significant stronger negative preferences against high copay costs compared to high-income individuals. CONCLUSION: These results can help to inform physicians' counseling about surgical management of urethral stricture disease to better align patient preferences with treatment selection and encourage shared decision making. PMID- 28664241 TI - The epidemiology of current depression in Macau, China: towards a plan for mental health action. AB - PURPOSE: Macau is a Special Administrative Region in China that has experienced tremendous development in its gambling industry during its post-colonial years. To inform mental health planning, this study presents the first population estimates and correlates of the current depression in Macau. METHODS: A population-representative sample of 1068 Macau Chinese citizens aged 18 or above responded to a household telephone survey in January, 2015. The Patient Health Questionnaire-9 measured the current depression. Logistic regression models assessed the association between depression and potential correlates. RESULTS: Overall, 8.0% (95% CI 6.3-9.7) of persons reported the current depression. A higher but non-significant proportion of women reported depression than men (9.3 vs. 6.6%) and older women reported higher prevalence (13.4%) than other demographic groups. Persons who were unemployed (OR = 4.9, 2.3-10.5), separated or divorced (OR = 3.1, 1.1-8.9), and reported poor self-rated health (OR = 5.0, 2.8-9.0), low quality of life (OR = 6.2, 3.1-12.7), lower social standing (OR = 2.4, 1.4-4.0), lower community trust (OR = 1.9, 1.2-3.1), lower perceived fairness (OR = 2.3, 1.4-3.8), lower social cohesion (OR = 3.8, 2.3-6.2), and lower social integration (OR = 3.0, 1.9-5.0) had greater odds of depression than their comparison group. CONCLUSIONS: The current study demonstrated the burden of depression among Macau adults disproportionately affects women during emerging adolescence and old age, and men during middle adulthood. Key strategies to improve mental health services in Macau are discussed. PMID- 28664243 TI - Optimal go/no-go ratios to maximize false alarms. AB - Despite the ubiquity of go/no-go tasks in the study of behavioral inhibition, there is a lack of evidence regarding the impact of key design characteristics, including the go/no-go ratio, intertrial interval, and number of types of go stimuli, on the production of different response classes of central interest. In the present study we sought to empirically determine the optimal conditions to maximize the production of a rare outcome of considerable interest to researchers: false alarms. As predicted, the shortest intertrial intervals (450 ms), intermediate go/no-go ratios (2:1 to 4:1), and the use of multiple types of go stimuli produced the greatest numbers of false alarms. These results are placed within the context of behavioral changes during learning. PMID- 28664244 TI - [Erratum to: Treatment of fibromyalgia syndrome with gamma-hydroxybutyrate : A randomized controlled study]. PMID- 28664242 TI - Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab. AB - BACKGROUND: Although rituximab effectively prevents relapses of complicated frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS), data of long-term outcomes and safety are limited. METHODS: Fifty-one patients (age, 3-38 years) with childhood-onset complicated FRNS or SDNS, who received rituximab in investigator-initiated multicenter prospective trials were enrolled. Rituximab was administered at 375 mg/m2 once weekly for 4 weeks, and immunosuppressive agents were discontinued according to the study protocol. We investigated relapses, re-administration of immunosuppressive agents, additional rituximab treatment, body height, renal function, and late adverse events during the observation period. RESULTS: Forty-eight patients (94%) developed relapses during the observation period (median, 59 months) and the 50% relapse-free survival was 261 days. Thirty patients (59%) developed SDNS, 44 (86%) required re-administration of immunosuppressive agents, and 22 (43%) received additional rituximab treatment. All patients who were receiving immunosuppressive agents at rituximab treatment required either immunosuppressive agents or additional rituximab treatment. On the contrary, 5 of the 13 patients without immunosuppressive agents at rituximab treatment required neither immunosuppressive agents nor additional rituximab treatment and 3 of them did not develop relapse during observation period. Growth failure due to steroid toxicity did not progress and none of the patients developed chronic renal insufficiency. None of the patients suffered from rituximab-related late adverse events. CONCLUSIONS: As most patients suffer from relapses after B-cell recovery, long term immunosuppressive agents or additional rituximab treatment is necessary. However, some patients who can discontinue immunosuppressive agents before rituximab treatment may achieve long-term remission after rituximab treatment without immunosuppressive agents. PMID- 28664246 TI - Babaodan Capsule () combined with Qingyi Huaji Formula () in advanced pancreatic cancer-a feasibility study. AB - OBJECTIVE: To observe the clinical effects of Babaodan Capsule (, BBD) combined with Qingyi Huaji Formula (, QYHJ) in treating patients with advanced pancreatic cancer. METHODS: Eighty-one patients with advanced pancreatic cancer (from January 1, 2013 to December 31, 2014) were enrolled. Patients were assigned to two groups: QYHJ plus BBD group (40 cases) and QYHJ only group (41 cases), and there were no significant differences for other treatment between two groups. The survival and cancer-related symptoms were compared between two groups over two cycles of treatment. RESULTS: The cancer-related symptoms of patients such as ascites, jaundice, pain, abdominal distension, anorexia and Karnofsky performance status of QYHJ plus BBD group were significantly improved as compared with those of the QYHJ group (P<0.01). In addition, the 1-year survival rate of patients in QYHJ plus BBD group was longer than that in the QYHJ group (65% vs. 33%, respectively, P=0.0023). CONCLUSIONS: BBD with QYHJ is feasible treatment to prolong the survival of patients with advanced pancreatic cancer. However, it deserves to be further investigated in randomized clinical trials. PMID- 28664245 TI - A semiquantitative MRI-Score can predict loss of lung function in patients with cystic fibrosis: Preliminary results. AB - OBJECTIVES: To evaluate the applicability of a semiquantitative MRI scoring system (MR-CF-S) as a prognostic marker for clinical course of cystic fibrosis (CF) lung disease. METHODS: This observational study of a single-centre CF cohort included a group of 61 patients (mean age 12.9 +/- 4.7 years) receiving morphological and functional pulmonary MRI, pulmonary function testing (PFT) and follow-up of 2 years. MRI was analysed by three raters using MR-CF-S. The inter rater agreement, correlation of score categories with forced expiratory volume in 1 s (FEV1) at baseline, and the predictive value of clinical parameters, and score categories was assessed for the whole cohort and a subgroup of 40 patients with moderately impaired lung function. RESULTS: The inter-rater agreement of MR CF-S was sufficient (mean intraclass correlation coefficient 0.92). MR-CF-S ( 0.62; p < 0.05) and most of the categories significantly correlated with FEV1. Differences between patients with relevant loss of FEV1 (>3%/year) and normal course were only significant for MR-CF-S (p < 0.05) but not for clinical parameters. Centrilobular opacity (CO) was the most promising score category for prediction of a decline of FEV1 (area under curve: whole cohort 0.69; subgroup 0.86). CONCLUSIONS: MR-CF-S is promising to predict a loss of lung function. CO seems to be a particular finding in CF patients with an abnormal course. KEY POINTS: * Lung imaging is essential in the diagnostic work-up of CF patients * MRI serves as a powerful, radiation-free modality in paediatric CF patients * Observational single-centre study showed significant correlation of MR-CF score and FEV 1 * MR-CF score is promising in predicting a loss of lung function. PMID- 28664247 TI - Association between leg bowing and serum alkaline phosphatase level regardless of the presence of a radiographic growth plate abnormality in pediatric patients with genu varum. AB - When children around 2 years of age show leg bowing and diseases are ruled out based on radiographic findings without conducting blood tests, they are classified as "physiologic" genu varum. Since whether or not physiologic genu varum is associated with bone metabolism is unclear, this study was conducted to clarify the association between genu varum and bone metabolism in children. Thirty-five pediatric patients with genu varm who visited our out-patient clinic were enrolled. While two of the 35 children had nutritional rickets, showing abnormalities on both blood test (ALP, >=1000 IU/L; iPTH, >65 pg/mL and 25(OH)D, <=20 ng/mL) and radiographs (such as cupping, fraying or splaying), five of 35 children showed abnormalities on blood tests but not radiographs. While metaphyseal-diaphyseal angle (MDA) correlated with serum 25-hydroxy vitamin D (r = -0.35, p = 0.04) and magnesium (r = -0.36, p = 0.04), MDA and femorotibial angle (FTA) correlated with alkaline phosphatase (r = 0.43, p = 0.01 and r = 0.51, p = 0.006, respectively). A ridge regression analysis adjusted for age and body mass index indicated that ALP was associated with MDA and FTA. A logistic regression analysis adjusted for age and BMI indicated that higher ALP influenced an MDA >11 degrees , which indicates the risk for the progression of genu varum (odds ratio 1.002, 95% confidence interval 1.0003-1.003, p = 0.021). The higher ALP (+100 IU), the higher risk of an MDA >11 degrees (odds ratio 1.22). In conclusion, genu varum is associated with the alkaline phosphatase level regardless of the presence of radiographic abnormalities in the growth plate in children. PMID- 28664248 TI - Biochar physicochemical parameters as a result of feedstock material and pyrolysis temperature: predictable for the fate of biochar in soil? AB - Biochar application is a widely investigated topic nowadays, and precisely described biochar parameters are key information for the understanding of its behaviour in soil and other media. Pore structure and surface properties determine biochar fate. However, there is lack of complex, investigative studies describing the influence of biomass properties and pyrolysis conditions on the pore structure of biochars. The aim of our study was to evaluate a wide range of gathered agriculture residues and elevated pyrolysis temperature on the biochar surface properties and pore composition, predicting biochar behaviour in the soil. The biomass of herbaceous and wood plants was treated by slow pyrolysis, with the final temperature ranging from 400 to 600 degrees C. Specific surface ranged from 124 to 511 cm2 g-1 at wood biochar and from 3.19 to 192 cm2 g-1 at herbaceous biochar. The main properties influencing biochar pore composition were increasing pyrolysis temperatures and lignin (logarithmically) and ash contents (linearly) of biomass. Increasing lignin contents and pyrolysis temperatures caused the highest biochar micropore volume. The total biochar pore volume was higher of wood biomass (0.08-0.3 cm-3 g-1). Biochars of wood origin were characterised by skeletal density ranging from 1.479 to 2.015 cm3 g-1 and herbaceous ones 1.506-1.943 cm3 g-1, and the envelope density reached 0.982 cm3 g 1 at biochar of wheat grain origin and was generally higher at biochars of herbaceous origin. Density was not pyrolysis temperature dependent. PMID- 28664249 TI - Hydrogeochemistry study and groundwater quality assessment in the north of Isfahan, Iran. AB - This study presents the groundwater quality assessment in the north of Isfahan, Iran. In the study area, assessment and measurement of groundwater hydrochemical parameters such as pH, total dissolved solids (TDS), electrical conductivity (EC), sodium absorption ratio (SAR), total hardness, major cations (K+, Na+, Ca2+ and Mg2+) and major anions (Cl-, [Formula: see text] and [Formula: see text]) concentrations were performed. Accordingly, the 66 water samples from different locations were collected during April and May 2015. Water samples collected in the field were analyzed in the laboratory for cations and anions using the standard methods. In this research, the analytical results of physiochemical parameters of groundwater were compared with the standard guideline values as recommended by the world health organization (WHO) for drinking and public health purposes. The pH values of groundwater samples varied from 7.05 to 8.95 with a mean of 7.78, indicating a neutral to slightly alkaline water. TDS values showed that 14% of the samples exceeds the desirable limit given by WHO. EC values varied from 213 to 4320 uS/cm, while 23% of the samples were more than the standard limit. Gibbs diagram had shown that 90% of the samples in the study area fall in the rock weathering zone, and this means that chemical weathering of rock forming minerals is the main factor controlling the water chemistry in the study area. Irrigation suitability and risk assessment of groundwater are evaluated by measuring EC, %Na, SAR and RSC. According to the dominant cations and anions, five types of water were identified in the water samples: Ca-HCO3, Ca-SO4, Na-Cl, Na-HCO3 and Na-SO4. The results show that the majority of samples (30 samples, 45%) belongs to the mixed Na-SO4 water type. Correlation analysis and principal component analysis was used to identify the relationship between ions and physicochemical parameters. Results indicated that 18 stations of the study area had the best quality and can be used for irrigation and drinking purposes in the future. PMID- 28664250 TI - Erratum to: Interpreting findings from Mendelian randomization using the MR-Egger method. PMID- 28664251 TI - Structure of unliganded membrane-proximal domains FN4-FN5-FN6 of DCC. PMID- 28664252 TI - Nutrition and Hyperglycemia Management in the Inpatient Setting (Meals on Demand, Parenteral, or Enteral Nutrition). AB - PURPOSE OF REVIEW: The goal of this paper is to provide the latest evidence and expert recommendations for management of hospitalized patients with diabetes or hyperglycemia receiving enteral (EN), parenteral (PN) nutrition support or, those with unrestricted oral diet, consuming meals on demand. RECENT FINDINGS: Patients with and without diabetes mellitus commonly develop hyperglycemia while receiving EN or PN support, placing them at increased risk of adverse outcomes, including in-hospital mortality. Very little new evidence is available in the form of randomized controlled trials (RCT) to guide the glycemic management of these patients. Reduction in the dextrose concentration within parenteral nutrition as well as selection of an enteral formula that diminishes the carbohydrate exposure to a patient receiving enteral nutrition are common strategies utilized in practice. No specific insulin regimen has been shown to be superior in the management of patients receiving EN or PN nutrition support. For those receiving oral nutrition, new challenges have been introduced with the most recent practice allowing patients to eat meals on demand, leading to extreme variability in carbohydrate exposure and risk of hypo and hyperglycemia. Synchronization of nutrition delivery with the astute use of intravenous or subcutaneous insulin therapy to match the physiologic action of insulin in patients receiving nutritional support should be implemented to improve glycemic control in hospitalized patients. Further RCTs are needed to evaluate glycemic and other clinical outcomes of patients receiving nutritional support. For patients eating meals on demand, development of hospital guidelines and policies are needed, ensuring optimization and coordination of meal insulin delivery in order to facilitate patient safety. PMID- 28664253 TI - Social Determinants of Health and Racial/Ethnic Disparities in Type 2 Diabetes in Youth. AB - PURPOSE OF REVIEW: Pervasive disparities in T2DM among minority adults are well documented, and scholars have recently focused on the role of social determinants of health (SDOH) in disparities. Yet, no research has summarized what is known about racial/ethnic disparities in youth-onset T2DM. This review summarizes the current literature on racial/ethnic disparities in youth-onset T2DM, discusses SDOH that are common among youth with T2DM, and introduces a conceptual model on the possible role of SDOH in youth-onset T2DM disparities. RECENT FINDINGS: Minority youth have disparities in the onset of T2DM, quality of life, and family burden. Low family income and parental education and high youth stress are common negative SDOH among families of youth with T2DM. No studies have examined the role of SDOH in racial/ethnic disparities in youth-onset T2DM. Future research should examine whether SDOH contribute to disparities in T2DM prevalence and psychosocial outcomes among minority youth. PMID- 28664254 TI - Hospital Volume and the Costs Associated with Surgery for Pancreatic Cancer. AB - BACKGROUND: Data evaluating the financial implications of volume-based referral are lacking. This study sought to compare in-hospital costs for pancreatic surgery by annual hospital volume. METHODS: Eleven thousand and eighty-one patients aged >=18 years undergoing an elective pancreatic resection for cancer were identified using the Nationwide Inpatient Sample 2002-2011. Multivariable regression analysis was performed to compare length-of-stay (LOS), postoperative morbidity and mortality, failure-to-rescue (FTR), and inpatient costs by annual hospital volume group. RESULTS: Patients undergoing surgery at high-volume hospitals (HVH) demonstrated 23% lower odds (odds ratio [OR] = 0.77, 95% confidence interval [95%CI] 0.63-0.95) of developing a postoperative complication, 59% lower odds of experiencing an LOS > 14 days (OR = 0.41, 95%CI 0.34-0.50), 51% lower odds of postoperative mortality (OR = 0.49, 95%CI 0.34 0.71), and 47% lower odds of FTR (OR = 0.53, 95%CI 0.37-0.76; all p<0.05). The overall mean in-hospital cost was $39,012 (SD = $15,214) with minimal differences observed across hospital volume groups. Rather, postoperative complications (no complication vs. complication $26,686 [SD = $5762] vs. $44,633 [SD = $11,637]) and FTR (rescue vs. FTR $42,413 [SD = $8481] vs. $69,546 [SD = $13,131]) were determinant of higher in-hospital costs. While this pattern was observed at all hospital volume groups, costs varied minimally between hospital volume groups after this stratification. CONCLUSIONS: Annual hospital surgical volume was not associated with in-hospital costs among patients undergoing pancreatic surgery. PMID- 28664256 TI - Who Gets Testosterone? PMID- 28664255 TI - Comparative Quantitative Lymph Node Assessment in Localized Esophageal Cancer Patients After R0 Resection With and Without Neoadjuvant Chemoradiation Therapy. AB - INTRODUCTION: The effects of neoadjuvant chemoradiation therapy on lymph node retrieval during esophagectomy for patients with esophageal cancer are unclear. The aim of this study was to quantify lymph node retrieval after R0 esophagectomy and to assess its impact on overall survival in induction therapy patients. METHODS: One hundred seventy-four consecutive patients underwent esophagectomy with or without induction therapy from 2008 to 2015 for esophageal cancer. Total lymph nodes, positive lymph nodes, and lymph node ratios were compared between two groups of patients: those treated with either upfront surgery or those treated with neoadjuvant chemoradiation therapy followed by surgery. Comparisons were made using Student's t test. Overall survival was obtained and compared using Kaplan Meier survival curves. RESULTS: Total lymph node counts were less in the induction therapy group (p = 0.027), while positive lymph node counts and lymph node ratios did not differ between groups (p = 0.262 and p = 0.310, respectively). In the neoadjuvant chemoradiation followed by surgery group, overall survival was significantly shorter for patients who had any positive lymph nodes in the pathologic specimen (p = 0.0065). CONCLUSIONS: Total lymph node counts were significantly lower in the induction therapy group, while positive lymph node counts and lymph node ratios did not differ from the upfront surgery group. Although overall survival was not different between groups, it was decreased within the induction therapy cohort among those who had any positive lymph nodes retrieved at surgery. This study confirms that unstratified gross lymph node counts do not substantially relate to prognosis in the heterogeneous population of locally advanced esophageal cancer patients who may or may not have had neoadjuvant chemoradiation. PMID- 28664258 TI - Five High-Cost Patient Groups. PMID- 28664257 TI - Running Out of Options: Rhabdomyolysis Associated with Cannabis Hyperemesis Syndrome. AB - Cannabis hyperemesis syndrome (CHS) is a condition in which some patients with long-term, frequent use of cannabis paradoxically develop recurrent episodes of nausea and vomiting. The pathophysiology underlying this condition is poorly understood, as is the explanation for its common association with patients' discovery that hot-water bathing alleviates symptoms. We describe the case of a 24-year-old male with daily marijuana use and a history of CHS who was found to have rhabdomyolysis induced by a period of 15 h of continuous jogging after he discovered that this activity helped to alleviate his symptoms. To our knowledge, this is the first reported case of exercise-alleviated CHS symptoms, and we propose that this case provides support to the theory of redistribution of enteric blood flow as the mechanism behind the learned hot-water bathing behavior seen so commonly in CHS. PMID- 28664259 TI - What's in a Number? Risk Thresholds in Different Statin Guidelines. PMID- 28664260 TI - Highlight report: co-cultures of hepatocytes and macrophages for hepatotoxicity testing. PMID- 28664261 TI - The fibular head projection is of limited use as a radiographic landmark in preoperative planning of total knee arthroplasty. AB - INTRODUCTION: The projection of the fibular head is recommended as a quality indicator of a correct radiographic projection. However, this landmark has yet to be sufficiently validated. METHODS: The MRIs of 334 knee joints were included. On the MRIs, the distance between the FH and lateral tibial cortical bone was simulated in projections parallel to surgically relevant axes. Then, the Pearson correlation coefficient between the distance of the FH to the lateral tibial cortical bone and the projection plane causing this was determined. RESULTS: A projection of the knee joint perpendicular to Akagi's line projected the center of the fibular head on average 4.8 +/- 2.9 mm laterally of the tibial cortical bone, parallel to the maximum mediolateral axis of the tibia 7.5 +/- 3.4 mm, parallel to the posterior condylar axis 5.6 +/- 3.6 mm and parallel to the surgical epicondylar axis 6.1 +/- 3.5 mm laterally of the tibial cortical bone. An almost linear correlation was seen, with 1.9 degrees tilting of the projection plane per mm change in distance between the fibular head and tibial cortical bone. At the same time, the interindividual scatter was over 60 degrees . CONCLUSIONS: The rule of thumb for a partial overlap of the fibular head by the tibia in the case of a correct antero-posterior projection plane was also confirmed. However, a considerable interindividual variability of the position of the FH was found, which limits a conclusion regarding the quality of the radiographic projection on the basis of the position of the fibular head. PMID- 28664262 TI - Editorial: How Does CORR (r) Evaluate Survey Studies? PMID- 28664263 TI - Erratum to: Acute Neuroinflammation Promotes Cell Responses to 1800 MHz GSM Electromagnetic Fields in the rat Cerebral Cortex. PMID- 28664264 TI - Behavioural changes, sharing behaviour and psychological responses after receiving direct-to-consumer genetic test results: a systematic review and meta analysis. AB - It has been hypothesised that direct-to-consumer genetic tests (DTC-GTs) could stimulate health behaviour change. However, genetic testing may also lead to anxiety and distress or unnecessarily burden the health care system. The aim is to review and meta-analyse the effects of DTC-GT on (1) behaviour change, (2) psychological response and (3) medical consumption. A systematic literature search was performed in three databases, using "direct-to-consumer genetic testing" as a key search term. Random effects meta-analyses were performed when at least two comparable outcomes were available. After selection, 19 articles were included involving 11 unique studies. Seven studies involved actual consumers who paid the retail price, whereas four included participants who received free genetic testing as part of a research trial (non-actual consumers). In meta-analysis, 23% had a positive lifestyle change. More specifically, improved dietary and exercise practices were both reported by 12%, whereas 19% quit smoking. Seven percent of participants had subsequent preventive checks. Thirty-three percent shared their results with any health care professional and 50% with family and/or friends. Sub-analyses show that behaviour change was more prevalent among non-actual consumers, whereas sharing was more prevalent among actual consumers. Results on psychological responses showed that anxiety, distress and worry were low or absent and that the effect faded with time. DTC-GT has potential to be effective as a health intervention, but the right audience needs to be addressed with tailored follow-up. Research is needed to identify consumers who do and do not change behaviour or experience adverse psychological responses. PMID- 28664265 TI - [Networks involved in motor cognition : Physiology and pathophysiology of apraxia]. AB - Apraxia is an umbrella term for different disorders of higher motor abilities that are not explained by elementary sensorimotor deficits (e. g. paresis or ataxia). Characteristic features of apraxia that are easy to recognize in clinical practice are difficulties in pantomimed or actual use of tools as well as in imitation of meaningless gestures. Apraxia is bilateral, explaining the cognitive motor disorders and occurs frequently (but not exclusively) after left hemispheric lesions, as well as in neurodegenerative diseases, such as corticobasal syndrome and Alzheimer's disease. Apraxic deficits can seriously impair activities of daily living, which is why the appropriate diagnosis is of great relevance. At the functional anatomical level, different cognitive motor skills rely on at least partly different brain networks, namely, a ventral processing pathway for semantic components, such as tool-action associations, a ventro-dorsal pathway for sensorimotor representations of learnt motor acts, as well as a dorso-dorsal pathway for on-line motor control and, probably, imitation of meaningless gestures. While these networks partially overlap with language relevant regions, more clear cut dissociations are found between apraxia deficits and disorders of spatial attention. In addition to behavioral interventions, noninvasive neuromodulation approaches, as well as human-computer interface assistance systems are a growing focus of interest for the treatment of apraxia. PMID- 28664266 TI - Halophytes can salinize soil when competing with glycophytes, intensifying effects of sea level rise in coastal communities. AB - Sea level rise (SLR) and land-use change are working together to change coastal communities around the world. Along Florida's coast, SLR and large-scale drying are increasing groundwater salinity, resulting in halophytic (salt-tolerant) species colonizing glycophytic (salt-intolerant) communities. We hypothesized that halophytes can contribute to increased soil salinity as they move into glycophyte communities, making soils more saline than SLR or drying alone. We tested our hypothesis with a replacement-series greenhouse experiment with halophyte/glycophyte ratios of 0:4, 1:3, 2:2, 3:1, 4:0, mimicking halophyte movement into glycophyte communities. We subjected replicates to 0, 26, and 380/00 salinity for one, one, and three months, respectively, taking soil salinity and stomatal conductance measurements at the end of each treatment period. Our results showed that soil salinity increased as halophyte/glycophyte ratio increased. Either osmotic or ionic stress caused decreases in glycophyte biomass, resulting in less per-plant transpiration as compared to halophytes. At 380/00 groundwater, soil salinity increased as halophyte density increased, making conditions more conducive to further halophyte establishment. This study suggests that coastal plant community turnover may occur faster than would be predicted from SLR and anthropogenic disturbance alone. PMID- 28664267 TI - Transdermally administered proline-arginine-rich host defense peptides show systemic efficacy in a lethal mouse bacteremia model. AB - Host defense peptides are preferably administered as topical therapeutic agents. We have investigated whether peptide A3-APO can enter the circulation when applied to the ear skin. Efficacy of peptide monotherapy as transdermal administration option was assessed in a systemic mouse Acinetobacter baumannii model. A3-APO reduced mortality and demonstrated a statistically significant reduction of blood bacterial counts, regardless whether it was administered prior or after bacterial challenge. The peptidic metabolite of A3-APO was efficacious when applied to the ear or tail. PMID- 28664268 TI - Biased selection of propagation-related TUPs from phage display peptide libraries. AB - Phage display is rapidly advancing as a screening strategy in drug discovery and drug delivery. Phage-encoded combinatorial peptide libraries can be screened through the affinity selection procedure of biopanning to find pharmaceutically relevant cell-specific ligands. However, the unwanted enrichment of target unrelated peptides (TUPs) with no true affinity for the target presents an important barrier to the successful screening of phage display libraries. Propagation-related TUPs (Pr-TUPs) are an emerging but less-studied category of phage display-derived false-positive hits that are displayed on the surface of clones with faster propagation rates. Despite long regarded as an unbiased selection system, accumulating evidence suggests that biopanning may create biological bias toward selection of phage clones with certain displayed peptides. This bias can be dependent on or independent of the displayed sequence and may act as a major driving force for the isolation of fast-growing clones. Sequence dependent bias is reflected by censorship or over-representation of some amino acids in the displayed peptide and sequence-independent bias is derived from either point mutations or rare recombination events occurring in the phage genome. It is of utmost interest to clean biopanning data by identifying and removing Pr-TUPs. Experimental and bioinformatic approaches can be exploited for Pr-TUP discovery. With no doubt, obtaining deeper insight into how Pr-TUPs emerge during biopanning and how they could be detected provides a basis for using cell targeting peptides isolated from phage display screening in the development of disease-specific diagnostic and therapeutic platforms. PMID- 28664269 TI - Pro-apoptotic cationic host defense peptides rich in lysine or arginine to reverse drug resistance by disrupting tumor cell membrane. AB - Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (DeltaPsim) demonstrated that the peptides induced DeltaPsim dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy. PMID- 28664270 TI - Curcin C, a novel type I ribosome-inactivating protein from the post-germinating cotyledons of Jatropha curcas. AB - A novel type I ribosome-inactivating protein (RIP), designated as curcin C, was purified from Jatropha curcas, an important feedback source of bio-fuel. Molecular mass and isoelectric point of curcin C were 31.398 kDa and 7.12 as detected by MALTI-TOF assay and capillary electrophoresis assay, respectively. N terminal sequence and LC-MS/MS analyses confirmed that curcin C is a type I RIP having high homology, but not the exactly the same with curcin, another type 1 RIP isolated from the endosperm of J. curcas. It exhibited N-glycosidase activity and in vitro translation inhibition activity. Moreover, curcin C displayed a strong selectively anti-tumor activity on human cancer cells. Its cytotoxicity against osteosarcoma cell line U20S is even higher than that of Paclitaxel with IC50 of 0.019 MUM. Purification and identification of curcin C not only suggested its potential in natural anticancer drug development, but also provide chance to understanding different cytotoxic action among different RIPs. PMID- 28664271 TI - [Changes in the German Medicinal Product Act imposed by the EU regulation on clinical trials]. AB - The entry into force of Regulation (EU) No. 536/2014 of the European Parliament, the Council of 16 April 2014 for clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC necessitated amendments to the national legislation on medicinal products. These changes mainly concern the sixth chapter of the German Medicinal Products Act (Arzneimittelgesetz, AMG) and the elimination of the GCP (good clinical practice) ordinance for clinical trials that will be covered by the regulation in the future. Sections 41a, 41b and 41c, which came into force in December 2016, regulate the registration procedure, the procedural rules and the business distribution plan according to which the responsibilities of the registered ethics committees for the authorisation procedures will be determined and cooperation with the federal higher authorities will be handled. All other amendments in the sixth chapter will not enter into force until the date of application of the regulation - presumably in the fourth quarter of 2018. In the future, Section 40a will regulate the general prerequisites - in particular the basic procedures for cooperation between the federal higher authority and the ethics committees - in addition to the provisions of the regulation. Section 40b governs special prerequisites for clinical trials and contains, in particular provisions for the informed consent in clinical trials with minors and incapacitated adults. Further changes concern, among other things, the transfer of previous regulations of the GCP ordinance into the AMG and adjustments regarding reporting obligations in the context of clinical trials in the AMG. PMID- 28664272 TI - [Solidarity in health. Report on the 2017 Poverty and Health Congress]. AB - The annual congress Armut und Gesundheit (Poverty and Health), which is organized by Gesundheit Berlin-Brandenburg e. V. and takes place at the Technical University of Berlin has become one of the biggest public health events in Germany. It constitutes an exchange platform for sciences, practice, and politics. This year's congress topic was solidarity in health, aiming to emphasize the responsibility that society and its actors have to bear in order to warrant health equity. Overall, 121 activities took place, with more than 500 experts and moderators discussing a wide range of subjects and questions including regional disparities in poverty, ethics in public health, the current situation of homeless and people without insurance, time trends in health inequalities, health and healthcare of refugees and asylum seekers, and the current progress and challenges in connection with the German prevention act. PMID- 28664273 TI - [Migrant-sensitive health care strategies in orthopedic rehabilitation : A postal survey in North Rhine-Westphalia and Schleswig-Holstein]. AB - BACKGROUND: Migrants utilize rehabilitative care less frequently than the majority population in Germany. They also have less favorable treatment outcomes. Little is known about migrant-sensitive measures implemented by rehabilitation hospitals in order to provide a more patient-centered health care for this population group. OBJECTIVES: The aim of the present study was to examine which measures of migrant-sensitive health care are used by rehabilitation hospitals in North Rhine-Westphalia and Schleswig-Holstein and to identify potential barriers that may affect the implementation of such measures. MATERIALS AND METHODS: We surveyed the administrative and medical management of all 122 orthopedic rehabilitation hospitals in North Rhine-Westphalia and Schleswig-Holstein by means of a postal questionnaire. The questionnaire comprised, amongst others, questions on the implementation of migrant-sensitive measures in accommodation and health care provision. After one postal reminder, a total of 55 hospitals responded to the survey. RESULTS: Of the hospitals surveyed, 83.6% consider migrant-sensitive health care to be important or partially important. Only a few migrant-sensitive measures are employed by hospitals. Thirty percent of all hospitals do not use measures of migrant-sensitive health care at all. Perceived barriers preventing an implementation of these measures are limited financial resources (71.0%) as well as structural (32.7%) and organizational (38.2%) problems. CONCLUSIONS: Rehabilitation hospitals are willing to implement measures of migrant-sensitive health care. Structural and organizational support is necessary in order to overcome existing implementation barriers. In addition, measures need to be cost-effective. PMID- 28664274 TI - [Joint pilot project of the German higher federal authorities and ethics committees on implementing the EU Regulation on clinical trials]. AB - BACKGROUND: The European Clinical Trials Regulation 536/2014 and the corresponding national legal transitions will require close cooperation between the federal higher authorities and ethics committees in the assessment of clinical trial applications involving medicinal products in humans. In preparation for this, a pilot project was launched to simulate the future processes of the regulation in line with current legal requirements and in order to give applicants, authorities and ethics committees the opportunity to familiarise themselves with the new procedures. OBJECTIVES: The aim of this paper is to examine all pilot project procedures of the first year since starting the pilot project at the end of 2015. MATERIALS AND METHODS: All 20 pilot projects completed in the first year were analysed for adherence to deadlines and results of the assessments. RESULTS: Within the time limits specified in the EU regulation, 17 of 20 procedures were fully completed. In two cases, the sponsors slightly exceeded the additional delivery period. In one case, the sponsor withdrew the application within the pilot procedure. All 20 applications were processed jointly by the federal authorities and ethics committees, and in all cases a coordinated assessment report was successfully compiled on time. All 20 applications were approved, five of which were subject to suspensive conditions. CONCLUSIONS: Compliance with the deadlines set by federal authorities and ethics committee shows that the technical infrastructures and processes established in the pilot procedure are fully functional. The cooperation between the federal higher authorities and ethics committees was very successful from the perspective of the parties involved. PMID- 28664275 TI - Barriers to secondary fracture prevention in primary care. AB - : This study of current osteoporosis management patterns in general practice found that the majority of patients presenting to their local health practitioner with a recent low-trauma fracture was not managed appropriately. The analysis demonstrated that failure to investigate was highly predictive of failure to treat and that one of the major barriers to effective osteoporosis management is a lack of specific knowledge about who to investigate and treat. INTRODUCTION: Osteoporotic fractures are associated with significant morbidity and mortality. The current study aimed (i) to determine the number of patients with osteoporotic fractures who were not investigated or treated for osteoporosis by their primary care physician and (ii) to identify factors that contribute to the ongoing gap in osteoporosis care. METHODS: We conducted an observational retrospective study (2012-2014) using explicit medical record review at three major general practices in metropolitan Sydney. Patients aged 55 years or older who had a documented minimal trauma fracture (MTF) were identified. Data collected included demographics, prior fractures, testing for vitamin D/bone mineral density and initiation of osteoporosis pharmacotherapy. The main outcome measures included the number of patients who did not undergo the following: (i) a bone density scan, (ii) vitamin D measurement and/or (iii) initiation of osteoporosis pharmacotherapy. RESULTS: Of the 87 patients (69% female; mean age 71.7 years) with prevalent MTF, 55 (63%) were not referred for a bone density scan. Vitamin D levels were not measured in 36 patients (41%) and 55 patients (63%) did not receive specific osteoporosis pharmacotherapy. Failure to investigate was highly predictive of failure to treat (p < 0.001). The presence of major osteoporotic risk factors did not affect the likelihood of investigation or treatment, indicating that a major barrier to effective osteoporosis management was a lack of knowledge. CONCLUSION: Management of patients with MTF's in primary care is poor. Systems aimed at improving the identification and treatment of patients with osteoporotic fractures in this setting is required in order to close the osteoporosis care gap. PMID- 28664277 TI - A congenital external carotid artery-external jugular vein arteriovenous fistula was successfully treated by coil embolization (case report and literature review). AB - OBJECT: Congenital arteriovenous fistula involving the external carotid system is rare. METHODS: This paper reports a case of congenital external carotid artery external jugular vein arteriovenous fistula admitted to Xuanwu Hospital, and reviews the literature. RESULTS: The patient was a boy, 9 years old, with a history of pulsatile mass and thrill in the right neck since his birth. External carotid artery-external jugular vein fistula was confirmed by the digital subtraction angio-graphy. And coil embolization was done later. Postoperative immediate angiography confirmed the complete occlusion of the fistula, and partial branch of the external carotid artery can be seen. The abnormal clinical manifestation disappeared after the procedure without any complications. CONCLUSION: This case and relevant literatures remind us that congenital external carotid artery-external jugular vein arteriovenous fistula has its unique features, and it can be treated by coil embolization safely and effectively. PMID- 28664276 TI - Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users. AB - : Osteonecrosis of the jaw (ONJ) is rare (2.53/10,000 person-years) among alendronate users, but long-term and compliant use are associated with an increased risk of surgically treated ONJ. Risk of surgically treated ONJ is higher in patients with rheumatoid diseases and use of proton pump inhibitors. INTRODUCTION: ONJ is a rare event in users of oral bisphosphonates. Our aims were to evaluate if the risk of surgically treated ONJ increases with longer or more compliant treatment with alendronate for osteoporosis and to identify risk factors for surgically treated ONJ. METHODS: Open nationwide register-based cohort study containing one nested case-control study. Patients were treatment naive incident users of alendronate 1996-2007 in Denmark, both genders, aged 50 94 at the time of beginning treatment (N = 61,990). Participants were followed to 31 December 2013. RESULTS: Over a mean of 6.8 years, 107 patients received surgery for ONJ or related conditions corresponding to an incidence rate of 2.53 (95% confidence interval (CI) 2.08 to 3.05) per 10,000 patient years. Recent use was associated with an adjusted odds ratio (OR) 4.13 (95% CI 1.94 to 8.79) compared to past use. Similarly, adherent users (medication possession ratio (MPR) >50%) were at two to threefold increased risk of ONJ compared to low adherence (MPR <50%), and long-term (>5 years) use was related with higher risk (adjusted OR 2.31 (95% CI (1.14 to 4.67)) than shorter-term use. History of rheumatoid disorders and use of proton pump inhibitors were independently associated with surgically treated ONJ. CONCLUSIONS: Our data suggest that recent, long-term, and compliant uses of alendronate are associated with an increased risk of surgically treated ONJ. Nevertheless, the rates remain low, even in long-term adherent users. ONJ risk appears higher in patients with conditions likely to indirectly affect the oral mucosa. PMID- 28664279 TI - Delayed diffuse cerebellar swelling after resection of medulloblastoma: case report and review of literature. AB - INTRODUCTION: Delayed diffuse cerebellar swelling is a rare life-threatening complication following medulloblastoma resection. PRESENTATION: We present our experience of managing a 4-year-old who developed diffuse cerebellar swelling with upward herniation 41 days after resection of a large cell anaplastic medulloblastoma. CONCLUSION: Emergency chemotherapy alone was sufficient in promoting regression of swelling and recovery from coma. Reports of similar cases are scant. Chemotherapy may be a critical component of treatment. PMID- 28664278 TI - The significance of polymorphisms in genes encoding Il-1beta, Il-6, TNFalpha, and Il-1RN in the pathogenesis of intraventricular hemorrhage in preterm infants. AB - INTRODUCTION: Intraventricular hemorrhage (IVH) is a significant morbidity seen in very low birth weight infants. Genes related to inflammation may be risk factors for IVH. MATERIAL AND METHODS: We examined five polymorphisms for an association with IVH in 100 preterm infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroid therapy, and without congenital abnormalities. These polymorphisms include interleukin-1beta 3953 C>T, interleukin-6 -174G>C and -596G>A, tumor necrosis factor -308 G>A, and 86 bp variable number tandem repeat polymorphism of interleukin-1 receptor antagonist (Il -1RN 86 bp VNTR). RESULTS: In our study population, 45 (45%) infants developed IVH, including 15 (33.33%) with stage 1, 19 (42.22%) with stage 2, 8 (17.77%) with stage 3, and 3 (6.66%) with stage 4. In contrast to the previously published data, the prevalence of IVH did not vary between infants with different IL-6 and TNFalpha alleles and genotypes. Our novel investigations in Il-1 +3953 C>T and Il-1RN 86 bp VNTR polymorphism did not show any significant link between those alleles or genotypes and IVH. CONCLUSIONS: IVH is a significant problem for preterm infants. In addition to little progress in preventing IVH in preterm babies, substantial research that are focused on understanding the etiology, mechanism and risk factors for IVH are imperative. In the era of personalized medicine, identification of genetic risk factors creates opportunities to generate preventative strategies. Further studies should be performed to confirm the role of genetic factors in etiology and pathogenesis of IVH. PMID- 28664281 TI - [Psoriatic arthritis : Current therapeutic standards]. AB - Psoriatic arthritis (PsA) is a heterogeneous immune-mediated disease that usually involves the skin and joints but can also affect the entheses, spine and other extra-articular structures. Furthermore, it can be coupled with associated comorbidities. The selection of a patient-oriented and effective therapy is based on the extent of various manifestations of the disease as well as further influencing factors. Various recommendations for selection and control are available for deciding on a suitable treatment. The recommendations of the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are most frequently used and are internationally acknowledged. Both recommendations were updated in 2016. German treatment recommendations are currently lacking. In analogy to the treat to-target strategy in the treatment of rheumatoid arthritis, minimal disease activity should at least be achieved with the therapeutic intervention used if remission as the therapeutic target cannot be reached. New treatment options, which target different molecules, provide possibilities for a more differentiated therapy for improvement in the treatment of PsA patients. PMID- 28664282 TI - [Current standards and new developments in psoriatic arthritis]. PMID- 28664280 TI - Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal. AB - RATIONALE: Endogenous gamma-aminobutyric acidA receptor (GABAAR)-active neurosteroids (e.g., allopregnanolone) regulate central nervous system excitability and many physiological functions, so fluctuations are implicated in several neuropsychiatric disorders. Pertinently, evidence supports an inverse relationship between endogenous GABAAR-active neurosteroid levels and behavioral changes in excitability during ethanol withdrawal (WD). OBJECTIVES: The present studies determined mouse genotype differences in ten neurosteroid levels in plasma, cortex, and hippocampus over the time course of ethanol WD in the WD Seizure-Prone (WSP) and WD Seizure-Resistant (WSR) selected lines and in the DBA/2J (DBA) inbred strain. METHODS: Gas chromatography-mass spectrometry was utilized to simultaneously quantify neurosteroid levels from control-treated male WSP-1, WSR-1, and DBA mice and during 8 and 48 h of WD. RESULTS: Combined with our prior work, there was a consistent decrease in plasma allopregnanolone levels at 8 h WD in all three genotypes, an effect that persisted at 48 h WD only in DBA mice. WSR-1 and WSP-1 mice exhibited unexpected divergent changes in cortical neurosteroids at 8 h WD, with the majority of neurosteroids (including allopregnanolone) being significantly decreased in WSR-1 mice, but unaffected or significantly increased in WSP-1 mice. In DBA mice, hippocampal allopregnanolone and tetrahydrodeoxycorticosterone were significantly decreased at 8 h WD. The pattern of significant correlations between allopregnanolone and other GABAAR active neurosteroid levels differed between controls and withdrawing mice. CONCLUSIONS: Ethanol WD dysregulated neurosteroid synthesis. Results in WSP-1 mice suggest that diminished GABAAR function is more important for their high WD phenotype than fluctuations in neurosteroid levels. PMID- 28664283 TI - [Positron emission tomography/computed tomography in rheumatology]. AB - Combined positron emission tomography/computed tomography (PET/CT) is a whole body imaging procedure, which enables sensitive detection of inflammatory changes. It may be used to simultaneously obtain both precise anatomical and molecular information in order to comprehensively characterize diseases. The glucose analogue 18F-fluorodeoxyglucose (FDG) represents a universally applicable radiotracer for imaging of inflammatory processes. Its accumulation in tissues can be semiquantitatively characterized by use of standardized uptake values (SUV). In principle, a broad spectrum of infectious and non-infectious inflammatory and malignant diseases can be imaged. 18F-FDG PET/CT has become a valuable modality and is increasingly being used for evaluation of large vessel vasculitis and for evaluation of elevated systemic inflammatory markers without known cause. Beside the radiotracer 18F-FDG, other radiopharmaceuticals enable a non-invasive analysis of additional parameters of inflammatory disorders, such as other metabolic pathways or the expression of surface receptors. PMID- 28664284 TI - [Differential diagnostic spectrum of psoriasis vs. psoriatic arthritis in skin and joints]. AB - Psoriasis and psoriatic arthritis are common disease entities in the daily routine of dermatologists and rheumatologists. The clinical management of the diseases profits tremendously from interdisciplinary contacts and shared decision making processes. For dermatologists, recognition of early clinical symptoms of inflammatory arthropathies is pivotal. Rheumatologists, on the other hand, are required to make an early assessment of skin and nail changes in patients, since they are important parameters in the clinical classification of inflammatory joint diseases, in particular for the diagnosis of psoriatic arthritis. In patients with psoriasis, lesions on the scalp, in the anal cleft, and nail changes as well as severe generalized skin disease are all regarded as risk factors for psoriatic arthritis. The symptoms of the associated joint and spinal afflictions can vary considerably and confirmation of the diagnosis, in particular in early stages of the disease often represents a considerable challenge. The most common clinical manifestations of psoriasis and psoriatic arthritis and their differential diagnostics are discussed. PMID- 28664285 TI - [Psoriasis vs. psoriatic arthritis : Similarities and differences in the pathophysiology]. AB - Psoriasis is a chronic inflammatory skin disease with genetic and (auto)immunological backgrounds. Up to 30% of patients with psoriasis also develop a mostly oligoarticular arthritis with spinal involvement that is termed psoriatic arthritis (PsA) and shows a specific joint pattern which differs from that of rheumatoid arthritis (RA). Both Psa and psoriasis share a common main axis, the interleukin (IL) 23/IL17 pathway as well as major overlaps in the functions of tumor necrosis factor alpha (TNFalpha). Recently acquired knowledge supports the concept that in both diseases, similar genetic dispositions and molecular pathways lead to organ-specific disease patterns. In some types of PsA, genetic predisposition and the relevance of acute inflammatory reactions appear to be greater that in psoriasis, while in the latter exogenous factors and T lymphocyte reactions in the skin seem to have a higher impact. A key difference between PsA and cutaneous psoriasis is the largely irreversible nature of inflammatory joint changes in PsA, whereas cutaneous plaques in psoriasis completely heal. The question of how interdependent both diseases are and whether immunologically primed T-lymphocytes from cutaneous lesions in PsA may transmit the disease to the synovial membranes and induce acute inflammation is not precisely known. A detailed analysis of these organ-specific differences may not only provide an explanation for the similar, but partly different efficacy of novel therapeutic strategies but may also lead to the development of personalized therapies that take into account the individually different manifestations of the diseases over time. PMID- 28664286 TI - Direct measurement of interaction forces between a platinum dichloride complex and DNA molecules. AB - The interaction forces between a platinum dichloride complex and DNA molecules have been studied using atomic force microscopy (AFM). The platinum dichloride complex, di-dimethylsulfoxide-dichloroplatinum (II) (Pt(DMSO)2Cl2), was immobilized on an AFM probe by coordinating the platinum to two amino groups to form a complex similar to Pt(en)Cl2, which is structurally similar to cisplatin. The retraction forces were measured between the platinum complex and DNA molecules immobilized on mica plates using force curve measurements. The histogram of the retraction force for lambda-DNA showed several peaks; the unit retraction force was estimated to be 130 pN for a pulling rate of 60 nm/s. The retraction forces were also measured separately for four single-base DNA oligomers (adenine, guanine, thymine, and cytosine). Retraction forces were frequently observed in the force curves for the DNA oligomers of guanine and adenine. For the guanine DNA oligomer, the most frequent retraction force was slightly lower than but very similar to the retraction force for lambda-DNA. A higher retraction force was obtained for the adenine DNA oligomer than for the guanine oligomer. This result is consistent with a higher retraction activation energy of adenine with the Pt complex being than that of guanine because the kinetic rate constant for retraction correlates to exp(FDeltax - DeltaE) where DeltaE is an activation energy, F is an applied force, and Deltax is a displacement of distance. PMID- 28664287 TI - [Musculoskeletal factors, sarcopenia and falls in old age]. AB - Falls in older adults are a major public health problem with a high incidence and severe consequences for the older individual. The age-related loss of muscle strength as well as muscle mass and muscle function (sarcopenia) are i) risk factors for falling, ii) associated with physical function and iii) markers of the frailty syndrome. Muscle function appears to play a bigger role than muscle mass. The operationalization of sarcopenia using the European Working Group on Sarcopenia in Older People (EWGSOP) algorithm is consistently associated with falling events. Structured physical exercise plays the key role in the prevention of falls and the management of functional decline caused by sarcopenia and frailty. The combined supplementation with proteins and vitamin D supports muscle protein synthesis in undersupplied persons and improves aspects of physical function. PMID- 28664288 TI - [Gerontological policy advice : Possibilities and limits of scientific counseling]. AB - In the first part of this article a comprehensive understanding of political advice is explicated. In this context reference is made to the value judgement dispute in German sociology and a differentiation between an enlightening and a critical function of scientific policy advice. Development of social scientific policy advice is considered against the background of the distinction between technocratic, decisionistic and pragmatic models of counseling. In the second part of the article, the committee of inquiry on demographic change, the national reports on aging and the reviews on the development of the healthcare system are considered as practical examples of policy advice. PMID- 28664289 TI - Countermeasures to survive excessive chromosome replication in Escherichia coli. AB - In Escherichia coli, like all organisms, DNA replication is coordinated with cell cycle progression to ensure duplication of the genome prior to cell division. Chromosome replication is initiated from the replication origin, oriC, by the DnaA protein associated with ATP. Initiations take place once per cell cycle and in synchrony at all cellular origins. DnaA also binds ADP with similar affinity as ATP and in wild-type cells the majority of DnaA molecules are ADP bound. In cells where the DnaAATP/DnaAADP ratio increases or in cells where DnaAATP has increased access to oriC, premature initiations take place, often referred to as overinitiation. Overinitiating cells are generally characterized by their slow growth and in the most severe cases lethal accumulation of DNA strand breaks. Here, we review the different strategies adopted by E. coli to survive overinitiation. We propose a unifying model where all mutations that suppress overinitiation keep replication forks separated in time and, thereby, reduce the formation of strand breaks. One group of mutations does so by lowering the activity of oriC and/or DnaA to reduce the frequency of initiations to an acceptable level. In the other group of mutations, replication forks are kept apart by preventing formation of damages that would otherwise cause replication blocks, by allowing bypass of replication blocks and/or by slowing down replication forks. This group of suppressors restores viability despite excessive chromosome replication and provides new insights into mechanisms that safeguard DNA integrity. PMID- 28664290 TI - Suicide in adolescents: findings from the Swiss National cohort. AB - Suicide in adolescents is the second most common cause of death in this age group and an important public health problem. We examined sociodemographic factors associated with suicide in Swiss adolescents and analysed time trends in youth suicide in the Swiss National Cohort (SNC). The SNC is a longitudinal study of the whole Swiss resident population, based on linkage of census and mortality records. We identified suicides in adolescents aged 10-18 years from 1991 to 2013. A total of 2.396 million adolescents were included and 592 suicides were recorded, corresponding to a rate of 3.7 per 100,000 [95% confidence interval (CI) 3.4-4.0]. Rates increased with age from 0.0 per 100,000 at age 10 years to 14.8 per 100,000 (95% CI 12.6-17.5) at 18 years in boys, and from 0.0 to 5.4 per 100,000 (4.1-7.2) in girls. Being a boy, living in a single parent household, being an only or middle-born child, and living in rural regions were factors associated with a higher rate of suicide. Hanging was the most common method in boys, and railway suicides were most frequent in girls. There was no clear evidence for an increase or decrease over calendar time. We conclude that familial and socioeconomic factors including type of household, birth order and urbanity are associated with youth suicide in Switzerland. These factors should be considered when designing prevention programmes for youth suicide. PMID- 28664291 TI - Histological study of the gastrointestinal tract in longfin yellowtail (Seriola rivoliana) larvae. AB - This work contributes basic knowledge on larval development of Seriola rivoliana. A histological study describes the development of the digestive tract and accessory glands in S. rivoliana larvae reared under laboratory conditions at 24 degrees C from hatching to 30 days post-hatching (DPH). At hatching (2.6 +/- 0.12 mm), larvae had an undifferentiated digestive tract with a closed straight tube and a large yolk sac with an oil globule. The liver and pancreas were observed at 1 and 2 days, and the mouth and anus opened at day 2. Enriched rotifers were visible in their digestive tract. At the beginning of the pre-flexion stage, a mixed nutritional period was observed. At day 3, exogenous feeding began; the digestive tract became differentiated into the buccopharynx, esophagus, an undifferentiated stomach, and the intestines. Zymogen granules were visible in the exocrine pancreas. At day 4, supranuclear vacuoles were present in the posterior intestine, indicating the beginning of intracellular digestion. At day 5, goblet cells were present in the esophagus and became functional at day 7 in the esophagus and intestine. The buccopharynx goblet cells developed at day 15. The presence of gastric glands and differentiation of the stomach in the fundic, cardiac, and pyloric regions during the post-flexion stage occurred at day 20. This was the onset of the juvenile period and the beginning of weaning; however, a long co-feeding phase is recommended. Pyloric caeca were observed at day 30 (13.6 +/- 1.6 mm). These results provide valuable information on S. rivoliana larvae biology and digestive physiology, which should be useful to improve cultivation techniques and identify ecological features involved in ontogeny. PMID- 28664292 TI - Uric acid is independent cardiovascular risk factor, as manifested by increased carotid intima-media thickness in rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is associated with increased cardiovascular disease (CVD) mortality and morbidity, due to the combined effects of traditional and non traditional cardiovascular risk factors (CV). A serum uric acid (SUA) level has been suggested as one of the non-traditional cardiovascular risk factors. Cardiovascular risk can be assessed by looking at the subclinical atherosclerosis such as ultrasound (US)-measured carotid intima-media thickness (cIMT). This paper aimed to determine the role of SUA as a cardiovascular risk factor, along with the traditional cardiovascular risk factors and inflammation, among RA population. RA patients with no clinically evident CV or renal disease were studied. cIMT US, SUA, traditional cardiovascular, and inflammatory markers were obtained and correlated with cIMT. Among 53 RA patients (5 males, 48 females, mean age 48 +/- 14 years), univariate linear-regression showed a positive linear relationship between cIMT and age (p < 0.001), age at RA symptoms onset and diagnosis (p = 0.010 and 0.003, respectively), number of cigarettes/day (p < 0.001), systolic and diastolic blood pressure (p = 0.005 and 0.030, respectively), and SUA (p = 0.007). Rheumatoid factor positivity and level were associated with thicker cIMT (p = 0.042 and 0.039, respectively). SUA maintained a significant correlation with cIMT in the multivariate analysis together with age, low-density lipoprotein, and triglyceride level. The model explained 55% (R2 55) of the causes of thick cIMT among RA population. SUA seems to be a cardiovascular risk factor in RA, as manifested by increase in the cIMT. PMID- 28664293 TI - Targeting autophagy to modulate cell survival: a comparative analysis in cancer, normal and embryonic cells. AB - Autophagy is linked to multiple cancer-related signaling pathways, and represents a defense mechanism for cancer cells under therapeutic stress. The crosstalk between apoptosis and autophagy is essential for both tumorigenesis and embryonic development. We studied the influence of autophagy on cell survival in pro apoptotic conditions induced by anticancer drugs in three model systems: human cancer cells (NCI-H460, COR-L23 and U87), human normal cells (HaCaT and MRC-5) and zebrafish embryos (Danio rerio). Autophagy induction with AZD2014 and tamoxifen antagonized the pro-apoptotic effect of chemotherapeutics doxorubicin and cisplatin in cell lines, while autophagy inhibition by wortmannin and chloroquine synergized the action of both anticancer agents. This effect was further verified by assessing cleaved caspase-3 and PARP-1 levels. Autophagy inhibitors significantly increased both apoptotic markers when applied in combination with doxorubicin while autophagy inducers had the opposite effect. In a similar manner, autophagy induction in zebrafish embryos prevented cisplatin induced apoptosis in the tail region while autophagy inhibition increased cell death in the tail and retina of cisplatin-treated animals. Autophagy modulation with direct inhibitors of the PI3kinase/Akt/mTOR pathway (AZD2014 and wortmannin) triggered the cellular response to anticancer drugs more effectively in NCI-H460 and zebrafish embryonic models compared to HaCaT suggesting that these modulators are selective towards rapidly proliferating cells. Therefore, evaluating the autophagic properties of chemotherapeutics could help determine more accurately the fate of different cell types under treatment. Our study underlines the importance of testing autophagic activity of potential anticancer agents in a comparative approach to develop more rational anticancer therapeutic strategies. PMID- 28664294 TI - Rare causes of early-onset dystonia-parkinsonism with cognitive impairment: a de novo PSEN-1 mutation. AB - Mutations in PSEN1 are responsible for familial Alzheimer's disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto temporal atrophy. Whole exome sequencing revealed a novel PSEN1 mutation and segregation within the family demonstrated the mutation arose de novo.We suggest considering PSEN1 mutations in cases of dystonia-parkinsonism with positive DAT Scan, later complicated by progressive cognitive decline and cortical myoclonus even without a dominant family history. PMID- 28664295 TI - Complete genome sequence of a Capsicum chlorosis virus in China and the structural variation and evolutionary origin of its S RNA intergenic region. AB - The complete genome sequence of a Capsicum chlorosis virus from China (CaCV Hainan) was determined. The tripartite genome of CaCV-Hainan consists of small (S), medium (M), and large (L) RNAs of 3629, 4859, and 8912 nucleotides (nt), respectively. The S and M RNAs contain intergenic regions (IGRs) of 1348 and 462 nt, respectively. Strikingly, sequence comparisons among CaCV isolates revealed that the S RNA IGR of CaCV-Hainan derived from the CaCV-Qld-3432 Australia isolate through deletion of two stretches of 25- and 325-nt sequences within the S RNA IGR of CaCV-Qld-3432. Moreover, the S RNA IGR of CaCV-Hainan was inserted with two stretches of 10- and 20-nt sequences of an unknown origin. The S RNA IGR of CaCV-Ph from Taiwan and CaCV-NRA from Thailand also derived from the CaCV-Qld 3432 through deletion of 218-nt sequences. Our findings provide valuable new insight into the structural variations and evolutionary origin of CaCV IGRs. PMID- 28664296 TI - Rapid virulence shift of an H5N2 avian influenza virus during a single passage in mice. AB - Influenza A viruses must undergo adaptation to acquire virulence in new host species. In mouse models, host adaptation for virulence is generally performed through 5 to 20 lung-to-lung passages. However, highly pathogenic avian influenza viruses (e.g., H5N1 and H7N7 subtypes) have been observed to acquire virulence in mice after only a few in vivo passages. In this study, a low-pathogenic avian influenza H5N2 virus, A/Aquatic Bird/Korea/CN2/2009, which was a prevalent subtype in South Korea in 2009, was serially passaged in mice to evaluate its potential to become highly pathogenic. Unexpectedly, the virus became highly pathogenic in mice after a single lung-to-lung passage, resulting in 100% lethality with a mean death time (MDT) of 6.1 days postinfection (DPI). Moreover, the pathogenicity gradually increased after subsequent in vivo passages with an MDT of 5.2 and 4.2 DPI after the second and third passage, respectively. Our molecular analysis revealed that two amino acid changes in the polymerase complex (a glutamate-to-lysine substitution at position 627 of PB2 and a threonine-to isoleucine substitution at position 97 of PA) were associated with the increased pathogenicity; the PB2 E627K mutation was responsible for the initial virulence conversion (0 to 100% lethality), while the PA T97I mutation acted as an accessory for the increased virulence. PMID- 28664297 TI - Navigating the Paradoxes of Neoliberalism: Quiet Subversion in Mentored Service Learning for the Pre-Health Humanities. AB - In describing the foundations of our pedagogical approaches to service-learning, we seek to go beyond the navel-gazing-at times, paralyzing-paradoxes of neoliberal forces, which can do "good" for students and their communities, yet which also call students into further calculative frameworks for understanding the "value" of pre-health humanities education and social engagement. We discuss methods to create quiet forms of subversion that call for a moral imagination in extending an ethics of care to students as well as to the communities with which they engage. While we recognize the partiality and limitations of our attempts, framing mentored service-learning in unexpected ways can help students and practitioners to understand their role within broader social, historical, cultural, and emotional contexts and encourage them to act intentionally toward the communities they seek to serve in response to this new self-knowledge. To that end, we outline an academically rigorous service-learning intervention at one of our universities. PMID- 28664298 TI - One-hour and two-hour postload plasma glucose concentrations are comparable predictors of type 2 diabetes mellitus in Southwestern Native Americans. AB - AIMS/HYPOTHESIS: Elevated 2-h plasma glucose concentration (2 h-PG) during a 75 g OGTT predict the development of type 2 diabetes mellitus. However, 1-h plasma glucose concentration (1 h-PG) is associated with insulin secretion and may be a better predictor of type 2 diabetes. We aimed to investigate the association between 1 h-PG and 2 h-PG using gold standard methods for measuring insulin secretion and action. We also compared 1 h-PG and 2 h-PG as predictors of type 2 diabetes mellitus. METHODS: This analysis included adult volunteers without diabetes, predominantly Native Americans of Southwestern heritage, who were involved in a longitudinal epidemiological study from 1965 to 2007, with a baseline OGTT that included measurement of 1 h-PG. Group 1 (n = 716) underwent an IVGTT and hyperinsulinaemic-euglycaemic clamp for measurement of acute insulin response (AIR) and insulin-stimulated glucose disposal (M), respectively. Some members of Group 1 (n = 490 of 716) and members of a second, larger, group (Group 2; n = 1946) were followed-up to assess the development of type 2 diabetes (median 9.0 and 12.8 years follow-up, respectively). RESULTS: Compared with 2 h PG (r = -0.281), 1 h-PG (r = -0.384) was more closely associated with AIR, whereas, compared with 1 h-PG (r = -0.340), 2 h-PG (r = -0.408) was more closely associated with M. Measures of 1 h-PG and 2 h-PG had similar abilities to predict type 2 diabetes, which did not change when both were included in the model. A 1 h PG cut-off of 9.3 mmol/l provided similar levels of sensitivity and specificity as a 2 h-PG cut-off of 7.8 mmol/l; the latter is used to define impaired glucose tolerance, a recognised predictor of type 2 diabetes mellitus. CONCLUSIONS/INTERPRETATION: The 1 h-PG was associated with important physiological predictors of type 2 diabetes and was as effective as 2 h-PG for predicting type 2 diabetes mellitus. The 1 h-PG is, therefore, an alternative method of identifying individuals with an elevated risk of type 2 diabetes mellitus. PMID- 28664299 TI - Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics. AB - Disrupted-in-schizophrenia 1 (DISC1) was initially identified as a gene disrupted by a translocation mutation co-segregating with a variety of psychotic and mood disorders in a Scottish pedigree. In agreement with this original finding, mouse models that perturb Disc1 display deficits of behaviors in specific dimensions, such as cognition and emotion, but not a motor dimension. Although DISC1 is not a risk gene for sporadic cases of specific psychiatric disorders defined by categorical diagnostic criteria (e.g., schizophrenia and major depressive disorder), DISC1 is now regarded as an important molecular lead to decipher molecular pathology for specific dimensions relevant to major mental illnesses. Emerging evidence points to the role of DISC1 in the regulation of intracellular trafficking of a wide range of neuronal cargoes. We will review recent progress in this aspect of DISC1 biology and discuss how we could utilize this body of knowledge to better understand the pathophysiology of mental illnesses. PMID- 28664300 TI - Brachytherapy in the treatment of breast cancer. AB - Brachytherapy is an important radio-therapeutic modality for a variety of malignancies, including prostate cancer, cervix cancer, breast cancer, vagina cancer, endometrium cancer, head and neck cancer, and many more. This technique has been shown to be an effective and safe non-pharmaceutical treatment with fewer serious complications and better outcome than other treatments for breast cancer. Every year, hundreds of thousands of patients around the world benefit from brachytherapy, which reliably delivers a relatively higher radiation dose to the intended target. However, the follow-up time, patient eligibility criteria, treatment strategy, and radiation doses used in published studies are somewhat inconsistent, making it difficult to strictly compare and evaluate the performance of the treatment. More rigorous studies are required to confirm the safety of this technique and to make outcome data more comparable. In this review, we focus on recent advances in breast brachytherapy techniques and provide an overview of outcomes, cosmetic outcome, toxicity, complications, and limitations of brachytherapy for the treatment of breast cancer. We also summarize the clinical outcomes and toxicity results in patients receiving or not receiving brachytherapy. PMID- 28664301 TI - Association of decreased mean platelet volume with renal cell carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC) is the third most common genitourinary cancer. Activated platelets play a pivotal role in cancer development and progression. Altered mean platelet volume (MPV) has been reported in several malignancies. The aim of the present study was to investigate the association of MPV with RCC. STUDY DESIGN: The study consisted of 145 patients with RCC, 110 patients with benign renal tumor and 132 healthy control subjects between January 2015 and December 2015. All participants' clinical and laboratory characteristics at initial diagnosis were collected. The odds ratios (ORs) for RCC were calculated using multivariate logistic regression analysis after adjusting for confounding variables across MPV quartiles. RESULTS: The patients with RCC had decreased pre-operative MPV compared to the patients with benign renal tumor and healthy control subjects. Furthermore, pre-operative MPV was reduced in benign renal tumor compared with healthy control subjects. Surgical tumor resection resulted in a significant increase in MPV levels (8.7 fL vs. 9.0 fL; p = 0.011). After adjusting for other risk factors, the ORs (95% CIs) for RCC in each MPV quartile were 25.725 (7.556-87.585), 7.447 (2.701-20.537), 0.703 (0.245-2.019), and 1.000, respectively. CONCLUSIONS: RCC patients have remarkably reduced MPV compared to patients with benign renal tumor and healthy control subjects. Moreover, decreased MPV was independently associated with RCC. Our results suggest that detection of MPV may be useful to assess the risk of RCC. PMID- 28664302 TI - Response to: Comment to "The Characteristics and Short-Term Surgical Outcomes of Adolescent Gynecomastia". PMID- 28664303 TI - Axillary Advancement Suture to Minimize Post-Implantation Deformity in Implant: Based Breast Reconstruction. PMID- 28664304 TI - Comment on: "Surgical Masculinization of the Breast: Clinical Classification and Surgical Procedures". PMID- 28664305 TI - Re: "The Role of Lipofilling After Breast Reconstruction: Evaluation of Outcomes and Patient Satisfaction with BREAST-Q". PMID- 28664306 TI - Axillary Advancement Suture to Minimize Post-Implantation Deformity in Implant Based Breast Reconstruction. AB - Patients who have undergone implant-based breast reconstruction after skin sparing mastectomy often complain about bulging on the upper flank or inferior axillary area. This is most likely because the subcutaneous tissue layer of the upper flank, which is continuous with the breast tissue, tends to show inferolateral drooping once the subcutaneous tissue becomes loose after eliminating the breast parenchyma. In addition, one of the weaknesses of implant surgery is that implants cannot completely replace the tissue removed during skin sparing mastectomy (SSM). This leads to the formation of a depression and a stepping effect superior and lateral to the implant on both sides. Notably, because the pectoralis major muscle is quite thin, when there is a depression around the superolateral area of the implant, it acts as a band, which then leads to tissue bulging and serious aesthetic problems. Here, we describe a simple advancement suture technique that can be used to resolve these two aesthetic problems in direct-to-implant breast reconstruction. The advancement sutures are performed after the implant and drains are inserted following SSM and before closing the incision. First, the surgeon confirms the depression in the superolateral area of the implant insertion site by redraping a skin flap lateral to the margin. If a depression is suspected, the surgeon uses forceps to pull the subcutaneous tissue in the lateral flank pocket over to the lateral border of the pectoralis major muscle, superolateral to the implant. At this point, correction of the lateral flank bulging and depression on the superolateral border is verified. If the result is not satisfactory, the surgeon may attempt advancing the subcutaneous fat from different areas; the more posterior the tissue is advanced, the better it eliminates the lateral bulging and superolateral depression. However, too much advancement may cause extra tension, potentially resulting in tearing of the tissue. A round needle is used to suture two to three stitches, before completing wound closure. By performing this simple advancement suture, we were able to successfully minimize post-implantation deformity-bulging on the lateral flank and depression at the superolateral implant margin. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28664307 TI - Lymphocele Following Liposuction in the Thigh. AB - : Lymphocele has not been reported as a complication after liposuction. In this study, we present the case of a patient who developed a cystic lesion after liposuction in her right thigh. The cyst could contract and evolve. The diagnosis of pseudobursa seroma (late seroma) was first considered. However, lymphoscintigraphy showed that lymphatic fluid accumulated in the cyst, and lymphatic vessel connected with it. The final diagnose was a lymphocele. After interventional therapy and conservative treatment failed, the lymphocele was resected. The subcutaneous soft tissue around the cyst was divided into bundles and then ligated with the purpose of blocking lymph leakage from the lymphatic duct. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28664308 TI - A cell clone strain from Mythimna separata (Lepidoptera: Noctuidae) highly susceptible to Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and M. separata NPV (MsNPV). AB - In this study, we describe a cell line, Ms-10C, cloned from the line QAU-Ms-E-10 (simplified Ms-10), an embryonic line from Mythimna separata. The cloned cell line was significantly more sensitive to nucleopolyhedrovirus (NPV). Ms-10C cells were mainly spherical with a diameter of 14.42 +/- 2.23 MUm. DNA amplification fingerprinting (DAF) confirmed the profile of PCR-amplified bands of the cloned cell line was consistent with those of the parental cell line, Ms-10. The sequencing result of the mitochondrial cytochrome c oxidase I (mtCO I) fragment confirmed that the amplified 636-bps mtCOI fragment was 100% identical to that of M. separata. Its chromosomes exhibited the typical characters of lepidopteran cell lines. Its population doubling time was 42.2 h at 27 degrees C. Ms-10C was more sensitive than Ms-10 to both Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and M. separata nucleopolyhedrovirus (MsNPV). At 4 d post infection, the infection rates of two viruses reached 94.2 and 92.3%, respectively. The availability of this cell clone strain will provide a useful tool for the basic research on nucleopolyhedrovirus and for potential application in expression of recombinant proteins with baculovirus expression vector system. PMID- 28664309 TI - Management of gastric neuro-endocrine tumours in a large French national cohort (GTE). AB - INTRODUCTION: Gastric neuro-endocrine tumours are rare. European guidelines for the management of neuro-endocrine tumours have been published in 2012. The aim of our survey was to study the management of gastric neuro-endocrine tumours registered in the national cohort. A prospective national cohort registers the Neuro-endocrine tumours in France since January 2003 (GTE network). We reviewed all the individual medical reports of gastric neuro-endocrine tumours in order to collect data on treatment. RESULTS: One hundred and ninety seven gastric neuro endocrine tumours diagnosed between 1964 and 2013 in 20 centres were registered. For 181 cases data were considered complete for our survey. Eighty four tumours were type 1 (46.4%); five types 2 (2.8%); 52 types 3 (28.7%) and 40 types 4 (22.1%). Types 1 and 2 were first endoscopically managed in 93 and 60% of cases, respectively, whereas surgery was first done in 45 and 42%, respectively, of types 3 and 4. Systemic treatment, chemotherapy and/or somatostatin analogue, was first administered exclusively for types 3 and 4. Near 3% of types 1 and 40% of types 2 received at a time somatostatin analogue treatment. Five-year survival rates were 98.3, 100, 63.2 and 31.8% for types 1, 2, 3 and 4, respectively. CONCLUSION: The great majority of gastric neuro-endocrine tumours registered in this national cohort are treated in accordance with the current guidelines. The survival rates we reported must be interpreted with caution, because this cohort registered preferentially selected patients eligible for treatment. The registration of all the gastric neuro-endocrine tumours, in particular type 1 considered as benign and type 4 not eligible for specific anti-cancer treatment must be encouraged. PMID- 28664310 TI - Plasma levels of relaxin-2 are higher and correlated to C-peptide levels in early gestational diabetes mellitus. PMID- 28664311 TI - Growth in Adolescent Self-Regulation and Impact on Sexual Risk-Taking: A Curve-of Factors Analysis. AB - Adolescent self-regulation is increasingly seen as an important predictor of sexual risk-taking behaviors, but little is understood about how changes in self regulation affect later sexual risk-taking. Family financial stress may affect the development of self-regulation and later engagement in sexual risk-taking. We examined whether family financial stress influences self-regulation in early adolescence (age 13) and growth in self-regulation throughout adolescence (from age 13-17 years). We then assessed the effects of family financial stress, baseline self-regulation, and the development of self-regulation on adolescent sexual risk-taking behaviors at age 18 years. Using a curve-of-factors model, we examined these relationships in a 6-year longitudinal study of 470 adolescents (52% female) and their parents from a large northwestern city in the United States. Results indicated that family financial stress was negatively associated with baseline self-regulation but not with growth in self-regulation throughout adolescence. Both baseline self-regulation and growth in self-regulation were predictive of decreased likelihood of engaging in sexual risk-taking. Family financial stress was not predictive of later sexual risk-taking. Intervening to support the development of self-regulation in adolescence may be especially protective against later sexual risk-taking. PMID- 28664312 TI - Is the Scoutreach Initiative of Boy Scouts of America Linked to Character Development among Socioeconomically, Racially, and Ethnically Diverse Youth?: Initial Explorations. AB - Youth development programs represent key tools in the work of youth-serving practitioners and researchers who strive to promote character development and other attributes of youth thriving, particularly among youth who may confront structural and social challenges related to their racial, ethnic, and/or economic backgrounds. This article conducts secondary analyses of two previously reported studies of a relatively recent innovation in Boy Scouts of America (BSA) developed for youth from low-income communities, Scoutreach. Our goal is to provide descriptive and admittedly preliminary exploratory information about whether these data sets-one involving a sample of 266 youth of color from socioeconomically impoverished communities in Philadelphia (M age = 10.54 years, SD = 1.58 years) and the other involving a pilot investigation of 32 youth of color from similar socioeconomic backgrounds in Boston (M age = 9.97 years, SD = 2.46 years)-provide evidence for a link between program participation and a key indicator of positive development; that is, character development. Across the two data sets, quantitative and qualitative evidence suggested the presence of character development among Scoutreach participants. Limitations of both studies are discussed and implications for future longitudinal research are presented. We suggest that future longitudinal research should test the hypothesis that emotional engagement is key to creating the conditions wherein Scoutreach participation is linked to character development. PMID- 28664313 TI - Improving the power generation of microbial fuel cells by modifying the anode with single-wall carbon nanohorns. AB - OBJECTIVES: To increase the power generation of microbial fuel cells (MFCs), anode modification with carbon materials (activated carbon, carbon nanotubes, and carbon nanohorns) was investigated. RESULTS: Maximum power densities of a stainless-steel anode MFC with a non-modified electrode (SS-MFC), an activated carbon-modified electrode (AC-MFC), a carbon nanotube-modified electrode (CNT MFC) and a carbon nanohorn-modified electrode (CNH-MFC) were 72, 244, 261 and 327 mW m-2, respectively. The total polarization resistance measured by electrochemical impedance spectroscopy were 3610 Omega for SS-MFC, 283 Omega for AC-MFC, 231 Omega for CNTs-MFC, and 136 Omega for CNHs-MFC, consistent with the anode resistances obtained by fitting the anode polarization curves. CONCLUSIONS: Single-wall carbon nanohorns are better than activated carbon and carbon nanotubes as a new anode modification material for improving anode performance. PMID- 28664314 TI - Avermectin biosynthesis: stable functional expression of branched chain alpha keto acid dehydrogenase complex from Streptomyces avermitilis in Escherichia coli by selectively regulating individual subunit gene expression. AB - OBJECTIVE: To improve the production of short branched-chain acyl-CoAs for avermectin biosynthesis, the functional expression of the branched chain alpha keto acid dehydrogenase complex (BKDH) from Streptomyces avermitilis was systematically optimized by selectively regulating individual subunit expression in Escherichia coli. RESULTS: Functional expression of the BKDH complex was achieved by independent and selective optimization of individual subunit genes of the complex. Codon optimization significantly improved the expression of complex component proteins BkdH and LpdA1 but expression of BkdF and BkdG depended on coexpression of the bkdH gene. The optimized BKDH complex supplied sufficient short branched-chain acyl-CoA to synthesize phlorisovalerophenone, a key intermediate in bitter acid (humulone) synthesis. We also developed a novel p15A origin-derived high-copy-number vector system for expression; the yield of PIVP was 350 ng/mOD. CONCLUSION: Through optimization strategies, we obtained stable, functional expression of the BKDH complex in E. coli, which could be applied in the heterologous production of numerous high-value-added chemicals, especially polyketides. PMID- 28664315 TI - The wound-healing effect of 7,3',4'-trimethoxyflavone through increased levels of prostaglandin E2 by 15-hydroxyprostaglandin dehydrogenase inhibition. AB - OBJECTIVE: To find an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15 PGDH) that rapidly metabolises Prostaglandin E2 (PGE2) as a mediator of wound healing, we examined seven flavonoids for this role. RESULTS: 7,3',4' Trimethoxyflavone (TMF) had the lowest IC50 value of 0.34 uM for 15-PGDH inhibition but >400 uM for cytotoxicity, indicating a high therapeutic index. TMF elevated PGE2 levels in a concentration-dependent manner in both A549 lung cancer and HaCaT cells. It also significantly increased mRNA expression of multidrug resistance-associated protein 4 (MRP4) and of prostaglandin transporter (PGT) slightly in HaCaT cells. In addition, TMF facilitated in vitro wound healing in a HaCaT scratch model, which was completely inhibited by adding both 15-PGDH and NAD+ as cofactor, confirming the involvement of PGE2 in its wound healing effect. CONCLUSION: TMF with a high therapeutic index can facilitate wound healing through PGE2 elevation by 15-PGDH inhibition. PMID- 28664317 TI - New Paradigm: Adaptive Approach. PMID- 28664316 TI - Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery. AB - PURPOSE: To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. METHODS: Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. RESULTS: Initial evaluation identified 1-(alpha-D-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer - it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24 h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60 MUM. CONCLUSIONS: Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action. PMID- 28664318 TI - Sorafenib-Induced Acute Pancreatitis: Case Report and Review of the Literature. PMID- 28664319 TI - Effect of resolution recovery using graph plots on regional cerebral blood flow in healthy volunteers. AB - PURPOSE: We evaluated the effect of resolution recovery (RR) using graph plots on regional cerebral blood flow (rCBF) in brain perfusion single-photon emission computed tomography (SPECT) images derived from healthy volunteers and patients diagnosed with probable Alzheimer's disease. METHOD: We acquired brain perfusion SPECT images with scatter correction (SC), computed tomography-based attenuation correction (CTAC), and RR from a three-dimensional brain phantom and from healthy volunteers. We then compared contrast-to-noise ratio, count density ratios, increase maps, and rCBF using statistical parametric mapping 8. RESULTS: Regional brain counts were significantly increased from 20-24% with SC, CTAC, and RR compared with SC and CTAC. Mean CBF in healthy volunteers was 42.5 +/- 5.4 mL/100 g/min. Average rCBF determined using SC, CTAC and RR increased 7.5, 2.0, and 3.7% at the thalamus, posterior cingulate, and whole brain, respectively, compared with SC and CTAC. CONCLUSION: Resolution recovery caused variations in normal rCBF because counts increased in cerebral regions. PMID- 28664320 TI - Usefulness of diffusion-weighted imaging for diagnosis of adrenal ischemia during pregnancy: a preliminary report. AB - This case report aims to illustrate the clinical usefulness of diffusion-weighted imaging for diagnosis of bilateral adrenal ischemia during pregnancy. We also provide a retrospective analysis of adrenal gland diffusion data in a control group of 12 pregnant women with no adrenal dysfunction, to assess the normal range of apparent diffusion coefficient of adrenal gland during pregnancy. PMID- 28664321 TI - Illumina sequencing of bacterial 16S rDNA and 16S rRNA reveals seasonal and species-specific variation in bacterial communities in four moss species. AB - In order to better understand the factors that influence bacterial diversity and community composition in moss-associated bacteria, a study of bacterial communities in four moss species collected in three seasons was carried out via high-throughput sequencing of 16S rDNA and 16S rRNA. Moss species included Cratoneuron filicinum, Pylaisiella polyantha, Campyliadelphus polygamum, and Grimmia pilifera, with samples collected in May, July, and October 2015 from rocks at Beijing Songshan National Nature Reserve. In total, the bacterial richness and diversity were high regardless of moss species, sampling season, or data source (DNA vs. RNA). Bacterial sequences were assigned to a total of 558 OTUs and 279 genera in 16 phyla. Proteobacteria and Actinobacteria were the two most abundant phyla, and Cellvibrio, Lapillicoccus, Jatrophihabitans, Friedmanniella, Oligoflexus, and Bosea the most common genera in the samples. A clustering algorithm and principal coordinate analysis revealed that C. filicinum and C. polygamum had similar bacterial communities, as did P. polyantha and G. pilifera. Metabolically active bacteria showed the same pattern in addition to seasonal variation: bacterial communities were most similar in summer and autumn, looking at each moss species separately. In contrast, DNA profiles lacked obvious seasonal dynamics. A partial least squares discriminant analysis identified three groups of samples that correlated with differences in moss species resources. Although bacterial community composition did vary with the sampling season and data source, these were not the most important factors influencing bacterial communities. Previous reports exhibited that mosses have been widely used in biomonitoring of air pollution by enriching some substances or elements in the moss-tag technique and the abundant moss associated bacteria might also be important components involved in the related biological processes. Thus, this survey not only enhanced our understanding of the factors which influence microbial communities in mosses but also would be helpful for better use and development of the moss-tag technique in the environmental biomonitoring. PMID- 28664322 TI - Identification and characterization of the steroid 15alpha-hydroxylase gene from Penicillium raistrickii. AB - Penicillium raistrickii ATCC 10490 is used for the commercial preparation of 15alpha-13-methy-estr-4-ene-3,17-dione, a key intermediate in the synthesis of gestodene, which is a major component of third-generation contraceptive pills. Although it was previously shown that a cytochrome P450 enzyme in P. raistrickii is involved in steroid 15alpha-hydroxylation, the gene encoding the steroid 15alpha-hydroxylase remained unknown. In this study, we report the cloning and characterization of the 15alpha-hydroxylase gene from P. raistrickii ATCC 10490 by combining transcriptomic profiling with functional heterologous expression in Saccharomyces cerevisiae. The full-length open reading frame (ORF) of the 15alpha hydroxylase gene P450pra is 1563 bp and predicted to encode a cytochrome P450 protein of 520 amino acids. Targeted gene deletion revealed that P450pra is solely responsible for 15alpha-hydroxylation activity on 13-methy-estr-4-ene-3,17 dione in P. raistrickii ATCC 10490. The identification of the 15alpha-hydroxylase gene from P. raistrickii should help elucidate the molecular basis of regio- and stereo-specificity of steroid 15alpha-hydroxylation and aid in the engineering of more efficient industrial strains for useful steroid 15alpha-hydroxylation reactions. PMID- 28664323 TI - Overproduction of Rummeliibacillus pycnus arginase with multi-copy insertion of the arg R.pyc cassette into the Bacillus subtilis chromosome. AB - A plasmid-less and marker-less strain with multi-copy integration of the arginase gene from Rummeliibacillus pycnus was constructed using Bacillus subtilis 168 as a host. A total of nine copies of the arg R.pyc cassettes, in which the R. pycnus arginase gene was fused with the strong promoter P43, were inserted into the recipient chromosome. These multiple insertions were completed via step-by-step integrations into designed (2 copies) and random (9 copies) sites, respectively. A strategy for random site integration was developed based on the construction of the arg R.pyc cassette sandwiched between "front" and "back" homologous arms which were randomly restricted from chromosomal DNA. An antibiotic resistance marker was applied in transformant selection and was eliminated via the Cre/lox system. Performance showed that the highest enzyme activity (14.5 U/mL) was obtained after culture in flasks, and this segregation stable strain could efficiently hydrolyze L-arginine with a 97.2% molar yield, showing potential application in the food industry. PMID- 28664324 TI - Considerations on bacterial nucleoids. AB - The classic genome organization of the bacterial chromosome is normally envisaged with all its genetic markers linked, thus forming a closed genetic circle of duplex stranded DNA (dsDNA) and several proteins in what it is called as "the bacterial nucleoid." This structure may be more or less corrugated depending on the physiological state of the bacterium (i.e., resting state or active growth) and is not surrounded by a double membrane as in eukayotic cells. The universality of the closed circle model in bacteria is however slowly changing, as new data emerge in different bacterial groups such as in Planctomycetes and related microorganisms, species of Borrelia, Streptomyces, Agrobacterium, or Phytoplasma. In these and possibly other microorganisms, the existence of complex formations of intracellular membranes or linear chromosomes is typical; all of these situations contributing to weakening the current cellular organization paradigm, i.e., prokaryotic vs eukaryotic cells. PMID- 28664325 TI - Cloning of phaCAB genes from thermophilic Caldimonas manganoxidans in Escherichia coli for poly(3-hydroxybutyrate) (PHB) production. AB - PHB biosynthesis pathway, consisting of three open reading frames (ORFs) that encode for beta-ketothiolase (phaA Cma , 1179 bp), acetoacetyl-CoA reductase (phaB Cma , 738 bp), and PHA synthase (phaC Cma , 1694 bp), of Caldimonas manganoxidans was identified. The functions of PhaA, PhaB, and PhaC were demonstrated by successfully reconstructing PHB biosynthesis pathway of C. manganoxidans in Escherichia coli, where PHB production was confirmed by OD600, gas chromatography, Nile blue stain, and transmission electron microscope (TEM). The protein sequence alignment of PHB synthases revealed that phaC Cma shares at least 60% identity with those of class I PHB synthase. The effects of PhaA, PhaB, and PhaC expression levels on PHB production were investigated. While the overexpression of PhaB is found to be important in recombinant E. coli, performances of PHB production can be quantified as follows: PHB concentration of 16.8 +/- 0.6 g/L, yield of 0.28 g/g glucose, content of 74%, productivity of 0.28 g/L/h, and Mw of 1.41 MDa. PMID- 28664326 TI - Manganese-enhanced degradation of lignocellulosic waste by Phanerochaete chrysosporium: evidence of enzyme activity and gene transcription. AB - Lignolytic fungi initiate lignocellulose decay by producing extracellular oxidative enzymes. For better understanding the enzymatic degradation of lignocellulose by white-rot fungi, we investigated the effect of manganese on the organic matter loss, manganese peroxidase (MnP) activity, and manganese peroxidase gene (mnp) transcription levels during solid-state fermentation of rice straw with Phanerochaete chrysosporium. The results showed that the addition of manganese improved MnP activity and made it reach the peak earlier, promoted fungal growth at the early period (0-9 days), and enhanced the degradation of lignocellulosic waste. The total organic matter loss had a good correlation with fungal biomass during 30 days of cultivation, and manganese amendment promoted the ability of P. chrysosporium to degrade lignocellulose. Quantitative real-time RT-PCR revealed the differential expression of mnp1, mnp2, and mnp3: manganese amendment increased the transcription of mnp1 and mnp2 but not mnp3. The results indicated that manganese stimulated mnp transcription levels and played a post transcriptional role in MnP production. These findings provide opportunity of development in enzymatic degradation of lignocellulosic waste by P. chrysosporium amended with manganese. PMID- 28664327 TI - Effects of Mindfulness Practice on Performance-Relevant Parameters and Performance Outcomes in Sports: A Meta-Analytical Review. AB - BACKGROUND: Mindfulness as a present-oriented form of mental training affects cognitive processes and is increasingly considered meaningful for sport psychological training approaches. However, few intervention studies have examined the effects of mindfulness practice on physiological and psychological performance surrogates or on performance outcomes in sports. OBJECTIVE: The aim of the present meta-analytical review was to examine the effects of mindfulness practice or mindfulness-based interventions on physiological and psychological performance surrogates and on performance outcomes in sports in athletes over 15 years of age. DATA SOURCES: A structured literature search was conducted in six electronic databases (CINAHL, EMBASE, ISI Web of Knowledge, PsycINFO, MEDLINE and SPORTDiscus). The following search terms were used with Boolean conjunction: (mindful* OR meditat* OR yoga) AND (sport* OR train* OR exercis* OR intervent* OR perform* OR capacity OR skill*) AND (health* OR adult* OR athlete*). STUDY SELECTION: Randomized and non-randomized controlled studies that compared mindfulness practice techniques as an intervention with an inactive control or a control that followed another psychological training program in healthy sportive participants were screened for eligibility. DATA EXTRACTION: Eligibility and study quality [Physiotherapy Evidence Database (PEDro)] scales were independently assessed by two researchers. A third independent researcher was consulted to achieve final consensus in case of disagreement between both researchers. Standardized mean differences (SMDs) were calculated as weighted Hedges' g and served as the main outcomes in comparing mindfulness practice versus control. Statistical analyses were conducted using a random-effects inverse-variance model. RESULTS: Nine trials of fair study quality (mean PEDro score 5.4, standard deviation 1.1) with 290 healthy sportive participants (athletics, cyclists, dart throwers, hammer throwers, hockey players, hurdlers, judo fighters, rugby players, middle-distance runners, long-distance runners, shooters, sprinters, volleyball players) were included. Intervention time varied from 4 weeks to over 2 years. The practice frequency lasted from twice daily to just once a week, and the mean session time covered 50-60 min. In favor of mindfulness practice compared with the control condition, large effects with narrow confidence limits and low heterogeneity were found for mindfulness scores [SMD 1.03, 90% confidence interval (CI) 0.67-1.40, p < 0.001, I 2 = 17%]. Physiological performance indices depicted wide confidence limits accompanied with very large heterogeneity. However, the effect sizes remained very large, with confidence limits that did not overlap zero (SMD 3.62, 90% CI 0.03-7.21, p = 0.10, I 2 = 98%). Moderate to large effects were observed for both psychological performance surrogates (SMD 0.72, 90% CI 0.46-0.98, p < 0.001, I 2 = 14%) and performance outcomes in shooting and dart throwing (SMD 1.35, 90% CI 0.61-2.09, p = 0.003, I 2 = 82%). CONCLUSIONS: Mindfulness practice consistently and beneficially modulates mindfulness scores. Furthermore, physiological and psychological surrogates improved to a meaningful extent following mindfulness practice, as well as performance outcomes in shooting and dart throwing. It seems reasonable to consider mindfulness practice strategies as a regular complementary mental skills training approach for athletes, at least in precision sports; however, more high quality, randomized, controlled trials on mindfulness practice and performance improvements in diverse sport settings are needed. PMID- 28664329 TI - In Type-2 Diabetes Subjects Trabecular Bone Score is Better Associated with Carotid Intima-Media Thickness than BMD. AB - Literature data reported that in elderly subjects, carotid intima-media thickness (IMT) was negatively associated with bone mineral density (BMD). Paradoxically, type-2 diabetes (T2DM) patients, despite having higher BMD, present an increased risk of fragility fractures and cardiovascular complications. Some studies have reported trabecular bone score (TBS), an index of trabecular bone quality, as possibly being reduced in T2DM. This study aimed to evaluate whether in T2DM subjects TBS was better associated with IMT with respect to BMD. In 131 consecutive T2DM subjects (55 men and 76 women; mean age: 60.0 +/- 7.3 years) and 265 consecutive non-T2DM subjects (107 men and 158 women; mean age: 58.9 +/- 7.8 years) we measured carotid IMT by high-resolution ultrasonography and BMD at lumbar spine (LS-BMD), at femoral neck FN-BMD and total hip TH-BMD; TBS was calculated using TBS iNsight software. LS-BMD, FN-BMD, and TH-BMD were all significantly higher in T2DM than in non-T2DM subjects, whereas TBS was significantly lower in T2DM subjects than in controls and inversely correlated with diabetes duration. In T2DM subjects multiple regression analysis showed that IMT was positively associated with age (b = 0.017; p < 0.001) and inversely associated with TBS (b = -0.473; p = 0.038). In non-T2DM subjects, only age was positively associated with IMT. To sum up, T2DM subjects present higher values of BMD and lower values of TBS with respect to non-diabetic controls. Moreover, in T2DM subjects TBS was found to be independently associated with carotid IMT. These findings suggest that TBS may not only capture bone fragility-related factors, but also some information associated with greater risk of developing cardiovascular diseases. PMID- 28664328 TI - Timeline of Intergenerational Child Maltreatment: the Mind-Brain-Body Interplay. AB - PURPOSE OF REVIEW: Still obscure mechanisms of intergenerational child maltreatment (ITCM) have been investigated partially, from various psychological and biological perspectives and from various time perspectives. This review is aimed at integrating the findings on different temporal ITCM pathways, emphasizing the mind-brain-body interplay. RECENT FINDINGS: Psychological mediators of ITCM involve attachment, mentalization, dissociation, social information processing, personality traits, and psychiatric disorders. Neurobiological findings mostly refer to the neural correlates of caregiving and attachment behaviors, affected by several physiological systems (stress-response, immune, oxytocin), which also affect physical health. The latest research clusters around the epigenetic pathways of ITCM, suggesting the additional, prenatal, and preconception forms of transmission. Data suggest that ITCM needs to be conceptualized as a longitudinal process, with various interrelated psychological, neurodevelopmental, and somatic paths. Future research and prevention should take into account both, each path and each phase of ITCM, in an integrative way. PMID- 28664330 TI - Long-term outcomes of ethanol injection therapy for locally recurrent papillary thyroid cancer. AB - The standard treatment regimen for locally recurrent lesions is total thyroidectomy, or complete removal of the recurrent thyroid lesion within the thyroid bed. However, reoperation increases the risk of complications and patients have to undergo general anesthesia. Percutaneous ethanol injection therapy represents a far less invasive procedure without general anesthesia and with lower risk of complications. Thirty-four patients who received PEIT at Yonsei University Medical Center between October 2002 and August 2009 for recurrent cervical nodal metastases of differentiated papillary thyroid cancer were included in this retrospective study. During a minimum follow-up of 60 months, treatment outcomes were determined by measuring the lesion size prior to the first injection and 3 months after the last injection. A total of 46 recurrent lesions were detected in 34 patients. Five patients underwent surgery and PEIT was administered to the remaining 19 and 22 lesions in the central compartment and lateral neck lymph nodes, respectively. Size increases were observed in seven (17.1%) lesions, whereas no changes in size and decreases were detected in 10 (24.4%) and 24 (58.5%) lesions. Patients with increased lymph nodes were significantly older (65.3 +/- 14.4 vs. 48.2 +/- 16.3 years; p = 0.02) and had smaller sizes (9.3 +/- 1.0 vs. 12.3 +/- 6.4 mm; p = 0.012). Although reoperation remains the first-line treatment for recurrent thyroid cancer, PEIT may be considered as a treatment option in selected patients with lesions larger than 1 cm who are ineligible for surgery or have refused reoperation. PMID- 28664331 TI - Benefit of the UltraZoom beamforming technology in noise in cochlear implant users. AB - The objectives of the study were to demonstrate the audiological and subjective benefits of the adaptive UltraZoom beamforming technology available in the Naida CI Q70 sound processor, in cochlear-implanted adults upgraded from a previous generation sound processor. Thirty-four adults aged between 21 and 89 years (mean 53 +/- 19) were prospectively included. Nine subjects were unilaterally implanted, 11 bilaterally and 14 were bimodal users. The mean duration of cochlear implant use was 7 years (range 5-15 years). Subjects were tested in quiet with monosyllabic words and in noise with the adaptive French Matrix test in the best-aided conditions. The test setup contained a signal source in front of the subject and three noise sources at +/-90 degrees and 180 degrees . The noise was presented at a fixed level of 65 dB SPL and the level of speech signal was varied to obtain the speech reception threshold (SRT). During the upgrade visit, subjects were tested with the Harmony and with the Naida CI sound processors in omnidirectional microphone configuration. After a take-home phase of 2 months, tests were repeated with the Naida CI processor with and without UltraZoom. Subjective assessment of the sound quality in daily environments was recorded using the APHAB questionnaire. No difference in performance was observed in quiet between the two processors. The Matrix test in noise was possible in the 21 subjects with the better performance. No difference was observed between the two processors for performance in noise when using the omnidirectional microphone. At the follow-up session, the median SRT with the Naida CI processor with UltraZoom was -4 dB compared to -0.45 dB without UltraZoom. The use of UltraZoom improved the median SRT by 3.6 dB (p < 0.0001, Wilcoxon paired test). When looking at the APHAB outcome, improvement was observed for speech understanding in noisy environments (p < 0.01) and in aversive situations (p < 0.05) in the group of 21 subjects who were able to perform the Matrix test in noise and for speech understanding in noise (p < 0.05) in the group of 13 subjects with the poorest performance, who were not able to perform the Matrix test in noise. The use of UltraZoom beamforming technology, available on the new sound processor Naida CI, improves speech performance in difficult and realistic noisy conditions when the cochlear implant user needs to focus on the person speaking at the front. Using the APHAB questionnaire, a subjective benefit for listening in background noise was also observed in subjects with good performance as well as in those with poor performance. This study highlighted the importance of upgrading CI recipients to new technology and to include assessment in noise and subjective feedback evaluation as part of the process. PMID- 28664332 TI - Heparin-gold nanoparticles for enhanced microdialysis sampling. AB - Cerebral microdialysis is a sampling technique which offers much potential for understanding inflammatory pathophysiology following traumatic brain injury (TBI). At present, the recovery of cytokines via microdialysis in clinical studies is not straightforward primarily due to their size, steric properties and low concentrations. Heparin and heparin-coated microspheres have previously shown promise as cytokine-binding agents for enhanced microdialysis sampling in animal models (Duo and Stenken in Anal Bioanal Chem 399(2):773-82, 2011; Anal Bioanal Chem 399(2):783-93, 2011). However, there are several factors limiting application for microdialysis in patients. The aim of this study was to produce heparin-coated gold nanoparticles as cytokine capture agents for enhanced microdialysis sampling, potentially applicable to a clinical setting. Gold nanoparticles (AuNP) were chemically conjugated to heparin via a bifunctional polyethylene glycol (PEG) linker. The heparin-AuNP (AuNP-Hep) were characterised, demonstrating the successful addition of heparin to the gold surface. The performance of the AuNP-Hep during in vitro testing was compared both to current methodology (Helmy et al. in J Neurotrauma 26(4):549-61, 2009) and to the heparin coated microspheres developed by Duo and Stenken (Anal Bioanal Chem 399(2):773 82, 2011; Anal Bioanal Chem 399(2):783-93, 2011). The AuNP-Hep yielded a higher recovery of cytokines compared to current methodology and heparin-coated microspheres, during in vitro testing designed to mimic the human environment and the intensive care unit. In this study, AuNP-Hep were developed for enhanced microdialysis sampling of cytokines, potentially applicable in a clinical setting. Based on the success of the AuNP-Hep in vitro, the proposed method offers an alternative to the use of current protocols that rely on a blood product (albumin) for microdialysis sampling of cytokines in patients. PMID- 28664333 TI - Preparation of electrochemically treated nanoporous pencil-graphite electrodes for the simultaneous determination of Pb and Cd in water samples. AB - A simple and rapid analytical method of determining Pb2+ and Cd2+ in water samples using an electrochemically pretreated pencil-graphite electrode (EP-PGE) is proposed for the first time in the literature. An electrochemically pretreated pencil-graphite electrode was prepared by performing potential cycling between 0.3 V and 2.0 V in 0.1 mol L-1 H3PO4 solution to improve its ability to electrochemically sense Pb2+ and Cd2+ ions. Square-wave anodic stripping voltammetry (SWASV) was used as the electroanalytical method. The electroanalytical parameters that influence the stripping determination of Pb2+ and Cd2+ were optimized based on experimental results. The magnitude of the peak oxidation current was adjusted in order to optimize the value of each parameter. Applying the resulting disposable electrode under the optimized conditions led to good selectivity and sensitivity in the determination of Pb2+ and Cd2+ ions. Interference from coexisting ions was also investigated. The resulting sensor was successfully tested by applying it to a standard reference water sample. Under the optimized conditions, the limits of detection were 0.46 MUg L-1 for Pb2+ and 1.11 MUg L-1 for Cd2+ using the electrode. Relative standard deviations (%RSD) were 2.76 for Pb2+ and 2.85 for Cd2+. The linear working ranges of the electrode for Pb2+ and Cd2+ ion detection were 5-45 MUg L-1 and 10-40 MUg L-1, respectively. Graphical abstract Preparation of nanoporous pencil-graphite electrode by cyclic voltammetry and stripping voltammetric screening of Pb and Cd. PMID- 28664334 TI - New approaches for extraction and determination of betaine from Beta vulgaris samples by hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - Betaine is one of most studied biologically active compounds, due its role in the main biological processes. Although it may be found in several plants and roots, such as the Beta vulgaris family, present in typical diets, just a few analytical methods have been developed for its extraction from roots. A new, quick and effective procedure for the isolation and determination of betaine from two different varieties of B. vulgaris (red and gold) is presented. For betaine extraction, an accelerated solvent extraction (ASE) was coupled with solid-phase extraction. For betaine determination, a separation method based on hydrophilic interaction chromatography coupled with tandem mass spectrometry was optimized for a sensible detection of betaine by means of experimental design. Recoveries were about 93%, with RSD <5%, for both the matrices, without evidence of interfering species. The total content of betaine in extracts of various parts of plants (juice, peel, root) have been determined, obtaining concentrations in the range 3000-4000 mg/L for the juice and in the range 2-5 mg/g for the pulp and for the peel. The B. vulgaris gold species exhibited a higher concentration of betaine, compared to the red variety. Additionally, a micro extraction by packed sorbent technique and a modified quick, easy, cheap, rugged and safe (QuEChERS) procedure, were also tested and compared. Despite the lower recoveries of the latter, with respect to the ASE/SPE procedure (75-89%, RSD <1.5%), the ease of the method, which can be applied without the SPE purification procedure, can represent a positive improvement. Graphical abstract Determination of betaine from Beta vulgaris samples. PMID- 28664335 TI - Rapid fluorescence detection of pathogenic bacteria using magnetic enrichment technique combined with magnetophoretic chromatography. AB - A rapid and sensitive analytical method was developed to detect pathogenic bacteria which combined magnetic enrichment, fluorescence labeling with polyethylene glycol (PEG) magnetophoretic chromatography. As pathogenic bacteria usually exist in complex matrixes at low concentration, an efficient enrichment is essential for diagnosis. In order to capture series types of pathogenic bacteria in samples, amino-modified magnetic nanoparticles (Fe3O4@SiO2-NH2) were prepared for efficient enrichment by the electrostatic interaction with pathogenic bacteria. It was shown that the capture efficiency reached up to 95.4% for Escherichia coli (E. coli). Furthermore, quantitative analysis of the bacteria was achieved by using acridine orange (AO) as a fluorescence probe for the captured E. coli due to its ability of staining series types of bacteria and rapid labeling. In order to remove the free magnetic nanoparticles and redundant fluorescent reagent, the labeled suspension was poured into a PEG separation column and was separated by applying an external magnetic field. The presence of 100 cfu mL-1 E. coli could be detected for semi-quantitative analysis by observing the separation column with the naked eye, and the concentration could be further evaluated by fluorescence detection. All the above processes were finished within 80 min. It was demonstrated that a good linear relationship existed between the fluorescence intensity and the concentration of E. coli ranging from 102 to 106 cfu mL-1, with a detection limit of 100 cfu mL-1 when E. coli acted as target bacteria. The recovery rate of E. coli was 93.6~102.0% in tap water and cooked meat samples, and the RSD was lower than 7% (n = 6); the result coincided with the conventional plate count method. Graphical abstract ?. PMID- 28664336 TI - A molecularly imprinted polymer synthesized using beta-cyclodextrin as the monomer for the efficient recognition of forchlorfenuron in fruits. AB - In this study, we have successfully synthesized a forchlorfenuron (CPPU) imprinted polymer in dimethyl sulfoxide by molecular imprinting technique. In the molecular imprinting, beta-cyclodextrin was used as the monomer with 1,6 hexamethylene diisocyanate (HMDI) as the cross-linking agent that formed a complex with forchlorfenuron by inclusion interactions. The adsorption equilibrium was attained in approximately 30 min and the maximum binding capacity was 26.79 mg/g, which indicated that the adsorption kinetics was relatively fast. The results of adsorption and selectivity experiments have shown that the imprinted polymer was able to bind forchlorfenuron specifically and reversibly. The specific recognition of the imprinted polymer for forchlorfenuron resulted from the cooperative effects of inclusion interaction and hydrophobic interaction. This imprinted polymer was also used to accurately determine forchlorfenuron residue in real fruit samples. In the standard spiked strawberry sample, the adsorption recoveries for forchlorfenuron were as high as 90.3, 84.5, and 90.8%, respectively. The binding specificity of the imprinted polymer for forchlorfenuron resulted from the imprinting effect. Therefore, as a reusable material possessing high affinity and selectivity, the imprinted polymer is promising in application to detect pesticide residues in fruit samples. In addition, because beta-cyclodextrin is water soluble and can include neutral compounds, this molecularly imprinted polymer can be used to recognize pesticides in aqueous solutions. Graphical abstract Schematic demonstration of molecular imprinting and re-binding of forchlorfenuron. PMID- 28664337 TI - Determination of mancozeb residue in fruit by derivatization and a modified QuEChERS method using ultraperformance liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method with derivatization and a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) sample preparation was developed for the determination of mancozeb in fruits. The target compound was determined in less than 4.0 min with use of an electrospray ionization source in positive mode. The limits of detection and the limits of quantification ranged from 1.0 to 3.2 MUg kg-1 and from 10 to 15 MUg kg-1 in fruit respectively. The linearity was excellent for mancozeb (R 2 >= 0.9920). Recoveries in five matrices were obtained at three spiking levels (0.02, 0.1, and 1 mg kg-1). For all concentrations, the mean recoveries ranged from 84.0% to 95.9%, with repeatability relative standard deviation (n = 5) of 0.6 - 7.0%. The interday reproducibility relative standard deviation (n = 3) ranged from 1.4% to 5.5%. This method could be used for the routine detection of mancozeb residues in fruit. Graphical abstract The derivation of mancozeb and the detection process of derivative product by UPLC-MS/MS. PMID- 28664338 TI - High-density lipoprotein sensor based on molecularly imprinted polymer. AB - Decreased blood level of high-density lipoprotein (HDL) is one of the essential criteria in diagnosing metabolic syndrome associated with the development of atherosclerosis and coronary heart disease. Herein, we report the synthesis of a molecularly imprinted polymer (MIP) that selectively binds HDL, namely, HDL-MIP, and thus serves as an artificial, biomimetic sensor layer. The optimized polymer contains methacrylic acid and N-vinylpyrrolidone in the ratio of 2:3, cross linked with ethylene glycol dimethacrylate. On 10 MHz dual electrode quartz crystal microbalances (QCM), such HDL-MIP revealed dynamic detection range toward HDL standards in the clinically relevant ranges of 2-250 mg/dL HDL cholesterol (HDL-C) in 10 mM phosphate-buffered saline (PBS, pH = 7.4) without significant interference: low-density lipoprotein (LDL) yields 5% of the HDL signal, and both very-low-density lipoprotein (VLDL) and human serum albumin (HSA) yield 0%. The sensor reveals recovery rates between 94 and 104% at 95% confidence interval with precision of 2.3-7.7% and shows appreciable correlation (R 2 = 0.97) with enzymatic colorimetric assay, the standard in clinical tests. In contrast to the latter, it achieves rapid results (10 min) during one-step analysis without the need for sample preparation. Graphical Abstract ?. PMID- 28664339 TI - Metabolite profiling of carbamazepine and ibuprofen in Solea senegalensis bile using high-resolution mass spectrometry. AB - The widespread occurrence of pharmaceuticals in the aquatic environment has raised concerns about potential adverse effects on exposed wildlife. Very little is currently known on exposure levels and clearance mechanisms of drugs in marine fish. Within this context, our research was focused on the identification of main metabolic reactions, generated metabolites, and caused effects after exposure of fish to carbamazepine (CBZ) and ibuprofen (IBU). To this end, juveniles of Solea senegalensis acclimated to two temperature regimes of 15 and 20 degrees C for 60 days received a single intraperitoneal dose of these drugs. A control group was administered the vehicle (sunflower oil). Bile samples were analyzed by ultra high-performance liquid chromatography-high-resolution mass spectrometry on a Q Exactive (Orbitrap) system, allowing to propose plausible identities for 11 metabolites of CBZ and 13 metabolites of IBU in fish bile. In case of CBZ metabolites originated from aromatic and benzylic hydroxylation, epoxidation, and ensuing O-glucuronidation, O-methylation of a catechol-like metabolite was also postulated. Ibuprofen, in turn, formed multiple hydroxyl metabolites, O glucuronides, and (hydroxyl)-acyl glucuronides, in addition to several taurine conjugates. Enzymatic responses after drug exposures revealed a water temperature dependent induction of microsomal carboxylesterases. The metabolite profiling in fish bile provides an important tool for pharmaceutical exposure assessment. Graphical abstract Studies of metabolism of carbamazepine and ibuprofen in fish. PMID- 28664340 TI - Qualitative characterization of SRM 1597a coal tar for polycyclic aromatic hydrocarbons and methyl-substituted derivatives via normal-phase liquid chromatography and gas chromatography/mass spectrometry. AB - A normal-phase liquid chromatography (NPLC) fractionation procedure was developed for the characterization of a complex mixture of polycyclic aromatic hydrocarbons (PAHs) from a coal tar sample (Standard Reference Material (SRM) 1597a). Using a semi-preparative aminopropyl (NH2) LC column, the coal tar sample was separated using NPLC based on the number of aromatic carbons; a total of 14 NPLC fractions were collected. SRM 1597a was analyzed before and after NPLC fractionation by using gas chromatography/mass spectrometry (GC/MS) with a 50% phenyl stationary phase. The NPLC-GC/MS method presented in this study allowed for the identification of 72 PAHs and 56 MePAHs. These identifications were based on the NPLC retention times for authentic reference standards, GC retention times for authentic reference standards, and the predominant molecular ion peak in the mass spectrum. Most noteworthy was the determination of dibenzo[a,l]pyrene, which could not be measured directly by GC/MS because of low concentration and co elution with dibenzo[j,l]fluoranthene. The NPLC-GC/MS procedure also allowed for the tentative identification of 74 PAHs and 117 MePAHs based on the molecular ion peak only. This study represents the most comprehensive qualitative characterization of SRM 1597a to date. Graphical abstract NPLC-GC/MS analysis for the six-ring MM 302 Da PAH isomers in SRM 1597a. PMID- 28664342 TI - Effect of supplemented intake of omega-3 fatty acids on arrhythmias in patients with ICD: fish oil therapy may reduce ventricular arrhythmia. AB - PURPOSE: The aim of this study was to evaluate the effects of fish oils, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on ventricular tachyarrhythmic episodes (VTEs) in implantable cardioverter defibrillator (ICD) recipients with ischemic cardiomyopathy. METHODS: One hundred five ICD recipients with ischemic cardiomyopathy received 3.6 g of EPA and DHA and placebo for 6 months, each at a random order, with a 4-month washout period between treatments. Eighty-seven patients completed the 16-month study protocol. The primary end point was any VTE (including sustained and non-sustained ventricular tachycardias at a rate of >150 bpm) as recorded by the ICDs. Secondary end points included device therapy (anti-tachycardia pacing (ATP) or shocks). RESULTS: During treatment with fish oils, there was a significant increase in EPA and DHA concentrations in red blood cells (RBCs) and subcutaneous fat tissue. Among 87 patients who completed the study protocol, the mean number of VTEs was significantly lower during treatment with fish oil (1.7) vs. placebo (5.6; p = 0.035). Appropriate device therapy for VTE occurred in 18 (21%) patients. Fish oil therapy was associated with a trend toward fewer VTEs terminated with ATP (2.8 +/- 13.7 vs. 0.5 +/- 2.1, respectively; p = 0.077). VTE terminated by ICD shocks, however, was rare, and rates were similar between both groups (0.11 +/- 0.6 vs. 0.10 +/- 0.4, p = not significant, respectively). CONCLUSIONS: Our data suggest that fish oil therapy may be associated with a reduction in the frequency of VTE in ICD recipients with ischemic cardiomyopathy. PMID- 28664341 TI - The activity of the serotonin receptor 2C is regulated by alternative splicing. AB - The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos. Most 5HT2C isoforms show constitutive activity, i.e., signal without ligand binding. The constitutive activity of 5HT2C is decreased by pre-mRNA editing as well as alternative pre-mRNA splicing, which generates a truncated isoform that switches off 5HT2C receptor activity through heterodimerization; showing that RNA processing regulates the constitutive activity of the 5HT2C system. RNA processing events influencing the constitutive activity target exon Vb that forms a stable double stranded RNA structure with its downstream intron. This structure can be targeted by small molecules and oligonucleotides that change exon Vb alternative splicing and influence 5HT2C signaling in mouse models, leading to a reduction in food intake. Thus, the 5HT2C system is a candidate for RNA therapy in multiple models of CNS disorders. PMID- 28664344 TI - Hypoxic dose, intensity distribution, and fatigue monitoring are paramount for "live high-train low" effectiveness. PMID- 28664343 TI - Catheter ablation of atypical atrial flutter: a novel 3D anatomic mapping approach to quickly localize and terminate atypical atrial flutter. AB - PURPOSE: This study aims to describe a novel method of High Density Activation Sequence Mapping combined with Voltage Gradient Mapping Overlay (HD-VGM) to quickly localize and terminate atypical atrial flutter. METHODS: Twenty-one patients presenting with 26 different atypical atrial flutter circuits after a previous catheter or surgical AF ablation were studied. HD-VGM was performed with a commercially available impedance-based mapping system to locate and successfully ablate the critical isthmus of each tachycardia circuit. The results were compared to 21 consecutive historical control patients who had undergone an atypical flutter ablation without HD-VGM. RESULTS: Twenty-six different atypical flutter circuits were evaluated. An average 3D anatomic mapping time of 12.39 +/- 4.71 min was needed to collect 2996 +/- 690 total points and 1016 +/- 172 used mapping points. A mean of 195 +/- 75 s of radiofrequency (RF) energy was needed to terminate the arrhythmias. The mean procedure time was 135 +/- 46 min. With a mean follow-up 16 +/- 9 months, 90% are in normal rhythm. In comparison to the control cohort, the study cohort had a shorter procedure time (135 +/- 46 vs. 210 +/- 41 min, p = 0.0009), fluoroscopy time (8.5 +/- 3.7 vs. 17.7 +/- 7.7 min, p = 0.0021), and success in termination of the arrhythmia during the procedure (100 vs. 68.2%, p = 0.0230). CONCLUSIONS: Ablation of atypical atrial flutter is challenging and time consuming. This case series shows that HD-VGM mapping can quickly localize and terminate an atypical flutter circuit. PMID- 28664345 TI - Hypoxic dose, intensity distribution, and fatigue monitoring are paramount for "live high-train low". PMID- 28664346 TI - Success of referral to genetic counseling after positive lynch syndrome screening test. AB - PURPOSE: Lynch syndrome (LS) is a hereditary condition that increases one's risk of developing colorectal, endometrial, and other extracolonic cancers. MD Anderson Cancer Center at Cooper implemented a reflex screening protocol for DNA mismatch repair (dMMR) deficiency. Those with findings suspicious for LS were referred for genetic counseling (GC). Our goal was to assess compliance with GC and factors associated with successful follow-up. METHODS: Immunohistochemistry (IHC) for the MMR proteins MSH2, MLH1, MSH6, and PMS2 was performed on all colorectal tumor resections from patients <=70 years old and all stage II cancers. Tumors with loss of MLH1/PMS2 were subsequently tested for BRAF mutation or MLH1 promoter methylation to identify tumors with likely epigenetic inactivation of MLH1. Patients with loss of MLH1/PMS2 without BRAF mutations or with absence of MLH1 promoter methylation and those with loss of MSH2/MSH6 were referred to GC. Compliance with GC was assessed. RESULTS: Between March 2014 and August 2016, 203 tumors were tested by IHC. Fifteen (7.4%) patients had abnormal MMR protein expression patterns in the absence of BRAF mutation or MLH1 promoter methylation suggestive of possible LS. GC compliance was 35.7% overall and 85.7% in those with family history of LS-associated cancers. CONCLUSIONS: Overall, GC compliance was relatively low in our study. Interestingly, patients with a strong family history of LS-associated neoplasms were more likely to pursue GC. In the future, assessing and addressing barriers to seeking GC will provide opportunities to improve patient care through increased identification of patients with cancer predisposition syndromes. PMID- 28664347 TI - Antibiotic treatment for uncomplicated and mild complicated diverticulitis: outpatient treatment for everyone. AB - PURPOSE: Antibiotic treatment is the treatment of choice for uncomplicated diverticulitis (uD) and can be performed for mild complicated diverticulitis (mcD). In several cases, outpatient treatment (OT) can be undertaken. This study assessed the 1-month failure rate of OT for uD/mcD compared to inpatient treatment (IT), and identified predictive factors for treatment failure. METHODS: All consecutive patients (2006-2012) diagnosed with uD/mcD by CT scan were retrospectively analyzed. Acute uD was defined as absence of the following: abscess, fistula, extraluminal contrast, pneumoperitoneum, and need for immediate percutaneous drainage/surgery. Acute mcD was defined as complicated diverticulitis with abscess <4 cm or pneumoperitoneum <2 cm. All patients received antibiotherapy. Treatment failure was defined as (re)hospitalization the first month after treatment onset or need of drainage/surgery during hospitalization. All patients were contacted using a standardized questionnaire. RESULTS: Out of 540 uD/mcD, IT was offered to 369 patients (68%) and OT to 171 patients (32%). The IT group had higher median age, more women, higher median Charlson Index, more severe median Ambrosetti score, longer median time in the emergency room, and higher median CRP. Response rates to the questionnaire were 56% (IT) vs. 62% (OT), p = 0.18. Failure rates were 32% in IT vs. 10% in OT group, p < 0.01. Among the uD/mcD patients, admission/CT time between midnight and 6 AM, Ambrosetti score of 4, and free air around the colon were risk factors for failure. CONCLUSIONS: Outpatient treatment for uncomplicated/mild complicated diverticulitis is feasible and safe. Prognostic factors of failure necessitating closer follow-up were admission/CT time, Ambrosetti score of 4, and free air around the colon. PMID- 28664348 TI - Paravertebral Blocks for Same-Day Breast Surgery. AB - PURPOSE OF REVIEW: Breast surgery, performed for medical or cosmetic reasons, remains one of the most frequently performed procedures, with over 500,000 cases performed annually in the USA alone. Historically, general anesthesia (GA) has been widely accepted as the gold-standard technique, while epidural anesthesia was largely considered too invasive and thus unnecessary for breast surgery. Over the past years, paravertebral block (PVB) has emerged as an alternative analgesic or even anesthetic technique. Substantial evidence supports the use of PVB for major breast surgery. RECENT FINDINGS: In patients receiving PVB, immediate and long-term analgesia is superior to systemic analgesia while opioid use and typical adverse effects of systemic analgesia such as nausea and vomiting are decreased. The benefits may also include an improved oncological survival with PVB after mastectomy for malignancy. PVB offers clinically significant benefits for perioperative care of patients undergoing breast surgery. The benefits of continuous PVB are most firmly supported for major breast surgery and include both effective short-term pain control and reduction in burden of chronic pain. On the other hand, minor breast surgery should be effectively manageable using multimodal analgesia in the majority of patients, with PVB reserved as analgesic rescue or for patients at high risk of excessive perioperative pain. PMID- 28664349 TI - The Effect of Citrulline/Malate on Blood Lactate Levels in Intensive Exercise. AB - The purpose of this study was to examine the effects of Citrulline/Malate supplementation with intensive training on blood lactate level in active handball players. The athletes were subjected to intense training for 4 weeks, 4 days a week, mainly pre-season strength and technique training. In this training period, stimol group (n = 11) athletes were given stimol 3 times a day as 1 g for breakfast, 1 g for lunch, and 1 g for dinner while the placebo group (n = 11) athletes were given only placebo in the same dosage and the same color at the same time. Blood lactate levels in athletes were measured 4 times, prior to and after a 1-month program as follows: rest (R), end effort (EE), recuperation 5 min (R5 m), and recuperation 20 min (R20 m). Blood lactate levels were compared both as intra-group and between the groups. In intra-group comparison, no change was observed in blood lactate levels in placebo group while a significant difference was found in the levels of stimol group as p < 0.05 with a 49.8% decrease in blood lactate level. In the measurements between groups, in the post-test measurements made after the training period, significant differences as p < 0.05 were found with a 60.7% decrease in blood lactate level EE. Considerable decline was seen especially immediately after exercise in blood lactate levels of the athletes being given stimol supplement. In this case, we can say that Citrulline/Malate supplementation may contribute positively to the performance of athletes and may help postpone fatigue at excessive or prolonged activity. PMID- 28664350 TI - Emergence of antimicrobial resistance to Pseudomonas aeruginosa in the intensive care unit: association with the duration of antibiotic exposure and mode of administration. AB - BACKGROUND: Antibiotics are frequently used in intensive care units (ICUs), and their use is associated with the emergence of bacterial resistance to antibiotics. The aim of this study was to investigate the association between the emergence of Pseudomonas aeruginosa resistance and the duration of antibiotic exposure or mode of administration in an ICU unit. METHODS: A 4-year cohort study of intensive care unit was performed in patients with P. aeruginosa isolates from clinical specimens, initially susceptible to the investigated antibiotics (piperacillin/tazobactam, ceftazidime, ciprofloxacin, meropenem and amikacin). Odds ratios (ORs) with 95% confidence interval (95% CI) of emergence of resistance were calculated using logistic regression analysis for various exposure periods to antibiotics (1-3, 4-7, 8-15 and >15 days) relative to no exposure with adjustment for age, sex, Simplified Acute Physiology Score 3 (SAPS 3) and length of stay. ORs on the emergence of P. aeruginosa resistance were also calculated for the various modes of administration. RESULTS: Included were 187 patients [mean age 61 years, 69% male, mean SAPS 3 score (SD): 59 (12.3)]. None of the antibiotics investigated showed the emergence of resistance within 1-3 days. Significant meropenem resistance emerged within 8-15 days [OR 79.1 (14.9 421.0)] after antibiotic exposure unlike other antibiotics (>15 days). No difference was observed between intermittent and extended administration of meropenem and between beta-lactam mono- or combined therapy. CONCLUSIONS: Use of meropenem was associated with the emergence of resistance as soon as 8 days after exposure to the antibiotic. PMID- 28664352 TI - Erratum to: Acyclovir resistance in herpes simplex virus type I encephalitis: a case report. PMID- 28664351 TI - Would brief alcohol intervention be helpful in facial trauma patients?A Narrative Review. AB - Facial trauma is commonly associated with excessive consumption of alcohol and is often associated with interpersonal violence or motor vehicle accidents. Alcohol related trauma presentation to hospitals causes a major service burden, and there have been efforts to reduce such trauma load with educational programs and social support. Brief alcohol intervention (BAI) in an acute setting (emergency department or trauma centre) has been shown as an effective means to reduce future alcohol intake and the incidence of future alcohol-related injuries, especially in the period immediately following injuries. Less is known about the potential benefit of BAI when provided by the surgical team in the same clinical context. This article explores the individual component of brief alcohol intervention and its provision by an acute surgical service by way of a narrative review. The progress of research into brief alcohol intervention for facial trauma patients is also reviewed. The methods and rationale behind screening patients for targeted BAI are discussed in a separate article. PMID- 28664353 TI - Adopting reciprocity theorem in deep transcranial magnetic stimulation problem to design an efficient single source coil array based on nerve cell direction. AB - Deep transcranial magnetic stimulation (dTMS) plays an important role in the treatment of many diseases. Previous designs rarely considered the direction of the induced electric field (E) with respect to nerve fibers. However, it can be observed from related formulae that the tangential component of E (E effective) has a more significant role in the stimulation of nerve cells. In this paper, a new approach is proposed for designing a single-source coil array (CA) by combining tractography and the reciprocity theorem (RT). This method is a non iterative procedure that can directly design CAs for the stimulation of each desired target zone without any complicated and slow iterative algorithm. Specifications of CA such as the optimum spatial angle and the best placement of coils are important because the location of the coil around the head and its spatial angle have been shown to have a major effect on induced E. Adoption of the RT yields the optimum specifications of CA and maximum E effective at the stimulation zone. This novel technique can introduce a new approach for the application of CA since it entails a high flexibility, high speed, and good accuracy. PMID- 28664354 TI - Impact of Medicine Withdrawal on Reporting of Adverse Events Involving Therapeutic Alternatives: A Study from the French Spontaneous Reporting Database. AB - INTRODUCTION: The consequences of the withdrawal of marketing authorisation of drugs have mostly been studied considering drug prescription patterns for the therapeutic alternatives of the withdrawn drugs. The potential concomitant changes in the reporting of adverse reactions concerning these alternatives have been studied less often. OBJECTIVE: The objective of this study was to analyse the changes in the reporting of adverse events (AEs) for therapeutic alternatives after the withdrawal of three medicines (dextropropoxyphene, pioglitazone and tetrazepam) from the market for safety reasons. METHODS: This study was performed using both the French pharmacovigilance database and the Echantillon Generaliste des Beneficiaires (a random sample of French health insurance affiliates). For dextropropoxyphene, pioglitazone and tetrazepam alternatives, the number and types of case reports were studied for both the year preceding the first official safety warning and the year following the withdrawal. Reporting rates expressed per 10,000 reimbursements (RRReimb) and per 10,000 treated patients (RRPat) were also compared for the two periods. RESULTS: After dextropropoxyphene withdrawal, case reports and reimbursements increased for tramadol (case reports: +23%, reimbursements: +13%) and codeine (case reports: +74%, reimbursements: +47%), RRPat being significantly increased for tramadol (0.92 vs. 1.06, p = 0.02). After pioglitazone withdrawal, case reports increased for dipeptidyl peptidase-4 (DPP 4) inhibitors, glinides, and glucagon-like peptide 1 (GLP-1) analogues (+84%, +22% and +5%, respectively) and reimbursements (+55, +11 and +50%, respectively); both decreased for sulfonylureas (case reports: -6%, reimbursements: -2%). RRPat increased for DPP-4 inhibitors (1.63 vs. 2.26, p = 0.008). After tetrazepam withdrawal, case reports increased for diazepam, methocarbamol and thiocolchicoside (+110, +86 and +157%, respectively), as lesser did reimbursements. RRPat increased for diazepam (1.78 vs. 2.41, p = 0.054) and thiocolchicoside (0.14 vs. 0.24, p = 0.013). CONCLUSION: For the three drug withdrawals investigated, the number of case reports involving alternatives increased to a larger extent than the numbers of prescriptions. This could relate to a higher occurrence of AEs in new users of alternatives who switched from the withdrawn medicines or to an increased awareness of possible AEs. PMID- 28664355 TI - Using Multiple Pharmacovigilance Models Improves the Timeliness of Signal Detection in Simulated Prospective Surveillance. AB - INTRODUCTION: Prospective pharmacovigilance aims to rapidly detect safety concerns related to medical products. The exposure model selected for pharmacovigilance impacts the timeliness of signal detection. However, in most real-life pharmacovigilance studies, little is known about which model correctly represents the association and there is no evidence to guide the selection of an exposure model. Different exposure models reflect different aspects of exposure history, and their relevance varies across studies. Therefore, one potential solution is to apply several alternative exposure models simultaneously, with each model assuming a different exposure-risk association, and then combine the model results. METHODS: We simulated alternative clinically plausible associations between time-varying drug exposure and the hazard of an adverse event. Prospective surveillance was conducted on the simulated data by estimating parametric and semi-parametric exposure-risk models at multiple times during follow-up. For each model separately, and using combined evidence from different subsets of models, we compared the time to signal detection. RESULTS: Timely detection across the simulated associations was obtained by fitting a set of pharmacovigilance models. This set included alternative parametric models that assumed different exposure-risk associations and flexible models that made no assumptions regarding the form/shape of the association. Times to detection generated using a simple combination of evidence from multiple models were comparable to those observed under the ideal, but unrealistic, scenario where pharmacovigilance relied on the single 'true' model used for data generation. CONCLUSIONS: Simulation results indicate that, if the true model is not known, an association can be detected in a more timely manner by first fitting a carefully selected set of exposure-risk models and then generating a signal as soon as any of the models considered yields a test statistic value below a predetermined testing threshold. PMID- 28664357 TI - Erratum to: Solitude, Religious and Cultural Uniqueness in a Foreign Environment: Adjustments as an Arab Student. PMID- 28664356 TI - Signal of Miscarriage with Aripiprazole: A Disproportionality Analysis of the Japanese Adverse Drug Event Report Database. AB - INTRODUCTION: With recent advances in medicines, many patients with schizophrenia have become able to conceive. One common second-generation antipsychotic given to patients with schizophrenia is aripiprazole. The label information of aripiprazole in Japan states that according to one case report "there is a report of miscarriage in clinical trial". OBJECTIVE: The aim of this study was to evaluate the relationship between aripiprazole and miscarriage by conducting a disproportionality analysis of an adverse drug event report database. METHODS: We conducted a disproportionality analysis of second-generation antipsychotic exposure during pregnancy using the Japanese Adverse Drug Event Report database, which is a spontaneous reporting database in Japan. We investigated aripiprazole and other approved second-generation antipsychotics in Japan. In accordance with the previous report, we created a data set for analysis consisting of pregnancy related reports. RESULTS: A potential signal for miscarriage was detected for aripiprazole [proportional reporting ratio: 2.39, chi 2: 13.77, reporting odds ratio (95% confidence interval): 2.76 (1.62-4.69); n = 18]. In contrast, no potential signal for miscarriage was detected for other second-generation antipsychotics. CONCLUSION: Through our analysis of the Japanese Adverse Drug Event Report database, we found a potential signal for miscarriage for aripiprazole. Safety information on the use of aripiprazole during pregnancy is very limited. Therefore, we suggest that the potential signal detected in our analysis be explored further. PMID- 28664358 TI - Oxytocin Intranasal Administration Affects Neural Networks Upstream of GNRH Neurons. AB - The last decade has witnessed a surge in studies on the clinical applications of intranasal oxytocin as a method of enhancing social interaction. However, the molecular and cellular mechanisms underlying its function are not completely understood. Since oxytocin is involved in the regulation of hypothalamic pituitary-gonadal axis by affecting the gonadotropin-releasing hormone (GNRH) system, the present study addressed whether intranasal application of oxytocin has a role in affecting GNRH expression in the male rat hypothalamus. In addition, we assessed expression of two excitatory (kisspeptin and neurokinin B) and two inhibitory (dynorphin and RFamide-related peptide-3) neuropeptides upstream of GNRH neurons as a possible route to relay oxytocin information. Here, adult male rats received 20, 40, or 80 MUg oxytocin intranasally once a day for 10 consecutive days, and then, the posterior (PH) and anterior hypothalamus (AH) dissected for evaluation of target genes. Using qRT-PCR, we found that oxytocin treatment increased Gnrh mRNA levels in both the PH and AH. In addition, oxytocin at its highest dose increased kisspeptin expression in the AH by around 400%, whereas treatments, dose dependently decreased kisspeptin mRNA in the PH. The expression of neurokinin B was increased from the basal levels following the intervention. Furthermore, although intranasal-applied oxytocin decreased hypothalamic RFamide-related peptide-3 mRNA level, the dynorphin mRNA was not affected. These observations are consistent with the hypothesis that applications of intranasal oxytocin can affect the GNRH system. PMID- 28664359 TI - Adverse cardiac events associated with incident opioid drug use among older adults with COPD. AB - PURPOSE: We evaluated whether incident opioid drug use was associated with adverse cardiac events among older adults with chronic obstructive pulmonary disease (COPD). METHODS: This was an exploratory, retrospective cohort study using health administrative data from Ontario, Canada, from 2008 to 2013. Using a validated algorithm, we identified adults aged 66 years and older with non palliative COPD. Hazard ratios (HR) were estimated for adverse cardiac events within 30 days of incident opioid receipt compared to controls using inverse probability of treatment weighting using the propensity score. RESULTS: There were 134,408 community-dwelling individuals and 14,685 long-term care residents with COPD identified, 67.0 and 60.6% of whom received an incident opioid. Incident use of any opioid was associated with significantly decreased rates of emergency room (ER) visits and hospitalizations for congestive heart failure (CHF) among community-dwelling older adults (HR 0.84; 95% CI 0.73-0.97), but significantly increased rates of ischemic heart disease (IHD)-related mortality among long-term care residents (HR 2.15; 95% CI 1.50-3.09). In the community dwelling group, users of more potent opioid-only agents without aspirin or acetaminophen combined had significantly increased rates of ER visits and hospitalizations for IHD (HR 1.38; 95% CI 1.08-1.77) and IHD-related mortality (HR 1.83; 95% CI 1.32-2.53). CONCLUSIONS: New opioid use was associated with elevated rates of IHD-related morbidity and mortality among older adults with COPD. Adverse cardiac events may need to be considered when administering new opioids to older adults with COPD, but further studies are required to establish if the observed associations are causal or related to residual confounding. PMID- 28664361 TI - Documentation, coding, and billing: what abdominal radiologists need to know. AB - This article reviews basic concepts of report documentation for abdominal imaging examinations, focusing on practical elements for ensuring appropriate physician reimbursement. Nuances of abdominal radiography, CT, MRI, and ultrasonography codes are highlighted. Special considerations for the coding of 3D-rendering and contrast administration are also described. Greater abdominal radiologist awareness of these codes and their reporting requirements can help ensure proper documentation within radiology reports, thereby optimizing legitimate reimbursement. PMID- 28664360 TI - Factors associated with antithrombotic treatment decisions for stroke prevention in atrial fibrillation in the Stockholm region after the introduction of NOACs. AB - PURPOSE: The purpose of this study was to investigate the influence of patient characteristics such as age and stroke and bleeding risks on decisions for antithrombotic treatment in patients with atrial fibrillation (AF). METHODS: This was a retrospective, population-based study including AF patients initiated with either warfarin, dabigatran, rivaroxaban, apixaban, or low-dose aspirin (ASA) between March 2015 and February 2016. Multivariate models were used to calculate adjusted odds ratios (aOR) for factors associated with treatment decisions. RESULTS: A total of 6765 newly initiated patients were included, most with apixaban (46.4%) and least with ASA (6.7%). There were more comorbidities in patients initiated with ASA or warfarin compared to the cohort average. Patients with high stroke risks had higher chances of receiving ASA (CHA2DS2-VASc >=5 vs 0; aOR 2.01; 95% confidence interval (CI) 1.12-3.33). Among patients receiving oral anticoagulants, patients with high bleeding risks more often received warfarin (ATRIA score 5-10 vs 0-3; aOR 1.40; CI 1.20-1.64). Among NOACs, apixaban was preferred for patients with higher stroke risks (aOR 1.78; CI 1.31-2.41), high bleeding risks (aOR 1.54; CI 1.26-1.88) and high age (age group >=85 vs 0 65; aOR 1.84; CI 1.44-2.35). Conversely, dabigatran treatment was associated with lower ages and lower risks. CONCLUSIONS: High stroke and bleeding risks favored choices of warfarin or ASA. Among patients receiving NOACs, apixaban was favored for elderly and high-risk patients whereas dabigatran was used in lower risk patients. The inadvertent use of ASA, especially among those with high stroke risks, should be further discouraged. PMID- 28664362 TI - Multifarious allelochemicals exhibiting antifungal activity from Bacillus subtilis MBCU5. AB - A potential antagonist, designated strain Bacillus subtilis MBCU5 was previously isolated from vermicompost-amended soils of Gandhinagar, Gujarat, India. Crude allelochemicals from strain MBCU5 displayed strong antifungal activity against Macrophomina phaseolina as well as Rhizoctonia solani. These crude allelochemicals were tentatively identified as iturin, fengycin and surfactin through TLC and HPTLC analysis. Lipopeptides produced by MBCU5 were identified by MALDI-TOF-MS and LC-ESI-MS/MS analysis showed that iturin homologues (m/z 1020 1120), surfactin (m/z 1008.7 and m/z 1022.7), fengycin A and fengycin B (m/z 1400 1550) types of allelochemicals which are responsible for antifungal activity against pathogens. PCR analysis showed presence of genes (i.e. Iturin A synthetase KJ531680 and Surfactin synthetase KJ601726) involved in the biosynthesis of allelochemicals. Many reports showed lipopeptides from Bacillus species; this is the first report executed of multifarious allelochemicals from vermicompost-amended soil due to the presence of predominant Bacillus species. PMID- 28664363 TI - A novel strain of Aureobasidium sp. TeO12 for theophylline production from caffeine. AB - A total of 40 fungal cultures were isolated for their ability to grow on caffeine as a sole source carbon and nitrogen, and further screened for theophylline producing activities under the growing cell system. Based on thin-layer chromatography and high-performance liquid chromatography analyses, the potent strain Aureobasidium sp. TeO12 was chosen for its capability to generate theophylline via biotransformation of caffeine. It was identified based on phenotypic characteristics and its ITS1-5.8S-ITS2 rDNA sequencing data (GenBank accession number no. KT439072). To improve theophylline yield, the effects of various factors, such as resting cell density, Fe(II) concentration, and course of the transformation of caffeine, were studied in a biotransformation reaction containing 0.1 M sodium phosphate buffer (pH 7), Aureobasidium sp. TeO12 resting cells as the whole-cell catalyst and caffeine (2.5 g/L) as the substrate, and the reaction was incubated at 30 degrees C on an orbital shaker (200 rpm). The results indicated that optimal combination included resting cell density 6 g/L, Fe(II) concentration 75 mg/L, and the biotransformation time 72 h. Under these optimal reaction conditions, the highest theophylline concentration of 1.55 g/L (molar yield of 67%) with an average degradation yield of the substrate of about 83% was obtained in the biotransformation process. This is the first report on the biotransformation of caffeine into theophylline by a novel strain of the genus Aureobasidium. PMID- 28664364 TI - Pyramiding of tea Dihydroflavonol reductase and Anthocyanidin reductase increases flavan-3-ols and improves protective ability under stress conditions in tobacco. AB - Tea (Camellia sinensis) is one of the richest sources of flavan-3-ols, an important class of flavonoids. The expression level of gene-encoded key regulatory enzymes of flavan-3-ol/anthocyanin biosynthetic pathway, dihydroflavonol 4-reductase (DFR) and anthocyanidin reductase (ANR), has been highly correlated with the flavan-3-ol contents and antioxidant activity in tea plant. In the present study, pyramiding of CsDFR and CsANR in tobacco was achieved. However, single transgenic tobacco overexpressing either CsDFR or CsANR was documented earlier. In continuation, pyramided transgenic lines were evaluated for the possible, either same or beyond, effect on flavan-3-ol accumulation and protective ability against biotic and abiotic stresses. The pyramided transgenic lines showed early flowering and improved seed yield. The transcript levels of flavan-3-ol/anthocyanin biosynthetic pathway and related genes in pyramided transgenic lines were upregulated as compared to control tobacco plants. The accumulations of flavan-3-ols were also found to be higher in pyramided transgenic lines than control tobacco plants. In contrast, anthocyanin content was observed to be decreased in pyramided transgenic lines, while DPPH activity was higher in pyramided transgenic lines. In pyramided transgenic lines, strong protective ability against feeding by Spodoptera litura was documented. The seeds of pyramided transgenic lines were also found to have better germination rate under aluminum toxicity as compared to control tobacco plants. Interestingly, the synergistic effect of these two selected genes are not beyond from transgenic lines expressing either CsDFR and CsANR alone as published earlier in terms of flavan-3-ols accumulation. However, the unique flower color and better seed germination rate are some interestingly comparable differences that were reported in pyramided lines in relation to individual transgenic plants. In conclusion, the present results reveal an interesting dynamic between CsDFR and CsANR in modulating flavan-3-ol/anthocyanin levels and functional analysis of stacked CsDFR and CsANR transgenic tobacco lines. PMID- 28664365 TI - Comparative in situ biodegradation studies of polyhydroxybutyrate film composites. AB - Application of polyhydroxybutyrate (PHB) to plastic industry has expanded over the last decades due to its attracting features over petro-based plastic, and therefore, its waste accumulation in nature is inevitable. In the present study, a total of four bacterial strains, viz., MK3, PN12, PW1, and Lna3, were formulated into a consortium and subsequently used as biological tool for degradation of biopolymers. The consortium was tested through lambda max shifts under in vitro conditions for utilization of PHB as sole carbon source. Talc based bioformulations of consortium were used for the degradation of PHB film composites under in situ conditions. After 9 months of incubation, the recovered samples were monitored through Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM), respectively. Analytical data, viz., changes in lambda max shifts (212-219 nm), FT-IR spectra, and SEM micrographs, revealed the biodegradation potential of developed consortium against PHB film composites, i.e., higher degradation of copolymer films was found over blend films. The used consortium had enhanced the rate of natural degradation and can be further used as a natural tool to maintain and restore global environmental safety. PMID- 28664366 TI - Production, characterization and structural modification of exopolysaccharide based bioflocculant by Rhizobium radiobacter SZ4S7S14 and media optimization. AB - Synthesis of the exopolysaccharide-based bioflocculant Rhizobium radiobacter SZ4S7S14 was researched and medium optimized for enhanced production of bioflocculant. D-Mannose and yeast extract were found to be best carbon and nitrogen sources for maximal yield of bioflocculant. The bioflocculant samples obtained in different media with different carbon and nitrogen sources were further analyzed by SEM-EDX and FT-IR. FT-IR spectroscopy of the bioflocculant samples, obtained in different carbon/nitrogen sources showed slight modification of the structures of biopolymers. SEM micrographs revealed that exopolysaccharide based bioflocculant of R. radiobacter SZ4S7S14 looks like bricks, and chemical structure of it can be varied due to utilized carbon and nitrogen source. PMID- 28664367 TI - A quick and effective in-house method of DNA purification from agarose gel, suitable for sequencing. AB - Sequencing of DNA fragments (e.g., ITS, 16S, 18S, particular genes, and molecular markers) is increasingly required in studies on microbial diversity, microbial genetic population and phylogeny, sequencing of alleles, and searching for SNPs, among others. The cost of obtaining these DNAs, in quantity and quality for sequencing, is high as it involves special kits to recover DNA from gel after PCR, or the cloning and purification of plasmids with commercial kits. Genetic population and other studies require the analyses of many samples, and therefore, the high cost represents an obstacle for carrying out such projects in countries where there is great biodiversity, such as the tropical and subtropical developing countries, where funds are limited. Modifying an already known method for DNA recovery from gel, the first in-house protocol of DNA recovery suitable for direct use in sequencing is presented herein. This protocol is broadly applicable on DNAs from all different living beings, e.g., bacteria, fungi, and plants. Its simplicity, speed, and low cost make this procedure amenable for high throughput DNA sequencings as required in microbial population studies, development of molecular markers, molecular identification of strains in microbial collections, and others. Recovery of DNA fragments from agarose gel is one of the most common tasks in molecular biology laboratories. Therefore, its potential of applicability of the protocol presented here is enormous. PMID- 28664368 TI - Comparative genomic analysis of Mycobacterium neoaurum MN2 and MN4 substrate and product tolerance. AB - The microbial bioconversion of sterols can afford valuable steroid precursors, such as 4-androstene-3,17-dione (AD) and androsta-1,4-diene-3,17-dione (ADD). The Mycobacterium neoaurum MN4 mutant strain can produce AD in high yield and can tolerate a higher concentration of the substrate phytosterol than the parent strain M. neoaurum MN2. In order to further investigate the mechanisms underlying the enhanced substrate and product tolerance, we performed a genomic analysis of the MN2 and MN4 strains. The genomes were sequenced using a high-throughput approach and analyzed using software for genome assembly, gene prediction and functional annotation, KEGG (Kyoto Encyclopedia of Genes and Genomes) annotation, COG (cluster of orthologous) group cluster analysis, GO cluster analysis, and SNP detection and annotation. Based on comparative genomics, 184 mutations were identified in MN4, the average variant rate of 1 variant every 27,249 bases, with a TS/TV value of 0.5877 and missense mutations in one key sterol degradation genes (ChoM1) and four side chain degradation genes that encode enzymes catalysing beta-oxidation. The results suggest the high AD yield might be due to mutation of ChoM and genes encoding FadE, FadB and FadA beta-oxidation enzymes. This study provides a theoretical basis for further functional genomics analysis and heterologous production of M. neoaurum MN2 secondary metabolites. PMID- 28664369 TI - Rapid and efficient method to extract metagenomic DNA from estuarine sediments. AB - Metagenomic DNA from sediments of selective estuaries of Goa, India was extracted using a simple, fast, efficient and environment friendly method. The recovery of pure metagenomic DNA from our method was significantly high as compared to other well-known methods since the concentration of recovered metagenomic DNA ranged from 1185.1 to 4579.7 ug/g of sediment. The purity of metagenomic DNA was also considerably high as the ratio of absorbance at 260 and 280 nm ranged from 1.88 to 1.94. Therefore, the recovered metagenomic DNA was directly used to perform various molecular biology experiments viz. restriction digestion, PCR amplification, cloning and metagenomic library construction. This clearly proved that our protocol for metagenomic DNA extraction using silica gel efficiently removed the contaminants and prevented shearing of the metagenomic DNA. Thus, this modified method can be used to recover pure metagenomic DNA from various estuarine sediments in a rapid, efficient and eco-friendly manner. PMID- 28664370 TI - Total crude protein extract of Trichoderma spp. induces systemic resistance in pearl millet against the downy mildew pathogen. AB - Several proteins and peptides of microbial origin are reported for their elicitor properties, which play a vital role in the development of local and systemic resistances in plants. In this study, the efficacy of total crude proteins (TCP) extracted from six different Trichoderma spp. (T. asperellum, T. harzianum, T. atroviride, T. virens, T. longibrachiatum, and T. brevicompactum) was evaluated for their ability to elicit defense responses in pearl millet against downy mildew disease. Priming of pearl millet seeds (with or without mannitol) with different concentrations of TCP from Trichoderma spp. does not affect the seed germination and seedling vigor significantly. Under greenhouse conditions, a varied level of disease protection was recorded with TCP of different Trichoderma spp., and furthermore, its efficacy was found increased when treated with mannitol. Total crude protein extracts of T. atroviride (75 ug/ml) with mannitol recorded significantly higher disease protection of 53.6% in comparison with respective controls. Furthermore, this observation was supported by elevated levels of peroxidase (7.7 U @ 36 h after inoculation) and lipoxygenase (29.5 U @ 48 h after inoculation) and hypersensitive necrotic spots (56% @ 24 h after inoculation). The present study illustrated the capability of TCP extracted from different Trichoderma spp. to elicit the disease resistance mechanism in pearl millet seedlings against Sclerospora graminicola. PMID- 28664371 TI - Production, purification and characterization of fibrinolytic enzyme from Serratia sp. KG-2-1 using optimized media. AB - Intravascular thrombosis is one of the major causes of variety of cardiovascular disorders leading to high mortality worldwide. Fibrinolytic enzymes from microbial sources possess ability to dissolve these clots and help to circumvent these problems in more efficient and safer way. In the present study, fibrinolytic protease with higher fibrinolytic activity than plasmin was obtained from Serratia sp. KG-2-1 isolated from garbage dump soil. Response surface methodology was used to study the interactive effect of concentration of maltose, yeast extract + peptone (1:1), incubation time, and pH on enzyme production and biomass. Maximum enzyme production was achieved at 33 degrees C after 24 h at neutral pH in media containing 1.5% Maltose, 4.0% yeast extract + peptone and other trace elements resulting in 1.82 folds increased production. The enzyme was purified from crude extract using ammonium sulfate precipitation and DEAE Sephadex chromatography resulting in 12.9 fold purification with 14.9% yield. The purified enzyme belongs to metalloprotease class and had optimal activity in conditions similar to physiological environment with temperature optima of 40 degrees C and pH optima of 8. The enzyme was found to be stable in various solvents and its activity was enhanced in presence of Na+, K+, Ba2+, Cu2+, Mn2+, Hg2+ but inhibited by Ca2+ and Fe3+. Hence, the obtained enzyme may be used as potential therapeutic agent in combating various thrombolytic disorders. PMID- 28664372 TI - Modeling and optimization of fermentation variables for enhanced production of lactase by isolated Bacillus subtilis strain VUVD001 using artificial neural networking and response surface methodology. AB - Modeling and optimization were performed to enhance production of lactase through submerged fermentation by Bacillus subtilis VUVD001 using artificial neural networks (ANN) and response surface methodology (RSM). The effect of process parameters namely temperature ( degrees C), pH, and incubation time (h) and their combinational interactions on production was studied in shake flask culture by Box-Behnken design. The model was validated by conducting an experiment at optimized process variables which gave the maximum lactase activity of 91.32 U/ml. Compared to traditional activity, 3.48-folds improved production was obtained after RSM optimization. This study clearly shows that both RSM and ANN models provided desired predictions. However, compared with RSM (R 2 = 0.9496), the ANN model (R 2 = 0.99456) gave a better prediction for the production of lactase. PMID- 28664373 TI - Chicken egg shell as a potential substrate for production of alkaline protease by Bacillus altitudinis GVC11 and its applications. AB - Chicken egg shell and membrane were used as substrate for production of alkaline protease by Bacillus altitudinis GVC11. Maltose as additional carbon source enhanced enzyme production up to 13%. Addition of organic nitrogen sources like peptone and yeast extract increased enzyme production by 9% and 5%, respectively and inorganic nitrogen sources did not have any positive effect. The resultant protein hydrolyzate after fermentation was found to have essential amino acids such as leucine, phenyl alanine, isoleucine, lysine, valine, methionine, arginine in considerable quantities and minute concentrations of cysteine. The protein hydrolyzate was also found to have good antioxidant activity. PMID- 28664374 TI - Multiple linear regression and artificial neural networks for delta-endotoxin and protease yields modelling of Bacillus thuringiensis. AB - The aim of the present work was to develop a model that supplies accurate predictions of the yields of delta-endotoxins and proteases produced by B. thuringiensis var. kurstaki HD-1. Using available medium ingredients as variables, a mathematical method, based on Plackett-Burman design (PB), was employed to analyze and compare data generated by the Bootstrap method and processed by multiple linear regressions (MLR) and artificial neural networks (ANN) including multilayer perceptron (MLP) and radial basis function (RBF) models. The predictive ability of these models was evaluated by comparison of output data through the determination of coefficient (R 2) and mean square error (MSE) values. The results demonstrate that the prediction of the yields of delta endotoxin and protease was more accurate by ANN technique (87 and 89% for delta endotoxin and protease determination coefficients, respectively) when compared with MLR method (73.1 and 77.2% for delta-endotoxin and protease determination coefficients, respectively), suggesting that the proposed ANNs, especially MLP, is a suitable new approach for determining yields of bacterial products that allow us to make more appropriate predictions in a shorter time and with less engineering effort. PMID- 28664375 TI - Human sperm DNA damage inhibition and antioxidant activity of T. arjuna bark: an in vitro study. AB - Complimentary or natural antioxidant type of alternative medicine is developed worldwide to treat male infertility. The aim of this study is to the extraction of T. arjuna bark and activity against human sperm DNA damage in asthenoteratospermic smoker's subjects-an in vitro study. All preliminary and antioxidant assays (DPPH, H2O2, and total antioxidant, reducing power activity) were done. T. arjuna bark metal analysis was done with AAS. On the other hand, patients were asked to fill a direct questionnaire about smoking history; 25 infertile smokers were identified as asthenoteratospermic; 34 fertile non-smokers (control) were assessed for semen parameters by CASA, seminal plasma Zinc analysis by AAS, DNA fragmentation by colorimetric method and semen genomic DNA damage inhibition by modified non-enzymatic salting out extraction method. Most of the antioxidants are highly present in the aqueous extract; meanwhile, the major content in this extract is zinc 16 ug/g (Ca = 0.5 ug/g; Se = 2.2 ug/g and Mg = 1.6 ug/g) along with FT-IR peaks which also confirmed the metal presence. The semen parameters in smokers that were noticed are low sperm count and morphological changes. Meanwhile, in the seminal plasma of smokers, zinc and DNA fragmentation results were positively correlated with sperm morphology (p < 0.001). Repaired DNA bands were noticed in the in vitro study of aqueous T. arjuna bark, in smokers' semen. T. arjuna bark will act as cryo protector as well as great zinc supplementary to maintain sperm motility and morphology in smokers. PMID- 28664376 TI - Functional analysis of selected deletion mutants in Candida glabrata under hypoxia. AB - Increased drug resistance in Candida glabrata (a model non-albicans Candida) calls for the identification of potential molecular targets for the development of effective drugs. Hypoxia (a state of low oxygen) is an important host factor, which affects the virulence of the pathogen and efficacy of drugs. In the present study, in vitro characterization of 13 null mutants of C. glabrata were done under hypoxic condition (1% O2). These mutants have a major role to play in cellular pathways, viability and pathogenesis (cell wall biosynthesis, ergosterol synthesis, calcium-calcineurin, etc.). The in vitro growth, biofilm formation and susceptibility of biofilm to antifungal drugs of these mutants were compared with the control. Hypoxia reduced the susceptibility of planktonic cells to fluconazole. The mutants ecm33Delta, kre1Delta, rox1Delta, and kre2Delta showed maximum reductions in their biofilm activities (>20%). The selected mutants (upc2BDelta, kre2 Delta, ecm7Delta, rox1 Delta, mid1Delta, ecm33Delta, cch1Delta, kre1Delta) showed reduced biofilm activities (>30%) in the presence of 16 MUg ml 1 fluconazole under hypoxia. Functional analysis revealed that Kre1, Ecm33, Upc2B, Kre2, Ecm7, Cch1, Mid1 and Rox1 can be explored as a potential drug target for developing novel antifungal drugs. PMID- 28664377 TI - Codon usage analysis of photolyase encoding genes of cyanobacteria inhabiting diverse habitats. AB - Nucleotide and amino acid compositions were studied to determine the genomic and structural relationship of photolyase gene in freshwater, marine and hot spring cyanobacteria. Among three habitats, photolyase encoding genes from hot spring cyanobacteria were found to have highest GC content. The genomic GC content was found to influence the codon usage and amino acid variability in photolyases. The third position of codon was found to have more effect on amino acid variability in photolyases than the first and second positions of codon. The variation of amino acids Ala, Asp, Glu, Gly, His, Leu, Pro, Gln, Arg and Val in photolyases of three different habitats was found to be controlled by first position of codon (G1C1). However, second position (G2C2) of codon regulates variation of Ala, Cys, Gly, Pro, Arg, Ser, Thr and Tyr contents in photolyases. Third position (G3C3) of codon controls incorporation of amino acids such as Ala, Phe, Gly, Leu, Gln, Pro, Arg, Ser, Thr and Tyr in photolyases from three habitats. Photolyase encoding genes of hot spring cyanobacteria have 85% codons with G or C at third position, whereas marine and freshwater cyanobacteria showed 82 and 60% codons, respectively, with G or C at third position. Principal component analysis (PCA) showed that GC content has a profound effect in separating the genes along the first major axis according to their RSCU (relative synonymous codon usage) values, and neutrality analysis indicated that mutational pressure has resulted in codon bias in photolyase genes of cyanobacteria. PMID- 28664378 TI - Cloning of D-lactate dehydrogenase genes of Lactobacillus delbrueckii subsp. bulgaricus and their roles in D-lactic acid production. AB - Lactobacillus delbrueckii subsp. bulgaricus is a heterogenous lactic acid bacterium that converts pyruvate mainly to D-lactic acid using D-lactate dehydrogenases (D-LDHs), whose functional properties remain poorly characterized. Here, the D-LDHs genes (ldb0101, ldb0813, ldb1010, ldb1147 and ldb2021) were cloned and overexpressed in Escherichia coli JM109 from an inducible pUC18 vector, respectively, and the resulting strains were compared in terms of D lactic acid production. The strain expressing ldb0101 and ldb1010 gene individually produced more D-lactate than other three strains. Further study revealed that Ldb0101 activity was down-regulated by the oxygen and, therefore, achieved a highest titer of D-lactate (1.94 g/L) under anaerobic condition, and introduction of ldb1010 gene enhanced D-lactate formation (0.94 and 0.85 g/L, respectively) both in aerobic and anaerobic conditions due to a relatively stable q d-lactate. Our results suggested that the enzyme Ldb0101 and Ldb1010 played a role of more importance in D-lactate formation. To the best of our knowledge, we demonstrate for the first time the roles of different D-LDH homologs from L. bulgaricus in D-lactic acid production. PMID- 28664379 TI - Development and characterization of novel microsatellite markers in Trillium govanianum: a threatened plant species from North-Western Himalaya. AB - Trillium govanianum is a temperate forest understory plant species of high value belonging to the family Melanthiaceae. It is endemic to Himalayan region and facing a bottleneck situation due to reckless extractions from its natural strands. In the present study, 21 microsatellite markers were developed and characterized in 20 accessions of T. govanianum. Collectively, the polymorphic markers amplified 31 alleles in a range of 2-4 with an average of 2.6 alleles per marker. The mean observed heterozygosity (H o), expected heterozygosity (H e), and Shannon information index (I) were 0.46, 0.48, and 0.73, respectively. Average polymorphism information content (PIC) was 0.385. The cross transferability in a related species, namely, Polygonatum verticillatum, showed amplification of ten markers. The newly developed microsatellite markers efficiently distinguished the different accessions on the basis of their geographic origin. Thus, these microsatellites can be useful in exploring genetic diversity in various existing populations of T. govanianum in north-western Himalaya, which may be useful for their conservation, management, and improvement in future. PMID- 28664380 TI - The influence of agitation on oil substrate dispersion and oxygen transfer in Pseudomonas aeruginosa USM-AR2 fermentation producing rhamnolipid in a stirred tank bioreactor. AB - Water-immiscible substrate, diesel, was supplied as the main substrate in the fermentation of Pseudomonas aeruginosa USM-AR2 producing rhamnolipid biosurfactant, in a stirred tank bioreactor. In addition to the typical gas aqueous system, this system includes gas-hydrocarbon-aqueous phases and the presence of surfactant (rhamnolipid) in the fermentation broth. The effect of diesel dispersion on volumetric oxygen transfer coefficient, k L a, and thus oxygen transfer, was evaluated at different agitations of 400, 500 and 600 rpm. The oxygen transfer in this oil-water-surfactant system was shown to be affected by different oil dispersion at those agitation rates. The highest diesel dispersion was obtained at 500 rpm or impeller tip speed of 1.31 m/s, compared to 400 and 600 rpm, which led to the highest k L a, growth and rhamnolipid production by P. aeruginosa USM-AR2. This showed the highest substrate mixing and homogenization at this agitation speed that led to the efficient substrate utilization by the cells. The oxygen uptake rate of P. aeruginosa USM-AR2 was 5.55 mmol/L/h, which showed that even the lowest k L a (48.21 h-1) and hence OTR (57.71 mmol/L/h) obtained at 400 rpm was sufficient to fulfill the oxygen demand of the cells. The effect of rhamnolipid concentration on k L a showed that k L a increased as rhamnolipid concentration increased to 0.6 g/L before reaching a plateau. This trend was similar for all agitation rates of 400, 500 and 600 rpm, which might be due to the increase in the resistance to oxygen transfer (k L decrease) and the increase in the specific interfacial area (a). PMID- 28664381 TI - Development of a mixed microbial culture for thiocyanate and metal cyanide degradation. AB - The degradation capacity of a mixed culture of Agrobacterium tumefaciens SUTS 1 and Pseudomonas monteilii SUTS 2 for thiocyanate and metal cyanide, in the form of zinc and cadmium, has been determined. The growth of a mixed culture of SUTS 1 and SUTS 2 in cyanide complexes and the cyanide removal efficiency of a fixed film bio-column system were studied. The results showed that the mixed culture of bacteria can survive and grow in broth media containing thiocyanate and metal cyanide complexes with a maximum cell of 1.03 * 108 CFU/mL on day 3. In addition, the optimal conditions of the fixed-film bio-column system were continuously tested for 24 h, and it was found that this system had the highest removal efficiency at a flow rate of 10 mL/min and 21 min of empty bed retention time, with decreasing thiocyanate, zinc, and cadmium from 85, 0.44, and 0.044 to 65, 0.21, and 0.038 mg/L, respectively; this is in contrast to cyanide, which was not found within 12 h. Next, the conditions were maintained for 30 days, and it was found that the system had removed more than 50% of cyanide complexes, except cadmium. The complex residues were 29.96, 0.16, 0.204, and 0.085 mg/L of thiocyanate, cyanide, zinc, and cadmium, respectively. In addition, the growth of the SUTS 1 and SUTS 2 mixed culture increased. The by-product compounds sulfate and nitrate were found throughout the experiment, whereas bicarbonate and ammonia were found only on certain days. PMID- 28664382 TI - Direct Determination of Nimesulide in Natural Waters and Wastewater by Cathodic Stripping Voltammetry. AB - Pharmaceuticals are included in a group of compounds considered as contaminants of emerging concern (CECs) in environmental matrices. The quantification of CECs is typically accomplished using chromatographic methods that require several sample pretreatment steps. The current study proposes a voltammetric method to quantify directly nimesulide (NIM) in aqueous samples. The voltammetric parameters were optimized and chosen based on the profile of the voltammograms and peak current intensity. The adequacy of the analytical method was evaluated using validation criteria, such as accuracy, selectivity, linearity, detection, and quantification limits. Linearity was assessed by a standard addition curve at a concentration range of 0.5-130 ug L-1 of NIM. The limit of quantification was 0.50 ug L-1, with 60 s of preconcentration time. Accuracy was expressed as recovery percentages of NIM and ranged from 111.4 to 119.8%. The voltammetric method herein proposed has several advantages over others already used to determine NIM, such as fewer sample pretreatment steps, faster, and cheaper analyses. NIM was detected in wastewater samples at concentration levels ranging from 101.7 to 385.0 ug L-1. This result is the first evidence about NIM occurrences in environmental matrices in the area surrounding the Itaipu Lake reservoir in Brazil. PMID- 28664383 TI - The slow progressive nature of duodenal neuroendocrine tumor: a case report of long-term observation over 14 years. AB - The number of duodenal neuroendocrine tumors has recently increased, but their natural history has not been well characterized. Here we report the case of a 59 year-old female undergoing complete resection by endoscopic mucosal resection after monitoring endoscopic morphologic changes and the size increment of a duodenal neuroendocrine tumor over the longest follow-up duration. An elevated lesion was initially detected on the duodenal bulb. Endoscopic biopsy from this lesion was performed three times during the follow-up, but all of the specimens simply demonstrated the presence of gastric metaplasia. Thereafter, in the esophagogastroduodenoscopy performed 14 years after the initial examination, a slight depression was detected in the center of the lesion together with an incremental change of its size. The histopathologic diagnosis of neuroendocrine tumor was made by deeper tissue sampling, and the patient subsequently underwent endoscopic mucosal resection for this tumor and was finally diagnosed with a G1 duodenal neuroendocrine tumor with pT2 cN0, cM0, stage IIa in the TNM classification. This is the first case demonstrating the slowly progressive nature of such a tumor with the longest follow-up of a duodenal neuroendocrine tumor ever reported, which could provide important information regarding the natural history and management of such tumors. PMID- 28664384 TI - A case of protein-losing enteropathy caused by sclerosing mesenteritis diagnosed with capsule endoscopy and double-balloon endoscopy. AB - A 75-year-old man presented with abdominal distension, hypoproteinemia, ascites and a 35-mm mass in the small bowel mesentery. Laparotomy was performed, and he was diagnosed with sclerosing mesenteritis. His clinical condition improved, with computed tomography (CT) showing tumor shrinkage and decreasing ascites after administration of prednisolone; however, on drug withdrawal, abdominal fullness recurred and CT revealed an enlarging tumor and increasing ascites. Capsule endoscopy (CE) and double-balloon enteroscopy (DBE) were performed to further investigate hypoalbuminemia, which revealed white villi, white nodules, white debris, and mucosal edema in the jejunum. Biopsies from the jejunal mucosa demonstrated infiltration by chronic inflammatory cells consisting mostly of lymphocytes and plasma cells, with marked lymphangiectasia of the lamina propria and submucosa. A fecal alpha-1-antitrypsin clearance test revealed abnormal leakage from the gastrointestinal tract, confirming that hypoalbuminemia was secondary to protein-losing enteropathy (PLE). The incidence of sclerosing mesenteritis accompanied by PLE is very rare. Only six cases have been reported so far. CE and DBE were helpful for diagnosing this condition, and should be performed in patients in whom the cause of hypoalbuminemia is unknown, and in those with PLE. PMID- 28664385 TI - Pazopanib: a Review in Advanced Renal Cell Carcinoma. AB - Pazopanib (Votrient(r)), an orally administered multi-targeted tyrosine kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor 1, -2 and -3, platelet-derived growth factor receptor-alpha and -beta, and the stem cell factor receptor c-Kit, is approved in the EU, the USA and other countries for the treatment of advanced renal cell carcinoma (RCC). In randomized controlled trials in patients with advanced, predominantly clear-cell RCC, pazopanib significantly improved progression-free survival (PFS) compared with placebo in both treatment-naive and cytokine-pretreated patients and, as a first line therapy, was noninferior to intermittent sunitinib with respect to PFS. However, pazopanib had a tolerability profile that was distinguishable from that of sunitinib, based on lower incidences of most adverse events, particularly those associated with discomfort, such as fatigue, hand-foot syndrome and stomatitis. Consistent with this, health-related quality of life (HR-QOL) measures evaluating fatigue, hand/foot soreness and mouth/throat soreness significantly favoured pazopanib over sunitinib. In addition, significantly more patients expressed a preference for pazopanib over sunitinib, primarily because of better overall HR-QOL and less fatigue. Efficacy and tolerability findings from these prospective clinical trials have been substantiated by evidence from a number of retrospective studies evaluating unselected real-world patients with metastatic RCC who received pazopanib (or sunitinib) as a first-line therapy. Thus, data from clinical trials supplemented with that from clinical practice support the use of pazopanib as a standard or alternative first-line treatment for advanced or metastatic RCC. PMID- 28664387 TI - Overview of Cancer Stem Cells and Stemness for Community Oncologists. AB - Advances in cancer research in the past have led to an evolving understanding of cancer pathogenesis and the development of novel drugs that significantly improve patient outcomes. However, many patients still encounter treatment resistance, recurrence, or metastasis and eventually die from progressing disease. Experimental evidence indicates that a subpopulation of cancer cells, called cancer stem cells (CSCs), possess "stemness" properties similar to normal stem cells, including self-renewal, differentiation, and proliferative potential. These stemness properties are lost during differentiation and are governed by pathways such as STAT3, NANOG, NOTCH, WNT, and HEDGEHOG, which are highly dysregulated in CSCs due to genetic and epigenetic changes. Promising results have been observed in preclinical models targeting these CSCs through the disruption of stemness pathways in combination with current treatment modalities. This has led to anti-CSC-based clinical trials in multiple stages of development. In this review, we discuss the role of CSCs and stemness pathways in cancer treatment and how they relate to clinical observations. Because CSCs and the stemness pathways governing them may explain the negative clinical outcomes observed during treatment, it is important for oncologists to understand how they contribute to cancer progression and how they may be targeted to improve patient outcomes. PMID- 28664388 TI - Effect of photobiomodulation therapy on reducing the chemo-induced oral mucositis severity and on salivary levels of CXCL8/interleukin 8, nitrite, and myeloperoxidase in patients undergoing hematopoietic stem cell transplantation: a randomized clinical trial. AB - Oral mucositis (OM) is the most common debilitating complication among patients undergoing hematopoietic stem cell transplantation (HSCT). Photobiomodulation therapy (PBM) has shown beneficial effects in the treatment of OM, but few studies have evaluated its biological effects. This study evaluated the effect of PBM on the reduction of OM severity in patients undergoing HSCT and its relation to the modulation of the inflammatory response. Fifty-one patients were randomly assigned to two groups: PBM [submitted to PBM from admission (AD) to D+7] (n = 27) and control (n = 24) [received oral hygiene]. OM severity was assessed daily using the WHO scale. Saliva samples were collected on AD, D+7, and hospital discharge (HD) to measure CXCL8/interleukin 8, using cytometric bead array analysis and nitrite (NO) and myeloperoxidase (MPO) using colorimetric methods. PBM significantly reduced the severity of OM from D+7 to D+11 (p < 0.05). All non interventional patients (controls) who developed grade 2 or higher OM induced an increase of CXCL8 in saliva (n = 14) on D+7. PBM led to a decrease in CXCL8 on D+7 in 85% of patients, while 70.8% of patients in the control group presented an increase in this chemokine (p = 0.007). NO decreased from AD to D+7 in the PBM group (p > 0.05). MPO significantly decreased on D+7 in both groups (p < 0.05). PBM brought about a reduction in the severity of OM in patients undergoing HSCT, and this reduction was associated with a decrease in CXCL8 salivary levels. PMID- 28664386 TI - Novel Therapies for Acute Myeloid Leukemia: Are We Finally Breaking the Deadlock? AB - Acute myeloid leukemia (AML) is one of the best studied malignancies, and significant progress has been made in understanding the clinical implications of its disease biology. Unfortunately, drug development has not kept pace, as the '7+3' induction regimen remains the standard of care for patients fit for intensive therapy 40 years after its first use. Temporal improvements in overall survival were mostly confined to younger patients and driven by improvements in supportive care and use of hematopoietic stem cell transplantation. Multiple forms of novel therapy are currently in clinical trials and are attempting to bring bench discoveries to the bedside to benefit patients. These novel therapies include improved chemotherapeutic agents, targeted molecular inhibitors, cell cycle regulators, pro-apoptotic agents, epigenetic modifiers, and metabolic therapies. Immunotherapies in the form of vaccines; naked, conjugated and bispecific monoclonal antibodies; cell-based therapy; and immune checkpoint inhibitors are also being evaluated in an effort to replicate the success seen in other malignancies. Herein, we review the scientific basis of these novel therapeutic approaches, summarize the currently available evidence, and look into the future of AML therapy by highlighting key clinical studies and the challenges the field continues to face. PMID- 28664389 TI - Preliminary study in a new protocol for the treatment of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and chemotherapy (CT). AB - Oral mucositis (OM) is a debilitating and serious side effect in patients undergoing hematopoietic stem cell transplantation (HSCT) and chemotherapy (CT). Laser therapy is becoming a promising treatment option in these patients, avoiding the necessity of enteral/parenteral nutrition. The aim of this study was to evaluate the efficacy of laser therapy in patients affected by oral mucositis induced by chemotherapy and HSCT. Sixteen onco-hematological pediatric patients receiving chemotherapy and hematopoietic stem cell transplantation, affected by oral mucositis, were enrolled in this study. They were divided in two randomized groups: the laser group and the placebo-control group. Patients in the laser group were treated with HPLT (970 +/- 15 nm, 3.2 W (50%), 35-6000 Hz, 240 s) for four consecutive days, once a day; and placebo group underwent sham treatment. The assessment of mucositis was recorded through WHO Oral Mucositis Grading Objective Scale, and pain was evaluated through Visual Analogue Scale (VAS). Patients were monitored and evaluated 3, 7, and 11 days after the first day of laser therapy. Once OM was diagnosed, the patients had mucositis grading assessments before laser or sham application at day 3, 7, and 11 after first application. All patients of laser group demonstrated improvement in pain sensation from day 3 after first application of laser (p < 0.05), ulcerations reduced their dimensions and erythema disappeared. The patients of placebo group had improvement from day 7. In laser group, all mucositis were fully resolved from day 7 (p < 0.05). Oral mucositis negatively impacts on nutritional intake, oral hygiene, and quality of life. Laser therapy appears to be a safe and innovative approach in the management of oral mucositis. In this preliminary study, HPLT encourages to consider laser therapy as a part of onco-hematological protocol, providing to decrease pain and duration of OM induced by CT and HSCT. Further researches will be needed, especially randomized, controlled clinical trials with a large number of enrolled patients and a long term of follow-up to confirm the efficacy of laser therapy in prevention and control of OM in onco hematological pediatric patients. PMID- 28664390 TI - Clinical application of intense pulsed light depilation technology in total auricular reconstruction. AB - Although ear reconstruction technology has been highly developed in recent years, hair growth on the reconstructed ear has plagued both surgeons and patients. In this paper, the authors introduce a clinical application of intense pulsed light depilation in total auricular reconstruction. From August 2012 to August 2013, 27 patients (28 ears) suffering from congenital microtia were treated by intense pulsed light depilation (650-950-nm filter, initial fluence of 14-16 J/cm2 and gradually increased, pulse width of 30-50 ms, spot size of 20 * 30 mm2, intervals of 6-8 weeks, a total of four sessions) either before or after auricular reconstruction. According to the treatment situation at diagnosis, the patients were divided into two groups: the preoperative group and the postoperative group. There were no differences between the two groups in terms of age or initial fluence for hair removal; however, there were less treatments in the former than in the latter group (preoperative group 4.1 +/- 0.3, postoperative group 4.7 +/- 0.7, F = 9.10, P = 0.006), and the maximum fluence used for hair removal was lower in the former than in the latter group (preoperative group 18-20 J/cm2, postoperative group 19-22 J/cm2, F = 22.31, P < 0.001). After follow-up for >=4-6 months, the effective rate was 100% in the preoperative group, and the effective rate was 80% in the postoperative group. Intense pulsed light depilation technology is a reasonable complementary approach to total auricular reconstruction. And preoperative depilation is recommended over postoperative depilation. The non-invasive modern photonic technology can resolve the problem of postoperative residual hair on the reconstructed auricle, improving auricular shape and increasing patient satisfaction. In addition, an adequately set preoperative hair removal area can provide surface skin that is most similar to normal auricle skin for auricular reconstruction. PMID- 28664391 TI - Dobutamine, a beta1 Adrenoceptor Agonist, Increases Cerebral Oxygenation During Acute Anemia and Apneic Hypoxia. AB - BACKGROUND: beta1 blockers increase the risk of cerebral hypoxia during acute anemia and apneic hypoxia. We hypothesized that beta1 stimulants conversely increase cerebral tolerance to anemia and hypoxia. METHODS: After induction with isoflurane, twelve swine (mean +/- SD: 25.2 +/- 0.6 kg) received 200 ug kg-1 min 1 landiolol and 20 ug kg-1 min-1 dobutamine. Reversal of the order of drug administration was performed in six animals each. Before and during each drug infusion, apnea was induced until reaching <70% oxygen saturation (SpO2) after 5 min of 100% oxygen ventilation. Hemodynamic and blood gas variables were measured, and the cerebral and peripheral tissue oxygenation index (TOI) was recorded by near-infrared spectroscopy (apnea experiment). Following this, anemia (isovolemic hemodilution) was induced and apnea experiments were conducted in three stages, similarly to those before anemia. RESULTS: Dobutamine increased cerebral TOI before apnea (fraction of inspired oxygen [FiO2]: 1.0), at 1 min after apnea, and at SpO2 < 70% by 7.9, 8.8, and 3.9%. Landiolol decreased TOI by 0.8, 2.6, and 4.4% from the respective values at baseline. During anemia, these changes decreased with dobutamine and increased with landiolol administration. Dobutamine (or landiolol) shifted the relationship between TOI and arterial hemoglobin oxygen saturation or arterial partial pressure of oxygen to the right (or left) and increased (or decreased) TOI at similar arterial blood oxygenation. CONCLUSIONS: Dobutamine increases cerebral oxygenation during hypoxia and/or anemia and might be effective in improving neurological outcomes in ischemic cerebral injury. PMID- 28664393 TI - Dual-isotope myocardial perfusion SPECT imaging: Past, present, and future. PMID- 28664392 TI - Validation of Near-Infrared Spectroscopy for Monitoring Cerebral Autoregulation in Comatose Patients. AB - BACKGROUND: Transcranial Doppler (TCD) noninvasively measures cerebral blood flow (CBF) velocity and is a well-studied method to monitor cerebral autoregulation (CA). Near-infrared spectroscopy (NIRS) has emerged as a promising noninvasive method to determine CA continuously by using regional cerebral oxygen saturation (rSO2) as a surrogate for CBF. Little is known about its accuracy to determine CA in patients with intracranial lesions. The purpose of this study was to assess the accuracy of rSO2-based CA monitoring with TCD methods in comatose patients with acute neurological injury. METHODS: Thirty-three comatose patients were monitored at the bedside to measure CA using both TCD and NIRS. Patients were monitored daily for up to three days from coma onset. The cerebral oximetry index (COx) was calculated as the moving correlation between the slow waves of rSO2 and mean arterial pressure (MAP). The mean velocity index (Mx) was calculated as a similar coefficient between slow waves of TCD-measured CBF velocity and MAP. Optimal blood pressure was defined as the MAP with the lowest Mx and COx. Averaged Mx and COx as well as optimal MAP, based on both Mx and COx, were compared using Pearson's correlation. Bias analysis was performed between these same CA metrics. RESULTS: The median duration of monitoring was 60 min (interquartile range [IQR] 48-78). There was a moderate correlation between the averaged values of COx and Mx (R = 0.40, p = 0.005). Similarly, there was a strong correlation between optimal MAP calculated for COx and Mx (R = 0.87, p < 0.001). Bland-Altman analysis showed moderate agreement with bias (+/-standard deviation) of -0.107 (+/-0.191) for COx versus Mx and good agreement with bias of 1.90 (+/-7.94) for optimal MAP determined by COx versus Mx. CONCLUSIONS: Monitoring CA with NIRS-derived COx is correlated and had good agreement with previously validated TCD-based method. These results suggest that COx may be an acceptable substitute for Mx monitoring in patients with acute intracranial injury. PMID- 28664394 TI - Discover mouse gene coexpression landscapes using dictionary learning and sparse coding. AB - Gene coexpression patterns carry rich information regarding enormously complex brain structures and functions. Characterization of these patterns in an unbiased, integrated, and anatomically comprehensive manner will illuminate the higher-order transcriptome organization and offer genetic foundations of functional circuitry. Here using dictionary learning and sparse coding, we derived coexpression networks from the space-resolved anatomical comprehensive in situ hybridization data from Allen Mouse Brain Atlas dataset. The key idea is that if two genes use the same dictionary to represent their original signals, then their gene expressions must share similar patterns, thereby considering them as "coexpressed." For each network, we have simultaneous knowledge of spatial distributions, the genes in the network and the extent a particular gene conforms to the coexpression pattern. Gene ontologies and the comparisons with published gene lists reveal biologically identified coexpression networks, some of which correspond to major cell types, biological pathways, and/or anatomical regions. PMID- 28664395 TI - Three new species of Begonia sect. Baryandra from Panay Island, Philippines. AB - BACKGROUND: The flora of Panay Island is under-collected compared with the other islands of the Philippines. In a joint expedition to the island, botanists from Taiwan and the Philippines found three unknown Begonia species and compared them with potentially allied species. RESULTS: The three species are clearly assignable to Begonia sect. Baryandra which is largely endemic to the Philippines. Studies of literature, herbarium specimens, and living plants support the recognition of the three new species: Begonia culasiensis, B. merrilliana, and B. sykakiengii. Somatic chromosomes at metaphase were determined to be 2n = 30 for B. culasiensis and 2n = 28 for both B. merrilliana and B. sykakiengii, congruent with those of most species in sect. Baryandra. Molecular phylogenetic evidence is consistent with B. culasiensis being a relict from the late Miocene and B. merrilliana and B. sykakiengii being younger species of Pleistocene origin. CONCLUSION: The continuing discovery of endemic Philippine species means the remaining fragments of both primary and secondary native vegetation in the archipelago are of increasing value in terms of natural capital. A secure future for the species could be realized through ex situ conservation collections and raising awareness with community groups. PMID- 28664396 TI - Allelopathy and resource competition: the effects of Phragmites australis invasion in plant communities. AB - BACKGROUND: Phragmites australis, a ubiquitous wetland plant, has been considered one of the most invasive species in the world. Allelopathy appears to be one of the invasion mechanisms, however, the effects could be masked by resource competition among target plants. The difficulty of distinguishing allelopathy from resource competition among plants has hindered investigations of the role of phytotoxic allelochemicals in plant communities. This has been addressed via experiments conducted in both the greenhouse and laboratory by growing associated plants, Melaleuca ericifolia, Rumex conglomeratus, and model plant, Lactuca sativa at varying densities with the allelopathic plant, P. australis, its litter and leachate of P. australis litter. This study investigated the potential interacting influences of allelopathy and resource competition on plant growth density relationships. RESULTS: In greenhouse, the root exudates mediated effects showed the strongest growth inhibition of M. ericifolia at high density whereas litter mediated results revealed increased growth at medium density treatments compared to low and high density. Again, laboratory experiments related to seed germination and seedling growth of L. sativa and R. conglomeratus exhibited phytotoxicity decreased showing positive growth as plant density increased and vice versa. Overall, the differential effects were observed among experiments but maximum individual plant biomass and some other positive effects on plant traits such as root and shoot length, chlorophyll content occurred at an intermediate density. This was attributed to the sharing of the available phytotoxin among plants at high densities which is compatible to density-dependent phytotoxicity model. CONCLUSIONS: The results demonstrated that plant-plant interference is the combined effect of allelopathy and resource competition with many other factors but this experimental design, target-neighbor mixed-culture in combination of plant grown at varying densities with varying level of phytotoxins, mono-culture, can successfully separate allelopathic effects from competition. PMID- 28664397 TI - Peripheral Blood Monocyte Tolerance Alleviates Intraperitoneal Lipopolysaccharides-Induced Neuroinflammation in Rats Via Upregulating the CD200R Expression. AB - Neuroinflammation is an important pathogenesis of Parkinson's disease (PD). The peripheral immune system could produce profound effects on central immunities. The peripheral blood monocyte (PBM) immune tolerance is the refractoriness of immune system to avoid overactive peripheral inflammation. The PBM are also actively involved in central immune activities. There is evidence implying the probable failure of immune tolerance and impairment of CD200/CD200R signaling in PD patients. Here we aimed to explore the effects of PBM tolerance in peripheral LPS-induced neuroinflammation as well as the specific roles of CD200/CD200R pathway in PBM tolerance. We found that repeated intraperitoneal administration of 0.3 mg/kg LPS was able to induce the PBM tolerance. PBM tolerance reduced peripheral LPS-induced elevation of serum TNF-alpha, IL-1beta expression and TLR4 expression in PBM. PBM tolerance and PBM depletion alleviated peripheral LPS induced neuroinflammation demonstrated by reduced proinflammatory cytokines in brain and blocked microglia activation. The CD200R expression in PBM was upregulated in PBM tolerance group after intraperitoneal administration of high dose LPS in vivo and the blockade of CD200/CD200R interaction induced the failure of PBM tolerance in vitro. These results suggested the PBM tolerance could attenuate the peripheral LPS-induced neuroinflammation via upregulating the CD200R expression and the CD200/CD200R signaling played a key role in PBM tolerance. Effective regulation of the PBM in periphery may be a potential way to limit neuroinflammation while the CD200R on PBM could be used as a potential therapeutic target to alleviate neuroinflammation. PMID- 28664398 TI - Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder characterized by impairing levels of hyperactivity, impulsivity and inattention. Oxidative and inflammatory parameters have been recognized among its multiple predisposing pathways, and clinical studies indicate that ADHD patients have increased oxidative stress. In this study, we aimed to evaluate oxidative (DCFH oxidation, glutathione levels, glutathione peroxidase, catalase and superoxide dismutase activities) and inflammatory (TNF-alpha, IL-1beta and IL-10) parameters in the most widely accepted animal model of ADHD, the spontaneously hypertensive rats (SHR). Prefrontal cortex, cortex (remaining regions), striatum and hippocampus of adult male SHR and Wistar Kyoto rats were studied. SHR presented increased reactive oxygen species (ROS) production in the cortex, striatum and hippocampus. In SHR, glutathione peroxidase activity was decreased in the prefrontal cortex and hippocampus. TNF-alpha levels were reduced in the prefrontal cortex, cortex (remaining regions), hippocampus and striatum of SHR. Besides, IL-1beta and IL-10 levels were decreased in the cortex of the ADHD model. Results indicate that SHR presented an oxidative profile that is characterized by an increase in ROS production without an effective antioxidant counterbalance. In addition, this strain showed a decrease in cytokine levels, mainly TNF-alpha, indicating a basal deficit. These results may present a new approach to the cognitive disturbances seen in the SHR. PMID- 28664399 TI - Metformin Attenuates Neurological Deficit after Intracerebral Hemorrhage by Inhibiting Apoptosis, Oxidative Stress and Neuroinflammation in Rats. AB - Intracerebral hemorrhage (ICH) can lead to brain damage and even death, and there is lack of effective therapeutic methods for treating ICH. Although recent studies have focused on the administration of metformin in treating stroke, there is no literature to support whether it can be used to treat ICH. Therefore, the aim of this study was to evaluate the possible effects of metformin on ICH and the underlying mechanisms of those effects. An ICH model was established in adult male Sprague-Dawley rats. Rats were randomly divided into three groups: sham group, ICH group, and ICH+metformin group. The neurobehavioral deficit scoring method was used to examine neurological function in rats. The levels of lipid peroxidation antioxidant enzyme and 8-iso-PGF2alpha were detected to evaluate oxidative stress. Survival of striatal neurons was examined by TUNEL staining, immunohistochemistry and HE staining. The levels of p-JNK, p-c-Jun and cleaved caspase-3 in the striatum were measured by western blotting. The results demonstrated that metformin protected rats from neurological deficits induced by ICH. Moreover, metformin reduced oxidative stress and preserved the survival of striatal neurons under ICH conditions. Furthermore, metformin downregulated the levels of apoptotic factors (p-JNK3, p-c-Jun and cleaved caspase-3) as well as pro-inflammatory cytokines (IL-1beta, IL-4 and IL-6 and TNF-alpha). Collectively, we speculate that metformin may be a potential clinical treatment for ICH patients. PMID- 28664401 TI - Preface for the Steve White Honorary Issue of Neurochemical Research. PMID- 28664400 TI - Astrocytes Provide Metabolic Support for Neuronal Synaptic Function in Response to Extracellular K. AB - It is an honour to have this opportunity write an article in recognition of the immense contributions of Bruce Ransom to the field of glial research. For me (BAM) personally there are many highlights both as a colleague and a friend that come to mind when I reflect on the many years that I have known Bruce. My own entry into the glial field was inspired by the early work by Ransom and his lab showing the sensitivity of astrocytes to neuronal activity. During my PhD and postdoctoral research I read these early papers and was inspired to ask the question when I first set up my independent lab in 1983: what if astrocytes also express some of the multitude of ion channels or transmitter receptors that were beginning to be described in neurons? Could they modify neuronal excitability during seizures or behaviour? As it turned out this was not only true but glial neuronal interactions continues to be a growing and exciting field that I am still working in. I first met Bruce at the 1984 Society for Neuroscience meeting in Anaheim at my poster describing voltage gated calcium channels in astrocytes in cell culture. That was the start of a great friendship and years of discussions and collaborations. This review describes recent work from my lab led by Hyun Beom Choi that followed and was inspired by the groundbreaking studies by Bruce on electrophysiological and pH recordings from astrocytes and on glycogen mobilization in astrocytes to protect white matter axons. PMID- 28664402 TI - Reduced Proliferation of Oligodendrocyte Progenitor Cells in the Postnatal Brain of Dystonia Musculorum Mice. AB - Dystonia musculorum (dt) mice show sensory neurodegeneration and movement disorder, such as dystonia and cerebellar ataxia. The causative gene Dystonin (Dst) encodes a cytoskeleton linker protein. Although sensory neurodegeneration has been well studied, glial cell responses in the central nervous system (CNS) are poorly understood. Here, we investigated cell proliferation in the CNS of Dst Gt homozygous mice using newly generated in situ hybridization (ISH) probes-Ki-67 and proliferating cell nuclear antigen (PCNA) probes-both of which effectively detect proliferating cells. We found that Ki-67-positive cells were significantly decreased in the corpus callosum and thalamus of dt brain at postnatal day 21 (P21). There is a similar but not significant tendency at postnatal day 14 (P14) in the dt brain. We also confirmed the reduced proliferation by PCNA ISH and Ki 67 immunohistochemistry. Double staining with cell-type-specific markers revealed that proliferating cells are oligodendrocyte progenitor cells (OPCs) in both wild type and dt brain. We also observed a reduced number of Olig2-positive cells in the corpus callosum of Dst Gt homozygous mice at P21, indicating that reduced proliferation resulted in a reduced number of OPCs. Our data indicate that OPCs proliferation is reduced in the dt mouse brain at the postnatal stage and that it subsequently results in the reduced number of OPCs. PMID- 28664403 TI - RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia. AB - Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the Abeta-induced inflammatory response by blocking the ligation of Abeta to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF kappaB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE. PMID- 28664404 TI - Chemical Evolution and the Evolutionary Definition of Life. AB - Darwinian evolution requires a mechanism for generation of diversity in a population, and selective differences between individuals that influence reproduction. In biology, diversity is generated by mutations and selective differences arise because of the encoded functions of the sequences (e.g., ribozymes or proteins). Here, I draw attention to a process that I will call chemical evolution, in which the diversity is generated by random chemical synthesis instead of (or in addition to) mutation, and selection acts on physicochemical properties, such as hydrolysis, photolysis, solubility, or surface binding. Chemical evolution applies to short oligonucleotides that can be generated by random polymerization, as well as by template-directed replication, and which may be too short to encode a specific function. Chemical evolution is an important stage on the pathway to life, between the stage of "just chemistry" and the stage of full biological evolution. A mathematical model is presented here that illustrates the differences between these three stages. Chemical evolution leads to much larger differences in molecular concentrations than can be achieved by selection without replication. However, chemical evolution is not open-ended, unlike biological evolution. The ability to undergo Darwinian evolution is often considered to be a defining feature of life. Here, I argue that chemical evolution, although Darwinian, does not quite constitute life, and that a good place to put the conceptual boundary between non-life and life is between chemical and biological evolution. PMID- 28664405 TI - Potential association between ITPKC genetic variations and Hirschsprung disease. AB - Hirschsprung disease (HSCR) is a congenital and complex disorder characterized by intestinal obstruction due to the absence of enteric neurons along variable lengths of the hindgut. Our recent genome-wide association study (GWAS) has revealed regional associations with HSCR at several loci of inositol trisphosphate 3-kinase C (ITPKC). For fine mapping, we additionally selected and genotyped a total of 12 single nucleotide polymorphisms (SNPs) of ITPKC in 187 HSCR patients and 283 unaffected controls, and performed a further combined imputation analysis based on genotype data from this second stage of fine mapping and our previous GWAS stage, totaling 902 subjects (187 HSCR cases and 715 controls). As a result, several SNPs (minimum P = 0.004) and a haplotype (P = 0.02) were found to be significantly associated with HSCR. In further in silico analyses to ascertain the potential functions of the significant variants, the change from the common allele to the rare allele of the highly conserved nonsynonymous rs76785336 showed a difference in mRNA folding structure. In the case of intronic SNPs, rs2607420 with a high consensus value was predicted to be a new splice site. Although this study has limitations (such as lack of functional evaluations, small number of cases, and further need of replication in other cohorts), our findings suggest that genetic variants of ITPKC may have a potential association with HSCR susceptibility and/or developmental diseases related to enteric nervous system development. PMID- 28664407 TI - Combined use of electron microscopy and intravital imaging captures morphological and functional features of podocyte detachment. AB - The development of podocyte injury and albuminuria in various glomerular pathologies is still incompletely understood due to technical limitations in studying the glomerular filtration barrier (GFB) in real-time. We aimed to directly visualize the early morphological and functional changes of the GFB during the development of focal segmental glomerulosclerosis (FSGS) using a combination of transmission electron microscopy (TEM) and in vivo multiphoton microscopy (MPM) in the rat puromycin aminonucleoside (PAN) model. We hypothesized that this combined TEM + MPM experimental approach would provide a major technical improvement that would benefit our mechanistic understanding of podocyte detachment. Male Sprague-Dawley (for TEM) or Munich-Wistar-Fromter (for MPM) rats were given a single dose of 100-150 mg/kg body weight PAN i.p. and were either sacrificed and the kidneys processed for TEM or surgically instrumented for in vivo MPM imaging at various times 2-14 days after PAN administration. Both techniques demonstrated hypertrophy and cystic dilatations of the subpodocyte space that developed as early as 2-3 days after PAN. Adhesions of the visceral epithelium to the parietal Bowman's capsule (synechiae) appeared at days 8-10. TEM provided unmatched resolution of podocyte foot process remodeling, while MPM revealed the rapid dynamics of pseudocyst filling, emptying, and rupture, as well as endothelial and podocyte injury, misdirected filtration, and podocyte shedding. Due to the complementary advantages of TEM and MPM, this combined approach can provide an unusally comprehensive and dynamic portrayal of the alterations in podocyte morphology and function during FSGS development. The results advance our understanding of the role and importance of the various cell types, hemodynamics, and mechanical forces in the development of glomerular pathology. PMID- 28664406 TI - Renal biopsy-driven molecular target identification in glomerular disease. AB - Chronic kidney disease has severe impacts on the patient and represents a major burden to the health care systems worldwide. Despite an increased knowledge of pathophysiological processes involved in kidney diseases, the progress in defining novel treatment strategies has been limited. One reason is the descriptive disease categorization used in nephrology based on clinical findings or histopathological categories irrespective of potential different molecular disease mechanisms. To accelerate progress toward a targeted treatment, a definition of human disease extending from phenotypic disease classification to mechanism-based disease definitions is needed. In recent years, we have witnessed a major transition in biomedical research from a single gene research to an information rich and collaborative science. Tissue-based analysis in renal disease allows to link structure to molecular function. In our review, we introduce the concept of precision medicine in nephrology, describe several large cohort studies established for molecular analysis of kidney diseases, and highlight examples of renal biopsy-driven target identification by integrative systems biology approaches. Furthermore, we give an outlook on how the new disease definitions can be used for patient stratification in clinical trial design. Finally, we introduce the concept of an informational commons of renal precision medicine for joint analyses of large-scale data sets in renal failure. PMID- 28664408 TI - Focal segmental glomerulosclerosis; why does it occur segmentally? AB - Podocyte loss is the fundamental basis of glomerulosclerosis. Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease, and its glomerular features are a prototype of podocyte loss-driven glomerulosclerosis. The glomerular pathology of FSGS is characterized by a focal and segmental location of the sclerotic lesions in human FSGS; segmental sclerosis often shows simultaneous intra- and extra-capillary changes, including parietal cell migration, capillary collapse, hyaline deposition, and intra-capillary thrombi and occasional hypercellularity. This suggests that local cellular events, initiated by podocyte loss, are the basis of the segmental lesions in FSGS. Using podocyte-specific injury by toxin administration, a series of recent works has identified the cellular basis of the glomerular response to podocyte loss. This review discusses the molecular pathway of the local response to podocyte loss and its progression to sclerosis. Recent results suggest that segmental sclerosis is a physiological tissue response aimed at halting protein leakage from a disrupted filtration barrier. PMID- 28664409 TI - Surfen is a broad-spectrum calcium channel inhibitor with analgesic properties in mouse models of acute and chronic inflammatory pain. AB - Multiple voltage-gated calcium channels (VGCCs) contribute to the processing of nociceptive signals in primary afferent fibers. In addition, alteration of calcium channel activity is associated with a number of chronic pain conditions. Therefore, VGCCs have emerged as prime target for the management of either neuropathic or inflammatory pain, and selective calcium channel blockers have been shown to have efficacy in animal models and in the clinic. However, considering that multiple calcium channels contribute pain afferent signaling, broad-spectrum inhibitors of several channel isoforms may offer a net advantage in modulating pain. Here, we have analyzed the ability of the compound surfen to modulate calcium channels, and assessed its analgesic potential. We show that surfen is an equipotent blocker of both low- and high-voltage-activated calcium channels. Furthermore, spinal (intrathecal) delivery of surfen to mice produces sustained analgesia against both acute and chronic pain. Collectively, our data establish surfen as a broad-spectrum calcium channel inhibitor with analgesic potential, and raise the possibility of using surfen-derived compounds for the development of new pain-relieving drugs. PMID- 28664411 TI - [The 2016 update of the S3 guideline for malignant tumours of the ovary : Role of pathology in diagnosis, therapy and clinical management of epithelial tumours]. AB - Tumor stage, residual postoperative tumor, histological type and grading are considered among the main prognostic parameters in the consensus-based recommendations in the new S3 guidelines for diagnosis, treatment and clinical follow-up of malignant tumours of the ovary. Based on the 2014 update of the WHO Classification of Tumours of the Female Reproductive Organs this article summarizes the most significant changes. For example now the same TNM and FIGO classification applies for tumours of the ovary, peritoneum or fallopian tube. Noninvasive implants of serous borderline tumours are now named implants. In contrast, invasive implants are regarded as low-grade serous carcinoma. By presenting the current background information, we want to provide a basis for discussion, regarding more detailed consensus recommendations for pathologists and clinicians in the future. PMID- 28664410 TI - Efficacy of Vonoprazan-Based Triple Therapy for Helicobacter pylori Eradication: A Multicenter Study and a Review of the Literature. AB - BACKGROUND: Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment. MATERIALS AND METHODS: Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature. RESULTS: The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6-96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0-101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies. CONCLUSIONS: Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature. PMID- 28664412 TI - Early Use of Ceftaroline Fosamil in the United States Veterans Health Care System. AB - BACKGROUND: Ceftaroline fosamil is US Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, but it is not known how ceftaroline is being used in real world settings or how adverse effects (AEs) and mortality compare to clinical trials. OBJECTIVE: This study describes ceftaroline use, AEs, and mortality in US Veterans Health Administration (VHA) hospital patients. METHODS: This phase IV, population-based, epidemiologic study analyzed patients >=18 years old who received one or more ceftaroline doses within 14 days of admission to 69 VHA hospitals in 41 US states/territories from 1 October 2010 to 30 September 2014. VHA repository data were linked using unique patient identifiers. Diagnoses and AEs were determined using ICD9-CM and CSS codes. Demographics, AEs within 30 days of therapy initiation, and all-cause in-hospital mortality were summarized using descriptive statistics. RESULTS: 764 Patients met study criteria. Patients were 97% male and 56% White, with a median age of 61 years and a Charlson score of 6. Diagnoses included skin (40%), sepsis (30%), osteomyelitis (25%), diabetic foot (22%), pneumonia (16%), bacteremia (11%), endocarditis (6%), meningitis (2%), and device (2%) infections. Ceftaroline was used first-line (37%), second-line (56%), and third-line or greater (7%). Patients received ceftaroline a median of 3 days after hospital admission. All-cause in-hospital mortality rates were: overall (5%), skin (2%), sepsis (9%), osteomyelitis (3%), diabetic foot (1%), pneumonia (13%), bacteremia (6%), endocarditis (11%), meningitis (6%), and device (13%). Eosinophilia, leukopenia, leukocytosis, fibromyalgia, myalgia and myositis, and polymyalgia rates were <1% each. CONCLUSIONS: Ceftaroline is used in VHA hospitals for various diagnoses. Mortality was low and comparable with rates from clinical trials. Additional studies comparing ceftaroline to other drugs used in similar situations are needed. PMID- 28664413 TI - Molecular profiling of sarcomas: new vistas for precision medicine. AB - Sarcoma is a large and heterogeneous group of malignant mesenchymal neoplasms with significant histological overlap. Accurate diagnosis can be challenging yet important for selecting the appropriate treatment approach and prognosis. The currently torrid pace of new genomic discoveries aids our classification and diagnosis of sarcomas, understanding of pathogenesis, development of new medications, and identification of alterations that predict prognosis and response to therapy. Unfortunately, demonstrating effective targets for precision oncology has been elusive in most sarcoma types. The list of potential targets greatly outnumbers the list of available inhibitors at the present time. This review will discuss the role of molecular profiling in sarcomas in general with emphasis on selected entities with particular clinical relevance. PMID- 28664414 TI - Do obstetric risk factors truly influence the etiopathogenesis of congenital muscular torticollis? AB - BACKGROUND: Congenital muscular torticollis (CMT) is seen in childhood and presents within months after birth. The etiology remains unknown; however, medical textbooks suggest trauma at birth as a main reason. The aim of this study was to systematically describe obstetric and perinatal outcomes in a population of children with a confirmed congenital muscular torticollis diagnosis. MATERIALS AND METHODS: Children with a validated diagnosis of congenital muscular torticollis born at Aarhus University Hospital from 2000 to 2014 were included in the study. Information on perinatal, intrapartum and neonatal characteristics were obtained from databases and from medical records, and systematically described. RESULTS: In this study, there were no differences in birth characteristics in children with left- and right-sided torticollis, between boys and girls or between the conservatively treated and the children who needed surgery. Most of the children with congenital muscular torticollis in this study were delivered at term without signs of birth complications or trauma. None experienced moderate or severe asphyxia. CONCLUSIONS: The results of the present study suggests that complicated birth or birth trauma may not be the main cause of congenital muscular torticollis and point towards intrauterine and prenatal reasons for its development. LEVEL OF EVIDENCE ACCORDING TO OCEBM LEVELS OF EVIDENCE WORKING GROUP: 3. PMID- 28664415 TI - Validation of three-dimensional models of the distal femur created from surgical navigation point cloud data for intraoperative and postoperative analysis of total knee arthroplasty. AB - PURPOSE: Despite the success of total knee arthroplasty, there continues to be a significant proportion of patients who are dissatisfied. One explanation may be a shape mismatch between pre- and postoperative distal femurs. The purpose of this study was to investigate methods suitable for matching a statistical shape model (SSM) to intraoperatively acquired point cloud data from a surgical navigation system and to validate these against the preoperative magnetic resonance imaging (MRI) data from the same patients. METHODS: A total of 10 patients who underwent navigated total knee arthroplasty also had an MRI scan <2 months preoperatively. The standard surgical protocol was followed which included partial digitization of the distal femur. Two different methods were employed to fit the SSM to the digitized point cloud data, based on (1) iterative closest points and (2) Gaussian mixture models. The available MRI data were manually segmented and the reconstructed three-dimensional surfaces used as ground truth against which the SSM fit was compared. RESULTS: For both approaches, the difference between the SSM-generated femur and the surface generated from MRI segmentation averaged less than 1.7 mm, with maximum errors occurring in less clinically important areas. CONCLUSION: The results demonstrated good correspondence with the distal femoral morphology even in cases of sparse datasets. Application of this technique will allow for measurement of mismatch between pre- and postoperative femurs retrospectively on any case done using the surgical navigation system and could be integrated into the surgical navigation unit to provide real-time feedback. PMID- 28664416 TI - A surgical robot with augmented reality visualization for stereoelectroencephalography electrode implantation. AB - PURPOSE: Using existing stereoelectroencephalography (SEEG) electrode implantation surgical robot systems, it is difficult to intuitively validate registration accuracy and display the electrode entry points (EPs) and the anatomical structure around the electrode trajectories in the patient space to the surgeon. This paper proposes a prototype system that can realize video see through augmented reality (VAR) and spatial augmented reality (SAR) for SEEG implantation. The system helps the surgeon quickly and intuitively confirm the registration accuracy, locate EPs and visualize the internal anatomical structure in the image space and patient space. METHODS: We designed and developed a projector-camera system (PCS) attached to the distal flange of a robot arm. First, system calibration is performed. Second, the PCS is used to obtain the point clouds of the surface of the patient's head, which are utilized for patient to-image registration. Finally, VAR is produced by merging the real-time video of the patient and the preoperative three-dimensional (3D) operational planning model. In addition, SAR is implemented by projecting the planning electrode trajectories and local anatomical structure onto the patient's scalp. RESULTS: The error of registration, the electrode EPs and the target points are evaluated on a phantom. The fiducial registration error is [Formula: see text] mm (max 1.22 mm), and the target registration error is [Formula: see text] mm (max 1.18 mm). The projection overlay error is [Formula: see text] mm, and the TP error after the pre-warped projection is [Formula: see text] mm. The TP error caused by a surgeon's viewpoint deviation is also evaluated. CONCLUSION: The presented system can help surgeons quickly verify registration accuracy during SEEG procedures and can provide accurate EP locations and internal structural information to the surgeon. With more intuitive surgical information, the surgeon may have more confidence and be able to perform surgeries with better outcomes. PMID- 28664417 TI - Epicardial adipose tissue: at the heart of the obesity complications. AB - In recent years, the anatomic and functional contiguity of epicardial adipose tissue (EAT) to myocardium and coronary arteries has gained increasing interest for its potential pathogenetic role in obesity-related cardiac diseases. Besides its known and attributed biochemical cardioprotective properties, it is becoming evident that, in metabolic disease states, EAT-secreted bioactive molecules may play an important role in the pathogenesis of coronary artery disease and cardiac arrhythmias. EAT-derived inflammatory cytokines and reactive oxidative species may, indeed, play a part in the development of a local proatherogenic milieu by paracrine and vasocrine mechanisms of interaction. In addition, initial clinical and in vitro studies have pointed out that EAT could be a determinant of the substrate of atrial fibrillation by contributing to the structural and electrical remodeling of myocardium. This article reviews the current state of knowledge on the association of EAT with cardiac dysfunction and the potential factors mediating the cross talk between this fat depot and the underlying cardiac structures. PMID- 28664418 TI - Diet-dependent heat emission reveals costs of post-diapause recovery from different nutritional sources in a carnivorous beetle. AB - Restoration of fat stores is metabolic first priority for many insects that emerge from hibernation with depleted fat bodies. To some extent, the animals must be flexible and use whatever foods available irrespective of their nutrient composition. Previously, the carabid beetles Anchomenus dorsalis have been found to refill their fat stores to the same extent over 9 days irrespective of the nutrient composition of their food. However, a higher cost of fat deposition when the food was rich in sugar or protein rather than lipid was indicated by higher total energy consumption. Here, we test the hypothesis of increased metabolic costs of building fat stores from sugar- or protein-rich food than from lipid rich food by microcalorimetry. We measured the heat emitted from beetles that had fed on sugar-, protein-, or lipid-rich food for 0 (common control), 2, 5, or 10 days. As predicted, heat emission was increased in beetles getting sugar- and protein-rich food compared with those getting lipid-rich food. However, we did not confirm the beetles' ability to rebuild fat stores from protein-rich food; instead, they increased in lean mass. Overall, sugar-rich food seems to be optimal for post-winter recovery, because it is better than lipid-rich food that allows concurrent rebuilding of fat stores and lean mass, which may benefit preparation for spring migration and reproduction. We propose that overwintered fruits may be highly preferred post-diapause food for these otherwise mostly carnivorous beetles. PMID- 28664419 TI - Females' sampling strategy to comparatively evaluate prospective mates in the peacock blenny Salaria pavo. AB - Emerging evidence suggests the occurrence of comparative decision-making processes in mate choice, questioning the traditional idea of female choice based on rules of absolute preference. In such a scenario, females are expected to use a typical best-of-n sampling strategy, being able to recall previous sampled males based on memory of their quality and location. Accordingly, the quality of preferred mate is expected to be unrelated to both the number and the sequence of female visits. We found support for these predictions in the peacock blenny, Salaria pavo, a fish where females have the opportunity to evaluate the attractiveness of many males in a short time period and in a restricted spatial range. Indeed, even considering the variability in preference among females, most of them returned to previous sampled males for further evaluations; thus, the preferred male did not represent the last one in the sequence of visited males. Moreover, there was no relationship between the attractiveness of the preferred male and the number of further visits assigned to the other males. Our results suggest the occurrence of a best-of-n mate sampling strategy in the peacock blenny. PMID- 28664420 TI - Treatment Beliefs Underlying Intended Treatment Choices in Knee and Hip Osteoarthritis. AB - PURPOSE: Patients' beliefs about treatment modalities for knee and hip osteoarthritis (OA) will underlie their treatment choices. Based on the Theory of Planned Behavior, it is hypothesized that patients' beliefs, subjective norm, and perceived behavioral control guide their treatment choices. Also, symptom severity and one's inherent tendency to approach or avoid situations are assumed to play a role. The objective of this study was to test whether these variables were associated with intended treatment choices in knee and hip OA. METHODS: Patients with knee and hip OA were randomly selected from hospital patient records. They completed the Treatment beliefs in OsteoArthritis questionnaire to assess positive and negative treatment beliefs regarding five treatment modalities: physical activities, pain medication, physiotherapy, injections, and arthroplasty. Other measures were intention, subjective norm, perceived behavioral control (ASES), symptom severity (WOMAC), and the person's general tendency to approach or avoid situations (RR/BIS scales). Three models were tested using path analyses to examine the hypothesized associations. RESULTS: Participants were 289 patients. Positive treatment beliefs and subjective norm were consistently associated with intended treatment choice across all treatment modalities. Negative treatment beliefs were associated with intended treatment choices for pain medication and arthroplasty. Other associations were not significant. CONCLUSIONS: This is the first study testing the Theory of Planned Behavior in the context of treatment choices in OA. Findings suggest that foremost positive beliefs about treatment modalities and the norms of one's social environment guide a specific treatment choice. Unexpectedly, symptom severity was not related to intended treatment choices. PMID- 28664421 TI - Identification and functional analysis of new peroxygenases in oat. AB - MAIN CONCLUSION: Two new peroxygenases for the biosynthesis of epoxy fatty acids in oat were identified and functionally analyzed by heterologous expression along with rationally designed site-directed mutagenesis. Oat (Avena sativa L.) contains a large family of peroxygenases, a group of heme-containing monooxygenases catalyzing hydroperoxide-dependent epoxidation of unsaturated fatty acids. Here, we report identification and functional analysis of two new peroxygenases AsPXG2 and AsPXG3 from oat. The open reading frame (ORF) of AsPXG2 contains 702 bps encoding a polypeptide of 233 amino acids, while the ORF of AsPXG3 is 627 bps coding for 208 amino acids. Both AsPXG2 and AsPXG3 comprise a single transmembrane domain, conserved histidines for heme binding and a conserved EF-hand motif for calcium binding, but they only share about 50% amino acid sequence identity with each other. When expressed in Escherichia coli and Pichia pastoris, AsPXG3 showed high epoxidation activity, while AsPXG2 exhibited no activity in E. coli and low activity in P. pastoris. AsPXG3 could effectively epoxidize both mono- and polyunsaturated fatty acids with linolenic acid being the most preferred substrate. Site-directed mutagenesis was employed to investigate the structure-function relationship of oat peroxygenase on 12 conserved residues of AsPXG3. Replacement of two conserved histidines, the ligands to the prosthetic heme group of the peroxygenase, by alanine resulted in complete loss of activity. Substitution of three conserved residues surrounding the two histidines resulted in reduction of the enzymatic activity by more than 80%. These results imply that these conserved residues might be located in or near the catalytic pocket, where the two histidine residues coordinate the heme group and the surrounding residues define the shape and size of the pocket for interaction with the heme as well as two substrates. PMID- 28664422 TI - Metabolite profiling of red and blue potatoes revealed cultivar and tissue specific patterns for anthocyanins and other polyphenols. AB - MAIN CONCLUSION: Metabolite profiling of tuber flesh and peel for selected colored potato varieties revealed cultivar and tissue specific profiles of anthocyanins and other polyphenols with variations in composition and concentration. Starchy tubers of Solanum tuberosum are a staple crop and food in many countries. Among cultivated potato varieties a huge biodiversity exists, including an increasing number of red and purple colored cultivars. This coloration relates to the accumulation of anthocyanins and is supposed to offer nutritional benefits possibly associated with the antioxidative capacity of anthocyanins. However, the anthocyanin composition and its relation to the overall polyphenol constitution in colored potato tubers have not been investigated closely. This study focuses on the phytochemical characterization of the phenolic composition of a variety of colored potato tubers, both for peel and flesh tissues. First, liquid chromatography (LC) separation coupled to UV and mass spectrometry (MS) detection of polyphenolic compounds of potato tubers from 57 cultivars was used to assign groups of potato cultivars differing in their anthocyanin and polyphenol profiles. Tissues from 19 selected cultivars were then analyzed by LC separation coupled to multiple reaction monitoring (MRM) to detect quantitative differences in anthocyanin and polyphenol composition. The measured intensities of 21 anthocyanins present in the analyzed potato cultivars and tissues could be correlated with the specific tuber coloration. Besides secondary metabolites well-known for potato tubers, the metabolic profiling led to the detection of two anthocyanins not described for potato tuber previously, which we tentatively annotated as pelargonidin feruloyl-xylosyl-glucosyl-galactoside and cyanidin 3-p-coumaroylrutinoside-5-glucoside. We detected significant correlations between some of the measured metabolites, as for example the negative correlation between the main anthocyanins of red and blue potato cultivars. Mainly hydroxylation and methylation patterns of the B-ring of dihydroflavonols, leading to the formation of specific anthocyanidin backbones, can be assigned to a distinct coloring of the potato cultivars and tuber tissues. However, basically the same glycosylation and acylation reactions occur regardless of the main anthocyanidin precursor present in the respective red and blue/purple tissue. Thus, the different anthocyanin profiles in red and blue potato cultivars likely relate to superior regulation of the expression and activities of hydroxylases and methyltransferases rather than to differences for downstream glycosyl- and acyltransferases. In this regard, the characterized potato cultivars represent a valuable resource for the molecular analysis of the genetic background and the regulation of anthocyanin side chain modification. PMID- 28664423 TI - Reconciling Work and Caregiving Responsibilities among Older Workers in New Zealand. AB - There are 432,000 individuals in New Zealand who provide unpaid care for someone who is ill or disabled and 65% of these carers are also in paid employment. The number of older people in the paid workforce is projected to increase in the next two decades. With the median age of carers in 2013 at 49 years, the ageing of both the population and workforce suggests that many carers may still be in paid work as they themselves age. Family care is an essential part of the health care system. Informal care provides many benefits including improved patient outcomes, reduced unnecessary re-hospitalisations and residential care placements, and considerable savings in health care expenditure. However, combining paid work and informal care is problematic for many carers and can impact on their health and wellbeing, and on work-related outcomes by way of reduced work hours, absenteeism, and employment exit. Recent policy initiatives have been implemented to support family carers in New Zealand to remain in or re-enter the workforce. This paper explores the challenges presented to older New Zealanders who combine paid work with caregiving responsibilities. We provide a profile of older workers (aged 55+) who are providing care and analyse the impact of combining paid work and care on their health, wellbeing and economic living standards. Finally, we situate these findings within the policy framework in New Zealand. PMID- 28664424 TI - Diagnostic staging laparoscopy in gastric cancer: a prospective cohort at a cancer institute in Japan. AB - BACKGROUND: There have been many studies that describe the value of diagnostic staging laparoscopy (DSL) in gastric cancer. However, different studies use different indications, making study results difficult to compare. This study aimed to clarify the diagnostic feasibility of DSL for gastric cancer in a prospective manner and investigated the impact of DSL on clinical decision-making in gastric cancer treatment. METHODS: The study was a prospective cohort study based at a single institution between January 2010 and December 2013. We treated 2213 patients with potentially resectable gastric cancer during this period. DSL was primarily indicated for asymptomatic patients with: (1) large Borrmann type 3 tumours >=8 cm, (2) Borrmann type 4 tumours (linitis plastica), (3) bulky lymph nodes or paraaortic lymph node swelling, or (4) clinical suspicion of peritoneal disease. The primary outcome is change in treatment strategy, and the secondary outcomes are diagnostic accuracy of the indications and false negative rate of DSL. RESULTS: DSL was performed on 156 (7%) of 2213 patients. Of these, peritoneal disease was found in 74 (47%) patients: (1) 56% for large type 3, (2) 54% for type 4, (3) 21% for bulky lymph nodes or paraaortic lymph node swelling, and (4) 20% for suspected peritoneal disease. The diagnostic accuracy of our indication for DSL was 92% for all patients and 74% for patients with cT3/T4 tumours. Among 82 patients without peritoneal disease, 66 patients (81%) underwent subsequent radical gastrectomy; peritoneal disease was discovered intraoperatively for 7 patients at laparotomy, indicating a false negative rate of 11%. CONCLUSION: We confirmed that DSL performed according to our indication, in the context of gastric cancer, possesses diagnostic feasibility. Approximately half of the patients who underwent DSL consequently avoided unnecessary laparotomy and were able to receive appropriate alternative treatment. PMID- 28664426 TI - Laparoscopic and endoscopic cooperative surgery is a feasible treatment procedure for intraluminal gastric gastrointestinal stromal tumors compared to endoscopic intragastric surgery. AB - BACKGROUND: Laparoscopic wedge resection of the stomach is an ideal procedure if the gastric gastrointestinal stromal tumors (GISTs) are located in the extraluminal stomach. When the tumor is located in the intraluminal stomach, two minimally invasive surgical procedures involving laparoscopic and endoscopic cooperative surgery (LECS) or endoscopic intragastric surgery (EIGS) are frequently performed. To date, there have been no comparative studies of LECS and EIGS in patients with intraluminal gastric GISTs regarding short-term and long term outcomes. The aim of this study was to compare the safety and feasibility of LECS and EIGS in patients with intraluminal gastric GISTs. METHODS: This was a single-center retrospective study of 46 consecutive patients with intraluminal gastric GISTs who underwent minimally invasive surgery. LECS (n = 21) was performed between 2013 and 2015 and EIGS (n = 26) was performed between 2001 and 2013. RESULTS: The overall incidence of perioperative complications was significantly higher in the EIGS group than in the LECS group (40 vs 4.8%; P = 0.006). In the EIGS group, three patients with intraoperative gastric mucosal injury were followed-up throughout surgical repair (12%). An esophageal tear was found in one patient during oral removal of tumor (4%). Postoperative gastric hemorrhage occurred in three patients (12%) and superficial surgical site infection was observed in three patients (12%). In the LECS group, anastomotic leakage requiring additional drainage was observed in one patient (4.8%). EIGS had less favorable results regarding median time to resumption of first oral intake (2 vs 1 days; P = 0.005). Two of 46 patients (4.3%), including one patient who underwent LECS and one patient who underwent EIGS developed recurrence. No cause-specific deaths were observed. CONCLUSION: LECS is a feasible and safe procedure for intraluminal gastric GISTs with regard to both short-term surgical and long-term oncological outcomes. Registration number: UMIN000026631. PMID- 28664425 TI - Risk factors for the late development of common bile duct stones after laparoscopic cholecystectomy. AB - BACKGROUND: The development of common bile duct (CBD) stones after laparoscopic cholecystectomy (LC) could be a stressful event for surgeons and patients. The purpose of this study was to investigate the risk factors for and the time of occurrence of CBD stones, which are detected at a certain period after LC in patients who have no history of having CBD stone before operation. METHODS: A total of 1938 patients who underwent LC for benign gallbladder lesion were retrospectively analyzed. The patients were categorized into two groups according to the development of CBD stones at least 6 months after LC (case group, control group). The risk factors for and the time of development of CBD stones after LC were evaluated. RESULTS: In a univariate analysis, the significant factors for the development of CBD stones were old age, acute cholecystitis, the presence of periampullary diverticulum, and the presence of gall bladder stones sized <0.55 cm. By multivariate analysis, acute cholecystitis (OR: 3.082, 95% CI: 1.306 7.272, p = 0.010), the presence of periampullary diverticulum (OR: 7.950, 95% CI: 3.425-18.457, p < 0.001), and the presence of gall bladder stones sized < 0.55 cm (OR: 5.647, 95% CI: 1.310-24.346, p = 0.020) were independent factors that could predict the development of CBD stones at least 6 months after LC. The time intervals of the development of CBD stones had evenly distributed during 50 months after LC. CONCLUSION: This study suggested that the surgeon should inform the possibility of the development of CBD stones who have the identified risk factors. PMID- 28664427 TI - Safety and efficacy of the endoscopic duodenal-jejunal bypass liner prototype in severe or morbidly obese subjects implanted for up to 3 years. AB - BACKGROUND: The duodenal-jejunal bypass liner (DJBL) is an endoscopic device that mimics the duodenal-jejunal exclusion component of the Roux-en-Y gastric bypass. Previous studies assessing the efficacy of the DJBL have shown 10-40% excess weight loss (%EWL) and improvements in obesity-associated comorbidities. The aim of this study was to evaluate the safety and efficacy of a new DJBL prototype over a 3-year period. METHODS: Morbidly obese subjects were enrolled in a single arm, open-label, prospective trial. The subjects were offered the opportunity to continue with the trial annually and signed a new consent form. The primary endpoint was safety. The secondary endpoints were changes in weight and biochemical parameters from baseline. RESULTS: The DJBL was implanted endoscopically in 80 subjects (age: 35+/-10 years; 69% female; weight: 109+/-17 kg; BMI: 42+/-5.4 kg/m2). Seventy-two severe adverse events (AEs) were observed in 55 patients (68%), of which nine subjects required a prolonged hospital stay and three subjects required major interventions. Overall, 23 subjects (29%) underwent early device removal due to AEs. Additionally, 95% of the patients experienced mild AEs that mainly consisted of abdominal pain. The severe AEs included a liver abscess (3), upper GI bleeding (4), cholangitis (1), and acute pancreatitis (1) and mostly occurred after 12 months of follow-up. Two patients presented a short esophageal perforation during explantation. These perforations were successfully managed with endoscopic closure in one subject and medical treatment in the other subject. In the completer population at 52 weeks (71 patients), 104 weeks (40 patients), and 156 weeks (11 patients), the mean %EWL were 44 +/- 16, 40 +/- 22, and 39 +/- 20, respectively (p < 0.001). CONCLUSION: This study shows significant and sustained weight loss after 3 years of treatment with the new DJBL. However, the high frequency and severity of AEs preclude the use of this prototype for periods longer than 1 year. PMID- 28664428 TI - Routine versus selective upper gastrointestinal contrast series after omental patch repair for gastric or duodenal perforation. AB - BACKGROUND: There are no guidelines on the routine or selective use of contrast upper gastrointestinal series (UGI) after omental patch repair (OPR) of a gastric (GP) or duodenal perforation (DP). This study aims to elucidate whether the use of selective versus routine contrast study will lead to worse clinical outcomes. METHODS: A retrospective analysis of 115 (n = 115) patients with OPR of GP or DP was performed. Data were obtained from seven Florida Hospital campuses. Patients aged 18 and older from 2006 to 2016 were identified by ICD9 billing information. Patients were divided into two groups: UGI and no UGI. The UGI group was subdivided into selective versus routine. A selective UGI was defined as one or more of the following after post-operative day 3: WBC >12,000, peritonitis, fever >100.4 F, tachycardia >110 bpm on three or more assessments, and any UGI performed after POD 7. Perioperative symptoms, perforation location, size, abdominal contamination, laparoscopic or open, leak detection, length of stay, mortality, and reoperation within 2 weeks were also examined. RESULTS: No differences between the UGI group and non-UGI group relating to preoperative symptoms, leak detection, death, and reoperation rate were revealed. Differences in length of stay were found to be statistically significant with the UGI group and non-UGI at a median of 15.5 and 8 days, respectively. In the UGI subgroup, 20 of the 29 patients received selective studies. There were no statistical differences identified in leak detection, death, and reoperation. CONCLUSIONS: Rates of leak detection, reoperation, and death in patients with GP or DP repaired with omental patch utilizing an UGI study were not statistically significant. An increased length of stay was observed within the UGI group. There was no advantage demonstrated between a selective versus routine UGI; therefore, the use of selective UGI should be based upon clinical indications. PMID- 28664429 TI - Laparoscopic versus open distal pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors: a large single-center study. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) account for 1-2% of all pancreatic neoplasms. Nonfunctioning PNETs (NF-PNETs) account for 60-90% of all PNETs. Laparoscopic distal pancreatectomy (LDP) is becoming the treatment of choice for benign lesions in the body and tail of the pancreas. However, LDP has not yet been widely accepted as the gold standard for NF-PNETs. The purpose of this study is to evaluate the clinical and oncologic outcomes after laparoscopic versus open distal pancreatectomy (ODP) for NF-PNETs. METHODS: Between April 1995 and September 2016, 94 patients with NF-PNETs underwent open or laparoscopic distal pancreatectomy at Samsung Medical Center. Patients were divided into two groups: those who underwent LDP and those who underwent ODP. Both groups were compared in terms of clinical and oncologic variables. RESULTS: LDP patients had a significantly shorter hospital stay compared with ODP patients, amounting to a mean difference of 2 days (p < 0.001). Overall complication rates did not differ significantly between the ODP and LDP groups (p = 0.379). The 3-year overall survival rates in the ODP and LDP groups were 93.7 and 100%, respectively (p = 0.069). CONCLUSIONS: In this study, LDP for NF-PNETs had similar oncologic outcomes compared with ODP. In addition, LDP was associated with a shorter hospital stay compared with ODP. Therefore, LDP is a safe and effective procedure for patients with NF-PNETs. A multicenter study and a randomized controlled trial are needed to better assess the clinical and oncologic outcomes. PMID- 28664430 TI - Supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. AB - BACKGROUND: The use of laparoscopic colectomy is becoming widespread and acquisition of its technique is challenging. In this study, we investigated whether supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. METHODS: The outcomes of 23 right colectomies and 19 high anterior resections for colon cancers performed by five novice surgeons (experience level of <10 cases) between 2014 and 2016 were assessed. A laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System (Japan Society for Endoscopic Surgery) participated in surgeries as the teaching assistant. RESULTS: In the right colectomy group, one patient (4.3%) required conversion to open surgery and postoperative morbidities occurred in two cases (8.6%). The operative time moving average gradually decreased from 216 to 150 min, and the blood loss decreased from 128 to 28 mL. In the CUSUM charts, the values for operative time decreased continuously after the 18th case, as compared to the Japanese standard. The values for blood loss also plateaued after the 18th case. In the high anterior resection group, one patient (5.2%) required conversion to open surgery and no postoperative complication occurred in any patient. The operative time moving average gradually decreased from 258 to 228 min, and the blood loss decreased from 33 to 18 mL. The CUSUM charts showed that the values of operative time plateaued after the 18th case, as compared to the Japanese standard. In the CUSUM chart for blood loss, no distinguishing peak or trend was noted. CONCLUSIONS: Supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. The trainee's learning curve in this study represents successful mentoring by the laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System. PMID- 28664431 TI - Investigation of operative outcomes of thoracoscopic esophagectomy after triplet chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for advanced esophageal squamous cell carcinoma. AB - BACKGROUND: Preoperative chemotherapy with cisplatin and 5-fluorouracil (CF) has become the standard treatment for resectable stage II/III thoracic esophageal carcinoma in Japan. Recently, preoperative triplet chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) has been reported to be effective for locally advanced esophageal cancer. Thoracoscopic esophagectomy (TE) has been increasingly accepted worldwide for the treatment of esophageal cancer. We conducted a retrospective study to evaluate the safety and outcomes of TE after DCF therapy for patients with advanced esophageal cancer. METHODS: The medical records of 63 consecutive patients with esophageal squamous cell carcinoma who underwent thoracoscopic surgery after chemotherapy were reviewed. Thirty-four patients received neoadjuvant chemotherapy with CF, and 29 received DCF as first line chemotherapy. RESULTS: The clinical T stage was significantly higher in the DCF group than in the CF group (p < 0.0001), including 17 patients with T4. Lymph node metastasis was more frequent in the DCF group (p = 0.0005), and the clinical stage of the tumor was significantly higher in the DCF group than in the CF group (p = 0.0001). No significant difference existed between the two groups in operation time for the thoracic procedure (DCF 277.2 min vs. CF 302 min). Blood loss during the thoracic procedure was less in the DCF group than in the CF group (DCF 46.9 mL vs. CF 88.8 mL; p = 0.0056). No significant differences existed between the two groups in postoperative morbidity (DCF 34.5% vs. CF 47%) or mortality (DCF 0% vs. CF 2.9%) rates. CONCLUSIONS: Our study suggests that TE after DCF therapy for advanced esophageal cancer is as safe as TE after CF therapy. PMID- 28664432 TI - Analysis of the posture pattern during robotic simulator tasks using an optical motion capture system. AB - BACKGROUND: Surgeons are sometimes forced to maintain uncomfortable joint positions during robotic surgery despite the high degree of instrument maneuverability. This study aimed to use an optical motion capture system to analyze the differences in posture patterns during robotic simulator tasks between surgeons at two skill levels. METHODS: Ten experienced and ten novice surgeons performed two tasks in a da Vinci Skills Simulator: Suture Sponge 1 (SP) and Tubes (TU). The participants' upper body motion during each task was captured, including the joint angles (axilla, elbow, and wrist), the percentage of time when the wrist height was lower than the elbow height (PTW), and the height of the elbow and wrist relative to the armrest. RESULTS: The novice group showed significantly more excess extension in both elbow angles and extension (>50 degrees ) in both wrist angles than did the experienced group. The novice group had significantly lower PTW than the experienced group on the right side in both tasks (both p < 0.001), and on the left side in SP (p < 0.001). Compared with the experienced group, the novice group had a significantly higher elbow relative to the armrest on the right side (SP, TU: p < 0.05), and a significantly lower wrist relative to the armrest on the right side (SP, TU: p < 0.05). CONCLUSIONS: An optical motion capture system can detect the differences in posture patterns in the positional relationship between the elbow and wrist and the joint angles of the upper limb between two groups of surgeons at different skill levels during robotic simulator tasks. PMID- 28664433 TI - Factors influencing the outcome of magnetic sphincter augmentation for chronic gastroesophageal reflux disease. AB - OBJECTIVES: Magnetic sphincter augmentation (MSA) is a surgical treatment option for patients with gastroesophageal reflux disease (GERD). MSA consistently improves quality of life, maintains freedom from PPIs, and objectively controls GERD. However, up to 24% of patients did not achieve these outcomes. We sought to identify factors predicting outcomes after MSA placement with the aim of refining selection criteria. METHODS: We retrospectively analyzed clinical, endoscopic, manometric, pH data, and intraoperative factors from two databases: Pivotal Trial (N = 99) and our prospectively maintained esophageal database (N = 71). A priori outcomes were defined as excellent (GERD-HRQL <5, no PPI, no esophagitis), good (GERD-HRQL 6-15, no PPI, grade A esophagitis), fair (GERD-HRQL 16 to 25, PPI use, grade B esophagitis), and poor (GERD-HRQL >25, PPI use, grade C/D esophagitis). Univariable and multivariable logistic regression analyses were performed to determine predictors of achieving an excellent/good outcome. RESULTS: A total of 170 patients underwent MSA with a median age of 53 years, [43-60] and a median BMI of 27 (IQR = 24-30). At baseline, 93.5% of patients experienced typical symptoms and 69% atypical symptoms. Median DeMeester score was 37.9 (IQR 27.9 51.2) with a structurally intact sphincter in 47%. Esophagitis occurred in 43%. At 48 [19-60] months after MSA, excellent outcomes were achieved in 47%, good in 28%, fair in 22%, and poor in 3%. Median DeMeester score was 15.6 (IQR = 5.8 26.6), esophagitis in 17.6% and daily PPI use in 17%. At univariable analysis, excellent/good outcomes were negatively impacted by BMI, preoperative LES residual pressure, Hill grade, and hiatal hernia. At multivariable analysis, BMI >35 (OR = 0.05, 0.003-0.78, p = 0.03), structurally defective LES (OR = 0.37, 0.13-0.99, p = 0.05), and preoperative LES residual pressure (OR = 0.89, 0.80 0.98, p = 0.02) were independent negative predictors of excellent/good outcome. CONCLUSIONS: Magnetic sphincter augmentation results in excellent/good outcomes in most patients but a higher BMI, structurally defective sphincter, and elevated LES residual pressure may prevent this goal. PMID- 28664434 TI - Clinical outcomes five years after POEM for treatment of primary esophageal motility disorders. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) is a novel operation for the treatment of achalasia and other esophageal motility disorders. While POEM has shown excellent short-term safety and efficacy, the long-term symptomatic outcomes after the procedure are unknown. METHODS: Patients from a single center that underwent POEM for treatment of esophageal motility orders and were greater than 5 years removed from their operation were studied. Patients were contacted to assess current symptoms and encouraged to undergo repeat endoscopy for objective follow-up. RESULTS: Thirty-six patients underwent POEM from October, 2010 to February, 2012 and current symptom scores were obtained from 29 patients at median 65-month follow-up. In the 23 patients with achalasia, Eckardt scores were significantly improved from preoperative baseline (mean current 1.7 vs. preoperative 6.4, p < 0.001). Nineteen patients (83%) with achalasia had a symptomatic success (Eckardt <=3) and none required retreatment for symptoms. Eckardt scores were dramatically improved at 6 months and maintained at 2 years; however, there was a small but significant worsening of symptoms between 2 and 5 years. Of the five patients with EGJ outflow obstruction, all had current Eckardt scores <=3 but two needed reintervention for persistent or recurrent symptoms, one with a laparoscopic Heller myotomy and another with an endoscopic cricomyotomy and proximal esophageal myotomy extension. At 6-month follow-up, repeat manometry showed decreased EGJ relaxation pressures and esophagram demonstrated improved emptying. 24-h pH monitoring showed abnormal distal esophageal acid exposure in 38% of patients. Fifteen patients underwent endoscopy at 5-years, revealing erosive esophagitis in two (13%), new hiatal hernia in two, and new non-dysplastic Barrett's esophagus in one. The patient with Barrett's underwent a subsequent laparoscopic hiatal hernia repair and Toupet fundoplication. CONCLUSIONS: POEM resulted in a successful palliation of symptoms in the majority of patients after 5 years, though these results emphasize the importance of long-term follow-up in all patients. PMID- 28664435 TI - Video analysis in basic skills training: a way to expand the value and use of BlackBox training? AB - BACKGROUND: Basic skills training in laparoscopic high-fidelity simulators (LHFS) improves laparoscopic skills. However, since LHFS are expensive, their availability is limited. The aim of this study was to assess whether automated video analysis of low-cost BlackBox laparoscopic training could provide an alternative to LHFS in basic skills training. METHODS: Medical students volunteered to participate during their surgical semester at the Karolinska University Hospital. After written informed consent, they performed two laparoscopic tasks (PEG-transfer and precision-cutting) on a BlackBox trainer. All tasks were videotaped and sent to MPLSC for automated video analysis, generating two parameters (Pl and Prtcl_tot) that assess the total motion activity. The students then carried out final tests on the MIST-VR simulator. This study was a European collaboration among two simulation centers, located in Sweden and Greece, within the framework of ACS-AEI. RESULTS: 31 students (19 females and 12 males), mean age of 26.2 +/- 0.8 years, participated in the study. However, since two of the students completed only one of the three MIST-VR tasks, they were excluded. The three MIST-VR scores showed significant positive correlations to both the Pl variable in the automated video analysis of the PEG transfer (RSquare 0.48, P < 0.0001; 0.34, P = 0.0009; 0.45, P < 0.0001, respectively) as well as to the Prtcl_tot variable in that same exercise (RSquare 0.42, P = 0.0002; 0.29, P = 0.0024; 0.45, P < 0.0001). However, the correlations were exclusively shown in the group with less PC gaming experience as well as in the female group. CONCLUSIONS: Automated video analysis provides accurate results in line with those of the validated MIST-VR. We believe that a more frequent use of automated video analysis could provide an extended value to cost-efficient laparoscopic BlackBox training. However, since there are gender-specific as well as PC gaming experience differences, this should be taken in account regarding the value of automated video analysis. PMID- 28664436 TI - Clinical implication of endoscopic gross appearance in superficial esophageal squamous carcinoma: revisited. AB - BACKGROUND: Standard endoscopic appearance is essential for the diagnosis and treatment of superficial esophageal squamous carcinoma (SESC). The aim of this study was to investigate the association between the endoscopic gross appearance and the clinicopathologic characteristics of SESC. METHODS: We retrospectively analyzed the clinicopathologic characteristics of SESC according to gross endoscopic appearance in 275 patients with SESC that underwent esophagectomy or endoscopic resection (ER). RESULTS: The proportion of type I or type III gross appearance, and that of types IIa, IIb, or IIc, were 26.2 and 73.8%, respectively. Type I or type III gross appearance was significantly associated with the female sex, submucosal invasion, lymphovascular invasion (LVI), and lymph node metastasis (LNM). In addition, younger age, larger tumor size, higher proportion of circumferential extension, type I or type III endoscopic gross appearance, submucosal invasion, moderate or poorly differentiated carcinoma, and LVI were significantly associated with LNM. Multivariate logistic regression analysis determined that independent predictors of LNM in patients with SESC included endoscopic gross appearance, submucosal invasion, and presence of LVI. Additionally, type I or type III endoscopic gross appearance lesions were more likely to have submucosal invasion than types IIa, IIb, or IIc. Risk factors for submucosal invasion included a gross appearance of type I or type III, moderately or poorly differentiated tumors, and presence of LVI. CONCLUSIONS: We found that SESC clinical features are correlated with the endoscopic appearance. Therefore, we suggest that the endoscopic gross appearance may be a candidate for additive criteria in the indications for ER. PMID- 28664437 TI - A modified endoscopic method for resection of gastric submucosal tumor. AB - BACKGROUND AND OBJECTIVE: Endoscopic mucosa-sparing lateral dissection (EMSLD) was developed by our group, and is used to remove gastric submucosal tumor (SMT). This study aims to evaluate the feasibility and safety of this method. METHODS: This retrospective study included 25 patients who underwent EMSLDs at an endoscopy center as a national key unit in china from October 2015 to July 2016. The main data collected were the size of the gastric SMT, its location and origin, en bloc resection rate, operating time, intraoperative and postoperative complications, hospitalization expense, hospital days, and follow-up after hospital discharge. RESULTS: The mean (SD) size of the gastric SMTs was 18.3 (5.9) mm; 96% (24/25) of the tumors originated in the muscularis propria; and 64% (16/25) and 28% (7/25) were located in the gastric fundus and gastric body, respectively. The rate of en bloc resection was 96% (24/25), and the rate of intraoperative perforations due to endoscopic full-thickness resection was 48% (12/25). All wounds and perforations were effectively closed using endoscopic clips combined with the retained mucosa. The mean operative time was 74.2 (38.0) min. Delayed bleeding and perforation were not observed. CONCLUSION: Endoscopic mucosa-sparing lateral dissection is safe and feasible for the removal of gastric SMTs. The wound can be effectively closed using the retained mucosa and endoscopic clips, even if perforation has occurred. EMSLD provides an alternative to the resection of gastric SMTs, especially for tumors with a risk of intraoperative perforation. PMID- 28664438 TI - Transoral outlet reduction with full thickness endoscopic suturing for weight regain after gastric bypass: a large multicenter international experience and meta-analysis. AB - BACKGROUND AND AIMS: Many patients who undergo bariatric surgery will experience weight regain and effective strategies are needed to help these patients. A dilated gastrojejunal anastomosis (GJA) has been associated with weight recidivism after Roux-en-Y gastric bypass surgery (RYGB). Endoscopic transoral outlet reduction (TORe) with a full thickness endoscopic suturing device (Overstitch, Apollo Endosurgery, Austin, TX) is a minimally invasive therapeutic option. The primary aim of this project was to examine the safety and long-term efficacy data from three bariatric surgery centers and to conduct a systematic review and meta-analysis of the existing literature. METHODS: Patients who underwent TORe with the Overstitch device from Jan 2013 to Nov 2016 at 3 participating bariatric surgery centers were included in the multicenter analysis. For the systematic review and meta-analysis, a comprehensive search of multiple English databases was conducted. Random effects model was used. RESULTS: 130 consecutive patients across three centers underwent TORe with an endolumenal suturing device. These patients (mean age 47; mean BMI 36.8) had experienced 24.6% weight regain from nadir weight after RYGB. Average weight lost at 6, 12, and 18 months after TORe was 9.31 +/- 6.7 kg (N = 84), 7.75 +/- 8.4 kg (N = 70), 8 +/- 8.8 kg (N = 46) (p < 0.01 for all three time points), respectively. The meta-analysis included 330 patients. The pooled weight lost at 12 months was 8.4 kg (95% CI 6.5-10.3) with no significant heterogeneity across included studies (p = 0.07). Overall, 14% of patients experienced nausea, 18% had pain and 8% required a repeat EGD. No serious adverse events reported. CONCLUSION: When implemented as part of a multidisciplinary intervention, TORe using endolumenal suturing is safe, reproducible, and effective approach to manage weight recidivism after RYGB and should be utilized early in the management algorithm of these patients. PMID- 28664439 TI - SAGES quality initiative: an introduction. AB - The Medicare program has transitioned to paying healthcare providers based on the quality of care delivered, not on the quantity. In May 2015, SAGES held its first ever Quality Summit. The goal of this meeting was to provide us with the information necessary to put together a strategic plan for our Society over the next 3-5 years, and to participate actively on a national level to help develop valid measures of quality of surgery. The transition to value-based medicine requires that providers are now measured and reimbursed based on the quality of services they provide rather than the quantity of patients in their care. As of 2014, quality measures must cover 3 of the 6 available National Quality domains. Physician quality reporting system measures are created via a vigorous process which is initiated by the proposal of the quality measure and subsequent validation. Commercial, non-profit, and governmental agencies have now been engaged in the measurement of hospital performance through structural measures, process measures, and increasingly with outcomes measures. This more recent focus on outcomes measures have been linked to hospital payments through the Value Based Purchasing program. Outcomes measures of quality drive CMS' new program, MACRA, using two formats: Merit-based incentive programs and alternative payment models. But, the quality of information now available is highly variable and difficult for the average consumer to use. Quality metrics serve to guide efforts to improve performance and for consumer education. Professional organizations such as SAGES play a central role in defining the agenda for improving quality, outcomes, and safety. The mission of SAGES is to improve the quality of patient care through education, research, innovation, and leadership, principally in gastrointestinal and endoscopic surgery. PMID- 28664440 TI - Bariatric surgery is associated with renal function improvement. AB - INTRODUCTION: Weight loss after bariatric surgery improves both blood pressure and glycemic control following surgery. The effect of bariatric surgery on renal function is not well characterized. In this study, we sought to quantify the change in renal function over time following surgery. METHODS: We retrospectively reviewed all patients who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) between 2012 and 2014 at our institution. The glomerular filtration rate (GFR, mL/min) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Body mass index (BMI, kg/m2) and percent weight loss (%WL) were calculated following the surgery. RESULTS: A total of 149 patients who underwent bariatric surgery were included in this study: LRYGB (n = 86 and LSG (n = 63). In LRYGB group, baseline BMI (kg/m2, +/-SD) and GFR (mL/min, +/-SD) were 48.5 +/- 6.8 and 94.7 +/ 23.8, respectively. In comparison, BMI and GFR were 49.1 +/- 11.9 kg/m2 and 93.1 +/- 28.0 mL/min in the LSG group, respectively. Over the follow-up period (19.89 +/- 10.93 months), the patients who underwent LRGYB lost a larger percentage of weight as compared to those in the LSG group (29.9 +/- 11.7% vs 22.3 +/- 10.7%; p = <0.0001). Overall, GFR improved in both LRYGB (101.0 +/- 25.8 mL/min) and LSG groups (97.9 +/- 25.8 mL/min) and was not significantly different between the two groups. Of patients with a GFR < 90 mL/min prior to weight loss surgery (n = 62), 42% had improvement of their GFR to > 90 mL/min postoperatively (p < 0.001). There was no relationship between weight loss percentage and GFR improvement (p = 0.8703). CONCLUSIONS: Bariatric surgery was associated with improvement in postoperative renal function at almost two years following surgery but was not different for LRYGB versus LSG. The gain in GFR was independent of percentage of weight lost suggesting an alternate mechanism in the improvement of renal function other than weight loss alone. PMID- 28664441 TI - The prognostic impact of bowel perforation following self-expanding metal stent as a bridge to surgery in colorectal cancer obstruction. AB - BACKGROUND: Self-expanding metallic stent (SEMS) as a bridge to surgery for obstructive colorectal cancer may cause perforation of the tumor and thereby induce tumor spread and increase risk of recurrence, and eventually death. Evidence of the prognostic impact of SEMS-related perforation is, however, sparse. We conducted a long-term follow-up study to compare characteristics, overall survival, and recurrence rates between patients with and without SEMS related bowel perforation. METHOD: This long-term follow-up study included obstructive colorectal cancer patients treated with SEMS as a bridge to surgery during a 10-year period at two primary and tertiary referral centers. The primary outcome was overall survival, and the secondary outcome was recurrence. We compared mortality and recurrence in patients with and without SEMS-related perforations by Cox proportion hazard regression, adjusting for age, comorbidity, and disease stage. The recurrence risk was examined for patients undergoing curative resection and computed treating death as a competing risk. RESULTS: From January 2004 to December 2013, 123 patients were treated with SEMS as a bridge to surgery. Of these patients, 15 (12%) had SEMS-related perforations. Median follow up was 4.8 years (range 0.0-10.9 years). The overall 5-year survival was 58% for the entire cohort, but 37 and 61% for patients with and without perforations, respectively, corresponding to an adjusted hazard ratio of 1.6 (95% CI 0.8-3.3) in favor of patient without perforation. The overall 5-year recurrence rate was 34%, but 45 and 33% for patients with and without perforation, respectively, corresponding to an adjusted hazard ratio of 1.4 (95% CI 0.5-3.7) in disfavor of patients with perforation. CONCLUSION: SEMS-related perforations are common and may be associated with decreased survival and increased recurrence, although estimates in this study were imprecise. PMID- 28664442 TI - Safe and successful resection of difficult GI lesions using a novel single-step full-thickness resection device (FTRD(r)). AB - BACKGROUND AND STUDY AIMS: Classic endoscopic resection techniques (EMR and ESD) are limited to mucosal lesions. In the case of deeper growth into the gut wall and anatomic sites prone to perforation, the novel full-thickness resection device (FTRD(r)) opens a new dimension of possibilities for endoscopic resection. PATIENTS AND METHODS: Sixty patients underwent endoscopic full-thickness resection (eFTR) at our institution. Safety, learning curve, R0 resection rate, and clinical outcome were studied. RESULTS: In 97% (58/60) of the interventions, the FTRD(r)-mounted endoscope reached the previously marked lesion and eFTR was performed (technical success). Full-thickness resection was achieved in 88% of the cases, with an R0 resection on histological examination in 79%. The clinical success rate based on follow-up histology was even higher (88%). Adverse events occurred in 7%. Appendicitis of the residual cecal appendix after eFTR of an adenoma arising in the appendix led to the only post-eFTR surgery (1/58, 2%). Minor bleeding at the eFTR site (2/58, 3%) and an eFTR performed accidently without proper prior deployment of the OTSC(r) (1/58, 2%) were successfully treated endoscopically. There was no secondary perforation or eFTR-associated mortality. CONCLUSIONS: After specific training, eFTR is a feasible, safe, and promising all-in-one endoscopic resection technique. Our data show that eFTR allows complete resection of lesions affecting layers of the gut wall beneath the mucosa with a low risk of adverse events. However, our preliminary results need to be confirmed in larger, controlled studies. PMID- 28664443 TI - Vacuum-assisted early transanal closure of leaking low colorectal anastomoses: the CLEAN study. AB - INTRODUCTION: Non-healing of anastomotic leakage can be observed in up to 50% after total mesorectal excision for rectal cancer. This study investigates the efficacy of early transanal closure of anastomotic leakage after pre-treatment with the Endosponge(r) therapy. METHODS: In this prospective, multicentre, feasibility study, transanal suturing of the anastomotic defect was performed after vacuum-assisted cleaning of the presacral cavity. Primary outcome was the proportion of patients with a healed anastomosis at 6 months after transanal closure. Secondary, healing at last follow-up, continuity, direct medical costs, functionality and quality of life were analysed. RESULTS: Between July 2013 and July 2015, 30 rectal cancer patients with a leaking low colorectal anastomosis were included, of whom 22 underwent neoadjuvant radiotherapy. Median follow-up was 14 (7-29) months. At 6 months, the anastomosis had healed in 16 (53%) patients. At last follow-up, anastomotic integrity was found in 21 (70%) and continuity was restored in 20 (67%) patients. Non-healing at 12 months was observed in 10/29 (34%) patients overall, and in 3/14 (21%) when therapy started within three weeks following the index operation. Major LARS was reported in 12/15 (80%) patients. The direct medical costs were ?8933 (95% CI 7268-10,707) per patient. CONCLUSION: Vacuum-assisted early transanal closure of a leaking anastomosis after total mesorectal excision with 73% preoperative radiotherapy showed that acceptable anastomotic healing rates and stoma reversal rates can be achieved. Early diagnosis and start of treatment seems crucial. PMID- 28664444 TI - Indication for en bloc pancreatectomy with colectomy: when is it safe? AB - INTRODUCTION: Aggressive en bloc resection of adjacent organs is often necessary to resect pancreatic or colonic lesions. However, it is debated whether simultaneous pancreatectomy with colectomy (P+C) is warranted as it potentially increases morbidity and mortality (MM). We hypothesized that MM would be increased in P+C, especially in cases of pancreatitis. METHODS: All patients who underwent pancreatectomy (P) and simultaneous pancreatectomy with colectomy (P+C) at a high-volume center from November 2006 to 2015 were prospectively collected using ACS-NSQIP at our institution. Patients with additional multivisceral or enucleation procedures were excluded. Data were augmented to 90-day outcomes using our institutional database. RESULTS: Forty-three patients with a mean age of 62 years (27:16 male: female) underwent P+C, accounting for 2.39% (43/1797) of pancreatectomies performed. Pancreatoduodenectomy (PD) was performed in 61% (n = 26), distal pancreatectomy (DP) in 37% (n = 16), and total pancreatectomy (TP) in 2% (n = 1) of patients. The 30- and 90-day MM were higher in P+C than P (30-day: 54 vs. 37%, p = 0.037 and 9 vs. 2%, p = 0.022; 90-day: 61 vs. 42%, p = 0.019 and 14 vs. 3%, p = 0.002). Logistical regression modeling revealed an association between 90-day mortality and colectomy (p = 0.013, OR = 3.556). When P+C MM were analyzed according to intraoperative factors, there was no significant difference according to type of pancreatectomy (PD vs. DP vs. TP), origin of primary lesion (pancreas vs. colon), surgical indication (malignant vs. non-malignant), or case status (planned colectomy vs. intraoperative decision). CONCLUSIONS: Addition of colectomy to pancreatectomy substantially increased MM. Subanalysis revealed that type of resection performed, etiology, and planning status did not account for increased risk when performing P+C. However, colectomy was found to be an independent risk factor for mortality. Therefore, patients should be informed of the risk of increased postoperative complications until a further study can identify potential patients or perioperative factors that can be used for risk stratification. PMID- 28664445 TI - Pediatric Cardiology Provider Attitudes About Palliative Care: A Multicenter Survey Study. AB - While availability of palliative care consultation for children with advanced heart disease increases, little is known about cardiologist attitudes towards palliative care. We sought to describe perspectives of cardiologists regarding palliative care and to characterize their perceived competence in palliative care concepts. A cross-sectional survey of pediatric cardiologists and cardiac surgeons from 19 pediatric medical centers was performed. Overall response rate was 31% (183/589). Respondents had a median of 18 years of experience since medical school (range 2-49) and most practiced at academic centers (91%). Sixty percent of respondents felt that palliative care consultations occur "too late" and the majority (85%) agreed that palliative care consultations are helpful. Barriers to requesting palliative care consultation were most frequently described as "referring to palliative care services too early will undermine parents' hope" (45%) and "concern that parents will think I am giving up on their child" (56%). Only 33% of cardiologists reported feeling "very" or "moderately" competent in prognosticating life expectancy while over 60% felt competent caring for children with heart disease around end of life, and nearly 80% felt competent discussing goals of care and code status. Greater perceived competence was associated with subspecialty (heart failure/intensivist vs. other) (OR 3.6, 95% CI 1.6-8.1, p = 0.003) and didactic training (OR 6.27, 95% CI 1.8-21.8, p = 0.004). These results underscore the need for further training in palliative care skills for pediatric cardiologists. Enhancing palliative care skills among cardiologists and facilitating partnership with subspecialty palliative care teams may improve overall care of children with advanced heart disease. PMID- 28664446 TI - Postnatal Outcomes of Fetal Supraventricular Tachycardia: a Multicenter Study. AB - Supraventricular tachycardia (SVT), the most common fetal tachycardia, can be difficult to manage in utero. We sought to better understand predictors of the postnatal clinical course in neonates who experienced fetal SVT. We hypothesized that fetuses with hydrops or those with refractory SVT (failure of first-line SVT therapy) are more likely to experience postnatal SVT. This was a retrospective multicenter cohort study of subjects diagnosed with fetal SVT between 2006 and 2014. Fetuses with structural heart disease were excluded. Descriptive comparative statistics and univariate analysis with logistic regression were utilized to determine factors that most strongly predicted postnatal SVT and preterm delivery. The cohort consisted of 103 subjects. Refractory SVT was found in 37% (N = 38) of the cohort with this group more likely to be delivered prematurely (median = 36 vs. 37.5 weeks, p = 0.04). Refractory SVT did not increase the risk of postnatal SVT (p = 0.09). Postnatal SVT was seen in 61% (N = 63). Of those, 68% (N = 43) had postnatal SVT at <=2 days of age. Postnatal SVT was associated with a later fetal SVT diagnosis (median = 30 vs. 27.5 weeks, p = 0.006). We found a strong correlation between postnatal SVT and later gestational age at fetal SVT diagnosis. Subjects with refractory SVT or hydrops did not have a higher risk of postnatal SVT. We propose strong consideration for term delivery in the absence of significant clinical compromise. Further studies to assess whether outcomes vary for preterm delivery versus expectant management in those with refractory SVT should be performed. PMID- 28664447 TI - Establishing an Integrated Health Care Clinic in a Community Mental Health Center: Lessons Learned. AB - Integrating primary care with behavioral health services at community mental health centers is one response to the disparity in mortality and morbidity experienced by adults with serious mental illnesses and co-occurring substance use disorders. Many integration models have been developed in response to the Primary and Behavioral Health Care Integration (PBHCI) initiative of the Substance Abuse and Mental Health Services Administration (SAMHSA). One model is a primary care clinic co-located within the mental health center. The Connecticut Mental Health Center (CMHC) Wellness Center is one such co-located clinic developed as a partnership between CMHC and a Federally Qualified Health Center (FQHC). In this article, we describe the process of developing this on-site clinic along with lessons learned during implementation. We review different aspects of building and maintaining such a clinic and outline lessons learned from both successes and challenges. We briefly describe the demographics and health characteristics of the patient population served in this clinic. We make recommendations for providers and agencies that are considering or are already developing a model for integrating care. Finally, we briefly review status of our clinic after completion of grant funding. PMID- 28664448 TI - Impact of a Health Information Technology Intervention on the Follow-up Management of Pulmonary Nodules. AB - Lung cancer is the leading cause of cancer deaths in the USA. The most common abnormalities suspicious for lung cancer on CT scan include pulmonary nodules. Recommendations to improve care for patients with pulmonary nodules require follow-up management. However, transitions in care, especially for patients undergoing transitions to ambulatory care sites from the emergency department (ED) and inpatient settings, can exacerbate failures in follow-up testing and compromise patient safety. We evaluate the impact of a discharge module that includes follow-up recommendations for further management of pulmonary nodules on the study outcome and follow-up management of patients with pulmonary nodules within 1 year after discharge. After IRB approval, we collected data on all patients undergoing chest or abdominal CT exams over a 12-month baseline and 12 month intervention period at an academic medical center. The inpatient discharge module was implemented in November 2011; the ED module was implemented in May 2012. Multivariable logistic regression was performed to account for care setting, imaging modality, recommendations, and patient demographics. Implementation of a discharge module resulted in improved follow-up of patients with pulmonary nodules within 1 year after discharge (OR = 1.64, p = 0.01); the ED implementation resulted in better follow-up compared to the inpatient module (OR = 2.24, p < 0.01). Twenty-seven percent of patients with pulmonary nodules received follow-up management, which, although significantly improved from the 18% baseline, remains low. An electronic discharge module is associated with improved follow-up management of patients with pulmonary nodules, and may be combined with interventions to further improve management of these patients. PMID- 28664450 TI - Factors That Affect Outcome Following Total Joint Arthroplasty: a Review of the Recent Literature. AB - PURPOSE OF REVIEW: It is well established that certain patient-specific risk factors affect outcomes following total joint arthroplasty. The goal of this paper is to summarize the latest data on several variables that have been investigated in the last 3 years and to characterize the effects these factors have on the success of hip and knee replacement. RECENT FINDINGS: Preoperative diagnoses of depression and anxiety, liver disease, hypoalbuminemia, vitamin D deficiency, and diabetes mellitus are associated with increased risk of postoperative complications and can lead to worse outcomes after joint replacement surgery. Recent investigations have clearly established a link between these patient-specific factors and poor outcomes after hip and knee arthroplasty, but future research is needed to determine best practices for stratifying and mitigating these risks for patients. PMID- 28664449 TI - Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing. AB - PURPOSE: BRCA1 and BRCA2 (BRCA1/2) are two major high-penetrance breast cancer predisposition genes, mutations in which can lead to high risks and early onset of breast cancer. This study was performed to comprehensively investigate the spectrum and prevalence of BRCA1/2 mutations in unselected Chinese breast cancer patients and evaluate the associations of BRCA1/2 mutations with related clinicopathological characteristics of the tumors. METHODS: By integrating microfluidic PCR-based target enrichment and next-generation sequencing, paired tumor and normal tissues from 313 unselected breast cancer patients were analyzed for both germline and somatic mutations of BRCA1/2 genes in Chinese Han population. RESULTS: Total 5 BRCA1 and 8 BRCA2 deleterious germline mutations were detected in 5 (1.60%) and 12 (3.83%) of the 313 patients, respectively. The entire frequency of deleterious germline mutations of BRCA1/2 was 5.43%. Among them, c.1069A > T and c.3418_3419insTGACTACT in BRCA1, c.8474_8487delCATACCCTATACAG and c.6547delG in BRCA2 were novel. In addition, 32 germline variants of unknown significance in 31 (9.90%) of the 313 patients were identified. We also detected 13 somatic mutations in ten patients (3.19%), including 4 (1.28%) deleterious mutations (c.1575delT, c.2677C > T, c.7024C > T, and c.7672G > T in BRCA2) and 5 novel mutations (c.4728A > G and c.4820T > C in BRCA1; c.2527G > A, c.4069C > G and c.7672G > T in BRCA2). Notably, BRCA1 mutation carriers were significantly younger, and more likely to be ER negative and basal-like breast cancers. CONCLUSIONS: Our study provided a reliable and effective platform for BRCA1/2 genetic testing, and suggested that there was a relatively high prevalence and special spectrum of BRCA1/2 mutations in unselected Chinese breast cancer patients. PMID- 28664451 TI - A patient with facial tube fixation scars. PMID- 28664452 TI - Risk factors for sepsis-associated encephalopathy. PMID- 28664453 TI - The clinical impact of 18F-FDG PET/CT in extracranial pediatric germ cell tumors. AB - BACKGROUND: Extracranial germ cell tumors are an uncommon pediatric malignancy with limited information on the clinical impact of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the literature. OBJECTIVE: The purpose of this study was to evaluate and compare the clinical impact on management of 18F-FDG PET/CT with diagnostic computed tomography (CT) in pediatric extracranial germ cell tumor. MATERIALS AND METHODS: The list of 18F FDG PET/CT performed for extracranial germ cell tumor between May 2007 and November 2015 was obtained from the nuclear medicine database. 18F-FDG PET/CT and concurrent diagnostic CT were obtained and independently reviewed. Additionally, the patients' charts were reviewed for duration of follow-up and biopsy when available. The impact of 18F-FDG PET/CT compared with diagnostic CT on staging and patient management was demonstrated by chart review, imaging findings and follow-up studies. RESULTS: During the study period, 9 children (5 males and 4 females; age range: 1.6-17 years, mode age: 14 years) had 11 18F-FDG PET/CT studies for the evaluation of germ cell tumor. Diagnostic CTs were available for comparison in 8 patients (10 18F-FDG PET/CT studies). The average interval between diagnostic CT and PET/CT was 7.2 days (range: 0-37 days). In total, five lesions concerning for active malignancy were identified on diagnostic CT while seven were identified on PET/CT. Overall, 18F-FDG PET/CT resulted in a change in management in 3 of the 9 patients (33%). CONCLUSION: 18F-FDG PET/CT had a significant impact on the management of pediatric germ cell tumors in this retrospective study. Continued multicenter studies are required secondary to the rarity of this tumor to demonstrate the benefit of 18F-FDG PET/CT in particular clinical scenarios. PMID- 28664454 TI - MicroRNA-Directed Neuronal Reprogramming as a Therapeutic Strategy for Neurological Diseases. AB - The loss of neurons due to injury and disease results in a wide spectrum of highly disabling neurological and neurodegenerative conditions, given the apparent limited capacity of endogenous repair of the adult central nervous system (CNS). Therefore, it is important to develop technologies that can promote de novo neural stem cell and neuron generation. Current insights in CNS development and cellular reprogramming have provided the knowledge to finely modulate lineage-restricted transcription factors and microRNAs (miRNA) to elicit correct neurogenesis. Here, we discuss the current knowledge on the direct reprogramming of somatic non-neuronal cells into neural stem cells or subtype specific neurons in vitro and in vivo focusing on miRNA driven reprogramming. miRNA can allow rapid and efficient direct phenotype conversion by modulating gene networks active during development, which promote global shifts in the epigenetic landscape pivoting cell fate decisions. Furthermore, we critically present state-of-the-art and recent advances on miRNA therapeutics that can be applied to the diseased CNS. Together, the advances in our understanding of miRNA role in CNS development and disease, recent progress in miRNA-based therapeutic strategies, and innovative drug delivery methods create novel perspectives for meaningful therapies for neurodegenerative disorders. PMID- 28664455 TI - Neuroprotective Effects of the Absence of JNK1 or JNK3 Isoforms on Kainic Acid Induced Temporal Lobe Epilepsy-Like Symptoms. AB - The activation of c-Jun-N-terminal kinases (JNK) pathway has been largely associated with the pathogenesis and the neuronal death that occur in neurodegenerative diseases. Altogether, this justifies why JNKs have become a focus of screens for new therapeutic strategies. The aim of the present study was to identify the role of the different JNK isoforms (JNK1, JNK2, and JNK3) in apoptosis and inflammation after induction of brain damage. To address this aim, we induced excitotoxicity in wild-type and JNK knockout mice (jnk1 -/- , jnk2 -/- , and jnk3 -/- ) via an intraperitoneal injection of kainic acid, an agonist of glutamic-kainate-receptors, that induce status epilepticus.Each group of animals was divided into two treatments: a single intraperitoneal dose of saline solution, used as a control, and a single intraperitoneal dose (30 mg/kg) of kainic acid. Our results reported a significant decrease in neuronal degeneration in the hippocampus of jnk1 -/- and jnk3 -/- mice after kainic acid treatment, together with reduced or unaltered expression of several apoptotic genes compared to WT treated mice. In addition, both jnk1 -/- and jnk3 -/- mice exhibited a reduction in glial reactivity, as shown by the lower expression of inflammatory genes and a reduction of JNK phosphorylation. In addition, in jnk3 -/- mice, the c-Jun phosphorylation was also diminished.Collectively, these findings provide compelling evidence that the absence of JNK1 or JNK3 isoforms confers neuroprotection against neuronal damage induced by KA and evidence, for the first time, the implication of JNK1 in excitotoxicity. Accordingly, JNK1 and/or JNK3 are promising targets for the prevention of cell death and inflammation during epileptogenesis. PMID- 28664456 TI - Pancreas specific expression of oncogenes in a porcine model. AB - Pancreatic cancer is the fourth leading course of cancer death and early detection of the disease is crucial for successful treatment. However, pancreatic cancer is difficult to detect in its earliest stages and once symptoms appear, the cancer has often progressed beyond possibility for curing. Research into the disease has been hampered by the lack of good models. We have generated a porcine model of pancreatic cancer with use of transgenic overexpression of an oncogene cassette containing MYC, KRAS G12D and SV40 LT. The expression was initiated from a modified Pdx-1 promoter during embryogenesis in a subset of pancreatic epithelial cells. Furthermore, cells expressing the oncogenes also expressed a yellow fluorescent protein (mVenus) and an inducible negative regulator protein (rtTR-KRAB). Cells where the Pdx-1 promoter had not been activated, expressed a red fluorescent protein (Katushka). In vitro analyses of cells obtained from the transgenic pigs showed increased proliferation and expression of the transgenes when activated. Induction of the repressor protein eliminated the oncogene expression and decreased cell proliferation. In vivo analysis identified foci of pancreatic cells expressing the oncogenes at day zero post farrowing. These populations expanded and formed hyperplastic foci, with beginning abnormality at day 45. Cells in the foci expressed the oncogenic proteins and the majority of the cells were positive for the proliferation marker, Ki67. We predict that this model could be used for advanced studies in pancreatic cancer in a large animal model with focus on early detection, treatment, and identification of new biomarkers. PMID- 28664457 TI - Hematological parameters and all-cause mortality: a prospective study of older people. AB - BACKGROUND: The effect of low and high concentration of some hematological parameters in the blood can have a negative impact on health. AIM: Therefore, we investigated the associations between hematological parameters and all-cause mortality among older people living in Poland. METHODS: The study was carried out among 75-80-year-old participants (n = 403) from Warsaw and Olsztyn regions, Poland. Information on lifestyle factors and food consumption were obtained at baseline (June 1, 1999) using a self-administered questionnaire. Red blood cell, haemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and mean corpuscular haemoglobin concentration (MCHC) were determined. The data on deaths from all-causes were collected from the baseline until October 31, 2006. During an average of 7.4 years of follow-up, we ascertained 154 cases of death from all-causes. RESULTS: Compared with men in the lowest tertile of MCV, MCH, and MCHC, the multivariable hazard ratios (HRs) of all-cause mortality in those in the highest tertile were 0.35 (95% CI, 0.17 0.73), 0.32 (95% CI, 0.16-0.67), and 0.44 (95% CI, 0.22-0.88), respectively. In contrast, among women after combining the second and the third tertiles of MCV, MCH, and MCHC, the HRs were 2.01 (95% CI, 1.01-3.99), 1.71 (95% CI, 0.85-3.43), and 1.09 (95% CI, 0.62-1.94), respectively. DISCUSSION/CONCLUSION: We observed inverse associations between some hematological parameters and all-cause mortality among men, but not among women. This may be explained by a difference in iron metabolism, iron status, hormone regulations, or the occurrence of some diseases. PMID- 28664459 TI - Long-term QALY-weights among spouses of dependent and independent midlife stroke survivors. AB - PURPOSE: The aim of this study was to investigate whether the dependency of midlife stroke survivors had any long-term impact on their spouses' QALY-weights. METHOD: Data on stroke survivors, controls, and spouses were collected from the 7 year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke. Health related quality of life was assessed by the SF-36, and the preference-based health state values were assessed with the SF-6D. Spouses of dependent and independent stroke survivors were categorized according to their scores on the modified Rankin Scale. An ordinary least squares regression analysis was used to evaluate whether the dependency of the stroke survivors had any impact on the spouses' QALY-weights. RESULT: Cohabitant dyads of 247 stroke survivors aged <70 at stroke onset and 245 dyads of controls were included in the study. Spouses of dependent stroke survivors (n = 50) reported a significant lower mean QALY-weight of 0.69 in comparison to spouses of independent stroke survivors (n = 197) and spouses of controls, (n = 245) who both reported a mean QALY-weight of 0.77. The results from the regression analysis showed that higher age of the spouse and dependency of the stroke survivor had a negative association with the spouses' QALY-weights. CONCLUSION: The QALY-weights for spouses of dependent midlife stroke survivors were significantly reduced compared to spouses of independent midlife stroke survivors. This indicates that the inclusion of spouses' QALYs in evaluations of early treatment and rehabilitation efforts to reduce stroke patients' dependency would capture more of the total effect in dyads of stroke survivors. PMID- 28664461 TI - The Human Condition. PMID- 28664458 TI - Quality of life assessment in musculo-skeletal health. AB - Musculoskeletal disorders affect morbidity, quality of life and mortality, and represent an increasing economic and societal burden in the context of population aging and increased life expectancy. Improvement of quality of life should be one of the priorities of any interventions to prevent and treat musculoskeletal disorders in the ageing population. Two main approaches, namely generic and disease-specific instruments, can be applied to measure health-related quality of life. Among the generic tools available in scientific literature, the short form 36 questionnaire (SF-36) and the Euroqol five item questionnaire (EQ-5D) are two of the most popular questionnaires used to quantify the health related quality of life in people with musculoskeletal disorders. However, because generic tools may not always be able to detect subtle effects of a specific condition on quality of life, a specific tool is highly valuable. Specific tools improve the ability to clinically characterize quality of life in subjects with a specific musculoskeletal disorder, as well as the capacity to assess changes over time in the QoL of these subjects. The recent development of specific tools should help to validate preventive and therapeutic interventions in this field. PMID- 28664460 TI - The prevalence and pattern of chemotherapy-induced peripheral neuropathy among women with breast cancer receiving care in a large community oncology practice. AB - PURPOSE: To describe the prevalence, severity, and risk factors of chemotherapy induced peripheral neuropathy (CIPN) and its impact on function and quality of life (QOL) among women treated for breast cancer in a large U.S. Community Oncology practice. METHODS: Women previously treated with taxane-based chemotherapy for early-stage breast cancer completed the EORTC QLQ-C30, QLQ-BR23, and QLQ-CIPN20. Subscales are scored 0-100; higher scores indicate greater symptom severity. Pre-specified hypotheses were tested. RESULTS: 126 women with mean age 56.7 years (SD 11.8) were stage I-II (79.4%) or stage III (20.6%) at the time of the survey; 65.1% were White and 27.8% were Black or African American. The mean time since last taxane chemotherapy cycle was 144.9 weeks (SD 112.9). 73.0% reported having CIPN. QLQ-CIPN20 mean scores for the sensory, motor, and autonomic subscales were 18.9 (SD 23.1), 18.6 (SD 18.7), and 17.1 (SD 21.8), respectively. CIPN symptom severity was negatively correlated with global health status/QOL and physical and role functioning (range of r = -0.46 to -0.72). It was not associated with age, body mass index, diabetes, or cumulative taxane dosage, but was greater for Black or African American women (e.g., sensory, p < 0.002). CIPN sensory impairment was marginally greater for patients treated with paclitaxel compared to docetaxel (p < 0.064). CONCLUSIONS: CIPN was prevalent in this community oncology practice and significantly impacts function and QOL. These data highlight the importance of developing methods to mitigate CIPN, and for screening for CIPN particularly among Black or African American women. PMID- 28664462 TI - Factors Associated with Depression and Anxiety Symptoms Among Medical Students in Bahrain. AB - OBJECTIVES: Medical training can be a stressful experience and may negatively impact mental health for some students. The purpose of this study was to identify the prevalence of depressive and anxiety symptoms among medical students in one international medical university in the Kingdom of Bahrain and to determine associations between these symptoms, the students' characteristics, and their satisfaction with life. METHODS: This is a cross sectional study using a self administered questionnaire, distributed to 350 enrolled medical students. We used Beck's Depression Inventory (BDI-II) and Beck's Anxiety Inventory (BAI) instruments to assess depressive and anxiety symptoms. The Satisfaction With Life Scale (SWLS) was used to measure global cognitive judgments of one's life satisfaction. Sociodemographic details including social background and academic information were also documented. RESULTS: Forty percent (n = 124) of the participants had depressive symptoms, of which 18.9% (n = 58) met the criteria for mild, 13% (n = 40) for moderate, and 8.5% (n = 26) for severe depressive symptoms. Depressive symptoms were associated with Arab ethnicity (chi 2 = 5.66, p = .017), female gender (chi 2 = 3.97, p = .046), relationship with peers (p < .001), year of study (chi 2 = 13.68, p = .008), and academic performance (p < 0.001). Anxiety symptoms were present in 51% (n = 158) of students. Anxiety symptoms were associated with female gender (chi 2 = 11.35, p < 0.001), year of study (chi 2 = 10.28, p = .036), and academic performance (chi 2 = 14.97, p = .002). CONCLUSION: The prevalence of depressive and anxiety symptoms among medical students was high. Medical universities in the Middle East may need to allocate more resources into monitoring and early detection of medical student distress. Medical education providers are encouraged to provide adequate pastoral and psychological support for medical students, including culturally appropriate self-care programs within the curriculum. PMID- 28664463 TI - Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. AB - Helminths have accompanied human throughout history by releasing immune-evasion molecules that could counteract an aberrant immune response within the host. In the past decades, helminth infections are becoming less prevalent possibly due to the developed sanitation. Meanwhile, the incidence of autoimmune diseases is increasing, which cannot be exclusively explained by the changes of susceptibility genes. While the hygiene hypothesis casts light on the problem. The infections of helminths are believed to interact with and regulate human immunity with the byproduct of suppressing the autoimmune diseases. Thus, helminths are potential to treat or cure the autoimmune diseases. The therapeutic progresses and possible immune suppression mechanisms are illustrated in the review. The helminths that are studied most intensively include Heligmosomoides polygyrus, Hymenolepis diminuta, Schistosoma mansoni, Trichinella spiralis, and Trichuris suis. Special attentions are paid on the booming animal models and clinical trials that are to detect the efficiency of immune-modulating helminth derived molecules on autoimmune diseases. These trials provide us with a prosperous clinical perspective, but the precise mechanism of the down-regulatory immune response remains to be clarified. More efforts are needed to be dedicated until these parasite-derived immune modulators could be used in clinic to treat or cure the autoimmune diseases under a standard management. PMID- 28664464 TI - Early identification of MCI converting to AD: a FDG PET study. AB - PURPOSE: Mild cognitive impairment (MCI) is a transitional pathological stage between normal ageing (NA) and Alzheimer's disease (AD). Although subjects with MCI show a decline at different rates, some individuals remain stable or even show an improvement in their cognitive level after some years. We assessed the accuracy of FDG PET in discriminating MCI patients who converted to AD from those who did not. METHODS: FDG PET was performed in 42 NA subjects, 27 MCI patients who had not converted to AD at 5 years (nc-MCI; mean follow-up time 7.5 +/- 1.5 years), and 95 MCI patients who converted to AD within 5 years (MCI-AD; mean conversion time 1.8 +/- 1.1 years). Relative FDG uptake values in 26 meta-volumes of interest were submitted to ANCOVA and support vector machine analyses to evaluate regional differences and discrimination accuracy. RESULTS: The MCI-AD group showed significantly lower FDG uptake values in the temporoparietal cortex than the other two groups. FDG uptake values in the nc-MCI group were similar to those in the NA group. Support vector machine analysis discriminated nc-MCI from MCI-AD patients with an accuracy of 89% (AUC 0.91), correctly detecting 93% of the nc-MCI patients. CONCLUSION: In MCI patients not converting to AD within a minimum follow-up time of 5 years and MCI patients converting within 5 years, baseline FDG PET and volume-based analysis identified those who converted with an accuracy of 89%. However, further analysis is needed in patients with amnestic MCI who convert to a dementia other than AD. PMID- 28664466 TI - Pink, Blue, and Gender: An Update. PMID- 28664465 TI - SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers. AB - The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) separate the brain and cerebrospinal fluid (CSF) from the systemic circulation and represent a barrier to the uptake of both endogenous compounds and xenobiotics into the brain. For compounds whose passive diffusion is limited due to their ionization or hydrophilicity, membrane transporters can facilitate their uptake across the BBB or BCSFB. Members of the solute carrier (SLC) and ATP binding case (ABC) families are present on these barriers. Differences exist in the localization and expression of transport proteins between the BBB and BCSFB, resulting in functional differences in transport properties. This review focuses on the expression, membrane localization, and different isoforms present at each barrier. Diseases that affect the central nervous system including brain tumors, HIV, Alzheimer's disease, Parkinson's disease, and stroke affect the integrity and expression of transporters at the BBB and BCSFB and will be briefly reviewed. PMID- 28664467 TI - Phylogenetic analysis of Puumala virus strains from Central Europe highlights the need for a full-genome perspective on hantavirus evolution. AB - Puumala virus (PUUV), carried by bank voles (Myodes glareolus), is the medically most important hantavirus in Central and Western Europe. In this study, a total of 523 bank voles (408 from Germany, 72 from Slovakia, and 43 from Czech Republic) collected between the years 2007-2012 were analyzed for the presence of hantavirus RNA. Partial PUUV genome segment sequences were obtained from 51 voles. Phylogenetic analyses of all three genome segments showed that the newfound strains cluster with other Central and Western European PUUV strains. The new sequences from Sumava (Bohemian Forest), Czech Republic, are most closely related to the strains from the neighboring Bavarian Forest, a known hantavirus disease outbreak region. Interestingly, the Slovak strains clustered with the sequences from Bohemian and Bavarian Forests only in the M but not S segment analyses. This well-supported topological incongruence suggests a segment reassortment event or, as we analyzed only partial sequences, homologous recombination. Our data highlight the necessity of sequencing all three hantavirus genome segments and of a broader bank vole screening not only in recognized endemic foci but also in regions with no reported human hantavirus disease cases. PMID- 28664468 TI - Tumor Treating Fields in Neuro-Oncological Practice. AB - Electric fields are known to produce biological effects. Depending on specific frequency, they can stimulate healing, directly damage tissues, or produce anti mitotic activity. Frequencies of 100-300 KHz have been shown to disrupt mitosis and lead to cellular death. Growth of cancer cell lines, both in vitro and in vivo, was shown to be inhibited by application of the electric fields. In the clinical setting, electric fields are available for treatment of brain tumors, specifically glioblastoma (GBM), through a portable device producing so-called tumor treating fields (TTF). Clinical trials conducted in patients with recurrent and newly diagnosed GBM indicated that this novel treatment modality is active and associated with minimal toxicity. This manuscript will review the available evidence supporting the use of TTF in neuro-oncologic practice. PMID- 28664469 TI - The Role of Telemedicine in Providing Thoracic Oncology Care to Remote Areas of British Columbia. AB - PURPOSE OF REVIEW: The purpose of this study is to review the role of telemedicine in providing oncology care; we describe our long-standing, high volume telemedicine experience. RECENT FINDINGS: The Interior Health Thoracic Surgical Group (IHTSG) uses telemedicine, through Virtual Thoracic Surgical Clinics (VTSC), to provide service to remote patients. The IHTSG serves a population of 1.01 million people over an area of 807,538 km2 (1.3 persons/km2) in the Interior and North of British Columbia, Canada. Between 2003 and 2015, the IHTSG conducted 15,073 telemedicine patient encounters at 63 geographic sites. Telemedicine saved these patients a total travel distance of 11.5 million km-an average of 766 km per patient. VTSC supports and strengthens the Hub and Spoke model of healthcare delivery-patients residing remotely can easily access centrally delivered service. Telemedicine makes specialized care available to all patients by overcoming a major impediment to access, namely distance. PMID- 28664470 TI - Early Cervical Cancer: Current Dilemmas of Staging and Surgery. AB - PURPOSE OF REVIEW: Advances in cervical cancer screening and treatment have resulted in high cure rates in developed countries for early-stage disease. Current research focuses on minimizing morbidity and maximizing quality of life. RECENT FINDINGS: Imaging has been disappointing in identifying small volume metastases. Sentinel lymph node biopsy represents a significant advantage with high sensitivity, low false negative rates, reduced morbidity, and equivalent survival in recent studies compared to pelvic lymphadenectomy. Non-radical surgical options are currently being investigated for early cervical cancer in a number of large prospective studies in patients at low risk for metastases. Evidence suggests that sentinel lymph node biopsy and non-radical surgery are safe approaches for the staging and management of early cervical cancer in appropriately selected patients with the potential to significantly reduce treatment-related morbidity. PMID- 28664471 TI - Current Management Strategy for Penile Cancer and Future Directions. AB - PURPOSE OF REVIEW: The aim of this review is to evaluate the trends in multidisciplinary management of localized penile cancer and systemic therapy for advanced disease in the evolving era of targeted and immune checkpoint therapy. RECENT FINDINGS: Organ preservation (surgical or incorporating radiation) and reconstructive techniques are important considerations for quality of life in penile cancer survivors. Although local recurrence may be higher with organ preservation, salvage therapy appears successful. Inguinal and pelvic node management requires multidisciplinary care, including chemotherapy; optimal use of radiation has not been fully defined. Advanced in understanding the biology of penile cancer, particularly with regard to epidermal growth factor receptor (EGFR) and HPV status, have led to clinical trials of targeted and immune therapy for patients with refractory disease. Refinements in the management of penile cancer are occurring, though level 1 evidence remains scarce. Referral to specialized centers will facilitate successful completion of clinical trials to advance standard care in this disease. PMID- 28664473 TI - Comparison of the ameliorative effects of Qingfei Tongluo formula and azithromycin on Mycoplasma pneumoniae pneumonia. AB - Mycoplasma pneumoniae pneumonia (MPP) is a common disease in children. Qingfei Tongluo formula (QTF) has been used for the treatment of MPP clinically, but the therapeutic effect remains unclear compared to conventional treatments with Western medicines. Therefore, the aim of this study was to assess changes in the expression levels of relevant factors associated with microcirculation after MPP and to compare the therapeutic effect of QTF with that of azithromycin (AZM) on experimental mice with MPP. A total of 174 children admitted with clinical diagnoses of pneumonia (80 MPP and 94 non-MPP) were used to identify differences in the expression patterns of factors in the microcirculation using an enzyme linked immunosorbent assay. A BALB/c mouse model of MPP infection was established to determine the therapeutic effect of QTF. The results showed that the expression level of thrombomodulin (TM), vascular endothelial growth factor (VEGF), d-dimer (D-D), interleukin (IL)-6, and IL-10 were upregulated after MPP both clinically in children and in the mouse model. After 3 days of therapy, the amount of total MPP DNA decreased, especially in the mid- and high-dose QTF treatment groups. The expression levels of VEGF, IL-6, and IL-10 also decreased in response to treatment with QTF or AZM. However, there was no influence on D-D levels. QTF treatment also decreased TM expression. In conclusion, QTF treatment inhibited the progression of MPP, reduced vascular permeability, and improved pulmonary microcirculation more effectively than conventional treatment with Western medicine. PMID- 28664472 TI - Trends in Research Literature Describing Dysphagia in Motor Neuron Diseases (MND): A Scoping Review. AB - Dysphagia in motor neuron diseases (MNDs) is highly complex, affecting all stages of swallowing and leading to impaired swallowing safety and efficiency. In order to explore the degree to which research is capturing the symptom of dysphagia in MND, we conducted a scoping review of the existing literature. The primary aims of this review were to identify common themes within the literature on dysphagia in MND, explore patterns and trends in research focus, and identify if any imbalances exist between the research themes related to dysphagia description and management. A comprehensive search strategy yielded 1690 unique articles for review. Following relevance screening, a total of 157 articles were included in the synthesis. Relevant data and keywords were extracted from each article and grouped into themes. Frequency estimates were calculated for each theme to identify trends across research literature. Swallowing impairment in MNDs is described in a variety of ways across current research. The most commonly reported theme was Aspiration/Penetration, mentioned in 73.2% of all included articles; a significant imbalance was identified between reports of swallowing safety and efficiency (p = 0.008). The most frequently reported theme related to dysphagia management was Enteral Nutrition, and very few studies have reported on the efficacy of Rehabilitation/Compensatory recommendations. It is suggested that researchers and clinicians remain mindful of imbalances and gaps in research, and aim to characterize dysphagia in MNDs in a comprehensive manner. Further research investigating discrete, measureable changes in swallowing pathophysiology would be beneficial to delineate the key factors contributing to impaired swallowing safety and efficiency. PMID- 28664474 TI - Intratumoral Heterogeneity of Frameshift Mutations of GLI1 Encoding a Hedgehog Signaling Protein in Colorectal Cancers. AB - GLI1 is a transcription factor for hedgehog signaling that plays a crucial role in signaling pathways for controlling cell proliferation, alterations of which are known to contribute to tumorigenesis. Aim of this study was to explore whether GLI1 gene is mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that GLI1 had a G7 mononucleotide repeat in the coding sequences that could be a mutation target in the cancers with microsatellite instability (MSI). In this study, we analyzed frameshift mutation of GLI1 in 79 GCs and 129 CRCs (high MSI (MSI-H) or microsatellite stable (MSS)) by single strand conformation polymorphism analysis and DNA sequencing. We found 10 frameshift mutations in the repeat, nine for CRCs and one for GC. All of the mutations were detected in cancers with MSI-H and there was a statistical difference in the frameshift mutation frequencies between the cancers with MSI-H (10/113) and MSS (0/90). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutation in 16 CRCs and found that the mutations exhibited regional ITH in three of the CRCs (18.8%). Our data indicate GLI1 harbored not only frameshift mutation but also its mutational ITH, which together could be a feature of GC and CRC with MSI-H. PMID- 28664475 TI - Discordance Rate of HER2 Status in Primary Gastric Cancer and Synchronous Lymph Node Metastases: Its Impact on Therapeutic Decision and Clinical Management. PMID- 28664476 TI - TERT Promoter Mutation and Telomere Length in Salivary Gland Tumors. PMID- 28664477 TI - Maximizing Ion Transmission in Differential Mobility Spectrometry. AB - We provide modeling and experimental data describing the dominant ion-loss mechanisms for differential mobility spectrometry (DMS). Ion motion is considered from the inlet region of the mobility analyzer to the DMS exit, and losses resulting from diffusion to electrode surfaces, insufficient effective gap, ion fragmentation, and fringing field effects are considered for a commercial DMS system with 1-mm gap height. It is shown that losses due to diffusion and radial oscillations can be minimized with careful consideration of residence time, electrode spacing, gas flow rate, and waveform frequency. Fragmentation effects can be minimized by limitation of the separation field. When these parameters were optimized, fringing field effects at the DMS inlet contributed the most to signal reduction. We also describe a new DMS cell configuration that improves the gas dynamics at the mobility cell inlet. The new cell provides a gas jet that decreases the residence time for ions within the fringing field region, resulting in at least twofold increase in ion signal as determined by experimental data and simulations. Graphical Abstract ?. PMID- 28664478 TI - The integrated value of sST2 and global longitudinal strain in the early stratification of patients with severe aortic valve stenosis: a translational imaging approach. AB - Aortic valve stenosis (AVS) is associated with significant myocardial fibrosis (MF). Global longitudinal strain (GLS) is a sensible indicator of systolic dysfunction. ST2 is a member of the interleukin (IL)-1 receptor family and a modulator of hypertrophic and fibrotic responses. We aimed at assessing: (a) the association between adverse LV remodeling, LV functional parameters (including GLS) and sST2 level. (b) The association between MF (detected by endo-myocardial biopsy) and sST2 in patients with AVS undergoing surgical valve replacement. Twenty-two patients with severe AVS and preserved EF underwent aortic valve replacement. They performed laboratory analysis, including serum ST2 (sST2), echocardiography and inter-ventricular septum biopsy to assess MF (%). We included ten controls for comparison. Compared to controls, patients showed higher sST2 levels (p < 0.0001). sST2 showed correlation with Age (r = 0.58; p = 0.0004), E/e' average (r = 0.58; p = 0.0007), GLS (r = 0.61; p = 0.0002), LAVi (r = 0.51; p = 0.003), LVMi (r = 0.43; p = 0.01), sPAP (r = 0.36; p = 0.04) and SVi (r = -0.47; p < 0.005). No correlation was found between MF and sST2. At ROC analysis, a sST2 >= 284 ng/mL had the best accuracy to discriminate controls from patients with impaired GLS, i.e. GLS <= 17% (AUC 0.80; p = 0.003; sensitivity 95%; specificity 83%) and increased E/e' average (AUC 0.87; p = 0.0001; sensitivity 96%; specificity 74%). At multivariate regression analysis GLS resulted the only independent predictor of sST2 levels (R2 = 0.35; p = 0.0004). Patients with severe AVS present elevated sST2 levels. LV GLS resulted the only independent predictor of sST2 levels. PMID- 28664479 TI - Comparison of syntax score and syntax score II to predict "no reflow phenomenon" in patients with ST-segment elevation myocardial infarction. AB - Even though the relationship between syntax score (SS) and coronary no-reflow phenomenon has been studied, the relation between SS and syntax score II (SS II) in patients with no-reflow phenomenon is unknown. We aimed to define the relationship between coronary no-reflow phenomenon and SS II as compared with SS. This study enrolled 193 patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction in whom 42 patients developed the no-reflow phenomenon. SS and SS II were calculated in all patients. Bland Altman analysis was used to compare receiver-operating characteristic (ROC) curve analysis results. SS and SS II values were significantly higher in the no-reflow group than the reflow group (28.3 +/- 5.5 vs. 18.8 +/- 10.1; p < 0.001 and 42.5 (22.1-58.5) vs. 26.1 (13-49.8); p < 0.001 respectively). SS II value >32.3 yielded an area under the curve value of 0.881 (95% CI 0.820-0.942; p < 0.001) and independently predicted no-reflow with a sensitivity of 88% and a specificity of 80% (OR 1.150, 95% CI 1.047-1.263, p = 0.003). Comparison of ROC curve results with Bland Altman analysis showed that area under curve of SS II was larger than that of SS (0.881 vs. 0.785, p = 0.01). SS II may be a more useful tool than SS for prediction no-reflow phenomenon after primary percutaneous coronary intervention in patients with ST elevation myocardial infarction. PMID- 28664481 TI - Comparison of conventional and cadmium-zinc-telluride single-photon emission computed tomography for analysis of thallium-201 myocardial perfusion imaging: an exploratory study in normal databases for different ethnicities. AB - The aim of this study was to clarify the differences in thallium-201-chloride (thallium-201) myocardial perfusion imaging (MPI) scans evaluated by conventional anger-type single-photon emission computed tomography (conventional SPECT) versus cadmium-zinc-telluride SPECT (CZT SPECT) imaging in normal databases for different ethnic groups. MPI scans from 81 consecutive Japanese patients were examined using conventional SPECT and CZT SPECT and analyzed with the pre installed quantitative perfusion SPECT (QPS) software. We compared the summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) for the two SPECT devices. For a normal MPI reference, we usually use Japanese databases for MPI created by the Japanese Society of Nuclear Medicine, which can be used with conventional SPECT but not with CZT SPECT. In this study, we used new Japanese normal databases constructed in our institution to compare conventional and CZT SPECT. Compared with conventional SPECT, CZT SPECT showed lower SSS (p < 0.001), SRS (p = 0.001), and SDS (p = 0.189) using the pre installed SPECT database. In contrast, CZT SPECT showed no significant difference from conventional SPECT in QPS analysis using the normal databases from our institution. Myocardial perfusion analyses by CZT SPECT should be evaluated using normal databases based on the ethnic group being evaluated. PMID- 28664480 TI - Usefulness of left ventricular speckle tracking echocardiography and novel measures of left atrial structure and function in diagnosing paroxysmal atrial fibrillation in ischemic stroke and transient ischemic attack patients. AB - Asymptomatic paroxysmal atrial fibrillation (PAF) is often assumed to be the cause of cryptogenic ischemic strokes (IS) and transient ischemic attacks (TIA). We examined the usefulness of measures obtained by 2D speckle tracking echocardiography and novel left atrial measurements, in the diagnosis of PAF in patients with IS and TIA. We retrospectively included 205 patients who after acute IS or TIA underwent an echocardiogram in sinus rhythm. Patients were designated as PAF-patients if they had one or more reported incidents of AF before or after their echocardiographic examination. None of the conventional echocardiographic parameters were significantly associated with PAF. Of the speckle tracking measurements, only early diastolic strain rate (0.7+/-0.2 s-1 vs. 0.8+/-0.3 s-1, p = 0.048) and global longitudinal displacement (GLD) (3.15 +/ 1.40 mm vs. 3.87 +/- 1.56 mm, p = 0.007) proved significantly different. Of the left atrial parameters both minimal and maximal left atrium volume divided by left ventricular length (min LAV/LVL and max LAV/LVL, respectively) were significantly impaired (min LAV/LVL: 3.7 +/- 2.1 cm2 vs. 2.8 +/- 1.11 cm2, p = 0.012; max LAV/LVL: 6.6 +/- 3.1 cm2 vs. 5.6 +/- 1.7 cm2, p = 0.012). GLD, min max LAV/LVL proved significant after adjustment for age, gender, CHA2DS2-VASc and NIHSS. By combining information regarding age, GLD, min and max LAV/LVL the diagnostic accuracy of PAF improved, resulting in a significantly increased area under the curve (p = 0.037). In patients with IS and TIA GLD, min and max LAV/LVL were independently associated with the presence of PAF. PMID- 28664482 TI - Prognostic value of a faster, low-radiation myocardial perfusion SPECT protocol in a CZT camera. AB - To determine the prognostic value of a new, ultrafast, low dose myocardial perfusion SPECT (MPS) protocol in a cadmium-zinc telluride (CZT) camera. CZT cameras have introduced significant progress in MPS imaging, offering high quality images despite lower doses and scan time. Yet, it is unknown if, with such protocol changes, the prognostic value of MPS is preserved. Patients had a 1 day 99 m-Tc-sestamibi protocol, starting with the rest (185-222 MBq) followed by stress (666-740 MBq). Acquisition times were 6 and 3 min, respectively. MPS were classified as normal or abnormal perfusion scans and summed scores of stress, rest, and difference (SSS, SRS and SDS), calculated. Patients were followed with 6-month phone calls. Hard events were defined as death or nonfatal myocardial infarction. Late revascularization was that occurring after 60 days of MPS. 2930 patients (age 64.0 +/- 12.1 years, 53.3% male) were followed for 30.7 +/- 7.5 months. Mean dosimetry was 6 mSv and mean total study time, 48 +/- 13 min. The annual hard event and late revascularization rate were higher in patients with greater extension of defect and ischemia. SSS was higher in patients with hard events compared to those without events (2.6 +/- 4.9 vs. 5.0 +/- 6.3, p < 0.001), as well as the SDS (0.7 +/- 1.9 vs. 1.7 +/- 3.4, p < 0.00). The same was true for patients with or without late revascularization (SSS: 2.5 +/- 4.7 vs. 6.6 +/- 7.1; SDS: 0.6 +/- 1.7 vs. 2.9 +/- 3.8, p < 0.01). A new, faster, low-radiation, MPS protocol in a CZT camera maintain the ability to stratify patients with increased risk of events, showing that, in the presence of greater extension of defect or ischemia, patients presented higher rates of hard events and late revascularization. PMID- 28664483 TI - Efficacy of dienogest in improving pain in women with endometriosis: a 12-month single-center experience. AB - PURPOSE: Dienogest has recently been marketed as a medical treatment for endometriosis. Given the recent introduction on the market of Dienogest, little data are available regarding its effectiveness in routine clinical practice. METHODS: The study is an observational, single-center, cohort study. Eligible was women with a surgical diagnosis of endometriosis dating back <24 months or a clinical/instrumental diagnosis of endometriosis and endometriosis-associated pelvic pain score of at least 40 mm on a 100-mm visual analog scale (VAS) at start of treatment and who had been taking Dienogest 2 mg once daily treatment at the time of study entry for no more than 30 days, consecutively observed between September 2013 to September 2014. In accordance with routine practice, women came back for clinical assessment and evaluation of pain after 1 (V1), 3 (V2), and 12 (V3) months. RESULTS: A total of 132 women were enrolled in the study. A total of 21 of the enrolled patients were released from the study during follow-up due to adverse effects. The mean pelvic pain VAS score at baseline was 8.9 (SD 1.3). The corresponding values were 6.7 (SD 3.2) and 5.7 (SD 3.7) for dyspareunia and dyschezia. The mean VAS scores progressively and significantly decreased to 0.9 (SD 1.6) for pelvic pain, 1.4 (SD 2.1) for dyspareunia and 0.2 (SD 0.9) for dyschezia, respectively, 12 months after start of treatment. CONCLUSION: This study confirms that in routine clinical practice, Dienogest 2 mg is an effective and well-tolerated treatment for endometriosis-related pain in women with endometriosis. PMID- 28664484 TI - The role of three-dimensional power Doppler hysterosonography (3-DPDS) in distinguishing atypical polypoid adenomyomas (APAs) from other intrauterine tumors: correlation with pathologic findings. AB - OBJECTIVE: This study was undertaken to describe the sonographic characteristics of atypical polypoid adenomyomas (APAs) of the uterus and to determine the value of three-dimensional power Doppler hysterosonography (3-DPDS) in distinguishing APA from other polypoid uterine tumors. METHODS: Ninety-five women with a mean age of 37 years (range 28-45) with a suspicious polypoid uterine tumor were referred for preoperative evaluation with 3-DPDS. Sonographic criteria used for the diagnosis of APA were based on a system that consisted of morphological characteristics, histological evaluation and power Doppler imaging. Biopsy samples of the intrauterine tumors were obtained via operative hysteroscopy. RESULTS: Fifteen lesions were histopathologically diagnosed as APAs, 25 as endometrial polyps and 55 as submucous myomas. In the present study, the sensitivity and specificity of 3-DPDSs in discriminating APA from other polypoid tumors was 82.5 and 86.7%, respectively. CONCLUSIONS: APAs can be accurately distinguished from other polypoid tumors of the uterus with the use of 3-DPDS demonstrating the following characteristics: lobular tumor with inhomogeneous echotexture, echogenicity similar to myometrium, broad base, acoustic shadow and linear vessel arrangement. PMID- 28664485 TI - "Per vaginam" topical use of hormonal drugs in women with symptomatic deep endometriosis: a narrative literature review. AB - PURPOSE: We aim to provide a comprehensive overview of the role of the vagina as a route for drug delivery and absorption, with a particular focus on the use of vaginal hormonal compounds for the treatment of deep infiltrating symptomatic endometriosis. METHODS: A MEDLINE search through PubMed was performed to identify all published studies in English language on vaginal hormonal treatments for symptomatic endometriosis. RESULTS: Main advantages of the vaginal route include avoidance of the hepatic-first pass metabolic effect, the possibility of using lower therapeutic dosages, and the reduction of side effects compared with the oral administration. Studies on endometriosis treatment mainly focused on the use of vaginal danazol (n = 6) and the contraceptive vaginal ring (n = 2). One pilot study evaluated the efficacy of vaginal anastrozole in women with rectovaginal endometriosis. Most investigations evaluated the vaginal use of hormonal agents in women with deep infiltrating endometriosis/rectovaginal endometriosis. Overall, a substantial amelioration of pelvic pain symptoms associated with endometriosis was observed, particularly of dysmenorrhea. A significant reduction in rectovaginal endometriotic nodule dimensions measured at ultrasound examination was detected by some but not all authors. CONCLUSIONS: The vaginal route represents a scarcely explored modality for drug administration. High local hormonal concentrations might achieve a greater effect on endometriotic lesions compared with alternative routes. Future studies should focus on the use of the vagina for delivering target therapies particularly in patients with deeply infiltrating rectovaginal lesions. PMID- 28664486 TI - Corpectomy and circumferential fusion for advanced thoracolumbar Kummell's disease. AB - BACKGROUND: The aim of this study was to investigate the surgical treatment of neurologically compromised advanced Kummell's disease. The surgical treatment of Kummell's disease has various options according to clinical and radiologic status. Far collapsed Kummell's disease patients with neurological deficit need to be treated surgically. MATERIALS AND METHODS: We retrospectively analyzed 22 patients operated to our hospital with neurologically compromised Kummell's disease between January 2011 and January 2014. Surgical approach was vertebrectomy, mesh cage insertion and segmental cement-augmented pedicle screw fixation. Corpectomy tissue was examined histopathologically. Anterior vertebral heights, kyphotic angle, the visual analog scale (VAS) and the Frankel classification were used to evaluate the effects of the surgery. RESULTS: The mean time of follow-up was 26 months (range, 13-40 months). The VAS, anterior vertebral heights, kyphotic angle and neurological state were improved significantly immediate postoperatively and at the last follow-up compared with the preoperative examinations (P < 0.05). Most of the patients in this study exhibited intravertebral clefts, and postoperative pathology revealed bone necrosis. CONCLUSION: Posterior vertebrectomy with mesh cage insertion and segmental cement-augmented pedicle screw fixation is an effective option for advanced Kummell's disease with neurological deficits. PMID- 28664487 TI - Comparative US-MRI evaluation of the Insall-Salvati index. AB - PURPOSE: To investigate whether the universally accepted range of normal patellar height ratio derived from MRI for the Insall-Salvati (IS) method could be similarly applied to ultrasound (US). MATERIALS AND METHODS: This study included 52 patients (age range 11-75 years) who underwent a bi-modality (US and MRI) examination, with a total of 60 knees evaluated. IS index (ratio of the patella tendon length to length of the patella) was acquired with both methods. Two operators, with different experiences of musculoskeletal imaging and blinded to the results of other investigators, separately performed the MRI and US measurements. RESULTS: For the two operators, MRI reported a mean value of patellar height ratio of 1.10 +/- 0.16 (mean +/- standard deviation SD), while US a mean value of 1.17 +/- 0.16 (mean +/- SD). For comparable results, the small addition of 0.16 is needed for the measurements on US compared with MRI. Inter observer agreements using intra-class correlation coefficient (ICC) was, respectively, 0.97 for MRI and 0.98 for US. The difference of mean values in patellar height ratios between MRI and US was not statistically significant (p = 0.15). The ICC between the two modalities was 0.94. CONCLUSION: According to our experience, IS index can be appropriately evaluated on US images, reducing the need of other imaging techniques. PMID- 28664488 TI - Radiologic findings for prediction of rehabilitation outcomes in patients with chronic symptomatic os subfibulare. AB - OBJECTIVE: To retrospectively evaluate the radiologic findings for predicting rehabilitation outcomes in patients with chronic symptomatic os subfibulare. MATERIALS AND METHODS: 38 patients with chronic lateral ankle pain and os subfibulare underwent a standardized rehabilitation program. Rehabilitation outcome was evaluated after >=3 months of intervention as the following: good response group (n = 20) without the need for further treatment and poor response group (n = 18) who underwent surgery after rehabilitation. Size, shape and location of os subfibulare, anterior talofibular ligament abnormality and attachment to the os subfibulare, interposition of fluid signal intensity between the os subfibulare and the fibula, and bone marrow edema in the os subfibulare on radiographs and MRI were evaluated by two radiologists blinded to rehabilitation outcomes and were compared between the two groups. RESULTS: The mean size of os subfibulare was significantly different between good and poor response groups: 7 versus 12 mm (p < 0.01), respectively. The prevalence of interposition of fluid signal intensity between the os subfibulare and the fibula and bone marrow edema in the os subfibulare on MRI was significantly different between the two groups (p < 0.01). However, other radiologic findings were not significantly different (p >= 0.08). The optimal size to classify the two groups was 9 mm with sensitivity of 83.3% and specificity of 80%. Inter-observer reliability was good to excellent (ICC = 0.991 for size and kappa = 0.735-0.923 for others). CONCLUSIONS: MRI may be used to predict rehabilitation outcome in patients with chronic symptomatic os subfibulare. PMID- 28664489 TI - Adsorptive removal of ascertained and suspected endocrine disruptors from aqueous solution using plant-derived materials. AB - The present study deals with the use of low-cost plant-derived materials, namely a biochar, spent coffee grounds, spent tea leaves, and a compost humic acid, for the adsorptive removal from water of two estrogens, 4-tert-octylphenol (OP) and 17-beta-estradiol (E2), and two pesticides, carbaryl and fenuron, each spiked at a concentration of 1 mg L-1. Kinetics and adsorption isotherms have been performed using a batch equilibrium method to measure the sorption capacities of the adsorbents towards the four molecules. Adsorption constants were calculated using the linear, Freundlich, and Langmuir models. Kinetics data obtained evidenced a rapid adsorption of each compound onto both biochar and coffee grounds with the attainment of a steady-state equilibrium in less than 4 h. Significant differences among the adsorbents and the compounds were found regarding the model and the extent of adsorption. In general, the estrogens were adsorbed more quickly and in greater amounts than the less hydrophobic pesticides, following the order: OP > E2 > carbaryl > fenuron. The ranges of Freundlich constants obtained for OP, E2, carbaryl, and fenuron onto the sorbents were 5049-2253, 3385-206, 2491-79, and 822-24 L kg-1, respectively. The maximum values of constants were obtained for biochar, except for OP that was more adsorbed by spent coffee grounds. Adsorption kinetic data followed a pseudo second-order model, thus indicating the occurrence of chemical interactions between the compounds and the substrates. The remarkable sorption capacities of all adsorbents towards the four molecules suggest the valuable exploitation of these materials for decontamination purposes, such as the treatment of wastewater before a feasible recycle in soil. PMID- 28664490 TI - Removal of organic contaminants in bioretention medium amended with activated carbon from sewage sludge. AB - Bioretention, also known as rain garden, allows stormwater to soak into the ground through a soil-based medium, leading to removal of particulate and dissolved pollutants and reduced peak flows. Although soil organic matter (SOM) is efficient at sorbing many pollutants, amending the bioretention medium with highly effective adsorbents has been proposed to optimize pollutant removal and extend bioretention lifetime. The aim of this research was to investigate whether soil amended with activated carbon produced from sewage sludge increases the efficiency to remove hydrophobic organic compounds frequently detected in stormwater, compared to non-amended soil. Three lab-scale columns (520 cm3) were packed with soil (bulk density 1.22 g/cm3); activated carbon (0.5% w/w) was added to two of the columns. During 28 days, synthetic stormwater-ultrapure water spiked with seven hydrophobic organic pollutants and dissolved organic matter in the form of humic acids-was passed through the column beds using upward flow (45 mm/h). Pollutant concentrations in effluent water (collected every 12 h) and polluted soils, as well as desorbed amounts of pollutants from soils were determined using GC-MS. Compared to SOM, the activated carbon exhibited a significantly higher adsorption capacity for tested pollutants. The amended soil was most efficient for removing moderately hydrophobic compounds (log K ow 4.0 4.4): as little as 0.5% (w/w), carbon addition may extend bioretention medium lifetime by approximately 10-20 years before saturation of these pollutants occurs. The column tests also indicated that released SOM sorb onto activated carbon, which may lead to early saturation of sorption sites on the carbon surface. The desorption test revealed that the pollutants are generally strongly sorbed to the soil particles, indicating low bioavailability and limited biodegradation. PMID- 28664491 TI - Photodegradation of multiclass fungicides in the aquatic environment and determination by liquid chromatography-tandem mass spectrometry. AB - The photodegradation behaviour for nine widespread fungicides (benalaxyl, cyprodinil, dimethomorph, fenhexamide, iprovalicarb, kresoxim-methyl, metalaxyl, myclobutanil and tebuconazole) was evaluated in different types of water. Two different systems, direct UV photolysis and UVC/H2O2 advanced oxidation process (AOP), were applied for the photodegradation tests. For the monitoring of the target compound degradation, a method based on direct injection liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Several fungicide photodegradation by-products were tentatively identified by high resolution mass spectrometry (HRMS) as well. For the photolysis studies, the efficiency of different types of radiation, UVC (lambda = 254 nm) and UVA (lambda = 365 nm), was compared. UVC photolysis provided the highest removal with a complete degradation for fenhexamide and kresoxim-methyl, and percentages between 48 and 78% for the other compounds, excluding iprovalicarb and myclobutanil with removals <35%, after 30 min of irradiation. Besides, the photodegradation tests were performed with different initial concentrations of fungicides, and the efficiency of two photoreactor systems was compared. In all cases, the kinetics followed pseudo-first order, and the half-life times could also be calculated. The addition of H2O2 under UVC light allowed an improvement of the reaction kinetics, especially for the most recalcitrant fungicides, obtaining in all cases removals higher than 82% in less than 6 min. Finally, in order to evaluate the suitability of the proposed systems, both UVC photolysis and UVC/H2O2 system were tested in different real water matrices (wastewater, tap water, swimming pool water and river water), showing that the UVC/H2O2 system had the highest removal efficiency in less than 6 min, for all water samples. PMID- 28664492 TI - The influence of growth form and substrate on lichen ecophysiological responses along an aridity gradient. AB - In this paper, we investigated whether growth form and substrate in lichens influence their physiological responses along an aridity gradient. Thalli of the foliose lichen Parmotrema perlatum and the fruticose lichen Ramalina canariensis were transplanted in selected rural/forested sites of Southern Portugal characterized by a different aridity index. Physiological parameters including photosynthetic performances, assimilation pigments, ergosterol content and sample viability were measured prior to exposure (winter) and after 6-month exposure (summer). Photosynthetic performances were also investigated in common native foliose and fruticose epiphytic lichens and in fruticose terricolous species. Both transplanted and native lichens showed a decrease in photosynthetic performances in summer and lower performances in sites classified as drier and higher performances in humid forested sites. No relevant differences occurred between epiphytic foliose and fruticose growth forms. However, terricolous fruticose samples showed a significant difference in humid and drier sites and between winter and summer, probably due to microclimatic conditions similarly to other biological crusts. PMID- 28664493 TI - Assessment of Pb and pyrene accumulation in Scirpus triqueter assisted by combined alkyl polyglucoside and nitrilotriacetic acid application. AB - To understand the accumulation and uptake of polycyclic aromatic hydrocarbons (PAHs) and heavy metals by plants is an important part of the assessment of phytoremediation for PAHs and heavy metals co-contaminated soil. This study was an investigation of the accumulation and uptake of pyrene and lead (Pb) by Scirpus triqueter under the condition of alkyl polyglucoside (APG) and nitrilotriacetic acid (NTA) combined application. The results indicated that the accumulation of Pb by S. triqueter was significantly improved by NTA and APG addition into the soil. The pyrene accumulation in plant was also increased after application of APG when compared to the control treatment. However, the pyrene accumulation was decreased when APG was applied together with NTA. SEM and TEM images of root surface suggested that more Pb in the soil transferred to the plant by combined application of APG and NTA. More importantly, TEM images of xylem cells of S.triqueter root showed that permeability of cell membrane was improved by application of APG. PMID- 28664494 TI - Can liming change root anatomy, biomass allocation and trace element distribution among plant parts of Salix * smithiana in trace element-polluted soils? AB - Willows (Salix spp.) are considered to be effective for the phytoremediation of trace elements from contaminated soils, but their efficiency is limited in heavily polluted soils because of poor growth. Liming can be a desirable measure to decrease the plant availability of elements, resulting in improved plant development. Notably, large root area and maximum soil penetration are basic parameters that improve the efficiency of phytoremediation. The impact of soil chemical properties on willow root anatomy and the distribution of trace elements below-ground have rarely been studied. The effect of liming on root parameters, biomass allocation and trace element distribution in non-harvestable (coarse roots, fine roots, stumps) and harvestable plant parts (twigs and leaves) of Salix * smithiana was assessed at the end of a 4-year pot experiment with two trace element-polluted soils that differed in terms of soil pH. Stump biomass predominated in weakly acidic soil. In neutral soil, the majority of biomass was located in fine roots and stumps; the difference from other plant parts was minor. Trace elements were the most concentrated in fine roots. Translocation to above-ground biomass increased as follows: Pb < As < Zn~Cd. In contrast to Cd and Zn, great differences in As and Pb mobility in plants were recorded after measurements of individual below-ground biomass (stumps < coarse roots < fine roots). Lime application decreased the concentrations of mobile Cd and Zn and related levels in plants, improved biomass production and root parameters and increased the removal of all trace elements in weakly acidic soil. None or minimum differences in the monitored parameters were recorded for dolomite treatments in both soils. The dose and source of liming had crucial effects on root anatomy. Growing willows in limed trace element-polluted soils is a suitable measure for combination of two remediation strategies, i.e. phytoextraction of Cd and Zn and assisted phytostabilization of As and Pb. PMID- 28664495 TI - Biogeochemical and engineered barriers for preventing spread of contaminants. AB - The intensive industrial development and urbanization, as well as the negligible return of hazardous components to the deeper layers of the Earth, increases the contamination load on the noosphere (i.e., the new status of the biosphere, the development of which is mainly controlled by the conscious activity of a human being). The need for reducing the spread and mobility of contaminants is growing. The insights into the role of the tree in the reduction of contaminant mobility through its life cycle are presented to show an important function performed by the living matter and its products in reducing contamination. For maintaining the sustainable development, natural materials are often used as the media in the environmental protection technologies. However, due to increasing contamination intensity, the capacity of natural materials is not sufficiently high. Therefore, the popularity of engineered materials, such as biochar which is the thermochemically modified lignocellulosic product, is growing. The new approaches, based on using the contaminant footprint, as well as natural (biogeochemical) and engineered barriers for reducing contaminant migration and their application, are described in the paper. PMID- 28664496 TI - Efficient model calibration method based on phase experiments for anaerobic anoxic/nitrifying (A2N) two-sludge process. AB - A systematic calibration and validation procedure for the complex mechanistic modeling of anaerobic-anoxic/nitrifying (A2N) two-sludge system is needed. An efficient method based on phase experiments, sensitivity analysis, and genetic algorithm is proposed here for model calibration. Phase experiments (anaerobic phosphorus release, aerobic nitrification, and anoxic denitrifying phosphate accumulation) in an A2N sequencing batch reactor (SBR) were performed to reflect the process conditions accurately and improve the model calibration efficiency. The calibrated model was further validated using 30 batch experiments and 3-month dynamic continuous flow (CF) experiments for A2N-SBR and CF-A2N process, respectively. Several statistical criteria were conducted to evaluate the accuracy of model predications, including the average relative deviation (ARD), mean absolute error (MAE), root mean square error (RMSE), and Janus coefficient. Visual comparisons and statistical analyses indicated that the calibrated model could provide accurate predictions for the effluent chemical oxygen demand (COD), ammonia nitrogen (NH4+-N), total nitrogen (TN), and total phosphorus (TP), with only one iteration. PMID- 28664497 TI - Bacterial periphytic communities related to mercury methylation within aquatic plant roots from a temperate freshwater lake (South-Western France). AB - Macrophyte floating roots are considered as hotspots for methylmercury (MeHg) production in aquatic ecosystems through microbial activity. Nevertheless, very little is known about periphyton bacterial communities and mercury (Hg) methylators in such ecological niches. The ability to methylate inorganic Hg is broadly distributed among prokaryotes; however, sulfate-reducers have been reported to be the most important MeHg producers in macrophyte floating roots. In the present work, the periphyton bacterial communities colonizing Ludwigia sp. floating roots were investigated through molecular methods. Among the 244 clones investigated, anaerobic microorganisms associated with the sulfur biogeochemical cycle were identified. Notably, members of the sulfur-oxidizing prokaryotes and the anoxygenic, purple non-sulfur bacteria (Rhodobacteraceae, Comamonadaceae, Rhodocyclaceae, Hyphomicrobiaceae) and the sulfate reducers (Desulfobacteraceae, Syntrophobacteraceae, and Desulfobulbaceae) were detected. In addition, 15 sulfate-reducing strains related to the Desulfovibrionaceae family were isolated and their Hg-methylation capacity was tested using a biosensor. The overall results confirmed that Hg methylation is a strain-specific process since the four strains identified as new Hg-methylators were closely related to non-methylating isolates. This study highlights the potential involvement of periphytic bacteria in Hg methylation when favorable environmental conditions are present in such ecological micro-niches. PMID- 28664498 TI - Mice exposure to tannery effluents changes their olfactory capacity, and their response to predators and to the inhibitory avoidance test. AB - The current study has assessed whether the oral and/or dermal exposure of C57Bl/6 J mice to tannery effluent (a complex pollutant consisting of xenobiotic mixtures) could damage their olfactory functions, as well as whether it changes their aversive behavior in the inhibitory avoidance test. Accordingly, the animals were distributed in groups which were exposed or not to this xenobiotic through two different routes (oral and dermal), for 15 days. The effluent group subjected to oral exposure received drinking water containing 5% tannery effluent, whereas the animals in the dermal group were exposed to raw tannery effluent for 1 h/day. The animals dermally exposed to the tannery effluent (males and females) have shown the highest latency to find palatable food in the buried food test. The shortest time spent by the animals (orally or dermally) exposed to tannery effluent in the safety zone of the apparatus used in the predator exposure test, as well as the longest time spent by them in the aversive zone, have shown failures in their perception to the risk represented by the presence of the predator (cat). The passive avoidance test results have shown that the dermal exposure to tannery effluent led to partial memory deficit in male and female mice; therefore, the present study has confirmed the tannery effluent toxicity to mammals. Moreover, the present study was pioneer in demonstrating that the dermal exposure to this xenobiotic, even for a short period-of-time, can change the olfactory and cognitive functions of animals, as well as lead to harmful consequences to their health. PMID- 28664499 TI - Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. AB - This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged >=20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received >=1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade >=3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039. PMID- 28664500 TI - Trend and treatment patterns of aplastic anemia in Korea, pure red cell aplasia and myelodysplastic syndrome in Korea: a nation-wide analysis. AB - Aplastic anemia (AA) and pure red cell aplasia (PRCA) appear to be more prevalent in Asian countries including Korea. However, there are no exact data regarding its prevalence and frequency of allogeneic hematopoietic cell transplantation (HCT) in Korea. Here, we present demographic data relating to AA/PRCA/MDS in Korea. Data were prepared by retrieval from a computerized database maintained by the National Health Insurance Service and Korea National Statistical Office. HCT data were collected from all HCT centers in Korea. The crude incidence rate of AA decreased from 2002 to 2010 and from 35 to 28 per million persons. Females were more affected by AA. The peak ages of onset of AA were in the seventh decade or older. The frequency of HCT for AA increased from 2002 to 2012 and from 69 to 131 per year. The crude incidence rates of MDS increased from 2002 to 2010, with 8-20 per million persons, and the frequency of HCT also increased, from 30 in 2002 to 132 in 2011. Even allowing for the possibility of overestimation, the crude incidence of AA is significantly higher in Korea than in western countries. PMID- 28664501 TI - Tarsal tunnel syndrome: still more opinions than evidence. Status of the art. AB - Tarsal tunnel syndrome is an entrapment neuropathy of the posterior tibial nerve or its terminal branches within its fibro-osseous tunnel beneath the flexor retinaculum on the medial side of the ankle. The condition is frequently underdiagnosed leading to controversies regarding its epidemiology and to an intense debate in the literature. With the advent of nerve imaging techniques, the diagnostic confirmation and the etiological identification have become more accurate. However, management of this entrapment neuropathy remains challenging because of many intervention strategies but limited robust evidence. Uncertainties still exist about the best conservative treatment, timing of surgical intervention, and best surgical approach. In the attempt to clarify these aspects and to provide the reader some understanding of the status of the art, we have reviewed the published literature on this controversial condition. PMID- 28664502 TI - Validating Stages of Change for Obesogenic Behaviors Across Filipino and Other Asian-American and Pacific Islander Adolescents. AB - Filipino adolescents are underrepresented in obesity research, although Filipinos are the second largest Asian-American and Pacific Islander (AAPI) subpopulation in the USA. An understanding of how well the theories of behavior change apply to Filipino and other AAPI adolescents is critical to addressing obesogenic behaviors in these groups. This study aimed to validate the transtheoretical model of behavior change (TTM) for physical activity (PA) and fruit and vegetable intake (FV) among a majority Filipino adolescent population. Adolescents in grades 9-11 (N = 159, 82.4% female) completed measures of PA and FV behaviors and PA and FV stages of change. One-way ANOVAs and Tukey's HSD post hoc tests were computed to assess the validity of the PA and FV stages of change with the respective behaviors. There was a significant effect for fruit (action > contemplation, preparation) and vegetable (maintenance, action > contemplation) intakes across the FV stages of change. There was a significant effect of strenuous PA (precontemplation/contemplation, preparation < action < maintenance) and moderate PA (precontemplation/contemplation < action, maintenance) across the PA stages of change. Some variability in associations emerged when the sample was stratified by gender. This study provides validity evidence for the TTM stages of change for FV and PA among Filipino and other AAPI adolescents. This validation, in turn, extends the generalizability of the stages of change construct to include this ethnic group and replicates other adolescent studies. PMID- 28664503 TI - Predictors of Colorectal Cancer Knowledge and Screening Among Asian Americans Aged 50-75 years old. AB - Colorectal cancer, the second leading cause of mortality in the USA, can be prevented with colorectal cancer screening. However, many people who should receive the screening do not get screened. To learn more, this study estimated the prevalence of up-to-date colorectal cancer (CRC) screening and examined the relationship between CRC knowledge and screening compliance among Asian Americans living in the Baltimore-Washington Metropolitan area. The study included a cross sectional sample of 274 Chinese, Korean, and Vietnamese Americans aged 50-75 years old. Participants completed a questionnaire regarding CRC knowledge in either their preferred native language or in English, and data were collected in person. The percentage of total participants with up-to-date overall CRC screening was 52.9%. Up-to-date fecal occult blood test (FOBT) screening was 15.0% and colonoscopy was 50.7%. The average CRC knowledge score was 6.10 out of 9 (SD = 2.91). Those with high education, high English proficiency, married, health insurance, and good physical health ratings had higher CRC knowledge. In multivariate analysis, CRC knowledge was significantly correlated with increasing up-to-date colonoscopy (aOR = 2.74, 1.13-6.64). Having health insurance (aOR = 4.40, 2.33-8.32) was another predictor of up-to-date colonoscopy. These findings suggest that CRC knowledge is a strong predictor of CRC screening behavior in Asian American populations. Lack of CRC screening knowledge still remains an important barrier to screening, and increased public awareness is necessary to achieve greater screening compliance. PMID- 28664504 TI - Assessment of gender and age effects on serum and hair trace element levels in children with autism spectrum disorder. AB - The primary objective of the present study was to investigate the levels of essential trace elements in hair and serum in children with autism spectrum disorder (ASD) and investigate the age and gender effects. Children with ASD were characterized by significantly higher levels of copper (Cu) (+8%), iron (Fe) (+5%), and selenium (Se) (+13%) levels in hair and only 8% higher serum Cu levels. After stratification for gender, ASD boys were characterized by significantly increased hair Cu (+ 25%), Fe (+ 25%), and Se (+ 9%) levels, whereas in girls only Se content was elevated (+ 15%). Boys and girls suffering from ASD were characterized by significantly higher serum manganese (Mn) (+20%) and Cu (+18%) as compared to the control values, respectively. In the group of younger children (2-5 years), no significant group difference in hair trace element levels was detected, whereas serum Cu levels were significantly higher (+7%). In turn, the serum concentration of Se in ASD children was 11% lower than that in neurotypical children. In the group of older children with ASD (6-10 years), hair Fe and Se levels were 21% and 16% higher, whereas in serum only Cu levels were increased (+12%) as compared to the controls. Correlation analysis also revealed a different relationship between serum and hair trace element levels with respect to gender and age. Therefore, it is highly recommended to assess several bioindicative matrices for critical evaluation of trace element status in patients with ASD in order to develop adequate personalized nutritional correction. PMID- 28664505 TI - SSADH deficiency in an Italian family: a novel ALDH5A1 gene mutation affecting the succinic semialdehyde substrate binding site. AB - SSADH deficiency (SSADHD) is a rare autosomal recessively inherited metabolic disorder. It is associated with mutations of ALDH5A1 gene, coding for the homotetrameric enzyme SSADH. This enzyme is involved in gamma-aminobutyric acid (GABA) catabolism, since it oxidizes succinic semialdehyde (SSA) to succinate. Mutations in ALDH5A1 gene result in the abnormal accumulation of gamma hydroxybutyrate (GHB), which is pathognomonic of SSADHD. In the present report, diagnosis of SSADHD in a three-month-old female was achieved by detection of high levels of GHB in urine. Sequence analysis of ALDH5A1 gene showed that the patient was a compound heterozygote for c.1226G > A (p.G409D) and the novel missense mutation, c.1498G > C (p.V500 L). By ALDH5A1 gene expression in transiently transfected HEK293 cells and enzyme activity assays, we demonstrate that the p.V500 L mutation, despite being conservative, produces complete loss of enzyme activity. In silico protein modelling analysis and evaluation of tetramer destabilizing energies suggest that structural impairment and partial occlusion of the access channel to the active site affect enzyme activity. These findings add further knowledge on the missense mutations associated with SSADHD and the molecular mechanisms underlying the loss of the enzyme activity. PMID- 28664506 TI - Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. AB - PURPOSE: To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population. METHODS: Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site. RESULTS: We found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86% for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also identified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites. CONCLUSION: Our data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations. PMID- 28664507 TI - Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial. AB - BACKGROUND: The prospective phase 3 PlanB trial used the Oncotype DX(r) Recurrence Score(r) (RS) to define a genomically low-risk subset of clinically high-risk pN0-1 early breast cancer (EBC) patients for treatment with adjuvant endocrine therapy (ET) alone. Here, we report five-year data evaluating the prognostic value of RS, Ki-67, and other traditional clinicopathological parameters. METHODS: A central tumour bank was prospectively established within PlanB. Following an early amendment, hormone receptor (HR)+ , pN0-1 RS <= 11 patients were recommended to omit chemotherapy. Patients with RS >= 12, pN2-3, or HR-negative/HER2-negative disease were randomised to anthracycline-containing or anthracycline-free chemotherapy. Primary endpoint: disease-free survival (DFS). PlanB Clinicaltrials.gov identifier: NCT01049425. FINDINGS: From 2009 to 2011, PlanB enrolled 3198 patients (central tumour bank, n = 3073) with the median age of 56 years, 41.1% pN+, and 32.5% grade 3 EBC. Chemotherapy was omitted in 348/404 (86.1%) eligible RS <= 11 patients. After 55 months of median follow-up, five-year DFS in ET-treated RS <= 11 patients was 94% (in both pN0 and pN1) versus 94% (RS 12-25) and 84% (RS > 25) in chemotherapy-treated patients (p < 0.001); five-year overall survival (OS) was 99 versus 97% and 93%, respectively (p < 0.001). Nodal status, central/local grade, tumour size, continuous Ki-67, progesterone receptor (PR), IHC4, and RS were univariate prognostic factors for DFS. In a multivariate analysis including all univariate prognostic markers, only pN2-3, central and local grade 3, tumour size >2 cm, and RS, but not IHC4 or Ki 67 were independent adverse factors. If RS was excluded, IHC4 or both Ki-67 and PR entered the model. The impact of RS was particularly pronounced in patients with intermediate Ki-67 (>10%, <40%) tumours. INTERPRETATION: The excellent five year outcomes in clinically high-risk, genomically low-risk (RS <= 11) pN0-1 patients without adjuvant chemotherapy support using RS with standardised pathology for treatment decisions in HR+ HER2-negative EBC. Ki-67 has the potential to support patient selection for genomic testing. PMID- 28664508 TI - Correlation Between Expression of Recombinant Proteins and Abundance of H3K4Me3 on the Enhancer of Human Cytomegalovirus Major Immediate-Early Promoter. AB - Role of epigenetic regulation in the control of gene expression is well established. The impact of several epigenetic mechanisms, such as DNA methylation and histone acetylation, on recombinant protein production in mammalian cells has been investigated recently. Here we investigate the correlation between the selected epigenetic markers and five trastuzumab biosimilar-producing Chinese hamster ovary (CHO) cell lines in which the expression of trastuzumab is driven by human cytomegalovirus (HCMV) major immediate-early (MIE) promoter. We chose the producing clones in which transcription was the determinative step for the production of recombinant trastuzumab. We found that the abundance of trimethylation of histone 3 at lysine 4 (H3K4Me3) on the enhancer of HCMV MIE promoter correlated well with the relative titers of recombinant trastuzumab among the clones. Such close correlation was not observed between the recombinant protein and other epigenetic markers examined in our study. Our results demonstrate that the HCMV MIE enhancer-bound H3K4Me3 epigenetic marker may be used as the epigenetic indicator to predict the relative production of recombinant proteins between the producing CHO cell lines. PMID- 28664510 TI - Creating Integrated Strategies for Increasing Access to Healthy Affordable Food in Urban Communities: A Case Study of Intersecting Food Initiatives. AB - In New York and other cities, substantial evidence documents that community food environments interact with inequitable allocation of power, wealth, and services to shape the distribution of diet-related diseases and food insecurity. This case study shows how one Central Brooklyn community organization, Bedford Stuyvesant Restoration Corporation, has launched multiple coordinated food initiatives in order to reduce the burden of food-related health problems and boost community development. The report used standard case study methods to document the implementation of the New York City Food and Fitness Partnership in Central Brooklyn. The case study shows how two distinct strands of activities, a Farm to Early Care Program that ultimately brought fresh food to 30 child care centers, and a food hub that sought to make fresh local food more available in Central Brooklyn, intersected and reinforced each other. It also shows how organizational, community, and municipal resources and policies in some cases supported these initiatives and in others served as obstacles. Finally, the case study shows that multiple coordinated strategies have the potential to empower low-income Black and Latino communities to act to make local food environments healthier and more equitable. PMID- 28664509 TI - Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. AB - Strong epidemiological and experimental evidence indicates that hypertension has detrimental effects on the cerebral microcirculation and thereby promotes accelerated brain aging. Hypertension is an independent risk factor for both vascular cognitive impairment (VCI) and Alzheimer's disease (AD). However, the pathophysiological link between hypertension-induced cerebromicrovascular injury (e.g., blood-brain barrier disruption, increased microvascular oxidative stress, and inflammation) and cognitive decline remains elusive. The present study was designed to characterize neuronal functional and morphological alterations induced by chronic hypertension and compare them to those induced by aging. To achieve that goal, we induced hypertension in young C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. We found that long-term potentiation (LTP) of performant path synapses following high-frequency stimulation of afferent fibers was decreased in hippocampal slices obtained from hypertensive mice, mimicking the aging phenotype. Hypertension and advanced age were associated with comparable decline in synaptic density in the stratum radiatum of the mouse hippocampus. Hypertension, similar to aging, was associated with changes in mRNA expression of several genes involved in regulation of neuronal function, including down-regulation of Bdnf, Homer1, and Dlg4, which may have a role in impaired synaptic plasticity. Collectively, hypertension impairs synaptic plasticity, reduces synaptic density, and promotes dysregulation of genes involved in synaptic function in the mouse hippocampus mimicking the aging phenotype. These hypertension-induced neuronal alterations may impair establishment of memories in the hippocampus and contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer's disease (AD). PMID- 28664512 TI - Microbial radiation-resistance mechanisms. AB - Organisms living in extreme environments have evolved a wide range of survival strategies by changing biochemical and physiological features depending on their biological niches. Interestingly, organisms exhibiting high radiation resistance have been discovered in the three domains of life (Bacteria, Archaea, and Eukarya), even though a naturally radiationintensive environment has not been found. To counteract the deleterious effects caused by radiation exposure, radiation- resistant organisms employ a series of defensive systems, such as changes in intracellular cation concentration, excellent DNA repair systems, and efficient enzymatic and non-enzymatic antioxidant systems. Here, we overview past and recent findings about radiation-resistance mechanisms in the three domains of life for potential usage of such radiationresistant microbes in the biotechnology industry. PMID- 28664511 TI - The Role of Nitrosamine (NNK) in Breast Cancer Carcinogenesis. AB - Smoking cigarettes is one of the most concerning issues that leads to tobacco related cancers and can even result in death. Therefore, these issues should be addressed with a great sense of urgency with low-cost and simple approaches. Over the past several years, the scientific community has attempted to find solutions to overcome this issue. Thus, a large number of excellent studies have been reported in this field, and summarizing these results and providing important roadmaps for future studies is currently of great importance. Finding an outstanding solution to address aforementioned issue would be of great value to the community and to the social. Tobacco contains thousands of chemicals, and sixty-nine compounds have been established as human carcinogens; specifically, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the strongest carcinogen among the tobacco-specific nitrosamines. Tobacco carcinogens are also linked to mammary gland pathogenesis and increased risk of developing many cancers, including breast cancer, the most common cancer in women worldwide. This mini review summarizes the role of NNK and the mechanisms of its receptor, nicotine acetylcholine receptor (nAChR), signaling in breast cancer based on publications identified using the keywords "secondhand smoke (SHS)", "Nitrosamines" and "breast cancer". Furthermore, this review considers the risk of NNK to the public in an effort to reduce exposure to SHS in women and their chances of developing breast cancer. PMID- 28664513 TI - Comparative genome analysis of the Flavobacteriales bacterium strain UJ101, isolated from the gut of Atergatis reticulatus. AB - Here we report the comparative genomic analysis of strain UJ101 with 15 strains from the family Flavobacteriaceae, using the CGExplorer program. Flavobacteriales bacterium strain UJ101 was isolated from a xanthid crab, Atergatis reticulatus, from the East Sea near Korea. The complete genome of strain UJ101 is a 3,074,209 bp, single, circular chromosome with 30.74% GC content. While the UJ101 genome contains a number of annotated genes for many metabolic pathways, such as the Embden-Meyerhof pathway, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle, genes for the Entner-Douddoroff pathway are not found in the UJ101 genome. Overall, carbon fixation processes were absent but nitrate reduction and denitrification pathways were conserved. The UJ101 genome was compared to genomes from other marine animals (three invertebrate strains and 5 fish strains) and other marine animal- derived genera. Notable results by genome comparisons showed that UJ101 is capable of denitrification and nitrate reduction, and that biotin-thiamine pathway participation varies among marine bacteria; fish-dwelling bacteria, freeliving bacteria, invertebrate dwelling bacteria, and strain UJ101. Pan-genome analysis of the 16 strains in this study included 7,220 non-redundant genes that covered 62% of the pan-genome. A core-genome of 994 genes was present and consisted of 8% of the genes from the pan-genome. Strain UJ101 is a symbiotic hetero-organotroph isolated from xanthid crab, and is a metabolic generalist with nitrate-reducing abilities but without the ability to synthesize biotin. There is a general tendency of UJ101 and some fish pathogens to prefer thiamine-dependent glycolysis to gluconeogenesis. Biotin and thiamine auxotrophy or prototrophy may be used as important markers in microbial community studies. PMID- 28664514 TI - Comparative and bioinformatics analyses of pathogenic bacterial secretomes identified by mass spectrometry in Burkholderia species. AB - Secreted proteins (secretomes) play crucial roles during bacterial pathogenesis in both plant and human hosts. The identification and characterization of secretomes in the two plant pathogens Burkholderia glumae BGR1 and B. gladioli BSR3, which cause diseases in rice such as seedling blight, panicle blight, and grain rot, are important steps to not only understand the disease-causing mechanisms but also find remedies for the diseases. Here, we identified two datasets of secretomes in B. glumae BGR1 and B. gladioli BSR3, which consist of 118 and 111 proteins, respectively, using mass spectrometry approach and literature curation. Next, we characterized the functional properties, potential secretion pathways and sequence information properties of secretomes of two plant pathogens in a comparative analysis by various computational approaches. The ratio of potential non-classically secreted proteins (NCSPs) to classically secreted proteins (CSPs) in B. glumae BGR1 was greater than that in B. gladioli BSR3. For CSPs, the putative hydrophobic regions (PHRs) which are essential for secretion process of CSPs were screened in detail at their N-terminal sequences using hidden Markov model (HMM)-based method. Total 31 pairs of homologous proteins in two bacterial secretomes were indicated based on the global alignment (identity >= 70%). Our results may facilitate the understanding of the species specific features of secretomes in two plant pathogenic Burkholderia species. PMID- 28664515 TI - Mucilaginibacter hankyongensis sp. nov., isolated from soil of ginseng field Baekdu Mountain. AB - A Gram-negative, non-motile, aerobic, and rod-shaped bacterial strain designated as BR5-28T was isolated from the soil of a ginseng field at Baekdu Mountain Korea, and its taxonomic position was investigated using a polyphasic approach. Strain BR5-28T grew at 10-42 degrees C (optimum temperature, 30 degrees C) and pH 5.5-8.5 (optimum pH, 7.0) on R2A agar medium without additional NaCl supplementation. Strain BR5- 28T exhibited beta-glucosidase activity, which was responsible for its ability to transform the ginsenosides Rb1 and Rd (the two dominant active components of ginseng) to compound-K. Based on 16S rRNA gene phylogeny, the novel strain showed a new branch within the genus Mucilaginibacter of the family Sphingobacteriaceae, and formed clusters with Mucilaginibacter frigoritolerans FT22T (95.8%) and Mucilaginibacter gotjawali SA3-7T (95.7%). The G+C content of the genomic DNA was 45.1%. The predominant respiratory quinone was MK-7 and the major fatty acids were summed feature 3 (comprising C16:1 omega6c and/or C16:1 omega7c), iso-C15:0 and anteiso-C15:0. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Strain BR5-28T was differentiated genotypically and phenotypically from the recognized species of the genus Mucilaginibacter. The isolate therefore represents a novel species, for which the name Mucilaginibacter hankyongensis sp. nov. is proposed, with the type strain BR5-28T (=KCTC 22274T =DSM 21151T). PMID- 28664516 TI - Evaluation and application of constitutive promoters for cutinase production by Saccharomyces cerevisiae. AB - Cutinase as a promising biocatalyst has been intensively studied and applied in processes targeted for industrial scale. In this work, the cutinase gene tfu from Thermobifida fusca was artificially synthesized according to codon usage bias of Saccharomyces cerevisiae and investigated in Saccharomyces cerevisiae. Using the alpha-factor signal peptide, the T. fusca cutinase was successfully overexpressed and secreted with the GAL1 expression system. To increase the cutinase level and overcome some of the drawbacks of induction, four different strong promoters (ADH1, HXT1, TEF1, and TDH3) were comparatively evaluated for cutinase production. By comparison, promoter TEF1 exhibited an outstanding property and significantly increased the expression level. By fed-batch fermentation with a constant feeding approach, the activity of cutinase was increased to 29.7 U/ml. The result will contribute to apply constitutive promoter TEF1 as a tool for targeted cutinase production in S. cerevisiae cell factory. PMID- 28664517 TI - Viridibacterium curvum gen. nov., sp. nov., isolated from freshwater. AB - A Gram stain-negative, yellowish green-pigmented, facultatively anaerobic, motile, curved rod-shaped bacterium designated as strain JJ016T was isolated from an artificial lake in South Korea, and characterized using a polyphasic approach. The 16S rRNA gene sequence of strain JJ016T indicated that the isolate belonged to the family Rhodocyclaceae and exhibited 95.0% identity to Uliginosibacterium gangwonense 5YN10-9T. The major cellular fatty acids of the novel strain were summed feature 3 (C16:1 omega6c and/or C16:1 omega7c), C16:0, C14:0, and summed feature 8 (C18:1 omega7c and/or C18:1 omega6c). The DNA G+C content of strain JJ016T was 61.9 mol%. The major respiratory quinone and major polar lipid of strain JJ016T were ubiquinone-8 and phosphatidylethanolamine, respectively. Based on the morphological and physiological properties and the biochemical evidence presented, we concluded that strain JJ016T represents a novel species of a new genus in the family Rhodocyclaceae, for which the name Viridibacterium curvum gen. nov., sp. nov. is proposed. The type strain is JJ016T (=KACC 16899T =JCM 18715T). PMID- 28664518 TI - Limnobacter humi sp. nov., a thiosulfate-oxidizing, heterotrophic bacterium isolated from humus soil, and emended description of the genus Limnobacter Spring et al. 2001. AB - Three Gram-negative, strictly aerobic, chemolithoheterotrophic bacterial strains, designated UCM-30, UCM-33, and UCM-39T, were isolated in South Korea. Based on their 16S rRNA gene sequences, the three isolated strains were found to be similar to Limnobacter thiooxidans CS-K2T (97.41-97.68%), Limnobacter litoralis KP1-19T (95.55-95.76%), and various genera belonging to the class Betaproteobacteria (90.34-93.34%). DNA-DNA hybridization showed 79.3-83.9% similarity between the genomic DNA of UCM-39T, UCM-30, and UCM-33, while the sequence similarity between UCM-39T and L. thiooxidans KACC 13837T or L. litoralis LMG 24869T was 23.7% and 18.6%, respectively. The DNA G+C content of UCM 39T was 59.7 mol%, the major ubiquinone was Q-8, and the optimal oxidation rate was observed at 10 mM thiosulfate. The major fatty acids (>= 10%) were summed features 3 (C16:1 omega7c and/or C16:1 omega6c) and 8 (C18:1 omega7c and/or C18:1 omega6c), and C16:0. The major polar lipids (diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylglycerol) were found in all members of genus Limnobacter. Based on phenotypic, physiological, and phylogenetic analyses, the UCM-39T strain was found to be significantly distinct to represent a novel species affiliated to the genus Limnobacter. We propose to name it Limnobacter humi sp. nov. with the type strain UCM-39T (=KACC 18574T =NBRC 111650T). PMID- 28664519 TI - Poly-gamma-glutamic acid productivity of Bacillus subtilis BsE1 has positive function in motility and biocontrol against Fusarium graminearum. AB - In this study, we investigate the relationship between gamma-PGA productivity and biocontrol capacity of Bacillus subtilis BsE1; one bacterial isolate displayed 62.14% biocontrol efficacy against Fusarium root rot. The gamma-PGA yield assay, motility assay, wheat root colonization assay, and biological control assay were analysed in different gamma-PGA yield mutants of BsE1. The pgsB (PGA-synthase CapB gene) deleted mutant of BsE1 reduced gamma-PGA yield and exhibited apparent decline of in vitro motile ability. Deletion of pgsB impaired colonizing capacity of BsE1 on wheat root in 30 days, also lowered biocontrol efficacies from 62.08% (wild type BsE1) to 14.22% in greenhouse experiment against Fusarium root rot. The knockout of pgdS and ggt (genes relate to two gamma-PGA degrading enzymes) on BsE1, leads to a considerable improvement in polymer yield and biocontrol efficacy, which attains higher level compared with wild type BsE1. Compared with DeltapgsB mutant, defense genes related to reactive oxygen species (ROS) and phytoalexin expressed changes by notable levels on wheat roots treated with BsE1, demonstrating the functional role gamma-PGA plays in biocontrol against Fusarium root rot. gamma-PGA is not only important to the motile and plant root colonization ability of BsE1, but also essential to the biological control performed by BsE1 against Fusarium root rot. Our goal in this study is to reveals a new perspective of BCAs screening on bacterial isolates, without good performance during pre-assays of antagonism ability. PMID- 28664520 TI - Identification of cyst wall proteins of the hypotrich ciliate Euplotes encysticus using a proteomics approach. AB - Euplotes encysticus is a species of Hypotrich ciliates, which form cyst wall by secreting the special substances on encounter of adverse environment. It has critical significance to study the component and mechanism underlying resting cyst, during resisting unfavorable conditions in dormancy induction. The present study was aimed to investigate the effects of cyst wall proteins of Euplotes encysticus by using biochemical methods. Therefore, protein extracts were separated by SDSPAGE, identified and analyzed by MALDI-TOF MS and Bioinformatics tools. We detected 42 cyst wall proteins, 26 were functional proteins and 16 proteins consist of unknown function; which is consistent with cyst wall specificity. These results partially revealed the components of resting cyst wall formed after the cells differentiation of Euplotes encysticus. In addition, our data suggested that the function of cyst wall proteins are more likely involved in the mechanical protection, signal transduction, material transport, protein degradation and energy metabolism to survival, with potentially importance implications in the molecular mechanism of eukaryocyte dormancy under stress condition. PMID- 28664521 TI - Ensifer collicola sp. nov., a bacterium isolated from soil in South Korea. AB - Strain Mol12T, which presented in the form of Gram-negative, motile, non-spore forming rod-shaped, was isolated from soil in South Korea and characterized to determine its taxonomic position. The strain grew at 20-30 degrees C (optimum 30 degrees C) and pH 7.0-10.0 (optimum pH 8.0) with 1% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that the strain Mol12T was most closely related to Ensifer terangae LMG 7834T (96.78%), Rhizobium daejeonense KCTC 12121T (96.43%), Ensifer adhaerens Casida AT (96.28%). Chemotaxonomic data showed that the predominant fatty acids were Summed Feature 8 (C18:1 omega7c and/or C18:1 omega6c; 53.02%) and C18:1 omega7c 11-methyl (24.01%). Its complex polar lipid contained major amounts of diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE) and Q-10 as the predominant ubiquinone. The DNA G+C content of strain Mol12T was determined to be 60.9 mol%. Based on the phylogenetic, chemotaxonomic, and phenotypic data, strain Mol12T (=KCTC 42816T =JCM 31049T) ought to be classified as a type strain of a novel species, for which the name Ensifer collicola sp. nov. is proposed. PMID- 28664522 TI - Comment on primary lymphocyte infection models for KSHV and its putative tumorigenesis mechanisms in B cell lymphomas (Journal of Microbiology 2017, 55(5): 319-329). PMID- 28664523 TI - A case of incisional hernia repair using Composix mesh prosthesis after antethoracic pedicled jejunal flap reconstruction following an esophagectomy. AB - BACKGROUND: An incisional hernia in a case of antethoracic pedicled jejunal flap esophageal reconstruction after esophagectomy is a very rare occurrence, and this hernia was distinctive in that the reconstructed jejunum had passed through the hernial orifice; a standard surgical treatment for such a presentation has not been established. Herein, we describe a case of repair using mesh prosthesis for an atypical and distinctive incisional hernia after antethoracic pedicled jejunal flap esophageal reconstruction. CASE PRESENTATION: A 77-year-old woman with a history of subtotal esophagectomy who had undergone antethoracic pedicled jejunal flap reconstruction complained of epigastric prominence and discomfort without pain. On examination, she had an abdominal protrusion between the xiphoid process and the umbilicus that contained the small bowel. Computed tomography showed that the fenestration of the abdominal wall that was intentionally created for jejunum pull-up was dehisced in a region measuring 9 * 15 cm and the small intestine protruded through it into the subcutaneous space without strangulation. Because the hernial orifice was too large and the reconstructed jejunum was passing through the hernial orifice in this case, we applied a parastomal hernia repair method that was modified from the inguinal hernia repair using the Lichtenstein technique. After 3 years and 5 months following surgery, the patient has recovered without hernia recurrence or other complications. CONCLUSION: We consider this to be the first case of repair using Composix mesh prosthesis for repair of an atypical and distinctive incisional hernia after an antethoracic pedicled jejunal flap reconstruction. This method seems to be useful and could potentially be widely adopted as the surgical treatment for this condition. PMID- 28664524 TI - Operational and Thermal Stability Analysis of Thermomyces lanuginosus Lipase Covalently Immobilized onto Modified Chitosan Supports. AB - The aim of this paper was to evaluate different strategies of chitosan activation using cross-linking reagent like glycidol, epichlorohydrin, and glutaraldehyde for Thermomyces lanuginosus lipase (TLL) immobilization. Operational activity and stability by esterification of oleic acid with ethanol and thermal inactivation using these derivatives were investigated. Derivative obtained by sequentially activation with glycidol, ethylenediamine, and glutaraldehyde and subsequent TLL immobilization showed the best performance, with high hydrolytic activity value. Its stability was 15-fold higher than solubilized TLL in the evaluated inactivation conditions (60 degrees C, 25 mM sodium phosphate buffer pH 7). After 5 cycles of oleic acid esterification, only a few percentage of its conversion has reduced. On the other hand, glycidol-activated chitosan derivative showed very low hydrolytic activity value. Epichlorohydrin-activated chitosan derivative showed regular hydrolytic activity value. Both derivatives showed low immobilization yields. Operational stability of this last derivative was very low, where after the first cycle of oleic acid esterification, only 56% of its initial conversion was obtained. Graphical Abstract ?. PMID- 28664525 TI - Structure and Functional Characterisation of a Distinctive beta-Lactamase from an Environmental Strain EMB20 of Bacillus cereus. AB - The rampant use and misuse of antibiotics in human medicine, agriculture and veterinary have become the key contributors to global antimicrobial resistance. One of the significant resistance mechanisms that inactivates antibiotics and impedes treatment of bacterial infections is the expression of beta-lactamases. Rising evidence of newer variants of beta-lactamases in the environment is therefore a serious threat to the presently available antibiotic armoury. The present work describes the purification of a variant beta-lactamase isolated from a soil strain EMB20 of Bacillus cereus. The lactamase was purified using three phase partitioning and gel filtration chromatography to a 30-fold purification and 15% recovery yield. Contrary to the general trend, the lactamase was not a metalloenzyme, but its activity was enhanced in the presence of Mg2+ and Mn2+. The EMB20 lactamase exhibited improved stability against inhibitors and denaturing agents such as urea and GdmCl as compared to its commercial analogue. The improved stability of EMB20 lactamase was further validated by circular dichroism and fluorescence spectroscopy. This study reemphasizes the rising prevalence of environmental lactamase variants. Decoding the structure-function correlation of such lactamases in the presence of inhibitors will provide insights into the response of this enzyme towards inhibitors as well as its substrates. PMID- 28664526 TI - Inhibitory Effect and Mechanism of Mesenchymal Stem Cells Cultured in 3D System on Hepatoma Cells HepG2. AB - Mesenchymal stem cells (MSCs) exhibit the feature of homing to tumor site and being immunosuppressive, which have broad prospects in tumor therapy. However, MSCs are commonly cultured in a two-dimensional (2D) condition, which would gradually loss some in vivo important properties. In this study, we built a three dimensional (3D) system with collagen/Matrigel scaffolds to culture MSCs. The results indicated that MSCs in 3D scaffolds showed higher proliferation ability than that of in 2D cells. In vitro, 3D-cultured MSC-conditioned media (CM) significantly inhibited the proliferation of hepatoma cells HepG2 than that of in 2D-cultured MSC-CM and control groups. In vivo, animal transplantation experiment showed that the treatment of 3D-cultured MSC-CM could further significantly delay the tumor initiation and decrease the tumor volume. The microarray, quantitative PCR, and ELISA assay found that MSCs cultured in the 3D system expressed and secreted more amounts of IL-24. RT-PCR and western blot results showed that IL-24 can activate JAK1-STAT3 pathway via IL22R1 and IL20R2, and further inhibit the proliferation of HepG2 cells. Taken together, these results demonstrated that MSCs cultured in the 3D system had an inhibitory effect on the proliferation of HepG2 cells, probably through secreting more IL-24, which activated JAK1-STAT3 signaling and finally inhibited the cell proliferation to delay tumor initiation. This study also provided a simpler and more reliable approach for MSCs to suppress tumor cells, and provided effective experimental data for clinical treatment of tumor and experimental basis. PMID- 28664527 TI - Humic Fertilizer and Vermicompost Applied to the Soil Can Positively Affect Population Growth Parameters of Trichogramma brassicae (Hymenoptera: Trichogrammatidae) on Eggs of Tuta absoluta (Lepidoptera: Gelechiidae). AB - The tomato leaf miner, Tuta absoluta (Meyrick), is a devastating pest of tomato worldwide. One of the control measures of T. absoluta is the use of biological control agents, such as Trichogramma wasps. Interactions between natural enemies and insect pests may be affected by application of fertilizers, because changes in plant quality through the fertilizer application may therefore affect herbivore characteristics and suitability of them to parasitism. Laboratory tests were carried out to evaluate the life table parameters of Trichogramma brassicae Bezdenko on T. absoluta eggs reared on tomato plants treated either with vermicompost (40%), humic fertilizer (2 g/kg soil), or control (suitable mixture of field soil and sand). Population growth parameters of T. brassicae were affected by fertilizer treatments. Significant differences were found for immature life period and total fecundity of T. brassicae on the treatments. Differences of intrinsic rate of natural increase (r m), finite rate of increase (lambda), net reproductive rate (R 0), mean generation time (T), and doubling time (DT) of T. brassicae among treatments were also significant. The lowest values of r m, lambda, and R 0 were recorded for T. brassicae developed on T. absoluta eggs on control treatment, whereas the highest values of these parameters were observed on 2 g/kg humic fertilizer. Furthermore, T. brassicae had the shortest T and DT values on 2 g/kg humic fertilizer and 40% vermicompost treatments. Our results showed that application of humic fertilizer and vermicompost could positively affect population growth parameters of T. brassicae on eggs of T. absoluta fed on tomato plants. PMID- 28664528 TI - Pollen Ingestion by Chrysoperla externa (Hagen) Adults in a Diversified Organic Agroecosystem. AB - Chrysoperla externa (Hagen) larvae prey on pest insects and mites in agroecosystems, and adults mainly feed on pollen, nectar, and honeydew. Therefore, preserving this lacewing in crop systems depends on having plants that provide these resources. The objectives of this research were to identify pollen grains ingested by Ch. externa adults collected in a diversified organic agroecosystem and to evaluate whether there is a difference in the amount of ingested pollen grains between males and females. The adults of Ch. externa were collected in four different crops during 13 months in Seropedica, state of Rio de Janeiro, Brazil, using a collecting net. The adults were killed and underwent acetolysis, in order to recover the pollen in the gut. A total of 37,441 pollen grains from 19 Angiospermae families were found, besides 16 Pteridophyte spores. Among the recognized pollen grains, those of Poaceae were the majority, both in frequency of occurrence (87.5%) and in quantity (33496), and were found and recovered in every month of collection. Females and males ingested, respectively, 71.9 and 28.1% of the total number of Angiospermae pollen grains consumed by both sexes. The highest number of Poaceae pollens was obtained from the females (72.1% of the total number of Poaceae pollen, recovered from females + males). Taken as a whole, this study showed that adults of Ch. externa find possibilities to maintain throughout the year, in different crops, but the main source of pollen to males and females was Poaceae plants. PMID- 28664530 TI - CME INSTRUCTIONS: Comprehensive review on cardio-oncology: Role of multimodality imaging. PMID- 28664529 TI - Phenology, sterility and inheritance of two environment genic male sterile (EGMS) lines for hybrid rice. AB - BACKGROUND: There is still limited quantitative understanding of how environmental factors affect sterility of Environment-conditioned genic male sterility (EGMS) lines. A model was developed for this purpose and tested based on experimental data from Ndiaye (Senegal) in 2013-2015. For the two EGMS lines tested here, it was not clear if one or more recessive gene(s) were causing male sterility. This was tested by studying sterility segregation of the F2 populations. RESULTS: Daylength (photoperiod) and minimum temperatures during the period from panicle initiation to flowering had significant effects on male sterility. Results clearly showed that only one recessive gene was involved in causing male sterility. The model was applied to determine the set of sowing dates of two different EGMS lines such that both would flower at the same time the pollen would be completely sterile. In the same time the local popular variety (Sahel 108, the male pollen donor) being sufficiently fertile to produce the hybrid seeds. The model was applied to investigate the viability of the two line breeding system in the same location with climate change (+2oC) and in two other potential locations: in M'Be in Ivory Coast and in the Nile delta in Egypt. CONCLUSIONS: Apart from giving new insights in the relation between environment and EGMS, this study shows that these insights can be used to assess safe sowing windows and assess the suitability of sterility and fertility period of different environments for a two line hybrid rice production system. PMID- 28664531 TI - The role of RhoC in malignant tumor invasion, metastasis and targeted therapy. AB - As an important member of the RhoGTPase family, RhoC has various biological functions, such as regulating cytoskeleton reorganization, influencing cell adhesion, and migration. During recent decades, RhoC has been proven to be involved in the invasion and metastasis of malignant tumor and is thus a promising target of tumor therapy. This review focuses on the molecular mechanism of RhoC in invasion and metastasis of malignant tumors, as well as its research prospects as a potential target for tumor therapy. PMID- 28664532 TI - Botryomycosis and coccidiomycosis of the foot. PMID- 28664533 TI - Prevalence of striae gravidarum in a multi-ethnic Asian population and the associated risk factors. PMID- 28664534 TI - Does triacylglycerol (TAG) serve a photoprotective function in plant leaves? An examination of leaf lipids under shading and drought. AB - Plant survival in many ecosystems requires tolerance of large radiation loads, unreliable water supply and suboptimal soil fertility. We hypothesized that increased production of neutral lipids (triacylglycerols, TAGs) in plant leaves is a mechanism for dissipating excess radiation energy. In a greenhouse experiment, we combined drought and shade treatments and examined responses among four species differing in life form, habitat, and drought- and shade-tolerance. We also present a lipid extraction protocol suitable for sclerophyllous leaves of native Australian trees (e.g. Acacia, Eucalyptus). Fluorescence measurements indicated that plants exposed to full sunlight experienced mild photoinhibition during our experiment. Accumulation of TAGs did not follow photosynthetic capacity, but instead, TAG concentration increased with non-photochemical quenching. This suggests that plants under oxidative stress may increase biosynthesis of TAGs. Moderate drought stress resulted in a 60% reduction in TAG concentration in wheat (Triticum aestivum). Shading had no effect on TAGs, but increased concentrations of polar lipids in leaves; for example, acclimation to shade in Austrodanthonia spp., a native Australian grass, resulted in a 60% increase in associated polar lipids and higher foliar chlorophyll concentrations. Shading also reduced the digalactosyldiacylglycerol:monogalactosyldiacylglycerol (DGDG:MGDG) ratio in leaves, with a corresponding increase in the degree of unsaturation and thus fluidity of thylakoid membranes of chloroplasts. Our results suggest that prevention of photodamage may be coordinated with accumulation of TAGs, although further research is required to determine if TAGs serve a photoprotective function in plant leaves. PMID- 28664535 TI - Characterizing levator-ani muscle stiffness pre- and post-childbirth in European and Polynesian women in New Zealand: a pilot study. AB - INTRODUCTION: The influence of levator-ani muscles on second-stage labor is poorly understood. The ability of these muscles to stretch without damage may affect birth outcomes, but little is known about material properties, effects of pregnancy and/or ethnicity on levator-ani stiffness. There are strong associations between muscle damage and subsequent pelvic floor disorders. This study aimed to quantify levator-ani muscle stiffness during the third trimester of pregnancy and postpartum in European and Polynesian women. Associations between stiffness, obstetric variables, and the risk of intrapartum levator-ani injury (avulsion) were investigated. MATERIAL AND METHODS: This was a prospective observational pilot study. A total of 167 (106 European and 61 Polynesian) nulliparous women were recruited antenatally; 129 returned postnatally. Participants were assessed between 36 and 38 weeks' gestation and three to five months postpartum. Assessments included pelvic floor ultrasound, elastometry testing, and validated questionnaires on pelvic floor function. Logistic regression, Student t-, Chi-square and Mann-Whitney tests were used as appropriate. RESULTS: There are significant differences between antenatal and postnatal muscle stiffness measurements (p < 0.01). Stiffness was significantly higher in the European cohort (p = 0.03). There were more avulsion injuries in European (20%) than in Polynesian (9%) women. There were no significant differences in antenatal stiffness between women with and without avulsion, but change in stiffness (antenatal to postnatal) was significantly less in the avulsion group. There were no associations between stiffness, and other obstetric variables, epidural anesthesia seemed protective (p = 0.03). CONCLUSIONS: Quantification of levator-ani muscle stiffness is feasible. Muscle stiffness is significantly different before and after birth. PMID- 28664536 TI - Metabolomics revealed the toxicity of cationic liposomes in HepG2 cells using UHPLC-Q-TOF/MS and multivariate data analysis. AB - Cationic liposomes (CLs) are novel nonviral vectors widely used for delivering drugs or genes. However, applications of CLs are largely hampered by their cytotoxicity, partly because the potential mechanism underlying the cytotoxicity of CLs remains unclear. The aim of the present study was to explore the underlying mechanism of cytotoxicity induced by CLs on HepG2 cells. Differential metabolites were identified and quantified using ultra-liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The toxicity of CLs on HepG2 cells was evaluated by multivariate data analysis and statistics. Additionally, CCK-8 assay, heatmap, pathway and co-expression network were carried out to explore the relations between the metabolites and the pathways. The results showed a dose-dependent toxic effect of CLs on HepG2 cells, with an IC50 value of 119.9 MUg/mL. Multivariate statistical analysis identified 42 potential metabolites between CLs exposure and control groups. Pathway analysis showed significant changes in pathways involving amino acid metabolism, energy metabolism, lipid metabolism and oxidative stress in the CLs exposure group vs the control group. Metabolites related to the above-mentioned pathways included phenylalanine, methionine, creatine, oxalacetic acid, glutathione, oxidized glutathione, choline phosphate and several unsaturated fatty acids, indicating that cells were disturbed in amino acid metabolism, energy and lipid supply when CLs exposure-induced injury occurred. It is concluded that CLs may induce cytotoxicity by enhancing reactive oxygen species in vitro, affect the normal process of energy metabolism, disturb several vital signaling pathways and finally induce cell death. PMID- 28664537 TI - A framework for the meta-analysis of Bland-Altman studies based on a limits of agreement approach. AB - Bland-Altman method comparison studies are common in the medical sciences and are used to compare a new measure to a gold-standard (often costlier or more invasive) measure. The distribution of these differences is summarized by two statistics, the 'bias' and standard deviation, and these measures are combined to provide estimates of the limits of agreement (LoA). When these LoA are within the bounds of clinically insignificant differences, the new non-invasive measure is preferred. Very often, multiple Bland-Altman studies have been conducted comparing the same two measures, and random-effects meta-analysis provides a means to pool these estimates. We provide a framework for the meta-analysis of Bland-Altman studies, including methods for estimating the LoA and measures of uncertainty (i.e., confidence intervals). Importantly, these LoA are likely to be wider than those typically reported in Bland-Altman meta-analyses. Frequently, Bland-Altman studies report results based on repeated measures designs but do not properly adjust for this design in the analysis. Meta-analyses of Bland-Altman studies frequently exclude these studies for this reason. We provide a meta analytic approach that allows inclusion of estimates from these studies. This includes adjustments to the estimate of the standard deviation and a method for pooling the estimates based upon robust variance estimation. An example is included based on a previously published meta-analysis. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28664538 TI - Integrative analysis of circRNAs acting as ceRNAs involved in ethylene pathway in tomato. AB - Circular RNAs (circRNAs) are a large class of non-coding endogenous RNAs that could act as competing endogenous RNAs (ceRNAs) to terminate the mRNA targets' suppression of miRNAs. To elucidate the intricate regulatory roles of circRNAs in the ethylene pathway in tomato fruit, deep sequencing and bioinformatics methods were performed. After strict screening, a total of 318 circRNAs were identified. Among these circRNAs, 282 were significantly differentially expressed among wild type and sense-/antisense-LeERF1 transgenic tomato fruits. Besides, 1254 target genes were identified and a large amount of them were found to be involved in ethylene pathway. In addition, a sophisticated regulatory model consisting of circRNAs, target genes and ethylene was set up. Importantly, 61 circRNAs were found to be potential ceRNAs to combine with miRNAs and some of the miRNAs had been revealed to participate in the ethylene signaling pathway. This research further raised the possibility that the ethylene pathway in tomato fruit may be under the regulation of various circRNAs and provided a new perspective of the roles of circRNAs. PMID- 28664539 TI - Imaging the elusive anomalous origin of left coronary artery from pulmonary artery. AB - A 7-year-old girl with severe mitral regurgitation and pulmonary artery hypertension with good ventricular function was planned for mitral valve repair, but was subsequently diagnosed to have anomalous left coronary artery from pulmonary artery. We describe the pitfalls in the diagnosis of this rare anomaly, particularly in the presence of severe pulmonary artery hypertension and absence of circumstantial evidence of coronary steal and ventricular dysfunction. PMID- 28664540 TI - Maintenance diets following rapid weight loss in obstructive sleep apnea: a pilot 1-year clinical trial. AB - Very low energy diets (VLED) appear to be the most efficacious dietary-based obesity reduction treatments in obstructive sleep apnea (OSA); however, effective weight loss maintenance strategies remain untested in this condition. Our study aimed to assess the feasibility, tolerability and efficacy of two common maintenance diets during a 10-month follow-up period after rapid weight loss using a 2-month VLED. In this two-arm, single-centre, open-label pilot trial, obese adult OSA patients received a 2-month VLED before being allocated to either the Australian Guide to Healthy Eating diet (AGHE) or a low glycaemic index high protein diet (LGHP). Outcomes were measured at 0, 2 and 12 months. We recruited 44 patients [113.1 +/- 19.5 kg, body mass index (BMI): 37.2 +/- 5.6 kg m-2 , 49.3 +/- 9.2 years, 12 females]. Twenty-four patients were on continuous positive airway pressure (CPAP) or mandibular advancement splint (MAS) therapy for OSA. Forty-two patients completed the VLED. The primary outcome of waist circumference was reduced by 10.6 cm at 2 months [95% confidence interval (CI): 9.2-12.1], and patients lost 12.9 kg in total weight (95% CI: 11.2-14.6). There were small but statistically significant regains in waist circumference between 2 and 12 months [AGHE = 3.5 cm (1.3-5.6) and LGHP = 2.8 cm (0.6-5.0]. Other outcomes followed a similar pattern of change. After weight loss with a 2-month VLED in obese patients with OSA, a structured weight loss maintenance programme incorporating commonly used diets was feasible, tolerable and efficacious for 10 months. This programme may be deployed easily within sleep clinics; however, future research should first test its translation within general clinical practice. PMID- 28664541 TI - Placebo response and its determinants in children with ADHD across multiple observers and settings: A randomized clinical trial. AB - This study aims to quantify placebo response (PR) in children with attention deficit hyperactivity disorder (ADHD) as assessed by parents and teachers and to explore some of its determinants. Five hundred and forty children with ADHD (ages 6-12) were recruited to a randomized, double-blind, placebo-controlled crossover trial with methylphenidate. The main outcome variable was Conners' Global Index (CGI), based on assessment of behaviour by parents (CGI-P) and teacher (CGI-T). PR was calculated as the difference between CGI-P/T scores at baseline and placebo week. There was a highly significant PR as assessed by the parents' and teachers' (p < 0.001). The magnitude of PR as assessed by parents was greater (10.57 points) compared to that assessed by teachers (3.93 points). The determinants of PR were different between parents and teachers. For parents, income, marital status, education, maternal smoking during pregnancy, and prior psychostimulant exposure (PPE) showed a significant effect on PR. For teachers, only ethnicity and PPE had an effect. The pattern of PR revealed two distinct profiles that may shed some light on the mechanisms involved in PR. PR in children with ADHD varies depending on the setting of the observations and the evaluator. Several psychosocial factors have been identified as modulators of PR. This is relevant for the design and interpretation of clinical trials and for clinical practice. PMID- 28664542 TI - Connecting active to passive fluorescence with photosynthesis: a method for evaluating remote sensing measurements of Chl fluorescence. AB - Recent advances in the retrieval of Chl fluorescence from space using passive methods (solar-induced Chl fluorescence, SIF) promise improved mapping of plant photosynthesis globally. However, unresolved issues related to the spatial, spectral, and temporal dynamics of vegetation fluorescence complicate our ability to interpret SIF measurements. We developed an instrument to measure leaf-level gas exchange simultaneously with pulse-amplitude modulation (PAM) and spectrally resolved fluorescence over the same field of view - allowing us to investigate the relationships between active and passive fluorescence with photosynthesis. Strongly correlated, slope-dependent relationships were observed between measured spectra across all wavelengths (Flambda , 670-850 nm) and PAM fluorescence parameters under a range of actinic light intensities (steady-state fluorescence yields, Ft ) and saturation pulses (maximal fluorescence yields, Fm ). Our results suggest that this method can accurately reproduce the full Chl emission spectra - capturing the spectral dynamics associated with changes in the yields of fluorescence, photochemical (PhiPSII), and nonphotochemical quenching (NPQ). We discuss how this method may establish a link between photosynthetic capacity and the mechanistic drivers of wavelength-specific fluorescence emission during changes in environmental conditions (light, temperature, humidity). Our emphasis is on future research directions linking spectral fluorescence to photosynthesis, PhiPSII, and NPQ. PMID- 28664543 TI - Assessment of left atrial mechanical function and synchrony in paroxysmal atrial fibrillation with two-dimensional speckle tracking echocardiography-utility of left atrial speckle tracking without left ventricular speckle tracking? PMID- 28664544 TI - Neutropenic enterocolitis (typhlitis) in a pediatric renal transplant patient. A case report and review of the literature. AB - NE (typhlitis) is a potentially life-threatening disease process characterized by bowel wall edema, ulceration, and hemorrhage in an immunosuppressed patient. We report a 15-year-old boy status post deceased donor renal transplantation who presented with fever, abdominal pain, and diarrhea. Laboratory studies revealed neutropenia 5 days prior to admission, and abdominal computed tomography revealed bowel wall thickening in the cecum consistent with NE. He was treated with piperacillin-tazobactam and gentamicin and recovered. To our knowledge, this is the first report of a case of NE in a pediatric kidney transplant recipient. PMID- 28664545 TI - Adherence to a pediatric diabetic ketoacidosis protocol in children presenting to a tertiary care hospital. AB - OBJECTIVE: To review adherence to a provincial diabetic ketoacidosis (DKA) protocol and to assess factors associated with intravenous fluid administration and the length time on an insulin infusion. METHODS: A retrospective chart review was conducted of all DKA admissions to British Columbia Children's Hospital (BCCH) during September 2008 to December 2013. Data collection included diabetes history, estimation of dehydration, insulin and fluid infusion rates, and frequency of laboratory investigations. Markers of adherence included appropriate use of a fluid bolus, normal saline and insulin infusion time, fluid intake and outputs, and the frequency of blood work during the insulin infusion. A log linear regression model was fitted to assess the factors associated with insulin infusion duration. RESULTS: Of 157 children (median [interquartile range] age: 10.6 years [5.0, 13.8]) hospitalized for DKA, 45% (n = 70) were male, 55% (n = 86) were transferred from other hospitals, and 26% (n = 40) were admitted to intensive care unit. Thirty-five percent of subjects estimated to have mild or moderate dehydration received fluid boluses. In the adjusted analysis, the average duration on DKA protocol was 39% (95% confidence interval [CI]: 12%, 67%) longer for children admitted with severe dehydration (compared to those with mild dehydration). CONCLUSIONS: Health care providers' adherence to the BCCH DKA protocol is poor. More severe dehydration at presentation is associated with longer duration of insulin infusion. Further knowledge translation initiatives focused on accurate estimation of volume depletion to ensure appropriate initial fluid resuscitation-as well as careful monitoring during DKA hospitalization-are important, especially in community centers. PMID- 28664546 TI - Diet-independent relevance of serum uric acid for blood pressure in a representative population sample. AB - A direct relationship between serum uric acid and blood pressure (BP) has been reported, but the possible confounding impact of diet on this association is unclear. The authors performed a cross-sectional analysis in the representative German Health Interview and Examination Survey for Adults (n=6788, aged 18-79 years). In adjusted regression models considering dietary factors, each 1-mg/dL higher uric acid value was associated with a 1.10-mm Hg (P=.0002) and a 0.60-mm Hg (P=.04) higher systolic BP among participants younger than 50 years and participants 50 years and older, respectively. For diastolic BP, uric acid was a significant predictor (beta=0.71 mm Hg, P=.0001) among participants younger than 50 years and for participants 50 years and older without antihypertensive treatment. Adjusted odds ratios of hypertension for participants with hyperuricemia were broadly similar in younger (odds ratio, 1.71; P=.02) and older (odds ratio, 1.81; P=.0003) participants. Uric acid is a significant predictor of systolic BP and hypertension prevalence in the general adult population in Germany independently of several known dietary BP influences. PMID- 28664548 TI - Cardiac magnetic resonance in cardiac angiosarcoma. AB - BACKGROUND: While echocardiography is effective for initial identification of anatomic location, magnetic resonance imaging (MRI) is a more advantageous modality for delineating tumor expanse, spread, and blood supply preoperatively. Emerging patterns may even help generate a specific diagnosis prior to biopsy and histopathology. CASE PRESENTATION: Our case of a 67-year-old male referred for cardiac magnetic resonance to further evaluate a cardiac mass highlights the sophisticated level of data which can be collected. Our case highlights the perfusion related findings associated with cardiac angiosarcoma. CONCLUSION: In this case, we present the diagnosis of right atrial cardiac angiosarcoma by multiple imaging modalities including MRI and subsequent angiography, allowing for prompt surgical intervention and initiation of adjuvant therapy that resulted in a survival time of 19 months. PMID- 28664547 TI - Vitamin D3 ameliorates podocyte injury through the nephrin signalling pathway. AB - Renal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in pathological conditions. In diabetic nephropathy (DN), podocytes become structurally and functionally compromised. Nephrin, a structural backbone protein of the slit diaphragm, acts as regulator of podocyte intracellular signalling with renoprotective role. Vitamin D3 through its receptor, VDR, provides renal protection in DN but limited data exist about its effect on podocytes. In this study, we used isolated rat glomeruli to assess podocalyxin and nephrin expression after treatment with the 1,25-dihydroxyvitamin D3 analogue paricalcitol in the presence of normal and diabetic glucose levels. The role of 1,25-dihydroxyvitamin D3 (calcitriol) and its analogue, paricalcitol, on podocyte morphology and survival was also investigated in the streptozotocin (STZ) diabetic animal model. In our ex vivo model, glomeruli exhibited high glucose mediated down-regulation of podocalyxin, and nephrin, while paricalcitol reversed the high glucose-induced decrease of nephrin and podocalyxin expression. Paricalcitol treatment enhanced VDR expression and promoted VDR and RXR co localization in the nucleus. Our data also indicated that hyperglycaemia impaired survival of cultured glomeruli and suggested that the implemented nephrin down regulation was reversed by paricalcitol treatment, initiating Akt signal transduction which may be involved in glomerular survival. Our findings were further verified in vivo, as in the STZ-diabetic animal model, calcitriol and paricalcitol treatment resulted in significant amelioration of hyperglycaemia and restoration of nephrin signalling, suggesting that calcitriol and paricalcitol may provide molecular bases for protection against loss of the permselective renal barrier in DN. PMID- 28664549 TI - Collagen balls on ThinPrep cervical cytology. PMID- 28664550 TI - Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency. AB - DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile. PMID- 28664551 TI - The impact of voluntary targets on the sodium content of processed foods in Brazil, 2011-2013. AB - Brazilians consume excessive dietary sodium (4700 mg/d); hence, the reduction of dietary sodium intake has been a Brazilian government priority. A set of strategies has been implemented that includes food and nutrition education initiatives and the reduction in the sodium content of processed foods and foods consumed out of the households. Since 2011, the Ministry of Health has selected priority food categories that contribute to over 90% of sodium intake from processed foods and have set biannual voluntary targets for sodium reduction with food industries to encourage food reformulation. Three rounds of monitoring of the sodium content on food labels have been conducted for instant pasta, commercially produced breads, cakes and cake mixes, cookies and crackers, snacks, chips, mayonnaise, salt-based condiments, and margarine. Between 90% and 100% of the food products achieved the first targets in the 2011-2013 period, and the average sodium content of food categories was reduced from 5% to 21% in these first 2 years. These data show that with close monitoring and government oversight, voluntary targets to reduce the sodium content in processed foods can have a significant impact even in a short time frame. The Brazilian strategy will be continuously monitored to maximize its impact, and, if necessary in the future, a transition to regulatory approaches with stronger enforcement may be considered. PMID- 28664552 TI - An ulcerated nodule over an implanted cardiac defibrillator: A journey from presumed infection to leiomyosarcoma. PMID- 28664553 TI - What hospitals need to know about guidelines-A mixed-method analysis of guideline implementation in Dutch hospitals. AB - RATIONALE, AIMS AND OBJECTIVES: This study provides insight into how Dutch hospitals ensure that guidelines are used in practice and identifies what key messages other hospitals can learn from existing practices. We examine current practices in handling compliance and, therefore, focus on hospitals that reported that they do not experience problems in the implementation of guidelines. METHOD: A survey of Dutch hospital boards and 9 semistructured interviews were conducted with a purposive sample of 3 hospitals. Interviews were held with 3 representatives of each hospital, specifically, with a member of the board of directors, a member of the executive medical staff, and the manager of the quality and safety department. RESULTS: Hospitals find guidelines necessary and useful. Hospitals have the power to improve implementation if boards of directors and medical staff are committed, intrinsically motivated, cooperate with each other, and use guidelines pragmatically. Even then, they prioritize guidelines, as resources are scarce. Despite their good work, all hospitals in this study appeared to struggle to adhere to guidelines. CONCLUSIONS: If hospitals experience problems with guideline implementation, they tend to focus more on external expectations, leading to defensive behaviour. Hospitals that do not experience implementation problems focus more on integrating guidelines into their own policies. PMID- 28664554 TI - New cell block containing agarose for cytopathological diagnosis of tumor samples. PMID- 28664555 TI - Hepatic expression of cytochrome P450 enzymes in non-human primate species. AB - Cytochromes P450 (P450) largely remain to be characterized in great apes. Comparative immunochemical detection of drug metabolizing forms of P450s 1A, 2A, 2B, 2C, 2D, 2E, 2J, 3A, 4A, and 4F in liver microsomes from chimpanzees, gorillas, orangutans, gibbons, cynomolgus and rhesus macaques, and common marmosets were carried out. PMID- 28664556 TI - A UPLC-TOF/MS-based metabolomics study of rattan stems of Schisandra chinensis effects on Alzheimer's disease rats model. AB - A UPLC-TOF/MS-based metabolomics method was established to explore the therapeutic mechanisms of rattan stems of S. chinensis (SCS) in Alzheimer's disease (AD). Experimental AD model was induced by intra-hippocampal Abeta1-42 injection in rats. Cognitive function and oxidative stress condition in brain of AD rats were assessed using Morris water maze tests and antioxidant assays [malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)], respectively. UPLC-TOF/MS combined with multivariate statistical analysis were conducted to study the changes in metabolic networks in serum of rats. The results indicated that the AD model was established successfully and the inducement of Abeta1-42 caused a decline in spatial learning and memory of rats. The injection of Abeta1-42 in rat brains significantly elevated the level of MDA, and reduced SOD and GSH-Px activities. In addition, SCS showed significant anti-AD effects on model rats. A total of 30 metabolites were finally identified as potential biomarkers of AD and 14 of them had a significant recovery compared with the AD model after SCS administration. Changes in AD metabolite profiling were restored to different levels through the regulation of 13 pathways. This is first report on the use of the UPLC-TOF/MS-based serum metabolomics method to investigate therapeutic effects of SCS on AD, and enrich potential biomarkers and metabolic networks of AD. PMID- 28664558 TI - Fractional carbon dioxide laser in recalcitrant vulvar lichen sclerosus. PMID- 28664557 TI - Effects of oxygen therapy on wall-motion score index in patients with ST elevation myocardial infarction-the randomized SOCCER trial. AB - BACKGROUND: Although oxygen (O2 ) is routinely used in patients with acute myocardial infarction (AMI), it may have negative effects. In this substudy of the SOCCER trial, we aimed to evaluate the effects of O2 -treatment on myocardial function in patients with ST elevation myocardial infarction (STEMI). METHODS: Normoxic (>=94%) STEMI patients were randomized in the ambulance to either supplemental O2 or room air until the end of the percutaneous coronary intervention (PCI). The patients underwent echocardiography on day 2-3 after the PCI and once again after 6 months. The study endpoints were wall-motion score index (WMSI) and left ventricular ejection fraction (LVEF). RESULTS: Forty-six patients in the O2 group and 41 in the air group were included in the analysis. The index echocardiography showed no significant differences between the groups in WMSI (1.32+/-0.27 for O2 group vs 1.28+/-0.28 for air group) or LVEF (47.0+/ 8.5% vs 49.2+/-8.1%). Nor were there differences at 6 months in WMSI (1.16+/-0.25 vs 1.14+/-0.24) or LVEF (53.5+/-5.8% vs 53.5+/-6.9%). CONCLUSION: The present findings indicate no harm or benefit of supplemental O2 on myocardial function in STEMI patients. Our results support that it is safe to withhold supplemental O2 in normoxic STEMI patients. PMID- 28664559 TI - Comparison of the intradermal irritant threshold concentrations of nine allergens from two different manufacturers in clinically nonallergic dogs in the USA. AB - BACKGROUND: The intradermal irritant threshold concentration for many allergens is unknown. OBJECTIVE: To determine the intradermal irritant threshold concentration (ITC) of nine allergens from two different manufacturers. ANIMALS: Twenty privately owned clinically nonallergic dogs. METHODS: Alternaria, cat dander, Dermatophagoides farinae, Chenopodium album (lamb's quarter), Xanthium strumarium (cocklebur), Prosopis glandulosa (mesquite), Morus alba (white mulberry), Cynodon dactylon (Bermuda grass) and Phleum pretense (Timothy grass) from two manufacturers (ALK; Round Rock, TX, USA and Greer(r) Laboratories; Lenoir, NC, USA) were injected intradermally at two dilutions and at 15 and 30 min evaluated subjectively (1-4) and objectively (horizontal wheal diameter) by two blinded investigators. A subjective score of 3 or 4 by either investigator at either timed reading was considered positive. If both concentrations resulted in positive reactions, two additional dilutions were performed. The ITC was defined as the lowest tested concentration that elicited a positive reaction in >=10% of animals. RESULTS: The ITCs were Alternaria >2,000 PNU/mL; cat dander 750 PNU/mL (ALK) and 2,000 PNU/mL (Greer(r) ); D. farinae <1:10,000 w/v; C. album <6,000 PNU/mL; X. strumarium <6,000 PNU/mL; P. glandulosa <500 PNU/mL; M. alba <6,000 PNU/mL; C. dactylon <10,000 PNU/mL (ALK) and <6,000 PNU/mL (Greer(r) ); and P. pretense <6,000 PNU/mL. CONCLUSIONS AND CLINICAL SIGNIFICANCE: There were significant differences in subjective scoring and objective measurement between manufacturers for Alternaria, cat dander and P. pretense. Results revealed significant positive correlation between subjective scoring and objective measurement for each time, investigator and manufacturer separately. PMID- 28664560 TI - Porokeratosis ptychotropica: A giant lesion in a Chinese man. PMID- 28664561 TI - A prospective 20-year longitudinal follow-up of dementia in persons with Down syndrome. AB - GOAL: To examine dementia characteristics, age at onset and associated co morbidities in persons with Down syndrome. METHOD: A total of 77 people with Down syndrome aged 35 years and older were followed up from 1996 to 2015. The diagnosis of dementia was established using the modified ICD 10 Criteria and a combination of objective and informant-based tests. Cognitive tests included the Test for Severe Impairment and the Down Syndrome Mental Status Examination; adaptive behaviour was measured using the Daily Living Skills Questionnaire, and data from the Dementia Questionnaire for People with Intellectual Disabilities have been available since 2005. RESULTS: Over the 20-year period, 97.4% (75 of 77) persons developed dementia with a mean age of dementia diagnosis of 55 years (SD = 7.1, median = 56 years). Clinical dementia was associated with cognitive and function decline and seizure activity. Risk for dementia increased from 23% in those aged 50 years to 80% in those aged 65 years and above. There were no differences by level of ID. CONCLUSION: The previously reported high risk levels for dementia among people with Down syndrome were confirmed in this data as was the relationship with late onset epilepsy. The value of the instruments utilised in tracking decline and helping to confirm diagnosis is further highlighted. PMID- 28664562 TI - Dermoscopy of a perforating lichen nitidus. PMID- 28664563 TI - Evaluating patient and public involvement in health research: from theoretical model to practical workshop. AB - BACKGROUND: There is a growing literature on evaluating aspects of patient and public involvement (PPI). We have suggested that at the core of successful PPI is the dynamic interaction of different forms of knowledge, notably lay and professional. We have developed a four-dimensional theoretical framework for understanding these interactions. AIM: We explore the practical utility of the theoretical framework as a tool for mapping and evaluating the experience of PPI in health services research. METHODS: We conducted three workshops with different PPI groups in which participants were invited to map their PPI experiences on wall charts representing the four dimensions of our framework. The language used to describe the four dimensions was modified to make it more accessible to lay audiences. Participants were given sticky notes to indicate their own positions on the different dimensions and to write explanatory comments if they wished. Participants' responses were then discussed and analysed as a group. RESULTS: The three groups were distinctive in their mapped responses suggesting different experiences in relation to having a strong or weak voice in their organization, having few or many ways of getting involved, addressing organizational or public concerns and believing that the organization was willing to change or not. DISCUSSION: The framework has practical utility for mapping and evaluating PPI interactions and is sensitive to differences in PPI experiences within and between different organizations. The workshops enabled participants to reflect collaboratively on their experiences with a view to improving PPI experiences and planning for the future. PMID- 28664564 TI - Clustering high-dimensional mixed data to uncover sub-phenotypes: joint analysis of phenotypic and genotypic data. AB - The LIPGENE-SU.VI.MAX study, like many others, recorded high-dimensional continuous phenotypic data and categorical genotypic data. LIPGENE-SU.VI.MAX focuses on the need to account for both phenotypic and genetic factors when studying the metabolic syndrome (MetS), a complex disorder that can lead to higher risk of type 2 diabetes and cardiovascular disease. Interest lies in clustering the LIPGENE-SU.VI.MAX participants into homogeneous groups or sub phenotypes, by jointly considering their phenotypic and genotypic data, and in determining which variables are discriminatory. A novel latent variable model that elegantly accommodates high dimensional, mixed data is developed to cluster LIPGENE-SU.VI.MAX participants using a Bayesian finite mixture model. A computationally efficient variable selection algorithm is incorporated, estimation is via a Gibbs sampling algorithm and an approximate BIC-MCMC criterion is developed to select the optimal model. Two clusters or sub phenotypes ('healthy' and 'at risk') are uncovered. A small subset of variables is deemed discriminatory, which notably includes phenotypic and genotypic variables, highlighting the need to jointly consider both factors. Further, 7 years after the LIPGENE-SU.VI.MAX data were collected, participants underwent further analysis to diagnose presence or absence of the MetS. The two uncovered sub-phenotypes strongly correspond to the 7-year follow-up disease classification, highlighting the role of phenotypic and genotypic factors in the MetS and emphasising the potential utility of the clustering approach in early screening. Additionally, the ability of the proposed approach to define the uncertainty in sub-phenotype membership at the participant level is synonymous with the concepts of precision medicine and nutrition. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28664565 TI - Relaxation of cellular K+ gradients by valinomycin induces diatoxanthin accumulation in Cyclotella meneghiniana cells and alters FCPa fluorescence yield in vitro. AB - Regulation of photosynthetic light harvesting involves all major thylakoid membrane complexes. One important factor is the proton motive force (pmf) driving ATP production. Its proton gradient (DeltapH) component regulates the high energy quenching. Potassium ions largely contribute to the formation of the electric field (DeltaPsi). DeltaPsi and DeltapH partially compensate each other to form pmf. Whilst in plants considerable progress has been made in analyzing the interplay of H+ and K+ gradients, in diatoms knowledge in this field is still scarce. We relaxed cellular K+ gradients by valinomycin in Cyclotella meneghiniana. We observed a slow decrease of PSII maximum quantum yield in the dark upon valinomycin addition correlating with diatoxanthin accumulation which we attribute to the breakdown of organellar K+ gradients (either plastid or mitochondria) which might compensate for the loss of the K+ gradient by adjustment of the thylakoid pH in a secondary step. This response is reversible when DeltapH is relaxed. Similarly, we found higher non-photochemical quenching (NPQ) caused by higher DT accumulation in the steady state in valinomycin-treated cells. In vitro fucoxanthin chlorophyll a (FCPa) antenna complexes in liposomes with natural lipid composition showed a decrease in fluorescence yield if a K+ gradient is built up. The effect reversed by relaxing the gradient. We interpret these fluorescence changes with surface charge dynamics and FCPa organization in the membrane rather than a direct influence of K+ gradients on FCPa complexes. Both experiments reveal that K+ gradients might contribute to fine tuning of light harvesting capacity in relation to pmf in diatoms. PMID- 28664566 TI - Some remaining challenges regarding multiple endpoints in clinical trials. AB - Despite recent advance in methods for handling multiple endpoints in clinical trials, some challenges remain. This paper discusses some of these challenges, including confusion surrounding the terminology used to describe the multiple endpoints, the justification for simultaneously testing for non-inferiority and superiority in a non-inferiority trial, lack of agreement on the situations under which multiple objectives do or do not lead to the need for a multiplicity correction, and choice of the most appropriate multiple comparisons procedure. In addition, this paper will discuss the position of the recent FDA draft guidance, Multiple Endpoints in Clinical Trials, on these issues. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28664567 TI - Mechanisms of callose deposition in rice regulated by exogenous abscisic acid and its involvement in rice resistance to Nilaparvata lugens Stal (Hemiptera: Delphacidae). AB - BACKGROUND: Callose is a plant cell wall polysaccharide controlled by beta-1,3 glucanase and synthase. Abscisic acid (ABA) is an important plant hormone. Exogenous ABA promotes rice resistance to pests. Whether exogenous ABA could reduce the decline in rice yield after brown planthopper (Nilaparvata lugens Stal; BPH) feeding is an important question, however, the mechanisms behind rice resistance induced by ABA remain obscure. RESULTS: Electronic penetration graph (EPG) recording indicated a significant increase in rice resistance to BPH, and the number of BPH eggs decreased significantly upon application of exogenous ABA. As the concentration of ABA increased, the reduction in rice yield decreased significantly after BPH feeding. Further studies showed that beta-1,3-glucanase activity was significantly lower, but synthase activity was higher after ABA treatment than in controls. CONCLUSIONS: Our results demonstrated that exogenous ABA suppressed beta-1,3-glucanase and induced synthase activity, and promoted callose deposition. This is an important defense mechanism that prevents BPH from ingesting phloem sap. These studies provide support for an insect-resistance mechanism after ABA treatment and provide a reference for the integrated management of other piercing-sucking pests. (c) 2017 Society of Chemical Industry. PMID- 28664568 TI - Circulating MicroRNA in patients with repaired tetralogy of Fallot. AB - BACKGROUND: Emerging data suggest that heart-related microRNAs (miRs) may serve as circulating biomarkers of myocardial injury. We aimed to determine the circulating profile of miRs in patients with volume-overloaded right ventricles after repair of tetralogy (TOF). MATERIALS AND METHODS: A total of 104 TOF patients and 70 controls were recruited. The study was conducted in two phases: (1) determination of circulating heart-related miRs described in left heart diseases (miR-1, miR-133a, miR-208a, miR-208b and miR423-5p) by quantitative real time PCR in 49 patients and 30 controls and followed by validation in an independent cohort of 55 patients and 40 controls; (2) expression profiling of serum samples from eight patients and eight controls, followed by validation. Alteration in circulating miRNA expression was related to cardiac functional indices as assessed by 2D speckle tracking and 3D echocardiography. RESULTS: No significant differences in serum levels of left heart-associated miRNAs were found between patients and controls. Of the candidate 19 miRNAs identified by profiling, upregulation of miR-99b and down-regulation of miR-766 were validated. However, no correlations were found between miRs levels and echo indices. CONCLUSION: In young adults with repaired TOF and volume-overloaded right ventricles, circulating levels of miR-99b and miR-766, but not left heart associated miRNAs, were significantly altered. PMID- 28664569 TI - Development and assessment of a new cage-like particle adjuvant. AB - OBJECTIVES: To obtain and assess stable cage-like particles with low surface charge density, which can be prepared using a standardized, economic and scalable method. METHODS: To form these nanoparticles, the lipid composition and proportion as well the method were modified in relation to cage-like particles previously described elsewhere. Bovine albumin was used to compare ISPA performance with that of other adjuvants in mice and to assess stability. Adjuvant efficacy was analysed using a mouse model of Trypanosoma cruzi infection, which shows protection against an intracellular infection that needs a strong cellular response. KEY FINDINGS: The new particles were better in terms of level, kinetics and profile of humoral responses than Freund Adjuvant, aluminium hydroxide and Montanide TM ISA 206; they also tended to improve ISCOMATRIXTM performance. Particle size and adjuvant performance were conserved during the 6 month period assessed after preparation. In the model of Trypanosoma cruzi infection, mice immunized with ISPA and trans-sialidase developed high protection. CONCLUSIONS: The obtained nanoparticles were stable and outperformed the other assessed adjuvants in joining together the capacity of most adjuvants to enhance the immune response against specific antigen, to reduce the number of doses, to homogenize the response between individuals and to reach a balanced TH1/TH2 response. PMID- 28664570 TI - Swedish population-based study of pupils showed that foster children faced increased risks for ill health, negative lifestyles and school failure. AB - AIM: This population-based study explored whether foster children faced a higher risk of health problems than children of the same age who were not in foster care. METHODS: Data for 13 739 pupils aged 10, 13 and 16 years were obtained from the Pupil Health Database in the county of Varmland, Sweden, for the school years 2012/2013 and 2013/2014. These included data on school performance, health, lifestyle and social relationships, based on children's interviews with school nurses. RESULTS: Of all the pupils, 171 (1.2%) were in foster care. Children in foster care were generally unhealthier than other children. Both girls and boys were at higher risk of chronic health problems, daily smoking, use of drugs and school failure. When the girls in foster care were compared to other girls, we found that they faced a higher risk of psychological and psychosomatic symptoms. This difference was not found for boys. Foster children were also more likely to express a more negative view on life. CONCLUSION: We confirmed earlier studies that children in foster care tended to have inferior health and well-being than other children. These findings emphasise that health, risky behaviour and school performance should be considered together when assessing foster children. PMID- 28664571 TI - Syringomatous carcinoma and its dermoscopic features. PMID- 28664572 TI - The use of contact lenses in low vision rehabilitation: optical and therapeutic applications. AB - Ocular pathology that manifests at an early age has the potential to alter the vision-dependent emmetropisation mechanism, which co-ordinates ocular growth throughout childhood. The disruption of this feedback mechanism in children with congenital or early-onset visual impairment often results in the development of significant ametropia, including high levels of spherical refractive error, astigmatism and anisometropia. This review examines the use of contact lenses as a refractive correction, low vision aid and therapeutic intervention in the rehabilitation of patients with bilateral, irreversible visual loss due to congenital ocular disease. The advantages and disadvantages of the use of contact lenses for increased magnification (telescopes and microscopes) or field expansion (reverse telescopes) are discussed, along with the benefits and practical considerations for the correction of pathological high myopia. The historical and present use of therapeutic tinted contact lenses to reduce photosensitivity and nystagmus in achromatopsia, albinism and aniridia are also presented, including clinical considerations for the contact lens practitioner. In addition to the known optical benefits in comparison to spectacles for high levels of ametropia (an improved field of view for myopes and fewer inherent oblique aberrations), contact lenses may be of significant psycho-social benefit for patients with low vision, due to enhanced cosmesis and reduced conspicuity and potential related effects of improved self-esteem and peer acceptance. The contact lens correction of patients with congenital vision impairment can be challenging for both practitioner and patient but should be considered as a potential optical or therapeutic solution in modern low vision rehabilitation. PMID- 28664573 TI - Occurrence of metachronous basal cell carcinomas: a prognostic model. AB - BACKGROUND: A third of patients with a first basal cell carcinoma (BCC) will develop subsequent (metachronous) BCCs. OBJECTIVES: To study the prognostic effect of the number of previous BCC diagnosis dates a patient has experienced to derive a prediction model to assess the risk of metachronous BCCs that may inform individualized decision making on surveillance. METHODS: We considered participants of north-western European ancestry from a prospective population based cohort study (Rotterdam Study). After linkage with the Dutch Pathology Registry, 1077 patients with a first BCC were included. Candidate predictors for metachronous BCCs included patient, lifestyle and tumour characteristics. The prognostic model was developed with Fine and Gray regression analysis to account for competing risk of death. We used bootstrapping to correct for within-patient correlation and statistical optimism in predictive performance. RESULTS: Second to fifth BCCs occurred in 293, 122, 58 and 36 patients, with median follow-up times of 3.0, 2.1, 1.7 and 1.8 years after the previous BCC, respectively. The risk of a new BCC was higher for patients with more metachronous BCCs. Having more than one BCC at diagnosis was another strong predictor of metachronous BCCs. Discriminative ability of the model was reasonable with an optimism-corrected c index of 0.70 at 3 years. CONCLUSIONS: The number of previous BCC diagnosis dates was a strong prognostic factor and should be considered when predicting the risk of metachronous BCCs. When the number of previous BCC diagnosis dates is combined with other readily available characteristics into a prognostic model, patients at high risk of a new BCC can be identified. PMID- 28664574 TI - The human cytomegalovirus nuclear egress complex unites multiple functions: Recruitment of effectors, nuclear envelope rearrangement, and docking to nuclear capsids. AB - BACKGROUND: Nuclear replication represents a common hallmark of herpesviruses achieved by a number of sequentially unrolled regulatory processes. A rate limiting step is provided by nucleo-cytoplasmic capsid export, for which a defined multiregulatory protein complex, namely, the nuclear egress complex (NEC), is assembled comprising both viral and cellular components. The NEC regulates at least 3 aspects of herpesviral nuclear replication: (1) multimeric recruitment of NEC-associated effector proteins, (2) reorganization of the nuclear lamina and membranes, and (3) the docking to nuclear capsids. Here, we review published data and own experimental work that characterizes the NEC of HCMV and other herpesviruses. METHODS: A systematic review of information on nuclear egress of HCMV compared to selected alpha-, beta-, and gamma herpesviruses: proteomics-based approaches, high-resolution imaging techniques, and functional investigations. RESULTS: A large number of reports on herpesviral NECs have been published during the last two decades, focusing on protein-protein interactions, nuclear localization, regulatory phosphorylation, and functional validation. The emerging picture provides an illustrated example of well-balanced and sophisticated protein networking in virus-host interaction. CONCLUSIONS: Current evidence refined the view about herpesviral NECs. Datasets published for HCMV, murine CMV, herpes simplex virus, and Epstein-Barr virus illustrate the marked functional consistency in the way herpesviruses achieve nuclear egress. However, this compares with only limited sequence conservation of core NEC proteins and a structural conservation restricted to individual domains. The translational use of this information might help to define a novel antiviral strategy on the basis of NEC-directed small molecules. PMID- 28664575 TI - Public awareness and misunderstanding about DrinkWise Australia: a cross sectional survey of Australian adults. AB - OBJECTIVE: DrinkWise Australia is an alcohol industry Social Aspects/Public Relations Organisation (SAPRO). We assessed the Australian public's awareness of DrinkWise, beliefs about its funding source, and associations between funding beliefs and perceptions of DrinkWise. METHODS: A total of 467 adult weekly drinkers completed an online cross-sectional survey in February 2016. RESULTS: Half the sample had heard of DrinkWise (48.6%); of these, the proportion aware that DrinkWise is industry funded (37.0%) was much smaller than the proportion believing it receives government funding (84.1%). Respondents who incorrectly believed DrinkWise receives government funding were more likely to hold a favourable perception of the organisation's credibility, trustworthiness and respectability than those who did not believe it receives government funding (75.9% vs. 58.3%; p=0.032). CONCLUSIONS: The drinking population is vulnerable to believing that alcohol industry public relations organisations such as DrinkWise are government funded, which in turn is associated with more favourable perceptions of the organisation's credibility, trustworthiness, and respectability. Implications for public health: Favourable perceptions of DrinkWise may enhance the industry's ability to delay or dilute potentially effective alcohol control policies. Future research should investigate whether educating the public about DrinkWise's alcohol industry funding alters the public's perception of how credible, trustworthy and respectable the organisation is. PMID- 28664577 TI - The medial pterygoid muscle: a stabiliser of horizontal jaw movement. AB - There is limited information of the normal function of the human medial pterygoid muscle (MPt). The aims were to determine whether (i) the MPt is active throughout horizontal jaw movements with the teeth apart and (ii) whether single motor units (SMUs) are active during horizontal and opening-closing jaw movements. Intramuscular electrodes were placed in the right MPt of 18 participants who performed five teeth-apart tasks: (i) postural position, (ii) ipsilateral (i.e. right) jaw movement, (iii) contralateral movement, (iv) protrusive movement and (v) opening-closing movement. Movement tasks were guided by a target and were divided into BEFORE, OUT, HOLDING, RETURN and AFTER phases according to the movement trajectories recorded by a jaw tracking system. Increased EMG activity was consistently found in the OUT, HOLDING and RETURN phases of the contralateral and protrusive movement tasks. An increased RETURN phase activity in the ipsilateral task indicates an important role for the MPt in the contralateral force vector. Of the 14 SMUs active in the opening-closing task, 64% were also active in at least one horizontal task. There were tonically active SMUs at the postural jaw position in 44% of participants. These new data point to an important role for the MPt in the fine control of low forces as required for stabilisation of vertical mandibular position not only to maintain postural position, but also throughout horizontal jaw movements with the teeth apart. These findings provide baseline information for future investigations of the possible role of this muscle in oro-facial pain conditions. PMID- 28664576 TI - Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease. AB - PURPOSE: Our aim was to determine whether pharmacologic vasodilation is an alternative to exercise stress during limb perfusion imaging for peripheral artery disease (PAD). METHODS: Quantitative contrast-enhanced ultrasound (CEU) perfusion imaging of the bilateral anterior thigh and calf was performed in nine control subjects and nine patients with moderate to severe PAD at rest and during vasodilator stress with dipyridamole. For those who were able, CEU of the calf was then performed during modest plantar flexion exercise (20 watts). CEU time intensity data were analyzed to quantify microvascular blood flow (MBF) and its parametric components of microvascular blood volume and flux rate. RESULTS: Thigh and calf skeletal muscle MBF at rest was similar between control and PAD patients. During dipyridamole, MBF increased minimally (= 18 years) receiving warfarin before the planned transfemoral CAG were randomly assigned to either heparin bridging or uninterrupted warfarin with targeted INR (2.0-3.0). The primary outcome was the incidence of major vascular access site complications. RESULTS: The baseline characteristics were comparable between two groups (mean age was 60.1 +/- 7.8 years, 49 males). The mean INR on the day of CAG of heparin bridging and uninterrupted warfarin groups was 1.2 +/- 0.3 and 2.2 +/- 0.5 (P < 0.001). The major vascular access site complications occurred in 3 of 55 (5.5%) heparin-bridging patients and in none of 55 uninterrupted warfarin patients (P = 0.243). The total vascular access site complications occurred in 6 (10.9%) heparin-bridging and one (1.8%) uninterrupted warfarin patients (P = 0.113). No patient developed either other bleeding or thromboembolic events during 7 days after CAG. CONCLUSIONS: We demonstrated that an uninterrupted warfarin strategy did not increase vascular access site complications in patients undergoing transfemoral CAG compared to heparin bridging therapy. Due to the safety and the ease of uninterrupted warfarin strategy, this approach should be encouraged in patients receiving long-term warfarin who undergo elective transfemoral CAG. PMID- 28664580 TI - Prostate health index significantly reduced unnecessary prostate biopsies in patients with PSA 2-10 ng/mL and PSA >10 ng/mL: Results from a Multicenter Study in China. AB - BACKGROUND: The performance of prostate health index (phi) in predicting prostate biopsy outcomes has been well established for patients with prostate-specific antigen (PSA) values between 2 and 10 ng/mL. However, the performance of phi remains unknown in patients with PSA >10 ng/mL, the vast majority in Chinese biopsy patients. We aimed to assess the ability of phi to predict prostate cancer (PCa) and high-grade disease (Gleason Score >=7) on biopsy in a Chinese population. METHODS: This is a prospective, observational, multi-center study of consecutive patients who underwent a transrectal ultrasound guided prostate biopsy at four hospitals in Shanghai, China from August 2013 to December 2014. RESULTS: In the cohort of 1538 patients, the detection rate of PCa was 40.2%. phi had a significantly better predictive performance for PCa than total PSA (tPSA). The areas under the receiver operating characteristic curve (AUC) were 0.90 and 0.79 for phi and tPSA, respectively, P < 0.0001. A considerable proportion of patients in the cohort had PSAs >10 ng/mL (N = 838, 54.5%). The detection rates of PCa were 35.9% and 57.7% in patients with tPSA 10.1-20 and 20.1-50 ng/mL, respectively. The AUCs of phi (0.79 and 0.89, for these two groups, respectively) were also significantly higher than tPSA (0.57 and 0.63, respectively), both P < 0.0001. If a phi <=35 was used as the cutoff, 599/1538 (39%) biopsies could have been avoided at a cost of missing small numbers of PCa patients: 49 (7.93%) PCa patients, including 18 (3.69%) high-grade tumors. CONCLUSIONS: Results from this study suggest that phi can be used to predict PCa and high-grade disease in Chinese men with high PSA levels (>10 ng/mL). PMID- 28664581 TI - Elevated levels of liver methylglyoxal and d-lactate in early-stage hepatitis in rats. AB - Methylglyoxal (MGO) is highly cytotoxic and its levels are elevated in diabetes, nephropathy and atherosclerosis. However, it has never been studied in liver disease. For this reason, we aimed to assess the levels of MGO and its metabolite d-lactate in an early hepatitis model. Wistar rats were administered CCl4 (0.75 mL/kg, i.p.) to induce hepatitis. In either CCl4 -treated or untreated rats, alanine transaminase and aspartate transaminase levels did not change over the course of the study, indicating that significant liver damage did not occur following CCl4 treatment. However, the levels of MGO and d-lactate were higher in the livers of CCl4 -treated animals than in untreated animals (MGO: 128.2 +/- 18.8 and 248.1 +/- 64.9 MUg/g protein, p < 0.01; d-lactate: 0.860 +/- 0.040 and 1.293 +/- 0.078 MUmol/g protein, respectively p < 0.01). Furthermore, in untreated and treated animals, serum d-lactate levels were 57.65 +/- 2.59 and 92.16 +/- 16.69 MUm and urine d-lactate levels were 1.060 +/- 0.007 and 1.555 +/- 0.366 MUmol/mg UCr, respectively (p < 0.01). These data show that in this model of early-stage liver damage, the levels of MGO and its metabolite d-lactate are elevated and that d-lactate could be useful as a reference marker for the early stage of hepatitis. PMID- 28664584 TI - Care professional's experiences about using Liverpool Care Pathway in end-of-life care in residential care homes. AB - BACKGROUND: Residential care homes (RCHs) play an important role in end-of-life care, being the most common place of death for elderly people in several European countries. Care pathways such as the Liverpool Care Pathway for the Dying Patient (LCP) are used to improve and ensure quality care at the end of life. There is a lack of scientific evidence supporting the use of care pathways. DESIGN: A descriptive qualitative study. OBJECTIVE: The aim was to describe care professionals' experiences of using the Liverpool Care Pathway for the Dying Patient in the care of dying residents in residential care homes. METHODS: Five focus group interviews and two individual interviews with enrolled nurses (n = 10), Registered Nurses (n = 9) and general practitioners (n = 5) were carried out and analysed using qualitative content analysis. RESULTS: Care professionals expressed that they became confident through a shared approach to care, were supported to tailor the care according to the residents' individual needs, were supported to involve family members in decision-making and care and became more aware of the care environment. CONCLUSION: The results of this study indicate that the LCP might be a useful tool for care professionals in improving end-of life care in RCHs through increased attention to the goals of care, the individual needs of residents and family involvement. PMID- 28664585 TI - Effect of fatigue loading on the fracture strength and failure mode of lithium disilicate and zirconia implant abutments. AB - OBJECTIVE: The aim of this study was to test five types of implant restorations using titanium, zirconia and lithium disilicate abutments after being subjected to long-term fatigue loading. MATERIALS AND METHODS: Forty single-tooth implant restorations were assembled on titanium implants (FairTwo; FairImplant). The restorations differed only in the type of abutment used and were divided into five groups [Ti: titanium; Zr: zirconia with no metal base; ZrT: zirconia with titanium base; LaT: lithium disilicate abutment with titanium base; and LcT: lithium disilicate hybrid-abutment-crown with titanium base]. Specimens were subjected to dynamic load of 49 N up to 1,200,000 cycles using a dual-axis chewing simulator (Kausimulator; Willytech). The surviving specimens were subjected to quasi-static loading using a universal testing machine (Z010; Zwick) until the implant-abutment connection failed. The values of force (N) at which fracture or plastic deformation of the restoration occurred were calculated and the rate of deformation was analyzed. The data was then analyzed using Mann Whitney tests. RESULTS: Groups Ti, ZrT, LaT and LcT withstood 1,200,000 fatigue load cycles and higher forces than physiological occlusal forces without fracture or debonding of the ceramic suprastructure. In group Zr, some specimen did not survive the chewing simulation and this group showed the lowest resistance to failure with a median of 198 N. CONCLUSIONS: Within the limitations of this study, it could be concluded that lithium disilicate abutments and hybrid abutment-crowns show promising durability and strength after long-term dynamic loading. The use of titanium base enhances the strength of the zirconia abutments. PMID- 28664586 TI - Australian primary school communities' understandings of SunSmart: a qualitative study. AB - OBJECTIVES: Skin cancer represents a major health issue for Australia. Childhood sun exposure is an important risk factor and evidence suggests the use of sun protection measures by Australian school children could be improved. This study examines how the SunSmart Program, a school-based skin cancer prevention resource, can be supported to further increase sun protection behaviours to assist in lowering skin cancer incidence. METHODS: The Health Promoting Schools (HPS) framework was adopted to select key stakeholders from a convenience sample of five school communities. Students, teaching staff and parents participated in semi-structured focus group and individual interviews. A thematic analysis was used to extract key themes from the data. RESULTS: Although these school communities were aware of sun protection practices and the risks associated with sun exposure, their understandings of the SunSmart Program were limited. Sun protection policy implementation was inconsistent and students were unlikely to engage in sun protection practices beyond the school setting. CONCLUSION AND IMPLICATIONS: School communities require additional support and engagement to holistically enforce the principles of the SunSmart Program. PMID- 28664583 TI - Corticosterone influences gerbil (Meriones unguiculatus) prostatic morphophysiology and alters its proliferation and apoptosis rates. AB - Glucocorticoids (GCs) are hormones that are widely used in medicine; but although side effects are generally recognised, little is known about the precise mechanisms that is implicated in many of these side effects. Furthermore, GCs are highly correlated with stress and behaviour disorders. This study evaluated the effects of the glucocorticoid corticosterone on the ventral prostate of the Mongolian gerbil. Male gerbils (Meriones unguiculatus) (n = 5) received intraperitoneal injections of saline or corticosterone in doses of 0.5 mg/kg/day and 1.5 mg/kg/day for 5 days; while some of the animals were killed immediately after the treatment, the others were killed 5 days after the treatment period. The data show that corticosterone influences the structure and functionality of this organ. This hormone has anti-proliferative and anti-apoptotic properties in the prostate. In addition, the frequencies of the androgen (AR), oestrogen (ERalpha, ERbeta) and glucocorticoid (GR) receptors changed. The frequencies of AR, GR and ERbeta decreased in the Ct1/5 group; in the groups with rest period, the frequencies of GR increased and ERbeta decreased in the epithelium. Changes in the proliferative index, apoptotic index and receptor activity may have contributed to the emergence of prostatic morphological alterations, such as the presence of cellular debris and inflammatory cells. Different doses of corticosterone had variable effects on the prostate, with a higher dose showing subtler effects and a lower dose showing more striking effects. The corticosterone effects on nuclear receptors were reverted or attenuated after a rest period, which was not observed for proliferation and apoptosis. In summary, we have demonstrated that corticosterone might influence the prostatic morphophysiology and that these changes may be linked in some way to the altered receptor distribution. PMID- 28664587 TI - The influence of rapid growth on sodium salicylate pharmacokinetics in male turkeys. AB - The aim of this study was to assess the influence of growth on the pharmacokinetics of sodium salicylate (SS) in male turkeys. SS was administered intravenously at a dose of 50 mg/kg. Plasma drug concentrations were assessed by high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental analysis. As the age increased from 6 to 13 weeks (body weight increase from 2.35 to 9.43 kg), median body clearance decreased from 1.34 to 0.87 ml/min/kg. This caused a significant increase in the median mean residence time from 3.42 to 4.44 hr. Elimination phase proved to be biphasic and two elimination half-lives (T1/2el ) were distinguished. Whereas T1/2el1 was found to increase with age by 128%, T1/2el2 represented a later but faster and less age-dependent phase of elimination (increase by 56% in the respective groups). Volume of distribution decreased with age. These effects may lead to different therapeutic response to SS in turkeys of different age and body weights. PMID- 28664582 TI - The macrolide antibiotic renaissance. AB - Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases. PMID- 28664588 TI - Welfare, wellness, and job satisfaction of Chinese physicians: A national survey of public tertiary hospitals in China. AB - Little national data are available on Chinese physicians' welfare, wellness, and job satisfaction. We conducted a self-administered smartphone-based national survey in early 2016 of 17 945 physicians from 136 tertiary hospitals across 31 provinces in China. In addition to collecting the physicians' basic information, we also measured 5 domains (the ethical and working environments, welfare, wellness, and job satisfaction). Half of the physicians reported a hospital-based annual income of less than RMB 72 000 ($10 300), and 60.31% of them did not think that the current medical pricing system reflects physicians' value. More than half (58.64%) of them did not have or did not know about medical malpractice insurance. These physicians worked long hours (an average of 10 h) and slept short hours (average 6 h). Only 35.78% of them thought that they were in good health, and 51.03% were in good mental health. Approximately, a quarter of them had helped to pay medical bills for patients who could not afford care, and 1 in 7 has been penalised for seeing patients who generated bad debts. Only 33.42% of them thought that their occupation receives social recognition and respect, and 70.98% would not encourage their children to pursue a medical career. The top 3 factors that may influence physician job satisfaction as chosen by the physicians were as follows: (1) the income distribution policy (45.92%), (2) working environment safety (25.86%), and (3) public trust and respect for their job (16.10%). In conclusion, we found that Chinese physicians bear heavy physical, mental, and financial stress, and many of them lack confidence that they receive trust and respect from society. PMID- 28664589 TI - High myopic astigmatism secondary to Descemet's membrane tears after forceps assisted delivery. PMID- 28664590 TI - GPs' perceived readiness to identify and respond to intimate partner abuse: development and preliminary validation of a multidimensional scale. AB - OBJECTIVES: To develop a scale to assess the perceived readiness of general practitioners (GPs) to identify and respond to intimate partner abuse (IPA) and to examine its psychometric properties. METHODS: A qualitative study of GPs' perceived readiness and a literature review were used to generate items for the General Practitioners' Perceived Readiness to identify and respond to Intimate Partner Abuse Scale (GRIPS). Responses of 287 Australian GPs and GP registrars were analysed to provide psychometric evaluation of the GRIPS. RESULTS: Principal components analysis generated a three-factor scale comprising 30 items with good internal consistency, (Cronbach's alpha from 0.67 to 0.88). The three distinct and reliable subscales consisting of 7 to 13 items are: Self-Efficacy; Motivational Readiness; and Emotional Readiness. The subscales were closely correlated with relevant theoretical constructs and demonstrated a unique relationship with IPA training and clinical experience. CONCLUSION: The GRIPS, a new scale with face-, content- and construct-validity, as well as internal consistency reliability, was validated in the general practice context. Further validation is warranted. Implications for public health: The GRIPS is a well defined and easily administered scale that can be used in research and training contexts to assess health practitioners' perceived self-efficacy, motivational and emotional readiness to identify and respond to IPA. This would facilitate IPA disclosure and identification. PMID- 28664591 TI - Development and enrolee satisfaction with basic medical insurance in China: A systematic review and stratified cluster sampling survey. AB - Basic Medical Insurance (BMI) has changed remarkably over time in China because of health reforms that aim to achieve universal coverage and better health care with adequate efforts by increasing subsidies, reimbursement, and benefits. In this paper, we present the development of BMI, including financing and operation, with a systematic review. Meanwhile, Pudong New Area in Shanghai was chosen as a typical BMI sample for its coverage and management; a stratified cluster sampling survey together with an ordinary logistic regression model was used for the analysis. Enrolee satisfaction and the factors associated with enrolee satisfaction with BMI were analysed. We found that the reenrolling rate superficially improved the BMI coverage and nearly achieved universal coverage. However, BMI funds still faced dual contradictions of fund deficit and insured under compensation, and a long-term strategy is needed to realize the integration of BMI schemes with more homogeneous coverage and benefits. Moreover, Urban Resident Basic Medical Insurance participants reported a higher rate of dissatisfaction than other participants. The key predictors of the enrolees' satisfaction were awareness of the premium and compensation, affordability of out of-pocket costs, and the proportion of reimbursement. These results highlight the importance that the Chinese government takes measures, such as strengthening BMI fund management, exploring mixed payment methods, and regulating sequential medical orders, to develop an integrated medical insurance system of universal coverage and vertical equity while simultaneously improving enrolee satisfaction. PMID- 28664592 TI - Electrospun polyethylene terephthalate/graphene oxide nanofibrous membrane followed by HPLC for the separation and determination of tamoxifen in human blood plasma. AB - An electrospun polyethylene terephthalate/graphene oxide nanofibrous mat was fabricated and used as an effective and novel membrane for the solid-phase extraction of tamoxifen in human blood plasma samples before detection by high performance liquid chromatography. The membrane was characterized by some identification techniques, such as FTIR spectroscopy, X-ray diffraction, and scanning electron microscopy. The effective variables of the extraction procedure including desorption condition (type and volume of the eluent), adsorbent dose, pH of sample solution, salt concentration, and sample loading time were investigated and their optimum values were obtained using one factor at a time methodology. Under the optimized conditions, the results showed wide linear concentration range of 5-2000 ng/mL with a determination coefficient of 0.992. The limits of detection and limits of quantification were 1.3 and 5.0 ng/mL, respectively. The intra-day and inter-day precisions were 3.4 and 4.6%, respectively. The method was successfully applied to determination of tamoxifen in the blood plasma samples and satisfactory relative recoveries (92.6-98.3 %) were achieved. PMID- 28664594 TI - Evaluation of baseline frequency of sister chromatid exchanges in an Italian population according to age, sex, smoking habits, and gene polymorphisms. AB - OBJECTIVES: Increased SCEs frequencies in human lymphocytes are an indicator of spontaneous chromosome instability and could be influenced by different exogenous and endogenous factors. In this study, we evaluated the influence of age, sex, smoking habits, and genetic polymorphisms on the background levels of SCEs in peripheral blood lymphocytes. METHODS: Two hundred-thirty healthy Italian subjects were recruited. Data about age, sex and smoking habits were recorded. Subjects were also genotyped for GSTT1, GSTM1, GSTP1 A/G, CYP1A1 Ile/Val, CYP2C19 G/A, ERCC2/XPD Lys751Gln, XRCC1 Arg194ATrp, XRCC1 Arg399Gln, and XRCC1Arg208His gene polymorphisms. RESULTS: The frequency of SCEs/cell was 5.15 +/- 1.87, with females showing a significantly higher SCEs value with respect to males (5.36 +/- 2.10 and 4.82 +/- 1.39, respectively). Smokers showed significantly increased levels of SCEs with respect to nonsmokers (5.93 +/- 1.75 and 4.70 +/- 1.79, respectively) whereas no differences were observed between heavy and light smokers. Age correlated with the RI value (P = .01) but not with the SCEs frequency (P = 07), although the 31-40 age group showed a significantly lower SCEs frequency with respect to the other age groups. A significant association was also found between GSTP2C19-AA, GSTT1-null, GSTM1-null, ERCC2/XPD Gln751Gln, and XRCC1 His208His genotypes, and higher frequencies of SCEs. CONCLUSION: We describe the association between some phase I, phase II, and DNA-repair gene polymorphisms with increased SCEs frequencies, reinforcing the importance of genetic analysis in biomonitoring studies. Sex and age were found to be important endogenous factors that affect the level of genomic damage and the replicative capacity of cells, respectively. PMID- 28664593 TI - Clinical surrogate markers for predicting metabolic syndrome in middle-aged and elderly Chinese. AB - AIMS/INTRODUCTION: The present study evaluated the ability of lipid accumulation product (LAP), visceral adiposity index (VAI), and the product of triglycerides and glucose (TyG), three novel markers, in identifying metabolic syndrome (MetS) with different criteria in middle-aged and elderly Chinese. MATERIALS AND METHODS: During June 2012 to January 2013, 992 consecutive patients (age >=40 years) were enrolled at Daping Hospital. The criteria of MetS were based on the International Diabetes Federation and the modified National Cholesterol Education Program's Adult Treatment Panel III. VAI, LAP and TyG were computed based on a published mathematical model. RESULTS: The prevalence of MetS was 42.8%. The receiver operating characteristic curve found LAP, VAI and TyG were positively related to MetS in both criteria. The optimal cut-offs of VAI, LAP and TyG for the modified National Cholesterol Education Program's Adult Treatment Panel III and International Diabetes Federation criteria were 2.015, 31.465 and 8.706, and 2.035, 37.99 and 8.697, respectively. After adjustment of potential confounding factors, VAI, LAP and TyG were significantly correlated with MetS in all criteria according to optimal cut-offs. For MetS, reliable predictive value was observed in different subgroups (age and sex). LAP showed the greatest area under the curve in MetS with the International Diabetes Federation definition (area under the curve 0.887, 95% confidence interval 0.852-0.922). CONCLUSIONS: AP, VAI and TyG were reliable surrogate markers for identifying MetS in middle-aged and elderly Chinese. LAP could be a better parameter than VAI and TyG for predicting MetS in the present study. PMID- 28664595 TI - Immunisation coverage and socioeconomic status - questioning inequity in the 'No Jab, No Pay' policy. PMID- 28664596 TI - Overexpression and cosuppression of xylem-related genes in an early xylem differentiation stage-specific manner by the AtTED4 promoter. AB - Tissue-specific overexpression of useful genes, which we can design according to their cause-and-effect relationships, often gives valuable gain-of-function phenotypes. To develop genetic tools in woody biomass engineering, we produced a collection of Arabidopsis lines that possess chimeric genes of a promoter of an early xylem differentiation stage-specific gene, Arabidopsis Tracheary Element Differentiation-related 4 (AtTED4) and late xylem development-associated genes, many of which are uncharacterized. The AtTED4 promoter directed the expected expression of transgenes in developing vascular tissues from young to mature stage. Of T2 lines examined, 42%, 49% and 9% were judged as lines with the nonrepeat type insertion, the simple repeat type insertion and the other repeat type insertion of transgenes. In 174 T3 lines, overexpression lines were confirmed for 37 genes, whereas only cosuppression lines were produced for eight genes. The AtTED4 promoter activity was high enough to overexpress a wide range of genes over wild-type expression levels, even though the wild-type expression is much higher than AtTED4 expression for several genes. As a typical example, we investigated phenotypes of pAtTED4::At5g60490 plants, in which both overexpression and cosuppression lines were included. Overexpression but not cosuppression lines showed accelerated xylem development, suggesting the positive role of At5g60490 in xylem development. Taken together, this study provides valuable results about behaviours of various genes expressed under an early xylem specific promoter and about usefulness of their lines as genetic tools in woody biomass engineering. PMID- 28664597 TI - Unusual case of ventral liver herniation. PMID- 28664598 TI - Comparison of fractionation proteomics for local SWATH library building. AB - For data-independent acquisition by means of sequential window acquisition of all theoretical fragment ion spectra (SWATH), a reference library of data-dependent acquisition (DDA) runs is typically used to correlate the quantitative data from the fragment ion spectra with peptide identifications. The quality and coverage of such a reference library is therefore essential when processing SWATH data. In general, library sizes can be increased by reducing the impact of DDA precursor selection with replicate runs or fractionation. However, these strategies can affect the match between the library and SWATH measurement, and thus larger library sizes do not necessarily correspond to improved SWATH quantification. Here, three fractionation strategies to increase local library size were compared to standard library building using replicate DDA injection: protein SDS-PAGE fractionation, peptide high-pH RP-HPLC fractionation and MS-acquisition gas phase fractionation. The impact of these libraries on SWATH performance was evaluated in terms of the number of extracted peptides and proteins, the match quality of the peptides and the extraction reproducibility of the transitions. These analyses were conducted using the hydrophilic proteome of differentiating human embryonic stem cells. Our results show that SWATH quantitative results and interpretations are affected by choice of fractionation technique. Data are available via ProteomeXchange with identifier PXD006190. PMID- 28664599 TI - Within-lake habitat heterogeneity mediates community response to warming trends. AB - Climate change is rapidly altering many aquatic systems, and life history traits and physiological diversity create differences in organism responses. In addition, habitat diversity may be expressed on small spatial scales, and it is therefore necessary to account for variation among both species and locations when evaluating climate impacts on biological communities. Here, we investigated the effects of temperature and spatial heterogeneity on long-term community composition in a large boreal lake. We used a five-decade time series of water temperature and relative abundance of fish species captured in the littoral zone throughout the summer at 10 discrete locations around the lake. We applied a spatial dynamic factor analysis (SDFA) model to this time series, which estimates the sensitivity of each species to changing water temperature while accounting for spatiotemporal variation. This analysis described the trend in community composition at each sampling location in the lake, given their different trends in temperature over time. The SDFA indicated different magnitude and direction of species responses to temperature; some species increased while others decreased in abundance. The model also identified five unique trends in species abundance across sites and time, indicating residual dynamics in abundance after accounting for temperature effects. Thus, different regions in the lake have experienced different trajectories in community change associated with different rates of temperature change. These results highlight the importance of considering habitat heterogeneity in explaining and predicting future species abundances, and our model provides a means of visualizing spatially-explicit temporal variation in species' dynamics. PMID- 28664600 TI - Liver enzymes are not directly involved in atrial fibrillation: a prospective cohort study. AB - BACKGROUND: Epidemiological evidence proposes the direct involvement of the liver enzymes in atrial fibrillation. These relationships are controversial and mechanistically unclear. As part of the British Regional Heart Study, we investigated whether change in liver enzymes over time associates with atrial fibrillation in men initially free of this heart condition. MATERIALS AND METHODS: We prospectively investigated change (delta) in liver enzymes and new onset atrial fibrillation in a representative sample of 1428 men aged 60-79 years. RESULTS: Mean follow-up was 12.3 years, after which 108 new atrial fibrillation cases were identified. The liver enzymes did not differ at baseline or follow-up, except for gamma-glutamyl transferase which was higher at follow-up in men who developed atrial fibrillation compared to those who did not (P < 0.0001). Change in GGT was greater in men who developed AF than those who did not (+6.12 vs. -2.60 U/L, P = 0.036). N-terminal pro-brain natriuretic peptide (baseline and follow-up, P < 0.0001) and total bilirubin (follow-up only, P < 0.0001) were also higher in men who developed atrial fibrillation while serum haemoglobin was similar at baseline and follow-up (P >= 0.74). Atrial fibrillation was associated with change in gamma-glutamyl transferase (OR, 1.18; 95% CI, 1.01-1.37) after multiple adjustments and exclusions. However, after adjusting for baseline (P = 0.088) or change (P = 0.40) in N-terminal pro-brain natriuretic peptide, the association between atrial fibrillation and change in gamma-glutamyl transferase was lost. CONCLUSION: The direct relationship between atrial fibrillation and liver enzymes is absent and depends, at least in part, on the progression of heart failure as captured by N-terminal pro-brain natriuretic peptide. PMID- 28664601 TI - Left atrial strain predicts hemodynamic parameters in cardiovascular patients. AB - BACKGROUND: We aimed to evaluate the predictive value of left atrial (LA) reservoir, conduit, and contractile function parameters as assessed by speckle tracking echocardiography (STE) for invasively measured hemodynamic parameters in a patient cohort with myocardial and valvular diseases. METHODS: Sixty-nine patients undergoing invasive hemodynamic assessment were enrolled into the study. Invasive hemodynamic parameters were obtained by left and right heart catheterization. Transthoracic echocardiography assessment of LA reservoir, conduit, and contractile function was performed by STE. RESULTS: Forty-nine patients had sinus rhythm (SR) and 20 patients had permanent atrial fibrillation (AF). AF patients had significantly reduced LA reservoir function compared to SR patients. In patients with SR, LA reservoir, conduit, and contractile function inversely correlated with pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure, and mean pulmonary artery pressure (PAP), and showed a moderate association with cardiac index. In AF patients, there were no significant correlations between LA reservoir function and invasively obtained hemodynamic parameters. In SR patients, LA contractile function with a cutoff value of 16.0% had the highest diagnostic accuracy (area under the curve, AUC: 0.895) to predict PCWP >=18 mm Hg compared to the weaker diagnostic accuracy of average E/E' ratio with an AUC of 0.786 at a cutoff value of 14.3. In multivariate analysis, LA contractile function remained significantly associated with PCWP >=18 mm Hg. CONCLUSION: In a cohort of patients with a broad spectrum of cardiovascular diseases LA strain shows a valuable prediction of hemodynamic parameters, specifically LV filling pressures, in the presence of SR. PMID- 28664603 TI - R. B. Woodward: A Larger-than-Life Chemistry Rock Star. AB - To mark the 100th birthday of R. B. Woodward (April 10, 1917-July 8, 1979), a discussion and analysis of Woodward's persona is given. The fundamental theme is that "Woodward experienced his own exceptionality," as described by Albert Eschenmoser, Woodward's partner in the vitamin B12 project. Woodward's rock star personality is explored and discussed as one of his legacies in addition to his scientific achievements. Woodward presented himself to his students, colleagues, and fellow chemists with an aura of nobility and romanticism. PMID- 28664602 TI - NEUROD1-deficient diabetes (MODY6): Identification of the first cases in Japanese and the clinical features. AB - AIMS: Only a few families with neuronal differentiation 1 (NEUROD1)-deficient diabetes, currently designated as maturity-onset diabetes of the young 6 (MODY6), have been reported, but mostly in Caucasian, and no mutation has been identified by family-based screening in Japanese. Accordingly, the phenotypic details of the disease remain to be elucidated. METHODS: We examined a total of 275 subjects having diabetes suspected to be MODY who were negative for mutations in MODY1-5 referred from 155 medical institutions throughout Japan. So as not to miss low penetrant cases, we examined non-obese Japanese patients with early-onset diabetes regardless of the presence of family history by direct sequencing of all exons and flanking regions of NEUROD1 . Large genomic rearrangements also were examined. RESULTS: Four patients with 3 frameshift mutations and 1 missense mutation, all of which were heterozygous and 3 of which were novel, were identified. Diabetic ketosis was found occasionally in these patients even under conditions of chronic hyperglycemia, for unknown reasons. Although the capacity of early-phase insulin secretion was low in these patients, the insulin secretory capacity was relatively preserved compared to that in hepatocyte nuclear factor (HNF)1A- and HNF1B-MODY. One of the patients and 2 of their diabetic mothers were found to have some mental or neuronal abnormality. CONCLUSIONS: This is the first report of NEUROD1 mutations in Japanese, who have a genetic background of intrinsically lower capacity of insulin secretion. NEUROD1-deficient diabetes appears to be low penetrant, and may occur in concert with other genetic factors. PMID- 28664604 TI - Urinary tract involvement of mantle cell lymphoma diagnosed by urine cytology. AB - Urinary tract lymphoma is unusual, with the kidney being the most commonly reported site of involvement. Urinary bladder involvement by lymphoma is rare. Mantle cell lymphoma (MCL) is a relatively uncommon type of lymphoma. Herein, we report a case of MCL of the urinary bladder diagnosed by urine cytology, with confirmatory immunocytochemical stains, which has not previously been reported in the literature. PMID- 28664605 TI - Case of giant paraesophageal hiatal hernia associated with Morgagni hernia. AB - Simultaneous paraesophageal and Morgagni hernias are very rare. Here, we report a case involving a 91-year-old woman with simultaneous paraesophageal and Morgagni hernias. Both hernias were repaired laparoscopically. The postoperative course was uneventful. Laparoscopic repair for hernias seems to be feasible and minimally invasive, but only a few reports have described such repairs of hernial orifices. PMID- 28664606 TI - Top-down control of pain. PMID- 28664607 TI - Formal caregivers' experiences of aggressive behaviour in older people living with dementia in nursing homes: A systematic review. AB - AIM: The purpose of this study was to investigate formal caregivers' experiences of aggressive behaviour in older people living with dementia in nursing homes. BACKGROUND: Aggressive behaviour symptoms among older people living with dementia are reported to be prevalent. As aggressive behaviour includes both verbal and physical behaviours, such as kicking, hitting and screaming, it causes an increased burden on formal caregivers. Professionals experiencing this aggression perceived it as challenging, causing physical and psychological damage, leading to anger, stress and depression. METHODS: A systematic review was conducted. A search of published research studies between 2000 and 2015 was conducted using appropriate search terms. Eleven studies were identified and included in this review. RESULTS: The analysis resulted in four categories: formal caregivers' views on triggers of aggression, expressions of aggression, the effect of aggressive behaviours on formal caregivers and formal caregivers' strategies to address aggression. The results show that aggressive behaviour may lead to negative feelings in formal caregivers and nursing home residents. CONCLUSION: The results of this study suggest that having the ability to identify triggers possibly assists caregivers with addressing aggressive behaviour. Aggressive behaviour might also affect quality of care. IMPLICATIONS FOR PRACTICE: Results from this systematic review indicate that caregivers prefer person-centred strategies to handle aggressive behaviour among older people, while the use of pharmaceuticals and coercion strategies is a last resort. PMID- 28664608 TI - Intima-media thickness at different arterial segments in pediatric type 1 diabetes patients and its relationship with advanced glycation end products. AB - BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) are at risk for premature atherosclerosis (AS), which has its origin in childhood. Carotid intima media thickness (IMT) is an established surrogate marker for subclinical AS in adults. The first macroscopically detectable AS changes, however, begin in the abdominal aorta. Advanced glycation end products (AGE) predict microvascular complications in diabetes. OBJECTIVES: To assess the sensitivity for early macrovascular changes of brachial, femoral, and aortic IMT compared to conventional carotid IMT in pediatric T1DM patients ; and the relationship of IMT with AGE. METHODS: Using high-resolution external ultrasound, carotid, brachial, femoral, and aortic IMT were prospectively analyzed in children and adolescents with established T1DM and in controls (Ctrls). AGE were estimated by skin intrinsic fluorescence (SIF). Other established cardiovascular risk factors were excluded. RESULTS: Seventy-six subjects (T1DM = 38; Ctrls = 38) with a mean age of 13.1 +/- 4.0 years (6-19, median 13) qualified for analysis. Carotid, brachial, femoral, and aortic IMT analyses were feasible in 100%, 74%, 84%, and 92% of subjects, respectively. Aortic and femoral IMT were increased in T1DM patients (0.60 +/- 0.11 vs 0.52 +/- 0.10 mm, P < .001; and 0.41 +/- 0.07 vs 0.36 +/- 0.07 mm, P < .01, respectively) while carotid and brachial IMT were not. AGE levels were elevated in T1DM patients and correlated with aortic IMT only. The influence of AGE on aIMT did not remain significant after adjusting for T1DM and age in our small population. CONCLUSION: We found aortic IMT-and to a lesser degree femoral IMT-to be more sensitive than carotid and brachial IMT for detecting early macrovascular changes in pediatric T1DM patients. PMID- 28664609 TI - Young Australians' use of pornography and associations with sexual risk behaviours. AB - OBJECTIVES: Amid public health concern that rising pornography use may have a negative impact on young people's health and wellbeing, we report prevalence of pornography viewing and explore factors associated with viewing frequency and age at first viewing. METHODS: Cross-sectional online survey in a convenience sample of Victorians aged 15 to 29 years recruited via social media. RESULTS: Ever viewing pornography was reported by 815 of 941 (87%) participants. The median age at first pornography viewing was 13 years for men and 16 years for women. More frequent pornography viewing was associated with male gender, younger age, higher education, non-heterosexual identity, ever having anal intercourse and recent mental health problems. Younger age at first pornography viewing was associated with male gender, younger current age, higher education, non-heterosexual identity, younger age at first sexual contact and recent mental health problems. CONCLUSIONS: Pornography use is common and associated with some health and behavioural outcomes. Longitudinal research is needed to determine the causal impact of pornography on these factors. Implications for public health: Viewing pornography is common and frequent among young people from a young age and this needs to be considered in sexuality education. PMID- 28664610 TI - Targeted functional investigations guided by integrative proteome network analysis revealed significant perturbations of renal tubular cell functions induced by high glucose. AB - Recently, several studies employed various proteomic approaches to define diabetes-induced changes in renal proteins. However, functional significance of those datasets in diabetic nephropathy remained unclear. We thus performed integrative proteome network analysis of such datasets followed by various targeted functional studies in distal renal tubular cells treated with high glucose (HG) (25 mM) compared to normal glucose (NG) (5.5 mM) and NG + mannitol (M) (5.5 + 19.5 mM). The data showed that at 96 h when cell proliferation/death, tight junction protein and beta-/F-actin expression and organization, and transepithelial resistance remained unchanged, only HG caused increased levels of HSP90, HSP70, and HSP60, and increased accumulation of intracellular protein aggregates. In addition, HG also induced overproduction of intracellular ROS, decreased catalase level, increased level of oxidatively modified proteins, increased intracellular ATP level, and defective transepithelial Ca2+ transport. However, both HG and M increased the levels of ubiquitinated proteins. Taken together, this study demonstrated significant perturbations of distal renal tubular cells induced by HG based on targeted functional studies guided by integrative proteome network analysis. These data may, at least in part, lead to better understanding of the pathogenic mechanisms of diabetic nephropathy. PMID- 28664611 TI - Value congruence and depressive symptoms among critical care clinicians: The mediating role of moral distress. AB - Clinicians working in intensive care units are often exposed to several job stressors that can negatively affect their mental health. Literature has acknowledged the role of value congruence and job control in determining clinicians' psychological well-being and depressive symptoms. However, potential mediators of this association have been scarcely examined. This study aimed to test the mediating role of moral distress in the relationship between value congruence and job control, on the one hand, and depression, on the other hand. A cross-sectional study involving physicians, nurses, and residents working in 7 intensive care units in the north of Italy was conducted. Clinicians were administered in the Italian Moral Distress Scale-Revised, the value and control subscales of the Areas of Worklife Scale, and the Beck Depression Inventory II. Structural equation modeling was used to test the mediation model. Analysis on 170 questionnaires (response rate 72%) found no relations between job control and moral distress. A total indirect effect of value congruence on depression through moral distress (beta = -.12; p = .02) was found. Moral distress contributes to the development of depressive symptoms among critical care clinicians who perceive a value incongruence with their organization and therefore should be addressed. PMID- 28664612 TI - Autoimmune arthritis induces paired immunoglobulin-like receptor B expression on CD4+ T cells from SKG mice. AB - The chronic, destructive autoimmune arthritis in SKG mice, which closely resembles human rheumatoid arthritis, is the result of self-reactive T cells escaping thymic deletion. Since the inhibitory receptor LIR-1 is up-regulated on auto-reactive T cells in human rheumatoid arthritis, the role of its murine ortholog PIR-B was investigated. Peripheral CD4+ T cells from SKG mice were found to frequently express PIR-B, and this population produces more frequently IL-17 upon in vitro stimulation compared to PIR-B- cells. A much larger fraction of PIR B+ T cells, however, was found to secret no IL-17, but IFN-gamma. With regards to the clinical course of the disease, high frequencies of PIR-B+ CD4+ T cells were found to be associated with a milder course of arthritis, suggesting that the net effect of PIR-B expression is suppression of autoreactive T cells. Our results indicate that overexpression of PIR-B on IL-17-producing SKG CD4+ T cells might represent an effective counter-regulatory mechanism against the destructive potential of those cells. More importantly, a major population of PIR-B+ T cells in SKG mice appears to play an inhibitory role by way of their IFN-gamma production, since high frequencies of those cells ameliorate the disease. PMID- 28664613 TI - YB-1 orchestrates onset and resolution of renal inflammation via IL10 gene regulation. AB - The Y-box-binding protein (YB)-1 plays a non-redundant role in both systemic and local inflammatory response. We analysed YB-1-mediated expression of the immune regulatory cytokine IL-10 in both LPS and sterile inflammation induced by unilateral renal ischaemia-reperfusion (I/R) and found an important role of YB-1 not only in the onset but also in the resolution of inflammation in kidneys. Within a decisive cis-regulatory region of the IL10 gene locus, the fourth intron, we identified and characterized an operative YB-1 binding site via gel shift experiments and reporter assays in immune and different renal cells. In vivo, YB-1 phosphorylated at serine 102 localized to the fourth intron, which was paralleled by enhanced IL-10 mRNA expression in mice following LPS challenge and in I/R. Mice with half-maximal expression of YB-1 (Yb1+/- ) had diminished IL-10 expression upon LPS challenge. In I/R, Yb1+/- mice exhibited ameliorated kidney injury/inflammation in the early-phase (days 1 and 5), however showed aggravated long-term damage (day 21) with increased expression of IL-10 and other known mediators of renal injury and inflammation. In conclusion, these data support the notion that there are context-specific decisions concerning YB-1 function and that a fine-tuning of YB-1, for example, via a post-translational modification regulates its activity and/or localization that is crucial for systemic processes such as inflammation. PMID- 28664615 TI - Cutaneous epithelioid hemangioendothelioma on the sole mimicking a pyogenic granuloma. PMID- 28664614 TI - Evolving concepts of chronic traumatic encephalopathy as a neuropathological entity. AB - Chronic traumatic encephalopathy (CTE) is a long-term neurodegenerative consequence of repetitive head impacts which can only be definitively diagnosed in post-mortem. Recently, the consensus neuropathological criteria for the diagnosis of CTE was published requiring the presence of the accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci in an irregular pattern as the mandatory features. The clinical diagnosis and antemortem prediction of CTE pathology remain challenging if not impossible due to the common co-existing underlying neurodegenerative pathologies and the lack of specific clinical pointers and reliable biomarkers. This review summarizes the historical evolution of CTE as a neuropathological entity and highlights the latest advances and future directions of research studies on the topic of CTE. PMID- 28664616 TI - The coagulation laboratory monitoring of Afstyla single-chain FVIII concentrate. PMID- 28664617 TI - Down-regulation of long non-coding RNA MALAT1 by RNA interference inhibits proliferation and induces apoptosis in multiple myeloma. AB - Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by abnormal proliferation of monoclonal plasma cells in the bone marrow. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1), an evolutionarily highly conserved long non-coding RNA was originally identified in metastatic non-small cell lung cancer and has been reported to be up-regulated in many other cancers. However, the function of MALAT1 in MM remains unknown. In the present study, by transfecting MM cells with MALAT1-specific short hairpin RNA (shRNA) expression plasmids, the role of MALAT1 in the proliferation and apoptosis of MM cells was investigated in vitro, and the tumorigenicity of MALAT1-silenced cells was evaluated in vivo. MALAT1 was found to be highly expressed in RPMI8226 and U266 cells. Down-regulation of MALAT1 via RNA interference significantly inhibited the proliferation of MM cells through cell cycle arrest at G1 phase. Moreover, knockdown of MALAT1 induced apoptosis, which was closely associated with the activation of caspase-3/-9, down-regulation of Bcl-2 and up-regulation of Bax. In addition, silencing of MALAT1 by intratumoral injection of MALAT1 shRNA attenuated the tumour growth in mice bearing myeloma xenograft and led to massive apoptosis in the xenograft tumour. Therefore, MALAT1 may serve as a promising target in the genetic therapeutic strategy for MM treatment. PMID- 28664618 TI - Examination of factor structure of the inventory of complicated grief (ICG) in a sample of bereaved military family members with persistent and elevated grief. AB - Knowledge about the effect of a US service member's death on surviving family members is limited. In order to identify their grief-related health care needs, a first step is to identify the characteristics of persistent and elevated grief in a military family sample. The present study identified military family members (n = 232) bereaved more than six months who endorsed an elevated level of grief. A confirmatory factor analysis and test of measurement invariance of factor structure were used to compare the factor structure of their Inventory of Complicated Grief (ICG) responses to that of a bereaved non-military-related clinical research sample with similar grief levels. Results confirmed an equivalent five-factor structure of the ICG in both the military family sample and the clinical research sample. The similarity in factor structure was present despite differences in demographic characteristics and bereavement experiences between samples. Thus, the ICG reliably measures persistent and elevated grief in military family samples and provides grief symptom profiles that facilitates better understanding of their grief-related needs. PMID- 28664619 TI - Heartwood extract from Dalbergia sissoo promotes fracture healing and its application in ovariectomy-induced osteoporotic rats. AB - OBJECTIVES: This study was undertaken to investigate the effects of a heartwood ethanolic extract (HEE) made from the Dalbergia sissoo on facture healing and in the prevention of pathological bone loss resulting from estrogen deficiency in ovariectomized (Ovx) rats. METHODS: Heartwood ethanolic extract (250, 500 and 1000 mg/kg per day) was administered orally immediately next day after drill-hole injury and continued for 2 weeks. Ovx rats received HEE at same doses for 12 weeks and compared with 17-beta estradiol (E2; 100 MUg/kg for 5 days/week subcutaneously) group. Confocal imaging for fracture healing, micro-architecture of long bones, biomechanical strength, formation of mineralized nodule by bone marrow osteoprogenitor cells, bone turnover markers and gene expression were studied. One-way ANOVA was used to test significance. KEY FINDINGS: Heartwood ethanolic extract treatment promoted fracture healing, formation of new bone at the drill-hole site and stimulated osteogenic genes at callus region. HEE administration to the Ovx rats exhibited better micro-architectural parameters at various anatomical positions, better bone biomechanical strength and more osteoprogenitor cells in the bone marrow compared with Ovx + vehicle group. HEE exhibited no uterine estrogenicity. CONCLUSIONS: Oral administration of HEE was found to promote fracture healing and exhibited osteoprotective effect by possibly stimulation of osteoblast function. PMID- 28664620 TI - Application of gas and liquid chromatography coupled to time-of-flight mass spectrometry in pesticides: Multiresidue analysis. AB - Analysis of pesticide residues in water and food matrices is an active research area closely related to food safety and environmental issues. In this aspect mass spectrometry (MS) coupled to gas chromatography (GC) and liquid chromatography (LC) has been increasingly used in the analysis of pesticide residues in water and food. The increasing interest in application of high-resolution mass spectrometry with time-of-flight (TOF) and hybrid triple quadrupole TOF in pesticide analysis is due to its capability of performing both targeted and nontargeted analysis. This article discusses an overview of the application of GC TOF-MS and LC-TOF-MS in water and food matrices. PMID- 28664621 TI - Duodenal adenoma overlying a lipoma treated with laparoscopic endoscopic collaborative surgery. PMID- 28664622 TI - Subclinical atherosclerosis in low Framingham risk HIV patients. AB - BACKGROUND: Pathogenesis of atherosclerosis is complex, and differences between HIV-infected patients and general population cannot be completely explained by the higher prevalence of traditional cardiovascular risk factors. We aimed to analyse the association between inflammation and subclinical atherosclerosis in HIV patients with low Framingham risk score. MATERIALS AND METHODS: Case-control study. SETTING: Outpatient Infectious Diseases clinic in a university hospital. SUBJECTS: HIV-1-infected patients aged > 35 years receiving antiretroviral treatment with viral load < 50 copies/mL and Framingham risk score < 10%. EXCLUSION CRITERIA: inflammatory diseases; dyslipidaemia requiring statins; smoking > 5 cigarettes/day; diabetes; hypertension; vascular diseases. MAIN OUTCOME: subclinical atherosclerosis determined by ultrasonography: common carotid intima-media thickness greater than 0.8 mm or carotid plaque presence. Explanatory variables: ribosomal bacterial DNA (rDNA), sCD14, interleukin-6 (IL 6) and TNF-alpha. RESULTS: Eighty-four patients were included, 75% male, mean age 42 years and mean CD4+ cells 657 +/- 215/mm3 . Median Framingham risk score was 1% at 10 years (percentile 25-75: 0.5-4%). Eighteen patients (21%) had subclinical atherosclerosis; the associated factors were older age (P = 0.001), waist-hip ratio (P = 0.01), time from HIV diagnosis (P = 0.02), rDNA (P = 0.04) and IL-6 (P = 0.01). In multivariate analysis, OR for subclinical atherosclerosis was 7 (95% CI, 1.3-40, P = 0.02) and 9 (95% CI, 1.0-85, P = 0.04) for patients older than 44 years and IL-6 > 6.6 pg/mL, respectively. CONCLUSIONS: Well controlled HIV patients with low Framingham risk score have a high prevalence of subclinical carotid atherosclerosis, and the main risk factors are age and inflammation. These patients are not receiving primary prophylaxis for cardiovascular events according to current guidelines. PMID- 28664623 TI - Severe colloid milium presenting as papillomatosis cutis associated with vitiligo. PMID- 28664625 TI - A comparison between the Mini-Mental State Examination and Montreal Cognitive Assessment in assessing cognitive function in patients with diabetes-related dementia. PMID- 28664626 TI - Morphological Integration and Alternative Life History Strategies: A Case Study in a Facultatively Paedomorphic Newt. AB - Tetrapod limbs are serially homologous structures that represent a particularly interesting model for studies on morphological integration, i.e. the tendency of developmental systems to produce correlated variation. In newts, limbs develop at an early larval stage and grow continuously, including after the habitat transition from water to land following metamorphosis. However, aquatic and terrestrial environments impose different constraints and locomotor modes that could affect patterns of morphological integration and evolvability. We hypothesize that this would be the case for alternative heterochronic morphs in newts, i.e. aquatic paedomorphs that keep gills at the adult stage and adult metamorphs that are able to disperse on land. To this end, we analyzed patterns and strengths of correlations between homologous skeletal elements of the fore- and hindlimbs as well as among skeletal elements within limbs in both phenotypes in the alpine newt, Ichthyosaura alpestris. Our results showed that metamorphs and paedomorphs had similar, general patterns of limb integration. Partial correlations between homologous limb elements and within limb elements were higher in paedomorphs when compared to metamorphs. A decrease in partial correlation between homologous limb elements in metamorphs is accompanied with a higher evolvability of the terrestrial morph. All these results indicate that environmental demands shaped the patterns of morphological integration of alpine newt limbs and that the observed diversity in correlation structure could be related to a qualitative difference in the modes of locomotion between the morphs. PMID- 28664624 TI - Adherence to a lifestyle program for youth with type 2 diabetes and its association with treatment outcome in the TODAY clinical trial. AB - OBJECTIVE: To assess the association of proxies of behavioral adherence to the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) lifestyle program with changes in glycemic control and obesity in a multi-ethnic sample of youth with type 2 diabetes. METHODS: The TODAY clinical trial included an intensive lifestyle intervention to promote weight reduction. Adherence was assessed with measures of attendance at intervention sessions and rates of self monitoring of diet and physical activity by participants and their caregivers. The relation between participant characteristics and consistency of proxies of adherence were examined across 3 phases of intervention. RESULTS: A total of 234 TODAY youth were randomized to the lifestyle program. Overall rate of session attendance was approximately 60% of planned sessions. Participants with an adequate dose of session attendance (>=75% attended) did not differ from those who attended <75% of sessions in glycemic control, but did have significantly greater reductions in percent overweight compared with those who attended fewer than 75% of sessions. Rates of self-monitoring were low and additional analysis was not possible. CONCLUSIONS: Rates of session attendance were moderate in a lifestyle program for youth with type 2 diabetes, but levels of self-monitoring, considered a key lifestyle change behavior, were low. Glycemic control was not significantly associated with session attendance but reductions in percent overweight were. Given the salience of program attendance and self-monitoring to lifestyle weight management established in other populations, future research is needed to understand, develop, and promote strategies and interventions targeting weight loss to achieve improved glycemic control in youth diagnosed with type 2 diabetes. PMID- 28664627 TI - Cysteine proteases and wheat (Triticum aestivum L) under drought: A still greatly unexplored association. AB - Bread wheat (Triticum aestivum L.) provides about 19% of global dietary energy. Environmental stress, such as drought, affects wheat growth causing premature plant senescence and ultimately plant death. A plant response to drought is an increase in protease-mediated proteolysis with rapid degradation of proteins required for metabolic processes. Among the plant proteases that are increased in their activity following stress, cysteine proteases are the best characterized. Very little is known about particular wheat cysteine protease sequences, their expression and also localization. The current knowledge on wheat cysteine proteases belonging to the five clans (CA, CD, CE, CF and CP) is outlined, in particular their expression and possible function under drought. The first successes in establishing an annotated wheat genome database are further highlighted which has allowed more detailed mining of cysteine proteases. We also share our thoughts on future research directions considering the growing availability of genomic resources of this very important food crop. Finally, we also outline future application of developed knowledge in transgenic wheat plants for environmental stress protection and also as senescence markers to monitor wheat growth under environmental stress conditions. PMID- 28664628 TI - Medication prescribed by Australian paediatricians: Psychotropics predominate. AB - AIM: The aims of this study were to examine: (i) medications prescribed by Australian general and community paediatricians, (ii) predictors of prescribing (child age, gender) and (iii) changes in medication prescription between 2008 and 2013. METHODS: Two patient-level practice national audits were conducted by the Australian Paediatric Research Network in 2008 and 2013. General and community paediatricians in outpatient clinics and private practices recorded demographic data, diagnoses and medications prescribed for all patients seen over a 2-week period. RESULTS: In 2008, 199 paediatricians submitted data on 8345 consultations, and in 2013, 180 paediatricians submitted data on 7102 consultations. The most frequently prescribed drug class was psychotropics, prescribed for 46.8% of patients with developmental-behavioural/mental health (DB/MH) diagnoses in 2008 and 49.8% in 2013 (P = 0.015). Within this class, in 2013, the stimulants were prescribed in 35.3% of DB/MH consultations, antidepressants in 7.8% and antipsychotics in 5.6%. The next most frequently prescribed drug classes were laxatives (4.6% of all consultations in 2013), asthma preventers (4.1%), melatonin (3.7%), asthma relievers (2.6%) and proton pump inhibitors (2.2%), topical corticosteroids (1.8%) and antihistamines (1.4%). Medication prescription was predicted by patient age (P < 0.001, both audits) and male gender (P < 0.01, both audits) but not by measured prescriber variables. The rates of prescribing of psychotropics, melatonin, laxatives and enuresis medications increased between 2008 and 2013. CONCLUSIONS: Australian paediatricians prescribe mostly psychotropic medications, and the amount prescribed appears to be increasing. Paediatricians need good training and professional development in mental health diagnosis and management and the rational prescribing of psychotropic medications. PMID- 28664629 TI - Mixture model with multiple allocations for clustering spatially correlated observations in the analysis of ChIP-Seq data. AB - Model-based clustering is a technique widely used to group a collection of units into mutually exclusive groups. There are, however, situations in which an observation could in principle belong to more than one cluster. In the context of next-generation sequencing (NGS) experiments, for example, the signal observed in the data might be produced by two (or more) different biological processes operating together and a gene could participate in both (or all) of them. We propose a novel approach to cluster NGS discrete data, coming from a ChIP-Seq experiment, with a mixture model, allowing each unit to belong potentially to more than one group: these multiple allocation clusters can be flexibly defined via a function combining the features of the original groups without introducing new parameters. The formulation naturally gives rise to a 'zero-inflation group' in which values close to zero can be allocated, acting as a correction for the abundance of zeros that manifest in this type of data. We take into account the spatial dependency between observations, which is described through a latent conditional autoregressive process that can reflect different dependency patterns. We assess the performance of our model within a simulation environment and then we apply it to ChIP-seq real data. PMID- 28664630 TI - Cross-sectional association of coffee and caffeine consumption with sex hormone binding globulin in healthy nondiabetic women. AB - OBJECTIVE: Low sex hormone-binding globulin (SHBG) is a consistent risk factor for type 2 diabetes, particularly in women. Coffee consumption has been associated with a lower risk of type 2 diabetes, but its effects on SHBG are less known. DESIGN AND METHODS: This was a cross-sectional study of 2377 nondiabetic pre- and postmenopausal women from the E3N cohort study whose baseline SHBG was measured. Information on diet (including coffee and caffeine consumption), lifestyle and medical conditions was collected through questionnaires. The relationship between coffee and caffeine consumption and SHBG was modelled, with adjustment for covariates and stratification by body mass index (BMI) categories (< or >=25 kg/m2 ) and menopausal status. RESULTS: The mean age was 57.2+/-6.4 years and 61% of the 2377 women were postmenopausal. High coffee (>=3 cups/day) and caffeine (>=265 mg/day) intakes were associated with a reduced risk of being in the 1st quartile of the SHBG level distribution (<46.3 nmol/L) in a multivariate adjusted model (OR: 0.72 [95% CI: 0.52-1.01] and OR: 0.71 [95% CI: 0.53-0.95], respectively). No association was found between tea consumption and SHBG levels. In multivariate models stratified on BMI categories and menopausal status, associations were restricted to women with a BMI >=25 kg/m2 or being postmenopausal. The association with SHBG was consistently noted with consumption of both caffeinated coffee and caffeine, but not decaffeinated coffee. CONCLUSIONS: Consumption of high coffee and caffeine is associated with a reduced risk of low SHBG, an established risk marker for T2DM, which might contribute to the protective effects of coffee for type 2 diabetes. PMID- 28664631 TI - Avian gametologs as molecular tags for sex identification in birds of prey of Iran. AB - Global environmental change and rapid destruction of natural habitats necessitate the conservation of endangered and threatened birds of prey. Recently, molecular sex identification methods based on amplification of introns of chromodomain helicase DNA binding protein1 (CHD1) have provided valuable tools for ecological study and conservation breeding programs of birds. These methods employ a primer pair flanking an intron which varies considerably in length between the avian gametologs CHD1Z and CHD1W. Herein, we test the applicability of CHD1Z and CHD1W as universal tags for molecular sex identification in birds of prey of Iran. We showed successful sex identification in 22 species of birds of prey using feathers as the source of DNA. The results suggest that the regions of CHD1W and CHD1Z amplified in this study are conserved among most of Falconiformes, enabling accurate sex identification in birds of prey. PMID- 28664632 TI - On the Reaction of Naphthalene Diimides with Fluoride Ions: Acid/Base versus Redox Reactions. AB - The characterization of a naphthalene diimide (NDI) radical anion is presented. Its properties allow a reliable comparison point for other systems involving the NDI radical anion, such as systems claimed to perform the oxidation of the fluoride anion. In addition to reiterating the obvious thermodynamic objections to such an unlikely oxidation, we present several observations that show that the fluoride anion does not act as a one-electron reducing agent toward the NDI investigated in this work. PMID- 28664633 TI - Participation of children on the autism spectrum in home, school, and community. AB - BACKGROUND: Children on the autism spectrum participate less frequently, and in a narrower range of activities, than their nonautistic peers, but little is known about exact participation patterns across contexts or how this is perceived by caregivers. This study aimed to document patterns of participation and caregiver views with regard to frequency and intensity of activities. METHOD: Caregivers of children on the spectrum aged 5 (n = 90) and 9-10 years (n = 128) completed the Participation and Environment Measure for Children and Youth for home, school, and community. Caregivers reported on frequency of child's participation, level of involvement, and caregivers' desire for change in participation patterns. RESULTS: Item-level analyses revealed similar patterns of participation across home, school, and community for both cohorts with some small age-appropriate differences. Caregivers generally desired increased diversity, frequency, and involvement in activities but a decreased use of electronics (computers, games, TV, and DVDs). CONCLUSION: The possibility of autism-specific participation patterns could inform future interventions aimed at enhancing social inclusion. This warrants further investigation through multiinformant designs that seek the perspectives of the child and caregivers. PMID- 28664634 TI - Comparable glycemic outcomes for pediatric type 1 diabetes patients in metropolitan and non-metropolitan regions of Western Australia: A population based study. AB - BACKGROUND: Pediatric patients diagnosed with type 1 diabetes (T1D) in Western Australia (WA) are managed by a single, specialist multidisciplinary diabetes service based at a central tertiary hospital in the capital city, Perth, which provides outreach care in regional centers. OBJECTIVE: To investigate the hypothesis that outcomes for a contemporary, population-based pediatric T1D cohort, managed by a single tertiary service are similar for metropolitan and non metropolitan patients using this model of care. To confirm that the cohort is indeed population based, a secondary aim of the study was to determine the case ascertainment of the Western Australian Children's Diabetes Database (WACDD). METHODS: Data for all T1D patients aged <18 years, who attended the diabetes clinics (metropolitan and non-metropolitan), at least once in 2014, were extracted from the WACDD and outcomes including HbA1c and severe hypoglycemia (SH) rates analyzed. RESULTS: In 2014, a total of 1017 patients (492 females, 525 males) attended the diabetes clinics (54% metropolitan and 46% non-metropolitan). After adjusting for age, sex, diabetes duration, and insulin regimen, region of clinic was not a significant predictor of mean HbA1c or SH rate. The case ascertainment of the WACDD was estimated to be 99.9% complete for children diagnosed with T1D aged <15 years between 2002 and 2012. CONCLUSIONS: This study reports similar glycemic outcomes for patients attending diabetes clinics in metropolitan and non-metropolitan areas of WA, suggesting that a model of care provided as outreach from a specialized diabetes service is effective in achieving equitable glycemic outcomes. PMID- 28664635 TI - Green Energetic Nitrogen-Rich Salts of 1,1'-Dinitramino-5,5'-bistetrazolate. AB - A series of nitrogen-rich energetic salts of 1,1'-dinitramino-5,5'-bistetrazolate (DNABT) guanidinium (1), aminoguanidinium (2), diaminoguanidinium (3), triaminoguanidinium (4), diaminouronium (5), 3,4-diamino-1,2,4-triazolium (6), and ethylenediammonium (7) was synthesized by a metathesis strategy and characterized by elemental analysis, mass spectrometry, and IR spectroscopy as well as single-crystal X-ray diffraction and differential scanning calorimetry (DSC). The natural bond orbitals (NBOs) and electrostatic potentials (ESPs) were further computed for a better understanding of the structures of the DNABT molecule. The heats of formation were calculated based on the Born-Haber energy cycle. The detonation parameters were evaluated by using the EXPLO5 program, and the sensitivities were measured according to BAM standers. These new salts exhibit highly positive heats of formation (407.0-1377.9 kJ mol-1 ) and good thermal stabilities (180-211 degrees C). Most of these compounds possess detonation velocities comparable to RDX and acceptable detonation pressures. The high volumes of explosion gases of the salts 3 and 4 (921 and 933 L kg-1 , respectively) further support their power as explosives. The enhancing performances, the fact of being free of metals, and the more moderate sensitivities than K2 DNABT, suggest that the salts 4 (D=8851 m s-1 , P=29.0 GPa), 5 (D=9053 m s-1 , P=32.3 GPa), and 6 (D=8835 m s-1 , P=30.2 GPa) might be potential environmentally friendly energetic materials. PMID- 28664637 TI - Author's response: Endoscopic biodegradable biliary stents in the treatment of benign biliary strictures: First report of clinical use in patients. PMID- 28664638 TI - The roles of the diffusion-weighted imaging in orbital masses. AB - INTRODUCTION: Causes of orbital masses can be either benign or malignant. An MRI with diffusion-weighted imaging (DWI) may be helpful to differentiate causes of orbital masses. This study aimed to evaluate the diagnostic properties of an apparent diffusion coefficient (ADC) in orbital masses. METHODS: We retrospectively reviewed patients with orbital masses who underwent DWI and had histopathological results. Orbital lesions were categorized as benign or malignant and compared with respect to the ADC and ADC ratio. A receiver operating characteristic curve (ROC) was plotted to evaluate the sensitivity and specificity of the ADC and ADC ratio threshold. RESULTS: The mean age of all 42 patients in this study was 36.31 years (S.D. 22.12) and 26 of the patients were male (61.9%). The malignant orbital masses accounted for 43% (18 patients). The most common cell type was meningioma (10 patients; 23.8%). There was no statistical difference between the ADC values of benign and malignant tumours (1.18 vs 0.99 *10-3 mm2 /s; P-value 0.200). The myxoid tumours had significantly higher ADC values than the non-myxoid (1.58 vs 0.99; P-value 0.008) tumours. Non metastatic non-myxoid tumours also had significantly lower ADC values than metastatic non-myxoid tumours (0.73 vs 1.32; P-values 0.006). The ADC cut-off point of greater than or equal to 0.95 * 10-3 mm2 /s was given a sensitivity of 87.50% for myxoid orbital masses, while the cut-off point of greater than or equal to 1.01 * 10-3 mm2 /s was given a sensitivity of 80.00% for metastatic, non-myxoid malignant orbital masses. CONCLUSIONS: Benign and malignant orbital masses cannot be distinguished by using the ADC values. However, the ADC values were useful in differentiating between myxoid vs non-myxoid orbital masses and metastatic non-myxoid vs non-metastatic non-myxoid orbital masses. PMID- 28664636 TI - Chemogenetic inhibition reveals midline thalamic nuclei and thalamo-accumbens projections mediate cocaine-seeking in rats. AB - Drug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical-basal ganglia-thalamic circuit. However, our understanding of how this circuit regulates drug-seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical-basal ganglia-thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, Gi/o -coupled DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a subset of the midline thalamic nuclei or in midline thalamic nuclei neurons projecting to either the nucleus accumbens or the amygdala. We examined the effect of transiently decreasing activity of these neuronal populations on cue-induced and cocaine-primed reinstatement of cocaine-seeking. Reducing activity of midline thalamic nuclei neurons attenuated both cue-induced and cocaine-primed reinstatement, but had no effect on cue-induced reinstatement of sucrose-seeking or locomotor activity. Interestingly, attenuating activity of efferent projections from the anterior portion of midline thalamic nuclei to the nucleus accumbens blocked cocaine-primed reinstatement but enhanced cue-induced reinstatement. Decreasing activity of efferent projections from either the posterior midline thalamic nuclei to the nucleus accumbens or the midline thalamic nuclei to amygdala had no effect. These results reveal a novel contribution of subsets of midline thalamic nuclei neurons in drug-seeking behaviors and suggest that modulation of midline thalamic nuclei activity may be a promising therapeutic target for preventing relapse. PMID- 28664639 TI - Increased efficacy and extended shelf life of spinosad formulated in phagostimulant granules against Spodoptera frugiperda. AB - BACKGROUND: Spinosad is recommended for control of Spodoptera frugiperda (J.E. Smith) larvae; its application with phagostimulants may reduce the quantity of active ingredient required for effective pest control. Spinosad (Tracer(r)) was formulated in maize flour matrix granules and three field tests compared 10-100 ppm a.i. granules (equivalent to 0.24-2.4 g a.i. ha-1 ) with Tracer as an aqueous spray (200 ppm a.i.; 60 g a.i. ha-1 ), and the recommended application rates of Bacillus thuringiensis, a chemical and an untreated controls were performed. RESULTS: The 100 ppm spinosad granules resulted in similar S. frugiperda mortality compared with the chemical treatments in all three field trials, and resulted in a significantly higher maize grain yield compared with unformulated and control treatments (4141 vs. 2857 and 2407 kg ha-1 , respectively) that was similar to the chemical treatment (3778 kg ha-1 ). Bioassays of granules stored at room and cold temperatures showed that after 5 years, ~ 70% of the original activity remained (OAR) of spinosad when formulated as granules. Nevertheless, after 9 years, efficacy was reduced (26.2% and 48.5% OAR) at both room (25 degrees C) and refrigerated temperatures (4 degrees C). CONCLUSION: Spinosad, in the granular phagostimulant formulations evaluated in this study, had advantages measured as high efficacy and long shelf life. (c) 2017 Society of Chemical Industry. PMID- 28664640 TI - Diazirines as Potential Molecular Imaging Tags: Probing the Requirements for Efficient and Long-Lived SABRE-Induced Hyperpolarization. AB - Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, 15 N2 -diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a 15 N2 -diazirine containing choline derivative demonstrates the potential of 15 N2 -diazirines as molecular imaging tags for biomedical applications. PMID- 28664641 TI - Comparison of online and paper survey participation rates in a child health survey by parents of secondary school students. PMID- 28664642 TI - Unexpected pharmacokinetics of recombinant porcine factor VIII in a patient with acquired factor VIII deficiency and spontaneous epidural haematoma. PMID- 28664643 TI - A sporadic case of Creutzfeldt-Jakob disease showing unilateral hemispheric involvement on magnetic resonance imaging. PMID- 28664645 TI - Treatment of peritoneal carcinomatosis with hyperthermic intraperitoneal chemotherapy in colorectal cancer. AB - The peritoneum is the second most common site of metastasis after the liver and the only site of metastatic disease in approximately 25% of patients with colorectal cancer (CRC). In the past, peritoneal carcinomatosis in CRC was thought to be equivalent to distant metastasis; however, the transcoelomic spread of malignant cells is an acknowledged alternative pathway. Metastasectomy with curative intent is well accepted in patients with liver metastasis in CRC despite the paucity of randomized trials. Therefore, there is rationale for local treatment with peritonectomy to eliminate macroscopic disease, followed by hyperthermic intraperitoneal chemotherapy to destroy any residual free tumour cells within the peritoneal cavity. The aim of this paper is to summarize the current evidence for cytoreduction and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis in CRC. PMID- 28664644 TI - Barriers to sexually transmitted infection testing in New Zealand: a qualitative study. AB - OBJECTIVE: To investigate the barriers that prevent or delay people seeking a sexually transmitted infection (STI) test. METHODS: Qualitative in-depth interviews were conducted with 24 university students, who are a group prone to behaviours putting them at risk of STIs, to understand the factors that had prevented or delayed them from going for an STI test in the past. Resulting data were thematically analysed employing a qualitative content analysis method, and a final set of themes identified. RESULTS: There were three main types of barrier to STI testing. These were: personal (underestimating risk, perceiving STIs as not serious, fear of invasive procedure, self-consciousness in genital examination and being too busy); structural (financial cost of test and clinician attributes and attitude); and social (concern of being stigmatised). Conclusions and implications for public health: These data will help health providers and policy-makers provide services that minimise barriers and develop effective strategies for improving STI testing rates. The results of this study suggest a holistic approach to encouraging testing is required, which includes addressing personal beliefs, working with healthcare providers to minimise structural barriers and developing initiatives to change social views about STIs. PMID- 28664646 TI - Psychological interventions on a specialist Early Intervention Inpatient Unit: An opportunity to engage? AB - BACKGROUND: This study explored engagement with psychology on a specialist early intervention psychosis inpatient unit, with a focus on whether demographics or admission factors impacted on engagement. METHOD: This was a retrospective cohort study using data extracted from patient notes for all service users who were admitted to an Early Intervention ward during a specified 6-month period. One hundred and one records were identified. RESULTS: Sixty-eight (67.3%) of the service users engaged in psychological therapy, 45.6% (n = 47) attended psychology groups and 58.4% (n = 59) engaged in individual psychology sessions. Service users admitted to the ward voluntarily were more likely to engage in individual psychology sessions in comparison to those admitted under section of the mental health act (beta = -0.270, P < .005). Length of admission predicted engagement with groups (beta = 0.38, P < .001) and individual psychology sessions (beta = 0.408, P < .001). Ethnicity, gender and number of admissions did not predict engagement in psychology. CONCLUSIONS: Psychological interventions are acceptable on a specialist early intervention psychosis inpatient ward and offer an opportunity to engage service users. Engagement was not predicted by demographic factors typically seen in community settings. Implications arising from these differences are discussed. PMID- 28664647 TI - Intermolecular Formation of Two C-C Bonds across Olefins Enabled by Boron-Based Relay Strategies. AB - Smooth handoff in the relay: Vinyl boronates enable the direct addition of nucleophilic and electrophilic or nucleophilic and radical-generating carbon reagents across the double bond with retention of the valuable boronate group. The key to the success of this difficult twofold C-C bond-formation strategy is the initial relay of the nucleophilic addition to boron and the rearrangement of a 1,2-metalate rearrangement, shuttling it to the carbon atom. PMID- 28664649 TI - A Dimeric NHC-Silicon Monotelluride: Synthesis, Isomerization, and Reactivity. AB - The reaction of the NHC-disilicon(0) complex [(IAr )Si=Si(IAr )] (1, IAr =:C{N(Ar)C(H)}2 , Ar=2,6-iPr2 C6 H3 ) with two equiv of elemental Te in toluene at room temperature for three days afforded a mixture of the first dimeric NHC silicon monotelluride [(IAr )Si=Te]2 (2) and its isomeric complex [(IAr )Si(MU Te)Si(IAr )=Te] (3). When the same reaction was performed for ten days, only 3 was isolated from the reaction mixture. Compound 1 reacted with four equiv of elemental Te in toluene for four weeks, which proceeded through the formation of 2, 3 and the NHC-disilicon tritelluride complex [{(IAr )Si(=Te)}2 Te] (5-Te), to form the dimeric NHC-silicon ditelluride [(IAr )Si(=Te)(MU-Te)]2 (4). The reactions are in line with theoretical mechanistic studies for the formation of 4. Compound 3 reacted with one equiv of elemental sulfur in toluene to form the first NHC-disilicon sulfur ditelluride complex [{(IAr )Si(=Te)}2 S] (5-S). PMID- 28664648 TI - Mental health nurses' use of Twitter for professional purposes during conference participation using #acmhn2016. AB - Scholars across different disciplines use Twitter to promote research and to communicate with society. Most conferences nowadays have their unique hashtag in which participants can communicate in real time. Previous research has reported on conference participants' use of Twitter, but no such studies are available in the field of mental health nursing. Thus, the explicit aim of the present study was to examine conference participants' use of Twitter during the 42nd International Mental Health Nursing Conference. Freely-accessible data were mined via a social media platform under the hashtag #acmhn2016. The total dataset consisted of 1973 tweets, and was analysed with descriptive statistics and a directed content analysis. The results demonstrated that 37% of the tweets were original posts, and 63% were engagements. In total, 184 individual accounts engaged in Twitter during the conference, and 16.4 tweets were posted hourly. Most tweets were categorized as conference/session-related content, but Twitter was also used for socializing with other participants. The most frequently-used words mirror a clear connection to a person-centred approach, and deviate from the biomedical terminology. However, not all of the conference participants engaged on Twitter, and might thereby risk being excluded from this backchannel. PMID- 28664650 TI - Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine-to-glutamate ratio and myo-inositol concentration in the mouse frontal cortex. AB - Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine-to-glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, p < 0.05) and larger Gln/Glu (+7.6%, p < 0.05), relative to those in group housing. Furthermore, glutathione deficiency caused a reduction in whole brain volume and enlargement of ventricles, but social isolation had no effect on these parameters. We conclude that social isolation caused neurochemical alterations that may add to those associated to impaired glutathione synthesis. PMID- 28664651 TI - Refining Stable Oxygen and Hydrogen Isoscapes for the Identification of Human Remains in Mississippi. AB - Isoscape refinement is an essential component for accurately predicting region-of origin in forensic investigations involving isotope analysis of unidentified human remains. Stable oxygen (delta18 O) and hydrogen (delta2 H) isotopes were measured from 57 tap water samples collected across Mississippi to model refined isoscapes for the state. A tap water conversion equation, delta18 Otw =1.64 delta18 Op-31.35, was developed for the southeastern USA to test the prediction accuracy of the delta18 Otw isoscape using individuals with known residential histories. A local Mississippi resident (USAFA-134) was assigned with 90% probability to the correct region-of-origin reported by the participant. Assignments for Georgia residents (USAFA-118 and USAFA-205) had variable results, predicting USAFA-118 from Mississippi and USAFA-205 as a nonlocal resident. Stable isotope values often overlap geographically and a multi-isotope approach should be used when narrowing region(s)-of-origin(s). This study demonstrates the utility of refining isoscapes and the importance of tissue calibration in prediction assignments of human remains. PMID- 28664652 TI - Laparoscopic ileopexy for afferent limb syndrome after ileal pouch-anal anastomosis. AB - Afferent limb syndrome (ALS) is caused by an obstruction of the afferent intestinal limb after ileal pouch-anal anastomosis. Here, we describe the first case of ALS to be successfully treated by a laparoscopic approach. A 27-year-old man underwent ileal pouch-anal anastomosis for ulcerative colitis. He was subsequently diagnosed with ALS and underwent ileopexy with laparotomy at 33 years old. Then, 21 months after the first ileopexy, he underwent laparoscopic ileopexy for ALS recurrence. The operative findings revealed a shortened fixed portion of the afferent limb adhering to the right pelvic retroperitoneum, which was regarded as the cause of the acute angulation. The portion of the afferent limb fixed to the abdominal wall was extended under laparoscopic visualization by suturing above the level of the iliac crest. At the 12-month follow-up, the patient remained free of symptoms of obstruction. Laparoscopic ileopexy should be the procedure of choice for patients with ALS. PMID- 28664653 TI - Care as narrative practice in the context of long-term care: Theoretical considerations. AB - AIMS AND OBJECTIVES: In this article, we introduce care itself as a narrative practice. We emphasise that all interactions between care providers and older adults in long-term care settings are narrative in nature and foreground experience. BACKGROUND: Every person consists of innumerable stories based on experiences over time. Some experiences can be recalled and told as narratives, while others are inscribed into our bodies; they are embodied. These narratives shape who we are and are becoming, and influence how care providers experience and provide nursing care in long-term care settings. MAIN CONTRIBUTIONS OF THE THEORETICAL CONSIDERATIONS: We highlight the importance of stories to narrative identities and focus on the embodied act of coconstructing new stories in interaction. We emphasise the idea that care in gerontological nursing would benefit from acknowledging and fostering embodied narratives in a systematic way with older adults. CONCLUSIONS: To foster, elicit, and coconstruct evolving and forward-looking narratives based on older adults' verbal and embodied narratives is essential for the quality of care in long-term settings. Care providers must be aware that they are co-authors of older adults' continuous storying and restorying of their lives. IMPLICATIONS FOR PRACTICE: To recognise that both residents and care providers are narrative beings shift the current culture of care away from rationalised and emotionally devoid consequences of care. Understanding the theoretical underpinnings of care itself as narrative practice is a first step in developing care practices that place relationships between residents and care providers at the centre of practice. There is a need for the implementation of strategies to think and work narratively in long-term care settings. PMID- 28664654 TI - Acne keloidalis nuchae: risk factors and associated disorders - a retrospective study. AB - BACKGROUND: Acne keloidalis nuchae (AKN) is a chronic scarring folliculitis which usually occurs in young adult males of African descent. Studies have suggested that AKN may be associated with other dermatologic conditions and even general medical disorders. The aim of this study was to identify cutaneous and extracutaneous associated disorders and to examine risk factors in our population for developing AKN. METHODS: The study was a retrospective, descriptive, and analytical study conducted at the Dermatology Outpatient department of the University Hospital of the West Indies. Data were obtained from the medical records of patients diagnosed over a 15-year period (2000-2014). RESULTS: There were 1031 new patients during the study period. Of these, 43 (4.2%) had AKN. The male to female ratio for AKN was approximately 7:1. Pseudofolliculitis barbae was associated with keloidal plaques on the scalp (OR = 6.22, P = 0.036). Also, when the duration of AKN was divided into two groups (0-5 years and greater than 5 years), there was an association between keloidal plaques and duration of greater than 5 years (OR = 7.5, P = 0.032). However, when the odds ratio was adjusted, only the duration of AKN remained significantly associated with keloidal plaques (OR = 7.08, P = 0.047). Chronic scalp folliculitis (P = 0.001) and the presence of any component disease of the metabolic syndrome (OR = 14, P = 0.008) and specifically hypertension (OR = 6.75, P = 0.036) were significantly associated with the extension of the lesions beyond the nape and occipital scalp. CONCLUSIONS: Pseudofolliculitis barbae, chronic scalp folliculitis, and aspects of the metabolic syndrome may be associated with acne keloidalis nuchae. PMID- 28664655 TI - Commentary on: "Influence of OATP1B1 Function on the Disposition of Sorafenib beta-D-Glucuronide". PMID- 28664656 TI - Combined laparoscopic resection of intestinal stenosis of Garre and open preperitoneal mesh repair for irreducible femoral hernia. AB - Intestinal stenosis of Garre is a rare condition caused by a benign fibrous bowel stricture due to complicated strangulated hernia. We present a case of intestinal stenosis of Garre associated with right femoral hernia in an 85-year-old woman. The patient visited our hospital with a 2-day history of vomiting. Her abdomen was slightly distended. A mass was palpated in the right groin region. CT showed prolapse of the small intestine in the right groin region. An incarcerated right femoral hernia was diagnosed and manually reduced. Thirteen days later, the patient complained of abdominal pain. CT revealed dilatation and caliber change in part of the small bowel, indicating a small bowel obstruction due to intestinal stenosis of Garre. Laparoscopic release of the bowel obstruction and femoral hernia repair via an anterior approach were performed simultaneously. No recurrence of femoral hernia or bowel obstruction was noted at the 15-month follow-up. PMID- 28664657 TI - Refractory venous leg ulcers: observational evaluation of innovative new technology. AB - This observational case series reports the evaluation of a novel neuromuscular electrical stimulation device (gekoTM) that stimulates the common peroneal nerve at the fibular head as an adjunctive therapy in patients with non-healing venous leg ulcers. The aim was to evaluate and determine if the gekoTM device was effective in this population and should be added to the medical supply formulary. Patients whose wounds had failed to heal within 24 weeks of standard therapy were identified in two community settings in Ontario. A total of 11 patients consented to the evaluation with a combined 107-year history of recalcitrant leg ulcers. Although the pre-gekoTM healing rate was unknown, all ulcers were considered non healing. With gekoTM, the average weekly percentage reduction in surface area for all patients was 4.5% and for the six adherent to gekoTM and best practices 7.0%. By comparison, the average weekly percentage reduction for measurable wounds in the five non-adherent patients was 1.8%. Requirements for success appear to include an arterial status adequate for healing, effective and prompt management of wound infections and adherence to the treatment schedule. The gekoTM device has been added to the medical supply formulary in one centre and is pending in the other. PMID- 28664658 TI - Effects of aspirin dose escalation on platelet function and urinary thromboxane and prostacyclin levels in normal dogs. AB - Established "low" aspirin dosages inconsistently inhibit platelet function in dogs. Higher aspirin dosages consistently inhibit platelet function, but are associated with adverse effects. The objectives of this study were to use an escalation in dosage to determine the lowest aspirin dosage that consistently inhibited platelet function without inhibiting prostacyclin synthesis. Eight dogs were treated with five aspirin dosages: 0.5 mg/kg q24h, 1 mg/kg q24h, 2 mg/kg q24h, 4 mg/kg q24h and 10 mg/kg q12h for 7 days. Utilizing aggregometry and a whole-blood platelet function analyzer (PFA-100), platelet function was evaluated before and after treatment. Urine 11-dehydro-thromboxane-B2 (11-dTXB2 ) and 6 keto-prostaglandin-F1alpha (6-keto-PGF1alpha ), were measured. Compared to pretreatment, there were significant post-treatment decreases in the maximum aggregometry amplitude and increases in the PFA-100 closure times for all dosages expect 0.5 mg/kg q24h. There was no difference in amplitude or closure time among the 2 mg/kg q24h, 4 mg/kg q24h, and 10 mg/kg q12h dosages. Compared to pretreatment values, there was a significant decrease in urinary 11-dTXB2 -to creatinine and 6-keto-PGF1alpha -to-creatinine ratios, but there was no dose dependent decrease for either metabolite. An aspirin dosage of 2 mg/kg q24h consistently inhibits platelet function without decreasing prostacyclin synthesis significantly more than lower aspirin dosages. PMID- 28664659 TI - A case of cutaneous metastatic lung cancer difficult to distinguish from malignant nodular hidradenoma. PMID- 28664660 TI - Unwarranted claims of drug efficacy in pharmaceutical sales visits: are drugs approved on the basis of surrogate outcomes promoted appropriately? AB - AIMS: This study compares physicians' recall of the claims of benefits on cardiovascular disease and diabetes made by pharmaceutical sales representatives for drugs approved on the basis of a surrogate outcome, i.e., an off-label claim, compared with those approved on the basis of a serious morbidity or mortality (clinical) outcome. METHODS: Physicians in primary care practices in Montreal, Vancouver, Sacramento and Toulouse, who saw sales representatives as part of their usual practice and served a non-referral population, were contacted in blocks of 25 from a randomized list of all physicians practising in the relevant metropolitan area. We compared how frequently physicians reported that sales reps made claims of serious morbidity or mortality (clinically meaningful) benefits for drugs approved on the basis of surrogate outcomes vs. drugs approved on the basis of clinical outcomes. RESULTS: There were 448 promotions for 58 unique brand name cardiovascular and diabetes drugs. Claims of clinically meaningful benefit were reported in 156 (45%) of the 347 promotions for surrogate outcome drugs, constituting unwarranted efficacy claims, i.e., off-label promotion. Claims of clinical benefit were reported in 72 of the 101 promotions (71%) for drugs approved on the basis of clinical outcomes, adjusted OR = 0.3 (95% CI 0.2, 0.6), P < 0.001. CONCLUSIONS: Claims of efficacy made in sales visit promotions for drugs approved only on the basis of surrogate outcomes extended beyond the regulator-approved efficacy information for the product in almost half of promotions. Unapproved claims of drug efficacy constitute a form of off-label promotion and merit greater attention from regulators. PMID- 28664661 TI - Randomized controlled trial comparing submucosal endoscopy with mucosal resection and endoscopic submucosal dissection in the esophagus and stomach: Animal study. AB - BACKGROUND AND AIM: In Western countries, endoscopic submucosal dissection (ESD) has not prevailed as a result of training problems and a target patient population. We have previously reported a hybrid ESD technique, submucosal endoscopy with mucosal resection (SEMR), in which the submucosal dissection is carried out chiefly by blunt balloon dissection. We have also reported successful application in the porcine colon. In the present study, we compared the safety and efficacy of SEMR with ESD in the porcine esophagus and stomach. METHODS: SEMR and ESD were carried out in eight domestic pigs under general anesthesia. Resection sites were marked by circumferential coagulation. After circumferential ESD knife mucosal incision, submucosal fluid cushion (SFC) was created. In the SEMR group, the balloon catheter was inserted deep into the SFC. The balloon was then inflated and pulled back toward the endoscope tip repeatedly, altering the direction, to disrupt the submucosa. Residual strands were cut with an IT-knife. En bloc resection rates, procedure times, complications and dissection difficulty scales (DDS) were recorded prospectively. DDS were rated using a visual analog scale. RESULTS: Thirty-two resections (8 SEMR/8 ESD in the esophagus; 8 SEMR/8 ESD in the stomach) were done with no major adverse events. There was no statistical difference between the two techniques in either location in the above categories measured. CONCLUSIONS: SEMR and traditional ESD are comparable techniques in safety and effectiveness when carried out in the esophagus and stomach. SEMR may serve as a more appealing technical option for endoscopists who are unable to sustain a traditional ESD practice volume. PMID- 28664662 TI - Functional joint model for longitudinal and time-to-event data: an application to Alzheimer's disease. AB - Functional data are increasingly collected in public health and medical studies to better understand many complex diseases. Besides the functional data, other clinical measures are often collected repeatedly. Investigating the association between these longitudinal data and time to a survival event is of great interest to these studies. In this article, we develop a functional joint model (FJM) to account for functional predictors in both longitudinal and survival submodels in the joint modeling framework. The parameters of FJM are estimated in a maximum likelihood framework via expectation maximization algorithm. The proposed FJM provides a flexible framework to incorporate many features both in joint modeling of longitudinal and survival data and in functional data analysis. The FJM is evaluated by a simulation study and is applied to the Alzheimer's Disease Neuroimaging Initiative study, a motivating clinical study testing whether serial brain imaging, clinical, and neuropsychological assessments can be combined to measure the progression of Alzheimer's disease. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28664663 TI - Skin cancer has a large impact on our public hospitals but prevention programs continue to demonstrate strong economic credentials. AB - OBJECTIVES: While skin cancer is still the most common cancer in Australia, important information gaps remain. This paper addresses two gaps: i) the cost impact on public hospitals; and ii) an up-to-date assessment of economic credentials for prevention. METHODS: A prevalence-based cost approach was undertaken in public hospitals in Victoria. Costs were estimated for inpatient admissions, using State service statistics, and outpatient services based on attendance at three hospitals in 2012-13. Cost-effectiveness for prevention was estimated from 'observed vs expected' analysis, together with program expenditure data. RESULTS: Combining inpatient and outpatient costs, total annual costs for Victoria were $48 million to $56 million. The SunSmart program is estimated to have prevented more than 43,000 skin cancers between 1988 and 2010, a net cost saving of $92 million. Skin cancer treatment in public hospitals ($9.20~$10.39 per head/year) was 30-times current public funding in skin cancer prevention ($0.37 per head/year). CONCLUSIONS: At about $50 million per year for hospitals in Victoria alone, the cost burden of a largely preventable disease is substantial. Skin cancer prevention remains highly cost-effective, yet underfunded. Implications for public health: Increased funding for skin cancer prevention must be kept high on the public health agenda. Hospitals would also benefit from being able to redirect resources to non-preventable conditions. PMID- 28664664 TI - Paediatricians should encourage the parents of children with special healthcare needs to disclose their use of complementary and alternative medicine. PMID- 28664665 TI - Imaging the right heart pulmonary circulation unit: Insights from advanced ultrasound techniques. AB - The right heart pulmonary circulation unit (RH-PCU) is a key determinant of prognosis in several cardiorespiratory diseases. Although right heart catheterization is considered the gold standard for pulmonary hemodynamic assessment, a comprehensive cardiovascular ultrasound approach is an essential step in the diagnostic-prognostic clinical pathway of patients with suspect or overt pulmonary hypertension. The exponential development of advanced ultrasound techniques (strain, 3-dimensional echocardiography and lung ultrasound) has led to new insights into the evaluation of RH-PCU structure and function, overcoming some limitations of standard Doppler echocardiography. In the near future, exercise Doppler echocardiography may become a useful technique for detecting a latent stage of pulmonary hypertension and for evaluating right ventricular contractile reserve. PMID- 28664666 TI - Judicial intervention in alcohol regulation: an empirical legal analysis. AB - OBJECTIVE: While governments draft law and policy to promote public health, it is through cases put before the judiciary that the implementation of law can be challenged and where its practical implications are typically determined. In this paper, we examine the role of court judgements on efforts in Australia to regulate the harmful use of alcohol. METHODS: Australian case law (2010 to June 2015) involving the judicial review of administrative decisions relating to development applications or liquor licences for retail liquor outlets (bottle shops), hotels, pubs and clubs was identified using a case law database (WestLaw AU). Data were extracted and analysed using standard systematic review techniques. RESULTS: A total of 44 cases were included in the analysis. Of these, 90% involved appeals brought by industry actors against local or state government stakeholders seeking to reject applications for development applications and liquor licences. The proportion of judicial decisions resulting in outcomes in favour of industry was 77%. CONCLUSIONS: Public health research evidence appeared to have little or no influence, as there is no requirement for legislation to consider public health benefit. Implications for public health: A requirement that the impact on public health is considered in legislation will help to offset its strong pro-competition emphasis, which in turn has strongly influenced judicial decision making in this area. PMID- 28664667 TI - Pitavastatin up-regulates eNOS production by suppressing miR-155 expression in lipopolysaccharide-stimulated human umbilical vein endothelial cells. AB - AIM: Pitavastatin (Pit) has been proved to efficiently inhibit the onset and progression of atherosclerosis. However, the mechanism by which Pit exerts nonlipid-related effects, such as antiinflammatory actions, is not quite clear. Our study aimed at investigating the effect of Pit on the expression of endothelial NO synthase (eNOS) and miR-155 in LPS-stimulated HUVECs to reveal the antiinflammatory mechanism of pitavastatin. METHODS: HUVECs were isolated from newborn umbilical cords and used in the experiments at passages 2-5. Cells were treated with LPS (0.05, 0.1, 1 MUg/L) or LPS (0.1 MUg/L)+Pit (0.01, 0.1, 1 MUmol/L), untreated cells were used as control. For LPS+Pit induction, cells were firstly incubated with Pit for 1 hour before coincubation with LPS for 24 hours. eNOS mRNA and miR-155 were detected by RT-PCR, and Western blotting was used to detect protein expression of eNOS. RESULTS: Treatment of HUVECs with LPS enhanced the expression of miR-155 and reduced the expression of eNOS in mRNA and protein level in a dose-dependent manner as revealed by RT-PCR and Western blotting, respectively. Pitavastatin ameliorated LPS-induced endothelial dysfunction through upregulation of eNOS expression and downregulation of miR-155 expression. CONCLUSION: Pitavastatin increases eNOS expression and inhibits of LPS-induced miR-155 expression. PMID- 28664668 TI - Human papillomavirus-related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum. AB - AIMS: Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype and molecular testing to identify potentially helpful features in distinguishing it from classic adenoid cystic carcinoma (AdCC). METHODS AND RESULTS: We retrospectively collected five HPV related carcinomas with adenoid cystic-like features and 14 AdCCs of the sinonasal tract. All histological slides were retrieved for morphological evaluation. As comparing with AdCC, HPV-related carcinomas with adenoid cystic like features were associated with squamous dysplasia of surface epithelium (80% versus 0%, P < 0.01) and the presence of a solid growth pattern (100% versus 29%, P = 0.01), but less densely hyalinized tumour stroma (20% versus 86%, P = 0.02). Squamous differentiation in the invasive tumour was seen in three HPV-related carcinomas with adenoid cystic-like features, two of them showing abrupt keratinization and one with scattered non-keratinizing squamous nests. Diffuse p16 staining in >=75% of tumour cells was noted in all HPV-related carcinomas with adenoid cystic-like features but in only one AdCC (100% versus 7%, P < 0.01). High-risk HPV testing gave positive results in all HPV-related carcinomas with adenoid cystic-like features (four associated with type 33 and one associated with type 16) but not in AdCCs. MYB rearrangement was tested in four HPV-related carcinomas with adenoid cystic-like features, and all were negative. CONCLUSIONS: This study has further clarified the histological spectrum of this tumour type, and reports the first HPV type 16-related case. Diffuse p16 staining followed by HPV molecular testing is useful in distinguishing HPV-related carcinomas with adenoid cystic features from classic AdCCs. PMID- 28664669 TI - Does three-dimensional transesophageal echocardiography provide incremental value in percutaneous closure of ascending aortic pseudoaneurysm? AB - Ascending aortic pseudoaneurysms (AO PSAs), if left untreated, are complicated by a high rate of rupture resulting in significant morbidity and mortality. New transcatheter modalities have emerged as acceptable surgical alternatives for their management. We present a case of an ascending aortic PSA in which intraoperative two- and three-dimensional transesophageal echocardiography (2DTEE and 3DTEE) provided a comprehensive assessment of the PSA in pre- and postclosure settings. PMID- 28664671 TI - Cobalt Phosphonates as Precatalysts for Water Oxidation: Role of Pore Size in Catalysis. AB - We report a simple approach for the synthesis of cobalt phosphonate (CoOP) nanocages with two distinct types of pore diameters by utilizing a novel tetra constituent assembly of CoCl2 ?6 H2 O, nitrilotris(methylene)triphosphonic acid (NMPA), F127 surfactant, and polyvinyl alcohol (PVA, co-surfactant). Transmission electron microscopy images revealed the formation of large nanocages in spheres (pore diameter: 20-60 nm) and the existence of narrow micro/mesopores (pore diameter: 1.5-5 nm) on their walls. Brunauer-Emmett-Teller adsorption/desorption experiments led to the observation of dual porosity and indicated that the contribution of micro/mesopores increased gradually with increasing concentration of PVA during synthesis from CoOP-0 to CoOP-15 (where the number gives the wt % of PVA used in CoOP synthesis). These materials acted as precatalysts for heterogeneous water oxidation at pH 13.9 (1 m KOH) and electrochemical studies revealed that the reactivity improved remarkably with increasing contribution of narrow micro/mesopores. Among these catalysts, the best catalyst (CoOP-15) exhibited an overpotential of 380 mV and turnover frequency of 1.6*10-2 s-1 . The improvement of reactivity was due to significant enhancement of electrochemically accessible surface area with increasing contribution of narrow micro/mesopores, which facilitated contact between the catalyst and water molecules by improving mass transport inside the nanomaterials. Hence, this study suggests narrow micro/mesopores are beneficial towards enhancement of water oxidation catalysis. PMID- 28664670 TI - Population pharmacokinetics of human antithrombin concentrate in paediatric patients. AB - AIMS: Antithrombin is increasingly used in paediatric patients, yet there are few age-specific pharmacokinetic data to guide dosing. We aimed to describe the pharmacokinetic profile of human (plasma-derived) antithrombin concentrate in paediatric patients. METHODS: A 5-year retrospective review was performed of patients <19 years of age admitted to our institution who received antithrombin concentrate, were not on mechanical circulatory support and had baseline (predose) and postdose plasma antithrombin activity levels available for analysis. Demographic and laboratory variables, antithrombin dosing information and data on the use of continuous infusion unfractionated heparin were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. The model developed was tested against a validation dataset from a cohort of similar patients, and a predictive value was calculated. RESULTS: A total 184 patients met the study criteria {46.7% male, median age [years] 0.35 [interquartile range (IQR) 0.07-3.9]}. A median of two antithrombin doses (IQR 1-4) were given to patients (at a dose of 46.3 +/- 13.6 units kg-1 ), with median of three (IQR 2-7) postdose levels per patient. Continuous infusion unfractionated heparin was administered in 87.5% of patients, at a mean dose of 34.1 +/- 22.7 units kg-1 h-1 . A one-compartment exponential error model best fit the data, and significant covariates included allometrically scaled weight on clearance and volume of distribution, unfractionated heparin dose on clearance, and baseline antithrombin activity level on volume of distribution. The model resulted in a median -1.75% prediction error (IQR -11.75% to 6.5%) when applied to the validation dataset (n = 30). CONCLUSIONS: Antithrombin pharmacokinetics are significantly influenced by the concurrent use of unfractionated heparin and baseline antithrombin activity. PMID- 28664672 TI - Progression of an untreated pseudotumor. PMID- 28664673 TI - Polyglycolic acid sheets for rectal ulcer caused by aluminum potassium sulfate and tannic acid sclerotherapy. PMID- 28664674 TI - Adaptive immunity is essential in preventing recrudescence of Plasmodium yoelii malaria parasites after artesunate treatment. AB - Artemisinin-based antimalarials, such as artesunate (ART), alone or in combination, are the mainstay of the therapy against malaria caused by Plasmodium falciparum. However, the emergence and spread of artemisinin resistance threatens the future success of its global malaria eradication. Although much of the reported artemisinin resistance can be attributed to mutations intrinsic to the parasite, a significant proportion of treatment failures are thought to be due to other factors such as the host's immune system. Exactly how the immune system participates in the clearance and elimination of malaria parasites during ART treatment is unknown. Here, we show that a developing primary immune response, involving both B and CD4+ T cells, is necessary for the complete elimination but not initial clearance, of Plasmodium yoelii YM parasites in mice treated with ART. Our study uncovers a dynamic interplay between ART and host adaptive immunity in Plasmodium sp. elimination. PMID- 28664676 TI - Stabilizing Otherwise Unstable Anions with Halogen Bonding. AB - Both hydrogen bonding (HB) and halogen bonding (XB) are essentially electrostatic interactions, but whereas hydrogen bonding has a well-documented record of stabilizing unstable anions, little is known about halogen bonding's ability to do so. Herein, we present a combined anion photoelectron spectroscopic and density functional theory study of the halogen bond-stabilization of the pyrazine (Pz) anion, an unstable anion in isolation due to its neutral counterpart having a negative electron affinity (EA). The halogen bond formed between the sigma-hole on bromobenzene (BrPh) and the lone pair(s) of Pz significantly lowers the energies of the Pz(BrPh)1- and Pz(BrPh)2- anions relative to the neutral molecule, resulting in the emergence of a positive EA for the neutral complexes. As seen through its charge distribution and electrostatic potential analyses, the negative charge on Pz- is diluted due to the XB. Thermodynamics reveals that the low temperature of the supersonic expansion plays a key role in forming these complexes. PMID- 28664675 TI - Heteroatom-doped Carbon Spheres from Hierarchical Hollow Covalent Organic Framework Precursors for Metal-Free Catalysis. AB - Covalent organic frameworks (COFs) with hollow structures hold great promise for developing new types of functional materials. Herein, we report a hollow spherical COF with a hierarchical shell, which serves as an effective precursor of B,N-codoped hierarchical hollow carbon spheres. Benefiting from the synergistic effects of hierarchical porosity, high surface area, and B,N codoping, the as-synthesized carbon spheres show prospective utility as metal free catalysts in nitroarene reduction. A mechanistic hypothesis is proposed based on theoretical and experimental studies. Boron atoms situated meta to pyridinic N atoms are identified to be the main catalytic active sites. The anti aromaticity originating from the codoping of B and pyridinic N atoms, not charge distribution and deformation energy, is confirmed to play a pivotal role in the catalytic reaction. PMID- 28664677 TI - Comparative evaluation of torasemide and spironolactone on adverse cardiac remodeling in a rat model of dilated cardiomyopathy. AB - BACKGROUND: Chronic heart failure (CHF) involves fluid retention and volume overload, leading to impaired cardiac function. In these conditions, diuretic agents are most commonly used to treat edema and thereby reducing the volume load on the failing heart. There are several other beneficial effects of diuretics apart from their action on urinary excretion. METHODS: To identify the effects of diuretic agents on adverse cardiac remodeling in CHF, this study was carried out, where we have compared the effects of torasemide and spironolactone in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin-mediated experimental autoimmune myocarditis. RESULTS: Cardiac protein expression levels of inflammation, endoplasmic reticulum stress, and fibrosis markers were upregulated in the hearts of CHF rats, while treatment with either torasemide or spironolactone has downregulated their expression. The effect produced by spironolactone on cardiac fibrosis markers was comparably lesser than torasemide. Further, immunohistochemical analysis and histopathological studies have provided evidence to confirm the beneficial effects of these drugs on adverse cardiac remodeling in rats with CHF. CONCLUSION: Torasemide treatment has benefits against adverse cardiac remodeling in CHF rats, which was better than the protection offered by spironolactone. PMID- 28664678 TI - Radiation oncology directors of training survey 2016: Perspectives and challenges. AB - INTRODUCTION: This paper reports the key findings of the first survey of Australian and New Zealand Radiation Oncology Directors of Training (DoTs) dealing with their perspectives, experiences and challenges. METHODS: The survey was conducted in September 2016 using a 34-question instrument. It was emailed to all radiation oncology DoTs listed on the Royal Australian and New Zealand College of Radiologists (RANZCR) database. The questions related to demographics, protected time, weekly activities, support, the value of curriculum assessments, challenges and suggested improvements. Respondents were assured that their responses were anonymous. RESULTS: The response rate was 59.6% (31/52). The median age of respondents was in the 41 to 45 age bracket, but nearly one quarter were over 45 years of age. The median time respondents had been in the role was three to five years (range <0.5 to >10) with the median number of trainees supervised being four (range 1-8). Thirty-five percent had a co DoT. DoTs spent a median of three hours per week on the role (range <1 to >8) with most respondents (67.7%) requiring time during and out of work performing the role, but ten percent claimed it was done out of hours only. Nearly all DoTs were aware they should have protected time, but only just half received it. The educational aspects of training dominated weekly activities, but rostering, specific trainee issues and administration were also featured. Time issues were the greatest challenge for respondents with clinical assignments the most challenging assessment. However, more emphasis on contouring and planning was thought to be required. All DoTs found the dedicated DoT workshops useful, but felt future discussions on trainees in difficulty could be emphasized. The vast majority felt supported by their training site and the College. All respondents believed in the role with most having an interest in educational activities. The majority of respondents (85%) intended to continue in the role for the next 1 to 2 years, but this dropped to 45% when asked about continuing for 5 years. CONCLUSIONS: This survey of predominantly experienced DoTs, indicated that the role was deemed to be of value in delivering optimal training. The most significant challenges faced by DoTs were finding sufficient time to deal with the responsibilities of the role and dealing with underperforming trainees. Feedback on the currently employed work based assessments will be considered as FRO transitions into programmatic assessment. Furthermore, a desire for training in how to deal with trainees in difficulty, underperforming or unsuitable trainees is noted. Future work is planned following refinements of the survey instrument; and, will also explore stress and burnout in the DoT cohort. PMID- 28664679 TI - The first case report of a patient with acquired factor XIII deficiency in the context of autoimmune encephalitis. PMID- 28664680 TI - Top predators determine how biodiversity is partitioned across time and space. AB - Natural ecosystems are shaped along two fundamental axes, space and time, but how biodiversity is partitioned along both axes is not well understood. Here, we show that the relationship between temporal and spatial biodiversity patterns can vary predictably according to habitat characteristics. By quantifying seasonal and annual changes in larval dragonfly communities across a natural predation gradient we demonstrate that variation in the identity of top predator species is associated with systematic differences in spatio-temporal beta-diversity patterns, leading to consistent differences in relative partitioning of biodiversity between time and space across habitats. As the size of top predators increased (from invertebrates to fish) habitats showed lower species turnover across sites and years, but relatively larger seasonal turnover within a site, which ultimately shifted the relative partitioning of biodiversity across time and space. These results extend community assembly theory by identifying common mechanisms that link spatial and temporal patterns of beta-diversity. PMID- 28664681 TI - Tuning the Composition of Electrodeposited Bimetallic Tin-Lead Catalysts for Enhanced Activity and Durability in Carbon Dioxide Electroreduction to Formate. AB - Bimetallic Sn-Pb catalysts with five different Sn/Pb atomic ratios were electrodeposited on Teflonated carbon paper and non-Teflonated carbon cloth using both fluoroborate- and oxide-containing deposition media to produce catalysts for the electrochemical reduction of CO2 (ERC) to formate (HCOO- ). The interaction between catalyst composition, morphology, substrate, and deposition media was investigated by using cyclic voltammetry and constant potential electrolysis at 2.0 V versus Ag/AgCl for 2 h in 0.5 m KHCO3 . The catalysts were analyzed before and after electrolysis by using SEM and XRD to determine the mechanisms of Faradaic efficiency loss and degradation. Catalysts that are mainly Sn with 15-35 at % Pb generated Faradaic efficiencies up to 95 % with a stable performance. However, pure Sn catalysts showed high initial stage formate production rates but experienced an extensive (up to 30 %) decrease of the Faradaic efficiency. The XRD results demonstrated the presence of polycrystalline SnO2 after electrolysis using Sn-Pb catalysts with 35 at % Pb and its absence in the case of pure Sn. It is proposed that the presence of Pb (15-35 at %) in mainly Sn catalysts stabilized SnO2 , which is responsible for the enhanced Faradaic efficiency and catalytic durability in the ERC. PMID- 28664682 TI - Response to comment on "Alert, but not alarmed" - a comment on "Towards more accurate HIV testing in sub-Saharan Africa: a multi-site evaluation of HIV RDTs and risk factors for false positives (Kosack et al. 2017)". PMID- 28664683 TI - Alert, but not alarmed - a comment on "Towards more accurate HIV testing in sub Saharan Africa: a multi-site evaluation of HIV RDTs and risk factors for false positives (Kosack et al. 2017)". PMID- 28664685 TI - WHO Alliance for the Global Elimination of Trachoma by 2020: progress report onelimination of trachoma, 2014-2016. PMID- 28664684 TI - Cross-cultural assessment of HIV-associated cognitive impairment using the Kaufman assessment battery for children: a systematic review. AB - INTRODUCTION: Despite improved efficacy of, and access to, combination antiretroviral therapy (cART), HIV-associated cognitive impairments remain prevalent in both children and adults. Neuropsychological tests that detect such impairment can help clinicians formulate effective treatment plans. The Kaufman Assessment Battery for Children (KABC), although developed and standardized in the United States, is used frequently in many different countries and cultural contexts to assess paediatric performance across various cognitive domains. This systematic review investigated the cross-cultural utility of the original KABC, and its 2nd edition (KABC-II), in detecting HIV-associated cognitive impairment in children and adolescents. METHODS: We entered relevant keywords and MeSH terms into the PubMed, PsycInfo, EBSCOHost, ProQuest, and Scopus databases, with search limits set from 1983-2017. Two independent reviewers evaluated the retrieved abstracts and manuscripts. Studies eligible for inclusion in the review were those that (a) used the KABC/KABC-II to assess cognitive function in children/adolescents aged 2-18 years, (b) featured a definition of cognitive impairment (e.g. >2 SD below the mean) or compared the performance of HIV infected and uninfected control groups, and (c) used a sample excluded from population on which the instruments were normed. RESULTS AND DISCUSSION: We identified nine studies (eight conducted in African countries, and one in the United Kingdom) to comprise the review's sample. All studies detected cognitive impairment in HIV-infected children, including those who were cART-naive or who were cART treated and clinically stable. KABC/KABC-II subtests assessing simultaneous processing appeared most sensitive. Evaluation of the methodological quality of the selected studies by two independent reviews suggested that shortcomings included reporting and selection biases. CONCLUSIONS: This systematic review provides evidence for the cross-cultural utility of the KABC/KABC-II, particularly the simultaneous processing subtests, in detecting cognitive impairment in HIV-infected children (including those who are clinically stable). Although the current results suggest there is justification for using the KABC/KABC-II primarily in East Africa, further investigation is required to explore the instrument's utility in other HIV-prevalent regions of the globe. PMID- 28664686 TI - Knowledge of parents from urban and rural areas vs. prevention methods of hearing loss threats seen as challenges for public health. AB - [b]Introduction.[/b] Parents as day-to-day caregivers looking after their children's health and upbringing are crucial in the process of hearing loss prevention among the young. The aim of the study was to assess the parents' knowledge and awareness of hazards bringing about hearing loss, possibilities to prevent this, as well as their reaction in the case of problems of their children with hearing. [b]Material and methods. [/b]The research group comprised respondents (402 persons), medical or paramedical professionals. None of the surveyed was a doctor. 56% of the surveyed were inhabitants of large cities, 24% of small towns, and 20% of village, mostly located in the area of Greater Poland (Wielkopolska) (97%). To perform the research a survey was devised. GSES scale was applied as an accessory tool. [b]Results. [/b]The subjects surveyed posses a great deal of knowledge concerning basic conditions that could adversely affect the hearing of children. Village inhabitants are half as afraid of hearing loss hazards as the inhabitants of large cities. More than 40% of the respondents claimed they do nothing to counteract their children's overexposure to noise. In 48.5% of cases, GPs had not drawn parents' attention to possible complications resulting from upper respiratory tract infections in children. Parents know where they should go to in case their children develop hearing problems or sudden hearing loss. [b]Conclusions.[/b] Knowledge and awareness of factors that may trigger hearing loss is not synonymous with avoidance of the problem. Main components of hearing loss prevention among children and youths should be administrative actions, extensive education, and proper childcare at home. PMID- 28664687 TI - Urban-rural differences in social capital in relation to self-rated health and subjective well-being in older residents of six regions in Poland. AB - The aim of the study was to assess the differences between rural and urban areas as regards the role of social capital and its effect on self-rated health and subjective well-being among older people in Poland. The sample was selected on the basis of multi-stage clustered design from the non-institutionalized adult population. Analysis was based on 1,299 elderly people aged 65 and over from the general Polish population who participated in the COURAGE in Europe project. Six regions of Poland were distinguished according to first level of Nomenclature of Units for Territorial Statistics (NUTS) classification . As an indicator of social capital, the COURAGE Social Network Index, the OSLO-3 Social Support Scale, and the three item UCLA Loneliness scale were used, as well as social participation and trust was assessed. Self-rated health (SRH) was measured by WHO Europe recommended version (ranging from 'very good' to 'very bad'). Well-being was assessed by the Day Reconstruction Method. Results: The results showed that in urban areas, social network and social participation supported positive self-rated health; in rural, older residents the number of years of education and social support played the same role, while self-rated health decreased with an increasing level of loneliness. Self-rated health decreased in both groups of older people with a growing number of diseases. The multivariate linear regression model of predictors of well-being in older age also confirmed differences between urban and rural elderly residents. In rural residents, subjective well-being significantly increased with the positive effect of the social network. In both urban and rural areas, poor assessment of subjective well being in older age increased with a higher level of loneliness and growing number of chronic diseases. PMID- 28664688 TI - Socio-demographic factors related to under-diagnosis of childhood asthma in Upper Silesia, Poland. AB - Introduction. The presented study of 4,535 children aged 7-17 years in the Upper Silesian region of Poland yielded 186 cases of previously known asthma, and 44 children with newly diagnosed asthma. The aim of the presented study was to identify non-medical factors that could explain why children with a newly established diagnosis ('undiagnosed asthma') had not been diagnosed in the past. Materials and method. The study was performed according to a case-control design. Parents of the children answered questionnaires on socio-economic status and family-related factors. Statistical determinants of undiagnosed asthma were explored using raw (OR) and logistic odds ratios with their 95% confidence intervals (logOR, 95%CI). Results. Children with undiagnosed asthma were younger compared to the group with previously known asthma (11.3+/-2.1 vs. 12.6+/ 2.5 years; p=0.0008). Newly diagnosed cases were more frequent in children who had less parental attention (less than 1 hour/day spent by parent with child - OR=4.36; 95%CI: 1.76-10.81) and who were not registered with specialized health care (OR=2.20; 95%CI: 0.95-5.06). Results of logistic regression analysis suggest that under-diagnosis of asthma is related to age below 12 years - logOR = 3.59 (95%CI: 1.28-10.36), distance to a health centre > 5 km - logOR = 3.45 (95%CI: 1.05-11.36), time spent with child < 1 hour/day - logOR = 6.28 (95%CI: 1.98 19.91). Conclusion. Among non-medical determinants of undiagnosed asthma the age of a child plays a major role. Another factors of importance is the large distance between residence and health centre, and low parental attention at home. PMID- 28664689 TI - Fatal cardiovascular risk in Poland as determined via Internet. AB - [b]Abstract Introduction.[/b] Web information systems can serve as a diagnostic tool for Internet users and to support the epidemiological work of doctors and health care providers. As part of this work, a system for detecting and calculating cardiovascular risk has been created. [b]Objectives[/b]. 1) Application of web-based risk assessment of cardiovascular death; 2) an attempt to evaluate the distribution of selected risk factors among the population of Polish Internet users; 3) implementation of the epidemiological imaging system of cardiovascular risk factors. [b]Materials and method[/b]. The 'Ryzyko' programme (www.ryzyko.gumed.edu.pl.) available on the Internet. To assess cardiovascular death risk in a ten year period the algorithm of the SCORE project was used. 28,320 solutions of the algorithm have been registered. [b]Results[/b]. Over 28,000 webpage visitors entered the required data and received the outcome. More than 71% of Internauts who entered the data received the recommendation for medical control. The result of the programme is a graphic presentation of the distribution of the calculated risk of death, based on previously gathered information given by the Internauts in particular provinces in Poland. [b]Conclusion[/b]. Automatic monitoring of the incidence of cardiovascular risk factors in Poland provides information for epidemiological studies. The system meets the characteristics of diagnostic programmes that can assist epidemiologic based and therapeutic decisions. PMID- 28664690 TI - Plasma magnesium concentration in patients undergoing coronary artery bypass grafting. AB - [b]Introduction[/b]. Magnesium (Mg) plays a crucial role in cell physiology and its deficiency may cause many disorders which often require intensive treatment. The aim of this study was to analyse some factors affecting preoperative plasma Mg concentration in patients undergoing coronary artery bypass grafting (CABG). [b]Materials and method[/b]. Adult patients scheduled for elective CABG with cardio-pulmonary bypass (CPB) under general anaesthesia were studied. Plasma Mg concentration was analysed before surgery in accordance with age, domicile, profession, tobacco smoking and preoperative Mg supplementation. Blood samples were obtained from the radial artery just before the administration of anaesthesia. [b]Results. [/b]150 patients were studied. Mean preoperative plasma Mg concentration was 0.93 +/- 0.17 mmol/L; mean concentration in patients - 1.02 +/- 0.16; preoperative Mg supplementation was significantly higher than in patients without such supplementation. Moreover, intellectual workers supplemented Mg more frequently and had higher plasma Mg concentration than physical workers. Plasma Mg concentration decreases in elderly patients. Patients living in cities, on average, had the highest plasma Mg concentration. Smokers had significantly lower plasma Mg concentration than non-smokers. [b]Conclusions. [/b]1. Preoperative magnesium supplementation increases its plasma concentration. 2. Intellectual workers frequently supplement magnesium. 3. Smoking cigarettes decreases plasma magnesium concentration. PMID- 28664691 TI - Influence of protein deficient diet, vitamin B[sub]2[/sub] supplementation and physical training on serum composition of polyunsaturated fatty acids (PUFAs) in rats. AB - [b]Introduction[/b]. Prolonged shortages of protein in the diet significantly alter the composition and content of polyunsaturated fatty acids (PUFA) in tissues and body fluids. One of nutritional factors which may reduce negative effects of protein malnutrition might be vitamin B[sub]2[/sub] due to its influence on lipids metabolism. [b]Objective. [/b]The aim of the study was to investigate the influence of low protein (LP) diet enriched with vitamin B[sub]2[/sub] on the content and composition of PUFA in the blood serum of rats treated with dosed physical exercise. [b]Materials and method. [/b]The experiment was carried out for 3 months on 72 growing male Wistar rats divided into 5 groups. Animals were fed ad libitum on a diet with an energy value of 350 kcal/100 g, in which 4.5% of the energy was provided by protein. In the control diet, 20% of the energy was provided by protein. Two groups were fed the diet enriched with vitamin B2. The two groups of tested animals were trained for 5 days a week. [b]Results.[/b] LP diet caused a decrease in alpha-linolenic acid (ALA) after 30 days, and a decrease in docosahexaenoic acid (DHA) after 60 days of experiment, compared with rats fed the control diet. After 60 and 90 days of the experiment, a significant decrease was noted in arachidonic acid (AA) in serum of trained rats, compared with sedentary rats fed the LP diet. Physical activity increased LA (mainly on day 30), EPA (on day 90) and reduced AA content (on day 90) in serum of rats fed the LP diet. B2 supplementation in the trained LP group did not change the EPA and AA dependence; however, there was a decrease in LA content in comparison to the non-supplemented trained group. [b]Conclusions. [/b] Results of this study suggest that all investigated factors (protein deficiency, physical exercise and supplementation of vitamin B2) have significant impact on PUFA composition of serum in rats. PMID- 28664692 TI - The direct costs of drug-induced skin reactions. AB - [b] Abstract Objective.[/b] The aim of the study was an assessment of direct costs of patients hospitalised for for skin adverse drug reactions during 2002 2012 in the Department of Dermatology at the Military Institute of Medicine (Ministry of Defence) in Warsaw. The analysis was carried out from the perspectives of the public payer and service provider. [b]Materials and method. [/b]The retrospective study was carried out in a group of 164 adult patients due to skin adverse drug reactions. Analysis was based on data from patient medical records and medical orders which provided information on the used resources, including diagnostic tests, medical consultations, medicinal products, hospitalisation duration, together with cost estimation, regardless of the treatment being the cause of the skin reaction. [b]Results[/b]. According to the International Statistical Classification of Diseases and Related Health Problems(ICD) diagnosis and scores, assigned by the National Healthcare Fund, it has been estimated that patient hospitalisation at the Department of Dermatology for skin drug reaction incurred costs at the average amount of ?717.00 per patient. The complex diagnostics and pharmacotherapy of the same group of patients generated costs for the hospital at the average amount of ?680 per patient. [b]Conclusions[/b]. As a result of the analysis, the therapy for skin adverse drug effects generates significant costs, both for the payer and the service provider. Since the costs are comparable, it seems that the pricing of medical procedures by the public payer is adequate for the costs incurred by the medical service provider. PMID- 28664693 TI - Readiness of adolescents to use genetically modified organisms according to their knowledge and emotional attitude towards GMOs. AB - INTRODUCTION: Agriculture based on genetically modified organisms plays an increasingly important role in feeding the world population, which is evidenced by a considerable growth in the size of land under genetically modified crops (GM). Uncertainty and controversy around GM products are mainly due to the lack of accurate and reliable information, and lack of knowledge concerning the essence of genetic modifications, and the effect of GM food on the human organism, and consequently, a negative emotional attitude towards what is unknown. OBJECTIVE: The objective of the presented study was to discover to what extent knowledge and the emotional attitude of adolescents towards genetically modified organisms is related with acceptance of growing genetically modified plants or breeding GM animals on own farm or allotment garden, and the purchase and consumption of GM food, as well as the use of GMOs in medicine. MATERIALS AND METHOD: The study was conducted by the method of a diagnostic survey using a questionnaire designed by the author, which covered a group of 500 adolescents completing secondary school on the level of maturity examination. The collected material was subjected to statistical analysis. Research hypotheses were verified using chi-square test (chi 2 ), t-Student test, and stepwise regression analysis. RESULTS: Stepwise regression analysis showed that the readiness of adolescents to use genetically modified organisms as food or for the production of pharmaceuticals, the production of GM plants or animals on own farm, depends on an emotional-evaluative attitude towards GMOs, and the level of knowledge concerning the essence of genetic modifications. PMID- 28664694 TI - Assessment of knowledge on cardiovascular disease risk factors by postal survey in residents of Malopolska Voivodeship. Malopolska CArdiovascular PReventive Intervention Study (M-CAPRI). AB - [b]Introduction.[/b] Education is a key tool in the prevention of cardiovascular disease (CVD). Education programmes require monitoring of their effectiveness. [b]Objectives. [/b]1) to introduce postal screening for the assessment of knowledge on CVD risk factors (RFs) for the Polish population, 2) to assess this knowledge in adult residents of Malopolska Voivodeship, and 3) to assess whether knowledge on RFs is related to age, gender, place of residence, level of education and family history of CVD. [b]Materials and method.[/b] Anonymous questionnaires were posted to a random sample of 5,000 residents of Malopolska Voivodeship in Poland. Results were presented as proportions of participants who listed RFs correctly. A series of multiple logistic regression models was used to assess the associations of knowledge on RFs with the potential determinants. [b]Results.[/b] 1,126 completed questionnaires were returned. Over 35% of respondents could not list a single RF and 14 % listed only 1-2 RFs. About 40% named 3-5 and only 12% listed 6 or more RFs. About a half of the respondents listed incorrectly from 1-8 characteristics as being associated with higher risk of CVD. In the multivariate analysis, knowledge on RFs was not significantly associated with age. Level of education was the strongest determinant of knowledge. Male rural and small town residents had less knowledge, whereas women with a family history of CVD had more knowledge on some CVD RFs. [b]Conclusions.[/b] Using a postal questionnaire for the assessment of knowledge of CVD RFs in the population of Malopolska Voivodeship appeared to have serious limitations due to low participation in the study. Despite this, the results of the study indicate that knowledge on CVD RFs is insufficient. Female gender and higher education were related to more prevalent knowledge on RFs. Family history of CVD was related to better knowledge in women only. Male residents of rural areas and small towns had slightly less knowledge on CVD RFs. PMID- 28664695 TI - Are agricultural and natural sources of bio-products important for modern regenerative medicine? A review. AB - [b] Abstract Introduction and objectives[/b]. As tissue engineering and regenerative medicine have continued to evolve within the field of biomedicine, the fundamental importance of bio-products has become increasingly apparent. This true not only in cases where they are derived directly from the natural environment, but also when animals and plants are specially bred and cultivated for their production. [b]Objective.[/b] The study aims to present and assess the global influence and importance of selected bio-products in current regenerative medicine via a broad review of the existing literature. In particular, attention is paid to the matrices, substances and grafts created from plants and animals which could potentially be used in experimental and clinical regeneration, or in reconstructive procedures. [b]Summary.[/b] Evolving trends in agriculture are likely to play a key role in the future development of a number of systemic and local medical procedures within tissue engineering and regenerative medicine. This is in addition to the use of bio-products derived from the natural environment which are found to deliver positive results in the treatment of prospective patients. PMID- 28664696 TI - Human health cost of hydrogen sulfide air pollution from an oil and gas Field. AB - Introduction and objective. The Karachaganak oil and gas condensate field (KOGCF), one of the largest in the world, located in the Republic of Kazakhstan (RoK) in Central Asia, is surrounded by 10 settlements with a total population of 9,000 people. Approximately73% of this population constantly mention a specific odour of rotten eggs in the air, typical for hydrogen sulfide (H2S) emissions, and the occurrence of low-level concentrations of hydrogen sulfide around certain industrial installations (esp. oil refineries) is a well known fact. Therefore, this study aimed at determining the impact on human health and the economic damage to the country due to H2S emissions. Materials and method. Dose-response dependency between H2S concentrations in the air and cardiovascular morbidity using multiple regression analysis was applied. Economic damage from morbidity was derived with a newly-developed method, with Kazakhstani peculiarities taken into account. Results.Hydrogen sulfide air pollution due to the KOGCF activity costs the state almost $60,000 per year. Moreover, this is the reason for a more than 40% rise incardiovascular morbidity in the region. Conclusion. The reduction of hydrogen sulfide emissions into the air is recommended, as well as successive constant ambient air monitoring in future. Economic damage evaluation should be made mandatory, on a legal basis, whenever an industrial facility operation results in associated air pollution. PMID- 28664697 TI - Variations in physical activity of male and female students from the Ukraine in health-promoting life style. AB - [b]Introduction. [/b]A large-scale research was performed concerning issues relating to physical activity as an important factor in a healthy lifestyle and involved observing the differences among males and females as future elites of the Ukraine. [b]Objective. [/b]The objective of the research is to assess the physical activity of students from the Ukraine, considering such factors as: gender, leisure time, time spent sitting, sports performed or intended to be performed, and the BMI. [b]Materials and method.[/b] The extended version of the IPAQ, supplemented with 3 original questions by the authors, was applied to a 2,125-strong student group from 12 majors of the University of Luck, Ukraine. [b]Results. [/b]Students from Ukraine portrayed a positive picture of physical activity with significantly higher values in male students of both total activity and its fields, i.e. sports activity and work (studying). The male students performed better in their fitness (condition) self-assessment and the amount of time spent sitting, whereas the female students had better BMI results. Both genders differed considerably in their choice of sport-recreational activities. [b]Conclusions. [/b]Females more than males demonstrated lower indices of participation in physical activity, which did not permit the formulation of a positive assessment of their lifestyle. A positive phenomenon is the normal BMI and trace values of overweight in women, exactly the reverse to males. PMID- 28664698 TI - Puffed cereals with added chamomile - quantitative analysis of polyphenols and optimization of their extraction method. AB - : [b]Abstract Introduction[/b]. Functional food plays an important role in the prevention, management and treatment of chronic diseases. One of the most interesting techniques of functional food production is extrusion-cooking. Functional foods may include such items as puffed cereals, breads and beverages that are fortified with vitamins, some nutraceuticals and herbs. Due to its pharmacological activity, chamomile flowers are the most popular components added to functional food. OBJECTIVE: Quantitative analysis of polyphenolic antioxidants, as well as comparison of various methods for the extraction of phenolic compounds from corn puffed cereals, puffed cereals with an addition of chamomile (3, 5, 10 and 20%) and from [i]Chamomillae anthodium. [/i] [b]Materials and Methods[/b]. Two modern extraction methods - ultrasound assisted extraction (UAE) at 40 degrees C and 60 degrees C, as well as accelerated solvent extraction (ASE) at 100 degrees C and 120 degrees C were used for the isolation of polyphenols from functional food. Analysis of flavonoids and phenolic acids was carried out using reversed-phase high-performance liquid chromatography and electrospray ionization mass spectrometry (LC-ESI-MS/MS). [b]Results and Conclusions[/b]. For most of the analyzed compounds, the highest yields were obtained by ultrasound assisted extraction. The highest temperature during the ultrasonification process (60 degrees C) increased the efficiency of extraction, without degradation of polyphenols. UAE easily arrives at extraction equilibrium and therefore permits shorter periods of time, reducing the energy input. Furthermore, UAE meets the requirements of 'Green Chemistry'. PMID- 28664699 TI - Antibody reactivity in patients with IgE-mediated wheat allergy to various subunits and fractions of gluten and non-gluten proteins from omega-gliadin-free wheat genotypes. AB - : [b]Abstract Introduction and objective[/b]. Gluten proteins (gliadins and glutenins) are polymorphic wheat storage proteins of allergenic properties. Significant differences in chemical composition between both protein groups allow to expect highly specific immunological response of individual subunits and fractions in reactions with IgE sera of people allergic to wheat. The aim of these studies was to identify and characterize the most allergenic gluten proteins (GP) and nongluten proteins (NGP) occurred in two closely related wheat hybrid genotypes. [b]Materials and method.[/b] 3xC and 3xN wheat hybrids, which differ strongly in regard of gliadin composition, were analyzed. Seven people manifesting different symptoms of wheat allergy donated sera for the experiment. The technique of immunoblotting after SDS-PAGE was used for identification of allergenic subunits and fractions among GP and NGP. Immunologically active protein bands were visualized by chemiluminescence. [b]Results[/b]. Great variation of immunodetection spectra was observed. Results of immunoblotting showed LMW glutenins to be of highest, gliadins of medium, while NGP of lowest allergenicity for selected patients. The 43-kDa and 47-kDa LMW glutenin subunits, 40-kDa and 43-kDa gamma-gliadin fractions and 49-kDa NGP can be considered as the most immunoreactive among all protein bands [b]separated by SDS-PAGE. CONCLUSION: [/b] The observed differentiation of immunodetection spectra allows to model highly specific IgE-binding profiles of allergenic wheat proteins attributed to individual patients with symptoms of gluten intolerance. Highly immunoreactive subunits and fractions among GP and NGP were identified. The observed immunoreactivity of 49 kDa NGP is worth to emphasize, as it has never been reported as wheat allergenic protein before. PMID- 28664700 TI - Cerebral toxoplasmosis after haematopoietic stem cell transplantation. AB - Toxoplasmosis is an opportunistic infection caused by the parasite Toxoplasma gondii. The infection is severe and difficult to diagnose in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT). It frequently involves the central nervous system. The case is presented of cerebral toxoplasmosis in a 17-year-old youth with Fanconi anaemia treated with haematopoietic stem cell transplantation (HSCT). PMID- 28664701 TI - Incidence and prevalence of Systemic Sclerosis (SSc) in Poland - differences between rural and urban regions. AB - : [b] Abstract Introduction.[/b] Systemic sclerosis (SSc) is a rare and potentially severe connective tissue disease, characterized by skin fibrosis and involvement of internal organs. Because of its rarity and heterogeneous clinical presentation, reliable epidemiological studies on SSc have been particularly difficult to carry out. [b]Objectives[/b]. The purpose of this study was to present SSc epidemiology among hospitalized patients in Poland. MATERIALS AND METHOD: The analysis was based on population-based administrative data, taken from a Polish hospital morbidity study carried out by the National Institute of Public Health between January 2008 - December 2012. [b]Results[/b]. Analyzed data covered 9,049 hospitalization records. The final sample comprised 3,653 patients with first-time hospitalizations for SSc. The average age of the sample was 53 years (SD 16.2; range 0-91 years); 84% of patients were female and 16% male. Based on hospitalization registers, the average SSc incidence was estimated to be 1.9/100,000 per year and peak age of incidence was 55 years. The point prevalence was estimated to be 9.4/100,000 at the end of 2012. SSc was more common in females, with F:M ratio ranging from 6.2:1-4.6:1 depending on the year. Analysis of hospitalization trends revealed that overall numbers of SSc hospitalizations increased, while first-time hospitalizations decreased between 2008-2012. Clusters of higher incidence were observed in more rural regions vs. urban regions. [b]Conclusion[/b]. Estimated incidence of SSc in Poland was comparable to reported incidence in other European countries. Analysis of demographic factors and reports of clusters of higher incidence may suggest the existence of environmental risk factors for the development of SSc. These observations may require further research. PMID- 28664702 TI - Invasive forms of canine endoparasites as a potential threat to public health - A review and own studies. AB - [b]Abstract [/b] Dogs serve as the vectors of serious zoonotic parasitic diseases. In the month of May 2012 - 2014, 339 dog faeces samples from seven public sites in Chelmno, a town in northern Poland, were collected and examined to determine the gastrointestinal parasite fauna of dogs. Each faecal sample was dissected with a needle, checked for tapeworm segments and examined for parasite eggs and oocysts using the flotation and decantation method and a modified Baermann technique. Differences were observed in the degree of parasite species occurrence. The most dominant were [i]Toxocara canis[/i] and Ancylostomatidae. The detected species included: [i]T. canis [/i]and [i]Toxascaris leonina[/i] eggs (23.4% and 10.2%, respectively), as well as eggs from the[i] Ancylostomatidae[/i] family (16.2%),[i] Trichuris vulpis [/i]eggs (6.6%), [i]Taenia[/i] type eggs (4.6%),[i] Dipylidium caninum[/i] (5.2%) and [i]Cystoisospora [/i](Isospora) spp. oocysts (10.9%). PMID- 28664703 TI - The quality of life and satisfaction with life of women who are childless by choice. AB - Objective. The study attempts to identify and analyze factors affecting the quality of life and satisfaction with life of women who are childless by choice. Materials and method. The research instruments used were: the WHOQOL-Bref questionnaire and the Satisfaction with Life Scale (SWLS), and author's own questionnaire. Results. A better overall quality of life, perception of own health and quality of life in all the specific domains analyzed was found among childless women living in cities, college/university-educated, and with a good or very good financial standing. Conclusions. A positive correlation was found between satisfaction with life and overall quality of life, general perceived health, and all quality of life domains. Higher satisfaction with life scores in childless women are correlated with a higher quality of life scores and better perceived health. PMID- 28664704 TI - Human infections caused by free-living amoebae. AB - [b]Abstract Introduction[/b]. Among free-living amoebae that are widely distributed in nature only four genera/species are known as agents of human infections:[i] Acanthamoeba spp., Naegleriafowleri, Balamuthia mandrillaris[/i] and[i] Sappiniapedata[/i]. These amoebae are not well adapted to parasitism, and could exist in the human environment without the need for a host. Infections due to these amoebae, despite low morbidity, are characterized by relatively high mortality rate and pose serious clinical problems. [b]Objectve[/b]. This review study presents and summarizes current knowledge about infections due to pathogenic and opportunistic free-living amoebae focused on epidemiology, clinical manifestations, diagnosis and treatment based on global literature. [b]State of knowledge[/b]. All four genera have been recognized as etiologic factors of fatal central nervous system infections and other serious diseases in humans. [i]N. fowleri[/i] causes an acute fulminating meningoencephalitis in children and young adults. [i]Acanthamoeba spp[/i]. and [i]B.mandrillaris[/i] are opportunistic pathogens causing granulomatous amoebic encephalitis and disseminated or localized infections which could affect the skin, sinuses, lungs, adrenals and/or bones. [i]Acanthamoeba spp[/i]. is also the main agent of acute eye infection -[i] Acanthamoeba keratitis, [/i]mostly in contact lens wearers. However, there is only one recognized case of encephalitis caused by [i]S. pedata. [/i] [b]Conclusions[/b]. Amoebic diseases are difficult to diagnose which leads to delayed treatment, and result in a high mortality rate. Considering those issues, there is an urgent need to draw more attention to this type of diseases. PMID- 28664705 TI - Lawn mower injuries as a cause of serious visual acuity impairment - Case reports. AB - : [b]Abstract Objective.[/b] The aim of the study is to present four cases of lawn mowers injuries as a cause of serious visual acuity impairment. [b]Materials and Method[/b]. A retrospective study of four patients admitted in 2013-2015 to the Department of Vitreoretinal Surgery in Lublin with severe open or closed globe injury, one with an intraocular foreign body (IOFB). The presence of eye protective equipment was assessed, as well as visual acuity, eye tissue condition before and after treatment, and applied therapy. RESULTS: In all cases an improvement was achieved in local conditions. The intraocular foreign body was removed, wounds sutured and damaged tissues placed in position. All eyeballs were saved. In three cases, visual acuity was improved to a usable level. Three patients underwent pars plana vitrectomy, one with IOFB removal from the vitreous cavity. [b]Conclusions[/b]. Lawn mower induced eye injuries are a significant cause of serious visual acuity impairment or blindness. The presented study shows that lawn mower eye injuries are still a therapeutic, social and economic problem, yet are very preventable with proper eye protection and patients' education. Current prevention strategies are inadequate, and therefore should be updated. PMID- 28664706 TI - Neuromarkers of Post-Traumatic Stress Disorder (PTSD) in a patient after bilateral hand amputation - ERP case study. AB - Introduction. There is a lack in the worldwide literature of reports on the Neuromarkers of Post-Traumatic Stress Disorder (PTSD) in patients after bilateral hand amputation The aim of this study was to test a hypothesis regarding developing Post-Traumatic Stress Disorder (PTSD) in a patient after bilateral hand amputation with the use of Event Related Potentials (ERPs). On the basis of previous research, the amplitudes of P3 ERP components elicited in the cued GO/NOGO tasks have been chosen as candidates for neuromarkers of PTSD. Case study. A 24-year-old patient had undergone bilateral hand amputation 12 months previously. The patient was repeatedly operated on (he had undergone successful bilateral hand replantation) and despite the severity of the injuries, he recovered. However, the patient complained of flashbacks, anxiety and sleep difficulties. Specialist tests showed the presence of PTSD. The patient participated in the cued GO/NOGO task (Kropotov, 2009) with recording 19-channel EEG. P3 GO and NOGO waves in this task were found to be significantly smaller, in comparison to a group of healthy control subjects of the same age (N=23) taken from the HBI normative database (https://www.hbimed.com/). This observed pattern of ERP waves in the patient corresponds to the pattern found in PTSD patients. Conclusions. ERPs in a GO/NOGO task can be used in the assessment of the functional brain changes induced by chronic PTSD. PMID- 28664707 TI - Locomotor activity of adult Dermacentor reticulatus ticks (Ixodida: Ixodidae) in natural conditions. AB - [b] Abstract Introduction and objective[/b]. Expansion into new areas and the great epidemiological significance of the D. reticulatus tick in Europe prompts investigations of its ethology. Therefore, the locomotor activity of D. reticulatus adult stages in an optimal habitat during the spring and autumn activity periods was analysed. [b]Materials and method[/b]. Marked D. reticulatus adults were placed at the central point of each experimental plot. At regular time intervals, specimens attached to the cloth used in the flagging method were collected, and the distance covered by the ticks was measured. In each collection round, the temperature and humidity level in the habitat was also measured. [b]Results.[/b] Within 7 weeks, adult D. reticulatus ticks can cover an average distance of 60.71+/-44 cm. The locomotor activity of adult stages is greater during the spring than the autumn activity period. Questing, females cover a greater distance (66.35+/-100 cm) than male ticks (54.85+/-45 cm). Adult stages are characterised by greater aggressiveness 24 hours after being released, i.e. 30% of females and 19% of males attempt to attach to host skin. The locomotor activity in adult ticks depends on the humidity of the habitat (Z=-1.198; p=0.050). The temperature does not affect tick walking. [b]Conclusions[/b]. Given the low rates of horizontal locomotion of adult D. reticulatus ticks, the prevalence of the species in nature is determined by the presence of their hosts and humidity conditions ensuring their further development and survival. The dependence of D. reticulatus locomotor activity and aggressiveness on the humidity level implies an increased risk of host attacks in locations and periods that offer favourable humidity conditions for this species. PMID- 28664708 TI - Legionella risk assessment in cruise ships and ferries. AB - Introduction. The increasing development of marine traffic has led to a rise in the incidence of legionellosis among travellers. It occurs in similar environments, especially closed and crowded, and aboard ships Legionella survives and multiplies easily in water pipes, spreading into the environment through air conditioning systems and water distribution points. Although in recent years in the construction of cruise ships preventive measures aimed at curbing the proliferation of Legionella (design, materials, focus on the operation and maintenance of the water system), have been taken account, little or no attention has been paid to small ships which, in many cases, are old and not well maintained. Objective. The aim of the study was to evaluate the frequency and severity of Legionella contamination in ferries and cruise ships in order to adopt more specific control measures. Materials and method. A prevalence study was carried out on 10 ferries and 6 cruise ships docking or in transit across the port of Messina (Sicily, Italy). Water and air samples collected from many critical points were tested for qualitative and quantitative identification of Legionella. Results and conclusions. Legionella pneumophila sg 1 was isolated from the samples of shower and tap water in 7 (70%) of the 10 ferries examined, and in 3 (33%) of the 6 cruise ships examined, and L. pneumophila sg 2 14 in 8 (80%) and 1 (16.7%) of these ships, respectively. No Legionella contamination was found in whirlpool baths, air and ice samples. In conclusion, the data obtained confirm higher levels of Legionella contamination in local ferries and cruise ships, underlining the need to adopt corrective actions more specific for these smaller vessels. PMID- 28664709 TI - The quality of life of farmers with chronic obstructive pulmonary disease (COPD). AB - Introduction and objective. COPD is a medical state characterized by chronically poor airflow, and typically worsens over time. Farmers have an increased risk of COPD because of being exposed to ammonia, hydrogen sulfide, inorganic dust, and organic dust. The quality of life of the ill depends on biomedical as well as psychosocial factors, the impact of which has not been a frequent subject of studies among COPD patients. The aim of the study was to indicate the factors that have negative and positive influence on the quality of life of farmers suffering from COPD. Materials and method. The study was conducted among 84 farmers treated for COPD in the Department of Pneumology, Oncology and Allergology of the Medical University in Lublin, Poland. The differences between the farmers concerned: severity of the disease, level of education and income, frequency of smoking tobacco and drinking alcohol, kinds of support they receive from their families, and the level of depression and anxiety experienced by the patients. Results. The study revealed that most patients suffered from depressive and anxiety disorders, and the level of depression higher among the patients who smoked more. Lack of family support had significant influence on exacerbation of the patient's depressive and anxiety symptoms. Patients who had recently experienced a critical situation presented with more severe COPD symptoms, lower quality of life and a higher level of depression. Higher income of the patients had positive influence on their quality of life. Farmers addicted to alcohol suffered from a higher level of anxiety. PMID- 28664710 TI - High levels of vitamin D associated with less ischemic heart disease - a nested case-control study among rural men in Sweden. PMID- 28664711 TI - COMPARATIVE DETERMINATION OF THE PHYSICAL STRESS AND STRAIN ON MILKERS IN MILKING PARLORS IN UPPER AUSTRIAN DAIRY FARMS (WITH AN ECG AND ACTIVITY SENSOR AND SPIROMETER). PMID- 28664712 TI - Comparative study on usefulness of gentamycin-containing collagen implants in the treatment of patients with osteitis and osteomyelitis of the craniofacial skeleton. AB - Introduction and objective. A reduction in incidences of peri-surgical complications due to infections is achieved by antibiotic prophylaxis The objective of the study was to assess the usefulness of gentamycin-containing collagen implants (GCCI) in the treatment of patients with osteitis and osteomyelitis of the craniofacial skeleton. Materials and method. The retrospective study included 103 patients with osteitis and osteomyelitis. 54 patients were treated intra-operatively with GCCI (Garamycin, EusaPharma, Europe). 49 patients were treated according to standard procedures. Light microscopy and in vitro culture techniques were applied for bacteria specific identification, and to investigate the resistance of detected microbiota to antibiotics. Patients received one dose of antibiotic pre-operatively. Post operative antibiotic treatment was administered individually, according to clinical course and microbiological tests. The patients were followed-up on days 3, 7 and 14 after discharge for local complications; radiographic follow-up was performed 3, 6 and 12 months after surgery. Results. The course of post operative antibiotic therapy was shorter in GCCI patients than in the control group (median 1 vs. 7 days); they also required shorter hospitalization (median 3 vs. 4 days). Implantation of GCCI significantly reduced the incidence of local complications (OR 0.30, 95%CI 0.11-0.83, p<0.0001), independently of the use of postoperative antibiotic therapy. On follow-up after 3-12 months, all patients presented with good soft tissue and bone healing. Conclusions. The results of this comparative study advocate the use of GCCI in osteomyelitis of various origin in oral and maxillofacial surgery, as they seemed to reduce the incidence of local complications, shorten antibiotic administration time and hospital stay. PMID- 28664713 TI - Predictors of Hepatitis B Surface Antigen Titers two decades after vaccination in a cohort of students and post-graduates of the Medical School at the University of Palermo, Italy. AB - Introduction and objective. The introduction of a vaccine against hepatitis B virus (HBV) for newborn babies in Italy in 1991, extended to 12-year old children for the first 12 years of application, has been a major achievement in terms of the prevention of HBV infection. The objective of this study was to analyse the long-term immunogenicity and effectiveness of HBV vaccination among healthcare students with different working seniorities. Materials and method. A cross-sectional observational study of undergraduate and postgraduate students attending the Medical School of the University of Palermo was conducted from January 2014 - July 2016. HBV serum markers were performed with commercial chemiluminescence assays. Categorical variables were analyzed using the chi-square test (Mantel-Haenszel), whereas means were compared by using the Student's t test. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated by a multivariable logistic regression, using a model constructed to examine predictors of anti-HBs titer above 10 mIU/mL, assumed as protective. Results. Of the 2,114 subjects evaluated - all vaccinated at infancy or at the age of 12 years and were HBsAg/anti-HBc negative - 806 (38.1%) had an anti-HBs titre <10 IU/L. The latter were younger, more likely to be attending a healthcare profession school (i.e., nursing and midwifery), than a medical postgraduate level school, and more likely to have been vaccinated in infancy (p <0.001, 95% CI 2.63-5.26, adjusted OR 3.70). Conclusion. The results of the study suggest that assessment of HBV serum markers in workers potentially exposed to hospital infections is useful for identifying small numbers of unvaccinated subjects, or vaccinated subjects with low antibody titre, all of whom should be referred to a booster series of vaccinations. PMID- 28664714 TI - Analysis of Acinetobacter baumannii resistance patterns in patients with chronic obstructive pulmonary disease (COPD) in terms of choice of effective empiric antibiotic therapy. AB - Introduction. Multi-resistant Acinetobacter baumannii isolated from patients has become one of the most hazardous pathogens in health care settings. The aim of the study was to analyze pneumonia caused by Acinetobacter baumannii in patients hospitalized because of exacerbation of chronic obstructive pulmonary diseases (COPD), who were admitted to the Pulmonology Ward of the Masovian Specialistic Hospital in Radom (MSS). The incidence and drug sensitivity of these non-fermenting rods were evaluated, and compliance with antimicrobial procedure with the algorithm of the guidelines in applicable recommendations, was estimated. This should result in determining the local patterns of resistance and verifying therapeutic procedures in accordance with the assumptions of hospital antibiotic policy. In addition, the study examined the effectiveness of empiric and targeted therapy according to the clinical condition of the patient, and the eradication of A. baumannii, in comparison with the aggravating factors of the patient. Materials and Method. The retrospective study included 90 patients with exacerbation of COPD whose etiological factor of infection was A. baumannii, hospitalized in the Department of Pulmonology (MSS) in 2012-2016. Results. Studies were conducted on 90 patients with COPD exacerbation from which A. baumannii was isolated. Co-infections with other bacterial species among 41 patients were additionally noted. The majority of A. baumannii strains showed a high resistance (90%) to fluoroquinolones, ceftazidime, piperacillin/tazobactam. For strains causing a co-infection, drug resistance was successively 44-56%, 44%, 44%. All of patients received empirical therapy. The most commonly used drug was amoxicillin with a clavulanic acid, often combined with fluoroquinolone. This type of therapy was effective among 10% of patients. The mortality in this group was determined at 29%. Among 79% of patients with COPD, a targeted therapy was performed which proved to be effective in 58% of treated cases by susceptibility testing. The highest efficacy was observer after the use of colistin and carbapenems. Conclusion. In the performed study, the infections caused by multi-resistant Acinetobacter baumannii, were observed in COPD, which should be taken into consideration in choosing empirical antibiotic therapy. Simultaneously, the local resistance patterns of multi-drug resistant (MDR) Gram-negative strains co-infecting COPD should be considered in empirical treatment. Moreover, both additional clinical complication and co infections contribute to a more severe course of diseases. In this study, the mortality percent exceeded 29%. PMID- 28664715 TI - The history of arsenical pesticides and health risks related to the use of Agent Blue. AB - Arsenicals in agriculture. Beginning in the 1970s, the use of arsenic compounds for such purposes as wood preservatives, began to grow. By 1980, in the USA, 70% of arsenic had been consumed for the production of wood preservatives. This practice was later stopped, due to the US Environmental Protection Agency (EPA) ban of the arsenic-and chromium-based wood preservative chromated copper arsenate. In the past, arsenical herbicides containing cacodylic acid as an active ingredient have been used extensively in the USA, from golf courses to cotton fields, and drying-out the plants before harvesting. The original commercial form of Agent Blue was among 10 toxic insecticides, fungicides and herbicides partially deregulated by the US EPA in February 2004, and specific limits on toxic residues in meat, milk, poultry and eggs, were removed. Today, however, they are no longer used as weed-killers, with one exception - monosodium methanearsonate (MSMA), a broadleaf weed herbicide for use on cotton. Severe poisonings from cacodylic acid caused headache, dizziness, vomiting, profuse and watery diarrhea, followed by dehydration, gradual fall in blood pressure, stupor, convulsions, general paralysis and possible risk of death within 3-14 days.The relatively frequent use of arsenic and its compounds in both industry and agriculture points to a wide spectrum of opportunities for human exposure. This exposure can be via inhalation of airborne arsenic, contaminated drinking water, beverages, or from food and drugs. Today, acute organic arsenical poisonings are mostly accidental. Considerable concern has developed surrounding its delayed effects, for its genotoxic and carcinogenic potential, which has been demonstrated in epidemiological studies and subsequent animal experiments. Conclusions. There is substantial epidemiological evidence for an excessive risk, mostly for skin and lung cancer, among humans exposed to organic arsenicals in occupational and environmental settings. Furthermore, the genotoxic and carcinogenic effects have only been observed at relatively high exposure rates. Current epidemiological and experimental studies are attempting to elucidate the mechanism of this action, pointing to the question whether arsenic is actually a true genotoxic, or rather an epigenetic carcinogen. Due to the complexity of its effects, both options remain plausible. Its interactions with other toxic substances still represent another important field of interest. PMID- 28664716 TI - Prevalence and antimicrobial resistance of Salmonella in meat and meat products in Latvia. PMID- 28664717 TI - Health in old age, and patients' approaches to telemedicine in Poland. AB - INTRODUCTION: Polish ageing society still experiences health-related problems and the increasing difficulties in receiving medical care. The initiation of telemedicine programmes can change this situation for better. The question arises if telemedicine is a solution that the elderly are willing to accept and take advantage of in order to raise their quality of life. MATERIAL AND METHODS: Questionnaire based research was conducted in 2015 on a sample group of 312 seniors. The respondents completed the Diener Satisfaction with Life Scale (SWLS) and the subscale of Health States from Fragebogen zur Lebenszufriedenheit (FLZ) by Fahrenberg et al. Each participant gave their consent to take part in the research. RESULTS: SWLS presents a relatively stable value in the subsequent decades of being old (60-69 years M=21.93 SD=6.25; 70-79 years M=21.70 SD=5.52; 80+ M=21.38 SD=5.82). The health related quality of life (the FLZ subscale), varied in the analysed subgroups (F=7.783 p=0.000), and was related to comorbidity and polytherapy. A positive attitude towards telemedicine was expressed by 40% of those surveyed. However the seniors' need for telemedical services was more limited and did not exceed the 10%. CONCLUSIONS: In Poland in ageing there still dominates the experience of multiple ailments and polytherapy, something which justifies a search for new, easily accessible, and economically sound solutions for health care. Telemedicine is a promising solution although there is a need for concrete steps to be taken to raise willingness amongst geriatric patients to take advantage of telemedicine. PMID- 28664718 TI - Validation of automated detection of physical and mental stress during work in a Huhnermobil 225. AB - Introduction. The effects of the use of mobile henhouses and their equipment on the physical and mental stress of farmers in the organic egg production, and the reliability of the sensor-based detection of these in work processes are insufficiently known. There are neither measurement results nor key figures, according to operation and gender especially, available in the literature. Objective. The aim of this case study is to quantify the physical and mental stress of work processes on the basis of heart rate and the Baevsky Stress Index, as measured by the ECG- and activity sensor Movisens(r), which is used mainly in the sports and rehabilitation sectors. To analyse the impact, daily routine work was divided into operations and the data collected for this purpose analysed descriptively and analytically. Conclusions. In summary, it can be concluded that measurement technology has the potential to capture the activity-related exceedances of the endurance limit of the work severity by means of the heart rate reliably, to identify risk areas of employment and to quantify stress situations. The accuracy and reliability of data acquisition with Movisens(r) should be validated by a larger sample size and further measurements. In particular, the algorithm for calculating the data to quantify the mental and physical stress without movement needs to be improved significantly through further development. PMID- 28664719 TI - Differences in the expression of selected genes associated with cell stress response in a PTSD patient and in healthy individuals - a case study. AB - Objective. The aim of the study was determination of the level in expression genes associated with cell stress response in a patient with PTSD. Case study. A 57-year-old PTSD patient, A.P., was the subject of the study. Blood samples were taken from the ulnar vein to assess the relative expression of the tested genes in leukocytes via a quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results. A considerably decreased level in the expression HSF-1, NF-kB, Hif-1 and IL6 m-RNA was observed in the patient when compared to the control group. A low expression in HSPA1A, HSPB1, IL10 and CRP m-RNA compared with the control group was also noted. Conclusion. It is possible that the lower level of transcriptional factors: HSF-1, NF-kB and Hif-1 as well as IL6 m-RNA may be associated with the effect of the PTSD patient's treatment. PMID- 28664720 TI - Resistance to the tetracyclines and macrolide-lincosamide-streptogramin group of antibiotics and its genetic linkage - a review. AB - An excessive use of antimicrobial agents poses a risk for the selection of resistant bacteria. Of particular interest are antibiotics that have large consumption rates in both veterinary and human medicine, such as the tetracyclines and macrolide-lincosamide-streptogramin (MLS) group of antibiotics. A high load of these agents increases the risk of transmission of resistant bacteria and/or resistance determinants to humans, leading to a subsequent therapeutic failure. An increasing incidence of bacteria resistant to both tetracyclines and MLS antibiotics has been recently observed. This review summarizes the current knowledge on different tetracycline and MLS resistance genes that can be linked together on transposable elements. PMID- 28664721 TI - Evaluation of anticancer activity of water and juice extracts of young Hordeum vulgare in human cancer cell lines HT-29 and A549. AB - Introduction and objective. Barley (Hordeum vulgare L.) is known as a rich source of different bioactive compounds. At present, considerable attention of researchers is focused on young barley grass. It can be a good source of dietary minerals, vitamins, carbohydrates, amino acids, phenolic compounds and proteins. It is possible that the composition of chemical ingredients beneficial for health may induce an anticancer potential of young barley in human colon adenocarcinoma (HT-29) and human lung adenocarcinoma (A549) cell lines. Materials and method. Hordeum vulgare water extract (HWE) and Hordeum vulgare juice extract (HJE) were prepared. Cell proliferation and viability were examined with the use of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and NR (neutral red) methods. Induction of necrosis was assessed by propidium iodide/Hoechst staining. Progress of the cell cycle involved in cell proliferation, apoptosis, and regulation of transcription was estimated using flow cytometry analysis. Additionally, the capability of free radical scavenging was evaluated with the DPPH assay. Results. The study revealed that extracts inhibited the proliferation of cancer cells. The NR study confirmed the low cytotoxic activity of the tested extracts to normal human colon epithelial cells (CCD 841 CoTr) and human skin fibroblasts (HSF). Furthermore, a dose dependent cytotoxicity against HT-29 cells, but not A549 cells, has been reported. The free radical scavenging activity was observed in the case of the HWE but not the HJE. Conclusions. The obtained results indicate a cancer chemopreventive potential of young barley as a safe dietary agent in colon carcinoma. PMID- 28664722 TI - Monitoring risk behaviour in adolescent pupils regarding consumption of psychoactive substances. AB - Introduction. Taking psychoactive substances constitutes a significant problem for Public Health, particularly in preventing drug abuse and addiction. Objectives. To estimate the amount and incidence of drug consumption in middle and high school pupils, including the circumstances in which drug taking first started, and to determine pupils' knowledge about the consequences of taking psychoactive substances and designer drugs (DDs). Materials and methods. A randomised study was conducted throughout Poland on 9,360 pupils attending middle school (junior high school) in 2009 and 7,971 pupils from middle and high school pupils in 2011. The survey consisted of a questionnaire devised by the Chief Sanitary Inspectorate (GIS) and the replies obtained were subject to the relevant statistical analyses. Results. Drug taking was found to have increased between 2009-2011, especially among those attending high school; proportionally rising from 4% - 11%. The numbers who had ever taken designer drugs were 3% for middle school pupils and 4% from high school. Conclusions. 1) Adolescent drug consumption has increased, particularly in those of older age and in boys. 2) Despite the only brief interval for which designer drugs were legal, they have gained high popularity among the young. 3) Adolescents have insufficient knowledge about the dangers of using DDs. 4) Faced with the growing threat of a dynamic designer drug market, appropriate counter measures in education and prevention are therefore necessary. PMID- 28664723 TI - Delivery and Release of Small-Molecule Probes in Mitochondria Using Traceless Linkers. AB - Mitochondria-penetrating peptides (MPPs) are specific targeting vectors for the localization of small molecules to the mitochondrial matrix. Mitochondrial targeting of small molecules has enabled the development of a number of potential therapeutics and chemical probes. However, the need for covalent conjugation of small molecules to MPPs can negatively affect the activity of the appended cargo against its cellular target. Here, we describe cleavable linkers designed for the traceless release of chemical cargo from MPPs following mitochondrial transit. The cleavage kinetics of a number of disulfides were investigated using a fluorescent reporter system in order to optimize linker stability for mitochondrial release. The stability of mono- and disubstituted disulfides was determined to be sufficient during transit through the cytosol while still allowing for release of the cargo within 24 h. This linker system successfully released the compound Luminespib, an HSP90 inhibitor, which was deactivated by direct MPP conjugation. The releasable conjugate regenerated Luminespib activity and induced mitochondrial phenotypes of HSP90 inhibition. This linker may prove useful in expanding the repertoire of small molecules that can be used with mitochondrial targeting vectors. PMID- 28664724 TI - Analysis of Interfacial Layer-Induced Open-Circuit Voltage Burn-In Loss in Polymer Solar Cells on the Basis of Electroluminescence and Impedance Spectroscopy. AB - Stable and robust open-circuit voltage (VOC) is essential to achieve a long lifetime for polymer solar cells (PSCs). Here, we investigate the VOC burn-in loss mechanism on the basis of the analysis of electroluminescence quantum efficiency (EQEEL) and impedance measurements in amorphous PSCs, with an inverted structure having different electron transport layers (ETLs) of ZnO nanoparticles (NPs) and the sol-gel processed ZnO layer. We found that both charge recombination and energetic disorder account for a substantial proportion of the VOC burn-in loss. Moreover, varying the ETL significantly affected the degree of VOC burn-in loss, although relative contribution of these two factors remained constant. To accurately extract charge recombination-induced VOC loss, we applied a novel yet effective method that relates the EQEEL of PSCs to charge recombination-induced VOC loss. Additional analyses, including those focused on light intensity (Plight)-dependent VOC and density of states, will provide an inclusive perspective on the degradation mechanism of VOC and development of stable PSCs. PMID- 28664725 TI - Synthesis of Isoquinolines from Benzimidates and Alkynes via Cobalt(III) Catalyzed C-H Functionalization/Cyclization. AB - C-H alkenylation/annulation of benzimidates with alkynes has been realized by using a Cp*Co(III) catalyst under air. A series of substituted isoquinolines were obtained with moderate to good yields under mild reaction conditions. PMID- 28664726 TI - Ex Vivo and in Vivo Evaluation of the Effect of Coating a Coumarin-6-Labeled Nanostructured Lipid Carrier with Chitosan-N-acetylcysteine on Rabbit Ocular Distribution. AB - This study is focused on further understanding the characteristics of chitosan-N acetylcysteine surface-modified nanostructured lipid carriers (CS-NAC-NLCs) in their interaction with ocular mucosa. Coumarin-6 (C6)-labeled NLCs, including uncoated NLCs, chitosan hydrochloride (CH)-, and CS-NAC-coated NLCs, were developed using a melt-emulsification technique and subsequently decorated with different types or portions of chitosan derivatives. Mucoadhesion was evaluated ex vivo using a flow-through process with fluorescence detection. The results demonstrated that the presence of CS-NAC on the C6-NLC surface provided the most obvious enhancement in adhesion due to the formation of both noncovalent (ionic) and covalent (disulfide bridges) interactions with mucus chains. Meanwhile, the concentration of CS-NAC in the formulation positively influenced the viscosity of the nanoparticles and hence prolonged their retention in the ocular tissue. Transcorneal penetration studies revealed that CS-NAC-NLC particles were able to penetrate through the entire corneal epithelium primarily via a transcellular route. The transport depth and velocity strongly relied on the modification material and the particle size. Ex vivo fluorescence imaging and in vivo ocular distribution investigations showed that C6 was broadly distributed in rabbit eye tissues and absorbed by aqueous humor after CS-NAC-NLC instillation. In relation to C6 eye drops, CS-NAC-NLCs achieved considerably higher Cmax (4.01-fold), MRT0 infinity (1.87-fold), and AUC0-infinity (16.29-fold) in the aqueous humor. Moreover, the increase in drug absorption was greater in the cornea than in the conjunctiva. Thereby, it is possible to draw a conclusion that CS-NAC-NLCs presented great potential for drug application to the front portion of the eye. PMID- 28664728 TI - Computational Study of Ni-Catalyzed C-H Functionalization: Factors That Control the Competition of Oxidative Addition and Radical Pathways. AB - The mechanisms of Ni-catalyzed C-H arylation, alkylation, and sulfenylation with N,N-bidentate directing groups are investigated using density functional theory (DFT) calculations. While the C-H cleavage occurs via the concerted metalation deprotonation (CMD) mechanism in all types of reactions, the subsequent C-C and C X bond formation steps may occur via either oxidative addition to form a Ni(IV) intermediate or radical pathways involving Ni(III) complexes generated from homolytic dissociation of disulfides/peroxides or halide-atom transfer from alkyl halides. DFT calculations revealed that radical mechanisms are preferred in reactions with sterically hindered coupling partners with relatively low bond dissociation energies (BDE) such as dicumyl peroxide, heptafluoroisopropyl iodide and diphenyl disulfide. In contrast, these radical processes are highly disfavored when generating unstable phenyl and primary alkyl radicals. In such cases, the reaction proceeds via an oxidative addition/reductive elimination mechanism involving a Ni(IV) intermediate. These theoretical insights into the substrate-controlled mechanisms in the C-H functionalizations were employed to investigate a number of experimental phenomena including substituent effects on reactivity, chemo- and regioselectivity and the effects of oxidant in the intermolecular oxidative C-H/C-H coupling reactions. PMID- 28664727 TI - Mutational Replacements at the "Glycine Hinge" of the Escherichia coli Chemoreceptor Tsr Support a Signaling Role for the C-Helix Residue. AB - Bacterial chemoreceptors are dimeric membrane proteins that transmit signals from a periplasmic ligand-binding domain to the interior of the cells. The highly conserved cytoplasmic domain consists of a long hairpin that in the dimer forms a four-helix coiled-coil bundle. The central region of the bundle couples changes in helix packing that occur in the membrane proximal region to the signaling tip, controlling the activity of an associated histidine kinase. This subdomain contains certain glycine residues that are postulated to form a hinge in chemoreceptors from enteric bacteria and have been largely postulated to play a role in the coupling mechanism, and/or in the formation of higher-order chemoreceptor assemblies. In this work, we directly assessed the importance of the "glycine hinge" by obtaining nonfunctional replacements at each of its positions in the Escherichia coli serine receptor Tsr and characterizing them. Our results indicate that, rather than being essential for proper receptor receptor interaction, the "glycine hinge" residues are involved in the ability of the receptor to switch between different signaling states. Mainly, the C-helix residue G439 has a key role in shifting the equilibrium toward a kinase activating conformation. However, we found second-site mutations that restore the chemotactic proficiency of some of the "glycine hinge" mutants, suggesting that a complete hinge is not strictly essential. Rather, glycine residues seem to favor the coupling activity that relies on some other structural features of the central subdomain. PMID- 28664729 TI - Synthesis of Pyrrolotriazoloisoquinoline Frameworks by Intramolecular Cu-Mediated or Free Radical Arylation of Triazoles. AB - The cyclization of (2-bromophenyl)pyrrolyl-1,2,4-triazoles via copper-mediated intramolecular direct C-arylation of 1,2,4-triazoles was first accomplished under triazole-NHC control to give unknown fused heterocyclic skeletons, pyrrolo[3,2 c][1,2,4]triazolo[5,1-a] or [3,4-a]isoquinolines. The primary products underwent a triazole ring opening under the basic arylation conditions, providing N-(1H pyrrolo[3,2-c]isoquinolin-5-yl)cyanamides. The formation of the cyanamides from isomeric pyrrolo[3,2-c][1,2,4]triazolo[3,4-a]isoquinolines involves, besides the triazole ring opening, the unusual migration of the cyano group. Cyanamides can be easily reduced to 1H-pyrrolo[3,2-c]isoquinolin-5-amines, the first NH2 substituted derivatives of 1H-pyrrolo[3,2-c]isoquinoline. An insight into the mechanism of the triazole ring cleavage was achieved by performing a DFT study at the B3LYP/6-31G+(d,p) level. Free radical cyclization of (2-bromophenyl)pyrrolyl 1,2,4-triazoles with TTMSS/AIBN under neutral conditions allows obtaining pyrrolo[3,2-c][1,2,4]triazolo[5,1-a] and [3,4-a]isoquinolines, as well two more new heterocyclic systems, pyrrolo[3,4-c][1,2,4]triazolo[5,1-a] and [3,4 a]isoquinolines, in good yields without triazole ring cleavage. The developed cyclizations provide a concise, atom-economical route to novel fluorescent fused polyheterocycles containing pyrrole and 1,2,4-triazole moieties. PMID- 28664730 TI - Mixed Phenyl and Thiophene Oligomers for Bridging Nitronyl Nitroxides. AB - The synthesis of four nitronyl nitroxide (NN) biradicals is described which are conjugatively linked through p-ter-phenyl (PPP), ter-thiophene (TTT) and alternating phenylene (P) and thiophene (T) units as PTP and TPT. We first utilized Suzuki and Stille coupling reactions through protection and deprotection protocols to synthesize these (NN) biradicals. Single crystals were efficiently grown for radical precursors of 3, 5, 6, PPP-NNSi, PTP-NNSi, and final biradicals of TTT-NN, TPT-NN, and PPP-NN, whose structures and molecular packing were examined by X-ray diffraction studies. As a result, much smaller torsions between the NN and thiophene units (~10 degrees ) in TTT-NN and TPT-NN than for NN and phenyl units (~29 degrees ) in PPP-NN were observed due to smaller hindrance for a five vs a six membered ring. All four biradicals TTT-NN, TPT-NN, PTP-NN, and PPP-NN were investigated by EPR and optical spectroscopy combined with DFT calculations. The magnetic susceptibility was studied by SQUID measurements for TTT-NN and TPT-NN. The intramolecular exchange interactions for TPT-NN and TTT-NN were found in good agreement with the ones calculated by broken symmetry DFT calculations. PMID- 28664731 TI - Biocatalytic Synthesis of the Rare Sugar Kojibiose: Process Scale-Up and Application Testing. AB - Cost-efficient (bio)chemical production processes are essential to evaluate the commercial and industrial applications of promising carbohydrates and also are essential to ensure economically viable production processes. Here, the synthesis of the naturally occurring disaccharide kojibiose (2-O-alpha-d-glucopyranosyl-d glucopyranoside) was evaluated using different Bifidobacterium adolescentis sucrose phosphorylase variants. Variant L341I_Q345S was found to efficiently synthesize kojibiose while remaining fully active after 1 week of incubation at 55 degrees C. Process optimization allowed kojibiose production at the kilogram scale, and simple but efficient downstream processing, using a yeast treatment and crystallization, resulted in more than 3 kg of highly pure crystalline kojibiose (99.8%). These amounts allowed a deeper characterization of its potential in food applications. It was found to have possible beneficial health effects, including delayed glucose release and potential to trigger SCFA production. Finally, we compared the bulk functionality of highly pure kojibiose to that of sucrose, hereby mapping its potential as a new sweetener in confectionery products. PMID- 28664732 TI - Palladium-Mediated Synthesis of a Near-Infrared Fluorescent K+ Sensor. AB - Potassium (K+) exits electrically excitable cells during normal and pathophysiological activity. Currently, K+-sensitive electrodes and electrical measurements are the primary tools to detect K+ fluxes. Here, we describe the synthesis of a near-IR, oxazine fluorescent K+ sensor (KNIR-1) with a dissociation constant suited for detecting changes in intracellular and extracellular K+ concentrations. KNIR-1 treatment of cells expressing voltage gated K+ channels enabled the visualization of intracellular K+ depletion upon channel opening and restoration of cytoplasmic K+ after channel closing. PMID- 28664733 TI - NetProt: Complex-based Feature Selection. AB - Protein complex-based feature selection (PCBFS) provides unparalleled reproducibility with high phenotypic relevance on proteomics data. Currently, there are five PCBFS paradigms, but not all representative methods have been implemented or made readily available. To allow general users to take advantage of these methods, we developed the R-package NetProt, which provides implementations of representative feature-selection methods. NetProt also provides methods for generating simulated differential data and generating pseudocomplexes for complex-based performance benchmarking. The NetProt open source R package is available for download from https://github.com/gohwils/NetProt/releases/ , and online documentation is available at http://rpubs.com/gohwils/204259 . PMID- 28664734 TI - Active Site Dynamics in Substrate Hydrolysis Catalyzed by DapE Enzyme and Its Mutants from Hybrid QM/MM-Molecular Dynamics Simulation. AB - The mechanism of the catalytic hydrolysis of N-succinyl diaminopimelic acid (SDAP) by the microbial enzyme DapE in its wild-type (wt) form as well as three of its mutants (E134D, H67A, and H349A) is investigated employing a hybrid quantum mechanics/molecular mechanics (QM/MM) method coupled with molecular dynamics (MD) simulations, wherein the time evolution of the atoms of the QM and MM regions are obtained from the forces acting on the individual atoms. The free energy profiles along the reaction coordinates of this multistep hydrolysis reaction process are explored using a combination of equilibrium and nonequilibrium (umbrella sampling) QM/MM-MD simulation techniques. In the enzyme substrate complexes of wt-DapE and the E134D mutant, nucleophilic attack is found to be the rate-determining step involving a barrier of 15.3 and 21.5 kcal/mol, respectively, which satisfactorily explains the free energy of activation obtained from kinetic experiments in wt-DapE-SDAP (15.2 kcal/mol) and the 3 orders of magnitude decrease in the catalytic activity due to E134D mutation. The catalysis is found to be quenched in the H67A and H349A mutants of DapE due to conformational rearrangement in the active site induced by the absence of the active site His residues that prohibits activation of the catalytic water molecule. PMID- 28664735 TI - Regioselective Synthesis of 2-Vinylanilines Using O-aroyloxycarba-mates by Sequential Decarboxylation/Amination/Heck Reaction. AB - A new sequential approach for 2-vinylanilines utilizing aryl carboxylic acids as stable, inexpensive and widely available arylating reagents is described. Employing a Pd-POVs catalyst system, this protocol is not only overcoming the restriction barrier of decarboxylative coupling to ortho-substituted substrates, but also provides site-special to create new C(sp2)-N and C(sp2)-C(sp2) bonds. Mechanistic experiments suggest the cleavage of C(sp2)-COOH gives priority to C(sp2)-X bond in this reaction. PMID- 28664736 TI - Aluminum Nanocrystals: A Sustainable Substrate for Quantitative SERS-Based DNA Detection. AB - Since its discovery in the 1970s, surface-enhanced Raman scattering (SERS) has been primarily associated with substrates composed of nanostructured noble metals. Here we investigate chemically synthesized nanocrystal aggregates of aluminum, an inexpensive, highly abundant, and sustainable metal, as SERS substrates. Al nanocrystal aggregates are capable of substantial near-infrared SERS enhancements, similar to Au nanoparticles. The intrinsic nanoscale surface oxide of Al nanocrystals supports molecule-substrate interactions that differ dramatically from noble metal substrates. The preferential affinity of the single stranded DNA (ssDNA) phosphate backbone for the Al oxide surface preserves both the spectral features and nucleic acid cross sections relative to conventional Raman spectroscopy, enabling quantitative ssDNA detection and analysis. PMID- 28664737 TI - Correction to "Evidence of Catalase Mimetic Activity in Ce3+/Ce4+ Doped Bioactive Glasses". PMID- 28664738 TI - Danger of very high HDL levels. PMID- 28664739 TI - Neutrophil-to-lymphocyte ratio. Sixteen-year-long history since publication of our article in Bratislava Medical Journal. PMID- 28664740 TI - The impact of physiological peripartal stress on the lifelong health of newborn. AB - In the last decades the exponential increase in frequency of Caesarean sections is being observed. At the same time, there is growing amount of epidemiologic data showing higher lifetime risk of incidence of several diseases in offspring who do not experience natural labour. These findings lead to investigation of mechanisms which are responsible for maladaptation of several organ systems. Authors of this article describe these mechanisms, focusing especially on epigenetic programming, production of microbiome and positive effect of peripartal stress on successful beginning of extrauterine life.The best prevention strategy is following the strict indications of elective Caesarean sections. The current trend worldwide is to prepare the chronically ill patient for vaginal birth instead of indicating elective Caesarean section. From obstetric point of view it is possible to offer the external version of the foetus in breech presentation, the possibility of vaginal birth after Caesarean section and leave out controversial indications. The inevitable elective Caesarean sections should be planned close to term or after the beginning of spontaneous labour. The composition of intestinal microbiome could be partially influenced by application of vaginal secretion on newborn born by Caesarean section but there is not enough data proving long term positive outcomes (Ref. 48). PMID- 28664741 TI - Risk of anal incontinence in women with inflammatory bowel diseases after delivery. AB - AIM: The aim of our prospective study was to evaluate the development of postpartum anal incontinence in patients with inflammatory bowel disease (IBD) compared to healthy women. MATERIAL AND METHODS: Patients with IBD and healthy controls enrolled in the study from January 1st 2013 to November 30th 2016 and filled in the anal incontinence questionnaire in the beginning of pregnancy and after vaginal delivery. The results were statistically processed using suitable tests. RESULTS: A total of 57 women were enrolled, 17 (29.8 %) with ulcerative colitis, 23 (40.4 %) with Crohn's disease, and 17 (29.8 %) healthy controls. Incidence of postpartum anal incontinence is comparable across all groups; there was no statistically significant difference between the IBD and control groups (Kruskal-Wallis test by ranks with Dunn correction, non-significant). Postpartum anal incontinence was strongly correlated with the extent of perineal injury (r = 0.80; p < 0.0001; Pearson's linear correlation). CONCLUSIONS: Women with inflammatory bowel disease in remission do not exhibit higher incidence of postpartum anal incontinence (PPAI) compared to healthy controls; the key correlate of PPAI appears to be the extent of obstetric injury, consistently across all study groups. These results suggest that concerns about postpartum anal incontinence development should not be an indication for Caesarean section in IBD patients (Tab. 6, Fig. 1, Ref. 34). PMID- 28664742 TI - Delivery of HIV-1 Nef linked to heat shock protein 27 using a cationic polymer is more effective than cationic lipid in mammalian cells. AB - BACKGROUND: Different adjuvants and delivery systems have been used to enhance the potency of DNA vaccines against viral diseases. Among them, heat shock proteins (HSPs) are stress proteins that have multiple roles such as chaperon activity and anti-apoptotic and adjuvant properties. The goal of this study was to compare the expression of HIV-1 Nef, Hsp27 and Hsp27-Nef genes transfected in HEK-293T mammalian cells by TurboFect and Lipofectamine as a cationic polymer and lipid, respectively. METHODS: At first, the pEGFP eukaryotic vectors encoding HIV 1 Nef, Hsp27 and Hsp27-Nef genes were generated and transfected in HEK-293T using TurboFect and Lipofectamine delivery systems. Then, the expression of proteins was evaluated and compared using fluorescent microscopy, flow cytometry and western blotting 48 hr after transfection. RESULTS: The accuracy of the DNA constructs was confirmed on agarose gel electrophoresis to be ~ 720 bp, ~ 648 bp, and ~ 1368 bp bands for Hsp27, Nef, and Hsp-Nef, respectively. The expression analysis in the transfected cells showed that the delivery of genes using TurboFect was significantly higher than that using Lipofectamine. Furthermore, transfection of Hsp27 gene was more effective than that of Nef gene using both delivery systems. Hsp27 linked to Nef could also increase its delivery and expression in HEK-293T cells. CONCLUSION: Generally, Hsp27 can be used as a suitable carrier in DNA vaccine design against HIV-1 infections (Fig. 5, Ref. 28). PMID- 28664743 TI - MAPK pathway regulated the cardiomyocyte apoptosis in mice with post-infarction heart failure. AB - BACKGROUND: To explore the role of the MAPK signaling pathway in the cardiomyocyte apoptosis of mice with post-infarction heart failure (HF). METHODS: Mice were divided into sham and myocardial infarction (MI) groups. Before surgery, the MI group was divided into SB203580 and PBS subgroups. A post infarction HF model was established by ligating the left anterior descending coronary artery. Ventricular dilatation and cardiac function were observed by small animal echocardiography. The growth of primary cardiomyocytes was observed under an inverted phase contrast microscope. The mRNA and protein expressions of endoplasmic reticulum stress (ERS) markers, GRP78 and CHOP, were detected by qRT PCR and immunofluorescence assay, respectively. RESULTS: The MI group had enlarged left ventricle and decreased cardiac function. GRP78 and CHOP protein expressions in myocardial tissues, especially those of SB203580 subgroup, significantly increased (p < 0.05). The expressions of p-JNK and cleaved caspase 12 proteins, especially those of SB203580 subgroup, were significantly up regulated. Cardiomyocytes of MI group were significantly more prone to apoptosis (p < 0.05), with SB203580 subgroup being more obvious. CONCLUSION: MI was accompanied by ERS, probably involving the MAPK signaling pathway. SB203580, a specific inhibitor of this pathway, can relieve cardiomyocyte apoptosis and protect the myocardium by suppressing such stress (Tab. 3, Fig. 7, Ref. 20). PMID- 28664744 TI - Therapeutic effects of melatonin and quercetin in improvement of hepatic steatosis in rats through supression of oxidative damage. AB - BACKGROUND: Non-alcoholic steatohepatitis, a cause of cirrhosis, is characterized by fatty infiltration of the liver, inflammation, hepatocellular damage and fibrosis. The aim of the present study was to investigate the effects of melatonin and quercetin on CCl4-induced steatosis characterized by fatty infiltration of the liver, inflammation, hepatocellular damage and fibrosis. METHODS: Rats were divided into 5 groups: Ethanol, Olive oil, CCl4, CCl4+Melatonin (CCl4+Mel), CCl4+Quercetin. Rats were sacrificed and livers were removed for being evaluated by histopathological, immunohistochemical and biochemical methods. RESULTS: In CCI4 group, vacuolization, vascular congestion, haemorrhage, necrosis, and inflammatory infiltration were identified. The mean tissue MDA level was increased, whereas GSH level and SOD and CAT activities were decreased in comparison with ethanol and olive oil groups. MDA levels were decreased in CCI4+Quercetin and CCI4+Mel groups versus CCI4 group. CAT activity of CCI4+Mel group was higher than that of CCI4 and CCI4+Quercetin groups. The mean tissue GSH level of CCI4+Mel group versus CCI4 group was significantly increased. CONCLUSIONS: By the means of histopathological examination, we suggest that both agents are beneficial against necrotic and apoptotic cell death during steatosis. Thus, melatonin and quercetin might be beneficial in the improvement of hepatic steatosis by supporting conventional therapy in humans (Tab. 1, Fig. 5, Ref. 53). PMID- 28664746 TI - The influence of food restriction on the small bowel: Does intensive short-term food restriction lead to weight loss? AB - The objective of this study was to show morphological changes in the small intestine of Hyplus broiler rabbits following an eight-day food restriction programme. The control group (C) received food ad libitum (ADL) for the duration of the experiment. Group R1 received 50g of food per day, and group R2 received 65g of food per day. After the food restriction diet had been completed, groups R1 and R2 were returned to ad libitum feeding. After food restriction and at the end of the experiment, the longest small bowel measurement was recorded in the C group. In the C group, after food restriction, the villi height was significantly higher, compared to that in R1 and R2 groups and at the end of the experiment, the villi were significantly higher in R1 and R2 groups. After food restriction, the values of crypts depth were approximately similar in all groups, and the end of experiment, the depth of crypts were deepest in R1and R2 groups, as compared to that in C group. The full process is followed by weight loss to the end of the experiment. These data suggest that intensive short-term food restriction followed by ADL feeding has effect on weight loss (Fig. 3, Ref. 30). PMID- 28664745 TI - Association between pentraxin 3 and growth differentiation factor-15 in adolescent male swimmers. AB - BACKGROUND: The purpose of this study was to evaluate plasma pentraxin 3 (PTX3) and growth differentiation factor-15 (GDF-15) concentrations in adolescent male swimmers and compare any possible interactions with canonical biochemical parameters. METHODS: Twenty-six adolescent male swimmers and 29 gender- and age matched sedentary controls participated in this study. Fasting blood samples were taken from the participants. Biochemical values and plasma PTX3 and GDF-15 levels were measured. RESULTS: Plasma PTX-3 levels were markedly higher in the adolescent male swimmers than in the sedentary controls (378.44 +/- 173.93 vs 257.82 +/- 103.20 pg mL-1, p = 0.002). There was no significant difference in GDF 15 levels between the two groups (186.12 +/- 40.65 vs 203.60 +/- 36.77 pg mL-1 in the swimmers and the sedentary, respectively, P = 0.068). Relationship between PTX3 and GDF-15 was linear. CONCLUSIONS: This is the first study showing that adolescent male swimmers have higher PTX3 levels than sedentary controls and that there is a linear relationship between PTX3 and GDF-15 (Tab. 3, Fig. 2, Ref. 26). PMID- 28664747 TI - Association between the heart rate early after heart transplantation and the long term clinical outcomes. AB - BACKGROUND: A strong correlation between a lower heart rate and survival has been demonstrated in various patient populations. The optimal heart rate for heart transplant patients is still unknown. The aim of our study was to evaluate the association between an early heart rate and survival after heart transplantation. MATERIAL AND METHODS: We retrospectively analysed a group of 330 patients, who underwent heart transplantation in our institution from 1994 to 2014 and complete datasets, including 24-hour heart rate monitoring one month after the heart transplantation. Patients were divided in 2 groups: Group A (n = 278) with the average 24-hour heart rate <90 bpm, and Group B (n = 52) with >= 90 bpm. RESULTS: The average period of monitoring was 7.5 +/- 5.3 years. No differences in baseline characteristics were observed in both groups of recipients and respective donors. One-year survival in groups A and B was 92 % and 81 %, respectively; 5-year survival was 79 % and 60 %, respectively; and 10-year survival was 66 % and 50 %, respectively (p = 0.001). CONCLUSION: Increased heart rate in the early post-transplant period was significantly associated with a poorer survival rate in patients after heart transplantation (Tab. 2, Fig. 1, Ref. 25). PMID- 28664748 TI - Impact of cleft lip and/or palate in children on family quality of life before and after reconstructive surgery. AB - BACKGROUND: The aim of the study was to evaluate the impact of cleft lip/palate children together with consequent treatment on quality of family life using standardized questionnaire. Different to previous studies the evaluation of quality of family life by questionnaire was realized twice in the same group of families (before the reconstructive surgery and several months after palatoplasty). METHODS: The study was conducted in 40 families divided in two groups: 20 families with children with cleft lip (CL), 20 families with children with cleft lip and palate (CLP). The questionnaire of the Impact on Family Scale was used for evaluation of the influence of orofacial clefts on parent's quality of life. Evaluations were made at the second month of child's life and at one year of child's life with reciprocally comparison. RESULTS: The higher impact of children with CLP on quality of family life was noted at 2 months and 1 year of child's age as compared to the impact of children with CL. The reduction of impact on quality of life after surgical correction was observed in families of children with CL at one year of child's age. This decrease of influence on family quality of life was due to significantly lower impact in strain and economic dimensions in families with CL children after operation. However, in the group of families with CLP children no significant changes in the impact on family quality of life were noted when compared to the values before and shortly after the reconstructive surgery. CONCLUSIONS: This study showed that orofacial clefts in children influence markedly the quality of their family life. The higher impact of children with CLP on quality of family life as compared to children with CL was noted and this impact in CLP group was not influenced shortly after reconstructive surgery. It is suggested that appropriate medical care in Cleft Centre with special psychological support may lead to improvement in quality of life for families with cleft lip and palate children (Tab. 2, Fig. 2, Ref. 14). PMID- 28664749 TI - The age at onset in Multiple Sclerosis is associated with patient's prognosis. AB - BACKGROUND: The causes of the individual differences in the rate of disability progression in multiple sclerosis (MS) are still not completely clear. According to the long-term prognosis of MS patients, the search for new valuable prognostic markers of "benign" or "malign" MS is necessary. OBJECTIVES: Our aim was to assess the possible association of MS onset age with the disease disability progression rate in Slovak patients with MS. METHODS: By the unique pattern of evaluation of disability progression rate using Multiple Sclerosis Severity Score (MSSS), each of 270 MS patients was defined as slow-progressing, mid-rate progressing or rapidly progressing. RESULTS: We found a significant differences in the age at onset between MS patients with different rate of disability progression (p(K-W)<0,00005). The faster was a disability progression assessed by MSSS score, the higher was the MS onset age. CONCLUSION: We showed for the first time in Central European Slovak population that MS onset age is an early marker that is in the positive correlation with disease disability progression rate, evaluated by MSSS score. We conclude that relapsing-remitting MS patients older at clinical onset have a higher risk of unfavorable prognosis (Tab. 2, Fig. 1, Ref. 21). PMID- 28664750 TI - Preemptive Ethanol Lock Therapy in Pediatric Hematology/Oncology Patients With Catheter-Associated Bloodstream Infection: Impact on Length of Stay, Cost, and Catheter Salvage. AB - BACKGROUND: Ethanol lock therapy (ELT) with systemic antimicrobial therapy is a promising therapy for catheter-related infection (CRI). The impact of ELT timing on treatment efficacy and costs is unknown. PROCEDURES: A prospective study was conducted in the Hematology/Oncology Unit at the Children's Hospital of Michigan. Patients with suspected CRI were randomized to Preemptive ELT arm or Rescue ELT arm after positive culture. RESULTS: Five cases in Preemptive arm and 9 in Rescue arm had a confirmed CRI. All cases cleared infection with line salvage with no adverse events due to ELT or recurrence within 14 days. Our data showed a trend toward 36% reduction in average hospital costs and 40% reduction in average length of stay in Preemptive arm over Rescue arm. CONCLUSION: Although a small study, our data on preemptive ELT with systemic antimicrobial therapy suggest a potentially important treatment strategy in reducing length of stay as well as hospital costs. PMID- 28664751 TI - The latest advances in the discovery of nitric oxide hybrid drug compounds. AB - INTRODUCTION: There is a great interest in Nitric oxide (NO) within medicinal chemistry since it's involved in human signaling pathways. Prodrugs or hybrid compounds containing NO-donor scaffolds linked to an active compound are valuable, due to their potential for modulating many pathological conditions due to NO's biological properties when released in addition to the native drug. Compounds that selectively inhibit nitric oxide synthase isoforms (NOS) can also increase therapeutic capacity, particularly in the treatment of chronic diseases. However, search for bioactive compounds to efficiently and selectively modulate NO is still a challenge in drug discovery. Areas covered: In this review, the authors highlight the recent advances in the strategies used to discover NO hybrid derivatives, especially those related to anti-inflammatory, cardiovascular, anticancer and anti-microorganism activities. They also focus on: nitric oxide synthase inhibitors, NO delivery materials and other related activities. Expert opinion: The process of molecular hybridization can be used to obtain NO-releasing compounds that also interact with different targets. The main problem with this approach is to control NO multiple actions in the right biological system. However, the use of NO-releasing groups with many different scaffolds leads to new molecular structures for bioactive compounds, suggesting synergies. PMID- 28664752 TI - Comment: Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir. PMID- 28664753 TI - Atypical Cyanotic Breath-Holding Spells in an Infant With 16p11.2 Microdeletion Syndrome. PMID- 28664754 TI - Safety and benefit considerations for menopausal hormone therapy. AB - INTRODUCTION: While benefits and risks of hormone therapy (HT) have been shown in rigorous randomized, controlled trials, clinical use and further study have discovered effects of age, time of HT initiation, and differential effects of various regimens and administration routes on its safety profile. Areas covered: The safety of HT with regard to cardiovascular disease, thrombosis, the endometrium, the breast, and cognition was reviewed. Differential safety effects of estradiol versus conjugated equine estrogens, and progesterone versus synthetic progestins are reported. Expert opinion: Perceived safety of HT has evolved based on data from observational studies, the Women's Health Initiative and its subsequent analyses, more recent randomized, controlled trials, and studies examining the differences between different estrogens and between different progestogens. Unexpected safety concerns with HT became apparent with release of the first results from WHI. Differences between estrogen-alone versus estrogen-progestogen therapies, estradiol versus conjugated equine estrogens, and progesterone versus progestins were found in subsequent WHI analyses and studies examining components of various regimens. The decision to use HT depends on balancing risks and benefits for each individual and determining the most appropriate choice of therapy, dosing, and route of administration, while also considering the safety evidence of different estrogens and progestogens. PMID- 28664755 TI - Non-locomotive physical activity intervention using a tri-axial accelerometer reduces sedentary time in type 2 diabetes. AB - OBJECTIVES: The purpose of this study is to examine whether the use of a tri axial accelerometer can reduce sedentary time and increase non-locomotive physical activity (N-LPA), and to investigate the effect of this intervention on parameters of glucose and fat metabolism in patients with type 2 diabetes. METHODS: Thirty-eight patients with type 2 diabetes (Age: 61.8 +/- 1.4 years, BMI: 24.8 +/- 0.6, HbA1c: 6.6 +/- 0.1 %) participated in this 12-week randomized controlled study, and 31 patients were included in the final analyses. Patients were randomly assigned to one of three groups: control, N-LPA or locomotive physical activity (LPA). Patients in the N-LPA and LPA groups were asked to increase their N-LPA and LPA, respectively, using tri-axial accelerometer feedback. Glucose and fat metabolic parameters were evaluated before and after 12 week intervention. RESULTS: Only the N-LPA intervention significantly reduced sedentary time (p < 0.05) and increased N-LPA (p < 0.05). However, these changes were insufficient to improve parameters associated with glucose and fat metabolism (p > 0.05), despite a significant positive correlation between the change in sedentary time and HbA1c levels (p < 0.05). CONCLUSION: Our results showed that the N-LPA intervention using a tri-axial accelerometer successfully reduced sedentary time in patients with type 2 diabetes, however that induced no significant improvement of glucose and fat metabolism. Further research is required to determine the degree of reduction in sedentary time and increase in N LPA needed to improve glucose and fat metabolism. PMID- 28664756 TI - Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report. AB - Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations. PMID- 28664757 TI - TRAP1: a viable therapeutic target for future cancer treatments? AB - INTRODUCTION: HSP90 molecular chaperones (i.e., HSP90alpha, HSP90beta, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors. Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria. Expert opinion: TRAP1 targeting may represent a promising strategy for cancer therapy, based on the increasing and compelling evidence supporting TRAP1 involvement in human carcinogenesis. However, considering the complexity of TRAP1 biology, future strategies of drug discovery need to improve selectivity and specificity toward TRAP1 respect to other HSP90 paralogs. The characterization of specific human malignancies suitable for TRAP1 targeting is also mandatory. PMID- 28664758 TI - The current implementation status of the integration of sports and physical activity into Dutch rehabilitation care. AB - PURPOSE: To describe the current status of the nationwide implementation process of a sports and physical activity stimulation programme to gain insight into how sports and physical activity were integrated into Dutch rehabilitation care. METHODS: The current implementation status of a sports and physical activity stimulation programme in 12 rehabilitation centres and 5 hospitals with a rehabilitation department was described by scoring fidelity and satisfaction. Seventy-one rehabilitation professionals filled out a questionnaire on how sports and physical activity, including stimulation activities, were implemented into rehabilitation care. Total fidelity scores (in %) were calculated for each organization. Professionals' satisfaction was rated on a scale from 1 to 10. RESULTS: In most organizations sports and physical activity were to some extent integrated during and after rehabilitation (fidelity scores: median = 54%, IQR = 23%). Physical activity stimulation was not always embedded as standard component of a rehabilitation treatment. Professionals' satisfaction rated a median value of 8.0 (IQR = 0.0) indicating high satisfaction rates. CONCLUSIONS: The fidelity outcome showed that activities to stimulate sports and physical activity during and after rehabilitation were integrated into rehabilitation care, but not always delivered as standardized component. These findings have emphasized the importance to focus on integrating these activities into routines of organizations. Implications for Rehabilitation Components of an evidence-based programme to stimulate sports and physical activity during and after rehabilitation can be used to measure the current status of the integration of sports and physical activity in rehabilitation care in a structural and effective way. The method described in the current study can be used to compare the content of the rehabilitation care regarding the integration of sports and physical activity among organizations both on a national and international level. Sports and physical activity are seen as important ingredients for successful rehabilitation care in The Netherlands. PMID- 28664759 TI - The psychosocial impact of wheelchair tennis on participants from developing countries. AB - PURPOSE: Individuals with physical disabilities in developing countries can experience many instances of psychosocial hardship. Although scholars have suggested that participation in sport can positively impact psychosocial health, few studies have explored this phenomenon within the disabled population of developing nations. METHODS: Sixteen wheelchair tennis players were recruited across six developing countries and interviewed in regards to their experiences. Data were collected using semi-structured interviews, transcribed verbatim and subject to thematic analysis. RESULTS: Wheelchair tennis players perceived their participation in sport enhanced their psychosocial well-being. Three broad themes emerged from analysis of the interviews; (1) developed transferrable skills, (2) perceived personal growth and (3) benefits of an athletic identity. CONCLUSIONS: Sports participation, in this case wheelchair tennis, may be a viable means to promote psychosocial well-being in disabled populations within developing nations. Moreover, sport holds the potential to challenge negative perceptions of disability at an individual and societal level within these cultures. Implication for Rehabilitation Individuals with physical disabilities in developing countries may experience psychosocial hardship and cultural stigma. Wheelchair sport may be a viable means to enhance psychosocial well-being in this population. Skills learnt "on court" are transferrable to everyday life potentially improving independence and quality of life. Identifying as an athlete can challenge negative cultural perceptions of disability. PMID- 28664760 TI - A systematic review of the published literature on team-based learning in health professions education. AB - PURPOSE: Summarize the published literature on team-based learning (TBL) in health professions education (HPE) using the TBL conceptual framework to identify gaps that can guide future research Methods: PubMed, Web of Science, ERIC, and Google Scholar were searched through May 2016 for English-language articles regarding the use of TBL in HPE. Reviewers independently extracted data and coded for the seven elements in Michaelsen's Model of TBL. RESULTS: A total of 118 articles met inclusion criteria. The number of articles published yearly on TBL has grown steadily, more than tripling between 2011 and 2016. Most studies (55; 47%) involved undergraduate medical students and took place in the US (72; 61%). The most commonly studied framework component was Teacher and Learner Attitudes (97; 82%). Other commonly studied elements included Learning Outcomes (85; 72%) and Team Characteristics (25; 21%). Contextual Factors affecting TBL was addressed in one study. CONCLUSIONS: A substantial body of literature examines the effect that TBL has on traditional measures of achievement. However, many dimensions of TBL have not been well studied, including Teacher Decisions about TBL, Contextual Factors that affect TBL, Learners' Engagement, and Pattern of Engagement within Teams. Future research in these areas could determine the best use of TBL in HPE. PMID- 28664761 TI - Hydrogeochemistry and delta13CDIC and delta18OH2O composition of three Chinese Tibetan Plateau lakes. AB - This study established the hydrochemistry and stable isotope variations in three lakes, namely brackish Zigetang Co, freshwater Cona and Ranwu lakes located in the central and southeastern Tibetan Plateau of China. Vertical profile fluctuations in the water column, such as temperature and dissolved oxygen (DO) concentration, displayed significant differences which were linked to the thermocline. The hydrochemistry of the three lakes showed that [Formula: see text] as the dominant anion, whereas Na+ is the main cation in Zigetang Co and Cona lake and Ca2+ is the prevailing cation in Ranwu lake. In Zigetang Co, K+ and Na+ concentrations decreased by 42 % from 1999 to 2012, caused by the enlargement of the lake area, documented by field investigations carried out in 1998, 2002, 2006 and 2012. The delta13CDIC and delta18OH2O values analysed from the three lakes varied from -6.0 to 2.0 0/00, and from -14.8 to -6.4 0/00, respectively. The closed Zigetang lake showed higher delta13CDIC and delta18OH2O values compared to those of the rivers, the semi-closed Cona and open Ranwu lakes. The delta13CDIC values of lake water in Zigetang Co were mainly controlled by CO2 exchange between lake water and atmosphere; the delta18OH2O values were dominated by the evaporation/freshwater input ratios. PMID- 28664762 TI - Induced pluripotent stem cell-based therapy for age-related macular degeneration. AB - INTRODUCTION: In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor. Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells. Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive. Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression. PMID- 28664763 TI - Brief compassion focused imagery for treatment of severe head injury. AB - OBJECTIVE: To determine whether participants with severe head injury (SHI) allocated to a brief compassion focused imagery (CFI) intervention show greater change in compassion than those exposed to relaxation imagery (RI). METHOD: Participants were exposed to a preparatory video to promote engagement and then randomly allocated to intervention. Pre- and post-preparatory measures were Motivation for Intervention and Fears of Compassion Scales, State-Trait Anxiety Inventory (STAI) and PANAS. Pre- and post-intervention self-report measures were the Empathy Quotient, Self-Compassion Scale, STAI and Relaxation Scale. Heart rate variability (HRV) was monitored throughout. RESULTS: Motivation for therapy increased after the preparatory video (z = 3.44, p = 0.001). Across the intervention, group differences were not found on self-report measures or HRV changes. When CFI and RI groups were pooled, improvement in relaxation (r = .41, p < 0.01) and state anxiety (r = .29, p < 0.05) were found across the intervention; these outcomes were not associated with changes in self-compassion or HRV. CONCLUSION: Brief CFI, a central aspect of compassion focused therapy, did not produce a reliable change in people with SHI. Enhanced motivation for psychological therapy after a brief preparatory video is relevant and underlines the need to understand mechanisms of action rather than the pursuing whole protocol approaches to therapy. PMID- 28664765 TI - Abstracts of the 7th Joint Meeting of teh Belgian and Dutch Working Groups of Invasive Cardiology. PMID- 28664766 TI - Exploring mobility & workplace choice in a flexible office through post-occupancy evaluation. AB - Developments in information and communication systems, organisational structure and the nature of work have contributed to the restructuring of work environments. In these new types of work environments, employees do not have assigned workplaces. This arrangement helps organisations to minimise rent costs and increase employee interaction and knowledge exchange through mobility. This post-occupancy evaluation (POE) study focuses on a flexible office in a Gold Leadership in Energy and Environmental Design-certified building in Istanbul. An integrated qualitative and quantitative POE technique with occupancy tracking via barcode scanning and instant surveying has been introduced. Using this unique approach, we examined the directives/drivers in workplace choice and mobility from different perspectives. The aggregated data was used to discern work-related consequences such as flexibility, workplace choice, work and indoor environment satisfaction, place attachment and identity. The results show that employees who have a conventional working culture develop a new working style: 'fixed-flexible working'. Practitioner Summary: This paper introduces a new POE approach for flexible offices based on occupancy tracking through barcode scanning to explore workplace choice and mobility. More than half (52.1%) of the participants have tended to choose the same desk every day. However, the satisfaction level of the 'mobile' employees was higher than that of the 'fixed flexible' employees. PMID- 28664767 TI - Health Research Ethics: Between Ethics Codes and Culture. AB - This article is meant to describe and analyze some of the ethical difficulties encountered in a pilot research on treatment decisions of patients with chronic viral hepatitis C infection in Romania. It departs from an overview of the main ethics codes, and it shows that social health research on patients falls in between institutional codes of ethics. Furthermore, the article moves on to analyze so-called "important moments" of empirical research, such as the implementation of the ethical protocol, dealing with informal payments and with information on shady actions, as well as requests of information from interviewed patients and deciding when and if to breach confidentiality. In an attempt to evaluate the ad hoc solutions found in the field, the concluding remarks discuss these issues at the threshold of theory and practice. PMID- 28664769 TI - Raised compartment pressures are frequently observed with tibial shaft fractures despite the absence of compartment syndrome: A prospective cohort study. AB - PURPOSE: To measure the intracompartmental pressures surrounding tibial fractures not exhibiting any clinical evidence of compartment syndrome. Our hypothesis was that pressures often exceed the recommended threshold of fasciotomy despite the absence of compartment syndrome, and hence diagnosis based on pressure measurements alone is unreliable. METHODS: Thirteen consecutive patients with closed tibial shaft fractures without clinical suspicion of compartment syndrome, and who were planned for intramedullary nailing, were prospectively enrolled. Compartment pressures ( P) in all four compartments of the affected leg were measured at the start of surgery and immediately after tibial reaming, and differential pressures (delta P) were calculated based on the diastolic blood pressure prior to induction of anaesthesia. RESULTS: No patients required reoperation in the post-operative period, as a result of an undiagnosed compartment syndrome. Using commonly quoted threshold pressure criteria, 62% (using P > 30 mmHg) and 23% of patients (using delta P < 30 mmHg) have been incorrectly diagnosed with compartment syndrome. CONCLUSIONS: We conclude that raised compartment pressures are frequently seen in patients with tibial shaft fractures; but in most cases, it does not equate to the presence of compartment syndrome. Diagnosis of compartment syndrome based on intracompartmental pressure measurements alone may result in unnecessary fasciotomies in a sizeable number of patients. Compartment syndrome remains a clinical diagnosis, and one which always needs to be considered when managing tibial fractures. PMID- 28664768 TI - A biomechanical comparison of the two- and four-hole side-plate dynamic hip screw in an osteoporotic composite femur model. AB - OBJECTIVES: The objectives of this study were (1) to compare the axial and torsional stiffness of a dynamic hip screw with a two- and four-hole side-plate in a synthetic model of a healed and stable intertrochanteric femur fracture and (2) to evaluate the load to failure, as well as propensity to peri-implant fracture. METHODS: Fourth-generation synthetic composite femur models, simulating osteoporotic bone, were implanted with 135 degrees dynamic hip screws (DHS) with either a two- or four-hole side-plate with or without a stable intertrochanteric fracture. Specimens were cyclically loaded up to a nondestructive load to determine the axial and torsional stiffness. Constructs were then loaded to failure in axial compression emulating physiologic forces. Failure load and location of the peri-implant fractures were recorded. RESULTS: Axial and torsional stiffness did not differ significantly between the two- and four-hole constructs in either model. Likewise, there was no significant difference in the load to failure. In the intact femurs, failure occurred either at the end of the plate at the distal screw or through the lag screw hole. CONCLUSION: The results of this study demonstrate that DHS constructs with a two- or four-hole side-plate are biomechanically comparable with regard to axial and torsional stiffness and load to failure in an osteoporotic composite femur model. In a healed intertrochanteric fracture model, a two-hole construct did not appear to be more prone to peri-implant fracture. To date, a biomechanical comparison of these two implants with regard to torsional forces has not been reported. PMID- 28664770 TI - Advanced MRI measures like DTI or fMRI should be outcome measures in future clinical trials - NO. PMID- 28664771 TI - Social support relationships for sexual minority women in Mumbai, India: a photo elicitation interview study. AB - Little research exists on women who do not identify as heterosexual in India. Social support for sexual minority women may protect against the effects of discrimination. An examination of significant social relationships may point to both strengths and weaknesses in this support. We aimed to understand relationship prioritisation and communication patterns associated with the social support of sexual minority women in Mumbai. In partnership with the Humsafar Trust, India's oldest and largest sexual and gender minority-advocacy organisation, we conducted photo-elicitation interviews with 18 sexual minority women, using participants' photographs to prompt dialogue about their social support. Intimate partners were a source of dependable support and many of those without relationships were seeking them. Participants' extended networks included friends and family as well as less formal relationships of social support. Participants mediated their communication with particular social network members, which involved filtering information sexual identity, romantic interests, and personal aspirations, among others. The diverse relationships that sexual minority women have in their social support networks may be used to guide programmes to improve health outcomes. PMID- 28664772 TI - Bendamustine hydrochloride in patients with B-cell malignancies who have comorbidities - is there an optimal dose? AB - INTRODUCTION: The majority of patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) present with comorbidities. Many of them are poor candidates for intensive chemo-immunotherapy regimens, such as FCR (fludarabine, cyclophosphamide, rituximab). Still, most clinical trials aim to enroll 'fit' patients, who poorly represent the community oncology population. Areas covered: In the past decade, bendamustine hydrochloride, a cytotoxic agent with structural similarities to both alkylating agents and purine analogs, has received widespread use in therapy of NHL and CLL, and has demonstrated a relatively favorable toxicity profile. However, bendamustine has not been well studied in patients with hematologic malignancies who have comorbidities. Here we review the clinical data on use of bendamustine in older and unfit patients with NHL and CLL, and analyze whether there is an optimal dose of bendamustine in patients who have significant comorbidities, including renal dysfunction. Expert commentary: Reduced intensity regimens of bendamustine are effective in CLL patients with comorbidities and renal dysfunction. Even with the introduction of targeted therapies, bendamustine will likely continue to be an important therapeutic option in patients with comorbidities because of its tolerability, efficacy and cost. PMID- 28664774 TI - Impact of Knowledge of Health Conditions on Sugar-Sweetened Beverage Intake Varies Among US Adults. AB - PURPOSE: This study examined associations between knowledge of sugar-sweetened beverage (SSB)-related health conditions and SSB intake among US adults. DESIGN: Quantitative, cross-sectional study. SUBJECT: The 2014 SummerStyles survey data for 4163 US adults (>=18 years) were used. MEASURES: The outcome measure was frequency of SSB intake (regular soda, fruit drinks, sports or energy drinks, sweetened coffee/tea drinks). Exposure measures were knowledge of 6 SSB-related health conditions: weight gain, diabetes, cavities, high cholesterol, heart disease, and hypertension. ANALYSIS: Six logistic regression models were used to estimate adjusted odds ratios (ORs) for consuming SSBs >=2 times/d according to knowledge of SSB-related health conditions. RESULTS: Overall, 37.8% of adults reported consuming SSBs >=2 times/d. Although most adults identified that weight gain (80.2%), diabetes (73.6%), and cavities (71.8%) are related to drinking SSBs, fewer adults identified high cholesterol (24.1%), heart disease (31.5%), and hypertension (33.0%) as being related to drinking SSBs. Crude analyses indicated that lower SSB intake was significantly associated with knowledge of the associations between SSBs and weight gain, diabetes, cavities, and heart disease. However, after adjustment for covariates, only lack of knowledge of the association between heart disease and SSBs was significantly associated with consuming SSBs >=2 times/d (OR = 1.29) than non-SSB consumers. CONCLUSIONS: The finding that knowledge of SSB-related health conditions, in general, was not associated with high SSB intake suggests that knowledge on SSB-related health conditions alone may not be sufficient for adult behavior change. PMID- 28664773 TI - The role of cardiac rehabilitation in secondary prevention after coronary events. AB - Background Coronary risk factor control in Europe is suboptimal and there are large variations in the nature of cardiac rehabilitation (CR) programmes offered to coronary heart disease patients. We aim to explore characteristics and risk factor control in patients recruited from two neighbouring hospitals offering CR with different content. Methods In a cross-sectional study, 1127 Norwegian patients hospitalized with acute myocardial infarction and/or a revascularization procedure attended a clinical visit and completed a questionnaire at 2-36 months' follow-up. The hospital of Vestfold provides comprehensive CR, while the hospital of Drammen provides mainly exercise-based CR. Results At follow-up, patients in Vestfold performed more physical activity ( p = 0.02), were less obese ( p = 0.02) and reported better medication adherence ( p = 0.02) than patients in Drammen. The perceived need for information and follow-up was higher in Drammen than Vestfold ( p < 0.001). The CR participation rate in Vestfold was 75% compared with 18% in Drammen. CR participation in Vestfold was associated with higher prevalence of smoking cessation ( p = 0.001), lower low-density lipoprotein cholesterol ( p = 0.01) and better medication adherence ( p = 0.02) compared with non-CR, in adjusted analyses. No differences in diet, body weight, or blood pressure control were found between CR and non-CR. Conclusions Vestfold, with comprehensive CR, had a higher participation rate and more risk factors on target than Drammen. Participation in CR in Vestfold was associated with higher levels of smoking cessation and medication adherence, and lower low-density lipoprotein cholesterol, but overall risk factor control is still deficient, underlining the need for improved understanding of barriers to optimal risk factor control. PMID- 28664775 TI - The Efficacy of Yoga as a Form of Treatment for Depression. AB - The purpose of this article was to systematically review yoga interventions aimed at improving depressive symptoms. A total of 23 interventions published between 2011 and May 2016 were evaluated in this review. Three study designs were used: randomized control trials, quasi-experimental, and pretest/posttest, with majority being randomized control trials. Most of the studies were in the United States. Various yoga schools were used, with the most common being Hatha yoga. The number of participants participating in the studies ranged from 14 to 136, implying that most studies had a small sample. The duration of the intervention period varied greatly, with the majority being 6 weeks or longer. Limitations of the interventions involved the small sample sizes used by the majority of the studies, most studies examining the short-term effect of yoga for depression, and the nonutilization of behavioral theories. Despite the limitations, it can be concluded that the yoga interventions were effective in reducing depression. PMID- 28664778 TI - A Fully Customized Baseline Removal Framework for Spectroscopic Applications. AB - The task of proper baseline or continuum removal is common to nearly all types of spectroscopy. Its goal is to remove any portion of a signal that is irrelevant to features of interest while preserving any predictive information. Despite the importance of baseline removal, median or guessed default parameters are commonly employed, often using commercially available software supplied with instruments. Several published baseline removal algorithms have been shown to be useful for particular spectroscopic applications but their generalizability is ambiguous. The new Custom Baseline Removal (Custom BLR) method presented here generalizes the problem of baseline removal by combining operations from previously proposed methods to synthesize new correction algorithms. It creates novel methods for each technique, application, and training set, discovering new algorithms that maximize the predictive accuracy of the resulting spectroscopic models. In most cases, these learned methods either match or improve on the performance of the best alternative. Examples of these advantages are shown for three different scenarios: quantification of components in near-infrared spectra of corn and laser-induced breakdown spectroscopy data of rocks, and classification/matching of minerals using Raman spectroscopy. Software to implement this optimization is available from the authors. By removing subjectivity from this commonly encountered task, Custom BLR is a significant step toward completely automatic and general baseline removal in spectroscopic and other applications. PMID- 28664779 TI - Luminescence Study of the Samarium(II) Sites in Samarium: Barium Octaborate as Differentiated by Excitation Wavelength and Temperature. AB - Divalent samarium incorporated in a barium octaborate matrix prepared by firing homogeneous precipitates has been studied with emission spectroscopy. One of the samarium sites associated with this product exhibits an extremely strong temperature dependence upon using an excitation wavelength of 532 nm. This effect allows for specific differentiation between the two major Sm(II) sites associated with this compound. Based on the assignment of the emission features to specific sites, the symmetry of the first samarium environment is thought to be C3 or C3v while that associated with the second site appears to be C2v. PMID- 28664780 TI - Adsorption of Water to Collagen as Studied Using Infrared (IR) Microspectroscopy Combined with Relative Humidity Control System and Quartz Crystal Microbalance. AB - Infrared (IR) microspectroscopy combined with a quartz crystal microbalance (QCM) together with an original relative humidity (RH) control system has been developed for studying water adsorption on a collagen film. The adsorbed water weights measured by QCM are almost similar for wetting and drying processes at 28 C, indicating that the collagen film is close to the water adsorption/desorption equilibria. A broad OH + NH stretching band area (3000-3700 cm-1) in the IR spectra of the collagen film increased linearly with the adsorbed weight until about 1.2 MUg/8.0 MUg dry collagen film at relative humidity (RH) = 40%, while at higher RH (60%, 80%), the band area deviates from the linear trend to the lower side, due to viscoelasticity and others. The OH + NH band can be simulated by four Gaussian components at 3440, 3330, 3210, and 3070 cm-1 with the relatively constant band areas of 3330 and 3070 cm-1 components due to amide A and B (NH) for increasing and decreasing RH. Bound water (3210 cm-1 component: short H bond) constitutes around 70% of total water (3440 + 3210 cm-1 band areas) at RH = 4.9% but decreases to 23% at RH = 80.3%, where free water (3440 cm-1 component: long H bond) becomes dominant over 70%. The peak shifts of C=O stretching (Amide I) and N-H bending (Amide II) can be understood by increasing hydrogen bonding of water molecules (bound water) bound to peptides at lower RH. The higher wavenumber shifts of CH stretching can be due to the loose binding of water molecules (free water) to aliphatic chains on the collagen surface, especially at higher RH. The present combined QCM-IR method is useful for studying amounts and natures of water adsorbing on biomolecules. PMID- 28664781 TI - Broadband Mid-Infrared Stand-Off Reflection-Absorption Spectroscopy Using a Pulsed External Cavity Quantum Cascade Laser. AB - Broadband mid-infrared molecular spectroscopy is essential for detection and identification of many chemicals and materials. In this report, we present stand off mid-infrared spectra of 1,3,5-trinitro-1,3,5-triazine or cyclotrimethylene trinitramine (RDX) residues on a stainless-steel surface measured by a broadband external cavity quantum cascade laser (QCL) system. The pulsed QCL is continuously scanned over 800 cm-1 in the molecular fingerprint region and the amplitude of the reflection signal is measured by either a boxcar-averager-based scheme or a lock-in-amplifier-based scheme with 1 MHz and 100 kHz quartz crystal oscillators. The main background noise is due to the laser source instability and is around 0.1% of normalized intensity. The direct absorption spectra have linewidth resolution around 0.1 cm-1 and peak height sensitivity around 10-2 due to baseline interference fringes. Stand-off detection of 5-50 ug/cm2 of RDX trace adsorbed on a stainless steel surface at the distance of 5 m is presented. PMID- 28664782 TI - Fast High-Resolution Screening Method for Reactive Surfaces by Combining Atomic Force Microscopy and Surface-Enhanced Raman Scattering. AB - A fast high-resolution screening method for reactive surfaces is presented. Atomic force microscopy (AFM) and surface-enhanced Raman spectroscopy (SERS) are combined in one method in order to be able to obtain both morphological and chemical information about processes at a surface. In order to accurately align the AFM and SERS images, an alignment pattern on the substrate material is exploited. Subsequent SERS scans with sub-micron resolution are recorded in 30 min per scan for an area of 100 * 100 um2 and are accompanied by morphological information, supplied by a fast AFM, of the same area. Hence, a complete reactivity overview is obtained within several hours with only a monolayer of reactant. To demonstrate the working principle of this method, a SERS substrate containing the alignment pattern and silver nanoparticle aggregates as catalytic sites is prepared to study the photo-catalytic reduction of p-nitrothiophenol ( p NTP). PMID- 28664783 TI - Discrete Spectrum Reconstruction Using Integral Approximation Algorithm. AB - An inverse problem in spectroscopy is considered. The objective is to restore the discrete spectrum from observed spectrum data, taking into account the spectrometer's line spread function. The problem is reduced to solution of a system of linear-nonlinear equations (SLNE) with respect to intensities and frequencies of the discrete spectral lines. The SLNE is linear with respect to lines' intensities and nonlinear with respect to the lines' frequencies. The integral approximation algorithm is proposed for the solution of this SLNE. The algorithm combines solution of linear integral equations with solution of a system of linear algebraic equations and avoids nonlinear equations. Numerical examples of the application of the technique, both to synthetic and experimental spectra, demonstrate the efficacy of the proposed approach in enabling an effective enhancement of the spectrometer's resolution. PMID- 28664784 TI - A Quantitative Fourier Transform Infrared Study of the Grafting of Aminosilane Layers on Lithium Niobate Surface. AB - Due to its impressive optical properties, lithium niobate (LiNbO3) is considered to be one of the most important ferroelectric materials. Its uses in sensing platforms require functionalization at the surface to enable the capture and quantifying of molecules. The current paper aims to demonstrate the covalent bonding of aminosilane layers to the LiNbO3 surface. Fourier transform infrared (FT-IR) analysis reveals the presence of an NbO-Si bond observable as a shoulder at the same wavenumber (975 cm-1) on the surfaces of LiNBO3 as well as on those of Nb2O5, using 3-(aminopropyl)trimethoxysilane (APTMS) or 3 (aminopropyl)methyldimethoxysilane (APDMS) precursors. This covalent bonding is confirmed by the insolubility of the silane coating in dimethyl sulfoxide (DMSO). A kinetic study of the aminosilane layer growth obtained by quantitative FT-IR analysis is also carried out. PMID- 28664785 TI - A Pragmatic Smoothing Method for Improving the Quality of the Results in Atomic Spectroscopy. AB - A new smoothing method for improvement on the quantification of spectral signals, which requires the previous knowledge of the functions that should be quantified, is presented. These functions are used as weighted coefficients in the proposed smoothing algorithm. This method is extremely effective in reducing the scatter of signals obtained by the multichannel analyzer and it could be applied in atomic and nuclear spectroscopies, preferably to these techniques where net counts are a linear function of the acquisition time, like total reflection X-ray fluorescence, micro X-ray fluorescence, etc. If this algorithm is properly applied, it does not distort the form or the intensity of the signal, so it is well suited for use in all kinds of spectroscopic techniques. However, it should not be applied to data obtained from systems depending on time, e.g., control sciences, time series, sound analysis, etc. We applied this method over simulated data and real experimental measurements. As with all smoothing techniques, the proposed method improves the precision of the results, but when it was applied to computer-simulated spectra, we found a systematic enhancement on the accuracy of the results. We still do not have an answer for this apparent paradox. We also have to evaluate, in spectral analysis, the improvement produced by this smoothing procedure over detection and quantification limits. When this algorithm is applied over experimental results, it is mandatory that the sought characteristic functions, required for this weighted smoothing method, should be obtained from a system with strong stability. If the sought signals are not perfectly clean, this method should be applied with care. PMID- 28664786 TI - Combining Dispersed Particle Extraction with Dried-Droplet Laser Ablation ICP-MS for Determining Platinum in Airborne Particulate Matter. AB - A combination of analyte pre-concentration using dispersed particle extraction (DPE) and dried-droplet laser ablation inductively coupled mass spectrometry (LA ICP-MS) was developed with the aim to quantify Pt and Pd in urban particulate matter with an aerodynamic diameter <=2.5 um (PM2.5). The PM2.5 aerosol was collected on cellulose ester filters during a sampling period of three days, with sampling intervals of 4 h only. Each of the filters was chemically digested, and the resulting solution was pre-concentrated using DPE. Droplets taken from the pre-concentrated sample were deposited on polymeric disks and dried. These dry spots were then analyzed by means of LA-ICP-MS. This approach allowed ICP-MS analysis of solutions with high content of dissolved sorbent particles coming from the DPE procedure. Furthermore, spectral interferences arising from sample inherent matrix elements as well as solvent-related interferences could be removed by the proposed approach. The method was validated by determining the Pt concentration in Bureau Communautaire de Reference certified reference material (BCR CRM) 723 road dust certified reference material and a good agreement with the certified value was obtained. The temporal variation of Pt during the three day sampling period is discussed, with respect to automotive traffic. The daily average of Pt measured in the air corresponds to typical values observed in urban areas in Central Europe. Although the pre-concentration of palladium is feasible with dispersed particle extraction, the method detection limits achieved here did not allow to quantify this element in the CRM or in the PM2.5 samples. The source for these high method detection limits for palladium are blank values arising from the filter material as well as the digestion procedure of the PM2.5 samples. Instrumental sensitivity of the approach would, however, suggest that palladium quantification is possible, provided the abovementioned blank issues are controlled better. PMID- 28664787 TI - Behavioral tracing demonstrates dietary nutrient discrimination in two-spotted crickets Gryllus bimaculatus. AB - Animals select appropriate diets to meet their nutritional requirements. Here, we demonstrate the availability for analysis of feeding preference using an orthopteran, the two-spotted cricket Gryllus bimaculatus. A time-course study of these insects, involving continuous recording and tracing behavior for 9 h, allowed us to monitor discrimination of diet that contained various nutrients. PMID- 28664789 TI - Advanced MRI measures like DTI or fMRI should be outcome measures in future clinical trials - YES. PMID- 28664788 TI - Will the recent hypertension trials change the guidelines? PMID- 28664790 TI - Current management strategies for peritoneal mesothelioma. AB - Mesothelioma of the peritoneum is a distinct entity that requires multidisciplinary care to improve oncological outcomes. In this article, we review the current management strategies discussed at the PSOGI meeting in Washington DC 2016 and provide evidence based recommendations for diagnosis and management of this disease. PMID- 28664791 TI - FOREWORD - special issue of International Journal of Hyperthermia - cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases. PMID- 28664792 TI - End of life planning for 'hard to reach' communities. AB - Do 'hard to reach' communities exist? Or is more required of us as healthcare professionals to explore creative ways of engaging those who experience significant barriers in accessing health services? PMID- 28664794 TI - Making the right moves. AB - Liaison psychiatry team lead Nicola Wood's collaborative approach to improving the care of older patients with dementia is enabling nurses to reduce the risk of delirium and distress. PMID- 28664795 TI - Social interaction is the best research strategy. AB - Last year, I visited some senior citizen centres in rural areas of the western United States to recruit older people at risk of developing depression for a study on social interaction and mental well-being. PMID- 28664796 TI - Excellent Dementia Care in Hospitals: A Guide to Supporting People with Dementia and their Carers James Jo Cotton Beth Knight Jules et al Excellent Dementia Care in Hospitals: A Guide to Supporting People with Dementia and their Carers 192pp L16.99 Jessica Kingsley 9781785921087 1785921088 [Formula: see text]. AB - Specialist nurse Jo James and colleagues in the dementia team at Imperial College Healthcare NHS Trust share their expertise and profound understanding of the needs of people with dementia in hospital in this useful guide for nurses and healthcare assistants. PMID- 28664797 TI - Nurse awareness of patients who may have incident delirium. AB - Delirium is a disturbance of attention and cognition that cannot be explained by pre-existing neurocognitive disorders. It can have serious consequences, including falls, increased mortality, longer hospital stays and an increased risk of long-term cognitive impairment. Delirium may be present on admission to hospital but, where it is not, nurses should identify people at risk. PMID- 28664798 TI - Doll Therapy in Dementia Care Mitchell Gary Doll Therapy in Dementia Care 136pp L17.99 Jessica Kingsley 9781849055703 184905570X [Formula: see text]. AB - This book is an engaging read from the beginning to end. It explains the needs of people with advanced dementia, particularly that for attachment, and how doll therapy is one of many approaches to engaging in person-centred care. PMID- 28664799 TI - Dabigatran versus warfarin in patients with atrial fibrillation. AB - Atrial fibrillation is associated with an increased risk of ischaemic stroke and mortality. Guidelines recommend non-vitamin K antagonist oral anticoagulants, or novel oral anticoagulants, as first choice of drug. While they do not require the meticulous dose adjustments that are required for warfarin, a clinical evaluation of appropriate dose is still necessary. Age and chronic kidney disease in patients with atrial fibrillation increase the risk of bleeding during anti thrombotic treatment. PMID- 28664800 TI - Use of probiotics for infection prevention in trauma patients. AB - Probiotics is a general term to describe the different species of healthy microbes that are usually found in our gastrointestinal tract and support our immune system. When ingested in adequate amounts, probiotics can provide health benefits to the host. Their ingestion is thought to replenish microbiota that may have been depleted from injury, medication or diet. When there is a depletion of microbiota, pathogenic bacteria can flourish and cause disease. PMID- 28664801 TI - World Health Organization endorses global action plan on rising incidence of dementia. AB - A global action plan on dementia endorsed by World Health Organization (WHO) member states has been welcomed by health experts. PMID- 28664802 TI - Poor outdoor access linked to depression. AB - Lack of access to gardens and outdoor spaces could harm care home residents' mental health, a study published in The Gerontologist has found. PMID- 28664803 TI - Simple ideas that could help remove the stigma associated with Alzheimer's disease. AB - Shelagh Robinson loves literature and helping others, yet like many other people with dementia, she feels as if she is defined her by her condition. PMID- 28664805 TI - Nursing care after death in Northern Ireland. AB - Essential facts According to the Registrar General Annual Report published in August 2016 there were 15,548 deaths in Northern Ireland in 2015, with almost two thirds being of people aged 75 or more. Almost half (48%) occurred in NHS hospitals, with a further 20% in other hospitals or nursing homes. PMID- 28664806 TI - Older people's experiences of cancer pain: a qualitative study. AB - Aim To consider how the older person constructs the experience of cancer pain and how this is informed by expectations and experiences. Method Nine older people with cancer were asked to keep diaries and subsequently interviewed about their experiences of living with cancer and pain. Findings Five themes were identified better to be old than to be dying with cancer, maintaining control and independence, loss of identity in adapting and grieving for a former self, dislike of analgesia and denial of pain. The themes give a perspective on the embodied meaning of 'pain' in daily life. Conclusion Clinical pain assessment alone, without listening to people's pain stories, does not always identify pain or problems with daily living. Appreciation of the individuality of the lived experience of cancer can advance our understanding of pain and end of life care. PMID- 28664807 TI - Two more nurses enter parliament. AB - The nursing presence in parliament increased last month after two nurses were elected to the House of Commons. PMID- 28664808 TI - 'You are not doing your best - you can always do better'. AB - Why did you become a nurse? What might you have done otherwise? I wanted to make a positive contribution to society and have always liked to care for people. I worked as a staff nurse on acute medical wards and an intensive care unit before working for social services in older people's residential care. I returned to nursing as an infection control nurse. PMID- 28664810 TI - RCN's case of memories helps people remember. AB - Boxes containing ear syringes, blood pressure monitors (pictured) and other nursing items from early in the NHS's history are being shared with people with dementia to help them recall the past. PMID- 28664809 TI - Importance of nutrition in preventing and treating pressure ulcers. AB - Pressure ulcers are painful, and affect patients' health, mobility and well being. They also cost the NHS between L1.4-2.1 billion a year. Although a large proportion of pressure ulcers are avoidable, many still occur and, because pressure ulcer incidence is an indicator of care quality, it can put carers under scrutiny. The National Institute for Health and Care Excellence states that adequate risk assessment of pressure ulcer development, including the role of malnutrition, improves care. Adequate nutrition is vital for the prevention of pressure ulcers and malnutrition can hinder healing when pressure ulcers have developed. The risk of malnutrition should be assessed with a recognised tool, such as the Malnutrition Universal Screening Tool, and appropriate treatment plans should be drawn up for patients identified as being at risk of malnutrition to improve their nutritional state. For example, the dietary intake of people with poor appetite can be supplemented with nutritious snacks between meals. The aims of this article are to help readers understand risk factors for malnutrition and how dietary intake can be manipulated to improve patients' nutritional state. It also aims to highlight how improving nutritional intake helps to prevent pressure ulcers. On completing the article, readers will be able to consider and review their own practice. PMID- 28664811 TI - How can I help older people in hospital get home sooner and prevent deconditioning? AB - Concerns about the complications of prolonged bed rest were raised as far back as 1947 ( Asher 1947 ). Hospital stays are associated with iatrogenic infections, medication errors, increased risk of delirium and side effects of prolonged bed rest ( Inouye and Charpentier 1996 , Covinsky et al 2011 ). PMID- 28664812 TI - Preserving vision and promoting visual health in older people. AB - Reduction in vision is not inevitable but a manageable consequence of getting older. Some physiological and disease processes associated with ageing may reduce vision and, in some cases, this reduction in vision cannot be treated. Much of it can be prevented, however. Prevention of visual loss is one of the keys to the maintenance of independence in older people. This article describes the main visual conditions associated with ageing and considers what can and should be done by the older person and their network of friends, relatives and carers to ensure that vision is maintained by the early detection and treatment of eye problems and that independence is maintained by putting strategies in place to help the person manage any untreatable vision loss. PMID- 28664813 TI - Healthcare innovations could save NHS billions of pounds. AB - Seven healthcare innovations could save the NHS L18.5 billion and the social care sector L6.3 billion in 15 years, according to the International Longevity Centre UK (ILC-UK). PMID- 28664814 TI - Nicola Wood's achievements can help inspire others. AB - The RCNi Nurse Awards ceremony is a showcase of talent and achievement that lives on beyond the event. Many of this year's shortlisted entries in the Nursing Older People category are examples of practice by nurses who are unafraid of challenging established ways of working or of championing improved outcomes for older people. PMID- 28664817 TI - Advanced MRI measures like DTI or fMRI should be outcome measures in future clinical trials - Commentary. PMID- 28664816 TI - CYP2C19*17 protects against metabolic complications of clozapine treatment. AB - OBJECTIVES: Clozapine (CZ) is the most effective drug for managing treatment resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients. METHODS: We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes. RESULTS: Thirty-nine percent of genotyped patients were carriers of the CYP2C 19*17 polymorphism. This group demonstrated significantly higher NCZ serum levels, and significantly lower fasting glucose (5.66 +/- 1.19 vs 6.72 +/- 3.01 mmol/l, P = 0.009) and Hb1Ac (35.36 +/- 4.78 vs 49.40 +/- 20.60 mmol/mol, P = 0.006) levels compared to non-carriers of this polymorphism. CZ-treated patients with CYP2C19*17/*17 had a significantly lower prevalence of diabetes as well as a higher likelihood of clinical improvement of their schizophrenia, compared to those without this polymorphism (P = 0.012 and P = 0.031, respectively). CONCLUSIONS: Our data suggest that CYP2C19*17 ultra-rapid-metaboliser status is a protective factor against the development of diabetes during clozapine treatment, and increases the likelihood of improvement in schizophrenia. The role of NCZ in treatment response and side effects, including metabolic syndrome, warrants further pharmacogenetic, pharmacokinetic and pharmacodynamic studies. PMID- 28664819 TI - Referees 2016. PMID- 28664818 TI - Erratum. PMID- 28664821 TI - De Novo IgA Nephropathy in a Renal Allograft. AB - Posttransplant glomerulonephritis is a complication of kidney transplant that can impair graft function and long-term graft survival. De novo immunoglobulin A disease in kidney allografts appears to be much less common than the recurrent disease, and in most cases it is diagnosed in protocol biopsies with no clinical evidence of disease or in association with other renal transplant pathologies such as chronic rejection. We present a case of de novo immunoglobulin A nephropathy presenting with overt proteinuria, microscopic hematuria, and progressive deterioration of renal function 30 months after renal transplant. PMID- 28664820 TI - Ten thousand kilometre transfer of cardiogenic shock patients on venoarterial extracorporeal membrane oxygenation for emergency heart transplantation: Cooperation between Reunion Island and Metropolitan France. AB - BACKGROUND: There is no heart transplantation centre on the French overseas territory of Reunion Island (distance of 10,000 km). The aim of this study was to describe the characteristics of cardiogenic shock adult patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO) who were transferred from Reunion Island to mainland France for emergency heart transplantation. METHODS: This retrospective observational study was conducted between 2005 and 2015. The characteristics and outcome of cardiogenic shock patients on VA-ECMO were compared with those of cardiogenic shock patients not on VA-ECMO. RESULTS: Thirty three cardiogenic shock adult patients were transferred from Reunion Island to Paris for emergency heart transplantation. Among them, 19 (57.6%) needed mechanical circulatory support in the form of VA-ECMO. Median age was 51 (33-57) years and 46% of the patients had ischaemic heart disease. Patients on VA-ECMO presented higher Sequential Organ Failure Assessment score ( p = 0.03). No death occurred during the medical transfer by long flight, while severe complications occurred in 10 patients (30.3%). Incidence of thromboembolic events, severe infectious complications and major haemorrhages was higher in the group of patients on VA-ECMO than in the group of patients not on VA-ECMO ( p <0.01). Seven patients from the VA-ECMO group (36.8%) and six patients from the non-VA ECMO group (42.9%, p=0.7) underwent heart transplantation after a median delay of 10 (4-29) days on the emergency waiting list. After heart transplantation, one year survival rates were 85.7% for patients on VA-ECMO and 83.3% for patients not on VA-ECMO ( p=0.91). CONCLUSIONS: This study suggests the feasibility of very long-distance medical evacuation of cardiogenic shock patients on VA-ECMO for emergency heart transplantation, with acceptable long-term results. PMID- 28664822 TI - Passenger Lymphocyte Syndrome in the ABO-Incompatible Kidney Transplant Recipient Receiving Rituximab. AB - Passenger lymphocyte syndrome is a rare but important disease in which the donor lymphocytes produce antibodies to the red blood cell antigens of the recipient, causing alloimmune hemolysis. It occurs in ABO blood group-mismatched solid-organ and/or bone marrow transplant. We report a case of passenger lymphocyte syndrome occurring after ABO-incompatible kidney transplant. The recipient received rituximab as a desensitization protocol. On posttransplant day 18, the recipient showed a fall in her hemoglobin levels without identifiable bleeding source and an elevation of total bilirubin. Although hemolytic anemia was suspected, schizocytes on the peripheral smear were not observed. Anti-B-type antibodies were detected, and a diagnosis of passenger lymphocyte syndrome was confirmed. The patient was successfully treated with steroid pulse therapy, an increase of mycophenolate mofetil to 2 g/day, and conversion from cyclosporine to tacrolimus. To our knowledge, this is the first demonstration of passenger lymphocyte syndrome in an ABO-incompatible kidney recipients receiving rituximab. PMID- 28664823 TI - EDITORIAL: New Avenues in Controlling Infectious Diseases. PMID- 28664824 TI - EDITORIAL: Validation Techniques for Therapeutic Molecules in Drug Discovery. PMID- 28664825 TI - Interlaboratory Comparison Test as an Evaluation of Applicability of an Alternative Edible Oil Analysis by 1H NMR Spectroscopy. AB - A proton (1H) NMR spectroscopic method was established for the quality assessment of vegetable oils. To date, several research studies have been published demonstrating the high potential of the NMR technique in lipid analysis. An interlaboratory comparison was organized with the following main objectives: (1) to evaluate an alternative analysis of edible oils by using 1H NMR spectroscopy; and (2) to determine the robustness and reproducibility of the method. Five different edible oil samples were analyzed by evaluating 15 signals (free fatty acids, peroxides, aldehydes, double bonds, and linoleic and linolenic acids) in each spectrum. A total of 21 NMR data sets were obtained from 17 international participant laboratories. The performance of each laboratory was assessed by their z-scores. The test was successfully passed by 90.5% of the participants. Results showed that NMR spectroscopy is a robust alternative method for edible oil analysis. PMID- 28664828 TI - Phage Therapy Approaches to Reducing Pathogen Persistence and Transmission in Animal Production Environments: Opportunities and Challenges. AB - The era of genomics has allowed for characterization of phages for use as antimicrobials to treat animal infections with a level of precision never before realized. As more research in phage therapy has been conducted, several advantages of phage therapy have been realized, including the ubiquitous nature, specificity, prevalence in the biosphere, and low inherent toxicity of phages, which makes them a safe and sustainable technology for control of animal diseases. These unique qualities of phages have led to several opportunities with respect to emerging trends in infectious disease treatment. However, the opportunities are tempered by several challenges to the successful implementation of phage therapy, such as the fact that an individual phage can only infect one or a few bacterial strains, meaning that large numbers of different phages will likely be needed to treat infections caused by multiple species of bacteria. In addition, phages are only effective if enough of them can reach the site of bacterial colonization, but clearance by the immune system upon introduction to the animal is a reality that must be overcome. Finally, bacterial resistance to the phages may develop, resulting in treatment failure. Even a successful phage infection and lysis of its host has consequences, because large amounts of endotoxin are released upon lysis of Gram-negative bacteria, which can lead to local and systemic complications. Overcoming these challenges will require careful design and development of phage cocktails, including comprehensive characterization of phage host range and assessment of immunological risks associated with phage treatment. PMID- 28664829 TI - Quantification of Induced Hypothermia from Aseptic Scrub Applications during Rodent Surgery Preparation. AB - Laboratory mice (Mus musculus) are prone to develop hypothermia during anesthesia for surgery, thus potentially impedinganesthetic recovery, wound healing, and future health. The core body temperatures of isoflurane-anesthetized mice areinfluenced by the choice of supplemental heat sources; however, the contribution of various surgical scrubs on the bodytemperatures of mice under gas anesthesia has not been assessed. We sought to quantify the effect of using alcohol (70%isopropyl alcohol [IPA]) compared with saline to rinse away surgical scrub on the progression of hypothermia in anesthetizedmice (n = 47). IPA, room temperature saline, or warmed saline (37 degrees C) was combined with povidone iodine and thenassessed for effects on core (rectal) and surface (infrared) temperatures. Agents were applied to a 2*2-cm shaved abdominalarea of mice maintained on a water-recirculating blanket (at 38 degrees C) under isoflurane anesthesia (1.5% to 2.0% at 0.6 L/min)for 30 min. Although all scrub regimens significantly decreased body temperature at the time of application, treatments thatincluded povidone-iodine led to the coldest core temperatures, which persisted while mice were anesthetized. Comparedwith room-temperature saline and when combined with povidone-iodine, warming of saline did not ameliorate heat loss.IPA alone demonstrated the most dramatic cooling of both surface and core readings at application but generated an unanticipatedwarming (rebound) phase during which body temperatures equilibrated with those of controls within minutes ofapplication. Although alcohol is inappropriate as a stand-alone agent for surgical skin preparation, IPA is a viable alternativeto saline-based rinses in this context, and its use should be encouraged within institutional guidance for rodent surgicalprocedures without concern for prolonged hypothermia in mice. PMID- 28664827 TI - Smoking behavior and beliefs about the impact of smoking on anti-tuberculosis treatment among health care workers. AB - SETTING: Tuberculosis (TB) health care facilities throughout Georgia. OBJECTIVE: To describe smoking behaviors among health care workers (HCWs) at TB facilities and determine HCWs' knowledge and beliefs regarding the impact of tobacco use on anti-tuberculosis treatment. DESIGN: Cross-sectional survey from May to December 2014 in Georgia. Adult HCWs (age ?18 years) at TB facilities were eligible. We administered a 60-question anonymous survey about tobacco use and knowledge of the effect of smoking on anti-tuberculosis treatment. RESULTS: Of the 431 HCWs at TB facilities who participated, 377 (87.5%) were female; the median age was 50 years (range 20-77). Overall, 59 (13.7%) HCWs were current smokers and 35 (8.1%) were past smokers. Prevalence of current smoking was more common among physicians than among nurses (18.6% vs. 7.9%, P < 0.0001). Among HCWs, 115 (26.7%) believed smoking does not impact anti-tuberculosis treatment, and only 25.3% of physicians/nurses received formal training in smoking cessation approaches. Physicians who smoked were significantly more likely to believe that smoking does not impact anti-tuberculosis treatment than non-smoking physicians (aOR 5.11, 95%CI 1.46-17.90). CONCLUSION: Additional education about the effect of smoking on TB treatment outcomes is needed for staff of TB health care facilities in Georgia. Nurses and physicians need more training about smoking cessation approaches for patients with TB. PMID- 28664830 TI - Genome-wide expression and methylation profiling reveal candidate genes in osteoarthritis. AB - OBJECTIVES: Osteoarthritis (OA) is a common degenerative disease of the synovial joints. Although numerous studies have been performed, the aetiology of OA remains unclear. Evidence suggests that DNA methylation plays important roles in OA. METHODS: Integrated analysis of five gene expression and one methylation profilings in OA was performed to identify differentially expressed genes (DEGs) and differentially methylated genes (DMGs), respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were then conducted to reveal the biological functions of DEGs and DMGs. The protein protein interaction network was finally constructed. RESULTS: A set of 500 DEGs and 1219 DMGs in OA was found when compared with normal tissues. Function analysis of DEGs and DMGs revealed 3 critical OA-related pathways. A total of 20 DEGs were screened whose expressions showed strongly negative correlations with DNA methylation levels. Among them, 4 up-regulated DEGs (BST2, HDAC4, ITGB2 and VCAM1) may be closely related to the pathogenesis of OA. CONCLUSIONS: The results of integrated analysis explored 3 OA-related pathways (rheumatoid arthritis, osteoclast differentiation and ECM-receptor interaction) and 4 candidate genes of OA (BST2, HDAC4, ITGB2 and VCAM1) that may be therapeutic targets. PMID- 28664831 TI - Opioid use in patients with polymyalgia rheumatica. AB - OBJECTIVES: To examine the trends of chronic opioid use in patients with polymyalgia rheumatica (PMR) over an 11-year period in Olmsted County, Minnesota, USA and compare use to subjects without the disease. METHODS: Retrospective data on opioid prescriptions were collected from 2005 to 2015 in a population-based incidence cohort of patients meeting the 2012 American College of Rheumatology classification criteria for PMR alongside comparison subjects. Poisson regression methods were used to compare opioid use between these groups. RESULTS: 244 patients with PMR and 211 non-PMR comparator subjects were included in the study. Rates of chronic opioid use were not significantly different between the two groups. 7.5% of patients with PMR were identified as chronic users by the end of the study period compared with 5.2% of non-PMR subjects. Any opioid use was also not significantly higher in PMR, with relative risk of 1.10 (95% CI 0.97, 1.26, p=0.14). Rates of chronic use among patients over 80 years were higher in both groups. CONCLUSIONS: Patients with PMR do not appear to have higher rates of opioid use compared with the general population. PMID- 28664832 TI - Clinical determinants of elevated systolic pulmonary artery pressure measured by transthoracic Doppler echocardiography in early systemic sclerosis. AB - OBJECTIVES: To explore the prevalence and clinical associations of elevated systolic pulmonary artery pressure (sPAP), measured by Transthoracic Doppler echocardiography (TTE) in patients with early systemic sclerosis (SSc). METHODS: A cross-sectional analysis of the prospective EULAR Scleroderma Trial and Research (EUSTAR) database was performed. SSc patients with <3 years from the first non-Raynaud's phenomenon (RP) symptom at baseline EUSTAR visit, were selected. Elevated sPAP was defined as sPAP>40 mmHg on baseline TTE. First visit SSc related variables, including disease subsets, antibodies and visceral involvement, were examined. RESULTS: From 1,188 patients, 81% were women. Mean (SD) age at first non-RP symptom was 50 (14) years, 55% had limited cutaneous SSc (lcSSc) and 42% active disease. Elevated sPAP was found in 17% of patients, both lcSSc and diffuse cutaneous SSc (dcSSc). In lcSSc, older age at first non-RP symptom, ACA positivity, joint contractures, restrictive defect and lower DLCO, were independently associated with elevated sPAP. In dcSSc, older age at first non-RP symptom, longer time between RP onset and first non-RP symptom, digital ulcers, cardiac blocks, and proteinuria were associated with elevated sPAP. CONCLUSIONS: The prevalence of elevated sPAP on TTE in early SSc patients is considerable. Association with cardiac, lung and renal involvement suggests that, although some patients might have pulmonary arterial hypertension, others may present pulmonary hypertension secondary to lung or heart involvement. Our findings emphasize the need to consider right heart catheterisation in selected early SSc patients with PH suspicion, to clearly determine the cause of PH. PMID- 28664833 TI - Significance of pentraxin-3 in patients with juvenile scleroderma. PMID- 28664834 TI - Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCISTM). AB - OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). The pathological pathways involved in fibrogenesis in IPF and interstitial lung disease associated with systemic sclerosis (SSc-ILD) show commonalities; both involve fibroblast activation, myofibroblast accumulation and deposition of extracellular matrix. The SENSCISTM trial is a randomised, placebo-controlled Phase III trial that will evaluate the efficacy and safety of nintedanib in patients with SSc-ILD (NCT02597933). METHODS: Approximately 520 patients with SSc (based on 2013 American College of Rheumatology/European League Against Rheumatism criteria) and ILD (>=10% fibrosis of the lungs, confirmed by central assessment of chest high resolution computed tomography), forced vital capacity (FVC) >=40% predicted and diffusing capacity for carbon monoxide of 30-89% predicted will be enrolled. Patients will be randomised (1:1) to nintedanib 150 mg twice daily or placebo, stratified by the presence of anti-topoisomerase I antibody. To reflect real-world management, patients receiving prednisone (<=10 mg/day) and/or a stable dose of mycophenolate or methotrexate, will be eligible. The primary endpoint is the annual rate of decline in FVC (mL/ year) assessed over 52 weeks. Patients will remain on blinded study treatment until the last patient completes 52 weeks of treatment or for a maximum of 100 weeks of treatment. Key secondary endpoints are absolute changes from baseline in modified Rodnan skin score and St George's Respiratory Questionnaire at week 52. RESULTS: Recruitment for the trial began in November 2015. CONCLUSIONS: This trial will assess the efficacy and safety of nintedanib in patients with SSc-ILD. PMID- 28664835 TI - Prevalence and significance of anti-saccharomyces cerevisiae antibodies in primary Sjogren's syndrome. AB - OBJECTIVES: Saccharomyces cerevisiae is a common yeast used in the food industry. IgG and IgA antibodies against the phosphopeptidomannan of the S. cerevisiae cell wall (ASCA) are a well known marker of disease severity in Crohn's disease. Moreover, a number of studies assessed ASCA in several systemic and organ specific autoimmune diseases postulating molecular mimicry as a possible link between ASCA and autoimmunity. However, since they have never been tested in primary Sjogren's syndrome (pSS), the purpose of this study was to investigate these antibodies in a large cohort of pSS patients, compared to healthy donors (HD), and their significance as potentially helpful biomarker in a clinical setting. METHODS: ASCA IgG+IgA were assessed with ASCA screen dot for Blue Diver instrument (Alphadia sa/nv, Belgium). The comparison between the aminoacid sequence of mannan of S. cerevisiae and well characterised auto-antigens peculiar to pSS (52kD and 60kD Ro/SSA, La/SSB) was performed with the Basic Local Alignment Search Tool (BLAST). RESULTS: The prevalence of ASCA in our pSS cohort was 4.8%. We also reported that the ASCA target protein has a high similarity with Ro60/SSA protein further supporting the molecular mimicry hypothesis. Finally, we observed that ASCA positivity is associated with pSS specific clinical and serological features. ASCA+ pSS patients displayed a triple combination of circulating anti-Ro52/SSA, anti-Ro60/SSA and anti-La/SSB antibodies, associated with low complement and cutaneous involvement. CONCLUSIONS: Our data suggest a possible pathogenic/prognostic significance of ASCA in pSS. PMID- 28664836 TI - The use of hand perfusion scintigraphy to assess Raynaud's phenomenon associated with hand-arm vibration syndrome. AB - OBJECTIVES: This study aimed to evaluate the hand perfusion scintigraphic features of hand-arm vibration syndrome (HAVS) and to compare these with the features of primary and secondary Raynaud's phenomenon (RP) associated with systemic sclerosis (SSc). METHODS: Hand perfusion scintigraphy was performed in 57 patients with primary RP, 71 patients with HAVS-related RP, and 15 patients with SSc-related RP. We calculated 6 ratios: chilled to ambient hand and wrist ratios of the first peak height, initial slope, and blood pool uptake. We analysed 3 morphologic characteristics: slow progress pattern, paradoxically increased uptake pattern, and inhomogeneous radioactivity uptake. RESULTS: All of the 71 patients with HAVS-related RP were mine workers. The chilled to ambient hand ratios of the first peak height, the initial slope, and the blood pool uptake were significantly lower in patients with HAVS-related occupational RP than in patients with primary RP. The presence of a paradoxically increased uptake pattern was significantly lower in HAVS than in primary RP. CONCLUSIONS: There were significant differences in hand perfusion scintigraphic features between primary RP and HAVS. These results suggest that the underlying pathophysiology of the two diseases differs. PMID- 28664837 TI - Rituximab for the treatment of membranous nephropathy: a single-center experience. AB - BACKGROUND: Treatment of idiopathic membranous nephropathy with rituximab was introduced more than a decade ago following experimental data that suggested involvement of B-cell-mediated reactions in its pathogenesis. It was a logical step towards a more selective therapy with less severe side effects as compared to the recommended first-line immunosuppressive therapy with corticosteroids and different immunosuppressant drugs. METHODS: We retrospectively analyzed the anonymous data of patients who were treated with rituximab for idiopathic membranous nephropathy at our institution from January 2006 to July 2016. Daily proteinuria and serum creatinine were analyzed 3, 6, 9, and 12 months after rituximab application. The patients were divided into 4 groups according to proteinuria. We separately analyzed remission rates in the whole group and in groups with different quantity of daily proteinuria. Other history data and laboratory parameters were also compared within different groups of patients. RESULTS: The study involved 29 rituximab treatments in 26 patients: 7 (26.9%) female and 19 (73.1%) male patients. In 16 out of 29 treatment cases (55.1%), patients had been previously treated with cyclophosphamide and steroids, or cyclosporine with low dose of steroids, or both. In 72.4% of patients, antiphospholipase A2 receptor antibodies were present. In 2 cases of treatment (6.9%), patients received rituximab 375 mg/m2 of body surface area in 3 and 4 weekly doses, respectively. In all other cases, repeated rituximab applications were given as needed according to the levels of circulating CD-20 B-cells. The total remission rate in our cohort of patients was 37.9% (11 out of 29 cases). The average serum creatinine in the group of patients who achieved remission was significantly lower than in the group without remission (86.5 vs. 155.5 umol/L, p = 0.003). There was no difference in the duration of the disease prior to treatment with rituximab between the groups (53.6 and 56.4 months, respectively). The remission rate was highest in the group with daily proteinuria less than 4 g per day (83.3%). There were no remissions in the group of patients with daily proteinuria more than 12 g per day. CONCLUSION: The remission rate after rituximab treatment in our cohort of patients with idiopathic membranous nephropathy was lower than in other studies. The reason for this is possibly the application of a single dose of rituximab in the majority of patients, which might have been insufficient in patients with higher proteinuria.?. PMID- 28664838 TI - Treatment of antibody-mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: experience of Slovene National Center. AB - BACKGROUND: The aim of our study was to determine outcomes of standard treatment of antibody-mediated rejection (ABMR) of kidney grafts as compared to the addition of bortezomib or rituximab. METHODS: The cohort of this retrospective study included patients treated for ABMR of kidney grafts at our national center in the period of 2005 - 2017, divided into two groups: standard (ST) group treated standardly with plasmapheresis or immunoadsorption, intravenous immunoglobulins, and corticosteroids, and BR group treated with the addition of bortezomib and/or rituximab. Patient and graft survival at 2 years was analyzed by Kaplan-Meier method, and predictors of graft survival were analyzed by Cox regression. RESULTS: There were 78 patients with ABMR (48 in the ST group, 30 in the BR group), 41 (53%) were men, mean age 49.5 +/- 13.8 years. In ST and BR, respectively, mean serum creatinine was 267 +/- 164 and 208 +/- 112 umol/L (p = 0.088), donor-specific antibodies (DSA) were positive in 75% and 97% (p = 0.022), and ABMR was acute in 50% and 33% (p = 0.149). Patient survival at 2 years was 89% in the ST and 100% in the BR group (p = 0.125). Cumulative proportion of kidney graft survival at 1 and 2 years was 67% and 53% in the ST group and 73% and 48% in the BR group, respectively, (p = 0.641). Chronic ABMR (HR 5.22, p = 0.004) was significant, while dialysis dependency at biopsy (HR 3.28, p = 0.072), serum creatinine at kidney biopsy (HR 1.003, p = 0.082), and presence of DQ-DSA (HR 3.37, p = 0.062) were borderline significant predictors of worse graft outcome. Infections were relatively common in both groups, with a trend towards more rehospitalizations due to infections in the first 6 months after treatment in the BR group (p = 0.066). In 5 patients (17%), treatment with bortezomib was discontinued prematurely due to cytopenia. CONCLUSIONS: Bortezomib or rituximab, added to standard treatment, did not significantly improve kidney graft survival and was also not associated with significant side effects, except cytopenia in some cases. Treatment of acute ABMR resulted in better graft survival than chronic ABMR.?. PMID- 28664839 TI - Effects of paricalcitol on biomarkers of inflammation and fibrosis in kidney transplant recipients: results of a randomized controlled trial. AB - AIMS: Paricalcitol, a selective vitamin D activator, decreases proteinuria and may reduce graft failure risk in kidney transplant recipients. In this study, we evaluated the effect of paricalcitol on renin-angiotensin system (RAS) activity as well as interleukin (IL)-6 and transforming growth factor (TGF)-beta plasma concentrations as biomarkers of inflammation and fibrosis. METHODS: This placebo controlled, double-blind trial enrolled a national cohort of kidney transplant recipients with urinary protein-to-creatinine ratio (UPCR) >= 20 mg/mmol despite optimization of the RAS blockade. Patients were randomly assigned to receive 24 weeks of treatment with 2 ug/day paricalcitol or placebo. The primary endpoint was the percent change in geometric mean UPCR. In this secondary analysis, we examined the effect of paricalcitol on plasma renin activity (PRA) and aldosterone levels as well as IL-6 and TGF-beta plasma concentrations from baseline to last measurement during treatment. RESULTS: Of the 168 patients with UPCR >= 20 mg/mmol who consented to undergoing randomization, 83 were allocated to paricalcitol and 85 to placebo. Baseline patient demographics, clinical characteristics, PRA, and aldosterone levels were similar between groups. Mean change in IL-6 was -29% (from 2.53 to 2.02 pg/mL) in the paricalcitol group and 23% (from 2.07 to 2.54 pg/mL) in the placebo group (p < 0.001). Mean change in TGF-beta was -12% (from 8,011 to 6,935 pg/mL) in the paricalcitol group and 21% (from 7,418 to 8,992 pg/mL) in the placebo group (p < 0.001). CONCLUSION: In kidney transplant recipients, the addition of 2 ug/day paricalcitol to RAS inhibition lowers IL-6 and TGF-beta concentrations, which may be beneficial for reducing graft inflammation and fibrosis.?. PMID- 28664840 TI - Anticoagulation assessment methods in plasma exchange with regional citrate anticoagulation: evaluation of post-filter and filtered plasma ionized calcium. AB - AIM: To assess the possibility of using filtered plasma instead of postfilter ionized calcium (iCa) for the assessment of anticoagulation in plasma exchange (PE) with citrate anticoagulation. METHODS: 140 PE treatments were performed using either 4% or 15% citrate at a comparable dose. Paired samples of postfilter blood and filtered plasma were taken for iCa measurements with a point-of-care analyzer. Anticoagulation was also assessed with a bedside clotting time and visual assessment of the circuit after procedures. RESULTS: In 490 paired samples, mean postfilter iCa was 0.39 +/- 0.14 mmol/L, and filtered plasma iCa was 0.33 +/- 0.11 mmol/L. Mean bedside clotting time was 18 +/- 7 minutes. Neither the postfilter (r = 0.03, p = 0.73) nor the filtered plasma iCa (r = 0.09, p = 0.25) correlated significantly with bedside clotting time. Bland-Altman analysis showed a modest agreement between filtered plasma and postfilter iCa values (mean difference -0.07 mmol/L, upper and lower 95% limits of agreement 0.10 and -0.23 mmol/L). Median visual assessment score was excellent at all three checkpoints. CONCLUSIONS: A modest agreement between filtered plasma and postfilter iCa values could be acceptable if only a confirmation of anticoagulant effect is required. Measuring filtered plasma instead of postfilter iCa would reduce blood loss with sampling, which could be important in some settings.?. PMID- 28664842 TI - Difference between biomarkers of tibial bone marrow and adipose tissue. AB - BACKGROUND: Stem cells, with their regeneration capacity, long-term viability, and differentiation characteristics, have indispensable biological properties. As described by Hauner and Grigoradis et al., mesenchymal stem cell originating from adipose or bone marrow can be differentiated into many tissues such as adipocyte, chondrocyte, myeloblast, and osteoblast. The aim of our study is to compare the use of adipose and tibial bone marrow derived stem cells for therapeutic purposes in orthopedic surgery, which has not been clearly evaluated in the literature to our knowledge and to also evaluate their use. MATERIAL AND METHOD: Our study was performed between May 2014 and December 2016 in our clinic (Istanbul Medipol University, Department of Orthopedics and Traumatology) in 40 patients. Twelve patients were excluded. The ages of the 28 included patients ranged from 19 to 61 years, with a mean of 41.18 +/- 13.39 years. The stem cell samples of these patients were analyzed by flow cytometry. RESULTS: Tibial bone marrow stem cells were used in 15 cases and the mean age was 49.33 +/- 9.15. Adipose-derived stem cells were used in 13 patients and the mean age was 31.77 +/- 11.25. None of the patients had any minor/major complication in the areas where stem cells were collected. DISCUSSION: Tibial-derived bone marrow has better results with regard to the complications, economic burden, and surgery time. Tibial-derived bone marrow harvesting and stem cell preparation time are one-fourth of the stem cell treatment prepared from adipose tissue and the surgical duration is shortened by 45 min. CONCLUSION: If stem cell use is the preference of the surgeon, we have found that the tibial-derived stem cell system is more advantageous for ease of acquisition, cost analysis, and surgical time. PMID- 28664841 TI - Is Galba schirazensis (Mollusca, Gastropoda) an intermediate host of Fasciola hepatica (Trematoda, Digenea) in Ecuador? AB - Fasciolosis is a widely distributed disease in livestock in South America but knowledge about the epidemiology and the intermediate hosts is relatively scarce in Ecuador. For three months, lymnaeid snails were sampled (n = 1482) in Pichincha Province at two sites located in a highly endemic area. Snails were identified (based on morphology and ITS-2 sequences) and the infection status was established through microscopic dissection and a multiplex polymerase chain reaction (PCR)-based technique. Techniques based on morphology were not useful to accurately name the collected snail species. Comparison with available DNA sequences showed that a single snail species was collected, Galba schirazensis. Live rediae were observed in 1.75% (26/1482) and Fasciola sp. DNA was detected in 6% (89/1482) of collected snails. The COX-1 region permitted identification of the parasite as Fasciola hepatica. The relative sensitivity and specificity of the microscope study, compared to PCR results, were 25.84% and 99.78%, respectively. The mean size of the snails recorded positive for F. hepatica through crushing and microscopy was significantly higher than the mean size of negative snails, but there was no such difference in PCR-positive snails. The role of G. schirazensis as an intermediate host of F. hepatica in Ecuador is discussed and the hypothesis of an adaptation of the parasite to this invasive snail is proposed. For the first time, an epidemiological survey based on molecular biology-based techniques assessed the possible role of lymnaeid snails in the epidemiology of fasciolosis in Ecuador. PMID- 28664843 TI - Management of soft tissue tumors of the upper extremity: a review. AB - INTRODUCTION: Management of malignant tumors of the hand and wrist is challenging and is generally approached by limb salvage or amputation. With advances in care, amputation has been superseded by limb salvage as the treatment of choice. METHODS: A narrative literature review was performed to identify articles on the topic of management of soft tissue tumors of the upper extremity, including surgical management, adjuvant radiation therapy, and chemotherapy. RESULTS: A total of 29 articles were selected. Earlier reports favored radical tumor resection, which often led to amputation, whereas later articles demonstrated limb salvage as the preferential treatment modality. CONCLUSIONS: Given the detrimental effects on function and psychologic outcomes, amputation has been superseded by limb salvage in most cases, although it can occasionally be the only option. A variety of adjuvant therapies have been described, including radiation or brachytherapy, chemotherapy, and regional hyperthermia. Radiation treatment, and specifically brachytherapy, is beneficial to select patients. Controversy surrounds chemotherapy in certain subtypes, and regional hyperthermia requires further investigation. PMID- 28664845 TI - Whose advance directives are they, after all? PMID- 28664844 TI - Longus colli tendinitis. A review of literature and case series. AB - PURPOSE: To increase the awareness of longus colli tendinitis (LCT) among spine specialists and to present a practical overview of diagnostic and treatment options, so that unnecessary interventions are avoided. Five sample cases from a German spine center will also be presented. METHODS: Literature review and case series. A PubMed search was performed in May 2015, and the articles found were reviewed for clinical presentation, investigations, and treatment. The frequency of publication of LCT cases and the specialty of journals were also noted. Recent cases treated in our institution were also reviewed. The clinical findings, investigations, and therapeutic interventions were summarized. RESULTS: The PubMed search from May 2015 found 104 articles, published over 51 years, on the topic of LCT. Only four were published in spine journals. A review of this literature yielded a total of 242 cases. The classic clinical triad included neck pain, limitation of movements, and swallowing complaints. C-reactive Protein (CRP) values were available in 21 cases (mean 23.66 mg/dL). A contrast-enhanced computed tomography (CT) scan was the best diagnostic modality. LCT is usually a self-limiting condition, but non-steroidal anti-inflammatory drugs (NSAIDs) may help alleviate discomfort. Five cases of LCT were diagnosed and treated in our center over the past three years. CONCLUSIONS: LCT, which is uncommon and has non specific symptoms, is often referred to spine centers. Spine specialists should be aware of its clinical presentation and radiographic findings in order to avoid unnecessary interventions. The condition is self-limiting and can be treated conservatively. PMID- 28664846 TI - Clinical trial research in focus: time to reflect on the design of exacerbation trials in COPD. PMID- 28664847 TI - Thomas L Petty. PMID- 28664848 TI - Mesenchymal stem cell treatment for IPF-time for phase 2 trials? PMID- 28664849 TI - David Ashbaugh reminisces. PMID- 28664850 TI - Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome. AB - In the 50 years since acute respiratory distress syndrome (ARDS) was first described, substantial progress has been made in identifying the risk factors for and the pathogenic contributors to the syndrome and in characterising the protein expression patterns in plasma and bronchoalveolar lavage fluid from patients with ARDS. Despite this effort, however, pharmacological options for ARDS remain scarce. Frequently cited reasons for this absence of specific drug therapies include the heterogeneity of patients with ARDS, the potential for a differential response to drugs, and the possibility that the wrong targets have been studied. Advances in applied biomolecular technology and bioinformatics have enabled breakthroughs for other complex traits, such as cardiovascular disease or asthma, particularly when a precision medicine paradigm, wherein a biomarker or gene expression pattern indicates a patient's likelihood of responding to a treatment, has been pursued. In this Review, we consider the biological and analytical techniques that could facilitate a precision medicine approach for ARDS. PMID- 28664851 TI - Clinical trials in acute respiratory distress syndrome: challenges and opportunities. AB - This year is the 50th anniversary of the first description of acute respiratory distress syndrome (ARDS). Since then, much has been learned about the pathogenesis of lung injury in ARDS, with an emphasis on the mechanisms of injury to the lung endothelium and the alveolar epithelium. In terms of treatment, major progress has been made in reducing mortality from ARDS with lung-protective ventilation, using a tidal volume of 6 mL per kg of predicted bodyweight and a plateau airway pressure of less than 30 cm H2O. In more severely hypoxaemic patients with ARDS, neuromuscular blockade and prone positioning have further reduced mortality, probably by extending the therapeutic effects of lung protective ventilation. Fluid-conservative therapy has also increased ventilator free days in patients with ARDS. The lack of success of pharmacological therapies for ARDS, however, presents a continued challenge in the field. In addition to presenting a brief summary of previous experience with clinical trials in ARDS, we focus in this Review on future opportunities to improve clinical trial design to maximise the likelihood of identifying beneficial pharmacological therapies. In view of the heterogeneity in ARDS, both prognostic and predictive enrichment strategies are needed that target therapies toward specific subgroups of patients with ARDS on the basis of both severity and biology. Approaches to reducing heterogeneity in ARDS clinical trials include using physiological, radiographic, and biological criteria to select patients for both phase 2 and 3 trials. Additionally, interest is growing in the design of preventive clinical trials in ARDS and to initiate early treatment of patients with acute lung injury before the need for endotracheal intubation. We also present promising new approaches to treating ARDS, including combination therapies, cell-based therapies, and generic pharmacological compounds with low-risk profiles that are already in routine clinical use for other clinical indications. PMID- 28664852 TI - Reappraisal of the clinical effect of mepolizumab. PMID- 28664853 TI - Reappraisal of the clinical effect of mepolizumab - Authors' reply. PMID- 28664854 TI - Maximal bronchodilation: a therapeutic target in COPD? PMID- 28664855 TI - Clinical trial research in focus: improving drug development and trial design in pulmonary arterial hypertension. PMID- 28664856 TI - Controversies and conundrums in vocal cord dysfunction. PMID- 28664857 TI - Vocal cord dysfunction or inducible laryngeal obstruction: whatever it is, it exists. PMID- 28664858 TI - Australia's respiratory health in focus. PMID- 28664859 TI - Fighting for health: meet the doctor-activists. PMID- 28664860 TI - Clearing the air: do facemasks protect health? PMID- 28664862 TI - Lung volume reduction for emphysema. PMID- 28664861 TI - Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers? AB - Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2 receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF. PMID- 28664863 TI - Lung volume reduction for emphysema - Authors' reply. PMID- 28664865 TI - Corrections. PMID- 28664864 TI - The TRINITY study: Twitter discussion from a respirology journal club. PMID- 28664866 TI - The TRINITY study: Twitter discussion from a respirology journal club - Authors' reply. PMID- 28664867 TI - Corrections. PMID- 28664868 TI - Observations on non-random distribution of spores of Henneguya spp. (Cnidaria: Myxosporea: Myxobolidae) within plasmodia. AB - Species of the cnidarian genus Henneguya Thelohan, 1892 (Myxosporea: Myxobolidae) are histozoic parasites commonly found in freshwater and, more rarely, in marine fish. The development of these parasites in fish tissues includes the formation of plasmodia within which occurs the sporogony originating spores with two caudal processes, which are usually randomly distributed within the plasmodia. In this report the authors present some cases of non-random distribution of the spores of six species of Henneguya within their plasmodia. Two different patterns of non random distribution were found based on a literature survey. These patterns and their origin are discussed. Apparently this non-random distribution of the spores is due to both internal and external factors. PMID- 28664869 TI - Transparent p-CuI/n-BaSnO3-delta heterojunctions with a high rectification ratio. AB - Transparent p-CuI/n-BaSnO3-delta heterojunction diodes were successfully fabricated by the thermal evaporation of a (1 1 1) oriented gamma-phase CuI film on top of an epitaxial BaSnO3-delta (0 0 1) film grown by the pulsed laser deposition. Upon the thickness of the CuI film being increased from 30 to 400 nm, the hole carrier density was systematically reduced from 6.0 * 1019 to 1.0 * 1019 cm-3 and the corresponding rectification ratio of the pn diode was proportionally enhanced from ~10 to ~106. An energy band diagram exhibiting the type-II band alignment is proposed to describe the behavior of the heterojunction diode. A shift of a built-in potential caused by the hole carrier density change in the CuI film is attributed to the thickness-dependent rectification ratio. The best performing p-CuI/n-BaSnO3-delta diode exhibited a high current rectification ratio of 6.75 * 105 at +/-2 V and an ideality factor of ~1.5. PMID- 28664870 TI - Understanding the effects of packing and chemical terminations on the optical excitations of azobenzene-functionalized self-assembled monolayers. AB - In a first-principles study based on many-body perturbation theory, we analyze the optical excitations of azobenzene-functionalized self-assembled monolayers (SAMs) with increasing packing density and different terminations, considering for comparison the corresponding gas-phase molecules and dimers. Intermolecular coupling increases with the density of the chromophores independently of the functional groups. The intense [Formula: see text] resonance that triggers photo isomerization is present in the spectra of isolated dimers and diluted SAMs, but it is almost completely washed out in tightly packed architectures. Intermolecular coupling is partially inhibited by mixing differently functionalized azobenzene derivatives, in particular when large groups are involved. In this way, the excitation band inducing the photo-isomerization process is partially preserved and the effects of dense packing partly counterbalanced. Our results suggest that a tailored design of azobenzene functionalized SAMs which optimizes the interplay between the packing density of the chromophores and their termination can lead to significant improvements in the photo-switching efficiency of these systems. PMID- 28664871 TI - Influence of TiO2 and Si on the exciton-phonon interaction in PbI2 and CdS semiconductors evidenced by Raman spectroscopy. AB - The exciton-phonon interaction, considered as a stimulated Raman scattering process, is studied in different semiconductor mixtures: PbI2/TiO2, PbI2/Si and CdS/Si. Raman spectra recorded at excitation wavelengths of 514.5 and 488 nm for PbI2 and CdS, respectively, reveal a strong enhancement of the Raman lines peaked at 97 and 305 cm-1, evaluated by the ratio I TK/I 300 K between the relative intensities of the spectra recorded in the temperature range of 88-300 K. It is found that PbI2 and CdS exhibit a decrease in the Raman intensity modes with decreasing temperature, while in TiO2 and Si an increase in the Raman lines intensities peaked at 138 and 520 cm-1 is observed. This behavior can be explained by an energy transfer process from PbI2 or CdS towards TiO2 and Si. This explanation is supported by the schematic potential energy levels diagram obtained from the density of states, which is calculated using the density functional theory. According to this energy levels diagram, the electrons are expected to migrate directly from the conduction band (CB) energetic levels of the PbI2 and CdS towards the CB levels of TiO2 and Si. PMID- 28664872 TI - Exploring the effect of hole localization on the charge-phonon dynamics of hole doped delafossite. AB - For weak or moderate doping, electrical measurement is not suitable for detecting changes in the charge localization inside a semiconductor. Here, to investigate the nature of charge-phonon coupling in the presence of gradually delocalized holes within a weak doping regime (~1016 cm-3), we examine the temperature dependent Raman spectra (303-817 K) of prototype hole doped delafossite [Formula: see text] (x = 0/0.03, y = 0/0.01). For both [Formula: see text] and [Formula: see text] phonons, negative lineshape asymmetry and relative thermal hardening are distinctly observed upon [Formula: see text] and [Formula: see text] doping. Using Allen formalism, charge density of states at the Fermi level per spin and molecule, and charge delocalization associated to [Formula: see text] plane, are estimated to increase appreciably upon codoping compared to the [Formula: see text]-axis. We delineate the interdependence between charge-phonon coupling constant ([Formula: see text]) and anharmonic phonon lifetime ([Formula: see text]), and deduce that excitation of delocalized holes weakly coupled with phonons of larger [Formula: see text] is the governing feature of observed Fano asymmetry ([Formula: see text]) reversal. PMID- 28664873 TI - Efficient room temperature hydrogen sensor based on UV-activated ZnO nano network. AB - Room temperature hydrogen sensors were fabricated from Au embedded ZnO nano networks using a 30 mW GaN ultraviolet LED. The Au-decorated ZnO nano-networks were deposited on a SiO2/Si substrate by a chemical vapour deposition process. X ray diffraction (XRD) spectrum analysis revealed a hexagonal wurtzite structure of ZnO and presence of Au. The ZnO nanoparticles were interconnected, forming nano-network structures. Au nanoparticles were uniformly distributed on ZnO surfaces, as confirmed by FESEM imaging. Interdigitated electrodes (IDEs) were fabricated on the ZnO nano-networks using optical lithography. Sensor performances were measured with and without UV illumination, at room temperate, with concentrations of hydrogen varying from 5 ppm to 1%. The sensor response was found to be ~21.5% under UV illumination and 0% without UV at room temperature for low hydrogen concentration of 5 ppm. The UV-photoactivated mode enhanced the adsorption of photo-induced O- and O2- ions, and the d-band electron transition from the Au nanoparticles to ZnO-which increased the chemisorbed reaction between hydrogen and oxygen. The sensor response was also measured at 150 degrees C (without UV illumination) and found to be ~18% at 5 ppm. Energy efficient low cost hydrogen sensors can be designed and fabricated with the combination of GaN UV LEDs and ZnO nanostructures. PMID- 28664874 TI - In situ visualization and detection of surface potential variation of mono and multilayer MoS2 under different humidities using Kelvin probe force microscopy. AB - The surface potential (SP) variations in mono and multilayer molybdenum disulfide (MoS2) are visualized in situ and detected using Kelvin probe force microscopy (KPFM) in different humidity conditions for the first time. N-type doping, which originates from the SiO2 substrate, is discovered in the exfoliated MoS2 and is accompanied by a screening length of five layers. The influence of water, which serves as an environmental gating for MoS2, is investigated by controlling the relative humidities (RHs) in the environmental chamber. A monotonic decrease in the SP is observed when the threshold concentration is achieved. This corresponds to the Fermi level variation, which is dominated by different processes. The results also indicate that water adsorption could result in MoS2 p-type doping and provide compensation that partially counteracts the substrate effect. Under this condition, the interlayer screening effect is influenced because of the water dipole-induced electric field. Density functional theory calculations are performed to determine the band structure variations and the interactions between water molecules and between water molecules and the MoS2 surface in mono and trilayer MoS2 under different RHs. The calculations are in excellent agreement with the experimental results. We propose that in situ measurements of the SP using KPFM under different environmental regimes is a noninvasive and effective method to provide real-time visualization and detection of electronic property variations in two-dimensional materials. PMID- 28664875 TI - Surface potential modeling and reconstruction in Kelvin probe force microscopy. AB - Kelvin probe force microscopy (KPFM) measurement has been extensively applied in metallic, semiconductor and organic electronic or photovoltaic devices, to characterize the local contact potential difference or surface potential of the samples at the nanoscale. Here, a comprehensive modeling of surface potential in KPFM is established, from the well-known single capacitance model to a precise electrodynamic model, considering the long range property of the electrostatic force in KPFM. The limitations and relations of different models are also discussed. Besides, the feedback condition of the KPFM system is reconsidered and modified, showing that the influence of the cantilever has been overestimated by about 20% in previous reports. Afterwards, the surface potential of charged Si nanocrystals is reconstructed based on the electrodynamic model, and the calculated surface charge density is very consistent with the macroscopic capacitance-voltage (C-V) measurement. A deep understanding and correct reconstruction of surface potential is crucial to the quantitative analysis of KPFM results. PMID- 28664876 TI - Scaling-up of a HepaRG progenitor cell based bioartificial liver: optimization for clinical application and transport. AB - A new generation of bioartificial livers, based on differentiated proliferative hepatocyte sources, has been developed. Several practicable and regulatory demands have to be addressed before these can be clinically evaluated. We identified three main hurdles: (1) expansion and preservation of the biocomponent, (2) development of scaled-up culture conditions and (3) transport of the device to the bedside. In this study we address these three issues for the HepaRG-progenitor cell line-loaded AMC-Bioartificial Liver. (1) HepaRG cells were expanded in large quantities and then cryopreserved or loaded directly into bioreactors. After 3 weeks of culture, key hepatic functions (ammonia/lactate elimination, apolipoprotein A1 synthesis and cytochrome P450 3A4 activity) did not differ significantly between the two groups. (2) Bioartificial livers were scaled up from 9 ml to 540 ml priming volume, with preservation of normalized hepatic functionality. Quantification of amino acid consumption revealed rapid depletion of several amino acids. (3) Whole-device cryopreservation and cooled preservation induced significant loss of hepatic functionality, whereas simulated transport from culture-facility to the bedside in a clinical-grade transport unit with controlled temperature maintenance, medium perfusion and gas supply did not affect functionality. In addition, we assessed tumorigenicity of HepaRG cells in immune-incompetent mice and found no tumor formation of HepaRG cells (n = 12), while HeLa cells induced formation of carcinomas in eight out of 12 mice in 140 days. PMID- 28664877 TI - Birefringence of flow-assembled chitosan membranes in microfluidics. AB - Biopolymer membrane assembly in microfluidics offers precise spatial and temporal resolution for biomolecular and cellular interactions during and after assembly. Control over molecular transport across the biofabricated membranes requires microstructural characterization. This study investigates, for the first time, the birefringence of chitosan membranes assembled with flow in a microfluidic environment, and the effects of pH and flow rate on the membrane's micro alignment. The optical anisotropy of the formed membranes was quantified using a de Senarmont compensator for transmitted quantitative polarized light microscopy. The chitosan membranes were biofabricated within a small aperture in a microfluidic network with various flow and pH conditions of chitosan and alginate solutions. The measured optical retardance and parallelism index clearly indicate that the microstructure of the flow-assembled membrane was well organized and aligned along the direction of chitosan flow. Optical retardance increased significantly with the pH of the alginate solution, but was less sensitive to the variation of the flow rates of the polymer solutions during the biofabrication process. It was also determined that the birefringence signal dropped significantly across the membrane growth direction regardless of the molecular density in the membrane. The mechanism of the micro-alignment was discussed, which was presumably due to the molecular un-wrapping by shear flow. We envision that the current study paves a path to further understand and actively manipulate the microstructure of flow-assembled membranes for broad lab-on-a-chip applications. PMID- 28664879 TI - Numerical simulations of the hard X-ray pulse intensity distribution at the Linac Coherent Light Source. AB - Numerical simulations of the current and future pulse intensity distributions at selected locations along the Far Experimental Hall, the hard X-ray section of the Linac Coherent Light Source (LCLS), are provided. Estimates are given for the pulse fluence, energy and size in and out of focus, taking into account effects due to the experimentally measured divergence of the X-ray beam, and measured figure errors of all X-ray optics in the beam path. Out-of-focus results are validated by comparison with experimental data. Previous work is expanded on, providing quantitatively correct predictions of the pulse intensity distribution. Numerical estimates in focus are particularly important given that the latter cannot be measured with direct imaging techniques due to detector damage. Finally, novel numerical estimates of improvements to the pulse intensity distribution expected as part of the on-going upgrade of the LCLS X-ray transport system are provided. We suggest how the new generation of X-ray optics to be installed would outperform the old one, satisfying the tight requirements imposed by X-ray free-electron laser facilities. PMID- 28664878 TI - Three-dimensional reconstruction for coherent diffraction patterns obtained by XFEL. AB - The three-dimensional (3D) structural analysis of single particles using an X-ray free-electron laser (XFEL) is a new structural biology technique that enables observations of molecules that are difficult to crystallize, such as flexible biomolecular complexes and living tissue in the state close to physiological conditions. In order to restore the 3D structure from the diffraction patterns obtained by the XFEL, computational algorithms are necessary as the orientation of the incident beam with respect to the sample needs to be estimated. A program package for XFEL single-particle analysis based on the Xmipp software package, that is commonly used for image processing in 3D cryo-electron microscopy, has been developed. The reconstruction program has been tested using diffraction patterns of an aerosol nanoparticle obtained by tomographic coherent X-ray diffraction microscopy. PMID- 28664880 TI - Using refractive optics to broaden the focus of an X-ray mirror. AB - X-ray mirrors are widely used at synchrotron radiation sources for focusing X rays into focal spots of size less than 1 um. The ability of the beamline optics to change the size of this spot over a range up to tens of micrometres can be an advantage for many experiments such as X-ray microprobe and X-ray diffraction from micrometre-scale crystals. It is a requirement that the beam size change should be reproducible and it is often essential that the change should be rapid, for example taking less than 1 s, in order to allow high data collection rates at modern X-ray sources. In order to provide a controlled broadening of the focused spot of an X-ray mirror, a series of refractive optical elements have been fabricated and installed immediately before the mirror. By translation, a new refractive element is moved into the X-ray beam allowing a variation in the size of the focal spot in the focusing direction. Measurements using a set of prefabricated refractive structures with a test mirror showed that the focused beam size could be varied from less than 1 um to over 10 um for X-rays in the energy range 10-20 keV. As the optics is in-line with the X-ray beam, there is no effect on the centroid position of the focus. Accurate positioning of the refractive optics ensures reproducibility in the focused beam profile and no additional re-alignment of the optics is required. PMID- 28664881 TI - Very efficient spin polarization analysis (VESPA): new exchange scattering-based setup for spin-resolved ARPES at APE-NFFA beamline at Elettra. AB - Complete photoemission experiments, enabling measurement of the full quantum set of the photoelectron final state, are in high demand for studying materials and nanostructures whose properties are determined by strong electron and spin correlations. Here the implementation of the new spin polarimeter VESPA (Very Efficient Spin Polarization Analysis) at the APE-NFFA beamline at Elettra is reported, which is based on the exchange coupling between the photoelectron spin and a ferromagnetic surface in a reflectometry setup. The system was designed to be integrated with a dedicated Scienta-Omicron DA30 electron energy analyzer allowing for two simultaneous reflectometry measurements, along perpendicular axes, that, after magnetization switching of the two targets, allow the three dimensional vectorial reconstruction of the spin polarization to be performed while operating the DA30 in high-resolution mode. VESPA represents the very first installation for spin-resolved ARPES (SPARPES) at the Elettra synchrotron in Trieste, and is being heavily exploited by SPARPES users since autumn 2015. PMID- 28664882 TI - Structural variation in a synchrotron-induced contamination layer (a-C:H) deposited on a toroidal Au mirror surface. AB - A carbon layer deposited on an optical component is the result of complex interactions between the optical surface, adsorbed hydrocarbons, photons and secondary electrons (photoelectrons generated on the surface of optical elements). In the present study a synchrotron-induced contamination layer on a 340 mm * 60 mm Au-coated toroidal mirror has been characterized. The contamination layer showed a strong variation in structural properties from the centre of the mirror to the edge region (along the long dimension of the mirror) due to the Gaussian distribution of the incident photon beam intensity/power on the mirror surface. Raman scattering measurements were carried out at 12 equidistant (25 mm) locations along the length of the mirror. The surface contamination layer that formed on the Au surface was observed to be hydrogenated amorphous carbon film in nature. The effects of the synchrotron beam intensity/power distribution on the structural properties of the contamination layer are discussed. The I(D)/I(G) ratio, cluster size and disordering were found to increase whereas the sp2:sp3 ratio, G peak position and H content decreased with photon dose. The structural parameters of the contamination layer in the central region were estimated (thickness ? 400 A, roughness ? 60 A, density ? 72% of bulk graphitic carbon density) by soft X-ray reflectivity measurements. The amorphous nature of the layer in the central region was observed by grazing incidence X-ray diffraction. PMID- 28664884 TI - Protective radiolucent aluminium oxide coatings for beryllium X-ray optics. AB - Beryllium, being one of the most transparent materials to X-ray radiation, has become the material of choice for X-ray optics instrumentation at synchrotron radiation sources and free-electron laser facilities. However, there are concerns due to its high toxicity and, consequently, there is a need for special safety regulations. The authors propose to apply protective coatings in order to seal off beryllium from the ambient atmosphere, thus preventing degradation processes providing additional protection for users and prolonging the service time of the optical elements. This paper presents durability test results for Be windows coated with atomic-layer-deposition alumina layers run at the European Synchrotron Radiation Facility. Expositions were performed under monochromatic, pink and white beams, establishing conditions that the samples could tolerate without radiation damage. X-ray treatment was implemented in various environments, i.e. vacuum, helium, nitrogen, argon and dry air at different pressures. Post-process analysis revealed their efficiency for monochromatic and pink beams. PMID- 28664883 TI - Normal tracing deflectometry using a secondary light source. AB - Scanning deflectometric profilers based on an f-theta system are typical optical tools used to measure mirror profiles at many synchrotron facilities. Unlike these profilers, which are based on a pencil beam, here a secondary light source and a pinhole are used to construct a system that automatically selects a beam that will always pass through the pinhole and propagate along the normal direction of the measured area on the surface under test. By measuring the angle variation of the selected beam, slope variations of the surface under test can be measured. Systematic errors introduced by manufacturing defects or aberrations of an optical element, which greatly degrade the performance of traditional profilers, could be minimized by using the developed method. Simulation values of the proposed method and a conventional method are compared. PMID- 28664885 TI - A method to stabilize the incident X-ray energy for anomalous diffraction measurements. AB - A method to calibrate and stabilize the incident X-ray energy for anomalous diffraction data collection is provided and has been successfully used at the single-crystal diffraction beamline 1W2B at the Beijing Synchrotron Radiation Facilities. Employing a feedback loop to control the movement of the double crystal monochromator, this new method enables the incident X-ray energy to be kept within a 0.2 eV range at the inflection point of the absorption edge. PMID- 28664886 TI - In situ electrochemical high-energy X-ray diffraction using a capillary working electrode cell geometry. AB - The ability to generate new electrochemically active materials for energy generation and storage with improved properties will likely be derived from an understanding of atomic-scale structure/function relationships during electrochemical events. Here, the design and implementation of a new capillary electrochemical cell designed specifically for in situ high-energy X-ray diffraction measurements is described. By increasing the amount of electrochemically active material in the X-ray path while implementing low-Z cell materials with anisotropic scattering profiles, an order of magnitude enhancement in diffracted X-ray signal over traditional cell geometries for multiple electrochemically active materials is demonstrated. This signal improvement is crucial for high-energy X-ray diffraction measurements and subsequent Fourier transformation into atomic pair distribution functions for atomic-scale structural analysis. As an example, clear structural changes in LiCoO2 under reductive and oxidative conditions using the capillary cell are demonstrated, which agree with prior studies. Accurate modeling of the LiCoO2 diffraction data using reverse Monte Carlo simulations further verifies accurate background subtraction and strong signal from the electrochemically active material, enabled by the capillary working electrode geometry. PMID- 28664887 TI - X-ray reflectivity measurement of interdiffusion in metallic multilayers during rapid heating. AB - A technique for measuring interdiffusion in multilayer materials during rapid heating using X-ray reflectivity is described. In this technique the sample is bent to achieve a range of incident angles simultaneously, and the scattered intensity is recorded on a fast high-dynamic-range mixed-mode pixel array detector. Heating of the multilayer is achieved by electrical resistive heating of the silicon substrate, monitored by an infrared pyrometer. As an example, reflectivity data from Al/Ni heated at rates up to 200 K s-1 are presented. At short times the interdiffusion coefficient can be determined from the rate of decay of the reflectivity peaks, and it is shown that the activation energy for interdiffusion is consistent with a grain boundary diffusion mechanism. At longer times the simple analysis no longer applies because the evolution of the reflectivity pattern is complicated by other processes, such as nucleation and growth of intermetallic phases. PMID- 28664888 TI - Accuracy of stress measurement by Laue microdiffraction (Laue-DIC method): the influence of image noise, calibration errors and spot number. AB - Laue microdiffraction, available at several synchrotron radiation facilities, is well suited for measuring the intragranular stress field in deformed materials thanks to the achievable submicrometer beam size. The traditional method for extracting elastic strain (and hence stress) and lattice orientation from a microdiffraction image relies on fitting each Laue spot with an analytical function to estimate the peak position on the detector screen. The method is thus limited to spots exhibiting ellipsoidal shapes, thereby impeding the study of specimens plastically deformed. To overcome this difficulty, the so-called Laue DIC method introduces digital image correlation (DIC) for the evaluation of the relative positions of spots, which can thus be of any shape. This paper is dedicated to evaluating the accuracy of this Laue-DIC method. First, a simple image noise model is established and verified on the data acquired at beamline BM32 of the European Synchrotron Radiation Facility. Then, the effect of image noise on errors on spot displacement measured by DIC is evaluated by Monte Carlo simulation. Finally, the combined effect of the image noise, calibration errors and the number of Laue spots used for data treatment is investigated. Results in terms of the uncertainty of stress measurement are provided, and various error regimes are identified. PMID- 28664889 TI - Alternative difference analysis scheme combining R-space EXAFS fit with global optimization XANES fit for X-ray transient absorption spectroscopy. AB - Time-resolved X-ray absorption spectroscopy (TR-XAS), based on the laser-pump/X ray-probe method, is powerful in capturing the change of the geometrical and electronic structure of the absorbing atom upon excitation. TR-XAS data analysis is generally performed on the laser-on minus laser-off difference spectrum. Here, a new analysis scheme is presented for the TR-XAS difference fitting in both the extended X-ray absorption fine-structure (EXAFS) and the X-ray absorption near edge structure (XANES) regions. R-space EXAFS difference fitting could quickly provide the main quantitative structure change of the first shell. The XANES fitting part introduces a global non-derivative optimization algorithm and optimizes the local structure change in a flexible way where both the core XAS calculation package and the search method in the fitting shell are changeable. The scheme was applied to the TR-XAS difference analysis of Fe(phen)3 spin crossover complex and yielded reliable distance change and excitation population. PMID- 28664890 TI - Insight into growth of Au-Pt bimetallic nanoparticles: an in situ XAS study. AB - Au-Pt bimetallic nanoparticles have been synthesized through a one-pot synthesis route from their respective chloride precursors using block copolymer as a stabilizer. Growth of the nanoparticles has been studied by simultaneous in situ measurement of X-ray absorption spectroscopy (XAS) and UV-Vis spectroscopy at the energy-dispersive EXAFS beamline (BL-08) at Indus-2 SRS at RRCAT, Indore, India. In situ XAS spectra, comprising both X-ray near-edge structure (XANES) and extended X-ray absorption fine-structure (EXAFS) parts, have been measured simultaneously at the Au and Pt L3-edges. While the XANES spectra of the precursors provide real-time information on the reduction process, the EXAFS spectra reveal the structure of the clusters formed in the intermediate stages of growth. This insight into the formation process throws light on how the difference in the reduction potential of the two precursors could be used to obtain the core-shell-type configuration of a bimetallic alloy in a one-pot synthesis method. The core-shell-type structure of the nanoparticles has also been confirmed by ex situ energy-dispersive spectroscopy line-scan and X-ray photoelectron spectroscopy measurements with in situ ion etching on fully formed nanoparticles. PMID- 28664891 TI - Rotatable high-resolution ARPES system for tunable linear-polarization geometry. AB - A rotatable high-resolution angle-resolved photoemission spectroscopy (ARPES) system has been developed to utilize tunable linear-polarization geometries on the linear undulator beamline (BL-1) at Hiroshima Synchrotron Radiation Center. By rotating the whole ARPES measurement system, the photoelectron detection plane can be continuously changed from parallel to normal against the electric field vector of linearly polarized undulator radiation. This polarization tunability enables us to identify the symmetry of the initial electronic states with respect to the mirror planes, and to selectively observe the electronic states based on the dipole selection rule in the photoemission process. Specifications of the rotatable high-resolution ARPES system are described, as well as its capabilities with some representative experimental results. PMID- 28664892 TI - Potential of propagation-based synchrotron X-ray phase-contrast computed tomography for cardiac tissue engineering. AB - Hydrogel-based cardiac tissue engineering offers great promise for myocardial infarction repair. The ability to visualize engineered systems in vivo in animal models is desired to monitor the performance of cardiac constructs. However, due to the low density and weak X-ray attenuation of hydrogels, conventional radiography and micro-computed tomography are unable to visualize the hydrogel cardiac constructs upon their implantation, thus limiting their use in animal systems. This paper presents a study on the optimization of synchrotron X-ray propagation-based phase-contrast imaging computed tomography (PCI-CT) for three dimensional (3D) visualization and assessment of the hydrogel cardiac patches. First, alginate hydrogel was 3D-printed into cardiac patches, with the pores filled by fibrin. The hydrogel patches were then surgically implanted on rat hearts. A week after surgery, the hearts including patches were excised and embedded in a soft-tissue-mimicking gel for imaging by using PCI-CT at an X-ray energy of 25 keV. During imaging, the sample-to-detector distances, CT-scan time and the region of interest (ROI) were varied and examined for their effects on both imaging quality and radiation dose. The results showed that phase-retrieved PCI-CT images provided edge-enhancement fringes at a sample-to-detector distance of 147 cm that enabled visualization of anatomical and microstructural features of the myocardium and the implanted patch in the tissue-mimicking gel. For visualization of these features, PCI-CT offered a significantly higher performance than the dual absorption-phase and clinical magnetic resonance (3 T) imaging techniques. Furthermore, by reducing the total CT-scan time and ROI, PCI CT was examined for lowering the effective dose, meanwhile without much loss of imaging quality. In effect, the higher soft tissue contrast and low-dose potential of PCI-CT has been used along with an acceptable overall animal dose to achieve the high spatial resolution needed for cardiac implant visualization. As a result, PCI-CT at the identified imaging parameters offers great potential for 3D assessment of microstructural features of hydrogel cardiac patches. PMID- 28664893 TI - Preclinical radiotherapy at the Australian Synchrotron's Imaging and Medical Beamline: instrumentation, dosimetry and a small-animal feasibility study. AB - Therapeutic applications of synchrotron X-rays such as microbeam (MRT) and minibeam (MBRT) radiation therapy promise significant advantages over conventional clinical techniques for some diseases if successfully transferred to clinical practice. Preclinical studies show clear evidence that a number of normal tissues in animal models display a tolerance to much higher doses from MRT compared with conventional radiotherapy. However, a wide spread in the parameters studied makes it difficult to make any conclusions about the associated tumour control or normal tissue complication probabilities. To facilitate more systematic and reproducible preclinical synchrotron radiotherapy studies, a dedicated preclinical station including small-animal irradiation stage was designed and installed at the Imaging and Medical Beamline (IMBL) at the Australian Synchrotron. The stage was characterized in terms of the accuracy and reliability of the vertical scanning speed, as this is the key variable in dose delivery. The measured speed was found to be within 1% of the nominal speed for the range of speeds measured by an interferometer. Furthermore, dose measurements confirm the expected relationship between speed and dose and show that the measured dose is independent of the scan direction. Important dosimetric parameters such as peak dose, valley dose, the collimator output factor and peak to-valley dose ratio are presented for 5 mm * 5 mm, 10 mm * 10 mm and 20 mm * 20 mm field sizes. Finally, a feasibility study on three glioma-bearing rats was performed. MRT and MBRT doses were prescribed to achieve an average dose of 65 Gy in the target, and magnetic resonance imaging follow-up was performed at various time points after irradiation to follow the tumour volume. Although it is impossible to draw conclusions on the different treatments with such a small number of animals, the feasibility of end-to-end preclinical synchrotron radiotherapy studies using the IMBL preclinical stage is demonstrated. PMID- 28664894 TI - Comparison of phantom materials for use in quality assurance of microbeam radiation therapy. AB - Microbeam radiation therapy (MRT) is a promising radiotherapy modality that uses arrays of spatially fractionated micrometre-sized beams of synchrotron radiation to irradiate tumours. Routine dosimetry quality assurance (QA) prior to treatment is necessary to identify any changes in beam condition from the treatment plan, and is undertaken using solid homogeneous phantoms. Solid phantoms are designed for, and routinely used in, megavoltage X-ray beam radiation therapy. These solid phantoms are not necessarily designed to be water-equivalent at low X-ray energies, and therefore may not be suitable for MRT QA. This work quantitatively determines the most appropriate solid phantom to use in dosimetric MRT QA. Simulated dose profiles of various phantom materials were compared with those calculated in water under the same conditions. The phantoms under consideration were RMI457 Solid Water (Gammex-RMI, Middleton, WI, USA), Plastic Water (CIRS, Norfolk, VA, USA), Plastic Water DT (CIRS, Norfolk, VA, USA), PAGAT (CIRS, Norfolk, VA, USA), RW3 Solid Phantom (PTW Freiburg, Freiburg, Germany), PMMA, Virtual Water (Med-Cal, Verona, WI, USA) and Perspex. RMI457 Solid Water and Virtual Water were found to be the best approximations for water in MRT dosimetry (within +/-3% deviation in peak and 6% in valley). RW3 and Plastic Water DT approximate the relative dose distribution in water (within +/-3% deviation in the peak and 5% in the valley). PAGAT, PMMA, Perspex and Plastic Water are not recommended to be used as phantoms for MRT QA, due to dosimetric discrepancies greater than 5%. PMID- 28664895 TI - Effects of temperature, mechanical motion and source positional jitter on the resolving power of beamline 02B at the SSRF. AB - A detailed analysis of the effects of temperature excursions, instrumental mechanical motion and source position jitter on the energy-resolving power of beamline 02B at the Shanghai Synchrotron Radiation Facility (SSRF) is presented in this study. This beamline uses a bending-magnet-based source and includes a variable-line-spacing grating monochromator with additional optics. Expressions are derived for the monochromator output photon energy shifts for each of the performance challenges considered. The calculated results indicate that measured temperature excursions of +/-1 K produce an energy shift of less than 11% of the system's energy resolution. Mechanical displacements and vibrations measured at amplitudes of less than 0.5 um produce changes of less than 5%, while measured source location jitter results in a change of less than 10%. Spectroscopic test experiments at 250 and 400 eV provide energy resolutions of over 104. This analysis, combined with the measured results, confirms the operational stability of the beamline, indicating that it meets the performance requirements for experimental use. PMID- 28664897 TI - The relativistic foundations of synchrotron radiation. AB - Special relativity (SR) determines the properties of synchrotron radiation, but the corresponding mechanisms are frequently misunderstood. Time dilation is often invoked among the causes, whereas its role would violate the principles of SR. Here it is shown that the correct explanation of the synchrotron radiation properties is provided by a combination of the Doppler shift, not dependent on time dilation effects, contrary to a common belief, and of the Lorentz transformation into the particle reference frame of the electromagnetic field of the emission-inducing device, also with no contribution from time dilation. Concluding, the reader is reminded that much, if not all, of our argument has been available since the inception of SR, a research discipline of its own standing. PMID- 28664896 TI - Pump-probe experiments at the TEMPO beamline using the low-alpha operation mode of Synchrotron SOLEIL. AB - The SOLEIL synchrotron radiation source is regularly operated in special filling modes dedicated to pump-probe experiments. Among others, the low-alpha mode operation is characterized by shorter pulse duration and represents the natural bridge between 50 ps synchrotron pulses and femtosecond experiments. Here, the capabilities in low-alpha mode of the experimental set-ups developed at the TEMPO beamline to perform pump-probe experiments with soft X-rays based on photoelectron or photon detection are presented. A 282 kHz repetition-rate femtosecond laser is synchronized with the synchrotron radiation time structure to induce fast electronic and/or magnetic excitations. Detection is performed using a two-dimensional space resolution plus time resolution detector based on microchannel plates equipped with a delay line. Results of time-resolved photoelectron spectroscopy, circular dichroism and magnetic scattering experiments are reported, and their respective advantages and limitations in the framework of high-time-resolution pump-probe experiments compared and discussed. PMID- 28664898 TI - Anticancer Activity of Pterostilbene in Human Ovarian Cancer Cell Lines. AB - BACKGROUND Epithelial ovarian cancer is a major cause of mortality in women and one of the most common gynecologic disorders. Pterostilbene (PTS), a trans-3,5 dimethoxy-4'-hydroxystilbene, was chosen for this work due to its reported effectiveness as a chemotherapeutic agent in cancer studies. In this work, we studied underlying molecular mechanisms of PTS treatment in various ovarian cancer cell lines such as OVCAR8, OV1063, IGROV-1, and SKOV3. MATERIAL AND METHODS We used the cytometric bead array (CBA) method and real-time PCR analysis to analyze the secretion level of tumor necrosis factor alpha (TNF-alpha) and to measure the TNF-alpha mRNA expression. NF-kappa B (NF-kappaB) promoter analysis, Western blot analysis, electrophoresis mobility shift assay (EMSA), and immunostaining analyses were performed to measure the NF-kappaB activity and other relative proteins levels. RESULTS The PTS treatment decreased the release of TNF-alpha in IGROV-1 ovarian cancer cells. It also showed significant inhibitory effect on nuclear NF-kappaB p50, and NF-kappaB p65 protein levels. CONCLUSIONS From the results obtained, we suggest that PTS has the potential to treat ovarian cancer by reducing the level of TNF-alpha cytokine and to have a limited effect on NF-kappaB, AKT, and ERK signaling pathways. PMID- 28664899 TI - Corrigendum: Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth. AB - This corrects the article DOI: 10.1038/srep25521. PMID- 28664900 TI - Corrigendum: Resisting majesty: Apis cerana, has lower antennal sensitivity and decreased attraction to queen mandibular pheromone than Apis mellifera. AB - This corrects the article DOI: 10.1038/srep44640. PMID- 28664901 TI - Corrigendum: N-terminal pro b-type natriuretic peptide (NT-pro-BNP) -based score can predict in-hospital mortality in patients with heart failure. AB - This corrects the article DOI: 10.1038/srep29590. PMID- 28664902 TI - Corrigendum: Flow cytometry may allow microscope-independent detection of holocentric chromosomes in plants. AB - This corrects the article DOI: 10.1038/srep27161. PMID- 28664903 TI - Erratum: Uricase alkaline enzymosomes with enhanced stabilities and anti hyperuricemia effects induced by favorable microenvironmental changes. AB - This corrects the article DOI: 10.1038/srep20136. PMID- 28664904 TI - Corrigendum: What drives phenotypic divergence in Leymus chinensis (Poaceae) on large-scale gradient, climate or genetic differentiation? AB - This corrects the article DOI: 10.1038/srep26288. PMID- 28664905 TI - Air pressure changes in the creation and bursting of the type-1 big bubble in deep anterior lamellar keratoplasty: an ex vivo study. AB - PurposeTo measure the pressure and volume of air required to create a big bubble (BB) in simulated deep anterior lamellar keratoplasty (DALK) in donor eyes and ascertain the bursting pressure of the BB.Patients and methodsTwenty-two human sclera-corneal discs were used. Air was injected into the corneal stroma to create a BB and the pressure measured by means of a pressure converter attached to the system via a side port. A special clamp was designed to prevent air leak from the periphery of the discs. The pressure at which air emerged in the corneal tissue; the bursting pressure measured after advancing the needle into the bubble cavity and injecting more air; the volume of air required to create a BB and the volume of the BB were ascertained.ResultsType-1 BB were achieved in 19 and type-2 BB in 3 eyes. The maximum pressure reached to create a BB was 96.25+/- 21.61 kpa; the mean type-1 intrabubble pressure was 10.16 +/- 3.65 kpa. The mean bursting pressure of a type-1 BB was 66.65 +/- 18.65 kpa, while that of a type-2 BB was 14.77 +/- 2.44 kpa. The volume of air required to create a type-1 BB was 0.54 ml and the volume of a type-1 BB was consistently 0.1 ml.ConclusionsDua's layer baring DALK can withstand high intraoperative pressures compared to Descemet's membrane baring DALK. The study suggests that it could be safe to undertake procedures such as DALK-triple with a type-1 BB but not with a type-2 BB. PMID- 28664906 TI - Identification of pterygium-related mRNA expression profiling by microarray analysis. AB - PurposePterygium is a common degenerative and proliferative disease of the ocular surface. In some severe cases, pterygium may lead to irregular corneal astigmatism and corneal stromal scarring with visual impairment. The proliferative capacities of pterygial cells make them appear similar to tumorigenesis. Although considerable progress has been made towards understanding the etiology of the disease, the pathogenesis of pterygium has not been completely understood. In our previous study, we constructed pterygium-related lncRNA libraries by using microarray to investigate the potential roles of lncRNAs in pterygium. In this study, our objective was to explore the role of mRNA in pterygium.Patients and methodsIn this study, we constructed pterygium related mRNA libraries by using microarray to investigate the potential roles of mRNAs in pterygium. Quantitative real-time PCR (qRT-PCR) was performed to validate some of the deregulated mRNAs in 10 patients.ResultsA total of 1485 upregulated and 2978 downregulated mRNAs were identified in pterygium tissues compared with paired adjacent normal conjunctival tissues (log fold change>2.0). qRT-PCR was performed to validate four overregulated and two underregulated mRNAs in 10 patients.ConclusionsOur results reveal differentially expressed mRNAs in pterygium and suggest that mRNAs may be the novel molecular targets for therapy of pterygium. PMID- 28664908 TI - Parkinson disease: T cells recognize alpha-synuclein peptides in Parkinson disease. PMID- 28664907 TI - Erratum: Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions. AB - This corrects the article DOI: 10.1038/srep20069. PMID- 28664910 TI - Corrigendum: Engineering the residual side chains of HAP phytases to improve their pepsin resistance and catalytic efficiency. AB - This corrects the article DOI: 10.1038/srep42133. PMID- 28664911 TI - Corrigendum: Electrical Detection of Dengue Biomarker Using Egg Yolk Immunoglobulin as the Biological Recognition Element. AB - This corrects the article DOI: 10.1038/srep07865. PMID- 28664909 TI - Chemotherapy-induced peripheral neurotoxicity: management informed by pharmacogenetics. AB - The increasing availability of sophisticated methods to characterize human genetic variation has enabled pharmacogenetic data to be used not only to predict responses to treatment (in the context of so-called personalized medicine), but also to identify patients at high or low risk of specific treatment-related adverse effects. Over the past two decades, extensive attempts have been made to understand the genetic basis of chemotherapy-induced peripheral neurotoxicity (CIPN), one of the most severe non-haematological adverse effects of cancer treatment. Despite substantial efforts, however, the identification of a genetic profile that can detect patients at high risk of CIPN still represents an unmet need, as the information obtained from pharmacogenetic studies published so far is inconsistent at best. Among the reasons for these inconsistencies, methodological flaws and the poor reliability of existing tools for assessing CIPN features and severity are particularly relevant. This Review provides a critical update of the pharmacogenetics of CIPN, focusing on the studies published since 2011. Strategies for improving the reliability of future pharmacogenetic studies of CIPN are also discussed. PMID- 28664912 TI - A combined biomarker panel shows improved sensitivity for the early detection of ovarian cancer allowing the identification of the most aggressive type II tumours. AB - BACKGROUND: There is an urgent need for biomarkers for the early detection of ovarian cancer (OC). The purpose of this study was to assess whether changes in serum levels of lecithin-cholesterol acyltransferase (LCAT), sex hormone-binding globulin (SHBG), glucose-regulated protein, 78 kDa (GRP78), calprotectin and insulin-like growth factor-binding protein 2 (IGFBP2) are observed before clinical presentation and to assess the performance of these markers alone and in combination with CA125 for early detection. METHODS: This nested case-control study used samples from the United Kingdom Collaborative Trial of Ovarian Cancer Screening trial. The sample set consisted of 482 serum samples from 49 OC subjects and 31 controls, with serial samples spanning up to 7 years pre diagnosis. The set was divided into the following: (I) a discovery set, which included all women with only two samples from each woman, the first at<14 months and the second at >32 months to diagnosis; and (ii) a corroboration set, which included all the serial samples from the same women spanning the 7-year period. Lecithin-cholesterol acyltransferase, SHBG, GRP78, calprotectin and IGFBP2 were measured using ELISA. The performance of the markers to detect cancers pre diagnosis was assessed. RESULTS: A combined threshold model IGFBP2 >78.5 ng ml-1 : LCAT <8.831 MUg ml-1 : CA125 >35 U ml-1 outperformed CA125 alone for the earlier detection of OC. The threshold model was able to identify the most aggressive Type II cancers. In addition, it increased the lead time by 5-6 months and identified 26% of Type I subjects and 13% of Type II subjects that were not identified by CA125 alone. CONCLUSIONS: Combined biomarker panels (IGFBP2, LCAT and CA125) outperformed CA125 up to 3 years pre-diagnosis, identifying cancers missed by CA125, providing increased diagnostic lead times for Type I and Type II OC. The model identified more aggressive Type II cancers, with women crossing the threshold dying earlier, indicating that these markers can improve on the sensitivity of CA125 alone for the early detection of OC. PMID- 28664913 TI - KIBRA attains oncogenic activity by repressing RASSF1A. AB - BACKGROUND: KIBRA-initially identified as a neuronal associated protein is now shown to be functionally associated with other tissue types as well. KIBRA interacts with dyenin light chain 1 and this interaction is essential for oestrogen receptor transactivation in breast cancer cells. KIBRA as a substrate of Cdk1, Aurora kinase and ERK plays an important role in regulating cell cycle, cell proliferation and migration. Despite these evidences, the exact role of KIBRA in cancer progression is not known. METHODS: We studied the expression of KIBRA in breast tissues and breast cancer cell lines by western blotting, immunohistochemisry (IHC) and RT-PCR. Stable over expression and knockdown clones were generated to study the transforming properties of KIBRA by conventional assays. Xenograft studies were performed in nude mice to study the in vivo tumourigenic efficacy of KIBRA. qPCR array was performed to understand the molecular mechanism behind oncogenic activity of KIBRA. RESULTS: Our results showed that KIBRA is upregulated in breast cancer cells and in malignant human breast tumours by both western blotting and IHC. Interestingly, we found that KIBRA expression level goes up with increase in breast cancer progression in well established MCF10A model system. Further, results from stable overexpression clones of KIBRA in fibroblasts (Rat-1) and epithelial breast cancer cells (ZR75) and lentiviral short hairpin RNA-mediated knockdown (KD) clones of KIBRA in ZR75 showed increase in transforming properties with KIBRA overexpression and vice versa. Results also showed that fibroblasts stably overexpressing KIBRA showed increased tumourigenic potential in nude mice. By adopting a quantitative PCR array-based approach, we identified RASSF1A, a tumour suppressor, as a transcriptional target of KIBRA. CONCLUSIONS: This is the first study to demonstrate the in vivo tumourigenic property of KIBRA in a nude mouse model and also unravel the underlying molecular mechanism of KIBRA-mediated transformation via repression of RASSF1A.British Journal of Cancer advance online publication, 29 June 2017; doi:10.1038/bjc.2017.192 www.bjcancer.com. PMID- 28664914 TI - LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression. AB - BACKGROUND: LIM kinase 1 (LIMK1) is a key regulator of the cytoskeletal organisation involved in cell proliferation and migration. Even though LIMK1 is frequently dysregulated in epithelial cancers, the role and mechanisms of LIMK1 in colorectal cancer (CRC) remains unclear. METHODS: Immunohistochemical analysis was performed to examine the expression and clinical significance of LIMK1 in CRC samples. Loss- and gain-of-function assay was performed to investigate the effects of aberrant expression on cellular biological behaviour of CRC cells in vitro and in vivo. Immunoblotting and immunoprecipitation was used to screen LIMK1-related signalling pathways and downstream factors. RESULTS: In this study, our results showed that LIMK1 was upregulated in CRC tissues and localised in both the cytoplasm and the nucleus of CRC cells. Overexpression of LIMK1 in cytoplasmic and nuclear subcellular compartments was closely related to tumour metastasis and poor prognosis of CRC patients. Enhanced expression of cytoplasmic and nuclear LIMK1 significantly increased cell proliferation and migration by driving epithelial-mesenchymal transition and activating the PI3K/Akt signal pathway in vitro as well as promoting growth and metastasis of CRC xenografts, whereas opposite effects were achieved in LIMK1-silenced cells. Furthermore, we identified two tumour metastasis-associated proteins, MYH9 and ACTN4, as direct targets of LIMK1, which were required for a LIMK1-mediated aggressive phenotype. CONCLUSIONS: These findings indicate that LIMK1 plays a critical role in promoting CRC progression at subcellular level. Our findings provide new insights into the metastasis of CRC and advocate for the development of clinical intervention strategies against advanced CRC. PMID- 28664915 TI - Kinase-driven metabolic signalling as a predictor of response to carboplatin paclitaxel adjuvant treatment in advanced ovarian cancers. AB - BACKGROUND: The biological mechanisms underlying early- and advanced-stage epithelial ovarian cancers (EOCs) are still poorly understood. This study explored kinase-driven metabolic signalling in early and advanced EOCs, and its role in tumour progression and response to carboplatin-paclitaxel treatment. METHODS: Tumour epithelia were isolated from two independent sets of primary EOC (n=72 and 30 for the discovery and the validation sets, respectively) via laser capture microdissection. Reverse phase protein microarrays were used to broadly profile the kinase-driven metabolic signalling of EOC with particular emphasis on the LBK1-AMPK and AKT-mTOR axes. Signalling activation was compared between early and advanced lesions, and carboplatin-paclitaxel-sensitive and -resistant tumours. RESULTS: Advanced EOCs were characterised by a heterogeneous kinase driven metabolic signature and decreased phosphorylation of the AMPK-AKT-mTOR axis compared to early EOC (P<0.05 for AMPKalpha T172, AMPKalpha1 S485, AMPKbeta1 S108, AKT S473 and T308, mTOR S2448, p70S6 S371, 4EBP1 S65, GSK-3 alpha/beta S21/9, FOXO1 T24/FOXO3 T32, and FOXO1 S256). Advanced tumours with low relative activation of the metabolic signature and increased FOXO1 T24/FOXO3 T32 phosphorylation (P=0.041) were associated with carboplatin-paclitaxel resistance. CONCLUSIONS: If validated in a larger cohort of patients, the decreased AMPK-AKT mTOR activation and phosphorylation of FOXO1 T24/FOXO3 T32 may help identify carboplatin-paclitaxel-resistant EOC patients. PMID- 28664916 TI - Geriatric assessment is superior to oncologists' clinical judgement in identifying frailty. AB - BACKGROUND: Frailty is a syndrome associated with increased vulnerability and an important predictor of outcomes in older cancer patients. Systematic assessments to identify frailty are seldom applied, and oncologists' ability to identify frailty is scarcely investigated. METHODS: We compared oncologists' classification of frailty (onc-frail) based on clinical judgement with a modified geriatric assessment (mGA), and investigated associations between frailty and overall survival. Patients ?70 years referred for medical cancer treatment were eligible. mGA-frailty was defined as impairment in at least one of the following: daily activities, comorbidity, polypharmacy, physical function or at least one geriatric syndrome (cognitive impairment, depression, malnutrition, falls). RESULTS: Three hundred and seven patients were enroled, 288 (94%) completed the mGA, 286 (93%) were rated by oncologists. Median age was 77 years, 56% had metastases, 85% performance status (PS) 0-1. Overall, 104/286 (36%) were onc frail and 140/288 (49%) mGA-frail, the agreement was fair (kappa value 0.30 (95% CI 0.19; 0.41)), and 67 mGA-frail patients who frequently had localised disease, good PS and received curative treatment, were missed by the oncologists. Only mGA frailty was independently prognostic for survival (HR 1.61, 95% CI 1.14; 2.27; P=0.007). CONCLUSIONS: Systematic assessment of geriatric domains is needed to aid oncologists in identifying frail patients with poor survival. PMID- 28664917 TI - Harmonisation of biobanking standards in endometrial cancer research. AB - BACKGROUND: Endometrial cancer is the most common gynaecological cancer and its incidence is predicted to escalate by 50-100% in 2025 with a parallel increase in associated mortality. Variations in the collection, processing and storage of biospecimens can affect the generalisability of the scientific data. We aimed to harmonise the collection of biospecimens, clinical data relevant to endometrial cancer and to develop standard operative procedures for the collection, processing and storage of endometrial cancer biospecimens. METHODS: We designed research tools, which were evaluated and revised through three consensus rounds - to obtain local/regional, national and European consensus. Modified final tools were disseminated to a panel (n=40) representing all stakeholders in endometrial cancer research for consensus generation. RESULTS: The final consensus demonstrated unanimous agreement with the minimal surgical and patient data collection tools. A high level of agreement was also observed for the other remaining standard tools. CONCLUSIONS: We here present the final versions of the tools, which are freely available and easily accessible to all endometrial cancer researchers. We believe that these tools will facilitate rapid progress in endometrial cancer research, both in future collaborations and in large-scale multicentre studies. PMID- 28664918 TI - Embracing model-based designs for dose-finding trials. AB - BACKGROUND: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). METHODS: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. RESULTS: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators' preference for algorithm based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. CONCLUSIONS: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia. PMID- 28664919 TI - Type 2 diabetes mellitus and psychological stress - a modifiable risk factor. AB - Psychological stress is common in many physical illnesses and is increasingly recognized as a risk factor for disease onset and progression. An emerging body of literature suggests that stress has a role in the aetiology of type 2 diabetes mellitus (T2DM) both as a predictor of new onset T2DM and as a prognostic factor in people with existing T2DM. Here, we review the evidence linking T2DM and psychological stress. We highlight the physiological responses to stress that are probably related to T2DM, drawing on evidence from animal work, large epidemiological studies and human laboratory trials. We discuss population and clinical studies linking psychological and social stress factors with T2DM, and give an overview of intervention studies that have attempted to modify psychological or social factors to improve outcomes in people with T2DM. PMID- 28664921 TI - Metabolism: New insights into the BAT-liver-gut axis. PMID- 28664922 TI - Diabetes: Could broccoli have a role in combating type 2 diabetes mellitus? PMID- 28664923 TI - Genetics: New insights into Turner syndrome. PMID- 28664920 TI - FGF1 - a new weapon to control type 2 diabetes mellitus. AB - A hypercaloric diet combined with a sedentary lifestyle is a major risk factor for the development of insulin resistance, type 2 diabetes mellitus (T2DM) and associated comorbidities. Standard treatment for T2DM begins with lifestyle modification, and includes oral medications and insulin therapy to compensate for progressive beta-cell failure. However, current pharmaceutical options for T2DM are limited in that they do not maintain stable, durable glucose control without the need for treatment intensification. Furthermore, each medication is associated with adverse effects, which range from hypoglycaemia to weight gain or bone loss. Unexpectedly, fibroblast growth factor 1 (FGF1) and its low mitogenic variants have emerged as potentially safe candidates for restoring euglycaemia, without causing overt adverse effects. In particular, a single peripheral injection of FGF1 can lower glucose to normal levels within hours, without the risk of hypoglycaemia. Similarly, a single intracerebroventricular injection of FGF1 can induce long-lasting remission of the diabetic phenotype. This Review discusses potential mechanisms by which centrally administered FGF1 improves central glucose-sensing and peripheral glucose uptake in a sustained manner. Specifically, we explore the potential crosstalk between FGF1 and glucose-sensing neuronal circuits, hypothalamic neural stem cells and synaptic plasticity. Finally, we highlight therapeutic considerations of FGF1 and compare its metabolic actions with FGF15 (rodents), FGF19 (humans) and FGF21. PMID- 28664924 TI - Erratum: The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes. AB - This corrects the article DOI: 10.1038/srep46560. PMID- 28664925 TI - Evidence for Immune Activation and Resistance to Glucocorticoids Following Childhood Maltreatment in Adolescents Without Psychopathology. AB - Early-life stress (ELS) increases the risk for psychopathology. Immune and endocrine changes have been reported in adults and are associated with maladaptation of stress-responsive systems. Here we investigated the effects of ELS on endocrine and immune pathways in adolescents without psychopathology. Thirty adolescents with a history of childhood maltreatment and 27 adolescents without ELS history were recruited. Blood and hair samples were obtained from all participants. Lymphocytes were isolated and stimulated in vitro. Flow cytometry was used to evaluate lymphocyte subsets, Th1/Th2/Th17 cytokines, mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB) signaling pathways, as well as lymphocyte sensitivity to dexamethasone. Brain-derived neurotrophic factor (BDNF) and hair cortisol were assessed with enzyme-linked immunosorbent assays (ELISAs). Adolescents with a history of ELS had increased percentages of T-cell activation markers (CD3+CD4+CD25+ and CD3+CD69+) and senescent T cells (CD8+CD28- and CD4+CD28-), as well as decreased percentages of NK (CD3-CD56+) and NK T cells (CD3+CD56+). Following stimulation, lymphocytes of ELS+ adolescents produced significantly more IL-2, IL-4, IFN-gamma, and IL-17 and engaged more MAPK ERK and NF-kappaB signaling. ELS was associated with increased hair cortisol levels in parallel with increased lymphocyte resistance to dexamethasone and low plasma BDNF levels. These data provide the first indication of the presence of immune activation and pro-inflammatory profiles in healthy adolescents exposed to ELS, which could contribute to increased vulnerability of trauma-related psychopathology later in life. The underlying mechanisms of this impairment may include the enhanced activation of both MAPK and NF-kappaB signaling in parallel to partial resistance to glucocorticoids. PMID- 28664927 TI - Low Striatal Dopamine D2-type Receptor Availability is Linked to Simulated Drug Choice in Methamphetamine Users. AB - Individuals with drug use disorders seek drugs over other rewarding activities, and exhibit neurochemical deficits related to dopamine, which is involved in value-based learning and decision-making. Thus, a dopaminergic disturbance may underpin drug-biased choice in addiction. Classical drug-choice assessments, which offer drug-consumption opportunities, are inappropriate for addicted individuals seeking treatment or abstaining. Fifteen recently abstinent methamphetamine users and 15 healthy controls completed two laboratory paradigms of 'simulated' drug choice (choice for drug-related vs affectively pleasant, unpleasant, and neutral images), and underwent positron emission tomography measurements of dopamine D2-type receptor availability, indicated by binding potential (BPND) for [18F]fallypride. Thirteen of the methamphetamine users and 10 controls also underwent [11C]NNC112 PET scans to measure dopamine D1-type receptor availability. Group analyses showed that, compared with controls, methamphetamine users chose to view more methamphetamine-related images on one task, with a similar trend on the second task. Regression analyses showed that, on both tasks, the more methamphetamine users chose to view methamphetamine images, specifically vs pleasant images (the most frequently chosen images across all participants), the lower was their D2-type BPND in the lateral orbitofrontal cortex, an important region in value-based choice. No associations were observed with D2-type BPND in striatal regions, or with D1-type BPND in any region. These results identify a neurochemical correlate for a laboratory drug-seeking paradigm that can be administered to treatment-seeking and abstaining drug-addicted individuals. More broadly, these results refine the central hypothesis that dopamine-system deficits contribute to drug-biased decision-making in addiction, here showing a role for the orbitofrontal cortex. PMID- 28664926 TI - Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala. AB - The orbitofrontal cortex (OFC) is thought to link stimuli and actions with anticipated outcomes in order to sustain flexible behavior in an ever-changing environment. How it retains these associations to guide future behavior is less well-defined. Here we focused on one subregion of this heterogeneous structure, the ventrolateral OFC (VLO). CaMKII-driven inhibitory Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) were infused and subsequently activated by their ligand Clozapine-N-oxide (CNO) in conjunction with fear extinction training (a form of aversive conditioning) and response outcome conditioning (a form of appetitive conditioning). Gi-DREADD-mediated inactivation of the VLO during extinction conditioning interfered with fear extinction memory, resulting in sustained freezing when mice were later tested drug-free. Similarly, Gi-DREADD-mediated inactivation in conjunction with response-outcome conditioning caused a later decay in goal-directed responding that is, mice were unable to select actions based on the likelihood that they would be rewarded in a sustainable manner. By contrast, inhibitory Gi-DREADDs in the basolateral amygdala (BLA) impaired the acquisition of both conditioned fear extinction and response-outcome conditioning, as expected based on prior studies using other inactivation techniques. Meanwhile, DREADD-mediated inhibition of the dorsolateral striatum enhanced response-outcome conditioning, also in line with prior reports. Together, our findings suggest that learning-related neuroplasticity in the VLO may be necessary for memory retention in both appetitive and aversive domains. PMID- 28664929 TI - Erratum: Ground state potential energy surfaces around selected atoms from resonant inelastic x-ray scattering. AB - This corrects the article DOI: 10.1038/srep20054. PMID- 28664928 TI - Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation. AB - Activation of beta-adrenergic receptors (betaARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with betaARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A1 adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal betaARs on excitatory transmission. On the basis of this, we postulated that activation of the specific mGlu receptor subtype that mediates this response could inhibit betaAR-mediated effects on hippocampal synaptic plasticity and cognitive function. Using novel mGlu receptor subtype-selective allosteric modulators along with knockout mice we now report that the effects of mGlu2/3 agonists on betaAR-mediated increases in cAMP accumulation are exclusively mediated by mGlu3. Furthermore, mGlu3 activation inhibits the ability of the betaAR agonist isoproterenol to enhance hippocampal LTP, and this effect is absent in slices treated with either a glial toxin or an adenosine A1 receptor antagonist. Finally, systemic administration of the mGlu2/3 agonist LY379268 disrupted contextual fear memory in a manner similar to the effect of the betaAR antagonist propranolol, and this effect was reversed by the mGlu3-negative allosteric modulator VU0650786. Taken together, these data suggest that mGlu3 can influence astrocytic signaling and modulate betaAR-mediated effects on hippocampal synaptic plasticity and cognitive function. PMID- 28664930 TI - Erratum: Boolean Models of Biological Processes Explain Cascade-Like Behavior. AB - This corrects the article DOI: 10.1038/srep20067. PMID- 28664932 TI - Inflammatory myofibroblastic tumor of the uterus: a clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum. AB - Inflammatory myofibroblastic tumors of the uterus are rare, and although most have a favorable prognosis, a small subset exhibit extrauterine disease, recur, or cause death. In this study, we evaluated the morphology and immunoprofile of 13 uterine inflammatory myofibroblastic tumors, including four with aggressive behavior. ALK rearrangements were detected by fluorescence in situ hybridization and fusion partners by anchored multiplex assay. Patients ranged from 8 to 63 (mean 39) years and tumors from 2.5 to 20 (mean 7.4) cm. Myxoid, compact, and hyalinized patterns were noted in 13, 12, and 2 tumors, ranging from 1 to 100%, 5 to 99%, and 0 to 5%, respectively. Nuclear atypia was mild in six (46%), moderate in five (38%), and severe in two (15%), with ganglion-like cells in two tumors. Mitoses ranged from 0 to 24 (mean 5) per 10 high-power fields. Inflammation was mild in five (38%), moderate in three (23%), and marked in five (38%), consisting of a lymphoplasmacytic infiltrate that was lymphocyte-predominant in six (46%). Lymphovascular invasion was noted in two (15%) and necrosis in eight (62%). All but one tumor were ALK-positive by immunohistochemistry, with granular cytoplasmic staining in nine (82%). ALK rearrangements (tested in 10) were detected in eight and was absent in one. The remaining tumor showed an isolated green 5' ALK signal. Fusion partners were identified in 10 (77%) and included THBS1 (n=3), IGFBP5 (n=2), DES (n=2), SEC31 (n=1), TPM3 (n=1), and TIMP3 (n=1). Size >=8 cm was predictive of aggressive behavior (P<0.01), with increased mitoses (>=7 per 10 high-power fields), lymphovascular invasion, and compact predominance approaching statistical significance. These data show that inflammatory myofibroblastic tumors of the uterus are morphologically heterogenous with frequent ALK expression and a variety of ALK fusion partners. Recognition of this rare mesenchymal neoplasm is crucial as those with aggressive behavior can potentially be treated with tyrosine kinase inhibitors. PMID- 28664933 TI - Frequent homozygosity in both mature and immature ovarian teratomas: a shared genetic basis of tumorigenesis. AB - Although homozygosity is well documented in mature teratomas, the genetic zygosity of ovarian immature teratomas and mixed germ cell tumors is less well studied. Ten cases of mature cystic teratomas, eleven cases of grade 2 or 3 immature teratomas, and seven cases of mixed germ cell tumors with an immature teratoma component were investigated by short tandem repeat genotyping to interrogate their genetic zygosity. DNA genotyping was informative in eight mature teratomas, seven immature teratomas and six cases of mixed germ cell tumors. Out of the eight mature teratomas, five cases showed partial or complete homozygosity (63%) with two cases demonstrating complete homozygosity (25%). Of the immature teratomas, six cases showed partial or complete homozygosity (86%) with two cases demonstrating complete homozygosity (29%). For the mixed germ cell tumors, two cases showed partial homozygosity (33%) and none displayed complete homozygosity. Long-term clinical follow-up was available for five immature teratomas (mean follow-up 110 months) and five mixed germ cell tumors (mean follow-up 66 months). None of the five patients with pure immature teratoma had a recurrence; in contrast, four out of five mixed ovarian germ cell tumors recurred between 4 months to 8 years (P=0.048). In conclusion, both immature and mature teratomas harbor frequent genetic homozygosity suggesting a common cellular origin involving germ cells at the same developmental stage. The difference in the rate of homozygosity and tumor recurrence between pure immature teratomas and mixed germ cell tumors suggests that the two entities may involve different pathogenetic pathways and likely pursue different biological behaviors. PMID- 28664931 TI - The evolution of brachytherapy for prostate cancer. AB - Brachytherapy (BT), using low-dose-rate (LDR) permanent seed implantation or high dose-rate (HDR) temporary source implantation, is an acceptable treatment option for select patients with prostate cancer of any risk group. The benefits of HDR BT over LDR-BT include the ability to use the same source for other cancers, lower operator dependence, and - typically - fewer acute irritative symptoms. By contrast, the benefits of LDR-BT include more favourable scheduling logistics, lower initial capital equipment costs, no need for a shielded room, completion in a single implant, and more robust data from clinical trials. Prospective reports comparing HDR-BT and LDR-BT to each other or to other treatment options (such as external beam radiotherapy (EBRT) or surgery) suggest similar outcomes. The 5 year freedom from biochemical failure rates for patients with low-risk, intermediate-risk, and high-risk disease are >85%, 69-97%, and 63-80%, respectively. Brachytherapy with EBRT (versus brachytherapy alone) is an appropriate approach in select patients with intermediate-risk and high-risk disease. The 10-year rates of overall survival, distant metastasis, and cancer specific mortality are >85%, <10%, and <5%, respectively. Grade 3-4 toxicities associated with HDR-BT and LDR-BT are rare, at <4% in most series, and quality of life is improved in patients who receive brachytherapy compared with those who undergo surgery. PMID- 28664934 TI - Cytologic predictors of malignancy in bile duct brushings: a multi-reviewer analysis of 60 cases. AB - Diagnosing malignancy in bile duct brushings is highly challenging. Seven reviewers of variable backgrounds and levels of participation in bile duct brushing sign out blindly reviewed 60 specimens (30 malignant with histologic confirmation and 30 benign (15 stented) with resection or >=18 months of uneventful follow-up), testing the utility of 14 malignant characteristics. Eleven characteristics were statistically significantly associated with malignancy including 3-dimensional clusters (63% in malignant vs 3% in benign, odds ratio 50, P=0.0003), pleomorphism (62 vs 3, odds ratio 48, P=0.0004), 2-cell population (60% vs 3, odds ratio 44, P=0.0005), chromatin pattern (hypo/hyperchromasia) changes (70% vs 7%, odds ratio 33, P<0.0001), high nuclear to-cytoplasmic ratio (48 vs 3%, odds ratio 27, P=0.0023), cytoplasmic vacuoles (43 vs 3%, odds ratio 22, P=0.0042), nuclear irregularity (70 vs 10%, odds ratio 21, P<0.0001), cellular discohesion (38 vs 3%, odds ratio 18, P=0.0082), hypercellularity (23% vs 0), nuclear molding (20% vs 0) and prominent nucleoli (21% vs 0). Necrosis and infiltrating inflammation were not helpful in identifying malignancy ('neutrophil cannibalism' was noted in 43% malignant); 21/30 (70%) malignant brushings had >=3 malignant characteristics, while 23 (77%) benign brushings had none. Of 20 brushings with >=4 characteristics, 1(5%) proved benign and showed detachment atypia, a close malignant mimicker in brushings. Identification of 3 characteristics maximized the combined sensitivity (70%), specificity (97%) and accuracy (83%), but sensitivity dropped as number of characteristics increased. Identification of 3/11 characteristics (3-dimensional clusters, pleomorphism, high nuclear-to-cytoplasmic ratio, nuclear irregularity, hypercellularity, discohesion, chromatin changes, vacuoles, prominent nucleoli, molding and 2-cell population) improves pathologists' overall performance greatly. PMID- 28664935 TI - Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease. AB - Rosai-Dorfman disease is a histiocytic disorder with a poorly defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim-Chester disease. However, cases of Rosai-Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai-Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3-82). In all, 13 had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 vs 53 years, P=0.0347) with more pediatric patients (4/7 vs 1/14, P=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated vs 1/14 (7%) unmutated cases (P=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (P=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7-352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contribute to the understanding of the biology of Rosai-Dorfman disease and point to potential diagnostic and therapeutic targets. PMID- 28664936 TI - PD-L1 immunohistochemistry in clinical diagnostics of lung cancer: inter pathologist variability is higher than assay variability. AB - Assessment of programmed cell death ligand 1 (PD-L1) immunohistochemical staining is used for decision on treatment with programmed cell death 1 and PD-L1 checkpoint inhibitors in lung adenocarcinomas and squamous cell carcinomas. This study aimed to compare the staining properties of tumor cells between the antibody clones 28-8, 22C3, SP142, and SP263 and investigate interrater variation between pathologists to see if these stainings can be safely evaluated in the clinical setting. Using consecutive sections from a tissue microarray with tumor tissue from 55 resected lung cancer cases, staining with five PD-L1 assays (28-8 from two different vendors, 22C3, SP142, and SP263) was performed. Seven pathologists individually evaluated the percentage of positive tumor cells, scoring each sample applying cutoff levels used in clinical studies: <1% positive tumor cells (score 0), 1-4% (score 1), 5-9% (score 2), 10-24% (score 3), 25-49% (score 4), and >50% positive tumor cells (score 5). Pairwise analysis of antibody clones showed weighted kappa values in the range of 0.45-0.91 with the highest values for comparisons with 22C3 and 28-8 and the lowest involving SP142. Excluding SP142 resulted in kappa 0.75-0.91. Weighted kappa for interobserver variation between pathologists was 0.71-0.96. Up to 20% of the cases were differently classified as positive or negative by any pathologist compared with consensus score using >=1% positive tumor cells as cutoff. A significantly better agreement between pathologists was seen using >=50% as cutoff (0-5% of cases). In conclusion, the concordance between the PD-L1 antibodies 22C3, 28-8 and SP263 is relatively good when evaluating lung cancers and suggests that any one of these assays may be sufficient as basis for decision on treatment with nivolumab, pembrolizumab, and durvalumab. The scoring of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores. PMID- 28664937 TI - Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases. AB - Leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome and leiomyomas with bizarre nuclei often show overlapping morphological features, in particular cells with prominent eosinophilic nucleoli, perinucleolar halos, and eosinophilic cytoplasmic inclusions. Although hereditary leiomyomatosis and renal cell carcinoma syndrome is defined by fumarate hydratase (FH) germline mutations, resulting in S-(2-succino)-cysteine (2SC) formation, it is unknown whether leiomyomas with bizarre nuclei show similar alterations. In this study, we evaluated the morphology and FH/2SC immunoprofile of 31 leiomyomas with bizarre nuclei. DNA from tumor and normal tissues from 24 cases was subjected to massively parallel sequencing targeting 410 key cancer genes. Somatic genetic alterations were detected using state-of-the-art bioinformatics algorithms. No patient reported a personal history of renal neoplasia or cutaneous leiomyomas, but one had a family history of renal cell carcinoma while another had a family history of uterine leiomyomas. Aberrant FH/2SC expression was noted in 17 tumors (16 FH-negative/2SC-positive, 1 FH-positive/2SC-positive). On univariate analysis, staghorn vessels, eosinophilic cytoplasmic inclusions, diffuse distribution of prominent eosinophilic nucleoli with perinucleolar halos, and an 'alveolar pattern of edema' were associated with an abnormal immunoprofile, but only staghorn vessels remained significant on multivariate analysis. Massively parallel sequencing analysis (n=24) revealed that 13/14 tumors with aberrant FH/2SC immunoprofile harbored somatic FH somatic genetic alterations, including homozygous deletions (n=9), missense mutations coupled with loss of heterozygosity (n=3), and a splice site mutation (n=1), whereas no somatic FH mutations/deletions were found in tumors with normal immunoprofile (n=10; P<0.0001). Leiomyomas with bizarre nuclei with normal FH/2SC staining pattern more frequently harbored TP53 and/or RB1 alterations than those with aberrant FH/2SC immunoprofile (60 vs 14%; P=0.032). These data demonstrate that leiomyomas with bizarre nuclei are morphologically and genetically heterogeneous and that hereditary leiomyomatosis and renal cell carcinoma syndrome-related morphological features, abnormal FH/2SC staining, and somatic FH mutations/deletions can be seen in a subset of sporadic tumors. PMID- 28664938 TI - LEF1 is preferentially expressed in the tubal-peritoneal junctions and is a reliable marker of tubal intraepithelial lesions. AB - Recently it has been reported that serous tubal intraepithelial carcinoma (STIC), the likely precursor of ovarian/extra-uterine high-grade serous carcinoma, are frequently located in the vicinity of tubal-peritoneal junctions, consistent with the cancer-prone features of many epithelial transitional regions. To test if p53 (aka TP53)-signatures and secretory cell outgrowths (SCOUTs) also localize to tubal-peritoneal junctions, we examined these lesions in the fallopian tubes of patients undergoing salpingo-oophorectomy for sporadic high-grade serous carcinomas or as a prophylactic procedure for carriers of familial BRCA1 or 2 mutations. STICs were located closest to the tubal-peritoneal junctions with an average distance of 1.31 mm, while SCOUTs were not detected in the fimbriated end of the fallopian tube. As many epithelial transitional regions contain stem cells, we also determined the expression of stem cell markers in the normal fallopian tube, tubal intraepithelial lesions and high-grade serous carcinomas. Of those, LEF1 was consistently expressed in the tubal-peritoneal junctions and all lesions, independent of p53 status. All SCOUTs demonstrated strong nuclear expression of beta-catenin consistent with the LEF1 participation in the canonical WNT pathway. However, beta-catenin was preferentially located in the cytoplasm of cells comprising STICs and p53 signatures, suggesting WNT independent function of LEF1 in those lesions. Both frequency of LEF1 expression and beta-catenin nuclear expression correlated with the worst 5-year patient survival, supporting important role of both proteins in high-grade serous carcinoma. Taken together, our findings suggest the existence of stem cell niche within the tubal-peritoneal junctions. Furthermore, they support the notion that the pathogenesis of SCOUTs is distinct from that of STICs and p53 signatures. The location and discrete patterns of LEF1 and beta-catenin expression may serve as highly sensitive and reliable ancillary markers for the detection and differential diagnosis of tubal intraepithelial lesions. PMID- 28664943 TI - Obituary: HIV/AIDS researcher Mark Wainberg passed away. PMID- 28664942 TI - Darunavir Stands Up as Preferred HIV Protease Inhibitor. AB - Current antiretroviral therapy reaches and maintains viral suppression over the years in more than 90% of treated HIV-infected individuals. Although integrase inhibitors are the preferred third agent in antiretroviral therapy in the current guidelines, rilpivirine, a non-nucleoside reverse transcrip- tase inhibitor, and darunavir (DRV), a second-generation protease inhibitor, are the preferred third companion to be used along with a backbone of two nucleos(t)ide reverse transcriptase inhibitors as first-line triple HIV combination treatment. However, rilpivirine is not recommended in patients with plasma HIV-RNA above 100,000 copies/mL. Raltegravir requires uncomfortably twice daily dosing, whereas dolutegravir is often given as coformulation with abacavir, a drug that requires prior HLA-B5701 testing. Antiretroviral combinations based on DRV provide a unique robustness in terms of antiviral potency and resistance barrier, rendering this drug pivotal as part of rescue regimens for the treatment failures. Furthermore, dual antiretroviral therapy with DRV plus lami- vudine has been tested with success as maintenance therapy. Finally, DRV has demonstrated its safety and efficacy in special patient populations, including pregnant women, pediatrics, HIV-2 infection, and individuals coinfected with viral hepatitis. Single-tablet regimens containing DRV coformulated with cobicistat alone or with other antiretrovirals should improve drug adherence. These fixed-dose combinations represent a step forward universal antiretroviral regimen, ensuring maximal efficacy, tolerability, and convenience. PMID- 28664941 TI - Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns. AB - Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (beta-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear beta-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat beta-catenin-positive dysplasia, and of Crohn's disease associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis. PMID- 28664940 TI - Clinical implications of cytogenetic heterogeneity in multiple myeloma patients with TP53 deletion. AB - TP53 deletion (DeltaTP53) in myeloma is known to be a high-risk finding associated with poorer prognosis. The prognostic impact of underlying cytogenetic heterogeneity in patients with myeloma associated with DeltaTP53 is unknown. We studied 90 patients with myeloma associated with DeltaTP53 identified by interphase fluorescence in situ hybridization and assessed the impact of karyotype and coexisting alterations of IGH, RB1, and CKS1B. There were 54 men and 36 women with a median age of 59 years (range 38-84); 14 patients had a normal karyotype (NK/DeltaTP53), 73 had a complex karyotype (CK/DeltaTP53), and 3 had a non-complex abnormal karyotype. Patients with CK/DeltaTP53 showed a significantly poorer overall survival compared with patients with NK/DeltaTP53 (P=0.0243). Furthermore, in the CK/DeltaTP53 group, patients with IGH rearrangement other than t(11;14)(q13;q32)/CCND1-IGH, designated as adverse-IGH, had an even worse outcome (P=0.0045). In contrast, RB1 deletion, CKS1B gain, ploidy, additional chromosome 17 abnormalities, or DeltaTP53 clone size did not impact prognosis. Stem cell transplant did not improve overall survival in either the NK/DeltaTP53 or CK/DeltaTP53 (P=0.8810 and P=0.1006) groups, but tandem stem cell transplant did improve the overall survival of patients with CK/DeltaTP53 (P=0.0067). Multivariate analysis confirmed in this cohort that complex karyotype (hazard ratio 1.976, 95% CI 1.022-3.821, P=0.043), adverse-IGH (hazard ratio 3.126, 95% CI 1.192-8.196, P=0.020), and tandem stem cell transplant independently correlate with overall survival (hazard ratio 0.281, 95% CI 0.091 0.866, P=0.027). We conclude that comprehensive genetic assessment adds to TP53 status in the risk stratification of myeloma patients. PMID- 28664944 TI - Findings of Research Misconduct. PMID- 28664945 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2041669517707769.]. PMID- 28664939 TI - Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms. AB - Genomic profiling studies have provided new insights into the pathogenesis of mature B-cell neoplasms and have identified markers with prognostic impact. Recurrent mutations in tumor-suppressor genes (TP53, BIRC3, ATM), and common signaling pathways, such as the B-cell receptor (CD79A, CD79B, CARD11, TCF3, ID3), Toll-like receptor (MYD88), NOTCH (NOTCH1/2), nuclear factor-kappaB, and mitogen activated kinase signaling, have been identified in B-cell neoplasms. Chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia, hairy cell leukemia, and marginal zone lymphomas of splenic, nodal, and extranodal types represent examples of B-cell neoplasms in which novel molecular biomarkers have been discovered in recent years. In addition, ongoing retrospective correlative and prospective outcome studies have resulted in an enhanced understanding of the clinical utility of novel biomarkers. This progress is reflected in the 2016 update of the World Health Organization classification of lymphoid neoplasms, which lists as many as 41 mature B-cell neoplasms (including provisional categories). Consequently, molecular genetic studies are increasingly being applied for the clinical workup of many of these neoplasms. In this review, we focus on the diagnostic, prognostic, and/or therapeutic utility of molecular biomarkers in mature B-cell neoplasms. PMID- 28664946 TI - The influence of polyanion molecular weight on polyelectrolyte multilayers at surfaces: elasticity and susceptibility to saloplasticity of strongly dissociated synthetic polymers at fluid-fluid interfaces. AB - We studied the interfacial mechanical properties of polyelectrolyte multilayer assemblies of poly(diallylamine hydrochloride) (PAH) and poly(4 styrenesulfonate)sodium salt (PSS) at the air-water interface using axisymmetric drop shape analysis (ADSA) during hydrostatic inflation as a function of aqueous salt concentration and two different polyanion molecular weights (Mw ~ 13 and 70 kDa). Surface elastic moduli (Gs) ranged from 50 to 300 mN m-1. Using the measured film thickness, the bulk moduli (G) ranged from 10 to 90 MPa consistent with elastomeric solids. This solid-like interface was evidenced by a systematic departure of the inflated shape from the Young-Laplace equation, which assumes a liquid-like interface. Surface elastic moduli increased and bulk elastic moduli decreased with increasing nanomembrane transverse dimension, and multilayers with the lower molecular weight anion were more transversely compact than those of higher molecular weight and displayed a larger elastic modulus. The bulk moduli of both types of multilayer assemblies asymptotically approach a constant value for films with more than two bilayers of polyelectrolyte, consistent with the observed transition from a 'glassy' to 'rubbery' state. Both types of multilayer assemblies displayed plasticization with increasing sodium chloride concentration in the adjoining aqueous phase, i.e. saloplasticity, and exhibited a transition from elastic to plastic response to deformation. The restored mobility of the polyelectrolyte resulting from the shift from intrinsic to extrinsic charge complexation, restores fluidity to the interface and is evidenced by experimental observation of a liquid-like interface when loaded. The higher molecular weight polyanion multilayers plasticized at lower salt concentrations suggesting that the lower melting point of the higher molecular weight polyanion assembly is attributable to a lesser extent of electrostatic cross-linking underscoring the unconventional dependence of molecular weight on saloplasticity in strongly dissociated polyelectrolytes. PMID- 28664947 TI - Mechanism of gelation in low-concentration aqueous solutions of silver nitrate with l-cysteine and its derivatives. AB - We discuss the results of experimental studies of the processes of gelation in aqueous solutions of silver nitrate with l-cysteine and its derivatives. We focus on understanding what determines if these small molecules will self-assemble in water at their extremely low concentration to form a gel. A mechanism of gel formation in a cysteine-silver solution (CSS) is proposed. The analysis of the results indicates that filamentary aggregates of a gel network are formed via interaction of NH3+ and C(O)O- groups that belong to neighboring silver mercaptide (SM) aggregates. In turn, formation of sulphur-silver bonds between silver mercaptide molecules is responsible for self-assembling these molecules into SM aggregates which can be considered as supramonomers. Free polar groups located on the surfaces of the aggregates can form hydrogen bonds with water molecules, which explains the unique ability of CSS hydrogels to trap water at low concentrations of low-molecular-weight hydrogelators. PMID- 28664948 TI - Experimental review: chemical reduction of graphene oxide (GO) to reduced graphene oxide (rGO) by aqueous chemistry. AB - The electrical conductivity of reduced graphene oxide (rGO) obtained from graphene oxide (GO) using sodium borohydride (NaBH4) as a reducing agent has been investigated as a function of time (2 min to 24 h) and temperature (20 degrees C to 80 degrees C). Using a 300 mM aqueous NaBH4 solution at 80 degrees C, reduction of GO occurred to a large extent during the first 10 min, which yielded a conductivity increase of 5 orders of magnitude to 10 S m-1. During the residual 1400 min of reaction, the reduction rate decreased significantly, eventually resulting in a rGO conductivity of 1500 S m-1. High resolution XPS measurements showed that C/O increased from 2.2 for the GO to 6.9 for the rGO at the longest reaction times, due to the elimination of oxygen. The steep increase in conductivity recorded during the first 8-12 min of reaction was mainly due to the reduction of C-O (e.g., hydroxyl and epoxy) groups, suggesting the preferential attack of the reducing agent on C-O rather than C[double bond, length as m-dash]O groups. In addition, the specular variation of the percentage content of C-O bond functionalities with the sum of Csp2 and Csp3 indicated that the reduction of epoxy or hydroxyl groups had a greater impact on the restoration of the conductive nature of the graphite structure in rGO. These findings were reflected in the dramatic change in the structural stability of the rGO nanofoams produced by freeze-drying. The reduction protocol in this study allowed to achieve the highest conductivity values reported so far for the aqueous reduction of graphene oxide mediated by sodium borohydride. The 4-probe sheet resistivity approach used to measure the electrical conductivity is also, for the first time, presented in detail for filtrate sheet assemblies' of stacked GO/rGO sheets. PMID- 28664949 TI - A two-photon ratiometric ESIPT probe for fast detection and bioimaging of palladium species. AB - A novel ratiometric ESIPT fluorescent probe, which is specific for palladium species of all the typical oxidation states (0, +2, and +4), has been designed. Notably, based on the excited state intramolecular proton transfer (ESIPT) process, the probe exhibits a ratiometric fluorescent response to palladium species with a low detection limit (9.0 nM, 0.96 ppb) in about 1.5 min at room temperature. Moreover, it has been successfully used as a two-photon ratiometric fluorescent palladium probe for in vivo and three-dimensional imaging with low cytotoxicity and autofluorescence. Compared with other reported palladium probes, the probe displays a shorter ratiometric response time and lower detection limit in milder test conditions. All of the results indicate that the probe may be favorable for environmental and biological applications. PMID- 28664950 TI - Cation solvation with quantum chemical effects modeled by a size-consistent multi partitioning quantum mechanics/molecular mechanics method. AB - In the condensed phase, quantum chemical properties such as many-body effects and intermolecular charge fluctuations are critical determinants of the solvation structure and dynamics. Thus, a quantum mechanical (QM) molecular description is required for both solute and solvent to incorporate these properties. However, it is challenging to conduct molecular dynamics (MD) simulations for condensed systems of sufficient scale when adapting QM potentials. To overcome this problem, we recently developed the size-consistent multi-partitioning (SCMP) quantum mechanics/molecular mechanics (QM/MM) method and realized stable and accurate MD simulations, using the QM potential to a benchmark system. In the present study, as the first application of the SCMP method, we have investigated the structures and dynamics of Na+, K+, and Ca2+ solutions based on nanosecond scale sampling, a sampling 100-times longer than that of conventional QM-based samplings. Furthermore, we have evaluated two dynamic properties, the diffusion coefficient and difference spectra, with high statistical certainty. Furthermore the calculation of these properties has not previously been possible within the conventional QM/MM framework. Based on our analysis, we have quantitatively evaluated the quantum chemical solvation effects, which show distinct differences between the cations. PMID- 28664951 TI - Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density. AB - An electron density (ED)-based methodology is developed for the automatic identification of intermolecular interactions using pro-molecular density. The expression of the ED gradient in terms of atomic components furnishes the basis for the Independent Gradient Model (IGM). This model leads to a density reference for non interacting atoms/fragments where the atomic densities are added whilst their interaction turns off. Founded on this ED reference function that features an exponential decay also in interference regions, IGM model provides a way to identify and quantify the net ED gradient attenuation due to interactions. Using an intra/inter uncoupling scheme, a descriptor (deltaginter) is then derived that uniquely defines intermolecular interaction regions. An attractive feature of the IGM methodology is to provide a workflow that automatically generates data composed solely of intermolecular interactions for drawing the corresponding 3D isosurface representations. PMID- 28664952 TI - Quantifying ultrafast charge carrier injection from methylammonium lead iodide into the hole-transport material H101 and mesoporous TiO2 using Vis-NIR transient absorption. AB - Organic-inorganic hybrid lead halide perovskites already reach very high power conversion efficiencies above 22% on architectures employing mesoporous TiO2, but the carrier injection processes across the different interfaces are still not fully understood. Here we use ultrafast broadband transient absorption spectroscopy to determine time constants and yields for hole and electron injection. We show that hole transfer from the perovskite valence band (VB) to the hole-transport material (HTM) H101 at the perovskite/HTM interface occurs in less than 500 fs, but is limited by imperfections of the contact layer and poor infiltration of the HTM into the mesoporous structure. Electron injection from the perovskite conduction band (CB) into the CB of mesoporous TiO2 is only a small channel (25%). Electron transport inside mesoporous MAPI/TiO2 architectures therefore mainly occurs via the perovskite. We also show that electron injection from H101 into the perovskite is feasible for excitation at 400 nm resulting in light-harvesting of high-energy photons by the HTM. Accurate absolute NIR absorption coefficients for CB electrons in mesoporous TiO2 are provided. PMID- 28664953 TI - Stoichiometric network analysis of spontaneous mirror symmetry breaking in chemical reactions. AB - We apply stoichiometric network analysis (SNA) to study enantioselective chemical reaction schemes, subject to various thermodynamic architectures, which may lead to spontaneous mirror symmetry breaking (SMSB). Stoichiometric matrices are used to calculate extreme currents or fluxes: the vector basis for the convex polyhedral cone of all stationary reaction rates. A major emphasis is given to the constraints that the rate constants must obey and how to express these in terms of the convex parameters and stationary inverse concentrations. We evaluate the corresponding Jacobians in terms of the constrained convex parameters and the inverse stationary concentrations and carry out stability analyses for the steady state racemic configurations. A geometric visualization of SMSB is proposed, based on the structures of the convex cones, the angles between currents, and the cone's subspaces that result from enforcing the pertinent thermodynamic and chiral constraints. PMID- 28664955 TI - Anomalous lattice behavior of vanadium pentaoxide (V2O5): X-ray diffraction, inelastic neutron scattering and ab initio lattice dynamics. AB - We present structural and dynamical studies of layered vanadium pentaoxide (V2O5). The temperature dependent X-ray diffraction measurements reveal highly anisotropic and anomalous thermal expansion from 12 K to 853 K. The results do not show any evidence of structural phase transition or decomposition of alpha V2O5, contrary to the previous transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS) experiments. The inelastic neutron scattering measurements performed up to 673 K corroborate the result of our X-ray diffraction measurements. The analysis of the experimental data is carried out using ab initio lattice dynamics calculations. The important role of van der Waals dispersion and Hubbard interactions in the structure and dynamics is revealed through ab initio calculations. The calculated anisotropic thermal expansion behavior agrees well with temperature dependent X-ray diffraction. The mechanism of anisotropic thermal expansion and anisotropic linear compressibility is discussed in terms of calculated anisotropy in the Gruneisen parameters and elastic coefficients. The calculated Gibbs free energy in various phases of V2O5 is used to understand the high pressure and temperature phase diagram of the compound. PMID- 28664954 TI - Soft, skin-mounted microfluidic systems for measuring secretory fluidic pressures generated at the surface of the skin by eccrine sweat glands. AB - During periods of activity, sweat glands produce pressures associated with osmotic effects to drive liquid to the surface of the skin. The magnitudes of these pressures may provide insights into physiological health, the intensity of physical exertion, psychological stress factors and/other information of interest, yet they are currently unknown due to absence of means for non-invasive measurement. This paper introduces a thin, soft wearable microfluidic system that mounts onto the surface of the skin to enable precise and routine measurements of secretory fluidic pressures generated at the surface of the skin by eccrine sweat glands (surface SPSG, or s-SPSG) at nearly any location on the body. These platforms incorporate an arrayed collection of unit cells each of which includes an opening to the skin, an inlet through which sweat can flow, a capillary bursting valve (CBV) with a unique bursting pressure (BP), a corresponding microreservoir to receive sweat and an outlet to the surrounding ambient to allow release of backpressure. The BPs systematically span the physiologically relevant range, to enable a measurement precision approximately defined by the ratio of the range to the number of unit cells. Human studies demonstrate measurements of s-SPSG under different conditions, from various regions of the body. Average values in healthy young adults lie between 2.4 and 2.9 kPa. Sweat associated with vigorous exercise have s-SPSGs that are somewhat higher than those associated with sedentary activity. For all conditions, the forearm and lower back tend to yield the highest and lowest s-SPSGs, respectively. PMID- 28664956 TI - Multifunctional optofluidic lab-on-chip platform for Raman and fluorescence spectroscopic microfluidic analysis. AB - A multifunctional lab-on-a-chip platform for spectroscopic analysis of liquid samples based on an optofluidic jet waveguide is reported. The optofluidic detection scheme is achieved through the total internal reflection arising in a liquid jet of only 150 MUm diameter, leading to highly efficient signal excitation and collection. This results in an optofluidic chip with an alignment free spectroscopic detection scheme, which avoids any background from the sample container. This platform has been designed for multiwavelength fluorescence and Raman spectroscopy. The chip integrates a recirculation system that reduces the required sample volume. The evaluation of the device performance has been accomplished by means of fluorescence measurements performed on eosin Y in water solutions, achieving a limit of detection of 33 pM. The sensor has been applied in Raman spectroscopy of water-ethanol solutions, leading to a limit of detection of 0.18%. As additional application, analysis of riboflavin using fluorescence detection demonstrates the possibility of detecting this vitamin at the 560 pM level (0.21 ng l-1). Although measurements have been performed by means of a compact and low-cost spectrometer, in both cases the micro-jet optofluidic chip achieved similar performances if not better than high-end benchtop based laboratory equipment. This approach paves the way towards portable lab-on-a-chip devices for high sensitivity environmental and biochemical sensing, using optical spectroscopy. PMID- 28664957 TI - Monoradical-containing four-coordinate Co(iii) complexes: homolytic S-S and Se-Se bond cleavage and catalytic isocyanate to urea conversion under sunlight. AB - Four-coordinate, monoradical-containing Co(iii) complexes participated in the non innocent ligand driven homolytic cleavage of S-S and Se-Se bonds and catalyzed the conversion of RNCO (R = phenyl and naphthyl) to the corresponding urea derivatives (TON 480) in dry CH2Cl2 under sunlight stimulus. PMID- 28664958 TI - Role of ligands in the stability of BnXn and CBn-1Xn (n = 5-10; X = H, F, CN) and their potential as building blocks of electrolytes in lithium ion batteries. AB - Stabilizing small multiply charged negative ions in the gas phase has been of considerable interest in recent years. B12H122- is one of the most well-known dianions which is stable against auto-detachment of its second electron in the gas phase by 0.9 eV, whereas BnHn2- with n < 12 is unstable. Using density functional theory, we have examined systematically the role of ligands in stabilizing smaller mono- and di-anions of BnXn and CBn-1Xn (n = 5-10; X = H, F, CN). We show that the stability of the negative ions of these complexes increases with the electron affinity of the ligand and Bn(CN)n2- can even be stable against electron emission for n>= 5. We also show that CBn-1(CN)n2- is stable against electron emission for n>= 8, even though these moieties contain one electron more than needed to satisfy the Wade-Mingos rule. We have examined the potential of these stable negative ions as building blocks of electrolytes in Li-ion batteries. By calculating the binding energies between the CBn-1Xn1-,2- and Li+, we find that some of these clusters may even outperform CB11H12- as electrolytes in metal-ion batteries. PMID- 28664959 TI - Synthesis, characterization and solution behavior of a systematic series of pentapyridyl-supported RuII complexes: comparison to bimetallic analogs. AB - A series of RuII complexes stabilized with the pentapyridyl ligand Py5Me2 (Py5Me2 = 2,6-bis(1,1-bis(2-pyridyl)ethyl)pyridine) and with an axial X ligand (X = Cl-, H2O, N3-, MeCN) were prepared and characterized in the solid state and in non aqueous solution. The cyclic voltammograms of these complexes in MeCN reflect a reversible substitution of the axial X ligand with MeCN. Irreversible ligand substitution of [(Py5Me2)RuN3]+ is also observed in propylene carbonate, but only at oxidizing potentials that decompose the azide ligand. The monometallic chloride and azide species are compared with analogous Ru2 metal-metal bonded complexes, which have been reported to undergo irreversible chloride dissociation upon reduction. PMID- 28664960 TI - The influence of polyanion molecular weight on polyelectrolyte multilayers at surfaces: protein adsorption and protein-polysaccharide complexation/stripping on natural polysaccharide films on solid supports. AB - Two different fucoidan polymers (unfractionated Fucus vesiculosus fucoidan, and fractionated low molecular weight Fucus vesiculosus fucoidan) have been used to create substrates for protein adsorption studies. Polyelectrolyte multilayers were formed using the fucoidans (polyanions) with chitosan as the corresponding polycation. Multilayer formation was studied using zeta potential measurements, quartz crystal microbalance with dissipation monitoring (QCM-D) and attenuated total reflectance (ATR) FTIR spectroscopy. The formation studies reveal that the low molecular weight (LMW) fucoidan produces a less hydrated multilayer, with a significantly increased adsorbed mass, and with fucoidan as the diffusing species during formation. Protein adsorption studies using bovine serum albumin (BSA) were undertaken for solution conditions designed to mimic biological conditions, and to minimise the role of electrical double layer forces in influencing adsorption. Under these conditions, and as revealed by ATR FTIR spectroscopy, BSA is seen to adsorb less substantially to multilayers formed with the LMW fucoidan, and to cause extraction/stripping of the LMW fucoidan from the multilayer. FTIR spectra reveal that the protein adopts a different conformation when adsorbed to the LMW fucoidan multilayer, both relative to the protein in solution and when adsorbed at the surface of the multilayer formed from unfractionated fucoidan. PMID- 28664961 TI - Carbon dots as photosensitisers for solar-driven catalysis. AB - Artificial photosynthesis is the mimicry of the natural process of solar energy conversion into chemical energy carriers. Photocatalytic systems that combine light-harvesting materials and catalysts in solution or suspension provide a promising route towards this goal. A key requirement for a sustainable solar fuel production system is a low-cost, stable and non-toxic light harvester. Photoluminescent carbon nanoparticles, carbon dots (CDs), are promising emerging light-harvesters for photocatalytic fuel production systems. CDs possess many desirable properties for this purpose, such as inexpensive, scalable synthetic routes, low-toxicity and tuneable surface chemistry. In this tutorial review, the integration of CDs in photocatalytic fuel generation systems with metallic, molecular and enzymatic catalysts is discussed. An overview of CD types, synthesis and properties is given along with a discussion of tuneable CD properties that can be optimised for applications in photocatalysis. Current understanding of the photophysical electron transfer processes present in CD photocatalytic systems is outlined and various avenues for their further development are highlighted. PMID- 28664962 TI - Initial contact guidance during cell spreading is contractility-independent. AB - A wide variety of cell types exhibit substrate topography-based behavior, also known as contact guidance. However, the precise cellular mechanisms underlying this process are still unknown. In this study, we investigated contact guidance by studying the reaction of human endothelial cells (ECs) to well-defined microgroove topographies, both during and after initial cell spreading. As the cytoskeleton plays a major role in cellular adaptation to topographical features, two methods were used to perturb cytoskeletal structures. Inhibition of actomyosin contractility with the chemical inhibitor blebbistatatin demonstrated that initial contact guidance events are independent of traction force generation. However, cell alignment to the grooved substrate was altered at later time points, suggesting an initial 'passive' phase of contact guidance, followed by a contractility-dependent 'active' phase that relies on mechanosensitive feedback. The actin cytoskeleton was also perturbed in an indirect manner by culturing cells upside down, resulting in decreased levels of contact guidance and suggesting that a possible loss of contact between the actin cytoskeleton and the substrate could lead to cytoskeleton impairment. The process of contact guidance at the microscale was found to be primarily lamellipodia driven, as no bias in filopodia extension was observed on micron-scale grooves. PMID- 28664963 TI - Dynamical behavior of microgels of interpenetrated polymer networks. AB - Microgel suspensions of an interpenetrated Polymer Network (IPN) of PNIPAM and PAAc in D2O have been investigated through dynamic light scattering as a function of temperature, pH and concentration across the Volume Phase Transition (VPT). The dynamics of the system is slowed down under H/D isotopic substitution due to different balance states between polymer/polymer and polymer/solvent interactions suggesting the crucial role played by H-bonding. The swelling behavior, reduced with respect to PNIPAM and water, has been described by the Flory-Rehner theory, tested for PNIPAM microgel and successfully expanded to higher order for IPN microgels. Moreover the concentration dependence of the relaxation time at neutral pH has highlighted two different routes to approach the glass transition: Arrhenius and super-Arrhenius (Vogel Fulcher Tammann) respectively below and above the VPT and a fragility plot has been derived. Fragility can be tuned by changing temperature: across the VPT particles undergo a transition from soft strong to stiff-fragile. PMID- 28664964 TI - Liquid-solid directional composites and anisotropic dipolar phases of polar nanoregions in disordered perovskites. AB - Using temperature-resolved dielectric spectroscopy in the range of 75-320 K we have inspected the solid-like and liquid-like arrangements of nanometric dipoles (polar nanoregions) embedded in sodium-enriched potassium-tantalate-niobate (KNTN), a chemically-substituted complex perovskite crystal hosting inherent substitutional disorder. The study of order versus direction is carried out using Frohlich entropy measurements and indicates the presence of four long-range symmetry phases, two of which are found to display profoundly anisotropic features. Exotic phases are found for which the dipoles at one fixed temperature manifest a liquid reorientational response along one crystal axis and a solid like behavior along another axis. The macroscopic anisotropy observed in the sequence of different phases is found to match a microscopic order-disorder sequence typical of nominally pure perovskites. Moreover, experimental demonstration of the onset of a frozen state above transitions is provided. PMID- 28664965 TI - New PCBM/carbon based electron transport layer for perovskite solar cells. AB - Carbon is inherently abundant in nature and relatively inexpensive, which can potentially reduce the manufacturing cost of solar cells. In recent years, carbon has been used as a hole transport layer or counter electrode in perovskite solar cells. Herein, we demonstrate that carbon can also be used as a charge transport layer capable of enhancing the energy conversion efficiency of a CH3NH3PbI3-xClx solar cell when carbon is combined with PCBM. Particularly, we have been able to deposit an ultra-flat carbon layer using an e-beam irradiation method, which exhibited much better conductivity than the competitive PCBM/C60 layer. In addition, quantitative analysis of interfacial charge dynamics shows that the quenching efficiency of PCBM/carbon is comparable to that of PCBM/C60 but better interface defect passivation and improved series and shunt resistances were observed when PCBM/carbon was employed. For the photovoltaic performance, the reference perovskite solar cell fabricated from the widely used PCBM/C60 has a power conversion efficiency (PCE) of 14% while the perovskite solar cell with PCBM/carbon has an increased PCE of 16%. Our results demonstrate the potential of the use of cost-effective carbon for perovskite solar cells, which could reduce production costs. PMID- 28664966 TI - Water-chromophore electron transfer determines the photochemistry of cytosine and cytidine. AB - Many of the UV-induced phenomena observed experimentally for aqueous cytidine were lacking the mechanistic interpretation for decades. These processes include the substantial population of the puzzling long-lived dark state, photohydration, cytidine to uridine conversion and oxazolidinone formation. Here, we present quantum-chemical simulations of excited-state spectra and potential energy surfaces of N1-methylcytosine clustered with two water molecules using the second order approximate coupled cluster (CC2), complete active space with second-order perturbation theory (CASPT2), and multireference configuration interaction with single and double excitation (MR-CISD) methods. We argue that the assignment of the long-lived dark state to a singlet npi* excitation involving water chromophore electron transfer might serve as an explanation for the numerous experimental observations. While our simulated spectra for the state are in excellent agreement with experimentally acquired data, the electron-driven proton transfer process occurring on the surface may initiate the subsequent damage in the vibrationally hot ground state of the chromophore. PMID- 28664967 TI - Two coexisting liquid phases in switchable ionic liquids. AB - Switchable ionic liquids (SWILs) derived from organic bases and alcohols are attractive due to their applications in gas capture, separations, and nanomaterial synthesis. However, their exact solvent structure still remains a mystery. We present the first chemical mapping of a SWIL solvent structure using in situ time-of-flight secondary ion mass spectrometry. In situ chemical mapping discovers two coexisting liquid phases and molecular structures vastly different from conventional ionic liquids. SWIL chemical speciation is found to be more complex than the known stoichiometry. Dimers and ionic clusters have been identified in SIMS spectra; and confirmed to be the chemical species differentiating from non-ionic liquids via spectral principal component analysis. Our unique in situ molecular imaging has advanced the understanding of SWIL chemistry and how this "heterogeneous" liquid structure may impact SWILs' physical and thermodynamic properties and associated applications. PMID- 28664968 TI - Direct visualization of fluid dynamics in sub-10 nm nanochannels. AB - Optical microscopy is the most direct method to probe fluid dynamics at small scales. However, contrast between fluid phases vanishes at ~10 nm lengthscales, limiting direct optical interrogation to larger systems. Here, we present a method for direct, high-contrast and label-free visualization of fluid dynamics in sub-10 nm channels, and apply this method to study capillary filling dynamics at this scale. The direct visualization of confined fluid dynamics in 8-nm high channels is achieved with a conventional bright-field optical microscope by inserting a layer of a high-refractive-index material, silicon nitride (Si3N4), between the substrate and the nanochannel, and the height of which is accurately controlled down to a few nanometers by a SiO2 spacer layer. The Si3N4 layer exhibits a strong Fabry-Perot resonance in reflection, providing a sharp contrast between ultrathin liquid and gas phases. In addition, the Si3N4 layer enables robust anodic bonding without nanochannel collapse. With this method, we demonstrate the validity of the classical Lucas-Washburn equation for capillary filling in the sub-10 nm regime, in contrast to the previous studies, for both polar and nonpolar liquids, and for aqueous salt solutions. PMID- 28664969 TI - Theoretical insights into the effect of terrace width and step edge coverage on CO adsorption and dissociation over stepped Ni surfaces. AB - Vicinal surfaces of Ni are model catalysts of general interest and great importance in computational catalysis. Here we report a comprehensive study conducted with density functional theory on Ni[n(111) * (100)] (n = 2, 3 and 4) surfaces to explore the effect of terrace width and step edge coverage on CO adsorption and dissociation, a probe reaction relevant to many industrial processes. The coordination numbers (CN), the generalized coordination numbers and the d band partial density of states (d-PDOS) of Ni are identified as descriptors to faithfully reflect the difference of the step edge region for Ni[n(111) * (100)]. Based on analysis of the energy diagrams for CO activation and dissociation as well as the structural features of the Ni(311), Ni(211) and Ni(533) surfaces, Ni(211) (n = 3) is proposed as a model of adequate representativeness for Ni[n(111) * (100)] (n>= 3) surface groups in investigating small molecule activation over such stepped structures. Further, a series of Ni(211) surfaces with the step edge coverage ranging from 1/4 to 1 monolayer (ML) were utilized to assess their effect on CO activation. The results show that CO adsorption is not sensitive to the step edge coverage, which could readily approach 1 ML under a CO-rich atmosphere. In contrast, CO dissociation manifests strong coverage dependence when the coverage exceeds 1/2 ML, indicating that significant adsorbate-adsorbate interactions emerge. These results are conducive to theoretical studies of metal-catalyzed surface processes where the defects play a vital role. PMID- 28664970 TI - Proton conduction in a new 3-D open-framework vanadoborate with an abundant hydrogen bond system. AB - Herein, a novel open-framework vanadoborate, (H2en)4H2[V12B18O54(OH)6(H2O)].11H2O (1, en = ethylenediamine), was hydrothermally synthesized and structurally characterized. The framework was constructed by discrete [V12B18O54(OH)6(H2O)]10- polyanion clusters with H2en2+ as counterions. An extended network of hydrogen bonds among polyanions, cations, and crystal water molecules links the structure in three dimensions. These structural features endow the present vanadoborate with unique proton conduction properties. This material shows a high proton conductivity of 1.87 * 10-4 S cm-1 at 333 K under the condition of 100% relative humidity, and the activation energy was estimated to be 0.38 eV. PMID- 28664971 TI - Luminescent Tb(iii) and Sm(iii) complexes with a 1,4,7-triazacyclononane-based tris-aryloxide ligand for high-performance oxygen sensors. AB - Taking advantage of the outstanding oxygen-sensitive luminescence properties of the previously synthesised Tb(iii) complex [{(MeMeArO)3tacn}LnIII(THF)] (1Tb, Ln = Tb), herein, we have prepared an oxygen sensor based on 1Tb embedded in polystyrene film (1Tb/PS) and found that 1Tb/PS shows the highest sensitivity (I0/I100 = 14.9) and the fastest response (response/recovery time = 1.9 s/2.9 s), among the lanthanide(iii)-based oxygen sensors with f-f emission. Moreover, we have prepared the lanthanide(iii)-based colorimetric luminescent oxygen sensor (1TbSm/PS) with green-yellow-red responses, by using 1Tb and a newly synthesised oxygen-insensitive Sm(iii) complex (1Sm, Ln = Sm; Phi = 0.010 and tau = 12.2 MUs). PMID- 28664972 TI - Structural irregularities and peculiarities of low-temperature thermal properties of Sn24P19.4Br8 clathrate. AB - Temperature changes of the heat capacity and unit cell parameters of Sn24P19.4Br8 clathrate were experimentally determined in the temperature range of 2 to 300 K. The data obtained were analyzed using Debye-Einstein approximation and taking into account the impact of both disorder in the host matrix and the presence of vacancies in the framework. Anomalous negative contribution to the thermal expansion was revealed and related to the defect mode influence on the clathrate thermal properties as a result of vibrations of two-level systems (TLS). The guest atoms that have the opportunity to occupy spatially close yet energetically non-equivalent positions in the asymmetric environment of the host matrix atoms play a principal role in the TLS formation. The results are compared with those previously obtained for semiclathrate Ge31P15Se8. PMID- 28664973 TI - Cyclic voltammetry modeling of proton transport effects on redox charge storage in conductive materials: application to a TiO2 mesoporous film. AB - Cyclic voltammetry is a particularly useful tool for characterizing charge accumulation in conductive materials. A simple model is presented to evaluate proton transport effects on charge storage in conductive materials associated with a redox process coupled with proton insertion in the bulk material from an aqueous buffered solution, a situation frequently encountered in metal oxide materials. The interplay between proton transport inside and outside the materials is described using a formulation of the problem through introduction of dimensionless variables that allows defining the minimum number of parameters governing the cyclic voltammetry response with consideration of a simple description of the system geometry. This approach is illustrated by analysis of proton insertion in a mesoporous TiO2 film. PMID- 28664974 TI - Gibberellic acid promoting phytic acid degradation in germinating soybean under calcium lactate treatment. AB - BACKGROUND: Phytic acid as a phosphorus storage vault provides phosphorus for plant development. It is an anti-nutritional factor for humans and some animals. However, its degradation products lower inositol phosphates have positive effects on human health. In this study, the effect of gibberellic acid (GA) on phytic acid degradation under calcium lactate (Ca) existence was investigated. RESULTS: The results showed that Ca + GA treatment promoted the growth status, hormone metabolism and phytic acid degradation in germinating soybean. At the same time, the availability of phosphorus, the activity of phytic acid degradation associated enzyme and phosphoinositide-specific phospholipase C (PI-PLC) increased. However, the relative genes expression of phytic acid degradation associated enzymes did not vary in accordance with their enzymes activity. CONCLUSION: The results revealed that GA could mediate the transport and function of calcium and a series of physiological and biochemical changes to regulate phytic acid degradation of soybean sprouts. (c) 2017 Society of Chemical Industry. PMID- 28664975 TI - Regression away from the mean: Theory and examples. AB - Using a standard repeated measures model with arbitrary true score distribution and normal error variables, we present some fundamental closed-form results which explicitly indicate the conditions under which regression effects towards (RTM) and away from the mean are expected. Specifically, we show that for skewed and bimodal distributions many or even most cases will show a regression effect that is in expectation away from the mean, or that is not just towards but actually beyond the mean. We illustrate our results in quantitative detail with typical examples from experimental and biometric applications, which exhibit a clear regression away from the mean ('egression from the mean') signature. We aim not to repeal cautionary advice against potential RTM effects, but to present a balanced view of regression effects, based on a clear identification of the conditions governing the form that regression effects take in repeated measures designs. PMID- 28664977 TI - Successful treatment of low-dose methotrexate in combination with systemic steroids for juvenile multiple and symmetrical circumscribed morphea. PMID- 28664976 TI - Diet of the prehistoric population of Rapa Nui (Easter Island, Chile) shows environmental adaptation and resilience. AB - OBJECTIVES: The Rapa Nui "ecocide" narrative questions whether the prehistoric population caused an avoidable ecological disaster through rapid deforestation and over-exploitation of natural resources. The objective of this study was to characterize prehistoric human diets to shed light on human adaptability and land use in an island environment with limited resources. MATERIALS AND METHODS: Materials for this study included human, faunal, and botanical remains from the archaeological sites Anakena and Ahu Tepeu on Rapa Nui, dating from c. 1400 AD to the historic period, and modern reference material. We used bulk carbon and nitrogen isotope analyses and amino acid compound specific isotope analyses (AA CSIA) of collagen isolated from prehistoric human and faunal bone, to assess the use of marine versus terrestrial resources and to investigate the underlying baseline values. Similar isotope analyses of archaeological and modern botanical and marine samples were used to characterize the local environment. RESULTS: Results of carbon and nitrogen AA-CSIA independently show that around half the protein in diets from the humans measured came from marine sources; markedly higher than previous estimates. We also observed higher delta15 N values in human collagen than could be expected from the local environment. DISCUSSION: Our results suggest highly elevated delta15 N values could only have come from consumption of crops grown in substantially manipulated soils. These findings strongly suggest that the prehistoric population adapted and exhibited astute environmental awareness in a harsh environment with nutrient poor soils. Our results also have implications for evaluating marine reservoir corrections of radiocarbon dates. PMID- 28664978 TI - Extensive auricular necroses as an initial symptom of cryofibrinogenemia occurring secondary to gastric diffuse large B-cell lymphoma. PMID- 28664979 TI - Intensive induction chemotherapy vs hypomethylating agent-based regimen in patients aged >=70 years with newly diagnosed acute myeloid leukemia. PMID- 28664980 TI - Experimental test of genetic rescue in isolated populations of brook trout. AB - Genetic rescue is an increasingly considered conservation measure to address genetic erosion associated with habitat loss and fragmentation. The resulting gene flow from facilitating migration may improve fitness and adaptive potential, but is not without risks (e.g., outbreeding depression). Here, we conducted a test of genetic rescue by translocating ten (five of each sex) brook trout (Salvelinus fontinalis) from a single source to four nearby and isolated stream populations. To control for the demographic contribution of translocated individuals, ten resident individuals (five of each sex) were removed from each recipient population. Prior to the introduction of translocated individuals, the two smallest above-barrier populations had substantially lower genetic diversity, and all populations had reduced effective number of breeders relative to adjacent below-barrier populations. In the first reproductive bout following translocation, 31 of 40 (78%) translocated individuals reproduced successfully. Translocated individuals contributed to more families than expected under random mating and generally produced larger full-sibling families. We observed relatively high (>20%) introgression in three of the four recipient populations. The translocations increased genetic diversity of recipient populations by 45% in allelic richness and 25% in expected heterozygosity. Additionally, strong evidence of hybrid vigour was observed through significantly larger body sizes of hybrid offspring relative to resident offspring in all recipient populations. Continued monitoring of these populations will test for negative fitness effects beyond the first generation. However, these results provide much-needed experimental data to inform the potential effectiveness of genetic rescue motivated translocations. PMID- 28664981 TI - Temperature variation, bacterial diversity and fungal infection dynamics in the amphibian skin. AB - Host-associated bacterial communities on the skin act as the first line of defence against invading pathogens. Yet, for most natural systems, we lack a clear understanding of how temperature variability affects structure and composition of skin bacterial communities and, in turn, promotes or limits the colonization of opportunistic pathogens. Here, we examine how natural temperature fluctuations might be related to changes in skin bacterial diversity over time in three amphibian populations infected by the pathogenic fungus Batrachochytrium dendrobatidis (Bd). Our focal host species (Eleutherodactylus coqui) is a direct developing frog that has suffered declines at some populations in the last 20 years, while others have not experienced any changes. We quantified skin bacterial alpha- and beta-diversity at four sampling time points, a period encompassing two seasons and ample variation in natural infections and environmental conditions. Despite the different patterns of infection across populations, we detected an overall increase in bacterial diversity through time, characterized by the replacement of bacterial operational taxonomic units (OTUs). Increased frog body temperatures possibly allowed the colonization of bacteria as well as the recruitment of a subset of indicator OTUs, which could have promoted the observed changes in diversity patterns. Our results suggest that natural environmental fluctuations might be involved in creating opportunities for bacterial replacement, potentially attenuating pathogen transmission and thus contributing to host persistence in E. coqui populations. PMID- 28664982 TI - Host-specific associations affect the microbiome of Philornis downsi, an introduced parasite to the Galapagos Islands. AB - The composition and diversity of bacteria forming the microbiome of parasitic organisms have implications for differential host pathogenicity and host-parasite co-evolutionary interactions. The microbiome of pathogens can therefore have consequences that are relevant for managing disease prevalence and impact on affected hosts. Here, we investigate the microbiome of an invasive parasitic fly Philornis downsi, recently introduced to the Galapagos Islands, where it poses extinction threat to Darwin's finches and other land birds. Larvae infest nests of Darwin's finches and consume blood and tissue of developing nestlings, and have severe mortality impacts. Using 16s rRNA sequencing data, we characterize the bacterial microbiota associated with P. downsi adults and larvae sourced from four finch host species, inhabiting two islands and representing two ecologically distinct groups. We show that larval and adult microbiomes are dominated by the phyla Proteobacteria and Firmicutes, which significantly differ between life stages in their distributions. Additionally, bacterial community structure significantly differed between larvae retrieved from strictly insectivorous warbler finches (Certhidea olivacea) and those parasitizing hosts with broader dietary preferences (ground and tree finches, Geospiza and Camarhynchus spp., respectively). Finally, we found no spatial effects on the larval microbiome, as larvae feeding on the same host (ground finches) harboured similar microbiomes across islands. Our results suggest that the microbiome of P. downsi changes during its development, according to dietary composition or nutritional needs, and is significantly affected by host-related factors during the larval stage. Unravelling the ecological significance of bacteria for this parasite will contribute to the development of novel, effective control strategies. PMID- 28664983 TI - Changes in Hospital Inpatient Utilization Following Health Care Reform. AB - OBJECTIVE: To estimate the effects of 2014 Medicaid expansions on inpatient outcomes. DATA SOURCES: Health Care Cost and Utilization Project State Inpatient Databases, 2011-2014; population and unemployment estimates. STUDY DESIGN: Retrospective study estimating effects of Medicaid expansions using difference-in differences regression. Outcomes included total admissions, referral-sensitive surgical and preventable admissions, length of stay, cost, and patient illness severity. FINDINGS: In 2014 quarter four, compared with nonexpansion states, Medicaid admissions increased (28.5 percent, p = .006), and uninsured and private admissions decreased (-55.1 percent, p = .001, and -6.6 percent, p = .052), whereas all-payer admissions showed little change. Uninsured expansion effects were negative for preventable admissions (-24.4 percent, p = .068), length of stay (-9.3 percent, p = .039), total cost (-9.2 percent, p = .128), and illness severity (-4.5 percent, p = .397). Significant positive expansion effects were found for Medicaid referral-sensitive surgeries (11.8 percent, p = .021) and patient illness severity (2.3 percent, p = .015). Private and all-payer expansion effects for outcomes other than admission volume were small and mainly nonsignificant (p > .05). CONCLUSION: Medicaid expansions did not change all payer admission volumes, but they were associated with increased Medicaid and decreased uninsured volumes. Results suggest those previously uninsured with greater needs for inpatient services were most likely to gain coverage. Compositional changes in uninsured and Medicaid admissions may be due to selection. PMID- 28664984 TI - An integrative review on coping skills in nursing students: implications for policymaking. AB - AIM: This study critically appraised both quantitative and qualitative studies describing coping strategies utilized by nursing students when faced with stress. BACKGROUND: Stress in nursing students during clinical training is well documented in the nursing literature. The need to utilize positive-coping strategies is necessary to effectively deal with stress and its accompanying stressors. METHODS: An integrative review method was used in this review. PsycINFO, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), MEDLINE and Scopus were the databases used in searching for relevant literature using the following search terms; 'coping', 'nursing students', clinical training', 'ways of coping' and 'clinical practice'. A total of 27 studies published from 2001 to 2016 were included in this review. FINDINGS: Findings demonstrated that nursing students utilized problem-focused coping strategies rather than emotion-focused coping strategies. Specific coping behaviours utilized included problem-solving behaviours, self-confident approaches and seeking of support from family and friends. CONCLUSION: The review contributes to the growing literature on coping strategies in nursing students and may have implications on nursing education and nursing policy. This review also demonstrated a scarcity of studies that links specific coping strategies to nursing school stressors and examines predictors of coping skills in nursing students. IMPLICATIONS FOR NURSING EDUCATION: Institutionalization of structured student orientation programme, implementation of well-planned mentoring programmes and establishment of support unit/centres may be helpful in supporting nursing students during their clinical placement. By developing empirically based interventions, nursing faculty can assist nursing students in strengthening their positive-coping skills to effectively deal with various stressors encountered. PMID- 28664985 TI - Sample size determination for a matched-pairs study with incomplete data using exact approach. AB - This research was motivated by a clinical trial design for a cognitive study. The pilot study was a matched-pairs design where some data are missing, specifically the missing data coming at the end of the study. Existing approaches to determine sample size are all based on asymptotic approaches (e.g., the generalized estimating equation (GEE) approach). When the sample size in a clinical trial is small to medium, these asymptotic approaches may not be appropriate for use due to the unsatisfactory Type I and II error rates. For this reason, we consider the exact unconditional approach to compute the sample size for a matched-pairs study with incomplete data. Recommendations are made for each possible missingness pattern by comparing the exact sample sizes based on three commonly used test statistics, with the existing sample size calculation based on the GEE approach. An example from a real surgeon-reviewers study is used to illustrate the application of the exact sample size calculation in study designs. PMID- 28664986 TI - Betaine and arginine supplementation of low protein diets improves plasma lipids but does not affect hepatic fatty acid composition and related gene expression profiling in pigs. AB - BACKGROUND: The individual and combined effects of betaine and arginine supplemented to reduced protein diets were investigated on plasma metabolites, hepatic fatty acid composition and mRNA levels of lipid-sensitive factors in commercial pigs. Betaine has previously been shown to reduce carcass fat deposition and arginine improves meat quality of finishing pigs. Forty male crossbred pigs were randomly assigned to one of five diets (n = 8): 160 g kg-1 of crude protein (NPD), 130 g kg-1 of crude protein (RPD), RPD with 3.3 g kg-1 of betaine, RPD with 15 g kg-1 of arginine, and RPD with 3.3 g kg-1 of betaine and 15 g kg-1 of arginine. RESULTS: The restriction of dietary protein increased total lipids (P < 0.001), total cholesterol (P < 0.001), high-density lipoprotein cholesterol (P < 0.001) and low-density lipoprotein cholesterol (P < 0.001). Betaine and arginine, individually or combined, reduced the majority of plasma lipids (P < 0.05) without affecting total fatty acids in the liver and the overall gene expression pattern. CONCLUSION: These findings suggest a positive effect of betaine and arginine, singly or combined, by reversing plasma lipids increase promoted by dietary protein restriction. (c) 2017 Society of Chemical Industry. PMID- 28664987 TI - In vitro antioxidant and cytoprotective properties of Maillard reaction products from phloridzin-amino acid model systems. AB - BACKGROUND: The aim of this study was to investigate in vitro antioxidant activities and cytoprotective effect of Maillard reaction products (MRPs) from phloridzin (Pz)-amino acid model systems. Their structures were also characterised by Fourier transform-infrared spectroscopy (FTIR). RESULTS: MRPs were prepared from the Pz-methionine (Met), Pz-lysine (Lys), Pz-isoleucine (Ile), Pz-histidine (His) or Pz-glutamic acid (Glu) model system. The Pz-Lys MRPs, rich in antioxidant potency, were subjected to ultrafiltration to yield four MRPs fractions with different molecular weights (Mw). The fraction with Mw 30-50 kDa had significantly (P < 0.05) higher antioxidant activity than other fractions. Moreover, it significantly (P < 0.05) attenuated the 2,2'-azobis(2 methylpropionamidine) dihydrochloride (AAPH)-elicited decrease in cell viability in HepG2 cells in a concentration-dependent manner. FTIR analysis indicated that the fraction with Mw 30-50 kDa had the strong stretching vibration for the O?H, N?H, C?H, C?O and C?C groups, suggesting the formation of intermediate MRPs during Maillard reaction. CONCLUSION: The results obtained in this study may provide some basis for the purported health-promoting effects of MRPs and their potential application as antioxidant agents in food industry. Also, it is important for our understanding of the variation of bioactive substances in food during thermal processing. (c) 2017 Society of Chemical Industry. PMID- 28664989 TI - Evolution of Spitz Nevi. AB - BACKGROUND/OBJECTIVES: Spitz nevi are melanocytic lesions with clinical, dermoscopic, and histopathologic presentations that may resemble those of melanoma. The evolution of Spitz nevi is a well-known feature. The objectives of this study were to investigate the clinical and dermoscopic features of Spitz nevi and define their evolution. METHODS: A retrospective observational study was performed and 70 Spitz nevi were analyzed using clinical and dermoscopic examination. RESULTS: Seventy patients were included in the study. The most common dermoscopic pattern was globular (n = 35 [50%]) followed by starburst (n = 24 [34.3%]), reticular (n = 8 [11.4%]), and homogeneous (n = 3 [4.3%]). Follow-up data were available for 27 of 70 patients. Of these, 21 demonstrated evolution on the follow-up images. A stable pattern (no evolution) was noted in 6 of 27 lesions. The patients who exhibited evolution were younger on average than the stable group (p = 0.04). CONCLUSION: Based on our study, the most common biologic behavior for Spitz nevi is evolution. Although no significant differences were observed in other clinical features, the inverse relationship between evolution and age is important to consider when attempting to differentiate Spitz nevus from melanoma. PMID- 28664988 TI - Hepatitis C virus-induced tumor-initiating cancer stem-like cells activate stromal fibroblasts in a xenograft tumor model. AB - : Hepatitis C virus (HCV) often causes persistent infection and is an increasingly important factor in the etiology of fibrosis/cirrhosis and hepatocellular carcinoma, although the mechanisms for the disease processes remain unclear. We have shown previously that HCV infection generates an epithelial-mesenchymal transition state and tumor-initiating cancer stem-like cells in human hepatocytes. In this study, we investigated whether HCV-induced tumor-initiating cancer stem-like cells when implanted into mice activate stromal fibroblasts. A number of fibroblast activation markers, including matrix metalloproteinase 2, were significantly increased at the mRNA or protein level in the xenograft tumors, suggesting the presence of tumor-associated fibroblasts. Fibroblast activation markers of murine origin were specifically increased in tumor, suggesting that fibroblasts migrate to form stroma. Next, we demonstrated that conditioned medium from HCV-infected human hepatocytes activates fibrosis related markers in hepatic stellate cells. We further observed that these HCV infected hepatocytes express transforming growth factor beta, which activates stromal fibroblast markers. Subsequent analysis suggested that anti-transforming growth factor beta neutralizing antibody, when incubated with conditioned medium from HCV-infected hepatocytes, inhibits fibrosis marker activation in primary human hepatic stellate cells. CONCLUSION: HCV-infected hepatocytes induce local fibroblast activation by secretion of transforming growth factor beta, and a preneoplastic or tumor state of the hepatocytes influences the network for the tumor-associated fibroblast environment. (Hepatology 2017;66:1766-1778). PMID- 28664990 TI - Widespread epidermal nevus with a postzygotic FGFR3 mutation. PMID- 28664992 TI - The outcome of ulcerative colitis patients undergoing pouch surgery is determined by pre-surgical factors. AB - BACKGROUND: Pouch surgery, a common intervention for ulcerative colitis (UC) complications, is often associated with the development of pouchitis. AIM: To identify predictors of pouch outcome in a cohort of patients with UC. METHODS: We conducted a retrospective unmatched case-cohort study in a tertiary IBD referral centre. Adult patients with UC were classified into the worst phenotype throughout follow-up: normal pouch, a form of chronic pouchitis (either chronic pouchitis or Crohn's like disease of pouch [CLDP]), or episodic recurrent acute pouchitis (RAP). Risk factors for pouchitis (chronic forms) were detected using statistical models. RESULTS: Two hundred and fifty-three pouch patients were followed up for 13.1+/-7.3 years. Only 71 patients (28.1%) maintained a favourable outcome of a sustained normal pouch. These patients were older at UC diagnosis (27.8+/-12.5 vs 23.0+/-11.4 years), had longer UC duration until surgery (13.4+/-9.5 vs 8.2+/-7.9 years), and had higher rates of referral to surgery due to nonrefractory (dysplasia/neoplasia) complications (42.3% vs 16.2%) compared with pouchitis patients. Median survival for sustained normal pouch was 10.8 years (95% CI 8.9-12.7 years), and it was longer in the nonrefractory group (20.3 vs 9.4 years for the refractory group, HR=2.37, 95% CI 1.25-3.52, P=.004). CONCLUSIONS: Most patients with UC undergoing pouch surgery will develop pouchitis. Patients operated for nonrefractory indications have a more favourable outcome. These results may contribute to pre- and post-surgical decision-making. The findings imply that the processes determining UC severity may be similar to that causing pouchitis. PMID- 28664991 TI - Artificial human antigen-presenting cells are superior to dendritic cells at inducing cytotoxic T-cell responses. AB - Peptide recognition through the MHC class I molecule by cytotoxic T lymphocytes (CTLs) leads to the killing of cancer cells. A potential challenge for T-cell immunotherapy is that dendritic cells (DCs) are exposed to the MHC class I peptide complex for an insufficient amount of time. To improve tumour antigen presentation to T cells and thereby initiate a more effective T-cell response, we generated artificial antigen-presenting cells (aAPCs) by incubating human immature DCs (imDCs) with poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs) encapsulating tumour antigenic peptides, followed by maturation with lipopolysaccharide. Tumour antigen-specific CTLs were then induced using either peptide-loaded mature DCs (mDCs) or aAPCs, and their activities were analysed using both ELISpot and cytotoxicity assays. We found that the aAPCs induced significantly stronger tumour antigen-specific CTL responses than the controls, which included both mDCs and aAPCs loaded with empty nanoparticles. Moreover, frozen CTLs that were generated by exposure to aAPCs retained the capability to eradicate HLA-A2-positive tumour antigen-bearing cancer cells. These results indicated that aAPCs are superior to DCs when inducing the CTL response because the former are capable of continuously presenting tumour antigens to T cells in a sustained manner. The development of aAPCs with PLGA-NPs encapsulating tumour antigenic peptides is a promising approach for the generation of effective CTL responses in vitro and warrants further assessments in clinical trials. PMID- 28664993 TI - Medicaid Expansions and Cervical Cancer Screening for Low-Income Women. AB - OBJECTIVE: Medicaid coverage for low-income women may play an important role in ensuring access to preventive care. This study examines how Medicaid eligibility expansions to nonelderly adults impact cervical cancer screening among low-income women. DATA SOURCES: We use data from the Behavioral Risk Factor Surveillance System from 2000 to 2010. The primary outcome of interest is whether women in the relevant guideline consistent age range reported having a Pap test in the previous year. STUDY DESIGN: We use a difference-in-differences approach with matched treatment and comparison states and a simulated eligibility approach based on a continuous measure of Medicaid generosity. PRINCIPAL FINDINGS: Our results indicate that cervical cancer screening increased among low-income women in expansion states relative to comparison states. Increases in screening rates are largest among low-income Hispanic women. CONCLUSIONS: Medicaid expansions during the period from 2000 to 2010 were associated with improved cervical cancer screening rates, which is critical for early cervical cancer detection and prevention of cancer morbidity and mortality in women. The results suggest that more widespread Medicaid expansions may have positive effects on preventive health care for women. PMID- 28664995 TI - Assessment of beer quality based on foamability and chemical composition using computer vision algorithms, near infrared spectroscopy and machine learning algorithms. AB - BACKGROUND: Beer quality is mainly defined by its colour, foamability and foam stability, which are influenced by the chemical composition of the product such as proteins, carbohydrates, pH and alcohol. Traditional methods to assess specific chemical compounds are usually time-consuming and costly. This study used rapid methods to evaluate 15 foam and colour-related parameters using a robotic pourer (RoboBEER) and chemical fingerprinting using near infrared spectroscopy (NIR) from six replicates of 21 beers from three types of fermentation. Results from NIR were used to create partial least squares regression (PLS) and artificial neural networks (ANN) models to predict four chemometrics such as pH, alcohol, Brix and maximum volume of foam. RESULTS: The ANN method was able to create more accurate models (R2 = 0.95) compared to PLS. Principal components analysis using RoboBEER parameters and NIR overtones related to protein explained 67% of total data variability. Additionally, a sub-space discriminant model using the absorbance values from NIR wavelengths resulted in the successful classification of 85% of beers according to fermentation type. CONCLUSION: The method proposed showed to be a rapid system based on NIR spectroscopy and RoboBEER outputs of foamability that can be used to infer the quality, production method and chemical parameters of beer with minimal laboratory equipment. (c) 2017 Society of Chemical Industry. PMID- 28664994 TI - Trauma induces overexpression of Cx43 in human fetal membrane defects. AB - OBJECTIVE: We developed an in vitro model to examine whether trauma induces connexin 43 (Cx43) expression and collagen organisation in the amniotic membrane (AM) of fetal membrane (FM) defects. METHOD: Term human FM was traumatised in vitro. Cell morphology and Cx43 were examined in the wound edge AM by immunofluorescence (IMF) confocal microscopy and compared to control AM. Collagen microstructure was examined by second harmonic generation (SHG) imaging. Cell viability was assessed with calcein and ethidium staining. RESULTS: After trauma, the AM showed a dense region of cells, which had migrated towards the wound edge. In wound edge AM, Cx43 puncta was preferentially distributed in mesenchymal cells compared to epithelial cells with significant expression in the fibroblast layer than epithelial layer (p < 0.001). In the fibroblast layer, the collagen fibres were highly polarised and aligned in parallel to the axis of the wound edge AM. There was an absence of cell migration across the defect with no healing after 168 h. Cell viability of the FM after trauma was maintained during culture. CONCLUSION: Cx43 overexpression in wounded AM drives structural changes in collagen that slows down efficacy of cell migration across the FM defect. (c) 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. PMID- 28664996 TI - Gaps and opportunities for the World Heritage Convention to contribute to global wilderness conservation. AB - Wilderness areas are ecologically intact landscapes predominantly free of human uses, especially industrial-scale activities that result in substantial biophysical disturbance. This definition does not exclude land and resource use by local communities who depend on such areas for subsistence and bio-cultural connections. Wilderness areas are important for biodiversity conservation and sustain key ecological processes and ecosystem services that underpin planetary life-support systems. Despite these widely recognized benefits and values of wilderness, they are insufficiently protected and are consequently being rapidly eroded. There are increasing calls for multilateral environmental agreements to make a greater and more systematic contribution to wilderness conservation before it is too late. We created a global map of remaining terrestrial wilderness following the established last-of-the-wild method, which identifies the 10% of areas with the lowest human pressure within each of Earth's 62 biogeographic realms and identifies the 10 largest contiguous areas and all contiguous areas >10,000 km2 . We used our map to assess wilderness coverage by the World Heritage Convention and to identify gaps in coverage. We then identified large nationally designated protected areas with good wilderness coverage within these gaps. One quarter of natural and mixed (i.e., sites of both natural and cultural value) World Heritage Sites (WHS) contained wilderness (total of 545,307 km2 ), which is approximately 1.8% of the world's wilderness extent. Many WHS had excellent wilderness coverage, for example, the Okavango Delta in Botswana (11,914 km2 ) and the Central Suriname Nature Reserve (16,029 km2 ). However, 22 (35%) of the world's terrestrial biorealms had no wilderness representation within WHS. We identified 840 protected areas of >500 km2 that were predominantly wilderness (>50% of their area) and represented 18 of the 22 missing biorealms. These areas offer a starting point for assessing the potential for the designation of new WHSs that could help increase wilderness representation on the World Heritage list. We urge the World Heritage Convention to ensure that the ecological integrity and outstanding universal value of existing WHS with wilderness values are preserved. PMID- 28664997 TI - Differentiating predatory scholarship: best practices in scholarly publication. AB - OBJECTIVE: The intent of this article is to define predatory publishing, identify the risks and costs associated with publishing scholarship with these types of organizations and to provide recommendations for best practices how a potential author can protect themselves against predatory organizations. METHODS: A thorough review of the literature concerning predatory publishing was conducted and gleaned for best practices along with the authors' experiences. KEY FINDINGS: Pharmacy scholars and researchers worldwide recognize the virtues of the open access (OA) publication system, which is intended to freely disseminate research electronically, stimulate innovation and improve access to scholarship. Both subscription-based and OA publication systems, however, have potential areas of conflicts, including coordination of the peer-review process and the potential for the publisher to capitalize on selling the commodity in a capitalistic society. The intent of OA is welcomed; however, publishers are still in a business and profits need to be made. It is by the exploitation of the model that has given rise to a small but growing subset known as predatory publishers. CONCLUSIONS: Pharmacy researchers and clinicians alike need to be aware of predatory organizations, both publishers and meeting organizers, when seeking a venue to publish their own scholarly research. Additionally, this knowledge is critical when evaluating medical literature in providing direct patient care services to assure the best available evidence is utilized. PMID- 28664998 TI - Genomic footprints of adaptation in a cooperatively breeding tropical bird across a vegetation gradient. AB - Identifying the genetic basis of phenotypic variation and its relationship with the environment is key to understanding how local adaptations evolve. Such patterns are especially interesting among populations distributed across habitat gradients, where genetic structure can be driven by isolation by distance (IBD) and/or isolation by environment (IBE). Here, we used variation in ~1,600 high quality SNPs derived from paired-end sequencing of double-digest restriction site associated DNA (ddRAD-Seq) to test hypotheses related to IBD and IBE in the Yucatan jay (Cyanocorax yucatanicus), a tropical bird endemic to the Yucatan Peninsula. This peninsula is characterized by a precipitation and vegetation gradient-from dry to evergreen tropical forests-that is associated with morphological variation in this species. We found a moderate level of nucleotide diversity (pi = .008) and little evidence for genetic differentiation among vegetation types. Analyses of neutral and putatively adaptive SNPs (identified by complementary genome-scan approaches) indicate that IBD is the most reliable explanation to account for frequency distribution of the former, while IBE has to be invoked to explain those of the later. These results suggest that selective factors acting along a vegetation gradient can promote local adaptation in the presence of gene flow in a vagile, nonmigratory and geographically restricted species. The putative candidate SNPs identified here are located within or linked to a variety of genes that represent ideal targets for future genomic surveys. PMID- 28665000 TI - Cytoskeleton during aerenchyma formation in plants. AB - Aerenchyma is a plant tissue characterized by prominent intercellular spaces facilitating gas diffusion between roots and the aerial environment. The classical formation of intercellular spaces is thought to be the result of schizogeny and lysogeny during development of wetland species and in some dry land species in response to different abiotic stress, including drought, high temperature, and nutrient deficiency. The plant cytoskeleton is known to play a major role in cellular organization and signaling pathways. It is emphasized a lot of ambiguity as to the cytoskeleton function in the constitutive and induced aerenchyma development, especially at the earliest stages of this process. In the present review, we focus on some aspects of the cytoskeleton behavior during the formation of schizogenous and lysigenous aerenchyma in wetland and terrestrial plants growing both in the nature and experimental conditions. PMID- 28664999 TI - Abrupt changes in the composition and function of fungal communities along an environmental gradient in the high Arctic. AB - Fungi play a key role in soil-plant interactions, nutrient cycling and carbon flow and are essential for the functioning of arctic terrestrial ecosystems. Some studies have shown that the composition of fungal communities is highly sensitive to variations in environmental conditions, but little is known about how the conditions control the role of fungal communities (i.e., their ecosystem function). We used DNA metabarcoding to compare taxonomic and functional composition of fungal communities along a gradient of environmental severity in Northeast Greenland. We analysed soil samples from fell fields, heaths and snowbeds, three habitats with very contrasting abiotic conditions. We also assessed within-habitat differences by comparing three widespread microhabitats (patches with high cover of Dryas, Salix, or bare soil). The data suggest that, along the sampled mesotopographic gradient, the greatest differences in both fungal richness and community composition are observed amongst habitats, while the effect of microhabitat is weaker, although still significant. Furthermore, we found that richness and community composition of fungi are shaped primarily by abiotic factors and to a lesser, though still significant extent, by floristic composition. Along this mesotopographic gradient, environmental severity is strongly correlated with richness in all fungal functional groups: positively in saprotrophic, pathogenic and lichenised fungi, and negatively in ectomycorrhizal and root endophytic fungi. Our results suggest complex interactions amongst functional groups, possibly due to nutrient limitation or competitive exclusion, with potential implications on soil carbon stocks. These findings are important in the light of the environmental changes predicted for the Arctic. PMID- 28665001 TI - NMR spectroscopic conformational analysis of 4-methylene-cyclohexyl pivalate-The effect of sp2 hybridization. AB - The conformational equilibrium of the axial/equatorial conformers of 4-methylene cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153 K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (-DeltaG degrees ) can be examined, and the barrier to ring interconversion (DeltaG# ) can be determined. The structural influence of sp2 hybridization on both DeltaG degrees and DeltaG# of the cyclohexyl moiety can be quantified. PMID- 28665002 TI - What do employers think their role is in ensuring language proficiency of internationally trained pharmacists. AB - OBJECTIVES: Until 2016, internationally trained pharmacists (ITPs) from the European Economic Area (EEA) did not need to prove sufficient language proficiency to the pharmacy regulator upon registration. Pharmacists themselves have a professional responsibility to ensure they can communicate and work effectively, but some responsibility also rests with employers, yet very little research has explored this. The aim of this study was to explore employer views of the communicative proficiency of ITPs whose first language was not English, their role as employers and potential implications for patient safety. METHODS: Semi-structured, telephone interviews were conducted with seven community and two hospital employers with experience of employing EEA pharmacists, between May and July 2010. Verbatim interview transcripts were coded and analysed in NVivo using the framework approach. KEY FINDINGS: All participants mentioned the importance of having processes in place to assure EEA pharmacists' linguistic competency in the workplace. During recruitment, different strategies were used to assure language competency. Some employers only conducted interviews while others required candidates to pass English language assessments. Participants were most familiar with the International English Language Testing System, which was described as too general and not unique to pharmacy. Other pharmacy-specific tests such as the University of Bath English Language Test and Linguarama English Assessment Test for Pharmacists were alternatives. CONCLUSIONS: Currently, there is no one standard procedure in place to check the communicative competency of EEA pharmacists. The findings from this study suggest that there is need to establish a uniform assessment system so all the EEA pharmacists could be tested justly and consistently. PMID- 28665003 TI - Multicentre evaluation of the new ORTHO VISION(r) analyser. AB - BACKGROUND: Implementation of fully automated analysers has become a crucial security step in the blood bank; it reduces human errors, allows standardisation and improves turnaround time (TAT). OBJECTIVES: We aimed at evaluating the ease of use and the efficiency of the ORTHO VISION(r) Analyser (VISION) in comparison to the ORTHO AutoVue(r) Innova System (AutoVue) in six different laboratories. METHODS: After initial training and system configuration, VISION was used in parallel to AutoVue following the daily workload, both automates being based on ORTHO BioVue(r) System column agglutination technology. Each participating laboratory provided data and scored the training, system configuration, quality control, maintenance and system efficiency. A total of 1049 individual samples were run: 266 forward and reverse grouping and antibody screens with 10 urgent samples, 473 ABD forward grouping and antibody screens with 22 urgent samples, 160 ABD forward grouping, 42 antibody screens and a series of 108 specific case profiles. RESULTS: The VISION instrument was more rapid than the AutoVue with a mean performing test time of 27.9 min compared to 36 min; for various test type comparisons, the TAT data obtained from VISION was shorter than that from AutoVue. Moreover, VISION analysed urgent STAT samples faster. Regarding the ease of use, VISION was intuitive and user friendly. CONCLUSIONS: VISION is a robust, reproducible system performing the most types of analytical determinations needed for pre-transfusion testing today, thus accommodating a wide range of clinical needs. VISION brings appreciated new features that could further secure blood transfusions. PMID- 28665004 TI - Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages. AB - : Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell-culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV-infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high-level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. CONCLUSION: HBV behaves like a "stealth" virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long "window period" during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779-1793). PMID- 28665006 TI - Partial deletion of the ALK gene in ALK-positive anaplastic large cell lymphoma. AB - Anaplastic lymphoma kinase (ALK) protein is an orphan receptor tyrosine kinase that is constitutively activated by aberrant translocations of the ALK gene in anaplastic large cell lymphoma, ALK-positive and several other cancers. Additionally, aberrant mutation and amplification of the ALK gene, resulting in ALK kinase activation, were detected mainly in neuroblastoma. Recently, truncated ALK protein was also reported in neuroblastoma. Here, we describe a novel truncated form of the ALK transcript with in-frame skipping through exons 2 to 17 (ALKDelta2-17) in anaplastic large cell lymphoma, ALK-positive. The ALKDelta2-17 showed ligand-independent deregulated phosphorylation that initiated strong STAT3 signalling in NIH3T3 cells. The ALKDelta2-17-transduced NIH3T3 cells showed oncogenic potential in a colony formation assay. Our data indicate that the aberrant deletion of the ALK gene might be oncogenic, providing a novel insight into the oncogenic role of the ALK pathway. PMID- 28665005 TI - Toll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function. AB - We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on CD4+ T cells and up-regulate T-cell receptor (TCR) triggered Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4+ T-cell differentiation and function, we conducted a gene expression analysis of murine naive CD4+ T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naive CD4+ T-cells co-stimulated via TLR2 showed a significant up-regulation of Il9 mRNA compared to cells co stimulated via CD28. Under TH9 differentiation, we observed up-regulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants in the presence of TLR2 agonist both in polyclonal and Ag85B cognate peptide specific stimulations. Under non-polarizing conditions, TLR2 engagement on CD4+ T-cells had minimal effect on IL-9 secretion and TH9 differentiation, likely due to a prominent effect of TLR2 signaling on IFN-gamma secretion and TH1 differentiation. We also report that, TLR2 signaling in CD4+ T cells increased expression of transcription factors BATF and PU.1, known to positively regulate TH9 differentiation. These results reveal a novel role of T-cell expressed TLR2 in enhancing the differentiation and function of TH9 T cells. PMID- 28665007 TI - Case of cholinergic urticaria accompanied by anaphylaxis. AB - Cholinergic urticaria occasionally occurs in combination with anaphylactic symptoms. However, this has not been widely reported. Herein, we report the case of a 14-year-old Japanese male who was diagnosed with cholinergic urticaria accompanied by anaphylaxis. The patient, who was suffering from atopic dermatitis and bronchial asthma, had developed wheals after exercising or bathing, which would have increased his core body temperature, since summer 2014. He experienced two episodes of severe systemic symptoms and wheal development when he took a bath after eating in December 2014 and the following January. His symptoms included wheezing, numbness of the lips, respiratory distress, blindness and fainting. Laboratory tests revealed the following results: serum IgE level, 7060 IU/mL; titers of specific immunoglobulin E antibodies against Malassezia and MGL_1304, 31.70 UA/mL and 112.5 ng/mL, respectively. A histamine release test against human sweat revealed a class 4 response. Skin prick and intradermal tests against autologous sweat produced immediate-type positive reactions. According to these findings, we diagnosed him with the sweat-hypersensitivity type of cholinergic urticaria accompanied by anaphylaxis. He was successfully treated with lafutidine, a histamine H2 receptor antagonist, in combination with fexofenadine. It is important for dermatologists to be aware that cholinergic urticaria can progress to anaphylaxis. PMID- 28665008 TI - Understanding how coping strategies and quality of life maintain hope in patients deliberating phase I trial participation. AB - OBJECTIVE: This study aimed to understand how hope and motivation of patients considering phase I trial participation are affected by psychological factors such as coping strategies and locus of control (LoC) and general well-being as measured by the quality of life (QoL). METHODS: An exploratory cross-sectional study was performed in patients with incurable cancer (N = 135) referred to our phase I unit for the first time. Patients were potentially eligible for phase I trial participation and participated in our study while deliberating phase I trial participation. We used questionnaires on hope, motivation to participate, coping, LoC, and QoL. To investigate the nature and magnitude of the relationships between the scales, a structural equation modeling (SEM) was fitted to the data. RESULTS: Hope significantly predicted the motivation to participate in phase I trials. Predictors of hope were a combination of flexible and tenacious goal pursuit (both P < .01), internal LoC (P < .01), and QoL (P < .01). The SEM showed an exact fit to the data, using a null hypothesis significance test: chi-square (8) = 9.30, P = .32. CONCLUSIONS: Patients considering phase I trial participation seem to use a pact of tenacious and flexible coping and control to stay hopeful. Furthermore, hope and QoL positively affected each other. The psychological pact may promote an adaptation enabling them to adjust to difficult circumstances by unconsciously ignoring information, called dissonance reduction. This mechanism may impair their ability to provide a valid informed consent. We suggest including a systematic exploration of patients' social context and values before proposing a phase I trial. PMID- 28665009 TI - Bromination of Cycloparaphenylenes: Strain-Induced Site-Selective Bis-Addition and Its Application for Late-Stage Functionalization. AB - Bromination of [n]cycloparaphenylenes (CPPs) is herein reported. Small [n]CPPs (n<8) underwent a bis-bromine addition reaction with high site selectively to produce tetrabromo adducts in moderate to excellent yields. Theoretical calculations revealed that thermodynamic stability dictates both the reactivity and site selectivity of the reaction. The addition product was further converted into the octabromo product by a FeBr3 -catalyzed site-selective bromination reaction. The tetra- and octabromine adducts were then transformed into mono- to tetrabromo CPPs, which were further converted into several CPP derivatives. Therefore, bromination and subsequent transformations provide a path for late stage functionalization of CPPs. PMID- 28665010 TI - Reduction in social activities mediates the relationship between diarrhea and distress in rectal/anal cancer survivors. PMID- 28665011 TI - Demographic model selection using random forests and the site frequency spectrum. AB - Phylogeographic data sets have grown from tens to thousands of loci in recent years, but extant statistical methods do not take full advantage of these large data sets. For example, approximate Bayesian computation (ABC) is a commonly used method for the explicit comparison of alternate demographic histories, but it is limited by the "curse of dimensionality" and issues related to the simulation and summarization of data when applied to next-generation sequencing (NGS) data sets. We implement here several improvements to overcome these difficulties. We use a Random Forest (RF) classifier for model selection to circumvent the curse of dimensionality and apply a binned representation of the multidimensional site frequency spectrum (mSFS) to address issues related to the simulation and summarization of large SNP data sets. We evaluate the performance of these improvements using simulation and find low overall error rates (~7%). We then apply the approach to data from Haplotrema vancouverense, a land snail endemic to the Pacific Northwest of North America. Fifteen demographic models were compared, and our results support a model of recent dispersal from coastal to inland rainforests. Our results demonstrate that binning is an effective strategy for the construction of a mSFS and imply that the statistical power of RF when applied to demographic model selection is at least comparable to traditional ABC algorithms. Importantly, by combining these strategies, large sets of models with differing numbers of populations can be evaluated. PMID- 28665012 TI - Prescribing trends and indications of antipsychotic medication in Hong Kong from 2004 to 2014: General and vulnerable patient groups. AB - PURPOSE: Antipsychotic-prescribing patterns remain unclear in Asia. The aims of our study were to investigate prescribing trends of antipsychotic medication in the general population, children, and older patients by drug generation (first or second), the prescribing trend in pregnant women, the probable indication for antipsychotic prescription, and the prescribing trend by dosage form. METHODS: This descriptive study identified and included all patients prescribed with antipsychotic in Hong Kong from 2004 to 2014 using the Clinical Data Analysis and Report System. This study calculated and reported the prevalence of antipsychotic prescribing in patient groups of interest, the percentage with diagnoses of mental disorders were derived, and the prevalence of antipsychotic by dosage forms. RESULTS: The study included 10 109 206 prescriptions of any antipsychotics to 256 903 patients. Over the study period, the prevalence of antipsychotic prescribing increased from 1.06% to 1.54% in the general population, from 0.10% to 0.23% in children (3-17 years old), and from 2.61% to 3.26% in older patients (>=65 years old). The prevalence of second-generation antipsychotics increased, but the prevalence of first-generation antipsychotics did not. Prevalence of antipsychotic prescribing in prepregnancy, pregnancy, and postpartum timeframes varied from 0.18% to 0.38%. The percentage of incident prescriptions with a diagnosis of psychosis decreased from 54.1% to 47.5%. CONCLUSIONS: Antipsychotics have been increasingly prescribed in the general population, children, and older patients. There is an increase in second-generation antipsychotic prescribing. Over half of incident users had a recent diagnosis of a nonpsychotic mental disorder in 2014, suggesting that off-label prescribing of antipsychotics might be common. PMID- 28665014 TI - Ferromagnetism and Half-Metallicity in Atomically Thin Holey Nitrogenated Graphene Based Systems. AB - Metal-free half-metallicity has been the subject of immense research focus in the field of spintronic devices. By using density functional theoretical (DFT) calculations, atomically thin holey nitrogenated graphene (C2 N) based systems are studied for possible spintronic applications. Ferromagnetism is observed in all the C-doped holey nitrogenated graphene. Interestingly, the holey nitrogenated graphene (C2 N) based system shows strong half-metallicity with a Curie temperature of approximately 297 K when a particular C-doping concentration is reached. It shows a strong half-metallicity compared with any metal-free systems studied to date. Thus, such carbon nitride based systems can be used for a 100 % spin polarized current. Furthermore, such C-doped systems show excellent dynamical, thermal, and mechanical properties. Thus, we predict a metal-free planar ferromagnetic half-metallic holey nitrogenated graphene based system for room-temperature spintronic devices. PMID- 28665013 TI - Epigenetic regulation by G9a/GLP complex ameliorates amyloid-beta 1-42 induced deficits in long-term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons. AB - Altered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer's disease (AD). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD. We have recently reported that the inhibition of G9a/GLP complex promotes long-term potentiation (LTP) and its associative mechanisms such as synaptic tagging and capture (STC). However, the role of this complex in plasticity impairments remains elusive. Here, we investigated the involvement of G9a/GLP complex in alleviating the effects of soluble Amyloid-beta 1-42 oligomers (oAbeta) on neuronal plasticity and associativity in the CA1 region of acute hippocampal slices from 5- to 7-week-old male Wistar rats. Our findings demonstrate that the regulation of G9a/GLP complex by inhibiting its catalytic activity reverses the amyloid-beta oligomer-induced deficits in late-LTP and STC. This is achieved by releasing the transcription repression of the brain-derived neurotrophic factor (Bdnf) gene. The catalytic inhibition of G9a/GLP complex leads to the upregulation of Bdnf expression in the slices treated with oAbeta. This further ensures the availability of BDNF that subsequently binds its receptor tyrosine kinase B (TrkB) and maintains the late LTP. Furthermore, the capture of BDNF by weakly activated synapses re-establishes STC. Our findings regarding the reinstatement of functional plasticity and associativity in AD-like conditions provide the first evidence for the role of G9a/GLP complex in AD. We propose G9a/GLP complex as the possible target for preventing oAbeta-induced plasticity deficits in hippocampal neurons. PMID- 28665015 TI - Autotransporter Adhesins in Escherichia coli Pathogenesis. AB - Most bacteria produce adhesion molecules to facilitate the interaction with host cells and establish successful infections. An important group of bacterial adhesins belong to the autotransporter (AT) superfamily, the largest group of secreted and outer membrane proteins in Gram-negative bacteria. AT adhesins possess diverse functions that facilitate bacterial colonisation, survival and persistence, and as such are often associated with increased bacterial fitness and pathogenic potential. In this review, we will describe AIDA-I type AT adhesins, which comprise the biggest and most diverse group in the AT family. We will focus on Escherichia coli proteins and define general aspects of their biogenesis, distribution, structural properties and key roles in infection. PMID- 28665016 TI - Biogeography and ecological diversity patterns of rare and abundant bacteria in oil-contaminated soils. AB - Revealing the biogeographies and ecologies of rare and abundant microorganisms is crucial to understand ecosystem diversity and function. In this study, we investigated the biogeographic assemblies and ecological diversity patterns of rare and abundant bacteria in long-term oil-contaminated soils at intervals of 46 360 km by performing high-throughput sequencing of 16S rRNA genes. The results clearly revealed distinct distribution patterns for rare and abundant bacteria in soil samples. Rare taxa were unevenly distributed; however, abundant taxa were ubiquitous across all samples. Both rare and abundant subcommunities showed significant distance-decay relationships, and their assemblies were driven by different factors. The rare subcommunity primarily exhibited a spatially structured distribution (i.e., stochastic processes), while edaphic factors (i.e., deterministic processes) largely contributed to the structure of the abundant subcommunity. A network analysis revealed closer relationships between abundant bacteria and their heightened influence on other co-occurrences in the community compared with rare species. In conclusion, rare microbial taxa may play potential roles in maintaining ecosystem diversity, although they do not appear to be central to microbial networks. Abundant microbes are vital for microbial co occurrences in oil-contaminated soils, and high relative abundance and ubiquitous distribution suggest potential roles in the degradation of organic pollutants. PMID- 28665017 TI - Three-microneedle device as an effective option for intralesional corticosteroid administration for the treatment of alopecia areata. PMID- 28665018 TI - Extracellular vesicles mediate intercellular communication: Transfer of functionally active microRNAs by microvesicles into phagocytes. AB - Cell activation and apoptosis lead to the formation of extracellular vesicles (EVs) such as exosomes or microvesicles (MVs). EVs have been shown to modulate immune responses; recently, MVs were described to carry microRNA (miRNA) and a role for MVs in the pathogenesis of autoimmune diseases has been discussed. Here we systematically characterized MVs and exosomes according to their release stimuli. The miRNA content of viable or apoptotic human T lymphocytes and the corresponding MVs was analyzed. miRNA, protein and surface marker expression, as well as cytokine release by human monocytes was measured after EV engulfment. Finally, miRNA expression in T lymphocytes and MVs of healthy individuals was compared with those of systemic lupus erythematosus (SLE) patients. We demonstrate that, depending on the stimuli, distinct subtypes of EVs are released, differing in size and carrying a specific RNA profile. We observed an accumulation of distinct miRNAs in MVs after induction of apoptosis and the transfer of functional miRNA by MVs into human monocytes. MVs released from apoptotic cells provoke less of an inflammatory response than those released from viable cells. MiR-155*, miR-34b and miR-34a levels in T lymphocytes and corresponding MVs were deregulated in SLE when compared to healthy individuals. PMID- 28665020 TI - Green leaf volatile production by plants: a meta-analysis. AB - 666 I. Introduction 667 II. Biosynthesis 667 III. Meta-analysis 669 IV. The type of stress influences the total amount of GLVs released 669 V. Herbivores can modulate the wound-induced release of GLVs 669 VI. Fungal infection greatly induces GLV production 672 VII. Monocots and eudicots respond differentially to different types of stress 673 VIII. The type of stress does not influence the proportion of GLVs per chemical class 673 IX. The type of stress does influence the isomeric ratio within each chemical class 674 X. GLVs: from signal perception to signal transduction 676 XI. GLVs influence the C/N metabolism 677 XII. Interaction with plant hormones 678 XIII. General conclusions and unanswered questions 678 Acknowledgements 679 References 679 SUMMARY: Plants respond to stress by releasing biogenic volatile organic compounds (BVOCs). Green leaf volatiles (GLVs), which are abundantly produced across the plant kingdom, comprise an important group within the BVOCs. They can repel or attract herbivores and their natural enemies; and they can induce plant defences or prime plants for enhanced defence against herbivores and pathogens and can have direct toxic effects on bacteria and fungi. Unlike other volatiles, GLVs are released almost instantly upon mechanical damage and (a)biotic stress and could thus function as an immediate and informative signal for many organisms in the plant's environment. We used a meta-analysis approach in which data from the literature on GLV production during biotic stress responses were compiled and interpreted. We identified that different types of attackers and feeding styles add a degree of complexity to the amount of emitted GLVs, compared with wounding alone. This meta-analysis illustrates that there is less variation in the GLV profile than we presumed, that pathogens induce more GLVs than insects and wounding, and that there are clear differences in GLV emission between monocots and dicots. Besides the meta-analysis, this review provides an update on recent insights into the perception and signalling of GLVs in plants. PMID- 28665021 TI - Proteomes and Phosphoproteomes of Anther and Pollen: Availability and Progress. AB - In flowering plants, anther development plays crucial role in sexual reproduction. Within the anther, microspore mother cells meiosis produces microspores, which further develop into pollen grains that play decisive role in plant reproduction. Previous studies on anther biology mainly focused on single gene functions relying on genetic and molecular methods. Recently, anther development has been expanded from multiple OMICS approaches like transcriptomics, proteomics/phosphoproteomics, and metabolomics. The development of proteomics techniques allowing increased proteome coverage and quantitative measurements of proteins which can characterize proteomes and their modulation during normal development, biotic and abiotic stresses in anther development. In this review, we summarize the achievements of proteomics and phosphoproteomics with anther and pollen organs from model plant and crop species (i.e. Arabidopsis, rice, tobacco). The increased proteomic information facilitated translation of information from the models to crops and thus aid in agricultural improvement. PMID- 28665019 TI - Cis-regulatory evolution in a wild primate: Infection-associated genetic variation drives differential expression of MHC-DQA1 in vitro. AB - Few studies have combined genetic association analyses with functional characterization of infection-associated SNPs in natural populations of nonhuman primates. Here, we investigate the relationship between host genetic variation, parasitism and natural selection in a population of red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. We collected parasitological, cellular and genomic data to test the following hypotheses: (i) MHC-DQA1 regulatory genetic variation is associated with control of whipworm (Trichuris) infection in a natural population of red colobus; (ii) infection associated SNPs are functional in driving differential gene expression in vitro; and (iii) balancing selection has shaped patterns of variation in the MHC-DQA1 promoter. We identified two SNPs in the MHC-DQA1 promoter, both in transcription factor binding sites, and both of which are associated with decreased control of Trichuris infection. We characterized the function of both SNPs by testing differences in gene expression between the two alleles of each SNP in two mammalian cell lines. Alleles of one of the SNPs drove differential gene expression in both cell lines, while the other SNP drove differences in expression in one of the cell lines. Additionally, we found evidence of balancing selection acting on the MHC-DQA1 promoter, including extensive trans-species polymorphisms between red colobus and other primates, and an excess of intermediate-frequency alleles relative to genome-wide, coding and noncoding RADseq data. Our data suggest that balancing selection provides adaptive regulatory flexibility that outweighs the consequences of increased parasite infection intensity in heterozygotes. PMID- 28665022 TI - "What's going to happen when we're gone?" Family caregiving capacity for older people with an intellectual disability in Ireland. AB - BACKGROUND: Changing family sociodemographic factors, increased life expectancy for people with an intellectual disability, deinstitutionalization and policy prioritization of the family as the principal care provider, presents new challenges to care sustainability. METHOD: A qualitative study design was employed, entailing focus groups and semistructured interviews, with purposive sampling via the parent study population of the Intellectual Disability Supplement to The Irish Longitudinal Database on Ageing. RESULTS: The traditional sociodemographic facilitators of family caregiving are in rapid decline. Families perceived limited support from services and limited future care options. Few future care plans have been formulated. A strong possibility exists of placement of older family members with an intellectual disability in out-of-family home care. CONCLUSION: To anticipate and provide for quality care supports, there is a need to establish proactive initiatives, for both people with an intellectual disability and their families', to facilitate the early formation of long-term care plans. PMID- 28665023 TI - Physiological, molecular and ultrastructural analyses during ripening and over ripening of banana (Musa spp., AAA group, Cavendish sub-group) fruit suggest characteristics of programmed cell death. AB - BACKGROUND: Programmed cell death (PCD) is a part of plant development that has been studied for petal senescence and vegetative tissue but has not been thoroughly investigated for fleshy fruits. The purpose of this research was to examine ripening and over-ripening in banana fruit to determine if there were processes in common to previously described PCD. RESULTS: Loss of cellular integrity (over 40%) and development of senescence related dark spot (SRDS) occurred after day 8 in banana peel. Nuclease and protease activity in the peel increased during ripening starting from day 2, and decreased during over ripening. The highest activity was for proteases and nucleases with apparent molecular weights of 86 kDa and 27 kDa, respectively. Images of SRDS showed shrinkage of the upper layers of cells, visually suggesting cell death. Decrease of electron dense areas was evident in TEM micrographs of nuclei. CONCLUSION: This study shows for the first time that ripening and over-ripening of banana peel share physiological and molecular processes previously described in plant PCD. SRDS could represent a morphotype of PCD that characterizes a structural and biochemical failure in the upper layers of the peel, thereafter spreading to lower and adjacent layers of cells. (c) 2017 Society of Chemical Industry. PMID- 28665024 TI - Beyond topology: coevolution of structure and flux in metabolic networks. AB - Interactions between the structure of a metabolic network and its functional properties underlie its evolutionary diversification, but the mechanism by which such interactions arise remains elusive. Particularly unclear is whether metabolic fluxes that determine the concentrations of compounds produced by a metabolic network, are causally linked to a network's structure or emerge independently of it. A direct empirical study of populations where both structural and functional properties vary among individuals' metabolic networks is required to establish whether changes in structure affect the distribution of metabolic flux. In a population of house finches (Haemorhous mexicanus), we reconstructed full carotenoid metabolic networks for 442 individuals and uncovered 11 structural variants of this network with different compounds and reactions. We examined the consequences of this structural diversity for the concentrations of plumage-bound carotenoids produced by flux in these networks. We found that concentrations of metabolically derived, but not dietary carotenoids, depended on network structure. Flux was partitioned similarly among compounds in individuals of the same network structure: within each network, compound concentrations were closely correlated. The highest among-individual variation in flux occurred in networks with the strongest among-compound correlations, suggesting that changes in the magnitude, but not the distribution of flux, underlie individual differences in compound concentrations on a static network structure. These findings indicate that the distribution of flux in carotenoid metabolism closely follows network structure. Thus, evolutionary diversification and local adaptations in carotenoid metabolism may depend more on the gain or loss of enzymatic reactions than on changes in flux within a network structure. PMID- 28665025 TI - Determination of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in human serum using programmable-temperature vaporization gas chromatography with high-resolution mass spectrometry. AB - The determination of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in blood from a non occupational population is essential for the investigation of adverse health effects from these pollutants. In this study, a sensitive method based on programmable-temperature vaporization with large-volume injection coupled with gas chromatography with high-resolution mass spectrometry was developed to determine these pollutants in 1-2 mL of human serum samples. Various key parameters of programmable-temperature vaporization injector, including vent temperature, vent time, vent flow, transfer temperature and transfer time were optimized by factorial design. The accuracy and precision as well as applicability were assessed by determining polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in calibration standard solutions, standard reference materials and real human serum samples from non-occupational population. The method detection limits of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, and dioxin like polychlorinated biphenyls were 1.5-9.0 and 0.005-0.02 ng/kg wet weight, respectively. By comparing with typically splitless injection, the application of programmable-temperature vaporization injector could effectively lead to higher detectable rate of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in 1-2 mL of human serum samples. PMID- 28665026 TI - Trifluoroacetic Anhydride Promoted Copper(I)-Catalyzed Interrupted Click Reaction: From 1,2,3-Triazoles to 3-Trifluoromethyl-Substituted 1,2,4 Triazinones. AB - A copper(I)-catalyzed interrupted click reaction in the presence of trifluoroacetic anhydride has been developed, wherein an N-trifluoroacetyl group is used to accelerate the ring-opening of the putative 5-copper(I) triazolide intermediate. Under the optimized reaction conditions, a broad range of azides and alkynes were found to participate in this transformation, thus affording 3 trifluoromethyl-substituted 1,2,4-triazinones in moderate to excellent yields. The reaction has proven to be compatible with a variety of electron-withdrawing and electron-donating groups, halogens, and nitrogen- and sulfur-containing heterocycles, as well as pharmaceutically relevant molecules. PMID- 28665027 TI - Nerve conduction study of lower extremities in cutaneous arteritis patients with neurological manifestations. AB - Some patients originally diagnosed with cutaneous arteritis (CA) could develop additional disease manifestations, including peripheral neurological involvement. We evaluated the biological neurological parameters among CA patients who underwent nerve conduction studies for neurological involvement in the lower extremities. We reviewed 164 patients who were originally diagnosed with CA at our dermatology department between 2004 and 2015. Seventeen (10.4%) of the CA patients underwent further nerve conduction studies to determine their peripheral neurological manifestations, primarily in the lower extremities, in our neurology division. The frequency of low compound muscle action potential (CMAP) was significantly higher compared with that of delayed latency in both the peroneal nerve and sural nerve based on nerve conduction studies. The frequency of low CMAP was significantly higher compared with that of prolonged distal latency in both the peroneal and sural nerves. We suggest that impairment of the nerve axon pathways in the peroneal and sural nerves could result in the peripheral neurological manifestations in the lower extremities in CA patients. PMID- 28665030 TI - Idea worthy to explore: Connecting global and local in teaching about diseases. PMID- 28665028 TI - Small RNAs induce the activation of the pro-inflammatory TLR7 signaling pathway in aged rat kidney. AB - We have recently reported that TLR-related genes, including TLR7, are upregulated during aging. However, the role of TLR7 and its endogenous ligand in inflammation related to aging is not well defined. Here, we established that small RNAs trigger age-related renal inflammation via TLR7 signaling pathway. We first investigated the expression changes of nine different TLRs in kidney of 6-month old young rats and 20-month-old aged rats. The results revealed that the expression of TLR7 was the highest among nine TLRs in kidney of old rats compared to the young aged rats. Next, to assess the role of cellular RNA as a TLR7 ligand, we treated a renal tubular epithelial cell line with total RNA isolated from the kidney of young and old rats. The results showed that RNA isolated from old rats showed higher expression of TLR7, IL1beta, and TNFalpha compared to that from young rats. Furthermore, RNA isolated from old rats induced IKKalpha/beta/JNK/NF-kappaB activation. To identify RNA that activates TLR7, we isolated small and large RNAs from old rat kidney and found that small RNAs increased TLR7 expression in cells. Finally, to investigate the local inflammatory response by small RNA, C57B/L6 mice were intraperitoneally injected with small RNAs isolated from young and old rats; thereby, RNA isolated from old rats induced higher inflammatory responses. Our study demonstrates that renal small RNAs from aged rats induce pro-inflammatory processes via the activation of the TLR7/IKKalpha/beta/JNK/NF-kappaB signaling pathway, and highlights its causative role as a possible therapeutic target in age-related chronic renal inflammation. PMID- 28665029 TI - Impact of Macroporosity on Catalytic Upgrading of Fast Pyrolysis Bio-Oil by Esterification over Silica Sulfonic Acids. AB - Fast pyrolysis bio-oils possess unfavorable physicochemical properties and poor stability, in large part, owing to the presence of carboxylic acids, which hinders their use as biofuels. Catalytic esterification offers an atom- and energy-efficient route to upgrade pyrolysis bio-oils. Propyl sulfonic acid (PrSO3 H) silicas are active for carboxylic acid esterification but suffer mass transport limitations for bulky substrates. The incorporation of macropores (200 nm) enhances the activity of mesoporous SBA-15 architectures (post-functionalized by hydrothermal saline-promoted grafting) for the esterification of linear carboxylic acids, with the magnitude of the turnover frequency (TOF) enhancement increasing with carboxylic acid chain length from 5 % (C3 ) to 110 % (C12 ). Macroporous-mesoporous PrSO3 H/SBA-15 also provides a two-fold TOF enhancement over its mesoporous analogue for the esterification of a real, thermal fast pyrolysis bio-oil derived from woodchips. The total acid number was reduced by 57 %, as determined by GC*GC-time-of-flight mass spectrometry (GC*GC-ToFMS), which indicated ester and ether formation accompanying the loss of acid, phenolic, aldehyde, and ketone components. PMID- 28665031 TI - Heritable variation in circulating glucocorticoids and endocrine flexibility in a free-living songbird. AB - Phenotypic flexibility is a central way that organisms cope with challenging and changing environments. As endocrine signals mediate many phenotypic traits, heritable variation in hormone levels, or their context-dependent flexibility, could present an important target for selection. Several studies have estimated the heritability of circulating glucocorticoid levels under acute stress conditions, but little is known about the potential for either baseline hormone levels or rapid endocrine flexibility to evolve. Here, we assessed the potential for selection to operate on the elevation (circulating hormone levels) and flexibility of glucocorticoid reaction norms to acute restraint stress. Multivariate animal models revealed low but significant heritability in baseline (h2 = 0.13-0.14) and stress-induced glucocorticoids (h2 = 0.18), and moderate heritability in glucocorticoid flexibility in response to acute stress (h2 = 0.38) in free-living juvenile tree swallows (Tachycineta bicolor; n = 408). Baseline glucocorticoids were not genetically correlated with either stress induced glucocorticoids or glucocorticoid flexibility. These findings indicate that baseline glucocorticoids and the acute stress response are distinct traits that can be independently shaped by selection. Microevolutionary changes that influence the expression or flexibility of these endocrine mediators of phenotype may be an important way that populations adapt to changing environments and novel threats. PMID- 28665033 TI - Resveratrol and polydatin as modulators of Ca2+ mobilization in the cardiovascular system. AB - In the cardiovascular system, Ca2+ controls cardiac excitation-contraction coupling and vascular contraction and dilation. Disturbances in intracellular Ca2+ homeostasis induce malfunctions of the cardiovascular system, including cardiac pump dysfunction, arrhythmia, remodeling, and apoptosis, as well as hypertension and impairment of vascular reactivity. Therefore, developing drugs and strategies manipulating Ca2+ handling are highly valued in the treatment of cardiovascular disease. Resveratrol (Res) and polydatin (PD), a Res glucoside, have been well established to have beneficial effects on improving cardiovascular function. Studies from our laboratory and others have demonstrated that they exhibit inotropic effects on normal heart and therapeutic effects on hypertension, cardiac ischemia/reperfusion injury, hypertrophy, and heart failure by manipulating Ca2+ mobilization. The actions of Res and PD on Ca2+ signals delicately manipulated by multiple Ca2+ -handling proteins are pleiotropic and somewhat controversial, depending on cellular species and intracellular oxidative status. Here, we focus on the effects of Res and PD on controlling Ca2+ homeostasis in the heart and vasculature under normal and diseased conditions and highlight the key direct and indirect molecules mediating these effects. PMID- 28665032 TI - Sex differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents. AB - : Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy-related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy-related characteristics and NAFLD in 1,170 adolescent offspring aged 17 years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age (P = 0.02), higher maternal prepregnancy BMI (P < 0.001), higher maternal weight gain by 18 weeks' gestation (P < 0.001), and maternal smoking during pregnancy (P = 0.04). Paternal age or body mass index (BMI) were not associated with NAFLD in female offspring. In contrast, higher paternal BMI (P < 0.001), maternal prepregnancy BMI (P < 0.001), and lower family socioeconomic status (SES) at time of birth (P = 0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.49-8.05; P = 0.004) and maternal weight gain >=6.0 kg by the 18th week of gestation (OR, 1.10; 95% CI, 1.04-1.15; P < 0.001). In adolescent males, family SES at the time of birth (OR, 9.07; 95% CI, 1.54-53.29; P = 0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. CONCLUSION: Early-life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early-mid gestational weight gain were associated with NAFLD in female offspring, whereas lower family SES at birth was associated with NAFLD in male offspring independent of adolescent obesity. (Hepatology 2018;67:108-122). PMID- 28665034 TI - Ultrahigh dose gentamicin alters inflammation and angiogenesis in vivo and in vitro. AB - Skin quality outcome after skin grafting is adversely affected by wound bed inflammation. Neomycin, gentamicin, and other aminoglycoside antibiotics are known to modulate inflammation, and topical application affords the use of higher doses than are possible to use systemically. Previous data suggest that clinically relevant doses of neomycin, but not gentamicin, may impair angiogenesis, which is critical to the durable survival of skin grafts. The role of gentamicin at ultrahigh doses compared with clinically relevant neomycin doses in regulating inflammatory expression and angiogenesis has been examined. In a porcine skin replacement excisional wound model, continuous exposure to gentamicin increased anti-angiogenic and inflammatory expression at 7 days postgrafting. In in vitro studies, gentamicin also impaired angiogenesis in a human umbilical vein endothelial cell (HUVEC) tube formation model, increased the expression of the anti-angiogenic gene C-X-C motif chemokine 10 (CXCL10) in HUVECs and macrophages, and increased pro-inflammatory cytokine expression of macrophages in a dose-dependent manner. Neomycin exerted similar effects in vitro at clinically relevant doses on HUVEC tube formation and macrophage pro inflammatory expression. CXCL10 was upregulated in macrophages, but did not exhibit a change in HUVECs with neomycin treatment. Ultrahigh doses of gentamicin and clinically relevant doses of neomycin affect inflammation and angiogenesis in in vivo and in vitro models. These findings suggest that topical administration of aminoglycosides have the potential to adversely influence early skin graft survival. PMID- 28665035 TI - RpeakChrom: Novel R package for the automated characterization and optimization of column efficiency in high-performance liquid chromatography analysis. AB - Characterization of chromatographic columns using the traditional van Deemter method is limited by the necessity of calculating extra-column variance, issue particularly relevant when modeling asymmetrical peaks eluted from monolithic columns. A novel R package that implements Parabolic Variance Modified Gaussian approach for accurate peak modeling, van Deemter equation and two alternatives approaches, based on van Deemter, has been developed to calculate the height equivalent to a theoretical plate (HETP). To assess package capabilities conventional packed reverse-phase and monolithic HPLC columns were characterized. Peaks eluted from the monolithic column showed a high value of factor asymmetry due, in part, to the contribution of extra-column factors. Such deviation can be circumvented by the two alternatives approaches implemented in the R-package. Furthermore, increased values of eddy diffusion and mass transfer kinetics terms in HETP were observed for the packed column, while accuracy was below 9% in all cases. These results showed the usefulness of the R-package for both modeling chromatographic peaks and assessing column efficiency. The RpeakChrom package could become a helpful tool for testing new stationary phases during column development and to evaluate column during its lifetime. This R tool is freely available from CRAN (https://CRAN.R-project.org/package=RpeakChrom). PMID- 28665036 TI - GhJAZ2 attenuates cotton resistance to biotic stresses via the inhibition of the transcriptional activity of GhbHLH171. AB - Plants have evolved effective mechanisms to protect themselves against multiple stresses, and employ jasmonates (JAs) as vital defence signals to defend against pathogen infection. The accumulation of JA, induced by signals from biotic and abiotic stresses, results in the degradation of Jasmonate-ZIM-domain (JAZ) proteins, followed by the de-repression of JAZ-repressed transcription factors (such as MYC2) to activate defence responses and developmental processes. Here, we characterized a JAZ family protein, GhJAZ2, from cotton (Gossypium hirsutum) which was induced by methyl jasmonate (MeJA) and inoculation of Verticillium dahliae. The overexpression of GhJAZ2 in cotton impairs the sensitivity to JA, decreases the expression level of JA-response genes (GhPDF1.2 and GhVSP) and enhances the susceptibility to V. dahliae and insect herbivory. Yeast two-hybrid and bimolecular fluorescence complementation assays showed that GhJAZ2 may be involved in the regulation of cotton disease resistance by interaction with further disease-response proteins, such as pathogenesis-related protein GhPR10, dirigent-like protein GhD2, nucleotide-binding site leucine-rich repeat (NBS-LRR) disease-resistant protein GhR1 and a basic helix-loop-helix transcription factor GhbHLH171. Unlike MYC2, overexpression of GhbHLH171 in cotton activates the JA synthesis and signalling pathway, and improves plant tolerance to the fungus V. dahliae. Molecular and genetic evidence shows that GhJAZ2 can interact with GhbHLH171 and inhibit its transcriptional activity and, as a result, can restrain the JA-mediated defence response. This study provides new insights into the molecular mechanisms of GhJAZ2 in the regulation of the cotton defence response. PMID- 28665037 TI - Prevalence of potentially serious drug-drug interactions among South African elderly private health sector patients using the Mimica Matanovic/Vlahovic Palcevski protocol. AB - OBJECTIVES: To determine the prevalence of potentially serious drug-drug interactions (DDIs) and their relationship with gender and age, among elderly in South Africa. METHODS: A cross-sectional study was conducted using pharmaceutical claims data for 2013, for a total of 103 420 medical scheme beneficiaries' >=65 years. All medications dispensed within one calendar month where the days' supply of medication dispensed overlapped, were grouped as one prescription. DDIs per prescription were then identified using the Mimica Matanovic/Vlahovic-Palcevski DDI protocol. Results were interpreted using effect sizes, that is Cramer's V, Cohen's d and Cohen's f2 . KEY FINDINGS: A total of 331 659 DDIs were identified on 235 870 (25.8%, N = 912 713) prescriptions (mean 0.36 (SD 0.7) (95% CI, 0.36 to 0.37)). Women encountered 63.5% of all DDIs. Effect sizes for the association between DDIs and age group (Cramer's V = 0.06), and gender (Cramer's V = 0.05) was negligible. There was no difference between men and women regarding the mean number of DDIs identified per prescription (Cohen's d = 0.10). The number of medicine per prescription (f2 = 0.51) was the biggest predictor of the DDIs. The most frequent interacting drug combinations were between central nervous system medicines (30.6%). CONCLUSION: Our study is the first to report the prevalence of potentially serious DDIs among an elderly population in the South African private health sector utilising the Mimica Matanovic/Vlahovic-Palcevski DDI protocol. Overall, we identified DDIs in approximately 26% of the prescriptions in our study. Age and gender were not found to be predictors of potentially serious DDIs. PMID- 28665038 TI - Efficacy of a standardized extract of Matricariae chamomilla L., Melissa officinalis L. and tyndallized Lactobacillus acidophilus (HA122) in infantile colic: An open randomized controlled trial. AB - BACKGROUND: Infant colic (IC) is a prevalent physiological event of infants, which can disrupt the child's home environment. We aimed to investigate the effectiveness of a mixture of Matricariae chamomilla L., Melissa officinalis L. and tyndallized Lactobacillus acidophilus (HA122) compared with Lactobacillus reuteri DSM 17938 and with simethicone for the treatment of IC. METHODS: A multicenter randomized comparative study was conducted in infants with colic, according to Rome III criteria, who were randomly assigned to receive M. chamomilla L., M. officinalis L. and tyndallized L. acidophilus (HA122) (Colimil(r) Plus(r) ; Milte Italia Spa, Milan, Italy) (Group A), L. reuteri DSM 17938 (Group B) and simethicone (Group C). Treatment was given to subjects for 28 days. KEY RESULTS: One-hundred and seventy-six patients completed the study. Mean daily crying time at day 28 was significantly lower in group A (-44, 95% CI: -58 to -30, P<.001) and group B (-35, 95% CI: -49 to -20, P<.001) when compared to group C. No significant difference was observed between Group A and Group B (mean difference: -9 minutes, 95% CI -23 to +5, P=.205). At day 28, 39 of 57 (68.4%) of infants in Group C responded to the treatment compared with 57 out of 60 patients (95%) of Group A and 51 out of 59 (86.4%) of Group B (P<.001). CONCLUSIONS: This study suggests that administration of M. chamomilla L., M. officinalis L. and tyndallized L. acidophilus (HA122) and L. reuteri DSM 17938 are significantly more effective than simethicone in IC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02708238. PMID- 28665039 TI - Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain. AB - Anterior gradient 2 (AGR2), a member of protein disulfide isomerase (PDI) family, is both located in cytoplasm and secreted into extracellular matrix. The orthologs of AGR2 have been linked to limb regeneration in newt and wound healing in zebrafish. In mammals, AGR2 influences multiple cell signaling pathways in tumor formation and in normal cell functions related to new tissue formation like angiogenesis. However, the function of AGR2 in mammalian wound healing remains unknown. This study aimed to investigate AGR2 expression and its function during skin wound healing and the possible application of external AGR2 in cutaneous wound to accelerate the healing process. Our results showed that AGR2 expression was induced in the migrating epidermal tongue and hyperplastic epidermis after skin excision. Topical application of recombinant AGR2 significantly accelerated wound-healing process by increasing the migration of keratinocytes (Kera.) and the recruitment of fibroblasts (Fibro.) near the wounded area. External AGR2 also promoted the migration of Kera. and Fibro. in vitro in a dose-dependent manner. The adhesion domain of AGR2 was required for the formation of focal adhesions in migrating Fibro., leading to the directional migration along AGR2 gradient. These results indicate that recombinant AGR2 accelerates skin wound healing through regulation of Kera. and Fibro. migration, thus demonstrating its potential utility as an alternative strategy of the therapeutics to accelerate the healing of acute or chronic skin wounds. PMID- 28665040 TI - Multifunctional enzymes from reduced genomes - model proteins for simple primordial metabolism? AB - Billions of years of evolution have yielded today's complex metabolic networks driven by efficient and highly specialized enzymes. In contrast, the metabolism of the earliest cellular life forms was likely much simpler with only a few enzymes of comparatively low activity. It has been speculated that these early enzymes had low specificities and in turn were able to perform multiple functions. In this issue of Molecular Microbiology, Ferla et al. describe examples of enzymes that catalyze chemically distinct reactions while using the same active site. Most importantly, the authors demonstrated that the comparatively weak activities of these multifunctional enzymes are each physiologically relevant. These findings contrast with simply promiscuous enzyme activities, which have been described numerous times but are not physiologically relevant. Ferla et al. elegantly combined initial bioinformatics searches for enzyme candidates with sound kinetic measurements, evolutionary considerations and even structural discussions. The phenomenon of multifunctionality appears to be a mechanism for bacteria with reduced genomes to compensate for their lack of certain enzymes. In the broader context of evolution, these organisms could be considered living model systems to study features of long-extinct early cellular life. PMID- 28665041 TI - Measurement and modeling of diffusion time dependence of apparent diffusion coefficient and fractional anisotropy in prostate tissue ex vivo. AB - The purpose of this study was to measure and model the diffusion time dependence of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) derived from conventional prostate diffusion-weighted imaging methods as used in recommended multiparametric MRI protocols. Diffusion tensor imaging (DTI) was performed at 9.4 T with three radical prostatectomy specimens, with diffusion times in the range 10-120 ms and b-values 0-3000 s/mm2 . ADC and FA were calculated from DTI measurements at b-values of 800 and 1600 s/mm2 . Independently, a two-component model (restricted isotropic plus Gaussian anisotropic) was used to synthesize DTI data, from which ADC and FA were predicted and compared with the measured values. Measured ADC and FA exhibited a diffusion time dependence, which was closely predicted by the two-component model. ADC decreased by about 0.10-0.15 MUm2 /ms as diffusion time increased from 10 to 120 ms. FA increased with diffusion time at b-values of 800 and 1600 s/mm2 but was predicted to be independent of diffusion time at b = 3000 s/mm2 . Both ADC and FA exhibited diffusion time dependence that could be modeled as two unmixed water pools - one having isotropic restricted dynamics, and the other unrestricted anisotropic dynamics. These results highlight the importance of considering and reporting diffusion times in conventional ADC and FA calculations and protocol recommendations, and inform the development of improved diffusion methods for prostate cancer imaging. PMID- 28665043 TI - Iridium-Catalyzed Enantioselective Synthesis of Pyrrole-Annulated Medium-Sized Ring Compounds. AB - Enantioselective synthesis of pyrrole-annulated medium-sized-ring compounds by an iridium-catalyzed allylic dearomatization/retro-Mannich/hydrolysis sequence is presented. Various substituted pyrrole-annulated seven- and eight-membered-ring products were obtained under mild reaction conditions with moderate to good yields and excellent enantioselectivity. Additionally, these products contain a scaffold widely distributed in natural products and biologically active compounds. The current method provides a convenient way for accessing such pyrrole-anuulated medium-sized-ring compounds. PMID- 28665042 TI - Long-term outcome of concurrent chemoradiotherapy with elective nodal irradiation for inoperable esophageal cancer. AB - Elective nodal irradiation (ENI) might improve overall survival in patients with inoperable esophageal cancer. We conducted a retrospective analysis to assess the long-term survival and toxicity of esophageal cancer patients treated with ENI versus conventional-field irradiation (CFI). All data in the present study were based on our institutional experience from 2000 to 2005 of patients with inoperable esophageal cancer treated with ENI or CFI plus two concurrent cycles of paclitaxel/cisplatin. Based on the inclusion and exclusion criteria, 89 patients were included in the analysis. Of these patients, 51 were treated with ENI, whereas 38 were treated with CFI. For the per-protocol population, the patients in the ENI group significantly improved in terms of their 10-year disease-specific overall survival (43.1% vs 10.5%, P = 0.019), 10-year disease free survival (36.7% vs 10.2%, P = 0.040) and 10-year local recurrence-free survival (47.2% vs 17.2%, P = 0.018) compared with the CFI group. Aside from radiation esophagitis, the incidence of grade 3 or greater acute toxicities did not differ between the two groups. Multivariate analysis showed that radiation field, tumor length and clinical stage were independent prognostic factors associated with OS. Concurrent chemoradiotherapy with ENI improves both disease specific overall survival and loco-regional control in patients with inoperable esophageal cancer receiving per-protocol treatment. The regimen has a manageable tolerability profile. PMID- 28665044 TI - Mood symptoms in pregnant and postpartum women with bipolar disorder: a naturalistic study. AB - OBJECTIVE: We conducted a prospective naturalistic study of pregnant women with bipolar disorder (BD) to evaluate symptoms of BD across childbearing and assess whether pharmacotherapy reduced their severity. METHODS: Assessments were scheduled at 20, 30, and 36 weeks' gestation and 2, 12, 26, and 52 weeks postpartum. Symptoms were assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale-Atypical Depression Supplement (SIGH-ADS) and Mania Rating Scale (MRS). RESULTS: Pregnant women (N=152) with BD were evaluated; 88 women (58%) were treated and 64 untreated (42%) with psychotropic drugs during pregnancy. Among the 88 women treated, 23 (26%) discontinued their medication in the first trimester and the remaining 65 (74%) were exposed throughout pregnancy or in the second and third trimesters. More than two-thirds (73%) of the women who remained in the study took psychotropic agents postpartum. The mean scores on the SIGH-ADS were in the mild range of depressive symptoms in both the psychotropic-treated and untreated groups in both pregnancy and postpartum. The majority of women had no or few symptoms of mania. Of the pregnant women treated with psychotropic agents, 66% received a guideline-concordant drug, and 34% received either antidepressant monotherapy (for BD I) or mono- or polypharmacy with a variety of other agents. CONCLUSIONS: This sample of perinatal women with BD was characterized by mild residual symptoms of depression independent of pharmacotherapy, which poses a risk for recurrence and impaired parenting. The treatment of childbearing women with BD deserves urgent clinical and research attention to improve psychiatric outcomes. PMID- 28665046 TI - Features of lineage-specific hematopoietic metabolism revealed by mitochondrial proteomics. AB - Hematopoietic bone marrow is a regenerative tissue of high clinical relevance, yet relatively little is known about the metabolism of the stem and progenitor populations concerned. We have used a multipotent murine cell line to generate sufficient numbers of cells undergoing self-renewal, erythroid or myeloid differentiation to allow a proteomics analysis of enriched mitochondria. Stringent analysis identified 37 mitochondria-associated proteins changing on differentiation in this system. Those induced during differentiation were commonly associated with mature cell functions, while those inactivated upon differentiation indicate widespread changes in mitochondrial transport, fatty acid catabolism and oxidative phosphorylation. An erythroid specific reduction in glutamate pyruvate amino transferase 2 was confirmed at the protein level by Western blotting and at the functional level by assays of metabolite turnover. In addition to validating the dataset, these findings suggest significant differences in the core-metabolism between erythropoiesis and myelopoiesis. This knowledge is of relevance to the in vitro production of cell therapy products and to studies of the interdependence of metabolic and signaling pathways in regenerative tissues. Data are available via ProteomeXchange with identifier PXD002968. PMID- 28665045 TI - Extraction of dynamic functional connectivity from brain grey matter and white matter for MCI classification. AB - Brain functional connectivity (FC) extracted from resting-state fMRI (RS-fMRI) has become a popular approach for diagnosing various neurodegenerative diseases, including Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). Current studies mainly construct the FC networks between grey matter (GM) regions of the brain based on temporal co-variations of the blood oxygenation level-dependent (BOLD) signals, which reflects the synchronized neural activities. However, it was rarely investigated whether the FC detected within the white matter (WM) could provide useful information for diagnosis. Motivated by the recently proposed functional correlation tensors (FCT) computed from RS-fMRI and used to characterize the structured pattern of local FC in the WM, we propose in this article a novel MCI classification method based on the information conveyed by both the FC between the GM regions and that within the WM regions. Specifically, in the WM, the tensor-based metrics (e.g., fractional anisotropy [FA], similar to the metric calculated based on diffusion tensor imaging [DTI]) are first calculated based on the FCT and then summarized along each of the major WM fiber tracts connecting each pair of the brain GM regions. This could capture the functional information in the WM, in a similar network structure as the FC network constructed for the GM, based only on the same RS fMRI data. Moreover, a sliding window approach is further used to partition the voxel-wise BOLD signal into multiple short overlapping segments. Then, both the FC and FCT between each pair of the brain regions can be calculated based on the BOLD signal segments in the GM and WM, respectively. In such a way, our method can generate dynamic FC and dynamic FCT to better capture functional information in both GM and WM and further integrate them together by using our developed feature extraction, selection, and ensemble learning algorithms. The experimental results verify that the dynamic FCT can provide valuable functional information in the WM; by combining it with the dynamic FC in the GM, the diagnosis accuracy for MCI subjects can be significantly improved even using RS-fMRI data alone. Hum Brain Mapp 38:5019-5034, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28665047 TI - External tooth resorption associated with a peripheral odontogenic fibroma: review and case report. AB - The purpose of the study is to document a rare case of a peripheral odontogenic fibroma with associated cervical and coronal tooth resorption in a 38 year old woman. Histopathological features are described, the clinical management outlined and follow-up observations over 27 years detailed. The exophytic firm lesion, coral pink in appearance, located on the labial aspect of a maxillary right lateral incisor was excised, fixed in formalin and prepared for histological evaluation. The resorption cavity and adjacent soft tissue were treated by the topical application of trichloroacetic acid prior to restoration with a glass ionomer cement and subsequent root canal treatment. Histologically, the body of the lesion was characterized by the presence of odontogenic epithelium embedded in a mature fibrous stroma. Areas of dystrophic calcification could also be identified. The features were consistent with a diagnosis of a peripheral odontogenic fibroma. The clinical result of treatment assessed 27 years postoperatively showed no evidence of recurrence of the peripheral odontogenic fibroma. External cervical and coronal tooth resorption can, on rare occasions, prove to be a clinical feature associated with peripheral odontogenic fibroma. Treatment of the tumour mass and the resorptive lesion can provide a successful outcome. PMID- 28665048 TI - A toxic imbalance of Hsp70s in Saccharomyces cerevisiae is caused by competition for cofactors. AB - Molecular chaperones are responsible for managing protein folding from translation through degradation. These crucial machines ensure that protein homeostasis is optimally maintained for cell health. However, 'too much of a good thing' can be deadly, and the excess of chaperones can be toxic under certain cellular conditions. For example, overexpression of Ssa1, a yeast Hsp70, is toxic to cells in folding-challenged states such as [PSI+]. We discovered that overexpression of the nucleotide exchange factor Sse1 can partially alleviate this toxicity. We further argue that the basis of the toxicity is related to the availability of Hsp70 cofactors, such as Hsp40 J-proteins and nucleotide exchange factors. Ultimately, our work informs future studies about functional chaperone balance and cautions against therapeutic chaperone modifications without a thorough examination of cofactor relationships. PMID- 28665049 TI - The regulatory role of Dipeptidyl peptidase I on the activation of immune granulocytes. AB - Dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease, required for activation of serine proteases of granulocytes including mast cells (MCs), neutrophils (NPs) and others, which were found in synovial tissue of patients with rheumatoid arthritis (RA). But, the role of DPPI associated with those cells in RA development is unclear. In this study, the collagen-induced-arthritis (CIA) rat-model was employed to investigate the expression and activity levels of DPPI and its association with RA progress. Primary granulocytes were freshly extracted from bone-marrows of normal or CIA rats, human mast cell line LAD-2 and primary neutrophils, human-recombinant-DPPI, DPPI-inhibitor Gly-Phe-CHN2 , LTB4, anti-IgE antibody, calcium ionophore were used to study the regulatory role of DPPI in cell activations. The increased DPPI activities in synovial fluids, serum, and bone-marrow homogenates of CIA rats associated with RA severities progress were observed after injections. MMP2/9 expressions in SFs and bone-marrow were in different patterns. Regular-Blood-Tests have shown the high leveled DPPI activities associated with granulocytes differentiations in-vivo in blood of CIA rats. In-vitro cell models, DPPI up-regulated the proliferation of primary bone marrow granulocytes of normal rats, but inhibited that of CIA rats. DPPI up regulated and Gly-Phe-CHN2 down-regulated MCs intracellular DPPI and chymase activities. Gly-Phe-CHN2 also inhibited the LTB4 -activated-NPs and NP-elastase activities. Following stimulation of calcium ionophore, the net-releases of DPPI and beta-hexosaminidase from MCs were increased over a time-course, while Gly-Phe CHN2 down-regulated MCs and NPs activation. Our findings demonstrate the role of DPPI in regulating MCs and NPs activation, and modulating proteolysis in the process of RA. PMID- 28665050 TI - Assessing the public acceptability of proposed policy interventions to reduce the misuse of antibiotics in Australia: A report on two community juries. AB - OBJECTIVE: To elicit the views of well-informed community members on the acceptability of proposed policy interventions designed to improve community use of antibiotics in Australia. DESIGN: Two community juries held in 2016. SETTING AND PARTICIPANTS: Western Sydney and Dubbo communities in NSW, Australia. Twenty nine participants of diverse social and cultural backgrounds, mixed genders and ages recruited via public advertising: one jury was drawn from a large metropolitan setting; the other from a regional/rural setting. MAIN OUTCOME MEASURE: Jury verdict and rationale in response to a prioritization task and structured questions. RESULTS: Both juries concluded that potential policy interventions to curb antibiotic misuse in the community should be directed towards: (i) ensuring that the public and prescribers were better educated about the dangers of antibiotic resistance; (ii) making community-based human and animal health-care practitioners accountable for their prescribing decisions. Patient-centred approaches such as delayed prescribing were seen as less acceptable than prescriber-centred approaches; both juries completely rejected any proposal to decrease consumer demand by increasing antibiotic prices. CONCLUSION: These informed citizens acknowledged the importance of raising public awareness of the risks, impacts and costs of antibiotic resistance and placed a high priority on increasing social and professional accountability through restrictive measures. Their overarching aim was that policy interventions should be directed towards creating collective actions and broad social support for changing antibiotic use through establishing and explaining the need for mechanisms to control and support better prescribing by practitioners, while not transferring the burdens, costs and risks of interventions to consumers. PMID- 28665052 TI - Discovery of putative breast cancer antigens using an integrative platform of genomics-driven immunoproteomics. AB - Recent advances in cancer immuno-therapeutics such as checkpoint inhibitors, chimeric antigen-receptor T cells, and tumor infiltrating T cells (TIL) are now significantly impacting cancer patients in a positive manner. Although very promising, reports indicate no more than 25% of cases result in complete remission. One of the limitations of these treatments is the identity of putative cancer antigens in each patient, as it is technically challenging to identify cancer antigens in a rapid fashion. Thus, identification of cancer antigens followed by targeted treatment will increase the efficacy of cancer immunotherapies. To achieve this goal, a combined technologies platform of deep genomic sequencing and personalized immune assessment was devised, termed Genomics Driven Immunoproteomics (GDI). Using this technological platform, we report the discovery of 149 tumor antigens from human breast cancer patients. Significant number of these putative cancer antigens arise from single nucleotide variants (SNVs), as well as insertions and deletions that results into frame shift mutations. We propose a general model of anti-cancer immunity and suggest that the GDI platform may help identify patient-specific tumor antigens in a timely fashion for precision immunotherapies. PMID- 28665051 TI - Phase 1 dose-escalation study of single-agent veliparib in Japanese patients with advanced solid tumors. AB - Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase 1 and -2 inhibitor. This phase 1 study evaluated the tolerability, pharmacokinetic profile, safety, and preliminary antitumor activity of single agent veliparib in Japanese patients with advanced solid tumors. Eligible patients were assigned to treatment with veliparib at 200 or 400 mg dose; veliparib was self-administered orally twice daily on days 1-28 of 28-day cycles. Dose escalation, following a 3 + 3 design, defined dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose. Sixteen patients were enrolled (median age, 59 years). Fourteen patients had high-grade serous ovarian cancer, one had primary peritoneal cancer, and one had BRCA-mutated breast cancer. The most frequent treatment-emergent adverse events were nausea and vomiting (93.8% each), decreased appetite (62.5%), abdominal pain, diarrhea, and malaise (31.3% each). A grade >=3 toxicity was observed in 50% of patients; one patient each in the 200 mg (n = 4) and 400 mg (n = 12) cohorts experienced serious adverse events. Dose-limiting toxicities were observed for one patient at the 400 mg dose. No toxicities leading to death were reported. The recommended phase 2 dose was defined as 400 mg twice daily. The veliparib pharmacokinetic profile was consistent with that reported for the Western population. Two patients, both with ovarian cancer, had a RECIST partial response. Veliparib monotherapy showed manageable tolerability and safety profiles and a predictable pharmacokinetic profile at a 400 mg twice-daily dose, and supports the inclusion of Japanese patients in the multinational phase 3 study (NCT02470585). PMID- 28665053 TI - Increasing Burden of Nontuberculous Mycobacteria in Korea. PMID- 28665054 TI - Dysphagia due to Upper Esophageal Sphincter Disorder after Suicide Attempts. PMID- 28665055 TI - Plagiarism in the Context of Education and Evolving Detection Strategies. AB - Plagiarism may take place in any scientific journals despite currently employed anti-plagiarism tools. The absence of widely acceptable definitions of research misconduct and reliance solely on similarity checks do not allow journal editors to prevent most complex cases of recycling of scientific information and wasteful, or 'predatory,' publishing. This article analyses Scopus-based publication activity and evidence on poor writing, lack of related training, emerging anti-plagiarism strategies, and new forms of massive wasting of resources by publishing largely recycled items, which evade the 'red flags' of similarity checks. In some non-Anglophone countries 'copy-and-paste' writing still plagues pre- and postgraduate education. Poor research management, absence of courses on publication ethics, and limited access to quality sources confound plagiarism as a cross-cultural and multidisciplinary phenomenon. Over the past decade, the advent of anti-plagiarism software checks has helped uncover elementary forms of textual recycling across journals. But such a tool alone proves inefficient for preventing complex forms of plagiarism. Recent mass retractions of plagiarized articles by reputable open-access journals point to critical deficiencies of current anti-plagiarism software that do not recognize manipulative paraphrasing and editing. Manipulative editing also finds its way to predatory journals, ignoring the adherence to publication ethics and accommodating nonsense plagiarized items. The evolving preventive strategies are increasingly relying on intelligent (semantic) digital technologies, comprehensively evaluating texts, keywords, graphics, and reference lists. It is the right time to enforce adherence to global editorial guidance and implement a comprehensive anti-plagiarism strategy by helping all stakeholders of scholarly communication. PMID- 28665056 TI - Improvement in the Survival Rates of Very Low Birth Weight Infants after the Establishment of the Korean Neonatal Network: Comparison between the 2000s and 2010s. AB - The survival rate (SR) of very low birth weight infants (VLBWIs) and extremely low birth weight infants (ELBWIs) is a health indicator of neonatal intensive care unit (NICU) outcomes. The Korean Neonatal Network (KNN) was established in 2013, and a system has been launched to manage the registration and quality improvement of VLBWIs. The SR of the VLBWIs significantly increased to 85.7% in the 2010s compared with 83.0% in the 2000s. There was also a significant increase in the SR of the ELBWIs from 66.1% to 70.7%. The equipment, manpower, and assistance systems of NICUs also improved in quantity and quality. In the international comparison of the SRs of VLBWIs, the SRs were 93.8%, 92.2%, 90.2%, 89.4%, 86.4%, 85.1%, and 80.6% in Japan, Australia and New Zealand, Canada, Europe, Korea, Taiwan, and United States, respectively. In conclusion, the SRs of the VLBWIs and ELBWIs improved in the 2010s compared with those in the 2000s in Korea. This improvement is considered to have been related to the role of the KNN built in 2013. However, the latest VLBWI and ELBWI SRs in 2015 are still low compared with those in Japan, Australia and New Zealand, Canada, and Europe. In the future, we must establish and develop the tasks that are presented as future tasks in this review. PMID- 28665057 TI - Publication Delay of Korean Medical Journals. AB - Publication lag is a determinant to journal efficiency that was not yet studied concerning Korean medical journals. To measure publication lag, we investigated the publication timestamps of 4,762 articles published by 10 Korean medical journals indexed in Scopus database, randomly selected from the KoreaMed Synapse since 2013. The total publication lag was 246.5 (Q1, Q3; 178.0, 347.0) days. The overall acceptance lag was 102.0 (65.0, 149.0) days. The overall lead lag was 123.0 (63.0, 236.0) days. The year of publication did not significantly affect the acceptance lag (P = 0.640), supposedly shortening it by about 1.4 (97.5% confidence interval [CI], ?5.2 to 8.0) days/year, while the date affected the lead lag (P = 0.028), shortening it by about 12.9 (1.3 to 24.5) days/year. The Korean medical journals have reduced the total publication delay entirely by means of reducing the lead lag, not by reducing the acceptance lag. PMID- 28665058 TI - Decoding Saccadic Directions Using Epidural ECoG in Non-Human Primates. AB - A brain-computer interface (BCI) can be used to restore some communication as an alternative interface for patients suffering from locked-in syndrome. However, most BCI systems are based on SSVEP, P300, or motor imagery, and a diversity of BCI protocols would be needed for various types of patients. In this paper, we trained the choice saccade (CS) task in 2 non-human primate monkeys and recorded the brain signal using an epidural electrocorticogram (eECoG) to predict eye movement direction. We successfully predicted the direction of the upcoming eye movement using a support vector machine (SVM) with the brain signals after the directional cue onset and before the saccade execution. The mean accuracies were 80% for 2 directions and 43% for 4 directions. We also quantified the spatial spectro-temporal contribution ratio using SVM recursive feature elimination (RFE). The channels over the frontal eye field (FEF), supplementary eye field (SEF), and superior parietal lobule (SPL) area were dominantly used for classification. The alpha-band in the spectral domain and the time bins just after the directional cue onset and just before the saccadic execution were mainly useful for prediction. A saccade based BCI paradigm can be projected in the 2D space, and will hopefully provide an intuitive and convenient communication platform for users. PMID- 28665059 TI - Occupational Risk of Latent Tuberculosis Infection in Health Workers of 14 Military Hospitals. AB - Tuberculosis (TB) is a known occupational risk to health workers. Identifying risk factors in health care settings is critical to the prevention of TB for health workers and patients. In 2014, we carried out a TB screening and survey for 902 health workers from 14 selected military hospitals to determine the prevalence rate of latent tuberculosis infection (LTBI) as well as occupational risk factors. Of all subjects, 19.5% reported having provided TB patient care for 1 year or more (176/902), and 26.9% (243/902) were positive for the tuberculin skin test (TST) (10 mm or more of induration). Additionally, 21.4% (52/243) of those who tested positive were also positive for the interferon-gamma release assay (IGRA). The proportion of LTBI in the study population was 5.8% (52/902). In a multivariate logistic regression analysis, providing TB patient care for one year or more was the only significant occupational risk factor (adjusted odds ratio [aOR], 2.27; 95% confidence interval [CI], 1.13-4.56). This study suggests that military health workers working with TB patients should be regularly examined by chest radiography, TST and IGRA to detect LTBI in the early stage and control nosocomial infection of TB. PMID- 28665060 TI - Clinical Impacts of Donor Types of Living vs. Deceased Donors: Predictors of One Year Mortality in Patients with Liver Transplantation. AB - Transplantation studies about the clinical differences according to the type of donors are mostly conducted in western countries with rare reports from Asians. The aims of this study were to evaluate the clinical impacts of the type of donor, and the predictors of 1-year mortality in patients who underwent liver transplantation (LT). This study was performed for liver transplant recipients between May 2010 and December 2014 at the Pusan National University Yangsan Hospital. A total of 185 recipients who underwent LT were analyzed. Of the 185 recipients, 109 (58.9%) belonged to the living donor liver transplantation (LDLT) group. The median age was 52.4 years. LDLT recipients had lower model for end stage liver disease (MELD) score compared with better liver function than deceased donor liver transplantation (DDLT) recipients (mean +/- standard deviation [SD], 12.5 +/- 8.3 vs. 24.9 +/- 11.7, respectively; P < 0.001), and had more advanced hepatocellular carcinoma (HCC) (62.4% vs. 21.1%, respectively; P = 0.001). In complications and clinical outcomes, LDLT recipients showed shorter stay in intensive care unit (ICU) (mean +/- SD, 10.8 +/- 8.8 vs. 23.0 +/- 13.8 days, respectively, P < 0.001), ventilator care days, and post-operative admission days, and lower 1-year mortality (11% vs. 27.6%, respectively, P = 0.004). Bleeding and infectious complications were less in LDLT recipients. Recipients with DDLT (P = 0.004) showed higher mortality in univariate analysis, and multi-logistic regression analysis found higher MELD score and higher pre operative serum brain natriuretic peptide (BNP) were associated with 1-year mortality. This study may guide improved management before and after LT from donor selection to post-operation follow up. PMID- 28665061 TI - Recovery Rates of Non-Tuberculous Mycobacteria from Clinical Specimens Are Increasing in Korean Tertiary-Care Hospitals. AB - Non-tuberculous mycobacteria (NTM) are being recognized increasingly as the causative agents of opportunistic infections in humans. This study investigated the epidemiologic trends of NTM recovery from various clinical specimens in 2 Korean tertiary-care hospitals. We reviewed the laboratory records of patient samples cultured for mycobacteria between 2009 and 2015 at 2 tertiary-care hospitals in Korea. The medical records for patients with positive NTM samples were also reviewed. During the study period, 144,540 specimens were cultured for mycobacteria. The proportion of NTM-positive samples increased from 23.3% in 2009 to 48.2% in 2015. The 2 most frequently isolated NTM were Mycobacterium intracellulare (38.3%) and M. avium (23.1%). The number of clinically significant diseases caused by NTM in inpatients and outpatients increased from 6.8 to 12.9 per 100,000 patients over the same period. The rates of recovery of NTM from clinical specimens and the number of patients with NTM infections increased significantly (P < 0.001, testing for trend) between 2009 and 2015. PMID- 28665062 TI - Metabolic Complications among Korean Patients with HIV Infection: The Korea HIV/AIDS Cohort Study. AB - Currently, metabolic complications are the most common problem among human immunodeficiency virus (HIV)-infected patients, with a high incidence. However, there have been very few studies regarding metabolic abnormalities published in Asia, especially in Korea. This cross-sectional study was performed to investigate the prevalence of and risk factors for metabolic abnormalities in 1,096 HIV-infected patients of the Korea HIV/AIDS cohort study enrolled from 19 hospitals between 2006 and 2013. Data at entry to cohort were analyzed. As a result, the median age of the 1,096 enrolled subjects was 46 years, and most patients were men (92.8%). The metabolic profiles of the patients were as follows: median weight was 63.8 kg, median body mass index (BMI) was 22.2 kg/m2, and 16.4% of the patients had a BMI over 25 kg/m2. A total of 5.5% of the patients had abdominal obesity (waist/hip ratio >= 1 in men, >= 0.85 in women). Increased levels of fasting glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were present in 10.4%, 6.0%, 5.5%, and 32.1% of the patients. Decreased high-density lipoprotein (HDL) cholesterol levels were observed in 44.2% of the patients. High systolic blood pressure was present in 14.3% of the patients. In multivariate analysis, high BMI and the use of protease inhibitors (PIs) were risk factors for dyslipidemia in HIV-infected patients. In conclusion, proper diagnosis and management should be offered for the prevalent metabolic complications of Korean HIV-infected patients. Further studies on risk factors for metabolic complications are needed. PMID- 28665063 TI - Uric Acid Level Has a U-shaped Association with Clinical Outcomes in Patients with Vasospastic Angina. AB - No data are available on the association of serum uric acid and vasospastic angina (VSA) which has endothelial dysfunction as a possible pathophysiologic mechanism. Low uric acid level might cause adverse outcomes in VSA in connection with endothelial dysfunction. We enrolled 818 VSA patients whose uric acid level was measured at admission. Patients were categorized according to tertiles of uric acid level: group I, <= 4.8 mg/dL; group II, 4.9-5.9 mg/dL; and group III, >= 6.0 mg/dL. Primary outcome was major adverse cardiac events (MACEs), defined as a composite of cardiac death, acute myocardial infarction (MI), ischemic stroke, coronary revascularization, and rehospitalization for angina. Median follow-up duration was 49.2 months. Median uric acid values were 4.1 mg/dL for group I, 5.4 mg/dL for group II, and 6.7 mg/dL for group III. In the overall population, group II had a significantly lower incidence of MACE compared to group I (47 [17.1%] vs. 66 [24.6%]; hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.02-2.26; P = 0.040) and a tendency of lower incidence of MACEs compared to Group III (47 [17.1%] vs. 62 [22.5%]; HR, 1.44; 95% CI, 0.98-2.13; P = 0.067). Among group I patients, those who received nitrates had a higher incidence of MACEs than those without nitrate therapy (P < 0.001). Low uric acid level was associated with adverse clinical outcomes, while high uric acid level had a trend toward an increase in it. Use of nitrate in patients with low uric acid level might have adverse effects on clinical outcomes of VSA. PMID- 28665064 TI - Is Colonoscopic Screening Necessary for Patients Younger than 50 Years with Gastric Adenoma or Cancer? AB - Patients, aged >= 50 years, with gastric neoplasm are reported to be at increased risk for colorectal neoplasia (CRN), while data regarding the risk of CRN in young patients, aged < 50 years with gastric neoplasm are limited. We aimed to investigate the risk of CRN according to the presence of gastric neoplasm in patients, aged < 50 years, and conducted a cross-sectional study on 131,888 asymptomatic examinees who underwent both esophagogastroduodenoscopy (EGD) and colonoscopy as part of a health screening program between 2010 and 2014. The prevalence of overall CRN (8.6% vs. 13.2%, P = 0.251) and advanced colorectal neoplasia (ACRN) (0.0% vs. 1.3%, P = 0.345) did not significantly differ according to the presence of gastric neoplasm in subjects, aged < 50 years. However, among subjects aged >= 50 years, patients with gastric neoplasm had a significantly higher proportion of overall CRN (48.2% vs. 31.7%, P < 0.001) and ACRN (12.5% vs. 4.5%, P < 0.001) compared with those without gastric neoplasm. Particularly, gastric neoplasm was an independent risk factor for ACRN after controlling for confounding factors among subjects, aged >= 50 years. In conclusion, gastric neoplasm was a risk factor for CRN in patients, aged >= 50 years, but not in patients, aged < 50 years. Young patients, aged < 50 years with gastric neoplasm do not need to undergo colonoscopy, whereas patients, aged >= 50 years with gastric neoplasm, should be considered a higher priority for colonoscopy. PMID- 28665065 TI - Prophylactic versus Early Rescue Surfactant Treatment in Preterm Infants Born at Less than 30 Weeks Gestation or with Birth Weight Less than or Equal 1,250 Grams. AB - Prophylactic surfactant is known to be effective to reduce chronic lung disease in preterm infants compared with rescue surfactant treatment. In Korea, early prophylactic surfactant therapy was introduced in 2011. However, recently, the increased utilization of antenatal steroids and early stabilization through continuous positive airway pressure (CPAP) in the delivery room may have changed the risks and benefits of prophylactic surfactant therapy of infants at high risk of respiratory distress syndrome (RDS). We compared the effects and safety of prophylactic surfactant therapy (within 30 minutes after birth) and early selective surfactant therapy (within 3 hours after birth) in preterm infants born at < 30 weeks gestation or with birth weight <= 1,250 g. The clinical data of 193 infants in period 1 (from 2008 to 2010, early selective surfactant therapy group) were collected retrospectively; those of 191 infants in period 2 (from 2012 to 2014, prophylactic surfactant therapy group) were collected prospectively. Compared to period 1, the rate of intubation and surfactant use were significantly increased in period 2. The use of multiple doses of surfactant in period 2 was significantly increased compared with period 1. Despite more invasive and aggressive management in period 2, there was no difference in the duration of mechanical ventilation, the incidence of bronchopulmonary dysplasia (BPD) or death, and the risk of other adverse neonatal outcomes between the 2 groups. In conclusion, the benefit of prophylactic surfactant therapy in infants treated under current practices is no longer clear compared to early selective surfactant therapy. PMID- 28665066 TI - Comparison of Follow-up Courses after Discharge from Neonatal Intensive Care Unit between Very Low Birth Weight Infants with and without Home Oxygen. AB - In order to investigate the clinical impact of home oxygen use for care of premature infants, we compared the follow-up courses after neonatal intensive care unit (NICU) discharge between very low birth weight infants (VLBWIs) with and without home oxygen. We retrospectively identified 1,232 VLBWIs born at 22 to 32 weeks of gestation, discharged from the NICU of 43 hospitals in Korea between April 2009 and March 2010, and followed them up until April 2011. Clinical outcomes, medical service uses, and readmission and death rates during follow-up after the NICU discharge were compared between VLBWIs with (HO, n = 167) and those without (CON, n = 1,056) home oxygen at discharge. The HO infants comprised 13.7% of the total VLBWIs with significant institutional variations and showed a lower gestational age (GA) and birth weight than the CON infants. The HO infants had more frequent regular pediatric outpatient clinic visits (12.7 +/- 7.5 vs. 9.5 +/- 6.6; P < 0.010) and emergency center visits related to respiratory problems (2.5 +/- 2.2 vs. 1.8 +/- 1.4; P < 0.010) than the CON infants. The HO infants also had significantly increased readmission (adjusted hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.25-2.04) and death risks (adjusted HR, 7.40; 95% CI, 2.06-26.50) during up to 2 years following the NICU discharge. These increased readmission and death risks in the HO infants were not related to their prematurity degree. In conclusion, home oxygen use after discharge increases the risks for healthcare utilization, readmission, and death after NICU discharge in VLBWIs, regardless of GA, requiring more careful health care monitoring during their follow-up. PMID- 28665068 TI - Comparison of the Birth Statistics between Multi-cultural and Korean Families in Korea (2015). AB - Since 2002, the number of marriages, births, and family members among multi cultural families (MCFs) has increased. Beginning in 2006, the government initiated a planned management for such families and has implemented the MCF policy basic plan since 2010. In 2015, with multiple socio-economic and medical support initiatives for MCF being available, we analyzed the statistics for several factors related to birth, to determine whether there are significant adverse birth outcomes in MCF. We analyzed the birth data of MCFs in 2015, from Statistics Korea. This study compared the birth data of MCF and Korean families (KF) by geography, neonatal birth weight (BW), gestational age (GA), birth order of the neonates, place of delivery, cohabitation period of parents before the first child, and parental education level. The distribution of BW and the prevalence of low BW (< 2,500 g) or very low BW (< 1,500 g) were similar between both groups. The incidence of preterm birth was lower in the MCF group (6.5% vs. 7.0%, P = 0.015) than in the KF group. In the MCF group, parental education level was lower, and incidence of out-of-hospital births was higher than that of the KF group. Adverse birth outcomes, such as preterm birth and low BW in MCF are similar or better than KF. This study could be a good basis to present the status of MCF birth and newborn care in 2015. PMID- 28665067 TI - The Different Clinical Aspects of Pediatric Primary Airway Tumors in the Larynx, Trachea, and Bronchi. AB - Primary airway tumors are rare in children and no literature reviewed their characteristics each location. We evaluate the clinical characteristics and outcomes of Korean children with primary airway tumors, from the larynx to bronchi. A retrospective chart review of children with primary tumors of the larynx, trachea, and bronchi at Asan Medical Center from January 2000 to July 2016 was conducted. Nineteen children were diagnosed with primary airway tumors of the larynx (47.4%), trachea (10.5%), and bronchi (42.1%). Median follow-up duration was 2.8 years and there were recurrences in 21.1%. Laryngeal tumors were associated with a younger median age at onset (2 months) and diagnosis (4 months), and most were relatively small (median size = 5.3 mm) and symptomatic. Tracheal and bronchial tumors were found in older children (age at onset and diagnosis > 11 years) and large (> 15.0 mm). Most (75%) patients with bronchial tumors were asymptomatic and all the patients with tracheal tumors were symptomatic. This study suggests that we should consider different the locations in primary airway tumor based on the age at onset and diagnosis, initial symptoms or signs, and size of tumor. PMID- 28665069 TI - Trends in Fetal and Perinatal Mortality in Korea (2009-2014): Comparison with Japan and the United States. AB - Fetal death is an important indicator of national health care. In Korea, the fetal mortality rate is likely to increase due to advanced maternal age and multiple births, but there is limited research in this field. The authors investigated the characteristics of fetal deaths, the annual changes in the fetal mortality rate and the perinatal mortality rate in Korea, and compared them with those in Japan and the United States. Fetal deaths were restricted to those that occurred at 20 weeks of gestation or more. From 2009 to 2014, the overall mean fetal mortality rate was 8.5 per 1,000 live births and fetal deaths in Korea, 7.1 in Japan and 6.0 in the United States. While the birth rate in Korea declined by 2.1% between 2009 and 2014, the decrease in the number of fetal deaths was 34.5%. The fetal mortality rate in Korea declined by 32.9%, from 11.0 in 2009 to 7.4 in 2014, the largest decline among the 3 countries. In addition, rates for receiving prenatal care increased from 53.9% in 2009 to 75.0% in 2014. Perinatal mortality rate I and II were the lowest in Japan, followed by Korea and the United States, and Korea showed the greatest decrease in rate of perinatal mortality rate II. In this study, we identified that the indices of fetal deaths in Korea are improving rapidly. In order to maintain this trend, improvement of perinatal care level and stronger national medical support policies should be maintained continuously. PMID- 28665070 TI - Identification of Downstream Genes of the mTOR Pathway that Predict Recurrence and Progression in Non-Muscle Invasive High-Grade Urothelial Carcinoma of the Bladder. AB - Microarray analysis was used to investigate the lack of identified mammalian target of rapamycin (mTOR) pathway downstream genes to overcome cross-talk at non muscle invasive high-grade (HG)-urothelial carcinoma (UC) of the bladder, gene expression patterns, gene ontology, and gene clustering by triple (p70S6K, S6K, and eIF4E) small interfering RNAs (siRNAs) or rapamycin in 5637 and T24 cell lines. We selected mTOR pathway downstream genes that were suppressed by siRNAs more than 2-fold, or were up-regulated or down-regulated by rapamycin more than 2 fold. We validated mTOR downstream genes with immunohistochemistry using a tissue microarray (TMA) of 125 non-muscle invasive HG-UC patients and knockout study to evaluate the synergistic effect with rapamycin. The microarray analysis selected mTOR pathway downstream genes consisting of 4 rapamycin up-regulated genes (FABP4, H19, ANXA10, and UPK3A) and 4 rapamycin down-regulated genes (FOXD3, ATP7A, plexin D1, and ADAMTS5). In the TMA, FABP4, and ATP7A were more expressed at T1 and FOXD3 was at Ta. ANXA10 and ADAMTS5 were more expressed in tumors <= 3 cm in diameter. In a multivariate Cox regression model, ANXA10 was a significant predictor of recurrence and ATP7A was a significant predictor of progression in non-muscle invasive HG-UC of the bladder. In an ATP7A knock-out model, rapamycin treatment synergistically inhibited cell viability, wound healing, and invasion ability compared to rapamycin only. Activity of the ANXA10 and ATP7A mTOR pathway downstream genes might predict recurrence and progression in non-muscle invasive HG-UC of the bladder. ATP7A knockout overcomes rapamycin cross-talk. PMID- 28665071 TI - Feasibility and Safety of Mild Therapeutic Hypothermia in Poor-Grade Subarachnoid Hemorrhage: Prospective Pilot Study. AB - Therapeutic hypothermia (TH) improves the neurological outcome in patients after cardiac arrest and neonatal hypoxic brain injury. We studied the safety and feasibility of mild TH in patients with poor-grade subarachnoid hemorrhage (SAH) after successful treatment. Patients were allocated randomly to either the TH group (34.5 degrees C) or control group after successful clipping or coil embolization. Eleven patients received TH for 48 hours followed by 48 hours of slow rewarming. Vasospasm, delayed cerebral ischemia (DCI), functional outcome, mortality, and safety profiles were compared between groups. We enrolled 22 patients with poor-grade SAH (Hunt & Hess Scale 4, 5 and modified Fisher Scale 3, 4). In the TH group, 10 of 11 (90.9%) patients had a core body temperature of < 36 degrees C for > 95% of the 48-hour treatment period. Fewer patients in the TH than control group (n = 11, each) had symptomatic vasospasms (18.1% vs. 36.4%, respectively) and DCI (36.3% vs. 45.6%, respectively), but these differences were not statistically significant. At 3 months, 54.5% of the TH group had a good-to moderate functional outcome (0-3 on the modified Rankin Scale [mRS]) compared with 9.0% in the control group (P = 0.089). Mortality at 1 month was 36.3% in the control group compared with 0.0% in the TH group (P = 0.090). Mild TH is feasible and can be safely used in patients with poor-grade SAH. Additionally, it may reduce the risk of vasospasm and DCI, improving the functional outcomes and reducing mortality. A larger randomized controlled trial is warranted. PMID- 28665072 TI - The Relationship between Physical Activity Intensity and Mental Health Status in Patients with Breast Cancer. AB - The aim of this study was to investigate the correlation between physical activity (PA) level and mental health status in a population-based sample of Korean female patients with breast cancer. Our analysis included 76 patients with breast cancer and 44 healthy controls. The Korean versions of the International Physical Activity Questionnaire (IPAQ), Beck Depressive Inventory (BDI), State Trait Anxiety Inventory-KY (STAI-KY), and Somatosensory Amplification Scale (SSAS), and Quality of Life (QOL) scale were assessed. The frequency of moderate PA level in breast cancer patients was significantly lower than that of healthy control subjects (t = -2.6; P = 0.011). In turn, the incidence of low PA level in breast cancer patients was significantly higher than that observed in healthy controls (t = 2.85; P = 0.005). A moderate PA level was inversely correlated with BDI score (r = -0.35; P = 0.008) and was positively correlated with QOL score (r = 0.38; P = 0.011). A low level of PA was inversely correlated with SSAS score (r = -0.39; P < 0.001). In healthy controls, a high level of PA was positively correlated with QOL score (r = 0.50; P = 0.043). Moderate PA level was inversely correlated with SSAS score (r = -0.59; P < 0.001). A low level of PA was also positively correlated with BDI score (r = 0.35; P = 0.008). A moderate or low intensity of PA was inversely correlated with depression and somatosensory amplification and was positively correlated with QOL in breast cancer patients. Finally, we suggest that progressively low-to-moderate levels of PA can be well adapted to positively impact several measures of mental health. PMID- 28665073 TI - Sebaceous Carcinoma: Clinicopathologic Analysis of 29 Cases in a Tertiary Hospital in Korea. AB - Sebaceous carcinoma (SC) is a neoplasm derived from the adnexal epithelium of the sebaceous glands, and most studies on this neoplasm have been conducted in Caucasians. We retrospectively reviewed the records of 29 patients with SC (16 extraocular and 13 ocular lesions) who were diagnosed from 2001 to 2014 to analyze the clinical and histopathological features of SC in the Korean population. Sixteen of the patients were women and 13 were men. There was an equal sex distribution for extraocular lesions, and a female predilection (M:F = 1:1.6) for ocular lesions. The mean ages at presentation of extraocular and ocular lesions were 69.19 +/- 37.19 (range, 32-87) and 67.46 +/- 24.46 (range, 43 85) years, respectively. Most lesions occurred in the eyelid (13/29, 44.83%), and most extraocular lesions occurred in the head and neck area (13/16, 81.25%). There was no recurrence or death during the follow-up period. Most lesions were poorly differentiated (extraocular, 43.75%; ocular, 38.46%), had a lobular infiltrative growth pattern (extraocular, 68.75%; ocular, 76.92%), and were basaloid (extraocular, 56.25%; ocular, 61.54%). Only 5 cases (2 extraocular and 3 ocular lesions) showed pagetoid spread. Extraocular lesions were marginally more common than the ocular form. There were higher incidences in elderly patients, who also had the highest incidence of eyelid lesions. The proportion of cells with sebaceous differentiation and prominent growth patterns were variable. Our results show that SC may not be very aggressive in Koreans. PMID- 28665074 TI - Clinical Features of Atopic Dermatitis in Adults Are Different according to Onset. AB - Few studies of atopic dermatitis (AD) in adult patients have evaluated differences in clinical features of AD according to onset age. We aimed to characterize the clinical features of AD in adult patients according to age of onset. Subjects with AD outpatient visiting the Department of Dermatology at Kangnam Sacred Heart Hospital were recruited for this study. A dermatologist conducted clinical evaluation, a survey of demographics, and onset of AD associated signs and symptoms for each participant. Total immunoglobulin E (IgE) was also tested. A total of 280 adult AD patients were enrolled, among which 232 patients (82.86%) showed pre-adult-onset (age < 18 years) and 48 patients (17.14%) had adult-onset (age >= 18 years) of AD. There were significant differences between the 2 groups in the area of initial involvement (P = 0.017) and in treatment history (P = 0.010). Interestingly, patients with body mass index (BMI) >= 25 showed significantly higher Eczema Area and Severity Index (EASI) scores than did patients with BMI < 25 in the pre-adult-onset adult AD group (P = 0.048). On the other hand, there were no significant differences in sex, family history, BMI, EASI, and total IgE between patients with pre-adult onset AD and patients with adult-onset AD. Our findings suggest that, even though many common features exist, there are significant differences between the clinical characteristics of pre-adult-onset and adult-onset AD subgroups, in adult patients with AD. PMID- 28665075 TI - Rapid Health Needs Assessment after Typhoons Bolaven and Tembin Using the Public Health Assessment for Emergency Response Toolkit in Paju and Jeju, Korea 2012. AB - Following natural disasters, rapid health needs assessments are required to quickly assess health status and help decision making during the recovery phase. The Korean Centers for Disease Control and Prevention (KCDC) developed the Public Health Assessment for Emergency Response (PHASER) Toolkit which was optimized for a weather disaster in Korea. The goal of this study is to assess public health needs following the 2012 typhoons Bolaven and Tembin in both urban and rural areas in Korea. We conducted pilot trials using the PHASER toolkit to assess health needs following typhoons Bolaven and Tembin in Paju and Jeju during summer 2012. We sampled 400 households in Jeju and 200 households in Paju using a multistage cluster sampling design method. We used a standardized household tracking sheet and household survey sheet to collect data on the availability of resource for daily life, required health needs, clinical results and accessibility of medical services. The primary outcomes were clinical results and accessibility of medical service after the typhoons. We completed surveys for 190 households in Paju and 386 households in Jeju. Sleeping disorders were identified in 6.8% (95% confidence interval [CI], 2.8%-10.8%) surveyed in Paju and 17.4% (95% CI, 12.8%-22.0%) in Jeju. We used the PHASER toolkit to assess healthcare needs rapidly after 2 typhoons in Korea. Sleeping disorders were frequently identified in both Paju and Jeju following the 2 typhoons. PMID- 28665077 TI - Letter to the Editor: Plagiarism in Scientific Writings: Is There Any Way Out? PMID- 28665076 TI - Congenital Syphilis Presenting with Only Nephrotic Syndrome: Reemergence of a Forgotten Disease. AB - Syphilis infection has re-emerged after years of declining incidence. The prevalence of congenital syphilis (CS) has increased in Korea and other countries during the last few decades. Untreated infants develop symptoms such as rhinorrhea, anemia, jaundice, cutaneous lesions, hepatosplenomegaly, and pseudoparalysis within weeks or months. Significant renal disease is uncommon in CS, and clinical renal involvement varies from mild transient proteinuria to frank nephrosis. We report a 2-month-old infant with CS who presented with only nephrotic syndrome (NS). The previously healthy infant presented with NS and showed no other syphilitic manifestations. Remission of the NS was achieved with adequate penicillin treatment. No recurrence of proteinuria was observed during the 1 year of follow-up. Although rare, this long forgotten disease continues to affect pregnant women, resulting in prenatal or postnatal mortality. We still consider the possibility of syphilitic nephropathy and therefore serologic testing for congenital NS. PMID- 28665078 TI - Letter to the Editor: Appropriate Statistical Analysis and Research Reporting. PMID- 28665080 TI - Towards A High Integrity Health System. PMID- 28665079 TI - Letter to the Editor: Sharing Image Data from Clinical Trials. PMID- 28665081 TI - Incidence of Hospital Acquired Thrombosis (HAT) in a Tertiary Care Hospital. AB - Venous thromboembolism (VTE) is a major cause of preventable morbidity and mortality in hospitalized patients. In spite of guidelines, VTE prophylaxis continues to be underutilised, and hospital acquired thrombosis (HAT) continues to be a problem. This study was conducted to estimate the incidence of HAT in a tertiary referral centre and to examine whether VTE risk assessment and thromboprophylaxis (TP) were implemented. Patients 18 years and above, with a radiologically-confirmed acute VTE during the study period of 15 weeks were included. Acute VTE was diagnosed in 100 patients and HAT was diagnosed in 48. There were 12,024 admissions over the study period, therefore the incidence of HAT was 0.4%. TP was prescribed in only 35% of patients, and 65% did not receive any or appropriate TP. Hospitals without active implementation of a formal risk assessment tool and TP policy are likely to continue to have increased incidence of HAT. PMID- 28665082 TI - Caring for Obese Children- A change in Paradigm. AB - Childhood Obesity is a problem of epidemic proportions. The causes are complex and treatment results are variable with much research ongoing. We analysed the initial assessment forms of a group of patients attending the W82GO! Healthy Lifestyle service at The Children's University Hospital, Temple Street to look at the population and their specific needs. Our analysis revealed a high proportion of emotional and behavioural problems along with bullying. This group of patients are complex and a multi-disciplinary team approach is essential in their treatment. PMID- 28665083 TI - Ireland's recent contribution to the radiological literature; a bibliometric analysis. AB - The aim of this study was to identify and analyse all articles published by Irish radiology departments in the medical literature since the year 2000. The PubMed database was searched to identify and review all articles published by radiologists based in the Republic of Ireland or Northern Ireland. Citation counts were then obtained and the top ten most cited articles were identified. There were 781 articles published during the study period. Of these, 558 (71%) were published in radiology journals and the remaining 223 (29%) were published in general medical journals. Abdominal radiology was the most represented sub specialty (33% of all articles). There was a general trend of increased publications per year. Only 75 (9.6%) of articles were collaborative efforts by more than one radiology department. Irish radiology departments have a considerable research output and this has increased since the year 2000. More collaborative research between Irish radiology departments is encouraged. PMID- 28665084 TI - An audit of empiric antibiotic choice in the inpatient management of community acquired pneumonia. AB - Adherence to antimicrobial guidelines for empiric antibiotic prescribing in community-acquired pneumonia (CAP) has been reported to be worryingly low. We conducted a review of empiric antibiotic prescribing for sixty consecutive adult patients admitted to the Mercy University Hospital with a diagnosis of CAP. When analysed against local antimicrobial guidelines, guideline concordant empiric antibiotics were given in only 48% of cases, lower than the average rate in comparable studies. Concordance was 100% in cases where the CURB-65 pneumonia severity assessment score, on which the guidelines are based, was documented in the medical notes. The use of excessively broad spectrum and inappropriate antibiotics is a notable problem. This study supports the theory that lack of knowledge regarding pneumonia severity assessment tools and unfamiliarity with therapeutic guidelines are key barriers to guideline adherence, which remains a significant problem despite increased focus on antimicrobial stewardship programs in Ireland. PMID- 28665085 TI - Rotavirus Gastroenteritis is Associated with Increased Morbidity and Mortality in Children with Inherited Metabolic Disorders. AB - Rotavirus is the leading cause of infantile diarrhoea worldwide in children <5 years1. Although mortality rates are low in Ireland, certain populations are more susceptible to the associated morbidity and mortality of infection. A retrospective chart review of 14 patients with confirmed IMDs who were admitted to Temple Street Children's Hospital between 2010 to 2015 with rotavirus infection were compared with 14 randomly selected age matched controls. The median length of stay was 7 days (SD25.3) in IMD patients versus 1.5 days (SD 2.1) in the controls. IV fluids were required on average for 4.5 days (range 0 17) in IMD patients versus 0.63 days (range 0-3) in controls. This report highlights the increased morbidity of rotavirus infection in patients with IMD compared to healthy children. This vulnerable population are likely to benefit from the recent introduction of the rotavirus oral vaccination in October 2016. PMID- 28665086 TI - Hospital Acquired Thrombosis (HAT) Prevention in an Acute Hospital; A Single Centre Cross-Sectional Study. AB - Evidence based guidelines are effective in reducing incidence of venous thromboembolism (VTE) which is associated with morbidly, mortality and economic burden. This study aimed to identify the proportion of inpatients who had a VTE risk assessment (RA) performed and who received thromboprophylaxis (TP), in Cork University Hospital. There was no structured RA tool at the time; information was obtained from medical and drug charts to ascertain if a RA was performed. Patients were then RA by researchers and stratified as per NICE guidelines and the proportion who received TP was calculated. One thousand and nineteen inpatients were screened. Risk was documented in 24% of cases. TP was prescribed in 43.2% of inpatients. Following application of a RA tool >80% were at high risk of VTE with low risk of bleeding with TP prescription in 46.3% of inpatients. A national collaborative effort should be encouraged to develop a standardized approach for safe RA of inpatients and prescription of TP for prevention of HAT. PMID- 28665087 TI - Barriers to dental attendance in older patients. AB - Health professionals in Ireland are increasingly concerned about the quality of oral health in older patients. The aim of this study is to identify the obstacles that face this age-group when accessing dental care, so that we are in a better position to address them. A questionnaire was completed by 105 patients attending a geriatric outpatient clinic. Over 50 percent of respondents had not attended a dentist in over 36 months, for the reasons that 'I have no problem or need for treatment' (62%) and 'I have no teeth, and therefore I have no need to go' (54%). While it is common to assume that no teeth means no need to see a dentist, research shows that regular dental visits are vital for ensuring the early screening of oral cancer and other mucosal pathologies, and the optimisation of existing rosthesis/restorations. The chief recommendation of this paper is thus to provide better education and access to older people on the importance of visiting the dentist. PMID- 28665088 TI - A role for susceptibility weighted imaging in progressive multifocal leukoencephalopathy. AB - We report a radiologic finding on magnetic resonance imaging (MRI) of the brain of two cases of progressive multifocal leukoencephalopathy (PML) of hypointense signal of subcortical U-fibres on susceptibility weighted (SW) sequence. The first case is a 50-year-old man recently treated with chemotherapy including rituximab for non-Hodgkin's lymphoma. The second case is a 64-year-old woman with human immunodeficiency virus (HIV) infection. Iron deposition is a likely causative factor. We propose that SWI may be especially useful in the assessment of indeterminate cases to reduce the likelihood of a missed diagnosis of PML. PMID- 28665089 TI - Post Traumatic Tension Pneumocephalus: The Mount Fuji Sign. AB - Pneumocephalus is defined as the presence of intracranial air. This is most commonly secondary to a traumatic head injury. Tension pneumocephalus presents radiologically with compression of the frontal lobes and widening of the interhemispheric space between the frontal lobes. It is often termed the Mount Fuji sign due to a perceived similarity with an iconic mountain peak in Japan. We present the case of a 52-year-old gentleman who presented to the emergency department shortly before 8am on a Saturday morning following an assault. He was alert and ambulatory with no clinical evidence of raised intracranial pressure. A plain radiograph of the facial bones showed significant pneumocephalus. A later CT was consistent with a tension pneumocephalus which usually necessitates urgent decompression.The patient showed no clinical signs or symptoms of raised intracranial pressure and was managed conservatively. He was discharged home 16 days later with no neurological deficit. PMID- 28665090 TI - The Bingo Card Sign as an Early Symptom of Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized pathologically by irreversible protein misfolding-induced neuronal loss, and clinically by progressive impairments in memory, judgment, decision making, literacy and numeracy. We report a patient referred to Memory Clinic with a single complaint, "reduced capacity to play bingo." We suggest that the capacity to successfully play bingo may afford clinical clues indicating an early symptom of dementia and inquiries about bingo participation may be a useful when assessing individuals for dementia. Bingo requires the use of multiple cognitive skills which are impaired by AD, including number recognition, letter recognition, short term memory and concentration. With the game of bingo steadily gaining in popularity it may become an easily utilized line of questioning to detect indications of dementia prior to the development of currently recognized clinical symptoms. PMID- 28665091 TI - Potential impact of cycle of care on Diabetes services in secondary care. AB - Diabetes Cycle of Care is a new initiative recently introduced by the Health Service Executive (HSE). In this review we found that a quarter of patients attending a secondary care diabetes outpatient clinic in a large teaching hospital could potentially be managed in primary care upon implementation of Diabetes Cycle of Care. PMID- 28665092 TI - Establishing a mentoring system for anaesthetic trainees. AB - Mentoring for doctors has been identified as an area requiring development. Currently, there is a void of trained mentors available. This article considers the evidence basis to support mentoring, and outlines the mentoring programme recently introduced by trainees in the College of Anaethetists. PMID- 28665093 TI - Books to Blogs - The Top Layer Of FOAM. PMID- 28665094 TI - A breathtakingly rare presentation of pyloric stenosis. PMID- 28665095 TI - A Turn for the Worse. PMID- 28665096 TI - Cancer Care Costs and Clinical Trials. PMID- 28665097 TI - How to interpret meta-analysis results. PMID- 28665098 TI - Food supplements, stress and gastrointestinal diseases. PMID- 28665100 TI - Nanotechnology: potential tool for immunology. PMID- 28665099 TI - Improvement in behavioral and psychological symptoms of dementia by rivastigmine patch in a group of Italian elderly patients with Alzheimer's disease. PMID- 28665101 TI - UCA1 lncRNA in metastases and prognosis. PMID- 28665102 TI - Identifying Emergency Department Patients With Chest Pain who are at Low Risk for Acute Coronary Syndromes AB - Though a minority of patients presenting to the emergency department with chest pain have acute coronary syndromes, identifying the patients who may be safely discharged and determining whether further testing is needed remains challenging. From the prehospital care setting to disposition and follow-up, this systematic review addresses the fundamentals of the emergency department evaluation of patients determined to be at low risk for acute coronary syndromes or adverse outcomes. Clinical risk scores are discussed, as well as the evidence and indications for confirmatory testing. The emerging role of new technologies, such as high-sensitivity troponin assays and advanced imaging techniques, are also presented. PMID- 28665103 TI - Nucleation and Assembly of Silica into Protein-Based Nanocomposites as Effective Anticancer Drug Carriers Using Self-Assembled Silk Protein Nanostructures as Biotemplates. AB - Bombyx mori (B. mori) silk fibroin and sericin can act as a great candidate in delivering drugs or other bioactive substances. Silica also has a great application in the field of drug delivery. To the best of our knowledge, there has been no report on the design of a nanocomposite made of silk protein and silica for drug delivery. Here, for the first time, we used B. mori silk fibroin (SF) and sericin (SS), self-assembled into nanospheres and nanofibers in situ in the aqueous solution, respectively, as a biotemplate to regulate the nucleation and self-assembly of silica for designing anticancer drug delivery. SF and SS mediated the nucleation and assembly of silica into monodispersed nanospheres (termed Si/SF) and nanofibers (termed Si/SS), respectively. The size and topography of the silica assemblies were dependent on the concentration of SF or SS as well as reaction conditions. Both Si/SF nanospheres and Si/SS nanofibers showed a high loading capability and sustained release profile of an anticancer drug, doxorubicin (DOX), in vitro. Si/SF nanospheres were found to be efficiently internalized in human cervical carcinoma (HeLa) cells and accumulate around the cell nuclei. Si/SS nanofibers could only adhere to the surface of the cancer cells. This indicates that DOX-loaded Si/SF nanospheres and Si/SS nanofibers are more effective in cancer therapy than free DOX. Our results suggest that the self assembled Si/SF spheres and Si/SS nanofibers are potential effective anticancer drug carriers. PMID- 28665104 TI - Gas-Flow Tailoring Fabrication of Graphene-like Co-Nx-C Nanosheet Supported Sub 10 nm PtCo Nanoalloys as Synergistic Catalyst for Air-Cathode Microbial Fuel Cells. AB - In this work, we presented a novel, facile, and template-free strategy for fabricating graphene-like N-doped carbon as oxygen reduction catalyst in sustainable microbial fuel cells (MFCs) by using an ion-inducing and spontaneous gas-flow tailoring effect from a unique nitrogen-rich polymer gel precursor which has not been reported in materials science. Remarkably, by introduction of trace platinum- and cobalt- precursor in polymer gel, highly dispersed sub-10 nm PtCo nanoalloys can be in situ grown and anchored on graphene-like carbon. The as prepared catalysts were investigated by a series of physical characterizations, electrochemical measurements, and microbial fuel cell tests. Interestingly, even with a low Pt content (5.13 wt %), the most active Co/N codoped carbon supported PtCo nanoalloys (Co-N-C/Pt) exhibited dramatically improved catalytic activity toward oxygen reduction reaction coupled with superior output power density (1008 +/- 43 mW m-2) in MFCs, which was 29.40% higher than the state of the art Pt/C (20 wt %). Notability, the distinct catalytic activity of Co-N-C/Pt was attributed to the highly efficient synergistic catalytic effect of Co-Nx-C and PtCo nanoalloys. Therefore, Co-N-C/Pt should be a promising oxygen reduction catalyst for application in MFCs. Further, the novel strategy for graphene-like carbon also can be widely used in many other energy conversion and storage devices. PMID- 28665105 TI - Characterization of a Novel Drosophila SERT Mutant: Insights on the Contribution of the Serotonin Neural System to Behaviors. AB - A better comprehension on how different molecular components of the serotonergic system contribute to the adequate regulation of behaviors in animals is essential in the interpretation on how they are involved in neuropsychiatric and pathological disorders. It is possible to study these components in "simpler" animal models including the fly Drosophila melanogaster, given that most of the components of the serotonergic system are conserved between vertebrates and invertebrates. Here we decided to advance our understanding on how the serotonin plasma membrane transporter (SERT) contributes to serotonergic neurotransmission and behaviors in Drosophila. In doing this, we characterized for the first time a mutant for Drosophila SERT (dSERT) and additionally used a highly selective serotonin-releasing drug, 4-methylthioamphetamine (4-MTA), whose mechanism of action involves the SERT protein. Our results show that dSERT mutant animals exhibit an increased survival rate in stress conditions, increased basal motor behavior, and decreased levels in an anxiety-related parameter, centrophobism. We also show that 4-MTA increases the negative chemotaxis toward a strong aversive odorant, benzaldehyde. Our neurochemical data suggest that this effect is mediated by dSERT and depends on the 4-MTA-increased release of serotonin in the fly brain. Our in silico data support the idea that these effects are explained by specific interactions between 4-MTA and dSERT. In sum, our neurochemical, in silico, and behavioral analyses demonstrate the critical importance of the serotonergic system and particularly dSERT functioning in modulating several behaviors in Drosophila. PMID- 28665106 TI - Cancer Cell Membrane Camouflaged Cascade Bioreactor for Cancer Targeted Starvation and Photodynamic Therapy. AB - Selectively cuting off the nutrient supply and the metabolism pathways of cancer cells would be a promising approach to improve the efficiency of cancer treatment. Here, a cancer targeted cascade bioreactor (designated as mCGP) was constructed for synergistic starvation and photodynamic therapy (PDT) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane camouflaged porphyrin metal-organic framework (MOF) of PCN-224 (PCN stands for porous coordination network). Due to biomimetic surface functionalization, the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, mCGP was found to promote microenvironmental oxygenation by catalyzing the endogenous hydrogen peroxide (H2O2) to produce oxygen (O2), which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen (1O2) under light irradiation. Consequently, mCGP displayed amplified synergistic therapeutic effects of long term cancer starvation therapy and robust PDT, which would efficiently inhibit the cancer growth after a single administration. This cascade bioreactor would further facilitate the development of complementary modes for spatiotemporally controlled cancer treatment. PMID- 28665107 TI - Stepwise Assembly of beta-Sheet Structure during the Folding of an SH3 Domain Revealed by a Pulsed Hydrogen Exchange Mass Spectrometry Study. AB - Dissecting temporally the sequence of secondary structural changes, and determining how these specific changes modulate conformational heterogeneity, remain major goals of protein folding studies. In this study, the folding of the SH3 domain of PI3 kinase has been characterized using pulsed hydrogen exchange mass spectrometry (HX-MS). The folding could be described as a four-state process, U <-> IVE <-> IE <-> N, where IVE and IE are structurally heterogeneous intermediate ensembles. Compared to U, early intermediate IVE has a marginally increased level of protection against HX of amides along the entire length of the polypeptide. Sequential assembly into beta-sheet structure has been resolved temporally. Three of the five beta-strands acquire nativelike structure before the rate-limiting step. beta-Strands 2 and 5 acquire nativelike structure in IVE, while beta-strand 4 does so in IE. beta-Strand 1 acquires nativelike structure only during the last step of the folding process. Hence, the HX-MS study has resolved the order of assembly of the beta-strands for the formation of the two beta-sheets, which previous studies utilizing Phi-value analysis of several different SH3 domains had been unable to accomplish. Moreover, it is shown that structural heterogeneity decreases in a stepwise manner during the three stages of folding. PMID- 28665108 TI - Stretchable Polymer Dielectrics for Low-Voltage-Driven Field-Effect Transistors. AB - A stretchable and mechanical robust field-effect transistor is essential for soft wearable electronics. To realize stretchable transistors, elastic dielectrics with small current hysteresis, high elasticity, and high dielectric constants are the critical factor for low-voltage-driven devices. Here, we demonstrate the polar elastomer consisting of poly(vinylidene fluoride-hexafluoropropylene) (PVDF HFP):poly(4-vinylphenol) (PVP). Owing to the high dielectric constant of PVDF HFP, the device can be operated under less than 5 V and shows a linear-regime hole mobility as high as 0.199 cm2 V-1 s-1 without significant current hysteresis. Specifically, the PVDF-HFP:PVP blends induce the vertical phase separation and significantly reduce current leakage and reduce the crystallization of PVDF segments, which can contribute current hysteresis in the OFET characteristics. All-stretchable OFETs based on these PVDF-HFP:PVP dielectrics were fabricated. The device can still keep the hole mobility of approximately 0.1 cm2/(V s) under a low operation voltage of 3 V even as stretched with 80% strain. Finally, we successfully fabricate a low-voltage driven stretchable transistor. The low voltage operating under strains is the desirable characteristics for soft and comfortable wearable electronics. PMID- 28665109 TI - Role of Site-Specific Asparagine Deamidation in Islet Amyloid Polypeptide Amyloidogenesis: Key Contributions of Residues 14 and 21. AB - Deamidation of an asparagine residue is a spontaneous non-enzymatic post translational modification that results in the conversion of asparagine into a mixture of aspartic acid and isoaspartic acid. This chemical conversion modulates protein conformation and physicochemical properties, which could lead to protein misfolding and aggregation. In this study, we investigated the effects of site specific Asn deamidation on the amyloidogenicity of the aggregation-prone peptide islet amyloid polypeptide (IAPP). IAPP is a 37-residue peptidic hormone whose deposition as insoluble amyloid fibrils is closely associated with type 2 diabetes. Asn residues were successively substituted with an Asp or isoAsp, and amyloid formation was evaluated by a thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and transmission electron microscopy. Whereas deamidation at position 21 inhibited IAPP conformational conversion and amyloid formation, the N14D mutation accelerated self-assembly and led to the formation of long and thick amyloid fibrils. In contrast, IAPP was somewhat tolerant to the successive deamidation of Asn residues 22, 31, and 35. Interestingly, a small molar ratio of IAPP deamidated at position 14 promoted the formation of nucleating species and the elongation from unmodified IAPP. Besides, using the rat pancreatic beta cell line INS-1E, we observed that site-specific deamidation did not significantly alter IAPP-induced toxicity. These data indicate that Asn deamidation can modulate IAPP amyloid formation and fibril morphology and that the site of modification plays a critical role. Above all, this study reinforces the notion that IAPP amyloidogenesis is governed by precise intermolecular interactions involving specific Asn side chains. PMID- 28665110 TI - Curvature-Induced Metal-Support Interaction of an Islands-by-Islands Composite of Platinum Catalyst and Carbon Nano-onion for Durable Oxygen Reduction. AB - Geometry of carbon supports significantly affected electrochemical durability of Pt/C (platinum electrocatalyst supported by carbon) for oxygen reduction reaction (ORR). Carbon nano-onion (CNO) was used as the support, which is characterized by its nanosize (similar to Pt size) and high curvature. Superior ORR durability was guaranteed by Pt/CNO due to (1) its islands-by-islands configuration to isolate each Pt nanoparticle from its neighbors by CNO particles; (2) highly tortuous void structure of the configuration to suppress Ostwald ripening; and (3) the curvature-induced strong interaction between CNO and Pt. The finding that highly curved carbon surface encourages electron donation to catalysts was first reported. PMID- 28665111 TI - Zwitterionic Temperature/Redox-Sensitive Nanogels for Near-Infrared Light Triggered Synergistic Thermo-Chemotherapy. AB - Ideal anticancer nano drug delivery systems (NDDSs) need to overcome a series of physiological barriers including blood circulation, tumor accumulation, tumor penetration, internalization by cancer cells, lysosomal escape, and on-demand intracellular drug release following systemic administration. However, it remains a big challenge to construct NDDSs that can overcome all the barriers at the same time. Here, we develop zwitterionic temperature/redox-sensitive nanogels loaded with near-infrared (NIR) dye Indocyanine green (ICG) and anticancer drug doxorubicin (I/D@NG). I/D@NG exhibits enhanced photothermal effects, and NIR irradiation markedly decreases its diameter. NIR irradiation at tumor sites significantly enhances tumor accumulation, tumor penetration, and cellular uptake of I/D@NG with prolonged blood circulation time. Furthermore, I/D@NG can effectively escape from lysosomes by singlet oxygen-induced lysosomal disruption, and DOX is then sufficiently released from the nanogels to the nucleus in response to high intracellular GSH and photothermal effects. This nanoplatform for thermo-chemotherapy not only efficiently exerts synergistic cytotoxicity but also overcomes all the physiological barriers of therapeutic agent, thereby providing a substantial in vivo anticancer effect. The multiple functions of I/D@NG provide new insights into designing nanoplatforms for synergistic cancer therapy. PMID- 28665112 TI - Nacre Topography Produces Higher Crystallinity in Bone than Chemically Induced Osteogenesis. AB - It is counterintuitive that invertebrate shells can induce bone formation, yet nacre, or mother of pearl, from marine shells is both osteoinductive and osteointegrative. Nacre is composed of aragonite (calcium carbonate) and induces production of vertebrate bone (calcium phosphate). Exploited by the Mayans for dental implants, this remarkable phenomenon has been confirmed in vitro and in vivo, yet the characteristic of nacre that induces bone formation remains unknown. By isolating nacre topography from its inherent chemistry in the production of polycaprolactone (PCL) nacre replica, we show that, for mesenchymal stem cells, nacre topography is osteoinductive. Gene expression of specific bone marker proteins, osteopontin, osteocalcin, osteonectin, and osterix, is increased 10-, 2-, 1.7-, and 1.8-fold, respectively, when compared to planar PCL. Furthermore, we demonstrate that bone tissue that forms in response to the physical topographical features of nacre has a higher crystallinity than bone formed in response to chemical cues with a full width half-maximum for PO43- Raman shift of 7.6 +/- 0.7 for mineral produced in response to nacre replica compared to a much broader 34.6 +/- 10.1 in response to standard osteoinductive medium. These differences in mineral product are underpinned by differences in cellular metabolism. This observation can be exploited in the design of bone therapies; a matter that is most pressing in light of a rapidly aging human population. PMID- 28665113 TI - AWE-somes: All Water Emulsion Bodies with Permeable Shells and Selective Compartments. AB - Living cells exploit compartmentalization within organelles to spatially and temporally control reactions and pathways. Here, we use the all aqueous two phase system (ATPS) of poly(ethylene glycol) (PEG) and dextran to develop all water emulsion bodies, AWE-somes, a new class of encapsulated double emulsions as potential cell mimics. AWE-somes feature rigid polyelectrolyte (PE)/nanoparticle (NP) shells and double emulsion interiors. The shells form via complexation of PE and NP at interfaces of ATPS. The NPs, excluded from the drop phase, create an osmotic stress imbalance that removes water from the encapsulated phase and draws droplets of external PEG phase into the shells to form the double emulsion interior. We demonstrate that molecules can permeate the AWE-some shells, selectively partition into the internal droplets, and undergo reaction. AWE-somes have significant potential for creating functional, biocompatible protocell systems. PMID- 28665114 TI - Anion Recognition Strategies Based on Combined Noncovalent Interactions. AB - This review highlights the most significant examples of an emerging field in the design of highly selective anion receptors. To date, there has been remarkable progress in the binding and sensing of anions. This has been driven in part by the discovery of ways to construct effective anion binding receptors using the dominant N-H functional groups and neutral and cationic C-H hydrogen bond donors, as well as underexplored strong directional noncovalent interactions such as halogen-bonding and anion-pi interactions. In this review, we will describe a new and promising strategy for constructing anion binding receptors with distinct advantages arising from their elaborate design, incorporating multiple binding sites able to interact cooperatively with anions through these different kinds of noncovalent interactions. Comparisons with control species or solely hydrogen bonding analogues reveal unique characteristics in terms of strength, selectivity, and interaction geometry, representing important advances in the rising field of supramolecular chemistry. PMID- 28665115 TI - Boosting Photocatalytic Performance of Inactive Rutile TiO2 Nanorods under Solar Light Irradiation: Synergistic Effect of Acid Treatment and Metal Oxide Co catalysts. AB - In the present work, we accomplish the boosting of photocatalytic performance by the synergistic effect of acid treatment and transition metal oxide co-catalysts on molten salt rutile TiO2 nanorods. FT-IR and XPS (oxygen deconvolution) results confirmed that the amount of hydroxyl groups increased on the surface of rutile TiO2 nanorods (TO-NRs) after acid treatment. HR-TEM analysis revealed fine dispersion of metal oxide on the surface of acid treated TiO2 nanorods (ATO-NRs). The photocatalytic activities of as-prepared (TO-NRs), acid treated (ATO-NRs), metal oxide loaded (MTO-NRs), and both acid treated and metal oxide loaded (MATO NRs) nanorods were compared based on the rate kinetics and dye degradation efficiencies. Cobalt oxide (1 wt %) loaded and 1.0 M acid treated TiO2 nanorods (Co/ATO-NR) exhibited the higher photocatalytic degradation efficiency for Orange II dye degradation and inactivation of S. typhimurium pathogen compared to other photocatalysts under solar irradiation. Photoelectrochemical analysis demonstrated that the charge transfer process in Co/ATO-NR is significantly higher than that in the untreated samples. The improved photocatalytic activity of inactive TO-NRs might be due to enhanced charge transfer of finely dispersed metal oxides on the OH-rich surface of acid treated TiO2 nanorods. PMID- 28665116 TI - High-Sensitivity Rheo-NMR Spectroscopy for Protein Studies. AB - Shear stress can induce structural deformation of proteins, which might result in aggregate formation. Rheo-NMR spectroscopy has the potential to monitor structural changes in proteins under shear stress at the atomic level; however, existing Rheo-NMR methodologies have insufficient sensitivity to probe protein structure and dynamics. Here we present a simple and versatile approach to Rheo NMR, which maximizes sensitivity by using a spectrometer equipped with a cryogenic probe. As a result, the sensitivity of the instrument ranks highest among the Rheo-NMR spectrometers reported so far. We demonstrate that the newly developed Rheo-NMR instrument can acquire high-quality relaxation data for a protein under shear stress and can trace structural changes in a protein during fibril formation in real time. The described approach will facilitate rheological studies on protein structural deformation, thereby aiding a physical understanding of shear-induced amyloid fibril formation. PMID- 28665117 TI - Second-Coordination-Sphere Assisted Selective Colorimetric Turn-on Fluoride Sensing by a Mono-Metallic Co(II) Hexacarboxamide Cryptand Complex. AB - The preparation of a selective turn-on colorimetric fluoride sensor was achieved through single cobalt(II) ion insertion into a macrobicyclic cryptand. Monometallic [Co(mBDCA-5t-H3)]- (1) and [Zn(mBDCA-5t-H3)]- (2) complexes were prepared in 74 and 84% yields, respectively. Structural characterization of 1 confirmed the presence of a proximal hydrogen-bonding network consisting of carboxamide N-H donors. The reaction of 1 with F- was accompanied by a distinct colorimetric turn-on response in mixed aqueous/organic media, and 1 was capable of selective fluoride sensing in the presence of large quantities of potentially competitive anions. Complex 1 represents a unique example of a fluoride sensor wherein selective F- binding takes place directly at a transition-metal center and induces a color change based upon metal-centered transitions. The metal(II) fluoride complexes [F?Co(mBDCA-5t-H3)]2- (3) and [F?Zn(mBDCA-5t-H3)]2- (4) were both fully characterized, including single crystal X-ray analyses. Fluoride binding is synergistic involving hydrogen-bond donors from the second coordination sphere together with metal(II) ion complexation. PMID- 28665118 TI - Single-Molecule Magnet Behavior Enhanced by Synergic Effect of Single-Ion Anisotropy and Magnetic Interactions. AB - As the simplest entity carrying intramolecular magnetic interactions, a dinuclear lanthanide complex serves as a model to investigate the effects of magnetic interactions on relaxation of magnetization, and importantly, it proves to be an efficient method to obtain robust single-molecule magnets via improving the communication between lanthanide centers. Here, three Dy2 complexes (1, 2, 3) with a similar structural motif, namely, [Dy2(HL)2(NO3)2(CH3CN)2].2CH3CN (1), [Dy2(HL)2(NO3)2(DMF)2].2H2O (2), and Dy2(HL)2(NO3)2(DMF)4 (3), were successfully assembled. One critical difference found in this series of complexes is that the Dy center in complex 3 is coordinated by one more solvent molecule. Surprisingly, complex 3 exhibits the best magnet-like behavior, as evidenced by the high effective barrier and butterfly-type hysteresis, although the crystal field effect around Dy ions is weakened heavily. Ab initio calculations revealed the crucial reason is the significant synergic effect between single-ion anisotropy and magnetic interactions, i.e., not only the axiality of the Dy ion is improved efficiently but also the exchange magnetic interactions increased to the same order of magnitude to the dipolar interaction in 3. This effect mainly benefits from the elaborate modification of the local coordinate environment around the Dy ion, which results in a special arrangement of anisotropy axes different from the other two complexes. It demonstrates that the magnetic interactions could be effectively enhanced by means of deliberate local structural modulation. PMID- 28665119 TI - Modeling Flexible Molecules in Solution: A pKa Case Study. AB - Continuum solvation models have been incredibly successful for the computationally efficient study of chemical reactions in solution. However, their development and application has generally been on focused on investigations of small, rigid molecules. Additional factors must be considered when studying large, flexible and multiply ionizable species. These include whether the use of thermocycle or entirely solution-phase approaches are more appropriate for the calculation of solution-phase free energies, which metrics can be used to reliably identify the conformation(s) adopted by flexible molecules in solution, and how errors due to inaccuracies in the prediction of low energy vibrational frequencies can be avoided. Here we explore these issues using the calculation of pKas for a diverse set of amine-containing species as a case study. We show that thermocycle-based approaches should only be applied where there are relatively small structural changes between the gas- and solution-phase molecular geometries, and that these methods are generally not appropriate for conformational searching. Using gas- or solution-phase energies or gas-phase free energies can also lead to errors in the identification of the most stable molecular conformation(s). Scaling of low energy vibrational modes (i.e., use of the quasi-harmonic oscillator approximation) is helpful, however care must be taken to ensure modes that change as part of the reaction are not disregarded. Entirely solution-phase approaches to the Gibbs free energy and hence pKa calculations were found to yield accurate pKa values for the amine test set studied when each charged site is complexed with an explicit water molecule and a proton exchange scheme is applied with an appropriately chosen reference acid. PMID- 28665120 TI - Fabrication of Lithium Silicates As Highly Efficient High-Temperature CO2 Sorbents from SBA-15 Precursor. AB - A series of lithium silicates with improved CO2 sorption capacity were successfully synthesized using SBA-15 as the silicon precursor. The influence of Li/Si ratio, calcination temperature, and calcination duration on the chemical composition and CO2 capture capacity of obtained lithium silicates was systematically investigated. The correlation between CO2 sorption performance and crystalline phase abundance was determined using X-ray diffraction and a normalized reference intensity ratio method. Under the optimized condition, Li SBA15-4 prepared using Li/Si = 4 that contains mainly Li4SiO4 achieved an extremely high CO2 capture capacity of 36.3 wt % (corresponding to 99% of the theoretical value of 36.7 wt % for Li4SiO4), which is much higher than the Li4SiO4 synthesized from conventional SiO2 sources. It also showed very high cycling stability with only 1.0 wt % capacity loss after 15 cycles. Li-SBA15-10 (Li/Si = 10) that mainly contains Li8SiO6 displayed an extremely high CO2 uptake of 62.0 wt %, but its regeneration capacity was poor, with only 10.5 wt % of reversible CO2 capture capacity. The influence of CO2 concentration on the CO2 capture performance of Li-SBA15-4 and Li-SBA15-10 samples was also studied. With the decrease in CO2 concentration, relatively lower temperatures are needed for its maximum CO2 capture capacity. The CO2 sorption kinetics and mechanism for Li SBA15-4 and Li-SBA15-10 samples were explored. Overall, we have shown that the lithium silicates synthesized from SBA-15 possessed much improved CO2 sorption performance than that attained from conventional SiO2. PMID- 28665121 TI - Role of Snow Deposition of Perfluoroalkylated Substances at Coastal Livingston Island (Maritime Antarctica). AB - Perfluoroalkyl substances (PFAS) are ubiquitous in the environment, including remote polar regions. To evaluate the role of snow deposition as an input of PFAS to Maritime Antarctica, fresh snow deposition, surface snow, streams from melted snow, coastal seawater, and plankton samples were collected over a three-month period (December 2014-February 2015) at Livingston Island. Local sources of PFASs were significant for perfluoroalkyl sulfonates (PFSAs) and C7-14 perfluoroalkyl carboxylates (PFCAs) in snow but limited to the transited areas of the research station. The concentrations of 14 ionizable PFAS (?PFAS) in freshly deposited snow (760-3600 pg L-1) were 1 order of magnitude higher than those in background surface snow (82-430 pg L-1). ?PFAS ranged from 94 to 420 pg L-1 in seawater and from 3.1 to 16 ng gdw-1 in plankton. Ratios of individual PFAS concentrations in freshly deposited snow relative to surface snow (CSD/CSnow), snowmelt (CSD/CSM), and seawater (CSD/CSW) were close to 1 (from 0.44 to 1.4) for all perfluorooctanesulfonate (PFOS) isomers, suggesting that snowfall does not contribute significantly to PFOS in seawater. Conversely, these ratios for PFCAs ranged from 1 to 33 and were positively correlated with the number of carbons in the PFCA alkylated chain. These trends suggest that snow deposition, scavenging sea-salt aerosol bound PFAS, plays a role as a significant input of PFCAs to the Maritime Antarctica. PMID- 28665122 TI - A Water-Stable 3D Luminescent Metal-Organic Framework Based on Heterometallic [EuIII6ZnII] Clusters Showing Highly Sensitive, Selective, and Reversible Detection of Ronidazole. AB - A water-stable 3D luminescent metal-organic framework (MOF), [Eu6Zn(MU3 OH)8(NDC)6(H2O)6]n (1), constructed from heterometallic [EuIII6ZnII] clusters and electron-rich pi-conjugated 1,4-naphthalenedicarboxylic acid (H2NDC) ligands exhibits highly sensitive, selective, and reversible detection of ronidazole, which represents the first example of luminescent MOFs based on Ln-TM heterometallic clusters for the detection of antibiotics in aqueous solution. PMID- 28665123 TI - Lutein Activates the Transcription Factor Nrf2 in Human Retinal Pigment Epithelial Cells. AB - The degeneration of the retinal pigment epithelium caused by oxidative damage is a stage of development in age-related macular degeneration (AMD). The carotenoid lutein is a major macular pigment that may reduce the incidence and progression of AMD, but the underlying mechanism is currently not fully understood. Carotenoids are known to be direct antioxidants. However, carotenoids can also activate cellular pathways resulting in indirect antioxidant effects. Here, we investigate the influence of lutein on the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes in human retinal pigment epithelial cells (ARPE-19 cells) using lutein-loaded Tween40 micelles. The micelles were identified as a suitable delivery system since they were nontoxic in APRE-19 cells up to 0.04% Tween40 and led to a cellular lutein accumulation of 62 MUM +/- 14 MUM after 24 h. Lutein significantly enhanced Nrf2 translocation to the nucleus 1.5 +/- 0.4-fold compared to that of unloaded micelles after 4 h. Furthermore, lutein treatment for 24 h significantly increased the transcripts of NAD(P)H:quinone oxidoreductase 1 (NQO1) by 1.7 +/- 0.1-fold, glutamate-cysteine ligase regulatory subunit (GCLm) by 1.4 +/- 0.1-fold, and heme oxygenase-1 (HO-1) by 1.8 +/- 0.3-fold. Moreover, we observed a significant enhancement of NQO1 activity by 1.2 +/- 0.1-fold. Collectively, this study indicates that lutein not only serves as a direct antioxidant but also activates Nrf2 in ARPE-19 cells. PMID- 28665124 TI - Enantioselective Rhodium(III)-Catalyzed Markovnikov Hydroboration of Unactivated Terminal Alkenes. AB - We report the first enantioselective Rh-catalyzed Markovnikov hydroboration of unactivated terminal alkenes. Using a novel sp2-sp3 hybridized diboron reagent and water as a proton source, a broad range of alkenes undergo hydroboration to provide secondary boronic esters with high regio- and enantiocontrol. PMID- 28665125 TI - Construction of Pentacyclic Lamellarin Skeleton via Grob Reaction: Application to Total Synthesis of Lamellarins H and D. AB - An efficient construction of phenyl-substituted coumarin-pyrrole-isoquinoline fused pentacycle via base-promoted Grob-type coupling of 3-nitrocoumarin and papaverine in a sealed tube is reported. This reaction is further applied to the total synthesis of lamellarin H in three linear steps and lamellarin D in eight linear steps with overall yields of 31% and 14%, respectively. PMID- 28665126 TI - Mixed-Substituent Cyclophosphazenes with Calamitic and Polycatenar Mesogens. AB - A synthetic strategy has been developed to prepare liquid crystalline cyclotriphosphazenes that have two different types of mesogenic units linked to the same phosphorus atom. Hexachlorocyclotriphosphazene, N3P3Cl6, was reacted with 3 mol of the calamitic unit 4-cyano-4'-hydroxybiphenyl to give a mixture of compounds in which the nongem-trans-trisubstituted derivative N3P3Cl3(OC6H4C6H4{CN}-p)3 was the major product. The substitution of all three chlorine atoms in this nongeminal compound gave rise to the hydroxyl-functional phosphazenes, nongem-trans-N3P3(OC6H4C6H4{CN}-p)3(OC6H4{OH}-p)3 or nongem-trans N3P3(OC6H4C6H4{CH3}-p)3(OC6H4{OH}-p)3, from which the second mesogenic unit, a polycatenar one, was introduced. The chemical structure of the resulting materials, deduced from spectroscopic and MALDI-TOF techniques, was in accordance with monodisperse, fully functionalized cyclotriphosphazenes. Mesomorphism is highly dependent on the terminal group of the calamitic units, and liquid crystal phases were only detected on the cyano-derivatives. The calamitic or columnar nature of the mesophase depends on the number of alkyl chains of the polycatenar moieties. PMID- 28665127 TI - Activity of (+)-Discadenine as a Plant Cytokinin. AB - Discadenine (1), a self-spore germination inhibitor from the cellular slim mold Dictyostelium discoideum, is structurally related to the plant hormone cytokinin. This compound was synthesized from l-aspartic acid, and its activities were confirmed by three classical cytokinin bioassays as well as by using binding and activation assays with the Arabidopsis cytokinin receptors AHK3 and CRE1/AHK4. PMID- 28665128 TI - Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1 yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3 d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors. AB - Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor. PMID- 28665129 TI - Topochemical Reduction of YMnO3 into a Composite Structure. AB - Topochemical modification methods for solids have shown great potential in generating metastable structures inaccessible through classical synthetic routes. Here, we present the enhanced topotactic reduction of the multiferroic compound YMnO3. At moderate temperature in ammonia flow, the most reduced YMnO3-delta (delta = 0.5) phase could be stabilized. XRD, PND, and HREM results show that phase separation occurs into two intimately intergrown layered sublattices with nominal compositions infinity[YMn2+O2+x](1-2x)+ and infinity[YMn2+O3-x](1-2x)- containing versatile Mn2+ coordinations. The former sublattice shows original AA stacking between Mn layers, while AB stacking in the latter results from oxygen removal from the parent YMnO3 crystal structure. PMID- 28665130 TI - Rigidity Strengthening: A Mechanism for Protein-Ligand Binding. AB - Protein-ligand binding is essential to almost all life processes. The understanding of protein-ligand interactions is fundamentally important to rational drug and protein design. Based on large scale data sets, we show that protein rigidity strengthening or flexibility reduction is a mechanism in protein ligand binding. Our approach based solely on rigidity is able to unveil a surprisingly apparently long-range contribution of apparently four residue layers to protein-ligand binding, which has ramifications for drug and protein design. Additionally, the present work reveals that among various pairwise interactions, the short-range ones within the distance of the van der Waals diameter are most important. It is found that the present approach outperforms all other state-of the-art scoring functions for protein-ligand binding affinity predictions of two benchmark test sets. PMID- 28665131 TI - A Comprehensive Database and Analysis Framework To Incorporate Multiscale Data Types and Enable Integrated Analysis of Bioactive Polyphenols. AB - The development of a given botanical preparation for eventual clinical application requires extensive, detailed characterizations of the chemical composition, as well as the biological availability, biological activity, and safety profiles of the botanical. These issues are typically addressed using diverse experimental protocols and model systems. Based on this consideration, in this study we established a comprehensive database and analysis framework for the collection, collation, and integrative analysis of diverse, multiscale data sets. Using this framework, we conducted an integrative analysis of heterogeneous data from in vivo and in vitro investigation of a complex bioactive dietary polyphenol rich preparation (BDPP) and built an integrated network linking data sets generated from this multitude of diverse experimental paradigms. We established a comprehensive database and analysis framework as well as a systematic and logical means to catalogue and collate the diverse array of information gathered, which is securely stored and added to in a standardized manner to enable fast query. We demonstrated the utility of the database in (1) a statistical ranking scheme to prioritize response to treatments and (2) in depth reconstruction of functionality studies. By examination of these data sets, the system allows analytical querying of heterogeneous data and the access of information related to interactions, mechanism of actions, functions, etc., which ultimately provide a global overview of complex biological responses. Collectively, we present an integrative analysis framework that leads to novel insights on the biological activities of a complex botanical such as BDPP that is based on data-driven characterizations of interactions between BDPP-derived phenolic metabolites and their mechanisms of action, as well as synergism and/or potential cancellation of biological functions. Out integrative analytical approach provides novel means for a systematic integrative analysis of heterogeneous data types in the development of complex botanicals such as polyphenols for eventual clinical and translational applications. PMID- 28665133 TI - Molecular Dynamics Studies of Overbased Detergents on a Water Surface. AB - Molecular dynamics (MD) simulations are reported of model overbased detergent nanoparticles on a model water surface which mimic their behavior on a Langmuir trough or large water droplet in engine oil. The simulations predict that the structure of the nanoparticle on a water surface is different to when it is immersed in a bulk hydrophobic solvent. The surfactant tails are partly directed out of the water, while the carbonate core maximizes its extent of contact with the water. Umbrella sampling calculations of the potential of mean force between two particles showed that they are associated with varying degrees with a maximum binding free energy of ca. 10 kBT for the salicylate stabilized particle, ca. 8 kBT for a sulfurized alkyl phenate stabilized particle, and ca. 5 kBT for a sulfonate stabilized particle. The differences in the strength of attraction depend on the proximity of nearest approach and the energy penalty associated with the disruption of the hydration shell of water molecules around the calcium carbonate core when the two particles approach. This is greatest for the sulfonate particle, which partially loses the surfactant ions to the solution, and least for the salicylate, which forms the weakest water "cage". The particles are separated by a water hydration layer, even at the point of closest approach. PMID- 28665132 TI - Molecular Self-Assembly of Bile Acid-Phospholipids Controls the Delivery of Doxorubicin and Mice Survivability. AB - Lipid composition in general determines the drug encapsulation efficacy and release kinetics from liposomes that impact the clinical outcomes of cancer therapy. We synthesized three bile acid phospholipids by conjugating the phosphocholine headgroup to the 3'-hydroxyl group of benzylated lithocholic acid (LCA), deoxycholic acid (DCA), and cholic acid (CA); and investigated the impact of membrane rigidity on drug encapsulation efficacy, drug release kinetics, anticancer effects, and mice survival. Liposomes with a hydrodynamic diameter of 100-110 nm were subsequently developed using these phospholipids. Fluorescence probe based quantification revealed a more fluidic nature of DCA-PC- and CA-PC derived liposomes, whereas the LCA-PC-derived ones are rigid in nature. Doxorubicin encapsulation studies showed ~75% encapsulation and ~38% entrapment efficacy of doxorubicin using more fluidic DCA-PC and CA-PC derived liposomes as compared to ~58% encapsulation and ~18% entrapment efficacy in the case of LCA-PC derived liposomes. In vivo anticancer studies in the murine model confirmed that doxorubicin entrapped CA-PC liposomes compromise mice survival, whereas rigid drug entrapped LCA-PC-derived-liposomes increased mice survival with ~2-fold decrease in tumor volume. Pharmacokinetic and biodistribution studies revealed an ~1.5-fold increase in plasma drug concentration and an ~4.0-fold rise in tumor accumulation of doxorubicin on treatment with drug entrapped LCA-PC liposomes as compared to doxorubicin alone. In summary, this study presents the impact of bile acid derived liposomes with different rigidities on drug delivery and mice survivability. PMID- 28665134 TI - Monolithic OLED-Microwire Devices for Ultrastrong Magnetic Resonant Excitation. AB - Organic light-emitting diodes (OLEDs) make highly sensitive probes to test magnetic resonance phenomena under unconventional conditions since spin precession controls singlet-triplet transitions of electron-hole pairs, which in turn give rise to distinct recombination currents in conductivity. Electron paramagnetic resonance can therefore be detected in the absence of spin polarization. We exploit this characteristic to explore the exotic regime of ultrastrong light-matter coupling, where the Rabi frequency of a charge carrier spin is of the order of the transition frequency of the two-level system. To reach this domain, we have to lower the Zeeman splitting of the spin states, defined by the static magnetic field B0, and raise the strength of the oscillatory driving field of the resonance, B1. This is achieved by shrinking the OLED and bringing the source of resonant radio frequency (RF) radiation as close as possible to the organic semiconductor in a monolithic device structure, which incorporates an OLED fabricated directly on top of an RF microwire within one monolithic thin-film device structure. With an RF driving power in the milliwatt range applied to the microwire, the regime of bleaching and inversion of the magnetic resonance signal is reached due to the onset of the spin-Dicke effect. In this example of ultrastrong light-matter coupling, the individual resonant spin transitions of electron-hole pairs become indistinguishable with respect to the driving field, and superradiance of the magnetic dipole transitions sets in. PMID- 28665135 TI - Synthesis and Structural Characterization of a CHA-type AlPO4 Molecular Sieve with Penta-Coordinated Framework Aluminum Atoms. AB - The structure-directing effects of a series of polymethylimidazolium cations with different numbers of methyl groups as organic structure-directing agents (OSDAs) in the synthesis of aluminophosphate (AlPO4)-based molecular sieves in both fluoride and hydroxide media are investigated. On the one hand, among the OSDAs studied here, the smallest 1,3-dimethylimidazolium and the largest 1,2,3,4,5 pentamethylimidazolium cations were found to direct the synthesis of a new variant of the triclinic chabazite (CHA)-type AlPO4 material, designated AlPO4 34(t)V, and the one-dimensional small-pore silicoaluminophosphate (SAPO) molecular sieve STA-6 in hydroxide media, respectively. On the other hand, the intermediate-sized 1,2,3,4-tetramethylimidazolium cation gave SSZ-51, a two dimensional large-pore SAPO material, in fluoride media. Synchrotron powder X-ray diffraction and Rietveld analyses reveal that as-made AlPO4-34(t)V contains penta coordinated framework Al species connected by hydroxyl groups, as well as tetrahedral framework Al, which contrasts with the distortions arising from the two F- or OH- bridges between octahedral Al atoms in all already known AlPO4-34 materials. The presence of Al-OH-Al linkages in this triclinic AlPO4-34 molecular sieve has been further corroborated by thermal analysis, variable-temperature IR,27Al magic-angle spinning NMR, and dispersion-corrected density functional theory calculations. PMID- 28665136 TI - Coordination-Driven Self-Assembly Using Ditopic Pyridyl-Pyrazolyl Donor and p Cymene Ru(II) Acceptors: [2]Catenane Synthesis and Anticancer Activities. AB - Coordination-driven self-assembly of m-bis[3-(4-pyridyl)pyrazolyl]xylene (L) and [(p-cymene)2Ru2(OO?OO)2(OTf)2] (A1) (OO?OO = 6,11-dioxido-5,12-naphthacenedione) in methanol resulted in a mixture of [2]catenane 1 and macrocycle 2, and self assembly in nitromethane resulted in pure macrocycle 2, whereas the coordination driven self-assembly of L and similar acceptors [(p-cymene)2Ru2(OO?OO)2(OTf)2] [OO?OO = 5,8-dioxido-1,4-naphthoquinonnato (A2); 2,5-dioxido-1,4-benzoquinonato (A3); oxalato (A4)] resulted in the formations of monomeric macrocycles 3-5, respectively. All self-assembled macrocycles were obtained in excellent yields (>90%) as triflate salts and were fully characterized by multinuclear NMR, elemental analysis, and electrospray ionization mass spectrometry (ESI-MS). The structures of [2]catenane 1 and macrocycles 5 were confirmed by single-crystal X ray diffraction analysis. The X-ray structure of 1 confirmed an edge-to-face interaction between the tetracene moiety in parallel-displaced pi-pi stacks (3.5 A), and CH...pi (2.5 A) stabilizes the [2]catenane topology. Macrocycles 2-5 were assessed for anticancer activities using human cancer cell lines of different origins, and the macrocycle 3 was found to exhibit the best inhibitory effect and to do so in a dose-dependent manner. Further examination with the Tali apoptosis assay suggested the growth inhibitory effect of 3 involved the induction of the programmed cell death, and this suggestion was supported by observations of PARP and caspase 3 cleavage after treating cells with 3. In addition, exposure to 3 increased the expression of Bax and repressed the expression of Bcl-2, thus indicating the involvement of macrocycle 3 upstream of Bax and Bcl-2 in the apoptotic signaling pathway. Macrocycle 3 also tended to repress metastasis as evidenced by changes in the transcriptional expressions E- and N-cadherin (markers of metastasis). Furthermore, a stability assay demonstrated macrocycle 3 remained stable at high concentration. PMID- 28665137 TI - Influence of Asymmetry on the Redox Properties of Phenoxo- and Hydroxo-Bridged Dicopper Complexes: Spectroelectrochemical and Theoretical Studies. AB - The redox properties and electronic structures of a series of phenoxo- and hydroxo-bridged dicopper(II) complexes have been explored. Complexes (1a-c)2+ are based on symmetrical ligands with bis(2-methylpyridyl)aminomethyl as complexing arms bearing different substituting R groups (CH3, OCH3, or CF3) in the para position of the phenol moiety. Complex 2a2+ is based on a symmetrical ligand with bis(2-ethylpyridyl)aminomethyl arms and R = CH3, while complex 3a2+ involves an unsymmetrical ligand with two different complexing arms (namely bis(2 ethylpyridyl)aminomethyl and bis(2-methylpyridyl)aminomethyl). Investigations have been done by electrochemical and spectroelectrochemical means and correlated to theoretical calculations as this series of complexes offers a unique opportunity of an in-depth comparative analysis. The voltammetric studies have shown that the redox behavior of the dicopper complexes is not influenced by the nature of the solvent. However, the increase of the spacer chain length and the unsymmetrical design induce significant modifications of the voltammetric responses for both oxidation and reduction processes. DFT calculations of the redox potentials using a computational reference redox couple calculated at the same level of theory to reduce systematic errors confirm these results. Ligand contributions to the electronic structure of the different species have been analyzed in detail. The good agreement between experimental and theoretical results has validated the developed calculation method, which would be used in the following to design new dinuclear copper complexes. These studies demonstrate that subtle modification of the ligand topology can significantly affect the redox and spectroscopic properties. In particular, the unsymmetrical design allows the formation of a transient mixed-valent Cu(II)-Cu(III) phenoxo complex detected upon spectroelectrochemical experiments at room temperature, which evolves toward a dicopper (II,II) phenoxyl complex. The latter displays an intense pi -> pi* transition band at 393 nm in the UV-vis spectrum compared to the less intense ligand to metal charge transfer band at 518 nm observed for the mixed-valent Cu(II)-Cu(III) phenoxo complex. PMID- 28665138 TI - Alternative Electron-Transfer Channels Ensure Ultrafast Deactivation of Light Induced Excited States in Riboflavin Binding Protein. AB - Flavoproteins, containing flavin chromophores, are enzymes capable of transferring electrons at very high speeds. The ultrafast photoinduced electron transfer (ET) kinetics of riboflavin binding protein to the excited riboflavin was studied by femtosecond spectroscopy and found to occur within a few hundred femtoseconds [ Zhong and Zewail, Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 11867 11872 ]. This ultrafast kinetics was attributed to the presence of two aromatic rings that could transfer the electron to riboflavin: the side chains of tryptophan 156 and tyrosine 75. However, the underlying ET mechanism remained unclear. Here, using a hybrid quantum mechanical-molecular dynamics approach, we perform ET dynamics simulations taking into account the motion of the protein and the solvent upon ET. This approach reveals that ET occurs via a major reaction channel involving tyrosine 75 (83%) and a minor one involving tryptophan 156 (17%). We also show that the protein environment is designed to ensure the fast quenching of the riboflavin excited state. PMID- 28665139 TI - Intraoperative Retrograde Perfusion Sphincterometry to Evaluate Efficacy of Autologous Vas Deferens 6-Branch Suburethral Sling to Properly Restore Sphincteric Apparatus During Robot-Assisted Radical Prostatectomy. AB - OBJECTIVE: The aim of this study is to describe (urodynamically) the effect of the use of a 6-branch autologous suburethral sling, made with absorbable sutures and vas deferens, to support the bladder neck and urethra during robot-assisted laparoscopic prostatectomy (RALP) to improve early urinary continence (EUC) recovery. MATERIALS AND METHODS: Retrograde leak point pressure (RLPP) was intraoperatively evaluated, by means of retrograde perfusion sphincterometry (RPS), in 77 patients (mean age +/- standard deviation [SD]: 65.64 +/- 7.23 years, mean body mass index +/- SD: 26.69 +/- 3.89) scheduled to undergo RALP at our institution. RLPP was evaluated before (RLPPb) and after pneumoperitoneum induction (RLPPp). RLPP was then evaluated after urethrovesical anastomosis (RLPPa) and after proper sling tensioning (RLPPs), with the aim to obtain the same pressure as after pneumoperitoneum induction. EUC recovery, defined as the use of no pad, was assessed 10 days, 30 days, and 6 months after catheter removal. RESULTS: RPS and proper autologous 6-branch sling positioning were feasible in all patients, without perioperative complications and negligible impact on overall operative time. Pneumoperitoneum induction increased, similarly, RLPP in all patients. An important decrease of sphincteric capability was evident after prostate removal and the following urethrovesical anastomosis, while proper sling tensioning allowed for restoration of sphincteric apparatus capability to its presurgical status (mean RLPPs 40.84 cmH2O vs RLPPp 40.39 cmH2O, p = 0.942). EUC recovery within 10 days after catheter removal was achieved in 59 (77%) patients and progressively improved over time. CONCLUSIONS: RPS, intraoperatively performed during RALP, allows for precise evaluation of the impact of the surgical procedure on sphincteric apparatus competence. Moreover, the use of the 6-branch suburethral sling, in association with RPS, allows for restoration of the proper supporting system to the urethral sphincter, similar to the preoperative condition, offering the basis for EUC recovery after radical prostate surgery. PMID- 28665140 TI - An Empirical Study on Raman Peak Fitting and Its Application to Raman Quantitative Research. AB - Fitting experimentally measured Raman bands with theoretical model profiles is the basic operation for numerical determination of Raman peak parameters. In order to investigate the effects of peak modeling using various algorithms on peak fitting results, the representative Raman bands of mineral crystals, glass, fluids as well as the emission lines from a fluorescent lamp, some of which were measured under ambient light whereas others under elevated pressure and temperature conditions, were fitted using Gaussian, Lorentzian, Gaussian Lorentzian, Voigtian, Pearson type IV, and beta profiles. From the fitting results of the Raman bands investigated in this study, the fitted peak position, intensity, area and full width at half-maximum (FWHM) values of the measured Raman bands can vary significantly depending upon which peak profile function is used in the fitting, and the most appropriate fitting profile should be selected depending upon the nature of the Raman bands. Specifically, the symmetric Raman bands of mineral crystals and non-aqueous fluids are best fit using Gaussian Lorentzian or Voigtian profiles, whereas the asymmetric Raman bands are best fit using Pearson type IV profiles. The asymmetric O-H stretching vibrations of H2O and the Raman bands of soda-lime glass are best fit using several Gaussian profiles, whereas the emission lines from a florescent light are best fit using beta profiles. Multiple peaks that are not clearly separated can be fit simultaneously, provided the residuals in the fitting of one peak will not affect the fitting of the remaining peaks to a significant degree. Once the resolution of the Raman spectrometer has been properly accounted for, our findings show that the precision in peak position and intensity can be improved significantly by fitting the measured Raman peaks with appropriate profiles. Nevertheless, significant errors in peak position and intensity were still observed in the results from fitting of weak and wide Raman bands having unnormalized intensity/FWHM ratios lower than 200 counts/cm-1. PMID- 28665141 TI - A Multicentre and stratified study of the attitude of medical students towards organ donation in Spain. AB - INTRODUCTION: Medical students represent a new generation of medical thought, and if they have a favourable attitude towards organ donation this will greatly encourage its promotion. OBJECTIVE: To analyse the attitude of medical students in Spanish universities towards the donation of their own organs and to determine the factors affecting this attitude. MATERIAL AND METHODS: Type of study: A sociological, interdisciplinary, multicentre, and observational study in Spain. STUDY POPULATION: Students studying a degree in medicine enrolled in Spain (n = 34,000). SAMPLE SIZE: A sample of 9598 students (confidence of 99% and precision of +/-1%), stratified by geographical area and academic year. Instrument of measurement: A validated questionnaire of attitude towards organ donation and transplantation (PCID-DTO RIOS) was self-administered and completed anonymously. RESULTS: The questionnaire completion rate was 95.7% (n = 9.275). 80% were in favour of donation, 2% against and 18% were undecided. The following main variables were related to a favourable attitude: being of the female sex (Odds Ratio = 1.739); being in the sixth year of the degree (OR = 2.506); knowing a donor (OR = 1.346); having spoken about the subject with one's family (OR = 2.132) and friends (OR = 1.333); having a family circle that is in favour, more specifically, having a father (OR = 1.841), mother (OR = 2.538) or partner in favour (OR = 2.192); being a blood donor (OR = 2.824); acceptance of the mutilation of the body if it were necessary (OR = 2.958); and being an atheist or an agnostic (OR = 1.766). CONCLUSIONS: Spanish medical students generally have a favourable attitude towards organ donation, although 20% are not in favour. PMID- 28665142 TI - Targeting One-Hour Postmeal Glucose: Is It Time for a Paradigm Switch in Diabetes Management? AB - In the management of diabetes, postprandial glycemia (PPG) is usually targeted 2 h after the start of meal. Recent evidences, however, suggest that the value of glycemia at 1 h during an oral glucose tolerance test (OGTT) is a stronger predictor for developing diabetes than the value at 2 h and that it is an independent risk factor for cardiovascular disease. Studies in cells, animals, and humans suggest that 1-h high glucose is a sufficient stimulus for increasing several cardiovascular risk factors, such as inflammation, thrombosis, and endothelial dysfunction, with oxidative stress generation as the possible pathogenetic factor. One-hour glucose might be more dangerous than that at 2 h simply because glycemia is higher at 1 h, during an OGTT and postmeal. The new drugs, able to target better 1 h glycemia and the new noninvasive technologies for glucose monitoring, nowadays may help to change the therapeutic paradigm of targeting PPG at 2 h. PMID- 28665143 TI - Suppression of Lipogenesis via Reactive Oxygen Species-AMPK Signaling for Treating Malignant and Proliferative Diseases. AB - AIMS: Systemic diseases often have common characteristics. The aim of this study was to investigate the feasibility of targeting common pathological metabolism to inhibit the progression of malignant and proliferative diseases. RESULTS: Gefitinib-resistant (G-R) nonsmall-cell lung cancer (NSCLC) and rheumatoid arthritis (RA) were studied as conditions representative of malignant and proliferative diseases, respectively. Strong lipogenic activity and high expression of sterol regulatory element-binding protein 1 (SREBP1) were found in both G-R NSCLC cells and synovial fibroblasts from RA patients (RASFs). Berberine (BBR), an effective suppressor of SREBP1 and lipogenesis regulated through reactive oxygen species (ROS)/AMPK pathway, selectively inhibited the growth of G R NSCLC cells and RASFs but not that of normal cells. It effectively caused mitochondrial dysfunction, activated ROS/AMPK pathway, and finally suppressed cellular lipogenesis and cell proliferation. Addition of ROS blocker, AMPK inhibitor, and palmitic acid significantly reduced the effect of BBR. In an in vivo study, treatment of BBR led to significant inhibition of mouse tumor xenograft growth and remarkably slowed down the development of adjuvant-induced arthritis in rats. Innovation and Conclusion: Targeting ROS/AMPK/lipogenesis signaling pathway selectively inhibited the growth of G-R NSCLC cells and the progress of RASFs in vitro and in vivo, which provides a new avenue for treating malignancies and proliferative diseases. Antioxid. Redox Signal. 28, 339-357. PMID- 28665144 TI - Examining the Application of the Opening Minds Survey in the Community Health Centre Setting. AB - OBJECTIVE: Stigma has been identified as a complex and problematic issue. It acts as a major barrier to accessing care and can exacerbate the experience of a health condition, particularly for clients with mental illness and substance use issues. Scales designed to assess stigmatising attitudes towards those with mental illness and substance use problems among health care providers are necessary to evaluate programs designed to reduce that stigma. The goal of this study was to evaluate the internal reliability and external validity of the Opening Minds Survey for Health Care Providers (OMS-HC). METHODS: The current study examined the use of the OMS-HC in assessing stigma held by Community Health Centre (CHC) staff towards clients with mental and/or substance use problems. Participants represented staff from 6 CHCs in the Greater Toronto Area ( n = 190). RESULTS: The OMS-HC was found to have acceptable internal reliability for the 15-item version of the scale (alpha = 0.766) and mixed reliability for its subscales (alpha = 0.792-0.673). Confirmatory factor analysis showed good absolute (root mean square error of approximation = 0.013) and relative fit (Tucker-Lewis index = 0.996) for the current data. The OMS-HC was also shown to correlate with a series of scales commonly used in stigma research. CONCLUSIONS: After testing for internal validity and comparing the OMS-HC to other commonly used scales for assessing stigma and attitudes concerning recovery, the scale was found to be appropriate for the CHC setting and may be advantageous over the use of multiple scales. PMID- 28665145 TI - Suture-Button Device Stabilization Following Ring Finger Ray Amputation: A Comparative Cadaver Study. AB - BACKGROUND: The purpose of this study was to determine whether placing the suture button device between the long and small finger metacarpals following ring finger ray amputation may better close the intermetacarpal gap and allow early range of motion without increasing the risk of malrotation than soft tissue repair alone. METHODS: We performed ray amputation of the ring finger of 14 cadaver specimens by performing an osteotomy of the base of the ring finger metacarpal and then excising the remainder of the digit. We first performed a soft tissue repair of the transverse metacarpal ligaments and then cycled the fingers in simulated active flexion and extension on a custom computer-controlled device to re-create 6 weeks of range of motion. We then placed a suture-button device across the long and small finger metacarpals and tested the specimens again, thereby using each hand as an internal control. RESULTS: The distance between the ring and small finger metacarpals was reduced following suture-button device placement compared with the initial control; this spacing was maintained following complete cycling of the fingers. The angle between the metacarpals was divergent following soft tissue repair, and then became slightly convergent after insertion of the suture button device. None of the hands developed clinically relevant scissoring of the digits before or after application of the suture-button device. CONCLUSIONS: The suture-button device provides stable fixation to withstand early range of motion following ring finger ray amputation and significantly closes the gap and angle between the adjacent metacarpals without causing scissoring. PMID- 28665146 TI - Pressure- and dose-controlled transcutaneous pneumatic injection of hypertonic glucose solution for the treatment of atrophic skin disorders. AB - BACKGROUND: Needleless transcutaneous pneumatic injections (TPIs) are a minimally invasive way to deliver the solution into the skin for therapeutic purposes. The suggested action mechanisms of TPI therapy include mechanical stimulation, immediate tissue shrinkage and late wound healing. METHODS: Thirteen Korean patients were treated with TPI for atrophic skin disorders, including acne scars, striae albae, post-furuncle, or carbuncle scars, and horizontal wrinkles with lipoatrophy. At each TPI treatment session, a single pass was made along with the atrophic skin lesions without overlapping. Thereafter, two dermatologists objectively evaluated the clinical improvement in the lesions in the photographs via the global aesthetic improvement scale (GAIS). RESULTS: One month after the final treatment, the overall mean GAIS score was 2.3 +/- 0.8. Six of the 13 (46.2%) patients exhibited clinical improvement of grade 3, five (38.5%) patients grade 2 and two (15.4%) patients grade 1. The overall mean subjective satisfaction score with the TPI treatment was 2.3 +/- 0.9. Six of the 13 (46.2%) patients achieved subjective satisfaction of grade 3, six (46.2%) patients grade 2 and one (7.7%) patient grade 0. CONCLUSIONS: The present study demonstrated that the TPI treatment is effective and safe for treating atrophic skin disorders of varying causes in Korean patients. PMID- 28665147 TI - S/MAR Element Facilitates Episomal Long-Term Persistence of Adeno-Associated Virus Vector Genomes in Proliferating Cells. AB - Adeno-associated virus (AAV) vectors are one of the most frequently applied gene transfer systems in research and human clinical trials. Since AAV vectors do not possess an integrase activity, application is restricted to terminally differentiated tissues if transgene expression is required long term. To overcome this limitation and to generate AAV vectors that persist episomally in dividing cells, AAV vector genomes were equipped with a scaffold/matrix attachment region (S/MAR). After a mild antibiotic selection, cells transduced with AAV-S/MAR established colonies that maintained long-term transgene expression (>50 population doublings) from replicating AAV vector episomes in the absence of further selection. Unexpectedly, with a lesser but still significant efficiency, the control vector (AAV-DeltaS/MAR), a standard single-stranded AAV vector, also established stable transgene-expressing colonies, most of which were maintained as replicating episomes rather than integrated vector genomes. Thus, based on the result in HeLa cells, it is concluded that AAV vector genomes per se possess the ability to establish episomal maintenance in proliferating cells, a feature that can be enhanced by incorporation of a foreign genomic element such as an S/MAR element. PMID- 28665148 TI - Primary healthcare for refugees: The Ponton experience. PMID- 28665149 TI - Verbal Selective Reminding Test (six-trial administration): Regression-based norms for a portuguese version. AB - The Verbal Selective Reminding Test (VSRT) is a widely used measure to evaluate verbal learning and memory associated with different neurological conditions. The goal of this study was to extend the use of the six-version trial of this test to the Portuguese population, through the production of adjusted normative data. The normative sample consists of 309 healthy participants aged between 20 and 70, with an educational level ranging from 4 to 23 years of formal. Gender, education, and age effects were explored. In addition, the reliability of the test was also analyzed and normative data produced. Gender, age, and education were significantly associated with VSRT performance. The test revealed excellent inter-rater reliability and good test-retest reliability. The normative data is presented as a regression-based formula to adjust test scores for gender, education and age. The correspondence between adjusted scores and percentile distribution was calculated. Since a test with appropriate norms is fundamental to an appropriate assessment of memory functioning, the normative data produced in this study improves the applicability of VRST for both clinical and research proposes in the Portuguese population. Further studies might also explore the adequacy of these norms for other Portuguese-speaking countries. PMID- 28665150 TI - Association Between Plasma N-Acylethanolamides and High Hemoglobin Concentration in Southern Peruvian Highlanders. AB - Alarcon-Yaquetto, Dulce E., Lidia Caballero, and Gustavo F. Gonzales. Association between plasma N-acylethanolamides and high hemoglobin concentration in Southern Peruvian highlanders. High Alt Med Biol 18:322-329, 2017.-High-altitude (HA) hypoxia is a stressful condition endured by organisms through different mechanisms. Failing to adapt to chronic HA exposure leads to a disease called chronic mountain sickness (CMS) characterized by excessive erythrocytosis (hemoglobin [Hb] >=19 g/dL for women and >=21 g/dL for men). Genes encoding for peroxisome proliferator-activated receptor (PPAR) subunits alpha and gamma have been proposed as candidate genes for HA adaptation. N-acylethanolamides (NAEs) are endogenous fatty acid substances that bind to PPAR-alpha and -gamma. NAEs are also able to modulate the endocannabinoid system, a signaling pathway activated in physiological stressful conditions. In the frame of a metabolomic study, we measured plasma levels of four NAEs: palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoyl ethanolamide (SEA), and linoleoyl ethanolamide (LEA) in natives from Puno (3830 m), a city located in the Peruvian Southern Andes, and Lima (150 m). All NAEs were significantly higher in the HA population (p < 0.001, q < 0.001). Subjects with higher NAE values were those with higher Hb concentration and lower pulse oxygen saturation. However, there was no association between NAEs and CMS score. Our results suggest that PEA and OEA could be involved in physiological regulation following long-term HA exposure. PMID- 28665151 TI - New nanomicelle curcumin formulation for ocular delivery: improved stability, solubility, and ocular anti-inflammatory treatment. AB - CONTEXT: A stable topical ophthalmic curcumin formulation with high solubility, stability, and efficacy is needed for pharmaceutical use in clinics. OBJECTIVES: The objective of this article was to describe a novel curcumin containing a nanomicelle formulation using a polyvinyl caprolactam-polyvinyl acetate polyethylene glycol (PVCL-PVA-PEG) graft copolymer. METHODS: Nanomicelle curcumin was formulated and optimized and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vitro cellular uptake/in vivo corneal permeation, and in vitro antioxidant activity/in vivo anti-inflammatory efficacy. RESULTS: The solubility, chemical stability, and antioxidant activity were greatly improved after the encapsulation of the PVCL-PVA-PEG nanomicelles. The nanomicelle curcumin ophthalmic solution was simple to prepare and the nanomicelles are stable to the storage conditions, and it had good cellular tolerance. Nanomicelle curcumin also had excellent ocular tolerance in rabbits. The use of nanomicelles significantly improved in vitro cellular uptake and in vivo corneal permeation as well as improved anti-inflammatory efficacy when compared with a free curcumin solution. CONCLUSIONS: These findings indicate that nanomicelles could be promising topical delivery systems for the ocular administration of curcumin. PMID- 28665152 TI - Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson's disease: physical characterization and ex vivo drug permeation through buccal mucosa. AB - OBJECTIVE: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson's disease. METHODS: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa. RESULTS: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6 h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets. CONCLUSION: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson's disease. PMID- 28665153 TI - Risk of peripheral edema in cancer patients treated with MEK inhibitors: a systematic review and meta-analysis of clinical trials. AB - BACKGROUND: MEK inhibitors are a group of drugs that have shown reliable effects in the treatment of metastatic melanoma and non-small-cell lung cancer. Peripheral edema is an adverse event associated with MEK inhibitors; however, there has been no systematic attempt to evaluate peripheral edema data observed with these agents. This meta-analysis aimed to determine the risk of peripheral edema in cancer patients treated with MEK inhibitors. MATERIALS AND METHODS: The authors searched PubMed, the Cochrane Library, EMBASE, and Clinical Trials.gov without language restriction. The final search was conducted on January 9, 2017. Risk ratios (RR) with 95% confidence intervals (CI) were calculated for dichotomous data. Heterogeneity was calculated and reported via Tau2, Chi2, and I2 analyses. RESULTS: A total of 13 eligible studies were obtained. Patients treated with MEK inhibitors (Trametinib and Selumetinib) had an increased risk overall of peripheral edema (RR = 3.05, 95% CI = 1.98-4.70; p < .00001), but the MEK inhibitors (Trametinib and Selumetinib) did not increase the risk of high grade edema (RR = 1.88, 95% CI = 0.66-5.35; p = .24). Sub-group analysis, based on cancer type (melanoma vs non-melanoma), found that the peripheral edema risk in melanoma patients is higher than that in non-melanoma patients (p = .03). However, no significant difference was observed in terms of high-grade edema and other sub-groups (trametinib vs selumetinib; monotherapy vs combination). Due to the absence of cobimetinib data, the result about cobimetinib was not involved. CONCLUSION: This meta-analysis reveals that the use of MEK inhibitors is associated with an increased risk of peripheral edema in cancer patients. Oncologists should be aware of the risk and perform regular assessments. PMID- 28665154 TI - Choline- versus imidazole-based ionic liquids as functional ingredients in topical delivery systems: cytotoxicity, solubility, and skin permeation studies. AB - BACKGROUND: Poor drug solubility represents a problem for the development of topical formulations. Since ionic liquids (ILs) can be placed in either lipophilic or hydrophilic solutions, they may be advantageous vehicles in such delivery systems. Nonetheless, it is vital to determine their usefulness when used at concentrations were cell viability is maintained, which was considered herein. METHOD: Five different ILs were prepared-three imidazole-based ILs: [C2mim][Br], [C4mim][Br], and [C6mim][Br]; and two choline-based ILs: [Cho][Phe] and [Cho][Glu]. Their cytotoxicity in human keratinocytes (HaCat cells), their influence in drug solubility and in percutaneous permeation, using pig skin membranes, was evaluated. RESULTS: Caffeine and salicylic acid were used as model actives. Choline-based ILs proved to be more suitable as functional ingredients, since they showed higher impact on drug solubility and a lower cytotoxicity. The major solubility enhancement was observed for caffeine and further solubility studies were carried out with this active in several concentrations of the choline-based ILs (0.1; 0.2; 0.5; 1.0; 3.0 and 5.0%, w/w) at 25 degrees C and 32 degrees C. Solubility was greatly influenced by concentrations up to 0.5%. The choline-based ILs showed no significant impact on the skin permeation, for both actives. The size of the imidazole-based ILs alkyl chain enhances the caffeine solubility and permeation, but also the ILs cytotoxicity. Stable O/W emulsions and gels were prepared containing the less toxic choline-based ILs and caffeine. CONCLUSIONS: Our results indicate that the choline-based ILs were effective functional ingredients, since, when used at nontoxic concentrations, they allowed a higher drug loading, while maintaining the stability of the formulations. PMID- 28665155 TI - Effects of high power-pulsed Nd:YAG laser irradiation on the release of transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) from human gingival fibroblasts. AB - The purpose of this study was to investigate the effect of different high-power energy settings of a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (1064 nm) on cell viability of human gingival fibroblasts (GFs) and release of transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) on these cells. GFs were isolated from human gingival connective tissues during the crown lengthening procedure. GFs were irradiated with different laser parameters as follows: group 1: 1 W (100 mJ, 10 Hz) 10 seconds; group 2: 1.5 W (150 mJ, 10 Hz) 10 seconds; group 3: 2 W (200 mJ, 10 Hz) 10 seconds; group 4: 1 W (100 mJ, 10 Hz) 20 seconds; group 5: 1.5 W (150 mJ, 10 Hz) 20 seconds; and group 6: 2 W (200 mJ, 10 Hz) 20 seconds. Cell viability/cell proliferation was analyzed with XTT (tetrazolium salt, cell proliferation kit) staining. The release levels of TGF beta and VEGF were analyzed by the enzyme-linked immunosorbent assay. No significant differences were observed in the different laser irradiation groups compared to the control group in terms of cell viability (p > 0.05). The release of TGF-beta was not affected by different laser irradiation settings (p > 0.05). Only group 6 promoted significantly higher VEGF release from GFs in 24 hours compared to the control group (p ? 0.05). These findings suggest that high-power Nd:YAG laser is probably safe but has a very limited effect for wound healing. PMID- 28665156 TI - Fluency adaptation in speakers with Parkinson disease: a motor learning perspective. AB - PURPOSE: Fluency adaptation is characterised by a reduction in stuttering-like behaviours over successive readings of the same speech material and is an effect that is typically observed in developmental stuttering. Prominent theories suggest that short-term motor learning associated with practice explain, in part, fluency adaptation. The current investigation examined the fluency adaptation effect in a group of speakers with Parkinson disease (PD) who exhibited stuttering-like disfluencies. METHOD: Individuals with PD (n = 21) and neurologically healthy controls (n = 19) read a passage five times. Per cent syllables stuttered was measured and calculated for each reading passage. RESULT: Participants in the PD group exhibited significantly more stuttering-like disfluencies than control speakers. Twelve individuals in the PD group exhibited at least three per cent syllable stuttered on at least one reading. Statistical trends revealed that the subgroup of individuals with PD who stuttered exhibited a significant reduction in stuttering moments over the five successive readings. CONCLUSION: A significant fluency adaptation effect was observed for the group of speakers with PD who exhibited stuttering-like disfluencies. Results of the current study are discussed within the framework of the motor learning hypothesis of fluency adaptation. PMID- 28665157 TI - Sex-related differences in autoimmune-induced lung lesions in MRL/MpJ-faslpr mice are mediated by the development of mediastinal fat-associated lymphoid clusters. AB - MRL/MpJ-Faslpr (lpr) mice are a model for autoimmune diseases such as systemic lupus erythematosus (SLE). These diseases mainly affect women, with a 10:1 female to-male ratio, and cause pleuropulmonary lesions. We previously revealed a correlation between mediastinal fat-associated lymphoid cluster (MFALC) development and cellular infiltration in the lungs of lpr male mice; however, we did not report on MFALCs in females. The purpose of this investigation was to reveal sex-related differences in MFALCs in lpr mice. We compared the morphological features of MFALCs and lung mononuclear cell aggregates (LMCAs) in 5-month-old male and female lpr mice. The females showed significantly elevated anti-dsDNA autoantibody titers and larger MFALCs, with a higher ratio of lymphatic vessel (LV) and high endothelial venule (HEV) areas to MFALC area, and greater numbers of T- and B-cells, macrophages, and proliferating and dendritic cells in MFALCs and LMCAs than males. Our data indicated that MFALCs were more developed and lung lesions were more severe in female than in male lpr mice, thereby suggesting a potential role for LVs and HEVs in the establishment of MFALCs and lung lesions. Further investigation in female lpr mice will be needed for treatment of human respiratory diseases and autoimmune disorders. PMID- 28665158 TI - Dissolution and bioavailability enhancement of alpha-asarone by solid dispersions via oral administration. AB - Alpha (alpha)-asarone (1-propenyl-2,4,5-methoxybenzol) (ARE) has been extensively used to treat chronic obstructive pulmonary diseases (COPD), bronchial asthma, pneumonia, and epilepsy. Due to its poor solubility and bioavailability, ARE was clinically administered via intravenous injection. However, severe allergies were often reported due to the presence of solublizers in the injection formulation. In our study, we sought to explore the biopharmaceutical classification of ARE, elucidate the mechanisms behind ARE absorption, and to develop a viable formulation to improve the oral bioavailability of ARE. ARE was not a P glycoprotein substrate, which was absorbed in the passive mode without site specificity in the gastrointestinal tract. Solid dispersions prepared using hydrophilic matrix materials such as Pluronic F68, and polyethylene glycol (PEG) of varying molecular weights (PEG4K, PEG10K, and PEG20K) were proven to significantly improve the dissolution of ARE in vitro and the oral bioavailability of ARE in rats, which represent a promising strategy for the oral administration of ARE and other BCS II compounds. PMID- 28665159 TI - New drugs or alternative therapy to blurring the symptoms of fibromyalgia-a patent review. AB - INTRODUCTION: Fibromyalgia (FM) is a musculoskeletal condition characterized by chronic widespread pain, tenderness and often accompanied by other comorbid conditions such as depression, anxiety, chronic fatigue, among others. Now, we aimed to survey the recent patents describing new drugs or alternative therapy for FM. Areas covered: This review covers the therapeutic patents published between 2010 and 2017 from specialized search databases (WIPO, DERWENT, INPI, ESPANET and USPTO) that report the discovery of new drugs or pharmacologic alternative for the treatment of FM. Expert opinion: New therapeutic substances have been proposed in the last seven years. At least as it has been found in our survey, most are still in the pre-clinical phase of the study, and its clinical applicability is unclear. However, other therapeutic approaches were found in patents such as well-established drugs in the market in combination or drug repositioning that combines the 'new analgesic' effects with the old side effects. Hence, it is a safe approach for pharmaceutical market, but poorer to patients who need a radical innovation. So, there is the emerging need for further studies on the safety and efficacy of such therapeutic measures and the search for improvement of side effects, as well as the development of new drugs that are unorthodox for different FM symptoms. PMID- 28665160 TI - Use of Complementary Traditional Chinese Medicines by Adult Cancer Patients in Taiwan: A Nationwide Population-Based Study. AB - BACKGROUND: Many patients with cancer seek complementary and alternative medicine treatments. We investigated the use of traditional Chinese medicine (TCM) by adult cancer patients in Taiwan. METHODS: We reviewed the Registry for Catastrophic Illness Patients Database of Taiwan, and included all adult patients diagnosed cancer, based on the International Classification of Diseases (ninth revision), from 2001 to 2009 and followed until 2011. This database allowed categorization of patients as TCM users (n = 74 620) or non-TCM users (n = 508 179). All demographic and clinical claims data were analyzed. RESULTS: Compared with non-TCM users, TCM users were younger and more likely to be female, white collar workers, and reside in highly urbanized areas. The average interval between cancer diagnosis and TCM consultation was 15.3 months. The most common cancer type was breast cancer in TCM users (19.4%), and intrahepatic bile duct cancer in non-TCM users (13.6%). The major condition for which TCM users visited clinics were endocrine, nutritional and metabolic diseases, and immunity disorders (23.2%). A total of 33.1% of TCM users visited TCM clinics more than 9 times per year and their time from diagnosis to first TCM consultation was 5.14 months. The most common TCM treatment was Chinese herbal medicine. The common diseases for which cancer patients sought TCM treatment were insomnia, malaise and fatigue, dizziness and headache, gastrointestinal disorders, myalgia and fasciitis, anxiety, and depression. Overall, TCM users had a lower adjusted hazard ratio (aHR) for mortality (aHR = 0.69, 95% CI = 0.68-0.70) after adjustment for age, sex, urbanization of residence, occupation, annual medical center visits, and annual non-medical center visits. CONCLUSIONS: This study provides an overview of TCM usage among adult cancer patients in Taiwan. TCM use varied among patients with different types of cancer. Physicians caring for cancer patients should pay more attention to their patients' use of complementary TCM. PMID- 28665161 TI - Long-term results of the treatment of pregnancy-induced striae distensae using a 1550-nm non-ablative fractional laser. AB - BACKGROUND: Striae distensae (SD) are a type of dermal scarring that is quite common and difficult to treat. Two forms are known: striae rubrae (SR) and striae albae (SA). OBJECTIVE: We compared the long-term clinical effectiveness of a 1550 nm non-ablative fractional laser (NAFL) in treating SR and SA. MATERIALS AND METHODS: We included 16 female patients (8 with SR and 8 with SA) who had developed abdominal SD during pregnancy. All underwent five moderately high energy sessions of 1550-nm NAFL treatment at 4-week intervals. The strial widths and lengths were measured before, and 1 month and 1 year after treatment. RESULTS: The mean strial width decreased from 6.94 mm before treatment to 3.25 mm at the first follow-up visit (p = 3.95 * 10-5) and to 3.13 mm at the second follow-up visit (p = 2.44 * 10-5). Similarly, the mean strial length decreased from 6.06 to 2.88 cm at the first follow-up visit (p = 1.7 * 10-4) and to 2.75 cm at the second follow-up visit (p = 9.52 * 10-5). CONCLUSION: NAFL treatment was effective long term in both SR and SA patients. PMID- 28665162 TI - The effect of pulsed dye laser on cutaneous leishmaniasis and its impact on the Dermatology Life Quality Index. AB - BACKGROUND AND OBJECTIVE: Cutaneous leishmaniasis is a prevalent skin condition especially in the Middle Eastern region. The use of pulsed dye laser (PDL) for the treatment of cutaneous leishmaniasis (CL) has not been thoroughly evaluated. We assessed primarily the efficacy of 595-nm PDL in the treatment of CL lesions and interpreted its impact on the quality of life (QOL) of affected patients as measured by the Dermatology Life Quality Index (DLQI). PATIENTS AND METHODS: Twenty-five lesions from 12 patients were treated with a single pass of PDL over the whole lesions to develop a purpuric end point. Parameters used for this treatment were 7 J/cm2 fluence, 10-mm spot size, and 0.45-ms pulse duration. The laser settings were maintained in all subsequent treatments. RESULTS: Excellent response was noted in 13 of the 25 lesions after 3 sessions, while 12 of the remaining 25 lesions required 4 sessions toward complete recovery. The mean DLQI scores pre- and post-laser treatments were 12.67 and 4.25, respectively. All patients experienced a statistically significant improvement in their QOL (p < 0.05, paired t-test). CONCLUSION: The PDL is a new safe modality for treating cases of CL with further larger-scale studies could better determine its role. PMID- 28665163 TI - What's new in treatment of pancreatic cancer: a patent review (2010-2017). AB - INTRODUCTION: Pancreatic cancer (PC) is one of the most lethal cancers, with a median overall survival of less than 1 year and a 5-year survival of ~5%. The poor survival rate is likely due to lack of early diagnosis, fast disease course, high metastasis rate and disappointing treatment outcome. Therefore, at this stage, any new method that provides a treatment against PC without the undesirable side effects of chemotherapy and radiation is urgently needed. Areas covered: This review summarizes the latest advances in the treatment of PC through the patents published from 2010 to 2017. The patents reviewed include both new combinations of existing drugs and novel structures. New targets are proposed for developing new drugs. Expert opinion: The patents reviewed entail different approaches which, on the one hand, improve the administration of existing drugs and therapies and, on the other, develop new drugs to act on novel targets. However, most of the new methods are in the first stage of development and need to be tested in vivo, in pre-clinical approaches and in clinical trials. Therefore, further assays will help confirm the activity, mechanisms of action, drug-drug interactions and other aspects that make a compound a good antitumoral agent. PMID- 28665164 TI - Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis. AB - AIM: To develop novel siRNA delivery system overcoming the limitations of synthetic nanoparticles, such as potential side effects, nonspecificity and economic production for ulcerative colitis therapy. MATERIALS & METHODS: Nanoparticles composed of edible ginger-derived lipid, termed ginger-derived lipid vehicles (GDLVs) were generated from ginger lipids through hydration of a lipid film, a commonly used method for a liposome fabrication. The morphology, biocompatibility and transfection efficiency of GDLVs loaded with siRNA-CD98 (siRNA-CD98/GDLVs) were characterized by standard methods. RESULTS: Orally administered siRNA-CD98/GDLVs were effectively targeted specifically to colon tissues, resulting in reduced expression of CD98. CONCLUSION: These GDLVs have great promise as efficient siRNA-delivery vehicles while potentially obviating issues related to the traditional synthetic nanoparticles. As such, they help shift the current paradigm of siRNA delivery away from artificially synthesized nanoparticles toward the use of naturally derived nanovehicles from edible plants. PMID- 28665165 TI - Use of a controlled subdermal radio frequency thermistor for treating the aging neck: Consensus recommendations. AB - INTRODUCTION: A new temperature-controlled device has been used as a percutaneous radio frequency probe to treat lax submental and other facial areas. It has significant advantages over other esthetic devices as it provides the dual benefit of fat lipolysis and skin tightening. Our goal here is to present consensus recommendations for treating the aging neck. METHODS: A panel of 11 expert physicians convened in Dallas, Texas, on October 15, 2016 to arrive at a consensus on the best current practice for submental skin tightening and contour improvement. Prior to the meeting, a comprehensive review of the literature was performed and a survey was sent to esthetic dermatologists and plastic surgeons who were queried about various aspects of neck rejuvenation. RESULTS: The literature search revealed 10 different technologies for neck rejuvenation evaluated in double-blind (n = 2) and single-blind (n = 1) clinical trials and other clinical evaluations (n = 21). The survey was sent via an email to 1248 individuals and was completed by 92 respondents. Review of the data and discussion by meeting attendees generated eight consensus recommendations. DISCUSSION: Subdermal monopolar radio frequency represents an effective means for disrupting fat volume and skin tightening of the face, neck, and jawline. For suitable patients, this treatment can be used to achieve significant esthetic improvements. PMID- 28665166 TI - Mild Traumatic Brain Injury Reduces Spine Density of Projection Neurons in the Medial Prefrontal Cortex and Impairs Extinction of Contextual Fear Memory. AB - Epidemiology studies have found that a comorbidity exists between traumatic brain injury (TBI) and stress-related disorders. However, the anatomical and cellular bases for this association is poorly understood. An inability to extinguish the memory of a traumatic event lies at the core of many stress-related disorders. Experimental studies have shown that the medial pre-frontal cortex (mPFC), especially the infralimbic (IL) cortex, is required for extinction and for storing the memory of extinction. The output from the central nucleus of amygdala projects to the lateral hypothalamus, paraventricular nucleus, and central gray to regulate heart rate, stress hormone release, and freezing behavior, respectively. Projection neurons of the IL (layers II/III pyramidal neurons) are thought to stimulate GABAergic neurons in the amygdala, which, in turn, inhibit central amygdala output and reduce fear expression. Thus, loss and/or altered morphology of projection neurons of IL as a result of a mild TBI (mTBI) can compromise their ability to effectively inhibit the central amygdala, allowing the original fear memory to drive behavior. Using lateral mild fluid percussion injury (mFPI) in rats, we found that mFPI did not reduce neuronal numbers in the IL, but caused a significant reduction in overall dendritic spine density of both basal and apical dendrites on layer II/III pyramidal neurons. Spine numbers on layer V/VI pyramidal neurons were not significantly changed as a result of mFPI. The reduction in spine density on layer II/III pyramidal neurons we observed may diminish the efficacy of these neurons to inhibit the output of the central amygdala, thereby reducing the ability of the IL to suppress fear responses after extinction training. Consistent with this, mFPI rats display enhanced freezing behavior during and after extinction training as compared to sham-operated controls, although the ability to form contextual fear memories was not impaired. These results may have implications in stress-related disorders associated with mTBI. PMID- 28665167 TI - Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment. AB - 1. Hepatic drug-metabolizing activity was investigated in vitro with liver microsomes prepared from rats suffering from hypoxemia with experimentally induced acute lung impairment (ALI). 2. Male Wistar rats received an intrabronchial administration of dilute hydrochloride solution for ALI induction. Pooled liver microsomes were prepared for the normal and ALI rats, and the hepatic drug metabolism mediated by cytochrome P450 (CYP) 3 A was examined in an incubation study with the microsomes. 3. The NADPH-dependent metabolism of midazolam significantly increases in ALI rats as compared with that in normal rats. Testosterone 6beta-hydroxylation was also observed to significantly increase in ALI rats. 4. When the hepatic expression of CYP3A proteins was examined, the protein expression of CYP3A1 was shown to significantly increase and that of CYP3A2 remained unaltered in ALI rats. The hepatic expression of NADPH-cytochrome P450 reductase (POR), a protein mediating electron transfer in CYP-mediated drug metabolism, was also revealed to significantly increases in ALI rats. 5. With the findings regarding the midazolam elimination, the hepatic drug metabolizing activity seems to increase in response to acute hypoxemia, partly due to an altered expression of the CYP3A enzymes, and an augmented electron transfer with an increased POR expression is probably involved in the increase. PMID- 28665168 TI - Cerebral hyperperfusion on arterial spin labeling MRI after reperfusion therapy is related to hemorrhagic transformation. AB - Early detection of hemorrhagic transformation after reperfusion therapy is crucial in acute stroke treatment. Here, we evaluated the relationship between hemorrhagic transformation and post-reperfusion hyperperfusion using pulsed arterial spin labeling (ASL) perfusion MRI and 123I-iodoamphetamine single-photon emission-computed tomography. Patients who developed hemorrhagic transformation showed significantly higher cerebral blood flow in the affected lesion after thrombolysis and/or endovascular intervention. Focal hyperperfusion (ipsilateral to contralateral ratio >1.5) was associated with hemorrhagic transformation after reperfusion (odds ratio, 9.3; 95% confidence interval, 1.4-64.0). Our findings suggest that post-reperfusion hyperperfusion on ASL could represent a reliable marker of hemorrhagic transformation. PMID- 28665170 TI - Dynamic tomographic studies of interscapular feline injection-site sarcoma: essential or useless practice? AB - Objectives Feline injection-site sarcomas (FISSs) are soft tissue tumours typically characterised by an interscapular location and highly infiltrative behaviour. CT is considered the modality of choice for FISS staging and double positioning (dynamic approach) was reported to successfully detect the exact extent of infiltration into the muscles. The aim of the present study was to investigate the utility of the dynamic approach in feline patients referred for preoperative staging of interscapular FISS. Methods Tumour volume estimates were compared between the ellipsoid and the semi-automated segmentation methods. Two radiologists blinded to the patient coding used images from each position to assess the extent of muscular infiltration. The distance between the neoplasm and the adjacent skeletal structures (scapulae, spinous processes) was recorded in both positions by a single radiologist. Results Fifty-nine of 84 neoplasms invaded the adjacent muscular structures, with up to 15 muscles infiltrated. Between the extended and flexed position the average estimated numbers of muscles infiltrated were 1.9 (extended) and 1.84 (flexed) for observer A and 1.89 (extended) and 1.85 (flexed) for observer B. Good agreement between observers was established, with higher tumour volumes detected via the ellipsoid method. Moreover, tumours with smaller volumes showed slightly decreased muscular infiltration. Marked difference in the recorded distance between the skeletal structures and the neoplasm in the two different positions was established (mean +/- SD difference spinous processes: 9.74 +/- 9.57 mm; mean +/- SD difference scapulae: 15.15 +/- 11.76 mm). Conclusions and relevance A dynamic approach should be used for a complete evaluation of the invasiveness of FISS along with appropriate methodology for tumour volume measurement, which could potentially alter the tomographic estimation of the real dimension of the neoplasms. PMID- 28665169 TI - Morgellons disease: experiences of an integrated multidisciplinary dermatology team to achieve positive outcomes. AB - BACKGROUND: In recent years, there has been a reported increase in affliction of the skin with small fibres or other particles. The condition has been referred to as Morgellons disease. Patients present with stinging, burning or crawling sensations of the skin, with perceived extrusion of inanimate material alongside fatigue and other systemic symptoms. Sufferers often experience significant morbidity and reduction in quality of life. OBJECTIVES: We aimed to explore the various clinical presentations, management strategies and outcomes employed to treat this condition in our patients. METHODS: We conducted a retrospective case notes review of 35 patients referred to our multidisciplinary psycho-dermatology clinic at the Royal London Hospital between January 2004 and January 2017. RESULTS: The majority of patients were women (25) 71.4%, with a mean age of 54.6 years (26-80 years). Most (26) 74.2% were living alone. The average duration of illness prior to presentation was 3.8 years (4 months-20 years). Many patients had perceived precipitating factors (54.2%) and often self-diagnosed (28.5%). Psychiatric co-morbidities included 42.8% with depressive symptoms and 25.7% with anxiety. Substance misuse was elicited in five patients (14%). Management of patients included both the treatment of skin disease and psychosocial co morbidities. Out of the 35 patients who attended (14) 40% cleared or showed significant improvement. Sixteen (45.7%) patients were stable and under review. One patient declined treatment and three did not attend review. One patient died from disease unrelated to her skin condition. CONCLUSIONS: Morgellons disease is a condition, which is widely discussed on the internet and patients often self diagnose. The course of the disease can be chronic and debilitating. For a positive outcome, it is important that a strong physican-patient relationship is cultivated. As demonstrated in this case series, managing patients holistically in an integrated multidisciplinary dermatology setting helps achieve positive outcomes. PMID- 28665171 TI - Infarct volume predicts outcome after decompressive hemicraniectomy for malignant hemispheric stroke. AB - The decision to perform decompressive hemicraniectomy (DHC) by default in malignant hemispheric stroke (MHS) remains controversial. Even under ideal conditions, DHC usually results in moderate to severe disability. The present study for the first time uses neuroimaging to identify independent outcome predictors in a prospective cohort of 96 MHS patients undergoing DHC. The primary outcome was functional status according to the modified Rankin Scale (mRS) at 12 months and categorized as favorable (mRS 0-3) or unfavorable (mRS 4-6). At 12 months, 19 patients (20%) reached favorable and 77 patients (80%) unfavorable outcome. The overall mean infarct volume was 328 +/- 114 ml. Multivariable logistic regression identified age per year (OR 1.14, 95% CI 1.04-1.24; p = 0.005), infarct volume per cm3 (OR 1.012, 95% CI 1.003-1.022; p = 0.013), thalamic involvement (OR 8.65, 95% CI 1.04-72.15; p = 0.046) and postoperative pneumonia (OR 5.52, 95% CI 1.03-29.57; p = 0.046) as independent outcome predictors, which was confirmed by multivariable ordinal regression for age ( p = 0.004) and infarct volume ( p = 0.015). The infarct volume threshold for reasonable prediction of unfavorable outcome in our patients was 270 cm3, which in the future may help prognostication and development of clinical trials on DHC and outcome in MHS. PMID- 28665172 TI - Treatment with low dose fasudil for acute ischemic stroke in chronic hypertension. AB - We investigated the effect of Rho kinase inhibition on changes in cerebral blood flow (CBF), brain injury and vascular function after ischemic stroke in spontaneously hypertensive rats (SHR). Changes in core MCA and collateral perfusion were measured by a validated laser Doppler method. Animals underwent 2 h tMCAO and 2 h reperfusion. Fasudil (0.1 mg/kg, i.v.) or vehicle was given at 30 min ischemia (n = 9/group; mean (SD)). Brain injury was determined by 2,3,5 triphenyltetrazolium chloride staining. To determine the effect of fasudil on vascular function, fasudil was given 10 min before reperfusion and parenchymal arterioles studied isolated (n = 6/group; mean(SD)). Collateral perfusion was low in vehicle-treated SHR (-8(32)%) that changed minimally with fasudil (6(24)%, p > 0.05, effect size: 0.47;95% CI-0.49-1.39). Reperfusion CBF was below baseline in vehicle (-27(26)%) and fasudil (-32(25)%, p > 0.05, effect size: 0.19; 95% CI 0.74-1.11) groups, suggesting incomplete reperfusion in both groups. Fasudil had little effect on brain injury volume (28(13)% vs. 36(7)% in vehicle, p > 0.05, effect size: 0.75; 95% CI-0.24-1.66). In isolated parenchymal arterioles, myogenic tone was similar between groups (37(6)% vs. 38(10)% in vehicle, p > 0.05, effect size: 0.09; 95% CI-1.05-1.21). There were no differences with fasudil treatment vs. vehicle in perfusion, brain injury and vascular function that may be related to the low dose that had minimal blood pressure lowering effect. PMID- 28665173 TI - Serial Assessment of Gray Matter Abnormalities after Sport-Related Concussion. AB - There is an urgent need to characterize the acute physiological effects of sport related concussion (SRC). We investigated the effects of SRC on gray matter structure and diffusion metrics in collegiate athletes at 1.64 (T1; n = 33), 8.33 (T2; n = 30), and 32.15 days (T3; n = 36) post-concussion, with healthy collegiate contact-sport athletes serving as controls (HA; n = 46). Plasma levels of glial fibrillary acidic protein (GFAP) were assessed in a subset of athletes. We hypothesized that acute SRC would be associated with increased fractional anisotropy (FA), decreased mean diffusivity (MD), and increased GFAP relative to noninjured HA, without acute differences in gray matter volume or cortical thickness. Further, we hypothesized that neither diffusion nor structure would show longitudinal changes across the first month post-SRC. Finally, we hypothesized that gray matter diffusion metrics would correlate with plasma GFAP levels, as indicated by pre-clinical literature. Consistent with our hypothesis, acute SRC was associated with decreased MD in the left pallidum, increased FA in the right amygdala, and a significantly greater number and volume of subject specific clusters with increased FA compared to HA. No differences in gray matter volume, cortical thickness, or GFAP were observed between groups. There were no longitudinal changes in any measure across the first month post-SRC. Finally, FA in the right amygdala was inversely correlated with GFAP at T2. These results suggest that gray matter diffusion metrics may be useful in determining the physiological effects of SRC. PMID- 28665174 TI - Inappropriate use of arthroscopic meniscal surgery in degenerative knee disease. AB - Background and purpose - Current evidence suggests that arthroscopic knee surgery has no added benefit compared with non-surgical management in degenerative meniscal disease. Yet in many countries, arthroscopic partial meniscectomy (APM) remains among the most frequently performed surgeries. This study quantifies and characterizes the dynamics of the current use of knee arthroscopies in Switzerland in a distinctively non-traumatic patient group. Methods - We assessed a non-accident insurance plan of a major Swiss health insurance company for surgery rates of APM, arthroscopic debridement and lavage in patients over the age of 40, comparing the years 2012 and 2015. Claims were analyzed for prevalence of osteoarthritis, related interventions and the association of surgery with insurance status. Results - 648,708 and 647,808 people were examined in 2012 and 2015, respectively. The incidence of APM, debridement, and lavage was 388 per 105 person-years in 2012 and 352 per 105 person-years in 2015 in non-traumatic patients over the age of 40, consisting mostly of APM (96%). Between years, APM surgery rates changed in patients over the age of 65 (p < 0.001) but was similar in patients aged 40-64. Overall prevalence of osteoarthritis was 25%. Insurance status was independently associated with arthroscopic knee surgery. Interpretation - APM is widely used in non-traumatic patients in Switzerland, which contrasts with current evidence. Many procedures take place in patients with degenerative knee disease. Surgery rates were similar in non-traumatic middle-aged patients between 2012 and 2015. Accordingly, the potential of inappropriate use of APM in non-traumatic patients in Switzerland is high. PMID- 28665175 TI - Identification of three new phase II metabolites of a designer drug methylone formed in rats by N-demethylation followed by conjugation with dicarboxylic acids. AB - 1. Methylone (3,4-methylenedioxy-N-methylcathinone, MDMC), which appeared on the illicit drug market in 2004, is a frequently abused synthetic cathinone derivative. Known metabolic pathways of MDMC include N-demethylation to normethylone (3,4-methylenedioxycathinone, MDC), aliphatic chain hydroxylation and oxidative demethylenation followed by monomethylation and conjugation with glucuronic acid and/or sulphate. 2. Three new phase II metabolites, amidic conjugates of MDC with succinic, glutaric and adipic acid, were identified in the urine of rats dosed subcutaneously with MDMC.HCl (20 mg/kg body weight) by LC-ESI HRMS using synthetic reference standards to support identification. 3. The main portion of administered MDMC was excreted unchanged. Normethylone, was a major urinary metabolite, of which a minor part was conjugated with dicarboxylic acids. 4. Previously identified ring-opened metabolites 4-hydroxy-3-methoxymethcathinone (4-OH-3-MeO-MC), 3-hydroxy-4-methoxymeth-cathinone (3-OH-4-MeO-MC) and 3,4 dihydroxymethcathinone (3,4-di-OH-MC) mostly in conjugated form with glucuronic and/or sulphuric acids were also detected. 5. Also, ring-opened metabolites derived from MDC, namely, 4-hydroxy-3-methoxycathinone (4-OH-3-MeO-C), 3-hydroxy 4-methoxycathinone (3-OH-4-MeO-C) and 3,4-dihydroxycathinone (3,4-di-OH-C) were identified for the first time in vivo. PMID- 28665176 TI - Does Acinetobacter baumannii Serve as a Source for blaNDM Dissemination into Enterobacteriaceae in Hospitalized Patients? AB - The goal was to study the possibility that Acinetobacter baumannii serve as an epidemiologically significant source for transmission of the blaNDM gene to Enterobacteriaceae by horizontal gene transfer (HGT) in hospitalized patients. The study was done at the Tel-Aviv Sourasky Medical Center from December 2014 until August 2015. Clinical and surveillance rectal cultures were collected as per hospital policies and were analyzed for the presence of New Delhi metallo beta-lactamase-producing Enterobacteriaceae (NDME) and A. baumannii (NDMAb). Isolates were typed by pulsed-field gel electrophoresis (PFGE). The location of the blaNDM gene within the Tn125 transposon was studied by sequencing. A transmission event (TE) was determined if patients shared the same PFGE type of either NDME or NDMAb and were simultaneous in the same ward. HGT-related TE was considered if the two isolates shared identical blaNDM gene allele and transposon. There were 16 NDMAb- (clinical, 10; surveillance, 4; both, 2) and 13 NDME- (clinical, 3; surveillance, 8; both, 2) infected/colonized patients. All NDMAb isolates except two harbored the blaNDM-1 allele that was located within a Tn125 transposon and was plasmid borne. The majority of patients (n = 10/16) were infected by one PFGE type of NDMAb, and five clonal TEs were identified. NDME were either Escherichia coli (n = 4) or Klebsiella pneumoniae (n = 9) of different PFGE types with only one NDME TE. The blaNDM gene was within a Tn125 in three K. pneumoniae isolates. Although one HGT-related TE between NDMAb and K. pneumoniae was epidemiologically suspected, the low similarity between the Tn125 transposons (75.7%) excluded that possibility. In conclusion, whereas NDMAb appears to disseminate by clonal spread, we did not find evidence for HGT mediated transmission in NDME in hospitalized patients. PMID- 28665177 TI - Epigenetics and ADHD: Toward an Integrative Approach of the Disorder Pathogenesis. AB - OBJECTIVE: Epigenetic hypothesis is one of the research pathways used to explain the complex etiology of neurodevelopmental disorders. This review highlights the findings of recent studies in the field of epigenetics in ADHD. METHODS: An electronic literature search using Medline. RESULTS: In the Gene * Environment interaction model, several clinical, genetic and molecular arguments support the epigenetic hypothesis in ADHD etiology. Environmental ADHD risk factors including toxic, nutritional factors and stressful life events lead to changes in DNA methylation and in histone modification levels. One critical CpG site located in the promoter of the DRD4 gene exhibited a specific pattern in ADHD children. A methylome wide exploration of DNA showed decreased methylation in vasoactive intestinal peptide receptor 2 gene, which was not replicated by further research. CONCLUSION: Current data require consolidation and could lead to the identification of biomarkers and the introduction of new modalities of treatment. PMID- 28665178 TI - Xanthogranulomatous colloid cyst of the third ventricle: Alter your surgical strategy. AB - Colloid cysts are the most common benign neoplasms of the anterior third ventricle, mostly located at the level of the foramen of Monro and can often manifest as sudden onset headache or loss of consciousness. These cysts often have a well-defined cyst wall, mucinous or watery intracystic fluid and have a fairly good plane with the surrounding parenchyma. Occasionally, intracystic haemorrhage can lead to xanthogranulomatous inflammatory changes within the cyst resulting in focal thickening of the cyst wall and adhesion to the surrounding structures. Here we describe a case of xanthogranulomatous colloid cyst which is a very rare variant of colloid cyst. PMID- 28665179 TI - Fever of unknown origin with rashes in early infancy is indicative of adenosine deaminase type 2 deficiency. PMID- 28665180 TI - Evaluating Effectiveness of Abstinence Education. AB - PURPOSE: This study examined the effectiveness of an abstinence education program that was sensitive to federally mandated curriculum and measures. METHODS: The intervention was delivered to 5,772 middle school and high school students. Effectiveness was assessed by a measure that was anchored on A-H themes, which are components of federally mandated curricular components of abstinence education. To better understand the relationship of different variables and determine the significance of student's improvements on the A-H measure scores, the ANCOVA was used with the pretest score and age as covariates and the use of gender and ethnicity as fixed factors in the analysis. RESULTS: While controlling for the effects of the pretest, the analyses showed that age and gender were main effects but that ethnicity did not prove to be related to the outcome scores. Results demonstrated that the effectiveness of the program decreased as adolescent boys aged. There were no significant interactions in the gender and ethnicity variables. CONCLUSIONS: The findings of this study will be beneficial to program developers in understanding what variations and demographics are most receptive to this particular abstinence-only education model. Further studies in this area are needed to evaluate the effectiveness of currently available programs. PMID- 28665181 TI - Eye gaze influences working memory for happy but not angry faces. AB - Previous research has shown that angry and happy faces are perceived as less emotionally intense when shown with averted versus direct gaze. Other work reports that long-term memory (LTM) for angry (but not happy) faces was poorer when they were encoded with averted versus direct gaze, suggesting that threat signals are diluted when eye contact is not engaged. The current study examined whether gaze modulates working memory (WM) for angry and happy faces. In stark contrast to LTM effects, WM for angry faces was not significantly modulated by gaze direction. However, WM for happy faces was significantly enhanced when gaze was averted versus direct. These findings suggest that in WM - when rapid processing and an immediate response is required - averted gaze may alter the meaning behind a smile, and make this kind of expression particularly salient for short-term processing. PMID- 28665182 TI - Systemic Administration of Exosomes Released from Mesenchymal Stromal Cells Attenuates Apoptosis, Inflammation, and Promotes Angiogenesis after Spinal Cord Injury in Rats. AB - Spinal cord injury (SCI) is one of the most common devastating injuries, which causes permanent disabilities such as paralysis and loss of movement or sensation. The precise pathogenic mechanisms of the disease remain unclear, and, as of yet, there is no effective cure. Mesenchymal stem cells (MSCs) show promise as an effective therapy in the experimental models of SCI. MSCs secrete various factors that can modulate a hostile environment, which is called the paracrine effect. Among these paracrine molecules, exosome is considered to be the most valuable therapeutic factor. Thus, exosomes from MSCs (MSCs-exosomes) can be a potential candidate of therapeutic effects of stem cells. The present study was designed to investigate the effect of whether systemic administration of exosomes generated from MSCs can promote the function recovery on the rat model of SCI in vivo. In the present study, we observed that systemic administration of MSCs exosomes significantly attenuated lesion size and improved functional recovery post-SCI. Additionally, MSCs-exosomes treatment attenuated cellular apoptosis and inflammation in the injured spinal cord. Expression levels of proapoptotic protein (Bcl-2-associated X protein) and proinflammatory cytokines (tumor necrosis factor alpha and interleukin [IL]-1beta) were significantly decreased after MSCs-exosomes treatment, whereas expression levels of antiapoptotic (B-cell lymphoma 2) and anti-inflammatory (IL-10) proteins were upregulated. Further, administration of MSCs-exosomes significantly promoted angiogenesis. These results show, for the first time, that systemic administration of MSCs-exosomes attenuated cell apoptosis and inflammation, promoted angiogenesis, and promoted functional recovery post-SCI, suggesting that MSCs-exosomes hold promise as a novel therapeutic strategy for treating SCI. PMID- 28665183 TI - One-Stage Positron Emission Tomography and Magnetic Resonance Imaging to Assess Mesenchymal Stem Cell Survival in a Canine Model of Intervertebral Disc Degeneration. AB - Intervertebral disc degeneration (IVDD) is a major health problem. Although mesenchymal stem cells (MSCs) have been used to promote IVD regeneration, the actual survival time of implanted MSCs in IVDs has never been studied noninvasively and continuously in vivo. To investigate survival of implanted MSCs in vivo, this study used a canine model of degenerated IVD and MSCs transfected with a mutant herpes simplex type-1 virus thymidine kinase and labeled with magnetic iron oxide nanoparticles (MION). One-stage positron emission tomography (PET) and magnetic resonance (MR) imaging were carried out 3 days and 2 weeks, 3 weeks, and 4 weeks after implantation of MSCs into IVDs with surgically induced degeneration. Pfirrmann disc degeneration grade determined from the MR images indicated that the repair progress of degenerated IVD stopped 3 weeks after MSC implantation. Meanwhile, MION signal strength, signal contrast ratio (%), and low signal area (mm2) did not change significantly from that seen 3 days after cell implantation until 4 weeks [751.43 (4 weeks) +/-52.67 (3 days) vs. 225.34 +/- 35.62; 47.37 +/- 5.01 vs. 85.37 +/- 10.54; 1.78 +/- 0.31 vs. 5.29 +/- 1.35; P < 0.01, respectively]. Accumulation of the PET reporter probe, 9-(4-[18F]-fluoro-3 hydroxymethylbutyl)-guanine, was dramatically decreased at 3 weeks after MSC implantation. These results demonstrated that MSCs could survive no more than 3 weeks after implantation into IVDs with surgically induced degeneration, suggesting that MSCs could contribute to IVD repair for the first 3 weeks after implantation. The results also indicate that PET imaging could be used reliably to quantify the survival of implanted MSCs, whereas MION with MR imaging would likely be unsuitable for long-term tracking of MSCs in IVDs. PMID- 28665184 TI - Spectral Sensitivity Change May Precede Habitat Shift in the Developing Retina of the Atlantic Tarpon (Megalops atlanticus). AB - Fish that undergo ontogenetic migrations between habitats often encounter new light environments that require changes in the spectral sensitivity of the retina. For many fish, sensitivity of the retina changes to match the environmental spectrum, but the timing of retinal change relative to habitat shift remains unknown. Does retinal change in fish precede habitat shift, or is it a response to encountered changes in environmental light? Spectral sensitivity changes were examined over the development of the Atlantic tarpon (Megalops atlanticus) retina relative to ontogenetic shifts in habitat light. Opsin gene isoform expression and inferred chromophore use of visual pigments were examined over the course of M. atlanticus development. Spectral sensitivity of the retina was then determined by electroretinography and compared to the spectroradiometric measurements of habitat light encountered by M. atlanticus from juveniles to adults. These data, along with previously known microspectrophotometric measurements of sensitivity in M. atlanticus, indicate retinal spectral sensitivity that matches the dominant wavelengths of environmental light for juvenile and adult fish. For the intervening subadult stage, however, spectral sensitivity does not match the dominant wavelength of light it occupies but better matches the dominant wavelengths of light in the habitat of its forthcoming migration. These results first indicate that the relationship between environmental light spectrum and spectral sensitivity of the retina changes during M. atlanticus development and then suggest that such changes may be programmed to support visual anticipation of new photic environments. PMID- 28665185 TI - The Interplay of Energy Balance and Daily Timing of Activity in a Subterranean Rodent: A Laboratory and Field Approach. AB - The tuco-tuco (Ctenomys aff. knighti) is among the rodent species known to be nocturnal under standard laboratory conditions and diurnal under natural conditions. The circadian thermoenergetics (CTE) hypothesis postulates that switches in activity timing are a response to energetic challenges; daytime activity reduces thermoregulatory costs by consolidating activity to the warmest part of the day. Studying wild animals under both captive and natural conditions can increase understanding of how temporal activity patterns are shaped by the environment and could serve as a test of the CTE hypothesis. We estimated the effects of activity timing on energy expenditure for the tuco-tuco by combining laboratory measurements of metabolic rate with environmental temperature records in both winter and summer. We showed that, in winter, there would be considerable energy savings if activity is allocated at least partially during daylight, lending support to the CTE hypothesis. In summer, the impact of activity timing on energy expenditure is small, suggesting that during this season other factors, such as predation risk, water balance, and social interaction, may have more important roles than energetics in the determination of activity time. PMID- 28665186 TI - Structural insights into the binding mode and conformational changes of BSA induced by bixin and crocin. AB - Bixin and crocin are natural apocarotenoids utilized as food colorants and additives in food industries worldwide. For safety assessment, it is necessary to understand the biological interaction of food colorants. In our present study, we report the interaction of two apocarotenoids with bovine serum albumin (BSA) at physiological pH using spectroscopic techniques and in silico tools. The binding constant and the mode of binding sites have been studied. The enthalpic and entropic contribution to the intermolecular binding event was analyzed and it was found that the contribution of hydrogen bonding and hydrophobic interactions was dominant. The adverse temperature dependence in the unusual static quenching is found to be a reasonable consequence of the large activation energy requirement in the binding process, which is required to overcome the fundamental block and is a direct result of the unique microstructure of the binding sites. To confirm the experimental analysis, we investigated the binding patterns using different in silico tools. A combination of molecular docking, molecular dynamics, and toxicity analysis was performed, and the obtained results revealed that both the apocarotenoids had high binding affinity with a binding energy of -5.44 and -5.93 kcal/mol for bixin and crocin, respectively, with no toxic effects and are in accordance with our experimental analysis. The results directly revealed the flexibility of the protein toward bixin and crocin which has a great impact on the interaction. Thus bixin and crocin can guardedly be used as food colorants in food industries. PMID- 28665188 TI - Molecular dynamics simulations of lysozyme-lipid systems: probing the early steps of protein aggregation. AB - Using the molecular dynamics simulation, the role of lipids in the lysozyme transition into the aggregation-competent conformation has been clarified. Analysis of the changes of lysozyme secondary structure upon its interactions with the model bilayer membranes composed of phosphatidylcholine and its mixtures with phosphatidylglycerol (10, 40, and 80 mol%) within the time interval of 100 ns showed that lipid-bound protein is characterized by the increased content of beta-structures. Along with this, the formation of protein-lipid complexes was accompanied by the increase in the gyration radius and the decrease in RMSD of polypeptide chain. The results obtained were interpreted in terms of the partial unfolding of lysozyme molecule on the lipid matrix, with the magnitude of this effect being increased with increasing the fraction of anionic lipids. Based on the results of molecular dynamics simulation, a hypothetical model of the nucleation of lysozyme amyloid fibrils in a membrane environment was suggested. PMID- 28665187 TI - Is contrast enhanced ultrasonography a useful tool for the evaluation of muscular microcirculation in patients with critical limb ischaemia? AB - BACKGROUND: Evaluation of skin microcirculation in patients with critical limb ischemia (CLI) may be achieved by the measurement of transcutaneous oxygen pressure or skin perfusion pressure, but there is no practical method available for the evaluation of muscle microcirculation. Contrast enhanced ultrasonography (CEUS) has been used to assess muscle perfusion in patients with peripheral arterial disease. We conducted a monocentric pilot study evaluating the ability of CEUS to assess the impact of arterial revascularization on the perfusion of the calf muscle in patients with CLI. PATIENTS AND METHODS: Patients with CLI (TASC II criteria) and a possibility of proximal or medial revascularization were included. In addition to TcPO2 and toe systolic blood pressure measurements, CEUS of the calf muscle was performed just before and one month after the therapeutic procedure. Parameters derived from muscular perfusion curves were evaluated in a blinded fashion and compared with the clinical outcome. RESULTS: Thirty eight patients were included (74 % men, median age 71 years, 53 % diabetics). Thirty benefited from revascularization with a clinical success rate of 70 %. Twenty three patients could benefit from analysis before and after revascularization. No significant difference was shown in time to peak (22.3 s vs 24.0 s, P = 0.61) nor in peak intensity (2.30 dB vs 1.27 db, P = 0,26), contrasting with significant improvements of TcPO2 (43 mm Hg vs 20 mm Hg, P = 0.007) and toe systolic blood pressure (54 mm Hg vs 32 mm Hg, P = 0.002). CONCLUSIONS: The evaluation of muscular microvascular perfusion by CEUS as performed in this study is not enough sensitive to change to allow a clinically relevant evaluation of the improvement in muscle microvascular perfusion in patients with CLI benefiting from revascularization procedures. PMID- 28665189 TI - Schools must include faculty and staff in sexual violence prevention efforts. AB - Creating a normative campus environment intolerant to sexual violence is important for prevention. While prevention initiatives focusing on students are vital, faculty and staff have a central role in supporting and sustaining a comprehensive strategy for preventing campus sexual violence. Nationwide, colleges and universities recently implemented campus climate surveys. At Emory, we decided to survey faculty and staff as well as students, motivated by our use of an ecological framing of campus sexual violence. Faculty and staff are long term members of the community, and can provide stability and continuity that reinforces prevention efforts prioritized for students. We recommend that schools use a trauma-informed approach to guide the involvement of faculty and staff in prevention. We encourage colleges and universities to consider the experiences and needs of their faculty and staff, as professionals who serve as leaders on campus and as those who guide students through their academic experiences. PMID- 28665190 TI - Numerical Nudging: Using an Accelerating Score to Enhance Performance. AB - People often encounter inherently meaningless numbers, such as scores in health apps or video games, that increase as they take actions. This research explored how the pattern of change in such numbers influences performance. We found that the key factor is acceleration-namely, whether the number increases at an increasing velocity. Six experiments in both the lab and the field showed that people performed better on an ongoing task if they were presented with a number that increased at an increasing velocity than if they were not presented with such a number or if they were presented with a number that increased at a decreasing or constant velocity. This acceleration effect occurred regardless of the absolute magnitude or the absolute velocity of the number, and even when the number was not tied to any specific rewards. This research shows the potential of numerical nudging-using inherently meaningless numbers to strategically alter behaviors-and is especially relevant in the present age of digital devices. PMID- 28665191 TI - I've changed, but I'm not less happy: Interview study among nonclinical relatives of long-term missing persons. AB - Twenty-three nonclinical relatives of long-term missing persons were interviewed. Patterns of functioning over time were studied retrospectively by instructing participants to draw a graph that best described their pattern. Patterns most frequently drawn were a recovery and resilient/stable pattern. Participants were also asked to select 5 out of 15 cards referring to coping strategies, which they considered most helpful in dealing with the disappearance. Acceptance, emotional social support, mental disengagement, and venting emotions were most frequently chosen. This study provided some indication of coping strategies that could be strengthened in treatment for those in need of support. PMID- 28665192 TI - Adipose Tissue-Derived Stem Cell Sheet Application for Tissue Healing In Vivo: A Systematic Review. AB - Adipose tissue-derived stem cells (ASCs) are known to be tissue-healing promoters due to their cellular plasticity and secretion of paracrine factors. Cultured ASC sheets provide a novel method of ASC application and can retain ASCs at the targeted tissue. The purpose of this systematic review is to evaluate preclinical studies using ASC sheet transplantation therapy for promoting tissue healing. First, we searched databases to identify studies of ASC sheet therapy in different experimental animal models, and then determined the quality score of studies using SYRCLE's risk bias tool. A total of 18 included studies examined the role of ASC sheets on tissue healing and function in models for myocardial infarction, dilated cardiomyopathy, full-thickness skin wounds, hind limb ischemia, esophageal strictures, and oral ulcers. ASC sheet application after myocardial infarction improved survival rate, cardiac function, and capillary density and reduced the extent of fibrosis. Application of ASC sheets to a full thickness skin wound decreased the wound size and stimulated wound maturation. In the hind limb ischemia model, ASC sheet application improved limb perfusion and capillary density, and decreased the amount of ischemic tissue and inflammation. ASC sheet application to mucosal wounds of the digestive tract accelerated wound healing and decreased the degree of stricture and fibrosis. Taken together, transplanted ASC sheets had a positive effect on tissue healing and reconstruction in these preclinical studies. The reported favorable effects of ASC sheet therapy in various tissue healing applications may be implemented in future translational studies. It is suggested that future preclinical animal model studies of ASC sheet therapy should concern standardization of culture techniques and investigate the mechanisms of action. In addition, clearly indicated experimental setups according to the SYRCLE's guidelines should improve study quality and validity. PMID- 28665193 TI - Importance of the enteric nervous system in the control of the migrating motility complex. AB - The migrating motility complex (MMC), a cyclical phenomenon, represents rudimentary motility pattern in the gastrointestinal tract. The MMC is observed mostly in the stomach and gut of man and numerous animal species. It contains three or four phases, while its phase III is the most characteristic. The mechanisms controlling the pattern are unclear in part, although the neural control of the MMC seems crucial. The main goal of this article was to discuss the importance of intrinsic innervation of the gastrointestinal tract in MMC initiation, migration, and cessation to emphasize that various MMC-controlling mechanisms act through the enteric nervous system. Two main neural regions, central and peripheral, are able to initiate the MMC. However, central regulation of the MMC may require cooperation with the enteric nervous system. When central mechanisms are not active, the MMC can be initiated peripherally in any region of the small bowel. The enteric nervous system affects the MMC in response to the luminal stimuli which can contribute to the initiation and cessation of the cycle, and it may evoke irregular phasic contractions within the pattern. The hormonal regulators released from the endocrine cells may exert a modulatory effect upon the MMC mostly through the enteric nervous system. Their central action could also be considered. It can be concluded that the enteric nervous system is involved in the great majority of the MMC-controlling mechanisms. PMID- 28665194 TI - The impact of pretreatment with simvastatin on kidney tissue of rats with acute sepsis. AB - It has been reported that changes in cytokine levels affect mitochondrial functions, levels of hypoxia-inducible factor alpha (HIF-1alpha), and tissue damage during sepsis. We aimed to investigate the effects of simvastatin pretreatment on mitochondrial enzyme activities, and on levels of ghrelin, HIF 1alpha, and thiobarbituric acid reactive substances (TBARS) in kidney tissue during sepsis. Rats were separated into four groups, namely, control, lipopolysaccharides (LPS) (20 mg/kg), simvastatin (20 mg/kg), and simvastatin + LPS. We measured the levels of mitochondrial enzyme activities and TBARS in the kidney using spectrophotometry. The histological structure of the kidney sections was examined after staining with hematoxylin and eosin. Tumor necrosis factor alpha (TNF-alpha), IL-10, HIF-1alpha, and ghrelin immunoreactivity were examined using proper antibodies. In tissue, TNF-alpha (p < 0.01) and HIF-1alpha (p < 0.05) levels were increased in the simvastatin + LPS and LPS groups. TBARS levels were higher in the LPS group than in the other groups (p < 0.01), but they were similar in the simvastatin + LPS and control groups (p > 0.05). Ghrelin immunoreactivity was lower in the LPS group (p < 0.05) and higher in the simvastatin + LPS group than in the LPS group (p < 0.01). We observed tubular damage in the sections of the LPS group. There were no differences in mitochondrial enzyme activities between the groups (p > 0.05). We observed that pretreatment of simvastatin caused favorable changes on ghrelin and TBARS levels in rats with sepsis. PMID- 28665195 TI - Editorial. PMID- 28665196 TI - Rural and urban injection drug use in Puerto Rico: Network implications for human immunodeficiency virus and hepatitis C virus infection. AB - Understanding the short- and long-term transmission dynamics of blood-borne illnesses in network contexts represents an important public health priority for people who inject drugs and the general population that surrounds them. The purpose of this article is to compare the risk networks of urban and rural people who inject drugs in Puerto Rico. In the current study, network characteristics are drawn from the sampling "trees" used to recruit participants to the study. We found that injection frequency is the only factor significantly related to clustering behavior among both urban and rural people who inject drugs. PMID- 28665197 TI - Increased IgE+ B Cells in Sputum, but Not Blood, Bone Marrow, or Tonsils, after Inhaled Allergen Challenge in Subjects with Asthma. PMID- 28665198 TI - Whole-Exome Sequencing Insights into Adult Pulmonary Fibrosis. Repeating the Telomere Theme. PMID- 28665199 TI - Is This Intensive Care Unit Patient Frail? Unraveling the Complex Interplay between Frailty and Critical Illness. PMID- 28665200 TI - Putative Mechanisms of Action of Endobronchial Coils. PMID- 28665201 TI - What Is Obstructive Sleep Apnea in Adults? PMID- 28665202 TI - Changing Intensivists' Behaviors: A Challenge in Need of New Solutions. PMID- 28665203 TI - We Need to "Think Different" about Particulate Matter. PMID- 28665204 TI - Primary Ciliary Dyskinesia Diagnosis. Is Color Better Than Black and White? PMID- 28665205 TI - Recurrent Wheezing in Childhood and Palivizumab. PMID- 28665206 TI - Primary aorto-enteric fistula as a rare cause of massive gastrointestinal haemorrhage. AB - The incidence of primary aorto-enteric fistula (PAEF) is low with only few case reports and case series published. Depending on the location of the PAEF, the perforation leads to upper or lower gastrointestinal haemorrhages. We conducted a MEDLINE search according to the PRISMA statement. Articles with publication dates from 2000 to 2016 were included and present an own case report. We considered all case reports and series reporting on PAEF and identified 85 individual patients from 32 case reports and five case series. The majority of PAEF is associated with atherosclerotic or aneurysmatic findings of the aorta and in particular with inflammatory aortic diseases. Most commonly, the duodenum (64 %) was mentioned as location of the perforation. Other cases involved the jejunum (< 10 %) and the colon (5 %). Almost all patients were diagnosed either with gastrointestinal haemorrhage, abdominal or back pain, or anaemia due to bleeding. The immediate and correct diagnosis of this entity remains difficult. Therefore, treatment is delayed leading to an extraordinary high mortality of almost 100 % in untreated cases. Duplex ultrasound and contrast-enhanced CT angiography have high diagnostic sensitivity and specificity to rule out acute abdominal aortic pathologies. New endovascular approaches can help to lower mortality. PMID- 28665207 TI - Until I get off parole ... then I can swim in it if I want to: Facilitators of and barriers to drug use among formerly incarcerated Black drug offenders. AB - Black Americans are overrepresented among those incarcerated for drug-related offenses. Drug use, postincarceration, is associated with high risk of recidivism and overdose deaths. We explored factors influencing drug use among former Black drug offenders. Qualitative interviews with 30 Black Americans released from prison within the past year explored drug behavior as well as institutional, environmental, and social factors that influence drug use. Findings show participants reentered drug-enticing environments and social networks. Being on parole, drug programs, and social support influenced abating drug use. Drug interventions postincarceration should consider the environment and social networks as leverage points for behavior change. PMID- 28665208 TI - Association between rivaroxaban use and length of hospital stay, treatment costs and early outcomes in patients with pulmonary embolism: a systematic review of real-world studies. AB - BACKGROUND: In the EINSTEIN-Pulmonary Embolism (PE) trial, subjects randomized to rivaroxaban versus enoxaparin bridging to vitamin K antagonist (VKA) therapy experienced a reduced index hospital length of stay (LOS). We sought to conduct a systematic review of real-world studies comparing LOS, costs and early outcomes among patients treated with rivaroxaban or parenterally bridged VKA in routine practice. METHODS: We searched Medline and Scopus from 1 January 2011 to 30 November 2016 to identify observational studies comparing acute PE patients anticoagulated with rivaroxaban or parenterally bridged VKA and reporting data on index hospital LOS, costs and/or early post-PE outcomes. Studies not using appropriate methods for minimizing confounding bias or not published in English were excluded. RESULTS: Five studies met inclusion criteria. Rivaroxaban use was associated with decreased index hospital LOS (range: 1.36-1.70 days) and treatment costs (range: $1818-$2688) during an index stay compared to parenterally bridged warfarin. No differences in early readmission for recurrent thrombosis were noted between anticoagulation strategies. Readmission for major bleeding was rare in both cohorts. Similar reductions in LOS (range: 0.23-4.3 days) and costs (range: $251-$7094) were observed with rivaroxaban in studies restricted to patients deemed low risk for early complications by clinical gestalt or by a clinical- or claims-based risk stratification tool. CONCLUSIONS: Regardless of patient predicted risk of post-PE complications, real-world studies suggest that rivaroxaban is associated with a reduced hospital LOS and costs versus parenterally bridged warfarin, without increasing readmission. PMID- 28665209 TI - Speech-language pathology in paediatric palliative care: A scoping review of role and practice. AB - PURPOSE: Attempts have been made within the literature to clarify the role and scope of speech-language pathologists (SLPs) within paediatric palliative care (PPC). As SLP literature regarding adult/geriatric populations is gaining traction, it is fitting to investigate the role of SLPs in the management of infants and children in end-of-life care. METHOD: Arksey and O'Malley's ( 2005 ) scoping review method was utilised for searching multiple databases. Two database searches were undertaken. The first located literature in which SLP PPC intervention is specifically addressed. The second search utilised internationally recognised SLP scope of practice areas. Manual searching of reference lists was also utilised. RESULT: Themes identified included management of communication, feeding, upper-airway and oral health as well as the role of SLPs within a multidisciplinary PPC team. CONCLUSION: There is acknowledgement that SLPs have a role in PPC. However, there is little information identifying SLP involvement in the diagnosis and management of swallowing, cognition/communication, oral hygiene and upper airway issues. The available literature predominantly relies on limited adult palliative care research and does not address age-specific management approaches across the paediatric life stage. Given an absence of SLP PPC guidelines, further research is warranted to explicitly define SLP scope of practice within this population. PMID- 28665210 TI - Does Depression Screening in Schools Reduce Adolescent Racial/Ethnic Disparities in Accessing Treatment? AB - Although placing mental health services in schools increases access to care, racial/ethnic disparities persist within the scope of school-based mental health services. Universal mental health screening is a potential strategy to increase problem detection and reduce disparities in care provision. However, no study has experimentally tested the effect of universal screening on patterns of service utilization across racial groups and the potential to reduce disparities. Using a cluster randomized design, we compared service linkage patterns among 7th- and 8th-grade Asian American and Latino students (N = 2,494; Mage = 13.65) in schools that either conducted or did not conduct universal depression screening. Multilevel analyses showed that enrollment in a universal screening school, Latino ethnicity, and low academic performance were associated with greater likelihood of referral. However, these factors were not related to caregiver consent or treatment initiation. Screening-triggered referrals were less likely to result in caregiver consent compared to routine referrals. Furthermore, universal screening did not result in a statistically significant reduction in racial/ethnic disparities in treatment referral. Implications for engaging ethnic minority families beyond the point of problem recognition and referral are discussed. PMID- 28665211 TI - Effects of omega-3 fatty acids on the frequency, severity, and duration of migraine attacks: A systematic review and meta-analysis of randomized controlled trials. AB - The present systematic review with meta-analysis of randomized controlled trials (RCTs) aimed to analyze the effectiveness of omega-3 fatty acids on the frequency, severity, and duration of migraine. This systematic review was performed by searching several databases for controlled clinical trials. Of the 13 trials, five, two, and three RCTs met the eligibility criteria to evaluate the efficacy of omega-3 on the frequency, duration, and severity of migraine attacks, respectively. The Jadad scale was used to evaluate the risk of bias analysis. Overall estimates of the intervention effect were obtained from random-effect meta-analysis. The studies' heterogeneity was evaluated using the chi-squared test (chi2) (Cochran's test (Q test)) and I2 Index. Potential sources of heterogeneity among the trials were investigated by meta-regression analyses. The results showed that omega-3 intake had no effect on frequency (WMD = -0.20; 95%CI -0.67, 0.27; P = 0.401, and I2 = 4.6%; P = 0.380) and severity (SMD = -0.59; 95%CI -1.85, 0.66; P = 0.35, and I2 = 88.8%; P = 0.000) of migraine but had a reduction effect on the duration of migraine attacks (WMD = -3.44; 95%CI -5.70, 1.19; P = 0.003, and I2 = 0.0%; P = 0.926). In conclusion, omega-3 intake leads to a significant reduction of approximately 3.44 hours in the duration of migraine. Further randomized controlled trials of high methodological quality with adequate sample sizes are required to confirm the results of the meta analyses. PMID- 28665213 TI - Twenty Years of European Union Support to Gene Therapy and Gene Transfer. AB - For 20 years and throughout its research programmes, the European Union has supported the entire innovation chain for gene transfer and gene therapy. The fruits of this investment are ripening as gene therapy products are reaching the European market and as clinical trials are demonstrating the safety of this approach to treat previously untreatable diseases. PMID- 28665212 TI - ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement. AB - Enzyme replacement is a viable treatment for diseases caused by genetic deficiency of lysosomal enzymes. However, suboptimal access of enzymes to target sites limits this strategy. Polymer nanocarriers (NCs) coated with antibody against intercellular adhesion molecule 1 (ICAM-1), a protein overexpressed on most cells under disease states, enhanced biodistribution and lysosomal delivery of these therapeutics. Whether this can be achieved using more biocompatible ICAM 1-targeting moieties is unknown, since intracellular uptake via this route is sensitive to the receptor epitope being targeted. We examined this using polymer NCs coated with an ICAM-1-targeting peptide derived from the fibrinogen sequence. Scrambled-sequence peptide and anti-ICAM were used as controls. NCs carried acid sphingomyelinase (ASM), used for treatment of type B Niemann-Pick disease, and fluorescence microscopy was employed to examine cellular performance. Peptide coated/enzyme NCs efficiently targeted ICAM-1 (22-fold over non-specific counterparts; Bmax ~180 NCs/cell; t1/2 ~28 min), recognised human and mouse cells (1.2- to 0.7-fold binding vs. antibody/enzyme NCs), were efficiently endocytosed (71% at 1 h chase), and trafficked to lysosomes (30--45% of internalised NCs; 2 h chase). This restored lysosomal levels of sphingomyelin and cholesterol within 5 h chase (~95% reduction over disease levels), similar to antibody-enzyme NCs. This fibrinogen-derived ICAM-1-targeting peptide holds potential for lysosomal enzyme replacement therapy. PMID- 28665214 TI - The evolving role of targeted drugs in the treatment of Hodgkin lymphoma. AB - INTRODUCTION: Hodgkin lymphoma (HL) is a B-cell-derived malignancy mostly affecting young adults. More than 80% of patients are cured after stage-adapted first-line treatment with chemotherapy and/or radiotherapy. About 50% of patients with disease recurrence achieve long-term remission with second-line treatment consisting of high-dose chemotherapy and autologous stem cell transplantation. However, HL treatment is often associated with acute toxicity and in part life threatening late effects. Implementing targeted drugs may reduce toxicity and potentially further optimize efficacy. In recent years, the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) and anti-PD-1 antibodies, nivolumab and pembrolizumab, underwent extensive evaluation in HL. They have exhibited encouraging single agent activity and a favorable toxicity profile in patients with multiple relapses. Therefore, they are currently under investigation in different additional indications. Areas covered: This article gives an overview over clinical trials evaluating targeted drugs either as single agent or as part of combination therapies in HL patients. Expert commentary: A multitude of targeted drugs are investigated in HL. Promising data have particularly emerged from studies with BV and anti-PD-1 antibodies. However, mature data needed for final conclusions are still pending. PMID- 28665215 TI - Neurocognitive profile of HIV-positive adults on combined antiretroviral therapy: A single-centre study in Serbia. AB - The advent of combined antiretroviral therapy (cART) has prolonged the life expectancy of HIV + individuals and decreased the incidence of HIV-associated dementia. However, milder forms of neurocognitive impairment remain common and are often associated with poor daily functioning and lower medication adherence. This paper presents a research aimed at exploring the cognitive status differences between HIV + subjects (N = 39) on cART therapy and a group of demographically comparable healthy subjects (N = 39) in Serbia. The significance of differences between the HIV + group and the healthy control group in performance in six cognitive domains was tested using the multivariate analysis of variance. Results showed a lower performance of the HIV + group in the domains of attention/working memory, and learning. HIV-related clinical variables were not significantly associated with cognitive performance. An older age in HIV + patients was significantly related to a lower performance in all six cognitive domains, as opposed to healthy subjects, implying a synergistic interaction between HIV and aging, resulting in accentuated cognitive difficulties. Our findings suggest that even with the absence of a subjective experience of cognitive deficits and with a good basic control of the illness, a certain degree of cognitive deficit can be observed in the tested group. PMID- 28665216 TI - Lung Interstitial Macrophages: Establishing Identity and Uncovering Heterogeneity. PMID- 28665217 TI - Chronic Obstructive Pulmonary Disease Meta Genome-Wide Association Studies. New Insights into the Genetics of Chronic Obstructive Pulmonary Disease. PMID- 28665219 TI - Unwinding the Collagen Fibrils: Elucidating the Mechanism of Pirfenidone and Nintedanib in Pulmonary Fibrosis. PMID- 28665220 TI - Air Pollution-Who "Nose" What Chronic Exposure Models Will Reveal Next? PMID- 28665221 TI - Reply: Parenchymal Airspace Profiling Has Its Merits and Is a Valuable Addition to Existing Methods for Lung Morphometry. PMID- 28665222 TI - A Critical Comment on a Recent Publication Using Parenchymal Airspace Profiling. PMID- 28665223 TI - Understanding Interstitial Lung Disease: It's in the Mucus. PMID- 28665224 TI - Understanding the Relevance of the Mouse Cigarette Smoke Model of COPD: Peering through the Smoke. PMID- 28665225 TI - Linking Vascular Remodeling and Inflammation in Pulmonary Arterial Hypertension: Is There a Common Root Cause? PMID- 28665226 TI - Is a long leg a risk for hip or knee osteoarthritis? AB - Background and purpose - 7% of the asymptomatic population has leg-length inequality (LLI) greater than 12 mm. It has been proposed that LLI of >5 mm can be associated with an increased risk of osteoarthritis (OA) of the knee and hip. We studied a possible association between LLI and OA of the knee and hip joint. Patients and methods - We followed 193 individuals (97 women, 96 men) for 29 years. The initial mean age of the participants was 43 (34-54) years, and they had no clinical histories or signs of leg symptoms. The initial standing radiographs of their hips were re-examined and measured for LLI and signs of OA. None had any signs of OA. At the follow-up, data on performed hip or knee arthroplasties were obtained. Results - 24 (12%) of the subjects had no discernible leg-length difference, 62 (32%), had LLIs of 1-4 mm, 74 (38%) of 5-8 mm, 21 (11%) of 9-12 mm, and 12 (6%) of over 12 mm. 16 (8%) of the subjects had undergone arthroplasty for primary OA during follow-up, and of those, 8 for both hip and knee OA. 10 individuals had undergone an arthroplasty of the longer leg and only 3 of the shorter leg. In the group of equal leg length, 3 had had an arthroplasty of hip or knee. Interpretation - We noted that hip or knee arthroplasty due to primary OA had been done 3 times more often to the longer leg than to the shorter. PMID- 28665227 TI - Reciprocal within-day associations between incidental affect and exercise: An EMA study. AB - : Previous research suggests that how people feel throughout the course of a day (i.e. incidental affect) is predictive of exercise behaviour. A mostly separate literature suggests that exercise can lead to more positive incidental affect. OBJECTIVE: This study examines the potential reciprocal effects of incidental affect and exercise behaviour within the same day. DESIGN: Fifty-nine low-active (exercise <60 min/week), overweight (BMI: 25.0-39.9) adults (ages 18-65) participated in a six-month print-based exercise promotion programme. MAIN OUTCOME MEASURES: Ecological momentary assessment was used to record self reported exercise sessions in real time and incidental affective valence (feeling good/bad) as assessed by the 11-point Feeling Scale at random times throughout the day. RESULTS: Use of a within-subjects cross-lagged, autoregressive model showed that participants were more likely to exercise on days when they experienced more positive incidental affect earlier in the day (b = .58, SE = .10, p < .01), and participants were more likely to experience more positive incidental affect on days when they had exercised (b = .26, SE = .03, p < .01), with the former association significantly stronger than the latter (t = 23.54, p < .01). CONCLUSION: The findings suggest a positive feedback loop whereby feeling good and exercising are reciprocally influential within the course of a day. PMID- 28665228 TI - Absorption, metabolism and excretion of [14C]omarigliptin, a once-weekly DPP-4 inhibitor, in humans. AB - 1. Omarigliptin (MARIZEV(r)) is a once-weekly DPP-4 inhibitor approved in Japan for the treatment of type 2 diabetes. The objective of this study was to investigate the absorption, metabolism and excretion of omarigliptin in humans. 2. Six healthy subjects received a single oral dose of 25 mg (2.1 MUCi) [14 C]omarigliptin. Blood, plasma, urine and fecal samples were collected at various intervals for up to 20 days post-dose. Radioactivity levels in excreta and plasma/blood samples were determined by accelerator mass spectrometry (AMS). 3. [14 C]Omarigliptin was rapidly absorbed, with peak plasma concentrations observed at 0.5-2 h post-dose. The majority of the radioactivity was recovered in urine (~74.4% of the dose), with less recovered in feces (~3.4%), suggesting the compound was well absorbed. 4. Omarigliptin was the major component in urine (~89% of the urinary radioactivity), indicating renal excretion of the unchanged drug as the primary clearance mechanism. Omarigliptin accounted for almost all the circulating radioactivity in plasma, with no major metabolites detected. 5. The predominantly renal elimination pathway, combined with the fact that omarigliptin is not a substrate of key drug transporters, suggest omarigliptin is unlikely to be subject to pharmacokinetic drug-drug interactions with other commonly prescribed agents. PMID- 28665229 TI - The Importance of Epitope Density in Selecting a Sensitive Positive IHC Control. AB - Clinical Immunohistochemistry (IHC) laboratories face unique challenges in performing accurate and reproducible immunostains. Among these challenges is the use of homemade controls derived from pathological discard samples. Such positive controls have an unknown number of analyte molecules per cell (epitope density). It is unclear how the lack of defined analyte concentrations affects performance of the control. To address this question, we prepared positive IHC controls ( IHControls) for human epidermal growth factor receptor type II (HER-2), estrogen receptor (ER), or progesterone receptor (PR) with well-defined, homogeneous, and reproducible analyte concentrations. Using the IHControls, we examined the effect of analyte concentration on IHC control sensitivity. IHControls and conventional tissue controls were evaluated in a series of simulated primary antibody reagent degradation experiments. The data demonstrate that the ability of a positive IHC control to reveal reagent degradation depends on (1) the analyte concentration in the control and (2) where that concentration falls on the immunostain's analytic response curve. The most sensitive positive IHC controls have analyte concentrations within or close to the immunostain's concentration-dependent response range. Strongly staining positive controls having analyte concentrations on the analytic response curve plateau are less sensitive. These findings emphasize the importance of selecting positive IHC controls that are of intermediate (rather than strong) stain intensity. PMID- 28665230 TI - Documentation of Malaria Parasite ( Plasmodium spp.) Infection and Associated Mortality in a Common Loon (Gavia immer). AB - We report malaria parasite infection ( Plasmodium spp.) and associated mortality in a Common Loon (Gavia immer) found dead on Lake Umbagog in New Hampshire, US. Necropsy findings showed the bird to be in good body condition but with pericardial edema and splenomegaly. Histopathological examination of brain and heart revealed intraendothelial and intrahistiocytic proliferation of Plasmodium merozoites with myocarditis. By PCR, the presence of Plasmodium parasites was confirmed from all tissues screened including spleen, muscle, and kidney. Sequencing of nested-PCR products revealed two different Plasmodium lineages, CATUST05 and PADOM11, indicating a mixed malaria parasite infection. Clinical findings strongly support malaria-induced mortality in a Common Loon. PMID- 28665231 TI - Erythropoietin in umbilical cord blood transplantation: defining the role and implications. PMID- 28665232 TI - Integrating novel drugs to chemoimmunotherapy in diffuse large B-cell lymphoma. AB - INTRODUCTION: Diffuse Large B-cell Lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), with an incidence in Europe of 3.8/100.000/year. A multi-drugs chemoimmunotherapy regimen, containing rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP) administrated every 21 days, is the standard therapy for DLBCL patients. The discovery of several biological features of DLBCL has encouraged the introduction of novel drugs in the treatment. Areas covered: In this article, the use of standard therapies will be reviewed and will be investigated adoption of novel drugs such as Bortezomib, Bruton's tyrosine kinase, IMiDs, Venetoclax, mTOR inhibitors and other biological agents. Expert commentary: A better knowledge of the biology of DLBCL is mandatory to tailor treatment and to ameliorate the poor prognosis of DLBCL. The addition of novel drugs to standard RCHOP should represent a modern approach in the treatment of DLBCL. Ibrutinib and lenalidomide showed important results in DLBCL and the integration of these drugs in first line treatment is under investigation. Despite encouraging results using novel drugs in the setting of relapsed/refractory DLBCL, the rate of failures still remains at 40%; for these reason, continued participation in clinical trials should be encouraged. PMID- 28665233 TI - Decellularization of Whole Human Liver Grafts Using Controlled Perfusion for Transplantable Organ Bioscaffolds. AB - Liver transplantation is the only effective treatment for end-stage liver disease, but absolute donor shortage remains a limiting factor. Recent advances in tissue engineering focus on generation of native extracellular matrix (ECM) by decellularized complete livers in animal models. Although proof of concept has been reported for human livers, this study aims to perform whole liver decellularization in a clinically relevant series using controlled machine perfusion. In this study, we describe a mild nondestructive decellularization protocol, effective in 11 discarded human whole liver grafts to generate constructs that reliably maintain hepatic architecture and ECM components using machine perfusion, while completely removing cellular DNA and RNA. The decellularization process preserved the ultrastructural ECM components confirmed by histology, electron microscopy, and proteomic analysis. Anatomical characteristics of the native microvascular network and biliary drainage of the liver were confirmed by contrast computed tomography scanning. Decellularized vascular matrix remained suitable for normal suturing and no major histocompatibility complex molecules were detected, suggesting absence of allo reactivity when used for transplantation. After extensive washing, decellularized scaffolds were nontoxic for cells after reseeding human mesenchymal stromal or umbilical vein endothelial endothelium cells. Indeed, evidence of effective recellularization of the vascular lining was obtained. In conclusion, we established an effective method to generate clinically applicable liver scaffolds from human discarded whole liver grafts and show proof of concept that reseeding of normal human cells in the scaffold is feasible. This supports new opportunities for bioengineering of transplantable grafts in the future. PMID- 28665234 TI - Magnesium Levels and Neurologic Outcomes in Patients Undergoing Therapeutic Hypothermia After Cardiac Arrest. AB - Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest by mitigating cerebral reperfusion injury. Serum magnesium (Mg) inhibits glutamate release, restores blood-brain barrier integrity, and decreases brain edema. The neuroprotective role of Mg in cardiac arrest patients undergoing TH is not well established. We analyzed 438 survivors of cardiac arrest who completed a TH protocol from 2008 through 2016. Multivariate and receiver operating characteristic (ROC) analyses examined the association between Mg supplementation and Mg levels before, during, and after TH with neurologic outcomes. Participants were 65.5 +/- 15.9 years old, 47% received bystander cardiopulmonary resuscitation, and time to target temperature was 286 +/- 196 minutes. Patients with favorable neurologic outcomes had lower Mg levels at presentation (2.1 mg/dL vs. 2.2 mg/dL, p = 0.010; OR [95% CI] = 0.531 [0.329-0.857]) and more frequently received Mg supplementation (39% vs. 25%, p = 0.009; OR [95% CI] = 1.936 [1.171 3.202]). Mg levels on presentation inversely correlated with favorable neurologic outcomes (r = -0.134, p = 0.036). Stratification of patients based on Mg levels demonstrated trends toward worse neurological outcomes at the extremes of the range, though sample sizes were small and the point estimate was not significant. ROC analysis showed no significant Mg level determining favorable outcomes. Mg levels at presentation inversely correlated with neurologic outcomes in cardiac arrest survivors undergoing TH. Intracellular shift and increased renal excretion of Mg may be responsible for the low Mg levels seen in some patients undergoing TH. Whether Mg supplementation could potentiate the beneficial effects of TH remains unclear and deserves further investigation. PMID- 28665235 TI - Facial feature tracking: a psychophysiological measure to assess exercise intensity? AB - The primary aim of this study was to determine whether facial feature tracking reliably measures changes in facial movement across varying exercise intensities. Fifteen cyclists completed three, incremental intensity, cycling trials to exhaustion while their faces were recorded with video cameras. Facial feature tracking was found to be a moderately reliable measure of facial movement during incremental intensity cycling (intra-class correlation coefficient = 0.65-0.68). Facial movement (whole face (WF), upper face (UF), lower face (LF) and head movement (HM)) increased with exercise intensity, from lactate threshold one (LT1) until attainment of maximal aerobic power (MAP) (WF 3464 +/- 3364mm, P < 0.005; UF 1961 +/- 1779mm, P = 0.002; LF 1608 +/- 1404mm, P = 0.002; HM 849 +/- 642mm, P < 0.001). UF movement was greater than LF movement at all exercise intensities (UF minus LF at: LT1, 1048 +/- 383mm; LT2, 1208 +/- 611mm; MAP, 1401 +/- 712mm; P < 0.001). Significant medium to large non-linear relationships were found between facial movement and power output (r2 = 0.24-0.31), HR (r2 = 0.26 0.33), [La-] (r2 = 0.33-0.44) and RPE (r2 = 0.38-0.45). The findings demonstrate the potential utility of facial feature tracking as a non-invasive, psychophysiological measure to potentially assess exercise intensity. PMID- 28665236 TI - Formation of Adipose Stromal Vascular Fraction Cell-Laden Spheroids Using a Three Dimensional Bioprinter and Superhydrophobic Surfaces. AB - The therapeutic infusion of adipose-derived stromal vascular fraction (SVF) cells for the treatment of multiple diseases, has progressed to numerous human clinical trials; however, the often poor retention of the cells following implantation remains a common drawback of direct cell injection. One solution to cellular retention at the injection site has been the use of biogels to encapsulate cells within a microenvironment before and upon implantation. The current study utilized three-dimensional bioprinting technology to evaluate the ability to form SVF cell-laden spheroids with collagen I as a gel-forming biomatrix. A superhydrophobic surface was created to maintain the bioprinted structures in a spheroid shape. A hydrophilic disc was printed onto the hydrophobic surface to immobilize the spheroids during the gelation process. Conditions for the automated rapid formation of SVF cell-laden spheroids were explored, including time/pressure relationships for spheroid extrusion during bioprinting. The formed spheroids maintain SVF viability in both static culture and dynamic spinner culture. Spheroids also undergo a time-dependent contraction with the retention of angiogenic sprout phenotype over the 14-day culture period. The use of a biphilic surface exhibiting both superhydrophobicity to maintain the spheroid shape and a hydrophilicity to immobilize the spheroid during gel formation produces SVF cell-laden spheroids that can be immediately transplanted for therapeutic applications. PMID- 28665237 TI - Genital angiokeratomas of Fordyce 595-nm variable-pulse pulsed dye laser treatment. AB - BACKGROUND: Angiokeratoma of Fordyce (AF) represents dark red or blue-black papules with a scaly surface located on scrotum, labia majora, and penis. Though usually asymptomatic, bleeding after mechanical trauma and sexual intercourse may occur. AF should be differentiated from malignant melanoma, angiosarcoma, and other pigmented lesions. The treatment, usually asked from patients as the result of anxiety and social embarrassment, should be performed in a non-aggressive manner. OBJECTIVES: To determine the safety and effectiveness of 595-nm variable pulse pulsed dye laser (VPPDL) with a Dynamic Cooling Device (DCD) in the treatment of AF. METHODS: Twenty-four patients (22 men and two women) aged 40.88 +/- 12.48 years with AF were included in the retrospective study. Lesions located on scrotum, labia majora, and penis were treated with 595-nm VPPDL in the intervals of one to three months. Variable spot, fluence, and pulse-width parameters were used with and/or without DCD skin cooling. RESULTS: AF were successfully removed in all patients in one to seven (mean +/- SD = 3.38 +/- 2.16) treatment sessions with no permanent side effects or complications such as dyspigmentations or scarring. Recidives were observed in four patients after 0.5 1 year intervals. CONCLUSIONS: 595-nm VPPDL with DCD represents an efficient and safe method for the removal of multiple lesions of AF in genital localization. PMID- 28665238 TI - Abstracts of Presentations at the 2017 Potomac Division Meeting. PMID- 28665239 TI - Abstracts of Presentations at the 56th Annual Meeting of the APS Caribbean Division. PMID- 28665240 TI - Editorial. The challenges of implementing evidence-based practices in pediatric neurosurgery. PMID- 28665241 TI - Shunt-dependent hydrocephalus: management style among members of the American Society of Pediatric Neurosurgeons. AB - OBJECTIVE The authors conducted a survey to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among members of the American Society of Pediatric Neurosurgeons (ASPN). METHODS Surveys were sent to all 204 active ASPN members in September 2014. One hundred thirty responses were received, representing a 64% response rate. Respondents were asked 13 multiple-choice and free-response questions regarding 4 fundamental problems encountered in shunted-hydrocephalus management: shunt malfunction, chronic cerebrospinal fluid (CSF) overdrainage, chronic headaches, and slit ventricle syndrome (SVS). RESULTS Respondents agreed that shunt malfunction occurs most often as the result of ventricular catheter obstruction. Despite contrary evidence in the literature, most respondents (66%) also believed that choroid plexus is the tissue most often found in obstructed proximal catheters. However, free-text responses revealed that the respondents' understanding of the underlying pathophysiology of shunt obstruction was highly variable and included growth, migration, or adherence of choroid plexus, CSF debris, catheter position, inflammatory processes, and CSF overdrainage. Most respondents considered chronic CSF overdrainage to be a rare complication of shunting in their practice and reported wide variation in treatment protocols. Moreover, despite a lack of evidence in the literature, most respondents attributed chronic headaches in shunt patients to medical reasons (for example, migraines, tension). Accordingly, most respondents managed headaches with reassurance and/or referral to pain clinics. Lastly, there were variable opinions on the etiology of slit ventricle syndrome (SVS), which included early shunting, chronic overdrainage, and/or loss of brain compliance. Beyond shunt revision, respondents reported divergent SVS treatment preferences. CONCLUSIONS The survey shows that there is wide variability in the understanding and management of shunt-dependent hydrocephalus and its complications. Such discrepancies appear to be derived partly from inconsistent familiarity with existing literature but especially from a paucity of high-quality publications. PMID- 28665242 TI - Changes in use of cervical spine magnetic resonance imaging for pediatric patients with nonaccidental trauma. AB - OBJECTIVE Past studies have suggested correlations between abusive head trauma and concurrent cervical spine (c-spine) injury. Accordingly, c-spine MRI (cMRI) has been increasingly used in radiographic assessments. This study aimed to determine trends in cMRI use and treatment, and outcomes related to c-spine injury in children with nonaccidental trauma (NAT). METHODS A total of 503 patients with NAT who were treated between 2009 and 2014 at a single pediatric health care system were identified from a prospectively maintained database. Additional data on selected clinical events were retrospectively collected from electronic medical records. In 2012, a clinical pathway on cMRI usage for patients with NAT was implemented. The present study compared cMRI use and clinical outcomes between the prepathway (2009-2011) and postpathway (2012-2014) periods. RESULTS There were 249 patients in the prepathway and 254 in the postpathway groups. Incidences of cranial injury and Injury Severity Scores were not significantly different between the 2 groups. More patients underwent cMRI in the years after clinical pathway implementation than before (2.8% vs 33.1%, p < 0.0001). There was also a significant increase in cervical collar usage from 16.5% to 27.6% (p = 0.004), and more patients were discharged home with cervical collar immobilization. Surgical stabilization occurred in a single case in the postpathway group. CONCLUSIONS Heightened awareness of potential c-spine injury in this population increased the use of cMRI and cervical collar immobilization over a 6-year period. However, severe c-spine injury remains rare, and increased use of cMRI might not affect outcomes markedly. PMID- 28665243 TI - Editorial. Screening for spine injury in abusive head trauma. PMID- 28665244 TI - Symptomatic spinal extradural arachnoid cyst with cord compression in a family: case report. AB - A family with familial spinal extradural arachnoid cyst is presented. A 14-year old boy had an extensive T-8 through L-2 dorsal extradural arachnoid cyst with spinal cord compression and slowly progressive myelopathy. His mother had presented 4 years earlier with acute excruciating back pain due to the combination of a lumbar extradural arachnoid cyst at L2-4 and an extruded disc at L3-4. The literature is reviewed in light of the pathogenesis, imaging, and surgical technique required for treatment. PMID- 28665245 TI - Prophylactic use of intraoperative vancomycin powder and postoperative infection: an analysis of microbiological patterns in 1200 consecutive surgical cases. AB - OBJECTIVE Wound infections following spinal surgery for deformity place a high toll on patients, providers, and the health care system. The prophylactic application of intraoperative vancomycin powder has been shown to lower the infection risk after thoracolumbar decompression and fusion for deformity correction. The purpose of this study was to assess the microbiological patterns of postoperative surgical site infections (SSIs) after prophylactic use of vancomycin powder in adult patients undergoing spinal deformity surgery. METHODS All cases involving adult patients who underwent spinal deformity reconstruction at Duke University Medical Center between 2011 and 2013 with a minimum of 3 months of clinical follow-up were retrospectively reviewed. In all cases included in the study, crystalline vancomycin powder was applied to the surgical bed for infection prophylaxis. Baseline characteristics, operative details, rates of wound infection, and microbiological data for each case were gathered by direct medical record review. RESULTS A total of 1200 consecutive spine operations were performed for deformity between 2011 and 2013. Review of the associated records demonstrated 34 cases of SSI, yielding an SSI rate of 2.83%. The patients' mean age (+/- SD) was 62.08 +/- 14.76 years. The patients' mean body mass index was 30.86 +/- 7.15 kg/m2, and 29.41% had a history of diabetes. The average dose of vancomycin powder was 1.41 +/- 2.77 g (range 1-7 g). Subfascial drains were placed in 88% of patients. All SSIs occurred within 30 days of surgery, with deep wound infections accounting for 50%. In 74% of the SSIs cultures were positive, with about half the organisms being gram negative, such as Citrobacter freundii, Proteus mirabilis, Morganella morgani, and Pseudomonas aeruginosa. There were no adverse clinical outcomes related to the local application of vancomycin. CONCLUSIONS Our study suggests that in the setting of prophylactic vancomycin powder use, the preponderance of SSIs are caused by gram-negative organisms or are polymicrobial. Further randomized control trials of prophylactic adjunctive measures are warranted to help guide the choice of empirical antibiotic therapy while awaiting culture data. PMID- 28665246 TI - Intraosseous hemangioblastoma of the cervical spine: case report. AB - A 69-year-old woman presented with bilateral upper-extremity radiculopathy and neck pain after a mechanical fall. Admission CT and MRI of the cervical spine demonstrated a pathological C-4 fracture. Subsequent malignancy workup was negative. A CT-guided biopsy of the lesion showed intraosseous hemangioblastoma. Hemangioblastoma is a highly vascular, slow-growing tumor of the CNS; intraosseous location of this tumor is extremely rare. The authors review the diversity of its presentation and the treatment techniques of this rare tumor in an extremely rare location. PMID- 28665247 TI - The impact of vestibular status prior to cochlear implantation on postural control: A multiple case study. AB - OBJECTIVE: The goal of the present study was to investigate the impact of unilateral cochlear implantation on postural control in relation to the vestibular status before CI surgery. METHODS: We recruited 17 participants (four CI candidates and 13 hearing controls) and performed complete vestibular evaluation (cVEMP, oVEMP, vHIT) and postural evaluation using a force platform, prior and following unilateral cochlear implant surgery. RESULTS: Our study suggests that an increase in postural sway following cochlear implant was present only for the participants that received the implant in the ear with the better vestibular function. cVEMP and oVEMP measures in the implanted ear prior to unilateral cochlear implantation may help to predict postural control performance following surgery. DISCUSSION: A thorough evaluation of the vestibular function, as described in the present study, could not only be helpful to make a more accurate prognosis of the risks of fall following cochlear implantation, but also to provide proper vestibular rehabilitation for at-risk patients. PMID- 28665248 TI - Wavelength-specific lighted suction instrument for 5-aminolevulinic acid fluorescence-guided resection of deep-seated malignant glioma: technical note. AB - Surgery guided by 5-aminolevulinic acid (ALA) fluorescence has become a valuable adjunct in the resection of malignant intracranial gliomas. Furthermore, the fluorescence intensity of biopsied areas of a resection cavity correlates with histological identification of tumor cells. However, in the case of lesions deep within a resection cavity, light penetration may be suboptimal, resulting in less excitation of 5-ALA metabolites, leading to decreased fluorescence emission. To address this obstacle, the authors report on the use of a 400-nm wavelength fiber optic lighted suction instrument that can be used both during resection of a tumor and to provide direct light to deeper areas of a resection cavity. In the presented case, this wavelength-specific lighted suction instrument improved the fluorescence intensity of patches of malignant tissue within the resection cavity. This technique may further improve the utility of 5-ALA in identifying tumor-infiltrated tissue for deep-seated lesions. Additionally, this tool may have implications for scoring systems that correlate 5-ALA fluorescence intensity with histological identification of malignant cells. PMID- 28665249 TI - Improved operative efficiency using a real-time MRI-guided stereotactic platform for laser amygdalohippocampotomy. AB - OBJECTIVE MR-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive method for thermal destruction of benign or malignant tissue that has been used for selective amygdalohippocampal ablation for the treatment of temporal lobe epilepsy. The authors report their initial experience adopting a real-time MRI-guided stereotactic platform that allows for completion of the entire procedure in the MRI suite. METHODS Between October 2014 and May 2016, 17 patients with mesial temporal sclerosis were selected by a multidisciplinary epilepsy board to undergo a selective amygdalohippocampal ablation for temporal lobe epilepsy using MRgLITT. The first 9 patients underwent standard laser ablation in 2 phases (operating room [OR] and MRI suite), whereas the next 8 patients underwent laser ablation entirely in the MRI suite with the ClearPoint platform. A checklist specific to the real-time MRI-guided laser amydalohippocampal ablation was developed and used for each case. For both cohorts, clinical and operative information, including average case times and accuracy data, was collected and analyzed. RESULTS There was a learning curve associated with using this real-time MRI-guided system. However, operative times decreased in a linear fashion, as did total anesthesia time. In fact, the total mean patient procedure time was less in the MRI cohort (362.8 +/- 86.6 minutes) than in the OR cohort (456.9 +/- 80.7 minutes). The mean anesthesia time was significantly shorter in the MRI cohort (327.2 +/- 79.9 minutes) than in the OR cohort (435.8 +/- 78.4 minutes, p = 0.02). CONCLUSIONS The real-time MRI platform for MRgLITT can be adopted in an expedient manner. Completion of MRgLITT entirely in the MRI suite may lead to significant advantages in procedural times. PMID- 28665250 TI - Prognostic value of changes in brain tissue oxygen pressure before and after decompressive craniectomy following severe traumatic brain injury. AB - OBJECTIVE In severe traumatic brain injury (TBI), the effects of decompressive craniectomy (DC) on brain tissue oxygen pressure (PbtO2) and outcome are unclear. The authors aimed to investigate whether changes in PbtO2 after DC could be used as an independent prognostic factor. METHODS The authors conducted a retrospective, observational study at 2 university hospital ICUs. The study included 42 patients who were admitted with isolated moderate or severe TBI and underwent intracranial pressure (ICP) and PbtO2 monitoring before and after DC. The indication for DC was an ICP higher than 25 mm Hg refractory to first-tier medical treatment. Patients who underwent primary DC for mass lesion evacuation were excluded. However, patients were included who had undergone previous surgery as long as it was not a craniectomy. ICP/PbtO2 monitoring probes were located in an apparently normal area of the most damaged hemisphere based on cranial CT scanning findings. PbtO2 values were routinely recorded hourly before and after DC, but for comparisons the authors used the first PbtO2 value on ICU admission and the number of hours with PbtO2 < 15 mm Hg before DC, as well as the mean PbtO2 every 6 hours during 24 hours pre- and post-DC. The end point of the study was the 6-month Glasgow Outcome Scale; a score of 4 or 5 was considered a favorable outcome, whereas a score of 1-3 was considered an unfavorable outcome. RESULTS Of the 42 patients included, 26 underwent unilateral DC and 16 bilateral DC. The median Glasgow Coma Scale score at the scene of the accident or at the initial hospital before the patient was transferred to one of the 2 ICUs was 7 (interquartile range [IQR] 4-14). The median time from admission to DC was 49 hours (IQR 7-301 hours). Before DC, the median ICP and PbtO2 at 6 hours were 35 mm Hg (IQR 28-51 mm Hg) and 11.4 mm Hg (IQR 3-26 mm Hg), respectively. In patients with favorable outcome, PbtO2 at ICU admission was higher and the percentage of time that pre-DC PbtO2 was < 15 mm Hg was lower (19 +/- 4.5 mm Hg and 18.25% +/- 21.9%, respectively; n = 28) than in those with unfavorable outcome (12.8 +/- 5.2 mm Hg [p < 0.001] and 59.58% +/- 38.8% [p < 0.001], respectively; n = 14). There were no significant differences in outcomes according to the mean PbtO2 values only during the last 12 hours before DC, the hours of refractory intracranial hypertension, the timing of DC from admission, or the presence/absence of previous surgery. In contrast, there were significant differences in PbtO2 values during the 12- to 24-hour period before DC. In most patients, PbtO2 increased during the 24 hours after DC but these changes were more pronounced in patients with favorable outcome than in those with unfavorable outcome (28.6 +/- 8.5 mm Hg vs 17.2 +/- 5.9 mm Hg, p < 0.0001; respectively). The areas under the curve for the mean PbtO2 values at 12 and 24 hours after DC were 0.878 (95% CI 0.75-1, p < 0.0001) and 0.865 (95% CI 0.73-1, p < 0.0001), respectively. CONCLUSIONS The authors' findings suggest that changes in PbtO2 before and after DC, measured with probes in healthy-appearing areas of the most damaged hemisphere, have independent prognostic value for the 6-month outcome in TBI patients. PMID- 28665251 TI - Stereotactic radiosurgery for medically refractory multiple sclerosis-related tremor. AB - OBJECTIVE Multiple sclerosis (MS) is a neurodegenerative disease that can lead to severe intention tremor in some patients. In several case reports, conventional radiotherapy has been reported to possibly exacerbate MS. Radiosurgery dramatically limits normal tissue irradiation to potentially avoid such a problem. Gamma Knife thalamotomy (GKT) has been established as a minimally invasive technique that is effective in treating essential tremor and Parkinson's disease-related tremor. The goal in this study was to analyze the outcomes of GKT in patients suffering from medically refractory MS-related tremor. METHODS The authors retrospectively studied the outcomes of 15 patients (mean age 46.5 years) who had undergone GKT over a 15-year period (1998-2012). Fourteen patients underwent GKT at a median maximum dose of 140 Gy (range 130-150 Gy) using a single 4-mm isocenter. One patient underwent GKT at a dose of 140 Gy delivered via two 4-mm isocenters (3 mm apart). The posteroinferior region of the nucleus ventralis intermedius (VIM) was the target for all GKTs. The Fahn-Tolosa-Marin clinical tremor rating scale was used to evaluate tremor, handwriting, drawing, and drinking. The median time to the last follow-up was 39 months. RESULTS After GKT, 13 patients experienced tremor improvement on the side contralateral to surgery. Four patients noted tremor arrest at a median of 4.5 months post-GKT. Seven patients had excellent tremor improvement and 6 had good tremor improvement. Four patients noted excellent functional improvement, 8 noted good functional improvement, and 1 noted satisfactory functional improvement. Three patients experienced diminished tremor relief at a median of 18 months after radiosurgery. Two patients experienced temporary adverse radiation effects. Another patient developed a large thalamic cyst 60 months after GKT, which was successfully managed with Ommaya reservoir placement. CONCLUSIONS Gamma Knife thalamotomy was found to be a minimally invasive and beneficial procedure for medically refractory MS tremor. PMID- 28665252 TI - Deep brain stimulation for Parkinson's disease: meta-analysis of results of randomized trials at varying lengths of follow-up. AB - OBJECTIVE Deep brain stimulation (DBS) is effective in the management of patients with advanced Parkinson's disease (PD). While both the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are accepted targets, their relative efficacy in randomized controlled trials (RCTs) has not been established beyond 12 months. The objective of this study was to conduct a meta-analysis of RCTs to compare outcomes among adults with PD undergoing DBS of GPi or STN at various time points, including 36 months of follow-up. METHODS The MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases were searched. Registries for clinical trials, selected conference proceedings, and the table of contents for selected journals were also searched. Screens were conducted independently and in duplicate. Among the 623 studies initially identified (615 through database search, 7 through manual review of bibliographies, and 1 through a repeat screen of literature prior to submission), 19 underwent full-text review; 13 of these were included in the quantitative meta-analysis. Data were extracted independently and in duplicate. The Cochrane Collaboration tool was used to assess the risk of bias. The GRADE evidence profile tool was used to assess the quality of the evidence. Motor scores, medication dosage reduction, activities of daily living, depression, dyskinesias, and adverse events were compared. The influence of disease duration (a priori) and the proportion of male patients within a study (post hoc) were explored as potential subgroups. RESULTS Thirteen studies (6 original cohorts) were identified. No difference in motor scores or activities of daily living was identified at 36 months. Medications were significantly reduced with STN stimulation (5 studies, weighted mean difference [WMD] -365.46, 95% CI -599.48 to -131.44, p = 0.002). Beck Depression Inventory scores were significantly better with GPi stimulation (3 studies; WMD 2.53, 95% CI 0.99-4.06 p = 0.001). The motor benefits of GPi and STN DBS for PD are similar. CONCLUSIONS The motor benefits achieved with GPi and STN DBS for PD are similar. DBS of STN allows for a greater reduction of medication, but not as significant an advantage as DBS of GPi with respect to mood. This difference is sustained at 36 months. Further long-term studies are necessary. PMID- 28665253 TI - The benefit of radiosurgery for ARUBA-eligible arteriovenous malformations: a practical analysis over an appropriate follow-up period. AB - OBJECTIVE The authors of this study found that, given the latency period required for arteriovenous malformation (AVM) obliteration after stereotactic radiosurgery (SRS), a study with limited follow-up cannot assess the benefit of SRS for unruptured AVMs. METHODS The authors reviewed their institutional experience with "ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) eligible" AVMs treated with SRS between 1987 and 2016, with the primary outcome defined as stroke (ischemic or hemorrhagic) or death (AVM related or AVM unrelated). Patients with at least 3 years of follow-up in addition to those who experienced stroke or died during the latency period were included. Secondary outcome measures included obliteration rates, patients with new seizure disorders, and those with new focal deficits without stroke. RESULTS Of 233 patients included in this study, 32 had a stroke or died after SRS over the mean 8.4-year follow-up (14%). Utilizing the 10% stroke or death rate at a mean 2.8 year follow-up for untreated AVMs in ARUBA, the rate in the authors' study is significantly lower than that anticipated at the 8.4-year follow-up for an untreated cohort (14% vs 30%, p = 0.0003). Notwithstanding obliteration, in this study, annualized rates of hemorrhage and stroke or death after 3 years following SRS were 0.4% and 0.8%, respectively. The overall obliteration rate was 72%; new seizure disorders, temporary new focal deficits without stroke, and permanent new focal deficits without stroke occurred in 2% of patients each. CONCLUSIONS After a sensible follow-up period exceeding the latency period, there is a lower rate of stroke/death for patients with treated, unruptured AVMs with SRS than for patients with untreated AVMs. PMID- 28665254 TI - Alcohol Habits and Health Care Use in Patients with Psychiatric Disorders. AB - OBJECTIVE: It is common for persons with psychiatric disorders to also have alcohol problems. Studies in the general population as well as in clinical samples have found hazardous or harmful alcohol habits to be particularly prevalent in the presence of psychiatric disorders. This study sought to explore the relationships between drinking habits and health care utilization (psychiatric as well as general medical) in persons seeking psychiatric treatment and to investigate the associations among age, sex, and type or number of diagnoses and health care use and costs. For the planning of targeted interventions, we also sought to identify subgroups with a high prevalence of hazardous drinking habits. METHODS: From a psychiatric clinic for affective disorders at a university hospital in Sweden, patients who had been screened for hazardous drinking (N = 609) were selected. Patients with primary psychosis or substance use disorder receive treatment at other clinics and did not participate. Medical records data were grouped and compared. The International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) was used for diagnoses and the Alcohol Use Disorders Identification Test for screening. Patients were grouped by drinking habits and sex, age, and diagnosis group, and their psychiatric as well as general medical health care use was compared. RESULTS: Abstainers used psychiatric care more than all other drinking groups (p < .001). Psychiatric health care costs were higher in abstainers and low-risk drinkers (1.64 to 1). No differences in general medical care could be identified between drinking groups. Specific subgroups with higher rates of hazardous drinking could not be identified (44% of all males and 34% of all females reported such habits). Inconclusive results from previous research are most likely due to different methods used to classify drinking problems. CONCLUSIONS: Abstainers and low-risk drinkers used psychiatric health care to a higher cost than the other drinking groups. Possible explanations are discussed from a clinical and scientific perspective. This study clarifies the need for uniform measures when classifying alcohol use in studies of relationships between alcohol use and health care use. There is also a need to separate former drinkers from abstainers in future studies. PMID- 28665255 TI - Hypothermia Identifies Dynamin as a Potential Therapeutic Target in Experimental Stroke. AB - Apoptosis is a cell death pathway that is activated in ischemic stroke. The interaction between Fas and its ligand (FasL) initiates a complex pattern of intracellular events involving the recruitment of specific adaptor proteins and the development of apoptosis. We recently reported that dynamin is increased after experimental stroke, and its inhibition improves neurological outcome. Dynamin has been shown to transport Fas from the endoplasmic reticulum to the cell surface where it can be bound by its ligand, FasL. Hypothermia has been shown to improve outcome in numerous stroke models, and this protection is associated with reduced apoptosis and Fas expression. To explore the contribution of dynamin to hypothermic neuroprotection, we subjected mice to distal middle cerebral artery occlusion (dMCAO) and applied one of two cooling paradigms: one where cooling began at the onset of dMCAO (early hypothermia) and another where cooling began 1 hour later (delayed hypothermia), compared with normothermia (Norm). Both cooling paradigms reduced numbers of apoptotic cells, as well as Fas and dynamin compared with Norm. Fas and dynamin were co-expressed in neurons. Neuronal cultures were exposed to oxygen glucose deprivation. Hypothermia decreased dynamin as well as surface expression of Fas, and this correlated to reduced cell death. The results of this study suggest that dynamin may participate in the Fas-mediated apoptotic pathway, and its reduction may be linked to hypothermic neuroprotection. PMID- 28665256 TI - Strategies new graduate registered nurses require to care and advocate for themselves: A literature review. AB - BACKGROUND: New graduate registered nurses (NGRNs) are confronted with a complex, demanding and resource-constrained environment where gaining acceptance into the workplace culture may be difficult. Existing evidence suggests that preparing undergraduate nursing students for this reality can assist with adjustment. OBJECTIVES: To identify the strategies that NGRNs require to care and advocate for themselves during their first year of practice. METHODS: A search of the literature published between 2001 and 2016 was undertaken. Individual articles were synthesized narratively and the results entered to a summary table. RESULTS: A total of 274 articles were considered relevant to this narrative review. This paper synthesized the narrative of 80 articles. Synthesis revealed 22 resilience factors and 33 issues. Eight strategies with potential to assist NGRNs to care and advocate for themselves were identified. All of them are socioemotional in nature. CONCLUSIONS: This review of the literature provides a valuable resource that can be used to prepare nursing students for the workplace culture during their first year as a registered nurse. Scenarios can be developed for educational activities such as simulation, role play, discussion and self reflection. Further development through research is recommended. PMID- 28665257 TI - Morphological and Molecular Assessment of Pentastomes from Gulls in Portugal. AB - During 2016, 153 gulls, including 64 Larus fuscus and 89 Larus michahellis, were found crippled in south Portugal. They died in Wildlife Rehabilitation and Investigation Center-RIAS and were necropsied. Reighardia sternae infected 2 (3%, n = 64) L. fuscus and 4 (4%, n = 89) L. michahellis. Molecular analysis confirmed the morphological identification on the basis of total body length, maximum body width, length of anterior and posterior hooks, total length of oral apparatus, and other features of oral apparatus of R. sternae. Both sequenced individuals in this study displayed 100% sequence identity to R. sternae individuals obtained previously from Larus ridibundus in Spain and to Reighardia sp. from Larus belcheri in Peru. Reighardia sternae is reported here for the first time in L. michahellis and for the first time from Portugal. PMID- 28665258 TI - Morphology, Molecular Characteristics, and Demonstration of a Definitive Host for Sarcocystis rommeli from Cattle (Bos taurus) in China. AB - Sarcocysts of Sarcocystis rommeli were found for the first time in 6 of 34 (17.6%) cattle (Bos taurus) in China. With light microscopy, sarcocysts of S. rommeli were up to 1,130 MUm long, with a striated, 4-8-MUm-thick cyst wall. Using transmission electron microscopy, the villar protrusions (vp) were 4.7-5.2 * 0.2-0.3 MUm, and 0.3-0.5 MUm apart from each other. The vp contained microtubules extending from the top of the vp to the middle of the ground substance layer (gsl). A BLAST search of the near full-length 18S rRNA and partial mitochondrial cox1 sequences of S. rommeli revealed 98.7% identity and 99.2% identity with sequences of Sarcocystis bovini in GenBank, respectively. Two domestic cats (Felis catus) fed sarcocysts of S. rommeli shed oocysts/sporocysts in their feces with a prepatent period of 14 to 15 days; the partial mitochondrial cox1 sequences of these oocysts/sporocysts shared the high identities, that is, 99.4% and 99.5%, with cox1 sequences of S. rommeli sarcocysts and S. bovini sarcocysts, respectively. This is the first demonstration of a definitive host for S. rommeli. PMID- 28665261 TI - The onset and progression of alcohol use disorders: A qualitative study from Goa, India. AB - Quantitative evidence about the burden of alcohol use disorders (AUDs) needs to be complemented with a nuanced qualitative understanding of explanatory models to help supplement public health strategies that are too often steeped uncritically in biomedical models. The aim of this study was to identify the role of various factors in the onset and persistence of AUD and recovery from AUD. This was a qualitative study nested in a population cohort from Goa, India. In-depth interviews of men with incident, recovered, and persistent AUD covered topics such as changes in drinking habits over time, perceptions and experiences about starting/stopping drinking, and so on. Data were analyzed using thematic analysis. Reasons to begin drinking included social drinking, functional use of alcohol, stress, and boredom. Progression to problematic drinking patterns was characterized by drinking alone, alternating between abstinent and heavy drinking periods, and drinking based on the availability of finances. Some enablers to reduce/stop drinking included consequences of drinking lifestyle and personal resolve; some barriers included availability of alcohol at social events and stress. Some reasons for persisting heavy use of alcohol included lack of family support, physical withdrawal symptoms, peer pressure, stress, and easy availability. This article offers a strong conceptualization and nuanced understanding of AUD across a spectrum of developmental courses. This adds to the limited literature on explanatory models of AUD in India and identifies potential targets for prevention and treatment strategies for AUD in low- and middle-income country settings. PMID- 28665260 TI - Weight Changes and Metabolic Outcomes in Calorie-Restricted Obese Mice Fed High Fat Diets Containing Corn or Flaxseed Oil: Physiological Role of Sugar Replacement with Polyphenol-Rich Grape. AB - OBJECTIVE: Because diet components are important during dieting in obesity treatment, we examined possible beneficial effects of substituting corn oil and sugar with flaxseed oil and grape in calorie-restricted high-fat diets on weight changes as well as improvement in some metabolic markers and related gene expression. METHODS: Seventy-five C57BL/6J male mice were given free access to a high-fat (36% of energy from fat) diet containing corn oil plus sugar (CO + S). After 11 weeks, 15 mice were sacrificed and another 60 were divided among 4 high fat diet groups with 30% calorie restriction (CR) for the next 12 weeks. The diets contained corn oil (CO) or flaxseed oil (FO) with sugar (S) or grape (G). RESULTS: Despite CR, a weight loss trend was observed only during the first 4 weeks in all groups. CR did not significantly increase SIRT1 gene expression. Higher liver weight was observed in mice consuming FO (p < 0.05). Proliferator activated receptor gamma (PPARgamma) expression decreased in FO + G-CR significantly and even with a reduction of adiposity and higher adiponectin levels, fasting blood sugar (FBS) was significantly higher than in CO + G-CR. Grape intake increased Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) expression and decreased insulin resistance in CO + G-CR. CONCLUSIONS: Sugar replacement with polyphenol-rich grape along with CR improved glucose homeostasis, and substituting corn oil with flaxseed oil in obese mice reduced fat mass, but even with no change in adiponectin levels it could not decrease insulin resistance. However, none of the food item combinations facilitated weight reduction in the long-term CR. Therefore, regardless of the total calorie intake, different diet components and fat contents may have unexpected effects on metabolic regulation. PMID- 28665259 TI - Defining Radioiodine-Refractory Differentiated Thyroid Cancer: Efficacy and Safety of Lenvatinib by Radioiodine-Refractory Criteria in the SELECT Trial. AB - BACKGROUND: While there is a clear consensus for defining radioiodine-refractory differentiated thyroid cancer (RR-DTC), it is unknown whether these criteria are equally valid for determining when radioiodine (RAI) therapy is no longer beneficial and systemic treatment should be considered. Lenvatinib, a multikinase inhibitor, significantly prolonged progression-free survival (PFS) compared to placebo in a Phase 3 trial in RR-DTC (SELECT; hazard ratio [HR]: 0.21 [99% confidence interval (CI) 0.14-0.31]; p < 0.001). This sub-analysis compared clinical outcomes of lenvatinib-treated patients in SELECT stratified by RR-DTC inclusion criteria. METHODS: In SELECT, patients with measurable RR-DTC and radiologic evidence of disease progression <=13 months prior to study entry were randomized 2:1 to lenvatinib (24 mg/day; 28-day cycle) or placebo. In this analysis, patients were stratified based on the following RR-DTC inclusion criteria: no RAI uptake, disease progression within 12 months of RAI therapy despite RAI avidity at the time of treatment, and extensive (>600 mCi) cumulative RAI exposure. All had disease progression as an inclusion criterion for SELECT. RESULTS: Of 392 patients (261 lenvatinib; 131 placebo) enrolled, 275, 235, and 73 patients met the inclusion criteria for no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. There was significant overlap between the patient groups, with 167 (42.6%) patients meeting more than one inclusion criterion. Lenvatinib improved median PFS compared to placebo in all groups ("no RAI uptake": lenvatinib not quantifiable [NQ; CI 14.8 NQ] vs. placebo, 3.7 months [CI 2.5-5.3]; "disease progression despite RAI avidity": lenvatinib 16.5 months [CI 12.8-NQ] vs. placebo, 3.7 months [CI 1.9 5.4]; "extensive RAI exposure": lenvatinib 18.7 months [CI 10.7-NQ] vs. placebo, 3.6 months [CI 1.9-5.5]). Objective response rates were 71.8%, 60.0%, and 56.0% for patients with no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. Lenvatinib-related adverse events were similar across groups. CONCLUSIONS: Comparable efficacy and safety profiles were observed in lenvatinib-treated patients regardless of RR-DTC criteria, possibly because of a large overlap among patients fulfilling each criterion. However, differing definitions for RR-DTC may be equally valid because both lenvatinib and placebo arms exhibited similar PFS outcomes across groups. PMID- 28665262 TI - Nesterenkonia cremea sp. nov., a bacterium isolated from a soda lake. AB - A Gram-stain-positive, aerobic, non-motile, rod-shaped, non-endospore-forming bacterial strain, 10CT, was isolated from Lonar soda lake in India. Based on the 16S rRNA gene sequence analysis, this strain was identified as belonging to the genus Nesterenkonia and was most closely related to the type strains of Nesterenkonia lacusekhoensis (99.1 %, sequence similarity), Nesterenkonia aethiopica (96.9 %), Nesterenkonia flava (96.9 %) and related of the genus Nesterenkonia (<96.6 %, sequence similarity). However, the DNA-DNA relatedness of strain 10CT with N. lacusekhoensis KCTC 19283T was only 34.6+/-0.9. The DNA G+C content of strain 10CT was 68.6 mol%. Strain 10CT was an aerobic microbe with optimal growth at 37 degrees C, pH 7.5-8.0 and 5-6 % (w/v) NaCl. The cell-wall peptidoglycan of strain 10CT was of the type A4alpha (l-Lys-l-Glu). The major polar lipids present were phosphatidylglycerol, diphosphatidylglycerol and phosphatidylcholine. The major isoprenoid quinones were MK-7, MK-8 and MK-9. Major fatty acids of strain 10CT were anteiso-C15 : 0, anteiso-C17 : 0 and iso C16 : 0. The results of phylogenetic, chemotaxonomic and biochemical tests allowed a clear differentiation of strain 10CT, which represents a novel member of the genus Nesterenkonia for which the name Nesterenkonia cremea sp. nov. is proposed. The type strain is 10CT (=LMG 29100T=KCTC 39636T=CGMCC 1.15388T). PMID- 28665264 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 67, part 4, of the IJSEM. PMID- 28665263 TI - Photobacterium proteolyticum sp. nov., a protease-producing bacterium isolated from ocean sediments of Laizhou Bay. AB - A protease-producing bacterial strain, 13-12T, was isolated from the ocean sediment of Laizhou Bay, PR China and systematically studied. The bacterium was Gram-stain negative, non spore-forming rods, which were motile with two flagella. It was positive for oxidase, the hydrolysis of starch, agar and gelatin, and for nitrate reduction. It was negative for catalase, esterase and the degradation of CM-cellulose. Optimum growth was observed at 28 degrees C, pH 6.5-7.0 and in the presence of 2-3 % (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene, and whole genome data, affiliated it to the genus Photobacterium. It was most closely related to Photobacterium jeanii R-40508T (96.7 % 16S rRNA gene similarity). Strain 13-12T was found to have less than 86.1 % similarities with the type strains of its most closely related species in multi-locus sequence analysis, less than 75.2 % using genome average nucleotide identities (ANI), and less than 18.5 % in DNA-DNA relatedness studies. Q8 was the predominant respiratory menaquinone. Phosphatidylethanolamine, phosphoaminolipid and phospholipid were the major polar phospholipids and summed feature 3 (48.2 %), C16 : 0 (18.4 %) and C18 : 1omega5c (14.1 %) the major fatty acids. The combined phenotypic, phylogenetic, genomic and chemotaxonomic data support this strain representing a novel species of the genus Photobacterium, for which the name Photobacterium proteolyticum sp. nov. is proposed, with 13-12T (=KCTC 42764T=CGMCC 1.14970) as the type strain. The genome size of 13-12T is 6.2 Mbp, comprising 5806 predicted genes and the DNA G+C content is 47.9 mol%. PMID- 28665265 TI - Polaribacter litorisediminis sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated OITF-11T, was isolated from a tidal flat in Oido, an island of South Korea, and subjected to a polyphasic taxonomic study. Strain OITF-11T grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences showed that strain OITF-11T belonged to the genus Polaribacter. Strain OITF-11T exhibited 16S rRNA gene sequence similarity values of 97.4-98.1 % to Polaribacter haliotis RA4-7T, Polaribacter atrinae KACC 17473T, Polaribacter dokdonensis DSW-5T and Polaribacter marinaquae KCTC 42664T, and of 94.1-96.9 % to the type strains of the other Polaribacter species. Strain OITF-11T contained menaquinone MK-6 as the predominant menaquinone and iso-C15 : 0, iso-C15 : 1 G, iso-C15 : 0 3-OH, iso-C17 : 0 3-OH and C15 : 1omega6c as the major fatty acids. The major polar lipids detected in strain OITF-11T were phosphatidylethanolamine, phosphatidylmonomethylethanolamine and one unidentified lipid. The DNA G+C content of strain OITF-11T was 32.2 mol% and its DNA-DNA relatedness values with the type strains of P. haliotis, P. atrinae, P. dokdonensis and P. marinaquae were 14-33 %. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain OITF-11T is separated from recognized species of the genus Polaribacter. On the basis of the data presented, strain OITF-11T is considered to represent a novel species of the genus Polaribacter, for which the name Polaribacter litorisediminis sp. nov. is proposed. The type strain is OITF-11T (=KCTC 52500T=NBRC 112457T). PMID- 28665266 TI - Corrigendum: There is inadequate evidence to support the division of the genus Borrelia. PMID- 28665267 TI - International Committee on Systematics of Prokaryotes Subcommittee on the taxonomy of the suborder Micrococcineae Minutes of the meeting, 29 July 2014, Montreal, Canada. PMID- 28665268 TI - Evaluation of 5 Commercially Available Zika Virus Immunoassays. AB - Because of the global spread of Zika virus, accurate and high-throughput diagnostic immunoassays are needed. We compared the sensitivity and specificity of 5 commercially available Zika virus serologic assays to the recommended protocol of Zika virus IgM-capture ELISA and plaque-reduction neutralization tests. Most commercial immunoassays showed low sensitivity, which can be increased. PMID- 28665269 TI - Improving the safety of whole blood-derived transfusion products with a riboflavin-based pathogen reduction technology. AB - Worldwide safety of blood has been positively impacted by technological, economic and social improvements; nevertheless, growing socio-political changes of contemporary society together with environmental changes challenge the practice of blood transfusion with a continuous source of unforeseeable threats with the emergence and re-emergence of blood-borne pathogens. Pathogen reduction (PR) is a proactive strategy to mitigate the risk of transfusion-transmitted infections. PR technologies for the treatment of single plasma units and platelet concentrates are commercially available and have been successfully implemented in more than 2 dozen countries worldwide. Ideally, all labile blood components should be PR treated to ensure a safe and sustainable blood supply in accordance with regional transfusion best practices. Recently, a device (Mirasol(r) Pathogen Reduction Technology System) for PR treatment of whole blood using riboflavin and UV light has received CE marking, a significant step forward in realising blood safety where WB transfusion is the norm, such as in sub-Saharan Africa and in far forward combat situations. There is also keen interest in the ability to derive components from Mirasol(r)-treated whole blood, as it is seen as a more efficient and economical means to implement universal PR in the blood centre environment than treatment of components with different PR systems. PMID- 28665270 TI - Meru couples planar cell polarity with apical-basal polarity during asymmetric cell division. AB - Polarity is a shared feature of most cells. In epithelia, apical-basal polarity often coexists, and sometimes intersects with planar cell polarity (PCP), which orients cells in the epithelial plane. From a limited set of core building blocks (e.g. the Par complexes for apical-basal polarity and the Frizzled/Dishevelled complex for PCP), a diverse array of polarized cells and tissues are generated. This suggests the existence of little-studied tissue-specific factors that rewire the core polarity modules to the appropriate conformation. In Drosophila sensory organ precursors (SOPs), the core PCP components initiate the planar polarization of apical-basal determinants, ensuring asymmetric division into daughter cells of different fates. We show that Meru, a RASSF9/RASSF10 homologue, is expressed specifically in SOPs, recruited to the posterior cortex by Frizzled/Dishevelled, and in turn polarizes the apical-basal polarity factor Bazooka (Par3). Thus, Meru belongs to a class of proteins that act cell/tissue-specifically to remodel the core polarity machinery. PMID- 28665271 TI - Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids. AB - The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated. PMID- 28665272 TI - Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage. AB - CaV-channel dependent activation of BK channels is critical for feedback control of both calcium influx and cell excitability. Here we addressed the functional and spatial interaction between BK and CaV1.3 channels, unique CaV1 channels that activate at low voltages. We found that when BK and CaV1.3 channels were co expressed in the same cell, BK channels started activating near -50 mV, ~30 mV more negative than for activation of co-expressed BK and high-voltage activated CaV2.2 channels. In addition, single-molecule localization microscopy revealed striking clusters of CaV1.3 channels surrounding clusters of BK channels and forming a multi-channel complex both in a heterologous system and in rat hippocampal and sympathetic neurons. We propose that this spatial arrangement allows tight tracking between local BK channel activation and the gating of CaV1.3 channels at quite negative membrane potentials, facilitating the regulation of neuronal excitability at voltages close to the threshold to fire action potentials. PMID- 28665273 TI - Moderate nucleotide diversity in the Atlantic herring is associated with a low mutation rate. AB - The Atlantic herring is one of the most abundant vertebrates on earth but its nucleotide diversity is moderate (pi = 0.3%), only three-fold higher than in human. Here, we present a pedigree-based estimation of the mutation rate in this species. Based on whole-genome sequencing of four parents and 12 offspring, the estimated mutation rate is 2.0 * 10-9 per base per generation. We observed a high degree of parental mosaicism indicating that a large fraction of these de novo mutations occurred during early germ cell development. The estimated mutation rate - the lowest among vertebrates analyzed to date - partially explains the discrepancy between the rather low nucleotide diversity in herring and its huge census population size. But a species like the herring will never reach its expected nucleotide diversity because of fluctuations in population size over the millions of years it takes to build up high nucleotide diversity. PMID- 28665274 TI - Statistical Approaches for Estimating Sex-Specific Effects in Endocrine Disruptors Research. AB - BACKGROUND: When a biologic mechanism of interest is anticipated to operate differentially according to sex, as is often the case in endocrine disruptors research, investigators routinely estimate sex-specific associations. Less attention has been given to potential sexual heterogeneity of confounder associations with outcomes. When relationships of covariates with outcomes differ according to sex, commonly applied statistical approaches for estimating sex specific endocrine disruptor effects may produce divergent estimates. OBJECTIVES: We discuss underlying assumptions and evaluate the performance of two traditional approaches for estimating sex-specific effects, stratification and product terms, and introduce a simple modeling alternative: an augmented product term approach. METHODS: We describe the impact of assumptions regarding sexual heterogeneity of confounder relationships on estimates of sex-specific effects of the exposure of interest for three approaches: stratification, traditional product terms, and augmented product terms. Using simulated and applied examples, we demonstrate properties of each approach under a range of scenarios. RESULTS: In simulations, sex-specific exposure effects estimated using the traditional product term approach were biased when confounders had sex-dependent associations with the outcome. Sex-specific estimates from stratification and the augmented product term approach were unbiased but less precise. In the applied example, the three approaches yielded similar estimates, but resulted in some meaningful differences in conclusions based on statistical significance. CONCLUSIONS: Investigators should consider sexual heterogeneity of confounder associations when choosing an analytic approach to estimate sex-specific effects of endocrine disruptors on health. In the presence of sex-dependent confounding, our augmented product term approach may be advantageous over stratification when there is prior knowledge available to fit reduced models or when investigators seek an automated test for effect measure modification. https://doi.org/10.1289/EHP334. PMID- 28665275 TI - Immune disorders induced by exposure to pyrethroid insecticides. AB - Pyrethroids are biocides, which belong to the third generation of insecticides. They are used as biocides, insecticides and medicines. These agents react selectively, because they are less harmful to birds and mammals (due to poor intestinal absorption and rapid detoxification in the body of homeothermic organisms) and they are poisonous for fish and insects. The aim of the article is to present the current state of knowledge on the effects of pyrethroids on the immune system based on the latest scientific research. The mechanism of action of pyrethroids include the delaying closure of voltage- sensitive sodium and chloride channels (including GABA- dependent channels). These compounds are neurotoxic. Studies have shown that they cause numerous immune disorders contributing to lowering of immunity in humans and animals. Exposure to pyrethroids can cause inhibition of proliferation of peripheral blood leukocytes and reducing the concentration of IgG immunolgobulines. They also cause reduced macrophages and decrease in interleukin 2 (IL-2), interleukin 8 (IL-8), interleukin 12p70 (IL-12p70), and interferon gamma (IFN-gamma). Some of these compounds cause increase of liver weight and increase of bone marrow cellularity, and may induce apoptosis of the thymus. Pyrethroids can cause allergies and asthma. Their immunosuppressive effects can impair host resistance against infections. Exposure to these compounds can also contribute to induction of the cancer, especially in patients with impaired immune function. PMID- 28665276 TI - Mitochondria: Target organelles for estrogen action. AB - Estrogens belong to a group of sex hormones, which have been shown to act in multidirectional way. Estrogenic effects are mediated by two types of intracellular receptors: estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). There are two basic mechanisms of estrogen action: 1) classical-genomic, in which the ligand-receptor complex acts as a transcriptional factor and 2) a nongenomic one, which is still not fully understood, but has been seen to lead to distinct biological effects, depending on tissue and ligand type. It is postulated that nongenomic effects may be associated with membrane signaling and the presence of classical nuclear receptors within the cell membrane. Estrogens act in a multidirectional way also within cell organelles. It is assumed that there is a mechanism which manages the migration of ESR into the mitochondrial membrane, wherein the exogenous estrogen affect the morphology of mitochondria. Estrogen, through its receptor, can directly modulate mitochondrial gene expression. Moreover, by regulating the level of reactive oxygen species, estrogens affect the biology of mitochondria. The considerations presented in this paper indicate the pleiotropic effects of estrogens, which represent a multidirectional pathway of signal transduction. PMID- 28665277 TI - Adipose tissue - morphological and biochemical characteristic of different depots. AB - Adipose tissue is an organ that performs a lot of significant physiological functions, which is why its excess in the body results in pathological states in many of its organs and systems. Adipose tissue is not only a tissue which stores fat and plays a protective role. It is an important endocrine organ where signals sent from different tissues are generated and integrated. Adipose tissue is both morphologically and physiologically differentiated. However, due to their plasticity, adipocytes can undergo a transformation and change their structure and metabolism depending on the physiological state of the organism and the conditions to which it is exposed. PMID- 28665278 TI - Stress and its molecular consequences in cancer progression. AB - Stress, caused by psychological, physiological and physical factors has an adverse impact on human body homeostasis. There are two kind of stress: short term and chronic. Cancer patients usually live under chronic stress, caused by diagnosis-related strong emotional experience and depression, resulting from various difficulties associated with disease progression and treatment. At the molecular level, stress factors induce production and secretion of stress-related hormones, such as catecholamines, glucocorticoids and dopamine (as a part of adaptational body response), which influence both normal and transformed cells through their specific receptors. The particular effects exerted by these molecules on cancer cells have been also observed in in vitro cultures and include changes in proliferation, apoptosis susceptibility and migration/invasion potential. As a result, it has been suggested that stress hormones may be responsible for progression of malignancy and thus accelerate the metastasis formation in cancer patients. However, the clinical data on correlation between stress and the patients survival, as well as the molecular analysis of stress hormone receptors expression and action in cancer cell, have not yet provided an unequivocal answer. For this reason, extensive studies, on molecular and clinical level are needed to fully determine stress impact on cancer progression and on the effectiveness of anti-cancer treatment. Nowadays, it seems reasonable that the personalization of anti-cancer therapy should also focus on mental state of cancer patients, and provide them with psychological tools or techniques for stress management. PMID- 28665279 TI - Modified methods for efficiently differentiating human embryonic stem cells into chondrocyte-like cells. AB - INTRODUCTION: Human articular cartilage has a poor regenerative capacity. This often results in the serious joint disease- osteoarthritis (OA) that is characterized by cartilage degradation. An inability to self-repair provided extensive studies on AC regeneration. The cell-based cartilage tissue engineering is a promising approach for cartilage regeneration. So far, numerous cell types have been reported to show chondrogenic potential, among others human embryonic stem cells (hESCs). MATERIALS AND METHODS: However, the currently used methods for directed differentiation of human ESCs into chondrocyte-like cells via embryoid body (EB) formation, micromass culture (MC) and pellet culture (PC) are not highly efficient and require further improvement. In the present study, these three methods for hESCs differentiation into chondrocyte-like cells in the presence of chondrogenic medium supplemented with diverse combination of growth factors (GFs) were evaluated and modified. RESULTS: The protocols established here allow highly efficient, simple and inexpensive production of a large number of chondrocyte-like cells suitable for transplantation into the sites of cartilage injury. The most crucial issue is the selection of appropriate GFs in defined concentration. The obtained stem-derived cells reveal the presence of chondrogenic markers such as type II collagen, Sox6 and Sox9 as well as the lack or significantly lower level of pluripotency markers including Nanog and Oct3/4. DISCUSSION: The most efficient method is the differentiation throughout embryoid bodies. In turn, chondrogenic differentiation via pellet culture is the most promising method for implementation on clinical scale. The most useful GFs are TGF-beta1, -3 and BMP-2 that possess the most chondrogenic potential. These methods can also be used to obtain chondrocyte-like cells from differentiating induced pluripotent stem cells (iPSCs). PMID- 28665280 TI - Application of three-dimensional neuronal cell cultures in the studies of mechanisms of neurodegenerative diseases. AB - In vitro models utilizing cells in planar two-dimensional (2D) cultures do not reflect the in vivo environment and are increasingly replaced by three dimensional (3D) cultures. Fundamental differences between 2D and 3D cell cultures systems include cell attach, spread and grow, their morphology, proliferation, differentiation or gene and protein expression. For that reason 3D models have been proven to be invaluable tools of study for the various fields of science, such as drug discovery, cancer research, differentiation studies or neuroscience. In the present review, we discuss 3D neural in vitro models that might provide important insides about the mechanisms of pathogenesis of neurodegenerative diseases. PMID- 28665281 TI - Experimental model for acute kidney injury caused by uropathogenic Escherichia coli. AB - INTRODUCTION: Acute kidney injury (AKI) is the rapid deterioration of renal function, diagnosed on the basis of an increase in serum creatinine and abnormal urinary parameters. AKI is associated with increased risk of mortality or chronic kidney disease (CKD). The aim of the study was to develop an experimental model for AKI resulting from Escherichia coli-induced pyelonephritis. E. coli was isolated from a patient with clinical symptoms of urinary tract infection (UTI). MATERIAL/METHODS: The study included three groups of female Wistar rats (groups 1, 2 and 3), in which pyelonephritis was induced by transurethral inoculation with highly virulent E. coli (105, 107 and 109 cfu/ml, respectively). Urine and blood samples for analysis were obtained prior to the inoculation (day 0), as well as 7, 14 and 21 days thereafter. RESULTS: Aside from a microbiological examination of urine samples, daily urine output, serum creatinine (CreaS), creatinine clearance (CrCl), interleukin 6 (IL-6), fractional excretion of sodium (FENa) and fractional excretion of urea (FEUrea) were determined. A histopathological examination of kidney and urinary bladder specimens was conducted as well. While UTI-related pyelonephritis developed irrespective of E. coli inoculum size, AKI was observed only following transurethral administration of E. coli at the intermediate and high dose, i.e. 107 and 109 cfu/ml, respectively (group 2 and 3). DISCUSSION: An increase in CreaS and abnormal diuresis were accompanied by changes in parameters specific for various forms of AKI, i.e. FENa and FEUrea. Based on these changes, administration of E. coli at 107 cfu/ml was demonstrated to induce renal AKI, whereas inoculation with 109 cfu/ml seemed to cause not only ascending pyelonephritis, but perhaps also bacteremia and urosepsis (prerenal component of AKI). PMID- 28665282 TI - Plant storage proteins - the main nourisching products - from biosynthesis to cellular storage depots. AB - Storage proteins of legumes are one of the main components of the human and animal diet. The substances collected in their seeds have the pro-health values, supporting the prevention of many civilization diseases. However, there are still many uncertainties about the mechanisms leading to the production of nutritious seeds. It is also difficult to identify which of their constituents and in what final form are responsible for the observed protective effects in vivo. In this work, on the background of different types of storage proteins, these deposited mainly in legumes were in the focus of interest. They were characterized on the example of pea (Pisum sativum) proteins. Mechanisms associated with their biosynthesis and transport to specific cellular compartments was presented. Ways of their post-translational processing, segregation and storage in the specific vacuoles were also discussed. Therefore, the paper presents the state-of-the-art knowledge concerning the processes making the accumulated protein deposits ready to use by plants, animals and humans. PMID- 28665283 TI - Glutathione S - transferases class Pi and Mi and their significance in oncology. AB - In this article the current data, which shows that glutathione S-transferases (GST) class Pi and Mi are interesting and promising biomarkers in acute and chronic inflammatory processes as well as in the oncology, were presented based on the review of the latest experimental and clinical studies. The article shows their characteristics, functions and participation (direct - GST Pi, indirect - GST Mi) in the regulation of signaling pathways of JNK kinases, which are involved in cell differentiation. Overexpression of glutathione S-transferases class Pi and Mi in many cancer cells plays a key role in cancer treatment, making them resistant to chemotherapy. GST isoenzymes are involved in the metabolism of various types of xenobiotics and endogenous substrates, so their altered expression in cancer tissues as well as in serum and urine could be an important potential marker of the cancer and an indicator of oxidative stress. The study shows the role of glutathione S-transferases in redox homeostasis of tumor cells and in the mechanism of resistance to anticancer drugs. PMID- 28665284 TI - Multiple sclerosis - etiology and diagnostic potential. AB - Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of autoimmune originate. The main agents responsible for the MS development include exogenous, environmental, and genetic factors. MS is characterized by multifocal and temporally scattered central nervous system (CNS) damage which lead to the axonal damage. Among clinical courses of MS it can be distinguish relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPSM), primary progressive multiple sclerosis (PPMS), and progressive-relapsing multiple sclerosis (RPMS). Depending on the severity of signs and symptoms MS can be described as benign MS or malignant MS. MS diagnosis is based on McDonald's diagnostic criteria, which link clinical manifestation with characteristic lesions demonstrated by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and visual evoked potentials. Among CSF laboratory tests used to the MS diagnosis are applied: Tibbling & Link IgG index, reinbegrams, and CSF isoelectrofocusing for oligoclonal bands detection. It should be emphasized, that despite huge progress regarding MS as well as the availability of different diagnostics methods this disease is still a diagnostic challenge. It may result from fact that MS has diverse clinical course and there is a lack of single test, which would be of appropriate diagnostic sensitivity and specificity for quick and accurate diagnosis. PMID- 28665285 TI - [Need painmeds?[Editorial]]. PMID- 28665286 TI - [Is the new approach to providing healthcare to children a safety threat?[Editorial]]. PMID- 28665287 TI - [A prospective study on acute poisonings presenting to the Emergency Department at Landspitali University Hospital in Iceland 2012]. AB - INTRODUCTION: The purpose of the study was to assess the incidence and type of toxic exposures presenting to the Emergency Department (ED) at Landspitali University Hospital in Iceland over one year and compare the results to another study performed eleven years before. METHODS: The study was prospective and included all visits due to acute poisoning to the ED between January 1, and December 31, 2012. RESULTS: A total of 977 toxic exposures were documented. Females were 554 (57%) and males 423 (43%). The age range was from 2 months to 96 years old. More than half of the patients were under 30 years old. The majority of exposures occurred in private homes and ingestion was the most common route of exposure. Deliberate poisonings accounted for 66% of all the poisonings and 76% had drugs and/or alcohol as their main cause. Exposures to chemicals other than drugs were usually unintentional and 31% of them were occupational exposures. 80% of patients received treatment and were discharged from the ED, 20% were admitted to other departments, thereof 21% to ICU. Two patients died (0.2%). CONCLUSION: A slight but statistically unsignificant increase in incidence was observed. Females outnumbered males. Self-poisonings by ingestion of drugs and/or alcohol accounted for the majority of cases. The age range was wide, but the incidence was higher with young people. Mortality was low. Key words: toxicology, acute poisoning, epidemiology, self-poisoning. Correspondence: Gudborg Audur Gudjonsdottir, gudborgg@gmail.com. PMID- 28665288 TI - [Dietary intake of young Icelanders with psychotic disorders and weight development over an 8-12 months period]. AB - INTRODUCTION: The prevalence of lifestyle related diseases is higher among people with psychotic disorders than the general population. The aim was to assess dietary intake of young people with psychotic disorders for the first time in Iceland. MATERIAL AND METHODS: Subjects were young people (n=48, age 18-30y) with psychotic disorders. Dietary intake was assessed by a 24-hour recall in July August 2016, and compared with official recommendations and intake of the general public (n=250, age 18-30y). Body weight in the past eight to 12 months, was retrieved from medical records. RESULTS: Consumption of fruits, fish, dairy products, vegetable and fish oil was significantly lower among subjects when compared with the general public, while their soft drink and sweets consumption was higher (p<0.001). Furthermore, the contribution of added sugar was higher (15E% vs. 12E%) and protein intake lower (16E% vs. 18E%). Consumption of omega-3 fatty acids and vitamin D was lower among subjects than the general public and lower than recommended (0.04+/-0.3% omega-3 of total energy vs. 1.2+/-0.6%, p<0.001 and 3.1+/-4.2 ug vitamin D/day vs. 5.6+/-6.5 ug/day, p<0.001). Almost 40% of the subjects had gained >5% of their initial body weight in the past 8-2 months. CONCLUSION: Diet of young people with psychotic disorders is not consistent with recommendations and is worse than the diet of their peers in the general population. It is important to find ways to improve the diet and thereby nutrient intake of the group. Key words: psychotic disorders, schizophrenia, recommended dietary allowances, fatty acids, omega-3, vitamin D. Correspondence: Ingibjorg Gunnarsdottir, ingigun@landspitali.is. PMID- 28665289 TI - Design of patient-specific focused ultrasound arrays for non-invasive brain therapy with increased trans-skull transmission and steering range. AB - The use of a phased array of ultrasound transducer elements to sonicate through the skull has opened the way for new treatments and the delivery of therapeutics beyond the blood-brain barrier. The limited steering range of current clinical devices, particularly at higher frequencies, limits the regions of the brain that are considered treatable by ultrasound. A new array design is introduced that allows for high levels of beam steering and increased transmission throughout the brain. These improvements are achieved using concave transducers normal to the outer-skull surface in a patient-specific configuration to target within the skull, so that the far-field of each beam is within the brain. It is shown that by using pulsed ultrasound waves timed to arrive in-phase at the desired target, sufficient levels of acoustic energy are delivered for blood-brain barrier opening throughout the brain. PMID- 28665290 TI - Orbital dependent coherence temperature and optical anisotropy of V2O3 quasiparticles. AB - We report on an orbital and temperature dependent study of the onset of coherent quasiparticles in V2O3 single crystal. By using polarized infrared spectroscopy we demonstrate that the electronic coherence temperature is strongly orbital dependent, being about 400 K for [Formula: see text] orbitals and 500 K for the [Formula: see text]. This suggests that V2O3 low energy electrodynamics can be described in terms of two electron liquids differently renormalized by electronic correlations. PMID- 28665291 TI - The compressed breast during mammography and breast tomosynthesis: in vivo shape characterization and modeling. AB - To characterize and develop a patient-based 3D model of the compressed breast undergoing mammography and breast tomosynthesis. During this IRB-approved, HIPAA compliant study, 50 women were recruited to undergo 3D breast surface imaging with structured light (SL) during breast compression, along with simultaneous acquisition of a tomosynthesis image. A pair of SL systems were used to acquire 3D surface images by projecting 24 different patterns onto the compressed breast and capturing their reflection off the breast surface in approximately 12-16 s. The 3D surface was characterized and modeled via principal component analysis. The resulting surface model was combined with a previously developed 2D model of projected compressed breast shapes to generate a full 3D model. Data from ten patients were discarded due to technical problems during image acquisition. The maximum breast thickness (found at the chest-wall) had an average value of 56 mm, and decreased 13% towards the nipple (breast tilt angle of 5.2 degrees ). The portion of the breast not in contact with the compression paddle or the support table extended on average 17 mm, 18% of the chest-wall to nipple distance. The outermost point along the breast surface lies below the midline of the total thickness. A complete 3D model of compressed breast shapes was created and implemented as a software application available for download, capable of generating new random realistic 3D shapes of breasts undergoing compression. Accurate characterization and modeling of the breast curvature and shape was achieved and will be used for various image processing and clinical tasks. PMID- 28665292 TI - Hydrodynamics of mangrove-type root models: the effect of porosity, spacing ratio and flexibility. AB - Mangrove trees play a prominent role in coastal tropic and subtropical regions, providing habitats for many organisms and protecting shorelines against high energy flows. In particular, the species Rhizophora mangle (red mangrove) exhibits complex cluster roots interacting with different hydrological flow conditions. To better understand the resilience of mangrove trees, we modeled the roots as a collection of cylinders with a circular pattern subject to unidirectional flow. We investigated the effect of porosity and spacing ratio between roots by varying both the diameter of the patch, D, and inset cylinders, d. In addition, we modeled hanging roots of red mangroves as cantilevered rigid cylinders on a hinge. Force and velocity measurements were performed in a water tunnel (Reynolds numbers from 2200 to 11 000). Concurrently, we performed 2D flow visualization using a flowing soap film. We found that the frequency of the vortex shedding increases as the diameter of the small cylinders decreases while the patch diameter is constant, therefore increasing the Strouhal number, [Formula: see text]. By comparing the change of Strouhal numbers with a single solid cylinder, we introduced a new length scale, the effective diameter. The effective diameter of the patch decreases as the porosity increases. In addition, we found that patch drag scales linearly with the patch diameter but decreases linearly as the spacing ratio increases. After a spacing ratio of ([Formula: see text]), the force scales linearly with the free stream velocity, and the mean velocity behind the patch is independent of the Reynolds number and the patch effect disappears. For flexible cylinders, we found that a decrease in stiffness increases both patch drag and the wake deficit behind the patch in a similar fashion as increasing the blockage of the patch. This information has the potential to help in the development of methods to design resilient bio-inspired coastline structures. PMID- 28665293 TI - An original piecewise model for computing energy expenditure from accelerometer and heart rate signals. AB - OBJECTIVE: Activity energy expenditure (EE) plays an important role in healthcare, therefore, accurate EE measures are required. Currently available reference EE acquisition methods, such as doubly labeled water and indirect calorimetry, are complex, expensive, uncomfortable, and/or difficult to apply on real time. To overcome these drawbacks, the goal of this paper is to propose a model for computing EE in real time (minute-by-minute) from heart rate and accelerometer signals. APPROACH: The proposed model, which consists of an original branched model, uses heart rate signals for computing EE on moderate to vigorous physical activities and a linear combination of heart rate and counts per minute for computing EE on light to moderate physical activities. Model parameters were estimated from a given data set composed of 53 subjects performing 25 different physical activities (light-, moderate- and vigorous intensity), and validated using leave-one-subject-out. A different database (semi controlled in-city circuit), was used in order to validate the versatility of the proposed model. Comparisons are done versus linear and nonlinear models, which are also used for computing EE from accelerometer and/or HR signals. MAIN RESULTS: The proposed piecewise model leads to more accurate EE estimations ([Formula: see text], [Formula: see text] and [Formula: see text] J kg-1 min-1 and [Formula: see text], [Formula: see text], and [Formula: see text] J kg-1 min 1 on each validation database). SIGNIFICANCE: This original approach, which is more conformable and less expensive than the reference methods, allows accurate EE estimations, in real time (minute-by-minute), during a large variety of physical activities. Therefore, this model may be used on applications such as computing the time that a given subject spent on light-intensity physical activities and on moderate to vigorous physical activities (binary classification accuracy of 0.8155). PMID- 28665294 TI - Nonlinear dielectric effects in liquids: a guided tour. AB - Dielectric relaxation measurements probe how the polarization of a material responds to the application of an external electric field, providing information on structure and dynamics of the sample. In the limit of small fields and thus linear response, such experiments reveal the properties of the material in the same thermodynamic state it would have in the absence of the external field. At sufficiently high fields, reversible changes in enthalpy and entropy of the system occur even at constant temperature, and these will in turn alter the polarization responses. The resulting nonlinear dielectric effects feature field induced suppressions (saturation) and enhancements (chemical effect) of the amplitudes, as well as time constant shifts towards faster (energy absorption) and slower (entropy reduction) dynamics. This review focuses on the effects of high electric fields that are reversible and observed at constant temperature for single component glass-forming liquids. The experimental challenges involved in nonlinear dielectric experiments, the approaches to separating and identifying the different sources of nonlinear behavior, and the current understanding of how high electric fields affect dielectric materials will be discussed. Covering studies from Debye's initial approach to the present state-of-the-art, it will be emphasized what insight can be gained from the nonlinear responses that are not available from dielectric relaxation results obtained in the linear regime. PMID- 28665295 TI - Broadband, monochromatic and quasi-monochromatic x-ray propagation in multi-Z media for imaging and diagnostics. AB - With the advent of monochromatic and quasi-monochromatic x-ray sources, we explore their potential with computational and experimental studies on propagation through a combination of low and high-Z (atomic number) media for applications to imaging and detection. The multi-purpose code GEANT4 and a new code PHOTX are employed in numerical simulations, and a variety of x-ray sources are considered: conventional broadband devices with well-known spectra, quasi monochromatic laser driven sources, and monochromatic synchrotron x-rays. Phantom samples consisting of layers of low-Z and high-Z material are utilized, with atomic-molecular species ranging from H2O to gold. Differential and total attenuation of x-ray fluxes from the different x-ray sources are illustrated through simulated x-ray images. Main conclusions of this study are: I. It is shown that a 65 keV Gaussian quasi-monochromatic source is capable of better contrast with less radiation exposure than a common 120 kV broadband simulator. II. A quantitative measure is defined and computed as a metric to compare the efficacy of any two x-ray sources, as a function of concentration of high-Z moieties in predominantly low-Z environment and depth of penetration. III. Characteristic spectral features of [Formula: see text], [Formula: see text] fluorescent emission and Compton scattering indicate pathways for accelerating x ray photoexcitation and absorption; in particular, we model the tungsten [Formula: see text] at 59 keV alongside experimental measurements at the European synchrotron research facility to search for the signature of induced [Formula: see text] resonance fluorescence. The present study should contribute to the understanding of diagnostic potential of new x-ray sources under development, as well as the underlying fundamental physical processes and features for biomedical applications. PMID- 28665296 TI - Comparison of feasibility and estimates of central and peripheral nitric oxide parameters by different mathematical models. AB - INTRODUCTION: Assessment of the central and peripheral nitric oxide (NO) dynamics of the lung provides information on the severity and anatomical site of pulmonary inflammation. Several mathematical methods for calculating alveolar and bronchial NO parameters have been introduced. Our aim was to compare these methods. METHODS: The study included 69 healthy adults, 66 healthy children, 73 asbestos exposed subjects and 72 subjects with chronic obstructive pulmonary disease (COPD). Exhaled NO was measured at multiple flow rates and we used five mathematical methods (Tsoukias and George, Pietropaoli, Condorelli, Hogman and Merilainen, and Silkoff) to estimate alveolar and bronchial NO parameters. RESULTS: The Hogman and Merilainen method was less frequently feasible than the other methods but it had the highest degree of agreement with the measured data. The methods were most often feasible in healthy or asbestos-exposed adults but distinctly more infrequently in children and adults with COPD, suggesting difficulties in NO measurements in these groups. The linear methods (Tsoukias and George, Pietropaoli) yielded higher alveolar NO concentration and lower bronchial NO flux than the two non-linear methods (Hogman and Merilainen, Silkoff) and a linear method with correction for axial back-diffusion of NO (Condorelli). CONCLUSION: In differentiating central and peripheral NO sources we recommend using linear methods, as low flow rates are not needed and the feasibility of the methods is good. If bronchial wall NO concentration (C awNO) and diffusing capacity (D awNO) are of interest, non-linear methods are needed, and we recommend using the Hogman and Merilainen method as only three flow rates are needed. However, the agreement between the model and measured data needs to be checked in real time to ensure feasibility. If the subject has difficulties with the extremely low or high flow rates, we then recommend using the Silkoff method to improve feasibility, but more flow rates and measurements are then needed and the agreement between the model and the measured data may be poorer. PMID- 28665297 TI - Respiratory signal prediction based on adaptive boosting and multi-layer perceptron neural network. AB - To improve the prediction accuracy of respiratory signals using adaptive boosting and multi-layer perceptron neural network (ADMLP-NN) for gated treatment of moving target in radiation therapy. The respiratory signals acquired using a real time position management (RPM) device from 138 previous 4DCT scans were retrospectively used in this study. The ADMLP-NN was composed of several artificial neural networks (ANNs) which were used as weaker predictors to compose a stronger predictor. The respiratory signal was initially smoothed using a Savitzky-Golay finite impulse response smoothing filter (S-G filter). Then, several similar multi-layer perceptron neural networks (MLP-NNs) were configured to estimate future respiratory signal position from its previous positions. Finally, an adaptive boosting (Adaboost) decision algorithm was used to set weights for each MLP-NN based on the sample prediction error of each MLP-NN. Two prediction methods, MLP-NN and ADMLP-NN (MLP-NN plus adaptive boosting), were evaluated by calculating correlation coefficient and root-mean-square-error between true and predicted signals. For predicting 500 ms ahead of prediction, average correlation coefficients were improved from 0.83 (MLP-NN method) to 0.89 (ADMLP-NN method). The average of root-mean-square-error (relative unit) for 500 ms ahead of prediction using ADMLP-NN were reduced by 27.9%, compared to those using MLP-NN. The preliminary results demonstrate that the ADMLP-NN respiratory prediction method is more accurate than the MLP-NN method and can improve the respiration prediction accuracy. PMID- 28665298 TI - A change in editorship. AB - This edition of the Journal of Clinical Investigation marks the transition to a new editorial team from Johns Hopkins University. It is with great humility and excitement that we assume the mantle of the leading translational science journal in the world and the flagship of the American Society for Clinical Investigation. PMID- 28665300 TI - Transplant trials with Tregs: perils and promises. AB - Modern immunosuppression regimens effectively control acute rejection and decrease graft loss in the first year after transplantation; however, these regimens do not have a durable effect on long-term graft survival owing to a combination of drug toxicities and the emergence of chronic alloimmune responses. Eliminating drugs and their toxicities while maintaining graft acceptance has been the primary aim of cellular therapies. Tregs suppress both autoimmune and alloimmune responses and are particularly effective in protecting allografts in experimental transplant models. Further, Treg-based therapies are selective, do not require harsh conditioning, and do not have a risk of graft-versus-host disease. Trial designs should consider the distinct immunological features of each transplanted organ, Treg preparations, dose, and frequency, and the ability to detect and quantify Treg effects in a given transplant environment. In this Review, we detail the ongoing clinical trials of Treg therapy in liver and kidney transplantation. Integration of Treg biology gleaned from preclinical models and experiences in human organ transplantation should allow for optimization of trial design that will determine the potential efficacy of a given therapy and provide guidelines for further therapeutic development. PMID- 28665302 TI - Glucose Content and In Vitro Bioaccessibility in Sweet Potato and Winter Squash Varieties during Storage. AB - Glucose content and in vitro bioaccessibility were determined in raw and cooked pulp of Arapey, Cuabe, and Beauregard sweet potato varieties, as well as Maravilla del Mercado and Atlas winter squash, after zero, two, four, and six months of storage (14 degrees C, 80% relative humidity (RH)). The total glucose content in 100 g of raw pulp was, for Arapey, 17.7 g; Beauregard, 13.2 g; Cuabe, 12.6 g; Atlas, 4.0 g; and in Maravilla del Mercado, 4.1 g. These contents were reduced by cooking process and storage time, 1.1 to 1.5 times, respectively, depending on the sweet potato variety. In winter squash varieties, the total glucose content was not modified by cooking, while the storage increased glucose content 2.8 times in the second month. After in vitro digestion, the glucose content released was 7.0 times higher in sweet potato (6.4 g) than in winter squash (0.91 g) varieties. Glucose released by in vitro digestion for sweet potato stored for six months did not change, but in winter squashes, stored Atlas released glucose content increased 1.6 times. In conclusion, in sweet potato and winter squash, the glucose content and the released glucose during digestive simulation depends on the variety and the storage time. These factors strongly affect the supply of glucose for human nutrition and should be taken into account for adjusting a diet according to consumer needs. PMID- 28665303 TI - Citrus Pectin-Derived Carbon Microspheres with Superior Adsorption Ability for Methylene Blue. AB - In this study, citrus pectin-derived, green, and tunable carbon microspheres with superior adsorption capacity and high adsorption rate, as well as good reusability toward methylene blue adsorption, were prepared by a facile hydrothermal method without any hazardous chemicals. The materials hold great potential for the treatment of methylene blue wastewater. PMID- 28665299 TI - Cytokine mediators of chronic graft-versus-host disease. AB - Substantial preclinical and clinical research into chronic graft-versus-host disease (cGVHD) has come to fruition in the last five years, generating a clear understanding of a complex cytokine-driven cellular network. cGVHD is mediated by naive T cells differentiating within IL-17-secreting T cell and follicular Th cell paradigms to generate IL-21 and IL-17A, which drive pathogenic germinal center (GC) B cell reactions and monocyte-macrophage differentiation, respectively. cGVHD pathogenesis includes thymic damage, impaired antigen presentation, and a failure in IL-2-dependent Treg homeostasis. Pathogenic GC B cell and macrophage reactions culminate in antibody formation and TGF-beta secretion, respectively, leading to fibrosis. This new understanding permits the design of rational cytokine and intracellular signaling pathway-targeted therapeutics, reviewed herein. PMID- 28665301 TI - Comparative Proteomic Profiling Reveals Molecular Characteristics Associated with Oogenesis and Oocyte Maturation during Ovarian Development of Bactrocera dorsalis (Hendel). AB - Time-dependent expression of proteins in ovary is important to understand oogenesis in insects. Here, we profiled the proteomes of developing ovaries from Bactrocera dorsalis (Hendel) to obtain information about ovarian development with particular emphasis on differentially expressed proteins (DEPs) involved in oogenesis. A total of 4838 proteins were identified with an average peptide number of 8.15 and sequence coverage of 20.79%. Quantitative proteomic analysis showed that a total of 612 and 196 proteins were differentially expressed in developing and mature ovaries, respectively. Furthermore, 153, 196 and 59 potential target proteins were highly expressed in early, vitellogenic and mature ovaries and most tested DEPs had the similar trends consistent with the respective transcriptional profiles. These proteins were abundantly expressed in pre-vitellogenic and vitellogenic stages, including tropomyosin, vitellogenin, eukaryotic translation initiation factor, heat shock protein, importin protein, vitelline membrane protein, and chorion protein. Several hormone and signal pathway related proteins were also identified during ovarian development including piRNA, notch, insulin, juvenile, and ecdysone hormone signal pathways. This is the first report of a global ovary proteome of a tephritid fruit fly, and may contribute to understanding the complicate processes of ovarian development and exploring the potentially novel pest control targets. PMID- 28665304 TI - Occurrence and Biosynthesis of Alkyl Hydroxycinnamates in Plant Lipid Barriers. AB - The plant lipid barriers cuticle and suberin represent one of the largest biological interfaces on the planet. They are comprised of an insoluble polymeric domain with associated organic solvent-soluble waxes. Suberin-associated and plant cuticular waxes contain mixtures of aliphatic components that may include alkyl hydroxycinnamates (AHCs). The canonical alkyl hydroxycinnamates are comprised of phenylpropanoids, typically coumaric, ferulic, or caffeic acids, esterified with long chain to very long chain fatty alcohols. However, many related structures are also present in the plant kingdom. Although their functions remain elusive, much progress has been made on understanding the distribution, biosynthesis, and deposition of AHCs. Herein a summary of the current state of knowledge on plant AHCs is provided. PMID- 28665305 TI - Plantago asiatica L. Seed Extract Improves Lipid Accumulation and Hyperglycemia in High-Fat Diet-Induced Obese Mice. AB - Obesity and its common association with type 2 diabetes, dyslipidemia, and cardiovascular diseases are worldwide epidemics. Currently, to prevent or treat obesity and associated metabolic disorders, herbal dietary supplements or medicines have attracted more and more attention owing to their relative effectiveness with fewer significant side effects. We investigate the therapeutic effects and underlying mechanisms of Plantago asiatica L. seed extract (PSE) on obesity and associated metabolic disorders in high-fat (HF) diet-induced mice. Our results displayed that PSE did not modify food intake or body weight but decreased abdominal white adipose tissue ratio, white/brown adipocyte size, serum total cholesterol, triglyceride (TG), low density lipoprotein cholesterol, free fatty acid, and hepatic TG concentrations when compared with the HF group. The levels of fasting blood glucose and glucose tolerance were improved in the PSE group when compared with the HF group. Furthermore, PSE upregulated mRNA expressions of peroxisome proliferator activated receptors (PPARs) and target genes related to fatty acid metabolism and energy expenditure in liver and adipose tissue of obese mice when compared with the HF group. PSE treatment effectively improved lipid and glucose metabolism in HF diet-induced obese mice. These effects might be attributed to the upregulation of PPAR signaling. PMID- 28665306 TI - Standard Immunohistochemical Assays to Assess Autophagy in Mammalian Tissue. AB - Autophagy is a highly conserved lysosomal degradation pathway with major impact on diverse human pathologies. Despite the development of different methodologies to detect autophagy both in vitro and in vivo, monitoring autophagy in tissue via immunohistochemical techniques is hampered due to the lack of biomarkers. Immunohistochemical detection of a punctate pattern of ATG8/MAP1LC3 proteins is currently the most frequently used approach to detect autophagy in situ, but it depends on a highly sensitive detection method and is prone to misinterpretation. Moreover, reliable MAP1LC3 immunohistochemical staining requires correct tissue processing and high-quality, isoform-specific antibodies. Immunohistochemical analysis of other autophagy-related protein targets such as SQSTM1, ubiquitin, ATG5 or lysosomal proteins is not recommended as marker for autophagic activity in tissue for multiple reasons including aspecific labeling of cellular structures and a lack of differential protein expression during autophagy initiation. To better understand the role of autophagy in human disease, novel biomarkers for visualization of the autophagic process with standard histology techniques are urgently needed. PMID- 28665307 TI - Assessing Lead, Nickel, and Zinc Pollution in Topsoil from a Historic Shooting Range Rehabilitated into a Public Urban Park. AB - Soil contamination is a persistent problem in the world. The redevelopment of a site with a historical deposition of metals might conceal the threat of remaining pollution, especially when the site has become a public place. In this study, human health risk assessment is performed after defining the concentrations of Pb, Ni, and Zn in the topsoil of a former shooting range rehabilitated into a public park in the Municipality of Kesariani (Athens, Greece). A methodology that uses inductively coupled plasma mass spectrometry (ICP-MS, 13 samples), another that uses portable X-ray fluorescence (XRF) following a dense sample design (91 samples), and a hybrid approach that combines both, were used to obtain the concentrations of the trace elements. The enrichment factor and geoacummulation index were calculated to define the degree of pollution of the site. The hazard quotient and cancer risk indicators were also computed to find the risk to which the population is exposed. The present study reveals high non-carcinogenic health risk due to Pb pollution with ingestion as the main exposure pathway. The carcinogenic risk for Pb is within tolerable limits, but the definition of land use might alter such a statement. Lastly, regarding Ni and Zn, the site is unpolluted and there is insignificant carcinogenic and non-carcinogenic risks. PMID- 28665308 TI - Substrate Oxide Layer Thickness Optimization for a Dual-Width Plasmonic Grating for Surface-Enhanced Raman Spectroscopy (SERS) Biosensor Applications. AB - This work investigates a new design for a plasmonic SERS biosensor via computational electromagnetic models. It utilizes a dual-width plasmonic grating design, which has two different metallic widths per grating period. These types of plasmonic gratings have shown larger optical enhancement than standard single width gratings. The new structures have additional increased enhancement when the spacing between the metal decreases to sub-10 nm dimensions. This work integrates an oxide layer to improve the enhancement even further by carefully studying the effects of the substrate oxide thickness on the enhancement and reports ideal substrate parameters. The combined effects of varying the substrate and the grating geometry are studied to fully optimize the device's enhancement for SERS biosensing and other plasmonic applications. The work reports the ideal widths and substrate thickness for both a standard and a dual-width plasmonic grating SERS biosensor. The ideal geometry, comprising a dual-width grating structure atop an optimal SiO2 layer thickness, improves the enhancement by 800%, as compared to non-optimized structures with a single-width grating and a non optimal oxide thickness. PMID- 28665309 TI - Primary Esophageal Motility Disorders: Beyond Achalasia. AB - The best-defined primary esophageal motor disorder is achalasia. However, symptoms such as dysphagia, regurgitation and chest pain can be caused by other esophageal motility disorders. The Chicago classification introduced new manometric parameters and better defined esophageal motility disorders. Motility disorders beyond achalasia with the current classification are: esophagogastric junction outflow obstruction, major disorders of peristalsis (distal esophageal spasm, hypercontractile esophagus, absent contractility) and minor disorders of peristalsis (ineffective esophageal motility, fragmented peristalsis). The aim of this study was to review the current diagnosis and management of esophageal motility disorders other than achalasia. PMID- 28665310 TI - ArtinM Mediates Murine T Cell Activation and Induces Cell Death in Jurkat Human Leukemic T Cells. AB - The recognition of cell surface glycans by lectins may be critical for the innate and adaptive immune responses. ArtinM, a d-mannose-binding lectin from Artocarpus heterophyllus, activates antigen-presenting cells by recognizing TLR2 N-glycans and induces Th1 immunity. We recently demonstrated that ArtinM stimulated CD4+ T cells to produce proinflammatory cytokines. Here, we further studied the effects of ArtinM on adaptive immune cells. We showed that ArtinM activates murine CD4+ and CD8+ T cells, augmenting their positivity for CD25, CD69, and CD95 and showed higher interleukin (IL)-2 and interferon (IFN)-gamma production. The CD4+ T cells exhibited increased T-bet expression in response to ArtinM, and IL-2 production by CD4+ and CD8+ T cells depended on the recognition of CD3epsilongamma-chain glycans by ArtinM. The ArtinM effect on aberrantly-glycosylated neoplastic lymphocytes was studied in Jurkat T cells, in which ArtinM induced IL-2, IFN gamma, and IL-1beta production, but decreased cell viability and growth. A higher frequency of AnnexinV- and propidium iodide-stained cells demonstrated the induction of Jurkat T cells apoptosis by ArtinM, and this apoptotic response was reduced by caspases and protein tyrosine kinase inhibitors. The ArtinM effects on murine T cells corroborated with the immunomodulatory property of lectin, whereas the promotion of Jurkat T cells apoptosis may reflect a potential applicability of ArtinM in novel strategies for treating lymphocytic leukemia. PMID- 28665312 TI - Temperature Measurement and Numerical Prediction in Machining Inconel 718. AB - Thermal issues are critical when machining Ni-based superalloy components designed for high temperature applications. The low thermal conductivity and extreme strain hardening of this family of materials results in elevated temperatures around the cutting area. This elevated temperature could lead to machining-induced damage such as phase changes and residual stresses, resulting in reduced service life of the component. Measurement of temperature during machining is crucial in order to control the cutting process, avoiding workpiece damage. On the other hand, the development of predictive tools based on numerical models helps in the definition of machining processes and the obtainment of difficult to measure parameters such as the penetration of the heated layer. However, the validation of numerical models strongly depends on the accurate measurement of physical parameters such as temperature, ensuring the calibration of the model. This paper focuses on the measurement and prediction of temperature during the machining of Ni-based superalloys. The temperature sensor was based on a fiber-optic two-color pyrometer developed for localized temperature measurements in turning of Inconel 718. The sensor is capable of measuring temperature in the range of 250 to 1200 degrees C. Temperature evolution is recorded in a lathe at different feed rates and cutting speeds. Measurements were used to calibrate a simplified numerical model for prediction of temperature fields during turning. PMID- 28665311 TI - Antioxidant Activity of Yichun Blue Honeysuckle (YBHS) Berry Counteracts CCl4 Induced Toxicity in Liver Injury Model of Mice. AB - Yichun Blue Honeysuckle (YBHS) is reported to have a broad range of health benefits including protection against a number of chronic diseases. The objective of our study was to determine whether YBHS exhibits antioxidant activity, and if so, determine how it provides protection against oxidative stress. Eight-week old mice (25 male and 25 female) were randomized into five groups (n = 10 per group). YBHS extract (at 6.25%, 12.5%, or 25%) was administrated via intra-gastric tube to mice at 0.1 mL/10 g body weight once daily for 7 days. On the 8th day, all animals except for the controls received 250 mg/kg of CCl4 through an intra gastric tube. The animals were sacrificed 6 h after CCl4 administration. Liver samples obtained from these mice were analyzed for the levels of Thiobarbituric Acid Reactive Substances (TBARS) and glutathione and the activities of Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase (GPx), using biochemical assay kits. Our results showed that YBHS indeed reduces lipid peroxidation, suggesting that YBHS decreases the Reactive Oxygen Species (ROS) levels. We also found that YBHS activated the endogenous antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase and its co enzyme glutathione reductase. In addition, we showed that glutathione levels were increased by YBHS treatment. Furthermore, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay revealed that YBHS has potent free radical scavenging activity. Based on the results from our study, we conclude that YBHS scavenges ROS by enhancing the activity of the endogenous antioxidant defense system activity for conferring liver protective effects. PMID- 28665314 TI - Subtitling for d/Deaf and Hard-of-Hearing Children: Current Practices and New Possibilities to Enhance Language Development. AB - In order to understand and fully comprehend a subtitle, two parameters within the linguistic code of audiovisual texts are key in the processing of the subtitle itself, namely, vocabulary and syntax. Through a descriptive and experimental study, the present article explores the transfer of the linguistic code of audiovisual texts in subtitling for deaf and hard-of-hearing children in three Spanish TV stations. In the first part of the study, we examine current practices in Spanish TV captioning to analyse whether syntax and vocabulary are adapted to satisfy deaf children's needs and expectations regarding subtitle processing. In the second part, we propose some alternative captioning criteria for these two variables based on the needs of d/Deaf and hard-of-hearing (DHH) children, suggesting a more appropriate way of displaying the written linguistic code for deaf children. Although no specific distinction will be made throughout this paper, it is important to refer to these terms as they have been widely used in the literature. Neves (2008) distinguishes between the "Deaf", who belong to a linguistic minority, use sign language as their mother tongue, and usually identify with a Deaf community and culture; the "deaf", who normally have an oral language as their mother tongue and feel part of the hearing community; and the "hard of hearing", who have residual hearing and, therefore, share the world and the sound experience of hearers. In the experimental study, 75 Spanish DHH children aged between 8 and 13 were exposed to two options: the actual broadcast captions on TV, and the alternative captions created by the authors. The data gathered from this exposure were used to analyse the children's comprehension of these two variables in order to draw conclusions about the suitability of the changes proposed in the alternative subtitles. PMID- 28665313 TI - Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer. AB - Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host's anti-tumor immune response are being explored. Hence, upcoming anti angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential. PMID- 28665316 TI - Erratum: Ksiksi, T., et al. Antioxidant, Lipoxygenase and Histone Deacetylase Inhibitory Activities of Acridocarpus orientalis from Al Ain and Oman. Molecules 2012, 17, 12521-12532. PMID- 28665318 TI - GNSS Spoofing Detection and Mitigation Based on Maximum Likelihood Estimation. AB - Spoofing attacks are threatening the global navigation satellite system (GNSS). The maximum likelihood estimation (MLE)-based positioning technique is a direct positioning method originally developed for multipath rejection and weak signal processing. We find this method also has a potential ability for GNSS anti spoofing since a spoofing attack that misleads the positioning and timing result will cause distortion to the MLE cost function. Based on the method, an estimation-cancellation approach is presented to detect spoofing attacks and recover the navigation solution. A statistic is derived for spoofing detection with the principle of the generalized likelihood ratio test (GLRT). Then, the MLE cost function is decomposed to further validate whether the navigation solution obtained by MLE-based positioning is formed by consistent signals. Both formulae and simulations are provided to evaluate the anti-spoofing performance. Experiments with recordings in real GNSS spoofing scenarios are also performed to validate the practicability of the approach. Results show that the method works even when the code phase differences between the spoofing and authentic signals are much less than one code chip, which can improve the availability of GNSS service greatly under spoofing attacks. PMID- 28665317 TI - Biological Fate of Fe3O4 Core-Shell Mesoporous Silica Nanoparticles Depending on Particle Surface Chemistry. AB - The biological fate of nanoparticles (NPs) for biomedical applications is highly dependent of their size and charge, their aggregation state and their surface chemistry. The chemical composition of the NPs surface influences their stability in biological fluids, their interaction with proteins, and their attraction to the cell membranes. In this work, core-shell magnetic mesoporous silica nanoparticles (Fe3O4@MSN), that are considered as potential theranostic candidates, are coated with polyethylene glycol (PEG) or 1,2-dimyristoyl-sn glycero-3-phosphocholine (DMPC) lipid bilayer. Their biological fate is studied in comparison to the native NPs. The physicochemical properties of these three types of NPs and their suspension behavior in different media are investigated. The attraction to a membrane model is also evaluated using a supported lipid bilayer. The surface composition of NPs strongly influences their dispersion in biological fluids mimics, protein binding and their interaction with cell membrane. While none of these types of NPs is found to be toxic on mice four days after intravenous injection of a dose of 40 mg kg-1 of NPs, their surface coating nature influences the in vivo biodistribution. Importantly, NP coated with DMPC exhibit a strong accumulation in liver and a very low accumulation in lung in comparison with nude or PEG ones. PMID- 28665319 TI - Synthesis, Characterization, and Nanomedical Applications of Conjugates between Resorcinarene-Dendrimers and Ibuprofen. AB - Ibuprofen has been reported to possess anticancer activity. In the present work, four ibuprofen conjugates of resorcinarene-Polyamidoamine PAMAM-dendrimers were synthesized with eight or 16 ibuprofen moieties. The ibuprofen was released from the dendrimers in a dependent manner. The drug-conjugated nanoresorcinarene dendrimers showed higher cellular uptake than free ibuprofen. In vitro cytotoxicity studies were performed with free ibuprofen and with the synthesized conjugates in U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and MDA-MB 231 (human mammary adenocarcinoma) cancer cell lines by different cytotoxicity assays. Ibuprofen conjugates of the first and second generations showed significant cytotoxic effects towards the human glioblastoma (U251) and human mammary adenocarcinoma (MCF-7, MDA) cell lines. Moreover, the ibuprofen conjugates improved cytotoxicity compared to free ibuprofen. Increased therapeutic efficacy was observed with specific ibuprofen conjugates of the second generation using low doses. PMID- 28665315 TI - MYC Modulation around the CDK2/p27/SKP2 Axis. AB - MYC is a pleiotropic transcription factor that controls a number of fundamental cellular processes required for the proliferation and survival of normal and malignant cells, including the cell cycle. MYC interacts with several central cell cycle regulators that control the balance between cell cycle progression and temporary or permanent cell cycle arrest (cellular senescence). Among these are the cyclin E/A/cyclin-dependent kinase 2 (CDK2) complexes, the CDK inhibitor p27KIP1 (p27) and the E3 ubiquitin ligase component S-phase kinase-associated protein 2 (SKP2), which control each other by forming a triangular network. MYC is engaged in bidirectional crosstalk with each of these players; while MYC regulates their expression and/or activity, these factors in turn modulate MYC through protein interactions and post-translational modifications including phosphorylation and ubiquitylation, impacting on MYC's transcriptional output on genes involved in cell cycle progression and senescence. Here we elaborate on these network interactions with MYC and their impact on transcription, cell cycle, replication and stress signaling, and on the role of other players interconnected to this network, such as CDK1, the retinoblastoma protein (pRB), protein phosphatase 2A (PP2A), the F-box proteins FBXW7 and FBXO28, the RAS oncoprotein and the ubiquitin/proteasome system. Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment. PMID- 28665320 TI - Dimension-Reduced Analog-Digital Mixed Measurement Method of Inductive Proximity Sensor. AB - Inductive proximity sensors (IPSs) present a unique no-contact advantage. They are widely preferred for displacement measurement in various industrial fields (e.g., aviation and aerospace), and they are improved continuously. When the inductance and resistance components of the IPS sensing core are separated, the influence of temperature drift on measurement can be eliminated. The complexity of online computation of component separation can be reduced using a two dimensional look-up table method. However, this method exhibits disadvantages, such as large capacity of the look-up table, dependency on precision measurement of sensing core parameter, and nonlinear distribution of measurement resolution. This study aims to overcome these disadvantages by examining the nonlinear relationship between the response of the sensing core and the ambient temperature, and proposes a dimension-reduced measurement method. The proposed method extracts the characteristics of the response curves at two temperatures and calculates the characteristics of the response curves at any temperature using a linear approximation. The look-up table capacity is less than 0.37% of the two-dimensional look-up table capacity (condensed) under the same condition; dimension reduction enables the construction of a complete look-up table directly by calibration procedures and avoids precise measurement on sensing core parameters; the calibration procedures establish uniform mapping of the distribution of measurement resolution. The experiment shows that, when the measurement ranges are 0-6, 0-5, and 0-4 mm, the maximum measurement errors are 0.140, 0.065, and 0.040 mm, respectively, under temperature ranging from 20 ? C to 110 ? C. This study extends the measurement range from 0-5 mm to 0-7 mm and improves the measurement accuracy over 0.1 mm (50% at 5 mm) compared with the two dimensional look-up table method. Therefore, the proposed method not only inherits the advantages of the original method but also achieves the above mentioned expected capacity improvements effectively. PMID- 28665321 TI - Capsaicin-Sensitive Sensory Nerves Are Necessary for the Protective Effect of Ghrelin in Cerulein-Induced Acute Pancreatitis in Rats. AB - Ghrelin was shown to exhibit protective and therapeutic effect in the gut. Aim of the study was to investigate the role of sensory nerves (SN) in the protective effect of ghrelin in acute pancreatitis (AP). Studies were performed on male Wistar rats or isolated pancreatic acinar cells. After capsaicin deactivation of sensory nerves (CDSN) or treatment with saline, rats were pretreated intraperitoneally with ghrelin or saline. In those rats, AP was induced by cerulein or pancreases were used for isolation of pancreatic acinar cells. Pancreatic acinar cells were incubated in cerulein-free or cerulein containing solution. In rats with intact SN, pretreatment with ghrelin led to a reversal of the cerulein-induced increase in pancreatic weight, plasma activity of lipase and plasma concentration of tumor necrosis factor-alpha (TNF-alpha). These effects were associated with an increase in plasma interleukin-4 concentration and reduction in histological signs of pancreatic damage. CDSN tended to increase the severity of AP and abolished the protective effect of ghrelin. Exposure of pancreatic acinar cells to cerulein led to increase in cellular expression of mRNA for TNF-alpha and cellular synthesis of this cytokine. Pretreatment with ghrelin reduced this alteration, but this effect was only observed in acinar cells obtained from rats with intact SN. Moreover, CDSN inhibited the cerulein- and ghrelin-induced increase in gene expression and synthesis of heat shock protein 70 (HSP70) in those cells. Ghrelin exhibits the protective effect in cerulein-induced AP on the organ and pancreatic acinar cell level. Sensory nerves ablation abolishes this effect. PMID- 28665322 TI - Pre-Replicative Repair of Oxidized Bases Maintains Fidelity in Mammalian Genomes: The Cowcatcher Role of NEIL1 DNA Glycosylase. AB - Genomic fidelity in the humans is continuously challenged by genotoxic reactive oxygen species (ROS) generated both endogenously during metabolic processes, and by exogenous agents. Mispairing of most ROS-induced oxidized base lesions during DNA replication induces mutations. Although bulky base adducts induced by ultraviolet light and other environmental mutagens block replicative DNA polymerases, most oxidized base lesions do not block DNA synthesis. In 8-oxo-G:A mispairs generated by the incorporation of A opposite unrepaired 8-oxo-G, A is removed by MutYH (MYH) for post-replicative repair, and other oxidized base lesions must be repaired prior to replication in order to prevent mutation fixation. Our earlier studies documented S phase-specific overexpression of endonuclease VIII-like 1 (NEIL1) DNA glycosylase (DG), one of five oxidized base excision repair (BER)-initiating enzymes in mammalian cells, and its high affinity for replication fork-mimicking single-stranded (ss)DNA substrates. We recently provided experimental evidence for the role of NEIL1 in replicating strand repair, and proposed the "cowcatcher" model of pre-replicative BER, where NEIL1's nonproductive binding to the lesion base in ssDNA template blocks DNA chain elongation, causing fork regression. Repair of the lesion in the then re annealed duplex is carried out by NEIL1 in association with the DNA replication proteins. In this commentary, we highlight the critical role of pre-replicative BER in preventing mutagenesis, and discuss the distinction between pre replicative vs. post-replicative BER. PMID- 28665323 TI - Characterization of Polyelectrolyte Complex Formation Between Anionic and Cationic Poly(amino acids) and Their Potential Applications in pH-Dependent Drug Delivery. AB - Polyelectrolyte complexes (PECs) are self-assembling nano-sized constructs that offer several advantages over traditional nanoparticle carriers including controllable size, biodegradability, biocompatibility, and lack of toxicity, making them particularly appealing as tools for drug delivery. Here, we discuss potential application of PECs for drug delivery to the slightly acidic tumor microenvironment, a pH in the range of 6.5-7.0. Poly(l-glutamic acid) (En), poly(l-lysine) (Kn), and a copolymer composed of histidine-glutamic acid repeats ((HE)n) were studied for their ability to form PECs, which were analyzed for size, polydispersity, and pH sensitivity. PECs showed concentration dependent size variation at residue lengths of E51/K55 and E135/K127, however, no complexes were observed when E22 or K21 were used, even in combination with the longer chains. (HE)20/K55 PECs could encapsulate daunomycin, were stable from pH 7.4 6.5, and dissociated completely between pH 6.5-6.0. Conversely, the E51-dauno/K55 PEC dissociated between pH 4.0 and 3.0. These values for pH-dependent particle dissociation are consistent with the pKa's of the ionizable groups in each formulation and indicate that the specific pH-sensitivity of (HE)20-dauno/K55 PECs is mediated by incorporation of histidine. This response within a pH range that is physiologically relevant to the acidic tumors suggests a potential application of these PECs in pH-dependent drug delivery. PMID- 28665324 TI - Diosmin, a Citrus Nutrient, Activates Imidazoline Receptors to Alleviate Blood Glucose and Lipids in Type 1-Like Diabetic Rats. AB - Diosmin is a nutrient that is widely contained in citrus and that has been indicated to improve glucose metabolism in diabetic disorders. Recently, we demonstrated that diosmin induces beta-endorphin to lower hyperglycemia in diabetic rats. However, the mechanisms of diosmin in opioid secretion were unclear. Therefore, we focused on the secretion of opioids from isolated adrenal glands induced by diosmin. The changes in the released beta-endorphin-like immunoreactivity (BER) were determined using ELISA. Diosmin increased the BER level in a dose-dependent manner, and this effect was markedly reduced in the absence of calcium ions. Activation of the imidazoline I-2 receptor (I-2R) has been introduced to induce opioid secretion. Interestingly, we observed that diosmin activates CHO cells expressing I-R. Additionally, diosmin-increased BER was inhibited by the blockade of I-2R in isolated adrenal glands. Additionally, an antagonist of I-2R blocked diosmin-induced effects, including the reduction in hyperglycemia and the increase in plasma BER in streptozotocin-induced diabetic rats (STZ-diabetic rats). Repeated treatment of STZ-diabetic rats with diosmin for one week induced changes in hepatic glycogen, lipid levels, and the expression of phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, an antagonist of I-2R blocked the diosmin-induced changes. Additionally, plasma lipids modified by diosmin were also reversed by the blockade of I-2R in STZ diabetic rats. Taken together, we suggest that diosmin may activate I-2R to enhance the secretion of beta-endorphin from adrenal glands and to influence metabolic homeostasis, resulting in alleviation of blood glucose and lipids in STZ-diabetic rats. PMID- 28665325 TI - Risk Analysis of a Fuel Storage Terminal Using HAZOP and FTA. AB - The size and complexity of industrial chemical plants, together with the nature of the products handled, means that an analysis and control of the risks involved is required. This paper presents a methodology for risk analysis in chemical and allied industries that is based on a combination of HAZard and OPerability analysis (HAZOP) and a quantitative analysis of the most relevant risks through the development of fault trees, fault tree analysis (FTA). Results from FTA allow prioritizing the preventive and corrective measures to minimize the probability of failure. An analysis of a case study is performed; it consists in the terminal for unloading chemical and petroleum products, and the fuel storage facilities of two companies, in the port of Valencia (Spain). HAZOP analysis shows that loading and unloading areas are the most sensitive areas of the plant and where the most significant danger is a fuel spill. FTA analysis indicates that the most likely event is a fuel spill in tank truck loading area. A sensitivity analysis from the FTA results show the importance of the human factor in all sequences of the possible accidents, so it should be mandatory to improve the training of the staff of the plants. PMID- 28665326 TI - Calcium Intake and the Risk of Ovarian Cancer: A Meta-Analysis. AB - Several epidemiological studies have evaluated the association between calcium intake and the risk of ovarian cancer. However, the results of these studies remain controversial. Thus, we performed a meta-analysis to explore the association between calcium intake and the risk of ovarian cancer. Pubmed, Embase and Web of Science were searched for eligible publications up to April 2017. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Small-study effect was estimated using Egger's test and the funnel plot. Among 15 epidemiological studies involving 493,415 participants and 7453 cases eligible for this meta-analysis, 13 studies were about dietary calcium intake, 4 studies about dairy calcium intake and 7 studies about dietary plus supplemental calcium intake. When comparing the highest with the lowest intake, the pooled RRs of ovarian cancer were 0.80 (95% CI 0.72-0.89) for dietary calcium, 0.80 (95% CI 0.66-0.98) for dairy calcium and 0.90 (95% CI 0.65-1.24) for dietary plus supplemental calcium, respectively. Dietary calcium was significantly associated with a reduced risk of ovarian cancer among cohort studies (RR = 0.86, 95% CI 0.74-0.99) and among case-control studies (RR = 0.75, 95% CI 0.64-0.89). In subgroup analysis by ovarian cancer subtypes, we found a statistically significant association between the dietary calcium (RR = 0.78, 95% CI 0.69-0.88) and the risk of epithelial ovarian cancer (EOC). This meta-analysis indicated that increased calcium intake might be inversely associated with the risk of ovarian cancer; this still needs to be confirmed by larger prospective cohort studies. PMID- 28665327 TI - Green Mind Theory: How Brain-Body-Behaviour Links into Natural and Social Environments for Healthy Habits. AB - We propose a Green Mind Theory (GMT) to link the human mind with the brain and body, and connect the body into natural and social environments. The processes are reciprocal: environments shape bodies, brains, and minds; minds change body behaviours that shape the external environment. GMT offers routes to improved individual well-being whilst building towards greener economies. It builds upon research on green exercise and nature-based therapies, and draws on understanding derived from neuroscience and brain plasticity, spiritual and wisdom traditions, the lifeways of original cultures, and material consumption behaviours. We set out a simple metaphor for brain function: a bottom brain stem that is fast acting, involuntary, impulsive, and the driver of fight and flight behaviours; a top brain cortex that is slower, voluntary, the centre for learning, and the driver of rest and digest. The bottom brain reacts before thought and directs the sympathetic nervous system. The top brain is calming, directing the parasympathetic nervous system. Here, we call the top brain blue and the bottom brain red; too much red brain is bad for health. In modern high-consumption economies, life has often come to be lived on red alert. An over-active red mode impacts the gastrointestinal, immune, cardiovascular, and endocrine systems. We develop our knowledge of nature-based interventions, and suggest a framework for the blue brain-red brain-green mind. We show how activities involving immersive attention quieten internal chatter, how habits affect behaviours across the lifecourse, how long habits take to be formed and hard-wired into daily practice, the role of place making, and finally how green minds could foster prosocial and greener economies. We conclude with observations on twelve research priorities and health interventions, and ten calls to action. PMID- 28665328 TI - Metal Atom Effect on the Photophysical Properties of Mg(II), Zn(II), Cd(II), and Pd(II) Tetraphenylporphyrin Complexes Proposed as Possible Drugs in Photodynamic Therapy. AB - The effects of Mg, Zn, Cd, and Pd dications on the photophysical properties of the tetraphenylporphyrin ligand have been explored, considering the corresponding complexes and by using the density functional theory and its time-dependent extension. Results show that absorption wavelengths do not change significantly when the metal ion changes contrary to what happens to the singlet-triplet energy gaps (DeltaES-T) and the spin-orbit matrix elements PsiSnHsoPsiTm. The most probable intersystem spin crossing (ISC) pathways for the population of the lowest triplet states have been explored. Our findings can contribute to rationalize the available experimental data and promote the potential therapeutic use of these compounds as photosensitizers in photodynamic therapy (PDT). PMID- 28665329 TI - Treatment of Intrusive Suicidal Imagery Using Eye Movements. AB - Suicide and suicidal behavior are major public health concerns, and affect 3-9% of the population worldwide. Despite increased efforts for national suicide prevention strategies, there are still few effective interventions available for reducing suicide risk. In this article, we describe various theoretical approaches for suicide ideation and behavior, and propose to examine the possible effectiveness of a new and innovative preventive strategy. A model of suicidal intrusion (mental imagery related to suicide, also referred to as suicidal flash forwards) is presented describing one of the assumed mechanisms in the etiology of suicide and the mechanism of therapeutic change. We provide a brief rationale for an Eye Movement Dual Task (EMDT) treatment for suicidal intrusions, describing techniques that can be used to target these suicidal mental images and thoughts to reduce overall behavior. Based on the available empirical evidence for the mechanisms of suicidal intrusions, this approach appears to be a promising new treatment to prevent suicidal behavior as it potentially targets one of the linking pins between suicidal ideation and suicidal actions. PMID- 28665330 TI - Effects of Epigallocatechin-3-Gallate on Autophagic Lipolysis in Adipocytes. AB - Previous studies demonstrated effects of green tea on weight loss; however, green tea-induced modulation of adipocyte function is not fully understood. Here, we investigated effects of the major green tea phytochemical, epigallocatechin-3 gallate (EGCG) on triglyceride contents, lipolysis, mitochondrial function, and autophagy, in adipocytes differentiated from C3H10T1/2 cells and immortalized pre adipocytes in vitro. EGCG reduced the triglycerol content significantly in adipocytes by 25%, comparable to the nutrient starvation state. EGCG did not affect protein kinase A signaling or brown adipocyte marker expression in adipocytes; however, EGCG increased autophagy, as measured by autophagy flux analysis and immunoblot analysis of LC3B, ATG7, and Beclin1. EGCG treatment reduced mitochondrial membrane potential by 56.8% and intracellular ATP levels by 49.1% compared to controls. Although mammalian target of rapamycin signaling was not upregulated by EGCG treatment, EGCG treatment induced AMP-activated protein kinase phosphorylation, indicating an energy-depleted state. In addition, EGCG increased the association between RAB7 and lipid droplets, suggesting that lipophagy was activated. Finally, knockdown of Rab7 attenuated the EGCG-dependent reduction in lipid contents. Collectively, these results indicated that EGCG upregulated autophagic lipolysis in adipocytes, supporting the therapeutic potential of EGCG as a caloric restriction mimetic to prevent obesity and obesity related metabolic diseases. PMID- 28665331 TI - Natural Docosahexaenoic Acid in the Triglyceride Form Attenuates In Vitro Microglial Activation and Ameliorates Autoimmune Encephalomyelitis in Mice. AB - Many neurodegenerative diseases are associated, at least in part, to an inflammatory process in which microglia plays a major role. The effect of the triglyceride form of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (TG-DHA) was assayed in vitro and in vivo to assess the protective and anti inflammatory activity of this compound. In the in vitro study, BV-2 microglia cells were previously treated with TG-DHA and then activated with Lipopolysaccharide (LPS) and Interferon-gamma (IFN-gamma). TG-DHA treatment protected BV-2 microglia cells from oxidative stress toxicity attenuating NO production and suppressing the induction of inflammatory cytokines. When compared with DHA in the ethyl-ester form, a significant difference in the ability to inhibit NO production in favor of TG-DHA was observed. TG-DHA inhibited significantly splenocyte proliferation but isolated CD4+ lymphocyte proliferation was unaffected. In a mice model of autoimmune encephalomyelitis (EAE), 250 mg/kg/day oral TG-DHA treatment was associated with a significant amelioration of the course and severity of the disease as compared to untreated animals. TG-DHA treated EAE mice showed a better weight profile, which is a symptom related to a better course of encephalomyelitis. TG-DHA may be a promising therapeutic agent in neuroinflammatory processes and merit to be more extensively studied in human neurodegenerative disorders. PMID- 28665332 TI - Farmers' Risk Preferences in Rural China: Measurements and Determinants. AB - This study measures farmers' risk attitudes in rural China using a survey instrument and a complementary experiment conducted in the field with the same sample of subjects. Using a question asking people about their willingness to take risks "in general", we found that the average response of our sample is slightly risk averse. Farmers' exogenous factors (age, gender, and height) and self-reported happiness have a significant impact on farmers' willingness to take risks. The experiment results show that approximately 44% of farmers in the study area are risk averse. We compare farmers' self-reported measures of risk preferences derived from the survey instrument to preferences elicited through the experimental task. Results show that answers to the general risk attitude question in the survey can predict farmers' behaviors in the experiment to a statistically significant degree. This paper can contribute to the empirical literature on comparing local farmers' risk attitudes across different risk preference measurement methods in the developing world. PMID- 28665333 TI - Public Support for Electronic Cigarette Regulation in Hong Kong: A Population Based Cross-Sectional Study. AB - This study aimed to gauge the Hong Kong's public support towards new e-cigarette regulation, and examine the associated factors of the support. We conducted a two stage, randomized cross-sectional telephone-based survey to assess the public support towards the banning of e-cigarette promotion and advertisement, its use in smoke-free venues, the sale to people aged under 18, and regulating the sale of nicotine-free e-cigarettes. Adults (aged 15 years or above) who were never smoking (n = 1706), ex-smoking (n = 1712) or currently smoking (n = 1834) were included. Over half (57.8%) supported all the four regulations. Banning of e cigarette promotion and advertisement (71.7%) received slightly less support than the other three regulations (banning of e-cigarette use in smoke-free venues (81.5%); banning of e-cigarette sale to minors (93.9%); sale restriction of nicotine-free e-cigarettes (80.9%)). Current smokers, and perceiving e-cigarettes as less harmful than traditional cigarettes or not knowing the harmfulness, were associated with a lower level of support. Our findings showed a strong public support for further regulation of e-cigarettes in Hong Kong. Current stringent measures on tobacco and e-cigarettes, and media reports on the harmfulness of e cigarettes may underpin the strong support for the regulation. PMID- 28665334 TI - Early Desquamating Perineal Erythema in a Febrile Infant: A Characteristic Clinical Feature of Kawasaki Disease. AB - Background: The occurrence of a distinctive perineal eruption that appears early in infants with Kawasaki disease (KD), the most relevant type of febrile vasculitis of childhood, has received little attention in pediatric reports. KD diagnosis is based on clinical criteria, which can be supported by laboratory abnormalities or positive echocardiography findings: difficulty in diagnosis can be increased by incomplete or atypical presentations, but a timely diagnostic process is essential in the youngest patients who are more prone to the risk of cardiac sequelae resulting from KD. Case Presentation: In this report, we present the case of a 2-month-old infant with an unusual presentation of KD, in whom diagnosis was made despite fever remission on the fourth day of hospitalization following intravenous corticosteroid therapy to treat concomitant bronchoconstriction. The presence of early desquamating perineal erythema led to the consideration of KD diagnosis, confirmed by the echocardiographic assessment of right and left coronary artery dilatations with pericardial effusion on the fifth day of hospital stay. Conclusions: Diagnosis of KD represents a demanding challenge, mainly when the illness starts with an incomplete or nuanced presentation. An erythematous desquamating perineal rash is a valuable early clinical clue, which might facilitate a prompt diagnosis of KD. This case emphasizes that an accurate assessment of all clinical features, including perineal erythema with early tendency to desquamation, and an eventual echocardiography, are necessary in an infant displaying fever to corroborate the suspicion of KD. PMID- 28665336 TI - Factors that Influence Intake to One Municipal Animal Control Facility in Florida: A Qualitative Study. AB - This qualitative study identified a study area by visualizing one year of animal intake from a municipal animal shelter on geographic information systems (GIS) maps to select an area of high stray-dog intake to investigate. Researchers conducted semi-structured interviews with residents of the selected study area to elucidate why there were high numbers of stray dogs coming from this location. Using grounded theory, three themes emerged from the interviews: concerns, attitudes, and disparities. The residents expressed concerns about animal welfare, personal safety, money, and health. They held various attitudes toward domestic animals in the community, including viewing them as pets, pests, or useful commodities (products). Residents expressed acceptance as well as some anger and fear about the situation in their community. Interviewees revealed they faced multiple socioeconomic disparities related to poverty. Pet abandonment can result when pet owners must prioritize human needs over animal needs, leading to increased shelter intake of stray dogs. Community-specific strategies for reducing local animal shelter intake should address the issue of pet abandonment by simultaneously targeting veterinary needs of animals, socioeconomic needs of residents, and respecting attitude differences between residents and shelter professionals. PMID- 28665335 TI - Prenylflavonoid Isoxanthohumol Sensitizes MCF-7/ADR Cells to Doxorubicin Cytotoxicity via Acting as a Substrate of ABCB1. AB - Isoxanthohumol is a unique prenylflavonoid with the highest content in beer. Isoxanthohumol has multiple bioactivities and has recently received considerable attention in the scientific community. Nonetheless; its effect on drug resistant cancer cells has rarely been studied. In this paper; we investigated the synergistic effect of isoxanthohumol and doxorubicin on doxorubicin resistant MCF 7/ADR cells. Our results showed that isoxanthohumol sensitized the cytotoxic effect of doxorubicin on MCF-7/ADR cells via increased proliferation inhibition and apoptosis stimulation. Molecular mechanism studies further demonstrated that isoxanthohumol inhibited ABCB1-mediated doxorubicin efflux; stimulated the ATPase activity of ABCB1 (ATP-binding cassette sub-family B member 1); and acted as an ABCB1 substrate. Molecular docking results suggested that isoxanthohumol bound to the central transmembrane domain of ABCB1 and its binding site overlapped with the doxorubicin binding site. The present studies demonstrated that isoxanthohumol was a competitive ABCB1 inhibitor which reversed ABCB1-mediated doxorubicin resistance in MCF-7/ADR cells; and therefore could be further developed to help with overcoming ABCB1-mediated drug resistance. PMID- 28665337 TI - First-Principles Study of Structural, Electronic and Magnetic Properties of Metal Centered Tetrahexahedral V15+ Cluster. AB - The V-centered bicapped hexagonal antiprism structure (A), as the most stable geometry of the cationic V15+ cluster, is determined by using infrared multiple photo dissociation (IR-MPD) in combination with density functional theory computations. It is found that the A structure can be stabilized by 18 delocalized 3c-2e sigma-bonds on outer V3 triangles of the bicapped hexagonal antiprism surface and 12 delocalized 4c-2e sigma-bonds on inner trigonal pyramidal V4 moiety, and the features are related to the strong p-d hybridization of the cluster. The total magnetic moments on the cluster are predicted to be 2.0 uB, which come mainly from the central vanadium atom. PMID- 28665338 TI - Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives. AB - A new series of quinazoline-4(3H)-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip) injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H)-ones (1-24) were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204-0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100%) against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II). The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution. PMID- 28665339 TI - Crystal Structure of the Carboxy-Terminal Region of the Bacteriophage T4 Proximal Long Tail Fiber Protein Gp34. AB - Long tail fibers of bacteriophage T4 are formed by proteins gp34, gp35, gp36, and gp37, with gp34 located at the phage-proximal end and gp37 at the phage-distal, receptor-binding end. We have solved the structure of the carboxy-terminal region of gp34, consisting of amino acids 894-1289, by single-wavelength anomalous diffraction and extended the structure to amino acids 744-1289 using data collected from crystals containing longer gp34-fragments. The structure reveals three repeats of a mixed alpha-beta fibrous domain in residues 744 to 877. A triple-helical neck connects to an extended triple beta-helix domain (amino acids 900-1127) punctuated by two beta-prism domains. Next, a beta-prism domain decorated with short helices and extended beta-helices is present (residues 1146 1238), while the C-terminal end is capped with another short beta-helical region and three beta-hairpins. The structure provides insight into the stability of the fibrous gp34 protein. PMID- 28665340 TI - The Buffer Effect of Therapy Dog Exposure on Stress Reactivity in Undergraduate Students. AB - Stress is an insidious health risk that is commonly reported among university students. While research suggests that dog exposure may facilitate recovery from a stress response, little is known about the buffer effect of dog exposure on the stress response to a future stressor. This study examined whether interaction with a therapy dog could reduce the strength of the physiological stress response when exposed to a subsequent stressor. Sixty-one university students were randomly assigned to either a therapy dog (TD, n = 31) or a no-dog control (C, n = 30) group. The stress response was measured by electrodermal activity (EDA) in response to the Paced Auditory Serial Addition Test (PASAT). Participants also completed questionnaires that assessed pet attitude, general stress levels, and affect. Analyses of covariance (ANCOVAs) showed that increase in EDA was significantly more pronounced in the C group than in the TD group (p < 0.01). Pet attitudes did not modulate the buffer effect of therapy dog exposure. Results suggest that therapy dog exposure may buffer the stress response in university students, which has implications for the promotion of a viable stress management program on university campuses. PMID- 28665341 TI - Chemical Composition, Antibacterial and Antifungal Activities of Crude Dittrichia viscosa (L.) Greuter Leaf Extracts. AB - The small amount of data regarding the antifungal activity of Dittrichia viscosa (L.) Greuter against dermatophytes, Malassezia spp. and Aspergillus spp., associated with the few comparative studies on the antimicrobial activity of methanolic, ethanolic, and butanolic extracts underpins the study herein presented. The total condensed tannin (TCT), phenol (TPC), flavonoid (TFC), and caffeoylquinic acid (CQC) content of methanol, butanol, and ethanol (80% and 100%) extracts of D. viscosa were assessed and their bactericidal and fungicidal activities were evaluated. The antibacterial, anti-Candida and anti-Malassezia activities were evaluated by using the disk diffusion method, whereas the anti Microsporum canis and anti-Aspergillus fumigatus activities were assessed by studying the toxicity effect of the extracts on vegetative growth, sporulation and germination. The methanolic extract contained the highest TPC and CQC content. It contains several phytochemicals mainly caffeoylquinic acid derivatives as determined by liquid chromatography with photodiode array and electrospray ionisation mass spectrometric detection (LC/PDA/ESI-MS) analysis. All extracts showed an excellent inhibitory effect against bacteria and Candida spp., whereas methanolic extract exhibited the highest antifungal activities against Malassezia spp., M. canis and A. fumigatus strains. The results clearly showed that all extracts, in particular the methanolic extract, might be excellent antimicrobial drugs for treating infections that are life threatening (i.e., Malassezia) or infections that require mandatory treatments (i.e., M. canis or A. fumigatus). PMID- 28665342 TI - Exogenous Feeding of Fructose and Phenylalanine Further Improves Betulin Production in Suspended Betula platyphylla Cells under Nitric Oxide Treatment. AB - The aim of this study was to assay by NMR the metabolites which contribute to betulin production. 8-day-old suspended birch (Betula platyphylla) cells were treated by sodium nitroprusside (SNP) treatment, an NO donor, and 2-(4 carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (cPTIO), an NO specific scavenger. The results showed that betulin production was increased by five times after SNP treatment, similar with that of the control under cPTIO treatment. Forty one metabolites were detected after SNP treatment or cPTIO treatment. Among them, 10 were found to significantly contribute to the differences observed between controls and treated cell culture samples. To validate the contribution of the above 10 metabolites to betulin production, myo inositol, fructose and phenylalanine based on correlation analysis between the content of 12 metabolites and betulin were used to feed birch suspension cell cultures under SNP treatment. Exogenous feeding of fructose or phenylalanine further enhanced the betulin production under SNP treatment, but myo-inositol had the opposite result. PMID- 28665344 TI - Sustainable Use of Pesticide Applications in Citrus: A Support Tool for Volume Rate Adjustment. AB - Rational application of pesticides by properly adjusting the amount of product to the actual needs and specific conditions for application is a key factor for sustainable plant protection. However, current plant protection product (PPP) labels registered for citrus in EU are usually expressed as concentration (%; rate/hl) and/or as the maximum dose of product per unit of ground surface, without taking into account those conditions. In this work, the fundamentals of a support tool, called CitrusVol, developed to recommend mix volume rates in PPP applications in citrus orchards using airblast sprayers, are presented. This tool takes into consideration crop characteristics (geometry, leaf area density), pests, and product and application efficiency, and it is based on scientific data obtained previously regarding the minimum deposit required to achieve maximum efficacy, efficiency of airblast sprayers in citrus orchards, and characterization of the crop. The use of this tool in several commercial orchards allowed a reduction of the volume rate and the PPPs used in comparison with the commonly used by farmers of between 11% and 74%, with an average of 31%, without affecting the efficacy. CitrusVol is freely available on a website and in an app for smartphones. PMID- 28665343 TI - Tricholides A and B and Unnarmicin D: New Hybrid PKS-NRPS Macrocycles Isolated from an Environmental Collection of Trichodesmium thiebautii. AB - Bioassay-guided isolation of the lipophilic extract of Trichodesmium thiebautii bloom material led to the purification and structure characterization of two new hybrid polyketide-non-ribosomal peptide (PKS-NRPS) macrocyclic compounds, tricholides A and B (1 and 2). A third macrocyclic compound, unnarmicin D (3), was identified as a new depsipeptide in the unnarmicin family, given its structural similarity to the existing compounds in this group. The planar structures of 1-3 were determined using 1D and 2D NMR spectra and complementary spectroscopic and spectrometric procedures. The absolute configurations of the amino acid components of 1-3 were determined via acid hydrolysis, derivitization with Marfey's reagent and HPLC-UV comparison to authentic amino acid standards. The absolute configuration of the 3-hydroxydodecanoic acid moiety in 3 was determined using a modified Mosher's esterification procedure on a linear derivative of tricharmicin (4) and additionally by a comparison of 13C NMR shifts of 3 to known depsipeptides with beta-hydroxy acid subunits. Tricholide B (2) showed moderate cytotoxicity to Neuro-2A murine neuroblastoma cells (EC50: 14.5 +/- 6.2 MUM). PMID- 28665345 TI - In Vitro Effect of 8-Prenylnaringenin and Naringenin on Fibroblasts and Glioblastoma Cells-Cellular Accumulation and Cytotoxicity. AB - Gliomas are one of the most aggressive and treatment-resistant types of human brain cancer. Identification and evaluation of anticancer properties of compounds found in plants, such as naringenin (N) and 8-prenylnaringenin (8PN), are among the most promising applications in glioma therapy. The prenyl group seems to be crucial to the anticancer activity of flavones, since it may lead to enhanced cell membrane targeting and thus increased intracellular activity. It should be noted that 8PN content in hop cones is 10 to 100 times lower compared to other flavonoids, such as xanthohumol. In the study presented, we used a simple method for the synthesis of 8PN from isoxanthohumol-O-demethylation, with a high yield of 97%. Cellular accumulation and cytotoxicity of naringenin and 8 prenylnaringenin in normal (BJ) and cancer cells (U-118 MG) was also examined. Obtained data indicated that 8-prenylnaringenin exhibited higher cytotoxicity against used cell lines than naringenin, and the effect of both flavones was stronger in U-118 MG cells than in normal fibroblasts. The anticancer properties of 8PN correlated with its significantly greater (37%) accumulation in glioblastoma cells than in normal fibroblasts. Additionally, naringenin demonstrated higher selectivity for glioblastoma cells, as it was over six times more toxic for cancer than normal cells. Our results provide evidence that examined prenylated and non-prenylated flavanones have different biological activities against normal and cancer cell lines, and this property may be useful in designing new anticancer drugs for glioblastoma therapy. PMID- 28665346 TI - A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide. AB - Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and 1H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production. PMID- 28665347 TI - Early Onset of Type 1 Diabetes and Educational Field at Upper Secondary and University Level: Is Own Experience an Asset for a Health Care Career? AB - Ill health in early life has a significant negative impact on school grades, grade repetition, educational level, and labor market outcomes. However, less is known about qualitative socio-economic consequences of a health shock in childhood or adolescence. We investigate the relationship between onset of type 1 diabetes up to age 15 and the probability of choosing and completing a health oriented path at upper secondary and university level of education. We analyze the Swedish Childhood Diabetes Register, the National Educational Register, and other population registers in Sweden for 2756 people with type 1 diabetes and 10,020 matched population controls. Educational decisions are modeled as unsorted series of binary choices to assess the choice of educational field as a potential mechanism linking early life health to adult outcomes. The analyses reject the hypothesis of no systematic differences in choice of educational field between people with and without type 1 diabetes at both levels. The results are robust to selection on ability proxies and across sensitivity analysis. We conclude that the observed pro health-oriented educational choices among people with type 1 diabetes in our data are consistent with disease onset in childhood and adolescence having qualitative impact on life-course choices. PMID- 28665348 TI - Kinetics, Mechanism and Theoretical Studies of Norbornene-Ethylene Alternating Copolymerization Catalyzed by Organopalladium(II) Complexes Bearing Hemilabile alpha-Amino-pyridine. AB - Cationic methylpalladium complexes bearing hemilabile bidentate alpha-amino pyridines can serve as effective precursors for catalytic alternating copolymerization of norbornene (N) and ethylene (E), under mild conditions. The norbornyl palladium complexes in the formula of {[RHNCH2(o C6H4N)]Pd(C7H10Me)(NCMe)}(BF4) (R = iPr (2a), tBu (2b), Ph (2c), 2,6-Me2C6H3 (2d), 2,6-iPr2C6H3 (2e)) were synthesized via single insertion of norbornene into the corresponding methylpalladium complexes 1a-1e, respectively. Both square planar methyl and norbornyl palladium complexes exhibit facile equilibria of geometrical isomerization, via sterically-controlled amino decoordination recoordination of amino-pyridine. Kinetic studies of E-insertion, N-insertion of complexes 1 and 2, and the geometric isomerization reactions have been examined by means of VT-NMR, and found in excellent agreement with the results estimated by DFT calculations. The more facile N-insertion in the cis-isomers, and ready geometric isomerization, cooperatively lead to a new mechanism that accounts for the novel catalytic formation of alternating COC. PMID- 28665349 TI - Perna canaliculus and the Intestinal Microbiome. AB - Natural medicines are often an attractive option for patients diagnosed with chronic conditions. Three main classes of bioactives that have been reported from marine mussel extracts include proteins, lipids and carbohydrates. Commercially, the most relevant species of marine mollusks belong to two genera, Perna and Mytilus. Specifically, the Perna canaliculus species has been repeatedly demonstrated to harbor anti-inflammatory compounds such as omega-3 polyunsaturated fatty acids (omega-3 PUFAs) that can ameliorate pro-inflammatory conditions, or proteins that can promote thrombin inhibitory activity. Recent clinical studies have posited that extracts from green-lipped mussels may lead to prebiotic activity in the intestinal microbiome that in turn has been reported to improve symptoms of osteoarthritis of the knee. Prebiotics have been reported to favorably interact with the intestinal microbiome through the proliferation of beneficial bacteria in the gut, suppressing exogenous and endogenous intestinal infections and promoting homeostasis by balancing local pro- and anti inflammatory actions. Bioactive compounds from Perna canaliculus are functional foods and, in this regard, may positively interact with the intestinal microbiome and provide novel therapeutic solutions for intra-intestinal and extra-intestinal inflammatory conditions. PMID- 28665350 TI - Histone Lysine Methylation and Neurodevelopmental Disorders. AB - Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases. PMID- 28665352 TI - Covariates of Identified Stress and Depression among Seasonal Farmworkers. AB - Many noted difficulties of farmworker life result in increased risk for stress and depression. To date, limited research has focused primarily on seasonal farmworkers; much of the prior research examines migrant farmworkers or both groups collectively. This study aims to: (1) describe levels of stress and depression among a sample of seasonal farmworkers; and (2) identify if covariates (age, gender, marital status, education level, years of residency, problems obtaining healthcare due to documentation, language barriers, transportation, costs, medical insurance, and stress level) are significant predictors of depressive symptoms. Survey data were collected from 150 Latino seasonal farmworkers. A hierarchical binary logistic regression was conducted to identify significant covariates. The results indicated that the only statistically significant covariates were health insurance coverage (p = 0.025) and stress (p = 0.008). Those farmworkers without health insurance were 1.8 times more likely than those with health insurance to possess depressive symptoms, while those demonstrating higher stress levels were over 7 times more likely to demonstrate symptoms of depression. The implications of the results are discussed in the manuscript. PMID- 28665353 TI - Identification of Direct Activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by Structure-Based Virtual Screening and Molecular Docking Approach. AB - Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of energy metabolism and has been targeted for drug development of therapeutic intervention in Type II diabetes and related diseases. Recently, there has been renewed interest in the development of direct beta1-selective AMPK activators to treat patients with diabetic nephropathy. To investigate the details of AMPK domain structure, sequence alignment and structural comparison were used to identify the key amino acids involved in the interaction with activators and the structure difference between beta1 and beta2 subunits. Additionally, a series of potential beta1-selective AMPK activators were identified by virtual screening using molecular docking. The retrieved hits were filtered on the basis of Lipinski's rule of five and drug-likeness. Finally, 12 novel compounds with diverse scaffolds were obtained as potential starting points for the design of direct beta1-selective AMPK activators. PMID- 28665351 TI - Specific Depletion of Leukemic Stem Cells: Can MicroRNAs Make the Difference? AB - For over 40 years the standard treatment for acute myeloid leukemia (AML) patients has been a combination of chemotherapy consisting of cytarabine and an anthracycline such as daunorubicin. This standard treatment results in complete remission (CR) in the majority of AML patients. However, despite these high CR rates, only 30-40% (<60 years) and 10-20% (>60 years) of patients survive five years after diagnosis. The main cause of this treatment failure is insufficient eradication of a subpopulation of chemotherapy resistant leukemic cells with stem cell-like properties, often referred to as "leukemic stem cells" (LSCs). LSCs co exist in the bone marrow of the AML patient with residual healthy hematopoietic stem cells (HSCs), which are needed to reconstitute the blood after therapy. To prevent relapse, development of additional therapies targeting LSCs, while sparing HSCs, is essential. As LSCs are rare, heterogeneous and dynamic, these cells are extremely difficult to target by single gene therapies. Modulation of miRNAs and consequently the regulation of hundreds of their targets may be the key to successful elimination of resistant LSCs, either by inducing apoptosis or by sensitizing them for chemotherapy. To address the need for specific targeting of LSCs, miRNA expression patterns in highly enriched HSCs, LSCs, and leukemic progenitors, all derived from the same patients' bone marrow, were determined and differentially expressed miRNAs between LSCs and HSCs and between LSCs and leukemic progenitors were identified. Several of these miRNAs are specifically expressed in LSCs and/or HSCs and associated with AML prognosis and treatment outcome. In this review, we will focus on the expression and function of miRNAs expressed in normal and leukemic stem cells that are residing within the AML bone marrow. Moreover, we will review their possible prospective as specific targets for anti-LSC therapy. PMID- 28665354 TI - A Validation Study of an Interviewer-Administered Short Food Frequency Questionnaire in Assessing Dietary Vitamin D and Calcium Intake in Swedish Children. AB - Vitamin D and calcium are essential nutrients with a range of biological effects of public health relevance. This study aimed to validate a short food frequency questionnaire (SFFQ) against a three-day food record (3D record), assessing the intake of vitamin D and calcium in Swedish children during wintertime. In a double-blinded, randomized food-based intervention study on the effect of feeding different daily doses of vitamin D supplement to 5-7-year-old children (n = 85), 79 (93%) participants completed SFFQ1 at baseline and SFFQ2 after the intervention, and 72 were informed to fill in a 3D record. The 28 (39%) children who completed the 3D record were included in this validation study. The baseline level of serum-25 hydroxy vitamin D [S-25(OH)D] was used as a biomarker. The correlation between all three instruments were moderate to strong. SFFQ2 and the 3D record correlated moderately to S-25(OH)D. Bland-Altman analysis showed that SFFQ2 overestimated vitamin D intake by on average 0.6 MUg/day, (limits of agreement (LOA) 5.7 and -4.6 MUg/day), whereas the intake of calcium was underestimated by on average 29 mg/day, (LOA 808 and -865 mg/day). Finally, the validity coefficient calculated for vitamin D using the method of triad was high (0.75). In conclusion, this SFFQ, assessed by a dietician, is a valid tool to assess dietary vitamin D and calcium intake in groups of young children. PMID- 28665356 TI - Sleep Apnea and Hypoventilation in Patients with Down Syndrome: Analysis of 144 Polysomnogram Studies. AB - Patients with Down syndrome (DS) are at risk for both obstructive sleep apnea (OSA) and central sleep apnea (CSA); however, it is unclear how these components evolve as patients age and whether patients are also at risk for hypoventilation. A retrospective review of 144 diagnostic polysomnograms (PSG) in a tertiary care facility over 10 years was conducted. Descriptive data and exploratory correlation analyses were performed. Sleep disordered breathing was common (seen in 78% of patients) with an average apnea-hypopnea index (AHI) = 10. The relative amount of obstructive apnea was positively correlated with age and body mass index (BMI). The relative amount of central sleep apnea was associated with younger age in the very youngest group (0-3 years). Hypoventilation was common occurring in more than 22% of patients and there was a positive correlation between the maximum CO2 and BMI. Sleep disordered breathing, including hypoventilation, was common in patients with DS. The obstructive component increased significantly with age and BMI, while the central component occurred most in the very young age group. Due to the high risk of hypoventilation, which has not been previously highlighted, it may be helpful to consider therapies to target both apnea and hypoventilation in this population. PMID- 28665355 TI - In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans. AB - Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides (n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines (n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds (n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects. PMID- 28665357 TI - Enantioselective Michael Addition of Cyclic beta-Diones to alpha,beta-Unsaturated Enones Catalyzed by Quinine-Based Organocatalysts. AB - An enantioselective (52-98% ee) Michael addition between cyclic beta-diones and alpha,beta-unsaturated enones was established in the presence of quinine-based primary amine or squaramide. A variety of cinnamones were smoothly converted into the desired 3,4-dihydropyrans in moderate to high yields (63-99%). Chalcones were also suitable acceptors and gave rise to the expected adducts in satisfactory yields (31-99%). The resulting adducts readily underwent further modification to form fused 4H-pyran or 2,3-dihydrofuran. PMID- 28665358 TI - Meat and Seafood Consumption in Relation to Plasma Metabolic Profiles in a Chinese Population: A Combined Untargeted and Targeted Metabolomics Study. AB - We examined the relationship between different patterns of meat and seafood consumption and plasma metabolic profiles in an Asian population. We selected 270 ethnic Chinese men and women from the Singapore Prospective Study Program based on their dietary habits assessed with a validated food frequency questionnaire. Participants were divided into four subgroups: high meat and high seafood (n = 60), high meat and low seafood (n = 64), low meat and high seafood (n = 60), and low meat and low seafood (n = 86) consumers. Plasma metabolites were measured using both targeted and untargeted mass spectroscopy-based analyses. A total of 42 metabolites differed significantly by dietary group. Higher concentrations of essential amino acids, polyunsaturated fatty acids, and d-glucose were found in high meat and/or seafood consumers as compared with the group with a low consumption of these animal foods. Red meat, poultry, fish, shellfish, soy products, and dairy were each correlated with at least one differential metabolite (r = -0.308 to 0.448). Some observations, such as the correlation between fish and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), confirmed previous studies. Other observations, such as the correlation between shellfish and phosphatidylethanolamine (p36:4), were novel. We also observed significant correlations between plasma metabolites and clinical characteristics, such as CMPF with fasting blood glucose (r = 0.401). These findings demonstrate a significant influence of meat and seafood consumption on metabolic profiles in the Asian population. PMID- 28665360 TI - An Automatic Car Counting System Using OverFeat Framework. AB - Automatic car counting is an important component in the automated traffic system. Car counting is very important to understand the traffic load and optimize the traffic signals. In this paper, we implemented the Gaussian Background Subtraction Method and OverFeat Framework to count cars. OverFeat Framework is a combination of Convolution Neural Network (CNN) and one machine learning classifier (like Support Vector Machines (SVM) or Logistic Regression). With this study, we showed another possible application area for the OverFeat Framework. The advantages and shortcomings of the Background Subtraction Method and OverFeat Framework were analyzed using six individual traffic videos with different perspectives, such as camera angles, weather conditions and time of the day. In addition, we compared the two algorithms above with manual counting and a commercial software called Placemeter. The OverFeat Framework showed significant potential in the field of car counting with the average accuracy of 96.55% in our experiment. PMID- 28665359 TI - Estrogen Promotes Hepatic Synthesis of Long-Chain Polyunsaturated Fatty Acids by Regulating ELOVL5 at Post-Transcriptional Level in Laying Hens. AB - The very long chain fatty acid elongase (ELOVL) plays an important role in the synthesis of long-chain polyunsaturated fatty acids (LCPUFA). Previous studies suggest that chicken could be an alternate source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In this study, we detected that ELOVL5, which plays a key role in the biosynthesis of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA), was highly expressed in the liver of laying hens and increased rapidly after sexual maturity. Bioinformatic analysis revealed ELOVL fatty acid elongase 5 (ELOVL5) gene as a putative target of miR-218-5p, miR 19a-3p, miR-19b-3p, miR-30a-5p, miR-30b-5p, and miR-30e-5p. We demonstrated estrogen downregulated microRNA (miRNA), and that ELOVL5 is a direct target of miR-218-5p, which was located in intron 14 of the Slit guidance ligand 2 (SLIT2) gene and co-expressed with the host gene. Overall, estrogen enhanced hepatic synthesis of LCPUFA by functioning as a negative regulator of miRNA thereby augmenting the expression of these miRNA target genes, especially ELOVL5, which plays a key role in the biosynthesis of n-3 and n-6 LCPUFA. This study provides a novel model for the use of estrogen in the poultry industry as an inducer of ELOVL5 expression to enhance hepatic n-3 and n-6 LCPUFA synthesis at the post transcriptional level. PMID- 28665361 TI - A Study of Deep CNN-Based Classification of Open and Closed Eyes Using a Visible Light Camera Sensor. AB - The necessity for the classification of open and closed eyes is increasing in various fields, including analysis of eye fatigue in 3D TVs, analysis of the psychological states of test subjects, and eye status tracking-based driver drowsiness detection. Previous studies have used various methods to distinguish between open and closed eyes, such as classifiers based on the features obtained from image binarization, edge operators, or texture analysis. However, when it comes to eye images with different lighting conditions and resolutions, it can be difficult to find an optimal threshold for image binarization or optimal filters for edge and texture extraction. In order to address this issue, we propose a method to classify open and closed eye images with different conditions, acquired by a visible light camera, using a deep residual convolutional neural network. After conducting performance analysis on both self-collected and open databases, we have determined that the classification accuracy of the proposed method is superior to that of existing methods. PMID- 28665363 TI - [The frequency of cerebrovascular disorders in patients with different forms of atrial fibrillation]. AB - AIM: To study the frequency of blood circulation disorders (BCD) in patients with different forms of atrial fibrillation (AF) and its relationship with AF duration and treatment with anticoagulants. MATERIAL AND METHODS: Medical records and medical history of 1626 patients with non-valvural AF were analyzed in Moscow from 2009 to 2015. RESULTS: Patients with persistent AF were older and had a higher risk of thromboembolic and hemorrhagic complications. In the group of patients with paroxysmal and persistent AF, percentage of patients with BCD (including recurrent ones) was decreased by 13.1 and 28.9% compared to the patients with persistent form. There was no correlation between AF duration and BCD frequency. The frequency of using anticoagulants was 10.8% in outpatients and 42.8% in inpatients. Patients with persistent AF received anticoagulants less frequently than patients with less persistent forms. CONCLUSION: Persistent AF is associated with the higher risk of BCD. The prevention of BCD in patients with persistent AF was insufficient compared to that in patients with less persistent forms. PMID- 28665362 TI - Ciguatoxins and Maitotoxins in Extracts of Sixteen Gambierdiscus Isolates and One Fukuyoa Isolate from the South Pacific and Their Toxicity to Mice by Intraperitoneal and Oral Administration. AB - Ciguatoxins (CTXs), and possibly maitotoxins (MTXs), are responsible for Ciguatera Fish Poisoning, an important health problem for consumers of reef fish (such as inhabitants of islands in the South Pacific Ocean). The habitational range of the Gambierdiscus species is expanding, and new species are being discovered. In order to provide information on the potential health risk of the Gambierdiscus species, and one Fukuyoa species (found in the Cook Islands, the Kermadec Islands, mainland New Zealand, and New South Wales, Australia), 17 microalgae isolates were collected from these areas. Unialgal cultures were grown and extracts of the culture isolates were analysed for CTXs and MTXs by liquid chromatography tandem mass spectrometry (LC-MS/MS), and their toxicity to mice was determined by intraperitoneal and oral administration. An isolate of G. carpenteri contained neither CTXs nor MTXs, while 15 other isolates (including G. australes, G. cheloniae, G. pacificus, G.honu, and F. paulensis) contained only MTX-1 and/or MTX-3. An isolate of G. polynesiensis contained both CTXs and MTX-3. All the extracts were toxic to mice by intraperitoneal injection, but those containing only MTX-1 and/or -3 were much less toxic by oral administration. The extract of G. polynesiensis was highly toxic by both routes of administration. PMID- 28665364 TI - [Clinical and neuroimaging signs of cardioembolic stroke laboratory in children]. AB - AIM: To study clinical and neuroimaging signs of cardioembolic stroke (CES) in children. MATERIAL AND METHODS: Ten children (mean age 3.5+/-3.5 years) were examined. Eight children met the diagnostic criteria of CES CASCADE, two children were diagnosed with CES based on the complex of symptoms. A comparison group consisted of 90 children with other subtypes of ischemic stroke (IS). The diagnosis was confirmed by MRI and magnetic-resonance angiography; symptom severity was assessed with PedNIHSS and PSOM. RESULTS AND CONCLUSION: The PedNIHSS score in the acute stage of CES was higher (18.4+/-9.34) compared to patients with other subtypes of IS (12.6+/-6.2; p=0.0065). Six patients had large cerebral infarctions with the involvement of basal ganglia, internal capsule, white matter and cerebral cortex. In two patients, the infarction affected the cerebral cortex and underlying white matter, in one patient it affected the cortex from one side and the basal ganglia from the other. A damage of the cortex was noted in one patient. The frequency of recurrent CES was 30%, of fatal cases 20%. Recurrent IS and severe residual neurological deficit were more frequent in CES. CONCLUSION: Early disease onset, acute development and progression of neurological deficit up to the maximal level in the first 5 min, marked severity of the acute stage (PedNIHSS score >15), early onset of neurological function recovery, marked residual neurological deficit (PSOM score >2) are the additional signs of CES. PMID- 28665365 TI - [Difficulties in the diagnosis of stroke in pregnant women]. AB - AIM: To study the features of the clinical picture of stroke and results of laboratory/instrumental study in pregnant women. MATERIAL AND METHODS: A study included 44 women at different periods of gestation (mean age 33.4+/-9.7 years) with clinical symptoms of stroke hospitalized within 4-11h after stroke. Neuroimaging, clinical/instrumental and laboratory examinations were carried out in the first 40 min after admission. RESULTS: A routine screening examination during the management of pregnancy in women's consultation clinics does not always reduce the risk of life threatening events. The operative delivery can decrease the severity of the focal neurological deficit. Intensive treatment and dynamic management of patients with intracranial pathology in intensive care stroke unit improves outcome of stroke. CONCLUSION: A timely differential diagnosis of pathological conditions with different symptoms of stroke at the different stages of medical care of pregnant women helps to choose an optimal treatment plan and improve the outcome. PMID- 28665366 TI - [Clinical and laboratory predictors of outcome in acute period of atherothrombotic ischemic stroke]. AB - AIM: To clarify clinical and pathogenetic predictors of outcome in acute period of atherothrombotic stroke (ATS). MATERIAL AND METHODS: One hundred and nineteen patients with ATS were examined. Characteristics of the clinical picture, a number of white blood cells in peripheral blood in the stage of apoptosis, necrosis as well as the state of intracellular antioxidant protective system were studied. RESULTS: Among the clinical factors that can worsen the course of acute period of ATS, the most important are the size of the focus, consciousness disorders in the first day, basal systolic blood pressure, age of the patient (r=0.496; p=0.01 on the 1st day, r=0.739; p<0.0001 on the 7th day and r=0.620, p<0.0001on the 14th day). A direct influence of mitochondrial dysfunction and mitochondrial-induced apoptosis on the course of ATS in the acute period was shown. There was a direct correlation between the severity of ATS and quantity of Mito + cells on the 1st (r=0.742; p=0.009) and on the 7th day (r=0.717; p=0.002). The correlation was revealed between the severity of ATS and content of ANV+ white blood cells on the 7th day (r=0.595; p=0.015) and on the 14th day (r=0.670; p=0.007). Negative correlation was found between the activity of total SOD and Mn SOD on the 1st day and the severity of ATS on the 7th day (r=0.628; p=0.010) and (r=0.675; p=0.008), respectively. The last finding indicates the prognostic value of these parameters. PMID- 28665367 TI - [Algorithms of the correction of fluid and electrolyte disorders in patients with severe ischemic stroke]. AB - AIM: To develop a practical algorithm for the correction of sodium levels and osmolality of blood plasma during the acute period of severe ischemic stroke (IS). MATERIAL AND METHODS: One hundred and fifty patients with cardioembolic or atherothrombotic stroke, aged from 30 to 80 years, hospitalized in the first 12 h after symptom emergence, were examined. Neurological deficit was assessed with the NIHSS. The monitoring of blood plasma sodium level and osmolality of blood plasma in the 1st and 5th day after stroke as well as of blood circulation volume was performed. The level of antidiuretic hormone (ADH) was measured in patients with hyperosmolar syndrome with hypernatremia. RESULTS AND CONCLUSION: It has been shown that hyponatremia is not an independent predictor of outcome of IS, but requires a diagnostic search of the causes of this condition with subsequent correction of sodium levels. For hypernatremia therapeutic tactics varies depending on the timing of the beginning of IS. A conservative strategy for the correction of hypernatremia to plasma sodium blood levels of 150 mmol/L on the first day of IS and to 155 mg/dL since the third day can be used. If these values are exceeded, the most rapid correction of hypernatremia is necessary. PMID- 28665368 TI - [An effect of cerebral hemodynamics in patients with cerebrovascular disorders on the in-hospital transportation]. AB - In-hospital transportation of 76 patients with cerebrovascular disorders, including those in the first postoperative day, was performed. Two cerebral hemodynamic measurements were carried out five minutes before and immediately after transportation using transcranial Doppler sonography. Significant changes in cerebral blood flow in the operated patients were shown. No significant effect on the rate of cerebral blood flow was identified in patients with ischemic lesions. PMID- 28665369 TI - [Changes in cerebral perfusion in patients undergoing revascularization of carotid artery stenosis]. AB - Ischemic stroke is caused by atherosclerotic lesions in extra- and intracranial arteries in about 25% of cases. Revascularization surgery has been long and widely used for secondary prevention of ischemic stroke in patients with atherosclerotic lesions of the carotid arteries. However, currently the changes in cerebral perfusion in patients with atherosclerotic lesions of brachiocephalic arteries, who underwent surgical revascularization, are still not fully understood. This article highlights the issues of changes of cerebral hemodynamics in patients undergoing surgery on the carotid arteries. PMID- 28665370 TI - [An effect of education and health literacy on the efficacy of rehabilitation of post-stroke patients]. AB - AIM: To study an effect of education, health literacy and adherence to treatment on the efficacy of rehabilitation of post-stroke patients. MATERIAL AND METHODS: The study included 1317 post-stroke patients. Information on education, health literacy and implementation of complex rehabilitation was obtained using anonymous survey. The duration of follow-up was 18 month. Patients were examined at baseline and after 6, 12 and 18 month. RESULTS: A significant correlation between adherence to rehabilitation treatment and the level of health literacy and education was shown. An analysis of the efficacy of comprehensive rehabilitation demonstrated the statistically significant prevalence of patients with positive dynamics of neurological disorders among those who had fully completed the program. CONCLUSION: Differentiated and individual personal selection of rehabilitation programs improves their efficacy. PMID- 28665371 TI - [Results of a randomized double blind multicenter placebo-controlled, in parallel groups trial of the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (EPICA)]. AB - AIM: To evaluate the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (IS). MATERIAL AND METHODS: A randomized double blind multicenter placebo controlled, in parallel groups trial included 151 patients (62 men and 89 women) with hemispheric IS. Using a method of simple randomization, 150 patients (62 men and 88 women), aged 40-79 years, were randomized into two groups. Patients of Group I were treated with mexidol: 500 mg/day IV infusion for 10 days, followed by 125 mg tid (375 mg/day) PO for 8 weeks. Patients of Group II received the placebo according to the same scheme. The total duration of patients' participation in trial ranged from 67 to 71 days. RESULTS: By the end of treatment, the mean score on the modified Rankin scale (mRS) was lower in Group I compared to Group II (p=0.04). In Group I, the decrease in mRS mean score (Visit 1-5) was more prominent (p=0.023), percentage of patients with 0-2 scores by mRS scale (Visit 5) was higher (p=0.039), mean NIHSS score lower (p=0.035) in Visit 5 compared to group II. By the end of treatment, the decrease in mean NIHSS score in patients with diabetes mellitus was more prominent in Group I in comparison with Group II (p=0.038). In Group I, the dynamic of improvement of quality of life was more prominent and started from Visit 2 in general population and subpopulation of patients with diabetes mellitus. The share of patients with no problems with movement in space was higher in Group I (p=0.022). There were no statistically significant differences in frequency of side effects in patients of both groups. CONCLUSION: It is recommended to include mexidol in therapy of patients with IS in the acute and early rehabilitation stages. PMID- 28665372 TI - [The brain after ischemic stroke: a clinical/histological study]. AB - AIM: To analyze the histological features of changes in the brain tissue after ischemic stroke. MATERIAL AND METHODS: Brain tissue samples obtained in autopsy from 9 people died as a result of a left middle cerebral artery ischemic stroke from 3 to 7 days after admission were studied. Tissue samples were taken from 3 areas of the brain: 1) contiguous to the tissue necrotic damage site zone, 2) 5 10 cm distant from the previous one, 3) the contralateral hemisphere zone symmetrical to damage site. Samples were Nissl and hematoxylin-eosin stained. Detection of p53 protein, NSE, GFAP was performed by indirect immunoperoxidase immunohistochemistry. RESULTS: A decrease in the total number of neurons and glial elements, their spatial redistribution, change in cell structure and their functional activity was found. The changes of the artery wall and impaired regional blood flow were detected. The more intense NSE reactivity; p53-positive neurons, reduced neuron-astrocytes distance were identified in zones 2 and 3. CONCLUSION: Ischemic stroke is accompanied by severe histological changes. These changes with varying degrees of severity occur both in the areas adjacent to necrotic core, and in remote areas, and it is a substrate for neuroplasticity. PMID- 28665373 TI - [Functional neuroimaging of the brain structures associated with language in healthy individuals and patients with post-stroke aphasia]. AB - The introduction of non-invasive functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI), in the practice of scientific and clinical research can increase our knowledge about the organization of cognitive processes, including language, in normal and reorganization of these cognitive functions in post-stroke aphasia. The article discusses the results of fMRI studies of functional organization of the cortex of a healthy adult's brain in the processing of various voice information as well as the main types of speech reorganization after post-stroke aphasia in different stroke periods. The concepts of 'effective' and 'ineffective' brain plasticity in post-stroke aphasia were considered. It was concluded that there was an urgent need for further comprehensive studies, including neuropsychological testing and several complementary methods of functional neuroimaging, to develop a phased treatment plan and neurorehabilitation of patients with post-stroke aphasia. PMID- 28665374 TI - [Reciprocal organization of constructive activity in patients with ischemic stroke]. AB - AIM: To study the organization of reciprocal constructive activity in patients with ischemic stroke based on hemispheric localization of the lesion and the profile of lateral organization in a segment of leading hand. MATERIAL AND METHODS: The study included 57 post-stroke patients. An experimental method and a set of neuropsychological tests were used. RESULTS AND CONCLUSION: There was an overall decline in the parameters of constructive activity (accuracy and rate) in patients with ischemic stroke, regardless of localization of the lesion and the profile of lateral brain organization in the segment of leading hand. Constructive activities of left-handed patients with right-hemisphere stroke and right-handed patients with left-hemisphere lesions are regulated by reciprocal and dynamic organization of praxis functions. In right-handed patients with right hemisphere ischemic stroke and left-handed patients with left-hemisphere lesions, constructive activities are regulated by the kinetic-kinesthetic organization of the motor act, dynamic organization of the motor act that characterizes the reciprocal organization. PMID- 28665375 TI - [The comprehensive step-by-step rehabilitation of the patients after acute disturbances of the cerebral circulation]. AB - AIM: The objective of the present study was to evaluate the therapeutic effectiveness of the comprehensive one- and two-stage rehabilitation including the application of mirror therapy and orthetics on an individual basis. MATERIAL AND METHODS: The study included 125 patients (66 men and 59 women) at the medium age of 57 (52; 63) years who had undergone the acute disorders of cerebral circulation (the diagnosis was verified based on the results of CT or MRI of the brain). The localization of stroke in the basin of the left middle cerebral artery was documented in 41,1% of the patients and in the basin of the right middle cerebral artery in 58,9% of them. The severity of neurologic deficit was estimated with use of the Stolyarova scale, Ashfort spastic scale, the Timed Walking Test with pegs and nine holes, the Bartel index of the activities of the daily life. Also estimated were the severity of anxiety and depressive disorders (based on the Spilberger and Beck scales). The state of the cognitive functions was evaluated by means of the mini-mental state examination (MMSE) and the Clock Drawing Test). The Medical Outcomes Study Short Form-36 (scores of MOS SF-36) was employed to estimate the quality of life of the patients. The rehabilitation of the patients was conducted either in 1 or 2 stages, i.e. during the early and (or) late post-treatment periods. In the early period, the medicamental treatment, therapeutic physical exercises, paraffinic and ozoceritic applications, hand massage, electrostimulation of the antagonists of the spastic muscles as well as mirror therapy were used. The rehabilitative process during the late post-treatment period was completed using orthetics of the affected (paretic) hand on an individual basis. RESULTS: The two-stage medical rehabilitation exercised during the early post-treatment period after the stroke with the application of mirror therapy promoted the decrease of the degree of paresis in the affected hands from 2.50 (1.68; 3.19) to 1,12 (0.81; 1.75) scores (p<0,001) and the increase of the motor activity of the affected extremities (the volume of movements, walking skills, the ability to fulfil biomechanical tests). The program of the comprehensive rehabilitation based on the use of orthetics of the paretic hand on an individual basis made it possible to achieve the maximum lowering of muscle hypertonia in the hand affected by paresis (to less than 0.50 scores, i.e. by 0.625 scores) [0.06; 0.75] (p<0.05). The maximum efficiency (83%) was achieved by means of two-stage rehabilitation. CONCLUSION: The comprehensive two-stage medical rehabilitation of the patients who had undergone the acute disorder of cerebral circulation with use of mirror therapy in the combination with orthetics on an individual basis produces the high therapeutic effect, with the effectiveness of the treatment amounting to 83% and the considerable positive dynamics of motor functions documented in 59% of the patients. PMID- 28665376 TI - [The problems encountered in connection with the provision of the physiotherapeutic treatment for the patients presenting with tuberculosis in Saint-Petersburg]. AB - The main statistical indicators of the activities of physiotherapy units (PTU) in the tuberculosis dispensaries (TBD) of Saint Petersburg are presented. Monitoring the compliance of the equipment available in PTU of TBD with the requirements of the modern Health Care Standard for the patients suffering from tuberculosis (TB) as approved by the Ministry of Health of the Russian Federation has been carried out. It has demonstrated that the current state of medical care in this country provides but the limited availability of the physiotherapeutic treatment for the TB patients. At the same time, the high coverage of the patients suffering from tuberculosis with physical therapy based at the day tuberculosis dispensaries of Saint Petersburg has been documented. PMID- 28665377 TI - [The novel approaches to the rehabilitation of the patients presenting with gastroesophageal reflux disease and co-morbid pathology]. AB - : This paper was designed to discuss the problems of co-morbidity and approaches to the rehabilitation of the patients presenting with gastroesophageal reflux disease and a concomitant pathology and to analyze the issues concerning the possible vertebro-visceral correlations inherent in the diseases of the internal organs. AIM: To evaluate the vertebro-neurological status of the thoracic segment of the vertebral column in the patients suffering from gastroesophageal reflux disease and to further improve the methods for their treatment taking into consideration the concomitant pathology, if any. MATERIAL AND METHODS: A total of 290 patients at the age varying from 25 to 60 (mean 44,3+/-11,3) years with the non-erosive form of gastroesophageal reflux disease were examined in the phase of its exacerbation. They included 132 (45.5%) men and 158 (54.5%) women. The duration of the disease averaged 13.1+/-3.3 years and that of the exacerbation period 1.2+/-0.5 months. All the patients underwent the vertebro-neurological examination. The visual analog scale was used to obtain the subjective characteristics of the pain syndrome associated with thoracalgia The quality of life of the patients was estimated based on the Medical Outcomes Study Short Form 36 (scores of MOS SF-36). To evaluate the effectiveness of the proposed approach to the treatment of the gastroesophageal reflux disease, the 260 participants of the study were randomly allocated to two groups, the main and control ones. The latter group was comprised of 130 patients given the standard treatment including the use of histamine H2-receptor antagonists, proton pump inhibitors, stimulators of the motility of the gastrointestinal tract, alginates, and other drugs, as indicated. The former group consisted of the remaining 130 patients undergoing the standard course of pharmacopuncture to correct the functional disorders in the thoracic segment of the vertebral column. The medications of choice for the purpose were the anti-homotoxic agents, such as placental compositum, co-enzyme compositum, and ubichinon compositum (Biologische Heilmittel Heel GmbH, Germany). The statistical analysis was performed with the use of the non-parametric methods based on the Statistica application software package ('StatSoft Inc.', SSHA). RESULTS: The present article reports the results of the study that demonstrate significant strong positive correlation between the clinical manifestations of gastroesophageal reflux disease (the frequency and severity of symptoms) and thoracalgia and provides a rationale for the assessment of the vertebro neurological status of the thoracic spine in the patients exhibiting the clinical signs of gastroesophageal reflux disease. The study substantiated the inclusion of pharmacopuncture with placenta compositum, co-enzyme compositum, and ubichinon compositum anti-homotoxic medications in the complex rehabilitation programs for the patients presenting with the clinical signs of gastroesophageal reflux disease and the concomitant thoracalgia symptoms. To assess the effectiveness of the proposed method for the treatment of this condition, such diagnostic criteria as the vertebro-neurological symptoms, coefficient of the thoracalgia-associated pain syndrome, the frequency and intensity of the gastroesophageal reflux disease symptoms, and the quality of life parameters were used. CONCLUSION: The results of the present study provide strong evidence that pharmacopuncture helps to improve the quality of life of the patients, alleviate thoracalgia symptoms and clinical signs of gastroesophageal reflux disease, and reduce the intensity of the pain syndrome caused by thoracalgia. PMID- 28665378 TI - [The application of general magnetic therapy for the rehabilitation of the patients following the surgical treatment of herniated intervertebral discs]. AB - AIM: The objective of the present work was to rehabilitate more efficiently the patients who had undergone the surgical treatment for herniated discs in the lumbosacral spine by applying general magnetic therapy during the combined treatment. MATERIAL AND METHODS: A total of 73 patients underwent the medical examination and treatment. The patients matched for age and sex presenting with similar clinical symptoms were divided into two groups. All of them received initial therapy that included medication, therapeutic physical exercises, and aquatic therapy. The patients in the main study group were given, in addition, general magnetic therapy. All the patients had their lower back examined before and after the treatment; moreover, they were asked to report their pain intensity based on the visual-analogue scale. The patients had their spinal and lower extremity temperature measured by means of thermal scanning with the use of remote infrared thermography and the non-invasive thermal imaging to check temperature fluctuations. To evaluate the psycho-emotional condition of the patients and to obtain their quality of life characteristics, they were asked to fill up the WAM (wellbeing, activity, mood) questionnaire; moreover, the disability Index was determined using the Oswestry questionnaire (version 2.1.), and the State-Trait Anxiety Inventory (STAI) was employed. RESULTS: 75.7% of the patients in the main group had the positive treatment results in the form of improvement of the affected movement skills, sensory processing abilities, and reflex functions as compared with the 58,3% success rate among the patients in the control groupd. Based on the data of non-invasive infrared thermal imaging, the patients of the main group had significantly lower post-treatment topical hyperthermia in the region of the surgical intervention in comparison with the controls which suggested the reduction of the severity of the inflammatory process and the manifestations of the muscular-tonic syndrome. Their temperature dropped by 1,46+/-0,07 degrees S in contrast to the patients of the control group whose temperature decreased only by 0,91+/-0,04 degrees S (r<0.05). These observations gave evidence that the inflammation had been alleviated and the muscle tension relieved. The adopted recovery program promoted, in addition, a temperature drop at the area of the skin innervated by the affected root. It has been found that not only the pain subsided and the compromised motor skills and sensory processing abilities improved but also the quality of life tended to ameliorate resulting in the occupational rehabilitation of the patients following the surgical treatment of herniated intervertebral discs. CONCLUSION: It has been found that the addition of general magnetic therapy to the combined treatment of the patients who had undergone the surgical treatment of herniated intervertebral discs favourably affects the clinical symptoms of the disease, intensifies regeneration, as well as improves blood circulation in the area affected by surgery, improves the psychoemotional state and the quality of life of the patients in such conditions thus making therapy considerably more efficient by preventing the complications and significantly shortening the duration of the treatment. . PMID- 28665379 TI - [Chronorehabilitation of the patients suffering from chronic cholecystitis with concomitant gallbladder dysfunction and opisthorchiasis]. AB - The importance of the development of the effective rehabilitative measures for the patients suffering from chronic cholecystitis with concomitant gallbladder dysfunction and opisthorchiasis is beyond question. The adequate methods for the rehabilitation of the patients after an intensive de-worming remain to be developed. It is known that de-worming is not infrequently followed by the immediate amplification of the manifestations of the stagnation of bile in the gallbladder that become even more pronounced than before the de-worming procedure. With the purpose of improving the effectiveness of the spa and health resort-based rehabilitation and prevention of the complications, it is recommended to make use of the modern therapeutic physical factors to be prescribed taking into consideration the characteristics of the biological rhythms in the functional activity of the biliary system in the individual patients. The most effective rehabilitation methods for the treatment of the pathology in question include the application of the therapeutic physical factors known to produce the beneficial effect on the functional state of the biliary system and exert the normalizing influence on the structure of the biological rhythms of the functional activity of various organs and systems. We used a range of approaches for the treatment of 123 patients with chronic cholecystitis and concomitant gallbladder dysfunction plus opisthorchiasis including extremely high frequency electromagnetic irradiation (EHF therapy) in the combination with the oral intake of the choleretic herbal remedies followed by the transverse galvanization of the epigastric region with due regard for the phase of the rhythm of the functional activity of the gallbladder. The results of such treatment gave evidence of the positive dynamics of all the studied indicators of the functional activity of the biliary system and the organism as a whole which suggests the highest therapeutic effect (87.9%) of the proposed treatment that was maintained during 6 to 12 months. PMID- 28665380 TI - [The mechanisms underlying the therapeutic effects of reflexotherapy and drinking mineral waters in the patients presenting with metabolic syndrome]. AB - : Both acupuncture and drinking mineral water can influence the metabolism of carbohydrates and lipids as well as their hormonal regulation, but the possibility of the application of these therapeutic factors for the correction of insulin resistance has not been studied in the patients presenting with metabolic syndrome. AIM: The objective of the present study was to evaluate the effects produced by the intake of drinking mineral water and acupuncture on the various parameters characterizing the patients suffering from metabolic syndrome in combination with altered insulin resistance. MATERIAL AND METHODS: Ninety patients with this condition included in the study underwent the analysis of their the blood pressure, body mass index, blood glucose and lipid levels, insulin and cortisol secretion. RESULTS: We undertook the analysis of the effects of the single and repeated intakes of Essentuki No 17 mineral water included in the combined treatment of the patients with metabolic syndrome and revealed many common responses of the organism to its therapeutic action. Specifically, the stress-type reactions suggested the initiation of the adaptive processes in the system of hormonal regulation of carbohydrate and lipid metabolism. Simultaneously, the manifestations of insulin resistance became less pronounced indicating that both acupuncture and drinking mineral water suppressed the action of the main pathogenic mechanisms underlying the development of metabolic syndrome. Moreover, it was shown that acupuncture had a stronger hypotensive effect in the combination with the decrease of the overproduction of cortisol whereas the intake of the mineral water had a greater metabolic potential and contributed to the intensification of the basal secretion of glucocorticoids. Both reflexotherapy and drinking mineral water have a well apparent effect on the pathogenetic reactions of the metabolic syndrome and therefore can be used in addition to the standard therapy to activate the non-specific, phylogenetically established and enshrined at the genetic level self-healing responses by mainstreaming the adaptation processes and the formation of the adaptive reactions initiated by stressor components. CONCLUSION: The addition of acupuncture or domestic mineral water intake to the standard therapy of the patients suffering from metabolic syndrome significantly enhances the effectiveness of the treatment. The beneficial therapeutic action of acupuncture and drinking mineral water is underlain by their impact on the mechanisms of resistance to insulin that manifests itself as a decrease of the fasting secretion of this hormone and optimization of carbohydrate and lipid metabolism. The therapeutic effect of acupuncture and drinking mineral water is realized through the induction of the stress-initiating reactions which activate the processes of adaptation, with reflexotherapy largely acting on the cardiovascular system and drinking mineral water on the system responsible for insulin regulation of the metabolic processes. PMID- 28665381 TI - [Dynamics of the intestinal biocenosis, indicators of the blood lipid profile, antioxidant system, and energy metabolism in the patients presenting with chronic non-calculous cholecystitis under the influence of the therapeutic physical factors in the combination with probiotics]. AB - The present study included 60 patients presenting with chronic non-calculous cholecystitis and intestinal dysbiosis. It has been demonstrated that the application of the 'Nor Narine' probiotic in the combination with 'Djermuk' hydrocarbon sodium sulfate mineral water and the pre-formed physical factors, in the first place the magnetic laser radiation, increases the effectiveness of the rehabilitative treatment of the patients. Such treatment resulted not only in the positive dynamics of the clinical picture of disease but also in the well apparent marked tendency toward normalization of the intestinal biocenosis, the lipid blood spectrum, the antioxidant system, and the energetic exchange. PMID- 28665382 TI - [The influence of the comprehensive spa and health resort-based treatment on the system of hormonal regulation in the women presenting with gynecological pathology depending on the plasma prolactin level]. AB - AIM: The objective of the present study was to evaluate the influence of the comprehensive spa and health resort-based treatment on the system of hormonal regulation in the women presenting with bacterial vaginosis and concomitant chronic inflammatory diseases of the pelvic organs depending on the plasma prolactin level. MATERIAL AND METHODS: We investigated the indicators of hormonal regulation in 186 women suffering from bacterial vaginosis and concomitant chronic inflammatory diseases of the pelvic organs depending on the level of prolactin in blood plasma. The first group consisted of 128 women with the normal plasma prolactin levels whereas the second group was comprised of 58 women having hyperprolactinemia. The relevant laboratory data were obtained before and after peloid therapy. RESULTS: The application of the therapeutic peloids for the treatment of the women presenting with the normal level of prolactin in blood plasma was shown to contribute to the positive clinical dynamics of the patients' condition and have a modulating effect on the level of pituitary hormones as well as a stimulating effect on the function of the ovaries. The peloid therapy given to the women with hyperprolactinemia exacerbates the hormonal imbalance as a result of the increase of the initial level of prolactin, discoordination of the hormonal regulation at the level of the pituitary-ovarian system, and enhancement of the adrenal gland function regardless of the level of prolactin. CONCLUSION: The results of the study give evidence of the possibility to use the plasma prolactin level as an indicator of the effectiveness of the spa and health resort based treatment of the women presenting with gynecological pathology. Moreover, they suggest the necessity of a differentiated approach to the application of the therapeutic peloids for the treatment of gynecological patients with the disturbances of the hormonal regulation taking into consideration the initial level of prolactin in the blood plasma and the presence of hyperprolactinemia prior to the prescription of the spa and health resort-based treatment including peloid therapy. PMID- 28665383 TI - [About the definition of notions and classification of the physical factors and methods for the physiotherapeutic treatment]. PMID- 28665384 TI - [The phenomenon of long-term survival in glioblastoma patients. Part I: the role of clinical and demographic factors and an IDH1 mutation (R 132 H)]. AB - : The median overall survival of glioblastoma patients is about 15 months. Only a small number of patients survive 3 years. The factors of a favorable prognosis for the 'longevity phenomenon' in glioblastoma patients are not fully understood. OBJECTIVE: to determine the occurrence rate of long-living patients with glioblastomas, identify clinical predictors of a favorable prognosis, and identify the presence and prognostic significance of an IDH1 mutation. MATERIAL AND METHODS: Among 1494 patients operated on for glioblastoma at the Burdenko Neurosurgical Institute from 2007 to 2012, there were 84 (5.6%) patients who lived more than 3 years after primary surgery. In all the cases, histological specimens were reviewed, and immunohistochemical detection of a mutant IDH1 protein was performed. Overall survival was calculated from the time of first surgery to the date of the last consultation or death, and the recurrence-free period was calculated from the time of first surgery to MRI-verified tumor progression. RESULTS: The median age of long-living patients with glioblastoma was 45 years (19-65 years). All tumors were located supratentorially. The median Karnofsky performance status score at the time of surgery was 80 (range, 70-100). All patients underwent microsurgical resection of the tumor, followed by chemoradiotherapy. The median recurrence-free period was 36 months (5-98 months). Overall survival of 48, 60, and 84 months was achieved in 23, 15 and 6% of patients, respectively. Among 49 specimens available for the IDH1 analysis, 14 (28.6%) specimens had a mutant protein. There was no significant difference in survival rates in patients with positive and negative results for IDH1 (44.1 vs. 40.8 months; p>0.05). CONCLUSION: The significance of various factors that may be predictors of a favorable course of the disease is discussed in the literature. This work is the first part of analysis of prognostically significant factors positively affecting overall survival of glioblastoma patients. In our series, the predictors of a favorable prognosis for long-living patients with the verified diagnosis of glioblastoma were as follows: young age, the supratentorial location of the tumor, a high Karnofsky score before surgery, and tumor resection. In our series, we used immunohistochemical tests and found no prognostic significance of the IDH1 gene mutation; further analysis will require application of direct sequencing. We plan to study other morphological and molecular genetic features of tumors, which explain prolonged survival of glioblastoma patients, as well as the role of various types of combined chemoradiation treatment. PMID- 28665385 TI - [Dynamics of functional MRI and speech function in patients after resection of frontal and temporal lobe tumors]. AB - RATIONALE: There are no studies on application of functional MRI (fMRI) for long term monitoring of the condition of patients after resection of frontal and temporal lobe tumors. PURPOSE: The study purpose was to correlate, using fMRI, reorganization of the speech system and dynamics of speech disorders in patients with left hemisphere gliomas before surgery and in the early and late postoperative periods. MATERIAL AND METHODS: A total of 20 patients with left hemisphere gliomas were dynamically monitored using fMRI and comprehensive neuropsychological testing. The tumor was located in the frontal lobe in 12 patients and in the temporal lobe in 8 patients. Fifteen patients underwent primary surgery; 5 patients had repeated surgery. Sixteen patients had WHO Grade II and Grade III gliomas; the others had WHO Grade IV gliomas. Nineteen patients were examined preoperatively; 20 patients were examined at different times after surgery. Speech functions were assessed by a Luria's test; the dominant hand was determined using the Annette questionnaire; a family history of left-handedness was investigated. Functional MRI was performed on an HDtx 3.0 T scanner using BrainWavePA 2.0, Z software for fMRI data processing program for all calculations >7, p<0.001. RESULTS: In patients with extensive tumors and recurrent tumors, activation of right-sided homologues of the speech areas cold be detected even before surgery; but in most patients, the activation was detected 3 months or more after surgery. Therefore, reorganization of the speech system took time. Activation of right-sided homologues of the speech areas remained in all patients for up to a year. Simultaneous activation of right-sided homologues of both speech areas, the Broca's and Wernicke's areas, was detected more often in patients with frontal lobe tumors than in those with temporal lobe tumors. No additional activation foci in the left hemisphere were found at the thresholds used to process fMRI data. Recovery of the speech function, to a certain degree, occurred in all patients, but no clear correlation with fMRI data was found. CONCLUSION: Complex fMRI and neuropsychological studies in 20 patients after resection of frontal and temporal lobe tumors revealed individual features of speech system reorganization within one year follow-up. Probably, activation of right-sided homologues of the speech areas in the presence of left hemisphere tumors depends not only on the severity of speech disorder but also reflects individual involvement of the right hemisphere in enabling speech function. This is confirmed by right-sided activation, according to the fMRI data, in right sided patients without aphasia and, conversely, the lack of activation of right sided homologues of the speech areas in several patients with severe postoperative speech disorders during the entire follow-up period. PMID- 28665386 TI - [Modern diagnosis and treatment in children with congenital basal encephalocele]. AB - : Basal encephalocele is a rare disease that predominantly occurs in children. Its most common symptoms include nasal liquorrhea, difficulty in nasal breathing, and deformity of the naso-orbital region. MATERIAL AND METHODS: The study group included 19 patients with basal encephalocele, aged 2 months to 18 years. Ten (59%) patients were operated on through a transnasal endoscopic approach; 3 (17.5%) patients were operated on through a transcranial approach; 4 (23.5%) patients were operated on using a combined approach: the patients underwent simultaneous elimination of a cranio-orbital region deformity using the basal transcranial approach as well as hernial sac resection and hernioplasty using the transnasal endoscopic approach. Two children had no surgery due to minimal symptoms and a lack of cerebrospinal fluid leak. RESULTS: Application of the algorithms for diagnosis and treatment of encephalocele, suggested by the authors, enabled making the timely diagnose, defining the optimal surgical tactics, and achieving good treatment results. CONCLUSION: A differentiated approach to the choice of a surgical technique for basal encephalocele, the use of auto-tissues for skull base reconstruction, intraoperative and postoperative lumbar drainage, and simultaneous elimination of deformity of the fronto-naso orbital region enable avoiding complications and achieving good functional and aesthetic results. PMID- 28665387 TI - [Treatment of syringomyelia associated with adhesive arachnoiditis]. AB - : The prevalence of syringomyelia (SM) caused by adhesive arachnoiditis (AA) is 2 to 4 cases per 100000 population. Surgical treatment of this pathology usually includes implantation of shunts into the cyst cavity or opening and drainage of the cavity. In this case, SM continues to progress in 72-100% of patients. Unsatisfactory outcomes of this surgical approach necessitate searching for other treatment options. PURPOSE: To define the optimal amount of surgery for SM associated with AA and the criteria for assessment of surgery outcomes. MATERIAL AND METHODS: The authors treated 47 SM patients in the period from 2010 to 2015. Of these, 34 (72.3%) patients underwent surgery; a total of 40 operations were performed. The patients' age ranged from 18 to 64 years (mean, 43.5 years). Tethering of the spinal cord was eliminated in 25 patients; 9 patients underwent cyst shunting. RESULTS: Among operated patients, 5 patients had grade 1 arachnopathy, 13 patients had grade 2 arachnopathy, 12 patients had grade 3 arachnopathy, and 4 patients had grade 4 arachnopathy. The minimal postoperative follow-up period was 11 months. After shunting, the condition improved in 8 of 9 patients; in 7 patients, the condition returned to the baseline level within the first postoperative year; in 6 (66.7%) of these patients, the disease continued to progress. After surgical release of spinal cord tethering, satisfactory long term results were achieved in 13 (86.6%) patients with grade 1-2 arachnopathy. In 3 (50%) patients with grade 3 arachnopathy, the condition was stabilized. Among patients with grade 4 arachnopathy, progression of the disease was stopped in 1 patient; the condition worsened in 2 (50%) patients. Among all the operated patients, complications developed in 7 patients. There were no lethal outcomes. CONCLUSIONS: In grade 1-2 arachnopathy, progression of SM after release of spinal cord tethering occurs only in 13.4% of patients. Therefore, release of spinal cord tethering is recommended for these patients. In grade 3-4 arachnopathy, the rate of relapse after this surgery is more than 80%. Therefore, given the simplicity and a lower risk of complications of cyst shunting, this procedure is advisable for these patients. PMID- 28665388 TI - [Posterior decompression of the craniovertebral junction in syringomyelia combined with Chiari-1 malformation in children]. AB - OBJECTIVE: to develop the algorithm for defining the amount of posterior decompression of the craniovertebral junction in children with syringomyelia combined with Chiari-1 malformation. MATERIAL AND METHODS: Sixty eight children with syringomyelia and Chiari-1 malformation, under age of 18 years, underwent posterior decompression of the craniovertebral junction (PDCVJ) in the period from January 2001 to June 2016. Seven (10%) patients underwent extradural decompression (EDD), 16 (24%) patients underwent extra-arachnoid duraplasty (EAD), 25 (37%) patients underwent intra-arachnoid dissection (IAD) and duraplasty, and 20 (29%) patients underwent PDCVJ and placement of a fourth ventricle-subarachnoid shunt. RESULTS: Clinical improvement occurred in 85% of patients, and stabilization was observed in 11% of patients. Syringomyelia regressed in 78% of cases. There were no complications associated with EDD; however, re-operation was required in 3 (43%) cases. In the case of EAD, treatment results were satisfactory in 11 (79%) patients; re-operation was required in 2 (12.5%) cases; there were no complications in the early postoperative period. The highest complication rate of 6 (30%) cases was associated with shunt placement and duraplasty. However, long-term results in this group of patients were satisfactory in 16 (94%) cases, and MRI-based positive changes were observed in 100% of cases. CONCLUSION: According to our analysis, EAD is the method of choice for PDCVJ in children with syringomyelia and Chiari-1 malformation without myelopathy symptoms. In the presence of myelopathy symptoms, intra-arachnoid dissection (with or without shunting) is an acceptable alternative. To our opinion, the use of EDD in syringomyelia is unadvisable. PMID- 28665389 TI - [Syringosubarachnoid shunting in treatment of syringomyelia: a literature review and a clinical case report]. AB - In the article, we describe a clinical case of syringomyelia associated with an Arnold-Chiari type 1 malformation, evaluate the efficacy of syringosubarachnoid shunting, and analyze the literature data of domestic and international researchers involved in investigation and treatment of the pathology. Application of syringosubarachnoid shunting in the described case resulted in a clinical improvement in the form of regression of paresis and hypoesthesia, which demonstrated the efficacy of the shunting technique for correction of the syringomyelia symptoms. PMID- 28665390 TI - [Surgical treatment of acoustic neuromas (vestibular schwannomas)]. AB - Clinical guidelines are topical systematically developed provisions designed to help the doctor make a decision about a treatment approach in certain clinical situations; they provide information on conducting diagnostic and screening tests, the amount of medical and surgical care, and other aspects of clinical practice. Vestibular schwannomas account for 8% of all intracranial lesions, up to 30% of posterior cranial fossa tumors, and 85% of cerebellopontine angle tumors. The incidence rate of acoustic neuromas is approximately 1 case per 100000 population per year. The paper addresses the issues of classification, diagnosis, and treatment of acoustic neuromas. The guidelines discuss in detail the key aspects of formulation of clinical diagnosis, classification features, definition of the indications for surgical or radiation treatment, and principles of expectant treatment in vestibular schwannomas. The article pays particular attention to surgical treatment of acoustic neuromas and describes the criteria for choosing a surgical approach, use of modern surgical equipment, and stages of tumor resection. On the basis of the accepted clinical classification, we propose the algorithms of action depending on the disease stage, pathological process dynamics, patient's age, and clinical manifestations. The key points of the clinical guidelines rely on evidence-based criteria. The work is intended for neurosurgery practitioners. PMID- 28665391 TI - [Tactics of reconstructive closure of basal defects after resection of midline tumors of the anterior skull base (a literature review)]. AB - The purpose of this review is to analyze the techniques used to reconstruct midline defects in the anterior skull base after transcranial and endoscopic endonasal resection of skull base tumors. We provide brief information on the technique for preparing various flaps, indications and contraindications, and advantages and disadvantages. We analyze the international experience in the use of vascularized and non-vascularized flaps as well as the existing algorithms for reconstruction of complex defects of the midline structures of the skull base. The literature data demonstrate the absence of a conventional tactics of reconstructive closure of the discussed defects. To resolve this issue, a meta analysis in combination with an original prospective study is required. PMID- 28665393 TI - [Radiotherapy and radiosurgery in treatment of craniopharyngiomas]. AB - Craniopharyngiomas are benign epithelial tumors having a dysembryogenetic origin, which are usually located in the sellar/parasellar and/or third ventricle regions. Gross total resection is the modern standard of treatment for these tumors because of a low recurrence rate. However, this surgery in some patients with craniopharyngioma often leads to the development or worsening of diencephalic disorders poorly responding to treatment. Perhaps, in these cases, subtotal or partial tumor resection or implantation of an Ommaya reservoir into the tumor cyst followed by stereotactic radiotherapy/radiosurgery may provide better functional outcomes and higher life quality in patients, with tumor growth control being reasonable (according to the published data, the mean 10-year disease-free survival is 66.9% after total tumor resection and 79.6% after combined treatment). The paper presents a review of the literature on radiological treatment of craniopharyngiomas. We discuss the issues of indications, optimal timing of radiotherapy/radiosurgery, its efficacy, and treatment outcomes in terms of complications and quality of life. Particular attention is paid to enlargement of craniopharyngioma cysts during and after radiological treatment. PMID- 28665392 TI - [Glibenclamide as a promising agent for prevention and treatment of cerebral edema]. AB - The article presents a review of the literature on the use of a fundamentally new technique for prevention and treatment of cerebral edema. A drug glibenclamide, which is used to treat type 2 diabetes mellitus, is able to reduce cerebral edema and neuronal damage as evidenced by the results of preclinical trials in rodents and the first results of drug application in patients. The article describes the mechanism of glibenclamide action and discusses the potential for its application. PMID- 28665394 TI - [Optical coherence tomography in neurosurgery]. PMID- 28665397 TI - Food security: Ghana rice revolution falters. PMID- 28665396 TI - MicroRNAs in crop improvement: fine-tuners for complex traits. AB - One of the most common challenges for both conventional and modern crop improvement is that the appearance of one desirable trait in a new crop variety is always balanced by the impairment of one or more other beneficial characteristics. The best way to overcome this problem is the flexible utilization of regulatory genes, especially genes that provide more efficient and precise regulation in a targeted manner. MicroRNAs (miRNAs), a type of short non coding RNA, are promising candidates in this area due to their role as master modulators of gene expression at the post-transcriptional level, targeting messenger RNAs for cleavage or directing translational inhibition in eukaryotes. We herein highlight the current understanding of the biological role of miRNAs in orchestrating distinct agriculturally important traits by summarizing recent functional analyses of 65 miRNAs in 9 major crops worldwide. The integration of current miRNA knowledge with conventional and modern crop improvement strategies is also discussed. PMID- 28665395 TI - Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer. AB - Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kdelta inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa. PMID- 28665398 TI - Magnetic turbulence in a table-top laser-plasma relevant to astrophysical scenarios. AB - Turbulent magnetic fields abound in nature, pervading astrophysical, solar, terrestrial and laboratory plasmas. Understanding the ubiquity of magnetic turbulence and its role in the universe is an outstanding scientific challenge. Here, we report on the transition of magnetic turbulence from an initially electron-driven regime to one dominated by ion-magnetization in a laboratory plasma produced by an intense, table-top laser. Our observations at the magnetized ion scale of the saturated turbulent spectrum bear a striking resemblance with spacecraft measurements of the solar wind magnetic-field spectrum, including the emergence of a spectral kink. Despite originating from diverse energy injection sources (namely, electrons in the laboratory experiment and ion free-energy sources in the solar wind), the turbulent spectra exhibit remarkable parallels. This demonstrates the independence of turbulent spectral properties from the driving source of the turbulence and highlights the potential of small-scale, table-top laboratory experiments for investigating turbulence in astrophysical environments. PMID- 28665400 TI - Pest control: Reproductive strategy. PMID- 28665399 TI - Corrigendum: The non-canonical mitochondrial inner membrane presequence translocase of trypanosomatids contains two essential rhomboid-like proteins. AB - This corrects the article DOI: 10.1038/ncomms13707. PMID- 28665401 TI - PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF. AB - Smac-mimetics are emerging as promising anti-cancer agents and are being evaluated in clinical trials for a variety of malignancies. Smac-mimetics can induce TNF production from a subset of tumor cells and simultaneously sensitize them to TNF-induced apoptosis. However, TNF derived from other cellular sources, such as cytotoxic lymphocytes (CLs) within the tumor, may also contribute to the anti-tumor activity of SMs. Here, we show that CD8+ T cells and NK cells potently kill tumor cells in the presence of the SM, birinapant. Enhanced CL killing occurred through TNF secretion upon tumor antigen recognition or NK-activating receptor ligation. Importantly, the perforin/granzyme route to CL-mediated tumor cell killing was dispensable for the efficacy of birinapant, emphasizing the importance of the TNF-mediated apoptosis pathway. Time-lapse microscopy revealed that birinapant sensitized tumor cells to apoptosis as bystanders and to membrane bound TNF delivered to tumor cells within the immunological synapse. Furthermore, PD-L1 expression on tumor cells suppressed antigen-driven TNF production by CD8+ T cells, which could be antagonized through PD-1 blockade. Importantly, the elevated levels of TNF produced upon PD-1 blockade further enhanced tumor cell killing when combined with birinapant. The combined anti-tumor activity of IAP antagonism and PD-1 blockade occurred independently of perforin-mediated tumor cell death. Taken together, we identify CL-derived TNF as a potent effector of birinapant mediated anti-tumor immunity and opportunity for combination therapy through co-inhibition of immune checkpoints. PMID- 28665403 TI - DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose. AB - This corrects the article DOI: 10.1038/cdd.2015.26. PMID- 28665402 TI - Germline BAP1 mutations induce a Warburg effect. AB - Carriers of heterozygous germline BAP1 mutations (BAP1+/-) develop cancer. We studied plasma from 16 BAP1+/- individuals from 2 families carrying different germline BAP1 mutations and 30 BAP1 wild-type (BAP1WT) controls from these same families. Plasma samples were analyzed by liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS), ultra-performance liquid chromatography triple quadrupole mass spectrometry (UPLC-TQ-MS), and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found a clear separation in the metabolic profile between BAP1WT and BAP1+/- individuals. We confirmed the specificity of the data in vitro using 12 cell cultures of primary fibroblasts we derived from skin punch biopsies from 12/46 of these same individuals, 6 BAP1+/- carriers and 6 controls from both families. BAP1+/- fibroblasts displayed increased aerobic glycolysis and lactate secretion, and reduced mitochondrial respiration and ATP production compared with BAP1WT. siRNA-mediated downregulation of BAP1 in primary BAP1WT fibroblasts and in primary human mesothelial cells, led to the same reduced mitochondrial respiration and increased aerobic glycolysis as we detected in primary fibroblasts from carriers of BAP1+/- mutations. The plasma and cell culture results were highly reproducible and were specifically and only linked to BAP1 status and not to gender, age or family, or cell type, and required an intact BAP1 catalytic activity. Accordingly, we were able to build a metabolomic model capable of predicting BAP1 status with 100% accuracy using data from human plasma. Our data provide the first experimental evidence supporting the hypothesis that aerobic glycolysis, also known as the 'Warburg effect', does not necessarily occur as an adaptive process that is consequence of carcinogenesis, but rather that it may also predate malignancy by many years and facilitate carcinogenesis. PMID- 28665404 TI - Single-molecule quantum dot as a Kondo simulator. AB - Structural flexibility of molecule-based systems is key to realizing the novel functionalities. Tuning the structure in the atomic scale enables us to manipulate the quantum state in the molecule-based system. Here we present the reversible Hamiltonian manipulation in a single-molecule quantum dot consisting of an iron phthalocyanine molecule attached to an Au electrode and a scanning tunnelling microscope tip. We precisely controlled the position of Fe2+ ion in the molecular cage by using the tip, and tuned the Kondo coupling between the molecular spins and the Au electrode. Then, we realized the crossover between the strong-coupling Kondo regime and the weak-coupling regime governed by spin-orbit interaction in the molecule. The results open an avenue to simulate low-energy quantum many-body physics and quantum phase transition through the molecular flexibility. PMID- 28665405 TI - Damage tolerance of nuclear graphite at elevated temperatures. AB - Nuclear-grade graphite is a critically important high-temperature structural material for current and potentially next generation of fission reactors worldwide. It is imperative to understand its damage-tolerant behaviour and to discern the mechanisms of damage evolution under in-service conditions. Here we perform in situ mechanical testing with synchrotron X-ray computed micro tomography at temperatures between ambient and 1,000 degrees C on a nuclear grade Gilsocarbon graphite. We find that both the strength and fracture toughness of this graphite are improved at elevated temperature. Whereas this behaviour is consistent with observations of the closure of microcracks formed parallel to the covalent-sp2-bonded graphene layers at higher temperatures, which accommodate the more than tenfold larger thermal expansion perpendicular to these layers, we attribute the elevation in strength and toughness primarily to changes in the residual stress state at 800-1,000 degrees C, specifically to the reduction in significant levels of residual tensile stresses in the graphite that are 'frozen in' following processing. PMID- 28665406 TI - Ultrafast water sensing and thermal imaging by a metal-organic framework with switchable luminescence. AB - A convenient, fast and selective water analysis method is highly desirable in industrial and detection processes. Here a robust microporous Zn-MOF (metal organic framework, Zn(hpi2cf)(DMF)(H2O)) is assembled from a dual-emissive H2hpi2cf (5-(2-(5-fluoro-2-hydroxyphenyl)-4,5-bis(4-fluorophenyl)-1H-imidazol-1 yl)isophthalic acid) ligand that exhibits characteristic excited state intramolecular proton transfer (ESIPT). This Zn-MOF contains amphipathic micropores (<3 A) and undergoes extremely facile single-crystal-to-single-crystal transformation driven by reversible removal/uptake of coordinating water molecules simply stimulated by dry gas blowing or gentle heating at 70 degrees C, manifesting an excellent example of dynamic reversible coordination behaviour. The interconversion between the hydrated and dehydrated phases can turn the ligand ESIPT process on or off, resulting in sensitive two-colour photoluminescence switching over cycles. Therefore, this Zn-MOF represents an excellent PL water-sensing material, showing a fast (on the order of seconds) and highly selective response to water on a molecular level. Furthermore, paper or in situ grown ZnO-based sensing films have been fabricated and applied in humidity sensing (RH<1%), detection of traces of water (<0.05% v/v) in various organic solvents, thermal imaging and as a thermometer. PMID- 28665407 TI - Polar rotor scattering as atomic-level origin of low mobility and thermal conductivity of perovskite CH3NH3PbI3. AB - Perovskite CH3NH3PbI3 exhibits outstanding photovoltaic performances, but the understanding of the atomic motions remains inadequate even though they take a fundamental role in transport properties. Here, we present a complete atomic dynamic picture consisting of molecular jumping rotational modes and phonons, which is established by carrying out high-resolution time-of-flight quasi-elastic and inelastic neutron scattering measurements in a wide energy window ranging from 0.0036 to 54 meV on a large single crystal sample, respectively. The ultrafast orientational disorder of molecular dipoles, activated at ~165 K, acts as an additional scattering source for optical phonons as well as for charge carriers. It is revealed that acoustic phonons dominate the thermal transport, rather than optical phonons due to sub-picosecond lifetimes. These microscopic insights provide a solid standing point, on which perovskite solar cells can be understood more accurately and their performances are perhaps further optimized. PMID- 28665408 TI - GroEL actively stimulates folding of the endogenous substrate protein PepQ. AB - Many essential proteins cannot fold without help from chaperonins, like the GroELS system of Escherichia coli. How chaperonins accelerate protein folding remains controversial. Here we test key predictions of both passive and active models of GroELS-stimulated folding, using the endogenous E. coli metalloprotease PepQ. While GroELS increases the folding rate of PepQ by over 15-fold, we demonstrate that slow spontaneous folding of PepQ is not caused by aggregation. Fluorescence measurements suggest that, when folding inside the GroEL-GroES cavity, PepQ populates conformations not observed during spontaneous folding in free solution. Using cryo-electron microscopy, we show that the GroEL C-termini make physical contact with the PepQ folding intermediate and help retain it deep within the GroEL cavity, resulting in reduced compactness of the PepQ monomer. Our findings strongly support an active model of chaperonin-mediated protein folding, where partial unfolding of misfolded intermediates plays a key role. PMID- 28665410 TI - Erratum: Free-standing supramolecular hydrogel objects by reaction-diffusion. AB - This corrects the article DOI: 10.1038/ncomms15317. PMID- 28665411 TI - Erratum: Seepage from an arctic shallow marine gas hydrate reservoir is insensitive to momentary ocean warming. AB - This corrects the article DOI: 10.1038/ncomms15745. PMID- 28665409 TI - Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. AB - Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the paediatric, elderly and immune-compromised populations1,2. A gap in our understanding of hRSV disease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists3 6; however, the role of these proteins in viral pathogenesis is incompletely understood. Here, we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralogue of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 wild type or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I interferon responses, suppression of dendritic cell maturation and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV-associated morbidity and mortality. PMID- 28665412 TI - Cryo-EM structure of haemoglobin at 3.2 A determined with the Volta phase plate. AB - With the advent of direct electron detectors, the perspectives of cryo-electron microscopy (cryo-EM) have changed in a profound way. These cameras are superior to previous detectors in coping with the intrinsically low contrast and beam induced motion of radiation-sensitive organic materials embedded in amorphous ice, and hence they have enabled the structure determination of many macromolecular assemblies to atomic or near-atomic resolution. Nevertheless, there are still limitations and one of them is the size of the target structure. Here, we report the use of a Volta phase plate in determining the structure of human haemoglobin (64 kDa) at 3.2 A. Our results demonstrate that this method can be applied to complexes that are significantly smaller than those previously studied by conventional defocus-based approaches. Cryo-EM is now close to becoming a fast and cost-effective alternative to crystallography for high resolution protein structure determination. PMID- 28665413 TI - Giant linear strain gradient with extremely low elastic energy in a perovskite nanostructure array. AB - Although elastic strains, particularly inhomogeneous strains, are able to tune, enhance or create novel properties of some nanoscale functional materials, potential devices dominated by inhomogeneous strains have not been achieved so far. Here we report a fabrication of inhomogeneous strains with a linear gradient as giant as 106 per metre, featuring an extremely lower elastic energy cost compared with a uniformly strained state. The present strain gradient, resulting from the disclinations in the BiFeO3 nanostructures array grown on LaAlO3 substrates via a high deposition flux, induces a polarization of several microcoulomb per square centimetre. It leads to a large built-in electric field of several megavoltage per metre, and gives rise to a large enhancement of solar absorption. Our results indicate that it is possible to build up large-scale strain-dominated nanostructures with exotic properties, which in turn could be useful in the development of novel devices for electromechanical and photoelectric applications. PMID- 28665415 TI - Cryptic t(3;8)(q27;q24) and/or MYC-BCL6 linkage associated with MYC expression by immunohistochemistry is frequent in multiple-hit B-cell lymphomas. PMID- 28665414 TI - ETX2514 is a broad-spectrum beta-lactamase inhibitor for the treatment of drug resistant Gram-negative bacteria including Acinetobacter baumannii. AB - Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of beta-lactamases, enzymes that inactivate beta-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new beta-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded spectrum serine beta-lactamase inhibitors that potently inhibit clinically relevant class A, C and D beta-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of beta-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam-ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need. PMID- 28665416 TI - A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma. AB - Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options. PMID- 28665417 TI - VEGF, VEGFR2 and GSTM1 polymorphisms in outcome of multiple myeloma patients treated with thalidomide-based regimens. PMID- 28665418 TI - Significance of the absolute lymphocyte/monocyte ratio as a prognostic immune biomarker in newly diagnosed multiple myeloma. PMID- 28665420 TI - Intricate kinetics: in situ FTIR-spectroscopy discloses a phase change during ionic liquid synthesis. AB - The kinetics of the methylation of triethylamine (NEt3) with dimethyl carbonate (DMC) in methanol have been investigated by means of in situ ATR-IR-spectroscopy. The data show an autocatalytic influence of the ionic product on reaction kinetics. A bend in the reaction rate progress indicates a sudden change from solvated ions to a microstructured biphasic system, which is reflected in the dependence of the reaction rate constant on the product concentration and the Hildebrand parameter. PMID- 28665421 TI - Multifunctional electrospun polymeric nanofibrous mats for catalytic reduction, photocatalysis and sensing. AB - Fabrication and decoration of flexible Nylon 6,6 polymeric nanofibrous mats for production of multifunctional electrospun material was accomplished via visible light-emitting surface-protected silicon quantum dots (Si QD), ZnO nanoparticles (ZnO NP) and Pd nanocubes (Pd NC). UV-range light was utilized for Si QD production and, after hydrolysis/condensation together with nucleation and growth reactions, amine-modified, fluorescent Si QD were obtained. Additionally, available molecular groups on the Si QD coated onto the polymeric nanofibrous mats provided further attachment of metal oxide and metal NP for various catalytic purposes. Analytical investigations showed that visible-light emission could be maintained on the Nylon 6,6 mats for trinitrotoluene (TNT) sensing. Also, due to consecutive NP decoration, multifunctional, polymeric, flexible nanofibrous mats were obtained. Experiments revealed that fabricated multifunctional mats could reduce molecules such as paranitrophenol effectively or decompose waste dyes such as methylene blue via photocatalytic experiments, and sense the pollutant TNT in aqueous solutions as an all-in-one concept. PMID- 28665422 TI - Coordination polymer nanoparticles from nucleotide and lanthanide ions as a versatile platform for color-tunable luminescence and integrating Boolean logic operations. AB - Novel supramolecular coordination polymer nanoparticles (CPNs) were synthesized via the self-assembly of guanosine monophosphate (GMP) and lanthanide ions (Ln3+, including Tb3+, Eu3+ and Ce3+) in aqueous solution. These CPNs (GMP/Tb3+, GMP/Eu3+ and GMP/Ce3+) have an identical coordination environment but exhibit completely different luminescence properties responding to external stimuli such as dipicolinic acid (DPA), ethylene diamine tetraacetic acid (EDTA), pH and metal ions, which has inspired us to tune the emission color of the CPNs and perform multiple logic operations. Firstly, color-tunable luminescence from red to green can be easily achieved by modulating the doping ratio of Tb3+ and Eu3+ into GMP. Notably, trichromatic white light emitting CPNs can be successfully realized by simultaneously doping Tb3+, Eu3+ and Ce3+ into the host or just adjusting the pH of the solution. What's more, by employing GMP/Tb3+ CPNs as a logic operator, we have achieved the implementation of multilayered gate cascades (INH-INH, NOR-OR). When GMP/Eu3+ CPNs served as a logic operator, the logic elements can be integrated as another combinatorial gate (AND-INH). Moreover, by employing the red emission of Eu3+ and blue emission of GMP as the dual-output signal transducer, a set of parallel logic gates was established successfully. These results help elucidate the design rules by which simple logic can be integrated to construct cascaded logic gates and expand the applications of CPNs in light emitting diode (LED) lamps and biological systems. PMID- 28665419 TI - Acute lymphoblastic leukemia: a comprehensive review and 2017 update. AB - Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL. PMID- 28665423 TI - An integrated biorefinery concept for conversion of sugar beet pulp into value added chemicals and pharmaceutical intermediates. AB - Over 8 million tonnes of sugar beet are grown annually in the UK. Sugar beet pulp (SBP) is the main by-product of sugar beet processing which is currently dried and sold as a low value animal feed. SBP is a rich source of carbohydrates, mainly in the form of cellulose and pectin, including d-glucose (Glu), l arabinose (Ara) and d-galacturonic acid (GalAc). This work describes the technical feasibility of an integrated biorefinery concept for the fractionation of SBP and conversion of these monosaccharides into value-added products. SBP fractionation is initially carried out by steam explosion under mild conditions to yield soluble pectin and insoluble cellulose fractions. The cellulose is readily hydrolysed by cellulases to release Glu that can then be fermented by a commercial yeast strain to produce bioethanol at a high yield. The pectin fraction can be either fully hydrolysed, using physico-chemical methods, or selectively hydrolysed, using cloned arabinases and galacturonases, to yield Ara rich and GalAc-rich streams. These monomers can be separated using either Centrifugal Partition Chromatography (CPC) or ultrafiltration into streams suitable for subsequent enzymatic upgrading. Building on our previous experience with transketolase (TK) and transaminase (TAm) enzymes, the conversion of Ara and GalAc into higher value products was explored. In particular the conversion of Ara into l-gluco-heptulose (GluHep), that has potential therapeutic applications in hypoglycaemia and cancer, using a mutant TK is described. Preliminary studies with TAm also suggest GluHep can be selectively aminated to the corresponding chiral aminopolyol. The current work is addressing the upgrading of the remaining SBP monomer, GalAc, and the modelling of the biorefinery concept to enable economic and Life Cycle Analysis (LCA). PMID- 28665424 TI - Exploring a wider range of Mg-Ca-Zn metallic glass as biocompatible alloys using combinatorial sputtering. AB - In order to bypass the limitation of bulk metallic glasses fabrication, we synthesized thin film metallic glasses to study the corrosion characteristics of a wide atomic% composition range, Mg(35.9-63%)Ca(4.1-21%)Zn(17.9-58.3%), in simulated body fluid. We highlight a clear relationship between Zn content and corrosion current such that Zn-medium metallic glasses exhibit minimum corrosion. In addition, we found higher Zn content leads to a poor in vitro cell viability. These results showcase the benefit of evaluating a larger alloy compositional space to probe the limits of corrosion resistance and prescreen for biocompatible applications. PMID- 28665426 TI - A paper-based touch sensor with an embedded micro-probe array fabricated by double-sided laser printing. AB - Touch sensor is one of the key components for human interfacing devices. However, although various touch sensors have been demonstrated, their sophisticated fabrication processes and complicated structures make them expensive and delicate, and thus they are not considered to be practical for wide application in daily life. Herein, we present a low-cost and scalable paper-based touch sensor suitable for practical applications. The sensor is based on the novel structure of embedded silver nanowire micro-probe arrays in a paper substrate, which exhibits high sensitivity to multiple touch inputs and compact structure with a total thickness of ca. 100 MUm. Silver nanowire electrodes on two sides are manufactured at the same time via an original double-sided laser printing technique. Since this technique is mask-free, solvent-free and highly efficient, it is very suitable for paper substrates that cannot endure solvent processing. The sensing properties of the sensor in various extreme situations are examined and the spatial distributions of touch pressure are detected by arranging the sensing units in arrays. Demonstration examples of the touch sensor and pressure mapping are presented, and finally, the successful application of the sensor array in an electronic lock system is shown to further illustrate its applicability. PMID- 28665425 TI - A systematic study of the influence of mesoscale structuring on the kinetics of a chemical reaction. AB - In this contribution, we (i) link the mesoscopic structuring of the binary structured solvent mixture H2O/tert-butanol (TBA) to the kinetics and the efficacy of the oxidation of benzyl alcohol (BA) to the corresponding aldehyde catalyzed by H5PMo10V2O40. We also compare the catalytic efficacy of this reaction in the mesoscopically structured solvent H2O/TBA to an unstructured (or very weakly structured) solvent H2O/ethanol (EtOH). In this context, we (ii) also give a methodological outline on how to study systematically the catalytic efficacy of chemical reactions as a function of the mesoscale structuring of a binary solvent. We demonstrate that the obtained yields of benzyl aldehyde depend on the type of mesoscopic structuring of the binary solvent H2O/TBA. An elevated catalytic performance of at least 100% is found for unstructured binary mixtures H2O/TBA compared to compartmented binary mixtures H2O/TBA. We conclude that compartmentation of both the organic substrate and the catalyst in TBA and water rich micro phases seems to be unfavorable for the catalytic efficacy. PMID- 28665427 TI - Effects of bioactive compounds on senescence and components of senescence associated secretory phenotypes in vitro. AB - Senescence is a permanent cell cycle arrest that is accompanied by changes in cell morphology and physiology occurring in vitro and in vivo. Senescence evolved as a beneficial response to damage promoting wound healing, limiting fibrosis, fighting against cancer and helping embryonic development. However, excessive accumulation of senescent cells is considered to play a substantial role in the development of aging-related diseases and other morphological and physiological changes associated with aging. Therefore, the aim of many researchers is to find out a way to eliminate senescent cells and improve the health condition of aging people. Bioactive compounds e.g. polyphenols, vitamins, phenols, carotenoids, ginsenosides, omega-3 fatty acids, and compounds isolated from algae (phloroglucinol, sargachromal) are known to affect important biological functions. Recent in vitro studies have revealed that they can protect different types of cells against stress induced senescence (SISP), delay replicative senescence, rejuvenate senescent cells and exert senolytic effects. This review summarizes how the biological compounds listed above affect cell morphology, cell proliferation, specific cell functions, the activity of senescence-associated beta-galactosidase (SA-beta-gal), the shortening of telomeres and reduction of telomerase activity, production of intracellular reactive oxygen species (ROS) and lipid peroxidation products, expression of antioxidant enzymes, expression of p53 and p21 - key effectors of cell cycle arrest leading to senescence - and expression of some key components of senescence associated secretory phenotype (SASP) in replicative senescence, stress induced senescence (SISP) and under conditions which may lead to the development of senescence such as UV-A and UV-B irradiation of cells and the production of matrix metalloproteinases (a component of the SASP) in cells. Finally, future perspectives of this research are discussed. PMID- 28665428 TI - Scaling down contact length in complementary carbon nanotube field-effect transistors. AB - We performed an experimental investigation on contact length (Lc) scaling of carbon nanotube (CNT) complementary field-effect transistors (FETs). Contact resistances of Sc-contacted (for n-type) and Pd-contacted (for p-type) CNT FETs are respectively retrieved based on the experimental data through the transfer length method (TLM). The performance of Lc scaling of Sc/CNT is proved to be comparable to that of the Pd/CNT contact with Lc larger than approximately 40 nm, but it degrades sharply when further scaling down Lc mainly owing to the surface oxidation of the Sc film. After decoupling the effect of oxide thickness, the intrinsic contact scaling behavior of Sc-contacted CNT FETs is found to be as good as that of the Pd-contacted ones, which can further satisfy the requirement of developing complementary CNT FET technology scaled down to the 14 nm node. PMID- 28665429 TI - Watching mesoporous metal films grow during templated electrodeposition with in situ SAXS. AB - In this paper, we monitor the real-time growth of mesoporous platinum during electrodeposition using small-angle X-ray scattering (SAXS). Previously, we have demonstrated that platinum films featuring the 'single diamond' (Fd3m) morphology can be produced from 'double diamond' (Pn3m) lipid cubic phase templates; the difference in symmetry provides additional scattering signals unique to the metal. Taking advantage of this, we present simultaneous in situ SAXS/electrochemical measurement as the platinum nanostructures grow within the lipid template. This measurement allows us to correlate the nanostructure appearance with the deposition current density and to monitor the evolution of the orientational and lateral ordering of the lipid and platinum during deposition and after template removal. In other periodic metal nanomaterials deposited within any of the normal topology liquid crystal, mesoporous silica or block copolymer templates previously published, the template and emerging metal have the same symmetry, so such a study has not been possible previously. PMID- 28665430 TI - Concurrent fast growth of sub-centimeter single-crystal graphene with controlled nucleation density in a confined channel. AB - The synthesis of large-domain-sized graphene requires a low nucleation density, which inevitably leads to a reduced growth rate. To achieve both a large domain size and high growth rate, we designed a simple channel structure that allowed us to control the nucleation density by tuning the flow dynamics and by introducing an additional catalyst inside to control the growth kinetics at the same time. The designed channel structure plays three roles in the growth of graphene: (1) it retains oxygen to passivate the active nucleation sites; (2) it restricts the mass transfer of CH4 to control the supersaturation for nucleation; and (3) it provides additional catalytic sites for the decomposition of CH4 to boost the graphene growth rate. Our strategy allowed the successful preparation of sub centimeter-domain-sized graphene in 1 h with an average growth rate of 70 MUm min 1, and with a hole mobility of 5500 cm2 V-1 S-1, which is sufficient for practical applications. Our method paves the way for the large-scale production of single-crystal graphene or other 2D materials at a highly efficient level. PMID- 28665431 TI - Inelastic neutron scattering study of reline: shedding light on the hydrogen bonding network of deep eutectic solvents. AB - The solids choline chloride and urea, mixed in a 1 : 2 molar proportion, form the iconic deep eutectic solvent "Reline". A combination of computational and vibrational spectroscopy tools, including inelastic neutron scattering (INS), have been used to probe intermolecular interactions in the eutectic mixture. Reline's experimental spectra were estimated using discrete and periodic ab initio calculations of a molecular aggregate with two choline chloride and four urea units. This is the minimum size required to achieve satisfactory agreement with experiment, as smaller clusters cannot represent all of reline's significant intermolecular interactions. The INS spectrum of reline, compared with that of pure choline chloride, reveals a displacement of chloride anions away from their preferred positions on top of choline's methyl groups, whose torsional movement becomes less hindered in the mixture. Urea, which adopts a planar (sp2) shape in the crystal, becomes non-planar (sp3) in reline, a feature herein discussed for the first time. In reline, urea molecules form a wide range of hydrogen bonds, from soft contacts to stronger associations, the latter being responsible for the deviation from ideality. The chloride's interactions with choline are largely conserved at the hydroxyl end while becoming weaker at the cationic headgroup. The interplay of soft and strong interactions confers flexibility to the newly formed hydrogen-bond network and allows the ensemble to remain liquid at room temperature. PMID- 28665432 TI - A cracking-assisted micro-/nanofluidic fabrication platform for silver nanobelt arrays and nanosensors. AB - Nanowires (NWs) with a high surface-to-volume ratio are advantageous for bio- or chemical sensor applications with high sensitivity, high selectivity, rapid response, and low power consumption. However, NWs are typically fabricated by combining several nanofabrication and even microfabrication processes, resulting in drawbacks such as high fabrication cost, extensive labor, and long processing time. Here, we show a novel NW fabrication platform based on "crack photolithography" to produce a micro-/nanofluidic channel network. Solutions were loaded along the microchannel, while chemical synthesis was performed in the nanoslit-like nanochannels for fabricating silver nanobelts (AgNBs). In addition, the NW/NB fabrication platform not only made it possible to produce AgNBs in a repeatable, high-throughput, and low-cost manner but also allowed the simultaneous synthesis and alignment of AgNBs on a chip, eliminating the need for special micro- and/or nanofabrication equipment and dramatically reducing the processing time, labor, and cost. Finally, we demonstrated that the AgNBs can be used as chemical sensors, either as prepared or when integrated in a flexible substrate, to detect target analytes such as hydrogen peroxide. PMID- 28665433 TI - Fast microwave-assisted acidolysis: a new biorefinery approach for the zero-waste utilisation of lignocellulosic biomass to produce high quality lignin and fermentable saccharides. AB - Generally, biorefineries convert lignocellulosic biomass into a range of biofuels and further value added chemicals. However, conventional biorefinery processes focus mainly on the cellulose and hemicellulose fractions and therefore produce only low quality lignin, which is commonly burnt to provide process heat. To make full use of the biomass, more attention needs to be focused on novel separation techniques, where high quality lignin can be isolated that is suitable for further valorisation into aromatic chemicals and fuel components. In this paper, three types of lignocellulosic biomass (softwood, hardwood and herbaceous biomass) were processed by microwave-assisted acidolysis to produce high quality lignin. The lignin from the softwood was isolated largely intact in the solid residue after acidolysis. For example, a 10 min microwave-assisted acidolysis treatment produced lignin with a purity of 93% and in a yield of 82%, which is superior to other conventional separation methods reported. Furthermore, py-GC/MS analysis proved that the isolated lignin retained the original structure of native lignin in the feedstock without severe chemical modification. This is a large advantage, and the purified lignin is suitable for further chemical processing. To assess the suitability of this methodology as part of a biorefinery system, the aqueous phase, produced after acidolysis of the softwood, was characterised and assessed for its suitability for fermentation. The broth contained some mono- and di-saccharides but mainly contained organic acids, oligosaccharides and furans. While this is unsuitable for S. cerevisiae and other common ethanol producing yeasts, two oleaginous yeasts with known inhibitor tolerances were selected: Cryptococcus curvatus and Metschnikowia pulcherrima. Both yeasts could grow on the broth, and demonstrated suitable catabolism of the oligosaccharides and inhibitors over 7 days. In addition, both yeasts were shown to be able to produce an oil with a similar composition to that of palm oil. This preliminary work demonstrates new protocols of microwave-assisted acidolysis and therefore offers an effective approach to produce high purity lignin and fermentable chemicals, which is a key step towards developing a zero-waste lignocellulosic biorefinery. PMID- 28665434 TI - Surface restructuring of Cu-based single-atom alloy catalysts under reaction conditions: the essential role of adsorbates. AB - The stabilities and catalytic performances of single-atom alloy (SAA) structures under the reaction conditions of acetylene hydrogenation are thoroughly examined utilizing density functional theory (DFT) calculations. Four Cu-based alloys with stable SAA structures reported before, namely PdCu, PtCu, RhCu and NiCu alloys, are investigated here. We find that the SAA structures of PdCu and PtCu are stable during the reaction, whilst the RhCu-SAA and NiCu-SAA structures are thermodynamically unstable upon acetylene adsorption and surface restructuring through the aggregation of the Rh and Ni atoms on the surfaces may also happen. It is also found that all the investigated structures of RhCu and NiCu alloys may give rise to the further hydrogenation of ethylene. However, desorption of ethylene is favored over the PdCu-SAA and PtCu-SAA surfaces, indicating that acetylene could be selectively hydrogenated to ethylene over these two surfaces, which is consistent with the experimental observations reported in the literature. Our work provides new understandings regarding SAA surface structures under reaction conditions and their catalytic reaction performances upon aggregation of the doped metal atoms. PMID- 28665435 TI - The role of the zinc transporter SLC30A2/ZnT2 in transient neonatal zinc deficiency. AB - Breast milk is the optimal nutrient mix for infants until the age of 6 months. However, in some cases, due to genetic alterations as well as nutrient deficiencies in nursing mothers, infants may suffer from inadequate levels of micronutrients upon exclusive breastfeeding. In this respect, transient neonatal zinc deficiency (TNZD) is caused by loss-of-function mutations in the zinc transporter SLC30A2/ZnT2 gene, resulting in poor secretion of zinc into the breast milk. Consequently, infants exclusively breastfed with zinc-deficient breast milk develop severe zinc deficiency. The main initial symptoms of zinc deficiency are dermatitis, diarrhea, alopecia, and loss of appetite. Importantly, zinc supplementation of these zinc-deficient infants effectively and rapidly resolves these TNZD symptoms. In the current review, we present the major steps towards the identification of the molecular mechanisms underlying TNZD and propose novel approaches that could be implemented in order to achieve an early diagnosis of TNZD towards the prevention of TNZD morbidity. We also discuss the importance of assessing the prevalence of TNZD in the general population, while taking into consideration its autosomal dominant inheritance that was recently established, also supported by a large number of SLC30A2/ZnT2 variants recently identified in American lactating mothers. These findings indicating that TNZD is more frequent than initially thought, along with the increasing number of TNZD cases that were recently reported worldwide, prompted us here to highlight the importance of early diagnosis of SLC30A2/ZnT2 variants in order to supplement zinc-deficient infants in real-time, thus preventing TNZD morbidity and enhancing newborn health. This early genetic diagnosis of zinc deficiency could possibly prove to be a useful platform for the identification of other micronutrient deficiencies, which could be readily resolved by proper real-time supplementation of the infant's diet. PMID- 28665436 TI - Effects of sodium cationization versus protonation on the conformations and N glycosidic bond stabilities of sodium cationized Urd and dUrd: solution conformation of [Urd+Na]+ is preserved upon ESI. AB - Uridine (Urd) is one of the naturally occurring pyrimidine nucleosides of RNA. 2' Deoxyuridine (dUrd) is a naturally occurring modified form of Urd, but is not one of the canonical DNA nucleosides. In order to understand the effects of sodium cationization on the conformations and energetics of Urd and dUrd, infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and density functional theory (DFT) calculations are performed. By comparing the calculated IR spectra of [Urd+Na]+ and [dUrd+Na]+ with the measured IRMPD spectra, the stable low-energy conformers populated in the experiments are determined. Anti oriented bidentate O2 and O2' binding conformers of [Urd+Na]+ are the dominant conformers populated in the experiments, whereas syn oriented tridentate O2, O4', and O5' binding conformers of [dUrd+Na]+ are dominantly populated in the experiments. The 2'-hydroxyl substituent of Urd stabilizes the anti oriented O2 binding conformers of [Urd+Na]+. Significant differences between the measured IRMPD and calculated IR spectra for complexes of [Urd+Na]+ and [dUrd+Na]+ involving minor tautomeric forms of the nucleobase make it obvious that none are populated in the experiments. Survival yield analyses based on energy-resolved collision-induced dissociation (ER-CID) experiments suggest that the relative stabilities of protonated and sodium cationized Urd and dUrd follow the order: [dUrd+H]+ < [Urd+H]+ < [dUrd+Na]+ < [Urd+Na]+. The 2'-deoxy modification is found to weaken the glycosidic bond of dUrd versus that of Urd for the sodium cationized uridine nucleosides. PMID- 28665437 TI - Action spectra in semiconductor photocatalysis. AB - Action spectra are an increasingly important part of semiconductor photocatalyst research, and comprise a plot of photonic efficiency, eta, versus excitation wavelength, lambda. The features and theory behind an ideal photocatalytic system are discussed, and used to identify: (i) the key aspect of an ideal action spectrum, namely: it is a plot of eta vs. lambda which has the same shape as that of the fraction of radiation absorbed by the semiconductor photocatalyst, f, versus lambda and (ii) the key requirement when running an action spectrum, namely, that the initial rate of the photocatalytic process is directly proportional to incident photon flux, rho, at wavelengths where eta > 0. The Pt/TiO2/MeOH system is highlighted as an example of a photosystem that yields an ideal action spectrum. Most photocatalytic systems exhibit non-ideal action spectra, mostly due to one or more of the following: light intensity effects, crystal phase effects, dye-sensitisation, dye photolysis, charge transfer complex, CTC, formation and localized surface plasmon radiation, LSPR, absorption by a deposited noble metal catalyst. Each of these effects is illustrated using examples taken from the literatures and discussed. A suggested typical protocol for recording the action spectrum and absorption/diffuse reflectance spectrum of a photocatalytic system is described. The dangers of using a dye to probe the activity of a photocatalysts are also discussed, and a possible way to avoid this, via reductive photocatalysis, is suggested. PMID- 28665438 TI - Crumpled sheets of reduced graphene oxide as a highly sensitive, robust and versatile strain/pressure sensor. AB - Sensing of mechanical stimuli forms an important communication pathway between humans/environment and machines. The progress in such sensing technology has possible impacts on the functioning of automated systems, human machine interfacing, health-care monitoring, prosthetics and safety systems. The challenges in this field range from attaining high sensitivity to extreme robustness. In this article, sensing of complex mechanical stimuli with a patch of taped crumpled reduced graphene oxide (rGO) has been reported which can typically be assembled under household conditions. The ability of this sensor to detect a wide variety of pressures and strains in conventional day-to-day applications has been demonstrated. An extremely high gauge factor (~103) at ultralow strains (~10-4) with fast response times (<20.4 ms) could be achieved with such sensors. Pressure resulting from a gentle touch to over human body weight could be sensed successfully. The capability of the sensor to respond in a variety of environments could be exploited in the detection of water and air pressures both below and above atmospheric, with a single device. PMID- 28665439 TI - Multiphoton autofluorescence lifetime imaging of induced pluripotent stem cells. AB - The multiphoton fluorescence lifetime imaging tomograph MPTflex with its flexible 360-deg scan head, articulated arm, and tunable femtosecond laser source was employed to study induced pluripotent stem cell (iPS) cultures. Autofluorescence (AF) lifetime imaging was performed with 250-ps temporal resolution and submicron spatial resolution using time-correlated single-photon counting. The two-photon excited AF was based on the metabolic coenzymes NAD(P)H and flavin adenine dinucleotide/flavoproteins. iPS cells generated from mouse embryonic fibroblasts (MEFs) and cocultured with growth-arrested MEFs as feeder cells have been studied. Significant differences on AF lifetime signatures were identified between iPS and feeder cells as well as between their differentiating counterparts. PMID- 28665440 TI - Detection of an Iris Pigmented Epithelium Cyst in a Child by High Frequency Ultrasonography. AB - An 18-month-old boy presented with an iris pigmented epithelium cyst. The diagnosis was confirmed using high frequency ultrasonography. The cyst was determined to be in an intermediate location, thus needing no treatment provided that any potential complications were noted. However, continued monitoring is required to detect any changes to adapt management. [J Pediatr Ophthalmol Strabismus. 2017;54:e31-e33.]. PMID- 28665441 TI - Giant Retinal Tear With Retinal Detachment in Regressed Aggressive Posterior Retinopathy of Prematurity Treated by Laser. AB - Rhegmatogenous retinal detachment after successfully regressed retinopathy of prematurity is a rare occurrence. Late onset rhegmatogenous retinal detachment has been reported infrequently. The authors report a case of aggressive posterior retinopathy of prematurity that underwent uneventful regression after laser photocoagulation and later developed an inoperable closed funnel retinal detachment due to a giant retinal tear. This case represents the earliest development of such complications in regressed aggressive posterior retinopathy of prematurity treated by laser. Development of a giant retinal tear has also not been previously reported after laser treatment. This case highlights that successful regression of severe retinopathy of prematurity does not safeguard against future complications and requires frequent long-term follow-up. [J Pediatr Ophthalmol Strabismus. 2017;54:e34-e36.]. PMID- 28665442 TI - A Case of Endophthalmitis After Bilateral Medial Rectus Recession. AB - A 9-month-old male infant with a history of Down syndrome underwent bilateral medial rectus recession. Two weeks postoperatively, he developed leukocoria of the left eye with a white opacity posterior to the lens, numerous undulations, necrosis, and hemorrhages in the retrolental space. His contralateral eye had white retinal lesions nasally. Ultrasound examination of the left eye showed a funnel retinal detachment, loculated debris, and a small, central, hyperechoic area concerning for calcification. He underwent enucleation because retinoblastoma could not be definitively ruled out. Given this patient's low visual potential, enucleation was a definitive and safe treatment option. Ocular pathology showed significant inflammation and necrosis. There was an area of scleral perforation by a suture adherent to the retina and vitreous, surrounded by inflammatory cells. This case uniquely demonstrates pediatric endophthalmitis following strabismus surgery, secondary to scleral perforation confirmed by histopathological analysis. Care must be taken during scleral passage of sutures to prevent inadvertent scleral perforation and the potential complication of endophthalmitis. [J Pediatr Ophthalmol Strabismus. 2017;54:e37-e41.]. PMID- 28665443 TI - Management of Presumed Endogenous Fungal Endophthalmitis in a Child With Acute Lymphoblastic Leukemia. AB - The authors describe a case of presumed endogenous fungal endophthalmitis in an immunocompetent pediatric patient with acute lymphoblastic leukemia. A 15-year old boy with a history of high-risk B-cell acute lymphoblastic leukemia status post-chemotherapy presented with acute changes in vision in his left eye. Fundus examination revealed a white bi-lobed chorioretinal lesion with overlying vitritis and associated subretinal fluid. Magnetic resonance imaging of the brain revealed small ring-enhancing lesions in the right parietal and left occipital lobes. Blood, cerebrospinal fluid, aqueous, and vitreous cultures were all negative. Bone marrow and vitreous cytology were negative for malignant cells. The patient was treated for presumed fungal endophthalmitis with systemic and intravitreal voriconazole, followed by pars plana vitrectomy with intravitreal voriconazole and amphotericin B injections. The chorioretinal lesion resolved and visual acuity recovered to 20/20. Chorioretinal infiltrates in a patient with leukemia may require treatment even in the absence of a definitive diagnostic test result. Intervention should be guided by risk analysis and clinical judgment. [J Pediatr Ophthalmol Strabismus. 2017;54:e42-e46.]. PMID- 28665444 TI - Prevalence of sarcopenia and its association with dysphagia in cancer patients who require rehabilitation. AB - OBJECTIVE: To assess the prevalence of sarcopaenia and the association between sarcopaenia, activities of daily living, and dysphagia in cancer patients who require rehabilitation. METHODS: A cross-sectional study was performed in 83 consecutive cancer patients referred to the Department of Rehabilitation Medicine. Skeletal muscle index was calculated as total psoas muscle area assessed via abdominal computed tomography divided by height squared. Sarcopaenia was diagnosed using the Asian Working Group for Sarcopenia criteria. Activities of daily living were evaluated with the Barthel Index. Dysphagia was assessed with the 10-item Eating Assessment Tool (EAT-10). RESULTS: Study participants were 50 males and 33 females (mean age 71, standard deviation 12 years). Sarcopaenia was observed in 66 (80%) patients. The median Barthel Index score was 55 (interquartile range: 25-75). Thirty-five (42%) patients were diagnosed as having dysphagia. Logistic regression analysis of dysphagia adjusted for sarcopaenia, Barthel Index score, age, and reason for hospitalization showed that sarcopaenia (odds ratio (OR) 3.616; 95% confidence interval (95% CI) 0.926 14.114; p = 0.064) and Barthel Index score (OR 0.984; 95% CI 0.966-1.002; p = 0.073) did not reach statistical significance. CONCLUSION: The prevalence of sarcopaenia in cancer patients who require rehabilitation is very high. The power of this study was too low to observe a significant association between sarcopaenia and dysphagia. PMID- 28665445 TI - Medical rehabilitation in disaster relief: Towards a new perspective. AB - With increasing frequency of natural disasters, there has been greater focus recently on the importance and role of rehabilitation services in disaster management. In past disasters, rehabilitative needs were often neglected, with emphasis on acute response plans focused on saving lives and treating acute injuries. There was a lack of, or inadequate, rehabilitation-inclusive disaster response plans and rehabilitation services in many disaster-prone developing countries. The World Health Organization (WHO) Emergency Medical Team (EMT) initiative recognizes rehabilitation as an integral part of medical response and patient-centred care in disaster settings. Current developments under this initiative include: the development of minimum standards for rehabilitation in emergencies to allow rapid, professional, coordinated medical response by both national and international EMTs. These guidelines ensure that EMTs deliver effective and coordinated patient care during disasters and continuum of care beyond their departure. The aim is to strengthen national capacity, foster an environment of self-empowerment of EMTs and local health services, and work in rehabilitation within defined coordination mechanisms in disaster-affected areas. A brief overview of rehabilitation in natural disasters, highlighting current developments, challenges; and gaps in the implementation of WHO guidelines for Minimum Standards for Rehabilitation in Emergencies is discussed in order to improve care for victims of future disasters. PMID- 28665446 TI - First experience on bilirubin removal with a hemoadsorption column (Lixelle(r)) in a child with cardiogenic liver injury. AB - INTRODUCTION: Hyperbilirubinemia may have deleterious effects on many organs, even after the neonatal age. Blood purification is effective in the treatment of hyperbilirubinemia. Recently some reports suggest the potential role of hemoadsorption columns in this setting. METHODS: We present the case of a 6-year old child with severe hyperbilirubinemia due to congestive liver dysfunction, complicated by persistent inflammation, immunosuppression and catabolism syndrome (PICS). The patient was treated with a hemoadsorption column (Lixelle(r)) in combination with continuous veno-venous hemodiafiltration (CVVHDF). RESULTS: During treatment, a significant and rapid decrease in total bilirubin (TB) and other indices of cholestasis was observed. Furthermore, a progressive reduction in the inflammatory biomarkers (Procalcitonin, C-reactive protein) occurred. These results persisted at the discontinuation of therapy. CONCLUSIONS: To our knowledge this is the first case in which hemoadsorption with the Lixelle(r) adsorbing column in combination with CVVHDF has been used to manage pediatric hyperbiliribinemia secondary to cardiogenic liver injury. PMID- 28665447 TI - Effect of artificial saliva with different pH levels on the cytotoxicity of soft denture lining materials. AB - BACKGROUND: The aim of this study was to evaluate the cytotoxic effects of 9 different soft denture liners on the viability of L-929 mouse fibroblast cells at different incubation periods by storing them in artificial saliva (AS) with different pH levels. METHODS: 96 disk samples from each lining material were prepared and divided into 4 groups: GI: No treatment; GII: Stored in artificial saliva with pH 3 for 21 days; Group III: Stored in artificial saliva with pH 7 for 21 days; and Group IV: Stored in artificial saliva with pH 14 for 21 days. The cytotoxicity of the extracts to cultured mouse fibroblasts (L-929) was measured by MTT (tetrazolium salt 3-[4,5-dimethylthiazol-2-yl]-2,5 dipHnyltetrazolium bromide) assay. Data were analyzed using 1-way analysis of variation (ANOVA). RESULTS: It was found that for the pH 3 values of New Truliner, Trusoft, Mollosil Plus, Dentusil, TDV, and HydroCast(r); for the pH 7 values of Ufi Gel P and Elite plus; and for the pH 14 values of HydroCast(r), there was a noncytotoxic effect during both the 24-hour and 48-hour incubation periods. In the control group 48-hour incubation period, HydroCast(r), TDV, Mollosil, 24-hour incubation period Elite plus, for pH 3 values; Elite Plus 24 hour incubation period, for pH 7 values Trusoft 48-hour incubation period there was a moderately cytotoxic effect. CONCLUSIONS: This in vitro study revealed that storage in artificial saliva with different pH levels can affect the cytotoxicity of soft lining materials. PMID- 28665448 TI - Erratum to: Int J Artif Organs. 2016; 39(6): 294-299. PMID- 28665449 TI - High expression of IL-4R enhances proliferation and invasion of hepatocellular carcinoma cells. AB - OBJECTIVE: In this study, we aimed to investigate the expression and function of interleukin-4 receptor (IL-4R) in hepatocellular carcinoma (HCC). METHODS: We collected 40 pairs of human HCC and adjacent normal tissue specimens and examined the expression levels of IL-4R. After IL-4R knockdown in HCC cell lines, cell proliferation and invasion ability were examined. Cell cycle and apoptosis were analyzed by flow cytometry. The activity of multiple signaling pathways was examined by Western blot. RESULTS: IL-4R was overexpressed in HCC tumors compared with adjacent normal control tissues and was associated with tumor differentiation status. IL-4R knockdown resulted in enhanced apoptosis, impaired proliferation and reduced invasion of HCC cells. Furthermore, IL-4R knockdown abolished IL-4-induced activation of the Janus Kinase 1 (JAK1)/signal transducer and activator of transcription 6 (STAT6) and JUN N-terminal kinase (JNK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. CONCLUSIONS: IL-4R plays an important role in regulating HCC cell survival and metastasis, and regulates the activity of the JAK1/STAT6 and JNK/ERK1/2 signaling pathways. We therefore suggest that IL-4/IL-4R may be a new therapeutic target for HCC. PMID- 28665450 TI - Predicting miRNA targets for head and neck squamous cell carcinoma using an ensemble method. AB - BACKGROUND: This study aimed to uncover potential microRNA (miRNA) targets in head and neck squamous cell carcinoma (HNSCC) using an ensemble method which combined 3 different methods: Pearson's correlation coefficient (PCC), Lasso and a causal inference method (i.e., intervention calculus when the directed acyclic graph (DAG) is absent [IDA]), based on Borda count election. METHODS: The Borda count election method was used to integrate the top 100 predicted targets of each miRNA generated by individual methods. Afterwards, to validate the performance ability of our method, we checked the TarBase v6.0, miRecords v2013, miRWalk v2.0 and miRTarBase v4.5 databases to validate predictions for miRNAs. Pathway enrichment analysis of target genes in the top 1,000 miRNA-messenger RNA (mRNA) interactions was conducted to focus on significant KEGG pathways. Finally, we extracted target genes based on occurrence frequency >=3. RESULTS: Based on an absolute value of PCC >0.7, we found 33 miRNAs and 288 mRNAs for further analysis. We extracted 10 target genes with predicted frequencies not less than 3. The target gene MYO5C possessed the highest frequency, which was predicted by 7 different miRNAs. Significantly, a total of 8 pathways were identified; the pathways of cytokine-cytokine receptor interaction and chemokine signaling pathway were the most significant. CONCLUSIONS: We successfully predicted target genes and pathways for HNSCC relying on miRNA expression data, mRNA expression profile, an ensemble method and pathway information. Our results may offer new information for the diagnosis and estimation of the prognosis of HNSCC. PMID- 28665451 TI - Discordance in RAS mutations between primary colon tumor and metastases: a real event or a matter of methodology? AB - BACKGROUND: Analysis of K- and N-RAS mutations is mandatory before planning treatment of metastatic colorectal cancer, because only RAS wild-type (WT) patients can benefit from treatment with anti-EGFR monoclonal antibodies (cetuximab and panitumumab). CASE REPORT: Here we report the case of a 69-year old male patient affected by metastatic sigmoid cancer. He underwent left hemicolectomy, and histology diagnosed a well-differentiated, pT4, node-positive adenocarcinoma; KRAS analysis performed with direct sequencing identified a mutation in exon 2 of the KRAS gene (GGT->GTT). After first-line chemotherapy with FOLFOX6 plus bevacizumab, the patient underwent surgical resection of residual liver metastases. Histology showed metastatic deposits from colic adenocarcinoma with extensive coagulative necrosis. Mutational analysis of the KRAS gene was also performed on liver metastases by pyrosequencing assay, and no mutation was identified. Due to the discordant results (GGT->GTT exon 2 KRAS mutation in the primary tumor, and KRAS-WT in the liver metastases), mutational analysis on liver metastasis was repeated using next-generation sequencing and enriching the sample in tumor cells by manual microdissection; the same type of mutation of the primary tumor (GGT->GTT exon 2 KRAS gene) was confirmed. CONCLUSIONS: Accurate tissue sampling and adequately sensitive assays are essential to correctly identify colorectal cancer patients who can be treated with an anti-EGFR monoclonal antibody. PMID- 28665453 TI - Good mid-term clinical results of a cemented dual mobility cup: a single-centre experience. AB - INTRODUCTION AND METHODS: From January 2004 to December 2008, 188 total hip arthroplasties were performed using a cemented dual mobility cup. 174 patients were available for final analysis. Their mean age was 76.8 (range 54-98 years). The mean follow-up was 7.7 years (range 5-10 years). RESULTS: There were no dislocations. Survivorship rates of the femoral and acetabular components were 100% at a minimum of 5 years. At the latest follow-up, the mean Harris Hip Score significantly increased from 31.6 (only arthritic patients) points preoperatively to 84.5 points. No patients had progressive osteolysis, component migration, or loosening on radiographs. 2 patients presented with periprosthetic fractures treated conservatively. 2 patients presented with infection treated without implant removal and 1 patient presented with transient femoral palsy. CONCLUSIONS: The results of this consecutive series confirmed the good performance of the cemented dual mobility cup at mean 7.7 years follow-up with no revision and no dislocations. PMID- 28665452 TI - Genetic polymorphisms of vitamin D metabolism genes and serum level of vitamin D in colorectal cancer. AB - BACKGROUND: The metabolism of vitamin D is complex, its receptor (VDR) and proteins encoded by the genes CYP27B2 and CYP24A1 can influence vitamin D serum levels. The aim of this study was to investigate the relationship of the polymorphisms of VDR (ApaI and BsmI), CYP27B1 and CYP24A1 with serum vitamin D levels in both forms, 25(OH)D3 (circulating form) and 1,25(OH)2D3 (active form), in colorectal cancer (CRC) patients. METHODS: One hundred fifty-two CRC patients and 321 controls were included. DNA was extracted from peripheral blood. Polymorphisms of BsmI and ApaI were identified by PCR-RFLP. Those of CYP24A1 (rs6013897, rs158552 and rs17217119) and CYP27B1 (rs10877012) were determined by gene sequencing. RESULTS: The median serum levels of circulating vitamin D were not different between CRC patients and controls; however, the percentage of those with deficient vitamin D was higher in patients with cancer. The active form of the vitamin D was higher in CRC patients. VDR, CYP27B1 and CYP24A1 polymorphic genotypes had no influence on serum levels of circulating vitamin D. The correlation between circulating and active vitamin D forms was lower among patients with CRC, regardless of the presence or absence of any genetic polymorphism. The mean serum levels of active vitamin D were higher among patients with polymorphic genotype variants of Apa1 or Bsm1. CONCLUSIONS: CRC patients had a higher frequence of insufficient vitamin D and a higher concentration of active vitamin D. These concentration were higher between patients with polymorphic genotypes variants of ApaI and BsmI, CYP24A1 and CYP27B1. Polymorphic genotypes cause a lower correlation between the forms of vitamin D. PMID- 28665454 TI - Outcomes of nondisplaced intracapsular femoral neck fractures with internal screw fixation in elderly patients: a systematic review. AB - INTRODUCTION: Although the preferred treatment for displaced femoral neck fractures in the elderly is hip arthroplasty, the treatment for impacted or undisplaced femoral neck fractures (UFNF) is still a subject of controversy. Our purpose was to systematically review studies of elderly patients with UFNF treated with internal fixation using screws: (i) what is the reported mortality; (ii) what is the reoperation rate; (iii) what are the clinical and radiological outcomes; and (iv) what is the methodological quality of the included studies? METHODS: This systematic review was performed through a search of PubMed and the Cochrane database using a structured search algorithm including studies enrolling patients older than 60 years old, with UFNF treated with internal fixation using screws. Our literature search returned 950 studies and 11 were selected for final abstraction. RESULTS: 6 studies reported mortality rate. At 1-year follow-up mortality was reported by 3 studies: 18.8%; 22%, and 19%. At 5 years, 1 study reported mortality rate of 42%. Overall reoperation rate was reported by 9 studies and ranged from 8%-19%, while conversion to hip arthroplasty was performed in the range between 8% and 16% according to 6 studies. CONCLUSIONS: Internal fixation with cannulated screws for UFNF in the elderly is a valuable option, although it has substantial reoperation and mortality rates. Further prospective high-quality, randomised controlled trials are required to establish the optimal approach for the treatment of UFNF. PMID- 28665455 TI - Leiomyoma of the deferens: a curious and extremely rare disease. AB - INTRODUCTION: Leiomyomas are rare benign tumors that can occur in the male urinary tract. We present a unique case of leiomyoma of the vas deferens. CASE DESCRIPTION: We present the clinical case of a 69-year-old patient with a suspected bulk close to the right epididymis, which turned out to be a leiomyoma of the vas deferens. To our knowledge, it is the fourth case in literature. CONCLUSIONS: A proper identification and the knowledge of this pathology, even if it is a very unusual event, is necessary to avoid a surgical over treatment and preserve the testicle, by removing only the tumor. PMID- 28665456 TI - Is early benign prostatic hyperplasia (BPH) treatment worthwhile? AB - BACKGROUND: The medical armamentaria for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) have been extensively implemented over the past decade. Nevertheless, the timeliest moment for a possible treatment has not been fully established. EVIDENCE ACQUISITION: A systematic literature search in January 1996 until June 2016 was performed to answer the following question: in men with LUTS due to BPH, does early treatment result in better outcome? An ad hoc Population/patient Intervention/indicator Comparator/control Outcome (PICO) was developed.The Medline, PubMed and Scopus databases were searched. Each article title and abstract were reviewed for relevance and appropriateness with regard to the topic of this review. EVIDENCE SYNTHESIS: Overtime, the introduction of novel medications and the implementation of surgical techniques have significantly improved the treatment outcomes and markedly reduced the rate of BPH surgery. Early treatments in patients at risk of disease progression may result in better clinical outcomes than a delayed approach. However, the evidence to support early intervention remains weak and criteria to identify the patient phenotype that could best benefit from immediate treatment remain ill-defined.On the contrary, the patients who ultimately undergo surgery following prolonged pharmacological treatment present with larger prostates, older age and comorbidities. At the same time, the technological progress has partly compensated this critical scenario, and commonly, a nonpejorative trend has been recorded in perioperative complications. CONCLUSIONS: The ideal moment to begin a treatment in LUTS/BPH patients is still uncertain, and surprisingly, rare good quality studies are available on this topic. PMID- 28665457 TI - Perineal schwannoma: an unusual tumor and clinical presentation - first case with erectile dysfunction associated with this neoplasm. AB - INTRODUCTION: Perineal schwannomas (PS) are very rare benign tumors with few cases reported in literature and none of these reports erectile dysfunction among clinical presentations. CASE DESCRIPTION: We report a case of PS with unusual clinical presentation showing erectile dysfunction associated with perineal pain and discomfort during defecation, and the postoperative residual pain and erectile dysfunction treatment. CONCLUSIONS: On the basis of a literature review of all cases reported and on our case reported, we have delineated a clinical, diagnostic, and therapeutic profile of PS, summarized in a useful table. PMID- 28665458 TI - A robotic needle driver to facilitate vescico-urethral anastomosis during laparoscopic radical prostatectomy. AB - PURPOSE: The completion of the vescico-urethral anastomosis (VUA) represents the most critical step of laparoscopic radical prostatectomy (LRP), and it can often discourage the use of minimally invasive surgery in less experienced laparoscopic surgeons. The aim of this paper is to evaluate the usefulness of a new robotic needle driver named Dexterite in performing the VUA after LRP. MATERIALS AND METHODS: This prospective randomized clinical study enrolled 40 consecutive patients eligible for LRP, which were randomized into four groups: group A, patients undergoing LRP done by an expert surgeon; group B, patients undergoing robotic-assisted radical prostatectomy (RARP) performed by the same expert surgeon; group C, patients undergoing LRP performed by a young surgeon at the beginning of the learning curve; group D, patients undergoing LRP performed by another young surgeon at the beginning of the learning curve with the aid of Dexterite needle driver for completion of the VUA. The two young urologists performed the same steps of LRP so that they are at the same step of the learning curve. All the anastomosis were performed with the same technique in order to be comparable. We use interrupted sutures with Vicryl 2/0 and a 5/8 needle; we performed the Rocco stitch technique before all the anastomosis (6) and we applied bladder neck sparing technique. All patients underwent an ultrasound control of the anastomosis on the seventh postoperative day, as we usually do (9, 10). We consider continent who utilised no pad. RESULTS: Operative VUA completion time was 24.9 vs. 25 vs. 86.7 vs. 61 minutes, respectively. When comparing VUA completion time in group 3 and 4, the use of the Dexterite needle driver resulted in a reduction in VUA time. Urinary leakage was seen in zero out of 10 patients in groups 1 and 2 and in three out of 10 and one in 10 patients, respectively, in groups 3 and 4. All urinary leakages were managed conservatively. One-year continence rates were 95%, 97%, 93% and 95%, respectively. Only one patient in group C developed a bladder neck contracture 6 months after the procedure, but he underwent adiuvant radiotherapy after surgery. CONCLUSIONS: Our data suggest that the use of Dexterite needle holder significantly reduces operative time of VUA completion and reduces the incidence of urinary leakage in laparoscopic surgeons at the beginning of the learning curve. PMID- 28665459 TI - Comparison of serum vitamin D between fertile and infertile men in a vitamin D deficient endemic area: a case-control study. AB - INTRODUCTION: The aim of this study was to compare serum vitamin D between fertile and infertile men in endemic area of vitamin D deficiency. The role of vitamin D in all aspects of human health has attracted a great interest. Vitamin D effect on female fertility and to a lesser extent in men is under investigation. Previous researchers have found meaningful positive relationship between semen quality and serum vitamin D level. However, in endemic area of vitamin D deficiency, this effect is under question. METHODS: Serum 25-OH-Vitamin D was compared between infertile male patients and fertile control group.Infertile cases were from patients of our infertility clinic and fertile controls from healthy cases with at least one child below 5 years of age.SPSS version 19 was used for statistical analysis (Kolmogorov-Smirnov test and Mann Whitney test). RESULTS: Between 116 fertile and 114 infertile men who entered the study, serum level of 20 was a critical point, which patients with upper serum level had significantly better spermogram. In addition to it, even in vitamin D deficient patients and controls, fertile controls had higher serum vitamin D. CONCLUSIONS: There is a positive correlation between serum level of vitamin D and spermogram quality, even in vitamin D deficient areas. Fertile people have a higher level of serum vitamin D in comparison to infertile patient in aforementioned areas. PMID- 28665460 TI - Ischemic monomelic neuropathy: a long-term follow-up of two cases. AB - INTRODUCTION: Ischemic monomelic neuropathy (IMN) is the most dreaded complication of an arteriovenous access creation. While uncommon, it can lead to pain, paresthesia or/and hand weakness. Creation of an arteriovenous connection causing a sudden diversion of blood away from the nerves can lead to ischemic injury to the neural tissue and cause IMN. Immediate surgical ligation has been traditionally recommended to limit ongoing neural tissue injury. CASE DESCRIPTION: We present two diabetic patients who developed IMN after the creation of a left upper extremity brachial-cephalic fistula and refused to undergo surgical ligation. The clinical examination revealed paresthesia localized to the volar aspect of the left forearm with mild weakness of the thumb, index and middle finger. Rehabilitation therapy was initiated in both and revealed a significant improvement in weakness but paresthesia persisted. Fistula maturation was achieved in both patients with an access flow of 1100-1200 cc/min. At 4 months, fistula was used successfully for dialysis in both patients. At a follow-up of 11 months, hand weakness did not progress and paresthesia disappeared. CONCLUSIONS: These cases demonstrate sensory-motor improvement with time and rehabilitation therapy and challenge the traditional approach of fistula ligation. The approach presented in this paper also results in the preservation of the lifeline of a patient. Future investigations should focus on identifying candidates who could benefit from physical therapy and rehabilitation. PMID- 28665462 TI - Emergent endovascular repair for PTA-induced venous rupture in a nonagenarian dialysis patient. PMID- 28665461 TI - Clinical predictors of recurrent stenosis and need for re-intervention in the cephalic arch in patients with brachiocephalic AV fistulas. AB - INTRODUCTION: Cephalic arch stenosis is one of the most common reasons for repeated endovascular intervention and eventual abandonment of access in hemodialysis patients. There is no prediction model to identify risk factors for recurrent cephalic arch stenosis. We have developed a mathematical model to predict the need for reintervention in brachiocephalic (BC) fistulas with recurrent cephalic arch stenosis. METHODS: Single-center retrospective analysis of 143 patients with a BC fistula referred to the vascular clinic for access dysfunction who underwent cephalic arch angioplasty were included for the analysis. Twelve-month post-index angioplasty data were analyzed using parametric, non-parametric and multiple regression models using SPSS software. RESULTS: The mean need for re-intervention in 1 year since first index visit was 2.46 +/- 1.404. Statistically significant correlation (p<=0.001) for re intervention was observed with the severity of stenosis at index visit, access flow, vessel wall diameter proximal to the stenosis, average venous pressure >50% of the delivered blood flow rate and prolonged bleeding for >30 minutes as a reason for referral. Three equations have been derived for calculating the need for re-intervention based on the diameter of the vessel wall proximal to the stenosis. CONCLUSIONS: Risk stratification of BC fistulas utilizing the above parameters could enable clinicians to identify accesses that are at risk for multiple re-interventions. Early identification of accesses that are at high risk for re-interventions at the cephalic arch might prolong access survival and reduce the cost for intervention by utilizing alternate strategies. PMID- 28665463 TI - Port in oncology practice: 3-monthly locking with normal saline for catheter maintenance, a preliminary report. AB - INTRODUCTION: Patients with cancer need stable venous access using central vascular devices like central venous ports and peripherally inserted central catheters that can be used for a wide range of indications. Numerous flushing protocols exist including different frequencies for catheter locking to maintain catheter patency. The aim of this retrospective study was to evaluate the incidence of lumen occlusion of central venous ports in a group of adult cancer patients, adopting a policy of locking with normal saline every three months. METHODS: This is a single-center retrospective observational study. During follow up, we analyzed adult cancer patients who had undergone port insertion from January 1st, 2007 to August 31st, 2014. Flushing and locking were performed every three months with a syringe containing normal saline. RESULTS: We collected data from 381 patients with ports inserted in subclavian vein (379 patients) and in the right jugular vein (2 patients). Locking was performed during 3-monthly follow-up visits. Median follow-up was 810 days (90-2700 days). Among 381 ports, 59 were removed; the reasons for removal were: end of use (45 cases), catheter rupture (9 cases), dislocation (3 cases) and catheter-related bloodstream infection (2 cases). We had no reports of lumen occlusion. CONCLUSIONS: Our data suggest that locking ports with normal saline every three months is not associated with an increased risk of lumen occlusion. PMID- 28665464 TI - Transitioning from anatomic landmarks to ultrasound guided central venous catheterizations: guidelines applied to clinical practice. AB - INTRODUCTION: Centrally inserted central catheter (CICC) insertion is a commonly performed procedure that may give rise to different complications. Despite the suggestion of guidelines to use ultrasound guidance (USG) for vascular access, not all centers use it systematically. The aim of this study is to illustrate the experience with ultrasound in CICC placement at a high-volume oncological center, in a country where the landmark technique is standard. METHODS: Retrospective analysis of a prospective database was performed on CICC placement under USG in the Central Venous Catheter Unit of Instituto Portugues de Oncologia de Lisboa Francisco Gentil, from 2012 to 2015. RESULTS: Three thousand five hundred and seventy-two procedures were recorded. From 2728 CICC placements, 1187 (43.5%) were done using USG. The majority of CICC placements were successful without immediate complications (96.1%). In 55 cases (4.6%), more than three attempts were necessary to puncture the vein. Pneumothorax occurred in 5 cases (0.4%) and arterial puncture was registered in 41 cases (3.5%). An increasing use of USG for placing CICCs was planned and observed over the years and, in the last year of the study, 67.3% of the CICC placements were with USG. CONCLUSIONS: CICC placement with USG is a safe and effective technique. Despite some resistance that is observed, these results support that it is worth following the guidelines that advocate the use of the USG in the placement of CICC. PMID- 28665465 TI - Outcomes of a nephrologist-driven tunnelled dialysis catheter insertion service in South East Asia. AB - INTRODUCTION: Tunnelled dialysis catheters (TDCs) are being increasingly inserted by nephrologists globally but there is limited experience and paucity of published outcomes data from South-East Asia (SEA). This study was conducted to analyse the outcomes of TDC insertion by nephrologists from a single centre in SEA. METHODS: All patients who underwent TDC insertion by nephrologists from October 2013 to June 2016 were included. TDC survival was calculated using Kaplan Meier survival method. Impact of variables was assessed using Cox proportional hazards model. RESULTS: A total of 344 TDCs were inserted in 274 patients. The most common indication was haemodialysis initiation (60.2%) followed by existing catheter dysfunction (CD) (12.2%), failed vascular access (10.2%) and catheter related bacteraemia (CRB) (9.9%). Insertion was successful in 97% patients. The most common location was the right internal jugular vein (87%). The cumulative survival for all TDCs inserted, as defined by the time to non-elective removal of a TDC, at 3, 6 and 9 months was 83%, 61%, and 44%, respectively. Median catheter survival was 231 days. Common indications for removal were CD (13.4%) and CRB or suspected infection (12.5%). Common complications were bleeding (8.72%), infection (13.7%) and CD (16.5%). Median time to infection was 103 days. In multivariate analysis, male gender was associated with poor catheter survival, for primary insertions (p = 0.015, HR 0.62) and diabetes was associated with TDC infection (p = 0.024, OR 1.1). CONCLUSIONS: This is one of the first reports of TDC insertion by nephrologists from SEA. Our outcomes compare favourably with those reported in the literature. PMID- 28665466 TI - Long-term clinical outcomes of the single-incision technique for implantation of implantable venous access ports via the axillary vein. AB - PURPOSE: To evaluate long-term clinical outcomes and complications of the single incision technique for implantation of totally implantable venous access ports (TIVAPs) via the axillary vein. MATERIALS AND METHODS: A total of 932 TIVAPs were placed in 927 patients between May 2012 and October 2014 using a single-incision technique. Patients included 620 men and 307 women with a mean age of 60.0 years. TIVAPs were placed via the left (n = 475) and right (n = 457) axillary veins after making a single oblique vertical incision and medial side pocket without subcutaneous tunneling. We retrospectively reviewed medical records to evaluate status of the patients and TIVAPs, complications, and reasons for explantation. In patients who still had a TIVAP in place, we calculated the duration of TIVAP use from the cut-off day of November 1, 2015. RESULTS: Clinical follow-up was obtained for a total device service period of 311,069 days with a median indwelling time of 467 days (range: 3-1097 days). A total of 37 (4.0%) complications developed. Early complications (n = 4) were one case each of stenosis of the brachiocephalic vein by tumor growth, thrombosis of axillary vein, intravascular migration, and malfunction depending on patient's position. Late complications (n = 33) were suspected catheter-related blood stream infection (n = 23), local infection of the pocket (n = 4), symptomatic stenosis and thrombosis of central vein (n = 4), malfunction by fibrin sleeve (n = 1), and intravascular migration (n = 1). CONCLUSIONS: A single-incision technique for TIVAP implantation via the axillary vein seems to be safe with a low risk of complication. PMID- 28665467 TI - Single-center comparison of the efficacy and complications of arterial vascular closure devices in interventional radiology. AB - INTRODUCTION: Vascular closure devices (VCDs) are commonly used to achieve hemostasis of arterial access sites, but there is little comparative data on the variety of VCDs currently in clinical use. We reviewed the VCD experience at our institution to determine the safest and most effective VCD. MATERIALS AND METHODS: Retrospective analysis of 907 consecutive arterial procedures in interventional radiology from June 2012 to June 2014 was performed. Five VCDs were used: Angio-Seal (n = 478), FISH (n = 56), Mynx (n = 56), Perclose (n = 61), and Starclose (n = 68). Patients who underwent manual compression (n = 188) without use of VCDs were also studied as a comparison group. Patient demographics and pre-procedural laboratory parameters were recorded. The technical success rate for achievement of hemostasis and complication rates were noted. RESULTS: Complete hemostasis rate (aka technical success rate) was 93.5% for Angio-Seal, 83.9% for FISH, 53.6% for Mynx, 73.7% for Perclose, 76.5% for Starclose, and 91.5% for manual compression. The differences among the devices were statistically significant (p<0.001). Fourteen major complications (1.5%) were encountered: nine with Angio-Seal (1.9%), one with Mynx (1.8%), one with Starclose (1.5%), and three with manual compression (1.6%); these differences were not statistically significant. Of the demographic and laboratory parameters studied, none were significantly correlated with hemostasis failure or development of complications. CONCLUSIONS: In our single-center institutional experience, Angio-Seal is the device with the best technical success rate. Major complications of VCDs were rare, with no statistically significant difference between devices. PMID- 28665468 TI - Impact of arm selection on the incidence of PICC complications: results of a randomized controlled trial. AB - INTRODUCTION: The aim of this study is to determine if right arm peripherally inserted central catheters (PICCs) experienced fewer complications while controlling for gender, hand dominance, history of malignancy, dwell time and catheter size. METHODS: This was an intention-to-treat randomized controlled trial conducted in an academic medical center on two different sites between September 2012 and September 2015. All patients older than 18 years or age without known history of previous central line, contraindication to the use of a specific arm or hospitalized in the intensive care unit regardless of coagulation status, were considered for the study. Participants were randomized to the left or right arm group and were followed until catheter removal. Data collected included: PICC characteristics, insertion details, gender, arm dominance, history of malignancy, reason for insertion/removal, incidence of a complication and total dwell time. One-tailed hypothesis testing using a univariate logistic regression with odds ratio (OR) calculation was used to analyze the results. There were 202 patients randomly assigned, totaling 7657 catheter-days; 103 patients to the right-side group and 99 patients to the left-side group. RESULTS: Participants in both groups were statistically equivalent for right handedness, gender, oncologic status, average dwell time and total catheter days. The overall incidence of complications on the right side was 23% versus 34% on the left side, confirming the hypothesis that right-sided insertions led to fewer complications (p = 0.046). The risk of a complication was reduced by 40% with right-sided insertion (OR 0.58 (CI: 0.31-1.09). CONCLUSIONS: This study indicated fewer complications with right-sided insertion irrespective of hand dominance. PMID- 28665469 TI - Central venous pressure monitoring via peripherally or centrally inserted central catheters: a systematic review and meta-analysis. AB - INTRODUCTION: The central venous pressure (CVP) is the most commonly used static marker of preload for guiding fluid therapy in critically ill patients, though its usefulness remains controversial. Centrally inserted central catheters (CICCs) are the gold-standard devices for CVP monitoring but peripherally inserted central catheters (PICCs) may represent a valid alternative. We undertook a systematic review and meta-analysis with the aim to investigate whether the difference between PICC- and CICC-measured CVP is not significant. METHODS: We searched for clinical studies published in PubMed and EMBASE databases from inception until December 21st 2016. We included studies providing data on paired and simultaneous CVP measurement from PICCs and CICCs. We conducted two analyses on the values of CVP, the first one according to the total number of CVP assessments, the second one considering the number of patients recruited. RESULTS: Four studies matched the inclusion criteria, but only three of them provided data for the meta-analyses. Both analyses showed non-significant differences between PICC-measured and CICC-measured CVP: 1489 paired simultaneous CVP assessments (MD 0.16, 95%CI -0.14, 0.45, p = 0.30) on a total of 57 patients (MD 0.22, 95%CI -1.46, 1.91, p = 0.80). Both analyses showed no heterogeneity (I2 = 0%). CONCLUSIONS: Available evidence supports that CVP monitoring with PICCs is accurate and reproduces similar values to those obtained from CICCs. The possibility to monitor CVP should not be used among clinical criteria for preferring a CICC over a PICC line. PMID- 28665470 TI - Outcomes of surgery followed by local brain radiotherapy compared with surgery followed by whole brain radiotherapy for single brain metastasis. AB - PURPOSE: To determine the clinical efficacy of surgery followed by local brain radiotherapy (LBRT) for patients with a single brain metastasis, by comparing the results with those of postoperative whole brain radiotherapy (WBRT). METHODS: We performed a retrospective analysis to compare the survival rate, recurrence-free rates, and causes of death for single brain metastasis patients who underwent surgery followed by LBRT or WBRT in the 2010-2015 period. RESULTS: After their surgery, 22 and 32 patients were treated by LBRT and WBRT, respectively. The median survival times for these LBRT and WBRT groups were 18.3 months and 19.2 months, respectively (p = 0.356). The local recurrence-free rates were 81.2% at 1 year and 81.2% at 2 years after LBRT, and 63.8% at 1 year and 58.9% at 2 years after WBRT (p = 0.589). The distant brain recurrence-free rates were 42.5% at 1 year and 25.5% at 2 years after LBRT, and 69.8% at 1 year and 52.4% at 2 years after WBRT (p = 0.044). Distant brain recurrences were observed significantly more frequently in the LBRT group, but the rates of salvage treatment application and survival were not significantly different between the LBRT and WBRT groups. The probability of neurologic death was not significantly higher in the LBRT group compared with the WBRT group. CONCLUSIONS: Surgery followed by LBRT for single brain metastasis is not inferior to postoperative WBRT, because survival and the necessity of salvage treatment after LBRT were equivalent to those after WBRT. PMID- 28665471 TI - Effect of Delayed Radical Cystectomy for Invasive Bladder Tumors on Lymph Node Positivity, Cancer-Specific Survival and Total Survival. AB - Introduction Radical cystectomy (RC) is the main treatment option for patients with muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC), which carry the highest risk of progression. In this study, we investigated the effect of time from transurethral resection of the bladder (TUR B) to cystectomy on lymph node positivity, cancer-specific survival and overall survival in patients with MIBC. Methods The records were reviewed of 530 consecutive patients who had RC and pelvic lymphadenectomy procedures with curative intent performed by selected surgeons between May 2005 and April 2016. Our analysis included only patients with transitional cell carcinoma of the bladder; we excluded 23 patients with other types of tumor histology. Results Patients who underwent delayed RC were compared with patients who were treated with early RC; both groups were similar in terms of age, gender, T stage, tumor grade, tumor differentiation, lymph node status and metastasis status. However, when both groups were compared for disease-free survival and overall survival, patients of the early-RC group had a greater advantage. Conclusions The optimal time between the last TUR-B and RC is still controversial. A reasonable time for preoperative preparation can be allowed, but long delays, especially those exceeding 3 months, can lead to unfavorable outcomes in cancer control. PMID- 28665472 TI - Hypofractionated Radiotherapy for Complicated Bone Metastases in Patients with Poor Performance Status: A Phase II International Trial. AB - Purpose To evaluate the efficacy and safety of hypofractionated radiotherapy (16 Gy in 2 fractions, 1 week apart) in patients with complicated bone metastases and poor performance status. Methods A prospective single-arm phase II clinical trial was conducted from July 2014 to May 2016. The primary endpoint was pain response as defined in the International Consensus on Palliative Radiotherapy Endpoints. Secondary endpoints included quality of life as measured by quality of life questionnaire (QLQ) PAL-15 and QLQ-BM22 European Organisation for Research and Treatment of Cancer guidelines, pain flare, adverse events, re-irradiation, and skeletal complications. Results Fifty patients were enrolled. There were 23 men with a median age of 58 years (range 26-86). Of the 50 patients, 38 had an extraosseous soft tissue component, 18 needed postsurgical radiation, 3 had neuropathic pain, and 3 had an impending fracture in a weight-bearing bone. At 2 months, 33 patients were alive (66%). Four (12.5%) had a complete response and 12 (37.5%) had a partial response. A statistically significant improvement was seen in the functional interference (p = 0.01) and psychosocial aspects (p = 0.03) of the BM22. No patient had spinal cord compression. One patient required surgery for pathologic fracture, and another re-irradiation. Conclusions Hypofractionated radiotherapy (16 Gy in 2 fractions of 8 Gy 1 week apart) achieved satisfactory pain relief and safety results in patients with complicated bone metastases and poor performance status. PMID- 28665473 TI - Winners' Cup: a national football tournament brings together adolescent patients with cancer from all over Italy. AB - Societa Scientifiche Italiane Insieme per gli Adolescenti con Malattie Onco ematologiche (SIAMO) is an Italian nationwide scheme that focuses on adolescent patients with cancer. Some of its activities include promoting dedicated local projects at the various oncology centers all over the country and organizing events to improve awareness regarding cancer in adolescence. It is with these aims in mind that it organized the Winners' Cup, a football tournament between Italian adolescents who had (or had had) pediatric cancers. There were 144 young people 15 to 24 years old who arrived from 16 different treatment centers around the country to take part in the tournament and share their stories. Such an event had never been attempted before, in Italy at least. The Winners' Cup was a great success and an opportunity to focus attention on the particular clinical, psychological, and social needs of cancer patients in this age group. PMID- 28665474 TI - Evaluation of pain during intravitreal aflibercept injections. AB - PURPOSE: To evaluate the pain associated with intravitreal aflibercept injections. METHODS: The study included 119 patients who received intravitreal aflibercept injection at a single institution. Pain was evaluated by visual analog scale (VAS) immediately after the injection of 2 mg/0.05 mL aflibercept into the vitreous cavity using a 27-G needle. Additional variables including age, sex, indication for the injection, injection site by quadrant (superotemporal or inferotemporal), position during injection (sitting or supine), number of previous intravitreal injections in the study eye, presence of diabetes mellitus or hypertension, and lens status (phakic or pseudophakic) were recorded and assessed with self-reported pain scores. RESULTS: Pain scores on the VAS ranged from 9 to 70, with a median of 18. Indications for injection included diabetic macular edema (21.0%), macular edema secondary to central retinal vein occlusion (12.6%), and neovascular age-related macular degeneration (66.38%). Pain did not significantly correlate with any of the recorded variables. CONCLUSIONS: This is the first series evaluating the pain associated with intravitreal aflibercept injections. We demonstrated that pain associated with intravitreal aflibercept injection is generally mild with low pain scores. PMID- 28665475 TI - Autologous cultivated limbal stem cell transplantation after failed previous limbal graft. AB - PURPOSE: To describe a case of unilateral limbal stem cell deficiency (LSCD) with previously failed autologous graft, resolved by ocular surface reconstruction using cultured autologous limbal stem cells from the contralateral eye. CASE REPORT: A 35-year-old patient presented to our clinic with LSCD due to a unilateral alkali burn. The patient had received a previous limbal graft from the contralateral eye that had failed to impede corneal conjunctivalization. We decided to repeat limbal stem cell transplantation using an ex vivo cultivation procedure to reduce the risk of tissue harvesting on the healthy fellow eye. A small limbal biopsy (1.5 * 1.5 mm) near the previously excised limbus was performed. Stem cells were then isolated and cultured on fibrin and a 3T3 feeder cell layer using a standard protocol. Four months later, the cultivated cells on fibrin were grafted after pannus removal. In the subsequent months, the ocular surface stabilized and inflammation decreased. Two years later, the patient underwent large tectonic lamellar keratoplasty for severe corneal thinning involving the entire cornea, and 6 months later central penetrating keratoplasty and extracapsular cataract extraction with intraocular lens implantation and pupilloplasty was performed. Following reconstruction, the patient showed improved best-corrected vision from count fingers to 20/200 due to amblyopia, and the ocular surface was stable with a transparent corneal graft. CONCLUSIONS: Ex vivo limbal stem cell transplantation is a valid technique for treating LSCD and can be utilized for treating patients who have had previous failed limbal grafts. PMID- 28665476 TI - Incidence and Evolution of Subretinal Precipitates in Optic Disc Pit Maculopathy. AB - PURPOSE: To study the evolution of subretinal precipitates coexistent with optic disc pit (ODP) maculopathy from their appearance at baseline examination until their absorption after successful treatment. METHODS: Participants in this retrospective, multicenter study were 42 patients with ODP maculopathy, in whom complete ocular examination was performed, including visual acuity (VA) measurement, slit-lamp examination, color or red-free fundus photography, and optical coherence tomography at baseline after surgical treatment. RESULTS: Out of 42 cases, 17 (40.5%) cases of ODP maculopathy, which were examined between 2002 and 2015, were found to have subretinal precipitates associated with multilayer fluid accumulation at baseline. Precipitates were located at the outer part of the photoreceptor layer and remained for 3-6 months after successful treatment and absorption of subretinal fluid. The mean VA was 0.99 +/- 0.21 logMAR at baseline and improved to 0.54 +/- 0.25 logMAR at the final examination. CONCLUSIONS: Macular precipitates in association with signs of disease chronicity, such as multilayer fluid accumulation, became evident at baseline examination. Precipitates' disappearance in 15 out of 17 cases coincided with the absorption of subretinal fluid. The relative low VA at baseline probably could be attributed to the chronicity of the disease. PMID- 28665477 TI - Visual acuity and image quality in 5 diffractive intraocular lenses. AB - PURPOSE: To compare objective image quality at distant, intermediate, and near foci with the corresponding visual acuity (VA) in patients symmetrically implanted with 5 different diffractive multifocal intraocular lenses (IOLs) (ReSTOR SV25T0, Tecnis ZKB00, Tecnis ZLB00, AT LISA 809, and AT LISA Tri 839MP) and a monofocal lens (Tecnis ZA9003) 3 months after cataract intervention. METHODS: Objective image quality, measured as the area under the modulation transfer function curve (AMTF), was tested in vitro in an eye model. In addition, corrected distance visual acuity and distance-corrected intermediate and near visual acuities (DCIVA and DCNVA) were assessed in a group of 79 patients, randomly implanted with one of the lenses. RESULTS: Image quality and VA at the distant focus was good for all lens designs, but was similarly compromised at the intermediate focus, where the best DCIVA corresponded to the low add ZKB00. At the near focus, the monofocal lens and the distance dominant SV25T0 had the worst AMTF values, with the ZLB00 presenting the best DCNVA. The relationship between AMTF and VA was found not to be linear, with VA being similarly good for AMTF values over a certain threshold. CONCLUSIONS: Visual acuity of pseudophakic patients reflected the optical quality of the specific IOL design within a certain range of measurements, beyond which maximum VA is limited by other ocular, optical, and neuropsychophysical factors. PMID- 28665478 TI - Phacoemulsification Outcomes with Different Illumination Techniques. AB - PURPOSE: To compare surgeon experience and the outcomes of phacoemulsification using 2 different illumination techniques for cataract extraction. METHODS: A prospective interventional case series was performed on 20 consecutive patients (20 eyes) with senile cataract who underwent phacoemulsification enhanced with a 23-G endoillumination probe. The main outcome measures were the surgeon's perception of depth of field and quality of visibility of intraocular structures, ease of performance of the surgical procedure, effectiveness, and complications related to the procedure. A surgeon-specific questionnaire was administered at the end of the procedure. RESULTS: Surgery was successfully performed in all patients without any complications. The surgeon indicated that lateral endoillumination markedly enhanced the details of the lens structures, mainly the posterior capsule visualization, better than the coaxial lighting with the surgical microscope. Lateral endoillumination created an enhanced 3D effect and improved the depth perception of lens intraoperatively. CONCLUSIONS: The lateral illumination technique with a 23-G endoilluminator probe placed in the anterior chamber through a paracentesis creates an enhanced 3D effect and improves depth perception of lens during phacoemulsification. These benefits increase the safety of the procedure. PMID- 28665479 TI - Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710. PMID- 28665480 TI - Simultaneous pancreas/kidney transplant recipients are predisposed to tissue invasive cytomegalovirus disease and concomitant infectious complications. AB - BACKGROUND: Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with cytomegalovirus (CMV) infection being the most important viral infection with adverse impact on patient and allograft outcomes. METHODS: We studied all primary SPKTRs and deceased-donor kidney transplant recipients (KTRs) between 2008 and 2015 for the development of CMV infection. A total of 21/62 SPKTRs (33.9%) and 90/335 KTRs (26.9%) were diagnosed with CMV infection. A control group of 41 SPKTRs without CMV infection was used for comparison. RESULTS: SPKTRs showed an increased incidence of CMV infection compared with KTRs. SPKTRs were more likely to develop CMV disease, CMV pneumonia, recurrent CMV infection, higher initial and peak CMV loads, and more need for intravenous antiviral therapy compared with KTRs (P<.05). High-risk CMV serostatus (D+R-) and 2 HLA-B/-DR mismatches increased the risk of CMV infection in SPKTRs (P<.05). No differences were observed for patient and allograft outcomes (P>.05). SPKTRs with CMV infection were more likely to show concomitant Epstein-Barr virus (EBV) viremia compared with SPKTRs without CMV infection (P<.05). SPKTRs with CMV infection showed higher incidences of concomitant BK polyomavirus-associated nephropathy, EBV viremia, and sepsis compared with KTRs with CMV infection (P<.05). CONCLUSION: Our results suggest a higher incidence and more severe course of CMV infection in SPKTRs compared with KTRs. The increased incidence of concomitant infectious complications among SPKTRs with CMV infection suggests an overall impaired immunity, and calls for more intense screening. PMID- 28665481 TI - The PKR regulatory subunit of protein kinase A (PKA) is involved in the regulation of growth, sexual and asexual development, and pathogenesis in Fusarium graminearum. AB - Fusarium graminearum is a causal agent of wheat scab disease and a producer of deoxynivalenol (DON) mycotoxins. Treatment with exogenous cyclic adenosine monophosphate (cAMP) increases its DON production. In this study, to better understand the role of the cAMP-protein kinase A (PKA) pathway in F. graminearum, we functionally characterized the PKR gene encoding the regulatory subunit of PKA. Mutants deleted of PKR were viable, but showed severe defects in growth, conidiation and plant infection. The pkr mutant produced compact colonies with shorter aerial hyphae with an increased number of nuclei in hyphal compartments. Mutant conidia were morphologically abnormal and appeared to undergo rapid autophagy-related cell death. The pkr mutant showed blocked perithecium development, but increased DON production. It had a disease index of less than unity and failed to spread to neighbouring spikelets. The mutant was unstable and spontaneous suppressors with a faster growth rate were often produced on older cultures. A total of 67 suppressor strains that grew faster than the original mutant were isolated. Three showed a similar growth rate and colony morphology to the wild-type, but were still defective in conidiation. Sequencing analysis with 18 candidate PKA-related genes in three representative suppressor strains identified mutations only in the CPK1 catalytic subunit gene. Further characterization showed that 10 of the other 64 suppressor strains also had mutations in CPK1. Overall, these results showed that PKR is important for the regulation of hyphal growth, reproduction, pathogenesis and DON production, and mutations in CPK1 are partially suppressive to the deletion of PKR in F. graminearum. PMID- 28665482 TI - The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon gamma in a humanized mouse model of graft-versus-host disease. AB - Graft-versus-host disease (GVHD) remains a major problem after allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. Previous studies have demonstrated a role for the adenosine triphosphate (ATP)-gated P2X7 receptor channel in allogeneic mouse models of GVHD. In this study, injection of human peripheral blood mononuclear cells (PBMCs) into immunodeficient non-obese diabetic-severe combined immunodeficiency interleukin (NOD-SCID-IL)-2Rgammanull (NSG) mice established a humanized mouse model of GVHD. This model was used to study the effect of P2X7 blockade in this disease. From five weeks post-PBMC injection, humanized mice exhibited clinical signs and histopathology characteristic of GVHD. The P2X7 antagonist, Brilliant Blue G (BBG), blocked ATP-induced cation uptake into both murine and human cells in vitro. Injection of BBG (50 mg/kg) into NSG mice did not affect engraftment of human leucocytes (predominantly T cells), or the clinical score and survival of mice. In contrast, BBG injection reduced circulating human interferon (IFN)-gamma significantly, which was produced by human CD4+ and CD8+ T cells. BBG also reduced human T cell infiltration and apoptosis in target organs of GVHD. In conclusion, the P2X7 antagonist BBG reduced circulating IFN-gamma in a humanized mouse model of GVHD supporting a potential role for P2X7 to alter the pathology of this disease in humans. PMID- 28665483 TI - Understanding the relationship between the Centers for Medicare and Medicaid Services' Hospital Compare star rating, surgical case volume, and short-term outcomes after major cancer surgery. AB - BACKGROUND: Both the Centers for Medicare and Medicaid Services' (CMS) Hospital Compare star rating and surgical case volume have been publicized as metrics that can help patients to identify high-quality hospitals for complex care such as cancer surgery. The current study evaluates the relationship between the CMS' star rating, surgical volume, and short-term outcomes after major cancer surgery. METHODS: National Medicare data were used to evaluate the relationship between hospital star ratings and cancer surgery volume quintiles. Then, multilevel logistic regression models were fit to examine the association between cancer surgery outcomes and both star rankings and surgical volumes. Lastly, a graphical approach was used to compare how well star ratings and surgical volume predicted cancer surgery outcomes. RESULTS: This study identified 365,752 patients undergoing major cancer surgery for 1 of 9 cancer types at 2,550 hospitals. Star rating was not associated with surgical volume (P < .001). However, both the star rating and surgical volume were correlated with 4 short-term cancer surgery outcomes (mortality, complication rate, readmissions, and prolonged length of stay). The adjusted predicted probabilities for 5- and 1-star hospitals were 2.3% and 4.5% for mortality, 39% and 48% for complications, 10% and 15% for readmissions, and 8% and 16% for a prolonged length of stay, respectively. The adjusted predicted probabilities for hospitals with the highest and lowest quintile cancer surgery volumes were 2.7% and 5.8% for mortality, 41% and 55% for complications, 12.2% and 11.6% for readmissions, and 9.4% and 13% for a prolonged length of stay, respectively. Furthermore, surgical volume and the star rating were similarly associated with mortality and complications, whereas the star rating was more highly associated with readmissions and prolonged length of stay. CONCLUSIONS: In the absence of other information, these findings suggest that the star rating may be useful to patients when they are selecting a hospital for major cancer surgery. However, more research is needed before these ratings can supplant surgical volume as a measure of surgical quality. Cancer 2017;123:4259 4267. (c) 2017 American Cancer Society. PMID- 28665484 TI - Utilization of integrated correlative light and electron microscopy (iCLEM) for imaging sedimentary organic matter. AB - We report here a new microscopic technique for imaging and identifying sedimentary organic matter in geologic materials that combines inverted fluorescence microscopy with scanning electron microscopy and allows for sequential imaging of the same region of interest without transferring the sample between instruments. This integrated correlative light and electron microscopy technique is demonstrated with observations from an immature lacustrine oil shale from the Eocene Green River Mahogany Zone and mid-oil window paralic shale from the Upper Cretaceous Tuscaloosa Group. This technique has the potential to allow for identification and characterization of organic matter in shale hydrocarbon reservoirs that is not possible using either light or electron microscopy alone, and may be applied to understanding the organic matter type and thermal regime in which organic nanoporosity forms, thereby reducing uncertainty in the estimation of undiscovered hydrocarbon resources. PMID- 28665485 TI - Efficient and Highly Selective Solvent-Free Oxidation of Primary Alcohols to Aldehydes Using Bucky Nanodiamond. AB - Selective oxidation of alcohols to aldehydes is widely applicable to the synthesis of various green chemicals. The poor chemoselectivity for complicated primary aldehydes over state-of-the-art metal-free or metal-based catalysts represents a major obstacle for industrial application. Bucky nanodiamond is a potential green catalyst that exhibits excellent chemoselectivity and cycling stability for the selective oxidation of primary alcohols in diverse structures (22 examples, including aromatic, substituted aromatic, unsaturated, heterocyclic, and linear chain alcohols) to their corresponding aldehydes. The results are comparable to reported transition-metal catalysts including conventional Pt/C and Ru/C catalysts for certain substrates under solvent-free conditions. The possible activation process of the oxidant and substrates by the surface oxygen groups and defect species are revealed with model catalysts, ex situ electrochemical measurements, and ex situ attenuated total reflectance. The zigzag edges of sp2 carbon planes are shown to play a key role in these reactions. PMID- 28665487 TI - Effects of pulsed electromagnetic fields on postmenopausal osteoporosis. AB - Postmenopausal osteoporosis (PMOP) is considered to be a well-defined subject that has caused high morbidity and mortality. In elderly women diagnosed with PMOP, low bone mass and fragile bone strength have been proven to significantly increase risk of fragility fractures. Currently, various anabolic and anti resorptive therapies have been employed in an attempt to retain healthy bone mass and strength. Pulsed electromagnetic fields (PEMFs), first applied in treating patients with delayed fracture healing and nonunions, may turn out to be another potential and effective therapy for PMOP. PEMFs can enhance osteoblastogenesis and inhibit osteoclastogenesis, thus contributing to an increase in bone mass and strength. However, accurate mechanisms of the positive effects of PEMFs on PMOP remain to be further elucidated. This review attempts to summarize recent advances of PEMFs in treating PMOP based on clinical trials, and animal and cellular studies. Possible mechanisms are also introduced, and the future possibility of application of PEMFs on PMOP are further explored and discussed. Bioelectromagnetics. 38:406-424, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28665486 TI - Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat. AB - Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found 3 H-PregS to enter more rapidly than 3 H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of 3 H-DHEAS and 3 H PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the 3 H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory. PMID- 28665488 TI - Chemical composition and antioxidant activity of the volatile fraction extracted from air-dried fruits of Tunisian Eryngium maritimum L. ecotypes. AB - BACKGROUND: Eryngium maritimum L., also known as 'sea holly', is a typical dune plant species belonging to the Apiaceae family and commonly used in Tunisia for therapeutic purposes in folk medicine. In the present study, the chemical composition and antioxidant activity of the volatile fraction extracted from air dried fruits of five Tunisian E. maritimum ecotypes were determined. RESULTS: The total volatile amount ranged from 0.31% to 0.93% (w d.w.-1 ). Sixty-six volatile components were identified by means of GC-MS and accounted for 77.05-86.65% of the total extracted volatile oil. The majority of the identified metabolites were hydrocarbon sesquiterpenes and oxygenated sesquiterpenes, amounting on average to 46.69% and 30.01% of total volatiles, respectively. The principal individual components were germacrene D (13.62-31.71%), 15-hydroxy-alpha-muurolene (12.04 18.58%), and germacrene B (6.77-15.04%). Significant differences were noticed among E. maritimum populations. The volatile profile of E. maritimum fruits was consistently different from those of the aerial parts and roots of plants of the same species reported in previous investigations. Average radical scavenging capacity of the volatile fraction, as determined by DPPH and ABTS tests, was twice higher than that of the Trolox control. CONCLUSION: This study characterised for the first time the fruits of E. maritimum for the composition and radical-scavenging capacity of their volatile fraction. The growth location confirmed as a pivotal factor in influencing the volatile profile of the fruits. (c) 2017 Society of Chemical Industry. PMID- 28665489 TI - Proof-of-concept prototype time-of-flight PET system based on high-quantum efficiency multianode PMTs. AB - PURPOSE: Time-of-flight (TOF) information in positron emission tomography (PET) scanners enhances the diagnostic power of PET scans owing to the increased signal to-noise ratio of reconstructed images. There are numerous additional benefits of TOF reconstruction, including the simultaneous estimation of activity and attenuation distributions from emission data only. Exploring further TOF gains by using TOF PET scanners is important because it can broaden the applications of PET scans and expand our understanding of TOF techniques. Herein, we present a prototype TOF PET scanner with fine-time performance that can experimentally demonstrate the benefits of TOF information. METHODS: A single-ring PET system with a coincidence resolving time of 360 ps and a spatial resolution of 3.1/2.2 mm (filtered backprojection/ordered-subset expectation maximization) was developed. The scanner was based on advanced high-quantum-efficiency (high-QE) multianode photomultiplier tubes (PMTs). The impact of its fine-time performance was demonstrated by evaluating body phantom images reconstructed with and without TOF information. Moreover, the feasibility of the scanner as an experimental validator of TOF gains was verified by investigating the improvement of images under various conditions, such as the use of joint estimation algorithms of activity and attenuation, erroneous data correction factors (e.g., without normalization correction), and incompletely sampled data. RESULTS: The prototype scanner showed excellent performance, producing improved phantom images, when TOF information was employed in the reconstruction process. In addition, investigation of the TOF benefits using the phantom data in different conditions verified the usefulness of the developed system for demonstrating the practical effects of TOF reconstruction. CONCLUSIONS: We developed a prototype TOF PET scanner with good performance and a fine-timing resolution based on advanced high QE multianode PMTs and demonstrated its feasibility as an experimental validator of TOF gains, suggesting its usefulness for investigating new applications of PET scans and clarifying TOF techniques in detail. PMID- 28665490 TI - Impact of China's essential medicines scheme and zero-mark-up policy on antibiotic prescriptions in county hospitals: a mixed methods study. AB - OBJECTIVE: To evaluate the impact of the national essential medicines scheme and zero-mark-up policy on antibiotic prescribing behaviour. METHODS: In rural Guangxi, a natural experiment compared one county hospital which implemented the policy with a comparison hospital which did not. All outpatient and inpatient records in 2011 and 2014 were extracted from the two hospitals. Primary outcome indicator was antibiotic prescribing rate (APR) among children aged 2-14 presenting in outpatients with a primary diagnosis of upper respiratory tract infection (URTI). We organised independent physician reviews to determine inappropriate prescribing for inpatients. Difference-in-difference analyses based on multivariate regressions were used to compare APR over time after adjusting potential confounders. We conducted 12 in-depth interviews with paediatricians, hospital directors and health officials. RESULTS: A total of 8219 and 4142 outpatient prescriptions of childhood URTIs were included in the intervention and comparison hospitals, respectively. In 2011, APR was 30% in the intervention and 88% in the comparison hospital. In 2014, the intervention hospital significantly reduced outpatient APR by 21% (95% CI:-23%, -18%), intravenous infusion by 58% (95% CI: -64%, -52%) and prescription cost by 31 USD (95% CI: -35, -28), compared with the controls. We collected 251 inpatient records, but did not find reductions in inappropriate antibiotic use. Interviews revealed that the intervention hospital implemented a thorough antibiotics stewardship programme containing training, peer review of prescriptions and restrictions for overprescribing. CONCLUSION: The national essential medicines scheme and zero mark-up policy, when implemented with an antimicrobial stewardship programme, may be associated with reductions in outpatient antibiotic prescribing and intravenous infusions. PMID- 28665491 TI - Feasibility of dynamic adaptive passive scattering proton therapy with computed tomography image guidance in the lung. AB - PURPOSE: Hypo-fractionated proton beam therapy (PBT) is an approach that has been increasingly explored over the past decade. It requires high geometric accuracy for targeting of the PBT beams. However, image-guided PBT is currently commonly performed with kV X-ray images of bony anatomy. A dynamic adaptive passive scattering PBT system using computed tomography-based three-dimensional image guidance was developed, and its effectiveness was then evaluated retrospectively in patients with nonsmall cell lung cancer (NSCLC). METHODS: The dynamic adaptive PBT system consisted of computed tomography-based image registration and proton dose calculation using a simplified Monte Carlo algorithm, with a range adaptation system that could adjust the range shifter thickness to alter the dose distribution. Three patients were retrospectively analyzed. All plans, which each had a total dose of 60 Gy (relative biological effectiveness; RBE), were generated using two fields (Gantry angles: 270 degree and 180 degree) in a passive scattering method. Three dose distributions were generated for each patient according to the following different registrations: bone registration, tumor registration, and tumor registration with range adaptation. The following dosimetric parameters were compared with the original plan: target dose coverage at D95% for the clinical target volume (CTV), homogeneity of D5% to D95% for the CTV, and dose distributions in normal tissue (Dmax of Spinal cord and V20 Gy of lung). RESULTS: For the bone registration method, the average D95% and D5% to D95% for the CTV showed average differences from the original plan of -3.7 +/- 4.1 Gy (mean +/- 1SD; RBE) and 3.6 +/- 3.9 Gy (RBE) respectively. The tumor registration method achieved better coverage than the bone registration method, although the dosimetric parameters for coverage and homogeneity still showed average differences in -2.0 +/- 2.3 Gy (RBE) and 1.9 +/- 2.2 Gy (RBE) respectively. The range adaptive plan showed comparable coverage and homogeneity [D95%: -1.0 +/- 1.3 Gy (RBE) and D5% to D95%: 0.9 +/- 1.0 Gy (RBE) on average] to the original plan, as well as demonstrating similar normal tissue sparing. The approach could be completed in less than 10 min, including CT acquisition, image registration, dose recalculation with range optimization, and the operator's visual verification. CONCLUSIONS: The tumor dose coverage in patients with NSCLC may deteriorate as a result of respiratory or body movement if daily proton range adaptation is not performed. Our approach may provide higher geometric accuracy for localization of the tumor, and the dynamic range adaptation enables us to achieve the planned dose distribution for hypo-fractionated PBT in the lung. PMID- 28665492 TI - Antigen presenting cell-targeted proinsulin expression converts insulin-specific CD8+ T-cell priming to tolerance in autoimmune-prone NOD mice. AB - Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic beta cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8+ T cells transferred to mice in which proinsulin was transgenically expressed in APCs underwent several rounds of division and the majority were deleted. Residual insulin-specific CD8+ T cells were rendered unresponsive and this was associated with TCR downregulation, loss of tetramer binding and expression of a range of co-inhibitory molecules. Notably, accumulation and effector differentiation of insulin-specific CD8+ T cells in pancreatic lymph nodes was prominent in non-transgenic recipients but blocked by transgenic proinsulin expression. This shift from T-cell priming to T-cell tolerance exemplifies the tolerogenic capacity of autoantigen expression by APC and the capacity to overcome genetic tolerance defects. PMID- 28665493 TI - Assessment of the inhibitory effects and molecular docking of some sulfonamides on human serum paraoxonase 1. AB - Paraoxonase-1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. Due to the PON1's crucial functions, inhibitors and activators of PON1 must be known for pharmacological applications. In this study, we investigated the in vitro effects of some sulfonamides compounds on human serum PON1 (hPON1). For this aim, we purified the hPON1 from human serum with high specific activity by using simple chromatographic methods, and after the purification processes, we investigated in vitro interactions between the enzyme and some sulfonamides (2 amino-5-methyl-1,3-benzenedisulfonamide, 2-chloro-4-sulfamoilaniline, 4-amino-3 methylbenzenesulfanilamide, sulfisoxazole, sulfisomidine, and 5-amino-2 methylbenzenesulfonamide). IC50 , Ki values, and inhibition types were calculated for each sulfonamide. 2-amino-5-methyl-1,3-benzenedisulfonamide and 2-chloro-4 sulfamoilaniline exhibited noncompetitive inhibition effect, whereas 4-amino-3 methylbenzenesulfanilamide, sulfisoxazole, and sulfisomidine exhibited mixed type inhibition. On the other hand, 5-amino-2-methylbenzenesulfonamide showed competitive inhibition and so molecular docking studies were performed for this compound in order to assess the probable binding mechanism into the active site of hPON1. PMID- 28665494 TI - Hypofractionated radiation therapy in the treatment of canine thymoma: Retrospective study of eight cases. AB - Thymomas are one of the most common tumors of the cranial mediastinum in dogs; however there is limited information available on the use of radiation therapy for treating this neoplasm. Objectives of the current retrospective observational study were to describe outcomes and side effects of a hypofractionated radiation therapy protocol in a group of dogs with confirmed thymoma. A total of eight dogs were included. To generate individualized treatment plans, we designed the planning target volume according to the limits on mean lung dose and the percentage of the total lung volume exceeding 20 Gy (V20). The total administered dose was 48-49 Gy, with one fraction per week for a total of six to seven fractions. After therapy, two dogs achieved complete responses, two achieved partial responses, and the disease remained stable in two. Two dogs died during the radiation therapy protocol and were not classified. The median mean lung dose and V20 were 6.0 Gy (range: 3.1-15.0 Gy) and 12.4% (range: 2.3-27.5%), respectively. The overall response rate was 50.0%, and the median time to response following treatment initiation was 22 days (range: 14-115 days). Acute and late side effects were common in the skin and/or lung and were self-limiting or asymptomatic. The median survival time was not reached (range: 8-1128 days) and the 1 year survival rate was 75.0%. Hypofractionated radiation therapy was well tolerated in this sample of dogs with thymoma and may be considered when owners decline surgical treatment or the tumor is deemed unresectable. PMID- 28665495 TI - Characterization of bulk and shear properties of basmati and non-basmati rice flour. AB - BACKGROUND: Flours are often unstable in relation to their flow performance, which is evident when a free-flowing material ceases to flow and the processing, handling, and production parameters depend on the inherent powder characteristics and their bulk behaviour. The present study was conducted to compare the flowability of basmati and non-basmati rice flour affecting bulk handling, which could be related to its particle size, shape and surface roughness (measured by atomic force microscopy) as well as bulk and shear properties, depending upon the processing conditions. RESULTS: Particle size (171.1-171.9 MUm) of both samples was not significantly different. However, the flowability of the non-basmati rice flour was significantly affected by its particle shape (circularity 0.487), surface roughness (124.23 nm) and compressibility (25.32%) in comparison to basmati rice flour (circularity 0.653, surface roughness 113.59 nm and compressibility 21.09%), making it more cohesive than basmati rice flour. Also, basic flow energy was significantly higher in non-basmati flour, thus requiring more energy (147.54 mJ) to flow than basmati rice flour (130.15 mJ). CONCLUSION: Overall, flowability was analysed by applying three different pressures (3, 6 and 9 kPa), among which non-basmati rice flour was found to be less flowable (flow function coefficient (FFC) 2.33 at 9 kPa) in comparison to basmati (FFC 3.35 at 9 kPa), making bulk handling difficult. This study could be useful in designing processing equipment, hoppers and silos for rice flour handling. (c) 2017 Society of Chemical Industry. PMID- 28665496 TI - Limitations of the interpretation and extrapolation of clinical trial data in kidney transplant recipients. AB - OBJECTIVE: The risks and benefits of the participation of kidney transplant recipients in randomized clinical trials (RCTs) investigating new immunosuppressive therapies are unknown. DESIGN AND SETTING: We included patients from 12 prospective phase II/III RCTs randomized to the experimental (G1, n=319) or standard-of-care internal control group (G2, n=118). We constructed two additional external control groups with (G3, n=319) or without (G4, n=319) matching inclusion/exclusion criteria based on transplant date. The primary outcome analysis was the composite clinical efficacy failure, defined as biopsy proven acute rejection (BPAR), graft loss, death, or loss to follow-up 12 months after kidney transplantation. RESULTS: Survival free of composite clinical efficacy failure was higher among participants in RCT, without difference between experimental or standard-of-care therapy (80?3 vs 78?0 vs 69?9 vs 66?1%, P<.001), respectively. Patient (98.1 vs 99.2 vs 96.9 vs 91.8 P<.001) and graft (94.0 vs 98.3 vs 90.9 vs 82.4) survivals were also higher in G1 compared to G4, but no differences in survival free of BPAR were observed (85.3 vs 78.8 vs 82.8 vs 81.2 P>.05), respectively. CONCLUSION: These findings suggested that new treatments investigated in kidney transplant recipients are not associated with detectable harm compared to standard of care. PMID- 28665498 TI - Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis. AB - BACKGROUND & AIMS: Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. METHODS: Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH ). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. RESULTS: Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. CONCLUSIONS: Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis. PMID- 28665497 TI - Protein and modified vaccinia virus Ankara-based influenza virus nucleoprotein vaccines are differentially immunogenic in BALB/c mice. AB - Because of the high variability of seasonal influenza viruses and the eminent threat of influenza viruses with pandemic potential, there is great interest in the development of vaccines that induce broadly protective immunity. Most probably, broadly protective influenza vaccines are based on conserved proteins, such as nucleoprotein (NP). NP is a vaccine target of interest as it has been shown to induce cross-reactive antibody and T cell responses. Here we tested and compared various NP-based vaccine preparations for their capacity to induce humoral and cellular immune responses to influenza virus NP. The immunogenicity of protein-based vaccine preparations with Matrix-MTM adjuvant as well as recombinant viral vaccine vector modified Vaccinia virus Ankara (MVA) expressing the influenza virus NP gene, with or without modifications that aim at optimization of CD8+ T cell responses, was addressed in BALB/c mice. Addition of Matrix-MTM adjuvant to NP wild-type protein-based vaccines significantly improved T cell responses. Furthermore, recombinant MVA expressing the influenza virus NP induced strong antibody and CD8+ T cell responses, which could not be improved further by modifications of NP to increase antigen processing and presentation. PMID- 28665499 TI - Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2. AB - NEW FINDINGS: What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg-1 ) and corticotrophin releasing factor receptor 2 agonist (urocortin 2; 30 MUg kg-1 ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-gamma-induced protein 10 and macrophage inflammatory protein 3alpha were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated. PMID- 28665500 TI - Provider attitudes and practice patterns of obesity management with pharmacotherapy. AB - BACKGROUND AND PURPOSE: More than one third of American adults are obese. Extreme obesity is rapidly rising. Nine medications are approved for weight loss yet they remain underutilized with the focus primarily on lifestyle modifications. The objective was to determine current prescribing patterns and attitudes of weight loss medications in the management of obesity among primary care providers (PCPs). METHODS: PCPs were surveyed to determine practice patterns, attitudes, barriers, and facilitators for prescribing weight loss medications. CONCLUSIONS: Ninety-four surveys were analyzed. Seventy-six percent of all PCPs did not prescribe weight loss medications for long-term weight loss and 58% of PCPs had negative perceptions of pharmacotherapy. Differences existed between prescribing patterns and attitudes of advanced practice clinicians and physicians. Safety concerns were the greatest barrier. Having 2+ comorbidities and severe obesity were facilitators for prescribing weight loss medications. Underutilization of pharmacotherapy suggests that PCPs may not have sufficient knowledge about medication safety profiles and efficacy. Delaying treatment until patients have reached a high level of morbidity may be less efficacious than earlier treatment. IMPLICATIONS FOR PRACTICE: Education regarding effectiveness and risks of weight loss medications for obesity management is needed and earlier interventions with pharmacotherapy may prevent significant morbidity and mortality. PMID- 28665501 TI - Photo-Induced Bending Behavior of Post-Crosslinked Liquid Crystalline Polymer/Polyurethane Blend Films. AB - Photoresponsive blend films with post-crosslinked liquid crystalline polymer (CLCP) as a photosensitive component and flexible polyurethane (PU) as the matrix are successfully fabricated. After being uniaxially stretched, even at low concentration, the azobenzene-containing CLCP effectively transfers its photoresponsiveness to the photoinert PU matrix, resulting in the fast photo induced bending behavior of whole blend film thanks to the effective dispersion of CLCP. Specifically, the blend film shows photo-induced deformations upon exposure to unpolarized UV light at ambient temperature. The film unbends after thermal treatment, and the randomly orientated mesogens in the film can be realigned by the mechanical stretching, which endows the film with a reversible deformation behavior. The photosensitive blend film possesses favorable mechanical property and good processability at low cost, and it is a promising candidate for a new generation of actuators. PMID- 28665502 TI - NOAH: NMR Supersequences for Small Molecule Analysis and Structure Elucidation. AB - Nested NMR experiments combining up to five conventional NMR pulse sequences into one supersequence are introduced. The core 2D NMR techniques routinely employed in small molecule NMR spectroscopy, such as HSQC, HMQC, HMBC, COSY, NOESY, TOCSY, and similar, can be recorded in a single measurement. In this way the data collection time may be dramatically reduced and sample throughput increased for basic NMR applications, such as structure elucidation and verification in synthetic, medicinal, and natural product chemistry. PMID- 28665503 TI - Mental health near miss indicators in maternity care: a missed opportunity? A commentary. PMID- 28665504 TI - Prognostic value of nasal cytology and clinical factors in nasal polyps development in patients at risk: can the beginning predict the end? AB - BACKGROUND: We evaluated the prognostic value of nasal cytology and clinical factors in predicting nasal polyp (NP) development in patients with history of nonallergic chronic sinonasal inflammation. METHODS: This was a retrospective case-control study of 295 patients followed at our institution for a mean of 85.70 +/- 19.41 months. According to the inclusion criteria we enrolled 84 cases with persistent eosinophilic nonallergic sinonasal inflammation (group A) and 106 cases with neutrophilic inflammation (group B), both without evidence of NPs at the baseline. We considered as controls 105 patients affected by nonallergic noninfectious vasomotor rhinitis without evidence of inflammation at nasal cytology (group C). Patients were checked every 6 months for NPs. Temporal analyses was performed by Kaplan-Mayer curves and odds ratios were evaluated by logistic regression analyses. RESULTS: The percentage of patients that developed NPs was higher in group A (29/84 [34.52%]) than in group B (17/106 [16.03%]) and group C (5/104 [4.7%]) (p < 0.05). Logistic regression analyses showed that eosinophilic patients had a higher risk of NP development over the years than neutrophilic patients compared to controls (odds ratio [OR], 10.55 vs 3.2). We also demonstrated that hypereosinophilia, asthma, and aspirin intolerance may increase the OR differently in eosinophilic patients. CONCLUSION: Our data suggest that early identification of inflammatory patterns and associated clinical factors in patients affected by chronic nonallergic sinonasal inflammation have a prognostic value that can help to identify patients with different risks of NP development. Our data confirm that detection of nasal eosinophilic inflammation represents an early marker for identification of a more aggressive inflammatory phenotype. PMID- 28665505 TI - Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides. AB - A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. Replacement of the trimethoxybenzoyl moiety with a nicotinoyl group, in order to overcome solubility issues, led to a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative, N-(3',5'-difluoro-3-nitro-[1,1' biphenyl]-4-yl)nicotinamide (3), displayed antiproliferative activity against MCF 7 and MDA-MB-231 cells in the nanomolar range. The search for a bioisostere of the nitro group led to nitrile analogue N-(3-cyano-4'-fluoro-[1,1'-biphenyl]-4 yl)nicotinamide (36), which shows a strong increase in activity against MCF-7 and MDA-MB-231 cells. Compound 36 induced a dose-dependent accumulation of G2 - and M phase MCF-7 cell populations, and a decrease in S-phase cells. Relative to vinblastine, a well-known potent antimitotic agent, compound 36 also induced G1 phase arrest at low doses (20-40 nm), but did not inhibit in vitro tubulin polymerization. PMID- 28665506 TI - Simultaneous endo and exo Complex Formation of Pyridine[4]arene Dimers with Neutral and Anionic Guests. AB - The formation of complexes between hexafluorophosphate (PF6- ) and tetraisobutyloctahydroxypyridine[4]arene has been thoroughly studied in the gas phase (ESI-QTOF-MS, IM-MS, DFT calculations), in the solid state (X-ray crystallography), and in chloroform solution (1 H, 19 F, and DOSY NMR spectroscopy). In all states of matter, simultaneous endo complexation of solvent molecules and exo complexation of a PF6- anion within a pyridine[4]arene dimer was observed. While similar ternary complexes are often observed in the solid state, this is a unique example of such behavior in the gas phase. PMID- 28665508 TI - A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome. AB - CONTEXT: Steroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower hypercortisolism in patients with Cushing's syndrome (CS). Cortisol normalization is not reached in all patients taking these medications. OBJECTIVE: To test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS. PATIENTS AND METHODS: Fifty-four CS patients (46 women; mean [+/-SD] age, 39.7+/-12.7; 83% with Cushing's disease [CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms (SNPs) were analysed: rs6410 (CYP11B1 gene), rs1799998 and rs4546 (CYP11B2 gene), and rs6163 (CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated. RESULTS: Normalization of urinary free cortisol (UFC) was achieved in 50% of patients after 5 months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/AA (OR 0.25 [95%CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range (IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/AC carriers (4 [4.57] months vs 5.2 [6.1] months; P=.026). CONCLUSIONS: A polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents. PMID- 28665507 TI - Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge. AB - Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 MUL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor alpha and adenohypophyseal mRNA expression of Tnfalpha and Il1beta increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS administration. PMID- 28665509 TI - Direct Reprogramming of Human Suspension Cells into Mesodermal Cell Lineages via Combined Magnetic Targeting and Photothermal Stimulation by Magnetic Graphene Oxide Complexes. AB - Suspension cells can provide a source of cells for cellular reprogramming, but they are difficult to transfect by nonviral vectors. An efficient and safe nonviral vector (GO-Fe3 O4 -PEI complexes) based on iron oxide nanoparticle (Fe3 O4 )-decorated graphene oxide (GO) complexed with polyethylenimine (PEI) for the first time is developed for delivering three individual episomal plasmids (pCXLE hOCT3/4-shp53, pCXLE-hSK, and pCXLE-hUL) encoding pluripotent-related factors of Oct3/4, shRNA against p53, Sox2, Klf4, L-Myc, and Lin28 into human peripheral blood mononuclear cells (PBMCs) simultaneously. The combined treatment of magnetic stirring and near-infrared (NIR)-laser irradiation, which can promote contact between the complexes and floating cells and increase the cell membrane permeability, respectively, is used to conduct multiple physical stimulations for suspension PBMCs transfection. The PCR analysis shows that the combinatorial effect of magnetic targeting and photothermal stimulation obviously promoted the transfection efficiency of suspension cells. The transfected cells show positive expression of the pluripotency markers, including Nanog, Oct4, and Sox2, and have potential to differentiate into mesoderm and ectoderm cells. The results demonstrate that the GO-Fe3 O4 -PEI complex provides a safe, convenient, and efficient tool for reprogramming PBMCs into partially induced pluripotent stem cells, which are able to rapidly transdifferentiate into mesodermal lineages without full reprogramming. PMID- 28665510 TI - Effect of Terminal Modification on the Molecular Assembly and Mechanical Properties of Protein-Based Block Copolymers. AB - Accurate prediction and validation of the assembly of bioinspired peptide sequences into fibers with defined mechanical characteristics would aid significantly in designing and creating materials with desired properties. This process may also be utilized to provide insight into how the molecular architecture of many natural protein fibers is assembled. In this work, computational modeling and experimentation are used in tandem to determine how peptide terminal modification affects a fiber-forming core domain. Modeling shows that increased terminal molecular weight and hydrophilicity improve peptide chain alignment under shearing conditions and promote consolidation of semicrystalline domains. Mechanical analysis shows acute improvements to strength and elasticity, but significantly reduced extensibility and overall toughness. These results highlight an important entropic function that terminal domains of fiber-forming peptides exhibit as chain alignment promoters, which ultimately has notable consequences on the mechanical behavior of the final fiber products. PMID- 28665511 TI - Home-based versus centre-based cardiac rehabilitation. AB - BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation. This is an update of a review previously published in 2009 and 2015. OBJECTIVES: To compare the effect of home based and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease. SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 21 September 2016. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials, including parallel group, cross-over or quasi-randomised designs) that compared centre-based cardiac rehabilitation (e.g. hospital, gymnasium, sports centre) with home-based programmes in adults with myocardial infarction, angina, heart failure or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on pre-defined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Quality of evidence was assessed using GRADE principles and a Summary of findings table was created. MAIN RESULTS: We included six new studies (624 participants) for this update, which now includes a total of 23 trials that randomised a total of 2890 participants undergoing cardiac rehabilitation. Participants had an acute myocardial infarction, revascularisation or heart failure. A number of studies provided insufficient detail to enable assessment of potential risk of bias, in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported.No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in clinical primary outcomes up to 12 months of follow up: total mortality (relative risk (RR) = 1.19, 95% CI 0.65 to 2.16; participants = 1505; studies = 11/comparisons = 13; very low quality evidence), exercise capacity (standardised mean difference (SMD) = -0.13, 95% CI -0.28 to 0.02; participants = 2255; studies = 22/comparisons = 26; low quality evidence), or health-related quality of life up to 24 months (not estimable). Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate quality evidence). However, there was evidence of marginally higher levels of programme completion (RR 1.04, 95% CI 1.00 to 1.08; participants = 2615; studies = 22/comparisons = 26; low quality evidence) by home-based participants. AUTHORS' CONCLUSIONS: This update supports previous conclusions that home- and centre-based forms of cardiac rehabilitation seem to be similarly effective in improving clinical and health related quality of life outcomes in patients after myocardial infarction or revascularisation, or with heart failure. This finding supports the continued expansion of evidence-based, home-based cardiac rehabilitation programmes. The choice of participating in a more traditional and supervised centre-based programme or a home-based programme may reflect local availability and consider the preference of the individual patient. Further data are needed to determine whether the effects of home- and centre-based cardiac rehabilitation reported in the included short-term trials can be confirmed in the longer term and need to consider adequately powered non-inferiority or equivalence study designs. PMID- 28665512 TI - "Treat me with respect". A systematic review and thematic analysis of psychiatric patients' reported perceptions of the situations associated with the process of coercion. AB - : WHAT IS KNOWN ON THE SUBJECT?: Psychiatric patients have generally negative experiences of being exposed to coercive measures. Existing research has generally not investigated coercion as a process; that is, it does not address issues that arise before, during and after exposure to coercion. A part of existing research within the area does not clarify and define the type of coercive measure(s) investigated. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Patients place great significance on the link between the positive and negative perceived impact of a coercive situation and the professionals' ability and willingness to interact and communicate respectfully. Psychiatric patients associate the use of seclusion, physical restraint/holding, mechanical restraint and forced medication with strong negative perceptions and wish to be treated with respect by professionals, rather than being subjected to the professionals' control. What patients perceive as moderating factors in regard to the use of coercive measures is currently under-researched. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Increased sensitivity to the patient's views of the situation at each point in the coercive process would help professionals to respond to the patients' individual needs. Professionals need to articulate concern and empathy towards patients and to improve communication skills before, during and after a coercive incident. Greater emphasis should be placed on de-escalation and the use of non-coercive strategies or coping skills before the initiation of coercive measures. ABSTRACT: Introduction There is a lack of research into psychiatric patients' perceptions of coercion that discriminates between different types of coercive measures, while also investigating patients' perceptions of undergoing coercion as a process. This knowledge is required to improve our understanding and provide a foundation for improving clinical practice. Aims To review existing research literature in order to investigate adult psychiatric patients' reported perceptions of situations before, during and after specific and defined types of coercive measures, and to investigate what patients perceive as moderating factors, in regard to the use of these coercive measures. Method A systematic review and thematic analysis of 26 peer-reviewed studies was undertaken. Results The analysis identified six themes and additional subthemes, where "interactions with professionals" and "communication" were predominant themes across the timeline of coercion. Altogether, themes were associated with either "positive or negative patient-perceived impact." Implications for practice Increased sensitivity to patients' views of the situation at each point in the process is desirable in order to respond to the patients' individual needs. Professionals also need to articulate concern and empathy towards the patient and to improve communication skills before, during and after a coercive incident. Use of de escalation and noncoercive strategies is required. Relevance statement Coercion within psychiatric/mental health care remains controversial, and repeated international calls have recommended a reduction of their use. This review indicates that greater attention to how patients perceive the use of coercive measures (before, during, and after incidents) needs to be considered in order to improve the evidence-based and clinical practice. PMID- 28665513 TI - Effects of feeding a Moringa oleifera rachis and twig preparation to dairy cows on their milk production and fatty acid composition, and plasma antioxidants. AB - BACKGROUND: We determined how supplementing the diet of lactating, multiparous Holstein dairy cows with a preparation of Moringa oleifera rachises and twigs affected their milk production and quality and the levels of plasma antioxidants. RESULTS: We found that milk yield increased in cows receiving the 6% (w/w) moringa supplement compared with that of the control. Addition of the moringa supplement increased the concentration of milk fat and decreased the somatic cell count in the milk. However, protein, glucose and total solid and urea nitrogen concentrations in the milk were the same for all treatments. The concentration of glutathione peroxidase increased for cows fed the moringa supplement compared with the control. The percentages of total unsaturated fatty acids, mono unsaturated fatty acids, and polyunsaturated fatty acids including n-3 polyunsaturated fatty acid increased in the milk of cows fed the moringa supplement compared with those of the controls. CONCLUSION: Addition of the moringa supplement into the diet of lactating multiparous cows improved milk production and health status and modified milk fatty acid profile positively. The results suggested that moringa supplement could be used as a diet supplement for producing high quality and healthier milk. (c) 2017 Society of Chemical Industry. PMID- 28665514 TI - Microguided Endodontics: a method to achieve minimally invasive access cavity preparation and root canal location in mandibular incisors using a novel computer guided technique. AB - AIM: To present a novel miniaturized and minimally invasive treatment approach for root canal localization in mandibular incisors with pulp canal calcification and apical periodontitis. SUMMARY: A 51-year-old male patient presented with pain from his mandibular incisors. The patient had a history of severe dental trauma over 30 years ago. Both mandibular central incisors (teeth 31, 41) were tender to percussion and had a yellowish discoloration. They did not respond to thermal and electrical sensitivity tests. Two periapical radiographs from different projections revealed severe pulp canal calcifications and signs of periapical periodontitis. To facilitate the 'Microguided Endodontics' technique, a CBCT and an intra-oral surface scan were aligned using special software. This allowed the virtual planning of optimal access cavities up to the apical third of the root. In this technique, a 3D-printed template guides a customized drill to the orifice of the root canal. After negotiation of the root canals, conventional root canal treatment was performed. This case report demonstrates that minimally invasive and apically extended access cavities are feasible in mandibular incisors with this technique. KEY LEARNING POINTS: The 'Microguided Endodontics' technique is a safe and minimally invasive method for root canal location and prevention of technical failures in anterior teeth with pulp canal calcification. PMID- 28665515 TI - Effect of harvest, drying and storage on the bitterness, moisture, sugars, free amino acids and phenolic compounds of jujube fruit (Zizyphus jujuba cv. Junzao). AB - BACKGROUND: The taste of dried jujube fruit when compared with fresh ones is less palatable, as it develops bitterness during drying and storage. Therefore, identifying the methods by which bitterness occurs is essential for developing strategies for processing and storage. RESULTS: Bitterness in fresh jujube fruit was negligible; however, it increased by 0.9-, 1.5- and 1.8-fold during drying and storage over 6 and 12 months. The moisture significantly decreased during harvesting and drying. Free amino acids, except proline and tyrosine, significantly decreased during drying and storage. Fructose, glucose and sucrose hardly changed during harvest, drying and storage. Titratable acidity, total phenolic and total flavonoids contents were stable during harvest and drying, but increased upon storage. Additionally, protocatechuic and ellagic acids were not detected in fresh jujube fruit, however, were found to increase during drying and storage. CONCLUSION: Bitterness in fresh jujube fruit tasted negligible because of meagre amount of phytochemicals, while the condensation effect of moisture reduction, the loss of free amino acids, and the formation of protocatechuic and ellagic acids could aggravate the bitterness of jujube fruit during drying and storage. (c) 2017 Society of Chemical Industry. PMID- 28665516 TI - Proximate, mineral composition and antioxidant activity of traditional small millets cultivated and consumed in Rayalaseema region of south India. AB - BACKGROUND: Millets are a diverse group of small seeded grasses, widely grown around the world as cereal foods. This communication details the proximate, mineral profile and antioxidant activity of six different small millets (Finger, Foxtail, Proso, Little, Barnyard and Kodo millets) and their 21 cultivars that are traditionally cultivated and consumed in the region of Ralayaseema, south India. RESULTS: The proximate analysis revealed that these millets are rich in protein, fat, ash (mineral), total dietary fibre and total phenols with appreciable antioxidant activity. However, starch and amylose content was comparatively lower as compared to major millet sorghum. ICP-MS analysis of small millets demonstrated that they are rich in minerals such as Ca, P, K, Mg, Fe, Cu, Zn, Mn, Cr, Mo and Se. CONCLUSION: Finger and kodo millets were found to be nutritionally superior over other small millets. The results suggest that small millets have a potential to provide food security and can combat micronutrient malnutrition. (c) 2017 Society of Chemical Industry. PMID- 28665517 TI - A Cumulative Deficit Laboratory Test-based Frailty Index: Personal and Neighborhood Associations. AB - OBJECTIVES: To explore the association between a newly developed cumulative laboratory-based frailty index (FI) and intrinsic (personal) and extrinsic (social, environmental) characteristics. DESIGN: Cross-sectional longitudinal study. SETTING: The third and fourth waves of the community-representative, five county, 10-year Duke Established Populations for Epidemiologic Studies of the Elderly study, carried out in a health service-rich area. PARTICIPANTS: Cognitively intact survivors of the third wave (N = 1,740), who provided blood samples for standard laboratory work. MEASUREMENTS: Biomarkers (n = 28) were measured to develop a cumulative deficit laboratory test-based FI (Duke FI) derived from standard laboratory tests: SMAC-24 chemistry panel, high-density lipoprotein cholesterol panel, and complete blood count. Information was gathered on scales assessing intrinsic characteristics (personal locus of control, life satisfaction, self-esteem, depressive symptomatology) and extrinsic characteristics (support received from and provided to family and friends, stressful life events, neighborhood disadvantage). RESULTS: The newly developed Duke FI had content, construct, concurrent, and predictive validity. In addition to sex, race, and income, the Duke FI was associated at the intrinsic level with locus of control, self-esteem, life satisfaction, and depressive symptomatology (each P < .01) and at the extrinsic level with provision (P < .01) and with receipt of instrumental help (P < .10), social stressors (P < .03), and neighborhood disadvantage (P < .01) in unadjusted analysis; race fully explained neighborhood disadvantage. CONCLUSION: Intrinsic (personality) characteristics and personally close extrinsic characteristics (contacts with family and friends, personal stressors) are associated with laboratory test-based frailty, as is neighborhood disadvantage, although in this accessible, health service-rich environment, race fully explained association with neighborhood disadvantage, suggesting that interventions to reduce frailty in residents in such an environment should pay particular attention to characteristics that immediately affect the individual. PMID- 28665518 TI - Increased expression of TIPE2 in alternatively activated macrophages is associated with eosinophilic inflammation and disease severity in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disorder characterized by exaggerated local immune responses. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is a novel protein with potential immune modulating function. The expression and function of TIPE2 in human airway diseases are unclear. METHODS: The expression of TIPE2 in sinonasal mucosal samples was assessed by means of quantitative reverse transcript-polymerse chain reaction, immunohistochemistry, and Western blotting. The human monocytic/macrophage cell line, THP-1 cells, was stimulated with various cytokines. Computed tomography (CT) scan images, endoscopic findings, and symptoms were scored. RESULTS: Compared with non-eosinophilic polyps and control mucosa, the mRNA and protein expression of TIPE2 was significantly upregulated in eosinophilic polyps, with a further increase in those with asthma. The number of CD68+ CD163+ alternatively activated (M2) macrophages was increased in eosinophilic polyps. TIPE2 was mainly expressed by M2 macrophages in sinonasal mucosa and its expression was upregulated in M2 macrophages in eosinophilic polyps. Interleukin (IL)-4 and IL-13, but not interferon (IFN)-gamma or IL-17A, induced TIPE2 expression in differentiated THP-1 cells. The mRNA levels of IL-4 and IL-13 correlated with the mRNA levels of TIPE2 and M2 macrophage markers in sinonasal mucosa. Importantly, the number of TIPE2+ cells, particularly TIPE2+ CD163+ CD68+ M2 macrophages, correlated positively with the number of eosinophils and total inflammatory cells in sinonasal mucosa, as well as disease duration, CT scores, hyposmia scores, and polyp size in CRSwNP. CONCLUSION: The T-helper 2 milieu is able to induce TIPE2 expression in macrophages. TIPE2-positive M2 macrophages potentially contribute to eosinophilic inflammation and disease progression in CRSwNP. PMID- 28665519 TI - Unearthing [3-(Dimethylamino)propyl]aluminium(III) Complexes as Novel Atomic Layer Deposition (ALD) Precursors for Al2 O3 : Synthesis, Characterization and ALD Process Development. AB - Identification and synthesis of intramolecularly donor-stabilized aluminium(III) complexes, which contain a 3-(dimethylamino)propyl (DMP) ligand, as novel atomic layer deposition (ALD) precursors has enabled the development of new and promising ALD processes for Al2 O3 thin films at low temperatures. Key for this promising outcome is the nature of the ligand combination that leads to heteroleptic Al complexes encompassing optimal volatility, thermal stability and reactivity. The first ever example of the application of this family of Al precursors for ALD is reported here. The process shows typical ALD like growth characteristics yielding homogeneous, smooth and high purity Al2 O3 thin films that are comparable to Al2 O3 layers grown by well-established, but highly pyrophoric, trimethylaluminium (TMA)-based ALD processes. This is a significant development based on the fact that these compounds are non-pyrophoric in nature and therefore should be considered as an alternative to the industrial TMA-based Al2 O3 ALD process used in many technological fields of application. PMID- 28665520 TI - Vaccine potential of HLA-A2 epitopes from Leishmania Cysteine Protease Type III (CPC). AB - Although the precise host-defence mechanisms are not completely understood, T cell-mediated immune responses are believed to play a pivotal role in controlling parasite infection. In this study, the potential HLA*A2 restricted peptides were predicted and the ability of peptides to bind HLA-A*02 was confirmed by a MHC stabilization assay. Two of the peptides tested stabilized HLA-A*02: (a) LLATTVSGL (P1) and (b) LMTNGPLEV (P3). The potential of the peptides to generate protective immune response was evaluated in patients with treated visceral leishmaniasis as well as in healthy control subjects. Our data suggest that CD8+ T-cell proliferation against the selected peptide was significantly higher compared to unstimulated culture conditions. The stimulation of peripheral blood mononuclear cells with epitopes individually or as a cocktail upregulated IFN gamma production, which indicates its pivotal role in protective immune response. The IFN-gamma production was mainly in a CD8+ T-cells-dependent manner, which suggested that these epitopes had an immunoprophylactic potential in a MHC class I-dependent manner. Moreover, no role of the CD3+ T cell was observed in the IL 10 production against the selected peptides, and no role was found in disease pathogenesis. Further studies on the role of these synthetic peptides may contribute significantly to developing a polytope vaccine idea towards leishmaniasis. PMID- 28665521 TI - Traumatic stress in patients with acute leukemia: A prospective cohort study. AB - OBJECTIVE: Acute leukemia (AL) is associated with an immediate threat to life, an unpredictable clinical course, and substantial physical suffering. Traumatic stress symptoms that may meet criteria for acute stress disorder (ASD) may be common and disabling in this context, but have received little clinical attention. We investigated the incidence over time and risk factors for traumatic stress symptoms and ASD in the 3 months following diagnosis or relapse of AL. METHODS: Individuals with AL were recruited at a tertiary cancer center in Canada within one month of diagnosis or relapse. Participants (N = 230) completed self report measures, including the Stanford Acute Stress Reaction Questionnaire, at baseline and monthly over 3 months. The incidence of traumatic stress symptoms over time was examined, and a generalized logistic model was used to identify factors associated with ASD. RESULTS: Participants were 60% male, with a mean age of 48.9 +/- 15.2 years. Symptoms of ASD were identified on >=1 assessment over the study period in 24.4% of participants at baseline and in an additional 12.6% at a subsequent follow-up. Of these, 55.3% reported symptoms on >=2 assessments. ASD was associated with having young children, being unmarried, acute lymphocytic leukemia, and greater physical symptom burden. Persistent or recurrent ASD was associated with female sex, acute lymphocytic leukemia, greater attachment anxiety, less spiritual well-being, and less satisfactory patient-clinician communication. CONCLUSIONS: Symptoms of ASD are common and often persist or recur following diagnosis or relapse of AL. Research is urgently needed to determine the impact of interventions to prevent and treat psychological distress in this population. PMID- 28665522 TI - Reply to Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710. PMID- 28665523 TI - Emotional labor and professional practice in sports medicine and science. AB - The aim of this study was to explore how sport medicine and science practitioners manage their emotions through emotional labor when engaging in professional practice in elite sport. To address the research aim a semistructured interview design was adopted. Specifically, eighteen professional sport medicine and science staff provided interviews. The sample comprised sport and exercise psychologists (n=6), strength and conditioning coaches (n=5), physiotherapists (n=5), one sports doctor and one generic sport scientist. Following a process of thematic analysis, the results were organized into the following overarching themes: (a) factors influencing emotional labor enactment, (b) emotional labor enactment, and (c) professional and personal outcomes. The findings provide a novel contribution to understanding the professional demands faced by practitioners and are discussed in relation to the development of professional competencies and the welfare and performance of sport medics and scientists. PMID- 28665524 TI - Rapid screening for malignancy in organ donors: 15-year experience with the Verona "Alert" protocol and review of the literature. AB - BACKGROUND: Prevention of transmission of malignancy from donors to recipients is an aim of donor assessment. We report the most stringent interpretation of the Italian National Guidelines. METHODS: A two-step ALERT process was used: ALERT1 consisting of clinical, radiological, and laboratory tests; ALERT2, consisting of intraoperative assessment in suspicious lesions. RESULTS: Four hundred of 506 potential deceased donors entered the ALERT system. Forty-one of 400 (10%) donors were excluded due to unacceptable risk of transmission. Of the remaining 359 193 required histopathology, which excluded malignancy or determined acceptable risk in 161/193 (83%). Thirty-five malignancies were identified: 19 (54%) at ALERT1, four (11%) at ALERT2, nine (26%) picked up at ALERT1 and confirmed by ALERT2. Three (9%) were missed by ALERT and diagnosed at postmortem examination. Prostate (n=12%, 34%) and renal cell (n=7%, 20%) were the most frequent carcinomas. The majority (92%) of prostate adenocarcinomas were of low risk and donation proceeded compared to 43% of renal carcinomas. Four renal carcinomas, two breast carcinomas, and a single case of nine different malignancies excluded donation. Positive ALERT donors had statistically more malignant reports than negative ALERT donors (P=<.05). CONCLUSION: Histopathology is an essential component of the multidisciplinary assessment of donors. PMID- 28665525 TI - Capillary electrophoresis and nanomaterials - Part I: Capillary electrophoresis of nanomaterials. AB - Nanomaterials are in analytical science used for a broad range of purposes, covering the area of sample pretreatment as well as separation, detection, and identification of target molecules. This part of the review covers capillary electrophoresis (CE) of nanomaterials and focuses on the application of CE as a method for characterization used during nanomaterial synthesis and modification as well as the monitoring of their properties and interactions with other molecules. The heterogeneity of the nanomaterial family is extremely large. Depending on different definitions of the term Nanomaterial/Nanoparticle, the group may cover metal and polymeric nanoparticles, carbon nanomaterials, liposomes and even dendrimers. Moreover, these nanomaterials are usually subjected to some kind of surface modification or functionalization, which broadens the diversity even more. Not only for purposes of verification of nanomaterial synthesis and batch-to-batch quality check, but also for determination the polydispersity and for functionality characterization on the nanoparticle surface, has CE offered very beneficial capabilities. Finally, the monitoring of interactions between nanomaterials and other (bio)molecules is easily performed by some kind of capillary electromigration technique. PMID- 28665527 TI - DNA decontamination methods for internal quality management in clinical PCR laboratories. AB - BACKGROUND: The polymerase chain reaction (PCR) technique, one of the most commonly applied methods in diagnostic and molecular biology, has a frustrating downside: the occurrence of false-positive signals due to contamination. In previous research, various DNA decontamination methods have been developed to overcome this limitation. Unfortunately, the use of random or poorly focused sampling methods for monitoring air and/or object surfaces leads to the incomplete elimination during decontamination procedures. We herein attempted to develop a novel DNA decontamination method (environmental surveillance, including surface and air sampling) and quality management program for clinical molecular diagnostic laboratories (or clinical PCR laboratories). METHODS: Here, we performed a step-by-step evaluation of current DNA decontamination methods and developed an effective procedure for assessing the presence of decontaminating DNA via PCR analysis. Performing targeted environmental surveillance by sampling, which reached optimal performance over 2 weeks, and the decontamination process had been verified as reliable. Additionally, the process was validated to not affect PCR amplification efficiency based on a comparative study. RESULTS: In this study, effective guidelines for DNA decontamination were developed. The method employed ensured that surface DNA contamination could be effectively identified and eliminated. Furthermore, our study highlighted the importance of overall quality assurance and good clinical laboratory practices for preventing contamination, which are key factors for compliance with regulatory or accreditation requirements. CONCLUSIONS: Taken together, we provided the evidence that the presented scheme ranged from troubleshooting to the elimination of surface contamination, could serve as critical foundation for developing regular environmental surveillance guidelines for PCR laboratories. PMID- 28665526 TI - Cognitive Emotion Regulation Strategies Associated With the DSM-5 Posttraumatic Stress Disorder Criteria. AB - Maladaptive cognitive emotion regulation strategies have been proposed to contribute to the maintenance of posttraumatic stress disorder (PTSD). Prior work has focused on the relationship between these strategies and PTSD as a whole, rather than on how they are related to each PTSD symptom cluster. The purpose of the current study was to determine whether cognitive emotion regulation strategies are predictive of certain PTSD symptom clusters under the Diagnostic and Statistical Manual of Mental Disorders 5th ed. (DSM-5; American Psychiatric Association, 2013) criteria (intrusive thoughts, avoidance, negative alterations in cognitions and mood, and hyperarousal). Participants included 365 treatment seeking, active-duty military personnel with PTSD. The negative alterations in cognitions and mood cluster were associated with dysfunctional cognitions: greater negative cognitions about the self, negative cognitions about the world, and self-blame, as well as catastrophizing (Rc2 = .519). The negative alterations in cognitions and mood cluster did not show a strong relationship with blaming others, possibly due to the complex nature of self- and other-blame in this primarily deployment-related PTSD sample. Finally, the intrusive thoughts cluster was associated with catastrophizing (Rc2 = .211), suggesting an association between frequent intrusive memories and excessively negative interpretation of those memories. PMID- 28665528 TI - Trauma hazards in children: An update for the busy clinician. AB - Trauma and injury continue to be common in children and remain an important cause of mortality and morbidity. Legislation mandating the use of helmets for all cyclists appears to have been effective in reducing the incidence and severity of head and facial injuries, with no clear evidence of a reduction in cycling usage or activity. Straddle injuries, whilst uncommon and generally minor, require careful clinical assessment as they may be associated with urethral trauma. Quad bikes remain highly dangerous with continuing reports of deaths in child riders due to their inherent lack of stability: a ban on their use by children would seem the most effective solution. The popularity of mobile devices and toys, coupled with the development of higher voltage, lithium button batteries have seen a surge in the number of cases and subsequent complications from ingestion. The problems seen in children following ingestion of high-powered, rare earth magnets in the late 1990s and 2000s has now receded due to legislation introduced in 2012. Inhaled, typically organic foreign bodies remain a diagnostic challenge with rigid bronchoscopy still the most effective diagnostic and therapeutic modality. Corrosive ingestion, now seen much less commonly, continues to be a potentially devastating injury when occurring as a result of caustic soda. Recent publicity concerning the problem of childhood drowning highlights the need for constant parental vigilance, the limitations of pool fencing and the importance of community cardiopulmonary resuscitation training, together with repeated education of the risk of rips when swimming in the sea. PMID- 28665529 TI - A novel and fast method for proton range verification using a step wedge and 2D scintillator. AB - PURPOSE: To implement and evaluate a novel and fast method for proton range verification by using a planar scintillator and step wedge. METHODS: A homogenous proton pencil beam plan with 35 energies was designed and delivered to a 2D flat scintillator with a step wedge. The measurement was repeated 15 times (3 different days, 5 times per day). The scintillator image was smoothed, the Bragg peak and distal fall off regions were fitted by an analytical equation, and the proton range was calculated using simple trigonometry. The accuracy of this method was verified by comparing the measured ranges to those obtained using an ionization chamber and a scanning water tank, the gold standard. The reproducibility was evaluated by comparing the ranges over 15 repeated measurements. The sensitivity was evaluated by delivering to same beam to the system with a film inserted under the wedge. RESULTS: The range accuracy of all 35 proton energies measured over 3 days was within 0.2 mm. The reproducibility in 15 repeated measurements for all 35 proton ranges was +/-0.045 mm. The sensitivity to range variation is 0.1 mm for the worst case. This efficient procedure permits measurement of 35 proton ranges in less than 3 min. The automated data processing produces results immediately. The setup of this system took less than 5 min. The time saving by this new method is about two orders of magnitude when compared with the time for water tank range measurements. CONCLUSIONS: A novel method using a scintillator with a step wedge to measure the proton range was implemented and evaluated. This novel method is fast and sensitive, and the proton range measured by this method was accurate and highly reproducible. PMID- 28665530 TI - Models to Guide the Implementation and Sustainability of Evidence-Based Practice: A Call to Action for Further Use and Research. PMID- 28665531 TI - Radial Extracorporeal Shock Wave Therapy for Relief of Arthralgia in Rheumatoid Arthritis. AB - More than one-third of the population with rheumatoid arthritis requires adjuvant analgesic treatment after antirheumatic therapy. In addition to analgesics, another option is radial extracorporeal shock wave therapy (rESWT), a novel physical therapy that has been successfully used in the treatment of many types of chronic soft tissue pain. We report a series of 15 patients who suffered from arthralgia after being on disease-modifying antirheumatic drugs for more than 3 months. Participants received rESWT for 3 months as an adjuvant therapy. Compared to the pretherapy baseline, follow-up at 3 months post-therapy revealed a significant reduction in resting state visual analog scale scores from 2.90 +/- 0.74 to 0.80 +/- 0.79 (P = 0.004), active state visual analog scale scores from 5.70 +/- 1.33 to 2.20 +/- 0.63 (P < 0.001), morning stiffness duration from 2.25 +/- 0.79 to 1.05 +/- 0.69 hours (P = 0.004), disease activity score with 28-joint counts based on erythrocyte sedimentation rate from 6.34 +/- 0.72 to 4.19 +/- 0.59 (P = 0.001), and Health Assessment Questionnaire scores from 10.20 +/- 2.35 to 5.00 +/- 2.62 (P = 0.005). The pre-post changes in erythrocyte sedimentation rate and C-reactive protein were not statistically significant. By the end of treatment, 11 participants stopped analgesics completely; the other 4 participants were on a smaller dosage. No severe adverse effects related to rESWT were observed. To our knowledge, this is the first report using this therapy to treat arthralgia in rheumatoid arthritis. PMID- 28665533 TI - Radiographic assessment of humeroulnar congruity in a medium and a large breed of dog. AB - Elbow joint incongruity is recognized as an important factor in the development, treatment, and prognosis of canine elbow dysplasia. Elbow incongruity has been measured based on radiographic joint space widths, however these values can be affected by the degree of elbow joint flexion. Recent studies have reported radiographic curvature radii as more precise measures of humeroulnar congruity in dogs. The aim of this prospective observational study was to describe radiographic curvature radii measured from flexed and extended elbow radiographs for a sample of dogs representing a medium breed (Portuguese Pointing Dog) and a large breed (Estrela Mountain Dog). The curvature radii from the ulnar trochlear notch and humeral trochlea were measured in 114 mediolateral elbow extended radiographic views (30 Portuguese Pointing Dog and 27 Estrela Mountain Dog), and 84 mediolateral flexed views (22 Portuguese Pointing Dog and 20 Estrela Mountain Dog). The sampled animals' ages ranged from 12 to 84 months (34.6 +/- 17.8 months). Good agreement was observed between curvature radii measurements for flexed vs. extended views in both breed groups. Ulnar trochlear notch curvature radii measurements were greater than humeral trochlea curvature radii measurements in both breed groups. Both curvature radii were greater in the large breed dog group vs. the medium-breed dog group. Both breed groups had ulnar and humeral curves with similar typology. However, the large breed group had greater intermediate differences between the humeroulnar surface curvature radii. Results from this study supported the use of curvature radii as measures of humeroulnar congruity in mediolateral flexed elbow radiographs of medium and large breed dogs. PMID- 28665534 TI - Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma. AB - BACKGROUND: Tiotropium is a long acting muscarinic antagonist (LAMA), licensed as triple therapy with inhaled corticosteroid and long-acting beta-agonist (ICS/LABA). There may be a synergistic benefit between LAMA and LABA as a consequence of receptor cross-talk, which in turn could modify beta-2 receptor downregulation and associated tolerance induced by LABA. OBJECTIVE: We hypothesize this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy. METHODS: We evaluated 14 non smoking asthmatics using an open-label, randomized crossover design. ICS with Indacaterol and Tiotropium (IND/TIO) vs ICS with Indacaterol (IND) over 4 weeks with challenge performed after first and last doses at trough. RESULTS: We found no significant difference in mannitol sensitivity, expressed as the provocative dose of mannitol required to reach a 15% drop in FEV1 , or mannitol reactivity, expressed as the response dose ratio (RDR: max % fall in FEV1 /cumulative dose), when comparing ICS/IND/TIO to ICS/IND. Geometric mean fold differences for RDR comparing single and chronic dosing were 3.26-fold (95% CI 1.46-7.29) and 2.51 fold (95% CI 1.32-4.79) for IND and IND/TIO, respectively. Furthermore, salbutamol recovery post-challenge was significantly blunted after chronic compared to single dosing with either ICS/IND (P<.005) or ICS/IND/TIO (P<.05). CONCLUSION AND CLINICAL RELEVANCE: Our data suggest that concomitant tiotropium does not modify the bronchoprotective tolerance induced by Indacaterol, in turn suggesting that cross-talk may not be clinically relevant when using triple therapy. This study was registered on clinicaltrials.gov as NCT02039011. PMID- 28665535 TI - Pre-Dialysis Neutrophil-Lymphocyte Ratio, a Novel and Strong Short-Term Predictor of All-Cause Mortality in Patients With Diabetic Nephropathy: Results From a Single-Center Study. AB - Neutrophil-lymphocyte ratio (NLR) is an inflammatory marker affecting the prognosis of end-stage renal disease (ESRD) patients. This study aimed to evaluate NLR levels predicting all-cause mortality in ESRD patients with diabetic nephropathy (DN), which have not been evaluated. We recruited 151 isolated DN patients who started hemodialysis between January 2009 and December 2014 at the Japanese Red Cross Ishinomaki Hospital. The primary outcomes were 1- and 3-year survival rates. The association between NLR and survival rate was evaluated using the Kaplan-Meier method and Cox proportional hazard regression analysis. Patients with an NLR >= 3.5 had a significantly higher mortality rate than did those with an NLR < 3.5 (log rank P = 0.02). The area under the curve (AUC) of 1-year survival for NLR was significantly larger than that for other commonly used nutritional and inflammatory variables. NLR was a more accurate predictor than other well-known markers. PMID- 28665536 TI - MIXED-METHODS EVALUATION OF PARTICIPANT RECRUITMENT AND RETENTION IN THE MOM POWER PARENTING INTERVENTION PROGRAM. AB - Parenting group success begins with attendance. Using archival pilot data from 99 mothers who enrolled in the Mom Power (MP) parenting intervention, this study sought to understand the factors that influenced participant engagement and retention. MP is a group-based, early intervention program grounded in attachment theory that utilizes motivational interviewing as a core component to enhance program engagement. Study aims were to qualitatively describe the reasons why mothers were interested in participating in the program, including what they hoped to gain from the experience, and to quantitatively examine the extent to which attendance was associated with demographic, experiential, and psychosocial factors. The qualitative analysis of intake interviews revealed that mothers expected the MP intervention to provide a warm environment for themselves and their children as well as to support and enhance their parenting, and 95% revealed their hopes that the intervention would help them grow and develop as women. Attendance rates were relatively high, with 62% of mothers missing less than one group session. Quantitative analyses using multiple regression to test associations of demographic, experiential, and psychosocial factors with attendance rates were not significant. Results suggest that motivational interviewing may be an important component in promoting participant engagement efforts in parenting interventions. PMID- 28665537 TI - MiR-195 promotes abdominal aortic aneurysm media remodeling by targeting Smad3. AB - INTRODUCTION: MiR-195 has been implicated in the development of abdominal aortic aneurysms (AAA). However, the underlying mechanisms have not been fully addressed. AIM: To explore the roles of miR-195 in regulating the proliferation and apoptosis of vascular smooth muscle cells (VSMCs), as well as its molecular basis in vitro. METHODS: qRT-PCR was used to determine the expression levels of miR-195 and Smad3 in aortic media specimens or VSMCs. Western blot was performed to detect the protein levels of Smad3, osteopontin (OPN), and collagen III in aortic media specimens and VSMCs. Luciferase reporter assay was applied to confirm the target of miR-195 in VSMCs. Proliferation and apoptosis of VSMCs were measured by MTT and flow cytometry, respectively. RESULTS: In comparison with the normal controls, the levels of miR-195, OPN, and collagen III were significantly increased in AAA tissue. Smad3 was validated to be a direct target of miR-195. miR-195 inhibited proliferation and induced apoptosis of VSMCs, which was abated by Smad3 overexpression. Expression of OPN and collagen III was improved in VSMCs after transfection with miR-195 mimics, while up-regulation of Smad3 reversed this effect. CONCLUSION: MiR-195 promotes media remodeling by targeting Smad3 in AAA progression. This study suggests that miR-195 contributes to the pathogenesis of AAA and reveals a new targeted therapy strategy for AAA patients. PMID- 28665538 TI - alpha-Glucosidase Inhibitory Xanthones from the Roots of Garcinia fusca. AB - Two new compounds, fuscaxanthones J (1) and K (2), together with eight known xanthones (3 - 10) were isolated from an ethyl acetate extract of the roots of Garcinia fusca. Their structures were determined using spectroscopic methods, mainly 1D- and 2D-NMR. alpha-Glucosidase inhibitory activity of the isolated compounds was evaluated and fuscaxanthone J (1) showed the most significant effect with an IC50 value of 8.3 +/- 1.8 MUm (compared with acarbose, IC50 = 214.5 +/- 2.3 MUm). PMID- 28665539 TI - Minimalistic Liquid-Assisted Route to Highly Crystalline alpha-Zirconium Phosphate. AB - Zirconium phosphates have potential applications in areas of ion exchange, catalysis, photochemistry, and biotechnology. However, synthesis methodologies to form crystalline alpha-zirconium phosphate (Zr(HPO4 )2 ?H2 O) typically involve the use of excess phosphoric acid, addition of HF or oxalic acid and long reflux times or hydrothermal conditions. A minimalistic sustainable route to its synthesis has been developed by using only zirconium oxychloride and concentrated phosphoric acid to form highly crystalline alpha-zirconium phosphate within hours. The morphology can be changed from platelets to rod-shaped particles by fluoride addition. By varying the temperature and time, alpha-zirconium phosphate with particle sizes from nanometers to microns can be obtained. Key features of this minimal solvent synthesis are the excellent yields obtained with high atom economy under mild conditions and ease of scalability. PMID- 28665540 TI - IMPLEMENTING AN ATTACHMENT-BASED PARENTING INTERVENTION WITHIN HOME-BASED EARLY HEAD START: HOME-VISITORS' PERCEPTIONS AND EXPERIENCES. AB - Implementation of evidence-based interventions in "real-world" settings is enhanced when front-line staff view the intervention as acceptable, appropriate, and feasible. This qualitative study addresses Early Head Start (EHS) home visitors' perceptions and experiences of an evidence-based parenting intervention, the Attachment and Biobehavioral Catch-up program (M. Dozier, O. Lindhiem, & J. Ackerman, 2005), when added to EHS services as usual within the context of a research-practice partnership. Thematic analysis of in-depth, qualitative interviews indicates that home visitors experienced the intervention as positive and helpful for EHS families. Some challenges included scheduling and uncertainty regarding the goals of the intervention. Concerns over participation in the research centered on information exchange, confidentiality, and time limitations. PMID- 28665541 TI - Feasibility of the mobile mindfulness-based stress reduction for breast cancer (mMBSR(BC)) program for symptom improvement among breast cancer survivors. AB - OBJECTIVE: The purpose of this pilot study was to test the feasibility of delivering the mobile mindfulness-based stress reduction for breast cancer (mMBSR(BC)) program using an iPad and to evaluate its impact on symptom improvement. METHODS: A single group, pre-posttest design was implemented among female stages 0-III breast cancer survivors (BCS) who completed treatment. Data were collected at baseline and week 6 on measures of psychological and physical symptoms and quality of life. The mMBSR(BC) program is a standardized, stress reducing intervention that combines sitting and walking meditation, body scan, and yoga and is designed to deliver weekly 2-hour sessions for 6 weeks using an iPad. RESULTS: The mean age of the 15 enrolled BCS was 57 years; one participant was non-Hispanic black, and 14 were non-Hispanic white. Of the 13 who completed the study, there were significant improvements from baseline to 6 weeks post mMBSR(BC) in psychological and physical symptoms of depression, state anxiety, stress, fear of recurrence, sleep quality, fatigue, and quality of life (P's < .05). Effect sizes for improvements of multiple symptoms ranged from medium to large. CONCLUSIONS: These results provide preliminary support that the mMBSR(BC) program may be feasible and acceptable, showing a clinical impact on decreasing psychological and physical symptoms. This mobile-based program offers a delivery of a standardized MBSR(BC) intervention to BCS that is convenient for their own schedule while decreasing symptom burden in the survivorship phase after treatment for breast cancer. PMID- 28665542 TI - Effects of stepped psychooncological care on referral to psychosocial services and emotional well-being in cancer patients: A cluster-randomized phase III trial. AB - OBJECTIVE: Emotional distress in cancer patients often goes unnoticed in daily routine; therefore, distress screening is now recommended in many national guidelines. However, screening alone does not necessarily translate into better well-being. We examined whether stepped psychooncological care improves referral to consultation-liaison (CL) services and improves well-being. METHODS: In a cluster-randomized trial, wards were randomly allocated to stepped versus standard care. Stepped care comprised screening for distress, consultation between doctor and patient about the patient's need for CL services, and provision of CL service. Primary outcomes were referral to psychosocial services and emotional well-being half a year after baseline, measured with the Hospital Anxiety and Depression Scale. A secondary endpoint was uptake of outpatient health care. Analysis employed mixed-effects multivariate regression modeling. RESULTS: Thirteen wards were randomized; 1012 patients participated. With stepped care (N = 570; 7 wards), 22% of the patients were referred to CL services and 3% with standard care (N = 442; 6 wards; odds ratio [OR] 10.0; P < .001). Well-being 6 months after baseline was 9.5 after stepped care (N = 341) and 9.4 after standard care (N = 234, beta -0.3; P = .71). After stepped care, patients with psychiatric comorbidity went more often to psychotherapists (OR 4.0, P = .05) and to psychiatrists (OR 2.3, P = .12), whereas patients without comorbidity used psychiatrists less often (OR 0.4, P = .04) than in standard care. CONCLUSIONS: Stepped care resulted in better referral to CL services. The patients' emotional well-being was not improved, but uptake of outpatient psychiatric help was increased in patients with psychiatric comorbidity and decreased in patients without. PMID- 28665543 TI - Recent Publications of Interest. PMID- 28665544 TI - Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits. AB - BACKGROUND/AIMS: Recent evidence indicates that peroxisome proliferator-activated receptor (PPAR)-gamma activators exert anti-inflammatory and antioxidant actions. However, the underlying mechanisms by which these agents prevent atrial remodeling in diabetes are not completely elucidated. We sought to investigate the potential effects of pioglitazone, a PPAR-gamma activator, on atrial remodeling and atrial fibrillation (AF) inducibility in diabetic rabbits. METHODS: Alloxan-induced diabetic rabbits were randomly divided into three groups: diabetes only, diabetes treated with low-dose pioglitazone (4 mg/day/kg), or diabetes treated with high-dose pioglitazone (8 mg/day/kg) (n=24 for each group). A total of 24 healthy rabbits served as controls. Eight weeks later, hemodynamic, echocardiographic, and electrophysiological parameters were recorded. Left atrial whole-cell patch-clamp studies, histological examination, and Western blot analysis were also performed. RESULTS: In the DM group (6/8 vs 1/8, P<.05), higher AF inducibility, increased amount of fibrosis, lower INa , and higher ICaL were observed in the DM group compared to controls. Western blot analysis showed that DM increased the expression of extracellular signal regulated kinase 2 (ERK2), phosphorylation ERK, transforming growth factor beta 1, Toll-like receptor 4, nuclear factor-kappaB p50, and heat-shock protein 70. All of these electrophysiological, histological, ion current density, and protein expression changes were all reduced by pioglitazone. CONCLUSION: Pioglitazone attenuates diabetes-induced structural and electrophysiological remodeling in the atria, thereby reducing the vulnerability to AF. PMID- 28665545 TI - Inhibition of mevalonate pathway prevents ischemia-induced cardiac dysfunction in rats via RhoA-independent signaling pathway. AB - AIM: We previously demonstrated that anoxia-mediated Ca2+ handling dysfunction could be ameliorated through inhibition of mevalonate pathway via RhoA- and Ras related mechanisms in H9c2 cells. In this study, we further explored whether inhibition of mevalonate pathway is associated with cardiac remodeling and dysfunction in ischemic cardiomyopathy, and discussed the possible role of Ras, Rac and RhoA in cardiac dysfunction. METHODS: We investigated the role of mevalonate pathway in cardiac remodeling and cardiomyocyte Ca2+ handling proteins expression in a rat model of cardiac dysfunction due to myocardial infarction (MI). After MI, adult male Sprague-Dawley rats were treated with drugs that antagonize key components in mevalonate pathway, including 3-hydroxy-3 methylglutaryl-CoA reductase, farnesyl pyrophosphate synthase, and Rho-kinase for 10 weeks. The protein expression of ryanodine receptor 2 (RyR2), sarcoplasmic reticulum Ca2+ ATPase (SERCA) 2a, phospholamban (PLB), phospho-PLB at serine-16 (PSer16-PLB), FKBP12.6, and RhoA as well as RyR2 and FKBP12.6 mRNA levels was evaluated. RESULTS: Rosuvastatin and alendronate treatment prevented myocardial remodeling, improved cardiac function and reduced infarct size. Furthermore, rosuvastatin and alendronate promoted an increase in the protein expression of SERCA2a and PSer16-PLB/PLB ratio as well as partially restored the RyR2 and FKBP12.6 gene and protein expression. Fasudil failed to exert these beneficial effects. CONCLUSIONS: These findings indicate that mevalonate pathway inhibition by rosuvastatin and alendronate prevents cardiac remodeling and dysfunction possibly through RhoA-independent mechanisms. PMID- 28665547 TI - Effects of different-intensity laser acupuncture at two adjacent same-meridian acupoints on nitric oxide and soluble guanylate cyclase releases in human. AB - OBJECTIVES: The aim of this study was to detect the influences of LA at nonacupoint and two adjacent acupoints of pericardium meridian on the releases of NO and sGC in 20 healthy subjects. METHODS: Different intensities (12, 24, 48 mW) of infrared laser were used for irradiating Jianshi (PC5), Ximen (PC4) acupoints and nonacupoint for 20, 40 minutes, respectively. Semi-circular tubes were taped to the skin surface and filled with NO-scavenging compound for 20 minutes to capture NO and sGC, which were measured using spectrophotometry in a blinded fashion. RESULTS: As the increase in the intensity of LA stimulation, the levels of NO releases over acupoints all were significantly increased, NO releases in nonacupoints following the same treatment only changed slightly, sGC amounts were observably enhanced over acupoints, but did not any change in nonacupoint area. Different intensities of LA treatments can sensitively affect the NO and sGC releases over acupoints. This indicated that LA-induced releases of the NO and sGC were specific to acupoints. CONCLUSIONS: This is the first evidence reporting that LA induced significant elevations of NO-sGC releases over acupoints, and the enhanced signal molecules contribute to local circulation, which improves the beneficial effects of the therapy. PMID- 28665548 TI - Effect of astaxanthin and aluminum chloride on erythrocyte G6PD and 6PGD enzyme activities in vivo and on erythrocyte G6PD in vitro in rats. AB - In this study, we investigated the effect of astaxanthin (Ast) and aluminum (Al) on the erythrocyte glucose-6-phosphate dehydrogenase (G6PD) and 6 phosphogluconate dehydrogenase (6PGD) enzymes activities in vivo and on G6PD enzyme in vitro in rats. For in vitro studies, G6PD enzyme was purified from rat erythrocyte by using 2',5'-ADP-Sepharose 4B affinity gel. The effects of Ast and Al3+ ion were investigated on the purified enzyme. It was determined that Ast increased the enzyme activity, whereas Al3+ inhibited the enzyme activity noncompetitively (IC50 values; 0.679 mM, Ki values 1.32 mM). For in vivo studies, the rats were divided into the groups: control (Cont.), Al, Ast, and Al + Ast. The last three groups were compared with the control group. In Al group, a significant degree of inhibition was observed in the activity of G6PD and 6PGD enzymes when compared with the control group (P < 0.05), whereas there was an increase in the activities of G6PD and 6PGD enzymes in Ast and Al + Ast groups (P < 0.05). PMID- 28665549 TI - Quality measurement for rhinosinusitis: a review from the Quality Improvement Committee of the American Rhinologic Society. AB - BACKGROUND: Measuring quality outcomes is an important prerequisite to improve quality of care. Rhinosinusitis represents a high value target to improve quality of care because it has a high prevalence of disease, large economic burden, and large practice variation. In this study we review the current state of quality measurement for management of both acute (ARS) and chronic rhinosinusitis (CRS). METHODS: The major national quality metric repositories and clearinghouses were queried. Additional searches included the American Academy of Otolaryngology-Head and Neck Surgery database, PubMed, and Google to attempt to capture any additional quality metrics. RESULTS: Seven quality metrics for ARS and 4 quality metrics for CRS were identified. ARS metrics focused on appropriateness of diagnosis (n = 1), antibiotic prescribing (n = 4), and radiologic imaging (n = 2). CRS quality metrics focused on appropriateness of diagnosis (n = 1), radiologic imaging (n = 1), and measurement of patient quality of life (n = 2). The Physician Quality Reporting System (PQRS) currently tracks 3 ARS quality metrics and 1 CRS quality metric. There are no outcome-based rhinosinusitis quality metrics and no metrics that assess domains of safety, patient centeredness, and timeliness of care. CONCLUSIONS: The current status of quality measurement for rhinosinusitis has focused primarily on the quality domain of efficiency and process measures for ARS. More work is needed to develop, validate, and track outcome-based quality metrics along with CRS-specific metrics. Although there has been excellent work done to improve quality measurement for rhinosinusitis, there remain major gaps and challenges that need to be considered during the development of future metrics. PMID- 28665546 TI - Astroglial vesicular network: evolutionary trends, physiology and pathophysiology. AB - Intracellular organelles, including secretory vesicles, emerged when eukaryotic cells evolved some 3 billion years ago. The primordial organelles that evolved in Archaea were similar to endolysosomes, which developed, arguably, for specific metabolic tasks, including uptake, metabolic processing, storage and disposal of molecules. In comparison with prokaryotes, cell volume of eukaryotes increased by several orders of magnitude and vesicle traffic emerged to allow for communication between distant intracellular locations. Lysosomes, first described in 1955, a prominent intermediate of endo- and exocytotic pathways, operate virtually in all eukaryotic cells including astroglia, the most heterogeneous type of homeostatic glia in the central nervous system. Astrocytes support neuronal network activity in particular through elaborated secretion, based on a complex intracellular vesicle network dynamics. Deranged homeostasis underlies disease and astroglial vesicle traffic contributes to the pathophysiology of neurodegenerative (Alzheimer's disease, Huntington's disease), neurodevelopmental diseases (intellectual deficiency, Rett's disease) and neuroinfectious (Zika virus) disorders. This review addresses astroglial cell-autonomous vesicular traffic network, as well as its into primary and secondary vesicular network defects in diseases, and considers this network as a target for developing new therapies for neurological conditions. PMID- 28665550 TI - Industry relationships are associated with performing a greater number of sinus balloon dilation procedures. AB - BACKGROUND: Industry outreach promotes awareness of novel technologies. However, concerns have been raised that such relationships may also unduly impact medical decision-making. Our objective in this study was to evaluate industry relationships among practitioners who frequently employ balloon dilation (BD), characterizing whether there is any association between financial relationships and BD utilization. METHODS: Provider utilization data (FY-2014) was accessed for individuals billing BD procedures to Medicare, the largest healthcare payor in the United States. The names of individuals included in these data sets were cross-referenced with the Centers for Medicare and Medicaid Services Open Payment site to determine the extent of industry relationships during this same year. Individuals included in this analysis were organized by those with "significant" ($1,000 to $10,000) and "major" (> $10,000) industry relationships. Practice setting, training, and experience were also evaluated. RESULTS: Of the 302 otolaryngologists who billed enough BDs for inclusion in this data set, 99.3% were in private practice, 89.7% were board-certified, 8.3% had facial plastic and reconstructive fellowship training, and 1.3% had rhinology fellowship training. There was a significant increase in BDs performed with increasing BD company financial contributions (analysis of variance, p = 0.0003). Individuals without "significant" relationships with BD companies billed fewer BDs than those with at least "significant" (>$1,000) relationships (57.0 +/- 4.3 vs 87.7 +/- 10.0, p = 0.001). CONCLUSION: There is an association between receiving money from industry and the frequency with which otolaryngologists employ BD. Although our analysis demonstrates an association, these results in no way imply causation. Further analysis exploring the reasons for this association may be necessary. PMID- 28665551 TI - Mechanistic differences in the uptake of salicylic acid glucose conjugates by vacuolar membrane-enriched vesicles isolated from Arabidopsis thaliana. AB - Salicylic acid (SA) is a plant hormone involved in a number of physiological responses including both local and systemic resistance of plants to pathogens. In Arabidopsis, SA is glucosylated to form either SA 2-O-beta-d-glucose (SAG) or SA glucose ester (SGE). In this study, we show that SAG accumulates in the vacuole of Arabidopsis, while the majority of SGE was located outside the vacuole. The uptake of SAG by vacuolar membrane-enriched vesicles isolated from Arabidopsis was stimulated by the addition of MgATP and was inhibited by both vanadate (ABC transporter inhibitor) and bafilomycin A1 (vacuolar H+ -ATPase inhibitor), suggesting that SAG uptake involves both an ABC transporter and H+ -antiporter. Despite its absence in the vacuole, we observed the MgATP-dependent uptake of SGE by Arabidopsis vacuolar membrane-enriched vesicles. SGE uptake was not inhibited by vanadate but was inhibited by bafilomycin A1 and gramicidin D providing evidence that uptake was dependent on an H+ -antiporter. The uptake of both SAG and SGE was also inhibited by quercetin and verapamil (two known inhibitors of multidrug efflux pumps) and salicin and arbutin. MgATP-dependent SAG and SGE uptake exhibited Michaelis-Menten-type saturation kinetics. The vacuolar enriched membrane vesicles had a 46-fold greater affinity and a 10-fold greater transport activity with SGE than with SAG. We propose that in Arabidopsis, SAG is transported into the vacuole to serve as a long-term storage form of SA while SGE, although also transported into the vacuole, is easily hydrolyzed to release the active hormone which can then be remobilized to other cellular locations. PMID- 28665552 TI - Comorbidities in adults with asthma: Population-based cross-sectional analysis of 1.4 million adults in Scotland. AB - BACKGROUND: Comorbidity in people with asthma can significantly increase asthma morbidity and lower adherence to asthma guidelines. OBJECTIVE: The objective of this study was to comprehensively measure the prevalence of physical and mental health comorbidities in adults with asthma using a large nationally representative population. METHODS: Cross-sectional analysis of routine primary care electronic medical records for 1 424 378 adults in the UK, examining the prevalence of 39 comorbidities in people with and without asthma, before and after adjustment for age, sex, social deprivation and smoking status using logistic regression. RESULTS: Of 39 comorbidities measured, 36 (92%) were significantly more common in adults with asthma; 62.6% of adults with asthma had >=1 comorbidity vs 46.2% of those without, and 16.3% had >=4 comorbidities vs 8.7% of those without. Comorbidities with the largest absolute increase in prevalence in adults with asthma were as follows: chronic obstructive pulmonary disease (COPD) (13.4% vs 3.1%), depression (17.3% vs 9.1%), painful conditions (15.4% vs 8.4%) and dyspepsia (10.9% vs 5.2%). Comorbidities with the largest relative difference in adults with asthma compared to those without were as follows: COPD (adjusted odds ratio [aOR] 5.65, 95% CI 5.52-5.79), bronchiectasis (aOR 4.65, 95% CI 4.26-5.08), eczema/psoriasis (aOR 3.30, 95% CI 3.14-3.48), dyspepsia (aOR 2.20, 95% CI 2.15-2.25) and chronic sinusitis (aOR 2.12, 95% CI 1.99-2.26). Depression and anxiety were more common in adults with asthma (aOR 1.60, 95% CI 1.57-1.63, and aOR 1.53, 95% CI 1.48-1.57, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Physical and mental health comorbidities are the norm in adults with asthma. Appropriate recognition and management should form part of routine asthma care. PMID- 28665553 TI - RECOGNIZING INFANTS' EMOTIONAL EXPRESSIONS: ARE ADOLESCENTS LESS SENSITIVE TO INFANTS' CUES? AB - Previous studies have shown that adolescent mothers interact less sensitively with their infants than do adult mothers. This difference might be due to developmental difficulties in the recognition of infants' emotional states in adolescents. Therefore, the aim of the current study was to explore differences in the recognition of infant signals between nonparous adolescent girls and boys as compared to female and male adults. To this end, we examined 54 childless adolescents and 54 childless adults (50% female). Participants were shown a series of 20 short videos of infants aged 3 to 6 months presenting different emotional states ranging from very distressed to very happy. In addition, participants were asked to report their own parental experiences using the German version, Fragebogen zum erinnerten elterlichen Erziehungsverhalten (J. Schumacher, M. Eisemann, & E. Brahler, ), of the Egna Minnen Befraffande Uppfostran (Own Memories of Parental Rearing Experiences in Childhood; C. Perris, L. Jacobsson, H. Lindstrom, L. von Knorring, & H. Perris, ). Adolescents rated distressed infants as more distressed than did the adults. Furthermore, female participants rated the very distressed infants as more distressed than did male participants. These data suggest that adolescents, in general, are not impaired in recognizing infant emotional states, as compared to adults. Thus, we suggest that more extreme ratings of infant signals of discomfort together with immature sociocognitive regulation processes during adolescence might contribute to reduced sensitivity observed in adolescent mothers. PMID- 28665554 TI - eHealth and mHealth interventions in the treatment of fatigued cancer survivors: A systematic review and meta-analysis. AB - OBJECTIVES: To (1) evaluate existing eHealth/mHealth interventions developed to help manage cancer-related fatigue (CRF); and (2) summarize the best available evidence on their effectiveness. METHODS: A comprehensive literature search of PubMed, MEDLINE, EMBASE, and the Cochrane Library up to November 2016 was conducted. Study outcomes were extracted, tabulated, and summarized. Random effects meta-analyses were conducted for the primary outcome (fatigue), and the secondary outcomes quality of life and depression, yielding pooled effect sizes (r), and 95% confidence intervals (CI). RESULTS: For eHealth interventions, our search of published papers identified 9 completed studies and 6 protocols for funded projects underway. No studies were identified for mHealth interventions that met our inclusion criteria. A meta-analysis of the 9 completed eHealth studies revealed a statistically significant beneficial effect of eHealth interventions on CRF (r = .27, 95% CI [.1109 - .4218], P < 0.01). Therapist guided eHealth interventions were more efficacious then self-guided interventions (r = .58, 95% CI: [.3136 - .5985, P < 0.001). Small to moderate therapeutic effects were also observed for HRQoL (r = .17, 95% CI [.0384 - .3085], P < 0.05) and depression (r = .24, 95% CI [.1431 - .3334], P < 0.001). CONCLUSIONS: eHealth interventions appear to be effective for managing fatigue in cancer survivors with CRF. Continuous development of eHealth interventions for the treatment of CRF in cancer survivors and their testing in long-term, large-scale efficacy outcome studies is encouraged. The degree to which mHealth interventions can change CRF in cancer survivors need to be assessed systematically and empirically. PMID- 28665556 TI - Comparison of effectiveness of temporary positive expiratory pressure versus oscillatory positive expiratory pressure in severe COPD patients. AB - INTRODUCTION: In chronic obstructive pulmonary disease (COPD) patients few modalities of airway clearance have demonstrated effectiveness in reducing hypersecretion and bronchial obstruction. Positive expiratory pressure (PEP) is one of these. OBJECTIVE: Our goal was to compare the effectiveness of 2 devices Temporary PEP (T-PEP) and Oscillatory PEP (O-PEP) which use PEP applied at a low expiratory pressure of 1 cm H2 O which creates oscillations that decrease bronchial obstruction in reducing COPD exacerbations and improving respiratory and health status assessment parameters. Each has different mechanism of action. METHODS: A 26 week randomized controlled study evaluated their efficacy in reducing exacerbations and improving health status assessment tests as well as respiratory function parameters in severe to very severe COPD patients. One hundred-twenty patients were enrolled: 40 patients received T-PEP therapy; 40 underwent treatment with O-PEP; 40 constituted the control group. The primary outcome was the reduction of exacerbations after 1, 3 and 6 months; secondary outcomes were improvement of lung function and health status assessment tests [Modified Medical Research Council (MMRC) scale, Breathlessness, Cough, and Sputum Scale (BCSS) scale, and COPD Assessment Test (CAT) score]. RESULTS: Only T PEP statistically reduced the exacerbations after 1 and 3 months compared to the control group. Both the 2 devices improved dyspnea scale (MMRC), lung function parameters, and health status assessment (CAT) tests compared to the control group. Both interventions were well-tolerated by our patients. CONCLUSIONS: O-PEP and T-PEP are useful for COPD treatment but only T-PEP reduces exacerbations. Adding tools for airway clearance to medical therapy can help the management of COPD. PMID- 28665555 TI - CD1b-mycolic acid tetramers demonstrate T-cell fine specificity for mycobacterial lipid tails. AB - Mycobacterium tuberculosis synthesizes a thick cell wall comprised of mycolic acids (MA), which are foreign antigens for human T cells. T-cell clones from multiple donors were used to determine the fine specificity of MA recognition by human alphabeta T cells. Most CD1-presented lipid antigens contain large hydrophilic head groups comprised of carbohydrates or peptides that dominate patterns of T-cell specificity. MA diverges from the consensus antigen motif in that it lacks a head group. Using multiple forms of natural and synthetic MA and MA-specific T-cells with different T-cell receptors, we found that, unlike antigens with larger head groups, lipid length strongly controlled T-cell responses to MA. In addition, the three forms of MA that naturally occur in M. tuberculosis that differ in modifications on the lipid tail, differ in their potency for activating MA-specific T-cell clones. Thus, naturally occurring MA forms should be considered as separate, partly cross-reactive antigens. Two of the three forms of MA could be loaded onto human CD1b proteins, creating working CD1b-MA tetramers. The creation of CD1b-MA tetramers represents a new tool for future studies that track the effector functions and kinetics of MA-specific T cells ex vivo. PMID- 28665557 TI - Treatment strategies for chronic osteomyelitis in low- and middle-income countries: systematic review. AB - OBJECTIVES: To identify a standard treatment regime or highly successful procedure for chronic osteomyelitis in low- and middle-income countries. METHODS: Systematic review following PRISMA guidelines. RESULTS: The initial search resulted in 102 studies of which nine met the inclusion criteria and were analysed qualitatively. The included studies involved 1173 patients from Africa and Asia. All patients were diagnosed with chronic osteomyelitis. Surgical and antibiotic treatment regimens differed substantially. No better judgement than moderate risk of selection bias could be made due to the study designs. CONCLUSIONS: The evidence is not sufficiently robust to identify the most effective treatment, or to even allow a recommendation of the best suitable treatment of chronic osteomyelitis in low-income countries. PMID- 28665558 TI - The Spontaneous Adhesion of BMMC onto Self-Assembled Peptide Nanoscaffold without Activation Inhibits Its IgE-Mediated Degranulation. AB - Mast cells play a distinct role in the innate immune response. Engineered microenvironments for the express purpose of influencing mast cell activity will provide a novel means of designing biomaterials, as well as a means to systematically investigate mast cell biology in a 3D setting. Here, the effect of nanoscaffolds composed of self-assembling peptides, namely (RADA)4 , on bone marrow-derived murine mast cell (BMMC) activity is reported. Unlike most studies that stimulate mast cells to induce adhesion, this results show that BMMCs spontaneously adhere to the artificial nanoscaffold without initiating their activation. It is observed that the classical immunoglobulin (IgE) antigen mediated degranulation of adhered BMMC is inhibited by the nanoscaffold, while non-IgE (A23187)-induced degranulation is unaffected. The inhibition of IgE antigen-mediated degranulation is likely a result of inhibited molecular diffusion within the matrix; antigen diffusion, IgE-FcepsilonRI complex shuttling, and/or formation of multiple IgE-FcepsilonRI clusters may be physically hindered in the presence of the polyvalent nanofiber network. Moreover, the IgE/antigen-induced inflammatory cytokine tumor necrosis factor alpha release from adherent BMMCs is significantly reduced likely due to interaction with the nanofiber matrix. This work is considered the first step in quantifying mast cell activity in artificial matrices composed of self-assembling peptides. PMID- 28665559 TI - ? PMID- 28665560 TI - [Female athlete triad : what's new ?] AB - The Relative Energy Deficiency in Sport has been suggested as the new and wider denomination of the Female athlete triad. This new terminology enables a wider approach to the different consequences of an insufficient energy intake amongst regular athletes. In fact, this energy dysbalance leads to a wider pathological phenomenon touching many systems (e.g. cardiovascular, psychological, hematological...). This designation is no longer restricted to the female gender, and now also includes men, whom are nowadays less affected or maybe only less assessed. This syndrome is still unknown to most primary care physicians and specialists, thereby its incidence and prevalence is probably greatly underestimated. PMID- 28665561 TI - [The travelling sports physician]. AB - Travelling around your own country or even further abroad with a sports team or individual athletes as a sports physician is to be considered as a fundamental part of the various activities of a sports medicine practitioner.However, in our modern and quickly changing world, it is imperative to understand the different aspects of caring for athletes, also the legal ones. These may include licensing issues, malpractice coverage, access to care at outside institutions and prescribing and transporting medication of all sorts, including narcotics and substances of the list of prohibited ones (doping).With significant changes in healthcare at state and national levels, physicians must be aware of how these policy differences can affect their way of working, their ability to provide the expected care. PMID- 28665562 TI - [What do we know about the exercise-related transient abdominal pain ?] AB - Exercise-related transient abdominal pain or " side stitch " is a very common problem among athletes, whatever their level of participation. This pain may be present in different areas of the abdomen, even in the shoulder, usually well localized, and described as cramping or stabbing depending on the severity. The etiology is still debated, with many possible theories. It is a benign problem but other pathologies, often more severe, must be excluded in case of any atypical presentation. There are simple preventive measures recommended. This pain usually disappears within minutes by slowing or stopping the effort and / or using different methods without scientific validation until now. PMID- 28665563 TI - [Update on the postsurgical shoulder rotator cuff rehabilitation]. AB - Primary care physicians play a crucial role in rehabilitation following rotator cuff surgery. This synthesis paper aims to address essential issues of postsurgical rehabilitation, based on recent recommendations. The rehabilitation comprises 4 phases, which are determined by the tendon healing process.For each phase, this article presents the stage of tendon healing, the allowed mechanical constraints, the exercise and physiotherapy modalities, the possible activities and the potential complications. Information and counseling to support the patient implication in the rehabilitation are also detailed. This article contributes to an enhanced comprehension of the healing process, which is a prerequisite for appropriate follow-up and efficient complication detection. PMID- 28665564 TI - [Current treatment strategy of meniscal lesions in athletes]. AB - The primary goal of meniscal treatment in elite athletes is to guarantee knee function for sports performance and to prevent osteoarthritic changes. The meniscus acts not only as cushion in the femorotibial joint but also as a major secondary stabilizer with its posterior medial and lateral horns. Therefore, the integrity of the meniscal tissue is crucial for knee function and needs to be preserved, especially when the meniscal lesion is found in the periphery (vascularized zone). For ideal tissue healing, a stable knee is prerequisite.Partial meniscectomy as little as possible is only performed, if the lesion cannot be sutured, is highly degenerative or localized in the non vascularized (white-white) area which has low to none healing potential. PMID- 28665565 TI - [Isolated lesions of the distal tibiofibular syndesmosis]. AB - A tibiofibular syndesmotic injury is rare, accounting 6 % of ankle sprain. The diagnosis can be difficult and is often likened to a lateral ankle sprain. Clinical signs are more subtle and pains are located above the joint line tibiotalar. These lesions should be considered in athletes with pain or trauma to the ankle. Late diagnosis is associated with significant morbidity up to osteoarthritis of the ankle. The management of these lesions is paramount and surgery may be necessary. The purpose of our article is to highlight this condition to increase the diagnosis rate and get our patients optimum recovery. PMID- 28665566 TI - [Pediatric diabetes health Service from East canton of Vaud : towards a model of proximity care delivery ?] AB - Learning to live with a chronic condition is one of the greatest challenges regarding health today, either at individual or societal level. Type 1 diabetes affecting young people and their family raises new care delivery. Proximity structures, inserted into the regional network, accessible and responsive to the needs of patients and their families, are thus promising to encourage empowerment in persons affected by a chronic disease as well as in their entourage. PMID- 28665567 TI - ? PMID- 28665568 TI - ? PMID- 28665569 TI - ? PMID- 28665570 TI - ? PMID- 28665571 TI - ? PMID- 28665572 TI - ? PMID- 28665573 TI - ? PMID- 28665574 TI - Nonaccidental Injury in Pediatric Patients: Detection, Evaluation, and Treatment AB - Emergency clinicians are likely to encounter physical abuse in children, and they must be prepared to recognize its many manifestations and take swift action. Pediatric nonaccidental injury causes considerable morbidity and mortality that can often be prevented by early recognition. Nonaccidental injuries present with a wide array of symptoms that may appear to be medically inconsequential (such as bruising in a premobile infant), but are actually sentinel injuries indicative of child abuse. This issue provides guidance regarding factors that contribute to abuse in children, key findings on history and physical examination that should trigger an evaluation for physical abuse, and laboratory and radiologic tests to perform when child abuse is suspected. PMID- 28665575 TI - A pH-Responsive Yolk-Like Nanoplatform for Tumor Targeted Dual-Mode Magnetic Resonance Imaging and Chemotherapy. AB - Incorporation of T1 and T2 contrast material in one nanosystem performing their respective MR contrast role and simultaneously serving as an efficient drug delivery system (DDS) has a significant potential application for clinical diagnosis and chemotherapy of cancer. However, inappropriate incorporation always encountered many issues, such as low contact area of T1 contrast material with water-proton, inappropriate distance between T2 contrast material and water molecule, and undesirable disturbance of T2 contrast material for T1 imaging. Those issues seriously limited the T1 or T2 contrast effect. In this work, we developed a yolk-like Fe3O4@Gd2O3 nanoplatform functionalized by polyethylene glycol and folic acid (FA), which could efficiently exert their tumor targeted T1 T2 dual-mode MR imaging and drug delivery role. First, this nanoplatform possessed a high longitudinal relaxation rate (r1) (7.91 mM-1 s-1) and a stronger transverse relaxation rate (r2) (386.5 mM-1 s-1) than that of original Fe3O4 (268.1 mM-1 s-1). Second, cisplatin could be efficiently loaded into this nanoplatform (112 mg/g) and showed pH-responsive release behavior. Third, this nanoplatform could be effectively internalized by HeLa cells with time and dosage dependence. Fourth, the FA receptor-mediated nanoplatform displayed excellent T1 T2 dual mode MR contrast enhancement and anticancer activity both in vitro and in vivo. Fifth, no apparent toxicity for vital organs was observed with systemic delivery of the nanoplatform in vivo. Thus, this nanoplatform could be a potential nanotheranostic for tumor targeted T1-T2 dual-mode MR imaging and chemotherapy. PMID- 28665576 TI - Superoleophilic and Flexible Thermoplastic Polymer Nanofiber Aerogels for Removal of Oils and Organic Solvents. AB - Chemical cross-linked poly(vinyl alcohol-co-ethylene) (EVOH) nanofiber aerogels (NFAs) were fabricated employing an economical and facile freeze-drying process. The manufactured chemical cross-linking nanofiber aerogel was successfully confirmed by scanning electron microscopy, attenuated total reflection-Fourier transform infrared spectrometer, and X-ray diffraction. The resulting aerogels showed high porosity (>99%), superior elasticity, elastic durability, high hydrophobicity, and superoleophilicity without any other hydrophobic modification. The cross-linked EVOH NFAs exhibited excellent absorption capacity (ranging from 45 to 102 times their own weight) when exposed to various oils and organic solvents, which was observed to be higher than that for most sorbents reported in the literature. Consequently, it is envisaged that the cross-linked EVOH NFA would play an important role in many fields of pollution removal. PMID- 28665577 TI - Atomic Layer Deposition of Stable LiAlF4 Lithium Ion Conductive Interfacial Layer for Stable Cathode Cycling. AB - Modern lithium ion batteries are often desired to operate at a wide electrochemical window to maximize energy densities. While pushing the limit of cutoff potentials allows batteries to provide greater energy densities with enhanced specific capacities and higher voltage outputs, it raises key challenges with thermodynamic and kinetic stability in the battery. This is especially true for layered lithium transition-metal oxides, where capacities can improve but stabilities are compromised as wider electrochemical windows are applied. To overcome the above-mentioned challenges, we used atomic layer deposition to develop a LiAlF4 solid thin film with robust stability and satisfactory ion conductivity, which is superior to commonly used LiF and AlF3. With a predicted stable electrochemical window of approximately 2.0 +/- 0.9 to 5.7 +/- 0.7 V vs Li+/Li for LiAlF4, excellent stability was achieved for high Ni content LiNi0.8Mn0.1Co0.1O2 electrodes with LiAlF4 interfacial layer at a wide electrochemical window of 2.75-4.50 V vs Li+/Li. PMID- 28665578 TI - Built Structure of Ordered Vertically Aligned Codoped Carbon Nanowire Arrays for Supercapacitors. AB - We report an ingenious yet efficient method to fabricate ordered vertically aligned nitrogen- and sulfur-codoped carbon nanowire (NS-CNW) arrays by direct carbonization of the finely designed copolymer. The as-prepared vertically aligned NS-CNWs with unique electronic features and very narrow diameters facilitate ion diffusion to further exhibit ideal electrochemical properties (243.0 F g-1 at the current density of 0.1 A g-1) and excellent cycle stability (10 000 cycles) when applied to a supercapacitor electrode. The controllable design and copolymerization of conducting polymers, which can provide doped carbon nanowire array electrodes having high surface area with controllable components and uniform dimensions in a neat way, provide more flexibility to tailor the carbon-based electrodes toward specific applications. PMID- 28665579 TI - General Strategy toward Dual-Scale-Controlled Metallic Micro-Nano Hybrid Structures with Ultralow Reflectance. AB - Functional metal surfaces with minimum optical reflection over a broadband spectrum have essential importance for optical and optoelectronic devices. However, the intrinsically large optical impedance mismatch between metals and the free space causes a huge obstacle in achieving such a purpose. We propose and experimentally demonstrate a general pulse injection controlled ultrafast laser direct writing strategy for fabricating highly effective antireflection structures on metal surfaces. The presented strategy can implement separate and flexible modifications on both microscale frame structures and nanoscale particles, a benefit from which is that optimized geometrical light trapping and enhanced effective medium effect reducing the surface reflection can be simultaneously achieved within one hybrid structure. Thus, comprehensively improved antireflection performances can be realized. Hybrid structures with substantial nanoparticles hierarchically attached on regularly arrayed microcones are generally constructed on different metal surfaces, achieving highly efficient light absorption over ultraviolet to near-infrared broadband spectrum regions. Reflectance minimums of 1.4%, 0.29%, and 2.5% are reached on Cu, Ti, and W surfaces, respectively. The presented strategy is simple in process, adaptable for different kinds of metals, reproduceable in dual-scale structural features, and feasible for large-area production. All these advantages make the strategy as well as the prepared antireflection structures excellent candidates for practical applications. PMID- 28665580 TI - Rational Design of Hierarchical Carbon/Mesoporous Silicon Composite Sponges as High-Performance Flexible Energy Storage Electrodes. AB - Nanostructuring silicon (Si) and combining Si with carbon shells have been studied in recent Li-ion battery electrodes, yet it remains a grand challenge to overcome the low electrical conductivity and associated volume change of Si. Here, by first coating a mesoporous SiO2 (meso-SiO2) onto carbon nanotube (CNT) networks and then converting it into a meso-Si layer covered by carbon, we obtained a freestanding, highly porous composite sponge electrode consisting of three-dimensionally interconnected sandwiched carbon-Si-CNT skeletons. In this hierarchical structure, the macropores among the sponge connect to mesopores in the meso-Si layer so that Li+ diffusion is facilitated, whereas the underlying CNT networks serve as conductive paths for electrons transport. Meanwhile, the outer carbon coating on meso-Si could buffer the volume expansion and prevent material shedding. As a result, our sandwiched carbon-Si-CNT electrodes exhibit large specific capacity, high rate capability and long cycle life. The combination of carbon-wrapped meso-Si and CNT sponges might be a potential strategy for developing efficient electrodes in various energy storage systems. PMID- 28665581 TI - Pathways to Structure-Property Relationships of Peptide-Materials Interfaces: Challenges in Predicting Molecular Structures. AB - An in-depth appreciation of how to manipulate the molecular-level recognition between peptides and aqueous materials interfaces, including nanoparticles, will advance technologies based on self-organized metamaterials for photonics and plasmonics, biosensing, catalysis, energy generation and harvesting, and nanomedicine. Exploitation of the materials-selective binding of biomolecules is pivotal to success in these areas and may be particularly key to producing new hierarchically structured biobased materials. These applications could be accomplished by realizing preferential adsorption of a given biomolecule onto one materials composition over another, one surface facet over another, or one crystalline polymorph over another. Deeper knowledge of the aqueous abiotic biotic interface, to establish clear structure-property relationships in these systems, is needed to meet this goal. In particular, a thorough structural characterization of the surface-adsorbed peptides is essential for establishing these relationships but can often be challenging to accomplish via experimental approaches alone. In addition to myriad existing challenges associated with determining the detailed molecular structure of any molecule adsorbed at an aqueous interface, experimental characterization of materials-binding peptides brings new, complex challenges because many materials-binding peptides are thought to be intrinsically disordered. This means that these peptides are not amenable to experimental techniques that rely on the presence of well-defined secondary structure in the peptide when in the adsorbed state. To address this challenge, and in partnership with experiment, molecular simulations at the atomistic level can bring complementary and critical insights into the origins of this abiotic/biotic recognition and suggest routes for manipulating this phenomenon to realize new types of hybrid materials. For the reasons outlined above, molecular simulation approaches also face challenges in their successful application to model the biotic-abiotic interface, related to several factors. For instance, simulations require a plausible description of the chemistry and the physics of the interface, which comprises two very different states of matter, in the presence of liquid water. Also, it is essential that the conformational ensemble be comprehensively characterized under these conditions; this is especially challenging because intrinsically disordered peptides do not typically admit one single structure or set of structures. Moreover, a plausible structural model of the substrate is required, which may require a high level of detail, even for single-element materials such as Au surfaces or graphene. Developing and applying strategies to make credible predictions of the conformational ensemble of adsorbed peptides and using these to construct structure-property relationships of these interfaces have been the goals of our efforts. We have made substantial progress in developing interatomic potentials for these interfaces and adapting advanced conformational sampling approaches for these purposes. This Account summarizes our progress in the development and deployment of interfacial force fields and molecular simulation techniques for the purpose of elucidating these insights at biomolecule-materials interfaces, using examples from our laboratories ranging from noble-metal interfaces to graphitic substrates (including carbon nanotubes and graphene) and oxide materials (such as titania). In addition to the well-established application areas of plasmonic materials, biosensing, and the production of medical implant materials, we outline new directions for this field that have the potential to bring new advances in areas such as energy materials and regenerative medicine. PMID- 28665582 TI - Exploring Closed-Shell Cationic Phenalenyl: From Catalysis to Spin Electronics. AB - The odd alternant hydrocarbon phenalenyl (PLY) can exist in three different forms, a closed-shell cation, an open-shell radical, and a closed-shell anion, using its nonbonding molecular orbital (NBMO). The chemistry of PLY-based molecules began more than five decades ago, and so far, the progress has mainly involved the open-shell neutral radical state. Over the last two decades, we have witnessed the evolution of a range of PLY-based radicals generating an array of multifunctional materials. However, it has been admitted that the practical applications of PLY radicals are greatly challenged by the low stability of the open-shell (radical) state. Recently, we took a different route to establish the utility of these PLY molecules using the closed-shell cationic state. In such a design, the closed-shell unit of PLY can readily accept free electrons, stabilizing in its NBMO upon generation of the open-shell state of the molecule. Thus, one can synthetically avoid the unstable open-shell state but still take advantage of this state by in situ generating the radical through external electron transfer or spin injection into the empty NBMO. It is worth noting that such approaches using closed-shell phenalenyl have been missing in the literature. This Account focuses on our recent developments using the closed shell cationic state of the PLY molecule and its application in broad multidisciplinary areas spanning from catalysis to spin electronics. We describe how this concept has been utilized to develop a variety of homogeneous catalysts. For example, this concept was used in designing an iron(III) PLY-based electrocatalyst for a single-compartment H2O2 fuel cell, which delivered the best electrocatalytic activity among previously reported iron complexes, organometallic catalysts for various homogeneous organic transformations (hydroamination and polymerization), an organic Lewis acid catalyst for the ring opening of epoxides, and transition-metal-free C-H functionalization catalysts. Moreover, this concept of using the empty NBMO present in the closed-shell cationic state of the PLY moiety to capture electron(s) was further extended to an entirely different area of spin electronics to design a PLY-based spin-memory device, which worked by a spin-filtration mechanism using an organozinc compound based on a PLY backbone deposited over a ferromagnetic substrate. In this Account, we summarize our recent efforts to understand how this unexplored closed shell state of the phenalenyl molecule, which has been known for over five decades, can be utilized in devising an array of materials that not only are important from an organometallic chemistry or organic chemistry point of view but also provide new understanding for device physics. PMID- 28665583 TI - One-Dimensional Luminous Nanorods Featuring Tunable Persistent Luminescence for Autofluorescence-Free Biosensing. AB - Persistent luminescence nanoparticles (PLNPs), which can remain luminescent after cessation of excitation, have emerged as important materials in biomedicine due to their special ability to eliminate tissue autofluorescence. Even though significant advances have been made in bioimaging, studies on controlled synthesis of PLNPs with tunable properties are lacking. Until now, only a few studies have reported the synthesis of quasi-spherical ZnGa2O4:Cr PLNPs, and direct synthesis of PLNPs with other shapes and chemical compositions has not been reported. Herein, we report the direct synthesis of Zn2GeO4:Mn (ZGO:Mn) persistent luminescence nanorods (NRs). The length and persistent luminescence of ZGO:Mn NRs can be fine-tuned by simply changing the pH of the hydrothermal reaction system. Moreover, ZGO:Mn NRs exhibit rapid growth rate, and NRs with strong persistent luminescence can be obtained within 30 min of hydrothermal treatment. Aptamer-guided ZGO:Mn bioprobes were further constructed and applied to serum lysozyme analysis. Serum samples from patients with lung cancer, gastric cancer, and colorectal cancer were collected, and the concentrations of lysozyme in these samples were determined. Since the bioprobes displayed long persistent luminescence, serum autofluorescence interference was completely eliminated. The lysozyme quantification results were in good agreement with those obtained using a clinical method, suggesting the good potential of the bioprobes in the analysis of clinical samples. The developed ZGO:Mn NRs possess tunable length and persistent luminescence, and they are ideal for eliminating autofluorescence interference in biosensing, making them valuable in research areas such as studying the functions of biomolecules and monitoring of molecular/cellular networks in their native contexts. PMID- 28665584 TI - Geometric Phase Effects in Nonadiabatic Dynamics near Conical Intersections. AB - Dynamical consideration that goes beyond the common Born-Oppenheimer approximation (BOA) becomes necessary when energy differences between electronic potential energy surfaces become small or vanish. One of the typical scenarios of the BOA breakdown in molecules beyond diatomics is a conical intersection (CI) of electronic potential energy surfaces. CIs provide an efficient mechanism for radiationless electronic transitions: acting as "funnels" for the nuclear wave function, they enable rapid conversion of the excessive electronic energy into the nuclear motion. In addition, CIs introduce nontrivial geometric phases (GPs) for both electronic and nuclear wave functions. These phases manifest themselves in change of the wave function signs if one considers an evolution of the system around the CI. This sign change is independent of the shape of the encircling contour and thus has a topological character. How these extra phases affect nonadiabatic dynamics is the main question that is addressed in this Account. We start by considering the simplest model providing the CI topology: two dimensional two-state linear vibronic coupling model. Selecting this model instead of a real molecule has the advantage that various dynamical regimes can be easily modeled in the model by varying parameters, whereas any fixed molecule provides the system specific behavior that may not be very illustrative. After demonstrating when GP effects are important and how they modify the dynamics for two sets of initial conditions (starting from the ground and excited electronic states), we give examples of molecular systems where the described GP effects are crucial for adequate description of nonadiabatic dynamics. Interestingly, although the GP has a topological character, the extent to which accounting for GPs affect nuclear dynamics profoundly depends on topography of potential energy surfaces. Understanding an extent of changes introduced by the GP in chemical dynamics poses a problem of capturing GP effects by approximate methods of simulating nonadiabatic dynamics that can go beyond simple models. We assess the performance of both fully quantum (wave packet dynamics) and quantum-classical (surface-hopping, Ehrenfest, and quantum-classical Liouville equation) approaches in various cases where GP effects are important. It has been identified that the key to success in approximate methods is a method organization that prevents the quantum nuclear kinetic energy operator to act directly on adiabatic electronic wave functions. PMID- 28665586 TI - Family of Papain-Like Fungal Chimerolectins with Distinct Ca2+-Dependent Activation Mechanism. AB - An important function of fungal lectins is to protect their host. Marasmius oreades agglutinin (MOA) is toxic to nematodes and exerts its protective effect through protease activity. Its proteolytic function is associated with a papain like dimerization domain. The closest homologue of MOA is Polyporus squamosus lectin 1a (PSL1a). Here, we probed PSL1a for catalytic activity and confirmed that it is a calcium-dependent cysteine protease, like MOA. The X-ray crystal structures of PSL1a (1.5 A) and MOA (1.3 A) in complex with calcium and the irreversible cysteine protease inhibitor E-64 elucidated the structural basis for their mechanism of action. The comparison with other calcium-dependent proteases (calpains, LapG) reveals a unique metal-dependent activation mechanism relying on a calcium-induced backbone shift and intradimer cooperation. Intriguingly, the enzymes appear to use a tyrosine-gating mechanism instead of pro-peptide processing. A search for potential MOA orthologues suggests the existence of a whole new family of fungal chimerolectins with these unique features. PMID- 28665585 TI - CryoTEM as an Advanced Analytical Tool for Materials Chemists. AB - Morphology plays an essential role in chemistry through the segregation of atoms and/or molecules into different phases, delineated by interfaces. This is a general process in materials synthesis and exploited in many fields including colloid chemistry, heterogeneous catalysis, and functional molecular systems. To rationally design complex materials, we must understand and control morphology evolution. Toward this goal, we utilize cryogenic transmission electron microscopy (cryoTEM), which can track the structural evolution of materials in solution with nanometer spatial resolution and a temporal resolution of <1 s. In this Account, we review examples of our own research where direct observations by cryoTEM have been essential to understanding morphology evolution in macromolecular self-assembly, inorganic nucleation and growth, and the cooperative evolution of hybrid materials. These three different research areas are at the heart of our approach to materials chemistry where we take inspiration from the myriad examples of complex materials in Nature. Biological materials are formed using a limited number of chemical components and under ambient conditions, and their formation pathways were refined during biological evolution by enormous trial and error approaches to self-organization and biomineralization. By combining the information on what is possible in nature and by focusing on a limited number of chemical components, we aim to provide an essential insight into the role of structure evolution in materials synthesis. Bone, for example, is a hierarchical and hybrid material which is lightweight, yet strong and hard. It is formed by the hierarchical self-assembly of collagen into a macromolecular template with nano- and microscale structure. This template then directs the nucleation and growth of oriented, nanoscale calcium phosphate crystals to form the composite material. Fundamental insight into controlling these structuring processes will eventually allow us to design such complex materials with predetermined and potentially unique properties. PMID- 28665587 TI - Organohalide Respiration with Chlorinated Ethenes under Low pH Conditions. AB - Bioremediation at chlorinated solvent sites often leads to groundwater acidification due to electron donor fermentation and enhanced dechlorination activity. The microbial reductive dechlorination process is robust at circumneutral pH, but activity declines at groundwater pH values below 6.0. Consistent with this observation, the activity of tetrachloroethene (PCE) dechlorinating cultures declined at pH 6.0 and was not sustained in pH 5.5 medium, with one notable exception. Sulfurospirillum multivorans dechlorinated PCE to cis-1,2-dichloroethene (cDCE) in pH 5.5 medium and maintained this activity upon repeated transfers. Microcosms established with soil and aquifer materials from five distinct locations dechlorinated PCE-to-ethene at pH 5.5 and pH 7.2. Dechlorination to ethene was maintained following repeated transfers at pH 7.2, but no ethene was produced at pH 5.5, and only the transfer cultures derived from the Axton Cross Superfund (ACS) microcosms sustained PCE dechlorination to cDCE as a final product. 16S rRNA gene amplicon sequencing of pH 7.2 and pH 5.5 ACS enrichments revealed distinct microbial communities, with the dominant dechlorinator being Dehalococcoides in pH 7.2 and Sulfurospirillum in pH 5.5 cultures. PCE-to-trichloroethene- (TCE-) and PCE-to-cDCE-dechlorinating isolates obtained from the ACS pH 5.5 enrichment shared 98.6%, and 98.5% 16S rRNA gene sequence similarities to Sulfurospirillum multivorans. These findings imply that sustained Dehalococcoides activity cannot be expected in low pH (i.e., <= 5.5) groundwater, and organohalide-respiring Sulfurospirillum spp. are key contributors to in situ PCE reductive dechlorination under low pH conditions. PMID- 28665588 TI - Biochemical Investigation of Rv3404c from Mycobacterium tuberculosis. AB - The causative agent of tuberculosis, Mycobacterium tuberculosis, is a bacterium with a complex cell wall and a complicated life cycle. The genome of M. tuberculosis contains well over 4000 genes thought to encode proteins. One of these codes for a putative enzyme referred to as Rv3404c, which has attracted research attention as a potential virulence factor for over 12 years. Here we demonstrate that Rv3404c functions as a sugar N-formyltransferase that converts dTDP-4-amino-4,6-dideoxyglucose into dTDP-4-formamido-4,6-dideoxyglucose using N10-formyltetrahydrofolate as the carbon source. Kinetic analyses demonstrate that Rv3404c displays a significant catalytic efficiency of 1.1 * 104 M-1 s-1. In addition, we report the X-ray structure of a ternary complex of Rv3404c solved in the presence of N5-formyltetrahydrofolate and dTDP-4-amino-4,6-dideoxyglucose. The final model of Rv3404c was refined to an overall R-factor of 16.8% at 1.6 A resolution. The results described herein are especially intriguing given that there have been no published reports of N-formylated sugars associated with M. tuberculosis. The data thus provide a new avenue of research into this fascinating, yet deadly, organism that apparently has been associated with human infection since ancient times. PMID- 28665589 TI - Visualization and Quantification of IgG Antibody Adsorbed at the Cellulose-Liquid Interface. AB - Quantification of adsorbed biomolecules (enzymes, proteins) at the cellulose interface is a major challenge in developing eco-friendly biodiagnostics. Here, a novel methodology is developed to visualize and quantify the adsorption of antibody from solution to the cellulose-liquid interface. The concept is to deuterate cellulose by replacing all nonexchangeable hydrogens from the glucose rings with deuterium in order to enhance the scattering contrast between the cellulose film surface and adsorbed antibody molecules. Deuterated cellulose (DC) was obtained from bacterial (Gluconacetobacter xylinus strain) cellulose, which was grown in heavy water (D2O) media with a deuterated glycerol as a carbon source. For comparison, hydrogenated cellulose (HC) was obtained from cellulose acetate. Both HC and DC thin films were prepared on silicon substrate by spin coating. X-ray reflectivity (XR) shows the formation of homogeneous and smooth film. Neutron reflectivity (NR) at the liquid/film interface reveals swelling of the cellulose film by a factor of 2-3* its initial thickness. An Immunoglobulin G (IgG), used as a model antibody, was adsorbed at the liquid-solid interface of cellulose (HC) and deuterated cellulose (DC) films under equilibrium and surface saturation conditions. NR measurements of the IgG antibody layer adsorbed onto the DC film can clearly be visualized, in sharp contrast in comparison to the HC film. The average thickness of the IgG adsorbed layer onto cellulose films is 127 +/- 5 A and a partial monolayer is formed. Visualization and quantification of adsorbed IgG is shown by large difference in scattering length density (SLD) between DC (7.1 * 10-6 A-2) and IgG (4.1 * 10-6 A-2) in D2O, which enhanced the scattering contrast in NR. Quartz crystal measurements (QCM-D) were used as a complementary method to NR to quantify the adsorbed IgG over the cellulose interface. PMID- 28665590 TI - Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp. teitensis. AB - A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 MUM, respectively. PMID- 28665592 TI - Enantioselective Conjugate Addition of 2-Acetyl Azaarenes to beta,beta Disubstituted Nitroalkene for the Construction of All-Carbon Quaternary Stereocenters. AB - The first highly enantioselective conjugate addition of 2-acetyl azaarenes to alpha-substituted-beta-nitroacrylates was successfully realized under mild conditions by a Ni(II)-bisoxazoline complex, providing the desired adducts bearing an all-carbon quaternary stereocenter in high yield with excellent enantioselectivity. The products obtained in this system could be readily converted into optically active beta2,2-amino esters, succinates, lactones, and lactams. PMID- 28665593 TI - Panoramic Synthesis as an Effective Materials Discovery Tool: The System Cs/Sn/P/Se as a Test Case. AB - The common approach to the synthesis of a new material involves reactions held at high temperatures under certain conditions such as heating in a robust vessel in the dark for a period until it is judged to have concluded. Analysis of the vessel contents afterward provides knowledge of the final products only. Intermediates that may form during the reaction process remain unknown. This lack of awareness of transient intermediates represents lost opportunities for discovering materials or understanding how the final products form. Here we present new results using an emerging in situ monitoring approach that shows high potential in discovering new compounds. In situ synchrotron X-ray diffraction studies were conducted in the Cs/Sn/P/Se system. Powder mixtures of Cs2Se2, Sn, and PSe2 were heated to 650 degrees C and then cooled to room temperature while acquiring consecutive in situ synchrotron diffraction patterns from the beginning to the end of the reaction process. The diffraction data was translated into the relationship of phases present versus temperature. Seven known crystalline phases were observed to form on warming in the experiment: Sn, Cs2Se3, Cs4Se16, Cs2Se5, Cs2Sn2Se6, Cs4P2Se9, and Cs2P2Se8. Six unknown phases were also detected; using the in situ synchrotron data as a guide three of them were isolated and characterized ex situ. These are Cs4Sn(P2Se6)2, alpha-Cs2SnP2Se6, and Cs4(Sn3Se8)[Sn(P2Se6)]2. Cs4(Sn3Se8)[Sn(P2Se6)]2 is a two-dimensional compound that behaves as an n-type doped semiconductor below 50 K and acts more like a semimetal at higher temperatures. Because all crystalline phases are revealed during the reaction, we call this approach "panoramic synthesis". PMID- 28665591 TI - Biochemical Characterization and Structural Basis of Reactivity and Regioselectivity Differences between Burkholderia thailandensis and Burkholderia glumae 1,6-Didesmethyltoxoflavin N-Methyltransferase. AB - Burkholderia glumae converts the guanine base of guanosine triphosphate into an azapteridine and methylates both the pyrimidine and triazine rings to make toxoflavin. Strains of Burkholderia thailandensis and Burkholderia pseudomallei have a gene cluster encoding seven putative biosynthetic enzymes that resembles the toxoflavin gene cluster. Four of the enzymes are similar in sequence to BgToxBCDE, which have been proposed to make 1,6-didesmethyltoxoflavin (1,6-DDMT). One of the remaining enzymes, BthII1283 in B. thailandensis E264, is a predicted S-adenosylmethionine (SAM)-dependent N-methyltransferase that shows a low level of sequence identity to BgToxA, which sequentially methylates N6 and N1 of 1,6 DDMT to form toxoflavin. Here we show that, unlike BgToxA, BthII1283 catalyzes a single methyl transfer to N1 of 1,6-DDMT in vitro. In addition, we investigated the differences in reactivity and regioselectivity by determining crystal structures of BthII1283 with bound S-adenosylhomocysteine (SAH) or 1,6-DDMT and SAH. BthII1283 contains a class I methyltransferase fold and three unique extensions used for 1,6-DDMT recognition. The active site structure suggests that 1,6-DDMT is bound in a reduced form. The plane of the azapteridine ring system is orthogonal to its orientation in BgToxA. In BthII1283, the modeled SAM methyl group is directed toward the p orbital of N1, whereas in BgToxA, it is first directed toward an sp2 orbital of N6 and then toward an sp2 orbital of N1 after planar rotation of the azapteridine ring system. Furthermore, in BthII1283, N1 is hydrogen bonded to a histidine residue whereas BgToxA does not supply an obvious basic residue for either N6 or N1 methylation. PMID- 28665594 TI - Oxidation of Bromide to Bromine by Ruthenium(II) Bipyridine-Type Complexes Using the Flash-Quench Technique. AB - Six ruthenium complexes, [Ru(bpy)3]2+ (1), [Ru(bpy)2(deeb)]2+ (2), [Ru(deeb)2(dmbpy)]2+ (3), [Ru(deeb)2(bpy)]2+ (4), [Ru(deeb)3]2+ (5), and [Ru(deeb)2(bpz)] 2+ (6) (bpy: 2,2'-bipyridine; deeb: 4,4'-diethylester-2,2' bipyridine; dmbpy: 4,4'-dimethyl-2,2'-bipyridine, bpz: 2,2'-bipyrazine), have been employed to sensitize photochemical oxidation of bromide to bromine. The oxidation potential for complexes 1-6 are 1.26, 1.36, 1.42, 1.46, 1.56, and 1.66 V vs SCE, respectively. The bimolecular rate constants for the quenching of complexes 1-6 by ArN2+ (bromobenzenediazonium) are determined as 1.1 * 109, 1.6 * 108, 1.4 * 108, 1.2 * 108, 6.4 * 107, and 8.9 * 106 M-1 s-1, respectively. Transient kinetics indicated that Br- reacted with photogenerated Ru(III) species at different rates. Bimolecular rate constants for the oxidation of Br- by the Ru(III) species derived from complexes 1-5 are observed as 1.2 * 108, 1.3 * 109, 4.0 * 109, 4.8 * 109, and 1.1 * 1010, M-1 s-1, respectively. The last reaction kinetics observed in the three-component system consisting of a Ru sensitizer, quencher, and bromide is shown to be independent of the Ru sensitizer. The final product was identified as bromine by its reaction with hexene. The last reaction kinetics is assigned to the disproportionation reaction of Br2-* ions, for which the rate constant is determined as 5 * 109 M-1 s-1. Though complex 6 has the highest oxidation potential in the Ru(II)/Ru(III) couple, its excited state fails to react with ArN2+ sufficiently for subsequent reactions. The Ru(III) species derived from complex 1 reacts with Br- at the slowest rate. Complexes 2-5 are excellent photosensitizers to drive photooxidation of bromide to bromine. PMID- 28665595 TI - Symmetry-Breaking for Formation of Rectangular CdSe Two-Dimensional Nanocrystals in Zinc-Blende Structure. AB - Formation of CdSe nanocrystals with two-dimensional quantum confinement (CdSe 2D nanocrystals) was studied with preformed CdSe nanocrystals in the size range between 1.7 and 2.2 nm as seeds. Specifically, the 2D CdSe nanocrystals were encased with six {100} facets of the zinc-blende (face-center-cubic) structure, that is, 1.5 nm in thickness with quite large atomically flat {100} basal planes (~8 nm width and X ~ 45 nm length). Symmetry breaking between the thickness and lateral directions occurred in the early stage by rapid formation of single-dot intermediates with flat yet polar {100} basal planes and the desired thickness from the seeds through intraparticle ripening. Two single-dot intermediates fused together through their reactive side facets-mostly the nonpolar {110} ones-to form 2D embryos with the same thickness. Such oriented attachment continued selectively onto the reactive side facets of the 2D embryos. Simultaneously, intraparticle ripening occurred slowly on the side facets of the 2D nanocrystals, which converted unstable side facets gradually to four stable {100} ones. When ~3 stable {100} side facets were developed, oriented attachment would continue on the remaining active one, which would result in the second symmetry breaking between two lateral directions. Cadmium acetate assisted both formation of single dot intermediates and oriented attachment. Cadmium alkanoates with a long hydrocarbon chain selectively stabilized polar {100} facets on the nanocrystals including single-dot intermediates and shuttled insoluble acetate to the reactive surface of the nanocrystals. PMID- 28665596 TI - Modular Access to N-Substituted cis 5-Amino-3-hydroxypiperidines. AB - A sequence of oxidative cleavage/reductive amination/reductive cleavage enables the preparation of N-substituted cis 5-amino-3-hydroxypiperidines from a readily available bicyclic adduct. This new route provides straightforward and versatile access to drug-relevant scaffolds or fragments. PMID- 28665597 TI - Atomically Precise Bimetallic Au19Cu30 Nanocluster with an Icosidodecahedral Cu30 Shell and an Alkynyl-Cu Interface. AB - Bimetallic nanoclusters Au19Cu30 with chemical composition of [Au19Cu30(C=CR)22(Ph3P)6Cl2](NO3)3 (where RC=C is from 3-ethynylthiophene (H3C4S 3-C=CH) or ethynylbenzene (PhC=CH)) has been synthesized. Single X-ray structural analysis reveals that Au19Cu30 has a multishelled core structure of Au@Au12@Cu30@Au6, comprising a centered icosahedral Au13 (Au@Au12) surrounded by an icosidodecahedral Cu30 shell and an outmost shell of a chairlike hexagonal Au6. The alkynyl carbon is bound to the hollow sites on the Au19Cu30 nanocluster surface, which is a novel interfacial binding mode in alkynyl-protected alloy nanoclusters. The Cu30 icosidodecahedron is unprecedented and Au19Cu30 represents the first alkynyl-protected Au-Cu alloy nanocluster. PMID- 28665598 TI - Isolation and Characterization of Sesquiterpenoids from Cassia Buds and Their Antimicrobial Activities. AB - Cassia buds, the immature fruits of Cinnamomum cassia (Lauraceae), are widely consumed as a food spice, dietary supplements, flavoring agents, and preservatives. In this study, cassia buds were phytochemically investigated for the first time, leading to the isolation of 2 new sesquiterpenoids (1 and 2) and 10 known sesquiterpenoids (3-12). Their structures were determined by spectrometric and spectroscopic analyses, including nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, and circular dichroism. Cinnamosim A (1) represents the ninth example of the rare cyperane type sesquiterpenoids. All of the compounds (1-12) isolated from cassia buds were evaluated for antimicrobial activities, with compounds 1-3, 5-8, 11, and 12 exhibiting strong antimicrobial activities against Candida albicans and compounds 6, 7, and 11 showing moderate antibacterial activities against Escherichia coli and Staphylococcus aureus. The present investigation indicated that sesquiterpenoids from cassia buds might be used as potential antimicrobial agents to preserve food. PMID- 28665599 TI - Importance of R-CF3...O Tetrel Bonding Interactions in Biological Systems. AB - In this article, ab initio calculations have been combined with a search in the Protein Data Bank (PDB) to demonstrate the importance of sigma-hole tetrel bonding interactions in biological systems. In particular, we focus our attention on the ability of the -CF3 group to participate in noncovalent interactions as Lewis acids, and we show the importance of this interaction in the inhibition mechanism of a NADP+-dependent isocitrate dehydrogenase (IDH) enzyme that converts isocitrate to alpha-ketoglutarate. IDH mutations are found in multiple hematologic and solid tumors, inducing premalignant disorders. A potent triazine based inhibitor of the mutant IDH (enasidenib) presents two -CF3 groups in the structure. One establishes a tetrel bonding interaction with an aspartate residue that contributes to the binding and selectivity of the inhibitor to the active site. PMID- 28665600 TI - Boosting Gas Involved Reactions at Nanochannel Reactor with Joint Gas-Solid Liquid Interfaces and Controlled Wettability. AB - The low solubility of gases in aqueous solution is the major kinetic limitation of reactions that involve gases. To address this challenge, we report a nanochannel reactor with joint gas-solid-liquid interfaces and controlled wettability. As a proof of concept, a porous anodic alumina (PAA) nanochannel membrane with different wettability is used for glucose oxidase (GOx) immobilization, which contacts with glucose aqueous solution on one side, while the other side gets in touch with the gas phase directly. Interestingly, it is observed that the O2 could participate in the enzymatic reaction directly from gas phase through the proposed nanochannels, and a hydrophobic interface is more favorable for the enzymatic reaction due to the rearrangement of GOx structure as well as the high gas adhesion. As a result, the catalytic efficiency of GOx in the proposed interface is increased up to 80-fold compared with that of the free state in traditional aqueous air-saturated electrolyte. This triphase interface with controlled wettability can be generally applied to immobilize enzymes or catalysts with gas substrates for high efficiency. PMID- 28665601 TI - Predicting the Ecological Quality Status of Marine Environments from eDNA Metabarcoding Data Using Supervised Machine Learning. AB - Monitoring biodiversity is essential to assess the impacts of increasing anthropogenic activities in marine environments. Traditionally, marine biomonitoring involves the sorting and morphological identification of benthic macro-invertebrates, which is time-consuming and taxonomic-expertise demanding. High-throughput amplicon sequencing of environmental DNA (eDNA metabarcoding) represents a promising alternative for benthic monitoring. However, an important fraction of eDNA sequences remains unassigned or belong to taxa of unknown ecology, which prevent their use for assessing the ecological quality status. Here, we show that supervised machine learning (SML) can be used to build robust predictive models for benthic monitoring, regardless of the taxonomic assignment of eDNA sequences. We tested three SML approaches to assess the environmental impact of marine aquaculture using benthic foraminifera eDNA, a group of unicellular eukaryotes known to be good bioindicators, as features to infer macro invertebrates based biotic indices. We found similar ecological status as obtained from macro-invertebrates inventories. We argue that SML approaches could overcome and even bypass the cost and time-demanding morpho-taxonomic approaches in future biomonitoring. PMID- 28665602 TI - Complexation of Actinide(III) and Lanthanide(III) with H4TPAEN for a Separation of Americium from Curium and Lanthanides. AB - Previous studies have identified the TPAEN ligand as a potentially appropriate complexing agent in solvent extraction processes for the separation of americium (Am(III)) from the fission products including lanthanide (Ln(III)) and curium (Cm(III)) ions, a challenging issue for advanced nuclear fuel recycling. To get insight into the selectivity of this ligand, the complexation of selected trivalent Ln(III) and actinide (An(III)) cations with TPAEN was investigated in solution. First, the structure and stoichiometry of the TPAEN complex with Am(III) were characterized by extended X-ray absorption fine structure spectroscopy (EXAFS). Then complexation constants and thermodynamics data were acquired for the complexes using different methods: microcalorimetry for the Ln(III) cations, time-resolved laser fluorescence spectroscopy (TRLFS) for Eu(III) and Cm(III), and UV-visible spectroscopy for Nd(III) and Am(III). PMID- 28665604 TI - Chromium(III) Bis-Arylterpyridyl Complexes with Enhanced Visible Absorption via Incorporation of Intraligand Charge-Transfer Transitions. AB - A series of chromium(III) bis-arylterpyridyl complexes containing intraligand charge-transfer (ILCT) excited states were prepared and characterized. These complexes show significant absorption in the visible region due to the ILCT bands. The ILCT bands are tunable across the UV and visible spectrum via incorporation of electron-withdrawing and electron-donating groups on the aryl ring. The absorption of Cr(4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine)23+ (4) in particular is much stronger in the visible region (epsilon = 11 900 M-1 cm-1 at 450 nm and epsilon = 5090 M-1 cm-1 at 500 nm) than that of the parent complex Cr(tpy)23+ (tpy = 2,2':6',2"-terpyridine; epsilon = 2160 M-1 cm-1 at 450 nm, and epsilon = 170 M-1 cm-1 at 500 nm). Emission experiments on this series reveal Cr(III)-based phosphorescence with lifetimes from 140 to 600 ns upon excitation into the ILCT bands, which indicates funneling of the excitation energy from ligand-localized excited states to Cr(III)-based excited states. Cyclic voltammograms exhibit at least three reversible ligand-based reductions. The first reduction shows shifts of up to -160 mV compared to Cr(tpy)23+. The excited state reduction potential of these complexes ranges from +0.95 to +1.04 V vs the ferrocene/ferrocenium couple, making them potent photooxidants. PMID- 28665603 TI - Experimental and Theoretical Evidences of p-Type Conductivity in Nickel Carbodiimide Nanoparticles with a Delafossite Structure Type. AB - Nickel carbodiimide (NiCN2) was synthesized using a two-step precipitation decomposition route leading to a brown powder with gypsum-flower-like morphology and a large specific surface area (75 m2/g). This layered material crystallizes in the 2H structure type of delafossite (space group P63/mmc), which is built upon infinite 2/infinity[NiN2] layers connected by linear carbodiimide ([N?C?N]2 ) bridges. An X-ray diffraction Rietveld refinement and thermal analyses pointed out some nickel deficiencies in the material, and band structure calculations carried out on the defect compound predicted p-type conductivity in relation to a slight amount of N2-. This p-type conductivity was demonstrated by electrochemical impedance spectroscopy measurements, and a flat band potential of 0.90 V vs SCE at pH 9.4 was measured. This value, which is more positive than those of CuGaO2 and CuCrO2 delafossite oxides and NiO, prompted us to test NiCN2 nanoparticles as a photocathode in p-type dye-sensitized solar cells. PMID- 28665605 TI - Anharmonicity of Coupled Torsions: The Extended Two-Dimensional Torsion Method and Its Use To Assess More Approximate Methods. AB - In this work we present the extended two-dimensional torsion (E2DT) method and use it to analyze the performance of several methods that incorporate torsional anharmonicity more approximately for calculating rotational-vibrational partition functions. Twenty molecules having two hindered rotors were studied for temperatures between 100 and 2500 K. These molecules present several kinds of situations; they include molecules with nearly separable rotors, molecules in which the reduced moments of inertia change substantially with the internal rotation, and molecules presenting compound rotation. Partition functions obtained by the rigid-rotor harmonic oscillator approximation, a method involving global separability of torsions and the multistructural methods without explicit potential coupling [MS-T(U)] and with explicit potential coupling [MS-T(C)] of torsions, are compared to those obtained with a quantized version - called the extended two-dimensional torsion (E2DT) method - of the extended hindered rotor approximation of Vansteenkiste et al. ( Vansteenkiste et al. J. Chem. Phys. 2006 , 124 , 044314 ). In the E2DT method, quantum effects due to the torsional modes were incorporated by the two-dimensional nonseparable method, which is a method that is based on the solution of the torsional Schrodinger equation and that includes full coupling in both the kinetic and potential energy. By comparing other methods to the E2DT method and to experimental thermochemical data, this study concludes that the harmonic approximation yields very poor results at high temperatures; the global separation of torsions from the rest of the degrees of freedom is not justified even when an accurate method to treat the torsions is employed; it is confirmed that methods based on less complete potential energy coupling of torsions, such as MS-T(U), are not accurate when dealing with rotors with different barrier heights, and more complete inclusion of torsional coupling to the method in MS-T(C) improves substantially the results in such a way that it could be used in cases where the E2DT method is unaffordable. PMID- 28665606 TI - Large Area Co-Assembly of Nanowires for Flexible Transparent Smart Windows. AB - Electrochromic devices with controllable color switching, low cost, and energy saving advantages have been widely used as smart windows, rear-view car mirrors, displays, and so on. However, the devices are seriously limited for flexible electronics as they are traditionally fabricated on indium tin oxide (ITO) substrates which will lose their conductivity after bending cycles (the resistance significantly changed from 200 Omega to 6.56 MOmega when the bending radius was 1.2 cm). Herein, we report a new route for large area coassembly of nanowires (NWs), resulting in the formation of multilayer ordered nanowire (NW) networks with tunable conductivity (7-40 Omega/sq) and transmittance (58-86% at 550 nm) for fabrication of flexible transparent electrochromic devices, showing good stability of electrochromic switching behaviors. The electrochromic performance of the devices can be tuned and is strongly dependent on the structures of the Ag and W18O49 NW assemblies. Unlike the ITO-based electronics, the electrochromic films can be bent to a radius of 1.2 cm for more than 1000 bending cycles without obvious failure of both conductivity (DeltaR/R ~ 8.3%) and electrochromic performance (90% retention), indicating the excellent mechanical flexibility. The present method for large area coassembly of NWs can be extended to fabricate various NW-based flexible devices in the future. PMID- 28665608 TI - Correction for "Experimental and Theoretical Investigations of Infrared Multiple Photon Dissociation Spectra of Glutamine Complexes with Zn2+ and Cd2+". PMID- 28665607 TI - European Starlings (Sturnus vulgaris) As Sentinels of Urban Air Pollution: A Comprehensive Approach from Noninvasive to Post Mortem Investigation. AB - Urban, traffic-related air pollution remains a concern to health-care and environmental professionals, with mounting evidence connecting diverse disease conditions with exposure. Wildlife species such as European starlings (Sturnus vulgaris) cohabit urban neighborhoods and may serve as sentinels for these contaminants. In this novel approach, we use passive, personal-type air samplers to provide site-specific measurements of nitrogen dioxide (NO2), sulfur dioxide (SO2) and volatile organic compounds (VOCs, such as benzene, toluene, ethylbenzene, and xylenes, or BTEX), and account for the effects of confounding environmental factors when teasing out the responses to exposure. This study examines biomarkers of exposure to predominately traffic-related, urban air contaminants in European starlings, including morphometric measurements, immunotoxicology, oxidative stress and hepatic detoxification, and analyses responses in the context of multilayered factors including year, hatch date, weather and location, confirming that this experimental approach and the selected health indicators can be used for comparing locations with different levels of contaminants. PMID- 28665609 TI - Understanding Ultrafast Dynamics of Conformation Specific Photo-Excitation: A Femtosecond Transient Absorption and Ultrafast Raman Loss Study. AB - Excited state ultrafast conformational reorganization is recognized as an important phenomenon that facilitates light-induced functions of many molecular systems. This report describes the femtosecond and picosecond conformational relaxation dynamics of middle-ring and terminal ring twisted conformers of the acetylene pi-conjugated system bis(phenylethynyl)benzene, a model system for molecular wires. Through excitation wavelength dependent, femtosecond-transient absorption measurements, we found that the middle-ring and terminal ring twisted conformers relax at femtosecond (400-600 fs) and picosecond (20-24 ps) time scales, respectively. Actinic pumping into the red flank of the absorption spectrum leads to excitation of primarily planar conformers, and results in very different excited state dynamics. In addition, ultrafast Raman loss spectroscopic studies revealed the vibrational mode dependent relaxation dynamics for different excitation wavelengths. To corroborate our experimental findings, DFT and time dependent DFT calculations were carried out. The Franck-Condon simulation indicated that the vibronic structure observed in the electronic absorption and the fluorescence spectra are due to progressions and combinations of several vibrational modes corresponding to the phenyl ring and the acetylenic groups. Furthermore, the middle ring torsional rotation matches the room-temperature electronic absorption, in stark contrast to the terminal ring torsional rotation. Finally, we show that the middle-ring twisted conformer undergoes femtosecond torsional planarization dynamic, whereas the terminal rings relax on a few tens of picosecond time scale. PMID- 28665610 TI - Activation of Sodium Storage Sites in Prussian Blue Analogues via Surface Etching. AB - Sodium-ion battery technologies are known to suffer from kinetic problems associated with the solid-state diffusion of Na+ in intercalation electrodes, which results in suppressed specific capacity and degraded rate performance. Here, a controllable selective etching approach is developed for the synthesis of Prussian blue analogue (PBA) with enhanced sodium storage activity. On the basis of time-dependent experiments, a defect-induced morphological evolution mechanism from nanocube to nanoflower structure is proposed. Through in situ X-ray diffraction measurement and computational analysis, this unique structure is revealed to provide higher Na+ diffusion dynamics and negligible volume change during the sodiation/desodiation processes. As a sodium ion battery cathode, the PBA exhibits a discharge capacity of 90 mA h g-1, which is in good agreement with the complete low spin FeLS(C) redox reaction. It also demonstrates an outstanding rate capability of 71.0 mA h g-1 at 44.4 C, as well as an unprecedented cycling reversibility over 5000 times. PMID- 28665611 TI - Comprehensive Myocardial Proteogenomics Profiling Reveals C/EBPalpha as the Key Factor in the Lipid Storage of ARVC. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is hereditary cardiomyopathy characterized by the fibro-fatty replacement of the myocardium. A small number of noncomprehensive profiling studies based on human cardiac tissues have been conducted and reported; consequently, ARVC's gene expression pattern characteristics remain largely undocumented. Our study applies large-scaled, quantitative proteomics based on TMT-labeled LC-MS/MS to analyze the left and right ventricular myocardium of four ARVC and four DCM explanted hearts to compare them with normal hearts. Our objective is to reveal the characteristic proteome pattern in ARVC compared with DCM as well as nondiseased heart. We also conducted the RNA sequencing of 10 right ventricles from ARVC hearts paired with four nondiseased donor hearts to validate the proteome results. In a manner similar to that of the well-defined DCM heart failure model, the ARVC model demonstrates the downregulation of mitochondrial function proteins and the effects of many heart failure regulators such as TGFB, RICTOR, and KDM5A. In addition, the inflammatory signaling, especially the complement system, was activated much more severely in ARVC than in DCM. Our most significant discovery was the lipid metabolism reprogramming of both ARVC ventricles in accordance with the upregulation of lipogenesis factors such as FABP4 and FASN. We identified the key upstream regulator of lipogenesis as C/EBPalpha. Transcriptome profiling verified the consistency with proteome alterations. This comprehensive proteogenomics profiling study reveals that an activation of C/EBPalpha, along with the upregulation of its lipogenesis targets, accounts for lipid storage and acts as a hallmark of ARVC. PMID- 28665612 TI - Configurational Stability of [5]Helicenes. AB - A series of [5]helicenes difunctionalized in the fjord region with either fluoro, methoxy, or methyl groups was synthesized via photochemical and benzylic coupling route. Resolution of each compound into enantiomers and determination of the Gibbs activation energies of enantiomerization (DeltaG?(T)) revealed high configurational stability in all three cases. The DeltaG?(T) values of difunctionalized [5]helicenes were compared with those of their monofunctionalized analogues and the parent [5]helicene. Within this series, an exponential correlation between the torsional twist and DeltaG?(T) was found. The dimethyl derivative exhibits one of the highest configurational stabilities among [n]helicenes reported to date, comparable to that of [9]helicene. PMID- 28665613 TI - Conformational Heterogeneity and the Role of the C(2)-H Donor in Mono- and Dihydrated Clusters of Benzoxazole. AB - The significance of the heteroatom in influencing the acidity and binding affinity of the C(2)-H donor in five-membered heterocyclic rings is explored. The water clusters of benzoxazole (BOX) are studied in a supersonic jet by IR-UV double resonance spectroscopy and compared with those of benzimidazole (BIM) and its N-methyl derivative (MBIM). Two conformers are identified for the monohydrated cluster, both of which are O-H...N bound and differ in their orientation with respect to the intermolecular hydrogen bond. IR spectroscopy of the doubly hydrated cluster shows the presence of an intensity enhanced C(2)-H (carbon atom between the heteroatoms in the five-membered ring) stretching mode in addition to two red-shifted bound OH stretches, indicating that the water molecules form a hydrogen-bonded bridge encompassing the N acceptor and the weakly activated C(2)-H bond in oxazole. Comparison of the topological parameters of electron density, natural bond orbital analyses, and computed binding energies of the analogous hydrated structures of BOX, BIM, and MBIM indicates that the C(2)-H bond in the former is a more potent H-bond donor. PMID- 28665614 TI - Room-Temperature Strong Light-Matter Interaction with Active Control in Single Plasmonic Nanorod Coupled with Two-Dimensional Atomic Crystals. AB - Strong light-matter coupling manifested by Rabi splitting has attracted tremendous attention due to its fundamental importance in cavity quantum electrodynamics research and great potentials in quantum information applications. A prerequisite for practical applications of the strong coupling in future optoelectronic devices is an all-solid-state system exhibiting room temperature Rabi splitting with active control. Here we realized such a system in heterostructure consisted of monolayer WS2 and an individual plasmonic gold nanorod. By taking advantages of the small mode volume of the nanorod and large transition dipole moment of the WS2 exciton, giant Rabi splitting energies of 91 133 meV can be achieved at ambient conditions, which only involve a small number of excitons. The strong light-matter coupling can be dynamically tuned either by electrostatic gating or temperature scanning. These findings can pave the way toward active nanophotonic devices operating at room temperature. PMID- 28665615 TI - Triplet Energy and pi-Conjugation Effects on Photoisomerization of Chiral N,C Chelate Organoborons with PAH Substituents. AB - Chiral, PAH substituted N,C-chelate boron compounds are systematically investigated to establish the effect of triplet energy and substitution position on their photoreactivity. They all undergo regioselective photoisomerization, forming new dark isomers with quantum efficiencies reflecting these various factors. New PAH fused 4bH-azaborepins are obtained via thermal isomerization of the dark isomers. These results further implicate a photoactive triplet state in the photoisomerization process and its utility in achieving rare PAH-fused azaborepin-like heterocycles. PMID- 28665617 TI - Synthesis of a Multifunctional Graphene Oxide-Based Magnetic Nanocomposite for Efficient Removal of Cr(VI). AB - A novel magnetic nanocomposite was synthesized using graphene oxide (GO), polyethylenimine (PEI), and Fe3O4 to removal hexavalent chromium (Cr(VI)) from water and soil. Therein, GO was functionalized with plenty of -NH2 by the modification of PEI through an amidation reaction, and the resulting GO/PEI reacted with FeSO4.7H2O and NaBH4 to obtain RGO/PEI/Fe3O4 (the optimal one is designated as ORPF) through an oxidation-reduction reaction. ORPF could effectively adsorb Cr(VI) through electrostatic attraction, and the adsorbed Cr(VI) ions were partially reduced to trivalent chromium (Cr(III)) with low toxicity by RGO (pi electron). Afterward, the resulting ORPF-Cr could be conveniently removed from water with a magnet, achieving the maximum Cr(VI) removal capacity of 266.6 mg/g. Importantly, ORPF, once carried by sponge particles, could efficiently remove Cr(VI) from soil, and the resulting mixture could be facilely collected with a magnet on a filter net. Besides, the leaching experiment suggested that, when supported by filter paper, ORPF was able to decrease the number of leached Cr(VI) ions and meanwhile reduce them to Cr(III). This work provides a promising approach to remediate Cr(VI)-contaminated water and soil using a nanocomposite, which has a huge number of application prospects. PMID- 28665616 TI - Quantitative Proteomics Reveals Extensive Changes in the Ubiquitinome after Perturbation of the Proteasome by Targeted dsRNA-Mediated Subunit Knockdown in Drosophila. AB - The ubiquitin-proteasome system (UPS), a highly regulated mechanism including the active marking of proteins by ubiquitin to be degraded, is critical in regulating proteostasis. Dysfunctioning of the UPS has been implicated in diseases such as cancer and neurodegenerative disorders. Here we investigate the effects of proteasome malfunctioning on global proteome and ubiquitinome dynamics using SILAC proteomics in Drosophila S2 cells. dsRNA-mediated knockdown of specific proteasome target subunits is used to inactivate the proteasome. Upon this perturbation, both the global proteome and the ubiquitinome become modified to a great extent, with the overall impact on the ubiquitinome being the most dramatic. The abundances of ~10% of all proteins are increased, while the abundances of the far majority of over 14 000 detected diGly peptides are increased, suggesting that the pool of ubiquitinated proteins is highly dynamic. Remarkably, several proteins show heterogeneous ubiquitination dynamics, with different lysine residues on the same protein showing either increased or decreased ubiquitination. This suggests the occurrence of simultaneous and functionally different ubiquitination events. This strategy offers a powerful tool to study the response of the ubiquitinome upon interruption of normal UPS activity by targeted interference and opens up new avenues for the dissection of the mode of action of individual components of the proteasome. Because this is to our knowledge the first comprehensive ubiquitinome screen upon proteasome malfunctioning in a fruit fly cell system, this data set will serve as a valuable repository for the Drosophila community. PMID- 28665618 TI - Microfluidic Surface Titrations of Electroactive Thin Films. AB - We report the use of microfluidic surface titrations (MSTs) for studying electroactive self-assembled monolayers (eSAMs) and other thin films. The technique of MST utilizes a microfluidic generation-collection dual channel electrode (DCE) configuration to quantify the charge associated with electroactive thin films that might or might not be in direct contact with an electrode surface. This technique allows for quantitative measurement of surface coverages, Gamma, as low as 30 pmol cm-2 for electrodeposited Cu thin films. Additionally, we show that it is possible to quantify Gamma for ferrocene (Fc) terminated alkylthiols in mixed-monolayer eSAMs. Interestingly, MSTs sometimes reveal a two-fold higher eSAM concentration compared to direct electrochemical measurements. This finding suggests that in these instances not all the constituent Fc-moieties of the eSAM are in sufficiently close proximity to the surface to be addressable via direct electrochemistry. PMID- 28665619 TI - Cu-Mediated C-H 18F-Fluorination of Electron-Rich (Hetero)arenes. AB - This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C(sp2)-H functionalization of an electron-rich arene with MesI(OH)OTs to form a (mesityl)(aryl)iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [18F]KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. The radiofluorination has been automated to access a 41 mCi dose of an 18F-labeled nimesulide derivative in high (2800 +/- 700 Ci/mmol) specific activity. PMID- 28665620 TI - Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development. AB - New bifunctional hexa- and octadentate analogues of the hydroxamate-containing siderophore desferrichrome (DFC) have been synthesized and evaluated as 89Zr chelating agents for immunoPET applications. The in vitro and in vivo inertness of these new ligands, Orn3-hx (hexadentate) and Orn-4hx derivatives (octadentate), was compared to the gold standard hexadentate, hydroxamate containing chelator for 89Zr desferrioxamine (DFO). Density functional theory was employed to model the geometries of the resulting Zr(IV) complexes and to predict their relative stabilities as follows: Zr(Orn4-hx) > Zr(DFC) > Zr(Orn3-hx). Transchelation challenge experiments of the corresponding radiochemical complexes with excess ethylenediaminetetraacetate (EDTA) indicated complex stability in accordance with DFT calculations. Radiolabeling of these ligands with 89Zr was quantitative (0.25 MUmol of ligand, pH 7.4, room temperature, 20 min). For antibody conjugation, the isothiocyanate (NCS) functional group was introduced to the N terminus of Orn3-hx and Orn-4hx. An additional trifunctional derivative that bears a silicon-rhodamine fluorophore on the C-terminus and NCS on the N terminus was also furnished. As proof of concept, all NCS derivatives were conjugated to the HER2-targeting antibody, trastuzumab. Radiolabeling of immunoconjugates with 89Zr was accomplished with radiochemical yields of 16 +/- 2% to 95 +/- 2%. These constructs were administered to naive mice (male, C57BL/6J, n = 4) to assess in vivo inertness, which is inversely correlated with uptake of 89Zr in bone, after 96 h circulation time. We found bone uptake to range from 7.0 +/- 2.2 to 10.7 +/- 1.3% ID/g, values that compare well to the corresponding DFO conjugate (7.1 +/- 0.8% ID/g). In conclusion, we have rationally designed linear, bifunctional and trifunctional desferrichrome analogues suitable for the mild and inert radiolabeling of antibodies with the radionuclide 89Zr. PMID- 28665621 TI - Observation of Conductance Quantization in InSb Nanowire Networks. AB - Majorana zero modes (MZMs) are prime candidates for robust topological quantum bits, holding a great promise for quantum computing. Semiconducting nanowires with strong spin orbit coupling offer a promising platform to harness one dimensional electron transport for Majorana physics. Demonstrating the topological nature of MZMs relies on braiding, accomplished by moving MZMs around each other in a certain sequence. Most of the proposed Majorana braiding circuits require nanowire networks with minimal disorder. Here, the electronic transport across a junction between two merged InSb nanowires is studied to investigate how disordered these nanowire networks are. Conductance quantization plateaus are observed in most of the contact pairs of the epitaxial InSb nanowire networks: the hallmark of ballistic transport behavior. PMID- 28665622 TI - Short Approach toward the Nonracemic A,B,E Tricyclic Core of Calyciphylline B Type Alkaloids. AB - A suitably functionalized tricyclic adduct containing the common A,B,E rings found in calyciphylline B-type alkaloids was obtained in nine linear steps. The key transformation features an efficient one-pot sequence of intramolecular Vilsmeier-Haack cyclization and azomethine ylide 1,3-dipolar cycloaddition in which three cycles, three new carbon-carbon bonds, and three stereocenters are formed, one being fully substituted. This work also demonstrates the first use of a chiral, nonracemic cyclic enol ether as an internal carbon nucleophile. PMID- 28665623 TI - Pd-Catalyzed Desulfonative Cross-Coupling of Benzylic Sulfone Derivatives with 1,3-Oxazoles. AB - The Pd-catalyzed desulfonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles via a deprotonative pathway has been developed. Broad substrate scope for both sulfone and 1,3-oxazole partners is observed, affording a variety of 1,3-oxazole-containing triarylmethanes. Sulfone partners that are primary benzylic, secondary benzylic, and benzhydryl are all effective. Using this method, the straightforward synthesis of multiply arylated structures has been demonstrated. PMID- 28665624 TI - Dehydrative Cp*Co(III)-Catalyzed C-H Bond Allenylation. AB - An efficient, unprecedented reactivity of Cp*Co(III) for the synthesis of tetrasubstituted allenes under mild conditions is disclosed. Electron-rich and highly nucleophilic cobalt facilitates the dehydrative C-H bond allenylation directly from propargylic alcohols without any derivatization. The reaction proceeds via reversible cyclometalation followed by alcohol-directed regioselective alkyne insertion and beta-hydroxy elimination to provide the tetrasubstituted allenes. PMID- 28665625 TI - Complexation of Linear DNA and Poly(styrenesulfonate) with Cationic Copolymer Micelles: Effect of Polyanion Flexibility. AB - The complexation of linear double stranded DNA and poly(styrenesulfonate) (PSS) with cationic poly(dimethylamino ethyl methacrylate)-block-poly(n-butyl methacrylate) micelles was compared in aqueous solutions at various pH values and ionic strengths. The complexation process was monitored by turbidimetric titration, as a function of the ratio (N/P) of amine groups in the micelle corona to the number of phosphates (or sulfonates) in the polyanion. The size, structure and stability of the resulting micelleplexes were studied by dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM). In the short chain regime, where the contour lengths of the polyanions are shorter than or comparable to the micelle corona thickness, micelleplexes with DNA oligomers show very similar behavior to complexes with short PSS chains, in terms of titration curves and structural evolution of the complexes as a function of charge ratio. However, in the long chain regime, where the contour length of the polyanion far exceeds the micelle radius, micelleplexes of linear DNA show titration curves shifted toward lower N/P ratios, reduced stability at N/P < 1, and a higher percentage of small complexes at N/P > 1 compared to complexes with long chain PSS. Furthermore, at 1 M ionic strength, the cationic micelles could still complex with long chain PSS, but not with DNA of the same total charge. These differences are attributed to the flexibility difference between the polyanion chains, and possible mechanisms are proposed. This work highlights the importance of chain flexibility in complexation of dissimilar polyelectrolyte pairs, a factor that could therefore help guide the future design of micelleplexes for various applications. PMID- 28665626 TI - Incidence of Campylobacter intestinal infections, active component, U.S. Armed Forces, 2007-2016. AB - During 2007-2016, there were 1,753 diagnosed cases of Campylobacter intestinal infection among active component service members. The overall rate for the period was 14.1 cases per 100,000 person-years (p-yrs), but the annual incidence rates steadily increased from 7.6 cases per 100,000 p-yrs in 2007 to 22.1 cases per 100,000 p-yrs in 2016. Overall rates were higher in females, those aged 45 years or older, members of the Air Force and Army, offi cers, and those in military healthcare occupations. Incidence rates were lowest among service members who were recruit trainees, younger than 20 years of age, non-Hispanic blacks, and Marines. For the entire 10-year surveillance period, more cases were diagnosed in the warmer months of the year. Only eight cases were diagnosed in deployment settings during the 10-year period. Discussion of the recognized risk factors for Campylobacter infections reviewed the hazards of undercooked meats (especially poultry), unpasteurized milk, and untreated surface water in the environment. The limitations of the study methodology were described. PMID- 28665627 TI - Incidence of nontyphoidal Salmonella intestinal infections, active component, U.S. Armed Forces, 2007-2016. AB - During 2007-2016, there were 1,536 incident cases of nontyphoidal Salmonella infection among active component service members, with an overall crude incidence rate of 12.4 cases per 100,000 person-years (p-yrs). The overall rate for the period was higher among female service members than males. Service members aged 50 years or older and those aged 25-29 years had the highest rates of nontyphoidal Salmonella infection. Compared to their respective counterparts, overall rates were highest among non-Hispanic white service members, members of the Air Force, junior officers, recruits, and service members in healthcare occupations. Annual incidence rates were relatively stable during the first 9 years of the surveillance period. Rates peaked in 2016 at 15.9 cases per 100,000 p-yrs. The monthly distribution of the cumulative number of cases during the period showed a pattern of seasonality with a summer peak and the largest number of infections in July. During 2008-2016, a total of 132 cases were diagnosed in deployment settings, with an overall crude incidence rate of 12.6 cases per 100,000 p-yrs. Standard measures for the prevention of salmonellosis are reviewed. PMID- 28665628 TI - Incidence of Shigella intestinal infections, active component, U.S. Armed Forces, 2007-2016. AB - During 2007-2016, there were 428 incident cases of Shigella infection among active component service members, with an overall crude incidence rate of 3.4 cases per 100,000 person-years (p-yrs). Compared to their respective counterparts, overall incidence rates were highest among females, non-Hispanic black service members, those aged 35-39 years, members of the Army, and those in military healthcare occupations. With the exception of 2015, the annual incidence rates of shigellosis from 2007 through 2016 were relatively stable. The annual incidence rate in 2015 was twice that of the rate in 2014 (6.4 cases per 100,000 p-yrs and 3.1 cases per 100,000 p-yrs, respectively). This peak was followed by a decrease to 3.4 cases per 100,000 p-yrs in 2016. There was no marked pattern of seasonality of Shigella infections during the 10-year surveillance period. During 2008-2016, a total of 23 cases of Shigella infection were diagnosed in deployment settings. Risk factors for Shigella infection and standard measures for the prevention of shigellosis are reviewed. PMID- 28665629 TI - Using records of diagnoses from healthcare encounters and laboratory test results to estimate the incidence of norovirus infections, active component, U.S. Armed Forces, 2007-2016: limitations to this approach. AB - During the 10-year surveillance period, there were 709 incident cases of norovirus (NoV) infection identified among active component service members, with an overall crude incidence rate of 5.7 cases per 100,000 person-years (p-yrs). The overall incidence rate of NoV infection was slightly higher among female service members than males. Compared to their respective counterparts, service members aged 24 years or younger, members of the Army, junior enlisted, and recruits had the highest rates of NoV infection. Overall rates were similar across all race/ethnicity groups. Service members in "other" occupations had the highest overall incidence rate, compared to service members in other occupational groups. Annual incidence rates of NoV infection ranged from a low of 2.5 cases per 100,000 p-years in 2008 to 11.2 cases per 100,000 p-yrs in 2010. The monthly distribution of the cumulative number of incident cases of NoV infection during the surveillance period showed a pattern of seasonality with higher numbers of diagnosed cases from November through March. Comparing the results of this analysis to modeled estimates of the underreported incidence of NoV infections demonstrated the limited utility of using only medical encounter diagnoses, reportable events, and laboratory data to report on NoV incidence. The disparity between such estimates highlights the importance of developing and using other methodologies to derive estimates of norovirus incidence and burden in future analyses. PMID- 28665631 TI - Surveillance snapshot: Annual incidence rates and monthly distribution of cases of gastrointestinal infection, active component, U.S. Armed Forces, 2007-2016. PMID- 28665630 TI - Incidence of Escherichia coli intestinal infections, active component, U.S. Armed Forces, 2007-2016. AB - During 2007-2016, there were 290 incident cases of Escherichia coli infection among active component service members, with an overall crude incidence rate of 2.3 cases per 100,000 person-years (p-yrs). Subgroup-specific rates were higher among service members aged 50 years or older and those aged 25-29 years than those in other age groups. Compared to their respective counterparts, females, non-Hispanic white service members, members of the Air Force, and service members in healthcare occupations had the highest rates of E. coli infection. Crude overall incidence rates were highest among senior enlisted service members and junior officers, compared to those in other ranks/grades. Annual incidence rates of E. coli infection among active component service members peaked in 2011 (3.4 cases per 100,000 p-yrs) and in 2016 (4.7 cases per 100,000 p-yrs) but otherwise were relatively stable. The monthly distribution of the cumulative number of incident cases of infections during the 10-year period showed a modest pattern of seasonality. During 2008-2016, a total of 14 incident cases of E. coli infection were identified among active component service members during deployments. Standard measures for the prevention of intestinal E. coli infection are reviewed. PMID- 28665632 TI - Searching for Primordial Black Holes in the Radio and X-Ray Sky. AB - We model the accretion of gas onto a population of massive primordial black holes in the Milky Way and compare the predicted radio and x-ray emission with observational data. We show that, under conservative assumptions on the accretion process, the possibility that O(10)M_{?} primordial black holes can account for all of the dark matter in the Milky Way is excluded at 5sigma by a comparison with a Very Large Array radio catalog at 1.4 GHz and at ?40sigma by a comparison with a Chandra x-ray catalog (0.5-8 keV). We argue that this method can be used to identify such a population of primordial black holes with more sensitive future radio and x-ray surveys. PMID- 28665633 TI - Density-Dependent Quantum Hall States and Zeeman Splitting in Monolayer and Bilayer WSe_{2}. AB - We report a study of the quantum Hall states (QHS) of holes in mono- and bilayer WSe_{2}. The QHS sequence transitions between predominantly even and predominantly odd filling factors as the hole density is tuned in the range 1.6 12*10^{12} cm^{-2}. Measurements in tilted magnetic fields reveal an insensitivity of the QHS to the in-plane magnetic field, evincing that the hole spin is locked perpendicular to the WSe_{2} plane. Furthermore, the QHS sequence is insensitive to an applied electric field. These observations imply that the QHS sequence is controlled by the Zeeman-to-cyclotron energy ratio, which remains constant as a function of perpendicular magnetic field at a fixed carrier density, but changes as a function of density due to strong electron-electron interaction. PMID- 28665634 TI - Nuclear Magnetic Resonance Signature of the Spin-Nematic Phase in LiCuVO_{4} at High Magnetic Fields. AB - We report a ^{51}V nuclear magnetic resonance investigation of the frustrated spin-1/2 chain compound LiCuVO_{4}, performed in pulsed magnetic fields and focused on high-field phases up to 56 T. For the crystal orientations H?c and H?b, we find a narrow field region just below the magnetic saturation where the local magnetization remains uniform and homogeneous, while its value is field dependent. This behavior is the first microscopic signature of the spin-nematic state, breaking spin-rotation symmetry without generating any transverse dipolar order, and is consistent with theoretical predictions for the LiCuVO_{4} compound. PMID- 28665636 TI - X-ray Phase-Contrast Radiography and Tomography with a Multiaperture Analyzer. AB - We present a multiaperture analyzer setup for performing x-ray phase contrast imaging in planar and three-dimensional modalities. The method is based on strongly structuring the x-ray beam with an amplitude modulator, before it reaches the sample, and on a multiaperture analyzing element before detection. A multislice representation of the sample is used to establish a quantitative relation between projection images and the corresponding three-dimensional distributions, leading to successful tomographic reconstruction. Sample absorption, phase, and scattering are retrieved from the measurement of five intensity projections. The method is tested on custom-built phantoms with synchrotron radiation: sample absorption and phase can be reliably retrieved also in combination with strong scatterers, simultaneously attaining high sensitivity and dynamic range. PMID- 28665637 TI - Shell Evolution towards ^{78}Ni: Low-Lying States in ^{77}Cu. AB - The level structure of the neutron-rich ^{77}Cu nucleus is investigated through beta-delayed gamma-ray spectroscopy at the Radioactive Isotope Beam Factory of the RIKEN Nishina Center. Ions of ^{77}Ni are produced by in-flight fission, separated and identified in the BigRIPS fragment separator, and implanted in the WAS3ABi silicon detector array, surrounded by Ge cluster detectors of the EURICA array. A large number of excited states in ^{77}Cu are identified for the first time by correlating gamma rays with the beta decay of ^{77}Ni, and a level scheme is constructed by utilizing their coincidence relationships. The good agreement between large-scale Monte Carlo shell model calculations and experimental results allows for the evaluation of the single-particle structure near ^{78}Ni and suggests a single-particle nature for both the 5/2_{1}^{-} and 3/2_{1}^{-} states in ^{77}Cu, leading to doubly magic ^{78}Ni. PMID- 28665638 TI - Nonlinear Electron-Phonon Coupling in Doped Manganites. AB - We employ time-resolved resonant x-ray diffraction to study the melting of charge order and the associated insulator-to-metal transition in the doped manganite Pr_{0.5}Ca_{0.5}MnO_{3} after resonant excitation of a high-frequency infrared active lattice mode. We find that the charge order reduces promptly and highly nonlinearly as function of excitation fluence. Density-functional theory calculations suggest that direct anharmonic coupling between the excited lattice mode and the electronic structure drives these dynamics, highlighting a new avenue of nonlinear phonon control. PMID- 28665635 TI - Shape Evolution in Neutron-Rich Krypton Isotopes Beyond N=60: First Spectroscopy of ^{98,100}Kr. AB - We report on the first gamma-ray spectroscopy of low-lying states in neutron-rich ^{98,100}Kr isotopes obtained from ^{99,101}Rb(p,2p) reactions at ~220 MeV/nucleon. A reduction of the 2_{1}^{+} state energies beyond N=60 demonstrates a significant increase of deformation, shifted in neutron number compared to the sharper transition observed in strontium and zirconium isotopes. State-of-the-art beyond-mean-field calculations using the Gogny D1S interaction predict level energies in good agreement with experimental results. The identification of a low lying (0_{2}^{+}, 2_{2}^{+}) state in ^{98}Kr provides the first experimental evidence of a competing configuration at low energy in neutron-rich krypton isotopes consistent with the oblate-prolate shape coexistence picture suggested by theory. PMID- 28665639 TI - Intradomain Textures in Block Copolymers: Multizone Alignment and Biaxiality. AB - Block copolymer (BCP) melt assembly has been studied for decades, focusing largely on self-organized spatial patterns of periodically ordered segment density. Here, we demonstrate that underlying the well-known composition profiles (i.e., ordered lamella, cylinders, spheres, and networks) are generic and heterogeneous patterns of segment orientation that couple strongly to morphology, even in the absence of specific factors that promote intra or interchain segment alignment. We employ both self-consistent field theory and coarse-grained simulation methods to measure polar and nematic order parameters of segments in a freely jointed chain model of diblock melts. We show that BCP morphologies have a multizone texture, with segments predominantly aligned normal and parallel to interdomain interfaces in the respective brush and interfacial regions of the microdomain. Further, morphologies with anisotropically curved interfaces (i.e., cylinders and networks) exhibit biaxial order that is aligned to the principal curvature axes of the interface. PMID- 28665640 TI - Quantum Synchronization Blockade: Energy Quantization Hinders Synchronization of Identical Oscillators. AB - Classically, the tendency towards spontaneous synchronization is strongest if the natural frequencies of the self-oscillators are as close as possible. We show that this wisdom fails in the deep quantum regime, where the uncertainty of amplitude narrows down to the level of single quanta. Under these circumstances identical self-oscillators cannot synchronize and detuning their frequencies can actually help synchronization. The effect can be understood in a simple picture: Interaction requires an exchange of energy. In the quantum regime, the possible quanta of energy are discrete. If the extractable energy of one oscillator does not exactly match the amount the second oscillator may absorb, interaction, and thereby synchronization, is blocked. We demonstrate this effect, which we coin quantum synchronization blockade, in the minimal example of two Kerr-type self oscillators and predict consequences for small oscillator networks, where synchronization between blocked oscillators can be mediated via a detuned oscillator. We also propose concrete implementations with superconducting circuits and trapped ions. This paves the way for investigations of new quantum synchronization phenomena in oscillator networks both theoretically and experimentally. PMID- 28665641 TI - Nonlinear Surface Lattice Resonance in Plasmonic Nanoparticle Arrays. AB - We study experimentally second-harmonic generation from arrays of split-ring resonators at oblique incidence and find conditions of more than 30-fold enhancement of the emitted second harmonic with respect to normal incidence. We show that these conditions agree well with a nonlinear Rayleigh-Wood anomaly relation and the existence of a surface lattice resonance at the second harmonic. The existence of a nonlinear surface lattice resonance is theoretically confirmed by extending the coupled dipole approximation to the nonlinear case. We further show that the localized surface plasmon modes that collectively contribute to the surface lattice resonance are inherently dark modes that become highly bright due to the collective interaction. PMID- 28665643 TI - Scaling of the Quantum Anomalous Hall Effect as an Indicator of Axion Electrodynamics. AB - We report on the scaling behavior of V-doped (Bi,Sb)_{2}Te_{3} samples in the quantum anomalous Hall regime for samples of various thickness. While previous quantum anomalous Hall measurements showed the same scaling as expected from a two-dimensional integer quantum Hall state, we observe a dimensional crossover to three spatial dimensions as a function of layer thickness. In the limit of a sufficiently thick layer, we find scaling behavior matching the flow diagram of two parallel conducting topological surface states of a three-dimensional topological insulator each featuring a fractional shift of 1/2e^{2}/h in the flow diagram Hall conductivity, while we recover the expected integer quantum Hall behavior for thinner layers. This constitutes the observation of a distinct type of quantum anomalous Hall effect, resulting from 1/2e^{2}/h Hall conductance quantization of three-dimensional topological insulator surface states, in an experiment which does not require decomposition of the signal to separate the contribution of two surfaces. This provides a possible experimental link between quantum Hall physics and axion electrodynamics. PMID- 28665645 TI - Microscopic Perspective on Photovoltaic Reciprocity in Ultrathin Solar Cells. AB - The photovoltaic reciprocity theory relates the electroluminescence spectrum of a solar cell under applied bias to the external photovoltaic quantum efficiency of the device as measured at short circuit conditions. Its derivation is based on detailed balance relations between local absorption and emission rates in optically isotropic media with nondegenerate quasiequilibrium carrier distributions. In many cases, the dependence of density and spatial variation of electronic and optical device states on the point of operation is modest and the reciprocity relation holds. In nanostructure-based photovoltaic devices exploiting confined modes, however, the underlying assumptions are no longer justifiable. In the case of ultrathin absorber solar cells, the modification of the electronic structure with applied bias is significant due to the large variation of the built-in field. Straightforward use of the external quantum efficiency as measured at short circuit conditions in the photovoltaic reciprocity theory thus fails to reproduce the electroluminescence spectrum at large forward bias voltage. This failure is demonstrated here by numerical simulation of both spectral quantities at normal incidence and emission for an ultrathin GaAs p-i-n solar cell using an advanced quantum kinetic formalism based on nonequilibrium Green's functions of coupled photons and charge carriers. While coinciding with the semiclassical relations under the conditions of their validity, the theory provides a consistent microscopic relationship between absorption, emission, and charge carrier transport in photovoltaic devices at arbitrary operating conditions and for any shape of optical and electronic density of states. PMID- 28665644 TI - Kondo Insulator to Semimetal Transformation Tuned by Spin-Orbit Coupling. AB - Recent theoretical studies of topologically nontrivial electronic states in Kondo insulators have pointed to the importance of spin-orbit coupling (SOC) for stabilizing these states. However, systematic experimental studies that tune the SOC parameter lambda_{SOC} in Kondo insulators remain elusive. The main reason is that variations of (chemical) pressure or doping strongly influence the Kondo coupling J_{K} and the chemical potential MU-both essential parameters determining the ground state of the material-and thus possible lambda_{SOC} tuning effects have remained unnoticed. Here, we present the successful growth of the substitution series Ce_{3}Bi_{4}(Pt_{1-x}Pd_{x})_{3} (0<=x<=1) of the archetypal (noncentrosymmetric) Kondo insulator Ce_{3}Bi_{4}Pt_{3}. The Pt-Pd substitution is isostructural, isoelectronic, and isosize, and it therefore is likely to leave J_{K} and MU essentially unchanged. By contrast, the large mass difference between the 5d element Pt and the 4d element Pd leads to a large difference in lambda_{SOC}, which thus is the dominating tuning parameter in the series. Surprisingly, with increasing x (decreasing lambda_{SOC}), we observe a Kondo insulator to semimetal transition, demonstrating an unprecedented drastic influence of the SOC. The fully substituted end compound Ce_{3}Bi_{4}Pd_{3} shows thermodynamic signatures of a recently predicted Weyl-Kondo semimetal. PMID- 28665647 TI - Multiple-Quantum Transitions and Charge-Induced Decoherence of Donor Nuclear Spins in Silicon. AB - We study single- and multiquantum transitions of the nuclear spins of an ensemble of ionized arsenic donors in silicon and find quadrupolar effects on the coherence times, which we link to fluctuating electrical field gradients present after the application of light and bias voltage pulses. To determine the coherence times of superpositions of all orders in the 4-dimensional Hilbert space, we use a phase-cycling technique and find that, when electrical effects were allowed to decay, these times scale as expected for a fieldlike decoherence mechanism such as the interaction with surrounding ^{29}Si nuclear spins. PMID- 28665648 TI - Quantum Zeno Effects from Measurement Controlled Qubit-Bath Interactions. AB - The Zeno and anti-Zeno effects are features of measurement-driven quantum evolution where frequent measurement inhibits or accelerates the decay of a quantum state. Either type of evolution can emerge depending on the system environment interaction and measurement method. In this experiment, we use a superconducting qubit to map out both types of Zeno effect in the presence of structured noise baths and variable measurement rates. We observe both the suppression and acceleration of qubit decay as repeated measurements are used to modulate the qubit spectrum causing the qubit to sample different portions of the bath. We compare the Zeno effects arising from dispersive energy measurements and purely dephasing "quasimeasurements," showing energy measurements are not necessary to accelerate or suppress the decay process. PMID- 28665642 TI - Beam-Target Helicity Asymmetry for gamma[over ->]n[over ->]->pi^{-}p in the N^{*} Resonance Region. AB - We report the first beam-target double-polarization asymmetries in the gamma+n(p) >pi^{-}+p(p) reaction spanning the nucleon resonance region from invariant mass W=1500 to 2300 MeV. Circularly polarized photons and longitudinally polarized deuterons in solid hydrogen deuteride (HD) have been used with the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The exclusive final state has been extracted using three very different analyses that show excellent agreement, and these have been used to deduce the E polarization observable for an effective neutron target. These results have been incorporated into new partial wave analyses and have led to significant revisions for several gammanN^{*} resonance photocouplings. PMID- 28665649 TI - Ultrafast Formation of a Charge Density Wave State in 1T-TaS_{2}: Observation at Nanometer Scales Using Time-Resolved X-Ray Diffraction. AB - Femtosecond time-resolved x-ray diffraction is used to study a photoinduced phase transition between two charge density wave (CDW) states in 1T-TaS_{2}, namely the nearly commensurate (NC) and the incommensurate (I) CDW states. Structural modulations associated with the NC-CDW order are found to disappear within 400 fs. The photoinduced I-CDW phase then develops through a nucleation and growth process which ends 100 ps after laser excitation. We demonstrate that the newly formed I-CDW phase is fragmented into several nanometric domains that are growing through a coarsening process. The coarsening dynamics is found to follow the universal Lifshitz-Allen-Cahn growth law, which describes the ordering kinetics in systems exhibiting a nonconservative order parameter. PMID- 28665650 TI - Logarithmic Exchange Kinetics in Monodisperse Copolymeric Micelles. AB - Experimental measurements of the relaxation kinetics of copolymeric surfactant exchange for micellar systems unexpectedly show a peculiar logarithmic decay. Several authors use polydispersity as an explanation for this behavior. However, in coarse-grained simulations that preserve microscopic details of the surfactants, we find evidence of the same logarithmic behavior. Since we use a strictly monodisperse distribution of chain lengths such a relaxation process cannot be attributed to polydispersity, but has to be caused by an inherent physical process characteristic of this type of system. This is supported by the fact that the decay is specifically logarithmic and not a power law with an exponent inherited from the particular polydispersity distribution of the sample. We suggest that the degeneracy of the energy states of the hydrophobic block in the core, which is broken on leaving the micelle, can qualitatively explain the broad distribution of energy barriers, which gives rise to the observed nonexponential relaxation. PMID- 28665651 TI - Infrared Topological Plasmons in Graphene. AB - We propose a two-dimensional plasmonic platform-periodically patterned monolayer graphene-which hosts topological one-way edge states operable up to infrared frequencies. We classify the band topology of this plasmonic system under time reversal-symmetry breaking induced by a static magnetic field. At finite doping, the system supports topologically nontrivial band gaps with mid-gap frequencies up to tens of terahertz. By the bulk-edge correspondence, these band gaps host topologically protected one-way edge plasmons, which are immune to backscattering from structural defects and subject only to intrinsic material and radiation loss. Our findings reveal a promising approach to engineer topologically robust chiral plasmonic devices and demonstrate a realistic example of high-frequency topological edge states. PMID- 28665652 TI - Observation of Topological Bloch-State Defects and Their Merging Transition. AB - Topological defects in Bloch bands, such as Dirac points in graphene, and their resulting Berry phases play an important role for the electronic dynamics in solid state crystals. Such defects can arise in systems with a two-atomic basis due to the momentum-dependent coupling of the two sublattice states, which gives rise to a pseudospin texture. The topological defects appear as vortices in the azimuthal phase of this pseudospin texture. Here, we demonstrate a complete measurement of the azimuthal phase in a hexagonal optical lattice employing a versatile method based on time-of-flight imaging after off-resonant lattice modulation. Furthermore, we map out the merging transition of the two Dirac points induced by beam imbalance. Our work paves the way to accessing geometric properties in optical lattices also with spin-orbit coupling and interactions. PMID- 28665653 TI - Probing a Dissipative Phase Transition via Dynamical Optical Hysteresis. AB - We experimentally explore the dynamical optical hysteresis of a semiconductor microcavity as a function of the sweep time. The hysteresis area exhibits a double power law decay due to the influence of fluctuations, which trigger switching between metastable states. Upon increasing the average photon number and approaching the thermodynamic limit, the double power law evolves into a single power law. This algebraic behavior characterizes a dissipative phase transition. Our findings are in good agreement with theoretical predictions for a single mode resonator influenced by quantum fluctuations, and the present experimental approach is promising for exploring critical phenomena in photonic lattices. PMID- 28665654 TI - Filling-Fraction Fluctuation Leading to Glasslike Ultralow Thermal Conductivity in Caged Skutterudites. AB - It is generally believed that filling atoms randomly and uniformly distribute in caged crystals, such as skutterudite compounds. Here, we report first-principles and experimental discovery of a multiscale filling-fraction fluctuation in the RFe_{4}Sb_{12} system. La_{0.8}Ti_{0.1}Ga_{0.1}Fe_{4}Sb_{12} spontaneously separates into La-rich and La-poor skutterudite phases, leading to multiscale strain field fluctuations. As a result, glasslike ultralow lattice thermal conductivity approaching the theoretical minimum is achieved, mainly due to strain field scattering of high-energy phonons. These findings reveal that an uneven distribution of filling atoms is efficient to further reduce the lattice thermal conductivity of caged crystals. PMID- 28665655 TI - Real-Time Observation of Internal Motion within Ultrafast Dissipative Optical Soliton Molecules. AB - Real-time access to the internal ultrafast dynamics of complex dissipative optical systems opens new explorations of pulse-pulse interactions and dynamic patterns. We present the first direct experimental evidence of the internal motion of a dissipative optical soliton molecule generated in a passively mode locked erbium-doped fiber laser. We map the internal motion of a soliton pair molecule by using a dispersive Fourier-transform imaging technique, revealing different categories of internal pulsations, including vibrationlike and phase drifting dynamics. Our experiments agree well with numerical predictions and bring insights to the analogy between self-organized states of lights and states of the matter. PMID- 28665656 TI - Probing Phase Coupling Between Two Spin-Torque Nano-Oscillators with an External Source. AB - Phase coupling between auto-oscillators is central for achieving coherent responses such as synchronization. Here we present an experimental approach to probe it in the case of two dipolarly coupled spin-torque vortex nano-oscillators using an external microwave field. By phase locking one oscillator to the external source, we observe frequency pulling on the second oscillator. From coupled phase equations we show analytically that this frequency pulling results from concerted actions of oscillator-oscillator and source-oscillator couplings. The analysis allows us to determine the strength and phase shift of coupling between two oscillators, yielding important information for the implementation of large interacting oscillator networks. PMID- 28665657 TI - Time Strengthening of Crystal Nanocontacts. AB - We demonstrate how an exponentially saturating increase of the contact area between a nanoasperity and a crystal surface, occurring on time scales governed by the Arrhenius equation, is consistent with measurements of the static friction and lateral contact stiffness on a model alkali-halide surface at different temperatures in ultrahigh vacuum. The "contact ageing" effect is attributed to atomic attrition and is eventually broken by thermally activated slip of the nanoasperity on the surface. The combination of the two effects also leads to regions of strengthening and weakening in the velocity dependence of the friction, which are well-reproduced by an extended version of the Prandtl Tomlinson model. PMID- 28665658 TI - Ultrafast Magnetization of a Dense Molecular Gas with an Optical Centrifuge. AB - Strong laser-induced magnetization of oxygen gas at room temperature and atmospheric pressure is achieved experimentally on the subnanosecond time scale. The method is based on controlling the electronic spin of paramagnetic molecules by means of manipulating their rotation with an optical centrifuge. Spin rotational coupling results in a high degree of spin polarization on the order of one Bohr magneton per centrifuged molecule. Owing to the nonresonant interaction with the laser pulses, the demonstrated technique is applicable to a broad class of paramagnetic rotors. Executed in a high-density gas, it may offer an efficient way of generating macroscopic magnetic fields remotely (as shown in this work) and producing a large amount of spin-polarized electrons. PMID- 28665659 TI - Nucleon Structure Functions from Operator Product Expansion on the Lattice. AB - Deep-inelastic scattering, in the laboratory and on the lattice, is most instructive for understanding how the nucleon is built from quarks and gluons. The long-term goal is to compute the associated structure functions from first principles. So far this has been limited to model calculations. In this Letter we propose a new method to compute the structure functions directly from the virtual, all-encompassing Compton amplitude, utilizing the operator product expansion. This overcomes issues of renormalization and operator mixing, which so far have hindered lattice calculations of power corrections and higher moments. PMID- 28665660 TI - Solving the Quantum Many-Body Problem via Correlations Measured with a Momentum Microscope. AB - In quantum many-body theory, all physical observables are described in terms of correlation functions between particle creation or annihilation operators. Measurement of such correlation functions can therefore be regarded as an operational solution to the quantum many-body problem. Here, we demonstrate this paradigm by measuring multiparticle momentum correlations up to third order between ultracold helium atoms in an s-wave scattering halo of colliding Bose Einstein condensates, using a quantum many-body momentum microscope. Our measurements allow us to extract a key building block of all higher-order correlations in this system-the pairing field amplitude. In addition, we demonstrate a record violation of the classical Cauchy-Schwarz inequality for correlated atom pairs and triples. Measuring multiparticle momentum correlations could provide new insights into effects such as unconventional superconductivity and many-body localization. PMID- 28665661 TI - Adsorption-Mediated Mass Streaming in a Standing Acoustic Wave. AB - Oscillating flows can generate nonzero, time-averaged fluxes despite the velocity averaging zero over an oscillation cycle. Here, we report such a flux, a nonlinear resultant of the interaction between oscillating velocity and concentration fields. Specifically, we study a gas mixture sustaining a standing acoustic wave, where an adsorbent coats the solid boundary in contact with the gas mixture. It is found that the sound wave produces a significant, time averaged preferential flux of a "reactive" component that undergoes a reversible sorption process. This effect is measured experimentally for an air-water vapor mixture. An approximate model is shown to be in good agreement with the experimental observations, and further reveals the interplay between the sound wave characteristics and the properties of the gas-solid sorbate-sorbent pair. The preferential flux generated by this mechanism may have potential in separation processes. PMID- 28665662 TI - Adiabatic Invariant Approach to Transverse Instability: Landau Dynamics of Soliton Filaments. AB - Consider a lower-dimensional solitonic structure embedded in a higher-dimensional space, e.g., a 1D dark soliton embedded in 2D space, a ring dark soliton in 2D space, a spherical shell soliton in 3D space, etc. By extending the Landau dynamics approach [Phys. Rev. Lett. 93, 240403 (2004)PRLTAO0031 900710.1103/PhysRevLett.93.240403], we show that it is possible to capture the transverse dynamical modes (the "Kelvin modes") of the undulation of this "soliton filament" within the higher-dimensional space. These are the transverse stability or instability modes and are the ones potentially responsible for the breakup of the soliton into structures such as vortices, vortex rings, etc. We present the theory and case examples in 2D and 3D, corroborating the results by numerical stability and dynamical computations. PMID- 28665663 TI - Skyrmion Knots in Frustrated Magnets. AB - A magnetic Skyrmion is a stable two-dimensional nanoparticle describing a localized winding of the magnetization in certain magnetic materials. Skyrmions are the subject of intense experimental and theoretical investigation and have potential technological spintronic applications. Here we show that numerical computations of frustrated magnets predict that Skyrmions can be tied into knots to form new stable three-dimensional nanoparticles. These stable equilibria of twisted loops of Skyrmion strings have an integer-valued topological charge, known as the Hopf charge, that counts the number of particles. Rings are formed for low values of this charge, but for higher values it is energetically favorable to form links and then knots. This computational study provides a novel impetus for future experimental work on these nanoknots and an exploration of the potential technological applications of three-dimensional nanoparticles encoding knotted magnetization. PMID- 28665664 TI - Conformational Properties of a Back-Folding Wormlike Chain Confined in a Cylindrical Tube. AB - When a semiflexible chain is confined in a narrow cylindrical tube, the formation of a polymer hairpin is a geometrical conformation that accompanies an exponentially large local free energy and, hence, is a relatively rare event. Numerical solutions of the hairpin distribution functions for persistence-length to-tube-radius ratios over a wide range are obtained in high precision, by using the Green's function approach for the wormlike-chain model. The crossover region between the narrow and moderately narrow tubes is critically investigated in terms of the hairpin free energy, global persistence length, mean hairpin-tip distance from the tube axis, and hairpin-plane orientational properties. Accurate representations of the solutions by simple interpolation formulae are suggested. PMID- 28665665 TI - Time-Local Equation for the Exact Optimized Effective Potential in Time-Dependent Density Functional Theory. AB - A long-standing challenge in the time-dependent density functional theory is to efficiently solve the exact time-dependent optimized effective potential (TDOEP) integral equation derived from orbital-dependent functionals, especially for the study of nonadiabatic dynamics in time-dependent external fields. In this Letter, we formulate a completely equivalent time-local TDOEP equation that admits a unique real-time solution in terms of time-dependent Kohn-Sham and effective memory orbitals. The time-local formulation is numerically implemented, with the incorporation of exponential memory loss to address the unaccounted for correlation component in the exact-exchange-only functional, to enable the study of the many-electron dynamics of a one-dimensional hydrogen chain. It is shown that the long time behavior of the electric dipole converges correctly and the zero-force theorem is fulfilled in the current implementation. PMID- 28665666 TI - Long-Range Critical Exponents near the Short-Range Crossover. AB - The d-dimensional long-range Ising model, defined by spin-spin interactions decaying with the distance as the power 1/r^{d+s}, admits a second-order phase transition with continuously varying critical exponents. At s=s_{*}, the phase transition crosses over to the usual short-range universality class. The standard field-theoretic description of this family of models is strongly coupled at the crossover. We find a new description, which is instead weakly coupled near the crossover, and use it to compute critical exponents. The existence of two complementary UV descriptions of the same long-range fixed point provides a novel example of infrared duality. PMID- 28665667 TI - Dimensional, Geometrical, and Physical Constraints in Skull Growth. AB - After birth, the skull grows and remodels in close synchrony with the brain to allow for an increase in intracranial volume. Increase in skull area is provided primarily by bone accretion at the sutures. Additional remodeling, to allow for a change in curvatures, occurs by resorption on the inner surface of the bone plates and accretion on their outer surfaces. When a suture fuses too early, normal skull growth is disrupted, leading to a deformed final skull shape. The leading theory assumes that the main stimulus for skull growth is provided by mechanical stresses. Based on these ideas, we first discuss the dimensional, geometrical, and kinematic synchrony between brain, skull, and suture growth. Second, we present two mechanical models for skull growth that account for growth at the sutures and explain the various observed dysmorphologies. These models demonstrate the particular role of physical and geometrical constraints taking place in skull growth. PMID- 28665668 TI - Light Meets Water in Nonlocal Media: Surface Tension Analogue in Optics. AB - Shallow water wave phenomena find their analogue in optics through a nonlocal nonlinear Schrodinger (NLS) model in 2+1 dimensions. We identify an analogue of surface tension in optics, namely, a single parameter depending on the degree of nonlocality, which changes the sign of dispersion, much like surface tension does in the shallow water wave problem. Using multiscale expansions, we reduce the NLS model to a Kadomtsev-Petviashvili (KP) equation, which is of the KPII (KPI) type, for strong (weak) nonlocality. We demonstrate the emergence of robust optical antidark solitons forming Y-, X-, and H-shaped wave patterns, which are approximated by colliding KPII line solitons, similar to those observed in shallow waters. PMID- 28665669 TI - Nonequilibrium GW+EDMFT: Antiscreening and Inverted Populations from Nonlocal Correlations. AB - We study the dynamics of screening in photodoped Mott insulators with long-ranged interactions using a nonequilibrium implementation of the GW plus extended dynamical mean-field theory formalism. Our study demonstrates that the complex interplay of the injected carriers with bosonic degrees of freedom (charge fluctuations) can result in long-lived transient states with properties that are distinctly different from those of thermal equilibrium states. Systems with strong nonlocal interactions are found to exhibit a self-sustained population inversion of the doublons and holes. This population inversion leads to low energy antiscreening which can be detected in time-resolved electron-energy-loss spectra. PMID- 28665670 TI - Novel Superhard sp^{3} Carbon Allotrope from Cold-Compressed C_{70} Peapods. AB - Design and synthesis of new carbon allotropes have always been important topics in condensed matter physics and materials science. Here we report a new carbon allotrope, formed from cold-compressed C_{70} peapods, which most likely can be identified with a fully sp^{3}-bonded monoclinic structure, here named V carbon, predicted from our simulation. The simulated x-ray diffraction pattern, near K edge spectroscopy, and phonon spectrum agree well with our experimental data. Theoretical calculations reveal that V carbon has a Vickers hardness of 90 GPa and a bulk modulus ~400 GPa, which well explains the "ring crack" left on the diamond anvils by the transformed phase in our experiments. The V carbon is thermodynamically stable over a wide pressure range up to 100 GPa, suggesting that once V carbon forms, it is stable and can be recovered to ambient conditions. A transition pathway from peapod to V carbon has also been suggested. These findings suggest a new strategy for creating new sp^{3}-hybridized carbon structures by using fullerene@nanotubes carbon precursor containing odd-numbered rings in the structures. PMID- 28665671 TI - Role of Magnetic Reconnection in Magnetohydrodynamic Turbulence. AB - The current understanding of magnetohydrodynamic (MHD) turbulence envisions turbulent eddies which are anisotropic in all three directions. In the plane perpendicular to the local mean magnetic field, this implies that such eddies become current-sheetlike structures at small scales. We analyze the role of magnetic reconnection in these structures and conclude that reconnection becomes important at a scale lambda~LS_{L}^{-4/7}, where S_{L} is the outer-scale (L) Lundquist number and lambda is the smallest of the field-perpendicular eddy dimensions. This scale is larger than the scale set by the resistive diffusion of eddies, therefore implying a fundamentally different route to energy dissipation than that predicted by the Kolmogorov-like phenomenology. In particular, our analysis predicts the existence of the subinertial, reconnection interval of MHD turbulence, with the estimated scaling of the Fourier energy spectrum E(k_{?})?k_{?}^{-5/2}, where k_{?} is the wave number perpendicular to the local mean magnetic field. The same calculation is also performed for high (perpendicular) magnetic Prandtl number plasmas (Pm), where the reconnection scale is found to be lambda/L~S_{L}^{-4/7}Pm^{-2/7}. PMID- 28665672 TI - Ion Motion Induced Emittance Growth of Matched Electron Beams in Plasma Wakefields. AB - Plasma-based acceleration is being considered as the basis for building a future linear collider. Nonlinear plasma wakefields have ideal properties for accelerating and focusing electron beams. Preservation of the emittance of nano Coulomb beams with nanometer scale matched spot sizes in these wakefields remains a critical issue due to ion motion caused by their large space charge forces. We use fully resolved quasistatic particle-in-cell simulations of electron beams in hydrogen and lithium plasmas, including when the accelerated beam has different emittances in the two transverse planes. The projected emittance initially grows and rapidly saturates with a maximum emittance growth of less than 80% in hydrogen and 20% in lithium. The use of overfocused beams is found to dramatically reduce the emittance growth. The underlying physics that leads to the lower than expected emittance growth is elucidated. PMID- 28665673 TI - How to create successful alternative payment models in oncology. PMID- 28665674 TI - An oncologist's perspective: preparation for new payment models in cancer care. PMID- 28665675 TI - CMS needs to address Medicare underfunding in 2017 hospital inpatient rule for bone marrow transplantation. PMID- 28665676 TI - The oncogenic hepatitis C virus and direct-acting antivirals: economic implications for hepatocellular carcinoma in Medicaid beneficiaries with cirrhosis. PMID- 28665677 TI - Value-based payment models in oncology: will they help or hinder patient access to new treatments? PMID- 28665678 TI - Why oncologists need technology to succeed in alternative payment models. PMID- 28665679 TI - Making sense of advanced payment models. PMID- 28665680 TI - Detecting Darwinism from Molecules in the Enceladus Plumes, Jupiter's Moons, and Other Planetary Water Lagoons. AB - To the astrobiologist, Enceladus offers easy access to a potential subsurface biosphere via the intermediacy of a plume of water emerging directly into space. A direct question follows: If we were to collect a sample of this plume, what in that sample, through its presence or its absence, would suggest the presence and/or absence of life in this exotic locale? This question is, of course, relevant for life detection in any aqueous lagoon that we might be able to sample. This manuscript reviews physical chemical constraints that must be met by a genetic polymer for it to support Darwinism, a process believed to be required for a chemical system to generate properties that we value in biology. We propose that the most important of these is a repeating backbone charge; a Darwinian genetic biopolymer must be a "polyelectrolyte." Relevant to mission design, such biopolymers are especially easy to recover and concentrate from aqueous mixtures for detection, simply by washing the aqueous mixtures across a polycharged support. Several device architectures are described to ensure that, once captured, the biopolymer meets two other requirements for Darwinism, homochirality and a small building block "alphabet." This approach is compared and contrasted with alternative biomolecule detection approaches that seek homochirality and constrained alphabets in non-encoded biopolymers. This discussion is set within a model for the history of the terran biosphere, identifying points in that natural history where these alternative approaches would have failed to detect terran life. Key Words: Enceladus-Life detection Europa-Icy moon-Biosignatures-Polyelectrolyte theory of the gene. Astrobiology 17, 840-851. PMID- 28665681 TI - Benefit of the Shorter Multidrug-Resistant Tuberculosis Treatment Regimen in California and Modified Eligibility Criteria. PMID- 28665682 TI - The role of neratinib in HER2-driven breast cancer. AB - Up to 25% of patients with early-stage HER2+ breast cancer relapse despite adjuvant trastuzumab-based regimens and virtually all patients with metastatic disease eventually die from resistance to existing treatment options. In addition, recent studies indicate that activating HER2 mutations without gene amplification could drive tumor growth in a subset of HER2-ve breast cancer that is not currently eligible for HER2-targeted agents. Neratinib is an irreversible HER kinase inhibitor with activity as extended adjuvant therapy following standard trastuzumab-based adjuvant treatment in a Phase III trial. Phase II trials of neratinib demonstrate promising activity in combination with cytotoxic agents in trastuzumab resistant metastatic HER2+ breast cancer, and either as monotherapy or in combination with fulvestrant for HER2-mutated breast cancers. We anticipate a potential role for neratinib in the therapy of these patient populations. PMID- 28665683 TI - Multi-Phase Equilibrium and Solubilities of Aromatic Compounds and Inorganic Compounds in Sub- and Supercritical Water: A Review. AB - Supercritical water oxidation (SCWO), as a novel and efficient technology, has been applied to wastewater treatment processes. The use of phase equilibrium data to optimize process parameters can offer a theoretical guidance for designing SCWO processes and reducing the equipment and operating costs. In this work, high pressure phase equilibrium data for aromatic compounds+water systems and inorganic compounds+water systems are given. Moreover, thermodynamic models, equations of state (EOS) and empirical and semi-empirical approaches are summarized and evaluated. This paper also lists the existing problems of multi phase equilibria and solubility studies on aromatic compounds and inorganic compounds in sub- and supercritical water. PMID- 28665685 TI - Advances of electronic nose and its application in fresh foods: A review. AB - The science and technology aspects of electronic nose (E-nose) has been developed rapidly in last decade (2006-2016). This paper reviews of the publications that that cover the developments in science and technological aspects of electronic nose together with its application in fresh foods. The first part of this review covers the sensing and pattern recognition system (PR) of E-nose. The second part covers the application of E-nose in classification, flavor detection, and evaluation of spoilage in fresh foods area. With more new sensor materials to be found and more combination between E-nose and other analysis technologies, the usages of E-nose in fresh foods will have wider prospects. PMID- 28665684 TI - Maturation of the Infant Respiratory Microbiota, Environmental Drivers, and Health Consequences. A Prospective Cohort Study. AB - RATIONALE: Perinatal and postnatal influences are presumed important drivers of the early-life respiratory microbiota composition. We hypothesized that the respiratory microbiota composition and development in infancy is affecting microbiota stability and thereby resistance against respiratory tract infections (RTIs) over time. OBJECTIVES: To investigate common environmental drivers, including birth mode, feeding type, antibiotic exposure, and crowding conditions, in relation to respiratory tract microbiota maturation and stability, and consecutive risk of RTIs over the first year of life. METHODS: In a prospectively followed cohort of 112 infants, we characterized the nasopharyngeal microbiota longitudinally from birth on (11 consecutive sample moments and the maximum three RTI samples per subject; in total, n = 1,121 samples) by 16S-rRNA gene amplicon sequencing. MEASUREMENTS AND MAIN RESULTS: Using a microbiota-based machine learning algorithm, we found that children experiencing a higher number of RTIs in the first year of life already demonstrate an aberrant microbial developmental trajectory from the first month of life on as compared with the reference group (0-2 RTIs/yr). The altered microbiota maturation process coincided with decreased microbial community stability, prolonged reduction of Corynebacterium and Dolosigranulum, enrichment of Moraxella very early in life, followed by later enrichment of Neisseria and Prevotella spp. Independent drivers of these aberrant developmental trajectories of respiratory microbiota members were mode of delivery, infant feeding, crowding, and recent antibiotic use. CONCLUSIONS: Our results suggest that environmental drivers impact microbiota development and, consequently, resistance against development of RTIs. This supports the idea that microbiota form the mediator between early-life environmental risk factors for and susceptibility to RTIs over the first year of life. PMID- 28665686 TI - Cardiovascular Disease Does Not Predict Exacerbation Rate or Mortality in Chronic Obstructive Pulmonary Disease. PMID- 28665687 TI - Elevated Expression of ERCC6 Confers Resistance to 5-Fluorouracil and Is Associated with Poor Patient Survival in Colorectal Cancer. AB - Excision repair cross-complementation (ERCC) enzymes are key members of the nucleotide excision repair pathway. Dysregulation of ERCC family members has been shown to be involved in chemoresistance in several malignancies. However, the function of ERCC6 in regulating chemo response has not been evaluated in colorectal cancer (CRC). We stably knocked down ERCC6 expression using short hairpin RNA (shRNA) in HCT116 and DLD1 human colon cancer cell lines, followed by chemosensitivity assay. In vivo chemosensitizing effects of ERCC6 were examined in xenograft experiments. Downregulation of ERCC6 conferred sensitivity to 5 fluorouracil (5-FU) in HCT116 and DLD1 cells. Stable knockdown of ERCC6 significantly enhanced antitumor activity of 5-FU in HCT116 xenograft mouse model. ERCC6 was upregulated in CRC tissues compared to matched noncancerous adjacent tissues and was also upregulated in patients who were resistant to 5-FU treatment. In addition, high expression of ERCC6 was associated with poor overall survival in CRC patients with or without receiving 5-FU therapy. Elevated expression of ERCC6 contributes to chemoresistance in CRC cells. Low ERCC6 expression is associated with better chemo response and survival in CRC patients. Therefore, this protein represents a novel therapeutic target for improvement of chemotherapeutic efficacy and predictive biomarker for patient survival. PMID- 28665688 TI - Epistaxis as an Unexpected Side Effect of Aripiprazole and Risperidone Treatment in Two Children with Two Different Psychiatric Diagnosis. PMID- 28665689 TI - Recent advances in nanofabrication techniques for SERS substrates and their applications in food safety analysis. AB - The ability to analyze food safety and quality in a quick, sensitive, and reliable manner is of high importance in food industry. Surface-enhanced Raman scattering (SERS), which is popular for its significant enhancement, excellent sensitivity, and the fingerprinting ability to identify special molecules, has shown vast potential for rapid detection of chemical constitutes, chemical contaminants, and pathogens in food sample. For SERS, the enhancement of Raman signals is related to not only the SERS-active substrates, but also the interactions between sample and substrates. In the current review, colloidal and solid surface-based substrates are briefly described, fabrication techniques for SERS substrates are presented, and applications of SERS for food matrixes, correlation between substrates and food samples are also introduced. Finally, some outlook on further developments is presented. The current review is therefore intended to provide a comprehensive overview on the nanofabrication of SERS substrates, and the potential of applying SERS as an important food analysis platform. PMID- 28665691 TI - Dietary DHA, bioaccessibility, and neurobehavioral development in children. AB - Docosahexaenoic acid (DHA) is a key nutritional n-3 polyunsaturated fatty acid and needs to be supplied by the human diet. High levels of DHA intake appear to reduce the risk of depression, bipolar disorder, and mood disorders. On the basis of these connections between DHA and neurological health, this paper reviews what is currently known about DHA and children neurodevelopment as well as the benefits of DHA intake to prevention of autism and behavior disorders through a selective and representative revision of different papers ranging from pure observational studies to randomized controlled trials (RCTs). This review also highlights the issue of DHA bioaccessibility and its implications to the performance of studies. As main conclusions, it can be mentioned that high DHA intake may prevent autism disorder. However, more studies are required to strengthen the connection between autism and dietary DHA. Regarding behavioral disorders, the evidence is also contradictory, thereby raising the need of further studies. From all screened studies on autism, attention deficit/hyperactivity disorder, and other disorders, it can be concluded that study samples should be larger for greater statistical significance and RCTs should be more carefully designed. PMID- 28665690 TI - Reducing concussion symptoms among teenage youth: Evaluation of a mobile health app. AB - OBJECTIVE: To evaluate whether a mobile health application that employs elements of social game design could compliment medical care for unresolved concussion symptoms. DESIGN: Phase I and Phase II (open-label, non-randomized, ecological momentary assessment methodology). SETTING: Outpatient concussion clinic. PARTICIPANTS: Youth, aged 13-18 years, with concussion symptoms 3+ weeks after injury; Phase I: n = 20; Phase II: n = 19. INTERVENTIONS: Participants received standard of care for concussion. The experimental group also used a mobile health application as a gamified symptoms journal. OUTCOME MEASURES: Phase I: feasibility and satisfaction with intervention (7-point Likert scale, 1 high). Phase II: change in SCAT-3 concussion symptoms (primary), depression and optimism. RESULTS: Phase 1: A plurality of participants completed the intervention (14 of 20) with high use (110 +/- 18% play) and satisfaction (median +/- interquartile range (IQR) = 2.0+/- 0.0). Phase II: Groups were equivalent on baseline symptoms, intervention duration, gender distribution, days since injury and medication prescription. Symptoms and optimism improved more for the experimental than for the active control cohort (U = 18.5, p = 0.028, effect size r = 0.50 and U = 18.5, p = 0.028, effect size r = 0.51, respectively). CONCLUSIONS: Mobile apps incorporating social game mechanics and a heroic narrative may promote health management among teenagers with unresolved concussion symptoms. PMID- 28665692 TI - Excess Ventilation in Chronic Obstructive Pulmonary Disease-Heart Failure Overlap. Implications for Dyspnea and Exercise Intolerance. AB - RATIONALE: An increased ventilatory response to exertional metabolic demand (high [Formula: see text]e/[Formula: see text]co2 relationship) is a common finding in patients with coexistent chronic obstructive pulmonary disease and heart failure. OBJECTIVES: We aimed to determine the mechanisms underlying high [Formula: see text]e/[Formula: see text]co2 and its impact on operating lung volumes, dyspnea, and exercise tolerance in these patients. METHODS: Twenty-two ex-smokers with combined chronic obstructive pulmonary disease and heart failure with reduced left ventricular ejection fraction undertook, after careful treatment optimization, a progressive cycle exercise test with capillary (c) blood gas collection. MEASUREMENTS AND MAIN RESULTS: Regardless of the chosen metric (increased [Formula: see text]e-[Formula: see text]co2 slope, [Formula: see text]e/[Formula: see text]co2 nadir, or end-exercise [Formula: see text]e/[Formula: see text]co2), ventilatory inefficiency was closely related to PcCO2 (r values from -0.80 to -0.84; P < 0.001) but not dead space/tidal volume ratio. Ten patients consistently maintained exercise PcCO2 less than or equal to 35 mm Hg (hypocapnia). These patients had particularly poor ventilatory efficiency compared with patients without hypocapnia (P < 0.05). Despite the lack of between-group differences in spirometry, lung volumes, and left ventricular ejection fraction, patients with hypocapnia had lower resting PaCO2 and lung diffusing capacity (P < 0.01). Excessive ventilatory response in this group was associated with higher exertional PcO2. The group with hypocapnia, however, had worse mechanical inspiratory constraints and higher dyspnea scores for a given work rate leading to poorer exercise tolerance compared with their counterparts (P < 0.05). CONCLUSIONS: Heightened neural drive promoting a ventilatory response beyond that required to overcome an increased "wasted" ventilation led to hypocapnia and poor exercise ventilatory efficiency in chronic obstructive pulmonary disease-heart failure overlap. Excessive ventilation led to better arterial oxygenation but at the expense of earlier critical mechanical constraints and intolerable dyspnea. PMID- 28665693 TI - Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation. AB - Asthma is an airway epithelium disorder involving allergic lung inflammation. IL 1 receptor-associated kinase M (IRAK-M) is a negative regulator of Toll-like receptor (TLR) signaling on airway epithelial cells and macrophages, and it is known to limit the overproduction of cytokines during the inflammatory process. However, the direct role of IRAK-M in asthma pathogenesis is unclear. In the present study, we found a significant elevation of IRAK-M expression in mouse lungs after ovalbumin (OVA) exposure. Compared with wild-type mice, IRAK-M knockout (KO) mice responded to OVA challenge with significantly worse infiltration of airway inflammatory cells, greater airway responsiveness, higher proinflammatory cytokine levels in lung homogenates, and more prominent T-helper cell type 2 (Th2) and Th17 deviation. OVA exposure also induced higher activities of dendritic cells (DCs) and macrophages from IRAK-M KO mouse lungs. Furthermore, adoptive transfer of either IRAK-M KO bone-marrow-derived DCs or macrophages into wild-type mice aggravated OVA-induced airway inflammation. In vitro experiments showed that IRAK-M KO naive CD4+ T cells were more prone to differentiate into Th17 cells, but not regulatory T cells. Consistently, activation of IkappaBzeta was significantly increased in the absence of IRAK-M, facilitating Th17 polarization. These findings suggest that IRAK-M plays a crucial role in the regulation of allergic airway inflammation by modifying the function of airway epithelia, DCs, and macrophages, and the differentiation of naive CD4+ T cells. Modulation of IRAK-M may provide a novel target for the control of asthma. PMID- 28665694 TI - Surveying the opinions of Pennsylvania Chiefs of Police toward officers carrying and administering naloxone. AB - BACKGROUND: Recent legislation in Pennsylvania allows police officers to administer naloxone to individuals in an opioid overdose. Pressure has subsequently been placed on police departments to adopt naloxone programs. OBJECTIVE: To survey Pennsylvania Chiefs of Police regarding potential obstacles to officer-administered naloxone, and their overall opinion toward such programs. METHODS: A confidential survey was administered at the Annual Conference for the Pennsylvania Chiefs of Police Association and online over the organization's listserv. Respondents rated their level of concern toward four potential obstacles on a Likert scale from 1 to 5. A fifth question asked the degree to which they agree that the benefits of naloxone programs outweigh the risks. RESULTS: Of 180 attendees, 36 Chiefs of Police responded at the conference and 48 to the online survey. The potential agitation of revived victims was their largest reported concern, with 60% responding either a 4 or 5; this was followed by officers correctly identifying situations to use naloxone (42%), the cost of the medication (38%), and the additional administrative duties of the department (32%). Overall 60% responded they "Strongly Agree" or "Agree" the benefits of naloxone programs outweigh the risks, while 23% responded "Strongly Disagree" or "Disagree." No significant differences were seen when separating participants from rural and urban counties or from counties with high, medium, and low rates of overdose fatalities. CONCLUSIONS: The results suggest that although a significant subset shows concern for the above obstacles, the majority of Chiefs of Police believe that the benefits of equipping officers with naloxone outweigh the risks. PMID- 28665695 TI - Smart storage technologies applied to fresh foods: A review. AB - Fresh foods are perishable, seasonal and regional in nature and their storage, transportation, and preservation of freshness are quite challenging. Smart storage technologies can online detection and monitor the changes of quality parameters and storage environment of fresh foods during storage, so that operators can make timely adjustments to reduce the loss. This article reviews the smart storage technologies from two aspects: online detection technologies and smartly monitoring technologies for fresh foods. Online detection technologies include electronic nose, nuclear magnetic resonance (NMR), near infrared spectroscopy (NIRS), hyperspectral imaging and computer vision. Smartly monitoring technologies mainly include some intelligent indicators for monitoring the change of storage environment. Smart storage technologies applied to fresh foods need to be highly efficient and nondestructive and need to be competitively priced. In this work, we have critically reviewed the principles, applications, and development trends of smart storage technologies. PMID- 28665696 TI - Association Analysis of Single Nucleotide Polymorphisms in C1QTNF6, RAC2, and an Intergenic Region at 14q32.2 with Graves' Disease in Chinese Han Population. AB - BACKGROUND: Variation within the C1QTNF6 gene at 22q12.3, the RAC2 gene at 22q13.1, and an intergenic region at 14q32.2 were found to be associated with risk to Graves' disease (GD) in a recent study. We aimed to validate these associations with GD in an independent sample set of Han Chinese population. METHODS: We investigated these associations by genotyping the most significantly associated single nucleotide polymorphisms (SNPs) located in these three regions. Rs1456988 within the intergenic region at 14q32.2, rs229527 within C1QTNF6 at 22q12.3, and rs2284038 within RAC2 at 22q13.1 were selected for genotyping. These three SNPs were genotyped using a case-control study that included 2382 GD patients and 3092 unrelated healthy controls from Northern Han Chinese ancestry. The genotyping was performed using TaqMan assays on the ABI7900 platform. RESULTS: We found both the rs229527 allele within C1QTNF6 (odds ratio [OR] = 1.23, confidence interval [95% CI]: 1.12-1.33, pAllelic = 4.60 * 10-6) and the rs2284038 allele within RAC2 (OR = 1.10, 95% CI: 1.01-0.19, pAllelic = 3.00 * 10 2) showed significant associations with GD susceptibility. However, rs1456988 located in 14q32.2 (OR = 1.08, 95% CI: 0.99-1.16, pAllelic = 7.01 * 10-2) showed no association. Analysis of models of inheritance suggested that both the dominant and recessive models showed significant associations for rs229527 (OR = 1.24, 95% CI: 1.13-1.38, pDominant = 9.90 * 10-5; OR = 1.49, 95% CI: 1.19-1.86, pRecessive = 3.90 * 10-4), with the dominant model being preferred. For rs2284038, the recessive model was preferred (OR = 1.18, 95% CI: 1.00-1.40, pRecessive = 4.76 * 10-2), whereas analysis of dominant model showed no association (OR = 1.10, 95% CI: 0.98-1.22, pDominant = 0.10). CONCLUSIONS: Our findings confirmed that chromosome 22q12.3 and 22q13.1 variants are associated with GD in an independent Han Chinese population; however, 14q32.2 showed no association with GD. PMID- 28665697 TI - Feasibility, stability and validity of the four square step test in typically developed children and children with brain damage. AB - PURPOSE: To assess feasibility, test-retest reliability and validity of the Four Square Step Test (FSST) in typically developed children (TD), and children with cerebral palsy (CP) and acquired brain injury (ABI). METHODS: 30 TD children, 20 with CP and 12 with ABI participated in the study. The FSST while sitting and standing, the Timed Up and Go (TUG) and the balance subtest of the Bruininks Oseretsky Test (BOT-2) were assessed. Each child attempted the FSST twice within 1 week. The scores for the FSST were assigned according to the original test: two successes in four trials, and according to a more lenient test, one success in four trials. RESULTS: The original form of the FSST is not feasible for children with CP or ABI. In TD children the lenient version is feasible (93%) and has moderate stability (Interclass correlation, ICC = 0.723), with a significant, positive correlation with the TUG (rs = 0.56). In children with CP the lenient test is feasible (80%), stable (rs = 0.83) and negatively correlates with the BOT 2 (rs=-0.69). In children with ABI the test is less feasible (67%) and neither stable nor valid. CONCLUSIONS: The lenient form of the FSST is feasible, reliable and valid in TD children and children with CP. PMID- 28665699 TI - Reply: A Cautionary Tale and Opportunities for Improvement in Transbronchial Cryobiopsy. PMID- 28665700 TI - Use of Sclerotherapy for the Treatment of Massive Hemoptysis due to a Bleeding Bronchial Varix. PMID- 28665698 TI - An Official American Thoracic Society Workshop Report: Noninvasive Identification of Inspiratory Flow Limitation in Sleep Studies. AB - This report summarizes the proceedings of the American Thoracic Society Workshop on the Noninvasive Identification of Inspiratory Flow Limitation in Sleep Studies held on May 16, 2015, in Denver, Colorado. The goal of the workshop was to discuss methods for standardizing the scoring of flow limitation from nasal cannula pressure tracings. The workshop began with presentations on the physiology underlying flow limitation, existing methods of scoring flow limitation, the effects of signal acquisition and filtering on flow shapes, and a review of the literature examining the adverse outcomes related to flow limitation. After these presentations, the results from online scoring exercises, which were crowdsourced to workshop participants in advance of the workshop, were reviewed and discussed. Break-out sessions were then held to discuss potential algorithms for scoring flow limitation. Based on these discussions, subsequent online scoring exercises, and webinars after the workshop, a consensus-based set of recommendations for a scoring algorithm for flow limitation was developed. Key conclusions from the workshop were: (1) a standardized and automated approach to scoring flow limitation is needed to provide a metric of nonepisodic elevated upper airway resistance, which can then be related to clinical outcomes in large cohorts and patient groups; (2) at this time, the most feasible method for standardization is by proposing a consensus-based framework, which includes scoring rules, developed by experts (3) hardware and software settings of acquisition devices, including filter settings, affect the shape of the flow curve, and should be clearly specified; and (4) a priority for future research is the generation of an open-source, expert-derived training set to encourage and support validation of automated flow limitation scoring algorithms. PMID- 28665701 TI - Transbronchial Cryobiopsy: A Cautionary Tale and Opportunities for Improvement. PMID- 28665702 TI - Careful Planning Reduces Cryobiopsy Complications. PMID- 28665704 TI - A 55-Year-Old Man with a Trachea Undressed. PMID- 28665703 TI - Reply: Careful Planning Reduces Cryobiopsy Complications. PMID- 28665705 TI - Summary for Clinicians: Lymphangioleiomyomatosis Diagnosis and Management Clinical Practice Guideline. PMID- 28665706 TI - Posterior Tracheal Laceration Treated with a Stent. PMID- 28665707 TI - Advancing a Common Understanding and Approach to Dyspnea Management. Consensus Proposal for the Chronic Breathlessness Syndrome. PMID- 28665708 TI - Environmental Mycobacterial Latency: A Role in Human Disease? PMID- 28665709 TI - Oxygen Delivery during Severe Anemia When Blood Transfusion Is Refused on Religious Grounds. PMID- 28665711 TI - Giving Doctors' Daily Progress Notes to Hospitalized Patients and Families: A Reflection. PMID- 28665712 TI - Left ventricular end-diastole hemodynamics is strongly associated with spontaneous cardiac baroreflex in humans. AB - BACKGROUND: In animals, hemodynamic conditions during left ventricular (LV) end diastole are crucial for the excitation of autonomic afferents distributed throughout cardiac chambers and large thoracic vessels. The objective of the study was to select the echocardiographic indices of LV diastolic function that are the most potent predictors of the heart's spontaneous baroreflex in humans. METHODS: In 47 untreated hypertensive patients (26 with normal and 21 with increased left atrium diameter) and 24 healthy controls, baroreflex sensitivity (BRS) was assessed in the low (alphaLF; 0.04-0.15 Hz) and high frequency (alphaHF; 0.15-0.4 Hz) components in the supine and during tilting. The [Formula: see text] normalized to LV end-diastolic diameter (the [Formula: see text] index) is a marker of the septum late diastolic distension rate ([Formula: see text] denotes peak late diastolic velocity at the septal mitral annulus) under the corresponding transmitral pressure gradient that determines the peak velocity of blood flow (A) into the LV chamber. RESULTS: The [Formula: see text] markedly stronger than [Formula: see text] ratio correlated with the BRS. In the best-fit models of multivariable linear regression, the [Formula: see text] index was the independent predictor of the alphaLF BRS at tilting (beta = -0.3; p = 0.01). Independent of clinical and echocardiographic parameters, the [Formula: see text] index predicted also both the alphaHF BRS in the supine position (beta = -0.23; p = 0.01) and the alphaHF BRS reinforcement due to increased preload (beta = -0.28; p = 0.001). CONCLUSIONS: The [Formula: see text] index is a reliable marker of diastolic dysfunction that evokes significant heart's baroreflex impairment and is markedly stronger than [Formula: see text] ratio associated with these systemic consequences of altered LV diastole hemodynamics. PMID- 28665714 TI - Conflicted. PMID- 28665713 TI - mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats. AB - Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect. PMID- 28665716 TI - A Study on Campylobacter jejuni and Campylobacter coli through Commercial Broiler Production Chains in Thailand: Antimicrobial Resistance, the Characterization of DNA Gyrase Subunit A Mutation, and Genetic Diversity by Flagellin A Gene Restriction Fragment Length Polymorphism. AB - Contaminated poultry meat is regarded as the main source of human campylobacteriosis. During September 2014 and February 2015, breeder flocks, hatcheries, and broiler farms from two chicken production chains were investigated chronologically. Five commercial breeder flocks (Breeder Flocks 1 5), two hatcheries (Hatcheries A and B), and five broiler flocks (Broiler Flocks 1-5) were sampled in this study. Campylobacter colonization of both breeder and broiler flocks was determined from cloacal swabs and environmental samples (pan feeders, footwear, darkling beetles, flies, feed, and water). The eggs from the breeder flocks were followed to hatcheries. At the hatcheries, early embryonic deaths, egg trays, eggshells, hatchers, and water were investigated. Cloacal swabs were taken from broilers at Days 1, 14, and 28 (all broiler flocks), and either 35 (Broiler Flocks 1 and 2) or 43 (Broiler Flocks 3-5). Thirty-six Campylobacter jejuni and 94 Campylobacter coli isolates collected through two broiler production chains were tested by twofold agar dilution for their susceptibility to antimicrobial agents. Most Campylobacter isolates were multidrug resistant (MDR), defined as being resistant to three or more antimicrobial classes ( C. jejuni : 100%; C. coli : 98.9%), and exhibited high resistance to enrofloxacin ( C. jejuni : 100%; C. coli : 98.9%). The vast majority of C. coli were resistant to tetracycline (97.9%), trimethoprim sulfamethoxazole (81.9%), and doxycycline (79.8%), but only 55.6%, 36.1%, and 50% of C. jejuni isolates revealed resistance to these antimicrobial agents, respectively. A selected subset of 24 C. jejuni and 24 C. coli were characterized for their mutations in the quinolone resistance determining region of the DNA gyrase subunit A gene by nucleotide sequence analysis. The Thr-86-Ile substitution (ACA-ATA in C. jejuni or ACT-ATT in C. coli ) was found in all isolates. Moreover, a total of 130 Campylobacter isolates were typed with the use of polymerase chain reaction-restriction fragment length polymorphism of the flagellin A gene (flaA-RFLP) to determine their genetic relationships. Ten distinct clusters were recognized by flaA-RFLP typing. The results showed that horizontal transmission was the major route of Campylobacter transmission in this study. In conclusion, the emergence of MDR and high resistance rates to several antimicrobials are major concerns identified in this study. The prudent use of these agents and active surveillance of resistance at the farm level are essential steps to reduce the public health risks identified in this work. PMID- 28665717 TI - Hematology and Serum Biochemistry Reference Intervals for Six-Week-Old, Farm Reared Chinese Ring-Necked Pheasants ( Phasianus colchicus ) from Minnesota. AB - Chinese ring-necked pheasants ( Phasianus colchicus ) are commonly farmed in intensive operations for purposes such as meat production, hunting preserves, or research. Under these conditions, pheasants frequently suffer medical ailments such as bacterial, viral, and parasitic infections or nutritional or metabolic disorders. Relatively little scientific information exists regarding clinical pathology reference intervals (RIs) for farm-reared pheasants. The objective of this study was to determine RIs for hematologic and serum biochemical variables for Chinese ring-necked pheasants from Minnesota at 6 wk of age. Blood samples from 119 clinically healthy Chinese ring-necked pheasants were analyzed using standard techniques. Reference intervals were generated in Microsoft(r) Excel(r) 2013 (Microsoft, Redmond, WA) using Reference Value Advisor freeware version 2.1 (Microsoft). Ninety-five percent RIs were determined using nonparametric methods that followed Clinical and Laboratory Standards Institute guidelines. These RIs will be useful for the monitoring of health and diagnosis of disease in confined Chinese ring-necked pheasant populations that are approximately 6 wk old. PMID- 28665718 TI - Relationship Between Broiler Body Weights, Eimeria maxima Gross Lesion Scores, and Microscores in Three Anticoccidial Sensitivity Tests. AB - Anticoccidial sensitivity tests (ASTs) serve to determine the efficacy of anticoccidial drugs against Eimeria field isolates in a controlled laboratory setting. The most commonly measured parameters are body weight gain, feed conversion ratio, gross intestinal lesion scores, and mortality. Due to the difficulty in reliably scoring gross lesion scores of Eimeria maxima , microscopic analysis of intestinal scrapings (microscores) can be used in the field to indicate the presence of this particular Eimeria. The goal of this study was to determine the relationship between E. maxima microscores and broiler body weights and gross E. maxima lesion scores in three ASTs. Day-old broiler chicks were raised for 12 days on a standard corn-soy diet. On Day 12, chicks were placed in Petersime batteries and treatment diets were provided. There were six birds per pen, four pens per treatment, and 12 treatments, for a total of 288 chicks per AST. The treatments were as follows: 1) nonmedicated, noninfected; 2) nonmedicated, infected; 3) lasalocid, infected; 4) salinomycin, infected; 5) diclazuril, infected; 6) monensin, infected; 7) decoquinate, infected; 8) narasin + nicarbazin, infected; 9) narasin, infected; 10) nicarbazin, infected; 11) robenidine, infected; and 12) zoalene, infected. On Day 14, chicks were challenged with an Eimeria field isolate by oral gavage. On Day 20, broilers were weighed, and gross lesion scores and microscores were classified from 0 to 4 depending on the severity of the gross lesion scores and E. maxima microscores. Data from three trials using different field isolates were statistically analyzed using a logarithmic regression model. There was no relationship (P = 0.1224) between microscores and body weight gain. There was a positive relationship between microscores and gross lesion scores (P = 0.004). However, there was also an interaction between isolate and treatment (P < 0.0001). Lastly, the interaction between isolate and gross lesion scores (P = 0.0041) demonstrates that the significance of the relationship between microscores and gross lesion scores may be dependent on pathogenicity of the challenge Eimeria or the amount of E. maxima in the inoculum. PMID- 28665719 TI - Eimeria Oocyst Concentrations and Species Composition in Litter from Commercial Broiler Farms During Anticoccidial Drug or Live Eimeria Oocyst Vaccine Control Programs. AB - The purpose of this study was to determine if Eimeria oocyst concentrations and species composition in commercial broiler house litter changed during different cycles of anticoccidial drug (ACD) or live Eimeria oocyst vaccine (VAC) control programs and if there was a correlation between Eimeria oocyst levels and broiler performance. Litter samples were collected from a total of 15 different broiler farms encompassing a total of 45 individual houses during at least one complete grow-out cycle over a 21-mo period. Of these 15 broiler farms, three were followed for the entire 21-mo period spanning three ACD and four VAC cycles. Samples were collected at 2, 4, and 7-8 wk of grow-out corresponding to starter, grower, and withdraw periods of the ACD cycle. On a number of occasions, litter samples were obtained just prior to chick placement. Eimeria oocysts were isolated from all samples, counted by microscopy, and extracted for DNA to identify Eimeria species by ITS1 PCR. In general, Eimeria oocyst concentration in litter reached peak levels at 2-4 wk of grow-out regardless of coccidiosis control measure being used. However, peak oocyst numbers were sometimes delayed until 7-8 wk, indicating some level of Eimeria spp. drug resistance or incomplete vaccine coverage. Eimeria maxima , Eimeria acervulina , Eimeria praecox, and Eimeria tenella were generally present in all samples, and no difference in the species composition was noted between houses on a particular farm. While Eimeria species composition was similar among houses, Eimeria spp. oocyst levels exhibited sporadic peaks in one house of a given location's houses. Of particular interest was the observed correlation between E. maxima oocyst abundance and chick mortality. However, no correlation was observed in E. maxima oocyst levels, and the performance parameters adjusted feed conversion ratio and average daily weight gain. This study showed that understanding the dynamics of Eimeria spp. oocyst levels and species composition in litter during ACD or VAC programs may provide insight into the effectiveness of coccidiosis control measures in commercial broiler production. PMID- 28665720 TI - Characterization of Clostridium perfringens Strains Isolated from Healthy and Necrotic Enteritis-Afflicted Broiler Chickens. AB - Necrotic enteritis (NE) is an important enteric disease in poultry, and Clostridium perfringens (CP) type A strains are the primary etiology. NE is responsible for annual losses of US $6 billion to the poultry industry in the United States. An increase in the incidence of NE has been also associated with withdrawal of antibiotic growth promoters from poultry feed. In this study, CP strains isolated from healthy and NE-afflicted birds were characterized microbiologically and molecularly, and their virulence was experimentally tested in chickens. All strains were hemolytic, lecithinase positive, and identified as CP by biochemical tests. Three distinct colony morphologies were seen in brain heart infusion media with 0.3% agarose, FeSO4, and ZnCl2. The CP strains responded differently to iron chelation with 2,2'-bidypinol. PCR toxinotyping showed that all tested strains were alpha toxin-positive, seven (N11, N10, CP1, CP5, CP13, JGS, and Del1) were beta2-toxin-positive, and only one (Del1) was necrotic enteritis toxin B-like-positive. In vivo studies indicated that most isolates, including strain N11 isolated from the normal chicken gut, were sufficiently virulent to produce NE disease in the Eimeria/CP dual infection model. The Del1 and N11 strains merit further investigation to identify their virulence factors and immune-protective antigens. PMID- 28665721 TI - Esophagitis and Pharyngitis Associated with Avian Infectious Laryngotracheitis in Backyard Chickens: Two Cases. AB - Infectious laryngotracheitis (ILT) is a contagious viral respiratory disease of great economic importance for the global poultry industry caused by Gallid herpesvirus 1 (GaHV-1). Lesions of the upper digestive tract caused by this virus have not been reported before. Two small flocks of backyard chickens experienced an outbreak of ILT, one in 2006 and the other in 2014. These birds had typical ILT lesions, characterized by a necrohemorrhagic laryngitis and tracheitis but were also affected by a severe erosive and necrotic esophagitis and pharyngitis. On microscopic examination of the esophagus and pharynx, numerous individual epithelial cells were degenerated or necrotic. Syncytial cells were present in the mucosa or sloughed in the overlying inflammatory crust, and some of these cells contained an amphophilic intranuclear viral inclusion. GaHV-1 was detected in tissues, from respiratory and digestive tracts, either by PCR, immunohistochemistry, or both diagnostic assays. This case stresses the importance for veterinarians, owners, and technicians to pay attention to different or atypical clinical manifestations of ILT given its highly contagious nature. PMID- 28665722 TI - First Report of Avian Metapneumovirus Subtype B Field Strain in a Romanian Broiler Flock During an Outbreak of Respiratory Disease. AB - Avian metapneumovirus (aMPV) represents one of the most prevalent diseases of turkey, especially in combination with other pathogens, and its frequency is also increasing among chickens. Despite this evidence, epidemiologic data are poor and scattered, severely preventing control of the disease even in highly developed areas such as Europe. In the present study, the detection and characterization of an aMPV subtype B strain circulating in a vaccinated but symptomatic Romanian broiler flock is reported for the first time. The phylogenetic analysis based on the partial G gene sequence demonstrates the close relationship of the Romanian virus with a group of recently emerged Italian field strains for which vaccine induced protection was experimentally proven to be partial. These preliminary results allow us to hypothesize the spreading of vaccine-escaping aMPV subtype B strains through Europe and, consequently, dictate the carrying out of a more systematic survey to confirm this theory and enforce adequate countermeasures. PMID- 28665723 TI - Kidney Cell-Adapted Infectious Bronchitis ArkDPI Vaccine is Stable and Protective. AB - We previously demonstrated that adaptation of an embryo-attenuated infectious bronchitis virus (IBV) Arkansas (Ark) Delmarva Poultry Industry (DPI)-derived vaccine to chicken embryo kidney (CEK) cells (CEKp7) shifted the virus population towards homogeneity in spike (S) and nonstructural protein genes. Moreover, the typical Ark vaccine subpopulations emerging in chickens vaccinated with commercial Ark vaccines were not detected in chickens vaccinated with CEKp7, indicating that kidney-cell adaptation drastically increased the stability of the vaccine virus population in chickens. In the current study both conventional and next-generation sequencing results show that the changes achieved during CEK adaptation remained after five back passages in embryonated chicken egg (ECE). In a first protection study 1-day-old chickens were vaccinated with 104.0 or 105.0 50% embryo infectious doses (EID50)/chicken of the second ECE back passage of CEKp7 (CEKp7e2) and demonstrated protection against Ark virulent (106.0 EID50) challenge. In a second protection trial, protection by CEKp7e2 was compared with protection conferred by an attenuated commercial ArkDPI-derived vaccine different from that which the CEK-adapted virus originated. All vaccinated chicken groups showed a significant reduction of respiratory signs and viral load after Ark virulent challenge compared to unvaccinated-challenged controls. In CEKp7e2 vaccinated chickens viral subpopulations different from the challenge virus were detected after challenge in a marginal number (7%-8%) of chickens. In contrast, IBV S1 sequences that differed from the predominant population in the challenge virus were detected after challenge in a large number (77%) of chickens vaccinated with the commercial Ark attenuated vaccine. The CEK-adapted IBV ArkDPI derived vaccine is a stable and effective vaccine, which drastically reduces the emergence of Ark-like viruses both at vaccination and after challenge. PMID- 28665724 TI - Establishment of an In Vitro Intestinal Epithelial Cell Culture Model of Avian Origin. AB - The role of intestinal epithelial cells (IECs) in the physiology of the gastrointestinal tract (GIT) of chickens and pathogenesis of various diseases in chickens is still poorly understood. IECs line the GIT and represent the border between the unsterile environment and the sterile internal tissues. Bacterial, viral, fungal, or parasitic pathogens are able to invade or pass IECs under certain circumstances and cause various diseases. Pathogen-host interactions in the chicken gut are poorly understood because of the lack of suitable in vitro and ex vivo models. In this context, there is a need to optimize the cell isolation and culture conditions to be able to provide reproducible IEC cultures with defined epithelial characteristics. We compared different mechanical IEC isolation protocols and cell culture media and established a reproducible primary intestinal epithelial cell culture model from specific-pathogen-free layer-type chickens. By using isolated crypts from the duodenum of 5- to 12-wk-old birds to create the starting material, we were able to culture replicating cells between 7 and 10 days. Cells built an almost closed monolayer and showed epithelial-like characteristics, such as the expression of cytokeratin and epithelial cadherin. The primary IEC cultures described in this study represent a suitable model with which to investigate in vitro pathogen-host interactions relevant to the chicken gut. PMID- 28665725 TI - Industry-Wide Surveillance of Marek's Disease Virus on Commercial Poultry Farms. AB - Marek's disease virus is a herpesvirus of chickens that costs the worldwide poultry industry more than US$1 billion annually. Two generations of Marek's disease vaccines have shown reduced efficacy over the last half century due to evolution of the virus. Understanding where the virus is present may give insight into whether continued reductions in efficacy are likely. We conducted a 3-yr surveillance study to assess the prevalence of Marek's disease virus on commercial poultry farms, determine the effect of various factors on virus prevalence, and document virus dynamics in broiler chicken houses over short (weeks) and long (years) timescales. We extracted DNA from dust samples collected from commercial chicken and egg production facilities in Pennsylvania, USA. Quantitative PCR was used to assess wild-type virus detectability and concentration. Using data from 1018 dust samples with Bayesian generalized linear mixed effects models, we determined the factors that correlated with virus prevalence across farms. Maximum likelihood and autocorrelation function estimation on 3727 additional dust samples were used to document and characterize virus concentrations within houses over time. Overall, wild-type virus was detectable at least once on 36 of 104 farms at rates that varied substantially between farms. Virus was detected in one of three broiler-breeder operations (companies), four of five broiler operations, and three of five egg layer operations. Marek's disease virus detectability differed by production type, bird age, day of the year, operation (company), farm, house, flock, and sample. Operation (company) was the most important factor, accounting for between 12% and 63.4% of the variation in virus detectability. Within individual houses, virus concentration often dropped below detectable levels and reemerged later. These data characterize Marek's disease virus dynamics, which are potentially important to the evolution of the virus. PMID- 28665726 TI - Epidemiologic Investigation of Highly Pathogenic H5N2 Avian Influenza Among Upper Midwest U.S. Turkey Farms, 2015. AB - In 2015, an outbreak of H5N2 highly pathogenic avian influenza (HPAI) occurred in the United States, severely impacting the turkey industry in the upper midwestern United States. Industry, government, and academic partners worked together to conduct a case-control investigation of the outbreak on turkey farms in the Upper Midwest. Case farms were confirmed to have HPAI-infected flocks, and control farms were farms with noninfected turkey flocks at a similar stage of production. Both case and control farms were affiliated with a large integrated turkey company. A questionnaire administered to farm managers and supervisors assessed farm biosecurity, litter handling, dead bird disposal, farm visitor and worker practices, and presence of wild birds on operations during the 2 wk prior to HPAI confirmation on case premises and the corresponding time frame for control premises. Sixty-three farms, including 37 case farms and 26 control farms were included in the analysis. We identified several factors significantly associated with the odds of H5N2 case farm status and that may have contributed to H5N2 transmission to and from operations. Factors associated with increased risk included close proximity to other turkey operations, soil disruption (e.g., tilling) in a nearby field within 14 days prior to the outbreak, and rendering of dead birds. Observation of wild mammals near turkey barns was associated with reduced risk. When analyses focused on farms identified with H5N2 infection before April 22 (Period 1), associations with H5N2-positive farm status included soil disruption in a nearby field within 14 days prior to the outbreak and a high level of visitor biosecurity. High level of worker biosecurity had a protective effect. During the study period after April 22 (Period 2), factors associated with HPAI-positive farm status included nonasphalt roads leading to the farm and use of a vehicle wash station or spray area. Presence of wild birds near dead bird disposal areas was associated with reduced risk. Study results indicated that the initial introduction and spread of H5N2 virus likely occurred by both environmental and between-farm pathways. Transmission dynamics appeared to change with progression of the outbreak. Despite enhanced biosecurity protocols, H5N2 transmission continued, highlighting the need to review geographic/topologic factors such as farm proximity and potential dust or air transmission associated with soil disruption. It is likely that biosecurity improvements will reduce the extent and speed of spread of future outbreaks, but our results suggest that environmental factors may also play a significant role in farms becoming infected with HPAI. PMID- 28665727 TI - Characterization and Epidemiology of Pigeon Paramyxovirus Type-1 Viruses (PPMV-1) Isolated in Macedonia. AB - We have characterized in this study 10 PPMV-1 isolated from domestic pigeons and one PPMV-1 isolated from a feral pigeon in the period 2007-2012, using both classical methods (HI test and ICPI test) and molecular methods (RT-qPCR, RT-PCR, and nucleotide sequencing). Using phylogenetic analysis of partial fusion gene sequences, these viruses clustered with recent European PPMV-1 isolates (EU/re) within the genotype VIb/1. All isolates possessed virulent cleavage site motifs with variable morbidity and mortality in pigeons. The intracerebral pathogenecity indices of the five isolates ranged from 0.59 to 1.53. The repetitive isolation of PPMV-1 viruses for several consecutive years led toward establishing enzootic presence of the disease in pigeons. A high nucleotide sequence homology between the Macedonian isolates and EU/re isolates was shown. Co-circulation of different isolates in the same holdings was detected. This is the first study to extensively describe the molecular epidemiology of PPMV-1 isolated in Macedonia. PMID- 28665729 TI - Letters to the Editor. PMID- 28665728 TI - Acute Lameness in a Roller Pigeon ( Columba livia ) with Multicentric Lymphosarcoma. AB - A 3-yr-old adult female roller pigeon ( Columba livia ) used as part of a breeding pair for an ongoing research study presented with acute left limb lameness. Palpation of the left leg and region revealed a large lump near the coxofemoral joint. The bird was able to ambulate in the cage, but would not brood her hatchling. The bird was humanely euthanized and necropsy was performed. Grossly, multiple large white to pale tan nodules were noted in the pancreas, lung, rib cage, intestines, and unilaterally in the left kidney. Microscopic examination of the various organs revealed neoplastic proliferation of round cells consistent with lymphoblasts. Immunohistochemistry was performed with the use of antibodies to CD3, CD79a, CD20, and CD21 to phenotype the cells. The results indicated that the neoplastic infiltrating cells were predominantly of T cell origin. PMID- 28665730 TI - Cutaneous Leiomyosarcoma with Multiple Visceral Metastases in a Domestic Pigeon. AB - A clinical examination of a 4-yr-old fantail pigeon revealed a large skin tumor in the area of the left wing. The tumor had solid consistency and a single cavity filled with fluid. During necropsy, multiple tumors of varied size and diameter were found in the liver, spleen, pancreas, and kidneys. A histopathological examination of the skin tumor revealed extensive multifocal neoplasia with a tendency to infiltrate, composed of polygonal, round, oval, and elongated cells forming a solid system with cellular bands and obliteration of intercellular boundaries. Multifocal necrosis was detected in the foci of neoplastic infiltration. Similar foci were present in the liver, pancreas, and lungs. In an immunohistochemical examination, tumor cells tested positive for smooth-muscle actin and vimentin. The diagnosis was cutaneous leiomyosarcoma with an uncommon feature of visceral metastases. PMID- 28665732 TI - Highly Pathogenic Avian Influenza H5N1 Clade 2.3.2.1c Virus in Lebanon, 2016. AB - We report the phylogenetic analysis of the first outbreak of H5N1 highly pathogenic avian influenza virus detected in Lebanon from poultry in April 2016. Our whole-genome sequencing analysis revealed that the Lebanese H5N1 virus belongs to genetic clade 2.3.2.1c and clusters with viruses from Europe and West Africa. PMID- 28665731 TI - H7N7 Highly Pathogenic Avian Influenza in Poultry Farms in Italy in 2016. AB - After the H7N7 highly pathogenic (HP) avian influenza (AI) outbreak in 2013, and a single case of H5N8 HPAI in 2014, in April 2016, a H7N7 HPAI virus was detected in northeastern Italy. The case occurred in an organic free-range laying hen farm located in proximity with one of the highest densely populated poultry areas (DPPAs) in Italy. Control measures provided by the Council of the European Union in directive 2005/94/CE were promptly applied, and enhanced surveillance activities were implemented in the DPPAs. On May 16, 2016, a second case was confirmed in a fattening turkey farm within the protection zone of the previous outbreak. Following an epidemiologic inquiry, another turkey farm was considered at risk of transmission and was subjected to preemptive culling. Epidemiologic data and phylogenetic analyses indicated that the virus was likely introduced from wild birds as a low pathogenicity AI strain, through direct contact. The rapid containment of the outbreak proves the level of preparedness of the veterinary public health sector in Italy. Nevertheless, the recurrent introductions from wild birds indicate the need of improving both the biosecurity levels in the DPPA and the surveillance activities in wild birds to quickly detect the presence of AI in the territory. PMID- 28665733 TI - Repeated Challenge with Virulent Newcastle Disease Virus Does Not Decrease the Efficacy of Vaccines. AB - Globally, poultry producers report that birds well-vaccinated for Newcastle disease (ND) often present clinical disease and mortality after infection with virulent strains of Newcastle disease (vNDV), which is contrary to what is observed in experimental settings. One hypothesis for this discrepancy is that the birds in the field may be exposed to multiple successive challenges with vNDV, rather than one challenge dose, and that the repeated infection may overwhelm the immune system and neutralizing antibodies available to prevent clinical disease. In this study, we evaluated this hypothesis under highly controlled conditions. We challenged well-vaccinated chickens with high doses of vNDV daily for 10 days, and looked for signs of clinical disease, changes in antibody titers, and mortality. All sham-vaccinated birds died by the fourth day postchallenge. No morbidity or mortality was observed in any of the NDV vaccinated birds up to 14 days postchallenge; repeated high-dose challenges of vNDV was not sufficient to overcome vaccine immunity. PMID- 28665736 TI - Erratum. PMID- 28665735 TI - Longitudinal Study of Avian Influenza and Newcastle Disease in Village Poultry, Mali, 2009-2011. AB - Newcastle disease (ND) is endemic in West Africa, which has also experienced outbreaks of highly pathogenic avian influenza (AI) H5N1 since 2006. We aimed to estimate the prevalence and incidence of AI and ND in village poultry in Mali and to identify associated risk factors. A longitudinal serologic study was conducted between November 2009 and February 2011 using ELISA commercial kits to detect antibodies. Sera (5963) were collected from 4890 different poultry. AI was rare, with a seroprevalence of 2.9% (95% confidence interval [CI] 2.3-3.5) and a seroincidence rate of 0.7 birds per 100 bird-months at risk (95% CI 0.4-1.0). AI antibodies were short lived, with a seroreversion rate of 25.4 birds per 100 bird months at risk (95% CI 19.0-31.7). Risk factors for AI were limited: temporal variation occurred, but proximity to a water body was a risk factor only when large populations of wild waterbirds were present. ND was very common, with seroprevalence of 68.9% (95% CI 61.9-76.0) and a seroincidence rate of 15.9 birds per 100 bird-months at risk (95% CI 11.9-19.8). ND seroreversion rate was 6.2 birds per 100 bird-months at risk (95% CI 3.6-8.9). Regarding risk factors for ND, temporal variations occurred, and ND was more likely to be present in the Sudanian agro-ecological zone than in the Sahelian zone, in chickens than in other species, in flocks with higher numbers of Guinea fowl, and in flocks that had access to a waterbody. Control efforts would benefit from further increasing the ND vaccination coverage of village poultry, although this was already quite high (54.9%) for an African country. Seroconversion seemed satisfactory in vaccinated poultry, since 90.0% (95% CI 87.6-92.4) of these had ND antibodies. Further research should investigate the apparent lack of an epidemiologic role of domestic ducks for AI in Mali (unlike in Southeast Asia) and the potential role of Guinea fowl as a reservoir for ND. PMID- 28665737 TI - Fowl Adenoviruses D and E Cause Inclusion Body Hepatitis Outbreaks in Broiler and Broiler Breeder Pullet Flocks. AB - Twenty-four fowl adenoviruses (FAdVs) were isolated from broiler and broiler breeder pullet flocks in Iran during 2013-2016 and were identified and characterized. All FAdVs were from inclusion body hepatitis (IBH) cases, showing an enlarged and pale yellow liver with multiple petechial hemorrhages. Phylogenetic analyses of partial hexon gene sequences are an adequate and quick method for differentiation and genotyping. The isolates were subjected to PCR to amplify a 590-bp fragment from the hexon gene. Sequence analysis revealed the presence of two species D and E. Eighty FAdV isolates were genetically related to the strain EU979378 of FAdV-11 (96.5% to 97.6% identity), and six isolates were related to the strain EU979375 of FAdV-8b (97% identity). The results indicated that two FAdV serotypes (11 and 8b) are high prevalence serotypes of FAdVs in Iran and are pathogenic enough to cause IBH in young chicks. Therefore, preventive measures against FAdV infection on poultry farms should be implemented. PMID- 28665738 TI - Development of a Dry Medium for Isolation of Histomonas meleagridis in the Field. AB - Blackhead disease is caused by Histomonas meleagridis, an anaerobic protozoan parasite, and results in mortality rates of up to 100% in turkeys and 30% in chickens. Outbreaks of blackhead disease are unpredictable, and the harvesting of H. meleagridis strains from the field would be a great resource for researchers to study its epidemiology. Therefore, the objective of this study was to develop a dry medium that would allow storage at ambient temperatures until needed. Fifty milliliters of horse serum was dried and then mixed with dry medium M199 with Hanks balanced salts (10.6 g), sodium bicarbonate (0.35 g), and rice powder (0.8 g). To test the ability of reconstituted medium to support growth of H. meleagridis, groups of 10 flasks containing 0.2 g of dry medium were stored for 24 hr at 25 and 60 C before testing. Other groups of flasks containing dry medium were stored at 25, 37, and 42 C for 1, 3, or 6 mo. At each test period, the flasks were reconstituted with 10 ml of water, inoculated with 100 000 H. meleagridis cells, and incubated at 40 C for 48 hr. Fresh liquid medium was used as a control. There were no differences in cell counts in medium stored at 25 or 60 C for 24 hr. After 1 mo, cell counts in reconstituted medium were about half that of fresh liquid medium after 48 hr of incubation. But after 3 and 6 mo, the cell counts were not significantly different in all groups (P < 0.05) after 72 hr of incubation. These results show that dried Dwyer medium can be stored at ambient temperatures for extended times and would be an effective tool for obtaining isolates of H. meleagridis from the field. PMID- 28665739 TI - The placental vascular endothelial growth factor polymorphisms and preeclampsia/preeclampsia severity. AB - Preeclampsia (PE) is a serious pregnancy-specific condition, which originates from placenta and finishes after delivery. The present study has investigated the association between placental VEGF I/D (rs35569394), -1154G/A (rs1570360), and 634G/C(rs2010963) polymorphisms and maternal VEGF -2549 I/D (rs35569394) polymorphism with PE and PE severity. In this case-control study, the maternal blood of 217 women with PE and 210 normotensive pregnant women and the placenta of 84 PE women and 103 normotensive women were collected after delivery. Genotyping was done by PCR or PCR-RFLP methods. The maternal VEGF-2549I/D genotypes were not associated with PE or PE severity. The placental VEGF -2549 I/D genotypes were not associated with PE too; however; the placental VEGF-2549 DD genotype was statistically different between women with severe PE and mild PE or the controls. The placental VEGF -634GC and CC genotypes were significantly higher in PE women and associated with 2.6 and 2-fold higher risk of PE, respectively. The VEGF -634GC and CC genotypes were associated with PE severity. No association was found between placental VEGF -1154G/A polymorphism and PE or PE severity. The placental DGC haplotype of VEGF -2549 I/D, -1154G/A, and -634G/C polymorphisms was associated with 2.9-fold higher risk of PE. However, the placental IAG haplotype was associated with 0.3-fold lower risk of PE. In conclusion, the placental VEGF -2549 DD genotype was associated with severe PE and the placental -634GC and CC genotypes were associated with PE and severe PE. No association was found between VEGF -1154G/A polymorphism and PE or PE severity. PMID- 28665740 TI - Transcribing rhotics in normal and disordered speech. AB - The IPA's comparative lack of dedicated symbols for sonorant consonants as compared to obstruents presents some difficulties for clinical phoneticians. Among these are the ways of transcribing apical versus bunched approximant-/r/, the bilabial approximant realisation of target approximant-/r/, and fricative rhotic realisations of approximant-/r/ in normal and disordered speech. This note reports some developments in transcription that would allow clinical phoneticians to avoid the use of difficult-to-read diacritics when transcribing these sounds. PMID- 28665742 TI - The Economic Impact of Blindness in Europe. AB - PURPOSE: To estimate the annual loss of productivity from blindness and moderate to severe visual impairment (MSVI) in the population aged >50 years in the European Union (EU). METHODS: We estimated the cost of lost productivity using three simple models reported in the literature based on (1) minimum wage (MW), (2) gross national income (GNI), and (3) purchasing power parity-adjusted gross domestic product (GDP-PPP) losses. In the first two models, assumptions included that all individuals worked until 65 years of age, and that half of all visual impairment cases in the >50-year age group would be in those aged between 50 and 65 years. Loss of productivity was estimated to be 100% for blind individuals and 30% for those with MSVI. None of these models included direct medical costs related to visual impairment. RESULTS: The estimated number of blind people in the EU population aged >50 years is ~1.28 million, with a further 9.99 million living with MSVI. Based on the three models, the estimated cost of blindness is ?7.81 billion, ?6.29 billion and ?17.29 billion and that of MSVI ?18.02 billion, ?24.80 billion and ?39.23 billion, with their combined costs ?25.83 billion, ?31.09 billion and ?56.52 billion, respectively. The estimates from the MW and adjusted GDP-PPP models were generally comparable, whereas the GNI model estimates were higher, probably reflecting the lack of adjustment for unemployment. CONCLUSION: The cost of blindness and MSVI in the EU is substantial. Wider use of available cost-effective treatment and prevention strategies may reduce the burden significantly. PMID- 28665741 TI - A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma. AB - Stereotactic body radiation therapy (SBRT) of local tumor would induce an abscopal effect that has been observed in several kinds of human cancers; one important mechanism may involve the improved activation of the host immune system. The immune checkpoint inhibitor can overcome immune tolerance and enhance the activation of antitumor T cells. The combined treatment of SBRT and checkpoint inhibitor may represent a new promising therapeutic approach. Herein, we reported a patient with metastatic renal cell carcinoma (RCC) treated with concurrent SBRT and anti-PD-1 antibody, pembrolizumab, by which the patient achieved an amazingly systemic complete response in only 2.2 months after starting treatment. This case report indicates that the advanced RCC may benefit from the combining treatment of local SBRT and PD-1 inhibitor and provide a useful paradigm worthy of establishing a clinical trial for patients with advanced renal cell carcinoma. PMID- 28665743 TI - Polymerase Chain Reaction and its Correlation with Clinical Features and Treatment Response in Tubercular Uveitis. AB - PURPOSE: Correlation of results of polymerase chain reaction for Mycobacterium tuberculosis (MTB PCR) with clinical features and treatment response in tubercular uveitis. METHODS: Retrospective case study. RESULTS: Among 56 patients, 31 (55.3%) had acute and 25 (44.6%) had chronic uveitis. Uveitis was unilateral in 40 (71.4%) and bilateral in the remaining 16 (28.6%). Anatomical subtypes of uveitis were: anterior in 10 (13.9%) eyes, intermediate in 9 (12.5%), posterior in 17 (23.6%), and pan uveitis in 36 (50%) eyes. MTB PCR was positive in 24 patients. There was an 80% correlation between clinical response to antitubercular therapy (ATT) and PCR results. Twenty-two patients with positive PCR had a good clinical response. The sensitivity and specificity was 73.3% and 92.3%, respectively. CONCLUSIONS: The diagnosis of intraocular TB requires strong clinical suspicion with corroborative laboratory and radiological evidence. A positive PCR is reliable whereas negative results should be correlated with clinical features. An adequate response to ATT supports PCR results. PMID- 28665746 TI - Ovarian Suppression for Women Younger Than 35 Years: New Data to Support Informed Decision Making. PMID- 28665744 TI - If We Don't Ask, Our Patients Might Never Tell: The Impact of the Routine Use of a Patient Values Assessment. AB - PURPOSE: Good communication can be associated with better end-of-life outcomes. The US Oncology Network developed and tested a Values Assessment (VA) for facilitating advance care planning (ACP). The results of the first 1,268 patients are reported. METHODS: The VA consists of 10 questions of the format "How valuable is it to me to..." (eg, "...know that I am not a burden to my family, friends, or helpers?"). Responses were on a four-point scale from unsure to very valuable. VA data on 1,286 patients with metastatic cancer from April 1, 2013, to July 31, 2015, were extracted from the electronic health record, including demographics, diagnosis, stage, chemotherapy, and outcomes (hospice enrollment, place of death). These demographics were compared by using the chi2 or Fisher's exact test or the Wilcoxon rank sum test for continuous variables. RESULTS: A total of 1,268 patients completed the VA (56.7% were >= 65 years of age, 57.8% completed advance directives [ADs]). There were 438 deaths of which 308 had a place of death or a hospice enrollment recorded. Of these, 78% died at home or inpatient hospice; 14.6% died in the hospital. Hospice enrollment with ADs was 76.1% and without, 60.9%. Median length of stay in hospice was 21 days with ADs versus 12.5 days without. Chemotherapy in the last 14 days of life was 8.8% with ADs and 15.5% without. The VA was well accepted by patients. CONCLUSION: A VA as a routine part of practice is feasible and scalable. It facilitates ACP discussions that lead to ADs. The results suggest that VA and ACP lead to less aggressive care at the end of life. PMID- 28665745 TI - Ovine recombinant PrP as an inhibitor of ruminant prion propagation in vitro. AB - Prion diseases are fatal and incurable neurodegenerative diseases of humans and animals. Despite years of research, no therapeutic agents have been developed that can effectively manage or reverse disease progression. Recently it has been identified that recombinant prion proteins (rPrP) expressed in bacteria can act as inhibitors of prion replication within the in vitro prion replication system protein misfolding cyclic amplification (PMCA). Here, within PMCA reactions amplifying a range of ruminant prions including distinct Prnp genotypes/host species and distinct prion strains, recombinant ovine VRQ PrP displayed consistent inhibition of prion replication and produced IC50 values of 122 and 171 nM for ovine scrapie and bovine BSE replication, respectively. These findings illustrate the therapeutic potential of rPrPs with distinct TSE diseases. PMID- 28665748 TI - SUMOylation of HSP27 by small ubiquitin-like modifier 2/3 promotes proliferation and invasion of hepatocellular carcinoma cells. AB - Primary hepatocellular carcinoma (PHC) is a major health problem worldwide and is one of the 10 most commonly diagnosed cancers in China. Heat shock protein 27 (HSP27) were found to be overexpressed in a wide range of malignancies including PHC, however, post-translational modification of HSP27 still needs exploration in PHC. Recently, SUMOylation, an important post-translational modification associating with the development of many kinds of cancers has been intensively studied. In the current study, mRNA and protein level of HSP27 in archived tumor samples representing various pathological characteristics of PHC were examined, and modification of HSP27 by SUMO2/3 was investigated. HSP27 were expressed abundantly in patients' tumor tissues, and found to be associated with pathological progression. Besides, HSP27 was also elevated significantly in liver cancer cell lines Huh7 and HepG2 compared with human hepatocyte cells L02. Furthermore, knockdown of HSP27 was found to be associated with the decreased proliferation and invasion ability in Huh7 and HepG2 cells. Immunofluorescence assay showed that HSP27 and SUMO2/3 were co-localized in the subcellular, and co immunoprecipitation verified the interaction between HSP27 and SUMO2/3. Overexpression of SUMO2/3 upregulated the HSP27 protein level and promotes Huh7 and HepG2 cell proliferation and invasion, and vice versa when the SUMO2/3 was knockdown. Taken together, increased protein level of HSP27 through SUMO2/3 mediated SUMOylation plays crucial roles in the progression of PHC, and this finding may shed light on developing potential therapeutic targets for PHC. PMID- 28665750 TI - Cat Scratch Disease: Not a Benign Condition. AB - PURPOSE: Describe a case series of ocular Cat-scratch-disease (CSD) with vision threatening findings and poor outcomes, indicating severity of disease. METHODS: Retrospective case series from the Uveitis Department of Sao Paulo Federal University from 2011 to 2015. RESULTS: In this period, six eyes of four patients had confirmed diagnosis of CSD. Two were male and two female. Mean age was 24.8 years old [7-45]. Two had bilateral disease. Visual acuity at presentation ranged from no light perception to 20/25. Three patients were treated with doxycycline and one with clarithromycin and prednisone. Visual outcome after treatment ranged from counting fingers to 20/20: 5/6 eyes had final visual acuity of less than 20/40 and 3/6 had final visual acuity equal or less than 20/400. CONCLUSION: Although usually described as a benign disease with spontaneous resolution, CSD can present with atypical manifestations such as vascular angiomatous lesions, serous retinal detachment, and vascular occlusion syndromes, carrying a severe course and guarded prognosis. PMID- 28665747 TI - Analysis of immunological mechanisms exerted by HBsAg-HBIG therapeutic vaccine combined with Adefovir in chronic hepatitis B patients. AB - An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-beta and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-beta and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-alpha in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses. PMID- 28665749 TI - Children who have received no routine polio vaccines in Nigeria: Who are they and where do they live? AB - Nigeria has made remarkable progress against polio, but 2 wild polio virus cases were reported in August 2016; putting an end to 2 y without reported cases. We examined the extent of geographical disparities in childhren not vaccinated against polio and examined individual- and community-level predictors of non vaccination in Nigeria. We applied multilevel logistic regression models to the recent Nigeria Demographic and Health Survey. The percentage of children not routinely vaccinated against polio in Nigeria varied greatly and clustered geographically, mainly in north-eastern states, with a great risk of spread of transmission within these states and potential exportation to neighboring states and countries. Only about one-third had received all recommended 4 routine oral polio vaccine doses. Non-vaccinated children tended to have a mother who had no formal education and who was currently not working, live in poorer households and were from neighborhoods with higher maternal illiteracy rates. PMID- 28665751 TI - Urinary Incontinence and Quality of Death in the Intensive Care Unit. PMID- 28665752 TI - Signaling Pathways Critical for Tooth Root Formation. AB - Tooth is made of an enamel-covered crown and a cementum-covered root. Studies on crown dentin formation have been a major focus in tooth development for several decades. Interestingly, the population prevalence for genetic short root anomaly (SRA) with no apparent defects in crown is close to 1.3%. Furthermore, people with SRA itself are predisposed to root resorption during orthodontic treatment. The discovery of the unique role of Nfic (nuclear factor I C; a transcriptional factor) in controlling root but not crown dentin formation points to a new concept: tooth crown and root have different control mechanisms. Further genetic mechanism studies have identified more key molecules (including Osterix, beta catenin, and sonic hedgehog) that play a critical role in root formation. Extensive studies have also revealed the critical role of Hertwig's epithelial root sheath in tooth root formation. In addition, Wnt10a has recently been found to be linked to multirooted tooth furcation formation. These exciting findings not only fill the critical gaps in our understanding about tooth root formation but will aid future research regarding the identifying factors controlling tooth root size and the generation of a whole "bio-tooth" for therapeutic purposes. This review starts with human SRA and mainly focuses on recent progress on the roles of NFIC-dependent and NFIC-independent signaling pathways in tooth root formation. Finally, this review includes a list of the various Cre transgenic mouse lines used to achieve tooth root formation-related gene deletion or overexpression, as well as strengths and limitations of each line. PMID- 28665754 TI - Challenges in the Treatment of Sarcomas of Adolescents and Young Adults. AB - Adolescent and young adult (AYA) sarcoma patients do not fare as well as their younger counterparts. A variety of factors theorized to underlie such disparate outcomes have been identified including distinct tumor and host biology. Compared to younger patients, AYA patients often develop genetically distinct tumors and are more likely to suffer characteristic therapy-related toxicities. Compounding factors faced by AYA patients include education, finances, employment, and obstacles to treatment adherence. Lack of clinical trial participation among AYA patients has slowed the establishment of optimized age-specific treatment protocols and hindered the collection of biospecimens for scientific investigation. The relative rarity of sarcomas among adult cancers may limit the familiarity of oncologists with state of the art diagnostic and therapeutic aspects of sarcomas in young adults. Among other interventions, improved enrollment on clinical trials is a critical step in addressing the challenges faced by AYA patients. Further insight into unique tumor and host biology among AYA patients is also an important need. PMID- 28665753 TI - The effects of glutamine/asparagine content on aggregation and heterologous prion induction by yeast prion-like domains. AB - Prion-like domains are low complexity, intrinsically disordered domains that compositionally resemble yeast prion domains. Many prion-like domains are involved in the formation of either functional or pathogenic protein aggregates. These aggregates range from highly dynamic liquid droplets to highly ordered detergent-insoluble amyloid-like aggregates. To better understand the amino acid sequence features that promote conversion to stable, detergent-insoluble aggregates, we used the prediction algorithm PAPA to identify predicted aggregation-prone prion-like domains with a range of compositions. While almost all of the predicted aggregation-prone domains formed foci when expressed in cells, the ability to form the detergent-insoluble aggregates was highly correlated with glutamine/asparagine (Q/N) content, suggesting that high Q/N content may specifically promote conversion to the amyloid state in vivo. We then used this data set to examine cross-seeding between prion-like proteins. The prion protein Sup35 requires the presence of a second prion, [PIN+], to efficiently form prions, but this requirement can be circumvented by the expression of various Q/N-rich protein fragments. Interestingly, almost all of the Q/N-rich domains that formed SDS-insoluble aggregates were able to promote prion formation by Sup35, highlighting the highly promiscuous nature of these interactions. PMID- 28665756 TI - Stuttering on function words in bilingual children who stutter: A preliminary study. AB - Evidence suggests young monolingual children who stutter (CWS) are more disfluent on function than content words, particularly when produced in the initial utterance position. The purpose of the present preliminary study was to investigate whether young bilingual CWS present with this same pattern. The narrative and conversational samples of four bilingual Spanish- and English speaking CWS were analysed. All four bilingual participants produced significantly more stuttering on function words compared to content words, irrespective of their position in the utterance, in their Spanish narrative and conversational speech samples. Three of the four participants also demonstrated more stuttering on function compared to content words in their narrative speech samples in English, but only one participant produced more stuttering on function than content words in her English conversational sample. These preliminary findings are discussed relative to linguistic planning and language proficiency and their potential contribution to stuttered speech. PMID- 28665757 TI - Functional Epitopes for Anti-Aquaporin 5 Antibodies in Sjogren Syndrome. AB - We recently reported the presence of anti-aquaporin 5 (AQP5) immunoglobulin G (IgG) in patients with primary Sjogren syndrome (SS) with a sensitivity of 0.73 and a specificity of 0.68. The aim of this study was to identify functional epitopes for the anti-AQP5 autoantibodies detected in control subjects and patients with SS. Recognition of epitopes by anti-AQP5 autoantibodies in sera ( n = 13 for control and n = 24 for SS) or purified IgG ( n = 1 for control and n = 3 for SS) was evaluated by indirect immunofluorescence (IIF) assay performed in the presence or absence of peptides corresponding to the second transmembrane helix and extracellular loops A, C, and E of AQP5. Functional epitopes were determined by measuring the effects of purified IgG and neutralizing peptides on transepithelial osmotic permeability (PfT) of MDCK cells expressing AQP5. In the IIF assay, 89% of SS samples were inhibited by at least 1 peptide, while only half of control samples were inhibited by any peptide. Overall, SS samples were inhibited by peptides corresponding to extracellular loops A, C, and E by 40% to 50%, whereas control samples were inhibited only by peptides corresponding to loop E by <20%. A cyclized peptide (E1) mimicking loop E was most frequently recognized and best differentiated between the SS and control samples. Incubation of MDCK-AQP5 cells with SS but not with control IgG, significantly decreased PfT, which was reversed by neutralization of IgG binding to any of the extracellular loops. In conclusion, the anti-AQP5 autoantibodies detected in control and SS groups showed differences in fine specificity to the functional epitopes of AQP5. The prevalent recognition of functional epitopes by anti-AQP5 autoantibodies from SS patients suggests that anti-AQP5 autoantibodies act as mediators of glandular hypofunction and are a potential therapeutic target in SS. PMID- 28665755 TI - Depletion of carbonic anhydrase IX abrogates hypoxia-induced overexpression of stanniocalcin-1 in triple negative breast cancer cells. AB - Carbonic anhydrase IX (CAIX) is a pH-regulating enzyme that plays a key role in maintaining an alkaline intracellular pH under hypoxic conditions. It is overexpressed in a variety of solid cancers, including breast cancer (BC), and has been implicated in the migration, invasion and stemness of breast cancer cells. Therefore, CAIX recently emerged as a novel therapeutic target for the treatment of BC. To gain an insight into the mechanism of action of CAIX inhibitors, we investigated the impact of CAIX knock-down on the transcriptional response to hypoxia in 2 BC cell lines - MCF7 and MDA-MB-231, by performing a global gene expression analysis. This showed that CAIX knock-down had a relatively minor effect on the global transcriptional response to hypoxia, however it blocked hypoxia-induced upregulation of stanniocalcin-1 (STC1), a secreted glycoprotein that has been shown to promote tumor progression and metastasis in BC. Kaplan-Meier survival analysis showed that high STC1 expression is significantly associated with poor survival in patients with basal-type breast cancer but not luminal A and HER2+ subtypes. Moreover, the association was particularly high in a subgroup of basal-type BC patients with TP53 mutations thus revealing a putative cooperation of STC1 with mutated TP53 in generating highly aggressive BC subgroup. Taken together, these findings show that CAIX inhibitors at least partially act through blocking STC1 induction in BC cells and reveal a subgroup of BC patients, who potentially would benefit most from the treatment with CAIX inhibitors. PMID- 28665759 TI - Prevent-teach-reinforce for families: A model of individualized positive behavior support for home and community, by G. Dunlap, P. S. Strain, J. K. Lee, J. D. Joseph, C. Vatland, & L. Fox. PMID- 28665758 TI - Multilingual issues in qualitative research. AB - This study is a reflective account of how problem solving was accomplished during the translation of semi-structured interviews from a source language to a target language. Data are drawn from two qualitative research studies in which Interpretative Phenomenological Analysis was used to obtain insights into the lived experience of parents of children with disabilities in India and Turkey. The authors discuss challenges to interpretation that arise when participants and the main researcher speak the same non-English native language and the results of the study are intended for an English-speaking audience. A common theme in both the Turkish and Indian data relates to parents' understanding of their children's symptomology and the prognosis. Implications include the need for both reflective conversation within the research team to address the translation of problematic utterances, and documentation of the translation process in the presentation of research findings. PMID- 28665761 TI - Spectral Patterns Reveal Early Resistance Reactions of Barley Against Blumeria graminis f. sp. hordei. AB - Differences in early plant-pathogen interactions are mainly characterized by using destructive methods. Optical sensors are advanced techniques for phenotyping host-pathogen interactions on different scales and for detecting subtle plant resistance responses against pathogens. A microscope with a hyperspectral camera was used to study interactions between Blumeria graminis f. sp. hordei and barley (Hordeum vulgare) genotypes with high susceptibility or resistance due to hypersensitive response (HR) and papilla formation. Qualitative and quantitative assessment of pathogen development was used to explain changes in hyperspectral signatures. Within 48 h after inoculation, genotype-specific changes in the green and red range (500 to 690 nm) and a blue shift of the red edge inflection point were observed. Manual analysis indicated resistance specific reflectance patterns from 1 to 3 days after inoculation. These changes could be linked to host plant modifications depending on individual host-pathogen interactions. Retrospective analysis of hyperspectral images revealed spectral characteristics of HR against B. graminis f. sp. hordei. For early HR detection, an advanced data mining approach localized HR spots before they became visible on the RGB images derived from hyperspectral imaging. The link among processes during pathogenesis and host resistance to changes in hyperspectral signatures provide evidence that sensor-based phenotyping is suitable to advance time consuming and cost-expensive visual rating of plant disease resistances. PMID- 28665762 TI - Preparation and optimization of submicron chitosan capsules by water-based electrospraying for food and bioactive packaging applications. AB - In the present study, a well-defined set of chitosans, with different degrees of acetylation (DA) and degrees of polymerization (DP), were processed by solution electrospraying from a water-based solvent. The solution properties, in terms of surface tension, conductivity, viscosity, and pH, were characterized and related to the physico-chemical properties of the chitosans. It was observed that both DA and DP values of a given chitosan, in combination with biopolymer concentration, mainly determined solution viscosity. This was, in turn, the major driving factor that defined the electrosprayability of chitosan. In addition, the physico chemical properties of chitosans highly influenced solution conductivity and results indicated that the chitosan solutions with low or low-to-medium values of conductivity were the most optimal for electrospraying. The results obtained here also demonstrate that a good process control can be achieved by adjusting the working conditions, i.e. applied voltage, flow-rate, and tip-to-collector distance. Finally, it was also shown that electrosprayability of chitosan with inadequate physico-chemical properties can be improved by solution mixing of very different kinds of this polysaccharide. The resultant electrosprayed submicron chitosan capsules can be applied for encapsulation of food additives and to develop bioactive coatings of interest in food packaging, where these particles alone or containing functional ingredients can be released from the package into the food to promote a health benefit. PMID- 28665763 TI - Overall and specific migration from multilayer high barrier food contact materials - kinetic study of cyclic polyester oligomers migration. AB - Most multilayer high barrier materials used in food packaging have a polyurethane adhesive layer in their structures. In order to assess the safety of these materials, it is important to determine the compounds intentionally added to the adhesives (IAS) as well as those non-intentionally added substances (NIAS). During the manufacture of polyurethane adhesives, some by-products can be formed, such as cyclic polyester oligomers coming from the reaction between dicarboxylic acids and glycols. Since these compounds are not listed in the Regulation 10/2011/EU, they should not be found in migration above 0.01 mg/kg of simulant. In this study two flexible multilayer packaging materials were used and migration was evaluated in simulant A (ethanol 10% v/v), simulant B (acetic acid 3% w/v) and simulant ethanol 95% v/v during 10 days at 60oC. Identification and quantification of non-volatile compounds was carried out by UPLC-MS-QTOF. Most of migrants were oligomers such as cyclic polyesters and caprolactam oligomers. Overall migration and specific migration of adipic acid-diethylene glycol and phthalic acid-diethylene glycol were monitored over time and analysed by UPLC-MS TQ. In most cases, ethanol 95% v/v was the simulant with the highest concentration values. Overall migration kinetics followed a similar pattern than specific migration kinetics. PMID- 28665760 TI - The barrier hypothesis and Oncostatin M: Restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease. AB - Mucosal epithelium maintains tissue homeostasis through many processes, including epithelial barrier function, which separates the environment from the tissue. The barrier hypothesis of type 2 inflammatory disease postulates that epithelial and epidermal barrier dysfunction, which cause inappropriate exposure to the environment, can result in allergic sensitization and development of type 2 inflammatory disease. The restoration of barrier dysfunction once it's lost, or the prevention of barrier dysfunction, have the potential to be exciting new therapeutic strategies for the treatment of type 2 inflammatory disease. Neutrophil-derived Oncostatin M has been shown to be a potent disrupter of epithelial barrier function through the induction of epithelial-mesenchymal transition (EMT). This review will discuss these events and outline several points along this axis at which therapeutic intervention could be beneficial for the treatment of type 2 inflammatory diseases. PMID- 28665764 TI - Determination of Sudan I and a newly synthesized Sudan III positional isomer in the color additive D&C Red No. 17 using high-performance liquid chromatography. AB - Specifications in the Code of Federal Regulations for the color additive D&C Red No. 17 (Colour Index 26100) limit the levels of two subsidiary colors, 1 (phenylazo)-2-naphthol (Sudan I) and 1-[[2-(phenylazo)phenyl]azo]-2-naphthalenol (Sudan III o-isomer), to 3% and 2%, respectively. The present work reports the development of a high-performance liquid chromatography (HPLC) method for the quantitative determination of these subsidiary colors. Since Sudan III o-isomer needed to be synthesized for use as a reference material, a two-step procedure was devised: (i) preparative-scale synthesis of the intermediate 2 aminoazobenzene (2AAB) and its purification by counter-current chromatography and (ii) diazotization of 2AAB and coupling with 2-naphthol. Characterization of the newly synthesized Sudan III o-isomer is also reported. Sudan I and Sudan III o isomer were quantified by using five-point calibration curves with data points ranging from 0.108 to 3.240% and 0.077 to 2.227% by weight, respectively. The HPLC method is rapid (14 min for the total analysis cycle) and simple to implement. It was applied to the analysis of test portions from 25 batches of D&C Red No. 17 submitted to the U.S. Food and Drug Administration (USFDA) for certification, and it has recently been implemented by USFDA for routine batch certification of that color additive. PMID- 28665765 TI - The association between COMT rs4680 and 5-HTTLPR genotypes and concussion history in South African rugby union players. AB - The objective was to investigate the relationship between Catechol-O methyltransferase (COMT) rs4680 and serotonin-transporter-linked polymorphic region (5-HTTLPR) genotypes with concussion history and personality traits. Rugby players ("all levels": n = 303), from high schools ("junior", n = 137), senior amateur, and professional teams ("senior", n = 166), completed a self-reported concussion history questionnaire, Cloninger's Tridimensional Personality Questionnaire, and donated a DNA sample. Participants were allocated into control (non-concussed, n = 140), case (all) (previous suspected or diagnosed concussions, n = 163), or case (diagnosed only) (previous diagnosed concussion, n = 140) groups. COMT rs4680 Val/Val genotypes were over-represented in controls in all levels (P = 0.013, OR:2.00, 95% CI:1.15-3.57) and in juniors (P = 0.003, OR:3.57, 95% CI:1.45-9.09). Junior Val/Val participants displayed increased "anticipatory worry" (P = 0.023). The 5-HTTLPR low expressing group was under represented in controls when all levels were considered (P = 0.032; OR:2.02, 95% CI:1.05-3.90) and in juniors (P = 0.021; OR:3.36, 95% CI:1.16-9.72). Junior 5 HTTLPR low and intermediate expressing groups displayed decreased "harm avoidance" (P = 0.009), "anticipatory worry" (P = 0.041), and "fear of uncertainty" (P < 0.001). This study provides preliminary indications that personality associated genetic variants can influence concussion in rugby. PMID- 28665766 TI - Administrator Leadership Styles and Their Impact on School Nursing. AB - In comparison to other professional staff in an educational based setting, the registered professional school nurse has unique roles, responsibilities, education, training, and scope of practice. In carrying out this unique and specialized role, school nurses operate under a building administrator, the leader of the building and often the immediate supervisor of the school nurse. In addition, many school nurses in small districts are the only registered professional nurse employed by the school. The building administrator's leadership style not only sets the tone for the day-to-day operations in the school but also impacts the school nurse functioning and program implementation. This article reviews the three most common types of leadership styles as defined by Kurt Lewin-laissez-faire, democratic, and coercive/authoritarian-and their potential impact on school nursing practice. In addition, the article provides recommendations for school nurses for successful practice with regard to supervisor leadership styles. PMID- 28665767 TI - Increasing Sexual and Reproductive Health Education Equity for Hispanics in Schools. AB - In the United States, the overall teen birth rate has been decreasing. In 1991, the teen birth rate was 61.8 births for every 1,000 teen females, but in 2014, the same overall rate decreased to 24.2 births for every 1,000 teen females. Unfortunately, this decrease has not reflected equally across all the races/ethnic groups. In 2014, the teen birth rate for Hispanics was 38 births per 1,000 teen females. The NASN is aware about the disparities on teen birth among racial/ethnical groups and has released a specific statement about the role of school nurses on the improvement of pregnancy outcomes. This article explains the cultural, linguistic, and educational barriers faced by Hispanic teens with limited English proficiency when preventing pregnancy and describes the development and implementation of a sexual and reproductive health education curriculum. The implications for school nurses will be discussed. PMID- 28665768 TI - Identification of a sensitive urinary biomarker, selenium-binding protein 1, for early detection of acute kidney injury. AB - Acute kidney injury (AKI) is associated with increased mortality rate in patients but clinically available biomarkers for disease detection are currently not available. Recently, a new biomarker, selenium-binding protein 1 (SBP1), was identified for detection of nephrotoxicity using proteomic analysis. The aim of this study was to assess the sensitivity of urinary SBP1 levels as an early detection of AKI using animal models such as cisplatin or ischemia/reperfusion (I/R). Sprague-Dawley rats were injected with cisplatin (6 mg/kg, once i.p.) and sacrificed at 1, 3, or 5 days after treatment. Ischemia was achieved by bilaterally occluding both kidneys with a microvascular clamp for 45 min and verified visually by a change in tissue color. After post-reperfusion, urine samples were collected at 9, 24, and 48 hr intervals. Urinary excretion of protein-based biomarkers was measured by Western blot analysis. In cisplatin treated rats, mild histopathologic alterations were noted at day 1 which became severe at day 3. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at day 3. Levels of urinary excretion of SBP1, neutrophil gelatinase-associated lipocalin (NGAL), and a tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly elevated at day 3 and 5 following drug treatment. In the vehicle-treated I/R group, serum levels of BUN and SCr and AST activity were significantly increased compared to sham. Urinary excretion of SBP1 and NGAL rose markedly following I/R. The urinary levels of SBP1, NGAL, TIMP-1, and KIM-1 proteins excreted by AKI patients and normal subjects were compared. Among these proteins, a marked rise in SBP1 was observed in urine of patients with AKI compared to normal subjects. Based upon receiver-operator curves (ROC), SBP1 displayed a higher area under the curve (AUC) scores than levels of SCr, BUN, total protein, and glucose. In particular, SBP1 protein was readily detected in small amounts of urine without purification. Data thus indicate that urinary excretion of SBP1 may be useful as a reliable biomarker for early diagnosis of AKI in patients. PMID- 28665769 TI - Lack of evidence for microplastic contamination in honey. AB - Honey samples from Switzerland were investigated with regard to their microplastic particle burden. Five representative honey samples of different origin were processed following a standardized protocol to separate plastic-based microparticles from particles of natural origin, such as pollen, propolis, wax, and bee-related debris. The procedure was optimized to minimize post-sampling microplastic cross-contamination in the laboratory. The isolated microplastic particles were characterized and grouped by means of light microscopy as well as chemically characterized by microscopically coupled Raman and Fourier transform infrared spectroscopy. Five particle classes with an abundance significantly above blank levels were identified: black particles (particle count between 1760/kg and 8680/kg), white transparent fibres (particle count between 132/kg and 728/kg), white transparent particles (particle count between 60/kg and 172/kg), coloured fibres (particle count between 32/kg and 108/kg), and coloured particles (particle count between 8/kg and 64/kg). The black particles, which represented the majority of particles, were identified as char or soot and most probably originated from the use of smokers, a widespread practice in beekeeping. The majority of fibres were identified as cellulose or polyethylene terephthalate and were most likely of textile origin. In addition to these particle and fibre groups lower numbers of fragments were detected that were related to glass, polysaccharides or chitin, and few bluish particles contained copper phthalocyanine pigment. We found no indications that the honey samples were significantly contaminated with microplastic particles. PMID- 28665770 TI - Blocking landing techniques in volleyball and the possible association with anterior cruciate ligament injury. AB - The number and type of landings performed after blocking during volleyball matches has been related to the potential risk of ACL injury. The aim of the present study was to determine whether gender affects the frequency of specific blocking landing techniques with potential risk of ACL injury from the perspective of foot contact and subsequent movement after the block used by volleyball players during competitive matches. Three matches involving four female volleyball teams (fourteen sets) and three matches involving four male volleyball teams (thirteen sets) in the Czech Republic were analyzed for this study. A Pearson chi-square test of independence was used to detect the relationship between gender and different blocking techniques. The results of the present study showed that gender affected single-leg landings with subsequent movement in lateral direction and double-leg landings. Although the total number of landings was lower for male athletes than for female athletes, a larger portion of male athletes demonstrated single leg landings with a subsequent movement than female athletes. Single leg landings with a subsequent movement have a higher potential risk of ACL injury. PMID- 28665771 TI - Increased Antimicrobial Resistance in a Novel CMY-54 AmpC-Type Enzyme with a GluLeu217-218 Insertion in the Omega-Loop. AB - During a Spanish surveillance study, a natural variant of a CMY-type beta lactamase related to CMY-2 with a GluLeu217-218 insertion in the Omega-loop (designated CMY-54) was found to increase the minimum inhibitory concentractions to beta-lactams in a clinical strain of Escherichia coli. The aim of this study was to characterize CMY-54 by genetic, microbiological, and biochemical analysis. The blaCMY-54 gene is encoded by a plasmid of around 100 kb that hybridizes with K and FIB probes. The genetic context of blaCMY-54 and blaCMY-2 genes was found to be very similar. E. coli expressing CMY-54 under isogenic conditions showed a clear fourfold to eightfold increase in MICs to penicillins, cefotaxime, ceftazidime, and aztreonam compared with CMY-2. The catalytic efficiencies of pure CMY-2 and CMY-54 proteins correlated with their microbiological parameters. CMY-2 protein was more resistant to thermal denaturation than CMY-54, indicating that the Omega-loop of CMY-54 may be wider and more relaxed and probably enables better accommodation of these antimicrobials. Otherwise, the higher stabilization of CMY-2 may induce a slight reduction of the dynamics of this enzyme and primarily affect the hydrolysis of some of the bulkiest antibiotics. In summary, the GluLeu217-218 insertion observed in CMY-54 compared to CMY-2 produces a beta lactamase with a distinctive catalytic efficacy for beta-lactam antimicrobials likely caused by an increased flexibility slightly affecting the active site shape, highlighting the relevance of single mutations on the hydrolytic spectrum in class C beta-lactamases. PMID- 28665772 TI - Conflict between Family Caregivers and Staff in Nursing Homes: Feasibility of the Daily Diary Method. AB - OBJECTIVE: The purpose of this study was to investigate the daily diary method (DDM) for assessing family-staff conflicts in nursing homes, to provide descriptive information on conflict, and to examine the relationship between conflict and mood among family caregivers. METHODS: Participants were nine caregivers that experienced conflict with staff on an ongoing basis. They were contacted daily by telephone for 14 days and were asked (1) whether a conflict had occurred, (2) to describe the severity and type of conflict, and (3) to rate their positive and negative affect. RESULTS: Compliance was excellent with no attrition, and there were only 2 missing data points over 126 potential observations. Conflicts occurred on 22% of the days, were rated as moderately severe, and were related to poor resident care, lack of information, and staff attitudes. Participants reported significantly lower positive affect (p < .05) and higher negative affect (p < .001) on conflict versus no-conflict days. Exit interviews indicated positive attitudes towards the DDM. CONCLUSIONS: These results support the feasibility of the DDM for providing an in-depth understanding of family-staff conflict and its relationship to caregivers' mood. CLINICAL IMPLICATIONS: The DDM would ideally be used as an outcome measure in studies that assess interventions that target high-conflict family-staff relationships. PMID- 28665773 TI - Implementing and Sustaining Team-Based Telecare for Bipolar Disorder: Lessons Learned from a Model-Guided, Mixed Methods Analysis. AB - BACKGROUND: Telemental health interventions have empirical support from clinical trials and structured demonstration projects. However, their implementation and sustainability under less structured clinical conditions are not well demonstrated. INTRODUCTION: We conducted a follow-up analysis of the implementation and sustainability of a clinical video teleconference-based collaborative care model for individuals with bipolar disorder treated in the Department of Veterans Affairs to (a) characterize the extent of implementation and sustainability of the program after its establishment and (b) identify barriers and facilitators to implementation and sustainability. MATERIALS AND METHODS: We conducted a mixed methods program evaluation, assessing quantitative aspects of implementation according to the Reach, Efficacy, Adoption, Implementation, and Maintenance implementation framework. We conducted qualitative analysis of semistructured interviews with 16 of the providers who submitted consults, utilizing the Integrated Promoting Action on Research Implementation in the Health Services implementation framework. RESULTS: The program demonstrated linear growth in sites (n = 35) and consults (n = 915) from late 2011 through mid-2016. Site-based analysis indicated statistically significant sustainability beyond the first year of operation. Qualitative analysis identified key facilitators, including consult content, ease of use via electronic health record, and national infrastructure. Barriers included availability of telehealth space, equipment, and staff at the sites, as well as the labor-intensive nature of scheduling. DISCUSSION: The program achieved continuous growth over almost 5 years due to (1) successfully filling a need perceived by providers, (2) developing in a supportive context, and (3) receiving effective facilitation by national and local infrastructure. CONCLUSION: Clinical video teleconference-based interventions, even multicomponent collaborative care interventions for individuals with complex mental health conditions, can grow vigorously under appropriate conditions. PMID- 28665775 TI - The Use of Tablet Technology by Older Adults in Health Care Settings-Is It Effective and Satisfying? A Systematic Review and Meta Analysis. AB - OBJECTIVES: This systematic review/meta-analysis examines the potential for older people to accept and use tablet technology in clinical settings by assessing satisfaction and effectiveness. METHODS: A comprehensive literature search was conducted of PubMed, SCOPUS, and CINAHL through March 2017. Inclusion criteria included studies with any clinical use of a tablet technology with a median patient age above 65 years. RESULTS: We included a total of 12 studies (4 randomized controlled trials, 4 cross-sectional studies, and 4 pre/post studies). Interventions included the use of tablet technology for medication self management, post-surgery education, memory retention, cognitive rehabilitation, and exercise promotion. The use of tablet technology by older people in clinical settings was associated with high satisfaction with a pooled prevalence of satisfaction of 78%; 95% CI 27-100. We did not find evidence for effectiveness in improving clinical or behavioral outcomes. CONCLUSIONS: Older people can use and are satisfied with table technology in clinical settings. More studies are needed to evaluate the effectiveness of tablet technology at promoting health outcomes. CLINICAL IMPLICATIONS: Clinicians should be encouraged to utilize tablet technology in the care of older patients. PMID- 28665774 TI - New DRB complexes for new DRB functions in plants. AB - Double-stranded RNA binding (DRB) proteins are generally considered as promoting cofactors of Dicer or Dicer-like (DCL) proteins that ensure efficient and precise production of small RNAs, the sequence-specificity guide of RNA silencing processes in both plants and animals. However, the characterization of a new clade of DRB proteins in Arabidopsis has recently challenged this view by showing that DRBs can also act as potent inhibitors of DCL processing. This is achieved through sequestration of a specific class of small RNA precursors, the endogenous inverted-repeat (endoIR) dsRNAs, thereby selectively preventing production of their associated small RNAs, the endoIR-siRNAs. Here, we concisely summarize the main findings obtained from the characterization of these new DRB proteins and discuss how the existence of such complexes can support a potential, yet still elusive, biological function of plant endoIR-siRNAs. PMID- 28665777 TI - Longevity of Anterior Composite Restorations in a General Dental Practice-Based Network. AB - This practice-based study investigated the performance of a large set of anterior composite restorations placed by a group of 24 general practices. Based on data from electronic patient files, the longevity of 72,196 composite restorations was analyzed, as placed in 29,855 patients by 47 general dental practitioners between 1996 and 2011. Annual failure rates (AFRs) were calculated, and variables associated with failure were assessed by multivariate Cox regression analysis with shared frailty for 2 age groups (5 to 24 y and >=25 y). The observation time of restorations varied from 2 wk to 13 y, with a mean of 4.8 y, resulting in a mean AFR of 4.6% (95% confidence interval [95% CI], 4.5% to 4.6%) at 5 y. Among dentists, a relevant variation in clinical performance of restorations was observed, with an AFR between 2% and 11%. The risk for restoration failure increased in individuals up to 12 y old, having a 17% higher risk for failure when compared with the age group of 18 to 25 y (hazard ratio, 1.17; 95% CI, 1.03 to 1.34), and for the age group >65 y, having a 81% higher risk for failure when compared with 25 to 35 y (hazard ratio, 1.81; 95% CI, 1.66 to 1.98). In both multivariate models, there was a difference in longevity of restorations for different teeth in the arch, with fillings in central incisors being the most prone to failure and replacement. It was concluded that anterior composite restorations placed by general dental practitioners showed an adequate clinical performance, with a relevant difference in outcome among operators. PMID- 28665776 TI - Scaffolding proteins in the development and maintenance of the epidermal permeability barrier. AB - The skin of mammals and other terrestrial vertebrates protects the organism against the external environment, preventing heat, water and electrolyte loss, as well as entry of chemicals and pathogens. Impairments in the epidermal permeability barrier function are associated with the genesis and/or progression of a variety of pathological conditions, including genetic inflammatory diseases, microbial and viral infections, and photodamage induced by UV radiation. In mammals, the outside-in epidermal permeability barrier is provided by the joint action of the outermost cornified layer, together with assembled tight junctions in granular keratinocytes found in the layers underneath. Tight junctions serve as both outside-in and inside-out barriers, and impede paracellular movements of ions, water, macromolecules and microorganisms. At the molecular level, tight junctions consist of integral membrane proteins that form an extracellular seal between adjacent cells, and associate with cytoplasmic scaffold proteins that serve as links with the actin cytoskeleton. In this review, we address the roles that scaffold proteins play specifically in the establishment and maintenance of the epidermal permeability barrier, and how various pathologies alter or impair their functions. PMID- 28665779 TI - A New Laser-Processing Strategy for Improving Enamel Erosion Resistance. AB - In the present study, a new automatic laser-processing strategy allowing standardized irradiation of natural tooth areas was investigated. The objective was to find a combination of laser parameters that could cause over a 600 degrees C temperature increase at the enamel surface while not damaging enamel, avoiding temperature change above 5.5 degrees C in the pulp and increasing enamel erosion resistance. Seventy-seven bovine enamel samples were randomly divided into 6 laser groups and 1 negative control (C/no treatment/ n = 11). A scanning strategy (7 * 3 mm) was used for the CO2 laser treatment (lambda = 10.6 um, 0.1-18 J/cm2) with different pulse durations-namely, 20 us (G20), 30 us (G30), 55 us (G55), and 490 us (G490), as well as 2 modified pulse distances (G33d, G40d). Measurements of temperature change were performed at the surface (thermal camera/50 Hz), at the underside (thermocouples), and at the pulp chamber using a thermobath and human molars ( n = 10). In addition, histology and X-ray diffraction (XRD/ n = 10) were performed. Erosion was tested using an erosive cycling over 6 d, including immersion in citric acid (2 min/0.05 M/pH = 2.3) 6 times daily. Surface loss was measured using a profilometer and statistical analysis with a 2-way repeated-measures analysis of variance (alpha = 0.05). Only G20 fulfilled the temperature requirements at the surface (619 +/- 21.8 degrees C), at the underside (5.3 +/- 1.4 degrees C), and at the pulp (2.0 +/- 1.0 degrees C), and it caused no mineral phase change and significant reduction of enamel surface loss (-13.2 +/- 4.0 um) compared to C (-37.0 +/- 10.1 um, P < 0.05). A laser scanning strategy (20 us/2 kHz/1.25 J/cm2, 3.4 mm/s) has been established that fulfilled the criteria for biological safety and significantly increased enamel erosion resistance (64%) in vitro. PMID- 28665780 TI - Viscoless Manual Small Incision Cataract Surgery with Trabeculectomy. AB - PURPOSE: To compare the efficacy of combined manual small incision cataract and glaucoma surgery with anterior chamber maintainer (ACM) alone versus that with intraoperative viscoelastics. METHODS: Hospital electronic medical records of patients who underwent small incision cataract and trabeculectomy and intraocular lens implantation without Mitomycin-C from 2014 to 2016 were identified from the hospital operation theater database for this retrospective, hospital-based comparative study. All MSICS surgeries were performed by a single surgeon under peribulbar block. Data retrieved from all patients undergoing surgery with viscoelastic (group 2) or under AC maintainer without viscoelastic (group 1) included preoperative visual acuity, preoperative treated intraocular pressure, number of anti-glaucoma medications before surgery, total surgical time, intraoperative complications, postoperative best-corrected visual acuity and IOP at one week and one month, need for additional procedures, and corneal clarity. Differences in surgical time and postoperative course in both groups were compared. RESULTS: Of 268 manual combined cataract and glaucoma surgeries done from 2014-2016, we identified 147 eyes of 130 age-matched patients, which included 51 PACG, 50 POAG, 12 NTG, and 24 PXG eyes with a mean age of 66 +/-11.2 years and 64+/- 10.8 years in group 2 (n=74) and group 1 (n=73), respectively; p=0.9. The surgical time was significantly lower in group 1 (16+/-4.8 minutes compared to 44+/-14.6 minutes for group 2; p<0.001) with transient edema seen <1 week after surgery in 24 eyes of group 2 and seven eyes of group 1; p=0.02. The postoperative IOP at all postoperative visits dropped to >50% in both groups with 11 eyes (PXG n=6, PACG n=5) requiring medications for rise in intraocular pressure at a median time of 1.2 months (r=0.2-3 months). The final visual acuity improved >4 snellen lines in all cases with two patients with advanced damage having 1 line improvement in Snellen acuity at final follow-up. CONCLUSION: The ACM can help completely avoid the use of viscoelastic during surgery, which can be an effective technique for MSICS with trabeculectomy in low resource stings. Training for such procedures should be incorporated into residency training programs. PMID- 28665778 TI - dRNA-seq transcriptional profiling of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis NRRL18488 and general analysis of the transcriptome. AB - FK506 (tacrolimus) is a valuable immunosuppressant produced by several Streptomyces strains. In the genome of the wild type producer Streptomyces tsukubaensis NRRL18488, FK506 biosynthesis is encoded by a gene cluster that spans 83.5 (kb). A whole transcriptome differential shotgun sequencing (dRNA-seq) of S. tsukubaensis was performed to analyze transcription at 2 different time points; before and during active FK506 production. In total, 8,914 transcription start sites were identified in either condition, which enabled precise determination of the 5'-UTR length of the corresponding transcripts as well as the identification of 2 consensus sequence motifs in the promoter regions. The transcription start sites of all gene operons within the FK506 cluster were identified, including 3 examples of leaderless RNA transcripts. These data provide detailed insight into the transcription of the FK506 biosynthetic gene cluster to support future regulatory studies, genetic manipulation, and industrial production. PMID- 28665781 TI - How Often Is End-of-Life Care in the United States Inconsistent with Patients' Goals of Care? AB - BACKGROUND: Despite its importance, little is known about the prevalence of, and factors associated with, end-of-life care that is consistent with patients' wishes. OBJECTIVE: To document the proportion of bereaved respondents who reported care inconsistent with patients' wishes and characterize the predictors of end-of-life care associated with inconsistent care. DESIGN: Retrospective analysis of nationally representative survey data of persons aged >65 years. Settings/Subjects: Bereaved family members responding to the last month of life component of the National Health and Aging Trends Study. Methods/Measurements: Bereaved family members assessed treatment decisions and their consistency with patients' wishes, unmet needs, and quality of care. We examined differences between patients receiving inconsistent versus consistent care. RESULTS: A total of 1212 family members were interviewed, representing (when weighted) 4.8 million decedents. Thirteen percent stated that care was inconsistent with decedent's wishes. Consistent care was unassociated with patient's sex, age, or race/ethnicity. Death at home was more likely to represent consistent care, and death in the hospital or nursing home was more likely to represent inconsistent care (p = 0.052). Respondents reporting inconsistent care were more likely to rate the quality of care as fair or poor (19.1% vs. 4.8%, p < 0.001), reported more unmet needs for pain management (30.5% vs. 19.4%, p = 0.037), and reported more concerns with communication (29.8% vs. 17.0%, p = 0.003). CONCLUSIONS: One in eight respondents stated care in the last months of life was inconsistent with patients' wishes; such care was associated with worse ratings of care, pain management, and communication with clinicians. PMID- 28665782 TI - Antipodocalyxin Antibody chPcMab-47 Exerts Antitumor Activity in Mouse Xenograft Models of Colorectal Adenocarcinomas. AB - Podocalyxin (PODXL) is expressed in several cancers, including brain tumors and colorectal cancers. PODXL overexpression is an independent predictor of progression, metastasis, and poor outcome. We recently immunized mice with recombinant human PODXL, which was produced using LN229 glioblastoma cells, and produced a clone PcMab-47 that could be used for investigating PODXL expression by flow cytometry and immunohistochemical analysis. Herein, we produced a human mouse chimeric PcMab-47 (chPcMab-47) and investigated its antitumor activity against PODXL-expressing tumors. chPcMab-47 reacted with LN229, LN229/PODXL, and Chinese hamster ovary (CHO)/PODXL cells, but it did not react with CHO-K1 or PODXL-knockout LN229 cell line (PDIS-13). chPcMab-47 exerted antitumor activity against a mouse xenograft model using CHO/PODXL. Furthermore, chPcMab-47 was reactive with colorectal cancer cell lines such as HCT-15, Caco-2, HCT-8, and DLD 1. chPcMab-47 also exhibited antitumor activity against a mouse xenograft model using HCT-15. These results suggest that chPcMab-47 could be useful for antibody therapy against PODXL-expressing cancers. PMID- 28665783 TI - Cervical Cancer Screening Preferences Among Trans-Masculine Individuals: Patient Collected Human Papillomavirus Vaginal Swabs Versus Provider-Administered Pap Tests. AB - PURPOSE: Trans-masculine (TM, i.e., persons who have a masculine spectrum gender identity, but were assigned female sex at birth) individuals face disparities in cervical cancer screening rates compared to cisgender women. Some unique barriers to screening in this population are specific to Pap tests. Introduction of self collected frontal (i.e., vaginal) swabs for human papillomavirus (HPV) testing as a screening strategy may obviate these barriers. This study elucidates cervical cancer screening preferences among TM individuals. METHODS: TM individuals participated in in-depth interviews (n = 31) and online surveys (n = 32) to explore perceptions and experiences regarding cervical cancer screening, including the acceptability of self-collected frontal HPV swabs for cervical cancer screening compared to provider-administered Pap tests. Provider-collected frontal HPV swab acceptability was also explored. RESULTS: Most TM individuals (94% in-person and 91% online participants) preferred either the self- or provider-collected frontal HPV swab to the Pap test. Participants perceived self- and provider-collected frontal HPV swabs to be less invasive, provoke less gender discordance, and promote a greater sense of agency compared to Pap tests. However, some participants expressed concern about HPV swab accuracy and, regarding the self-collected swab, discomfort about the need to engage with genitals they may not want to acknowledge. Individuals who reported positive provider relationships found Pap tests and provider-collected frontal swabs more acceptable than those who did not. CONCLUSION: Frontal HPV swabs have the potential to promote regular cervical cancer screening among TM individuals and to narrow screening disparities. Work is ongoing to establish swab accuracy and develop shared decision-making tools. PMID- 28665784 TI - The evidence for a microRNA product of human DROSHA gene. AB - MicroRNAs are short RNA molecules that regulate function and stability of a large subset of eukaryotic mRNAs. In the main pathway of microRNA biogenesis, a short "hairpin" is excised from a primary transcript by ribonuclease DROSHA, followed by additional nucleolytic processing by DICER and inclusion of the mature microRNA into the RNA-induced silencing complex. We report that a microRNA-like molecule is encoded by human DROSHA gene within a predicted stem-loop element of the respective transcript. This putative mature microRNA is complementary to DROSHA transcript variant 1 and can attenuate expression of the corresponding protein. The findings suggest a possibility for a negative feedback loop, wherein DROSHA processes its own transcript and produces an inhibitor of its own biosynthesis. PMID- 28665785 TI - Informatics for Health 2017: Advancing both science and practice. AB - INTRODUCTION: The Informatics for Health congress, 24-26 April 2017, in Manchester, UK, brought together the Medical Informatics Europe (MIE) conference and the Farr Institute International Conference. This special issue of the Journal of Innovation in Health Informatics contains 113 presentation abstracts and 149 poster abstracts from the congress. DISCUSSION: The twin programmes of "Big Data" and "Digital Health" are not always joined up by coherent policy and investment priorities. Substantial global investment in health IT and data science has led to sound progress but highly variable outcomes. Society needs an approach that brings together the science and the practice of health informatics. The goal is multi-level Learning Health Systems that consume and intelligently act upon both patient data and organizational intervention outcomes. CONCLUSION: Informatics for Health demonstrated the art of the possible, seen in the breadth and depth of our contributions. We call upon policy makers, research funders and programme leaders to learn from this joined-up approach. PMID- 28665787 TI - Effects of procalcitonin testing on antibiotic use and clinical outcomes in patients with upper respiratory tract infections. An individual patient data meta analysis. AB - BACKGROUND: Several trials found procalcitonin (PCT) helpful for guiding antibiotic treatment in patients with lower respiratory tract infections and sepsis. We aimed to perform an individual patient data meta-analysis on the effects of PCT guided antibiotic therapy in upper respiratory tract infections (URTI). METHODS: A comprehensive search of the literature was conducted using PubMed (MEDLINE) and Cochrane Library to identify relevant studies published until September 2016. We reanalysed individual data of adult URTI patients with a clinical diagnosis of URTI. Data of two trials were used based on PRISMA-IPD guidelines. Safety outcomes were (1) treatment failure defined as death, hospitalization, ARI-specific complications, recurrent or worsening infection at 28 days follow-up; and (2) restricted activity within a 14-day follow-up. Secondary endpoints were initiation of antibiotic therapy, and total days of antibiotic exposure. RESULTS: In total, 644 patients with a follow up of 28 days had a final diagnosis of URTI and were thus included in this analysis. There was no difference in treatment failure (33.1% vs. 34.0%, OR 1.0, 95% CI 0.7-1.4; p=0.896) and days with restricted activity between groups (8.0 vs. 8.0 days, regression coefficient 0.2 (95% CI -0.4 to 0.9), p=0.465). However, PCT guided antibiotic therapy resulted in lower antibiotic prescription (17.8% vs. 51.0%, OR 0.2, 95% CI 0.1-0.3; p<0.001) and in a 2.4 day (95% CI -2.9 to -1.9; p<0.001) shorter antibiotic exposure compared to control patients. CONCLUSIONS: PCT guided antibiotic therapy in the primary care setting was associated with reduced antibiotic exposure in URTI patients without compromising outcomes. PMID- 28665786 TI - Maternal and Cord Blood Manganese Concentrations and Early Childhood Neurodevelopment among Residents near a Mining-Impacted Superfund Site. AB - BACKGROUND: Environmental manganese exposure has been associated with adverse neurodevelopmental outcomes among school-aged children; yet, few studies have evaluated prenatal exposure. OBJECTIVES: Our study examines associations between prenatal manganese concentrations and placental transfer of manganese with neurodevelopment in 224 2-y-old children residing near the Tar Creek Superfund Site. METHODS: We collected maternal and cord blood at delivery, measured manganese using inductively coupled plasma mass spectrometry, and assessed neurodevelopment using the Bayley Scales of Infant Development-II. Associations between manganese and mental (MDI) and psychomotor (PDI) development indices were estimated in multivariable models. Placental transfer, approximated by cord/maternal manganese ratio, cord/total manganese ratio (total=maternal+cord), and by joint classification according to high or low (above or below median) maternal and cord manganese, was evaluated as a predictor of neurodevelopment. RESULTS: Median levels [interquartile ranges (IQR)] of manganese in maternal and cord blood, respectively, were 24.0 (19.5-29.7) and 43.1 (33.5-52.1) MUg/L. Adjusting for lead, arsenic, and other potential confounders, an IQR increase in maternal manganese was associated with -3.0 (95% CI: -5.3, -0.7) points on MDI and -2.3 (95% CI: -4.1, -0.4) points on PDI. Cord manganese concentrations were not associated with neurodevelopment scores. Cord/maternal and cord/total manganese ratios were positively associated with MDI [cord/maternal: beta=2.6 (95% Cl: -0.04, 5.3); cord/total: beta=22.0 (95% Cl: 3.2, 40.7)] and PDI (cord/maternal: beta=1.7 (95% Cl: -0.5, 3.9); cord/total: beta=15.6 (95% Cl: 0.3, 20.9)). Compared to mother-child pairs with low maternal and cord manganese, associations with neurodevelopment scores were negative for pairs with either high maternal, high cord, or high maternal and cord manganese. CONCLUSIONS: Maternal blood manganese concentrations were negatively associated with early childhood neurodevelopment scores in our study. Findings highlight the importance of understanding maternal exposures during pregnancy and factors influencing placental transfer. https://doi.org/10.1289/EHP925. PMID- 28665788 TI - Heavy chain disease: our experience. PMID- 28665789 TI - Return to work program efficacy with Self-Regulation Therapy (SRT(r)): Case study with complex trauma and concurrent disorders. AB - Background This study shows the efficacy of treating complex cases neurobiologically using Self-Regulation Therapy (SRT(r)) within the context of return to work goals. Case presentation This is a single case study of a 32-year old white female. This case study follows a client with concurrent diagnoses of post-traumatic stress disorder (PTSD), bipolar disorder I and substance abuse over the course of 2 years of treatment with SRT(r). Using SRT(r) as primary modality and Likert Scale self-report on the Zettl Scale of Dysregulation, psychiatric medication monitoring and pharmaceutical tracking, this study shows session summaries and progress. Results After six sessions the client was cleared by her psychiatrist for return to work. Her medications were reduced and her post traumatic symptoms abated. She no longer met diagnostic criteria for PTSD or substance abuse after nine sessions. She returned to work successfully and maintained sobriety and continued symptom reduction. Follow up over a 2-year time period showed consistency and continued improvements in both her professional and her personal life. Conclusions Clients with complex traumatic history with concurrent diagnosis are typically difficult to treat in traditional psychotherapy with limited long-term success. This creates challenges in therapy because the traumas occur during key developmental periods of life. This study shows the efficacy of treating complex cases neurobiologically using SRT(r). Using SRT(r), clinicians are able to address both developmental and complex trauma to reduce sympathetic arousal in the nervous system providing symptom reduction and even resolution of previous clinical diagnoses. PMID- 28665790 TI - Effects of quinine on gastric ulcer healing in Wistar rats. AB - Background Quinine (QT) is an important anti-malarial drug; however, there is little information about its effects on the gut. Therefore, this study aimed to investigate the effects of a therapeutic dose of QT on the healing of gastric ulcer in rats. Methods Male Wistar rats weighing 150-200 g were divided into three groups: control rats without ulcer (group 1), ulcerated rats treated with 1 mL/kg (p.o.) normal saline (NS) (group 2), and ulcerated rats treated with 10 mg/kg (p.o.) QT (group 3). Ulcers were induced by serosal application of 80 % acetic acid to the stomach of rats anaesthetized with 50 mg/kg thiopentone sodium and treatment was given three times daily. Healing was assessed on days 3, 7 and 10 after ulcer induction by macroscopic measurement of: ulcer area, histology, lipid peroxidation, superoxide dismutase activity and gastric mucus secretion. Results At day 3, there was no significant difference (p>0.05) in ulcer areas between NS- and QT-treated rats. By day 10, however, the percentage area healed in NS treated (59.6+/-2.35 %) was significantly higher (p<0.05) than in QT rats (49.0+/-2.20 %) and clearing of inflammatory cells and re-epithelization was greater in NS-treated group. By days 7 and 10, lipid peroxidation was significantly higher in QT animals, when compared with NS-treated rats and controls (p<0.05). Superoxide dismutase activity and mucus secretion were significantly (p<0.05) higher in NS-treated than QT-treated rats. Conclusions QT delayed ulcer healing by prolonging the inflammatory phase of healing, increasing oxidative stress, reducing antioxidant activity and gastric mucus secretion. PMID- 28665791 TI - Circulating soluble fms-like tyrosine kinase-1 and placental growth factor from 10 to 40 weeks' pregnancy in normotensive women. AB - INTRODUCTION: Circulating soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are potential markers for preeclampsia. The objective was to construct and analyse the reference ranges of serum levels of sFlt-1 and PlGF throughout the course of pregnancy in low-risk Thai pregnant women. METHODS: We enrolled 110 low-risk, Thai women singleton pregnancy from 10 to 40 gestational weeks. Serum concentrations of sFlt-1 and PlGF were measured with an automated assay. The reference ranges of serum levels of sFlt-1, PlGF and sFlt-1/PlGF ratio were constructed and assessed for possible correlations with gestational age, maternal factors [age, parity, tobacco use, artificial reproductive technologies (ARTS) and body mass index (BMI)], and pregnancy outcomes (gestational age at delivery, development of preeclampsia, neonatal birth weight and placental weight). RESULTS: None of the subjects developed preeclampsia. Serum sFlt-1 concentrations significantly elevated from 20 to 40 gestational weeks (P=0.003). Significant elevation and dropping of serum PlGF levels and sFlt-1/PlGF ratios were observed at 10 to 29 and 30 to 40 weeks of gestation, respectively (P<0.001). There was an inversed correlation between serum PlGF levels at 20 to 29 gestational weeks and neonatal birth weights (r= 0.48, P<0.05). There were no associations between serum levels of sFlt-1, PlGF, or sFlt-1/PlGF ratios and maternal BMI, gestational age at delivery, or placental weight (P>0.05). Effects from parity, smoking and ARTS were inconclusive. CONCLUSION: Robust change of serum PlGF levels suggests for its broader clinical application compared to sFlt-1. Prediction of preeclampsia using serum analytes may be gestational period specific. PMID- 28665792 TI - Status of essential elements in autism spectrum disorder: systematic review and meta-analysis. AB - Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder that imposes heavy financial burden on governments and families of affected children. It is considered a multifactorial condition, where trace elements are among environmental factors that may contribute to ASD. Meanwhile, the between-study variance is high. The present systematic review was designed to investigate the difference in trace element measures between patients with ASD and control subjects. Meta-analyses showed that the hair concentrations of chromium (p=0.024), cobalt (p=0.012), iodine (p=0.000), iron (p=0.017), and magnesium (p=0.007) in ASD patients were significantly lower than those of control subjects, while there were higher magnesium levels in the hair of ASD patients compared to that of controls (p=0.010). Patients with ASD had higher blood levels of copper (p=0.000) and lower levels of zinc compared to controls (p=0.021). Further urinary iodine levels in patients with ASD were decreased in comparison with controls (p=0.026). Sensitivity analyses showed that ASD patients in non Asian but not in Asian countries had lower hair concentrations of chromium compared to controls. Also, such analyses indicated that ASD patients in Asian countries had lower hair zinc concentrations, whereas ASD patients in non-Asian countries had higher hair zinc concentrations in comparison with control subjects. This study found significant differences in the content of trace elements between patients with ASD compared to controls. The findings help highlighting the role of trace elements as environmental factors in the etiology of ASD. PMID- 28665793 TI - A succinct access to omega-hydroxylated jasmonates via olefin metathesis. AB - In higher plants, jasmonates are lipid-derived signaling molecules that control many physiological processes, including responses to abiotic stress, defenses against insects and pathogens, and development. Among jasmonates, omega-oxidized compounds form an important subfamily. The biological roles of these omega modified derivatives are not fully understood, largely due to their limited availability. Herein, a brief (two-step), simple and efficient (>80% yield), versatile, gram-scalable, and environmentally friendly synthetic route to omega oxidized jasmonates is described. The approach utilizes olefin cross-metathesis as the key step employing inexpensive, commercially available substrates and catalysts. PMID- 28665794 TI - Facts about phthalate toxicity in humans and their occurrence in alcoholic beverages. AB - Phthalates are esters of phthalic acid and aliphatic alcohol added to plastic to improve its softness, flexibility, and extensibility. They easily migrate from plastic products into the environment because of their physical and chemical properties. This review summarises their characteristics, distribution in the environment, monitoring, use, toxic effects on human health, regulatory limits in different matrices and products, and tolerable daily intake. The studies we have reviewed suggest that phthalates have a potential to affect reproduction and development in humans. Due to the inconsistent data, further studies are needed and, in the meantime, precautionary policies must be implemented. Here we draw attention to the methods of determining phthalate levels in alcoholic beverages and reported levels in plum spirits produced in Croatia. Legally produced and moderately consumed plum spirits do not seem to increase the risk of phthalate toxicity for human health. We conclude with recommendations for the effective monitoring of phthalate exposure in humans and for the implementation of alternative materials in alcohol production. PMID- 28665795 TI - Electromagnetic fields at a mobile phone frequency (900 MHz) trigger the onset of general stress response along with DNA modifications in Eisenia fetida earthworms. AB - Eisenia fetida earthworms were exposed to electromagnetic field (EMF) at a mobile phone frequency (900 MHz) and at field levels ranging from 10 to 120 V m-1 for a period of two hours (corresponding to specific absorption rates ranging from 0.13 to 9.33 mW kg-1). Potential effects of longer exposure (four hours), field modulation, and a recovery period of 24 h after two hours of exposure were addressed at the field level of 23 V m-1. All exposure treatments induced significant DNA modifications as assessed by a quantitative random amplified polymorphic DNA-PCR. Even after 24 h of recovery following a two hour-exposure, the number of probe hybridisation sites displayed a significant two-fold decrease as compared to untreated control earthworms, implying a loss of hybridisation sites and a persistent genotoxic effect of EMF. Expression of genes involved in the response to general stress (HSP70 encoding the 70 kDa heat shock protein, and MEKK1 involved in signal transduction), oxidative stress (CAT, encoding catalase), and chemical and immune defence (LYS, encoding lysenin, and MYD, encoding a myeloid differentiation factor) were up-regulated after exposure to 10 and modulated 23 V m-1 field levels. Western blots showing an increased quantity of HSP70 and MTCO1 proteins confirmed this stress response. HSP70 and LYS genes were up-regulated after 24 h of recovery following a two hour-exposure, meaning that the effect of EMF exposure lasted for hours. PMID- 28665796 TI - Contamination of pine and birch wood dust with microscopic fungi and determination of its sterol contents. AB - Wood compounds, especially sterols, are connected with the level of contamination with microscopic fungi. Within this study, tests were conducted on wood dust samples collected at various work stations in a pine and birch timber conversion plant. Their contamination with mycobiota was measured as the concentration of ergosterol (ERG) by ultra performance liquid chromatography (UPLC). Another aim of this study was to assess the effect of contamination with microscopic fungi on the sterol contents in wood dusts. Analyses were conducted on five sterols: desmosterol, cholesterol, lanosterol, stigmasterol, and beta-sitosterol using UPLC and their presence was confirmed using gas chromatography/mass spectrometry (GC/MS). The results of chemical analyses showed the greatest contamination with mycobiota in birch wood dust. We also observed varied contents of individual sterols depending on the wood dust type. Their highest concentration was detected in birch dust. The discriminant analysis covering all tested compounds as predictors showed complete separation of all tested wood dust types. The greatest discriminatory power was found for stigmasterol, desmosterol, and ergosterol. PMID- 28665797 TI - Surveillance of bacterial colonisation on contact surfaces in different medical wards. AB - This study was conducted to determine the bacterial colonization of some bacterial groups, including extended-spectrum beta-lactamase (ESBLs) producers and methicillin-resistant Staphylococcus aureus (MRSA), on surfaces of the equipment and instruments in patient rooms and other workspaces in three different medical wards. The number of microorganisms on swabs was determined with the colony count method on selective microbiological mediums. The aerobic mesophylic microorganisms were found in 73.5 % out of 102 samples, with the average and maximum values of 2.6 * 102 and 4.6 * 103 colony forming units (CFU) 100 cm-2, respectively. Members of the family Enterobacteriaceae, coagulase positive staphylococci, coagulase-negative staphylococci, and enterococci were detected in 23.4, 31.4, 53.2, and 2.9 % of samples, respectively. The differences in bacterial counts on the surfaces of the psychiatric, oncology, and paediatric wards were statistically significant (P<0.001). About 40 % out of 19 isolates from the family Enterobacteriaceae showed multiple resistance to three or more different groups of tested antibiotics, while ESBL was confirmed for only one strain. Staphylococci isolates were mostly resistant to penicillin. MRSA was confirmed in 5.2 % of the tested S. aureus isolates. Greater attention should be paid to cleaning and the appropriate choice of disinfectants, especially in the psychiatric ward. Employees should be informed about the prevention of the spreading of nosocomial infections. Routine application of rapid methods for hygiene control of surfaces is highly recommended. PMID- 28665798 TI - Consumer knowledge and attitudes toward healthy eating in Croatia: a cross sectional study. AB - Unlike fast and restaurant food, diet rich in fibre is known to contribute significantly to health. The aim of our study was to assess eating habits such as consumption of fibre-rich, fast, and restaurant food of the general population in Croatia. For this purpose we used a validated survey designed by the Polytechnic Institute Viseu in Portugal, which includes questions about demographics, good eating habits related to the consumption of the main sources of dietary fibre (fruit, vegetables, and whole grains), and unhealthy eating habits related to the consumption of fast food and restaurant meals. Between October 2014 and March 2015 we received answers from 2,536 respondents aged between 18-70 years, of whom 67.4 % were women and 32.6 % were men. Most respondents reported consuming one serving of vegetables and one piece of fruit a day, and whole grains every other day. Women and urban residents reported consuming larger amounts of fruit, vegetables, and whole grains than men (p<0.001). Men, in turn, reported eating out and eating fast food more often than women (p<0.001). Eating out highly correlated with eating fast food, which translates to lower consumption of dietary fibre (p<0.001). Higher education correlated positively with the consumption of fibre-rich food, but it also correlated positively with the consumption of fast and restaurant food (p<0.001). While eating fast food is not the predominant dietary practice in Croatia, over 50 % of respondents have reported eating fast food at least once a week. Our data also indicate that consumption of fruit, vegetables, and whole grains falls below the national and international dietary recommendations. PMID- 28665799 TI - Lycopene restores trace element levels in ochratoxin A-treated rats. AB - This study was designed to investigate the in vivo effects of ochratoxin A (OTA) and/or lycopene on the levels of selenium, zinc, and copper in the liver, kidneys, and testes of male Sprague-Dawley rats. The rats were treated with OTA (0.5 mg kg-1 day-1) and/or lycopene (5 mg kg-1 day-1) by gavage for 7 or 14 days. Trace element levels were measured by atomic absorption spectrometry. OTA significantly lowered selenium (20 % in the liver, 17 % in the kidney, and 40 % in the testis), zinc (24 % in the liver, 23 % in the kidney, and 26 % in the testis), and copper levels (40 % in the liver and 10 % in the kidney). Lycopene alone did not affect the trace element levels in any of the organs. In combination with OTA, however, it significantly restored liver, kidney, and testis selenium and zinc levels compared to the group treated with OTA alone. Our results have confirmed that depletion of trace elements in different organs is one of the mechanisms of action of OTA. They also suggest that lycopene interferes with this depleting effect and restores trace element levels, the implications of which need to be further investigated. PMID- 28665800 TI - The influence of shear stress on the adhesion capacity of Legionella pneumophila. AB - Bacterial adhesion is a complex process influenced by many factors, including hydrodynamic conditions. They affect the transfer of oxygen, nutrients, and bacterial cells in a water supply and cooling systems. The aim of this study was to identify hydrodynamic effects on bacterial adhesion to and detachment from stainless steel surfaces. For this purpose we observed the behaviour of bacterium L. pneumophila in no-flow and laminar and turbulent flow conditions simulated in a fluid flow chamber. The bacterial growth in no-flow and laminar flow conditions was almost identical in the first 24 h, while at 48 and 72 h of incubation, the laminar flow stimulated bacterial growth. In the second part of this study we found that laminar flow accelerated bacterial adhesion in the first 48 h, but after 72 h the amount of bacterial cells exposed to the flow dropped, probably due to detachment. In the third part we found that the turbulent flow detached more bacterial cells than the laminar, which indicates that the strength of shear forces determines the rate of bacterial removal. PMID- 28665801 TI - A new, simplified model for the estimation of polyphenol oxidation potentials based on the number of OH groups. AB - We present a new and simpler regression model for the estimation of the first oxidation potentials (Ep1) of flavonoids based on the number of phenolic, alcoholic, and carboxylic OH groups. In the regression we included the Ep1 of 12 polyphenols (mostly flavonols and catechins) that were measured in our laboratory at pH 3. The model yielded r=0.986 and SE=0.040. Later successive inclusions of previously reported Ep values into the regression model, 7 at pH 3, the model (N=19) yielded r=0.980, SE=0.046 and 19 at pH 7 the model (N=38), yielded r=0.985, SE=0.044. PMID- 28665802 TI - The double face of light effects: circadian adjustment or disruption. PMID- 28665804 TI - Septic Arthritis of the Shoulder: A Comparison of Treatment Methods. AB - INTRODUCTION: In-hospital outcomes were compared among patients with shoulder septic arthritis treated with arthrocentesis, open irrigation and debridement, or arthroscopic irrigation and debridement. METHODS: The Nationwide Inpatient Sample database was queried for all cases of native shoulder septic arthritis between 2002 and 2011. Patient demographics, comorbidities, and hospitalization complications were compared for the shoulder arthrocentesis (nonsurgical) and open or arthroscopic irrigation and debridement (surgical) groups. RESULTS: Data for 7,145 patients were analyzed. Medical comorbidities and complications were more common in the nonsurgical group than in the open surgical group (septicemia, 36.7% versus 23.6%, P < 0.001; death, 6.5% versus 2.5%, P < 0.001; pneumonia, 11.3% versus 6.2%, P < 0.001; septic shock, 4% versus 2.2%, P < 0.001; and urinary tract infection, 15.5% versus 10.2%, P < 0.001). The mean length of stay was longer in the nonsurgical group compared with the open surgical group (11.5 days versus 10.5 days, respectively; P = 0.002) and the percentage of patients discharged to home was lower (55.1% versus 64.0%, respectively; P < 0.001). Compared with the open surgical group, the arthroscopic surgical group had higher incidences of perioperative septicemia and urinary tract infection and similar average length of stay, hospital charges, and blood transfusion rates, but a lower incidence of osteomyelitis (P < 0.001). In a subgroup of patients with septicemia, Staphylococcus aureus was the most frequently cultured causative organism. DISCUSSION: Septic arthritis in the shoulder is challenging to manage, and patients often have medical comorbidities and complications. In this study, the nonsurgically treated patients had substantially more preexisting comorbidities and in-hospital complications than the surgically treated patients had, which likely contributed to the longer average length of stay and lower discharge percentage in the nonsurgical group. CONCLUSION: Patients with septic arthritis of the shoulder frequently experience substantial systemic complications regardless of the treatment method. Septicemia was a common complication among all treatment groups, with cultures most frequently indicating Staphylococcus aureus as the causative organism. LEVEL OF EVIDENCE: Therapeutic level III. PMID- 28665803 TI - Methylation differences reveal heterogeneity in preterm pathophysiology: results from bipartite network analyses. AB - BACKGROUND: Recent studies have shown that epigenetic differences can increase the risk of spontaneous preterm birth (PTB). However, little is known about heterogeneity underlying such epigenetic differences, which could lead to hypotheses for biological pathways in specific patient subgroups, and corresponding targeted interventions critical for precision medicine. Using bipartite network analysis of fetal DNA methylation data we demonstrate a novel method for classification of PTB. METHODS: The data consisted of DNA methylation across the genome (HumanMethylation450 BeadChip) in cord blood from 50 African American subjects consisting of 22 cases of early spontaneous PTB (24-34 weeks of gestation) and 28 controls (>39 weeks of gestation). These data were analyzed using a combination of (1) a supervised method to select the top 10 significant methylation sites, (2) unsupervised "subject-variable" bipartite networks to visualize and quantitatively analyze how those 10 methylation sites co-occurred across all the subjects, and across only the cases with the goal of analyzing subgroups and their underlying pathways, and (3) a simple linear regression to test whether there was an association between the total methylation in the cases, and gestational age. RESULTS: The bipartite network analysis of all subjects and significant methylation sites revealed statistically significant clustering consisting of an inverse symmetrical relationship in the methylation profiles between a case-enriched subgroup and a control-enriched subgroup: the former was predominantly hypermethylated across seven methylation sites, and hypomethylated across three methylation sites, whereas the latter was predominantly hypomethylated across the above seven methylation sites and hypermethylated across the three methylation sites. Furthermore, the analysis of only cases revealed one subgroup that was predominantly hypomethylated across seven methylation sites, and another subgroup that was hypomethylated across all methylation sites suggesting the presence of heterogeneity in PTB pathophysiology. Finally, the analysis found a strong inverse linear relationship between total methylation and gestational age suggesting that methylation differences could be used as predictive markers for gestational length. CONCLUSIONS: The results demonstrate that unsupervised bipartite networks helped to identify a complex but comprehensible data-driven hypotheses related to patient subgroups and inferences about their underlying pathways, and therefore were an effective complement to supervised approaches currently used. PMID- 28665805 TI - HIV in Orthopaedic Surgery. AB - The emergence of HIV in the United States has had important implications in the surgical setting. This blood-borne pathogen poses risks to both the surgeon and the patient undergoing an orthopaedic procedure. Although there has been research regarding the likelihood of orthopaedic surgeons contracting HIV during a surgical procedure, the correlation of HIV with postoperative prognosis has not been extensively examined. Because HIV-positive patients may be immunodeficient, they are at increased risk for certain postoperative complications, especially infection. Orthopaedic surgeons should have a thorough understanding of the effects of this disease on patients to optimize preoperative decision making, intraoperative care, and postoperative recovery. PMID- 28665806 TI - Pediatric ophthalmologists wear many hats. PMID- 28665807 TI - New paradigms in the conservative surgical and interventional management of adenomyosis. AB - PURPOSE OF REVIEW: Adenomyosis is commonly diagnosed in women of reproductive age. Interest in conservative interventions has grown as more women desire fertility preservation or avoidance of hysterectomy. This review discusses surgical and interventional methods for treatment of symptomatic adenomyosis. The technique, evidence, and utility of each method are described. RECENT FINDINGS: Hysteroscopic ablative techniques are associated with lower morbidity than with hysterectomy but may result in an unacceptable risk of treatment failure. Surgical adenomyomectomy may provide good symptomatic improvement, especially when combined with preoperative gonadotropin-releasing hormone agonist treatment. Laparoscopic myometrial coagulation is associated with high rates of future pregnancy complications. Uterine artery ligation has limited value as an isolated approach but, coupled with other techniques, provides adequate therapeutic control. Bilateral uterine artery embolization may improve symptoms, without significantly compromising fertility. Focused ultrasonic surgical methods also show promise in alleviating symptoms without compromising reproductive outcomes. SUMMARY: A multitude of surgical and interventional options are available for young women with symptomatic adenomyosis. These treatment methods have unique associated risks and benefits, and may have varying impacts on long-term symptom control, fertility, and reproductive outcomes. PMID- 28665809 TI - The rapid evolution of molecular genetic diagnostics in neuromuscular diseases. AB - PURPOSE OF REVIEW: The development of massively parallel sequencing (MPS) has revolutionized molecular genetic diagnostics in monogenic disorders. The present review gives a brief overview of different MPS-based approaches used in clinical diagnostics of neuromuscular disorders (NMDs) and highlights their advantages and limitations. RECENT FINDINGS: MPS-based approaches like gene panel sequencing, (whole) exome sequencing, (whole) genome sequencing, and RNA sequencing have been used to identify the genetic cause in NMDs. Although gene panel sequencing has evolved as a standard test for heterogeneous diseases, it is still debated, mainly because of financial issues and unsolved problems of variant interpretation, whether genome sequencing (and to a lesser extent also exome sequencing) of single patients can already be regarded as routine diagnostics. However, it has been shown that the inclusion of parents and additional family members often leads to a substantial increase in the diagnostic yield in exome wide/genome-wide MPS approaches. In addition, MPS-based RNA sequencing just enters the research and diagnostic scene. SUMMARY: Next-generation sequencing increasingly enables the detection of the genetic cause in highly heterogeneous diseases like NMDs in an efficient and affordable way. Gene panel sequencing and family-based exome sequencing have been proven as potent and cost-efficient diagnostic tools. Although clinical validation and interpretation of genome sequencing is still challenging, diagnostic RNA sequencing represents a promising tool to bypass some hurdles of diagnostics using genomic DNA. PMID- 28665808 TI - Disparities in access to pediatric hearing health care. AB - PURPOSE OF REVIEW: There are significant disparities in care facing children with hearing loss. The objective of this review is to assess the current disparities in pediatric hearing healthcare delivery, describe the barriers of efficient and effective pediatric hearing health care, and explore the innovations to improve pediatric hearing healthcare delivery. RECENT FINDINGS: Children with hearing loss from certain geographic regions or ethnic background are significantly delayed in diagnosis and treatment. Multiple patient characteristics (presentation of hearing loss), parental factors (insurance status, socioeconomic status, educational status, and travel distance to providers), and provider barriers (specialist shortage and primary care provider challenges) prevent the delivery of timely hearing health care. Advances, such as improved screening programs and the expansion of care through remote services, may help to ameliorate these disparities. SUMMARY: Timely identification and treatment of pediatric hearing loss is critical to prevent lifelong language complications. Children from vulnerable populations, such as rural residents, face significant disparities in care. Careful assessment of these barriers and implementation of culturally acceptable interventions are paramount to maximize communication outcomes of children with hearing loss. PMID- 28665810 TI - Diabetic Myopathy: current molecular understanding of this novel neuromuscular disorder. AB - PURPOSE OF REVIEW: Here we summarize the evidence from human studies of the impairments to the structural, functional, and metabolic capacities in skeletal muscle in those with type 1 diabetes (T1D) - a condition known as diabetic myopathy. Given the importance of skeletal muscle for blood lipid and glucose management, the development and progression of diabetic myopathy would not only lead to increased insulin resistance, but also impact the ability to mitigate dysglycemic/dyslipidemic burdens. RECENT FINDINGS: Despite the importance of skeletal muscle in whole-body metabolic control, studies investigating diabetic myopathy are startling limited. Recent findings have demonstrated that those with T1D exhibit decreased force production, increased fatigability, loss of muscle stem cells, and a greater reliance on glycolytic metabolism, as a result of reduced mitochondrial capacity. SUMMARY: We propose a mechanistic model for the development of diabetic myopathy based on the human findings to date. This model suggests that repeated insulin injections in those with T1D leads to recurrent periods of intracellular hyperglycemia in myofibers. Resultant reductions in mitochondrial function lead to greater reliance on glycolytic metabolism and a concomitant shift in fiber type composition. Studies defining the scope and magnitude of diabetic myopathy and testing the veracity of this model are urgently needed in order to develop appropriate therapeutic strategies to maximize muscle health in those with T1D. PMID- 28665811 TI - Small fibre neuropathy. AB - PURPOSE OF REVIEW: To provide a review on the state-of-art of clinical features, diagnostics, genetics and treatments of small fibre neuropathy (SFN). RECENT FINDINGS: The spectrum of clinical features has been widened from the classical presentation of burning feet as length-dependent SFN to that of small fibre dysfunction and/or degeneration associated with focal, diffuse and episodic neuropathic pain syndromes. The involvement of small nerve fibres in neurodegenerative diseases has been further defined, challenging the relationship between neuropathic pain symptoms and small fibre loss. The clinical reliability of skin biopsy has been strengthened by the availability of normative values for both the immunohistochemistry techniques used and their comparison, and by side and short-term follow-up analyses. Corneal confocal microscopy has implemented its diagnostic potentiality because of the availability of age-adjusted and sex adjusted normative values. Genetic studies expanded the panel on genes involved in SFN because of the discovery of new mutations in SCN10A and SCN11A, besides the first found in SCN9A, and identification of mutations in COL6A5 in patients with itching. SUMMARY: In the last 5 years, the chapter of SFN has been widened by new clinical and genetics descriptions leading to a more comprehensive approach to patients in clinical practice and research. PMID- 28665812 TI - Interventions to increase uptake of faecal tests for colorectal cancer screening: a systematic review. AB - International guidelines promote screening by faecal tests in asymptomatic individuals at average risk of colorectal cancer (CRC), but uptake does not reach recommended levels in most countries. The aim of this study was to synthetize evidence on (a) interventions aiming to increase uptake of faecal tests for CRC screening, in asymptomatic individuals at average risk of CRC, (b) interventions that targeted general practitioner (GP) involvement and (c) interventions that targeted nonresponders or disadvantaged groups. A systematic review of randomized controlled trials, searching PubMed, Embase and the Cochrane Library database, based on the Cochrane's Preferred Reporting Items for Systematic Review and Meta Analysis Protocols 2015 guidelines was performed. The risk of bias of included trials was assessed. From 24 included RCTs, the following interventions increase uptake of faecal tests: advance notification letter (OR 1.20-1.51), postal mailing (OR 1.31-7.70), telephone contacts with an advisor (OR 1.36-7.72). Three interventions showed positive effects of GP involvement such as a GP-signed invitation letter [odds ratio (OR)=1.26], GP communication training (OR=1.22) or mailing reminders to GPs (OR=14.8). Inconclusive results were found for studies comparing different types of faecal tests and those testing the effectiveness of providing various types of written information. Advance notification letters, postal mailing of the faecal tests, written reminders and telephone contacts with an advisor increase patient uptake of faecal tests. There was only limited evidence on the effect of GP involvement on screening test uptake and a lack of studies focusing on nonresponders or disadvantaged groups. PMID- 28665813 TI - Current directions in research and treatment of fear of cancer recurrence. AB - PURPOSE OF REVIEW: An expert meeting in Ottawa in 2015 galvanized efforts to answer key questions relevant to the understanding and management of fear of cancer recurrence (FCR). The aim of this review is to summarize key developments. RECENT FINDINGS: A consensus on the definition of FCR has helped to further research in this area. There have been a number of theories put forward to account for the development of FCR, all of which share key components. Importantly, a number of important trials have been published that confirm both brief and more intensive interventions can successfully treat FCR. SUMMARY: The consensus definition of FCR is an important development, as is the development of treatments for FCR. There are now evidence-based options for the management of patients with clinical levels of FCR. Future research priorities include determining the optimal cut-off points for identifying clinically significant FCR, testing the major tenets of the recent theoretical formulations of FCR; and determining the relative efficacy and cost-effectiveness of different treatment approaches for managing FCR. PMID- 28665814 TI - Investigation of Slow-wave Activity Saturation during Surgical Anesthesia Reveals a Signature of Neural Inertia in Humans. AB - BACKGROUND: Previously, we showed experimentally that saturation of slow-wave activity provides a potentially individualized neurophysiologic endpoint for perception loss during anesthesia. Furthermore, it is clear that induction and emergence from anesthesia are not symmetrically reversible processes. The observed hysteresis is potentially underpinned by a neural inertia mechanism as proposed in animal studies. METHODS: In an advanced secondary analysis of 393 individual electroencephalographic data sets, we used slow-wave activity dose response relationships to parameterize slow-wave activity saturation during induction and emergence from surgical anesthesia. We determined whether neural inertia exists in humans by comparing slow-wave activity dose responses on induction and emergence. RESULTS: Slow-wave activity saturation occurs for different anesthetics and when opioids and muscle relaxants are used during surgery. There was wide interpatient variability in the hypnotic concentrations required to achieve slow-wave activity saturation. Age negatively correlated with power at slow-wave activity saturation. On emergence, we observed abrupt decreases in slow-wave activity dose responses coincident with recovery of behavioral responsiveness in ~33% individuals. These patients are more likely to have lower power at slow-wave activity saturation, be older, and suffer from short-term confusion on emergence. CONCLUSIONS: Slow-wave activity saturation during surgical anesthesia implies that large variability in dosing is required to achieve a targeted potential loss of perception in individual patients. A signature for neural inertia in humans is the maintenance of slow-wave activity even in the presence of very-low hypnotic concentrations during emergence from anesthesia. PMID- 28665815 TI - Bleeding manifestations in heterozygotes with prothrombin deficiency or abnormalities vs. unaffected family members as observed during a long follow-up study. AB - : To investigate the prevalence of bleeding in heterozygotes for prothrombin deficiencies. Homozygotes or compound heterozygotes with Factor II (FII) levels of less than 10% of normal are always severely symptomatic.On the contrary little is known about the heterozygous population who have FII levels around 40-50% of normal.Forty-four patients heterozygous for this defect, in comparison with age and sex matched 44 unaffected family members, have been followed during a mean observational period of 22.5 years (range 4-35 years). The study was carried out in Padua between the years 1971 and 2010.The mean prothrombin activity was 0.49 IU/dl (range 0.38-0.62) and 0.91 IU/dl (range 0.81-1.10) in the heterozygotes and in the normal counterparts, respectively.In total, 14 patients showed bleeding manifestations vs. only three among the controls. Bleeding was sometimes spontaneous but more frequently occurred after tooth extractions, surgery, or delivery.Some heterozygous patients had also to be given replacement therapy to control the bleeding. No substitution therapy was ever needed for the normal counterparts.The prothrombin activity levels in the patients who were symptomatic tended to be lower than in those who remained asymptomatic.The difference in the frequency of bleeding and in the bleeding score between patients and unaffected family members was statistically significant (P = 0.007 and 0.0007).Prothrombin levels of about 40-50% of normal may not represent well tolerated hemostatic levels in case of surgical procedures, tooth extraction, or delivery. These data may have general clinical significance even for patients who have acquired defects. PMID- 28665816 TI - Ultrasound-Guided Injection to the Fifth Cervical Spinal Nerve Root Level. PMID- 28665817 TI - Physiatric Patient Care, Graduate Medical Education Training, and Graduate Medical Education Funding: A Call for Alignment. PMID- 28665818 TI - Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: A Case-Control Study With a Pair of Identical Twins. PMID- 28665819 TI - Targeting EZH2 in cancer therapy. AB - PURPOSE OF REVIEW: The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZH2 in cancer therapy. We discuss the active development of small molecules targeting the enzymatic activity of EZH2/polycomb repressive complex 2 (PRC2). RECENT FINDINGS: Genetic, transcriptional, and posttranscriptional dysregulation of EZH2 is frequently observed in many cancer types. EZH2 promotes tumorigenesis by altering the expression of numerous tumor suppressor genes. Furthermore, the executive molecular processes initiated by EZH2, such as NF-kappaB activation, microRNA silencing, tumor immune evasion, and noncanonical transcription regulation, appear to be the fundamental characteristics of each cancer. Systematic investigations have suggested coordinated regulation of the cancer epigenome wherein antagonistic complexes of both polycomb and SWI/SNF are involved. Frequent loss-of-function mutations in epigenetic factors, such as ARID1A, SMARCA4, SMARCB1, BAP1, and KDM6A, are likely to elicit the EZH2/PRC2-addicted situation. Our comprehensive understanding encourages the development of advanced strategies for the appropriate manipulation of the cancer epigenome. Moreover, a couple of small molecules that can effectively inhibit the enzymatic activity of EZH2/PRC2 have been translated into early-phase clinical trials. SUMMARY: The EZH2-mediated epigenome and subsequent transcriptome define cellular identity. Effective and specific strategies for the manipulation of EZH2/PRC2 may lead to the development of more precise cancer medicines. PMID- 28665820 TI - Magnetoencephalographic Recordings in Infants Using a Standard-Sized Array: Technical Adequacy and Diagnostic Yield. AB - PURPOSE: Although a few magnetoencephalography (MEG) systems have been built specifically for infants (<2 years), most children are routinely examined using MEG systems designed primarily to accommodate adult subjects. The practicality of the adult MEG device has not been systematically reviewed in infants with epilepsy. The aim of this study is to investigate whether infant epilepsy patients, whose heads are small relative to the sensor helmet, can have clinically successful MEG recordings using the conventional adult-size MEG device. METHODS: We reviewed our database of 964 patients who were referred for routine MEG epilepsy examination between January 2008 and May 2015. We reanalyzed the original data of the infant patients to investigate whether epileptiform discharges of the usual amplitudes could be detected. RESULTS: Nine patients (about 1%) were infants. All the infant MEG records were processed with temporally extended signal space separation to remove environmental artifacts. Seven of the nine were processed with movement compensation processing using continuous head position monitoring. Magnetoencephalography captured epileptic abnormalities in all the infants: interictal in nine and ictal in five. The source amplitudes of 10 representative interictal dipoles from each of the infants ranged from 46.0 to 437.2 (mean: 180.1, SD: +/-92.5) nA-m. CONCLUSIONS: Despite increased brain to sensor distance, the conventional MEG device can detect epileptic abnormalities in infants, facilitated by monitoring head position and postprocessing with temporally extended signal space separation, with or without movement compensation. Magnetoencephalography is useful for managing infants with epilepsy using the conventional adult machine, without special adaptations for small heads. PMID- 28665821 TI - Spine and Thoracic Height Measurements Have Excellent Interrater and Intrarater Reliability in Patients With Early Onset Scoliosis. AB - STUDY DESIGN: Reproducibility of measurements. OBJECTIVE: This study investigates the reliability and standard error of measurement of spine and thoracic height radiographic measurements in patients with early onset scoliosis (EOS). SUMMARY OF BACKGROUND DATA: Spine and thoracic height radiographic measurements are often used as a surrogate for pulmonary development in patients with EOS. There is limited literature validating the reliability of spine and thoracic height measurements in the EOS population. METHODS: Using pilot data, we determined measuring 49 unique radiographs would provide 80% power to obtain a 95% confidence interval (CI) width of 0.05 for the interclass correlation coefficients (ICCs). A random sampling strategy, stratified by underlying diagnosis from the Classification of Early Onset Scoliosis (C-EOS), was used to distribute the diagnoses in the study sample. Two attending pediatric spine surgeons, two pediatric orthopedic fellows, and two research assistants measured coronal spine (T1-S1) and thoracic (T1-T12) height on digital radiographs using imaging software (Surgimap; Nemaris, Inc, New York) on two separate occasions at least 3 weeks apart. Order of images was randomized for the second iteration. Linear mixed model regression analyses were used to estimate interrater and intrarater reliability. RESULTS: The study sample included subjects (N = 48) with idiopathic (N = 17, 35%), congenital (N = 16, 33%, 1 patient excluded), neuromuscular (N = 11, 23%), and syndromic (N = 4, 8%) scoliosis. Overall interrater reliability estimates for spine height (ICC: 0.894, 95% CI: 0.847 0.932) and thoracic height (ICC: 0.890, 95% CI: 0.844-0.929) were excellent. Intrarater reliability estimates for spine height (ICC: 0.906, 95% CI: 0.830 0.943) and thoracic height (ICC: 0.898, 95% CI: 0.817-0.938) were also excellent. CONCLUSION: There is excellent interrater and intrarater reliability for radiographic measurements of spine and thoracic height in the EOS population at our institution. LEVEL OF EVIDENCE: 2. PMID- 28665822 TI - A Pragmatic Approach to the Application of the Code of Ethics in Nursing Education. AB - The code of ethics for nurses was written for nurses in all settings. However, the language focuses primarily on the nurse in context of the patient relationship, which may make it difficult for nurse educators to internalize the code to inform practice. The purpose of this article is to explore the code of ethics, establish that it can be used to guide nurse educators' practice, and provide a pragmatic approach to application of the provisions. PMID- 28665823 TI - Students and Faculty Perceptions of an Undergraduate Nursing Research Internship Program. AB - Nursing students in baccalaureate programs report that research is not visible in practice, and faculty conducting research report rarely interacting with students in undergraduate nursing programs. We examined student and faculty perceptions of a research internship embedded in an existing evidence-based practice course. Students (n = 15) and faculty (n = 5) viewed the internship as a positive experience that provided meaningful hands-on skills while generating interest in a potential research career. The internship also provided faculty the opportunity to identify potential doctoral students. PMID- 28665824 TI - Building DNP Essential Skills in Clinical Data Management and Analysis. AB - Effectively teaching clinical data management and analysis in a doctor of nursing (DNP) program requires attention to developing skills that foster improvement at the bedside. The purpose of this article is to describe a DNP clinical data management and analysis course specific to translation and improvement in practice. The student evaluation scores are high; however, faculty evaluation identifies opportunities to improve translation and application at the point of the scholarly practice project. PMID- 28665825 TI - Rightsizing Projects for Non-Research-Intensive Schools of Nursing via Academic Clinical Partnerships. AB - Most academic-clinical partnerships are described as formal agreements between schools of nursing at research-intensive universities and large teaching hospitals. This article demonstrates less formal versions of academic-clinical partnerships established between a small, private liberal arts university school of nursing and 2 regional clinical agencies. In both exemplars, students, faculty, and staff contributed to evidence-based practice projects. Schools of nursing in non-research-intensive environments can develop right-size academic clinical partnerships that are beneficial for all parties involved. PMID- 28665826 TI - Unrecognized Left Heart Failure in LVAD Recipients: The Role of Routine Invasive Hemodynamic Testing. AB - The role of routine right heart catheterizations (RHCs) in left ventricular assist device (LVAD) patients is undefined. We analyzed 105 continuous-flow LVAD recipients who underwent an RHC approximately 3 months after implant. In 38 patients, LVAD speed was ramped with the goal of optimizing hemodynamics. Our cohort consisted of 71 (68%) HeartMate II (HMII) and 34 (32%) HeartWare (HVAD) patients. Thirty patients (29%) had either a reduced cardiac index (CI <= 2.2 L/min/m), elevated pulmonary capillary wedge pressure (PCWP > 18 mm Hg), or both. A subgroup of 38 patients (19 with abnormal hemodynamics) underwent LVAD ramping. With LVAD ramping, normalization of hemodynamics was achieved in 13 (68%) patients with abnormal hemodynamics. In ramped patients, the CI increased from 2.1 L/min/m (2.0-2.3) to 2.5 L/min/m (2.3-2.6; p = 0.004), and the PCWP dropped from 21 mm Hg (20-26) to 18 mm Hg (14-21, p < 0.001). The 6-minute walk distance improved from 338 m (253-394) to 353 m (320-442, p = 0.041). A 400 rpm change in HMII speed was like a 130 rpm change in HVAD speed and led to a change in cardiac output (CO) of 0.3 L/min. The correlation between device-reported flow and measured CO for both the HMII (Rs = 0.50, p < 0.001) and HVAD (Rs = 0.47, p < 0.001) was moderate. At 3 months after LVAD implant, most patients have normal hemodynamics. Of those patients with abnormal hemodynamics, LVAD ramping results in normalization of hemodynamics and improvement in 6-minute walk distance. PMID- 28665827 TI - Cessation of Continuous Flow Left Ventricular Assist Device-Related Gastrointestinal Bleeding After Heart Transplantation. AB - Gastrointestinal bleeding (GIB) is a major complication of continuous flow left ventricular assist device (CF LVAD) therapy. The precise pathophysiology of CF LVAD-related bleeding remains poorly understood, and the effect of pump removal at the time of transplantation on actual bleeding frequency has not previously been studied. A single-center retrospective review was conducted on patients who received CF LVAD and subsequently developed GIB. Baseline demographics and markers of pulsatility (aortic valve opening and the HeartMate II [HM2] pulse index) were compared between those with and without GIB. In those patients who had GIB and proceeded to heart transplantation, the frequency and etiology of recurrent GIB post-transplant was assessed. A total of 88 GIBs occurred in 54 of 214 patients who received CF LVAD implantation (25%, 0.36 events per patient year). Median time to first bleeding was 65 (interquartile range [IQR]: 37-229) days, and arteriovenous malformation (AVM) was the etiology in 36% of all episodes. On multivariate analysis, age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.01-1.09; p = 0.006) and HM2 pulse index (OR: 0.57; 95% CI: 0.35 0.90; p = 0.017) were significantly associated with GIB. There were 28 patients who had at least one GIB event during LVAD support and proceeded to transplant. None of these patients had recurrent bleeding after heart transplantation. This is the first documentation that transplantation effectively eliminates CF LVAD related GIB. Current guidelines recommending prioritization for transplant for patients who develop recurrent GIB after CF LVAD are justified. PMID- 28665828 TI - Monitoring Volume Status Using Bioelectrical Impedance Analysis in Chronic Hemodialysis Patients. AB - Fluid overload can be an independent risk factor of cardiovascular events and all cause death in end-stage renal disease (ESRD) patients on chronic hemodialysis. We performed a retrospective study to investigate whether intermittent control of fluid status decreases the rate of these complications using bioelectrical impedance analysis (BIA). In ESRD patients on chronic hemodialysis, we identified the ratio of extracellular water to total body water (ECW/TBW) every 6 months using InBody S10 (Biospace, Seoul, Korea), which was measured within 30 minutes after dialysis initiation on the first dialysis day of the week. The uncontrolled group included 57 (40.1%) patients with all ECW/TBW measurements >=0.40; in contrast, the controlled group included 85 (59.9%) with any measured ECW/TBW <0.40. Included patients were followed for 29 (12-42) months. The risk of cardiovascular events was higher in the uncontrolled group (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2-5.1; p < 0.05) than it was in the controlled group; however, this difference disappeared after adjusting for age, sex, and Charlson comorbidity index (not significant). On the other hand, the patients in the uncontrolled group had a higher risk of all-cause death than did those in the controlled group, independent of age, sex, and Charlson comorbidity index (HR, 4.7; 95% CI, 1.4-16.1; p < 0.05). In conclusion, monitoring volume status using BIA may help to predict all-cause death in chronic hemodialysis patients. Further controlled studies are needed to confirm that strict volume control could reduce the rates of cardiovascular events and mortality in this population. PMID- 28665829 TI - A Membrane Lung Design Based on Circular Blood Flow Paths. AB - Current hollow fiber membrane lungs feature a predominantly straight blood path length across the fiber bundle, resulting in limited O2 transfer efficiency because of the diffusion boundary layer effect. Using computational fluid dynamics and optical flow visualization methods, a hollow fiber membrane lung was designed comprising unique concentric circular blood flow paths connected by gates. The prototype lung, comprising a fiber surface area of 0.28 m, has a rated flow of 2 L/min, and the oxygenation efficiency is 357 ml/min/m. The CO2 clearance of the lung is 200 ml/min at the rated blood flow. Given its high gas transfer efficiency, as well as its compact size, low priming volume, and propensity for minimal thrombogenicity, this lung design has the potential to be used in a range of acute and chronic respiratory support applications, including providing total respiratory support for infants and small children and CO2 clearance in adults. PMID- 28665830 TI - Undiagnosed Pheochromocytoma Simulating Malignant Hyperthermia. AB - INTRODUCTION: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors. They are surgically curable but can be lethal if remain undiagnosed. We report a patient earlier diagnosed with malignant hyperthermia but later found to have pheochromocytoma on autopsy. CASE REPORT: After a preprocedural pain block for elective right shoulder arthroscopy, a 53-year-old hypertensive white man developed chest pain. In the operating room, he had increased blood pressure. Postoperatively, his blood pressures dropped from 220/100 to 80/30 mm Hg. He later developed high fever with core temperature reaching a peak of 42.2 degrees C, rapid breathing, and died after unsuccessful attempts to stabilize him. AUTOPSY: Autopsy revealed a tumor in his right adrenal gland, measuring 10 cm in greatest dimension and weighing 530 g. It was red brown with a hemorrhagic and cystic cut surface. A thin rim of yellow-orange adrenal cortex was visible at the margin of the tumor, indicating that it originated from the underlying adrenal medulla. The left adrenal gland was unremarkable.Sections showed hypercellular tumor with zellballen architecture. The tumor cells were round to oval with finely granular basophilic cytoplasm and mild pleomorphism. A 24-hour urine sample collected before his death showed greater than 22727 MUg/g Ratio to Creatinine metanephrines and normetanephrine, indicating that the tumor was active and secreted high levels of catecholamine. The cause of death was established as the complications of pheochromocytoma in the settings of general anesthesia for shoulder arthroscopy. The manner of death was natural. CONCLUSIONS: Pheochromocytoma can mimic malignant hyperthermia, and it should always be considered and managed appropriately in such scenarios to avoid untoward consequences. Pathologists must also be aware of this when conducting an autopsy in cases with a previous clinical diagnosis of malignant hyperthermia. PMID- 28665831 TI - An Unusual Medicolegal Case of 32-Year-Old Mother and Her 29-Week Fetus With Hemolysis, Elevated Liver Enzymes, and Low Platelet Count Syndrome: Case Report and Short Literature Review. AB - Forensic medicine experts are well aware of blunt abdominal trauma, which often lead to death because of serious internal organ injury with severe blood loss. Sometimes careful examination of such cases may reveal some other underlying conditions, such as an existing disease that had contributed to the death or life threatening complications. Our article presents a rare case of spontaneous hepatic rupture and intraperitoneal hemorrhage in a 32-year-old primigravida and her 29-week fetus, which was a result of hemolysis, elevated liver enzymes, and low platelet count syndrome. The said syndrome is a life-threatening obstetric complication usually considered to be a variant or complication of pre-eclampsia, which is characterized by hemolysis with microangiopathy, elevated liver enzymes, and low platelet count. PMID- 28665832 TI - Fourth-Degree Perineal Laceration in Nonconsenual Fisting: A Case Report, Brief Review of the Literature, and Medicolegal Issues. AB - We present the case of an 18-year-old girl who was sexually assaulted with transanal forearm penetration resulting in a fourth-degree perineal laceration. Fisting is an uncommon sexual practice consisting in the penetration of the vagina, anus, or both of them with fingers, hand (fist) or forearm.Perineal lacerations are a relatively common finding in both consensual and nonconsensual fisting victims. Even though cases of fisting with first-, second-, and third degree lacerations have been reported in literature, only one previous case of fourth-degree perineal laceration has been described in a woman, who died after anal fisting.The clinical and morphological findings related to this sexual practice have been presented. No previous reports concerning nonfatal cases of fourth-degree perineal laceration, due to anal fisting, exists in literature. We report a case in which the forensic evaluation and the identification of the sexual assault were delayed because of both the atypical and uncommon pattern of injury and the unconsciousness of the patient. The information gathered thanks to this article would support forensic pathologists and sexual assault forensic examiners in recognizing doubtful cases, and this is particularly important when the suspect of sexual assault arise. PMID- 28665833 TI - Why an Open Disclosure Procedure Is and Is not Followed After an Avoidable Adverse Event. AB - OBJECTIVE: The aim of the study was to analyze the relationships between factors that contribute to healthcare professionals informing and apologizing to a patient after an avoidable adverse event (AAE). METHODS: A secondary study based on the analysis of data collected in a cross-sectional study conducted in 2014 in Spain was performed. Health professionals from hospitals and primary care completed an online survey. RESULTS: The responses from 1087 front-line healthcare professionals were analyzed. The willingness of the professionals to fully disclose an AAE was greater among those who were backed by their institution (odds ratio [OR] = 72.6, 95% confidence interval [CI] = 37.5-140.3) and who had experience with that type of communication (OR = 2.4, 95% CI = 1.3 4.5). An apology for the patient was more likely when there was institutional support (OR = 31.3, 95% CI = 14.4-68.2), the professional was not aware of lawsuits (OR = 2.7, 95% CI = 1.2-6.1), and attributed most AAE to human error (OR = 2.2, 95% CI = 1.1-4.2). The fear of lawsuits was determined by the lack of support from the center in disclosing AAE (OR = 5.5, 95% CI = 2.8-10.6) and the belief that being open would result in negative consequences (OR = 2.0, 95% CI = 1.1-3.6). CONCLUSIONS: The culture of safety, the experience of blame, and the expectations about the outcome from communicating an AAE to patients affect the frequency of open disclosure. Nurses are more willing than physicians to participate in open disclosure. Health care organizations must act to establish a framework of legal certainty for professionals. PMID- 28665834 TI - A Prospective Assessment of Adverse Events in 3 Digestive Surgery Departments From Central Tunisia. AB - OBJECTIVE: The aim of the study was to prospectively assess the incidence, the preventability, and the factors contributing to adverse events (AEs) in surgical departments of Tunisian hospitals. METHODS: A prospective longitudinal study evaluated the incidence of AEs in surgical departments of three university hospitals in central Tunisia. The study followed 1687 admitted patients until their discharge from the hospitals based on a standard two-stage method that first included staff interviews and review of medical records based on 18 criteria and later was followed by an expert review to confirm or reject the presence of an AE. RESULTS: The overall incidence of AEs was 18.1% (95% confidence interval = 16.26-19.94), with an incidence density of 21.6 events per 1000 patient-days. The most frequent AEs were those related to operative procedures (34.9%) and to hospital-acquired infections (30.3%).The multivariate analysis shows that the proportion of AEs increased significantly with intrinsic risk factors (odds ratio [OR] = 2.51, P < 0.001), extrinsic risk factors (OR = 1.38, P = 0.02), length of stay of greater than 7 days (OR = 2.27, P < 0.001), and unplanned admissions (OR = 2.59, P < 0.01). Overall, the major consequences of suffering an AE were that 90% had a prolonged hospital stay, 6% had a permanent disability, and 4% encountered death. More than 60% of the identified AEs were considered to be preventable. CONCLUSIONS: Surgical AEs have a significant impact on patient outcomes in terms of length of stay, disability, and mortality, and a considerable proportion of them are preventable. Prospective studies provide better insight regarding AEs under circumstances where hospital records are not optimal. Patient safety programs led by qualified health professionals can reduce patient harm in surgical departments of hospitals in most situations. PMID- 28665835 TI - Occupational Health and the Arts. AB - OBJECTIVE: Work in the visual arts, performing arts, and writing can involve exposures to occupational hazards, including hazardous materials, equipment, and conditions, but few art workplaces have strong occupational health resources. Literature searches were conducted for articles that illustrate these concerns. METHODS: Medical databases were searched for art-related health articles. Other sources were also reviewed, including, unindexed art-health publications, and popular press articles. RESULTS: Information was located that described some exposed populations, art-related hazards, and resulting disorders. Anecdotal reports were used when more complete data were not available. CONCLUSIONS: Health hazards in the arts are significant. Occupational health professionals are familiar with most of these concerns and understand their treatment and prevention. The occupational health approach can reduce the health hazards encountered by at-risk art workers. Additional research would benefit these efforts. Resources for further information are available. PMID- 28665836 TI - Mortality Among Hardmetal Production Workers: A Retrospective Cohort Study in the Austrian Hardmetal Industry. AB - OBJECTIVE: This study retrospectively investigates causes of death among workers of a hardmetal plant in Austria. METHODS: A retrospective cohort was formed of 1965 workers still employed in or after 1970. Follow-up was until end of 2014 based on national databases. Cobalt exposure was assessed through industrial hygiene data and urine analyses. Cox proportional hazards models were calculated for selected causes of death. RESULTS: During 45,598 years of observation in total 177 deaths were observed. Forty-nine workers died from any cancer, 10 from lung cancer, and three from chronic obstructive pulmonary disease. Only the latter showed a significant association with cumulative exposure. CONCLUSIONS: Although this is a young study population with little power to detect subtle effects, at least it does not indicate a pronounced cancer risk among tungsten carbide workers due to cobalt. PMID- 28665837 TI - Utility of Lung Clearance Index Testing as a Noninvasive Marker of Deployment related Lung Disease. AB - OBJECTIVE: The aim of this study was to determine utility and sensitivity of lung clearance index (LCI) testing as a marker of lung injury in symptomatic military deployers compared with healthy controls. METHODS: We tested 24 healthy controls and 28 deployers with respiratory symptoms (17 of 28 with definite and 11 of 28 with probable deployment-related lung disease). We compared mean LCI scores between deployers and controls using t tests; adjusted tests were derived from multiple regression models. RESULTS: Mean LCI scores were significantly higher (P = 0.001) in deployers [7.76, 95% confidence interval (95% CI) 7.34 to 8.17] than controls (6.95, 95% CI 6.73 to 7.17). Adjusting for body mass index (BMI), smoking, and age, there were no significant differences (P = 0.10) between mean LCI scores in deployers (7.42, 95% CI 7.13 to 7.71) and controls (7.06, 95% CI 6.74 to 7.39). CONCLUSIONS: The trend toward higher LCI scores in symptomatic deployers may be linked to underlying lung disease and/or BMI but requires further investigation in a larger population. PMID- 28665838 TI - Work-Related Violent Deaths in the US Taxi and Limousine Industry 2003 to 2013: Disparities Within a High-Risk Working Population. AB - OBJECTIVE: We describe the magnitude and distribution of violent work-related deaths among taxi and limousine drivers, a high-risk population. METHODS: We analyzed rates using the Bureau of Labor Statistics Census of Fatal Occupational Injuries (CFOI) for all violent work-related deaths in the taxi and limousine industry from 2003 to 2013. We described demographics, work characteristics, and other injury details, examining temporal trends for nativity and race/ethnicity. RESULTS: Men (adjusted rate ratio [RRadj] 6.1 [95% confidence interval [CI] 2.6 14.1]), blacks (RRadj 2.3 [95% CI 1.6-3.4]), Hispanics (RRadj 2.1 [95% CI 1.3 3.4]), and drivers in the South (RRadj 2.7 [95% CI 1.9-3.9]) had significantly higher fatality rates than comparison groups. Over time, the rates remained substantially higher compared with all workers. CONCLUSIONS: The taxi and limousine industry continues to face a disproportionately dangerous working environment. Recommended safety measures implemented uniformly by cities, companies, and drivers could mitigate disparities. PMID- 28665839 TI - Does Implementation Follow Design? A Case Study of a Workplace Health Promotion Program Using the 4-S Program Design and the PIPE Impact Metric Evaluation Models. AB - OBJECTIVE: The aim of this study was to describe the content of a multiyear market-based workplace health promotion (WHP) program and to evaluate design and implementation processes in a real-world setting. METHODS: Data was collected from the databases of the employer and the service provider. It was classified using the 4-S (Size, Scope, Scalability, and Sustainability) and PIPE Impact Metric (Penetration, Implementation) models. Data analysis utilized both qualitative and quantitative methods. RESULTS: Program design covered well the evidence-informed best practices except for clear path toward sustainability, cooperation with occupational health care, and support from middle-management supervisors. The penetration rate among participants was high (99%) and majority (81%) of services were implemented as designed. CONCLUSION: Study findings indicate that WHP market would benefit the use of evidence-based design principles and tendentious decisions to anticipate a long-term implementation process already during the planning phase. PMID- 28665840 TI - Occupational Health and the Visual Arts: An Introduction. AB - OBJECTIVE: Occupational hazards in the visual arts often involve hazardous materials, though hazardous equipment and hazardous work conditions can also be found. Occupational health professionals are familiar with most of these hazards and are particularly qualified to contribute clinical and preventive expertise to these issues. METHODS: Articles illustrating visual arts health issues were sought and reviewed. Literature sources included medical databases, unindexed art health publications, and popular press articles. RESULTS: Few medical articles examine health issues in the visuals arts directly, but exposures to pigments, solvents, and other hazards found in the visual arts are well described. The hierarchy of controls is an appropriate model for controlling hazards and promoting safer visual art workplaces. CONCLUSIONS: The health and safety of those working in the visual arts can benefit from the occupational health approach. Sources of further information are available. PMID- 28665841 TI - Asymmetric Multisutural Craniosynostosis: an Algorithm of Early Intervention to Prevent Evolving Deformity. AB - BACKGROUND: Asymmetric multisutural craniosynostosis (AMC) is characterized by fusion of a midline suture combined with unilateral fusion of at least 1 nonmidline suture. Due to its rarity, complexity, and high rate of reoperation, the purpose of this study is to evaluate outcomes of our staged approach to AMC. METHODS: Patients treated for craniosynostosis between January 2004 and December 2013 were identified retrospectively. Only patients with AMC and a minimum follow up of 2 years were included. The 3-staged algorithm includes: extended strip craniectomy of fused sutures; postoperative helmet molding; and fronto-orbital advancement versus a touch-up procedure. Morphologic, aesthetic, and functional outcomes were evaluated. RESULTS: Nine patients (6.8% of cases) were treated for AMC (mean follow-up: 4.1 years). Sixty-seven percent of patients (6 of 9) demonstrated signs of elevated intracranial pressure. Patients were divided into 2 groups: "Group A" included patients treated according to the staged algorithm (n = 5); "Group B" included those treated by traditional techniques (n = 4). Group A underwent their first calvarial vault procedure earlier than those from Group B (2.7 vs. 13.2 months; P < 0.02). Postoperatively, no Group A patients had developmental delay, signs of elevated intracranial pressure, or reoperation. Three of 5 patients (60%) were rated Whitaker Classification II and the others (40%) rated Whitaker Classification III. CONCLUSIONS: Asymmetric multisutural synostosis results in a complex and evolving deformity involving the entire craniofacial complex. However, when asymmetric multisutural synostosis is approached in stages with early intervening helmet therapy, acceptable functional and appearance-related outcomes can be obtained with minimal complications. LEVEL OF EVIDENCE: III. PMID- 28665842 TI - Variations in Current Procedural Terminology Coding for Craniofacial Surgery: A Need for Review and Change. AB - BACKGROUND: A survey was utilized to study the coding practices of surgeons performing craniofacial procedures, in order to determine whether coding for these procedures might be standardized or expanded. METHODS: An online survey was designed with 6 sample cases to cover a variety of procedures encountered in the field of craniofacial surgery which was sent to members of 3 professional organizations centered around the practice of craniofacial/maxillofacial surgery. Surgeons were asked to read the vignettes and choose from a series of multiple choice responses to code the cases, or write in their own response. Codes were based on the American Medical Association current procedural terminology listings. Responses were compiled and tabulated. RESULTS: One hundred twenty eight people initiated the survey. The largest common coding responses for each vignette were selected by 45.2% of respondents for the case describing placement of an internal mandibular distractor; 45.3% for the case of scaphocephaly remodeling; 67.1% for a case of cranioplasty for trigonocephaly; 47.2% for hypertelorism repair with periorbital osteotomies; 60% for LeFort III advancement with external distractors; and 53.6% for the case describing the removal of an internal mandibular distractor. Between 4 and 12 codes were identified for possible use in each clinical scenario. CONCLUSION: There appears to be wide variability among those who routinely perform craniofacial surgery as to the appropriate ways to code these procedures. We hope to bring this to the attention of coding committees for further discussion to hopefully bring about more accurate and descriptive codes for craniofacial surgical procedures. PMID- 28665843 TI - Speech Perceptions and Health-Related Quality of Life Among Children With Cleft Lip and Palate. AB - BACKGROUND: The association between perception of speech and health-related quality of life (HRQOL) among patients with cleft palate is not well understood. The purpose of this study was to determine: the agreement between patient and parent perception of speech, the correlation between patient/parent speech perception and objective analysis by a speech-language pathologist (SLP), and the relationship between objective speech analysis and HRQOL among children with cleft lip with or without palate (CLCP). METHODS: The authors surveyed 108 CLCP patients who received treatment at a large tertiary medical center from 2013 to 2014. Patients and parents were queried regarding their difficulty with speech, and an SLP performed perceptual speech analysis with each patient. Patient reported survey instruments were used to assess anxiety, depression, anger, peer relationships, stigma, and overall psychosocial health. The authors assessed the agreement between patients and SLP analysis as well as association between speech and HRQOL. RESULTS: Patient and parent-reported speech quality demonstrated moderate agreement regarding the quality of the child's speech (r = 0.46-0.64). Parent and patient speech perception was not well associated with SLP analysis (V = 0.06-0.30). Patient speech perception was correlated with depression (P = 0.03), while SLP analysis was correlated with anger (P = 0.03, P = 0.004), depression (P = 0.007), and difficulty with peer relationships (P = 0.02). CONCLUSIONS: Patients and parents have different perceptions of the quality of the child's speech, and their ratings differ from SLP perceptual speech analysis. Both patient speech perception and SLP analysis are correlated with important aspects of quality of life, and should be considered when evaluating children with CLCP. PMID- 28665845 TI - The Effect of Anterior Palatoplasty Plus Modified Expansion Sphincter Pharyngoplasty on Voice Performance in Obstructive Sleep Apnea Syndrome. AB - OBJECTIVE: We aimed to investigate the effect of anterior palatoplasty (AP) plus modified expansion sphincter pharyngoplasty (MESP) on voice performance in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Fourteen OSAS patients who had AP + MESP procedure were included in the study. Voice performances of the patients were analyzed with acoustic voice analysis before surgery, and 6 months after surgery. RESULTS: Preoperative and postoperative F0, jitter percentage, and shimmer percentage were compared. Mean preoperative F0 was 129.85 Hz, and mean postoperative F0 was 138.07 Hz, with a significant difference in between (P = 0.017). Mean preoperative jitter percentage was 0.65, and mean shimmer percentage was 0.88, while those values were 0.67 and 0.84, respectively, in the postoperative period. The differences were not statistically significant (P = 0.801 and 0.652). CONCLUSION: The AP + MESP procedure performed for OSAS results in improvement of F0 in the long term; however, there were no differences in jitter percentage and shimmer percentage. PMID- 28665846 TI - Three-Dimensional Anthropometric Evaluation of Facial Morphology. AB - OBJECTIVES: The objectives of this study were to evaluate sexual dimorphism for facial features within Colombian and Mexican-American populations and to compare the facial morphology by sex between these 2 populations. MATERIALS AND METHODS: Three-dimensional facial images were acquired by using the portable 3dMDface system, which captured 223 subjects from 2 population groups of Colombians (n = 131) and Mexican-Americans (n = 92). Each population was categorized into male and female groups for evaluation. All subjects in the groups were aged between 18 and 30 years and had no apparent facial anomalies. A total of 21 anthropometric landmarks were identified on the 3-dimensional faces of each subject. The independent t test was used to analyze each data set obtained within each subgroup. RESULTS: The Colombian males showed significantly greater width of the outercanthal width, eye fissure length, and orbitale than the Colombian females. The Colombian females had significantly smaller lip and mouth measurements for all distances except upper vermillion height than Colombian males. The Mexican American females had significantly smaller measurements with regard to the nose than Mexican-American males. Meanwhile, the heights of the face, the upper face, the lower face, and the mandible were all significantly less in the Mexican American females. The intercanthal and outercanthal widths were significantly greater in the Mexican-American males and females. Meanwhile, the orbitale distance of Mexican-American sexes was significantly smaller than those of the Colombian males and females. The Mexican-American group had significantly larger nose width and length of alare than the Colombian group regarding both sexes. With respect to the nasal tip protrusion and nose height, they were significantly smaller in the Colombian females than in the Mexican-American females. The face width was significantly greater in the Colombian males and females. CONCLUSIONS: Sexual dimorphism for facial features was presented in both the Colombian and Mexican-American populations. In addition, there were significant differences in facial morphology between these 2 populations. PMID- 28665847 TI - Double Vision After Minimally Invasive Orbital Decompression. AB - INTRODUCTION: New onset Diplopia following orbital decompression in thyroid eye disease patients is estimated to occur in up to 30% to 40% of decompression patients, mostly related to deep lateral and medial wall decompressions. METHODS: A retrospective chart review of all minimally invasive (fat and minimal bone orbital decompression performed at the UCLA Stein Eye Institute between 2005 and 2015. Inclusion criteria were thyroid eye disease patients older than 18 years undergoing fat only orbital decompression with no previous muscle surgery. RESULTS: The chart review revealed only 5 patients with new onset diplopia after this surgery. The cases are discussed and a possible mechanism for the diplopia is proposed. DISCUSSION: Double vision following minimally invasive orbital decompression is rare and the mechanisms are poorly understood. PMID- 28665848 TI - Change in Posterior Pharyngeal Space After Counterclockwise Rotational Orthognathic Surgery for Class II Dentofacial Deformity Diagnosed With Obstructive Sleep Apnea Based on Cephalometric Analysis. AB - Although maxillomandibular advancement (MMA) is an orthognathic surgical procedure used to manage obstructive sleep apnea (OSA) in individuals who are noncompliant with continuous positive airway pressure therapy, simple MMA encounters problems in terms of aesthetic outcomes in Asian populations with preexisting dentoalveolar protrusion. Our current prospective investigation describes changes in posterior pharyngeal space and aesthetic outcomes after counterclockwise rotational orthognathic surgery, which is known to be quite difficult in terms of the maintenance of the skeletal stability in skeletal class II patients with OSA. This prospective study investigated the surgical outcome of patients who suffered from OSA following counterclockwise rotational orthognathic surgery. The patients were skeletal class II patients who underwent orthognathic surgery between March 2013 and December 2014. Cephalometric posterior airway analysis and a questionnaire for facial perception were used to assess pharyngeal airway and patient perception of facial appearance. A total of 14 patients were included. Satisfactory results were achieved without complications in all OSA patients. The airway parameters for anteroposterior length significantly increased. Thirteen patients answered a questionnaire on their facial appearance, and the visual analog scale averaged 7.31 points, indicating a favorable facial appearance. Counterclockwise rotational orthognathic surgery without maxilla advancement for the correction of OSA can effectively increase the posterior pharyngeal space, with favorable aesthetic results. With thoughtful application, this novel approach may be an alternative to standard approaches for the correction of OSA using orthognathic surgery. PMID- 28665849 TI - Aesthetic Lateral Canthoplasty: a Gray Line Split Approach. AB - BACKGROUND: Many women in Asian countries chase larger and brighter eyes, but to most Asian people only double eye plasty and epicanthoplasty is not enough. As a result, aesthetic lateral canthoplasty, another procedure to lengthen the palpebral fissure, is becoming more and more popular. However, the current procedure of aesthetic lateral canthoplasty has many potential complications, restricting the wide application of this procedure. METHODS: Here, the authors developed a minimally invasive method through gray line split and canthopexy to achieve lateral canthoplasty. Eighty-seven patients from February 2013 to January 2016 were included and had the procedure. The lengthen of the palpebral fissure was measured and photographs were also taken before the surgery and in the follow up periods. Besides, the complications related to this procedure were also investigated. RESULTS: The authors have performed aesthetic lateral canthoplasty in 87 patients, almost all of the follow-up patients have satisfactory results with a lengthen of palpebral fissure ranging from 2.3 to 4.2 mm. Through the long term follow-up the authors found the lengthen of the palpebral fissure is stable. No serious complications like lacrimal system fistula or hypertrophic scars emerged except 1 patient with conjunctival exposure. CONCLUSIONS: Through this gray line split method, the authors can acquire larger and brighter eyes without serious complications. The authors think that this is a good method and worthy of promotion. PMID- 28665850 TI - Displacement of a Broken Dental Injection Needle Into the Perivertebral Space. AB - Dental injection needle breakage is an uncommon problem in dental practice. Displacement of the broken fragment into anatomical spaces is, on the other hand, a serious complication that occurs most commonly during inferior alveolar nerve blocks as a result of material wear, incorrect application of the anesthesia technique, or sudden movement of the patient during injection. Further complications such as infection, trismus, and nerve paralysis may exacerbate the condition and, if not treated adequately, life-threatening conditions may develop over time as the fragment dislodges deeper in soft tissues. Clinical symptoms of the patient, as well as the findings gathered from detailed physical examination and radiographic evaluation, are important factors to consider before performing an exploratory surgery. Removal of a broken needle may be troublesome due to its proximity to vital anatomic structures. Multislice computed tomography is a reliable imaging modality that provides accurate information to pinpoint the exact location of the needle fragment.This report describes a case of needle breakage occurred during inferior alveolar nerve block which was performed to extract a third molar tooth and the migration of the broken fragment from the right mandibular ramus area into the perivertebral space, with special emphasis on the surgical retrieval technique with multiplanar computed tomography imaging guidance. PMID- 28665851 TI - Demarcative Necrosis Along Previous Laceration Line After Filler Injection. AB - In recent years, fillers have been widely used for soft tissue augmentation. Although they are generally considered to be safe, many complications have been reported to date. Nose and nasolabial fold augmentations with fillers can lead to an implementation of nasal skin necrosis, possibly caused by intravascular embolism and/or extravascular compression. Herein, we present a case of a successfully treated patient who experienced skin necrosis after an injection of dermal fillers into the nasolabial fold. Interestingly, we discovered that the patient had experienced a laceration 8 years ago around the area in which the filler was injected. PMID- 28665852 TI - Mozart Ear Deformity: a Rare Diagnosis in the Ear Reconstruction Clinic. AB - Mozart ear is a rare auricular deformity; clinically the auricle is characterized by the bulging appearance of the anterosuperior portion of the auricle due to fusion of the crura of the antihelix, an inversion in the normal form of the cavum conchae resulting in its convexity and a slit-like narrowing of the orifice of the external auditory meatus.A retrospective review of clinical and photographic records of patients attended at the ear reconstruction clinic of our hospital between June of 2010 and May 2016 was performed; out of 576 consecutive patients only 3 fulfilled the inclusion criteria, with a prevalence of 0.5%. The authors present these patients.Surgical interventions mainly focus on the correction of the convex concha; however, the procedure should be tailored to the severity of the deformity and the wishes of the patient. PMID- 28665854 TI - Morphometric Analysis of the Posterior Cranial Fossa in Syndromic and Nonsyndromic Craniosynostosis. AB - Posterior cranial fossa (PCF) anatomy can be abnormal in craniosynostosis, and hindbrain herniation may occur. This study analyzed PCF anatomy in single suture and complex craniosynostosis.Children with craniosynostosis and age-matched controls were identified. Cephalic index (CI) for cranial vault and PCF as well as tentorial (TA) and occipital angles (OA) were measured on preoperative imaging.Children with syndromic (N = 6), bicoronal (N = 4), sagittal (N = 12), and metopic synostosis (N = 4) as well as controls (N = 10) were enrolled. Mean CI for cranial vault was 0.89, 0.93, 0.65, 0.74, and 0.78, respectively. Corresponding CI for PCF was 0.81, 0.93, 0.62, 0.74, and 0.78. Mean TA and OA were 45.4 degrees and 96.6 degrees in syndromic, 39.7 degrees and 87.0 degrees in bicoronal, 34.0 and 75.0 degrees in sagittal, 39.7 degrees and 87.0 degrees in metopic synostosis, and 42.9 degrees and 88.3 degrees in controls.While CI, TA, and OA in metopic synostosis were similar to controls, abnormalities were found in syndromic, bicoronal, and sagittal synostosis. Syndromic and bicoronal craniosynostosis patients had a higher CI for both cranial vault and PFC as well as larger TA and OA, indicating a brachycephalic skull with steep tentorium and narrow PCF. In sagittal synostosis, CI for cranial vault and PCF were lower and TA and OA smaller, reflecting scaphocephalic deformity also at PCF, with a flat tentorium. This study provides basic PCF morphometry in craniofacial conditions. PMID- 28665855 TI - Lower Eyelid Reconstruction After Ablation of Skin Malignancies: How Far Can We Get in a Single-Stage Procedure? AB - : : Reconstruction of full-thickness lower eyelid defects tends to be a devastating procedure, especially when big amount of tissue has to be removed because of oncological reasons. The applied techniques are mostly difficult to execute and multistaged, often require extensive dissection, and result in scarring and facial disfigurement.The aim of the present study is to demonstrate the authors' experience in single-staged reconstructions of full-thickness defects of the lower eyelid with local tissue only. MATERIAL AND METHODS: A retrospective analysis was conducted identifying patients with postexcisional defects after skin cancer occurring in the lower eyelid, reconstructed in 1 stage. Appropriate demographic, pathological, preoperative, and postoperative clinical data and photo documentation were collected and analyzed. RESULTS: After excluding patients with partial thickness defects (n=5), a total of 13 patients with lower eyelid full-thickness defects were studied, including 9 women and 4 men with mean age 66.5 years (age range 53-79 years). The most common malignancy was basal cell carcinoma (n = 11). In one of the patients 2 synchronous neoplasms were excised simultaneously from the same lower eyelid. The reconstruction was successfully performed in 1 stage in all the patients by recruiting the same eyelid tissue and/or temporal tissue. No additional surgery was needed at a minimal follow-up of 9 months. CONCLUSION: Local tissue flaps have proven to be a reliable option for a single-stage reconstruction of large full-thickness defects. Tenzel flap technique seems to be a reliable option for repair of defects as large as 60% of the total eyelid length. PMID- 28665856 TI - Nasal Septal Deformity in Relation to the Mode of Delivery. AB - OBJECTIVE: The aim of this study was to find the relation between mode of delivery and the types of septal deviation. MATERIALS AND METHODS: Records of patients treated for a deviated nasal septum from March 2003 to October 2015 were reviewed. Those with previous facial trauma were excluded. Information retrieved included basic demographic data, mode of delivery, sibling birthing order, type and date of surgery, and postoperational outcomes. RESULTS: A total of 130 records were recovered. According to Guyuron's classification of nasal septal deviation, we found that type 5 was the most common type for patients delivered normally, whereas type 2 was the most common type for those who were delivered by cesarean section. CONCLUSION: Mode of delivery may be related to a certain type of deviation. However, studies with larger samples are required to support the finding in our study. PMID- 28665857 TI - Open Craniosynostosis Surgery: Effect of Early Intraoperative Blood Transfusion on Postoperative Course. AB - Correction of craniosynostosis can result in blood loss when the patient already has physiologic anemia. The aim of this study was to determine whether patients benefit from early blood transfusion and whether the timing of blood transfusion affects metabolic disturbances and the postoperative course. In this retrospective review, 71 patients who underwent open calvarial vault remodeling for correction of craniosynostosis were separated into 2 groups according to whether they received blood transfusions early (within the first 30 minutes of surgery) or later (after the first 30 minutes of surgery). Patients were further separated into nonsyndromic and syndromic cohorts. Tracked variables included hemoglobin, hematocrit, arterial blood gas values, lactate level, length of stay, estimated blood loss, and amount of blood transfused in the operating room, amount transfused postoperatively, and total amount transfused.Among all patients, the early transfusion group had a higher hemoglobin nadir overall and received less postoperative blood. Within the nonsyndromic cohort, the early transfusion group had a higher estimated blood loss and received more transfused blood. In the syndromic cohort, the early transfusion group had a hemoglobin nadir that was significantly higher than in the late transfusion group and a lower estimated blood loss, shorter pediatric intensive care unit stay, and less postoperative blood transfused. Syndromic patients also received significantly more blood overall. For syndromic patients undergoing open calvarial vault remodeling, transfusion within the first 30 minutes of surgery should be considered. PMID- 28665858 TI - Post-Surgical Relapse in Metopic Synostosis and Limitations of the Interfrontal Angle as an Outcome Measure. AB - BACKGROUND: The interfrontal angle (IFA) has been utilized as a surrogate for morphologic assessment of the anterior cranial region in metopic synostosis with success in characterizing presenting severity. Its utility as an outcome measure has not been assessed similarly. In this study, we aimed to determine whether meaningful information relative to shape, and relapse in particular, could be assessed using the IFA. METHODS: Patients with operatively treated isolated metopic synostosis were identified and included based on the availability of "previously obtained" low-dose computerized tomography (CT) scans at (1) preoperative and 2 postoperative (2) postoperative day-3 and (3) 1 year time points. Relapse was calculated as the percentage of the operatively induced change in IFA that was retained after the first postoperative year. RESULTS: After exclusionary criteria, 19 patients were identified. The mean IFA values at the 3 time points were 119.3 degrees (+/-9.8), 139.6 degrees (+/-6.3), and 135.3 degrees (+/-7.1), chronologically. Of the 19 patients, 14 (73.7%) experienced relapse, with this subgroup averaging 62.4% retention of their surgical change after 1 year. Increased preoperative severity and delayed age at surgical intervention were concurrently associated with an increased occurrence of relapse (P = 0.011). Another model utilizes preoperative IFA to predict the change in IFA that would accompany surgery on a case-by-case basis (P < 0.0001). CONCLUSIONS: (1) Fronto-orbital advancement offers immediate correction in the frontal bandeau. (2) Surgical impact, using fronto-orbital advancement, can be predicted using preoperative severity. (3) A component of postoperative relapse occurs within the frontal bandeau and is detectable at 1 year via the IFA. Exclusively, the IFA cannot characterize holistic postoperative relapse due to its inherent anatomical constraints; this supports the cessation of routine postoperative computerized tomography scans for determining outcomes. PMID- 28665860 TI - Our Surgical Past: An Aid to Understanding the Present and a Guide to the Future. PMID- 28665859 TI - Surgical Outcomes of Endonasal Conjunctivodacryocystorhinostomy According to Jones Tube Location. AB - PURPOSE: The aim of this study was to compare surgical outcomes and complications of endonasal conjunctivodacryocystorhinostomy (CDCR) according to Jones tube location. METHODS: Patients who underwent endonasal CDCR owing to proximal obstruction of the lacrimal drainage system between 2009 and 2016 were retrospectively reviewed. Patients were divided into 2 groups according to the location of the proximal end of the Jones tube. The canthal-based group included patients in which the proximal end of the Jones tube was located in the medial canthal angle, and the fornix-based group included patients in which the proximal end of the Jones tube was located in the inferomedial conjunctival fornix. Success rates were evaluated at 3 months and 6 months after surgery. Causes of failure, incidence of tube migration, and incidence of canthal deformity were also evaluated. RESULTS: The success rate at 3 months postoperative was 95% in the canthal-based group and 78.6% in the fornix-based group (P = 0.283). Success rates at 6 months postoperative were 85% in the canthal-based group and 71.4% in the fornix-based group, respectively (P = 0.410). The main cause of failure was granuloma in the canthal-based group (2/20) and medial migration in the fornix based group (3/14). Medial canthal deformity occurred in 12 of 20 cases in the canthal-based group, but none occurred in the fornix-based group. CONCLUSION: The canthal-based group had a lower migration rate and slightly better surgical success rate than the fornix based group, but canthal deformity was more prevalent. PMID- 28665861 TI - Reconstruction of a Marjolin Ulcer Defect of the Scalp Invading Brain and Causing Brain Abscess Formation Using Free Latissimus Dorsi Flap. AB - Marjolin ulcers are known as aggressive malignant tumors that mostly arise over chronic wounds and cutaneous scars. Brain abscess is a serious medical condition that requires surgical drainage along with antibiotic treatment. Here, we report a case with a Marjolin ulcer located over the right parietal bone with intracranial abscess formation along with tumor invasion into brain parenchyma. This patient was a 64-year-old man and had a 4 * 4 cm open wound on his scalp from which a purulent discharge was coming. This wound required surgical excision with security margins, resection of bone, evacuation of the cystic cavity, and excision of the walls of the cystic cavity, which were invaded by the tumor. Duraplasty and reconstruction of the defect with a free lattisimus dorsi flap are performed. To the best of our knowledge, the case reported here is unique because of the formation of brain abscess in the background of a long-lasting Marjolin ulcer invading brain parenchyma. It must be remembered that on the background of cutaneous scars located over the scalp, a Marjolin ulcer may develop, and if left untreated, tumor cells may invade even the brain parenchyma. Long-term asymptomatic brain infections may also accompany the given scenario, and complicate differential diagnosis. PMID- 28665862 TI - A Legacy of Leadership: John M. Converse, Joseph McCarthy, and NYU Plastic Surgery. PMID- 28665863 TI - The Role of Skeletal Stem Cells in the Reconstruction of Bone Defects. AB - Craniofacial surgery, since its inauguration, has been the culmination of collaborative efforts to solve complex congenital, dysplastic, oncological, and traumatic cranial bone defects. Now, 50 years on from the first craniofacial meeting, the collaborative efforts between surgeons, scientists, and bioengineers are further advancing craniofacial surgery with new discoveries in tissue regeneration. Recent advances in regenerative medicine and stem cell biology have transformed the authors' understanding of bone healing, the role of stem cells governing bone healing, and the effects of the niche environment and extracellular matrix on stem cell fate. This review aims at summarizing the advances within each of these fields. PMID- 28665864 TI - Comparison of the FaroArm Laser Scanner With the MicroScribe Digitizer Using Basicranial Measurements. AB - PURPOSE: To compare the results of a mechanical 3-dimensional laser scanner for craniofacial measurements of the basicranium to a validated coordinate device. METHODS: Access was granted by the Cleveland Natural History Museum to evaluate the Hamann-Todd Human Osteological Collection for this study. The MicroScribe and the FaroArm were used to gather coordinate data of various bony landmarks measurements including the prosthion, staphylion, hormion, and basion. Seventy three human skulls were measured and scanned. Distances calculated from the coordinates were tested for agreement using the Bland-Altman test. RESULTS: There were no significant differences in the bias or slope measures between the MicroScribe and the FaroArm. In addition to the univariate test for slope significance, multivariable analysis using age, gender, and race as additional predictors showed no significant difference in any variable (P < 0.05). CONCLUSION: This is the first study demonstrating agreement of the FaroArm in any human skull measurement with the validated MicroScribe digitizer. Compared with the MicroScribe digitizer, the FaroArm allows for 3-dimensional imaging and the ability to store, handle, and view data digitally. Future use of real-time facial measurements using the FaroArm offers potential for improved surgical planning and outcomes. PMID- 28665865 TI - Is Distraction Osteogenesis of the Irradiated Craniofacial Skeleton Contraindicated? AB - BACKGROUND: Craniofacial distraction osteogenesis (DO) is a common treatment modality today. Despite its numerous advantages, however, concerns have been expressed regarding the use of DO in the irradiated setting. METHODS: A systematic review was performed to identify all published reports of patients who underwent DO of the irradiated craniofacial skeleton. The following parameters were of particular interest: postoperative complications, specifically, insufficient bone formation, fracture, and hardware exposure (intraoral and cutaneous), as well as the need for additional bone grafting. RESULTS: The initial search retrieved a total of 183 articles of which 20 articles (38 patients) met predetermined inclusion criteria. The most common site of distraction was the mandible (76.3%). The median radiation dose was 50.7 Gy (range, 30-70 Gy). Bone defects ranged from 30 to 80 mm (median, 42.5 mm). Complications were encountered in 19 patients (50%), with insufficient bone formation being most common (9 patients; 23%). The overall incidence of complications was not significantly associated with radiation dosage (P = 0.79). The remaining procedural and demographic variables also failed to meet statistical significance when compared against the overall complication rate (P = 0.27-0.97). CONCLUSION: The complication rate associated with craniofacial DO of the irradiated skeleton does not appear to be substantially higher than what is reported for DO in the nonirradiated setting. As such, patients should be offered this treatment modality, particularly in light of the fact, that it offers the option to decrease patient morbidity as well as treatment complexity. PMID- 28665866 TI - Intracranial Aneurysms of Neuro-Ophthalmologic Relevance. AB - BACKGROUND: Intracranial saccular aneurysms are acquired lesions that often present with neuro-ophthalmologic symptoms and signs. Recent advances in neurosurgical techniques, endovascular treatments, and neurocritical care have improved the optimal management of symptomatic unruptured aneurysms, but whether the chosen treatment has an impact on neuro-ophthalmologic outcomes remains debated. EVIDENCE ACQUISITION: A review of the literature focused on neuro ophthalmic manifestations and treatment of intracranial aneurysms with specific relevance to neuro-ophthalmologic outcomes was conducted using Ovid MEDLINE and EMBASE databases. Cavernous sinus aneurysms were not included in this review. RESULTS: Surgical clipping vs endovascular coiling for aneurysms causing third nerve palsies was compared in 13 retrospective studies representing 447 patients. Complete recovery was achieved in 78% of surgical patients compared with 44% of patients treated with endovascular coiling. However, the complication rate, hospital costs, and days spent in intensive care were reported as higher in surgically treated patients. Retrospective reviews of surgical clipping and endovascular coiling for all ocular motor nerve palsies (third, fourth, or sixth cranial nerves) revealed similar results of complete resolution in 76% and 49%, respectively. Improvement in visual deficits related to aneurysmal compression of the anterior visual pathways was also better among patients treated with clipping than with coiling. The time to treatment from onset of visual symptoms was a predictive factor of visual recovery in several studies. Few reports have specifically assessed the improvement of visual deficits after treatment with flow diverters. CONCLUSIONS: Decisions regarding the choice of therapy for intracranial aneurysms causing neuro-ophthalmologic signs ideally should be made at high-volume centers with access to both surgical and endovascular treatments. The status of the patient, location of the aneurysm, and experience of the treating physicians are important factors to consider. Although a higher rate of visual recovery was reported with neurosurgical clipping, this must be weighed against the potentially longer intensive care stays and increased early morbidity. PMID- 28665867 TI - Perioperative Retinal Artery Occlusion: Incidence and Risk Factors in Spinal Fusion Surgery From the US National Inpatient Sample 1998-2013. AB - BACKGROUND: Retinal artery occlusion (RAO) is a rare but devastating complication of spinal fusion surgery. We aimed to determine its incidence and associated risk factors. METHODS: Hospitalizations involving spinal fusion surgery were identified by searching the National Inpatient Sample, a database of hospital discharges, from 1998 to 2013. RAO cases were identified using ICD-9-CM codes. Using the STROBE guidelines, postulated risk factors were chosen based on literature review and identified using ICD-9-CM codes. Multivariate logistic models with RAO as outcome, and risk factors, race, age, admission, and surgery type evaluated associations. RESULTS: Of an estimated 4,784,275 spine fusions in the United States from 1998 to 2013, there were 363 (CI: 291-460) instances of RAO (0.76/10,000 spine fusions, CI: 0.61-0.96). Incidence ranged from 0.35/10,000 (CI: 0.11-1.73) in 2001-2002 to 1.29 (CI: 0.85-2.08) in 2012-2013, with no significant trend over time (P = 0.39). Most strongly associated with RAO were stroke, unidentified type (odds ratio, OR: 14.33, CI: 4.54-45.28, P < 0.001), diabetic retinopathy (DR) (OR: 7.00, CI: 1.18-41.66, P = 0.032), carotid stenosis (OR: 4.94, CI: 1.22-19.94, P = 0.025), aging (OR for age 71-80 years vs 41-50 years referent: 4.07, CI: 1.69-10.84, P = 0.002), and hyperlipidemia (OR: 2.96, CI: 1.85-4.73, P < 0.001). There was an association between RAO and transforaminal lumbar interbody fusion (OR: 2.95, CI: 1.29-6.75, P = 0.010). RAO was more likely to occur with spinal surgery performed urgently or emergently compared with being done electively (OR: 0.40, CI: 0.23-0.68, P < 0.001). CONCLUSIONS: Patient-specific associations with RAO in spinal fusion include aging, carotid stenosis, DR, hyperlipidemia, stroke, and specific types of surgery. DR may serve as an observable biomarker of heightened risk of RAO in patients undergoing spine fusion. PMID- 28665868 TI - AGE-RELATED MACULAR DEGENERATION AND THE RISK OF ALL-CAUSE AND CARDIOVASCULAR MORTALITY: A Meta-Analysis of Cohort Studies. AB - PURPOSE: We evaluated the association between age-related macular degeneration (AMD) and the risk of all-cause and cardiovascular mortality by meta-analyses of data from prospective studies. METHODS: A literature search was performed in PubMed, Web of Science, Embase, Cocharne Library, and China National Knowledge Infrastructure for relevant articles published up to December 2016. We estimated hazard ratios with 95% confidence intervals with fixed-effect models and conducted meta-regression to explore the potential sources of heterogeneity. Small-study effect was estimated by Egger's test and funnel plot. RESULTS: We identified 13 population-based prospective cohort studies that examined the relationship between AMD and all-cause and cardiovascular mortality. Overall, the hazard ratios (95% confidence intervals) of all-cause mortality and cardiovascular mortality associated with any AMD were 1.15 (1.05-1.27) and 1.05 (95% confidence intervals: 0.87-1.26), respectively. The risk of all-cause mortality and cardiovascular mortality associated with early AMD were 1.08 (1.00 1.18) and 1.05 (0.89-1.24), and the associations with late AMD were 1.23 (1.11 1.36) and 1.28 (1.04-1.57), respectively. No evidence of small-study effect was found. CONCLUSION: This meta-analysis indicated that AMD, especially late AMD, was associated with increased risk of all-cause mortality and cardiovascular mortality based on comparisons with people who did not have AMD and who were of similar age and sex. PMID- 28665869 TI - THE RELATIONSHIP BETWEEN FOVEAL AVASCULAR ZONE AREA, VESSEL DENSITY, AND CYSTOID CHANGES IN DIABETIC RETINOPATHY: AN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY STUDY. AB - PURPOSE: To measure the foveal avascular zone (FAZ) areas and vessel densities of patients with diabetic retinopathy and to study their relationship with diabetic cystoid changes and retinal thickness. METHODS: Prospective case series of 51 eyes of 31 patients with diabetic retinopathy. The eyes were grouped based on the presence or absence of cystoid edema and evaluated using optical coherence tomography angiography. The FAZ areas and vessel density were compared. RESULTS: The FAZ area at the superficial capillary plexus level was equal between the eyes with and without cystoid edema. Vessel density did not differ as well. There was no correlation with retinal thickness. In eyes with cystoid changes, FAZ area changes at the deep capillary plexus level were difficult to interpret. CONCLUSION: The FAZ area and vessel density at the superficial capillary plexus level are reproducible and independent of the presence of cystoid edema. PMID- 28665870 TI - MOLECULAR PROGNOSTICS FOR UVEAL MELANOMA. AB - PURPOSE: To review laboratory methods, currently available commercial tests, caveats and clinical tips regarding prognostic analysis of uveal melanoma tissue. METHODS: A review of the literature was performed focused on the genetic abnormalities found in uveal melanoma cells, their correlation to the development of metastases, the validity of various laboratory approaches in their detection, and the existing commercially available tests for uveal melanoma prognostication. RESULTS: Numerous laboratory methods exist for analyzing genetic material obtained from uveal melanoma cells. Older tests have been gradually replaced with contemporary methods that are simpler with greater accuracy. Two commercially available assays exist which have not been directly compared-a gene expression profiling test has been validated directly through a large, prospective multicenter study and a DNA-based test which uses laboratory methods supported by extensive historical data. CONCLUSION: There are myriad laboratory methods for prognostic analysis of uveal melanoma tissue. These tests were historically only available to those with access to an outfitted laboratory. Newer commercially available assays have increased the accessibility of prognostic biopsy for uveal melanoma. The various caveats that exist when considering and performing prognostic biopsy of uveal melanoma are discussed. PMID- 28665871 TI - PREDICTIVE FACTORS OF VISUAL OUTCOME FOR VITREOMACULAR TRACTION SYNDROME AFTER VITRECTOMY. AB - PURPOSE: To assess the long-term functional and anatomical outcomes for vitreomacular traction syndrome (VMT) after vitrectomy and to analyze the predictive factors regarding visual outcome. METHODS: A retrospective, consecutive case series of 22 eyes in 22 patients with VMT who underwent vitrectomy to relieve macular edema were studied. Eyes were classified into two groups according to the diameter of vitreomacular adhesion based on spectral domain optical coherence tomography: Group 1 (14 eyes) focal attachment <=1,500 MUm; and Group 2 (eight eyes) broad attachment >1,500 MUm. RESULTS: Mean postoperative follow-up was 25.4 months (range, 6-68). The preoperative mean logarithm of the minimal angle of resolution visual acuity was 0.73 (20/107), which significantly improved to 0.49 (20/62) postoperatively (P < 0.01). Seventeen eyes (77%) had Snellen visual acuity improvement ? two lines, and nine eyes had improvement ? three lines. The improvement of visual acuity was significantly better in Group 1 than in Group 2 (2.7 lines vs. 0.8 lines) (P = 0.03). The preoperative mean central macular thickness was 563 MUm +/- 176 MUm, which significantly improved to 298 MUm +/- 69 MUm postoperatively (P < 0.01). In multivariate analysis, better final visual acuity was significantly associated with Group 1 VMT (P < 0.01) and with shorter symptom duration (P < 0.01). Greater improvement of visual acuity was also significantly associated with younger age of patients (P = 0.02) and with Group 1 VMT (P < 0.01). In linear regression analysis, patients with longer symptom duration had worse final visual acuity (beta = 0.02) and patients of younger age had greater visual acuity improvement (beta = 0.008). CONCLUSION: Most patients of VMT gained significant functional and anatomical improvements after vitrectomy. Group 1 optical coherence tomography pattern, shorter symptom duration, and younger age are significant predictive factors of better visual outcome. PMID- 28665872 TI - Saving the Posterior Dislocated Intraocular Lens: The "Air Support Technique" for Iris Fixation. PMID- 28665873 TI - Induction Failure in Acute Leukemia or Parvovirus B19 Infection? AB - Parvovirus B19 infection may be seen in acute leukemia patients and clinical findings and cytopenia caused by the viral infection may complicate the evaluation of the remission status. Herein we present a standard risk pediatric acute lymphobiastic leukemia patient who developed myalgia, bone pain, bone marrow aplasia and sinusoidal obstruction syndrome at the end of the induction treatment and was diagnosed as having parvovirus B19 infection. PMID- 28665874 TI - Single-Injection Versus Multiple-Injection Technique of Ultrasound-Guided Paravertebral Blocks: A Randomized Controlled Study Comparing Dermatomal Spread. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to investigate the extent of dermatomal spread following an ultrasound-guided thoracic paravertebral block (PVB) when equal volumes of local anesthetic are injected at 1 versus 5 vertebral levels. METHODS: Seventy patients undergoing a unilateral mastectomy were randomized to receive either single or multiple injections of a PVB under real-time ultrasound guidance using a parasagittal approach. The patients in the single-injection group received a PVB at T3-T4 level with 25 mL of 0.5% ropivacaine and 4 subcutaneous sham injections. Patients in the multiple injection group received 5 injections of a PVB from T1 to T5 level. Five milliliters of 0.5% ropivacaine was injected at each level. Evaluation of the sensory block was carried out 20 minutes following the completion of the PVB. RESULTS: The median (interquartile range) dermatomal spread was not significantly different for the single-injection group (5 [4-6]) compared with the multiple injection group (5 [5-6]), with a median difference of 0 segments (95% confidence interval, -1 to 0 segments; P = 0.22). The median time to performance of the single-injection PVB was shorter compared with the multiple-injection group (10 minutes), with a mean difference of -4 minutes (95% confidence interval, -6 to -3 minutes; P < 0.001). CONCLUSIONS: An ultrasound-guided single-injection PVB provides equivalent dermatomal spread and duration of analgesia compared with a multiple-injection PVB. The single-injection technique takes less time to perform and hence may be preferred over a multiple-injection technique.The trial was registered prospectively at ClinicalTrials.gov (NCT02852421) on July 15, 2016. PMID- 28665875 TI - Neuralgic Amyotrophy Attributed Incorrectly to Block-Related Injury: Understanding Errors in Clinical Reasoning. AB - OBJECTIVE: We report a case of misdiagnosed neuralgic amyotrophy (brachial plexus neuritis, Parsonage-Turner syndrome). Our primary objective is to review the scientific basis for errors in clinical reasoning. CASE REPORT: We herein report a patient in whom signs and symptoms compatible with neuralgic amyotrophy presented after shoulder surgery. The patient's brachial plexopathy was attributed incorrectly as a complication of interscalene brachial plexus block. The true diagnosis was made only after the patient developed neuralgic amyotrophy in the contralateral upper extremity after a subsequent shoulder surgery on that side, this time without a brachial plexus block. CONCLUSIONS: Cognitive bias may lead to errors in clinical reasoning and consequent misdiagnosis. Temporal proximity may falsely implicate regional anesthesia as the causative agent. PMID- 28665876 TI - Adolescents, young people, and the 90-90-90 goals: a call to improve HIV testing and linkage to treatment. AB - : The current low rates of HIV diagnosis and treatment initiation among adolescents and young people ages 15-24 continues to present a significant challenge to the epidemic control of HIV. With a 'business as usual' approach to HIV testing and linkage to treatment, new infections among adolescents and youth will likely increase, with the burden compounded by the increasing number of youth in Africa, expected to reach 293 million by 2025. Recent studies reveal significant gaps in the HIV clinical cascade among young people as the global community pursues the Joint United Nations Programme on HIV and AIDS 90-90-90 targets. This AIDS supplement was commissioned with the goal of informing program planners, researchers, policymakers, and funding agencies about the development and design of effective adolescent and youth programs, policies, and strategies for improving the first two 90s among adolescents and youth: HIV testing and diagnosis and linkage to care and treatment. Emerging evidence should inform efforts to better target the youth and adolescents who are most at risk, aiming for early diagnosis and treatment initiation for those who are HIV positive, while also ensuring appropriate primary prevention so that those identified as HIV negative remain so. PMID- 28665877 TI - Youth engagement in developing an implementation science research agenda on adolescent HIV testing and care linkages in sub-Saharan Africa. AB - BACKGROUND: The importance of youth engagement in designing, implementing and evaluating programs has garnered more attention as international initiatives seek to address the HIV crisis among this population. Adolescents, however, are not often included in HIV implementation science research and have not had opportunities to contribute to the development of HIV-related research agendas. Project Supporting Operational AIDS Research (SOAR), a United States Agency for International Development-funded global operations research project, involved youth living with HIV in a meeting to develop a strategic implementation science research agenda to improve adolescent HIV care continuum outcomes, including HIV testing and counseling (HTC) and linkage to care. METHODS: Project SOAR convened a 2-day meeting of 50 experts, including four youth living with HIV. Participants examined the literature, developed research questions, and voted to prioritize these questions for the implementation science research agenda. This article presents the process of involving youth, how they shaped the course of discussions, and the resulting priority research gaps identified at the meeting. RESULTS: Youth participation influenced working group discussions and the development of the implementation science agenda. Research gaps identified included how to engage vulnerable adolescents, determining the role that stigma, peers, and self-testing have in shaping adolescent HTC behaviors, and examining the costs of different HTC and linkage to care strategies. CONCLUSION: The meeting participants developed the research agenda to guide future implementation science research to improve HIV outcomes among adolescents in sub-Saharan Africa. This process highlighted the importance of youth in shaping implementation science research agendas and the need for greater youth engagement. PMID- 28665878 TI - 'I will choose when to test, where I want to test': investigating young people's preferences for HIV self-testing in Malawi and Zimbabwe. AB - OBJECTIVES: The current study identifies young people's preferences for HIV self testing (HIVST) delivery, determines the relative strength of preferences and explores underlying behaviors and perceptions to inform youth-friendly services in southern Africa. DESIGN: A mixed methods design was adopted in Malawi and Zimbabwe and includes focus group discussions, in-depth interviews and discrete choice experiments. METHODS: The current study was conducted during the formative phase of cluster-randomized trials of oral-fluid HIVST distribution. Young people aged 16-25 years were purposively selected for in-depth interviews (n = 15) in Malawi and 12 focus group discussions (n = 107) across countries. Representative samples of young people in both countries (n = 341) were administered discrete choice experiments on HIVST delivery, with data analyzed to estimate relative preferences. The qualitative results provided additional depth and were triangulated with the quantitative findings. RESULTS: There was strong concordance across methods and countries based on the three triangulation parameters: product, provider and service characteristics. HIVST was highly accepted by young people, if provided at no or very low cost. Young people expressed mixed views on oral-fluid tests, weighing perceived benefits with accuracy concerns. There was an expressed lack of trust in health providers and preference for lay community distributors. HIVST addressed youth-specific barriers to standard HIV testing, with home-based distribution considered convenient. Issues of autonomy, control, respect and confidentiality emerged as key qualitative themes. CONCLUSION: HIVST services can be optimized to reach young people if products are provided through home-based distribution and at low prices, with respect for them as autonomous individuals. PMID- 28665879 TI - "At our age, we would like to do things the way we want: " a qualitative study of adolescent HIV testing services in Kenya. AB - OBJECTIVES: Adolescents in Africa have low HIV testing rates. Better understanding of adolescent, provider, and caregiver experiences in high-burden countries such as Kenya could improve adolescent HIV testing programs. DESIGN: We conducted 16 qualitative interviews with HIV-positive and HIV-negative adolescents (13-18 years) and six focus group discussions with Healthcare workers (HCWs) and caregivers of adolescents in Nairobi, Kenya. METHODS: Semi-structured interviews and focus groups were recorded and transcribed. Analysis employed a modified constant comparative approach to triangulate findings and identify themes influencing testing experiences and practices. RESULTS: All groups identified that supportive interactions during testing were essential to the adolescent's positive testing experience. HCWs were a primary source of support during testing. HCWs who acted respectful and informed helped adolescents accept results, link to care, or return for repeat testing, whereas HCWs who acted dismissive or judgmental discouraged adolescent testing. Caregivers universally supported adolescent testing, including testing with the adolescent to demonstrate support. Caregivers relied on HCWs to inform and encourage adolescents. Although peers played less significant roles during testing, all groups agreed that school-based outreach could increase peer demand and counteract stigma. All groups recognized tensions around adolescent autonomy in the absence of clear consent guidelines. Adolescents valued support people during testing but wanted autonomy over testing and disclosure decisions. HCWs felt pressured to defer consent to caregivers. Caregivers wanted to know results regardless of adolescents' wishes. CONCLUSION: Findings indicate that strengthening HCW, caregiver, and peer capacities to support adolescents while respecting their autonomy may facilitate attaining '90-90-90' targets for adolescents. PMID- 28665880 TI - Community intervention improves knowledge of HIV status of adolescents in Zambia: findings from HPTN 071-PopART for youth study. AB - OBJECTIVE: To determine the uptake of home-based HIV counselling and testing (HCT) in four communities of the HPTN 071 (PopART) trial in Zambia among adolescents aged 15-19 years and explore factors associated with HCT uptake. DESIGN: The PopART for youth study is a three-arm community-randomized trial in 12 communities in Zambia and nine communities in South Africa which aims to evaluate the acceptability and uptake of a HIV prevention package, including universal HIV testing and treatment, among young people. The study is nested within the HPTN 071 (PopART) trial. METHODS: Using a door-to-door approach that includes systematically revisiting households, all adolescents enumerated were offered participation in the intervention and verbal consent was obtained. Data were analysed from October 2015 to September 2016. RESULTS: Among 15 456 enumerated adolescents, 11 175 (72.3%) accepted the intervention. HCT uptake was 80.6% (8707/10 809) and was similar by sex. Adolescents that knew their HIV positive status increased almost three-fold, from 75 to 210. Following visits from community HIV care providers, knowledge of HIV status increased from 27.6% (3007/10 884) to 88.5% (9636/10 884). HCT uptake was associated with community, age, duration since previous HIV test; other household members accepting HCT, having an HIV-positive household member, circumcision, and being symptomatic for STIs. CONCLUSION: Through a home-based approach of offering a combination HIV prevention package, the proportion of adolescents who knew their HIV status increased from ~28 to 89% among those that accepted the intervention. Delivering a community-level door-to-door combination, HIV prevention package is acceptable to many adolescents and can be effective if done in combination with targeted testing. PMID- 28665881 TI - Voluntary medical male circumcision among adolescents: a missed opportunity for HIV behavioral interventions. AB - OBJECTIVE: Voluntary medical male circumcision (VMMC) is one of the first opportunities for adolescent males in African countries to interact with the healthcare system. This study explored the approaches used during adolescent VMMC counseling and whether these strategies maximize broader HIV prevention opportunities. METHODS: Qualitative interviews were conducted with 92 VMMC clients ages 10-19 years in South Africa (n = 36), Tanzania (n = 36), and Zimbabwe (n = 20) and 33 VMMC providers across the three countries. Discussions explored HIV prevention counseling, testing, and disclosure of results. Audio recordings were transcribed, translated into English, and coded thematically by two individuals. RESULTS: Male adolescents in all three countries reported that limited information was provided about HIV prevention and care, and adolescents were rarely provided condoms. Although VMMC protocols require opt-out HIV testing, adolescents recounted having blood taken without knowing the purpose, not receiving results, nor completely understanding the link between VMMC and HIV. Most males interviewed assumed they had tested negative because they were subsequently circumcised without knowing test results. Providers reported spending little time talking about HIV prevention, including condom use. They admitted that younger adolescent clients often receive little information if assumed they are not sexually active or too young to understand and instead discussed nonsexually transmitted routes of HIV. CONCLUSION: In the sites of the three countries studied, HIV prevention and care messages were inconsistent and sometimes totally absent from VMMC counseling sessions. VMMC appears to be a missed opportunity to engage in further HIV prevention and care with adolescents. PMID- 28665882 TI - Continuous quality improvement intervention for adolescent and young adult HIV testing services in Kenya improves HIV knowledge. AB - OBJECTIVES: To determine whether continuous quality improvement (CQI) improves quality of HIV testing services for adolescents and young adults (AYA). DESIGN: CQI was introduced at two HIV testing settings: Youth Centre and Voluntary Counseling and Testing (VCT) Center, at a national referral hospital in Nairobi, Kenya. METHODS: Primary outcomes were AYA satisfaction with HIV testing services, intent to return, and accurate HIV prevention and transmission knowledge. Healthcare worker (HCW) satisfaction assessed staff morale. T tests and interrupted time series analysis using Prais-Winsten regression and generalized estimating equations accounting for temporal trends and autocorrelation were conducted. RESULTS: There were 172 AYA (Youth Centre = 109, VCT = 63) during 6 baseline weeks and 702 (Youth Centre = 454, VCT = 248) during 24 intervention weeks. CQI was associated with an immediate increase in the proportion of AYA with accurate knowledge of HIV transmission at Youth Centre: 18 vs. 63% [adjusted risk difference (aRD) 0.42,95% confidence interval (CI) 0.21 to 0.63], and a trend at VCT: 38 vs. 72% (aRD 0.30, 95% CI -0.04 to 0.63). CQI was associated with an increase in the proportion of AYA with accurate HIV prevention knowledge in VCT: 46 vs. 61% (aRD 0.39, 95% CI 0.02-0.76), but not Youth Centre (P = 0.759). In VCT, CQI showed a trend towards increased intent to retest (4.0 vs. 4.3; aRD 0.78, 95% CI -0.11 to 1.67), but not at Youth Centre (P = 0.19). CQI was not associated with changes in AYA satisfaction, which was high during baseline and intervention at both clinics (P = 0.384, P = 0.755). HCW satisfaction remained high during intervention and baseline (P = 0.746). CONCLUSION: CQI improved AYA knowledge and did not negatively impact HCW satisfaction. Quality improvement interventions may be useful to improve adolescent-friendly service delivery. PMID- 28665883 TI - Optimizing linkage to care and initiation and retention on treatment of adolescents with newly diagnosed HIV infection. AB - OBJECTIVE: Unsuccessful linkage to care and treatment increases adolescent HIV related morbidity and mortality. This study evaluated the effect of a novel adolescent and youth Red Carpet Program (RCP) on the timing and outcomes of linkage to care. DESIGN: A prepost implementation evaluation of the pilot RCP program. SETTINGS: Healthcare facilities (HCFs) and schools in Homa Bay County, Kenya. STUDY PARTICIPANTS: HIV-infected adolescents (15-19 years) and youth (20 21 years). INTERVENTIONS: RCP provided fast-track peer-navigated services, peer counseling, and psychosocial support at HCFs and schools in six Homa Bay subcounties in 2016. RCP training and sensitization was implemented in 50 HCFs and 25 boarding schools. MAIN OUTCOME MEASURES: New adolescent and youth HIV diagnosis, linkage to and retention in care and treatment. RESULTS: Within 6 months of program rollout, 559 adolescents and youths (481 women; 78 men) were newly diagnosed with HIV (15-19 years n = 277; 20-21 years, n = 282). The majority (n = 544; 97.3%) were linked to care, compared to 56.5% at preimplementation (P < 0.001). All (100.0%; n = 559) adolescents and youths received peer counseling and psychosocial support, and the majority (n = 430; 79.0%) were initiated on treatment. Compared to preimplementation, the proportion of adolescents and youths who were retained on treatment increased from 66.0 to 90.0% at 3 months (P < 0.001), and from 54.4 to 98.6% at 6 months (P < 0.001). CONCLUSION: Implementation of RCP was associated with significant improvement in linkage to and early retention in care among adolescent and youth. The ongoing study will fully assess the efficacy of this linkage-to-care approach. PMID- 28665884 TI - HIV testing in nonhealthcare facilities among adolescent MSM. AB - OBJECTIVES: To describe the extent to which Centers for Disease Control and Prevention (CDC)-funded HIV testing in nonhealthcare facilities reaches adolescent MSM, identifies new HIV infections, and links those newly diagnosed to medical care. METHODS/DESIGN: We describe HIV testing, newly diagnosed positivity, and linkage to medical care for adolescent MSM who received a CDC funded HIV test in a nonhealthcare facility in 2015. We assess outcomes by race/ethnicity, HIV-related risk behaviors, and US geographical region. RESULTS: Of the 703 890 CDC-funded HIV testing events conducted in nonhealthcare facilities in 2015, 6848 (0.9%) were provided to adolescent MSM aged 13-19 years. Among those tested, 1.8% were newly diagnosed with HIV, compared with 0.7% among total tests provided in nonhealthcare facilities regardless of age and sex. The odds of testing positive among black adolescent MSM were nearly four times that of white adolescent MSM in multivariable analysis (odds ratio = 3.97, P < 0.001). Among adolescent MSM newly diagnosed with HIV, 67% were linked to HIV medical care. Linkage was lower among black (59%) and Hispanic/Latino adolescent MSM (71%) compared with white adolescent MSM (88%). CONCLUSION: CDC-funded nonhealthcare facilities can reach and provide HIV tests to adolescent MSM and identify new HIV infections; however, given the low rate of HIV testing overall and high engagement in HIV-related risk behaviors, there are opportunities to increase access to HIV testing and linkage to care for HIV-positive adolescent MSM. Efforts are needed to identify and address the barriers that prevent black and Hispanic/Latino adolescent MSM from being linked to HIV medical care in a timely manner. PMID- 28665885 TI - The Metropolitan Atlanta community adolescent rapid testing initiative study: closing the gaps in HIV care among youth in Atlanta, Georgia, USA. AB - OBJECTIVE: To determine the effectiveness of the Metropolitan Atlanta community adolescent rapid testing initiative (MACARTI) intervention relative to standard of care (SOC), in achieving early diagnosis, linkage, and retention among HIV infected youth ages 18-24 years. DESIGN: MACARTI was a pilot single-center, prospective, nonrandomized study. METHODS: MACARTI combined nontraditional venue HIV testing, motivational interviewing, and case management. We collected demographic, clinical variables and calculated linkage and appointment adherence rates. We obtained SOC data from an adolescent HIV clinic. Longitudinal data were analyzed using inverse propensity treatment-weighted linear growth models; medians, interquartile ranges (IQR), means, and 95% confidence intervals are provided. RESULTS: MACARTI screened 435 participants and identified 49 (11.3%) HIV infections. The SOC arm enrolled 49 new HIV-infected individuals. The 98 participants, (49 in each arm) were: 85% men; 91% Black; mean age = 21 years (SD : 1.8). Overall, 63% were linked within 3 months of diagnosis; linkage was higher for MACARTI compared to SOC (96 vs. 57%, P < 0.001). Median linkage time for MACARTI participants compared to SOC was 0.39 (IQR : 0.20-0.72) vs. 1.77 (IQR : 1.12-12.65) months (P < 0.001). MACARTI appointment adherence was higher than SOC (86.1 vs. 77.2%, P = 0.018). In weight-adjusted models, mean CD4 T-cell counts increased and mean HIV-1 RNA levels decreased in both arms over 12 months, but the differences were more pronounced in the MACARTI arm. CONCLUSION: MACARTI successfully identified and linked HIV-infected youth in Atlanta, USA. MACARTI may serve as an effective linkage and care model for clinics serving HIV-infected youth. PMID- 28665886 TI - Ablation of Toll-like receptor 4 mitigates central blood pressure response during hyperhomocysteinemia. AB - OBJECTIVE: The objective of this study was to define the mechanisms of homocysteine-induced effects on the aortic wall that promote vascular remodeling and hypertension as well as explore the role of Toll-like receptor 4 in homocysteine-induced effects. METHOD: Five strains of mice were utilized in this study: C57BL/6J, C3H/HeOuJ, CBS+/-, C3H/HeJ and CBS+/-/C3H. Aorta, heart and blood were collected at the end of the experiments. Blood pressure (BP) was recorded using noninvasive tail cuff method. To determinate effects of vasoactive agent and endothelial-dependent vasodilator on aorta contractility, we performed vascular function measurements. In addition, the expression of mitochondrial fusion and fission proteins, antioxidant markers and collagen fragments were assessed. RESULTS: BP measurements demonstrated a significant increase in SBP and DBPs in CBS+/- mice compared with other groups. CBS+/- mice aorta had lower response to phenylephrine and acetylcholine compared with other groups; however, CBS+/-/C3H mice response was improved. Dynamin-related protein 1 protein expression was significantly upregulated in CBS+/- mice, whereas C3H mice showed downregulation. In addition, CBS+/- mice showed increased oxidative stress, inflammation and decreased nitric oxide. These effects were normalized in CBS+/ /C3H mice. CONCLUSION: Our findings demonstrate the dominance of endothelial cell mitochondrial fission over mitochondrial fusion in hyperhomocysteinemia and oxidative stress. This may explain the endothelial cell loss and dysfunction that follows collagen deposition, which contributes to inward aorta remodeling in hypertension. PMID- 28665887 TI - Serum podocalyxin is significantly increased in early-onset preeclampsia and may represent a novel marker of maternal endothelial cell dysfunction. AB - OBJECTIVE: Podocalyxin is a glomerular podocyte protein and increased in urine of preeclampsia. However, podocalyxin is also expressed in endothelial cells of other organs. Here we investigated whether podocalyxin is detectable in pregnant serum and whether the levels are altered in preeclampsia. METHODS: Podocalyxin was determined by ELISA in sera collected from normal pregnancy across gestation (n = 44) and from preeclamptic pregnancies at diagnosis (n = 34) with gestation age-matched controls (n = 68). Immunohistochemistry examined podocalyxin in placentas and in 32 human tissues on a tissue array. Human umbilical vein endothelial cells (HUVECs) were treated with interleukin (IL)-6 and podocalyxin was analysed by ELISA and western blotting. RESULTS: Podocalyxin was detected in serum of normal pregnancy, with levels increasing progressively with advancing gestation. Podocalyxin serum levels were significantly elevated in preeclampsia, especially the early-onset subtype. Within the placenta, blood vessels but not trophoblasts expressed podocalyxin, and preeclampsia didn't differ from controls. Endothelial cells in all 32 human organs examined, as well as HUVECs, expressed podocalyxin. Its levels increased in the conditioned media but decreased in the lysates when HUVECs were treated with IL-6. CONCLUSION: Podocalyxin likely derived from maternal endothelial cells is present in pregnant serum and significantly increased in early-onset preeclampsia. Podocalyxin release was stimulated by IL-6 in HUVECs. PMID- 28665888 TI - A health profile associated with excessive alcohol use independently predicts aortic stiffness over 10 years in black South Africans. AB - OBJECTIVE: Black populations exhibit higher arterial stiffness than whites and suffer a disproportionate burden of cardiovascular disease. It is therefore important to identify modifiable health behaviours predicting large artery stiffness in blacks. We examined whether traditional cardiovascular risk factors and health behaviours of black South Africans predict large artery stiffness 10 years later. METHODS: We included 650 HIV-free participants (32.8% men) and collected data in rural and urban areas of the North West Province in 2005 and 2015. We collected questionnaire data, anthropometry, blood pressure and determined cardiometabolic and inflammatory markers from blood samples. We measured carotid-femoral pulse wave velocity (PWV) at follow-up. RESULTS: A total of 25.3% of our population, aged 65 +/- 9.57 years, had a PWV exceeding 10 m/s. In multivariable-adjusted regression analyses, the strongest predictors of PWV were mean arterial pressure, age and heart rate (all P < 0.024). Urban locality (R = 0.31, beta = 0.12, P = 0.001), self-reported alcohol use (beta = 0.11, P = 0.018) and plasma glucose (beta = 0.08 P = 0.023) associated positively with PWV at follow-up. We found a negative association between PWV and BMI (beta = -0.15, P = 0.001), and no associations with sex, smoking, inflammatory markers, lipids, liver enzymes or antihypertensive medication. When replacing self-reported alcohol with gamma-glutamyltransferase, the latter associated positively with PWV (beta = 0.09, P = 0.023). CONCLUSION: A health profile associated with excessive alcohol use, including an urban setting, elevated plasma glucose and lower BMI predicts large artery stiffness independently of age and blood pressure in black South Africans over 10 years. This observation prompts urgent public health strategies to target alcohol overuse. PMID- 28665889 TI - MRI of the Central Lymphatic System: Indications, Imaging Technique, and Pre Procedural Planning. AB - Magnetic resonance imaging is increasingly being used to evaluate the lymphatic system. Advances in magnetic resonance (MR) software and hardware allow improved visualization of lymph nodes and lymphatic vessels. We describe how MR lymphangiography can be used to diagnose central lymphatic system anatomy and pathology, which can be used for diagnostic purposes or for pre-procedural planning. PMID- 28665890 TI - The Impact of Liver Graft Injury on Cancer Recurrence Posttransplantation. AB - Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts. PMID- 28665891 TI - Incidence of Hepatitis B Viral Reactivation After Kidney Transplantation With Low Dose Rituximab Administration. AB - BACKGROUND: In hematological malignancy patients intended to receive rituximab, hepatitis B virus (HBV) serology screening, viral reactivation monitoring, are recommended. However, the effect of single-dose rituximab (RIT) on HBV reactivation in kidney transplant patients with previous HBV infection is still unclear. METHODS: In this retrospective cohort study consisting of 1294 kidney transplant patients, we identified 76 patients showing preoperative hepatitis B surface antigen-negative, hepatitis B core antibody-positive, and HBV-DNA negative results. A rituximab dose of 200 mg/body was administered to 48 patients, 46 of whom did not receive prophylaxis (RIT+ group). Twenty-eight patients received neither rituximab nor prophylaxis (RIT- group). We monitored HBV-DNA by polymerase chain reaction every 1 to 3 months, and HBV reactivation was defined as detectable HBV-DNA. RESULTS: HBV reactivation was found in 1 patient in the RIT+ group (2.2%) and 1 patient in the RIT- group (3.6%) at 6 weeks and 5.5 years posttransplant, respectively, but spontaneously cleared. Both patients showed positive hepatitis B surface antibody preoperatively. HBV reactivation was not found in 6 patients lacking anti-hepatitis B surface preoperatively. CONCLUSIONS: Low-dose RIT administration in kidney transplant patients without prophylaxis is associated with low incidence of HBV reactivation. However, the comparisons among standard-dose RIT, low-dose RIT, and controls with high-quality study design is necessary. PMID- 28665892 TI - Aggregating Marginal Gains in Posttransplant CMV Risk Stratification. PMID- 28665893 TI - The Use of Ex Vivo Generated Regulatory T-Cell Preparations in a Canine Lung Allograft Model. PMID- 28665894 TI - Non-HLA Antibodies Impact on C4d Staining, Stellate Cell Activation and Fibrosis in Liver Allografts. AB - BACKGROUND: Recent data have shown an increased risk for rejection, fibrosis progression, and death in liver transplantation (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1 of 2000 to 4 of 2009 with known HLA DSA status for angiotensin II type-1 receptor and endothelin-1 type A receptor autoantibodies pre-LT, and year 1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death (hazard ratio [HR], 1.66; P = 0.02) especially if the HLA DSA was of the IgG3 subclass (HR, 2.28; P = 0.01). A single de novo non-HLA autoantibody was associated with an increased risk for T cell-mediated rejection or antibody-mediated rejection (68% vs 41%, P = 0.01) and fibrosis progression (HR, 1.84; P = 0.02). Biopsies with de novo non HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared with HLA DSA (71% vs 3%; P < 0.001). Liver sinusoidal endothelial cell activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-angiotensin II type-1 receptor and anti endothelin-1 type A receptor autoantibodies are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to liver sinusoidal endothelial cell capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding. PMID- 28665895 TI - DRESS Syndrome or Hematologic Malignancy?: A Case Report of a 4-Year-Old Boy. AB - Drug reaction with eosinophilia and systemic symptom (DRESS) is a serious idiosyncratic drug reaction. It is characterized by skin eruption, fever, hematologic abnormalities, and multi-organ involvement. Diagnosis is challenging because of the wide clinical spectrum. Its association with aromatic antiepileptic drugs, such as phenytoin, phenobarbital, and carbamazepine, has been well described in adults. There are few reports of DRESS syndrome in children, and knowledge about the relationship between new antiepileptic drugs such as oxcarbazepine and this syndrome is limited. The DRESS syndrome is a challenging entity and probably underdiagnosed because many of its clinical findings can mimic those of other serious systemic disorders such as infections and hematologic disorders. Virus reactivation and use of some drugs together with suspected drugs, such as amoxicillin, can trigger the symptoms of DRESS syndrome. This is a case report of a 4-year-old boy with oxcarbazepine-induced DRESS syndrome possibly triggered by amoxicillin; hematologic malignancy was included in the differential diagnosis. PMID- 28665896 TI - DRESS Syndrome: Drug Reaction With Eosinophilia and Systemic Symptoms. AB - DRESS syndrome is a cutaneous and systemic drug reaction with severe complications and a long course that can be fatal. Recognition may be difficult, and the condition is just rare enough that clinicians will eventually see it but may not be familiar with it. This review will focus on key elements to help clinicians with the challenges of recognition and differential diagnosis. PMID- 28665898 TI - A Case of Testicular Rupture Diagnosed by Point-of-Care-Ultrasound. AB - Point-of-care ultrasound is an expanding diagnostic tool in the pediatric emergency department. We describe a case of testicular rupture diagnosed by ultrasound at the bedside, which led to prompt surgical intervention and repair. PMID- 28665899 TI - Gastric Outlet Obstruction From a Button-Type Percutaneous Gastrostomy Tube. PMID- 28665900 TI - ECGs in the ED. PMID- 28665901 TI - Ultrasound Case Reviews-Looking Back; Looking Ahead. PMID- 28665902 TI - The Search for Perpetual Motion: Fatigue, Friction, and Drag in Quality Improvement. AB - Most people who have worked on continuous quality improvement (QI) with teams in the clinical microsystem have experienced "change fatigue." Application of the "Limit-to-Growth" system archetype to QI teams within health care can be used to understand negative feedback loops generated by successful QI that can limit future progress. Awareness of these factors can result in actions designed to reduce drag on forward momentum. Leaders in health care QI can anticipate and minimize negative feedback loops that accumulate to slow subsequent progress of highly functioning improvement teams within clinical microsystems. PMID- 28665903 TI - Man Versus Machine: Comparing Double Data Entry and Optical Mark Recognition for Processing CAHPS Survey Data. AB - OBJECTIVE: Historically, double data entry (DDE) has been considered the criterion standard for minimizing data entry errors. However, previous studies considered data entry alternatives through the limited lens of data accuracy. This study supplies information regarding data accuracy, operational efficiency, and cost for DDE and Optical Mark Recognition (OMR) for processing the Consumer Assessment of Healthcare Providers and Systems 5.0 survey. METHODS: To assess data accuracy, we compared error rates for DDE and OMR by dividing the number of surveys that were arbitrated by the total number of surveys processed for each method. To assess operational efficiency, we tallied the cost of data entry for DDE and OMR after survey receipt. Costs were calculated on the basis of personnel, depreciation for capital equipment, and costs of noncapital equipment. RESULTS: The cost savings attributed to this method were negated by the operational efficiency of OMR. There was a statistical significance between rates of arbitration between DDE and OMR; however, this statistical significance did not create a practical significance. CONCLUSIONS: The potential benefits of DDE in terms of data accuracy did not outweigh the operational efficiency and thereby financial savings of OMR. PMID- 28665904 TI - Evaluating a Collaborative Approach to Improve Prior Authorization Efficiency in the Treatment of Hepatitis C Virus. AB - OBJECTIVE: A team-based approach to obtaining prior authorization approval was implemented utilizing a specialty pharmacy, a clinic-based pharmacy technician specialist, and a registered nurse to work with providers to obtain approval for medications for hepatitis C virus (HCV) infection. The objective of this study was to evaluate the time to approval for prescribed treatment of HCV infection. METHODS: A retrospective observational study was conducted including patients treated for HCV infection by clinic providers who received at least 1 oral direct acting antiviral HCV medication. Patients were divided into 2 groups, based on whether they were treated before or after the implementation of the team-based approach. Student t tests were used to compare average wait times before and after the intervention. RESULTS: The sample included 180 patients, 68 treated before the intervention and 112 patients who initiated therapy after. All patients sampled required prior authorization approval by a third-party payer to begin therapy. There was a statistically significant reduction (P = .02) in average wait time in the postintervention group (15.6 +/- 12.1 days) once adjusted using dates of approval. CONCLUSIONS: Pharmacy collaboration may provide increases in efficiency in provider prior authorization practices and reduced wait time for patients to begin treatment. PMID- 28665905 TI - Implementation of Practice Transformation: Patient Experience According to Practice Leaders. AB - OBJECTIVE: Examine practice leaders' perceptions and experiences of how patient centered medical home (PCMH) transformation improves patient experience. SUBJECTS: Thirty-six interviews with lead physicians (n = 13), site clinic administrators (n = 13), and nurse supervisors (n = 10). METHODS: Semi-structured interviews at 14 primary care practices within a large urban Federally Qualified Health Center (FQHC) delivery system to identify critical patient experience domains and mechanisms of change. Identified patient experience domains were compared with Consumer Assessment of Healthcare Providers and Systems (CAHPS) items. RESULTS: We identified 28 patient experience domains improved by PCMH transformation, of which 22 are measured by CAHPS, and identified 24 mechanisms of change commonly reported by practice leaders during PCMH transformation. CONCLUSIONS: PCMH practice transformation can improve patient experience. Most patient experience domains reported as improved during PCMH efforts are measured by CAHPS items. Practices would benefit from collecting specific information on staff behaviors related to teamwork, team-based communication, scheduling, emergency and inpatient follow-up, and referrals. All 3 types of practice leaders reported 4 main mechanisms of PCMH change that improved patient experience. Our findings provide guidance for practice leaders on which strategies of PCMH practice transformation lead to specific improvements in patient experience measures. Further research is needed on the relationship between PCMH changes and changes in CAHPS patient experience scores. PMID- 28665906 TI - Characteristics of Patients With Congestive Heart Failure or Chronic Obstructive Pulmonary Disease Readmissions Within 30 Days Following an Acute Exacerbation. AB - BACKGROUND: The Hospital Readmissions Reduction Program targets Medicare patients with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) and penalizes hospitals that have increased 30-day readmission rates for these patients. The main goals of this study were to determine the clinical explanations for readmissions within 30 days, to identify possible deficiencies in patient care, and to identify typical characteristics of patients who were readmitted to the hospital. METHODS: The medical records department at University Medical Center in Lubbock, Texas, generated a list of patients with a primary discharge diagnosis of either acute exacerbation of CHF or an acute exacerbation of COPD who were readmitted within 30 days of discharge. Data collected from the electronic medical records included demographic information, clinical information, laboratory data, electrocardiographic information, echocardiographic results, and radiographic information for the index admission and readmission hospitalization. The indication for readmission was determined after review of all clinical data. RESULTS: The final study cohorts included 58 admission readmission events for acute exacerbations of CHF (47 patients) and 27 admission readmission events for acute exacerbations of COPD (16 patients). Patients in both cohorts had significant comorbidity and frequent admissions during the 12 months prior to their index admissions. Patients with COPD had predominantly an emphysematous phenotype. Chest radiographs in patients with CHF showed cardiomegaly, pulmonary edema, and pleural effusions. Patients with CHF were discharged with suboptimal medication regimens. Referral to outpatient rehabilitation programs was low in both groups. CONCLUSIONS: Patients with acute exacerbations of COPD or CHF who require readmission within 30 days have complex comorbidity. They appear to have typical clinical profiles (emphysematous-type COPD patients and CHF patients with fluid overload), are frequently discharged with suboptimal medication regimens, and are not referred to outpatient rehabilitation. These patients had frequent hospitalizations prior to index hospitalizations. This information provides the basis for a focused review of patients admitted to the hospital to identify factors that might contribute to readmission. PMID- 28665907 TI - Exploring the Relationship Between Volume and Outcomes in Hospital Cardiovascular Care. AB - BACKGROUND: Management theories of learning and experience curve effects state that greater levels of scale produce learnings and improved performance. In cardiovascular care, guidelines suggest that high-volume facilities produce better patient outcomes; yet, there are contradictory findings from the few studies conducted. Our goals were to assess the volume-outcome relationship for interventional cardiovascular care. METHODS: We examined 9360 patients with ST segment elevation myocardial infarction who underwent percutaneous intervention (PCI). We analyzed 6 years of data (2010-2015) using systematic extracts provided by 33 PCI-capable hospitals in the Dallas Texas region from the National Cardiovascular Data Registry. We stratified hospitals into 3 procedural volume categories (low, intermediate, and high) to identify changes in 2 key outcome metrics (ie, door-to-balloon times and mortality). Multivariate analyses and tests of differences were utilized. RESULTS: Door-to-balloon performance outcome was significantly different between volume categories, with the highest-volume hospitals performing significantly better than intermediate- and low-volume hospitals (47, 60, and 75 minutes, respectively; P < .001). Mortality followed a similar pattern, with a 3.3% unadjusted absolute lower mortality rate for the high-volume hospitals. Multivariate regressions confirm that volume is statistically significant in both mortality and treatment times. CONCLUSIONS: Higher-volume PCI hospitals have 37% shorter treatment times and 53% lower mortality rates than smaller facilities. This study provides evidence of a positive volume-outcome relationship in interventional cardiovascular care. PMID- 28665908 TI - Small Rural Hospitals Have a Harder Time Achieving Success in Continuous Quality Improvement: An Example From a Stroke Care Network. AB - BACKGROUND: University of Kentucky HealthCare established a Stroke Care Network (SCN) in 2008 to address the challenges of rural stroke care and improve care quality. METHODS: The SCN collects quality data from each affiliate that include volumes, mortality, length of stay, turnaround times, rt-PA door-to-needle time, 8 stroke core measures, and dysphagia screen measure. Characteristics of affiliate hospital studies include number of beds, Stroke Disease-Specific Care (DSC) certification by The Joint Commission, Appalachian designated county or not, time dedicated to stroke coordinator, submission of quality data for the calendar year, success of data, and utilization of American Heart Association's Get With the Guidelines. RESULTS: Seventeen of 23 (74%) affiliate hospitals submitted data. Highest scoring quality measures were antithrombotic by discharge (96%), antithrombotic by end of day 2 (93%), and assessed for rehabilitation (92%). Hospitals with DSC certification were more likely to succeed in stroke quality than those without (P = .0357). Hospitals in Appalachian counties were less likely to succeed in quality measures than those in non-Appalachian designated counties (P = .02). CONCLUSIONS: Our results demonstrate successful collection of quality data among hospitals bound only by an affiliation agreement. Areas to improve quality identified are door to computed tomographic interpretation, thrombolytic therapy, and dysphagia screening. We suspect that DSC certification is driving quality success in our network hospitals. That Appalachian affiliate hospitals are less likely to succeed could be due to a number of reasons such as the fewer resources available in Appalachian counties and may reflect the financial plight of rural hospitals more generally. PMID- 28665909 TI - What a Real Preoccupation With Failure Could Look Like. PMID- 28665910 TI - A Lean Tool Supporting Continuous Improvement at Intermountain. PMID- 28665915 TI - Prognostic Significance of Periostin and Mammalian Target of Rapamycin (mTOR) in Locally Advanced Esophageal Squamous Cell Carcinoma. AB - BACKGROUND Periostin and the mammalian target of rapamycin (mTOR) are involved in several cancers. This study aimed to evaluate the expression level of periostin and mTOR in locally advanced esophageal squamous cell carcinoma (ESCC) and to analyze their correlations with prognostic value. MATERIAL AND METHODS Expression levels of periostin and mTOR were examined by immunohistochemistry in locally advanced ESCC and corresponding adjacent normal tissue of 71 patients. The expression of periostin and mTOR were correlated with clinicopathologic characteristics by chi2 test or Kruskal-Wallis analysis. The prognostic factors of periostin and mTOR on overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier and Cox regression methods, respectively. RESULTS The high expression of periostin was significantly correlated to tumor stage (P=0.000), vascular invasion (P=0.027), differentiation (P=0.002), invasion depth (P=0.023), and lymph node metastasis (P=0.017). The high expression of mTOR was associated with tumor stage (P=0.001), lymphatic metastasis (P=0.014), and differentiation (P=0.036). Expression levels of periostin and mTOR was positively correlated (r=0.416, P=0.000). The OS and DFS in patients in the high-periostin group were significantly shorter than those in the low-periostin group, (both P<0.001). Similar results were found in mTOR analysis. Moreover, Cox regression analysis showed that the expressions of periostin and mTOR, along with tumor stage, were the independent factors affecting the survival time of ESCC patients. CONCLUSIONS Expressions of periostin and mTOR are related to multiple clinicopathologic features. High expression of periostin and mTOR were independent risk factors of ESCC patients, which might offer a potential target strategy for ESCC treatment in the future. PMID- 28665916 TI - Misinformation online and its impact on the physician-patient relation. PMID- 28665917 TI - Brief psychosis induced by methylphenidate in a child with attention deficit disorder: a case report and literature review. AB - Methylphenidate-induced psychosis has been scarcely studied due to bioethical and neurobiological issues regarding its research. Although some authors have hypothesized that there might be a vulnerability for the development of a major psychiatric disorder in the long term, there is no agreement about the predictive value of this type of psychosis in children and adolescents, and its origin is also uncertain. It has been suggested that higher dopamine levels in some cerebral regions and a family history of mental disorders might increase the risk of psychosis secondary to psychostimulants. We present the case of a nine-year old child diagnosed with attention deficit disorder and oppositional defiant disorder, who exhibited visual and auditory hallucinations and delirious ideas about harm during methylphenidate treatment. The patient?s symptoms regressed after drug removal. We discuss the key issues related to the origin, causality, management, and prognosis of psychostimulant-induced psychosis. PMID- 28665918 TI - Topical corticosteroids or vitamin D analogues for plaque psoriasis? AB - Psoriasis is a frequent chronic inflammatory disease. The plaque variant being its most common form of presentation. Although there is still no cure, treatment alternatives that induce remission and reduce lesions are available. Topical therapies, particularly corticosteroids and vitamin D analogues, are considered effective, but it is still not clear which would be the best alternative. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified eight systematic reviews including 26 studies overall, of which 22 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded there might be little or no difference in clinical response between topical corticosteroids and topical vitamin D analogues, but topical corticosteroids are less irritating at the site of application. No studies evaluating their long term adverse effects were found. PMID- 28665919 TI - Medical compliance to evidence-based clinical guidelines on secondary prevention of coronary heart disease in a hospital from Lima, Peru: a retrospective study. AB - INTRODUCTION: Cardiovascular disease is the leading cause of mortality worldwide. When an acute myocardial infarction occurs, it is necessary to establish secondary prevention measures, which can reduce mortality by 50%. Clinical guidelines state that the optimal medical treatment is based upon four groups of drugs: antiplatelet drugs, statins, beta-blockers and angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. OBJECTIVE: To determine physician compliance to evidence-based clinical practice guidelines on secondary prevention of coronary heart disease. METHODS: Retrospective, observational study in Hospital Cayetano Heredia in Lima, Peru. The study included patients with confirmed acute coronary syndrome from February 2011 to February 2013. Medical records, laboratory results and medical therapy at discharge were collected and were compared to the American Heart Association type I, evidence level A recommendations. In addition, patient follow-up visits to the outpatient cardiology clinic at 1, 3 and 6 months after discharge were analyzed. RESULTS: The study population included 143 patients. Eighty-nine (89) patients were admitted with the diagnosis of unstable angina and non-ST-segment elevation (62.2%) and 54 had ST-segment elevation myocardial infarction (37.8%). Forty patients (28%) received all four recommended medications at discharge, which decreased at 1, 3 and 6 months after discharge to 12.6%, 7% and 3.5% respectively. The results showed a significant reduction in patient compliance to follow-up visits with a 48% reduction at the first visit to 10% on the last visit. CONCLUSION: Medical compliance to guidelines recommendations in secondary cardiovascular prevention is suboptimal with a compliance score under 50%. PMID- 28665920 TI - Lineage conversion of mouse fibroblasts to pancreatic alpha-cells. AB - alpha-cells, which synthesize glucagon, also support beta-cell survival and have the capacity to transdifferentiate into beta-cells. However, the role of alpha cells in pathological conditions and their putative clinical applications remain elusive due in large part to the lack of mature alpha-cells. Here, we present a new technique to generate functional alpha-like cells. alpha-like cells (iAlpha cells) were generated from mouse fibroblasts by transduction of transcription factors, including Hhex, Foxa3, Gata4, Pdx1 and Pax4, which induce alpha-cell specific gene expression and glucagon secretion in response to KCl and Arg stimulation. The cell functions in vivo and in vitro were evaluated. Lineage specific and functional-related gene expression was tested by realtime PCR, insulin tolerance test (ITT), glucose tolerance test (GTT), Ki67 and glucagon immunohistochemistry analysis were done in iAlpha cells transplanted nude mice. iAlpha cells possess alpha-cell function in vitro and alter blood glucose levels in vivo. Transplantation of iAlpha cells into nude mice resulted in insulin resistance and increased beta-cell proliferation. Taken together, we present a novel strategy to generate functional alpha-like cells for the purposes of disease modeling and regenerative medicine. PMID- 28665921 TI - Rhododendrin inhibits toll-like receptor-7-mediated psoriasis-like skin inflammation in mice. AB - Many active compounds present in Rhododendron brachycarpum have been used in traditional Oriental medicine for the treatment of various skin diseases. However, the precise mechanism of action of the compounds isolated from R. brachycarpum and their relevance as therapeutics for the treatment of psoriasis remain elusive. In this study, we report that rhododendrin isolated from R. brachycarpum strongly inhibits imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. We showed that topical treatment with rhododendrin reduces IMQ-induced skin hyperplasia, inflammatory mononuclear cell infiltration and the expression of pro-inflammatory mediators in mouse skin. In addition, we found that rhododendrin inhibits the activation of the TLR-7/NF-kappaB and mitogen activated protein kinase pathways in both IMQ-induced psoriasis-like skin inflammation in mice and in normal human epidermal keratinocytes treated with IMQ. These results suggest that rhododendrin has an anti-inflammatory effect and can be used as a therapeutic to fight against psoriasis and other inflammatory skin diseases. PMID- 28665922 TI - Association of the gut microbiota mobilome with hospital location and birth weight in preterm infants. AB - BackgroundThe preterm infant gut microbiota is vulnerable to different biotic and abiotic factors. Although the development of this microbiota has been extensively studied, the mobilome-i.e. the mobile genetic elements (MGEs) in the gut microbiota-has not been considered. Therefore, the aim of this study was to investigate the association of the mobilome with birth weight and hospital location in the preterm infant gut microbiota.MethodsThe data set consists of fecal samples from 62 preterm infants with and without necrotizing enterocolitis (NEC) from three different hospitals. We analyzed the gut microbiome by using 16S rRNA amplicon sequencing, shot-gun metagenome sequencing, and quantitative PCR. Predictive models and other data analyses were performed using MATLAB and QIIME.ResultSThe microbiota composition was significantly different between NEC positive and NEC-negative infants and significantly different between hospitals. An operational taxanomic unit (OTU) showed strong positive and negative correlation with NEC and birth weight, respectively, whereas none showed significance for mode of delivery. Metagenome analyses revealed high levels of conjugative plasmids with MGEs and virulence genes. Results from quantitative PCR showed that the plasmid signature genes were significantly different between hospitals and in NEC-positive infants.ConclusionOur results point toward an association of the mobilome with hospital location in preterm infants. PMID- 28665923 TI - Noninvasive continuous cardiac output and cerebral perfusion monitoring in term infants with neonatal encephalopathy: assessment of feasibility and reliability. AB - BackgroundNoninvasive hemodynamic monitoring of infants with neonatal encephalopathy (NE) undergoing therapeutic hypothermia (TH) would be a potentially useful clinical tool. We aimed to assess the feasibility and reliability of noninvasive cardiac output monitoring (NICOM) and near-infrared spectroscopy (NIRS) in this cohort.MethodsNICOM and NIRS were commenced to measure cardiac output (CO), systemic vascular resistance (SVR), blood pressure (BP), and cerebral regional oxygen saturations (SctO2) during TH and rewarming. NICOM measures of CO were also compared with simultaneous echocardiography derived CO (echo-CO).ResultsTwenty infants with a median gestation of 40 weeks were enrolled. There was a strong correlation between NICOM- and echo-CO (r2=0.79, P<0.001). NICOM-CO was systematically lower than echo-CO with a bias of 27% (limits of agreement 3-51%). NICOM illustrated lower CO during TH, which increased during rewarming. SctO2 increased over the first 30 h of TH and stayed high for the remainder of the study. There was a rise in SVR over the first 30 h of TH and a decrease during rewarming (all P<0.05).ConclusionsNoninvasive hemodynamic assessment of infants with NE is feasible and illustrates potentially important changes. Larger studies are needed to assess the clinical applicability of those methods in this cohort. PMID- 28665924 TI - Somatic PIK3CA mutations are present in multiple tissues of facial infiltrating lipomatosis. AB - BackgroundFacial infiltrating lipomatosis (FIL) is a congenital disorder that causes overgrowth of one side of the face. The purpose of this study was to determine whether PIK3CA mutations are present in tissues outside of the subcutaneous adipose.MethodsFIL tissues from three patients were dissected to enrich for cells from skin, subcutaneous tissue, orbicularis oris muscle, buccal fat, zygomatic bone, and mucosal neuroma. Endothelial cells within the affected tissue also were enriched using CD31 microbeads. Laser capture microdissection on formalin-fixed paraffin-embedded histologic sections was performed to collect specific cell types. DNA was extracted from each tissue and cell type, and measured for the abundance of mutant PIK3CA alleles using droplet digital PCR.ResultsWe detected mutant PIK3CA alleles in every tissue and cell type tested from each overgrown face; frequencies ranged from 1.5 to 53%. There were fewer mutant endothelial cells compared with nonendothelial cells, and the stromal cell compartment had the highest frequency of mutant cells in each tissue.ConclusionsPIK3CA mutations are not restricted to a single tissue or cell type in FIL. Overgrowth in this condition is likely due to the mutation arising in a cell that contributes to several different facial structures during embryogenesis. PMID- 28665925 TI - Neonatal adaptation following intrauterine antidepressant exposure: assessment, drug assay levels, and infant development outcomes. AB - BackgroundAlthough a meta-analysis has confirmed the association between antidepressant exposure in utero and subsequent poor neonatal adaptation, few identified studies included drug levels or standardized measures and only two studies followed up children who developed symptoms beyond infancy.MethodsThe study draws on the Mercy Pregnancy and Emotional Wellbeing Study and reports on 42 women/infant pairs at delivery. In all, 31 women continued to take antidepressants until delivery and 11 ceased earlier in pregnancy. Poor neonatal adaptation was assessed twice daily for up to 6 days by using the Neonatal Abstinence Scoring System (NASS). Drug levels were analyzed in umbilical cord blood and maternal blood obtained at delivery.ResultsIn total, 76% (32 of 42) of neonates exposed to antidepressants had symptoms observed on the NASS. These symptoms occurred up to 5 days postpartum with 25% having symptoms that persisted for more than 3 days. The most frequent symptoms were correlated most closely to antidepressant drug levels. Elevated NASS scores were found to be associated with poorer fine motor development at 6 months of age.ConclusionsPoor neonatal adaptation may be more common than previously recognized. The NASS was observed to be an effective assessment and monitoring measure. Research following symptomatic infants beyond the neonatal period is required. PMID- 28665926 TI - Exome sequencing reveals a novel homozygous splice site variant in the WNT1 gene underlying osteogenesis imperfecta type 3. AB - BackgroundOsteogenesis imperfecta (OI) is a heritable bone fragility disorder usually caused by dominant variants in COL1A1 or COL1A2 genes. Over the last few years, 17 genes including 12 autosomal recessive and five autosomal dominant forms of OI, involved in various aspects of bone formation, have been identified.MethodsWhole-exome sequencing followed by conventional Sanger sequencing was performed in a single affected individual (IV-3) in a family.ResultsHere, we report the clinical and genetic characterization of OI type 3 in a consanguineous family with four affected members. Clinical examinations revealed low bone density, short stature, severe vertebral compression fractures, and multiple long bone fractures in the affected members. Exome sequencing revealed a biallelic pathogenic splice acceptor site variant (c.359-3C>G) in a wingless-type mouse mammary tumor virus integration site family 1 (WNT1) gene located on chromosome 12q13.12.ConclusionWe report a biallelic splice site variant underlying OI type 3 and the first case from the Pakistani population. PMID- 28665927 TI - Age-dependent sensitivity of the mouse kidney to chronic nicotine exposure. AB - BackgroundMany adolescents are exposed to nicotine via smoking, e-cigarette use, or second-hand smoke. Nicotine-induced renal oxidative stress and its long-term consequences may be higher in adolescents than in adults because of intrinsic factors in the adolescent kidney.MethodsAdolescent and adult male C57Bl/6J mice were subjected to 2 or 200 MUg/ml nicotine, which closely emulates passive or active smoking, respectively, for 4 weeks. Extent of nicotine exposure (cotinine content), oxidative stress (HNE), renal function (creatinine), tubular injury (KIM-1), and pretreatment renal levels of select pro-oxidant (p66shc) and antioxidant (Nrf2/MnSOD) genes were determined. Impact of p66shc overexpression or Nrf2/MnSOD knockdown on low-/high-dose nicotine-induced oxidative stress was determined in cultured renal proximal tubule cells.ResultsDespite similar plasma/renal cotinine levels, renal HNE and KIM-1 contents were higher in adolescents compared with those in adults, whereas renal function was unaltered after passive or active smoking-equivalent nicotine exposure. Pretreatment levels of p66shc were higher, whereas Nrf2/MnSOD levels were lower in the adolescent kidney. In agreement with this, overexpression of p66shc or knockdown of Nrf2/MnSOD augmented nicotine-induced ROS production in renal proximal tubule cells.ConclusionChronic nicotine exposure incites higher oxidative stress in the adolescent than in adult kidney because of a pre-existent pro-oxidant milieu. PMID- 28665928 TI - The role of breast milk in the colonization of neonatal gut and skin with coagulase-negative staphylococci. AB - BackgroundWe aimed to determine the genetic relatedness between Staphylococcus epidermidis colonizing breast milk (BM) and BM-fed neonates during the first month of life.MethodsS. epidermidis was isolated from the stool and skin swabs of 20 healthy term and 49 preterm neonates hospitalized in the neonatal intensive care unit and from the BM of mothers once a week and typed by multilocus variable number tandem-repeat analysis. Virulence-related genes were determined by PCR.ResultsThe gut (95%) and skin (100%) of term neonates were colonized with strains genetically similar to those in BM and carrying mecA and IS256 at low rate (both <6.7%). In preterm neonates, colonization with strains genetically similar to those in BM was low on the skin (34.7%) and in the gut in the first week of life (14.3%), but the prevalence of mecA (>90.6%) and IS256 (>61.7%) was high. By the fourth week, in the gut of preterm neonates the prevalence of mecA (73.8%) and IS256 (18.4%) decreased, but colonization with strains genetically similar to those in BM increased (83.7%).ConclusionDuring early life, the skin and gut of preterm neonates is colonized with S. epidermidis that is distinct from strains found in BM, but gradually the gut is enriched with strains genetically similar to those in BM, as in term neonates. PMID- 28665929 TI - Effect of frequency on pressure cost of ventilation and gas exchange in newborns receiving high-frequency oscillatory ventilation. AB - BackgroundWe hypothesized that ventilating at the resonant frequency of the respiratory system optimizes gas exchange while limiting the mechanical stress to the lung in newborns receiving high-frequency oscillatory ventilation (HFOV). We characterized the frequency dependence of oscillatory mechanics, gas exchange, and pressure transmission during HFOV.MethodsWe studied 13 newborn infants with a median (interquartile range) gestational age of 29.3 (26.4-30.4) weeks and body weight of 1.00 (0.84-1.43) kg. Different frequencies (5, 8, 10, 12, and 15 Hz) were tested, keeping carbon dioxide diffusion coefficient (DCO2) constant. Oscillatory mechanics and transcutaneous blood gas were measured at each frequency. The attenuation of pressure swings (DeltaP) from the airways opening to the distal end of the tracheal tube (TT) and to the alveolar compartment was mathematically estimated.ResultsBlood gases were unaffected by frequency. The mean (SD) resonant frequency was 16.6 (3.5) Hz. Damping of DeltaP increased with frequency and with lung compliance. DeltaP at the distal end of the TT was insensitive to frequency, whereas DeltaP at the peripheral level decreased with frequency.ConclusionThere is no optimal frequency for gas exchange when DCO2 is held constant. Greater attenuation of oscillatory pressure at higher frequencies offers more protection from barotrauma, especially in patients with poor compliance. PMID- 28665930 TI - Kidneys in 5-year-old preterm-born children: a longitudinal cohort monitoring of renal function. AB - BackgroundBeing aware of the impact of low birth weight on late-onset hypertension, our aim was to describe systolic blood pressure (sBP) and renal function in 3-5-year-old preterm-born children and to determine which perinatal factors or childhood factors were associated with an altered renal function at 5 years in these children.MethodsThis was a prospective longitudinal cohort study of children born at 27-31 weeks of gestation and included at birth and examined at 3, 4, and 5 years of age. The primary outcome was renal function at 5 years: BP, estimated glomerular filtration rate, and albuminuria.ResultsOne hundred and sixty five children were examined, of whom 93 (56.4%) were male. Gestational age was 29.2+/-1.4 weeks and birth weight was 1,217+/-331 g. Overall, 25% children had sBP >=90th percentile at age 3 and 4 years and 11% at 5 years. In multivariate analysis, sBP >=90th percentile at 5 years was associated with the use of antenatal steroids (OR=0.19(0.05;0.65)). There was a significant association between protein intake on day 28 and sBP at 5 years (beta=2.1+/-1.0, P=0.03). Glomerular filtration rate at 5 years was significantly decreased in case of hyaline membrane disease or necrotizing enterocolitis. High urine albumin was not predictable from one year to another.ConclusionIn preterm-born children, sBP was often high and neonatal protein intake was associated with increased blood pressure during childhood. PMID- 28665931 TI - Foxd1 is an upstream regulator of the renin-angiotensin system during metanephric kidney development. AB - BackgroundWe tested the hypothesis that Foxd1, a transcription factor essential for normal kidney development, is an upstream regulator of the renin-angiotensin system (RAS) during ureteric bud (UB)-branching morphogenesis.MethodsUB branching, RAS gene, and protein expression were studied in embryonic mouse kidneys. RAS mRNA expression was studied in mesenchymal MK4 cells.ResultsThe number of UB tips was reduced in Foxd1-/- compared with that in Foxd1+/+ metanephroi on embryonic day E12.5 (14+/-2.1 vs. 28+/-1.3, P<0.05). Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) demonstrated that renin, angiotensin I-converting enzyme (ACE), and angiotensin (Ang) II receptor type 1 (AT1R) mRNA levels were decreased in Foxd1-/- compared with those in Foxd1+/+ E14.5 metanephroi. Western blot analysis and immunohistochemistry showed decreased expression of AGT and renin proteins in Foxd1-/- metanephroi compared with that in Foxd1+/+ metanephroi. Foxd1 overexpression in mesenchymal MK4 cells in vitro increased renin, AGT, ACE, and AT1R mRNA levels. Exogenous Ang II stimulated UB branching equally in whole intact E12.5 Foxd1-/- and Foxd1+/+ metanephroi grown ex vivo (+364+/-21% vs. +336+/-18%, P=0.42).ConclusionWe conclude that Foxd1 is an upstream positive regulator of RAS during early metanephric development and propose that the cross-talk between Foxd1 and RAS is essential in UB-branching morphogenesis. PMID- 28665932 TI - Surfactant phospholipid composition of gastric aspirate samples differs between male and female very preterm infants. AB - BackgroundAmong preterm infants, males have a greater incidence of respiratory distress and death than do females born at the same gestational age, likely due to sex-related differences in lung maturation. Our aim was to determine whether surfactant phospholipid composition differs between male and female preterm infants.MethodsGastric aspirate samples from male and female infants born between 25 and 30 weeks of gestation at The Royal Women's Hospital, Melbourne, Australia, were collected within 1 h after birth. Phospholipid composition was analyzed by electrospray ionization tandem mass spectrometry.ResultsPreterm males had higher proportions of total phosphatidylinositol (PI) and phosphatidylserine 36:2, lower proportions of total sphingomyelin (S) and S 33:1 and 35:1, and a greater phosphatidylcholine (PC)/S ratio than did females. The proportions of PC 30:0, PC 34:0, PC 34:2, PC 36:2, PC 36:3, and PC 38:2 differed between the sexes at different gestational weeks of birth; the proportion of PC 32:0 (dipalmitoylphosphatidylcholine) in males was lower than that in females at 25 weeks of gestation but higher at 27 weeks.ConclusionPhospholipid composition in pulmonary surfactant is different between male and female preterm infants of the same gestational age, which may contribute to the increased risk for respiratory morbidities in one sex. PMID- 28665933 TI - Preventing harmful effects of epileptic seizures on cerebrovascular functions in newborn pigs: does sex matter? AB - BackgroundThe potential contribution of sex-related variables to cerebrovascular functions in neonates remains elusive. Newborn piglets provide a translationally relevant model for studying the effects of seizures in the neonatal brain. The present study investigated whether sex differences contribute to cerebrovascular functions in healthy and epileptic newborn pigs.MethodsEpileptic seizures were induced in female and male newborn pigs by bicuculline. An antioxidant drug, the carbon monoxide-releasing molecule CORM-A1, was administered enterally before or during seizures. The responses of pial arterioles to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested in intact and 48-h postictal piglets using the cranial window technique.ResultsIn intact newborn pigs, we did not observe any sex-related differences in cerebrovascular functions. In the postictal male and female newborn pigs, a marked reduction in responses of pial arterioles to endothelium- and astrocyte-dependent vasodilators was detected. CORM-A1, administered before or during seizures, greatly improved the outcome of seizures on cerebrovascular functions in both male and female piglets.ConclusionWe found no evidence of sex-related differences in cerebral vasodilator functions in control and epileptic newborn pigs. In both male and female newborns, epileptic seizures lead to prolonged cerebral vascular dysfunction that is effectively prevented by CORM-A1 therapy. PMID- 28665935 TI - 2017 Outstanding Contributions to ISCB Award: Fran Lewitter. PMID- 28665934 TI - Active Vertex Model for cell-resolution description of epithelial tissue mechanics. AB - We introduce an Active Vertex Model (AVM) for cell-resolution studies of the mechanics of confluent epithelial tissues consisting of tens of thousands of cells, with a level of detail inaccessible to similar methods. The AVM combines the Vertex Model for confluent epithelial tissues with active matter dynamics. This introduces a natural description of the cell motion and accounts for motion patterns observed on multiple scales. Furthermore, cell contacts are generated dynamically from positions of cell centres. This not only enables efficient numerical implementation, but provides a natural description of the T1 transition events responsible for local tissue rearrangements. The AVM also includes cell alignment, cell-specific mechanical properties, cell growth, division and apoptosis. In addition, the AVM introduces a flexible, dynamically changing boundary of the epithelial sheet allowing for studies of phenomena such as the fingering instability or wound healing. We illustrate these capabilities with a number of case studies. PMID- 28665936 TI - 2017 ISCB Innovator Award: Aviv Regev. PMID- 28665937 TI - Cholecalciferol decreases inflammation and improves vitamin D regulatory enzymes in lymphocytes in the uremic environment: A randomized controlled pilot trial. AB - It has been reported that vitamin D regulates the immune system. However, whether vitamin D repletion modulates inflammatory responses in lymphocytes from dialysis patients is unclear. In the clinical trial, thirty-two (32) dialysis patients with 25 vitamin D <= 20ng/mL were randomized to receive either supplementation of cholecalciferol 100,000 UI/week/3 months (16 patients) or placebo (16 patients). In the in vitro study, B and T lymphocytes from 12 healthy volunteers (HV) were incubated with or without uremic serum in the presence or absence of 25 or 1,25 vitamin D. We evaluated the intracellular expression of IL-6, IFN-gamma TLR7, TLR9, VDR, CYP27b1 and CYP24a1 by flow cytometry. We observed a reduction in the expression of TLR7, TLR9, INF-gamma and CYP24a1 and an increase in VDR and CYP27b1 expression in patients which were supplemented with cholecalciferol, whereas no differences were found in the placebo group. Uremic serum increased the intracellular expression of IL-6, IFN-gamma, TLR7, TLR9, VDR, CYP27b1 and CYP24a1. Treatment with 25 or 1,25 vitamin D decreased IL-6 and TLR9. CYP24a1 silencing plus treatment with 25 and/or 1,25 vitamin D had an additional reduction effect on IL-6, IFN-gamma, TLR7 and TLR9 expression. This is the first study showing that cholecalciferol repletion has an anti-inflammatory effect and improves vitamin D intracellular regulatory enzymes on lymphocytes from dialysis patients. PMID- 28665938 TI - Trends and outcomes of late initiation of combination antiretroviral therapy driven by late presentation among HIV-positive Taiwanese patients in the era of treatment scale-up. AB - OBJECTIVES: The international and national HIV treatment guidelines in 2016 have focused on scaling up access to combination antiretroviral therapy (cART). We aimed to assess the trends and treatment outcomes of late cART initiation in Taiwan. METHODS: Between June 2012 and May 2016, we retrospectively included antiretroviral-naive HIV-positive adults who initiated cART. Late initiation was defined as when cART was initiated in patients with a CD4 count <200 cells/mm3 or having experienced AIDS-defining illnesses. The treatment outcomes were assessed up to 6 months after starting cART. RESULTS: We included 3655 HIV-positive patients, and the majority of the patients were male (95.4%) with a median age of 31 years and initiated non-nucleoside reverse-transcriptase inhibitor-containing regimens (87.0%). The median CD4 count at cART initiation increased from 207 cells/mm3 in 2012 to 298 cells/mm3 in 2016, and the overall proportion of late cART initiation decreased from 49.1% in 2012 to 29.0% in 2016 (P for trend <0.001). Late cART initiation mainly resulted from late presentation for HIV care and was associated with older age (per 1-year increase, adjusted odds ratio [AOR], 1.05; 95% CI, 1.04-1.06), HBsAg seropositivity (AOR, 1.31; 95% CI, 1.04 1.64), HIV care in central and southern Taiwan, initiating cART in earlier year, non-intravenous drug users (AOR, 1.96; 95% CI, 1.33-2.86), and negative hepatitis C serostatus (AOR, 1.47; 95% CI, 1.04-2.08). Compared with non-late initiators, late initiators had a higher rate of all-cause mortality (1.7% vs. 0.3%) and regimen modification due to virological failure (7.1% vs. 2.6%). The predicting factors of all-cause mortality were late cART initiation (adjusted hazard ratio [AHR], 5.40; 95% CI, 2.14-13.65) and older age (AHR, 1.06; 95% CI, 1.03-1.10). CONCLUSIONS: While the proportion of late cART initiation decreased over time in Taiwan, late initiation remained in a substantial proportion of HIV-positive patients. The late initiators had higher risk for poor outcomes. The need for strategies to earlier detection of HIV infection and expediting cART initiation should be highlighted, especially among the older population. PMID- 28665939 TI - The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses. AB - Alveolar macrophages orchestrate pulmonary innate immunity and are essential for early immune surveillance and clearance of microorganisms in the airways. Inflammatory signaling must be sufficiently robust to promote host defense but limited enough to prevent excessive tissue injury. Macrophages in the lungs utilize multiple transcriptional and post-transcriptional mechanisms of inflammatory gene expression to delicately balance the elaboration of immune mediators. RNA terminal uridyltransferases (TUTs), including the closely homologous family members Zcchc6 (TUT7) and Zcchc11 (TUT4), have been implicated in the post-transcriptional regulation of inflammation from studies conducted in vitro. In vivo, we observed that Zcchc6 is expressed in mouse and human primary macrophages. Zcchc6-deficient mice are viable and born in Mendelian ratios and do not exhibit an observable spontaneous phenotype under basal conditions. Following an intratracheal challenge with S. pneumoniae, Zcchc6 deficiency led to a modest but significant increase in the expression of select cytokines including IL-6, CXCL1, and CXCL5. These findings were recapitulated in vitro whereby Zcchc6 deficient macrophages exhibited similar increases in cytokine expression due to bacterial stimulation. Although loss of Zcchc6 also led to increased neutrophil emigration to the airways during pneumonia, these responses were not sufficient to impact host defense against infection. PMID- 28665941 TI - Experimental and theoretical study of magnetohydrodynamic ship models. AB - Magnetohydrodynamic (MHD) ships represent a clear demonstration of the Lorentz force in fluids, which explains the number of students practicals or exercises described on the web. However, the related literature is rather specific and no complete comparison between theory and typical small scale experiments is currently available. This work provides, in a self-consistent framework, a detailed presentation of the relevant theoretical equations for small MHD ships and experimental measurements for future benchmarks. Theoretical results of the literature are adapted to these simple battery/magnets powered ships moving on salt water. Comparison between theory and experiments are performed to validate each theoretical step such as the Tafel and the Kohlrausch laws, or the predicted ship speed. A successful agreement is obtained without any adjustable parameter. Finally, based on these results, an optimal design is then deduced from the theory. Therefore this work provides a solid theoretical and experimental ground for small scale MHD ships, by presenting in detail several approximations and how they affect the boat efficiency. Moreover, the theory is general enough to be adapted to other contexts, such as large scale ships or industrial flow measurement techniques. PMID- 28665940 TI - Adiposity and adipogenic gene expression in four different muscles in beef cattle. AB - Anatomical site and divergent functionalities of muscles can be related to differences in IMF content, metabolism and adipogenic gene expression. Then, potential differences in different muscles in beef cattle were studied. As a second objective, the main sources of experimental variability associated to RT qPCR results were analyzed following a nested design in order to implement appropriate experimental designs minimizing gene expression variability. To perform the study Longissimus thoracis (LT), Semitendinosus (SM), Masseter (MS), Sternomandibularis (ST) and subcutaneous adipose tissue (SAT) samples of Pirenaica young bulls (n = 4) were collected for IMF, collagen and protein quantification, analysis of adipocyte size distribution and gene expression (PPARG, CEBPA, FAPB4 and WNT10B). A greater IMF content was observed in MS and SM muscles, which had a bimodal adipocyte size distribution while it was unimodal in the muscles LT and ST. This suggest that the different IMF accretion in the muscles studied might be related to different rates of hyperplasia and hypertrophy and that IMF might develop later in LT and ST muscles. The former differences were not mirrored by the expression of the genes analyzed, which might be related to the different contribution of mature and non-mature adipocytes to the total gene expression. When comparing IMF and SAT gene expression, late and early developing tissues respectively, expression of PPARG, CEBPA and FABP4 was higher in the SAT, in agreement with bigger cell size and numbers. The variability study indicates that the analytical factors that add higher variability to the gene expression are the sampling and RT and therefore, it would be appropriate to include those replicates in the design of future experiments. Based on the results, the use of MS and SM muscles could allow less expensive experimental designs and bigger sample size that could permit the detection of lower relevant differences in gene expression. PMID- 28665942 TI - The impact of mobile phone use on where we look and how we walk when negotiating floor based obstacles. AB - Pedestrians regularly engage with their mobile phone whilst walking. The current study investigated how mobile phone use affects where people look (visual search behaviour) and how they negotiate a floor based hazard placed along the walking path. Whilst wearing a mobile eye tracker and motion analysis sensors, participants walked up to and negotiated a surface height change whilst writing a text, reading a text, talking on the phone, or without a phone. Differences in gait and visual search behaviour were found when using a mobile phone compared to when not using a phone. Using a phone resulted in looking less frequently and for less time at the surface height change, which led to adaptations in gait by negotiating it in a manner consistent with adopting an increasingly cautious stepping strategy. When using a mobile phone, writing a text whilst walking resulted in the greatest adaptions in gait and visual search behaviour compared to reading a text and talking on a mobile phone. Findings indicate that mobile phone users were able to adapt their visual search behaviour and gait to incorporate mobile phone use in a safe manner when negotiating floor based obstacles. PMID- 28665943 TI - Anaplastic lymphoma kinase-positive large B-cell lymphoma: Clinico-pathological study of 17 cases with review of literature. AB - We retrospectively analysed 17 cases of anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+, LBCL) according to the morphological, immunohistochemical, molecular and clinical features, using which we intend to elucidate the clinicopathological characteristics of this rare entity. In this study, all cases de facto share common features that defined them as a single entity, and various characteristics may expand the spectrum. Among 15 cases, 60% followed an aggressive clinical course with advanced stage and high IPI scores; the median survival of these patients was only 8 months. An analysis showed that both the IPI score and the Ann Arbor stage were significant prognostic factors. Most patients received a chemotherapy regimen including CHOP, CHOEP, EPOCH, and CVAD, and some also underwent localized radiotherapy. However, ALK+, LBCL cases display a dismal clinical outcome and can only be cured with conventional chemotherapy protocols at the stage of localized disease. Novel front-line intensive chemotherapy regimens should therefore be evaluated in this group of patients. PMID- 28665945 TI - 2017 ISCB Overton Prize awarded to Christoph Bock. PMID- 28665944 TI - Molecular mechanics of Staphylococcus aureus adhesin, CNA, and the inhibition of bacterial adhesion by stretching collagen. AB - Bacterial adhesion to collagen, the most abundant protein in humans, is a critical step in the initiation and persistence of numerous bacterial infections. In this study, we explore the collagen binding mechanism of the multi-modular cell wall anchored collagen adhesin (CNA) in Staphylococcus aureus and examine how applied mechanical forces can modulate adhesion ability. The common structural-functional elements and domain organization of CNA are present across over 50 genera of bacteria. Through the use of molecular dynamics models and normal mode analysis, we shed light on the CNA's structural and conformational dynamics and its interactions with collagen that lead to collagen binding. Our results suggest that the linker region, CNA165-173, acts as a hinge exhibiting bending, extensional, and torsional modes of structural flexibility and its residues are key in the interaction of the CNA-collagen complex. Steered molecular dynamics simulations were conducted with umbrella sampling. During the course of these simulations, the 'locking' latch from the CNA N2 domain was dissociated from its groove in the CNA N1 domain, implying the importance of the latch for effective ligand binding. Finally, we observed that the binding efficiency of the CNA N1-N2 domains to collagen decreases greatly with increasing tensile force application to the collagen peptides. Thus, CNA and similar adhesins might preferentially bind to sites in which collagen fibers are cleaved, such as in wounded, injured, or inflamed tissues, or in which the collagenous tissue is less mature. As alternative techniques for control of bacterial infection are in-demand due to the rise of bacterial antibiotic resistance, results from our computational studies with respect to the mechanoregulation of the collagen binding site may inspire new therapeutics and engineering solutions by mechanically preventing colonization and/or further pathogenesis. PMID- 28665946 TI - Psycho-educational interventions for children and young people with Type 1 Diabetes in the UK: How effective are they? A systematic review and meta analysis. AB - AIMS: To synthesise evidence from UK-based randomised trials of psycho educational interventions in children and young people (CYP) with Type 1 Diabetes (T1D) to inform the evidence-base for adoption of such interventions into the NHS. METHODS: We searched Medline, Embase, Cochrane, PsycINFO, CINAHL, and Web of Science up to March 2016. Two reviewers independently selected UK-based randomised trials comparing psycho-educational interventions for improving management of T1D for CYP with a control group of usual care or attention control. The main outcome was glycaemic control measured by percentage of glycated haemoglobin (HbA1c); secondary outcomes included psychosocial functioning, diabetes knowledge, adverse and other clinical outcomes. A narrative synthesis and meta-analysis were conducted. Pooled effect sizes of standardised mean difference (SMD) were calculated. RESULTS: Ten eligible trials of three educational and seven psycho-educational interventions were identified. Most interventions were delivered by non-psychologists and targeted adolescents with more than one year duration of diabetes. Meta-analysis of nine of these trials (N = 1,838 participants) showed a non-significant reduction in HbA1c attributable to the intervention (pooled SMD = -0.06, 95% CI: -0.21 to 0.09). Psycho-educational interventions aiming to increase children's self-efficacy had a moderate, beneficial effect (SMD = 0.50, 95% CI: 0.13 to 0.87). No benefits on diabetes knowledge and other indicators of psychosocial functioning were identified. CONCLUSIONS: There is insufficient evidence to recommend the use of particular psycho-educational programme for CYP with T1D in the UK. Further trials with sufficient power and reporting standards are needed. Future trials could consider active involvement of psychological specialists in the delivery of psychologically informed interventions and implementation of psycho-educational interventions earlier in the course of the disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015010701. PMID- 28665947 TI - A score test for comparing cross-sectional survival data with a fraction of non susceptible patients and its application in clinical immunology. AB - OBJECTIVES: In cross-sectional studies of time-to-event data collected by patient examinations at a single random point in time, a fraction of them will not experience the event regardless of the length of the follow-up time. This is the case in clinical immunology studies that include a mixed population, with both immune-reactive and immune-tolerant (or non-susceptible) patients. In these cases, classical tests of current status data may perform poorly. New methods for testing these data are needed. METHODS: In the two-sample comparison setting, we propose a score test for testing the null hypothesis that survival does not differ in either the non-susceptible fraction or the time-to-event distribution among the susceptible fraction. RESULTS: In a wide range of scenarios, simulation results show interesting improvements in power for the proposed score test compared to the logrank-type test in most of the configurations we investigated. In a cross-sectional study of drug immunogenicity among treated multiple sclerosis patients, the proposed score test reveals that gender is associated with the immunogenicity of interferon. PMID- 28665948 TI - Quaternary structure is an essential component that contributes to the sophisticated allosteric regulation mechanism in a key enzyme from Mycobacterium tuberculosis. AB - The first enzyme of the shikimate pathway, 3-deoxy-D-arabino-heptulosonate 7 phosphate synthase (DAH7PS), adopts a range of distinct allosteric regulation mechanisms in different organisms, related to different quaternary assemblies. DAH7PS from Mycobacterium tuberculosis (MtuDAH7PS) is a homotetramer, with the allosteric sites in close proximity to the interfaces. Here we examine the importance of the quaternary structure on catalysis and regulation, by amino acid substitution targeting the tetramer interface of MtuDAH7PS. Using only single amino acid substitutions either in, or remote from the interface, two dimeric variants of MtuDAH7PS (MtuDAH7PSF227D and MtuDAH7PSG232P) were successfully generated. Both dimeric variants maintained activity due to the distance between the sites of amino acid substitution and the active sites, but attenuated catalytic efficiency was observed. Both dimeric variants showed significantly disrupted allosteric regulation with greatly impaired binding affinity for one of the allosteric ligands. Molecular dynamics simulations revealed changes in protein dynamics and average conformations in the dimeric variant caused by amino acid substitution remote to the tetramer interface (MtuDAH7PSG232P), which are consistent with the observed reduction in catalytic efficiency and loss of allosteric response. PMID- 28665949 TI - Possible mechanisms of pollination failure in hybrid carrot seed and implications for industry in a changing climate. AB - Approximately one-third of our food globally comes from insect-pollinated crops. The dependence on pollinators has been linked to yield instability, which could potentially become worse in a changing climate. Insect-pollinated crops produced via hybrid breeding (20% of fruit and vegetable production globally) are especially at risk as they are even more reliant on pollinators than open pollinated plants. We already observe a wide range of fruit and seed yields between different cultivars of the same crop species, and it is unknown how existing variation will be affected in a changing climate. In this study, we examined how three hybrid carrot varieties with differential performance in the field responded to three temperature regimes (cooler than the historical average, average, and warmer that the historical average). We tested how temperature affected the plants' ability to set seed (seed set, pollen viability) as well as attract pollinators (nectar composition, floral volatiles). We found that there were significant intrinsic differences in nectar phenolics, pollen viability, and seed set between the carrot varieties, and that higher temperatures did not exaggerate those differences. However, elevated temperature did negatively affect several characteristics relating to the attraction and reward of pollinators (lower volatile production and higher nectar sugar concentration) across all varieties, which may decrease the attractiveness of this already pollinator limited crop. Given existing predictions of lower pollinator populations in a warmer climate, reduced attractiveness would add yet another challenge to future food production. PMID- 28665950 TI - Mortality among PCR negative admitted Ebola suspects during the 2014/15 outbreak in Conakry, Guinea: A retrospective cohort study. AB - Non-cases are suspect Ebola Virus Disease (EVD) cases testing negative by EVD RT PCR after admission to an Ebola Treatment Centre (ETC). Admitting non-cases to an ETC prompts concerns on case- and workload in the ETC, risk for nosocomial EVD infection, and delays in diagnosis and disease-specific treatment. We retrospectively analysed characteristics, outcomes and determinants of death of EVD cases and non-cases admitted to the Conakry ETC in Guinea between 03/2014 and 09/2015. Of the 2362 admitted suspects who underwent full confirmatory PCR testing, 1540 (65.2%) were non-cases; among them 727 needed repeated confirmatory PCR testing resulting in 2.5 days (average) in the ETC isolation ward. Twenty-one patients tested positive on the repeat test, most in a period of flawed sampling for the initial test and none after introduction of PCR confirmation with geneXpert. No readmissions following nosocomial EVD infection were recorded. No combination of symptoms yielded acceptable sensitivity and specificity to allow differentiating confirmed from non-cases. Symptoms as ocular bleeding/redness have high specificity, but limited usefulness as not common. Admission delay and age distribution were not different for both groups. In total, 98 (20.6%) of 475 deaths in the ETC were non-cases. Most died within 24 hours after admission. Living in Conakry (aOR 1.78 (1.08-2.96)) was the strongest risk factor for death. Weeks with higher admission load had lower case fatality among non-cases, probably because more acute (and treatable) illnesses of contacts of known cases were admitted. These findings show high numbers of potentially critically ill non cases need to be considered when setting up triage and referral of EVD suspect cases. Symptoms and risk factors alone do not allow differentiating the non cases. Integration of highly-sensitive EVD diagnostic methods with short turnaround time in the triage of peripheral hospitals and dropping the systematic 2nd PCR for symptomatic early presenters could limit delays in access to adapted care of cases and seriously ill non-cases. Whether feasible without compromising outbreak control, and under which conditions, should be further assessed. PMID- 28665951 TI - Low satisfaction of clients for the health service provision in West Amhara region, Ethiopia. AB - INTRODUCTION: Client satisfaction is a key indicator to measure quality of healthcare and provides information on the level of success forproviders whether client expectations and values are met. Although there are some institutional based studies done in Ethiopia, still client satisfaction in our settings is not well addressed. Thus, this study was aimed to assess client satisfaction level and identify the underlying factors of poor health service provision in West Amhara, Ethiopia. METHODS: A cross-sectional study design was conducted from July to August, 2013. A structured questionnaire was used to collect data from 422 outpatient diagnosis (OPD) service users. The data were entered into EPI Info version 3.5.2 and analyzed usingSPSS version 16. RESULTS: Among the 422 study participants, 234 (55.5%) males, the mean (+/-SD) age was 37.3 (+/-16.4) years. The overall satisfaction level of the study participants was 39.3%. Poor cleanliness of the facility, fewer service access provision, lack of prescribed drugs within the facility and longer waiting time to get the health care service wasreported by 73.2%, 67.8%, 65.6% and 59.2% of the clients respectively. Paying service users (AOR: 2.03, 95% CI: 1.22-3.39, P: 0.007), divorced clients (AOR: 4.26, 95% CI: 1.11-16.26, P: 0.034) and hospital users (AOR: 2.18, 95% CI: 1.29 3.69, P: 0.004) were more dissatisfied. CONCLUSIONS: Client satisfaction was lowin the health provision in West Amhara region. Expansion of health facilities in remote areas, maintaining continuous availability of prescribed drugs, improving cleanliness of health facilities, and fast health service provision are recommended to satisfy clients in the setting. PMID- 28665953 TI - 2017 ISCB Accomplishment by a Senior Scientist Award given to Pavel Pevzner. PMID- 28665952 TI - Intrinsic and extrinsic factors related to pathogen infection in wild small mammals in intensive milk cattle and swine production systems. AB - BACKGROUND: Understanding the ecological processes that are involved in the transmission of zoonotic pathogens by small mammals may aid adequate and effective management measures. Few attempts have been made to analyze the ecological aspects that influence pathogen infection in small mammals in livestock production systems. We describe the infection of small mammals with Leptospira spp., Brucella spp., Trichinella spp. and Cysticercus fasciolaris and assess the related intrinsic and extrinsic factors in livestock production systems in central Argentina at the small mammal community, population and individual levels. METHODOLOGY/PRINCIPAL FINDINGS: Ten pig farms and eight dairy farms were studied by removal trapping of small mammals from 2008 to 2011. Each farm was sampled seasonally over the course of one year with cage and Sherman live traps. The 505 small mammals captured (14,359 trap-nights) included three introduced murine rodents, four native rodents and two opossums. Leptospira spp., anti-Brucella spp. antibodies and Trichinella spp. were found in the three murine rodents and both opossums. Rattus norvegicus was also infected with C. fasciolaris; Akodon azarae and Oligoryzomys flavescens with Leptospira spp.; anti Brucella spp. antibodies were found in A. azarae. Two or more pathogens occurred simultaneously on 89% of the farms, and each pathogen was found on at least 50% of the farms. Pathogen infections increased with host abundance. Infection by Leptospira spp. also increased with precipitation and during warm seasons. The occurrence of anti-Brucella spp. antibodies was higher on dairy farms and during the winter and summer. The host abundances limit values, from which farms are expected to be free of the studied pathogens, are reported. CONCLUSIONS/SIGNIFICANCE: Murine rodents maintain pathogens within farms, whereas other native species are likely dispersing pathogens among farms. Hence, we recommend preventing and controlling murines in farm dwellings and isolating farms from their surroundings to avoid contact with other wild mammals. PMID- 28665954 TI - Prevalence and correlation of cytokine-specific autoantibodies with epidemiological factors and C-reactive protein in 8,972 healthy individuals: Results from the Danish Blood Donor Study. AB - Natural cytokine-specific autoantibodies (c-aAb) have been measured in healthy and diseased individuals, and have been considered as both endogenous immune regulators and pathogenic factors. Overall, the etiology and potential pathology of c-aAb are still undefined. To further characterize the sero-prevalence, predictors and consequences of high c-aAb levels, we performed the largest population-based study of c-aAb to date, using participants and epidemiological data from the Danish Blood Donor Study. Using a validated bead-based multiplex assay we assessed plasma levels of IL-1alpha, IL-6, IL-10, IFNalpha and GM-CSF specific c-aAb in 8,972 healthy blood donors. Trace levels of at least one of the investigated c-aAb could be measured in 86% of the participants. The presence of high levels of potentially inhibitory c-aAb was generally associated with increasing age and male or female sex, depending on the c-aAb in question. A negative correlation between high levels of IL-6-specific c-aAb and plasma levels of C-reactive protein was observed, indicating cytokine-neutralizing levels of c aAb in healthy blood donors. There was no substantial correlation between high levels of the five individual c-aAb investigated in this study. These data suggest that autoimmunity against endogenous cytokines is a relatively common phenomenon in healthy individuals, and that predictive factors for high, potentially neutralizing c-aAb levels vary depending on the cytokine in question, and may differ from predictors of general c-aAb presence. PMID- 28665955 TI - Pro-fibrotic compounds induce stellate cell activation, ECM-remodelling and Nrf2 activation in a human 3D-multicellular model of liver fibrosis. AB - BACKGROUND & AIMS: Currently most liver fibrosis research is performed in vivo, since suitable alternative in vitro systems which are able to recapitulate the cellular events leading to liver fibrosis are lacking. Here we aimed at generating a system containing cells representing the three key players of liver fibrosis (hepatocyte, Kupffer cells and stellate cells) and assess their response to pro-fibrotic compounds such as TGF-beta1, methotrexate (MTX) and thioacetamide (TAA). METHODS: Human cell lines representing hepatocytes (HepaRG), Kupffer cell (THP-1 macrophages) and stellate cells (hTERT-HSC) were co-cultured using the InSphero hanging drop technology to generate scaffold-free 3D microtissues, that were treated with pro-fibrotic compounds (TGF-beta1, MTX, TAA) for up to 14 days. The response of the microtissues was evaluated by determining the expression of cytokines (TNF-alpha, TGF-beta1 and IL6), the deposition and secretion of ECM proteins and induction of gene expression of fibrosis biomarkers (e.g. alphaSMA). Induction of Nrf2 and Keap1, as key player of defence mechanism, was also evaluated. RESULTS: We could demonstrate that the multicellular 3D microtissue cultures could be maintained in a non-activated status, based on the low expression levels of activation markers. Macrophages were activated by stimulation with LPS and hTERT-HSC showed activation by TGF-beta1. In addition, MTX and TAA elicited a fibrotic phenotype, as assessed by gene-expression and protein-deposition of ECM proteins such as collagens and fibronectin. An involvement of the antioxidant pathway upon stimulation with pro-fibrotic compounds was also observed. CONCLUSION: Here, for the first time, we demonstrate the in vitro recapitulation of key molecular and cellular events leading to liver fibrosis: hepatocellular injury, antioxidant defence response, activation of Kupffer cells and activation of HSC leading to deposition of ECM. PMID- 28665956 TI - Gender-differences in the associations between circulating creatine kinase, blood pressure, body mass and non-alcoholic fatty liver disease in asymptomatic asians. AB - BACKGROUND: Creatine kinase (CK) is a pivotal regulatory enzyme in energy metabolism linked to both blood pressure and cardio-metabolic components. However, data is lacking in a large population of asymptomatic Asians. METHODS AND RESULTS: Cardio-metabolic assessment including anthropometric measures and non-alcoholic fatty liver disease (NAFLD) were evaluated by abdominal echo in 4,562 consecutive subjects who underwent an annual health survey. Serum CK levels were related to blood pressure components [systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP)], anthropometric measures, and excessive adiposity in liver as indicated by NAFLD. Circulating CK levels ranged from 4 to 1842 IU/L (mean [SE]: 108.7 [1.1] IU/L) in the study population which consisted of 2522 males (mean age: 48.7 +/- 11.2) and 2040 females (mean age: 49.4+/-11.5). In general, male subjects presented with higher circulating CK levels than females (mean +/- SE: 127.3 +/- 1.5 vs. 85.5 +/- 1.3 IU/L, respectively, p < .001). Gender-differences in circulating CK levels were also observed with increasing age, which showed a more pronounced positive relationship with age in female subjects (gender interaction: p < .05). Furthermore, an elevated circulating CK level was independently associated with higher blood pressure, waist circumference and fat mass (FM), greater body mass index (BMI), increased lower estimated glomerular filtration rate (eGFR) and presence of NAFLD in multivariate analysis (all p < .05), with CK elevation more pronounced with greater BMI and FM in males compared with females (sex interaction: p < .05). CONCLUSION: In a large asymptomatic Asian population, circulating CK levels were increased with more advanced age, higher blood pressure, and greater body mass with gender differences. Our findings may be useful in interpreting elevated CK from subjects free of ongoing myocardial damage. PMID- 28665958 TI - Effects of fire disturbance on soil respiration in the non-growing season in a Larix gmelinii forest in the Daxing'an Mountains, China. AB - In boreal forests, fire is an important part of the ecosystem that greatly influences soil respiration, which in turn affects the carbon balance. Wildfire can have a significant effect on soil respiration and it depends on the fire severity and environmental factors (soil temperature and snow water equivalent) after fire disturbance. In this study, we quantified post-fire soil respiration during the non-growing season (from November to April) in a Larix gmelinii forest in Daxing'an Mountains of China. Soil respiration was measured in the snow covered and snow-free conditions with varying degrees of natural burn severity forests. We found that soil respiration decreases as burn severity increases. The estimated annual C efflux also decreased with increased burn severity. Soil respiration during the non-growing season approximately accounted for 4%-5% of the annual C efflux in all site types. Soil temperature (at 5 cm depth) was the predominant determinant of non-growing season soil respiration change in this area. Soil temperature and snow water equivalent could explain 73%-79% of the soil respiration variability in winter snow-covering period (November to March). Mean spring freeze-thaw cycle (FTC) period (April) soil respiration contributed 63% of the non-growing season C efflux. Our finding is key for understanding and predicting the potential change in the response of boreal forest ecosystems to fire disturbance under future climate change. PMID- 28665957 TI - Post-dengue acute disseminated encephalomyelitis: A case report and meta analysis. AB - BACKGROUND: Dengue is one of the most common infectious diseases. The aim of this study was to systematically review acute disseminated encephalomyelitis (ADEM) and to represent a new case. METHODOLOGY/PRINCIPAL FINDINGS: We searched for articles in nine databases for case reports, series or previous reviews reporting ADEM cases in human. We used Fisher's exact and Mann-Whitney U tests. Classification trees were used to find the predictors of the disease outcomes. We combined findings using fixed- and random-effects models. A 13-year-old girl was admitted to the hospital due to fever. She has a urinary retention. The neurological examinations revealed that she became lethargic and quadriplegic. She had upper limbs weakness and lower limbs complete paraplegia. Her status gradually improved after the treatment. She was nearly intact with the proximal part of her legs had a mild weakness in discharge. The prevalence of ADEM among dengue patients was 0.4% [95% confidence intervals (95% CI) 0.1-2.5%], all neurological disorders among dengue was 2.6% [95% CI 1.8-3.8%], and ADEM among neurological disorders was 6.8% [95% CI 3.4-13%]. The most frequent manifestation of ADEM was altered sensorium/consciousness (58%), seizures and urination problems (35%), vision problems (31%), slurred speech (23%), walk problems (15%) then ataxia (12%). There was a significant difference between cases having complete recovery or bad outcomes in the onset day of neurological manifestations being earlier and in temperature being higher in cases having bad outcomes (p value < 0.05). This was confirmed by classification trees which included these two variables. CONCLUSIONS/SIGNIFICANCE: The prevalence of ADEM among dengue and other dengue-related neurological disorders is not too rare. The high fever of ADEM cases at admission and earlier onset day of neurological manifestations are associated with the bad outcomes. PMID- 28665959 TI - Increased migration of antigen presenting cells to newly-formed lymphatic vessels in transplanted kidneys by glycol-split heparin. AB - BACKGROUND: Chronic renal transplant dysfunction is characterized by loss of renal function and tissue remodeling, including chronic inflammation and lymph vessel formation. Proteoglycans are known for their chemokine presenting capacity. We hypothesize that interruption of the lymphatic chemokine proteoglycan interaction interferes with the lymphatic outflow of leukocytes from the renal graft and might decrease the anti-graft allo-immune response. METHODS: In a rat renal chronic transplant dysfunction model (female Dark-Agouti to male Wistar Furth), chemokines were profiled by qRT-PCR in microdissected tubulo interstitial tissue. Disruption of lymphatic chemokine-proteoglycan interaction was studied by (non-anticoagulant) heparin-derived polysaccharides in vitro and in renal allografts. The renal allograft function was assessed by rise in plasma creatinine and urea. RESULTS: Within newly-formed lymph vessels of transplanted kidneys, numerous CD45+ leukocytes were found, mainly MHCII+, ED-1-, IDO-, HIS14 , CD103- antigen presenting cells, most likely representing a subset of dendritic cells. Treatment of transplanted rats with regular heparin and two different (non )anticoagulant heparin derivatives revealed worsening of kidney function only in the glycol-split heparin treated group despite a two-fold reduction of tubulo interstitial leukocytes (p<0.02). Quantitative digital image analysis however revealed increased numbers of intra-lymphatic antigen-presenting cells only in the glycol-split heparin group (p<0.01). The number of intra-lymphatic leukocytes significantly correlates with plasma creatinine and urea, and inversely with creatinine clearance. CONCLUSIONS: Treatment of transplanted rats with glycol split heparin significantly increases the number of intra-lymphatic antigen presenting cells, by increased renal diffusion of lymphatic chemokines, thereby increasing the activation and recruitment of antigen presenting cells towards the lymph vessel. This effect is unwanted in the transplantation setting, but might be advantageous in e.g., dendritic cell vaccination. PMID- 28665960 TI - Dynamics of organizational culture: Individual beliefs vs. social conformity. AB - The complex nature of organizational culture challenges our ability to infer its underlying dynamics from observational studies. Recent computational studies have adopted a distinctly different view, where plausible mechanisms are proposed to describe a wide range of social phenomena, including the onset and evolution of organizational culture. In this spirit, this work introduces an empirically grounded, agent-based model which relaxes a set of assumptions that describes past work-(a) omittance of an individual's strive for achieving cognitive coherence; (b) limited integration of important contextual factors-by utilizing networks of beliefs and incorporating social rank into the dynamics. As a result, we illustrate that: (i) an organization may appear to be increasingly coherent in terms of its organizational culture, yet be composed of individuals with reduced levels of coherence; (ii) the components of social conformity-peer-pressure and social rank-are influential at different aggregation levels. PMID- 28665961 TI - Optimal teaching strategy in periodic impulsive knowledge dissemination system. AB - Accurately describing the knowledge dissemination process is significant to enhance the performance of personalized education. In this study, considering the effect of periodic teaching activities on the learning process, we propose a periodic impulsive knowledge dissemination system to regenerate the knowledge dissemination process. Meanwhile, we put forward learning effectiveness which is an outcome of a trade-off between the benefits and costs raised by knowledge dissemination as objective function. Further, we investigate the optimal teaching strategy which can maximize learning effectiveness, to obtain the optimal effect of knowledge dissemination affected by the teaching activities. We solve this dynamic optimization problem by optimal control theory and get the optimization system. At last we numerically solve this system in several practical examples to make the conclusions intuitive and specific. The optimal teaching strategy proposed in this paper can be applied widely in the optimization problem of personal education and beneficial for enhancing the effect of knowledge dissemination. PMID- 28665962 TI - Biochemical characterization of functional domains of the chaperone Cosmc. AB - Cosmc is an endoplasmic reticulum chaperone necessary for normal protein O-GalNAc glycosylation through regulation of T-synthase, its single client. Loss-of function of Cosmc results in expression of the Tn antigen, which is associated with multiple human diseases including cancer. Despite intense interest in dysregulated expression of the Tn antigen, little is known about the structure and function of Cosmc, including domain organization, secondary structure, oligomerization, and co-factors. Limited proteolysis experiments show that Cosmc contains a structured N-terminal domain (CosmcDelta256), and biochemical characterization of CosmcDelta256 reveals wild type chaperone activity. Interestingly, CosmcE152K, which shows loss of function in vivo, exhibits wild type-like activity in vitro. Cosmc and CosmcE152K heterogeneously oligomerize and form monomeric, dimeric, trimeric, and tetrameric species, while CosmcDelta256 is predominantly monomeric as characterized by chemical crosslinking and blue native page electrophoresis. Additionally, Cosmc selectively binds divalent cations in thermal shift assays and metal binding is abrogated by the CosmcDelta256 truncation, and perturbed by the E152K mutation. Therefore, the N-terminal domain of Cosmc mediates T-synthase binding and chaperone function, whereas the C terminal domain is necessary for oligomerization and metal binding. Our results provide new structure-function insight to Cosmc, indicate that Cosmc behaves as a modular protein and suggests points of modulation or regulation of in vivo chaperone function. PMID- 28665963 TI - Morphology-based optical separation of subpopulations from a heterogeneous murine breast cancer cell line. AB - Understanding tumor heterogeneity is an urgent and unmet need in cancer research. In this study, we used a morphology-based optical cell separation process to classify a heterogeneous cancer cell population into characteristic subpopulations. To classify the cell subpopulations, we assessed their morphology in hydrogel, a three-dimensional culture environment that induces morphological changes according to the characteristics of the cells (i.e., growth, migration, and invasion). We encapsulated the murine breast cancer cell line 4T1E, as a heterogeneous population that includes highly metastatic cells, in click crosslinkable and photodegradable gelatin hydrogels, which we developed previously. We observed morphological changes within 3 days of encapsulating the cells in the hydrogel. We separated the 4T1E cell population into colony- and granular-type cells by optical separation, in which local UV-induced degradation of the photodegradable hydrogel around the target cells enabled us to collect those cells. The obtained colony- and granular-type cells were evaluated in vitro by using a spheroid assay and in vivo by means of a tumor growth and metastasis assay. The spheroid assay showed that the colony-type cells formed compact spheroids in 2 days, whereas the granular-type cells did not form spheroids. The tumor growth assay in mice revealed that the granular-type cells exhibited lower tumor growth and a different metastasis behavior compared with the colony-type cells. These results suggest that morphology-based optical cell separation is a useful technique to classify a heterogeneous cancer cell population according to its cellular characteristics. PMID- 28665964 TI - Therapy options in deep sternal wound infection: Sternal plating versus muscle flap. AB - BACKGROUND: Management of deep sternal wound infection (DSWI) in cardiac surgical patients still remains challenging. A variety of treatment strategies has been described. Aim of this cohort study was to analyse two different treatment strategies for DSWI: titanium sternal plating system (TSFS) and muscle flap coverage (MFC). METHODS: Between January 2007 and December 2011, from 3122 patients undergoing cardiac surgery 42 were identified with DSWI and treated with one of the above mentioned strategies. In-hospital data were collected, follow-up performed by telephone and assessment of Quality of Life (QoL) using the SF-12 Health Survey Questionnaire. RESULTS: 20 patients with deep sternal wound infection were stabilized with TSFS and 22 patients treated with MFC. Preoperative demographics and risk factors did not reveal any significant differences. Patients treated with TSFS had a significantly shorter operation time (p<0.05) and shorter hospitalization (p<0.05). A tendency towards lower mortality rate (p = n.s.) and less re-interventions were also noted (plating 0.6 vs. flap 1.17 per patient, n.s.). Quality of Life in the TSFS group for the physical-summary-score was significantly elevated compared to the MFC group (p<0.05). Relating to chest stability and cosmetic result the treatment with TSFS showed superior results, but the usage of MFC gave the patients more freedom in breathing and less chest pain. CONCLUSION: Our results demonstrate that the use of TSFS is a feasible and safe alternative in DSWI. However, MFC remains an absolutely essential option for complicated DSWI since the amount of perfused tissue can be the key for infection control. PMID- 28665966 TI - Feature point based 3D tracking of multiple fish from multi-view images. AB - A feature point based method is proposed for tracking multiple fish in 3D space. First, a simplified representation of the object is realized through construction of two feature point models based on its appearance characteristics. After feature points are classified into occluded and non-occluded types, matching and association are performed, respectively. Finally, the object's motion trajectory in 3D space is obtained through integrating multi-view tracking results. Experimental results show that the proposed method can simultaneously track 3D motion trajectories for up to 10 fish accurately and robustly. PMID- 28665965 TI - The internal structure of foster-parent completed SDQ for school-aged children. AB - Mental health problems are common in foster-children, and tools to measure the mental health of these children are needed. One candidate instrument is the Strengths and Difficulties Questionnaire (SDQ), a measure of child psychological adjustment that is increasingly being employed by Child Protection services. The aim of the current study was to examine the structural validity of the foster parent completed SDQ in a sample of 237 school aged foster children. Confirmatory factor analysis demonstrated an excellent fit of the foster parent completed SDQ data to a five-factor model (CFI = 0.96, RMSEA = 0.05, 90% CI [0.04, 0.06]), thus confirming the structural validity of the five-factor model for the parent version of the SDQ in Norwegian foster children. Measurement invariance analyses indicated that boys had lower thresholds for fighting with or bullying other children than girls. Girls were on their side more likely to be rated as less popular than boys with a similar level of peer problems. PMID- 28665967 TI - Effects of canagliflozin on weight loss in high-fat diet-induced obese mice. AB - Canagliflozin, an inhibitor of sodium glucose co-transporter (SGLT) 2, has been shown to reduce body weight during the treatment of type 2 diabetes mellitus (T2DM). In this study, we sought to determine the role of canagliflozin in body weight loss and liver injury in obesity. C57BL/6J mice were fed a high-fat diet to simulate diet-induced obesity (DIO). Canagliflozin (15 and 60 mg/kg) was administered to DIO mice for 4 weeks. Orlistat (10 mg/kg) was used as a positive control. The body weight, liver weight, liver morphology, total cholesterol (TC) and triglyceride (TG) levels were examined. Signaling molecules, including diacylgycero1 acyltransferase-2 (DGAT2), peroxisome proliferation receptor alpha 1 (PPARalpha1), PPARgamma1, PPARgamma2 mRNA levels and the protein expression of SGLT2 were evaluated. Canagliflozin reduced body weight, especially the high-dose canagliflozin, and resulted in increased body weight loss compared with orlistat. Moreover, canagliflozin reduced the liver weight and the ratio of liver weight to body weight, lowered the serum levels of TC and TG, and ameliorated liver steatosis. During the canagliflozin treatment, SGLT2, DGAT2, PPARgamma1 and PPARgamma2 were inhibited, and PPARalpha1 was elevated in the liver tissues. This finding may explain why body weight was reduced and secondary liver injury was ameliorated in response to canagliflozin. Together, the results suggest that canagliflozin may be a potential anti-obesity strategy. PMID- 28665968 TI - High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3 deficient mice. AB - SLC19A3 deficiency, also called thiamine metabolism dysfunction syndrome-2 (THMD2; OMIM 607483), is an autosomal recessive neurodegenerative disorder caused by mutations in SLC19A3, the gene encoding thiamine transporter 2. To investigate the molecular mechanisms of neurodegeneration in SLC19A3 deficiency and whether administration of high-dose thiamine prevents neurodegeneration, we generated homozygous Slc19a3 E314Q knock-in (KI) mice harboring the mutation corresponding to the human SLC19A3 E320Q, which is associated with the severe form of THMD2. Homozygous KI mice and previously reported homozygous Slc19a3 knock-out (KO) mice fed a thiamine-restricted diet (thiamine: 0.60 mg/100 g food) died within 30 and 12 days, respectively, with dramatically decreased thiamine concentration in the blood and brain, acute neurodegeneration, and astrogliosis in the submedial nucleus of the thalamus and ventral anterior-lateral complex of the thalamus. These findings may bear some features of thiamine-deficient mice generated by pyrithiamine injection and a thiamine-deficient diet, suggesting that the primary cause of THMD2 could be thiamine pyrophosphate (TPP) deficiency. Next, we analyzed the therapeutic effects of high-dose thiamine treatment. When the diet was reverted to a conventional diet (thiamine: 1.71 mg/100 g food) after thiamine restriction, all homozygous KO mice died. In contrast, when the diet was changed to a high-thiamine diet (thiamine: 8.50 mg/100 g food) after thiamine restriction, more than half of homozygous KO mice survived, without progression of brain lesions. Unexpectedly, when the high-thiamine diet of recovered mice was reverted to a conventional diet, some homozygous KO mice died. These results showed that acute neurodegeneration caused by thiamine deficiency is preventable in most parts, and prompt high-dose thiamine administration is critical for the treatment of THMD2. However, reduction of thiamine should be performed carefully to prevent recurrence after recovery of the disease. PMID- 28665969 TI - Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV. AB - BACKGROUND: There is a clinical need for new therapeutic products against Herpes simplex virus (HSV). The pomegranate, fruit of the tree Punica granatum L, has since ancient times been linked to activity against infection. This work probed the activity of pomegranate rind extract (PRE) and co-administered zinc (II) ions. MATERIALS AND METHODS: PRE was used in conjunction with zinc (II) salts to challenge HSV-1 and aciclovir-resistant HSV in terms of virucidal plaque assay reduction and antiviral activities in epithelial Vero host cells. Cytotoxicity was determined by the MTS assay using a commercial kit. RESULTS: Zinc sulphate, zinc citrate, zinc stearate and zinc gluconate demonstrated similar potentiated virucidal activity with PRE against HSV-1 by up to 4-fold. A generally parabolic relationship was observed when HSV-1 was challenged with PRE and varying concentrations of ZnSO4, with a maximum potentiation factor of 5.5. Punicalagin had 8-fold greater virucidal activity than an equivalent mass of PRE. However, antiviral data showed that punicalagin had significantly lower antiviral activity compared to the activity of PRE (EC50 = 0.56 MUg mL-1) a value comparable to aciclovir (EC50 = 0.18 MUg mL-1); however, PRE also demonstrated potency against aciclovir-resistant HSV (EC50 = 0.02 MUg mL-1), whereas aciclovir showed no activity. Antiviral action of PRE was not influenced by ZnSO4. No cytotoxicity was detected with any test solution. CONCLUSIONS: The potentiated virucidal activity of PRE by coadministered zinc (II) has potential as a multi-action novel topical therapeutic agent against HSV infections, such as coldsores. PMID- 28665970 TI - Cholesterol crystal depth in coronary atherosclerotic plaques: A novel index of plaque vulnerability using optical frequency domain imaging. AB - BACKGROUND: The involvement of cholesterol crystals (CCs) in plaque progression and destabilization of atherosclerotic plaques has been recently recognized. This study aimed to evaluate the association between the intraplaque localization of CCs and plaque vulnerability. METHODS: We investigated 55 acute coronary syndrome (ACS) and 80 stable angina pectoris (stable AP) lesions using optical frequency domain imaging (OFDI) prior to percutaneous coronary intervention. The distance between CCs and the luminal surface of coronary plaques was defined as CC depth. RESULTS: Although the incidence of CCs had similar frequencies in the ACS and stable AP groups (95% vs. 89%, p = 0.25), CC depth was significantly less in patients with ACS than in those with stable AP (median [25th to 75th percentile]: 68 MUm [58 to 92 MUm] vs. 152 MUm [115 to 218 MUm]; p < 0.001). The incidences of plaque rupture, thrombus, lipid-rich plaques, and thin-cap fibroatheroma were significantly greater in patients with ACS than in those with stable AP (62% vs. 18%, p < 0.001; 67% vs. 16%, p < 0.001; 84% vs. 57%, p < 0.01; and 56% vs. 19%, p < 0.001, respectively). CONCLUSION: OFDI analysis revealed that CCs were found in the more superficial layers within the coronary atherosclerotic plaques in patients with ACS than in those with stable AP, suggesting that CC depth is associated with plaque vulnerability. CC depth, a novel OFDI-derived parameter, could be potentially used as an alternative means of evaluating plaque vulnerability in coronary arteries. PMID- 28665971 TI - Biophysical induction of cell release for minimally manipulative cell enrichment strategies. AB - The use of autologous cells harvested and subsequently transplanted in an intraoperative environment constitutes a new approach to promote regeneration. Usually cells are isolated by selection methods such as fluorescence- or magnetic activated cell sorting with residual binding of the antibodies or beads. Thus, cell-based therapies would benefit from the development of new devices for cell isolation that minimally manipulate the target cell population. In the clinic, 5 to 10 percent of fractures do not heal properly and CD31+ cells have been identified as promising candidates to support bone regeneration. The aim of this project was to develop and prototype a simple system to facilitate the enrichment of CD31+ cells from whole blood. After validating the specificity of a commercially available aptamer for CD31, we combined this aptamer with traditional magnetic bead strategies, which led to enrichment of CD31+ cells with a purity of 91+/-10%. Subsequently, the aptamer was attached to agarose beads (O = 100-165 um) that were incorporated into a column-based system to enable capture and subsequent release of the CD31+ enriched cells. Different parameters were investigated to allow a biophysical-based cell release from beads, and a simple mixing was found sufficient to release initially bound cells from the optimized column without the need for any chemicals that promote disassociation. The system led to a significant enrichment of CD31+ cells (initial population: 63+/-9%, released: 87+/-3%) with excellent cell viability (released: 97+/-1%). The composition of the released CD31+ fraction indicated an enrichment of the monocyte population. The angiogenic and osteogenic potential of the released cell population were confirmed in vitro. These results and the simplicity of this system highlight the potential of such approach to enable cell enrichment strategies in intraoperative settings. PMID- 28665972 TI - Sample size determination for a specific region in multiregional clinical trials with multiple co-primary endpoints. AB - Recently, multi-regional clinical trials (MRCTs), which incorporate subjects from many countries/regions around the world under the same protocol, have been widely conducted by many global pharmaceutical companies. The objective of such trials is to accelerate the development process for a drug and shorten the drug's approval time in key markets. Several statistical methods have been purposed for the design and evaluation of MRCTs, as well as for assessing the consistency of treatment effects across all regions with one primary endpoint. However, in some therapeutic areas (e.g., Alzheimer's disease), the clinical efficacy of a new treatment may be characterized by a set of possibly correlated endpoints, known as multiple co-primary endpoints. In this paper, we focus on a specific region and establish three statistical criteria for evaluating consistency between the specific region and overall results in MRCTs with multiple co-primary endpoints. More specifically, two of those criteria are used to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other criterion is used to assess the consistency of the treatment effect of the specific region achieving a pre-specified threshold. The sample size required for the region of interest can also be evaluated based on these three criteria. PMID- 28665973 TI - Negative expectations interfere with the analgesic effect of safety cues on pain perception by priming the cortical representation of pain in the midcingulate cortex. AB - It is well known that the efficacy of treatment effects, including those of placebos, is heavily dependent on positive expectations regarding treatment outcomes. For example, positive expectations about pain treatments are essential for pain reduction. Such positive expectations not only depend on the properties of the treatment itself, but also on the context in which the treatment is presented. However, it is not clear how the preceding threat of pain will bias positive expectancy effects. One hypothesis is that threatening contexts trigger fearful and catastrophic thinking, reducing the pain-relieving effects of positive expectancy. In this study, we investigated the disruptive influence of threatening contexts on positive expectancy effects while 41 healthy volunteers experienced laser-induced heat pain. A threatening context was induced using pain threatening cues that preceded the induction of positive expectancies via subsequent pain-safety cues. We also utilised electroencephalography (EEG) to investigate potential neural mechanisms underlying these effects. Lastly, we used the Fear of Pain Questionnaire to address whether the disruptive effect of negative contexts on cued pain relief was related to the degree of fear of pain. As predicted, participants responded less to pain-safety cues (i.e., experienced more pain) when these were preceded by pain-threatening cues. In this threatening context, an enhancement of the N2 component of the laser-evoked potential was detected, which was more pronounced in fearful individuals. This effect was localised to the midcingulate cortex, an area thought to integrate negative affect with pain experience to enable adaptive behaviour in aversive situations. These results suggest that threatening contexts disrupt the effect of pain relief cues via an aversive priming mechanism that enhances neural responses in the early stages of sensory processing. PMID- 28665974 TI - Hazardous alcohol consumption is not associated with CD4+ T-cell count decline among PLHIV in Kampala Uganda: A prospective cohort study. AB - INTRODUCTION: There is limited data on the effects of alcohol on immunological response among persons living with HIV (PLHIV) in sub-Saharan Africa. We assessed the relationship between hazardous alcohol use and CD4+ T-cell count, among PLHIV in Uganda. METHODS: PLHIV aged >= 18 years were enrolled in a cohort study at the Infectious diseases clinic Kampala, Uganda. Alcohol consumption was assessed at enrolment (baseline) and 6 monthly thereafter using the alcohol use disorders identification test (AUDIT). The CD4+ T-cell counts, assessed at baseline and over the next 12 months were compared between alcohol use strata, using linear mixed effects regression. Using longitudinal mediation analysis methods, we estimated the effect of alcohol induced ART non-adherence on CD4+ T-cell count. RESULTS: Of the 1566 participants enrolled, 863(44.1%) were non-alcohol users (AUDIT score = 0), 433(27.7%) were non-hazardous (AUDIT score 1-7) alcohol users while 270 (17.2%) were hazardous (AUDIT score >= 8) alcohol users. The overall median (IQR) baseline CD4+ T-cell count was 356 (243-516) cells/MUl. There were no differences in the median baseline CD4+ T-cell count between hazardous and non hazardous alcohol users compared to non-alcohol users in both the non-ART (p = 0.43) and ART group (p = 0.77). The mean CD4+ T-cell count over 12 months was not different between hazardous alcohol users and non-alcohol users (non-ART group p = 0.88 and ART group p = 0.62), nor between non-hazardous alcohol users and non alcohol users (and non-ART group p = 0.66 and ART group p = 0.20). Alcohol use was not associated with a significant natural direct effect on CD4+ T-cell count (1.37 95%CI [-1.78, 4.52] cells/MUl, p = 0.39) but had a statistically significant natural indirect effect on reduction of CD4+ T-cell count (-0.91 cells/MUl [-1.36, -0.45], p < 0.001) mediated through ART non-adherence. CONCLUSION: Hazardous alcohol use among PLHIV was not directly associated with lower CD4+ T-cell count but had a significant natural indirect effect on CD4+ T cell count mediated through ART non-adherence. Among PLHIV with lower than expected CD4+ T-cell count, alcohol consumption should be excluded as an underlying factor for non-adherence to ART and any interventions targeting alcohol use should tackle possible ART non-adherence. PMID- 28665975 TI - Involvement of c-Fos in cell proliferation, migration, and invasion in osteosarcoma cells accompanied by altered expression of Wnt2 and Fzd9. AB - Osteosarcoma (OS) is an aggressive bone tumor, and proto-oncogene c-Fos is involved in this lethal disease. However, the role and molecular mechanism of c Fos in the development and progression of OS remain enigmatic. As one of the Wnt family members, Wnt2 is closely associated with the development of several malignant tumors. In the present study, the expression of c-Fos, Wnt2, and its receptor Fzd9 in human OS tissues, MG63 OS cell line, and human osteoblast hFOB 1.19 cell line was detected by Western blot analysis, immunohistochemical staining, or reverse transcription-polymerase chain reaction. The role of c-Fos in the OS was clarified by treating MG63 cells with small interfering RNA to knockdown c-Fos. Then, cell migration and invasion were assayed by transwell assays and wound healing assay; cell proliferation was assayed by MTS method and 5-ethynyl-2'-deoxyuridine DNA proliferation in vitro detection; cell apoptosis was assayed by flow cytometric method. Co-immunoprecipitation kit was used to confirm the relationship between c-Fos and Wnt2/Fzd9. We found that the expression of c-Fos, Wnt2, and Fzd9 protein was distinctly higher in human OS tissues than that in the adjacent non-cancerous tissues, and their expression in the MG63 OS cell line was markedly increased compared with that in the human osteoblast hFOB 1.19 cell line. Knockdown of c-Fos inhibited the proliferation, migration, and invasion of MG63 cells, and promoted the apoptosis of MG63 cells. Moreover, knockdown of c-Fos inhibited the expression of Wnt2 and Fzd9 mRNA and protein. Our data enforced the evidence that knockdown of c-Fos inhibited cell proliferation, migration, and invasion, and promoted the apoptosis of OS cells accompanied by altered expression of Wnt2 and Fzd9. These findings offer new clues for OS development and progression, and c-Fos may be a potential therapeutic target for OS. PMID- 28665976 TI - The PAPI-1 pathogenicity island-encoded small RNA PesA influences Pseudomonas aeruginosa virulence and modulates pyocin S3 production. AB - Small non-coding RNAs (sRNAs) are post-transcriptional regulators of gene expression that have been recognized as key contributors to bacterial virulence and pathogenic mechanisms. In this study, we characterized the sRNA PesA of the opportunistic human pathogen Pseudomonas aeruginosa. We show that PesA, which is transcribed within the pathogenicity island PAPI-1 of P. aeruginosa strain PA14, contributes to P. aeruginosa PA14 virulence. In fact, pesA gene deletion resulted in a less pathogenic strain, showing higher survival of cystic fibrosis human bronchial epithelial cells after infection. Moreover, we show that PesA influences positively the expression of pyocin S3 whose genetic locus comprises two structural genes, pyoS3A and pyoS3I, encoding the killing S3A and the immunity S3I proteins, respectively. Interestingly, the deletion of pesA gene results in increased sensitivity to UV irradiation and to the fluoroquinolone antibiotic ciprofloxacin. The degree of UV sensitivity displayed by the PA14 strain lacking PesA is comparable to that of a strain deleted for pyoS3A-I. These results suggest an involvement of pyocin S3 in DNA damage repair and a regulatory role of PesA on this function. PMID- 28665977 TI - MicroRNA-148a overexpression improves the early development of porcine somatic cell nuclear transfer embryos. AB - Incomplete epigenetic reprogramming of donor cell nuclei is one of the main contributors to the low efficiency of somatic cell nuclear transfer (SCNT). To improve the success of SCNT, somatic cell DNA methylation levels must be reduced to those levels found in totipotent embryonic cells. Recent studies have demonstrated that miR-148a can affect DNA methylation via DNMT1 modulation in various cancers. Therefore, the focus of this study was to examine the influence of miR-148a on DNA methylation in donor cells and in SCNT embryo development. Thus, a stable cell line overexpressing miR-148a was established and used to produce SCNT embryos. Upon examination, DNMT1 was found to be a miR-148a target in porcine fetal fibroblasts (PFF). Furthermore, miR-148a overexpression in PFFs significantly decreased DNMT1 expression and global DNA methylation levels (P < 0.05). Moreover, miRNA-148a expression levels in SCNT embryos were significantly lower at the 2-cell and 4-cell stages when compared to IVF and parthenogenetic embryos. The group overexpressing miRNA-148a also showed a significant increase in blastocyst formation and total cell numbers (P < 0.05). Additionally, miR-148a overexpression altered the immunofluorescence signal of 5-mC and H3K9ac, and enhanced pluripotent gene (Oct4 and Nanog) expression levels during embryo development. These results indicate that miR-148a overexpression enhances the developmental potential of SCNT embryos and modifies epigenetic status. PMID- 28665979 TI - Risk map for wolf threats to livestock still predictive 5 years after construction. AB - Risk maps are spatial models of environmental hazards such as predation on livestock. We tested the long-term validity of a published risk map built from locations where Wisconsin wolves attacked livestock from 1999-2006. Using data collected after model construction, we verified the predictive accuracy of the risk map exceeded 91% for the period 2007-2011. Predictive power lasting 5 years or more substantiates the claim that risk maps are both valid and verified tools for anticipating spatial hazards. Classification errors coincided with verifier uncertainty about which wolves might be responsible. Perceived threats by wolves to domestic animals were not as well predicted (82%) as verified attacks had been and errors in classification coincided with incidents involved domestic animals other than bovids and verifier uncertainty about which wolves were involved. We recommend risk maps be used to target interventions selectively at high-risk sites. PMID- 28665978 TI - Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway. AB - Prostatitis is a common condition in adult men of all ages. Uropathogenic Escherichia coli (UPEC) are most frequent pathogen involved in bacterial prostatitis by refluxing the infected urine into prostatic ducts and resulting in an ascending urethral infection. However, the study about the mechanisms of UPEC to invade, replicate and persist in normal prostate epithelial cell is only few. Given the fact that UPEC is pathogen most frequently involved in prostatitis and that testosterone has been demonstrated to attenuate prostate inflammation caused by other etiologies. In this study we investigated whether the testosterone reduces the prostatitis and related mechanism by regulating IFN-gamma/STAT1 signaling pathway. In the current study aimed to clarify whether testosterone influences the process of UPEC-induced prostate inflammation and invasion into the prostate epithelial cells. In addition, we set up a normal prostate cell model for UPEC infection to evaluate the ability to invade the urothelial cells as well as the colonization of intercellular bacterial communities in vitro. By using the model, we examine the effects of testosterone to suppress effectively the invasion and survival of UPEC in the prostate cells, and inhibit LPS-induced inflammatory responses through the JAK/STAT1 pathway have also been indicated. Our results demonstrated testosterone not only suppressed the invasion and colonization of UPEC, but also inhibited the expression of pro-inflammatory IL 1beta, IL-6 and IL-8 cytokines expression induced by UPEC in a dose-dependent manner. We found the effective dose of testosterone to suppress UPEC infect prostate cells may be appropriate under 40MUg/ml. Our data also revealed 20MUg/ml testosterone treated PZ-HPV-7 cells significantly suppressed the LPS-induced JAK/STAT1 pathway and inflammatory responses, and reached to maximal effects at 40MUg/ml treatment. These results indicate that testosterone plays an anti inflammatory role in LPS-induced prostate cell inflammation by down-regulating JAK/STAT1 signaling pathway. Interestingly, the JAK inhibitor and testosterone for 24hr pretreatment rather markedly induced the colonization of UPEC in the PZ HPV-7 cells. Based on the above data, the suppression of UPEC colonization in the prostate cells by testosterone seems to be unrelated with JAK/STAT signaling pathway, whereas the JAK may involve into the UPEC infection. Summing up these data, our findings have demonstrated the suppressive effects of testosterone on the invasion and survival of UPEC and induced inflammation in prostate epithelial cells. These findings indicate the action mechanism of testosterone as an anti inflammatory mediator in the prostate cells is regulated through JAK/STAT1 signaling pathway, may be beneficial in treating prostate inflammation. Altogether, this study has provided the possibility that using testosterone in the prevention and clinical treatment of prostatitis is a new direction. PMID- 28665980 TI - The effects of name and religious priming on ratings of a well-known political figure, President Barack Obama. AB - Priming with race-typed names and religious concepts have been shown to activate stereotypes and increase prejudice towards out-groups. We examined the effects of name and religious word priming on views of a specific and well-known person, President Barack Obama. We predicted that politically conservative participants primed with President Obama's middle name (Hussein) would rate him more negatively and be more likely to view him as a Muslim than those not shown his middle name. We also examined whether conservatives primed with concrete religious words would rate President Obama more negatively and be more likely to view him as Muslim than those primed with other word types. Furthermore, we predicted that those who mis-identify President Obama as Muslim would rate him more negatively than would those who view him as Christian. The results provided mixed support for these hypotheses. Conservatives primed with President Obama's middle name rated him significantly more negatively than did those in the control condition. This effect was not found for politically liberal or moderate participants. Name priming did not significantly affect views of President Obama's religious affiliation. Although not statistically significant, conservatives primed with abstract religious words tended to rate President Obama more negatively than did those primed with other word types. Religious word priming significantly influenced views of President Obama's religious affiliation; interestingly, participants primed with abstract religious words were more likely to think President Obama is Muslim than were those primed with religious agent or non-religious words. As predicted, participants who thought president Obama was Muslim rated him significantly more negatively than did those who thought he was Christian. Overall, our results provide some evidence that ethnic name and religious word priming can significantly influence opinions, even with a well-known and specific person. PMID- 28665981 TI - HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6. AB - All-trans retinoic acid (ATRA) induces complete remission in almost all patients with acute promyelocytic leukemia (APL) via its ability to induce the in vivo differentiation of APL blasts. However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-drug-resistant HL60/ATRA cell line and found it to contain a new drug resistance-related gene segment, HA117. In this study, we demonstrate that ATRA induces multi-drug resistant subpopulations of HL60 cells with a putative stem-like signature by up regulating the expression of the new gene segment HA117. Western blot analysis and quantitative real-time PCR demonstrated that HA117 causes alternative splicing of regulator of G-protein signaling 6 (RGS6) and down-regulation of the expression of the GGL domain of RGS6, which plays an important role in DNA methyltransferase 1 (DNMT1) degradation. Moreover, DNMT1 expression was increased in multi-drug resistance HL60/ATRA cells. Knockdown of HA117 restored expression of the GGL domain and blocked DNMT1 expression. Moreover, resistant cells displayed a putative stem-like signature with increased expression of cancer steam cell markers CD133 and CD123. The stem cell marker, Nanog, was significantly up-regulated. In conclusion, our study shows that HA117 potentially promotes the stem-like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulating the expression of the GGL domain of RGS6. These results throw light on the cellular events associated with the ATRA-induced multi-drug resistance phenotype in acute leukemia. PMID- 28665982 TI - The SERTAD protein Taranis plays a role in Polycomb-mediated gene repression. AB - The Polycomb group (PcG) proteins have been implicated in epigenetic transcriptional repression in development, stem cell maintenance and in cancer. The chromodomain protein Polycomb (Pc) is a key member of the PcG. Pc binds to the histone mark, trimethylated histone 3 lysine 27 (H3K27me3), to initiate transcriptional repression. How PcG proteins are recruited to target loci is not fully understood. Here we show that the Drosophila SERTA domain protein Taranis (Tara) is involved in transcriptional regulation of Pc target genes. Embryos lacking Tara exhibit a partial homeotic transformation of cuticular the segments, a phenotype associated with the loss of Pc function. Moreover, Drosophila embryos homozygous for a tara hypomorphic allele also misexpress engrailed, a Pc regulated gene, and this phenotype is associated with the loss of Pc binding to the cis response element in the engrailed enhancer. In relation to that, Pc recruitment is reduced on the salivary gland polytene chromosomes and specifically at the engrailed locus. These results suggest that Tara might be required for positioning Pc to a subset of its target genes. PMID- 28665984 TI - Potential using of infrared thermal imaging to detect volatile compounds released from decayed grapes. AB - Previous studies have demonstrated variations in volatile compound content during fruit spoilage. Infrared spectroscopy was proposed as an alternative method to discriminate the various states of decayed fruit through the makeup of their volatile compounds. Based on the infrared spectra of volatile compounds obtained from decayed grapes, this study simplified the extraction of their feature spectra and visualized their gas plumes by using a commercial infrared thermal camera equipped with a custom-made wavelength filter. As a function of volatilization gradients, accumulated gray value and imaging area were proposed as indicators for semi-quantitative analysis in a volatilization range similar to that of ethanol solutions ranging from 10% to 70%. Fresh, seriously decayed, and slightly or moderately decayed grapes were rapidly discriminated through their alcoholic volatiles by thermal images with correct classification ratings of 100%, 93.3%, and 90%, respectively. PMID- 28665983 TI - Different levels of let-7d expression modulate response of FaDu cells to irradiation and chemotherapeutics. AB - : The implication of the let-7 family in cancer development is multifaceted. The family acts as tumor suppressor miRNA although overexpression of let-7 has also been described in many types of cancer, including head and neck squamous cell carcinoma (HNSCC). The aim of this study includes whether different expression levels of let-7d has an influence on chemo- and radiosensitivity. FaDu cell line models with a gradually increased level of let-7d (models from A to E) were generated with the lentiviral system. Expression levels of pluripotency, chemo radioresistance/apoptosis, and targets of mRNAs were analyzed by real-time reverse transcription-PCR (qRT-PCR). Radiosensitivity was analyzed using a clonogenic assay after irradiation. Response to cisplatin, 5-FU, doxorubicin, and paclitaxel was done with MTT assay. Statistically significant decrease of K-RAS (p = 0.0369) and CASPASE3 (p = 0.0342) were observed with the growing expression level of let-7d. Cisplatin, 5-FU and doxorubicin caused similar decreased of cell survival with the increase of let-7d level (p = 0.004, post-trend p = 0.046; p = 0.004, post trend p = 0.0005 and p<0.0001, post trend p = 0.0001, respectively). All models were resistant to paclitaxel, irrespective of let-7d expression levels. Only two of the generated models (A and C) were radiosensitive (p = 0.0002). CONCLUSION: the above results indicated that the level of let-7d expression is an important factor for cell response to irradiation and chemotherapeutics. PMID- 28665985 TI - Early decreased neutrophil responsiveness is related to late onset sepsis in multitrauma patients: An international cohort study. AB - BACKGROUND: Severe trauma can lead to the development of infectious complications after several days, such as sepsis. Early identification of patients at risk will aid anticipating these complications. The aim of this study was to test the relation between the acute (<24 hours) inflammatory response after injury measured by neutrophil responsiveness and the late (>5 days) development of septic complications and validate this in different trauma populations. METHODS AND FINDINGS: Two prospective, observational, cohort series in the Netherlands and South Africa, consisting of severely injured trauma patients. Neutrophil responsiveness by fMLF-induced active FcgammaRII was measured in whole blood flowcytometry, as read out for the systemic immune response within hours after trauma. Sepsis was scored daily. Ten of the 36 included Dutch patients developed septic shock. In patients with septic shock, neutrophils showed a lower expression of fMLF-induced active FcgammaRII immediately after trauma when compared to patients without septic shock (P = 0.001). In South Africa 11 of 73 included patients developed septic shock. Again neutrophils showed lower expression of fMLF induced active FcgammaRII (P = 0.001). In the combined cohort, all patients who developed septic shock demonstrated a decreased neutrophil responsiveness. CONCLUSIONS: Low responsiveness of neutrophils for the innate stimulus fMLF immediately after trauma preceded the development of septic shock during admission by almost a week and did not depend on a geographical/racial background, hospital protocols and health care facilities. Decreased neutrophil responsiveness appears to be a prerequisite for septic shock after trauma. This might enable anticipation of this severe complication in trauma patients. PMID- 28665986 TI - Impact of prenatal screening on the prevalence of Down syndrome in Slovenia. AB - OBJECTIVES: To evaluate the impact of prenatal screening and genetic testing for trisomy 21 (T21) on the prevalence of T21 in Slovenia. DESIGN AND SETTING: Data about all prenatally and postnatally confirmed cases of T21 in Slovenia between 1981 and 2012 were collected retrospectively from all genetic laboratories in Slovenia. The expected number of babies with T21 according to maternal age was calculated. MAIN OUTCOME MEASURES: The primary outcomes measures were number of fetuses and newborn infants with T21 diagnosed prenatally and postnatally and the impact of advances in screening and genetic diagnostics on the prevalence of newborns with T21 in Slovenia. RESULTS: Despite a significantly increased mean maternal age from 25.4 years in year 1981 to 30.3 years in year 2012 the prevalence of newborn infants with T21 was 0.51 per 1000 births compared to 0.55 per 1000 births, respectively. The prevalence of prenatally diagnosed cases increased from 0.03 per 1000 births to 2.06 per 1000. The detection rate of T21 in year 2012 was 78,9%. The total number of prenatal invasive procedures (chorionic villous sampling and amniocenteses) carried out during that period was rising until 2002, since when it is stable at around 7%. CONCLUSION: The advancement and implementation of screening tests and prenatal diagnostic procedures in Slovenia caused an important improvement in the efficiency of the prenatal detection of T21. PMID- 28665987 TI - Prions amplify through degradation of the VPS10P sorting receptor sortilin. AB - Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion infected cells. PMID- 28665988 TI - Oxidative stress induced in E. coli by the human antimicrobial peptide LL-37. AB - Antimicrobial peptides (AMPs) are thought to kill bacterial cells by permeabilizing their membranes. However, some antimicrobial peptides inhibit E. coli growth more efficiently in aerobic than in anaerobic conditions. In the attack of the human cathelicidin LL-37 on E. coli, real-time, single-cell fluorescence imaging reveals the timing of membrane permeabilization and the onset of oxidative stress. For cells growing aerobically, a CellROX Green assay indicates that LL-37 induces rapid formation of oxidative species after entry into the periplasm, but before permeabilization of the cytoplasmic membrane (CM). A cytoplasmic Amplex Red assay signals a subsequent burst of oxidative species, most likely hydrogen peroxide, shortly after permeabilization of the CM. These signals are much stronger in the presence of oxygen, a functional electron transport chain, and a large proton motive force (PMF). They are much weaker in cells growing anaerobically, by either fermentation or anaerobic respiration. In aerobic growth, the oxidative signals are attenuated in a cytochrome oxidase-bd deletion mutant, but not in a -bo3 deletion mutant, suggesting a specific effect of LL-37 on the electron transport chain. The AMPs melittin and LL-37 induce strong oxidative signals and exhibit O2-sensitive MICs, while the AMPs indolicidin and cecropin A do not. These results suggest that AMP activity in different tissues may be tuned according to the local oxygen level. This may be significant for control of opportunistic pathogens while enabling growth of commensal bacteria. PMID- 28665989 TI - Addition of transcranial direct current stimulation to quadriceps strengthening exercise in knee osteoarthritis: A pilot randomised controlled trial. AB - A randomised, assessor- and participant-blind, sham-controlled trial was conducted to assess the safety and feasibility of adding transcranial direct current stimulation (tDCS) to quadriceps strengthening exercise in knee osteoarthritis (OA), and provide data to inform a fully powered trial. Participants were randomised to receive active tDCS+exercise (AT+EX) or sham tDCS+exercise (ST+EX) twice weekly for 8 weeks whilst completing home exercises twice per week. Feasibility, safety, patient-perceived response, pain, function, pressure pain thresholds (PPTs) and conditioned pain modulation (CPM) were assessed before and after treatment. Fifty-seven people were screened for eligibility. Thirty (52%) entered randomisation and 25 (84%) completed the trial. One episode of headache in the AT+EX group was reported. Pain reduced in both groups following treatment (AT+EX: p<0.001, partial eta2 = 0.55; ST+EX: p = 0.026, partial eta2 = 0.18) but no between-group differences were observed (p = 0.18, partial eta2 = 0.08). Function improved in the AT+EX (p = 0.01, partial eta2 = 0.22), but not the ST+EX (p = 0.16, partial eta2 = 0.08) group, between group differences did not reach significance (p = 0.28, partial eta2 = 0.052). AT+EX produced greater improvements in PPTs than ST+EX (p<0.05) (superolateral knee: partial eta2 = 0.17; superior knee: partial eta2 = 0.3; superomedial knee: partial eta2 = 0.26). CPM only improved in the AT+EX group but no between-group difference was observed (p = 0.054, partial eta2 = 0.158). This study provides the first feasibility and safety data for the addition of tDCS to quadriceps strengthening exercise in knee OA. Our data suggest AT+EX may improve pain, function and pain mechanisms beyond that of ST+EX, and provides support for progression to a fully powered randomised controlled trial. PMID- 28665990 TI - Molecular evolutionary analysis of a gender-limited MID ortholog from the homothallic species Volvox africanus with male and monoecious spheroids. AB - Volvox is a very interesting oogamous organism that exhibits various types of sexuality and/or sexual spheroids depending upon species or strains. However, molecular bases of such sexual reproduction characteristics have not been studied in this genus. In the model species V. carteri, an ortholog of the minus mating type-determining or minus dominance gene (MID) of isogamous Chlamydomonas reinhardtii is male-specific and determines the sperm formation. Male and female genders are genetically determined (heterothallism) in V. carteri, whereas in several other species of Volvox both male and female gametes (sperm and eggs) are formed within the same clonal culture (homothallism). To resolve the molecular basis of the evolution of Volvox species with monoecious spheroids, we here describe a MID ortholog in the homothallic species V. africanus that produces both monoecious and male spheroids within a single clonal culture. Comparison of synonymous and nonsynonymous nucleotide substitutions in MID genes between V. africanus and heterothallic volvocacean species suggests that the MID gene of V. africanus evolved under the same degree of functional constraint as those of the heterothallic species. Based on semi quantitative reverse transcription polymerase chain reaction analyses using the asexual, male and monoecious spheroids isolated from a sexually induced V. africanus culture, the MID mRNA level was significantly upregulated in the male spheroids, but suppressed in the monoecious spheroids. These results suggest that the monoecious spheroid-specific down regulation of gene expression of the MID homolog correlates with the formation of both eggs and sperm in the same spheroid in V. africanus. PMID- 28665991 TI - Anti-inflammatory effects of ursodeoxycholic acid by lipopolysaccharide stimulated inflammatory responses in RAW 264.7 macrophages. AB - PURPOSE: The aim of this study was to investigate the anti-inflammatory effects of Ursodeoxycholic acid (UDCA) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. METHODS: We induced an inflammatory process in RAW 264.7 macrophages using LPS. The anti-inflammatory effects of UDCA on LPS-stimulated RAW 264.7 macrophages were analyzed using nitric oxide (NO). Pro-inflammatory and anti inflammatory cytokines were analyzed by quantitative real time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 in mitogen-activated protein kinase (MAPK) signaling pathways and nuclear factor kappa-light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaBalpha) signaling pathways were evaluated by western blot assays. RESULTS: UDCA decreased the LPS-stimulated release of the inflammatory mediator NO. UDCA also decreased the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin 1-alpha (IL-1alpha), interleukin 1-beta (IL 1beta), and interleukin 6 (IL-6) in mRNA and protein levels. In addition, UDCA increased an anti-inflammatory cytokine interleukin 10 (IL-10) in the LPS stimulated RAW 264.7 macrophages. UDCA inhibited the expression of inflammatory transcription factor nuclear factor kappa B (NF-kappaB) in LPS-stimulated RAW 264.7 macrophages. Furthermore, UDCA suppressed the phosphorylation of ERK, JNK, and p38 signals related to inflammatory pathways. In addition, the phosphorylation of IkappaBalpha, the inhibitor of NF-kappaB, also inhibited by UDCA. CONCLUSION: UDCA inhibits the pro-inflammatory responses by LPS in RAW 264.7 macrophages. UDCA also suppresses the phosphorylation by LPS on ERK, JNK, and p38 in MAPKs and NF-kappaB pathway. These results suggest that UDCA can serve as a useful anti-inflammatory drug. PMID- 28665992 TI - Gene expression allelic imbalance in ovine brown adipose tissue impacts energy homeostasis. AB - Heritable trait variation within a population of organisms is largely governed by DNA variations that impact gene transcription and protein function. Identifying genetic variants that affect complex functional traits is a primary aim of population genetics studies, especially in the context of human disease and agricultural production traits. The identification of alleles directly altering mRNA expression and thereby biological function is challenging due to difficulty in isolating direct effects of cis-acting genetic variations from indirect trans acting genetic effects. Allele specific gene expression or allelic imbalance in gene expression (AI) occurring at heterozygous loci provides an opportunity to identify genes directly impacted by cis-acting genetic variants as indirect trans acting effects equally impact the expression of both alleles. However, the identification of genes showing AI in the context of the expression of all genes remains a challenge due to a variety of technical and statistical issues. The current study focuses on the discovery of genes showing AI using single nucleotide polymorphisms as allelic reporters. By developing a computational and statistical process that addressed multiple analytical challenges, we ranked 5,809 genes for evidence of AI using RNA-Seq data derived from brown adipose tissue samples from a cohort of late gestation fetal lambs and then identified a conservative subgroup of 1,293 genes. Thus, AI was extensive, representing approximately 25% of the tested genes. Genes associated with AI were enriched for multiple Gene Ontology (GO) terms relating to lipid metabolism, mitochondrial function and the extracellular matrix. These functions suggest that cis-acting genetic variations causing AI in the population are preferentially impacting genes involved in energy homeostasis and tissue remodelling. These functions may contribute to production traits likely to be under genetic selection in the population. PMID- 28665993 TI - Knowledge, attitudes, and practice on the prevention of central line-associated bloodstream infections among nurses in oncological care: A cross-sectional study in an area of southern Italy. AB - The objectives of the cross-sectional study were to delineate the knowledge, attitudes, and behavior among nurses regarding the prevention of central line associated bloodstream infections (CLABSIs) and to identify their predisposing factors. A questionnaire was self-administered from September to November 2011 to nurses in oncology and outpatient chemotherapy units in 16 teaching and non teaching public and private hospitals in the Campania region (Italy). The questionnaire gathered information on demographic and occupational characteristics; knowledge about evidence-based practices for the prevention of CLABSIs; attitudes towards guidelines, the risk of transmitting infections, and hand-washing when using central venous catheter (CVC); practices about catheter site care; and sources of information. The vast majority of the 335 nurses answered questions correctly about the main recommendations to prevent CLABSIs (use sterile gauze or sterile transparent semipermeable dressing to cover the catheter site, disinfect the needleless connectors before administer medication or fluid, disinfect with hydrogen peroxide the catheter insertion site, and use routinely anticoagulants solutions). Nurses aged 36 to 50 years were less likely to know these main recommendations to prevent CLABSIs, whereas this knowledge was higher in those who have received information about the prevention of these infections from courses. Nurses with lower education and those who do not know two of the main recommendations on the site's care to prevent the CLABSIs, were more likely to perceive the risk of transmitting an infection. Higher education, attitude toward the utility allow to dry antiseptic, and the need of washing hands before wearing gloves for access to port infusion were predictors of performing skin antiseptic and aseptic technique for dressing the catheter insertion site. Educational interventions should be implemented to address the gaps regarding knowledge and practice regarding the prevention of CLABSIs and to ensure that nurses use evidence-based prevention interventions. PMID- 28665994 TI - A novel role of Kruppel-like factor 4 in Zhikong scallop Chlamys farreri during spermatogenesis. AB - Kruppel-like factor 4 (KLF4) is a kind of zinc finger transcription factor, which is involved in terminal differentiation of epithelial cells and reprogramming of somatic cells to induced pluripotent stem (iPS) cells in mammals. In the present study, we identified a full-length cDNA of Klf4 in Zhikong scallop Chamys farreri (Cf-Klf4) and found that Cf-Klf4 presented a sexual dimorphic expression characteristic in C. farreri gonads. Cf-Klf4 expression was significantly higher in testes than in ovaries from growing stage to mature stage detected by quantitative real-time PCR, and was located in male gametes, except for spermatozoa during spermatogenesis through in situ hybridization and immunohistochemistry, while no positive signal was visible in female gametes during oogenesis. Furthermore, the knockdown of Cf-Klf4 in testes by means of in vivo RNA interference led to an obviously developmental retardance, lower gonadosomatic index, less male gametes and more apoptotic spermatocytes. Interestingly, we found that two out of eight scallops showed a hermaphroditic phenotype characteristic of male-to-female sex reversal when the Klf4 mRNA and protein levels were knocked down in males. These results verified that Klf4 plays an important role in testis functional maintenance and is necessary in spermatogenesis of C. farreri. PMID- 28665996 TI - Long-term patterns of adherence to medication therapy among patients with type 2 diabetes mellitus in Denmark: The importance of initiation. AB - AIMS: Poor adherence to medication therapy among type 2 diabetes patients is a clinical challenge. We aimed to determine which factors are associated with the three phases of long-term adherence to medication: initiation, implementation and discontinuation in a register-based study. METHODS: Adherence to six medicine groups (metformin, sulfonylureas, acetylsalicylic acid, thiazide diuretics, renin angiotensin system inhibitors, and statins) were analysed among 5,232 patients with type 2 diabetes at a tertiary referral hospital during 1998-2009. Rate ratios of initiation of treatment, recurrent gaps in supply of medication, and discontinuation of treatment were analysed using Poisson regression. RESULTS: Poor initiation rather than poor implementation or discontinuation was the main contributor to medication nonadherence. Polypharmacy was a risk factor for slower initiation of treatment for all six medicine groups (rate ratio ranging 0.79 95%CI [0.72-0.87] to 0.89 95%CI [0.82-0.96] per already prescribed medicine), but once patients were in treatment, polypharmacy was not associated with recurrence of gaps in supply of medication, and polypharmacy was associated with lower risk of discontinuation (rate ratio ranging 0.93 95%CI [0.86-1.00] to 0.96 95%CI [0.93 0.99] per prescribed medicine). Other identified risk factors for slow initiation, poor implementation, and discontinuation were diabetes duration, younger age, and Turkish/Pakistani origin. DISCUSSION: This study showed that a risk factor does not necessarily have the same association with all three elements of adherence (initiation, implementation and discontinuation), and that efforts supporting patients introduced to more complex drug combinations should be prioritized. PMID- 28665995 TI - Transcriptomes of six mutants in the Sen1 pathway reveal combinatorial control of transcription termination across the Saccharomyces cerevisiae genome. AB - Transcriptome studies on eukaryotic cells have revealed an unexpected abundance and diversity of noncoding RNAs synthesized by RNA polymerase II (Pol II), some of which influence the expression of protein-coding genes. Yet, much less is known about biogenesis of Pol II non-coding RNA than mRNAs. In the budding yeast Saccharomyces cerevisiae, initiation of non-coding transcripts by Pol II appears to be similar to that of mRNAs, but a distinct pathway is utilized for termination of most non-coding RNAs: the Sen1-dependent or "NNS" pathway. Here, we examine the effect on the S. cerevisiae transcriptome of conditional mutations in the genes encoding six different essential proteins that influence Sen1 dependent termination: Sen1, Nrd1, Nab3, Ssu72, Rpb11, and Hrp1. We observe surprisingly diverse effects on transcript abundance for the different proteins that cannot be explained simply by differing severity of the mutations. Rather, we infer from our results that termination of Pol II transcription of non-coding RNA genes is subject to complex combinatorial control that likely involves proteins beyond those studied here. Furthermore, we identify new targets and functions of Sen1-dependent termination, including a role in repression of meiotic genes in vegetative cells. In combination with other recent whole-genome studies on termination of non-coding RNAs, our results provide promising directions for further investigation. PMID- 28665997 TI - Independent regulation of gene expression level and noise by histone modifications. AB - The inherent stochasticity generates substantial gene expression variation among isogenic cells under identical conditions, which is frequently referred to as gene expression noise or cell-to-cell expression variability. Similar to (average) expression level, expression noise is also subject to natural selection. Yet it has been observed that noise is negatively correlated with expression level, which manifests as a potential constraint for simultaneous optimization of both. Here, we studied expression noise in human embryonic cells with computational analysis on single-cell RNA-seq data and in yeast with flow cytometry experiments. We showed that this coupling is overcome, to a certain degree, by a histone modification strategy in multiple embryonic developmental stages in human, as well as in yeast. Importantly, this epigenetic strategy could fit into a burst-like gene expression model: promoter-localized histone modifications (such as H3K4 methylation) are associated with both burst size and burst frequency, which together influence expression level, while gene-body localized ones (such as H3K79 methylation) are more associated with burst frequency, which influences both expression level and noise. We further knocked out the only "writer" of H3K79 methylation in yeast, and observed that expression noise is indeed increased. Consistently, dosage sensitive genes, such as genes in the Wnt signaling pathway, tend to be marked with gene-body-localized histone modifications, while stress responding genes, such as genes regulating autophagy, tend to be marked with promoter-localized ones. Our findings elucidate that the "division of labor" among histone modifications facilitates the independent regulation of expression level and noise, extend the "histone code" hypothesis to include expression noise, and shed light on the optimization of transcriptome in evolution. PMID- 28665998 TI - IGFN1_v1 is required for myoblast fusion and differentiation. AB - Igfn1 is a complex locus that codes for multiple splicing variants of Immunoglobulin- and Fibronectin-like domain containing proteins predominantly expressed in skeletal muscle. To reveal possible roles for Igfn1, we applied non selective knock-down by shRNAs as well as specific targeting of Igfn1 exon 13 by CRISPR/Cas9 mutagenesis in C2C12 cells. Decreased expression of Igfn1 variants via shRNAs against the common 3'-UTR region caused a total blunting of myoblast fusion, but did not prevent expression of differentiation markers. Targeting of N terminal domains by elimination of exon 13 via CRISPR/Cas9 mediated homologous recombination, also resulted in fusion defects as well as large multinucleated cells. Expression of IGFN1_v1 partially rescued fusion and myotube morphology in the Igfn1 exon 13 knock-out cell line, indicating a role for this variant in myoblast fusion and differentiation. However, in vivo overexpression of IGFN1_v1 or the Igfn1 Exon 13 CRISPR/Cas9 targeting vector did not result in significant size changes in transfected fibres. PMID- 28665999 TI - Analysis of the role of intratecal liposomal cytarabine in the prophylaxis and treatment of central nervous system lymphomatosis: The Balearic Lymphoma Group experience. AB - Central nervous system (CNS) lymphomatosis is a fatal complication of aggressive non-Hodgkin lymphoma (NHL). In lymphoblastic or Burkitt lymphoma, without specific CNS prophylaxis the risk of CNS relapse is 20-30%. DLBCL has a lower risk of relapse (around 5%) but several factors increase its incidence. There is no consensus or trials to conclude which is the best CNS prophylaxis. Best results seem to be associated with the use of intravenous (iv) high-dose methotrexate (HDMTX) but with a significant toxicity. Other options are the administration of intrathecal (IT) MTX, cytarabine or liposomal cytarabine (ITLC). Our aim is to analyze the experience of the centers of the Balearic Lymphoma Group (BLG) about the toxicity and efficacy of ITLC in the prophylaxis and therapy of CNS lymphomatosis. We retrospectively reviewed cases from 2005 to 2015 (n = 58) treated with ITLC. Our toxicity results were: 33% headache, 20% neurological deficits, 11% nausea, 9% dizziness, 4% vomiting, 4% fever, 2% transient blindness and 2% photophobia. In the prophylactic cohort (n = 26) with a median follow-up of 55 months (17-81) only 3 CNS relapses (11%) were observed (testicular DLBCL, Burkitt and plasmablastic lymphoma, with a cumulative incidence of 8%, 14% and 20% respectively). In the treatment cohort (n = 32), CSF complete clearance was obtained in 77% cases. Median OS was 6 months (0-16). Death causes were lymphoma progression (19 patients, 79%), treatment toxicity (2 patients) and non-related (3 patients, 12%). Toxicity profile was good especially when concomitant dexamethasone was administered. In the prophylactic cohort the incidence of CNS relapse in DLBCL group was similar to previously reported for HDMTX and much better than IT MTX. A high number of ITLC injections was associated with better rates of CSF clearance, clinical responses, PFS and lower relapses. Survival is still poor in CNS lymphomatosis and new therapeutic approaches are still needed. PMID- 28666000 TI - Dynamic wheelchair seating positions impact cardiovascular function after spinal cord injury. AB - BACKGROUND: Innovative wheelchairs allow individuals to change position easily for comfort and social situations. While these wheelchairs are beneficial in multiple ways, the effects of position changes on blood pressure might exacerbate hypotension and cerebral hypoperfusion, particularly in those with spinal cord injury (SCI) who can have injury to autonomic nerves that regulate cardiovascular control. Conversely, cardiovascular benefits may be obtained with lowered seating. Here we investigate the effect of moderate changes in wheelchair position on orthostatic cardiovascular and cerebrovascular reflex control. METHODS: Nineteen individuals with SCI and ten neurologically-intact controls were tested in supine and seated positions (neutral, lowered, and elevated) in the ElevationTM wheelchair. Participants with SCI were stratified into two groups by the severity of injury to cardiovascular autonomic pathways. Beat-to-beat blood pressure, heart rate and middle cerebral artery blood flow velocity (MCAv) were recorded non-invasively. RESULTS: Supine blood pressure and MCAv were reduced in individuals with lesions to autonomic pathways, and declined further with standard seating compared to those with preserved autonomic control. Movement to the elevated position triggered pronounced blood pressure and MCAv falls in those with autonomic lesions, with minimum values significantly reduced compared to the seated and lowered positions. The cumulative duration spent below supine blood pressure was greatest in this group. Lowered seating bolstered blood pressure in those with lesions to autonomic pathways. CONCLUSIONS: Integrity of the autonomic nervous system is an important variable that affects cardiovascular responses to orthostatic stress and should be considered when individuals with SCI or autonomic dysfunction are selecting wheelchairs. SPONSORSHIP: This work was supported in part by the Heart and Stroke Foundation of British Columbia and the Yukon (V.E.C). PMID- 28666002 TI - Hopping into a hot seat: Role of DNA structural features on IS5-mediated gene activation and inactivation under stress. AB - Insertion sequence elements (IS elements) are proposed to play major roles in shaping the genetic and phenotypic landscapes of prokaryotic cells. Recent evidence has raised the possibility that environmental stress conditions increase IS hopping into new sites, and often such hopping has the phenotypic effect of relieving the stress. Although stress-induced targeted mutations have been reported for a number of E. coli genes, the glpFK (glycerol utilization) and the cryptic bglGFB (beta-glucoside utilization) systems are among the best characterized where the effects of IS insertion-mediated gene activation are well characterized at the molecular level. In the glpFK system, starvation of cells incapable of utilizing glycerol leads to an IS5 insertion event that activates the glpFK operon, and enables glycerol utilization. In the case of the cryptic bglGFB operon, insertion of IS5 (and other IS elements) into a specific region in the bglG upstream sequence has the effect of activating the operon in both growing cells, and in starving cells. However, a major unanswered question in the glpFK system, the bgl system, as well as other examples, has been why the insertion events are promoted at specific locations, and how the specific stress condition (glycerol starvation for example) can be mechanistically linked to enhanced insertion at a specific locus. In this paper, we show that a specific DNA structural feature (superhelical stress-induced duplex destabilization, SIDD) is associated with "stress-induced" IS5 insertion in the glpFK, bglGFB, flhDC, fucAO and nfsB systems. We propose a speculative mechanistic model that links specific environmental conditions to the unmasking of an insertional hotspot in the glpFK system. We demonstrate that experimentally altering the predicted stability of a SIDD element in the nfsB gene significantly impacts IS5 insertion at its hotspot. PMID- 28666001 TI - Mammographic density and ageing: A collaborative pooled analysis of cross sectional data from 22 countries worldwide. AB - BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the ?PD difference per 10-year increase in age was 0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in ?PD (-0.38 cm [95% CI: 0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction. PMID- 28666003 TI - Diversity of fruit-feeding butterflies in a mountaintop archipelago of rainforest. AB - We provide the first description of the effects of local vegetation and landscape structure on the fruit-feeding butterfly community of a natural archipelago of montane rainforest islands in the Serra do Espinhaco, southeastern Brazil. Butterflies were collected with bait traps in eleven forest islands through both dry and rainy seasons for two consecutive years. The influence of local and landscape parameters and seasonality on butterfly species richness, abundance and composition were analyzed. We also examined the partitioning and decomposition of temporal and spatial beta diversity. Five hundred and twelve fruit-feeding butterflies belonging to thirty-four species were recorded. Butterfly species richness and abundance were higher on islands with greater canopy openness in the dry season. On the other hand, islands with greater understory coverage hosted higher species richness in the rainy season. Instead, the butterfly species richness was higher with lower understory coverage in the dry season. Butterfly abundance was not influenced by understory cover. The landscape metrics of area and isolation had no effect on species richness and abundance. The composition of butterfly communities in the forest islands was not randomly structured. The butterfly communities were dependent on local and landscape effects, and the mechanism of turnover was the main source of variation in beta diversity. The preservation of this mountain rainforest island complex is vital for the maintenance of fruit-feeding butterfly community; one island does not reflect the diversity found in the whole archipelago. PMID- 28666004 TI - A novel association between relaxin receptor polymorphism and hematopoietic stem cell yield after mobilization. AB - Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to the peripheral blood is a complex mechanism that involves adhesive and chemotactic interactions of HSCs as well as their bone marrow microenvironment. In addition to a number of non-genetic factors, genetic susceptibilities also contribute to the mobilization outcome. Identification of genetic factors associated with HSC yield is important to better understand the mechanism behind HSC mobilization. In the present study, we enrolled 148 Korean participants (56 healthy donors and 92 patients) undergoing HSC mobilization for allogeneic or autologous HSC transplantation. Among a total of 53 polymorphisms in 33 candidate genes, one polymorphism (rs11264422) in relaxin/insulin-like family peptide receptor 4 (RXFP4) gene was significantly associated with a higher HSC yield after mobilization in Koreans. However, in a set of 101 Europeans, no association was found between circulating CD34+ cell counts and rs11264422 genotype. Therefore, we suggest that the ethnic differences in subjects' genetic background may be related to HSC mobilization. In conclusion, the relaxin-relaxin receptor axis may play an important role in HSC mobilization. We believe that the results of the current study could provide new insights for therapies that use relaxin and HSC populations, as well as a better understanding of HSC regulation and mobilization at the molecular level. PMID- 28666005 TI - Genetic structure of coral-Symbiodinium symbioses on the world's warmest reefs. AB - Corals in the Arabian/Persian Gulf (PAG) survive extreme sea temperatures (summer mean: >34 degrees C), and it is unclear whether these corals have genetically adapted or physiologically acclimated to these conditions. In order to elucidate the processes involved in the thermal tolerance of PAG corals, it is essential to understand the connectivity between reefs within and outside of the PAG. To this end, this study set out to investigate the genetic structure of the coral, Platygyra daedalea, and its symbiotic algae in the PAG and neighbouring Gulf of Oman. Using nuclear markers (the ITS region and an intron of the Pax-C gene), this study demonstrates genetic divergence of P. daedalea on reefs within the thermally extreme PAG compared with those in the neighbouring Gulf of Oman. Isolation by distance of P. daedalea was supported by the ITS dataset but not the Pax-C intron. In addition, the symbiont community within the PAG was dominated by C3 symbionts, while the purportedly thermotolerant clade D was extremely rare and was common only at sites outside of the PAG. Analysis of the psbAncr indicates that the C3 variant hosted by P. daedalea in the PAG belongs to the newly described species, Symbiodinium thermophilum. The structuring of the coral and symbiont populations suggests that both partners of the symbiosis may contribute to the high bleaching thresholds of PAG corals. While limited gene flow has likely played a role in local adaptation within the PAG, it also indicates limited potential for natural export of thermal tolerance traits to reefs elsewhere in the Indian Ocean threatened by climate change. PMID- 28666007 TI - Atomic resolution studies detect new biologic evidences on the Turin Shroud. AB - We performed reproducible atomic resolution Transmission Electron Microscopy and Wide Angle X-ray Scanning Microscopy experiments studying for the first time the nanoscale properties of a pristine fiber taken from the Turin Shroud. We found evidence of biologic nanoparticles of creatinine bounded with small nanoparticles of iron oxide. The kind, size and distribution of the iron oxide nanoparticles cannot be dye for painting but are ferrihydrate cores of ferritin. The consistent bound of ferritin iron to creatinine occurs in human organism in case of a severe polytrauma. Our results point out that at the nanoscale a scenario of violence is recorded in the funeral fabric and suggest an explanation for some contradictory results so far published. PMID- 28666006 TI - Prevalence of and risk for gastrointestinal bleeding and peptic ulcerative disorders in a cohort of HIV patients from a U.S. healthcare claims database. AB - The primary study objectives were to estimate the frequencies and rates of gastrointestinal bleeding and peptic ulcerative disorder in HIV-positive patients compared with age- and sex-matched HIV-negative subjects. Data from a US insurance claims database was used for this analysis. Among 89,207 patients with HIV, 9.0% had a GI bleed, 1.0% had an upper gastrointestinal bleed, 5.6% had a lower gastrointestinal bleed, 1.9% had a peptic ulcerative disorder diagnosis, and 0.6% had both gastrointestinal/peptic ulcerative disorder. Among 267,615 HIV negative subjects, the respective frequencies were 6.9%, 0.6%, 4.3%, 1.4%, and 0.4% (p<0.0001 for each diagnosis subcategory). After combining effect measure modifiers into comedication and comorbidity strata, gastrointestinal bleeding hazard ratios (HRs) were higher for HIV-positive patients without comedication/comorbidity, and those with comedication alone (HR, 2.73; 95% confidence interval [CI], 2.62-2.84; HR, 1.59; 95% CI, 1.47-1.71). The rate of peptic ulcerative disorder among those without a history of ulcers and no comorbidity/comedication was also elevated (HR, 2.72; 95% CI, 2.48-2.99). Hazard ratios of gastrointestinal bleeding, and peptic ulcerative disorder without a history of ulcers were lower among patients infected with HIV with comedication/comorbidity (HR, 0.64; 95% CI, 0.56-0.73; HR, 0.46; 95% CI, 0.33 0.65). Rates of gastrointestinal bleeding plus peptic ulcerative disorder followed a similar pattern. In summary, the rates of gastrointestinal/peptic ulcerative disorder events comparing HIV-infected subjects to non-HIV-infected subjects were differential based on comorbidity and comedication status. PMID- 28666008 TI - The whole set of the constitutive promoters recognized by four minor sigma subunits of Escherichia coli RNA polymerase. AB - The promoter selectivity of Escherichia coli RNA polymerase (RNAP) is determined by the sigma subunit. The model prokaryote Escherichia coli K-12 contains seven species of the sigma subunit, each recognizing a specific set of promoters. For identification of the "constitutive promoters" that are recognized by each RNAP holoenzyme alone in the absence of other supporting factors, we have performed the genomic SELEX screening in vitro for their binding sites along the E. coli K 12 W3110 genome using each of the reconstituted RNAP holoenzymes and a collection of genome DNA segments of E. coli K-12. The whole set of constitutive promoters for each RNAP holoenzyme was then estimated based on the location of RNAP-binding sites. The first successful screening of the constitutive promoters was achieved for RpoD (sigma70), the principal sigma for transcription of growth-related genes. As an extension, we performed in this study the screening of constitutive promoters for four minor sigma subunits, stationary-phase specific RpoS (sigma38), heat-shock specific RpoH (sigma32), flagellar-chemotaxis specific RpoF (sigma28) and extra-cytoplasmic stress-response RpoE (sigma24). The total number of constitutive promoters were: 129~179 for RpoS; 101~142 for RpoH; 34~41 for RpoF; and 77~106 for RpoE. The list of constitutive promoters were compared with that of known promoters identified in vivo under various conditions and using varieties of E. coli strains, altogether allowing the estimation of "inducible promoters" in the presence of additional supporting factors. PMID- 28666009 TI - Delivery of gene targeting siRNAs to breast cancer cells using a multifunctional peptide complex that promotes both targeted delivery and endosomal release. AB - RNA interference has been used to dissect the importance of individual gene products in various human disease processes, including cancer. Small-interfering RNA, or siRNA, is one of the tools utilized in this regard, but specially designed delivery agents are required to allow the siRNA to gain optimal access to the cell interior. Our laboratory has utilized two different siRNA-binding delivery peptides containing a polyarginine core, and modified by myristoylation and targeting motifs (iRGD or Lyp-1). A third peptide was designed to assist with endosomal release. Various ratios of the peptides and siRNA were combined and assayed for the ability to form stable complexes, and optimized ratios were determined. The complexes were found to form particles, with the majority having a diameter of 100-300 nm, as visualized by electron microscopy. These siRNA complexes have enhanced protection from nucleases present in serum, as compared to "naked" unprotected siRNA. The particles were internalized by the cells and could be detected in the cell cytoplasm by confocal fluorescence microscopy. In functional assays, peptide/siRNA complexes were shown to cause the knock down of corresponding targeted proteins. The peptide with the LyP-1 targeting motif was more effective at knockdown in MDA-MB-231 breast cancer cells than the peptide with the iRGD motif. Inclusion of the endosomal release peptide in the complexes greatly enhanced the peptide/siRNA effects. Peptide/siRNA complexes simultaneously targeting Stat3 and c-Myc caused a marked reduction in anchorage independent growth, a property correlated with tumorigenicity. This study demonstrates the ability of a peptide-based siRNA-delivery system to deliver siRNA into breast cancer cells and cause both protein knockdown and suppression of the malignant phenotype. Such peptide complexes are likely to become highly useful siRNA-delivery vehicles for the characterization, and potentially for the treatment, of human cancer. PMID- 28666010 TI - Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia. AB - Telomeres are protective repeats of TTAGGG sequences located at the end of human chromosomes. They are essential to maintain chromosomal integrity and genome stability. Telomerase is a ribonucleoprotein complex containing an internal RNA template (hTR) and a catalytic subunit (hTERT). The human hTR gene consists of three major domains; among them the H/ACA domain is essential for telomere biogenesis. H/ACA ribonucleoprotein (RNP) complex is composed of four evolutionary conserved proteins, including dyskerin (encoded by DKC1 gene), NOP10, NHP2 and GAR1. In this study, we have evaluated the expression profile of the H/ACA RNP complex genes: DKC1, NOP10, NHP2 and GAR1, as well as hTERT and hTR mRNA levels, in patients with chronic lymphocytic leukemia (CLL). Results were correlated with the number and type of genetic alteration detected by conventional cytogenetics and FISH (fluorescence in situ hybridization), IGHV (immunoglobulin heavy chain variable region) mutational status, telomere length (TL) and clinico-pathological characteristics of patients. Our results showed significant decreased expression of GAR1, NOP10, DKC1 and hTR, as well as increased mRNA levels of hTERT in patients compared to controls (p<=0.04). A positive correlation between the expression of GAR1-NHP2, GAR1-NOP10, and NOP10 NHP2 (p<0.0001), were observed. The analysis taking into account prognostic factors showed a significant increased expression of hTERT gene in unmutated-IGHV cases compared to mutated-CLL patients (p = 0.0185). The comparisons among FISH groups exhibited increased expression of DKC1 in cases with two or more alterations with respect to no abnormalities, trisomy 12 and del13q14, and of NHP2 and NOP10 compared to those with del13q14 (p = 0.03). The analysis according to TL showed a significant increased expression of hTERT (p = 0.0074) and DKC1 (p = 0.0036) in patients with short telomeres compared to those with long TL. No association between gene expression and clinical parameters was found. Our results suggest a role for these telomere associated genes in genomic instability and telomere dysfunction in CLL. PMID- 28666012 TI - Ordered lamellar supermicroporous titania templating by rosin-derived quaternary ammonium salt. AB - By using dehydroabietyltrimethyl ammonium bromine (DTAB), a novel rosin-derived quaternary ammonium salt, as template and peroxotitanium acid as precursor, ordered lamellar supermicroporous titania has been synthesized via a hydrothermal process. The template agent:titanium source molar ratio in the synthesis system and the hydrothermal temperature have great impact on the microstructure characteristics of the samples. The increase of DTAB:TiO2 molar ratio from 0.04:1 to 0.10:1 is favorable to the increase of regularity of pore structures, but has no significant effects on the crystalline structures. The increase of the hydrothermal temperature from 343 to 393 K can induce an increase in crystallinity of the samples. However, the exorbitant hydrothermal temperature will reduce the regularity of pore structures. When the mole ratio of DTAB:TiO2 is 0.10:1 and the hydrothermal temperature is 373 K, the as-synthesized sample possesses pore structure with the highest level of long-range order, as well as pore wall with semicrystallized anatase phase. The pore size and the pore wall thickness are about 2.0 nm and 1.0 nm, respectively. PMID- 28666011 TI - Differential effects of Calca-derived peptides in male mice with diet-induced obesity. AB - Key metabolic hormones, such as insulin, leptin, and adiponectin, have been studied extensively in obesity, however the pathophysiologic relevance of the calcitonin family of peptides remains unclear. This family includes calcitonin (CT), its precursor procalcitonin (PCT), and alpha calcitonin-gene related peptide (alphaCGRP), which are all encoded by the gene Calca. Here, we studied the role of Calca-derived peptides in diet-induced obesity (DIO) by challenging Calcr-/- (encoding the calcitonin receptor, CTR), Calca-/-, and alphaCGRP-/- mice and their respective littermates with high-fat diet (HFD) feeding for 16 weeks. HFD-induced pathologies were assessed by glucose tolerance, plasma cytokine and lipid markers, expression studies and histology. We found that DIO in mice lacking the CTR resulted in impaired glucose tolerance, features of enhanced nonalcoholic steatohepatitis (NASH) and adipose tissue inflammation compared to wildtype littermates. Furthermore, CTR-deficient mice were characterized by dyslipidemia and elevated HDL levels. In contrast, mice lacking Calca were protected from DIO, NASH and adipose tissue inflammation, and displayed improved glucose tolerance. Mice exclusively lacking alphaCGRP displayed a significantly less improved DIO phenotype compared to Calca-deficient mice. In summary, we demonstrate that the CT/CTR axis is involved in regulating plasma cholesterol levels while Calca, presumably through PCT, seems to have a detrimental effect in the context of metabolic disease. Our study provides the first comparative analyses of the roles of Calca-derived peptides and the CTR in metabolic disease. PMID- 28666013 TI - Exploitation rates of two benthic resources across management regimes in central Chile: Evidence of illegal fishing in artisanal fisheries operating in open access areas. AB - There is an urgent need to quantify the impacts of artisanal fisheries and define management practices that allow for the recovery and conservation of exploited stocks. The extent of illegal catch is particularly critical as a driver of overexploitation in artisanal fisheries. However, the lack of data at proper spatial scales limits the evaluation of illegal fishing and effectiveness of management practices. We used a catch curve analysis to estimate total instantaneous mortality as a proxy of fishing pressure in the artisanal benthic fishery in central Chile. We compared the patterns of total mortality in fishing grounds under the well-studied territorial use rights for fisheries system (TURF) immersed in a landscape of open access areas (OAA; no access restriction), and from these patterns determined the extent of illegal fishing in open access areas focusing on the two most frequently extracted resources: locos (Concholepas concholepas) and keyhole limpets (Fissurella spp.). The beauty of this seascape is the presence of the no-take (NT) area of Las Cruces as control (no fishing), allowing us to estimate natural mortality. Loco exploitation is banned in OAAs. However, loco mortality in OAAs was 92% higher than in the NT, and 42% higher than in TURFs. Keyhole limpet mortality was similar between TURFs and the NT, but doubled in OAAs. We also found strong differences in mortality among fishing grounds with the same level of protection (i.e. TURFs), and over time. Our results highlight (a) the high level of illegal fishing that may occur in artisanal fisheries under traditional management regimes, and (b) that TURFs can be effective to reduce fishing mortality. However, large variability among TURFs suggests the need for a deeper understanding of the drivers of success of TURFs. PMID- 28666015 TI - First longitudinal study of seal-feeding killer whales (Orcinus orca) in Norwegian coastal waters. AB - Killer whales (Orcinus orca) have been documented preying on either fish or marine mammals in several regions, suggesting that this odontocete species has the ability to specialize on different types of prey. Off Norway, killer whales have been shown to rely on the Atlantic herring (Clupea harengus) as a main prey resource. Infrequent observations have revealed seals as an additional component of their diet, yet the extent of predation on marine mammals has remained largely unknown. Here, we present the findings of 29 years of photographic and observational data on seal-feeding killer whale groups identified in Norwegian coastal waters. Four groups have been observed preying and feeding on seals over several years, taking both harbor (Phoca vitulina) and grey (Halichoerus grypus) seals. These stable groups are shown to adopt small group sizes, were typically observed in near-shore areas and were not encountered on herring wintering grounds. Behavioral and social traits adopted by these groups are similar to those of pinniped-feeding killer whales from other regions. The potential ecological reasons and the extent of such prey specializations are discussed. PMID- 28666014 TI - Radiologic pleuroparenchymal fibroelastosis-like lesion in connective tissue disease-related interstitial lung disease. AB - BACKGROUND: Radiologic pleuroparenchymal fibroelastosis (PPFE)-like lesion including pulmonary apical cap can be occasionally observed in clinical settings. However, the significance of radiologic PPFE-like lesion is unclear in connective tissue disease (CTD)-related interstitial lung disease (ILD). MATERIALS AND METHODS: A total of 113 patients with CTD-related ILD were enrolled and assessed for radiologic PPFE-like lesion, which was defined as bilateral, upper lobe, and subpleural dense consolidations with or without pleural thickening on chest high resolution computed tomography. The clinical, radiologic, and pathologic characteristics were evaluated. RESULTS: Radiologic PPFE-like lesion was found in 21 patients (19%) and were relatively frequent in those with systemic sclerosis (6/14: 43%) and primary Sjogren's syndrome (4/14: 29%). Patients with PPFE-like lesion were significantly older, had lower body mass index, higher ratio of residual volume to total lung capacity, and higher complication rate of pneumothorax and/or pneumomediastinum than those without. Twelve of the 21 patients were diagnosed radiologically as usual interstitial pneumonia (UIP) or possible UIP pattern. Two of three patients who underwent surgical lung biopsy of the upper lobes showed UIP on histopathology. Another patient was confirmed to have upper lobe PPFE on autopsy. During the clinical course, progression of the radiologic PPFE-like lesions was observed in 13 of 21 patients. Six patients died (mortality rate: 29%) and their PPFE-like lesions were commonly progressive. In the total cohort, our multivariate analysis identified the presence of PPFE-like lesion as a significant risk factor for respiratory death (hazard ratio: 4.10, 95% confidence interval: 1.33-12.65, p = 0.01). CONCLUSION: In patients with CTD related ILD, radiologic PPFE-like lesion, which may present as not only PPFE but also apical cap and upper lobe subpleural fibrosis commonly due to UIP, was not uncommon and was associated with poor prognosis. Clinicians should be cautious with this radiologic finding, particularly when it is progressive. PMID- 28666016 TI - Detection of colonic dysplasia in patients with ulcerative colitis using a targeted fluorescent peptide and confocal laser endomicroscopy: A pilot study. AB - AIM: Targeted molecular probes have been used to detect sporadic colonic dysplasia during confocal laser endomicroscopy (CLE) with promising results. This is a feasibility pilot study aiming to assess the potential role of CLE combined with a fluorescent-labeled peptide to stain and detect dysplasia associated with Ulcerative Colitis. METHOD: A phage-derived heptapeptide with predicted high binding affinity for dysplastic tissue, was synthesized and labeled with fluorescein. Eleven lesions with suspected dysplasia at endoscopy were excised from nine patients with long-standing ulcerative colitis. Specimens were sprayed with the peptide and examined by CLE. The CLE images were then compared to the corresponding histological sections. RESULTS: At definitive histology, 4 lesions were diagnosed as inflammatory polyps, 6 as dysplastic lesions and one as invasive cancer. In inflammatory polyps, the fluorescence signal came from peri cryptal spaces and crypt lumen due to passive accumulation of the peptide in these areas. Dysplasia was associated with active binding of the peptide to dysplastic colonocytes. CONCLUSION: Ex vivo staining of ulcerative colitis associated dysplasia using a fluorescent labeled molecular probe and CLE is feasible. In vivo studies on larger populations are required to evaluate the safety and the effective contribution of molecular probes in cancer surveillance of ulcerative colitis. PMID- 28666017 TI - Potential of Eucalyptus camaldulensis for phytostabilization and biomonitoring of trace-element contaminated soils. AB - Soil pollution by trace elements (TEs) from mining and industrial activity is widespread and presents a risk to humans and ecosystems. The use of trees to immobilize TEs (phytostabilization) is a low-cost and effective method of soil remediation. We aimed to determine the chemical composition of leaves and flower buds of Eucalyptus camaldulensis in seven sites along the Guadiamar River valley (SW Spain), an area contaminated by a mine-spill in 1998. E. camaldulensis trees in the spill-affected area and adjacent non affected areas were growing on a variety of soils with pH from 5.6 to 8.1 with low concentration of plant nutrients. The spill affected soils contained up to 1069 mg kg-1 of As and 4086 mg kg-1 of Pb. E. camaldulensis tolerated elevated TE concentrations in soil and, compared to other species growing in the same environment, had low TE concentrations in the aerial portions. Besides tolerance to soil contamination, E. camaldulensis had low bioaccumulation coefficients for soil contaminants. TE concentrations in the aboveground portions were below levels reported to be toxic to plants or ecosystems. Flower buds had even lower TE concentrations than leaves. Despite the relatively low concentration of TEs in leaves they were significantly correlated with the soil extractable (0.01 M CaCl2) Cd, Mn and Zn (but not Cu and Pb). The general features of this tree species: tolerance to impoverished and contaminated soils, fast growth and deep root system, and low transfer of TEs from soil to aboveground organs makes it suitable for phytostabilization of soils contaminated by TEs. In addition, eucalyptus leaves could be used for biomonitoring the soil extractability of Cd, Mn and Zn but not Cu or Pb. PMID- 28666018 TI - Indole-3-carbinol, a plant nutrient and AhR-Ligand precursor, supports oral tolerance against OVA and improves peanut allergy symptoms in mice. AB - In general, dietary antigens are tolerated by the gut associated immune system. Impairment of this so-called oral tolerance is a serious health risk. We have previously shown that activation of the ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) by the environmental pollutant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) affects both oral tolerance and food allergy. In this study, we determine whether a common plant-derived, dietary AhR-ligand modulates oral tolerance as well. We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high affinity ligand 3,3'-diindolylmethane (DIM). I3C feeding robustly induced the AhR target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy. In contrast to the tolerance-breaking effect of TCDD, feeding mice with chow containing 2 g/kg I3C lowered the serum anti-ovalbumin IgG1 response in an experimental oral tolerance protocol. Moreover, I3C feeding attenuated symptoms of peanut allergy. In conclusion, the dietary compound I3C can positively influence a vital immune function of the gut. PMID- 28666019 TI - Distribution and community composition of lichens on mature mangroves (Avicennia marina subsp. australasica (Walp.) J.Everett) in New Zealand. AB - Mangrove forests of a single trees species, Avicennia marina subsp. australasica are widespread in the upper North Island of New Zealand, but there is little available information on the diversity of epiphytes such as lichens within them. A survey of 200 trees from 20 mangrove sites recorded a total of 106 lichen species from 45 genera. Two of these species are considered to be 'Threatened', five 'At Risk' and 27 'Data Deficient'. Multiple regression indicated that tree diameter (DBH) and mean annual rain days positively influenced site species richness. Multidimensional scaling showed that sites from the same geographical region generally formed distinct clusters. Redundancy analysis indicated that mean annual wet days, latitude and DBH measurably influenced species composition. PMID- 28666020 TI - Modulating glioma-mediated myeloid-derived suppressor cell development with sulforaphane. AB - Glioblastoma is the most common primary tumor of the brain and has few long-term survivors. The local and systemic immunosuppressive environment created by glioblastoma allows it to evade immunosurveillance. Myeloid-derived suppressor cells (MDSCs) are a critical component of this immunosuppression. Understanding mechanisms of MDSC formation and function are key to developing effective immunotherapies. In this study, we developed a novel model to reliably generate human MDSCs from healthy-donor CD14+ monocytes by culture in human glioma conditioned media. Monocytic MDSC frequency was assessed by flow cytometry and confocal microscopy. The resulting MDSCs robustly inhibited T cell proliferation. A cytokine array identified multiple components of the GCM potentially contributing to MDSC generation, including Monocyte Chemoattractive Protein-1, interleukin-6, interleukin-8, and Macrophage Migration Inhibitory Factor (MIF). Of these, Macrophage Migration Inhibitory Factor is a particularly attractive therapeutic target as sulforaphane, a naturally occurring MIF inhibitor derived from broccoli sprouts, has excellent oral bioavailability. Sulforaphane inhibits the transformation of normal monocytes to MDSCs by glioma-conditioned media in vitro at pharmacologically relevant concentrations that are non-toxic to normal leukocytes. This is associated with a corresponding increase in mature dendritic cells. Interestingly, sulforaphane treatment had similar pro-inflammatory effects on normal monocytes in fresh media but specifically increased immature dendritic cells. Thus, we have used a simple in vitro model system to identify a novel contributor to glioblastoma immunosuppression for which a natural inhibitor exists that increases mature dendritic cell development at the expense of myeloid derived suppressor cells when normal monocytes are exposed to glioma conditioned media. PMID- 28666021 TI - Divergent roles for Ly6C+CCR2+CX3CR1+ inflammatory monocytes during primary or secondary infection of the skin with the intra-phagosomal pathogen Leishmania major. AB - Inflammatory monocytes can be manipulated by environmental cues to perform multiple functions. To define the role of monocytes during primary or secondary infection with an intra-phagosomal pathogen we employed Leishmania major-red fluorescent protein (RFP) parasites and multi-color flow cytometry to define and enumerate infected and uninfected inflammatory cells in the skin. During primary infection, infected monocytes had altered maturation and were the initial mononuclear host cell for parasite replication. In contrast, at a distal site of secondary infection in mice with a healed but persistent primary infection, this same population rapidly produced inducible nitric oxide synthase (iNOS) in an IFN gamma dependent manner and was critical for parasite killing. Maturation to a dendritic cell-like phenotype was not required for monocyte iNOS-production, and enhanced monocyte recruitment correlated with IFN-gamma dependent cxcl10 expression. In contrast, neutrophils appeared to be a safe haven for parasites in both primary and secondary sites. Thus, inflammatory monocytes play divergent roles during primary versus secondary infection with an intra-phagosomal pathogen. PMID- 28666022 TI - Intravitreal itraconazole inhibits laser-induced choroidal neovascularization in rats. AB - Choroidal neovascularization (CNV) is a major cause of severe visual loss in patients with age-related macular degeneration (AMD). Recently, itraconazole has shown potent and dose-dependent inhibition of tumor-associated angiogenesis. We evaluated the anti-angiogenic effect of itraconazole in a rat model of laser induced CNV. After laser photocoagulation in each eye to cause CNV, right eyes were administered intravitreal injections of itraconazole; left eyes received balanced salt solution (BSS) as controls. On day 14 after laser induction, fluorescein angiography (FA) was used to assess abnormal vascular leakage. Flattened retinal pigment epithelium (RPE)-choroid tissue complex was stained with Alexa Fluor 594-conjugated isolectin B4 to measure the CNV area and volume. Vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression was determined 1, 4, 7, and 14 days after intravitreal injection by quantitative RT-PCR or Western blot. VEGF levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Intravitreal itraconazole significantly reduced leakage from CNV as assessed by FA and CNV area and volume on flat mounts compared with intravitreal BSS (p = 0.002 for CNV leakage, p<0.001 for CNV area and volume). Quantitative RT-PCR showed significantly lower expression of VEGFR2 mRNA in the RPE-choroid complexes of itraconazole-injected eyes than those of BSS injected eyes on days 7 and 14 (p = 0.003 and p = 0.006). Western blots indicated that VEGFR2 was downregulated after itraconazole treatment. ELISA showed a significant difference in VEGF level between itraconazole-injected and BSS injected eyes on days 7 and 14 (p = 0.04 and p = 0.001). Our study demonstrated that intravitreal itraconazole significantly inhibited the development of laser induced CNV in rats. Itraconazole had anti-angiogenic activity along with the reduction of VEGFR2 and VEGF levels. Itraconazole may prove beneficial for treating CNV as an alternative or adjunct to other therapies. PMID- 28666023 TI - Reduction in serum sphingosine 1-phosphate concentration in malaria. AB - Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin which is involved in the endothelial permeability and inflammation. Although the plasma S1P concentration is reportedly decreased in patients with cerebral malaria, the role of S1P in malaria is still unclear. The purpose of this study was to examine the impact of malaria on circulating S1P concentration and its relationship with clinical data in malaria patients. Serum S1P levels were measured in 29 patients with P. vivax, 30 patients with uncomplicated P. falciparum, and 13 patients with complicated P. falciparum malaria on admission and on day 7, compared with healthy subjects (n = 18) as control group. The lowest level of serum S1P concentration was found in the complicated P. falciparum malaria group, compared with P. vivax, uncomplicated P. falciparum patients and healthy controls (all p < 0.001). In addition, serum S1P level was positively correlated with platelet count, hemoglobin and hematocrit levels in malaria patients. In conclusions, low levels of S1P are associated with the severity of malaria, and are correlated with thrombocytopenia and anemia. These findings highlight a role of S1P in the severity of malaria and support the use of S1P and its analogue as a novel adjuvant therapy for malaria complications. PMID- 28666024 TI - Outcomes after major surgery in patients with myasthenia gravis: A nationwide matched cohort study. AB - OBJECTIVE: To validate the comprehensive features of adverse outcomes after surgery for patients with myasthenia gravis. METHODS: Using reimbursement claims from Taiwan's National Health Insurance Research Database, we analyzed 2290 patients who received major surgery between 2004 and 2010 and were diagnosed with myasthenia gravis preoperatively. Surgical patients without myasthenia gravis (n = 22,900) were randomly selected by matching procedure with propensity score for comparison. The adjusted odds ratios and 95% confidence intervals of postoperative adverse events associated with preoperative myasthenia gravis were calculated under the multiple logistic regressions. RESULTS: Compared with surgical patients without myasthenia gravis, surgical patients with myasthenia gravis had higher risks of postoperative pneumonia (OR = 2.09; 95% CI: 1.65 2.65), septicemia (OR = 1.31; 95% CI: 1.05-1.64), postoperative bleeding (OR = 1.71; 95% CI: 1.07-2.72), and overall complications (OR = 1.70; 95% CI: 1.44 2.00). The ORs of postoperative adverse events for patients with myasthenia gravis who had symptomatic therapy, chronic immunotherapy, and short-term immunotherapy were 1.76 (95% CI 1.50-2.08), 1.70 (95% CI 1.36-2.11), and 4.36 (95% CI 2.11-9.04), respectively. CONCLUSIONS: Patients with myasthenia gravis had increased risks of postoperative adverse events, particularly those experiencing emergency care, hospitalization, and thymectomy for care of myasthenia gravis. Our findings suggest the urgency of revising protocols for perioperative care for these populations. PMID- 28666025 TI - Comparison of the CBA-H and SF-36 for the screening of the psychological and behavioural variables in chronic dialysis patients. AB - The aim of the study was to perform an analysis of the emotional reactions, perception of stressful life and behavioural changes related to Haemodialysis (HD) in order to identify those variables that can improve lifestyle and the adherence to treatment. Some psychometric assessment, such as the Cognitive Behavioural Assessment, Hospital Form, (CBA-H) and the Health Survey (SF-36), which provides two indexes: the Physical Component Score (PCS) and the Mental Component Score (MCS), are suitable to assess a patient's psychological and behavioural style and their health-related quality of life. The study involved 37 Italian out-patients with end-stage renal disease under HD therapy. We calculated the Spearman correlation between variables of CBA-H, SF-36, age and time on HD. We also performed a multivariate linear regression using the CBA-H variables as predictors and PCS and MCS as dependent variables. From the CBA-H, 95% of participants self-reported psychological characteristics comparable to Type A personality, which identifies an anxious, hyperactive and hostile subject. Physical limitations were found to be directly proportional to the time on dialysis (rs = -0.42). The condition of perceived stress worsens the state of mental health (rs = -0.68) and general health perception (rs = -0.44). The condition of vital exhaustion correlates both the PCS and the MCS (p<0.01) with possible outcomes of physical and mental illness. The psychological wellbeing of a dialyzed patient could be due to the combination of several factors, including life parameters, the positive perception of psychosocial outcomes, and the perceived quality of life. A multidisciplinary team (neurologists, psychiatrists, psychologists, and nurses) is essential to plan effective psychological and psychotherapeutic interventions to improve a mind-body integration. PMID- 28666026 TI - Assessing agreement between preclinical magnetic resonance imaging and histology: An evaluation of their image qualities and quantitative results. AB - One consequence of demographic change is the increasing demand for biocompatible materials for use in implants and prostheses. This is accompanied by a growing number of experimental animals because the interactions between new biomaterials and its host tissue have to be investigated. To evaluate novel materials and engineered tissues the use of non-destructive imaging modalities have been identified as a strategic priority. This provides the opportunity for studying interactions repeatedly with individual animals, along with the advantages of reduced biological variability and decreased number of laboratory animals. However, histological techniques are still the golden standard in preclinical biomaterial research. The present article demonstrates a detailed method comparison between histology and magnetic resonance imaging. This includes the presentation of their image qualities as well as the detailed statistical analysis for assessing agreement between quantitative measures. Exemplarily, the bony ingrowth of tissue engineered bone substitutes for treatment of a cleft-like maxillary bone defect has been evaluated. By using a graphical concordance analysis the mean difference between MRI results and histomorphometrical measures has been examined. The analysis revealed a slightly but significant bias in the case of the bone volume [Formula: see text] and a clearly significant deviation for the remaining defect width [Formula: see text] But the study although showed a considerable effect of the analyzed section position to the quantitative result. It could be proven, that the bias of the data sets was less originated due to the imaging modalities, but mainly on the evaluation of different slice positions. The article demonstrated that method comparisons not always need the use of an independent animal study, additionally. PMID- 28666027 TI - Hyperuricemia and risk of increased arterial stiffness in healthy women based on health screening in Korean population. AB - Hyperuricemia is a risk factor for cardiovascular disease and is associated with increased arterial stiffness in high-risk populations. However, given the possible sex-related differences in the prevalence of hyperuricemia, the association between elevated serum uric acid (SUA) level and increased arterial stiffness has yielded conflicting results. We investigated the relationship between SUA and arterial stiffness in asymptomatic healthy subjects who underwent a health examination. Subjects who underwent a comprehensive health examination were enrolled. After exclusion of extensive confounding factors, 2,704 healthy subjects with coronary calcium score < 100 were evaluated in the final analysis. All subjects underwent brachial-ankle pulse wave velocity (baPWV) to detect arterial stiffness. The SUA was divided into quartiles for its association with arterial stiffness and was analyzed separately for men and women. The mean SUA level was significantly lower in women than in men. The baPWV was significantly elevated in subjects with the highest quartile of SUA in women, but not in men. After adjusting for age, smoking, systolic blood pressure, body mass index, estimated glomerular filtration rate, fasting plasma glucose, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and coronary artery calcium score, the highest quartile of SUA in women was significantly associated with increased risk of high baPWV compared with the lowest quartile of SUA (OR = 1.7, p = 0.018), whereas in men, SUA level was not associated with high baPWV. Our study showed that elevated SUA is independently associated with increased baPWV in healthy Korean women, but not in men. PMID- 28666029 TI - Expected accuracy of proximal and distal temperature estimated by wireless sensors, in relation to their number and position on the skin. AB - A popular method to estimate proximal/distal temperature (TPROX and TDIST) consists in calculating a weighted average of nine wireless sensors placed on pre defined skin locations. Specifically, TPROX is derived from five sensors placed on the infra-clavicular and mid-thigh area (left and right) and abdomen, and TDIST from four sensors located on the hands and feet. In clinical practice, the loss/removal of one or more sensors is a common occurrence, but limited information is available on how this affects the accuracy of temperature estimates. The aim of this study was to determine the accuracy of temperature estimates in relation to number/position of sensors removed. Thirteen healthy subjects wore all nine sensors for 24 hours and reference TPROX and TDIST time courses were calculated using all sensors. Then, all possible combinations of reduced subsets of sensors were simulated and suitable weights for each sensor calculated. The accuracy of TPROX and TDIST estimates resulting from the reduced subsets of sensors, compared to reference values, was assessed by the mean squared error, the mean absolute error (MAE), the cross-validation error and the 25th and 75th percentiles of the reconstruction error. Tables of the accuracy and sensor weights for all possible combinations of sensors are provided. For instance, in relation to TPROX, a subset of three sensors placed in any combination of three non-homologous areas (abdominal, right or left infra clavicular, right or left mid-thigh) produced an error of 0.13 degrees C MAE, while the loss/removal of the abdominal sensor resulted in an error of 0.25 degrees C MAE, with the greater impact on the quality of the reconstruction. This information may help researchers/clinicians: i) evaluate the expected goodness of their TPROX and TDIST estimates based on the number of available sensors; ii) select the most appropriate subset of sensors, depending on goals and operational constraints. PMID- 28666028 TI - Regeneration of hyaline-like cartilage in situ with SOX9 stimulation of bone marrow-derived mesenchymal stem cells. AB - Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage. PMID- 28666030 TI - Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension is associated with a decreased antioxidant capacity. However, neither the contribution of reactive oxygen species to pulmonary vasoconstrictor sensitivity, nor the therapeutic efficacy of antioxidant strategies in this setting are known. We hypothesized that reactive oxygen species play a central role in mediating both vasoconstrictor and arterial remodeling components of severe pulmonary arterial hypertension. We examined the effect of the chemical antioxidant, TEMPOL, on right ventricular systolic pressure, vascular remodeling, and enhanced vasoconstrictor reactivity in both chronic hypoxia and hypoxia/SU5416 rat models of pulmonary hypertension. SU5416 is a vascular endothelial growth factor receptor antagonist and the combination of chronic hypoxia/SU5416 produces a model of severe pulmonary arterial hypertension with vascular plexiform lesions/fibrosis that is not present with chronic hypoxia alone. The major findings from this study are: 1) compared to hypoxia alone, hypoxia/SU5416 exposure caused more severe pulmonary hypertension, right ventricular hypertrophy, adventitial lesion formation, and greater vasoconstrictor sensitivity through a superoxide and Rho kinase-dependent Ca2+ sensitization mechanism. 2) Chronic hypoxia increased medial muscularization and superoxide levels, however there was no effect of SU5416 to augment these responses. 3) Treatment with TEMPOL decreased right ventricular systolic pressure in both hypoxia and hypoxia/SU5416 groups. 4) This effect of TEMPOL was associated with normalization of vasoconstrictor responses, but not arterial remodeling. Rather, medial hypertrophy and adventitial fibrotic lesion formation were more pronounced following chronic TEMPOL treatment in hypoxia/SU5416 rats. Our findings support a major role for reactive oxygen species in mediating enhanced vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat models, despite a paradoxical effect of antioxidant therapy to exacerbate arterial remodeling in animals with severe pulmonary arterial hypertension in the hypoxia/SU5416 model. PMID- 28666031 TI - The association between the number of office visits and the control of cardiovascular risk factors in Iranian patients with type2 diabetes. AB - INTRODUCTION: Patients with diabetes type2 should receive regular medical care. We aimed at investigating the association between the number of office visits and improvement of their cardiovascular-risk factors. METHODS: Four hundred and ninety patients with type 2 diabetes mellitus who were followed in a tertiary center were enrolled in this longitudinal study. The minimum follow up period was 3 years. Patient data were extracted from manual or electronic records. RESULTS: Sixty- four percent of cases were females, the mean age was 61 +/- 12.45 years, and the mean disease duration was 6.5 +/-7.9 years. The mean number of office visits was 2.69 +/- 0.91 per year. Comparing the means of each of the cardio vascular risk factors showed a significant decrease in all cardiovascular risk factors, while there was a significant weight gain over the same period. The association between changes in these parameters and the number of patients' office visits per year were not statistically significant. In patients with disease duration less than 5 years, each additional office visits by one visit per year was associated with a decrease in serum total cholesterol by 6.94 mg/dl. The mean number of office visits per year in patients older than 60 years old was more than younger patient (p = 0.001). CONCLUSION: The decrease in the mean values of the investigated parameters was statistically significant between the first year of follow up and the following years. Yet, these changes were not related to the mean number of patients' office visits per year, which may reflect the poor compliance of patients to treatment regardless of the number of their office visits. PMID- 28666032 TI - Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide. AB - BACKGROUND: Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes. METHODS: Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed. RESULTS: LPS exposure increased CD3-positive and myeloperoxidase positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone. CONCLUSION: Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals. PMID- 28666034 TI - The End of a Season. PMID- 28666033 TI - Dorso-ventral skin characterization of the farmed fish gilthead seabream (Sparus aurata). AB - The skin is the first barrier of defence in fish, protecting against any external stressor and preserving the integrity and homeostasis of the fish body. The aim of this study was to characterise gilthead seabream skin by isolating cells and studying the cell cycle by flow cytometry, to study the skin histology by scanning electron microscopy and the transcription level of some immune-relevant genes by RT-PCR. Furthermore, the results obtained from samples taken from the dorsal and the ventral part of the specimens are compared. No differences were observed in the cell cycle of cells isolated from the dorsal and ventral zones of the skin or in the gene expression of the genes studied in both epidermal zones. However, the epidermis thickness of the ventral skin was higher than that of the dorsal skin, as demonstrated by image analysis using light microscopy. Besides, scanning electron microscopy pointed to a greater cell size and area of microridges in the apical part of the dorsal epidermal cells compared with ventral skin epidermal cells. This study represents a step forward in our knowledge of the skin structure of an important farmed teleost, gilthead seabream, one of the most commonly farmed fish worldwide. Furthermore, for functional characterization, experimental wounds were carried out comparing the wound healing rate between the dorsal and ventral regions of skin over the time. The results showed higher ratio of wound healing in the ventral region, whose wounds were closed after 15 days, compared to dorsal region of skin. Taking into account all together, this study represents a step forward in our knowledge of the skin structure and skin regeneration of an important farmed teleost, gilthead seabream, one of the most commonly farmed fish worldwide. PMID- 28666035 TI - Head, Neck, and Shoulder Injuries in Ice Hockey: Current Concepts. AB - Ice hockey is a fast-paced contact sport that is becoming increasingly popular in North America. More than 1 million men, women, and juniors are playing hockey in the United States and Canada. With players colliding forcefully with one another and with the boards surrounding the ice, injury rates are among the highest in all of competitive sports. Physicians caring for a hockey team should be aware of the more common injuries, involving the head, the neck, and the shoulder. In this review, we discuss evaluation and treatment of these hockey injuries, return to play, and, where applicable, prevention strategies. PMID- 28666036 TI - Arthroscopic Excision of Bipartite Patella With Preservation of Lateral Retinaculum in an Adolescent Ice Hockey Player. AB - Bipartite patella usually is an asymptomatic anatomical variant. However, in some adolescent athletes, it causes anterior knee pain, resulting in decreased participation and performance. We report the case of a high-level adolescent ice hockey player who underwent successful arthroscopic excision with preservation of the lateral retinaculum of a symptomatic bipartite patella after failed nonoperative treatment. The patient returned to play by 6 weeks, and 31-month subjective follow-up scores showed high satisfaction and good clinical outcomes. For patients with a symptomatic bipartite patella, arthroscopic surgery is a good option for reducing pain and returning the athlete to competition. PMID- 28666037 TI - Joint-Preserving Osteotomies for Isolated Patellofemoral Osteoarthritis: Alternatives to Arthroplasty. AB - Patellofemoral osteotomies can provide excellent symptomatic relief for selected patients with isolated patellofemoral osteoarthritis (PFOA). Isolated PFOA is a relatively common disorder, seen in 24% of women and 11% of men over the age of 55 years. In up to 89% of these patients, PFOA occurs at the lateral facet of the patella, and is especially amenable to surgical treatment. Particularly in younger patients, joint-preserving osteotomies can provide excellent and reliable relief while delaying the need for partial or joint arthroplasty and subsequent revision. These osteotomies, such as partial lateral patellar facetectomy (PLPF), patella-thinning osteotomy (PTO), tibial tubercle anteromedialization (AMZ) osteotomy, and sulcus-deepening trochleoplasty (SDT), are reviewed for indications, technique, and results. In particular, patients with primarily lateral facet or distal and lateral lesions have excellent outcomes with patellofemoral osteotomies. PMID- 28666038 TI - Measuring Malalignment on Imaging in the Treatment of Patellofemoral Instability. AB - Assessment of malalignment is an important factor in determining surgical treatment options for patellar instability. Measurement of tibial tubercle trochlear groove (TT-TG) distance is valuable in planning surgical treatment for patellar instability, because it quantifies a component of malalignment and aids in deciding whether to perform tibial tuberosity osteotomy. In this paper we review how TT-TG distance should be understood in the context of many measurement factors to allow for an individualized procedure that addresses the specific contributors to patellar instability in each patient. Understanding the limitations of and variability in radiographic assessments of TT and TG positions can help in deciding whether to perform TT osteotomy for patellar instability. PMID- 28666039 TI - Ultrasound-Guided Percutaneous Repair of Medial Patellofemoral Ligament: Surgical Technique and Outcomes. AB - A lateral patellar dislocation causes a medial patellofemoral ligament (MPFL) tear that begins affecting patellar biomechanics. Reconstruction is difficult because of the inability to reliably and accurately determine proper placement of sockets. Studies of MPFL anatomy have found significant variability in attachment site locations, which suggests MPFL procedures cannot be used universally and must be approached differently for each patient. Recurrent dislocations result in patellar and trochlear chondral and bony damage. In this article, we present a novel technique that uses ultrasound to locate the MPFL tear and the MPFL attachment sites, and perform anatomical repair of the native tissue at the patellar attachment site, the femoral attachment site, or both. We also describe our retrospective analysis of 10 cases of this ultrasound-guided percutaneous procedure, performed since its development in 2013. In each case, patellar stability was restored completely and without complications. The promising results, the ease of the surgery, and the limited rate of complications indicate this surgical technique should be considered before reconstruction and early in trauma cases, before onset of chondral or bony damage. PMID- 28666040 TI - Internal Carotid Artery Dissection After Indirect Blunt Cervical Trauma in an Ice Hockey Goaltender. AB - Internal carotid artery dissections are rare injuries that can result from both direct cervical trauma and indirect trauma causing sudden cervical hyperextension. Depending on the magnitude of the dissection, clinical presentation ranges from neurologic symptoms, such as Horner syndrome, to relatively mild but persistent headache symptoms, as in the case reported in this article. High clinical suspicion with subsequent neuroimaging is recommended in similar clinical scenarios. Our patient, an ice hockey goaltender, was conservatively treated with rest and serial neuroimaging studies to ensure resolution of the dissection. Eight weeks later, he returned to athletic competition with resolved symptoms and radiologically improved arterial stenosis. PMID- 28666041 TI - Encapsulated Fat Necrosis Lesion Caused by Morel-Lavallee Lesion in a Professional Ice Hockey Player. AB - Morel-Lavallee (ML) lesions occur when subcutaneous tissue is stripped from fascia and replaced with hematoma or necrotic fat. Encapsulated fat necrosis lesions, which are rare, can occur with disruption of the blood supply in the subcutaneous area, which occurs with ML lesions. In this article, we report the case of a professional ice hockey player with an ML lesion that caused a symptomatic encapsulated fat necrosis lesion to develop. The encapsulated lesion required surgical removal. PMID- 28666042 TI - Primary Total Knee Arthroplasty for Distal Femur Fractures: A Systematic Review of Indications, Implants, Techniques, and Results. AB - Distal femur fractures (DFFs) in elderly patients historically were difficult to treat because of osteoporotic bone, comminution, and intra-articular involvement. Current surgical treatment options, including intramedullary nailing, internal fixation, and external fixation, are complicated by prolonged immobility, malunion, and nonunion. Furthermore, fixation increases the complexity of subsequent arthroplasty. Primary total knee arthroplasty (TKA) is a rarely used treatment for acute DFF but may be of benefit in select patients. For a systematic review of the reported indications, techniques, implants, outcomes, and complications of TKA for DFF, we searched the major databases Medline, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library. Few studies of this technique have been reported, and the majority of published studies have been level III and level IV, with heterogeneous results and outcomes. Many of the patients in these studies achieved early weight-bearing with primary TKA. Complication rates varied and may be higher for older patients with more comorbidities, but whether these rates are higher than those of patients treated with internal fixation is unclear. Modular constrained implants may be appropriate for comminuted intra-articular fractures, whereas extra-articular fractures may be sufficiently managed with unconstrained implants supplemented with fracture fixation. PMID- 28666043 TI - Difficult-to-Detect Low-Grade Infections Responsible for Poor Outcomes in Total Knee Arthroplasty. AB - In this article, we present the case of a patient with a stiff, painful knee after total knee arthroplasty, and with erythrocyte sedimentation rate, C reactive protein level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed Propionibacterium acnes prosthetic joint infection, which was successfully treated with 2-stage revision and intravenous antibiotics. PMID- 28666044 TI - Electronic Health Record Implementation Is Associated With a Negligible Change in Outpatient Volume and Billing. AB - The Health Information Technology for Economic and Clinical Health (HITECH) Act mandated that hospitals begin using electronic health records (EHRs). To investigate potential up-coding, we reviewed billing data for changes in patient volumes and up-coding around the time of EHR implementation at our academic medical center. We identified all new, consultation, and return outpatient visits on a monthly basis in the general internal medicine and orthopedics departments at our center. We compared the volume of patient visits and the level of billing coding in these 2 departments before and after their transitions to ambulatory EHRs. Pearson chi2 test was used when appropriate. Patient volumes remained constant during the transition to EHRs. There were small changes in the level of billing coding with EHR implementation. In both departments, these changes accounted for minor, but statistically significant shifts in billing coding (Pearson chi2, P < .001). However, the 44.7% relative increase in level 5 coding in our orthopedics department represented only 1.7% of patient visits overall. These findings indicate that lay media reports about an association between dramatic up-coding and EHRs could be misleading. PMID- 28666045 TI - Lower Leg Fracture Irreducibility Resulting From Entrapment of the Fibula Within the Tibial Shaft. AB - The tibia is the most commonly fractured long bone. Tibia fractures are simple, and most are amenable to immediate closed reduction. Reported cases of irreducibility resulting from entrapment of soft-tissue structures are rare. We report the case of a 23-year-old man who, in a high-speed motor vehicle crash, sustained a closed lower leg fracture that was later found to have a unique pattern in which the fibula was entrapped in the medullary cavity of the tibia. Limited open reduction was performed, and the entrapped distal fibula was removed with use of a bone hook. The tibia was reduced, and a nail placed in standard fashion. The postoperative course leading to full recovery was unremarkable. This irreducible fracture pattern, not previously reported, should be considered during difficult closed reductions in order to prevent unnecessary neurovascular or bony injury. PMID- 28666046 TI - 5 Points on Pyogenic Flexor Tenosynovitis of the Hand. PMID- 28666047 TI - Acute Intraprosthetic Dissociation of a Dual-Mobility Hip in the United States. AB - After decades of use in Europe, dual-mobility (DM) components for total hip arthroplasty (THA) were approved by the US Food and Drug Administration (FDA) in 2011 for use in the United States. DM-THAs are designed with an inner articulation between the femoral head and a larger polyethylene insert, and an outer articulation between the mobile polyethylene and a highly polished metal insert, to increase motion and minimize impingement. Intraprosthetic dissociation (IPD), defined as separation of the femoral head from the inner polyethylene articulation, is usually caused by polyethylene wear, and occurs 3 to 10 years after implantation. Early recognition of this complication is important for appropriate treatment. Late chronic IPD is caused by polyethylene wear, blocked motion of the outer bearing, or acetabular loosening. Acute IPD (AIPD), which occurs within 1 year after implantation, is rare and poorly understood. Only 2 cases of this early complication have been reported in the United States. The exact mechanism of injury is unknown, but AIPD may be associated with closed reduction maneuvers or neck impingement (large-diameter femoral neck, femoral head with skirted neck). In this article, we report the case of a nondemented 63 year-old man who developed AIPD 3 months after implantation of a DM component for recurrent dislocation. PMID- 28666048 TI - Readability of Orthopedic Trauma Patient Education Materials on the Internet. AB - In this study, we used the Flesch-Kincaid Readability Scale to determine the readability levels of orthopedic trauma patient education materials on the American Academy of Orthopaedic Surgeons (AAOS) website and to examine how subspecialty coauthorship affects readability level. Included articles from the AAOS online patient education library and the AAOS OrthoPortal website were categorized as trauma or broken bones and injuries on the AAOS online library or were screened by study authors for relevance to orthopedic trauma. Subsequently, the Flesch-Kincaid scale was used to determine each article's readability level, which was reported as a grade level. Subspecialty coauthorship was noted for each article. A total of 115 articles from the AAOS website were included in the study and reviewed. Mean reading level was grade 9.1 for all articles reviewed. Nineteen articles (16.5%) were found to be at or below the eighth-grade level, and only 1 article was at or below the sixth-grade level. In addition, there was no statistically significant difference between articles coauthored by the various orthopedic subspecialties and those authored exclusively by AAOS. Orthopedic trauma readability materials on the AAOS website appear to be written at a reading comprehension level too high for the average patient to understand. PMID- 28666049 TI - Does Preoperative Pneumonia Affect Complications of Geriatric Hip Fracture Surgery? AB - Preoperative pneumonia, reported in 0.3% to 3.2% of hip fracture patients, may be a risk factor for adverse outcomes of hip fracture repair. No studies have reported on baseline differences or adverse outcomes in surgically managed geriatric hip fracture patients with and without preoperative pneumonia, and no data argue for or against delaying surgery in these patients. A retrospective cohort of geriatric patients with operatively treated hip fractures from 2005 to 2012 was identified in the National Surgical Quality Improvement Program database. Preoperative pneumonia was present in 82 (1.2%) of 7128 geriatric hip fracture patients identified and was associated with male sex, transfer status, functional status, preoperative anemia, confusion, dyspnea at rest, and chronic obstructive pulmonary disease. Multivariate analysis of 30-day outcomes of hip fracture repair revealed that preoperative pneumonia was associated with a higher risk for any adverse event (relative risk [RR] = 1.44), serious adverse event (RR = 1.79), and death (RR = 2.08) after hip fracture repair. Underweight body mass index at time of surgery (<18.5 kg/m2) was predictive of 30-day mortality (RR = 4.67). Surgical delay of 1 to 4 days was not associated with adverse events. Geriatric hip fracture patients with preoperative pneumonia, especially the underweight, are at increased risk for complications and death after hip fracture repair. We cannot recommend against early hip fracture surgery in this population. PMID- 28666050 TI - Open Navicular Dislocation With Midfoot Dissociation in a 45-Year-Old Man. AB - Traumatic dislocation of an intact tarsal navicular is an uncommon injury. In this article, we report a case of open medial navicular dislocation in a 45-year old man. The injury was managed with open reduction and stabilization with Kirschner wires within the acute period. Ten months after injury, the patient developed avascular necrosis of the navicular and exhibited progressive collapse of the medial midfoot. He underwent naviculocuneiform arthrodesis 1 year after the index surgery. Two years after fusion, he was pain-free and ambulating independently. Successful treatment of midfoot fractures and dislocations requires an intimate understanding of anatomy, biomechanics, and both short- and long-term sequelae of injury. PMID- 28666051 TI - Multimodality Approach to a Stener Lesion: Radiographic, Ultrasound, Magnetic Resonance Imaging, and Surgical Correlation. AB - The ulnar collateral ligament (UCL) of the thumb metacarpophalangeal joint is a static stabilizer that may rupture from a hyperabduction injury. Although some UCL tears may heal with immobilization, outcomes are worse for Stener lesions, in which the proximal ligament stump slips out from beneath the adductor pollicis aponeurosis and is entrapped proximal and superficial to the aponeurosis, preventing primary healing. We report the case of a patient with a Stener lesion with radiographic, ultrasound, and magnetic resonance imaging correlation, subsequently confirmed with intraoperative photographs. Physicians must be familiar with the regional anatomy to understand the injury pathogenesis and the need for surgical intervention to optimize patient outcomes. PMID- 28666052 TI - Rare Dual Lesion: Extraskeletal Osteosarcoma Developing Within a Simple Lipoma. AB - Extraosseous osteosarcoma is a rare malignancy, but simple lipomas are common. This article is the first report of a case of radiation-induced extraosseous osteosarcoma that developed within a simple lipoma in a 72-year-old woman. We correlate the magnetic resonance imaging, computed tomography, positron emission tomography, and plain radiographic findings. The patient, treated with systemic therapy and wide surgical resection of the neoplasm, remained clinically free of disease during the first 22 months of follow-up. PMID- 28666054 TI - Conversion of a Dehalogenase into a Nitroreductase by Swapping its Flavin Cofactor with a 5-Deazaflavin Analogue. AB - Natural and engineered nitroreductases have rarely supported full reduction of nitroaromatics to their amine products, and more typically, transformations are limited to formation of the hydroxylamine intermediates. Efficient use of these enzymes also requires a regenerating system for NAD(P)H to avoid the costs associated with this natural reductant. Iodotyrosine deiodinase is a member of the same structural superfamily as many nitroreductases but does not directly consume reducing equivalents from NAD(P)H, nor demonstrate nitroreductase activity. However, exchange of its flavin cofactor with a 5-deazaflavin analogue dramatically suppresses its native deiodinase activity and leads to significant nitroreductase activity that supports full reduction to an amine product in the presence of the convenient and inexpensive NaBH4 . PMID- 28666055 TI - Developing and validating a new nomogram for diagnosing bladder outlet obstruction in women. AB - OBJECTIVE: To develop and validate a nomogram for assessing bladder outlet obstruction (BOO) in women derived from concurrent Pdet.Qmax and Qmax based on radiographic evidence of increased urethral resistance. PATIENTS AND METHODS: Retrospective analysis of prospectively acquired video-urodynamics and clinical data of 185 women (development cohort) was performed. The Pdet.Qmax were plotted against Qmax and cluster analysis was performed to determine an axis that best divided the definitively obstructed and unobstructed. Using data from a further 350 women (validation cohort), the sensitivity and specificity of the derived criterion was calculated. Finally, the data from both groups was pooled together and using binary logistic regression analysis, a nomogram was produced. RESULTS: Of the 535 patients in the two cohorts, (122 [22.8%]) demonstrated radiographic evidence of BOO. Cluster analysis identified the axis that best separates the radiographically obstructed and unobstructed as Pdet.Qmax = 2*Qmax . Using the data from the validation cohort, the sensitivity and specificity for this was calculated as 0.94 and 0.93, respectively. A nomogram, representing the probability of BOO for concurrent Pdet.Qmax and Qmax measurements was derived by pooling data from both cohorts. Alternatively, a female BOO index (BOOIf) may be calculated mathematically using the formula BOOIf = Pdet.Qmax - 2.2*Qmax, that is, BOOIf < 0, <10% probability of obstruction, BOOIf > 5 likely obstructed (50%) and If BOOIf > 18, obstruction almost certain (>90%). CONCLUSION: A female BOO nomogram (the SG nomogram) with high sensitivity and specificity is proposed. The nomogram can be used to stratify the degree of BOO or assess response to treatment. PMID- 28666053 TI - Background and design of the symptom burden in end-stage liver disease patient caregiver dyad study. AB - Over half a million Americans are affected by cirrhosis, the cause of end-stage liver disease (ESLD). Little is known about how symptom burden changes over time in adults with ESLD and their informal caregivers, which limits our ability to develop palliative care interventions that can optimize symptom management and quality of life in different patient-caregiver dyads. The purpose of this article is to describe the background and design of a prospective, longitudinal descriptive study, "Symptom Burden in End-Stage Liver Disease Patient-Caregiver Dyads," which is currently in progress. The study is designed to (i) identify trajectories of change in physical and psychological symptom burden in adults with ESLD; (ii) identify trajectories of change in physical and psychological symptom burden in caregivers of adults with ESLD; and (iii) determine predictors of types of patient-caregiver dyads that would benefit from tailored palliative care interventions. We aim for a final sample of 200 patients and 200 caregivers who will be followed over 12 months. Integrated multilevel and latent growth mixture modeling will be used to identify trajectories of change in symptom burden, linking those changes to clinical events, and quality of life outcomes and characterizing types of patient-caregiver dyads based on patient-, caregiver , and dyad-level factors. Challenges we have encountered include unexpected attrition of study participants, participants not returning their baseline questionnaires, and hiring and training of research staff. The study will lay the foundation for future research and innovation in ESLD, end-of-life and palliative care, and caregiving. PMID- 28666057 TI - Silencing OsSLR1 enhances the resistance of rice to the brown planthopper Nilaparvata lugens. AB - DELLA proteins, negative regulators of the gibberellin (GA) pathway, play important roles in plant growth, development and pathogen resistance by regulating multiple phytohormone signals. Yet, whether and how they regulate plant herbivore resistance remain unknown. We found that the expression of the rice DELLA gene OsSLR1 was down-regulated by an infestation of female adults of the brown planthopper (BPH) Nilaparvata lugens. On one hand, OsSLR1 positively regulated BPH-induced levels of two mitogen-activated protein kinase and four WRKY transcripts, and of jasmonic acid, ethylene and H2 O2 . On the other hand, silencing OsSLR1 enhanced constitutive levels of defence-related compounds, phenolic acids, lignin and cellulose, as well as the resistance of rice to BPH in the laboratory and in the field. The increased resistance in rice with silencing of OsSLR1 is probably due to impaired JA and ethylene pathways, and, at least in part, to the increased lignin level and mechanical hardness of rice leaf sheaths. Our findings illustrate that OsSLR1, acting as an early negative regulator, plays an important role in regulating the resistance of rice to BPH by activating appropriate defence-related signalling pathways and compounds. Moreover, our data also provide new insights into relationships between plant growth and defence. PMID- 28666058 TI - Real-time registration of 3D to 2D ultrasound images for image-guided prostate biopsy. AB - PURPOSE: During image-guided prostate biopsy, needles are targeted at tissues that are suspicious of cancer to obtain specimen for histological examination. Unfortunately, patient motion causes targeting errors when using an MR transrectal ultrasound (TRUS) fusion approach to augment the conventional biopsy procedure. This study aims to develop an automatic motion correction algorithm approaching the frame rate of an ultrasound system to be used in fusion-based prostate biopsy systems. Two modes of operation have been investigated for the clinical implementation of the algorithm: motion compensation using a single user initiated correction performed prior to biopsy, and real-time continuous motion compensation performed automatically as a background process. METHODS: Retrospective 2D and 3D TRUS patient images acquired prior to biopsy gun firing were registered using an intensity-based algorithm utilizing normalized cross correlation and Powell's method for optimization. 2D and 3D images were downsampled and cropped to estimate the optimal amount of image information that would perform registrations quickly and accurately. The optimal search order during optimization was also analyzed to avoid local optima in the search space. Error in the algorithm was computed using target registration errors (TREs) from manually identified homologous fiducials in a clinical patient dataset. The algorithm was evaluated for real-time performance using the two different modes of clinical implementations by way of user initiated and continuous motion compensation methods on a tissue mimicking prostate phantom. RESULTS: After implementation in a TRUS-guided system with an image downsampling factor of 4, the proposed approach resulted in a mean +/- std TRE and computation time of 1.6 +/- 0.6 mm and 57 +/- 20 ms respectively. The user initiated mode performed registrations with in-plane, out-of-plane, and roll motions computation times of 108 +/- 38 ms, 60 +/- 23 ms, and 89 +/- 27 ms, respectively, and corresponding registration errors of 0.4 +/- 0.3 mm, 0.2 +/- 0.4 mm, and 0.8 +/- 0.5 degrees . The continuous method performed registration significantly faster (P < 0.05) than the user initiated method, with observed computation times of 35 +/- 8 ms, 43 +/- 16 ms, and 27 +/- 5 ms for in-plane, out-of-plane, and roll motions, respectively, and corresponding registration errors of 0.2 +/- 0.3 mm, 0.7 +/- 0.4 mm, and 0.8 +/- 1.0 degrees . CONCLUSIONS: The presented method encourages real-time implementation of motion compensation algorithms in prostate biopsy with clinically acceptable registration errors. Continuous motion compensation demonstrated registration accuracy with submillimeter and subdegree error, while performing < 50 ms computation times. Image registration technique approaching the frame rate of an ultrasound system offers a key advantage to be smoothly integrated to the clinical workflow. In addition, this technique could be used further for a variety of image-guided interventional procedures to treat and diagnose patients by improving targeting accuracy. PMID- 28666056 TI - High-frequency oscillations: The state of clinical research. AB - Modern electroencephalographic (EEG) technology contributed to the appreciation that the EEG signal outside the classical Berger frequency band contains important information. In epilepsy, research of the past decade focused particularly on interictal high-frequency oscillations (HFOs) > 80 Hz. The first large application of HFOs was in the context of epilepsy surgery. This is now followed by other applications such as assessment of epilepsy severity and monitoring of antiepileptic therapy. This article reviews the evidence on the clinical use of HFOs in epilepsy with an emphasis on the latest developments. It highlights the growing literature on the association between HFOs and postsurgical seizure outcome. A recent meta-analysis confirmed a higher resection ratio for HFOs in seizure-free versus non-seizure-free patients. Residual HFOs in the postoperative electrocorticogram were shown to predict epilepsy surgery outcome better than preoperative HFO rates. The review further discusses the different attempts to separate physiological from epileptic HFOs, as this might increase the specificity of HFOs. As an example, analysis of sleep microstructure demonstrated a different coupling between HFOs inside and outside the epileptogenic zone. Moreover, there is increasing evidence that HFOs are useful to measure disease activity and assess treatment response using noninvasive EEG and magnetoencephalography. This approach is particularly promising in children, because they show high scalp HFO rates. HFO rates in West syndrome decrease after adrenocorticotropic hormone treatment. Presence of HFOs at the time of rolandic spikes correlates with seizure frequency. The time-consuming visual assessment of HFOs, which prevented their clinical application in the past, is now overcome by validated computer-assisted algorithms. HFO research has considerably advanced over the past decade, and use of noninvasive methods will make HFOs accessible to large numbers of patients. Prospective multicenter trials are awaited to gather information over long recording periods in large patient samples. PMID- 28666059 TI - alpha-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative. AB - A practical one-pot cascade reaction protocol provides direct access to valuable 1,2,4-trisubstituted pyrroles. The process involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type hydroformylation using glycolaldehyde dimer as a novel C1 building-block, followed by a Paal-Knorr condensation with primary amines. The reaction makes use of simple and commercially available starting materials and catalyst, an important feature regarding applicability and utility. Low catalyst loading under mild reaction conditions afforded a variety of 1,2,4 substituted pyrroles in a transition-metal-free reaction with high step economy and good yields. This methodology is applied in the synthesis of a versatile Atorvastatin precursor, in which a variety of modifications at the pyrrole core structure are possible. PMID- 28666060 TI - SSRIs associated with decreased risk of hepatocellular carcinoma: A population based case-control study. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cancer-related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited. OBJECTIVE: The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population-based study. METHODS: The nationwide population-based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables. RESULTS: All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose-dependent (eg, fluoxetine: 1-28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73 0.89; 29-365 DDD: aOR: 0.71, 95% CI, 0.64-0.79; and >=366 DDD: aOR: 0.55, 95% CI, 0.45-0.67) (P for trend < .001). CONCLUSIONS: All kinds of SSRIs were associated with decreased risk of HCC. PMID- 28666061 TI - Conditional neuromodulation of neurogenic detrusor overactivity using transrectal stimulation in patients with spinal cord injury: A proof of principle study. AB - AIMS: A proof of principle study of a novel wearable device to control neurogenic detrusor over-activity in eight male spinal cord injured subjects using conditional neuromodulation. METHODS: Transrectal stimulation was delivered through the device in response to simultaneously recorded external anal sphincter (EAS) contraction as a marker for neurogenic detrusor overactivity (NDO). The effect of conditional neuromodulation on bladder capacity and maximum detrusor pressure was investigated in addition to reliability of dyssynergic sphincter contraction as a marker for NDO. RESULTS: Conditional neuromodulation through the novel device showed a statistically significant increase in bladder capacity and reduction in maximum detrusor pressure in six male subjects with spinal cord injury (SCI). EAS activity was a reliable surrogate for detection of NDO. CONCLUSIONS: It has been shown for the first time that conditional neuromodulation can be delivered and triggered via a single biocompatible device placed in the anal canal. The pudendal nerves lying in Alcock's canal were stimulated through the wall of the anal canal, and the dyssynergic activity of the EAS was used to detect NDO and trigger neuromodulation giving significant increases in bladder capacity and reduction in detrusor pressure in six male subjects with SCI. PMID- 28666062 TI - A populational-based survey on the prevalence, incidence, and risk factors of urinary incontinence in older adults-results from the "SABE STUDY". AB - AIMS: To estimate the prevalence and incidence of urinary incontinence (UI) and identify the associated risk factors in a cohort of elderly individuals in Brazil. METHODS: In 2006, individuals aged >=60 years were selected from the SABE Study (Health, Well-being, and Aging). The dependent variable was reported UI in 2009. UI was assessed using the International Consultation on Incontinence Questionnaire Urinary Incontinence-Short Form (ICIQ-UI SF). Incidence was measured in units of 1000 person-years, and Cox regression was applied for data analysis. Multivariate analysis was used to assess risk factors for UI. Incidence risk ratio (IRR) was used for comparison. RESULTS: This is the first study to examine the incidence of UI in Brazilian elderly individuals. In total, 1413 individuals were included; the mean age was 74.5 years, and 864 (61.8%) participants were female. The risk of UI was greater among women with cancer (other than skin) and among those with diabetes. In men, the risk of UI was greater for those in Instrumental Activities of Daily Living (IADL) category "5 8" and those who self-reported a "fair" health status. The prevalence of UI was 14.2% and 28.2% for men and women, respectively. The incidence rate of UI was 25.6 and 39.3 (*1000 person-years) for men and women, respectively. CONCLUSIONS: The incidence rate of UI among older adults in the Brazilian community was high for elderly individuals. The identified risk factors were diabetes and IADL category 5-8 (women) as well as cancer (other than skin) and self-reported health status (male). PMID- 28666064 TI - Evaluating the Benefits of Adaptation of Critical Infrastructures to Hydrometeorological Risks. AB - Infrastructure adaptation measures provide a practical way to reduce the risk from extreme hydrometeorological hazards, such as floods and windstorms. The benefit of adapting infrastructure assets is evaluated as the reduction in risk relative to the "do nothing" case. However, evaluating the full benefits of risk reduction is challenging because of the complexity of the systems, the scarcity of data, and the uncertainty of future climatic changes. We address this challenge by integrating methods from the study of climate adaptation, infrastructure systems, and complex networks. In doing so, we outline an infrastructure risk assessment that incorporates interdependence, user demands, and potential failure-related economic losses. Individual infrastructure assets are intersected with probabilistic hazard maps to calculate expected annual damages. Protection measure costs are integrated to calculate risk reduction and associated discounted benefits, which are used to explore the business case for investment in adaptation. A demonstration of the methodology is provided for flood protection of major electricity substations in England and Wales. We conclude that the ongoing adaptation program for major electricity assets is highly cost beneficial. PMID- 28666065 TI - A Red-Light-Activated Ruthenium-Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells. AB - We describe two water-soluble ruthenium complexes, [1]Cl2 and [2]Cl2 , that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm-2 ) of red light in an oxygen independent manner. Using a specific NAMPT activity assay, up to an 18-fold increase in inhibition potency was measured upon red-light activation of [2]Cl2 , while [1]Cl2 was thermally unstable. For the first time, the dark and red-light induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O2 ). In skin (A431) and lung (A549) cancer cells, a 3- to 4-fold increase in cytotoxicity was found upon red-light irradiation for [2]Cl2 , whether the cells were cultured and irradiated with 1 % or 21 % O2 . These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient. PMID- 28666066 TI - Ni3 FeN-Supported Fe3 Pt Intermetallic Nanoalloy as a High-Performance Bifunctional Catalyst for Metal-Air Batteries. AB - Electrocatalysts for both the oxygen reduction and evolution reactions (ORR and OER) are vital for the performances of rechargeable metal-air batteries. Herein, we report an advanced bifunctional oxygen electrocatalyst consisting of porous metallic nickel-iron nitride (Ni3 FeN) supporting ordered Fe3 Pt intermetallic nanoalloy. In this hybrid catalyst, the bimetallic nitride Ni3 FeN mainly contributes to the high activity for the OER while the ordered Fe3 Pt nanoalloy contributes to the excellent activity for the ORR. Robust Ni3 FeN-supported Fe3 Pt catalysts show superior catalytic performance to the state-of-the-art ORR catalyst (Pt/C) and OER catalyst (Ir/C). The Fe3 Pt/Ni3 FeN bifunctional catalyst enables Zn-air batteries to achieve a long-term cycling performance of over 480 h at 10 mA cm-2 with high efficiency. The extraordinarily high performance of the Fe3 Pt/Ni3 FeN bifunctional catalyst makes it a very promising air cathode in alkaline electrolyte. PMID- 28666068 TI - Airborne nitric oxide: Inflammatory marker and aerocrine messenger in man. PMID- 28666067 TI - Tornado Warning Perception and Response: Integrating the Roles of Visual Design, Demographics, and Hazard Experience. AB - Recent advancements in severe weather detection and warning dissemination technologies have reduced, but not eliminated, large-casualty tornado hazards in the United States. Research on warning cognition and behavioral response by the public has the potential to further reduce tornado-related deaths and injuries; however, less research has been conducted in this area compared to tornado research in the physical sciences. Extant research in this vein tends to bifurcate. One branch of studies derives from classic risk perception, which investigates cognitive, affective, and sociocultural factors in relation to concern and preparation for uncertain risks. Another branch focuses on psychological, social, and cultural factors implicated in warning response for rapid onset hazards, with attention paid to previous experience and message design. Few studies link risk perceptions with cognition and response as elicited by specific examples of warnings. The present study unites risk perception, cognition, and response approaches by testing the contributions of hypothesized warning response drivers in one set of path models. Warning response is approximated by perceived fear and intended protective action as reported by survey respondents when exposed to hypothetical tornado warning scenarios. This study considers the roles of hazard knowledge acquisition, information-seeking behaviors, previous experience, and sociodemographic factors while controlling for the effects of the visual warning graphic. Findings from the study indicate the primacy of a user's visual interpretation of a warning graphic in shaping tornado warning response. Results also suggest that information-seeking habits, previous tornado experience, and local disaster culture play strong influencing roles in warning response. PMID- 28666071 TI - Highly Syndiotactic or Isotactic Polyhydroxyalkanoates by Ligand-Controlled Yttrium-Catalyzed Stereoselective Ring-Opening Polymerization of Functional Racemic beta-Lactones. AB - Reported herein is the first stereoselective controlled ROP of a specific family of racemic functional beta-lactones, namely 4-alkoxymethylene-beta-propiolactones (BPLOR s). This process is catalyzed by an yttrium complex stabilized by a nonchiral tetradentate amino alkoxy bisphenolate ligand {ONOOR'2 }2- , which features both a good activity and a high degree of control over the molar masses of the resulting functional poly(3-hydroxyalkanoate)s. A simple modification of the R' substituents in ortho and para position on the ligand platform allows for a complete reversal from virtually pure syndioselectivity (Ps up to 0.91 with R'=cumyl) to very high isoselectivity (Pi up to 0.93 with R'=Cl), as supported by DFT insights. This is the first example of a highly isoselective ROP of a racemic chiral beta-lactone. PMID- 28666069 TI - Setting the dry weight and its cardiovascular implications. AB - Volume overload is common and associated with adverse outcomes in the hemodialysis population including systemic hypertension, pulmonary hypertension, left ventricular hypertrophy, and mortality. Since the beginning of the era of maintenance dialysis, prescribing and maintaining a dry weight remains the standard of care for managing volume overload on hemodialysis. Reducing dry weight even by relatively small amounts has been shown to improve blood pressure and has been associated with reductions in left ventricular hypertrophy. Maintaining an adequately low dry weight requires attention to sodium intake and adequate time on dialysis, as well as a high index of suspicion for volume overload. Reducing dry weight can provoke decreased cardiac chamber filling and is associated with risks including intradialytic hypotension. The ideal method to minimize intradialytic morbidity is unknown, but more frequent dialysis should be considered. Experimental methods of assessing volume status may allow identification of patients most likely both to tolerate and to benefit from dry weight reduction, but further study is needed. PMID- 28666070 TI - Reduced risk of hepatocellular carcinoma by achieving a subcirrhotic liver stiffness through antiviral agents in hepatitis B virus-related advanced fibrosis or cirrhosis. AB - BACKGROUND AND AIM: A subcirrhotic range of liver stiffness (sc-LS), assessed by transient elastography, is associated with better outcomes in patients with chronic hepatitis B (CHB). We investigated whether the achievement of sc-LS by antiviral therapy (AVT) reduced the risk of developing hepatocellular carcinoma (HCC) in patients with CHB-related advanced fibrosis or cirrhosis. METHODS: In total, 209 patients with CHB-related advanced fibrosis or cirrhosis, who received paired transient elastography examinations during AVT between 2007 and 2012, were enrolled. The cut-off LS value for ultrasonographic cirrhosis was defined as 11.6 kPa. RESULTS: The median age of the study population was 51 years, with males predominating (n = 138, 66.0%). The median LS value at enrollment was 14.1 kPa (interquartile range: 9.5-24.1 kPa). After 2 years of AVT, 140 (67.0%) patients achieved sc-LS. During the study period, 28 (13.4%) patients developed HCC after 2 years of AVT. On multivariate analysis, the achievement of sc-LS after AVT was independently associated with a decreased risk of HCC development (hazard ratio [HR] = 0.485, P = 0.047), whereas older age (HR = 1.071) and male gender (HR = 3.704) were independently associated with an increased HCC risk (both P < 0.05). Patients with a cirrhotic range of LS value after 2 years of AVT were at a higher risk of HCC development than those with sc-LS (log-rank test, P = 0.020). CONCLUSIONS: The achievement of sc-LS after AVT can reduce the risk of HCC development in patients with CHB, even when advanced fibrosis or cirrhosis is apparent on starting AVT. PMID- 28666072 TI - Special situations: Intradialytic hypertension/chronic hypertension and intradialytic hypotension. AB - Hypertension is a comorbidity that is present in the majority of end-stage renal disease patients on maintenance hemodialysis. This population is particularly unique because of the dynamic nature of blood pressure (BP) during dialysis. Modest BP decreases are expected in most hemodialysis patients, but intradialytic hypotension and intradialytic hypertension are two special situations that deviate from this as either an exaggerated or paradoxical response to the dialysis procedure. Both of these phenomena are particularly important because they are associated with increased mortality risk compared to patients with modest decreases in BP during dialysis. While the detailed pathophysiology is complex, intradialytic hypotension occurs more often in patients prescribed fast ultrafiltration rates, and reducing this rate is recommended in patients that regularly exhibit this pattern. Patients with intradialytic hypertension have a poorly explained increase in vascular resistance during dialysis, but the consistent associations with extracellular volume overload point toward more aggressive fluid management as the initial management choices for these patients. This up to date review provides the most recent evidence supporting these recommendations as well as the most up to date epidemiologic and mechanistic research studies that have added to this area of dialysis management. PMID- 28666073 TI - To cool, or too cool: Is reducing dialysate temperature the optimal approach to preventing intradialytic hypotension? AB - Abnormal decreases in blood pressure during hemodialysis are frequent in end stage renal disease (ESRD) patients treated with hemodialysis, and thought to be largely due to an inadequate cardiovascular response to the rapid blood volume decline. Intradialytic hypotension (IDH) and cardiac instability during dialysis can increase risks for negative health consequences and is possibly preventable though several types of interventions. One intervention that holds promise for prevention of IDH in hemodialysis patients is to reduce the temperature of the dialysate to or below the patient's core temperature. A considerable number of randomized studies have demonstrated a short term benefit of using a cooler dialysate temperature for the prevention of IDH and improved cardiac stability. Despite this, a key observational study was not able to show long term improvements with lower dialysate temperatures utilized in routine clinical practice, albeit possibly confounded by indication. It appears that cooling the dialysate may be reasonable to consider on an individual basis for patients who suffer from persistent IDH if they can tolerate the adjustment and it is effective. However, careful assessment of the etiology of IDH should be performed when considering treatment options. In this review, we detail the current body of evidence on the effectiveness of using low dialysate temperatures for prevention of IDH in ESRD patients, and suggest areas where further research is needed. PMID- 28666074 TI - Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma-A meta-analysis. AB - INTRODUCTION: The use of molecular markers, especially BRAF and TERT promoter mutations, for risk stratification in papillary thyroid carcinoma (PTC) is subject to continuing debate. In this study, we aimed to investigate the clinicopathological implication of each genotype when combining BRAF and TERT promoter mutations in PTCs. METHODS: We searched four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library for relevant studies. Pooled estimates of odds ratios and corresponding 95% confidence intervals were calculated using random-effect model. RESULTS: From 111 results, we finally included 11 studies with 3911 PTC patients for meta-analyses. Our results demonstrated that PTCs with concurrent BRAF and TERT promoter mutations were associated with increased tumour aggressiveness in comparison with PTCs harbouring BRAF or TERT promoter mutation alone. The combination of BRAF and TERT promoter mutations could classify PTCs into four distinct risk groups with decreasing aggressiveness as follows: coexisting BRAF and TERT > TERT alone=BRAF alone > no mutations. CONCLUSION: The risk stratification of PTC based on these four genotypes can help improve the clinical management of PTCs by identifying the group of PTCs with the highest aggressiveness. PMID- 28666075 TI - The effect of treatment time, dialysis frequency, and ultrafiltration rate on intradialytic hypotension. AB - Dialysis treatment time, the frequency of dialysis treatments, and the rate of fluid ultrafiltration-each impacts the incidence of intradialytic hypotension. These factors influence blood pressure independently and together. The strongest evidence supports that rapid ultrafiltration increases the likelihood of intradialytic hypotension and that combined strategies leading to a reduction in ultrafiltration rate have the greatest impact on reducing intradialytic hypotension. A practical approach to avoiding the effects of ultrafiltration on systemic hemodynamics would be to set a maximum ultrafiltration rate needed to achieve the desired fluid removal and vary the duration of the treatment to achieve that target volume. Randomized, controlled clinical trials of such strategies are warranted. PMID- 28666077 TI - Editorial: Is Rheumatoid Arthritis a Mortal Disease? PMID- 28666078 TI - Public Perceptions of How Long Air Pollution and Carbon Dioxide Remain in the Atmosphere. AB - The atmospheric residence time of carbon dioxide is hundreds of years, many orders of magnitude longer than that of common air pollution, which is typically hours to a few days. However, randomly selected respondents in a mail survey in Allegheny County, PA (N = 119) and in a national survey conducted with MTurk (N = 1,013) judged the two to be identical (in decades), considerably overestimating the residence time of air pollution and drastically underestimating that of carbon dioxide. Moreover, while many respondents believed that action is needed today to avoid climate change (regardless of cause), roughly a quarter held the view that if climate change is real and serious, we will be able to stop it in the future when it happens, just as we did with common air pollution. In addition to assessing respondents' understanding of how long carbon dioxide and common air pollution stay in the atmosphere, we also explored the extent to which people correctly identified causes of climate change and how their beliefs affect support for action. With climate change at the forefront of politics and mainstream media, informing discussions of policy is increasingly important. Confusion about the causes and consequences of climate change, and especially about carbon dioxide's long atmospheric residence time, could have profound implications for sustained support of policies to achieve reductions in carbon dioxide emissions and other greenhouse gases. PMID- 28666076 TI - Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential. PMID- 28666079 TI - Factors Influencing the Mechanical Properties of Formamidinium Lead Halides and Related Hybrid Perovskites. AB - The mechanical properties of formamidinium lead halide perovskites (FAPbX3 , X=Br or I) grown by inverse-temperature crystallization have been studied by nanoindentation. The measured Young's moduli (9.7-12.3 GPa) and hardnesses (0.36 0.45 GPa) indicate good mechanical flexibility and ductility. The effects of hydrogen bonding were evaluated by performing ab initio molecular dynamics on both formamidinium and methylammonium perovskites and calculating radial distribution functions. The structural and chemical factors influencing these properties are discussed by comparison with corresponding values in the literature for other hybrid perovskites, including double perovskites. Our results reveal that bonding in the inorganic framework and hydrogen bonding play important roles in determining elastic stiffness. The influence of the organic cation becomes more important for structures at the limit of their perovskite stability, indicated by high tolerance factors. PMID- 28666080 TI - A Phase III Study Evaluating Continuation, Tapering, and Withdrawal of Certolizumab Pegol After One Year of Therapy in Patients With Early Rheumatoid Arthritis. AB - OBJECTIVE: In disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) who had achieved sustained low disease activity (a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate of <=3.2 at both week 40 and week 52) after 1 year of treatment with certolizumab pegol (CZP) at a standard dose (200 mg every 2 weeks plus optimized methotrexate [MTX]), we evaluated whether continuation of CZP treatment at a standard dose or at a reduced frequency (200 mg every 4 weeks plus MTX) was superior to stopping CZP (placebo plus MTX) in maintaining low disease activity for 1 additional year. METHODS: A total of 293 patients from period 1 of our study were re-randomized 2:3:2 in period 2 to CZP at a standard dose (n = 84), CZP at a reduced frequency (n = 127), or placebo plus MTX (CZP stopped) (n = 82). The primary end point was the percentage of patients who maintained low disease activity throughout weeks 52-104 without flares. We used a hierarchical testing scheme, comparing CZP at a standard dose with CZP stopped. If P < 0.05 was achieved, then CZP at a reduced frequency was compared with CZP stopped (nonresponder imputation). RESULTS: The 293 patients from period 1 represented 36% fewer patients than projected, yielding a smaller number of patients eligible for period 2. Higher proportions of patients treated with the standard and reduced frequency regimens maintained low disease activity than those who had stopped CZP (48.8% and 53.2%, respectively, versus 39.2% [P = 0.112 and P = 0.041, respectively; nominal P value, first hierarchical test not significant]). Similar trends were observed for radiographic nonprogression (change from baseline of <=0.5 in modified Sharp/van der Heijde score; 79.2% and 77.9% of patients, respectively, versus 70.3%) and normative physical function (Health Assessment Questionnaire disability index score of <=0.5; 71.4% and 70.6% of patients, respectively, versus 57.0%). Safety profiles were similar between all groups, with no new safety signals identified for continuing CZP to week 104. No deaths were reported. CONCLUSION: The study failed to meet its primary end point. However, there were no clinically meaningful differences between the standard and reduced frequency doses of CZP plus MTX; both controlled RA more effectively than stopping CZP. PMID- 28666081 TI - Major Histocompatibility Complex Class II Alleles Influence Induction of Pathogenic Antiphospholipid Antibodies in a Mouse Model of Thrombosis. AB - OBJECTIVE: Both environmental and genetic factors are important in the development of antiphospholipid antibodies (aPL) in patients with antiphospholipid syndrome (APS). Currently, the only available data on predisposing genetic factors have been obtained from epidemiologic studies, without mechanistic evidence. Therefore, we studied the influence of major histocompatibility complex (MHC) class II alleles on the production of aPL in a mouse model of APS. METHODS: Three groups of mice, MHC class II-deficient (MHCII /- ) mice, MHCII-/- mice transgenic for human HLA-DQ6 (DQ6), DQ8, or DR4 alleles, and the corresponding wild-type (WT) mouse strains were immunized; half were immunized with human beta2 -glycoprotein I (beta2 GPI), and the other half were immunized with control ovalbumin (OVA) protein. Thrombus formation in vivo, tissue factor activity in carotid and peritoneal macrophages, and serum levels of tumor necrosis factor (TNF), IgG anticardiolipin (aCL), antibodies, and anti-OVA antibodies were determined. RESULTS: Immunization with beta2 GPI induced significant production of aCL and anti-beta2 GPI in WT mice compared with control mice immunized with OVA (P < 0.001) but diminished aCL (P < 0.001) and anti-beta2 GPI (P = 0.016) production in MHCII-/- mice. Anti-beta2 GPI production was fully restored in DQ6 and DQ8 mice, while levels of anti-beta2 GPI in DR4 mice and aCL in all transgenic lines were only partially restored (P < 0.001 to P < 0.046). Thrombus size in WT mice was twice that in MHCII-/- mice (P < 0.001) but similar to that in all transgenic lines. Carotid and peritoneal macrophage tissue factor levels decreased by >50% in MHCII-/- mice compared with wild-type B6 mice and were restored in DQ8 mice but not DR4 mice or DQ6 mice. TNF levels decreased 4 fold in MHCII-/- mice (P < 0.001) and were not restored in transgenic mice. CONCLUSION: Our mechanistic study is the first to show that MHC class II alleles influence not only quantitative aPL production but also the pathogenic capacity of induced aPL. PMID- 28666082 TI - Intradialytic hypotension in acute kidney injury requiring renal replacement therapy. AB - The treatment of severe acute kidney injury (AKI) with dialytic support for renal replacement therapy can be life sustaining and permit recovery from critical illness. Like any interventional therapy, however, renal replacement therapy with intermittent hemodialysis or continuous therapy can cause complications. Intradialytic hypotension is a common complication and can cause further ischemic injury to the recovering kidneys, thereby reducing the probability of renal recovery. The optimal dialytic technique-continuous or intermittent-has not been conclusively demonstrated in randomized controlled trials. In general, treatment or prophylactic strategies for intradialytic hypotension in AKI have not been comprehensively tested. Given the frequency of intradialytic hypotension in dialytic treatment of AKI and its adverse clinical consequences, future research should rigorously compare dialytic techniques and other prevention strategies in adequately powered, randomized controlled trials. PMID- 28666083 TI - Maternal thyroid function, prepregnancy obesity and gestational weight gain-The Generation R Study: A prospective cohort study. AB - OBJECTIVE: Maternal prepregnancy obesity and excessive gestational weight gain are associated with pregnancy complications. Thyroid function is related to differences in body mass index (BMI) in adult populations. We examined the associations of maternal thyroid function in early pregnancy with maternal BMI and weight gain during pregnancy. DESIGN AND METHODS: In a population-based prospective cohort study among 5726 mothers, we measured maternal TSH and FT4 levels at 13.5 weeks of gestation (95% range: 9.7-17.6 weeks). Maternal weight was assessed before pregnancy and in each trimester. RESULTS: Higher maternal TSH levels were associated with higher prepregnancy BMI (difference: 0.18 kg/m2 [95% CI: 0.01, 0.36] per SD increase in maternal TSH level) and higher total gestational weight gain (difference: 0.02 kg/wk [95% CI: 0.01, 0.03] per SD increase in maternal TSH level). Higher maternal FT4 levels were associated with lower prepregnancy BMI (difference: -0.44 kg/m2 [95% CI: -0.63, -0.26] per SD increase in maternal FT4 level) and lower total gestational weight gain (difference: -0.01 kg/wk [95% CI: -0.02, -0.01] per SD increase in maternal FT4 level). The associations of maternal thyroid function with weight gain in early pregnancy were stronger than those with weight gain in mid and late-pregnancy. Maternal hypothyroidism was associated with higher prepregnancy BMI and early pregnancy weight gain, whereas opposite effects were observed for maternal hyperthyroidism (P<.05). CONCLUSIONS: Higher maternal TSH level and lower FT4 level in early pregnancy are associated with higher prepregnancy BMI and higher gestational weight gain. Further studies are needed to explore maternal and foetal consequences. PMID- 28666085 TI - Effect of Solid-State Polarization on Charge-Transfer Excitations and Transport Levels at Organic Interfaces from a Screened Range-Separated Hybrid Functional. AB - We develop a robust approach for the description of the energetics of charge transfer (CT) excitations and transport levels at organic interfaces based on a screened range-separated hybrid (SRSH) functional. We find that SRSH functionals correctly capture the effect of solid-state electronic polarization on transport gap renormalization and on screening of the electrostatic electron-hole interaction. With respect to calculations based on nonscreened optimally tuned RSH (long-range corrected) functionals, the SRSH-based calculations can be performed for both isolated molecular complexes and systems embedded in a dielectric medium with the same range-separation parameter, which allows a clear physical interpretation of the results in terms of solid-state polarization without any perturbation of the molecular electronic structure. By considering weakly interacting donor/acceptor complexes of pentacene with C60 and poly-3 hexylthiophene (P3HT) with PCBM, we show that this new approach provides CT-state energies that compare very well with experimental data. PMID- 28666084 TI - Bacterial Cell Mechanics. AB - Cellular mechanical properties play an integral role in bacterial survival and adaptation. Historically, the bacterial cell wall and, in particular, the layer of polymeric material called the peptidoglycan were the elements to which cell mechanics could be primarily attributed. Disrupting the biochemical machinery that assembles the peptidoglycan (e.g., using the beta-lactam family of antibiotics) alters the structure of this material, leads to mechanical defects, and results in cell lysis. Decades after the discovery of peptidoglycan synthesizing enzymes, the mechanisms that underlie their positioning and regulation are still not entirely understood. In addition, recent evidence suggests a diverse group of other biochemical elements influence bacterial cell mechanics, may be regulated by new cellular mechanisms, and may be triggered in different environmental contexts to enable cell adaptation and survival. This review summarizes the contributions that different biomolecular components of the cell wall (e.g., lipopolysaccharides, wall and lipoteichoic acids, lipid bilayers, peptidoglycan, and proteins) make to Gram-negative and Gram-positive bacterial cell mechanics. We discuss the contribution of individual proteins and macromolecular complexes in cell mechanics and the tools that make it possible to quantitatively decipher the biochemical machinery that contributes to bacterial cell mechanics. Advances in this area may provide insight into new biology and influence the development of antibacterial chemotherapies. PMID- 28666086 TI - Periodic Arrays of Phosphorene Nanopores as Antidot Lattices with Tunable Properties. AB - A tunable band gap in phosphorene extends its applicability in nanoelectronic and optoelectronic applications. Here, we propose to tune the band gap in phosphorene by patterning antidot lattices, which are periodic arrays of holes or nanopores etched in the material, and by exploiting quantum confinement in the corresponding nanoconstrictions. We fabricated antidot lattices with radii down to 13 nm in few-layer black phosphorus flakes protected by an oxide layer and observed suppression of the in-plane phonon modes relative to the unmodified material via Raman spectroscopy. In contrast to graphene antidots, the Raman peak positions in few-layer BP antidots are unchanged, in agreement with predicted power spectra. We also use DFT calculations to predict the electronic properties of phosphorene antidot lattices and observe a band gap scaling consistent with quantum confinement effects. Deviations are attributed primarily to self passivating edge morphologies, where each phosphorus atom has the same number of bonds per atom as the pristine material so that no dopants can saturate dangling bonds. Quantum confinement is stronger for the zigzag edge nanoconstrictions between the holes as compared to those with armchair edges, resulting in a roughly bimodal band gap distribution. Interestingly, in two of the antidot structures an unreported self-passivating reconstruction of the zigzag edge endows the systems with a metallic component. The experimental demonstration of antidots and the theoretical results provide motivation to further scale down nanofabrication of antidots in the few-nanometer size regime, where quantum confinement is particularly important. PMID- 28666088 TI - Dynamic Changes of Disinfection Byproduct Precursors following Exposures of Microcystis aeruginosa to Wildfire Ash Solutions. AB - Wildfires can elevate dissolved organic matter (DOM) levels due to ash input and algal growth in source waters, and consequently impacting disinfection byproduct (DBP) formation in finished water; however, it remains unclear how quality and quantity of overall allochthonous and autochthonous DOM as well as associated DBP formation are changed during an entire algal life cycle. Microcystis aeruginosa was cultured in the medium containing low and high concentrations [10% and 65% (v/v)] of black and white ash water extracts (BE and WE) to study dynamic changes of carbonaceous, nitrogenous, and oxygenated DBP precursors during algal growth. DOM was characterized by absorption and fluorescence spectroscopy and chlorination/chloramination-based DBP formation experiments. Throughout the entire experiment, C-DBP precursors in the control ranged from 2.41 to 3.09 mmol/mol-C. In the treatment with 10% BE, the amount of C-DBP precursors decreased from 6.8 to 3.0 mmol/mol-C at initial-exponential phase then increased to 4.2 mmol/mol-C at death phase. The same trend was observed for O-DBP precursors. However, these dynamic changes of C- and O-DBP precursors exhibited opposite patterns in 65% extracts. Similar patterns were also observed in the WE treatments. On the other hand, N-DBP precursors continuously declined in all treatments. These results indicate that postfire ash loading and algal bloom stage may significantly affect DBP formation in source water. PMID- 28666089 TI - De Novo Development of Hamartomatous Duodenal Polyps in a Patient With Short Bowel Syndrome During Teduglutide Therapy: A Case Report. AB - Teduglutide (TG) is approved for the treatment of parenteral nutrition (PN) dependent adult patients with short bowel syndrome (SBS). Its well-known adverse effect is expedited growth of colon polyps and potential formation of new polyps. Apart from animal studies, de novo development of duodenal polyps in a patient during TG therapy has not been reported in the literature. We report a case of a 71-year-old man with SBS on TG who developed multiple new duodenal polyps that were found incidentally during a diagnostic endoscopy. Furthermore, an accelerated growth of duodenal polyps was noted while on TG therapy, suggesting a potential trophic effect of TG on these polyps. There are no current recommendations for the surveillance of intestinal polyps in patients on TG therapy, but we recommend exercising caution and possible need for surveillance based on this case report. PMID- 28666090 TI - Emerging role of immunotherapy in precursor B-cell acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia that carries poor prognosis in adults especially in the setting of high risk cytogenetics and relapsed/refractory (R/R) disease. Advancements in immunotherapy have led to the development of several monoclonal antibodies (MoAbs) and chimeric antigen receptor (CAR) T cells that are capable of targeting certain surface antigens on leukemic cells, resulting in their destruction. Areas covered: This article reviews the mechanism of action, outcomes of various trials, and adverse effects of MoAbs and CAR-T cells used in the treatment of precursor B-cell ALL. Expert commentary: Some of the immunotherapeutic agents that have been approved for the treatment of R/R precursor B-cell ALL have shown superior efficacy and safety profile compared to chemotherapy in advanced disease. Several trials are now being conducted to evaluate the role of certain MoAbs in combination with chemotherapy in the treatment of B-cell ALL. Additionally, their use in the frontline setting with more favorable host characteristics may also result in superior outcomes compared to the current standard of care. PMID- 28666091 TI - A Combined Use of Intravoxel Incoherent Motion MRI Parameters Can Differentiate Early-Stage Hepatitis-b Fibrotic Livers from Healthy Livers. AB - This study investigated a combined use of intravoxel incoherent motion (IVIM) parameters, Dslow ( D), PF ( f), and Dfast ( D*), for liver fibrosis evaluation. Sixteen healthy volunteers (F0) and 33 hepatitis-b patients (stage F1 = 15, stage F2-4 = 18) were included. With a 1.5 T MR scanner and respiration gating, IVIM diffusion-weighted imaging was acquired using a single-shot echo-planar imaging sequence with 10 b values of 10, 20, 40, 60, 80, 100, 150, 200, 400, and 800 s/mm2. Signal measurement was performed on right liver parenchyma. With a three dimensional tool, Dslow, PF, and Dfast values were placed along the x axis, y axis, and z axis, and a plane was defined to separate healthy volunteers from patients. The three-dimensional tool demonstrated that healthy volunteers and all patients with liver fibrosis could be separated. Classification and regression tree showed that a combination of PF (PF < 12.55%), Dslow (Dslow < 1.152 * 10-3 mm2/s), and Dfast (Dfast < 13.36 * 10-3 mm2/s) could differentiate healthy subjects and all fibrotic livers (F1-4) with an area under the curve of logistic regression (AUC) of 0.986. The AUC for differentiation of healthy livers versus F2-4 livers was 1. PF offered the best diagnostic value, followed by Dslow; however, all three parameters of PF, Dslow, and Dfast contributed to liver fibrosis detection. PMID- 28666087 TI - Crowding in Cellular Environments at an Atomistic Level from Computer Simulations. AB - The effects of crowding in biological environments on biomolecular structure, dynamics, and function remain not well understood. Computer simulations of atomistic models of concentrated peptide and protein systems at different levels of complexity are beginning to provide new insights. Crowding, weak interactions with other macromolecules and metabolites, and altered solvent properties within cellular environments appear to remodel the energy landscape of peptides and proteins in significant ways including the possibility of native state destabilization. Crowding is also seen to affect dynamic properties, both conformational dynamics and diffusional properties of macromolecules. Recent simulations that address these questions are reviewed here and discussed in the context of relevant experiments. PMID- 28666092 TI - Characterization of genome in tetraploid StY species of Elymus (Triticeae: Poaceae) using sequential FISH and GISH. AB - Genomes of ten species of Elymus, either presumed or known as tetraploid StY, were characterized using fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH). These tetraploid species could be grouped into three categories. Type I included StY genome reported species-Roegneria pendulina, R. nutans, R. glaberrima, R. ciliaris, and Elymus nevskii, and StY genome presumed species-R. sinica, R. breviglumis, and R. dura, whose genome could be separated into two sets based on different GISH intensities. Type I genome constitution was deemed as putative StY. The St genome were mainly characterized with intense hybridization with pAs1, fewer AAG sites, and linked distribution of 5S rDNA and 18S-26S rDNA, while the Y genome with less intense hybridization with pAs1, more varied AAG sites, and isolated distribution of 5S rDNA and 18S-26S rDNA. Nevertheless, further genomic variations were detected among the different StY species. Type II included E. alashanicus, whose genome could be easily separated based on GISH pattern. FISH and GISH patterns suggested that E. alashanicus comprised a modified St genome and an unknown genome. Type III included E. longearistatus, whose genome could not be separated by GISH and was designated as StlYl. Notably, a close relationship between Sl and Yl genomes was observed. PMID- 28666093 TI - The impact of moderate altitude on exercise metabolism in recreational sportsmen: a nuclear magnetic resonance metabolomic approach. AB - Although it is known that altitude impairs performance in endurance sports, there is no consensus on the involvement of energy substrates in this process. The objective of the present study was to determine whether the metabolomic pathways used during endurance exercise differ according to whether the effort is performed at sea level or at moderate altitude (at the same exercise intensity, using proton nuclear magnetic resonance, 1H NMR). Twenty subjects performed two 60-min endurance exercise tests at sea level and at 2150 m at identical relative intensity on a cycle ergometer. Blood plasma was obtained from venous blood samples drawn before and after exercise. 1H NMR spectral analysis was then performed on the plasma samples. A multivariate statistical technique was applied to the NMR data. The respective relative intensities of the sea level and altitude endurance tests were essentially the same when expressed as a percentage of the maximal oxygen uptake measured during the corresponding incremental maximal exercise test. Lipid use was similar at sea level and at altitude. In the plasma, levels of glucose, glutamine, alanine, and branched-chain amino acids had decreased after exercise at altitude but not after exercise at sea level. The decrease in plasma glucose and free amino acid levels observed after exercise at altitude indicated that increased involvement of the protein pathway was necessary but not sufficient for the maintenance of glycaemia. Metabolomics is a powerful means of gaining insight into the metabolic changes induced by exercise at altitude. PMID- 28666094 TI - Alcohol extract of North American ginseng (Panax quinquefolius) reduces fatty liver, dyslipidemia, and other complications of metabolic syndrome in a mouse model. AB - We investigated whether North American ginseng (Panax quinquefolius) could reduce development of the metabolic syndrome phenotype in a mouse model (ETKO) of the disease. Young ETKO mice have no disease but similar to humans start to develop the fatty liver, hypertriglyceridemia, obesity, and insulin resistance at 25-30 weeks of age, and the disease continues to progress with ageing. ETKO mice were orally given an ethanol extract of ginseng roots at 4 and 32 weeks of age. Treatments with ginseng eliminated the ETKO fatty liver, reduced hepatic and intestinal lipoprotein secretion, and reduced the level of circulating lipids. Improvements by ginseng treatments were manifested as a reduction in the expression of genes involved in the regulation of fatty acid and triglyceride (fat) synthesis and secretion by the lipoproteins on one hand, and the stimulation of fatty acid oxidation and triglyceride degradation by lipolysis on the other hand. These processes altogether improved glucose, fatty acid, and triglyceride metabolism, reduced liver fat load, and reversed the progression of metabolic syndrome. These data confirm that treatments with North American ginseng could alleviate metabolic syndrome through the maintenance of a better balance between glucose and fatty acid metabolism, lipoprotein secretion, and energy homeostasis in disease-prone states. PMID- 28666095 TI - Efficacy of Early Enteral Immunonutrition on Immune Function and Clinical Outcome for Postoperative Patients With Gastrointestinal Cancer. AB - BACKGROUND: Nutrition support is crucial for patients with gastrointestinal (GI) cancer after the operation. However, the controversy over the application of parenteral nutrition (PN) and early enteral immunonutrition (EEIN) has no determinate conclusion. MATERIALS AND METHODS: We compared the effects of PN and EEIN on the postoperative nutrition condition, immune status, inflammation level, long-term survival, and quality of life of the patients with GI cancer. Seventy eight patients were randomly divided into the PN group (n = 44) or EEIN group (n = 34). After an 8-day nutrition treatment, clinical and immunological parameters were evaluated. RESULTS: The EEIN group had a significantly shorter hospital stay and higher body mass index level on postoperative day 30 than those in the PN group ( P < .05). However, total hospital cost and incidences of short-term postoperative complications had no significant difference ( P > .05). The percentages of CD4+, natural killer, and natural killer T lymphocyte cells and the ratio of CD4+/CD8+ in peripheral blood were significantly increased. Compared with the PN group, the EEIN group had a higher expression of activated cell surface markers such as CD27 and CD28. In addition, the secretion of interleukin (IL)-2 and interferon-gamma was significantly higher, and the secretion of tumor necrosis factor-alpha and IL-10 was lower. Complication-free survival in the EEIN group were longer than those in the PN group ( P = .04). CONCLUSION: EEIN is superior to PN in improving nutrition status, enhancing immune function, and elevating quality of life. PMID- 28666096 TI - A Comparative Study on the Efficacy of Submucosal Injection of Dexamethasone Versus Methylprednisolone in Reducing Postoperative Sequelae After Third Molar Surgery. AB - PURPOSE: To compare the efficacy of preoperative submucosal injection of 4 mg of dexamethasone versus 40 mg of methylprednisolone in reducing postoperative sequelae after surgical removal of impacted mandibular third molars. PATIENTS AND METHODS: This prospective, randomized, double-blind study included 65 patients who required surgical removal of impacted mandibular third molars with Class II or position B impaction (Pell and Gregory classification). Patients were randomly assigned to 1 of 3 groups: dexamethasone, methylprednisolone, or placebo (control). Surgery was performed with patients under local anesthesia. Baseline measurements were obtained preoperatively, and subsequent assessments were made on postoperative day 1, 2, 5, and 7 to measure postoperative facial swelling by use of 2 linear measurements: interincisal mouth opening width and visual analog scale score for pain. The amount of analgesics consumed was recorded. Wound healing also was assessed on postoperative day 7. Descriptive and multivariate statistics were computed, and significance was set at P < .05. RESULTS: Both methylprednisolone and dexamethasone significantly reduced swelling and trismus (P < .05, Kruskal-Wallis test), whereas the methylprednisolone group had significantly less pain (P < .05, Kruskal-Wallis test) and consumed a lower amount of analgesics (P < .05, chi2 test) during the early postoperative days. CONCLUSIONS: The study findings suggest that a single preoperative dose of dexamethasone versus methylprednisolone was equally effective in reducing postoperative swelling and trismus. Pain control by these corticosteroids, however, was variable. PMID- 28666097 TI - Novel Transgenic Mouse Model of Polycystic Kidney Disease. AB - Transmembrane protein 207 (TMEM207) is characterized as an important molecule for invasiveness of gastric signet-ring cell carcinoma cells. To clarify the pathobiological effects of TMEM207, we generated 13 transgenic mouse strains, designated C57BL/6-transgenic (Tg) (ITF-TMEM207), where the mouse Tmem207 is ectopically expressed under the proximal promoter of the murine intestinal trefoil factor gene. A C57BL/6-Tg (ITF-TMEM207) mouse strain unexpectedly exhibited a high incidence of spontaneous kidney cysts with histopathological features resembling human polycystic kidney disease, which were found in approximately all mice within 1 year. TMEM207 immunoreactivity was found in noncystic kidney tubules and in renal cysts of the transgenic mice. The ITF TMEM207 construct was inserted into Mitf at chromosome 6. Cystic kidney was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse strains. Although several genetically manipulated animal models exist, this mouse strain harboring a genetic mutation in Mitf and overexpression of Tmem207 protein was not reported as a model of polycystic kidney disease until now. This study demonstrates that the C57BL/6-Tg (ITF-TMEM207) mouse may be a suitable model for understanding human polycystic kidney disease. PMID- 28666098 TI - Anti-RhoJ antibody functionalized Au@I nanoparticles as CT-guided tumor vessel targeting radiosensitizers in patient-derived tumor xenograft model. AB - The clinical success of radiotherapy is greatly hampered due to its intolerable off-target cytotoxicity induced by the high dose of radiation. Meanwhile, low dose of irradiation greatly potentiates the intratumoral angiogenesis, which promotes the local relapse and metastasis of tumor. Therefore, it is essential to reduce the irradiation dosage while inhibiting the tumor angiogenesis during radiotherapy. In this work, tumor vessel specific ultrafine Au@I nanoparticles (AIRA NPs) are fabricated and used as targeted radiosensitizers. Due to the presence of Au and iodine, these AIRA NPs exhibit superb X-ray attenuation for contrast-enhanced computed tomography (CT). Once injected, these AIRA NPs bind specifically to both newly formed tumor vessels in peri- and intratumoral regions and pre-existing tumor vessels. Upon radiation under CT guidance, AIRA NPs remarkably enhanced the killing efficacy against tumors in vivo with respect to radiation alone or anti-angiogenesis chemotherapy. Meanwhile, down-regulation of the level of circulating VEGF cytokine further indicates that our strategy can eradicate tumor without risking the recurrence of hypoxia and angiogenesis. Our demonstration provides a robust method of cancer therapy integrating good biocompatibility, high specificity and relapse-free manner alternative to traditional metal NPs enhanced radiotherapy. PMID- 28666099 TI - Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth in vitro and in orthotopic murine. AB - Small active RNA (saRNA)-induced gene activation (RNAa) is a novel strategy to treat cancer. Our previous work proved that the p21-saRNA-322 successfully hindered colorectal cancer growth by activating p21 gene. However, the barrier for successful saRNA therapy is lack of efficient drug delivery. In the present study, a rectal delivery system entitled p21-saRNA-322 encapsulated tumor selective lipopolyplex (TSLPP-p21-saRNA-322) which consist of PEI/p21-saRNA-322 polyplex core and hyaluronan (HA) modulated lipid shell was developed to treat colorectal cancer. Our results showed that this system maintained at the rectum for more than 6 h and preferentially accumulated at tumor site. CD44 knock down experiment instructed that the superb cellular uptake of TSLPP-p21-saRNA-322 attributed to HA-CD44 recognition. An orthotopic model of bio-luminescence human colorectal cancer in mice was developed using microsurgery and TSLPP-p21-saRNA 322 demonstrated a superior antitumor efficacy in vitro and in vivo. Our results provide preclinical proof-of-concept for a novel method to treat colorectal cancer by rectal administration of TSLPP formulated p21-saRNA-322. PMID- 28666100 TI - Augmented glioma-targeted theranostics using multifunctional polymer-coated carbon nanodots. AB - Overcoming biological barriers to imaging-guided site-specific delivery of therapeutics is the goal of current nanomedicine designs. Here, multifunctional polymer-coated carbon nanodots with an interleukin-6 (IL-6) fragment peptide for receptor-targeting (pCDPI) were prepared for drug delivery. The pCDPI exhibits small hydrodynamic diameters, high water solubility and biocompatibility. In vitro and in vivo results demonstrated that pCDPI can overcome the blood-brain barrier (BBB) and deeply penetrate into orthotopic glioma in mice, to inhibit IL 6-induced cell proliferation and achieve imaging-guided targeted drug delivery. Simultaneously, a pH-sensitive sustained release of doxorubicin (DOX) accompanied with real-time fluorescence monitoring was realized. A distinct synergistic therapeutic outcome could be achieved which suggests the presented nanomedicine having promising potential for future cancer treatments. PMID- 28666101 TI - NIR-triggered high-efficient photodynamic and chemo-cascade therapy using caspase 3 responsive functionalized upconversion nanoparticles. AB - Stimuli-responsive nanoparticles with multiple therapeutic/diagnostic functions are highly desirable for effective tumor treatment. Herein novel caspase-3 responsive functionalized upconversion nanoparticles (CFUNs) were fabricated with three-in-one functional integration: near-infrared (NIR) triggered photodynamic damage along with caspase-3 activation, subsequent caspase-3 responsive drug release, and cascade chemotherapeutic activation. CFUNs were formulated from the self-assembly of caspase-3 responsive doxorubicin (DOX) prodrug tethered with DEVD peptide (DEVD-DOX), upconversion nanoparticles (UCNP), a photosensitizer (pyropheophorbide-a methyl ester, MPPa), and tumor-targeting cRGD-PEG-DSPE to afford multifunctional CFUNs, MPPa/UCNP-DEVD-DOX/cRGD. Upon cellular uptake and NIR irradiation, the visible light emission of UCNP could excite MPPa to produce reactive oxygen species for photodynamic therapy (PDT) along with the activation of caspase-3, which further cleaved DEVD peptide to release DOX within tumor cells, thus accomplishing NIR-triggered PDT and cascade chemotherapy. CFUNs presented silent therapeutic potency and negligible cytotoxicity in the dark, whereas in vitro and in vivo experiments demonstrated the NIR-triggered cascade therapeutic activation and tumor inhibition due to consecutive PDT and chemotherapy. Current NIR-activated cascade tumor therapy with two distinct mechanisms is significantly favorable to overcome multidrug resistance and tumor heterogeneity for persistent tumor treatment. PMID- 28666102 TI - Corrigendum to "Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCdelta pathway" Cancer Lett. 385 (28 Jan 2017) 261-270. PMID- 28666103 TI - Kuwait bone marrow transplantation activities. AB - Kuwait is located in the Arabian Gulf and has a population of 3.5million. The stem cell transplantation program started in 2000. Autologous peripheral blood stem cell transplantation started first, as it was easier technically to establish. In 2011, the allogeneic program started with focus on acute leukemia and hemoglobinopathies. The success of both programs required teamwork and support of health planners. The Kuwait National Bone Marrow Registry was established in 2012. The issue of donor availability and drug shortage remain the two main obstacles for expanding the bone marrow transplantation program. PMID- 28666104 TI - Hematopoietic stem cell transplantation for acute myeloid leukemia: A review. AB - Increasing numbers of patients are receiving allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Scientific and clinical advances in supportive care, donor selection, and conditioning regimens have resulted in lower transplant-related mortality, extension of care to a wider population of patients, and improvements in survival. Recent era has witnessed an explosive information about the molecular pathophysiology of AML. By early identification of patients at a high risk of relapse, it is expected that a majority of eligible patients will receive HCT in first complete remission. Novel conditioning regimens have been explored to improve transplant outcomes in AML. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. This area of investigation will likely continue to be of intense interest in terms of optimizing transplant outcomes. PMID- 28666105 TI - Comparison of pancreatic beta cells and alpha cells under hyperglycemia: Inverse coupling in pAkt-FoxO1. AB - Type 2 diabetes manifests beta cell deficiencies and alpha cell expansion which is consistent with relative insulin deficiency and glucagon oversecretion. The effects of hyperglycemia on alpha cells are not as understood in comparison to beta cells. Hyperglycemia increases oxidative stress, which induces Akt activation or FoxO activation, depending on cell type. Several studies independently reported that FoxO1 translocations in alpha cells and beta cells were opposite. We compared the responses of pancreatic alpha cells and beta cells against hyperglycemia. Alpha TC-1 cells and Beta TC-6 cells were incubated with control (5mM Glucose) or high glucose (33mM Glucose) with or without PI3K inhibitor or FoxO1 inhibitor. We assessed PI3K, pAkt and phosphorylated FoxO1 (pFoxO1) in both cell lines. Immunostaining of BrdU and FoxO1 was detected by green fluorescence microscopy and confocal microscopy. Hyperglycemia and H2O2 decreased PI3K and pAKT in beta cells, but increased them in alpha cells. FoxO1 localizations and pFoxO1 expressions between alpha cells and beta cells were opposite. Proliferation of beta cells was decreased, but alpha cell proliferation was increased under hyperglycemia. Antioxidant enzymes including superoxide dismutase (SOD) and catalase were increased in beta cells and they were reversed with FoxO1 inhibitor treatment. Increased proliferation in alpha cells under hyperglycemia was attenuated with PI3K inhibitor. In conclusion, hyperglycemia increased alpha cell proliferation and glucagon contents which are opposite to beta cells. These differences may be related to contrasting PI3K/pAkt changes in both cells and subsequent FoxO1 modulation. PMID- 28666106 TI - Super high sensitive plate acoustic wave humidity sensor based on graphene oxide film. AB - The changes of density and elastic modules due to water vapor adsorption are measured for graphene oxide film at room temperature. Dominant mechanism for acoustic wave humidity sensing by the film is shown to be related with variation of its electric conductivity. Basing on the data, super high sensitive humidity sensor employing high-order Lamb wave with large coupling constant, standard lithium niobate plate, and graphene oxide sorbent film is developed. The minimal detectable level of the sensor is as low 0.03% RH, response times are 60/120s, and reproducibility is +/-2.5%. The sensor is completely selective towards H2, CO, CH4, NO, O2. PMID- 28666107 TI - Properties of context-driven control revealed through the analysis of sequential congruency effects. AB - The context specific proportion congruent (CSPC) effect refers to the reduction in the size of the congruency effect at locations with a high proportion of incongruent trials compared to locations with a high proportion of congruent trials. The CSPC effect is commonly taken as evidence for context-driven modulation of cognitive control. Current models of context-driven control suggest that variations in the efficiency of control across locations are due to variations in the occurrence of conflict across locations (context). Moreover, these models predict that control settings are updated on a trial-to-trial basis. In Experiment 1, we investigated this prediction. If variations in conflict drive variations in the efficiency of control, and these location-based control settings are updated on each trial, then the occurrence of conflict at one location should lead to more efficient processing when the location repeats, but not when the location switches. Consistent with this prediction, we observed a sequential congruency effect when the location repeats, but not when the location switches. In Experiment 2, we looked for evidence of sequential congruency effects within and between locations in a manipulation in which an equal proportion of congruent and incongruent trials appear at each location. In contrast to the results of Experiment 1, we observed sequential congruency effects both when location repeated and when location switched. Thus, location appears to be a salient dimension on which to implement control settings when it is used in conjunction with variations in the proportion of congruent and incongruent trials. PMID- 28666108 TI - Effect of oregano essential oil supplementation to a reduced-protein, amino acid supplemented diet on meat quality, fatty acid composition, and oxidative stability of Longissimus thoracis muscle in growing-finishing pigs. AB - This study investigated the effects of reduced-protein, amino acid-supplemented diet supplementation with oregano essential oil (OEO) in pigs, from growing period to slaughter, on the meat quality, fatty acid composition, and oxidative stability of Longissimus thoracis (LT) muscle. Thirty-six barrows were randomly divided into three experimental treatments, namely, normal protein diet (NPD), reduced-protein, amino acid-supplemented diet (RPD), and identical RPD supplemented (250mg/kg feed) with OEO (OEO) treatments. Dietary RPD and OEO increased the b*45min, tenderness, overall acceptance, and intramuscular fat (IMF) content of pork compared with dietary NPD. The percentage of n-3 polyunsaturated fatty acid (n-3 PUFA) and the percentage of monounsaturated fatty acid in OEO muscle were higher and lower than those in RPD muscle, respectively. Dietary OEO improved oxidative stability, total antioxidative capacity, and catalase but decreased drip loss in LT muscle. Results indicated that dietary OEO enhanced the sensory attributes and anti-oxidative status of pork meat by improving IMF and n-3 PUFA proportion and antioxidative capacity. PMID- 28666109 TI - Subspecies and diet affect the expression of genes involved in lipid metabolism and chemical composition of muscle in beef cattle. AB - Fourteen Nellore and 14 Angus young bulls with BW of 381+/-11.8kg were randomly assigned into 2 feeding groups (whole shelled corn without forage (WSC) or corn silage and ground corn (GC)) to evaluate chemical composition and expression of genes involved in lipid metabolism in the longissimus thoracis (LT). We hypothesized that bulls fed the WSC diet have greater amounts of intramuscular fat and Angus have higher expression levels of PPAR and SREBF. Meat from Angus bulls had greater ether extract compared to Nellore (P<0.05). Muscle from bulls fed the WSC diet had greater expression of PPARA (P<0.05) and lower levels of SREBF1 expression (P<0.01). The LT of Nellore fed GC had greater expression of FABP4, ACACA and SCD genes (P<0.01). In conclusion, the greater concentration of starch in the WSC diet did not increase marbling in the beef of bulls fed this diet due to the reduced expression of SREBF1. PMID- 28666111 TI - One (Cell) in a Million. PMID- 28666110 TI - Supplementing entire male pig diet with hydrolysable tannins: Effect on carcass traits, meat quality and oxidative stability. AB - The purpose of the present study was to investigate the potential impact on carcass and meat quality of a sweet chestnut wood extract (SCWE)diet supplement for pigs, in particular on oxidative stability and fatty acid composition. Entire (non-castrated) male pigs (n=24) were assigned to treatment groups within litter and offered one of 4 finisher diets on an ad libitum basis: T0 (control), T1, T2 or T3, supplemented with 0, 1, 2 or 3% of commercially available SCWE, respectively. The highest SCWE supplementation reduced carcass fat deposition and water holding capacity of meat (higher thawing loss). In fresh meat, SCWE supplementation increased lipid (malondialdehyde) and protein oxidation (carbonyl groups in myofibril isolates). With regard to fat tissue, SCWE supplementation increased the proportion of polyunsaturated fatty acids. PMID- 28666112 TI - How the Gut Feels, Smells, and Talks. AB - Gut-brain signaling plays a central role in a range of homeostatic processes, yet details of this cross-talk remain enigmatic. In this issue of Cell, Bellono and colleagues identify a variety of luminal stimuli acting on serotonin-secreting enteroendocrine cells and, for the first time, demonstrate a functional synaptic interaction with neurons. PMID- 28666113 TI - A Natural Allele of a Transcription Factor in Rice Confers Broad-Spectrum Blast Resistance. AB - Rice feeds half the world's population, and rice blast is often a destructive disease that results in significant crop loss. Non-race-specific resistance has been more effective in controlling crop diseases than race-specific resistance because of its broad spectrum and durability. Through a genome-wide association study, we report the identification of a natural allele of a C2H2-type transcription factor in rice that confers non-race-specific resistance to blast. A survey of 3,000 sequenced rice genomes reveals that this allele exists in 10% of rice, suggesting that this favorable trait has been selected through breeding. This allele causes a single nucleotide change in the promoter of the bsr-d1 gene, which results in reduced expression of the gene through the binding of the repressive MYB transcription factor and, consequently, an inhibition of H2O2 degradation and enhanced disease resistance. Our discovery highlights this novel allele as a strategy for breeding durable resistance in rice. PMID- 28666114 TI - A New Drug Target for Type 2 Diabetes. AB - Genetic studies can identify novel therapeutic targets for common complex diseases. In this issue of Cell, Rusu et al. demonstrate that a cluster of genetic variants associated with an increased risk of type 2 diabetes affect the function of a monocarboxylate transporter involved in nutrient flux and hepatic lipid metabolism. PMID- 28666116 TI - Friction at the BAR Leads to Membrane Breakup. AB - A long-standing question in cell biology is how endocytic vesicles and tubules detach from the plasma membrane in the absence of constriction by dynamin. In this issue of Cell, Simunovic et al. describe an elegant biophysical model in which friction between lipids and BAR-domain proteins drives the scission of elongating membrane tubules. PMID- 28666115 TI - IFNgamma-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment. AB - Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNgamma is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNgamma-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNgamma. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment. PMID- 28666117 TI - Complement-Related Regulates Autophagy in Neighboring Cells. AB - Autophagy degrades cytoplasmic components and is important for development and human health. Although autophagy is known to be influenced by systemic intercellular signals, the proteins that control autophagy are largely thought to function within individual cells. Here, we report that Drosophila macroglobulin complement-related (Mcr), a complement ortholog, plays an essential role during developmental cell death and inflammation by influencing autophagy in neighboring cells. This function of Mcr involves the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Interestingly, Mcr function in epithelial cells is required for macrophage autophagy and migration to epithelial wounds, a Draper-dependent process. This study reveals, unexpectedly, that complement-related from one cell regulates autophagy in neighboring cells via an ancient immune signaling program. PMID- 28666120 TI - SnapShot: Electrochemical Communication in Biofilms. AB - The role of electricity in biological systems was first appreciated through electrical stimulation experiments performed by Luigi Galvani in the 18th century. These pioneering experiments demonstrated that the behavior of living tissues is governed by the flow of electrochemical species-an insight that gave rise to the modern field of electrophysiology. Since then, electrophysiology has largely remained a bastion of neuroscience. However, exciting recent developments have demonstrated that even simple bacteria residing in communities use electrochemical communication to coordinate population-level behaviors. These recent works are defining the emerging field of bacterial biofilm electrophysiology. To view this SnapShot, open or download the PDF. PMID- 28666118 TI - RAS Proteins and Their Regulators in Human Disease. AB - RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS' interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases. PMID- 28666121 TI - Massively Parallel Biophysical Analysis of CRISPR-Cas Complexes on Next Generation Sequencing Chips. AB - CRISPR-Cas nucleoproteins target foreign DNA via base pairing with a crRNA. However, a quantitative description of protein binding and nuclease activation at off-target DNA sequences remains elusive. Here, we describe a chip-hybridized association-mapping platform (CHAMP) that repurposes next-generation sequencing chips to simultaneously measure the interactions between proteins and ~107 unique DNA sequences. Using CHAMP, we provide the first comprehensive survey of DNA recognition by a type I-E CRISPR-Cas (Cascade) complex and Cas3 nuclease. Analysis of mutated target sequences and human genomic DNA reveal that Cascade recognizes an extended protospacer adjacent motif (PAM). Cascade recognizes DNA with a surprising 3-nt periodicity. The identity of the PAM and the PAM-proximal nucleotides control Cas3 recruitment by releasing the Cse1 subunit. These findings are used to develop a model for the biophysical constraints governing off-target DNA binding. CHAMP provides a framework for high-throughput, quantitative analysis of protein-DNA interactions on synthetic and genomic DNA. PAPERCLIP. PMID- 28666123 TI - Splicing-Correcting Therapy for SMA. AB - Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C->T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF. PMID- 28666122 TI - Structure Basis for Directional R-loop Formation and Substrate Handover Mechanisms in Type I CRISPR-Cas System. AB - Type I CRISPR systems feature a sequential dsDNA target searching and degradation process, by crRNA-displaying Cascade and nuclease-helicase fusion enzyme Cas3, respectively. Here we present two cryo-EM snapshots of the Thermobifida fusca type I-E Cascade: (1) unwinding 11 bp of dsDNA at the seed-sequence region to scout for sequence complementarity, and (2) further unwinding of the entire protospacer to form a full R-loop. These structures provide the much-needed temporal and spatial resolution to resolve key mechanistic steps leading to Cas3 recruitment. In the early steps, PAM recognition causes severe DNA bending, leading to spontaneous DNA unwinding to form a seed-bubble. The full R-loop formation triggers conformational changes in Cascade, licensing Cas3 to bind. The same process also generates a bulge in the non-target DNA strand, enabling its handover to Cas3 for cleavage. The combination of both negative and positive checkpoints ensures stringent yet efficient target degradation in type I CRISPR Cas systems. PMID- 28666119 TI - Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms. AB - Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT. PMID- 28666124 TI - What Is the Future of Developmental Biology? PMID- 28666125 TI - LTR-Retrotransposon Control by tRNA-Derived Small RNAs. AB - Transposon reactivation is an inherent danger in cells that lose epigenetic silencing during developmental reprogramming. In the mouse, long terminal repeat (LTR)-retrotransposons, or endogenous retroviruses (ERV), account for most novel insertions and are expressed in the absence of histone H3 lysine 9 trimethylation in preimplantation stem cells. We found abundant 18 nt tRNA-derived small RNA (tRF) in these cells and ubiquitously expressed 22 nt tRFs that include the 3' terminal CCA of mature tRNAs and target the tRNA primer binding site (PBS) essential for ERV reverse transcription. We show that the two most active ERV families, IAP and MusD/ETn, are major targets and are strongly inhibited by tRFs in retrotransposition assays. 22 nt tRFs post-transcriptionally silence coding competent ERVs, while 18 nt tRFs specifically interfere with reverse transcription and retrotransposon mobility. The PBS offers a unique target to specifically inhibit LTR-retrotransposons, and tRF-targeting is a potentially highly conserved mechanism of small RNA-mediated transposon control. PMID- 28666126 TI - Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle. AB - Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere replication is altered at shortened telomeres. R-loop persistence at short telomeres contributes to activation of the DNA damage response (DDR) and promotes recruitment of the Rad51 recombinase. Thus, the telomere length-dependent regulation of TERRA and TERRA R-loops is a critical determinant of the rate of replicative senescence. PMID- 28666127 TI - Approaching TERRA Firma: Genomic Functions of Telomeric Noncoding RNA. AB - Functions of the telomeric repeat-containing RNA (TERRA), the long noncoding RNA (lncRNA) transcribed from telomeres, have eluded researchers. In this issue of Cell, Graf el al. and Chu et al. uncover new regulatory roles for TERRA at the telomere and at distant genomic sites. PMID- 28666129 TI - Microbial community profiling of fresh basil and pitfalls in taxonomic assignment of enterobacterial pathogenic species based upon 16S rRNA amplicon sequencing. AB - Application of 16S rRNA (gene) amplicon sequencing on food samples is increasingly applied for assessing microbial diversity but may as unintended advantage also enable simultaneous detection of any human pathogens without a priori definition. In the present study high-throughput next-generation sequencing (NGS) of the V1-V2-V3 regions of the 16S rRNA gene was applied to identify the bacteria present on fresh basil leaves. However, results were strongly impacted by variations in the bioinformatics analysis pipelines (MEGAN, SILVAngs, QIIME and MG-RAST), including the database choice (Greengenes, RDP and M5RNA) and the annotation algorithm (best hit, representative hit and lowest common ancestor). The use of pipelines with default parameters will lead to discrepancies. The estimate of microbial diversity of fresh basil using 16S rRNA (gene) amplicon sequencing is thus indicative but subject to biases. Salmonella enterica was detected at low frequencies, between 0.1% and 0.4% of bacterial sequences, corresponding with 37 to 166 reads. However, this result was dependent upon the pipeline used: Salmonella was detected by MEGAN, SILVAngs and MG-RAST, but not by QIIME. Confirmation of Salmonella sequences by real-time PCR was unsuccessful. It was shown that taxonomic resolution obtained from the short (500bp) sequence reads of the 16S rRNA gene containing the hypervariable regions V1-V3 cannot allow distinction of Salmonella with closely related enterobacterial species. In conclusion 16S amplicon sequencing, getting the status of standard method in microbial ecology studies of foods, needs expertise on both bioinformatics and microbiology for analysis of results. It is a powerful tool to estimate bacterial diversity but amenable to biases. Limitations concerning taxonomic resolution for some bacterial species or its inability to detect sub dominant (pathogenic) species should be acknowledged in order to avoid overinterpretation of results. PMID- 28666128 TI - TERRA RNA Antagonizes ATRX and Protects Telomeres. AB - Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis. PMID- 28666130 TI - Tracking of Listeria monocytogenes in meat establishment using Whole Genome Sequencing as a food safety management tool: A proof of concept. AB - Repeated Listeria outbreaks particularly associated with Ready-To-Eat (RTE) delicatessen meat products have been reported annually at global level. The most frequent scenario that led to foodborne outbreaks was the post-thermal treatment cross-contamination of deli meat products during slicing and modified atmosphere packaging (MAP). The precondition for such cross contamination is the previous introduction of Listeria into meat processing facilities and subsequent colonization of the production environment, associated with formation of biofilms resilient to common sanitation procedures regularly applied in meat establishments. The use of Whole Genome Sequencing (WGS) can facilitate the understanding of contamination and colonization routes of pathogens within the food production environment and enable efficient pathogen tracking among different departments. This study aimed to: a) provide a proof of concept on practical use of WGS in a meat establishment to define the entry routes and spread pattern of L. monocytogenes, and b) to consider the regular use of WGS in meat processing establishments as a strong support of food safety management system. The results revealed that Listeria spp. was present in slaughter line, chilling chambers, deboning, slicing, MAP, as well as in corridors and dispatch (53 positive samples, out of 240). Eight L. monocytogenes isolates (out of 53) were identified from the slaughterhouse, chilling chambers, deboning, MAP and dispatch. L. monocytogenes isolates were of three different serotypes (1/2a, 1/2c, 4b) and correspondingly of three MLST sequence types. Overall, two pairs of L. monocytogenes isolates were genetically identical, i.e. two serotype 4b isolates (ST1), isolated from water drain at dispatch unit and two isolates obtained from slaughterhouse (floorwall junction at the carcass wash point) and MAP (water drain). These findings indicated that L. monocytogenes isolates identified in meat processing units (MAP, chilling chamber and dispatch) originated from the slaughter line. Further, all eight L. monocytogenes isolates were confirmed to be biofilm producers on glass and stainless steel surfaces. The identification of the main entry routes of L. monocytogenes into meat establishments and tracking the routes for spread of the pathogen are of essential importance to define appropriate risk mitigation strategies for L. monocytogenes in meat production environment. The routine use of WGS for bacterial characterization, as a strong support of food safety management system in meat establishments, will require the cost-effective approach. It may encompass in-house sequencing when sequencing equipment is used for multiple applications (e.g. WGS of pathogens, starter cultures and spoilage organisms). PMID- 28666131 TI - A shell-formation related carbonic anhydrase in Crassostrea gigas modulates intracellular calcium against CO2 exposure: Implication for impacts of ocean acidification on mollusk calcification. AB - Ocean acidification (OA) could decrease the shells and skeletons formation of mollusk by reducing the availability of carbonate ions at calcification sites. Carbonic anhydrases (CAs) convert CO2 to HCO3- and play important roles in biomineralization process from invertebrate to vertebrate. In the present study, a CA (designated as CgCA) was identified and characterized in Pacific oyster C. gigas. The cDNA of CgCA was of 927bp encoding a predicted polypeptide of 308 amino acids with a signal peptide and a CA catalytic function domain. The mRNA transcripts of CgCA were constitutively expressed in all tested tissues with the highest levels in mantle and hemocytes. During the early development period, the mRNA transcripts of CgCA could be detected in all the stages with the highest level in D-veliger larvae. Elevated CO2 increased the mRNA transcripts of CgCA in muscle, mantle, hepatopancreas, gill and hemocytes significantly (p<0.05) and induced the translocation of CgCA in hemocytes and mantle. Moreover, elevated CO2 also caused the decrease of intracellular Ca2+ in hemocytes (p<0.05). The inhibition of CA by acetazolamide and suppression of CgCA gene via RNA interference could increase the intracellular Ca2+ in hemocytes (p<0.05). Besides, the decrease of intracellular Ca2+ content caused by Ca2+ reagent ionomycin could affect localization of CgCA in mantle tissue. The results indicated CgCA played essential roles in calcification and elevated CO2 accelerated the mutual modulation between calcium and CgCA, implying reduced calcification rate and dissolved shells under OA. PMID- 28666132 TI - Neuropsychological function in relation to dysmenorrhea in adolescents. AB - OBJECTIVE: Hormonal variations during the menstrual cycle may affect emotional regulation. We aimed to investigate the association between dysmenorrhea (the severe abdominal pain and cramps associated with menstruation) and cognitive abilities, emotional function and sleep patterns in adolescent girls. Moreover, we evaluated the frequency of premenstrual syndrome (PMS) in our population and then divided them into 4 groups: subjects with only PMS; subjects with only dysmenorrhea; individuals with both PMS and dysmenorrhea and normal subjects. STUDY DESIGN: In this cross sectional study, 897 adolescent girls who had entered menarche were recruited. Of these, 35.9% had only dysmenorrhea, 14.9% had only PMS, 32.7% had both PMS and dysmenorrhea while 16.5% had no PMS and/or dysmenorrhea (Normal). We assessed the tests for cognitive, emotional function and sleep patterns were compared for these groups. RESULTS: Individuals in the dysmenorrhea group had significantly higher depression, aggression, insomnia, daytime sleepiness and sleep apnea scores compared to normal controls and the PMS group, but did not have significantly different cognitive ability (P value <0.05). These differences were strongly correlated to pain intensity (P<0.001). However, there were no significant differences between those with only PMS and control subjects with regard to cognitive ability, emotional function and sleep pattern tests. CONCLUSIONS: Dysmenorrhea is highly prevalent among adolescents and appears to be associated with depressive mood, a tendency to aggressive behavior and sleep disorders among adolescent girls. PMID- 28666133 TI - Water stress mitigates the negative effects of ozone on photosynthesis and biomass in poplar plants. AB - Tropospheric ozone (O3) pollution frequently overlaps with drought episodes but the combined effects are not yet understood. We investigated the physiological and biomass responses of an O3 sensitive hybrid poplar clone ('546') under three O3 levels (charcoal-filtered ambient air, non-filtered ambient air (NF), and NF plus 40 ppb) and two watering regimes (well-watered (WW) and reduced watering (RW), i.e. 40% irrigation) for one growing season. Water stress increased chlorophyll and carotenoid contents, protecting leaves from pigment degradation by O3. Impairment of photosynthesis by O3 was also reduced by stomatal closure due to water stress, which preserved light-saturated CO2 assimilation rate, and the maximum carboxylation efficiency. Water stress increased water use efficiency of the leaves while O3 decreased it, showing significant interactions. Effects were more evident in older leaves than in younger leaves. Water stress reduced biomass production, but the negative effects of O3 were less in RW than in WW for total biomass per plant. A stomatal O3 flux-based dose-response relationship was parameterized considering water stress effects, which explained biomass losses much better than a concentration-based approach. The O3 critical level of Phytotoxic Ozone Dose over a threshold of 7 nmol O3.m-2.s-1 (POD7) for a 4% biomass loss in this poplar clone under different water regimes was 4.1 mmol m-2. Our results suggest that current O3 levels in most parts of China threaten poplar growth and that interaction with water availability is a key factor for O3 risk assessment. PMID- 28666134 TI - Capturing the sensitivity of land-use regression models to short-term mobile monitoring campaigns using air pollution micro-sensors. AB - The development of reliable measures of exposure to traffic-related air pollution is crucial for the evaluation of the health effects of transportation. Land-use regression (LUR) techniques have been widely used for the development of exposure surfaces, however these surfaces are often highly sensitive to the data collected. With the rise of inexpensive air pollution sensors paired with GPS devices, we witness the emergence of mobile data collection protocols. For the same urban area, can we achieve a 'universal' model irrespective of the number of locations and sampling visits? Can we trade the temporal representation of fixed point sampling for a larger spatial extent afforded by mobile monitoring? This study highlights the challenges of short-term mobile sampling campaigns in terms of the resulting exposure surfaces. A mobile monitoring campaign was conducted in 2015 in Montreal; nitrogen dioxide (NO2) levels at 1395 road segments were measured under repeated visits. We developed LUR models based on sub-segments, categorized in terms of the number of visits per road segment. We observe that LUR models were highly sensitive to the number of road segments and to the number of visits per road segment. The associated exposure surfaces were also highly dissimilar. PMID- 28666135 TI - Statistical polarization in greenhouse gas emissions: Theory and evidence. AB - The current debate on climate change is over whether global warming can be limited in order to lessen its impacts. In this sense, evidence of a decrease in the statistical polarization in greenhouse gas (GHG) emissions could encourage countries to establish a stronger multilateral climate change agreement. Based on the interregional and intraregional components of the multivariate generalised entropy measures (Maasoumi, 1986), Gigliarano and Mosler (2009) proposed to study the statistical polarization concept from a multivariate view. In this paper, we apply this approach to study the evolution of such phenomenon in the global distribution of the main GHGs. The empirical analysis has been carried out for the time period 1990-2011, considering an endogenous grouping of countries (Aghevli and Mehran, 1981; Davies and Shorrocks, 1989). Most of the statistical polarization indices showed a slightly increasing pattern that was similar regardless of the number of groups considered. Finally, some policy implications are commented. PMID- 28666136 TI - The biological significance of bornavirus-derived genes in mammals. AB - The discoveries of sequences derived from non-retroviral viruses in eukaryotic genomes have significantly expanded our knowledge about virus evolution as well as the co-evolution between viruses and eukaryotes. However, the biological functions of such sequences in the host are largely unknown. Endogenous bornavirus-like elements (EBLs) have been relatively well studied by molecular biological methods, which have provided evidence that some EBLs have been co opted by their hosts. This review highlights the current knowledge on the biological significance of EBLs, and discusses possible functions of EBLs. Further, we highlight the importance of extensive surveillance of exogenous viruses for a better understanding of endogenous viral sequences as well as the co-evolution of viruses and eukaryotes. PMID- 28666137 TI - Axial geometrical aberration correction up to 5th order with N-SYLC. AB - We present N-SYLC (N-fold symmetric line currents) models to correct 5th order axial geometrical aberrations in electron microscopes. In our previous paper, we showed that 3rd order spherical aberration can be corrected by 3-SYLC doublet. After that, mainly the 5th order aberrations remain to limit the resolution. In this paper, we extend the doublet to quadruplet models also including octupole and dodecapole fields for correcting these higher order aberrations, without introducing any new unwanted ones. We prove the validity of our models by analytical calculations. Also by computer simulations, we show that for beam energy of 5keV and initial angle 10mrad at the corrector object plane, beam size of less than 0.5nm is achieved at the corrector image plane. PMID- 28666138 TI - An aperture design for single side band imaging in the transmission electron microscope. PMID- 28666139 TI - Development of laser-based scanning u-ARPES system with ultimate energy and momentum resolutions. AB - We have developed a laser-based scanning angle-resolved photoemission spectroscopy system (u-ARPES) equipped with a high precision 6-axis control system, realizing not only high-resolution photoemission spectroscopy in energy and momentum, but also spatial resolution of a um scale. This enables our u-ARPES system to probe fine details of intrinsic electronic states near the Fermi level such as the superconducting gaps and lifetime broadening. PMID- 28666140 TI - Bandgap measurement of high refractive index materials by off-axis EELS. AB - In the present work Cs aberration corrected and monochromated scanning transmission electron microscopy electron energy loss spectroscopy (STEM-EELS) has been used to explore experimental set-ups that allow bandgaps of high refractive index materials to be determined. Semi-convergence and -collection angles in the urad range were combined with off-axis or dark field EELS to avoid relativistic losses and guided light modes in the low loss range to contribute to the acquired EEL spectra. Off-axis EELS further supressed the zero loss peak and the tail of the zero loss peak. The bandgap of several GaAs-based materials were successfully determined by simple regression analyses of the background subtracted EEL spectra. The presented set-up does not require that the acceleration voltage is set to below the Cerenkov limit and can be applied over the entire acceleration voltage range of modern TEMs and for a wide range of specimen thicknesses. PMID- 28666141 TI - Computational design of peptide ligands to target the intermolecular interaction between viral envelope protein and pediatric receptor. AB - The recognition and binding of viral envelope protein to pediatric receptor subverts the membrane-trafficking apparatus to mediate virion export in young children. Here, we described a successful computational design of peptide ligands to target the intermolecular interaction between the virus large envelope protein (LHB) and adaptin receptor (ADT). Based on the crystal structure of ADT in complex with an oligopeptide segment corresponding to the core binding site of LHB, a sequence-specific amino acid preference profile was determined systematically for the ADT-binding peptides using structural bioinformatics approach. With the information harvested from the profile, a genetic evolution procedure was run to improve the biological potency of a peptide population generated randomly from the LHB. A number of potential hits were obtained from the evolution, and four were measured to interact with ADT at micromolar level. A high-affinity hit peptide was then optimized according to computational structural analysis. It is revealed that a potent peptide can be divided into three regions, i.e. a negatively charged region at N-terminus, a hydrophobic core region in middle, and a small, polar region at C-terminal tail. In addition, the two termini of peptide are partially out of the active pocket of ADT, thus contributing moderately to the peptide binding. PMID- 28666142 TI - Distinct sesquiterpene pyridine alkaloids from in Salvadoran and Peruvian Celastraceae species. AB - As part of a bioprospecting program aimed at the discovery of undescribed natural products from Salvadoran and Peruvian flora, the phytochemical investigations of four Celastraceae species, Celastrus vulcanicola, Maytenus segoviarum, Maytenus jeslkii, and Maytenus cuzcoina, were performed. The current study reports the isolation and structural characterization of five previously undescribed macrolide sesquiterpene pyridine alkaloids, named vulcanicoline-A, cuzcoinine, vulcanicoline-B, jelskiine, and vulcanicoline-C, along with sixteen known alkaloids. The structures of the alkaloids were established by spectrometric and extensive 1D and 2D NMR spectroscopic analysis, including COSY, HSQC, HMBC, and ROESY experiments. The absolute configurations of alkaloids were proposed based on optical rotation sign, and biogenetic considerations. This study represents the first phytochemical analysis of Maytenus segoviarum. PMID- 28666143 TI - Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives. AB - BACKGROUND: No studies have assessed the comparative effectiveness of guideline recommended interventions to reduce risk of prescription opioid use disorder among chronic opioid therapy (COT) patients. We compared the prevalence of prescription opioid use disorder among COT patients from intervention clinics that had implemented opioid dose and risk reduction initiatives for more than 4 years relative to control clinics that had not. METHODS: After a healthcare system in Washington State implemented interventions to reduce opioid dose and risks, we surveyed 1588 adult primary care COT patients to compare the prevalence of prescription opioid use disorder among COT patients from the intervention and control clinics. Intervention clinics managed COT patients at lower COT doses and with more consistent use of risk reduction practices. Control clinics cared for similar COT patients but prescribed higher opioid doses and used COT risk reduction practices inconsistently. Prescription opioid use disorder was assessed with the Psychiatric Research Interview for Substance and Mental Disorders. RESULTS: The prevalence of prescription opioid use disorder was 21.5% (95% CI=18.9% to 24.4%) among COT patients in the intervention clinics and 23.9% (95% CI=20.5% to 27.6%) among COT patients in the control clinics. The adjusted relative risk of prescription opioid use disorder was 1.08 (95% CI=0.89, 1.32) among the control clinic patients relative to the intervention clinic patients. CONCLUSIONS: Long-term implementation of opioid dose and risk reduction initiatives was not associated with lower rates of prescription opioid use disorder among prevalent COT patients. Extreme caution should be exercised by clinicians considering COT for patients with chronic non-cancer pain until benefits of this treatment and attendant risks are clarified. PMID- 28666144 TI - Investigation of Turkish nurses frequency and knowledge of administration of intramuscular injections to the ventrogluteal site: Results from questionnaires. AB - BACKGROUND: Intramuscular injection is important in the administration of parenteral medication and is a frequently-performed nursing responsibility. OBJECTIVE: The objective of this study was to identify the frequency of use of the ventrogluteal site and the level of nurses' knowledge of administering an intramuscular injection to this site. DESIGN: A descriptive cross-sectional study was conducted of nurses working in four hospitals (n=362). Data collection tools included a 12 item sociodemographic questionnaire and a 24 item questionnaire on knowledge of the ventrogluteal site for intramuscular injection. FINDINGS: 17.1% of participants reported using the VG site frequently in intramuscular injections. On the other hand, 35.9% reported that they do not use the VG site in intramuscular injections just because they are not used to giving injections on this site. Level of knowledge of ventrogluteal site was also limited with the mean score of correct answers from 24 questions being 14.37. CONCLUSION: It was found in the study that nurses' knowledge of the ventrogluteal site was limited, and they are not preferentially using the ventrogluteal site for intramuscular injections to adults even though it is recommended in recent nursing literature. PMID- 28666145 TI - Simple and effective generation of transgene-free induced pluripotent stem cells using an auto-erasable Sendai virus vector responding to microRNA-302. AB - Transgene-free induced pluripotent stem cells (iPSCs) are valuable for both basic research and potential clinical applications. We previously reported that a replication-defective and persistent Sendai virus (SeVdp) vector harboring four reprogramming factors (SeVdp-iPS) can efficiently induce generation of transgene free iPSCs. This vector can express all four factors stably and simultaneously without chromosomal integration and can be eliminated completely from reprogrammed cells by suppressing vector-derived RNA-dependent RNA polymerase. Here, we describe an improved SeVdp-iPS vector (SeVdp(KOSM)302L) that is automatically erased in response to microRNA-302 (miR-302), uniquely expressed in pluripotent stem cells (PSCs). Gene expression and genome replication of the SeVdp-302L vector, which contains miRNA-302a target sequences at the 3' untranslated region of L mRNA, are strongly suppressed in PSCs. Consequently, SeVdp(KOSM)302L induces expression of reprogramming factors in somatic cells, while it is automatically erased from cells successfully reprogrammed to express miR-302. As this vector can reprogram somatic cells into transgene-free iPSCs without the aid of exogenous short interfering RNA (siRNA), the results we present here demonstrate that this vector may become an invaluable tool for the generation of human iPSCs for future clinical applications. PMID- 28666146 TI - Intraleaflet hemorrhages are a common finding in symptomatic aortic and mitral valves. AB - INTRODUCTION: Intraleaflet hemorrhage (ILH) has been reported to occur in calcified degenerated aortic valves. At present, no such information is available for mitral valves or for other types of valvular disease. We examined the prevalence, age, and potential source of ILH in a consecutive series of surgically removed aortic and mitral valves, and related the findings to specific types of heart valve pathology. METHODS: A total of 105 aortic (n=85) and mitral (n=20) valves were retrieved from 100 symptomatic patients. Pathological diagnosis was made on photographic images and histology. Presence, extent, and age of ILH; its possible association with calcification; microvessels; and microvascular leakage were assessed with conventional and immunohistochemical staining methods and related to the type of underlying valvular disease. RESULTS: Pathological diagnosis revealed degenerative aortic valve disease (n=70), postinflammatory disease (n=16), endocarditis (n=12), myxoid degenerative mitral valve disease (n=6), and one normal valve. ILH was found in 86% of aortic and 75% of mitral valves. Microvessels were present in 91% of all valves. Microvascular leakage was noted in 70% of aortic and 84% of mitral valves; in both groups, colocalization with ILH was found in 48%. Most aortic valves (91%) contained calcium deposits, of which 54% showed colocalization with ILH. In 66% of valves with ILH, a combination of recent hemorrhage and iron deposits was seen, indicating an ongoing process of episodic hemorrhages. CONCLUSION: The prevalence of ILH is very high in resected heart valves. Both aortic and mitral valves showed an association of ILH with microvessels, microvascular leakage, and calcifications. We speculate that repetitive microvascular-leakage-related ILH may contribute to valve dysfunction on the (very) long term. PMID- 28666147 TI - Sudden unexpected death in early Parkinson's disease: neurogenic or cardiac death? AB - We present two cases of sudden unexpected death (SUD) in elderly individuals in whom autopsy unexpectedly showed Lewy pathology, a hallmark of Parkinson's disease. Both individuals were 68-year-old men who were found dead in their homes without lethal trauma or poisoning. Inquests into their deaths suggested that nonmotor cardiovascular signs of Parkinson's disease might have appeared just before their deaths, although few typical motor signs were present. Autopsy showed Lewy pathology in the heart and peripheral autonomic nervous system in addition to lesser involvement of the brainstem that was consistent with Braak stage 3. In case 1, an atrial septal defect of the secundum type with advanced fibrosis of the atrium was present. In case 2, severe stenosis of the atrioventricular node artery with some microscars and diffuse interstitial fibrosis of the basilar ventricular septum were found. These two cases show some premotor Parkinson's disease with a symptom suggestive of autonomic dysregulation which may be a risk of SUD. In addition, coexistence of structural change of the heart with possibly arrhytthmogenic potential may increase the risk of SUD with Parkinson's disease. Present two cases showed neuropathological examination to detect Lewy pathology in the peripheral nervous system may be important for revealing the cause of some cases of SUD in the elderly, even if typical motor signs were not evident before death. PMID- 28666148 TI - Corn bran bioprocessing: Development of an integrated process for microbial lipids production. AB - This study investigated the potential of corn bran as a feedstock for microbial lipid production using oleaginous yeast, Trichosporon oleaginosus ATCC20509. Different conditions (solid loading of biomass, acid loading, and pretreatment duration) were applied to optimize pretreatment processes using the Box-Behnken design. The highest sugar yield of 0.53g/g was obtained from corn bran hydrolysates at a pretreatment condition of 5% solid loading and 1% acid loading for 30min. Compared with synthetic media, up to 50% higher lipid accumulations in T. oleaginosus were achieved using corn bran hydrolysates during fermentation. Also, the direct effect of pretreatment condition on the lipid accumulation of T. oleaginosus was investigated using response surface methodology (RSM). Solid loading of biomass during the pretreatment process significantly affected the fermentation process for lipid accumulation of T. oleaginosus. The RSM model can provide useful information to design an integrated bioconversion platform. PMID- 28666149 TI - Phosphorus removal performance and biological dephosphorization process in treating reclaimed water by Integrated Vertical-flow Constructed Wetlands (IVCWs). AB - Phosphorous removal in adsorption had been extensively researched; however, the biological dephosphorization process and optimum operating parameters have not been discussed or quantified in Integrated Vertical-flow Constructed Wetlands (IVCWs). In this study, IVCWs planted with different plants were employed to evaluate total phosphorus (TP) treatment performance under different hydraulic retention times (HRTs), in summer and autumn. The results showed that the systems planted with Canna generalis showed the highest TP removal efficiency (77%) under a three-day HRT in autumn. The activities of exopolyphosphatase (PPX) and polyphosphate kinase (PPK) were determined, and it was found that PPK activity was seasonably variable and had been more active in autumn than that in summer (p<0.05). Highly significant correlation was revealed between PPK activity and TP removal efficiency (p<0.05). The 16S rDNA high-throughput sequencing results indicated that Pseudomonas genus might be the main participant in phosphorus aerobic biological adsorption in IVCWs. PMID- 28666150 TI - Mesenteric desmoid tumour presenting with recurrent abdominal abscess and duodenal fistula: A case report and review of literature. AB - INTRODUCTION: Desmoid tumors are locally destructive but histologically benign. Their management involves close observation and surgical, medical, or hormonal treatment. PRESENTATION OF THE CASE: A 36-year-old male was admitted for abdominal pain and fever. A CT scan showed fluid collections and air within a mesenteric mass. Diagnostic laparotomy was performed with drainage of the abscess and biopsy of the mass. The pathology suggested a desmoid tumor. His fever and abdominal pain persisted. An endoscopy was performed, which demonstrated a fistula track in the third part of the duodenum. After a multidisciplinary discussion, consensus was to pursue surgical intervention. The patient underwent an en bloc resection of the tumor including a portion of the wall of the third part of the duodenum. The final pathology confirmed a desmoid tumor with a fistula track to the duodenum. The patient had a re-laparotomy on POD2 for intra abdominal bleeding but was discharged without further events on POD7. He had no evidence of recurrence on follow-up at 11 months. DISCUSSION: Desmoid tumors are rarely complicated by abscess formation or fistulization. The management of intra abdominal desmoids in this setting is challenging, as patients are often symptomatic and unresponsive to medical management. Percutaneous drainage and antibiotics are often initiated as first-line treatment, followed by surgery or medical therapy after evaluation of resectability and tumor stage. CONCLUSION: Rare complications can arise with intra-abdominal desmoid tumors. Principles of infection control should be applied in combination with optimization of oncologic outcome. A multidisciplinary approach helps to achieve both these objectives. PMID- 28666151 TI - Triceps nerve to deltoid nerve transfer after an unsatisfactory intra-plexus neurotization of the posterior division of the upper trunk. AB - INTRODUCTION: Our literature review did not reveal any study on the results of triceps to deltoid nerve transfer done as a secondary procedure after an unsatisfactory primary intraplexus neurotization of the posterior division of the upper trunk. PRESENTATION OF CASES: We report on three adults with C5-C6 brachial plexus injury who had an unsatisfactory deltoid function following primary intraplexus neurotization. Patients presented to our clinic late (14-16 months after injury). All patients had poor shoulder abduction (<40 degrees ) despite the presence of visible and palpable deltoid contractions. A triceps to deltoid nerve transfer resulted in an excellent shoulder abduction (> 150 degrees ) in all patients. DISCUSSION: The primary surgery in our patients acted as a "baby sitter" procedure; explaining the good results of the late secondary distal nerve transfer. CONCLUSION: Good results may be obtained from a late distal nerve transfer for the deltoid muscle as long as there is partial innervation of the muscle. PMID- 28666152 TI - Pharmacodynamic and pharmacokinetic interactions between simvastatin and diazepam in rats. AB - BACKGROUND: Statins and benzodiazepines are widely used drugs, especially in ischemic heart disease, where exacerbation caused by anxiety can even lead to cardiac death. There have not been any reports of statin drug interaction with anxiolytics so far, but it is possible that these drugs interact with each other. We examined the effect of chronic oral administration of simvastatin on the anxiolytic activity and pharmacokinetics of diazepam in rats. METHODS: Studies were conducted on male Wistar Han rats treated with simvastatin (2.5, 5, 10, 20mg/kg) for 4-6 weeks, and/or diazepam (2.5, 5, 10mg/kg) administered once on the day of the study. Evaluation of potential pharmacodynamic interaction was based on the behavioral tests: elevated plus maze (EPM) test and the Vogel conflict test (VCT). The assessment of the potential pharmacokinetic interaction was based on measurements of concentrations of diazepam and its metabolites in the blood of animals. RESULTS: Diazepam 5 and 10mg/kg given together with simvastatin 10 and 20mg/kg showed no anxiolytic effect in the EPM test. In the VCT diazepam combinations with simvastatin did not produce any anxiolytic effect either, with an exception of the co-administration of diazepam 10mg/kg and simvastatin 10mg/kg. Simvastatin (20mg/kg) significantly reduced the area under curve (AUC) of diazepam by 51.6% and temazepam by 54.6%. CONCLUSIONS: Abolition of diazepam anxiolytic effect during concomitant use of simvastatin is probably caused by diminished bioavailability of diazepam, although pharmacodynamic interaction between these drugs cannot be excluded. PMID- 28666153 TI - Electroencephalographic findings in patients with circumscribed thalamic lesions. AB - INTRODUCTION: Thalamo-cortical networks have mainly been studied in the generation of idiopathic (genetic) epilepsies. The purpose of this study was to analyze EEG patterns and the occurrence of focal (symptomatic) epileptic seizures in patients with acquired circumscribed thalamic lesions. PATIENTS AND METHODS: Among 596 patients with thalamic lesions, we identified 47 patients in whom circumscribed thalamic lesions were detected by MRI and who underwent an EEG examination at the same stay at hospital. EEG findings were divided into normal findings, unspecific pathological changes and epileptiform discharges. The EEG findings were correlated to the localisation of the lesion within the thalamus and to the patients symptoms. RESULTS: In 32 patients (68%) pathological EEG findings were observed. They were heterogeneous and comprised regional and generalized slowing, triphasic waves, generalized periodic and regional epileptiform discharges. However, some characteristic findings were seen: Regional slowing was associated with ipsilateral thalamic lesions independent of the thalamic subarea, epileptiform discharges were related to lesions in the ipsilateral medial thalamus and periodic generalized discharges/triphasic waves with lesions in the anterior-ventromedial thalamus. Epileptic seizures were also more common in patients with medial thalamic lesions. Patients with regional epileptiform discharges responded to antiepileptic treatment whereas patients with triphasic waves and generalized periodic patterns did not. In some cases, it remained difficult to decide whether the thalamic lesion was the cause or consequence of epileptic activity. CONCLUSION: Pathological EEG findings are common in patients with acute and chronic thalamic lesions. EEG patterns associated with circumscribed thalamic lesions were influenced by the affected thalamic subregion. As in idiopathic generalized epilepsy, also in symptomatic epilepsy, the medial thalamus revealed to play a role in the generation of epileptiform discharges. In the patients with generalized periodic discharges and acute lesions in the ventral-anterior-medial thalamus, however, EEG changes were more likely caused by a disinhibition of cortico-thalamic networks than by a status epilepticus and thus risks and benefits of an aggressive antiepileptic treatment must be thoroughly balanced. PMID- 28666154 TI - Respiratory problems and anxiety sensitivity in smoking lapse among treatment seeking smokers. AB - PURPOSE: The current study examined whether the interaction of lower respiratory symptoms and anxiety sensitivity is related to smoking lapse in the context of smoking cessation. METHOD: Participants were adult daily smokers (N=60) exposed to the World Trade Center (WTC) disaster who were in a smoking cessation treatment program (75.0% male, 50.6years old [SD=9.2], and current smoking rate was 17.6 cigarettes per day (SD=10.6). RESULTS: Results indicated that the interaction between lower respiratory symptoms and anxiety sensitivity was a significant predictor of greater risk for lapse (i.e., lower survival time; B=0.005, OR=1.01, p=0.039). Follow-up analysis showed that greater respiratory symptoms were a significant predictor of lapse risk among those with high (B=0.116, OR=1.12, p=0.025), but not those with low (B=-0.048, OR=0.95, p=0.322), levels of anxiety sensitivity. DISCUSSION: The findings from the current study suggest that smokers with greater respiratory symptoms and higher levels of anxiety sensitivity may be associated with early lapse to smoking following smoking cessation treatment. Future work has the potential to inform the development of tailored cessation interventions for smokers who experience varying levels of lower respiratory symptoms and anxiety sensitivity. PMID- 28666155 TI - Impact of the equatorial coordination sphere on the rate of reduction, lipophilicity and cytotoxic activity of platinum(IV) complexes. AB - The impact of the equatorial coordination sphere on the reduction behavior (i.e. rate of reduction) of platinum(IV) complexes with axial carboxylato ligands was studied. Moreover, the influence of equatorial ligands on the stability, lipophilicity and cytotoxicity of platinum(IV) compounds was evaluated. For this purpose, a series of platinum(IV) complexes featuring axial carboxylato ligands (succinic acid monoesters) was synthesized; anionic carboxylato (OAc-, oxalate) and halido (Cl-, Br-, I-) ligands served as leaving groups and am(m)ine carrier ligands were provided by monodentately (isopropylamine, ammine+cyclohexaneamine) or bidentately (ethane-1,2-diamine) coordinating am(m)ines. All platinum(IV) products were fully characterized based on elemental analysis, high resolution mass spectrometry and multinuclear (1H, 13C, 15N, 195Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The rate of reduction in the presence of ascorbic acid was determined by NMR spectroscopy and the lipophilicity of the complexes was investigated by analytical reversed phase HPLC measurements. Cytotoxic properties were studied by means of a colorimetric microculture assay in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1) as well as cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549). PMID- 28666156 TI - Family support liaison in the witnessed resuscitation: A phenomenology study. AB - BACKGROUND: Family-witnessed resuscitation remains controversial among clinicians from implementation to practice and there are a number of countries, such as Iran, where that is considered a low priority. OBJECTIVE: To explore the lived experience of resuscitation team members with the presence of the patient's family during resuscitation. DESIGN: The hermeneutic phenomenology. SETTINGS: The emergency departments and critical care units of 6 tertiary hospitals in Tabriz, Iran. PARTICIPANTS: There were potentially 380 nurses and physicians working in the emergency departments and acute care settings of 6 tertiary hospitals in Tabriz. A purposive sample of these nurses and physicians was used to recruit participants who had at least 2 years of experience, had experienced an actual family witnessed resuscitation event, and wanted to participate. The sample size was determined according to data saturation. Data collection ended when the data were considered rich and varied enough to illuminate the phenomenon, and no new themes emerged following the interview of 12 nurses and 8 physicians. METHODS: Semi-structured, face- to- face interviews were held with the participants over a period of 6 months (April 2015 to September 2015), and Van Manen's method of data analysis was adopted. RESULTS: Three main themes emerged from the data analysis, including 'Futile resuscitation', 'Family support liaison', and 'Influence on team's performance'. A further 9 sub-themes emerged under the 3 main themes, which included 'futile resuscitation in end-stage cancer patients', 'when a patient dies', 'young patients', 'care of the elderly', 'accountable person', 'family supporter', 'no influence', 'positive influence', and 'negative influence'. CONCLUSIONS: Participants noted both positive and negative experiences of having family members present during cardiopulmonary resuscitation. Welltrained and expert resuscitation team members are less likely to be stressed in the presence of family. A family support liaison would act to decrease family anxiety levels and to de-escalate any potentially aggressive person during the resuscitation. It is recommended that an experienced health care professional be designated to be responsible for explaining the process of resuscitation to the patient's family. PMID- 28666157 TI - Application of FT-IR spectroscopy on breast cancer serum analysis. AB - Breast cancer is regarded as the most malignant tumor among women throughout the world. Therefore, early detection and proper diagnostic methods have been known to help save women's lives. Fourier Transform Infrared (FT-IR) spectroscopy, coupled with PCA-LDA analysis, is a new technique to investigate the characteristics of serum in breast cancer. In this study, 43 breast cancer and 43 healthy serum samples were collected, and the FT-IR spectra were recorded for each one. Then, PCA analysis and linear discriminant analysis (LDA) were used to analyze the spectral data. The results showed that there were differences between the spectra of the two groups. Discriminating wavenumbers were associated with several spectral differences over the 950-1200cm-1(sugar), 1190-1350cm-1 (collagen), 1475-1710cm-1 (protein), 1710-1760cm-1 (ester), 2800-3000cm-1 (stretching motions of -CH2 & -CH3), and 3090-3700cm-1 (NH stretching) regions. PCA-LDA performance on serum IR could recognize changes between the control and the breast cancer cases. The diagnostic accuracy, sensitivity, and specificity of PCA-LDA analysis for 3000-3600cm-1 (NH stretching) were found to be 83%, 84%, 74% for the control and 80%, 76%, 72% for the breast cancer cases, respectively. The results showed that the major spectral differences between the two groups were related to the differences in protein conformation in serum samples. It can be concluded that FT-IR spectroscopy, together with multivariate data analysis, is able to discriminate between breast cancer and healthy serum samples. PMID- 28666158 TI - Interaction of sucralose with whey protein: Experimental and molecular modeling studies. AB - The objective of this research was to study the interactions of sucralose with whey protein isolate (WPI) by using the three-dimensional fluorescence spectroscopy, circular dichroism spectroscopy and molecular modeling. The results showed that the peptide strands structure of WPI had been changed by sucralose. Sucralose binding induced the secondary structural changes and increased content of aperiodic structure of WPI. Sucralose decreased the thermal stability of WPI and acted as a structure destabilizer during the thermal unfolding process of protein. In addition, the existence of sucralose decreased the reversibility of the unfolding of WPI. Nonetheless, sucralose-WPI complex was less stable than protein alone. The molecular modeling result showed that van der Waals and hydrogen bonding interactions contribute to the complexation free binding energy. There are more than one possible binding sites of WPI with sucralose by surface binding mode. PMID- 28666159 TI - Optimization of expression and purification of human mortalin (Hsp70): Folding/unfolding analysis. AB - Human mortalin is a Hsp70 mitochondrial protein that plays an essential role in the biogenesis of mitochondria. The deregulation of mortalin expression and its functions could lead to several age-associated disorders and some types of cancers. In the present study, we optimized the expression and purification of recombinant human mortalin by the use of two-step chromatography. Low temperature (18 degrees C) and 0.5mM (IPTG) was required for optimum mortalin expression. Chaperone activity of mortalin was assessed by the citrate synthase and insulin protection assay, which suggested their protective role in mitochondria. Folding and unfolding assessments of mortalin were carried out in the presence of guanidine hydrochloride (GdnHCl) by intrinsic fluorescence measurement, ANS (8 analino 1-nephthlene sulfonic acid) binding and CD (circular dichroism) analysis. Under denaturing conditions, mortalin showed decrease in tryptophan fluorescence intensity along with a red shift of 11nm. Moreover, ANS binding studies illustrated decrease in hydrophobicity. CD measurement of mortalin showed a predominant helical structure. However, the secondary structure was lost at low concentration of GdnHCl (1M). We present a simple and robust method to produce soluble mortalin and warranted that chaperones are also susceptible to unfolding and futile to maintain protein homeostasis. PMID- 28666160 TI - On-line coupling of molecularly imprinted solid phase extraction with liquid chromatography for the fast determination of coumarins from complex samples. AB - In this work, an on-line SPE-HPLC method with spectrophotometric detection was developed for the determination of coumarins in complex samples. For the on-line cleanup of samples, a molecularly imprinted polymer was packed into the column cartridge and coupled directly with HPLC (MISPE-HPLC) using a column switching system. The separation of coumarins was performed on a C18 core-shell column (100*4.6mm, 5MUm) with a mobile phase consisting of 0.3% acetic acid/acetonitrile with gradient elution at a flow-rate of 1mLmin-1. The total time of the whole analytical run, including the extraction step, was 13.25min. The on-line MISPE HPLC method was optimized and validated. The results showed good linearity (0.10 100MUgmL-1) with correlation coefficients higher than 0.99. The LOD values were from 0.03 to 0.15MUgmL-1. The proposed method was successfully applied for analysis of real samples (Cassia cinnamon, chamomile tea, and Tokaj specialty wines) and obtained recoveries varied from 78.7% to 112.2% with an RSD less than 9%. PMID- 28666161 TI - Rapid analysis of benzalkonium chloride using paper spray mass spectrometry. AB - A paper spray mass spectrometry (PS-MS) method for rapid and reliable analysis of benzalkonium chloride (BAC) in compound eye drops and body surface disinfectant was developed. The sample was dropped onto triangular filter paper, and high voltage (3.5kV) was applied to form an electrospray. This method can provide the composition of benzalkonium chloride in samples without pretreatment, solvent or chromatographic separation, and the analysis time is only 10s. The primary homologues C12-BAC, C14-BAC and C16-BAC of benzalkonium chloride were quantitatively analyzed using PS-MS. Samples were subjected to simple dilution and quantified using the internal standard method. Ion trap mass spectrometry was scanned using SIM mode. The linear ranges of C12-BAC, C14-BAC and C16-BAC were 1 100MUgmL-1; the linear regression coefficients were 0.998-0.999; the detection limits (LODs) were 0.1MUgmL-1; the limit of quantifications (LOQs) was <1MUgmL-1, and the method validation indicated that the method precision and accuracy were good. Compared with HPLC-UV methods, there was no significant difference in the quantitative determination of the actual samples, but the analysis time for PS-MS is shorter (2min). In addition, reagent consumption in PS-MS is small, and no chromatographic separation is needed, suggesting that PS-MS is especially suitable for high-throughput analysis. PMID- 28666162 TI - Metabolic profiling analysis of Siraitia grosvenorii revealed different characteristics of green fruit and saccharified yellow fruit. AB - Siraitia grosvenorii is an economic and medicinal plant, its fruit is considered to be good to health for its diverse bioactive ingredients. However, the clarification of chemical composition and their changes after saccharification procedure are not well performed. In present study, a metabolomics method based on ultra-high-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry was developed for metabolic profiling acquisition of Siraitia grosvenorii extract. Furthermore, information dependent analysis (IDA) combined with self-constructed LC-MS/MS identification system for metabolites were employed to identify primary and secondary metabolites in Siraitia grosvenorii. A total of 126 metabolites were identified or tentatively identified. The obvious differences of metabolic profiling between green fruit and saccharified yellow fruit were observed, and metabolites showed their own distribution characteristics in peel, flesh and seed. The majority of the nutrients and effective components were more distributed in flesh and peel, and saccharification was conducive to accumulation of sweet glycosides. This study not only expanded metabolite composition information of Siraitia grosvenorii, but also specified distribution characteristics of identified metabolites. PMID- 28666163 TI - Macroporous monoliths for biodegradation study of polymer particles considered as drug delivery systems. AB - Nanostructures based on biodegradable polymers are often considered as drug delivery systems. The properties of these nanomaterails towards in vitro biodegradation are very important and usually are studied using the model physiological conditions. In this work the novel approach based on application of monolithic immobilized enzyme reactors (IMERs) as the systems for biodegradation study of the nanoobjects of different nature and morphology was suggested. Rigid nanospheres based on poly(lactic acid) and self-assembled nanoobjects formed from block-copolymer of glutamic acid and phenylalanine were applied as model nanomaterials. For that, two enzymes, namely, esterase and papain were chosen for preparation of the monolithic IMERs. The properties of immobilized enzymes were compared to those obtained for soluble biocatalysts in the reaction of poly(lactic acid) and poly(glutamic acid) degradation. The monitoring of substrate destruction process was carried out using different HPLC modes (anion exchange, cation-exchange or precipitation-redissolution based process) also based on application of the same modern stationary phase, namely, macroporous monoliths (CIM disks and lab-made column). Finally, the applicability of monolithic immobilized enzyme reactors for degradation of polyester and polypetide-based particles was demonstrated and compared to the process observed in human blood plasma. PMID- 28666164 TI - Quantitative determination of dobutamine in newborn pig plasma samples by HPLC MS/MS. AB - A novel gradient reverse phase high performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) was performed as a method for the determination of dobutamine hydrochloride (DOB) in newborn pig plasma samples. It was developed and validated after optimization of sample treatment and various chromatographic and mass spectrometric conditions. Trimethoxydobutamine (TMD) was used as internal standard. Heptafluorobutyric acid (HFBA) and ethyl acetate were used for the treatment of plasma samples. The separation of dobutamine and internal standard was done using a Kinetex F5 (50*2.1mm, 2.6MUm, 100A) analytical column. The mobile phase was a mixture of acetonitrile and HCOOH 0.01%. The column oven temperature was optimized at 40 degrees C and the flow rate was 0.25mL/min. DOB and TMD were detected by multiple reaction monitoring (MRM) mode in ESI+, using a cone voltage (CV) of 25V and a collision energy (CE) of 25eV. The weighted calibration curve (1/x2) was found to be linear over the concentration range of 1 100ng/mL (r2>0.999). The limit of quantification (LLOQ) of the method was 1ng/mL. The values of selectivity, carryover, LLOQ, linearity, accuracy, precision, matrix effect, stability and recovery obtained meet the acceptable range according to European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. The method was efficiently applied to quantify DOB in plasma samples from a pharmacokinetic/pharmacodynamic study in a disease model of newborn piglet. PMID- 28666165 TI - A novel enantioseparation approach based on liposome electrokinetic capillary chromatography. AB - As a novel separation mode of capillary electrophoresis (CE), liposome electrokinetic capillary chromatography (LEKC) has aroused considerable attention in recent years; however, the enantioseparation based on this new system has not been previously investigated. In this study, we proposed a brand-new LEKC chiral separation approach using liposomes comprised of phosphatidylcholine (PC) and cholesterol as pseudo-stationary phase and sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) as chiral selector. Compared with the single CD system and CD-SDS MEKC system, this LEKC method presented an obviously preferable enantioseparation of four model drugs (naproxen, warfarin, ketoprofen and amlodipine). In this new established system, all the enantiomers represented baseline separations with the resolution and selectivity respectively achieving 1.584/1.067 (for naproxen), 2.226/1.045 (for warfarin), 1.537/1.038 (for ketoprofen) and 2.592/1.097 (for amlodipine), while other two comparative systems demonstrated no separation or a poor separation. Several important parameters affecting the enantioseparation, such as buffer pH, concentration of liposomes, phosphate buffer solution (PBS) and chiral selector (SBE-beta-CD), and applied voltage were systematically investigated. Satisfactory repeatability was achieved through intra-day, inter day and batch-to-batch investigations with relative standard deviations less than 3.40%. Furthermore, the established method was successfully applied to test the chiral impurity of naproxen sample. PMID- 28666166 TI - Comparison of alpha-glucosidase inhibitory effect and bioactive constituents of Anemarrhenae Rhizoma and Fibrous Roots. AB - Comprehensive utilization of medicinal plant resources is of great significance for sustainable development of traditional Chinese medicines. In the present study, the alpha-glucosidase inhibitory activities of the rhizome and fibrous root of Anemarrhena Asphodeloides Bunge, were compared detailedly, and a high performance liquid chromatography coupled with electrospray ionization tandem triple quadrupole mass spectrometry (HPLC-QQQ/MS) method was developed for simultaneous quantification of seven bioactive constituents including neomangiferin, mangiferin, isomangiferin, timosaponin BII, timosaponin B, timosaponin AIII, and timosaponin N in 40 batches of samples. The results demonstrated that fibrous root extracts had more potent alpha-glucosidase inhibitory activity than rhizome extracts. Mangiferin and isomangiferin were abundant in fibrous root, while the analyzed saponins were rich in rhizome. Based on the chemometrics methods including principal component analysis (PCA), orthogonal partial least square discriminant analysis (OPLS-DA), and partial least square (PLS), mangiferin and isomangiferin might be mainly responsible for alpha-glucosidase inhibitory activity of the genus. These findings indicate that the established HPLC-QQQ/MS method was proven to be useful and efficient for quality control of Anemarrhena materials, and fibrous root had the potential to be utilized as anti-diabetic medicinal resource. PMID- 28666167 TI - Characterization of forced degradation products of torasemide through MS tools and explanation of unusual losses observed during mass fragmentation of drug and degradation products through density functional theory. AB - Mass spectrometry tools (HRMS/LC-HRMS, MSn, and/or on-line H/D exchange) were employed to establish mass fragmentation pattern of torasemide and to characterize its degradation products. During collision-induced dissociation, multiple rearrangement processes and unusual losses of sulfur (S), sulfanyl (HS), sulfur dioxide (SO2), sulphinic acid radical (HSO2), sulfur monoxide (SO), carbon monoxide (CO), formyl radical (CHO) and C5H3NOS were observed. The same were successfully explained by study of energy profiles, established by application of density functional theory (DFT). PMID- 28666168 TI - Full cycle rapid scan EPR deconvolution algorithm. AB - Rapid scan electron paramagnetic resonance (RS EPR) is a continuous-wave (CW) method that combines narrowband excitation and broadband detection. Sinusoidal magnetic field scans that span the entire EPR spectrum cause electron spin excitations twice during the scan period. Periodic transient RS signals are digitized and time-averaged. Deconvolution of absorption spectrum from the measured full-cycle signal is an ill-posed problem that does not have a stable solution because the magnetic field passes the same EPR line twice per sinusoidal scan during up- and down-field passages. As a result, RS signals consist of two contributions that need to be separated and postprocessed individually. Deconvolution of either of the contributions is a well-posed problem that has a stable solution. The current version of the RS EPR algorithm solves the separation problem by cutting the full-scan signal into two half-period pieces. This imposes a constraint on the experiment; the EPR signal must completely decay by the end of each half-scan in order to not be truncated. The constraint limits the maximum scan frequency and, therefore, the RS signal-to-noise gain. Faster scans permit the use of higher excitation powers without saturating the spin system, translating into a higher EPR sensitivity. A stable, full-scan algorithm is described in this paper that does not require truncation of the periodic response. This algorithm utilizes the additive property of linear systems: the response to a sum of two inputs is equal the sum of responses to each of the inputs separately. Based on this property, the mathematical model for CW RS EPR can be replaced by that of a sum of two independent full-cycle pulsed field modulated experiments. In each of these experiments, the excitation power equals to zero during either up- or down-field scan. The full-cycle algorithm permits approaching the upper theoretical scan frequency limit; the transient spin system response must decay within the scan period. Separation of the interfering up- and down-field scan responses remains a challenge for reaching the full potential of this new method. For this reason, only a factor of two increase in the scan rate was achieved, in comparison with the standard half-scan RS EPR algorithm. It is important for practical use that faster scans not necessarily increase the signal bandwidth because acceleration of the Larmor frequency driven by the changing magnetic field changes its sign after passing the inflection points on the scan. The half-scan and full-scan algorithms are compared using a LiNC-BuO spin probe of known line-shape, demonstrating that the new method produces stable solutions when RS signals do not completely decay by the end of each half-scan. PMID- 28666169 TI - Assessing the effects of UVA photocatalysis on soot-coated TiO2-containing mortars. AB - The deposition of soot on building surfaces darkens their colour and leads to undesirable black crusts, which are one of the most serious problems on the conservation of built cultural heritage. As a preventive strategy, self-cleaning systems based on the use of titanium dioxide (TiO2) coatings have been employed on building materials for degrading organic compounds deposited on building surfaces, improving their durability and performance. In this study, the self cleaning effect of TiO2-containing mortars coated with diesel soot has been appraised under laboratory conditions. The mortar samples were manufactured using lime putty and two different doses of TiO2 (2.5% and 5%). The lime mortars were then coated with diesel engine soot and irradiated with ultraviolet A (UVA) illumination for 30days. The photocatalytic efficiency was evaluated by visual inspection, field emission scanning electron microscopy (FESEM) and colour spectrophotometry. Changes in the chemical composition of the soot particles (including persistent organic pollutants) were assessed by analytical pyrolysis (Py-GC/MS) and solid state 13C NMR spectroscopy. The FESEM and colour spectrophotometry revealed that the soot-coated TiO2-containing mortars promoted a self-cleaning effect after UVA irradiation. The combination of analytical pyrolysis and 13C solid state NMR showed that the UVA irradiation caused the cracking of polycyclic aromatic structures and n-alkyl compounds of the diesel soot and its transformation into methyl polymers. Our findings also revealed that the inclusion of TiO2 in the lime mortar formulations catalysed these transformations promoting the self-cleaning of the soot-stained mortars. The combined action of TiO2 and UVA irradiation is a promising proxy to clean lime mortars affected by soot deposition. PMID- 28666170 TI - Estimating heroin abuse in major Chinese cities through wastewater-based epidemiology. AB - Heroin consumption in major cities across China was estimated for the first time via wastewater-based epidemiology. Influent and effluent wastewater samples were collected from 49 wastewater treatment plants (WWTPs) in 24 major cities that cover all the geographic regions of the country. Concentrations of morphine, 6 acetylmorphine, and codeine were measured. Near complete removal of morphine by wastewater treatment processes was observed, whereas removal rates of codeine were slightly lower. Morphine loads were much higher than codeine loads at most WWTPs in China, a trend opposite to that in many European countries. In addition, morphine and codeine loads were strongly correlated at most WWTPs, indicating morphine and codeine in wastewater were predominantly from the same source, street heroin. At WWTPs in Guangzhou and Shenzhen, codeine loads were considerably higher than morphine loads, consistent with previous reports of codeine abuse (e.g., as cough syrup) among middle and high school students in Guangdong province. Heroin consumption was derived based on morphine loads and taking into account therapeutic use of morphine and codeine, as well as contribution of codeine and acetylcodeine in street heroin. Highest heroin consumption was observed in northwestern and southwestern China. The average heroin consumption of the sampled cities was 64.6+/-78.7mg/1000inh/d. The nation wide average heroin consumption was much lower than that of methamphetamine, consistent with seizure data and numbers of registered heroin and methamphetamine users in China. PMID- 28666171 TI - Ranking nano-enabled hybrid media for simultaneous removal of contaminants with different chemistries: Pseudo-equilibrium sorption tests versus column tests. AB - The underlying hypothesis of this study was that pseudo-equilibrium and column testing conditions would provide the same sorbent ranking trends although the values of sorbents' performance descriptors (e.g. sorption capacity) may vary because of different kinetics and competition effects induced by the two testing approaches. To address this hypothesis, nano-enabled hybrid media were fabricated and its removal performances were assessed for two model contaminants under multi point batch pseudo-equilibrium and continuous-flow conditions. Calculation of simultaneous removal capacity indices (SRC) demonstrated that the more resource demanding continuous-flow tests are able to generate the same performance rankings as the ones obtained by conducing the simpler pseudo-equilibrium tests. Furthermore, continuous overlap between the 98% confidence boundaries for each SRC index trend, not only validated the hypothesis that both testing conditions provide the same ranking trends, but also pointed that SRC indices are statistically the same for each media, regardless of employed method. In scenarios where rapid screening of new media is required to obtain the best performing synthesis formulation, use of pseudo-equilibrium tests proved to be reliable. Considering that kinetics induced effects on sorption capacity must not be neglected, more resource demanding column test could be conducted only with the top performing media that exhibit the highest sorption capacity. PMID- 28666172 TI - Chemical characterization and toxicity assessment of fine particulate matters emitted from the combustion of petrol and diesel fuels. AB - Fuel consumption is one of the major contributors to air pollution worldwide. Plenty of studies have demonstrated that the diesel and petrol exhaust fine particulate matters (FPMs) are associated with increases of various diseases. However, the influences of different fuel types and their chemical components on toxicity have been less investigated. In this study, four kinds of fuels that widely used in China were burned in a laboratory simulation, and the FPMs were collected and analyzed. Transmission electron microscopy showed that black carbon was mainly soot with a dendritic morphology. For light diesel oil, marine heavy diesel oil, 93 octane petrol and 97 octane petrol diesel oil, the emission factors of FPMs were 3.05+/-0.29, 3.21+/-0.54, 2.36+/-0.33, and 2.28+/-0.25g/kg fuel, respectively. And the emission factors for the "16 US EPA" PAHs of FPM were 0.45+/-0.20, 0.80+/-0.22, 1.00+/-0.20, and 1.05+/-0.19mg/g FPMs, respectively. Fe is the most abundant metal in these FPMs, and the emission factors of FPMs were 2.58+/-1.70, 4.45+/-0.11, 8.18+/-0.58, and 9.24+/-0.17mg/g FPMs, respectively. We ranked the cytotoxicity of the FPMs emission from fuels combustion: marine heavy diesel oil>97 octane petrol>93 octane petrol>light diesel oil, and the genotoxicity of FPMs emission from fuels combustion: marine heavy diesel oil>light diesel oil>93 octane petrol>97 octane petrol. Significant correlations were found between PAH concentrations and reactive oxygen species (ROS) generation. Our results demonstrated that fuels exhaust FPMs have strong association with ROS activity, cytotoxicity and genotoxicity. These results indicated that fuels exhaust FPMs pose a potentially serious health, and emphasized the importance of assessing the health risks posed by the particulate pollutants in vehicle exhausts. PMID- 28666173 TI - Linking routinely collected social work, education and health data to enable monitoring of the health and health care of school-aged children in state care ('looked after children') in Scotland: a national demonstration project. AB - BACKGROUND AND OBJECTIVES: Children in state care ('looked after children') have poorer health than children who are not looked after. Recent developments in Scotland and elsewhere have aimed to improve services and outcomes for looked after children. Routine monitoring of the health outcomes of looked after children compared to those of their non-looked after peers is currently lacking. Developing capacity for comparative monitoring of population-based outcomes based on linkage of routinely collected administrative data has been identified as a priority. To our knowledge there are no existing population-based data linkage studies providing data on the health of looked after and non-looked after children at national level. Smaller scale studies that are available generally provide very limited information on linkage methods and hence do not allow scrutiny of bias that may be introduced through the linkage process. STUDY DESIGN AND METHODS: National demonstration project testing the feasibility of linking routinely collected looked after children, education and health data. PARTICIPANTS: All children in publicly funded school in Scotland in 2011/12. RESULTS: Linkage between looked after children data and the national pupil census classified 10,009 (1.5%) and 1757 (0.3%) of 670,952 children as, respectively, currently and previously looked after. Recording of the unique pupil identifier (Scottish Candidate Number, SCN) on looked after children returns is incomplete, with 66% of looked after records for 2011/12 for children of possible school age containing a valid SCN. This will have resulted in some under-ascertainment of currently and, particularly, previously looked after children within the general pupil population. Further linkage of the pupil census to the National Health Service Scotland master patient index demonstrated that a safe link to the child's unique health service (Community Health Index) number could be obtained for a very high proportion of children in each group (94%, 95% and 95% of children classified as currently, previously, and non-looked after, respectively). In general, linkage rates were higher for older children and those living in more affluent areas. Within the looked after group, linkage rates were highest for children with the fewest placements and for those in permanent fostering. CONCLUSIONS: This novel data linkage demonstrates the feasibility of monitoring population-based health outcomes of school-aged looked after and non looked after children using linked routine administrative data. Improved recording of the unique pupil identifier number on looked after data returns would be beneficial. Extending the range of personal identifiers on looked after children returns would enable linkage to health data for looked after children who are not in publicly funded schooling (i.e. those who are preschool or postschool, home schooled or in independent schooling). PMID- 28666174 TI - Safety, feasibility and patient reported outcome measures of outpatient treatment of pulmonary embolism. AB - BACKGROUND: Despite growing evidence on safe and feasible outpatient treatment for acute pulmonary embolism (PE), the majority of patients is still treated in an inpatient setting. This is probably due to a lack of clear guidelines on this subject. OBJECTIVES: To evaluate safety and patient reported outcome measures (PROM) on outpatient treatment of acute PE. METHODS: We conducted a prospective cohort study. 250 patients presenting with acute PE and Pulmonary Embolism Severity Index (PESI) class I or II were enrolled. Safety of outpatient treatment was assessed by measuring all-cause mortality, recurrent venous thromboembolism (VTE) and episodes of relevant bleeding, with a follow-up period of four weeks and six months. Additionally, PROM's on outpatient treatment were evaluated by repeatedly measuring VAS-scores for pain and dyspnea during the recovery, and by assessing the improvement in SF-36 scores between admission and after six months. RESULTS: We found an all-cause mortality rate of 0.4% (95% CI 0.07-2.23), rate of recurrent VTE of 0% (95% CI 0-1.51) and rate of relevant bleeding episodes of 6.4% (95% CI 3.98-10.14). VAS-scores improved significantly during the first 24-h after admission, and continued to improve significantly after five days of home treatment. SF-36 scores on 6 out of 8 domains improved significantly between admission and after six months. CONCLUSIONS: Our study shows that outpatient treatment is safe in selected low-risk patients based on their PESI score. Additionally, our data on patient reported outcome measures support the presumption of a good course of recovery during outpatient treatment. PMID- 28666175 TI - Precision and accuracy of commonly used dental age estimation charts for the New Zealand population. AB - Little research has been undertaken for the New Zealand population in the field of dental age estimation. This research to date indicates there are differences in dental developmental rates between the New Zealand population and other global population groups, and within the New Zealand population itself. Dental age estimation methods range from dental development charts to complex biometric analysis. Dental development charts are not the most accurate method of dental age estimation, but are time saving in their use. They are an excellent screening tool, particularly for post-mortem identification purposes, and for assessing variation from population norms in living individuals. The aim of this study was to test the precision and accuracy of three dental development charts (Schour and Massler, Blenkin and Taylor, and the London Atlas), used to estimate dental age of a sample of New Zealand juveniles between the ages of 5 and 18 years old (n=875). Percentage 'best fit' to correct age category and to expected chart stage were calculated to determine which chart was the most precise for the sample. Chronological ages were compared to estimated dental ages using a two tailed paired t-test (P<0.05) for each of the three methods. The mean differences between CA and DA were calculated to determine bias and the absolute mean differences were calculated to indicate accuracy. The results of this study show that while accuracy and precision were low for all charts tested against the New Zealand population sample, the Blenkin and Taylor Australian charts performed best overall. PMID- 28666176 TI - Nitrous oxide, methane and carbon dioxide patterns and dynamics from an experimental pig mass grave. AB - The objective of the three-year study was to examine spatial and temporal patterns of fluxes and soil pore air concentrations of methane (CH4), carbon dioxide (CO2) and nitrous oxide (N2O) from an experimental mass grave located in a temperate environment. The mass grave (5*10m) contained twenty pig carcasses at a depth of approximately 1m was compared to a plot of the same dimensions containing only disturbed soil, as well as an undisturbed plot. Soil pore air CH4 concentrations were sub-ambient (<1.8ppm) except at 75 and 100cm depths at the mass grave in years 1 and 2 but decreased in year 3. The consumption of CH4 within the aerobic soil resulted in small negative fluxes at the soil surface. Soil pore air CO2 concentration showed an increase with depth in all three plots, with the largest increase (>100,000ppm at 1m) in the mass grave, though there was a marked decrease from years 1 to 3. Surface fluxes of CO2 showed strong seasonal variations, peaking in summer. Soil pore air N2O concentration showed major increases in the mass grave, compared to the other two plots with the pattern maintained over the three years, resulting in larger surface fluxes of N2O. To establish the role of the carcasses in N2O dynamics, we incubated a soil sample containing carcass material which resulted in fast rates of N2O production and consumption. The maintenance of elevated pore air concentration and surface flux of N2O throughout the 3 years suggests that this is a long-term pattern and likely the best of the three gases to use to detect graves. Thus, we suggest that measurement of soil pore air concentrations, especially of N2O, could be a simple and effective approach to help determine the location of clandestine graves. PMID- 28666177 TI - Accuracy of step count measured by physical activity monitors: The effect of gait speed and anatomical placement site. AB - INTRODUCTION: Consumer-based physical activity monitors (PAMs) are becoming increasingly popular, with multiple global organisations recommending physical activity levels that equate to 10,000 steps per day for optimal health. We therefore aimed to compare the step count of five PAMs to a visual step count to identify the most accurate monitors at varying gait speeds, along with the optimal anatomical placement site. METHODS: Participants completed 3min on a treadmill for five speeds (5.0km/h, 6.5km/h, 8.0km/h, 10km/h, 12km/h). An Actigraph wGT3XBT-BT was placed on the waist and wrist, a FitBit One on the waist, and a Fitbit Flex, Fitbit Charge HR and Jawbone UP24 on both wrists. A video of participant's lower limbs was recorded for visual count. Analyses of variance (ANOVAs) were conducted to examine the effects of gait speed and device placement site on step count accuracy. RESULTS: Thirty-one participants (mean age 24.3+/-5.2yrs) took part. Step count error ranged from 41.3+/-13.8% for the wrist worn Actigraph to only 0.04+/-4.3% and -0.3+/-4.0% for the waist-worn Fitbit One and Actigraph, respectively. Across all gait speeds, waist-worn devices achieved better accuracy than those on the wrist (p<0.001). The Jawbone was the most accurate wrist-worn consumer-based device at slower speeds (p=0.026), with the Fitbit Flex, and Fitbit Charge HR increasing in accuracy to match the Jawbone at higher speeds. CONCLUSION: The accuracy and reliability of consumer-based PAMs and the Actigraph is affected by anatomical placement site and walking speed. The Fitbit One and Actigraph on the waist were the strongest performers across all speeds. PMID- 28666178 TI - A systematic review of gait analysis methods based on inertial sensors and adaptive algorithms. AB - The conventional methods to assess human gait are either expensive or complex to be applied regularly in clinical practice. To reduce the cost and simplify the evaluation, inertial sensors and adaptive algorithms have been utilized, respectively. This paper aims to summarize studies that applied adaptive also called artificial intelligence (AI) algorithms to gait analysis based on inertial sensor data, verifying if they can support the clinical evaluation. Articles were identified through searches of the main databases, which were encompassed from 1968 to October 2016. We have identified 22 studies that met the inclusion criteria. The included papers were analyzed due to their data acquisition and processing methods with specific questionnaires. Concerning the data acquisition, the mean score is 6.1+/-1.62, what implies that 13 of 22 papers failed to report relevant outcomes. The quality assessment of AI algorithms presents an above average rating (8.2+/-1.84). Therefore, AI algorithms seem to be able to support gait analysis based on inertial sensor data. Further research, however, is necessary to enhance and standardize the application in patients, since most of the studies used distinct methods to evaluate healthy subjects. PMID- 28666179 TI - Computing dispersion curves of elastic/viscoelastic transversely-isotropic bone plates coupled with soft tissue and marrow using semi-analytical finite element (SAFE) method. AB - We present a semi-analytical finite element (SAFE) scheme for accurately computing the velocity dispersion and attenuation in a trilayered system consisting of a transversely-isotropic (TI) cortical bone plate sandwiched between the soft tissue and marrow layers. The soft tissue and marrow are mimicked by two fluid layers of finite thickness. A Kelvin-Voigt model accounts for the absorption of all three biological domains. The simulated dispersion curves are validated by the results from the commercial software DISPERSE and published literature. Finally, the algorithm is applied to a viscoelastic trilayered TI bone model to interpret the guided modes of an ex-vivo experimental data set from a bone phantom. PMID- 28666180 TI - History of cannabis use is associated with altered gait. AB - BACKGROUND: Despite evidence that cannabinoid receptors are located in movement related brain regions (e.g., basal ganglia, cerebral cortex, and cerebellum), and that chronic cannabis use is associated with structural and functional brain changes, little is known about the long-term effect of cannabis use on human movement. The aim of the current study was to investigate balance and walking gait in adults with a history of cannabis use. We hypothesised that cannabis use is associated with subtle changes in gait and balance that are insufficient in magnitude for detection in a clinical setting. METHODS: Cannabis users (n=22, 24+/-6years) and non-drug using controls (n=22, 25+/-8years) completed screening tests, a gait and balance test (with a motion capture system and in-built force platforms), and a clinical neurological examination of movement. RESULTS: Compared to controls, cannabis users exhibited significantly greater peak angular velocity of the knee (396+/-30 versus 426+/-50 degrees /second, P=0.039), greater peak elbow flexion (53+/-12 versus 57+/-7 degrees , P=0.038) and elbow range of motion (33+/-13 versus 36+/-10 degrees , P=0.044), and reduced shoulder flexion (41+/-19 versus 26+/-16 degrees , P=0.007) during walking gait. However, balance and neurological parameters did not significantly differ between the groups. CONCLUSIONS: The results suggest that history of cannabis use is associated with long-lasting changes in open-chain elements of walking gait, but the magnitude of change is not clinically detectable. Further research is required to investigate if the subtle gait changes observed in this population become more apparent with aging and increased cannabis use. PMID- 28666181 TI - Prescribing of benzodiazepines and opioids to individuals with substance use disorders. AB - BACKGROUND: Benzodiazepines are recommended for short-term use due to risk of dependence. This study examined characteristics associated with benzodiazepine and opioid dispensing of 7+ days in a Medicaid population with substance use disorder (SUD). METHODS: Using 2014 MarketScan(r) data, we performed zero inflated negative binomial regression to ascertain characteristics associated with longer-term use of these medications. RESULTS: Nearly 14% of those with SUDs received 1+ fills of benzodiazepines of 7+ days. The highest rates were among those aged 45-64 (IRR=2.38, p<0.0001) and with non-alcohol SUDs (IRR=1.12, p<0.0001). Individuals with co-occurring psychiatric disorders, particularly anxiety and depression (IRR=1.41, p<0.0001), had high rates of benzodiazepine fills. Receiving a 7+ day oral opioid fill (IRR=1.30, p<0.0001) coincided with increased benzodiazepine dispensing. Similar results occurred for longer-term prescribing of opioids, with higher rates among those with non-alcohol SUDs (IRR=1.23, p< 0.0001). CONCLUSIONS: For many people with SUDs, receiving a benzodiazepine or opioid prescription of 7+ days is not a single occurrence; patients in our sample were more likely to receive 2+ fills than to receive one. Longer-term prescribing is most pronounced among those with co-occurring anxiety disorders. This suggests that anxiety in those with SUD should preferentially not be treated using benzodiazepines. Longer-term polypharmacy with benzodiazepines and opioids coincided. Overdoses among those using both drugs are growing and this study provides evidence that attention to the opioid epidemic should include attention to polypharmacy that includes benzodiazepines. PMID- 28666183 TI - The impact of simulation sequencing on perceived clinical decision making. AB - An emerging nursing education trend is to utilize simulated learning experiences as a means to optimize competency and decision making skills. The purpose of this study was to examine differences in students' perception of clinical decision making and clinical decision making-related self-confidence and anxiety based on the sequence (order) in which they participated in a block of simulated versus hospital-based learning experiences. A quasi-experimental crossover design was used. Between and within group differences were found relative to self-confidence with the decision making process. When comparing groups, at baseline the simulation followed by hospital group had significantly higher self-confidence scores, however, at 14-weeks both groups were not significantly different. Significant within group differences were found in the simulation followed by hospital group only, demonstrating a significant decrease in clinical decision making related anxiety across the semester. Finally, there were no significant difference in; perceived clinical decision making within or between the groups at the two measurement points. Preliminary findings suggest that simulated learning experiences can be offered with alternating sequences without impacting the process, anxiety or confidence with clinical decision making. This study provides beginning evidence to guide curriculum development and allow flexibility based on student needs and available resources. PMID- 28666182 TI - Serum cystatin C in youth with diabetes: The SEARCH for diabetes in youth study. AB - AIMS: We compared cystatin C in youth with versus without diabetes and determined factors associated with cystatin C in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D). METHODS: Youth (ages 12-19years) without diabetes (N=544) were ascertained from the NHANES Study 2000-2002 and those with T1D (N=977) and T2D (N=168) from the SEARCH for Diabetes in Youth Study. Adjusted means of cystatin C concentrations were compared amongst the 3 groups. Next, we performed multivariable analyses within the T1D and T2D SEARCH samples to determine the association between cystatin C and race, sex, age, diabetes duration, HbA1c, fasting glucose, and BMI. RESULTS: Adjusted cystatin C concentrations were statistically higher in NHANES (0.85mg/L) than in either the T1D (0.75mg/L) or T2D (0.70mg/L) SEARCH groups (P<0.0001). Fasting glucose was inversely related to cystatin C only in T1D (P<0.001) and BMI positively associated only in T2D (P<0.01) while HbA1c was inversely associated in both groups. CONCLUSIONS: Cystatin C concentrations are statistically higher in youth without diabetes compared to T1D or T2D, however the clinical relevance of this difference is quite small, especially in T1D. In youth with diabetes, cystatin C varies with BMI and acute and chronic glycemic control, however their effects may be different according to diabetes type. PMID- 28666184 TI - Pregnancy outcome in women with epilepsy in Western China: A prospective hospital based study. AB - OBJECTIVE: Gaps exist in the diagnosis and treatment of women with epilepsy (WWE) between China and Euro-American countries. We aim to find out and share our experience of the multidisciplinary integrated treatment for WWE. METHODS: We prospectively registered WWE who were diagnosed by both epileptologists and obstetrician in our green way system for the past 5years (2009-2015). Registration information include years of education, epilepsy history, seizure type and frequency, pregnancy and delivery complications, delivery mode, and Apgar score of newborn. All data were analyzed by SAS 9.3 version. RESULTS: We included 137 cases of maternal epilepsy (155 pregnancies with average maternal age of 26years old). 18 cases underwent epilepsy surgery before pregnancy. 103 pregnancies (66.45%) were cesarean section, 52 (33.55%) were natural childbirth, only 10 pregnancies have pregnancy complications, 2 have delivery complication, and 15 have seizures during delivery process. Most offspring were healthy when they were born (only 11 newborn got Apgar score<7). For drug treatment, patients never took AEDs or withdrew AEDs in 55 (35.48%) pregnancies. For folic acid supplementation, only 9 (5.81%) achieved the dose recommended by ILAE guideline (5mg/day). For the seizure frequency, 108 pregnancies (69.68%) did not changed, 3 (1.94%) reduced, 44(28.39%) increased and mainly increased in the first and last trimesters. For feeding way, 90 (58.06%) chose artificial feeding, followed by 39 (16.77%) of mixed feeding and 26 of breastfeeding. CONCLUSION: Clinical features and perinatal outcome of Chinese WWE are similar to western WWE. For mode of delivery, even suggested by our epileptologists and obstetrician to deliver naturally, more patients selected cesarean section. Moreover, withdrawal of AEDs during pregnancy is common. Therefore, it is necessary to pay more attention to standard management of WWE and establish a more practical green way for WWE in China, to keep up with developed countries and improve the health level of birth in China. PMID- 28666185 TI - Multilevel analysis of individual differences in regularities of grapheme-color associations in synesthesia. AB - Grapheme-color synesthesia is a neurological phenomenon where visual perception of letters and numbers stimulates perception of a specific color. Grapheme-color correspondences have been shown to be systematically associated with grapheme properties, including visual shape difference, ordinality, and frequency. However, the contributions of grapheme factors differ across individuals. In this study, we applied multilevel analysis to test whether individual differences in regularities of grapheme-color associations could be explained by individual styles of processing grapheme properties. These processing styles are reflected by the type of synesthetic experience. Specifically, we hypothesized that processing focusing on shape differences would be associated with projector synesthetes, while processing focusing on ordinality or familiarity would be associated with associator synesthetes. The analysis revealed that ordinality and familiarity factors were expressed more strongly among associators than among projectors. This finding suggests that grapheme-color associations are partly determined by the type of synesthetic experience. PMID- 28666186 TI - EEG correlates of cognitive time scales in the Necker-Zeno model for bistable perception. AB - The Necker-Zeno model of bistable perception provides a formal relation between the average duration of meta-stable percepts (dwell times T) of ambiguous figures and two other basic time scales (t0, DeltaT) underlying cognitive processing. The model predicts that dwell times T covary with t0, DeltaT or both. We tested this prediction by exploiting that observers, in particular experienced meditators, can volitionally control dwell times T. Meditators and non-meditators observed bistable Necker cubes either passively or tried to hold their current percept. The latencies of a centro-parietal event-related potential (CPP) were recorded as a physiological correlate of t0. Dwell times T and the CPP latencies, correlated with t0, differed between conditions and observer groups, while DeltaT remained constant in the range predicted by the model. The covariation of CPP latencies and dwell times, as well as their quadratic functional dependence extends previous psychophysical confirmation of the Necker-Zeno model to psychophysiological measures. PMID- 28666188 TI - Cone-beam Breast Computed Tomography: CT Density Does Not Reflect Proliferation Potential and Receptor Expression of Breast Carcinoma. AB - PURPOSE: Recently, cone-beam breast computed tomography (CBCT) is established for the breast investigation. The purpose of the present study was to investigate possible associations between CBCT findings and histopathological features in breast cancer. METHODS: Overall, 59 female patients, mean age of 64.6 years with histological proven breast cancer were included into the study. In all cases, non contrast CBCT examination was done. The diagnosis of the identified lesions was confirmed histologically by biopsy. Immunohistochemical staining against estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 was performed for every lesion. Collected data were evaluated by means of descriptive statistics. Spearman's correlation coefficient was used to analyze the association between CT density and Ki-67 values. P values <0.05 were taken to indicate statistical significance in all instances. RESULTS: The size of the lesion varied from 2.7 to 90.0, mean size, 15.88+/-13.0 mm. The mean value of CT density of the lesions was 63.95+/-38.18 HU. The density tended to be higher in tubular carcinoma. Correlation analysis identified no significant correlations between CT density and Ki-67 level (r=-0.031, P=.784). There were no statistically significant differences of CT density between tumors with different receptor status. CONCLUSIONS: No significant associations between CT density and receptor status in breast cancer. Tubular carcinoma tended to have higher CT density in comparison to other subtypes of breast carcinomas. PMID- 28666187 TI - Evaluation of the Prognostic Value of RANK, OPG, and RANKL mRNA Expression in Early Breast Cancer Patients Treated with Anthracycline-Based Adjuvant Chemotherapy. AB - BACKGROUND: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS: Median age was 52.7years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P=.002 and P<.001, respectively). In the univariate analysis, low RANKL mRNA expression was found to be an unfavorable factor for DFS [hazard ratio (HR)=1.33, 95% confidence interval (CI) 1.05-1.68, Wald's P=.018] and bone metastasis-free survival (HR=1.67, 95% CI 1.09-2.56, P=.018), although it did not retain its significance in the multivariate analysis. CONCLUSIONS: Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts. PMID- 28666189 TI - Oral Metronomic Topotecan Sensitizes Crizotinib Antitumor Activity in ALKF1174L Drug-Resistant Neuroblastoma Preclinical Models. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) inhibitor crizotinib has proven to be effective in the treatment of ALK-mutated neuroblastoma, but crizotinib resistance was commonly observed in patients. We aimed to overcome crizotinib resistance by combining with the MEK inhibitor trametinib or low-dose metronomic (LDM) topotecan in preclinical neuroblastoma models. METHODS: We selected a panel of neuroblastoma cell lines carrying various ALK genetic aberrations to assess the therapeutic efficacy on cell proliferation in vitro. Downstream signals of ALK activation, including phosphorylation of ERK1/2, Akt as well as HIF-1alpha expression were evaluated under normoxic and hypoxic conditions. Tumor growth inhibition was further assessed in NOD/SCID xenograft mouse models. RESULTS: All NBL cell lines responded to crizotinib treatment but at variable ED50 levels, ranging from 0.25 to 5.58 MUM. ALK-mutated cell lines SH-SY5Y, KELLY, LAN-5, and CHLA-20 are more sensitive than ALK wild-type cell lines. In addition, we demonstrated that under hypoxic conditions, all NBL cell lines showed marked decrease of ED50s when compared to normoxia except for KELLY cells. Taking into consideration the hypoxia sensitivity to crizotinib, combined treatment with crizotinib and LDM topotecan demonstrated a synergistic effect in ALKF1174L mutated SH-SY5Y cells. In vivo, single-agent crizotinib showed limited antitumor activity in ALKF1174L-mutated SH-SY5Y and KELLY xenograft models; however, when combined with topotecan, significantly delayed tumor development was achieved in both SH-SY5Y and KELLY tumor models. CONCLUSIONS: Oral metronomic topotecan reversed crizotinib drug resistance in the ALKF1174L-mutated neuroblastoma preclinical model. PMID- 28666190 TI - Chemotherapy Induces Oral Mucositis in Mice Without Additional Noxious Stimuli. AB - Oral mucositis (OM) is a serious side effect of cancer chemotherapy. The pathobiology of oral mucositis remains incompletely understood due to lack of appropriate models which recapitulate the human condition. Existing rodent models are intraperitoneal and require radiation, chemical or mechanical injury to the chemotherapy protocol to induce oral lesions. We aimed to develop an OM mouse model that is induced solely by chemotherapy and reproduces macroscopic, histopathologic and inflammatory characteristics of the human condition. Female C57BL/6 mice were given intravenous 5-Fluorouracil (5-FU) injections every 48 hours, for 2 weeks. A high daily dose of intraperitoneal administration was tested for comparison. Mice were monitored daily for weight loss. Epithelial histomorphometric analyses in tongue, esophageal and intestinal tissues were conducted coupled with assessment of apoptosis, cell proliferation, neutrophilic infiltration and the integrity of adherens junctions by immunohistochemistry. Neutropenia was assessed in peripheral blood and bone marrow. Tissues were analyzed for pro-inflammatory cytokines at the protein and mRNA levels. Daily intraperitoneal administration of 5-FU led to rapid weight loss and intestinal mucositis, but no oral inflammatory changes. Intravenous administration triggered atrophy of the oral and esophageal epithelium accompanied by reduction in cell proliferation and increased apoptosis. Coincidental with these changes were up regulation of NF-kappaB, TNFalpha, IL-1beta, GM-CSF, IL-6 and KC. Despite neutropenia, increased oral neutrophilic infiltration and reduced E-cadherin was observed in oroesophageal mucosae. We developed a novel experimental tool for future mechanistic studies on the pathogenesis of chemotherapy-induced OM. PMID- 28666191 TI - Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti influenza activity. AB - With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18-1.2 MUM) at no toxic concentrations (CC50 > 250 MUM). This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents. PMID- 28666192 TI - Preventing obesity across the preconception, pregnancy and postpartum cycle: Implementing research into practice. PMID- 28666193 TI - Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: A meta-analysis of 68 patients. AB - RATIONALE: Dravet Syndrome (DS) is a severe epileptic encephalopathy of childhood involving intractable seizures, recurrent status epilepticus and cognitive decline. Because DS is a rare disease, available data is limited and evidence based treatment guidelines are lacking. Vagus nerve stimulation (VNS) is an established neurostimulation treatment for intractable epilepsy, however little evidence is published on its efficacy in patients with DS. METHODS: We performed a meta-analysis of all peer-reviewed English language studies reporting seizure outcomes of patients with DS treated with adjunctive vagus nerve stimulation. The primary and secondary outcome measures were >=50% reduction of seizures or of the most-debilitating seizure type and seizure reduction per patient. RESULTS: 13 studies comprising 68 patients met the inclusion criteria of which 11 were single center retrospective case series, one was a multi-center retrospective analysis and one was a case report. 52.9% of patients experienced a >=50% reduction of seizures and the average seizure reduction, which could only be assessed in n=28 patients was 50.8%. 7 out of 13 studies reported additional benefits of VNS, however this could not be assessed systematically. CONCLUSION: Vagus nerve stimulation appears to reduce seizure frequency in patients with DS. Based on this preliminary analysis, controlled trials of VNS in this rare condition using patient-centric outcome measures are indicated. PMID- 28666194 TI - Dietary cholesterol-induced transcriptome differences in the intestine, hepatopancreas, and muscle of Oriental River prawn Macrobrachium nipponense. AB - Cholesterol is an important nutrient for crustaceans. In this study, we performed comparative transcriptome analyses to explore the transcriptome differences in the intestine, hepatopancreas, and muscle of Macrobrachium nipponense fed either a low cholesterol (LC) or high cholesterol (HC) diet (2.8 or 17.1g cholesterol per kg diet). High-throughput RNA-Seq was conducted, resulting in 7.65, 5.88, and 7.59G clean bases from the intestine, hepatopancreas, and muscle of the LC group, respectively, and 7.59, 6.73, and 6.70G clean bases from the same tissues of the HC group. Assembly of clean reads resulted in 230,946 unigenes. The following enriched pathways were identified: xenobiotic and drug metabolism by cytochrome P450; chloroalkane and chloroalkene degradation; metabolic and biosynthetic pathways; fatty acid metabolism and biosynthesis; and immune-related pathways. To the best of our knowledge, this is the first study to describe how functional unigenes and biosynthetic and metabolic pathways are affected by dietary cholesterol in aquatic crustaceans. Thus, these results contribute to our understanding of the molecular mechanisms underlying the cholesterol requirement of crustaceans. PMID- 28666195 TI - Political and environmental attitude toward participatory energy and environmental governance: A survey in post-Fukushima Japan. AB - The Great East Japan Earthquake and subsequent Fukushima nuclear accident triggered citizen dialogue on energy and environmental management in Japan. However, an international survey has shown that the willingness of Japanese citizens to participate in political and social activities has declined since the Fukushima accident. Employing an internet-based survey in four urban or nuclear power plant-hosting prefectures in Japan, this study examines the willingness to participate in random sampling deliberation on post-disaster energy and environmental policy. It focuses on the effects of political, environmental, and social attitudes towards willingness to participate in citizen dialogue. The survey shows around 40% of respondents may participate in energy and environmental deliberation. Statistical analysis reveals that environmental consciousness raises the propensity to participate in deliberation, while political obedience and social hesitation decreases the will to participate. The effect of environmental attitudes is larger than that of political and social attitudes. The survey also finds that governmental response to deliberation, i.e., information generation and disclosure based on requests from citizen dialogue, encourages participation in deliberation in a conservative prefecture, when citizen dialogue is held at the national level. Random sampling deliberation opens a new mode of environmental governance regardless of local political and social characteristics. PMID- 28666196 TI - Dynamics of soil organic carbon in density fractions during post-agricultural succession over two lithology types, southwest China. AB - Agricultural abandonment has been proposed as an effective way to enhance soil organic carbon (SOC) sequestration. Nevertheless, SOC sequestration in the long term is largely determined by whether the stable SOC fractions will increase. Here the dynamics of SOC fractions during post-agricultural succession were investigated in a karst region, southwest China using a space-for-time substitution approach. Cropland, grassland, shrubland and secondary forest were selected from areas underlain by dolomite and limestone, respectively. Density fractionation was used to separate bulk SOC into free light fraction (FLFC) and heavy fraction (HFC). FLFC contents were similar over dolomite and limestone, but bulk SOC and HFC contents were greater over limestone than over dolomite. FLFC content in the forest was greater than in the other vegetation types, but bulk SOC and HFC contents increased from the cropland through to the forest for areas underlain by dolomite. The contents of bulk SOC and its fractions were similar among the four vegetation types over limestone. The proportion of FLFC in bulk SOC was higher over dolomite than over limestone, but the case was inverse for the proportion of HFC, indicating SOC over limestone was more stable. However, the proportions of both FLFC and HFC were similar among the four vegetation types, implying that SOC stability was not changed by cropland conversion. Exchangeable calcium explained most of the variance of HFC content. Our study suggests that lithology not only affects SOC content and its stability, but modulates the dynamics of SOC fractions during post-agricultural succession. PMID- 28666197 TI - Evaluation of pyritic mine tailings as a plant growth substrate. AB - At the Kidston gold mine, Australia, the direct establishment of vegetation on tailings was considered as an alternative to the use of a waste rock cover. The tailings acid/base account was used to predict plant growth limitation by acidity, and thus methods capable of identifying tailings that would acidify to pH 4.5 or lower were sought. Total S was found to be poorly correlated with acid generating sulfide, and total C was poorly correlated with acid-neutralizing carbonate, precluding the use of readily determined total S and C as predictors of net acid generation. Therefore, the selected approach used assessment of sulfide content as a predictor of acid generation, and carbonate content as a measure of the acid-neutralizing capacity available at pH 5 and above. Using this approach, the majority of tailings (67%) were found to be non-acid generating. However, areas of potentially acid-generating tailings were randomly distributed across the dam, and could only be located by intensive sampling. The limitations imposed by the large sample numbers, and costly analysis of sulfide and carbonate, make it impractical to identify and ameliorate acid-generating areas prior to vegetation establishment. However, as only a small proportion of the tailings will acidify, a strategy of re-treating acid areas following oxidation is suggested. The findings of the present study will assist in the selection of appropriate methods for the prediction of net acid generation, particularly where more conservative measurements are required to allow vegetation to be established directly in tailings. PMID- 28666198 TI - Decision-making criteria for plant-species selection for phytostabilization: Issues of biodiversity and functionality. AB - In polluted protected areas, using phytoremediation raises the question of the choice of the plant species to select. As an example, Atriplex halimus has been identified as a proliferative plant species that needs to be eradicated in the Calanques National Park (PNCal). Since it has been proven that the spontaneous populations of this plant species could phytostabilize shore waste deposits generated by past industrial activities within the PNCal territory, its status seems controversial, presenting a dilemma between biodiversity management of a protected area and ecological solutions for pollution management. To address this issue, we assessed the ability of A. halimus to grow on different soils from this territory, in order to estimate the potential invasiveness of this plant in this territory. Petri dish germinations and pot-growth experiments showed 50% germination of seeds collected on local individuals from the most polluted PNCal soil and 20% growth reduction of seedlings. Soil analysis showed that limitation of growth was caused by high pH value and sparsely available micronutrients as well as metal and metalloid contamination. Our results suggested that local populations of A. halimus may stabilize the highly metal and metalloid polluted salt-affected soils of the PNCal, with low seed germination potential lowering the eventuality of a propagation over the PNCal territory. As a consequence of this study, the administration of the PNCal decided not to remove A. halimus populations along the polluted coastline until another solution to prevent pollution dispersal had been found. This laboratory approach may be extended to other similar situations where plant species may be evaluated not only in term of phytoremediation potential but also in term of biodiversity preservation. PMID- 28666199 TI - The big-fish-little-pond effect on mathematics self-concept: Evidence from the United Arab Emirates. AB - This study examined the big-fish-little-pond effect (BFLPE; Marsh, 1987) on mathematics self-concept of 7404 adolescents (female = 3767 [51%], male = 3637 [49%]; Mage = 15.85 years, SD = 0.28) from 456 schools in the United Arab Emirates, one of the Arab states of the Persian Gulf. The results of multilevel regression analyses indicated good support for the BFLPE's theoretical predictions: the effect of individual student mathematics achievement on individual student mathematics self-concept was positive and statistically significant, whereas the effect of school-average mathematics achievement on individual student mathematics self-concept was negative and statistically significant. Moreover, the interaction between school-average mathematics achievement and individual student mathematics achievement was small and non significant. Implications of the findings for policy and practice are briefly discussed. PMID- 28666200 TI - Polyunsaturated fatty acid composition and childhood adversity: Independent correlates of depressive symptom persistence. AB - Childhood experiences, personality, and polyunsaturated essential fatty acid (PUFA) composition have all been shown to affect the likelihood of depressive symptoms. Few studies have addressed relationships between these factors in their influence on the occurrence or course of depressive symptoms. The following analysis was designed to do so. Subjects, 15-20 years old, had either begun antidepressant treatment within the preceding month (n = 88), or had never taken psychiatric medications (n = 92). Baseline assessments included a structured diagnostic interview, the self-completed Multiphasic Personality Questionnaire, and a determination of plasma PUFA phospholipid composition. Depressive symptom levels were assessed at baseline and again at 4, 8 and 12 months. Omega-3 composition and general childhood trauma scores were unrelated to each other but both correlated, in predicted directions, with negative emotionality. Low omega-3 composition and history of childhood trauma were associated with persistence of depressive symptoms during follow-up, largely through their effects on negative emotionality. Negative emotionality appears to comprise a final common pathway to depressive disorder through which the diverse risk factors of childhood adversity and low omega-3 composition are expressed. PMID- 28666201 TI - Screening for generalized anxiety disorder in Spanish primary care centers with the GAD-7. AB - The aim of the study was to determine the criterion validity of a computerized version of the General Anxiety Disorder-7 (GAD-7) questionnaire to detect general anxiety disorder in Spanish primary care centers. A total of 178 patients completed the GAD-7 and were administered the Composite International Diagnostic Interview (CIDI) for DSM-IV Axis I Disorders, which was used as a reference standard. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated. A cut-off of 10 yielded a sensitivity of .87, a specificity of .78, a positive predictive value of .93, a negative predictive value of .64, a positive likelihood ratio of 3.96 a negative likelihood ratio of .17 and Younden's Index of .65. The GAD-7 performed very well with a cut-off value of 10, the most frequently used cut-off point. Thus, a computerized version of the GAD-7 is an excellent screening tool for detecting general anxiety disorder in Spanish primary care settings. PMID- 28666202 TI - The impact of cocaine use in patients enrolled in opioid agonist therapy in Ontario, Canada. AB - BACKGROUND: Opioid agonist therapy is the gold standard of care for opioid use disorder; however, the efficacy of this treatment may be hindered by concurrent drug use, including the use of cocaine. This study examines the impact of cocaine use on treatment retention, while accounting for various risk factors, including geographic location, age, gender, and first-month cocaine use. METHODS: We conducted a retrospective cohort study using anonymized electronic medical records from 58 opioid agonist therapy clinics in Ontario between 2011 and 2013. One-year treatment retention was the primary outcome of interest and was measured by differing frequencies of cocaine use - as well as baseline use - with an additional focus on geographic location (Northern Ontario vs. Southern Ontario). RESULTS: Our cohort consisted of 3835 patients, with the average retention rate of 44%. Baseline cocaine users had a retention rate of 39% and non-users had a retention rate of 46%. Patients who were cocaine-negative on admission benefited from an increased median days retained (302 vs. 212 days). Patients who used cocaine at higher frequencies had decreased retention rates compared to those who used less often. Despite increased levels of cocaine use, Northern patients were better retained than Southern patients. CONCLUSION: Northern patients and patients from urban communities are more likely to be baseline cocaine users. Both baseline and continued cocaine use is predictive of treatment dropout in Northern and Southern patients. The higher the frequency of cocaine use, the more likely a patient is to terminate treatment. Patients in Northern Ontario are retained in treatment at higher rates than their Southern counterparts. PMID- 28666203 TI - Understanding experiences of and rationales for sharing crack-smoking equipment: A qualitative study with persons who smoke crack in Montreal. AB - BACKGROUND: The distribution of safer crack-smoking equipment has been implemented in several Canadian cities to reduce potential health risks such as transmission of blood borne viruses (BBV). Little is known about the perspectives of persons who smoke crack (PWSC) on sharing crack-smoking materials or using in settings where safer crack-smoking equipment is provided. This paper presents data from the perspective of PWSC in Montreal on their experiences of, and rationales for, sharing crack-smoking equipment, in light of the risks of BBV transmission. METHODS: This qualitative study is based on analyses of BBV risk behaviours among people who use cocaine. Thirty-two semi-structured interviews were conducted in low-threshold community centres for persons who use drugs. Twenty-six interviewees who used cocaine also smoked crack, and constitute a subsample for analyses. Interview transcripts were coded inductively and analyzed thematically from a symbolic interactionist perspective. RESULTS: Participants demonstrated personal agency by adopting strategies to minimise sharing of smoking equipment. These included being firm in refusal to share, smoking alone, and keeping an extra pipe to give to others. Nonetheless, sharing seemed to be commonplace and was attributed to contextual and personal factors. These were linked to the social dynamics among smokers; economic reasons such as wanting to keep the accumulated crack resin; practical reasons such as lacking own smoking equipment; being ashamed to purchase or acquire crack pipes; fatalism; poor personal agency; and ambivalence or scepticism towards BBV transmission risks. CONCLUSION: To reinforce harm reduction for PWSC, interventions aimed at reducing barriers to safer smoking practices should be developed at both structural and individual levels. PMID- 28666204 TI - Assessing support for supervised injection services among community stakeholders in London, Canada. AB - OBJECTIVES: Few qualitative studies have examined support for supervised injection services (SIS), and these have been restricted to large cities. This study aimed to assess support for SIS among a diverse representation of community stakeholders in London, a mid-sized city in southwestern Ontario, Canada. METHODS: This qualitative study was undertaken as part of the Ontario Integrated Supervised Injection Services Feasibility Study. We used purposive sampling methods to recruit a diversity of key informants (n=20) from five sectors: healthcare; social services; government and municipal services; police and emergency services; and the business and community sector. Interview data, collected via one-to-one semi structured interviews, were coded and analyzed using thematic analyses through NVivo 10 software. RESULTS: Interview participants unanimously supported the implementation of SIS in London. However, participant support for SIS was met with some implementation-related preferences and/or conditions. These included centralization or decentralization of SIS; accessibility of SIS for people who inject drugs; proximity of SIS to interview participants; and other services and strategies offered alongside SIS. DISCUSSION: The results of this study challenge the assumptions that smaller cities like London may be unlikely to support SIS. Community stakeholders were supportive of the implementation of SIS with some preferences or conditions. Interview participants had differing perspectives, but ultimately supported similar end goals of accessibility and reducing community harms associated with injection drug use. Future research and SIS programming should consider these factors when determining optimal service delivery in ways that increase support from a diversity of community stakeholders. PMID- 28666205 TI - Re-examining blood donor deferral criteria relating to injecting drug use. AB - BACKGROUND AND AIMS: Potential Australian blood donors are deferred indefinitely if they report a history of injecting drug use (IDU), or for 12 months if they report having engaged in sexual activity with someone who might have ever injected. Given incremental improvements in blood safety, this study sought to examine whether Australia's IDU-related eligibility criteria reflected current scientific evidence, were consistent with international best practice and, if current IDU-related policies were to be changed, how this should happen. METHODS: An expert committee was formed to review relevant literature with a focus on issues including: the epidemiology of IDU in Australia and key transfusion transmissible infections (TTIs) among Australian people who inject drugs (PWID); and, 'non-compliance' among PWID regarding IDU-related blood donation guidelines. International policies relating to blood donation and IDU were also reviewed. Modelling with available data estimated the risk of TTIs remaining undetected if the Blood Service's IDU-related guidelines were changed. RESULTS: Very few (<1%) Australians engage in IDU, and IDU risk practices are reported by only a minority of PWID. However, the prevalence of HCV remains high among PWID, and IDU remains a key transmission route for various TTIs. Insufficient data were available to inform appropriate estimates of cessation and relapse among Australian PWID. Modelling findings indicated that the risk of not detecting HIV becomes greater than the reference group at a threshold of non-admission of being an active PWID of around 1.8% (0.5-5.1%). Excluding Japan, all Organisation for the Economic Co operation and Development member countries permanently exclude individuals with a history of IDU from donating. CONCLUSION: Numerous research gaps meant that the study's expert Review Committee was unable to recommend altering Australia's current IDU-related blood donation guidelines. However, having identified critical knowledge gaps and future areas of research, the review made important steps toward changing the criteria. PMID- 28666206 TI - Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. AB - BACKGROUND: Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system. METHODS: The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD). RESULTS: Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 +/- 8.4 (S.D) and dropped to 16.8 +/- 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (>= 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion. LIMITATIONS: Retrospective nature of this study, lack of control group and use of self-report depression ratings scales. CONCLUSIONS: This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population. PMID- 28666207 TI - Urinary albumin and 8-oxo-7,8-dihydroguanosine as markers of mortality and cardiovascular disease during 19 years after diagnosis of type 2 diabetes - A comparative study of two markers to identify high risk patients. AB - Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8 oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death. PMID- 28666208 TI - MiR-542-3p inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting UBE3C. AB - Accumulating evidence demonstrates that aberrant miRNAs contribute to hepatocellular carcinoma (HCC) development and progression. However, the roles of various miRNAs in HCC remain to be determined. In present research, we confirmed that a reduced miR-542-3p expression was present in HCC tissues and cell lines. Our clinical analysis revealed that the down-regulated miR-542-3p expression was significantly correlated with poor prognostic features including advanced TNM stage and venous infiltration. Moreover, we confirmed that miR-542-3p was a novel independent prognostic marker for predicting 5-year survival of HCC patients. The ectopic overexpression of miR-542-3p inhibited cell migration, invasion and EMT progress, while down-regulated miR-542-3p reversed the effect. In addition, miR 542-3p could regulate UBE3C by directly binding to its 3'-UTR. In clinical samples of HCC, miR-542-3p inversely correlated with UBE3C, which was upregulated in HCC. Alternation of UBE3C expression at least partially abolished the migration, invasion and EMT progress effects of miR-542-3p on HCC cells. In conclusion, our results indicated that miR-542-3p functioned as a tumor suppressor gene in regulating the EMT and metastasis of HCC via targeting UBE3C, and may represent a novel potential therapeutic target and prognostic marker for HCC. PMID- 28666209 TI - The role of ROS and NF-kappaB pathway in olmesartan induced-toxicity in HeLa and mcf-7 cell lines. AB - We have recently shown that olmesartan could induce toxicity in HeLa and MCF-7 cell lines. In this study we investigated toxicity mechanism of olmesartan in HeLa and MCF-7 cell lines. HeLa and MCF-7 cells were cultured in DMEM in optimum conditions. Cells were pretreated with rutin as an antioxidant and treated with olmesartan as a cytotoxic agent. Cell proliferation was determined by MTT assay. The role of ROS was determined using DCFH-DA by flow cytometry analysis. Also, cells were treated with olmesartan (5mM) and Bay 11-7-82 (25MUM) for 24h, then expression of apoptotic proteins including Bax, caspase3 and IkappaB were investigated in both cell lines by western blotting. Cell viability decreased with olmesartan in malignant cell lines. Kinetic of ROS assay showed increment of ROS generation starting at 2h which peaked at 4h after treatment. Pretreatment with antioxidant rutin decreased ROS increment which was consistent with improved viability of olmesartan-treated cells. Apoptosis results showed that olmesartan and Bay 11-7082 increased expression of apoptotic proteins such as Bax, caspase3 and IkappaB. Results proposed ROS increment and apoptosis could be involving mechanisms in olmesartan-induced toxicity in HeLa and MCF-7 cell lines. PMID- 28666210 TI - miR-489 inhibits proliferation, cell cycle progression and induces apoptosis of glioma cells via targeting SPIN1-mediated PI3K/AKT pathway. AB - microRNA-489 (miR-489), a newly identified tumor-related miRNA, functions as an oncogene or tumor suppressor via regulating growth and metastasis of human cancers. But, the clinical significance, biological function and underlying mechanisms of miR-489 in glioma remain rarely known. Here, we showed that the levels of miR-489 in glioma tissues were notably underexpressed compared to corresponding non-tumor tissues. In accordance, the relative levels of miR-489 were decreased in glioma cell lines compared with NHA cells. Kaplan-Meier plots indicated that miR-489 low expressing glioma patients showed a prominent shorter overall survival. In addition, miR-489 overexpression prohibited proliferation and cell cycle progression, and promoted apoptosis in U251 cells. While, miR-489 knockdown showed opposite effects on these cellular processes of U87 cells. In vivo experiments demonstrated that miR-489 restoration reduced the tumor volume and weight of subcutaneous glioma xenografts in nude mice. Notably, Spindlin 1 (SPIN1) was inversely and directly regulated by miR-489 in glioma cells. A negative correlation between the expression of miR-489 and SPIN1 mRNA was confirmed in glioma tissues. Interestingly, miR-489 inversely modulated activation of PI3K/AKT pathway and expression of downstream targets including p mTOR, Cyclin D1 and BCL-XL. SPIN1 re-expression abolished the effects of miR-489 on U251 cells with enhanced activation of PI3K/AKT pathway and malignant phenotype. Meanwhile, AKT inhibitor MK-2206 blocked activation of PI3K/AKT pathway and resulted in reduced proliferation, cell cycle arrest and increased apoptosis in miR-489 down-regulating U87 cells. Altogether, our data support that miR-489 loss facilitates malignant phenotype of glioma cells probably via SPIN1 mediated PI3K/AKT pathway. PMID- 28666211 TI - Carnitine/organic cation transporter 2 (OCTN2) contributes to rat epididymal epithelial cell growth and proliferation. AB - Carnitine/organic cation transporter 2 (OCTN2) is localized at the basolateral membrane of epididymal epithelial cells, and mainly serves to reabsorb carnitine as an essential factor for sperm maturation; however, its functional features in epididymal epithelial cells have remained unclear. We isolated primary epididymal epithelial cells from rat epididymides and verified their phenotype by detecting the presence of cytokeratin-19 (CK-19, an epithelial cell marker) and the absence vimentin (an interstitial cell marker). We found that cultured epididymal epithelial cells isolated from rat epididymides expressed high levels of CK-19 but barely expressed vimentin. Gain-of-function assays, which included the CCK-8 assay and EdU flow cytometry assay, indicated that overexpression of OCTN2 significantly promoted epididymal epithelial cell growth and proliferation. Moreover, forced expression of OCTN2 inhibited the cell apoptosis process, and at the same time increased expression of the pro-apoptosis factor BAX, and decreased expression of the anti-apoptosis factors BCL-2 and Survivin. Furthermore, we also found that OCTN2 overexpression dramatically increased the levels of biomarkers associated with spermatogenesis, including azoospermia-like (DAZL), phosphoglycerate kinase 2 (PGK2), and protamine 2 (PRM2). These results demonstrate that OCTN2 plays a positive role in epididymal epithelial cells, and might be useful in the clinical treatment of male infertility by serving as a key regulatory factor. PMID- 28666212 TI - Time-kill kinetic analysis of antimicrobial chemotherapy based on hydrogen peroxide photolysis against Streptococcus mutans biofilm. AB - A recently developed antimicrobial technique utilizing hydroxyl radicals generated by hydrogen peroxide (H2O2) photolysis represents a promising new therapy for preventing and treating dental caries. The present study compared the antimicrobial time-kill kinetics of H2O2 photolysis, conventional antiseptics, and antimicrobial photodynamic therapy (aPDT) against biofilm-forming Streptococcus mutans (cariogenic bacteria) grown on hydroxyapatite disks. H2O2 photolysis was performed by irradiating the biofilm immersed in 3% H2O2 with 365 nm light-emitting diode (LED) light at an irradiance of 1000mW/cm2 for up to 1.5min. Antiseptic treatments consisted of 0.2% chlorhexidine gluconate, 0.5% povidone-iodine, and 3% H2O2. The biofilm was immersed in each antiseptic for up to 4min. aPDT was performed by irradiating the biofilm immersed in 100MUM methylene blue or toluidine blue O with 655-nm laser light at 1000mW/cm2 for up to 4min. Based on the time-kill assay, the decimal reduction value (D-value) of each treatment was determined. With a D-value of 0.06min, H2O2 photolysis exhibited the highest bactericidal effect against biofilm-forming S. mutans. In contrast, antiseptics and aPDT exerted a slower bactericidal effect, with D values of 0.9-2.7min. In conclusion, the antimicrobial technique based on H2O2 photolysis using 365-nm LED represents a strong adjunctive chemotherapy for dental caries treatment. PMID- 28666213 TI - Comparing the predictive value of three definitions of frailty: Results from the Three-City study. AB - BACKGROUND: Despite several attempts to reach a single definition of frailty, no consensus has been reached. The definitions previously published have tried to prove its utility in predicting negative health outcomes. The objective of the present study is to compare the predictive value of 3 different frailty instruments, for selected outcomes. METHODS: The study sample includes 1278 participants of the Three-City study, a French prospective population-based study, assessed for frailty using Fried's phenotype criteria, Rockwood's Frailty Index and Tilburg Frailty Indicator. To assess the risk of mortality, incident disability, falls, institutionalization and hospitalization for a follow up period of 12 years, Cox proportional hazard models with delayed entry have been used. The area under the time-dependent ROC curve has been used to estimate and compare the ability of the three instruments of frailty to predict the previous adverse outcomes at 12 years. RESULTS: Five hundred ninety four participants were identified as non-robust with Fried's criteria; 169 with Rockwood's FI and 303 with TFI. The three scales consistently identified 91 participants as non-robust and 574 as robust. Rockwood's FI was a statistically significant predictor of mortality, incident disability and falls, and a strong predictor of hospitalization. CONCLUSION: In the absence of a "gold standard" definition of frailty, a debate on what measures and how to include them is open. A clue may be that one should select the appropriate definition according to the to-be predicted outcome, the setting and the underlying etiology of frailty. PMID- 28666214 TI - Efficient belief tracking in adults: The role of task instruction, low-level associative processes and dispositional social functioning. AB - A growing body of evidence suggests that adults can monitor other people's beliefs in an efficient way. However, the nature and the limits of efficient belief tracking are still being debated. The present study addressed these issues by testing (a) whether adults spontaneously process other people's beliefs when overt task instructions assign priority to participants' own belief, (b) whether this processing relies on low-level associative processes and (c) whether the propensity to track other people's beliefs is linked to empathic disposition. Adult participants were asked to alternately judge an agent's belief and their own belief. These beliefs were either consistent or inconsistent with each other. Furthermore, visual association between the agent and the object at which he was looking was either possible or impeded. Results showed interference from the agent's belief when participants judged their own belief, even when low-level associations were impeded. This indicates that adults still process other people's beliefs when priority is given to their own belief at the time of computation, and that this processing does not depend on low-level associative processes. Finally, performance on the belief task was associated with the Empathy Quotient and the Perspective Taking scale of the Interpersonal Reactivity Index, indicating that efficient belief processing is linked to a dispositional dimension of social functioning. PMID- 28666215 TI - Just look away: Gaze aversions as an overt attentional disengagement mechanism. AB - During visual exploration of a scene, the eye-gaze tends to be directed toward more salient image-locations, containing more information. However, while performing non-visual tasks, such information-seeking behavior could be detrimental to performance, as the perception of irrelevant but salient visual input may unnecessarily increase the cognitive-load. It would be therefore beneficial if during non-visual tasks, eye-gaze would be governed by a drive to reduce saliency rather than maximize it. The current study examined the phenomenon of gaze-aversion during non-visual tasks, which is hypothesized to act as an active avoidance mechanism. In two experiments, gaze-position was monitored by an eye-tracker while participants performed an auditory mental arithmetic task, and in a third experiment they performed an undemanding naming task. Task irrelevant simple motion stimuli (drifting grating and random dot kinematogram) were centrally presented, moving at varying speeds. Participants averted their gaze away from the moving stimuli more frequently and for longer proportions of the time when the motion was faster than when it was slower. Additionally, a positive correlation was found between the task's difficulty and this aversion behavior. When the task was highly undemanding, no gaze aversion behavior was observed. We conclude that gaze aversion is an active avoidance strategy, sensitive to both the physical features of the visual distractions and the cognitive load imposed by the non-visual task. PMID- 28666216 TI - Assessment of 28 trace elements and 17 amino acid levels in muscular tissues of broiler chicken (Gallus gallus) suffering from arsenic trioxide. AB - The contents of 28 trace elements, 17 amino acid were evaluated in muscular tissues (wings, crureus and pectoralis) of chickens in response to arsenic trioxide (As2O3). A total of 200 one-day-old male Hy-line chickens were fed either a commercial diet (C-group) or an As2O3 supplement diet containing 7.5mg/kg (L-group), 15mg/kg (M-group) or 30mg/kg (H-group) As2O3 for 90 days. The elements content was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Under As2O3 exposure, the concentration of As were elevated 8.87-15.76 fold, 7.93-15.63 fold and 5.94-12.45 fold in wings, crureus and pectoralis compared to the corresponding C-group, respectively. 19 element levels (lithium (Li), magnesium (Mg), aluminum (Al), silicon (Si), kalium (K), vanadium (V), chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), selenium (Se), strontium (Sr), molybdenum (Mo), cadmium (Cd), tin (Sn), antimony (Sb), barium (Ba), mercury (Hg) and lead (Pb), 9 element levels (K, Co, Ni, Cu, As, Se, Sr, Sn, Ba and Hg) and 4 element levels (Mn, cobalt (Co), As, Sr and Ba) were significantly increased (P < 0.05) in wing, crureus and pectoralis, respectively. 2 element levels (sodium (Na) and zinc (Zn)), 5 element levels (Li, Na, Si, titanium (Ti and Cr), 13 element levels (Li, Na, Mg, K, V, Cr, iron (Fe), Cu, Zn, Mo, Sn, Hg and Pb) were significantly decreased (P < 0.05) in wing muscle, crureus and pectoralis, respectively. Additionally, in crureus and pectoralis, the content of total amino acids (TAA) was no significant alterations in L and M-group and then increased approximately 10.2% and 7.6% in H-group, respectively (P < 0.05). In wings, the level of total amino acids increased approximately 10% in L-group, whereas it showed unchanged in M and H-group compared to the corresponding C group. We also observed that significantly increased levels of proline, cysteine, aspartic acid, methionine along with decrease in the tyrosine levels in muscular tissues compared to the corresponding C-group. In conclusion, the residual of As in the muscular tissues of chickens were dose-dependent and disrupts trace element homeostasis, amino acids level in muscular tissues of chickens under As2O3 exposure. Additionally, the response (trace elements and amino acids) were different in wing, thigh and pectoral of chick under As2O3 exposure. This study provided references for further study of heavy metal poisoning and may be helpful to understanding the toxicological mechanism of As2O3 exposure in muscular tissues of chickens. PMID- 28666217 TI - Toxicity of coal fly ash (CFA) and toxicological response of switchgrass in mycorrhiza-mediated CFA-soil admixtures. AB - Increasing support for the use of Coal fly ash (CFA) in agriculture has necessitated a better understanding of the effects of the CFA in various cropping schemes. Experiments were conducted to assess mutagenic response of a mutant strain of Salmonella enterica serovar Typhimurium (TA100) to varying concentrations of CFA-water extracts, determine oxidative stress in switchgrass (Panicum virgatum L.) at varying levels of CFA-soil admixtures, and evaluate mycorrhiza-mediated modulation of oxidative stress responses of CFA-grown switchgrass. The TA100 exposed to 0%, 5%, 10%, 15%, 20% and 25% (w/v) CFA-water extracts elicited significant (p < 0.05) mutagenic responses at 20% and 25% extract levels but not below the 15% level. In greenhouse pot experiment, CFA soil admixtures at 7.5% and 15% (w/w) significantly (p < 0.05) decreased the activities of superoxide dismutase (SOD) by 19.1% and 28.3% respectively, compared to control soil (0% w/w CFA/soil). Under the same conditions, activities of glutathione peroxidase (GPx) decreased by 75.9% and 66.9%. In contrast to the antioxidant enzyme activities, levels of malondialdehyde (MDA) an indicator of lipid peroxidation increased significantly (p < 0.05) by 30.49% and 38.38%. Inoculation of 7.5% and 15% CFA-soil admixtures with arbuscular mycorrhizal fungi (AMF), Rhizophaga clarus enhanced the activities of both SOD and GPx in the switchgrass, while it significantly (p < 0.05) reduced the levels of MDA. The study demonstrated that incorporation of CFA (at concentrations considered to be non-mutagenic against TA100) as soil amendment produced concentration-dependent oxidative stress responses in switchgrass; however, inoculation of the CFA-soil admixtures with AMF significantly modulated the oxidative stress responses. PMID- 28666218 TI - BTEX exposure assessment and quantitative risk assessment among petroleum product distributors. AB - The aim of this study was to evaluate benzene, toluene, ethylbenzene, and xylene (BTEX) exposure among workers at four stations of a major oil distribution company. Personal BTEX exposure samples were collected over working shift (8h) for 50 workers at four stations of a major oil distribution company in Iran. Measured mean values for workers across four sites were benzene (2437, 992, 584, and 2788MUg/m3 respectively), toluene (4415, 2830, 1289, and 9407MUg/m3), ethylbenzene (781, 522, 187, and 533MUg/m3), and xylene (1134, 678, 322, and 525MUg/m3). The maximum mean concentration measured across sites for benzene was 2788MUg/m3 (Station 4), toluene was 9407MUg/m3 (Station 4), ethylbenzene was 781MUg/m3 (Station 1) and xylene was 1134MUg/m3 (Station 1). The 8h averaged personal exposure benzene concentration exceeded the recommended value of 1600MUg/m3 established by the Iranian Committee for Review and Collection of Occupational Exposure Limit and American Conference of Governmental Industrial Hygienists. Mean values for excess lifetime cancer risk for exposure to benzene were then calculated across workers at each site. Estimates of excess risk ranged from 1.74 +/- 4.05 (Station 4) to 8.31 +/- 25.81 (Station 3). Risk was assessed by calculation of hazard quotients and hazard indexes, which indicated that xylene and particularly benzene were the strongest contributors. Tanker loading was the highest risk occupation at these facilties. Risk management approaches to reducing exposures to BTEX compounds, especially benzene, will be important to the health of workers in Iran. PMID- 28666219 TI - Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene and characterized by elevated levels of very long-chain fatty acids (VLCFA) in plasma and tissues, with the most pronounced increase in the central nervous system. Virtually all male patients develop adrenal insufficiency and myelopathy (adrenomyeloneuropathy), but a subset develops a fatal cerebral demyelinating disease (known as cerebral ALD). Female patients may also develop myelopathy, but adrenal insufficiency or leukodystrophy are very rare. ALD has been associated with mitochondrial dysfunction, oxidative stress and bioenergetic failure, but the mechanism by which VLCFA accumulation triggers these effects has not been resolved thus far. In this study, we used primary human fibroblasts from normal subjects and ALD patients to investigate whether VLCFA can induce endoplasmic reticulum stress. We show that saturated VLCFA (C26:0) induce endoplasmic reticulum stress in fibroblasts from ALD patients, but not in controls. Furthermore, there is a clear correlation between the chain-length of the fatty acid and the induction of endoplasmic reticulum stress. Exposure of ALD fibroblasts to C26:0, resulted in increased expression of additional endoplasmic reticulum stress markers (EDEM1, GADD34 and CHOP) and in lipoapoptosis. This new insight into the underlying mechanism of VLCFA-induced toxicity is of great importance for the development of a disease modifying treatment for ALD aimed at the normalization of VLCFA levels in tissues. PMID- 28666220 TI - MnO doped SnO2 nanocatalysts: Activation of wide band gap semiconducting nanomaterials towards visible light induced photoelectrocatalytic water oxidation. AB - Semiconducting nanomaterials are very important by means of their stability and wide band gap tunability. Visible light induced photoelectrocatalytic water oxidation based on these material are challenging as they have large band gap energies. Herein, we report that MnO doping can activate wide band gap semiconductors like SnO2 towards visible light induced water oxidation. Rutile SnO2 nanoparticles (band gap 3.6eV), usually absorbing at UV region, was capable of harvesting visible light when doped with MnO thereby minimizing the energy requirement for photoelctrocatalytic water splitting. The system was characterized using UV-Vis, TEM and XPS. Photoelectrocatalytic activity was examined by LSV and CPE. The highly stable catalyst showed very good photoelectrocatalytic activity for the oxidation of water under alkaline condition with low overpotential of ~370mV at 1.0mAcm-2. PMID- 28666221 TI - Tailoring the electrochemical properties of ED ion exchange membranes based on the synergism of TiO2 nanoparticles-co-GO nanoplates. AB - In this paper, the synergetic influence of various weight ratios of TiO2 nanoparticles (NPs)/graphene oxide nanoplates (GONs) in the matrix of ion exchange membranes was examined in order to adapt their electrokinetic properties based on the combination of the high specific surface area of GONs and the antifouling ability of TiO2 nanoparticles. The morphology, physico-chemical features and ionic transport behavior of prepared membranes was studied. Scanning optical microscopy (SOM) and scanning electron microscopy (SEM) images showed a uniform surface for the lab-made membranes relatively. It was found that surface hydrophilicity of the membrane was increased in the presence of GONs and TiO2 NPs. All modified membranes showed a higher water uptake than unmodified membranes. Furthermore, a higher ion exchange capacity, fixed ionic concentration, ionic permeability and flux were observed for all modified membranes in comparison with unmodified membranes. The membrane potential, transport number and selectivity improved in NaCl solutions by using GONs and TiO2 nanoparticles. Furthermore, the membrane ionic conductivity showed an increasing trend by utilizing TiO2-co-GONs NPs. As an overall conclusion, the modified membrane containing 3wt% GONs and 1wt% TiO2 NPs with superior transport number and permselectivity (~99%), highest current density and cation flux and the lowest areal electrical resistance (~4-5Omegacm2) showed the best performance. PMID- 28666222 TI - Chemical vapor deposition growth of bilayer graphene in between molybdenum disulfide sheets. AB - Direct growth of flat micrometer-sized bilayer graphene islands in between molybdenum disulfide sheets is achieved by chemical vapor deposition of ethylene at about 800 degrees C. The temperature assisted decomposition of ethylene takes place mainly at molybdenum disulfide step edges. The carbon atoms intercalate at this high temperature, and during the deposition process, through defects of the molybdenum disulfide surface such as steps and wrinkles. Post growth atomic force microscopy images reveal that circular flat graphene islands have grown at a high yield. They consist of two graphene layers stacked on top of each other with a total thickness of 0.74nm. Our results demonstrate direct, simple and high yield growth of graphene/molybdenum disulfide heterostructures, which can be of high importance in future nanoelectronic and optoelectronic applications. PMID- 28666223 TI - Protocols for the analytical characterization of therapeutic monoclonal antibodies. II - Enzymatic and chemical sample preparation. AB - The analytical characterization of therapeutic monoclonal antibodies and related proteins usually incorporates various sample preparation methodologies. Indeed, quantitative and qualitative information can be enhanced by simplifying the sample, thanks to the removal of sources of heterogeneity (e.g. N-glycans) and/or by decreasing the molecular size of the tested protein by enzymatic or chemical fragmentation. These approaches make the sample more suitable for chromatographic and mass spectrometric analysis. Structural elucidation and quality control (QC) analysis of biopharmaceutics are usually performed at intact, subunit and peptide levels. In this paper, general sample preparation approaches used to attain peptide, subunit and glycan level analysis are overviewed. Protocols are described to perform tryptic proteolysis, IdeS and papain digestion, reduction as well as deglycosylation by PNGase F and EndoS2 enzymes. Both historical and modern sample preparation methods were compared and evaluated using rituximab and trastuzumab, two reference therapeutic mAb products approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA). The described protocols may help analysts to develop sample preparation methods in the field of therapeutic protein analysis. PMID- 28666224 TI - Determination of urinary 15alpha-hydroxyestrogen levels via immunoaffinity extraction. AB - 15alpha-Hydroxyestrogens (15alpha-OHEs) are metabolites of the female hormone estradiol. In this study, to discover physiological markers that can be utilized for monitoring fetal conditions and estrogen-induced cancers, we established a method for quantifying 15alpha-OHEs in rat urine via immunoaffinity column extraction and HPLC-electrochemical detection, and detected 15alpha-OHEs in urine obtained male rats treated with estradiol. Notably, the standard curves for quantification obtained using the column were linear over a range of 0.5-50ng 15alpha-OHEs. The accuracy of the analytical method with cleanup was 97-109% for the three kinds of 15alpha-OHEs examined, and the intra-assay precision of the measured values had a coefficient of variation of <=20.6%. Therefore, the theoretical limit of quantification was 0.5ng. However, the actual measured values obtained from the urine of male rats indicated that the detection limits were 0.425, 0.103, and 0.047ng for estetrol, 15alpha-hydroxyestradiol, and 15alpha-hydroxyestrone, respectively. Our newly established method for measuring 15alpha-OHE concentrations in urine could facilitate characterization of the in vivo metabolic profile of 15alpha-OHEs in mammals under various physiological conditions, which could comprise clinical markers for monitoring human fetal health conditions in mammals. PMID- 28666225 TI - HPLC-MS/MS targeted metabolic profiling reveals distinct metabolic profiles from Staphylococcus aureus small-colony variants. AB - Staphylococcus aureus is a world-wide health threat due to its prevalence and possible resistance to antibiotic treatment. A variety reasons can contribute to S. aureus antibiotic resistance and one group of phenotypes that may be discovered from S. aureus is named small-colony variants (SCVs). This study focused on applying a HPLC-MS/MS based targeted metabolic profiling approach to detect a set of metabolites that are dysregulated during S. aureus SCVs formation. Over one hundred and eighty metabolites were confidently detected and their difference between S. aureus SCVs and wild type control groups was compared via univariate and multivariate statistical analyses. Twenty metabolites, including 3',5'-cyclic AMP, tyrosine and adenine were identified as SCV specific metabolic features in comparison to the control group. Metabolic profile differences between individually isolated SCV were also observed and compared. Principal component analyses demonstrated clear metabolic profile differentiation between wild type control to SCVs. Metabolic pathway impact analysis also identified multiple metabolic pathways, including alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism, that were significantly impacted during SCV formation. To the best of our knowledge, our study is the very first report to detect a large set of altered metabolites induced by S. aureus SCV formation. We believe our method can be used in combination with genomic, transcriptomic and proteomic approaches to achieve a better understanding of the unique physiological and metabolic changes during S. aureus SCV formation, and to assist the potential future development of targeted treatment for S. aureus SCV infections. PMID- 28666226 TI - Comprehensive analysis of the tryptophan metabolome in urine of patients with acute intermittent porphyria. AB - BACKGROUND: Acute intermittent porphyria (AIP) is a rare metabolic disorder due to a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. This low enzymatic activity may predispose to the appearance of acute neurological attacks. Seminal studies suggested that AIP was associated with changes in tryptophan homeostasis with inconclusive results. Therefore, the aim of this study was to analyze the urinary metabolome of AIP patients focusing on tryptophan metabolism using state-of-the-art technology. METHODS: This was a case-control study including a group of 25 AIP patients with active biochemical disease and increased excretion of heme-precursors and 25 healthy controls. Tryptophan and related compounds and metabolites including: large neutral amino acids (LNAAs), serotonin, kynurenine, kynurenic acid and anthranilic acid were quantified in urine by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Twenty-nine biological markers (including metabolic ratios and absolute concentrations) were compared between patients and controls. RESULTS: Significant differences were found in the tryptophan-kynurenine metabolic pathway. Compared to controls, AIP patients showed: (a) increased urinary excretion of kynurenine and anthranilic acid (P<0.005); (b): elevation of the kynurenine/tryptophan ratio (P<0.001) and (c): decrease of the kynurenic acid/kynurenine ratio (P=0.001). In contrast, no differences were found in the serotonin metabolic pathway independently of the markers and ratios used. CONCLUSIONS: The results of the study demonstrate that there is an imbalance in the kynurenine metabolic pathway in AIP patients, with an increase of the kynurenine/tryptophan ratio in urine and a reduction of the kynurenic acid/kynurenine ratio. The modified ratios suggest induction of indoleamine 2,3 deoxygenase and decreased activity of kynurenine aminotransferase in the liver. The results confirm that LC-MS/MS is useful for the characterization of the urinary metabolome of hepatic porphyrias. PMID- 28666227 TI - Comprehensive profiling and characterization of chemical constituents of rhizome of Anemarrhena asphodeloides Bge. AB - The rhizome of Anemarrhena asphodeloides Bge. is commonly used as an herbal medicine in China. In this study, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) was used, in both negative and positive ion modes, to comprehensively analyze the chemical constituents of A. asphodeloides. From the intact precursor ions, MS/MS fragmentation information, and previous reports, we identified 89 compounds. These compounds included 8 cyclic peptides, 11 flavones (9 xanthones), 45 steroidal saponins, 15 fatty acids, 3 lignans, and 7 other compounds. Dimer xanthones and cyclic peptides are reported for the first time in A. asphodeloides. The analytical method we have developed is simple, reliable, and effective. The results provide comprehensive information on the metabolite profile of A. asphodeloides, which may benefit the quality control and further utilization of A. asphodeloides. PMID- 28666228 TI - High-throughput quantification of 8 antihypertensive drugs and active metabolites in human plasma using UPLC-MS/MS. AB - BACKGROUND: To assess drug adherence of patients with hypertension, an analytical method was developed and validated using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The method includes eight frequently prescribed antihypertensive drugs from four classes and their active metabolites: angiotensin converting enzyme inhibitors enalapril and perindopril (active metabolites respectively enalaprilate and perindoprilate), angiotensin II receptor blockers losartan (with the active metabolite losartan carboxylic acid) and valsartan, calcium channel blockers amlodipine and nifedipine and diuretics hydrochlorothiazide and spironolactone (with the active metabolite canrenone). METHODS: The antihypertensive drugs were analyzed using a simple and fast sample preparation protocol with protein precipitation followed by chromatographic separation using a gradient elution on a reversed phase column. Mass spectrometric detection was conducted by applying both positive and negative electrospray ionization (ESI+/ESI-) and selected reaction monitoring mode (MS/MS). Only 50MUl of plasma sample is needed for the simultaneous quantification of all 12 compounds within 6min run-to-run analysis time. Enalapril-d5 was applied as internal standard for all compounds except hydrochlorothiazide (internal standard: Hydrochlorothiazide-13C,d2). RESULTS: The method was validated according to FDA guidelines. Matrix effects were examined using the method of Matuszewski. Correlation coefficients were higher than 0.995 for all compounds. Intra- and inter-day accuracies were <15% for all analytes except spironolactone (-16.8%) in the established linear range. Intra- and inter day precision were <15% for all analytes. As a result of the lower sensitivity of hydrochlorothiazide, the lowest three calibration levels were excluded. DISCUSSION/CONCLUSIONS: The described method is suitable for the simultaneous quantitative analysis of the most commonly used antihypertensive drugs and their corresponding active metabolites. Major advantages are minimal sample volume and clean up and a short runtime. The method is now available to monitor drug adherence of patients with resistant hypertension in our hospital. PMID- 28666229 TI - Structural characterization and identification of cyclic lipopeptides produced by Bacillus methylotrophicus DCS1 strain. AB - Bacillus methylotrophicus DCS1 strain was isolated from diesel contaminated soil and screened for its ability to produce biosurfactants; it was found effective for the production of surface active molecules. The structural characterization of the isolated lipopeptides was studied by a variety of analytical techniques. The organic extract of DCS1 lipopeptides was fractionated by silica gel column chromatography (60Mesh). Fractions containing lipopeptides were collected and identified by tandem mass spectrometry MALDI-TOF-MS and MALDI-TOF MS2. The crude biosurfactants contains a mixture of homologous lipopeptides with molecular weights between 1016 and 1556Da. Mass spectrometry analysis of partially purified lipopeptides revealed that it contains different isoforms belonging to three families: surfactin, iturin and fengycin. To identify lipopeptides isoforms, MALDI-TOF MS2 was used and ions representing characteristic fragmentations were detected. The mass spectrometry characterization revealed the presence of four variants of surfactin lipopeptides, four variants of pumilacidin that differ according to the beta-hydroxy fatty acid chain length as well as the type of amino acid at position 7, five variants of iturin A/mycosubtilin varying in the beta-amino fatty acid chain length from C12 to C16, C16 iturin C1, five isoforms of bacillomycin D varying in the beta-amino fatty acid chain length from C14 to C18, and six fengycin isoforms that differ according to the length of the beta hydroxy fatty acid side chain as well as the amino acid at position 6. The capacity of B. methylotrohicus DCS1 strain to produce many lipopeptides isoforms belonging to different families and having a structural diversity is a very interesting characteristic that allows them to be used in various fields of biotechnological applications. PMID- 28666230 TI - Simultaneous quantification of methiocarb and its metabolites, methiocarb sulfoxide and methiocarb sulfone, in five food products of animal origin using tandem mass spectrometry. AB - A simultaneous analytical method was developed for the determination of methiocarb and its metabolites, methiocarb sulfoxide and methiocarb sulfone, in five livestock products (chicken, pork, beef, table egg, and milk) using liquid chromatography-tandem mass spectrometry. Due to the rapid degradation of methiocarb and its metabolites, a quick sample preparation method was developed using acetonitrile and salts followed by purification via dispersive- solid phase extraction (d-SPE). Seven-point calibration curves were constructed separately in each matrix, and good linearity was observed in each matrix-matched calibration curve with a coefficient of determination (R2) >= 0.991. The limits of detection and quantification were 0.0016 and 0.005mg/kg, respectively, for all tested analytes in various matrices. The method was validated in triplicate at three fortification levels (equivalent to 1, 2, and 10 times the limit of quantification) with a recovery rate ranging between 76.4-118.0% and a relative standard deviation<=10.0%. The developed method was successfully applied to market samples, and no residues of methiocarb and/or its metabolites were observed in the tested samples. In sum, this method can be applied for the routine analysis of methiocarb and its metabolites in foods of animal origins. PMID- 28666231 TI - A molecular dynamic study on the dissociation mechanism of SI methane hydrate in inorganic salt aqueous solutions. AB - Gas hydrate is not only a potential energy resource, but also almost the biggest challenge in oil/gas flow assurance. Inorganic salts such as NaCl, KCl and CaCl2 are widely used as the thermodynamic inhibitor to reduce the risk caused by hydrate formation. However, the inhibition mechanism is still unclear. Therefore, molecular dynamic (MD) simulation was performed to study the dissociation of structure I (SI) methane hydrate in existence of inorganic salt aqueous solution on a micro-scale. The simulation results showed that, the dissociation became stagnant due to the presence of liquid film formed by the decomposed water molecules, and more inorganic ions could shorten the stagnation-time. The diffusion coefficients of ions and water molecules were the largest in KCl system. The structures of ion/H2O and H2O/H2O were the most compact in hydrate/NaCl system. The ionic ability to decompose hydrate cells followed the sequence of: Ca2+>2K+>2Cl->2Na+. PMID- 28666233 TI - 5-Aminolevulinic acid improves DNA damage and DNA Methylation changes in deltamethrin-exposed Phaseolus vulgaris seedlings. AB - Deltamethrin, synthetic type II pyrethroid, is one of the most widely used pesticide in agriculture. Intense use of deltamethrin can cause permanant or temporary damages in nontarget plant species. In this study, we aimed to determine DNA methylation change and DNA damage level in Phaseolus vulgaris seedlings subjected to different concentrations of deltamethrin (0.02, 0.1 and 0.5 ppm). Coupled Restriction Enzyme Digestion-Random Amplification (CRED-RA) was performed to analyze the changes of DNA methylation as well as Randomly Amplified Polymorphic DNA (RAPD) was used for genotoxic influences estimation and genomic stability. The results showed that deltamethrin caused to increase in RAPD profile changes (DNA damage) and reduce in Genomic Template Stability (GTS). GTS declined markedly in relation to increasing concentration of deltamethrin applied. The lowest GTS value (71.4%) observed in 0.5 ppm deltamethrin treatment. Also, DNA hypermethylation was occurred in all treatments. Moreover, alleviative effect of 5-aminolevulinic acid (ALA) (20, 40 and 80 mg/l), one of the plant growth regulators, was tested against the 0.5 ppm deltamethrin. Adverse effects of deltamethrin on GTS decreased after ALA treatments, especially 20 mg/l concentration. As a result, we concluded that ALA has a strong anti-genotoxic agent against deltamethrin and it could be an alternative chemical to reduce genetic damage in plants under deltamethrin stress conditions. PMID- 28666232 TI - Investigating tangible and mental resources as predictors of perceived household food insecurity during pregnancy among women in a South African birth cohort study. AB - RATIONALE: Food insecurity during pregnancy is concerning given the increased nutritional needs of the mother for proper fetal development. However, research is lacking within the South African context to investigate the association of economic and psychosocial factors and food insecurity among pregnant women, using comprehensive, conceptually driven models. OBJECTIVE: This study applies the Network-Individual-Resource (NIR) Model to investigate individual, intimate dyadic, and family level predictors of perceived household food insecurity for pregnant women. METHODS: 826 pregnant women enrolled in the Drakenstein Child Health Study (DCHS), a birth cohort in two communities in a peri-urban area of South Africa. Hierarchical logistic regressions were used to investigate the impact of household/family, intimate dyads, and individual tangible and mental resources on perceived household food insecurity during the critical period of pregnancy. Perceived household food insecurity was assessed through an adapted version of the USDA Household Food Security Scale - Short Form. RESULTS: Among 826 pregnant women in South Africa, individual-level tangible resources (e.g. income, social assistance, HIV status) and mental resources (e. g. depression, childhood trauma) predicted perceived household food insecurity and these predictors differed by community. Intimate dyadic and family level resources did not predict household food insecurity. CONCLUSIONS: Our findings of the economic and psychosocial predictors of perceived household food insecurity among pregnant women in South Africa, mirror findings in general populations. This study provides support for the extension of the NIR model to perceived household food insecurity, particularly regarding individual-level mental and tangible resources, as well as the impact of community-level factors. Future research should investigate the extent to which resource sharing occurs within networks. PMID- 28666234 TI - Physio-biochemical basis of iron-sulfide nanoparticle induced growth and seed yield enhancement in B. juncea. AB - Metal nanoparticles have been reported to influence plant growth and productivity. However, the molecular mechanisms underlying the effects have not been completely understood yet. Current work describes the physio-biochemical basis of iron sulfide nanoparticle induced growth and yield enhancement in Brassica juncea. Iron sulfide nanoparticles (0, 2, 4, 6, 8 and 10 ppm) were used for foliar treatment of B. juncea at 30, 45 and 60 days after sowing, under field conditions. Foliar treatment of 4 ppm iron sulfide nanoparticle solution at 30 days after sowing brought maximal enhancement in agronomic attributes of the treated plants. Results of assays i.e. total chlorophyll, electrolyte leakage, Malondialdehyde (MDA), proline, H2O2 and antioxidant enzyme activities indicated the benign effect of iron sulfide nanoparticles on plants. Consequently, improved redox status of the treated plants, enabled them to assimilate higher photosynthate. The augmentation in growth and seed yield in iron sulfide nanoparticle treated plants was amply supported by activation of RUBISCO small subunit (rubisco S), RUBISCO large subunit (rubisco L), glutamine synthetase (gs) and glutamate synthase (gogat) genes. Thus, iron sulfide nanoparticle induced growth and yield enhancement is proposed to be mediated through activation of carbon and nitrogen assimilatory pathways at specific growth stage. The iron content in the leaves and root tissues of the treated plants was also significantly improved. PMID- 28666235 TI - How do moving and other major life events impact mental health? A longitudinal analysis of UK children. AB - Research has suggested that children who move home report poorer mental health than those who remain residentially stable. However, many previous studies have been based on cross sectional data and have failed to consider major life events as confounders. This study uses longitudinal data from ALSPAC, a UK population based birth cohort study, and employs within-between random effect models to decompose the association between moving in childhood and poor mental health. Results suggest that while unobserved between-individual differences between mobile and non-mobile children account for a large portion of this association, within-individual differences remain and indicate that moving may have a detrimental impact upon subsequent mental health. There is heterogeneity in children's response to moving, suggesting that a dichotomy of movers vs stayers is overly simplistic. PMID- 28666236 TI - Do greener areas promote more equitable child health? AB - Several recent studies have suggested that people in socioeconomically disadvantaged circumstances may benefit more from local green space ('equigenesis'). This study provides a test of this hypothesis in children aged 0 13 years old. Results from multilevel models suggest the odds of sub-optimal general health were 14% lower among children in areas containing >21.5% green space compared to those with <10%. Higher parent-reported quality green space was associated with 18% lower odds of sub-optimal child health. However, no effect modification of the association between child health and area disadvantage across strata of green space quantity or quality was observed. PMID- 28666237 TI - Excitability of the masseter inhibitory reflex after high frequency rTMS over the motor cortex: A study in healthy humans. AB - OBJECTIVE: We aimed to investigate the influence of high frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex on excitability of the masseter inhibitory reflex (MIR) in healthy subjects. Our goal in conducting this study was to obtain a better understanding of the subcortical and cortical networks related to the excitability of the central masticatory pathway. METHODS: Twenty healthy volunteers participated in this study. MIRs were evaluated both before and after high frequency rTMS to elicit motor evoked potentials (MEPs) using single- and double-shock techniques over the motor cortex. During measurements, the latency and duration of silent periods (SPs) with single magnetic stimulation, and the recovery of SP2 with the double-shock technique, were recorded in basal conditions and immediately after high frequency rTMS. The "real" rTMS condition consisted of 20 stimulus trains delivered at 10Hz with a 5 s stimulation duration and an intensity of 70% of the active motor threshold (AMT) over the right optimal motor spot for the masseter muscle. RESULTS: were also compared to those obtained after "sham" rTMS 1 week later RESULTS: Using the double-shock technique, SP2 recovery time was significantly shorter after high frequency rTMS compared to the basal condition (from 100 to 400ms; p<0.001), while at ISIs of 500 and 600ms, no significant effect was observed (p=0.084, p=0.948). There was also no significant change in the SP latency or duration between groups (p>0.05). CONCLUSIONS: High frequency, sub-threshold rTMS of the motor cortex had a facilitative after-effect on the excitability of the MIR. This effect was likely mediated through increased cortical drive to brainstem reflex pathways, which would ultimately accelerate MIR recovery. PMID- 28666238 TI - Protective effects of paeoniflorin on TNBS-induced ulcerative colitis through inhibiting NF-kappaB pathway and apoptosis in mice. AB - Paeoniflorin is traditionally used to treat inflammatory disorders. In our laboratory, we have scientifically validated the anti-inflammatory effect of paeoniflorin. In this study, it has been aimed to evaluate in vivo anti inflammatory effect of paeoniflorin isolated from the dried peeled root of Paeonia lactiflora Pall. It was further intended to find out the probable mechanism of anti-inflammatory effect of paeoniflorin. The anti-inflammatory effect of paeoniflorin (15, 30 and 45mg/kg) was measured employing TNBS-induced ulcerative colitis model of acute inflammation. The TNBS injection resulted significant colitis formation when compared with un-injected mice. The anti inflammatory effects of paeoniflorin for ulcerative colitis were assessed by body weight, colonic weight and length, macroscopic scores, and histopathological examinations. In addition, the colonic tissue levels of inflammation markers, including myeloperoxidase (MPO), IL-2, IL-6, IL-10, IL-12, IL-1beta, TNF-alpha and IFN-gamma were also determined to assess the effect of paeoniflorin. In addition, western blot demonstrated that paeoniflorin inhibited NF-kappaB signaling pathway and apoptosis in TNBS-induced ulcerative colitis tissues. In conclusion, all the findings of this study suggested that paeoniflorin has the anti-inflammatory effect in ulcerative colitis via inhibiting MAPK/NF-kappaB pathway and apoptosis in mice. PMID- 28666239 TI - Cryptotanshinone protects against IL-1beta-induced inflammation in human osteoarthritis chondrocytes and ameliorates the progression of osteoarthritis in mice. AB - Osteoarthritis (OA) is a common degenerative disease characterized by progressive erosion of articular cartilage, subchondral bone sclerosis and synovitis. Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge, has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of CTS on human OA chondrocytes and mice OA models. Human OA chondrocytes were pretreated with CTS (5, 10 and 20MUM) for 2h and subsequently stimulated with IL-1beta for 24h. Production of NO, PGE2, IL-6, TNF-alpha was evaluated by the Griess reaction and ELISA. The protein expression of COX-2, iNOs, MMP-3, MMP13, COX-2, ADAMTS-5, JNK, p-JNK, ERK, p-ERK, p38, p-p38, p IKKalpha/beta, p65, p-p65, IkappaB-alpha, and p-IkappaB-alpha was tested by Western blot. In vivo, the severity of OA was determined by histological analysis. We found that CTS significantly inhibited the IL-1beta-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-3, MMP-13, and ADAMTS 5. Furthermore, CTS in dramatically suppressed IL-1beta-stimulated NF-kappaB and MAPK activation. Immunofluorescence staining demonstrated that CTS could suppress IL-1beta-induced phosphorylation of p65 nuclear translocation. In vivo, treatment of CTS prevented the destruction of cartilage and the thickening of subchondral bone in mice OA models. These results indicate that the therapeutic effect of CTS on OA is accomplished through the inhibition of both NF-kappaB and MAPK signaling pathways. Our findings provide the evidence to develop CTS as a potential therapeutic agent f or patients with OA. PMID- 28666240 TI - Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors. AB - The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2-12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon. PMID- 28666242 TI - Thorn in My Spine: A case of a retained intradural extramedullary foreign body. AB - Foreign bodies in the spine are most commonly traumatic and managed in an acute setting. A few case reports describe foreign bodies resulting in delayed neurologic dysfunction, most commonly iatrogenic or from penetrating injury. We present a 30-year old man with lower extremity weakness from an intradural extramedullary foreign body granuloma secondary to a thorn, which was initially thought to represent an aggressive malignant process with intra and extramedullary involvement on MR. Postoperatively, the patient endorsed a causative trauma several years prior. We also present a review of the few similar published cases as well as the described prototypical imaging features and pathologic process. PMID- 28666241 TI - Paternal and maternal urinary phthalate metabolite concentrations and birth weight of singletons conceived by subfertile couples. AB - BACKGROUND: Prenatal phthalate exposure has been inconsistently associated with fetal growth and infant birth weight. However, the effect of exposure during the paternal and maternal preconception period remains understudied. OBJECTIVES: To investigate associations of paternal and maternal preconception and maternal prenatal urinary phthalate metabolite concentrations with birth weight. METHODS: The study comprised 364 singletons born to 364 mothers and 195 fathers (195 couples) from the EARTH Study, a prospective cohort of couples from Boston, MA. Births were categorized by mode of conception: in-vitro fertilization based (IVF) (n=208) or non-IVF based (n=156, intrauterine insemination or non-medically assisted/natural conception). We measured urinary concentrations of eleven phthalate metabolites in maternal (n=1425) and paternal (n=489) preconception and maternal prenatal (n=781) samples. Birth weight was abstracted from delivery records. Covariate-adjusted associations between loge-phthalate metabolite concentrations and birth weight were evaluated separately by mode of conception using multivariable linear regression. RESULTS: Each loge-unit increase in paternal urinary concentration of the sum of di(2-ethylhexyl) phthalate (SigmaDEHP) metabolites was associated with a 90 gram (95% CI: -165, -15) decrease in birth weight among IVF singletons, but not among non-IVF singletons (18g; 95% CI: -76, 113). Additional adjustment for maternal prenatal SigmaDEHP concentrations modestly strengthened findings among IVF singletons. While few associations were found with maternal preconception phthalate metabolites, we observed an inverse relationship between several maternal prenatal urinary phthalate metabolite concentrations and birth weight among IVF singletons in covariate-adjusted models. However, with further adjustment for specific paternal phthalate metabolite concentrations, these associations were attenuated and no longer significant. CONCLUSIONS: Paternal preconception urinary concentration of SigmaDEHP metabolites was associated with a decrease in birth weight among IVF conceived singletons. These results, if replicated, highlight the importance of preconception health, especially among subfertile couples. PMID- 28666243 TI - A universal laboratory method for determining physical parameters of radon migration in dry granulated porous media. AB - The particle size and heaped methods of exhalation media have important effects on physical parameters, such as the free radon production rate, porosity, permeability, and radon diffusion coefficient. However, existing methods for determining those parameters are too complex, and time-consuming. In this study, a novel, systematic determining method was proposed based on nuclide decay, radon diffusion migration theory, and the mass conservation law, and an associated experimental device was designed and manufactured. The parameters of uranium ore heap and sandy soil of radon diffusion coefficient (D), free radon production rate (alpha), media permeability (k), and porosity (epsilon) were obtained. At the same time, the practicality of the novel determining method was improved over other methods, with the results showing that accuracy was within the acceptable range of experimental error. This novel method will be of significance for the study of radon migration and exhalation in granulated porous media. PMID- 28666244 TI - Evidence for the Psychometric Validity, Internal Consistency and Measurement Invariance of Warwick Edinburgh Mental Well-being Scale Scores in Scottish and Irish Adolescents. AB - Mental well-being is an important indicator of current, but also the future health of adolescents. The 14-item Warwick Edinburgh Mental Well-being Scale (WEMWBS) has been well validated in adults world-wide, but less work has been undertaken to examine the psychometric validity and internal consistency of WEMWBS scores in adolescents. In particular, little research has examined scores on the short 7-item version of the WEMWBS. The present study used two large samples of school children in Scotland and Northern Ireland and found that for both forms of the WEMWBS, scores were psychometrically valid, internally consistent, factor saturated, and measurement invariant by country. Using the WEMWBS full form, males reported significantly higher scores than females, and Northern Irish adolescents reported significantly higher scores than their Scottish counterparts. Last, the lowest overall levels of well-being were observed among Scottish females. PMID- 28666245 TI - Testing a decades' old assumption: Are individuals with lower sensory gating indeed more easily distracted? AB - The sensory gating deficits in schizophrenia have been theorized to associate with increased distractibility. We explore the potential associations between sensory and sensorimotor gating and subjective and objective indices of distraction in healthy subjects. Forty healthy males were assessed with the P50 suppression and pre-pulse inhibition of the startle reflex (PPI) paradigms. Additionally, a neurocognitive test battery was administered in a cross-over design: with/without auditory distraction. Significant effects of distraction were found in response inhibition, and verbal working memory and attention. Parameters from the PPI and P50 suppression paradigms were significantly associated with the distractor effects on strategy formation, cognitive inhibition and flexibility, visual short-term memory, and the level of subjective distraction. Subjectively reported distraction was significantly associated with verbal working memory and attention as well as executive and supervisory processes. Sensory and sensorimotor gating efficiency do not reflect the effect of distraction across executive and attention functions i.e. we did not observe a generalized distractor effect. Gating only related to the effect of distraction on strategy formation, cognitive inhibition and flexibility, as well as visual short term memory. Future studies should investigate if gating deficits affect the distractibility of the same specific cognitive functions in patients with schizophrenia. PMID- 28666246 TI - The correlation between CVP-derived parameters and the prognosis of critically ill patients. AB - OBJECTIVE: To investigate the effect of central venous pressure on the organ dysfunction and prognosis of critically ill patients. METHODS: We conducted a retrospective observational cohort study of 488 ICU patients with central venous pressure and its derived parameters in a half-year period in one single ICU centre to compare the length of ICU stay, critical illness scores (SOFA and APACHE II), serum creatinine and lactate levels. RESULTS: The initial, peak and mean CVP levels of critically ill patients and length of ICU stay, peak lactate levels and SOFA scores were significantly correlated. While the peak CVP and peak creatinine levels were significantly correlated, the correlation of initial and mean CVP levels with peak creatinine was not significant. Subgroup analysis showed that in the patients with a peak CVP value above 12mmHg, the length of stay was significantly prolonged, organ function was significantly worse, and the SOFA score was significantly higher. ROC analysis showed peak levels of CVP above 11.5mmHg had the greatest ability to predict mortality of critically ill patients. CONCLUSION: Exposure to higher levels of central venous pressure in critically ill patients is associated with a poorer prognosis and worse organ function. Therefore, central venous pressure should be kept as low as possible during hemodynamic therapy in critically ill patients. PMID- 28666247 TI - Associations between psychopathic traits and brain activity during instructed false responding. AB - Lying is one of the characteristic features of psychopathy, and has been recognized in clinical and diagnostic descriptions of the disorder, yet individuals with psychopathic traits have been found to have reduced neural activity in many of the brain regions that are important for lying. In this study, we examine brain activity in sixteen individuals with varying degrees of psychopathic traits during a task in which they are instructed to falsify information or tell the truth about autobiographical and non-autobiographical facts, some of which was related to criminal behavior. We found that psychopathic traits were primarily associated with increased activity in the anterior cingulate, various regions of the prefrontal cortex, insula, angular gyrus, and the inferior parietal lobe when participants falsified information of any type. Associations tended to be stronger when participants falsified information about criminal behaviors. Although this study was conducted in a small sample of individuals and the task used has limited ecological validity, these findings support a growing body of literature suggesting that in some contexts, individuals with higher levels of psychopathic traits may demonstrate heightened levels of brain activity. PMID- 28666248 TI - White matter abnormalities in treatment-naive adolescents at the earliest stages of Anorexia Nervosa: A diffusion tensor imaging study. AB - Few studies have examined white matter (WM) integrity in long-lasting Anorexia Nervosa (AN) patients using Diffusion Tensor Imaging (DTI). In this paper, we investigated WM integrity at the earliest stages of AN (i.e. less than 6 months duration). Fourteen treatment-naive female adolescents with AN restrictive type (AN-r) in its earliest stages and 15 age-matched healthy females received brain MRI. Fractional Anisotropy (FA), Axial Diffusivity (AD), Radial diffusivity (RD), and Mean Diffusivity (MD) maps were computed from DTI data using Tract-Based Spatial Statistics analysis. AN-r patients showed FA decreases compared to controls (pFWE < 0.05) mainly in left anterior and superior corona radiata and left superior longitudinal fasciculus. AN-r patients also showed decreased AD in superior longitudinal fasciculus bilaterally and left superior and anterior corona radiata, (pFWE < 0.05). No significant differences were found in RD and MD values between the two groups. FA and AD integrity appears to be specifically affected at the earliest stages of AN. Alterations in the microstructural properties of the above mentioned tracts, also involved in cognitive control and visual perception and processing, may be early mechanisms of vulnerability/resilience of WM in AN and sustain the key symptoms of AN, such as impaired cognitive flexibility and body image distortion. PMID- 28666249 TI - Systematic review and meta-analysis of the efficacy of different exercise programs in pilocarpine induced status epilepticus models. AB - PURPOSE: To conduct a systematic review and meta-analysis of studies testing exercise in animal models of pilocarpine induced status epilepticus (SE) and to compare the efficacy of different training strategies used in those studies. METHODS: We searched 2 online databases (Pubmed and Web of Science) for studies analyzing the efficacy of different trainings in pilocarpine-induced SE models. Training was categorized into forced physical training (PT), voluntary PT and resistance PT. Two reviewers independently extracted data on study quality, behavioral seizures, and histological, chemical and cognitive outcomes. Data were pooled by means of a meta-analysis. RESULTS: Among 17 selected studies; 174 animals from 8 studies with 10 comparison groups showed that exercise intervention after induction of SE significantly decreased spontaneous recurrent seizures with [mean difference (MD)=-1.80, 95% confidence interval (CI): -3.22, 0.37, p=0.02] and 60 animals showed statistically significant decrease in latency in Morris water maze (standardized mean difference (SMD)=-2.57, 95% CI: -4.06, 1.08, p=0.0007). Although not statistically significant, still a remarkable increase in number of CA1 neurons and hippocampal BDNF level (MD=2.27, [95% CI: 1.20, 5.73], p=0.19, SMD=1.07, [95% CI: -0.36, 2.51], p=0.14 respectively) and a decrease in mossy fibers sprouting (SMD=-1.03, [95% CI: -3.06, 1.00], p=0.32) were observed. PT interventions in 72 animals before induction of SE showed favorable increase in latency to develop SE (MD=8.34, [95% CI: -3.10, 19.78], p=0.15) but no remarkable improvements in latency for the first motor sign and motor signs intensity. CONCLUSIONS: PT after SE reduces the recurrent seizures and improves the morphological, biochemical and cognitive profiles of pilocarpine epileptic models. Resistance PT was identified as particularly effective in reducing behavioral seizures. The efficacy of training was also dependent upon duration. PMID- 28666276 TI - Language and False-Belief Task Performance in Children With Autism Spectrum Disorder. AB - Purpose: Language is related to false-belief (FB) understanding in both typically developing children and children with autism spectrum disorder (ASD). The current study examined the role of complementation and general language in FB understanding. Of interest was whether language plays similar or different roles in the groups' FB performance. Method: Participants were 16 typically developing children (mean age = 5.0 years; mental age = 6.7) and 18 with ASD (mean age = 7.3 years; mental age = 8.3). Children were administered FB and language tasks (say- and think-complements), receptive and expressive vocabulary tests, and relative clauses. Results: When mental age and receptive and expressive vocabulary were used as separate covariates, the typical control group outperformed the children with ASD in FB task performance. Chi-square analyses indicated that passing both complementation tasks was linked to the FB understanding of children with ASD. Children with ASD who passed FB tasks all passed say- and think-complement tasks. However, some children in the control group were able to pass the FB tasks, even if they failed the say- and think-complement tasks. Conclusion: The results indicate that children with ASD relied more on complement understanding to pass FB than typically developing children. Results are discussed regarding the developmental pathways for FB understanding. PMID- 28666277 TI - Electroretinogram Findings in Early-Stage Sickle Cell Retinopathy According to Hemoglobin Type. AB - Purpose: Although extensive clinical research has been performed on structural analysis of sickle cell (SC) retinopathy, functional aspects have been poorly investigated. Our purpose was to report full-field electroretinogram (ffERG) findings in patients with early SC retinopathy according to the following hemoglobin types: HbSS or HbSC (homozygous or heterozygous mutations, respectively). Methods: In this monocentric retrospective observational study, patients affected by nonproliferative SC retinopathy were included from November 2014 to April 2016. Patients were separated into one of the following three groups: HbSS, HbSC, and control. All groups underwent full ophthalmologic examination (fundus examination) and ffERG. For SC patients, additional imaging testing was also performed (fluorescein angiography and spectral domain optical coherence tomography). Results: A total of 24 eyes from 12 patients (6 HbSS and 6 HbSC) and 12 eyes from 6 controls were included. The HbSS group exhibited a dramatic decrease of the b-wave amplitudes for all dark-adapted (DA) ffERG responses when compared with the control group (P = 0.02, P = 0.003, P = 0.005, respectively, after DA 0.01, DA 3.0, and DA 10.0 cd.s.m-2 stimulations) and decreased a-wave amplitudes for light-adapted responses (P = 0.03 after light adapted 3.0 cd.s.m-2 stimulations). The a-Wave amplitudes were significantly reduced for all dark-adapted and light-adapted responses in HbSC group compared to the control group (P = 0.03, P = 0.01, P = 0.03, respectively, after DA 3.0, DA 10.0, and light-adapted 3.0 cd.s.m-2 stimulations). The HbSS+HbSC groups presented decreased a-wave amplitudes for DA and light-adapted responses and decreased b-wave amplitude after DA 0.01 and 10.0 cd.s.m-2 stimulations when compared to the control group. Conclusions: These results could suggest an early involvement of the inner retinal cells in the disease process in HbSS patients and of the outer retinal cells in HbSC patients. This could provide new insights on the pathophysiology of the retinal affection in HbSS/HbSC SC disease. PMID- 28666278 TI - The Effect of Change in Intraocular Pressure on Choroidal Structure in Glaucomatous Eyes. AB - Purpose: Choroidal thickness increases linearly with intraocular pressure (IOP) lowering. We studied the relationship between the change in size of the choroidal vasculature and IOP lowering after glaucoma procedures. Methods: Thirty eyes of twenty-nine patients were examined pre- and postoperatively for up to 6 months with standard clinical assessment, enhanced depth imaging spectral-domain optical coherence tomography (OCT), and axial length measurement. Each enhanced depth imaging spectral-domain OCT image was analyzed using three separate methods to determine the choroidal thickness, choroidal vessel thickness, choroidal interstitial thickness, large choroidal vessel layer thickness, medium choroidal vessel layer thickness, and light-dark ratio. Bivariate linear regression analysis was completed with largest change in IOP as the independent variable. The dependent variables included choroidal thickness, choroidal vessel thickness, and choroidal interstitial thickness, at the largest change in IOP. Multivariable regression analysis using a generalized estimating equation to account for multiple measurements per eye was also completed. Results: Mean choroidal vessel thickness increases 1.5 MUm for every 1 mm Hg decrease in IOP (P < 0.0001; 95% confidence interval [CI], 0.8, 2.1) and choroidal interstitial thickness increases 1.3 MUm for every 1 mm Hg change in IOP (P < 0.0001; 95% CI, 0.8, 1.8). There was no significant association between change in IOP and change in large choroidal vessel layer temporally (P = 0.13), nasally (P = 0.20), or subfoveally (P = 0.18). There was also no association between IOP and the light-dark ratio (P = 0.16). Conclusions: The increase in choroidal thickness at lower IOP is associated with approximately equal increases in its intravascular and extravascular compartments. PMID- 28666280 TI - Amyloid beta1-43 Accumulates in the Lens Epithelium of Cortical Opacification in Japanese Patients. AB - Purpose: We investigated the accumulation of amyloid beta (Abeta1-40, Abeta1-42, Abeta1-43) in the lens epithelium of patients with opacification of five different types (cortical cataract [COR]; nuclear cataract [NUC]; posterior subcapsular cataract [PSC]; retrodots [RD]; and water clefts [WC]). Methods: Samples were collected from Japanese patients taken during cataract surgery; Abeta levels and mRNA expression were determined by ELISA and a real-time RT-PCR method, respectively. Results: Levels of Abeta1-40 and Abeta1-42 in the lens epithelium of patients with COR, NUC, PSC, RD, and WC showed no significant differences in comparison with transparent lens epithelium. Levels of Abeta1-43 in the lens epithelium of patients with PSC and WC were not detected, and NUC and RD were slightly elevated. In contrast to the results in these cataract types, high Abeta1-43 levels were observed in the lens epithelium of patients with COR, and a close relationship was observed between Abeta1-43 levels and the degree of lens opacification (R = 0.8229, n = 6). The levels of Abeta1-43 were also higher in the lens epithelium of patients with mixed-cataract showing cortical opacification, and the Abeta1-43 levels in the lens epithelium of mixed-cataract patients with cortical opacification was significantly higher than in that of mixed-cataract patients without cortical opacification. In addition, the level of an amyloid precursor protein mRNA in the lens epithelium of mixed-cataract patients with cortical opacification was significantly higher than in transparent lens and mixed-cataract patients without cortical opacification. Conclusions: We found high levels of Abeta1-43 accumulation in the lens epithelium of Japanese patients with cortical opacification. PMID- 28666279 TI - Sodium Iodate Produces a Strain-Dependent Retinal Oxidative Stress Response Measured In Vivo Using QUEST MRI. AB - Purpose: We identify noninvasive biomarkers that measure the severity of oxidative stress within retina layers in sodium iodate (SI)-atrophy vulnerable (C57BL/6 [B6]) and SI-atrophy resistant (129S6/SvEvTac [S6]) mice. Methods: At 24 hours after administering systemic SI to B6 and S6 mice we measured: (1) superoxide production in whole retina ex vivo, (2) excessive free radical production in vivo based on layer-specific 1/T1 values before and after alpha lipoic acid (ALA) administration while the animal was inside the magnet (QUEnch assiSTed MRI [QUEST MRI]), and (3) visual performance (optokinetic tracking) +/- antioxidants; control mice were similarly assessed. Retinal layer spacing and thickness in vivo also were evaluated (optical coherence tomography, MRI). Results: SI-treated B6 mice retina had a significantly higher superoxide production than SI-treated S6 mice. ALA-injected SI-treated B6 mice had reduced 1/T1 in more retinal layers in vivo than in SI-treated S6 mice. Uninjected and saline-injected SI-treated B6 mice had similar transretinal 1/T1 profiles. Notably, the inner segment layer 1/T1 of SI-treated B6 mice was responsive to ALA but was unresponsive in SI-treated S6 mice. In both SI-treated strains, antioxidants improved contrast sensitivity to similar extents; antioxidants did not change acuity in either group. Retinal thicknesses were normal in both SI treated strains at 24 hours after treatment. Conclusions: QUEST MRI uniquely measured severity of excessive free radical production within retinal layers of the same subject. Identifying the mechanisms underlying genetic vulnerabilities to oxidative stress is expected to help in understanding the pathogenesis of retinal degeneration. PMID- 28666281 TI - Structural Changes in Optical Coherence Tomography Underlying Spots of Increased Autofluorescence in the Perilesional Zone of Geographic Atrophy. AB - Purpose: To investigate structural correlates corresponding to the appearance of increased fundus autofluorescence (FAF) in the perilesional area of geographic atrophy (GA) secondary to age-related macular degeneration. Methods: Serial FAF images of 181 eyes with GA of 134 patients participating in the Directional Spread in Geographic Atrophy study (NCT02051998) were screened for increased FAF spots that had developed during the review period. Thickness and reflectivity of the retinal pigment epithelium (RPE)-basal lamina complex, as well as the integrity of the external limiting membrane (ELM) and the ellipsoid zone (EZ), respectively, in corresponding optical coherence tomography (OCT) scans were compared between the time points before and after the appearance of increased FAF. Adjacent areas without development of abnormal FAF were assessed as internal control. Results: A total of 36 areas (15 eyes) with de novo developed increased FAF spots and 54 control areas were included. Analysis of the corresponding OCT images revealed an increase in RPE-basal lamina complex thickness (31.8 +/- 7.3 to 42.1 +/- 11.9 MUm [P < 0.001]) and reflectivity (reflectivity ratio: 1.42 +/- 0.11 to 1.54 +/- 0.27 [P = 0.009]) corresponding to an increased FAF signal while there was no significant change in control areas. Development of increased FAF spots was associated with disruption of the ELM and the EZ. Conclusions: Increase of RPE-basal lamina complex thickness and reflectivity was spatially and temporally associated with the development of increased FAF spots in eyes with GA. In addition, outer retinal disruption may contribute to the corresponding increased FAF signal. PMID- 28666282 TI - [Physicians at the Interface to the Non-Medical Sector of Home- and Community Based Services for People with Dementia]. AB - Objective The study examined the function of physicians between the medical and nonmedical sector of home- and community-based services in the ambulatory care of people with dementia and their relatives. Therefore, the study took a differentiated look at the status quo of physicians' activities regarding non medical home- and community-based services as well as approaches for optimizing the current situation from the physicians' perspective. Methods An explorative cross-sectional study was conducted using a standardized postal survey (based on a qualitative preliminary study with 6 physicians). Data from 177 GPs and specialists in Hamburg could be collected and analyzed with descriptive statistics. Results The majority of physicians (88.1%) inform their patients with dementia and their carers about home- and community-based services. 'Home care' presents the most often and 'services for carers' the least considered aspect. Approaches that address the optimization of information material are assessed as most supportive. Conclusion The results can be used as a basis for further development of the care landscape in Hamburg. What has to be discussed is the monoperspective data collection only from physician's point of view. The utilization of the results requires an inclusion of the perspective of affected persons themselves as well as other actors in the non-medical care landscape. PMID- 28666283 TI - [Hereditary malformation of the inner ear in consecutive generations of one family]. PMID- 28666284 TI - ? PMID- 28666285 TI - [Endoscopic Browlift via Endotine Forehead Device in Patients with Facial Palsy]. AB - Objective Forehead and brows form a critical aesthetic and functional subunit of the face. Chronical pPeripheral paralysis of the facial nerve or its frontal branch may cause brow ptosis and eyelid deformities with a limited field of vision and loss of facial symmetry. Techniques, especially endoscopic methods have evolved significantly. Endotine Forehead Device, an adsorbable device, is a promising tool for brow suspension. Material and Methods 9 patients underwent brow and forehead lift surgery via Endotine Forehead Device. Intraoperative handling, complications, and the surgical outcome were assessed. To analyze postoperative symmetry FACEgram software was used. Follow-up was about 3,6 months after surgery. As a patient oriented outcome parameter the Glasgow Benefit Inventory Questionnaire was assessed about 10 months after surgery. Results Using the Endotine Forehead Device via an endoscopic approach was helpful to recreate a symmetrical upper third of the face. Few adverse effects could be observed:. One relapse was detected, one patient complained about the palpability of the device. Patients stated an improved quality of life after surgery, overall benefit in quality of life was +29,2 (SD 13,6). Conclusions Endotine Forehead Device is a successful minimally invasive tool for endoscopic brow and forehead lift surgery in patients with facial paralysis. PMID- 28666286 TI - [Musical abilities in children with an auditory processing disorder]. AB - Objective Difficulties in solving musical tasks are observed in clinical practice in children with an auditory processing disorder (APD). There is a paucity of research on musical ability in children with an APD. Material and Methods To assess musical skills we had 15 children aged 6-11 years with the diagnosis of APD perform a test, and compared them to a control group of 15 children. Results APD children did significantly worse in pitch discrimination, reproduction of rhythm and singing. Correlations between language-based and musical skills in the APD-group were observed. Conclusions Greater attention should be paid to musical skills in APD diagnostics. The positive impact of musical training on language development and cognitive abilities in general has been demonstrated in numerous studies. Musical training should be the focus of further discussion for therapeutic methods of APD in the presence of musical deficits. PMID- 28666287 TI - The Impact of cfDNA Screening on the Frequency of Invasive Procedures in a Geographically Diverse Private Network. PMID- 28666288 TI - Wilson's Disease Should Be Treated with Zinc rather than Trientine or Penicillamine. PMID- 28666289 TI - Intractable Epilepsy due to MTR Deficiency: Importance of Homocysteine Analysis. PMID- 28666290 TI - [Venous Paravasation After Augmentation of Pedicle Screws - An Underestimated Risk]. AB - Cement-augmented pedicle screws can increase the stability of fixators for unstable vertebral fractures in the elderly. Fixators can be inserted quickly and with minimally invasive techniques, reducing surgical risks. From March 2012 until July 2014, we treated 40 patients with percutaneous augmented fixators for unstable vertebral fractures. Average age was 77.5 years. During the six month observation period, no patients died. There were no neurological deficits. On VAS, average pain decreased from 8.5 to 4.1 points postoperatively. The average Cobb angle of 4.1 degrees was improved after surgery. After 6 months, bony consolidation yielded angles of 1 to 4 degrees , average 2.6 degrees . There was often venous extravasation of cement leaking from the augmented vertebrae, even extending to pulmonary embolism. The emboli were usually asymptomatic. We report a case where the patient required resuscitation immediately after cement application because of pulmonary emboli. The patient survived because of the immediately implemented critical care measures. Little has been published about this risk, which is underestimated despite increasing numbers of augmented fixator operations. The risk can be reduced with slower cement injection, smaller cement applicators, and short term positive pressure ventilation with PEEP. PMID- 28666291 TI - Biomechanics of Knee Joints after Anterior Cruciate Ligament Reconstruction. AB - This study aimed to investigate the biomechanical properties of anterior cruciate ligament (ACL); tibial, femoral articular cartilage; and meniscus in knee joints receiving computer-aided or conventional ACL reconstruction. Three-dimensional (3D) knee joint finite element models were established for healthy volunteers (normal group) and patients receiving computer-aided surgery (CAS) or conventional (traditional surgery [TS]) ACL reconstruction. The stress and stress distribution on the ACL, tibial, femoral articular cartilage, and meniscus were examined after force was applied on the 3D knee joint finite element models. No significant differences were observed in the stress on ACL among normal group, CAS group, and TS group when a femoral backward force was loaded. However, when a vertical force of 350 N was loaded on the knee joints, TS group had significant higher stress on the articular cartilage and meniscus than the other two groups at any flexion angle of 0, 30, 60, and 90 degrees. However, no significant differences were observed between CAS group and normal group. In conclusion, computer-aided ACL reconstruction has advantages over conventional surgery approach in restoring the biomechanical properties of knee joints, thus reducing the risk of damage to the knee joint cartilage and meniscus after ACL reconstruction. PMID- 28666293 TI - Does Patient Perception of Pain Influence How Patients Rate Their Experience after Total Knee Arthroplasty? PMID- 28666292 TI - Outcomes of Posterior-Stabilized Compared with Cruciate-Retaining Total Knee Arthroplasty. AB - The aim of this systematic review is to compare clinical outcome scores, rate of complications, and range of motion (ROM) of posterior-stabilized (PS) and cruciate-retaining (CR) total knee arthroplasties (TKAs) both pre- and postoperatively to establish which of the two kinds of implants have the best efficiency. A comprehensive search was performed of studies comparing CR and PS TKAs on PubMed, OVID/Medline, Cochrane, CINAHL, Google scholar, and Embase databases. Finally, 37 studies were selected with a total of 5,407 knees in 4,445 patients. For the PS knees, the Knee Society Functional Score (KSFS) improved from 44.6 to 77.6 (p = 0.04), extension decreased from 6.6 to 1.8 degrees (p value), and flexion increased from 115.2 to 119.4 degrees (p < 0.00001), compared with the CR knees. No significant difference in the Knee Society objective score (KSOS) (p = 0.82) or complication rates (p = 0.29) was found. The overall complication rate was 3.9%, 213 in 5,407 knees. Surgeons must be careful in interpreting these results, as an improved ROM for the PS group may not correlate to better patient outcomes. This meta-analysis has demonstrated that PS TKA has a statistically significant greater postoperative improvement of KSFS (p = 0.04), flexion (p < 0.00001), and extension (p = 0.02), compared with the CR group. These findings seem to lead the surgeons to prefer the PS design for TKAs especially to achieve a higher postoperative ROM in patients with high functional demands. On the contrary, the CR and PS TKAs have similar results in terms of complications and most of clinical outcomes analyzed in the included studies. Therefore, the long-term follow-up of high-quality randomized controlled trials is needed to clarify which of the two types of prosthesis provide the better clinical outcome and the lower rate of complications for osteoarthritis patients in particular cohorts. This is a systematic review (level II). PMID- 28666294 TI - Epigallocatechin-3-Gallate Protects against Homocysteine-Induced Brain Damage in Rats. AB - High levels of homocysteine are implicated in many neurovascular and neurodegeneration diseases. Epigallocatechin 3-gallate (EGCG), one of green tea polyphenols, has potential anti-oxidative and anti-inflammatory activities. However, it has not been explored whether EGCG has an effect on homocysteine induced neuro-inflammation and neurodegeneration. In this study, we investigated the effects of EGCG on memory deficit, oxidative stress, neuro-inflammation, and neurodegeneration in hyper-homocysteinemic rats after a 2 wk homocysteine injection by vena caudalis. We found that supplementation of EGCG could rescue deficit of spatial memory induced by homocysteine. Treatment of EGCG significantly reduced the expression of malondialdehyde, glial fibrillary acidic protein, tumor necrosis factor-alpha, and interleukin-1beta and increased glutathione level in the homocysteine-treated group. In TdT-mediated dUTP nick end labeling (TUNEL) assay and Fluoro-Jade B staining, supplementation of EGCG could attenuate the apoptotic neurons and neurodegeneration. Interestingly, EGCG significantly ameliorated homocysteine-induced cerebrovascular injury. Our data suggest that EGCG could be a promising candidate for arresting homocysteine induced neurodegeneration and neuro-inflammation in the brain. PMID- 28666295 TI - [Occupational Health Physicians and Rehabilitation - A Cross-sectional Study on Occupational Health Care in Schleswig-Holstein and Baden-Wurttemberg]. AB - Objective Description and explanation of involvement of occupational health physicians in rehabilitation Methods Data were collected by a survey of occupational health physicians in Schleswig-Holstein and Baden-Wurttemberg. Logistic regression models were calculated to identify determinants of the involvement of occupational health physicians before, during and after rehabilitation. Results During the last year 70% of the occupational health physicians have supported at least one worker when applying for medical rehabilitation. About a half has had at least once contact to a rehabilitation facility during the rehabilitation treatment of an employee, and 9 out of 10 physicians have supported at least one employee after her or his rehabilitation when returning to work. Support by occupational health physicians is more likely when they feel responsible for rehabilitation, are well informed and frequently involved in occupational reintegration management. Conclusions Occupational health physicians may be important stakeholders for preparing and supporting rehabilitation. PMID- 28666296 TI - [Facilitating Processes of Disintegration instead of Occupational Reintegration: A Qualitative Study on Employer-Involvement in Rehabilitation]. AB - Purpose To explore the patient's perspective on the involvement of employers into rehabilitation. Methods 8 participants of a work-related medical rehabilitation were interviewed by telephone 4 weeks after discharge. Qualitative content analysis was used to analyze generated data. Results Beside a poor employer involvement, the interviews revealed that the process of returning to work was characterized and hampered by unused measures of supporting vocational reintegration during rehabilitation, intersection problems in the health care and social security system, and a strategy of waiting by all involved actors. Conclusion Beside an improved employer-involvement, systematic intersection management and full usage of existing measures are demanded to support vocational reintegration. PMID- 28666297 TI - [Adolescents and Young Adults: What Would a "Perfect Therapy" Look Like?] AB - PRINCIPAL OBJECTIVE: Obesity is a major indication for pediatric and adolescent rehabilitation. Age-specific therapies for "emerging adults" are lacking. The aim was to examine the patients' preferences with respect to the contents and methods of the "perfect therapy" within an inpatient setting. METHOD: In the context of the YOUTH study 147 obese male and female adolescents (aged 15-21 years) filled in standardized questionnaires. RESULTS: Overall little age- and gender-specific differences were observed. The participants expressed a preference for interdisciplinary coordinated and coeducational group approaches with involvement of the parents. Major topics were healthy nutrition and psychosocial aspects. Prevention of relapses is considered as important as well. CONCLUSION: Psychosocial aspects and preparing coping with risk situations should be an integral part of treatment programs. PMID- 28666298 TI - Food Insecurity, Prenatal Care and Other Anemia Determinants in Pregnant Women from the NISAMI Cohort, Brazil: Hierarchical Model Concept. AB - Objective To identify the prevalence of anemia and its relation to food insecurity (FI) and other determinants in pregnant women. Methods A cross sectional, cohort-nested study, with the participation of 245 pregnant women who were cared for at Family Health Units in the municipality of Santo Antonio de Jesus, Bahia, Brazil. The participants underwent blood tests for hemoglobin levels, anthropometric examinations, and answered a structured questionnaire. The hemoglobin (Hb) parameter (Hb < 11 g/dL) was used for the classification of the diagnosis of anemia. Food insecurity was evaluated using the North American short scale food insecurity assessment. Logistic regression was adopted for the statistical analyses, based on a hierarchical conceptual model that enabled the measurement of the decomposition of the total effect of its non-mediated and mediated components using the proposed hierarchical levels. Results The prevalence of anemia in the studied population was of 21.8%, and the average hemoglobin was 12.06 g/dL (standard deviation [SD]: 1.27). Food insecurity was identified in 28.16% of the pregnant women. The average maternal age was 25.82 years (SD: 5.94). After ranking, the variables positively associated with anemia remained significant: FI (odds ratio [OR] =3.63; 95% confidence interval [95%CI]: 1.77-7.45); not undergoing prenatal care (OR = 5.15; 95%CI: 1.43-18.50); multiparity (OR = 2.27; 95%CI: 1.02-5.05); and non-supplementation of iron medication (OR = 2.45; 95%CI: 1.04-5.76). The results also indicated that the socioeconomic and environmental factors were largely mediated by food insecurity and factors regarding prenatal care. Conclusions In the present study, the chance of occurrence of anemia in pregnant women was significantly higher, mainly among women: in situations of food insecurity, not undergoing prenatal care, not having received iron supplements, and who are multiparous. PMID- 28666299 TI - Incidence of Bacteriuria after Urodynamic Study with or without Antibiotic Prophylaxis in Women with Urinary Incontinence. AB - Introduction The presence of bacteria in urine is called bacteriuria, which may be symptomatic or asymptomatic. The manipulation of the urinary tract during urodynamic study (UDS), which is an invasive procedure, can result in urinary tract infection (UTI). Studies on the use of prophylactic antibiotics for UDSs are contradictory. Some investigators concluded that they were valuable and others did not. The objective of this study is to evaluate the efficacy of antibiotic prophylaxis before UDS. This is a placebo-control randomized double blind study. Methods Two-hundred and seventeen women affected by urinary incontinence were eligible for this study. All patients had presented negative urine culture previous to the UDS. They were randomized in four groups: group A received placebo, group B received 500 mg of levofloxacin, group C received 80 mg trimethoprim and 400 mg sulfamethoxazole and group D received 100 mg of nitrofurantoin. A urine culture was performed 14 days after the UDS. Results We observed asymptomatic bacteriuria after the UDS in five patients in group A, one in group B, one in group C and one in group D. Only one patient on group A had symptomatic bacteriuria. We didn't observe statistical difference between the groups. When we recategorized the patients in two groups, the incidence of bacteriuria was significantly higher in the placebo group compared with the antibiotic group. Conclusion The conclusion is that antibiotic prophylaxis before the UDS did not reduce the incidence of UTI in women within the target population. PMID- 28666300 TI - Is Pethidine Safe during Labor? Systematic Review. AB - Purpose To verify if pethidine is safe for the conceptus when used during labor. Methods Systematic review in the Capes Periodicals/PubMed and MEDLINE/Virtual Health Library (BVS, in the Portuguese acronym) databases. Results A total of 17 studies published from January 1st, 2000, to September 2nd, 2016, with a total of 1,688 participants involved were included in the present review. There was no record of conceptus vitality decrease associated with low doses of pethidine being administered to mothers during labor. Conclusions Intramuscular (IM) or intravenous (IV) pethidine at low doses, of up to 50 mg, is safe to administer during labor. PMID- 28666301 TI - [Not Available]. PMID- 28666302 TI - [Motherhood at the Age of 35 and Over: The Risk of Advanced Maternal Age as Perceived by Women - a Literature Study]. AB - Background Delaying motherhood is an ongoing trend in industrialized countries worldwide. The higher the mother's age, the greater the risks for fertility, pregnancy, childbearing, and for the newborn. The psychosocial situation of women who are conscious of pregnancy risks is thus negatively affected. This paper aims to answer the question as to how women experience the risks of age. Methodology An systematic search of the international literature was carried out between December 2015 and March 2016, using the electronic databases PubMed, CINAHL, PsycINFO, Sowiport, as well as a manual search. The inclusion criterion was the perception of reproductive age risks of motherhood at an advanced age, defined as >= 35 years. Results Eleven studies with different designs were evaluated. The participants were sufficiently informed about decreasing fertility rates and the increasing risk of trisomy 21, but less knowledge was shown about the remaining age-associated risks. The awareness of these risks made women feel anxious and scared. They showed various strategies for dealing with their concern: information management, associated with problems of overand misinformation and, in contrast, information avoidance. Other strategies were distraction from thinking about the risks, the need for control and good preparation, or emotional distancing from the pregnancy. The women's personal risk assessment was complex. They related their social circumstances and their lifestyle and thought about the medical attributions in relative terms. By focusing on giving birth to a healthy child, the mothers often neglected to prepare themselves for living with the newborn. Postpartum they were overwhelmed by the care needed by the newborn child. Discussion The age risk cannot be assessed adequately by those affected. Various phenomena determined through risk research may also appear. There was a meaningful difference between the medically assessed risk and the women's perceived risk. Taking the women's experience with ageassociated risks and the consequences of motherhood into consideration, it seems necessary to discuss the concept of age risk. Healthcare professionals should focus on health support and encourage older pregnant women to familiarize themselves with family-orientated care of a newborn family member. PMID- 28666304 TI - ? PMID- 28666303 TI - ? PMID- 28666305 TI - Prevalence of Multidrug Resistant Bacteria in Refugees: A Prospective Case Control Study in an Obstetric Cohort. AB - Purpose To determine the prevalence of multidrug resistant (MDR) bacteria in a cohort of pregnant refugee women. Methods In a prospective case control study, surveillance cultures for MDR bacteria (methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci [VRE], MDR Gram-negative bacteria [MRGN]) were analysed between October 2015 and June 2016 from a cohort of 50 pregnant refugee women and 50 resident controls in the obstetric unit of a German tertiary referral hospital. Results Prevalence of MRSA was noticeably higher among refugee women compared to residents (6 vs. 0%). In addition, a trend towards a higher prevalence of VRE and MDR Gram-negative bacteria in refugees was shown (1.8 vs. 0%). Conclusions Due to the higher prevalence of MDR bacteria, surveillance cultures are justified in order to prevent nosocomial spread of MDR bacteria. PMID- 28666306 TI - [Simulation Training in Obstetrics: Survey of participants in a low-fidelity training]. AB - Background Childbirth is a physiological process. However a normal delivery may suddenly turn into a life-threatening emergency. In this case, maternal and infant health depends largely on appropriate and timely interventions, and effective teamwork of all professionals. In order to meet the complex requirements, different concepts for interdisciplinary simulation training in obstetric emergencies have been developed and evaluated mainly in Scandinavian and English-speaking countries. In this context, both high-fidelity and low fidelity trainings have been found to be effective. In German-speaking countries, the effectiveness of simulation in obstetric emergency training for multidisciplinary teams has not been evaluated extensively or systematically. The objective of this study was to explore whether or not simulation training is effective in improving obstetric emergency management. Method Quantitative and qualitative data was derived and evaluated via questionnaire from obstetric pre training and 4 months post-training. Participants were asked how they perceived their own competence and how confident they felt in emergency situations, how they rated their team's cooperation and communication, whether they felt secure in how to proceed in emergencies, and how important they considered the patient's perspective in such situations to be. Results 48 questionnaires pre- and post training were analysed. Nearly all items changed significantly. In open questions, participants were invited to suggest potential for improvement to their work environment; these suggestions were analysed descriptively. Conclusion Professionals felt that simulation training was effective. They experienced better management of obstetric emergencies post-training. PMID- 28666307 TI - ? PMID- 28666308 TI - ADAM, a hands-on patient simulator for teaching principles of drug disposition and compartmental pharmacokinetics. AB - AIMS: To design, construct and validate a pharmacokinetics simulator that offers students hands-on opportunities to participate in the design, administration and analysis of oral and intravenous dosing regimens. METHODS: The Alberta Drug Administration Modeller (ADAM) is a mechanical patient in which peristaltic circulation of water through a network of silicone tubing and glass bottles creates a representation of the outcomes of drug absorption, distribution, metabolism and elimination. Changing peristaltic pump rates and volumes in bottles allows values for pharmacokinetic constants to be varied, thereby simulating differences in drug properties and in patient physiologies and pathologies. Following administration of methylene blue dye by oral or intravenous routes, plasma and/or urine samples are collected and drug concentrations are determined spectrophotometrically. The effectiveness of the simulator in enhancing student competence and confidence was assessed in two undergraduate laboratory classes. RESULTS: The simulator effectively models one- and two-compartment drug behaviour in a mathematically-robust and realistic manner. Data allow calculation of numerous pharmacokinetic constants, by traditional graphing methods or with curve-fitting software. Students' competence in solving pharmacokinetic problems involving calculations and graphing improved significantly, while an increase in confidence and understanding was reported. CONCLUSIONS: The ADAM is relatively inexpensive and straightforward to construct, and offers a realistic, hands-on pharmacokinetics learning opportunity for students that effectively complements didactic lectures. PMID- 28666309 TI - Rediscover the clinical value of small intestinal bacterial overgrowth in patients with intestinal Behcet's disease. AB - BACKGROUND AND AIMS: Many patients with intestinal Behcet's disease (BD) still suffer from gastrointestinal symptoms despite the disease being in endoscopic or radiological remission. Previous studies report that small intestinal bacterial overgrowth (SIBO) can be associated with inflammatory bowel disease. However, there have been no reports about SIBO in patients with intestinal BD. We sought to identify the frequency of SIBO in patients with inactive intestinal BD by hydrogen breath test (HBT) and to investigate the efficacy of rifaximin as a treatment for SIBO. METHODS: Twenty-five patients with intestinal BD who had gastrointestinal symptoms even in endoscopic or radiological remission status were enrolled between January 2012 and January 2016. The patients filled out a questionnaire regarding their subjective gastrointestinal symptoms and took an HBT. Patients with positive HBT results were recommended to take 800-mg rifaximin daily for 14 days. RESULTS: Nine patients (9/25, 36%) had a positive HBT test. Eight (8/9, 88.9%) were women, and their mean age was 48.7 years. The most common symptom was abdominal distension (8/9, 88.9%), followed by abdominal discomfort (6/9, 66.7%). Rifaximin was prescribed to the nine patients with positive HBT, but two patients refused to take the medication. Four weeks later, six of the seven patients taking rifaximin (85.7%) reported symptom improvement, and none of them reported adverse events. CONCLUSIONS: More than one-third of the patients with inactive intestinal BD who had gastrointestinal symptoms were accompanied by SIBO using HBT. Rifaximin might be an effective and safe drug to treat these patients. PMID- 28666310 TI - Effectiveness of Self-management Support in Maintenance Haemodialysis Patients with Hypertension: A Pilot Cluster Randomized Controlled Trial. AB - BACKGROUND: Uncontrolled hypertension is an independent risk factor for cardiovascular disease and is the leading cause of mortality in haemodialysis patients. The aim of this study was to examine the effectiveness of self management support SMS) for blood pressure (BP) control and health behaviors. METHODS: We conducted a cluster randomized controlled trial (RCT) in which 90 adult haemodialysis patients were assigned to either an SMS or common intervention (CI) group. The SMS group received an intervention consisting of self-management education and motivational interviewing. The CI group received standard care and routine health education. The primary outcome was the BP monitored before each haemodialysis. Secondary outcomes included salt intake (measured using a balance formula), home BP monitoring (HBPM)(assessed using two self-administered questions), and medication adherence (measured using the 4-item Morisky Medication Adherence Scale). Data were collected at baseline and at 1, 3 and 6 months post-intervention. RESULTS: The SMS group showed continuous reductions in systolic BP from baseline:-9.2, -8.7, and -8.4 mmHg at 1, 3 and 6 months after the intervention, respectively (P<0.01). Compared with the CI group, the SMS group had a greater decrease in systolic BP at 1 month:-5.9 mmHg (P=0.0388), but no significant difference was found at 3 or 6 months(P>0.05). SMS patients showed an improvement in health behaviors relative to baseline (less salt intake, more consistent HBPM, and greater medication adherence) (P<0.05). CONCLUSIONS: SMS obtained short-term success in improving salt restriction, regular performance of HBPM and medication adherence, which led to better BP control. PMID- 28666311 TI - Fully automatic and precise data analysis developed for time-of-flight mass spectrometry. AB - Scientific objectives of current and future space missions are focused on the investigation of the origin and evolution of the solar system with the particular emphasis on habitability and signatures of past and present life. For in situ measurements of the chemical composition of solid samples on planetary surfaces, the neutral atmospheric gas and the thermal plasma of planetary atmospheres, the application of mass spectrometers making use of time-of-flight mass analysers is a technique widely used. However, such investigations imply measurements with good statistics and, thus, a large amount of data to be analysed. Therefore, faster and especially robust automated data analysis with enhanced accuracy is required. In this contribution, an automatic data analysis software, which allows fast and precise quantitative data analysis of time-of-flight mass spectrometric data, is presented and discussed in detail. A crucial part of this software is a robust and fast peak finding algorithm with a consecutive numerical integration method allowing precise data analysis. We tested our analysis software with data from different time-of-flight mass spectrometers and different measurement campaigns thereof. The quantitative analysis of isotopes, using automatic data analysis, yields results with an accuracy of isotope ratios up to 100 ppm for a signal-to-noise ratio (SNR) of 104 . We show that the accuracy of isotope ratios is in fact proportional to SNR-1 . Furthermore, we observe that the accuracy of isotope ratios is inversely proportional to the mass resolution. Additionally, we show that the accuracy of isotope ratios is depending on the sample width Ts by Ts0.5 . Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28666312 TI - Antithrombin III for portal vein thrombosis in patients with liver disease: A randomized, double-blind, controlled trial. AB - AIM: Portal vein thrombosis (PVT) is one of the most critical disorders in liver disease patients. These patients have the imbalance of coagulation and coagulation inhibition resulting from decreased levels of coagulation inhibitory factors, such as protein C, protein S, and antithrombin III (AT-III). We designed this randomized, double-blind, placebo-controlled trial comparing the safety and efficacy of AT-III for PVT in liver disease patients with those who received no treatment. METHODS: Eligible patients were diagnosed with the association of thrombus, without tumor thrombus, and thrombus in more than 50% of the cross sectional lumen of the portal vein. Patients with 70% or less serum level of AT III were included. The study drug was given up to three times in a 5-day consecutive infusion interval if the thrombus decreased in size. Efficacy was evaluated by contrast enhanced computed tomography using a five-grade scale (complete response, partial response, slight response, no response, and progression). From October 2014 through to March 2016, 36 patients were randomly assigned to the AT-III group and 37 patients to the placebo group. RESULTS: The proportion of patients with complete response or partial response of PVT was significantly higher in the AT-III group (55.6%; 20/36 patients; 95% confidence interval, 38.1-72.1) than in the placebo group (19.4%; 7/36 patients, 95% confidence interval, 8.2-36.0) (P = 0.003). The overall incidence of adverse events and adverse drug reactions did not differ significantly between the two groups. CONCLUSION: Antithrombin III is one of the essential therapies for patients with PVT in cases with lower concentration levels of AT-III. PMID- 28666314 TI - GPU-powered model analysis with PySB/cupSODA. AB - Summary: A major barrier to the practical utilization of large, complex models of biochemical systems is the lack of open-source computational tools to evaluate model behaviors over high-dimensional parameter spaces. This is due to the high computational expense of performing thousands to millions of model simulations required for statistical analysis. To address this need, we have implemented a user-friendly interface between cupSODA, a GPU-powered kinetic simulator, and PySB, a Python-based modeling and simulation framework. For three example models of varying size, we show that for large numbers of simulations PySB/cupSODA achieves order-of-magnitude speedups relative to a CPU-based ordinary differential equation integrator. Availability and implementation: The PySB/cupSODA interface has been integrated into the PySB modeling framework (version 1.4.0), which can be installed from the Python Package Index (PyPI) using a Python package manager such as pip. cupSODA source code and precompiled binaries (Linux, Mac OS/X, Windows) are available at github.com/aresio/cupSODA (requires an Nvidia GPU; developer.nvidia.com/cuda-gpus). Additional information about PySB is available at pysb.org. Contact: paolo.cazzaniga@unibg.it or c.lopez@vanderbilt.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28666313 TI - An update of the WCRF/AICR systematic literature review and meta-analysis on dietary and anthropometric factors and esophageal cancer risk. AB - Background: In the 2007 World Cancer Research Fund/American Institute for Cancer Research Second Expert Report, the expert panel judged that there was strong evidence that alcoholic drinks and body fatness increased esophageal cancer risk, whereas fruits and vegetables probably decreased its risk. The judgments were mainly based on case-control studies. As part of the Continuous Update Project, we updated the scientific evidence accumulated from cohort studies in this topic. Methods: We updated the Continuous Update Project database up to 10 January 2017 by searching in PubMed and conducted dose-response meta-analyses to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) using random effects model. Results: A total of 57 cohort studies were included in 13 meta analyses. Esophageal adenocarcinoma risk was inversely related to vegetable intake (RR per 100 g/day: 0.89, 95% CI: 0.80-0.99, n = 3) and directly associated with body mass index (RR per 5 kg/m2: 1.47, 95% CI: 1.34-1.61, n = 9). For esophageal squamous cell carcinoma, inverse associations were observed with fruit intake (RR for 100 g/day increment: 0.84, 95% CI: 0.75-0.94, n = 3) and body mass index (RR for 5 kg/m2 increment: 0.64, 95% CI: 0.56-0.73, n = 8), and direct associations with intakes of processed meats (RR for 50 g/day increment: 1.59, 95% CI: 1.11-2.28, n = 3), processed and red meats (RR for 100 g/day increment: 1.37, 95% CI: 1.04-1.82, n = 3) and alcohol (RR for 10 g/day increment: 1.25, 95% CI: 1.12-1.41, n = 6). Conclusions: Evidence from cohort studies suggested a protective role of vegetables and body weight control in esophageal adenocarcinomas development. For squamous cell carcinomas, higher intakes of red and processed meats and alcohol may increase the risk, whereas fruits intake may play a protective role. PMID- 28666315 TI - Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer. PMID- 28666316 TI - Two-year Test-Retest Reliability in High School Athletes Using the Four- and Two Factor ImPACT Composite Structures: The Effects of Learning Disorders and Headache/Migraine Treatment History. AB - Objective: This study examined the test-retest reliability of the four- and two factor structures (i.e., Memory and Speed) of ImPACT over a 2-year interval across multiple groups with premorbid conditions, including those with a history of special education or learning disorders (LD; n = 114), treatment history for headache/migraine (n = 81), and a control group (n = 792). Methods: Nine hundred and eighty seven high school athletes completed baseline testing using online ImPACT across a 2-year interval. Paired-samples t-tests documented improvement from initial to follow-up assessments. Test stability was examined using Regression-based measures (RBM) and Reliable change indices (RCI). Reliability was examined using intraclass correlation coefficients (ICC). Results: Significant improvement on all four composites were observed for the control group over a 2-year interval; whereas significant differences were observed only on Visual Motor Speed for the LD and headache/migraine treatment history groups. ICCs ranges were similar across groups and greater or comparable reliability was observed for the two-factor structure on Memory (0.67-0.73) and Speed (0.76-0.78) composites. RCIs and RBMs demonstrated stability for the four- and two-factor structures, with few cases falling outside the range of expected change within a healthy sample at the 90% and 95% CIs. Conclusion: Typical practices of obtaining new baselines every 2 years in the high school population can be applied to athletes with a history of special education or LD and headache/migraine treatment. The two-factor structure has potential to increase test-retest reliability. Further research regarding clinical utility is needed. PMID- 28666317 TI - Right ventricular and tricuspid valve function in patients chronically implanted with leadless pacemakers. AB - Aims: Leadless cardiac pacing has recently been proposed as alternative to conventional right ventricular (RV) pacing. With this approach, devices are directly screwed or fixed with tines in the RV wall, but the possible consequences on RV and tricuspid valve (TV) structure and function remain unknown. We thus conducted a study to evaluate this potential impact in chronically implanted patients. Methods and results: Repeated echocardiographic studies were performed prior to implantation, at discharge, and 2 months thereafter on all consecutive patients implanted with a leadless pacemaker at our centre between October 2014 and end-December 2015. Whenever possible, patients were evaluated in non-paced rhythm. Anatomical and functional parameters of RV, TV, and left cardiac structures were assessed. Overall, 23 patients (12 females, aged 85.2 +/- 6.3 years) were included, with 14 implanted using NanostimTM (Saint Jude Medical) and 9 with MicraTM (Medtronic). Indications for pacing were paroxysmal atrio-ventricular block in 12 patients, intermittent sinus bradycardia in 5, unexplained syncope in 3, and atrial fibrillation with slow ventricular rate in the remaining 3. The pacing percentage was 34 +/- 42% at the last visit. Most devices were implanted in the septo-apical or mid-septal region. There were no significant changes in echocardiographic parameters observed. One patient developed significantly increased TV regurgitation, without abnormal leaflet motion or TV annulus size changes, suggesting it to be due to RV pressure changes. Conclusion: In patients chronically implanted with leadless pacemakers, there were no significant changes in heart structure and function observed, especially concerning the RV and TV. PMID- 28666319 TI - Cause-of-death analysis in patients with cardiac resynchronization therapy with or without a defibrillator: a systematic review and proportional meta-analysis. AB - Aims: The additional benefit of a defibrillator in cardiac resynchronization therapy (CRT) patients is a matter of debate. Cause-of-death analysis in a CRT population has been recently proposed as a useful approach to gain insight into this problem. We performed a systematic review and meta-analysis looking at cause of death in studies involving CRT subjects with (CRT-D) or without (CRT-P) a defibrillator. Methods and results: Literature search performed from inception to 31 March 2016 for relevant studies. Proportional and conventional meta-analyses were performed to obtain and compare causes of death in CRT-D vs. CRT-P patients, including sudden cardiac death (SCD), all-cause mortality, heart failure, cardiovascular, and non-cardiovascular mortalities. The systematic review included a total of 44 studies and 18 874 patients (13 248 receiving CRT-D and 5626 receiving CRT-P), representing 48 504 patient-years of follow-up. CRT-D recipients were younger, more often male, had lower NYHA class, less atrial fibrillation, more ischaemic heart disease and were more often on beta-blockers than those receiving CRT-P. There were an additional 42 deaths per 1000 patient years in the CRT-P group compared with CRT-D (97 +/- 9, 95% CI 79-115 vs. 55 +/- 5, 95% CI 44-65, respectively), of which 35.7% were due to SCD (20 +/- 2, 95% CI 15-24 vs. 5 +/- 1, 95% CI 3-6) and the remaining 64.3% due to non-SCD. Of all deaths reported in CRT-D and CRT-P patients, 9.1% and 20.6% were due to SCD, respectively. The extent of SCD in CRT-P patients significantly increased in studies with higher percentage of males, ischaemic cardiomyopathy and NYHA class 3. Conclusion: Overall, compared with CRT-D patients, unadjusted mortality rate was almost two-fold higher in CRT-P recipients, with SCD representing one third of the excess mortality. Rate of SCD was significantly higher in certain subgroups (males, ischaemic cardiomyopathy, NYHA class 3), where a CRT-D may be of more pronounced benefit. This deserves further focused investigation. PMID- 28666318 TI - Autologous intramuscular transplantation of engineered satellite cells induces exosome-mediated systemic expression of Fukutin-related protein and rescues disease phenotype in a murine model of limb-girdle muscular dystrophy type 2I. AB - alpha-Dystroglycanopathies are a group of muscular dystrophies characterized by alpha-DG hypoglycosylation and reduced extracellular ligand-binding affinity. Among other genes involved in the alpha-DG glycosylation process, fukutin related protein (FKRP) gene mutations generate a wide range of pathologies from mild limb girdle muscular dystrophy 2I (LGMD2I), severe congenital muscular dystrophy 1C (MDC1C), to Walker-Warburg Syndrome and Muscle-Eye-Brain disease. FKRP gene encodes for a glycosyltransferase that in vivo transfers a ribitol phosphate group from a CDP -ribitol present in muscles to alpha-DG, while in vitro it can be secreted as monomer of 60kDa. Consistently, new evidences reported glycosyltransferases in the blood, freely circulating or wrapped within vesicles. Although the physiological function of blood stream glycosyltransferases remains unclear, they are likely released from blood borne or distant cells. Thus, we hypothesized that freely or wrapped FKRP might circulate as an extracellular glycosyltransferase, able to exert a "glycan remodelling" process, even at distal compartments. Interestingly, we firstly demonstrated a successful transduction of MDC1C blood-derived CD133+ cells and FKRP L276IKI mouse derived satellite cells by a lentiviral vector expressing the wild-type of human FKRP gene. Moreover, we showed that LV-FKRP cells were driven to release exosomes carrying FKRP. Similarly, we observed the presence of FKRP positive exosomes in the plasma of FKRP L276IKI mice intramuscularly injected with engineered satellite cells. The distribution of FKRP protein boosted by exosomes determined its restoration within muscle tissues, an overall recovery of alpha-DG glycosylation and improved muscle strength, suggesting a systemic supply of FKRP protein acting as glycosyltransferase. PMID- 28666320 TI - Inferring transcriptional logic from multiple dynamic experiments. AB - Motivation: The availability of more data of dynamic gene expression under multiple experimental conditions provides new information that makes the key goal of identifying not only the transcriptional regulators of a gene but also the underlying logical structure attainable. Results: We propose a novel method for inferring transcriptional regulation using a simple, yet biologically interpretable, model to find the logic by which a set of candidate genes and their associated transcription factors (TFs) regulate the transcriptional process of a gene of interest. Our dynamic model links the mRNA transcription rate of the target gene to the activation states of the TFs assuming that these interactions are consistent across multiple experiments and over time. A trans-dimensional Markov Chain Monte Carlo (MCMC) algorithm is used to efficiently sample the regulatory logic under different combinations of parents and rank the estimated models by their posterior probabilities. We demonstrate and compare our methodology with other methods using simulation examples and apply it to a study of transcriptional regulation of selected target genes of Arabidopsis Thaliana from microarray time series data obtained under multiple biotic stresses. We show that our method is able to detect complex regulatory interactions that are consistent under multiple experimental conditions. Availability and implementation: Programs are written in MATLAB and Statistics Toolbox Release 2016b, The MathWorks, Inc., Natick, Massachusetts, United States and are available on GitHub https://github.com/giorgosminas/TRS and at http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software. Contact: giorgos.minas@warwick.ac.uk or b.f.finkenstadt@warwick.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28666322 TI - SVM-dependent pairwise HMM: an application to protein pairwise alignments. AB - Motivation: Methods able to provide reliable protein alignments are crucial for many bioinformatics applications. In the last years many different algorithms have been developed and various kinds of information, from sequence conservation to secondary structure, have been used to improve the alignment performances. This is especially relevant for proteins with highly divergent sequences. However, recent works suggest that different features may have different importance in diverse protein classes and it would be an advantage to have more customizable approaches, capable to deal with different alignment definitions. Results: Here we present Rigapollo, a highly flexible pairwise alignment method based on a pairwise HMM-SVM that can use any type of information to build alignments. Rigapollo lets the user decide the optimal features to align their protein class of interest. It outperforms current state of the art methods on two well-known benchmark datasets when aligning highly divergent sequences. Availability and implementation: A Python implementation of the algorithm is available at http://ibsquare.be/rigapollo. Contact: wim.vranken@vub.be. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28666323 TI - Exploring the in vitro potential of celecoxib derivative AR-12 as an effective antiviral compound against four dengue virus serotypes. AB - Objectives: With no clinically effective antiviral options available, infections and fatalities associated with dengue virus (DENV) have reached an alarming level worldwide. We have designed this study to evaluate the efficacy of the celecoxib derivative AR-12 against the in vitro replication of all four DENV serotypes. Methods: Each 24-well plate of Vero cells infected with all four DENV serotypes, singly, was subjected to treatments with various doses of AR-12. Following 48 h of incubation, inhibitory efficacies of AR-12 against the different DENV serotypes were evaluated by conducting a virus yield reduction assay whereby DENV RNA copy numbers present in the collected supernatant were quantified using qRT PCR. The underlying mechanism(s) possibly involved in the compound's inhibitory activities were then investigated by performing molecular docking on several potential target human and DENV protein domains. Results: The qRT-PCR data demonstrated that DENV-3 was most potently inhibited by AR-12, followed by DENV 1, DENV-2 and DENV-4. Our molecular docking findings suggested that AR-12 possibly exerted its inhibitory effects by interfering with the chaperone activities of heat shock proteins. Conclusions: These results serve as vital information for the design of future studies involving in vitro mechanistic studies and animal models, aiming to decipher the potential of AR-12 as a potential therapeutic option for DENV infection. PMID- 28666321 TI - Androgens Regulate Ovarian Gene Expression Through Modulation of Ezh2 Expression and Activity. AB - A substantial amount of evidence suggests that androgen signaling through classical androgen receptors is critical for both normal and pathologic ovarian physiology. Specifically, we and others have shown that, in mouse granulosa cells, androgen actions through both extranuclear and nuclear androgen receptor signaling are critical for normal follicle development and ovulation. Here, we show that androgens through the PI3K/Akt pathway rapidly (within minutes) phosphorylate and inhibit activity of the Polycomb group protein enhancer of zeste homolog 2 (Ezh2). Over the course of 24 to 48 hours, androgens then induce expression of the microRNA miR-101, which targets Ezh2 messenger RNA (mRNA), leading to a nearly complete loss of Ezh2 protein expression. This long-term androgen-induced loss of Ezh2 actions ultimately results in sustained reduction of the H3K27me3-repressive mark in the promoter region of the Runt-related transcription factor-1 (Runx1) gene, a luteinizing hormone (LH)-induced transcription factor essential for ovulation, leading to increased Runx1 mRNA expression. Accordingly, blocking androgen-induced inhibition of Ezh2 in vivo adversely affects LH-induced Runx1 mRNA expression and subsequent ovulation. Importantly, although estrogen treatment of granulosa cells similarly causes rapid activation of the PI3K/Akt pathway and short-term phosphorylation of Ezh2, it does not induce miR-101 expression and thereby does not reduce overall Ezh2 expression, demonstrating the androgen specificity of long-term Ezh2 suppression. Thus, this study provides insight regarding how androgen-induced extranuclear kinase signaling and intranuclear transcription through Ezh2 modifications may influence the expression pattern of genes, ultimately affecting various downstream physiological processes. PMID- 28666324 TI - XIAP upregulates expression of HIF target genes by targeting HIF1alpha for Lys63 linked polyubiquitination. AB - The cellular response to hypoxia is characterised by a switch in the transcriptional program, mediated predominantly by the hypoxia inducible factor family of transcription factors (HIF). Regulation of HIF1 is primarily controlled by post-translational modification of the HIF1alpha subunit, which can alter its stability and/or activity. This study identifies an unanticipated role for the X linked inhibitor of apoptosis (XIAP) protein as a regulator of Lys63-linked polyubiquitination of HIF1alpha. Lys63-linked ubiquitination of HIF1alpha by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys63-linked polyubiquitination promotes HIF1alpha nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys63-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1alpha, promoter occupancy, HIF-dependent gene expression and cell viability. Our data reveals an additional and significant level of control of the HIF1 by XIAP, with important implications in understanding the role of HIF1 and XIAP in human disease. PMID- 28666325 TI - Suami SIAGA: male engagement in maternal health in Indonesia. AB - Suami SIAGA, which translates literally as the 'alert husband', is a national campaign that was created in early 2000 to promote male participation in maternal and child health program in Indonesia. The purpose of this study was to identify the proportion of men who took part in Suami SIAGA and the factors associated with their participation using the 2012 Indonesia Demographic and Health Survey (IDHS). This study also examined the relationship between Suami SIAGA and the following results related to the national campaign: the presence of husbands at antenatal care (ANC) units and the place of delivery at health facilities. Data on the characteristics of husbands and wives, as well as other related factors, the perceived elements of Suami SIAGA, and the national campaign outcomes were obtained from a total of 1256 eligible male subjects, drawn from the matched couples' data set. The data was analysed using bivariate and multiple logistic regression to test the associations. This study found that 86% of the respondents were categorised as SIAGA husbands. After controlling all the variables, age and education of wife factors were significantly associated with Suami SIAGA, especially in the group of women aged 41-49 years old (OR = 2.4, 95% CI: 1.1-5.5) and women with a secondary level of education (OR = 1.8, 95% CI: 1.2-2.7) and higher (OR = 2.8, 95% CI: 1.4-5.6). SIAGA husbands were more likely to attend their wives' ANC (OR = 2.3; 95% CI: 1.4-3.7). This study provides evidence on the benefit of husband involvement in maternal health, especially to improve ANC attendance. Empowering women themselves should also be addressed in leveraging the impact of Suami SIAGA. PMID- 28666326 TI - IVIG-mediated effector functions in autoimmune and inflammatory diseases. AB - Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab')2 fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients. PMID- 28666328 TI - Amyotrophic lateral sclerosis-related mutant superoxide dismutase 1 aggregates inhibit 14-3-3-mediated cell survival by sequestration into the JUNQ compartment. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss in the spinal cord and brain. Mutations in the superoxide dismutase 1 (SOD1) gene have been linked to familial ALS. To elucidate the role of SOD1 mutations in ALS, we investigated 14-3-3, a crucial regulator of cell death that was identified in patients with familial ALS. In a transgenic mouse model (SOD1-G93A) of ALS, 14-3-3 co-localized with mutant SOD1 aggregates and was more insoluble in the spinal cords of mutant SOD1 transgenic mice than in those of wild-type mice. Immunofluorescence and co-immunoprecipitation experiments showed that the 14-3-3E and theta isoforms interact with mutant SOD1 aggregates in the juxtanuclear quality control compartment of N2a neuroblastoma cells. Fluorescence loss in photobleaching experiments revealed that movement of the isoforms of 14-3-3 was markedly reduced in SOD1 aggregates. Bax translocation into and cytochrome c release from the mitochondria were promoted by the sequestration of 14-3-3 into mutant SOD1 aggregates, increasing cell death. Mutant SOD1 aggregates were dissolved by the Hsp104 chaperone, which increased the interaction of 14-3-3 with Bax, reducing cell death. Our study demonstrates that mutant SOD1 inhibits 14-3-3-mediated cell survival. This information may contribute to the identification of a novel therapeutic target for ALS. PMID- 28666329 TI - Increased blood levels of transforming growth factor beta in patients with aortic dilatation. AB - OBJECTIVES: Recent studies have shown that patients with syndromic thoracic aortic aneurysm, particularly patients with bicuspid aortic valve, have increased blood levels of transforming growth factor beta1 (TGF-beta1), indicating this molecule as a prognostic biomarker. However, it is not known whether TGF-beta1 is also elevated in the blood of patients with tricuspid aortic valve and aortic dilatation. METHODS: We analysed the plasma levels of TGF-beta1 in 52 patients with tricuspid or bicuspid aortic valve and with normal or dilated ascending aorta who underwent cardiac surgery in our hospital. RESULTS: TGF-beta1 blood level was significantly increased two-fold in patients with tricuspid aortic valve and dilated aorta compared to patients with tricuspid aortic valve and normal aorta. CONCLUSIONS: Our results suggest that TGF-beta1 blood levels may serve as a prognostic biomarker for patients with syndromic and non-syndromic thoracic aortic aneurysm. Further studies with larger cohorts of patients should be performed to confirm these results. PMID- 28666327 TI - The RNA-binding protein, ZC3H14, is required for proper poly(A) tail length control, expression of synaptic proteins, and brain function in mice. AB - A number of mutations in genes that encode ubiquitously expressed RNA-binding proteins cause tissue specific disease. Many of these diseases are neurological in nature revealing critical roles for this class of proteins in the brain. We recently identified mutations in a gene that encodes a ubiquitously expressed polyadenosine RNA-binding protein, ZC3H14 (Zinc finger CysCysCysHis domain containing protein 14), that cause a nonsyndromic, autosomal recessive form of intellectual disability. This finding reveals the molecular basis for disease and provides evidence that ZC3H14 is essential for proper brain function. To investigate the role of ZC3H14 in the mammalian brain, we generated a mouse in which the first common exon of the ZC3H14 gene, exon 13 is removed (Zc3h14Deltaex13/Deltaex13) leading to a truncated ZC3H14 protein. We report here that, as in the patients, Zc3h14 is not essential in mice. Utilizing these Zc3h14Deltaex13/Deltaex13mice, we provide the first in vivo functional characterization of ZC3H14 as a regulator of RNA poly(A) tail length. The Zc3h14Deltaex13/Deltaex13 mice show enlarged lateral ventricles in the brain as well as impaired working memory. Proteomic analysis comparing the hippocampi of Zc3h14+/+ and Zc3h14Deltaex13/Deltaex13 mice reveals dysregulation of several pathways that are important for proper brain function and thus sheds light onto which pathways are most affected by the loss of ZC3H14. Among the proteins increased in the hippocampi of Zc3h14Deltaex13/Deltaex13 mice compared to control are key synaptic proteins including CaMK2a. This newly generated mouse serves as a tool to study the function of ZC3H14 in vivo. PMID- 28666331 TI - ALTRE: workflow for defining ALTered regulatory elements using chromatin accessibility data. PMID- 28666332 TI - RNA-MoIP: prediction of RNA secondary structure and local 3D motifs from sequence data. PMID- 28666330 TI - Monomolecular G-quadruplex structures with inversion of polarity sites: new topologies and potentiality. AB - In this paper, we report investigations, based on circular dichroism, nuclear magnetic resonance spectroscopy and electrophoresis methods, on three oligonucleotide sequences, each containing one 3'-3' and two 5'-5' inversion of polarity sites, and four G-runs with a variable number of residues, namely two, three and four (mTG2T, mTG3T and mTG4T with sequence 3'-TGnT-5'-5'-TGnT-3'-3' TGnT-5'-5'-TGnT-3' in which n = 2, 3 and 4, respectively), in comparison with their canonical counterparts (TGnT)4 (n = 2, 3 and 4). Oligonucleotides mTG3T and mTG4T have been proven to form very stable unprecedented monomolecular parallel G quadruplex structures, characterized by three side loops containing the inversion of polarity sites. Both G-quadruplexes have shown an all-syn G-tetrad, while the other guanosines adopt anti glycosidic conformations. All oligonucleotides investigated have shown a noteworthy antiproliferative activity against lung cancer cell line Calu 6 and colorectal cancer cell line HCT-116 p53-/-. Interestingly, mTG3T and mTG4T have proven to be mostly resistant to nucleases in a fetal bovine serum assay. The whole of the data suggest the involvement of specific pathways and targets for the biological activity. PMID- 28666333 TI - A Long and Winding Road from Tortuous Arteries to a Straightforward Diagnosis of FMD. PMID- 28666334 TI - Targeting Adrenomedullin to Improve Lipid Homeostasis in Diabetic Pregnancies. AB - Context: Gestational diabetes mellitus (GDM) is associated with disturbances in maternal lipid metabolism. Hypertriacylglycerolemia in GDM is associated with an increased risk of large for gestational age neonates, but the pathogenesis of disrupted lipid homeostasis remains unclear. Objectives: To determine the role of adrenomedullin (AM), a multifunctional peptide, in lipid metabolism in GDM. Design: Omental adipose biopsies were collected in term pregnancy from women with normal glucose tolerance (NGT, n = 10) and GDM (n = 10). Results: AM and its receptor components, calcitonin receptor-like receptor, receptor activity modifying protein 2, and receptor activity-modifying protein 3, were higher in adipose tissues from GDM compared with NGT pregnancies, and these expressions in normal adipose tissues were enhanced by glucose and tumor necrosis factor-alphain vitro. AM dose- and time-dependently stimulated lipolysis in human adipocytes, and this effect was reversed by AM antagonist AM22-52. Furthermore, AM inhibited phosphorylation of insulin receptor-beta and insulin receptor substrate-1 and enhanced the protein expression of leptin and resistin in adipose tissue from NGT women. The increased messenger RNA expression of leptin and resistin in adipose tissue from GDM was reduced by AM22-52 treatment. Conclusions: GDM pregnancies are associated with increased AM and its receptor expression in adipose tissues. AM stimulates lipolysis and leptin and resistin expression, and these effects can be reversed by AM antagonist. To our knowledge, manipulation of AM and its receptors in adipocytes might represent an approach in reducing the risk of GDM and fetal overgrowth. PMID- 28666335 TI - A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin. AB - Background: The activity of ginger in the management of chemotherapy-induced nausea and vomiting (CINV) has been suggested, but design inadequacies, heterogeneity of the population, small numbers and poor quality of tested products limit the possibility to offer generalizable results. Patients and methods: We conducted a randomized, double-blind, placebo-controlled, multicenter study in patients planned to receive >=2 chemotherapy cycles with high dose (>50 mg/m2) cisplatin. Patients received ginger 160 mg/day (with standardized dose of bioactive compounds) or placebo in addition to the standard antiemetic prophylaxis for CINV, starting from the day after cisplatin administration. CINV was assessed through daily visual-analogue scale and Functional Living Index Emesis questionnaires. The main objective was protection from delayed nausea; secondary end points included intercycle nausea and nausea anticipatory symptoms. Results: In total, 121 patients received ginger and 123 placebo. Lung (49%) and head and neck cancer (HNC; 35%) were the most represented tumors. No differences were reported in terms of safety profile or compliance. The incidence of delayed, intercycle and anticipatory nausea did not differ between the two arms in the first cycle and second cycle. A benefit of ginger over placebo in Functional Living Index Emesis nausea score differences (day 6-day 1) was identified for females (P = 0.048) and HNC patients (P = 0.038). Conclusions: In patients treated with high-dose cisplatin, the daily addition of ginger, even if safe, did not result in a protective effect on CINV. The favorable effect observed on nausea in subgroups at particular risk of nausea (females; HNC) deserves specific investigation. PMID- 28666337 TI - Context Memory in Alzheimer's Disease: The "Who, Where, and When". AB - Objective: Context memory, a component of episodic system, refers to the ability to retrieve conditions under which an event has occurred, such as who was present during that event and where and when it occurred. Context memory has been found to be compromised in older adults, an issue that we investigated in Alzheimer's disease (AD). Methods: Thirty-one participants with AD and 35 older adults were asked to generate three autobiographical events. Afterward, they were asked to remember the names of all people who were evoked during the events, and the names for any location that was mentioned during the events. Participants were also asked to remember the year, season, month and day of the week when the events occurred. Results: Compared to older adults, participants with AD showed lower memory for "who" (p < .001), "where" (p < .05), and "when" (p < .01). Compared to "who" and "where", both participants with AD and older adults showed pronounced difficulties in remembering the "when". Conclusion: these findings highlight difficulties in remembering temporal information as an indication of context memory decline in AD. The difficulties in retrieving temporal information are discussed in terms of timing failures and hippocampal degenerations in AD. PMID- 28666336 TI - Health systems facilitators and barriers to the integration of HIV and chronic disease services: a systematic review. AB - Integration of services for patients with more than one diagnosed condition has intuitive appeal but it has been argued that the empirical evidence to support it is limited. We report the findings of a systematic review that sought to identify health system factors, extrinsic to the integration process, which either facilitated or hindered the integration of services for two common disorders, HIV and chronic non-communicable diseases. Findings were initially extracted and organized around a health system framework, followed by a thematic cross-cutting analysis and validation steps. Of the 150 articles included, 67% (n = 102) were from high-income countries. The articles explored integration with services for one or several chronic disorders, the most studied being alcohol or substance use disorders (47.7%), and mental health issues (29.5%). Four cross-cutting themes related to the health system were identified. The first and most common theme was the requirement for effective collaboration and coordination: formal and informal productive relationships throughout the system between providers and within teams, and between staff and patients. The second was the need for adequate and appropriately skilled and incentivized health workers-with the right expertise, training and operational support for the programme. The third was the need for supportive institutional structures and dedicated resources. The fourth was leadership in terms of political will, effective managerial oversight and organizational culture, indicating that actual implementation is as important as programme design. A fifth theme, outside the health system, but underpinning all aspects of the system operation, was that placing the patient at the centre of service delivery and responding holistically to their diverse needs. This was an important facilitator of integration. These findings confirm that integration processes in service delivery depend substantially for their success on characteristics of the health systems in which they are embedded. PMID- 28666338 TI - Interictal epileptiform activity outside the seizure onset zone impacts cognition. AB - See Kleen and Kirsch (doi:10.1093/awx178) for a scientific commentary on this article.Cognitive deficits are common among epilepsy patients. In these patients, interictal epileptiform discharges, also termed spikes, are seen routinely on electroencephalography and believed to be associated with transient cognitive impairments. In this study, we investigated the effect of spikes on memory encoding and retrieval, taking into account the spatial distribution of spikes in relation to the seizure onset zone as well as anatomical regions of the brain. Sixty-seven patients with medication refractory epilepsy undergoing continuous intracranial electroencephalography monitoring engaged in a delayed free recall task to test short-term memory. In this task, subjects were asked to memorize and recall lists of common nouns. We quantified the effect of each spike on the probability of successful recall using a generalized logistic mixed model. We found that in patients with left lateralized seizure onset zones, spikes outside the seizure onset zone impacted memory encoding, whereas those within the seizure onset zone did not. In addition, spikes in the left inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, and fusiform gyrus during memory encoding reduced odds of recall by as much as 15% per spike. Spikes also reduced the odds of word retrieval, an effect that was stronger with spikes outside of the seizure onset zone. These results suggest that seizure onset regions are dysfunctional at baseline, and support the idea that interictal spikes disrupt cognitive processes related to the underlying tissue. PMID- 28666340 TI - An unusual adrenal cause of hypoglycaemia. PMID- 28666339 TI - Control of serine integrase recombination directionality by fusion with the directionality factor. AB - Bacteriophage serine integrases are extensively used in biotechnology and synthetic biology for assembly and rearrangement of DNA sequences. Serine integrases promote recombination between two different DNA sites, attP and attB, to form recombinant attL and attR sites. The 'reverse' reaction requires another phage-encoded protein called the recombination directionality factor (RDF) in addition to integrase; RDF activates attL * attR recombination and inhibits attP * attB recombination. We show here that serine integrases can be fused to their cognate RDFs to create single proteins that catalyse efficient attL * attR recombination in vivo and in vitro, whereas attP * attB recombination efficiency is reduced. We provide evidence that activation of attL * attR recombination involves intra-subunit contacts between the integrase and RDF moieties of the fusion protein. Minor changes in the length and sequence of the integrase-RDF linker peptide did not affect fusion protein recombination activity. The efficiency and single-protein convenience of integrase-RDF fusion proteins make them potentially very advantageous for biotechnology/synthetic biology applications. Here, we demonstrate efficient gene cassette replacement in a synthetic metabolic pathway gene array as a proof of principle. PMID- 28666341 TI - DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland. AB - Context: Thyroid dysgenesis (TD) is the leading cause of congenital hypothyroidism (CH). The etiology of TD remains unknown in ~90% of cases, the most common form being thyroid ectopia (TE) (48% to 61%). Objective: To search for candidate genes in hypothyroid children with TE. Design, Setting, and Participants: We followed a cohort of 268 children with TD and performed whole exome sequencing (WES) in three children with CH with TE (CHTE) and compared them with 18 thyroid-healthy controls. We then screened an additional 41 children with CHTE by Sanger sequencing and correlated the WES and Sanger molecular findings with in vitro functional analysis. Main Outcome Measures: Genotyping, mutation prediction analysis, and in vitro functional analysis. Results: We identified seven variants in the DUOX2 gene, namely G201E, L264CfsX57, P609S, M650T, E810X, M822V, and E1017G, and eight known variations. All children carrying DUOX2 variations had high thyroid-stimulating hormone levels at neonatal diagnosis. All mutations were localized in the N-terminal segment, and three of them led to effects on cell surface targeting and reactive oxygen species generation. The DUOX2 mutants also altered the interaction with the maturation factor DUOXA2 and the formation of a stable DUOX2/DUOXA2 complex at the cell surface, thereby impairing functional enzymatic activity. We observed no mutations in the classic genes related to TD or in the DUOX1 gene. Conclusion: Our findings suggest that, in addition to thyroid hormonogenesis, the DUOX2 N-terminal domain may play a role in thyroid development. PMID- 28666342 TI - Achieving accountability through maternal death reviews in Nigeria: a process analysis. AB - Maternal death reviews (MDRs) are part of the drive to increase accountability for maternal deaths and reduce their occurrence by identifying barriers to effective, quality care. However, conducting MDRs well is difficult; staff commitment and establishing a blame free environment are key challenges. By examining the communication strategies used in MDRs this study sought to understand how MDR members implement policy imperatives (e.g. 'no blame, no name') and manage the inevitable sensitivities of discussing a client's death in a multidisciplinary team. We observed and recorded four MDRs in Nigerian teaching hospitals and used conversation and discourse analysis to identify patterns in verbal and non-verbal interactions. MDRs were conducted in a structured way and had multidisciplinary representation. We grouped discursive strategies observed into three overlapping clusters: 'doing' no-name no-blame; fostering participation; and managing personal accountability. Within these clusters, explicit reminders, gentle enquiries and instilling a sense of togetherness were used in doing no-name, no-blame. Strategies such as questioning and invoking protocol were only partially successful in fostering participation. Regarding managing accountability, forms of communication which limit personal responsibility ('pass the buck') and resist passing the buck were observed. Detailed, lengthy eye witness accounts of dramatic events appeared to reduce staff's personal accountability. We conclude that interactional processes affect the meaningfulness of MDRs. In-depth, critical analysis depends on resisting 'passing the buck' by practitioners and chairs especially, who are also key to fostering participation and extracting value from multidisciplinary representation. Our innovative methods provide detailed insights into MDRs as an interactional process, which can inform design of training aimed at enhancing MDR members' skills. However, given the multitude of systemic challenges we should also adjust our expectations of MDRs and the individual practitioners tasked to perform them in the name of enhancing accountability for maternal death reduction. PMID- 28666343 TI - Intraoperative arrhythmias in children with congenital heart disease: transient, innocent events? AB - Aims: The significance and incidences of intraoperative arrhythmias occurring in the operating room (OR) in children with congenital heart disease (CHD) are unknown. Aims of this study were to determine incidences of intraoperative arrhythmias in children with CHD and to examine whether they are associated with persistent arrhythmias during follow-up. Methods and results: Continuous ECG recordings obtained from 134 consecutive paediatric CHD patients were manually examined from the moment the aortic cross-clamp (ACC) was removed [use of ACC and cardiopulmonary bypass (CPB)], when CPB was stopped (use of only CPB) or when the sternum was closed (no use of ACC and CPB) until departure from the OR. In the OR, 2nd (60%) and 3rd (34%) degree atrioventricular conduction block (AVB), ectopic atrial rhythm (30%), and junctional rhythm (32%) were most often observed in patients who underwent surgery with both ACC and CPB. Incidences of these arrhythmias decreased after cessation of CPB (P < 0.01). (Supra)ventricular premature beats were mostly observed between end of ACC time and sternum closure (64-84%), but decreased before departure from the OR (6-16%, P < 0.01). During a median follow-up of 37 months, 17 patients (13%) had new onset, late post operative arrhythmias. Of these patients, 88% had intraoperative arrhythmias compared with 85% of patients without late post-operative arrhythmias (P = 1). Conclusion: Intraoperative arrhythmias, mainly 2nd degree AVB and (supra)ventricular premature beats, were frequently observed in children with CHD undergoing cardiac surgery with use of CPB and ACC. Most arrhythmias were short lasting and transient and appeared not to be related to late post-operative arrhythmias. PMID- 28666344 TI - Hippocampal Engagement during Recall Depends on Memory Content. AB - The hippocampus is considered pivotal to recall, allowing retrieval of information not available in the immediate environment. In contrast, neocortex is thought to signal familiarity, contributing to recall only when called upon by the hippocampus. However, this view is not compatible with representational accounts of memory, which reject the mapping of cognitive processes onto brain regions. According to representational accounts, the hippocampus is not engaged by recall per se, rather it is engaged whenever hippocampal representations are required. To test whether hippocampus is engaged by recall when hippocampal representations are not required, we used functional imaging and a non associative recall task, with images (objects, scenes) studied in isolation, and image patches as cues. As predicted by a representational account, hippocampal activation was modulated by the content of the recalled memory, increasing during recall of scenes-which are known to be processed by hippocampus-but not during recall of objects. Object recall instead engaged neocortical regions known to be involved in object-processing. Further supporting the representational account, effective connectivity analyses revealed that changes in functional activation during recall were driven by increased information flow from neocortical sites, rather than by the spreading of recall-related activation from hippocampus back to neocortex. PMID- 28666345 TI - Thyroid Hemiagenesis: Incidence, Clinical Significance, and Genetic Background. AB - Context: Thyroid hemiagenesis (THA) constitutes a rare, congenital disorder that is characterized by an absence of one thyroid lobe. Because the pathogenesis and clinical significance of this malformation remain undefined, specific clinical recommendations are lacking, especially for asymptomatic cases. Evidence Acquisition: The PubMed database was searched (years 1970 to 2017), and the following terms were used to retrieve the results: "thyroid hemiagenesis," "thyroid hemiaplasia," "one thyroid lobe agenesis," and "one thyroid lobe aplasia." Subsequently, reference sections of the retrieved articles were searched. Evidence Synthesis: There is a noticeable susceptibility of subjects with THA to develop additional thyroid and nonthyroidal pathologies. In pathogenesis of concomitant thyroid pathologies, a chronic elevation in thyroid stimulating hormone values may play an important role. Thus far, genetic studies failed to find a common genetic background of the anomaly, and the potential underlying cause was identified in a minority of the cases. Conclusions: Patients with THA are prone to develop additional thyroid pathologies and theoretically might benefit from l-thyroxine treatment to lower the thyrotropin levels to those observed in the normal population. However, further research should be done to ascertain whether such intervention early in life would prevent development of associated thyroid conditions. At least, increased vigilance should be maintained to reveal all of the concomitant disorders as soon as possible during follow-up examinations. Application of high-throughput technologies enabling a genome-wide search for novel factors involved in thyroid embryogenesis might be the next step to expand the knowledge on THA pathogenesis. PMID- 28666346 TI - Insulin Secretion and Insulin Sensitivity Before and After Surgical Treatment of Pheochromocytoma or Paraganglioma. AB - Context: Pheochromocytoma and paraganglioma are catecholamine-producing tumors that often impair glucose tolerance. The effects of these tumors on insulin sensitivity and insulin secretion in patients have remained unclear, however. Objective: To characterize the influence of pheochromocytoma or paraganglioma on glucose tolerance, we comprehensively analyzed various parameters related to insulin secretion or insulin sensitivity in patients with these tumors. Design: Hyperglycemic and hyperinsulinemic-euglycemic clamps, as well as an oral glucose tolerance test (OGTT), were performed in patients before and after tumor excision. Setting: Patients underwent metabolic analyses on admission to Kobe University Hospital. Patients: Eleven patients with pheochromocytoma and two with paraganglioma were examined. Intervention: None. Main Outcome Measures: We evaluated various parameters related to insulin secretion or insulin sensitivity as determined by an OGTT and by hyperglycemic and hyperinsulinemic-euglycemic clamp analyses. Results: Surgical treatment of the tumor reduced urinary catecholamine excretion and improved glucose tolerance. The insulinogenic index, but not total insulin secretion, measured during the OGTT as well as the first phase, but not the second phase, of insulin secretion during the hyperglycemic clamp were improved after surgery. The insulin sensitivity index determined during the hyperinsulinemic-euglycemic clamp remained unchanged after surgery. Conclusion: These results suggest pheochromocytoma and paraganglioma impair glucose tolerance primarily through impairment of insulin secretion-in particular, that of the early phase of the insulin secretory response. A prospective study with more patients is warranted to further confirm these results. PMID- 28666348 TI - DebULKing fat in the heart: a fascinating role for autophagy. PMID- 28666347 TI - A contemporary picture of the burden of death and disability in Indian adolescents: data from the Global Burden of Disease Study. AB - Background: Adolescents (10-19 years old) comprise a fifth of the Indian population (253.2 million), yet there is very little published information about the burden of disease and injury for this age group. This paper aims to provide a contemporary picture of the leading causes of death and disability for Indian adolescent girls and boys for 2013, and changes in deaths and disability between 1990 and 2013. Methods: Data from the Global Burden of Disease (GBD) study for India, for the years 1990 and 2013, were accessed. Data were categorized into two age groups: 10 to 14 years (younger adolescents) and 15 to 19 years (older adolescents) and analysed separately for girls and boys. Results: The study shows that for both younger and older adolescent boys and for older adolescent girls, non-communicable diseases (NCDs) and injuries are responsible for a greater number of deaths and disability-adjusted life-years (DALYs) than communicable diseases. Communicable diseases are still important causes of death and disability for young adolescents. Among older adolescents there is an increasing burden of death and disability due to self-harm, road traffic injuries, fire- and heat-related injuries and mental disorders such as depressive disorders. Conclusions: Although strategies to reduce the burden of communicable diseases among adolescents must continue to be an important focus, innovative, evidence based strategies aimed at reducing the growing burden of NCDs and injuries must be elevated as a priority. PMID- 28666349 TI - Auxin homeostasis: the DAO of catabolism. AB - Nearly all programmed and plastic plant growth responses are at least partially regulated by auxins, such as indole-3-acetic acid (IAA). Although vectorial, long distance auxin transport is essential to its regulatory function, all auxin responses are ultimately localized in individual target cells. As a consequence, cellular auxin concentrations are tightly regulated via coordinated biosynthesis, transport, conjugation, and oxidation. The primary auxin oxidative product across species is 2-oxindole-3-acetic acid (oxIAA), followed by glucose and amino acid conjugation to oxIAA. Recently, the enzymes catalyzing the oxidative reaction were characterized in Arabidopsis thaliana. DIOXYGENASE OF AUXIN OXIDATION (DAO) comprises a small subfamily of the 2-oxoglutarate and Fe(II) [2-OG Fe(II)] dependent dioxygenase superfamily. Biochemical and genetic studies have revealed critical physiological functions of DAO during plant growth and development. Thus far, DAO has been identified in three species by homology. Here, we review historical and recent studies and discuss future perspectives regarding DAO and IAA oxidation. PMID- 28666350 TI - Memories of Ken Mason. AB - John Kenyon Mason (19 December 1919-26 January 2017), CBE, MD, LLD, FRCPath, DMJ, FRCPE, FRSE, and known as Ken Mason to us all, was Regius Professor of Forensic Medicine at the University of Edinburgh from 1973-1985 and thereafter Emeritus Professor of Forensic Medicine and Honorary Fellow in the School of Law at the University of Edinburgh. A formal obituary to Professor Mason is published in the Scotsman (http://www.scotsman.com/news/obituaries/obituary-professor-ken-mason medical-jurisprudence-pioneer-1-4357181). We offer some personal tributes to our friend and colleague. PMID- 28666351 TI - Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness. AB - Recent advances in functional neuroimaging have demonstrated novel potential for informing diagnosis and prognosis in the unresponsive wakeful syndrome and minimally conscious states. However, these technologies come with considerable expense and difficulty, limiting the possibility of wider clinical application in patients. Here, we show that high density electroencephalography, collected from 104 patients measured at rest, can provide valuable information about brain connectivity that correlates with behaviour and functional neuroimaging. Using graph theory, we visualize and quantify spectral connectivity estimated from electroencephalography as a dense brain network. Our findings demonstrate that key quantitative metrics of these networks correlate with the continuum of behavioural recovery in patients, ranging from those diagnosed as unresponsive, through those who have emerged from minimally conscious, to the fully conscious locked-in syndrome. In particular, a network metric indexing the presence of densely interconnected central hubs of connectivity discriminated behavioural consciousness with accuracy comparable to that achieved by expert assessment with positron emission tomography. We also show that this metric correlates strongly with brain metabolism. Further, with classification analysis, we predict the behavioural diagnosis, brain metabolism and 1-year clinical outcome of individual patients. Finally, we demonstrate that assessments of brain networks show robust connectivity in patients diagnosed as unresponsive by clinical consensus, but later rediagnosed as minimally conscious with the Coma Recovery Scale-Revised. Classification analysis of their brain network identified each of these misdiagnosed patients as minimally conscious, corroborating their behavioural diagnoses. If deployed at the bedside in the clinical context, such network measurements could complement systematic behavioural assessment and help reduce the high misdiagnosis rate reported in these patients. These metrics could also identify patients in whom further assessment is warranted using neuroimaging or conventional clinical evaluation. Finally, by providing objective characterization of states of consciousness, repeated assessments of network metrics could help track individual patients longitudinally, and also assess their neural responses to therapeutic and pharmacological interventions. PMID- 28666353 TI - Flavors and Risk: Perceptions of Flavors in Little Cigars and Cigarillos Among U.S. Adults, 2015. AB - Introduction: Flavored little cigars, cigarillos, and filtered cigars (LCCs) are popular and pose unique health risks. This study explored risk perceptions of flavors in LCCs and the relationship between perceptions and use among U.S. adults. Methods: Data were from the 2015 Tobacco Products and Risk Perceptions Survey of a national probability sample of 6051 adults, conducted online, August September, 2015. The analytic sample consisted of 5105 adults aware of LCCs and 2174 who had ever used any type of LCCs. Results: Just over half of adults reported flavors in LCCs as "very" or "somewhat" risky, while more than one-third of adults reported they did not know the risks of flavors in LCCs. Younger adults, males, and users of any LCCs were more likely than older adults, females and non-users, respectively, to perceive LCC flavors as less risky. Those who perceived LCC flavors as "not at all risky" or "a little risky" were roughly twice as likely to have ever used flavored LCCs compared to those who reported not knowing the risks (AOR = 2.07, 95% CI = 1.16 to 3.69 and AOR = 1.96, 95% CI = 1.26 to 3.06). Those who reported LCC flavors as "very risky" were also more likely to have ever used flavored LCCs than those who reported not knowing the risks (AOR = 1.50, 95% CI = 1.13 to 1.98). Conclusions: Though the proportion of adults assigning low risk to flavors in LCCs is small, these adults are more likely to use flavored LCCs. The association of use with risk perceptions of flavors in LCCs should be addressed in health risk campaigns. Implications: Flavored LCCs are popular, particularly among young adults. While understanding the impact of flavors is an FDA research priority, little is currently known about perceptions of risk associated with flavors in LCCs. This study explores the nature of risk perceptions of flavors in LCCs, and the relationship between perceptions and flavored LCC use. We conclude that perception of risk of flavors in LCCs is related to use of these products, particularly perception of less risk. Considering the relationship between use and risk perceptions would be helpful in constructing health risk messaging. PMID- 28666352 TI - A phosphorylation-and-ubiquitylation circuitry driving ATR activation and homologous recombination. AB - RPA-coated single-stranded DNA (RPA-ssDNA), a nucleoprotein structure induced by DNA damage, promotes ATR activation and homologous recombination (HR). RPA is hyper-phosphorylated and ubiquitylated after DNA damage. The ubiquitylation of RPA by PRP19 and RFWD3 facilitates ATR activation and HR, but how it is stimulated by DNA damage is still unclear. Here, we show that RFWD3 binds RPA constitutively, whereas PRP19 recognizes RPA after DNA damage. The recruitment of PRP19 by RPA depends on PIKK-mediated RPA phosphorylation and a positively charged pocket in PRP19. An RPA32 mutant lacking phosphorylation sites fails to recruit PRP19 and support RPA ubiquitylation. PRP19 mutants unable to bind RPA or lacking ubiquitin ligase activity also fail to support RPA ubiquitylation and HR. These results suggest that RPA phosphorylation enhances the recruitment of PRP19 to RPA-ssDNA and stimulates RPA ubiquitylation through a process requiring both PRP19 and RFWD3, thereby triggering a phosphorylation-ubiquitylation circuitry that promotes ATR activation and HR. PMID- 28666354 TI - mRNA detection in budding yeast with single fluorophores. AB - Quantitative measurement of mRNA levels in single cells is necessary to understand phenotypic variability within an otherwise isogenic population of cells. Single-molecule mRNA Fluorescence In Situ Hybridization (FISH) has been established as the standard method for this purpose, but current protocols require a long region of mRNA to be targeted by multiple DNA probes. Here, we introduce a new single-probe FISH protocol termed sFISH for budding yeast, Saccharomyces cerevisiae using a single DNA probe labeled with a single fluorophore. In sFISH, we markedly improved probe specificity and signal-to background ratio by using methanol fixation and inclined laser illumination. We show that sFISH reports mRNA changes that correspond to protein levels and gene copy number. Using this new FISH protocol, we can detect >50% of the total target mRNA. We also demonstrate the versatility of sFISH using FRET detection and mRNA isoform profiling as examples. Our FISH protocol with single-fluorophore sensitivity significantly reduces cost and time compared to the conventional FISH protocols and opens up new opportunities to investigate small changes in RNA at the single cell level. PMID- 28666356 TI - modPhEA: model organism Phenotype Enrichment Analysis of eukaryotic gene sets. AB - Motivation: Genome-scale phenotypic data are available for many model organisms, yet existing tools to functionally interpret gene sets from these phenotypic data are largely based on mutagenesis-derived phenotypes observed in mouse or human. Results: Data from both mutagenesis and knockdown experiments are incorporated into modPhEA to allow users to perform enrichment analyses based on phenotypes observed in budding yeast (Saccharomyces cerevisiae), roundworm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), zebrafish (Danio rerio), mouse (Mus musculus) and humans (Homo sapiens). The phenotypes analysed can be customized to investigate complex traits and gene sets from any fully sequenced animal or fungal genome are also supported by modPhEA. Availability and implementation: Freely available on the web at http://evol.nhri.org.tw/modPhEA/. Contact: liaoby@nhri.org.tw. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28666357 TI - Permitted Daily Exposure of the Androgen Receptor Antagonist Flutamide. AB - This report aims to determine the permitted daily exposure (PDE) of flutamide, an androgen receptor blocker, as directed by guideline EMA/CHMP/CVPM/SWP/169430/2012 that came into effect on June 2015. A literature review was conducted to identify toxicity studies of flutamide. Hazards and sensitive endpoints were determined. Based on the no adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) reported from both reproductive, developmental, and 28-day toxicity studies the PDE was calculated. Most of the toxicity studies converge toward a NOAEL of 1 mg/kg/d that translates to a PDE of 0.1 mg/d. However, taking into consideration the worst case scenarios for additional safety a PDE of 0.025 mg/d (25 MUg/d) was calculated based on a reported NOAEL of 0.25 mg/kg/d. A PDE of 0.05 mg/d (50 MUg/d) was also calculated from reproductive/developmental toxicity studies, which is in close agreement with the PDE from the 28-day toxicity studies. Considering the lowest PDE of 0.025 mg/d, residual flutamide at this dose is unlikely to pose any risk to humans. Nonmonotonic dose response (NMDR) effects of flutamide were not supported by literature. Oral route of administration was considered. PMID- 28666355 TI - mRNA cap analogues substituted in the tetraphosphate chain with CX2: identification of O-to-CCl2 as the first bridging modification that confers resistance to decapping without impairing translation. AB - Analogues of the mRNA 5'-cap are useful tools for studying mRNA translation and degradation, with emerging potential applications in novel therapeutic interventions including gene therapy. We report the synthesis of novel mono- and dinucleotide cap analogues containing dihalogenmethylenebisphosphonate moiety (i.e. one of the bridging O atom substituted with CCl2 or CF2) and their properties in the context of cellular translational and decapping machineries, compared to phosphate-unmodified and previously reported CH2-substituted caps. The analogues were bound tightly to eukaryotic translation initiation factor 4E (eIF4E), with CCl2-substituted analogues having the highest affinity. When incorporated into mRNA, the CCl2-substituted dinucleotide most efficiently promoted cap-dependent translation. Moreover, the CCl2-analogues were potent inhibitors of translation in rabbit reticulocyte lysate. The crystal structure of eIF4E in complex with the CCl2-analogue revealed a significantly different ligand conformation compared to that of the unmodified cap analogue, which likely contributes to the improved binding. Both CCl2- and CF2- analogues showed lower susceptibility to hydrolysis by the decapping scavenger enzyme (DcpS) and, when incorporated into RNA, conferred stability against major cellular decapping enzyme (Dcp2) to transcripts. Furthermore, the use of difluoromethylene cap analogues was exemplified by the development of 19F NMR assays for DcpS activity and eIF4E binding. PMID- 28666358 TI - Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation. AB - Aims: After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations. Methods and results: Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%). Conclusion: In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC. PMID- 28666359 TI - Cognition in Context: The Role of Objective and Subjective Measures of Neighborhood and Household in Cognitive Functioning in Later Life. AB - Background and Objectives: Although the role of place on health is not new, less is known about how place matters for cognition. By investigating both neighborhood and home as the sociospatial realms of older adults, we explore associations between health and place across multiple contexts. We also distinguish objective and subjective measures of place and disentangle their differential associations with cognition. Research Design and Methods: We analyzed place effects on cognition from the National Social Life, Health, and Aging Project (N = 2,260) linked to neighborhood characteristics and crime data. We measured place in four ways: (a) objective indicators of neighborhood such as police-reported crime rates and interviewer-reported on presence of disordered conditions on the streets; (b) perceptions of neighborhood by respondents (perceived danger and social cohesion); (c) objective conditions of home (interviewer's report on presence of clutters, odor, and messiness); (4) perceived social support, strain, and threat by household members. The MoCA-SA was used to assess cognitive functioning. Results: Subjective interpretations appeared to have more direct effects on cognition than did objective indicators of neighborhood or home. When examining these living environments together, we found the association between neighborhood and cognition is partially explained by characteristics of home environment, especially perceived social support. We found a buffering effect of social support on cognition for women, not for men. Discussion and Implications: Late life living environments are important contexts for aging. Aging-in-Place interventions should address subjective interpretations of place to reduce future risks of cognitive decline. PMID- 28666360 TI - Overnight Closed-Loop Control Improves Glycemic Control in a Multicenter Study of Adults With Type 1 Diabetes. AB - Context: Closed-loop control (CLC) for the management of type 1 diabetes (T1D) is a novel method for optimizing glucose control, and strategies for individualized implementation are being developed. Objective: To analyze glycemic control in an overnight CLC system designed to "reset" the patient to near-normal glycemic targets every morning. Design: Randomized, crossover, multicenter clinical trial. Participants: Forty-four subjects with T1D requiring insulin pump therapy. Intervention: Sensor-augmented pump therapy (SAP) at home vs 5 nights of CLC (active from 23:00 to 07:00) in a supervised outpatient setting (research house or hotel), with a substudy of 5 nights of CLC subsequently at home. Main Outcome Measure: The percentage of time spent in the target range (70 to 180 mg/dL measured using a continuous glucose monitor). Results: Forty subjects (age, 45.5 +/- 9.5 years; hemoglobin A1c, 7.4% +/- 0.8%) completed the study. The time in the target range (70 to 180 mg/dL) significantly improved in CLC vs SAP over 24 hours (78.3% vs 71.4%; P = 0.003) and overnight (85.7% vs 67.6%; P < 0.001). The time spent in a hypoglycemic range (<70 mg/dL) decreased significantly in the CLC vs SAP group over 24 hours (2.5% vs 4.3%; P = 0.002) and overnight (0.9% vs 3.2%; P < 0.001). The mean glucose level at 07:00 was lower with CLC than with SAP (123.7 vs 145.3 mg/dL; P < 0.001). The substudy at home, involving 10 T1D subjects, showed similar trends with an increased time in target (70 to 180 mg/dL) overnight (75.2% vs 62.2%; P = 0.07) and decreased time spent in the hypoglycemic range (<70 mg/dL) overnight in CLC vs SAP (0.6% vs 3.7%; P = 0.03). Conclusion: Overnight-only CLC increased the time in the target range over 24 hours and decreased the time in hypoglycemic range over 24 hours in a supervised outpatient setting. A pilot extension study at home showed a similar nonsignificant trend. PMID- 28666362 TI - Inference of Causative Genes for Alzheimer's Disease Due to Dosage Imbalance. AB - Copy number variations (CNVs) have recently drawn attention as an important genetic factor for diseases, especially common neuropsychiatric disorders including Alzheimer's disease (AD). Because most of the pathogenic CNV regions overlap with multiple genes, it has been challenging to identify the true disease causing genes amongst them. Notably, a recent study reported that CNV regions containing ohnologs, which are dosage-sensitive genes, are likely to be deleterious. Utilizing the unique feature of ohnologs could be useful for identifying causative genes with pathogenic CNVs, however its effectiveness is still unclear. Although it has been reported that AD is strongly affected by CNVs, most of AD-causing genes with pathogenic CNVs have not been identified yet. Here, we show that dosage-sensitive ohnologs within CNV regions reported in patients with AD are related to the nervous system and are highly expressed in the brain, similar to other known susceptible genes for AD. We found that CNV regions in patients with AD contained dosage-sensitive genes, which are ohnologs not overlapping with control CNV regions, frequently. Furthermore, these dosage sensitive genes in pathogenic CNV regions had a strong enrichment in the nervous system for mouse knockout phenotype and high expression in the brain similar to the known susceptible genes for AD. Our results demonstrated that selecting dosage-sensitive ohnologs out of multiple genes with pathogenic CNVs is effective in identifying the causative genes for AD. This methodology can be applied to other diseases caused by dosage imbalance and might help to establish the medical diagnosis by analysis of CNVs. PMID- 28666363 TI - Grandparents Raising Grandchildren: What Have We Learned Over the Past Decade? AB - Background and Objectives: In this manuscript, we update the literature over the last decade in addressing several new content areas that have emerged in the grandfamilies literature, along with issues that are still important to understanding grandparents raising their grandchildren today. Research Design and Methods: The social science and gerontological literature since 2004 was accessed, reviewed, organized topically, and integrated, based upon an exhaustive PsychINFO literature search. Results: Our review indicates an ongoing and/or growing emphasis on (a) the strengths of grandparent raising grandchildren, (b) diversity among grandfamilies along a number of parameters, (c) the social interpersonal, cultural, and policy-related contexts of grandfamilies, (d) process-focused research, (e) parenting, parenting skills, and family relationships, (f) grandparent psychological distress, (g) targets for and the efficacy of interventions with grandfamilies, and (h) methodological issues relevant to the study of grandfamilies. Implications: We discuss the implications of our findings in terms of more completely understanding grandfamilies along a number of parameters, as well as presenting specific recommendations for future research and practice. PMID- 28666364 TI - "Live Cadaver" Model for Internal Carotid Artery Injury Simulation in Endoscopic Endonasal Skull Base Surgery. AB - BACKGROUND: Intraoperative injury of the internal carotid artery (ICA) is the most dreaded complication in endoscopic endonasal surgery (EES) of skull base. Training for ICA injury is practically impossible in live operative settings. OBJECTIVE: To evaluate a pulsatile perfusion-based live cadaveric model for ICA injury simulation in a laboratory setting. The major emphasis of the study was to evaluate various means of controlling acute bleeding and evaluating the practical utility of this model for training purposes. METHODS: Five embalmed, uninjected cadaveric heads were prepared for study by connecting to a pulsatile perfusion pump system filled with artificial blood solution. EES approaches were used to evaluate different types of ICA injuries similar to operative scenarios. Various methods of managing ICA injuries such as packing, clipping, and trapping, were evaluated. The educational advantages of the live cadaver model were assessed using questionnaires given to participants in a hands-on dissection course. RESULTS: The trainee was faced with several scenarios similar to those encountered during an actual intraoperative ICA injury. Packing, clipping, and trapping of the ICA injury were successfully achieved in all segments of the ICA. Clip-based reconstruction techniques were successfully developed. All trainees reported gaining new knowledge, learning new techniques. The responses to the questionnaire confirmed the significant educational value of this model. CONCLUSION: The live cadaver model presented here provides real-life experience with major vessel injury during EES in a laboratory setting. This model could significantly improve current training for the management of intraoperative vascular injuries during EES. PMID- 28666361 TI - Identification of multiple roles for histone acetyltransferase 1 in replication coupled chromatin assembly. AB - Histone acetyltransferase 1 (Hat1) catalyzes the acetylation of newly synthesized histone H4 at lysines 5 and 12 that accompanies replication-coupled chromatin assembly. The acetylation of newly synthesized H4 occurs in the cytoplasm and the function of this acetylation is typically ascribed to roles in either histone nuclear import or deposition. Using cell lines from Hat1+/+ and Hat1-/- mouse embryos, we demonstrate that Hat1 is not required for either histone nuclear import or deposition. We employed quantitative proteomics to characterize Hat1 dependent changes in the composition of nascent chromatin structure. Among the proteins depleted from nascent chromatin isolated from Hat1-/- cells are several bromodomain-containing proteins, including Brg1, Baz1A and Brd3. Analysis of the binding specificity of their bromodomains suggests that Hat1-dependent acetylation of H4 is directly involved in their recruitment. Hat1-/- nascent chromatin is enriched for topoisomerase 2alpha and 2beta. The enrichment of topoisomerase 2 is functionally relevant as Hat1-/- cells are hyper-sensitive to topoisomerase 2 inhibition suggesting that Hat1 is required for proper chromatin topology. In addition, our results indicate that Hat1 is transiently recruited to sites of chromatin assembly, dissociating prior to the maturation of chromatin structure. PMID- 28666366 TI - Child Maltreatment and Clinical Outcome in Individuals at Ultra-High Risk for Psychosis in the EU-GEI High Risk Study. AB - Background: Child maltreatment has been associated with a wide range of mental disorders in adulthood. Whether child maltreatment is specifically associated with psychosis risk in individuals at ultra-high risk (UHR) for psychosis, or leads to a general vulnerability for overall psychopathology in the UHR stage remains unclear. The present study examines the association between child maltreatment and transition to psychosis and other mental disorders. Methods: The sample consisted of 259 UHR individuals from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Participants were followed-up for 2 years to assess clinical outcome. Clinical outcome was assessed at 6 months, 12 months, and 24 months after baseline. Child maltreatment before the age of 17 years was assessed at baseline. Results: Our findings show that a history of emotional abuse was associated with an increased risk for transition to psychosis (OR = 3.78, 95% CI = 1.17 to 12.39, P = .027). Apart from psychosis, a history of physical abuse was associated with depressive disorder (OR = 4.92, 95% CI = 2.12 to 11.39, P = .001), post-traumatic stress disorder (OR = 2.06, 95% CI = 1.10 to 3.86, P = .023), panic disorder (OR = 2.00, 95% CI = 1.00 to 3.99, P = .048) and social phobia (OR = 2.47, 95% CI = 1.18 to 5.16, P = .016) at follow-up. Conclusion: Our findings suggest that in the UHR stage child maltreatment is a pluripotent risk factor for developing psychosis, depressive disorder, post-traumatic stress disorder (PTSD), panic disorder, and social phobia in adulthood. PMID- 28666365 TI - Chronic Low-Dose Cadmium Exposure Impairs Cutaneous Wound Healing With Defective Early Inflammatory Responses After Skin Injury. AB - Impairment of the immune system is a developing concern in evaluating the toxicity of cadmium (Cd). In the present study, we investigated if Cd could impair cutaneous wound healing through interfering with inflammation after injury. We found that exposure of mice to CdCl2 through drinking water at doses of 10, 30, and 50 mg/l for 8 weeks significantly impaired cutaneous wound healing. Chronic 30 mg/l CdCl2 treatment elevated murine blood Cd level comparable to that of low dose Cd-exposed humans, had no effect on blood total and differential leukocyte counts, but reduced neutrophil infiltration, chemokines (CXCL1 and CXCL2), and proinflammatory cytokines (TNFalpha, IL-1beta, and IL-6) expression in wounded tissue at early stage after injury. Wounded tissue homogenates from CdCl2-treated mice had lower chemotactic activity for neutrophils than those from untreated mice. Mechanistic studies showed that chronic Cd treatment suppressed ERK1/2 and NF-kappaB p65 phosphorylation in wounded tissue at early stage after injury. Compared with neutrophils isolated from untreated mice, neutrophils from CdCl2 treated mice and normal neutrophils treated with CdCl2 invitro both had lower chemotactic response, calcium mobilization and ERK1/2 phosphorylation upon chemoattractant stimulation. Collectively, our study indicate that chronic low-dose Cd exposure impaired cutaneous wound healing by reducing neutrophil infiltration through inhibiting chemokine expression and neutrophil chemotactic response, and suppressing proinflammatory cytokine expression. Cd may suppress chemokine and proinflammatory expression through inactivating ERK1/2 and NF-kappaB, and inhibit neutrophil chemotaxis by attenuating calcium mobilization and ERK1/2 phosphorylation in response to chemoattractants. PMID- 28666367 TI - Adolescent Body Mass Index and Cardiovascular Disease-Specific Mortality by Midlife. AB - Context: As opposed to coronary heart disease (CHD) mortality, cardiovascular mortality attributed to non-CHD causes has increased. Objective: To evaluate the association of body mass index (BMI) in late adolescence with mortality attributed to non-CHD cardiovascular sequelae. Design and Setting: A nationwide cohort. Participants: A total of 2,294,139 adolescents examined between 1967 and 2010. Interventions: Height and weight were measured at age 17. All cardiovascular disease-specific outcomes, coded by the Central Bureau of Statistics from death notifications as the underlying cause of death, were obtained by linkage. Cox hazards models were applied. Main Outcome Measurements: Death attributed to fatal arrhythmias, hypertensive heart disease, cardiomyopathies, arterial disease, heart failure, and pulmonary embolism. Results: During 42,297,007 person-years of follow-up, there were 3178 deaths due to cardiovascular causes, of which 279, 122, 121, 114, 94, and 70 were attributed to the main outcomes, respectively. BMI was positively associated with all study outcomes with hazard ratios (HRs) per unit increment in BMI ranging from 1.09 [95% confidence interval (CI): 1.03 to 1.16] for arterial disease to 1.16 (95% CI: 1.11 to 1.21) for hypertensive heart disease. When BMI was treated as a categorical variable, a graded increase in risk was evident from the high-normal (22.0 to <25.0 kg/m2) to the overweight to the obese categories, with HRs of 1.4, 1.7, and 3.7 for arrhythmias; 1.9, 4.1, and 8.0 for hypertensive heart disease; 1.5, 2.4, and 4.0 for cardiomyopathies, 2.7, 5.0, and 3.5; for arterial disease, 1.7, 2.7, and 5.4 for heart failure; and 1.3, 1.8, and 3.0 for pulmonary embolism. Findings persisted in extensive sensitivity analyses. Conclusions: Adolescent BMI within the accepted normal range is associated with non-CHD nonstroke cardiovascular outcomes. PMID- 28666368 TI - Cost-effectiveness of radiation and chemotherapy for high-risk low-grade glioma. AB - Background: The addition of procarbazine, lomustine, vincristine (PCV) chemotherapy to radiotherapy (RT) for patients with high-risk (>=40 y old or subtotally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy. Methods: A decision tree with an integrated 3-state Markov model was created to follow patients with high-risk LGG after surgery treated with RT versus RT+PCV. Patients existed in one of 3 health states: stable, progressive, or dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the health care perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters. Results: Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs 5.17 for RT alone) at an incremental cost of $48635 ($188234 for RT+PCV vs $139598 for RT alone), resulting in an incremental cost effectiveness ratio of $10186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100000 per QALY. Conclusion: The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG. PMID- 28666369 TI - CausalR: extracting mechanistic sense from genome scale data. AB - Summary: Utilization of causal interaction data enables mechanistic rather than descriptive interpretation of genome-scale data. Here we present CausalR, the first open source causal network analysis platform. Implemented functions enable regulator prediction and network reconstruction, with network and annotation files created for visualization in Cytoscape. False positives are limited using the introduced Sequential Causal Analysis of Networks approach. Availability and implementation: CausalR is implemented in R, parallelized, and is available from Bioconductor. Contact: glyn.x.bradley@gsk.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28666370 TI - Assessment of HIV Screening Tests for Use in Preexposure Prophylaxis Programs. AB - Preexposure prophylaxis programs involve frequent human immunodeficiency virus (HIV) testing. We evaluated the sensitivity of 2 antigen/antibody immunoassays (Architect and Bioplex), 2 antibody-based rapid tests (Vikia-HIV-1/2 and Autotest VIH), and 1 antigen/antibody rapid test (Alere HIV Combo) for the diagnosis of HIV infection. Among the 31 HIV-1-infected participants in the ANRS-IPERGAY trial, HIV-1 RNA was detected alone in only 2. The sensitivities of the Architect and Bioplex assays were 83% (95% confidence interval [CI], 76%-99%) and 82% (95% CI, 63%-94%), respectively. The sensitivities of the Vikia, Autotest, and Alere tests were 54% (95% CI, 34%-72%), 50% (95% CI, 31%-69%), and 78% (95% CI, 58% 91%), respectively. Antigen/antibody tests should be preferred to avoid missing cases of acute HIV infection and to decrease the related risks of viral transmission and emergence of drug resistance. PMID- 28666372 TI - Origin of the AbGRI1 antibiotic resistance island found in the comM gene of Acinetobacter baumannii GC2 isolates. PMID- 28666371 TI - The identification of FANCD2 DNA binding domains reveals nuclear localization sequences. AB - Fanconi anemia (FA) is a recessive genetic disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. The FA pathway consists of at least 21 FANC genes (FANCA-FANCV), and the encoded protein products interact in a common cellular pathway to gain resistance against DNA interstrand crosslinks. After DNA damage, FANCD2 is monoubiquitinated and accumulates on chromatin. FANCD2 plays a central role in the FA pathway, using yet unidentified DNA binding regions. By using synthetic peptide mapping and DNA binding screen by electromobility shift assays, we found that FANCD2 bears two major DNA binding domains predominantly consisting of evolutionary conserved lysine residues. Furthermore, one domain at the N-terminus of FANCD2 bears also nuclear localization sequences for the protein. Mutations in the bifunctional DNA binding/NLS domain lead to a reduction in FANCD2 monoubiquitination and increase in mitomycin C sensitivity. Such phenotypes are not fully rescued by fusion with an heterologous NLS, which enable separation of DNA binding and nuclear import functions within this domain that are necessary for FANCD2 functions. Collectively, our results enlighten the importance of DNA binding and NLS residues in FANCD2 to activate an efficient FA pathway. PMID- 28666373 TI - Auxin, microtubules, and vesicle trafficking: conspirators behind the cell wall. AB - Plant morphogenesis depends on the synchronized anisotropic expansion of individual cells in response to developmental and environmental cues. The magnitude of cell expansion depends on the biomechanical properties of the cell wall, which in turn depends on both its biosynthesis and extensibility. Although the control of cell expansion by the phytohormone auxin is well established, its regulation of cell wall composition, trafficking of H+-ATPases, and K+ influx that drives growth is still being elucidated. Furthermore, the maintenance of auxin fluxes via the interaction between the cytoskeleton and PIN protein recycling on the plasma membrane remains under investigation. This review proposes a model that describes how the cell wall, auxin, microtubule binding protein CLASP and Kin7/separase complexes, and vesicle trafficking are co ordinated on a cellular level to mediate cell wall loosening during cell expansion. PMID- 28666374 TI - Genomic Epidemiology of a Major Mycobacterium tuberculosis Outbreak: Retrospective Cohort Study in a Low-Incidence Setting Using Sparse Time-Series Sampling. AB - Since 1992, Denmark has documented the largest outbreak of tuberculosis in Scandinavia ascribed to a single genotype, termed C2/1112-15. As of spring 2017, the International Reference Laboratory of Mycobacteriology in Copenhagen has collected and identified isolates from more than a thousand cases belonging to this outbreak via routine mycobacterial interspersed repetitive units-variable number of tandem repeats typing. Here, we present a retrospective analysis of the C2/1112-15 dataset, based on whole-genome data from a sparse time series consisting of 5 randomly selected isolates from 23 years of sampling. Even if these data are derived from only 12% of the collected isolates, we have been able to extract important key information, such as mutation rate and conserved single nucleotide polymorphisms to identify discrete transmission chains, as well as the possible historical origins of the outbreak. PMID- 28666375 TI - Role of Peptide YY3-36 and Glucose-Dependent Insulinotropic Polypeptide in Anorexia Induction by Trichothecences T-2 Toxin, HT-2 Toxin, Diacetoxyscirpenol, and Neosolaniol. AB - Trichothecences, secondary metabolites produced by Fusarium, are serious health risks to humans and animals worldwide. Although type A trichothecence-induced food refusal has been observed, the mechanism underlying the anorexia caused by these compounds is not fully understood. In this study, we hypothesized that anorexia induced by type A trichothecenes, including T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS), and neosolaniol (NEO), in mice corresponds to the changes in the gut satiety hormones peptide YY3-36 (PYY3-36) and glucose dependent insulinotropic polypeptide (GIP) in plasma. A well-characterized mouse food refusal model was used in this assay. Oral exposure to or intraperitoneal (ip) injection of 1 mg/kg bw T-2, HT-2, DAS, or NEO resulted in dramatically decreased food intake, and PYY3-36 and GIP concentrations were elevated accordingly. Specifically, the PYY3-36 and GIP concentrations peaked at 2 h following oral exposure to these 4 toxins individually, although the durations were not identical. After ip administration of T-2 or HT-2, PYY3-36 significantly increased within 6 h. However, no significant difference was found in the DAS and NEO groups. The GIP levels peaked within 2, 2, 0.5, and 0.5 h, respectively, and remained increased up to 6, 6, 2, and 6 h, respectively, following T-2, HT-2, DAS, or NEO ip exposure. The increase in GIP was greater than that of PYY3-36 after exposure to the 4 toxins using 2 administration routes. Together, these findings suggest that PYY3-36 and GIP play a role in T-2-, HT-2-, DAS-, and NEO induced anorexia. PMID- 28666376 TI - A massively parallel strategy for STR marker development, capture, and genotyping. AB - Short tandem repeat (STR) variants are highly polymorphic markers that facilitate powerful population genetic analyses. STRs are especially valuable in conservation and ecological genetic research, yielding detailed information on population structure and short-term demographic fluctuations. Massively parallel sequencing has not previously been leveraged for scalable, efficient STR recovery. Here, we present a pipeline for developing STR markers directly from high-throughput shotgun sequencing data without a reference genome, and an approach for highly parallel target STR recovery. We employed our approach to capture a panel of 5000 STRs from a test group of diademed sifakas (Propithecus diadema, n = 3), endangered Malagasy rainforest lemurs, and we report extremely efficient recovery of targeted loci-97.3-99.6% of STRs characterized with >=10x non-redundant sequence coverage. We then tested our STR capture strategy on P. diadema fecal DNA, and report robust initial results and suggestions for future implementations. In addition to STR targets, this approach also generates large, genome-wide single nucleotide polymorphism (SNP) panels from flanking regions. Our method provides a cost-effective and scalable solution for rapid recovery of large STR and SNP datasets in any species without needing a reference genome, and can be used even with suboptimal DNA more easily acquired in conservation and ecological studies. PMID- 28666377 TI - A Mechanistic Model for Predicting Lung Inflammogenicity of Oxide Nanoparticles. AB - This study presents a mechanistic model for identifying oxide nanoparticles that induce a high level of neutrophils in the bronchoalveolar lavage fluid, an important marker for lung inflammogenicity. The model is based on 4 nanoparticles' physicochemical properties, ie, the reactivity, surface charge, wettability, and dissolution. First, I calculate these properties and show that theoretical values reproduce acceptably the experimental measurements. Then, I combine these properties with mechanistic knowledge to build a classification model for the prediction of acute invivo lung inflammogenicity, measured as the total number of polymorphonuclear neutrophils. The model uses reactivity and dissolution properties of nanoparticles as toxicological initiating events, whereas surface charge and wettability are characteristics involved in the interactions between the nanoparticles and the lung surfactant, eventually leading to increased cellular uptake and bioaccumulation. The model is validated on a set of 43 oxide nanoparticles tested invivo to confirm that acute lung inflammation can be described using this mechanistic framework. In addition, I also develop a linear regression model for insoluble nanoparticles to quantitatively predict the polymorphonuclear neutrophil count as a function of reactivity and surface charge. The proposed models are based on mechanistic knowledge and can support the development of adverse outcome pathways, risk assessment frameworks and safe design strategies at early stages of material's R&D. PMID- 28666379 TI - Risks of serious infections in children treated with biologic response-modifying drugs. PMID- 28666378 TI - mTOR signaling pathway differently regulates central and peripheral axon regeneration. AB - Numerous studies have shown that the intrinsic axonal regenerative capacity of neurons differs between the peripheral and central nervous systems (CNSs). However, the molecular mechanisms controlling intrinsic axonal regenerative capacity are unclear. A better understanding of these mechanisms should aid in the development of effective therapeutic strategies for traumatic nervous system injury, including spinal cord injury. Here, we found that blocking mammalian target of rapamycin (mTOR) activity dramatically diminished axonal regrowth from embryonic cortical neurons. However, mTOR activity was not required for axonal regrowth from adult peripheral sensory neurons. By analyzing the levels of phospho-S6, a downstream target of mTOR, we found that embryonic cortical neurons had a much higher mTOR activity compared with adult peripheral sensory neurons. Our findings suggest that, in the CNS, the mTOR pathway plays a critical role in regulating the regenerative capacity of neurons, in contrast to the peripheral nervous system. PMID- 28666380 TI - Comparative analysis of chimeric ZFP-, TALE- and Cas9-piggyBac transposases for integration into a single locus in human cells. AB - Integrating DNA delivery systems hold promise for many applications including treatment of diseases; however, targeted integration is needed for improved safety. The piggyBac (PB) transposon system is a highly active non-viral gene delivery system capable of integrating defined DNA segments into host chromosomes without requiring homologous recombination. We systematically compared four different engineered zinc finger proteins (ZFP), four transcription activator like effector proteins (TALE), CRISPR associated protein 9 (SpCas9) and the catalytically inactive dSpCas9 protein fused to the amino-terminus of the transposase enzyme designed to target the hypoxanthine phosphoribosyltransferase (HPRT) gene located on human chromosome X. Chimeric transposases were evaluated for expression, transposition activity, chromatin immunoprecipitation at the target loci, and targeted knockout of the HPRT gene in human cells. One ZFP-PB and one TALE-PB chimera demonstrated notable HPRT gene targeting. In contrast, Cas9/dCas9-PB chimeras did not result in gene targeting. Instead, the HPRT locus appeared to be protected from transposon integration. Supplied separately, PB permitted highly efficient isolation of Cas9-mediated knockout of HPRT, with zero transposon integrations in HPRT by deep sequencing. In summary, these tools may allow isolation of 'targeted-only' cells, be utilized to protect a genomic locus from transposon integration, and enrich for Cas9-mutated cells. PMID- 28666381 TI - The evolution of hydrophobic cell wall biopolymers: from algae to angiosperms. AB - The transition from an aquatic ancestral condition to a terrestrial environment exposed the first land plants to the desiccating effects of air and potentially large fluctuations in temperature and light intensity. To be successful, this transition necessitated metabolic, physiological, and morphological modifications, among which one of the most important was the capacity to synthesize hydrophobic extracellular biopolymers such as those found in the cuticular membrane, suberin, lignin, and sporopollenin, which collectively reduce the loss of water, provide barriers to pathogens, protect against harmful levels of UV radiation, and rigidify targeted cell walls. Here, we review phylogenetic and molecular data from extant members of the green plant clade (Chlorobionta) and show that the capacity to synthesize the monomeric precursors of all four biopolymers is ancestral and extends in some cases to unicellular plants (e.g. Chlamydomonas). We also review evidence from extant algae, bryophytes, and early divergent tracheophytes and show that gene duplication, subsequent neo functionalization, and the co-option of fundamental and ancestral metabolic pathways contributed to the early evolutionary success of the land plants. PMID- 28666382 TI - The Structured Coalescent and Its Approximations. AB - Phylogeographic methods can help reveal the movement of genes between populations of organisms. This has been widely done to quantify pathogen movement between different host populations, the migration history of humans, and the geographic spread of languages or gene flow between species using the location or state of samples alongside sequence data. Phylogenies therefore offer insights into migration processes not available from classic epidemiological or occurrence data alone. Phylogeographic methods have however several known shortcomings. In particular, one of the most widely used methods treats migration the same as mutation, and therefore does not incorporate information about population demography. This may lead to severe biases in estimated migration rates for data sets where sampling is biased across populations. The structured coalescent on the other hand allows us to coherently model the migration and coalescent process, but current implementations struggle with complex data sets due to the need to infer ancestral migration histories. Thus, approximations to the structured coalescent, which integrate over all ancestral migration histories, have been developed. However, the validity and robustness of these approximations remain unclear. We present an exact numerical solution to the structured coalescent that does not require the inference of migration histories. Although this solution is computationally unfeasible for large data sets, it clarifies the assumptions of previously developed approximate methods and allows us to provide an improved approximation to the structured coalescent. We have implemented these methods in BEAST2, and we show how these methods compare under different scenarios. PMID- 28666383 TI - How routine use of a treat to target approach in PsA might impact on clinical decision making. PMID- 28666384 TI - Gut Microbial Transformation of the Dietary Imidazoquinoxaline Mutagen MelQx Reduces Its Cytotoxic and Mutagenic Potency. AB - The diverse community of microbes present in the human gut has emerged as an important factor for cancer risk, potentially by altering exposure to chemical carcinogens. In the present study, human gut bacteria were tested for their capacity to transform the carcinogenic heterocyclic amine 2-Amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MelQx). Eubacterium hallii, Lactobacillus reuteri, and Lactobacillus rossiae were able to convert MelQx to a new microbial metabolite characterized on the basis of high-resolution mass spectrometry and NMR as 9-hydroxyl-2,7-dimethyl-7,9,10,11-tetrahydropyrimido[2',1':2,3]imidazo[4,5 f]quinoxaline (MelQx-M1), resulting from conjugation with activated glycerol. Acrolein derived from the decomposition of 3-hydroxypropionaldehyde, which is the product of bacterial glycerol/diol dehydratase activity, was identified as the active compound responsible for the formation of MelQx-M1. A complex human gut microbial community obtained from invitro continuous intestinal fermentation was found to also transform MelQx to MelQx-M1. MelQx-M1 had slightly reduced cytotoxic potency toward human colon epithelial cells invitro, and diminished mutagenic potential toward bacteria after metabolic activation. As bacterially derived acrolein also transformed 2 other HCAs, namely 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine and 2-amino-3-methylimidazo[4,5-f]quinoline, these results generalize the capacity of gut microbiota to detoxify HCAs in the gut, potentially modulating cancer risk. PMID- 28666386 TI - Effect of Cholesterol on the Stability and Lubrication Efficiency of Phosphatidylcholine Surface Layers. AB - The lubrication properties of saturated PC lipid vesicles containing high cholesterol content under high loads were examined by detailed surface force balance measurements of normal and shear forces between two surface-attached lipid layers. Forces between two opposing mica surfaces bearing distearoylphosphatidylcholine (PC) (DSPC) small unilamellar vesicles (SUVs, or liposomes), or bilayers, with varying cholesterol content were measured across water, whereas dimyristoyl PC (DMPC), dipalmitoyl PC (DPPC), and DSPC SUVs containing 40% cholesterol were measured across liposome dispersions of SUVs of the same lipid composition as in the adsorbed layers. The results clearly demonstrate decreased stability and resistance to normal load with the increase in cholesterol content of DSPC SUVs. Friction coefficients between two 10% cholesterol PC-bilayers were in the same range as for 40% cholesterol bilayers (MU ~ 10-3), indicating that cholesterol has a more substantial effect on the mechanical properties of a bilayer than on its lubrication performance. We further find that the lubrication efficiency of DMPC and DPPC with 40% cholesterol is superior to that of DSPC 40% cholesterol, most likely because of enhanced hydration-lubrication in these systems. We previously found that when experiments are performed in the presence of a lipid reservoir, layers can self heal and therefore their robustness is less important under such conditions. We conclude that the effect of cholesterol in decreasing the stability is more pronounced than its effect on hydration, but the stability is, in turn, less important when a lipid reservoir is present. This study complements our previous work and sheds light on the effect of cholesterol, a prominent and important physiological lipid, on the mechanical and lubrication properties of gel-phase lipid layers. PMID- 28666385 TI - Human ribosomal protein eS1 is engaged in cellular events related to processing and functioning of U11 snRNA. AB - Ribosomal proteins are involved in many cellular processes through interactions with various RNAs. Here, applying the photoactivatable-ribonucleoside-enhanced cross-linking and immunoprecipitation approach to HEK293 cells overproducing ribosomal protein (rp) eS1, we determined the products of RNU5A-1 and RNU11 genes encoding U5 and U11 snRNAs as the RNA partners of ribosome-unbound rp eS1. U11 pre-snRNA-associated rp eS1 was revealed in the cytoplasm and nucleus where rp eS1-bound U11/U12 di-snRNP was also found. Utilizing recombinant rp eS1 and 4 thiouridine-containing U11 snRNA transcript, we identified an N-terminal peptide contacting the U-rich sequence in the Sm site-containing RNA region. We also showed that the rp eS1 binding site on U11 snRNA is located in the cleft between stem-loops I and III and that its structure mimics the respective site on the 18S rRNA. It was found that cell depletion of rp eS1 leads to a decrease in the splicing efficiency of minor introns and to an increase in the level of U11 pre snRNA with the unprocessed 3' terminus. Our findings demonstrate the engagement of human rp eS1 in events related to the U11 snRNA processing and to minor-class splicing. Contacts of rp eS1 with U5 snRNA in the minor pre-catalytic spliceosome are discussed. PMID- 28666387 TI - Toolkit for the Construction of Reproducing Kernel-Based Representations of Data: Application to Multidimensional Potential Energy Surfaces. AB - In the early days of computation, slow processor speeds limited the amount of data that could be generated and used for scientific purposes. In the age of big data, the limiting factor usually is the method with which large amounts of data are analyzed and useful information is extracted. A typical example from chemistry are high-level ab initio calculations for small systems, which have nowadays become feasible even if energies at many different geometries are required. Molecular dynamics simulations often require several thousand distinct trajectories to be run. Under such circumstances suitable analytical representations of potential energy surfaces (PESs) based on ab initio calculations are required to propagate the dynamics at an acceptable cost. In this work we introduce a toolkit which allows the automatic construction of multidimensional PESs from gridded ab initio data based on reproducing kernel Hilbert space (RKHS) theory. The resulting representations require no tuning of parameters and allow energy and force evaluations at ab initio quality at the same cost as empirical force fields. Although the toolkit is primarily intended for constructing multidimensional potential energy surfaces for molecular systems, it can also be used for general machine learning purposes. The software is published under the MIT license and can be downloaded, modified, and used in other projects for free. PMID- 28666388 TI - Adsorption Behavior and Mechanism of SCA-1 on a Calcite Surface: A Molecular Dynamics Study. AB - The crystallization mechanism for natural mineral, especially the role of biological molecules in biomineralization, is still under debate. Protein adsorption on material surfaces plays a key role in biomineralization. In this article, molecular dynamics (MD) simulations were performed to systematically investigate the adsorption behavior of struthio camelus eggshell protein struthiocalcin-1 (SCA-1) on the calcite (104) surface with several different starting orientations in an explicit water environment. For each binding configuration, detailed adsorption behaviors and a mechanism were presented with the analysis of interaction energy, binding residues, hydrogen bonding, and structures (such as DSSP, dipole moment, and the electrostatic potential calculation). The results indicate that the positively charged and polar residues are the dominant residues for protein adsorption on the calcite (104) surface, and the strong electrostatic interaction drives the binding of model protein to the surface. The hydrogen bond bridge was found to play an important role in surface interactions as well. These results also demonstrate that SCA-1 is relatively rigid in spite of strong adsorption with few structural changes in alpha-helix and beta-sheet contents. The results of the orientation calculation suggest that the dipole moment of the protein tends to remain parallel to calcite in most stable cases, which was confirmed by electrostatic potential isosurfaces analysis. PMID- 28666389 TI - Combined Chemoinformatics Approach to Solvent Library Design Using clusterSim and Multidimensional Scaling. AB - Reported here is a rational approach for the selection of solvents intended for use in physical form screening based on a novel chemoinformatics analysis of solvent properties. A comprehensive assessment of eight clustering methods was carried out on a series of 94 solvents described by calculated molecular descriptors using the clusterSim package in R. The effectiveness of clustering methods was evaluated using a range of statistical measures as well as increasing efficiency of solid form discovery using a cluster-based solvent selection approach. Multidimensional scaling was used to illustrate cluster analysis on a two-dimensional solvent map. The map presented here is a valuable tool to aid efficient solvent selection in physical form screens. This tool is equally applicable to any scientific area which requires a solubility dependent decision on solvent choice. PMID- 28666390 TI - Exploiting Femtoliter Microwells for the Sensitive Measurement of Protein Adsorption. AB - A method is described for the sensitive measurement of adsorbed proteins using femtoliter microwells. Quantitative measurement of adsorbed protein is demonstrated at surface densities from 10 fg/cm2 to 3 pg/cm2. Determination of the efficacy of barrier coatings is also demonstrated using femtoliter microwells. Adsorption at low surface densities is measured, indicating the highest affinity sites on the surface and therefore the initial stages of adsorption. The femtoliter microwell method is shown to be useful in detecting differences between effective protective coatings. PMID- 28666391 TI - The combined impact of social support and perceived stress on quality of life in adults with autism spectrum disorder and without intellectual disability. AB - Identifying modifiable correlates of good quality of life in adults with autism spectrum disorder is of paramount importance for intervention development as the population of adults with autism spectrum disorder increases. This study sought to examine social support and perceived stress as potential modifiable correlates of quality of life in adults with autism spectrum disorder. We hypothesized that adults with autism spectrum disorder without co-occurring intellectual disabilities ( N = 40; aged 18-44 years) would report lower levels of social support and quality of life than typical community volunteers who were matched for age, sex, and race ( N = 25). We additionally hypothesized that social support would buffer the effect of perceived stress on quality of life in adults with autism spectrum disorder. Results indicated that adults with autism spectrum disorder reported significantly lower levels of social support and quality of life than matched typical community volunteers. In addition, findings showed significant direct effects of social support and perceived stress on quality of life in adults with autism spectrum disorder. Social support did not buffer the effect of perceived stress on quality of life. Interventions that teach adults with autism spectrum disorder skills to help them better manage stress and cultivate supportive social relationships have the potential to improve quality of life. PMID- 28666392 TI - Organized leisure-time sport participation and academic achievement in preadolescents. AB - AIMS: The aims of this study were to study the correlation between lifestyle related factors, such as organized leisure-time sport participation (OLSP), cardiorespiratory fitness, and adiposity, and academic achievement among preadolescents. METHODS: A cross-sectional study involving 248 nine-year-old school children was carried out. OLSP was self-reported with parental assistance, categorized as <= 1* a week, 2-3* a week, and >= 4* times a week or more. Academic achievement was estimated with results from standardized test scores in Icelandic and math. Cardiorespiratory fitness was estimated using a maximal cycle ergometer test. The sum of four skinfolds was used to estimate adiposity. RESULTS: Tests of between-subjects effect indicated that OLSP significantly correlated with achievement in math only (F(2,235) = 3.81, p = 0.024). Further analysis showed that the two less active groups had significantly lower scores in math compared to the most active group with OLSP >= 4* times a week or more (2-3* times a week, unstandardized coefficient (b) = -4.08, 95% confidence interval (CI) [-7.09, -1.07]; <= 1* a week, b = -3.84, 95% CI [-7.59, -0.08]), independent of sex, age, maturity level (age to/from peak height velocity), family structure, and parental education. Neither cardiorespiratory fitness nor adiposity significantly correlated with academic achievements. CONCLUSIONS: The study's result indicates that frequent (four times per week or more often) sport participation is not harmful but may be beneficial to learning. However, further intervention-based study of this topic is needed to determine if this relationship is causal. PMID- 28666393 TI - Who initiates and organises situations for work-related alcohol use? The WIRUS culture study. AB - AIMS: Alcohol is one of the leading causes of ill health and premature death in the world. Several studies indicate that working life might influence employees' alcohol consumption and drinking patterns. The aim of this study was to explore work-related drinking situations, with a special focus on answering who initiates and organises these situations. METHODS: Data were collected through semi structured group interviews in six Norwegian companies from the private ( n=4) and public sectors ( n=2), employing a total of 3850 employees. The informants ( n=43) were representatives from management and local unions, safety officers, advisers from the social insurance office and human-resource personnel, health, safety and environment personnel, and members from the occupational environment committee. Both qualitative and quantitative content analyses were applied in the analyses of the material. RESULTS: Three different initiators and organisers were discovered: the employer, employees and external organisers. External organisers included customers, suppliers, collaborators, sponsors, subcontractors, different unions and employers' organisations. The employer organised more than half of the situations; external organisers were responsible for more than a quarter. The differences between companies were mostly due to the extent of external organisers. CONCLUSIONS: The employer initiates and organises most situations for work-related alcohol use. However, exposure to such situations seems to depend on how many external relations the company has. These aspects should be taken into account when workplace health-promotion initiatives are planned. PMID- 28666394 TI - Outcome of poor initial TIMI flow in patients presenting with acute coronary syndrome. AB - OBJECTIVES: We explored the predictors and outcome of poor, versus good, initial TIMI flow in patients with acute coronary syndrome (ACS). DESIGN: We performed post-hoc analysis of a randomized trial of patients presenting with ACS who received 2 comparative stents. Poor initial TIMI flow was defined as baseline TIMI flow grade 0/1 at the initial coronary angiography. The primary endpoint was major adverse cardiac events (MACE): a composite of cardiac death, non-fatal myocardial infarction or ischemia-driven target lesion revascularization. Stent thrombosis (ST) was adjudicated according to the criteria of definite ST described by the Academic Research Consortium. Propensity score-matched analysis was performed. We report data after 5-year follow-up. RESULTS: Of 827 patients enrolled, 279 (33.7%) had initial TIMI 0/1 flow. Median follow-up duration was 5.0 years. Presentation by ST-elevation myocardial infarction and target vessel other than left anterior descending artery predicted initial TIMI 0/1 flow. MACE rate was comparable between the 2 subgroups (14% versus 15.9%, in patients with poor versus good initial TIMI flow, respectively, p = .46). Individual endpoints were comparable (p > .05 for all). Definite ST was more frequent in patients with initial TIMI 0/1 flow (3.6% versus 1.5%, respectively, p = .048). This was driven by more frequent early events (30 days) (p = .036); late/very late events were comparable (p = 1.0). CONCLUSIONS: Predictors of poor initial TIMI flow included presentation by ST-elevation myocardial infarction, and target vessel other than left anterior descending artery. Definite ST occurred more in patients with poor, versus good, initial TIMI flow, mainly driven by difference in early events. PMID- 28666395 TI - Can a resting-state functional connectivity index identify patients with Alzheimer's disease and mild cognitive impairment across multiple sites? AB - Resting-state functional connectivity is one promising biomarker for Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, it is still not known how accurately network analysis identifies AD and MCI across multiple sites. In this study, we examined whether resting-state functional connectivity data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) could identify patients with AD and MCI at our site. We implemented an index based on the functional connectivity frequency distribution, and compared performance for AD and MCI identification with multi-voxel pattern analysis. The multi-voxel pattern analysis using a connectivity map of the default mode network showed good performance, with an accuracy of 81.9% for AD and MCI identification within the ADNI, but the classification model obtained from the ADNI failed to classify AD, MCI, and healthy elderly adults from our site, with an accuracy of only 43.1%. In contrast, a functional connectivity index of the medial temporal lobe based on the frequency distribution showed moderate performance, with an accuracy of 76.5 80.3% for AD identification within the ADNI. The performance of this index was similar for our data, with an accuracy of 73.9 - 82.6%. The frequency distribution-based index of functional connectivity could be a good biomarker for AD across multiple sites. PMID- 28666396 TI - Compensatory impingement of the dorsalis pedis artery in a property developer. PMID- 28666397 TI - The association of mobility disability and weight status with risk of disability pension: A prospective cohort study. AB - BACKGROUND/AIMS: Mobility disability (MD) and obesity are conditions which have been associated with weaker labour market attachment. This study investigates whether the combined burden of MD and obesity increase the risk of disability pension compared with having only one of these conditions (the reference group). METHODS: A nationwide cohort study, based on national surveys made between 1996 and 2011, was conducted including 50,015 individuals aged 19-64 years who were followed-up in a large database in terms of attainment of disability pension until 31 December 2012 (at the latest). Proportional hazards regression models were used to analyse the risk of all-cause and diagnosis-specific disability pension with six exposure groups, established by mobility and weight status (BMI) obtained through self-reports. RESULTS: A total of 2296 participants had received disability pension after a mean follow-up period of 7.2 years (SD 4.6). People with MD, regardless of weight, had 4-8 times higher risk of disability pension (for any reason) compared with the reference group (individuals with normal weight and no MD). CONCLUSIONS: No evidence of a double burden of MD and obesity with disability pension was observed in this study. MD seemed to contribute more to the risk of disability pension than weight status. In a long-term perspective, society and also people at risk of these disabling conditions would benefit from reallocation of resources from disability pensions to health-promoting and preventive policies, not least targeting MD. PMID- 28666398 TI - How Do We Meet the Challenge of Whiplash? AB - A previous special issue of JOSPT (October 2016) discussed whiplash in terms of the clinical problems and current research surrounding prevention, biomechanics of injury, emergent care, imaging advancements, recovery pathways and prognosis, pathogenesis of posttrauma pain, acute and chronic management, and new predictive clinical tools. While great strides have been made in the field of whiplash and are continuing in earnest, a key group of clinicians and academics have recognized that inconsistent outcomes in published literature hamper our ability to meaningfully synthesize research findings, leading to results of systematic reviews that provide very few concrete clinical recommendations. We are optimistic that improved outcomes for people with whiplash-associated disorder (WAD) are attainable in the near future, as interdisciplinary research efforts continue to align internationally, new mechanisms are identified and explored, and advanced statistical techniques allow complex questions to be answered in clinically meaningful ways. J Orthop Sports Phys Ther 2017;47(7):444-446. doi:10.2519/jospt.2017.0106. PMID- 28666399 TI - Toward Improving Outcomes in Whiplash: Implementing New Directions of Care. AB - This special issue of JOSPT is the second of a 2-part series on whiplash associated disorders (WADs). Part 1 was published in the October 2016 issue of the Journal. The articles in these 2 special issues highlight that, while we know a great deal about WAD, there are profound gaps in our understanding of how to more effectively work with patients to limit the consequences of this disorder. The information provided in the special-issue articles can help move physical therapy practice and research toward pragmatic and effective solutions for the perplexing condition of WAD. J Orthop Sports Phys Ther 2017;47(7):447-448. doi:10.2519/jospt.2017.0107. PMID- 28666400 TI - Neck Pain: Clinical Practice Guidelines Help Ensure Quality Care. AB - In 2008, physical therapists published the first neck pain clinical practice guidelines. These guidelines have been updated and are now available in the July 2017 issue of JOSPT. To update these guidelines, physical therapists teamed with the International Collaboration on Neck Pain to identify leading practices. These revised guidelines provide direction to clinicians as they screen, evaluate, diagnose, and make treatment-based classifications of neck pain. They also outline the best nonsurgical treatment options based on the published literature. At the end of the day, the best care is a combination of the leading science, the clinical expertise of your health care provider, and your input as the patient. These guidelines help inform the first step in this process. J Orthop Sports Phys Ther 2017;47(7):513. doi:10.2519/jospt.2017.0508. PMID- 28666401 TI - Practice Safe Driving. AB - More than 30,000 people die in motor vehicle collisions each year in the United States. Distracted, drowsy, and drunk driving cause most motor vehicle collision injuries and deaths. An editorial published in the October 2016 issue of JOSPT identified the global need for effective strategies to reduce, if not eliminate, preventable injuries, including whiplash-associated disorders and deaths from distracted driving. This is a call to action for everyone who gets behind the wheel of a car. J Orthop Sports Phys Ther 2017;47(7):449. doi:10.2519/jospt.2017.0506. PMID- 28666402 TI - Neck Pain Guidelines: Revision 2017: Using the Evidence to Guide Physical Therapist Practice. AB - Neck pain is a common and costly condition. Pain and disability from many types of neck pain can be improved by nonsurgical interventions provided by physical therapists. Best practice physical therapy requires an evidence-based approach, and clinical practice guidelines (CPGs), such as the revised CPG on neck pain published in the July 2017 issue of JOSPT, help clinicians to stay current and translate evidence into practice. J Orthop Sports Phys Ther 2017;47(7):511-512. doi:10.2519/jospt.2017.0507. PMID- 28666403 TI - Cervical Myelopathy in a Patient Referred for Lower Extremity Symptoms. AB - The patient was a 38-year-old male referred to physical therapy with complaints of right lower extremity radicular pain and left lower extremity weakness. Following physical therapy examination, the primary care physician referred the patient to a neurologist, who performed electromyography and nerve conduction studies and ordered a magnetic resonance image. Cervical spine imaging revealed a C5-6 disc extrusion with myelopathy. J Orthop Sports Phys Ther 2017;47(7):510. doi:10.2519/jospt.2017.5071. PMID- 28666404 TI - Neck Pain Associated With a Bony Metastatic Tumor. AB - A 78-year-old man was referred to physical therapy with a 5-month history of nontraumatic neck pain and reductions in active bilateral rotation without radiculopathy. Radiography and computed tomography taken 2 months prior demonstrated age-related multilevel degenerative disc disease. Following physical therapy with no improvement in symptoms, magnetic resonance imaging with contrast and bone scintigraphy were ordered by the physician. An expansile lesion in the right lateral mass of the atlas on magnetic resonance imaging was consistent with a metastatic activity. J Orthop Sports Phys Ther 2017;47(7):509. doi:10.2519/jospt.2017.6135. PMID- 28666405 TI - Neck Pain: Revision 2017. AB - The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these revised clinical practice guidelines is to review recent peer-reviewed literature and make recommendations related to neck pain. J Orthop Sports Phys Ther. 2017;47(7):A1 A83. doi:10.2519/jospt.2017.0302. PMID- 28666406 TI - Posttransplant Lymphoproliferative Disease and Inhibitors of Mammalian Target of Rapamycin: When a Quick Look Back Can Change the Perspective. AB - Posttransplant lymphoproliferative disease represents a heterogeneous group of diseases characterized by uncontrolled proliferation of lymphocytes, favored by immunosuppression. Several risk factors for its development have been described, with Epstein-Barr virus infection being a main cause of early-onset forms and chronic antigen stimulation of donors and/or accumulated immunosuppression as key factors of later forms of lymphocyte transformation. The present clinical case presents a patient diagnosed with posttransplant lymphoproliferative disease 3 years after renal transplant who had a potentially lethal complication related to conversion to inhibitors of mammalian target of rapamycin. Because clinical studies that establish the most suitable treatment are lacking, it is recommended to identify the strategy, defining possible risks versus benefits of conversion to inhibitors of mammalian target of rapamycin in cases of posttransplant lymphoproliferative disease, and to maintain a high level of surveillance in case of possible secondary effects that can be verified after their introduction. PMID- 28666407 TI - Small RNA fragments derived from multiple RNA classes - the missing element of multi-omics characteristics of the hepatitis C virus cell culture model. AB - BACKGROUND: A pool of small RNA fragments (RFs) derived from diverse cellular RNAs has recently emerged as a rich source of functionally relevant molecules. Although their formation and accumulation has been connected to various stress conditions, the knowledge on RFs produced upon viral infections is very limited. Here, we applied the next generation sequencing (NGS) to characterize RFs generated in the hepatitis C virus (HCV) cell culture model (HCV-permissive Huh 7.5 cell line). RESULTS: We found that both infected and non-infected cells contained a wide spectrum of RFs derived from virtually all RNA classes. A significant fraction of identified RFs accumulated to similar levels as miRNAs. Our analysis, focused on RFs originating from constitutively expressed non-coding RNAs, revealed three major patterns of parental RNA cleavage. We found that HCV infection induced significant changes in the accumulation of low copy number RFs, while subtly altered the levels of high copy number ones. Finally, the candidate RFs potentially relevant for host-virus interactions were identified. CONCLUSIONS: Our results indicate that RFs should be considered an important component of the Huh-7.5 transcriptome and suggest that the main factors influencing the RF biogenesis are the RNA structure and RNA protection by interacting proteins. The data presented here significantly complement the existing transcriptomic, miRnomic, proteomic and metabolomic characteristics of the HCV cell culture model. PMID- 28666408 TI - Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials. AB - BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue. METHODS: We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed. RESULTS: Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups. CONCLUSIONS: This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk of side effects. PMID- 28666409 TI - End stage renal disease in French Guiana (data from R.E.I.N registry): South American or French? AB - BACKGROUND: End-Stage renal disease (ESRD) causes considerable morbidity and mortality, and significantly alters patients' quality of life. There are very few published data on this problem in the French Overseas territories. The development of a registry on end stage renal disease in French Guiana in 2011 allowed to describe the magnitude of this problem in the region for the first time. METHODS: Using data from the French Renal Epidemiology and Information Network registry (R.E.I.N). Descriptive statistics on quantitative and qualitative variables in the registry were performed on prevalent cases and incident cases in 2011, 2012 and 2013. RESULTS: French Guiana has one of the highest ESRD prevalence and incidence in France. The two main causes of ESRD were hypertensive and diabetic nephropathies. The French Guianese population had a different demographic profile (younger, more women, more migrants) than in mainland France. Most patients had at least one comorbidity, predominantly (95.3%) hypertension. In French Guiana dialysis was initiated in emergency for 71.3% of patients versus 33% in France (p < 0.001). CONCLUSION: These first results give important public health information: i) End stage renal disease has a very high prevalence relative to mainland France ii) Patients have a different demographic profile and enter care late in the course of their renal disease. These data are closer to what is observed in the Caribbean or in Latin America than in Mainland France. PMID- 28666410 TI - BioNanoAnalyst: a visualisation tool to assess genome assembly quality using BioNano data. AB - BACKGROUND: Reference genome assemblies are valuable, as they provide insights into gene content, genetic evolution and domestication. The higher the quality of a reference genome assembly the more accurate the downstream analysis will be. During the last few years, major efforts have been made towards improving the quality of genome assemblies. However, erroneous and incomplete assemblies are still common. Complementary to DNA sequencing technologies, optical mapping has advanced genomic studies by facilitating the production of genome scaffolds and assessing structural variation. However, there are few tools available to comprehensively examine misassemblies in reference genome sequences using optical map data. RESULTS: We present BioNanoAnalyst, a software package to examine genome assemblies based on restriction endonuclease cut sites and optical map data. A graphical user interface (GUI) allows users to assess reference genome sequences on different computer platforms without the requirement of programming knowledge. The zoom function makes visualisation convenient, while a GFF3 format output file gives an option to directly visualise questionable assembly regions by location and nucleotides following import into a local genome browser. CONCLUSIONS: BioNanoAnalyst is a tool to identify misassemblies in a reference genome sequence using optical map data. With the reported information, users can rapidly identify assembly errors and correct them using other software tools, which could facilitate an accurate downstream analysis. PMID- 28666411 TI - Deep Super-SAGE transcriptomic analysis of cold acclimation in lentil (Lens culinaris Medik.). AB - BACKGROUND: Frost is one of the main abiotic stresses limiting plant distribution and crop production. To cope with the stress, plants evolved adaptations known as cold acclimation or chilling tolerance to maximize frost tolerance. Cold acclimation is a progressive acquisition of freezing tolerance by plants subjected to low non-freezing temperatures which subsequently allows them to survive exposure to frost. Lentil is a cool season grain legume that is challenged by winter frost in some areas of its cultivation. RESULTS: To better understand the genetic base of frost tolerance differential gene expression in response to cold acclimation was investigated. Recombinant inbred lines (RILs) from the cross Precoz x WA8649041 were first classified as cold tolerant or cold susceptible according to their response to temperatures between -3 to -15 degrees C. Then, RILs from both extremes of the response curve were cold acclimated and the leaf transcriptomes of two bulks each of eight frost tolerant and seven cold susceptible RILs were investigated by Deep Super-SAGE transcriptome profiling. Thus, four RNA bulks were analysed: the acclimated susceptible, the acclimated tolerant and the respective controls (non-acclimated susceptible and non-acclimated tolerant). Approximately 16.5 million 26 nucleotide long Super-SAGE tags were sequenced in the four sets (between ~3 and 5.4 millions). In total, 133,077 different unitags, each representing a particular transcript isoform, were identified in these four sets. Tags which showed a significantly different abundance in any of the bulks (fold change >=4.0 and a significant p-value <0.001) were selected and used to identify the corresponding lentil gene sequence. Three hundred of such lentil sequences were identified. Most of their known homologs coded for glycine-rich, cold and drought regulated proteins, dormancy-associated proteins, proline-rich proteins (PRPs) and other membrane proteins. These were generally but not exclusively over expressed in the acclimated tolerant lines. CONCLUSIONS: This set of candidate genes implicated in the response to frost in lentil represents an useful base for deeper and more detailed investigations into this important agronomic trait in future. PMID- 28666412 TI - An integrated study of human and animal infectious disease in the Lake Victoria crescent small-holder crop-livestock production system, Kenya. AB - BACKGROUND: The neglected zoonotic diseases (NZD) are an understudied group that are a major cause of illness throughout the developing world. In general, little is known about the prevalence and burden of NZDs in affected communities, particularly in relation to other infectious diseases with which they are often co-endemic. We describe the design and descriptive epidemiological outputs from an integrated study of human and animal zoonotic and non-zoonotic disease in a rural farming community in western Kenya. METHODS: This cross-sectional survey involved 2113 people, their cattle (n = 983) and pigs (n = 91). People and animals were tested for infection or exposure to a wide range of zoonotic and non zoonotic pathogens. Prevalence estimates, with adjustment for the complex study design, were derived. Evidence for spatial clustering in exposure or infection was identified using the spatial scan statistic. RESULTS: There was a high prevalence of human parasitism in the community, particularly with hookworm (Ancylostoma duodenale or Necator americanus) (36.3% (95% CI 32.8-39.9)), Entamoeba histolytica/dispar (30.1% (95% CI 27.5-32.8)), and Plasmodium falciparum (29.4% (95% CI 26.8-32.0)). Human infection with Taenia spp. was also prevalent (19.7% (95% CI 16.7-22.7)), while exposure to other zoonotic pathogens was comparatively rarer (Brucella spp., 0.6% (95% CI 0.2-0.9); Coxiella burnetii, 2.2% (95% CI 1.5-2.9); Rift Valley fever, 0.5% (95% CI 0.2-0.8)). A low prevalence of exposure to Brucella spp. was observed in cattle (0.26% (95% CI 0 0.56). This was higher for Rift Valley fever virus (1.4% (95% CI 0.5-2.22)) and C. burnetii (10.0% (95% CI 7.7-12.2)). The prevalence of Taenia spp. cysticercosis was 53.5% (95% CI 48.7-58.3) in cattle and 17.2% (95% CI 9.1-25.3) in pigs. Mycobacterium bovis infection was found in 2.2% of cattle (95% CI 1.3 3.2), while the prevalence of infection with Mycobacterium spp. was 8.2% (95% CI 6.8-9.6) in people. CONCLUSION: Zoonotic infections in people and animals occur in the context of a wide range of co-endemic pathogens in a rural community in western Kenya. The wide diversity of pathogens under study provides a unique opportunity to explore the distribution and determinants of infection in a multi pathogen, multi-host system. PMID- 28666413 TI - Co-morbidity and polypharmacy in Parkinson's disease: insights from a large Scottish primary care database. AB - BACKGROUND: Parkinson's disease is complicated by comorbidity and polypharmacy, but the extent and patterns of these are unclear. We describe comorbidity and polypharmacy in patients with and without Parkinson's disease across 31 other physical, and seven mental health conditions. METHODS: We analysed primary health care data on 510,502 adults aged 55 and over. We generated standardised prevalence rates by age-groups, gender, and neighbourhood deprivation, then calculated age, sex and deprivation adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for those with PD compared to those without, for the prevalence, and number of conditions. RESULTS: Two thousand six hundred forty (0.5%) had Parkinson's disease, of whom only 7.4% had no other conditions compared with 22.9% of controls (adjusted OR [aOR] 0.43, 95% 0.38-0.49). The Parkinson's group had more conditions, with the biggest difference found for seven or more conditions (PD 12.1% vs. controls 3.9%; aOR 2.08 95% CI 1.84-2.35). 12 of the 31 physical conditions and five of the seven mental health conditions were significantly more prevalent in the PD group. 44.5% with Parkinson's disease were on five to nine repeat prescriptions compared to 24.5% of controls (aOR 1.40; 95% CI 1.28 to 1.53) and 19.2% on ten or more compared to 6.2% of controls (aOR 1.90; 95% CI 1.68 to 2.15). CONCLUSIONS: Parkinson's disease is associated with substantial physical and mental co-morbidity. Polypharmacy is also a significant issue due to the complex nature of the disease and associated treatments. PMID- 28666415 TI - Soluble factors from biofilm of Candida albicans and Staphylococcus aureus promote cell death and inflammatory response. AB - BACKGROUND: The objective of this study was to better understand the effects of soluble factors from biofilm of single- and mixed-species Candida albicans (C. albicans) and methicillin-sensitive Staphylococcus aureus (MSSA) cultures after 36 h in culture on keratinocytes (NOK-si and HaCaT) and macrophages (J774A.1). Soluble factors from biofilms of C. albicans and MSSA were collected and incubated with keratinocytes and macrophages, which were subsequently evaluated by cell viability assays (MTT). Lactate dehydrogenase (LDH) enzyme release was measured to assess cell membrane damage to keratinocytes. Cells were analysed by brightfield microscopy after 2 and 24 h of exposure to the soluble factors from biofilm. Cell death was detected by labelling apoptotic cells with annexin V and necrotic cells with propidium iodide (PI) and was visualized via fluorescence microscopy. Soluble factors from biofilm were incubated with J774A.1 cells for 24 h; the subsequent production of NO and the cytokines IL-6 and TNF-alpha was measured by ELISA. RESULTS: The cell viability assays showed that the soluble factors of single-species C. albicans cultures were as toxic as the soluble factors from biofilm of mixed cultures, whereas the soluble factors of MSSA cultures were less toxic than those of C. albicans or mixed cultures. The soluble factors from biofilm of mixed cultures were the most toxic to the NOK-si and HaCaT cells, as confirmed by analyses of PI labelling and cell morphology. Soluble factors from biofilm of single-species MSSA and mixed-species cultures induced the production of IL-6, NO and TNF-alpha by J744A.1 macrophages. The production of IL-6 and NO induced by the soluble factors from biofilm of mixed cultures was lower than that induced by the soluble factors from biofilm of single-species MSSA cultures, whereas the soluble factors from biofilm of C. albicans cultures induced only low levels of NO. CONCLUSIONS: Soluble factors from 36-h-old biofilm of C. albicans and MSSA cultures promoted cell death and inflammatory responses. PMID- 28666416 TI - RGIFE: a ranked guided iterative feature elimination heuristic for the identification of biomarkers. AB - BACKGROUND: Current -omics technologies are able to sense the state of a biological sample in a very wide variety of ways. Given the high dimensionality that typically characterises these data, relevant knowledge is often hidden and hard to identify. Machine learning methods, and particularly feature selection algorithms, have proven very effective over the years at identifying small but relevant subsets of variables from a variety of application domains, including omics data. Many methods exist with varying trade-off between the size of the identified variable subsets and the predictive power of such subsets. In this paper we focus on an heuristic for the identification of biomarkers called RGIFE: Rank Guided Iterative Feature Elimination. RGIFE is guided in its biomarker identification process by the information extracted from machine learning models and incorporates several mechanisms to ensure that it creates minimal and highly predictive features sets. RESULTS: We compare RGIFE against five well-known feature selection algorithms using both synthetic and real (cancer-related transcriptomics) datasets. First, we assess the ability of the methods to identify relevant and highly predictive features. Then, using a prostate cancer dataset as a case study, we look at the biological relevance of the identified biomarkers. CONCLUSIONS: We propose RGIFE, a heuristic for the inference of reduced panels of biomarkers that obtains similar predictive performance to widely adopted feature selection methods while selecting significantly fewer feature. Furthermore, focusing on the case study, we show the higher biological relevance of the biomarkers selected by our approach. The RGIFE source code is available at: http://ico2s.org/software/rgife.html . PMID- 28666414 TI - Comparative transcriptome analysis reveals different strategies for degradation of steam-exploded sugarcane bagasse by Aspergillus niger and Trichoderma reesei. AB - BACKGROUND: Second generation (2G) ethanol is produced by breaking down lignocellulosic biomass into fermentable sugars. In Brazil, sugarcane bagasse has been proposed as the lignocellulosic residue for this biofuel production. The enzymatic cocktails for the degradation of biomass-derived polysaccharides are mostly produced by fungi, such as Aspergillus niger and Trichoderma reesei. However, it is not yet fully understood how these microorganisms degrade plant biomass. In order to identify transcriptomic changes during steam-exploded bagasse (SEB) breakdown, we conducted a RNA-seq comparative transcriptome profiling of both fungi growing on SEB as carbon source. RESULTS: Particular attention was focused on CAZymes, sugar transporters, transcription factors (TFs) and other proteins related to lignocellulose degradation. Although genes coding for the main enzymes involved in biomass deconstruction were expressed by both fungal strains since the beginning of the growth in SEB, significant differences were found in their expression profiles. The expression of these enzymes is mainly regulated at the transcription level, and A. niger and T. reesei also showed differences in TFs content and in their expression. Several sugar transporters that were induced in both fungal strains could be new players on biomass degradation besides their role in sugar uptake. Interestingly, our findings revealed that in both strains several genes that code for proteins of unknown function and pro-oxidant, antioxidant, and detoxification enzymes were induced during growth in SEB as carbon source, but their specific roles on lignocellulose degradation remain to be elucidated. CONCLUSIONS: This is the first report of a time-course experiment monitoring the degradation of pretreated bagasse by two important fungi using the RNA-seq technology. It was possible to identify a set of genes that might be applied in several biotechnology fields. The data suggest that these two microorganisms employ different strategies for biomass breakdown. This knowledge can be exploited for the rational design of enzymatic cocktails and 2G ethanol production improvement. PMID- 28666417 TI - Identifying differential miR and gene consensus patterns in peripheral blood of patients with cardiovascular diseases from literature data. AB - BACKGROUND: Numerous recent studies suggest the potential of circulating MicroRNAs (miRs) in peripheral blood samples as diagnostic or prognostic markers for coronary artery disease (CAD), acute coronary syndrome (ACS) and heart failure (HF). However, literature often remains inconclusive regarding as to which markers are most indicative for which of the above diseases. This shortcoming is mainly due to the lack of a systematic analyses and absence of information on the functional pathophysiological role of these miRs and their target genes. METHODS: We here provide an-easy-to-use scoring approach to investigate the likelihood of regulation of several miRs and their target genes from literature by identifying consensus patterns of regulation. We therefore have screened over 1000 articles that study mRNA markers in cardiovascular and metabolic diseases, and devised a scoring algorithm to identify consensus means for miRs and genes regulation across several studies. We then aimed to identify differential markers between CAD, ACS and HF. RESULTS: We first identified miRs (miR-122, -126, -223, -138 and -370) as commonly regulated within a group of metabolic disease, while investigating cardiac-related pathologies (CAD, ACS, HF) revealed a decisive role of miR-1, -499, -208b, and -133a. Looking at differential markers between cardiovascular disease revealed miR-1, miR-208a and miR-133a to distinguish ACS and CAD to HF. Relating differentially expressed miRs to their putative gene targets using MirTarBase, we further identified HCN2/4 and LASP1 as potential markers of CAD and ACS, but not in HF. Likewise, BLC-2 was found oppositely regulated between CAD and HF. Interestingly, while studying overlap in target genes between CAD, ACS and HF only revealed little similarities, mapping these genes to gene ontology terms revealed a surprising similarity between CAD and ACS compared to HF. CONCLUSION: We conclude that our analysis using gene and miR scores allows the extraction of meaningful markers and the elucidation of differential pathological functions between cardiac diseases and provides a novel approach for literature screening for miR and gene consensus patterns. The analysis is easy to use and extendable upon further emergent literature as we provide an Excel sheet for this analysis to the community. PMID- 28666418 TI - Progression of chronic kidney disease: an illness-death model approach. AB - BACKGROUND: Chronic kidney disease (CKD) is a major contributor to mortality in the general population. Understanding the factors that drive this process will help delay progression of CKD. The study aimed to estimate the risks of kidney failure and death prior to and after the development of kidney failure among patients with pre-existing CKD, and to identify potential prognostic factors. METHOD: Data were obtained from patients with CKD from Ubon Ratchathani province, Thailand from 1997 to 2011. The probability of each transition (i.e., CKD?death (T1), CKD?kidney failure (T2), and kidney failure?death (T3)) was estimated using a competing risk model. A parametric survival model with restricted cubic spline function was applied to assess prognostic factors. Illness-death models were constructed for the 3 transitions. Among 32,106 patients with CKD, 5576 (17.4%), 4768 (14.9%), and 3056 (9.5%) respectively moved through T1, T2, and T3. RESULTS: Diabetics had 22.6%, 13.5%, and 60.7% higher risks of T1, T2, and T3 than non diabetics respectively (p < 0.001). Hypertension increased risks of T2 and T3 by 8.7% (p = 0.01) and 27.2% (p < 0.001), whereas cardiovascular disease increased risk of T1 and T3 by 76% and 42.7%, respectively (p = 0.01). Increasing HDL by 10 units respectively decreased risk of T1 and T2 by 0.5% (p = 0.002) and 1.4% (p < 0.001). In addition, renin-angiotensin blockade decreased risk of T2 by 35% (p < 0.001). CONCLUSIONS: Diabetes and cardiovascular disease are associated with increasing mortality among CKD patients both before and after the development of kidney failure while hypertension is associated with increasing mortality mainly following kidney failure. Diabetes and hypertension are associated with an elevated risk of kidney failure while elevated HDL levels and renin-angiotensin blockade appear protective. PMID- 28666419 TI - Effectiveness of ATP bioluminescence assay for presumptive identification of microorganisms in hospital water sources. AB - BACKGROUND: Laboratory analysis of organisms in water include arduous methods, such as the multiple tube and membrane filter. The ATP bioluminescence system, proposes a new way of measuring cellular material in water by measuring adenosine triphosphate (ATP) levels, which are expressed in relative light units (RLU). The ATP bioluminescence assay has been increasingly used to assess the microbiological safety of the hospital environment. However, there are few studies investigating the use of this methodology to evaluate the microbiological quality of water. The objective of the present study was to verify whether ATP, as measured by the 3 MTM Clean-Trace WaterTM ATP test, can be used as an alternative tool for presumptive testing for the presence of microorganisms in hospital water. METHODS: Water samples (N = 88) were collected from faucets (74) and water purifiers (14) in a university hospital. The sample were filtered by the membrane filter technique (100 mL for bacterial analysis and 100 mL for fungal analysis) and then submitted to ATP bioluminescence assay to the determine quantity of RLU in each sample. In order to compare RLU and the presence of microorganisms, a receiver operating characteristic (ROC) curve was used to calculate sensitivity and specificity (levels higher than 90% were considered significant). In addition, control tests were conducted to compare RLU to the quantities of bacterial and fungal organisms added to distilled water (ANOVA and Tukey's tests; p <= 0.05). This inoculum was compared to RLU emission, and the data were analyzed by calculating the Pearson's correlation coefficient, with a 95% confidence interval. RESULTS: In the present study, 94.3% of the water samples presented bacterial growth. Of these, 15.6% showed heterotrophic bacteria above recommended levels and fungal contamination was detected in 55.6% of samples. Sensitivity and specificity of the samples were not significant (< 90%), and the correlation between ATP and the presence of these microorganisms in the samples (hospital water) was not significant, whereas, in distilled water, the results revealed a significant difference (p < 0.0001). CONCLUSIONS: These results demonstrated that the ATP test cannot be used as an alternative tool for presumptive assessment of the presence of microorganisms in water. PMID- 28666420 TI - Erratum to: Vector flow mapping analysis of left ventricular energetic performance in healthy adult volunteers. PMID- 28666421 TI - Dickkopf-4 is frequently overexpressed in epithelial ovarian carcinoma and promotes tumor invasion. AB - BACKGROUND: Dickkopf-4 (DKK4), a member of DKK family, appears to be a divergent protein. It remained multi-biological functions in carcinogenesis. The effect of DKK4 on the ovarian cancer cells remains unclear. This study detected the clinical significance of DKK4 in epithelial ovarian cancer (EOC) patients and its role in invasion. METHODS: QRT-PCR and western blot analysis were used to examine the levels of DKK4 mRNA and protein in 33 EOC tissues and 33 benign ovarian tumors. Immunohistochemical analysis was performed to assess DKK4 expression in 239 EOC samples. siRNA-mediated DKK4 silence was conducted. Transwell assay was used to detect the invasive ability. Phalloidin was used to stain the formations of actin filaments. RESULTS: The expressions of DKK4 mRNA and protein were elevated in EOC tissues as compared with those in benign ovarian tumors (p = 0.001 and <0.0001 respectively). Immunohistochemical results showed the strong expression of DKK4 protein was positively associated with late FIGO stage (p = 0.005) and poor disease free survival in univariate and multivariate analysis (p < 0.0001 and p = 0.001, respectively). SiRNA-mediated DKK4 knockdown inhibited cell invasive ability (all p < 0.0001) and the formations of actin filaments. DKK4 could promote the phosphration of c-JUN and JNK (p < 0.0001 and p = 0.001, respectively). CONCLUSIONS: Our results indicated that DKK4 might be contributed to predicting EOC progression and prognosis. DKK4 could promote the invasion of EOC through JNK activation. PMID- 28666422 TI - The role of hormonal therapy in patients with relapsed high-grade ovarian carcinoma: a retrospective series of tamoxifen and letrozole. AB - BACKGROUND: Hormonal therapy is used as a treatment option in high-grade ovarian carcinoma (HGOC), but the role and choice of treatment remains unclear. Agents used include tamoxifen and aromatase inhibitors. Our aim was to evaluate the efficacy of tamoxifen (T) and letrozole (L) in HGOC in clinical practice and investigate factors influencing clinical outcome. METHODS: A retrospective review of patients with relapsed HGOC treated with either tamoxifen or letrozole at the Royal Marsden Hospital between 2007 and 2012 was performed. The primary endpoint of the study was objective response rate (ORR). Secondary endpoints included CA125 response, clinical benefit rate (CBR) and duration of response. Platinum sensitivity and ER-status were evaluated as predictors of treatment response. RESULTS: 97 patients were included (43 T, 54 L); median age 63 years (20-92); 91% high-grade serous; median number of lines of prior chemotherapy 3 (1-8); 60% platinum-resistant, 40% platinum-sensitive; 52% ER + ve, 1% ER-ve, 47% unknown. 14 patients (6 T, 8 L) achieved a partial response, with ORR (RECIST) of 14% (T) and 15% (L). The CBR for >=3 months was 65% (22/43) for tamoxifen and 56% (22/54) for letrozole. There was no significant difference in ORR (p = 0.99) or CBR (p = 0.14) between tamoxifen and letrozole. 22 patients (23%) had a CA-125 response with hormonal therapy (10 T - 23% and 12 L - 22%). ORR did not differ by platinum sensitivity (p = 0.42); or ER-status (positive vs unknown, p = 0.12). Responders to letrozole had longer durations of response than responders to tamoxifen (26 vs 11.5 months, p = 0.03), but equivalent disease stability duration (9.6 vs 7.2 months respectively, p = 0.11). CONCLUSIONS: Within the constraints of a retrospective study, we identified that patients treated with letrozole had a significantly longer duration of response than those treated with tamoxifen. Treatment with either tamoxifen or letrozole is a rational treatment option for patients with ER + ve HGOC, with equivalent ORR, CBR and disease stability. PMID- 28666423 TI - Precision oncology using a limited number of cells: optimization of whole genome amplification products for sequencing applications. AB - BACKGROUND: Sequencing analysis of circulating tumor cells (CTCs) enables "liquid biopsy" to guide precision oncology strategies. However, this requires low template whole genome amplification (WGA) that is prone to errors and biases from uneven amplifications. Currently, quality control (QC) methods for WGA products, as well as the number of CTCs needed for reliable downstream sequencing, remain poorly defined. We sought to define strategies for selecting and generating optimal WGA products from low-template input as it relates to their potential applications in precision oncology strategies. METHODS: Single pancreatic cancer cells (HPAF-II) were isolated using laser microdissection. WGA was performed using multiple displacement amplification (MDA), multiple annealing and looping based amplification (MALBAC) and PicoPLEX. Quality of amplified DNA products were assessed using a multiplex/RT-qPCR based method that evaluates for 8-cancer related genes and QC-scores were assigned. We utilized this scoring system to assess the impact of de novo modifications to the WGA protocol. WGA products were subjected to Sanger sequencing, array comparative genomic hybridization (aCGH) and next generation sequencing (NGS) to evaluate their performances in respective downstream analyses providing validation of the QC-score. RESULTS: Single-cell WGA products exhibited a significant sample-to-sample variability in amplified DNA quality as assessed by our 8-gene QC assay. Single-cell WGA products that passed the pre-analysis QC had lower amplification bias and improved aCGH/NGS performance metrics when compared to single-cell WGA products that failed the QC. Increasing the number of cellular input resulted in improved QC-scores overall, but a resultant WGA product that consistently passed the QC step required a starting cellular input of at least 20-cells. Our modified-WGA protocol effectively reduced this number, achieving reproducible high-quality WGA products from >=5-cells as a starting template. A starting cellular input of 5 to 10-cells amplified using the modified-WGA achieved aCGH and NGS results that closely matched that of unamplified, batch genomic DNA. CONCLUSION: The modified-WGA protocol coupled with the 8-gene QC serve as an effective strategy to enhance the quality of low-template WGA reactions. Furthermore, a threshold number of 5-10 cells are likely needed for a reliable WGA reaction and product with high fidelity to the original starting template. PMID- 28666424 TI - Bilateral ptosis as first presentation of cytophagic histiocytic panniculitis: a case report. AB - BACKGROUND: Cytophagic histiocytic panniculitis (CHP) is a rare form of nodular panniculitis that may progress to panniculitis-like T-cell lymphoma. We report a case of CHP that first manifested as bilateral ptosis, which is the first reported case of this presentation. CASE PRESENTATION: A 25-year-old woman without medical history was referred to the neurology department of our hospital for evaluation of bilateral ptosis. Three months previously, she suddenly complained of bilateral ptosis without apparent cause. Simultaneously, non painful tender subcutaneous nodules and eschar-like skin lesions were observed on her extremities and trunk. A diagnosis of CHP was made based on skin biopsy from the left thigh showing lobular panniculitis, vasculitis, and adiponecrosis, with infiltration of inflammatory cells, including lymphocytes, histiocytes, and phagocytic histiocytes. Her condition continued to worsen with corticosteroid and immunosuppressive agent (thalidomide) treatment. Significant improvement was noticed after three cycles of chemotherapy of THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone). CONCLUSIONS: CHP is a rare condition whose clinical presentation may include bilateral ptosis and biopsy is required for diagnosis of CHP. PMID- 28666425 TI - A process evaluation exploring the lay counsellor experience of delivering a task shared psycho-social intervention for perinatal depression in Khayelitsha, South Africa. AB - BACKGROUND: Task sharing of psycho-social interventions for perinatal depression has been shown to be feasible, acceptable and effective in low and middle-income countries. This study conducted a process evaluation exploring the perceptions of counsellors who delivered a task shared psycho-social counselling intervention for perinatal depression in Khayelitsha, Cape Town together with independent fidelity ratings. METHODS: Post intervention qualitative semi-structured interviews were conducted with six counsellors from the AFrica Focus on Intervention Research for Mental health (AFFIRM-SA) randomised controlled trial on their perceptions of delivering a task shared psycho-social intervention for perinatal depression. Themes were identified using the framework approach and were coded and analysed using Nvivo v11. These interviews were supplemented with fidelity ratings for each counsellor and supervision notes. RESULTS: Facilitating factors in the delivery of the intervention included intervention related factors such as: the content of the intervention, ongoing training and supervision, using a counselling manual, conducting counselling sessions in the local language (isiXhosa) and fidelity to the manual; counsellor factors included counsellors' confidence and motivation to conduct the sessions; participant factors included older age, commitment and a desire to be helped. Barriers included contextual factors such as poverty, crime and lack of space to conduct counselling sessions and participant factors such as the nature of the participant's problem, young age, and avoidance of contact with counsellors. Fidelity ratings and dropout rates varied substantially between counsellors. CONCLUSION: These findings show that a variety of intervention, counsellor, participant and contextual factors need to be considered in the delivery of task sharing counselling interventions. Careful attention needs to be paid to ongoing supervision and quality of care if lay counsellors are to deliver good quality task shared counselling interventions in under-resourced communities. TRIAL REGISTRATION: Clinical Trials: NCT01977326 , registered on 24/10/2013; Pan African Clinical Trials Registry: PACTR201403000676264 , registered on 11/10/2013. PMID- 28666426 TI - Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling. AB - BACKGROUND: Bacterial pneumonia in pigs occurs widely and requires antimicrobial therapy. It is commonly caused by the pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. Marbofloxacin is an antimicrobial drug of the fluoroquinolone class, licensed for use against these organisms in the pig. In recent years there have been major developments in dosage schedule design, based on integration and modelling of pharmacokinetic (PK) and pharmacodynamic (PD) data, with the objective of optimising efficacy and minimising the emergence of resistance. From in vitro time-kill curves in pig serum, PK/PD breakpoint Area under the curve (AUC) 24h /minimum inhibitory concentration (MIC) values were determined and used in conjunction with published PK, serum protein binding data and MIC distributions to predict dosages based on Monte Carlo simulation (MCS). RESULTS: For three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count, mean AUC24h/MIC values were 20.9, 45.2 and 71.7 h, respectively, for P. multocida and 32.4, 48.7 and 55.5 h for A. pleuropneumoniae. Based on these breakpoint values, doses for each pathogen were predicted for several clinical scenarios: (1) bacteriostatic and bactericidal levels of kill; (2) 50 and 90% target attainment rates (TAR); and (3) single dosing and daily dosing at steady state. MCS for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 0.44 and 0.95 mg/kg (P. multocida) and 0.28 and 0.66 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 0.28 and 0.59 mg/kg (P. multocida) and 0.22 and 0.39 mg/kg (A. pleuropneumoniae) were required for pigs aged 12 weeks. Doses were also predicted for pigs aged 16 and 27 weeks. CONCLUSIONS: PK/PD modelling with MCS approaches to dose determination demonstrates the possibility of tailoring clinical dose rates to a range of bacterial kill end-points. PMID- 28666428 TI - Descriptive analysis of preschool physical activity and sedentary behaviors - a cross sectional study of 3-year-olds nested in the SKOT cohort. AB - BACKGROUND: Further collection of surveillance data is warranted, particularly in preschool populations, for optimizing future public health promotion strategies. This study aims to describe physical activity (PA) and sedentary behavior (SB) across different settings, including time in and out of daycare, and to determine the proportion of children complying with suggested PA recommendations in a high income country. METHODS: Valid PA was assessed in 231 children (36.4 +/- 1.1 months) with the Actigraph GT3X accelerometer, and information regarding date and time of dropping-off/picking-up children in daycare was provided by parents. Mean total PA (i.e., counts per minute (CPM)), moderate-to-vigorous physical activity (MVPA), SB time, and non-SB time was generated and compared across settings. Post hoc, PA and SB were examined in subgroups of low-active (1st quartile) and high active (4th quartile) children. RESULTS: Overall, boys and girls spent 1.4 +/- 0.3 h/day and 1.2 +/- 0.4 h/day in MVPA, respectively. Likewise, boys and girls accumulated 6.7 +/- 0.8 h and 6.8 +/- 0.9 h of SB time per day, respectively. Higher PA levels consistently co-occurred with lower SB time in the daycare setting. Girls accumulated less SB time in daycare than before and after daycare (beta = -12.2%, p < 0.001 & beta = -3.8%, p < 0.001, respectively). In boys, daycare-days contained more PA and less SB than non-daycare-days (CPM: beta =29, p = 0.046, %MVPA: beta = 0.83, p = 0.007, %SB: beta = -2.3, p < 0.001, respectively). All children fulfilled recommendations of at least 3 h of daily non-SB. Eighty-nine percent of boys and 72% of girls met the daily 1-h MVPA recommendation for 5 year-olds. Lower proportions of children, especially boys, fulfilled MVPA recommendation on days with no daycare attendance. Generally, large mean differences in MVPA and SB were observed across all settings between the most active and the least active children, and only 7% of the low-active girls and 59% of the low-active boys fulfilled MVPA recommendations. CONCLUSIONS: Overall, the majority of children fulfilled MVPA guidelines for 5 year-olds, and all children complied with suggested recommendations of 180 min of daily activity. Daycare time was found to represent an important setting for PA. Substantial and consistent differences observed in the amount of time spent physically active between high- and low-active children across all settings indicate substantial variations in young children's PA levels irrespective of the context. PMID- 28666427 TI - Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children. AB - BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population. PMID- 28666429 TI - Common adult psychiatric disorders in Swedish primary care where most mental health patients are treated. AB - BACKGROUND: The overall aim of this study is to present descriptive data regarding the treated prevalence of nine common psychiatric and substance use disorders in the first Primary Care Registry (PCR) in Sweden: Major Depression (MD), Anxiety Disorders (AD), Obsessive-Compulsive Disorder (OCD), Adjustment Disorder (AdjD), Eating Disorders (ED), Personality Disorder (PD), Attention Deficit Hyperactivity Disorder (ADHD), Alcohol Use Disorder (AUD) and Drug Abuse (DA). METHOD: We selected 5,397,675 individuals aged >=18. We examined patterns of comorbidity among these disorders and explored the association between diagnoses in the PCR and diagnoses obtained from Hospital and Specialist care. We explored the proportion of patients with these nine disorders that are only treated in primary health care. RESULTS: For four of our disorders, 80% or more of the cases were present only in the PCR: AdjD, DA, AD and MD. For two disorders (OCD and ED), 65-70% of cases were only found in the PCR. For three disorders (PD, AUD, and ADHD), 45-55% of the patients were only present in the PCR. CONCLUSION: The PCR will, in the future, likely prove to be an important tool for studies in psychiatric epidemiology. PMID- 28666431 TI - Immunization against GnRF in adult cattle: a prospective field study. AB - BACKGROUND: Suppression of cyclic activity in cattle is often desired in alpine farming and for feedlot cattle, not intended for breeding. A cattle specific anti GnRF vaccine (BoprivaTM) is registered for use in heifers and bulls in different countries. In adult cows vaccinated with BoprivaTM, the median period until recurrence of class III follicles was 78 days from the day of the 2nd vaccination and reversibility could be proven, as out of 11 experimental cows 10 cows became pregnant at first, and one cow at second insemination. In the present study, 76 healthy, cyclic Eringer heifers and cows were vaccinated twice with BoprivaTM 3-7 weeks apart, to prevent estrus during alpine pasturing. Blood samples were taken for progesterone and GnRF antibody titer analysis on the day of inclusion (7-9 d before the first vaccination) and at the first vaccination. At the same time, gynaecological examinations were performed. When estrus occurred in the course of the alpine pasturing season, a gynaecological examination was done including analysis of a blood sample (progesterone, anti-GnRF antibody titer). Cows were followed for fertility out to 26 months post second vaccination. RESULTS: Median duration of estrus suppression was 191 days after the second vaccination (when the 2 vaccinations were given 28-35 days apart). From n = 13 cows showing signs of estrus on the alpine pasture, n = 7 could not be confirmed in estrus (serum progesterone value >2 ng/ml, no class III follicles seen using ultrasonography). Median duration between second vaccination and next calving was 496 days (25%/75% quartiles: 478/532 days). CONCLUSION: BoprivaTM induced a reliable and reversible suppression of estrus for more than 3 months in over 90% of the cows. PMID- 28666430 TI - Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies. AB - BACKGROUND: Resident stem and progenitor cells have been identified in the lung over the last decade, but isolation and culture of these cells remains a challenge. Thus, although these lung stem and progenitor cells provide an ideal source for stem-cell based therapy, mesenchymal stem cells (MSCs) remain the most popular cell therapy product for the treatment of lung diseases. Surgical lung biopsies can be the tissue source but such procedures carry a high risk of mortality. METHODS: In this study we demonstrate that therapeutic lung cells, termed "lung spheroid cells" (LSCs) can be generated from minimally invasive transbronchial lung biopsies using a three-dimensional culture technique. The cells were then characterized by flow cytometry and immunohistochemistry. Angiogenic potential was tested by in-vitro HUVEC tube formation assay. In-vivo bio- distribution of LSCs was examined in athymic nude mice after intravenous delivery. RESULTS: From one lung biopsy, we are able to derive >50 million LSC cells at Passage 2. These cells were characterized by flow cytometry and immunohistochemistry and were shown to represent a mixture of lung stem cells and supporting cells. When introduced systemically into nude mice, LSCs were retained primarily in the lungs for up to 21 days. CONCLUSION: Here, for the first time, we demonstrated that direct culture and expansion of human lung progenitor cells from pulmonary tissues, acquired through a minimally invasive biopsy, is possible and straightforward with a three-dimensional culture technique. These cells could be utilized in long-term expansion of lung progenitor cells and as part of the development of cell-based therapies for the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). PMID- 28666432 TI - Development of a pilot cartilage surgery register. AB - BACKGROUND: Norway has no prospective surveillance system to monitor the outcome of knee cartilage surgery. In 2004 the Norwegian Registry of Knee Ligament (NKLR) was successfully established, and has yielded useful information on the treatment of patients with both knee ligament and combined knee injuries. Patients with focal cartilage defects (FCDs) in their knees have reduced function and the treatment is difficult. There are geographical variations in treatment, and the generalizability from randomized controlled studies is low. These patients would benefit from a standardized long-time follow-up through a cartilage surgery register. The aim of the present study was to describe the development and report baseline challenges during the setting up of a pilot of a knee cartilage surgery register. METHODS: The study was designed as a prospective cohort study in the form of a register. Patients with full-thickness FCDs in the knee with International Cartilage Repair Society (ICRS) grade 3-4 on arthroscopy were included. The pilot included two hospitals; Oslo University Hospital (OUS), Ulleval and Akershus University Hospital (Ahus). RESULTS: We registered 58 patients with isolated FCDs, whereas 16 additional patients with full-thickness FCDs were registered through the NKLR. The patient cohort of patients with isolated FCDs consisted of 65% men and had a mean age of 29.8 years. The data are incomplete and the compliance varies from 18 to 73%. The distribution of mean KOOS scores were similar to previous patient cohorts with FCDs, with low scores for the KOOS Sport/Recreation and Quality of Life subscales. CONCLUSION: The level of compliance demonstrated a large difference between the two participating hospitals. The compliance for the isolated FCDs were low in both locations, although it reached an acceptable level in one hospital when patients with combined injuries from the NKLR were included. The forms were incompletely filled out by the surgeons postoperatively and need to be revised prior the establishment of a nation-wide register. PMID- 28666433 TI - Establishing an ICD-10 code based SARI-surveillance in Germany - description of the system and first results from five recent influenza seasons. AB - BACKGROUND: Syndromic surveillance of severe acute respiratory infections (SARI) is important to assess seriousness of disease as recommended by WHO for influenza. In 2015 the Robert Koch Institute (RKI) started to collaborate with a private hospital network to develop a SARI surveillance system using case-based data on ICD-10 codes. This first-time description of the system shows its application to the analysis of five influenza seasons. METHODS: Since week 40/2015, weekly updated anonymized data on discharged patients overall and on patients with respiratory illness including ICD-10 codes of primary and secondary diagnoses are transferred from the network data center to RKI. Retrospective datasets were also provided. Our descriptive analysis is based on data of 47 sentinel hospitals collected between weeks 1/2012 to 20/2016. We applied three different SARI case definitions (CD) based on ICD-10 codes for discharge diagnoses of respiratory tract infections (J09 - J22): basic CD (BCD), using only primary diagnoses; sensitive CD (SCD), using primary and secondary diagnoses; timely CD (TCD), using only primary diagnoses of patients hospitalized up to one week. We compared the CD with regard to severity, age distribution and timeliness and with results from the national primary care sentinel system. RESULTS: The 47 sentinel hospitals covered 3.6% of patients discharged from all German hospitals in 2013. The SCD comprised 2.2 times patients as the BCD, and 3.6 times as many as the TCD. Time course of SARI cases corresponded well to results from primary care surveillance and influenza virus circulation. The patients fulfilling the TCD had been completely reported after 3 weeks, which was fastest among the CD. The proportion of SARI cases among patients was highest in the youngest age group of below 5-year-olds. However, the age group 60 years and above contributed most SARI cases. This was irrespective of the CD used. CONCLUSIONS: In general, available data and the implemented reporting system are appropriate to provide timely and reliable information on SARI in inpatients in Germany. Our ICD-10 based approach proved to be useful for fulfilling requirements for SARI surveillance. The exploratory approach gave valuable insights in data structure and emphasized the advantages of different CD. PMID- 28666434 TI - Reversible opacification of hydrophobic acrylic intraocular lens- two cases report. AB - BACKGROUND: The opacification of the intraocular lens (IOL) can cause significant visual deterioration. It is known that opacity of hydrophobic acrylic IOLs is rare. We report 2 cases of reversible optic opacification of hydrophobic acrylic intraocular lenses (Tecnis ZCB00, Abbott), observed within 2 months after uneventful cataract surgery. CASE PRESENTATION: Case 1: Uneventful cataract surgery was performed on the left eye of an 86-year-old diabetic man with chronic open-angle glaucoma. A hydrophobic acrylic intraocular lens (IOL; Tecnis ZCB00, Abbott, Lake Bluff, IL) was implanted in the bag. Eye drops containing 0.5% levofloxacin and 1.0% prednisolone were used after surgery along with topical anti-glaucoma medications. At 7 weeks postoperative, cloudy, concentric IOL opacification developed, accompanied by decreased visual acuity and increased intraocular pressure. However, the opacification completely disappeared after 9 weeks. Case 2: Uneventful cataract surgery was performed on the left eye of a 72 year-old woman. A hydrophobic acrylic IOL (Tecnis ZCB00) was implanted in the bag. At 2 weeks postoperative, cloudy, concentric IOL opacification developed, accompanied by ocular discomfort. After 4 weeks, opacification and discomfort completely disappeared. CONCLUSIONS: We observed two cases of completely reversible opacification of hydrophobic acrylic IOLs. The exact nature of the transient opacity remains unclear, but an inflammatory origin cannot be completely ruled out. PMID- 28666435 TI - Prevalence, patterns, and perceived value of complementary and alternative medicine among cancer patients: a cross-sectional, descriptive study. AB - BACKGROUND: Sophisticated conventional medicine (CM) has brought significant advances to cancer prevention, detection, and treatment. However, many cancer patients still turn to complementary and alternative medicine (CAM) treatment. This study explored the prevalence, patterns, and perceived value of CAM among cancer patients. METHODS: This quantitative descriptive study was conducted between March 1, 2015, and July 31, 2015, among a cross-sectional, convenience sample of patients from the Oncology Department of San Fernando General Hospital in Trinidad and Tobago. Face-to-face interviews were conducted at the oncology clinic and treatment suite after obtaining informed consent. Data analysis included descriptive analysis, chi-square tests, and binary logistic regression analysis. RESULTS: The prevalence of CAM use among a sample of 350 cancer patients was 39.1% (39.6% for breast cancer, 44.4% for prostate cancer, 37% for ovarian cancer, and 38.7% for colon cancer patients). Herbs were the most common type of CAM used (93.4%), followed by spiritual therapy (73.7%). CAM use was more prevalent among females (68.6%), Indo-Trinidadians (63.5%), and patients aged 41 50 years (37.2%). The majority (70%-80%) rated CAM efficacy on perceived value. CAM was used mainly because of a desire to try anything that might help (67.6%), followed by it being congruent with the patients' beliefs (59.1%). Patients knew about CAM mainly through friends (69.3%) and family (69.3%). Most patients were generally satisfied (93.6%) and considered CAM helpful (89.8%), but the majority never informed their health care provider of CAM use (78.8%). Patients reported the simultaneous use of more than one type of CAM, without considering or knowing of possible side-effects. The perceived value of CAM included empowerment, control, cure, and improved quality of life. CAM use was associated with age, but no predictors of CAM use could be identified. CONCLUSION: Medicinal herbs and spiritual therapy are commonly used among cancer patients because of perceived benefits and satisfaction. CAM use is more prevalent among females, Indo Trinidadians, and patients aged 41-50 years old. There are no useful predictors of CAM use. More than one type of CAM is commonly used simultaneously without disclosure to health care providers. PMID- 28666436 TI - In vitro characterization and in vivo toxicity, antioxidant and immunomodulatory effect of fermented foods; XenijiTM. AB - BACKGROUND: Xeniji, produced by fermenting various types of foods with lactic acid bacteria and yeast, has been commonly consumed as functional food. However, nutrition value, bioactivities and safety of different fermented products maybe varies. METHODS: Organic acid and antioxidant profiles of Xeniji fermented foods were evaluated. Moreover, oral acute (5 g/kg body weight) and subchronic toxicity (0.1, 1 and 2 g/kg body weight) of Xeniji were tested on mice for 14 days and 30 days, respectively. Mortality, changes of body weight, organ weight and serum liver enzyme level were measured. Liver and spleen of mice from subchronic toxicity study were subjected to antioxidant and immunomodulation quantification. RESULTS: Xeniji was rich in beta-carotene, phytonadione, polyphenol, citric acid and essential amino acids. No mortality and significant changes of body weight and serum liver enzyme level were recorded for both oral acute and subchronic toxicity studies. Antioxidant level in the liver and immunity of Xeniji treated mice were significantly upregulated in dosage dependent manner. CONCLUSION: Xeniji is a fermented functional food that rich in nutrients that enhanced antioxidant and immunity of mice. Xeniji that rich in beta-carotene, phytonadione, polyphenol, citric acid and essential amino acids promote antioxidant and immunity in mice without causing toxic effect. PMID- 28666437 TI - Olfactory coding from the periphery to higher brain centers in the Drosophila brain. AB - BACKGROUND: Odor information is processed through multiple receptor-glomerular channels in the first order olfactory center, the antennal lobe (AL), then reformatted into higher brain centers and eventually perceived by the fly. To reveal the logic of olfaction, it is fundamental to map odor representations from the glomerular channels into higher brain centers. RESULTS: We characterize odor response profiles of AL projection neurons (PNs) originating from 31 glomeruli using whole cell patch-clamp recordings in Drosophila melanogaster. We reveal that odor representation from olfactory sensory neurons to PNs is generally conserved, while transformation of odor tuning curves is glomerulus-dependent. Reconstructions of PNs reveal that attractive and aversive odors are represented in different clusters of glomeruli in the AL. These separate representations are preserved into higher brain centers, where attractive and aversive odors are segregated into two regions in the lateral horn and partly separated in the mushroom body calyx. CONCLUSIONS: Our study reveals spatial representation of odor valence coding from the AL to higher brain centers. These results provide a global picture of the olfactory circuit design underlying innate odor-guided behavior. PMID- 28666438 TI - What is appropriate care? An integrative review of emerging themes in the literature. AB - BACKGROUND: Health care improvement efforts should be aligned in order to make a meaningful impact on health systems. Appropriate care delivery could be a unifying goal to help coordinate efforts to improve health outcomes and ensure system sustainability. A more complete understanding of how appropriate care is currently conceived in research and clinical practice could help inform a more integrated and holistic concept of appropriate care that could guide health care policy and delivery practices. We examined the current understanding of appropriate care by identifying its use and definitions in recently published literature. METHODS: An integrated review of the practices, goals and perspectives of appropriate care in English language peer-reviewed articles published from 2011 to 2016. Inductive content analysis was used to describe emerging themes of appropriate care in articles meeting inclusion criteria. RESULTS: This integrative review included empirical studies, reviews, and commentaries with various health care settings, cultural contexts, and perspectives. Conceptualizations of appropriate care varied, however most descriptions fell into five main categories: evidence-based care, clinical expertise, patient-centeredness, resource use, and equity. These categories were often used in combination, indicating an integrated understanding of appropriate care. CONCLUSIONS: An understanding of how appropriate care is conceptualized in research and policy can help inform an integrated approach to appropriate care delivery in policy and practice according to the relevant priorities and circumstances. PMID- 28666439 TI - Preventing blood transfusion failures: FMEA, an effective assessment method. AB - BACKGROUND: Failure Mode and Effect Analysis (FMEA) is a method used to assess the risk of failures and harms to patients during the medical process and to identify the associated clinical issues. The aim of this study was to conduct an assessment of blood transfusion process in a teaching general hospital, using FMEA as the method. METHODS: A structured FMEA was recruited in our study performed in 2014, and corrective actions were implemented and re-evaluated after 6 months. Sixteen 2-h sessions were held to perform FMEA in the blood transfusion process, including five steps: establishing the context, selecting team members, analysis of the processes, hazard analysis, and developing a risk reduction protocol for blood transfusion. RESULTS: Failure modes with the highest risk priority numbers (RPNs) were identified. The overall RPN scores ranged from 5 to 100 among which, four failure modes were associated with RPNs over 75. The data analysis indicated that failures with the highest RPNs were: labelling (RPN: 100), transfusion of blood or the component (RPN: 100), patient identification (RPN: 80) and sampling (RPN: 75). CONCLUSION: The results demonstrated that mis transfusion of blood or blood component is the most important error, which can lead to serious morbidity or mortality. Provision of training to the personnel on blood transfusion, knowledge raising on hazards and appropriate preventative measures, as well as developing standard safety guidelines are essential, and must be implemented during all steps of blood and blood component transfusion. PMID- 28666440 TI - Do medical students and young physicians assess reliably their self-efficacy regarding communication skills? A prospective study from end of medical school until end of internship. AB - BACKGROUND: This prospective study from end of medical school through internship investigates the course and possible change of self- reported self-efficacy in communication skills compared with observers' ratings of such skills in consultations with simulated patients. METHODS: Sixty-two medical students (43 females) from four Norwegian universities performed a videotaped consultation with a simulated patient immediately before medical school graduation (T1) and after internship (internal medicine, surgery and family medicine, half a year each - T2). Before each consultation, the participants assessed their general self-efficacy in communication skills. Trained observers scored the videos and applied a well-validated instrument to rate the communication behaviour. Results from the two assessment methods were correlated at both time points and possible differences from T1 to T2 were explored. RESULTS: A close to zero correlation between self-efficacy and observed communication skills were found at T1. At T2, participants' self-efficacy scores were inversely correlated with levels of observed skills, demonstrating a lack of concordance between young physicians' own assessment of self-efficacy and observers' assessment. When dividing the sample in three groups based on the observers' scores (low <1/3-, medium 1/3 to 2/3-, high competence >2/3), the group of male physicians showed higher levels of self-efficacy than females in all the three performance groups at T1. At T2, those having a high performance score yielded a low self-efficacy, regardless of gender. CONCLUSIONS: The lack of positive correlations between self-efficacy assessment and expert ratings points to limitations in the applicability of self assessment measures of communication skills. Due to gender differences, groups of female and male physicians should be investigated separately. Those obtaining high-performance ratings from observers, through the period of internship, may become more conscious of how demanding clinical communication with patients may be. This insight may represent a potential for growth, but could in some physicians represent too much of a self-critical attitude. Active supervision of young physicians throughout internship is important in order to help physicians to be more aware of their strengths and weaknesses, in order to gain increased mastery in the art of doctoring. PMID- 28666442 TI - Strengthening health system to improve immunization for migrants in China. AB - BACKGROUND: Immunization is the most cost-effective method to prevent and control vaccine-preventable diseases. Migrant population in China has been rising rapidly, and their immunization status is poor. China has tried various strategies to strengthen its health system, which has significantly improved immunization for migrants. METHODS: This study applied a qualitative retrospective review method aiming to collect, analyze and synthesize health system strengthening experiences and practices about improving immunizations for migrants in China. A conceptual framework of Theory of Change was used to extract the searched literatures. 11 searched literatures and 4 national laws and policies related to immunizations for migrant children were carefully studied. RESULTS: China mainly employed 3 health system strengthening strategies to significantly improve immunization for migrant population: stop charging immunization fees or immunization insurance, manage immunization certificates well, and pay extra attentions on immunization for special children including migrant children. These health system strengthening strategies were very effective, and searched literatures show that up-to-date and age-appropriate immunization rates were significantly improved for migrant children. CONCLUSIONS: Economic development led to higher migrant population in China, but immunization for migrants, particularly migrant children, were poor. Fortunately various health system strengthening strategies were employed to improve immunization for migrants in China and they were rather successful. The experiences and lessons of immunization for migrant population in China might be helpful for other developing countries with a large number of migrant population. PMID- 28666441 TI - Lung function development after preterm birth in relation to severity of Bronchopulmonary dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a strong risk factor for respiratory morbidity in children born preterm. Our aims were to evaluate lung function in adolescents born preterm with and without a history of BPD, and to assess lung function change over time from school age. METHODS: Fifty-one individuals born in Stockholm, Sweden between gestational ages 24 to 31 weeks (23 neonatally diagnosed with respiratory distress syndrome (RDS) but not BPD, and 28 graded as mild (n = 17), moderate (n = 7) or severe (n = 4) BPD) were examined in adolescence (13-17 years of age) using spirometry, impulse oscillometry (IOS), plethysmography, and ergospirometry. Comparison with lung function data from school age (6-8 years of age) was also performed. RESULTS: Adolescents with a history of BPD had lower forced expiratory volume in 1 s (FEV1) compared to those without BPD (-0.61 vs.-0.02 z-scores, P < 0.05), with lower FEV1 values significantly associated with BPD severity (P for trend 0.002). Subjects with severe BPD had higher frequency dependence of resistance, R5-20, (P < 0.001 vs. non-BPD subjects) which is an IOS indicator of peripheral airway involvement. Between school age and adolescence, FEV1/FVC z-scores decreased in all groups and particularly in the severe BPD group (from -1.68 z-scores at 6-8 years to -2.74 z scores at 13-17 years, p < 0.05 compared to the non-BPD group). CONCLUSIONS: Our results of spirometry and IOS measures in the BPD groups compared to the non-BPD group suggest airway obstruction including involvement of peripheral airways. The longitudinal result of a decrease in FEV1/FVC in the group with severe BPD might implicate a route towards chronic airway obstruction in adulthood. PMID- 28666443 TI - The effect of health literacy and self-management efficacy on the health-related quality of life of hypertensive patients in a western rural area of China: a cross-sectional study. AB - BACKGROUND: Hypertension is a common and frequently occurring chronic disease of the cardiovascular system. Besides the pathological factors, the occurrence and exacerbation of hypertension are also associated with many factors of lifestyle and behaviors. Thus hypertensive patients' Health-related quality of life (HRQL) is not only influenced by the disease itself but also by many subjective factors such as health literacy and self-management efficacy, especially in the deeper part of southwestern China and thus is less developed compared to the other places. The purpose of this study was to examine the association between the HRQL of hypertensive patients and health literacy and self-management efficacy as well as how they affect the HRQL, so as to provide a theoretical reference for improving the HRQL of patients with hypertension in less developed areas. METHODS: This was a cross-sectional study of baseline data from a clustered randomized controlled trial. The study design had passed a cross-national peer review and accepted grants by the China Medical Board. It was also registered in the Chinese Clinical Trial Registry (ChiCTR-OOR-14005563). A standardized questionnaire adapted from a previous validated WHO questionnaire was used for the survey which included detailed questions about patient's socio-demographic characteristics and self-reported information. Patients' HRQL was measured by the Mandarin version of the 36-item Short Form. We used the validated Mandarin version of the Self-Efficacy for Managing Chronic Disease 6-Item Scale to assess patients' self-management efficacy. The validated three-item Brief Health Literacy Screening (BHLS) was used to measure the patients' health literacy. A structural equation model was constructed, and p <= 0.05 was taken as significant. RESULTS: Demographic characteristics, health literacy and self management efficacy have all significant effects on HRQL. Age, education level, self-management efficacy and health literacy were significantly related to the HRQL. The constructed model had a good fit for the data according to the model fit indices. Based on the model, health literacy (r = 0.604, p = 0.029) and Self management efficacy (r = 0.714, p = 0.018) have a significant impact on HRQL. Demographic characteristics were inversely related to HRQL (r = -0.419, p = 0.007), but have a significant impact on health literacy (r = 0.675, p = 0.029) and self-management efficacy (r = 0.379, p = 0.029). At the same time, self management efficacy was positively correlated to health literacy (r = 0.413, p < 0.01). CONCLUSIONS: Age, education level, self-management efficacy and health literacy were all related to the HRQL of patient with hypertension, which means that patients who are more elderly and have lower education level, low self management efficacy and poor health literacy get worse HRQL. This may imply the necessary to introduce routine assessment of health literacy and self-management efficacy into assessment procedures for hypertensive patients' health management. Such assessment can help professionals to identify the population at greatest risk for poor health outcomes and low well-being in the future. In clinical practice, effective interventions such as direct guidance and education to raise the self-management efficacy and enhance health literacy might improve the HRQL of patients with hypertension. TRIAL REGISTRATION: Retrospectively registered Chinese Clinical Trial Registry ( ChiCTR-OOR-14005563 ). Name of registry: Effects of the integrated delivery system and payment system of community-based intervention on rural patients of chronic diseases in Qianjiang District, China Date of registration: Retrospectively registered 23 November 2014. Date of enrolment of the first participant to the trial: 5 July 2012. PMID- 28666444 TI - Development of village doctors in China: financial compensation and health system support. AB - BACKGROUND: Since 1968, China has trained about 1.5 million barefoot doctors in a few years' time to provide basic health services to 0.8 billion rural population. China's Ministry of Health stopped using the term of barefoot doctor in 1985, and changed policy to develop village doctors. Since then, village doctors have kept on playing an irreplaceable role in China's rural health, even though the number of village doctors has fluctuated over the years and they face serious challenges. United Nations declared Sustainable Development Goals in 2015 to achieve universal health coverage by 2030. Under this context, development of Community Health workers (CHWs) has become an emerging policy priority in many resource-poor developing countries. China's experiences and lessons learnt in developing and maintaining village doctors may be useful for these developing countries. METHODS: This paper aims to synthesis lessons learnt from the Chinese CHW experiences. It summarizes China's experiences in exploring and using strategic partnership between the community and the formal health system to develop CHWs in the two stages, the barefoot doctor stage (1968 -1985) and the village doctor stage (1985-now). Chinese and English literature were searched from PubMed, CNKI and Wanfang. The information extracted from the selected articles were synthesized according to the four partnership strategies for communities and health system to support CHW development, namely 1) joint ownership and design of CHW programmes; 2) collaborative supervision and constructive feedback; 3) a balanced package of incentives, both financial and non-financial; and 4) a practical monitoring system incorporating data from the health system and community. RESULTS: The study found that the townships and villages provided an institutional basis for barefoot doctor policy, while the formal health system, including urban hospitals, county health schools, township health centers, and mobile medical teams provided training to the barefoot doctors. But After 1985, the formal health system played a more dominant role in the CHW system including both selection and training of village doctors. China applied various mechanisms to compensate village doctors in different stages. During 1960s and 1970s, the main income source of barefoot doctors was from their villages' collective economy. After 1985 when the rural collective economy collapsed and barefoot doctors were transformed to village doctors, they depended on user fees, especially from drug sale revenues. In the new century, especially after the new round of health system reform in 2009, government subsidy has become an increasing source of village doctors' income. CONCLUSION: The barefoot doctor policy has played a significant role in providing basic human resources for health and basic health services to rural populations when rural area had great shortages of health resources. The key experiences for this great achievement are the intersection between the community and the formal health system, and sustained and stable financial compensation to the community health workers. PMID- 28666445 TI - Challenges for gatekeeping: a qualitative systems analysis of a pilot in rural China. AB - BACKGROUND: Gatekeeping involves a generalist doctor who controls patients' access to specialist care, and has been discussed as an important policy option to rebalance the primary care and hospital sectors in low- and middle-income countries, despite thin evidence. A gatekeeping pilot in a Chinese rural setting launched in 2013 has offered an opportunity to study the functioning of gatekeeping under such conditions. METHODS: In this qualitative study within a mixed-method evaluation of the gatekeeping pilot, we developed an innovative systems analysis method, combining the World Health Organisation categorisation of health system building blocks, the "Framework" approach of policy analysis and causal loop analysis. We conducted in-depth interviews with 20 stakeholders from 4 groups (patients, doctors, health facility managers and government administrators) in the pilot area over two years. Based on information extracted from the interviews, we drew a causal loop diagram which highlighted the feedback loops within the system that had self-reinforcing or self-balancing characteristics, and used the diagram to examine systematically the mechanisms of intended and actual functioning of gatekeeping and analyse the systems level challenges that affected the effectiveness of gatekeeping. RESULTS: Had the gatekeeping pilot programme worked as intended, it would incentivize both providers and patients to increase service utilization at primary care level, as well as establish and enhance two reinforcing feedback loops to shift balance towards primary care. However, a performance-based salary policy undermined the motivation for clinical primary care. Furthermore, the primary care providers suffered from three reinforcing feedback loops (related to primary care capacity, human resource sustainability, patients' faith) that trapped primary care development in vicious cycles. At the interface between hospitals and primary care providers, there were also feedback loops exacerbating the existing hospital dominance. These feedback loops were intensified by the unintended consequences of concurrent policies (restrictions on technologies and medicines) and delayed reform in hospitals. Furthermore, the gatekeeping policy itself faced resistance to further development, due to the prevailing ineffective and ritualistic nature of gatekeeping, which formed a balancing loop. CONCLUSIONS: The study shows that the intended benefits of gatekeeping were illusionary largely due to weak and worsening primary care conditions, and delay, ineffectiveness or unintended consequences of several other ongoing reforms. One particularly dangerous development of the system, which deserves urgent attention, is the harming of the professional prospects of primary care doctors. Our findings highlight the need for coordination and prioritization in designing policies related to primary care and managing changes with multiple on-going reforms. The approach used here facilitates comprehensive study of intended and actual mechanisms, and demonstrates the challenges of a complex health system intervention in a dynamic environment. PMID- 28666446 TI - Estimating the prevalence of 26 health-related indicators at neighbourhood level in the Netherlands using structured additive regression. AB - BACKGROUND: Local policy makers increasingly need information on health-related indicators at smaller geographic levels like districts or neighbourhoods. Although more large data sources have become available, direct estimates of the prevalence of a health-related indicator cannot be produced for neighbourhoods for which only small samples or no samples are available. Small area estimation provides a solution, but unit-level models for binary-valued outcomes that can handle both non-linear effects of the predictors and spatially correlated random effects in a unified framework are rarely encountered. METHODS: We used data on 26 binary-valued health-related indicators collected on 387,195 persons in the Netherlands. We associated the health-related indicators at the individual level with a set of 12 predictors obtained from national registry data. We formulated a structured additive regression model for small area estimation. The model captured potential non-linear relations between the predictors and the outcome through additive terms in a functional form using penalized splines and included a term that accounted for spatially correlated heterogeneity between neighbourhoods. The registry data were used to predict individual outcomes which in turn are aggregated into higher geographical levels, i.e. neighbourhoods. We validated our method by comparing the estimated prevalences with observed prevalences at the individual level and by comparing the estimated prevalences with direct estimates obtained by weighting methods at municipality level. RESULTS: We estimated the prevalence of the 26 health-related indicators for 415 municipalities, 2599 districts and 11,432 neighbourhoods in the Netherlands. We illustrate our method on overweight data and show that there are distinct geographic patterns in the overweight prevalence. Calibration plots show that the estimated prevalences agree very well with observed prevalences at the individual level. The estimated prevalences agree reasonably well with the direct estimates at the municipal level. CONCLUSIONS: Structured additive regression is a useful tool to provide small area estimates in a unified framework. We are able to produce valid nationwide small area estimates of 26 health-related indicators at neighbourhood level in the Netherlands. The results can be used for local policy makers to make appropriate health policy decisions. PMID- 28666448 TI - Catastrophic healthcare expenditure and its inequality for households with hypertension: evidence from the rural areas of Shaanxi Province in China. AB - BACKGROUND: China has been undergoing tremendous demographic and epidemiological transitions during the past three decades and increasing burden from non communicable diseases and an ageing population have presented great health-care challenges for the country. Numerous studies examine catastrophic healthcare expenditures (CHE) worldwide on whole populations rather than specific vulnerable groups. As hypertension and other chronic conditions impose a growing share of the disease burden in China, they will become an increasingly important component of CHE. This study aims to estimate households with hypertension incurring CHE and its income-related inequality in the rural areas of Shaanxi Province. METHODS: Data were obtained from the National Household Health Service Surveys of Shaanxi Province conducted in 2013 and 13104 households were identified for analysis. The households were classified into three types: households with non chronic diseases, households with hypertension only and households with hypertension plus other chronic diseases. CHE was measured according to the proportion of out-of-pocket health payments to non-food household expenditures and the concentration index was employed to measure the extent of income-related inequality in CHE. A decomposition method based on a probit model was used to decompose the concentration index into its determining components. RESULTS: The incurring of CHE of households with hypertension is at a disconcerting level compared to households with non-chronic diseases. Households with hypertension only and households with hypertension plus other chronic diseases incurred CHE in 23.48% and 34.01% of cases respectively whereas households with non-chronic diseases incurred CHE in only 13.33%. The concentration index of households with non-chronic diseases is -0.4871. However, the concentration index of households with hypertension only and households with hypertension plus other chronic diseases is -0.4645 and -0.3410 respectively. The majority of observed inequalities in CHE were explained by household economic status and having elder members. CONCLUSIONS: The proportion of households incurring CHE in the rural areas of Shaanxi Province was considerably high in all three types of households and households with hypertension were at a higher risk of incurring CHE. Furthermore, there existed a strong pro-poor inequality of CHE in all three types of households and the results implied more inequality in households with non chronic diseases compared with two other groups. Our study suggests that more concern needs to be directed toward households with hypertension plus other chronic diseases and households having elder members. PMID- 28666447 TI - How female community health workers navigate work challenges and why there are still gaps in their performance: a look at female community health workers in maternal and child health in two Indian districts through a reciprocal determinism framework. AB - BACKGROUND: Accredited Social Health Activists (ASHAs) are community health workers tasked to deliver health prevention in communities and link them with the health care sector. This paper examines the social, cultural, and institutional influences that either facilitate or impede ASHAs' abilities to deliver services effectively through the lens of the reciprocal determinism framework of social cognitive theory. METHODS: We conducted 98 semi-structured, in-depth interviews with ASHAs (n = 49) and their family members (n = 49) in Gurdaspur and Mewat districts. Data were analyzed by comparing and contrasting codes leading to the identification of patterns which were explained with the help of a theoretical framework. RESULTS: We found that while the work of ASHAs led to some positive health changes in the community, thus providing them with a sense of self-worth and motivation, community norms and beliefs as well as health system attitudes and practices limited their capacity as community health workers. CONCLUSION: We outline potential mechanisms for improving ASHA capacity such as improved sensitization about religious, cultural, and gender norms; enhanced communication skills; and sensitization and advocating their work with health and state officials. PMID- 28666449 TI - Impact of health workforce availability on health care seeking behavior of patients with diabetes mellitus in China. AB - BACKGROUND: China has a high burden of diabetes mellitus (DM), and a large proportion of DM patients remain untreated for various reasons, including low availability of primary health care providers. DM patient management is one of the priorities in China's national essential public health programs. Shortage of health workforce has been a major barrier to improving access to health care for DM patients. This study examines the impact of the health workforce on outpatient utilization of DM patients. METHODS: Data were collected from China National Health Service Surveys in 2008 and 2013, covering 94 rural counties and 156 urban districts, respectively, with a total of 15,984 DM patients. Household data and facility-based data at county/district level were merged. The health workforce was measured by number of physicians per 1,000 population in county hospitals and primary health centers (PHCs), respectively. Health care seeking behavior was measured by health care utilization and distribution of health providers of the DM patients. Multilevel zero-inflated negative binomial regression was used to analyze the impact of the health workforce on outpatient visits by DM patients, and a multilevel, multinomial logit model was used to examine the impact of the health workforce on choice of health providers by DM patients. RESULTS: An increase in the number of physicians at both county hospitals and PHCs was associated with increased outpatient visits by DM patients, particularly more physicians at PHCs. With increased numbers of physicians at PHCs, outpatient visits among residents with DM in rural and western areas of China increased more than those in urban and eastern areas. More physicians at PHCs had a positive impact on improving the likelihood of outpatient visits at PHCs. The positive influence of increasing the number of physicians available to DM patients in rural and western areas was greater than that for urban and eastern DM patients. CONCLUSIONS: The health workforce is a key component of any healthcare system and is critical in improving health care accessibility. Strategies to increase coverage of health workforce at PHCs are crucial to achieving adequate levels of health services for DM patients. Allocation of health workforce should focus on PHCs in rural and low-income areas. PMID- 28666450 TI - Plants as highly diverse sources of construction wood, handicrafts and fibre in the Heihe valley (Qinling Mountains, Shaanxi, China): the importance of minor forest products. AB - BACKGROUND: Chinese rural communities living among species-rich forests have little documentation on species used to make handicrafts and construction materials originating from the surrounding vegetation. Our research aimed at recording minor wood uses in the Heihe valley in the Qinling mountains. METHODS: We carried out 37 semi-structured interviews in seven villages. RESULTS: We documented the use of 84 species of plants. All local large canopy trees are used for some purpose. Smaller trees and shrubs which are particularly hard are selectively cut. The bark of a few species was used to make shoes, hats, steamers and ropes, but this tradition is nearly gone. A few species, mainly bamboo, are used for basket making, and year-old willow branches are used for brushing off the chaff during wheat winnowing. CONCLUSIONS: The traditional use of wood materials documented suggests that some rare and endangered tree species may have been selectively cut due to their valuable wood, e.g. Fraxinus mandshurica and Taxus wallichiana var. chinensis. Some other rare species, e.g. Dipteronia sinensis, are little used and little valued. PMID- 28666451 TI - Autologous chondrocyte implantation-derived synovial fluids display distinct responder and non-responder proteomic profiles. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) can be used in the treatment of focal cartilage injuries to prevent the onset of osteoarthritis (OA). However, we are yet to understand fully why some individuals do not respond well to this intervention. Identification of a reliable and accurate biomarker panel that can predict which patients are likely to respond well to ACI is needed in order to assign the patient to the most appropriate therapy. This study aimed to compare the baseline and mid-treatment proteomic profiles of synovial fluids (SFs) obtained from responders and non-responders to ACI. METHODS: SFs were derived from 14 ACI responders (mean Lysholm improvement of 33 (17-54)) and 13 non-responders (mean Lysholm decrease of 14 (4-46)) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Label-free proteome profiling of dynamically compressed SFs was used to identify predictive markers of ACI success or failure and to investigate the biological pathways involved in the clinical response to ACI. RESULTS: Only 1 protein displayed a >=2.0-fold differential abundance in the preclinical SF of ACI responders versus non responders. However, there is a marked difference between these two groups with regard to their proteome shift in response to cartilage harvest, with 24 and 92 proteins showing >=2.0-fold differential abundance between Stages I and II in responders and non-responders, respectively. Proteomic data has been uploaded to ProteomeXchange (identifier: PXD005220). We have validated two biologically relevant protein changes associated with this response, demonstrating that matrix metalloproteinase 1 was prominently elevated and S100 calcium binding protein A13 was reduced in response to cartilage harvest in non-responders. CONCLUSIONS: The differential proteomic response to cartilage harvest noted in responders versus non-responders is completely novel. Our analyses suggest several pathways which appear to be altered in non-responders that are worthy of further investigation to elucidate the mechanisms of ACI failure. These protein changes highlight many putative biomarkers that may have potential for prediction of ACI treatment success. PMID- 28666453 TI - Beginning of a journey: unraveling the mystery of chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka. AB - BACKGROUND: Globally, chronic kidney disease of unknown aetiology (CKDu) is observed in several areas and among specific ethnic or occupational groups. Given the widespread environmental pollution and the proportions of agriculture workers world-wide, CKDu may be the next global public health issue demanding attention. Recent escalation of CKDu in Sri Lanka has caused a serious public health crisis in the country, made worse by lack of national data. MAIN TEXT: The specific geographic distribution, preponderance among farming population, similar histology findings and absence of usual risk factors for kidney disease indicate undetected nephrotoxic agents playing a role in causation. Some of the challenges for the country are uncoordinated preventive efforts, diverse opinions among stakeholders on causality and fragmented research efforts with limited focus on potential causes of CKDu. As a result, accurate estimation of the CKDu burden, identification of causative agents and implementation of effective actions have been delayed. Stakeholder engagement, with involvement of international experts has been the starting point for finalizing a working case definition to establish community based surveillance as a future platform to conduct long-term research. CONCLUSION: The country is now poised to contribute to global knowledge by solving the mystery of 'u' in CKDu. This commentary highlights the importance and the mechanisms of making an effective breakthrough as early as possible; failing which CKDu can progress rapidly as demonstrated by the situation in Sri Lanka. PMID- 28666452 TI - Identifying optimal threshold statistics for elimination of hookworm using a stochastic simulation model. AB - BACKGROUND: There is an increased focus on whether mass drug administration (MDA) programmes alone can interrupt the transmission of soil-transmitted helminths (STH). Mathematical models can be used to model these interventions and are increasingly being implemented to inform investigators about expected trial outcome and the choice of optimum study design. One key factor is the choice of threshold for detecting elimination. However, there are currently no thresholds defined for STH regarding breaking transmission. METHODS: We develop a simulation of an elimination study, based on the DeWorm3 project, using an individual-based stochastic disease transmission model in conjunction with models of MDA, sampling, diagnostics and the construction of study clusters. The simulation is then used to analyse the relationship between the study end-point elimination threshold and whether elimination is achieved in the long term within the model. We analyse the quality of a range of statistics in terms of the positive predictive values (PPV) and how they depend on a range of covariates, including threshold values, baseline prevalence, measurement time point and how clusters are constructed. RESULTS: End-point infection prevalence performs well in discriminating between villages that achieve interruption of transmission and those that do not, although the quality of the threshold is sensitive to baseline prevalence and threshold value. Optimal post-treatment prevalence threshold value for determining elimination is in the range 2% or less when the baseline prevalence range is broad. For multiple clusters of communities, both the probability of elimination and the ability of thresholds to detect it are strongly dependent on the size of the cluster and the size distribution of the constituent communities. Number of communities in a cluster is a key indicator of probability of elimination and PPV. Extending the time, post-study endpoint, at which the threshold statistic is measured improves PPV value in discriminating between eliminating clusters and those that bounce back. CONCLUSIONS: The probability of elimination and PPV are very sensitive to baseline prevalence for individual communities. However, most studies and programmes are constructed on the basis of clusters. Since elimination occurs within smaller population sub units, the construction of clusters introduces new sensitivities for elimination threshold values to cluster size and the underlying population structure. Study simulation offers an opportunity to investigate key sources of sensitivity for elimination studies and programme designs in advance and to tailor interventions to prevailing local or national conditions. PMID- 28666454 TI - Fluorescence optical imaging and musculoskeletal ultrasonography in juvenile idiopathic polyarticular disease before and during antirheumatic treatment - a multicenter non-interventional diagnostic evaluation. AB - BACKGROUND: Valid detection of inflamed joints is essential for correct classification, therapeutic decisions, prognosis and assessment of treatment efficacy in juvenile idiopathic arthritis (JIA). Fluorescence optical imaging (FOI) enables visualization of inflammation in arthritis of finger and hand joints and might be used for monitoring. METHODS: A 24-week observational study in polyarticular JIA patients newly starting treatment with methotrexate or an approved biologic was performed in three centers. Patients were evaluated clinically, by gray-scale ultrasonography (GSUS), power-Doppler ultrasonography (PDUS) and FOI at baseline, week 12 and week 24. RESULTS: Of 37 patients enrolled, 24 patients started methotrexate and 13 patients a biologic for the first time (etanercept n = 11, adalimumab and tocilizumab n = 1 each). Mean JADAS 10 decreased significantly from 17.7 at baseline to 12.2 and 7.2 at week 12 and 24 respectively. PedACR 30/50/70/100 response rates at week 24 were 85%/73%/50%/27%. The total number of clinically active joints in hand and fingers at baseline/week 12/week 24 was 262 (23.6%)/162 (16.4%)/162 (9.0%). By GSUS, at baseline/week 12/week 24, 192 (19.4%)/135 (16.1%)/83 (11.5%) joints showed effusions and 186 (18.8%)/107 (12.7%)/69 (9.6%) showed synovial thickening, and by PDUS 68 (6.9%)/15 (1.8%)/36 (5%) joints showed hyperperfusion. Any sign of arthritis was detected by US in a total of 243 joints (24.5%) at baseline, 161 joints (19.2%) at week 12 and 123 joints (17%) at week 24. By FOI at baseline/week 12/week 24, 430 (38.7%)/280 (29.2%)/215 (27.6%) showed a signal enhancement in at least one phase. Summarizing all three points of time, the highest numbers of signals were detected by FOI with 32% of joints, especially in phase 2, while by US 20.7% and by clinical examination 17.5% of joints were active. A high number of joints (21.1%) had FOI signals but were inactive by clinical examination. A total 20.1% of joints with signals in FOI did not show effusion, synovial thickening or hyperperfusion by US. Because of the high number of negative results, specificity of FOI compared with clinical examination/US/PD was high (84-95%), and sensitivity was only moderate. CONCLUSION: FOI and US could detect clinical but also subclinical inflammation. FOI detected subclinical inflammation to a higher extent than US. Improvement upon treatment with either methotrexate or a biologic can be visualized by FOI and US. TRIAL REGISTRATION: Deutsches Register Klinischer Studien DRKS00011579 . Registered 10 January 2017. PMID- 28666455 TI - Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. AB - BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling, and life-shortening genetic disorder that causes the formation of heterotopic bone within soft connective tissue. Previous studies found that the FOP prevalence was about one in every two million lives. The aim of this study is to estimate the FOP prevalence in France by probabilistic record-linkage of 2 national databases: 1) the PMSI (Programme de medicalisation des systemes d'information), an administrative database that records all hospitalization activities in France and 2) CEMARA, a registry database developed by the French Centres of Reference for Rare Diseases. RESULTS: Using a capture-recapture methodology to adjust the crude number of patients identified in both data sources, 89 FOP patients were identified, which results in a prevalence of 1.36 per million inhabitants (CI95% = [1.10; 1.68]). FOP patients' mean age was 25 years, only 14.9% were above 40 years, and 53% of them were males. The first symptoms - beside toe malformations- occurred after birth for 97.3% of them. Mean age at identified symptoms was 7 years and above 18 years for only 6.9% of patients. Mean age at diagnosis was 10 years, and above 18 years for 14.9% of the patients. FOP patients were distributed across France. CONCLUSIONS: Despite the challenge of ascertaining patients with rare diseases, we report a much higher prevalence of FOP in France than in previous studies elsewhere. We suggest that efforts to identify patients and confirm the diagnosis of FOP should be reinforced and extended at both national and European level. PMID- 28666456 TI - Effect of cholecystectomy on hepatic fat accumulation and insulin resistance in non-obese Hispanic patients: a pilot study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. Experimental studies have shown that cholecystectomy (XGB) increases hepatic fat content in mice and appears associated to NAFLD in large retrospective population-based studies. The aim of this study was to prospectively assess the effects of XGB on hepatic fat content (HFC) and insulin resistance (IR) in non-obese, middle aged Hispanic subjects. METHODS: Twenty-six gallstone patients undergoing elective XGB and 16 control subjects with normal livers and gallbladders at ultrasonography were prospectively followed 24 months for changes in HFC and IR. Clinical, biochemical determinations and hepatic imaging were performed at baseline and 24 months after surgery. MRI technique quantified HFC in four hepatic segments. IR was assessed by the Homeostasis Model Assessment (HOMA-IR) index. RESULTS: Initial body mass index (BMI) was 25.6 +/- 0.4 and 24.3 +/- 1.0 in the control and XGB groups of subjects, respectively. Serum insulin level increased from 8.1 +/- 0.7 to 10.0 +/- 1.9 (MUU/ml) 24 months after surgery in XGB patients (p < 0.05); no significant changes were detected in control individuals. Median HOMA-IR index increased from 1.31 (interquartile range, 1.01-1.68) to 2.20 (interquartile range, 1.57 - 2.60) 24 months after XGB, (p < 0.003). Median HOMA-IR index of control subjects remained unchanged at the end of the study. Serum apoB concentration increased from 61.5 +/- 3.4 to 79.0 +/ 7.8 (MUg/ml) in XGB patients (p < 0.03). Serum apoB levels remained within normal ranges in both periods of the study in control subjects. HFC significantly increased in 2 of the 4 segments 24 months after XGB: right posterior hepatic lobe (from 5.3 +/- 0.2% to 6.0 +/- 0.2%, p > 0.04) and right anterior hepatic lobe (from 5.8 +/- 0.2% to 6.6 +/- 0.3%, p < 0.02). The average HFC of the four hepatic segments studied slightly increased from 5.4 +/- 0.2 to 5.8 +/- 0.3 2 years after XGB (p < 0.03). No significant changes were found in HFC in the control subjects at the end of the study. CONCLUSIONS: Elective XGB increases HFC, HOMA-IR index and serum apoB concentration. These results support the notion that XGB is a risk factor non-alcoholic fatty liver disease and other IR - associated disease conditions. PMID- 28666457 TI - Neoadjuvant radiotherapy of early-stage breast cancer and long-term disease-free survival. AB - BACKGROUND: Compared with surgery alone, postoperative adjuvant radiotherapy (RT) improves relapse-free survival of patients with early-stage breast cancer. We evaluated the long-term overall and disease-free survival rates of neoadjuvant (presurgical) versus adjuvant RT in early-stage breast cancer patients. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database provided by the National Institutes of Health to derive an analytic dataset of 250,195 female patients with early-stage breast cancer who received RT before (n = 2554; 1.02%) or after (n = 247,641; 98.98%) surgery. Disease-free survival, defined as time to diagnosis of a second primary tumor at any location, was calculated from automated patient identification matching of all SEER records. RESULTS: Partial and complete mastectomies were performed in 94.4% and 5.6% of patients, respectively. In the largest cohort of estrogen receptor-positive women who underwent partial mastectomy, the HR of developing a second primary tumor after neoadjuvant compared with adjuvant RT was 0.64 (95% CI 0.55-0.75; P < 0.0001). Overall survival was independent of radiation sequence (HR 1; P = 0.95). Neoadjuvant RT also resulted in a lower HR for second primary cancer among estrogen receptor-positive patients who underwent mastectomy compared with those who received adjuvant RT (HR 0.48, 95% CI 0.26-0.87; P = 0.0162). CONCLUSIONS: Neoadjuvant RT may significantly improve disease-free survival without reducing overall survival, especially for estrogen receptor-positive patients with early stage breast cancer. This finding warrants further exploration of potential long term benefits of neoadjuvant radiotherapy for early-stage breast cancer in a controlled, prospective clinical trial setting, with correlative studies done to identify potential mechanisms of superiority. PMID- 28666458 TI - Risk score to predict false-positive ST-segment elevation myocardial infarction in the emergency department: a retrospective analysis. AB - BACKGROUND: The best treatment approach for ST-segment elevation myocardial infarction (STEMI) is prompt primary percutaneous coronary intervention (PCI). However, some patients show ST elevation on electrocardiography (ECG), but do not have myocardial infarction. We sought to identify the frequency of and to develop a prediction model for false-positive STEMI. METHODS: This study was conducted in the emergency departments (EDs) of two hospitals using the same critical pathway (CP) protocol to treat STEMI patients with primary PCI. The prediction model was developed in a derivation cohort and validated in internal and external validation cohorts. RESULTS: Of the CP-activated patients, those for whom ST elevation did not meet the ECG criteria were excluded. Among the patients with appropriate ECG patterns, the incidence of false-positive STEMI in the entire cohort was 16.3%. Independent predictors extracted from the derivation cohort for false-positive STEMI were age < 65 years (odds ratio [OR], 2.54; 95% confidence interval [CI], 1.35-4.89), no chest pain (OR, 12.04; 95% CI, 5.92-25.63), atypical chest pain (OR, 7.40; 95% CI, 3.27-17.14), no reciprocal change (OR, 4.80; 95% CI, 2.54-9.51), and concave-morphology ST elevation (OR, 14.54; 95% CI, 6.87-34.37). Based on the regression coefficients, we established a simplified risk score. In the internal and external validation cohorts, the areas under the receiver operating characteristic curves for our risk score were 0.839 (95% CI, 0.724-0.954) and 0.820 (95% CI, 0.727-0.913), respectively; the positive predictive values were 40.9% and 22.0%, respectively; and the negative predictive values were 94.9% and 96.7%, respectively. DISCUSSION: Our prediction model would help them make rapid decisions with better rationale. CONCLUSION: We devised a model to predict false-positive STEMI. Larger-scale validation studies are needed to validate our model, and a prospective study to determine whether this model is effective in reducing improper primary PCI in actual clinical practice should be performed. PMID- 28666459 TI - Towards a better understanding of preimplantation genetic screening for aneuploidy: insights from a virtual trial for women under the age of 40 when transferring embryos one at a time. AB - BACKGROUND: The aim of this theoretical study is to explore the cost effectiveness of aneuploidy screening in a UK setting for every woman aged under the age of 40 years when fresh and vitrified-warmed embryos are transferred one at a time in a first full cycle of assisted conception. METHODS: It is envisaged that a 24-chromosome genetic test for aneuploidy could be used to exclude embryos with an abnormal test result from transfer, or used only to rank embryos with the highest potential to be viable; the effect on cumulative outcome is assessed. The cost associated with one additional live birth event and one clinical miscarriage avoided is estimated, and the time taken to complete a cycle considered. The numbers of individual woman for whom testing is likely to be beneficial or detrimental is also evaluated. RESULTS: Adding aneuploidy screening to a first treatment cycle is unlikely to result in a higher chance of a live birth event, and can be detrimental for some women. Premature termination of a clinical trial is likely to be biased in favour of genetic testing. Testing is likely to be an expensive way of reducing the chance of clinical miscarriage and shortening treatment time without a substantial reduction in the cost of testing, and is likely to benefit a minority of women. Selecting out embryos is likely to reduce the treatment time for women whether or not they have a baby, whilst ranking embryos only to reduce the time for those that have a child and not for those who need another stimulated cycle. CONCLUSIONS: Adding aneuploidy screening to IVF treatment for women under the age of 40 years is unlikely to be beneficial for most women. To achieve an unbiased assessment of the cost-effectiveness of genetic testing for aneuploidy, clinical trials need to take account of women who still have embryos available for transfer at the end of the study period. Specifying the proportions of women for whom testing is likely to be beneficial and detrimental may help better inform couples who might be considering adding aneuploidy screening to their treatment cycle. PMID- 28666460 TI - Measuring inequalities in the distribution of the Fiji Health Workforce. AB - BACKGROUND: Despite the centrality of health personnel to the health of the population, the planning, production and management of human resources for health remains underdeveloped in many low- and middle-income countries (LMICs). In addition to the general shortage of health workers, there are significant inequalities in the distribution of health workers within LMICs. This is especially true for countries like Fiji, which face major challenges in distributing its health workforce across many inhabited islands. METHODS: In this study, we describe and measure health worker distributional inequalities in Fiji, using data from the 2007 Population Census, and Ministry of Health records of crude death rates and health workforce personnel. We adopt methods from the economics literature including the Lorenz Curve/Gini Coefficient and Theil Index to measure the extent and drivers of inequality in the distribution of health workers at the sub-national level in Fiji for three categories of health workers: doctors, nurses, and all health workers (doctors, nurses, dentists and health support staff). Population size and crude death rates are used as proxies for health care needs. RESULTS: There are greater inequalities in the densities of health workers at the provincial level, compared to the divisional level in Fiji six of the 15 provinces fall short of the recommended threshold of 2.3 health workers per 1,000 people. The estimated decile ratios, Gini co-efficient and Thiel index point to inequalities at the provincial level in Fiji, mainly with respect to the distribution of doctors; however these inequalities are relatively small. CONCLUSION: While populations with lower mortality tend to have a slightly greater share of health workers, the overall distribution of health workers on the basis of need is more equitable in Fiji than for many other LMICs. The overall shortage of health workers could be addressed by creating new cadres of health workers; employing increasing numbers of foreign doctors, including specialists; and increasing funding for health worker training, as already demonstrated by the Fiji government. Close monitoring of the equitable distribution of additional health workers in the future is critical. PMID- 28666461 TI - Glyceollins trigger anti-proliferative effects through estradiol-dependent and independent pathways in breast cancer cells. AB - BACKGROUND: Estrogen receptors (ER) alpha and beta are found in both women and men in many tissues, where they have different functions, including having roles in cell proliferation and differentiation of the reproductive tract. In addition to estradiol (E2), a natural hormone, numerous compounds are able to bind ERs and modulate their activities. Among these compounds, phytoestrogens such as isoflavones, which are found in plants, are promising therapeutics for several pathologies. Glyceollins are second metabolites of isoflavones that are mainly produced in soybean in response to an elicitor. They have potentially therapeutic actions in breast cancer by reducing the proliferation of cancer cells. However, the molecular mechanisms driving these effects remain elusive. METHODS: First, to determine the proliferative or anti-proliferative effects of glyceollins, in vivo and in vitro approaches were used. The length of epithelial duct in mammary gland as well as uterotrophy after treatment by E2 and glyceollins and their effect on proliferation of different breast cell line were assessed. Secondly, the ability of glyceollin to activate ER was assessed by luciferase assay. Finally, to unravel molecular mechanisms involved by glyceollins, transcriptomic analysis was performed on MCF-7 breast cancer cells. RESULTS: In this study, we show that synthetic versions of glyceollin I and II exert anti-proliferative effects in vivo in mouse mammary glands and in vitro in different ER-positive and ER negative breast cell lines. Using transcriptomic analysis, we produce for the first time an integrated view of gene regulation in response to glyceollins and reveal that these phytochemicals act through at least two major pathways. One pathway involving FOXM1 and ERalpha is directly linked to proliferation. The other involves the HIF family and reveals that stress is a potential factor in the anti-proliferative effects of glyceollins due to its role in increasing the expression of REDD1, an mTORC1 inhibitor. CONCLUSION: Overall, our study clearly shows that glyceollins exert anti-proliferative effects by reducing the expression of genes encoding cell cycle and mitosis-associated factors and biomarkers overexpressed in cancers and by increasing the expression of growth arrest-related genes. These results reinforce the therapeutic potential of glyceollins for breast cancer. PMID- 28666462 TI - Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis. AB - BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear. METHODS: Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2 dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays. RESULTS: We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)alpha did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility. CONCLUSION: These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2. PMID- 28666463 TI - Depressed patients treated by homeopaths: a randomised controlled trial using the "cohort multiple randomised controlled trial" (cmRCT) design. AB - BACKGROUND: Despite controversy regarding homeopathy, some patients consult homeopaths for depression. Evidence is required to determine whether this is an effective, acceptable and safe intervention for these patients. METHODS: A pragmatic trial using the "cohort multiple randomised controlled trial" design was used to test the effectiveness of adjunctive treatment by homeopaths compared to usual care alone, over a period of 12 months in patients with self-reported depression. One third of patients were randomly selected for an offer of treatment provided by a homeopath. The primary outcome measure was the Patient Health Questionnaire (PHQ-9) at 6 months. Secondary outcomes included depression scores at 12 months; and the Generalised Anxiety Disorder (GAD-7) outcome at 6 and 12 months. RESULTS: The trial over-recruited by 17% with a total of 566 patients. Forty percent took up the offer and received treatment. An intention-to treat analysis of the offer group at 6 months reported a 1.4-point lower mean depression score than the no offer group (95% CI 0.2, 2.5, p = 0.019), with a small standardized treatment effect size (d = 0.30). Using instrumental variables analysis, a moderate treatment effect size in favour of those treated was found (d = 0.57) with a between group difference of 2.6 points (95% CI 0.5, 4.7, p = 0.018). Results were maintained at 12 months. Secondary analyses showed similar results. Similar results were found for anxiety (GAD-7). No evidence suggested any important risk involved with the intervention. CONCLUSION: This trial provides preliminary support for both the acceptability and the effectiveness of treatment by a homeopath for patients with self-reported depression. Our results provide support for further pragmatic research to provide more precise estimates of treatment effect. TRIAL REGISTRATION: ISRCTN registry, ISRCTN02484593 . Registered on 7 January 2013. PMID- 28666464 TI - Animal models of rheumatoid pain: experimental systems and insights. AB - Severe chronic pain is one of the hallmarks and most debilitating manifestations of inflammatory arthritis. It represents a significant problem in the clinical management of patients with common chronic inflammatory joint conditions such as rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies. The functional links between peripheral inflammatory signals and the establishment of the neuroadaptive mechanisms acting in nociceptors and in the central nervous system in the establishment of chronic and neuropathic pain are still poorly understood, representing an area of intense study and translational priority. Several well-established inducible and spontaneous animal models are available to study the onset, progression and chronicization of inflammatory joint disease, and have been instrumental in elucidating its immunopathogenesis. However, quantitative assessment of pain in animal models is technically and conceptually challenging, and it is only in recent years that inflammatory arthritis models have begun to be utilized systematically in experimental pain studies using behavioral and neurophysiological approaches to characterize acute and chronic pain stages. This article aims primarily to provide clinical and experimental rheumatologists with an overview of current animal models of arthritis pain, and to summarize emerging findings, challenges and unanswered questions in the field. PMID- 28666465 TI - The association between physical activity and health-related quality of life among breast cancer survivors. AB - BACKGROUND: The quality of life for breast cancer survivors has become increasingly important because of their high survival rate and prolonged life expectancy. The purpose of this study was to examine the association of physical activity following diagnosis and health-related quality of life (HRQOL) in breast cancer survivors. METHODS: We conducted a cross-sectional study of breast cancer survivors. A total of 231 women aged 21-78 years who had been diagnosed with stages I to III breast cancer and had breast cancer surgery at least 6 months prior were recruited from three hospitals between September 2012 and April 2015 and were included in this study. We asked participants about their HRQOL and engagement in physical activity using structured questionnaires. We examined the association between HRQOL levels and physical activity using a generalized linear model. RESULTS: Breast cancer survivors in the high physical activity group (3rd tertile) were more likely to have lower scores for fatigue (p for trend = 0.001) and pain (p for trend = 0.02) and higher scores for sexual function (p for trend = 0.007) than those in the low physical activity group (1st tertile). When we stratified participants by stage, we found increasing scores for physical functioning (p for trend =0.01) and decreasing scores for fatigue (p for trend = 0.02) with increasing levels of physical activity in breast cancer survivors with stage I breast cancer. In survivors with stages II and III, we found statistically significant associations with fatigue (p for trend = 0.02) and sexual functioning (p for trend = 0.001). CONCLUSIONS: In conclusion, engagement in physical activity was related to better health-related quality of life among breast cancer survivors. Our findings may warrant further prospective and intervention studies to support the benefit of physical activity in improving the quality of life and survival of Korean breast cancer survivors. PMID- 28666466 TI - Beneficial effect of resveratrol on phenotypic features and activity of osteoarthritic osteoblasts. AB - BACKGROUND: Osteoarthritis (OA) is a complex disease, which affects multiple tissues, namely the subchondral bone, articular cartilage and synovial membrane. Alterations of the subchondral bone include an increased, yet under mineralized osteoid matrix, abnormal osteoblast cell phenotype including elevated alkaline phosphatase (ALP) activity, increased release of osteocalcin (OC) and transforming growth factor beta-1 (TGF-beta1). Previous studies have demonstrated an inhibition of the canonical Wnt signaling (cWnt) pathway in OA osteoblasts (Ob). As resveratrol (RSV) has been shown to upregulate the Wnt signaling pathway in different cell systems, we hypothesized that RSV could be beneficial for OA Ob. METHOD: We prepared primary human Ob using the subchondral bone plate of tibial plateaus of OA patients undergoing total knee arthroplasty, or tibial plateaus of normal individuals at autopsy. Sirtuin 1 (Sirt1) expression in normal and OA subchondral bone tissue was evaluated by immunohistochemical analysis. Expression of genes was evaluated by qRT-PCR and protein production by western blot analysis. ALP activity and osteocalcin secretion were evaluated respectively with substrate hydrolysis and enzyme immunoassay. Mineralization levels were evaluated with alizarin red staining. Wnt/beta-catenin signaling was evaluated by target gene expression using the TOPflash TCF/lef luciferase reporter assay and intracellular signaling using beta-catenin levels in western blot analysis. Extracellular signal-regulated kinase (Erk)1/2 and the Smad1/5/8 pathways were evaluated by western blot analysis. RESULTS: Sirt1 expression and production were reduced in OA subchondral bone tissue compared to normal tissue. RSV upregulated Sirt1 and its activity, and reduced the expression of leptin. RSV increased Erk1/2 phosphorylation in OA Ob; however, it had no effect on Smad 1/5/8 phosphorylation. RSV had little effect on cell proliferation and only slightly affected the Bax/Bcl2 ratio. The expression of Runx2/Cbfa1 and peroxisome proliferator-activated receptor (PPAR)gamma were not affected by increasing doses of RSV. The endogenous increased ALP activity and OC release observed in OA Ob compared to normal Ob were partly corrected only for ALP at high RSV levels but not for OC release. In contrast, RSV increased the mineralization of OA Ob. Moreover, whereas Wnt3a stimulates the Wnt/beta-catenin pathway in these cells, RSV further increased the response to Wnt3a. CONCLUSION: These data indicate that RSV promotes Sirt1 levels, inhibits the endogenous expression of leptin by OA osteoblasts and can promote the Wnt/beta-catenin and Erk1/2 signaling pathways, which are altered in these cells. PMID- 28666467 TI - The metabolic footprint of the airway bacterial community in cystic fibrosis. AB - BACKGROUND: Progressive, chronic bacterial infection of the airways is a leading cause of death in cystic fibrosis (CF). Culture-independent methods based on sequencing of the bacterial 16S rRNA gene describe a distinct microbial community that decreases in richness and diversity with disease progression. Understanding the functional characteristics of the microbial community may aid in identifying potential therapies and may assist in management, but current methods are cumbersome. Here, we demonstrate the use of an oxidative metabolic assay as a complement to sequencing methods to describe the microbiome in the airways of patients with CF. METHODS: Expectorated sputum was collected from 16 CF subjects and 8 control subjects. The Biolog Gen III Microplate was used in a community level physiological profiling (CLPP)-based assay to examine oxidative metabolic activity. 16S rRNA V4 amplicon sequencing was used to characterize the taxonomy and diversity of the samples. Correlations were then identified among the oxidative activity and taxonomy data. In an additional paired analysis, sputum from seven CF subjects were collected at two separate clinic visits and compared for oxidative activity, taxonomy, and diversity. RESULTS: Significant differences in oxidative metabolic activity, microbial taxonomy, and diversity were found between the CF and control sputum samples. Oxidative activity correlated positively with total genera but not with other measures of diversity or taxonomy, demonstrating that the metabolic assay complements the structural aspects of the microbiome. As expected, Pseudomonas was significantly enriched in CF samples, while Streptococcus and Prevotella were similarly abundant in both CF and control samples. Paired analysis of CF samples at separate clinic visits revealed comparable oxidative activity that correlated with similar stability in taxonomy and diversity. CONCLUSIONS: The CLPP assay used in this study complements existing sequencing methods to delineate the oxidative metabolic footprint of the CF airway bacterial community. This method may be useful to study the CF microbial community over time and with changes in disease state. PMID- 28666468 TI - Binge drinking among young adults in an urban tertiary care emergency department in Israel. AB - BACKGROUND: Alcohol use is a major preventable public health problem with serious health and social consequences especially among youth. In Israel, alcohol use has become an emerging problem during the last decade, and its use has increased among adolescents and young adults. Binge drinking is the common pattern of alcohol consumption among young adults who drink for recreational purposes. The present survey was conducted among 16-35 years old visitors to the ED. The aim was specifically to identify binge drinkers in order to assess the scope of the need for a brief counseling intervention among young people who arrive intoxicated to a large tertiary care urban ED in Israel. METHODS: The survey was conducted throughout a 1 week period (24 h per day) at the general EDs in a large, tertiary care center, situated in Tel Aviv. During the survey week, 946 individuals, aged 16-35, visited the ED and 573 (63%) of them were approached for an interview. 89% of those approached agreed to be interviewed. Consenting patients [N = 348] were asked whether they drink any alcohol, how often they drink and how much. RESULTS: About one fifth of those interviewed were in the habit of consuming more than four units of alcohol per occasion. Drinking several times a week or every day was reported by 19% of the males and 26% of the females. Frequency of the drinking episodes was highly correlated with the number of units of drink per occasion. CONCLUSIONS: The study found a very high rate of binge drinking among ED visitors, and this suggests a need for large scale ED based interventions. As binge drinkers are at elevated risk for accidents, violence and related problems, effective ED-based interventions could make an important contribution to public health. Accordingly, Israel is in the process of assessing the effectiveness of a large-scale ED-based counseling intervention. TRIAL REGISTRATION: Trial registration number 0230-13-TLV. PMID- 28666469 TI - On the implications of desexualizing vaccines against sexually transmitted diseases: health policy challenges in a multicultural society. AB - Two vaccines against sexually transmitted infections are included in many national vaccination programs: Hepatitis B Virus (HBV) vaccine and Human Papilloma Virus (HPV) vaccine. The trajectories of the implementation of these two programs were marked by differences in the way the sexual context of risk was communicated to the public. These trajectories fluctuated between full accounts of the sexual nature of the infection and attempts to desexualize the vaccines. Vaccine desexualization can be achieved by withholding information of sexual context, blurring information, and distancing the age of vaccination from the age of sexual debut. Desexualization may be advantageous in promoting public health and personal health of people who believe that HPV vaccination leads to increased promiscuity, people who believe that protection against STD is not relevant to their children, and people who are not comfortable discussing the sexuality of their children. On the other hand, desexualizing may be disadvantageous for children to parents who tend to express passiveness towards vaccination, parents who attribute importance to sex education, and teenagers with homosexual orientations. The ethical analysis of vaccine desexualization reveals a complex interplay of considerations related to utility, causation of harm, duty of transparency, right to know, and right not to know. This analysis suggests that the moral merits of applying desexualization are questionable. Lastly, a sociopolitical consideration of the matter, suggests that decisions on vaccine desexualization can have implications on the interrelationships between various social groups and subgroups composing a certain population, and may highlight intercultural schisms. All this indicates that shaping the sexual framework of vaccination programs bears implications far beyond the practical considerations of vaccine promotion. PMID- 28666470 TI - The effects of chronic and acute physical activity on working memory performance in healthy participants: a systematic review with meta-analysis of randomized controlled trials. AB - BACKGROUND: Understanding how physical activity (PA) influences cognitive function in populations with cognitive impairments, such as dementia, is an increasingly studied topic yielding numerous published systematic reviews. In contrast, however, there appears to be less interest in examining associations between PA and cognition in cognitively healthy individuals. Therefore, the objective of this review was to evaluate and synthesize randomized controlled trial (RCT) studies that investigated the effects of both chronic and acute PA on working memory performance (WMP) in physically and cognitively healthy individuals. METHODS: Following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, a systematic review of studies published between August 2009 and December 2016 was performed on RCTs investigating the effects of chronic and acute PA on WMP with healthy participants as the sample populations. Searches were conducted in Annual Reviews, ProQuest, PsycARTICLES, PsycINFO, PubMed, and Web of Science. Main inclusion criteria stipulated (1) healthy sample populations, (2) PA interventions, (3) WMP as an outcome, and (4) RCT designs. Descriptive statistics included cohort and intervention characteristics and a risk of bias assessment. Analytical statistics included meta-analyses and moderation analyses. RESULTS: From 7345 non-duplicates, 15 studies (eight chronic PA and seven acute PA studies) met the inclusion criteria and were evaluated. Overall, there was noticeable variance between both cohort and intervention characteristics. Sample populations ranged from primary school children to retirement community members with PA ranging from cycling to yoga. The majority of studies were characterized by "low" or "unclear" risk of selection, performance, detection, attrition, reporting, or other biases. Meta-analysis of chronic PA revealed a significant, small effect size while analysis of acute PA revealed a non-significant, trivial result. Age and intensity were significant moderators while allocation concealment, blinding, and intervention length were not. CONCLUSIONS: Chronic PA can significantly improve WMP while acute PA cannot. The limiting factors for acute PA studies point to the diversity of working memory instruments utilized, unequal sample sizes between studies, and the sample age groups. Large-scale, high-quality RCTs are needed in order to provide generalizable and more powerful analysis between PA and WMP in a systematic approach. PMID- 28666472 TI - Policy entrepreneurship in the reform of pediatric dentistry. AB - In a recently published IJHPR article, Cohen and Horev ask whether an individual who holds rightful governmental power is able to effectively "challenge the equilibrium" in ways that might "clash with the goals" of an influential group". This question is raised within the context of a shift in governmental policy that imposed the potential for cost management by HMOs acting as financial intermediaries for pediatric dental care in an effort to provide Israeli children better access to affordable dental care. The influential group referred to consists of Israel's private dentists and the individual seeking to challenge the equilibrium was an Israeli Minister of Health whom the authors consider to be a policy entrepreneur.The Israeli health care system is similar to that of the United States in that private benefit plans and self-pay financing dominate in dental care. This is in contrast to the substantial role of government in the financing and regulation of medical care in both countries (with Israel having universal coverage financed by government and the US having government financing the care of the elderly and the poor as well as providing subsidies through the tax system for the care of most other Americans).Efforts to expand governmental involvement in dental care in both countries have either been opposed by organized dentistry or have suffered from ineffective advocacy for increased public investment in dental care.In the U.S., philanthropic foundations have acted as or have supported health policy entrepreneurs. The recent movement to introduce the dental therapist, a type of allied dental professional trained to provide a narrow set of commonly-needed procedures, to the U.S. is discussed as an example of a successful challenge to the equilibrium by groups supported by these foundations. This is a somewhat different, and complementary, model of policy entrepreneurship from the individual policy entrepreneur highlighted in the Cohen-Horev paper.The political traction gained to change the equilibrium favored by organized dentistry - in both Israel and the U.S. - may reflect aspirations for care that is more accessible, patient-centered, accountable and equitable. Evolving aspirations may lead to policy changes to systematize the disparate, disaggregated dental care delivery system in both counties. A change in payment incentives to provide more value is being explored for medical care, and its expansion to dental care can be anticipated to be among the policies considered in the future. PMID- 28666471 TI - Heterogeneous ribonuclear protein E2 (hnRNP E2) is associated with TDP-43 immunoreactive neurites in Semantic Dementia but not with other TDP-43 pathological subtypes of Frontotemporal Lobar Degeneration. AB - Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP 43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD. PMID- 28666473 TI - Imaging characteristics of cardiac metastases in patients with malignant melanoma. AB - BACKGROUND: Due to prolonged survival and technical advances in CT imaging, cardiac metastases in patients with malignant melanoma are observed more frequently nowadays. The aim of the present study was to assess the anatomic distribution as well as the morphologic and histologic appearance of cardiac metastases from malignant melanoma. METHODS: Twenty five patients with known metastasized melanoma and with incidental finding of cardiac metastases during routine staging CT were retrospectively included in this study. CT images were assessed for the presence, localization and extent of cardiac metastases. Histological results, mutational analysis and tumor markers were reviewed. RESULTS: Fourteen out of 25 patients presented with singular cardiac mass (56%), whereas ten patients (40%) presented with multifocal and one patient with disseminated cardiac metastases. Twelve patients presented with endocardial (48%), eight with myocardial and two with pericardial metastases. Most frequent site involved in endocardial metastases was the right atrium (67%) followed by the right ventricle (33%). There seems to be a correlation between histological subtype and location of cardiac metastasis. Median survival after diagnosis of cardiac metastases was 8 months, with no significant difference regarding the localization of metastases within the heart. CONCLUSION: Cardiac metastases can involve every part of the heart possibly in dependence of histological subtype. The awareness of different types of cardiac metastases and their characteristic appearance on CT images is necessary for further investigations and might contribute to targeted therapy. PMID- 28666474 TI - Polyethyleneimine-treated polyacrylonitrile membrane hemofilter for critically ill patients receiving anticoagulant-free prolonged intermittent renal replacement therapy: a single-center, prospective, self-controlled pilot study. AB - BACKGROUND: Critically ill patients requiring renal replacement therapy (RRT) are at risk of disease-related bleeding. Systemic heparinization should be avoided. AN69ST, a polyethyleneimine-treated polyacrylonitrile (AN69) membrane hemofilter, can be primed with heparin, improving its local anticoagulative activity. Prolonged intermittent RRT (PI-RRT) is of shorter duration and cheaper, considered as an alternative to continuous RRT. This study was performed to compare the success rate of anticoagulant-free PI-RRT using AN69ST versus AN69 membrane hemofilter. We also evaluated risk factors for filter clotting. METHODS: This crossover, double-blind, randomized study included patients requiring PI-RRT but at high bleeding risk treated with AN69ST and AN69 hemo filters. The success rate of RRT, filter lifespan and severity of filter clotting were compared between the hemo filters. Factors associated with the filter clotting risk were analyzed with a Cox proportional hazards model. RESULTS: This study included 60 patients (mean age, 68.1 +/- 15.8 years). Thirty-three (55.0%) patients were in the intensive care unit, 34 (56.8%) had disease-related thrombocytopenia, and 14 (23.3%) had local hemorrhagic diseases. The success rate of PI-RRT with the AN69ST and AN69 hemofilter was 51.7% and 50.9%, respectively (P > 0.05). The mean PI-RRT duration was 543.1 +/- 119.0 min in the completed sessions and 387.3 +/- 140.8 min in the prematurely terminated sessions, without significant difference between AN69ST and AN69 hemofilters. Cox regression analysis showed that age (odds ratio [OR], 1.023 per year), platelet count (OR, 1.07 per 10 * 109/L), hemoglobin concentration (OR, 1.035 per 1 g/L), and activated partial thromboplastin time (aPTT; OR, 0.973 per second) were associated with a hemofilter clotting risk. The AN69ST hemofilter lifespan was significantly prolonged averaging an extra 251.7 min in patients with an aPTT of <35.3 s, hemoglobin concentration of >83 g/L and platelet count of <70 * 109/L. CONCLUSIONS: Anticoagulant-free PI-RRT by a heparin-primed AN69ST hemofilter reached a 51.7% success rate. The risk of premature clotting of the extracorporeal circuit remains unsatisfactory. For select patients at high risk of bleeding, the heparin-primed AN69ST hemofilter may be more appropriate for anticoagulation-free PI-RRT. TRIAL REGISTRATION: https://www.clinicaltrials.gov ; study number: NCT02355873 . Release Date 01/21/2015. PMID- 28666475 TI - A model to estimate effects of SNPs on host susceptibility and infectivity for an endemic infectious disease. AB - BACKGROUND: Infectious diseases in farm animals affect animal health, decrease animal welfare and can affect human health. Selection and breeding of host individuals with desirable traits regarding infectious diseases can help to fight disease transmission, which is affected by two types of (genetic) traits: host susceptibility and host infectivity. Quantitative genetic studies on infectious diseases generally connect an individual's disease status to its own genotype, and therefore capture genetic effects on susceptibility only. However, they usually ignore variation in exposure to infectious herd mates, which may limit the accuracy of estimates of genetic effects on susceptibility. Moreover, genetic effects on infectivity will exist as well. Thus, to design optimal breeding strategies, it is essential that genetic effects on infectivity are quantified. Given the potential importance of genetic effects on infectivity, we set out to develop a model to estimate the effect of single nucleotide polymorphisms (SNPs) on both host susceptibility and host infectivity. To evaluate the quality of the resulting SNP effect estimates, we simulated an endemic disease in 10 groups of 100 individuals, and recorded time-series data on individual disease status. We quantified bias and precision of the estimates for different sizes of SNP effects, and identified the optimum recording interval when the number of records is limited. RESULTS: We present a generalized linear mixed model to estimate the effect of SNPs on both host susceptibility and host infectivity. SNP effects were on average slightly underestimated, i.e. estimates were conservative. Estimates were less precise for infectivity than for susceptibility. Given our sample size, the power to estimate SNP effects for susceptibility was 100% for differences between genotypes of a factor 1.56 or more, and was higher than 60% for infectivity for differences between genotypes of a factor 4 or more. When disease status was recorded 11 times on each animal, the optimal recording interval was 25 to 50% of the average infectious period. CONCLUSIONS: Our model was able to estimate genetic effects on susceptibility and infectivity. In future genome-wide association studies, it may serve as a starting point to identify genes that affect disease transmission and disease prevalence. PMID- 28666476 TI - Household food insecurity and dietary patterns in rural and urban American Indian families with young children. AB - BACKGROUND: High food insecurity has been demonstrated in rural American Indian households, but little is known about American Indian families in urban settings or the association of food insecurity with diet for these families. The purpose of this study was to examine the prevalence of food insecurity in American Indian households by urban-rural status, correlates of food insecurity in these households, and the relationship between food insecurity and diet in these households. METHODS: Dyads consisting of an adult caregiver and a child (2-5 years old) from the same household in five urban and rural American Indian communities were included. Demographic information was collected, and food insecurity was assessed using two validated items from the USDA Household Food Security Survey. Factors associated with food insecurity were examined using logistic regression. Child and adult diets were assessed using food screeners. Coping strategies were assessed through focus group discussions. These cross sectional baseline data were collected from 2/2013 through 4/2015 for the Healthy Children, Strong Families 2 randomized controlled trial of a healthy lifestyles intervention for American Indian families. RESULTS: A high prevalence of food insecurity was determined (61%) and was associated with American Indian ethnicity, lower educational level, single adult households, WIC participation, and urban settings (p = 0.05). Food insecure adults had significantly lower intake of vegetables (p < 0.05) and higher intakes of fruit juice (<0.001), other sugar-sweetened beverages (p < 0.05), and fried potatoes (p < 0.001) than food secure adults. Food insecure children had significantly higher intakes of fried potatoes (p < 0.05), soda (p = 0.01), and sports drinks (p < 0.05). Focus group participants indicated different strategies were used by urban and rural households to address food insecurity. CONCLUSIONS: The prevalence of food insecurity in American Indian households in our sample is extremely high, and geographic designation may be an important contributing factor. Moreover, food insecurity had a significant negative influence on dietary intake for families. Understanding strategies employed by households may help inform future interventions to address food insecurity. TRIAL REGISTRATION: ( NCT01776255 ). Registered: January 16, 2013. Date of enrollment: February 6, 2013. PMID- 28666477 TI - Management of persistent caesarean scar pregnancy after curettage treatment failure. AB - BACKGROUND: Caesarean scar pregnancy (CSP) is a late serious complication of caesarean section. The incidence of CSP has increased worldwide in recent years. Early diagnosis and prompt therapy are crucial to avoid catastrophic complications. There are various strategies for CSP treatment, but there is no consensus on the best management for CSP. Dilation and curettage (D&C) and hysteroscopy are common and effective treatments with their advantages and disadvantages. No in-depth study of the clinical effects of hysteroscopic management of CSP after D&C treatment failure has been conducted. The purpose of this study is to evaluate the effectiveness and safety of hysteroscopic removal of residual CSP tissue (persistent CSP) as a rescue after failed D&C management. METHODS: This is a retrospective clinical research study. Forty-five patients underwent operative hysteroscopy to remove the residual gestational tissue in the caesarean scar after failed D&C treatment. The clinical characteristics and outcomes of hysteroscopic surgeries of 45 CSP cases were investigated. All data analyses were conducted with SPSS 17.0. RESULTS: Forty-three CSP cases after unsuccessful curettage treatment were successfully treated by operative hysteroscopy. The estimated intraoperative blood loss was 20.00 (10.00-500.00) mL, the hysteroscopic operating time was 20.00 (15.00-45.00) min, the decline of serum beta-hCG the day after surgery was 71.91 +/- 14.05%, the total hospitalisation time was 7.87 +/- 2.26 days, the medical cost was 13,682.71 +/- 3553.77 China Yuan (CNY), the time of bleeding after surgery was 7.42 +/- 2.48 days, and the time of serum beta-hCG resolution after surgery was 13.84 +/- 9.83 days. Follow-up after discharge demonstrated that there were no severe complications for any patients. CONCLUSIONS: Hysteroscopy therapy could treat persistent CSP effectively and safely after curettage treatment failure. Therapy should be individualised, and the risks and cost of the hysteroscopy procedure and anaesthesia must be considered and fully discussed with the patients before surgery. PMID- 28666478 TI - Cardiovascular risk factors predate the onset of symptoms of rheumatoid arthritis: a nested case-control study. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD). Our aim was to evaluate the impact of factors related to CVD, such as smoking, lipid levels, hypertension, body mass index (BMI) and diabetes, in individuals prior to the onset of symptoms of RA. METHODS: A nested case-control study was performed including data from 547 pre symptomatic individuals (i.e. individuals who had participated in population surveys in northern Sweden prior to onset of symptoms of RA, median time to symptom onset 5.0 (interquartile range 2.0-9.0) years) and 1641 matched controls. Within the survey, health examinations prior to symptom onset were performed, blood samples were analysed for plasma glucose and lipids, and data on lifestyle factors had been collected with a questionnaire. CVD risk factors were extracted and further analysed with conditional logistic regression models for association with subsequent RA development, including hypertension, apolipoprotein (Apo)B/ApoA1 ratio, BMI, diabetes and smoking habits. RESULTS: Smoking and BMI >= 25 (odds ratio (OR) (95% confidence interval (CI)) =1.86 (1.48-2.35) and OR = 1.28 (1.01-1.62), respectively) were associated with increased risk for future RA development. In women, elevated ApoB/ApoA1 ratio (OR = 1.36 (1.03-1.80)) and smoking (OR = 1.82 (1.37-2.41)) were significantly associated with being pre symptomatic for RA, whilst in men smoking (OR = 1.92 (1.26-2.92)) and diabetes (OR = 3.62 (95% CI 1.13-11.64)) were significant. In older (>50.19 years) individuals, only smoking (OR = 1.74 (1.24-2.45)) was significantly associated with increased risk of future RA, whereas in younger individuals the significant factors were elevated ApoB/ApoA1 ratio (OR = 1.39 (1.00-1.93)), BMI >= 25.0 (OR = 1.45 (1.04-2.02)) and smoking (OR = 2.11 (1.51-2.95)). Pre-symptomatic individuals had a higher frequency of risk factors: 41.5% had >=3 compared with 30.4% among matched controls (OR = 2.81 (1.78-4.44)). CONCLUSIONS: Several risk factors for CVD were present in pre-symptomatic individuals and significantly associated with increased risk for future RA. These factors differed in women and men. The CVD risk factors had a greater impact in younger individuals. These results urge an early analysis of cardiovascular risk factors for proposed prevention in patients with early RA. PMID- 28666479 TI - Desert dust outbreaks and respiratory morbidity in Athens, Greece. AB - BACKGROUND: Ambient particulate matter (PM) has an adverse effect on respiratory morbidity. Desert dust outbreaks contribute to increased PM levels but the toxicity of desert dust mixed with anthropogenic pollutants needs clarification. METHODS: We identified 132 days with desert dust episodes and 177 matched days by day of the week, season, temperature and humidity between 2001 and 2006 in Athens, Greece. We collected data on regulated pollutants and daily emergency outpatient visits and admissions for respiratory causes. We applied Poisson regression models adjusting for confounding effects of seasonality, meteorology, holidays and influenza epidemics. We evaluated the sensitivity of our results to co-pollutant exposures and effect modification by age and sex. RESULTS: A 10 MUg/m3 increase in PM10 concentration was associated with 1.95% (95% confidence interval (CI): 0.02%, 3.91%) increase in respiratory emergency room visits. No significant interaction with desert dust episodes was observed. Compared with non dust days, there was a 47% (95% CI: 29%, 68%) increase in visits in dust days not adjusting for PM10. Desert dust days were associated with higher numbers of emergency room visits for asthma, chronic obstructive pulmonary disease and respiratory infections with increases of 38%, 57% and 60%, respectively (p < 0.001 for all comparisons). Analyses of respiratory hospital admissions provided similar results. PM10 effects decreased when adjusting for desert dust days and were further confounded by co-pollutants. CONCLUSIONS: Desert dust episode days are associated with higher respiratory emergency room visits and hospital admissions. This effect is insufficiently explained by increased PM10 levels. PMID- 28666480 TI - Trend and causes of adult mortality in Kersa health and demographic surveillance system (Kersa HDSS), eastern Ethiopia: verbal autopsy method. AB - BACKGROUND: The health problems of adults have been neglected in many developing countries, yet many studies in these countries show high rates of premature mortality in adults. Measuring adult mortality and its cause through verbal autopsy (VA) methods is becoming an important process for mortality estimates and is a good indicator of the overall mortality rates in resource-limited settings. The objective of this analysis is to describe the levels, distribution, and trends of adult mortality over time (2008-2013) and causes of adult deaths using VA in Kersa Health and Demographic Surveillance System (Kersa HDSS). METHODS: Kersa HDSS is a demographic and health surveillance and research center established in 2007 in the eastern part of Ethiopia. This is a community-based longitudinal study where VA methods were used to assign probable cause of death. Two or three physicians independently assigned cause of death based on the completed VA forms in accordance with the World Health Organization's International Classification of Diseases. In this analysis, the VA data considered were of all deaths of adults age 15 years and above, over a period of six years (2008-2013). The mortality fractions were determined and the causes of death analyzed. Analysis was done using STATA and graphs were designed using Microsoft Excel. RESULTS: A total of 1535 adult deaths occurred in the surveillance site during the study period and VA was completed for all these deaths. In general, the adult mortality rate over the six-year period was 8.5 per 1000 adult population, higher for males (9.6) and rural residents (8.6) than females (7.5) and urban residents (8.2). There is a general decrease in the mortality rates over the study period from 9.4 in 2008-2009 to 8.1 in 2012-2013. Out of the total deaths, about one-third (32.4%) occurred due to infectious and parasitic causes, and the second leading cause of death was diseases of circulatory system (11.4%), followed by gastrointestinal disorders (9.2%). Tuberculosis (TB) showed an increasing trend over the years and has been the leading cause of death in 2012 and 2013 for all adult age categories (15-49, 50 64, and 65 years and over). Chronic liver disease (CLD) was indicated as leading cause of death among adults in the age group 15-49 years. CONCLUSION: The increasing TB-related mortality in the study years as well as the relative high mortality due to CLD among adults of age 15-49 years should be further investigated and triangulated with health service data to understand the root cause of death. PMID- 28666481 TI - Genetic diversity and natural selection of Plasmodium vivax multi-drug resistant gene (pvmdr1) in Mesoamerica. AB - BACKGROUND: The Plasmodium vivax multidrug resistant 1 gene (pvmdr1) codes for a transmembrane protein of the parasite's digestive vacuole. It is likely that the pvmdr1 gene mutations occur at different sites by convergent evolution. In here, the genetic variation of pvmdr1 at three sites of the Mesoamerican region was studied. Since 1950s, malarious patients of those areas have been treated only with chloroquine and primaquine. METHODS: Blood samples from patients infected with P. vivax were obtained in southern Mexico (SMX), in the Northwest (NIC-NW) and in the northeast (NIC-NE) of Nicaragua. Genomic DNA was obtained and fragments of pvmdr1 were amplified and sequenced. The nucleotide and amino acid changes as well as the haplotype frequency in pvmdr1 were determined per strain and per geographic site. The sequences of pvmdr1 obtained from the studied regions were compared with homologous sequences from the GenBank database to explore the P. vivax genetic structure. RESULTS: In 141 parasites, eight nucleotide changes (two changes were synonymous and other six were nonsynonymous) were detected in 1536 bp. The PvMDR1 amino acid changes Y976F, F1076FL were predominant in endemic parasites from NIC-NE and outbreak parasites in NIC-NW but absent in SMX. Thirteen haplotypes were resolved, and found to be closely related, but their frequency at each geographic site was different (P = 0.0001). The pvmdr1 codons 925-1083 gene fragment showed higher genetic and haplotype diversity in parasites from NIC-NE than the other areas outside Latin America. The haplotype networks suggested local diversification of pvmdr1 and no significant departure from neutrality. The F ST values were low to moderate regionally, but high between NIC-NE or NIC-NW and other regions inside and outside Latin America. CONCLUSIONS: The pvmdr1 gene might have diversified recently at regional level. In the absence of significant natural, genetic drift might have caused differential pvmdr1 haplotype frequencies at different geographic sites in Mesoamerica. A very recent expansion of divergent pvmdr1 haplotypes in NIC-NE/NIC-NW produced high differentiation between these and parasites from other sites including SMX. These data are useful to set a baseline for epidemiological surveillance. PMID- 28666482 TI - Urolithiasis secondary to primary obstructive megaureter in an adult: a case report. AB - BACKGROUND: Primary obstructive megaureter is relatively uncommon in adults. This condition usually regresses spontaneously or is treated during infancy. It can remain asymptomatic for decades until adulthood when symptoms may manifest in the event of complications or during a routine radiologic imaging. Primary obstructive megaureter has been reported to favor stone formation in the upper urinary tract. CASE PRESENTATION: We present the case of a 35-year-old Moroccan man who had a 10-year history of intermittent left flank pain and hematuria. A computed tomography urogram revealed a left megaureter with giant ureteral and renal calculi. CONCLUSIONS: Primary obstructive megaureter should be a differential diagnosis in an adult with hydroureteronephrosis associated with urolithiasis especially when there is kidney impairment. Through this case report we will discuss the diagnosis and management of primary obstructive megaureter associated with urolithiasis in adults. PMID- 28666483 TI - Ethnozoological study of animals based medicine used by traditional healers and indigenous inhabitants in the adjoining areas of Gibbon Wildlife Sanctuary, Assam, India. AB - BACKGROUND: India has an immense faunal, floral, as well as cultural diversity with many ethnic communities who are primarily dependent on the traditional medicinal system for their primary health care. Documentation and evaluation of this indigenous remedial knowledge may be helpful to establish new drugs for human health. The present study is intended to look into different zootherapeutic medicinal uses in the traditional health care system among the native inhabitants adjacent to the Gibbon Wildlife Sanctuary, Assam, India. METHODS: Field survey was carried out from March 2015 to August 2015 by personal interviews through semi-structured questionnaires. In some cases where participants were uncomfortable with the questionnaires, informal interviews and open group discussions were conducted with a total of 62 indigenous respondents (43 male and 19 female) who provided the information regarding various medicinal uses of animals and their products (local name of animal, mode of preparation, application etc). RESULTS: The study recorded a total of 44 different species, 44 genera and 36 families of animals which are used for the treatment of 40 different ailments. Insects occupied the highest uses (30.9%), followed by mammals (23.8%), fishes (16.7%), reptiles (11.9%), amphibians (7.1%), annelids (4.8%) and gastropods (4.8%). Further, some zootherapeutic animals i.e. cockroach (Periplaneta americana), praying mantis (Mantis religiosa) and earthworms (Metaphire houletti, Pheretima posthum) are used for the treatment of asthma, otorrhoea and cancer respectively. CONCLUSION: The findings suggest that the traditional zootherapeutic remedial measures followed by the native people adjacent to Gibbon Wildlife Sanctuary plays an important role in their primary health care. The documentation of this indigenous knowledge on animal based medicines should be very helpful in the formulation of strategies for sustainable management and conservation of bio-resources as well as providing potential for the novel drugs discovery. PMID- 28666484 TI - Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation. AB - BACKGROUND: Heat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy. METHODS: In the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models' validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein. RESULTS: The made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound. CONCLUSION: The QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites. PMID- 28666485 TI - Rheumatology in the Middle East in 2017: clinical challenges and research. AB - The World Health Organization (WHO) has ranked musculoskeletal diseases among the top ten leading causes of disability in the Middle East. The situation in the Middle East is unique as, although seventeen countries are geographical connected, there is considerable variability in the standard of rheumatology care and research between the countries. There are several factors contributing to this variability: allocated government resources to healthcare services, country demographics, the implemented healthcare system, the number of qualified rheumatologist, political stability, and the immigration to and from these countries. PMID- 28666487 TI - Mahaim Tachycardia Induced Cardiomyopathy. AB - We present the case report of a 22-year man, with incessant palpitations, chest pain, shortness of breath, and pulsations in his neck for the past 7 months. He was referred to the cardiology unit for workup of wide complex tachycardia (WCT). His echocardiography, 6 months earlier, had demonstrated severe left ventricular (LV) systolic dysfunction, severe global hypokinesia, mild tricuspid regurgitation (TR), and mild mitral regurgitation (MR) which resolved with medical therapy including beta-blockers. He underwent electrophysiological study, which revealed a decremental right sided atriofascicular pathway causing a WCT with left bundle branch block (LBBB) morphology and left axis deviation (LAD, Mahaim tachycardia). This was successfully ablated by radiofrequency ablation (RF) with abolition of the tachycardia. This case report highlights Mahaim tachycardia induced cardiomyopathy, a rare but curable cause of cardiomyopathy. PMID- 28666488 TI - Two Congenital Left-to-Right Shunt Anomalies in a Septuagenarian: ARare Occurrence. AB - Atrial septal defect (ASD) and patent ductus arteriosus (PDA) are common congenital anomalies presenting in childhood. Life expectancy of an uncorrected PDAis shortened to half; and ASD of a significant size has increased morbidity and mortality. Their co-existence in an elderly patient with first presentation at 70 years of age is a rarity. We present the case of a 70-year woman with one week history of dyspnea with high blood pressure and signs of heart failure. She was found to have a PDA and an ASD with left-to-right shunt. She was managed conservatively. She was offered cardiac catheterization, but she refused. This is the first documented case in local literature with two such congenital heart defects presenting in a septuagenarian. In a country where average life expectancy is in the 60's, the survival of the patient with two heart defects, beyond-average survival age, is interesting. PMID- 28666489 TI - Atresia of the Descending Aorta in a Young Woman Requiring Bypass Graft. AB - Congenital aortic atresia is a malformation accounting for 4 - 6% of all congenital heart diseases in children. Left ventricular outflow obstruction due to atresia is common at the aortic valve but rarely has atresia been identified in the descending aorta. We report the case of a 25-year woman who was evaluated for headache and uncontrolled hypertension. CTscan chest showed a short atretic segment in the descending aorta at the isthmus, distal to the takeoff of the subclavian artery. She underwent surgery; a 22 mm Dacron graft was taken and jump graft was placed between the arch of the aorta and the descending aorta, using partial occlusion clamps. Patient tolerated the procedure well and was discharged on ACE Inhibitors and beta blockers, which were then weaned off over a period of one year. She remained stable and had no further complaints. PMID- 28666490 TI - An Unusual Cause of Asystole: Insertion of a Central Venous Catheter. AB - Central venous catheters are a commonly used medical device which may sometimes cause complications. We present first case who had an asystolic cardiac arrest during insertion of a central venous catheter, needed cardiopulmonary resuscitation (CPR), and was resuscitated successfully. A46-year lady presented to the emergency department due to mushroom poisoning. Acentral venous catheter was inserted through the internal jugular vein. However, the patient suddenly lost consciousness and asystole was seen on the monitor immediately after the insertion of the catheter. Cardiopulmonary resuscitation was started, and the catheter was withdrawn nearly 5 cm. Spontaneous circulation returned 2 minutes later. The patient was hospitalised, hemodialysis was performed, and she was discharged the next day. Emergency physicians should be prepared for dysrhythmias and asystole during insertion of a central venous catheter. If cardiac arrest develops, the catheter should be withdrawn a few centimeters while CPR continues. PMID- 28666491 TI - New-Onset Type 2 Diabetes and Virilization in a Benign Sex Cord Tumor. AB - The stromal leydig cell tumor (SLCT) is a very rare benign tumor of ovary which occurs more often in young women in reproductive age. In this report, we describe a SLCTin a postmenopausal woman with high level of testosterone and triggering of type 2 diabetes, occurring 3 months after removal of the tumor. PMID- 28666493 TI - Sporadic Case of Peutz-Jeghers Polyp in a 14-Year Boy. AB - Peutz-Jeghers syndrome (PJS) is an autosomal dominant hamartomatous polyposis of the gastrointestinal tract, with pigmentation around lips, the buccal mucosa, and anal area. Patients have a strong family history. Patients of PJS present with abdominal pain, blood in stools, and occasionally melena because of polyps, along with classical mucocutaneous pigmentation. Very rarely a sporadic case of Peutz Jeghers syndrome occurs in early childhood and adolescent. The case of a 14-year boy is reported, who presented with intussussception and bleeding per rectum due to jejunal polyp and a rectal polyp. Intussussception was treated by resection anastomosis due to vascular impairment. Rectal polyp was removed during colonoscopy. There was no family history of Peutz-Jeghers syndrome or polyps but patient had classical mucocutaneous pigmentation of buccal mucosa. Therefore, this case is of sporadic Peutz-Jeghers polyp (PJP), which is a rare disorder. PMID- 28666492 TI - A Novel Technique for Detection and Suturing of Biliary Fistula in a Giant Hydatid Cyst: Video-assisted Biliary Fistula Suturing in Hydatid Cyst. AB - Hydatid disease remains an important health problem in endemic areas; and by the way of travel and immigration, it can also be encountered in non-endemic areas. The most common cases with complications following hydatid liver surgeries are biliary fistulas with a frequency of 14.6 - 27.5%. Postoperative biliary leakage is generally due to unnoticed biliary tract communications. It is technically difficult to determine and suture the biliary fistulas, particulary for deep located ones with giant cavities for patients with high body mass index. We report a novel technique viavideo-assisted suturing of potentially unnoticeable biliocystic fistula in open surgery for patients with hydatid disease. PMID- 28666494 TI - Quadro-Cornuate Uterus. AB - Congenital malformations of the female genital tract are a group of miscellaneous deviations from normal anatomy with diverse spectrum. Mullerian anomalies are thought to be present in 0.5% of female population. Three quarter of women remain asymptomatic, the remaining quarter presents with a variety of symptoms including primary amenorrhea, cyclical pain, severe dysmenorrhea, pelvic mass, ectopic pregnancy, infertility and recurrent miscarriages. The American Fertility Society (AFS) classification has been the most widely used classification for categorizing these abnormalities. Recently, European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) proposed another classification system of female genital anomalies which provides a comprehensive description and categorization of almost all of the currently known anomalies. This case report describes a 23-year, married, parous woman with severe dysmenorrhea. Workup revealed a right adnexal mass which preoperatively was consistent with noncommunicating horn(s) of uterus. Peroperatively a new entity, a uterus with four cornua, was seen. PMID- 28666495 TI - Philadelphia Chromosome Positive de novo Acute Myeloid Leukemia. AB - Philadelphia chromosome positive de novoacute myeloid leukemia (AML)is a rare disease with reported incidence of less than 1% of newly diagnosed cases of AML. Outcome of the disease is poor, owing to its resistance to conventional chemotherapy and variable response to imatinib besylate. We report a case of 24 year man who reported to our unit in November 2014 and was treated with conventional induction and consolidation chemotherapy with imatinib besylate. He achieved complete remission after induction chemotherapy and remained in remission. His cytogenetics also reverted to normal after consolidation chemotherapy. He relapsed after 3 months of maintenance imatinib besylate. PMID- 28666496 TI - Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, in a 5-Month Baby - ARare Presentation. AB - Atypical chronic myeloid leukemia (aCML) is a neoplasm with poor prognosis, characterized by myeloid hyperplasia, dysmyelopoiesis and absence of BCR-ABL1 gene. Clinically, the disease course may be similar to chronic myeloid leukemia (CML), BCR-ABL1 positive. It presents in seventh to eighth decade of life with few cases of paediatric aCML being reported. Here, we report a case of aCMLin a 5 month baby who presented with massive splenomegaly. The diagnosis was in accordance with the WHO criteria established in 2008. PMID- 28666497 TI - Paroxysmal Nocturnal Haemoglobinuria Type III Presenting as Portal and Mesenteric Vein Thrombosis in a Young Girl. AB - Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, life-threatening haematological disorder. It is characterised by complement induced haemolytic anaemia, thrombosis and impaired bone marrow function. Thrombosis most commonly occurs in the hepatic, portal, superior mesenteric and cerebral veins. A22-year female, previously diagnosed with severe aplastic anaemia treated with anti lymphocyte globulin (ALG) and cyclosporine, had become transfusion independent for more than 10 years. She presented with abdominal pain and vomiting, initially diagnosed with portal and superior mesenteric vein thrombosis. Immunophenotyping by flow cytometry revealed a diagnosis of paroxysmal nocturnal haemoglobinuria type III. She was treated with vitmamin K anatagonist and platelet transfusion. PMID- 28666498 TI - Stafne Bone Cavity Complicated By Periapical Infection. AB - Stafne bone cavity (SBC) is an uncommon lesion of the mandible; and generally found incidentally on routine radiographic examinations. The radiographic differential diagnosis of SBC includes a variety of lesions including odontogenic cysts, benign tumors, or bone metastases. In the present case, a 22-year female patient was admitted with chief complaint of pain in the right mandibular molar area. On panoramic radiographic examination, a non-specific large radiolucent lesion related to mandibular molar teeth was detected and extra-oral surgical intervention was planned. However, on examination with cone-beam CT(CBCT), a SBC was suspected due to lack of lingual cortical plate; and intraoral surgical exploration confirmed the diagnosis showing a cavity with small inflamed salivary gland tissue. Examination with CBCTon suspicious jaw lesions helps avoid unnecessary extraoral surgical interventions. PMID- 28666499 TI - Concurrence of Torus Palatinus, Torus Mandibularis and Buccal Exostosis. AB - Torus palatinus (TP), torus mandibularis (TM), and buccal exostosis are localised, benign, osseous projections, occurring in maxilla and mandible. Etiology is multifactorial and not well established. Tori and exostoses have been associated with parafunctional occlusal habits, temporomandibular joint (TMJ) disorders, migraine and consumption of fish. Concurrence of TP, TM, and exostosis in the same individual is very rare. Concurrence of TPand TM has not been reported from Pakistan. We report a case of a 22-year female patient manifesting concurrence of TP, bilateral TM, and maxillary buccal exostoses; with possible association of abnormal occlusal stresses and use of calcium and vitamin D supplements. PMID- 28666500 TI - Permanent Neonatal Diabetes (DEND Syndrome). AB - DEND syndrome is a very rare syndrome of permanent neonatal diabetes mellitus, with an incidence of < 1/1000,000. It is defined as a triad of developmental delay, epilepsy, and neonatal diabetes. We report the case of a 9-month infant girl who presented with the most severe form of neonatal diabetes mellitus spectrum along with developmental delay and epilepsy. Genetic mutation testing confirmed mutations in KCNJ11 gene encoding the Kir6.2 subunit of the K ATPchannel, which are involved in insulin secretion. The use of oral sulfonylureas in treatment of such patients is showing promising results worldwide. The authors strongly recommend early referral and checking for genetic mutations in all patients of neonatal diabetes mellitus. PMID- 28666501 TI - Spontaneous Rupture and Dissection of Aspergillus Infected Arteriovenous Fistula. AB - Patients with end stage renal disease need a vascular access like arteriovenous (AV) fistula, AV graft or central venous catheter for hemodialysis. However, AV fistula can be complicated due to infection, stenosis, ulceration etc. Among these, spontaneous rupture of AV fistula is rare and can be due to stenosis or infection. Fungal infection of AV fistula is very rare and the most common organism involved is Candida. Infection of native AV fistula with Aspergillusis not reported in the literature. This case discusses the spontaneous rupture and dissection of an Aspergillusinfected arteriovenous fistula, requiring urgent closure and repairing of vessel. PMID- 28666502 TI - Bilateral Intractable Trigeminal Neuralgia due to a Prepontine Epidermoid Tumour: An Unlikely Duo. AB - Prepontine epidermoid is a rare congenital tumour which arises during 3rd - 5th week of embryogenesis due to incomplete separation of neuroectoderm from surface ectoderm. This is slow growing benign tumour with late presentation in adult life. The clinical symptoms depend on the location of the tumour. In this case, the patient had intractable bilateral trigeminal neuralgia. The patient was given conservative treatment for 8 weeks with carbamazipine, but it did not respond to the neuralgic pain medication. Another trial of combined neuropathic medications including carbamazepine, gabapentin, pregabalin and baclofen were given for another 8 weeks, but the symptoms continued. MRI brain showed hypodense tumour on T1 weighted image which was hyperdense on T2 weighted images. The roots of both trigeminal nerves were involved in the prepontine area, proximal to the trigeminal ganglion. Surgical resection of the tumour was carried out in a two stage operation. After complete surgical removal, patient's symptom of pain along trigeminal nerve was relieved. PMID- 28666503 TI - Spontaneous Uterine Rupture Due to Placenta Percreta in a 17-Week Twin Pregnancy. AB - Spontaneous rupture of previous uterine scar due to placenta percreta in early second trimester is a very rare and serious complication. A27-year fourth gravida, second para with previous two lower segment caesarean sections, presented at 17-week of twin pregnancy with acute abdominal pain. Ultrasonograghy revealed 17-week diamniotic-dichorionic twin pregnancy with alive fetuses. The placenta of the first twin was anterior, low lying covering the internal os and penetrating through the entire thickness of the lower uterine wall laterally. Significant hemoperitoneum was seen. Emergency laparotomy showed rupture of previous uterine scar with placenta percreta bleeding actively. Atransverse fundal incision was given to deliver the twins and total abdominal hysterectomy with preservation of both ovaries was performed. The patient was discharged on fourth postoperative day without any complication. Histopathology of specimen of the uterus confirmed placenta percreta to be the cause of uterine rupture. PMID- 28666504 TI - Pregnancy in a Treated Case of Ectopia Vesicae. AB - The patient was born with bladder exstrophy and underwent multiple surgeries for its correction. Finally, she had ureterosigmoidostomy at the age of 9 years, which ultimately led her to live till reproductive age. The children born with this defect are capable of surviving till adult life. She was received by us with preterm labour, referred from Hafizabad. She also had hyperchloremic metabolic acidosis and mild hydronephrosis. She was managed with multidisciplinary, modified care but the pregnancy ended up in an emergency cesarean section due to non-reactive cardiotocograph and persistently reduced fetal movements. She had fortunately successful pregnancy outcome. To the authors'knowledge, this is the first reported case of pregnancy in a treated case of ectopia vesicae in Pakistan. PMID- 28666505 TI - Cystic Pleural Synovial Sarcoma. AB - Fewer than 40 cases of primary pleural synovial sarcoma have been reported so far with only 3 cases of cystic synovial sarcoma including cases originating from sites other than the pleura. Here, we present an exceedingly rare case of cystic synovial sarcoma originating from the mediastinal side of the visceral pleura in a 25-year man presenting with hemoptysis. On contrast-enhanced computed tomography (CT), cystic synovial sarcoma and cystic thymoma were difficult to be distinguished due to mediastinal location. Histopathological examination showed spindled morphology of tumor cells with hypercellularity and nuclear atypia. As these features are associated with both monophasic fibrous synovial sarcoma and type Athymoma, immunohistochemistry was performed. Adiagnosis of synovial sarcoma was confirmed by detection of CD99 and EMAand negativity of other markers. Fluorescence in situhybridization (FISH) was not done. Surgical excision was done and followed by oncology referral. PMID- 28666506 TI - Diagnosis and Therapy of Ectopic Hepatocellular Carcinoma Growing in the Intrahepatic Bile Duct. AB - A 63-year male was admitted with abdominal pain, fever and jaundice. The contrast enhanced computed tomography, magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiography showed a mass in the hepatic hilar region with dilation of the intrahepatic bile duct. The left branch of portal vein was also compressed by the mass. The patient was diagnosed as intrahepatic bile duct carcinoma and underwent the left hemihepatectomy together with right hepatic duct jejunum anastomosis (Roux-en-Y)combined with hepatoduodenal ligament lymphadenectomy. In the left intrahepatic bile duct, a mass of 3 x 2 x 2 cm was seen extending into the common hepatic bile duct. No tumor was detected in the liver parenchyma. The left portal vein compression by the tumor was confirmed during surgical exploration. Immunostaining showed hepatocyte(+), AFP(+/-), CK(+/ ), which indicated that the cancerous tumor cells were derived from hepatocytes but not from bile duct epithelial cells. The final diagnosis of this patient was hepatocellular carcinoma growing in the intrahepatic bile duct. PMID- 28666507 TI - An Unusual Metastasis of Prostate Cancer to Duodenum. AB - Prostate cancer is the second most common cancer in men in the world. The presentation of this cancer may range from microscopic to metastatic forms. Patients with prostate cancer may experience metastasis to the gastrointestinal system. Here, we present a case of prostate cancer metastasizing to the third portion of duodenum, a very uncommon site of metastasis. To the best of authors' knowledge, this is the first case report in the literature. PMID- 28666508 TI - Disseminated Kaposi's Sarcoma in an Immunosuppressed Patient after Long-Term Inhaled and Systemic Steroid Therapy. AB - Kaposi's sarcoma is associated with immunosuppressant treatment administered to patients with organ transplant and other immune related disorders. Several case reports have reported association of Kaposi's sarcoma and steroids. Almost all patients in those case reports had localised disease to skin and they responded to tapering doses or discontinuation of steroids. Here we present a case of an elderly asthmatic man who was using self-medication with systemic and inhaled steroids for about two decades. He presented with widespread skin lesions and anemia. Upper gastrointestinal endoscopy revealed multiple gastric lesions. Skin and gastric lesion biopsies established the diagnosis of disseminated Kaposi's sarcoma. Work-up for HIV, HTLV-1 and HHV-8 was negative. He had low lymphocytes and CD4 counts. He also had steroid-induced hypoadrenalism. Patient was treated with systemic chemotherapy due to visceral metastases to which he responded well and is in stable remission. PMID- 28666509 TI - Ophthalmological Features of Machado-Joseph Disease. AB - Machado-Joseph disease (MJD) or spinocerebellar ataxia type-3 (SCA3) is a rare and progressive neurodegenerative disorder, as well as the most frequently inherited spinocerebellar ataxia. It has extensive polymorphic features, described through a spectrum of neurological, and especially, ophthalmological manifestations. Besides the deterioration of the oculomotor systems, degeneration predominantly involves the cerebellar, pyramidal, extra-pyramidal, and peripheral motor systems. Few patients express Parkinsonian features as well. Through two separate cases, we present the major differences seen in the two patients, but also display their underlying similarities in the context of MJD; specifically, the ophthalmological features. The shared features include nystagmus in the horizontal direction, orbicularis oculi contractions, and bilateral esotropia. The findings indicate the importance of the inherent ophthalmological features expressed in MJD. PMID- 28666510 TI - Homocystinuria (HC) and Neurofibromatosis Type-1 (NF-1): An Unusual Presentation in a Child. AB - Homocystinuria (HC) and neurofibromatosis type-1 (NF-1) are two genetically determined conditions with variable clinical manifestations. HC is a neurocutaneous autosomal recessive condition while NF-1 is an autosomal dominant phacomatosis. Both HC and NF-1 present with distinct systemic as well as ocular manifestations; however, vascular complications can occur in both the conditions. A9-year boy diagnosed case of HC along with other two siblings is reported here. He was referred by his paediatrician with decreased vision secondary to ectopia lentis. When examined in detail, he turned out to be suffering from both HC and NF-1, based on raised serum homocysteine levels, biopsy report of NF-1 and presence of cafe au laitspots and ectopia lentisclinically. Lens anomaly was corrected surgically while he was given oral vitamin B6 for HC to which he responded well. PMID- 28666511 TI - Unilateral-external Ophthalmoplegia: ARare Presentation of Myasthenia Gravis. AB - Myasthenia gravis (MG) is a disease of autoimmunity with variable and diverse clinical presentations. The target tissue is neuromuscular junction of skeletal muscles, where efficient nerve impulse transmission is hampered leading to less effective muscle contraction. Patients of MG usually present with bilateral ptosis, diplopia and fatigability, which may or may not coexist with generalised weakness, dysphagia and dysarthria. A46-year male presented with unilateral ptosis and diplopia. Except for unilateral moderate ptosis and restriction of extraocular movements, ocular and systemic examination was normal. Both ice pack and tensilon tests revealed improvement in ptosis. Patient was advised tablet pyridostigmine and prednisolone; and a remarkable improvement was noticed within a week. PMID- 28666512 TI - Obturator Internus Abscess with Ipsilateral Septic Hip Arthritis. AB - Obturator internus muscle (OIM) abscess is an uncommon condition often mistaken for bacterial infection of the hip joint. If the OIM abscess is accompanied by a septic hip, it becomes more difficult to make a diagnosis. Surgical drainage of OIM abscess is difficult because it is located at a deep part of the pelvic cavity. Therefore, intravenous antibiotic therapy or image-guided aspiration were used as a treatment method instead of surgical drainage. When drainage of the abscess was inadequate, prolonged antibiotic treatment was necessary. Here, we report a 12-year boy with abscess in the OIM and ipsilateral pyogenic arthritis of the hip which was accompanied by acute osteomyelitis of the triradiate cartilage of the acetabulum. The patient was successfully treated by surgical drainage of the abscess using the Stoppa approach and arthroscopic irrigation of the hip joint. Staphylococcus aureuswas the causative organism which was sensitive to oxacillin. PMID- 28666513 TI - Context-specific Activity Repetition Training for Functional Outcome in Stroke Rehabilitation. AB - Task-oriented, activity repetition training brings a marked improvement in stroke individuals. Maximum repetitions of taskoriented training in stroke patients can be achieved easily in a therapy session. The subject of this report exhibited limitations of walking function, impaired balance, and strength of the upper and lower limbs. Task-oriented activity repetition training (ART) was performed by the patient for 5 days a week consisting of 60 minutes with maximum repetitions for 6 weeks. There was a gradual increase in repetitions per session and after 6 week exercise programme, overall body strength, balance, gait velocity, walking endurance, and functional mobility of the patient was improved remarkably. PMID- 28666514 TI - A Rare Neuropsychiatric Presentation of Adult-Onset Wilson's Disease. AB - Wilson's disease is characterised by deposition of copper in various tissues of the body, most markedly in the liver and the brain. Cerebral involvement, evident as neuropsychiatric symptoms, may be the presenting form of the illness in up to 50% of the adults. When patients present initially with psychiatric manifestations, the correct diagnosis is frequently missed. This case report describes an adult in his late 20's who presented with symptoms of major depressive disorder, but failed to respond to standard antidepressant treatment. He instead developed neurologic symptoms like tremor, gait disturbance, weakness of grip and clumsiness. Diagnosed as a case of conversion disorder, brain MRI showed abnormalities in the basal ganglia. Further investigations revealed that he had adult-onset Wilson's disease. Because of rarity, adult Wilson's disease patients with initial psychiatric presentations are frequently misdiagnosed and definitive treatment with chelating agents is not offered with continual organ damage from copper accumulation. PMID- 28666515 TI - The American Journal of Ophthalmology, Not an "American" Journal of Ophthalmology. PMID- 28666516 TI - [The roles and the impacts of pharmacists in the management of medical devices at the hospital: A literature review]. AB - OBJECTIVES: Identify the training profile and the published evidences about the roles and the impacts of hospital pharmacists in medical devices. METHODS: A literature review was conducted using Google, Google Scholar and Pubmed for 1990 2016 associated with a manual search conducted in three non-indexed pharmaceutical journals for 2000-2016. RESULTS: The analysis of training programs available did not allow us to identify a specific training profile. A total of 72 articles related to the roles and the impacts of the pharmacist were identified, 52 of which came from non-indexed journals. Those articles did not deal specifically about the roles and the impacts of pharmacist; however, articles were analyses for three spheres including the referencing of medical devices (n=36), the evaluation (n=19) and the distribution system (n=13). CONCLUSIONS: French pharmacists have many theoretical and practical training opportunities. There are a few articles describing precisely the roles and the impacts of hospital pharmacists in medical device. It appears urgent to better document this activity in professional and indexed literature. PMID- 28666517 TI - Evidence about success of endodontic treatment or retreatment versus tooth extraction and implant placement is not sufficient for making clinical decisions. PMID- 28666518 TI - Stepwise caries removal seems to result in more successful treatments than nonselective caries removal 5 years after treatment. PMID- 28666519 TI - Preformed-metal posts seem to have a lower cost than and similar effectiveness as cast-metal, glass-fiber, and carbon-fiber posts. PMID- 28666520 TI - Dental therapists can probably assess decayed, missing, and filled teeth with high accuracy in 5-year-old children. PMID- 28666521 TI - More than two-thirds of patients with localized aggressive periodontitis gained more than 2 millimeters of clinical attachment level after 4 years of maintenance treatment. PMID- 28666522 TI - Fluoride-releasing resin adhesive did not prevent formation of white-spot lesions related to fixed-orthodontic appliances compared with conventional adhesive. PMID- 28666523 TI - Reconstruction Techniques of Choice for the Facial Cosmetic Units. AB - BACKGROUND AND OBJECTIVES: A broad range of skin flaps can be used to repair facial surgical defects after the excision of a tumor. The aim of our study was to develop a practical guideline covering the most useful skin grafts for each of the distinct facial cosmetic units. MATERIAL AND METHODS: This was a multicenter study in which 10 dermatologists with extensive experience in reconstructive surgery chose their preferred technique for each cosmetic unit. The choice of flaps was based on personal experience, taking into account factors such as suitability of the reconstruction technique for the specific defect, the final cosmetic result, surgical difficulty, and risk of complications. Each dermatologist proposed 2 flaps in order of preference for each cosmetic subunit. A score of 10 was given to the first flap and a score of 5 to the second. RESULTS: The total score obtained for each of the options proposed by the participating dermatologists was used to draw up a list of the 3 best grafts for each site. There was notable unanimity of criteria among most of the dermatologists for reconstructive techniques such as the glabellar flap for defects of the medial canthus of the eye, the bilateral advancement flag flap or H flap for the forehead, the rotary door flap for the auricle of the ear, the Mustarde flap for the infraorbital cheek, the O-Z rotation flap for the scalp, the Tenzel flap for the lower eyelid, and the island flap for the upper lip. CONCLUSIONS: The results of this study will be useful as a practical guide to choosing the best reconstruction technique for each of the facial cosmetic units. PMID- 28666524 TI - Lichen Striatus in Childhood: Is It Associated With Atopic Dermatitis? PMID- 28666527 TI - Pediatric near-drowning events: do they warrant trauma team activation? PMID- 28666526 TI - [Comparison of results of open simple nephrectomy secondary to lithiasis in patients with and without nephrostomy]. AB - BACKGROUND: Simple nephrectomy is the procedure of choice in the treatment of excluded kidneys. The purpose of this study was to describe and compare surgical results in open simple retroperitoneal nephrectomies in patients with and without nephrostomy. METHODOLOGY: 58 patients were analyzed. The demographic parameters of patients with nephrostomy were compared to patients without nephrostomy (age, gender, weight, lithium localization, transoperative variables (surgical time, transoperative bleeding) and postoperative variables (need for intensive care, need for transfusion, surgical wound infection and hospital stay days) RESULTS: Statistically significant differences were found for the variables of operative bleeding (p=0.0442), surgical time (p=0.0093), hospital stay days (p=0.0040), and transfusion requirements (p=0.0170). There were no differences in the need for intensive care (p=0.6314), transoperative complications (p=0.7414) and surgical wound infection (p=0.2762). CONCLUSIONS: The presence of a nephrostomy catheter in patients undergoing open simple nephrectomy leads to an increased risk of morbidity, with increased bleeding, surgical time, need for transfusion, and hospital stay days. PMID- 28666528 TI - The assessment of medical competencies. AB - OBJECTIVE: To describe the most widely used tools in the assessment of medical competencies, analyse their prevalence of use, their advantages and disadvantages and propose an appropriate model for our context. METHODS: We conducted a narrative review of articles from MEDLINE, following the PRISM protocol, and analysed a total of 62 articles. RESULTS: The assessment of competencies is heterogeneous, especially in the educational and professional settings. The specific and technical competencies acquired during university education are mainly assessed using the objective structured clinical assessment. In the professional setting, core competencies are assessed using the 360 degrees technique. CONCLUSIONS: We need a rigorous empiric comparison of the efficiency of the tools according to the type of competency. We propose a competency management model for the "undergraduate/graduate/active professional" continuum, whose goal is to improve training and professional practice and thereby increase the quality of patient care. PMID- 28666525 TI - Untangling Genetic Risk for Alzheimer's Disease. AB - Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder caused by fully penetrant single gene mutations in a minority of cases, while the majority of cases are sporadic or show modest familial clustering. These cases are of late onset and likely result from the interaction of many genes and the environment. More than 30 loci have been implicated in AD by a combination of linkage, genome-wide association, and whole genome/exome sequencing. We have learned from these studies that perturbations in endolysosomal, lipid metabolism, and immune response pathways substantially contribute to sporadic AD pathogenesis. We review here current knowledge about functions of AD susceptibility genes, highlighting cells of the myeloid lineage as drivers of at least part of the genetic component in late-onset AD. Although targeted resequencing utilized for the identification of causal variants has discovered coding mutations in some AD-associated genes, a lot of risk variants lie in noncoding regions. Here we discuss the use of functional genomics approaches that integrate transcriptomic, epigenetic, and endophenotype traits with systems biology to annotate genetic variants, and to facilitate discovery of AD risk genes. Further validation in cell culture and mouse models will be necessary to establish causality for these genes. This knowledge will allow mechanism-based design of novel therapeutic interventions in AD and promises coherent implementation of treatment in a personalized manner. PMID- 28666529 TI - Accelerated benzene polycarboxylic acid analysis by liquid chromatography-time-of flight-mass spectrometry for the determination of petrogenic and pyrogenic carbon. AB - Pyrogenic carbon species are of particular interest due to their ubiquitous occurrence in the environment and their high sorption capacities for nonpolar organic compounds. It has recently been shown that the analysis of the molecular markers for complex aromatic carbon structures, benzene polycarboxylic acids (BPCA), has a high potential for aid in the identification of different carbon sources. In this study, the first LC method using mass spectrometry (MS) for reliable and accelerated (<24h) quantification of pyrogenic and petrogenic carbon by BPCA analysis has been developed. The main advantage of LC-MS compared to previous methods is the higher sensitivity, which is important if only small sample amounts are available. Sample pre-treatment could be reduced to a minimum. Deuterated phthalic acid was introduced as internal standard due to its structural similarity to BPCA and its lack of occurrence in the environment. Linear quantification with r2>=0997 was accomplished for all BPCA. Method validation showed an excellent quantification reproducibility (mean CV<5%) which is comparable to LC-DAD methods and more reliable than GC-FID measurements (CV 16 23%). In summary, the presented BPCA method is more economic, efficient and presumably attractive to use. Besides reference materials, various pyrogenic and petrogenic samples were analyzed to test if the sources were indicated by BPCA analysis. In addition to pyrogenic carbon, large amounts of petrogenic carbon species can also be present in urban soils and river sediments, especially in mining regions. They also to a large degree consist of aromatic carbon structures and therefore have an impact on source identification by BPCA analysis. Comparison of petrogenic and pyrogenic carbon samples shows similarities in the BPCA concentrations and patterns, in their aromaticity and degree of aromatic condensation. Thus, a differentiation between petrogenic and pyrogenic carbon only by BPCA analysis of samples with unknown carbon sources is not possible. For reliable source identification of the carbon species, the combination with other methods, such as e. g. analysis of polycyclic aromatic hydrocarbons may be successful. PMID- 28666530 TI - Development of a supercritical fluid chromatography method with ultraviolet and mass spectrometry detection for the characterization of biomass fast pyrolysis bio oils. AB - The characterization of complex mixtures is a challenging issue for the development of innovative processes dedicated to biofuels and bio-products production. The huge number of compounds present in biomass fast pyrolysis oils combined with the large diversity of chemical functions represent a bottleneck as regards analytical technique development. For the extensive characterization of complex samples, supercritical fluid chromatography (SFC) can be alternative to usual separation techniques such as gas (GC) or liquid chromatography (LC). In this study, an approach is proposed to define the best conditions for the SFC separation of a fast pyrolysis bio-oil. This approach was based on SFC data obtained directly from the bio-oil itself instead of selecting model compounds as usually done. SFC conditions were optimized by using three specific, easy-to-use and quantitative criteria aiming at maximizing the separation power. Polar stationary phases (ethylpyridine bonded silica) associated to a mix of acetonitrile and water as polarity modifier provided the best results, with more than 120 peaks detected in SFC-UV. PMID- 28666531 TI - The influence of ocean halogen and sulfur emissions in the air quality of a coastal megacity: The case of Los Angeles. AB - The oceans are the main source of natural halogen and sulfur compounds, which have a significant influence on the oxidizing capacity of the marine atmosphere; however, their impact on the air quality of coastal cities is currently unknown. We explore the effect of marine halogens (Cl, Br and I) and dimethyl sulfide (DMS) on the air quality of a large coastal city through a set of high-resolution (4-km) air quality simulations for the urban area of Los Angeles, US, using the Community Multiscale Air Quality (CMAQ model). The results indicate that marine halogen emissions decrease ozone and nitrogen dioxide levels up to 5ppbv and 2.5ppbv, respectively, in the city of Los Angeles. Previous studies suggested that the inclusion of chlorine in air quality models leads to the generation of ozone in urban areas through photolysis of nitryl chloride (ClNO2). However, we find that when considering the chemistry of Cl, Br and I together the net effect is a reduction of surface ozone concentrations. Furthermore, combined ocean emissions of halogens and DMS cause substantial changes in the levels of key urban atmospheric oxidants such as OH, HO2 and NO3, and in the composition and mass of fine particles. Although the levels of ozone, NO3 and HOx are reduced, we find a 10% increase in secondary organic aerosol (SOA) mean concentration, attributed to the increase in aerosol acidity and sulfate aerosol formation when combining DMS and bromine. Therefore, this new pathway for enhanced SOA formation may potentially help with current model under predictions of urban SOA. Although further observations and research are needed to establish these preliminary conclusions, this first city-scale investigation suggests that the inclusion of oceanic halogens and DMS in air quality models may improve regional air quality predictions over coastal cities around the world. PMID- 28666532 TI - EAS 2017 Congress Prague highlights. PMID- 28666533 TI - The ethics consultant. PMID- 28666534 TI - Prognostic value of interleukin-6 for death in patients with sepsis. PMID- 28666535 TI - Effects of a Preschool Intervention on Physical Activity and Body Composition. AB - OBJECTIVE: To investigate the effect of a preschool physical activity intervention program delivered in licensed childcare settings, with or without a parent-facilitated home component, on children's daily physical activity, sedentary time, and body composition. STUDY DESIGN: For this cluster randomized controlled trial, 18 childcare centers were randomly allocated in equal numbers to the typical curriculum comparison group, childcare intervention alone (CC), or childcare intervention with parental involvement. Accelerometers were used to asses physical activity and sedentary time, and body composition was measured by bioelectrical impedance. RESULTS: Linear mixed model regression analyses showed no differences between the CC, the childcare intervention with parental involvement, and the comparison groups in changes from baseline to 6 months in total physical activity (P for time * group interaction = .665) or moderate-to vigorous physical activity (P for time * group interaction = .164) when adjusted for baseline physical activity levels. Furthermore, no group differences were found for changes in light physical activity, sedentary time, or anthropometric variables. CONCLUSIONS: An affordable and easily scalable preschool intervention program delivered in licensed childcare settings, with or without the addition of a parent-driven home physical activity promotion, seems to have no significant effect on physical activity, sedentary time, or body composition. TRIAL REGISTRATION: ISRCTN: ISRCTN94022291. PMID- 28666536 TI - A Cost-Utility Analysis of 5 Strategies for the Management of Acute Otitis Media in Children. AB - OBJECTIVE: To assess whether antimicrobial therapy in young children with acute otitis media reduces time to resolution of symptoms, overall symptom burden, and persistence of otoscopic evidence of infection. We used a cost-utility model to evaluate whether immediate antimicrobial treatment seems to be worthwhile, and if so, which antimicrobial agent is most cost effective. STUDY DESIGN: We compared the cost per quality-adjusted life-day of 5 treatment regimens in children younger than 2 years of age with acute otitis media: immediate amoxicillin/clavulanate, immediate amoxicillin, immediate cefdinir, watchful waiting, and delayed prescription (DP) for antibiotic. RESULTS: The 5 treatment regimens, listed in order from least effective to most effective were DP, watchful waiting, immediate cefdinir, immediate amoxicillin, and immediate amoxicillin/clavulanate. Listed in order from least costly to most costly, the regimens were DP, immediate amoxicillin, watchful waiting, immediate amoxicillin/clavulanate, and immediate cefdinir. The incremental cost-utility ratio of immediate amoxicillin compared with DP was $101.07 per quality-adjusted life-day gained. The incremental cost-utility ratio of immediate amoxicillin/clavulanate compared with amoxicillin was $2331.28 per quality adjusted life-day gained. CONCLUSIONS: In children younger than 2 years of age with acute otitis media and no recent antibiotic exposure, immediate amoxicillin seems to be the most cost-effective initial treatment. PMID- 28666537 TI - Dermal exposure to weathered MC252 crude oil results in echocardiographically identifiable systolic myocardial dysfunction in double-crested cormorants (Phalacrocorax auritus). AB - During the Deepwater Horizon Natural Resource Damage Assessment, gross morphologic cardiac abnormalities, including softer, more distensible musculature, were noted upon gross necropsy in hearts from laughing gulls and double-crested cormorants exposed to weathered MC252 crude oil. A species specific, echocardiographic technique was developed for antemortem evaluation of function that was used to evaluate and better characterize cardiac dysfunction. Control (n=12) and treated (n=13) cormorant groups of similar sex-ratio and ages were dermally treated with approximately 13ml of water or weathered MC252 crude oil, respectively, every 3 days for 6 dosages. This resulted in a low to moderate external exposure. Upon visualization and clinical assessment of the hearts of all test subjects, comprehensive diagnostic cardiographic measurements were taken twice, prior to oil application and after a 21day dermal oil exposure. Oil treated birds showed a decrease in cardiac systolic function, as characterized by an increased left ventricular internal dimension-systole and left ventricular stroke volume as well as concurrent decreased left ventricular ejection fraction and left ventricular fractional shortening when compared to both control birds' and the treated birds' time zero values. These changes are indicative of a possible dilative cardiomyopathy induced by oil exposure, although further elucidation of possible collagen damage is recommended. Arrhythmias including tachycardia in two treated birds and bradycardia in all treated birds were documented, indicating further clinically significant abnormalities induced by MC252 oil that warrant further investigation. A statistically significant increase in free calcium concentration, important to muscular and neurologic function in treated birds was also noted. This study documents that weathered MC252 oil caused clinically significant cardiac dysfunction that could result in mortality and decrease recruitment. PMID- 28666538 TI - The relevance of looking for right bundle branch block in catheter ablation of Ebstein's anomaly. AB - INTRODUCTION: Ebstein's anomaly is the most commonly occurring congenital defect associated with the Wolff-Parkinson-White syndrome. In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of right bundle branch block (RBBB) in sinus rhythm is a highly sensitive and specific indicator of the presence of an ipsilateral accessory AP. CASE: We present an electrophysiology case of a patient with Ebstein's anomaly and 3 ipsilateral accessory pathways. After ablation was performed, RBBB was evident. CONCLUSION: In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of a RBBB pattern in the surface ECG after RFCA should raise suspicion for the presence of multiple accessory pathways. PMID- 28666539 TI - Type A chronic aortic dissection with obesity and preeclampsia. AB - Aortic dissection is a potentially lethal disease whose incidence in pregnant women can be up to 100 times that of the remaining adult population. In most cases, it presents as typical chest pain. We report the case of a 37yo obese woman diagnosed with chronic type A aortic dissection documented by a radiological finding 10 months after delivery. PMID- 28666540 TI - Complication during tracheostomy: Internal carotid artery ligation. PMID- 28666541 TI - Management of elderly women with endometrial cancer. AB - BACKGROUND: Elderly women with endometrial cancer receive less therapy in comparison with their younger counterparts. The exact reason(s) for this treatment strategy remains unclear. PATIENTS AND METHODS: We performed a multicenter, retrospective registry-based study of 1550 patients with endometrial cancer. The outcome measure was the reason for not performing the indicated treatment. RESULTS: Median follow-up was 76.8months. A total of 1550 women were eligible for analysis: 353 (22.7%) were younger than 60years, 521 (33.6%) 61 70years, 515 (33.2%) 71-80years, and 161 (10.4%) were aged 81years old and older. Elderly women were more likely to have non-endometrioid, undifferentiated endometrial cancer at an advanced stage. Patients younger than 60years were more likely to receive lymphadenectomy, brachytherapy, external-beam radiotherapy (EBRT) and systemic therapy compared with the group of patients aged older than 70years. We investigated the reason why elderly women were undertreated. The rate of indicated therapies that were not recommended by the physicians proportionally increased with an increase in patient age. Interestingly, the rate of contraindications because of performance status and/or medical disease also increased proportionally with increasing patient age. Notably, in the groups of patients older than 70years, patient refusal was a very uncommon reason for failure to perform the indicated therapy. CONCLUSIONS: Elderly women with EC are more likely undertreated because the therapy was not recommended by the physicians based on performance status and medical diseases rather than patient refusal. PMID- 28666542 TI - Recruitment challenges in clinical research: Survey of potential participants in a diagnostic study of ovarian cancer. AB - OBJECTIVE: Recruiting participants in clinical research is challenging. Certain groups, such as older adults, rural residents, and individuals with lower socio economic status, are typically underrepresented. Here, we explore perceived motivators and barriers among potential participants in a diagnostic study of ovarian cancer. METHODS: Women aged 50 and older who answered a mail survey in Montreal, Canada, were asked to assess their eligibility to participate in the ongoing Diagnosing Ovarian cancer Early (DOvE) Study. If 'eligible', they were asked whether they planned to participate in DOvE. Using modified Poisson regression, we examined responders' self-assessment of eligibility, intention to participate, and reasons for why or why not, as a function of socio-demographic and health indicators. RESULTS: Of 826 responders, 33.1% misclassified themselves with respect to eligibility. Among 532 self-assessed eligible women, 56.4% planned to participate in the study. The majority of women not planning to participate preferred to be assessed by their physicians (a reason more commonly reported by those with lower education or income) or believed they were not at risk of ovarian cancer (despite having no fewer risk factors). "Inconvenience" was also a commonly reported reason, especially among rural residents. Women who planned to participate often perceived a benefit (e.g. to rule out ovarian cancer, or to receive a quick check-up). CONCLUSIONS: Recruitment, particularly of underrepresented groups, in clinical studies may be enhanced by involving primary care providers, facilitating access to study sites, and providing clear information about the disease under study (including risk factors) and eligibility criteria. PMID- 28666543 TI - The vulnerable adult experiment: Situating vulnerability in adult safeguarding law and policy. AB - This article explores the intersection of English adult protection law and policy as it impacted on the lives of people with mental disabilities. It evaluates developments that were premised on the notion of the 'vulnerable adult', in light of recent theoretical interrogation of vulnerability and the normative shifts in law and policy advocated by the UNCRPD. I argue that the policy and legal conceptions of vulnerability developed in England and Wales, if reworked, have the potential to transform our understanding of what it is to be vulnerable into a more radical and socially-grounded framework for adult safeguarding. This article concludes with some reflections on what further conceptual and policy work must be done in order to effect that transformation. PMID- 28666544 TI - Advances in Alzheimer's Diagnosis and Therapy: The Implications of Nanotechnology. AB - Alzheimer's disease (AD) is a type of dementia that causes major issues for patients' memory, thinking, and behavior. Despite efforts to advance AD diagnostic and therapeutic tools, AD remains incurable due to its complex and multifactorial nature and lack of effective diagnostics/therapeutics. Nanoparticles (NPs) have demonstrated the potential to overcome the challenges and limitations associated with traditional diagnostics/therapeutics. Nanotechnology is now offering new tools and insights to advance our understanding of AD and eventually may offer new hope to AD patients. Here, we review the key roles of nanotechnologies in the recent literature, in both diagnostic and therapeutic aspects of AD, and discuss how these achievements may improve patient prognosis and quality of life. PMID- 28666545 TI - Biotechnological Perspectives of Pyrolysis Oil for a Bio-Based Economy. AB - Lignocellulosic biomass is an important feedstock for a potential future bio based economy. Owing to its compact structure, suitable decomposition technologies will be necessary to make it accessible for biotechnological conversion. While chemical and enzymatic hydrolysis are currently established methods, a promising alternative is provided by fast pyrolysis. The main resulting product thereof, referred to as pyrolysis oil, is an energy-rich and easily transportable liquid. Many of the identified constituents of pyrolysis oil, however, have previously been reported to display adverse effects on microbial growth. In this Opinion we discuss relevant biological, biotechnological, and technological challenges that need to be addressed to establish pyrolysis oil as a reliable microbial feedstock for a bio-based economy of the future. PMID- 28666546 TI - Ten years after the financial crisis: The long reach of austerity and its global impacts on health. PMID- 28666547 TI - Staff and patient perspectives of a smoke-free health services policy in South Australia: A state-wide implementation. AB - Few jurisdictions have implemented and evaluated a complete smoking ban across all health sites in their jurisdiction, with no designated smoking areas. This article examines staff and patient perceptions and experiences of a mandated smoke-free policy implemented across all government health facilities in South Australia, including mental health sites. An online survey of health staff was conducted prior to policy implementation (n=3098), 3 months post-implementation (n=2673) and 15 months post-implementation (n=2890). Consumer experiences of the policy were assessed via a telephone survey (n=1722; smokers n=254). Staff support for the policy was high across all time points. Two thirds of staff reported having witnessed some policy non-compliance, and self-reported exposure to second-hand smoke was comparable pre-implementation to 15 months post implementation. Under the policy, 56.3% of smoking patients abstained completely whilst hospitalised and 37.6% cut down the amount that they smoked. Furthermore, 34.7% reported having been offered cessation support during hospitalisation. Whilst the smoke-free policy was viewed positively and had benefits for staff and patients, reports of witnessing some non-compliance were prevalent. While the extent of non-compliance is not known, and the measure used was sensitive, complementary strategies may be needed to reduce exposure to second-hand smoke, particularly at entrances. Health-care staff should be further encouraged to offer support to nicotine-dependent patients to foster compliance and promote abstinence during hospitalisation. PMID- 28666548 TI - Evaluation of fatigability measurement: Integrative review. AB - Fatigability is defined as the extent of fatigue in the context of activity and differs from the term used in exercise literature to describe muscle endurance characteristics. Many fatigability measures are available, but no studies have thoroughly evaluated them for adequate incorporation of fatigability concepts. This integrative review provides an overall assessment of existing fatigability measures and then evaluates each in depth. A database search and hand search produced 14 studies for review. Fatigability measurement took three forms: self reported fatigability, perceived fatigability (self-reported fatigue following a defined performance test), and performance fatigability (performance deterioration). Of 17 measures identified, validity and/or reliability was reported for six (35.3%), and no measure was used in more than one study. Fatigability measures have been correlated with clinical measures, indicating that fatigability should be measured during routine clinical health screening. Refinement of measures and additional fatigability data collection will improve understanding and treatment of fatigue. PMID- 28666549 TI - Second-look US Using Real-time Virtual Sonography, a Coordinated Breast US and MRI System with Electromagnetic Tracking Technology: A Pilot Study. AB - Our aim was to retrospectively evaluate the utility of second-look ultrasound (US) using real-time virtual sonography (RVS) for detection of conventional B mode (cB-mode) occult magnetic resonance imaging (MRI)-detected breast lesions. Between July 2011 and May 2015, 53 consecutive patients who underwent second-look US to identify lesions detected by prone MRI were enrolled in this study. Second look US using RVS was performed for cB-mode occult MRI-detected breast lesions after an additional supine MRI. In the 53 patients, 59 lesions were initially detected by prone MRI, followed by second-look US. Of the 59 lesions, 20 (34%) were identified by second-look US using cB-mode. Of the 39 (66%) cB-mode occult lesions, 38 (97%) were detected in supine MRI and 33 (85%) were detected by second-look US using RVS. MRI morphology types of the 33 lesions were as follows: mass, 16; non-mass enhancement, 5; and focus, 12. US-guided biopsy under RVS or excisional biopsy demonstrated that of the 33 lesions, 8 (24%) were malignant and the remaining 25 (76%) were benign. A total of 53 (90%) MRI-detected lesions were sonographically identified using both cB-mode and RVS (p < 0.001). All five remaining US-occult lesions could be followed up under RVS after the enhancing area was marked on the breast surface using RVS. Although further prospective studies are required, the findings of our pilot study suggest that second-look US using RVS with additional supine MRI may improve the sonographic and histopathologic detection rate of cB-mode occult MRI-detected breast lesions. PMID- 28666550 TI - Evaluation of Antivascular Combretastatin A4 P Efficacy Using Supersonic Shear Imaging Technique of Ectopic Colon Carcinoma CT26. AB - A recent ultrasound imaging technique-shear wave elastography-showed its ability to image and quantify the mechanical properties of biological tissues, such as prostate or liver tissues. In the present study this technique was used to evaluate the relationship among tumor growth, stiffness and reduction of treatment with combretastatin (CA4 P) in allografted colon tumor CT26 in mice. During 12 d, CT26 tumor growth (n = 52) was imaged by ultrasound, and shear modulus was quantified, showing a good correlation between tumor volume and stiffness (r = 0.59). The treatment was initiated at d 12 and monitored every d during 4 d. Following the treatment, the tumor volume had decreased, while the elasticity of the tumor volume remained steady throughout the treatment. After segmentation using the shear modulus map, a detailed analysis showed a decrease in the stiffness after treatment. This reduction in the mechanical properties was shown to correlate with tissue reorganization, particularly, fibrosis and necrosis, assessed by histology. PMID- 28666551 TI - European Organization for Research and Treatment of Cancer (EORTC) recommendations for planning and delivery of high-dose, high precision radiotherapy for lung cancer. AB - PURPOSE: To update literature-based recommendations for techniques used in high precision thoracic radiotherapy for lung cancer, in both routine practice and clinical trials. METHODS: A literature search was performed to identify published articles that were considered clinically relevant and practical to use. Recommendations were categorised under the following headings: patient positioning and immobilisation, Tumour and nodal changes, CT and FDG-PET imaging, target volumes definition, radiotherapy treatment planning and treatment delivery. An adapted grading of evidence from the Infectious Disease Society of America, and for models the TRIPOD criteria, were used. RESULTS: Recommendations were identified for each of the above categories. CONCLUSION: Recommendations for the clinical implementation of high-precision conformal radiotherapy and stereotactic body radiotherapy for lung tumours were identified from the literature. Techniques that were considered investigational at present are highlighted. PMID- 28666552 TI - Single-dose high-dose-rate brachytherapy compared to two and three fractions for locally advanced prostate cancer. AB - BACKGROUND: Single-dose high-dose-rate brachytherapy (HDR-BT), in a Phase-II study, was compared to two or three fractions in intermediate and high-risk localized prostate cancer. PATIENTS AND METHODS: 293 patients received 1*19Gy or 1*20Gy (A=49), 2*13Gy (B=138), or 3*10.5Gy (C=106) and assessed with prospective measures of serum PSA, late genitourinary (GU) and gastrointestinal (GI) morbidity using RTOG scales and the International Prostate Symptom Score (IPSS). RESULTS: Median follow-up is 49, 63 and 108months (A, B and C, respectively). At 4years biochemical relapse free survival was 94% (A), 93% (B) and 91% (C) (p=0.54). Risk-category was the only significant independent predictor of relapse (p<0.0001). Kaplan-Meier 4-year-estimates of GU-3 were 2% (A and B) and 11% (C). GI-3 was 0% (A and B) and 1% (C). No GU or GI grade-4 events were observed. IPSS>=20 was 11% (A), 9% (B) and 16% (C) (p=0.9). Prevalence of GU-3 was <=4% in the 3 groups at all times; GI-3 was low or non-existent. Prevalence of catheter use was <=6% in all groups. CONCLUSIONS: A single dose of 19-20Gy achieves similar rates of late morbidity and biochemical control compared to 2 and 3 fractions. PMID- 28666553 TI - Binocular rivalry after right-hemisphere stroke: Effects of attention impairment on perceptual dominance patterns. AB - Binocular rivalry is when perception fluctuates while the stimuli, consisting of different images presented to each eye, remain unchanged. The fluctuation rate and predominance ratio of these images are regarded as information source for understanding properties of consciousness and perception. We administered a binocular rivalry task to 26 right-hemisphere stroke patients and 26 healthy control participants, using stimuli such as simple Gabor anaglyphs. Each single Gabor image was of unequal spatial frequency compared to its counterpart, allowing assessment of the effect of relative spatial frequency on rivalry predominance. Results revealed that patients had significantly decreased alternation rate compared to healthy controls, with severity of patients' attention impairment predicting alternation rates. The patient group had higher predominance ratio for high compared to low relative spatial frequency stimuli consistent with the hypothesis that damage to the right hemisphere may disrupt processing of relatively low spatial frequencies. Degree of attention impairment also predicted the effect of relative spatial frequencies. Lastly, both groups showed increased predominance rates in the right eye compared to the left eye. This right eye dominance was more pronounced in patients than controls, suggesting that right hemisphere stroke may additionally affect eye predominance ratios. PMID- 28666554 TI - Characterization of pharmaceutically relevant materials at the solid state employing chemometrics methods. AB - The understanding of materials and processes is a requirement when it comes to build quality into pharmaceutical products. This can be achieved through the development of rapid, efficient and versatile analytical methods able to perform qualification or quantification tasks along the manufacturing and control process. Process monitoring, capable of providing reliable real-time insights into the processes performance during the manufacturing of solid dosage forms, are the key to improve such understanding. In response to these demands, in recent times multivariate chemometrics algorithms have been increasingly associated to different analytical techniques, mainly vibrational spectroscopies [Raman, mid-infrared (MIR), near-infrared (NIR)], but also ultraviolet-visible (UV-vis) spectroscopy, X-ray powder diffraction and other methodologies. The resulting associations have been applied to the characterization and evaluation of different aspects of pharmaceutical materials at the solid state. This review examines the different scenarios where these methodological marriages have been successful. The list of analytical problems and regulatory demands solved by chemometrics analysis of solid-state multivariate data covers the whole manufacturing and control processes of both, active pharmaceutical ingredients in bulk and in their drug products. Hence, these combinations have found use in monitoring the crystallization processes of drugs and supramolecular drug associations (co-crystals, co-amorphous and salts), to access the correct crystal morphology, particle size, solubility and dissolution properties. In addition, they have been applied to identify and quantitate specific compounds, mainly active pharmaceutical ingredients in complex solid state mixtures. This included drug stability against different stimuli, solid-state transformations, or detection of adulterated or fraudulent medicines. The use of chemometrics assisted analytical methods as part of the modern concept of process analytical technology, where every process step of every product batch from raw materials to final product must take place in a controlled manner is discussed. Finally, but no less important, the application of chemometrics methods to chemical imaging, aiming to extract spatial and compositional information is also revised. PMID- 28666555 TI - Life cycle management of analytical methods. AB - In modern process management, the life cycle concept gains more and more importance. It focusses on the total costs of the process from invest to operation and finally retirement. Also for analytical procedures an increasing interest for this concept exists in the recent years. The life cycle of an analytical method consists of design, development, validation (including instrumental qualification, continuous method performance verification and method transfer) and finally retirement of the method. It appears, that also regulatory bodies have increased their awareness on life cycle management for analytical methods. Thus, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as well as the United States Pharmacopeial Forum discuss the enrollment of new guidelines that include life cycle management of analytical methods. The US Pharmacopeia (USP) Validation and Verification expert panel already proposed a new General Chapter <1220> "The Analytical Procedure Lifecycle" for integration into USP. Furthermore, also in the non-regulated environment a growing interest on life cycle management is seen. Quality-by-design based method development results in increased method robustness. Thereby a decreased effort is needed for method performance verification, and post-approval changes as well as minimized risk of method related out-of-specification results. This strongly contributes to reduced costs of the method during its life cycle. PMID- 28666556 TI - Consequences of inappropriate empirical antibiotic therapy depending on the patient's clinical situation. PMID- 28666557 TI - Citizens' perceptions of the presence and health risks of synthetic chemicals in food: results of an online survey in Spain. AB - OBJECTIVE: To explore factors influencing perceptions and viewpoints on the responsibility for the presence of toxic substances in food, on enforcement of laws and regulations that control human exposure to toxic substances in food, and on the effectiveness of such regulations. METHODS: An online survey was completed by 740 individuals from several parts of Spain (median age, 47 years; 67% were women; 70% had completed university studies). RESULTS: Over 87% of respondents said that it was possible that throughout their lives they could have accumulated in their body toxic substances potentially dangerous to their health. The attribution of the responsibility for toxic substances in food to a larger number of social groups was more frequent among respondents who consulted information about the problem more often (odds ratio [OR]: 1.92), who correctly identified factors that increase the likelihood of toxic substances in food being harmful to human health (OR: 2.86), who better knew the health problems that may be caused by such substances (OR: 2.48), and who recognised more food groups that tend to have concentrations of toxic substances potentially harmful to health (OR: 2.92) (all p values <0.001). Women were 65% less likely than men to answer that regulations on toxic substances in food are effective (p<0.001); and so were participants who identified more food groups with potentially toxic concentrations. CONCLUSIONS: Among study participants there was a widespread scepticism and distrust towards the enforcement and effectiveness of laws and regulations that in Spain aim to control human exposure to toxic substances in food. PMID- 28666558 TI - Systematic review of emerging and innovative technologies for meat tenderisation. AB - Consumers are the final step in the meat supply chain and meeting consumer expectations of quality and tenderness are important for satisfaction and repeat purchase. High pressure processing, shockwaves, ultrasound, pulsed electric field and muscle stretching can be applied to pre- and post-rigor meat for tenderisation. These non-thermal and thermal innovative technologies can be used with varying levels of success to cause physical disruption to muscle structure, enhanced proteolysis and ageing and muscle protein denaturation and solubilisation resulting in changes to texture and juiciness. Results of a meta analysis are used to compare the effects of these technologies on meat tenderisation. In the future, a combination of new and innovative technologies will be ideally suited to deliver a range of desired textures for meat products. PMID- 28666559 TI - Epidemiology of Benign External Hydrocephalus in Norway-A Population-Based Study. AB - BACKGROUND: Benign external hydrocephalus is defined as a rapidly increasing head circumference (occipitofrontal circumference) with characteristic radiological findings of increased subarachnoid cerebrospinal fluid spaces on neuroimaging. The incidence of benign external hydrocephalus has not been previously reported, and there is no available information on the ratio of benign external hydrocephalus in the population of hydrocephalic children. METHODS: This study is retrospective and population-based study, geographically covering two health regions in the southern half of Norway with a total mean population of 3.34 million in the ten-year study period, constituting approximately 75% of the Norwegian population. Children with a head circumference crossing two percentiles, or greater than the 97.5th percentile, and with typical imaging findings of enlarged frontal subarachnoid spaces with or without enlarged ventricles were included. Children were excluded if they had a history of head trauma, intracranial hemorrhage, central nervous system infection, other known causes of hydrocephalus, or were born preterm defined as birth before 37 weeks of gestation. RESULTS: A total of 176 children fitting the criteria were identified, giving an incidence of 0.4 per 1000 live births. One hundred fifty-two (86.4%) of the patients were male, and mean age at referral was 7.3 months. Increasing head circumference was the main reason for referral in 158 (89.8%) patients and the only finding in 60 (34.1%) patients. Thirty-seven (21%) children had normal ventricles on imaging; the remainder had increased ventricular size. The incidence of pediatric hydrocephalus in Norway is reported to be 0.75 per 1000 live births, thus benign external hydrocephalus accounts for approximately 50% of hydrocephalic conditions in this population. CONCLUSIONS: The incidence of benign external hydrocephalus was found to be 0.4 per 1000 live births in this population. PMID- 28666560 TI - Worldwide population variation in pelvic sexual dimorphism: A validation and recalibration of the Klales et al. method. AB - Sex estimation is an integral aspect of biological anthropology. Correctly estimating sex is the first step to many subsequent analyses, such as estimating living stature or age-at-death. Klales et al. (2012) [6] provided a revised version of the Phenice (1969) [3] method that expanded the original three traits (ventral arc, subpubic concavity/contour, and medial aspect of the ischio-pubic ramus) into five character states to capture varying degrees of expression within each trait. The Klales et al. (2012) [6] method also provided associated probabilities with each sex classification, which is of particular importance in forensic anthropology. However, the external validity of this method must be tested prior to applying the method to different populations from which the method was developed. A total of 1915 innominates from four diverse geographic populations: (1) U.S. Blacks and Whites; (2) South African Blacks and Whites; (3) Thai; and (4) unidentified Hispanic border crossers were scored in accordance with Klales et al. (2012) [6]. Trait scores for each innominate were entered into the equation provided by Klales et al. (2012) [6] for external validation. Additionally, recalibration equations were calculated with logistic regression for each population and for a pooled global sample. Validation accuracies ranged from 87.5% to 95.6% and recalibration equation accuracies ranged from 89.6% to 98% total correct. Pooling all samples and using Klales' et al. (2012) [6] equations achieved an overall validation accuracy of 93.5%. The global recalibration model achieved 95.9% classification accuracy and can be employed in diverse worldwide populations for accurate sex estimation without the need for population specific equations. PMID- 28666561 TI - Emergency Magnetic Resonance Imaging 3-Tiered Prioritization. AB - BACKGROUND/PURPOSE: Traditional methods for prioritization are limited and insufficient for today's magnetic resonance imaging (MRI) demands. In particular, the discrepancy in urgency of the heterogeneous emergency department (ED) patient population necessitates risk stratification to meet different degrees of urgency. The purpose of this study is to more effectively prioritize the MRI imaging needs of ED patients commensurate with the severity of their presenting illness. METHODS: A 3-level tiered classification system (tier 1: critical, tier 2: emergent, and tier 3: urgent) of ED patients with unambiguous hierarchically defined numerical classifications was implemented to replace a traditional method of MRI orders. Each tier was accompanied by guiding consensus-driven clinical definitions and common qualifying examples. Lastly, each tier imaging order was tied to a specific target "order to imaging start time" (OTST). After implementation, a month-by-month 1-year retrospective analysis of ED MRI imaging order volume was conducted to assess the percentage distribution of each category. In addition, a month-by-month 1-year retrospective analysis of the OTST for each tier was conducted. The OTST outcome measure was used to monitor the ability of the system to meet tier target times based on severity. RESULTS: The system effectively prioritized ED patients into 3 tiers based on acuity. An inverse relationship existed between ED MRI OTST and the tier severity into which the patient was stratified. We found that only 4% of the ED-specific volume is truly critical (tier 1). In addition, tier 3 MRI examinations constituted 75% of the ED volume. Month-by-month quality assurance analysis demonstrated consistent completion of examinations under or close to the target times tied to each tier. The average overall wait time from order time to begin scan time for all ED MRIs decreased from 245 minutes (4.1 hours) at baseline to less than 136 minutes (2.7 hours). CONCLUSIONS: We implemented and evaluated a 3-tiered system of ED MRI imaging orders based on patient severity. The system was unambiguous due to its numerical hierarchy, and each of the 3 tiers was accompanied by explicit guiding definitions for each category. A quality assurance process following implementation allowed us to monitor the ability of the system to meet target times tied to each tier. Our current ability to accurately predict a target performance time allows us to set accurate expectations for both providers and patients. PMID- 28666562 TI - Emergency Medicine Myths: Computed Tomography of the Head Prior to Lumbar Puncture in Adults with Suspected Bacterial Meningitis - Due Diligence or Antiquated Practice? AB - BACKGROUND: Various sources purport an association between lumbar puncture and brainstem herniation in patients with intracranial mass effect lesions. Several organizations and texts recommend head computed tomography (CT) prior to lumbar puncture in selected patients. OBJECTIVE: To review the evidence regarding the utility of obtaining head CT prior to lumbar puncture in adults with suspected bacterial meningitis. DISCUSSION: Observational studies report a risk of post lumbar puncture brainstem herniation in the presence of intracranial mass effect (1.5%) that is significantly lower than that reported among all patients with bacterial meningitis (up to 13.3%). It is unclear from existing literature whether identifying patients with intracranial mass effect decreases herniation risk. Up to 80% of patients with bacterial meningitis experiencing herniation have no CT abnormalities, and approximately half of patients with intracranial mass effect not undergoing lumbar puncture herniate. Decision rules to selectively perform CT on only those individuals most likely to have intracranial mass effect lesions have not undergone validation. Despite recommendations for immediate antimicrobial therapy prior to imaging, data indicate an association between pre-lumbar puncture CT and antibiotic delays. Recent data demonstrate shortened door-to-antibiotic times and lower mortality from bacterial meningitis after implementation of new national guidelines, which restricted generally accepted CT indications by removing impaired mental status as imaging criterion. CONCLUSIONS: Data supporting routine head CT prior to lumbar puncture are limited. Physicians should consider selective CT for those patients at risk for intracranial mass effect lesions based on decision rules or clinical gestalt. Patients undergoing head CT must receive immediate antibiotic therapy. PMID- 28666563 TI - Abdominal parametric perfusion imaging with respiratory motion-compensation based on contrast-enhanced ultrasound: In-vivo validation. AB - Parametric perfusion imaging (PPI) based on dynamic contrast-enhanced ultrasound (DCEUS) is a multi-parametric functional method that is increasingly used to characterize the hemodynamic features of abdominal tumors. Periodic respiratory kinetics adversely affects the signal-to-clutter ratio (SCR) and accuracy of abdominal PPI. This study proposed respiratory motion-compensation (rMoCo) employing non-negative matrix factorization combined with fast block matching algorithm to effectively remove these disturbances on abdominal PPI, which was validated through in-vivo perfusion experiments. The mean calculation efficiency of rMoCo was improved by 83.6% when the algorithm was accelerated in a unique matching sequence, which was formed from dozens of DCEUS subsequences at the same respiratory phase. The horizontal and vertical displacements induced by respiratory kinetics were estimated to correct the extraction of time-intensity curves and the peak SNR remained at 22.58+/-2.90dB. Finally, the abdominal PPIs of four perfusion parameters were formed with non-negative rMoCo, and their SCR was improved by 3.99+/-0.49dB (p<0.05). Compared with the results without rMoCo, the continuity and visualization of abdominal arterioles were clearly enhanced, and their perfusion details were accurately characterized by PPIs with non negative rMoCo. The proposed method benefits clinicians in providing accurate diagnoses and in developing appropriate therapeutic strategies for abdominal diseases. PMID- 28666564 TI - The dilatation of main pulmonary artery and right ventricle observed by enhanced chest computed tomography predict poor outcome in inoperable chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Dilatation of the pulmonary artery and right ventricle on chest computed tomography images is often observed in patients with pulmonary hypertension. The clinical significance of these image findings has not been defined in chronic thromboembolic pulmonary hypertension. We investigated whether the pulmonary arterial and right ventricle dilatation was associated with poor outcome in chronic thromboembolic pulmonary hypertension. METHODS: This was a retrospective cohort investigation in 60 subjects with inoperable chronic thromboembolic pulmonary hypertension diagnosed consecutively between 1997 and 2010 at Chiba University Hospital. Digital scout multi-detector chest computed tomography images were obtained. The main pulmonary arterial to ascending aortic diameter ratio and the right ventricular to left ventricular diameter ratio were calculated. RESULTS: Main pulmonary arterial to ascending aortic diameter ratio ranged from 0.85 to 1.84, and right ventricular to left ventricular diameter ratio ranged from 0.71 to 2.88. During the observation period of 1284.5days (range, 21-4550days), 13 patients required hospitalization due to worsening; 6 of them died. Kaplan-Meier analysis showed significant differences in hospitalization between the patients with main pulmonary arterial to ascending aortic diameter ratio of >=1.1 and <1.1 (log-rank test, p=0.014) and between the patients with right ventricular to left ventricular diameter ratio of >=1.2 and <1.2 (log-rank test, p=0.013). There was a significant difference in the prognosis between the patients with RV/LV ratio>=1.2 and those with RV/LV ratio<1.2 (log-rank test, p=0.033). CONCLUSIONS: Main pulmonary arterial to ascending aortic diameter ratio measured using enhanced CT images was associated with the risk for first clinical exacerbation, and right ventricular to left ventricular diameter ratio was associated with the risk for poor prognosis in inoperable chronic thromboembolic pulmonary hypertension. PMID- 28666565 TI - A novel strategy with combined assays for detection of anti-neutrophil cytoplasmic antibody (ANCA) in clinically ANCA-negative granulomatosis with polyangiitis patients. AB - OBJECTIVE: Granulomatosis with polyangiitis (GPA) that is localized to the upper airway presents a diagnostic challenge because of a tendency towards anti neutrophil cytoplasmic antibody (ANCA)-negativity. The purpose of this study was to investigate whether positivity of ANCA detection might be elicited with combined use of enzyme-linked immunosorbent assay (ELISA) kits. METHODS: Twenty nine serum samples obtained from GPA patients were used in this study. In addition to routine biochemical investigation for ANCA, tests for detecting PR3-, MPO-ANCAs, and minor ANCAs were performed with commercially available ELISA kits. Cytoplasmic (C)-ANCA and perinuclear (P)-ANCA were evaluated using the indirect immunofluorescence (IIF) technique. RESULTS: Twelve patients were positive for PR3- or MPO-ANCA in the clinical laboratory test, and 17 patients were negative for both ANCAs. Of the 17 ANCA-negative patients, four were positive for PR3- or MPO-ANCA, and three were positive for minor ANCA according to results obtained from six different ELISA kits. These findings indicated that performing detection tests with six different ELISA kits might improve the positivity of ANCA and might contribute to establishing the diagnosis of ANCA-associated vasculitis. Together with results from IIF, the samples of eight patients with clinically ANCA-negative results (8/17, 47.1%) were converted to ANCA-positive results, and the ANCA detection rate was significantly improved from 12/29 (41.4%) to 20/29 (69.0%, p=0.03). CONCLUSIONS: Additional detection techniques should be used to confirm the results of clinically ANCA-negative samples, particularly when vasculitis is suspected. Minor ANCAs should also be evaluated with detection tests when PR3- and MPO-ANCA are negative. PMID- 28666567 TI - Editorial Overview: Nanotechnology and biotechnology: Two way traffic. PMID- 28666566 TI - [Subacute cutaneous lupus erythematosus induced by 5-fluorouracil]. PMID- 28666568 TI - More than planned: Implementation intention effects in non-planned situations. AB - Forming implementation intentions (i.e., if-then planning) is a powerful self regulation strategy that enhances goal attainment by facilitating the automatic initiation of goal-directed responses upon encountering critical situations. Yet, little is known about the consequences of forming implementation intentions for goal attainment in situations that were not specified in the if-then plan. In three experiments, we assessed goal attainment in terms of speed and accuracy in an object classification task, focusing on situations that were similar or dissimilar to critical situations and required planned or different responses. The results of Experiments 1 and 3 provide evidence for a facilitation of planned responses in critical and in sufficiently similar situations, enhancing goal attainment when the planned response was required and impairing it otherwise. In Experiment 3, additional unfavorable effects however emerged in situations that were dissimilar to the critical one but required the planned response as well. We discuss theoretical implications as well as potential benefits and pitfalls emerging from these non-planned effects of forming implementation intentions. PMID- 28666569 TI - Multivariate fault isolation of batch processes via variable selection in partial least squares discriminant analysis. AB - In recent years, multivariate statistical monitoring of batch processes has become a popular research topic, wherein multivariate fault isolation is an important step aiming at the identification of the faulty variables contributing most to the detected process abnormality. Although contribution plots have been commonly used in statistical fault isolation, such methods suffer from the smearing effect between correlated variables. In particular, in batch process monitoring, the high autocorrelations and cross-correlations that exist in variable trajectories make the smearing effect unavoidable. To address such a problem, a variable selection-based fault isolation method is proposed in this research, which transforms the fault isolation problem into a variable selection problem in partial least squares discriminant analysis and solves it by calculating a sparse partial least squares model. As different from the traditional methods, the proposed method emphasizes the relative importance of each process variable. Such information may help process engineers in conducting root-cause diagnosis. PMID- 28666570 TI - Dead-space ventilation is linked to exercise capacity and survival in distal chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Cardiopulmonary exercise testing (CPET) is frequently used for the evaluation of patients with pulmonary hypertension (PH). Non-operable distal chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subgroup of PH where microvascular disease resembling pulmonary arterial hypertension (PAH) may predominate and efficacious medical therapy is now available. However, little is known regarding the detailed CPET profile of patients with distal CTEPH, and whether ventilation and gas exchange responses are different from PAH. METHODS: Forty-nine consecutive patients with non operable distal CTEPH according to multidisciplinary team assessment and 45 PAH patients underwent CPET and right heart catheterization. Patients were followed up for a median of 3.2 years (interquartile range: 1.8 to 4.4). RESULTS: Pulmonary hemodynamics were similar in distal CTEPH and PAH groups, but patients with distal CTEPH achieved a lower percent predicted peak oxygen consumption (59 +/- 13% vs 66 +/- 14%, p < 0.05). At peak exercise, higher physiologic dead-space fraction (VD/VT) (0.45 +/- 0.07 vs 0.35 +/- 0.07, p < 0.0001) and higher arterial to-end-tidal carbon dioxide gradient (9 +/- 3 vs 5 +/- 3 mm Hg, p < 0.0001) were observed in distal CTEPH compared with PAH. Ventilatory efficiency, expressed as VE/VCO2 slope, was also more impaired in distal CTEPH (52.2 +/- 10.1 vs 43.8 +/- 8.4 liters/min, p < 0.0001). In the distal CTEPH group only, higher VD/VT was associated with lower peak oxygen consumption (r = -0.46, p = 0.003) and worse survival. CONCLUSIONS: Compared with PAH, a distinct pattern of response to exercise was observed in distal CTEPH, characterized by increased dead-space ventilation that resulted in worse ventilatory efficiency and greater impairment of exercise capacity. In distal CTEPH, dead-space ventilation correlated with exercise capacity and was associated with survival. PMID- 28666571 TI - Usefulness of 2 centrifugal ventricular assist devices in a total artificial heart configuration: A preliminary report. PMID- 28666572 TI - Rare diagnosis of telethoninopathy (LGMD2G) in a Turkish patient. AB - Telethoninopathy is one of the rarest forms of Limb-girdle muscular dystrophy (LGMD). So far, only a small number of LGMD type 2 G (LGMD2G) patients have been described, mostly patients from Brazil. Here we present a 35-year-old female patient of Turkish ethnicity with LGMD2G due to a novel homozygous frame-shift mutation c.90_91del (p.Ser31Hisfs*11) in the telethonin gene, probably leading to truncated protein or nonsense mediated decay. Myalgia and walking on tiptoes were the first symptoms starting in early childhood, around age 22 proximal, later distal leg muscles became affected. Muscle biopsy showed a degenerative myopathy with lobulated fibers, creatine kinase levels were elevated to 1200 U/l. No cardiomyopathy has been detected but ventricular extrasystoles were treated with verapamil. Even though telethoninopathy represents a rare condition, testing for LGMD2G should be included into the diagnostic work-up of mild myopathies with early toe walking and distal and proximal involvement. PMID- 28666573 TI - MLKL, the Protein that Mediates Necroptosis, Also Regulates Endosomal Trafficking and Extracellular Vesicle Generation. AB - Activation of the pseudokinase mixed lineage kinase domain-like (MLKL) upon its phosphorylation by the protein kinase RIPK3 triggers necroptosis, a form of programmed cell death in which rupture of cellular membranes yields release of intracellular components. We report that MLKL also associated with endosomes and controlled the transport of endocytosed proteins, thereby enhancing degradation of receptors and ligands, modulating their induced signaling and facilitating the generation of extracellular vesicles. This role was exerted on two quantitative grades: a constitutive one independent of RIPK3, and an enhanced one, triggered by RIPK3, where the association of MLKL with the endosomes was enhanced, and it was found to bind endosomal sorting complexes required for transport (ESCRT) proteins and the flotillins and to be excluded, together with them, from cells within vesicles. We suggest that release of phosphorylated MLKL within extracellular vesicles serves as a mechanism for self-restricting the necroptotic activity of this protein. PMID- 28666574 TI - gamma-Independent through-space hetero-nuclear correlation between spin-1/2 and quadrupolar nuclei in solids. AB - We introduce novel sequences using indirect detection to correlate quadrupolar nuclei and spin-1/2 isotopes, other than 1H and 19F. These sequences use gamma encoded symmetry-based RNnnu schemes that reintroduce the space component |m| = 1 of the heteronuclear dipolar coupling. These schemes can be applied to the indirectly detected spin in Dipolar-mediated Heteronuclear Multiple-Quantum Correlation (D-HMQC) sequence or to the detected isotope in a novel sequence, named Dipolar-mediated Heteronuclear Universal-Quantum Correlation (D-HUQC). We show that the signal of these sequences using gamma-encoded recoupling does not depend on the gamma Euler angle relating the inter-nuclear vector between the coupled spins to the MAS rotor-fixed frame. Therefore, the transfer efficiency of these sequences is in principle higher than that of D-HMQC methods using non gamma-encoded recoupling. Furthermore, numerical simulations show that the heteronuclear correlation experiments employing gamma-encoded recoupling are more robust to Chemical Shift Anisotropy (CSA) of the irradiated spin and MAS frequency fluctuations. These results are confirmed by 13C-{15N} heteronuclear correlation on glycine and 31P-27Al ones on VPI-5 and Na7(AlP2O7)4PO4. These experiments indicate that R1635 recoupling produces the highest signal-to-noise ratio in heteronuclear correlation 2D experiments when the detected spin-1/2 nuclei are subject to large CSA. PMID- 28666575 TI - Alternans in atria: Mechanisms and clinical relevance. AB - Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca2+ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria. PMID- 28666576 TI - Assessment of Coronary Artery Aneurysms Caused by Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of Computerized Tomography Angiograms. AB - Patients with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend CAA diameter >=8 mm as the criterion for initiating systemic anticoagulation. Transluminal attenuation gradient (TAG) analysis has been proposed as a noninvasive method for evaluating functional significance of coronary stenoses using computerized tomography angiography (CTA), but has not previously been used in CAA. We hypothesized that abnormal hemodynamics in CAA caused by KD could be quantified using TAG analysis. We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries and aneurysm geometry was characterized using maximum diameter, aneurysm shape index, and sphericity index. A total of 55 coronary arteries were analyzed, 25 of which had at least 1 aneurysmal region. TAG in aneurysmal arteries was significantly lower than in normal arteries (-23.5 +/- 10.7 vs -10.5 +/- 9.0, p = 0.00002). Aneurysm diameter, aneurysm shape index, and sphericity index were weakly correlated with TAG (r2 = 0.01, p = 0.6; r2 = 0.15, p = 0.06; r2 = 0.16, p = 0.04). This is the first application of TAG analysis to CAA caused by KD, and demonstrates significantly different TAG values in aneurysmal versus normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide hemodynamic information not available from anatomy alone. TAG represents a possible extension to standard CTA for KD patients who may improve thrombotic risk stratification and aid in clinical decision making. PMID- 28666578 TI - Outpatient beta-blockers and survival from sepsis: Results from a national cohort of Medicare beneficiaries. AB - BACKGROUND: Elderly Americans suffer increased mortality from sepsis. Given that beta-blockers have been shown to be cardioprotective in critical care, we investigated outpatient beta-blocker prescriptions and mortality among Medicare beneficiaries admitted for sepsis. METHODS: We queried a 5% random sample of Medicare beneficiaries for patients admitted with sepsis. We used in-hospital and outpatient prescription drug claims to compare in-hospital and 30-day mortality based on pre-admission beta-blocker prescription and class of beta-blocker prescribed using univariate tests of comparison and multivariable logistic regression models and another class of medications for control. RESULTS: Outpatient beta-blocker prescription was associated with a statistically significant decrease in in-hospital and 30-day mortality. In multivariable modeling, beta-blocker prescription was associated with 31% decrease in in hospital mortality and 41% decrease in 30-day mortality. Both cardioselective and non-selective beta-blockers conferred mortality benefit. CONCLUSIONS: Our data suggests that there may be a role for preadmission beta-blockers in reducing sepsis-related mortality. PMID- 28666577 TI - Use of Evidence-Based Therapy for Cardiovascular Risk Factors in Canadian Outpatients With Atrial Fibrillation: From the Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation (FREEDOM AF) and Co ordinated National Network to Engage Physicians in the Care and Treatment of Patients With Atrial Fibrillation (CONNECT AF). AB - Using data collected from 2 national atrial fibrillation (AF) primary care physician chart audits (Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation [FREEDOM AF] and Co-ordinated National Network to Engage Physicians in the Care and Treatment of Patients With Atrial Fibrillation [CONNECT AF]), we evaluated the frequency of, and factors associated with, the use of cardiovascular (CV) evidence-based therapies in Canadian AF outpatients with at least 1 CV risk factor or co-morbidity. Of the 11,264 patients enrolled, 9,495 (84.3%) were eligible for one or more CV evidence-based therapies. The proportions of patients with AF receiving all eligible guideline recommended therapies were 40.8% of patients with coronary artery disease, 48.9% of patients with diabetes mellitus, 40.2% of patients with heart failure, 96.7% of patients with hypertension, and 55.1% of patients with peripheral arterial disease. Factors that were independently associated with nonreceipt of all indicated evidence-based therapies included sinus rhythm rather than AF at baseline and liver disease. In conclusion, although most Canadian outpatients with AF have CV risk factors or co-morbidities, a substantial portion of these patients did not receive all guideline-recommended therapies. These findings suggest that there is an opportunity to improve the quality of care for patients with AF in Canada. PMID- 28666579 TI - Women in surgery: A longer term follow-up. AB - BACKGROUND: There are an increasing number of women in surgery. Previously, many questions focused upon their ability to complete surgical training and contribute fully to the surgical workforce. More meaningful information lies in identifying the long-term follow-up of where, and in what specialty, women residents eventually practice. METHODS: All residents entering general surgery training at the University of Louisville between 1996 and 2009 were studied. Comparison between men and women was performed for program completion, length of residency training, and eventual specialty practice. RESULTS: One hundred and eight residents entered general surgery residency. Twenty-three (21%) did not complete training. There was no difference in attrition rates between men or women (22% vs. 19%, p = 0.77). Women completing residency were just as likely to practice general surgery (either private or academic practice) as their male counterparts (67% vs. 67% p = 0.96). CONCLUSIONS: Women are a valuable resource in surgery and are able to complete a vigorous residency. Long-term follow-up is crucial and permits us to evaluate this important group of trainees practicing surgery today. PMID- 28666580 TI - Current trends and challenges in the postoperative medical management of Crohn's disease: A systematic review. AB - BACKGROUND: Crohn's disease is an aggressive chronic inflammatory disorder, and despite medical advances no cure exists. There is a great risk of requiring an operative intervention, with evidence of recurrence developing in up to 80-90% of cases. Therefore, we sought to systematically review the current status in the postoperative medical management of Crohn's disease. DATA SOURCES: A systematic literature review of medications administered following respective therapy for Crohn's disease was performed from 1979 through 2016. Twenty-six prospective articles provided directed guidelines for recommendations and these were graded based on the level of evidence. CONCLUSIONS: The postoperative management of Crohn's disease faces multiple challenges. Current indicated medications in this setting include: antibiotics, aminosalicylates, immunomodulators, and biologics. Each drug has inherent risks and benefits, and the optimal regimen is still unknown. Initiating therapy in a prophylactic fashion compared to endoscopic findings, or escalating therapy versus treating with the most potent drug first is debated. Although a definitive consensus on postoperative treatment is necessary, aggressive and early endoluminal surveillance is paramount in the treatment of these complicated patients. PMID- 28666581 TI - Mobile health apps and recovery after surgery: What are patients willing to do? AB - BACKGROUND: Mobile health technologies (mHealth) may improve post-operative care but it is unknown if patients are willing to use this technology. METHODS: We surveyed 800 NY State residents to determine their willingness to engage in mHealth after surgery and compared socioeconomic factors that may affect willingness to engage. RESULTS: A majority of respondents reported willingness to wear a tracker on their wrist (80.6%), fill out a survey (74.3%), send pictures of their wound to their surgeon (66.3%), and share updates with friends/family (59.1%). Older age was associated with lower likelihood of having a smartphone, but not associated with willingness to engage with other features. Hispanic ethnicity was associated with lower likelihood of wearing a tracker while Black race was associated with lower willingness to send pictures. CONCLUSIONS: Overall, potential users of mHealth are interested and willing to use mHealth. Older respondents are as willing as younger respondents to engage with mHealth. Individuals with Hispanic ethnicity and Black race may be less willing to engage and therefore may require education regarding benefits of this technology. PMID- 28666583 TI - Pathophysiological mechanisms of Flavivirus infection of the central nervous system. AB - Flaviviruses are important human pathogens. Transmitted by the bite of infected mosquitoes, Flaviviruses such as West Nile and Japanese encephalitis may reach the central nervous system where they can elicit severe diseases. Their ability to cross the blood-brain-barrier is still poorly understood. The newly emerging Zika Flavivirus on the other hand very rarely reaches the brain of adults, but can infect neural progenitors in the developing central nervous system of fetuses, eliciting devastating congenital malformations including microcephaly. This short review focuses on selected aspects of West Nile, Japanese encephalitis and Zika virus pathophysiological features such as neuroinvasion and neurovirulence, and highlights what we know about some possible mechanisms involved in Flaviviral neuropathogenesis. PMID- 28666582 TI - Clonidine restores vascular endothelial growth factor expression and improves tissue repair following severe trauma. AB - BACKGROUND: We hypothesized that clonidine and propranolol would increase VEGF and VEGF-receptor expression and promote lung healing following severe trauma and chronic stress. METHODS: Sprague-Dawley rats were subjected to lung contusion (LC), lung contusion/hemorrhagic shock (LCHS), or lung contusion/hemorrhagic shock/daily restraint stress (LCHS/CS). Clonidine and propranolol were administered daily. On day seven, lung VEGF, VEGFR-1, VEGFR-2, and HMGB1 were assessed by PCR. Lung injury was assessed by light microscopy (*p < 0.05). RESULTS: Clonidine increased VEGF expression following LCHS (43%*) and LCHS/CS (46%*). Clonidine increased VEGFR-1 and R-2 expression following LCHS/CS (203%* and 47%*, respectively). Clonidine decreased HMGB1 and TNF-alpha expression following LCHS/CS (22%* and 58%*, respectively.) Clonidine decreased inflammatory cell infiltration and total Lung Injury Score following LCHS/CS. Propranolol minimally affected VEGF and did not improve lung healing. CONCLUSIONS: Clonidine increased VEGF and VEGF-receptor expression, decreased HMGB1 expression, decreased lung inflammation, and improved lung tissue repair. PMID- 28666584 TI - [Anatomoclinical study of annular elastolytic giant cell granuloma]. AB - BACKGROUND: Annular elastolytic giant cell granuloma (AEGCG), a rare entity first described in 1979, is very similar to O'Brien actinic granuloma (AG), first described in 1975. Since then, many cases have been published under one or other of the two names. We performed a single-centre histopathology study to identify the distinguishing features and determine whether there was any objective difference between AEGCG and AG. PATIENTS AND METHODS: Cases classed as AEGCG or AG at the dermatopathology laboratory in Strasbourg were included and analysed using haematoxylin-eosin, orcein and Alcian blue staining. The diagnosis was made in the event of granuloma rich in multi-nucleated giant cells and reduction or disappearance of elastic tissue. Clinical data were collected from the analysis requests and clinical files. RESULTS: We identified 73 cases: 12 classed as AEGCG and 61 classed as AG. Mean age was 60.5 years with a sex ratio of 0.55. The duration of the disease ranged from 8 days to 17 years. A single lesion was seen in 52% of cases with multiple lesions in the remaining cases. Lesions measured between 0.3 and 10cm and exhibited a predilection for photo-exposed areas, chiefly on the head, neck and upper limbs. In most cases, an annular erythematous edge was seen together with a light centre, and slow centrifugal spread. The diagnosis was made by a clinician in only 5.5% of cases. These granulomas were chiefly in the superficial and mid dermis and only rarely deep, and contained numerous giant cells with a constant contingent of lymphocytes, but plasma cells were also seen in half of the cases. Orcein staining revealed marked decrease or total disappearance of elastic tissue within the granulomatous area together with elastophagocytosis in practically all images. More rarely, there was evidence of necrobiosis, palisading granuloma, vascular involvement or orcein-stained asteroid bodies. There were no notable clinical or histological differences between the cases initially classed as AEGCG or AG. DISCUSSION: AEGCG is a separate entity from annular granuloma that must be assimilated with O'Brien actinic granuloma. The central role of elastic fibres seems clear, but that of ultraviolet radiation remains more controversial. The term annular elastolytic giant cell granuloma seems more appropriate since it is more descriptive and carries no physiopathological implications. There appears to be a significant association with sarcoidosis and with diabetes in a minority of cases, thus warranting screening for these diseases. PMID- 28666585 TI - Variability of nursing care by APR-DRG and by severity of illness in a sample of nine Belgian hospitals. PMID- 28666586 TI - Dravet syndrome, SUDEP, and omega-3 fatty acids: Lessons from the past, learning of the present, and perspectives for the future. PMID- 28666587 TI - Improving access to health care for people living with epilepsy. PMID- 28666588 TI - Perioperative management of obstructive sleep apnea in bariatric surgery: a consensus guideline. AB - BACKGROUND: The frequency of metabolic and bariatric surgery (MBS) is increasing worldwide, with over 500,000 cases performed every year. Obstructive sleep apnea (OSA) is present in 35%-94% of MBS patients. Nevertheless, consensus regarding the perioperative management of OSA in MBS patients is not established. OBJECTIVES: To provide consensus based guidelines utilizing current literature and, when in the absence of supporting clinical data, expert opinion by organizing a consensus meeting of experts from relevant specialties. SETTING: The meeting was held in Amsterdam, the Netherlands. METHODS: A panel of 15 international experts identified 75 questions covering preoperative screening, treatment, postoperative monitoring, anesthetic care and follow-up. Six researchers reviewed the literature systematically. During this meeting, the "Amsterdam Delphi Method" was utilized including controlled acquisition of feedback, aggregation of responses and iteration. RESULTS: Recommendations or statements were provided for 58 questions. In the judgment of the experts, 17 questions provided no additional useful information and it was agreed to exclude them. With the exception of 3 recommendations (64%, 66%, and 66% respectively), consensus (>70%) was reached for 55 statements and recommendations. Several highlights: polysomnography is the gold standard for diagnosing OSA; continuous positive airway pressure is recommended for all patients with moderate and severe OSA; OSA patients should be continuously monitored with pulse oximetry in the early postoperative period; perioperative usage of sedatives and opioids should be minimized. CONCLUSION: This first international expert meeting provided 58 statements and recommendations for a clinical consensus guideline regarding the perioperative management of OSA patients undergoing MBS. PMID- 28666589 TI - Influence of spinal disc translational stiffness on the lumbar spinal loads, ligament forces and trunk muscle forces during upper body inclination. AB - Inverse dynamic musculoskeletal human body models are commonly used to predict the spinal loads and trunk muscle forces. These models include rigid body segments, mechanical joints, active and passive structural components such as muscles, tendons and ligaments. Several studies used simple definition of lumbar spinal discs idealized as spherical joints with infinite translational stiffness. The aim of the current sensitivity study was to investigate the influence of disc translational stiffness (shear and compressive stiffness) on the joint kinematics and forces in intervertebral discs (L1-L5), trunk muscles and ligaments for an intermediately flexed position (55 degrees ). Based on in vitro data, a range of disc shear stiffness (100-200N/mm) and compressive stiffness (1900-2700N/mm) was considered in the model using the technique of force dependent kinematics (FDK). Range of variation in spinal loads, trunk muscle forces and ligaments forces were calculated (with & without load in hands) and compared with the results of reference model (RM) having infinite translational stiffness. The discs' centers of rotation (CoR) were computed for L3-L4 and L4-L5 motion segments. Between RM and FDK models, maximum differences in compressive forces were 7% (L1-L2 & L2 L3), 8% (L3-L4) and 6% (L4-L5) whereas in shear forces 35% (L1-L2), 47% (L2-L3), 45% (L3-L4) and more than 100% in L4-L5. Maximum differences in the sum of global and local muscle forces were approximately 10%, whereas in ligament forces were 27% (supraspinous), 40% (interspinous), 56% (intertransverse), 58% (lig. flavum) and 100% (lig. posterior). The CoRs were predicted posteriorly, below (L3-L4) and in the disc (L4-L5). FDK model predicted lower spinal loads, ligament forces and varied distribution of global and local muscle forces. Consideration of translational stiffnesses influenced the model results and showed increased differences with lower stiffness values. PMID- 28666590 TI - Regulation of DNA damage tolerance in mammalian cells by post-translational modifications of PCNA. AB - DNA damage tolerance pathways, which include translesion DNA synthesis (TLS) and template switching, are crucial for prevention of DNA replication arrest and maintenance of genomic stability. However, these pathways utilize error-prone DNA polymerases or template exchange between sister DNA strands, and consequently have the potential to induce mutations or chromosomal rearrangements. Post translational modifications of proliferating cell nuclear antigen (PCNA) play important roles in controlling these pathways. For example, TLS is mediated by mono-ubiquitination of PCNA at lysine 164, for which RAD6-RAD18 is the primary E2 E3 complex. Elaborate protein-protein interactions between mono-ubiquitinated PCNA and Y-family DNA polymerases constitute the core of the TLS regulatory system, and enhancers of PCNA mono-ubiquitination and de-ubiquitinating enzymes finely regulate TLS and suppress TLS-mediated mutagenesis. The template switching pathway is promoted by K63-linked poly-ubiquitination of PCNA at lysine 164. Poly ubiquitination is achieved by a coupled reaction mediated by two sets of E2-E3 complexes, RAD6-RAD18 and MMS2-UBC13-HTLF/SHPRH. In addition to these mono- and poly-ubiquitinations, simultaneous mono-ubiquitinations on multiple units of the PCNA homotrimeric ring promote an unidentified damage tolerance mechanism that remains to be fully characterized. Furthermore, SUMOylation of PCNA in mammalian cells can negatively regulate recombination. Other modifications, including ISGylation, acetylation, methylation, or phosphorylation, may also play roles in DNA damage tolerance and control of genomic stability. PMID- 28666591 TI - Educating for the marine environment: Challenges for schools and scientists. AB - Environmental education has long been recognized as critical for achieving environmental awareness, values and attitudes, skills and behaviour consistent with sustainable development and for effective participation in environmental decision-making. Since the Declaration of the 1972 United Nations Conference on the Human Environment concerns about marine pollution and ecotoxicology, among other environmental challenges, should be included in environmental education. However, in the more than forty years since this significant environmental Declaration, marine education has struggled to find a place in the school curriculum of most countries, even though issues such as climate change, chemical contamination of marine environments, coastal eutrophication, and seafood safety continue to threaten human and other species' well-being. This viewpoint discusses how marine education is marginalized in school education, and how marine specialists need to embed school education in their action plans. Particular questions include: who should be educated, about what, where and with what goals in mind? PMID- 28666592 TI - Regeneration of mesoporous silica aerogel for hydrocarbon adsorption and recovery. AB - Silica aerogel, with mesoporous structure and high hydrophobicity, is a promising adsorbent for oil spill clean-up. To make it economic and environmental-friendly, hydrocarbon desorption and silica aerogel regeneration were investigated. After hydrocarbon desorption at 80 degrees C, silica aerogel maintained its hydrophobicity. After toluene, petrol, and diesel desorption, shrinkage of mesopores (from 19.9 to 16.8, 13.5, and 13.4nm) of silica aerogels occurred, causing decreased adsorption capacities (from 12.4, 11.2, and 13.6 to 12.0, 6.5, and 2.3g/g). Low surface tension of petrol caused high stress on mesopores during its desorption, resulting in significant pore shrinkage. For diesel, its incomplete desorption and oxidation further hindered the regeneration. Therefore, diesel desorption was also conducted at 200 degrees C. Severe diesel oxidation occurred under aerobic condition and destroyed the mesopores. Under anaerobic condition, no diesel oxidation occurred and the decreases in pore size (to 13.2nm) and adsorption efficiency (to 10.0g/g) of regenerated silica aerogels were much less, compared with under aerobic condition. This study provided new insights on silica aerogel regeneration for oil spill clean-up. PMID- 28666593 TI - An ecotoxicological approach to evaluate the effects of tourism impacts in the Marine Protected Area of La Maddalena (Sardinia, Italy). AB - In the Marine Protected Area of La Maddalena Archipelago, environmental protection rules and safeguard measures for nautical activities have helped in reducing anthropogenic pressure; however, tourism related activities remain particularly significant in summer. With the aim of evaluating their impacts, the biomarker approach using transplanted Mytilus galloprovincialis as sentinel organisms coupled with POCIS deployment was applied. Mussels, translocated to four marine areas differently impacted by tourism activities, were sampled before, during and after the tourist season. Moreover, endocrine disruptors in passive samplers POCIS and the cellular toxicity of whole POCIS extracts on mussel haemocytes were evaluated to integrate ecotoxicological information. Lysosomal biomarkers, condition index and mortality rate, as well as metals in tissues suggested an alteration of the health status of mussels transplanted to the most impacted sites. The cellular toxicity of POCIS extracts was pointed out, notwithstanding the concentrations of the examined compounds were always below the detection limits. PMID- 28666594 TI - Toxicity of oil and dispersant on the deep water gorgonian octocoral Swiftia exserta, with implications for the effects of the Deepwater Horizon oil spill. AB - Benthic surveys of mesophotic reefs in the Gulf of Mexico post Deepwater Horizon (DWH) showed that Swiftia exserta octocorals exhibited significantly more injury than in years before the spill. To determine the vulnerability of S. exserta to oil and dispersants, 96h toxicity assays of surrogate DWH oil water-accommodated fractions (WAF), Corexit(r) 9500 dispersant, and the combination of both (CEWAF) were conducted in the laboratory. Fragment mortality occurred within 48h for some fragments in the dispersant-alone and oil-dispersant treatments, while the WAF group remained relatively unaffected. The 96h LC50 values were 70.27mg/L for Corexit-alone and 41.04mg/L for Corexit in CEWAF. This study provides new information on octocoral sensitivity to toxins, and indicates that combinations of oil and dispersants are more toxic to octocorals than exposure to oil alone. These results have important implications for the assessment of effects of the DWH spill on deep-water organisms. PMID- 28666595 TI - Comparisons of benthic filter feeder communities before and after a large-scale capital dredging program. AB - Changes in turbidity, sedimentation and light over a two year large scale capital dredging program at Onslow, northwestern Australia, were quantified to assess their effects on filter feeder communities, in particular sponges. Community functional morphological composition was quantified using towed video surveys, while dive surveys allowed for assessments of species composition and chlorophyll content. Onslow is relatively diverse recording 150 sponge species. The area was naturally turbid (1.1 mean P80 NTU), with inshore sites recording 6.5* higher turbidity than offshore localities, likely influenced by the Ashburton River discharge. Turbidity and sedimentation increased by up to 146% and 240% through dredging respectively, with corresponding decreases in light levels. The effects of dredging was variable, and despite existing caveats (i.e. bleaching event and passing of a cyclone), the persistence of sponges and the absence of a pronounced response post-dredging suggest environmental filtering or passive adaptation acquired pre-dredging may have benefited these communities. PMID- 28666596 TI - Council News. PMID- 28666598 TI - A meta-analysis of n-3 polyunsaturated fatty acids effects on circulating acute phase protein and cytokines in gastric cancer. AB - BACKGROUND & AIMS: Chronic inflammation is related with cancer and leads to worsening prognosis in cancer patients. n-3 polyunsaturated fatty acids (PUFAs) supplementation has been proposed as adjuvant treatment in cancer due anti inflammatory properties. In the present meta-analysis, we pooled randomized clinical trials (RCTs) assessing the effects of n-3 PUFAs (from fish oil isolated or added in an immunonutrition formula) on inflammatory markers in gastric cancer. METHODS: A comprehensive literature search was performed in Medline, Scopus, Cochrane library, Science Direct and Web of Science, besides GOOGLE Scholar and a hand searching of reference lists, through July 2016. We pooled the effect size from individual studies using a random-effect model and carried out heterogeneity and sensitivity analyses. RESULTS: Nine trials (698 patients) fulfilled the entry criteria and were included in the synthesis of the systematic review. Eight were carried out in surgical patients and one in patients that received chemotherapy. Four used only fish oil as intervention and five used an immunonutrition formula. Global meta-analysis demonstrated higher albumin (7 studies, SMD 0.28; 95% CI 0.07, 0.48) and prealbumin (4 studies, SMD 0.56; 95% CI 0.12, 1.00) concentrations, and lower IL-6 (2 studies, SMD -0.71; 95% CI -1.15, 0.27) and TNF-alpha (2 studies, SMD -0.92; 95% CI -1.58, -0.26) concentrations in patients of the intervention group as compared to control group. However, total protein, transferrin and CRP concentrations were not improved by n-3 PUFAs supplementation. CONCLUSION: This study provides evidence that n-3 PUFAs supplementation from fish oil or added an immunonutrition formula has favorable effects on inflammatory markers in gastric cancer patients undergoing surgical procedures. PMID- 28666597 TI - Diet quality, inflammation, and the ankle brachial index in adults with or without cardiometabolic conditions. AB - BACKGROUND & AIMS: Diet quality may influence non-traditional cardiovascular disease (CVD) risk factors - namely, C-reactive protein (CRP) and the ankle brachial index (ABI). Pre-existing traditional cardiometabolic conditions may confound this association. We aimed to determine whether diet quality was associated with high-risk CRP or ABI, independently from traditional cardiometabolic risk factors. METHODS: Baseline data were analyzed from US Hispanics/Latinos aged 18-74 y without previously-diagnosed CVD participating in the population-based Hispanic Community Health Study/Study of Latinos cohort. Included were 14,623 participants with CRP data, and 7892 participants (>=45 y) with ABI data. Diet quality was measured with the Alternate Healthy Eating Index (AHEI). RESULTS: Nearly 35% of Hispanics/Latinos had high-risk CRP concentration and 6.3% had high-risk ABI (peripheral artery disease (PAD): 4.2%; arterial stiffness: 2.1%). After adjusting for sociodemographic and lifestyle factors, diabetes, hypertension, hypercholesterolemia, and obesity, the odds (95% confidence interval) of having high-risk ABI were 37% (5, 44%) lower per 10-unit increase in AHEI (p = 0.018). The association was marginally significant for PAD (0.77 (0.58, 1.00); p = 0.05), and non-significant for arterial stiffness (p = 0.16). Each 10-unit increase in AHEI was associated with 21% (10, 30%) lower odds of high-risk CRP (p = 0.0002) after similar adjustments. There were no significant interactions between AHEI and age, sex, ethnicity, smoking, or pre existing cardiometabolic conditions for associations with ABI. The association between AHEI and high-risk CRP was stronger for those with diabetes (p interaction < 0.0001), obesity (p-interaction = 0.005), or ages 45-74 y (p interaction = 0.011). CONCLUSIONS: Higher diet quality is associated with lower inflammation and less adverse ABI among Hispanics/Latinos, independently from traditional cardiometabolic risk factors. PMID- 28666599 TI - [Electrocardiographic characteristics of fasciculo-ventricular accessory pathways in children: A comparative study with right anteroseptal accessory pathways]. AB - OBJECTIVES: Fasciculo-ventricular (FV) accessory pathways (AP's) and right anteroseptal (RAS) AP's share similar anatomic locations and electrocardiographic characteristics. The objective of this article is to compare these features in children. METHODS: All patients with manifest pre-excitation who underwent an electrophysiological study were included. Fasciculo-ventricular AP's were defined by the presence of an HV interval<=32ms and a prolongation of the AH without changes in the HV interval, or the level of pre-excitation during atrial pacing. Three independent and blind observers analysed the ECG's in both groups. RESULTS: Out of 288 patients, 15 (5.2%) had FV AP's and 14 (4.9%) right AS AP's. The PR interval was longer in FV AP's than in RAS (113+/-21 vs 86+/-13ms respectively; P<.001) and the QRS was narrower (95+/-12 vs 137+/-24ms respectively; P<.001). The ECG in patients with FV AP's showed a rapid low amplitude deflection at the begining of the QRS in 13 out of 15 patients (87%) and in 2 (14%) the RAS AP group (P=.003). CONCLUSIONS: The PR interval was longer and the QRS complex was narrower in patients with FV AP's. The presence of a rapid low amplitude deflection at the beginning of the QRS complex would allow to differentiate them from RAS AP's non-invasively. PMID- 28666600 TI - Pulmonary Foreign Body: An Unusual Cause of Recurrent Pneumonia. PMID- 28666601 TI - Impact of a cardiac intensivist on mortality in patients with cardiogenic shock. AB - BACKGROUND: This study aimed to evaluate the association between high-intensity staffing by a dedicated cardiac intensivist and clinical outcomes in CS. METHODS: We enrolled 2923 consecutive patients admitted to a cardiac care unit (CCU) from January 1, 2012 to December 31, 2015. In January 2013, the CCU changed from a low intensity to high-intensity staffing unit managed by a dedicated cardiac intensivist. Patients were eligible if they required inotropes or vasopressors to maintain a systolic blood pressure>90mmHg, and had serum lactate>=2.0mmol/L. Eligible patients (n=513) were treated by low-intensity CCU (n=352) or high intensity CCU (n=161). The primary outcome was CCU mortality. RESULTS: CCU mortality occurred in 49 patients (30.6%) of the low-intensity group versus 62 patients (17.6%) of the high-intensity group (adjusted odds ratio [aOR] 0.44, 95% confidence interval [CI] 0.25-0.75, p<0.001). In-hospital mortality was not significantly different between the groups (33.1% vs 24.4%, aOR 0.75, 95% CI 0.43 1.29, p=0.29). Among 135 patients treated with extracorporeal membrane oxygenation, the high-intensity model was associated with lower CCU mortality (54.5% vs 22.5%, aOR 0.24, 95% CI 0.07-0.77, p=0.02) and in-hospital mortality (57.6% vs 29.4%, aOR 0.28, 95% CI 0.10-0.81, p=0.02). CONCLUSION: High-intensity staffed CCU managed by a dedicated cardiac intensivist was associated with a significant reduction of CS-related mortality. PMID- 28666602 TI - Integrated cardiovascular/respiratory control in type 1 diabetes evidences functional imbalance: Possible role of hypoxia. AB - BACKGROUND: Cardiovascular (baroreflex) and respiratory (chemoreflex) control mechanisms were studied separately in diabetes, but their reciprocal interaction (well known for diseases like heart failure) had never been comprehensively assessed. We hypothesized that prevalent autonomic neuropathy would depress both reflexes, whereas prevalent autonomic imbalance through sympathetic activation would depress the baroreflex but enhance the chemoreflexes. METHODS: In 46 type-1 diabetic subjects (7.0+/-0.9year duration) and 103 age-matched controls we measured the baroreflex (average of 7 methods), and the chemoreflexes, (hypercapnic: ventilation/carbon dioxide slope during hyperoxic progressive hypercapnia; hypoxic: ventilation/oxygen saturation slope during normocapnic progressive hypoxia). Autonomic dysfunction was evaluated by cardiovascular reflex tests. RESULTS: Resting oxygen saturation and baroreflex sensitivity were reduced in the diabetic group, whereas the hypercapnic chemoreflex was significantly increased in the entire diabetic group. Despite lower oxygen saturation the hypoxic chemoreflex showed a trend toward a depression in the diabetic group. CONCLUSION: Cardio-respiratory control imbalance is a common finding in early type 1 diabetes. A reduced sensitivity to hypoxia seems a primary factor leading to reflex sympathetic activation (enhanced hypercapnic chemoreflex and baroreflex depression), hence suggesting a functional origin of cardio-respiratory control imbalance in initial diabetes. PMID- 28666603 TI - About conditions of application of logistic regression. PMID- 28666605 TI - Therapeutic requirements in active ulcerative proctitis: A single-centre study. AB - BACKGROUND: Ulcerative proctitis (UP) presents distinctive clinical characteristics, outcomes and therapeutic approaches as compared to left-sided and extensive ulcerative colitis (UC). AIM: To describe the current therapeutic requirements and clinical outcomes in patients with active UP. METHODS: Retrospective observational study conducted in a referral IBD centre. Patients with UP in follow-up between 1989 and 2014 were included. The clinical characteristics, as well as the different treatments and drug formulations administered to treat flares, were recorded. RESULTS: Out of 687 UC patients, 101 patients (15%) with UP were included. Median follow-up was 8 years (IQR 3-14) and 49% of patients presented disease activity during the study period. Topical mesalazine monotherapy (90%) was the most commonly administered treatment for disease activity (mostly as suppositories), followed by topical steroids (47%) and oral mesalazine (56%) in monotherapy or combination therapy. Only 14% and 16% of patients required oral prednisone and beclomethasone, respectively. CONCLUSIONS: In clinical practice, active UP presents mostly favourable outcomes. Mesalazine suppositories are by far the most used treatment for these patients. PMID- 28666606 TI - Gastrointestinal bleeding caused by neurofibroma of the ileum. PMID- 28666607 TI - Sodium glucose cotransporter 2 inhibitors and males lower urinary tract symptoms, an aspect to consider. PMID- 28666604 TI - A human time dose response model for Q fever. AB - The causative agent of Q fever, Coxiella burnetii, has the potential to be developed for use in biological warfare and it is classified as a bioterrorism threat agent by the Centers for Disease Control and Prevention (CDC) and as a category B select agent by the National Institute of Allergy and Infectious Diseases (NIAID). In this paper we focus on the in-host properties that arise when an individual inhales a dose of C. burnetii and establish a human time-dose response model. We also propagate uncertainty throughout the model allowing us to robustly estimate key properties including the infectious dose and incubation period. Using human study data conducted in the 1950's we conclude that the dose required for a 50% probability of infection is about 15 organisms, and that one inhaled organism of C. burnetti can cause infection in 5% of the exposed population. In addition, we derive a low dose incubation period of 17.6 days and an extracellular doubling time of half a day. In conclusion this paper provides a framework for detailing the parameters and approaches that would be required for risk assessments associated with exposures to C. burnetii that might cause human infection. PMID- 28666608 TI - Strict adherence rules to obtain monoclonal therapy might cost lives. PMID- 28666609 TI - The death of Mimi in Puccini's La Boheme: not an ordinary tubercular heroine. PMID- 28666610 TI - Spanish flu-the first horseman. PMID- 28666611 TI - Treatment of xanthelasma palpebrarum with a 1064-nm, Q-switched Nd:YAG laser. AB - BACKGROUND: Xanthelasma palpebrarum is the most common cutaneous xanthoma characterized by soft, yellow papules or plaques that arise on the periorbital skin. As these lesions can be cosmetically disfiguring, many patients seek medical help to remove these lesions. OBJECTIVE: To determine the effectiveness and minimum number of treatment sessions with a 1064-nm, Q-switched neodymium doped yttrium aluminum garnet (Nd:YAG) laser for the treatment of xanthelasma. METHODS: A retrospective review of patients with xanthelasma consecutively treated with Q-switched Nd:YAG laser was conducted. Forty-six patients with 103 lesions were identified from January 2012 through August 2015. Photographs taken of patients immediately before treatment and 4-8 weeks after treatment were independently evaluated by 2 dermatologists. RESULTS: After a single treatment session, 93.2% of lesions had some degree of clearance. All lesions had excellent to-complete clearance after at least 4 treatment sessions. Patients usually required 4 treatment sessions for optimal results. LIMITATIONS: This was a retrospective study. Treatment parameters varied, follow-up periods were not uniform, and response was not assessed with a validated scale. CONCLUSION: The Q switched Nd:YAG laser is effective and well tolerated in the treatment of xanthelasma in our study population. PMID- 28666612 TI - Nail findings in patients with psoriatic arthritis: A cross-sectional study with special reference to transverse grooves. AB - BACKGROUND: Patients with psoriatic arthritis (PsA) commonly present with nail manifestations; however, little is known about these manifestations. OBJECTIVE: This study investigated whether nail findings can be used to discriminate between PsA and psoriasis without arthritis. METHODS: We performed a retrospective analysis of 118 patients with PsA and 974 patients with psoriasis without arthritis who visited St. Luke's International Hospital (Tokyo, Japan) between July 2003 and February 2015. Patients with PsA were classified according to the Classification of Psoriatic Arthritis criteria. Skin lesion severity was assessed by using the Psoriasis Area and Severity Index, and 9 types of nail findings were investigated. RESULTS: The incidence of nail involvement in patients with PsA was 67.6%. Female sex, presence of transverse grooves, onycholysis, and splinter hemorrhages were significantly related to PsA, with transverse grooves demonstrating the strongest association (odds ratio, 5.01; 95% confidence interval, 2.31-10.8; P < .01). Furthermore, the presence of transverse grooves was strongly related to both distal interphalangeal arthritis and enthesitis. LIMITATIONS: The PsA population was relatively small. CONCLUSIONS: Nail findings enabled us to distinguish patients with PsA from those without arthritis. The presence of transverse grooves is significantly associated with PsA and may be associated with distal interphalangeal arthritis and enthesitis. PMID- 28666613 TI - The Economics of Transcatheter Valve Interventions. AB - A subset of patients who require correction of a stenotic or incompetent valve are deemed to be at excessive surgical risk, which precludes surgical repair or replacement. Transcatheter valve interventions are viable alternatives in these patients. However, these technologies are costly, and in the setting of a constrained Canadian health care budget, economic value is an important consideration to allow for fair allocation of scarce resources. Accordingly, we review the economic literature on transcatheter valve interventions, targeting a general audience. Our specific goals are highlighting how best to interpret these studies and discuss the implications of these technologies on the Canadian health care system. Transcatheter aortic valve replacement (TAVR) is a cost-effective alternative for inoperable patients who otherwise would receive medical therapy. When compared with surgical aortic valve replacement (SAVR), TAVR is associated with significant reductions in postprocedure hospital resource use, which offsets the substantially higher cost of the TAVR valve system relative to SAVR valves. Although cost-effectiveness estimates for TAVR in high-risk operable candidates vary widely across studies, based on contemporary data from the perspective of the Canadian health care system, TAVR is likely to provide economic value. Recent studies suggest that when compared with medical therapy for severe degenerative mitral regurgitation, the MitraClip (Abbott, Abbott Park, IL) may offer economic value in high-risk patients; however, in the absence of randomized controlled trials, this is speculative. Nonetheless, these transcatheter technologies represent a paradigm shift in the management of valvular disease; their dissemination will have substantial impact in cardiovascular care delivery. PMID- 28666614 TI - Multimodality Imaging for Planning and Follow-up of Transcatheter Aortic Valve Replacement. AB - The complementary modalities of Doppler echocardiography and multidetector computed tomography are most frequently used for the planning and follow-up of transcatheter aortic valve replacement (TAVR). TAVR is now a well-established modality in the treatment of high-risk and inoperable patients with symptomatic severe aortic stenosis. Furthermore, recent studies have shown that TAVR is equivalent or superior to surgical aortic valve replacement in patients at intermediate surgical risk. We review the most commonly used imaging modalities and discuss their respective strengths and contributions to optimal patient selection, procedure planning, implementation, and follow-up in TAVR. PMID- 28666615 TI - Aging Well in an Era of High-Tech Cardiovascular Care. PMID- 28666616 TI - The Cost of Frailty in Cardiac Surgery. PMID- 28666617 TI - Long-term Follow-up of the Implementation of a Venous Thromboembolism Prophylaxis Order Set on a Cardiology Ward: Still a Surprising Result? PMID- 28666618 TI - Troubleshooting Cardiac Resynchronization Therapy in Nonresponders. AB - Heart failure (HF) is a critical health issue. Despite the advancements in pharmacotherapy, HF-related morbidity and mortality remains high. Cardiac resynchronization therapy (CRT) has been revolutionary in medically refractory, symptomatic HF patients with reduced ejection fraction and a prolonged, abnormal QRS complex. Although CRT affects electromechanical dys-synchrony resulting in favourable ventricular remodelling, improved functional capacity and clinical outcomes with fewer HF hospitalizations and better survival, the response to CRT is not uniform. A reported 20%-40% of patients, depending on the criteria used, are considered CRT nonresponders. Identifying a cause for nonresponse is challenging and often multifactorial and therefore requires a complete approach involving the entire patient journey. Effort to improve response includes careful consideration of selected patients, optimal therapy delivery, and comprehensive postimplantation care. Because of the prevalence of HF and generally poor prognosis, CRT provides an important treatment option, however, further research is needed to better understand reasons for CRT nonresponse and potential solutions. PMID- 28666619 TI - Development of a multiplex PCR for identification of beta-hemolytic streptococci relevant to human infections and serotype distribution of invasive Streptococcus agalactiae in Thailand. AB - A multiplex polymerase chain reaction (mPCR) was developed for simultaneous detection (single reaction) of genes specific to five frequent clinically relevant beta-hemolytic streptococcal species: Streptococcus pyogenes (Spy1258), Streptococcus agalactiae (cfb and cpn60), Streptococcus dysgalactiae subsp. equisimilis (16S-23S intergenic spacer) , S. equi subsp. zooepidemicus (esaA and sorD), and Streptococcus anginosus group (moaC). No cross-reaction was observed with other bacterial species. This test was validated and successfully used with 725 clinical isolates involved in pathological conditions in Thailand and collected between March 2014 and December 2015. Results showed that S. agalactiae, mainly serotype III, was the most common Streptococcus isolated from invasive diseases. This assay should be useful for laboratory identification and surveillance of human infections by these species. PMID- 28666620 TI - Targeting the ubiquitin proteasome system in diabetic cardiomyopathy. PMID- 28666621 TI - Immunomodulatory Agents and Proteasome Inhibitors in the Treatment of Multiple Myeloma. AB - OBJECTIVE: To review the current evidence on the use of immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) in the treatment of multiple myeloma (MM). DATA SOURCES: Journal articles, research reports, state of the science papers, and clinical guidelines. CONCLUSION: There has been a tremendous increase of new agents to treat multiple myeloma in the last 15 years. The IMiDs and PIs remain essential components of many anti-myeloma regimens. IMPLICATIONS FOR NURSING PRACTICE: With these advances in the therapeutic landscape, knowledge of these drugs, side effects and nursing implications are essential to improve outcomes. Patient education is also of vital importance in achieving optimal responses to treatment. PMID- 28666622 TI - Joint ICMAN and IUPHAR natural products section meeting. Aberdeen UK 27-29th September 2017. AB - This special issue of Biochemical Pharmacology contains proceedings of a joint conference sponsored by the Natural Products Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the International Conference on the Mechanism of Action of Nutraceuticals (ICMAN), an organization dedicated to defining actions and clinical benefits of pharmaceuticals and nutraceuticals. Entitled "From Nutraceuticals to Pharmaceuticals: Common Challenges and Approaches", the conference was held in Aberdeen UK in September 2017. The aim of this gathering was to identify the challenges that must be overcome to identify and characterize novel therapeutics from natural products. Contained in this issue are reviews prepared by conference participants as well as abstracts describing oral and poster presentations. PMID- 28666623 TI - Geranylnaringenin (CG902) inhibits constitutive and inducible STAT3 activation through the activation of SHP-2 tyrosine phosphatase. AB - The roles and significance of signal transducer and activator of transcription 3 (STAT3) in human cancers have been extensively studied and STAT3 is a promising therapeutic target for cancer drug discovery. During the screening of natural products to identify STAT3 inhibitors, we identified geranylnaringenin (CG902), which decreased luciferase activity in a dose-dependent manner. CG902 specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cancer cells and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, the knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of CG902 to inhibit STAT3 activation and CG902 activated the phosphatase activity of SHP-2 through direct interaction with SHP-2 and induced the phosphorylation of SHP-2. The interactions between CG902 and SHP-2 were confirmed by pull-down assay using biotinylated CG902. The interactions were also further validated by the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). The inhibitory effect of CG902 on cell growth was confirmed using the DU145 mouse xenograft model. We propose that CG902 inhibits STAT3 activity through a mechanism that involves the interactions between CG902 and SHP-2, and the phosphorylation of SHP-2, which leads to SHP-2 activation in DU145 cells. CG902 is the first compound to regulate STAT3 activity via the modulation of SHP-2 activity, and our results suggest that CG902 is a novel inhibitor of the STAT3 pathway and an activator of SHP-2, and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor. PMID- 28666626 TI - Bonfils intubation endoscope for intubation during uninterrupted chest compressions- comparison with laryngoscope in manikins. PMID- 28666624 TI - Neoadjuvant chemotherapy or chemoradiation for patients with advanced adenocarcinoma of the oesophagus? A propensity score-matched study. AB - BACKGROUND: Multimodal therapies are the standard of care for advanced adenocarcinomas of the oesophagus and gastro-oesophageal junction (AEG Types I and II). Only three randomised trials have compared preoperative chemotherapy with and without radiation. The results showed a small benefit for combined chemoradiation. In the meantime, newer therapy protocols are available. AIM: In a propensity-score matched study, we analysed patients with locally advanced AEG type I or II, treated with chemotherapy (FLOT-protocol) or chemoradiation (CROSS protocol), followed by oesophagectomy, in a single high-volume centre. PATIENTS AND METHODS: Between 2011 and 2015, 137 patients with advanced (cT3NxcM0) adenocarcinoma received pre-operative therapy; 70% had chemoradiation (CROSS protocol) and 30% had chemotherapy (FLOT-protocol). After propensity-score matching, 40 patients from the CROSS-group were selected for analysis. Postoperative histopathological response and prognosis were analysed. RESULTS: The two groups were comparable according to the matching criteria age, gender, tumour location, and year of surgery. R0-resection was achieved in 97% of patients in the CROSS-group and 85% of the FLOT-group (p = 0.049). Major response of the primary tumour was evident more often in the CROSS-group (17/40 pts. 43%) versus FLOT-group (11/40 pts. 27%) as well no lymph node metastasis (ypN0 = 68% versus ypN0 = 40%) (p = 0.014). Prognosis were not significantly different between the two groups. In multivariate analysis, only ypN-category was an independent prognostic factor. CONCLUSION: Compared to FLOT-chemotherapy, neoadjuvant chemoradiotherapy with the CROSS-protocol in locally advanced adenocarcinoma AEG types I and II resulted in better response by the primary tumour and less lymph node metastasis but without superior survival. PMID- 28666625 TI - Is intralesional resection suitable for central grade 1 chondrosarcoma: A systematic review and updated meta-analysis. AB - BACKGROUND: The surgical choice for grade 1 chondrosarcoma has been debated for decades. Intralesional resection can minimize the damage caused by surgery and offer better functional outcome. However, controversy remains about whether it will result in higher rates of local recurrence and metastasis, fewer complications, and better functional outcome compared with resection with wide margin. This systematic review and updated meta-analysis therefore compared intralesional resection and resection with wide margin in terms of local recurrence, metastasis, complications, and functional outcome. METHODS: Medline, Embase, and the Cochrane Library were comprehensively searched in December 2016 to identify studies comparing intralesional resection and resection with wide margin for central grade 1 chondrosarcoma. Data of interest were extracted and analyzed using Review Manager 5.3. RESULTS: Ten studies involving 394 patients were included, with 214 patients who had intralesional resection and 180 patients who had resection with wide margin for grade 1 chondrosarcoma. Intralesional resection was associated with lower complication rates (P < 0.0001) and better Musculoskeletal Tumor Society score (MSTS). There were no significant differences in terms of overall local recurrence (P = 0.27), local recurrence based on adjuvant therapies (P = 0.22), local recurrence in studies that included lesions of the hand, foot, pelvis, and axial skeleton (P = 0.55), and metastasis (P = 0.74) between groups. CONCLUSION: Intralesional resection provides lower complications and better functional outcome with no significant increase in the risk of recurrence and metastasis. We think it is a suitable treatment for central grade 1 chondrosarcoma. PMID- 28666627 TI - Diagnostic performance of initial serum albumin level for predicting in-hospital mortality among aspiration pneumonia patients. AB - PURPOSE: The predictive value of serum albumin in adult aspiration pneumonia patients remains unknown. METHODS: Using data collected during a 3-year retrospective cohort of hospitalized adult patients with aspiration pneumonia, we evaluated the predictive value of serum albumin level at ED presentation for in hospital mortality. RESULTS: 248 Patients were enrolled; of these, 51 cases died (20.6%). The mean serum albumin level was 3.4+/-0.7g/dL and serum albumin levels were significantly lower in the non-survivor group than in the survivor group (3.0+/-0.6g/dL vs. 3.5+/-0.6g/dL). In the multivariable logistic regression model, albumin was associated with in-hospital mortality significantly (adjusted odds ratio 0.30, 95% confidential interval (CI) 0.16-0.57). The area under the receiver operating characteristics (AUROC) for in-hospital survival was 0.72 (95% CI 0.64-0.80). The Youden index was 3.2g/dL and corresponding sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratio were 68.6%, 66.5%, 34.7%, 89.1%, 2.05 and 0.47, respectively. High sensitivity (98.0%) was shown at albumin level of 4.0g/dL and high specificity (94.9%) was shown at level of 2.5g/dL. CONCLUSION: Initial serum albumin levels were independently associated with in-hospital mortality among adult patients hospitalized with aspiration pneumonia and demonstrated fair discriminative performance in the prediction of in-hospital mortality. PMID- 28666628 TI - Effect of mobile phone proliferation on crash notification times and fatality rates. AB - INTRODUCTION: The purpose of this study was to evaluate whether increased proliferation of mobile telephones has been associated with decreased MVC notification times and/or decreased MVC fatality rates in the United States (US). METHODS: We used World Bank annual mobile phone market penetration data and US Fatality Analysis Reporting System (FARS) fatal MVC data for 1994-2014. For each year, phone proliferation was measured as mobile phones per 100 population. FARS data were used to calculate MVC notification time (time EMS notified - time MVC occurred) in minutes, and to determine the MVC fatality rate per billion vehicle miles traveled (BVMT). We used basic vector auto-regression modeling to explore relationships between changes in phone proliferation and subsequent changes in median and 90th percentile MVC notification times, as well as MVC fatality rates. RESULTS: From 1994 to 2014, larger year-over-year increases in phone proliferation were associated with larger decreases in 90th percentile notification times for MVCs occurring during daylight hours (p=0.004) and on the national highway system (p=0.046) two years subsequent, and crashes off the national highway system three years subsequent (p=0.023). There were no significant associations between changes in phone proliferation and subsequent changes in median crash notification times, nor with subsequent changes in MVC fatality rates. CONCLUSION: Between 1994 and 2014 increased mobile phone proliferation in the U.S. was associated with shorter 90th percentile EMS notification times for some subgroups of fatal MVCs, but not with decreases in median notification times or overall MVC fatality rates. PMID- 28666630 TI - Hydrogen gas generation from metal aluminum-water interaction in municipal solid waste incineration (MSWI) bottom ash. AB - In the present research, municipal solid waste incineration (MSWI) bottom ash (BA) residues from three incinerators (N, K, and R) in Japan were collected for hydrogen gas generation purpose. The samples were split into four particle size fractions: (1) d<=0.6, (2) 0.6<=d<=1.0, (3) 1.0<=d<=2.0, and (4) 2.0<=d<=4.75mm for the characterization of metal aluminum, the relationship between the present metal aluminum and hydrogen gas production, and the influence of external metal aluminum on the enhancement of hydrogen gas. The batch experiments were performed for each BA fraction under agitated (200rpm) and non-agitated conditions at 40 degrees C for 20days. The highest amount of hydrogen gas (cumulative) was collected under agitation condition that was 39.4, 10.0, and 8.4 L/kg of dry ash for N2, R2, and K2 (all fraction 2), respectively. To take the benefit of the BA high alkalinity (with initial pH over 12), 0.1 and 1g of household aluminum foil were added to the fractions 2 and 3. A Significantly larger amount of hydrogen gas was collected from each test. For 0.1g of aluminum foil, the cumulative amount of gas was in the range of 62 to 78 L/kg of dry ash and for 1g of aluminum foil the cumulative amount of hydrogen was in the range of 119-126 L/kg of dry ash. This indicated that the hydrogen gas yield was significantly a function of supplementary aluminum and the intrinsic alkaline environment of the BA residues rather than ash source or particle size. PMID- 28666629 TI - Aging and ocular tissue stiffness in glaucoma. AB - Glaucoma is a progressive and chronic neurodegenerative disorder characterized by damage to the inner layers of the retina and deformation of the optic nerve head. The degeneration of retinal ganglion cells and their axons results in an irreversible loss of vision and is correlated with increasing age. Extracellular matrix changes related to natural aging generate a stiffer extracellular environment throughout the body. Altered age-associated ocular tissue stiffening plays a major role in a significant number of ophthalmic pathologies. In glaucoma, both the trabecular meshwork and the optic nerve head undergo extensive extracellular matrix remodeling, characterized by fibrotic changes associated with cellular and molecular events (including myofibroblast activation) that drive further tissue fibrosis and stiffening. Here, we review the literature concerning the role of age-related ocular stiffening in the trabecular meshwork, lamina cribrosa, sclera, cornea, retina, and Bruch membrane/choroid and discuss their potential role in glaucoma progression. Because both trabecular meshwork and lamina cribrosa cells are mechanosensitive, we then describe molecular mechanisms underlying tissue stiffening and cell mechanotransduction and how these cellular activities can drive further fibrotic changes within ocular tissues. An improved understanding of the interplay between age-related tissue stiffening and biological responses in the trabecular meshwork and optic nerve head could potentially lead to novel therapeutic strategies for glaucoma treatment. PMID- 28666631 TI - Biochar from green waste for phosphate removal with subsequent disposal. AB - Biochar prepared from cotton stalk solid waste provides a new material for contaminant removal. In the present study, experiments were conducted to investigate the removal of phosphate from aqueous solution by cotton stalk biochar (CSB). The characterization of CSB & phosphate adsorbed biochar (PCSB) were done to substantiate the adsorption of phosphate on CSB surface. FT-IR studies disclosed the functional groups present in CSB and supported adsorption phenomena. Scanning electron microscope showed the porous nature of CSB and EDS measurements justified the phosphate adsorption process. XRD analysis revealed that the calcium and magnesium ions of CSB were also responsible for adsorption process. Experimental results fitted nicely with the heterogeneous isotherm models viz Freundlich and Temkin isotherm. The calculated Freundlich constant (n) suggested the cooperative adsorption. The heat of adsorption calculated from Temkin isotherm indicated the process to be exothermic in nature. The free energy of adsorption calculated from equilibrium studies justified physical as well as chemical means of adsorption. Hence CSB serves as a good adsorptive material and can provide viable solution for environmental protection. However, discharging active site depleted CSB to environment may pose subsequent problems. To combat the same, the PCSB was tested as nutrient enhancer for plant growth in soil and population multipliers of microbes in microbial fuel cells-a device for power generation. The disposal study concluded the feasibility of safe PCSB removal. PMID- 28666632 TI - Single-chamber microbial fuel cells as on-line shock-sensors for volatile fatty acids in anaerobic digesters. AB - In anaerobic digesters (AD), volatile fatty acids (VFAs) concentration is a critical operative parameter, which is usually manually monitored to prevent inhibition of microbial consortia. An on-line VFAs monitoring system as early warning for increasing concentrations would be of great help for operators. Here, air-cathode membraneless microbial fuel cells (MFCs) were investigated as potential biosensors, whose electrical signal instantaneously moves from its steady value with the accumulation of VFAs in the anodic solution. MFCs were operated equipping four lab-scale ADs with carbon-based electrodes. Reactors were filled with the digestate from a full-scale AD and fed in batch with four kinds of feedstock (cheese whey, kitchen waste, citrus pulp and fishery waste). The MFC signal initially increased in parallel to VFAs production, then tended to a steady value for VFAs concentrations above 1000mgAcL-1. Peak concentrations of tVFAs (2500-4500mgAcL-1) and MFCs potentials were negatively correlated (r=0.916, p<0.05), regardless of the type of substrate. Inhibition of the MFC system occurred when VFAs increased fast above 4000mgAcL-1. Polarization curves of electrodes stressed that electroactive bacteria on bioanodes were strongly subjected to inhibition. The inhibition of electroactivity on bioanode trended like typical shock-sensors, opening to direct application as early-warning monitoring system in full-scale ADs. PMID- 28666633 TI - Mismatch negativity as a biomarker of theta band oscillatory dysfunction in schizophrenia. AB - Mismatch negativity (MMN) is among the best established biomarkers of cortical dysfunction in schizophrenia. MMN generators are localized primarily to primary and secondary auditory regions, and are known to reflect activity mediated by cortical N-methyl-d-aspartate-type glutamate receptors (NMDAR). Nevertheless, mechanisms underlying MMN generation at the local circuit level remain incompletely understood. This review synthesizes recent advances in circuit-level conceptualization of MMN based upon neuro-oscillatory findings. In the neuro oscillatory (aka event-related spectral perturbation, ERSP) approach, responses to sensory stimuli are decomposed into underlying frequency bands prior to analysis. MMN reflects activity primarily in theta (4-7Hz) frequency band, which is thought to depend primarily upon interplay between cortical pyramidal neurons and somatostatin (SST)-type local circuit GABAergic interneurons. Schizophrenia related deficits in theta generation are also observed not only in MMN, but also in other auditory and visual contexts. At the local circuit level, SST interneurons are known to maintain tonic inhibition over cortical pyramidal interneurons. SST interneurons, in turn, are inhibited by a class of interneurons expressing vasoactive intestinal polypeptide (VIP). In rodents, SST interneurons have been shown to respond differentially to deviant vs. standard stimuli, and inhibition of SST interneurons has been found to selectively inhibit deviance related activity in rodent visual cortex. Here we propose that deficits in theta frequency generation, as exemplified by MMN, may contribute significantly to cortical dysfunction in schizophrenia, and may be tied to impaired interplay between cortical pyramidal neurons and local circuit SST-type GABAergic interneurons. PMID- 28666634 TI - Defective compensation over early dysneurogenesis in schizophrenia and mood disorder. PMID- 28666635 TI - Initial outcomes of integrated community-based hepatitis C treatment for people who inject drugs: Findings from the Queensland Injectors' Health Network. AB - BACKGROUND: Integrated treatment and harm reduction services provide a unique opportunity to facilitate direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV)-infected people who inject drugs (PWID). We examine outcomes of community-based delivery of DAA therapy for PWID. METHODS: The Queensland Injectors' Health Network (QuIHN) is a community-based agency providing harm reduction and treatment services. Data (including current injecting, involvement in opioid substitution therapy and other treatment, level of case management support) for participants initiating DAA therapy were collected. The primary endpoint was sustained virological response at 12 weeks (SVR) after the end of therapy. RESULTS: By the end of February 2017, 127 treatment clients who consented for research had completed therapy and were due for post-treatment sustained virological response (SVR) testing. In an intent-to-treat analysis, 96% completed their course of prescribed treatment, 80% had confirmed SVR and 92% adhered to treatment. There were no confirmed cases of treatment non-response. The clients without confirmed SVR (20%) had not attended their post-treatment test. No client characteristics, including involvement in less-than-daily (odds ratio (OR) 0.27, 95% confidence interval (CI): 0.06-1.17) or daily injecting drug use (OR 0.65, 95% CI: 0.17-2.43) were associated with non-attendance at the SVR test. CONCLUSION: PWID can be effectively treated for HCV and comply with DAA therapy in an integrated community-based service. However, strategies are required to support client retention until SVR is confirmed. PMID- 28666636 TI - High hepatitis C incidence in relation to prescription opioid injection and poly drug use: Assessing barriers to hepatitis C prevention. AB - BACKGROUND: Prescription opioid (PO) injection and poly-drug use have been associated with hepatitis C virus (HCV) infection among people who inject drugs (PWID). Poly-drug use is often a barrier to key HCV preventive programmes including opioid agonist treatment. The contribution of specific drug combinations to high HCV incidence in poly-drug users has not been assessed previously. Addressing this knowledge gap could enhance HCV treatment and prevention efforts. We examined the association between specific drugs and number of drugs used in addition to injected POs, and HCV seroconversion. METHODS: PWID participating in a cohort study in Montreal (HEPCO), HCV-seronegative at baseline and followed between 2004 and 2013, were included. Data were collected by interview-administered questionnaires. Blood samples were tested for HCV new infections at each 3-6 month follow-up visit. Time-varying Cox regression models were utilized. RESULTS: Of 356 participants (81.5% males; mean age: 34.7 years), 123 (34.6%) reported injected POs in the past month at baseline. In univariate analyses, recent use of the following drugs was associated with HCV seroconversion: injected POs, injected cocaine, injected heroin, non-injected tranquilisers, and smoked crack/cocaine. The relative excess risk of HCV seroconversion due to interaction (RER1HR) was the highest for co-use of injected POs with the following substances: injected cocaine (RER1HR=3.44), smoked crack/cocaine (RER1HR=1.27), and non-injected tranquilisers (RER1HR=0.8). In addition, a significant linear trend (p<0.001) towards higher risk was observed with increasing the number of these three drugs used in combination with injected POs. CONCLUSION: Specific drugs and number of drugs used in addition to injected POs play a modulating role in the risk of HCV primary infection. Poly-drug use among people who inject POs has to be addressed in order to improve harm reduction programmes and reduce HCV transmission in this high-risk population. PMID- 28666638 TI - A study on the bioequivalence of lithium and valproate salivary and blood levels in the treatment of bipolar disorder. AB - Lithium (Li) and valproate (VPA) are used in the treatment of bipolar disorder (BD), with narrow therapeutic window requiring periodic control of serum levels. This prevents intoxication, lack of efficacy due to low serum concentrations, and allows monitoring adherence. We aimed at evaluating the bioequivalence of salivary and blood levels of LI or VPA in a sample of adult BD patients. Secondarily, lithium bioequivalence was evaluated across different patients' lifespans. BD patients treated with either Li or VPA underwent contemporary standard serum and salivary measurements. Blood levels of both drugs were taken according to standard procedures. Li salivary levels were performed by an adapted potentiometric method on the AVL9180 electrolyte analyzer. VPA salivary levels were taken with an immune-assay method with turbidimetric inhibition. A total of 50 patients (38 on Li, 12 on VPA) were enrolled. Blood-saliva bioequivalence for VPA was not found due to a high variability in salivary measures. Li measures resulted in a high correlation (r=0.767, p<0.001), showing no partial correlation with age (r=0.147, p=0.380). Li salivary test is a reliable method of measuring Li availability and is equivalent to serum levels. Potential advantages of Li salivary testing are its non-invasive nature and the possibility of doing the test during the usual appointment with the psychiatrist. PMID- 28666639 TI - Response to: Absence of GNAS and BRAF mutations but presence of KRAS mutation in urachal adenocarcinoma. PMID- 28666640 TI - Extremely low high-density lipoprotein cholesterol (HDL) in a patient with diffuse B-cell lymphoma. PMID- 28666641 TI - High-grade squamous intraepithelial lesion (HSIL) of the cervix with bizarre cytological appearances ('pleomorphic HSIL'): a review of 19 cases. AB - Cervical high-grade squamous intraepithelial lesions (HSILs) are typically characterised by a proliferation of immature basaloid cells with relatively uniform hyperchromatic nuclei. In this report we describe 19 cases of HSIL exhibiting focal but very marked nuclear atypia often associated with multinucleation ('pleomorphic HSIL'). The bizarre cytological changes mainly involved the basal epithelium particularly in endocervical crypts where the neoplastic cells undermined the native glandular epithelial cells. Superficially invasive squamous cell carcinoma (SISCCA) was present in three cases (16%) and while this was more common than in a comparative series of 40 'conventional' HSIL excision specimens (5%), the difference was not statistically significant. All three invasive cases demonstrated additional histological features that have been associated with increased risk of SISCAA (expansile crypt involvement by HSIL, luminal necrosis, and/or intraepithelial squamous maturation), and the invasive foci were associated microanatomically with conventional-type rather than pleomorphic HSIL. The bizarre cells expressed p16 and p63 proteins but usually lacked mitotic activity and showed less Ki-67 labelling than adjacent conventional HSIL. These findings suggest that pleomorphic epithelial changes in HSIL do not necessarily indicate more aggressive biological behaviour and may, in some cases, represent a degenerative phenomenon. PMID- 28666642 TI - Pathobiology of Notch2 in lung cancer. AB - Notch signalling has been reported to be involved in initiation, progression, and suppression in various types of cancer. The pathological significance of Notch1 has been well studied in lung cancer, but that of Notch2 remains unclear. An immunohistochemical study was performed to clarify the expression of NOTCH2 in non-neoplastic lung tissues and lung cancers in comparison with Clara (Club) cell 10 kDa protein (CC10), and western blotting analysis was performed to detect NOTCH2 in human cancer cell lines. A Notch2 gene knockdown experiment was carried out to reveal the function of Notch2. Transient transfection of the intracellular domain of the Notch2 (N2ICD) gene was used. In addition, the relationship of the expressions of Notch1, 2, and 3 was studied. Immunohistochemical study of lung tissues revealed that NOTCH2 was detected in bronchiolar epithelial cells and was often colocalised with CC10, and that adenocarcinoma tissues were more positively stained than those of squamous cell carcinoma and small cell carcinoma. In human lung cancer cell lines, expression of NOTCH2 was similar to that of NOTCH1, and preferentially detected in non-small cell lung carcinoma (NSCLC) cell lines. Knockdown of the Notch2 gene in NSCLC cell lines showed no remarkable changes in expression of molecules associated with cell differentiation, proliferation, apoptosis, and motility, and the seemingly unvalued effects of Notch2 gene knockdown could be masked by concomitant Notch1 activation, as indicated by an increase in the intracellular domain of NOTCH1. Additionally, transient transfection of the N2ICD gene induced CC10 expression in an adenocarcinoma cell line. The present study revealed that Notch2 is important in Club cell differentiation in normal lungs and adenocarcinoma. Notch2 is regulated mutually with Notch1, and the balance of the expression of Notch receptors could determine the biological behaviours of lung cancer cells. PMID- 28666643 TI - PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma. AB - Programmed cell death (PD-1) and its ligand (PD-L1) inhibitors have shown clinical response in many tumours. PD-L1 data are limited in head and neck cutaneous squamous cell carcinoma (HNcSCC) and no clinical trials of PD-1/PD-L1 inhibitors are published. We performed PD-L1 immunohistochemistry on 74 cases of high risk HNcSCC with 38 matched metastases and evaluated clinicopathological associations, prognostic significance and heterogeneity in matched metastases. We observed PD-L1 expression in >5% of primary tumour cells in 29 cases (39.2%), primary tumour infiltrating lymphocytes (TILs) in 40 cases (70.2%), metastatic tumour cells in 15 cases (39.5%), and metastatic TILs in 18 cases (47.4%). PD-L1 expression in >5% of primary tumour cells was associated with an inflammatory phenotype (p = 0.04), and in primary TILs with clear margins (p = 0.05). PD-L1 expression in >5% of primary tumour cells (p = 0.01), primary TILs (p = 0.001), and metastatic TILs (p = 0.02) was associated with improved disease free survival. PD-L1 expression in >5% of tumour cells was heterogeneous between primary and metastatic tumours in 13 cases (34.2%). PD-L1 expression is common in HNcSCC supporting the rationale for a clinical trial of PD-1/PD-L1 inhibitors. PD L1 expression in tumour cells or TILs predicts longer disease free survival and demonstrates temperospatial heterogeneity. PMID- 28666644 TI - Response to: Absence of GNAS and BRAF mutations but presence of KRAS mutation in urachal adenocarcinoma: author reply. PMID- 28666645 TI - Electrophysiological markers of prejudice related to sexual gender. AB - Previous studies have shown that Event-related potentials (ERPs) are sensitive to violations of gender-based stereotypes. In the present investigation, we used ERPs to measure the detection of a discrepancy between gender-based occupational stereotypes and written material presented to fifteen Italian viewers in a completely implicit task. No awareness or judgment about stereotypes was required, no decision had to be made on sentence acceptability or congruence, and no prime words related to gender were presented (which might reveal the matter of the investigation). EEG was recorded while participants engaged in a task that consisted of pressing a key in response to animal words, while ignoring the overall study's purpose. Two hundred forty sentences that did or did not violate gender stereotypes were presented randomly with 32 other sentences ending with an animal word. Terminal words violating gender stereotypes (such as "The notary is BREASTFEEDING" or "Here is the commissioner with HER HUSBAND") elicited a greater anterior N400 response and left anterior negativity (LAN) than words conforming to the gender stereotype (e.g., "The chemist put on a nice TIE"). LAN modulation suggests that gender stereotypes are processed automatically (as if they were morpho-syntactic errors) and hints at how they are deeply rooted in our linguistic brain. According to the inverse solution, the neural representation of gender-based stereotypes mostly involved the middle frontal gyrus (MFG). The temporo/parietal junction (TPJ) supporting theory of mind (TOM) processes was also engaged, along with the superior and middle temporal gyri representing person information. PMID- 28666646 TI - Body mass index as a predictor of outcome in total knee replace: A systemic review and meta-analysis. AB - BACKGROUND: To conduct a meta-analysis with randomized controlled trials (RCTs) published in full text to demonstrate database to show the associations of perioperative, postoperative outcomes of normal and high body mass index (BMI) to provide the predictive diagnosis for clinic. METHODS: Literature search was performed in PubMed, Embase, Web of Science and Cochrane Library for information from the earliest date of data collection to February. RCTs comparing the benefits and risks of normal BMI with those of high BMI in primary total knee arthroplasty (TKA) were included. Statistical heterogeneity was quantitatively evaluated by X2 test with the significance set P<0.10 or I2>50%. RESULTS: Seven RCTs consisting of 33,778 patients were included. (6065 normal BMI patient; 27,713 high BMI). The results showed that high BMI was related to a greater increase in operative time, post-operative range of motion (ROM), post-operative Knee Society and function scores (KSS), infection rate (P<0.1). No differences in pulmonary embolism and perioperative mortality rates were found between normal and high body mass index patients with follow-up>=5years (P>0.1). CONCLUSIONS: Compared with normal BMI patients, high BMI patients demonstrated an increased risk of perioperative and postoperative complications and clear difference about complications between normal and high BMI about TKA. PMID- 28666647 TI - Objective quantification of trochlear dysplasia: Assessment of the difference in morphology between control and chronic patellofemoral instability patients. AB - BACKGROUND: Trochlear dysplasia is an important risk factor associated with patellofemoral instability, but it remains difficult to classify with consistency. Currently there is no objective way to quantify the dysplasia. The purpose of this study is to define and quantify objectively the trochlear morphology by volume and length via computed tomography (CT). METHODS: One hundred control patients (136 knees) were retrospectively reviewed and compared to 36 consecutive patients (72 knees) who were treated surgically for recurrent patellar instability and known trochlear dysplasia based on a lateral radiograph. Trochlear morphology was analyzed from a pre-operative CT and data presented as trochlear sulcus volume trochlear length. To determine where along the trochlear length dysplasia is most variable, the trochlear length was radiographically divided into thirds, volume was quantified along that section and compared to control trochlear. RESULTS: A significant difference in trochlear morphology exists between cohorts, volume (1.98 vs 3.77cm3) and length (31.97 vs 34.66mm) (p<0.05). However, there appears to be a gender based difference in trochlea morphology. The trochlea volumetric analysis between the female cohorts (L: 2.02cm3 vs. 2.94cm3, R: 1.95cm3 vs. 2.93cm3) demonstrated significantly less volume in instability patients (p<0.001). The proximal third of the trochlear contributed the majority of dysplasia difference determined by comparing mean trochlear volume, 95% of the difference. This difference decreased in distal sections, 53% and 32% respectively. CONCLUSION: This reproducible technique can be used to quantify the trochlea morphology, in order to describe the severity of a dysplasia. PMID- 28666648 TI - Morning glory disc anomaly with an ipsilateral enlargement of the optic nerve pathway. AB - PURPOSE: To report three patients with an unilateral morning glory disc anomaly in association with an ipsilateral mild thickening of the optic nerve. METHODS: Three children with a morning glory disc anomaly underwent a magnetic resonance imaging (MRI) of the brain. Ophthalmological, genetic and MRI findings at follow up are reported. A literature search on the association of morning glory anomaly in association with optic nerve glioma is reported.1 RESULTS: Three children with an unilateral morning glory anomaly and ipsilateral poor visual acuity were found to have an ipsilateral mild optic nerve enlargement on brain MRI. At serial MRI scanning, there was no progression of this finding. CONCLUSIONS: The morning glory disc anomaly is a rare congenital malformation of the optic disc. It can be associated with central nervous system abnormalities. The association with an optic nerve glioma has been described once before.1 Our three cases confirm the possible association between a morning glory disc anomaly and an ipsilateral optic nerve enlargement. Serial MRI showed no growth at follow-up. The awareness of this association by the ophthalmologists is important. PMID- 28666649 TI - [We are a band: An anthropological vision of the medical community]. AB - In this paper we try to explain, using an anthropological point of view, how the medical community behaves like a tribe like those who inhabit the Amazon forests or the African Savanna. The Family as fundamental unit of a band of hunter gatherers also defines the Primary Care Centre and the professionals who work there, as an egalitarian group in which every member works for the good of the tribe. The leaders of the tribe, also called "Health Centre Managers", are also comparable to the "big men" of Polynesia or the aborigines, who leads hunting parties. Even the clashes between physicians about the responsibilities as regards patients have been described throughout history in the anthropological literature, and they repeat the patterns of the segmental groups. We finish by concluding that this vision of warring tribes has to be overcome in order to advance towards the improvement of our community's health. PMID- 28666650 TI - Functional characterization of duck LSm14A in IFN-beta induction. AB - Human LSm14A is a key component of processing body (P-body) assembly that mediates interferon-beta (IFN-beta) production by sensing viral RNA or DNA. To the best of our knowledge, we are the first to report duck LSm14A (duLSm14A) cloning from duck embryo fibroblasts (DEFs). Full-length duLSm14A encoded 461 amino acids and was highly homologous with chicken and swan goose sequences. More interestingly, the duLSm14A mRNA was extensively expressed in all the studied tissues. In DEFs, duLSm14A was localized in the cytoplasm as P-body-like dots. Expression of duLSm14A induced IFN-beta through the activation of interferon regulatory factor-1 and nuclear factor-kappaB in DEFs. Furthermore, knockdown of duLSm14A by small interfering RNA notably decreased poly(I:C)- or duck reovirus induced IFN-beta production. The present study results indicate that the duLSm14A is an essential sensor that mediates duck innate immunity against viral infections. PMID- 28666651 TI - Restrictions of cervical flexion after laminoplasty increase in the mechanical stress at the occipitocervical junction in non-rheumatoid arthritis patients. AB - Increased range of motion (ROM) at O-C2 after cervical laminoplasty is thought to be a compensatory change due to loss of cervical ROM after surgery. Retro odontoid pseudotumor in non-RA patients is also caused by loss of ROM at C2-C7 causing mechanical stress on upper cervical spine. The aim of this study was to measure the occipitocervical alignment before and after cervical laminoplasty, and examine the factors associated with postoperative retro-odontoid soft tissue (ROST) enlargement. The study comprised 72 non-RA patients (51 males and 21 females, mean age 65.2years) who underwent cervical laminoplasty. The cervical angles (O-C1, O-C2, C1-C2, and C2-C7) were measured and ROST thickness was evaluated on mid-sagittal T1-weighted MRI before surgery and 2years after surgery. Correlations between radiographic changes and postoperative ROST enlargement were examined. The results shows that postoperative ROM and kyphotic angle in flexion position at O-C2 significantly increased, and postoperative ROM and kyphotic angle in flexion position at C2-C7 significantly decreased compared with preoperative values. On stepwise multiple regression analysis, age (beta=0.273, p<0.01) and restriction of cervical flexion postoperatively (beta=0.235, p<0.01) were independently associated with ROST enlargement. In conclusion, occipitocervical ROM increased and C2-C7 ROM, especially C2-C7 kyphotic angle in flexion, reduced after cervical laminoplasty. The ROST enlargement was associated with reduction in cervical flexion. These results indicate that preservation of cervical ROM, especially kyphotic angle in flexion, after cervical laminoplasty contribute to reduction of mechanical stress at the occipitocervical junction. PMID- 28666652 TI - Osteosarcoma of the skull base: An analysis of 19 cases and literature review. AB - BACKGROUND: Osteosarcoma of the skull base is rarely observed; most published studies comprise case reports. The clinical features and optimal treatments have not been clearly established. The purpose of this article is to present 19 cases of skull base osteosarcoma and review the literature to analyse the clinical features and treatment of skull base osteosarcoma. METHODS: The clinical data of 19 patients with skull base osteosarcoma from January 2005 to December 2016 were retrospectively analysed; pertinent English literature from 1976 to 2016 was reviewed. RESULTS: Six female and 13 male patients were included. The ages ranged from 11 to 55years (mean 34years). Gross-total resection of the tumour was achieved in 13 cases, and nearly total resection was achieved in 6 cases. Five cases were treated with surgery alone, whereas 14 cases received comprehensive treatment. The follow-up period ranged from 3 to 132months (mean 33months) with 17 patients who underwent follow-up. The median survival durations of the patients who underwent surgery alone and who received comprehensive treatment were 18 and 50months, respectively. The literature results were similar to the current findings. Overall, the 5-year survival rates of the patients in our series and in the literature were 30.5% and 37.8%, respectively. CONCLUSIONS: Skull base osteosarcoma had a low complete resection rate, a high recurrence rate and a poor prognosis because of the complex anatomy and vital structures involved. Radical surgery with comprehensive treatment is most appropriate for this disease. PMID- 28666654 TI - Editorial Comment. PMID- 28666655 TI - Editorial Comment. PMID- 28666653 TI - The liver is a metabolic and immunologic organ: A reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM). AB - Metabolic decompensation in inborn errors of metabolism (IEM) is characterized by a rapid deterioration in metabolic status leading to life-threatening biochemical perturbations (e.g. hypoglycemia, hyperammonemia, acidosis, organ failure). Infection is the major cause of metabolic decompensation in patients with IEM. We hypothesized that activation of the immune system during infection leads to further perturbations in end-organ metabolism resulting in increased morbidity. To address this, we established model systems of metabolic decompensation due to infection. Using these systems, we have described the pathologic mechanisms of metabolic decompensation as well as changes in hepatic metabolic reserve associated with infection. First and foremost, our studies have demonstrated that the liver experiences a significant local innate immune response during influenza infection that modulates hepatic metabolism. Based on these findings, we are the first to suggest that the role of the liver as a metabolic and immunologic organ is central in the pathophysiology of metabolic decompensation due to infection in IEM. The dual function of the liver as a major metabolic regulator and a lymphoid organ responsible for immunosurveillance places this organ at risk for hepatotoxicity. Mobilization of hepatic reserve and the regenerative capacity of a healthy liver compensates for this calculated risk. However, activation of the hepatic innate immune system may be deleterious in IEM. Based on this assertion, strategies aimed at modulating the innate immune response may be a viable target for intervention in the treatment of hepatic metabolic decompensation. PMID- 28666656 TI - Reasons for and Experiences With Surgical Interventions for Female Genital Mutilation/Cutting (FGM/C): A Systematic Review. AB - BACKGROUND: Because female genital mutilation/cutting (FGM/C) leads to changes in normal genital anatomy and functionality, women are increasingly seeking surgical interventions for their FGM/C-related concerns. AIM: To conduct a systematic review of empirical quantitative and qualitative research on interventions for women with FGM/C-related complications. METHODS: We conducted systematic searches up to May 2016 in 16 databases to obtain references from different disciplines. We accepted all study designs consisting of girls and women who had been subjected to FGM/C and that examined a reparative intervention for a FGM/C related concern. We screened the titles, abstracts, and full texts of retrieved records for relevance. Then, we assessed the methodologic quality of the included studies and extracted and synthesized the study data. OUTCOMES: All outcomes were included. RESULTS: Of 3,726 retrieved references, 71 studies including 7,291 women were eligible for inclusion. We identified three different types of surgical intervention: defibulation or surgical separation of fused labia, excision of a cyst with or without some form of reconstruction, and clitoral or clitoral-labial reconstruction. Reasons for seeking surgical interventions consisted of functional complaints, sexual aspirations, esthetic aspirations, and identity recovery. The most common reasons for defibulation were a desire for improved sexual pleasure, vaginal appearance, and functioning. For cyst excision, cystic swelling was the main reason for seeking excision; for reconstruction, the main reason was to recover identity. Data on women's experiences with a surgical intervention are sparse, but we found that women reported easier births after defibulation. Our findings also suggested that most women were satisfied with defibulation (overall satisfaction = 50-100%), typically because of improvements in their sexual lives. Conversely, the results suggested that defibulation had low social acceptance and that the procedure created distress in some women who disliked the new appearance of their genitalia. Most women were satisfied with clitoral reconstruction, but approximately one third were dissatisfied with or perceived a worsening in the esthetic look. CLINICAL TRANSLATION: The information health care professionals give to women who seek surgical interventions for FGM/C should detail the intervention options available and what women can realistically expect from such interventions. STRENGTHS AND LIMITATIONS: The systematic review was conducted in accordance with guidelines, but there is a slight possibility that studies were missed. CONCLUSION: There are some data on women's motivations for surgery for FGM/C-related concerns, but little is known about whether women are satisfied with the surgery, and experiences appear mixed. Berg RC, Taraldsen S, Said MA, et al. Reasons for and Experiences With Surgical Interventions for Female Genital Mutilation/Cutting (FGM/C): A Systematic Review. J Sex Med 2017;14:977-990. PMID- 28666658 TI - Aortoesophageal fistula resulting from aortic endograft migration. PMID- 28666657 TI - Body Esteem as a Common Factor of a Tendency Toward Binge Eating and Sexual Dissatisfaction Among Women: The Role of Dissociation and Stress Response During Sex. AB - BACKGROUND: Several studies have suggested a relevant overlap between eating disorders and sexual dysfunction involving the emotional component of body image esteem and dissociative experiences. AIM: To evaluate the common maintaining factors of sexual dysfunction and vulnerability to pathologic eating behaviors and their relation to a physiologic stress response. METHODS: In the present cross-sectional study, we evaluated a non-clinical sample of 60 heterosexual women (25-35 years old) for dissociation during sex with a partner, body image disturbance, and tendency toward pathologic eating behaviors. We also evaluated the stress-induced hypothalamic-pituitary-adrenal axis activation in response to a sexual stimulus and its association with binge eating and dissociation. OUTCOMES: Participants completed the Clinician-Administered Dissociative States Scale, the Sexual Satisfaction Scale-Women, the Body Esteem Scale for Adolescents and Adults, and the Eating Attitudes Test Short Version. Furthermore, we assessed cortisol levels before, during, and after exposure to explicit sexual stimuli shown within a laboratory setting. RESULTS: Dysfunctional body image esteem and a tendency toward binge-eating behaviors were associated with greater sexual distress in women. In particular, body esteem was significantly associated with greater dissociation during sex with a partner. Moreover, women who reported greater dissociation during sex with a partner and a tendency toward binge-eating behaviors showed higher levels of cortisol in response to sexual stimuli. CLINICAL IMPLICATIONS: These results support further research based on trans diagnostic treatments targeted to dissociation and body image esteem, which could lessen sexual dysfunction and vulnerability to pathologic eating behaviors. STRENGTHS AND LIMITATIONS: Despite the small sample and self-reported questionnaires, this is the first study to consider the association of the stress response during sexual stimuli with sexual distress and with pathologic eating behaviors adopting a dimensional approach. CONCLUSION: Body uneasiness and dissociation represented factors underlying pathologic eating behaviors and sexual dysfunction. Women reporting a tendency toward binge-eating episodes and dissociation during sexual experiences represented a subpopulation with a higher stress response during sexual stimuli. Castellini G, Lo Sauro C, Ricca V, Rellini AH. Body Esteem as a Common Factor of a Tendency Toward Binge Eating and Sexual Dissatisfaction Among Women: The Role of Dissociation and Stress Response During Sex. J Sex Med 2017;14:1036-1045. PMID- 28666659 TI - Myxoma knocking on the mitral door: A singular mechanism of mitral regurgitation. PMID- 28666660 TI - What surgical improvements are needed to prove that anatomic repair is superior to physiologic repair in the majority of patients with corrected transposition of the great arteries? PMID- 28666661 TI - Living and growing valve replacements for children: So near yet so far. PMID- 28666662 TI - Squamous cell carcinomas and adenocarcinomas of the esophagus: One treatment does not rule them all. PMID- 28666663 TI - Time to dot the I's and cross the T's of high-sensitivity cardiac troponin. PMID- 28666664 TI - Young infants with severe tetralogy of Fallot: Early primary surgery versus transcatheter palliation. AB - BACKGROUND: Infants with severe tetralogy of Fallot may undergo (1) early primary surgical repair (EARLY) or (2) early transcatheter palliation (CATH) before delayed surgical repair. We compared these strategies with (3) elective single stage tetralogy of Fallot repair (IDEAL). METHODS: From 2000 to 2012, 453 children underwent tetralogy of Fallot repair (excluding systemic-pulmonary shunts), including 383 in the IDEAL (75%), 42 in the EARLY (9%), and 28 in the CATH (6%) groups. IDEAL repair at The Hospital for Sick Children occurs after 3 months. Risk-adjusted hazard analysis compared freedom from surgical or catheter reintervention. Somatic size, branch pulmonary artery size, and right ventricle systolic pressure were modeled using 2780 echocardiogram reports via mixed-model regression. RESULTS: CATH involved right ventricular outflow tract stent in 18 patients, right ventricular outflow tract balloon in 9 patients, and ductal-stent in 1 patient. Three patients died (1 per group). Risk-adjusted freedom from surgical reoperation was 89% +/- 4%, 88% +/- 5%, and 85% +/- 6% for the IDEAL, EARLY, and CATH groups, respectively, at 10 years. Patients in the EARLY and CATH groups had similar reoperation rates, except for neonates (<1 month), for whom EARLY repair conferred an increased risk of reoperation. Risk-adjusted freedom from catheter reintervention was lower in the EARLY group (76%) and especially for the CATH group (53%) at 10 years versus the IDEAL group (83%). Somatic growth and progression of right ventricle systolic pressure were similar among groups at 8 years. Although those undergoing EARLY (P = .02) and CATH (P = .09) tend to have smaller branch pulmonary arteries initially, late pulmonary artery size was not significantly different among groups. CONCLUSIONS: Early primary repair for neonates may increase surgical reoperation, whereas transcatheter palliation comes at a cost of increased catheter reintervention. However, overall outcomes between groups, in terms of survival, growth, and hemodynamic parameters, were comparable, suggesting that both strategies are a reasonable option for children with severe tetralogy of Fallot. PMID- 28666665 TI - Application of laser speckle flow graph for compensatory sweating. PMID- 28666666 TI - It ain't closed 'til it's closed. PMID- 28666667 TI - When should the elephant (frozen elephant trunk) enter the room (aorta)? PMID- 28666668 TI - Open thoracoabdominal aortic aneurysm repair: Is there a "sex problem"? PMID- 28666669 TI - Medical Treatment of Nocturia in Men with Lower Urinary Tract Symptoms: Systematic Review by the European Association of Urology Guidelines Panel for Male Lower Urinary Tract Symptoms. AB - CONTEXT: The treatment of nocturia is a key challenge due to the multi-factorial pathophysiology of the symptom and the disparate outcome measures used in research. OBJECTIVE: To assess and compare available therapy options for nocturia, in terms of symptom severity and quality of life. EVIDENCE ACQUISITION: Medical databases (Embase, Medline, Cochrane Systematic Reviews, Cochrane Central) were searched with no date restriction. Comparative studies were included which studied adult men with nocturia as the primary presentation and lower urinary tract symptoms including nocturia or nocturnal polyuria. Outcomes were symptom severity, quality of life, and harms. EVIDENCE SYNTHESIS: We identified 44 articles. Antidiuretic therapy using dose titration was more effective than placebo in relation to nocturnal voiding frequency and duration of undisturbed sleep; baseline serum sodium is a key selection criterion. Screening for hyponatremia (< 130 mmol/l) must be undertaken at baseline, after initiation or dose titration, and during treatment. Medications to treat lower urinary tract dysfunction (alpha-1 adrenergic antagonists, 5-alpha reductase inhibitors, phosphodiesterase type 5inhibitor, antimuscarinics, beta-3 agonist, and phytotherapy) were generally not significantly better than placebo in short-term use. Benefits with combination therapies were not consistently observed. Other medications (diuretics, agents to promote sleep, nonsteroidal anti inflammatories) were sometimes associated with response or quality of life improvement. The recommendations of the Guideline Panel are presented. CONCLUSIONS: Issues of trial design make therapy of nocturia a challenging topic. The range of contributory factors relevant in nocturia makes it desirable to identify predictors of response to guide therapy. Consistent responses were reported for titrated antidiuretic therapy. For other therapies, responses were less certain, and potentially of limited clinical benefit. PATIENT SUMMARY: This review provides an overview of the current drug treatments of nocturia, which is the need to wake at night to pass urine. The symptom can be caused by several different medical conditions, and measuring its severity and impact varies in separate research studies. No single treatment deals with the symptom in all contexts, and careful assessment is essential to make suitable treatment selection. PMID- 28666670 TI - Proteomic analysis of soybean seedling leaf under waterlogging stress in a time dependent manner. AB - Leaf is sensitive to environmental changes and exhibits specific responses to abiotic stress. To identify the response mechanism in soybean leaf under waterlogging stress, a gel-free/label-free proteomic technique combined with polyethylene glycol fractionation was used. Attenuated photosynthesis by waterlogging stress in the leaf of soybean seedlings was indicated from proteomic results. Defensive mechanisms such as reactive oxygen species (ROS) scavenging was also recognized. Cluster analysis revealed that proteins that exhibit characteristic dynamics in response to waterlogging were mainly related to photosynthesis. Among the identified photorespiration-related proteins, the protein abundance and enzyme activity of hydroxypyruvate reductase were transiently increased in control plants, but were clearly decreased in response to waterlogging stress. These results suggest that waterlogging directly impairs photosynthesis and photorespiration. Furthermore, hydroxypyruvate reductase may be a critical enzyme controlling the rate of photorespiration. PMID- 28666671 TI - Arthroscopic Management of Elbow Osteoarthritis. AB - The incidence of osteoarthritis in the general population is low, but it can be seen in manual laborers, throwing athletes, and people dependent on crutches and wheelchairs. Patients often complain of pain at the terminal extents of motion, and imaging shows osteophyte formation at the tips of the coronoid and olecranon processes as well as thickening of the bone between the coronoid and the olecranon fossae. Recent advances in arthroscopic instrumentation and techniques have led to a growing interest in the arthroscopic treatment of elbow osteoarthritis. This article provides a review of basic arthroscopic elbow anatomy and the most common procedures, including diagnostic arthroscopy, loose body removal, and arthroscopic osteocapsular and ulnohumeral arthroplasty. As techniques advance, there might be interest in further procedures including arthroscopic-assisted interpositional arthroplasty. Although complications such as persistent drainage and nerve injury are frequently mentioned with elbow arthroscopy, the actual incidence of such complications remains low. PMID- 28666672 TI - Radius Core Decompression for Kienbock Disease Stage IIIA: Outcomes at 13 Years Follow-Up. AB - PURPOSE: This study was designed to analyze the long-term clinical and radiological outcomes of a series of patients with Kienbock disease stage IIIA treated with radius core decompression. METHODS: This retrospective study included 15 patients with Kienbock disease (Lichtman stage IIIA) who underwent distal radius metaphyseal core decompression between 1998 and 2005 and who were followed-up for at least 10 years. At the last follow-up, the patients were evaluated for wrist range of motion and grip strength. The overall results were evaluated by the modified Mayo wrist score and visual analog scale pain score. We also compared the radiological changes between the preoperative and the final follow-up in their Lichtman classification and the modified carpal height ratio. RESULTS: The mean follow-up period was 13 years (range, 10-18 years). Based on the modified Mayo wrist score, clinical results were excellent in 6 patients, good in 8 patients, and poor in 1 patient who required a proximal row carpectomy as revision surgery. The mean preoperative pain according to the visual analog scale was 7 (range, 6-10) and was 1.2 (range, 0-6) at the final follow-up. Compared with the opposite side, the average flexion/extension arc was 77% and the grip strength was 80%. All patients, except 1, returned to their original employment. At the final follow-up, 3 patients had decreased modified carpal height ratio, 12 remained unchanged. Radiographic disease progression according to the Lichtman classification to stages IIIB to IV occurred in only 2 wrists. There were no complications related to the core decompression. CONCLUSIONS: In this limited series, the radius core decompression demonstrated favorable long term results and could be considered as a surgical alternative for stage IIIA of Kienbock disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28666673 TI - Diagnostic Testing Requested Before Surgical Evaluation for Carpal Tunnel Syndrome. AB - PURPOSE: We sought to evaluate how often physicians who perform carpal tunnel release in the state of Michigan routinely request electrodiagnostic studies (EDS) or other diagnostic tests prior to an initial consultation and whether provider or practice characteristics had an influence on requirements for preconsultation diagnostic tests. METHODS: Through online data sources, we identified 356 providers in 261 practices throughout the state of Michigan with profiles confirming hand surgery practice or surgical treatment of carpal tunnel syndrome (CTS). We recorded American Society for Surgery of the Hand (ASSH) membership, teaching facility status, practice size, and primary specialty for each provider. Using a standardized telephone script, 219 providers were contacted by telephone to determine whether any diagnostic tests were needed before an appointment. Using multivariable logistic regression, we evaluated the relationship between the requirement for preconsultation testing and surgeon and practice characteristics. RESULTS: Among the 134 providers who were confirmed to perform carpal tunnel release, 57% (n = 76) required and 9% (n = 12) recommended a diagnostic test prior to the initial consultation. Of the 88 physicians who required/recommended testing, 85% (n = 75) requested EDS, 22% (n = 19) requested magnetic resonance imaging, 13% (n = 11) requested a computed tomography scan, and 9% (n = 8) requested an x-ray. Patients were asked to have multiple studies by 19 (22%) of the 88 surgeons who requested/recommended testing. In the multivariable analysis, ASSH membership, size of practice, and teaching facility status did not have a significant relationship with the requirement for preconsultation testing. CONCLUSIONS: Most surgeons who treat CTS in the state of Michigan routinely request EDS before evaluation, rather than reserving the test for cases in which the diagnosis is unclear. CLINICAL RELEVANCE: In the quest for high-value care, providers must consider whether the benefit of diagnostic tests for CTS likely outweighs the costs, inconvenience, and potential for treatment delay. PMID- 28666674 TI - Blastomycotic Osteomyelitis: An Unusual Cause of Hand Swelling. AB - Isolated blastomycosis hand infections are extremely rare, and are often clinically unsuspected, leading to delays in clinical diagnosis. Conclusive diagnosis often necessitates fungal cultures and histopathological demonstration of budding yeasts in tissues. In this report, we describe the rare occurrence of isolated blastomycotic hand infection, without any other organ involvement, in a 42-year-old male patient. Analyzing tissue specimens with frozen section has been shown in the past to demonstrate granulomatous inflammation and yeast forms of the organism; however, as demonstrated in this patient, the presence of pseudoepitheliomatous cells may deceptively appear as malignant, causing substantial concern and anxiety. Definitive diagnosis often necessitates fungal culture and histopathological examination with special fungal stains including polymerase chain reaction for speciation. PMID- 28666675 TI - Focal Eosinophilic Myositis of the Hand Presenting as a Refractory Pyogenic Infection. AB - Eosinophilic myositis is a rare disorder in which eosinophils infiltrate muscle and supporting connective tissue structures. The disorder can be localized or diffuse, and it may be associated with various systemic features resembling autoimmune disease. Focal eosinophilic myositis is the most limited form of eosinophilic myositis, for which muscle involvement is generally limited to the lower extremity. We report on a rare case of focal eosinophilic myositis of the interosseous muscles of the hand, which presented as a refractory, pyogenic hand infection. PMID- 28666676 TI - Joint Survival Analysis and Clinical Outcome of Total Joint Arthroplasties With the ARPE Implant in the Treatment of Trapeziometacarpal Osteoarthritis With a Minimal Follow-Up of 5 Years. AB - PURPOSE: The ARPE joint arthroplasty was introduced in 1991 for the treatment of symptomatic trapeziometacarpal (TMC) osteoarthritis. The primary outcome of this prospective study is to report the medium- to long-term joint survival of this prosthesis. Our secondary outcomes are the clinical and functional results. METHODS: A prospective, consecutive case series study was done at our hand unit. Patients included in the study had at least 5 years follow-up after a total joint arthroplasty for osteoarthritis of the TMC joint using the ARPE implant. The Kaplan-Meier method was used to estimate implant survival over time. Clinical and radiological assessment was recorded prospectively: before surgery and at 1 year and 5 years or more after surgery. We compared the means of the Kapandji index (assessing the thumb range of motion and opposition), the grip strength, and the pinch strength before surgery and at the latest follow-up. RESULTS: We included all 166 prostheses in the survival analysis with a mean follow-up of 80 months. Five prostheses (3%) required revision surgery and 1 implant (0.6%) failed. Therefore, Kaplan-Meier survival probability was 96% with a mean follow-up of 80 months (95% confidence interval, 91-98). A total of 120 arthroplasties from 115 patients were included in the clinical analysis. At 5 years' follow-up, the median Disabilities of the Arm, Shoulder, and Hand (DASH) score was 4.6 (range, 0 86.6). There was a significant improvement of the mean opposition and grip strength of the affected thumb at final follow-up in comparison with the preoperative values. There was also a significant improvement in the mean pinch strength at 1 year and 5 years after surgery compared with preoperative measurements. CONCLUSIONS: In our series, the ARPE prosthesis of the thumb TMC joint has proven to be a reliable and effective implant. Mean motion and strength increased whereas pain decreased after surgery and these results remained constant within the follow-up period. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28666678 TI - Department of Error. PMID- 28666677 TI - Microstructural evaluation of the mucin balls and their relations to the corneal surface-Insights by in vivo confocal microscopy. AB - PURPOSE: The purpose of the current study was to observe and correlate the characteristics of mucin balls to the ocular surface properties, and furthermore, to report the effect of different mucin balls size and number on structural alteration of the anterior cornea. METHODS: The study included, two groups of patients fitted with one-month continuous, extended wear lenses for therapeutic (group 1) and optical (group 2) purposes; the later serving as a control group. Group 1 was comprised of patients with recurrent erosion syndrome, while group 2 included subjects with mild myopia and voluntary use of continuous wear lenses. The examination was performed when mucin balls were encountered during a routine visit. Clinical examination was reinforced with laser scanning in vivo confocal microscopy, which provided microstructural observations. The appearance and size of the mucin balls were described and measured at two independent time points. Qualitative analysis included shape (round, elliptical and irregular) and reflectivity (bright, homogenous and dark, heterogonous). RESULTS: Clinically 1460 mucin balls were encountered (822 in group 1 and 638 in group 2). The number of mucin balls analyzed by in vivo confocal microscopy was 820. Diversity was higher in group 1. The mucin balls of group 2, were more uniform - rounded in shape 81,2% and regular in reflectivity 98%. Qualitative analysis revealed a negative correlation between the size of the balls and impact on the basal epithelium morphology and also "activation" of the anterior stroma in adjacent areas. CONCLUSIONS: Mucin balls affect corneal surface including both epithelia disintegration as well as keratocyte "activation". The main predisposing factor for mucin ball formation appear to be the corneal surface irregularity. As structural alterations of the cornea are transient, mucin balls might be beneficial for corneal restoration due to mechanical and/or biochemical stimulation. In vivo, confocal microscopy is an innovative tool for evaluating mucin balls in their diversity and dynamics. PMID- 28666679 TI - Influenza vaccine: going through a sticky patch. PMID- 28666681 TI - Family-delivered rehabilitation services at home: is the glass empty? PMID- 28666680 TI - The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. AB - BACKGROUND: Microneedle patches provide an alternative to conventional needle-and syringe immunisation, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability, and safety. We describe safety, immunogenicity, and acceptability of the first-in-man study on single, dissolvable microneedle patch vaccination against influenza. METHODS: The TIV-MNP 2015 study was a randomised, partly blinded, placebo-controlled, phase 1, clinical trial at Emory University that enrolled non-pregnant, immunocompetent adults from Atlanta, GA, USA, who were aged 18-49 years, naive to the 2014-15 influenza vaccine, and did not have any significant dermatological disorders. Participants were randomly assigned (1:1:1:1) to four groups and received a single dose of inactivated influenza vaccine (fluvirin: 18 MUg of haemagglutinin per H1N1 vaccine strain, 17 MUg of haemagglutinin per H3N2 vaccine strain, and 15 MUg of haemagglutinin per B vaccine strain) (1) by microneedle patch or (2) by intramuscular injection, or received (3) placebo by microneedle patch, all administered by an unmasked health-care worker; or received a single dose of (4) inactivated influenza vaccine by microneedle patch self-administered by study participants. A research pharmacist prepared the randomisation code using a computer-generated randomisation schedule with a block size of 4. Because of the nature of the study, participants were not masked to the type of vaccination method (ie, microneedle patch vs intramuscular injection). Primary safety outcome measures are the incidence of study product-related serious adverse events within 180 days, grade 3 solicited or unsolicited adverse events within 28 days, and solicited injection site and systemic reactogenicity on the day of study product administration through 7 days after administration, and secondary safety outcomes are new-onset chronic illnesses within 180 days and unsolicited adverse events within 28 days, all analysed by intention to treat. Secondary immunogenicity outcomes are antibody titres at day 28 and percentages of seroconversion and seroprotection, all determined by haemagglutination inhibition antibody assay. The trial is completed and registered with ClinicalTrials.gov, number NCT02438423. FINDINGS: Between June 23, 2015, and Sept 25, 2015, 100 participants were enrolled and randomly assigned to a group. There were no treatment-related serious adverse events, no treatment-related unsolicited grade 3 or higher adverse events, and no new-onset chronic illnesses. Among vaccinated groups (vaccine via health-care worker administered microneedle patch or intramuscular injection, or self-administered microneedle patch), overall incidence of solicited adverse events (n=89 vs n=73 vs n=73) and unsolicited adverse events (n=18 vs n=12 vs n=14) were similar. Reactogenicity was mild, transient, and most commonly reported as tenderness (15 [60%] of 25 participants [95% CI 39-79]) and pain (11 [44%] of 25 [24-65]) after intramuscular injection; and as tenderness (33 [66%] of 50 [51-79]), erythema (20 [40%] of 50 [26-55]), and pruritus (41 [82%] of 50 [69-91]) after vaccination by microneedle patch application. The geometric mean titres were similar at day 28 between the microneedle patch administered by a health-care worker versus the intramuscular route for the H1N1 strain (1197 [95% CI 855-1675] vs 997 [703-1415]; p=0.5), the H3N2 strain (287 [192-430] vs 223 [160-312]; p=0.4), and the B strain (126 [86-184] vs 94 [73 122]; p=0.06). Similar geometric mean titres were reported in participants who self-administered the microneedle patch (all p>0.05). The seroconversion percentages were significantly higher at day 28 after microneedle patch vaccination compared with placebo (all p<0.0001) and were similar to intramuscular injection (all p>0.01). INTERPRETATION: Use of dissolvable microneedle patches for influenza vaccination was well tolerated and generated robust antibody responses. FUNDING: National Institutes of Health. PMID- 28666683 TI - Comment on: Patient autonomy-centered self-care checklist reduces hospital readmissions after ileostomy creation. PMID- 28666684 TI - Big gas bubble in the belly: Beware of giant sigmoid diverticulum. PMID- 28666682 TI - Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial. AB - BACKGROUND: Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting. METHODS: The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training including information provision, joint goal setting, carer training, and task specific training-that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3-6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707). FINDINGS: Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0.98, 95% CI 0.78-1.23, p=0.87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0.27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0.56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0.80). INTERPRETATION: Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care. FUNDING: The National Health and Medical Research Council of Australia. PMID- 28666685 TI - Antioxidant potential of Himanthalia elongata for protection against ischemia reperfusion injury in the small bowel. AB - BACKGROUND: Seaweed has been associated with the prevention and/or treatment of various diseases related to oxidative stress because of its antioxidant activity. We investigated the protective potential of extract of Himanthalia elongata against ischemia-reperfusion (I/R) injury in the intestine of rats. METHODS: Seventy-two (72) male Wistar albino rats were randomly assigned into 12 groups as follows: sham, I/R only, I/R plus vehicle at 3 time points, and I/R plus extract at 3 time points. The degree of intestinal injury was determined by oxidative stress using lipid peroxidation, superoxide dismutase, catalase, and glutathione peroxidase after mesenteric ischemia-reperfusion. A histological study was also performed. RESULTS: The algae extract helps to maintain normal enzymatic levels because, for all the studied parameters, groups treated with the extract showed significant differences (P < .05) compared with the I/R groups, and there were no differences compared with the sham group. The histological study showed that damage to the intestinal mucosa was less severe in animals treated with extract of H elongata after up to 24 hours of reperfusion compared with the I/R group. CONCLUSION: These results suggest that the extract of H elongata can protect intestinal tissue against ischemia-reperfusion injury. PMID- 28666686 TI - Value of lymph node positivity in treatment planning for early stage pancreatic cancer. AB - BACKGROUND: Multimodal therapy is recommended for early stage pancreatic cancer, although whether all patients benefit and the optimal timing of chemotherapy remain unclear. METHODS: Retrospective cohort study of patients aged 18-79 years with stage I-II pancreatic ductal adenocarcinoma in the National Cancer Database (2004-2012). Patients were grouped based on treatment strategy as surgery only, adjuvant, and preoperative. Accuracy of nodal staging and rate of nodal downstaging were ascertained using pretreatment clinical and postresection pathologic nodal status data. Association between overall risk of death and treatment strategy was evaluated with multivariable Cox regression. RESULTS: Among 19,031 patients, 31.1% underwent surgery only, 59.6% received adjuvant, and 9.3% preoperative therapy. Based on patients receiving upfront surgery, clinical nodal staging bore sensitivity, specificity, positive predictive value, and negative predictive value of 46.2%, 95.7%, 95.1%, and 49.8%, respectively. Preoperative therapy downstaged 38% of cN1 patients to ypN0; 5-year overall survival for this group was 27.2% vs 12.3% for ypN1 patients (P < .001). Relative to surgery only, adjuvant (HR 0.75, 95% CI [0.71-0.78]) and preoperative therapy (HR 0.66 [0.60-0.73]) were associated with lower risk of death among patients with pN1, but not pN0 (adjuvant-HR 1.01 [0.94-1.09]; preoperative-HR 1.10 [0.99 1.22]), disease. CONCLUSION: Our data provide strong support for preoperative chemotherapy for patients with node-positive pancreatic cancer, one third of whom may be downstaged. Among those with seemingly node-negative disease, half will be understaged with current clinical staging modalities. These results should be considered when planning treatment for patients with early stage pancreatic cancer. PMID- 28666687 TI - Autologous peritoneal grafts permit rapid reperitonealization and prevent postoperative abdominal adhesions in an experimental rat study. AB - BACKGROUND: Reperitonealization has attracted increasing attention for its potential to prevent postoperative abdominal adhesions and subsequent related complications. We studied the effect of an autologous peritoneal graft on reperitonealization and prevention of adhesions in a rat model. METHODS: A standardized peritoneal lesion was induced on the parietal peritoneum by electrocoagulation and sutures. Twenty adult rats sustaining these lesions were randomized to 1 of 4 groups: (1) autologuous peritoneal graft with the side of mesothelial cells exposed to the abdominal cavity; (2) autologuous peritoneal graft with the side of subserosa containing fibroblasts exposed to the abdominal cavity; (3) cell sheet consisting of autologuous mesothelial cells and fibroblasts; or (4) nontreated group (Control). Fourteen days after the operation, abdominal adhesions were evaluated by macroscopic observation and histologic assessment. RESULTS: Macroscopic observation revealed that in mesothelial cells/fibroblasts grafts, there was no adhesion on the surface of the peritoneal graft covering the lesion. In contrast, in the other 3 groups, all rats obviously revealed extended and severe adhesions. Histology showed that mesothelial cells exist on the surface of the graft in mesothelial cells/fibroblasts graft, but no mesothelial cells were observed in the samples from the other groups. CONCLUSION: Autologous peritoneal grafts prevented postoperative abdominal adhesions in this rat model. As the mechanism of this prevention, the mesothelial cells survived and contributed to reperitonealization, only when they were transplanted as a part of the autologous peritoneal grafts and were located on the surface exposed to the abdomen. PMID- 28666688 TI - Development of "Purple Endosperm Rice" by Engineering Anthocyanin Biosynthesis in the Endosperm with a High-Efficiency Transgene Stacking System. AB - Anthocyanins have high antioxidant activities, and engineering of anthocyanin biosynthesis in staple crops, such as rice (Oryza sativa L.), could provide health-promoting foods for improving human health. However, engineering metabolic pathways for biofortification remains difficult, and previous attempts to engineer anthocyanin production in rice endosperm failed because of the sophisticated genetic regulatory network of its biosynthetic pathway. In this study, we developed a high-efficiency vector system for transgene stacking and used it to engineer anthocyanin biosynthesis in rice endosperm. We made a construct containing eight anthocyanin-related genes (two regulatory genes from maize and six structural genes from Coleus) driven by the endosperm-specific promoters,plus a selectable marker and a gene for marker excision. Transformation of rice with this construct generated a novel biofortified germplasm "Purple Endosperm Rice" (called "Zijingmi" in Chinese), which has high anthocyanin contents and antioxidant activity in the endosperm. This anthocyanin production results from expression of the transgenes and the resulting activation (or enhancement) of expression of 13 endogenous anthocyanin biosynthesis genes that are silenced or expressed at low levels in wild-type rice endosperm. This study provides an efficient, versatile toolkit for transgene stacking and demonstrates its use for successful engineering of a sophisticated biological pathway, suggesting the potential utility of this toolkit for synthetic biology and improvement of agronomic traits in plants. PMID- 28666689 TI - Optimum Tools for Predicting Clinical Outcomes in Prostate Cancer Patients Undergoing Radical Prostatectomy: A Systematic Review of Prognostic Accuracy and Validity. AB - Prostate cancer is a heterogeneous disease whose therapies frequently have adverse effects. Informed patient counseling regarding likely clinical outcomes is therefore important. In this systematic review we aimed to identify all external validations of tools that are used to predict clinical outcomes in patients undergoing radical prostatectomy and evaluate which are optimum for clinical implementation. PubMed and EMBASE were searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, radical prostatectomy, and prognosis. Titles and abstracts were screened and relevant studies were advanced to full-text review. Reference lists were reviewed for further studies. The Centre for Evidence Based Medicine prognostic tool was used for critical appraisal. Seventy-three studies externally validated 13 pre- and 41 postoperative tools for the prediction of biochemical recurrence (BCR), aggressive BCR, metastasis, and prostate cancer-specific mortality (PCSM). Recommendations for clinical implementation were made on the basis of accuracy, cohort sizes, and consistency. The accuracy of recommended tools ranged from 68% to 79% and 72% to 92% among the largest validation cohorts for pre- and postoperative tools. For preoperative prognosis we recommended the Cancer of the Prostate Risk Assessment (CAPRA) and Stephenson nomograms for BCR, the CAPRA nomogram for aggressive BCR as well as metastasis, and the D'Amico criteria for PCSM. For postoperative prognosis we recommended the CAPRA-Surgery (CAPRA-S), Stephenson, Kattan, Duke prostate cancer (DPC), and the Suardi nomograms for the prediction of BCR, the DPC nomogram for aggressive BCR, the CAPRA-S and Eggener nomograms for metastasis, and the Eggener nomogram for PCSM. Use of these tools should help clinicians deliver accurate, evidence-based counseling to patients undergoing prostatectomy. PMID- 28666690 TI - Social-Ecological Network Approaches in Interdisciplinary Research: A Response to Bohan et al. and Dee et al. PMID- 28666691 TI - Direct targeting of cancer cells with antibodies: What can we learn from the successes and failure of unconjugated antibodies for lymphoid neoplasias? AB - Following approval in 1997 of the anti-CD20 antibody rituximab for the treatment of B-NHL and CLL, many other unconjugated IgG1 MAbs have been tested in pre clinical and clinical trials for the treatment of lymphoid neoplasms. Relatively few have been approved however and these are directed against a limited number of target antigens (CD20, CD52, CCR4, CD38, CD319). We review here the known biological properties of these antibodies and discuss which factors may have led to their success or may, on the contrary, limit their clinical application. Common factors of the approved MAbs are that the target antigen is expressed at relatively high levels on the neoplastic targets and their mechanism of action is mostly immune-mediated. Indeed most of these MAbs induce ADCC and phagocytosis by macrophages, and many also activate complement, leading to target cell lysis. In contrast direct cell death induction is not a common feature but may enhance efficacy in some cases. Interestingly, a key factor for the success of several MAbs appears to be their capacity to skew immunity towards an anti-tumour mode, by inhibiting/depleting suppressor cells and/or activating immune cells within the microenvironment, independently of FcgammaRs. We also expose here some of the strategies employed by industry to expand the clinical use of these molecules beyond their original indication. Interestingly, due to the central role of lymphocytes in the control of the immune response, several of the antibodies are now successfully used to treat many different autoimmune diseases and have also been formally approved for some of these new indications. There is little doubt that this trend will continue and that the precise mechanisms of therapeutic MAbs will be further dissected and better understood in the context of both tumour immunology and autoimmunity. PMID- 28666692 TI - Complex care models to achieve accountable care readiness: Lessons from two community hospitals. AB - Massachusetts' community hospitals face the challenge of achieving accountable care readiness with fewer financial and operational resources and a higher share of publicly-insured patients than their academic medical center counterparts. They are thus doubly constrained to make the investments necessary to perform in a value-based payment environment. Hallmark Health System and Lowell General Hospital are among 25 community hospital awardees engaged with the Massachusetts Health Policy Commission's Community Hospital Acceleration, Revitalization, and Transformation (CHART) investment program to implement clinical transformation programs to reduce unnecessary hospital utilization; enhance care for individuals with social, behavioral, and medical complexity; and improve post-acute community based care, as means to advance accountable care readiness. The programs are payer-blind and designed to operate at-scale based on clinical and/or utilization criteria. Using examples from Hallmark Health System and Lowell General Hospital, we report on early lessons learned, representative of experiences from across the Phase 2 cohort: 1) locally-derived data enables hospitals to plan and implement action-oriented initiatives that are tailored to their communities; 2) investments in appropriate technologies facilitate near real-time patient engagement upon presentation to the acute care setting and/or immediately post discharge; 3) non-medical providers are a cost-effective and high-value addition to complex care teams serving individuals with complex needs; and 4) collaboration with community partners improves care continuity and promotes stability outside the hospital-a promising approach to cost-effective population health management. PMID- 28666694 TI - Diagnosis of urethral diverticulum mimicking pelvic organ prolapse with translabial ultrasonography. PMID- 28666693 TI - Effect of severity of illness on cesarean delivery rates in Washington State. AB - BACKGROUND: Hospitals and providers are increasingly held accountable for their cesarean delivery rates. In the perinatal quality improvement arena, there is vigorous debate about whether all hospitals can be held to the same benchmark for an acceptable cesarean rate regardless of patient acuity. However, the causes of variation in hospital cesarean delivery rates are not well understood. OBJECTIVE: We sought to evaluate the association and temporal trends between severity of illness at admission and the primary term singleton vertex cesarean delivery rate among hospitals in Washington State. We hypothesized that hospitals with higher patient acuity would have higher cesarean delivery rates and that this pattern would persist over time. STUDY DESIGN: In this cross-sectional analysis, we analyzed aggregate hospital-level data for all nonmilitary hospitals in Washington State with >=100 deliveries/y during federal fiscal years 2010 through 2014 (287,031 deliveries). Data were obtained from the Washington State Comprehensive Hospital Abstract Reporting System, which includes inpatient demographic, diagnosis, procedure, and discharge information derived from hospital billing systems. Age, admission diagnoses and procedure codes were converted to patient-level admission severity-of-illness scores using the All Patient Refined Diagnosis Related Groups classification system. This system is widely used throughout the United States to adjust hospital data for severity of illness. Mean admission hospital-level severity-of-illness scores were calculated for each fiscal year among the term singleton vertex population with no history of cesarean delivery. We used linear regression to evaluate the association between hospital admission severity of illness and the primary term singleton vertex cesarean delivery rate, calculated Pearson correlation coefficients, and compared regression line slopes and 95% confidence intervals for each fiscal year. RESULTS: Hospitals were diverse with respect to delivery volume, level of care, and geographic location within Washington. Hospital aggregate admission severity-of-illness score correlated with primary term singleton vertex cesarean delivery rate in all fiscal years (R2 0.38-0.58, P < .001). For every year in the study interval, as admission severity of illness increased so did the primary term singleton vertex cesarean rate. The slope of the regression line decreased during the study interval, suggesting that statewide decrease in primary term singleton vertex cesarean rate occurred across the range of severity of illness. CONCLUSION: Admission severity-of-illness score is strongly associated with the primary term singleton vertex cesarean delivery rate among hospitals in Washington State. Approximately 50% of variation in hospital primary term singleton vertex cesarean delivery rates appeared to be related to admission severity of illness. This relationship persisted over time despite a statewide decrease in cesarean delivery, suggesting that patient acuity will likely continue to contribute to hospital variation in cesarean delivery rates despite perinatal quality improvement efforts. The major implication of this study is that patient acuity should be considered when determining optimal cesarean delivery rates. High-acuity hospitals are likely to have high cesarean rates because they provide a specific role in serving regional needs. To hold these centers to an arbitrary benchmark may jeopardize the funding necessary to support regional safety net institutions. PMID- 28666695 TI - Uterine lipoleiomyoma. PMID- 28666696 TI - Vulvar Crohn's disease: a rare presentation. PMID- 28666697 TI - Reply. PMID- 28666698 TI - A practical approach to training better qualified residents. PMID- 28666699 TI - Perioperative pain management: an update for obstetrician-gynecologists. AB - The opioid epidemic in the United States is unprecedented and continues to worsen. Many opioid abusers obtain their pills through legitimate prescriptions, directly or indirectly, from a medical provider. While practitioners have a responsibility to treat pain, it is now becoming clear that aggressive opioid prescription practices contribute to an epidemic of abuse. The medical community has to balance the unintended consequences of opioid misuse and abuse with the need to provide adequate pain control. Additionally, providers are being held accountable by the legal system and professional organizations for their prescribing practices. Responsible use of opioids is paramount and pain control does not supersede safety. Effective and safe pain management requires that providers perform risk assessments, understand medication risks, avoid excessive reliance on opioids, and adequately monitor and educate patients. Obstetricians and gynecologists are uniquely positioned to influence pain management practices as primary care providers and surgeons who regularly manage both acute and chronic pain conditions. Therefore, the objective of this publication was to familiarize obstetricians and gynecologists with contemporary concepts in pain management and summarize recent guidelines in a manner that is applicable to our specialty. We focus on perioperative pain management, which is the time period immediately before, during, and after surgery. Topics reviewed include proper risk assessment to evaluate a patient's potential for poor pain control or development of chronic pain or misuse of opioids; multimodal pain management with nonpharmacological, nonopioid alternatives, safe opioid-use strategies; education and documentation; and special considerations for women, veterans, and lactation concerns. PMID- 28666700 TI - Risk of metachronous ovarian cancer after ovarian conservation in young women with stage I cervical cancer. AB - BACKGROUND: While there is an increasing trend of ovarian conservation at the time of surgical treatment for young women with stage I cervical cancer, the risk for subsequent ovarian cancer after ovarian conservation has not been well studied. OBJECTIVE: We sought to examine the incidence of and risk factors for metachronous ovarian cancer among young women with stage I cervical cancer who had ovarian conservation at the time of hysterectomy. STUDY DESIGN: The Surveillance, Epidemiology, and End Results Program was used to identify women aged <50 years who underwent hysterectomy with ovarian conservation for stage I cervical cancer from 1983 through 2013 (n = 4365). Time-dependent analysis was performed for ovarian cancer risk after cervical cancer diagnosis. RESULTS: Mean age at cervical cancer diagnosis was 37 years, and the majority of patients had stage IA disease (68.2%) and squamous histology (72.9%). Median follow-up time was 10.8 years, and there were 13 women who developed metachronous ovarian cancer. The 10- and 20-year cumulative incidences of metachronous ovarian cancer were 0.2% (95% confidence interval, 0.1-0.4) and 0.5% (95% confidence interval, 0.2-0.8), respectively. Mean age at the time of diagnosis of metachronous ovarian cancer was 47.5 years, and stage III-IV disease was seen in 55.6%. Age (>=45 vs <45 years, hazard ratio, 4.22; 95% confidence interval, 1.16-15.4; P = .018), ethnicity (non-white vs white, hazard ratio, 4.29; 95% confidence interval, 1.31 14.0; P = .009), cervical cancer histology (adenocarcinoma or adenosquamous vs squamous, hazard ratio, 3.50; 95% confidence interval, 1.17-10.5; P = .028), and adjuvant radiotherapy use (yes vs no, hazard ratio, 3.69; 95% confidence interval, 1.01-13.4; P = .034) were significantly associated with metachronous ovarian cancer risk. The presence of multiple risk factors was associated with a significantly increased risk of metachronous ovarian cancer compared to the no risk factor group: 1 risk factor (hazard ratio range, 2.96-8.43), 2 risk factors (hazard ratio range, 16.6-31.0), and 3-4 risk factors (hazard ratio range, 62.3 109), respectively. CONCLUSION: Metachronous ovarian cancer risk after ovarian conservation for women with stage I cervical cancer is <1%. Older age, non-white ethnicity, adenocarcinoma or adenosquamous histology, and adjuvant radiotherapy may be associated with an increased metachronous ovarian cancer risk. PMID- 28666701 TI - The Perfect Storm of Trauma: The experiences of women who have experienced birth trauma and subsequently accessed residential parenting services in Australia. AB - BACKGROUND: There appears to be a chasm between idealised motherhood and reality, and for women who experience birth trauma this can be more extreme and impact on mental health. Australia is unique in providing residential parenting services to support women with parenting needs such as sleep or feeding difficulties. Women who attend residential parenting services have experienced higher rates of intervention in birth and poor perinatal mental health but it is unknown how birth trauma may impact on early parenting. AIMS AND OBJECTIVES: This study aims to explore the early parenting experiences of women who have accessed residential parenting services in Australia and consider their birth was traumatic. METHODS: In-depth interviews were conducted with eight women across Australia who had experienced birth trauma and accessed residential parenting services in the early parenting period. These interviews were conducted both face to face and over the telephone. The data was analysed using thematic analysis. FINDINGS: One overarching theme was identified: "The Perfect Storm of Trauma" which identified that the participants in this study who accessed residential parenting services were more likely to have entered pregnancy with pre-existing vulnerabilities, and experienced a culmination of traumatic events during labour, birth, and in the early parenting period. Four subthemes were identified: "Bringing Baggage to Birth", "Trauma through a Thousand Cuts", "Thrown into the Pressure Cooker", and "Trying to work it all out". CONCLUSION: How women are cared for during their labour, birth and postnatal period impacts on how they manage early parenthood. Support is crucial for women, including practical parenting support, and emotional support by health professionals and peers. PMID- 28666702 TI - Contralateral routing of signals disrupts monaural level and spectral cues to sound localisation on the horizontal plane. AB - OBJECTIVES: Contra-lateral routing of signals (CROS) devices re-route sound between the deaf and hearing ears of unilaterally-deaf individuals. This rerouting would be expected to disrupt access to monaural level cues that can support monaural localisation in the horizontal plane. However, such a detrimental effect has not been confirmed by clinical studies of CROS use. The present study aimed to exercise strict experimental control over the availability of monaural cues to localisation in the horizontal plane and the fitting of the CROS device to assess whether signal routing can impair the ability to locate sources of sound and, if so, whether CROS selectively disrupts monaural level or spectral cues to horizontal location, or both. DESIGN: Unilateral deafness and CROS device use were simulated in twelve normal hearing participants. Monaural recordings of broadband white noise presented from three spatial locations (-60 degrees , 0 degrees , and +60 degrees ) were made in the ear canal of a model listener using a probe microphone with and without a CROS device. The recordings were presented to participants via an insert earphone placed in their right ear. The recordings were processed to disrupt either monaural level or spectral cues to horizontal sound location by roving presentation level or the energy across adjacent frequency bands, respectively. Localisation ability was assessed using a three-alternative forced-choice spatial discrimination task. RESULTS: Participants localised above chance levels in all conditions. Spatial discrimination accuracy was poorer when participants only had access to monaural spectral cues compared to when monaural level cues were available. CROS use impaired localisation significantly regardless of whether level or spectral cues were available. For both cues, signal re-routing had a detrimental effect on the ability to localise sounds originating from the side of the deaf ear (-60 degrees ). CROS use also impaired the ability to use level cues to localise sounds originating from straight ahead (0 degrees ). CONCLUSIONS: The re-routing of sounds can restrict access to the monaural cues that provide a basis for determining sound location in the horizontal plane. Perhaps encouragingly, the results suggest that both monaural level and spectral cues may not be disrupted entirely by signal re-routing and that it may still be possible to reliably identify sounds originating on the hearing side. PMID- 28666703 TI - A comparative study of MED-EL FMT attachment to the long process of the incus in intact middle ears and its attachment to disarticulated stapes head. AB - The Vibrant Soundbridge(c) (VSB) active middle-ear implant provides an effective treatment for mild-to-severe sensorineural hearing loss in the case of normal middle ear anatomy and mixed hearing loss in middle ear malformation. The VSB floating mass transducer (FMT), with proper couplers, can be installed on various structures of the ossicular chain, e.g., the short and long process of the incus, the stapes head, and the stapes footplate. A long process (LP) coupler is most commonly used for FMT attachment to the long process of the incus with intact ossicular chain, while CliP and Bell couplers are two standardized and reliable methods for FMT attachment to the stapes head with missing incus and malleus. However, the difference and relationship of the vibration properties among these three FMT couplers remain unclear. In the present study, the stapes footplate velocity responses of the LP, CliP, and Bell couplers have been investigated in eight fresh temporal bones (TBs) to evaluate the vibration properties of these three couplers. Normal and reconstructed middle ear transfer functions (METFs) were determined from laser Doppler vibrometer (LDV) measurements. A mastoidectomy and a posterior tympanotomy were performed to expose the ossicular chain. The METFs of the normal middle ear and middle ear with LP-FMT-coupler were compared under acoustic stimulation, thus the mass effect of the FMT with LP coupler was evaluated. Additional comparisons were made between the stapes footplate vibrations of the LP-FMT-coupler (with the intact ossicular chain at the long process of the incus), CliP-FMT-coupler and Bell-FMT-coupler on the stapes head (after incus and malleus removed) under active electromechanical stimulation. After the installation of CliP-FMT-coupler and Bell-FMT-coupler to the middle ear, the average velocity amplitude of the stapes footplate, comparing to the LP FMT-coupler, was about 15 dB higher between 1 and 6 kHz, and 10 dB lower at about 0.5 kHz. Quantitatively, there was no significant difference between the CliP-FMT coupler and Bell-FMT-coupler. According to our study, installation of CliP-FMT coupler or Bell-FMT-coupler on the stapes head provides considerable improvement of the middle ear mechanical and functional responses, comparing with the LP-FMT coupler in the temporal bone experiments. Moreover, the installation of the Bell FMT-coupler to the stapes head produces essentially the same footplate velocity responses in comparison to the CliP-FMT-coupler. PMID- 28666704 TI - Systemic and tissue-specific effects of aliskiren on the RAAS and carbohydrate/lipid metabolism in obese patients with hypertension. AB - Aliskiren penetrates adipose and skeletal muscle in hypertensive patients with abdominal obesity and reduces renin-angiotensin-aldosterone system activity. After discontinuation, blood pressure-lowering effects are observed possibly through drug-tissue binding. We performed microdialysis evaluation of adipose tissue and skeletal muscle before and during an insulin-modified frequently sampled intravenous glucose tolerance test (IM-FSIGT). Aliskiren 300 mg (n = 8) or amlodipine 5 mg (n = 8) once daily were administered during a 12-week randomized treatment period. Aliskiren elicited variable changes in median interstitial angiotensin II (Ang II) in adipose (2.60-1.30 fmol/mL) and skeletal muscle (2.23-0.68 fmol/mL); amlodipine tended to increase adipose and skeletal muscle Ang II (P = .066 for skeletal muscle treatment difference). Glucose/insulin increased median plasma Ang II 1 hour after glucose injection (1.04-2.50 fmol/mL; P = .001), which was markedly attenuated by aliskiren but not amlodipine. Aliskiren increased glucose disposition index (P = .012) and tended to increase acute insulin response to glucose (P = .067). Fasting adipose glycerol (-17%; P = .064) and fasting muscle glucose dialysate (-17%; P = .025) were decreased by aliskiren but not amlodipine. In summary, aliskiren decreased Ang II production in response to glucose/insulin stimulus and elicited metabolic effects in adipose and skeletal muscle suggestive of increased whole-body glucose utilization. PMID- 28666705 TI - Evaluation of high blood pressure and obesity among US coal miners participating in the Enhanced Coal Workers' Health Surveillance Program. AB - Since 2005, the Enhanced Coal Workers' Health Surveillance Program (ECWHSP) has offered respiratory examinations to coal miners in a mobile examination unit. As little is known about the cardiovascular health of coal miners, we describe the prevalence of high blood pressure (BP) and obesity among ECWHSP participants. During 2015, 1402 ECWHSP health examinations were performed. The prevalence of BP consistent with hypertension (systolic BP >= 140 mm Hg or diastolic BP >= 90 mm Hg), prehypertension (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg), and hypertensive crisis (systolic BP >= 180 mm Hg or diastolic BP >= 110 mm Hg) were calculated and compared with the US adult population using standardized morbidity ratios (SMRs). Most participants were male (N = 1317, 94%), White (N = 1303, 93%) and non-Hispanic (N = 1316, 94%). Thirty-one percent (N = 440) of participants had BP in the hypertensive range and 87% (N = 1215) were overweight/obese. Twenty four participants (2%) had a BP reading consistent with a hypertensive crisis. Prevalence of obesity (52%, SMR = 1.52, 95% confidence interval = 1.41-1.64) and BP consistent with hypertension (31%, SMR = 1.60, 95% confidence interval = 1.45 1.76) was higher than the US adult population.The prevalence of obesity and BP consistent with hypertension in this population of coal miners is substantial, indicating a need for cardiovascular health interventions in coal mining communities. PMID- 28666706 TI - Prevalence, awareness, treatment, and control of hypertension among very elderly Chinese: results of a community-based study. AB - The epidemiologic distribution of hypertension among very elderly Chinese is still not clear. This study aimed to investigate the prevalence, awareness, treatment, and control rate of hypertension among very elderly in Chengdu. From May 2013 to May 2015, a total of 1056 participants from 20 residential communities were sampled. Standard face-to-face interviews, physical examinations, and biochemical analysis were undertaken. Participants had a mean age of 83.6 +/- 3.4 years (range: 80-100), and 49.8% were men. Mean systolic blood pressure (BP) and diastolic BP were 146.4 +/- 20.6 and 74.1 +/- 11.9 mm Hg, respectively, and both of the highest BP levels were among participants aged 80 84 years. Mean pulse pressure was 72.5 +/- 17.1 mm Hg, and the highest pulse pressure level was among participants aged 90 years and older. The overall estimated hypertension prevalence was 75.3% (95% confidence interval: 72.6% 77.9%), and among overall participants, 51.9% were aware of their hypertensive condition and 45.5% were treated. However, only 18.1% of hypertensive participants were controlled (BP < 140/90 mm Hg). Among very elderly Chinese in Chengdu, the prevalence of hypertension is predominantly high, whereas awareness, treatment, and control rates are considerably low. Effective primary and secondary prevention strategies are needed. PMID- 28666708 TI - Sound offset-related brain potentials show retained sensory processing, but increased cognitive control activity in older adults. AB - It has been hypothesized that age-related hearing loss is caused not only by peripheral but also central changes in the auditory system. Many studies used event-related potentials (ERPs) elicited by sound onsets to characterize the age related differences in central auditory processing. Age-related ERP enhancements in such studies have often been interpreted in terms of elevated sensitivity to auditory stimulation. Such ERPs, however, comprise various components reflecting different aspects of auditory and task-related processing. The composition of the waveforms may considerably differ for ERPs elicited by other auditory events. In the present study, ERPs elicited by tone offsets were used to characterize processing differences between younger and older adults in a short-go, tone duration discrimination paradigm. Whereas the onset-related auditory ERP was enhanced in the older adult group, no age-related differences were found in the offset-related auditory ERPs observable at temporal electrodes. In older adults, however, offset-related processing was dominated by an N2 that could reflect enhanced cognitive control activities. Because N2 was present regardless discrimination difficulty, younger adults may have framed the task as offset detection, whereas older adults represented the task as "genuine" discrimination. PMID- 28666707 TI - Differential alteration of hippocampal function and plasticity in females and males of the APPxPS1 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and impaired cognitive functions. The higher incidence of AD among women indicates that sex is one of the main risk factor for developing the disease. Using the transgenic amyloid precursor protein * presenilin 1 (APPxPS1) mouse model of AD, we investigated sex inequality with regards to memory capacities and hippocampal plasticity. We report that spatial memory is strongly affected in APPxPS1 females while remarkably spared in males, at all ages tested. Given the contribution of adult neurogenesis to hippocampal dependent memory processes, we examined whether impaired neurogenesis could account for age-related decline of memory functions in APPxPS1 mice. We show that not only limited numbers of new neurons are generated in these mice, but also, that new granule cells display reduced capacity for synaptic connectivity, a default that is exacerbated in females. Moreover, high densities of hypertrophic astrocytes are observed in the dentate gyrus of APPxPS1 females specifically. By revealing sex-dependent hippocampal alterations, our data may provide causal explanation to APPxPS1 females' memory deficits. PMID- 28666709 TI - Structural and functional brain signatures of C9orf72 in motor neuron disease. AB - This study investigated structural and functional magnetic resonance imaging abnormalities in hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) motor neuron disease (MND) relative to disease severity matched sporadic MND cases. We enrolled 19 C9orf72 and 67 disease severity matched sporadic MND patients, and 22 controls. Sporadic cases were grouped in patients with: no cognitive/behavioral deficits (sporadic-motor); same patterns of cognitive/behavioral impairment as C9orf72 cases (sporadic-cognitive); shorter disease duration versus other sporadic groups (sporadic-early). C9orf72 patients showed cerebellar and thalamic atrophy versus all sporadic cases. All MND patients showed motor, frontal, and temporoparietal cortical thinning and motor and extramotor white matter damage versus controls, independent of genotype and presence of cognitive impairment. Compared with sporadic-early, C9orf72 patients revealed an occipital cortical thinning. C9orf72 patients had enhanced visual network functional connectivity versus sporadic-motor and sporadic-early cases. Structural cerebellar and thalamic damage and posterior cortical alterations are the brain magnetic resonance imaging signatures of C9orf72 MND. Frontotemporal cortical and widespread white matter involvement are likely to be an effect of the disease evolution rather than a C9orf72 marker. PMID- 28666710 TI - Homozygous alpha-synuclein p.A53V in familial Parkinson's disease. AB - We have assessed the frequency of alpha-synuclein (SNCA) mutations in Japanese patients with familial or sporadic Parkinson's disease (PD) and surveyed their associated clinical manifestations. We screened SNCA exon 3 in 988 patients without SNCA multiplications (430 with autosomal dominant PD and 558 with sporadic PD). We detected 1 patient harboring a homozygous SNCA p.A53V substitution albeit with an autosomal dominant pattern of disease inheritance (frequency 2/860 = 0.2%). The proband manifested slow and progressive parkinsonism at 55 years. Later she complicated with cognitive decline and hallucinations. Several of her immediate family members also presented with parkinsonism, cognitive decline, and psychosis. Positron emission tomography imaging of 18F-6-fluoro-L-dopa (18F-DOPA) uptake, 11C(+)dihydrotetrabenzine (type 2 vesicular monoamine transporter), and 11C-d-threo-methylphenidate (a plasmalemmal dopamine transporter marker) binding in the striatum were significantly reduced. Hence, alpha-synuclein p.A53V homozygous mutation leads to a distinct phenotype of progressive parkinsonism and cognitive decline, commonly observed in patients with SNCA missense mutation or multiplications. PMID- 28666711 TI - Low high-density lipoprotein cholesterol and particle concentrations are associated with greater levels of endothelial activation markers in Multi-Ethnic Study of Atherosclerosis participants. AB - BACKGROUND: High-density lipoproteins (HDL) are well characterized for their role in reverse cholesterol transport but may confer other cardiovascular benefits specifically, HDL may suppress the endothelial activation cascade in the initiating stages of atherogenesis. OBJECTIVE: It was the primary aim of this study to examine the relations of HDL cholesterol (HDL-C), total HDL particle (HDL-P) concentrations, and HDL-P subclasses with circulating levels of endothelial activation markers in a subcohort of Multi-Ethnic Study of Atherosclerosis participants. METHODS: HDL-C was measured by enzymatic assay, and total HDL-P and subclass concentrations were assessed by nuclear magnetic resonance spectroscopy. Concentrations of circulating endothelial activation markers were determined through immunoassay. Multivariable linear regression was used to determine the cross-sectional associations between HDL variables and endothelial markers with statistical adjustment for age, race/ethnicity, sex, education, systolic blood pressure, hypertension medication use, body mass index, smoking status, lipid-lowering medication use, serum creatinine, diabetes, low density lipoprotein cholesterol, and coronary artery calcium. RESULTS: HDL-C and HDL-P were found to be inversely associated with soluble vascular cell adhesion molecule-1, soluble vascular intracellular adhesion molecule-1, sL-selectin, and sP-selectin; HDL-P was additionally inversely associated with sE-selectin. Participants with low levels of HDL-C (<40 mg/dL) or HDL-P (<25th percentile) showed 3%-12% higher mean levels of soluble vascular cell adhesion molecule and compared with those above these levels (all P < .01). CONCLUSION: Coupled with previous evidence, our findings suggest a modest to moderate relation of HDL and circulating levels of endothelial activation markers in humans. Whether this relationship may have clinical implications in suppressing atherogenesis or coronary heart disease development requires additional research. PMID- 28666712 TI - The association between six genetic variants and blood lipid levels in pregnant Chinese Han women. AB - BACKGROUND: Hyperlipidemia has unique adverse effects on pregnant women and their offspring. The underlying genetic factors related to lipid levels in pregnant populations need more studies. OBJECTIVE: This study aimed to investigate the relationship between 6 single-nucleotide polymorphisms (SNPs) and plasma lipid levels during pregnancy. METHODS: A total of 2060 pregnant women were recruited. Fasting plasma lipids were measured in the third trimester of pregnancy. Six SNPs (rs1260326 in GCKR, rs1800775 in CETP, rs515135 in APOB, rs1800588 in LIPC, rs964184 in ZPR1, and and rs4420638 in APOC1 of each participant were genotyped using TaqMan allelic discrimination assays. The relationships between the 6 loci and plasma lipids were analyzed using a multiple linear regression method. RESULTS: Two variants, rs1260326 (beta = 0.220, 95% confidence interval [CI] = 0.148-0.291; P = 2.048 * 10-9) and rs964184 (beta = 0.172, 95% CI = 0.085-0.258; P = 1.083 * 10-4) were significantly associated with triglyceride levels. Another 2 variants, rs1800775 (beta = -0.033, 95% CI = -0.065 to -0.002; P = .040) and rs1800588 (beta = 0.079, 95% CI = 0.046-0.112; P = 3.137 * 10-6), were associated with high-density lipoprotein cholesterol. In addition, rs1800775 (beta = -0.086, 95% CI = -0.156 to -0.012; P = .024) was associated with total cholesterol. No selected SNPs were associated with plasma low-density lipoprotein cholesterol levels in this study. CONCLUSIONS: Loci found by genome-wide association studies to be associated with plasma lipid levels in the general population were also related to lipid levels in the third trimester of pregnancy. This finding implies that changes to lipid profiles during gestation may be associated with SNPs of lipid-related genes. Variants of lipid-related genes are important predictors for estimating lipid concentrations during the pregnancy. PMID- 28666714 TI - Intensive preoperative rehabilitation improves functional capacity and postoperative hospital length of stay in elderly patients with lung cancer [synopsis]. PMID- 28666713 TI - GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia. AB - BACKGROUND: GPIHBP1, a glycolipid-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) in the interstitial spaces and transports it to the capillary lumen. GPIHBP1 deficiency prevents LPL from reaching the capillary lumen, resulting in low intravascular LPL levels, impaired intravascular triglyceride processing, and severe hypertriglyceridemia (chylomicronemia). A recent study showed that some cases of hypertriglyceridemia are caused by autoantibodies against GPIHBP1 ("GPIHBP1 autoantibody syndrome"). OBJECTIVE: Our objective was to gain additional insights into the frequency of the GPIHBP1 autoantibody syndrome in patients with unexplained chylomicronemia. METHODS: We used enzyme-linked immunosorbent assays to screen for GPIHBP1 autoantibodies in 33 patients with unexplained chylomicronemia and then used Western blots and immunocytochemistry studies to characterize the GPIHBP1 autoantibodies. RESULTS: The plasma of 1 patient, a 36-year-old man with severe hypertriglyceridemia, contained GPIHBP1 autoantibodies. The autoantibodies, which were easily detectable by Western blot, blocked the ability of GPIHBP1 to bind LPL. The plasma levels of LPL mass and activity were low. The patient had no history of autoimmune disease, but his plasma was positive for antinuclear antibodies. CONCLUSIONS: One of 33 patients with unexplained chylomicronemia had the GPIHBP1 autoantibody syndrome. Additional studies in large lipid clinics will be helpful for better defining the frequency of this syndrome and for exploring the best strategies for treatment. PMID- 28666716 TI - Fulminant multicentric Castleman's disease in a patient with well-controlled human immunodeficiency virus infection-lessons from the patient. PMID- 28666715 TI - [The role of erythroferrone in iron metabolism: From experimental results to pathogenesis]. AB - In case of erythropoiesis, body iron needs to increase to enable the production of new red blood cells. In the 1950s, the observation of an increased digestive iron absorption in the case of phlebotomies had led to propose the existence of an "erythroid factor", which regulate the availability of iron for erythropoiesis in this situation. The factor regulating iron stores has been identified in 2000 to be hepcidin. Recently, in 2014, a new factor was discovered, which regulates iron metabolism, independently of iron stores and responds to the increased requirements for iron after stimulation of erythropoiesis by erythropoietin. This factor has been referred to as erythroferrone. Thus, the regulation of iron stores depends on hepcidin, while the adaptation mechanisms of iron availability in case of anemia, are mediated by an erythroid factor that could be erythroferrone. This review summarizes the current knowledge on the role of erythroferrone in iron metabolism, starting from experimental results, obtained mainly on mouse models, and related to iron overload in beta-thalassemia, iron disturbances during anemia of chronic diseases and chronic renal failure. These results will have to be compared with those obtained in humans, as soon as a reliable assay for human erythroferrone is available. From a clinical point of view, erythroferrone could become a useful biological marker of iron metabolism and a therapeutic target. PMID- 28666717 TI - Drivers and barriers in the consistency approach for vaccine batch release testing: Report of an international workshop. AB - Safety and potency assessment for batch release testing of established vaccines still relies partly on animal tests. An important avenue to move to batch release without animal testing is the consistency approach. This approach is based on thorough characterization of the vaccine, and the principle that the quality of subsequent batches is the consequence of the application of consistent production of batches monitored by a GMP quality system. Efforts to implement the consistency approach are supported by several drivers from industry, government, and research, but there are also several barriers that must be overcome. A workshop entitled "Consistency Approach, Drivers and Barriers" was organized, which aimed to discuss and identify drivers and barriers for the implementation of the 3Rs in the consistency approach from three different perspectives/domains (industry, regulatory and science frameworks). The workshop contributed to a better understanding of these drivers and barriers and resulted in recommendations to improve the overall regulatory processes for the consistency approach. With this report, we summarise the outcome of this workshop and intend to offer a constructive contribution to the international discussion on regulatory acceptance of the consistency approach. PMID- 28666718 TI - Performance of microbiological, serological, molecular, and modified seminal plasma methods in the diagnosis of Brucella abortus in semen and serum of bovine bulls. AB - Brucellosis remains as a major infectious disease of domestic animals and is considered a re-emerging zoonosis in several countries. B. abortus infections in bulls are related to reproductive tract infections, although infected animals show transient serological titers or nonreactor status. Thus, diagnosis of bovine brucellosis based exclusively on serological tests probably underestimates B. abortus infections in bulls. In this scenario, three hundred thirty-five serum samples from reproductively mature bovine bulls were subjected simultaneously to standard serodiagnosis using the rose Bengal test (RBT), 2-mercaptoethanol (2 ME), complement fixation (CFT), and fluorescence polarization assay (FPA). Furthermore, conventional semen plasma agglutination (SPA) and modified 2-ME, FC and, FPA were carried out in all bulls replaing serum by seminal plasma. Semen from all bulls was also analyzed for sperm viability, microbiological culture in Farrell media, and polymerase chain reaction (PCR). Only eight (2.38%) semen samples were considered improper for reproduction services (necrospermia and azoospermia), although none of these animals was positive in any of the diagnosis methods used. Five bulls (1.49%) were simultaneously positive in conventional RBT, 2-ME, SPA, modified 2-ME, microbiological culture in Farrell media, and in PCR for B. abortus strain 19. Two (1.67%) bulls were positive in PCR for B. abortus field strains and negative in all other tests, although semen was considered viable to reproduction service. The identification of B. abortus B19 strain in serum and semen of bulls occurred probably due to improper vaccination of males or infection by B19 strain shedding by vaccinated females that could to contaminated environment of farms. In addition, detection of B. abortus field strains only using PCR in bulls without sperm viability abnormalities indicate the need for including molecular methods to improve diagnosis of the disease in bovine bulls. PMID- 28666719 TI - Stem cells from human-exfoliated deciduous teeth reduce tissue-infiltrating inflammatory cells improving clinical signs in experimental autoimmune encephalomyelitis. AB - Stem cells from human exfoliated deciduous teeth (SHED) have great therapeutic potential and here, by the first time, we evaluated their immunomodulatory effect on experimental model of autoimmune encephalomyelitis (EAE). Specifically, we investigated the effect of SHED administration on clinical signs and cellular patterns in EAE model using Foxp3 GFP + transgenic mice (C57Bl/6-Foxp3GFP). The results showed that SHED infusion ameliorated EAE clinical score with reduced number of infiltrating IFN-gamma+CD8+, IL-4+CD8+, IFN-gamma+CD4+ and IL-4+CD4+ T cells into the central nervous system (CNS). In addition, we observed that SHED promoted a significant increase in CD4+FOXP3+ T cells population in the spleen of EAE-affected animals. Taken together, our results provide strong evidence that SHED can modulate peripherally the CD4+ T cell responses suggesting that SHED would be explored as part of cellular therapy in autoimmune diseases associated with CNS. PMID- 28666720 TI - Clinicopathological implications to micropapillary bladder urothelial carcinoma of the presence of sialyl Lewis X-decorated mucin 1 in stroma-facing membranes. AB - OBJECTIVES: Bladder urothelial carcinoma (UC) comprises more than 90% of all bladder cancers. Among several UC variants, micropapillary UC (MPUC) is a rare one with high potential for lymphovascular invasion and subsequent lymph node metastasis. Histologically, MPUC is characterized by the presence of small papillary carcinoma cell clusters surrounded by lacunar spaces. Immunohistochemically, the outer circumference of these clusters, that is, the stroma-facing membrane of carcinoma cells, is reportedly almost invariably positive for mucin 1 (MUC1) protein and to a lesser extent for sialyl Lewis X (sLeX) carbohydrates; however, the clinicopathological implications of these expression patterns have not been fully investigated. MATERIALS AND METHODS: We performed immunohistochemical analysis of MPUC (n = 11) and conventional UC (n = 57) for MUC1 and sLeX to determine whether these factors immunolocalized. Dual immunofluorescence staining was also carried out to assess MUC1 and sLeX colocalization. We also performed Western blot analysis of Chinese hamster ovary cells misexpressing both recombinant epitope-tagged MUC1 and glycosyltransferases enabling sLeX biosynthesis. RESULTS: MPUC samples preferentially exhibited both MUC1 protein and sLeX carbohydrate expression on the stroma-facing membrane of carcinoma cells. Based on univariate analysis, MUC1 expression in that pattern was positively correlated with tumor extension, lymphovascular invasion, lymph node metastasis, disease stage, and relatively poor patient prognosis. A comparable sLeX expression pattern also correlated positively with tumor extension and nodal metastasis. Based on multivariate analysis, localization of MUC1 and sLeX on the stroma-facing side of the membrane was positively correlated with lymph node metastasis. CONCLUSIONS: Overall, our immunofluorescence findings as well as immunoprecipitation analyses of Chinese hamster ovary cell transfectants strongly suggest that MUC1 is a potential scaffold protein for sLeX carbohydrates in MPUC. Both MUC1 and sLeX may cooperatively contribute to MPUC histogenesis and clinicopathological characteristics. PMID- 28666721 TI - Follow-up of high-risk bladder cancer-Is it safe to perform fluorescence endoscopy multiple times in the same patient? AB - PURPOSE: As the use of fluorescence endoscopy is recommended today by different guidelines during the follow-up of high-grade non-muscle-invasive bladder cancer, the aim of this study is to analyze whether the multiple use of hexylaminolevulinate (HAL) for TUR-BT can be performed safely within the same patient over a time interval. METHODS: Data of patients diagnosed and treated with HAL-TUR-B at our institute between 2008 and 2013 were analyzed. Special interest was given to side effects observed during the instillation of the substance, on the whole day of the instillation and during the entire hospital stay. We focussed on side effects associated with the use of HAL, such as allergic reactions, urinary tract infections, photosensitization of the skin, and relevant changes in blood pressure. RESULTS: In the time between 2008 and 2013, 2480 HAL-TUR-BTs were performed in total at our institute. In 80 patients, HAL TUR-BT was used at least 2 times, and on average 4 times (2-12 times). Only patients with multiple uses were included for our final analysis. We observed no allergizations in any of the treated patients. Minor side effects were urinary tract infections (n = 4), dysuria (n = 4), pollakisuria (n = 9), and bladder spasms (n = 17). CONCLUSION: In our study cohort, the multiple use of HAL-TUR-BT within the same patient caused no major side effects or an induction of allergization against the substance. We, therefore, conclude that HAL-TUR-BT can be performed safely in the same patient during the follow-up of aggressive tumors as recommended by different guidelines today. PMID- 28666722 TI - Adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: A multi-institutional study. AB - PURPOSE: Few studies have examined the role of radiation therapy in advanced penile squamous cell carcinoma. We sought to evaluate the association of adjuvant pelvic radiation with survival and recurrence for patients with penile cancer and positive pelvic lymph nodes (PLNs) after lymph node dissection. MATERIALS AND METHODS: Data were collected retrospectively across 4 international centers of patients with penile squamous cell carcinoma undergoing lymph node dissections from 1980 to 2013. Further, 92 patients with available adjuvant pelvic radiation status and positive PLNs were analyzed. Disease-specific survival (DSS) and recurrence were analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards model. RESULTS: 43% (n = 40) of patients received adjuvant pelvic radiation after a positive PLN dissection. Median follow-up was 9.3 months (interquartile range: 5.2-19.8). Patients receiving adjuvant pelvic radiation had a median DSS of 14.4 months vs. 8 months in the nonradiation group, respectively (P = 0.023). Patients without adjuvant pelvic radiation were associated with worse overall survival (hazard ratio [HR] = 1.7; 95% CI: 1.01-2.92; P = 0.04) and DSS (HR = 1.9; 95% CI: 1.09-3.36; P = 0.02) on multivariable analysis. Median time to recurrence was 7.7 months vs. 5.3 months in the radiation and nonradiation arm, respectively (P = 0.042). Patients without adjuvant pelvic radiation was also independently associated with higher overall recurrence on multivariable analysis (HR = 1.8; 95% CI: 1.06-3.12; P = 0.03). CONCLUSIONS: Adjuvant pelvic radiation is associated with improved survival and decreased recurrence in this population of patients with penile cancer with positive PLNs. PMID- 28666723 TI - The Reproducibility of Changes in Diagnostic Figures of Merit Across Laboratory and Clinical Imaging Reader Studies. AB - RATIONALE AND OBJECTIVES: In this paper we examine which comparisons of reading performance between diagnostic imaging systems made in controlled retrospective laboratory studies may be representative of what we observe in later clinical studies. The change in a meaningful diagnostic figure of merit between two diagnostic modalities should be qualitatively or quantitatively comparable across all kinds of studies. MATERIALS AND METHODS: In this meta-study we examine the reproducibility of relative measures of sensitivity, false positive fraction (FPF), area under the receiver operating characteristic (ROC) curve, and expected utility across laboratory and observational clinical studies for several different breast imaging modalities, including screen film mammography, digital mammography, breast tomosynthesis, and ultrasound. RESULTS: Across studies of all types, the changes in the FPFs yielded very small probabilities of having a common mean value. The probabilities of relative sensitivity being the same across ultrasound and tomosynthesis studies were low. No evidence was found for different mean values of relative area under the ROC curve or relative expected utility within any of the study sets. CONCLUSION: The comparison demonstrates that the ratios of areas under the ROC curve and expected utilities are reproducible across laboratory and clinical studies, whereas sensitivity and FPF are not. PMID- 28666724 TI - "Rounding" the Size of Pulmonary Nodules: Impact of Rounding Methods on Nodule Management, as Defined by the 2017 Fleischner Society Guidelines. AB - RATIONALE AND OBJECTIVES: The objective of this study was to quantify the impact of different rounding methods on size measurements of pulmonary nodules and to determine the number of nodules that change management categories as a result of rounding. MATERIALS AND METHODS: For this retrospective institutional review board-approved study, we included 503 incidental pulmonary nodules (308 solid and 195 subsolid) from a data repository. Long and short axes were measured. Average diameters were calculated using four different rounding methods (method 1: no rounding; method 2: rounding only the average diameter to the closest millimeter; method 3: rounding only short and long axes; and method 4: rounding short and long axes and the average diameter to the closest millimeter). Nodules were classified for each rounding method according to the 2017 Fleischner Society guideline management categories. Measurements were compared among the four rounding methods using analysis of variance. RESULTS: Without rounding, the average nodule diameter was 15.67 +/- 5.97 mm. This increased between 0.03 and 0.29 mm using rounding methods 2-4 (range: P < 0.001-0.017). The nodule size was more frequently rounded up (range: 52.1%-77.5%) than rounded down (range: 17.7% 42.5%) using rounding methods 2-4, as compared to no rounding. In the 308 solid nodules, up to 2.9% of the nodules changed management category, whereas none of the 195 subsolid nodules changed category. CONCLUSIONS: Rounding methods have a small absolute but statically significant effect on nodule size, impacting management category in less than 3% of the nodules. This suggests that, in clinical practice, any rounding method can be used for determining nodule size without substantially biasing individual nodules toward given management categories. PMID- 28666725 TI - Implementation of Upright Digital Breast Tomosynthesis-guided Stereotactic Biopsy. AB - With growing adoption of digital breast tomosynthesis, an increasing number of imaging abnormalities are being identified only by tomosynthesis. Upright digital breast tomosynthesis-guided stereotactic biopsy is a proven method for sampling these abnormalities as well as abnormalities traditionally evaluated using conventional stereotactic biopsy. In this article, we describe the technique of upright digital breast tomosynthesis-guided stereotactic biopsy and outline a systematic operational approach to implementation of this technique in clinical radiology practices. PMID- 28666726 TI - Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models. AB - This study aimed to develop redox-sensitive and CD44-targeted liposomes to improve chemotherapy of osteosarcoma. Cationic liposomes were prepared and stabilized with a novel detachable polyethylene glycol (PEG2000) conjugated with cholesterol through a bio-reducible disulfide linker (Chol-SS-mPEG). Hyaluronic acid (HA, MW 20-40kDa), a ligand to CD44, was non-covalently coated on the cationic liposomes. Doxorubicin (DOX) was actively loaded in the liposomes as a model drug. The roles of HA and Chol-SS-mPEG on intracellular drug delivery efficiency, and antitumor efficacy were studied. The structure of Chol-SS-mPEG was confirmed with Fourier-transform infrared and nuclear magnetic resonance (1H NMR). The liposomes, Chol-SS-mPEG/HA-L had a mean diameter of 165nm, zeta potential -28.9mV, and destabilized in reducing or acidic (pH5-6) conditions. In vitro release of DOX was well-controlled at physiological conditions, but a burst release of 60% was observed in the presence of 10mM glutathione (GSH), in contrast to non-redox sensitive liposomes (Chol-mPEG/HA-L and Chol-mPEG-L). MTT cell viability assay showed that the dual-functional Chol-SS-mPEG/HA-L with a drug loading of 15.0% (w/w) had significantly higher cytotoxicity to MG63 osteosarcoma cells compared with non-reduction sensitive or non-HA coated liposomes (p<0.01), consistent with the cellular uptake and intracellular trafficking studies using confocal microscopy and flow cytometry. Furthermore, the HA-coated GSH-responsive liposomes preferentially internalized to MG63 over human liver cells LO2. In rats, liposomes stabilized with either Chol-SS-mPEG or Chol-mPEG, with or without HA, increased the half-life of DOX by >10-fold. In a MG63 xenograft mouse model, Chol-SS-mPEG/HA-L showed the most effective tumor suppression with minimal uptake by the liver compared with other liposomes. All animals treated with liposomal formulations survived, in contrast to those free DOX treated. In conclusion, the easily prepared Chol-SS-mPEG/HA-L was demonstrated as an excellent CD44-mediated intracellular delivery system capable of long-circulation and GSH-triggered cytoplasmic drug release. Further translational and multidisciplinary research is required to make it real clinical benefits to cancer patients. PMID- 28666728 TI - Near-infrared light-triggered drug release from a multiple lipid carrier complex using an all-in-one strategy. AB - The present study reports a drug delivery system comprising nanostructured lipid carrier (NLCs) within liposomes (Lip-NLCs). This multiple lipid carrier complex features laser-triggered responsive drug release. Both hydrophobic and hydrophilic drugs can be loaded into the same formulation by applying an all-in one strategy. We hypothesized that if we loaded the hydrophobic near-infrared (NIR) dye IR780 into the liposome phospholipid bilayer, the bilayer would be disrupted by laser irradiation so that drug release would be triggered remotely at the tumor site. We used in vitro and in vivo methods to verify that laser irradiation facilitated controlled release of both hydrophobic and hydrophilic drugs. The degree of drug release triggered by NIR laser light could be adjusted by varying the laser intensity and irradiation time. Following laser treatment, hydrophilic AMD3100 was released from the aqueous liposome chamber and then bound with CXCR4 receptors on the tumor cell surface to inhibit metastasis. NLCs carrying lipophilic IR780 were also released from the aqueous chamber of liposomes and taken up into tumor cells to enhance the photothermal therapeutic effect of IR780. More importantly, Lip-NLCs loaded with IR780 and AMD3100 (IR780 AMD-Lip-NLCs) exhibited enhanced anti-tumor and anti-metastasis effects. These results suggest that Lip-NLCs are a safe and simply prepared all-in-one platform for delivery of drugs with different solubilities. This system facilitates easily controlled release of cargoes to achieve multi-functional combined therapy. PMID- 28666727 TI - Liposomal temozolomide drug delivery using convection enhanced delivery. AB - Even though some progress in diagnosis and treatment has been made over the years, there is still no definitive treatment available for Glioblastoma multiforme (GBM). Convection-enhanced delivery (CED), a continuous infusion mediated pressure gradient via intracranial catheters, studied in clinical trials, enables in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. We hypothesized that the currently limited efficacy of CED could be enhanced by a liposomal formulation, thus achieving enhanced drug localization to the tumor site with minimal toxicity. We hereby describe a novel approach for treating GBM by CED of liposomes containing the known chemotherapeutic agent, temozolomide (TMZ). A new technique for encapsulating TMZ in hydrophilic (PEGylated) liposomes, characterized by nano-size (121nm), low polydispersity index (<0.13) and with near-neutral charge (-?,0.2mV), has been developed. Co-infusion of PEGylated Gd DTPA liposomes and TMZ-liposomes by CED in GBM bearing rats, resulted in enhanced tumor detection with longer residence time than free Gd-DTPA. Treatment of GBM bearing rats with either TMZ solution or TMZ-liposomes resulted in greater tumor inhibition and significantly higher survival. However, the longer survival and smaller tumor volumes exhibited by TMZ liposomal treatment in comparison to TMZ in solution were insignificant (p<0.053); and only significantly lower edema volumes were observed. Thus, there are no clear-cut advantages to use a liposomal delivery system of TMZ via CED over a drug solution. PMID- 28666729 TI - cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells. AB - Recalcitrant head and neck squamous cell carcinoma (HNSCC) usually relapses after therapy due to the enrichment of drug resistant cancer stem-like cells (CSCs). Nanomedicines have shown potential for eradicating both cancer cells and CSCs by effective intratumoral navigation for reaching particular cell populations and controlling drug delivery. The installation of ligands on nanomedicines is an attractive approach for improving the delivery to CSCs within tumors, though the development of CSC-selective ligand-receptor systems has been challenging. Herein, we found that the CSC subpopulation in HNSCC cells overexpresses alphavbeta5 integrins, which is preferentially expressed in tumor neovasculature and cancer cells, and can be effectively targeted by using cyclic Arg-Gly-Asp (cRGD) peptide. Thus, in this study, we propose installing cRGD peptide on micellar nanomedicines incorporating cisplatin for improving their activity against CSCs and enhancing survival. Both cisplatin-loaded micelles (CDDP/m) and cRGD-installed CDDP/m (cRGD-CDDP/m) were effective against HNSCC SAS-L1-Luc cells in vitro, though cRGD-installed CDDP/m was more potent than CDDP/m against the CSC fraction. In vivo, the cRGD-CDDP/m also showed significant antitumor activity against HNSCC orthotopic tumors, i.e. SAS-L1 and HSC-2. Moreover, cRGD-CDDP/m rapidly accumulated into the lymph node metastasis of SAS-L1 tumors, effectively inhibiting their growth, and prolonging mice survival. These findings indicate cRGD-installed nanomedicines as an advantageous strategy for targeting CSCs in HNSCC, and particularly, cRGD-CDDP/m as a significant therapeutic strategy against regionally advanced HNSCC. PMID- 28666730 TI - Risk Factors for Secondary Glaucoma in Herpetic Anterior Uveitis. AB - PURPOSE: To determine the incidence of elevated intraocular pressure (IOP) and secondary glaucoma in herpetic anterior uveitis (AU), owing to either herpes simplex or varicella zoster virus, by using the Standardization of Uveitis Nomenclature (SUN) criteria, and to identify risk factors for the development of glaucoma. DESIGN: Retrospective observational cohort study. METHODS: Patients with herpetic AU presenting themselves between 2001 and 2013 at the ophthalmology department of the University Medical Center Groningen were included. Main outcome measures were the incidence of elevated IOP and glaucoma and risk factors for the development of glaucoma. RESULTS: Seventy-three herpetic AU patients were included. Ocular complications most commonly seen during follow-up for uveitis were elevated IOP (75%), keratitis (59%), dry eyes (34%), posterior synechiae (34%), cataract (32%), and glaucoma (15%). Glaucoma patients, in comparison to non-glaucoma patients, had a higher number of IOP peaks during their follow-up for uveitis (P < .001). The majority of patients with elevated IOP (91%) had this already at the start of the uveitis. Nineteen percent of the patients needed glaucoma surgery. CONCLUSIONS: Using the SUN criteria, our study confirmed that elevated IOP and secondary glaucoma are major complications in herpetic AU. If an elevated IOP occurred, it was usually already present at the start of a uveitis episode. A risk factor for the development of glaucoma was the number of endured IOP peaks. Future studies are needed to evaluate whether early and prolonged use of antiviral and IOP-lowering medication may prevent glaucoma. PMID- 28666731 TI - The Auckland Cataract Study II: Reducing Complications by Preoperative Risk Stratification and Case Allocation in a Teaching Hospital. AB - PURPOSE: To assess the effect of preoperative risk stratification for phacoemulsification surgery on intraoperative complications in a teaching hospital. DESIGN: Prospective cohort study. METHODS: Prospective assessment of consecutive phacoemulsification cases (N = 500) enabled calculation of a risk score (M-score of 0-8) using a risk stratification system. M-scores of >3 were allocated to senior surgeons. All surgeries were performed in a public teaching hospital setting, Auckland, New Zealand, in early 2016. Postoperatively, data were reviewed for complications and corrected distance visual acuity (CDVA). Results were compared to a prospective study (N = 500, phase 1) performed prior to formal introduction of risk stratification. RESULTS: Intraoperative complications increased with increasing M-scores (P = .044). Median M-score for complicated cases was higher (P = .022). Odds ratio (OR) for a complication increased 1.269 per unit increase in M-score (95% confidence interval [CI] 1.007 1.599, P = .043). Overall rate of any intraoperative complication was 5.0%. Intraoperative complication rates decreased from 8.4% to 5.0% (OR = 0.576, P = .043) comparing phase 1 and phase 2 (formal introduction of risk stratification). The severity of complications also reduced. A significant decrease in complications for M = 0 (ie, minimal risk cases) was also identified comparing the current study (3.1%) to phase 1 (7.2%), P = .034. There was no change in postoperative complication risks (OR 0.812, P = .434) or in mean postoperative CDVA (20/30, P = .484) comparing current with phase 1 outcomes. CONCLUSION: A simple preoperative risk stratification system, based on standard patient information gathered at preoperative consultation, appears to reduce intraoperative complications and support safer surgical training by appropriate allocation of higher-risk cases. PMID- 28666732 TI - A Functional Variant of SMAD4 Enhances Thoracic Aortic Aneurysm and Dissection Risk through Promoting Smooth Muscle Cell Apoptosis and Proteoglycan Degradation. AB - Recent studies indicate important roles for SMAD4 in SMCs proliferation, extracellular matrix maintenance, and blood vessel remodeling. However, the genetic effects of SMAD4 in the pathogenesis of thoracic aortic aneurysm and dissection (TAAD) are still largely unknown. Here we identified a functional variant of SMAD4 which might be involved in the pathological progression of TAAD. Five tagging SNPs of SMAD4 were genotyped in 202 TAAD cases and 400 controls using MALDI-TOF. rs12455792 CT or TT variant genotypes was associated with an significantly elevated TAAD risk (adjusted OR=1.58, 95%CI=1.09-2.30) under a dominant genetic model. It was located in the 5'UTR and predicted to influence transcription activity and RNA folding of SMAD4. In luciferase reporter assay, rs12455792 T allele markedly decreased luciferase activities. Accordingly, SMAD4 expression in tissues was lower in patients with CT or TT genotypes, compared with CC. Movat's pentachrome showed that rs12455792 T allele enhanced SMCs loss and fibers accumulation. With angiotensin II induction, rate of Apoptotic SMCs was significantly higher while SMAD4 silenced. Moreover, rs12455792 T allele also increased Versican degradation via ADAMTS-4. In conclusion, this variant might promote SMCs apoptosis and proteoglycans degradation, and further facilitate the progress of TAAD. Our findings identified rs12455792 as a predictor for progression of vascular media pathological changes related thoracic aortic disorders. PMID- 28666734 TI - A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group. AB - Protein prenylation such as farnesylation and geranylgeranylation is associated with various diseases. Thus, many inhibitors of prenyltransferase have been developed. We report novel inhibitors of farnesyltransferase with a zinc-site recognition moiety and a farnesyl/dodecyl group. Molecular docking analysis showed that both parts of the inhibitor fit well into the catalytic domain of farnesyltransferase. The synthesized inhibitors showed activity against farnesyltransferase in vitro and inhibited proliferation of the pancreatic cell line AsPC-1. Among the compounds with farnesyl and dodecyl groups, the inhibitor with a farnesyl group was found to have stronger and more selective activity. PMID- 28666733 TI - Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents. AB - This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations. PMID- 28666735 TI - Influence of the cellular environment on ligand binding kinetics at membrane bound targets. AB - While historically 'in vitro' binding data were obtained by analyzing equilibrium experiments, kinetic data are increasingly appreciated to provide information on the time a particular compound remains bound to its target. This information is of biological importance to understand the molecular mechanism of a drug not only to evaluate the time a particular receptor/enzyme is blocked in the case of antagonists/inhibitors but also to investigate its contribution to the efficacy to mediate signaling in the case of agonists. There is accumulating evidence that many drugs binding to either membrane-bound receptors or enzymes are found to display long duration of action which can be ascribed to slow dissociation from their target proteins. In the present review three such examples are discussed which encompass ligands that bind to membrane-bound proteins and from which it appears that the tight binding kinetics is influenced by the cellular/membrane environment of the target protein. PMID- 28666737 TI - Design, synthesis, and biological evaluation of aryl N-methoxyamide derivatives as GPR119 agonists. AB - A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells. PMID- 28666736 TI - Synthesis and biological evaluation of novel steroidal 5alpha,8alpha epidioxyandrost-6-ene-3beta-ol-17-(O-phenylacetamide)oxime derivatives as potential anticancer agents. AB - Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel 5alpha,8alpha-epidioxyandrost-3beta-ol-17-(O-phenylacetamide)oxime derivatives (9a-o). The anti-proliferative activity of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, Sk-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compounds 9d, 9f, 9h, 9j and 9m displayed good anti-proliferative activity (most IC50<20MUM) in vitro. Furthermore, fluorescence imaging showed that the designed coumarin-9d conjugate (12) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure. PMID- 28666738 TI - Polydatin protects against carbon tetrachloride-induced liver fibrosis in mice. AB - Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Polydatin, a glucoside of resveratrol, has been shown to possess anti oxidative bioactivity. It has been demonstrated that resveratrol has many therapeutic effects on liver disorders including liver fibrosis. Recent study showed that polydatin prevented acute liver injury after carbon tetrachloride (CCl4) induction. However, the protective effects of polydatin on chronic liver injury and fibrosis has not been understood. Thus, we aimed to determine the roles of polydatin in chronic liver injury and fibrosis. Mice were induced by CCl4 for 6 weeks to develop chronic liver injury and fibrosis. Mice were treated with polydatin for 3 and 6 weeks, respectively. After 6 week injection of CCl4, the levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly increased. The hepatic expression of alpha-SMA, collagen deposition and macrophage filtration were also increased. Furthermore, hepatic 4 HNE production and NOX4 expression were also increased in CCl4-induced mice. In contrast, polydatin ameliorated impaired liver function and histology. Moreover, polydatin attenuated liver fibrosis and inflammation in mice induced by CCl4. Additionally, polydatin suppressed hepatic 4-HNE production and NOX4 expression. In conclusion, polydatin ameliorate chronic liver injury and fibrosis through inhibition of oxidative stress and inflammation. PMID- 28666739 TI - Spontaneous membrane insertion of a dengue virus NS2A peptide. AB - Non-structural NS2A protein of Dengue virus is essential for viral replication but poorly characterized because of its high hydrophobicity. We have previously shown experimentally that NS2A possess a segment, peptide dens25, known to insert into membranes and interact specifically with negatively-charged phospholipids. To characterize its membrane interaction we have used two types of molecular dynamics membrane model systems, a highly mobile membrane mimetic (HMMM) and an endoplasmic reticulum (ER) membrane-like model. Using the HMMM system, we have been able of demonstrating the spontaneous binding of dens25 to the negatively charged phospholipid 1,2-divaleryl-sn-glycero-3-phosphate containing membrane whereas no binding was observed for the membrane containing the zwitterionic one 1,2-divaleryl-sn-glycero-3-phosphocholine. Using the ER-like membrane model system, we demonstrate the spontaneous insertion of dens25 into the middle of the membrane, it maintained its three-dimensional structure and presented a nearly parallel orientation with respect to the membrane surface. Both charged and hydrophobic amino acids, presenting an interfacial/hydrophobic pattern characteristic of a membrane-proximal segment, are responsible for membrane binding and insertion. Dens25 might control protein/membrane interaction and be involved in membrane rearrangements critical for the viral cycle. These data should help us in the development of inhibitor molecules that target NS2A segments involved in membrane reorganisation. PMID- 28666741 TI - An introduction to the special issue on biomolecular NMR. PMID- 28666742 TI - [Functional evaluation of the elderly in primary care using the Short Physical Performance Battery]. PMID- 28666740 TI - The dihydroorotate dehydrogenases: Past and present. AB - The flavoenzyme dihydroorotate dehydrogenase catalyzes the stereoselective oxidation of (S)-dihydroorotate to orotate in the fourth of the six conserved enzymatic reactions involved in the de novo pyrimidine biosynthetic pathway. Inhibition of pyrimidine metabolism by selectively targeting DHODHs has been exploited in the development of new therapies against cancer, immunological disorders, bacterial and viral infections, and parasitic diseases. Through a chronological narrative, this review summarizes the efforts of the scientific community to achieve our current understanding of structural and biochemical properties of DHODHs. It also attempts to describe the latest advances in medicinal chemistry for therapeutic development based on the selective inhibition of DHODH, including an overview of the experimental techniques used for ligand screening during the process of drug discovery. PMID- 28666743 TI - [Prognostic factors of early 30-day mortality in elderly patients admitted to an emergency department]. AB - OBJECTIVE: The main aim of this study was to identify the variables related to early mortality in the elderly at the time of admission to the emergency department. METHODOLOGY: Using probability sampling, the study included patients 60 years old or older of both genders who were admitted for observation to the emergency department of the University Hospital of Narino, ?Colombia? in 2015. Using a questionnaire designed for this study, some multidimensional features that affect the health of the elderly were collected (demographic, clinical, psychological, functional, and social variables). The patients were then followed up for 30 days in order to determine the mortality rate during this time. Univariate and multivariate logistic regressions and survival analysis were performed. RESULTS: Data were collected from 246 patients, with a mean age of 75.27 years and the majority female. The 30-day mortality rate was 15%. The variables most associated with death were: being female, temperature problems, initial diagnosis of neoplasia, and unable to walk independently in the emergency department. CONCLUSION: It is possible to determine the multidimensional factors present in the older patient admitted to an emergency department that could affect their 30-day mortality prognosis. and which should be intervened. PMID- 28666744 TI - [Three years experience in the detection and follow-up of violence against the elderly in a tertiary hospital]. AB - OBJECTIVES: The Hospital Clinico San Carlos Committee against violence established a protocol in 2012 in order to detect and follow-up violence against elderly persons. This article presents the experience after 3years of its introduction, as well as an analysis comparing the differences between those younger and older than 65years of age. MATERIAL AND METHODS: All cases were collected during years 2013, 2014, and 2015, and were divided into two groups, A and B, according to age, younger or older than 65years. Parameters studied were: gender, place of detection (emergency department, during hospital admission, or outpatient clinics), type of professional worker who detected each case (social workers, nurses, or physicians), previous history of violence, type of aggression (physical, psychological, financial), institutional procedures once aggression was confirmed, and deaths after one year of follow-up. The SPPS v.18.0 package was used for the statistical analysis. RESULTS: A total of 172 cases were detected, of which 140 of them were included in groupA (<65years), and 32 in groupB (>65 years, 22.8%). Gender: GroupA: women: 93.5%. GroupB: women: 78.1% (P=.014). Registration site: GroupA: emergency department: 90.7%, hospital wards: 6.4%, outpatient wards: 3.0. GroupB: emergency department: 65.6%, hospital wards: 31.6%, outpatient wards: 2.8% (P=.001). Notification: GroupA: social worker: 25%, physician: 67.8%, nurse: 6.4%. GroupB: social worker: 65.2%, physician: 28.1%, nurse: 6.2% (P<.001). Previous violence history: GroupA: 62.1%. GroupB: 68.7%. Type of abuse: GroupA: physical: 56.4%, psychological: 2.8%, physical +psychological: 30.4%, physical +psychological +economic: 10.1%. GroupB: physical: 31.1%, psychological: 5.1%, neglect: 18.7%, physical +psychological: 10.1, physical +psychological +economic: 9.8, economic: 25.1 (P<.0001). Resources employed and follow-up: Injuries: Group A: 63.5%. Group B: 31.2% (P=.001). Judicial protection measures: GroupA: 12.8. GroupB: 15.6 (P=.773). Removal order: GroupA: 2.1. GroupB: 6.25 (P=.235). More than one-third of patients in groupB, and none of the patients in groupA, died in the year of follow-up. CONCLUSIONS: There are more problems detected in the Emergency Department. There is a history of previous violence in more than half of the cases in both age groups. The profile of the victim is an elderly woman with significant physical and cognitive impairment. Economic abuse and neglect are more frequent in the elderly population. In our series, more than one-third of elderly patients who are victims of ill-treatment die each year. The hospital registry is fundamental for the detection and follow-up of abuse in the elderly. PMID- 28666745 TI - The clinical spectrum of childhood narcolepsy. AB - Narcolepsy type 1 is a life-long, severe, multifaceted disease often arising in childhood or adolescence. Beyond the classical symptoms (excessive daytime sleepiness, cataplexy, hallucinations, sleep paralysis and nocturnal fragmented sleep), metabolic, endocrinological, psychiatric and psychosocial aspects must be considered. Despite the increased awareness after H1N1 pandemic influenza and vaccination, narcolepsy is still misdiagnosed and unrecognized. The peculiar presentation of symptoms in narcoleptic children could in part explain the misdiagnoses. Excessive daytime sleepiness presenting as chronic drowsiness or irritability could be stigmatized as laziness or misinterpreted as behavior or inattention disorder. The persistent hypotonia and the complex hyperkinetic movements that characterize cataplexy close to the onset, could be misdiagnosed as a movement disorder or as other neurologic conditions. The consequent therapeutic delay could turn into dramatic consequences. The narcolepsy onset, indeed, is associated with abrupt weight gain and sometimes with precocious puberty that require a prompt recognition and treatment to avoid auxological and metabolic complications. Moreover, narcoleptic children could have behavioral and psychiatric disorders ranging from mood to psychotic ones that need ad hoc management. Accordingly, spreading the awareness outside the sleep specialist community is necessary in order to reduce the diagnostic delay and to obtain prompt and multidisciplinary management. PMID- 28666746 TI - MicroRNAs as Important Regulators of Exercise Adaptation. AB - A significant body of evidence supports the protective role of exercise training (ET) in cardiovascular diseases, skeletal muscle dystrophies, several types of cancer, Alzheimer disease or even in the recovery of spinal cord injury. In spite of this, the molecular mechanisms underlying the beneficial effects of exercise training are not well understood and remain elusive. Several mechanisms have been proposed in the past, but more recently microRNAs (miRNAs), small non-coding RNA molecules involved in a variety of basic biological processes that negatively modulate gene expression, recognized as important regulatory molecules. In this review, we highlight recent advances on the miRNA involvement in the benefits of ET. Here, we assess the role of microRNAs expressed in the heart, in the skeletal muscle, detected in the circulation (serum and plasma), and in other conditions (e.g., spinal cord injury). Additionally, the long-term effects of diverse ET modalities (e.g., running, cycling, resistance training) in the cardiac miRNA profile are properly addressed. PMID- 28666747 TI - Combined immunotherapy: CTLA-4 blockade potentiates anti-tumor response induced by transcutaneous immunization. AB - BACKGROUND: The epidermal application of the Toll Like Receptor 7 agonist imiquimod and a T-cell peptide epitope (transcutaneous immunization, TCI) mediates systemic peptide-specific cytotoxic T-cell (CTL) responses and leads to tumor protection in a prophylactic tumor setting. However, it does not accomplish memory formation or permanent defiance of tumors in a therapeutic set-up. As a distinct immunologic approach, CTLA-4 blockade augments systemic immune responses and has shown long-lasting effects in preclinical experiments as well as in clinical trials. OBJECTIVE: The study investigates the vaccination capacity of TCI in combination with the checkpoint inhibitor CTLA-4 in matters of primary response, memory formation and tumor protection and characterizes the role of regulatory T cells (Tregs). METHODS: After performing TCI with IMI-Sol (containing 5% Imiquimod) and the model epitope SIINFEKL, 6-8 week old C57BL/6 mice received anti-CTLA-4 antibody either s.c or i.p. The CTL responses and frequency of peptide specific CD8+ T-cells were then evaluated on day 8. To determine anti-tumor effects, a therapeutic tumor challenge with B16 OVA melanoma was performed. RESULTS: The combination of s.c. anti-CTLA-4 antibody and TCI leads to an enhanced systemic cytotoxic response, to memory formation and allows significantly improved survival in a tumor setting with B16 OVA melanoma. Towards the mechanism, we show that in this vaccination protocol the CTLA-4 antibody acts mainly Treg-independent. CONCLUSION: We demonstrate that the combination of TCI with IMI-Sol and anti-CTLA-4 can confer potent immune responses and tumor protection. These results might contribute to the development of advanced vaccination approaches targeting tumors or persistent infectious diseases. PMID- 28666748 TI - Shewanella species as the origin of blaOXA-48 genes: insights into gene diversity, associated phenotypes and possible transfer mechanisms. AB - Chromosome-encoded beta-lactamases of Shewanella spp. have been indicated as probable progenitors of blaOXA-48-like genes. However, these have been detected in few Shewanella spp. and dissemination mechanisms are unclear. Thus, our main objective was to confirm the role of Shewanella species as progenitors of blaOXA 48-like genes. In silico analysis of Shewanella genomes was performed to detect blaOXA-48-like genes and context, and 43 environmental Shewanella spp. were characterised. Clonal relatedness was determined by BOX-PCR. Phylogenetic affiliation was assessed by 16S rDNA and gyrB sequencing. Antibiotic susceptibility phenotypes were determined. The blaOXA-48-like genes and genetic context were inspected by PCR, hybridisation and sequence analysis. Gene variants were cloned in Escherichia coli and MICs were determined. Shewanella isolates were screened for integrons, plasmids and insertion sequences. Analysis of Shewanella spp. genomes showed that putative blaOXA-48-like is present in the majority and in an identical context. Isolates presenting unique BOX profiles affiliated with 11 Shewanella spp. blaOXA-48-like genes were detected in 22 isolates from 6 species. Genes encoded enzymes identical to OXA-48, OXA-204, OXA 181, and 7 new variants differing from OXA-48 from 2 to 82 amino acids. IS1999 was detected in 24 isolates, although not in the vicinity of blaOXA-48 genes. Recombinant E. coli strains presented altered MICs. The presence/absence of blaOXA-48-like genes was species-related. Gene variants encoded enzymes with hydrolytic spectra similar to OXA-48-like from non-shewanellae. From the mobile elements previously described in association with blaOXA-48-like genes, only the IS1999 was found in Shewanella, which indicates its relevance in blaOXA-48-like genes transfer to other hosts. PMID- 28666749 TI - Prevalence of antimicrobial resistance and the cfiA resistance gene in Danish Bacteroides fragilis group isolates since 1973. AB - OBJECTIVES: The purpose of this study was to determine the prevalence of resistance and the cfiA carbapenemase-producing gene in historical Bacteroides fragilis group isolates. METHODS: Danish clinical B. fragilis group isolates (n = 444) from 1973 to 2015 were identified with Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF MS) on the Biotyper platform. Antimicrobial resistance was determined using a disk diffusion screening method and commercial antibiotic gradient strips. Division I (cfiA negative) and division II (cfiA-positive) B. fragilis strains were differentiated using MALDI-TOF MS and real-time polymerase chain reaction (PCR). RESULTS: From 1973-1980 to 2010-2015 the prevalence of antimicrobial resistance rose from 0% to 21.2%, 2.5%, and 1% for clindamycin, meropenem, and metronidazole, respectively. MALDI-TOF MS and real-time PCR identified 16 of 266 (6.0%) B. fragilis strains as division II, of which 4 strains, isolated between 2010 and 2015, were resistant to meropenem. CONCLUSIONS: Substantial increases in resistance were found throughout this study. This supports the general perception that antimicrobial resistance in the B. fragilis group has been established in the recent decades in Europe. Resistance to meropenem, facilitated by expression of the cfiA resistance gene, seems to be increasing; therefore, it is imperative to monitor the occurrence of this gene, e.g. using MALDI-TOF MS. PMID- 28666750 TI - New genetic environments of the macrolide-lincosamide-streptogramin resistance determinant erm(X) and their influence on potential horizontal transferability in bifidobacteria. AB - With the abuse of macrolide, lincosamide, and streptogramin (MLS), the traditionally safe bifidobacterial strains in the human intestine could serve as a reservoir of MLS resistance genes. In this study, the erm(X) gene was detected in 29 MLS-resistant strains and one MLS-susceptible strain among 92 bifidobacterial strains of human origin. This study is the first to report erm(X) mediated MLS resistance in Bifidobacterium pseudocatenulatum, Bifidobacterium breve and Bifidobacterium bifidum. The insertion sequences (ISs) flanking antibiotic resistance (AR) genes (i.e., the genetic environment of AR genes) could contribute to the horizontal spreading of AR. However, the potential transferability of erm(X) in bifidobacteria has not been previously verified. Here, we retrieved four genetic environments (I-IV) of erm(X) from 30 erm(X) positive bifidobacterial strains. This study is the first to identify the erm(X) gene in three new genetic environments (II, III and IV) in bifidobacteria. The erm(X) gene was individually flanked by IS1249 or IS3 in genetic environments I, II and IV and was simultaneously flanked by IS1249 and IS3 elements in genetic environment III. Only the transfer of erm(X) from genetic environment III simultaneously flanked by IS1249 and IS3 elements was successfully observed in filter mating experiments. These findings indicate a synergic effect of IS1249 and IS3 elements in the transfer of erm(X) in bifidobacteria, and further reveal that the various genetic environments of erm(X) result in significant differences in the transferability of erm(X) in bifidobacteria. PMID- 28666751 TI - Recently approved antibacterials for methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive pathogens: the shock of the new. AB - A number of novel antimicrobial drugs with activity against Gram-positive bacterial pathogens have been licensed in the past 4 years. These drugs have the potential to enrich the group of intravenous drugs already available that are in common use against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci and other antibiotic-resistant Gram-positive pathogens. The advantages and disadvantages of these drugs are not yet fully appreciated. Here we review the five most promising newly approved compounds, namely ceftaroline, ceftobiprole, oritavancin, dalbavancin and tedizolid. The advantages of their dosing regimens, mechanisms of action and adverse effect profiles as well as evidence for their clinical usefulness and the unique characteristics that distinguish them from one another and from older drugs are reviewed. PMID- 28666752 TI - Dosing of caspofungin based on a pharmacokinetic/pharmacodynamic index for the treatment of invasive fungal infections in critically ill patients on continuous venovenous haemodiafiltration. AB - INTRODUCTION: The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS: Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS: Concentration-time data were described by a two compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC<=0.06 mg/L) and aspergillosis (MEC<=0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC>=0.1 mg/L. CONCLUSION: The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection. PMID- 28666753 TI - First report of an Escherichia coli strain from swine carrying an OXA-181 carbapenemase and the colistin resistance determinant MCR-1. AB - Plasmid-mediated resistance to carbapenems and colistin in Enterobacteriaceae represents an emerging public health threat. Although animals have been identified as a relevant source of multidrug-resistant (MDR) bacteria, there are only a few reports on the presence of carbapenemases in animal isolates. In this study, 7850 faecal Escherichia coli isolates obtained from 2160 pigs were screened for carbapenem non-susceptibility using Mueller-Hinton agar supplemented with meropenem. Eleven isolates showed growth on meropenem-containing agar but only two proved positive by PCR for a carbapenemase gene, namely blaOXA-48-like. The two isolates were obtained from different pigs housed at the same farm in Italy and were not genetically related by multilocus sequence typing (MLST), comprising ST359 and ST641. Whole-genome sequencing revealed the presence of blaOXA-181 in both isolates; in addition, the colistin resistance gene mcr-1 and aminoglycoside resistance gene armA were found in one isolate. The blaOXA-181 resistance gene was located on a 51.5-kb non-conjugative plasmid of replicon type IncX3 and the mcr-1 gene on a 33.3-kb transferable IncX4 plasmid. The high nucleotide similarity (>99%) of plasmids pEcIHIT31346-OXA-181 and pEcIHIT31346 MCR-1 to published plasmids from various human and animal sources suggests that specific antibiotic resistance plasmids are circulating among E. coli strains worldwide and across vertebrate species barriers. Although carbapenems are not licensed for use in livestock and the overall prevalence of carbapenemases in porcine E. coli appears to be low, the current findings indicate that even pigs can host MDR strains with accumulated plasmid-mediated resistance against several last-line antibiotics. PMID- 28666754 TI - Antiparasitic activity of nerolidol in a mouse model of schistosomiasis. AB - Schistosomiasis is a major public health problem worldwide, especially in poor communities. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new antischistosomal drugs. Nerolidol is a sesquiterpene present as an essential oil in several plants that has been approved by the FDA. This study evaluated the in vivo antischistosomal activity of nerolidol in a mouse model of schistosomiasis infected with either adult or juvenile stages of Schistosoma mansoni. A single dose of nerolidol (100, 200 or 400 mg/kg) administered orally to mice infected with adult schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest nerolidol dose (400 mg/kg) caused significant reduction in a total worm burden of 70.06% (P < 0.001). Additionally, the technique of quantitative and qualitative oograms showed that a single 400 mg/kg nerolidol dose achieved an immature egg reduction of 84.6% (P < 0.001). In faecal samples, the Kato-Katz method also revealed a reduction of 75.2% in eggs/g at a dose of 400 mg/kg (P < 0.001). Furthermore, scanning electron microscopy revealed that nerolidol mediated worm killing was associated with tegumental damage. In contrast to activity against adult S. mansoni infection, oral treatment with nerolidol 400 mg/kg had low efficacy in mice harbouring juvenile schistosomes. Since nerolidol is already in use globally as a food additive and has a proven safety record, evaluation of this natural compound's potential for treatment of schistosomiasis could be entirely cost effective in the near future. PMID- 28666756 TI - Ampicillin for the treatment of complicated urinary tract infections caused by vancomycin-resistant Enterococcus spp (VRE): a single-center university hospital experience. AB - Vancomycin-resistant enterococci (VRE) are a common cause of urinary tract infections (UTIs) and are typically multidrug resistant, including ampicillin. This retrospective study evaluated outcomes of 84 adult patients hospitalized between January 2007 and December 2015 with ampicillin- and vancomycin-resistant enterococcus isolates causing UTI and treated with ampicillin. Treatment response was classified as clinical cure and microbiological eradication. Clinical cure was achieved in 88.1% (74/84) of patients. In patients with follow-up cultures, microbiological eradication was achieved in 86% (50/58) of patients. Cure rates were similar in patients with indwelling urinary catheters (n = 45) receiving catheter exchange/removal (90.47%; 19/21) versus catheter retention (87.5%; 21/24). Presence of co-morbidities, such as diabetes and chronic kidney disease, were not associated with increased risk of treatment failure. Immunocompromised patients achieved lower cure rates of 78.1% (25/32) compared with 94.2% (49/52) among those without immune impairment (P = 0.038). Presence of an underlying urinary tract abnormality was also associated with a lower cure rate of 71.4% (15/21) compared with 93.7% (59/63) in those without urinary tract abnormalities (P = 0.0135). Overall cure rates remained high in all groups providing good evidence to support ampicillin for the treatment of complicated UTI caused by ampicillin- and vancomycin-resistant enterococci. PMID- 28666755 TI - Activity of innate antimicrobial peptides and ivacaftor against clinical cystic fibrosis respiratory pathogens. AB - There is a clear need for new antimicrobials to improve current treatment of chronic lung infection in people with cystic fibrosis (CF). This study determined the activities of antimicrobial peptides (AMPs) and ivacaftor, a novel CF transmembrane conductance regulator potentiator, for CF treatment. Antimicrobial activities of AMPs [LL37, human beta-defensins (HbetaD) 1-4 and SLPI] and ivacaftor against clinical respiratory isolates (Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus spp., Achromobacter spp. and Stenotrophomonas maltophilia) were determined using radial diffusion and time kill assays, respectively. Synergy of LL37 and ivacaftor with tobramycin was determined by time-kill, with in vivo activity of ivacaftor and tobramycin compared using a murine infection model. LL37 and HbetaD3 were the most active AMPs tested, with MICs ranging from 3.2- >= 200 mg/L and 4.8- >= 200 mg/L, respectively, except for Achromobacter that was resistant. HbetaD1 and SLPI demonstrated no antimicrobial activity. LL37 demonstrated synergy with tobramycin against 4/5 S. aureus and 2/5 Streptococcus spp. isolates. Ivacaftor demonstrated bactericidal activity against Streptococcus spp. (mean log10 decrease 3.31 CFU/mL) and bacteriostatic activity against S. aureus (mean log10 change 0.13 CFU/mL), but no activity against other genera. Moreover, ivacaftor demonstrated synergy with tobramycin, with mean log10 decreases of 5.72 CFU/mL and 5.53 CFU/mL at 24 h for S. aureus and Streptococcus spp., respectively. Ivacaftor demonstrated immunomodulatory but no antimicrobial activity in a P. aeruginosa in vivo murine infection model. Following further modulation to enhance activity, AMPs and ivacaftor offer real potential as therapeutics to augment antibiotic therapy of respiratory infection in CF. PMID- 28666757 TI - A novel chimeric Hepatitis B virus S/preS1 antigen produced in mammalian and plant cells elicits stronger humoral and cellular immune response than the standard vaccine-constituent, S protein. AB - Chronic Hepatitis B Virus (HBV) infection leads to severe liver pathogenesis associated with significant morbidity and mortality. As no curable medication is yet available, vaccination remains the most cost-effective approach to limit HBV spreading and control the infection. Although safe and efficient, the standard vaccine based on production of the small (S) envelope protein in yeast fails to elicit an effective immune response in about 10% of vaccinated individuals, which are at risk of infection. One strategy to address this issue is the development of more immunogenic antigens. Here we describe a novel HBV antigen obtained by combining relevant immunogenic determinants of S and large (L) envelope proteins. Our approach was based on the insertion of residues 21-47 of the preS1 domain of the L protein (nomenclature according to genotype D), involved in virus attachment to hepatocytes, within the external antigenic loop of S. The resulting S/preS121-47 chimera was successfully produced in HEK293T and Nicotiana benthamiana plants, as a more economical recombinant protein production platform. Comparative biochemical, functional and electron microscopy analysis indicated assembly of the novel antigen into subviral particles in mammalian and plant cells. Importantly, these particles preserve both S- and preS1-specific epitopes and elicit significantly stronger humoral and cellular immune responses than the S protein, in both expression systems used. Our data promote this antigen as a promising vaccine candidate to overcome poor responsiveness to the conventional, S protein-based, HBV vaccine. PMID- 28666758 TI - The changing epidemiology of invasive Haemophilus influenzae disease: Emergence and global presence of serotype a strains that may require a new vaccine for control. AB - BACKGROUND: More than two decades after the implementation of the Hib conjugate vaccine in North America, Haemophilus influenzae serotype a (Hia) has emerged as a significant cause of invasive disease in Indigenous communities. However, little is known about the global presence of this pathogen. METHODS: We interrogated the H. influenzae Multi-Locus Sequence Typing (MLST) website (https://pubmlst.org/hinfluenzae/) by selecting for serotype a records. We also updated our previous literature review on this subject matter. RESULTS: Hia has been reported from at least 35 countries on six major continents. However, most Hia diseases were associated with Indigenous communities. Clonal analysis identified two clonal populations with one typified as ST-23 responsible for most invasive disease in North America and being the predominant clone described on the H. influenzae MLST website. Incidence of invasive Hia disease in Indigenous communities in North America are similar to the rates of Hib disease reported prior to the Hib conjugate vaccine era. Hia causes severe clinical diseases, such as meningitis, septicaemia, pneumonia, and septic arthritis with case-fatality rates between 5.6% and 33% depending on the age of the patient and the genetic makeup of the Hia strain. CONCLUSION: Although invasive Hia disease can be found globally, the current epidemiological data suggest that this infection predominantly affects Indigenous communities in North America. The clinical disease of Hia and the clonal nature of the bacteria resemble that of Hib. The high incidence of invasive Hia disease in Indigenous communities, along with potential fatality and severe sequelae causing long-term disability in survivors, may support the development of a new Hia conjugate vaccine for protection against this infection similar in design to the one introduced in the 1990s to control invasive Hib disease. PMID- 28666759 TI - A short hairpin RNA-based adjuvant targeting NF-kappaB repressor IkappaBalpha promotes migration of dermal dendritic cells to draining lymph nodes and antitumor CTL responses induced by DNA vaccination. AB - DNA vaccination is an attractive approach to elicit tumor-specific cytotoxic CD8+ T lymphocytes (CTL), which can mediate protective immunity against tumors. To initiate CTL responses, antigen-encoding plasmids employed for DNA vaccination need to activate dendritic cells (DC) through the stimulation of DNA-sensing innate immune receptors that converge in the activation of the master transcription factor NF-kappaB. To this end, NF-kappaB repressor IkappaBalpha needs to be degraded, allowing NF-kappaB to translocate to the nucleus and transcribe proinflammatory target genes, as well as its repressor IkappaBalpha. Therefore, NF-kappaB activation is self-limited by de novo synthesis of IkappaBa, which sequesters NF-kappaB in the cytosol. Hence, we tested whether co-delivering a shRNA-based adjuvant able to silence IkappaBalpha expression would further promote DNA-induced NFkappaB activation, DC activation and tumor-protective CTL responses induced by DNA vaccination in a preclinical model. First, an IkappaBalpha-targeting shRNA plasmid (shIkappaBalpha) was shown to reduce IkappaBalpha expression and promote NFkappaB-driven transcription in vitro, as well as up-regulate inflammatory target genes in vivo. Then, we showed that intradermal DNA electroporation induced the migration of skin migratory dendritic cells to draining lymph nodes and maturation of dermal dendritic cells (dDC). Interestingly, shIkappaBalpha further promoted the migration of mature skin migratory dendritic cells, in particular dDC, which are specialized in antigen cross-presentation and activation of CD8+ T cells. Consistently, mice vaccinated with a plasmid encoding the melanoma-associated antigen tyrosinase-related protein 2 (TRP2) in combination with shIkappaBalpha enhanced TRP2-specific CTL responses and reduced the number of lung melanoma foci in mice challenged with intravenous injection of B16F10 cells. Moreover, therapeutic vaccination with pTRP2 and shIkappaBalpha delayed the growth of B16F10 melanoma subcutaneous tumors. Our data suggest that adjuvants promoting NF-kappaB activation represent an attractive strategy to boost DC activation and promote the generation of tumor protective CTL responses elicited by DNA vaccines. PMID- 28666760 TI - Vaccination coverage among social and healthcare workers in ten countries of Samu social international sites. AB - BACKGROUND: We aim to determine the vaccination coverage of social and healthcare workers in International sites of Samusocial, providing emergency care to homeless people, and to assess factors associated with having received necessary doses at adulthood. METHODS: Data on immunization coverage of social and healthcare workers were provided by a cross-sectional survey, conducted from February to April 2015 among 252 Samusocial workers in 10 countries. Vaccination status and characteristics of participants were collected through a self administered questionnaire. Prevalence rate ratio (PRR) of vaccination status was calculated using Poisson regression models. RESULTS: Among 252 Samusocial social and health workers who felt a questionnaire, median age was 39years, 42.1% were female, 88.9% were in contact with homeless beneficiaries (19.1% health workers). Overall, 90.1% of Samusocial staff felt adult vaccinations was useful and 70.2% wished to receive booster doses in future. Vaccination coverage at adulthood was satisfactory for diphtheria and poliomyelitis (96%), but low for influenza (20.8%), meningococcus (50.5%), hepatitis B (56.3%), yellow fever (58.1%), measles (81.3%) and pertussis (90.7%). The main reasons for not having received vaccination booster doses were forgetting the dates of booster doses (38.4%) and not having received the information (13.5%). In adjusted analysis, prevalence of up-to-date for vaccination schedule was 35% higher among health workers than among social workers (aPRR=1.35, 95%CI: 1.01-1.82, P=0.05) and was 56% higher among workers who had a documentary evidence of vaccination than in those who did not (aPRR=1.56, 95%CI: 1.19-2.02, P=0.001). CONCLUSIONS: The Samusocial International workers vaccine coverage at adulthood was insufficient and disparate by region. It is necessary to strengthen the outreach of this staff and increase immunization policy for hepatitis B, diphtheria, tetanus, and measles, as well as for yellow fever, rabies and meningococcal ACYW135 vaccines in at risk regions. PMID- 28666761 TI - FDG PET/CT Overcomes Discordance Between Clinical and Pathologic TNM Classification of Small-size Primary Lung Cancer: Influence on Postoperative Prognosis. AB - INTRODUCTION: We aimed to determine the concordance between the clinical stage (c stage) and pathologic stage (p-stage) for patients with small-size lung cancer. Additionally we searched for prognostic factors other than the TNM stage. PATIENTS AND METHODS: We retrospectively reviewed the preoperative multidetector computed tomography (CT) and positron emission tomography/CT reports, surgical records, and pathologic reports of patients with primary lung cancer <= 3 cm. The Union for International Cancer Control TNM seventh edition classification of c stage and p-stage were compared. The tumors were classified into multiple subgroups by concordance or discordance between the c-stage and p-stage. Disease free survival (DFS) was assessed using survival analysis to assess the tumor characteristics that were predictive of prognosis. RESULTS: A total of 289 surgically resected primary lung cancers were evaluated. The concordance between c-stage and p-stage was 65.4%, with moderate reproducibility (kappa coefficient, 0.467). The upstaging rate from c-stage I to p-stage II-IV was 9.4%, and these patients had significantly worse DFS than those with a concordant stage I classification (P < .001). The main reason for upstaging was an underestimation of metastases to the hilar lymph nodes (n = 7) or mediastinal lymph nodes (n = 11). A multivariate Cox proportional hazards model showed that the significant predictive factors for DFS were p-stage (hazard ratio, 1.342; P = .003) and maximum standardized uptake value on positron emission tomography/CT (hazard ratio, 12.162; P = .001). CONCLUSION: The concordance rate between c-stage and p stage for small primary lung cancers had moderate reproducibility. Discordance between c-stage I and p-stage II-IV significantly affected DFS. The maximum standardized uptake value of the primary lesion was an independent prognostic factor, and combining it with c-stage might improve the prediction of therapeutic outcomes. PMID- 28666762 TI - The Impact of Baseline Edmonton Symptom Assessment Scale Scores on Treatment and Survival in Patients With Advanced Non-small-cell Lung Cancer. AB - BACKGROUND: Palliative systemic therapy is frequently underutilized in patients with advanced non-small-cell lung cancer (NSCLC), for many reasons. The aim of this study was to identify patient-reported factors that may predict for treatment decisions and survival in advanced NSCLC, using the Edmonton Symptom Assessment Scale (ESAS), which is a self-reported questionnaire that quantifies symptom burden by asking patients to rate the severity of 9 common symptoms. PATIENTS AND METHODS: With ethics approval, we analyzed ESAS scores at initial oncology consultation for 461 patients with advanced NSCLC seen at The Ottawa Hospital Cancer Centre from 2009 to 2012. Subgroup analysis was performed to determine if treatment strategies or overall survival (OS) were related to the total symptom burden, as defined by the sum of the individual ESAS symptom scores. RESULTS: The severity of the ESAS total symptom burden score was positively correlated with Eastern Cooperative Oncology Group performance status (R = 0.48; P < .0001). Furthermore, patients with a higher symptom burden were less likely to receive systemic chemotherapy than those with fewer symptoms (43% vs. 66%; P < .0001), and had a significantly reduced OS (5.5 vs. 9.9 months; P < .0001). A higher ESAS symptom burden score was also associated with reduced OS by univariate analysis (hazard ratio, 1.78; 95% confidence interval, 1.45-2.18; P < .0001), although multivariate analysis showed only a trend towards significance (hazard ratio, 1.27; 95% confidence interval, 0.99-1.62; P = .06). CONCLUSIONS: Overall, this demonstrates a novel role for the ESAS as a prognostic tool that could complement existing patient assessment models, such as Eastern Cooperative Oncology Group performance status, in the development of optimal treatment plans and estimation of survival, in patients with advanced lung cancer. PMID- 28666763 TI - Is the Current American Society of Clinical Oncology Guidance on Axillary Management Generalisable for Symptomatic or Unscreened Breast Cancers? PMID- 28666764 TI - Evolutionary dynamics and the evolution of multiplayer cooperation in a subdivided population. AB - The classical models of evolution have been developed to incorporate structured populations using evolutionary graph theory and, more recently, a new framework has been developed to allow for more flexible population structures which potentially change through time and can accommodate multiplayer games with variable group sizes. In this paper we extend this work in three key ways. Firstly by developing a complete set of evolutionary dynamics so that the range of dynamic processes used in classical evolutionary graph theory can be applied. Secondly, by building upon previous models to allow for a general subpopulation structure, where all subpopulation members have a common movement distribution. Subpopulations can have varying levels of stability, represented by the proportion of interactions occurring between subpopulation members; in our representation of the population all subpopulation members are represented by a single vertex. In conjunction with this we extend the important concept of temperature (the temperature of a vertex is the sum of all the weights coming into that vertex; generally, the higher the temperature, the higher the rate of turnover of individuals at a vertex). Finally, we have used these new developments to consider the evolution of cooperation in a class of populations which possess this subpopulation structure using a multiplayer public goods game. We show that cooperation can evolve providing that subpopulations are sufficiently stable, with the smaller the subpopulations the easier it is for cooperation to evolve. We introduce a new concept of temperature, namely "subgroup temperature", which can be used to explain our results. PMID- 28666765 TI - Cardioprotective effects of combined therapy with diltiazem and superoxide dismutase on myocardial ischemia-reperfusion injury in rats. AB - AIMS: Our experiments were designed to study the effect of diltiazem (DIL) combined with superoxide dismutase (SOD) on myocardial ischemia-reperfusion (MIRI) injury in a rat model. MAIN METHODS: Fifty rats were randomly separated into sham, ischemia-reperfusion (IR), DIL (5mg/kg), SOD (10,000U/kg) and combinatorial therapy (DIL plus SOD) groups. MIRI was induced by ligating the left anterior descending coronary artery for 30min and then reperfusing for 60min. The cardioprotective effects of combinatorial therapy were evaluated using hemodynamics, biochemical indices, histopathology and apoptotic-related proteins and gene expression. KEY FINDINGS: Compared with the IR group, combinatorial therapy significantly improved cardiac function and decreased arrhythmia, myocardial infarction area and release of myocardial enzyme. In addition, combinatorial therapy protected the myocardial cell structure as well as markedly alleviated oxidative stress, resulting in upregulation of Bcl-2 and adenine nucleotide transporter-1 expression as well as downregulation of Bax, caspase-3 and cleaved caspase-3 expression. SIGNIFICANCE: Our results indicated that DIL combined with SOD can provide protection against MIRI in rats, and these effects may be attributed to a reduction in oxygen stress damage, attenuation of calcium overload, and inhibition of cell apoptosis. PMID- 28666766 TI - Toxicogenomic responses of human alveolar epithelial cells to tungsten boride nanoparticles. AB - During the recent years, microarray analysis of gene expression has become an inevitable tool for exploring toxicity of drugs and other chemicals on biological systems. Therefore, toxicogenomics is considered as a fruitful area for searching cellular pathways and mechanisms including cancer, immunological diseases, environmental responses, gene-gene interactions and chemical toxicity. In this work, we examined toxic effects of Tungsten Borides NPs on gene expression profiling of the human lung alveolar epithelial cells (HPAEpiC). In line with this purpose, a single crystal of tungsten boride (mixture of WB and W2B) nanoparticles was synthesized by means of zone melting method, and characterized via using X-ray crystallography (XRD), transmission electron microscope (TEM), scanning electron microscope (SEM) and energy-dispersive X-ray spectroscopy (EDX) techniques. Cell viability and cytotoxicity were determined by 3-(4,5-dimethyl thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) release tests. The whole genome microarray expression analysis was performed to find out the effects of WB and W2B NPs mixture on gene expression of the HPAEpiC cell culture. 123 of 40,000 gene probes were assigned to characterize expression profile for WB/W2B NPs exposure. According to results; 70 genes were up-regulated and 53 genes were down-regulated (>=2 fold change). For further investigations, these genes were functionally classified by using DAVID (The Database for Annotation, Visualization and Integrated Discovery) with gene ontology (GO) analysis. In the light of the data gained from this study, it could be concluded that the mixture of WB/W2B NPs can affect cytokine/chemokine metabolism, angiogenesis and prevent migration/invasion by activating various genes. PMID- 28666767 TI - Towards breast cancer rotational radiotherapy with synchrotron radiation. AB - PURPOSE: We performed the first investigations, via measurements and Monte Carlo simulations on phantoms, of the feasibility of a new technique for synchrotron radiation rotational radiotherapy for breast cancer (SR3T). METHODS: A Monte Carlo (MC) code based on Geant4 toolkit was developed in order to simulate the irradiation with the SR3T technique and to evaluate the skin sparing effect in terms of centre-to-periphery dose ratio at different energies in the range 60 175keV. Preliminary measurements were performed at the Australian Synchrotron facility. Radial dose profiles in a 14-cm diameter polyethylene phantom were measured with a 100-mm pencil ionization chamber for different beam sizes and compared with the results of MC simulations. Finally, the dose painting feasibility was demonstrated with measurements with EBT3 radiochromic films in a phantom and collimating the SR beam at 1.5cm in the horizontal direction. RESULTS: MC simulations showed that the SR3T technique assures a tumour-to-skin absorbed dose ratio from about 7:1 (at 60keV photon energy) to about 10:1 (at 175keV), sufficient for skin sparing during radiotherapy. The comparison between the results of MC simulations and measurements showed an agreement within 5%. Two off-centre foci were irradiated shifting the rotation centre in the horizontal direction. CONCLUSIONS: The SR3T technique permits to obtain different dose distributions in the target with multiple rotations and can be guided via synchrotron radiation breast computed tomography imaging, in propagation based phase-contrast conditions. Use of contrast agents like iodinated solutions or gold nanoparticles for dose enhancement (DE-SR3T) is foreseen and will be investigated in future work. PMID- 28666768 TI - Strategies for improving early nutritional outcomes in children with oesophageal atresia and congenital diaphragmatic hernia. AB - Post-natal growth in surgical lung conditions, such as congenital diaphragmatic hernia and oesophageal atresia with tracheo-oesophageal fistula, is often sub optimal in the early years of life when lung growth is occurring. Whilst constitutional, behavioural and mechanical factors may contribute to poor feeding and weight gain, there is a common path of management with greater caloric supplementation that may change growth trajectories and potentially lead to better respiratory, anthropometric and cognitive outcomes. We provide simple, single page, feeding supplementation sheets in three age groups: 0-6months, 6 12months and 12-24months that have proven useful for enhancing weight gain in our patients. PMID- 28666770 TI - Marfan Syndrome (MFS): Visual Diagnosis and Early Identification. PMID- 28666769 TI - Nine genetic polymorphisms associated with power athlete status - A Meta Analysis. AB - OBJECTIVES: In this study the association between genetic polymorphisms and power athlete status with possible interference by race and sex was investigated to identify genetic variants favourable for becoming a power athlete. DESIGN: This meta-analysis included both, case-control and Cohort studies. METHODS: Databases of PubMed and Web of Science were searched for studies reporting on genetic polymorphisms associated with the status of being a power athlete. Thirty-five articles published between 2008 and 2016 were identified as eligible including a total number of 5834 power athletes and 14,018 controls. A series of meta analyses were conducted for each of the identified genetic polymorphisms associated with power athlete status. Odds ratios (ORs) based on the allele and genotype frequency with corresponding 95% confidence intervals (95%CI) were calculated per genetic variant. Heterogeneity of the studies was addressed by Chi square based Q-statistics at 5% significance level and a fixed or random effects model was used in absence or presence of heterogeneity respectively. Stratified analyses were conducted by race and sex to explore potential sources of heterogeneity. RESULTS: Significant associations were found for the genetic polymorphisms in the ACE (rs4363, rs1799752), ACTN3 (rs1815739), AGT (rs699), IL6 174 (rs1800795), MnSOD (rs1799725), NOS3 (rs1799983, rs2070744) and SOD2 (rs4880) genes. CONCLUSIONS: Nine genetic polymorphisms have been identified in the meta analyses to have a significant association with the status of being a power athlete. Nevertheless, more research on the investigated genes needs to be done to draw comprehensive conclusions. PMID- 28666771 TI - Physicians' psychophysiological stress reaction in medical communication of bad news: A critical literature review. AB - INTRODUCTION: Stress is a common phenomenon in medical professions. Breaking bad news (BBN) is reported to be a particularly distressing activity for physicians. Traditionally, the stress experienced by physicians when BBN was assessed exclusively using self-reporting. Only recently, the field of difficult physician patient communication has used physiological assessments to better understand physicians' stress reactions. METHOD: This paper's goals are to (a) review current knowledge about the physicians' psychophysiological stress reactions in BBN situations, (b) discuss methodological aspects of these studies and (c) suggest directions for future research. RESULTS: The seven studies identified all used scenarios with simulated patients but were heterogeneous with regard to other methodological aspects, such as the psychophysiological parameters, time points and durations assessed, comparative settings, and operationalisation of the communication scenarios. Despite this heterogeneity, all the papers reported increases in psychological and/or physiological activation when breaking bad news in comparison to control conditions, such as history taking or breaking good news. CONCLUSION: Taken together, the studies reviewed support the hypothesis that BBN is a psychophysiologically arousing and stressful task for medical professionals. However, much remains to be done. We suggest several future directions to advance the field. These include (a) expanding and refining the conceptual framework, (b) extending assessments to include more diverse physiological parameters, (c) exploring the modulatory effects of physicians' personal characteristics (e.g. level of experience), (d) comparing simulated and real-life physician-patient encounters and (e) combining physiological assessment with a discourse analysis of physician-patient communication. PMID- 28666772 TI - Relationship among clinical factors in childhood intermittent exotropia. AB - PURPOSE: To determine the relationships between stereoacuity, control of exotropia, and angle of deviation in children with intermittent exotropia (IXT). METHODS: Data collected for 652 participants 3 to <11 years of age with IXT meeting eligibility criteria for enrollment into one of two multicenter, randomized clinical trials were used to evaluate relationships between stereoacuity, control, and angle of deviation at enrollment. RESULTS: Any level of stereoacuity and angle of deviation could be accompanied by any level of control. Worse distance exotropia control was weakly associated with poorer distance stereoacuity (R = 0.26; 99% CI, 0.17-0.36) and larger angles of deviation at distance (R = 0.27; 99% CI, 0.17-0.36). Worse near exotropia control was weakly associated with poorer near stereoacuity (R = 0.17; 99% CI, 0.07-0.27) and moderately associated with larger angles of deviation at near (R = 0.37; 99% CI, 0.28-0.45). There was no association between stereoacuity and angle of deviation at distance (R = 0.07; 99% CI, -0.03 to 0.17) or at near (R = 0.02; 99% CI, -0.08 to 0.12). CONCLUSIONS: Although weak and moderate associations were found between stereoacuity, control, and angle of deviation, a child may exhibit any combination of stereoacuity, control, and angle of deviation. The specific roles of control, stereoacuity, and angle of deviation in the diagnosis, management, and pathogenesis of IXT are unclear, and each appears to yield somewhat independent information. PMID- 28666773 TI - Cyclocheck: a new web-based software for the assessment of objective cyclodeviation. AB - PURPOSE: To present a novel, free, web-based software tool (www.cyclocheck.com) for the assessment of objective cyclodeviation, based on measuring the disk foveal angle (DFA) and to evaluate reproducibility of the results. METHODS: Digital fundus photographs of both eyes of all study subjects were obtained using DRS CenterVue nonmydriatic fundus camera. Four separate measurements were made for each eye, and the DFA was calculated using Cyclocheck software independently by two observers to determine reproducibility and repeatability of the technique. The results were statistically analyzed using the interclass correlation coefficient (ICC) and the Bland-Altman method. RESULTS: A total of 32 subjects (mean age, 34.4; range, 12-83) were enrolled: 18 were orthophoric; 14, strabismic. The ICC for the intraobserver repeatability for one observer was 0.979 (95% CI, 0.970-0.985; P < 0.0005) and for the other was 0.988 (95% CI, 0.983-0.991; P < 0.0005). The ICC for the interobserver agreement was 0.994 (95% CI, 0.992-0.996; P < 0.0005), indicating high reproducibility of the measurements. CONCLUSIONS: Cyclocheck can assess ocular torsion quickly and easily. It provides reliable and reproducible measurements of the DFA and thus objective cyclodeviation in both orthophoric and strabismic subjects. PMID- 28666774 TI - Birth Order and Injury-Related Infant Mortality in the U.S. AB - INTRODUCTION: The purpose of this study was to evaluate the risk of death during the first year of life due to injury, such as unintentional injury and homicide, by birth order in the U.S. METHODS: Using national birth cohort-linked birth infant death data (births, 2000-2010; deaths, 2000-2011), risks of infant mortality due to injury in second-, third-, fourth-, and fifth or later-born singleton infants were compared with first-born singleton infants. Risk ratios were estimated using log-binomial models adjusted for maternal age, marital status, race/ethnicity, and education. The statistical analyses were conducted in 2016. RESULTS: Approximately 40%, 32%, 16%, 7%, and 4% of singleton live births were first, second, third, fourth, and fifth or later born, respectively. From 2000 to 2011, a total of 15,866 infants died as a result of injury (approximately 1,442 deaths per year). Compared with first-born infants (2.9 deaths per 10,000 live births), second or later-born infants were at increased risk of infant mortality due to injury (second, 3.6 deaths; third, 4.2 deaths; fourth, 4.8 deaths; fifth or later, 6.4 deaths). The corresponding adjusted risk ratios were as follows: second, 1.84 (95% CI=1.76, 1.91); third, 2.42 (95% CI=2.30, 2.54); fourth, 2.96 (95% CI=2.77, 3.16); and fifth or later, 4.26 (95% CI=3.96, 4.57). CONCLUSIONS: Singleton infants born second or later were at increased risk of mortality due to injury during their first year of life in the U.S. This study's findings highlight the importance of investigating underlying mechanisms behind this increased risk. PMID- 28666775 TI - Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. AB - BACKGROUND: In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status. METHODS: In this randomised, double-blind, placebo-controlled trial at 590 sites in 42 countries, we randomly assigned patients aged 18 years and older with type 2 diabetes and established cardiovascular disease (1:1:1) to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care until at least 691 patients experienced an adjudicated event included in the primary outcome. We did the randomisation with a computer-generated random sequence and interactive voice-response and web-response system, stratified by HbA1c, BMI, region, and estimated glomerular filtration rate. Patients, investigators, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary efficacy and safety endpoints of this trial have been reported previously. Here, we report urinary albumin-to creatinine ratio (UACR) data for the pooled empagliflozin group versus placebo according to albuminuria status at baseline (normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR >=30 to <=300 mg/g; and macroalbuminuria: UACR >300 mg/g). We did the analysis with mixed-model repeated measures including prespecified and post-hoc tests. This study is completed and registered with ClinicalTrials.gov, number NCT01131676. FINDINGS: Between Sept 1, 2010, and April 22, 2013, we randomly assigned 7028 patients to treatment groups and 7020 patients received treatment. At baseline, we had UACR data for 6953 patients: 4171 (59% of treated patients; 1382 assigned to placebo and 2789 assigned to empagliflozin) had normoalbuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had microalbuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macroalbuminuria. Median treatment duration was 2.6 years (IQR 2.0-3.4; 136 weeks) and median observation time was 3.1 years (2.2-3.6; 164 weeks). After short-term treatment at week 12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was -7% (95% CI -12 to -2; p=0.013) in patients with normoalbuminuria, -25% (-31 to -19; p<0.0001) in patients with microalbuminuria, and -32% (-41 to -23; p<0.0001) in patients with macroalbuminuria. The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks. At follow-up, after cessation of treatment for a median of 34 or 35 days, UACR was lower in the empagliflozin versus placebo group in those with baseline microalbuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: -22%, 95% CI -32 to -11; p=0.0003) or macroalbuminuria (-29%, -44 to -10; p=0.0048), but not for patients with baseline normoalbuminuria (1%, -8 to 10; p=0.8911). Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1.43, 95% CI 1.22 to 1.67; p<0.0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1.82, 1.40 to 2.37; p<0.0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0.84, 0.74 to 0.95; p=0.0077). The proportions of patients with any adverse events, serious adverse events, and adverse events leading to discontinuation increased with worsening UACR status at baseline, but were similar between treatment groups. The proportion of patients with genital infections was greater with empagliflozin than placebo in all subgroups by UACR status. INTERPRETATION: These results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients' albuminuria status at baseline. FUNDING: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. PMID- 28666776 TI - SGLT2 inhibition: a new era in renoprotective medicine? PMID- 28666777 TI - Quantitation of CRM197 using imaged capillary isoelectric focusing with fluorescence detection and capillary Western. AB - Maurice is a new instrument that can perform imaged capillary isoelectric focusing (icIEF). The standard detection for icIEF is UV absorbance at 280 nm, which limits its application to high protein concentration samples and non complex samples. Here we describe an icIEF instrument with fluorescence detection. We demonstrate the advantage of using either icIEF with fluorescence detection or quantitative Western Blot to measure diphtheria toxin mutant CRM197 protein titer in crude cell lysates and purified samples. These two techniques have great potentials to become standard methods to analyze protein titers in crude cell lysate or other complex samples types. PMID- 28666778 TI - PSMA ligands in prostate cancer - Probe optimization and theranostic applications. AB - Due to its selective overexpression in prostate cancer (PCa), the prostate specific membrane antigen (PSMA) has been recognized as a highly promising target for diagnostic and therapeutic applications. So far, various PSMA ligands have been developed for radiolabeling with radioisotopes such as 68Ga or 18F which can be used for specific visualization and diagnosis of PSMA-expressing PCa. In addition, PSMA ligands suitable for radiolabeling with 131I or 177Lu have become available to the clinics, allowing PSMA-based radioligand therapies. Here, we provide a comprehensive review of the most frequently used PSMA ligands, their structural modifications, and the impact of those on clinical applications. PMID- 28666779 TI - Ectopic expression of FGF5s induces wool growth in Chinese merino sheep. AB - Fibroblast growth factor 5 (FGF5) has been recognized as an inhibitor to cease animal hair growth, while in contrary, FGF5 short alternative transcript (FGF5s) can induce hair growth by antagonizing FGF5 function. To investigate the role of FGF5s in wool growth in Chinese Merino sheep, we generated transgenic sheep of ectopic expression of FGF5s by injection of recombinant lentivirus into zygote. Totally 20 transgenic sheep were obtained and 12 were alive after birth. Characterization of the transgene revealed that the transgenic sheep showed variety of integrant, ranged from 2 to 11 copies of transgene. The ectopic expression of FGF5s was observed in all transgenic sheep. Further study on the effect of ectopic expression of FGF5s revealed that the wool length of transgenic sheep were significantly longer than that of non-transgenic control, with 9.17cm of transgenic lambs versus 7.58cm of control animals. Notably, besides the increase of wool length, the yearling greasy fleece weight was also concordantly greater than that of wild-type (p<0.01), with 3.22kg of transgenic sheep versus 2.17kg of control lambs (p<0.01) in average. Our results suggested that overexpression of FGF5s could stimulate wool growth and resulted in increase of wool length and greasy wool weight. PMID- 28666780 TI - Impact of moving to a new hospital build, with a high proportion of single rooms, on healthcare-associated infections and outbreaks. AB - Clostridium difficile infection, meticillin-sensitive Staphylococcus aureus (MSSA) and Escherichia coli bacteraemia rates, and bed-days lost during norovirus outbreaks at North Bristol NHS Trust were analysed over a five-year period to determine whether moving to a new-build hospital with 75% single rooms reduced healthcare-associated infection rates. C. difficile, MSSA bacteraemia and E. coli bacteraemia showed no change in the rate of decline after the move. Bed-days lost due to norovirus were significantly lower after the move. Increased availability of single rooms had an impact on the transmission of highly contagious norovirus infection, dispersed via the airborne route, in contrast to bacterial infections, which may originate from patient's own colonizing flora and are not widely dispersed through airborne spread. PMID- 28666781 TI - Evaluation of sedation-related medication errors in patients on contact isolation in the intensive care unit. AB - BACKGROUND: Patients in intensive care units (ICUs) may be placed on contact isolation for meticillin-resistant Staphylococcus aureus (MRSA) colonization to prevent transmission. Prior studies suggest that isolated patients may receive substandard care compared with non-isolated patients. An optimal level of sedation is required to facilitate mechanical ventilation (MV) and to minimize adverse outcomes. AIM: To determine if patients on MV and isolated for MRSA colonization are at increased risk of oversedation compared with non-isolated patients. METHODS: Retrospective chart review of adult patients on MV who received an MRSA nasal polymerase chain reaction assay and sedation within 24 and 48 h of ICU admission, respectively. Endpoints included rate of inappropriate sedation, length of ICU stay, length of time on MV, and incidence of ventilator associated complications. FINDINGS: In total, 226 patients were included (114 MRSA positive, 112 MRSA negative). Baseline demographics were similar between the groups, with the exception of ICU admission diagnosis. Fifty-six (55%) isolated patients experienced inappropriate sedation compared with 49 (50%) non-isolated patients (P=0.482). Isolated patients spent longer in the ICU (10.4 vs 6.8 days, P=0.0006), longer on MV (8.98 vs 4.81 days, P<0.001), and required tracheostomies more frequently [37 (32%) vs 14 (13%), P=0.0003] than non-isolated patients. CONCLUSIONS: Isolated patients were not at increased risk of oversedation compared with non-isolated patients. There was an association between the use of contact isolation for MRSA nares colonization and prolonged ICU stay and prolonged MV. PMID- 28666782 TI - How bonobo communities deal with tannin rich fruits: Re-ingestion and other feeding processes. AB - This report describes bonobo (Pan paniscus, Hominidae) behavioral flexibility and inter-community differences with high tannin level fruit processing. In fruiting plants, tannin should discourage certain seed dispersers (direct deterrence hypothesis) such as primates. Based on data deriving from five study sites; LuiKotale, Lomako, Wamba, Malebo and Manzano, we compare consumption and dispersal of fruit species rich in tannins: Parinari and Musanga pulp was chewed across all communities probably for saliva tannin neutralisation. However, consumption of the fruits of Canarium schweinfurthii was observed in few communities only with differences in the food process: While bonobos of Wamba, Lomako and Manzano crunched and swallowed the pulp, bonobos of LuiKotale ingested entire fruits, extracted intact fruits from feces, and re-ingested their pulp, spitting the seed after a retention time of 24h in the digestive tract (i.e. endozoochory). We discuss potential functions of this peculiar feeding technique, likely to be a cultural behavior. PMID- 28666783 TI - Dependency distances in natural mixed languages: Comment on "Dependency distance: A new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28666785 TI - Systematic Review and Meta-Analysis of the Association Between C-Reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease. AB - BACKGROUND: Patients with peripheral artery disease (PAD) are at substantial risk of cardiovascular events. There is interest in using blood markers, such as C reactive protein (CRP), to monitor prognosis and treatment efficacy in PAD patients. The aim of this meta-analysis was to assess the association between CRP and major cardiovascular events in PAD patients. METHOD: Studies evaluating the association between CRP and major cardiovascular events (myocardial infarction, stroke, cardiac revascularisation and mortality) were identified using MEDLINE and the Cochrane library. Studies that did not include participants with PAD, measure CRP, or follow-up patients for cardiovascular events were excluded. Meta analyses of published adjusted hazard ratios (HR) were conducted using an inverse variance-weighted random effects model, and heterogeneity was assessed with the I2 index. RESULTS: A total of 16 studies involving 5041 participants met the inclusion criteria for the systematic review. Eight studies were included in the meta-analyses. Summary effect estimates were reported as HR comparing higher and lower quantiles, and HR per unit increase in logeCRP. PAD patients with higher CRP had a significantly greater risk of major cardiovascular events compared with those with lower CRP (HR 2.26, 95% CI 1.65-3.09, p < 0.001). The HR for major cardiovascular events was 1.38 (95% CI 1.16-1.63, p < 0.001) per unit increase in logeCRP. CONCLUSIONS: The present findings suggest that high circulating CRP is predictive of major cardiovascular events in PAD patients. PMID- 28666784 TI - Interpreting results of coronary computed tomography angiography-derived fractional flow reserve in clinical practice. AB - The application of computational fluid dynamics to coronary computed tomography angiography allows Fractional Flow Reserve (FFR) to be calculated non-invasively (FFRCT), enabling computation of FFR from coronary computed tomography angiography acquired at rest both for individual lesions as well as along the entire course of a coronary artery. FFRCT, validated in a number of accuracy studies and a large clinical utility trial, is beginning to penetrate clinical practice. Importantly, while accuracy trials compared FFRCT to invasively measured FFR at a single point in the coronary tree, clinical reports of FFRCT provide information regarding a patient's entire coronary vasculature. Specifically, in distal coronary segments, calculated FFRCT values may be low and below 0.80 even in the absence of localized stenoses within the course of the artery. As a result, the reporting physician needs to understand how to interpret the findings in a clinically useful and thoughtful fashion. This review provides a brief overview of the background of both invasively measured and computationally derived FFR, explains changes in FFR along the course of normal coronary arteries and those affected by coronary atherosclerosis, and outlines the relevance of measurement location when interpreting and reporting FFR and FFRCT results. PMID- 28666786 TI - Phylogenetic analysis of Placobdella (Hirudinea: Rhynchobdellida: Glossiphoniidae) with consideration of COI variation. AB - Placobdella is a genus of blood-feeding leeches in the family Glossiphoniidae. Historically, species of Placobdella have posed difficulty for systematists owing to a lack of informative morphological characters and the preponderance of inadequate or incomplete species descriptions. Here, we conduct a phylogenetic analysis of 55 individuals representing 20 of the 24 currently recognized nominal taxa using COI, ND1, 12S rDNA and ITS sequences under parsimony, maximum likelihood and Bayesian inference. We also examine the isolated COI phylogeny for the genus using an expanded dataset encompassing three additional species not included in the concatenated dataset. Finally, we assess genetic variation at the COI locus to validate initial specimen identifications and estimate how COI variation may reflect species boundaries. We conclude that Placobdella is a monophyletic group that places as the sister group to a clade formed by the genera Haementeria and Helobdella. We discuss the evolutionary implications of several internal relationships that are robustly resolved by all three optimality criteria, paying particular attention to the apparent fluidity of morphological characters exhibited by members of Placobdella. We also find preliminary evidence for the presence of cryptic and undescribed diversity within the genus. PMID- 28666787 TI - Author's reply: A systematic review of complications associated with direct implants vs. tissue expanders following Wise pattern skin-sparing mastectomy. PMID- 28666788 TI - Computer-generated three-dimensional modeling using passive stereophotogrammetry and structured light scanning for craniomaxillofacial imaging. PMID- 28666789 TI - WhatsApp: Improvement tool for surgical team communication. PMID- 28666790 TI - Surgical correction of cryptotia combined with an ultra-delicate split-thickness skin graft in continuity with a full-thickness skin rotation flap. AB - BACKGROUND: Cryptotia is a common congenital ear deformity in Asian populations. In cryptotia, a portion of the upper ear is hidden and fixed in a pocket of the skin of the mastoid. Here we describe our method for cryptotia correction by using an ultra-delicate split-thickness skin graft in continuity with a full thickness skin rotation flap. PATIENTS AND METHODS: We developed a new method for correcting cryptotia by using an ultra-delicate split-thickness skin graft in continuity with a full-thickness skin rotation flap. Following ear release, the full-thickness skin rotation flap is rotated into the defect, and the donor site is covered with an ultra-delicate split-thickness skin graft raised in continuity with the flap. RESULTS: All patients exhibited satisfactory release of cryptotia. No cases involved partial or total flap necrosis, and post-operative outcomes using this new technique for cryptotia correction have been more than satisfactory. CONCLUSIONS: Our method of using an ultra-delicate split-thickness skin graft in continuity with a full-thickness skin rotation flap to correct cryptotia is simple and reliable. PMID- 28666791 TI - Assessing the left main stem in the cardiac catheterization laboratory. What is "significant"? Function, imaging or both? AB - Revascularization of significant Left Main Stem (LMS) disease improves clinical outcomes. This can be achieved through either Coronary Artery Bypass Grafting or Percutaneous coronary intervention. Defining a significant stenosis of the LMS can be challenging and debatable, as most data have been derived using angiographic assessment alone, with a threshold of 50% luminal stenosis used as a marker of functional significance. The use of adjunctive technologies like Intravascular Ultrasound and Fractional Flow Reserve has improved our ability to accurately assess the anatomical severity and physiological significance of coronary artery stenoses, much more so, than can be achieved through conventional angiography alone. An improved assessment of LMS disease through these adjunctive techniques offers procedural and clinical benefits. Rather than focus on the preferred methods of revascularisation, this article aims to highlight the common pitfalls and misconceptions in the assessment of LMS stenoses. We also propose a simple algorithm for the assessment of LMS disease to help guide revascularisation decisions. PMID- 28666792 TI - Post-kidney Transplant Robot-assisted Laparoscopic Ureteral (Donor-receiver) Anastomosis for Kidney Graft Reflux or Stricture Disease. AB - OBJECTIVE: To report our experience with robot-assisted ureteral anastomosis for kidney graft. Kidney graft complex ureteral strictures or symptomatic vesicoureteral reflux may require complex reconstruction. This is classically done through an open surgical access, which adds to the morbidity of kidney transplantation. The da Vinci robot enables performance of complex laparoscopic procedures and may hence be used for such reconstructions. PATIENTS AND METHODS: We retrospectively reviewed all patients undergoing robotic surgical revision for stricture or reflux disease over a 3-year period. Contemporary patients who underwent open surgery were used as a control group. RESULTS: Ten patients underwent a robotic attempt, of whom 4 needed conversion to open surgery. Seven patients underwent an open surgery. Preoperative demographics were similar in both groups. The median operative time was 293 minutes, with a shorter operative time in the open group. The group of patients who could be completed robotically had a significantly lower postoperative length of stay (5 vs 9 days), quicker return to normal food intake (postoperative day 1 vs 3), and quicker control of pain without opiates (postoperative day 1 vs 4) than the converted or open group. Morbidity was comparable with 1 late Clavien IIIb complication in each subgroup (open, converted, and robotic group). After a median follow-up of 43 months, renal function was stable and there were no recurrent graft infections. CONCLUSION: Robotic ureteral reconstruction for kidney graft patients is feasible and efficient, and offers the classical advantages of minimally invasive surgery with outcomes comparable with open series. PMID- 28666793 TI - Gaze-based Technology as a Tool for Surgical Skills Assessment and Training in Urology. AB - OBJECTIVE: To assess the sensitivity of gaze-based metrics in detecting cognitive demands imposed by surgical procedures. We analyzed urologists' gaze entropy and velocity while performing 2 standardized high-fidelity simulated stone procedures with different levels of complexity. METHODS: Using a wearable eye tracker device (mounted onto an eyeglass frame), we measured gaze entropy and velocity in 15 urologists, members of the Andalusian health-care system, while they performed an extraction of a stone in the bladder (low complexity) and an extraction of a stone in the lumbar ureter (high complexity). We also collected performance and subjective data. RESULTS: Gaze entropy and velocity were significantly higher when surgeons performed the most complex surgical procedure: the visual exploration pattern became less stereotyped (ie, more random) and faster. Surgeons' performance and perceived task complexity differed accordingly, confirming the gaze-based results. CONCLUSION: Gaze-based metrics might have great potential as objective and nonintrusive indices to assess surgeons' cognitive (over)load, potentially being a complementary assessment tool to quantify the learning curve for surgical procedures. PMID- 28666794 TI - Measuring contraceptive prevalence among women who are at risk of pregnancy. AB - OBJECTIVES: The contraceptive prevalence rate (CPR) is generally reported among in-union women ages 15-49. Here, union status and age serve as proxies for exposure to the risk of pregnancy. As a result of changing dynamics, age and union status proxies may be insufficient for determining the rate of contraceptive use among women at risk of pregnancy. Our objectives are to define a measure of contraceptive use among women at risk, to measure contraceptive use among such women and to compare this rate with conventional CPR. STUDY DESIGN: Using data from the United States 2011-2013 National Survey of Family Growth (NSFG), we explore self-reported data on contraceptive use, sexual recency, pregnancy status and fecundity to develop an alternative CPR (ACPR) measure, contraceptive prevalence among women at risk of pregnancy. After defining and measuring ACPR, we compare ACPR and conventional CPR estimates using NSFG and Demographic and Health Survey data from 48 surveys completed from 2000 to 2015 in low- and middle-income countries. RESULTS: For measuring ACPR, it is best to limit sexual activity recency component to "four weeks" to minimize underreport of coital-specific methods. It is best to limit the contraceptive use component to "current use" rather than "use at last sex" to minimize underreport of permanent methods. In the United States, 86% of women at risk of pregnancy are currently using contraception. CONCLUSION: Women at risk of pregnancy report higher levels of contraceptive use than the conventional CPR indicates. IMPLICATIONS STATEMENT: Development of ACPR exposed some potential family planning measurement weaknesses. Specifically, because CPR is based on report of "current use," our analyses show that CPR may underreport coital-specific methods. As a result, CPR estimates may be somewhat deflated, and unmet need estimates may be somewhat inflated. PMID- 28666795 TI - Future directions in performance measures for contraceptive care: a proposed framework. PMID- 28666796 TI - Etonogestrel contraceptive implant-associated secondary anorgasmia. AB - : The etonogestrel contraceptive implant is a 4-cm radio-opaque subdermal rod, inserted in the nondominant arm, providing up to 3 years of continuous contraception. We describe a 21-year-old nulligravid, nondepressed female who experienced new-onset secondary anorgasmia 1 month after etonogestrel insertion. Off-label, oral use of bupropion and sildenafil did not restore orgasmic ability. Finally, 1 week after implant removal (41/2 months after insertion), spontaneous return of orgasmic ability occurred. Anorgasmia after etonogestrel implant use is a rare adverse event; nonetheless, clinicians should be alert to its possibility. IMPLICATION STATEMENT: This report documents secondary anorgasmia in a nondepressed female temporally associated with etonogestrel implant insertion. Clinicians should be aware that this rare event can occur but is quickly reversible with implant removal. PMID- 28666797 TI - GAS5 suppresses malignancy of human glioma stem cells via a miR-196a-5p/FOXO1 feedback loop. AB - Glioma stem cells (GSCs) make up highly tumorigenic subpopulations within gliomas, and aberrant expression of GSC genes is a major underlying cause of glioma pathogenesis and treatment failure. The present study characterized the expression and function of long non-coding RNA growth arrest specific 5 (GAS5) in GSCs in order to elucidate the molecular mechanisms by which GAS5 contributes to glioma pathogenesis. We demonstrate that GAS5 suppresses GSC malignancy by binding to miR-196a-5p. miR-196a-5p, an onco-miRNA, stimulates GSC proliferation, migration, and invasion, in addition to reducing levels of apoptosis. miR-196a-5p specifically downregulates the expression of forkhead box protein O1 (FOXO1) by targeting its 3' untranslated region (3'-UTR). FOXO1 upregulates expression of phosphotyrosine interaction domain containing 1 (PID1), thereby inhibiting GSC tumorigenicity and growth. FOXO1 also upregulates migration and invasion inhibitory protein (MIIP), resulting in attenuation of migration and invasion activities. Interestingly, we also show that FOXO1 promotes GAS5 transcription, thus forminga positive feedback loop. These data provide insights into potential new pathways for GSC molecular therapy and suggest that GAS5 may be an efficacious target for glioma treatments. PMID- 28666798 TI - Insights into the mevalonate pathway in the anticancer effect of a platinum complex on human gastric cancer cells. AB - A platinum(II) complex [Pt(en)]2ZL [en = ethylenediamine; ZL = 1-hydroxy-3(1H imidazol-1-yl)ethane-1,1-diylbisphosphonic acid, commonly called as zoledronic acid] has been designed and synthesized recently in order to look for new anticancer drugs with high efficacy and low side effects. It exhibited cytotoxic effects on the human cancer cells SGC7901, HepG2, MCF-7, MDA-MB-231, HCT116, and U2OS, and the cytotoxicity against SGC7901 is particularly remarkable. It also showed higher cytotoxicity and better selectivity than the corresponding ligand ZL in inhibiting cancer cells SGC7901 and HepG2 rather than normal cells GES-1 and LO2. To investigate the role of mevalonate pathway involved in the mechanism of anticancer action of [Pt(en)]2ZL, the effects of farnesol (FOH) and geranylgeraniol (GGOH), precursors of important mevalonate pathway intermediates farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), on the cytotoxic effects of [Pt(en)]2ZL against the human gastric cancer cells SGC7901 were investigated systematically, since inhibition of the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway was acknowledged as the mechanism of most anticancer actions of the ligand ZL. The experiments revealed that FOH and GGOH both rescued the SGC7901 cells, especially FOH. The cell cycle arrest and apoptosis of SGC7901 cells induced by [Pt(en)]2ZL was decreased by the addition of FOH, and the prenylation of small guanine-nucleotide-binding regulatory proteins (small G proteins) down-regulated by [Pt(en)]2ZL was recovered by the addition of FOH, demonstrating that [Pt(en)]2ZL exerted anticancer effects on SGC7901 via inhibiting the mevalonate pathway. This will provide deep insights into the mechanism of action of [Pt(en)]2ZL. PMID- 28666799 TI - Ovatodiolide suppresses allergic airway inflammation and hyperresponsiveness in a murine model of asthma. AB - Asthma, a complex pulmonary allergic disease, major therapy is applied of drugs to control the disease, but quickly recur after the drugs are stopped. In patients with severe asthma may show steroid resistance and would benefit from the development of novel therapeutic drugs. Ovatodiolide, a unique macrocyclic diterpenoid isolated from Anisomeles indica, showed therapeutic potential for the treatment of allergic asthma. As a model of allergic inflammation, we used ovalbumin (OVA)-immunized mice, which displayed T helper cell type 2 (TH2) cytokine expression in bronchoalveolar lavage fluid (BALF), as well as airway inflammation and hyperresponsiveness (AHR). The results showed that ovatodiolide suppressed TH2 activation, including cell proliferation and production of the TH2 related cytokines, interleukin (IL)-4, IL-5, IL-13, IL-33, eosinophil chemotactic protein (eotaxin), and also reduced airway hyperresponsiveness. In this study, ovatodiolide inhibited allergic asthma through downregulation of TH2 responses in a murine model of asthma. PMID- 28666800 TI - A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease. AB - Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients. PMID- 28666801 TI - Methylsulfonylmethane is effective against gastric mucosal injury. AB - Methylsulfonylmethane (MSM) is a natural organosulfur compound has been widely used as a dietary supplement. MSM has protective effects against various disorders through its anti-inflammatory and antioxidant properties however the effect of MSM on gastric mucosal injury remains unclear. The aim of the present study is to determine whether MSM has beneficial effects on ethanol/HCl-induced gastric ulcer in mice. Macroscopic and histopathological evaluation of gastric mucosa revealed that ethanol/HCl administration produced apparent mucosal injuries, while pretreatment with MSM (200 and 400mg/kg, orally) could effectively protect gastric mucosa against the injuries caused by acidified ethanol. MSM significantly increased the levels of glutathione (GSH), catalase (CAT) and prostaglandin E2 (PGE2), and decreased the levels of malondialdehyde (MDA), myeloperoxidase (MPO), carbonyl protein, and nitric oxide (NO) in gastric tissues compared with those in the ethanol group. MSM suppressed gastric inflammation by reducing the levels of proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9. Moreover, pretreatment of mice with MSM decreased the expression of nuclear factor kappa B (NF-kappaB) as a key regulator of inflammation in gastric mucosa. Taken together, these data suggest that MSM is able to decrease the severity of ethanol/HCl-induced gastric mucosal injury through inhibition of oxidative stress and inflammation. PMID- 28666802 TI - A novel modified physiologically relevant model for cardiac angiogenesis. AB - Angiogenesis assays are important tools for studying both the mechanisms of cardiac angiogenesis and the potential development of therapeutic strategies to ischemic heart diseases. Currently, various assays have been used to quantitate cardiac tubule formation, yet no consensus has been reached regarding a suitable assay for evaluating the efficacy of angiogenic stimulants or inhibitors. Most in vivo angiogenesis assays are complex and difficult to interpret, whereas traditional in vitro angiogenesis models measure only one aspect of this process. To bridge the gap between in vivo and in vitro angiogenesis assays, here, we have developed a novel modified cardiac explants matrigel assay. We observed the morphology of vascular sprouts formed in three forms of cardiac angiogenesis assays then used quantitative image analyses to further compare the morphological features of vascular sprouts formed in two cardiac explants angiogenesis assays. Vascular sprouts formed in the fibronectin group were less and short, whereas those formed in the matrigel group were significantly longer, consisting of more area and branch points. Moreover, we found the benefits of this matrigel model by observing the ability of cardiac explants to form vascular sprouts under normoxia or hypoxia condition in the presence of angiogenic stimulant and inhibitor, VEGF and PEDF. In summary, the above analyses revealed that the morphology of vascular sprouts formed in this model appears more representative of myocardial capillary formation in vivo, and this accessible, reliable angiogenic assay is a more physiologically relevant assay which allows further assessment of pharmacologic compounds on cardiac angiogenesis. PMID- 28666803 TI - Intra-Arterial Treatment for Patients with Severe Acute Vertebrobasilar Occlusion: A Single-Center Retrospective Study. AB - BACKGROUND: Recently, favorable outcomes from several randomized controlled trials of rapid endovascular treatment for acute ischemic stroke has emerged. OBJECTIVE: The aim of this retrospective study is to present our clinical experience in severe acute vertebrobasilar occlusion (AVBO) using intra-arterial treatment (IAT). METHODS: Twenty patients with ischemic stroke in the vertebrobasilar circulation treated by IAT between March 2011 and December 2014 were included. We retrospectively assessed National Institutes of Health Stroke Scale (NIHSS) score on admission and at discharge, Thrombolysis in Cerebral Infarction (TICI) scale, and clinical outcome using modified Rankin scale (mRs) at 90 days, and causes of stroke were prospectively assessed. RESULTS: The mean NIHSS score on admission was 26.4 +/- 7.9 (range 9-33) points. The mean time from symptom onset to revascularization was 349.5 +/- 124.0 (range 201-579) minutes. Successful recanalization (TICI >=2b) was achieved in 19 (95.0%) patients. The mean NIHSS score at discharge was 5.7 +/- 9.0 (range 0-30) points. A favorable clinical outcome (mRS <=2) was observed in 12 (60.0%) patients at 90 days and mortality was 25.0% (n = 5). CONCLUSION: IAT for AVBO provides high rate of recanalization, favorable clinical outcome, and improved survival. PMID- 28666804 TI - Cardiovascular Responses Associated with the Moving Beans Task: Influence of Psychological Characteristics. AB - BACKGROUND AND OBJECTIVE: High blood pressure (BP) after stroke is associated with a poor outcome. However, exercise training or speech therapy for patients with stroke can raise the BP. The aim of this study was to examine cardiovascular responses during the moving beans task (MBT) used in occupational therapy and to study the influence of psychological characteristics on cardiovascular responses during this task in healthy subjects. MATERIALS AND METHODS: In 34 healthy volunteers, the BP and the heart rate (HR) were continuously measured during the baseline period, the 5-minute MBT, and the 1-minute cold pressor test (CPT). All subjects completed self-reported questionnaires, including the Center for Epidemiologic Studies Depression Scale (CES-D), the State Trait Anxiety Inventory Y-2, and the Japanese version of the 20-item Toronto Alexithymia Scale (TAS-20). RESULTS: The systolic blood pressure (SBP), the diastolic blood pressure (DBP), and the mean blood pressure (MBP) significantly increased during the MBT and the CPT compared with the baseline values. SBP, DBP, and MBP responses during the MBT significantly correlated with the TAS-20 scores. Moreover, DBP response during the MBT correlated with the CES-D scores. CONCLUSIONS: The MBT significantly raised BP without increasing the HR. BP responses during this task were influenced by the psychological characteristics of depression and alexithymia. PMID- 28666805 TI - Change in Coefficient of Fatigability Following Rapid, Repetitive Movement Training in Post-Stroke Spastic Paresis: A Prospective Open-Label Observational Study. AB - BACKGROUND: In post-stroke patients, the possibility of performing an active ankle dorsiflexion movement is favorable for the recovery of gait. Moreover, the fatigue due to repetitive active ankle dorsiflexion could reduce the speed gait. We assessed the change in coefficient of fatigability of active ankle dorsiflexion after a home-based self-rehabilitative procedure in post-stroke patients. METHODS: In a prospective open-label observational study conducted in 2 university hospitals, a home-based self-rehabilitation treatment comprising two 12-minute sessions per day (3 times per week for 3 months) was performed by 10 outpatients with post-stroke lower limb impairment. Each session consisted of three 1-minute series of repeated active ankle dorsiflexion efforts at maximal speed on the paretic side, each one followed by 3-minute bouts of triceps surae stretch. Coefficients of fatigability of dorsiflexion and 10-meter barefoot ambulation speed were evaluated at baseline and at the end of the program. RESULTS: At 3 months of follow-up, there was a decrease in the coefficients of fatigability of ankle dorsiflexion, both with knee flexed and extended (respectively from 8% to 2% and from 6% to 2%; P < .01), associated with an increase in comfortable ambulation speed (from .24 to .26 m/s; P < .05). CONCLUSIONS: The reduction of coefficient of fatigability of ankle dorsiflexion, together with walking speed improvement, suggested the effectiveness of self rehabilitation using alternated periods of self-stretch and rapid alternating efforts in the paretic lower limb after stroke. PMID- 28666806 TI - PR Interval Prolongation and Cryptogenic Stroke: A Multicenter Retrospective Study. AB - BACKGROUND: Atrial dysfunction or "cardiopathy" has been recently proposed as a mechanism in cryptogenic stroke. A prolonged PR interval may reflect impaired atrial conduction and thus may be a biomarker of atrial cardiopathy. We aim to compare the prevalence of PR interval prolongation in patients with cryptogenic stroke (CS) when compared with known non-cryptogenic non-cardioembolic stroke (NCNCS) subtypes. METHODS: We used prospective ischemic stroke databases of 3 comprehensive stroke centers to identify patients 18 years or older with a discharge diagnosis of ischemic non-cardioembolic stroke between December 1, 2013 and August 31, 2015. The main outcome was ischemic stroke subtype (CS versus NCNCS). We compared PR intervals as a continuous and categorical variable (<200 milliseconds; >=200 milliseconds) and other clinical and demographic factors between the 2 groups and used multivariate regression analyses to determine the association between PR interval prolongation and CS. RESULTS: We identified 644 patients with ischemic non-cardioembolic stroke (224 CS and 420 NCNCS). Patients with CS were more likely to have a PR of 200 milliseconds or greater when compared with those with NCNCS (23.2% versus 13.8%, P = .009). After adjusting for factors that were significant in univariate analyses, a PR of 200 milliseconds or greater was independently associated with CS (odds ratio [OR] 1.70, 95% CI 1.08-2.70). The association was more pronounced when excluding patients on atrioventricular nodal blocking agents (OR 2.64, 95% CI 1.44-4.83). CONCLUSIONS: A PR of 200 milliseconds or greater is associated with CS and may be a biomarker of atrial cardiopathy in the absence of atrial fibrillation. Prospective studies are needed to confirm this association. PMID- 28666807 TI - Anesthetic agents, neurodevelopmental risk and the connection to bacterial infections. AB - This short communication identifies a significant flaw in research investigating the neurodevelopmental consequences of general anesthesia exposure. We have identified that chronic environmental exposure to pervasive air pollutants that are also widely used as anesthetic agents, specifically nitrous oxide (N2O), may contribute to the rising prevalence of neurodevelopmental disorders. Consistent with the emerging link between microbes and psychiatric illness risk, this epidemiological analysis extends our prior conclusions by proposing that such exposures may alter host immunity so as to enhance vulnerability to certain pathogenic microbes that have been implicated in neurodevelopmental disorders, including Pseudomonas aeruginosa and Clostridium difficile. PMID- 28666808 TI - Preface to the special issue bioeconomy. AB - The security of food, feed and energy supply, resource efficiency and the creation of sustainable economic value and jobs for a growing population represent interlinked global challenges demanding new approaches and paradigms. One of them is bioeconomy, which ranks very high on national and international agendas, strategies and blueprints. This special issue brings together a series of unique contributions by some of the leading experts on bioeconomy with a special focus on biotechnology as the pillar of bioeconomy. The articles cover different aspects and are structured into sections on global perspectives, regional dimensions, examples of national initiatives, examples of regional and local case studies, transnational clusters and technology platforms, intellectual property rights, bio-industry associations and new scientific and technological trends in bioeconomy. A final article discussing perspectives on bioeconomy concludes this series of publications. We hope that readers will enjoy the first comprehensive insight into bioeconomy at the global level. PMID- 28666809 TI - Bio-based Industries Joint Undertaking: The catalyst for sustainable bio-based economic growth in Europe. AB - This article discusses the preparation, structure and objectives of the Bio-based Industries Joint Undertaking (BBI JU). BBI JU is a public-private partnership (PPP) between the European Commission (EC) and the Bio-based Industries Consortium (BIC), the industry-led private not-for-profit organisation representing the private sectors across the bio-based industries. The model of the public-private partnership has been successful as a new approach to supporting research and innovation and de-risking investment in Europe. The BBI JU became a reality in 2014 and represents the largest industrial and economic cooperation endeavour financially ever undertaken in Europe in the area of industrial biotechnologies. It is considered to be one of the most forward looking initiatives under Horizon 2020 and demonstrates the circular economy in action. The BBI JU will be the catalyst for this strategy to mobilise actors across Europe including large industry, small and medium-sized enterprises (SMEs), all types of research organisations, networks and universities. It will support regions and in doing so, the European Union Member States and associated countries in the implementation of their bioeconomy strategies. PMID- 28666810 TI - Video-based assessment of foot strike pattern and step rate is valid and reliable in runners with patellofemoral pain. AB - OBJECTIVES: To evaluate, during treadmill running in runners with patellofemoral pain (PFP), the concurrent validity of determining foot strike pattern using 2D video and the intra- and inter-rater reliability of foot strike pattern and step rate assessments between a novice and experienced observer. DESIGN: Methodological study (validity/reliability). SETTING: Motion analysis laboratory. PARTICIPANTS: Sixty runners with PFP (37 females, 23 males; age = 30.8 +/- 6.5 years; height = 169.8 +/- 9.1 cm; weight = 66.6 +/- 12.9 kg). MAIN OUTCOME MEASURES: Running kinematics were recorded using 3D motion capture and a sagittal view 2D video camera. Concurrent validity, intra-, and inter-rater reliability of foot strike pattern determination (Gwet AC statistics), and reliability of step rate calculation (Intraclass correlation coefficients, ICC) were assessed. RESULTS: For foot strike pattern, agreement between the 3D motion analysis system and 2D video assessment was high for both raters (AC = 0.906-0.936, P < 0.001). Excellent intra (AC = 0.961-1.000, ICC = 0.984-0.998, respectively) and inter rater reliability (AC = 0.929-0.970, ICC = 0.980, respectively) was obtained for foot strike pattern and step rate. CONCLUSIONS: Video-based evaluation of foot strike pattern and step rate of runners with PFP is valid and highly reliable when performed by a novice or experienced assessor. Therefore, clinicians and researchers can use such methods confidently to guide their gait retraining interventions for runners with PFP. PMID- 28666812 TI - Single-Agent Oral Vinorelbine as First-Line Chemotherapy for Endocrine-Pretreated Breast Cancer With Bone Metastases and No Visceral Involvement: NORBREAST-228 Phase II Study. AB - PURPOSE: Single-agent oral chemotherapy is widely used in patients with bone metastases without visceral involvement, especially in hormone receptor-positive metastatic breast cancer (mBC). However, this option has been poorly evaluated in clinical trials. METHODS: Eligible patients had mBC with predominantly bone but not visceral metastases, were receiving bisphosphonate therapy, and had previously received endocrine therapy (any setting) but not chemotherapy for mBC. Patients received oral vinorelbine 60 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (escalating to 80 mg/m2 from cycle 2 in the absence of grade 3/4 toxicity) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included clinical benefit rate (complete/partial response or >=24 weeks' stable disease), overall survival, and safety. RESULTS: Seventy patients were treated for a median of 6 cycles (range 1-18). Most (73%) continued treatment until disease progression. After 43 months' median follow-up, median PFS was 8.2 months (95% confidence interval [CI], 5.5-9.8). The clinical benefit rate was 56% (95% CI, 43%-68%). Median overall survival was 35.2 months (95% CI, 26.8-47.1). The most common grade 3/4 adverse event was neutropenia (38% of patients); febrile neutropenia was absent. The most common grade 1/2 adverse events were bone pain, fatigue, and gastrointestinal toxicities. Alopecia was infrequent. CONCLUSIONS: In patients with hormone receptor-positive mBC, bone disease, and prior endocrine therapy, first-line oral vinorelbine chemotherapy demonstrated long PFS and good tolerability. In this setting, it could be considered as an active oral alternative to intravenous chemotherapy. PMID- 28666811 TI - alpha6beta2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high versus low-response to novelty. AB - Determining neurobiological factors that contribute to individual variance in drug addiction vulnerability allows for identification of at-risk populations, use of preventative measures and personalized medicine in the treatment of substance use disorders. Rodents that exhibit high locomotor activity when exploring an inescapable novel environment (high-responder; HR) are more susceptible to the reinforcing effects of many abused compounds, including nicotine, as compared to animals that exhibit low locomotor activity (low responder; LR). Given that nicotinic acetylcholine receptor (nAChR) modulation of reward-related dopamine signaling at accumbal dopamine terminals is critical for the acquisition of drug self-administration, we hypothesized that nAChR modulation of dopamine release would be predicted by an animal's novelty response. Using voltammetry in the nucleus accumbens core of rats, we found that nicotine produced opposite effects in HR and LR animals on stimulation frequencies that model phasic dopamine release, whereby release magnitude was either augmented or attenuated, respectively. Further, nicotine suppressed dopamine release elected by stimulation frequencies that model tonic release in LR animals, but had no effect in HR animals. The differential effects of nicotine were likely due to desensitization of nAChRs, since the nAChR antagonists mecamylamine (non-selective, 2 MUM), dihydro-beta-erythroidine (beta2-selective, 500 nM), and alpha-conotoxin MII [H9A; L15A] (alpha6-selective, 100 nM) produced effects similar to nicotine. Moreover, dihydro-beta-erythroidine failed to show differential effects in HR and LR rats when applied after alpha-conotoxin MII [H9A; L15A], suggesting a critical role of alpha6beta2 compared non alpha6 containing nAChRs in the differential effects observed in these phenotypes. These results delineate a potential mechanism for individual variability in behavioral sensitivity to nicotine. PMID- 28666813 TI - Patient Case Lessons: Endocrine Management of Advanced Breast Cancer. AB - Advances in treatment for women with advanced breast cancer (ABC) have led to improvements in survival. Although the condition remains incurable, treatment goals focus on stabilizing disease, prolonging life, and maintaining patient quality of life. Hormone receptor-positive (HR+) subtypes constitute the majority of breast cancers, and an increasing number of effective endocrine therapies are available. Although practice guidelines provide important recommendations and principles for treatment selection, the choice of specific agents from among existing options should be customized to the individual based on patient and disease characteristics, as well as the nature and duration of response to previous treatments. This review examines endocrine and endocrine-based options, including combinations with targeted agents, for HR+ and human epidermal growth factor receptor 2-negative (HER2-) ABC. It also elaborates on the factors that enter into treatment decision-making, using patient case examples to illustrate how ABC can present and the clinical issues involved in treatment selection. Case examples are included to provide evidence for the clinical scenarios of de novo HR+/HER2- ABC and progression during adjuvant treatment for early breast cancer. PMID- 28666815 TI - China's evolving fracture burden. PMID- 28666814 TI - National incidence of traumatic fractures in China: a retrospective survey of 512 187 individuals. AB - BACKGROUND: Traumatic fractures place a substantial burden on health-care systems worldwide. Although detailed information about incidence, distribution, and risk factors for traumatic fractures is vital for planning and prevention, in China, national data are unavailable. We aimed to do an up-to-date national survey on the population-weighted incidence of traumatic fractures in China. METHODS: The China National Fracture Study (CNFS) was a retrospective epidemiological study that recruited a nationally representative sample from eight provinces, 24 urban cities, and 24 rural counties in China using stratified random sampling and the probability proportional to size method. All eligible household members who had lived in their current residence for 6 months or longer were personally interviewed by trained research teams about traumatic fractures of the trunk, arms, or legs (not including the skull, sternum, and ribs) that had occurred in 2014. Telephone surveys were used for participants who were non-contactable after repeated visits. Fracture cases were verified by clinical records, medical history, and radiographs by orthopaedic surgeons and radiologists. We estimated incidence rates for traumatic fractures for the overall population and for subgroups by age and sex, as well as by demographic factors such as ethnic origin, occupation, geographical region, and residency category. We also studied potential associations between fractures and various factors of interest, such as age, ethnic origin, education, smoking, alcohol drinking, sleep time per day, and history of previous fracture. Data were weighted during statistical analysis to ascertain the national incidence rate. This study is registered with the Chinese Clinical Trial Registry, number ChiCTR-EPR-15005878. FINDINGS: Between Jan 19, 2015, and May 16, 2015, 535 836 individuals were selected and invited to participate in the study. Questionnaires from 23 649 (4%) individuals were excluded due to missing items, insufficient responses, or logical errors. Following exclusions, 512 187 (96%) individuals participated in the CNFS, consisting of 259 649 (51%) boys and men and 252 538 (49%) girls and women. Of these individuals, 1763 individuals had experienced traumatic fractures during 2014 (n=1833). The population-weighted incidence rate of traumatic fractures of the trunk, arms, or legs was 3.21 (95% CI 2.83-3.59) per 1000 population in 2014 (3.65, 3.12-4.18 in men and 2.75, 2.46-3.04 in women). For all ages, sleeping less than 7 h per day was identified as a risk factor for traumatic fractures. We identified previous fracture history as a risk factor for adults aged 15 years and older. Alcohol consumption incurred a risk effect for men aged 15 years and older and women aged 15-64 years. INTERPRETATION: Our results provide detailed information about fracture incidence, distribution, and risk factors, which can now be used as an up-to-date clinical evidence base for national health-care planning and preventive efforts in China and elsewhere. Specific public health policies that focus on decreasing alcohol consumption, prohibiting drunk driving, promoting smoking cessation, and encouraging individuals to obtain sufficient sleep and maintain a healthy bodyweight should be urgently implemented to help reduce the risk of traumatic fractures. FUNDING: The Hebei Province Medical Science Special Major Projects Research Fund. PMID- 28666816 TI - Application of the Consolidated Framework for Implementation Research to community pharmacy: A framework for implementation research on pharmacy services. AB - BACKGROUND: Community pharmacies are an increasingly important health care setting with opportunities for improving quality and safety, yet little is understood about determinants of implementation in this setting. OBJECTIVE: This paper presents an implementation framework for pharmacy based on the Consolidated Framework for Implementation Research (CFIR). METHODS: This study employed a critical review of 45 articles on professional services provided in community pharmacies, including medication therapy management (MTM), immunizations, and rapid HIV testing. RESULTS: The relevant domains and associated constructs for pharmacy services were as follows. Intervention Characteristics ultimately depend on the specific service; of particular note for pharmacy are relative advantage and complexity. The former because implementation of services can pose a cost benefit challenge where dispensing is the primary role and the latter because of the greater challenge implementing multi-faceted services like MTM compared to a discrete service like immunizations. "In terms of Outer Setting, pharmacies are affected by patient needs and acceptance, and external policies and incentives such as reimbursement and regulations. For Inner Setting, structural characteristics like pharmacy type, size and staff were important as was pharmacists' perception of their role and available resources to provide the service. Key Characteristics of Individuals include training, preparedness, and self-efficacy of the pharmacist for providing a new service. Few studies revealed relevant Process constructs, but if they did it was primarily related to engaging (e.g., champions). CONCLUSIONS: As pharmacists' roles in health care are continuing to expand, a framework to inform implementation research in community pharmacy (and other) settings is crucially needed. PMID- 28666817 TI - What supports hospital pharmacist prescribing in Scotland? - A mixed methods, exploratory sequential study. AB - While approximately half of all qualified hospital pharmacist independent prescribers (PIPs) in Scotland are active prescribers, there are major differences in prescribing activity across geographical areas. This study aimed to explore, through focus groups, interviews and a questionnaire, hospital PIPs' perceptions of factors associated with prescribing activity and to investigate the infrastructure required to better support active prescribing by PIPs. Findings reinforced the perceived positive impact of supportive pharmacy leadership within the organisation, recognition that prescribing is integral to the clinical pharmacist role and a work environment conducive to prescribing. PMID- 28666818 TI - Morphological and Biomechanical Features in Abdominal Aortic Aneurysm with Long and Short Neck-Case-Control Study in 64 Abdominal Aortic Aneurysms. AB - BACKGROUND: Both, open and endovascular, procedures are related to higher complication rate in abdominal aortic aneurysm (AAA) with shorter neck. Previous study showed that long-neck AAA might have lower risk of rupture. Estimation of biomechanical forces in AAA improves rupture risk assessment. The aim of this study was to compare morphological features and biomechanical forces in the short and long-neck AAA with threshold of 15 mm. METHODS: Digital Imaging and Communication in Medicine images of 64 aneurysms were prospectively collected and analyzed in a case-control study. Using commercially available software, Peak wall Stress (PWS) and Rupture Risk Equivalent Diameter (RRED) were determined. Difference between the maximal aneurysm diameter (MAD) and RRED was calculated and expressed as an absolute and relative (percentage of the MAD) value. In addition, volume of intraluminal thrombus (ILT) was calculated and expressed relative to AAA volume. RESULTS: Study included 64 AAA divided in group with long (36, 56.25%), and short (28, 43.75%) neck. There was no correlation between neck length and MAD, PWS, and RRED (P = 0.646, P = 0.421, and P = 0.405, respectively). Relative ILT volume was greater in the short-neck aneurysms (P = 0.033). Relative difference between RRED and MAD was -4% and -14.8% in short- and long-neck aneurysms, respectively (P = 0.029). The difference between RRED and MAD was positive in 14/28 patients (50%) with short neck and in 6/35 patients (17.14%) with long neck (P = 0.011). CONCLUSIONS: Based on our biomechanical analysis, in AAA with neck longer than 15 mm rupture risk might be lower than the risk estimated by its diameter. It might be explained with lower relative volume of ILT. PMID- 28666819 TI - Staged Definitive Repair after Carotid Blowout: A Case Report. AB - Carotid blowout syndrome is a highly morbid complication of head and neck cancer. We present the case of a 51-year-old woman with common carotid artery blowout, initially temporized with an endovascular stent graft and ultimately reconstructed using autologous superficial femoral artery. The patient recovered without sequelae and continues to be asymptomatic at 1 year. We present the modern hybrid management of this complex case. PMID- 28666820 TI - Cloning, expression and functional characterization of a D-superfamily conotoxin Lt28.1 with previously undescribed cysteine pattern. AB - As a class of peptides with 10 cysteine residues (-C-CC-C-CC-C-C-C-C-), D superfamily conotoxins (D-conotoxins) can specifically act on nicotinic acetylcholine receptors (nAChRs). According to the conserved signal peptides of D conotoxins, seven D-conotoxin precursor sequences with a previously undescribed Cys arrangement (-C-C-C-CC-C-C-C-C-C-) were identified by PCR-RACE methodology in the present study. The alignment of sequences revealed that signal peptide regions were same as D-VxXXA from Conus vexillum, and their mature peptides were almost different from the D-conotoxins. Analyses of the evolutionary tree demonstrated that they had low homology to those reported conotoxins with 10 cysteine residues (less than 35%) and lied in a separate branch in the evolutionary tree. Furthermore, a previously undescribed D-superfamily conotoxin Lt28.1 was further expressed in Pichia pastoris and then functionally characterized. The results showed that the recombinant Lt28.1 targeted alpha9alpha10 nAChRs but not other nAChRs subtypes. These findings defined a new branch of D-superfamily and expanded our knowledge of targets and potential application of D-conotoxins. PMID- 28666821 TI - Some chemicals that cause tumours of the urinary tract in rodents. PMID- 28666822 TI - Reduced high-density lipoprotein cholesterol: A valuable, independent prognostic marker in peripheral arterial disease. AB - OBJECTIVE: The prognosis of patients with peripheral arterial disease (PAD) is characterized by an exceptionally high risk for myocardial infarction, ischemic stroke, and death; however, studies in search of new prognostic biomarkers in PAD are scarce. Even though low levels of high-density lipoprotein cholesterol (HDL C) have been associated with higher risk of cardiovascular (CV) complications and death in different atherosclerotic diseases, recent epidemiologic studies have challenged its prognostic utility. The aim of this study was to test the predictive value of HDL-C as a risk factor for ischemic events or death in symptomatic PAD patients. METHODS: Clinical and demographic parameters of 254 symptomatic PAD patients were recorded. Amputation, ischemic coronary disease, cerebrovascular disease, and all-cause mortality were recorded during a mean follow-up of 2.7 years. RESULTS: Multivariate analyses showed that disease severity (critical limb ischemia) was significantly reduced in patients with normal HDL-C levels compared with the group with low HDL-C levels (multivariate analysis odds ratio, 0.09; 95% confidence interval [CI], 0.03-0.24). A decreased risk for mortality (hazard ratio, 0.46; 95% CI, 0.21-0.99) and major adverse CV events (hazard ratio, 0.38; 95% CI, 0.16-0.86) was also found in patients with normal vs reduced levels of HDL-C in both Cox proportional hazards models and Kaplan-Meier estimates, after adjustment for confounding factors. CONCLUSIONS: Reduced HDL-C levels were significantly associated with higher risk for development of CV complications as well as with mortality in PAD patients. These findings highlight the usefulness of this simple test for early identification of PAD patients at high risk for development of major CV events. PMID- 28666823 TI - Overstenting the hypogastric artery during endovascular aneurysm repair with and without prior coil embolization: A comparative analysis from the ENGAGE Registry. AB - BACKGROUND: Endovascular aneurysm repair of aortoiliac or iliac aneurysms is often performed with stent graft coverage of the origin of the hypogastric artery (HA) to ensure adequate distal seal. It is considered common practice to perform adjunctive coiling of the HA to prevent a type II endoleak. Our objective was to question the necessity of pre-emptive coiling by comparing the outcomes of HA coverage with and without prior coil embolization. METHODS: Data from the Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE), which prospectively enrolled 1263 endovascular aneurysm repair patients between March 2009 and April 2011 from multiple centers worldwide, were used for this study. We identified patients in whom the Endurant stent graft (Medtronic Vascular, Santa Rosa, Calif) covered one or both HAs and grouped them into cases in which prior HA embolization-coils or plugs-was performed (CE) and cases in which HA embolization was not performed (NE). The occurrence of covered HA-related endoleak and secondary interventions were compared between groups. RESULTS: In 197 patients, 225 HAs were covered. Ninety-one HAs were covered after coil embolization (CE group), and 134 HAs were covered without prior coil embolization (NE group). Both groups were similar at baseline and had comparable length of follow-up to last image (665.2 +/- 321.7 days for CE patients; 641.6 +/- 327.6 days for NE patients; P = .464). Importantly, both groups showed equivalent iliac morphology concerning common iliac artery proximal, mid, and distal dimensions and tortuosity, making them suitable for comparative analysis. During follow-up, HA-related endoleaks were sparse and occurred equally often in both groups (CE 5.5% vs NE 3.0%; P = .346). Secondary intervention to resolve an HA-related endoleak was performed twice in the CE group and three times in the NE group. Late non-HA-related endoleaks occurred more often in the CE group compared with the NE group, (25.0% vs 15.0%; P = .080). Secondary interventions for other reasons than HA-related endoleaks occurred in 7.5% of NE cases and 15.4% of CE cases (P = .057), mostly for occlusions in the ipsilateral iliac limb. During follow-up, 19 NE patients and 9 CE patients died, which is not significantly different (P = .225), and no deaths were related directly or indirectly to HA coverage. Also, no reports of gluteal necrosis and bowel ischemia were made. CONCLUSIONS: This study shows that HA coverage with the Endurant endograft without prior coil embolization does not increase the incidence of endoleak or related secondary interventions. These findings together with the already available evidence suggest that omission of coil embolization may be a more resource-effective strategy whenever HA coverage is required. PMID- 28666824 TI - Carotid artery revascularization in patients with contralateral carotid artery occlusion: Stent or endarterectomy? AB - BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) considers that contralateral carotid artery occlusion puts the patients at high risk for carotid endarterectomy (CEA) and agrees to reimburse for carotid artery stenting (CAS) in these patients. However, there is a paucity of evidence that support the superiority of CAS compared with CEA in patients with contralateral carotid occlusion. METHODS: All patients who underwent CEA or CAS with contralateral carotid artery occlusion were identified in the Vascular Quality Initiative (VQI) registry between 2005 and 2016. Outcomes examined were stroke, death, and myocardial infarction at 30 days and stroke and death at 2 years stratified by ipsilateral symptomatic status. Multivariable logistic regression analysis was implemented to estimate the odds ratios (ORs) of 30-day outcomes controlling for potential confounders. Life tables, robust Cox proportional hazard clustered by centers, and log-rank tests were implemented to estimate the hazard ratios (HRs) for long-term events. RESULTS: Overall, 4326 patients had contralateral carotid artery occlusion (CEA: 3274 [75.7%] vs CAS: 1052 [24.3%]). Patients' demographic and comorbidities were generally similar in both groups, except for race, in which nonwhite patients were more likely to have CAS (9.5% vs 7.6%; P = .048). History of stroke was twice as much prevalent in patients undergoing CEA (56.4% vs 24.0%; P < .001). CAS patients were more likely to present with ipsilateral symptoms (41.2% vs 24.2%; P < .05). In asymptomatic patients, the short-term outcomes and 2-year risk of ipsilateral stroke did not differ significantly between CAS and CEA; however, the adjusted risk of any stroke or death over 2 years was 42% higher with CAS (adjusted HR, 1.42; 95% confidence interval [CI], 1.08-1.86; P = .011). In symptomatic patients, CAS was associated with an almost threefold higher risk for 30-day stroke (OR, 2.90; 95% CI, 1.06-7.94; P = .038) and more than sixfold the 30-day mortality (OR, 6.10; 95% CI, 2.20-16.92; P = .001). The risk of stroke in the initial 2 years after surgery was 94% increased in a CAS patient relative to a CEA patient (adjusted HR, 1.94; 95% CI, 1.18-3.19; P = .009). CONCLUSIONS: In this exclusive large cohort of patients with contralateral carotid artery occlusion, CAS did not perform better compared with CEA in asymptomatic patients and had significantly worse outcomes in symptomatic patients in the perioperative period. The 2-year stroke rate was similar between the two procedures, but the risk of stroke or death was consistently higher for CAS patients. CAS is not safer than CEA in patients with contralateral carotid artery occlusion, and refinement of current guidelines is warranted to provide appropriate surgical care specifically tailored for the patient's presentation. PMID- 28666825 TI - Triptonide acts as a novel potent anti-lymphoma agent with low toxicity mainly through inhibition of proto-oncogene Lyn transcription and suppression of Lyn signal pathway. AB - Lyn is a proto-oncogene overexpressed and constitutively activated in lymphoma, and plays an important role in lymphoma initiation and malignant progression. Hence, the oncogenic Lyn has recently been targeted for novel anti-lymphoma drug discovery; however, the effective Lyn-targeted drug for lymphoma treatment with low toxicity is absent in the clinical setting. The goal of this study is to explore powerful and low toxic Lyn-targeted anti-lymphoma agent. Here we show that triptonide, a small molecule purified from the herb Tripterygium wilfordii Hook F, potently inhibits the proliferation of human B-lymphoma Raji and T lymphoma Jurkat cells with IC50 of 5.7nM and 4.8nM, respectively. Strikingly, triptonide at a dose of 5mg/kg/day almost completely inhibited the lymphoma growth in human lymphoma cells-xenografted mice without obvious side effects, particularly; the tumors in 6 mice among the 8 xenografted mice were completely eradicated in vivo. Cell biological studies showed that triptonide at the doses of 2.5-10nM notably suppressed B-lymphoma cell colony-forming capability, and that triptonide at the dose of 20nM promoted apoptosis through activation of PARP and caspase 3, but reduction of BCL2 protein levels in the lymphoma cells. Molecular studies revealed that triptonide markedly inhibited oncogenic Lyn transcription through suppressing the promoter activity of the gene, and that it remarkably reduced both total and phosphorylated Lyn proteins, and diminished Lyn downstream ERK and ATK signal pathways. Additionally, triptonide significantly enhanced p38 phosphorylation. Together, triptonide exerts potent anti-lymphoma effect with low toxicity mainly through inhibition of proto-oncogene Lyn transcription and suppression of Lyn downstream ERK and ATK signal pathways, providing an attractive drug candidate for development of novel anti-lymphoma therapeutics. PMID- 28666826 TI - Affective symptoms in schizophrenia are strongly associated with neurocognitive deficits indicating disorders in executive functions, visual memory, attention and social cognition. AB - The aim of this study was to assess the neurocognitive correlates of affective symptoms in schizophrenia. Towards this end, 40 healthy controls and 80 schizophrenia patients were investigated with six tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing spatial working memory, paired-association learning, one touch stocking, rapid visual information (RVP), emotional recognition test and intra/extradimensional set shifting. The Hamilton Depression (HDRS) and Anxiety (HAMA) Rating Scales and the Calgary Depression Scale for Schizophrenia (CDSS) as well as the Positive and Negative Syndrome Scale (PANSS) were also used. There were highly significant associations between all 6 CANTAB tests and HDRS, HAMA and CDSS (except RVP) scores. The most significant items associating with neurocognitive impairments in schizophrenia were self-depreciation (CDSS), fatigue, psychomotor retardation and agitation, psychic and somatic anxiety (HDRS), fears, cognitive symptoms, somatic-muscular, genito-urinary and autonomic symptoms and anxious behavior (HAMA). The selected HDRS and HAMA symptoms indicate fatigue, fears, anxiety, agitation, retardation, somatization and subjective cognitive complaints (SCC) and are therefore labeled "FAARS". Up to 28.8% of the variance in the 6 CANTAB measurements was explained by FAARS, which are better predictors of neurocognitive impairments than the PANSS negative subscale score. Neurocognitive deficits in schizophrenia are best predicted by FAARS combined with difficulties in abstract thinking. In conclusion, depression and anxiety symptoms accompanying the negative and positive symptoms of schizophrenia are associated with neurocognitive deficits indicating disorders in executive functions, attention, visual memory, and social cognition. Neurocognitive deficits in schizophrenia reflect difficulties in abstract thinking and FAARS, including subjective cognitive complaints. PMID- 28666828 TI - Structure-property relationships of Thai silk-microcrystalline cellulose biocomposite materials fabricated from ionic liquid. AB - Biomaterials made from natural proteins and polysaccharides have become increasingly popular in the biomedical field due to their good biocompatibility and tunable biodegradability. However, the low miscibility of polysaccharides with proteins presents challenges in the creation of protein-polysaccharide composite materials. In this study, neat 1-allyl-3-methylimidazolium chloride (AMIMCl) ionic liquid was used to regenerate Thailand gold Bombyx mori silk and microcrystalline cellulose blended films. This solvent was found to not only effectively dissolve both natural polymers, but also preserve the structure and integrity of the polymers. A single glass transition temperature for each blend was found in DSC curves, indicating good miscibility between the Thai silk and cellulose molecules. The structural composition as well as the morphology and thermal stability of blend films were then determined using FTIR, SEM and TGA. It was found that by varying the ratio of Thai silk to cellulose, the thermal and physical properties of the material could be tuned. Blended films tended to be more thermally stable which could be due to the presence of hydrophobic hydrophobic or electrostatic interactions between the silk and cellulose. These studies offered a new pathway to understand the tunable properties of protein polysaccharide composite biomaterials with controllable physical and biological properties. PMID- 28666829 TI - Epigallocatechin gallate, an active green tea compound inhibits the Zika virus entry into host cells via binding the envelope protein. AB - Emerging infections of Zika virus (ZIKV) are associated with serious consequences like microcephaly and Guillain-Barre syndrome. It leads to a situation of global health emergency and demand an intensive research investigation to develop safe and effective therapeutics. Various efforts have been made to reduce the pathological pressure of ZIKV, but no effective drug has been introduced against ZIKV infections. A recent study has reported the inhibition of ZIKV entry into the host cells by an active green tea ingredient, Epigallocatechin Gallate (EGCG) in Vero E6cells. The effect of EGCG seems remarkable but lacking the information of the mechanism of action. In this study, we have investigated the binding site (Site1) of EGCG on envelope protein and provided the insights into various interactions of molecule with the binding site using molecular docking studies. Further, using molecular dynamics approaches we proposed the possible associated mechanism of inhibition of ZIKV entry by EGCG molecule. EGCG has found to interact with several residues and providing stability to the protein conformations up to 50ns simulations. PMID- 28666830 TI - Sophora subprosrate polysaccharide inhibited cytokine/chemokine secretion via suppression of histone acetylation modification and NF-kappab activation in PCV2 infected swine alveolar macrophage. AB - In the present study, effect of Sophora subprosrate polysaccharide on PCV2 infection-induced inflammation and histone acetylation modification in swine alveolar macrophage 3D4/2 cells was described for the first time. The relationship between histone acetylation modifications and inflammation response was investigated. The results showed that PCV2 infection induced inflammation by promoting the secretion of TNF-alpha, IL-1beta, IL-6 and IL-10 in 3D4/2 cells. The production of TNF-alpha, IL-1beta and IL-6 and their mRNA expression levels markedly decreased while the level and mRNA expression of IL-10 were elevated when the cells were treated with Sophora subprosrate polysaccharide. The SSP also decreased the activity of HATs, histone H3 acetylation (Ac-H3) and histone H4 acetylation (Ac-H4), p65 phosphorylation (P-p65) in the cells infected with PCV2 while HDACs activity was down-regulated, which involved in the inhibitory effect of SSP on histone acetylation and NF-kappaB signaling pathways activation. Down regulation of HAT1 mRNA expression and up-regulation of HDAC1 mRNA expression further support the inhibitory effect of SSP on histone acetylation. In conclusion, Sophora subprosrate polysaccharide antagonized inflammatory responses induced by PCV2, via mechanisms involved in histone acetylation and NF-kappaB signaling pathways. PMID- 28666831 TI - Steroidogenic acute regulatory protein (StAR) gene expression construct: Development, nanodelivery and effect on reproduction in air-breathing catfish, Clarias batrachus. AB - Steroidogenic acute regulatory protein (StAR) is responsible for the relocation of cholesterol across mitochondrial membrane in vertebrates and is, therefore, a key factor in regulating the rate and timing of steroidogenesis. In the present study, we developed chitosan nanoparticle (CNP) conjugated StAR gene construct (CNP-pcDNA4-StAR) in a eukaryotic expression vector, pcDNA4/HisMax A. CNPs of 135.4nm diameter, 26.7mV zeta potential and 0.381 polydispersity index were used for conjugation. The loading efficiency (LE) of pcDNA4-StAR construct with CNPs was found to be 86%. After the 24h of intramuscular injection, the CNP-pcDNA4 StAR plasmid could be detected from testis, brain, kidney and muscle tissues of Clarias batrachus. The transcript levels of important reproductive genes viz. cyp11a1, cyp17a1, 3beta-hsd, 17beta-hsd and cyp19a1 in CNP-pcDNA4-StAR treated group were initially low up to 24h, but significantly increased subsequently up to 120h. In naked pcDNA4-StAR treated group, the mRNA level of 3beta-hsd, 17beta hsd and cyp19a1 increased initially up to 24h, while cyp11a1 and cyp17a1 increased up to 48h and then started declining. Similar results were obtained for 11-Ketotestosterone and 17beta-estradiol. The results indicate relatively long lasting effects of nano-conjugated construct compared to the construct alone. Furthermore, the histopathology of gonads and liver authenticates its possible role in the gonadal development in fish without any adverse effect. PMID- 28666827 TI - Physical exercise as an epigenetic modulator of brain plasticity and cognition. AB - A large amount of evidence has demonstrated the power of exercise to support cognitive function, the effects of which can last for considerable time. An emerging line of scientific evidence indicates that the effects of exercise are longer lasting than previously thought up to the point to affect future generations. The action of exercise on epigenetic regulation of gene expression seem central to building an "epigenetic memory" to influence long-term brain function and behavior. In this review article, we discuss new developments in the epigenetic field connecting exercise with changes in cognitive function, including DNA methylation, histone modifications and microRNAs (miRNAs). The understanding of how exercise promotes long-term cognitive effects is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders. PMID- 28666832 TI - Nano cellulose dispersed chitosan film with Ag NPs/Curcumin: An in vivo study on Albino Rats for wound dressing. AB - With an aim to develop chitosan film with controllable swelling behavior and maximum antimicrobial efficacy, we hereby report cellulose nano crystals loaded chitosan films with Curcumin/Ag nano particles embedded as strong antimicrobial agents. The CNC had average size of 40-90nm with poly dispersity index of 3.641. The TEM analysis of Ag NPs, produced via DMF reduction, revealed a particle size range of 15-25nm. The Surface Plasmon resonance (SPR) of these Ag NPs shifted from 380 to 440nm, with the increase in concentration of Ag (I). The TGA of the film samples Ch/CNC, and Ch/CNC (Ag463/Cur450) exhibited% weight loss of around 95 and 80 respectively, thus indicating higher stability due to presence of Ag NPs. In XRD analysis 2theta reflections at 38.12, 44.28 and 66.46 degrees , confirmed the presence planes (1 1), (2 0) and (2 0) respectively. In skin irritation test, the mean Erythema scores observed after 72h was zero for both the Curcumin and Ag NPs/Curcumin loaded films. The percent wound reduction, observed for the film samples Ch/CNC (Cur450) and Ch/CNC (Ag NP463/Cur450) was 57.8 and 97.2 respectively, indicating better suitability of Ag NPs/Curcumin loaded film. PMID- 28666833 TI - Ludwigia octovalvis extract improves glycemic control and memory performance in diabetic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ludwigia octovalvis (Jacq.) P.H. Raven (Onagraceae) extracts have historically been consumed as a healthful drink for treating various conditions, including edema, nephritis, hypotension and diabetes. AIM OF THE STUDY: We have previously shown that Ludwigia octovalvis extract (LOE) can significantly extend lifespan and improve age-related memory deficits in Drosophila melanogaster through activating AMP-activated protein kinase (AMPK). Since AMPK has become a critical target for treating diabetes, we herein investigate the anti-hyperglycemic potential of LOE. MATERIALS AND METHODS: Differentiated C2C12 muscle cells, HepG2 hepatocellular cells, streptozotocin (STZ)-induced diabetic mice and high fat diet (HFD)-induced diabetic mice were used to investigate the anti-hyperglycemic potential of LOE. The open field test and novel object recognition test were used to evaluate spontaneous motor activity and memory performance of HFD-induced diabetic mice. RESULTS: In differentiated C2C12 muscle cells and HepG2 hepatocellular cells, treatments with LOE and its active component (beta-sitosterol) induced significant AMPK phosphorylation. LOE also enhanced uptake of a fluorescent glucose derivative (2-NBDG) and inhibited glucose production in these cells. The beneficial effects of LOE were completely abolished when an AMPK inhibitor, dorsomorphin, was added to the culture system, suggesting that LOE requires AMPK activation for its action in vitro. In streptozotocin (STZ)-induced diabetic mice, we found that both LOE and beta-sitosterol induced an anti-hyperglycemic effect comparable to that of metformin, a drug that is commonly prescribed to treat diabetes. Moreover, LOE also improved glycemic control and memory performance of mice fed a HFD. CONCLUSIONS: These results indicate that LOE is a potent anti-diabetic intervention that may have potential for future clinical applications. PMID- 28666834 TI - A review of traditional and current methods used to potentially reduce toxicity of Aconitum roots in Traditional Chinese Medicine. AB - CONTEXT: Aconitum species are well-known for their medicinal value and high lethal toxicity in many Asian countries, notably China, India and Japan. The tubers are only used after processing in Traditional Chinese Medicine (TCM). They can be used safely and effectively with the methods of decoction, rational compatibility, and correct processing based on traditional experiences and new technologies. However, high toxicological risks still remain due to improper preparation and usage in China and other countries. Therefore, there is a need to clarify the methods of processing and compatibility to ensure their effectiveness and minimize the potential risks. OBJECT: The aim of this paper is to provide a review of traditional and current methods used to potentially reduce toxicity of Aconitum roots in TCM. MATERIALS AND METHODS: The use of Aconitum has been investigated and the methods of processing and compatibility throughout history, including recent research, have been reviewed. RESULTS AND CONCLUSIONS: Using of the methods of rational preparation, reasonable compatibility, and proper processing based on traditional experiences and new technologies, can enable Aconitum to be used safely and effectively. PMID- 28666835 TI - The mitochondrial VDAC of bean seeds recruits phosphatidylethanolamine lipids for its proper functioning. AB - The voltage-dependent anion-selective channel (VDAC) is the main pathway for inorganic ions and metabolites through the mitochondrial outer membrane. Studies recently demonstrated that membrane lipids regulate its function. It remains, however, unclear how this regulation takes place. In this study, we show that phospholipids are key regulators of Phaseolus VDAC function and, furthermore, that the salt concentration modulates this regulation. Both selectivity and voltage dependence of Phaseolus VDAC are very sensitive to a change in the lipid polar head from PC to PE. Interestingly enough, this dependence is observed only at low salt concentration. Furthermore, significant changes in VDAC functional properties also occur with the gradual methylation of the PE group pointing to the role of subtle chemical variations in the lipid head group. The dependence of PcVDAC gating upon the introduction of a small mole fraction of PE in a PC bilayer has prompted us to propose the existence of a specific interaction site for PE on the outer surface of PcVDAC. Eventually, comparative modeling and molecular dynamics simulations suggest a potential mechanism to get insight into the anion selectivity enhancement of PcVDAC observed in PE relative to PC. PMID- 28666836 TI - Flibanserin Efficacy and Safety in Premenopausal Women With Generalized Acquired Hypoactive Sexual Desire Disorder. AB - INTRODUCTION: Flibanserin is a postsynaptic 5-HT-1A agonist and 5-HT-2A antagonist for the treatment of generalized acquired hypoactive sexual desire disorder in premenopausal women. AIM: To review and evaluate the efficacy and safety of flibanserin. METHODS: We review and critique the appropriateness of the co-primary and secondary end points used in the flibanserin pivotal trial research program. We review the efficacy and safety parameters of this drug based on the published literature and related sources. MAIN OUTCOME MEASURES: Pivotal trial primary and secondary end points and safety profile data from the flibanserin development program. RESULTS: Our review identified instances of poor fit of two primary trial pivotal trial end points with the hypoactive sexual desire disorder construct: satisfying sexual events and electronic daily diary assessments of the most intense level of sexual desire experienced each day. Efficacy findings of the flibanserin pivotal trials program were positive for satisfying sexual events, not positive for electronic daily diary assessments of the most intense level of sexual desire experienced, and positive for secondary end points of the Female Sexual Function Index desire domain and overall measurements and the Female Sexual Distress Scale-Revised desire-specific and overall measurements. Safety data from the clinical trial program showed a reasonable safety profile. CONCLUSION: Flibanserin has demonstrated efficacy on appropriate measurements of the hallmarks of hypoactive sexual desire disorder experience of absent or decreased sexual desire that is persistent over time and distressing-and the safety profile of flibanserin is acceptable. Fisher WA, Pyke RE. Flibanserin Efficacy and Safety in Premenopausal Women With Generalized Acquired Hypoactive Sexual Desire Disorder. Sex Med Rev 2017:5;445-460. PMID- 28666838 TI - MMP-2: A modulator of neuronal precursor activity and cognitive and motor behaviors. AB - Matrix Metalloproteinase2, (MMP2, gelatinase A) is a zinc-containing enzyme with a broad substrate specificity including components of the extracellular matrix, cell surface molecules and a wide range bioactive molecules. MMP2 is known to play important roles in a variety of signaling pathways and processes in a wide range of cell types and tissues. In this report we elucidate the effects of the absence of MMP2 in Neural Precursor Cells (NPC) derived from C57BL/6 MMP2 KO mice and in primary and secondary neurosphere formation. We observed smaller neurosphere numbers and sizes, decreased NPC numbers, PCNA expression, DNA and Akt activation in MMP2 KO NPC compared to WT NPC. We also found decreased neurosphere formation and NPC migration outward from adherent neurospheres, decreased CXCR4 and nestin expression and increased GFAP and neuro-filament expression in MMP2 KO NPC compared to Wt NPC. MMP2 KO mice were found to exhibit increased anxiety manifested in open field activity assays compared to Wt mice. MMP2 KO mice also exhibited differences in motor activities manifested by decreased balance and endurance during Rota-rod testing. These studies illustrate an important role of MMP2 in cognitive and motor behaviors and confirm its importance in NPC activities crucial to brain development, growth and response to and recovery from injury. PMID- 28666839 TI - Dopamine transporter (DAT1/SLC6A3) polymorphism and the association between being born small for gestational age and symptoms of ADHD. AB - Being small for gestational age (SGA) has been established as a risk factor for Attention Deficit Hyperactivity Disorder (ADHD). Likewise, several molecular genetic studies have found a link between DAT1 and ADHD. This study investigated whether SGA moderates the effect of dopamine transporter gene variants on the risk of ADHD. A total of 546 children of European descent were genotyped at age 11 for seven DAT1 SNPs (rs6347, rs11564774, rs40184, rs1042098, rs2702, rs8179029 and rs3863145). The Strengths and Difficulties Questionnaire was used to measure symptoms of ADHD at ages 3.5, 7 and 11. We found significant gene-environment interactions between birth weight and DAT1 SNPs (rs6347, rs40184, rs1042098, rs3863145) on ADHD symptoms at 3.5 years only. Results suggest that genotypic variation of DAT1 may confer a relative protective effect against ADHD in SGA individuals. This study supports the idea that being born SGA moderates the effect of the DAT1 gene on ADHD symptoms in the preschool years and may help to explain some of the heterogeneity in ADHD outcomes. PMID- 28666837 TI - Operant responding for optogenetic excitation of LDTg inputs to the VTA requires D1 and D2 dopamine receptor activation in the NAcc. AB - Behavioral studies in rats and mice indicate that laterodorsal tegmental nucleus (LDTg) inputs to the ventral tegmental area (VTA) importantly contribute to reward function. Further evidence from anesthetized rat and mouse preparations suggests that these LTDg inputs may exert this effect by regulating mesolimbic dopamine (DA) signaling. Direct evidence supporting this possibility remains lacking however. To address this lack, rat LDTg neurons were transfected with adeno-associated viral vectors encoding channelrhodopsin2 and eYFP (ChR2) or eYFP alone (eYFP) and rats were subsequently trained to lever press for intracranial self-stimulation (ICSS) of the inputs of these neurons to the VTA. First, we found that DA overflow in the forebrain nucleus accumbens (NAcc) increased maximally during ICSS to approximately 240% of baseline levels in ChR2, but not in eYFP, rats. Based on these findings, we next tested the contribution of NAcc D1 and D2 DA receptors to the reinforcing effects of optogenetic excitation of LDTg inputs to the VTA. Microinjecting SCH23390 or raclopride, D1 and D2 DA receptor antagonists respectively, into the NAcc significantly reduced operant responding for this stimulation. Together these results demonstrate for the first time that optogenetic ICSS of LDTg inputs to the VTA increases DA overflow in the NAcc and requires activation of D1 and D2 DA receptors in this site. PMID- 28666841 TI - Synthesis and characterization of ZrO2 nanoparticles-antimicrobial activity and their prospective role in dental care. AB - Nanomaterials are exerting a pull on deal with biological and pharmaceutical applications. Biomedical grade of zirconia reveals potential mechanical features of oxide ceramics. In this study, antimicrobial activity and anti-tooth decay applications of the synthesized NPs of ZrO2 were determined. The as-prepared ZrO2 NPs were characterized by UV-vis spectroscopy, FTIR and XRD, which determined the formation of ZrO2NPs and their crystalline nature. SEM analysis further revealed spherical shaped NPs and TEM analysis determined the size of the particles in the range of 15-21 nm, respectively. The antimicrobial activity of different concentrations of the synthesized ZrO2NPs was examined against gram positive bacteria (Bacillus subtilis and Staphylococcus aureus), gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa), respectively. The synthesized ZrO2NPs displayed a better inhibitory action against Pseudomonas aeruginosa (inhibition zone size of 20 mm) at the concentration of 100 MUg/ml compared to other bacteria due to the negatively charged P. aeruginosa cell wall readily attracting positively charged ZrO2NPs and thereby inhibiting microbial actions. Moreover, the concentration of ZrO2NPs was directly proportional to their inhibitory actions against the tested microorganisms. Finally, the preventive role of ZrO2NPs in a tooth decay pathway has been elucidated. Hence, it could be concluded that the as-prepared ZrO2NPs possess viable biomedical applications. PMID- 28666842 TI - Risk factors for Neospora caninum infection in dairy cattle and their possible cause-effect relation for disease. AB - Neospora caninum causes reproductive problems in cattle such as abortion, premature birth, retention of fetal membranes, and metritis. Therefore, this study aimed to verify possible risk factors for N. caninum infection in dairy cattle and their cause-effect relation to neosporosis. Serum samples of 1518 dairy cows from the West of Santa Catarina State, Southern Brazil were analyzed by indirect immunofluorescence assay (IFA) for N. caninum, where 466 were found to be positives (30.69%-CI95%; 28.3-33.0). In addition, an epidemiological survey was conducted in order to verify possible risk factors for neosporosis and their relation to the disease. The presence of dogs in the farm was strongly associated with IFA positive results for N. caninum, and lack of history for neosporosis in the farm increased the chances of positivity in 66%. It was found a significant cause-effect relation between the occurrence of reproductive problems and the presence of antibodies against N. caninum (p = 0.05). It is possible to conclude that N. caninum is widely distributed in dairy farms of the Western part of Santa Catarina state, Brazil, and that the occurrence of reproductive problems is directly related to the disease with the presence of dogs as a risk factor for N. caninum infection. PMID- 28666840 TI - Behavioral activation sensitivity and default mode network-subgenual cingulate cortex connectivity in youth. AB - Increased resting-state functional connectivity (rsFC) between the default mode network (DMN) and subgenual anterior cingulate cortex (sgACC) is consistently reported in adults and youth with psychopathologies related to affect dysregulation (e.g. depression, posttraumatic stress disorder). This pattern of increased rsFC is thought to underlie ruminative thought patterns through integration of negative affect (via sgACC) into self-referential operations supported by the DMN. Neurobiological studies in adults show that behavioral activation system (BAS) sensitivity is a potential protective factor against the development of psychopathology, particularly in the context of stress and trauma exposure. However, whether BAS sensitivity is associated with variation in DMN sgACC stress-vulnerability circuitry in youth, particularly those at risk for affect dysregulation, has not yet been studied. This association was tested in a sample of ninety-eight children and adolescents (ages 6-17) at high sociodemographic risk for psychopathology (i.e., urban, lower income, high frequency of violence and abuse exposure). Participants underwent a six-minute resting-state functional magnetic resonance imaging scan. Using a targeted, small volume corrected approach, we found that youth with higher BAS sensitivity demonstrated lower DMN-sgACC rsFC, suggesting a potential link between the purported protective effects of BAS sensitivity and stress-vulnerability circuitry. This work suggests that interventions that augment BAS sensitivity, such as behavioral activation therapy, may protect against the development of stress-related psychopathology by modifying a critical rumination circuitry in the brain. Such interventions may be especially important for bolstering resiliency in at-risk urban youth, who are disproportionately burdened by early stress and associated psychopathology. PMID- 28666843 TI - Downregulated regulatory T cell function is associated with increased peptic ulcer in Helicobacter pylori-infection. AB - BACKGROUND: Helicobacter pylori (H. pylori) chronically colonizes gastric/duodenal mucosa and induces gastroduodenal disease such as gastritis and peptic ulcer and induces vigorous innate and specific immune responses; however, the infection is not removed, a state of chronic active gastritis persists for life if untreated. The objective of this study was to determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis and peptic ulcer and determined the relationship between main virulence factor of H. pylori and Tregs. METHODS AND MATERIALS: A total of 89 patients with gastritis, 63 patients with peptic ulcer and 40 healthy, H. pylori-negative subjects were enrolled in this study. Expression of CD4 and Foxp3 was determined by immunohistochemistry. Antrum biopsy was obtained for detection of H. pylori, bacterial virulence factors and histopathological assessments. TGF-beta1, IL-10 and FOXP3 expressions were determined by real-time polymerase chain reaction (qPCR). RESULTS: The numbers of CD4+ and Foxp3+ T cells as well as the expression of IL-10, TGF-beta1, FOXP3, INF-gamma and IL-17A in infected patients were significantly higher than the ones in uninfected patients. Also, the number of CD4+ T cells was independent on the vacuolating cytotoxin A (vacA) and outer inflammatory protein A (oipA), but it was positively correlated with cytotoxin associated gene A (cagA). Instead, the number of Foxp3+ T cells was dependent on the vacA and oipA, but it was independent on cagA. The number of Foxp3+ T cells and the expression of IL-10, TGF-beta1 and FOXP3 in infected patients with gastritis were significantly higher than the ones in infected patients with peptic ulcer. Moreover, the number of CD4+ T cells and the expression of IL-17A and INF-gamma was the lowest in the gastritis patients, however, increased progressively in the peptic ulcer patients. Additionally, the numbers of CD4+ and Foxp3+ T cells as well as the expression of IL-10, TGF-beta1, FOXP3 and INF-gamma were positively correlated with the degree of H. pylori density and chronic inflammation. CONCLUSION: Tregs are positively associated with vacA alleles and oipA status of H. pylori and histological grade but negatively associated with peptic ulcer disease. PMID- 28666844 TI - Esculentoside A inhibits LPS-induced acute kidney injury by activating PPAR gamma. AB - Acute kidney injury (AKI) is a major clinical problem associated with high morbidity and mortality. Esculentoside A (EsA), a kind of saponin isolated from the root of the Chinese herb Phytolaca esculenta, has been reported to have anti inflammatory effect. In this study, we aimed to investigate the protective effects of EsA on LPS-induced AKI in mice. The protective effects of EsA was evaluated by detecting kidney histological change, blood urea nitrogen (BUN) and creatinine levels, and inflammatory cytokines production. The results showed that EsA significantly attenuated LPS-induced kidney histological change, as well as BUN and creatinine levels. EsA also inhibited LPS-induced TNF-alpha, IL-1beta, and IL-6 production. LPS-induced NF-kappaB activation was significantly suppressed by treatment of EsA. In addition, EsA up-regulated the expression of PPAR-gamma in a dose-dependent manner. In conclusion, EsA protected mice effectively from LPS-induced AKI by PPAR-gamma, which subsequently inhibited LPS induced inflammatory response. PMID- 28666845 TI - A systematic review of studies comparing conventional complete denture and implant retained overdenture. AB - PURPOSE: Several studies reported better outcomes when restoring edentulous mandible with unsplinted IODs compared to CCDs; however, it is not clear if these outcomes remain when the full literature is considered. The aim of this systematic review is to compare conventional complete dentures (CCDs) to unsplinted implant-retained overdentures (IODs) with regard to efficacy, satisfaction and quality of life. STUDY SELECTION: The main question addressed was: How do CCDs compare to unsplinted IODs with regard to efficacy, satisfaction and quality of life? Three databases were electronically searched to identify articles comparing CCD to unsplinted IOD. Twenty-six articles were selected and reviewed in full. Of these selected articles, twenty-five compared CCDs restoring function in both arches to a maxillary CCD opposing a mandibular IOD retained by two unsplinted implants. Only one articles compared a maxillary CCDs to a maxillary IOD. RESULTS: Outcome measures varied among the studies, including the Oral Health Impact Profile (OHIP), visual analogue scales (VAS), and masticatory performance tests. Overall, IODs were associated with significantly better patient's masticatory performance and quality of life as indicated by Oral Health as Related to Quality of Life (OHRQoL). Mandibular unsplinted IODs were more likely than CCDs to be associated with improved OHRQoL for edentulous patients and were associated with significantly higher ratings of overall satisfaction, comfort, stability, ability to speak and ability to chew. CONCLUSIONS: Results of this systematic review indicate the superiority of IODs retained by two unsplinted mandibular implants when compared to CCDs with regards to efficacy, satisfaction and quality of life. PMID- 28666846 TI - [3D printing in neurosurgery: a specific model for patients with craniosynostosis]. AB - INTRODUCTION: Craniosynostosis is a rare condition and requires a personalised surgical approach, which is why we consider the use of 3D printed models beneficial in the surgical planning of this procedure. MATERIAL AND METHODS: Acrylonitrile butadiene styrene plastic skull models were designed and printed from CT images of patients between 3 and 6 months of age with craniosynostosis of different sutures. The models were used to simulate surgical procedures. RESULTS: Four models of four patients with craniosynostosis were produced: two with closure of the metopic suture and two with sagittal suture closure. The mean age of the patients was 5 months (3-6m) and the mean duration of the surgery was 286min (127-380min). The acrylonitrile butadiene styrene plastic models printed for the project proved to be optimal for the simulation of craniosynostosis surgeries, both anatomically and in terms of mechanical properties and reaction to surgical instruments. CONCLUSIONS: 3D printers have a wide range of medical applications and they offer an easy and affordable way to produce skull models. The acrylonitrile butadiene styrene material is suitable for the production of operable bone models as it faithfully reproduces the mechanical characteristics of bone tissue. PMID- 28666847 TI - Eicosapentaenoic acid modulates the synergistic action of CREB1 and ID/E2A family members in the rat pup brain and mouse embryonic stem cells. AB - The aim of this study was to investigate the molecular mechanism by which eicosapentaenoic acid (EPA) may exert neuroprotective effects through an "EPA cyclic AMP response element-binding protein (CREB)" signaling pathway. The current study reveals that EPA modulates the exquisite interplay of interaction of CREB1 with the inhibitor of DNA binding (ID) and E2A family members, thereby delivering mechanistic insights into specific neural differentiation program. In this scenario, our work provides evidence for the capability of CREB1 to sequester ID:E2A family members in brain tissues and neural differentiating mouse embryonic stem cells (mESCs) through formation of a [CREB1]2:ID2:E47 tetrameric complex.In essence, the molecular function of CREB1 is to dynamically regulate the location-specific assembly or disassembly of basic-helix-loop-helix (bHLH):HLH protein complexes to mediate the activation of neural/glial target genes. Together, these findings support the one-to-many binding mechanism of CREB1 and indicate that EPA treatment potentiates the integration of CREB dependent signaling with HLH/bHLH transcriptional network, adding specificity to the CREB1-mediated gene regulation during neural/glial differentiation. Our current research on the EPA-CREB axis could reveal new molecular targets for treating neurogenerative disease. PMID- 28666848 TI - A randomized crossover study of the effects of lidocaine on motor- and sensory evoked potentials during spinal surgery. AB - BACKGROUND CONTEXT: Lidocaine has emerged as a useful adjuvant anesthetic agent for cases requiring intraoperative monitoring of motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SSEPs). A previous retrospective study suggested that lidocaine could be used as a component of propofol-based intravenous anesthesia without adversely affecting MEP or SSEP monitoring, but did not address the effect of the addition of lidocaine on the MEP and SSEP signals of individual patients. PURPOSE: The purpose of this study was to examine the intrapatient effects of the addition of lidocaine to balanced anesthesia on MEPs and SSEPs during multilevel posterior spinal fusion. STUDY DESIGN: This is a prospective, two-treatment, two-period crossover randomized controlled trial with a blinded primary outcome assessment. PATIENT SAMPLE: Forty patients undergoing multilevel posterior spinal fusion were studied. OUTCOME MEASURES: The primary outcome measures were MEP voltage thresholds and SSEP amplitudes. Secondary outcome measures included isoflurane concentrations and hemodynamic parameters. METHODS: Each participant received two anesthetic treatments (propofol 50 mcg/kg/h and propofol 25 mcg/kg/h+lidocaine 1 mg/kg/h) along with isoflurane, ketamine, and diazepam. In this manner, each patient served as his or her own control. The order of administration of the two treatments was determined randomly. RESULTS: There were no significant within-patient differences between MEP threshold voltages or SSEP amplitudes during the two anesthetic treatments. CONCLUSIONS: Lidocaine may be used as a component of balanced anesthesia during multilevel spinal fusions without adversely affecting the monitoring of SSEPs or MEPs in individual patients. PMID- 28666849 TI - The indications of tautomeric conversion in amorphous bicalutamide drug. PMID- 28666851 TI - Cold atmospheric plasma restores tamoxifen sensitivity in resistant MCF-7 breast cancer cell. AB - Cancer recurrence, which is frequently accompanied by chemotherapy, has been a challenge in cancer treatment. This study was carried out to examine the potential applications of the reactive oxygen species (ROS)-producing cold atmospheric plasma (CAP) to overcome the cancer cells' drug resistance, which has been emerging as an alternative therapeutic tool for cancer. For this, we developed a tamoxifen (Tam)-resistant MCF-7 (MCF-7/TamR) breast cancer cell model and examined the effect of CAP on the recovery of Tam sensitivity at the cellular and molecular level. The ROS level was increased 1.9-fold in CAP-treated MCF 7/TamR cells compared to the non-treated cell. CAP was proven to restore sensitivity by up to 50% for MCF-7/TamR cells against Tam after CAP treatment. The comparison of genome-wide expression between the acquisition of Tam resistance and CAP treatment identified 20 genes that commonly showed significant expression changes. Notably, all the genes except two have been oppositely dysregulated in the two cellular statuses, and the majority of them are known to contribute to the acquisition of Tam resistance. The protein expression of selected genes, MX1 and HOXC6, was recovered to that of their parental cell by CAP. Furthermore, the dysregulation of MX1 and HOXC6 in MCF-7/TamR alleviated the drug sensitivity recovery effect of CAP. Taken together, CAP inhibited the growth of Tam-resistant MCF-7 cancer cells and reset it to the Tam-sensitive status by restoring the expression of drug resistance-related genes. These findings may lend credence to CAP as an alternative or complementary tool in the treatment or prevention of Tam-resistant cancer. PMID- 28666850 TI - Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes. AB - Previously published studies strongly suggested that insulin- and exercise induced skeletal muscle glucose uptake require nitric oxide (NO) production. However, the signal transduction mechanisms by which insulin and contraction regulated NO production and subsequent glucose transport are not known. In the present study, we utilized the myotube cell lines treated with insulin or hydrogen peroxide, the latter to mimic contraction-induced oxidative stress, to characterize these mechanisms. We found that insulin stimulation of neuronal nitric oxide synthase (nNOS) phosphorylation, NO production, and GLUT4 translocation were all significantly reduced by inhibition of either nNOS or Akt2. Hydrogen peroxide (H2O2) induced phosphorylation of nNOS at the same residue as did insulin, and also stimulated NO production and GLUT4 translocation. nNOS inhibition prevented H2O2-induced GLUT4 translocation. AMP activated protein kinase (AMPK) inhibition prevented H2O2 activation and phosphorylation of nNOS, leading to reduced NO production and significantly attenuated GLUT4 translocation. We conclude that nNOS phosphorylation and subsequently increased NO production are required for both insulin- and H2O2 stimulated glucose transport. Although the two stimuli result in phosphorylation of the same residue on nNOS, they do so through distinct protein kinases. Thus, insulin and H2O2-activated signaling pathways converge on nNOS, which is a common mediator of glucose uptake in both pathways. However, the fact that different kinases are utilized provides a basis for the use of exercise to activate glucose transport in the face of insulin resistance. PMID- 28666852 TI - A comparison of DNA fragmentation methods - Applications for the biochip technology. AB - The efficiency of hybridization signal detection in a biochip is affected by the method used for test DNA preparation, such as fragmentation, amplification and fluorescent labelling. DNA fragmentation is the commonest methods used and it is recognised as a critical step in biochip analysis. Currently methods used for DNA fragmentation are based either on sonication or on the enzymatic digestion. In this study, we compared the effect of different types of enzymatic DNA fragmentations, using DNase I to generate ssDNA breaks, NEBNext dsDNA fragmentase and SaqAI restrictase, on DNA labelling. DNA from different Desulfovibrio species was used as a substrate for these enzymes. Of the methods used, DNA fragmented by NEBNext dsDNA Fragmentase digestion was subsequently labelled with the greatest efficiency. As a result of this, the use of this enzyme to fragment target DNA increases the sensitivity of biochip-based detection significantly, and this is an important consideration when determining the presence of targeted DNA in ecological and medical samples. PMID- 28666853 TI - Recombinant bovine growth hormone (rBGH) enhances somatic growth by regulating the GH-IGF axis in fingerlings of gilthead sea bream (Sparus aurata). AB - The growth hormone (GH)/insulin-like growth factors (IGFs) endocrine axis is the main growth-regulator system in vertebrates. Some authors have demonstrated the positive effects on growth of a sustained-release formulation of a recombinant bovine GH (rBGH) in different fish species. The aim of this work was to characterize the effects of a single injection of rBGH in fingerlings of gilthead sea bream on growth, GH-IGF axis, and both myogenic and osteogenic processes. Thus, body weight and specific growth rate were significantly increased in rBGH treated fish respect to control fish at 6weeks post-injection, whereas the hepatosomatic index was decreased and the condition factor and mesenteric fat index were unchanged, altogether indicating enhanced somatic growth. Moreover, rBGH injection increased the plasma IGF-I levels in parallel with a rise of hepatic mRNA from total IGF-I, IGF-Ic and IGF-II, the binding proteins IGFBP-1a and IGFBP-2b, and also the receptors IGF-IRb, GHR-I and GHR-II. In skeletal muscle, the expression of IGF-Ib and GHR-I was significantly increased but that of IGF-IRb was reduced; the mRNA levels of myogenic regulatory factors, proliferation and differentiation markers (PCNA and MHC, respectively), or that of different molecules of the signaling pathway (TOR/AKT) were unaltered. Besides, the growth inhibitor myostatin (MSTN1 and MSTN2) and the hypertrophic marker (MLC2B) expression resulted significantly enhanced, suggesting altogether that the muscle is in a non-proliferative stage of development. Contrarily in bone, although the expression of most molecules of the GH/IGF axis was decreased, the mRNA levels of several osteogenic genes were increased. The histology analysis showed a GH induced lipolytic effect with a clear decrease in the subcutaneous fat layer. Overall, these results reveal that a better growth potential can be achieved on this species and supports the possibility to improve growth and quality through the optimization of its culture conditions. PMID- 28666855 TI - The effects of migratory stage and 11-ketotestosterone on the expression of rod opsin genes in the shortfinned eel (Anguilla australis). AB - The androgen 11-ketotestosterone (11KT) can induce many of the changes associated with silvering, i.e., the transformation of a non-migrating 'yellow' eel into a migrating 'silver' eel. We posited that plasticity in spectral sensitivity of the eye, accompanied by expression of different opsins in the retina during silvering, is controlled by 11KT. To test this hypothesis, mRNA levels of freshwater (fwo) and seawater (swo) opsins and of the two androgen receptors (ara and arb) in retinas of wild-caught female shortfinned eels, Anguilla australis were compared. Swo expression was much higher (3-4 orders of magnitude) and fwo expression substantially lower in silver than in yellow eels, whereas mRNA levels of both ars did not differ between stages. Yellow eel retinas exposed to 11KT in vitro exhibited a robust dose-dependent increase in swo, but weak decreasing effects on fwo transcript abundance were inconsistent. Similarly, increased retinal swo expression was seen after in vivo treatment of yellow eels with 11KT implants, whereas expression of fwo remained unaffected. Lastly, co-treatment with 11KT and the androgen receptor blocker flutamide was undertaken to determine whether 11KT exerts its effects through nuclear androgen receptors. Flutamide did not block 11KT-affected expression of any target gene, neither in vivo nor in vitro. We conclude that 11KT greatly increases the abundance of swo, identifying the androgen as an important regulator of the opsin switch during silvering in freshwater eels. PMID- 28666854 TI - Small interfering RNA mediated knockdown of irisin suppresses food intake and modulates appetite regulatory peptides in zebrafish. AB - Irisin is a myokine encoded in fibronectin type III domain containing 5 (FNDC5). FNDC5 forms an integral part of the muscle post-exercise, and causes an increase in energy expenditure in mammals. Irisin is abundantly expressed in cardiac and skeletal muscles and is secreted upon activation of peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1 alpha). Irisin regulates feeding behaviour and cardiovascular function in mammals. More recently, irisin has gained importance as a potential biomarker for myocardial infarction due to its abundance in cardiac muscle. The goal of this research was to determine whether irisin influences feeding, and regulates appetite regulatory peptides in zebrafish. Intraperitoneal injection of irisin [0.1, 1, 10 and 100ng/g body weight (BW)] did not affect feeding, but its knockdown using siRNA (10ng/g BW) caused a significant reduction in food intake. Knockdown of irisin reduced ghrelin and orexin-A mRNA expression, and increased cocaine and amphetamine regulated transcript mRNA expression in zebrafish brain and gut. siRNA mediated knockdown of irisin also downregulated brain derived neurotrophic factor mRNA in zebrafish. The role of endogenous irisin on food intake is likely mediated by its actions on other metabolic peptides. Collectively, these results indicate that unaltered endogenous irisin is required to maintain food intake in zebrafish. PMID- 28666856 TI - Production of recombinant salmon insulin-like growth factor binding protein-1 subtypes. AB - Insulin-like growth factor (IGF)-I is a growth promoting hormone that exerts its actions through endocrine, paracrine and autocrine modes. Local IGF-I is essential for normal growth, whereas circulating IGF-I plays a crucial role in regulating the production and secretion of growth hormone (GH) by the pituitary gland. These actions of IGF-I are modulated by six insulin-like growth factor binding proteins (IGFBPs). In teleosts, two subtypes of each IGFBP are present due to an extra round of whole-genome duplication. IGFBP-1 is generally inhibitory to IGF-I action under catabolic conditions such as fasting and stress. In salmon, IGFBP-1a and -1b are two of three major circulating IGFBPs and assumed to affect growth through modulating IGF-I action. However, exact functions of salmon IGFBP-1 subtypes on growth regulation are not known due to the lack of purified or recombinant protein. We expressed recombinant salmon (rs) IGFBP-1a and -1b with a fusion protein (thioredoxin, Trx) and a His-tag using the pET 32a(+) vector expression system in Escherichia coli. Trx.His.rsIGFBP-1s were isolated by Ni-affinity chromatography, enzymatically cleaved by enterokinase to remove the fusion partners and further purified by reversed-phase HPLC. We next examined effects of rsIGFBP-1a and -1b in combination with human IGF-I on GH release from cultured masu salmon (Oncorhynchus masou) pituitary cells. Unexpectedly, IGF-I increased GH release and an addition of rsIGFBP-1a, but not rsIGFBP-1b, restored GH levels. The results suggest that IGFBP-1a can inhibit IGF I action on the pituitary in masu salmon. Availability of recombinant salmon IGFBP-1s should facilitate further functional analyses and assay development. PMID- 28666857 TI - Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase. AB - Marine meroterpenoids, thiaplidiaquinones A and B and their respective non natural dioxothiazine regioisomers have been shown to inhibit mammalian and protozoal farnesyltransferase (FTase) with the regioisomers exhibiting activity in the nanomolar range. In order to explore the structure-activity relationship (SAR) of this class of marine natural products, analogues of thiaplidiaquinones A and B and their regioisomers were synthesised, with variation in the number of isoprene units present in their side chains to afford prenyl and farnesyl analogues. The previously reported geranyl series of compounds were found to be the most potent FTase inhibitors closely followed by the novel farnesyl series. The prenyl series exhibited the most potent anti-plasmodial activity but the series was also the most cytotoxic. Overall, the farnesyl series exhibited moderate anti-plasmodial activity with one analogue, 14 also exhibiting low cytotoxicity, identifying it as a scaffold worthy of further exploration. PMID- 28666858 TI - Potent haloperidol derivatives covalently binding to the dopamine D2 receptor. AB - The dopamine D2 receptor (D2R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D2R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D2R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments. PMID- 28666859 TI - A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues. AB - Herein, we report the development of continuous flow photoreactors for large scale ESIPT-mediated [3+2]-photocycloaddition of 2-(p-methoxyphenyl)-3 hydroxyflavone and cinnamate-derived dipolarophiles. These reactors can be efficiently numbered up to increase throughput two orders of magnitude greater than the corresponding batch reactions. PMID- 28666860 TI - Novel 4-acetamide-2-alkylthio-N-acetanilides resembling nimesulide: Synthesis, cell viability evaluation and in silico studies. AB - Since nimesulide, a nonsteroidal anti-inflammatory drug, is known to be a selective inhibitor of cyclooxygenase-2 and shows activity against cancer cells, there has been much interest in developing related molecules with enhanced anticancer properties. Taking in consideration structural features of nimesulide analogues ten new ortho-(akylthio)-N-alkylacetanilides were synthesized and fully characterized. The antiproliferative effect of these acetanilides was evaluated against human breast (MCF-7) and prostate (LNCaP) cancer cell lines as well as normal human dermal fibroblasts (NHDF). In particular, acetoacetanilides with methylcyclohexyl and/or 2,4-dimethylbenzyl groups linked to amide group and/or to sulfur atom had interesting cytotoxicities against human breast cancer cells. Moreover, these groups caused an increase in the antiproliferative effect against both cancer cells. Docking studies revealed the possibility of these acetoacetanilides to be potential ligands of the androgen receptor, though hormone-independent mechanisms may be involved in antiproliferative effects shown by these acetoacetanilides. In addition, 3D-QSAR studies demonstrated that the cytotoxic activity against the human breast cancer cell line was dependent on both bulkiness and electrostatic nature of the N- and S-alkyl groups of acetoacetanilides. PMID- 28666861 TI - Derivation and validation of the prediabetes self-assessment screening score after acute pancreatitis (PERSEUS). AB - BACKGROUND AND AIM: Approximately 40% of patients develop abnormal glucose metabolism after a single episode of acute pancreatitis. This study aimed to develop and validate a prediabetes self-assessment screening score for patients after acute pancreatitis. METHODS: Data from non-overlapping training (n=82) and validation (n=80) cohorts were analysed. Univariate logistic and linear regression identified variables associated with prediabetes after acute pancreatitis. Multivariate logistic regression developed the score, ranging from 0 to 215. The area under the receiver-operating characteristic curve (AUROC), Hosmer-Lemeshow chi2 statistic, and calibration plots were used to assess model discrimination and calibration. The developed score was validated using data from the validation cohort. RESULTS: The score had an AUROC of 0.88 (95% CI, 0.80 0.97) and Hosmer-Lemeshow chi2 statistic of 5.75 (p=0.676). Patients with a score of >=75 had a 94.1% probability of having prediabetes, and were 29 times more likely to have prediabetes than those with a score of <75. The AUROC in the validation cohort was 0.81 (95% CI, 0.70-0.92) and the Hosmer-Lemeshow chi2 statistic was 5.50 (p=0.599). Model calibration of the score showed good calibration in both cohorts. CONCLUSION: The developed and validated score, called PERSEUS, is the first instrument to identify individuals who are at high risk of developing abnormal glucose metabolism following an episode of acute pancreatitis. PMID- 28666862 TI - Primary jejunal malignant melanoma detected by 18F-FDG PET/CT and enteroscopy. PMID- 28666863 TI - Evaluating the molecular, physiological and behavioral impacts of CO2 narcosis in bumble bees (Bombus impatiens). AB - Exposure to carbon dioxide (CO2) has pleiotropic effects in many insect species, ranging from eliciting rapid behavioral responses such as attraction, to dramatic physiological changes, including ovary activation. In bumble bees, CO2 narcosis causes queens to bypass diapause and initiate egg laying, but its mode of action is not well-understood. Here, we evaluated the effects of CO2 narcosis on the behavior, physiology and immune function of virgin bumble bee queens (Bombus impatiens). We tested the hypothesis that CO2 induces these changes by stimulating oxidative stress response pathways. We found that CO2 stimulates ovarian activation and egg production and suppresses lipid (but not glycogen) accumulation in virgin queens. Additionally, CO2 treated queens were more active (particularly in terms of flight) and performed, but did not receive, more aggressive behaviors compared to controls. Moreover, CO2 positively affected immune function in queens, reduced transcript levels of 5/6 antioxidant enzyme genes and had no effect on longevity. Thus, although CO2 treatment stimulated reproduction, we did not observe any evidence of a trade-off in queen health parameters, aside from a reduction in lipids. Overall CO2 narcosis does not appear to stimulate a typical stress response in virgin bumble bee queens. On the contrary, CO2 narcosis appears to stimulate changes that prepare queens to cope with the nutritional, metabolic and behavioral challenges associated with reproduction and colony-founding. PMID- 28666865 TI - Different beta-glucans improve the growth performance and bacterial resistance in Nile tilapia. AB - The role of glucan as a biologically active immunomodulator has been well documented for more than 40 years. However, the wide diversity of beta-glucan forms and the extraction process has implications for the benefits of these compounds. Biorigin developed two samples of beta-glucans using different biotechnological processes. Thus, in the present study, we fed Nile tilapia (Oreochromis niloticus) diets containing these two beta-glucan molecules (BG01 and BG02) for 30 days prior to bacterial infection with Streptococcus agalactiae. The results showed that the different beta-glucan samples exhibited biologically differently behaviors, but both increased the resistance against bacterial infection. Specifically, BG01 increased immunostimulation, while BG02 improved growth performance. In summary, these findings confirm the benefits of beta glucans in aquaculture and also provide further evidence of the growth promotion of these compounds. PMID- 28666864 TI - spv locus aggravates Salmonella infection of zebrafish adult by inducing Th1/Th2 shift to Th2 polarization. AB - Salmonella enterica serovar typhimurium (S. typhimurium) are facultative intracellular enteric pathogens causing disease with a broad range of hosts. It was known that Th1-type cytokines such as IFN-gamma, IL-12, and TNF-alpha etc. could induce protective immunity against intracellular pathogens, while Th2-type cytokines such as IL-4, IL-10, and IL-13 etc. are proved to help pathogens survive inside hosts and cause severe infection. One of the critical virulence factor attributes to the pathogenesis of S. typhimurium is Salmonella plasmid virulence genes (spv). Until now, the interaction between spv locus and the predictable generation of Th1 or Th2 immune responses to Salmonella has not been identified. In this study, zebrafish adults were employed to explore the effect of spv locus on Salmonella pathogenesis as well as host adaptive immune responses especially shift of Th1/Th2 balance. The pathological changes of intestines and livers in zebrafish were observed by hematoxylin-eosin (HE) staining and electron microscopy. Levels of the transcription factors of Th1 (Tbx21) and Th2 (GATA3) were measured by real-time quantitative PCR (RT-qPCR). Expression of cytokines were determined by using RT-qPCR and ELISA, respectively. Results showed that spv operon aggravates damage of zebrafish. Furthermore, it demonstrated that spv locus could inhibit the transcription of tbx21 gene and suppress the expression of cytokines IFN-gamma, IL-12 and TNF-alpha. On the contrary, the transcription of gata3 gene could be promoted and the expression of cytokines IL-4, IL-10 and IL-13 were enhanced by spv locus. Taken together, our data revealed that spv locus could aggravate Salmonella infection of zebrafish adult by inducing an imbalance of Th1/Th2 immune response and resulting in a detrimental Th2 bias of host. PMID- 28666866 TI - NMR uncovers direct interaction between human NEDD4-1 and p34SEI-1. AB - PTEN, an important tumor suppressor and a key regulator of the PI3K/AKT signaling pathway, is often deleted/mutated in different types of cancer. The E3 ubiquitin ligase NEDD4-1 catalyzes the polyubiquitination of PTEN, thereby acting as a negative regulator of PTEN. Stability of NEDD4-1, in turn, is tightly controlled by a 34 kDa oncoprotein, p34SEI-1 and it regulates PTEN degradation and activates PI3K/AKT pathway, resulting in cancer metastasis. p34SEI-1 affects not only the expression of NEDD4-1 during transcription and translation but also the subcellular localization of PTEN. This emphasizes the need to understand, at molecular level, the interaction between NEDD4-1 and p34SEI-1. A recent study showed that NEDD4-1 interacts with p34SEI-1 via its WWI domain. However, a detailed interaction for molecular level is yet unknown. We report that the WW1 domain of NEDD4-1 recognizes the SERTA domain containing the proline rich region (PRR motif) in p34SEI-1. TALOS analysis based on NMR data confirms three conserved beta-sheets in NEDD4-1 WW1 and the central beta-sheet of NEDD4-1 WW1 plays a role for protein stability by the backbone dynamics experiments. NMR titration data revealed the binding site for p34SEI-1 with NEDD4-1. Our data will provide insights into the molecular mechanism of NEDD4-1 and p34SEI-1 interaction, which will be directly used for drug design which inhibits the molecular interaction involved in different cancer signaling. PMID- 28666867 TI - Enhancement of TGF-beta-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP). AB - c-Abl is a non-receptor-type tyrosine kinase that plays an important role in cell proliferation, migration, apoptosis, and fibrosis. Furthermore, although c-Abl is involved in transforming growth factor-beta (TGF-beta) signaling, its molecular functions in TGF-beta signaling are not fully understood. Here, we found that c Abl phosphorylates SKI-interacting protein (SKIP), a nuclear cofactor of the transcription factor Smad3. The c-Abl inhibitor imatinib suppressed TGF-beta induced expression of Smad3 targets as well as SKIP/Smad3 interaction. TGF-beta stimulation induced tyrosine phosphorylation of SKIP, and this phosphorylation was suppressed by imatinib. Tyr292, Tyr430, and Tyr433 residues in SKIP were shown to be involved in c-Abl-mediated phosphorylation. Phosphomimetic glutamic acid substitution at Tyr292 in SKIP enhanced, whereas its phospho-dead phenylalanine substitution attenuated TGF-beta-induced SKIP/Smad3 interaction. Moreover, the phosphomimetic mutant of SKIP augmented transcriptional activity of Smad3. Taken together, these results suggest that c-Abl phosphorylates SKIP mainly at Tyr292 and promotes SKIP/Smad3 interaction for the full activation of TGF-beta/Smad3 signaling. PMID- 28666868 TI - The polyanionic C-terminal tail of human Rad17 regulates interaction with the 9-1 1 complex. AB - In the activation and maintenance of ATR-dependent DNA damage checkpoint, the interaction between the Rad17-RFC2-5 and 9-1-1 complexes is essential, however, the regulatory mechanism of the interaction is not known. Here we show that vertebrate Rad17 proteins contain a polyanionic 12-amino acid sequence in the C terminal ends that is important for the 9-1-1 interaction. We demonstrate that the C-terminal tail contains a conserved sequence designated iVERGE that must be intact for the 9-1-1 interaction and contains potential posttranslational modification sites. Our data raise a possibility that the Rad17 C-terminal tail is a molecular switch that regulates the 9-1-1 interaction and the ATR pathway. PMID- 28666869 TI - Celecoxib induced apoptosis against different breast cancer cell lines by down regulated NF-kappaB pathway. AB - Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the effect of Celecoxib, a COX-2 inhibitor on two molecular breast cancer subtypes-MDA-MB-231 and SK-BR-3. Firstly, MDA-MB-231 and SK-BR-3 cells were treated with various concentration of Celecoxib for 24 and 48 h. Celecoxib-inhibition of NF-kappaB (p52 and p65) transcriptional activity and effect of Caspase 3 pathway were examined by western blotting. COX-2 mRNA was assessed by RT-PCR. Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide (MTT) assay. Both cell cycle profiles and apoptosis were analyzed using flow cytometry. We found that Celecoxib inhibited the proliferation of the MDA-MB-231 cell line in a dose time dependent manner versus SK-BR-3 in a dose dependent manner only (p < 0.05). Celecoxib induced apoptosis of the MDA-MB-231 and SK-BR-3 cell lines in a dose time dependent manner (p < 0.05) with more mean apoptotic cells in MDA-MB-231 than SK-BR-3. Significant cell-cycle arrest at the G1 phase in the MDA-MB-231 versus G2 phase in SK-BR-3 cell lines. NF-kappaB (p52 and p65) and COX-2 expressions were downregulated in a dose dependent manner, while Caspase 3 expression was upregulated in both cell lines. In this present study, our data indicated Celecoxib might affect each breast cancer subtype independently. Therefore, when using Celecoxib in treatment of breast cancer, it is imperative to consider the subtype of breast cancer on a molecular level. PMID- 28666870 TI - A novel role for earthworm peptide Lumbricusin as a regulator of neuroinflammation. AB - Recently, we reported that Lumbricusin, an antimicrobial peptide isolated from earthworm Lumbricus terrestris, enhanced neuronal proliferation and ameliorated motor dysfunction and dopaminergic neurodegeneration. Accumulating evidence suggests that neurodegeneration is the primary pathological feature of acute or chronic inflammation mediated by microglia, the resident macrophage of the central nervous system. Therefore, microglial activation inhibitors may be useful as therapeutic agents for neurodegenerative diseases. To determine whether Lumbricusin ameliorates neuroinflammation through inhibition of microglial activation by lipopolysaccharides (LPS), we newly synthesized 9-mer Lumbricusin analogues based on the amino acid sequence of Lumbricusin. One of these, Lumbricusin Analogue 5 (LumA5; QLICWRRFR-NH2), markedly reduced expression of enzymes (COX-2, iNOS), cytokines (IL-6, IL-1beta, TNF-alpha), and signal transduction factors (AKT, MAPKs, NF-kappaB) involved in inflammation triggered by LPS in vitro and in vivo. In addition, LumA5 inhibited the cytotoxicity of conditioned medium prepared by LPS-activated BV-2 microglia to neuronal SH-SY5Y cells and improved cell viability. These results indicate that LumA5 may be a potential therapeutic agent for the treatment of various neuroinflammatory conditions. PMID- 28666871 TI - Structural bases of the altered catalytic properties of a pathogenic variant of apoptosis inducing factor. AB - The apoptosis-inducing factor (AIF) is a FAD-containing protein playing critical roles in caspase-independent apoptosis and mitochondrial respiratory chain biogenesis and maintenance. While its lethal role is well known, the details of its mitochondrial function remain elusive. So far, nineteen allelic variants of AIF have been associated to human diseases, mainly affecting the nervous system. A strict correlation is emerging between the degree of impairment of its ability to stabilize the charge-transfer (CT) complex between FAD and NAD+ and the severity of the resulting pathology. Recently, we demonstrated that the G307E replacement in murine AIF (equivalent to the pathogenic G308E in the human protein) dramatically decreases the rate of CT complex formation through the destabilization of the flavoprotein interaction with NAD(H). To provide further insights into the structural bases of its altered functional properties, here we report the first crystal structure of an AIF pathogenic mutant variant in complex with NAD+ (murine AIF-G307ECT) in comparison with its oxidized form. With respect to wild type AIF, the mutation leads to an altered positioning of NAD+ adenylate moiety, which slows down CT complex formation. Moreover, the altered balance between the binding of the adenine/nicotinamide portions of the coenzyme determines a large drop in AIF-G307E ability to discriminate between NADH and NADPH. PMID- 28666872 TI - Disruption of TACE-filamin interaction can inhibit TACE-mediated ectodomain shedding. AB - Ectodomain shedding regulates functions of many membrane proteins through the cleavage of their juxtamembrane region mainly by a disintegrin and metalloproteinase family proteinases. Tumor necrosis factor-alpha converting enzyme (TACE) is known to be responsible for phorbol myristate acetate (PMA) induced shedding of various membrane proteins. How PMA regulates TACE-dependent shedding and how TACE exhibits substrate specificity without proteolysis of other membrane proteins are questionable. Here, we show that TACE can interact with an actin-binding protein, filamin, through 20th filamin repeat. We found that the interaction between TACE and filamin was increased by PMA treatment. In addition, loss of filamin or specific disruption of TACE-filamin interaction inhibited ectodomain shedding of representative TACE substrates, CD44 and amyloid protein precursor. From these data, we suggest that filamin may work as a scaffold that can recruit TACE and its substrates in a PMA-dependent manner to achieve substrate specificity for TACE. PMID- 28666873 TI - Overexpression of MicA induces production of OmpC-enriched outer membrane vesicles that protect against Salmonella challenge. AB - Outer membrane vesicles (OMVs) derived from bacteria are promising candidates for subunit vaccines. Stresses that modulate the composition of outer membrane proteins (OMPs) are important for OMV synthesis. Small RNAs (sRNAs) expressed in response to stress regulate OMPs, although the mechanism underlying sRNA-mediated OMV biogenesis and its utility for developing vaccine platforms remains to be elucidated. Here, we characterized the role of a sRNA, MicA, which regulates OmpA, a major OMP involved in both production of OMVs and reactive immunity against Salmonella challenge. A Salmonella strain overexpressing MicA generated more OMVs than a control strain. In addition, OmpC was the major component of MicA-derived OMV proteins. MicA-derived OMVs induced Th1- and Th17-type immune responses in vitro and reduced Salmonella-mediated lethality in a mouse model. Thus, OmpA-regulatory sRNA-derived OMVs may facilitate production of Salmonella protective vaccines. PMID- 28666874 TI - Anti-dengue virus activity of scytovirin and evaluation of point mutation effects by molecular dynamics and binding free energy calculations. AB - The absence of a specific treatment against DENV has led to intensive research into developing strategies for curing the infection. One lectin with high antiviral activity is scytovirin, which was isolated from the cyanobacterium Scytonema varium and has proven activity against HIV and Zaire Ebola Virus. To achieve the results presented here, we tested the affinity of full-length scytovirin, SD1 and SD2 separately, and six SD1 mutants for DENV glycoprotein E carbohydrate by Molecular Dynamics (MD) simulations and binding free energy calculations. It was possible to identify the key residues for protein-ligand interaction such as Glu10, Ala11, Pro17, Ans18, Arg30, Thr41, Ser42 and Arg43, which also has importance action against HIV. All binding free energy calculations showed negative values to DeltaGbind of protein-DENV carbohydrate complexation. Additionally, these results are similar to the values of scytovirin and HIV gp120 carbohydrate complexation (-32.20 kcal/mol). Furthermore, we found that SD1 individually has more affinity to the carbohydrate and the Asn9, Glu10, Asn18, Arg30 and Arg43 demonstrated an important role in this matter. We also found that mutant G48R has better affinity (-34.10 kcal/mol) for the DENV carbohydrate than the wild type protein (-27.15 kcal/mol). PMID- 28666875 TI - In vitro and in vivo inhibition of proangiogenic retinal phenotype by an antisense oligonucleotide downregulating uPAR expression. AB - Neoangiogenesis is the main pathogenic event involved in a variety of retinal diseases. It has been recently demonstrated that inhibiting the urokinase-type plasminogen activator receptor (uPAR) results in reduced angiogenesis in a mouse model of oxygen-induced retinopathy (OIR), establishing uPAR as a therapeutic target in proliferative retinopathies. Here, we evaluated in cultured human retinal endothelial cells (HRECs) and in OIR mice the potential of a specific antisense oligodeoxyribonucleotide (ASO) in blocking the synthesis of uPAR and in providing antiangiogenic effects. uPAR expression in HRECs was inhibited by lipofection with the phosphorotioated 5'-CGGCGGGTGACCCATGTG-3' ASO-uPAR, complementary to the initial translation site of uPAR mRNA. Inhibition of uPAR expression via ASO-uPAR was evaluated in HRECs by analyzing VEGF-induced tube formation and migration. In addition, the well-established and reproducible murine OIR model was used to induce retinal neovascularization in vivo. OIR mice were injected intraperitoneally with ASO-uPAR and retinopathy was evaluated considering the extent of the avascular area in the central retina and neovascular tuft formation. The ASO-uPAR specifically decreased uPAR mRNA and protein levels in HRECs and mitigated VEGF-induced tube formation and cell migration. Noteworthy, in OIR mice ASO-uPAR administration reduced both the avascular area and the formation of neovascular tufts. In conclusion, although the extrapolation of these experimental findings to the clinic is not straightforward, ASO-uPAR may be considered a potential therapeutic tool for treatment of proliferative retinal diseases. PMID- 28666876 TI - Endogenous peptide profile for elucidating biosynthetic processing of the ghrelin precursor. AB - Ghrelin is an orexigenic peptide primarily produced by gastric endocrine cells. The biosynthetic cleavage site of ghrelin has been well documented, but how its downstream region undergoes proteolytic processing remains poorly explored. Here, we provide the first snapshot of endogenous peptides from the ghrelin precursor by profiling the secretopeptidome of cultured mouse ghrelin-producing cells during exocytosis. Mapping of MS/MS sequenced peptides to the precursor highlighted three atypical monobasic processing sites, including the established C-terminus of ghrelin and the N-terminal cleavage site for obestatin, a putative 23-amino-acid C-terminally amidated peptide. However, we found that mouse obestatin does not occur in the form originally reported, but that a different amidation site is used to generate a shorter peptide. These data can be extended to study and characterize the precursor-derived peptides located downstream of ghrelin in different biological contexts. PMID- 28666877 TI - Microbial analysis of root canal and periradicular lesion associated to teeth with endodontic failure. AB - The quantification of ten microorganisms at the root ends and in the surrounding periradicular lesions was performed. Thirty 3 mm samples root ends and 30 samples of the surrounding chronic periapical infection were collected during apical microsurgery. Samples were triturated, and the bacterial DNA was obtained. The bacterial quantification was performed by using the SYBR Green system. At least one microorganism was detected in all patients. In both the root end and periapical samples, Fusobacterium nucleatum (71.6%), Dialister pneumosintes (58.3%) and Tannerella forsythia (48.3%) were the most prevalent species. Dialister pneumosintes showed statistically significant values in the root end, and F. nucleatum was also significant in the apical periodontitis samples. A statistically significant association between T. forsythia and Porphyromonas gingivalis in the root ends was observed. Bacterial associations from 2 to 7 species were observed in most samples. Extra-radicular and/or intra-radicular infections were present in all teeth with failed endodontic treatment, and showed polymicrobial infection in most cases, with a predominance of F. nucleatum, D. pneumosintes and T. forsythia. When present, Enterococcus faecalis was never found to be the most prevalent species. The presence of a microbial diversity in post-treatment apical periodontitis confirms the polymicrobial and synergistic characteristic of this process. Our results show that the bacterial array associated with the 3 mm root ends and periradicular lesions in post-treatment apical periodontitis are complex and with a high inter-individual variability. These results might be useful to delineate treatment strategies for microbial elimination in apical periodontitis. Further studies are necessary to elucidate the role of these microorganisms in endodontic treatment failures. PMID- 28666878 TI - A review on automatic fetal and neonatal brain MRI segmentation. AB - In recent years, a variety of segmentation methods have been proposed for automatic delineation of the fetal and neonatal brain MRI. These methods aim to define regions of interest of different granularity: brain, tissue types or more localised structures. Different methodologies have been applied for this segmentation task and can be classified into unsupervised, parametric, classification, atlas fusion and deformable models. Brain atlases are commonly utilised as training data in the segmentation process. Challenges relating to the image acquisition, the rapid brain development as well as the limited availability of imaging data however hinder this segmentation task. In this paper, we review methods adopted for the perinatal brain and categorise them according to the target population, structures segmented and methodology. We outline different methods proposed in the literature and discuss their major contributions. Different approaches for the evaluation of the segmentation accuracy and benchmarks used for the segmentation quality are presented. We conclude this review with a discussion on shortcomings in the perinatal domain and possible future directions. PMID- 28666880 TI - Connectopic mapping with resting-state fMRI. AB - Brain regions are often topographically connected: nearby locations within one brain area connect with nearby locations in another area. Mapping these connection topographies, or 'connectopies' in short, is crucial for understanding how information is processed in the brain. Here, we propose principled, fully data-driven methods for mapping connectopies using functional magnetic resonance imaging (fMRI) data acquired at rest by combining spectral embedding of voxel wise connectivity 'fingerprints' with a novel approach to spatial statistical inference. We apply the approach in human primary motor and visual cortex, and show that it can trace biologically plausible, overlapping connectopies in individual subjects that follow these regions' somatotopic and retinotopic maps. As a generic mechanism to perform inference over connectopies, the new spatial statistics approach enables rigorous statistical testing of hypotheses regarding the fine-grained spatial profile of functional connectivity and whether that profile is different between subjects or between experimental conditions. The combined framework offers a fundamental alternative to existing approaches to investigating functional connectivity in the brain, from voxel- or seed-pair wise characterizations of functional association, towards a full, multivariate characterization of spatial topography. PMID- 28666879 TI - Correction of metal-induced susceptibility artifacts for functional MRI during deep brain stimulation. AB - Functional magnetic resonance imaging (fMRI) is an emerging tool for investigating brain activation associated with, or modulated by, deep brain stimulation (DBS). However, DBS-fMRI generally suffers from severe susceptibility to artifacts in regions near the metallic stimulation electrodes, as well as near tissue/air boundaries of the brain. These result in strong intensity and geometric distortions along the phase-encoding (PE) (i.e., blipped) direction in gradient-echo echo-planar imaging (GE-EPI). Distortion presents a major challenge to conducting reliable data analysis and in interpreting the findings. A recent study showed that the point spread function (PSF) mapping-based reverse gradient approach has a potential to correct for distortions not only in spin-echo EPI, but also in GE-EPI acquired in both the forward and reverse PE directions. In this study, we adapted that approach in order to minimize severe metal-induced susceptibility artifacts for DBS-fMRI, and to evaluate the performance of the approach in a phantom study and a large animal DBS-fMRI study. The method combines the distortion-corrected GE-EPI pair with geometrically different intensity distortions due to the opposing encoding directions. The results demonstrate that the approach can minimize susceptibility artifacts that appear around the metallic electrodes, as well as in the regions near the tissue/air boundaries in the brain. We also demonstrated that an accurate geometric correction is important in improving BOLD contrast in the group dataset, especially in regions where strong susceptibility artifacts appear. PMID- 28666881 TI - Distinguishing early and late brain aging from the Alzheimer's disease spectrum: consistent morphological patterns across independent samples. AB - Alzheimer's disease (AD) is a debilitating age-related neurodegenerative disorder. Accurate identification of individuals at risk is complicated as AD shares cognitive and brain features with aging. We applied linked independent component analysis (LICA) on three complementary measures of gray matter structure: cortical thickness, area and gray matter density of 137 AD, 78 mild (MCI) and 38 subjective cognitive impairment patients, and 355 healthy adults aged 18-78 years to identify dissociable multivariate morphological patterns sensitive to age and diagnosis. Using the lasso classifier, we performed group classification and prediction of cognition and age at different age ranges to assess the sensitivity and diagnostic accuracy of the LICA patterns in relation to AD, as well as early and late healthy aging. Three components showed high sensitivity to the diagnosis and cognitive status of AD, with different relationships with age: one reflected an anterior-posterior gradient in thickness and gray matter density and was uniquely related to diagnosis, whereas the other two, reflecting widespread cortical thickness and medial temporal lobe volume, respectively, also correlated significantly with age. Repeating the LICA decomposition and between-subject analysis on ADNI data, including 186 AD, 395 MCI and 220 age-matched healthy controls, revealed largely consistent brain patterns and clinical associations across samples. Classification results showed that multivariate LICA-derived brain characteristics could be used to predict AD and age with high accuracy (area under ROC curve up to 0.93 for classification of AD from controls). Comparison between classifiers based on feature ranking and feature selection suggests both common and unique feature sets implicated in AD and aging, and provides evidence of distinct age-related differences in early compared to late aging. PMID- 28666882 TI - A second-order orientation-contrast stimulus for population-receptive-field-based retinotopic mapping. AB - Visual field or retinotopic mapping is one of the most frequently used paradigms in fMRI. It uses activity evoked by position-varying high luminance contrast visual patterns presented throughout the visual field for determining the spatial organization of cortical visual areas. While the advantage of using high luminance contrast is that it tends to drive a wide range of neural populations - thus resulting in high signal-to-noise BOLD responses - this may also be a limitation, especially for approaches that attempt to squeeze more information out of the BOLD response, such as population receptive field (pRF) mapping. In that case, more selective stimulation of a subset of neurons - despite reduced signals - could result in better characterization of pRF properties. Here, we used a second-order stimulus based on local differences in orientation texture - to which we refer as orientation contrast - to perform retinotopic mapping. Participants in our experiment viewed arrays of Gabor patches composed of a foreground (a bar) and a background. These could only be distinguished on the basis of a difference in patch orientation. In our analyses, we compare the pRF properties obtained using this new orientation contrast-based retinotopy (OCR) to those obtained using classic luminance contrast-based retinotopy (LCR). Specifically, in higher order cortical visual areas such as LO, our novel approach resulted in non-trivial reductions in estimated population receptive field size of around 30%. A set of control experiments confirms that the most plausible cause for this reduction is that OCR mainly drives neurons sensitive to orientation contrast. We discuss how OCR - by limiting receptive field scatter and reducing BOLD displacement - may result in more accurate pRF localization as well. Estimation of neuronal properties is crucial for interpreting cortical function. Therefore, we conclude that using our approach, it is possible to selectively target particular neuronal populations, opening the way to use pRF modeling to dissect the response properties of more clearly-defined neuronal populations in different visual areas. PMID- 28666883 TI - A macroporous heparin-releasing silk fibroin scaffold improves islet transplantation outcome by promoting islet revascularisation and survival. AB - : Islet transplantation is considered the most promising therapeutic option with the potential to cure diabetes. However, efficacy of current clinical islet transplantation is limited by long-term graft dysfunction and attrition. We have investigated the therapeutic potential of a silk fibroin macroporous (SF) scaffold for syngeneic islet transplantation in diabetic mice. The SF scaffold was prepared via lyophilisation, which enables incorporation of active compounds including cytokines, peptide and growth factors without compromising their biological activity. For the present study, a heparin-releasing SF scaffold (H SF) in order to evaluate the versatility of the SF scaffold for biological functionalisation. Islets were then co-transplanted with H-SF or SF scaffolds in the epididymal fat pad of diabetic mice. Mice from both H-SF and SF groups achieved 100% euglycaemia, which was maintained for 1year. More importantly, the H-SF-islets co-transplantation led to more rapid reversal of hyperglycaemia, complete normalisation of glucose responsiveness and lower long-term blood glucose levels. This superior transplantation outcome is attributable to H-SF facilitated islet revascularisation and cell proliferation since significant increase of islet endocrine and endothelial cells proliferation was shown in grafts retrieved from H-SF-islets co-transplanted mice. Better intra-islet vascular reformation was also evident, accompanied by VEGF upregulation. In addition, when H-SF was co-transplanted with islets extracted from vegfr2-luc transgenic mice in vivo, sustained elevation of bioluminescent signal that corresponds to vegfr2 expression was collected, implicating a role of heparin dependent activation of endogenous VEGF/VEGFR2 pathway in promoting islet revascularisation and proliferation. In summary, the SF scaffolds provide an open platform as scaffold development for islet transplantation. Furthermore, given the pro-angiogenic, pro-survival and minimal post-transplantation inflammatory reactions of H-SF, our data also support the feasibility of clinical implementation of H-SF to improve islet transplantation outcome. STATEMENT OF SIGNIFICANCE: 1) The silk fibroin scaffold presented in the present study provides an open platform for scaffold development in islet transplantation, with heparinisation as an example. 2) Both heparin and silk fibroin have been used clinically. The excellent in vivo therapeutic outcome reported here may therefore be clinically relevant and provide valuable insights for bench to bed translation. 3) Compared to conventional clinical islet transplantation, during which islets are injected via the hepatic portal vein, the physical/mechanical properties of silk fibroin scaffolds create a more accessible transplantation site (i.e., within fat pad), which significantly reduces discomfort. 4) Islet implantation into the fat pad also avoids an instant blood mediated inflammatory response, which occurs upon contact of islet with recipient's blood during intraportal injection, and prolongs survival and function of implanted islets. PMID- 28666884 TI - Bioinspired coupled helical coils for soft tissue engineering of tubular structures - Improved mechanical behavior of tubular collagen type I templates. AB - : The design of constructs for tubular tissue engineering is challenging. Most biomaterials need to be reinforced with supporting structures such as knittings, meshes or electrospun material to comply with the mechanical demands of native tissues. In this study, coupled helical coils (CHCs) were manufactured to mimic collagen fiber orientation as found in nature. Monofilaments of different commercially available biodegradable polymers were wound and subsequently fused, resulting in right-handed and left-handed polymer helices fused together in joints where the filaments cross. CHCs of different polymer composition were tested to determine the tensile strength, strain recovery, hysteresis, compressive strength and degradation of CHCs of different composition. Subsequently, seamless and stable hybrid constructs consisting of PDSII(r) USP 2 0 CHCs embedded in porous collagen type I were produced. Compared to collagen alone, this hybrid showed superior strain recovery (93.5+/-0.9% vs 71.1+/-12.6% in longitudinal direction; 87.1+/-6.6% vs 57.2+/-4.6% in circumferential direction) and hysteresis (18.9+/-2.7% vs 51.1+/-12.0% in longitudinal direction; 11.5+/-4.6% vs 46.3+/-6.3% in circumferential direction). Furthermore, this hybrid construct showed an improved Young's modulus in both longitudinal (0.5+/ 0.1MPavs 0.2+/-0.1MPa; 2.5-fold) and circumferential (1.65+/-0.07MPavs (2.9+/ 0.3)*10-2MPa; 57-fold) direction, respectively, compared to templates created from collagen alone. Moreover, hybrid template characteristics could be modified by changing the CHC composition and CHCs were produced showing a mechanical behavior similar to the native ureter. CHC-enforced templates, which are easily tunable to meet different demands may be promising for tubular tissue engineering. STATEMENT OF SIGNIFICANCE: Most tubular constructs lack sufficient strength and tunability to comply with the mechanical demands of native tissues. Therefore, we embedded coupled helical coils (CHCs) produced from biodegradable polymers - to mimic collagen fiber orientation as found in nature - in collagen type I sponges. We show that the mechanical behavior of CHCs is very similar to native tissue and strengths structurally weak tubular constructs. The production procedure is relatively easy, reproducible and mechanical features can be controlled to meet different mechanical demands. This is promising in template manufacture, hence offering new opportunities in tissue engineering of tubular organs and preventing graft failure. PMID- 28666885 TI - Sandwich-type PLLA-nanosheets loaded with BMP-2 induce bone regeneration in critical-sized mouse calvarial defects. AB - : To overcome serious clinical problems caused by large bone defects, various approaches to bone regeneration have been researched, including tissue engineering, biomaterials, stem cells and drug screening. Previously, we developed a free-standing biodegradable polymer nanosheet composed of poly(L lactic acid) (PLLA) using a simple fabrication process consisting of spin-coating and peeling techniques. Here, we loaded recombinant human bone morphogenetic protein-2 (rhBMP-2) between two 60-nm-thick PLLA nanosheets, and investigated these sandwich-type nanosheets in bone regeneration applications. The PLLA nanosheets displayed constant and sustained release of the loaded rhBMP-2 for over 2months in vitro. Moreover, we implanted the sandwich-type nanosheets with or without rhBMP-2 into critical-sized defects in mouse calvariae. Bone regeneration was evident 4weeks after implantation, and the size and robustness of the regenerated bone had increased by 8weeks after implantation in mice implanted with the rhBMP-2-loaded nanosheets, whereas no significant bone formation occurred over a period of 20weeks in mice implanted with blank nanosheets. The PLLA nanosheets loaded with rhBMP-2 may be useful in bone regenerative medicine; furthermore, the sandwich-type PLLA nanosheet structure may potentially be applied as a potent prolonged sustained-release carrier of other molecules or drugs. STATEMENTS OF SIGNIFICANCE: Here we describe sandwich type poly(L-lactic acid) (PLLA) nanosheets loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) as a novel method for bone regeneration. Biodegradable 60-nm-thick PLLA nanosheets display strong adhesion without any adhesive agent. The sandwich-type PLLA nanosheets displayed constant and sustained release of the loaded rhBMP-2 for over 2months in vitro. The nanosheets with rhBMP-2 markedly enhanced bone regeneration when they were implanted into critical-sized defects in mouse calvariae. In addition to their application for bone regeneration, PLLA nanosheets may be useful for various purposes in combination with various drugs or molecules, because they displays excellent capacity as a sustained-release carrier. PMID- 28666886 TI - Comparison of methods to evaluate bacterial contact-killing materials. AB - : Cationic surfaces with alkylated quaternary-ammonium groups kill adhering bacteria upon contact by membrane disruption and are considered increasingly promising as a non-antibiotic based way to eradicate bacteria adhering to surfaces. However, reliable in vitro evaluation methods for bacterial contact killing surfaces do not yet exist. More importantly, results of different evaluation methods are often conflicting. Therefore, we compared five methods to evaluate contact-killing surfaces. To this end, we have copolymerized quaternary ammonium groups into diurethane dimethacrylate/glycerol dimethacrylate (UDMA/GDMA) and determined contact-killing efficacies against five different Gram positive and Gram-negative strains. Spray-coating bacteria from an aerosol onto contact-killing surfaces followed by air-drying as well as ASTM E2149-13a (American Society for Testing and Materials) were found unsuitable, while the Petrifilm(r) system and JIS Z 2801 (Japanese Industrial Standards) were found to be excellent methods to evaluate bacterial contact-killing surfaces. It is recommended however, that these methods be used in combination with a zone of inhibition on agar assay to exclude that leakage of antimicrobials from the material interferes with the contact-killing ability of the surface. STATEMENT OF SIGNIFICANCE: Bacterial adhesion to surfaces of biomaterials implants can be life threatening. Antimicrobials to treat biomaterial-associated infections often fail due to the bacterial biofilm-mode-of-growth or are ineffective due to antibiotic resistance of causative organisms. Positively-charged, quaternized surfaces can kill bacteria upon contact and are promising as a non-antibiotic-based treatment of biomaterial-associated infections. Reliable methods to determine efficacies of contact-killing surfaces are lacking, however. Here, we show that three out of five methods compared, including an established ASTM, are unsuitable. Methods found suitable should be used in combination with a zone-of-inhibition-assay to establish absence of antimicrobial leaching, potentially interfering with contact killing. Identification of suitable assays for evaluating bacterial contact killing will greatly assist this emerging field as an alternative for antibiotic based treatment of biomaterial-associated-infections. PMID- 28666887 TI - Stevia and stevioside protect against cisplatin nephrotoxicity through inhibition of ERK1/2, STAT3, and NF-kappaB activation. AB - We investigated the effect of natural sweetener Stevia rebaudiana and its constituent stevioside in cisplatin (CP)-induced kidney injury. Male BALB/cN mice were orally administered 10, 20, and 50 mg/kg body weight of Stevia rebaudiana ethanol extract (SE) or stevioside 50 mg/kg, 48 h after intraperitoneal administration of CP (13 mg/kg). Two days later, CP treatment resulted in histopathological changes showing kidney injury. Increased expression of 4 hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT), and heme oxygenase-1 (HO-1) in mice kidneys suggested oxidative stress. CP treatment also increased renal expression of nuclear factor-kappaB (NF-kappaB) p65 subunit and phosphorylated inhibitor of NF-kappaB (IkappaBalpha), as well as expression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Induction of apoptosis and inhibition of the cell cycle in kidneys was evidenced by increased expression of p53, Bax, caspase-9, and p21, proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), with concomitant suppression of Bcl-2 and cyclin D1 expression. The number of apoptotic cells in kidneys was also assessed. CP administration resulted in activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3). Both SE and stevioside attenuated CP nephrotoxicity by suppressing oxidative stress, inflammation, and apoptosis through mechanism involving ERK1/2, STAT3, and NF-kappaB suppression. PMID- 28666888 TI - Antofine, a natural phenanthroindolizidine alkaloid, suppresses angiogenesis via regulation of AKT/mTOR and AMPK pathway in endothelial cells and endothelial progenitor cells derived from mouse embryonic stem cells. AB - Although antofine, a natural phenanthroindolizidine alkaloid, exerts potential biological activities, including anticancer effect and anti-angiogenic activity, the underlying mechanisms have not yet been investigated. In the present study, the inhibitory effect of antofine on angiogenesis was determined in cultured mouse embryonic stem (mES)/embryoid body (EB)-derived endothelial cells and vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs). Antofine effectively inhibited VEGF-induced cell migration and tube formation of HUVECs. Antofine also significantly decreased ex vivo microvessel sprouting in cultured mouse aortic rings, and inhibited the vascular formation and platelet/endothelial cell adhesion molecule (PECAM) expression of mES/EB-derived cells in 3-D collagen gel. The underlying mechanism of anti-angiogenic activity of antofine was, in part, associated with the modulation of AKT/mTOR and AMP-activated protein kinase (AMPK) signaling in VEGF stimulated HUVECs. PMID- 28666889 TI - Efficient genome editing by CRISPR/Cas9 with a tRNA-sgRNA fusion in the methylotrophic yeast Ogataea polymorpha. AB - The methylotrophic yeast Ogataea polymorpha (syn. Hansenula polymorpha) is an attractive industrial non-conventional yeast showing high thermo-tolerance (up to 50 degrees C) and xylose assimilation. However, genetic manipulation of O. polymorpha is often laborious and time-consuming because it has lower homologous recombination efficiency relative to Saccharomyces cerevisiae. To overcome this disadvantage, we applied the CRISPR/Cas9 system as a powerful genome editing tool in O. polymorpha. In this system, both single guide RNA (sgRNA) and endonuclease Cas9 were expressed by a single autonomously-replicable plasmid and the sgRNA portion could be easily changed by using PCR and In-Fusion cloning techniques. Because the mutation efficiency of the CRISPR/Cas9 system was relatively low when the sgRNA was expressed under the control of the OpSNR6 promoter, the tRNACUG gene was used for sgRNA expression. The editing efficiency of this system ranged from 17% to 71% of transformants in several target genes tested (ADE12, PHO1, PHO11, and PHO84). These findings indicate that genetic manipulation of O. polymorpha will be more convenient and accelerated by using this CRISPR/Cas9 system. PMID- 28666890 TI - Protection against mosquito vectors Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus using a novel insect repellent, ethyl anthranilate. AB - Growing concern on the application of synthetic mosquito repellents in the recent years has instigated the identification and development of better alternatives to control different mosquito-borne diseases. In view of above, present investigation evaluates the repellent activity of ethyl anthranilate (EA), a non toxic, FDA approved volatile food additive against three known mosquito vectors namely, Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus under laboratory conditions following standard protocols. Three concentration levels (2%, 5% and 10% w/v) of EA were tested against all the three selected mosquito species employing K & D module and arm-in-cage method to determine the effective dose (ED50) and complete protection time (CPT), respectively. The repellent activity of EA was further investigated by modified arm-in-cage method to determine the protection over extended spatial ranges against all mosquito species. All behavioural situations were compared with the well-documented repellent N,N-diethylphenyl acetamide (DEPA) as a positive control. The findings demonstrated that EA exhibited significant repellent activity against all the three mosquitoes species. The ED50 values of EA, against Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus were found to be 0.96%, 5.4% and 3.6% w/v, respectively. At the concentration of 10% w/v, it provided CPTs of 60, 60 and 30min, respectively, against Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus mosquitoes. Again in spatial repellency evaluation, EA was found to be extremely effective in repelling all the three tested species of mosquitoes. Ethyl anthranilate provided comparable results to standard repellent DEPA during the study. Results have concluded that the currently evaluated chemical, EA has potential repellent activity against some well established mosquito vectors. The study emphasizes that repellent activity of EA could be exploited for developing effective, eco-friendly, acceptable and safer alternative to the existing harmful repellents for personal protection against different hematophagous mosquito species. PMID- 28666891 TI - Neural signals of selective attention are modulated by subjective preferences and buying decisions in a virtual shopping task. AB - We investigated whether well-known neural markers of selective attention to motivationally-relevant stimuli were modulated by variations in subjective preference towards consumer goods in a virtual shopping task. Specifically, participants viewed and rated pictures of various goods on the extent to which they wanted each item, which they could potentially purchase afterwards. Using the event-related potentials (ERP) method, we found that variations in subjective preferences for consumer goods strongly modulated positive slow waves (PSW) from 800 to 3000 milliseconds after stimulus onset. We also found that subjective preferences modulated the N200 and the late positive potential (LPP). In addition, we found that both PSW and LPP were modulated by subsequent buying decisions. Overall, these findings show that well-known brain event-related potentials reflecting selective attention processes can reliably index preferences to consumer goods in a shopping environment. Based on a large body of previous research, we suggest that early ERPs (e.g. the N200) to consumer goods could be indicative of preferences driven by unconditional and automatic processes, whereas later ERPs such as the LPP and the PSW could reflect preferences built upon more elaborative and conscious cognitive processes. PMID- 28666892 TI - Pharmacotherapies for decreasing maladaptive choice in drug addiction: Targeting the behavior and the drug. AB - Drug addiction can be conceptualized as a disorder of maladaptive decision making in which drugs are chosen at the expense of pro-social, nondrug alternatives. The study of decision making in drug addiction has focused largely on the role of impulsivity as a facilitator of addiction, in particular the tendency for drug abusers to choose small, immediate gains over larger but delayed outcomes (i.e., delay discounting). A parallel line of work, also focused on decision making in drug addiction, has focused on identifying the determinants underlying the choice to take drugs over nondrug alternatives (i.e., drug vs. nondrug choice). Both tracks of research have been valuable tools in the development of pharmacotherapies for treating maladaptive decision making in drug addiction, and a number of common drugs have been studied in both designs. However, we have observed that there is little uniformity in the administration regimens of potential treatments between the designs, which hinders congruence in the development of single treatment strategies to reduce both impulsive behavior and drug choice. The current review provides an overview of the drugs that have been tested in both delay-discounting and drug-choice designs, and focuses on drugs that reduced the maladaptive choice in both designs. Suggestions to enhance congruence between the findings in future studies are provided. Finally, we propose the use of a hybridized, experimental approach that may enable researchers to test the effectiveness of therapeutics at decreasing impulsive and drug choice in a single design. PMID- 28666894 TI - Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo. AB - Cannabinoid receptor 1 (CB1R) antagonists have been proven to be effective anti obesity drugs; however, psychiatric side effects have halted their pharmaceutical development worldwide. Despite the emergence of next generation CB1R blockers, a preclinical head to head comparison of the anti-obesity and psychiatric side effect profiles of the key compounds has not been performed. Here, we compared classical CB1R antagonists (rimonabant, taranabant, otenabant, ibipinabant, and surinabant) and non-traditional CB1R blockers (the partial agonist O-1269, the neutral antagonists VCHSR and LH-21 and the peripherally acting inverse agonist JD-5037) using an in vivo screening cascade. First, the potencies of these compounds to reduce CB1R agonist-induced hypothermia and decrease fasting-induced food intake were determined. Then, equipotent doses of the non-toxic compounds were compared in a diet-induced obesity (DIO) test, which includes measurements of metabolic syndrome markers. Psychiatric side effects were assessed by measuring anxiogenicity in an ultrasonic vocalization test. All classical CB1R blockers were centrally acting appetite suppressants and decreased body weight and food intake in an obesity-dependent manner, with only slight effects on metabolic syndrome markers. In addition, all classical CB1R blockers increased ultrasonic vocalization. Surprisingly, none of the non-classical CB1R blockers was eligible for the DIO comparison and side effect profiling. O-1269 and LH-21 induced convulsive behavior, whereas VCHSR and JD-5037 were devoid of any in vivo activity. The classical CB1R blockers displayed similar therapeutic and side effect profiles in vivo, whereas the available non-traditional CB1R blockers were not appropriate tools for testing the therapeutic potential of alternative CB1R inhibitors. PMID- 28666895 TI - The microbiome and disorders of the central nervous system. AB - Alterations of the gut microbiota have been associated with stress-related disorders including depression and anxiety and irritable bowel syndrome (IBS). More recently, researchers have started investigating the implication of perturbation of the microbiota composition in neurodevelopmental disorders including autism spectrum disorders and Attention-Deficit Hypersensitivity Disorder (ADHD). In this review we will discuss how the microbiota is established and its functions in maintaining health. We also summarize both pre and post natal factors that shape the developing neonatal microbiota and how they may impact on health outcomes with relevance to disorders of the central nervous system. Finally, we discuss potential therapeutic approaches based on the manipulation of the gut bacterial composition. PMID- 28666896 TI - Circadian neurons in the lateral habenula: Clocking motivated behaviors. AB - The main circadian clock in mammals is located in the hypothalamic suprachiasmatic nucleus (SCN), however, central timing mechanisms are also present in other brain structures beyond the SCN. The lateral habenula (LHb), known for its important role in the regulation of the monoaminergic system, contains such a circadian clock whose molecular and cellular mechanisms as well as functional role are not well known. However, since monoaminergic systems show circadian activity, it is possible that the LHb-clock's role is to modulate the rhythmic activity of the dopamine, serotonin and norephinephrine systems, and associated behaviors. Moreover, the LHb is involved in different pathological states such as depression, addiction and schizophrenia, states in which sleep and circadian alterations have been reported. Thus, perturbations of circadian activity in the LHb might, in part, be a cause of these rhythmic alterations in psychiatric ailments. In this review the current state of the LHb clock and its possible implications in the control of monoaminergic systems rhythms, motivated behaviors (e.g., feeding, drug intake) and depression (with circadian disruptions and altered motivation) will be discussed. PMID- 28666893 TI - Neural underpinnings of maladaptive decision-making in addictions. PMID- 28666897 TI - Sequential acquisition of Potato virus Y strains by Myzus persicae favors the transmission of the emerging recombinant strains. AB - In the past decade recombinant strains of Potato virus Y (PVY) have overtaken the ordinary strain, PVYO, as the predominant viruses affecting the US seed potato crop. Aphids may be a contributing factor in the emergence of the recombinant strains, but studies indicate that differences in transmission efficiency of individual PVY strains either from single or mixed infections, although variable, are not generally significant. Multiple strains of PVY are present in all potato production areas and common in many potato fields. Therefore, it is likely that individual alate aphids moving through a potato field will sequentially encounter multiple strains as they "taste test" multiple potato plants while looking for a suitable host. This study examined the transmission likelihood and efficiency of three common PVY strains when acquired sequentially by individual aphids. Green peach aphids (Myzus persicae, Sulzer) were allowed a 2-3min acquisition access period (AAP) on potato leaves infected with PVYO, PVYN:O or PVYNTN, followed by another 2-3min AAP on a second potato leaf infected with a different PVY strain before being transferred to healthy potato seedlings for a 24h inoculation access period. All possible combinations of the three strains were tested. Strain specific infection of the recipient plants was determined by TAS-ELISA and RT-PCR 3-4wk post-inoculation. The recombinant strains, PVYN:O and PVYNTN, were transmitted more efficiently than PVYO when they were sequentially acquired regardless of the order acquired. PVYN:O and PVYNTN were transmitted with similar efficiencies when they were sequentially acquired regardless of the order. The recombinant strains appear to preferentially bind to the aphid stylet over PVYO or they may be preferentially released during inoculation. This may contribute to the increased incidence of the recombinant strains over PVYO in fields or production regions where multiple PVY strains are detected. PMID- 28666898 TI - Overexpression and characterization of the 100K protein of Fowl adenovirus-4 as an antiviral target. AB - 100K is an important scaffolding protein of adenoviruses including fowl adenovirus serotype 4 (FAdV-4) that causes inclusion body hepatitis hydropericardium syndrome (IBH-HPS) in poultry. 100K carries out the trimerization of the major capsid hexon protein of the virus for the generation of new virions inside the target host cells. Despite its critical role for FAdV 4, no structural study, in particular, has been conducted so far. Here, the overexpression of soluble 100K protein was successfully carried out in E. coli using various expression constructs and purification yield of 3mg per litre culture volume was obtained. Gel filtration chromatography suggested that 100K protein exists in trimeric form. Circular dichroism and Fourier transform infrared spectroscopy clearly reveal that 100K protein folds with a high content of alpha-helices. The 3-dimentional homology model of the 100K protein, refined with molecular dynamics tools also depicts higher alpha-helical content within the protein model. Moreover, overexpressed recombinant 100K protein could be used to differentiate vaccinated and FAdV-4 infected chickens on the basis of higher serum anti 100K antibody titres. Our work provides preliminary structural and functional results to study biological role of the 100K protein and for further investigations to develop 100K inhibitors to control IBH-HPS in poultry. PMID- 28666899 TI - Deep inspiration breathhold for left-sided breast cancer patients with unfavorable cardiac anatomy requiring internal mammary nodal irradiation. AB - PURPOSE: The purpose of this study was to evaluate the utility of moderate deep inspiration breathhold (mDIBH) in reducing heart exposure in left breast cancer patients who have unfavorable cardiac anatomy and need internal mammary lymph node (IMLN) radiation therapy (RT). METHODS AND MATERIALS: We used maximum heart distance (MHD), defined as the maximum distance of the heart within the treatment field, >1 cm as a surrogate for unfavorable cardiac anatomy. Twenty-two left breast cancer patients with unfavorable cardiac anatomy requiring IMLN-RT underwent free-breathing (FB) and mDIBH computed tomography simulation and planning. Three-dimensional partially wide tangents (3D-PWTs) and intensity modulated RT plans were generated. Dose-volume histograms were used to compare heart and lung dosimetric parameters. Duration of treatment delivery was recorded for all fractions. RESULTS: MHD decreased significantly in mDIBH scans. mDIBH significantly reduced mean heart dose (222.7 vs 578.4 cGy; P < .0001) and percentage of left lung receiving doses >=20 Gy (V20; 31.93 vs 38.41%; P = .0006) in both 3D-PWT and intensity modulated RT plans. The change in MHD after breathhold reliably predicted mean heart dose reduction after mDIBH. Radiation was effectively delivered in 11.31 +/- 3.40 minutes with an average of 10.06 +/- 2.74 breathholds per fraction. CONCLUSIONS: mDIBH is efficient and can effectively decrease mean heart dose in patients with unfavorable cardiac anatomy who need IMLN-RT, thus simplifying planning and delivery for them. The reduction in mean heart dose is proportional to the reduction in maximum heart distance. PMID- 28666900 TI - Radiation oncology residency selection: A postgraduate evaluation of factor importance and survey of variables associated with job securement. AB - BACKGROUND: Medical students often choose to pursue a career in radiation oncology with limited meaningful exposure to the field. We previously identified factors that were most influential to an applicant's rank list order. Here, we sought to assess if residency graduates had differing views regarding those factors. We also polled recent graduates' attitudes of the current job market. METHODS AND MATERIALS: An anonymous, internet-based survey was developed and distributed to graduates of radiation oncology residencies from 2003 through 2006 and 2012 through 2015 to assess the importance of factors with regard to residency selection, training, and job securement and attitudes toward the job market within the United States. RESULTS: Responses were received from 198 of 848 (23%) of those invited to participate. The respondents were divided into 2 cohorts for analysis, an "early" cohort (2001-2009) and a "contemporary" cohort (2010-2016). Respondents recalled "quality of clinical training," "perceived happiness of residents," and "sense of community among faculty and residents" as the 3 most important factors influencing the rank list. Postresidency, the most valued factors of the residency experience were "quality of clinical training," "geographic location," and "faculty mentorship." Factors that were assigned the greatest differential value in hindsight to influence the rank list included "faculty mentorship," "willingness of faculty to call employer," and "quality of alumni base." Sixty-four percent of respondents reported the job market to be difficult or very difficult. This perception was more common among contemporary graduates (P < .05). Sixty percent of respondents reported "far too many" or "somewhat too many" residency positions for the actual job needs in the United States. CONCLUSION: After training, residency graduates place higher value on factors in residency that can directly improve job procurement. This finding is more common among more recent graduates, potentially a result of the perception of a tightening job market with too many radiation oncologists in training. PMID- 28666901 TI - Characterization of the effect of a new commercial transmission detector on radiation therapy beams. AB - PURPOSE: To evaluate the influence of a new commercial transmission detector on radiation therapy beams. METHODS AND MATERIALS: A transmission detector designed for online treatment monitoring was characterized on a TrueBeam STx linear accelerator with 6-MV, 6-flattening filter free, 10-MV, and 10-flattening filter free beams. Measurements of percentage depth doses, in-plane and cross-plane off axis profiles at different depths, transmission factors, and skin dose were acquired with 3 * 3, 5 * 5, 10 * 10, 20 * 20, and 40 * 40 cm2 field sizes at 100 cm and 80 cm source-to-surface distance (SSD). A CC04 chamber was used for all profile and transmission factor measurements. Skin dose was assessed at 100, 90, and 80 cm SSD using a variety of detectors (Roos and Markus parallel-plate chambers and optically stimulated luminescent dosimeters [OSLDs]). Skin dose was also assessed for various patient sample plans with OSLDs. RESULTS: The percentage depth doses showed small differences between the unperturbed and perturbed beams for 100 cm SSD (<=4 mm depth of maximum dose difference, <1.2% average profile difference) for all field sizes. At 80 cm SSD, the differences were larger (<=8 mm depth of maximum dose difference, <3% average profile difference). The differences were larger for the flattened beams and larger field sizes. The off-axis profiles showed similar trends. Field penumbras looked similar with and without the transmission detector. Comparisons in the profile central 80% showed a maximum average (maximum) profile difference between all field sizes of 1.0% (2.6%) and 1.4% (6.3%) for 100 and 80 cm SSD, respectively. The average measured skin dose increase at 100 cm (80 cm) SSD for a 10 * 10 cm2 field size was <4% (<35%) for all energies. For a 40 * 40 cm2 field size, this increased to <31% (<=63%). For the sample patient plans, the average skin dose difference was 0.53% (range, -6.6% to 10.4%). CONCLUSIONS: The transmission detector has minimal effect on clinically relevant radiation therapy beams for intensity modulated radiation therapy and volumetric arc therapy (field sizes 10 * 10 cm2 and less). For larger field sizes, some perturbations are observable that would need to be assessed for clinical impact. PMID- 28666902 TI - Intensity modulated radiation therapy with pulsed reduced dose rate as a reirradiation strategy for recurrent central nervous system tumors: An institutional series and literature review. AB - BACKGROUND: Pulsed reduced dose rate (PRDR) is a reirradiation technique that potentially overcomes volume and dose limitations in the setting of previous radiation therapy for recurrent central nervous system (CNS) tumors. Intensity modulated radiation therapy (IMRT) has not yet been reported as a PRDR delivery technique. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for CNS reirradiation. METHODS AND MATERIALS: A total of 24 patients with recurrent brain tumors received PRDR reirradiation between August 2012 and December 2014. Twenty-two patients were planned with IMRT. Linear accelerators delivered an effective dose rate of 0.0667 Gy/minute. Data collected included number of prior interventions, diagnosis, tumor grade, radiation therapy dose and fractionation, normal tissue dose, radiation therapy planning parameters, time to progression, overall survival, and adverse events. RESULTS: The median time to PRDR from completion of initial radiation therapy was 47.8 months (range, 11-389.1 months). The median PRDR dose was 54 Gy (range, 38 60 Gy). The mean planning target volume was 369.1 +/- 177.9 cm3. The median progression-free survival and 6-month progression-free survival after PRDR treatment was 3.1 months and 31%, respectively. The median overall survival and 6 month overall survival after PRDR treatment was 8.7 months and 71%, respectively. Fifty percent of patients had >=4 chemotherapy regimens before PRDR. Toxicity was similar to initial treatment, including no cases of radiation necrosis. CONCLUSION: IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent CNS tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated. Prospective studies are necessary to determine the optimal timing of PRDR reirradiation, the role of concurrent systemic agents, and the ideal patient population who would receive the maximal benefit from this treatment approach. SUMMARY: Intensity modulated radiation therapy (IMRT) has not yet been reported as a pulsed reduced dose rate (PRDR) delivery technique for recurrent brain tumors and may allow for safe and comprehensive reirradiation for large volume tumors. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for recurrent central nervous system tumors. We conclude that IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent brain tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated. PMID- 28666903 TI - Dose dissonance in radiation oncology: Consensus needed when prescribing dose in radiation therapy. PMID- 28666904 TI - Actual target coverage after setup verification using surgical clips compared with external skin markers in postoperative breast cancer radiation therapy. AB - PURPOSE: After changing from offline setup verification to online setup verification using external skin markers in breast cancer patients, we noticed an increase in localized acute skin toxicity beneath the markers. Also, in vivo 3 dimensional dose measurements showed deviations between the delivered and the planned dose distributions; therefore, we investigated the accuracy of setup verification using surgical clips in the tumor bed, with a focus on target coverage of whole breast and tumor bed. METHODS AND MATERIALS: Orthogonal kilovoltage images were acquired before every fraction in 35 breast cancer patients, deriving an online 3-dimensional setup error by matching on external skin markers. In retrospect, a rematch was performed using surgical clips. For 155 fractions (ie, 5-6 fractions/patient), a cone beam computed tomography (CT) scan was available. Analysis concerned: (1) visibility of the clips, (2) migration of the clips, (3) comparison of setup errors according to both match methods, and (4) comparison of target coverage by recalculating the dose on the online setup-corrected cone beam CT scan with the patient setup according to both match methods. External validation of the surgical clip-based online setup verification was performed in 23 patients by analyzing kilovoltage images of 100 fractions, obtained after treatment. RESULTS: All types of surgical clips could be visualized. The clip to center-of-mass distance decreased on average by 2 mm (standard deviation, 1) over the course of treatment. Setup differences between match methods were on average <0.5 mm in all directions. The reconstructed dose distributions showed standard deviations of volumes receiving 95% or 107% of prescribed dose and mean dose of the breast and boost planning target volume were similar for the planning CT and the cone beam CTs, for both match procedures. An external validation in 23 patients showed reassuring setup errors <2 mm. CONCLUSIONS: Online setup verification using surgical clips results in comparable setup corrections and target volume coverage as verification using skin markers. By omitting skin markers acute skin toxicity beneath the markers is prevented. PMID- 28666905 TI - Triphasic contrast enhanced CT simulation with bolus tracking for pancreas SBRT target delineation. AB - PURPOSE: Bolus-tracked multiphasic contrast computed tomography (CT) is often used in diagnostic radiology to enhance the visibility of pancreas tumors, but is uncommon in radiation therapy pancreas CT simulation, and its impact on gross tumor volume (GTV) delineation is unknown. This study evaluates the lesion conspicuity and consistency of pancreas stereotactic body radiation therapy (SBRT) GTVs contoured in the different contrast phases of triphasic CT simulation scans. METHODS AND MATERIALS: Triphasic, bolus-tracked planning CT simulation scans of 10 consecutive pancreas SBRT patients were acquired, yielding images of the pancreas during the late arterial (LA), portal venous (PV), and either the early arterial or delayed phase. GTVs were contoured on each phase by a gastrointestinal-specialized radiation oncologist and reviewed by a fellowship trained abdominal radiologist who specializes in pancreatic imaging. The volumes of the registered GTVs, their overlap ratio, and the 3-dimensional margin expansions necessary for each GTV to fully encompass GTVs from the other phases were calculated. The contrast difference between tumor and normal pancreas was measured, and 2 radiation oncologists rank-ordered the phases according to their value for the lesion-contouring task. RESULTS: Tumor-to-pancreas enhancement was on average much larger for the LA and PV than the delayed phase or early arterial phases; the LA and PV phases were also consistently preferred by the radiation oncologists. Enhancement differences among the phases resulted in highly variable GTV volumes with no observed trends. Overlap ratios ranged from 18% to 75% across all 3 phases, improving to 43% to 91% when considering only the preferred LA and PV phases. GTV expansions necessary to encompass all GTVs ranged from 0.3 to 1.8 cm for all 3 phases, improving slightly to 0.1 to 1.4 cm when considering just the LA and PV phases. CONCLUSIONS: For pancreas SBRT, we recommend combining the GTVs from a multiphasic CT simulation with bolus-tracking, including, at a minimum, a Boolean "OR" of the LA and PV phases. PMID- 28666907 TI - Clinical outcomes of helical conformal versus nonconformal palliative radiation therapy for axial skeletal metastases. AB - PURPOSE: Palliative radiation therapy (RT) for bone metastases has traditionally been delivered with conventional, nonconformal RT (NCRT). Conformal RT (CRT) is potentially more complex and expensive than NCRT, but may reduce normal tissue dose and subsequently toxicity. In this retrospective analysis, we compared CRT with NCRT to investigate the association between conformality and toxicity. METHODS AND MATERIALS: A retrospective analysis of patients receiving palliative RT for axial skeletal bone metastases from 2012 to 2014 was conducted. Patient and treatment characteristics were obtained including dosimetric variables, acute toxicity, and subjective pain during treatment and in the acute posttreatment period (<=60 days after completion). Statistical analyses included t tests, chi2 tests, and multivariate logistic regression. RESULTS: A total of 179 patients and 254 bone metastases were identified (142 CRT, 112 NCRT). The CRT and NCRT groups were well matched for baseline characteristics (number of fractions, field size, treatment sites, and concurrent chemotherapy). In multivariate logistic regression models, technique (CRT vs NCRT) was not associated with development of acute toxicity. Regarding toxicity, Eastern Cooperative Oncology Group performance status and total dose were significantly associated with a higher rate of acute toxicity during RT (odds ratios, 0.649 and 1.129 and P = .027 and .044, respectively), and only a higher number of vertebral bodies in the treatment field was significantly associated with acute toxicity post-treatment (odds ratios, 1.219, P = .028). CRT was associated with improvement in bone pain during and posttreatment (P = .049 and .045, respectively). CONCLUSIONS: Our results demonstrate no difference in acute toxicity following palliative RT with CRT compared with NCRT for painful bone metastases; however, treatment volume did predict for increased toxicity. Larger studies may further elucidate the value of CRT including the impact of dose escalation for bone metastases and differences in patient reported outcomes between RT techniques. PMID- 28666906 TI - Craniospinal irradiation prior to stem cell transplant for hematologic malignancies with CNS involvement: Effectiveness and toxicity after photon or proton treatment. AB - PURPOSE/OBJECTIVE(S): Craniospinal irradiation (CSI) improves local control of leukemia/lymphoma with central nervous system (CNS) involvement; however, for adult patients anticipating stem cell transplant (SCT), cumulative treatment toxicity is a major concern. We evaluated toxicities and outcomes for patients receiving proton or photon CSI before SCT. METHODS AND MATERIALS: We identified 37 consecutive leukemia/lymphoma patients with CNS involvement who received CSI before SCT at our institution. Photon versus proton toxicities during CSI, transplant, and through 100 days posttransplant were compared using Fisher exact and Wilcoxon rank sum tests. Long-term neurotoxicity, disease response, and overall survival were analyzed. RESULTS: Thirty-seven patients (23 photon, 14 proton) underwent CSI for CNS involvement of acute lymphoblastic leukemia (49%), acute myeloblastic leukemia (22%), chronic lymphocytic leukemia (3%), chronic myelocytic leukemia (14%), lymphoma (11%), and myeloma (3%). CSI was used for consolidation (30 patients, 81%) and gross disease treatment (7 patients, 19%). Median radiation dose (interquartile range) was 24 Gy (23.4-24) for photons and 21.8 Gy (21.3-23.6) for protons (P = .03). Proton CSI was associated with lower rates of Radiation Therapy Oncology Group grade 1-3 mucositis during CSI (7% vs 44%, P = .03): 1 grade 3 with protons versus 5 grade 1, 3 grade 2, and 2 grade 3 with photons. During CSI, other toxicities (infection, gastrointestinal symptoms) did not differ. Allogeneic stem cell transplant (SCT) was used in 95% of patients, with 53% of patients in remission before SCT. Myeloablative conditioning was used for 76%. During SCT admission and 100 days post-SCT, toxicities did not differ by CSI technique. Successful engraftment occurred in 95% of patients (P = .67). Progression or death occurred for 47% of patients, with only 1 CNS relapse. CONCLUSION: In our cohort, CSI offered excellent local control for CNS-involved hematologic malignancies in the pre-SCT setting. Acute mucositis occurred less frequently with proton CSI with comparable peritransplant/long-term toxicity profile, suggesting the need to further explore the benefit/toxicity profile of this technique. PMID- 28666908 TI - Volumetric modulated Dynamic WaveArc therapy reduces the dose to the hippocampus in patients with pituitary adenomas and craniopharyngiomas. AB - PURPOSE: Reducing the radiation dose to the hippocampus is important to preserve cognitive function in patients with brain tumors. The Vero4DRT system can realize a new irradiation technique, termed volumetric-modulated Dynamic WaveArc therapy (VMDWAT), which allows the safe use of sequential noncoplanar volumetric modulated beams without couch rotation. Because VMDWAT appears to reduce the hippocampal dose in patients with pituitary adenomas and craniopharyngiomas, we performed a planning study to compare the dose distribution of volumetric modulated arc therapy using only a coplanar arc (coVMAT) and VMDWAT. METHODS AND MATERIALS: CoVMAT and VMDWAT plans were created for 30 patients with pituitary adenomas and craniopharyngiomas. The prescription dose was 52.2 Gy in 29 fractions, with 99% of each planning target volume covered by 90% of the prescribed dose. Optimization was performed for maximal reduction of the dose to the hippocampus. Treatment time was defined as the beam-on time. RESULTS: The mean equivalent dose in 2 Gy fractions to 40% of the volume of the bilateral hippocampus (EQD40%) for coVMAT/VMDWAT were 9.90/5.31 Gy, respectively (P < .001). The mean EQD40% in VMDWAT was less than 7.3 Gy, which is the threshold for predicting cognitive impairment. Although the volume of normal brain receiving 5 Gy (V5) was significantly larger in VMDWAT, compared with coVMAT, the normal brain volume receiving 10, 15, 20, 25, 30, 35, 40, 45, and 50 Gy (V10-50) was significantly smaller in VMDWAT. The conformity and homogeneity indices were significantly better in VMDWAT. The mean VMDWAT treatment time was longer compared with coVMAT (70.1 vs 67.1 seconds, respectively). CONCLUSIONS: Although VMDWAT increased brain V5 and the treatment time compared with coVMAT, it significantly reduced the dose to the hippocampus and brain V10 to V50 and improved target conformity and homogeneity. VMDWAT could be a promising treatment technique for pituitary adenomas and craniopharyngiomas. PMID- 28666909 TI - The healing influence of nature. PMID- 28666910 TI - Pregnancy discovered during radiation of an atypical meningioma. PMID- 28666911 TI - Geometrical Complexity of Cortical Microvascularization in Moyamoya Disease. AB - BACKGROUND: Dilatation of the microvascular diameter is recognized in moyamoya disease and referred to as microvascularization. The purpose of this study was to characterize the cortical microvascularization in moyamoya disease using imaging analysis, and to explore the developmental mechanism of the collateral network around the cortical surface. METHODS: A total of 20 hemispheric sides of 14 patients with moyamoya disease were included in this study. From the intraoperative images, cortical surface images were extracted, and binary images were subsequently created. Then the ratio of the microvessels of the brain surface (vascular fraction; VF) and the box-counting fractal dimension (Db) values were calculated. The VF and Db values in the moyamoya disease group were then compared with those in atherosclerotic disease and nonischemic disease groups, and assessed in terms of clinical and radiologic factors. RESULTS: VF was significantly higher in the moyamoya disease group compared with the atherosclerotic disease group, and Db was significantly higher in the moyamoya disease group compared with the atherosclerotic disease and nonischemic disease groups. In the moyamoya disease group, VF showed a moderate correlation with magnetic resonance angiography (MRA) score. Moreover, Db was significantly higher in the pediatric patients, in the presence of ischemic symptoms, and in the presence of ivy sign, and Db showed a moderate correlation with MRA score and cerebral blood flow in moyamoya disease. CONCLUSIONS: In the patients with moyamoya disease, the cortical microvascularization exhibited increased Db and dilatation of the pial arteries. In moyamoya disease, cortical microvascularization is associated with clinical and radiologic factors. This microvascularization might be a compensatory mechanism in the ischemic condition in moyamoya disease. PMID- 28666912 TI - Outcome After Subarachnoid Hemorrhage from Blood Blister-Like Aneurysm Rupture Depends on Age and Aneurysm Morphology. AB - BACKGROUND: Blood blister-like aneurysms (BBLA) are rare, challenging to treat, and prone to rerupture. We analyzed our results in relationship to type of BBLA and other prognostic factors. METHODS: Data on patient and aneurysm characteristics, clinical course, and treatment results, including data from patient records and review of imaging findings, were collected prospectively and analyzed retrospectively. RESULTS: There were 27 patients (mean age 56 years) with subarachnoid hemorrhage from BBLA. Of patients, 13 (48%) had BBLA of the internal carotid artery, 6 had BBLA of the anterior cerebral artery (22%), 5 had BBLA of the middle cerebral artery (19%), and 3 had BBLA of the basilar artery (11%). Most patients (n = 12) had a circumferential type IV BBLA (44%). BBLAs were treated by clip-reinforced wrapping in 13 patients (48%) and by clipping alone in 8 patients (30%); 3 (11%) patients received no treatment. The 3 remaining patients were treated endovascularly, by combined treatment, or by fenestration tube technique. Rerupture after treatment occurred in 4 patients (15%), all of whom had type IV BBLAs. Outcome was unfavorable (modified Rankin scale score 3-6) in 52% (n = 14). The highest rates of rerupture (33%), delayed infarctions (67%), unfavorable outcome (75%), and death (50%) were identified in type IV BBLAs; type I-III BBLAs had a better course. CONCLUSIONS: Treatment of BBLA is challenging. Patients with type IV BBLAs were especially prone to rerupture, delayed infarctions, unfavorable outcomes, and death. Independent risk factors for unfavorable outcome were advanced age (>=60 years) and type IV BBLA. PMID- 28666913 TI - Clinical and Molecular Prognostic Factors for Long-Term Survival of Patients with Glioblastomas in Single-Institutional Consecutive Cohort. AB - OBJECTIVE: The purpose of this study was to clarify the clinical and molecular characteristics associated with long-term survival in patients with glioblastoma. METHODS: We analyzed the characteristics of 96 glioblastoma patients. Long-term survivors (LTSs) were classified into moderate LTSs (mLTSs), who survived >3 years, and LTSs, who survived >5 years, and compared with short-term survivors (STSs). Clinical and molecular factors were investigated. RESULTS: Younger age, better recursive partitioning analysis class, lack of subventricular zone (SVZ) involvement, promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, and loss of 19q were associated with mLTSs as compared with STSs. After adjustment for these factors, younger age and MGMT methylation remained independently associated with mLTSs. Younger age, better recursive partitioning analysis class, lack of SVZ involvement, and loss of 19q were associated with LTSs as compared with STSs. After adjustment, younger age and better preoperative Karnofsky performance scale (KPS) score remained independently associated with LTSs. Kaplan-Meier analyses revealed that younger age (<50 years), better preoperative KPS score (>=70), lack of SVZ involvement, and loss of 19q were associated with longer overall survival. In the multivariate analysis, only age was significantly associated with overall survival. CONCLUSIONS: Younger age and better preoperative KPS score were the characteristics associated with LTSs as compared with STSs. MGMT promoter methylation was associated with mLTSs, but not with LTSs. In addition, lack of SVZ involvement and loss of 19q might be prognostic for longer survival. PMID- 28666914 TI - Trends in Management of Intracranial Meningiomas: Analysis of 49,921 Cases from Modern Cohort. AB - OBJECTIVE: We sought to characterize patterns and treatment for intracranial meningiomas in the Surveillance, Epidemiology, and End Results set of cancer registries. METHODS: SEER data was queried from 2004-2012 for cases of intracranial meningioma using appropriate topography and histology codes. RESULTS: A total of 49,921 patients with intracranial meningioma were identified. The vast majority of cases were associated with a benign histology (n = 47,047, 94.2%). There were 21,145 patients (42.4%) who underwent surgical management, 2783 who received radiation alone (5.6%), and 25,993 who underwent surveillance only (52.1%). Surgical management decreased in frequency from 48.8% of all cases in 2004 to 38.3% of cases in 2012 (P < 0.001). Radiation alone remained stable over time with a range of 4.8%-6.3% of cases. Observation increased from 45.0% of cases in 2004 to 56.7% of cases in 2012 (P < 0.001). On unadjusted analysis, surgical management was associated with younger age and larger tumor size. The incidence of tumors <2 cm in size increased significantly over the study period from 29.7% in 2004 to 41.7% in 2012 (P < 0.001). After adjusting for tumor size, multivariable analysis demonstrated that the odds of observation as a primary management strategy were greater in 2012 relative to 2004 (odds ratio 1.33, 95% confidence interval 1.21-1.45). CONCLUSION: The incidence of intracranial meningiomas increased, while tumor size at the time of diagnosis decreased. Moreover, the number undergoing no treatment increased as a treatment strategy and was more likely employed for older patients, those of African-American race, and those with smaller tumors. PMID- 28666915 TI - Dr. Norman Chater and Chater's Point. AB - Dr. Norman Chater, a University of California San Francisco-trained microvascular neurosurgeon, dedicated his career to the development of surgical bypass techniques. His work contributed to advancements in microvascular anatomy and the development of cerebral revascularization techniques. He identified Chater's point, an extracranial landmark that marks the posterior extent of the Sylvian fissure, which on craniectomy reliably exposes vessels of the angular gyrus, the vasculature found to be most appropriate for bypass procedures owing to its accessibility and vascular diameter. This surgical landmark continues to be essential for the successful execution of bypass surgeries to this day. PMID- 28666916 TI - Emerging roles for conjugated sterols in plants. AB - In plants, sterols are found in free form (free sterols, FSs) and conjugated as steryl esters (SEs), steryl glycosides (SGs) and acyl steryl glycosides (ASGs). Conjugated sterols are ubiquitously found in plants but their relative contents highly differ among species and their profile may change in response to developmental and environmental cues. SEs play a central role in membrane sterol homeostasis and also represent a storage pool of sterols in particular plant tissues. SGs and ASGs are main components of the plant plasma membrane (PM) that specifically accumulate in lipid rafts, PM microdomains known to mediate many relevant cellular processes. There are increasing evidences supporting the involvement of conjugated sterols in plant stress responses. In spite of this, very little is known about their metabolism. At present, only a limited number of genes encoding enzymes participating in conjugated sterol metabolism have been cloned and characterized in plants. The aim of this review is to update the current knowledge about the tissue and cellular distribution of conjugated sterols in plants and the enzymes involved in their biosynthesis. We also discuss novel aspects on the role of conjugated sterols in plant development and stress responses recently unveiled using forward- and reverse-genetic approaches. PMID- 28666917 TI - Blind ending vessels on diagnostic laparoscopy for nonpalpable testis: Is a nubbin present? AB - INTRODUCTION: The traditional management paradigm for nonpalpable testis (NPT) has been that inguinal or scrotal exploration for a nubbin may be omitted when blind ending vessels are observed during diagnostic laparoscopy. Our aim was to examine whether blind ending vessels excluded the presence of a nubbin in a series of boys who underwent exploration in this setting. MATERIALS AND METHODS: Using a surgical database and chart review, pre-pubertal boys (<=12 years) with the diagnosis of undescended or atrophic testis who underwent a diagnostic laparoscopy for unilateral NPT between 2000 and 2015 were retrospectively identified. Physical exam, procedural and pathologic findings were confirmed by chart review. RESULTS: 595 boys underwent diagnostic laparoscopy for NPT by 11 surgeons. Of these, 318 had an intra-abdominal testis and 18 underwent diagnostic laparoscopy alone. Of the remaining 259, 32 had an open internal ring and inguinal or scrotal exploration was performed. The remaining 227 with a closed ring comprised the cohort for our analysis, of whom 188 had vessels entering the ring, 36 had blind ending vessels, and in three the vessel status was unavailable. In the 188 boys with vessels entering the ring, 164 (87%) had a nubbin excised during inguinal or scrotal exploration, of which 93% were grossly identified as an atrophic testis. Pathology confirmed the presence of hemosiderin in 44% and calcifications in 54%. In the 36 boys with blind ending vessels, 26 (72%) had a nubbin excised during inguinal or scrotal exploration, of which 96% were grossly identified as an atrophic testis. Pathology confirmed hemosiderin in 54% and calcifications in 58%. All seven cases with both blind ending vas and vessels had an atrophic testis grossly identified. Of all 207 excised remnants in this series, nubbins with viable testicular elements (seminiferous tubules in 11, germ cells in two) were only excised during cases that reported a non-atretic vas or any vessels entering the internal ring. CONCLUSION: In this large multi institutional series, blind ending vessels were associated with a nubbin noted during inguinal or scrotal exploration in the majority of cases. Based on this series if the surgeon's goal is to remove all nubbins, exploration is necessary regardless of vessel appearance. However, viable testicular elements were rarely identified and only when either a non-atretic vas or any vessels were observed to enter the ring. PMID- 28666918 TI - Urinary tract infection after retrograde urethrogram in children: A multicenter study. AB - INTRODUCTION: The risk of post-procedural urinary tract infection (ppUTI) after retrograde urethrogram (RUG) has not been well quantified. Prophylactic antibiotics may reduce the risk, but must be weighed against the risks of antibiotic resistance. Prior research has shown that this risk is variable after voiding cystourethrogram (0-42% reported ppUTI rate) and appears to be low after urodynamics (0-4.8%) but this risk has not been well documented for patients undergoing RUG. OBJECTIVE: We aimed to (1) describe the rate of ppUTI after RUG, and (2) examine factors associated with use of antibiotics at the time of RUG. STUDY DESIGN: We conducted a retrospective cohort study of children undergoing RUG at two hospitals January 1, 2004, to December 31, 2014. ppUTI within 7 days was measured. Antibiotic prophylaxis was determined. Relationships between clinical characteristics and receipt of pre-procedure antibiotics were evaluated using univariate statistics. RESULTS: Forty-two patients (100% male, median age 11.7 years) underwent 47 RUGs. Indications included trauma (27%), hypospadias (17%), and non-hypospadias (27%) stricture. Study indication and antibiotic administration practices are illustrated in the Figure. Three patients (6.4%) had a history of posterior urethral valves (PUV); one had neurogenic bladder (NGB) (2.4%). Two (4%) studies were performed within 30 days of a clinical UTI and 11% had a positive urinalysis or culture within 30 days pre-RUG. UTI in the 30 days before RUG was not associated with antibiotic prescription (p > 0.99). One child (2.1%; 95% CI 0-6.3%) had a ppUTI: a 7-year-old, uncircumcised male with a history of PUV and voiding dysfunction who was asymptomatic at the time of RUG. DISCUSSION: Although the risk of ppUTI after RUG appears to be low, the rare occurrence of an iatrogenic UTI can lead to high cost and patient morbidity, particularly in cases similar to our patients who required inpatient admission for intravenous antibiotics. To help balance the risk of UTI with the associated healthcare costs and morbidity with the concerns about antibiotic overuse and potential exposure to drug reaction, data from this study may inform future development of evidence-based guidelines targeting only patients at highest risk for ppUTI with antibiotic prophylaxis. CONCLUSIONS: The risk of ppUTI after RUG is low. Antibiotic prophylaxis was unrelated pre-RUG UTI in our population. These results indicate the need for pre-procedural antibiotic prescribing guidelines, and suggest that routine antibiotics prior to RUG are not indicated unless the patient has another indication for antibiotics. PMID- 28666919 TI - Age, molecular subtypes and local therapy decision-making. AB - The relationship between age and breast cancer subtype is complex: both impact risk of locoregional recurrence (LRR) and survival. Young patients frequently present with aggressive tumors but the increased risk imparted by young age appears to differ among breast cancer subtypes. Dramatic improvements in local control among young women with breast cancer of all tumor subtypes have been observed, likely attributable to improved local therapy strategies, improvements in adjuvant therapies and implementation of subtype-specific targeted therapies. In the light of these improvements in local control, accumulating evidence demonstrates that there is no difference in LRR or survival between breast conserving therapy (BCT) and mastectomy in young patients. An increased risk of LRR in triple-negative cancers is apparent; yet this increased risk of LRR is present following surgical treatment with both BCT and mastectomy and does not significantly differ by age. Also, contralateral breast cancer rates remain low for all age groups and, although the use of contralateral prophylactic mastectomy (CPM) has increased, there is no evidence that CPM improves survival. At the other end of the age spectrum, there is a growing body of evidence demonstrating a favorable interaction between older age and molecular subtype such that many older women with estrogen receptor positive breast cancer may be spared axillary staging and/or radiation therapy without a detrimental impact on survival. Thus for both age and subtype, it appears that the intrinsic biology is the strongest predictor of outcome. Tumor biology, and not age, should be the driver in local therapy decision-making. PMID- 28666920 TI - Neoadjuvant therapy for triple negative and HER2-positive early breast cancer. AB - Today, neoadjuvant therapy can be considered a therapy standard in triple negative (TNBC) and in HER2-positive (HER2+) (particularly in HER2+ HR-) early breast cancer (EBC). Patients with a pathological complete response (pCR) will have a very favorable outcome. In TNBC, chemotherapy with anthracyclines and taxanes is standard. Data regarding addition of bevacizumab are rather heterogeneous. Addition of carboplatin improves pCR rates independent of BRCA status; whether this will translate into a survival benefit is still unclear. In HER2-positive (HER2+) disease, anti-HER2 antibody therapy with trastuzumab is given together with chemotherapy. For patients at high risk of relapse, dual HER2 blockade with trastuzumab and pertuzumab is standard. The chemotherapy backbone consists either of an anthracycline-taxane sequence or of an anthracycline-free regimen such as docetaxel and carboplatin. pCR rates depend on hormone receptor (HR) status. Anti-HER2 therapy is completed after surgery with trastuzumab for a total of one year. Future research needs to focus on avoiding overtreatment in patients with pCR (de-escalation) as well as on improved therapy options (escalation) for patients with non-pCR after standard neoadjuvant therapy. Here, early response markers (e.g. biomarkers, molecular imaging) as well as novel targeted agents may play an important role in the future. PMID- 28666921 TI - Intratumoral heterogeneity and subclonal diversification of early breast cancer. AB - Heterogeneity has long been recognized as a feature of some primary breast cancers manifesting as mixed histopathological subtypes or variable expression of the therapeutic targets ER, PgR and HER2. The recent emergence of next generation sequencing (NGS) technologies has revolutionized our understanding of the extent and nature of subclonal diversification. Careful examination of primary breast cancers often reveals multiple genomically distinct subclones that may contain driver alterations that follow spatial patterns of segregation. Subclonality is of clinical relevance as it forms the substrate of selection and can give rise to aggressive clinical features such as invasiveness, metastasis and treatment resistance. However, spatial and temporal intra-tumoral heterogeneity pose fundamental challenges to representative sampling and consequently the feasibility of a personalized medicine approach. Fundamental clinical and biological questions are starting to be addressed by applying NGS to the study of intra-tumoral heterogeneity and the insights that it provides should be used to better inform the prospective design of clinico-genomics trials. PMID- 28666922 TI - Controversies in treatment selection for patients with equivocal ER and HER2 results. AB - Formally, the term "equivocal" should not be used when reporting results of the assessment of ER status, but controversies exist about the prognostic and predictive value of a low ER expression (i.e. 1-9% positive cells) in breast cancer (so called ER-poor tumors). Because of the rarity of these cases, prospective clinical trials have not been conducted (and are unlikely to be conducted in the future) to define the optimal treatment strategy for the small subset of patients with ER-poor breast cancer. Therefore, the only available data stem from retrospective subgroup analyses of randomized clinical trials or from clinical datasets of individual Institutions. The still unanswered question is whether these tumors are responsive to endocrine treatment, and what is the magnitude of the benefit of endocrine interventions for patients with ER-poor breast cancer. Since a potentially life-saving benefit from empirical adjuvant endocrine therapy cannot be excluded, the safest clinical approach may be to consider both adjuvant endocrine therapy and chemotherapy in this rare subset of patients. Testing for HER2 overexpression by immunohistochemistry or for gene amplification by in situ hybridization techniques may end up with equivocal results. Patients with equivocal HER2 status were not eligible for the pivotal clinical trials of adjuvant trastuzumab, and the possible benefit of HER2 targeted therapies for this subset of patients is unknown. The clinical results of the NSABP B47 clinical trial will eventually clarify if trastuzumab is effective, and what is the magnitude of its effect, in this patient population. PMID- 28666923 TI - Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway. AB - Allopregnanolone, a neurosteroid whose levels rise throughout gestation, putatively stabilizes antenatal mood. The present study aimed to investigate associations of plasma allopregnanolone to antenatal depressive symptoms, as well as to genetic and obstetric factors. Allopregnanolone plasma levels from 284 pregnant women were measured around gestational week 18. Haplotype tag single nucleotide polymorphisms in the aldo-keto reductase family 1, members C2 and C4 (AKR1C2, AKR1C4), and steroid 5 alpha-reductase 1 and 2 (SRD5A1, and SRD5A2) genes were genotyped in a larger sample of pregnant women (n=1351). The Edinburgh Postnatal Depression Scale (EPDS) was administered via web-questionnaires in gestational weeks 17 and 32. Demographic and obstetric data was retrieved from web-questionnaires and medical records. There was no association between allopregnanolone levels and depressive symptoms. Furthermore, no associations between allopregnanolone level and synthesis pathway genotypes were found after accounting for multiple comparisons. However, exploratory analyses suggested that the women who were homozygous for the minor allele of the AKR1C2 polymorphism rs1937863 had nominally lower allopregnanolone levels and lower depression scores in gestational week 17, but also the highest increase in depression scores between week 17 and 32. Additionally, higher body mass index was associated with lower allopregnanolone levels. The results do not support second trimester plasma allopregnanolone as a mood stabilizing factor. However, we speculate that AKR1C2 variation may alter the susceptibility to depressive symptoms through effects on central allopregnanolone synthesis. Another implication of this study is that the relationship between neuroactive steroids and obesity in pregnancy deserves to be investigated. PMID- 28666924 TI - Role of carbon source in the shift from oxidative to hydrolytic wood decomposition by Postia placenta. AB - Brown rot fungi initiate wood decay using oxidative pretreatments to improve access for cellulolytic enzymes. These pretreatments are incompatible with enzymes, and we recently showed that Postia placenta overcomes this issue by delaying glycoside hydrolase (GH) gene upregulation briefly (<48h) until expression of oxidoreductases (ORs) is repressed. This implies an inducible cellulase system rather than a constitutive system, as often reported, and it remains unclear what cues this transition. To address this, we grew P. placenta along wood wafers and spatially mapped expression (via quantitative PCR) of twelve ORs and GHs targeted using functional genomics analyses. By layering expression patterns over solubilized sugar data (via HPLC) from wood, we observed solubilization of wood glucose, cellobiose, mannose, and xylose coincident with the OR-GH transition. We then tested effects of these soluble sugars, plus polymeric carbon sources (spruce powder, cellulose), on P. placenta gene expression in liquid cultures. Expression of ORs was strictly (aox1, cro5) or progressively repressed over time (qrd1, lcc1) by all soluble sugars, including cellobiose, but not by polymeric sources. Simple sugars repressed hemicellulase gene expression over time, but these sugars did not repress cellulases. Cellulase genes were upregulated, however, along with hemicellulases in the presence of soluble cellobiose and in the presence of polymeric carbon sources, relative to starvation (carbon-free). This verifies an inducible cellulase system in P. placenta that lacks carbon catabolite repression (CCR), and it suggests that brown rot fungi use soluble sugars, particularly cellobiose, to cue a critical oxidative-hydrolytic transition. PMID- 28666926 TI - Proliferation index of different Gleason pattern 4 histomorphologies and associated pattern 3 adenocarcinoma of the prostate. AB - Gleason grade is one of the most powerful prognostic indicators for adenocarcinoma of the prostate. A higher proliferation index of prostatic adenocarcinoma has been demonstrated in numerous studies to be significantly associated with more aggressive behavior. To date, the proliferation index of the different Gleason pattern 4 histomorphologies, including cribriform, fused glands, and poorly formed glands, has not been determined. The aim of this investigation was to quantitate and compare the proliferation index, as assessed by Ki67 labeling index, of different Gleason pattern 4 histomorphologies. We also analyzed the Ki67 labeling index of Gleason pattern 3 adenocarcinoma associated with and without cribriform adenocarcinoma. Among Gleason pattern 4 morphologies, cribriform adenocarcinoma exhibited a higher mean proliferation index at 5.3% compared to fused gland adenocarcinoma at 3.9% (P = .03) and poorly formed glands at 3.6% (P < .01). The mean Ki67 labeling index for Gleason pattern 3 associated with cribriform adenocarcinoma was higher at 4.1% compared to pure Gleason pattern 3 at 2.2% (P < .01) and Gleason pattern 3 associated with non-cribriform pattern 4 adenocarcinoma at 2.9% (P = .02). This higher proliferation index of Gleason pattern 3 adenocarcinoma associated with cribriform pattern 4 adenocarcinoma indicates that not all Gleason pattern 3 cells are identical and that cribriform adenocarcinoma may influence or be related to associated Gleason pattern 3. Gleason pattern 4 adenocarcinoma of the prostate with cribriform growth has a higher proliferation index than other grade 4 histomorphologies, consistent with the more clinically aggressive nature of cribriform adenocarcinoma of the prostate. PMID- 28666925 TI - EZH2 upregulation correlates with tumor invasiveness, proliferation, and angiogenesis in human pituitary adenomas. AB - Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb repressive complex 2, which epigenetically represses genes involved in tumorigenesis and is highly expressed in tumors. However, no studies have investigated EZH2 expression and its clinical significance in human pituitary adenomas (PAs). Therefore, we examined the expression pattern of EZH2 in PAs and studied the correlations between protein expression and invasiveness, proliferation, angiogenesis, hormone functioning, and some other factors. We measured EZH2 and MMP-14 protein and EZH2 mRNA expression in 62 samples of PAs by immunohistochemistry staining and quantitative real-time polymerase chain reaction and correlated protein expression relative to clinicopathologic features. The immunopositive rate of EZH2 was 88.7% (55/62). The extent of expression was associated with invasiveness, microvessel density, and proliferation (Ki-67 index). Moreover, EZH2 expression correlated with MMP-14 expression. We did not find any correlation between EZH2 overexpression and hormone-secreting function or patient age or sex. The quantitative real-time polymerase chain reaction analysis revealed that the amount of EZH2 mRNA was significantly higher in invasive than in noninvasive adenomas. This is the first report to describe EZH2 overexpression in human PAs, especially invasive adenomas. Thus, EZH2 is a potentially useful diagnostic marker and pharmacotherapeutic target for invasive PAs. PMID- 28666928 TI - Giant Thebesian Valve Appearing As a Right Atrial Mass. PMID- 28666927 TI - Prognostic significance of IgG4+ plasma cell infiltrates following neoadjuvant chemoradiation therapy for esophageal adenocarcinoma. AB - Lymphoplasmacytic infiltrates in esophageal adenocarcinoma (EAC) tissue following chemoradiotherapy (CRT) reflect alterations in the tumor immunoenvironment. The presence and role of plasma cells in this process are poorly understood. Our aim was to characterize the IgG4+ plasma cell population in EAC following CRT. Seventy-one esophagectomy specimens post-CRT were compared with a surgery-only group of 31 EACs. The distribution, density, and ratio of IgG4+ and IgG+ plasma cells were evaluated by immunohistochemistry and correlated with clinicopathologic features, treatment response, and survival. In the CRT group, the presence of higher numbers of IgG4+ (>= median of 94/high-power field) and IgG+ (>= median of 225/high-power field) plasma cells and increased IgG4+/IgG+ ratio (>= median of 41%) within ulcers was associated with complete or near complete treatment response (P = .0077, P = .0503, and P = .0063, respectively). Lower tumor grade, smaller tumor size, and higher levels of IgG4+ plasma cells in posttherapy ulcers significantly correlated with better overall survival, whereas pretherapy clinical stage, posttherapy pathologic stage, smaller tumor size, and lower tumor grade were associated with longer recurrence-free survival. Multivariate analysis revealed that both posttherapy pathologic stage and high IgG4+ plasma cells in ulcers were independent predictors of overall survival (P = .05 and P = .01), whereas only posttherapy pathologic stage was associated with recurrence-free survival (P < .01). This is the first study describing a dense IgG4+ plasma cell infiltrate in EAC following CRT. The presence of increased IgG4+ plasma cells may be a novel reliable factor to predict prognosis of EAC patients following CRT. PMID- 28666929 TI - Fluid Responsiveness After CArdiac Surgery (FRACAS): A Prospective Observational Study Using Peripheral Near-Infrared Spectroscopy. AB - OBJECTIVES: To describe tissue oxygen saturation (StO2) in response to a vascular occlusion test using thenar eminence and forearm near-infrared spectroscopy (NIRS) and the association with volume responsiveness after cardiac surgery. DESIGN: Single-center, prospective, observational cohort study. SETTING: Cardiothoracic intensive care unit. PARTICIPANTS: Seventy-six post-cardiac surgical adults. INTERVENTIONS: Immediately before and 10 minutes after a 250-to 500 mL fluid bolus, StO2 was measured in response to a vascular occlusion test to calculate tissue deoxygenation (Rdes) and reoxygenation (Rres) rates. Concurrently, systemic hemodynamic, metabolic, and blood gas variables were collected. MEASUREMENTS AND MAIN RESULTS: A total of 203 boluses were captured using thenar NIRS and 141 boluses using forearm NIRS. Approximately 25% of boluses increased cardiac output by >=15% (volume responders). Thenar and forearm Rdes decreased in responders, but increased (thenar) or remained unchanged (forearm) in nonresponders. A logistic regression model of the association among StO2, Rdes and Rres, and volume responsiveness was significant for thenar measurements (p = 0.001) with an area under the receiver operating characteristic of 0.69 (95% confidence interval: 0.62-0.75). It also was significant (p = 0.02) for forearm measurements, with an area under the receiver operating characteristic of 0.71 (0.62-0.79). Rdes was an independent variable in both instances (odds ratio 0.31 [0.14-0.69], thenar; odds ratio 0.60 [0.45-0.80], forearm). Thenar and forearm NIRS variables were correlated poorly with cardiac output, stroke volume, systemic oxygen delivery and consumption index, mixed venous, and central venous oxygen saturation (Spearman's coefficients, r = 0.17 0.46, p < 0.002). CONCLUSION: In post-cardiac surgical patients, thenar and forearm NIRS variables were associated with volume responsiveness although not achieving precision necessary for clinical management. PMID- 28666930 TI - Delirium Following Transcatheter Aortic Valve Replacement: National Inpatient Sample Analysis. AB - OBJECTIVE: To investigate the risk factors for postoperative delirium and the impact of delirium on mortality and morbidity following transcatheter aortic valve implantation (TAVI). DESIGN: Patients who underwent TAVI were identified using the International Classification of Diseases, 9th revision clinical modification codes from the National Inpatient Sample database. Statistical analysis of preoperative and perioperative risk factors was done to identify the independent risk factors for delirium after TAVI. SETTING: Multi-institutional. PARTICIPANTS: Patients who underwent TAVI from 2012 to 2013. INTERVENTIONS: TAVI. MEASUREMENTS AND MAIN RESULTS: Over the period of 2 years (2012-2013), 7,566 patients underwent TAVI. The incidence of delirium post-TAVI was 4.57% (345). Age >85 (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.01-1.05; p = 0.003), electrolyte abnormalities (OR 1.83; 95% CI 1.17-2.87; p = 0.008), prior neurologic illness (OR 1.67; 95% CI 1.10-3.15; p = 0.01), and weight loss in the hospital (OR 1.77; 95% CI 1.05-2.99; p = 0.03) were independent risk factors for postoperative delirium (POD). Unilateral or bilateral carotid stenosis did not predispose to the development of delirium. POD was an independent risk factor for procedural morbidity (OR 3.29; 95% CI 2.05-5.28; p < 0.001). POD did not increase the risk of in-house mortality after TAVI. CONCLUSION: Age of >85, electrolyte disturbance, pre-existing neurologic disease and weight loss were found to be independent risk factors for delirium. POD was associated significantly with morbidity. Owing to a significant increase in the morbidity, a thorough screening protocol and effective strategies to predict, prevent, and treat postoperative delirium would reduce the cost associated with TAVI. PMID- 28666931 TI - Perioperative Management of the Micra Leadless Pacemaker. PMID- 28666932 TI - Acute Type-B Aortic Dissection in Pregnancy: Therapeutic Challenges in a Multidisciplinary Setting. PMID- 28666933 TI - A Comment on "Anesthetic Management of Transapical Off-Pump Mitral Valve Repair With NeoChord Implantation". PMID- 28666934 TI - Flow Energy Loss Evaluation in a Systolic Anterior Motion Case After the Ross Procedure. PMID- 28666935 TI - Calibration and validation processes for relative humidity measurement by a Hygrochron iButton. AB - Accurate relative humidity (RH) measurement is demanded in studies of thermal comfort. Thermal discomfort occurs when the near-to-skin temperature or RH is outside of the thermal comfort zone. The Hygrochron, a small wireless device which measures both temperature and RH, would be suitable and convenient in exercise or sleep studies. However, the RH measurement has not been validated. This paper has three parts. Part 1: In evaluating the sensor surface for RH detection, four Hygrochrons were placed on a wet paper towel. Two were placed on the towel with the protruding surface facing up and the other two facing down. The results showed that the Hygrochron with the protruding side was the sensor surface for detecting RH. Part 2: Twenty-seven Hygrochrons were calibrated in a humidity calibration chamber at a RH range from 40 to 90% at a constant temperature from 32 to 37 degrees C. The mean bias was -1.08% between the Hygrochrons and the calibration chamber. The Hygrochron overestimated RH at the lower range (40-60%) and underestimated RH at the higher range (80-90%). The application of individual regression equations to each Hygrochron improved accuracy and reduced the mean bias to -0.002%. However, one Hygrochron showed outlier values that may be due to a manufacturing defect. Part 3: The reproducibility of Hygrochron for RH measurements was tested twice at the same condition of 35 degrees C over a three-month interval. The intra-class coefficient was 0.996 to 1.000 with non-significant differences in the mean RH between test and re-test results (p=0.159). Hygrochrons are valid for RH measurements which show high reproducibility. It is recommended that Hygrochrons be calibrated over a range of desired RH and temperature prior to use to improve accuracy and detect any manufacturing defects. PMID- 28666936 TI - Human induced pluripotent stem cell (hiPSC)-derived neurons respond to convulsant drugs when co-cultured with hiPSC-derived astrocytes. AB - Accurate risk assessment for drug-induced seizure is expected to be performed before entering clinical studies because of its severity and fatal damage to drug development. Induced pluripotent stem cell (iPSC) technology has allowed the use of human neurons and glial cells in toxicology studies. Recently, several studies showed the advantage of co-culture system of human iPSC (hiPSC)-derived neurons with rodent/human primary astrocytes regarding neuronal functions. However, the application of hiPSC-derived neurons for seizure risk assessment has not yet been fully addressed, and not at all when co-cultured with hiPSC-derived astrocytes. Here, we characterized hiPSC-derived neurons co-cultured with hiPSC-derived astrocytes to discuss how hiPSC-derived neurons are useful to assess seizure risk of drugs. First, we detected the frequency of spikes and synchronized bursts hiPSC-derived neurons when co-cultured with hiPSC-derived astrocytes for 8 weeks. This synchronized burst was suppressed by the treatment with 6-cyano-7 nitroquinoxaline-2,3-dione, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, and D-(-)-2-amino-5-phosphonopentanoic acid, an N-Methyl-d-aspartate (NMDA) receptor antagonist. These data suggested that co cultured hiPSC-derived neurons formed synaptic connections mediated by AMPA and NMDA receptors. We also demonstrated that co-cultured hiPSC-derived neurons showed epileptiform activity upon treatment with gabazine or kaliotoxin. Finally, we performed single-cell transcriptome analysis in hiPSC-derived neurons and found that hiPSC-derived astrocytes activated the pathways involved in the activities of AMPA and NMDA receptor functions, neuronal polarity, and axon guidance in hiPSC-derived neurons. These data suggested that hiPSC-derived astrocytes promoted the development of action potential, synaptic functions, and neuronal networks in hiPSC-derived neurons, and then these functional alterations result in the epileptiform activity in response to convulsant drugs. Our study indicates the possibility that co-culture system of hiPSC-derived neurons with hiPSC-derived astrocytes could be useful in the risk assessment of drug-induced seizure. PMID- 28666938 TI - Death of adrenocortical cells during murine acute T. cruzi infection is not associated with TNF-R1 signaling but mostly with the type II pathway of Fas mediated apoptosis. AB - Earlier studies from our laboratory demonstrated that acute experimental Trypanosoma cruzi infection promotes an intense inflammation along with a sepsis like dysregulated adrenal response characterized by normal levels of ACTH with raised glucocorticoid secretion. Inflammation was also known to result in adrenal cell apoptosis, which in turn may influence HPA axis uncoupling. To explore factors and pathways which may be involved in the apoptosis of adrenal cells, together with its impact on the functionality of the gland, we carried out a series of studies in mice lacking death receptors, such as TNF-R1 (C57BL/6 Tnfrsf1a tm1Imx or TNF-R1-/-) or Fas ligand (C57BL/6 Fas-deficient lpr mice), undergoing acute T. cruzi infection. Here we demonstrate that the late hypercorticosterolism seen in C57BL/6 mice during acute T. cruzi infection coexists with and hyperplasia and hypertrophy of zona fasciculata, paralleled by increased number of apoptotic cells. Apoptosis seems to be mediated mainly by the type II pathway of Fas-mediated apoptosis, which engages the mitochondrial pathway of apoptosis triggering the cytochrome c release to increase caspase-3 activation. Fas-induced apoptosis of adrenocortical cells is also related with an exacerbated production of intra-adrenal cytokines that probably maintain the late supply of adrenal hormones during host response. Present results shed light on the molecular mechanisms dealing with these phenomena which are crucial not only for the development of interventions attempting to avoid adrenal dysfunction, but also for its wide occurrence in other infectious-based critical illnesses. PMID- 28666937 TI - Re-evaluating Strategies to Define the Immunoregulatory Roles of miRNAs. AB - miRNAs play an important role in fine-tuning host immune homeostasis and responses through the regulation of mRNA stability and translation. Studies have demonstrated that miRNA-mediated regulation of gene expression has a profound impact on immune cell development, function, and response to invading pathogens. As we continue to examine the mechanisms by which miRNAs maintain the balance between robust protective host immune responses and dysregulated responses that promote immune pathology, careful consideration of the complexity of post transcriptional immune regulation is needed. Distinct tissue- and stimulus specific RNA-RNA and RNA-protein interactions can modulate the functions of a given miRNA. Thus, new challenges emerge in the identification of post transcriptional coregulatory modules and the genetic factors that impact miRNA function. PMID- 28666939 TI - Magnetic Resonance Fingerprinting with short relaxation intervals. AB - PURPOSE: The aim of this study was to investigate a technique for improving the performance of Magnetic Resonance Fingerprinting (MRF) in repetitive sampling schemes, in particular for 3D MRF acquisition, by shortening relaxation intervals between MRF pulse train repetitions. MATERIAL AND METHODS: A calculation method for MRF dictionaries adapted to short relaxation intervals and non-relaxed initial spin states is presented, based on the concept of stationary fingerprints. The method is applicable to many different k-space sampling schemes in 2D and 3D. For accuracy analysis, T1 and T2 values of a phantom are determined by single-slice Cartesian MRF for different relaxation intervals and are compared with quantitative reference measurements. The relevance of slice profile effects is also investigated in this case. To further illustrate the capabilities of the method, an application to in-vivo spiral 3D MRF measurements is demonstrated. RESULTS: The proposed computation method enables accurate parameter estimation even for the shortest relaxation intervals, as investigated for different sampling patterns in 2D and 3D. In 2D Cartesian measurements, we achieved a scan acceleration of more than a factor of two, while maintaining acceptable accuracy: The largest T1 values of a sample set deviated from their reference values by 0.3% (longest relaxation interval) and 2.4% (shortest relaxation interval). The largest T2 values showed systematic deviations of up to 10% for all relaxation intervals, which is discussed. The influence of slice profile effects for multislice acquisition is shown to become increasingly relevant for short relaxation intervals. In 3D spiral measurements, a scan time reduction of 36% was achieved, maintaining the quality of in-vivo T1 and T2 maps. CONCLUSIONS: Reducing the relaxation interval between MRF sequence repetitions using stationary fingerprint dictionaries is a feasible method to improve the scan efficiency of MRF sequences. The method enables fast implementations of 3D spatially resolved MRF. PMID- 28666940 TI - Atrial reverse electrical and structural remodeling by pacing: Good news for pacemaker patients. PMID- 28666941 TI - Lead reliability: How can we do better? PMID- 28666942 TI - Treadmill exercise is good for the heart but not to prevent shocks. PMID- 28666943 TI - Risk of arrhythmic events in drug-induced Brugada syndrome. PMID- 28666945 TI - Prevalence and diagnostic characteristics of non-clinical mitral regurgitation murmurs in North American Whippets. AB - OBJECTIVES: To assess the prevalence of functional ejection murmurs and murmurs of mitral regurgitation (MR) due to myxomatous mitral valve disease in healthy whippets; to assess the diagnostic value of auscultation to detect MR; and investigate the relationship between age and presence of echocardiographically documented MR (MRecho). ANIMALS: A total of 200 healthy client-owned Whippets, recruited at national shows between 2005 and 2009 were involved in this study. METHODS: Cross-sectional study. Dogs were examined by auscultation by one examiner and Doppler echocardiography by another, and results were compared. Prevalence of types of murmurs and MRecho were calculated and correlated to age. Accuracy of auscultation to predict MRecho was calculated. RESULTS: Left-sided systolic heart murmurs were detected in 185/200 (93%) of dogs. Left apical systolic murmurs (Lapex) were detected in 57/200 (29%) and left basilar systolic murmurs (Lbase) in 128/200 of the dogs (64%). MRecho was present in 76/200 (38%) dogs. Prevalence MRecho was correlated with age (r = 0.96, p=0.0028). Mitral regurgitation detected by echocardiography was present in 12/78 (15%) of the dogs <= 2 years of age and in 59% of the dogs at 7-8 years old. Detection of Lapex predicted MRecho with sensitivity 65%, specificity 94%, positive predictive value 86%, and negative predictive value 81%; and accuracy improved when only dogs with more intense Lapex (grade >= 3/6) were considered. CONCLUSIONS: Systolic murmurs are common in North American Whippets and this breed exhibits a high prevalence of MRecho, which may be documented at a relatively early age. Whippets with non clinical MRecho may not be identifiable by auscultation alone; echocardiographic examination may be required to exclude a diagnosis of MR. Louder heart murmurs allow more accurate localization in this population. PMID- 28666944 TI - Sodium-channel blocker challenge in the familial screening of Brugada syndrome: Safety and predictors of positivity. AB - BACKGROUND: Sodium-channel blocker challenge (SCBC) is frequently performed to unmask Brugada syndrome. OBJECTIVE: We aim to identify predictors of positivity and complications of SCBC in the setting of familial screening of Brugada syndrome. METHODS: All consecutive patients from 2000 to 2014 who benefit from a sodium-channel blocker and belong to a family with at least 2 subjects affected by the syndrome were enrolled and followed prospectively. Data were reviewed by 2 physicians blinded to the clinical and genetic status. RESULTS: Of the 672 SCBCs performed in 137 families, 337 (50%) were positive. Multivariate analysis identified ajmaline (odds ratio [OR] 2.98; 95% CI 1.65-4.91) and a significant S wave in lead DII (OR 3.11; 95% CI 2.12-4.58), DIII (OR 2.75; 95% CI 1.78-4.25), or V5 (OR 3.71; 95% CI 2.54-5.44) as predictors of a positive SCBC (P < .0001). Eleven patients (1.6%) presented complications (10 ventricular arrhythmias and 1 atrial flutter), but no deaths occurred. Familial history of complications (OR 41; lower quartile, upper quartile 10, 203; P < .0001), young age (P = .04), and decreased electrocardiographic conduction parameters at baseline (P = .04) were predictors of complications. QRS enlargement during SCBC was not associated with complications. During a median follow-up of 106 months (lower quartile, upper quartile 54, 143 months), 11 life-threatening arrhythmias occurred. CONCLUSION: SCBC in the screening of familial Brugada syndrome is safe. The risk of complication is considerably increased in the case of familial history of complicated SCBC, in young patients, and in the presence of decreased electrocardiographic conduction parameters. However, QRS enlargement during the test is not directly related to complications and should not be used to prematurely stop the test unless leading to false-negative results. PMID- 28666946 TI - Sarcina ventriculi in a Patient With Slipped Gastric Band and Gastric Distention. PMID- 28666947 TI - Treatment With Biologic Agents Has Not Reduced Surgeries Among Patients With Crohn's Disease With Short Bowel Syndrome. AB - BACKGROUND & AIMS: Little is known about the effects of biologic agents used to treat Crohn's disease (CD) on its long-term complications, such as short bowel syndrome and intestinal failure (SBS-IF). We evaluated trends in small bowel resections and health care utilization among patients with CD with and without SBS-IF. METHODS: We collected data on the National Inpatient Sample on 2,989,185 patients hospitalized with CD in the United States before the time period in which CD was treated with biologic agents (1993-1997) and after biologic therapy became widespread (1998-2014). We used Poisson and linear regression analyses to evaluate trends for small bowel resections and health care utilization among patients with CD with and without SBS-IF. Multivariable models were adjusted for age, sex, Charlson-Deyo comorbidity index, payer source, hospital size, region, and teaching status. RESULTS: The proportions of patients who underwent resection did not significantly change during the period before biologic therapy (121.8 per 1000 hospitalizations in 1993 to 110.1 per 1000 hospitalizations in 1997; P trend =.14) but decreased significantly during the period after biologic therapy began (99.0 per 1000 hospitalizations in 1998 to 64.6 per 1000 hospitalizations in 2014; P trend < .01). However, among patients with SBS-IF, similar proportions of patients underwent resection during the period before biologic therapy (0.7 per 1000 hospitalizations in 1993 to 0.7 per 1000 hospitalizations in 1997; P trend = .92) and during the period after biologic therapy (0.6 per 1000 hospitalizations in 1998 to 0.7 per 1000 hospitalizations in 2014; P trend = .06). Rates of hospitalization for patients with SBS-IF increased from 16.5 per 1000 hospitalizations in 1998 to 19.5 per 1000 hospitalizations in 2014 (P trend < .01). SBS-IF hospitalizations were associated with longer lengths of stay (P < .01) and greater total charges (P < .01). CONCLUSIONS: In a study of the United States population, we found that the use of biologic agents to treat CD reduced the proportion of patients undergoing resection, but not among patients with SBS IF. These findings indicate that biologic agents reduce some but not all features of CD. Studies are needed to identify patients at risk for SBS-IF, prevent and treat this complication, and identify new treatments. PMID- 28666949 TI - Bleeding With Direct Oral Anticoagulants: The Gastrointestinal Tract and Beyond. PMID- 28666948 TI - Bile Acid Deficiency in a Subgroup of Patients With Irritable Bowel Syndrome With Constipation Based on Biomarkers in Serum and Fecal Samples. AB - BACKGROUND & AIMS: Short-term administration of delayed-release chenodeoxycholic acid to patients with irritable bowel syndrome with constipation (IBS-C) accelerates colonic transit and reduces symptoms. A preliminary study has shown that patients with IBS-C have reduced levels of bile acids (BAs) in feces and reduced synthesis of BA. We compared the levels of primary and secondary BAs in fecal samples collected over a 48-hour period from patients with IBS-C on a diet that contained 100 g fat per day, and compared them with levels in samples from healthy volunteers (controls). We also examined the relationship between overall colonic transit and biomarkers of BAs in patients with IBS-C. METHODS: We performed a retrospective study of 45 patients with IBS-C and 184 controls. For controls, we estimated the 10th percentile of fasting serum levels of 7alpha hydroxy-4-cholesten-3-one (C4, n = 184) and 48-hour fecal BAs (n = 46), and the 90th percentile of the fasting serum level of fibroblast growth factor 19 (FGF19, n = 50). Colonic transit was measured in patients using a validated scintigraphic method. Data from patients with IBS-C were analyzed using Spearman correlations to determine the relationships among levels of C4, FGF19, fecal BAs, and colonic transit. RESULTS: Among the patients with IBS-C, 2 of 45 had low serum levels of C4, 4 of 43 had increased serum levels of FGF19, and 6 of 39 had low levels of BAs in feces collected over 48 hours. Patients with IBS-C had a significant increase in the proportions of fecal lithocholic acid compared with controls (P = .04), and a decrease in deoxycholic acid compared with controls (P = .03). In patients with IBS-C, there were inverse relationships between serum levels of C4 and FGF19 and correlations among levels of 48-hour fecal BAs, colonic transit, and serum C4 and FGF19. CONCLUSIONS: Approximately 15% of patients with IBS-C have reduced total BAs and level of deoxycholic acid in fecal samples collected over 48 hours on a 100 g fat diet. In these patients, lower levels of excretion of BAs into feces correlated with slower colonic transit. PMID- 28666950 TI - Intracerebral injections of DNA nanoparticles encoding for a therapeutic gene provide partial neuroprotection in an animal model of neurodegeneration. AB - This study reports proof of concept for administering compacted DNA nanoparticles (DNPs) intracerebrally as a means to protect against neurotoxin-induced neurodegeneration of dopamine (DA) neurons. In this study we used DNPs that encoded for human glial cell line-derived neurotrophic factor (hGDNF); GDNF is a potent neurotrophic factor for DA neurons. Intracerebral injections of DNPs into the striatum and/or substantia nigra were performed 1 week before treatment with a neurotoxin. We observed that the number of surviving DA cells, the density of DA fiber terminals and recovery of motor function were greater in animals injected with GDNF-encoding DNPs than in control animals receiving DNPs encoding for an inert reporter gene. The results of these studies are one of the first to demonstrate that a non-viral, synthetic nanoparticle can be used to deliver therapeutic genes to cells in the brain as a means to protect cells against neurotoxin-induced neurodegeneration. PMID- 28666951 TI - Peak Exercise Oxygen Uptake Predicts Recurrent Admissions in Heart Failure With Preserved Ejection Fraction. AB - INTRODUCTION AND OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with an elevated risk of morbidity and mortality. To date, there is scarce evidence on the role of peak exercise oxygen uptake (peak VO2) for predicting the morbidity burden in HFpEF. We sought to evaluate the association between peak VO2 and the risk of recurrent hospitalizations in patients with HFpEF. METHODS: A total of 74 stable symptomatic patients with HFpEF underwent a cardiopulmonary exercise test between June 2012 and May 2016. A negative binomial regression method was used to determine the association between the percentage of predicted peak VO2 (pp-peak VO2) and recurrent hospitalizations. Risk estimates are reported as incidence rate ratios. RESULTS: The mean age was 72.5 +/- 9.1 years, 53% were women, and all patients were in New York Heart Association functional class II to III. Mean peak VO2 and median pp-peak VO2 were 10 +/- 2.8mL/min/kg and 60% (range, 47-67), respectively. During a median follow-up of 276 days [interquartile range, 153 1231], 84 all-cause hospitalizations in 31 patients (41.9%) were registered. A total of 15 (20.3%) deaths were also recorded. On multivariate analysis, accounting for mortality as a terminal event, pp-peak VO2 was independently and linearly associated with the risk of recurrent admission. Thus, and modeled as continuous, a 10% decrease of pp-peak VO2 increased the risk of recurrent hospitalizations by 32% (IRR, 1.32; 95%CI, 1.03-1.68; P = .028). CONCLUSIONS: In symptomatic elderly patients with HFpEF, pp-peak VO2 predicts all-cause recurrent admission. PMID- 28666952 TI - Acute Coronary Syndrome in Patients With Thrombocytopenia. Response. PMID- 28666953 TI - Multimodality Imaging for Pulmonary Valve Papillary Fibroelastoma. PMID- 28666954 TI - 1700012B09Rik, a FOXJ1 effector gene active in ciliated tissues of the mouse but not essential for motile ciliogenesis. AB - In humans and mice, motile cilia occur on the surface of the embryonic ventral node, on respiratory and ependymal epithelia and in reproductive organs where they ensure normal left-right asymmetry of the organism, mucociliary clearance of airways, homeostasis of the cerebrospinal fluid and fertility. The genetic programme for the formation of motile cilia, thus critical for normal development and health, is switched on by the key transcription factor FOXJ1. In previous microarray screens for murine FOXJ1 effectors, we identified candidates for novel factors involved in motile ciliogenesis, including both genes that are well conserved throughout metazoa and beyond, like FOXJ1 itself, and genes without overt homologues outside higher vertebrates. Here we examine one of the novel murine FOXJ1 effectors, the uncharacterised 1700012B09Rik whose homologues appear to be restricted to higher vertebrates. In mouse embryos and adults, 1700012B09Rik is predominantly expressed in motile ciliated tissues in a FOXJ1 dependent manner. 1700012B09RIK protein localises to basal bodies of cilia in cultured cells. Detailed analysis of 1700012B09RiklacZ knock-out mice reveals no impaired function of motile cilia or non-motile cilia. In conclusion, this novel FOXJ1 effector is associated mainly with motile cilia but - in contrast to other known FOXJ1 targets - its putative ciliary function is not essential for development or health in the mouse, consistent with a late emergence during evolution of motile ciliogenesis. PMID- 28666955 TI - Dnases in health and disease. AB - DNA degradation is critical to healthy organism development and survival. Two nuclease families that play key roles in development and in disease are the Dnase1 and Dnase2 families. While these two families were initially characterized by biochemical function, it is now clear that multiple enzymes in each family perform similar, non-redundant roles in many different tissues. Most Dnase1 and Dnase2 family members are poorly characterized, yet their elimination can lead to a wide range of diseases, including lethal anemia, parakeratosis, cataracts and systemic lupus erythematosus. Therefore, understanding these enzyme families represents a critical field of emerging research. This review explores what is currently known about Dnase1 and Dnase2 family members, highlighting important questions about the structure and function of family members, and how their absence translates to disease. PMID- 28666956 TI - Coordination of cellular differentiation, polarity, mitosis and meiosis - New findings from early vertebrate oogenesis. AB - A mechanistic dissection of early oocyte differentiation in vertebrates is key to advancing our knowledge of germline development, reproductive biology, the regulation of meiosis, and all of their associated disorders. Recent advances in the field include breakthroughs in the identification of germline stem cells in Medaka, in the cellular architecture of the germline cyst in mice, in a mechanistic dissection of chromosomal pairing and bouquet formation in meiosis in mice, in tracing oocyte symmetry breaking to the chromosomal bouquet of meiosis in zebrafish, and in the biology of the Balbiani body, a universal oocyte granule. Many of the major events in early oogenesis are universally conserved, and some are co-opted for species-specific needs. The chromosomal events of meiosis are of tremendous consequence to gamete formation and have been extensively studied. New light is now being shed on other aspects of early oocyte differentiation, which were traditionally considered outside the scope of meiosis, and their coordination with meiotic events. The emerging theme is of meiosis as a common groundwork for coordinating multifaceted processes of oocyte differentiation. In an accompanying manuscript we describe methods that allowed for investigations in the zebrafish ovary to contribute to these breakthroughs. Here, we review these advances mostly from the zebrafish and mouse. We discuss oogenesis concepts across established model organisms, and construct an inclusive paradigm for early oocyte differentiation in vertebrates. PMID- 28666958 TI - At Home Preresidency Preparation for General Surgery Internship: A Pilot Study. AB - OBJECTIVE: To create a novel "at-home" preresidency preparatory adjunct for medical students entering surgical residency. DESIGN: Preparatory resources were mailed to match medical students before residency matriculation in 2015. This included "how-to" videos, low-cost models, and surgical instruments for 5 "stations" (arterial blood gas analysis, anatomy and imaging knowledge, knot tying ability, and suturing dexterity) of our program's biannual general surgery intern objective assessment activity (Surgical Olympics: total 13 stations, 10 points each). Scores from 2015 were compared with 2014 historical controls in a retrospective manner using the Student's t-test. SETTING: Academic, tertiary care referral center with a large general surgery training program. PARTICIPANTS: Postgraduate year 1 general surgery trainees (interns) from the years 2014 and 2015. RESULTS: Twenty-six interns participated in the 2015 assessment and were compared to thirty-two 2014 interns. Overall mean scores were low, but higher (19.7 vs. 15.4, p = 0.04) in the 2015 class. The largest increase was noted in the anatomy knowledge station (mean = 5.0 vs. 1.9, p < 0.01). Scores in stations assessing technical competence were similar to controls. The number of perfect scores among the 5 stations was higher (10 vs. 5) in the 2015 group. Mean scores from the other 8 stations, for which no resources were mailed, showed no difference (29.3 vs. 28.3, p = 0.75). CONCLUSIONS: Enacting a simple, home-based curriculum for medical students before surgical residency, improved performance on early knowledge assessments. PMID- 28666957 TI - Functional perturbation of forebrain principal neurons reveals differential effects in novel and well-learned tasks. AB - Neural circuits in mammalian brains consist of large numbers of different cell types having different functional properties. To better understand the separate roles of individual neuron types in specific aspects of spatial learning and memory, we perturbed the function of principal neurons in vivo during maze performance or in hippocampal slices during recording of evoked excitatory synaptic potentials. Transgenic mice expressing the Drosophila allatostatin receptor (AlstR) in cortical and hippocampal pyramidal cells were tested on an elevated plus maze, in a Y-maze, and in the Morris water maze. Relative to a control cohort, AlstR-positive mice treated with allatostatin exhibited no difference in open arm dwell time on the elevated plus maze or total number of arm entries in a Y-maze, but displayed reduced spontaneous alternation. When animals received massed or spaced training trials in the Morris water maze, and the peptide was delivered prior to an immediate probe, no effects on performance were observed. When the peptide was delivered during a probe trial performed 24h after seven days of spaced training, allatostatin delivery to AlstR positive mice enhanced direct navigation to the escape platform. Combined, these results suggest that cortical and hippocampal pyramidal neurons are required during spatial decision-making in a novel environment and compete with other neural systems after extended training in a long-term reference memory task. In hippocampal slices collected from AlstR positive animals, allatostatin delivery produced frequency dependent alterations in the Schaffer collateral fiber volley (attenuated accommodation at 100Hz) and excitatory postsynaptic potential (attenuated facilitation at 5Hz). Combined, the neural and behavioral discoveries support the involvement of short-term plasticity of Schaffer collateral axons and synapses during exploration of a novel environment and during initial orientation to a goal in a well-learned setting. PMID- 28666960 TI - Analysis of virus susceptibility in the invasive insect pest Drosophila suzukii. AB - The invasive insect pest Drosophila suzukii infests ripening fruits and causes massive agricultural damage in North America and Europe (Cini et al., 2012). Environmentally sustainable strategies are urgently needed to control the spread of this species, and entomopathogenic viruses offer one potential solution for global crop protection. Here we report the status of intrinsic and extrinsic factors that influence the susceptibility of D. suzukii to three model insect viruses: Drosophila C virus, Cricket paralysis virus and Flock house virus. Our work provides the basis for further studies using D. suzukii as a host system to develop viruses as biological control agents. PMID- 28666959 TI - A Multicenter Prospective Comparison of the Accreditation Council for Graduate Medical Education Milestones: Clinical Competency Committee vs. Resident Self Assessment. AB - OBJECTIVE: The Accreditation Council for Graduate Medical Education requires accredited residency programs to implement competency-based assessments of medical trainees based upon nationally established Milestones. Clinical competency committees (CCC) are required to prepare biannual reports using the Milestones and ensure reporting to the Accreditation Council for Graduate Medical Education. Previous research demonstrated a strong correlation between CCC and resident scores on the Milestones at 1 institution. We sought to evaluate a national sampling of general surgery residency programs and hypothesized that CCC and resident assessments are similar. DESIGN: Details regarding the makeup and process of each CCC were obtained. Major disparities were defined as an absolute mean difference of >=0.5 on the 4-point scale. A negative assessment disparity indicated that the residents evaluated themselves at a lower level than did the CCC. Statistical analysis included Wilcoxon rank sum and Sign tests. SETTING: CCCs and categorical general surgery residents from 15 residency programs completed the Milestones document independently during the spring of 2016. RESULTS: Overall, 334 residents were included; 44 (13%) and 43 (13%) residents scored themselves >=0.5 points higher and lower than the CCC, respectively. Female residents scored themselves a mean of 0.08 points lower, and male residents scored themselves a mean of 0.03 points higher than the CCC. Median assessment differences for postgraduate year (PGY) 1-5 were 0.03 (range: -0.94 to 1.28), -0.11 (range: -1.22 to 1.22), -0.08 (range: -1.28 to 0.81), 0.02 (range: 0.91 to 1.00), and -0.19 (range: -1.16 to 0.50), respectively. Residents in university vs. independent programs had higher rates of negative assessment differences in medical knowledge (15% vs. 6%; P = 0.015), patient care (17% vs. 5%; P = 0.002), professionalism (23% vs. 14%; P = 0.013), and system-based practice (18% vs. 9%; P = 0.031) competencies. Major assessment disparities by sex or PGY were similar among individual competencies. CONCLUSIONS: Surgery residents in this national cohort demonstrated self-awareness when compared to assessments by their respective CCCs. This was independent of program type, sex, or level of training. PGY 5 residents, female residents, and those from university programs consistently rated themselves lower than the CCC, but these were not major disparities and the significance of this is unclear. PMID- 28666961 TI - Assessing awareness and attitudes of healthcare professionals on the use of biosimilar medicines: A survey of physicians and pharmacists in Ireland. AB - Increasing numbers of biosimilar medicines are becoming available. The objective of this survey was to assess awareness of and attitudes to biosimilars amongst physicians (medical specialists and General Practitioners (GPs)) and community pharmacists in Ireland. Physicians were invited to complete an online questionnaire during April and May 2016. Community pharmacists received a postal questionnaire in August 2015. Responses from 102 medical specialists, 253 GPs and 125 community pharmacists were analysed. The majority of medical specialists (85%) and pharmacists (77%) claimed to be either very familiar or familiar with the term biosimilar, whereas many GPs (60%) were unable to define or had never heard of the term. One in five (21%) healthcare professionals responded that biosimilars were the same as generic medicines. The majority of medical specialists opposed pharmacist-led substitution of biological medicines but some thought it could be appropriate if agreed with the clinician in advance. Medical specialists who prescribe biosimilars (n = 43) were more likely to do so on treatment initiation (67%), than switch a patient from an originator medicine to a biosimilar (28%). The findings will aid the design of educational initiatives for healthcare professionals and highlight attitudes of healthcare professionals to biosimilars, so informing regulators, policy makers and industry. PMID- 28666962 TI - Decreased calcium flux in Niemann-Pick type C1 patient-specific iPSC-derived neurons due to higher amount of calcium-impermeable AMPA receptors. AB - Niemann-Pick disease type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene, resulting mainly in the accumulation of cholesterol and the ganglioside GM2. Recently, we described accumulations of these lipids in neuronal differentiated cells derived from NPC1 patient-specific induced pluripotent stem cells (iPSCs). As these lipids are essential for proper cell membrane composition, we were interested in the expression and function of voltage-gated ion channels and excitatory AMPA receptors (AMPARs) in neurons derived from three patient-specific iPSC lines. By means of patch clamp recordings and microfluorimetric measurements of calcium (Ca2+), we examined the expression of voltage-gated ion channels and AMPARs. Cells of the three used cell lines carrying the c.1836A>C/c.1628delC, the c.1180T>C or the c.3182T>C mutation demonstrated a significantly reduced AMPA induced Ca2+-influx, suggesting an altered expression profile of these receptors. RT-qPCR revealed a significant upregulation of mRNA for the AMPA receptor subunits GluA1 and GluA2 and western blot analysis showed increased protein level of GluA2. Thus, we conclude that the observed reduced Ca2+-influx is based on an increase of GluA2 containing Ca2+-impermeable AMPARs. An attenuated function of GluRs in neurons potentially contributes to the progressive neurodegeneration observed in NPC1 and might represent an objective in regard of the development of new therapeutic approaches in NPC1. PMID- 28666963 TI - A novel KCNA1 mutation in a patient with paroxysmal ataxia, myokymia, painful contractures and metabolic dysfunctions. AB - Episodic ataxia type 1 (EA1) is a human dominant neurological syndrome characterized by continuous myokymia, episodic attacks of ataxic gait and spastic contractions of skeletal muscles that can be triggered by emotional stress and fatigue. This rare disease is caused by missense mutations in the KCNA1 gene coding for the neuronal voltage gated potassium channel Kv1.1, which contributes to nerve cell excitability in the cerebellum, hippocampus, cortex and peripheral nervous system. We identified a novel KCNA1 mutation, E283K, in an Italian proband presenting with paroxysmal ataxia and myokymia aggravated by painful contractures and metabolic dysfunctions. The E283K mutation is located in the S3 S4 extracellular linker belonging to the voltage sensor domain of Kv channels. In order to test whether the E283K mutation affects Kv1.1 biophysical properties we transfected HEK293 cells with WT or mutant cDNAs alone or in a 1:1 combination, and recorded relative potassium currents in the whole-cell configuration of patch clamp. Mutant E283K channels display voltage-dependent activation shifted by 10mV toward positive potentials and kinetics of activation slowed by ~2 fold compared to WT channels. Potassium currents resulting from heteromeric WT/E283K channels show voltage-dependent gating and kinetics of activation intermediate between WT and mutant homomeric channels. Based on homology modeling studies of the mutant E283K, we propose a molecular explanation for the reduced voltage sensitivity and slow channel opening. Overall, our results suggest that the replacement of a negatively charged residue with a positively charged lysine at position 283 in Kv1.1 causes a drop of potassium current that likely accounts for EA-1 symptoms in the heterozygous carrier. PMID- 28666964 TI - Developing Quantitative In Vitro-In Vivo Correlation for Fenofibrate Immediate Release Formulations With the Biphasic Dissolution-Partition Test Method. AB - This study is to evaluate 3 fenofibrate (FEN) formulations including Fournier(r) 200 mg capsule, Lipidil(r) 145 mg tablet, and a clinical HME 160 mg tablet by an in vitro biphasic method. Key experimental parameters were evaluated including the selection of biorelevant media, the United States Pharmacopeia IV flow rate, and the United States Pharmacopeia paddle speed. Varying the hydrodynamic condition resulted in a significant impact on FEN concentration time profiles in both aqueous and octanol phases for these formulations. In vivo pharmacokinetic profiles of the HME tablet, the Lipidil tablet, and Fournier capsule under the fasting and low-fat fed states are reported. Their corresponding absorption-time profiles were obtained through deconvolution by the Wagner-Nelson method. When fed state simulated intestinal fluid version 2 was used, the partitioned FEN amount-time profiles in octanol from the 3 formulations under an appropriate hydrodynamic condition exhibited a good agreement with their in vivo absorbed amount-time profiles, permitting a quantitative in vitro-in vivo correlation. When fasted state simulated intestinal fluid version 2 was used, partitioned FEN amounts into octanol from these formulations are significantly lower than those from in vivo data. Although no food effect was observed for both HME and Lipidil tablets, the positive food effect of the Fournier capsules significantly overestimated by the biphasic test. PMID- 28666966 TI - AAPT Diagnostic Criteria for Central Neuropathic Pain. AB - : Central neuropathic pain, which is pain caused by a lesion or disease of the central somatosensory nervous system, is a serious consequence of spinal cord injury, stroke, multiple sclerosis, and other conditions affecting the central nervous system. A collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) initiative, invited a working group to develop diagnostic criteria for central neuropathic pain. The criteria for central neuropathic pain that were developed expand upon existing criteria for neuropathic pain and the International Classification of Diseases 11th Revision draft criteria to ensure consistency. This article focuses on central neuropathic pain associated with spinal cord injury, stroke, and multiple sclerosis, but the AAPT framework can be extended to central pain due to other causes such as traumatic brain injury. The classification of central neuropathic pain is organized according to the AAPT multidimensional framework, specifically: 1) core diagnostic criteria, 2) common features, 3) common medical and psychiatric comorbidities, 4) neurobiological, psychosocial, and functional consequences, and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. PERSPECTIVE: The AAPT chronic central neuropathic pain taxonomy provides a classification for central pain associated with spinal cord injury, stroke, and multiple sclerosis. The diagnostic criteria are organized according to the AAPT multidimensional framework, specifically: 1) core diagnostic criteria, 2) common features, 3) common medical and psychiatric comorbidities, 4) neurobiological, psychosocial, and functional consequences, and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. PMID- 28666965 TI - Individualizing duration of antibiotic therapy in community-acquired pneumonia. AB - International experts suggest tailoring antibiotic duration in community-acquired pneumonia (CAP) according to patients' characteristics. We aimed to assess the effectiveness of an individualized approach to antibiotic duration based on time in which CAP patients reach clinical stability during hospitalization. In a multicenter, non-inferiority, randomized, controlled trial hospitalized adult patients with CAP reaching clinical stability within 5 days after hospitalization were randomized to a standard vs. individualized antibiotic duration. In the Individualized group, antibiotics were discontinued 48 h after the patient reached clinical stability, with at least five days of total antibiotic treatment. Early failure within 30 days was the primary composite outcome. 135 patients were randomized to the Standard group and 125 to the Individualized group. The trial was interrupted by the safety committee because of an apparent inferiority of the Individualized group over the Standard treatment: 14 (11.2%) patients in the Individualized group experienced early failure vs. 10 (7.4%) patients in the Standard group, p = 0.200, at the intention-to-treat analysis. 30 day mortality rate was four-time higher in the Individualized group than the Standard group. Shortening antibiotic duration according to patients' characteristics still remains an open question. PMID- 28666967 TI - Signaling via Smad2 and Smad3 is dispensable for adult murine hematopoietic stem cell function in vivo. AB - Transforming growth factor-beta (TGFbeta) is a member of a large family of polypeptide growth factors. TGFbeta signals mainly through the intracellular proteins Smad2 and Smad3, which are highly similar in amino acid sequence identity. A number of studies have shown that these proteins, dependent on context, have distinct roles in the TGFbeta signaling pathway. TGFbeta is one of the most potent inhibitors of hematopoietic stem and progenitor cell proliferation in vitro, but its role in hematopoiesis in vivo is still being determined. To circumvent possible redundancies at the receptor level and to address specifically the role of the Smad circuitry downstream of TGFbeta and activin in hematopoiesis, we studied the effect of genetically deleting both Smad2 and Smad3 in adult murine hematopoietic cells. Indeed, TGFbeta signaling is impaired in vitro in primitive bone marrow (BM) cells of Smad2 and Smad3 single knockout models. However, blood parameters appear normal under steady state and in the transplantation setting. Interestingly, upon deletion of both Smad2 and Smad3 in vivo, mice quickly develop a lethal inflammatory disease, suggesting that activin/TGFbeta signaling is crucial for immune cell homeostasis in the adult context. Furthermore, concurrent deletion of Smad2 and Smad3 in BM cells in immune-deficient nude mice did not result in any significant alterations of the hematopoietic system. Our findings suggest that Smad2 and Smad3 function to mediate crucial aspects of the immunoregulatory properties of TGFbeta, but are dispensable for any effect that TGFbeta has on primitive hematopoietic cells in vivo. PMID- 28666968 TI - In vitro phase I metabolism of gamabufotalin and arenobufagin: Reveal the effect of substituent group on metabolic stability. AB - Bufadienolides are a major class of bioactive compounds derived from amphibian skin secretion. Gamabufotalin (GB) and arenobufagin (AB) are among the top of the intensively investigated natural bufadienolides for their outstanding biological activities. This study aimed to characterize the phase I metabolism of GB and AB with respect to the metabolic profiles, enzymes involved, and catalytic efficacy, thereafter tried to reveal substituent effects on metabolism. Two mono hydroxylated products of GB and AB were detected in the incubation mixtures, and they were accurately identified as 1- and 5-hydroxylated bufadienolides by NMR and HPLC-MS techniques. Reaction phenotyping studies demonstrated that CYP3A mediated the metabolism of the two bufadienolides with a high specific selectivity. Further kinetic evaluation demonstrated that the metabolism stability of GB and AB were better than other reported bufadienolides. Additionally, the CYP3A5 preference for hydroxylation of AB was observed, which was different to the selectivity of CYP3As for bufadienolides suggested by our previous report. This study can provide important data for elucidating the phase I metabolism of GB and AB and can lead to a better understanding of the bufadienolide-CYP3A interaction which is helpful for preclinical development and rational use of bufadienolides. PMID- 28666969 TI - Vitamin D regulates osteocyte survival and perilacunar remodeling in human and murine bone. AB - Osteocytes are the most abundant bone cells and are highly regulated by external stimuli. Vitamin D and osteocytes cooperatively regulate bone remodeling as well as phosphate and calcium homeostasis. However, it is unclear if vitamin D regulates osteocyte number, connectivity or size in the setting of altered bone formation or impaired mineralization. Sixty iliac crest biopsies of patients with varying vitamin D levels were examined to analyze osteocyte number, osteocyte connectivity and osteocyte viability using high-resolution imaging. Osteocyte parameters were also quantified in mice lacking the vitamin D receptor (Vdr-/-) and in wildtype littermates. The cortical and cancellous bone of patients with vitamin D deficiency exhibited a significant decrease in the number of viable osteocytes, as well as increased osteocyte apoptosis and impaired osteocyte connectivity, based on evaluation of the canalicular network. The number of osteocytes was also decreased in Vdr-deficient mice, in comparison to wildtype controls, and this was accompanied by enlargement of osteocyte lacunae. A high calcium diet normalized the osteocyte lacunar area in Vdr-deficient mice, but failed to normalize osteocyte number. Thus, a diet-independent decrease in osteocyte number in Vdr-deficient mice suggests a mechanism that is directly dependent on the VDR, since vitamin D may promote the transition from osteoblasts to osteocytes. The increase in lacunar area the in Vdr-deficient mice, which is normalized by the high calcium diet suggests this phenotype is due to osteocytic osteolysis. These investigations demonstrate that vitamin D plays a role in the regulation of osteocyte number and perilacunar remodeling. PMID- 28666970 TI - Relationships among ultrasonic and mechanical properties of cancellous bone in human calcaneus in vitro. AB - Clinical bone sonometers applied at the calcaneus measure broadband ultrasound attenuation and speed of sound. However, the relation of ultrasound measurements to bone strength is not well-characterized. Addressing this issue, we assessed the extent to which ultrasonic measurements convey in vitro mechanical properties in 25 human calcaneal cancellous bone specimens (approximately 2*4*2cm). Normalized broadband ultrasound attenuation, speed of sound, and broadband ultrasound backscatter were measured with 500kHz transducers. To assess mechanical properties, non-linear finite element analysis, based on micro computed tomography images (34-micron cubic voxel), was used to estimate apparent elastic modulus, overall specimen stiffness, and apparent yield stress, with models typically having approximately 25-30 million elements. We found that ultrasound parameters were correlated with mechanical properties with R=0.70-0.82 (p<0.001). Multiple regression analysis indicated that ultrasound measurements provide additional information regarding mechanical properties beyond that provided by bone quantity alone (p<=0.05). Adding ultrasound variables to linear regression models based on bone quantity improved adjusted squared correlation coefficients from 0.65 to 0.77 (stiffness), 0.76 to 0.81 (apparent modulus), and 0.67 to 0.73 (yield stress). These results indicate that ultrasound can provide complementary (to bone quantity) information regarding mechanical behavior of cancellous bone. PMID- 28666971 TI - Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency immune mechanisms link. AB - Rheumatoid arthritis (RA) is characterized, among other factors, by systemic bone loss, reaching ~50% prevalence of osteoporosis in postmenopausal women. This is roughly a doubled prevalence in comparison with age-matched non-RA women. Postmenopausal RA women are more likely to be sero-positive for the anti citrullinated peptide antibody (ACPA). Our extensive review of recent scientific literature enabled us to propose several mechanisms as responsible for the accelerated bone loss in ACPA(+) RA postmenopausal women. Menopause-associated estrogen deficiency plays a major role in these pathological mechanisms, as follows. PMID- 28666973 TI - ALA-PDT combined with antibiotics for the treatment of atypical mycobacterial skin infections: Outcomes and safety. AB - BACKGROUND: Photodynamic therapy (PDT) has been shown to be a very successful therapy in clinical practice, and its usefulness as a treatment for bacterial infections has been gradually recognized by researchers, who believe it has very good clinical prospects. Atypical mycobacterial skin infections are a type of rare refractory infection. The aim of this study was to evaluate the efficacy and safety of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with antibiotics for the treatment of atypical mycobacterial skin infections. METHODS: In this study, 4 patients with atypical mycobacterial skin infections were treated with ALA-PDT combined with antibiotic therapy. These patients were diagnosed with atypical mycobacterial skin infections by bacterial culture and microarray analysis, tests that were also useful for identifying the strains responsible for the infections. In addition to being treated with antibiotics, the skin was also treated locally with ALA-PDT (20% ALA was applied to the lesion and incubated in the dark, then, the lesion was irradiated with a red light with an energy density of 100J/cm2) every 10days for a total of 3-5 sessions. RESULTS: All four patients enrolled in the study were cured with 100% efficiency after receiving combination therapy with ALA-PDT and antibiotics for three months. All patients experienced redness and pain during treatment but did not experience any other forms of severe discomfort and were satisfied with the results of their treatments. CONCLUSION: Local ALA-PDT combined with antibiotics is a safe and effective method of treating atypical mycobacterial skin infections. PMID- 28666972 TI - Non-destructive NIR spectral imaging assessment of bone water: Comparison to MRI measurements. AB - Bone fracture risk increases with age, disease states, and with use of certain therapeutics, such as acid-suppressive drugs, steroids and high-dose bisphosphonates. Historically, investigations into factors that underlie bone fracture risk have focused on evaluation of bone mineral density (BMD). However, numerous studies have pointed to factors other than BMD that contribute to fragility, including changes in bone collagen and water. The goal of this study is to investigate the feasibility of using near infrared spectral imaging (NIRSI) to determine the spatial distribution and relative amount of water and organic components in whole cross-sections of bone, and to compare those results to those obtained using magnetic resonance imaging (MRI) methods. Cadaver human whole section tibiae samples harvested from 18 donors of ages 27-97years underwent NIRSI and ultrashort echo time (UTE) MRI. As NIRSI data is comprised of broad absorbances, second derivative processing was evaluated as a means to narrow peaks and obtain compositional information. The (inverted) second derivative peak heights of the NIRSI absorbances correlated significantly with the mean peak integration of the water, collagen and fat NIR absorbances, respectively, indicating that either processing method could be used for compositional assessment. The 5797cm-1 absorbance was validated as arising from the fat present in bone marrow, as it completely disappeared after ultrasonication. The MRI UTE determined bound water content in tibial cortical bone samples ranged from 62 to 91%. The NIRSI water peaks at 5152cm-1 and at 7008cm-1 correlated significantly with the UTE data, with r=0.735, p=0.016, and r=0.71, p=0.0096, respectively. There was also a strong correlation between the intensity of the NIRSI water peak at 7008cm-1 and the intensity of the collagen peak at 4608cm-1 (r=0.69, p=0.004). Since NIRSI requires minimal to no sample preparation, this approach has great potential to become a gold standard modality for the investigation of changes in water content, distribution, and environment in pre-clinical studies of bone pathology and therapeutics. PMID- 28666974 TI - Application of photodynamic therapy, laser therapy, and a cellulose membrane for calcaneal pressure ulcer treatment in a diabetic patient: A case report. AB - Diabetes mellitus is a metabolic disorder in which a person has high blood glucose levels due to inadequate insulin production by the pancreas. Wounds in these individuals cannot heal properly over time due to circulatory changes that hinder and stagnate the healing process. We report the case of an 82-year-old female type 2 diabetes mellitus carrier, presenting to clinical-dermatological examination pressure ulcer (PU) in the right calcaneus region. The patient was treated with photodynamic therapy using curcumin and blue light-emitting diodes (LEDs), laser therapy, and the application of a cellulose membrane in order to promote ulcer decontamination by local action, accelerate wound healing, and maintain favorable conditions of asepsis and moisture, respectively. The ulcer healing occurred after 30days of treatment and total epithelialization was observed. From the results obtained in this case report, we conclude that the combination of photodynamic therapy, laser therapy, and coating with a cellulose membrane is a promising treatment for the healing of PU in diabetic patients. PMID- 28666975 TI - Use of and Beliefs About Mobile Phone Apps for Diabetes Self-Management: Surveys of People in a Hospital Diabetes Clinic and Diabetes Health Professionals in New Zealand. AB - BACKGROUND: People with diabetes mellitus (DM) are using mobile phone apps to support self-management. The numerous apps available to assist with diabetes management have a variety of functions. Some functions, like insulin dose calculators, have significant potential for harm. OBJECTIVES: The study aimed to establish (1) whether people with DM in Wellington, New Zealand, use apps for DM self-management and evaluate desirable features of apps and (2) whether health professionals (HPs) in New Zealand treating people with DM recommend apps to patients, the features HPs regard as important, and their confidence with recommending apps. METHODS: A survey of patients seen at a hospital diabetes clinic over 12 months (N=539) assessed current app use and desirable features. A second survey of HPs attending a diabetes conference (n=286) assessed their confidence with app recommendations and perceived usefulness. RESULTS: Of the 189 responders (35.0% response rate) to the patient survey, 19.6% (37/189) had used a diabetes app. App users were younger and in comparison to other forms of diabetes mellitus, users prominently had type 1 DM. The most favored feature of the app users was a glucose diary (87%, 32/37), and an insulin calculator was the most desirable function for a future app (46%, 17/37). In non-app users, the most desirable feature for a future app was a glucose diary (64.4%, 98/152). Of the 115 responders (40.2% response rate) to the HPs survey, 60.1% (68/113) had recommended a diabetes app. Diaries for blood glucose levels and carbohydrate counting were considered the most useful app features and the features HPs felt most confident to recommend. HPs were least confident in recommending insulin calculation apps. CONCLUSIONS: The use of apps to record blood glucose was the most favored function in apps used by people with diabetes, with interest in insulin dose calculating function. HPs do not feel confident in recommending insulin dose calculators. There is an urgent need for an app assessment process to give confidence in the quality and safety of diabetes management apps to people with diabetes (potential app users) and HPs (potential app prescribers). PMID- 28666976 TI - Preferences for Internet-Based Mental Health Interventions in an Adult Online Sample: Findings From an Online Community Survey. AB - BACKGROUND: Despite extensive evidence that Internet interventions are effective in treating mental health problems, uptake of Internet programs is suboptimal. It may be possible to make Internet interventions more accessible and acceptable through better understanding of community preferences for delivery of online programs. OBJECTIVE: This study aimed to assess community preferences for components, duration, frequency, modality, and setting of Internet interventions for mental health problems. METHODS: A community-based online sample of 438 Australian adults was recruited using social media advertising and administered an online survey on preferences for delivery of Internet interventions, along with scales assessing potential correlates of these preferences. RESULTS: Participants reported a preference for briefer sessions, although they recognized a trade-off between duration and frequency of delivery. No clear preference for the modality of delivery emerged, although a clear majority preferred tailored programs. Participants preferred to access programs through a computer rather than a mobile device. Although most participants reported that they would seek help for a mental health problem, more participants had a preference for face-to face sources only than online programs only. Younger, female, and more educated participants were significantly more likely to prefer Internet delivery. CONCLUSIONS: Adults in the community have a preference for Internet interventions with short modules that are tailored to individual needs. Individuals who are reluctant to seek face-to-face help may also avoid Internet interventions, suggesting that better implementation of existing Internet programs requires increasing acceptance of Internet interventions and identifying specific subgroups who may be resistant to seeking help. PMID- 28666978 TI - David Oliver: Time for a truly independent NHS statistics authority. PMID- 28666977 TI - The Feasibility and Acceptability of a Web-Based Alcohol Management Intervention in Community Sports Clubs: A Cross-Sectional Study. AB - BACKGROUND: The implementation of comprehensive alcohol management strategies can reduce excessive alcohol use and reduce the risk of alcohol-related harm at sporting venues. Supporting sports venues to implement alcohol management strategies via the Web may represent an effective and efficient means of reducing harm caused by alcohol in this setting. However, the feasibility and acceptability of such an approach is unknown. OBJECTIVE: This study aimed to identify (1) the current access to and use of the Web and electronic devices by sports clubs; (2) the perceived usefulness, ease of use, and intention to use a Web-based program to support implementation of alcohol management policies in sports clubs; (3) the factors associated with intention to use such a Web-based support program; and (4) the specific features of such a program that sports clubs would find useful. METHODS: A cross-sectional survey was conducted with club administrators of community football clubs in the state of New South Wales, Australia. Perceived usefulness, ease of use and intention to use a hypothetical Web-based alcohol management support program was assessed using the validated Technology Acceptance Model (TAM) instrument. Associations between intention to use a Web-based program and club characteristics as well as perceived ease of use and usefulness was tested using Fisher's exact test and represented using relative risk (RR) for high intention to use the program. RESULTS: Of the 73 football clubs that were approached to participate in the study, 63 consented to participate and 46 were eligible and completed the survey. All participants reported having access to the Web and 98% reported current use of electronic devices (eg, computers, iPads/tablets, smartphones, laptops, televisions, and smartboards). Mean scores (out of a possible 7) for the TAM constructs were high for intention to use (mean 6.25, SD 0.87), perceived ease of use (mean 6.00, SD 0.99), and perceived usefulness (mean 6.17, SD 0.85). Intention to use the Web based alcohol management program was significantly associated with perceived ease of use (P=.02, RR 1.4, CI 1.0-2.9), perceived usefulness (P=.03, RR 1.5, CI 1.0 6.8) and club size (P=.02, RR 0.8, CI 0.5-0.9). The most useful features of such a program included the perceived ability to complete program requirements within users' own time, complete program accreditation assessment and monitoring online, develop tailored action plans, and receive email reminders and prompts to complete action. CONCLUSIONS: A Web-based alcohol management approach to support sports clubs in the implementation of recommended alcohol management policies appears both feasible and acceptable. Future research should aim to determine if such intended use leads to actual use and club implementation of alcohol management policies. PMID- 28666980 TI - Integrating occupational health with the NHS will not improve access. PMID- 28666982 TI - Tackling doping in sport: a call to take action on the dopogenic environment. PMID- 28666979 TI - Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. AB - Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies. PMID- 28666981 TI - Epidemiology of time loss groin injuries in a men's professional football league: a 2-year prospective study of 17 clubs and 606 players. AB - BACKGROUND/AIM: Groin injury epidemiology has not previously been examined in an entire professional football league. We recorded and characterised time loss groin injuries sustained in the Qatar Stars League. METHODS: Male players were observed prospectively from July 2013 to June 2015. Time loss injuries, individual training and match play exposure were recorded by club doctors using standardised surveillance methods. Groin injury incidence per 1000 playing hours was calculated, and descriptive statistics used to determine the prevalence and characteristics of groin injuries. The Doha agreement classification system was used to categorise all groin injuries. RESULTS: 606 footballers from 17 clubs were included, with 206/1145 (18%) time loss groin injuries sustained by 150 players, at an incidence of 1.0/1000 hours (95% CI 0.9 to 1.1). At a club level, 21% (IQR 10%-28%) of players experienced groin injuries each season and 6.6 (IQR 2.9-9.1) injuries were sustained per club per season. Of the 206 injuries, 16% were minimal (1-3 days), 25% mild (4-7 days), 41% moderate (8-28 days) and 18% severe (>28 days), with a median absence of 10 days/injury (IQR 5-22 days). The median days lost due to groin injury per club was 85 days per season (IQR 35-215 days). Adductor-related groin pain was the most common entity (68%) followed by iliopsoas (12%) and pubic-related (9%) groin pain. CONCLUSION: Groin pain caused time loss for one in five players each season. Adductor-related groin pain comprised 2/3 of all groin injuries. Improving treatment outcomes and preventing adductor-related groin pain has the potential to improve player availability in professional football. PMID- 28666983 TI - Items dispensed in England rise sharply in 10 years. PMID- 28666984 TI - The nuclear receptor NOR-1/NR4A3 regulates the multifunctional glycoprotein vitronectin in human vascular smooth muscle cells. AB - The nuclear receptor NOR-1 (NR4A3) has recently been involved in the regulation of extracellular matrix (ECM) proteins associated with neointimal thickening and the vascular control of hemostasis. We sought to find as-yet unidentified NOR-1 target genes in human vascular smooth muscle cells (VSMCs). An in silico analysis identified putative NOR-1 response elements in the proximal promoter region of several genes encoding for ECM proteins, including vitronectin (VTN). Lentiviral overexpression of NOR-1 strongly increased VTN mRNA and protein levels, whereas NOR-1 silencing significantly reduced VTN expression. Deletion and site-directed mutagenesis studies, as well as EMSA and chromatin immunoprecipitation, identified the NBRE(-202/-195) site in the VTN promoter as an essential element for NOR-1 responsiveness. Furthermore, NOR-1 and VTN colocalized in VSMCs in human atherosclerotic lesions. VTN levels were increased in cell supernatants from VSMCs that overexpress NOR-1. Cell supernatants from VSMCs overexpressing NOR-1 induced cell migration to a greater extent than supernatants from control cells, and this effect was attenuated when cell supernatants were preincubated with anti-VTN blocking antibodies or VTN was silenced in supernatant-generating cells. These results indicate that VTN is a target of NOR-1 and suggest that this multifunctional glycoprotein may participate in vascular responses mediated by this nuclear receptor.-Marti-Pamies, I., Canes, L., Alonso, J., Rodriguez, C., Martinez-Gonzalez, J. The nuclear receptor NOR-1/NR4A3 regulates the multifunctional glycoprotein vitronectin in human vascular smooth muscle cells. PMID- 28666985 TI - Keratins regulate beta-cell mitochondrial morphology, motility, and homeostasis. AB - Loss of the epithelial intermediate filament protein keratin 8 (K8) in murine beta cells leads to irregular insulin vesicles and decreased insulin levels. Because mitochondria are central in glucose-stimulated insulin secretion, the relationship between keratins and beta-cell mitochondrial function and morphology was investigated. beta cells in murine K8-knockout (K8-/-) islets of Langerhans have increased numbers of mitochondria, which are rounder and have diffuse cristae, as seen by electron microscopy. The mitochondrial network in primary cultured K8-/- beta cells is more fragmented compared with K8+/+ mitochondria, correlating with decreased levels of mitofusin 2 and the mitofusin 2- and keratin binding protein trichoplein. K8-/- beta-cell mitochondria have decreased levels of total and mitochondrial cytochrome c, which correlates with a reduction in electron transport complexes I and IV. This provokes loss of mitochondrial membrane potential and reduction of ATP and insulin amount, as seen in K8-/- beta cells. Mitochondria in K8 wild-type beta cells and MIN6 insulinoma cells overexpressing K8 and 18 are more stationary compared with mitochondria in keratin-deficient cells. In conclusion, keratins, likely through trichoplein mitofusin interactions, regulate both structural and dynamic functions of beta cell mitochondria, which could have implications for downstream insulin secretion.-Silvander, J. S. G., Kvarnstrom, S. M., Kumari-Ilieva, A., Shrestha, A., Alam, C. M., Toivola, D. M. Keratins regulate beta-cell mitochondrial morphology, motility, and homeostasis. PMID- 28666986 TI - Social anxiety apps: a systematic review and assessment of app descriptors across mobile store platforms. AB - QUESTION: The aim of this systematic review is twofold: (1) to characterise the purpose and description of available social anxiety apps and (2) to review the evidence on the effectiveness of social anxiety apps. STUDY SELECTION AND ANALYSIS: A search was conducted on three major mobile platforms: Apple iTunes, Google Play and Windows Store. Apps were included if they addressed social anxiety and used an English language interface. A systematic review of the literature from MEDLINE, EMBASE, PsycINFO, Cochrane, Scopus and Web of Science to identify evidence-based evaluations of social anxiety apps was also undertaken. FINDINGS: Of the 1154 apps identified, 38 apps met the inclusion criteria: iTunes (n=18), Google Play (n=16) and Windows Store (n=4). Over 60% of apps were exclusively focused on social anxiety, while the remainder targeted social anxiety and related conditions. Most developers did not provide information on their organisational affiliations or their content source. Most apps used multimedia while 17 apps used text only. Finally, although the systematic review of the literature identified 94 articles, none of which met inclusion criteria. CONCLUSIONS: Social anxiety apps have the potential to overcome barriers to accessing treatment; however, none of the apps identified have had studies on their effectiveness published. As the evidence base is lacking, it is therefore not currently possible to recommend their use. PMID- 28666987 TI - Online GP service prescribed drugs without safety checks, says CQC. PMID- 28666988 TI - Prospective Assessment of Sex-Related Differences in Symptom Status and Health Perception Among Patients With Atrial Fibrillation. AB - BACKGROUND: We prospectively assessed sex-specific differences in health perception, overall symptom status, and specific symptoms in a large cohort of patients with atrial fibrillation. METHODS AND RESULTS: We performed a prospective multicenter observational cohort study of 1553 patients with atrial fibrillation. Patients completed questionnaires about personal characteristics, comorbidities, and symptoms on a yearly basis. Mean age was 70+/-11 years among women and 67+/-12 years among men. Health perception on a visual analogue scale ranging from 0 to 100 (with higher scores indicating better health perception) was significantly lower in women than in men (70 [interquartile range: 50-80] versus 75 [interquartile range: 60-85]; P<0.0001). More women than men had any symptoms (85.0% versus 68.3%; P<0.0001), palpitations (65.2% versus 44.4%; P<0.0001), dizziness (25.6% versus 13.5%; P<0.0001), dyspnea (35.7% versus 21.8%; P<0.0001), and fatigue (25.3% versus 19.1%; P=0.006). At 1-year follow-up, symptoms decreased in both sexes but remained more frequent in women (49.1% versus 32.6%, P<0.0001). In multivariable adjusted longitudinal regression models, female sex remained an independent predictor for lower health perception (beta=-4.8; 95% CI, -6.5 to -3.1; P<0.0001), any symptoms (odds ratio [OR]: 2.6; 95% CI, 2.1-3.4; P<0.0001), palpitations (OR: 2.6; 95% CI, 2.1-3.2; P<0.0001), dizziness (OR: 2.9; 95% CI, 2.1-3.9; P<0.0001), dyspnea (OR: 2.1; 95% CI, 1.6 2.8; P<0.0001), fatigue (OR: 1.6; 95% CI, 1.2-2.2; P=0.0008), and chest pain (OR: 1.8; 95% CI, 1.3-2.6; P=0.001). CONCLUSIONS: Women with atrial fibrillation have a substantially higher symptom burden and lower health perception than men. These relationships persisted after multivariable adjustment and during prospective follow-up. PMID- 28666989 TI - Two-Year Changes in Proteinuria and the Risk of Stroke in the Chinese Population: A Prospective Cohort Study. AB - BACKGROUND: Whether changes in proteinuria are associated with incident stroke in the general population is unclear. This study aimed to investigate the association between changes in proteinuria and incident stroke and its subtypes. METHODS AND RESULTS: The current study included 60 940 Chinese participants (mean age, 50.69 years) who were free of stroke at the time of surveys (2006-2007 and 2008-2009). Participants were divided into 4 categories according to 2-year changes in proteinuria: no proteinuria, remittent proteinuria, incident proteinuria, and persistent proteinuria. Cox proportional hazards models were used to calculate hazard ratios and their 95% CIs for stroke. After a median follow-up period of 6.92 years, 1769 individuals developed stroke. After adjustment for confounding factors, incident proteinuria and persistent proteinuria were associated with increased risk of stroke (hazard ratio, 1.46 [95% CI, 1.26-1.68] and hazard ratio, 1.71 [95% CI, 1.42-2.06], respectively) compared with no proteinuria, which were higher than proteinuria detected at one single point (hazard ratio, 1.25; 95% CI, 1.09-1.43). The effect size for risk of stroke subtypes including ischemic stroke and hemorrhagic stroke was similar. CONCLUSIONS: Changes in proteinuria exposure, particularly persistent proteinuria, are more likely to reflect the risk of stroke, compared with proteinuria collected at a single time point in the general population. PMID- 28666990 TI - Gene Expression Profiles for the Identification of Prevalent Atrial Fibrillation. AB - BACKGROUND: Diagnosis of atrial fibrillation (AF) can be difficult, requiring cumbersome investigations. We aimed to determine the association of established whole-blood gene expression scores with prevalent AF and to evaluate their performance for the identification of AF in a SIRS (Steroids in Cardiac Surgery) trial cohort. METHODS AND RESULTS: Whole-blood, transcriptome-wide gene expression profiling was performed using the Illumina HumanHT-12 Expression BeadChip in 416 participants (65% men) before surgery, including 91 with a diagnosis of AF. An AF gene score (GS) calculated from 7 genes reported to be upregulated in AF and a validated GS for biological age based on 1254 genes related to aging were both independently associated with AF diagnosis before surgery in multivariate logistic regression analyses adjusting for known risk factors (P=0.0006 and P=0.003). Addition of AF and biological age GSs to clinical risk factors led to significant improvement in area under the receiver operating characteristic curve (from 0.77 to 0.80; P=0.03), continuous net reclassification improvement index (P<0.0001), and integrated discrimination improvement index (P=0.0002). When stratifying AF by subtype, AF GS was mainly associated with paroxysmal AF (P=0.003), whereas the biological age GS was mainly associated with permanent AF (P=0.017). CONCLUSIONS: We validated the existence of a blood gene expression signature for prevalent AF and showed that biological age derived from gene expression is significantly associated with prevalent AF. These findings suggest a potential utility of blood gene expression for the identification of patients with AF, particularly paroxysmal AF. This result could have implications for the prevention and management of cryptogenic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00427388. PMID- 28666991 TI - The Contribution of Inflammation to the Development of Hypertension Mediated by Increased Arterial Stiffness. AB - BACKGROUND: The mechanisms underlying the possible contribution of chronic inflammation to the development of hypertension remain unclear. We examined the longitudinal association of inflammation with the progression of vascular and/or renal abnormalities in the development of hypertension. METHODS AND RESULTS: In 3274 middle-aged Japanese men without hypertension at the study baseline, brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum CRP (C reactive protein) levels were measured annually during a 9-year period. During this study period, 474 participants (14.5%) developed hypertension. Analysis of the repeated-measures data revealed that sustained elevation of serum CRP levels was associated with a longitudinal increase of the brachial-ankle pulse wave velocity. A linear mixed model analysis revealed that higher log-transformed serum CRP values (log CRP) at each measurement were associated with a higher annual increase of the brachial-ankle pulse wave velocity (estimate=32.553+/-11.635 cm/s per log CRP, P=0.018), and that higher values of the brachial-ankle pulse wave velocity at each measurement were associated with a higher annual elevation of blood pressure (estimate=0.025+/-0.002 mm Hg per log CRP, P<0.001). CONCLUSIONS: In middle-aged Japanese men without hypertension at study baseline, long-term active inflammation appears to be associated with a longitudinal increase of arterial stiffness. In turn, this longitudinal increase of arterial stiffness appears to be associated with longitudinal elevation of blood pressure to the hypertensive range. Thus, systemic inflammation may play a role in the pathogenesis of hypertension by the progression of arterial stiffness. PMID- 28666992 TI - Oxygen Uptake Efficiency Slope Predicts Poor Outcome in Patients With Idiopathic Pulmonary Arterial Hypertension. AB - BACKGROUND: Few published studies have evaluated the power of the oxygen uptake efficiency slope (OUES) to predict outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH), who typically die of right-sided heart failure. Our study sought to evaluate the power of OUES to predict clinical worsening and mortality in patients with IPAH. METHODS AND RESULTS: Patients with newly diagnosed IPAH who underwent symptom-limited cardiopulmonary exercise testing from November 11, 2010, to June 25, 2015, in our hospital were prospectively enrolled and followed for up to 66 months. Clinical worsening and mortality were recorded. A total of 210 patients with IPAH (159 women; mean age, 32+/-10 years) were studied with a median follow-up of 41 months. Thirty-one patients died, 1 patient underwent lung transplantation, and 85 patients presented with clinical worsening. The univariate analysis revealed that OUES, OUESI (OUESI=OUES/body surface area), peak oxygen uptake (VO2), peak VO2/kg, ventilation (VE)/carbon dioxide output (VCO2) slope, peak systolic blood pressure, heart rate recovery, pulmonary vascular resistance, cardiac index, N-terminal prohormone brain natriuretic peptide, and World Health Organization functional class were all predictive of clinical worsening and mortality (all P<0.05). Multivariate analysis demonstrated that OUESI and cardiac index were independently predictive of clinical worsening, and OUESI and N-terminal prohormone brain natriuretic peptide were independently predictive of mortality. Patients with OUESI <=0.52 m 2 had a worse 5-year survival rate than patients with OUESI >0.52 m-2 (41.9% versus 89.8%, P<0.0001). CONCLUSIONS: The OUES, a submaximal parameter obtained from cardiopulmonary exercise testing, provides prognostic information for predicting clinical worsening and mortality in patients with IPAH. PMID- 28666993 TI - Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF-TIMI 48 Trial. AB - BACKGROUND: Digoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF). METHODS AND RESULTS: In the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow-up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10-2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36-2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all-cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P<0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction. CONCLUSIONS: In this observational analysis of patients with atrial fibrillation without investigator-reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391. PMID- 28666994 TI - A chief source of cancer and repair in stomachs. PMID- 28666996 TI - Erratum. PMID- 28666997 TI - Erratum. PMID- 28666995 TI - Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins. AB - Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. Spy1/RINGO (Spy1) proteins bind and activate Cdk but are resistant to canonical regulatory mechanisms that establish cell-cycle checkpoints. Cancer cells exploit Spy1 to stimulate proliferation through inappropriate activation of Cdks, yet the mechanism is unknown. We have determined crystal structures of the Cdk2-Spy1 and p27-Cdk2-Spy1 complexes that reveal how Spy1 activates Cdk. We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. Our structural description of Spy1 provides important mechanistic insights that may be utilized for targeting upregulated Spy1 in cancer. PMID- 28666999 TI - pVHL suppresses Akt/beta-catenin-mediated cell proliferation by inhibiting 14-3 3zeta expression. AB - The mechanisms controlling degradation of cytosolic beta-catenin are important for regulating beta-catenin co-transcriptional activity. Loss of von Hippel Lindau protein (pVHL) has been shown to stabilize beta-catenin, increasing beta catenin transactivation and beta-catenin-mediated cell proliferation. However, the role of phosphoinositide 3-kinase (PI3K)/Akt in the regulation of beta catenin signaling downstream from pVHL has never been addressed. Here, we report that hyperactivation of PI3K/Akt in cells lacking pVHL contributes to the stabilization and nuclear accumulation of active beta-catenin. PI3K/Akt hyperactivation is facilitated by the up-regulation of 14-3-3zeta and the down regulation of 14-3-3epsilon, 14-3-3eta and 14-3-3theta. Up-regulation of 14-3 3zeta in response to pVHL is important for the recruitment of PI3K to the cell membrane and for stabilization of soluble beta-catenin. In contrast, 14-3 3epsilon and 14-3-3eta enhanced PI3K/Akt signaling by inhibiting PI3K and PDK1, respectively. Thus, our results demonstrated that 14-3-3 family members enhance PI3K/Akt/beta-catenin signaling in order to increase proliferation. Inhibition of Akt activation and/or 14-3-3 function strongly reduces beta-catenin signaling and decreases cell proliferation. Thus, inhibition of Akt and 14-3-3 function efficiently reduces cell proliferation in 786-0 cells characterized by hyperactivation of beta-catenin signaling due to pVHL loss. PMID- 28667001 TI - Gender dysphoria: assessment and management for non-specialists. PMID- 28667002 TI - Women in Northern Ireland to get free abortion on NHS in England. PMID- 28667000 TI - Whole-exome sequencing identifies an alpha-globin cluster triplication resulting in increased clinical severity of beta-thalassemia. AB - Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited beta-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of beta-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire alpha-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of beta-thalassemia intermedia resulting from a single beta-thalassemia mutation in combination with an alpha-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis. PMID- 28667008 TI - A case of acute confusion: Cushing's syndrome presenting with primary hyperparathyroidism. AB - Cushing's syndrome is a rare disease. Cushing's syndrome presenting as acute psychosis is an exceptional occurrence. We present the case of a 37-year-old woman who was admitted with acute confusion associated with mild hypercalcaemia and was subsequently diagnosed with parathyroid and adrenal adenomas. Our hospital sees approximately 6000 endocrine patients per year, with an incidence of around four Cushing's cases annually. This is the first such case to occur in our hospital and one of few described in the literature. PMID- 28667009 TI - Congenital neonatal scalp arteriovenous malformation: a very rare entity. AB - Congenital arteriovenous malformations (AVMs) of scalp are rare congenital vascular malformations. They are usually not symptomatic at birth and are often misdiagnosed as haemangiomas. To date, only two cases of symptomatic neonatal scalp AVM have been reported in literature. Pathophysiology of congenital AVM is not completely understood but genetic and acquired causes are implicated. Diagnosis and management are often difficult and require multidisciplinary approach. We report a rare case of symptomatic congenital scalp AVM in a 10-day old neonate who was successfully managed at our unit. PMID- 28667010 TI - I am your trans patient. PMID- 28667006 TI - Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3' untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116-35. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1047. PMID- 28667011 TI - HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities. AB - When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders. PMID- 28667012 TI - Targeted therapies in 54 patients with Erdheim-Chester disease, including follow up after interruption (the LOVE study). PMID- 28667013 TI - Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis proceeds through a catalytic shunt pathway. AB - CYP121, the cytochrome P450 enzyme in Mycobacterium tuberculosis that catalyzes a single intramolecular C-C cross-linking reaction in the biosynthesis of mycocyclosin, is crucial for the viability of this pathogen. This C-C coupling reaction represents an expansion of the activities carried out by P450 enzymes distinct from oxygen insertion. Although the traditional mechanism for P450 enzymes has been well studied, it is unclear whether CYP121 follows the general P450 mechanism or uses a different catalytic strategy for generating an iron bound oxidant. To gain mechanistic insight into the CYP121-catalyzed reaction, we tested the peroxide shunt pathway by using rapid kinetic techniques to monitor the enzyme activity with its substrate dicyclotyrosine (cYY) and observed the formation of the cross-linked product mycocyclosin by LC-MS. In stopped-flow experiments, we observed that cYY binding to CYP121 proceeds in a two-step process, and EPR spectroscopy indicates that the binding induces active site reorganization and uniformity. Using rapid freeze-quenching EPR, we observed the formation of a high-spin intermediate upon the addition of peracetic acid to the enzyme-substrate complex. This intermediate exhibits a high-spin (S = 5/2) signal with g values of 2.00, 5.77, and 6.87. Likewise, iodosylbenzene could also produce mycocyclosin, implicating compound I as the initial oxidizing species. Moreover, we also demonstrated that CYP121 performs a standard peroxidase type of reaction by observing substrate-based radicals. On the basis of these results, we propose plausible free radical-based mechanisms for the C-C bond coupling reaction. PMID- 28667014 TI - The gluconate shunt is an alternative route for directing glucose into the pentose phosphate pathway in fission yeast. AB - Glycolysis and the pentose phosphate pathway both play a central role in the degradation of glucose in all domains of life. Another metabolic route that can facilitate glucose breakdown is the gluconate shunt. In this shunt glucose dehydrogenase and gluconate kinase catalyze the two-step conversion of glucose into the pentose phosphate pathway intermediate 6-phosphogluconate. Despite the presence of these enzymes in many organisms, their only established role is in the production of 6-phosphogluconate for the Entner-Doudoroff pathway. In this report we performed metabolic profiling on a strain of Schizosaccharomyces pombe lacking the zinc-responsive transcriptional repressor Loz1 with the goal of identifying metabolic pathways that were altered by cellular zinc status. This profiling revealed that loz1Delta cells accumulate higher levels of gluconate. We show that the altered gluconate levels in loz1Delta cells result from increased expression of gcd1 By analyzing the activity of recombinant Gcd1 in vitro and by measuring gluconate levels in strains lacking enzymes of the gluconate shunt we demonstrate that Gcd1 encodes a novel NADP+-dependent glucose dehydrogenase that acts in a pathway with the Idn1 gluconate kinase. We also find that cells lacking gcd1 and zwf1, which encode the first enzyme in the pentose phosphate pathway, have a more severe growth phenotype than cells lacking zwf1 We propose that in S. pombe Gcd1 and Idn1 act together to shunt glucose into the pentose phosphate pathway, creating an alternative route for directing glucose into the pentose phosphate pathway that bypasses hexokinase and the rate-limiting enzyme glucose-6 phosphate dehydrogenase. PMID- 28667016 TI - An RNA Recognition Motif-Containing Protein Functions in Meiotic Silencing by Unpaired DNA. AB - Meiotic silencing by unpaired DNA (MSUD) is a biological process that searches pairs of homologous chromosomes (homologs) for segments of DNA that are unpaired. Genes found within unpaired segments are silenced for the duration of meiosis. In this report, we describe the identification and characterization of Neurospora crassa sad-7, a gene that encodes a protein with an RNA recognition motif (RRM). Orthologs of sad-7 are found in a wide range of ascomycete fungi. In N. crassa, sad-7 is required for a fully efficient MSUD response to unpaired genes. Additionally, at least one parent must have a functional sad-7 allele for a cross to produce ascospores. Although sad-7-null crosses are barren, sad-7Delta strains grow at a wild-type (wt) rate and appear normal under vegetative growth conditions. With respect to expression, sad-7 is transcribed at baseline levels in early vegetative cultures, at slightly higher levels in mating-competent cultures, and is at its highest level during mating. These findings suggest that SAD-7 is specific to mating-competent and sexual cultures. Although the role of SAD-7 in MSUD remains elusive, green fluorescent protein (GFP)-based tagging studies place SAD-7 within nuclei, perinuclear regions, and cytoplasmic foci of meiotic cells. This localization pattern is unique among known MSUD proteins and raises the possibility that SAD-7 coordinates nuclear, perinuclear, and cytoplasmic aspects of MSUD. PMID- 28667017 TI - FlyExpress 7: An Integrated Discovery Platform To Study Coexpressed Genes Using in Situ Hybridization Images in Drosophila. AB - Gene expression patterns assayed across development can offer key clues about a gene's function and regulatory role. Drosophila melanogaster is ideal for such investigations as multiple individual and high-throughput efforts have captured the spatiotemporal patterns of thousands of embryonic expressed genes in the form of in situ images. FlyExpress (www.flyexpress.net), a knowledgebase based on a massive and unique digital library of standardized images and a simple search engine to find coexpressed genes, was created to facilitate the analytical and visual mining of these patterns. Here, we introduce the next generation of FlyExpress resources to facilitate the integrative analysis of sequence data and spatiotemporal patterns of expression from images. FlyExpress 7 now includes over 100,000 standardized in situ images and implements a more efficient, user-defined search algorithm to identify coexpressed genes via Genomewide Expression Maps (GEMs). Shared motifs found in the upstream 5' regions of any pair of coexpressed genes can be visualized in an interactive dotplot. Additional webtools and link outs to assist in the downstream validation of candidate motifs are also provided. Together, FlyExpress 7 represents our largest effort yet to accelerate discovery via the development and dispersal of new webtools that allow researchers to perform data-driven analyses of coexpression (image) and genomic (sequence) data. PMID- 28667018 TI - A High-Density Linkage Map Reveals Sexual Dimorphism in Recombination Landscapes in Red Deer (Cervus elaphus). AB - High-density linkage maps are an important tool to gain insight into the genetic architecture of traits of evolutionary and economic interest, and provide a resource to characterize variation in recombination landscapes. Here, we used information from the cattle genome and the 50 K Cervine Illumina BeadChip to inform and refine a high-density linkage map in a wild population of red deer (Cervus elaphus). We constructed a predicted linkage map of 38,038 SNPs and a skeleton map of 10,835 SNPs across 34 linkage groups. We identified several chromosomal rearrangements in the deer lineage relative to sheep and cattle, including six chromosome fissions, one fusion, and two large inversions. Otherwise, our findings showed strong concordance with map orders in the cattle genome. The sex-averaged linkage map length was 2739.7 cM and the genome-wide autosomal recombination rate was 1.04 cM/Mb. The female autosomal map length was 1.21 longer than that of males (2767.4 cM vs. 2280.8 cM, respectively). Sex differences in map length were driven by high female recombination rates in peri centromeric regions, a pattern that is unusual relative to other mammal species. This effect was more pronounced in fission chromosomes that would have had to produce new centromeres. We propose two hypotheses to explain this effect: (1) that this mechanism may have evolved to counteract centromeric drive associated with meiotic asymmetry in oocyte production; and/or (2) that sequence and structural characteristics suppressing recombination in close proximity to the centromere may not have evolved at neo-centromeres. Our study provides insight into how recombination landscapes vary and evolve in mammals, and will provide a valuable resource for studies of evolution, genetic improvement, and population management in red deer and related species. PMID- 28667020 TI - PHASES Score for the Management of Intracranial Aneurysm: A Cross-Sectional Population-Based Retrospective Study. AB - BACKGROUND AND PURPOSE: The aim of this study is to assess whether the PHASES score allows to (1) match decisions taken by multidisciplinary team whether to observe or intervene, (2) classify patients being diagnosed with a ruptured versus unruptured intracranial aneurysm (UIA), and (3) discriminate patients at low risk of rupture from the population of patients diagnosed with intracranial aneurysm. METHODS: Population-based prospective and consecutive data were collected between 2006 and 2014. Patients (n=841) were stratified into 4 groups: stable UIA; growing observed UIA; immediately treated UIA; and aneurysmal subarachnoid hemorrhage (aSAH). All patients initially observed were pooled in a follow-up UIA group; patients from growing observed UIA, immediately treated UIA, and aSAH were pooled in a high risk of rupture group. Results are expressed as median [quartile 1, quartile 3]. RESULTS: PHASES scores of immediately treated UIA patients were significantly higher than follow-up UIA group (5 [3, 7] versus 2 [1, 4]). Patients diagnosed with UIA and PHASES score of >3 were more likely to be treated, and the score <=3 was predictive for observation (areas under these curves=0.74). Odds of being diagnosed with an aSAH were associated with PHASES score of >3 (UIA, 4 [2, 6]; aSAH, 5 [4, 8]; areas under these curves=0.66). Scores of stable UIA patients were significantly lower than high risk of rupture group (2 [1, 4] versus 5 [4, 7]; stable UIA outcome prediction by PHASES score of <=3: areas under these curves=0.76). CONCLUSIONS: There is a progression of PHASES score between stable UIA, growing observed UIA, immediately treated UIA, and aSAH groups. PHASES score of <=3 is associated with a low but not negligible likelihood of aneurysm rupture, and specificity of the classifier is low. PMID- 28667021 TI - Early Prediction of Delayed Ischemia and Functional Outcome in Acute Subarachnoid Hemorrhage: Role of Diffusion Tensor Imaging. AB - BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) parameters are markers of cerebral lesion in some diseases. In patients with acute subarachnoid hemorrhage (SAH), we investigated whether DTI parameters measured at <72 hours might be associated with delayed cerebral ischemia (DCI) and with poor functional outcome at 3 months (modified Rankin Scale score >=3). METHODS: DTI was performed in a prospective cohort of 60 patients with nontraumatic SAH at <72 hours. Association of fractional anisotropy and apparent diffusion coefficient values at <72 hours with the occurrence of DCI and outcome at 3 months was evaluated with logistic regression models, adjusting for known predictors of prognosis. RESULTS: At <72 hours after SAH, fractional anisotropy values at the cerebellum were associated with DCI occurrence (78% less odds of DCI for each 0.1 increase in fractional anisotropy; P=0.019). Early apparent diffusion coefficient values were not associated with DCI. After adjusting for confounding variables, an increase of 10 U in apparent diffusion coefficient at the frontal centrum semiovale corresponded to 15% increased odds of poor outcome (P=0.061). CONCLUSIONS: DTI parameters at <72 hours post-SAH are independently associated with the occurrence of DCI and functional outcome. These preliminary results suggest the role of DTI parameters as surrogate markers of prognosis in nontraumatic SAH. PMID- 28667023 TI - Autophagy-Inflammasome Interplay in Heart Failure: A Systematic Review on Basics, Pathways, and Therapeutic Perspectives. AB - Aging of the population contributes to the increasing prevalence of heart failure. Autophagy is an evolutionarily conserved process aiming to degrade both long-lived proteins and damaged or excessive cyto-organelles via the lysosomal mediated pathway. Although autophagy is involved in the normal homeostasis of cardiovascular cells, upregulation of autophagy and its abnormal modulation by inflammation may lead to cardiovascular functional decline and heart failure. Despite major improvements in the prevention, diagnosis, and treatment of cardiovascular diseases, heart failure remains one of the major diagnostic and therapeutic challenges. Here, we review the cardiovascular autophagy and its interplay with inflammation which may lead to heart failure exploring some potential treatment options. PMID- 28667024 TI - Unusual Findings in Synovial Fluid Analysis: A Review. AB - Synovial fluid analysis is one of the most useful laboratory test in the diagnosis of joint diseases. It allows to determine the degree of synovial inflammation, the presence of pathogenic crystals and microorganisms, and to evaluate the effect of pharmacological treatments as well as the progression of the disease. Synovial fluid therefore represents a precious substrate able to give valuable information from both the clinical and the research points of view.In this educational review we present and discuss some unusual findings, at times associated with rare rheumatic conditions, observed while routine synovial fluid examination is performed. These findings can be highlighted under ordinary or polarized light using simple wet preparations and supravital staining. PMID- 28667025 TI - Value of Combined Detection of Serum CEA, CA72-4, CA19-9, CA15-3 and CA12-5 in the Diagnosis of Gastric Cancer. AB - BACKGROUND: To examine whether the combined detection of serum tumor markers (CEA, CA72-4, CA19-9, CA15-3 and CA12-5) improves the sensitivity and accuracy in the diagnosis of gastric cancer (GC). MATERIALS AND METHODS: An automatic chemiluminescence immune analyzer with matched kits was used to determine the levels of serum CEA, CA72-4, CA19-9, CA15-3, and CA12-5 in 87 patients with gastric cancer (GC group), 60 patients with gastric benign diseases (GBD group) who were hospitalized during the same period, and 40 healthy subjects undergoing a physical examination. The values of these 5 tumor markers in the diagnosis of gastric cancer were analyzed. RESULTS: The levels of serum CEA, CA72-4, CA19-9, and CA12-5 were higher in the GC group than in the GBD group and healthy subjects, and these differences were significant (P<0.001). Although the level of CA15-3 was higher than those of benign lesion and healthy control groups, the difference was not statistically significant (P>0.05). The combined detection of CEA, CA72-4, CA19-9, and CA12-5 had a higher diagnostic value for gastric cancer than did single detection, and the positive detection rate of the combined detection of the four tumor markers was 60.9%. The diagnostic power when using the combined detection of CA72-4, CEA, CA19-9, and CA12-5 was the best. CONCLUSIONS: The combined detection of serum CA72-4, CEA, CA19-9 and CA12-5 increases the sensitivity and accuracy in the diagnosis of GC and can thus be considered an important tool for early diagnosis. PMID- 28667026 TI - HtrA1 Down-regulation Induces Cisplatin Resistance in Colon Cancer by Increasing XIAP and Activating PI3K/Akt Pathway. AB - The high temperature requirement factor A1 (HtrA1), a member of serine protease family, has been reported to be down-regulated in various cancer types and correlate with chemoresistance. However, the function of HtrA1 in colon cancer remains unclear. This study investigated the role of HtrA1 in cisplatin (CDDP) resistance of colon cancer. We found that HtrA1 was up-regulated in colon cancer cell line SW480 incubated with CDDP. By treating SW480 cells to a continuous exposure to CDDP, we developed CDDP-resistant SW480/CDDP cells and found that the mRNA and protein levels of HtrA1 were reduced. Besides, the stable knock-down of HtrA1 in SW480 transfected with HtrA1 shRNA could also induce chemoresistance against CDDP. To the contrary, ectopic expression of HtrA1 in SW480/CDDP cells abrogated CDDP resistance. The mechanism underlying HtrA-1 down-regulation induced chemoresisance was also investigated. In SW480/CDDP cells and SW480 cells with HtrA1 knock-down, X-linked inhibitor of apoptosis protein (XIAP) was increased, while the interfering of XIAP impeded CDDP resistance in SW480/CDDP cells. We also found that Akt was activated in SW480/CDDP cells and SW480 cells with HtrA1 knock-down. The inhibition of Akt activation reversed CDDP resistance. In conclusion, our results indicate that HtrA1 down-regulation induces CDDP resistance in colon cancer by increasing XIAP and activating PI3K/Akt pathway. This study provides evidence that HtrA1 might be a therapeutic target for overcoming CDDP resistance in colon cancer. PMID- 28667027 TI - Synergy between Paclitaxel and Anti-Cancer Peptide PNC-27 in the Treatment of Ovarian Cancer. AB - OBJECTIVES: Paclitaxel is widely used in the treatment of gynecologic malignancies. It targets tumor cells in the M phase of the cell cycle. Cells in other phases survive the insult and repopulate the tumor. PNC-27 is a peptide synthesized of amino acids of the p53-MDM-2 binding domain. It kills various cancer cell lines in a dose-dependent manner. The goal of this study is to assess ovarian cancer cells' sensitivity to PNC-27 after surviving exposure to paclitaxel and to investigate the potential for synergy between PNC-27 and paclitaxel in the treatment of ovarian cancer. METHODS: The impact of exposure to paclitaxel on the surface expression of MDM-2 was assessed with the use of flow cytometry. For measurement of cytotoxicity in vitro, ID8 cells were exposed to paclitaxel for 12 hours in various concentrations. At 12 hours, the drug containing media was removed and the cells were cultured in media containing various concentrations of PNC-27 for 24 hours. Viability was assessed with the use of an MTT assay. Survival fractions were plotted against drug concentrations and the data were fit to logistic dose-response curves. Isoeffective combinations were used to create isobolograms. The combined treatment with weekly paclitaxel and PNC-27 was tested in an intraperitoneal mouse model of ovarian cancer (ID8). RESULTS: Exposure to paclitaxel rendered incomplete time-dependent killing, while PNC-27 mediated comprehensive, dose-dependent killing of ID8 cells. The cytotoxic effect of PNC-27 was dependent on its binding to MDM-2. Blocking MDM-2 inhibited the killing by PNC-27. ID8 cells surviving paclitaxel demonstrated increased expression of MDM-2 and increased susceptibility to PNC-27. Isobologram for dose combinations that were isoeffective indicates synergistic effect between the 2 agents (Combination index <1). In an in vivo model of ovarian cancer (ID8), the addition of PNC-27 to weekly paclitaxel administration significantly reduces tumor growth. CONCLUSIONS: These data demonstrate synergism between PNC-27 and paclitaxel. PNC-27 could target cells surviving paclitaxel and improve its antitumor effect. PMID- 28667028 TI - Prognostic Value of Elevated Red Blood Cell Distribution Width in Chinese Patients with Multiple Myeloma. AB - BACKGROUND: Red blood cell distribution width (RDW) is a parameter measured in blood routine test and has been reported as a biomarker for numerous diseases. It is closely related to iron metabolism, which plays an important role in multiple myeloma (MM). Therefore, we investigated the RDW relationship with the selected clinical parameters of MM patients to evaluate its prognostic value. METHODS: 166 MM patients (88 males and 78 females, average age: 61.6+/-10.8 years) were retrospectively observed between January 2009 and May 2015. Their baseline RDW levels and other clinical data were collected and the clinical characteristics were subsequently compared between high (>14.0%) and normal (<=14.0%) RDW level groups. RESULTS: High RDW levels had a significantly high correlation with some unfavorable clinical parameters and cytogenetic abnormalities. We did not find significant correlation between elevated RDW values and patients' age, gender, globulin, and treatment response. Importantly, an increased RDW value was found to be related to patients' progression free survival (PFS) and overall survival (OS). Moreover, multivariate COX analysis predicted that an elevated RDW value was independently associated with a poor PFS in MM patients. CONCLUSION: Elevated RDW value would be a readily available predictor of long-term adverse outcome among MM patients. PMID- 28667029 TI - Association of the Del1518 Promoter (rs3730485) Polymorphism in the MDM2 Gene with Breast Cancer in a Mexican Population. AB - INTRODUCTION: The MDM2 gene plays an important role in tumorigenesis. The data on the Del1518 promoter polymorphism in the MDM2 gene have revealed associations with cancer. MATERIAL AND METHODS: We examined the role of the MDM2 Del1518 polymorphism through a comparison of the genotypes of 345 healthy Mexican women with those of 742 Mexican women with breast cancer (BC). RESULTS: The genotype frequencies of the MDM2 Del1518 polymorphism in controls and patients with BC were 64% and 55.5% for ins/ins, 32% and 31.5% for ins/del, and 4% and 13% for del/del, respectively. The obtained odds ratio (OR) was 3.26, with a 95% confidence interval (95% CI) of 1.86-5.72 and p=0.0001, for the del/del genotype. An association was evident when we examined the distribution of the del/del genotype in patients with elevated levels of transaminase SGPT (OR=2.268; 95% CI=1.40-3.65; p=0.0001). Additionally, we observed an association of the genotypes del/del - ins/del in menopausal patients with BC with the following characteristics: tobacco consumption (OR = 1.93, 95% CI = 1.07-3.4, p=0.025), pregnancy loss (OR=2.44, 95% CI=1.37-4.35, p=0.0024), obesity (I-IV) (OR=1.8, 95% CI=1.1-2.9, p= 0.018), and elevated serum glucose levels (OR=3.72, 95% CI=2.0 6.85, p=0.0001). CONCLUSIONS: The MDM2 Del1518 polymorphism was associated with BC susceptibility, particularly in menopausal patients with BC who reported tobacco consumption, pregnancy loss, obesity and high glucose levels in the analyzed Mexican population. PMID- 28667030 TI - The Clinical Significance of Endometrial Cells Detected on Pap Testing: The Impact of Revisions to the 3rd Edition of the Bethesda System for Reporting Cervical Cytology. AB - GOALS: This study aims to examine the effects of raising the reporting age for benign endometrial cells (BEC) on Papanicolaou (Pap) tests according to the 2014 3rd edition of the Bethesda System for Cervical Cytology, as well as the sequelae of the 2012 American Society of Colposcopy and Cervical Pathology (ASCCP) guidelines recommending endometrial asessment only for postmenopausal or symptomatic premenopausal women. PROCEDURES: We retrospectively examined clinical and histologic data from 4438 women aged >=40 with BEC on Pap tests, of whom 608 (14%) were biopsied. RESULTS: Fifty-three (8.7%) histologic abnormalities were discovered upon biopsy. There was no significant difference (p=0.52) in abnormalities found between premenopausal women aged >=40 and premenopausal women aged >=45. Furthermore, there were no high-grade cancers in women between ages 40 44. There were also 3 high-grade cancers in patients aged 46, 46, and 49. Each of these women was asymptomatic and premenopausal. CONCLUSION: Our results affirm the raising of the reporting age of BEC on Pap tests from 40 to 45 in our patient population. Because there were 3 asymptomatic, premenopausal patients with high grade cancers in our 45-49 age group, we cannot completely adhere to the ASCCP guidelines nor can we advocate raising the reporting age further to 50. Other laboratories must review their own follow-up data to validate appropriate reporting criteria for BEC for their patients. PMID- 28667031 TI - Transcriptional Activity of Nuclear Factor kappaB Family Genes in Patients with Systemic Sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology and unclear pathogenesis. Evaluation of the activation of nuclear factor kappaB (NF-kappaB) family genes IkappaBalpha, p50, p52, p65, and c-Rel, potentially involved in the regulation of immunity, inflammation, angiogenesis, and tissue remodeling in SSc, was carried out. METHOD: The study included 19 patients with limited SSc, 11 patients with early SSc, and 10 healthy persons constituting the control group. Real-time QRT-PCR was used to evaluate the mRNAs in peripheral blood samples. RESULTS: The patients with early SSc showed a decrease in transcriptional activity of IkappaBalpha inhibitor and c-Rel subunit. Transcriptional activity decrease in the other patients with limited SSc included genes encoding c-Rel and p50, subunits of NF-kappaB factor. CONCLUSIONS: Deregulation of intracellular signal transduction by NF-kappaB takes place at the beginning of SSc and in its fibrosis stage. Associations between clinical variables and NF-kappaB related gene expression as well as the activation of NF kappaB family members in SSc patients should be addressed in future studies. PMID- 28667032 TI - Potential Role of Soluble TNF-alpha Receptors in Diagnosis of Patients with Chronic Kidney Disease. AB - OBJECTIVE: Soluble tumor necrosis factor alpha (TNF-alpha) receptors contain two subclasses: soluble tumor necrosis factor receptor (sTNFR)1 and sTNFR 2. The aim of our study was to investigate whether serum levels of them are biomarkers for diagnosis of chronic kidney disease (CKD) patients. MATERIALS AND METHODS: The serum samples were collected from 51 patients with CKD and 30 healthy controls. The presence of circulating sTNFR1 and 2 was quantified by ELISA and Cystain C (CysC), urea, creatinine (CREA), uric acid (UA), total protein (TP), Albumin (ALB), and 24 hours urinary protein (PRO) were examined by automatic biochemical analyzer. RESULTS: Levels of circulating sTNFR1 and sTNFR2 were significantly higher in CKD group than control (P<0.05). There was significant correlation between sTNFR1 and sTNFR2 (P<0.01). Both sTNFR1and sTNFR2 were positively related to serum urea, CREA, and CysC (P<0.01). Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of sTNFR1 and sTNFR2 were 0.987 and 0.986, respectively. CONCLUSION: This is the first study to show that combined detection of sTNFR1and sTNFR2 could be usable for CKD diagnosis. PMID- 28667033 TI - Percent cPRA (Calculated Panel Reactive Antibody) Value Predicts Percent of Positive Platelet Crossmatches. AB - BACKGROUND: Platelet refractoriness or lack of platelet increase after platelet transfusion is seen in patients receiving chronic platelet transfusion support. Antibodies may develop against human platelet antigens (HPA) and/or against HLA class I antigens. Crossmatch (XM) compatible platelets or HLA-identical or HLA compatible platelets are typically used to manage transfusion refractoriness. We aimed to determine if percent calculated Panel Reactive Antibody (% cPRA) against class I HLA antigens could predict percent positive platelet XM when looking for compatible transfusion products. METHODS: A retrospective review of all platelet XM performed at our institution between 2008-2012 was performed, and patient characteristics recorded. For each patient, the percentage of all positive platelet XM performed was calculated and compared with the corresponding % cPRA levels against class I HLA antigens. RESULTS: Mean and median % positive platelet XM for all 50 patients tested in the period 2008-2012 were 61% and 60% (range 0 100%), respectively. Mean and median % cPRA levels were 66% and 68% (range 0 100%), respectively. No correlation was seen between age, sex, race, or diagnosis and positive platelet XM results. CONCLUSION: The results of our study indicate that the % cPRA correlates well with the % positive platelet XM. Thus, a higher % cPRA alerts the blood bank that additional platelets will be required for XM and/or that it would be beneficial to request HLA-identical or compatible units. PMID- 28667019 TI - Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element. AB - The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (~5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb) in D. ananassae To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5' ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains. PMID- 28667034 TI - A Novel ALAS2 Mutation Resulting in Variable Phenotypes and Pyridoxine Response in a Family with X-linked Sideroblastic Anemia. AB - We report a novel ALAS2 gene mutation c.1315A>G (p.Lys439Glu) identified in a family, which caused evidently different hematologic phenotypes. The proband was a 17-year-old man with severe microcytic hypochromic anemia, excessive ring sideroblasts in the bone marrow, and iron overload. A hemizygous ALAS2 mutation in exon 9, c.1315A>G (p.Lys439Glu), was identified through sequence analysis. We assume that this amino acid substitution affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate, since the patient was responsive to pyridoxine treatment. This novel mutation likely accounts for variable hematologic phenotypes in the family of this patient: his 15-year-old hemizygous brother was asymptomatic, while his heterozygous mother was mildly anemic. PMID- 28667035 TI - Helicobacter Pylori - Specific Antigen Tests in Saliva to Identify an Oral Infection. AB - GOALS: Over the past twenty years, the existence of oral Helicobacter pylori (H. pylori) infection has been controversial and is still disputed. It proposes that living H. pylori do not exist in the oral cavity. However, the progressive loss of efficacy of standard eradication therapies has made the treatment of H. pylori more challenging than ever due to oral H. pylori infection. We conducted a study to explore the existence of oral H. pylori infection among 4321 adults. PROCEDURES: A total 4321 adults (age range, 20-89 years old) comprising 2849 men and 1472 women were recruited by annual physical exam and evaluated using the saliva H. pylori antigen test (HPS) to diagnose oral H. pylori infection and the urea breath test (UBT) to diagnose stomach H. pylori infection. According to the classification on age grouping of World Health Organization, patients were divided into three age groups: A group, the young age subgroup (<45 years); B group, the middle age subgroup (45 to 59 years); C group, the old age subgroup (60-74 years) and D group, the elder subgroup (75-89 years). RESULTS: We found the positive rate of oral H. pylori was 59.59% in the 95% confidence interval (CI) ranges on A group. The lowest positive rate of H. pylori in D group was 25.48% in the 95% confidence interval CI ranges. There was a statistically significant difference (p<0.001) between A, B, C, and D groups but no significant difference between men and women. CONCLUSION: HPS could identify oral H. pylori infection of individuals who have no risk for H. pylori gastric infection. The positive rate of oral H. pylori was 59.59% and this varies across different age groups. This information was not provided by UBT methods. It further identified that the prevalence of oral H. pylori infection is lower in the elder group that may be associated with fewer number of teeth. PMID- 28667036 TI - Clinical Evaluation of Seeplex(r) Diarrhea-V ACE Detection (V2.0) Kit for Detection of Rotavirus in Stool Specimens from Children with Acute Gastroenteritis. AB - Rotavirus is the most common cause of severe infectious diarrhea worldwide in children under 5 years of age. We have evaluated the performance of multiplex PCR [Seeplex(r) Diarrhea-V ACE Detection (V2.0) Kit] (the version 2.0 kit) for detecting rotaviruses in human stool specimens, in a comparison with ELISA (RIDASCREEN(r)) and the older Seeplex kit, namely Seeplex(r) Diarrhea-V ACE Detection Kit (the original kit). A total of 173 stool specimens, previously tested for rotavirus infection by ELISA from May 2014 to March 2016, were subjected to the two Seeplex(r) kits. The positive rate for the detection of rotavirus was 46.2% (80/173) by the version 2.0 kit. As compared with ELISA, the agreement rate of the original kit and the version 2.0 kit was 64.2% (positive agreement rate 23.1%, negative agreement rate 97.9%) and 97.7% (positive agreement rate 98.7%, negative agreement rate 96.8%), respectively. The agreement rate between the original kit and the version 2.0 kit was 65.3%. Thus, the Seeplex(r) Diarrhea-V ACE Detection (V2.0) Kit showed acceptable clinical performance and could be useful for detecting rotavirus infection with a performance superior to the original kit using the ELISA as the comparator. PMID- 28667037 TI - A Programmed Cell Death-1 Haplotype is Associated with Clearance of Hepatitis B Virus. AB - PURPOSE: Programmed cell death 1 (PD-1) is an important immune checkpoint of T cells response and plays a critical role in chronic hepatitis B virus (HBV) infection. The purpose of this study was to investigate the associations between PD-1 polymorphisms and susceptibility and disease progression of chronic HBV infection. METHODS: In this case-control study, 299 cases with chronic HBV infection comprised of 99 asymptomatic carriers (ASCs), 96 patients with chronic hepatitis B (CHB), and 104 patients with HBV-related acute on chronic liver failure (HBV-ACLF) were enrolled. A total of 82 spontaneously recovered subjects were enrolled as controls. Three single nucleotide polymorphisms (SNPs) of PD-1, including PD-1.1, PD-1.5, and PD-1.9 were analyzed by Sequenom MassARRAY system. RESULTS: The frequency of PD1.1 AA genotype was found to be significantly higher in the chronic HBV infection group compared with spontaneously recovered group (27.1% vs. 18.3%, P=0.049), and the frequency of PD-1.5 TT genotype and allele T were both significantly lower in chronic HBV infection group compared with spontaneously recovered group (genotype: 4.7% vs. 9.8%, P=0.04; allele: 22.1% vs. 30.5%, P=0.025). The frequency of haplotype GTC (PD-1.1 G, PD-1.5 T, PD-1.9 C) was significantly lower in patients with chronic HBV infection compared with spontaneous recovery cases (P=0.026). No significant differences were found in the genotype distributions of the three SNPs among the different clinical types of chronic HBV infection (P>0.53). CONCLUSIONS: Our results suggest that PD1 polymorphisms are associated with susceptibility to chronic HBV infection in the Chinese population. Future studies with larger sample sizes and different ethnic populations are required to validate our findings. PMID- 28667038 TI - Post-transplant Lymphoproliferative Disorder Presented in a Form of Primary Effusion Lymphoma with t (8; 14). AB - Post-transplant lymphoproliferative disorders (PTLD) are emergent complications of organ transplantation occurring in 2% to 10% of transplanted patients. Epstein Barr virus (EBV) infections are considered the most important factors for the development of these heterogeneous disorders. Primary effusion lymphoma (PEL) is a lymphoproliferative disorder predominantly described in patients with advanced AIDS and it is almost universally associated with human herpesvirus 8 (HHV8). In rare case, PEL also occurs in HHV8-negative patient, in the setting of hepatitis B and C virus infection. However, all these cases showed pan B-cell markers to be positive. Here, we report a case of PTLD presented as HHV8-negative and HIV negative primary effusion lymphoma lacking near all lymphoid markers except PAX5 on immunohistochemistry, which created a diagnostic challenge. The diagnosis requires multiple approaches including molecular and genetic tests. PMID- 28667039 TI - Sellar and Suprasellar Anaplastic Hemangiopericytoma in a 34-Year Old Man. AB - Central nervous system hemangiopericytomas are rare, representing <1% of all primary central nervous system tumors. Hemangiopericytomas of the sellar region are exceptionally rare. Here we present a case of a sellar/suprasellar anaplastic hemangiopericytoma.The patient is a 34 year old man with a history of a resected pituitary tumor, diagnosed as a pituitary adenoma per the patient, who presented with bitemporal hemianopsia. Radiology revealed a 3.7 cm enhancing sellar/suprasellar mass with local mass effect, consistent with a pituitary adenoma. On resection, the mass was diagnosed as anaplastic hemangiopericytoma, WHO grade III. The patient experienced residual tumor with two further resections before expiring of a pulmonary embolus seven months later.There are only 10 previously documented cases of sellar/suprasellar hemangiopericytoma in the English-speaking world literature. This is the third case of anaplastic hemangiopericytoma in this region. These cases should be recorded until meaningful conclusions about therapy and prognosis can be established. PMID- 28667040 TI - Mitochondrial Iron Accumulation in Parietal and Chief Cells in Iron Pill Gastritis Following Billroth II Gastrectomy: Case Report Including Electron Microscopic Examination. AB - Iron pill gastritis has been shown to be associated with superficial gastric erosion and deposition of iron in lamina propria and gastric antral glands. However, iron absorption in gastric parietal and chief cells is rare. We present a case of a 62-year-old man with iron deficiency anemia. His past medical history is significant for Billroth II surgery. His medications include ferrous sulphate 325mg. Esophagogastroduodenoscopy showed diffuse circumferential abnormal mucosa at the gastro-jejunal anastomosis. The mucosa was erythematous and violaceous. Biopsy showed reactive gastropathy with iron deposits predominantly in macrophages, parietal cells, and chief cells. These findings were confirmed by iron stain and later by electron micrography of the gastric mucosa that showed iron deposits in mitochondria and cytoplasm of the parietal and chief cells. PMID- 28667041 TI - Placental Fetal Thrombotic Vasculopathy Occurring in Association with Megacystis microcolon-intestinal Hypoperistalsis Syndrome: A Case Report. AB - Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disease of functional obstruction affecting the bladder and intestines, characterized by a markedly distended bladder, microcolon, and decreased or absent intestinal peristalsis. Afflicted neonates have very poor prognosis, usually with fatal outcomes in first days to months of life. Placental fetal thrombotic vasculopathy (FTV) is a thrombo-occlusive disorder of the chorionic plate and fetal circulation. Herein, we describe an undocumented association of MMIHS and placental FTV. We present the case of 32-year-old female G4P2-0-1-2, who gave birth to a viable female infant at 35 weeks of gestation via spontaneous vaginal delivery. Fetal MRI, completed at 24 weeks of gestation, revealed a massively distended urinary bladder, bilateral hydronephrosis in the presence of normal amniotic fluid, and poorly visualized bowel loops without meconium extending into the rectum. Given the constellation of these findings, a presumptive diagnosis of MMIHS was established. After birth, the neonate presented with clinical and radiological features consistent with MMIHS. An intact placenta was delivered and macroscopic examination showed numerous thrombi in fetal vasculature. Microscopic examination showed thrombosis and recanulization of fetal vessels in stem villi and histologic changes consistent with placental FTV. Neonatal course was complicated by hypoglycemia, malrotation, anemia, thrombocytopenia, and coagulopathy. The infant was subsequently discharged home with hospice and palliative care. To our knowledge, this is the first case of MMIHS associated with placental FTV documented in the English literature. Our report illustrates the value of pathological examination of the placenta in this rare disease. PMID- 28667042 TI - R132H Mutation in IDH1 Gene is Associated with Increased Tumor HIF1-Alpha and Serum VEGF Levels in Primary Glioblastoma Multiforme. AB - GOALS: Glioblastoma multiforme (GBM) is the most common form of primary brain tumors. Although mutations in isocitrate dehydrogenase-1 (IDH1) have been identified in a number of cancers, their role in tumor development has not been fully elucidated. In this study, we aimed to investigate the association between IDH1 mutations, tumor tissue HIF-1 alpha, and serum VEGF levels in patients with primary GBM for the first time. METHODS: 32 patients (mean age, years: 58+/-14.0) diagnosed with primary glioblastoma multiforme were screened for IDH1 mutations (R132H, R132S, R132C and R132L) by direct sequencing. Serum VEGF and tumor tissue HIF1-alpha levels were measured by enzyme-linked immunosorbent assay. Associations between categoric variables were determined using chi-square tests. Differences between two groups were compared with t test for continuous variables. RESULTS: Six percent of patients were found to be heterozygous for R132H mutation. Tumor HIF1-alpha and serum VEGF levels were found to be significantly increased in IDH1-mutated tumor tissues (p<0.0001 and p=0.0454, respectively). CONCLUSION: Our results suggest that mutated IDH1 may contribute to carcinogenesis via induction of HIF-1 alpha pathway in primary GBM. PMID- 28667043 TI - Abstracts of Presentations at the Association of Clinical Scientists 137th Meeting Birmingham, AL, May 17-20, 2017. PMID- 28667045 TI - Fifteen-minute consultation: An evidence-based approach to the child with preschool wheeze. AB - Preschool wheeze is very common and its prevalence is increasing. It consumes considerable healthcare resources and has a major impact on children and their families due to significant morbidity associated with acute episodes.History taking is the main diagnostic instrument in the assessment of preschool wheeze. Diagnosis and management is complicated by a broad differential and associations with many other diseases and conditions that give rise to noisy breathing, which could be misinterpreted as wheeze. Several clinical phenotypes have been described but they have limitations and do not clearly inform therapeutic decisions. New insights in aetiopathogenesis modify treatment options and lay foundation for further research. An understanding of the approach and available evidence to assess and manage wheeze informs best patient care and use of resources.Our objective is to demonstrate a focused history, examination and management options in a preschool child with wheeze. PMID- 28667046 TI - Core Outcome Sets. PMID- 28667047 TI - Fifteen-minute consultation-the child with a developmental disability: is there an ocular or visual abnormality? AB - OBJECTIVE: To present a structured approach for an outpatient consultation for a child with developmental disability who may have an ocular or visual disorder. METHOD: Review of relevant literature and description of the approach to ocular and visual assessment which could be used by any paediatrician. CONCLUSION: A systematic approach to history, observation and examination of a child with a developmental disability will assist in identifying a possible visual problem. A structured referral letter will ensure that the child will receive the most appropriate assessment to clarify the problem and appropriate management in the eye clinic. PMID- 28667048 TI - Monophyletic Origin and Evolution of the Largest Crucifer Genomes. AB - Clade E, or the Hesperis clade, is one of the major Brassicaceae (Crucifereae) clades, comprising some 48 genera and 351 species classified into seven tribes and is distributed predominantly across arid and montane regions of Asia. Several taxa have socioeconomic significance, being important ornamental but also weedy and invasive species. From the comparative genomic perspective, the clade is noteworthy as it harbors species with the largest crucifer genomes but low numbers of chromosomes (n = 5-7). By applying comparative cytogenetic analysis and whole-chloroplast phylogenetics, we constructed, to our knowledge, the first partial and complete cytogenetic maps for selected representatives of clade E tribes and investigated their relationships in a family-wide context. The Hesperis clade is a well-supported monophyletic lineage comprising seven tribes: Anchonieae, Buniadeae, Chorisporeae, Dontostemoneae, Euclidieae, Hesperideae, and Shehbazieae. The clade diverged from other Brassicaceae crown-group clades during the Oligocene, followed by subsequent Miocene tribal diversifications in central/southwestern Asia. The inferred ancestral karyotype of clade E (CEK; n = 7) originated from an older n = 8 genome, which also was the purported progenitor of tribe Arabideae (KAA genome). In most taxa of clade E, the seven linkage groups of CEK either remained conserved (Chorisporeae) or were reshuffled by chromosomal translocations (Euclidieae). In 50% of Anchonieae and Hesperideae species, the CEK genome has undergone descending dysploidy toward n = 6 (-5). These genomic data elucidate early genome evolution in Brassicaceae and pave the way for future whole-genome sequencing and assembly efforts in this as yet genomically neglected group of crucifer plants. PMID- 28667049 TI - Root Cortical Senescence Improves Growth under Suboptimal Availability of N, P, and K. AB - Root cortical senescence (RCS) in Triticeae reduces nutrient uptake, nutrient content, respiration, and radial hydraulic conductance of root tissue. We used the functional-structural model SimRoot to evaluate the functional implications of RCS in barley (Hordeum vulgare) under suboptimal nitrate, phosphorus, and potassium availability. The utility of RCS was evaluated using sensitivity analyses in contrasting nutrient regimes. At flowering (80 d), RCS increased simulated plant growth by up to 52%, 73%, and 41% in nitrate-, phosphorus-, and potassium-limiting conditions, respectively. Plants with RCS had reduced nutrient requirement of root tissue for optimal plant growth, reduced total cumulative cortical respiration, and increased total carbon reserves. Nutrient reallocation during RCS had a greater effect on simulated plant growth than reduced respiration or nutrient uptake. Under low nutrient availability, RCS had greater benefit in plants with fewer tillers. RCS had greater benefit in phenotypes with fewer lateral roots at low nitrate availability, but the opposite was true in low phosphorus or potassium availability. Additionally, RCS was quantified in field grown barley in different nitrogen regimes. Field and virtual soil coring simulation results demonstrated that living cortical volume per root length (an indicator of RCS) decreased with depth in younger plants, while roots of older plants had very little living cortical volume per root length. RCS may be an adaptive trait for nutrient acquisition by reallocating nutrients from senescing tissue and secondarily by reducing root respiration. These simulated results suggest that RCS merits investigation as a breeding target for enhanced soil resource acquisition and edaphic stress tolerance. PMID- 28667050 TI - Regional heterogeneity in the mechanisms of myogenic tone in hamster arterioles. AB - Myogenic tone is an important feature of arterioles and resistance arteries, but the mechanisms responsible for this hallmark characteristic remain unclear. We used pharmacological inhibitors to compare the roles played by phospholipase C (PLC; 10 MUM U73122), inositol 1,4,5-trisphosphate receptors (IP3Rs; 100 MUM 2 aminoethoxydiphenylborane), protein kinase C (10 MUM bisindolylmaleimide I), angiotensin II type 1 receptors (1 MUM losartan), Rho kinase (10 nM-30 MUM Y27632 or 300 nM H1152), stretch-activated ion channels (10 nM-1 MUM Gd3+ or 5 MUM spider venom toxin GsMTx-4) and L-type voltage-gated Ca2+ channels (0.3-100 MUM diltiazem) in myogenic tone of cannulated, pressurized (80 cmH2O), second-order hamster cremaster or cheek pouch arterioles. Effective inhibition of either PLC or IP3Rs dilated cremaster arterioles, inhibited Ca2+ waves, and reduced global Ca2+ levels. In contrast, cheek pouch arterioles did not display Ca2+ waves and inhibition of PLC or IP3Rs had no effect on myogenic tone or intracellular Ca2+ levels. Inhibition of Rho kinase dilated both cheek pouch and cremaster arterioles with equal efficacy and potency but also reduced intracellular Ca2+ signals in both arterioles. Similarly, inhibition of mechanosensitive ion channels with Gd2+ or GsMTx-4 produced comparable dilation in both arterioles. Inhibition of L-type Ca2+ channels with diltiazem was more effective in dilating cremaster (86 +/- 5% dilation, n = 4) than cheek pouch arterioles (54 +/- 4% dilation, n = 6, P < 0.05). Thus, there are substantial differences in the mechanisms underlying myogenic tone in hamster cremaster and cheek pouch arterioles. Regional heterogeneity in myogenic mechanisms could provide new targets for drug development to improve regional blood flow in a tissue-specific manner.NEW & NOTEWORTHY Regional heterogeneity in the mechanisms of pressure induced myogenic tone implies that resistance vessels may be able to alter myogenic signaling pathways to adapt to their environment. A better understanding of the spectrum of myogenic mechanisms could provide new targets to treat diseases that affect resistance artery and arteriolar function. PMID- 28667052 TI - Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity. AB - Cardiac ATP-sensitive K+ (KATP) channels couple changes in cellular metabolism to membrane excitability and are activated during metabolic stress, although under basal aerobic conditions, KATP channels are thought to be predominately closed. Despite intense research into the roles of KATP channels during metabolic stress, their contribution to aerobic basal cardiac metabolism has not been previously investigated. Hearts from Kir6.2+/+ and Kir6.2-/- mice were perfused in working mode, and rates of glycolysis, fatty acid oxidation, and glucose oxidation were measured. Changes in activation/expression of proteins regulating metabolism were probed by Western blot analysis. Despite cardiac mechanical function and metabolic efficiency being similar in both groups, hearts from Kir6.2-/- mice displayed an approximately twofold increase in fatty acid oxidation and a 0.45 fold reduction in glycolytic rates but similar glucose oxidation rates compared with hearts from Kir6.2+/+ mice. Kir6.2-/- hearts also possessed elevated levels of activated AMP-activated protein kinase (AMPK), higher glycogen content, and reduced mitochondrial density. Moreover, activation of AMPK by isoproterenol or diazoxide was significantly blunted in Kir6.2-/- hearts. These data indicate that KATP channel ablation alters aerobic basal cardiac metabolism. The observed increase in fatty acid oxidation and decreased glycolysis before any metabolic insult may contribute to the poor recovery observed in Kir6.2-/- hearts in response to exercise or ischemia-reperfusion injury. Therefore, KATP channels may play an important role in the regulation of cardiac metabolism through AMPK signaling.NEW & NOTEWORTHY In this study, we show that genetic ablation of plasma membrane ATP-sensitive K+ channels results in pronounced changes in cardiac metabolic substrate preference and AMP-activated protein kinase activity. These results suggest that ATP-sensitive K+ channels may play a novel role in regulating metabolism in addition to their well-documented effects on ionic homeostasis during periods of stress. PMID- 28667051 TI - Folic acid ingestion improves skeletal muscle blood flow during graded handgrip and plantar flexion exercise in aged humans. AB - Skeletal muscle blood flow is attenuated in aged humans performing dynamic exercise, which is due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole body heating through nitric oxide-dependent mechanisms. However, it is unclear whether folic acid improves vasodilation in other vascular beds during conditions of increased metabolism (i.e., exercise). The purpose of this study was to test the hypothesis that folic acid ingestion improves skeletal muscle blood flow in aged adults performing graded handgrip and plantar flexion exercise via increased vascular conductance. Nine healthy, aged adults (two men and seven women; age: 68 +/- 5 yr) performed graded handgrip and plantar flexion exercise before (control), 2 h after (acute, 5 mg), and after 6 wk (chronic, 5 mg/day) folic acid ingestion. Forearm (brachial artery) and leg (superficial femoral artery) blood velocity and diameter were measured via Duplex ultrasonography and used to calculate blood flow. Acute and chronic folic acid ingestion increased serum folate (both P < 0.05 vs. control). During handgrip exercise, acute and chronic folic acid ingestion increased forearm blood flow (both conditions P < 0.05 vs. control) and vascular conductance (both P < 0.05 vs. control). During plantar flexion exercise, acute and chronic folic acid ingestion increased leg blood flow (both P < 0.05 vs. control), but only acute folic acid ingestion increased vascular conductance (P < 0.05 vs. control). Taken together, folic acid ingestion increases blood flow to active skeletal muscle primarily via improved local vasodilation in aged adults.NEW & NOTEWORTHY Our findings demonstrate that folic acid ingestion improves blood flow via enhanced vascular conductance in the exercising skeletal muscle of aged humans. These findings provide evidence for the therapeutic use of folic acid to improve skeletal muscle blood flow, and perhaps exercise and functional capacity, in human primary aging.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/folic-acid-and-exercise-hyperemia-in-aging/. PMID- 28667053 TI - MicroRNA-124 controls human vascular smooth muscle cell phenotypic switch via Sp1. AB - Phenotypic switch of vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of atherosclerosis and aortic dissection. However, the mechanisms of phenotypic modulation are still unclear. MicroRNAs have emerged as important regulators of VSMC function. We recently found that microRNA-124 (miR 124) was downregulated in proliferative vascular diseases that were characterized by a VSMC phenotypic switch. Therefore, we speculated that the aberrant expression of miR-124 might play a critical role in human aortic VSMC phenotypic switch. Using quantitative RT-PCR, we found that miR-124 was dramatically downregulated in the aortic media of clinical specimens of the dissected aorta and correlated with molecular markers of the contractile VSMC phenotype. Overexpression of miR-124 by mimicking transfection significantly attenuated platelet-derived growth factor-BB-induced human aortic VSMC proliferation and phenotypic switch. Furthermore, we identified specificity protein 1 (Sp1) as the downstream target of miR-124. A luciferase reporter assay was used to confirm direct miR-124 targeting of the 3'-untranslated region of the Sp1 gene and repression of Sp1 expression in human aortic VSMCs. Furthermore, constitutively active Sp1 in miR-124-overexpressing VSMCs reversed the antiproliferative effects of miR-124. These results demonstrated a novel mechanism of miR-124 modulation of VSMC phenotypic switch by targeting Sp1 expression.NEW & NOTEWORTHY Previous studies have demonstrated that miR-124 is involved in the proliferation of a variety of cell types. However, miRNAs are expressed in a tissue-specific manner. We first identified miR-124 as a critical regulator in human aortic vascular smooth muscle cell differentiation, proliferation, and phenotype switch by targeting the 3'-untranslated region of specificity protein 1. PMID- 28667054 TI - Analysis of decreases in systemic arterial pressure and heart rate in response to the hydrogen sulfide donor sodium sulfide. AB - The actions of hydrogen sulfide (H2S) on the heart and vasculature have been extensively reported. However, the mechanisms underlying the effects of H2S are unclear in the anesthetized rat. The objective of the present study was to investigate the effect of H2S on the electrocardiogram and examine the relationship between H2S-induced changes in heart rate (HR), mean arterial pressure (MAP), and respiratory function. Intravenous administration of the H2S donor Na2S in the anesthetized Sprague-Dawley rat decreased MAP and HR and produced changes in respiratory function. The administration of Na2S significantly increased the RR interval at some doses but had no effect on PR or corrected QT(n)-B intervals. In experiments where respiration was maintained with a mechanical ventilator, we observed that Na2S-induced decreases in MAP and HR were independent of respiration. In experiments where respiration was maintained by mechanical ventilation and HR was maintained by cardiac pacing, Na2S-induced changes in MAP were not significantly altered, whereas changes in HR were abolished. Coadministration of glybenclamide significantly increased MAP and HR responses at some doses, but methylene blue, diltiazem, and ivabradine had no significant effect compared with control. The decreases in MAP and HR in response to Na2S could be dissociated and were independent of changes in respiratory function, ATP-sensitive K+ channels, methylene blue-sensitive mechanism involving L-type voltage-sensitive Ca2+ channels, or hyperpolarization-activated cyclic nucleotide-gated channels. Cardiovascular responses observed in spontaneously hypertensive rats were more robust than those in Sprague-Dawley rats.NEW & NOTEWORTHY H2S is a gasotransmitter capable of producing a decrease in mean arterial pressure and heart rate. The hypotensive and bradycardic effects of H2S can be dissociated, as shown with cardiac pacing experiments. Responses were not blocked by diltiazem, ivabradine, methylene blue, or glybenclamide. PMID- 28667056 TI - Endogenous endophthalmitis and osteomyelitis associated with interleukin 17 inhibitor treatment for psoriasis in a patient with diabetes. AB - A 64-year-old man with type 2 diabetes mellitus and plaque psoriasis presented to the emergency room with 3 days of progressive right eye pain and decreased vision. After extensive workup and multidisciplinary team effort, the patient was diagnosed with and treated for unilateral endogenous methicillin-sensitive Staphylococcus aureus endophthalmitis, bacteraemia and osteomyelitis of the foot. The patient had been started on the interleukin 17 (IL-17) inhibitor secukinumab for his treatment-resistant plaque psoriasis 4 weeks prior to presentation. After treatment, his final vision was light perception and the foot infection resolved without sequelae. To our knowledge, this is the first reported case of both endogenous endophthalmitis and osteomyelitis associated with an IL-17 inhibitor. PMID- 28667058 TI - Clinical Science: showcasing the breadth of the journal. AB - This Editorial introduces the review articles published in this issue to showcase the range of subject areas, such as neurology, the respiratory system, kidney disease and oxidative stress, covered by Clinical Science. PMID- 28667057 TI - An elusive ciliopathy: Joubert syndrome. AB - The police brought a 65-year-old female patient to the EADU after being found 'roaming the streets' in an apparent state of confusion. This was her third admission under the same circumstances during the last 3 years. Neurological examination revealed (1) cognitive impairment, (2) oculomotor apraxia, (3) abnormal cancellation of vestibular ocular reflex, (4) mild ataxia and (5) mild hypotonia. Renal function was abnormal and liver function was normal. No retinal disturbance was found. The head CT on admission was normal for stroke and the lumbar puncture was negative for encephalitis. Her brain MRI showed 'molar tooth sign', suggestive of Joubert syndrome, which was confirmed by genetic testing showing anomalous NPHP1 gene. PMID- 28667055 TI - Increased activity of the orexin system in the paraventricular nucleus contributes to salt-sensitive hypertension. AB - The orexin system is involved in arginine vasopressin (AVP) regulation, and its overactivation has been implicated in hypertension. However, its role in salt sensitive hypertension (SSHTN) is unknown. Here, we tested the hypothesis that hyperactivity of the orexin system in the paraventricular nucleus (PVN) contributes to SSHTN via enhancing AVP signaling. Eight-week-old male Dahl salt sensitive (Dahl S) and age- and sex-matched Sprague-Dawley (SD) rats were placed on a high-salt (HS; 8% NaCl) or normal-salt (NS; 0.4% NaCl) diet for 4 wk. HS intake did not alter mean arterial pressure (MAP), PVN mRNA levels of orexin receptor 1 (OX1R), or OX2R but slightly increased PVN AVP mRNA expression in SD rats. HS diet induced significant increases in MAP and PVN mRNA levels of OX1R, OX2R, and AVP in Dahl S rats. Intracerebroventricular infusion of orexin A (0.2 nmol) dramatically increased AVP mRNA levels and immunoreactivity in the PVN of SD rats. Incubation of cultured hypothalamus neurons from newborn SD rats with orexin A increased AVP mRNA expression, which was attenuated by OX1R blockade. In addition, increased cerebrospinal fluid Na+ concentration through intracerebroventricular infusion of NaCl solution (4 umol) increased PVN OX1R and AVP mRNA levels and immunoreactivity in SD rats. Furthermore, bilateral PVN microinjection of the OX1R antagonist SB-408124 resulted in a greater reduction in MAP in HS intake (-16 +/- 5 mmHg) compared with NS-fed (-4 +/- 4 mmHg) anesthetized Dahl S rats. These results suggest that elevated PVN OX1R activation may contribute to SSHTN by enhancing AVP signaling.NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate the involvement of the orexin system in salt-sensitive hypertension. Our results suggest that the orexin system may contribute to the Dahl model of salt-sensitive hypertension by enhancing vasopressin signaling in the hypothalamic paraventricular nucleus. PMID- 28667059 TI - Hypercholesterolaemia and vascular dementia. AB - Vascular dementia (VaD) is the second commonest cause of dementia. Stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death. Traditional vascular risk factors-diabetes, hypercholesterolaemia, hypertension and smoking-are implicated as risk factors for VaD. The associations between cholesterol and small vessel disease (SVD), stroke, cognitive impairment and subsequent dementia are complex and as yet not fully understood. Similarly, the effects of lipids and lipid-lowering therapy on preventing or treating dementia remain unclear; the few trials that have assessed lipid-lowering therapy for preventing (two trials) or treating (four trials) dementia found no evidence to support the use of lipid lowering therapy for these indications. It is appropriate to treat those patients with vascular risk factors that meet criteria for lipid-lowering therapy for the primary and secondary prevention of cardiovascular and cerebrovascular events, and in line with current guidelines. Managing the individual patient in a holistic manner according to his or her own vascular risk profile is recommended. Although the paucity of randomized controlled evidence makes for challenging clinical decision making, it provides multiple opportunities for on-going and future research, as discussed here. PMID- 28667060 TI - Small vessel disease, neurovascular regulation and cognitive impairment: post mortem studies reveal a complex relationship, still poorly understood. AB - The contribution of vascular disease to cognitive impairment is under-recognized and the pathogenesis is poorly understood. This information gap has multiple causes, including a lack of post-mortem validation of clinical diagnoses of vascular cognitive impairment (VCI) or vascular dementia (VaD), the exclusion of cases with concomitant neurodegenerative disease when diagnosing VCI/VaD, and a lack of standardization of neuropathological assessment protocols for vascular disease. Other contributors include a focus on end-stage destructive lesions to the exclusion of more subtle types of diffuse brain injury, on structural abnormalities of arteries and arterioles to the exclusion of non-structural abnormalities and capillary damage, and the use of post-mortem sampling strategies that are biased towards the identification of neurodegenerative pathologies. Recent studies have demonstrated the value of detailed neuropathology in characterizing vascular contributions to cognitive impairment (e.g. in diabetes), and highlight the importance of diffuse white matter changes, capillary damage and vasoregulatory abnormalities in VCI/VaD. The use of standardized, evidence-based post-mortem assessment protocols and the inclusion of biochemical as well as morphological methods in neuropathological studies should improve the accuracy of determination of the contribution of vascular disease to cognitive impairment and clarify the relative contribution of different pathogenic processes to the tissue damage. PMID- 28667061 TI - MicroRNA in glutamate receptor-dependent neurological diseases. AB - Glutamate-mediated excitotoxicity is the major neuropathological process contributing to numerous neurological diseases. Recently, emerging evidence indicates that microRNAs (miRNAs) play essential roles in the pathophysiology of a wide range of neurological diseases. Notably, there have been significant developments in understanding the biogenesis of miRNAs, their regulatory mechanisms, and their potential as effective biomarkers and therapies. In the present review, we summarize the recent literature that highlights the versatile roles played by miRNAs in glutamate receptor (GluR)-dependent neurological diseases. Based on the reported studies to date, modulation of miRNAs could emerge as a promising therapeutic target for a variety of neurological diseases that were discussed in this review. PMID- 28667062 TI - Epilepsy and optogenetics: can seizures be controlled by light? AB - Over the past decade, 'optogenetics' has been consolidated as a game-changing tool in the neuroscience field, by allowing optical control of neuronal activity with high cell-type specificity. The ability to activate or inhibit targeted neurons at millisecond resolution not only offers an investigative tool, but potentially also provides a therapeutic intervention strategy for acute correction of aberrant neuronal activity. As efficient therapeutic tools are in short supply for neurological disorders, optogenetic technology has therefore spurred considerable enthusiasm and fostered a new wave of translational studies in neuroscience. Epilepsy is among the disorders that have been widely explored. Partial epilepsies are characterized by seizures arising from excessive excitatory neuronal activity that emerges from a focal area. Based on the constricted seizure focus, it appears feasible to intercept partial seizures by acutely shutting down excitatory neurons by means of optogenetics. The availability of both inhibitory and excitatory optogenetic probes, along with the available targeting strategies for respective excitatory or inhibitory neurons, allows multiple conceivable scenarios for controlling abnormal circuit activity. Several such scenarios have been explored in the settings of experimental epilepsy and have provided encouraging translational findings and revealed interesting and unexpected new aspects of epileptogenesis. However, it has also emerged that considerable challenges persist before clinical translation becomes feasible. This review provides a general introduction to optogenetics, and an overview of findings that are relevant for understanding how optogenetics may be utilized therapeutically as a highly innovative treatment for epilepsy. PMID- 28667063 TI - Translational science in chronic kidney disease. AB - The KDIGO definition of chronic kidney disease (CKD) allowed a more detailed characterization of CKD causes, epidemiology and consequences. The picture that has emerged is worrisome from the point of view of translation. CKD was among the fastest growing causes of death in the past 20 years in age-adjusted terms. The gap between recent advances and the growing worldwide mortality appears to result from sequential roadblocks that limit the flow from basic research to clinical development (translational research type 1, T1), from clinical development to clinical practice (translational research T2) and result in deficient widespread worldwide implementation of already available medical advances (translational research T3). We now review recent advances and novel concepts that have the potential to change the practice of nephrology in order to improve the outcomes of the maximal number of individuals in the shortest possible interval. These include: (i) updating the CKD concept, shifting the emphasis to the identification, risk stratification and care of early CKD and redefining the concept of aging-associated 'physiological' decline of renal function; (ii) advances in the characterization of aetiological factors, including challenging the concept of hypertensive nephropathy, the better definition of the genetic contribution to CKD progression, assessing the role of the liquid biopsy in aetiological diagnosis and characterizing the role of drugs that may be applied to the earliest stages of injury, such as SGLT2 inhibitors in diabetic kidney disease (DKD); (iii) embracing the complexity of CKD as a network disease and (iv) exploring ways to optimize implementation of existing knowledge. PMID- 28667064 TI - Disposition and clinical implications of protein-bound uremic toxins. AB - In patients with chronic kidney disease (CKD), adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities, many of which are too large to be filtered and/or are protein bound. The renal excretion of protein bound toxins depends largely on active tubular secretion, which shifts the binding and allows for active secretion of the free fraction. To facilitate this process, renal proximal tubule cells are equipped with a range of transporters that co-operate in basolateral uptake and luminal excretion. Many of these transporters have been characterized as mediators of drug disposition, but have recently been recognized for their importance in the proximal renal tubular transport of uremic toxins as well. This also indicates that during uremia, drug disposition may be severely affected as a result of drug-uremic toxin interaction. In addition, CKD patients receive various drugs to treat their complications potentially resulting in drug-drug interactions (DDIs), also for drugs that are non-renally excreted. This review discusses the current knowledge on formation, disposition and removal of protein-bound uremic toxins. Furthermore, implications associated with drug treatment in kidney failure, as well as innovative renal replacement therapies targetting the protein-bound uremic toxins are being discussed. It will become clear that the complex problems associated with uremia warrant a transdisciplinary approach that unites research experts in the area of fundamental biomedical research with their colleagues in clinical nephrology. PMID- 28667065 TI - Current epigenetic aspects the clinical kidney researcher should embrace. AB - Chronic kidney disease (CKD), affecting 10-12% of the world's adult population, is associated with a considerably elevated risk of serious comorbidities, in particular, premature vascular disease and death. Although a wide spectrum of causative factors has been identified and/or suggested, there is still a large gap of knowledge regarding the underlying mechanisms and the complexity of the CKD phenotype. Epigenetic factors, which calibrate the genetic code, are emerging as important players in the CKD-associated pathophysiology. In this article, we review some of the current knowledge on epigenetic modifications and aspects on their role in the perturbed uraemic milieu, as well as the prospect of applying epigenotype-based diagnostics and preventive and therapeutic tools of clinical relevance to CKD patients. The practical realization of such a paradigm will require that researchers apply a holistic approach, including the full spectrum of the epigenetic landscape as well as the variability between and within tissues in the uraemic milieu. PMID- 28667067 TI - Oxidative and inflammatory signals in obesity-associated vascular abnormalities. AB - Obesity is associated with increased cardiovascular morbidity and mortality in part due to vascular abnormalities such as endothelial dysfunction and arterial stiffening. The hypertension and other health complications that arise from these vascular defects increase the risk of heart diseases and stroke. Prooxidant and proinflammatory signaling pathways as well as adipocyte-derived factors have emerged as critical mediators of obesity-associated vascular abnormalities. Designing treatments aimed specifically at improving the vascular dysfunction caused by obesity may provide an effective therapeutic approach to prevent the cardiovascular sequelae associated with excessive adiposity. In this review, we discuss the recent evidence supporting the role of oxidative stress and cytokines and inflammatory signals within the vasculature as well as the impact of the surrounding perivascular adipose tissue (PVAT) on the regulation of vascular function and arterial stiffening in obesity. In particular, we focus on the highly plastic nature of the vasculature in response to altered oxidant and inflammatory signaling and highlight how weight management can be an effective therapeutic approach to reduce the oxidative stress and inflammatory signaling and improve vascular function. PMID- 28667068 TI - Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries. AB - Bronchopulmonary dysplasia (BPD) is a chronic illness that usually originates in preterm newborns. Generally, BPD is a consequence of respiratory distress syndrome (RDS) which, in turn, comes from the early arrest of lung development and the lack of pulmonary surfactant. The need of oxygen therapy to overcome premature newborns' compromised respiratory function generates an increasing amount of reactive oxygen species (ROS), the onset of sustained oxidative stress (OS) status, and inflammation in the pulmonary alveoli deputies to respiratory exchanges. BPD is a severe and potentially life-threatening disorder that in the most serious cases, can open the way to neurodevelopmental delay. More importantly, there is no adequate intervention to hamper or treat BPD. This perspective article seeks to review the most recent and relevant literature describing the very early stages of BPD and hyperoxic lung injuries focussing on nuclear factor erythroid derived 2 (Nrf2)/heme oxygenase-1 (HO-1) axis. Indeed, Nrf2/HO1 activation in response to OS induced lung injury in preterm concurs to the induction of certain number of antioxidant, anti-inflammatory, and detoxification pathways that seem to be more powerful than the activation of one single antioxidant gene. These elicited protective effects are able to counteract/mitigate all multifaceted aspects of the disease and may support novel approaches for the management of BPD. PMID- 28667069 TI - Role of human metapneumovirus and respiratory syncytial virus in asthma exacerbations: where are we now? AB - Since its discovery in 2001, human metapneumovirus (hMPV) has been identified as an important cause of respiratory tract infection in young children, second only to the closely related respiratory syncytial virus (RSV). Clinical evidence suggests that hMPV is associated with acute exacerbations of asthma in both children and adults, and may play a role in initiating asthma development in children. Animal models have demonstrated that airway hyperresponsiveness (AHR) and inflammation are triggered following hMPV infection, and hMPV is able to persist in vivo by inhibiting innate immune responses and causing aberrant adaptive responses. In this review, we discuss the prevalence of hMPV infection in pediatric and adult populations and its potential role in asthma exacerbation. We also review recent advances made in animal models to determine immune responses following hMPV infection, and compare to what is known about RSV. PMID- 28667066 TI - Redox theory of aging: implications for health and disease. AB - Genetics ultimately defines an individual, yet the phenotype of an adult is extensively determined by the sequence of lifelong exposures, termed the exposome. The redox theory of aging recognizes that animals evolved within an oxygen-rich environment, which created a critical redox interface between an organism and its environment. Advances in redox biology show that redox elements are present throughout metabolic and structural systems and operate as functional networks to support the genome in adaptation to environmental resources and challenges during lifespan. These principles emphasize that physical and functional phenotypes of an adult are determined by gene-environment interactions from early life onward. The principles highlight the critical nature of cumulative exposure memories in defining changes in resilience progressively during life. Both plasma glutathione and cysteine systems become oxidized with aging, and the recent finding that cystine to glutathione ratio in human plasma predicts death in coronary artery disease (CAD) patients suggests this could provide a way to measure resilience of redox networks in aging and disease. The emerging concepts of cumulative gene-environment interactions warrant focused efforts to elucidate central mechanisms by which exposure memory governs health and etiology, onset and progression of disease. PMID- 28667070 TI - Pathogenesis of asthma: implications for precision medicine. AB - The pathogenesis of asthma is complex and multi-faceted. Asthma patients have a diverse range of underlying dominant disease processes and pathways despite apparent similarities in clinical expression. Here, we present the current understanding of asthma pathogenesis. We discuss airway inflammation (both T2HIGH and T2LOW), airway hyperresponsiveness (AHR) and airways remodelling as four key factors in asthma pathogenesis, and also outline other contributory factors such as genetics and co-morbidities. Response to current asthma therapies also varies greatly, which is probably related to the inter-patient differences in pathogenesis. Here, we also summarize how our developing understanding of detailed pathological processes potentially translates into the targeted treatment options we require for optimal asthma management in the future. PMID- 28667072 TI - BMA annual meeting: Senior trainees will be balloted on new consultant contract, says BMA. PMID- 28667071 TI - Pulmonary immunity to viruses. AB - Mucosal surfaces, such as the respiratory epithelium, are directly exposed to the external environment and therefore, are highly susceptible to viral infection. As a result, the respiratory tract has evolved a variety of innate and adaptive immune defenses in order to prevent viral infection or promote the rapid destruction of infected cells and facilitate the clearance of the infecting virus. Successful adaptive immune responses often lead to a functional state of immune memory, in which memory lymphocytes and circulating antibodies entirely prevent or lessen the severity of subsequent infections with the same virus. This is also the goal of vaccination, although it is difficult to vaccinate in a way that mimics respiratory infection. Consequently, some vaccines lead to robust systemic immune responses, but relatively poor mucosal immune responses that protect the respiratory tract. In addition, adaptive immunity is not without its drawbacks, as overly robust inflammatory responses may lead to lung damage and impair gas exchange or exacerbate other conditions, such as asthma or chronic obstructive pulmonary disease (COPD). Thus, immune responses to respiratory viral infections must be strong enough to eliminate infection, but also have mechanisms to limit damage and promote tissue repair in order to maintain pulmonary homeostasis. Here, we will discuss the components of the adaptive immune system that defend the host against respiratory viral infections. PMID- 28667073 TI - Cancer Cell-Autonomous Parainflammation Mimics Immune Cell Infiltration. AB - Parainflammation is a unique variant of inflammation, characterized by epithelial autonomous activation of inflammatory response. Parainflammation has been shown to strongly promote mouse gut tumorigenesis upon p53 loss. In a recent study, we explored the prevalence of parainflammation in human cancer and determined its relationship to certain molecular and clinical parameters affecting treatment and prognosis. Parainflammation can be identified from a 40-gene signature and is found in both carcinoma cell lines and a variety of primary tumors, independently of tumor microenvironment. Here, we discuss the implications of our findings in analyses of tumor microenvironment, suggesting that as tumor cell gene expression may often mimic immune and inflammatory infiltration, caution should be applied when interpreting tumor expression data. We also address the connection between parainflammation and prevalence of p53 mutations in specific types of tumors, and cancer prevention by regular usage of NSAIDs. We suggest that parainflammation may serve as a novel biomarker for screening patients who may particularly benefit from NSAID treatment. Cancer Res; 77(14); 3740-4. (c)2017 AACR. PMID- 28667075 TI - AXL-Driven EMT State as a Targetable Conduit in Cancer. AB - The receptor tyrosine kinase (RTK) AXL has been intrinsically linked to epithelial-mesenchymal transition (EMT) and promoting cell survival, anoikis resistance, invasion, and metastasis in several cancers. AXL signaling has been shown to directly affect the mesenchymal state and confer it with aggressive phenotype and drug resistance. Recently, the EMT gradient has also been shown to rewire the kinase signaling nodes that facilitate AXL-RTK cross-talk, protracted signaling, converging on ERK, and PI3K axes. The molecular mechanisms underplaying the regulation between the kinome and EMT require further elucidation to define targetable conduits. Therapeutically, as AXL inhibition has shown EMT reversal and resensitization to other tyrosine kinase inhibitors, mitotic inhibitors, and platinum-based therapy, there is a need to stratify patients based on AXL dependence. This review elucidates the role of AXL in EMT mediated oncogenesis and highlights the reciprocal control between AXL signaling and the EMT state. In addition, we review the potential in inhibiting AXL for the development of different therapeutic strategies and inhibitors. Cancer Res; 77(14); 3725-32. (c)2017 AACR. PMID- 28667074 TI - LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B. AB - T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo T 3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1 INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1. T-3775440 also inhibited proliferation of an SCLC cell line that overexpressed GFI1B, rather than INSM1, by disrupting the interaction between LSD1 and GFI1B. Taken together, our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC. Cancer Res; 77(17); 4652-62. (c)2017 AACR. PMID- 28667076 TI - RNA Editing in Pathogenesis of Cancer. AB - Several adenosine or cytidine deaminase enzymes deaminate transcript sequences in a cell type or environment-dependent manner by a programmed process called RNA editing. RNA editing enzymes catalyze A>I or C>U transcript alterations and have the potential to change protein coding sequences. In this brief review, we highlight some recent work that shows aberrant patterns of RNA editing in cancer. Transcriptome sequencing studies reveal increased or decreased global RNA editing levels depending on the tumor type. Altered RNA editing in cancer cells may provide a selective advantage for tumor growth and resistance to apoptosis. RNA editing may promote cancer by dynamically recoding oncogenic genes, regulating oncogenic gene expression by noncoding RNA and miRNA editing, or by transcriptome scale changes in RNA editing levels that may affect innate immune signaling. Although RNA editing markedly increases complexity of the cancer cell transcriptomes, cancer-specific recoding RNA editing events have yet to be discovered. Epitranscriptomic changes by RNA editing in cancer represent a novel mechanism contributing to sequence diversity independently of DNA mutations. Therefore, RNA editing studies should complement genome sequence data to understand the full impact of nucleic acid sequence alterations in cancer. Cancer Res; 77(14); 3733-9. (c)2017 AACR. PMID- 28667077 TI - Dietary LA and sex effects on oxylipin profiles in rat kidney, liver, and serum differ from their effects on PUFAs. AB - A vast literature on fatty acids in mammals exists, but comparable compositional data on oxylipins is lacking. Weanling Sprague-Dawley rats were therefore provided control diets or diets with higher linoleic acid (LA) or with higher LA and alpha-linolenic acid (LA+ALA) for 6 weeks. Kidneys, livers, and serum were analyzed for oxylipins and fatty acids. The proportion of tissue oxylipins derived from LA was greater than the relative proportion of LA itself, whereas arachidonic acid (AA) oxylipins were overrepresented in serum. Higher dietary LA increased kidney LA and AA oxylipins, despite not altering LA or AA. In liver, both LA and AA and their oxylipins were higher, whereas in serum only LA oxylipins were higher with higher dietary LA. Higher LA resulted in a higher ratio of n-6/n-3 PUFA-derived oxylipins; adding ALA to the LA diet mitigated this and many, but not all, effects of the LA diet. Approximately 40% of oxylipins detected were influenced by sex and, unlike their PUFA precursors, most (>90%) of these were higher in males. These differences in dietary LA and sex on oxylipin and fatty acid profiles further our understanding of the effects of fatty acids and may have implications for dietary LA recommendations. PMID- 28667080 TI - A Randomized Trial of Vitamin D Supplementation on Vascular Function in CKD. AB - Vitamin D deficiency associates with mortality in patients with CKD, and vitamin D supplementation might mitigate cardiovascular disease risk in CKD. In this randomized, double-blind, placebo-controlled trial, we investigated the effect of cholecalciferol supplementation on vascular function in 120 patients of either sex, aged 18-70 years, with nondiabetic CKD stage 3-4 and vitamin D deficiency (serum 25-hydroxyvitamin D <=20 ng/ml). We randomized patients using a 1:1 ratio to receive either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and 8 weeks. The primary outcome was change in endothelium-dependent brachial artery flow-mediated dilation at 16 weeks. Secondary outcome measures included changes in pulse wave velocity and circulating biomarkers. Cholecalciferol supplementation significantly increased endothelium-dependent brachial artery flow-mediated dilation at 16 weeks, whereas placebo did not (between-group difference in mean change: 5.49%; 95% confidence interval, 4.34% to 6.64%; P<0.001). Intervention also led to significant favorable changes in pulse wave velocity and circulating IL-6 levels. Thus, in nondiabetic patients with stage 3-4 CKD and vitamin D deficiency, vitamin D supplementation may improve vascular function. This study is registered with the Clinical Trials Registry of India (no.: CTRI/2013/05/003648). PMID- 28667081 TI - Estradiol for the mitigation of adverse effects of androgen deprivation therapy. AB - Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. Conventional endocrine treatment for PCa leads to global sex steroid deprivation. The ensuing severe hypogonadism is associated with well-documented adverse effects. Recently, it has become apparent that many of the biological actions attributed to androgens in men are in fact not direct, but mediated by estradiol. Available evidence supports a primary role for estradiol in vasomotor stability, skeletal maturation and maintenance, and prevention of fat accumulation. Hence there has been interest in revisiting estradiol as a treatment for PCa. Potential roles for estradiol could be in lieu of conventional androgen deprivation therapy or as low-dose add-back treatment while continuing androgen deprivation therapy. These strategies may limit some of the side effects associated with conventional androgen deprivation therapy. However, although available data are reassuring, the potential for cardiovascular risk and pro-carcinogenic effects on PCa via estrogen receptor signalling must be considered. PMID- 28667079 TI - Decreased Expression of Connexin 43 Blunts the Progression of Experimental GN. AB - GN refers to a variety of renal pathologies that often progress to ESRD, but the molecular mechanisms underlying this progression remain incompletely characterized. Here, we determined whether dysregulated expression of the gap junction protein connexin 43, which has been observed in the progression of renal disease, contributes to GN progression. Immunostaining revealed de novo expression of connexin 43 in damaged glomeruli in patients with glomerular diseases as well as in mice after induction of experimental GN. Notably, 2 weeks after the induction of GN with nephrotoxic serum, mice with a heterozygous deletion of the connexin 43 gene (connexin 43+/-) had proteinuria, BUN, and serum creatinine levels significantly lower than those of wild-type animals. Additionally, the connexin 43+/- mice showed less crescent formation, tubular dilation, monocyte infiltration, and interstitial renal fibrosis. Treatment of cultured podocytes with connexin 43-specific blocking peptides attenuated TGF beta-induced cytoskeletal and morphologic changes and apoptosis as did treatment with the purinergic blocker suramin. Finally, therapeutic treatment of GN mice with connexin 43-specific antisense oligodeoxynucleotide improved functional and structural renal parameters. These findings suggest that crosstalk between connexin 43 and purinergic signaling contributes to podocyte damage in GN. Given that this protein is highly induced in individuals with glomerular diseases, connexin 43 may be a novel target for therapeutic treatment of GN. PMID- 28667082 TI - New HIF2alpha inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas. AB - Two recent independent studies published in Nature show robust responses of clear cell renal cell carcinoma (ccRCC) cell lines, preclinical ccRCC xenograft models and, remarkably, a patient with progressive ccRCC despite receiving multiple lines of treatment, to the long-awaited, recently developed inhibitors of hypoxia inducible factor 2-alpha (HIF2alpha). This commentary published in Endocrine Related Cancer is based on the recognition of similar molecular drivers in ccRCC and the endocrine neoplasias pheochromocytomas and paragangliomas (PPGLs), ultimately leading to stabilization of HIFs. HIF-stabilizing mutations have been detected in the von Hippel-Lindau (VHL) gene, as well as in other genes, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH) and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF2alpha itself: EPAS1HIF2alpha Importantly, the recent discovery of EPAS1 mutations in PPGLs and the results of comprehensive in vitro and in vivo studies revealing their oncogenic roles characterized a hitherto unknown direct mechanism of HIF2alpha activation in human cancer. The now available therapeutic opportunity to successfully inhibit HIF2alpha pharmacologically with PT2385 and PT2399 will certainly spearhead a series of investigations in several types of cancers, including patients with SDHB-related metastatic PPGL for whom limited therapeutic options are currently available. Future studies will determine the efficacy of these promising drugs against the hotspot EPAS1 mutations affecting HIF2alpha amino acids 529-532 (in PPGLs) and amino acids 533-540 (in erythrocytosis type 4), as well as against HIF2alpha protein activated by VHL, SDHx and FH mutations in PPGL-derived chromatin cells. PMID- 28667083 TI - Editorial: Crystal death: it's not always the inflammasome... PMID- 28667084 TI - Editorial: The secrets of secretion. PMID- 28667086 TI - Suitable support for anxious hospice patients: what do nurses 'know', 'do' and 'need'? An explanatory mixed method study. AB - OBJECTIVE: To provide insight into what nurses know, do and need to provide support to anxious patients in hospice care (HC). METHODS: A mixed method study consisted of an online survey and focus groups (FGs) about what nurses know, do, and need was conducted. 336 HC nurses were invited to participate. Descriptive statistics were computed using SPSS. The chi2 and t-tests were conducted to compare. The FGs were transcribed verbatim and thematically analysed. RESULTS: The survey was completed by 265 nurses (79%), and five FGs (n=25) were conducted. Most nurses had >10 years working experience; mean age was 52. The majority (59%) felt that they were equipped with sufficient knowledge; however, lack of knowledge (31%) as well as lack of time (50%) were hampering factors. Identification of anxiety was difficult due to the variety of its expression. Tools for identifying were used by 37%. Interventions were generally chosen intuitively. A major responsibility was experienced in caring for patients with panic attacks during late night shifts, making immediate decisions necessary. CONCLUSION: This study highlights the struggles of nurses caring for anxious patients in HC. Anxiety management is dependent on the competencies and preferences of the individual nurse. One-third of the nurses require additional training. According to HC nurses, the intervention set should include guidelines for applying assessment tools, effective communication strategies and decision models as well as prediction models in order to select tailored interventions. Future research should focus on patients' perspectives in order to understand crucial measures for anxiety management. PMID- 28667085 TI - Biomarkers for Diagnosis and Prognosis of AKI in Children: One Size Does Not Fit All. AB - Pediatric AKI has become a significant health concern due to its rising incidence and association with adverse outcomes. Because of the limitations of serum creatinine, ongoing research has evaluated multiple novel biomarkers for the early detection of AKI. Identifying biomarkers that precede changes in serum creatinine is vital, because these biomarkers provide opportunities to improve outcomes through early diagnosis and timely disease management. In this review, we discuss salient findings on 16 candidate biomarkers and their association with AKI. We explore the differences in biomarker distribution by age and discuss why adult biomarker research findings cannot be directly extrapolated to children. With future research, more consideration needs to be given to how the maturing kidney affects biomarker levels and how we interpret biomarker performance in children. A comprehensive approach using age-specific biomarker reference ranges is required to develop pediatric biomarkers and improve outcomes for children with kidney disease. PMID- 28667087 TI - Development of tools to facilitate palliative and supportive care referral for patients with idiopathic pulmonary fibrosis. AB - OBJECTIVES: Palliative care is underused in non-malignant respiratory diseases, including interstitial lung diseases (ILDs). We investigated current practices around palliative and supportive care and explored the impact of a supportive care decision aid tool. METHODS: This was a single centre study in a UK ILD centre. Retrospective analysis of hospice referrals and patients with idiopathic pulmonary fibrosis (IPF) under the Bristol ILD (BILD) service were used to identify unmet palliative and supportive care needs. Using quality improvement methodology, we explored the impact of a supportive care decision aid on clinician behaviours for patients with ILD. RESULTS: 108 patients with ILD were referred for hospice care between 2010 and 2015, representing 0.15% of all referrals, compared with a population prevalence of IPF of 0.9%. The median interval between referral and death was 124 days.Records were reviewed for 64 deceased and 89 living patients with IPF seen on July-December 2014. The decision aid was prospectively assessed with 73 patients. The deceased patients had greater markers of severity. There were no other differences between the groups.After introduction, the decision aid tool was completed for 49.3% of patients and resulted in significant increases in documented discussion of referral to palliative care (11.2%vs53.6%, p<0.01) and end-of-life discussions (15.7%vs91.8%, p<0.01). Tool completion led to an increase in referral for palliative care (2.7%vs16.7%, p<0.01). CONCLUSION: Palliative care services are underused in ILD and a supportive care decision aid can prompt consideration of palliative and supportive care needs. PMID- 28667088 TI - CONSORT 2010 statement: extension checklist for reporting within person randomised trials. PMID- 28667089 TI - Orkambi(r) and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue. AB - The combination therapy of lumacaftor and ivacaftor (Orkambi(r)) is approved for patients bearing the major cystic fibrosis (CF) mutation: DeltaF508 It has been predicted that Orkambi(r) could treat patients with rarer mutations of similar "theratype"; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function-similar to DeltaF508-CFTR, are unlikely to yield a robust Orkambi(r) response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient-derived tissue. A CRISPR/Cas9-edited bronchial epithelial cell line bearing this mutation enabled studies showing that an "amplifier" compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi(r) response. Importantly, this "amplifier" effect was recapitulated in patient-derived nasal cultures-providing the first evidence for its efficacy in augmenting Orkambi(r) in tissues harboring a rare CF-causing mutation. We propose that this multi-disciplinary approach, including creation of CRISPR/Cas9-edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations. PMID- 28667090 TI - Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells. AB - Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape. LV escaped innate immune sensing that instead led to robust IFN responses upon transduction with a gamma-retroviral vector. However, reverse-transcribed LV DNA did trigger p53 signaling, activated also by non-integrating Adeno-associated vector, ultimately leading to lower cell recovery ex vivo and engraftment in vivo These effects were more pronounced in the short-term repopulating cells while long-term HSC frequencies remained unaffected. Blocking LV-induced signaling partially rescued both apoptosis and engraftment, highlighting a novel strategy to further dampen the impact of ex vivo gene transfer on HSPC. Overall, our results shed light on viral vector sensing in HSPC and provide critical insight for the development of more stealth gene therapy strategies. PMID- 28667091 TI - Associations between tobacco control mass media campaign expenditure and smoking prevalence and quitting in England: a time series analysis. AB - BACKGROUND: It has been established that mass media campaigns can increase smoking cessation rates, but there is little direct evidence estimating associations between government expenditure on tobacco control mass media campaigns and smoking cessation. This study assessed the association over 8 years between mass media expenditure in England and quit attempts, smoking cessation and smoking prevalence. METHODS: Autoregressive integrated moving average modelling with exogenous variables (ARIMAX) was applied to monthly estimates from the Smoking Toolkit Study between June 2008 and February 2016. We assessed the association between the trends in mass media expenditure and (1) quit attempts in the last two months, (2) quit success among those who attempted to quit and (3) smoking prevalence. Analyses were adjusted for trends in weekly spending on tobacco by smokers, tobacco control policies and the use of established aids to cessation. RESULTS: Monthly spending on mass media campaigns ranged from nothing to L2.4 million, with a mean of L465 054. An increase in mass media expenditure of 10% of the monthly average was associated with a 0.51% increase (of the average) in success rates of quit attempts (95% CI 0.10% to 0.91%, p=0.014). No clear association was detected between changes in mass media expenditure and changes in quit attempt prevalence (beta=-0.03, 95% CI -2.05% to 2.00%, p=0.979) or smoking prevalence (beta=-0.03, 95% CI -0.09% to 0.03%, p=0.299). CONCLUSION: Between 2008 and 2016, higher monthly expenditure on tobacco control mass media campaigns in England was associated with higher quit success rates. PMID- 28667092 TI - Implications and challenges for implementation of the FDA's final deeming rule for waterpipe tobacco. AB - For the first time, the Food and Drug Administration's (FDAs) Center for Tobacco Products now has regulatory authority over all tobacco products, including waterpipe tobacco. In the rule expanding its authority to cover all tobacco products, the FDA uses largely a one-size-fits-all approach. However, several aspects of waterpipe tobacco smoking make it unique from other tobacco products, which may require more specific, tailored rules. This paper describes the distinct features of waterpipe tobacco products and accessories, and identifies unique challenges to the current regulation posed by this form of tobacco use. Additionally, we highlight the need for further research-generated evidence to support additional rulemaking. PMID- 28667093 TI - Actual and potential use of Google Street View for studying tobacco issues: a brief review. PMID- 28667094 TI - Menthol levels in cigarettes from eight manufacturers. PMID- 28667095 TI - Cigarette package colour is associated with level of filter ventilation. PMID- 28667096 TI - The prevalence of illicit cigarette consumption and related factors in Turkey. AB - BACKGROUND: The tobacco industry claims that high cigarette taxes drive illicit trade and that governments should therefore not increase tobacco tax because it will increase the level of illicit trade. This study examines illicit cigarette consumption in Turkey after a tobacco tax increase and its related factors. METHOD: This national cross-sectional survey was conducted in March-June 2013 and 9717 people aged >=18 years participated in the interviewer-administered survey. Smokers were asked to show their last used cigarette pack to the interviewers and price paid for their cigarettes. Factors associated with smoking cigarettes with a tobacco tax stamp and paying >=5 TL (Turkish lira) for a pack of cigarettes were analysed with logistic regression. RESULTS: Among the observed cigarette packs, 12.1% did not have the Turkish tax stamp. More illicit cigarettes were observed in the East region than in other regions (p<0.001). The reported average amount paid for a pack of cigarettes was ?2.12 (?2.15 for men and ?1.97 for women, p<0.001). The amount paid for cigarettes with a tax stamp (?2.15) was higher than the amount paid for cigarettes without tax stamp (?1.08) (per cigarette pack) (p<0.001). CONCLUSION: Just over 1 in 10 smokers (12%) had an illicit cigarette pack about 5 months after the final tax increase; this was most common in the East region of Turkey. Estimates are comparable to those in previous studies and do not indicate that an increase occurred in the prevalence of illicit cigarette use compared with before the tobacco tax increase. PMID- 28667097 TI - Shortening-induced force depression is modulated in a time- and speed-dependent manner following a stretch-shortening cycle. AB - The steady-state isometric force following active muscle shortening or lengthening is smaller (force depression, FD) or greater (residual force enhancement, RFE) than a purely isometric contraction at the corresponding length. The mechanism underlying these phenomena is not explained within the context of the cross-bridge theory, with few studies investigating the effects of FD and RFE in stretching-shortening cycle (SSC). The purpose of this study was to perform SSC, where the time between the end of stretch and the end of shortening was manipulated by (1) adding a pause between stretch and shortening (protocol 1) or (2) performing the shortening contraction at different speeds (protocol 2). The results show that, in protocol 1, FD was reduced for SSC with a 0-sec and 0.5 sec interval between stretching and shortening, but was the same for SSC with a 1 sec interval compared to the pure FD condition. In protocol 2, FD was reduced for SSC with shortening speeds of 30 and 60 degrees /sec, but was the same for shortening speeds of 15 and 20 degrees /sec compared to the pure FD condition. These findings provide evidence that stretch preceding shortening affects FD in a time- and speed-dependent manner, providing new information on the potential mechanism of FD and RFE. PMID- 28667098 TI - Doctors commended for their bravery in response to terrorist incidents. PMID- 28667099 TI - NHS bosses soften cost cutting plans in response to concerns. PMID- 28667100 TI - Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium. AB - BACKGROUND: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload-induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload-induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. METHODS: Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. RESULTS: Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow-depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction-induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with alpha-smooth muscle actin or collagen 1alpha in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-beta-induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO FPCs compared with WT-FPCs. Polymerase chain reaction-based selective miRNA analysis revealed that transforming growth factor-beta-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-beta-induced fibrotic signaling in BM FPCs. CONCLUSIONS: Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad-miRNA-21 mediated activation of BM-FPCs and thus modulates cardiac fibrosis. PMID- 28667101 TI - Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes. AB - C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1alpha (IRE1alpha) phosphorylation and increased spliced X-box binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1alpha phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1alpha-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER stress response pathways eliciting cellular protection in cardiomyocytes. PMID- 28667102 TI - Adiponectin improves coronary no-reflow injury by protecting the endothelium in rats with type 2 diabetes mellitus. AB - To determine the effect of adiponectin (APN) on the coronary no-reflow (NR) injury in rats with Type 2 diabetes mellitus (T2DM), 80 male Sprague-Dawley rats were fed with a high-sugar-high-fat diet to build a T2DM model. Rats received vehicle or APN in the last week and then were subjected to myocardial ischemia reperfusion (MI/R) injury. Endothelium-dependent vasorelaxation of the thoracic aorta was significantly decreased and serum levels of endothelin-1 (ET-1), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were noticably increased in T2DM rats compared with rats without T2DM. Serum APN was positively correlated with the endothelium-dependent vasorelaxation, but negatively correlated with the serum level of ET-1. Treatment with APN improved T2DM-induced endothelium-dependent vasorelaxation, recovered cardiac function, and decreased both NR size and the levels of ET-1, ICAM-1 and VCAM-1. Hypoadiponectinemia was associated with the aggravation of coronary NR in T2DM rats. APN could alleviate coronary NR injury in T2DM rats by protecting the endothelium and improving microcirculation. PMID- 28667103 TI - Expression and prognostic value of HER-2/neu in primary breast cancer with sentinel lymph node metastasis. AB - The present study explores the correlation of human epidermal growth factor receptor-2 (HER-2) protein expression with sentinel lymph node (SLN) metastasis and prognosis of breast cancer. The breast cancer tissues and adjacent tissues were obtained from patients with primary breast cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the mRNA level of HER 2. Spearman correlation analysis was used to analyze the correlation of HER-2 expression with SLN metastasis. The disease-free survival (DFS) and overall survival (OS) of breast cancer patients were investigated. Univariate and multivariate analyses were performed to explore factors influencing SLN metastasis and prognosis of breast cancer. Compared with adjacent tissues, HER-2 expression was significantly up-regulated in breast cancer tissues. HER-2 expression was correlated with the pathological type, tumor node metastasis (TNM) staging, histological grade, blood vessel invasion, SLN metastasis, estrogen receptor (ER), and progesterone receptor (PR). The expression level of HER-2 was positively related to the SLN metastasis (r=0.548). Median DFS and OS were longer in patients with negative HER-2 expression than in patients with positive HER-2 expression. TNM staging, SLN metastasis, and expression levels of HER-2 and ER were independent factors for DFS of breast cancer patients, while TNM staging, blood vessel invasion, histological grade, SLN metastasis, and expression levels of HER-2 and PR were independent factors for OS of breast cancer patients. Our study suggests that high expression of HER-2 promoted SLN metastasis. HER-2 expression and SLN metastasis were the independent factors for the prognosis of breast cancer. PMID- 28667104 TI - Response of Microbial Community Function to Fluctuating Geochemical Conditions within a Legacy Radioactive Waste Trench Environment. AB - During the 1960s, small quantities of radioactive materials were codisposed with chemical waste at the Little Forest Legacy Site (Sydney, Australia) in 3-meter deep, unlined trenches. Chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a 6-week period immediately after a prolonged rainfall event to assess the impact of changing water levels upon the microbial ecology and contaminant mobility. Collectively, results demonstrated that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the potentially important role that the taxonomically diverse microbial community played in this transition. In particular, aerobes dominated in the first day, followed by an increase of facultative anaerobes/denitrifiers at day 4. Toward the mid-end of the sampling period, the functional and taxonomic profiles depicted an anaerobic community distinguished by a higher representation of dissimilatory sulfate reduction and methanogenesis pathways. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs.IMPORTANCE The role of chemical and microbiological factors in mediating the biogeochemistry of groundwaters from trenches used to dispose of radioactive materials during the 1960s is examined in this study. Specifically, chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a 6-week period immediately after a prolonged rainfall event to assess how changing water levels influence microbial ecology and contaminant mobility. Results demonstrate that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the important role that the taxonomically diverse microbial community played in this transition. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs. PMID- 28667105 TI - Bacteriocins of Non-aureus Staphylococci Isolated from Bovine Milk. AB - Non-aureus staphylococci (NAS), the bacteria most commonly isolated from the bovine udder, potentially protect the udder against infection by major mastitis pathogens due to bacteriocin production. In this study, we determined the inhibitory capability of 441 bovine NAS isolates (comprising 26 species) against bovine Staphylococcus aureus Furthermore, inhibiting isolates were tested against a human methicillin-resistant S. aureus (MRSA) isolate using a cross-streaking method. We determined the presence of bacteriocin clusters in NAS whole genomes using genome mining tools, BLAST, and comparison of genomes of closely related inhibiting and noninhibiting isolates and determined the genetic organization of any identified bacteriocin biosynthetic gene clusters. Forty isolates from 9 species (S. capitis, S. chromogenes, S. epidermidis, S. pasteuri, S. saprophyticus, S. sciuri, S. simulans, S. warneri, and S. xylosus) inhibited growth of S. aureus in vitro, 23 isolates of which, from S. capitis, S. chromogenes, S. epidermidis, S. pasteuri, S. simulans, and S. xylosus, also inhibited MRSA. One hundred five putative bacteriocin gene clusters encompassing 6 different classes (lanthipeptides, sactipeptides, lasso peptides, class IIa, class IIc, and class IId) in 95 whole genomes from 16 species were identified. A total of 25 novel bacteriocin precursors were described. In conclusion, NAS from bovine mammary glands are a source of potential bacteriocins, with >21% being possible producers, representing potential for future characterization and prospective clinical applications.IMPORTANCE Mastitis (particularly infections caused by Staphylococcus aureus) costs Canadian dairy producers $400 million/year and is the leading cause of antibiotic use on dairy farms. With increasing antibiotic resistance and regulations regarding use, there is impetus to explore bacteriocins (bacterially produced antimicrobial peptides) for treatment and prevention of bacterial infections. We examined the ability of 441 NAS bacteria from Canadian bovine milk samples to inhibit growth of S. aureus in the laboratory. Overall, 9% inhibited growth of S. aureus and 58% of those also inhibited MRSA. In NAS whole-genome sequences, we identified >21% of NAS as having bacteriocin genes. Our study represents a foundation to further explore NAS bacteriocins for clinical use. PMID- 28667106 TI - Discovery of Lysine Hydroxylases in the Clavaminic Acid Synthase-Like Superfamily for Efficient Hydroxylysine Bioproduction. AB - Hydroxylation via C-H bond activation in the absence of any harmful oxidizing reagents is technically difficult in modern chemistry. In this work, we attempted to generate pharmaceutically important hydroxylysine from readily available l lysine with l-lysine hydroxylases from diverse microorganisms. Clavaminic acid synthase-like superfamily gene mining and phylogenetic analysis led to the discovery of six biocatalysts, namely two l-lysine 3S-hydroxylases and four l lysine 4R-hydroxylases, the latter of which partially matched known hydroxylases. Subsequent characterization of these hydroxylases revealed their capacity for regio- and stereoselective hydroxylation into either C-3 or C-4 positions of l lysine, yielding (2S,3S)-3-hydroxylysine and (2S,4R)-4-hydroxylysine, respectively. To determine if these factors had industrial application, we performed a preparative production of both hydroxylysines under optimized conditions. For this, recombinant l-lysine hydroxylase-expressing Escherichia coli cells were used as a biocatalyst for l-lysine bioconversion. In batch-scale reactions, 531 mM (86.1 g/liter) (2S,3S)-3-hydroxylysine was produced from 600 mM l-lysine with an 89% molar conversion after a 52-h reaction, and 265 mM (43.0 g/liter) (2S,4R)-4-hydroxylysine was produced from 300 mM l-lysine with a molar conversion of 88% after 24 h. This report demonstrates the highly efficient production of hydroxylysines using lysine hydroxylases, which may contribute to future industrial bioprocess technologies.IMPORTANCE The present study identified six l-lysine hydroxylases belonging to the 2-oxoglutarate-dependent dioxygenase superfamily, although some of them overlapped with known hydroxylases. While the substrate specificity of l-lysine hydroxylases was relatively narrow, we found that (2S,3S)-3-hydroxylysine was hydroxylated by 4R-hydroxylase and (2S,5R)-5 hydroxylysine was hydroxylated by both 3S- and 4R-hydroxylases. Moreover, the l arginine hydroxylase VioC also hydroxylated l-lysine, albeit to a lesser extent. Further, we also demonstrated the bioconversion of l-lysine into (2S,3S)-3 hydroxylysine and (2S,4R)-4-hydroxylysine on a gram scale under optimized conditions. These findings provide new insights into biocatalytic l-lysine hydroxylation and thus have a great potential for use in manufacturing bioprocesses. PMID- 28667107 TI - The Two Cryptochrome/Photolyase Family Proteins Fulfill Distinct Roles in DNA Photorepair and Regulation of Conidiation in the Gray Mold Fungus Botrytis cinerea. AB - The plant-pathogenic leotiomycete Botrytis cinerea is known for the strict regulation of its asexual differentiation programs by environmental light conditions. Sclerotia are formed in constant darkness; black/near-UV (NUV) light induces conidiation; and blue light represses both differentiation programs. Sensing of black/NUV light is attributed to proteins of the cryptochrome/photolyase family (CPF). To elucidate the molecular basis of the photoinduction of conidiation, we functionally characterized the two CPF proteins encoded in the genome of B. cinerea as putative positive-acting components. B. cinerea CRY1 (BcCRY1), a cyclobutane pyrimidine dimer (CPD) photolyase, acts as the major enzyme of light-driven DNA repair (photoreactivation) and has no obvious role in signaling. In contrast, BcCRY2, belonging to the cry-DASH proteins, is dispensable for photorepair but performs regulatory functions by repressing conidiation in white and especially black/NUV light. The transcription of bccry1 and bccry2 is induced by light in a White Collar complex (WCC) dependent manner, but neither light nor the WCC is essential for the repression of conidiation through BcCRY2 when bccry2 is constitutively expressed. Further, BcCRY2 affects the transcript levels of both WCC-induced and WCC-repressed genes, suggesting a signaling function downstream of the WCC. Since both CPF proteins are dispensable for photoinduction by black/NUV light, the origin of this effect remains elusive and may be connected to a yet unknown UV-light-responsive system.IMPORTANCEBotrytis cinerea is an economically important plant pathogen that causes gray mold diseases in a wide variety of plant species, including high value crops and ornamental flowers. The spread of disease in the field relies on the formation of conidia, a process that is regulated by different light qualities. While this feature has been known for a long time, we are just starting to understand the underlying molecular mechanisms. Conidiation in B. cinerea is induced by black/near-UV light, whose sensing is attributed to the action of cryptochrome/photolyase family (CPF) proteins. Here we report on the distinct functions of two CPF proteins in the photoresponse of B. cinerea While BcCRY1 acts as the major photolyase in photoprotection, BcCRY2 acts as a cryptochrome with a signaling function in regulating photomorphogenesis (repression of conidiation). PMID- 28667108 TI - Cleaning and disinfection of biofilms composed of Listeria monocytogenes and background microbiota from meat processing surfaces. AB - Surfaces of food processing premises are exposed to regular cleaning and disinfection (C&D) regimes, using biocides that are highly effective against bacteria growing as planktonic cells. However, bacteria growing in surface associated communities (biofilms) are typically more tolerant towards C&D than their individual free cells counterparts, and survival of pathogens such as Listeria monocytogenes may be affected by interspecies interactions within biofilms. In this study, Pseudomonas and Acinetobacter were the most frequently isolated genera surviving on conveyor belts subjected to C&D in meat processing plants. In the laboratory, Pseudomonas, Acinetobacter and L. monocytogenes dominated the community both in suspensions and in biofilms formed on conveyor belts, when cultures were inoculated with eleven-genera cocktails of representative bacterial strains from the identified background flora. When biofilms were exposed to daily C&D cycles, mimicking treatments used in food industry, the levels of Acinetobacter and Pseudomonas mandelii diminished, and biofilms were instead dominated by Pseudomonas putida (65-76%), Pseudomonas fluorescens (11-15%) and L. monocytogenes (3-11%). The dominance of certain species after daily C&D correlated with high planktonic growth rates at 12 degrees C and tolerance to C&D. In single-species biofilms, L. monocytogenes developed higher tolerance to C&D over time, both for the peracetic acid and quaternary ammonium disinfectant, indicating that a broad-spectrum mechanism was involved. Survival after C&D appeared to be a common property of L. monocytogenes strains, as both persistent and sporadic subtypes showed equal survival in complex biofilms. Biofilms established preferentially in surface irregularities of conveyor belts, potentially constituting harborage sites for persistent contamination.IMPORTANCE In food industry, efficient production hygiene is a key measure to avoid accumulation of spoilage bacteria and eliminate pathogens. Persistence of bacteria is however a withstanding problem in food processing environments. This study demonstrated that environmental bacteria can survive foam cleaning and disinfection (C&D) at user concentrations in the industrial environment. The phenomenon was replicated in laboratory experiments. Important characteristics of persisting bacteria were high growth rate at low temperature, tolerance to the cleaning agent and ability to form biofilm. This study also supports other recent research suggesting that strain-to-strain variation cannot explain why certain subtypes of Listeria monocytogenes persist in food processing environments while others are found only sporadically. The present investigation highlights the failure of regular C&D and a need for research on improved agents efficiently detaching the biofilm matrix. PMID- 28667109 TI - Detection of Diazotrophy in the Acetylene-Fermenting Anaerobe Pelobacter sp. Strain SFB93. AB - Acetylene (C2H2) is a trace constituent of the present Earth's oxidizing atmosphere, reflecting a mixture of terrestrial and marine emissions from anthropogenic, biomass-burning, and unidentified biogenic sources. Fermentation of acetylene was serendipitously discovered during C2H2 block assays of N2O reductase, and Pelobacter acetylenicus was shown to grow on C2H2 via acetylene hydratase (AH). AH is a W-containing, catabolic, low-redox-potential enzyme that, unlike nitrogenase (N2ase), is specific for acetylene. Acetylene fermentation is a rare metabolic process that is well characterized only in P. acetylenicus DSM3246 and DSM3247 and Pelobacter sp. strain SFB93. To better understand the genetic controls for AH activity, we sequenced the genomes of the three acetylene fermenting Pelobacter strains. Genome assembly and annotation produced three novel genomes containing gene sequences for AH, with two copies being present in SFB93. In addition, gene sequences for all five compulsory genes for iron molybdenum N2ase were also present in the three genomes, indicating the cooccurrence of two acetylene transformation pathways. Nitrogen fixation growth assays showed that DSM3426 could ferment acetylene in the absence of ammonium, but no ethylene was produced. However, SFB93 degraded acetylene and, in the absence of ammonium, produced ethylene, indicating an active N2ase. Diazotrophic growth was observed under N2 but not in experimental controls incubated under argon. SFB93 exhibits acetylene fermentation and nitrogen fixation, the only known biochemical mechanisms for acetylene transformation. Our results indicate complex interactions between N2ase and AH and suggest novel evolutionary pathways for these relic enzymes from early Earth to modern days.IMPORTANCE Here we show that a single Pelobacter strain can grow via acetylene fermentation and carry out nitrogen fixation, using the only two enzymes known to transform acetylene. These findings provide new insights into acetylene transformations and adaptations for nutrient (C and N) and energy acquisition by microorganisms. Enhanced understanding of acetylene transformations (i.e., extent, occurrence, and rates) in modern environments is important for the use of acetylene as a potential biomarker for extraterrestrial life and for degradation of anthropogenic contaminants. PMID- 28667110 TI - Distribution, Community Composition, and Potential Metabolic Activity of Bacterioplankton in an Urbanized Mediterranean Sea Coastal Zone. AB - Bacterioplankton are fundamental components of marine ecosystems and influence the entire biosphere by contributing to the global biogeochemical cycles of key elements. Yet, there is a significant gap in knowledge about their diversity and specific activities, as well as environmental factors that shape their community composition and function. Here, the distribution and diversity of surface bacterioplankton along the coastline of the Gulf of Naples (GON; Italy) were investigated using flow cytometry coupled with high-throughput sequencing of the 16S rRNA gene. Heterotrophic bacteria numerically dominated the bacterioplankton and comprised mainly Alphaproteobacteria, Gammaproteobacteria, and Bacteroidetes Distinct communities occupied river-influenced, coastal, and offshore sites, as indicated by Bray-Curtis dissimilarity, distance metric (UniFrac), linear discriminant analysis effect size (LEfSe), and multivariate analyses. The heterogeneity in diversity and community composition was mainly due to salinity and changes in environmental conditions across sites, as defined by nutrient and chlorophyll a concentrations. Bacterioplankton communities were composed of a few dominant taxa and a large proportion (92%) of rare taxa (here defined as operational taxonomic units [OTUs] accounting for <0.1% of the total sequence abundance), the majority of which were unique to each site. The relationship between 16S rRNA and the 16S rRNA gene, i.e., between potential metabolic activity and abundance, was positive for the whole community. However, analysis of individual OTUs revealed high rRNA-to-rRNA gene ratios for most (71.6% +/- 16.7%) of the rare taxa, suggesting that these low-abundance organisms were potentially active and hence might be playing an important role in ecosystem diversity and functioning in the GON.IMPORTANCE The study of bacterioplankton in coastal zones is of critical importance, considering that these areas are highly productive and anthropogenically impacted. Their richness and evenness, as well as their potential activity, are very important to assess ecosystem health and functioning. Here, we investigated bacterial distribution, community composition, and potential metabolic activity in the GON, which is an ideal test site due to its heterogeneous environment characterized by a complex hydrodynamics and terrestrial inputs of varied quantities and quality. Our study demonstrates that bacterioplankton communities in this region are highly diverse and strongly regulated by a combination of different environmental factors leading to their heterogeneous distribution, with the rare taxa contributing to a major proportion of diversity and shifts in community composition and potentially holding a key role in ecosystem functioning. PMID- 28667112 TI - Molybdenum-based diazotrophy in a Sphagnum peatland in northern Minnesota. AB - Microbial N2 fixation (diazotrophy) represents an important nitrogen source to oligotrophic peatland ecosystems, which are important sinks for atmospheric CO2 and susceptible to changing climate. The objectives of this study were: (i) to determine the active microbial group and type of nitrogenase mediating diazotrophy in a ombrotrophic Sphagnum-dominated peat bog (the S1 peat bog, Marcell Experimental Forest, Minnesota, USA); and (ii) to determine the effect of environmental parameters (light, O2, CO2, CH4) on potential rates of diazotrophy measured by acetylene (C2H2) reduction and 15N2 incorporation. Molecular analysis of metabolically active microbial communities suggested that diazotrophy in surface peat was primarily mediated by Alphaproteobacteria (Bradyrhizobiaceae and Beijerinckiaceae). Despite higher dissolved vanadium (V; 11 nM) than molybdenum (Mo; 3 nM) in surface peat, a combination of metagenomic, amplicon sequencing and activity measurements indicated that Mo-containing nitrogenases dominate over the V-containing form. Acetylene reduction was only detected in surface peat exposed to light, with the highest rates observed in peat collected from hollows with the highest water content. Incorporation of 15N2 was suppressed 90% by O2 and 55% by C2H2, and was unaffected by CH4 and CO2 amendments. These results suggest that peatland diazotrophy is mediated by a combination of C2H2-sensitive and C2H2 insensitive microbes that are more active at low O2 and show similar activity at high and low CH4Importance Previous studies indicate that diazotrophy provides an important nitrogen source and is linked to methanotrophy in Sphagnum-dominated peatlands. However, the environmental controls and enzymatic pathways of peatland diazotrophy, as well as the metabolically active microbial populations that catalyze this process remain in question. Our findings indicate that oxygen levels and photosynthetic activity override low nutrient availability in limiting diazotrophy, and that members of the Alphaproteobacteria (Rhizobiales) catalyze this process at the bog surface using the molybdenum-based form of the nitrogenase enzyme. PMID- 28667111 TI - Aerobiology: Experimental Considerations, Observations, and Future Tools. AB - Understanding airborne survival and decay of microorganisms is important for a range of public health and biodefense applications, including epidemiological and risk analysis modeling. Techniques for experimental aerosol generation, retention in the aerosol phase, and sampling require careful consideration and understanding so that they are representative of the conditions the bioaerosol would experience in the environment. This review explores the current understanding of atmospheric transport in relation to advances and limitations of aerosol generation, maintenance in the aerosol phase, and sampling techniques. Potential tools for the future are examined at the interface between atmospheric chemistry, aerosol physics, and molecular microbiology where the heterogeneity and variability of aerosols can be explored at the single-droplet and single microorganism levels within a bioaerosol. The review highlights the importance of method comparison and validation in bioaerosol research and the benefits that the application of novel techniques could bring to increasing the understanding of aerobiological phenomena in diverse research fields, particularly during the progression of atmospheric transport, where complex interdependent physicochemical and biological processes occur within bioaerosol particles. PMID- 28667113 TI - A human gut commensal ferments cranberry carbohydrates to produce formate. AB - Commensal bifidobacteria colonize the human gastrointestinal tract and catabolize glycans that are impervious to host digestion. Accordingly, Bifidobacterium longum typically secrete acetate and lactate as fermentative endproducts. This study tested the hypothesis that B. longum utilize cranberry-derived xyloglucans in a strain-dependent manner. Interestingly, the B. longum strain that efficiently utilizes cranberry xyloglucans secrete 2.0-2.5 moles acetate:lactate. The 1.5 ratio theoretical yield obtained in hexose fermentations shifts during xyloglucan metabolism. Accordingly, this metabolic shift is characterized by increased acetate and formate production at the expense of lactate. alpha-L arabinofuranosidase, an arabinan endo-1,5-alpha-L-arabinosidase, and a beta xylosidase with a carbohydrate substrate-binding protein and carbohydrate ABC transporter membrane proteins are upregulated (> 2-fold change), which suggests carbon flux through this catabolic pathway. Finally, syntrophic interactions occurred with strains that utilize carbohydrate products derived from initial degradation from a heterologous bacterium.IMPORTANCE This is a study of bacterial metabolism of complex cranberry carbohydrates termed xyloglucans that are likely not digested prior to reaching the colon. This is significant as bifidobacteria interact with this dietary compound to potentially impact human host health through energy and metabolite production by bacterial utilization of these substrates. Specific bacterial strains utilize cranberry xyloglucans as a nutritive source indicating unknown mechanisms that are not universal in bifidobacteria. In addition, xyloglucan metabolism proceeds using an alternative pathway could lead to further research to investigate mechanisms underlying this interaction. Finally, we observed cross-feeding between bacteria in which one strain degrades the cranberry xyloglucan to make it available to a second strain. Similar nutritive strategies are known to occur within the gut. In aggregate, this study may lead to novel foods or supplements to impact human health through rational manipulations of their microbiome. PMID- 28667114 TI - Initial Gut Microbial Composition as a Key Factor Driving Host Response to Antibiotic Treatment, as Exemplified by the Presence or Absence of Commensal Escherichia coli. AB - Antibiotics are important for treating bacterial infection; however, efficacies and side effects of antibiotics vary in medicine and experimental models. A few studies have correlated microbiota composition variations with health outcomes in response to antibiotics; however, no study has demonstrated causality. We had noted variation in colonic expression of C-type lectins, regenerating islet derived protein 3beta (Reg3beta) and Reg3gamma, after metronidazole treatment in a mouse model. To investigate the effects of specific variations in the preexisting microbiome on host response to antibiotics, mice harboring a normal microbiota were allocated to 4 treatments in a 2-by-2 factorial arrangement with or without commensal Escherichia coli and with or without metronidazole in drinking water. E. coli colonized readily without causing a notable shift in the microbiota or host response. Metronidazole administration reduced microbiota biodiversity, indicated by decreased Chao1 and Shannon index values, and altered microbiota composition. However, the presence of E. coli strongly affected metronidazole-induced microbiota shifts. Remarkably, this single commensal bacterium in the context of a complex population led to variations in host responses to metronidazole treatment, including increased expression of antimicrobial peptides Reg3beta and Reg3gamma and intestinal inflammation indicated by tumor necrosis factor alpha levels. Similar results were obtained from 2-week antibiotic exposure and with additional E. coli isolates. The results of this proof-of-concept study indicate that even minor variations in initial commensal microbiota can drive shifts in microbial composition and host response after antibiotic administration. As well as providing an explanation for variability in animal models using antibiotics, the findings encourage the development of personalized medication in antibiotic therapies.IMPORTANCE This work provides an understanding of variability in studies where antibiotics are used to alter the gut microbiota to generate a host response. Furthermore, although providing evidence only for the one antibiotic, the study demonstrated that initial gut microbial composition is a key factor driving host response to antibiotic administration, creating a compelling argument for considering personalized medication based on individual variations in gut microbiota. PMID- 28667116 TI - A Third Type of Resistance to Cydia pomonella Granulovirus in Codling Moths Shows a Mixed Z-Linked and Autosomal Inheritance Pattern. AB - Different isolates of Cydia pomonella granulovirus (CpGV) are used worldwide to control codling moth larvae (Cydia pomonella) in pome fruit production. Two types of dominantly inherited field resistance of C. pomonella to CpGV have been recently identified: Z-chromosomal type I resistance and autosomal type II resistance. In the present study, a CpGV-resistant C. pomonella field population (termed SA-GO) from northeastern Germany was investigated. SA-GO individuals showed cross-resistance to CpGV isolates of genome group A (CpGV-M) and genome group E (CpGV-S), whereas genome group B (CpGV-E2) was still infective. Crossing experiments between individuals of SA-GO and the susceptible C. pomonella strain CpS indicated the presence of a dominant autosomal inheritance factor. By single pair inbreeding of SA-GO individuals for two generations, the genetically more homogenous strain CpRGO was generated. Resistance testing of CpRGO neonates with different CpGV isolates revealed that isolate CpGV-E2 and isolates CpGV-I07 and I12 were resistance breaking. When progeny of hybrid crosses and backcrosses between individuals of resistant strain CpRGO and susceptible strain CpS were infected with CpGV-M and CpGV-S, resistance to CpGV-S appeared to be autosomal and dominant for larval survivorship but recessive when success of pupation of the hybrids was considered. Inheritance of resistance to CpGV-M, however, is proposed to be both autosomal and Z linked, since Z linkage of resistance was needed for pupation. Hence, we propose a further type III resistance to CpGV in C. pomonella, which differs from type I and type II resistance in its mode of inheritance and response to CpGV isolates from different genome groups.IMPORTANCE The baculovirus Cydia pomonella granulovirus (CpGV) is registered and applied as a biocontrol agent in nearly all pome fruit-growing countries worldwide to control codling moth caterpillars in an environmentally friendly manner. It is therefore the most widely used commercial baculovirus biocontrol agent. Since 2005, field resistance of codling moth to CpGV products has been observed in more than 40 field plantations in Europe, threatening organic and integrated apple production. Knowledge of the inheritance and mechanism(s) of resistance is indispensable for the understanding of host response to baculovirus infection on the population level and the coevolutionary arms race between virus and host, as well as for the development of appropriate resistance management strategies. Here, we report a codling moth field population with a new type of resistance, which appears to follow a highly complex inheritance in regard to different CpGV isolates. PMID- 28667115 TI - CgMED3 Changes Membrane Sterol Composition To Help Candida glabrata Tolerate Low pH Stress. AB - Candida glabrata is a promising microorganism for organic acid production. The present study aimed to investigate the role of C. glabrata Mediator complex subunit 3 (CgMed3p) in protecting C. glabrata under low-pH conditions. To this end, genes CgMED3A and CgMED3B were deleted, resulting in the double-deletion Cgmed3ABDelta strain. The final biomass and cell viability levels of Cgmed3ABDelta decreased by 64.5% and 35.8%, respectively, compared to the wild type strain results at pH 2.0. In addition, lack of CgMed3ABp resulted in selective repression of a subset of genes in the lipid biosynthesis and metabolism pathways. Furthermore, C18:1, lanosterol, zymosterol, fecosterol, and ergosterol were 13.2%, 80.4%, 40.4%, 78.1%, and 70.4% less abundant, respectively, in the Cgmed3ABDelta strain. In contrast, the concentration of squalene increased by about 44.6-fold. As a result, membrane integrity, rigidity, and H+-ATPase activity in the Cgmed3ABDelta strain were reduced by 62.7%, 13.0%, and 50.3%, respectively. In contrast, overexpression of CgMED3AB increased the levels of C18:0, C18:1, and ergosterol by 113.2%, 5.9%, and 26.4%, respectively. Moreover, compared to the wild-type results, dry cell weight and pyruvate production increased, irrespective of pH buffering. These results suggest that CgMED3AB regulates membrane composition, which in turn enables cells to tolerate low-pH stress. We propose that regulation of CgMed3ABp may provide a novel strategy for enhancing low-pH tolerance and increasing organic acid production by C. glabrataIMPORTANCE The objective of this study was to investigate the role of Candida glabrata Mediator complex subunit 3 (CgMed3ABp) and its regulation of gene expression at low pH in C. glabrata We found that CgMed3ABp was critical for cellular survival and pyruvate production during low-pH stress. Measures of the levels of plasma membrane fatty acids and sterol composition indicated that CgMed3ABp could play an important role in regulating homeostasis in C. glabrata We propose that controlling membrane lipid composition may enhance the robustness of C. glabrata for the production of organic acids. PMID- 28667117 TI - Reduced Mutation Rate and Increased Transformability of Transposon-Free Acinetobacter baylyi ADP1-ISx. AB - The genomes of most bacteria contain mobile DNA elements that can contribute to undesirable genetic instability in engineered cells. In particular, transposable insertion sequence (IS) elements can rapidly inactivate genes that are important for a designed function. We deleted all six copies of IS1236 from the genome of the naturally transformable bacterium Acinetobacter baylyi ADP1. The natural competence of ADP1 made it possible to rapidly repair deleterious point mutations that arose during strain construction. In the resulting ADP1-ISx strain, the rates of mutations inactivating a reporter gene were reduced by 7- to 21-fold. This reduction was higher than expected from the incidence of new IS1236 insertions found during a 300-day mutation accumulation experiment with wild-type ADP1 that was used to estimate spontaneous mutation rates in the strain. The extra improvement appears to be due in part to eliminating large deletions caused by IS1236 activity, as the point mutation rate was unchanged in ADP1-ISx. Deletion of an error-prone polymerase (dinP) and a DNA damage response regulator (umuDAb [the umuD gene of A. baylyi]) from the ADP1-ISx genome did not further reduce mutation rates. Surprisingly, ADP1-ISx exhibited increased transformability. This improvement may be due to less autolysis and aggregation of the engineered cells than of the wild type. Thus, deleting IS elements from the ADP1 genome led to a greater than expected increase in evolutionary reliability and unexpectedly enhanced other key strain properties, as has been observed for other clean-genome bacterial strains. ADP1-ISx is an improved chassis for metabolic engineering and other applications.IMPORTANCEAcinetobacter baylyi ADP1 has been proposed as a next-generation bacterial host for synthetic biology and genome engineering due to its ability to efficiently take up DNA from its environment during normal growth. We deleted transposable elements that are capable of copying themselves, inserting into other genes, and thereby inactivating them from the ADP1 genome. The resulting "clean-genome" ADP1-ISx strain exhibited larger reductions in the rates of inactivating mutations than expected from spontaneous mutation rates measured via whole-genome sequencing of lineages evolved under relaxed selection. Surprisingly, we also found that IS element activity reduces transformability and is a major cause of cell aggregation and death in wild-type ADP1 grown under normal laboratory conditions. More generally, our results demonstrate that domesticating a bacterial genome by removing mobile DNA elements that have accumulated during evolution in the wild can have unanticipated benefits. PMID- 28667118 TI - The Gluco- and Liporegulatory and Vasodilatory Effects of Glucose-Dependent Insulinotropic Polypeptide (GIP) Are Abolished by an Antagonist of the Human GIP Receptor. AB - A truncated form of human glucose-dependent insulinotropic polypeptide (GIP), GIP(3-30)NH2, was recently identified as an antagonist of the human GIP receptor. This study examined the ability of GIP(3-30)NH2 to antagonize the physiological actions of GIP in glucose metabolism, subcutaneous abdominal adipose tissue blood flow (ATBF), and lipid metabolism in humans. Eight lean subjects were studied by measuring arteriovenous concentrations of metabolites and ATBF on three different occasions during hyperglycemic-hyperinsulinemic clamps with concomitant infusions of GIP, GIP(3-30)NH2, or both GIP and GIP(3-30)NH2 During infusion of GIP(3 30)NH2 alone and in combination with GIP, insulin levels and the total glucose amount infused to maintain the clamp were lower than during GIP alone. In addition, ATBF remained constant during the antagonist and increased only slightly in combination with GIP, whereas it increased fivefold during GIP alone. Adipose tissue triacylglyceride (TAG) and glucose uptake decreased, and the free fatty acid/glycerol ratio increased during the antagonist alone and in combination with GIP. The changes in glucose infusion rates and plasma insulin levels demonstrate an inhibitory effect of the antagonist on the incretin effect of GIP. In addition, the antagonist inhibited GIP-induced increase in ATBF and decreased the adipose tissue TAG uptake, indicating that GIP also plays a crucial role in lipid metabolism. PMID- 28667119 TI - MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic beta-Cells. AB - Induction of endoplasmic reticulum stress and activation of the intrinsic apoptotic pathway is widely believed to contribute to beta-cell death in type 1 diabetes (T1D). MCL-1 is an antiapoptotic member of the BCL-2 protein family, whose depletion causes apoptosis in rodent beta-cells in vitro. Importantly, decreased MCL-1 expression was observed in islets from patients with T1D. We report here that MCL-1 downregulation is associated with cytokine-mediated killing of human beta-cells, a process partially prevented by MCL-1 overexpression. By generating a beta-cell-specific Mcl-1 knockout mouse strain (betaMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. beta-Cells from betaMcl-1KO mice were, however, more susceptible to cytokine-induced apoptosis. Moreover, betaMcl-1KO mice displayed higher hyperglycemia and lower pancreatic insulin content after multiple low-dose streptozotocin treatment. We found that the kinase GSK3beta, the E3 ligases MULE and betaTrCP, and the deubiquitinase USP9x regulate cytokine mediated MCL-1 protein turnover in rodent beta-cells. Our results identify MCL-1 as a critical prosurvival protein for preventing beta-cell death and clarify the mechanisms behind its downregulation by proinflammatory cytokines. Development of strategies to prevent MCL-1 loss in the early stages of T1D may enhance beta-cell survival and thereby delay or prevent disease progression. PMID- 28667120 TI - Chronic cerebral hypoperfusion alters amyloid-beta peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice. AB - Cerebral hypoperfusion is an early feature of Alzheimer's disease (AD) that influences the progression from mild cognitive impairment to dementia. Understanding the mechanism is of critical importance in the search for new effective therapies. We hypothesized that cerebral hypoperfusion promotes the accumulation of amyloid-beta (Abeta) and degenerative changes in the brain and is a potential mechanism contributing to development of dementia. To address this, we studied the effects of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis on Abeta peptide pools in a transgenic mouse model of AD (transgenic mice with Swedish, Dutch and Iowa mutations in human amyloid precursor protein (APP) (Tg-SwDI)). Cerebrovascular integrity was characterized by quantifying the occurrence of microinfarcts and haemorrhages and compared with wild-type mice without Abeta. A significant increase in soluble Abeta peptides (Abeta40/42) was detected after 1 month of hypoperfusion in the parenchyma in parallel with elevated APP and APP proteolytic products. Following 3 months, a significant increase in insoluble Abeta40/42 was determined in the parenchyma and vasculature. Microinfarct load was significantly increased in the Tg-SwDI as compared with wild-type mice and further exacerbated by hypoperfusion at 1 and 3 months. In addition, the number of Tg-SwDI hypoperfused mice with haemorrhages was increased compared with hypoperfused wild-type mice. Soluble parenchymal Abeta was associated with elevated NADPH oxidase-2 (NOX2) which was exacerbated by 1-month hypoperfusion. We suggest that in response to hypoperfusion, increased Abeta production/deposition may contribute to degenerative processes by triggering oxidative stress promoting cerebrovascular disruption and the development of microinfarcts. PMID- 28667121 TI - RNA gets in phase. AB - Several neurological disorders are linked to tandem nucleotide repeat expansion in the mutated gene. Jain and Vale (2017. Nature. https://doi.org/10.1038/nature22386) show that, above a pathological threshold repeat number, base pairing interactions drive phase separation of RNA into membrane-less gels, suggesting that RNA can scaffold the assembly of phase separated compartments that sequester proteins/RNAs causing toxicity. PMID- 28667122 TI - A toddler with worsening gait and leopard skin sign on MRI. PMID- 28667123 TI - Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP. AB - Obesity and type 2 diabetes are significant risk factors for malignancies, being associated with chronic inflammation and hyperinsulinemia. In this context, insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 protein(s) (mutp53) can acquire oncogenic properties that increase metastasis, proliferation, and cell survival. We report that breast and prostate cancer cells with mutant p53 respond to insulin stimulation by increasing cell proliferation and invasivity, and that such a response depends on the presence of mutp53. Mechanistically, we find that mutp53 augments insulin-induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP (DAB2-interacting protein) in the cytoplasm. This molecular axis reveals a specific gain of function for mutant p53 in the response to insulin stimulation, offering an additional perspective to understand the relationship between hyperinsulinemia and cancer evolution. PMID- 28667124 TI - Distinct VASP tetramers synergize in the processive elongation of individual actin filaments from clustered arrays. AB - Ena/VASP proteins act as actin polymerases that drive the processive elongation of filament barbed ends in membrane protrusions or at the surface of bacterial pathogens. Based on previous analyses of fast and slow elongating VASP proteins by in vitro total internal reflection fluorescence microscopy (TIRFM) and kinetic and thermodynamic measurements, we established a kinetic model of Ena/VASP mediated actin filament elongation. At steady state, it entails that tetrameric VASP uses one of its arms to processively track growing filament barbed ends while three G-actin-binding sites (GABs) on other arms are available to recruit and deliver monomers to the filament tip, suggesting that VASP operates as a single tetramer in solution or when clustered on a surface, albeit processivity and resistance toward capping protein (CP) differ dramatically between both conditions. Here, we tested the model by variation of the oligomerization state and by increase of the number of GABs on individual polypeptide chains. In excellent agreement with model predictions, we show that in solution the rates of filament elongation directly correlate with the number of free GABs. Strikingly, however, irrespective of the oligomerization state or presence of additional GABs, filament elongation on a surface invariably proceeded with the same rate as with the VASP tetramer, demonstrating that adjacent VASP molecules synergize in the elongation of a single filament. Additionally, we reveal that actin ATP hydrolysis is not required for VASP-mediated filament assembly. Finally, we show evidence for the requirement of VASP to form tetramers and provide an amended model of processive VASP-mediated actin assembly in clustered arrays. PMID- 28667125 TI - Induction of experimental autoimmune orchitis in mice: responses to elevated circulating levels of the activin-binding protein, follistatin. AB - Experimental autoimmune orchitis (EAO) is a rodent model of chronic testicular inflammation that mimics the pathology observed in some types of human infertility. In a previous study, testicular expression of the inflammatory/immunoregulatory cytokine, activin A, was elevated in adult mice during the onset of EAO, indicating a potential role in the regulation of the disease. Consequently, we examined the development of EAO in mice with elevated levels of follistatin, an endogenous activin antagonist, as a potential therapeutic approach to testicular inflammation. Prior to EAO induction, mice received a single intramuscular injection of a non-replicative recombinant adeno associated viral vector carrying a gene cassette of the circulating form of follistatin, FST315 (FST group). Serum follistatin levels were increased 5-fold in the FST group compared with the control empty vector (EV) group at 30 and 50 days of EAO, but intra-testicular levels of follistatin or activin A were not significantly altered. Induction of EAO was reduced, but not prevented, with mild to-severe damage in 75% of the EV group and 40% of the FST group, at 50 days following immunisation with testicular homogenate. However, the EAO damage score (based on disruption of the blood-testis barrier, apoptosis, testicular damage and fibrosis) and extent of intratesticular inflammation (expression of inflammatory mediators) were directly proportional to the levels of activin A measured in the testis at 50 days. These data implicate activin A in the progression of EAO, thereby providing a potential therapeutic target; however, elevating circulating follistatin levels were not sufficient to prevent EAO development. PMID- 28667126 TI - Functional implications of the utero-placental relaxin (RLN) system in the dog throughout pregnancy and at term. AB - Relaxin (RLN) is a key hormone of pregnancy in mammals best known for its involvement in connective tissue remodeling. In the domestic dog, placental RLN is the only known endocrine marker of pregnancy. However, knowledge is sparse regarding the spatio-temporal expression of RLN and its receptors (RXFP1 and RXFP2) in the canine uterus and placenta. Here, their expression was investigated in the pre-implantation uterus and utero-placental compartments (UtPl) at selected time points during gestation: post-implantation, mid-gestation, and at normal and antigestagen-induced luteolysis/abortion. Immunohistochemistry with newly generated, canine-specific antisera, in situ hybridization and semi quantitative PCR were applied. In compartmentalization studies, placental and endometrial RLN increased continuously toward prepartum. The placental RXFP1 was time-related and highest during post-implantation and decreased together with RXFP2 at prepartum luteolysis. The endometrial levels of both receptors did not vary greatly, but myometrial RXFP2 decreased from mid-gestation to prepartum luteolysis. Antigestagen treatment resulted in suppression of RLN in UtPl and decreased RXFP1 and RXFP2 in the uterus. The placental RLN was localized mainly in the cytotrophoblast. Additionally, RXFP1 stained strongly in placental endothelial cells while RXFP2 was found mainly in maternal decidual cells. Uterine staining for all targets was found in epithelial cellular constituents and in myometrium. Finally, besides its endocrine functions, RLN seems to be involved in auto-/paracrine regulation of utero-placental functions in dogs in a time-dependent manner. New insights into feto-maternal communication was provided, in particular regarding the localization of RXFP2 in the maternal decidual cells, implying functional roles of RLN during the decidualization process. PMID- 28667127 TI - Effect of urokinase type plasminogen activator on in vitro bovine oocyte maturation. AB - This study examines the impacts of the urokinase-type plasminogen activator (uPA) on the in vitro maturation (IVM) of bovine oocytes. Cumulus-oocyte complexes in IVM medium were treated with uPA, amiloride (an uPA inhibitor), dimethyl sulfoxide (DMSO) or left untreated (control group). After 24 h of IVM, oocytes were recovered for testing or were in vitro fertilized and cultured to the blastocyst stage. The factors examined in all groups were: (i) oocyte nuclear maturation (Hoescht staining); (ii) oocyte cytoplasmic maturation (cortical granules, CGs, distribution assessed by LCA-FITC); (iii) oocyte and cumulus cell (CC) gene expression (RT-qPCR); and (iv) embryo development (cleavage rate and blastocyst yield). Oocytes subjected to uPA treatment showed rates of nuclear maturation and CG distribution patterns similar to controls (P > 0.05), whereas lower rates of oocyte maturation were recorded in the amiloride group (P < 0.05). Both in oocytes and CC, treatment with uPA did not affect the transcription of genes related to apoptosis, cell junctions, cell cycle or serpin protease inhibitors. In contrast, amiloride altered the expression of genes associated with cell junctions, cell cycle, oxidative stress and CC serpins. No differences were observed between the control and uPA group in cleavage rate or in blastocyst yield recorded on Days 7, 8 or 9 post-insemination. However, amiloride led to drastically reduced cleavage rate (28.5% vs 83.2%) and Day 9 embryo production (6.0% vs 21.0%) over the rates recorded for DMSO. These results indicate that the proteolytic activity of uPA is needed for successful oocyte maturation in bovine. PMID- 28667131 TI - Is India the answer to potential workforce issues following Brexit? PMID- 28667128 TI - Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes Predicts Poor Long-term Glycemic Control. AB - OBJECTIVE: This study tested the hypothesis that diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in children predicts poor long-term glycemic control independently of established risk factors. RESEARCH DESIGN AND METHODS: This was a prospective cohort study of 3,364 Colorado residents diagnosed with type 1 diabetes before 18 years of age, in 1998-2012, and monitored for up to 15 years. Of those, 1,297 (39%) had DKA at diagnosis (blood glucose >250 mg/dL, and venous pH <7.3 or bicarbonate <15 mEq/L). Severity of DKA was further classified as mild/moderate (pH 7.10-7.29 or bicarbonate 5-14 mEq/L) or severe (pH <7.10 or bicarbonate <5 mEq/L). HbA1c levels were measured an average of 2.8 times/year (median 20 HbA1c values/patient). A linear mixed model was used to examine the effect of DKA on long-term HbA1c levels, adjusting for age, race/ethnicity, sex, family history of diabetes, health insurance, and insulin pump use. RESULTS: DKA at diagnosis predicted persistently elevated HbA1c levels. Compared with children without DKA, HbA1c tracked 1.4% (15.3 mmol/mol) higher in those with severe DKA (P < 0.0001) and 0.9% (9.8 mmol/mol) higher in those with mild/moderate DKA at diagnosis (P < 0.0001). These effects were independent of ethnic minority status or lack of health insurance at diagnosis that predicted higher HbA1c by 0.5% (5.5 mmol/mol; P < 0.0001) and 0.2% (2.2 mmol/mol; P < 0.0001), respectively. Insulin pump use or having a parent or sibling with type 1 diabetes predicted lower long term HbA1c by, respectively, 0.4% (4.4 mmol/mol; P < 0.0001) and 0.2% (2.2 mmol/mol; P = 0.01). CONCLUSIONS: DKA at diagnosis of type 1 diabetes in children predicts poor long-term glycemic control, independent of demographic and socioeconomic factors. PMID- 28667132 TI - Tail docking decision condemned by vets. PMID- 28667133 TI - 'Good compromise' reached on withdrawal of zinc oxide medicines. PMID- 28667135 TI - First antibody therapy in veterinary medicine launched for dogs in the UK. PMID- 28667138 TI - Medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK. PMID- 28667139 TI - Disease surveillance in England and Wales, June 2017. AB - Current and emerging issues: update on Schmallenberg virusHighlights from the scanning surveillance networkUpdate on international disease threatsFocus on recognising clinical avian botulism in wild waterbirdsThese are among matters discussed in the Animal and Plant Health Agency's (APHA's) disease surveillance report for June 2017. PMID- 28667140 TI - Recognising clinical avian botulism in wild waterbirds. AB - This article has been prepared by Paul Duff and colleagues of the APHA Wildlife Expert Group. PMID- 28667142 TI - Selected highlights from other veterinary journals. AB - Clinical trial in dogs shows administering intranasal midazolam is best for terminating status epilepticus. PMID- 28667141 TI - When is the best time to vaccinate piglets against Mycoplasma hyopneumoniae. PMID- 28667145 TI - Responsible use of antimicrobials. PMID- 28667147 TI - Reporting animal abuse incidents. PMID- 28667146 TI - Responsible use of antimicrobials. PMID- 28667148 TI - Official controls in slaughterhouses. PMID- 28667149 TI - Complementary and alternative medicines. PMID- 28667151 TI - Fresh perspectives on old challenges: this year's BVA Congress debates. AB - BVA is excited to announce the topics for debates and the contentious issues that will be presented at this year's BVA Congress at London Vet Show (LVS) on November 16 and 17. Sally Burnell, director of policy, media and strategy, selects some highlights from the packed programme. BVA Congress is open to all LVS delegates. PMID- 28667152 TI - In the frame again: BVA's photo competition returns. AB - BVA is inviting entries to its second photo competition. Tara Schwenk, BVA digital content editor, recaps last year's competition and describes the entries the judges are hoping to see this time. PMID- 28667154 TI - Unexpected challenges. AB - Nicky Mansell, Young Vet Network representative on BVA Council, discusses the challenges graduates face on top of clinical work. PMID- 28667153 TI - BVA Gala Dinner. AB - Following the success of last year's sell out event, the 2017 BVA Gala Dinner, held during the London Vet Show, will return to the luxurious London Marriott Hotel West India Quay on Thursday, November 16. PMID- 28667155 TI - Branch President gives evidence at Scottish Parliament. AB - As the Scottish Government moves forward with its recently announced package of measures on animal health and welfare, Hayley Atkin, BVA Policy Officer, describes a busy month for the President of BVA Scottish Branch representing members in the Scottish Parliament. PMID- 28667156 TI - Debt recovery doesn't need to be expensive. AB - Michael Whitaker, head of business development at Legal Recoveries and Collections (LRC), explains that pursuing non- or late-paying clients (debtors) through the court doesn't have to be a risky and expensive process. He says it should be an effective part of a veterinary practice's overall debt recovery strategy. PMID- 28667157 TI - Developing teaching to improve the wellbeing of future vets. AB - Some people are under the impression that developing the educational experience of students at the Royal Veterinary College doesn't make you a 'real vet'. Here, Elizabeth Armitage-Chan explains how her role helps future vets gain in confidence and competence. PMID- 28667158 TI - More doctors are disclosing payments from drug companies. PMID- 28667159 TI - Judging the benefits and harms of medicines. PMID- 28667160 TI - Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease. AB - Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg+) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA) exposed Scnn1b-Tg+ (FA-Tg+) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed Scnn1b-Tg+ (SHS-Tg+) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg+ mice exhibited marked mucus obstruction and Th2 responses, SHS Tg+ mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, Th2 responses, and delayed bacterial clearance in SHS-Tg+ mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg+ mice, the SHS-Tg+ mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished Th2 response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations. PMID- 28667161 TI - CD36 and Platelet-Activating Factor Receptor Promote House Dust Mite Allergy Development. AB - Over 89% of asthmatic children in underdeveloped countries demonstrate sensitivity to house dust mites (HDMs). The allergic response to HDMs is partially mediated by epithelial cell-derived cytokines that activate group 2 innate lymphoid cells, induce migration and activation of dendritic cells, and promote effector differentiation of HDM-specific TH2 cells. However, the contribution of innate receptor engagement on epithelial or dendritic cells by HDMs that ultimately mediates said innate and adaptive allergic responses is poorly understood. We and other investigators have demonstrated that HDMs express phosphorylcholine (PC) moieties. The major PC receptors involved in immune responses include CD36 and platelet-activating factor receptor (PAFR). Because CD36 and PAFR are expressed by epithelial cells and dendritic cells, and expression of these receptors is higher in human asthmatics, we determined whether engagement of CD36 or PAFR on epithelial or dendritic cells contributes to HDM allergy development. Testing bone marrow chimeric mice revealed that CD36 engagement on radioresistant cells and PAFR engagement on radioresistant and radiosensitive cells in the lung promote allergic responses to HDMs. Additionally, passive anti-PC IgM Abs administered intratracheally with HDMs decreased allergen uptake by epithelial cells and APCs in the lungs of C57BL/6 mice but not CD36-/- or PAFR-/- mice. These results show that CD36 and PAFR are important mediators of HDM allergy development and that inhibiting HDM engagement with PC receptors in the lung protects against allergic airway disease. PMID- 28667162 TI - Regulation of Th17 Differentiation by IKKalpha-Dependent and -Independent Phosphorylation of RORgammat. AB - Transcription factor retinoid acid-related orphan receptor (ROR)gammat transcriptionally regulates the genes required for differentiation of Th17 cells that mediate both protective and pathogenic immunity. However, little is known about the function of posttranslational modifications in the regulation of RORgammat activity. Mass spectrometric analysis of immunoprecipitated RORgammat from Th17 cells identified multiple phosphorylation sites. Systematic mutation analysis of the identified phosphorylation sites found that phosphorylation of S376 enhances whereas phosphorylation of S484 inhibits Th17 differentiation. IkappaB kinase (IKK)alpha binds and phosphorylates RORgammat at S376 but not S484. Knockdown of IKKalpha, dominant-negative IKKalpha, and RORgammat mutants incapable of interacting with IKKalpha all decrease Th17 differentiation. Furthermore, nonphosophorylatable RORgammat mutant (S376A) impairs whereas phosphomimetic mutant (S376E) stimulates Th17 differentiation independent of IKKalpha. Therefore, IKKalpha-dependent phosphorylation of S376 stimulated whereas IKKalpha-independent phosphorylation of S484 inhibited RORgammat function in Th17 differentiation. PMID- 28667163 TI - Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation. AB - Asthma is a complex disease that is promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation; however, it is unclear whether lipid mediators, such as cysteinyl leukotrienes (CysLTs), which are present in asthma, could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. In this article, we show that airway challenges with the parent CysLT, leukotriene C4 (LTC4), given in combination with low-dose IL-33 to naive wild-type mice, led to synergistic increases in airway Th2 cytokines, eosinophilia, and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R, and candidate leukotriene E4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R, because CysLT1R-/- mice, but not CysLT2R-/- mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R-/- mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses. PMID- 28667164 TI - Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus. AB - Zika virus (ZIKV) is a mosquito-borne and sexually transmitted flavivirus that is associated with fetal CNS-damaging malformations during pregnancy in humans. This study documents the viral kinetics and immune responses in rhesus macaques infected with a clinical ZIKV Brazilian isolate. We evaluated the viral kinetics and immune responses induced after an i.v. infection with a Brazilian ZIKV clinical isolate (HS-2015-BA-01) in rhesus macaques for up to 142 d. ZIKV specific Ab-secreting cells, germinal center reactions, and monocyte, dendritic cell, NK, and T cell frequencies were monitored. ZIKV loads were readily detected in plasma (until day 5 or 7), semen and urine (until days 7 and 14), and saliva (until day 42), but the viremia was rapidly controlled. No detectable clinical manifestations were observed. However, lymph node hyperplasia was clearly visible postviremia but was associated with low frequencies of ZIKV-specific Ab-secreting cells in lymph nodes and bone marrow, correlating with low Ab titers. CD14+/CD16- monocytes and myeloid CD11chi dendritic cells decreased in blood, whereas NK and T cell numbers were only marginally altered during the course of the study. ZIKV infection caused a significant lymphoid tissue activation but limited induction of ZIKV-specific B cells, suggesting that these parameters need to be considered for ZIKV vaccine design. PMID- 28667167 TI - Expression of concern: car safety seats for children: rear facing for best protection. PMID- 28667165 TI - Association between the autophagy-related gene ULK1 and ankylosing spondylitis susceptibility in the Chinese Han population: a case-control study. AB - PURPOSE: Ankylosing spondylitis (AS), inflammatory bowel disease and Crohn's disease (CD) often coexist in the same patient and these diseases have remarkably strong overlaps in genetic association. The association between Unc51like kinase 1 (ULK1) gene polymorphisms and CD has been reported, and the aim of the current study was to investigate whether ULK1 polymorphisms are also associated with susceptibility to AS in the Chinese Han population. METHODS: Five tagging single nucleotide polymorphisms in the ULK1 gene (rs9652059, rs11616018, rs12303764, rs4964879 and rs7300908) were genotyped by the improved multiplex ligase detection reaction method in a cohort of patients with AS (n=649) and controls (n=628). Various genetic models were performed and haplotypes were constructed after linkage disequilibrium analysis. RESULTS: A statistically significant difference was found in the dominant model of the rs9652059 polymorphism (OR (95% CI) = 0.796 (0.638 to 0.994), chi2 = 4.064, p= 0.044). Haplotypes were conducted between rs9652059 and rs11616018, rs11616018 and rs4964879, rs9652059 and rs4964879 based on D' >=0.9 and r2 >= 0.6. Ht5 (rs9652059C-rs4964879G) haplotype was associated with AS (OR (95% CI) = 0.834 (0.706 to 0.985), chi2=4.555, p= 0.0328) and other two haplotypes were marginally correlated with AS (ht2 (rs9652059C-rs11616018T): OR (95% CI) = 0.846 (0.717 to 1.000), chi2= 3.864, p= 0.0493); ht3 (rs9652059T-rs11616018T): OR (95% CI) = 1.440 (0.999 to 2.076), chi2 = 3.849, p = 0.0498). CONCLUSIONS: Our findings suggest that rs9652059 variation (C->T) could increase AS susceptibility and haplotypes of rs9652059C-rs4964879G, rs9652059C-rs11616018T and rs9652059T-rs11616018T may be associatd with AS. PMID- 28667166 TI - Abnormal movements induced by methanol toxicity. PMID- 28667168 TI - Sixty seconds on . . . the CEP. PMID- 28667169 TI - Recurrent hemifacial oedema. PMID- 28667170 TI - Isolated cardiac sarcoidosis masquerading as right ventricular outflow tract ventricular tachycardia. AB - A 67-year-old man with coronary artery disease (CAD) and left anterior descending artery (LAD) stent presented with symptomatic monomorphic ventricular tachycardia (VT) at a rate of 190 bpm requiring cardioversion. ECG showed left bundle branch block pattern and inferior axis, suggestive of a right ventricular outflow tract (RVOT) focus rather than left ventricular scar due to LAD territory myocardial infarction (MI). Echocardiography showed normal wall motion. Angiography revealed a patent mid-LAD stent. Cardiac MRI with delayed postcontrast sequence revealed several regions of hyperenhancement abnormality within the basal portion of the interventricular septum. Increased metabolic activity on positron emission tomography confirmed active inflammatory sarcoidosis.Although VTs in patients with prior CAD are likely to be related to either scar or ischaemia, alternative diagnoses (eg, infiltrative disorders, RVOT-VT, arrhythmogenic right ventricular cardiomyopathy) should be considered in patients with an apparent right ventricular focus on ECG. PMID- 28667171 TI - Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif. AB - Hedgehog (HH) signaling critically regulates embryonic and postnatal development as well as adult tissue homeostasis, and its perturbation can lead to developmental disorders, birth defects, and cancers. Neuropilins (NRPs), which have well-defined roles in Semaphorin and VEGF signaling, positively regulate HH pathway function, although their mechanism of action in HH signaling remains unclear. Here, using luciferase-based reporter assays, we provide evidence that NRP1 regulates HH signaling specifically at the level of GLI transcriptional activator function. Moreover, we show that NRP1 localization to the primary cilium, a key platform for HH signal transduction, does not correlate with HH signal promotion. Rather, a structure-function analysis suggests that the NRP1 cytoplasmic and transmembrane domains are necessary and sufficient to regulate HH pathway activity. Furthermore, we identify a previously uncharacterized, 12-amino acid region within the NRP1 cytoplasmic domain that mediates HH signal promotion. Overall, our results provide mechanistic insight into NRP1 function within and potentially beyond the HH signaling pathway. These insights have implications for the development of novel modulators of HH-driven developmental disorders and diseases. PMID- 28667172 TI - A haplotype variant of the human chromogranin A gene (CHGA) promoter increases CHGA expression and the risk for cardiometabolic disorders. AB - The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicle biogenesis in neuronal/neuroendocrine cells. CHGA is dysregulated in several cardiovascular diseases, but the underlying mechanisms are not well established. Here, we sought to identify common polymorphisms in the CHGA promoter and to explore the mechanistic basis of their plausible contribution to regulating CHGA protein levels in circulation. Resequencing of the CHGA promoter in an Indian population (n = 769) yielded nine single-nucleotide polymorphisms (SNPs): G-1106A, A-1018T, T-1014C, T-988G, G-513A, G-462A, T-415C, C-89A, and C-57T. Linkage disequilibrium (LD) analysis indicated strong LD among SNPs at the -1014, -988, -462, and -89 bp positions and between the -1018 and -57 bp positions. Haplotype analysis predicted five major promoter haplotypes that displayed differential promoter activities in neuronal cells; specifically, haplotype 2 (containing variant T alleles at -1018 and -57 bp) exhibited the highest promoter activity. Systematic computational and experimental analyses revealed that transcription factor c-Rel has a role in activating the CHGA promoter haplotype 2 under basal and pathophysiological conditions (viz. inflammation and hypoxia). Consistent with the higher in vitro CHGA promoter activity of haplotype 2, individuals carrying this haplotype had higher plasma CHGA levels, plasma glucose levels, diastolic blood pressure, and body mass index. In conclusion, these results suggest a functional role of the CHGA promoter haplotype 2 (occurring in a large proportion of the world population) in enhancing CHGA expression in haplotype 2 carriers who may be at higher risk for cardiovascular/metabolic disorders. PMID- 28667173 TI - A time for promiscuity in a eukaryotic recombinase. AB - The exchange of DNA strands between broken and intact molecules lies at the heart of fundamental cellular processes ranging from repairing DNA damage by homologous recombination to generation of genetic diversity during sexual reproduction. New work by Lee and colleagues utilizes the DNA curtain method, an elegant single molecule technique, to demonstrate common and idiosyncratic features in the DNA strand exchange mechanisms of three RecA-family recombinases, bacterial RecA, and eukaryotic Rad51 and Dmc1 proteins. PMID- 28667174 TI - Erbb4 Deletion from Medium Spiny Neurons of the Nucleus Accumbens Core Induces Schizophrenia-Like Behaviors via Elevated GABAA Receptor alpha1 Subunit Expression. AB - Medium spiny neurons (MSNs), the major GABAergic projection neurons in the striatum, are implicated in many neuropsychiatric diseases such as schizophrenia, but the underlying mechanisms remain unclear. We found that a deficiency in Erbb4, a schizophrenia risk gene, in MSNs of the nucleus accumbens (NAc) core, but not the dorsomedial striatum, markedly induced schizophrenia-like behaviors such as hyperactivity, abnormal marble-burying behavior, damaged social novelty recognition, and impaired sensorimotor gating function in male mice. Using immunohistochemistry, Western blot, RNA interference, electrophysiology, and behavior test studies, we found that these phenomena were mediated by increased GABAA receptor alpha1 subunit (GABAAR alpha1) expression, which enhanced inhibitory synaptic transmission on MSNs. These results suggest that Erbb4 in MSNs of the NAc core may contribute to the pathogenesis of schizophrenia by regulating GABAergic transmission and raise the possibility that GABAAR alpha1 may therefore serve as a new therapeutic target for schizophrenia.SIGNIFICANCE STATEMENT Although ErbB4 is highly expressed in striatal medium spiny neurons (MSNs), its role in this type of neuron has not been reported previously. The present study demonstrates that Erbb4 deletion in nucleus accumbens (NAc) core MSNs can induce schizophrenia-like behaviors via elevated GABAA receptor alpha1 subunit (GABAAR alpha1) expression. To our knowledge, this is the first evidence that ErbB4 signaling in the MSNs is involved in the pathology of schizophrenia. Furthermore, restoration of GABAAR alpha1 in the NAc core, but not the dorsal medium striatum, alleviated the abnormal behaviors. Here, we highlight the role of the NAc core in the pathogenesis of schizophrenia and suggest that GABAAR alpha1 may be a potential pharmacological target for its treatment. PMID- 28667176 TI - miR-212-5p suppresses lipid accumulation by targeting FAS and SCD1. AB - MicroRNAs, a class of small noncoding RNAs, are implicated in controlling a variety of biological processes. We have shown that leucine deprivation suppresses lipogenesis by inhibiting fatty acid synthase (FAS) expression in the liver previously; the aim of our current study is to investigate which kind of microRNA is involved in the regulation of FAS expression in response to leucine deprivation. Here, we indicated that microRNA-212-5p specifically binds to mouse FAS 3'UTR and inhibits its activity. Leucine deficiency significantly increased the mRNA levels of miR-212-5p in the livers of mice. Further studies proved that miR-212-5p also directly binds to the 3'UTR of stearoyl-CoA desaturase-1 (SCD1) to inhibit its activity. Overexpression of miR-212-5p decreases the protein levels of FAS and SCD1 in vitro and in vivo, and silencing of miR-212-5p has the opposite effects in mouse primary hepatocytes. Moreover, overexpression of miR 212-5p significantly decreases triglyceride (TG) accumulation in primary hepatocytes and in the livers of mice injected with adenovirus-mediated overexpressing of miR-212-5p (Ad-miR-212). Interestingly, inhibition of miR-212 5p reverses the suppressive effects of leucine deficiency on FAS and SCD1 expression, as well as TG accumulation in mouse primary hepatocytes. Finally, we demonstrate that leucine deficiency induces the expression of miR-212-5p in a GCN2/ATF4-dependent manner. Taken together, our results demonstrate a novel function of hepatic miR-212-5p in the regulation of lipid metabolism which represents a potential therapeutic target for the treatment of non-alcohol fatty liver diseases (NAFLD). PMID- 28667175 TI - The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release. AB - Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of MU-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation.SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these cells remains poorly understood. To provide clarity to this circuit, we made electrophysiological recordings from mouse brain slices and found that AgRP neurons do not contribute spontaneously released GABA onto POMC neurons, although when activated with channelrhodopsin AgRP neurons inhibit POMC neurons through GABA-mediated transmission. These findings indicate that the relevance of AgRP to POMC neuron GABA connectivity depends on the state of AgRP neuron activity and suggest that different types of transmitter release should be considered when circuit mapping. PMID- 28667177 TI - Dementia with Lewy bodies: Diagnosis is only skin deep? PMID- 28667178 TI - A new potential biomarker for dementia with Lewy bodies: Skin nerve alpha synuclein deposits. AB - OBJECTIVE: To investigate whether (1) phosphorylated alpha-synuclein (p-syn) deposits in skin nerves could be useful in differentiating dementia with Lewy bodies (DLB) from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB. METHODS: We studied 18 well-characterized patients with DLB (11 with autonomic dysfunction), 23 patients with nonsynucleinopathy dementia (NSD; 13 with young-onset Alzheimer disease dementia, 6 frontotemporal dementia, and 4 vascular dementia), and 25 healthy controls. All participants underwent skin biopsies from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of p-syn, considered the pathologic form of alpha-synuclein. RESULTS: No p-syn was detected in any skin sample in patients with NSD and controls but was found in all patients with DLB. SFN was found in patients with DLB and the autonomic denervation of skin was more severe in patients with autonomic dysfunctions. CONCLUSIONS: (1) In autonomic skin nerves, p-syn is a sensitive biomarker for DLB diagnosis, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger, more representative sample; and (2) skin autonomic neuropathy is part of the DLB pathology and may contribute to autonomic symptoms. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that p-syn in skin nerve fibers on skin biopsy accurately distinguishes DLB from other forms of dementia. PMID- 28667179 TI - Residents don't just look miserable... they really are. PMID- 28667180 TI - Burnout, career satisfaction, and well-being among US neurology residents and fellows in 2016. AB - OBJECTIVE: To study prevalence of and factors contributing to burnout, career satisfaction, and well-being in US neurology residents and fellows. METHODS: A total of 938 US American Academy of Neurology member neurology residents and fellows were surveyed using standardized measures of burnout, career satisfaction, and well-being from January 19 to March 21, 2016. RESULTS: Response rate was 37.7% (354/938); about 2/3 of responders were residents and 1/3 were fellows. Median age of participants was 32 years and 51.1% were female. Seventy three percent of residents and 55% of fellows had at least one symptom of burnout, the difference largely related to higher scores for depersonalization among residents. For residents, greater satisfaction with work-life balance, meaning in work, and older age were associated with lower risk of burnout; for fellows, greater satisfaction with work-life balance and effective support staff were associated with lower risk of burnout. Trainees experiencing burnout were less likely to report career satisfaction. Career satisfaction was more likely among those reporting meaning in work and more likely for those working in the Midwest compared with the Northeast region. CONCLUSIONS: Burnout is common in neurology residents and fellows. Lack of work-life balance and lack of meaning in work were associated with reduced career satisfaction and increased risk of burnout. These results should inform approaches to reduce burnout and promote career satisfaction and well-being in US neurology trainees. PMID- 28667181 TI - DNM1 encephalopathy: A new disease of vesicle fission. AB - OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention. PMID- 28667182 TI - Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes: Mendelian randomization study. AB - OBJECTIVE: To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes. METHODS: MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNP stroke associations were derived from METASTROKE and the Stroke Genetics Network (n = 18,476 ischemic stroke cases and 37,296 controls). RESULTS: Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p = 3.3 * 10-7) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p = 8.9 * 10-5) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p = 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype. CONCLUSIONS: This study provides support that T2D may be causally associated with large artery stroke. PMID- 28667183 TI - Occipital headaches and neuroimaging in children. AB - OBJECTIVE: To investigate the common thinking, as reinforced by the International Classification of Headache Disorders, 3rd edition (beta), that occipital headaches in children are rare and suggestive of serious intracranial pathology. METHODS: We performed a retrospective chart review cohort study of all patients <=18 years of age referred to a university child neurology clinic for headache in 2009. Patients were stratified by headache location: solely occipital, occipital plus other area(s) of head pain, or no occipital involvement. Children with abnormal neurologic examinations were excluded. We assessed location as a predictor of whether neuroimaging was ordered and whether intracranial pathology was found. Analyses were performed with cohort study tools in Stata/SE 13.0 (StataCorp, College Station, TX). RESULTS: A total of 308 patients were included. Median age was 12 years (32 months-18 years), and 57% were female. Headaches were solely occipital in 7% and occipital-plus in 14%. Patients with occipital head pain were more likely to undergo neuroimaging than those without occipital involvement (solely occipital: 95%, relative risk [RR] 10.5, 95% confidence interval [CI] 1.4-77.3; occipital-plus: 88%, RR 3.7, 95% CI 1.5-9.2; no occipital pain: 63%, referent). Occipital pain alone or with other locations was not significantly associated with radiographic evidence of clinically significant intracranial pathology. CONCLUSIONS: Children with occipital headache are more likely to undergo neuroimaging. In the absence of concerning features on the history and in the setting of a normal neurologic examination, neuroimaging can be deferred in most pediatric patients when occipital pain is present. PMID- 28667185 TI - Low IgE Is Insufficiently Sensitive to Guide Genetic Testing of STAT3 Gain-of Function Mutations. PMID- 28667184 TI - Identification, Confirmation, and Replication of Novel Urinary MicroRNA Biomarkers in Lupus Nephritis and Diabetic Nephropathy. AB - BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing, leading to significant morbidity and mortality. Kidney biopsy remains the gold standard for diagnosing the underlying etiology of CKD, but the procedure carries complication risks. The aim of this study was to identify novel noninvasive biomarkers correlating with kidney function and histopathology in biopsy-proven CKD patients. METHODS: We profiled 2402 urinary microRNAs (miRNAs) to identify and confirm differentially expressed miRNAs associated with kidney function and histopathology in patients with diabetic nephropathy (n = 58) or lupus nephritis (n = 89), important etiologies of CKD, compared with healthy controls (n = 93 and 119, respectively). Top performing miRNAs were then measured in 2 independent multi-institutional cohorts of patients with diabetes mellitus with (n = 74) or without nephropathy (n = 71) and systemic lupus erythematosus with (n = 86) or without (n = 37) nephritis. RESULTS: In patients with diabetic nephropathy, miR 2861, miR-1915-3p, and miR-4532 were down-regulated (>10-fold, P < 0.0001) and were associated with estimated glomerular filtration rate (P < 0.01) and interstitial fibrosis/tubular atrophy (P < 0.05). The c-statistics for miR-2861, miR-1915-3p, and miR-4532 were 0.91, 0.86, and 0.85, respectively. In lupus nephritis patients, miR-3201 and miR-1273e were down-regulated (>3-fold, P < 0.0001) and associated with endocapillary glomerular inflammation (P < 0.01), with c-statistics of 0.97 and 0.91, respectively. CONCLUSIONS: We have identified novel miRNAs that correlate with histopathological lesions and functional markers of kidney damage to facilitate sensitive, specific, and noninvasive detection of diabetic nephropathy and lupus nephritis. PMID- 28667186 TI - Analytically Sensitive Protein Detection in Microtiter Plates by Proximity Ligation with Rolling Circle Amplification. AB - BACKGROUND: Detecting proteins at low concentrations in plasma is crucial for early diagnosis. Current techniques in clinical routine, such as sandwich ELISA, provide sensitive protein detection because of a dependence on target recognition by pairs of antibodies, but detection of still lower protein concentrations is often called for. Proximity ligation assay with rolling circle amplification (PLARCA) is a modified proximity ligation assay (PLA) for analytically specific and sensitive protein detection via binding of target proteins by 3 antibodies, and signal amplification via rolling circle amplification (RCA) in microtiter wells, easily adapted to instrumentation in use in hospitals. METHODS: Proteins captured by immobilized antibodies were detected using a pair of oligonucleotide conjugated antibodies. Upon target recognition these PLA probes guided oligonucleotide ligation, followed by amplification via RCA of circular DNA strands that formed in the reaction. The RCA products were detected by horseradish peroxidase-labeled oligonucleotides to generate colorimetric reaction products with readout in an absorbance microplate reader. RESULTS: We compared detection of interleukin (IL)-4, IL-6, IL-8, p53, and growth differentiation factor 15 (GDF-15) by PLARCA and conventional sandwich ELISA or immuno-RCA. PLARCA detected lower concentrations of proteins and exhibited a broader dynamic range compared to ELISA and iRCA using the same antibodies. IL-4 and IL-6 were detected in clinical samples at femtomolar concentrations, considerably lower than for ELISA. CONCLUSIONS: PLARCA offers detection of lower protein levels and increased dynamic ranges compared to ELISA. The PLARCA procedure may be adapted to routine instrumentation available in hospitals and research laboratories. PMID- 28667187 TI - Impact of Novel Psychoactive Substances on Clinical and Forensic Toxicology and Global Public Health. PMID- 28667188 TI - C reactive protein in healthy term newborns during the first 48 hours of life. AB - BACKGROUND: Early-onset neonatal sepsis (EOS) is a serious and potentially life threatening disease in newborns. C reactive protein (CRP) is the most used laboratory biomarker for the detection of EOS. Little is known about normal reference values of CRP during the perinatal period as several factors are able to influence it. OBJECTIVES: To identify an appropriate range of CRP values in healthy term newborns during the first 48 hours of life. DESIGN: CRP determination was performed in 859 term newborns at 12, 24 and 48 hours of life. Mode of delivery, maternal vaginal culture results, intrapartum antimicrobial prophylaxis (IAP) and other perinatal variables were recorded. RESULTS: CRP mean values were significantly higher at 48 hours (4.10 mg/L) than at both 24 (2.30 mg/L) and 12 hours of life (0.80 mg/L). CRP levels were affected by a number of perinatal proinflammatory variables. In particular, CRP mean values were significantly higher in babies born by vaginal delivery (3.80 mg/L) and emergency caesarean section (3.60 mg/L) than in babies born by elective caesarean section (2.10 mg/L). Completed course of IAP led to lower CRP mean values (2.90 mg/L) than IAP not completed (3.80 mg/L) or not performed (4.70 mg/L). CONCLUSIONS: Postnatal age and mode of delivery significantly influence CRP values. Reliable reference values are crucial in order to obtain an adequate diagnostic accuracy. PMID- 28667190 TI - 3-lead electrocardiogram is more reliable than pulse oximetry to detect bradycardia during stabilisation at birth of very preterm infants. AB - OBJECTIVES: Current neonatal resuscitation guidelines suggest the use of ECG in the delivery room (DR) to assess heart rate (HR). However, reliability of ECG compared with pulse oximetry (PO) in a situation of bradycardia has not been specifically investigated. The objective of the present study was to compare HR monitoring using ECG or PO in a situation of bradycardia (HR <100 beats per minute (bpm)) during preterm stabilisation in the DR. STUDY DESIGN: Video recordings of resuscitations of infants <32 weeks of gestation were reviewed. HR readings in a situation of bradycardia (<100 bpm) at any moment during stabilisation were registered with both devices every 5 s from birth. RESULTS: A total of 29 episodes of bradycardia registered by the ECG in 39 video recordings were included in the analysis (n=29). PO did not detect the start of these events in 20 cases (69%). PO detected the start and the end of bradycardia later than the ECG (median (IQR): 5 s (0-10) and 5 s (0-7.5), respectively). A decline in PO accuracy was observed as bradycardia progressed so that by the end of the episode PO offered significantly lower HR readings than ECG. CONCLUSIONS: PO detects the start and recovery of bradycardia events slower and less accurately than ECG during stabilisation at birth of very preterm infants. ECG use in this scenario may contribute to an earlier initiation of resuscitation manoeuvres and to avoid unnecessary prolongation of resuscitation efforts after recovery. PMID- 28667189 TI - Estimating Global Burden of Disease due to congenital anomaly: an analysis of European data. AB - OBJECTIVE: To validate the estimates of Global Burden of Disease (GBD) due to congenital anomaly for Europe by comparing infant mortality data collected by EUROCAT registries with the WHO Mortality Database, and by assessing the significance of stillbirths and terminations of pregnancy for fetal anomaly (TOPFA) in the interpretation of infant mortality statistics. DESIGN, SETTING AND OUTCOME MEASURES: EUROCAT is a network of congenital anomaly registries collecting data on live births, fetal deaths from 20 weeks' gestation and TOPFA. Data from 29 registries in 19 countries were analysed for 2005-2009, and infant mortality (deaths of live births at age <1 year) compared with the WHO Mortality Database. Eight EUROCAT countries were excluded from further analysis on the basis that this comparison showed poor ascertainment of survival status. RESULTS: According to WHO, 17%-42% of infant mortality was attributed to congenital anomaly. In 11 EUROCAT countries, average infant mortality with congenital anomaly was 1.1 per 1000 births, with higher rates where TOPFA is illegal (Malta 3.0, Ireland 2.1). The rate of stillbirths with congenital anomaly was 0.6 per 1000. The average TOPFA prevalence was 4.6 per 1000, nearly three times more prevalent than stillbirths and infant deaths combined. TOPFA also impacted on the prevalence of postneonatal survivors with non-lethal congenital anomaly. CONCLUSIONS: By excluding TOPFA and stillbirths from GBD years of life lost (YLL) estimates, GBD underestimates the burden of disease due to congenital anomaly, and thus declining YLL over time may obscure lack of progress in primary, secondary and tertiary prevention. PMID- 28667191 TI - Providing active antenatal care depends on the place of birth for extremely preterm births: the EPIPAGE 2 cohort study. AB - : Survival rates of infants born before 25 weeks of gestation are low in France and have not improved over the past decade. Active perinatal care increases these infants' likelihood of survival. OBJECTIVE: Our aim was to identify factors associated with active antenatal care, which is the first step of proactive perinatal care in extremely preterm births. METHODS: The population included 1020 singleton births between 220/6 and 260/6 weeks of gestation enrolled in the Etude Epidemiologique sur les Petits Ages Gestationnels 2 study, a French national population-based cohort of very preterm infants born in 2011. The main outcome was 'active antenatal care' defined as the administration of either corticosteroids or magnesium sulfate or delivery by caesarean section for fetal rescue. A multivariable analysis was performed using a two-level multilevel model taking into account the maternity unit of delivery to estimate the adjusted ORs (aORs) of receiving active antenatal care associated with maternal, obstetric and place of birth characteristics. RESULTS: Among the population of extremely preterm births, 42% received active antenatal care. After standardisation for gestational age, regional rates of active antenatal care varied between 22% (95% CI 5% to 38%) and 61% (95% CI 44% to 78%). Despite adjustment for individual and organisational characteristics, active antenatal care varied significantly between maternity units (p=0.03). Rates of active antenatal care increased with gestational age with an aOR of 6.46 (95% CI 3.40 to 12.27) and 10.09 (95% CI 5.26 to 19.36) for infants born at 25 and 26 weeks' gestation compared with those born at 24 weeks. No other individual characteristic was associated with active antenatal care. CONCLUSION: Even after standardisation for gestational age, active antenatal care in France for extremely preterm births varies widely with place of birth. The dependence of life and death decisions on place of birth raises serious ethical questions. PMID- 28667192 TI - Seasonality in airborne bacterial, fungal, and (1->3)-beta-D-glucan concentrations in two indoor laboratory animal rooms. AB - AIMS: The purpose of this study was to assess the temporal changes in the concentrations of bioaerosols in a laboratory mouse room (LMR) and laboratory rabbit room (LRR), and to determine environmental factors associated with the culturable bacteria, fungi and (1->3)-beta-D-glucan concentrations. METHOD: The concentrations of culturable airborne bacteria, fungi and (1->3)-beta-D-glucan in the LMR and LRR were sampled once a month from March 2011 to February 2012. A single-stage viable cascade impactor was used to sample bacteria and fungi, while a two-stage cyclone bioaerosol sampler was used to collect airborne (1->3)-beta-D glucan. RESULTS: The culturable bacterial concentrations in the LMR showed a gradual increase during the summer. The culturable fungal concentrations showed similar seasonal patterns of change in the LMR and LRR with a noticeable increase during the summer. The (1->3)-beta-D-glucan concentrations were highest during the warmer spring and summer months. Relative humidity (RH) was the environmental factor most associated with the concentrations of culturable bacteria and fungi. The overall airborne microbe concentrations were significantly higher in the LRR than in the LMR. CONCLUSIONS: Airborne microbe concentrations in the LMR and LRR varied greatly depending on season, and these changes were affected by environmental factors. PMID- 28667193 TI - PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry. AB - AIMS: Routine application of PD-L1 immunohistochemistry (IHC) in colorectal cancer (CRC) is limited due to lack of standardized scoring criteria, antibody clones, and intratumoral staining heterogeneity. We assessed PD-L1 protein expression on full face CRC tissue sections and applied two algorithms based on the published clinical trials that support the recent FDA approval for immune checkpoint inhibitors (ICPI) therapy in non-small cell lung cancer (NSCLC). METHODS: PD-L1/CD274 IHC (Roche/Ventana, clone SP142) was performed on representative tumour blocks from 52 mismatch repair-deficient (MMR-D) and 52 MMR proficient (MMR-P) CRCs. Membranous PD-L1 expression was scored for the tumour cell (TC) and tumour-infiltrating immune cell (IC) components. PD-L1 positivity status was determined based on the published NSCLC clinical trials that utilized the Ventana SP142 assay. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on a separate set of 2268 clinically advanced CRCs and the frequency of PD-L1/PD-L2 amplification was determined. RESULTS: PD-L1 expression in the TC and IC correlated with MMR-D (p=0.013, p<0.0001), T stage (p=0.036, p=0.0036) and clinical stage (p=0.022, p=0.0037). PD-L1 positivity status correlated with MMR-D by two algorithms. Five of 2268 (<1%) advansced CRCs demonstrated amplification of either the PD-L1 or PD-L2 genes by CGP. CONCLUSIONS: PD-L1 expression in TC and IC is associated with advanced stage and MMR-D. PD-L1 positivity status by the published algorithm is associated with MMR D. PD-L1 amplification is extremely uncommon in CRC. Evaluation of whole tissue section and incorporation of IC staining enhance the sensitivity to screen patients who may benefit from ICPI therapy. PMID- 28667194 TI - The role of environmental factors for the onset of restricted mobility outside the home among older adults with osteoarthritis: a prospective cohort study. AB - OBJECTIVES: The study examines how environmental factors contribute to the onset of restricted mobility outside the home among older adults with osteoarthritis. METHODS: This is a prospective cohort study of adults aged 50 years and older with osteoarthritis (n=1802). Logistic regression tested the association between the onset of restricted mobility outside the home and health, sociodemographic and perceived environmental barriers (hills and steep slopes, inaccessible public buildings, poor pavement condition, lack of access to public parks or sport facilities, heavy traffic or speeding cars and poor weather). The potential moderating role of environmental barriers on the association between health factors and onset was examined using interaction terms and stratified analysis. RESULTS: Of 1802 participants, 13.5% (n=243) reported the onset of restricted mobility outside the home at 3-year follow-up. Walking disability, anxiety, depression, cognitive impairment and obesity and all environmental barriers were associated with onset after adjustment for confounders. Environmental barriers had an added contribution to the effect of the health conditions on onset of restricted mobility, which was attenuated when adjusted for confounders. The added contribution remained only for walking disability and the presence of hills and steep slopes; in the presence of both, the association with onset of restricted mobility was stronger (OR 7.66, 95% CI 4.64 to 12.64) than in the presence of walking disability (3.60, 2.43 to 5.32) or the presence of hills and steep slopes alone (4.55, 2.89 to 7.16). CONCLUSION: For older adults with osteoarthritis, environmental barriers are associated and add a contribution to that of morbidities and walking disability on the onset of restricted mobility outside the home. Awareness of environmental barriers is important when aiming to maintain mobility and activities outside the home despite health conditions in older adults. PMID- 28667195 TI - Homeless people's access to primary care physiotherapy services: an exploratory, mixed-method investigation using a follow-up qualitative extension to core quantitative research. AB - OBJECTIVES: The purpose of this study was to appraise referrals of homeless patients to physiotherapy services and explore perceptions of barriers to access. DESIGN: This exploratory mixed-method study used a follow-up qualitative extension to core quantitative research design. Over 9 months, quantitative data were gathered from the healthcare records of homeless patients referred to physiotherapy by a general practitioner (GP) practice, including the number of referrals and demographic data of all homeless patients referred. Corresponding physiotherapy records of those people referred to physiotherapy were searched for the outcome of their care. Qualitative semi-structured telephone interviews, based on the quantitative findings, were carried out with staff involved with patient care from the referring GP practice and were used to expand insight into the quantitative findings. SETTING: Two primary care sites provided data for this study: a GP practice dedicated exclusively to homeless people and the physiotherapy department receiving their referrals. PARTICIPANTS: Quantitative data from the healthcare records of 34 homeless patient referrals to physiotherapy were collected and analysed. In addition, five staff involved in patient care were interviewed. RESULTS: 34 referrals of homeless people were made to physiotherapy in a 9-month period. It was possible to match 25 of these to records from the physiotherapy department. Nine (36%) patients did not attend their first appointment; seven (28%) attended an initial appointment, but did not attend a subsequent appointment and were discharged from the service; five (20%) completed treatment and four patients (16%) had ongoing treatment. Semi structured interviews revealed potential barriers preventing homeless people from accessing physiotherapy services, the complex factors being faced by those making referrals and possible ways to improve physiotherapy access. CONCLUSIONS: Homeless people with musculoskeletal problems may fail to access physiotherapy treatment, but opportunities exist to make access to physiotherapy easier. PMID- 28667196 TI - Patient safety during procedural sedation using capnography monitoring: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effect of capnography monitoring on sedation-related adverse events during procedural sedation and analgesia (PSA) administered for ambulatory surgery relative to visual assessment and pulse oximetry alone. DESIGN AND SETTING: Systematic literature review and random effects meta-analysis of randomised controlled trials (RCTs) reporting sedation-related adverse event incidence when adding capnography to visual assessment and pulse oximetry in patients undergoing PSA during ambulatory surgery in the hospital setting. Searches for eligible studies published between 1 January 1995 and 31 December 2016 (inclusive) were conducted in PubMed, the Cochrane Library and EMBASE without any language constraints. Searches were conducted in January 2017, screening and data extraction were conducted by two independent reviewers, and study quality was assessed using a modified Jadad scale. INTERVENTIONS: Capnography monitoring relative to visual assessment and pulse oximetry alone. PRIMARY AND SECONDARY OUTCOME MEASURES: Predefined endpoints of interest were desaturation/hypoxaemia (the primary endpoint), apnoea, aspiration, bradycardia, hypotension, premature procedure termination, respiratory failure, use of assisted/bag-mask ventilation and death during PSA. RESULTS: The literature search identified 1006 unique articles, of which 13 were ultimately included in the meta-analysis. Addition of capnography to visual assessment and pulse oximetry was associated with a significant reduction in mild (risk ratio (RR) 0.77, 95% CI 0.67 to 0.89) and severe (RR 0.59, 95% CI 0.43 to 0.81) desaturation, as well as in the use of assisted ventilation (OR 0.47, 95% CI 0.23 to 0.95). No significant differences in other endpoints were identified. CONCLUSIONS: Meta-analysis of 13 RCTs published between 2006 and 2016 showed a reduction in respiratory compromise (from respiratory insufficiency to failure) during PSA with the inclusion of capnography monitoring. In particular, use of capnography was associated with less mild and severe oxygen desaturation, which may have helped to avoid the need for assisted ventilation. PMID- 28667197 TI - Developing patient education to enhance recovery after colorectal surgery through action research: a qualitative study. AB - OBJECTIVES: To understand the role of preoperative education for patients undergoing colorectal surgery by involving patients, carers and staff in: (1) identifying its perceived value and deficits for enhanced recovery; (2) modifying current education practices to address educational deficits; and (3) evaluating these changes for preparing patients to enhance their recovery. DESIGN: Qualitative study of three cycles of action research using mixed methods within a 24-month naturalistic enquiry to identify, implement and evaluate changes through observations, questionnaires, semistructured longitudinal interviews, focus groups and documentation review. SETTING: A UK 1200-bed National Health Service (NHS) hospital providing colorectal surgery in a small city in a rural county. PARTICIPANTS: Ninety-sevenpatients having colorectal surgery, 19 carers and 22 clinical staff. RESULTS: Themes identified were: (1) knowledge and engagement; (2) situated understanding and confidence building; and (3) partnership and proactive involvement in enhancing recovery. All patients articulated needs to prepare mentally and physically to plan for colorectal surgery and rehabilitation. Patients and carers wanted to counter uncertainty about medical procedures: likely bodily changes, recovery timescales and future. They therefore sought as much personalised, relevant information as possible about their disease, planned surgery and recovery. Staff implemented preoperative education to more specifically inform and respond multimodally to individual needs. CONCLUSIONS: Patients wanted to be proactively involved in managing their recovery to re-engage with their everyday lives. Preoperative education supported this through developing patients' situated understanding of hospital and bodily processes related to colorectal surgery. Situated understanding was achieved through educational product to give knowledge and processes promoting engagement. Multimodal, comprehensive and timely preoperative education on the whole patient pathway facilitates active engagement. Situated understanding increased patients' confidence to work in partnership with healthcare professionals and proactively self-manage recovery. PMID- 28667200 TI - Quality of life, treatment satisfaction and efficacy of non-biological systemic therapies in patients with plaque psoriasis: study protocol for a prospective observational study. AB - INTRODUCTION: Psoriasis vulgaris often leads to a significant impaired quality of life and dissatisfaction with the existing therapeutic approaches. However, patients' quality of life and treatment satisfaction are of utmost importance, since it is positively related to therapy adherence and encourages patient's compliance. The study described herein evaluates the quality of life, treatment satisfaction and efficacy during the initial 6 months of treatment with a non biological systemic agent in a real-life clinical setting. METHODS AND ANALYSIS: This observational study compares quality of life, treatment satisfaction and the efficacy of non-biological systemic therapy between 60 patients suffering from plaque psoriasis receiving the non-biological systemic therapies with apremilast, methotrexate and fumaric acid esters. ETHICS AND DISSEMINATION: Ethics approval was provided by the ethics committee of the medical faculty of the University of Heidelberg. Ethics approval number is S-298/2015. The design and the final results of the study will be published and made available to the public. TRIAL REGISTRATION NUMBER: German Clinical Trial Register (DRKS): DRKS00008721 (https://www.germanctr.de/). PMID- 28667198 TI - Consequences of maternal morbidity on health-related functioning: a systematic scoping review. AB - OBJECTIVES: To assess the scope of the published literature on the consequences of maternal morbidity on health-related functioning at the global level and identify key substantive findings as well as research and methodological gaps. METHODS: We searched for articles published between 2005 and 2014 using Medline, Embase, Popline, CINAHL Plus and three regional bibliographic databases in January 2015. DESIGN: Systematic scoping review PRIMARY OUTCOME: Health-related functioning RESULTS: After screening 17 706 studies, 136 articles were identified for inclusion. While a substantial number of papers have documented mostly negative effects of morbidity on health-related functioning and well-being, the body of evidence is not spread evenly across conditions, domains or geographical regions. Over 60% of the studies focus on indirect conditions such as depression, diabetes and incontinence. Health-related functioning is often assessed by instruments designed for the general population including the 36-item Short Form or disease-specific tools. The functioning domains most frequently documented are physical and mental; studies that examined physical, mental, social, economic and specifically focused on marital, maternal and sexual functioning are rare. Only 16 studies were conducted in Africa. CONCLUSIONS: Many assessments have not been comprehensive and have paid little attention to important functioning domains for pregnant and postpartum women. The development of a comprehensive instrument specific to maternal health would greatly advance our understanding of burden of ill health associated with maternal morbidity and help set priorities. The lack of attention to consequences on functioning associated with the main direct obstetric complications is of particular concern. REVIEW REGISTRATION: CRD42015017774. PMID- 28667199 TI - Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study. AB - OBJECTIVES: Predicting mortality in middle-aged HIV-infected (HIV+) women on antiretroviral therapies (ART) is important for understanding the impact of HIV infection. Several health indices have been used to predict mortality in women with HIV infection. We evaluated: (1) an HIV biological index, Veterans Aging Cohort Study (VACS); (2) a physical index, Fried Frailty Index (FFI); and (3) a mental health index, Center for Epidemiologic Studies-Depression (CES-D). Proportional hazards regression analyses were used to predict death and included relevant covariates. DESIGN: Prospective, observational cohort. SETTING: Multicentre, across six sites in the USA. PARTICIPANTS: 1385 multirace/ethnic ART experienced HIV+ women in 2005. PRIMARY AND SECONDARY OUTCOMES: All deaths, AIDS deaths and non-AIDS deaths up to ~8 years from baseline. RESULTS: Included together in one model, VACS Index was the dominant, significant independent predictor of all deaths within 3 years (HR=2.20, 95% CI 1.83, 2.65, chi2=69.04, p<0.0001), and later than 3 years (HR=1.55, 95% CI 1.30, 1.84, chi2=23.88, p<0.0001); followed by FFI within 3 years (HR=2.06, 95% CI 1.19, 3.57, chi2=6.73, p=0.01) and later than 3 years (HR=2.43, 95% CI 1.58, 3.75, chi2=16.18, p=0.0001). CES-D score was not independently associated with mortality. CONCLUSIONS AND RELEVANCE: This is the first simultaneous evaluation of three common health indices in HIV+ adults. Indices reflecting physical and biological ageing were associated with death. PMID- 28667201 TI - Study protocol for a randomised controlled trial of cognitive processing therapy for post-traumatic stress disorder among Japanese patients: the Safety, Power, Intimacy, Esteem, Trust (SPINET) study. AB - INTRODUCTION: Cognitive processing therapy (CPT) is widely regarded as a safe and effective first-line treatment for individuals with post-traumatic stress disorder (PTSD); however, no comparative studies have been conducted to examine the treatment outcomes in an Asian population. The aim of the present trial is to investigate the efficacy of CPT (individual format) as a treatment for PTSD in a population of Japanese patients. METHODS AND ANALYSIS: A 16-week, single-centre, assessor-masked, randomised, parallel-group superiority trial has been designed to compare the efficacy of CPT in conjunction with treatment as usual (mostly pharmacotherapy and clinical monitoring) versus treatment as usual alone. The Clinician-Administered PTSD Scale for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) will be our primary outcome measure of the post-traumatic stress symptoms at 17 weeks, whereas the PTSD Checklist for DSM-5 and determination of the operationally defined responder status will be used to assess the secondary outcomes. An estimated sample size of 29 participants in each group will be required to detect an expected effect size of 1.4 (95% CI 0.85 to 1.95). ETHICS AND DISSEMINATION: The institutional review board at the National Center of Neurology and Psychiatry in Japan approved this study. The results of this clinical trial will be presented at conferences and disseminated through publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000021670 (registered on 1 April 2016). PMID- 28667202 TI - Pragmatic, consensus-based minimum standards and structured interview to guide the selection and development of cancer support group leaders: a protocol paper. AB - INTRODUCTION: Across the globe, peer support groups have emerged as a community led approach to accessing support and connecting with others with cancer experiences. Little is known about qualities required to lead a peer support group or how to determine suitability for the role. Organisations providing assistance to cancer support groups and their leaders are currently operating independently, without a standard national framework or published guidelines. This protocol describes the methods that will be used to generate pragmatic consensus-based minimum standards and an accessible structured interview with user manual to guide the selection and development of cancer support group leaders. METHODS AND ANALYSIS: We will: (A) identify and collate peer-reviewed literature that describes qualities of support group leaders through a systematic review; (B) content analyse eligible documents for information relevant to requisite knowledge, skills and attributes of group leaders generally and specifically to cancer support groups; (C) use an online reactive Delphi method with an interdisciplinary panel of experts to produce a clear, suitable, relevant and appropriate structured interview comprising a set of agreed questions with behaviourally anchored rating scales; (D) produce a user manual to facilitate standard delivery of the structured interview; (E) pilot the structured interview to improve clinical utility; and (F) field test the structured interview to develop a rational scoring model and provide a summary of existing group leader qualities. ETHICS AND DISSEMINATION: The study is approved by the Department Human Ethics Advisory Group of The University of Melbourne. The study is based on voluntary participation and informed written consent, with participants able to withdraw at any time. The results will be disseminated at research conferences and peer review journals. Presentations and free access to the developed structured interview and user manual will be available to cancer agencies. PMID- 28667203 TI - Epidemiology and risk factors of coronary artery aneurysm in Taiwan: a population based case control study. AB - OBJECTIVES: Coronary artery aneurysm (CAA) is usually an asymptomatic and rare disease. There are limited epidemiological data for CAA in Asian populations and in the rest of the world. DESIGN: A retrospective case control study. SETTING: A population based, database study from Taiwan's National Health Insurance Research Database, between 2005 and 2011. PARTICIPANTS: CAA patients identified using International Classification of Diseases, ninth revision, clinical modification (ICD-9-CM) code 414.11 with CAA examinations. OUTCOME MEASURES: The incidence rate and mortality rate of CAA were calculated. We also matched patients with non CAA patients according to age, gender and index year at a 1:10 ratio to explore the risk factors for CAA using conditional logistic regression. RESULT: A total of 1397 CAA patients were identified between 2005 and 2011; 41.9% were paediatric patients and 58.1% were adults. The incidence rate and mortality rate of CAA in Taiwan were 0.87 and 0.05 per 105 person-years, respectively. The adjusted odds ratios (aOR) for coronary atherosclerosis, hypertension, dyslipidaemia and diabetes were 7.97, 2.09, 2.48 and 1.51, respectively. Of note, aortic dissection (aOR 6.76), aortic aneurysm (aOR 5.82) and systemic lupus erythematosus (aOR 4.09) were found to be significantly associated with CAA. CONCLUSION: In Taiwan, CAA patients were distributed across both paediatric and adult populations. Apart from cardiovascular risk factors, aortic diseases and systemic lupus erythematosus need to be investigated further in CAA patients. PMID- 28667204 TI - Effect of corticosteroid administration on neurologically deceased organ donors and transplant recipients: a systematic review and meta-analysis. AB - OBJECTIVES: This review investigates the impact of corticosteroids on donation rates and transplant outcomes in light of findings from randomised controlled trials (RCTs) and to highlight the sources of uncertainty in this unresolved donor management issue. DATA SOURCES: We searched electronic databases, trial registries and conference proceedings for RCTs evaluating corticosteroid therapy in neurologically deceased donors. STUDY SELECTION AND DATA EXTRACTION: Independent reviewers assessed eligibility, evaluated risk of bias and abstracted data, including donor haemodynamic data, number of organs recovered and transplant outcomes. Where possible, we pooled results. For each outcome, we assessed the overall quality of evidence using The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. DATA SYNTHESIS: Eleven RCTs with different corticosteroid regimens were included. Most trials assessed a once-daily infusion of methylprednisolone. Aside from one study showing improved liver graft function, no individual study or pooled analysis showed benefit of corticosteroids for any outcome: vasopressor use (three trials; relative risk (RR) 0.96; 95% CI 0.89 to 1.05), multiple organs recovered (two trials; RR 0.82; 95% CI 0.61 to 1.11), acute graft rejection (three trials; RR 0.91; 95% CI 0.60 to 1.39) or graft dysfunction (eight trials; RR 1.01; 95% CI 0.83 to 1.24). Two trials investigated adverse effects and found similar rates between groups. Quality of evidence was moderate or low for all outcomes. CONCLUSION: Current clinical trials are limited in numbers and size to identify benefits or harms of corticosteroid therapy for deceased organ donors. In the face of these results, administering or withholding steroids both appear reasonable courses of action. PMID- 28667205 TI - Prospective observational study in two Dutch hospitals to assess the performance of inflammatory plasma markers to determine disease severity of viral respiratory tract infections in children. AB - INTRODUCTION: Respiratory viruses causing lower respiratory tract infections (LRTIs) are a major cause of hospital admissions in children. Since the course of these infections is unpredictable with potential fast deterioration into respiratory failure, infants are easily admitted to the hospital for observation. The aim of this study was to examine whether systemic inflammatory markers can be used to predict severity of disease in children with respiratory viral infections. METHODS: Blood and nasopharyngeal washings from children <3 years of age with viral LRTI attending a hospital were collected within 24 hours (acute) and after 4-6 weeks (recovery). Patients were assigned to a mild (observation only), moderate (supplemental oxygen and/or nasogastric feeding) or severe (mechanical ventilation) group. Linear regression analysis was used to design a prediction rule using plasma levels of C reactive protein (CRP), serum amyloid A (SAA), pentraxin 3 (PTX3), serum amyloid P component and properdin. This rule was tested in a validation cohort. RESULTS: One hundred and four children (52% male) were included. A combination of CRP, SAA, PTX3 and properdin was a better indicator of severe disease compared with any of the individual makers and age (69% sensitivity (95% CI 50 to 83), 90% specificity (95% CI 80 to 96)). Validation in 141 patients resulted in 71% sensitivity (95% CI 53 to 85), 87% specificity (95% CI 79 to 92), negative predictive value of 64% (95% CI 47 to 78) and positive predictive value of 90% (95% CI 82 to 95). The prediction rule was not able to identify patients with a mild course of disease. CONCLUSION: A combination of CRP, SAA, PTX3 and properdin was able to identify children with a severe course of viral LRTI disease, even in children under 2 months of age. To assess the true impact on clinical management, these results should be validated in a prospective randomised control study. PMID- 28667206 TI - A comparison of effectiveness between oral rapid testing and routine serum-based testing for HIV in an outpatient dental clinic in Yuxi Prefecture, China: a case control study. AB - OBJECTIVE: To compare the outcomes of routine provider-initiated HIV testing and counselling (PITC) and oral rapid HIV testing for dental clinic outpatients in a hospital. DESIGN: We employed a case-control study design and recruited dental outpatients into routine serum-based and oral rapid testing groups. We compared the acceptance, completion and result notification rate between groups. SETTING: A dental outpatient clinic in the Yuxi People's Hospital, Yunnan. PARTICIPANTS: A total of 758 and 816 dental outpatients were enrolled for routine and oral rapid testing, respectively. RESULTS: The percentage of participants willing to receive routine HIV testing was 28.1% (95% CI 24.9% to 31.3%) and 96.1% (95% CI 94.8% to 97.4%, chi2=186.4, p<0.001) for the rapid testing. Among accepted participants, the percentage of participants who received HIV testing was 26.8% (95% CI 20.9% to 32.7%) in the routine testing group and 100.0% in the oral rapid HIV testing group (chi2=77.5, p<0.001). About 93.0% of routine testers returned for the test results on the next day, whereas all rapid testers received their test results on the same day (chi2=34.6, p<0.001). These correspond to an overall completion rate of 7.0% (95% CI 5.2% to 8.8%) and 96.1% (95% CI 94.8% to 97.4%, p<0.001), respectively. Among the 545 patients who declined routine serum-based HIV testing, the main reasons included, an unnecessary hassle (254/545, 46.6%), having been previously tested (124/545, 22.8%) and self-perceived low risk of HIV infection (103/545, 18.9%). In contrast, only 32 individuals declined oral rapid testing, and having received a previous test was the primary reason. Three patients in the rapid testing group were later confirmed HIV-positive, yielding an HIV prevalence of 0.38%. CONCLUSION: Oral rapid HIV testing is a feasible and efficient approach in a clinical setting. PMID- 28667207 TI - A cluster-randomised, controlled proof-of-concept study to explore the feasibility and effect of a patient-directed intervention on quality of life in patients with advanced soft tissue sarcoma. AB - INTRODUCTION: Even with evolving and expanding therapeutical options for the treatment of advanced sarcomas over recent years, the balance between efficacy and toxicity still remains a major concern. Moreover, the symptom burden in patients with sarcoma remains high compared with other malignant diseases. It is, therefore, crucial to assess treatment effectiveness not only in terms of disease related outcomes (eg, overall survival) but also from an individual and patient centred perspective using the assessment of patient-reported outcomes (PROs). By focusing on PROs as a primary study endpoint, we aim to address key issues for patients with advanced soft tissue sarcoma (STS) undergoing palliative treatment. METHODS AND ANALYSIS: The protocol of the YonLife study describes a multicentre, cluster-randomised, controlled, open-label proof-of-concept study conducted in patients with advanced or metastatic STS treated with trabectedin in seven German hospitals. The primary objective of the study is to exploratively compare overall quality of life between the patients receiving a multidimensional intervention based on individual PROs and those receiving usual supportive treatment. This complex intervention consists of the (1) electronic assessment of PRO, (2) creation of a case vignette based on PRO and clinical data and (3) treatment suggestions based on the discussion of these vignettes in a regularly meeting expert panel. Additionally, the YonLife trial assesses the applicability of a tablet-based assessment of PROs. Patients' and physicians' acceptance and challenges concerning the implementation process will be evaluated. ETHICS AND DISSEMINATION: The YonLife trial has been approved by the Ethics Committee of the University Hospital Dresden as well as by the relevant institutions of each participating centre before patient enrolment. The findings will be reported via relevant peer-reviewed journals as well as through presentation at international conferences. TRIAL REGISTRATION NUMBER: NCT02204111, pre-results. PMID- 28667208 TI - Assessment of the effect of an Interactive Dynamic Referral Interface (IDRI) on the quality of referral letters from general practitioners to gastroenterologists: a randomised cross-over vignette trial. AB - OBJECTIVES: We evaluated whether interactive, electronic, dynamic, diagnose specific checklists improve the quality of referral letters in gastroenterology and assessed the general practitioners' (GPs') acceptance of the checklists. DESIGN: Randomised cross-over vignette trial. SETTING: Primary care in Norway. PARTICIPANTS: 25 GPs. INTERVENTION: The GPs participated in the trial and were asked to refer eight clinical vignettes in an internet-based electronic health record simulator. A referral support, consisting of dynamic diagnose-specific checklists, was created for the generation of referral letters to gastroenterologists. The GPs were randomised to refer the eight vignettes with or without the checklists. After a minimum of 3 months, they repeated the referral process with the alternative method. MAIN OUTCOME MEASURES: Difference in quality of the referral letters between referrals with and without checklists, measured with an objective Thirty Point Score (TPS).Difference in variance in the quality of the referral letters and GPs' acceptance of the electronic dynamic user interface. RESULTS: The mean TPS was 15.2 (95% CI 13.2 to 16.3) and 22.0 (95% CI 20.6 to 22.8) comparing referrals without and with checklist assistance (p<0.001), respectively. The coefficient of variance was 23.3% for the checklist group and 39.6% for the non-checklist group. Two-thirds (16/24) of the GPs thought they had included more relevant information in the referrals with checklists, and considered implementing this type of checklists in their clinical practices, if available. CONCLUSIONS: Dynamic, diagnose-specific checklists improved the quality of referral letters significantly and reduced the variance of the TPS, indicating a more uniform quality when checklists were used. The GPs were generally positive to the checklists. PMID- 28667209 TI - Factors associated with online victimisation among Malaysian adolescents who use social networking sites: a cross-sectional study. AB - OBJECTIVE: To determine the prevalence of online interpersonal victimisation and its association with patterns of social networking site (SNS) use, offline victimisation, offline perpetration and parental conflict among Malaysian adolescents using SNS. METHODS: A cross-sectional study of students from randomly selected public secondary schools in the state of Negeri Sembilan was conducted using an anonymous self-administered questionnaire. The questionnaire examined patterns of SNS use and included measures of online victimisation, online perpetration, offline victimisation and parental conflict. A response rate of 91% from a total of 1634 yielded a sample of 1487 students between 15 years and 16 years of age. RESULTS: Ninety-two per cent of respondents had used at least one SNS. More than half of SNS users (52.2%) reported experiences of online victimisation over the past 12 months. Boys were significantly more likely to experience online harassment compared with girls (52.2% vs 43.3%, p<0.001). There were no significant gender differences in experiences of unwanted sexual solicitation. Adolescents who engaged in perpetration behaviours online had almost six times higher odds of reporting frequent online victimisation compared with online behaviours involving personal disclosure. There was a significant dose-response relationship between engagement in multiple types of online behaviour and the risk of frequent online victimisation. Both online and offline perpetrations were associated with an increased risk of victimisation. Those who were victimised offline or experienced parental conflict were twice as likely to report online victimisation. CONCLUSION: Interventions to prevent online electronic aggression should target perpetration behaviour both online and offline. Youth should be equipped with skills in communication and decision making in relationships that can be applied across a spectrum of contexts both online and offline. PMID- 28667210 TI - Is the current level of training in the use of equipment for prehospital radio communication sufficient? A cross-sectional study among prehospital physicians in Denmark. AB - BACKGROUND: Physicians working in prehospital care are expected to handle radio communication both within their own sector as well as with other divisions of the National Emergency Services. To date, no study has been conducted on the level of training received by physicians in the use of the equipment provided or on the level of competency acquired by physicians. METHODS: In order to investigate the self-assessed skill level acquired in the use of the TETRA (TErrestrial Trunked RAdio) authority radio for communication in a prehospital setting, a cross sectional study was conducted by questionnaire circulated to all 454 physicians working in the Danish Emergency Medical Services. RESULTS: A lack of training was found among physicians working in prehospital care in Denmark in relation to the proper use of essential communication equipment. Prior to starting their first shift in a prehospital setting 38% of physicians reported having received no training in the use of the equipment, while 80% of physicians reported having received one1 hour of training or less. Among the majority of physicians their current level of training was sufficient for their everyday needs for prehospital communication but for 28% of physicians their current level of training was insufficient as they were unable to handle communication at this level. CONCLUSION: As the first study in its field, this study investigated the training received in the use of essential communication equipment among physicians working in prehospital care in Denmark. The study found that competency does not appear to have been prioritised as highly as other technical skills needed to function in these settings. For the majority of physicians their current level of training was sufficient for everyday use but for a substantial minority further training is required, especially if the redundancy of the prehospital system is to be preserved. PMID- 28667212 TI - Seroprevalence of hepatitis B virus infection in Cameroon: a systematic review and meta-analysis. AB - OBJECTIVE: Better knowledge of hepatitis B virus (HBV) infection prevalence at the national level can help to implement pertinent strategies to address HBV related burden. The aim was to estimate the seroprevalence of HBV infection in Cameroon. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: People residing in Cameroon. DATA SOURCES: Electronic databases including PubMed/MEDLINE, African Journals Online (AJOL), ScienceDirect, WHO-Afro Library, WHO-IRIS, African Index Medicus, National Institute of Statistics and National AIDS Control Committee, Cameroon; regardless of language and from 1 January 2000 to 30 September 2016. This was completed with a manual search of references of relevant papers. Risk of bias in methodology of studies was measured using the Newcastle-Ottawa Scale. RESULTS: Out of 511 retrieved papers, 44 studies with a total of 105 603 individuals were finally included. The overall pooled seroprevalence was 11.2% (95% CI 9.7% to 12.8%) with high heterogeneity between studies (I2=97.9%). Egger's test showed no publication bias (p=0.167). A sensitivity analysis excluding individuals at high risk of HBV infection and after adjustment using trim and fill method showed a pooled seroprevalence of 10.6% (95% CI 8.6% to 12.6%) among 100 501 individuals (general population, blood donors and pregnant women). Sources of heterogeneity included geographical regions across country and setting (rural 13.3% vs urban 9.0%), and implementation of HBV universal immunisation (born after 9.2% vs born before 0.7%). Sex, site, timing of data collection, HBV screening tools and methodological quality of studies were not sources of heterogeneity. LIMITATION: Only a third of the studies had low risk of bias in their methodology. CONCLUSION: The seroprevalence of HBV infection in Cameroon is high. Effective strategies to interrupt the transmission of HBV are urgently required. Specific attention is needed for rural settings, certain regions and people born before the implementation of the HBV universal immunisation programme in Cameroon in 2005. REGISTRATION: PROSPERO, CRD42016042654. PMID- 28667211 TI - Criteria for Return to Sport after Anterior Cruciate Ligament reconstruction with lower reinjury risk (CR'STAL study): protocol for a prospective observational study in France. AB - INTRODUCTION: The decision regarding when to return to sport after an anterior cruciate ligament reconstruction (ACLR) is an important one. Using a variety of subjective and objective parameters, various attempts have been made to determine an optimal timeline for a return to sport after ACLR, but none have been validated.The aim of the present study is therefore to determine which criteria or combination of criteria could allow to return to sport with the lowest possible risk of reinjury. METHODS AND ANALYSIS: This study is a prospective cohort, single-centre study, with repeated assessments at 6, 9 and 12 months post ACL surgical reconstruction and including a 3-year follow-up of patients' sporting activity and reinjuries. 275 patients will be included to test explanatory variables. Postural control analysis, knee laxity, questionnaires (International Knee Documentation Committee (IKDC), Tampa Scale of Kinesiophobia 11 (TSK-11), Anterior Cruciate Ligament-Return to Sport After Reinjury (ACL-RSI) and Single Assessment Numeric Evaluation (SANE)), modified Star Excursion Balance Test, running and sprinting biomechanics, Hop Tests and Isokinetic Tests will all be used. The primary outcome will be any reinjury during the follow-up period, defined as a graft rupture, a contralateral ACL rupture or any injury necessitating an interruption of training and requiring a medical consultation. Two groups will be constituted during the follow-up, separating reinjured from non-reinjured patients. In addition, classic analysis and data mining approaches will be used to build predictive models. ETHICS AND DISSEMINATION: The results of this study will be disseminated through peer-reviewed publications and scientific presentations. Ethical approval was obtained through the ethics committee of the University Hospital of Saint-Etienne (reference number IRBN522015/CHUSTE). PMID- 28667213 TI - Extrapulmonary effects of continuous airway pressure on patients with obstructive sleep apnoea: protocol for an overview of systematic reviews. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is associated with both pulmonary and extrapulmonary consequences. Continuous positive airway pressure (CPAP) is an effective treatment for pulmonary symptoms. However, it is not clear if CPAP modifies extrapulmonary symptoms, especially in the long term. To date, several studies addressing this issue have been performed, but the evidence is scattered across different reviews that address each outcome separately. Therefore, we will conduct an overview to assess and summarise all systematic reviews on the extrapulmonary effects of this intervention in patients with OSA. METHODS: This is a protocol for a systematic overview of reviews that will follow the guidelines from the Cochrane Handbook of Systematic Reviews of Interventions and PRISMA-P. We will conduct comprehensive literature searches using MEDLINE, EMBASE, Cochrane, CINAHL, DARE and Epistemonikos. We will consider systematic reviews and meta-analyses of randomised controlled trials evaluating the extrapulmonary effects of CPAP on OSA. Two reviewers will independently screen articles for inclusion using criteria that are determined a priori, assessing the quality of included reviews and extracting relevant information. We will create matrices of evidence in the Epistemonikos database, including all systematic reviews addressing a similar question and all studies addressing the question in those reviews. We will try to explain why studies are not included in individual reviews using the inclusion criteria, and we will estimate the overlap between different reviews in the same matrix of evidence. ETHICS AND DISSEMINATION: This review will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42014013036. PMID- 28667214 TI - Efficacy of non-invasive ventilation and oxygen therapy on immunocompromised patients with acute hypoxaemic respiratory failure: protocol for a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: The number of immunocompromised patients has increased in recent years. Acute respiratory failure is a common complication leading to intensive care unit (ICU) admission and high mortality among such patients. The use of non invasive ventilation (NIV) or oxygen therapy among these patients remains controversial, according to the inconsistent results of several randomised clinical trials (RCTs). This meta-analysis aims to evaluate whether NIV or oxygen therapy is the more appropriate initial oxygenation strategy for the immunocompromised patients with acute respiratory failure. METHOD: We will search all the RCTs that compared the efficacy of NIV and oxygen therapy on immunocompromised adult patients with acute hypoxaemic respiratory failure on the major databases (Cochrane Library, MEDLINE, EMBASE, Web of Science and others), conference proceedings and grey literature. Eligible RCTs will be included in accordance with the pre-specified eligibility criteria. The risk of bias will be assessed using the Cochrane Collaboration criteria and the quality of evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation system. Data will be extracted with a standardised form and analysed using RevMan V.5.3 analyses software. Heterogeneity will be assessed using I2 statistic and the source of which will be investigated. Publication bias will be identified with the funnel plot. ETHICS AND DISSEMINATION: Ethical approval is not required since it is not carried out in humans. The systematic review will be published in peer-reviewed journals and disseminated extensively through conferences. PMID- 28667215 TI - Association of prehypertension and cardiovascular risk factor clustering in Inner Mongolia: a cross-sectional study. AB - OBJECTIVES: To assess the clustering of cardiovascular disease (CVD) risk factors in Han and Mongolian adults with prehypertension or hypertension in Northern China. METHODS: We selected 3227 Han and Mongolian participants (20-80 years old) using a multistage cluster sampling method in 2014. The participants were interviewed by standard questionnaires and underwent anthropometric measurement and biochemical testing. Han and Mongolian participants were divided into optimal, prehypertension, and hypertension groups based on blood pressure. A multinomial logit analysis was performed to explore relationships between CVD risk factor clustering and prehypertension or hypertension, and the heterogeneity between Han and Mongolian was evaluated by the Cochran Q test. The differences between the ethnic groups in the proportions of risk factors was tested with the chi2 test. RESULTS: The clustering of two or three CVD risk factors in the prehypertension or hypertension groups was consistently higher than in the optimal group (Bonferroni, p<0.0167). The odds ratios (ORs) of prehypertension and hypertension increased with the number of CVD risk factors (ptrend <0.0001). In multivariate modelling, the adjusted ORs of one, two, and >=3 CVD risk factors versus no risk factors was, respectively, 1.95, 2.25, and 2.28 in Han prehypertensive participants, and 1.73, 2.83, and 3.69 in Mongolian prehypertensive participants. In addition, the adjusted ORs were 3.15, 4.75, and 6.49 in Han hypertensive participants, and 1.90, 5.29, and 8.13 in Mongolian hypertensive participants (all p<0.05). There was no significant heterogeneity between Han and Mongolian participants in the prehypertension or hypertension groups. The age-standardised prevalence of >=3 risk factors was 38.30% in Han men and 39.79% in Mongolian men. The rate was significantly lower in Han women than Mongolian women (9.18% vs 14.55%, p=0.002). CONCLUSIONS: These findings showed clustering of CVD risk factors in prehypertensive Han and Mongolian adults, and showed prehypertension may be a useful target for intervention. PMID- 28667216 TI - The epidemiological profile of hysterectomy in rural Chinese women: a population based study. AB - OBJECTIVES: Hysterectomy is one of the most common surgical procedures performed on women in developed countries; however, little is known about the epidemiology of hysterectomy in low-income to middle-income regions. This study seeks to evaluate the prevalence of hysterectomy and its risk factors in rural China. METHODS: Questionnaires were collected from 3328 female adults aged 25a?"69 years in rural Anyang, China, in 2009a?"2011. Hysterectomy status was ascertained by the gynaecologist at the time of cytological test. Univariate and multivariate regression analyses were performed to assess the risk factors for hysterectomy. RESULTS: The overall prevalence of hysterectomy was 3.31% (110/3328). Women above the age of 40 years had a higher prevalence of prior hysterectomy, compared with those aged 25a?"39 years (5.01% vs 0.33%). Obesity was marginally related with a higher risk of hysterectomy (adjusted OR=1.59; 95%a?0/00CI 0.99 to 2.56; body mass index (BMI) a0/00Y28.0 vs 18.5 a0/00 BMI <24.0). History of prior pregnancy loss conferred a greater risk for hysterectomy (adjusted OR=1.51; 95%a?0/00CI 1.02 to 2.23). Of the 75 (68.18%, 75/110) cases who provided further information on hysterectomy, 84.00% (63/75) had undergone total abdominal hysterectomy and 70.67% (53/75) had received surgery for leiomyoma. CONCLUSIONS: Rural Chinese women had a relatively low prevalence of hysterectomy, and the majority of reported hysterectomies were performed abdominally for leiomyoma. Hysterectomy prevalence differed significantly by age, BMI and history of pregnancy loss. This study expands the current understanding of the epidemiology of hysterectomy in lower resource areas. PMID- 28667217 TI - What techniques might be used to harness placebo effects in non-malignant pain? A literature review and survey to develop a taxonomy. AB - OBJECTIVES: Placebo effects can be clinically meaningful but are seldom fully exploited in clinical practice. This review aimed to facilitate translational research by producing a taxonomy of techniques that could augment placebo analgesia in clinical practice. DESIGN: Literature review and survey. METHODS: We systematically analysed methods which could plausibly be used to elicit placebo effects in 169 clinical and laboratory-based studies involving non-malignant pain, drawn from seven systematic reviews. In a validation exercise, we surveyed 33 leading placebo researchers (mean 12 yearsa?TM research experience, SD 9.8), who were asked to comment on and add to the draft taxonomy derived from the literature. RESULTS: The final taxonomy defines 30 procedures that may contribute to placebo effects in clinical and experimental research, proposes 60 possible clinical applications and classifies procedures into five domains: the patienta?TMs characteristics and belief (5 procedures and 11 clinical applications), the practitionera?TMs characteristics and beliefs (2 procedures and 4 clinical applications), the healthcare setting (8 procedures and 13 clinical applications), treatment characteristics (8 procedures and 14 clinical applications) and the patienta?"practitioner interaction (7 procedures and 18 clinical applications). CONCLUSION: The taxonomy provides a preliminary and novel tool with potential to guide translational research aiming to harness placebo effects for patient benefit in practice. PMID- 28667218 TI - Impact of participant attrition on child injury outcome estimates: a longitudinal birth cohort study in Australia. AB - BACKGROUND: Longitudinal research is subject to participant attrition. Systemic differences between retained participants and those lost to attrition potentially bias prevalence of outcomes, as well as exposure-outcome associations. This study examines the impact of attrition on the prevalence of child injury outcomes and the association between sociodemographic factors and child injury. METHODS: Participants were recruited as part of the Environments for Healthy Living (EFHL) birth cohort study. Baseline data were drawn from maternal surveys. Child injury outcome data were extracted from hospital records, 2006-2013. Participant attrition status was assessed up to 2014. Rates of injury-related episodes of care were calculated, taking into account exposure time and Poisson regression was performed to estimate exposure-outcome associations. RESULTS: Of the 2222 participating families, 799 families (36.0%) had complete follow-up data. Those with incomplete data included 137 (6.2%) who withdrew, 308 (13.8%) were lost to follow-up and 978 families (44.0%) who were partial/non-responders. Families of lower socioeconomic status were less likely to have complete follow-up data (p<0.05). Systematic differences in attrition did not result in differential child injury outcomes or significant differences between the attrition and non attrition groups in risk factor effect estimates. Participants who withdrew were the only group to demonstrate differences in child injury outcomes. CONCLUSION: This research suggests that even with considerable attrition, if the proportion of participants who withdraw is minimal, overall attrition is unlikely to affect the population prevalence estimate of child injury or measures of association between sociodemographic factors and child injury. PMID- 28667219 TI - Associations between maternal size and health outcomes for women undergoing caesarean section: a multicentre prospective observational study (The MUM SIZE Study). AB - OBJECTIVES: To investigate associations between maternal body mass index (BMI) at delivery (using pregnancy-specific BMI cut-off values 5 kg/m2 higher in each of the WHO groups) and clinical, theatre utilisation and health economic outcomes for women undergoing caesarean section (CS). DESIGN: A prospective multicentre observational study. SETTING: Seven secondary or tertiary referral obstetric hospitals. PARTICIPANTS: One thousand and four hundred and fifty-seven women undergoing all categories of CS. DATA COLLECTION: Height and weight were recorded at the initial antenatal visit and at delivery. We analysed the associations between delivery BMI (continuous and pregnancy-specific cut-off values) and total theatre time, surgical time, anaesthesia time, maternal and neonatal adverse outcomes, total hospital admission and theatre costs. RESULTS: Mean participant characteristics were: age 32 years, gestation at delivery 38.4 weeks and delivery BMI 32.2 kg/m2. Fifty-five per cent of participants were overweight, obese or super-obese using delivery pregnancy-specific BMI cut-off values. As BMI increased, total theatre time, surgical time and anaesthesia time increased. Super-obese participants had approximately 27% (17 min, p<0.001) longer total theatre time, 20% (9 min, p<0.001), longer surgical time and 40% (11 min, p<0.001) longer anaesthesia time when compared with normal BMI participants. Increased BMI at delivery was associated with increased risk of maternal intensive care unit admission (relative risk 1.07, p=0.045), but no increased risk of neonatal admission to higher acuity care. Total hospital admission costs were 15% higher in super-obese women compared with normal BMI women and theatre costs were 27% higher in super-obese women. CONCLUSIONS: Increased maternal BMI was associated with increased total theatre time, surgical and anaesthesia time, increased total hospital admission costs and theatre costs. Clinicians and health administrators should consider these clinical risks, time implications and financial costs when managing pregnant women. PMID- 28667220 TI - A prospective study on the variation in falling and fall risk among community dwelling older citizens in 12 European countries. AB - OBJECTIVES: The rate of falling among older citizens appears to vary across different countries, but the underlying aspects causing this variation are unexplained. We aim to describe between-country variation in falling and explore whether intrinsic fall risk factors can explain possible variation. DESIGN: Prospective study on data from the cross-national Survey of Health, Ageing and Retirement in Europe (SHARE). SETTING: Twelve European countries (Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland). PARTICIPANTS: Community-dwelling persons aged >=65 years (n=18 596). MEASUREMENTS: Socio-demographic factors (age, gender, education level and living situation) and intrinsic fall risk factors (less than good self-rated health (SRH), mobility limitations, limitations with activities of daily living (ADL), dizziness, impaired vision, depression and impaired cognition) were assessed in a baseline interview. Falling was assessed 2 years later by asking whether the participant had fallen within the 6 months prior to the follow-up interview. RESULTS: There was significant between-country variation in the rate of falling (varying from 7.9% in Switzerland to 16.2% in the Czech Republic). The prevalence of intrinsic fall risk factors varied twofold to fourfold between countries. Associations between factors age >=80 years, less than good SRH, mobility limitations, ADL limitations, dizziness and depression, and falling were different between countries (p<0.05). Between-country differences in falling largely persisted after adjusting for socio-demographic differences but strongly attenuated after adjusting for differences in intrinsic fall risk factors. CONCLUSION: There is considerable variation in the rate of falling between European countries, which can largely be explained by between country variation in the prevalence of intrinsic fall risk factors. There are also country-specific variations in the association between these intrinsic risk factors and falling. These findings emphasise the importance of addressing intrinsic fall risk in (inter)national fall-prevention strategies, while highlighting country-specific priorities. PMID- 28667221 TI - Effectiveness of behavioural change techniques in physiotherapy interventions to promote physical activity adherence in patients with hip and knee osteoarthritis: a systematic review protocol. AB - INTRODUCTION: Osteoarthritis (OA) is a common degenerative articular disease, the highest cause of individual level disability and a significant socioeconomic burden to healthcare services. Patient education and physical activity (PA) prescription are recommended components of interventions in several healthcare guidelines and are commonly provided by physiotherapists. However, these interventions lack long-term clinical effectiveness. Patient adherence to PA prescription requires patients to modify their PA behaviour and appears critical in maintaining symptomatic improvements. This systematic review aims to evaluate the effectiveness of behavioural change techniques (BCTs) used in physiotherapy interventions to improve PA adherence. METHODS AND ANALYSIS: Medline, Cochrane and PEDro registers of Controlled Trials, EMBASE, CINAHL and PsycInfo databases, and key grey literature sources will be rigorously searched for randomised controlled trials that compared a physiotherapy intervention incorporating BCTs with other therapies, placebo interventions, usual care or no-treatment. Two independent researchers will conduct literature searches, assess trial eligibility, extract data, conduct risk of bias assessment (using Cochrane risk of bias tool), classify BCTs and evaluate the quality of the body of literature following Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. Narrative synthesis of key outcomes will be presented and meta-analysis will be performed if included trials are clinically homogenous, based on their intervention and comparator groups and outcome measures. This review will be reported in line with the Preferred Reporting Items for Systematic review and Meta-Analysis guidelines. ETHICS AND DISSEMINATION: Research ethics approval is not required. This review will help inform clinicians and researchers on the most effective behavioural change techniques used in physiotherapy interventions to enhance adherence to PA prescription for patients with lower limb OA. The findings will be disseminated through publication in a peer-reviewed journal and conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016039932. PMID- 28667222 TI - Promoting Optimal Physical Exercise for Life (PROPEL): aerobic exercise and self management early after stroke to increase daily physical activity-study protocol for a stepped-wedge randomised trial. AB - INTRODUCTION: Physical exercise after stroke is essential for improving recovery and general health, and reducing future stroke risk. However, people with stroke are not sufficiently active on return to the community after rehabilitation. We developed the Promoting Optimal Physical Exercise for Life (PROPEL) programme, which combines exercise with self-management strategies within rehabilitation to promote ongoing physical activity in the community after rehabilitation. This study aims to evaluate the effect of PROPEL on long-term participation in exercise after discharge from stroke rehabilitation. We hypothesise that individuals who complete PROPEL will be more likely to meet recommended frequency, duration and intensity of exercise compared with individuals who do not complete the programme up to 6 months post discharge from stroke rehabilitation. METHODS AND ANALYSIS: Individuals undergoing outpatient stroke rehabilitation at one of six hospitals will be recruited (target n=192 total). A stepped-wedge design will be employed; that is, the PROPEL intervention (group exercise plus self-management) will be 'rolled out' to each site at a random time within the study period. Prior to roll-out of the PROPEL intervention, sites will complete the control intervention (group aerobic exercise only). Participation in physical activity for 6 months post discharge will be measured via activity and heart rate monitors, and standardised physical activity questionnaire. Adherence to exercise guidelines will be evaluated by (1) number of 'active minutes' per week (from the activity monitor), (2) amount of time per week when heart rate is within a target range (ie, 55%-80% of age-predicted maximum) and (3) amount of time per week completing 'moderate' or 'strenuous' physical activities (from the questionnaire). We will compare the proportion of active and inactive individuals at 6 months post intervention using mixed-model logistic regression, with fixed effects of time and phase and random effect of cluster (site). ETHICS AND DISSEMINATION: To date, research ethics approval has been received from five of the six sites, with conditional approval granted by the sixth site. Results will be disseminated directly to study participants at the end of the trial, and to other stake holders via publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02951338; Pre-results. PMID- 28667223 TI - Lipid-lowering drugs and risk of new-onset diabetes: a cohort study using Japanese healthcare data linked to clinical data for health screening. AB - OBJECTIVE: To investigate whether lipid-lowering drugs are associated with new onset diabetes after adjusting for baseline clinical risk factors for diabetes. DESIGN: A retrospective cohort study. SETTING: Japanese employees of large corporations and their dependents using health insurance claims data linked to clinical and laboratory data for annual health screenings. PARTICIPANTS: All persons aged 20 to 74 years with dyslipidaemia between 1 January 2005 and 31 March 2011. We defined the index date as the first date when the person met the criteria for dyslipidaemia. Persons were excluded if they had lipid-lowering drugs, or had a diagnosis, a treatment or a laboratory test result (haemoglobin A1c >=6.5% or fasting blood glucose >=126 mg/dL) indicating diabetes during the 6 month period before the index date. MAIN OUTCOME MEASURES: New-onset diabetes. RESULTS: We identified 68 620 persons with dyslipidaemia. During the mean follow up period of 1.96 years, 3674 persons started treatment with a lipid-lowering drug: 979 with a low potency statin, 2208 with a high potency statin and 487 with a fibrate. Of 3674 new users of a lipid-lowering drug, 3621 had a period of non use of any lipid-lowering drugs before starting a lipid-lowering drug. Among statin users, the incidence rate of new-onset diabetes was 124.6 per 1000 person years compared with 22.6 per 1000 person-years in non-users. After adjusting for confounding factors including clinical data in health screening using Cox proportional hazards models, the HR was 1.91 (95% CI 1.38 to 2.64) for low potency statins and 2.61 (2.11 to 3.23) for high potency statins. CONCLUSION: The use of statins was associated with a 1.9-fold to 2.6-fold increase in the risk of new-onset diabetes in a Japanese population of working age, despite adjusting for clinical risk factors for diabetes. PMID- 28667224 TI - Improving patient safety through better teamwork: how effective are different methods of simulation debriefing? Protocol for a pragmatic, prospective and randomised study. AB - INTRODUCTION: Medical errors have an incidence of 9% and may lead to worse patient outcome. Teamwork training has the capacity to significantly reduce medical errors and therefore improve patient outcome. One common framework for teamwork training is crisis resource management, adapted from aviation and usually trained in simulation settings. Debriefing after simulation is thought to be crucial to learning teamwork-related concepts and behaviours but it remains unclear how best to debrief these aspects. Furthermore, teamwork-training sessions and studies examining education effects on undergraduates are rare. The study aims to evaluate the effects of two teamwork-focused debriefings on team performance after an extensive medical student teamwork training. METHODS AND ANALYSES: A prospective experimental study has been designed to compare a well established three-phase debriefing method (gather-analyse-summarise; the GAS method) to a newly developed and more structured debriefing approach that extends the GAS method with TeamTAG (teamwork techniques analysis grid). TeamTAG is a cognitive aid listing preselected teamwork principles and descriptions of behavioural anchors that serve as observable patterns of teamwork and is supposed to help structure teamwork-focused debriefing. Both debriefing methods will be tested during an emergency room teamwork-training simulation comprising six emergency medicine cases faced by 35 final-year medical students in teams of five. Teams will be randomised into the two debriefing conditions. Team performance during simulation and the number of principles discussed during debriefing will be evaluated. Learning opportunities, helpfulness and feasibility will be rated by participants and instructors. Analyses will include descriptive, inferential and explorative statistics. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional office for data protection and the ethics committee of Charite Medical School Berlin and registered under EA2/172/16. All students will participate voluntarily and will sign an informed consent after receiving written and oral information about the study. Results will be published. PMID- 28667226 TI - A cross-sectional analysis of pharmaceutical industry-funded events for health professionals in Australia. AB - OBJECTIVES: To analyse patterns and characteristics of pharmaceutical industry sponsorship of events for Australian health professionals and to understand the implications of recent changes in transparency provisions that no longer require reporting of payments for food and beverages. DESIGN: Cross-sectional analysis. PARTICIPANTS AND SETTING: 301 publicly available company transparency reports downloaded from the website of Medicines Australia, the pharmaceutical industry trade association, covering the period from October 2011 to September 2015. RESULTS: Forty-two companies sponsored 116 845 events for health professionals, on average 608 per week with 30 attendees per event. Events typically included a broad range of health professionals: 82.0% included medical doctors, including specialists and primary care doctors, and 38.3% trainees. Oncology, surgery and endocrinology were the most frequent clinical areas of focus. Most events (64.2%) were held in a clinical setting. The median cost per event was $A263 (IQR $A153 1195) and over 90% included food and beverages. CONCLUSIONS: Over this 4-year period, industry-sponsored events were widespread and pharmaceutical companies maintained a high frequency of contact with health professionals. Most events were held in clinical settings, suggesting a pervasive commercial presence in everyday clinical practice. Food and beverages, known to be associated with changes to prescribing practice, were almost always provided. New Australian transparency provisions explicitly exclude meals from the reporting requirements; thus, a large proportion of potentially influential payments from pharmaceutical companies to health professionals will disappear from public view. PMID- 28667225 TI - Using Patient-Reported Outcome Measures (PROMs) to promote quality of care and safety in the management of patients with Advanced Chronic Kidney disease (PRO trACK project): a mixed-methods project protocol. AB - INTRODUCTION: Advanced chronic kidney disease (CKD) has a major effect on the quality of life and health status of patients and requires accurate and responsive management. The use of electronic patient-reported outcome measures (ePROMs) could assist patients with advanced pre-dialysis CKD, and the clinicians responsible for their care, by identifying important changes in symptom burden in real time. We report the protocol for 'Using Patient-Reported Outcome measures (PROMs) to promote quality of care and safety in the management of patients with Advanced Chronic Kidney Disease' (PRO-trACK) project, which will explore the feasibility and validity of an ePROM system for use in patients with advanced CKD. METHODS AND ANALYSIS: The project will use a mixed-methods approach in three studies: (1) usability testing of the ePROM system involving up to 30 patients and focusing on acceptability and technical performance/stability; (2) ascertaining the views of patient and clinician stakeholders on the optimal use and administration of the CKD ePROM system-this will involve qualitative face-to face/telephone interviewing with up to 30 patients or until saturation is achieved, focus groups with up to 15 clinical staff, management and IT team members; (3) psychometric assessment of the system, within a cohort of at least 180 patients with advanced CKD, to establish the measurement properties of the ePROM. ETHICS AND DISSEMINATION: This project was approved by the West Midlands Edgbaston Research Ethics Committee (Reference 17/WM/0010) and received Health Research Authority (HRA) approval on 24 February 2017.The findings from this project will be provided to clinicians at the Department of Renal Medicine, Queen Elizabeth Hospitals, Birmingham (QEHB), NHS England, presented at conferences and to the Kidney Patients' Association, British Kidney Patient Association and the British Renal Society. Articles based on the findings will be written and submitted for publication in peer-reviewed journals. PMID- 28667227 TI - Defining clinically important perioperative blood loss and transfusion for the Standardised Endpoints for Perioperative Medicine (StEP) collaborative: a protocol for a scoping review. AB - INTRODUCTION: 'Standardised Endpoints for Perioperative Medicine' (StEP) is an international collaboration undertaking development of consensus-based consistent definitions for endpoints in perioperative clinical trials. Inconsistency in endpoint definitions can make interpretation of trial results more difficult, especially if conflicting evidence is present. Furthermore, this inconsistency impedes evidence synthesis and meta-analyses. The goals of StEP are to harmonise definitions for clinically meaningful endpoints and specify standards for endpoint reporting in clinical trials. To help inform this endeavour, we aim to conduct a scoping review to systematically characterise the definitions of clinically important endpoints in the existing published literature on perioperative blood loss and transfusion. METHODS AND ANALYSIS: The scoping review will be conducted using the widely adopted framework developed by Arksey and O'Malley, with modifications from Levac. We refined our methods with guidance from research librarians as well as researchers and clinicians with content expertise. The electronic literature search will involve several databases including Medline, PubMed-not-Medline and Embase. Our review has three objectives, namely to (1) identify definitions of significant blood loss and transfusion used in previously published large perioperative randomised trials; (2) identify previously developed consensus-based definitions for significant blood loss and transfusion in perioperative medicine and related fields; and (3) describe the association between different magnitudes of blood loss and transfusion with postoperative outcomes. The multistage review process for each question will involve two reviewers screening abstracts, reading full-text articles and performing data extraction. The abstracted data will be organised and subsequently analysed in an iterative process. ETHICS AND DISSEMINATION: This scoping review of the previously published literature does not require research ethics approval. The results will be used to inform a consensus-based process to develop definitions of clinically important perioperative blood loss and transfusion. The results of the scoping review will be published in a peer reviewed scientific journal. PMID- 28667228 TI - PATHway I: design and rationale for the investigation of the feasibility, clinical effectiveness and cost-effectiveness of a technology-enabled cardiac rehabilitation platform. AB - INTRODUCTION: Exercise-based cardiac rehabilitation (CR) independently alters the clinical course of cardiovascular diseases resulting in a significant reduction in all-cause and cardiac mortality. However, only 15%-30% of all eligible patients participate in a phase 2 ambulatory programme. The uptake rate of community-based programmes following phase 2 CR and adherence to long-term exercise is extremely poor. Newer care models, involving telerehabilitation programmes that are delivered remotely, show considerable promise for increasing adherence. In this view, the PATHway (Physical Activity Towards Health) platform was developed and now needs to be evaluated in terms of its feasibility and clinical efficacy. METHODS AND ANALYSIS: In a multicentre randomised controlled pilot trial, 120 participants (m/f, age 40-80 years) completing a phase 2 ambulatory CR programme will be randomised on a 1:1 basis to PATHway or usual care. PATHway involves a comprehensive, internet-enabled, sensor-based home CR platform and provides individualised heart rate monitored exercise programmes (exerclasses and exergames) as the basis on which to provide a personalised lifestyle intervention programme. The control group will receive usual care. Study outcomes will be assessed at baseline, 3 months and 6 months after completion of phase 2 of the CR programme. The primary outcome is the change in active energy expenditure. Secondary outcomes include cardiopulmonary endurance capacity, muscle strength, body composition, cardiovascular risk factors, peripheral endothelial vascular function, patient satisfaction, health-related quality of life (HRQoL), well-being, mediators of behaviour change and safety. HRQoL and healthcare costs will be taken into account in cost-effectiveness evaluation. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the Declaration of Helsinki. This protocol has been approved by the director and clinical director of the PATHway study and by the ethical committee of each participating site. Results will be disseminated via peer-reviewed scientific journals and presentations at congresses and events. TRIAL REGISTRATION NUMBER: NCT02717806. This trial is currently in the pre-results stage. PMID- 28667229 TI - Corticosteroids in sepsis: an updated systematic review and meta-analysis (protocol). AB - INTRODUCTION: Sepsis is associated with a dysregulated host response to infection and impaired endogenous corticosteroid metabolism. As such, therapeutic use of exogenous corticosteroids is a promising adjunctive intervention. Despite a large number of trials examining this research question, uncertainty persists regarding the effect of corticosteroids on survival in sepsis. Several large randomised controlled trials have been published recently prompting a re-evaluation of the available literature. METHODS AND ANALYSIS: A rigorous and reproducible search and screening process from a Cochrane review on the same topic was comprehensive to October 2014. We will search MEDLINE, EMBASE, LILACS, the Cochrane trial registry and clinicaltrials.gov for eligible randomised controlled trials investigating the use of corticosteroids in patients with sepsis from September 2014. Outcomes have been chosen by a semi-independent guideline panel, created in the context of a parallel BMJ Rapid Recommendation on the topic. This panel includes clinicians, content experts, methodologists and patient representatives, who will help identify patient-important outcomes that are critical for deciding whether to use or not use corticosteroids in sepsis. Two reviewers will independently screen and identify eligible studies; a third reviewer will resolve any disagreements. We will use RevMan to pool effect estimates from included studies for each outcome using a random-effect model. We will present the results as relative risk with 95% CI for dichotomous outcomes and as mean difference or standardised mean difference for continuous outcomes with 95% CI. We will assess the certainty of evidence at the outcome level using the Grading of Recommendations, Assessment, Development and Evaluation approach. We will conduct a priori subgroup analyses, which have been chosen by the parallel BMJ Rapid Recommendation panel. ETHICS AND DISSEMINATION: The aim of this systematic review is to summarise the updated evidence on the efficacy and safety of corticosteroids in patients with sepsis. TRIAL REGISTRATION NUMBER: CRD42017058537. PMID- 28667232 TI - Disorders of Growth and Stature. PMID- 28667231 TI - Educational video to improve CPAP use in patients with obstructive sleep apnoea at risk for poor adherence: a randomised controlled trial. AB - BACKGROUND: Suboptimal adherence to CPAP limits its clinical effectiveness in patients with obstructive sleep apnoea (OSA). Although rigorous behavioural interventions improve CPAP adherence, their labour-intensive nature has limited widespread implementation. Moreover, these interventions have not been tested in patients at risk of poor CPAP adherence. Our objective was to determine whether an educational video will improve CPAP adherence in patients at risk of poor CPAP adherence. METHODS: Patients referred by clinicians without sleep medicine expertise to an urban sleep laboratory that serves predominantly minority population were randomised to view an educational video about OSA and CPAP therapy before the polysomnogram, or to usual care. The primary outcome was CPAP adherence during the first 30 days of therapy. Secondary outcomes were show rates to sleep clinic (attended appointment) and 30-day CPAP adherence after the sleep clinic visit date. RESULTS: A total of 212 patients met the eligibility criteria and were randomised to video education (n=99) or to usual care (n=113). There were no differences in CPAP adherence at 30 days (3.3, 95% CI 2.8 to 3.8 hours/day video education; vs 3.5, 95% CI 3.1 to 4.0 hours/day usual care; p=0.44) or during the 30 days after sleep clinic visit. Sleep clinic show rate was 54% in the video education group and 59% in the usual care group (p=0.41). CPAP adherence, however, significantly worsened in patients who did not show up to the sleep clinic. CONCLUSIONS: In patients at risk for poor CPAP adherence, an educational video did not improve CPAP adherence or show rates to sleep clinic compared with usual care. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02553694. PMID- 28667233 TI - Self-management and Transition to Adult Health Care in Adolescents and Young Adults: A Team Process. AB - As health care continues to evolve, the need for more effective health care transition (HCT) for all youth, but particularly children with chronic conditions and special health care needs, becomes even more important. With more than 90% of adolescents with chronic medical conditions now surviving into adulthood, suboptimal transition can lead to poorer quality of life and less successful adulthood.Through a series of clinical vignettes, the challenges of HCT are presented herein and accompanied by comments that underscore how these adolescents can best be helped to transition to successful adulthood. Several methods are presented to assess the readiness of adolescents and young adults (AYA) for transition. The process of transition can be divided into 3 stages: 1) setting the stage: initiation of HCT services and transition readiness assessment, 2) moving forward: ongoing provision of HCT services, and 3) reaching the goal: transfer of care and transition to adulthood.Several valuable suggestions for incorporating the HCT process into the health care system and improving HCT programs through a quality improvement (QI) approach are outlined. Future challenges in HCT include developing more precise assessments of transition status or transition readiness, better understanding the status and specific needs of AYA with chronic health care needs, continued program evaluation and QI efforts, and more reliance on patients and families to teach us about the challenges and methods in HCT that most effectively work for them. PMID- 28667230 TI - Efficacy evaluation of an anti-caries varnish: protocol for a phase II randomised controlled trial. AB - INTRODUCTION: Dental caries (tooth decay) is a common disease in which the products of sugar metabolism by certain bacteria that populate the tooth surface induce the development and progression of lesions (cavities). This is a phase II single-centre randomised, double-blind, active-controlled, parallel-group trial to assess the efficacy of a combination povidone iodine and sodium fluoride dental varnish to determine if it is superior to a varnish containing only sodium fluoride in the prevention of new caries lesions. The objective of this report is to describe the rationale and protocol for the trial. METHODS AND ANALYSIS: The study site is Pohnpei State, Federated States of Micronesia. The study population is 284 children 48-84 months old. The primary outcome will be the surface-level primary molar caries increment (d2-3mfs/DMFS) at 2 years post baseline. The incremental dental caries at 1 year will also be compared between the two interventions. The secondary outcome is the Facial Image Scale after the initial treatment and after the fifth treatment at 1 year that gauges the child's response to the treatment. ETHICS AND DISSEMINATION: The Western Institutional Review Board (designated IRB) and the Institutional Review Board of the College of Micronesia-FSM approved all study procedures. The US Food and Drug Administration (FDA) has issued IND 128835 covering this study. The study results will be published and submitted to the FDA in support of a new drug application. TRIALREGISTRATION NUMBER: NCT03082196. PMID- 28667234 TI - Allocation of Health Care Resources: Principles for Decision-making. PMID- 28667235 TI - Case 1: Persistent Tachypnea in an Infant. PMID- 28667236 TI - Case 2: Acute Onset of Vomiting, Abdominal Pain, and Constipation in an 18-month old Girl. PMID- 28667237 TI - Case 3: Chronic Muscle Pain in a 15-year-old Girl. PMID- 28667238 TI - Case 4: Hydrocephalus, Macrothrombocytopenia, Inclusion Bodies, and Nephropathy in a 9-year-old Boy. PMID- 28667239 TI - Case 5: Autoantibodies and an Elevated Creatinine in a 14-year-old Girl. PMID- 28667240 TI - Case 6: Acute-onset Respiratory Failure in a 4-month-old Girl. PMID- 28667241 TI - Mosquito-borne Infections. PMID- 28667242 TI - Visual Diagnosis: 7-week-old Girl with a Neck Mass. PMID- 28667243 TI - Biomineralization-related specialization of hemocytes and mantle tissues of the Pacific oyster Crassostrea gigas. AB - The molluscan exoskeleton (shell) plays multiple important roles including structural support, protection from predators and stressors, and physiological homeostasis. Shell formation is a tightly regulated biological process that allows molluscs to build their shells even in environments unfavorable for mineral precipitation. Outer mantle edge epithelial cells (OME) and hemocytes were implicated in this process; however, the exact functions of these cell types in biomineralization are not clear. Pacific oysters (Crassostrea gigas) were used to study differences in the expression profiles of selected biomineralization related genes in hemocytes and mantle cells, and the functional characteristics of hemocytes such as adhesion, motility and phagocytosis. The specialized role of OME in shell formation was supported by high expression levels of the extracellular matrix (ECM) related and cell-cell interaction genes. Density gradient separation of hemocytes revealed distinct phenotypes based on the cell morphology, gene expression patterns, motility and adhesion characteristics. These hemocyte fractions can be categorized into two functional groups, i.e. biomineralization and immune response cells. Gene expression profiles of the putative biomineralizing hemocytes indicate that in addition to their proposed role in mineral transport, hemocytes also contribute to the formation of the ECM, thus challenging the current paradigm of the mantle as the sole source of the ECM for shell formation. Our findings corroborate the specialized roles of hemocytes and the OME in biomineralization and emphasize complexity of the biological controls over shell formation in bivalves. PMID- 28667244 TI - Circularly polarized light detection in stomatopod crustaceans: a comparison of photoreceptors and possible function in six species. AB - A combination of behavioural and electrophysiological experiments have previously shown that two species of stomatopod, Odontodactylus scyllarus and Gonodactylaceus falcatus, can differentiate between left- and right-handed circularly polarized light (CPL), and between CPL and linearly polarized light (LPL). It remains unknown if these visual abilities are common across all stomatopod species, and if so, how circular polarization sensitivity may vary between and within species. A subsection of the midband, a specialized region of stomatopod eyes, contains distally placed photoreceptor cells, termed R8 (retinular cell number 8). These cells are specifically built with unidirectional microvilli and appear to be angled precisely to convert CPL into LPL. They are mostly quarter-wave retarders for human visible light (400-700 nm), as well as being ultraviolet-sensitive linear polarization detectors. The effectiveness of the R8 cells in this role is determined by their geometric and optical properties. In particular, the length and birefringence of the R8 cells are crucial for retardation efficiency. Here, our comparative studies show that most species investigated have the theoretical ability to convert CPL into LPL, such that the handedness of an incoming circular reflection or signal could be discriminated. One species, Haptosquilla trispinosa, shows less than quarter-wave retardance. Whilst some species are known to produce circularly polarized reflections (some Odontodactylus species and G. falcatus, for example), others do not, so a variety of functions for this ability are worth considering. PMID- 28667247 TI - Astragalus and Baicalein Regulate Inflammation of Mesenchymal Stem Cells (MSCs) by the Mitogen-Activated Protein Kinase (MAPK)/ERK Pathway. AB - BACKGROUND Mesenchymal stem cells (MSCs) have emerged as an attractive alternative to modulating immune response after transplantation. Recent studies have shown that systemically administered MSCs enter the inflamed intestine. In the present study, we propose a strategy to improve the efficacy of MSC-based cellular therapy for inflammation using Astragaloside and Baicalein to enhance cell survival, inhibit apoptosis, and modulate inflammatory response in vitro. MATERIAL AND METHODS MSCs were induced with lipopolysaccharide (LPS) as an inflammatory model before being treated for 48 h with Astragaloside, Baicalein, and the combination of both. MSCs proliferation was determined using the MTT method. The cell cycle situation was monitored using flow cytometry, and the apoptosis ability of MSCs was detected with Annexin-V flow cytometry. The levels of cytokine IL-1beta, IL-8, and TNF-alpha, and their relations with the ERK pathway were measured using ELISA, RT-PCR, and Western blot. RESULTS Compared to the control groups (containing no drug), each drug-treated group showed the ability to promote epithelial differentiation and cell growth and to inhibit apoptosis. The combination group had reduced levels of IL-1beta, IL-8, and TNF alpha in LPS-induced MSCs, much more than in the other 2 groups. Compared with the other groups, the combination of Astragaloside and Baicalin more efficiently reduced IL-1beta, IL-8, and TNF-alpha levels in the LPS-induced MSCs model, and ERK inhibitor was capable of recovering the inflammatory effect. CONCLUSIONS The results demonstrated that Astragaloside and Baicalin can promote epithelial differentiation and proliferation, inhibit apoptosis, and reduce inflammatory effects. PMID- 28667248 TI - Suppression of alphavbeta6 Integrin Expression by Polymicrobial Oral Biofilms in Gingival Epithelial Cells. AB - Periodontal diseases manifest by the formation of deep pockets between the gingiva and teeth where multispecies bacterial biofilms flourish, causing inflammation and bone loss. Epithelial cell receptor alphavbeta6 integrin that regulates inflammation by activating the anti-inflammatory cytokine transforming growth factor-beta1, is highly expressed in healthy junctional epithelium that connects the gingiva to the tooth enamel. However, its expression is attenuated in human periodontal disease. Moreover, Itgb6 -/- mice display increased periodontal inflammation compared to wild-type mice. We hypothesized that bacterial biofilms present in the periodontal pockets suppress alphavbeta6 integrin levels in periodontal disease and that this change aggravates inflammation. To this end, we generated three-week-old multi-species oral biofilms in vitro and treated cultured gingival epithelial cells (GECs) with their extracts. The biofilm extracts caused suppression of beta6 integrin expression and upregulation of pro-inflammatory cytokines, including interleukin 1beta and -6. Furthermore, GECs with beta6 integrin siRNA knockdown showed increased interleukin-1beta expression, indicating that alphavbeta6 integrin deficiency is associated with pro-inflammatory cytokine responsiveness. FSL-1, a synthetic bacterial lipopeptide, also suppressed beta6 integrin expression in GECs. Therefore, biofilm components, including lipopeptides, may downregulate alphavbeta6 integrin expression in the pocket epithelium and thus promote epithelial cell-driven pro-inflammatory response in periodontal disease. PMID- 28667249 TI - Conformational Heterogeneity of the HIV Envelope Glycan Shield. AB - To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp41 envelope (Env) trimer, and how the glycan shield impacts the accessibility of the underlying protein surface, we performed enhanced sampling molecular dynamics (MD) simulations of a model glycosylated HIV Env protein and related systems. Our simulation studies revealed a conformationally heterogeneous glycan shield with a network of glycan-glycan interactions more extensive than those observed to date. We found that partial preorganization of the glycans potentially favors binding by established broadly neutralizing antibodies; omission of several specific glycans could increase the accessibility of other glycans or regions of the protein surface to antibody or CD4 receptor binding; the number of glycans that can potentially interact with known antibodies is larger than that observed in experimental studies; and specific glycan conformations can maximize or minimize interactions with individual antibodies. More broadly, the enhanced sampling MD simulations described here provide a valuable tool to guide the engineering of specific Env glycoforms for HIV vaccine design. PMID- 28667251 TI - Boundary migration in a 3D deformed microstructure inside an opaque sample. AB - How boundaries surrounding recrystallization grains migrate through the 3D network of dislocation boundaries in deformed crystalline materials is unknown and critical for the resulting recrystallized crystalline materials. Using X-ray Laue diffraction microscopy, we show for the first time the migration pattern of a typical recrystallization boundary through a well-characterized deformation matrix. The data provide a unique possibility to investigate effects of both boundary misorientation and plane normal on the migration, information which cannot be accessed with any other techniques. The results show that neither of these two parameters can explain the observed migration behavior. Instead we suggest that the subdivision of the deformed microstructure ahead of the boundary plays the dominant role. The present experimental observations challenge the assumptions of existing recrystallization theories, and set the stage for determination of mobilities of recrystallization boundaries. PMID- 28667250 TI - Heart Failure and MEF2 Transcriptome Dynamics in Response to beta-Blockers. AB - Myocyte Enhancer Factor 2 (MEF2) mediates cardiac remodelling in heart failure (HF) and is also a target of beta-adrenergic signalling, a front-line treatment for HF. We identified global gene transcription networks involved in HF with and without beta-blocker treatment. Experimental HF by transverse aortic constriction (TAC) in a MEF2 "sensor" mouse model (6 weeks) was followed by four weeks of beta blockade with Atenolol (AT) or Solvent (Sol) treatment. Transcriptome analysis (RNA-seq) from left ventricular RNA samples and MEF2A depleted cardiomyocytes was performed. AT treatment resulted in an overall improvement in cardiac function of TAC mice and repression of MEF2 activity. RNA-seq identified 65 differentially expressed genes (DEGs) due to TAC treatment with enriched GO clusters including the inflammatory system, cell migration and apoptosis. These genes were mapped against DEGs in cardiomyocytes in which MEF2A expression was suppressed. Of the 65 TAC mediated DEGs, AT reversed the expression of 28 mRNAs. Rarres2 was identified as a novel MEF2 target gene that is upregulated with TAC in vivo and isoproterenol treatment in vitro which may have implications in cardiomyocyte apoptosis and hypertrophy. These studies identify a cohort of genes with vast potential for disease diagnosis and therapeutic intervention in heart failure. PMID- 28667252 TI - Nanoscale rheology at solid-complex fluid interfaces. AB - Here we present an approach to measure dynamic membrane properties of phospholipid membranes close to an interface. As an example we show results of the membrane dynamics of a phospholipid membrane multilayer-stack on a solid substrate (silicon). On this sample we were able to measure local interaction and friction parameters using Grazing Incidence Neutron Spin Echo Spectroscopy (GINSES), where an evanescent neutron wave probes the fluctuations close to a rigid interface. With this method it is possible to access length scales in the nano to micrometer region as well as energies in the MUeV range. Using a new neutron resonator structure we achieved the required intensity gain for this experiment. During our investigations we found an excitation mode of the phospholipid membrane that has not been reported previously and only became visible using the new methodology. We speculate that the energy transported by that undulation can also serve to distribute energy over a larger area of the membrane, stabilizing it. This new methodology has the capability to probe the viscoelastic effects of biological membranes, becoming a new tool for tribology on the nanoscale and has allowed the observation of the hitherto invisible property of phospholipid membranes using neutrons. PMID- 28667253 TI - Inhibitors Alter the Stochasticity of Regulatory Proteins to Force Cells to Switch to the Other State in the Bistable System. AB - The cellular behaviors under the control of genetic circuits are subject to stochastic fluctuations, or noise. The stochasticity in gene regulation, far from a nuisance, has been gradually appreciated for its unusual function in cellular activities. In this work, with Chemical Master Equation (CME), we discovered that the addition of inhibitors altered the stochasticity of regulatory proteins. For a bistable system of a mutually inhibitory network, such a change of noise led to the migration of cells in the bimodal distribution. We proposed that the consumption of regulatory protein caused by the addition of inhibitor is not the only reason for pushing cells to the specific state; the change of the intracellular stochasticity is also the main cause for the redistribution. For the level of the inhibitor capable of driving 99% of cells, if there is no consumption of regulatory protein, 88% of cells were guided to the specific state. It implied that cells were pushed, by the inhibitor, to the specific state due to the change of stochasticity. PMID- 28667254 TI - Quantity of alcohol drinking positively correlates with serum levels of endotoxin and markers of monocyte activation. AB - It is unknown if LPS (lipopolysaccharides) and markers of immune activation, soluble CD14 (sCD14) and CD163 (sCD163) are associated with the quantity of alcohol consumption. 148 subjects were enrolled (97 excessive drinkers (ED) and 51 controls). Time Line Follow-Back questionnaire was used to quantify the amount of alcohol consumed. Serum LPS, sCD14, and sCD163 were measured. Peripheral blood mononuclear cells (PBMCs) were also isolated. Compared to controls, ED had higher total drinks in the past 30 days, higher levels of LPS, sCD14 and sCD163. The levels of serum LPS, sCD14, and sCD163 were higher among ED with recent alcohol consumption (last drink <10 days before enrollment) compared to those without recent drinking. Similar bacterial genome copy numbers were detected in control and ED groups. We found that ethanol primed PBMCs for LPS-induced inflammatory responses. A positive correlation between serum LPS, sCD14, sCD163 and the quantity of alcohol drinking was observed after adjusting for covariates and that abstinence was associated with decline in the levels of LPS, sCD14 and sCd163. We found an increase in the levels of LPS and markers of monocyte activations in ED. Further studies are needed to determine whether these can be used as the biomarkers for excessive alcohol use. PMID- 28667256 TI - Clues on the origin of post-2000 earthquakes at Campi Flegrei caldera (Italy). AB - The inter-arrival times of the post 2000 seismicity at Campi Flegrei caldera are statistically distributed into different populations. The low inter-arrival times population represents swarm events, while the high inter-arrival times population marks background seismicity. Here, we show that the background seismicity is increasing at the same rate of (1) the ground uplift and (2) the concentration of the fumarolic gas specie more sensitive to temperature. The seismic temporal increase is strongly correlated with the results of recent simulations, modelling injection of magmatic fluids in the Campi Flegrei hydrothermal system. These concurrent variations point to a unique process of temperature-pressure increase of the hydrothermal system controlling geophysical and geochemical signals at the caldera. Our results thus show that the occurrence of background seismicity is an excellent parameter to monitor the current unrest of the caldera. PMID- 28667255 TI - Circulating Biomarkers to Identify Responders in Cardiac Cell therapy. AB - Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76-94% elevated) than non-responders. Several biomarkers had values that differed significantly (P < 0.05) between responders and non responders including stem cell factor, platelet-derived growth factor, and interleukin-15. We then used these lead candidates for ROC analysis and found multiple biomarkers with values areas under the curve >0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers. PMID- 28667257 TI - Long distance biotic dispersal of tropical seagrass seeds by marine mega herbivores. AB - Terrestrial plants use an array of animals as vectors for dispersal, however little is known of biotic dispersal of marine angiosperms such as seagrasses. Our study in the Great Barrier Reef confirms for the first time that dugongs (Dugong dugon) and green sea turtles (Chelonia mydas) assist seagrass dispersal. We demonstrate that these marine mega-herbivores consume and pass in faecal matter viable seeds for at least three seagrass species (Zostera muelleri, Halodule uninervis and Halophila decipiens). One to two seagrass seeds per g DW of faecal matter were found during the peak of the seagrass reproductive season (September to December), with viability on excretion of 9.13% +/- 4.61% (SE). Using population estimates for these mega-herbivores, and data on digestion time (hrs), average daily movement (km h) and numbers of viable seagrass seeds excreted (per g DW), we calculated potential seagrass seed dispersal distances. Dugongs and green sea turtle populations within this region can disperse >500,000 viable seagrass seeds daily, with a maximum dispersal distance of approximately 650 km. Biotic dispersal of tropical seagrass seeds by dugongs and green sea turtles provides a large-scale mechanism that enhances connectivity among seagrass meadows, and aids in resilience and recovery of these coastal habitats. PMID- 28667258 TI - C60 as fine fillers to improve poly(phenylene sulfide) electrical conductivity and mechanical property. AB - Electrical conductive poly(phenylene sulfide) (PPS)/fullerene (C60) composites were prepared by 1-chlornaphthalene blending method, and the interface effects of C60 and PPS on PPS/C60 properties were characterized. C60 is an excellent nanofiller for PPS, and 2 wt% PPS/C60 composite displayed the optimal conductivity which achieved 1.67 * 10-2 S/cm. However, when C60 concentration reached 2 wt%, the breaking strength and tensile modulus of PPS/C60 fiber achieved maximum 290 MPa and 605 MPa, and those values were 7.72 and 11.2 times as that of pure PPS. The excellent conductive and mechanical properties of PPS/C60 were attributed to the heterogeneous nucleation of C60 during PPS crystallization, formation of a large number of covalent bond by main C60-thiol adducts and minor C60-ArCl alkylation between C60 outer surface and PPS matrix. At same time, PPS/C60 thermal properties were also investigated. PMID- 28667259 TI - First-principles study of superconducting hydrogen sulfide at pressure up to 500 GPa. AB - We investigate the possibility of achieving the room-temperature superconductivity in hydrogen sulfide (H3S) through increasing external pressure, a path previously widely used to reach metallization and superconducting state in novel hydrogen-rich materials. The electronic properties and superconductivity of H3S in the pressure range of 250-500 GPa are determined by the first-principles calculations. The metallic character of a body-centered cubic Im[Formula: see text]m structure is found over the whole studied pressure. Moreover, the absence of imaginary frequency in phonon spectrum implies that this structure is dynamically stable. Furthermore, our calculations conducted within the framework of the Eliashberg formalism indicate that H3S in the range of the extremely high pressures is a conventional strong-coupling superconductor with a high superconducting critical temperature, however, the maximum critical temperature does not exceed the value of 203 K. PMID- 28667260 TI - User adaptation in Myoelectric Man-Machine Interfaces. AB - State of the art clinical hand prostheses are controlled in a simple and limited way that allows the activation of one function at a time. More advanced laboratory approaches, based on machine learning, offer a significant increase in functionality, but their clinical impact is limited, mainly due to lack of reliability. In this study, we analyse two conceptually different machine learning approaches, focusing on their robustness and performance in a closed loop application. A classification (finite number of classes) and a regression (continuous mapping) based projection of EMG into external commands were applied while artificially introducing non-stationarities in the EMG signals. When tested on ten able-bodied individuals and one transradial amputee, the two methods were similarly influenced by non-stationarities when tested offline. However, in online tests, where the user could adapt his muscle activation patterns to the changed conditions, the regression-based approach was significantly less influenced by the changes in signal features than the classification approach. This observation demonstrates, on the one hand, the importance of online tests with users in the loop for assessing the performance of myocontrol approaches. On the other hand, it also demonstrates that regression allows for a better user correction of control commands than classification. PMID- 28667261 TI - Epidemiology of self-rated health in rural China: a population-based cross sectional study. AB - Self-rated health (SRH) has been shown to be a good predictor of mortality. Data on SRH and its associated factors in the Chinese general population are limited. This study aims to assess the epidemiology of SRH in rural Anyang, China. SRH (categorized as "healthy", "fair" or "unhealthy") was measured in a population based study of 2,814 adults (including 697 couples) aged 25 to 69 who were recruited from rural Anyang in 2014. Of 2,814 subjects, 63.1% rated their health as "healthy", whereas 28.1% and 8.8% rated their health as "fair" and "unhealthy". Compared to males, females had a higher likelihood of reporting a better SRH. Health ratings declined with increasing age, unmarried status, lower education levels. Poor SRH was positively correlated with medical history as well as high levels of fasting plasma glucose and total cholesterol, but not with unhealthy lifestyle indicators including smoking, drinking, and obesity. High household income was predictive of better SRH in men but not in women. Among couples, a positive spousal SRH concordance was observed, although the strength of this concordance was low. These findings will be useful for formulation of appropriate strategies for improving risk perception and promoting general health in economically developing regions. PMID- 28667262 TI - The Hippo pathway acts downstream of the Hedgehog signaling to regulate follicle stem cell maintenance in the Drosophila ovary. AB - The Hippo pathway is conserved and plays important roles in organ size control. The core components of the Hippo pathway are two kinases Hippo (Hpo), Warts (Wts), and a transcription-co-activator Yorkie (Yki). Yki activity is regulated by phosphorylation, which affects its nuclear localization and stability. To determine the role of the Hippo pathway in stem cells, we examine follicle stem cells (FSCs) in the Drosophila ovary. Yki is detected in the nucleus of FSCs. Knockdown of yki in the follicle cell lineage leads to a disruption of the follicular epithelium. Mitotic clones of FSCs mutant for hpo or wts are maintained in the niche and tend to replace the other FSCs, and FSCs mutant for yki are rapidly lost, demonstrating that the Hippo pathway is both required and sufficient for FSC maintenance. Using genetic interaction analyses, we demonstrate that the Hedgehog pathway acts upstream of the Hippo pathway in regulating FSC maintenance. The nuclear localization of Yki is enhanced when the Hedgehog signaling is activated. Furthermore, a constitutively active but not a wild-type Yki promotes FSC maintenance as activation of the Hedgehog signaling does, suggesting that the Hedgehog pathway regulates Yki through a post translational mechanism in maintaining FSCs. PMID- 28667263 TI - Effect of boron deficiency on anatomical structure and chemical composition of petioles and photosynthesis of leaves in cotton (Gossypium hirsutum L.). AB - The main symptom of boron (B) deficiency in cotton is the formation of brown rings on leaf petioles. The objective of the present study was to determine the changes in the anatomical structure and chemical composition of petioles and photosynthesis of leaves in cotton under B deficiency. Compared to the control, B deficiency treatment resulted in large increases in the number of petioles with brown rings per plant (160.0%) and the number of rings on the petiole per functional leaf (711.1%) in cotton seedlings. The relative absorbance intensity in the fingerprint region of polysaccharide structure was decreased in petiole rings under B deficiency, while lignin contents were increased. Cotton plants mitigated the impairment of transport function in cotton petioles by increasing the areas of vascular bundles, phloem, xylem, and phloem fiber. Moreover, the stomatal conductance, photosynthetic rate, and transpiration rate in leaves were significantly decreased under B deficiency, thus impeding photosynthesis in cotton plants. Therefore, B deficiency reduces transport function in petioles and photosynthesis in leaves, and leads to the formation of noticeable brown rings on petioles of cotton seedlings. PMID- 28667264 TI - Charge tunable thin-film composite membranes by gamma-ray triggered surface polymerization. AB - Thin-film composite poly(amide) (PA) membranes have greatly diversified water supplies and food products. However, users would benefit from a control of the electrostatic interactions between the liquid and the net surface charge interface in order to benefit wider application. The ionic selectivity of the 100 nm PA semi-permeable layer is significantly affected by the pH of the solution. In this work, for the first time, a convenient route is presented to configure the surface charge of PA membranes by gamma ray induced surface grafting. This rapid and up-scalable method offers a versatile route for surface grafting by adjusting the irradiation total dose and the monomer concentration. Specifically, thin coatings obtained at low irradiation doses between 1 and 10 kGy and at low monomer concentration of 1 v/v% in methanol/water (1:1) solutions, dramatically altered the net surface charge of the pristine membranes from -25 mV to +45 mV, whilst the isoelectric point of the materials shifted from pH 3 to pH 7. This modification resulted in an improved water flux by over 55%, from 45.9 to up 70 L.m-2.h-1, whilst NaCl rejection was found to drop by only 1% compared to pristine membranes. PMID- 28667265 TI - Transcriptome analysis explores genes related to shikonin biosynthesis in Lithospermeae plants and provides insights into Boraginales' evolutionary history. AB - Shikonin and its derivatives extracted from Lithospermeae plants' red roots have current applications in food and pharmaceutical industries. Previous studies have cloned some genes related to shikonin biosynthesis. However, most genes related to shikonin biosynthesis remain unclear, because the lack of the genome/transcriptome of the Lithospermeae plants. Therefore, in order to provide a new understanding of shikonin biosynthesis, we obtained transcriptome data and unigenes expression profiles in three shikonin-producing Lithospermeae plants, i.e., Lithospermum erythrorhizon, Arnebia euchroma and Echium plantagineum. As a result, two unigenes (i.e., G10H and 12OPR) that are involved in "shikonin downstream biosynthesis" and "methyl jasmonate biosynthesis" were deemed to relate to shikonin biosynthesis in this study. Furthermore, we conducted a Lamiids phylogenetic model and identified orthologous unigenes under positive selection in above three Lithospermeae plants. The results indicated Boraginales was more relative to Solanales/Gentianales than to Lamiales. PMID- 28667266 TI - Noninvasive spatiotemporal imaging of neural transmission in the subcortical visual pathway. AB - Spatiotemporal signal transmission in the human subcortical visual pathway has not been directly demonstrated to date. To delineate this signal transmission noninvasively, we investigated the early latency components between 45 ms (P45m) and 75 ms (N75m) of visually-evoked neuromagnetic fields (VEFs). Four healthy volunteers participated in this study. Hemi-visual field light flash stimuli were delivered a total of 1200 times. Neuromagnetic responses were measured with a 160 channel whole-head gradiometer. In three participants, averaged waveforms indicated a subtle but distinct component that peaked with a very early latency at 44.7 +/- 2.1 ms with an initial rise latency of 36.8 +/- 3.1 ms, followed by a typical prominent cortical component at 75 ms. The moving equivalent current dipoles continuously estimated from P45m to N75m were first localized in the vicinity of the contralateral lateral geniculate body, then rapidly propagated along the optic radiation and finally terminated in the contralateral calcarine fissure. This result indicates that the source of P45m is the lateral geniculate body and that the early latency components P45m-N75m of the VEFs reflect neural transmission in the optic radiation. This is the first report to noninvasively demonstrate the neurophysiological transmission of visual information through the optic radiation. PMID- 28667267 TI - A green strategy for the synthesis of sulfone derivatives of p-methylaminophenol: Kinetic evaluation and antibacterial susceptibility. AB - This is one of the few examples in which the diverse products have been synthesized just by changing the applied potential. The synthesis of sulfonyl derivatives of p-methylaminophenol were carried out by reaction of the electrogenerated p-methylquinoneimine with sulfinic acids. Various types of mono (MSP), bis (BSP) and tris (TSP) sulfonyl p-methyl aminophenols were obtained by changing the electrode potential, in one pot under green conditions. The mono sulfonyl-p-(methylamino)phenol derivatives (MSP) were assessed for their in vitro antibacterial activity against the gram positive (Staphylococcus aureus) and gram negative (Escherichia coli) strains. It was found that the tested compounds were more active against Staphylococcus aureus than Escherichia coli. We also found that the antimicrobial activity of MSP derivatives to vary in the order MSP4 (R = CH3) > MSP1 (R = p-tolyl) ~ MSP2 (R = phenyl) > MSP3 (R = p-ClC6H4). Moreover, the observed homogeneous rate constants (k obs) of the reaction of p-methyl quinoneimine with sulfinic acids were estimated in various pH values, based on the EC and ECEC mechanisms, by comparing the simulated cyclic voltammograms with the experimental ones. PMID- 28667268 TI - Pyrocurrent anomalies and intrinsic magnetodielectric behavior near room temperature in Li2Ni2Mo3O12, a compound with distorted honeycomb and spin-chains. AB - Keeping current interests to identify materials with intrinsic magnetodielectric behaviour near room temperature and with novel pyroelectric current anomalies, we report temperature and magnetic-field dependent behavior of complex dielectric permittivity and pyroelectric current for an oxide, Li2Ni2Mo3O12, containing magnetic ions with (distorted) honey-comb and chain arrangement and ordering magnetically below 8 K. The dielectric data reveal the existence of relaxor ferroelectricity behaviour in the range 160-240 K and there are corresponding Raman mode anomalies as well in this temperature range. Pyrocurrent behavior is also consistent with this interpretation, with the pyrocurrent peak-temperature interestingly correlating with the poling temperature. 7Li NMR offer an evidence for crystallographic disorder intrinsic to this compound and we therefore conclude that such a disorder is apparently responsible for the randomness of local electric field leading to relaxor ferroelectric property. Another observation of emphasis is that there is a notable decrease in the dielectric constant with the application of magnetic field to the tune of about -2.4% at 300 K, with the magnitude varying marginally with temperature. Small loss factor values validate the intrinsic behaviour of the magnetodielectric effect at room temperature. PMID- 28667269 TI - Novel carbon quantum dots from egg yolk oil and their haemostatic effects. AB - In this study, the properties of egg yolk oil (EYO) were investigated. Water extraction, dialysis, and ultrafiltration were used to extract and purify EYO, and microscopy, spectrophotometry, and chromatography were used to identify carbon dots (CDs) present in EYO (EYO CDs). Morphology analyses demonstrated that CDs were almost spherical, with an average size of <10 nm, a lattice spacing of 0.267 nm, and a composition of mainly C, O, and Fe. The solution showed bright blue fluorescence at 365 nm. Tail haemorrhaging and liver haemorrhaging experiments showed that CD-treated mice had significantly shorter bleeding times than did control mice. Coagulation assays suggested that EYO CDs stimulate the intrinsic blood coagulation system and activate the fibrinogen system. Thus, EYO CDs possess the ability to activate haemostasis, which may lead to further investigations of this ingredient of traditional Chinese medicine. PMID- 28667270 TI - Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice. AB - Fetal cardiomyocytes actively proliferate to form the primitive heart in utero in mammals, but they stop dividing shortly after birth. The identification of essential molecules maintaining this active cardiomyocyte proliferation is indispensable for potential adult heart regeneration. A recent study has shown that this proliferation depends on a low fetal oxygen condition before the onset of breathing at birth. We have established an isolation protocol for mouse fetal cardiomyocytes, performed under strict low oxygen conditions to mimic the intrauterine environment, that gives the highest proliferative activities thus far reported. Oxygen exposure during isolation/culture markedly inhibited cell division and repressed cell cycle-promoting genes, and subsequent genome-wide analysis identified Fam64a as a novel regulatory molecule. Fam64a was abundantly expressed in hypoxic fetal cardiomyocyte nuclei, but this expression was drastically repressed by oxygen exposure, and in postnatal cardiomyocytes following the onset of breathing and the resulting elevation of oxygen tension. Fam64a knockdown inhibited and its overexpression enhanced cardiomyocyte proliferation. Expression of a non-degradable Fam64a mutant suggested that optimum Fam64a expression and subsequent degradation by anaphase-promoting complex/cyclosome (APC/C) during the metaphase-to-anaphase transition are required for fetal cardiomyocyte division. We propose that Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice. PMID- 28667271 TI - Sedimentation and mobility of PDCs: a reappraisal of ignimbrites' aspect ratio. AB - The aspect ratio of ignimbrites is a commonly used parameter that has been related to the energy of the parent pyroclastic density currents (PDCs). However this parameter, calculated as the ratio between the average thickness and the average lateral extent of ignimbrites, does not capture fundamental differences in pyroclastic flow mobility nor relates to lithofacies variations of the final deposits. We herein introduce the "topological aspect ratio" (ARt) as the ratio of the local deposit thickness (Ht) to the distance between the local site and the maximum runout distance (Lt), where Ht is a proxy for the PDC tendency to deposit, and Lt a proxy for the PDC mobility or its tendency to further transport the pyroclastic material. The positive versus negative spatial gradient d(ARt)/dx along flow paths discriminate zones where PDCs are forced (i.e. where they transport the total energy under the action of mass discharge rate) from zones where they are inertial (i.e. where they transport the total energy under the action of viscous or turbulent fluidization). Though simple to apply, the topological aspect ratio and its spatial gradient are powerful descriptors of the interplay between sedimentation and mobility of PDCs, and of the resulting lithofacies variations. PMID- 28667273 TI - Natural and induced loss of function mutations in SlMBP21 MADS-box gene led to jointless-2 phenotype in tomato. AB - Abscission is the mechanism by which plants disconnect unfertilized flowers, ripe fruits, senescent or diseased organs from the plant. In tomato, pedicel abscission is an important agronomic factor that controls yield and post-harvest fruit quality. Two non-allelic mutations, jointless (j) and jointless-2 (j-2), controlling pedicel abscission zone formation have been documented but only j-2 has been extensively used in breeding. J was shown to encode a MADS-box protein. Using a combination of physical mapping and gene expression analysis we identified a positional candidate, Solyc12g038510, associated with j-2 phenotype. Targeted knockout of Solyc12g038510, using CRISPR/Cas9 system, validated our hypothesis. Solyc12g038510 encodes the MADS-box protein SlMBP21. Molecular analysis of j-2 natural variation revealed two independent loss-of-function mutants. The first results of an insertion of a Rider retrotransposable element. The second results of a stop codon mutation that leads to a truncated protein form. To bring new insights into the role of J and J-2 in abscission zone formation, we phenotyped the single and the double mutants and the engineered alleles. We showed that J is epistatic to J-2 and that the branched inflorescences and the leafy sepals observed in accessions harboring j-2 alleles are likely the consequences of linkage drags. PMID- 28667272 TI - Adiponectin is an endogenous anti-fibrotic mediator and therapeutic target. AB - Skin fibrosis in systemic sclerosis (SSc) is accompanied by attrition of dermal white adipose tissue (dWAT) and reduced levels of circulating adiponectin. Since adiponectin has potent regulatory effects on fibroblasts, we sought to assess adiponectin signaling in SSc skin biopsies, and evaluate fibrosis in mice with adiponectin gain- and loss-of-function mutations. Furthermore, we investigated the effects and mechanism of action of agonist peptides targeting adiponectin receptors in vitro and in vivo. We found that adiponectin pathway activity was significantly reduced in a subset of SSc skin biopsies. Mice lacking adiponectin mounted an exaggerated dermal fibrotic response, while transgenic mice with constitutively elevated adiponectin showed selective dWAT expansion and protection from skin and peritoneal fibrosis. Adiponectin receptor agonists abrogated ex vivo fibrotic responses in explanted normal and SSc fibroblasts and in 3D human skin equivalents, in part by attenuating focal adhesion complex assembly, and prevented and reversed experimentally-induced organ fibrosis in mice. These results implicate aberrant adiponectin pathway activity in skin fibrosis, identifying a novel function for this pleiotropic adipokine in regulation of tissue remodeling. Restoring adiponectin signaling in SSc patients therefore might represent an innovative pharmacological strategy for intractable organ fibrosis. PMID- 28667274 TI - Proteomic shifts in multi-species oral biofilms caused by Anaeroglobus geminatus. AB - Anaeroglobus geminatus is a relatively newly discovered putative pathogen, with a potential role in the microbial shift associated with periodontitis, a disease that causes inflammatory destruction of the periodontal tissues, and eventually tooth loss. This study aimed to introduce A. geminatus into a polymicrobial biofilm model of relevance to periodontitis, and monitor the proteomic responses exerted to the rest of the biofilm community. A. geminatus was grown together with another 10-species in a well-established "subgingival" in vitro biofilm model. Its effects on the other species were quantitatively evaluated by qPCR and label-free proteomics. A. geminatus caused a significant increase in P. intermedia numbers, but not the other species in the biofilm. Whole cell proteome profiling of the biofilms by LC-MS/MS identified a total of 3213 proteins. Label free quantitative proteomics revealed that 187 proteins belonging to the other 10 species were differentially abundant when A. geminatus was present in the biofilm. The species with most up-regulated and down-regulated proteins were P. intermedia and S. oralis, respectively. Regulated proteins were of primarily of ribosomal origin, and other affected categories involved proteolysis, carbon metabolism and iron transport. In conclusion, A. geminatus can be successfully grown in a polymicrobial biofilm community, causing quantitative proteomic shifts commensurate with increased virulence properties. PMID- 28667275 TI - Tuberculosis infection in rural labor migrants in Shenzhen, China: Emerging challenge to tuberculosis control during urbanization. AB - During China's urbanization process, rural labor migrants have been suggested to be one important bridge population to change urban-rural distribution on tuberculosis (TB) burden. Aiming to estimate the prevalence of TB infection and to track the active disease development in rural labor migrants, a prospective study was conducted in Shenzhen city, southern China. TB infection was detected using interferon-gamma release assay (IGRA). Here we mainly report the characteristics of TB infection in the study population based on the baseline survey. A total of 4,422 eligible participants completed baseline survey in July 2013. QuantiFERON (QFT) positivity rates 17.87% (790/4,422) and was found to be consistent with the local TB epidemic of the areas where the participants immigrated from. Age, smoking, residence registered place, and present of BCG scars were found to be independently associated with QFT positivity. Additionally, evidence for interaction between smoking and age was observed (p for likelihood ratio test < 0.001). Our results suggested that the development of TB control strategy including latent TB infection management should pay more attention to the rural flowing population due to their high mobility and higher prevalence of TB infection. PMID- 28667276 TI - Diagnostic Performance of Contrast Enhanced Pulmonary Computed Tomography Angiography for the Detection of Angioinvasive Pulmonary Aspergillosis in Immunocompromised Patients. AB - Invasive pulmonary aspergillosis (IPA) is one of the major complications in immunocompromised patients. The mainstay of diagnostic imaging is non-enhanced chest-computed-tomography (CT), for which various non-specific signs for IPA have been described. However, contrast-enhanced CT pulmonary angiography (CTPA) has shown promising results, as the vessel occlusion sign (VOS) seems to be more sensitive and specific for IPA in hematologic patients. The aim of this study was to evaluate the diagnostic accuracy of CTPA in a larger cohort including non hematologic immunocompromised patients. CTPA studies of 78 consecutive immunocompromised patients with proven/probable IPA were analyzed. 45 immunocompromised patients without IPA served as a control group. Diagnostic performance of CTPA-detected VOS and of radiological signs that do not require contrast-media were analyzed. Of 12 evaluable radiological signs, five were found to be significantly associated with IPA. The VOS showed the highest diagnostic performance with a sensitivity of 0.94, specificity of 0.71 and a diagnostic odds ratio of 36.8. Regression analysis revealed the two strongest independent radiological predictors for IPA to be the VOS and the halo sign. The VOS is highly suggestive for IPA in immunocompromised patients in general. Thus, contrast-enhanced CTPA superior over non-contrast_enhanced chest-CT in patients with suspected IPA. PMID- 28667277 TI - Super-hydrophobic multilayer coatings with layer number tuned swapping in surface wettability and redox catalytic anti-corrosion application. AB - The wetting characteristic of a metal surface can be controlled by employing different coating materials and external stimuli, however, layer number (n) modulated surface swapping between hydrophobicity and hydrophilicity in a multilayer structure to achieve prolonged anti-corrosion ability was not taken into consideration. In this study, we proposed a layer-by-layer (LbL) spin assembled polyaniline-silica composite/tetramethylsilane functionalized silica nanoparticles (PSC/TMS-SiO2) coating with the combined effect of super hydrophobicity and enhanced anti-corrosion ability. Interestingly, the hierarchical integration of two coating materials with inherently different surface roughness and energy in a multilayer structure allows the wetting feature to swap from hydrophobic to hydrophilic state by modulating n with decreasing hydrophilicity. The samples with odd n (TMS-SiO2 surface) are hydrophobic while the samples with even n (PSC surface) exhibits the hydrophilic character. The TMS SiO2 content was optimized to achieve super-hydrophobic coating with significantly high water contact angle (CA) 153 degrees +/- 2 degrees and small sliding angle (SA) 6 degrees +/- 2 degrees . Beside its self-cleaning behavior, the electro-active PSC/TMS-SiO2 coating also exhibits remarkably enhanced corrosion resistance against aggressive media. The corrosion resistance of the coating was remained stable even after 240 h of exposure, this enhancement is attributed to super-hydrophobicity and anodic shift in corrosion potential. PMID- 28667278 TI - Anterior Cervical Spondylosis Surgical Interventions are Associated with Improved Lordosis and Neurological Outcomes at Latest Follow up: A Meta-analysis. AB - Aim of this study was to evaluate the effect of cervical spondylosis surgery on cervical lordosis and to identify factors affecting the change by latest follow up. Literature search was carried out in electronic databases and study selection followed a priori eligibility criteria. Random effects meta-analyses were performed to estimate effect size/s of change in lordosis after surgery (at latest follow-up) and metaregression analyses were performed to identify factors affecting this change. Nineteen studies (1845 patients; age 55.18 [95% CI: 54.78, 55.57] years; 60.99 [60.63, 61.36] % males; follow-up 25.59 [25.20, 25.99] months) were included. Whereas, corpectomy (4.06 [2.65, 5.46] degree; p < 0.00001) and discectomy (4.59 [2.07, 7.11] degree; p < 0.00001) were associated with increase, laminectomy (-1.87 [-8.40, 4.66] degree; p = 0.57) and laminoplasty (0.25 [-1.07, 1.56] degree; p = 0.711) were not associated with significant change in lordosis at latest follow-up. Change in Japanese Orthopedic Association (JOA)/modified JOA (mJOA) score at latest follow-up was also significantly (p = 0.0005) higher in anterior than in posterior surgery group. Change in lordosis at latest follow-up had significant positive relationship with follow-up duration but had significant inverse associations with age, male gender, and preoperative JOA/mJOA score, independently. In posterior surgery subjects, after adjusting for age and gender, preoperative JOA/mJOA score was significantly inversely related to change in lordosis. PMID- 28667279 TI - Short-term effects of ambient air pollution and childhood lower respiratory diseases. AB - The association between air pollution and childhood respiratory disease is inconsistent. In the present study, we investigated a short-term effect of ambient air pollutants and daily childhood lower respiratory diseases (CLRD). Daily air pollutants, weather data, and CLRD data were collected from January 2014 to April 2015 (452 days) in Nanjing, China. Time-series regression and generalized additive models were used to assess the effects of air pollutants (PM10, PM2.5, NO2, SO2, O3, and CO) on CLRD. We observed that an interquartile range (IQR) increase in concentrations of PM10, NO2, and SO2 significantly increased the daily CLRD with 6 days cumulative effects (difference of estimates: 2.8%, 95% CI: 0.6-5.0%; 4.1%, 1.2-7.0%; 5.6%, 2.6-8.6%, respectively). However, no significant association was found in IQR concentrations of PM2.5, O3, and CO. Specifically, elevated PM10, PM2.5, NO2, and SO2 significantly increased the numbers of CLRD in cool season (3.6%, 1.5-5.7%; 2.4%, 0.3-4.5%; 4.9%, 2.9-7.0%; 6.3%, 3.7-9.0%, respectively). Additionally, the effect estimates of PM10, NO2, and SO2 in female and age >27 months were more pronounced than in male and age <=27 months. This study suggested that short-term exposure to ambient PM10, NO2, and SO2 were associated with the increased CLRD numbers. PMID- 28667280 TI - Diagnostic accuracy of contrast enhanced ultrasound in patients with blunt abdominal trauma presenting to the emergency department: a systematic review and meta-analysis. AB - We aimed to investigate the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) in evaluating blunt abdominal trauma for patients presenting to the emergency department. Electronic search of Scopus and Pubmed was performed from inception to September 2016. Human studies investigating the diagnostic accuracy of CEUS in identifying abdominal solid organ injuries were included. Risk of bias was assessed using the QUADAS tool. A total of 10 studies were included in the study and 9 of them were included for meta-analysis. The log(DOR) values ranged from 3.80 (95% CI: 2.81-4.79) to 8.52 (95% CI: 4.58-12.47) in component studies. The combined log(DOR) was 6.56 (95% CI: 5.66-7.45). The Cochran's Q was 11.265 (p = 0.793 with 16 degrees of freedom), and the Higgins' I2 was 0%. The CEUS had a sensitivity of 0.981 (95% CI: 0.868-0.950) and a false positive rate of 0.018 (95% CI: 0.010-0.032) for identifying parenchymal injuries, with an AUC of 0.984. CEUS performed at emergency department had good diagnostic accuracy in identifying abdominal solid organ injuries. CEUS can be recommended in monitoring solid organ injuries, especially for patients managed with non-operative strategy. PMID- 28667281 TI - Mitochondrial genomes of two Australian fishflies with an evolutionary timescale of Chauliodinae. AB - Fishflies (Corydalidae: Chauliodinae) with a total of ca. 130 extant species are one of the major groups of the holometabolous insect order Megaloptera. As a group which originated during the Mesozoic, the phylogeny and historical biogeography of fishflies are of high interest. The previous hypothesis on the evolutionary history of fishflies was based primarily on morphological data. To further test the existing phylogenetic relationships and to understand the divergence pattern of fishflies, we conducted a molecule-based study. We determined the complete mitochondrial (mt) genomes of two Australian fishfly species, Archichauliodes deceptor Kimmins, 1954 and Protochauliodes biconicus Kimmins, 1954, both members of a major subgroup of Chauliodinae with high phylogenetic significance. A phylogenomic analysis was carried out based on 13 mt protein coding genes (PCGs) and two rRNAs genes from the megalopteran species with determined mt genomes. Both maximum likelihood and Bayesian inference analyses recovered the Dysmicohermes clade as the sister group of the Archichauliodes clade + the Protochauliodes clade, which is consistent with the previous morphology-based hypothesis. The divergence time estimation suggested that the divergence among the three major subgroups of fishflies occurred during the Late Jurassic and Early Cretaceous when the supercontinent Pangaea was undergoing sequential breakup. PMID- 28667282 TI - Maintaining ecosystem resilience: functional responses of tree cavity nesters to logging in temperate forests of the Americas. AB - Logging often reduces taxonomic diversity in forest communities, but little is known about how this biodiversity loss affects the resilience of ecosystem functions. We examined how partial logging and clearcutting of temperate forests influenced functional diversity of birds that nest in tree cavities. We used point-counts in a before-after-control-impact design to examine the effects of logging on the value, range, and density of functional traits in bird communities in Canada (21 species) and Chile (16 species). Clearcutting, but not partial logging, reduced diversity in both systems. The effect was much more pronounced in Chile, where logging operations removed critical nesting resources (large decaying trees), than in Canada, where decaying aspen Populus tremuloides were retained on site. In Chile, logging was accompanied by declines in species richness, functional richness (amount of functional niche occupied by species), community-weighted body mass (average mass, weighted by species densities), and functional divergence (degree of maximization of divergence in occupied functional niche). In Canada, clearcutting did not affect species richness but nevertheless reduced functional richness and community-weighted body mass. Although some cavity-nesting birds can persist under intensive logging operations, their ecosystem functions may be severely compromised unless future nest trees can be retained on logged sites. PMID- 28667283 TI - The role of the FliD C-terminal domain in pentamer formation and interaction with FliT. AB - Flagellar biogenesis is controlled by a negative feedback loop. When FliD was secreted at the late step of flagellar assembly, the FliD-FliT complex disassembled and free FliT bound to the FlhDC complex, a master regulator of flagellar biogenesis, subsequently inhibiting the overall expression of flagellar proteins. In this study, we analyzed the role of the FliD C-terminal domain in pentamer formation and interaction with FliT. Our study showed that the FliD L443R mutant exists as a monomer in solution, indicating that the Leu443 residue of FliD, which contributes to its interaction with FliT, plays a crucial role in the pentameric oligomerization of FliD. Consistently, the increased levels of free FliT proteins caused by FliD L443R mutation had negative effects on the gene expression of flagellar synthesis and reduced the expression of flagellar proteins. The lengths of flagella in each cell were significantly reduced in L443R mutant strain, suggesting that normal flagellar biogenesis was impeded. These results suggest that the C-terminal domain of FliD plays a crucial role in the pentameric oligmerization of FliD and the binding of FliT to the C-terminal domain of FliD is critical to inhibit the premature assembly of the FliD pentamer in the cytosol. PMID- 28667284 TI - A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer's Disease, Glioblastoma and Lung cancer. AB - Epidemiological studies indicate that patients suffering from Alzheimer's disease have a lower risk of developing lung cancer, and suggest a higher risk of developing glioblastoma. Here we explore the molecular scenarios that might underlie direct and inverse co-morbidities between these diseases. Transcriptomic meta-analyses reveal significant numbers of genes with inverse patterns of expression in Alzheimer's disease and lung cancer, and with similar patterns of expression in Alzheimer's disease and glioblastoma. These observations support the existence of molecular substrates that could at least partially account for these direct and inverse co-morbidity relationships. A functional analysis of the sets of deregulated genes points to the immune system, up-regulated in both Alzheimer's disease and glioblastoma, as a potential link between these two diseases. Mitochondrial metabolism is regulated oppositely in Alzheimer's disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases. Finally, oxidative phosphorylation is a good candidate to play a dual role by decreasing or increasing the risk of lung cancer and glioblastoma in Alzheimer's disease. PMID- 28667286 TI - ABO blood type correlates with survival in hepatocellular carcinoma following hepatectomy. AB - ABO blood types are associated with the prognosis of several malignancies. However, the role of the ABO blood type in hepatocellular carcinoma (HCC) remains elusive. Here, we evaluated the prognostic role of the ABO blood group in 691 HCC patients after hepatectomy by Cox regression analysis. A prognostic nomogram was generated to predict the 3 and 5-year overall survival (OS). A total of 262 HCC patients (37.9%) had blood group O, 199 (28.8%) had blood group A, 165 (23.9%) had blood group B, and 65 (9.4%) had blood group AB. The median OS was 55 months in patients with blood group O, 39 months for blood group A, 34 months for blood group B, and 34 months for blood group AB patients (P = 0.001, log-rank test). There were significant differences in OS between patients with blood groups O and A [hazard ratio (HR) = 1.416; 95% CI, 1.101-1.820; P = 0.007], blood group B (HR = 1.736; 95% CI, 1.333-2.262; P < 0.001), blood group AB (HR = 1.739; 95% CI, 1.210-2.499; P = 0.003) and non-O blood groups (HR = 1.485; 95% CI, 1.204-1.830; P < 0.001). Our constructed nomogram (c-index = 0.687) predicted the prognosis more accurately than the TNM stage alone(c-index = 0.601). In conclusion, non-O blood groups are poor prognostic indicators for HCC following hepatectomy. Our findings justify further external validation in larger cohorts. PMID- 28667285 TI - Oxidative Stress Challenge Uncovers Trichloroacetaldehyde Hydrate-Induced Mitoplasticity in Autistic and Control Lymphoblastoid Cell Lines. AB - Mitoplasticity occurs when mitochondria adapt to tolerate stressors. Previously we hypothesized that a subset of lymphoblastoid cell lines (LCLs) from children with autistic disorder (AD) show mitoplasticity (AD-A), presumably due to previous environmental exposures; another subset of AD LCLs demonstrated normal mitochondrial activity (AD-N). To better understand mitoplasticity in the AD-A LCLs we examined changes in mitochondrial function using the Seahorse XF96 analyzer in AD and Control LCLs after exposure to trichloroacetaldehyde hydrate (TCAH), an in vivo metabolite of the environmental toxicant and common environmental pollutant trichloroethylene. To better understand the role of reactive oxygen species (ROS) in mitoplasticity, TCAH exposure was followed by acute exposure to 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases ROS. TCAH exposure by itself resulted in a decline in mitochondrial respiration in all LCL groups. This effect was mitigated when TCAH was followed by acute DMNQ exposure but this varied across LCL groups. DMNQ did not affect AD-N LCLs, while it neutralized the detrimental effect of TCAH in Control LCLs and resulted in a increase in mitochondrial respiration in AD-A LCLs. These data suggest that acute increases in ROS can activate mitochondrial protective pathways and that AD-A LCLs are better able to activate these protective pathways. PMID- 28667287 TI - One-pot Synthesis of 6-Aza-chromone Derivatives Through Cascade Carbonylation Sonogashira-Cyclization. AB - We developed an efficient synthesis of aza-chromones from 3-iodo-4-(1H)-pyridones and terminal acetylenes via a cascade carbonylation-Sonogashira-cyclization reaction. By controlling the use of bases, both 6-aza-chromones 5 and 3-(4-oxo 1,4-dihydroquinoline-3-carbonyl)-4H-pyrano[3,2-c]quinolin-4-ones 6 could be selectively obtained in moderate to good yields. PMID- 28667288 TI - Brain functional connectivity difference in the complete network of an entire village: the role of social network size and embeddedness. AB - Social networks are known to protect cognitive function in old age. For the first time, this study examines how social network size and social network embeddedness measured by k-core score are associated with functional connectivity in the brain using the complete social network of an entire village. According to the results, social network size has both positive and negative associations with functional connectivity; showing no meaningful pattern relative to distance among brain regions. However, older adults deeply embedded in the complete network tend to maintain functional connectivity between long-distance regions even after controlling for other covariates such as age, gender, education, and Mini-Mental State Examination score. Network Based Statistics (NBS) also revealed strong and consistent evidence that social network embeddedness has component-level associations with functional connectivity among brain regions, especially between inferior prefrontal and occipital/parietal lobes. PMID- 28667289 TI - Near-Zero-Power Temperature Sensing via Tunneling Currents Through Complementary Metal-Oxide-Semiconductor Transistors. AB - Temperature sensors are routinely found in devices used to monitor the environment, the human body, industrial equipment, and beyond. In many such applications, the energy available from batteries or the power available from energy harvesters is extremely limited due to limited available volume, and thus the power consumption of sensing should be minimized in order to maximize operational lifetime. Here we present a new method to transduce and digitize temperature at very low power levels. Specifically, two pA current references are generated via small tunneling-current metal-oxide-semiconductor field effect transistors (MOSFETs) that are independent and proportional to temperature, respectively, which are then used to charge digitally-controllable banks of metal insulator-metal (MIM) capacitors that, via a discrete-time feedback loop that equalizes charging time, digitize temperature directly. The proposed temperature sensor was integrated into a silicon microchip and occupied 0.15 mm2 of area. Four tested microchips were measured to consume only 113 pW with a resolution of 0.21 degrees C and an inaccuracy of +/-1.65 degrees C, which represents a 628* reduction in power compared to prior-art without a significant reduction in performance. PMID- 28667290 TI - Activation of hepatic stellate cells by the ubiquitin C-terminal hydrolase 1 protein secreted from hepatitis C virus-infected hepatocytes. AB - Hepatitis C virus (HCV) infection of hepatocytes promotes liver fibrosis by activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix in liver tissue. Whether or not host factors released from the HCV-infected hepatocytes play role in HSCs activation is unclear. In this study, HSCs were activated by the conditioned medium derived from HCV replicon cells. Secretomic profiling of HCV replicon cells and the parental Huh7 cells revealed ubiquitin carboxy-terminal hydrolase L1 (UCHL1) as a novel secreted protein from HCV-infected hepatocytes. UCHL1 expression in hepatocytes was induced by HCV infection. UCHL1 was expressed in the liver and found in the plasma of patients with chronic hepatitis C. Molecular analysis by use of the anti-UCHL1 neutralization antibody and purified UCHL1 protein showed that secreted UCHL1 protein was bound to the cell surface of HSCs and activated JNK signaling leading to overexpression of alpha-smooth muscle actin and the activation of HSCs. These results provide further for understanding the underlying mechanism in HCV-mediated hepatic fibrogenesis. PMID- 28667291 TI - A Biomimetic Heparinized Composite Silk-Based Vascular Scaffold with sustained Antithrombogenicity. AB - Autologous grafts, as the gold standard for vascular bypass procedures, associated with several problems that limit their usability, so tissue engineered vessels have been the subject of an increasing number of works. Nevertheless, gathering all of the desired characteristics of vascular scaffolds in the same construct has been a big challenge for scientists. Herein, a composite silk-based vascular scaffold (CSVS) was proposed to consider all the mechanical, structural and biological requirements of a small-diameter vascular scaffold. The scaffold's lumen composed of braided silk fiber-reinforced silk fibroin (SF) sponge covalently heparinized (H-CSVS) using Hydroxy-Iron Complexes (HICs) as linkers. The highly porous SF external layer with pores above 60 MUm was obtained by lyophilization. Silk fibers were fully embedded in scaffold's wall with no delamination. The H-CSVS exhibited much higher burst pressure and suture retention strength than native vessels while comparable elastic modulus and compliance. H-CSVSs presented milder hemolysis in vitro and significant calcification resistance in subcutaneous implantation compared to non-heparinized ones. The in vitro antithrombogenic activity was sustained for over 12 weeks. The cytocompatibility was approved using endothelial cells (ECs) and vascular smooth muscle cells (SMCs) in vitro. Therefore, H-CSVS demonstrates a promising candidate for engineering of small-diameter vessels. PMID- 28667293 TI - Multiscale studies on the nonlinear vibration of delaminated composite laminates global vibration mode with micro buckles on the interfaces. AB - This paper presents a multiscale approach to study the nonlinear vibration of fiber reinforced composite laminates containing an embedded, through-width delamination dividing the laminate into four sub-laminates. The equations of motion are established from macroscopic nonlinear mechanics for plates and shells and micro-mechanics of composite material to allow for the influences of large amplitude, membrane stretching in the neutral plane, and the interactions of the sublaminates. Analytical solutions obtained in this paper reveal that the interaction penalty at the interfaces plays a coupling effect between sublaminates, which eventually alters the vibration characters of the four sublaminate lamina in macroscopic and microscopic mechanism. From a macro perspective, sub-laminates above and below the delamination vibrate in exactly the same mode in spite of their different stiffness and the four-sublaminate lamina has a consistent global vibration mode. In accompanying with the macro vibration, micro buckles occur on the interfaces of the delamination with amplitude about 10-3 times of that of the global mode. It is found that the vibration frequency is an eigenvalue of the delaminated lamina determined only by the geometry of the delamination. Authentication of the multiscale study is fulfilled by comparing the analytical solutions with the FEA results. PMID- 28667292 TI - Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B). AB - Oculocutaneous albinism (OCA) and ocular albinism (OA) are inherited disorders of melanin biosynthesis, resulting in loss of pigment and severe visual deficits. OCA encompasses a range of subtypes with overlapping, often hypomorphic phenotypes. OCA1 is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. However, there is a high level of reported missing heritability, where only a single heterozygous mutation is found in TYR. This is also the case for other OCA subtypes including OCA2 caused by mutations in the OCA2 gene. Here we have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism population by sequencing a broad gene panel and performing segregation studies on phenotyped family members. Of eighteen probands we can confidently diagnose three with OA and OCA2, and one with a PAX6 mutation. Of six probands with only a single heterozygous mutation in TYR, all were found to have the two common variants S192Y and R402Q. Our results suggest that a combination of R402Q and S192Y with a deleterious mutation in a 'tri-allelic genotype' can account for missing heritability in some hypomorphic OCA1 albinism phenotypes. PMID- 28667294 TI - 0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop. AB - DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular response profiling (TCRP) based on unique DNA-damage characteristics. We used human HCC cell lines and HCC xenograft mouse model to analyze the anti-cancer effects of 0404. Transcriptome and miRNA arrays were used to verify the anti-cancer mechanism of 0404. It was confirmed that p53 signaling pathway was crucial in 0404 anti-cancer activity and the expression of miR-34a, a key tumor-suppressive miRNA, was up-regulated in 0404-treated HepG2 cells. MiR-34a expression was also down-regulated in HCCs compared with corresponding non-cancerous hepatic tissues. We further identified the mechanisms of 0404 in HepG2 cells. 0404 increased miR-34a expression and acylation p53 protein levels and decreased SIRT1 protein levels in a concentration-dependent manner. The sensitivity of HepG2 cells to 0404 was significantly decreased by transfection with miR-34a inhibitors and SIRT1 protein levels were up-regulated by miR-34a inhibition. Our findings show that 0404 is probably an attractive agent for treating HCC, especially in HCC with wide type (WT) p53, through forming a p53/miR-34a/SIRT1 signal feedback loop to promote cell apoptosis. PMID- 28667295 TI - Moss survival through in situ cryptobiosis after six centuries of glacier burial. AB - Cryptobiosis is a reversible ametabolic state of life characterized by the ceasing of all metabolic processes, allowing survival of periods of intense adverse conditions. Here we show that 1) entire moss individuals, dated by 14C, survived through cryptobiosis during six centuries of cold-based glacier burial in Antarctica, 2) after re-exposure due to glacier retreat, instead of dying (due to high rates of respiration supporting repair processes), at least some of these mosses were able to return to a metabolically active state and remain alive. Moss survival was assessed through growth experiments and, for the first time, through vitality measurements. Future investigations on the genetic pathways involved in cryptobiosis and the subsequent recovery mechanisms will provide key information on their applicability to other systematic groups, with implications for fields as divergent as medicine, biodiversity conservation, agriculture and space exploration. PMID- 28667297 TI - The electro-optic mechanism and infrared switching dynamic of the hybrid multilayer VO2/Al:ZnO heterojunctions. AB - Active and widely controllable phase transition optical materials have got rapid applications in energy-efficient electronic devices, field of meta-devices and so on. Here, we report the optical properties of the vanadium dioxide (VO2)/aluminum doped zinc oxide (Al:ZnO) hybrid n-n type heterojunctions and the corresponding electro-optic performances of the devices. Various structures are fabricated to compare the discrepancy of the optical and electrical characteristics. It was found that the reflectance spectra presents the wheel phenomenon rather than increases monotonically with temperature at near-infrared region range. The strong interference effects was found in the hybrid multilayer heterojunction. In addition, the phase transition temperature decreases with increasing the number of the Al:ZnO layer, which can be ascribed to the electron injection to the VO2 film from the Al:ZnO interface. Affected by the double layer Al:ZnO, the abnormal Raman vibration mode was presented in the insulator region. By adding the external voltage on the Al2O3/Al:ZnO/VO2/Al:ZnO, Al2O3/Al:ZnO/VO2 and Al2O3/VO2/Al:ZnO thin-film devices, the infrared optical spectra of the devices can be real-time manipulated by an external voltage. The main effect of joule heating and assistant effect of electric field are illustrated in this work. It is believed that the results will add a more thorough understanding in the application of the VO2/transparent conductive film device. PMID- 28667296 TI - Somatosensory lateral inhibition processes modulate motor response inhibition - an EEG source localization study. AB - Motor inhibitory control is a central executive function, but only recently the importance of perceptual mechanisms for these processes has been focused. It is elusive whether basic mechanisms governing sensory perception affect motor inhibitory control. We examine whether sensory lateral inhibition (LI) processes modulate motor inhibitory control using a system neurophysiological approach combining EEG signal decomposition with source localization methods in a somatosensory GO/NOGO task. The results show that inter-individual variations in the strength of LI effects predominantly affect processes when information needs to be integrated between cerebral hemispheres. If information needs to be integrated between hemispheres, strong sensory suppression will lead to more impulsive errors. Importantly, the neurophysiological data suggest that not purely perceptual or motor processes are affected. Rather, LI affects the response selection level and modulates processes of stimulus categorization. This is associated with activity modulations in the posterior parietal cortex. The results suggest that when sensory suppression is high and when information needs to be integrated across hemispheres, these processes are less efficient, which likely leads to worse motor inhibitory control. The results show how basis principles modulating perceptual processes affect subsequent motor inhibitory control processes. PMID- 28667298 TI - Evolution of Gene Expression in the Uterine Cervix related to Steroid Signaling: Conserved features in the regulation of cervical ripening. AB - The uterine cervix is the boundary structure between the uterus and the vagina and is key for the maintenance of pregnancy and timing of parturition. Here we report on a comparative transcriptomic study of the cervix of four placental mammals, mouse, guinea pig, rabbit and armadillo, and one marsupial, opossum. Our aim is to investigate the evolution of cervical gene expression as related to putative mechanisms for functional progesterone withdrawal. Our findings are: 1) The patterns of gene expression in eutherian (placental) mammals are consistent with the notion that an increase in the E/P4 signaling ratio is critical for cervical ripening. How the increased E/P4 ratio is achieved, however, is variable between species. 2) None of the genes related to steroid signaling, that are modulated in eutherian species, change expression during opossum gestation. 3) A tendency for decreased expression of progesterone receptor co-activators (NCOA1, 2 and -3, and CREBBP) towards term is a shared derived feature of eutherians. This suggests that parturition is associated with broad scale histone de acetylation. Western-blotting on mouse cervix confirmed large scale histone de acetylation in labor. This finding may have important implications for the control of premature cervical ripening and prevention of preterm birth in humans. PMID- 28667299 TI - The beetle elytron plate: a lightweight, high-strength and buffering functional structural bionic material. AB - To investigate the characteristics of compression, buffering and energy dissipation in beetle elytron plates (BEPs), compression experiments were performed on BEPs and honeycomb plates (HPs) with the same wall thickness in different core structures and using different molding methods. The results are as follows: 1) The compressive strength and energy dissipation capacity in the BEP are 2.44 and 5.0 times those in the HP, respectively, when the plates are prepared using the full integrated method (FIM). 2) The buckling stress is directly proportional to the square of the wall thickness (t). Thus, for core structures with equal wall thicknesses, although the core volume of the BEP is 42 percent greater than that of the HP, the mechanical properties of the BEP are several times higher than those of the HP. 3) It is also proven that even when the single integrated method (SIM) is used to prepare BEPs, the properties discussed above remain superior to those of HPs by a factor of several; this finding lays the foundation for accelerating the commercialization of BEPs based on modern manufacturing processes. PMID- 28667300 TI - Association of plasma C-reactive protein level with the prevalence of colorectal adenoma: the Colorectal Adenoma Study in Tokyo. AB - Epidemiologic studies have identified a positive association between obesity and colorectal neoplasia. Adiposity induces systemic low-grade inflammation, which is commonly assessed with a sensitive biomarker, C-reactive protein (CRP). To understand the molecular mechanisms of obesity in the etiology of colorectal neoplasia, the present study was conducted in 782 adenoma cases and 738 controls who underwent total colonoscopy, and their plasma CRP level was evaluated in relation to colorectal adenoma prevalence. A logistic regression model was used to compute odds ratios (OR) and 95% confidence intervals (CI) of adenoma according to quartile of plasma CRP. Plasma CRP level was positively associated with higher adenoma prevalence in all subjects (OR 1.30; 95% CI 0.94-1.79 for the highest versus lowest quartile; P trend = 0.031). Further analysis by adenoma size and number revealed a pronounced association with a larger size (>=5 mm) and multiple numbers (>=2). These positive associations were reduced to non significance following further adjustment for body mass index, and OR for the highest versus lowest quartile of plasma CRP became 1.12 (95% CI 0.80-1.56; P trend = 0.25) in all subjects. In conclusion, this study suggests that obesity related systemic low-grade inflammation may play an important role in the early stages of colorectal carcinogenesis. PMID- 28667301 TI - Knockout of the peroxiredoxin 5 homologue PFAOP does not affect the artemisinin susceptibility of Plasmodium falciparum. AB - Artemisinins are the current mainstay of malaria chemotherapy. Their exact mode of action is an ongoing matter of debate, and several factors have recently been reported to affect an early stage of artemisinin resistance of the most important human malaria parasite Plasmodium falciparum. Here, we identified a locus on chromosome 7 that affects the artemisinin susceptibility of P. falciparum in a quantitative trait locus analysis of a genetic cross between strains 7G8 and GB4. This locus includes the peroxiredoxin gene PFAOP. However, steady-state kinetic data with recombinant PfAOP do not support a direct interaction between this peroxidase and the endoperoxide artemisinin. Furthermore, neither the overexpression nor the deletion of the encoding gene affected the IC50 values for artemisinin or the oxidants diamide and tert-butyl hydroperoxide. Thus, PfAOP is dispensable for blood stage parasite survival, and the correlation between the artemisinin susceptibility and chromosome 7 is probably based on another gene within the identified locus. PMID- 28667302 TI - E2F1-regulated long non-coding RNA RAD51-AS1 promotes cell cycle progression, inhibits apoptosis and predicts poor prognosis in epithelial ovarian cancer. AB - Long non-coding RNA RAD51 antisense RNA 1 (RAD51-AS1, also known as TODRA) has been shown to be down-regulated by E2F1, a key cell cycle and apoptosis regulator, in breast cancer. Little is known regarding the role of RAD51-AS1 in disease. Here, we investigate the role of RAD51-AS1 in epithelial ovarian cancer (EOC). Using luciferase reporter and chromatin immunoprecipitation experiments, we verified RAD51-AS1 as a target of E2F1 under negative regulation in EOC. We then examined RAD51-AS1 expression in EOC samples using in situ hybridization (ISH). RAD51-AS1 was localized to the nucleus and found to be a critical marker for clinical features that significantly correlated with poor survival in EOC patients. RAD51-AS1 was also an independent prognostic factor for EOC. Overexpression of RAD51-AS1 promoted EOC cell proliferation, while silencing of RAD51-AS1 inhibited EOC cell proliferation, delayed cell cycle progression and promoted apoptosis in vitro and in vivo. RAD51-AS1 may participate in carcinogenesis via regulation of p53 and p53-related genes. Our study highlights the role of RAD51-AS1 as a prognostic marker of EOC. Based on its regulation of the tumor suppressor p53, RAD51-AS1-based therapy may represent a viable therapeutic option for EOC in the near future. PMID- 28667303 TI - Measurement of Stokes-operator squeezing for continuous-variable orbital angular momentum. AB - We demonstrate experimentally a measurement scheme for the Stokes operators for the continuous-variable squeezed states of orbital angular momentum (OAM). An OAM squeezed state is generated by coupling a dim Hermite-Gauss HG01-mode quadrature squeezed light beam with a bright HG10-mode coherent light beam on a 98/2 beam splitter. Using an asymmetric Mach-Zehnder interferometer with an extra Dove prism in one arm, we measured the three orbital Stokes operators of the OAM squeezed states with a self-homodyne detection and finally characterized their positions and noise on the orbital Poincare sphere. PMID- 28667304 TI - Mitogenomic analyses support the recent division of the genus Orthotrichum (Orthotrichaceae, Bryophyta). AB - A recently presented taxonomical arrangement of the moss genus Orthotrichum Hedw. s.l. substantially changed the traditional view of the taxon that had been accepted throughout the twentieth century. This paper provides the results of mitogenomic studies that strongly support the new taxonomical concept. Comparative analyses presented in this study confirmed the stable structure of moss mitogenomes. Moreover, 17 complete mitogenome sequences were used to identify the major evolutionary groups, including 11 newly sequenced ones, for this study. The analysis of mitochondrial hotspots revealed intron 4 of the cox1 gene to be the most variable non-coding region. The most variable protein-coding genes in the tribe Orthotricheae were ccmFC and tatC. The intergenic and intronic hotspots of Orthotrichum s.l. identified in the present study do not correspond to those described in vascular plant mitogenomes. PMID- 28667305 TI - Symmetry-based indicators of band topology in the 230 space groups. AB - The interplay between symmetry and topology leads to a rich variety of electronic topological phases, protecting states such as the topological insulators and Dirac semimetals. Previous results, like the Fu-Kane parity criterion for inversion-symmetric topological insulators, demonstrate that symmetry labels can sometimes unambiguously indicate underlying band topology. Here we develop a systematic approach to expose all such symmetry-based indicators of band topology in all the 230 space groups. This is achieved by first developing an efficient way to represent band structures in terms of elementary basis states, and then isolating the topological ones by removing the subset of atomic insulators, defined by the existence of localized symmetric Wannier functions. Aside from encompassing all earlier results on such indicators, including in particular the notion of filling-enforced quantum band insulators, our theory identifies symmetry settings with previously hidden forms of band topology, and can be applied to the search for topological materials.Understanding the role of topology in determining electronic structure can lead to the discovery, or appreciation, of materials with exotic properties such as protected surface states. Here, the authors present a framework for identifying topologically distinct band-structures for all 3D space groups. PMID- 28667306 TI - Crystal structure of Pelagibacterium halotolerans PE8: New insight into its substrate-binding pattern. AB - Lysophospholipase_carboxylesterase (LPCE) has highly conserved homologs in many diverse species ranging from bacteria to humans, as well as substantial biological significance and potential therapeutic implications. However, its biological function and catalytic mechanism remain minimally investigated because of the lack of structural information. Here, we report the crystal structure of a bacterial esterase PE8 belonging to the LPCE family. The crystal structure of PE8 was solved with a high resolution of 1.66 A. Compared with other homologs in the family, significant differences were observed in the amino acid sequence, three dimensional structure, and substrate-binding pattern. Residue Arg79 undergoes configuration switching when binding to the substrate and forms a unique wall, leading to a relatively closed cavity in the substrate-binding pocket compared with the relatively more open and longer clefts in other homologs. Moreover, the mutant Met122Ala showed much stronger substrate affinity and higher catalytic efficiency because less steric repulsion acted on the substrates. Taken together, these results showed that, in PE8, Arg79 and Met122 play important roles in substrate binding and the binding pocket shaping, respectively. Our study provides new insight into the catalytic mechanism of LPCE, which may facilitate the development of structure-based therapeutics and other biocatalytic applications. PMID- 28667307 TI - Dmrt1 is required for primary male sexual differentiation in Chinese soft-shelled turtle Pelodiscus sinensis. AB - In vertebrates, the primary sex-determining signals that initiate sexual development are remarkably diverse, ranging from complete genetic to environmental cues. However, no sex determination-related genes have been functionally identified in reptiles. Here, we characterized a conserved DM domain gene, Dmrt1, in Chinese soft-shelled turtle Pelodiscus sinensis (P. sinensis), which exhibits ZZ/ZW sex chromosomes. Dmrt1 exhibited early male-specific embryonic expression, preceding the onset of gonadal sex differentiation. The expression of Dmrt1 was induced in ZW embryonic gonads that were masculinized by aromatase inhibitor treatment. Dmrt1 knockdown in ZZ embryos by RNA interference resulted in male to female sex reversal, characterized by obvious feminization of gonads, significant down-regulation of testicular markers Amh and Sox9, and remarkable up-regulation of ovarian regulators, Cyp19a1 and Foxl2. Conversely, ectopic expression of Dmrt1 led to largely masculinized genetic females, production of Amh and Sox9, and a decline in Cyp19a1 and Foxl2. These findings demonstrate that Dmrt1 is both necessary and sufficient to initiate testicular development, thereby acting as an upstream regulator of the male pathway in P. sinensis. PMID- 28667308 TI - Enhanced PM2.5 pollution in China due to aerosol-cloud interactions. AB - Aerosol-cloud interactions (aerosol indirect effects) play an important role in regional meteorological variations, which could further induce feedback on regional air quality. While the impact of aerosol-cloud interactions on meteorology and climate has been extensively studied, their feedback on air quality remains unclear. Using a fully coupled meteorology-chemistry model, we find that increased aerosol loading due to anthropogenic activities in China substantially increases column cloud droplet number concentration and liquid water path (LWP), which further leads to a reduction in the downward shortwave radiation at surface, surface air temperature and planetary boundary layer (PBL) height. The shallower PBL and accelerated cloud chemistry due to larger LWP in turn enhance the concentrations of particulate matter with diameter less than 2.5 MUm (PM2.5) by up to 33.2 MUg m-3 (25.1%) and 11.0 MUg m-3 (12.5%) in January and July, respectively. Such a positive feedback amplifies the changes in PM2.5 concentrations, indicating an additional air quality benefit under effective pollution control policies but a penalty for a region with a deterioration in PM2.5 pollution. Additionally, we show that the cloud processing of aerosols, including wet scavenging and cloud chemistry, could also have substantial effects on PM2.5 concentrations. PMID- 28667309 TI - An integrated hyperspectral imaging and genome-wide association analysis platform provides spectral and genetic insights into the natural variation in rice. AB - With progress of genetic sequencing technology, plant genomics has experienced rapid development and subsequently triggered the progress of plant phenomics. In this study, a high-throughput hyperspectral imaging system (HHIS) was developed to obtain 1,540 hyperspectral indices at whole-plant level during tillering, heading, and ripening stages. These indices were used to quantify traditional agronomic traits and to explore genetic variation. We performed genome-wide association study (GWAS) of these indices and traditional agronomic traits in a global rice collection of 529 accessions. With the genome-level suggestive P value threshold, 989 loci were identified. Of the 1,540 indices, we detected 502 significant indices (designated as hyper-traits) that exhibited phenotypic and genetic relationship with traditional agronomic traits and had high heritability. Many hyper-trait-associated loci could not be detected using traditional agronomic traits. For example, we identified a candidate gene controlling chlorophyll content (Chl). This gene, which was not identified based on Chl, was significantly associated with a chlorophyll-related hyper-trait in GWAS and was demonstrated to control Chl. Moreover, our study demonstrates that red edge (680 760 nm) is vital for rice research for phenotypic and genetic insights. Thus, combination of HHIS and GWAS provides a novel platform for dissection of complex traits and for crop breeding. PMID- 28667310 TI - Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood. AB - Corline Heparin Conjugate (CHC), a compound of multiple unfractionated heparin chains, coats cells with a glycocalyx-like layer and may inhibit (xeno)transplant associated activation of the plasma cascade systems. Here, we investigated the use of CHC to protect WT and genetically modified (GTKO.hCD46.hTBM) pig aortic endothelial cells (PAEC) in two pig-to-human in vitro xenotransplantation settings. Model 1: incubation of untreated or hTNFalpha-treated PAEC with 10% human plasma induced complement C3b/c and C5b-9 deposition, cellular activation and coagulation activation in WT and GTKO.hCD46.hTBM PAEC. Coating of untreated or hTNFalpha-treated PAEC with CHC (100 ug/ml) protected against human plasma induced endothelial activation and damage. Model 2: PAEC were grown on microcarrier beads, coated with CHC, and incubated with non-anticoagulated whole human blood. Genetically modified PAEC significantly prolonged clotting time of human blood (115.0 +/- 16.1 min, p < 0.001) compared to WT PAEC (34.0 +/- 8.2 min). Surface CHC significantly improved the human blood compatibility of PAEC, as shown by increased clotting time (WT: 84.3 +/- 11.3 min, p < 0.001; GTKO.hCD46.hTBM: 146.2 +/- 20.4 min, p < 0.05) and reduced platelet adhesion, complement activation, coagulation activation and inhibition of fibrinolysis. The combination of CHC coating and genetic modification provided the greatest compatibility with human blood, suggesting that pre-transplant perfusion of genetically modified porcine organs with CHC may benefit post-transplant xenograft function. PMID- 28667311 TI - Computational insights and the observation of SiC nanograin assembly: towards 2D silicon carbide. AB - While an increasing number of two-dimensional (2D) materials, including graphene and silicene, have already been realized, others have only been predicted. An interesting example is the two-dimensional form of silicon carbide (2D-SiC). Here, we present an observation of atomically thin and hexagonally bonded nanosized grains of SiC assembling temporarily in graphene oxide pores during an atomic resolution scanning transmission electron microscopy experiment. Even though these small grains do not fully represent the bulk crystal, simulations indicate that their electronic structure already approaches that of 2D-SiC. This is predicted to be flat, but some doubts have remained regarding the preference of Si for sp 3 hybridization. Exploring a number of corrugated morphologies, we find completely flat 2D-SiC to have the lowest energy. We further compute its phonon dispersion, with a Raman-active transverse optical mode, and estimate the core level binding energies. Finally, we study the chemical reactivity of 2D-SiC, suggesting it is like silicene unstable against molecular absorption or interlayer linking. Nonetheless, it can form stable van der Waals-bonded bilayers with either graphene or hexagonal boron nitride, promising to further enrich the family of two-dimensional materials once bulk synthesis is achieved. PMID- 28667312 TI - Fabrication of Fresnel plates on optical fibres by FIB milling for optical trapping, manipulation and detection of single cells. AB - The development of economical optical devices with a reduced footprint foreseeing manipulation, sorting and detection of single cells and other micro particles have been encouraged by cellular biology requirements. Nonetheless, researchers are still ambitious for advances in this field. This paper presents Fresnel zone and phase plates fabricated on mode expanded optical fibres for optical trapping. The diffractive structures were fabricated using focused ion beam milling. The zone plates presented in this work have focal distance of ~5 um, while the focal distance of the phase plates is ~10 um. The phase plates are implemented in an optical trapping configuration, and 2D manipulation and detection of 8 um PMMA beads and yeast cells is reported. This enables new applications for optical trapping setups based on diffractive optical elements on optical fibre tips, where feedback systems can be integrated to automatically detect, manipulate and sort cells. PMID- 28667313 TI - Nanoparticles for live cell microscopy: A surface-enhanced Raman scattering perspective. AB - Surface enhanced Raman scattering (SERS) nanoparticles are an attractive alternative to fluorescent probes for biological labeling because of their photostability and multiplexing capabilities. However, nanoparticle size, shape, and surface properties are known to affect nanoparticle-cell interactions. Other issues such as the formation of a protein corona and antibody multivalency interfere with the labeling properties of nanoparticle-antibody conjugates. Hence, it is important to consider these aspects in order to validate such conjugates for live cell imaging applications. Using SERS nanoparticles that target HER2 and CD44 in breast cancer cells, we demonstrate labeling of fixed cells with high specificity that correlates well with fluorescent labels. However, when labeling live cells to monitor surface biomarker expression and dynamics, the nanoparticles are rapidly uptaken by the cells and become compartmentalized into different cellular regions. This behavior is in stark contrast to that of fluorescent antibody conjugates. This study highlights the impact of nanoparticle internalization and trafficking on the ability to use SERS nanoparticle-antibody conjugates to monitor cell dynamics. PMID- 28667314 TI - Evaluation of muscular changes by ultrasound Nakagami imaging in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is the most common debilitating muscular disorder. Developing a noninvasive measure for monitoring the progression of this disease is critical. The present study tested the effectiveness of using ultrasound Nakagami imaging to evaluate the severity of the dystrophic process. A total of 47 participants (40 with DMD and 7 healthy controls) were recruited. Patients were classified into stage 1 (presymptomatic and ambulatory), stage 2 (early nonambulatory), and stage 3 (late nonambulatory). All participants underwent ultrasound examinations on the rectus femoris, tibialis anterior, and gastrocnemius. The results revealed that the ultrasound Nakagami parameter correlated positively with functional severity in the patients with DMD. The median Nakagami parameter of the gastrocnemius muscle increased from 0.50 to 0.85, corresponding to the largest dynamic range between normal and stage 3. The accuracy, sensitivity, and specificity of diagnosing walking function were 85.52%, 76.31%, and 94.73%, respectively. The Nakagami parameter of the rectus femoris and gastrocnemius muscles correlated negatively with the 6-minute walking distance in the ambulatory patients. Therefore, changes in the Nakagami parameter for the gastrocnemius muscle are suitable for monitoring disease progression in ambulatory patients and for predicting ambulation loss. Ultrasound Nakagami imaging shows potential for evaluating patients with DMD. PMID- 28667315 TI - Rare progerin-expressing preadipocytes and adipocytes contribute to tissue depletion over time. AB - Accumulation of progerin is believed to underlie the pathophysiology of Hutchinson-Gilford progeria syndrome, a disease characterized by clinical features suggestive of premature aging, including loss of subcutaneous white adipose tissue (sWAT). Although progerin has been found in cells and tissues from apparently healthy individuals, its significance has been debated given its low expression levels and rare occurrence. Here we demonstrate that sustained progerin expression in a small fraction of preadipocytes and adipocytes of mouse sWAT (between 4.4% and 6.7% of the sWAT cells) results in significant tissue pathology over time, including fibrosis and lipoatrophy. Analysis of sWAT from mice of various ages showed senescence, persistent DNA damage and cell death that preceded macrophage infiltration, and systemic inflammation. Our findings suggest that continuous progerin expression in a small cell fraction of a tissue contributes to aging-associated diseases, the adipose tissue being particularly sensitive. PMID- 28667316 TI - The Specific Vulnerabilities of Cancer Cells to the Cold Atmospheric Plasma Stimulated Solutions. AB - Cold atmospheric plasma (CAP), a novel promising anti-cancer modality, has shown its selective anti-cancer capacity on dozens of cancer cell lines in vitro and on subcutaneous xenograft tumors in mice. Over the past five years, the CAP stimulated solutions (PSS) have also shown their selective anti-cancer effect over different cancers in vitro and in vivo. The solutions used to make PSS include several bio-adaptable solutions, mainly cell culture medium and simple buffered solutions. Both the CAP-stimulated medium (PSM) and the CAP-stimulated buffered solution (PSB) are able to significantly kill cancer cells in vitro. In this study, we systematically compared the anti-cancer effect of PSM and PSB over pancreatic adenocarcinoma cells and glioblastoma cells. We demonstrated that pancreatic cancer cells and glioblastoma cells were specifically vulnerable to PSM and PSB, respectively. The specific response such as the rise of intracellular reactive oxygen species of two cancer cell lines to the H2O2 containing environments might result in the specific vulnerabilities to PSM and PSB. In addition, we demonstrated a basic guideline that the toxicity of PSS on cancer cells could be significantly modulated through controlling the dilutability of solution. PMID- 28667317 TI - An autoregressive logistic model to predict the reciprocal effects of oviductal fluid components on in vitro spermophagy by neutrophils in cattle. AB - After intercourse/insemination, large numbers of sperm are deposited in the female reproductive tract (FRT), triggering a massive recruitment of neutrophils (PMNs) into the FRT, possibly to eliminate excessive sperm via phagocytosis. Some bovine oviductal fluid components (BOFCs) have been shown to regulate in vitro sperm phagocytosis (spermophagy) by PMNs. The modeling approach-based logistic regression (LR) and autoregressive logistic regression (ALR) can be used to predict the behavior of complex biological systems. We, first, compared the LR and ALR models using in vitro data to find which of them provides a better prediction of in vitro spermophagy in bovine. Then, the best model was used to identify and classify the reciprocal effects of BOFCs in regulating spermophagy. The ALR model was calibrated using an iterative procedure with a dynamical search direction. The superoxide production data were used to illustrate the accuracy in validating logit model-based ALR and LR. The ALR model was more accurate than the LR model. Based on in vitro data, the ALR predicted that the regulation of spermophagy by PMNs in bovine oviduct is more sensitive to alpha-1 acid glycoprotein (AGP), PGE2, bovine serum albumin (BSA), and to the combination of AGP or BSA with other BOFCs. PMID- 28667318 TI - Automatic Detection of Galaxy Type From Datasets of Galaxies Image Based on Image Retrieval Approach. AB - This paper presents a new approach for the automatic detection of galaxy morphology from datasets based on an image-retrieval approach. Currently, there are several classification methods proposed to detect galaxy types within an image. However, in some situations, the aim is not only to determine the type of galaxy within the queried image, but also to determine the most similar images for query image. Therefore, this paper proposes an image-retrieval method to detect the type of galaxies within an image and return with the most similar image. The proposed method consists of two stages, in the first stage, a set of features is extracted based on shape, color and texture descriptors, then a binary sine cosine algorithm selects the most relevant features. In the second stage, the similarity between the features of the queried galaxy image and the features of other galaxy images is computed. Our experiments were performed using the EFIGI catalogue, which contains about 5000 galaxies images with different types (edge-on spiral, spiral, elliptical and irregular). We demonstrate that our proposed approach has better performance compared with the particle swarm optimization (PSO) and genetic algorithm (GA) methods. PMID- 28667319 TI - Infection is an Independent Predictor of Death in Diffuse Large B Cell Lymphoma. AB - To identify risk factors for infection in patients with diffuse large B cell lymphoma (DLBCL) undergoing rituximab, cyclophosphamide, vincristine, adriamycin and prednisolone (R-CHOP) treatment. All patients with DLBCL who received R-CHOP from 2004-2014 in a tertiary Australian hospital were identified and information collected from hospital admission data, laboratory results and medical record review. Infection was defined as hospitalisation with an ICD-10-AM diagnostic code for infection. Risk factors for infection and association between infection and survival were modelled using Cox proportional hazards regression. Over the 10 year period there were 325 patients; 191 (58.8%) males, median age 66 years. 206 (63.4%) patients experienced >=1 infection. Independent predictors of infection were Charlson comorbidity index score (hazard ratio [HR] 3.60, p = 0.002), Eastern Cooperative Oncology Group (ECOG) performance status (HR 2.09 p = <0.001) and neutropenia (HR 2.46, p = <0.001). 99 (31%) patients died. Infection was an independent predictor of survival (HR 3.27, p = <0.001, as were age (HR 2.49, p = 0.001), Charlson comorbidity index (HR 4.34, p = <0.001), ECOG performance status (HR 4.33, p = 0.045) and neutropenia (HR 1.95, p = 0.047). Infections are common and infection itself is an independent predictor of survival. Patients at highest risk of infection and death are those with multiple comorbidities, poor performance status and neutropenia. PMID- 28667320 TI - Complete genome sequence of the cellulose-producing strain Komagataeibacter nataicola RZS01. AB - Komagataeibacter nataicola is an acetic acid bacterium (AAB) that can produce abundant bacterial cellulose and tolerate high concentrations of acetic acid. To globally understand its fermentation characteristics, we present a high-quality complete genome sequence of K. nataicola RZS01. The genome consists of a 3,485,191-bp chromosome and 6 plasmids, which encode 3,514 proteins and bear three cellulose synthase operons. Phylogenetic analysis at the genome level provides convincing evidence of the evolutionary position of K. nataicola with respect to related taxa. Genomic comparisons with other AAB revealed that RZS01 shares 36.1%~75.1% of sequence similarity with other AAB. The sequence data was also used for metabolic analysis of biotechnological substrates. Analysis of the resistance to acetic acid at the genomic level indicated a synergistic mechanism responsible for acetic acid tolerance. The genomic data provide a viable platform that can be used to understand and manipulate the phenotype of K. nataicola RZS01 to further improve bacterial cellulose production. PMID- 28667321 TI - Validity Examination of the Dissipative Quantum Model of Olfaction. AB - Despite some inconclusive experimental evidences for the vibrational model of olfaction, the validity of the model has not been examined yet and therefore it suffers from the lack of conclusive experimental support. Here, we generalize the model and propose a numerical analysis of the dissipative odorant-mediated inelastic electron tunneling mechanism of olfaction, to be used as a potential examination in experiments. Our analysis gives several predictions on the model such as efficiency of elastic and inelastic tunneling of electrons through odorants, sensitivity thresholds in terms of temperature and pressure, isotopic effect on sensitivity, and the chiral recognition for discrimination between the similar and different scents. Our predictions should yield new knowledge to design new experimental protocols for testing the validity of the model. PMID- 28667322 TI - Mechanism of non-appearance of hiatus in Tibetan Plateau. AB - In the recent decade, hiatus is the hottest issue in the community of climate change. As the area of great importance, the Tibetan Plateau (TP), however, did not appear to have any warming stoppage in the hiatus period. In fact, the TP showed a continuous warming in the recent decade. To explore why the TP did not show hiatus, we divide the surface air temperature into dynamically-induced temperature (DIT) and radiatively-forced temperature (RFT) by applying the dynamical adjustment method. Our results show that DIT displayed a relatively uniform warming background in the TP, with no obvious correlations with dynamic factors. Meanwhile, as the major contribution to warming, the RFT effect over the TP played the dominant role. The warming role is illustrated using the temperature change between perturbed and control simulation responses to CO2 or black carbon (BC) forcing via Community Earth System Model (CESM). It shows that an obvious warming in the TP is induced by the CO2 warming effect, and BC exhibits an amplifying effect on the warming. Therefore, the continuous warming in the TP was a result of uniform DIT warming over a large scale and enhanced RFT warming at a regional scale. PMID- 28667323 TI - Surface Engineering for Mechanical Enhancement of Cell Sheet by Nano-Coatings. AB - Cell sheet technology is becoming increasingly popular in tissue engineering and regenerative medicine, due to integrity into versatile organ and manageable cell and tissue type from the bank, and no needs of large volume organ for transplantation. Cell sheets have still a room to resolve the mechanical resistance under load-bearing occasion, easy translocation into organ, and prompt shape modulation for regular application in vivo. Herein, a layer-by-layer (LbL) assembly of nanometer scaled film coating method was introduced to inter-planar cell sheet for multilayered cell sheet (M1) and a single cell before sheet formation (M2). Nano-films with collagen and alginate increased mechanical property of cell sheets without altering cell functions, viability, and proliferation. The moduli of triple layered cell sheet (M1) and (M2) were critically enhanced to 109% and 104%, compared to uncoated cell sheet (CON) with mono-layer, while modulus of CON with triple-layers were increased to 43%. LbL assembly to cell sheets offers increased modulus allowing cell sheet engineering to become a potential strategy under load-bearing environment. PMID- 28667324 TI - Dielectric properties of complex magnetic field induced states in PbCuSO4(OH)2. AB - Spin spirals, which coexist with collinear spin order in linarite PbCuSO4(OH)2, indicate electrical polarisation textures of spin-multipolar phases. We derive experimental evidence by a detailed investigation of the magnetic-field dependent dielectric and electric polarization properties at low temperatures. Linarite exhibits a quasi-one-dimensional frustrated S = 1/2 spin chain, which forms 3D spin-spiral order in zero magnetic field for T < 2.85 K. Recently, due to the monoclinic lattice of linarite with CuO2 ribbon chains, complex magnetic field induced states were found. These spin-multipolar phases, which compete with spin density waves at low magnetic fields, exist in close vicinity to the transition from the spin spiral into field induced spin polarized state. Via antisymmetric Dzyaloshinskii-Moriya interaction spin-driven ferroelectricity develops in the spin-spirals state. Via electric polarization measurements this allows to prove the transitions into complex magnetic field induced phases. Thorough analyses of the temperature and magnetic field dependent dielectric properties of a naturally grown single crystalline sample provide a detailed (T,H) phase diagrams for the three different crystallographic directions. PMID- 28667325 TI - XBP1-FoxO1 interaction regulates ER stress-induced autophagy in auditory cells. AB - The purpose of this study was to clarify the relationship among X-box-binding protein 1 unspliced, spliced (XBP1u, s), Forkhead box O1 (FoxO1) and autophagy in the auditory cells under endoplasmic reticulum (ER) stress. In addition, the relationship between ER stress that causes unfolded protein response (UPR) and autophagy was also investigated. The present study reported ER stress induction by tunicamycin treatment that resulted in IRE1alpha-mediated XBP1 mRNA splicing and autophagy. XBP1 mRNA splicing and FoxO1 were found to be involved in ER stress-induced autophagy. This inference was based on the observation that the expression of LC3-II was suppressed by knockdown of IRE1alpha, XBP1 or FoxO1. In addition, XBP1u was found to interact with XBP1s in auditory cells under ER stress, functioning as a negative feedback regulator that was based on two important findings. Firstly, there was a significant inverse correlation between XBP1u and XBP1s expressions, and secondly, the expression of XBP1 protein showed different dynamics compared to the XBP1 mRNA level. Furthermore, our results regarding the relationship between XBP1 and FoxO1 by small interfering RNA (siRNA) paradoxically showed negative regulation of FoxO1 expression by XBP1. Our findings revealed that the XBP1-FoxO1 interaction regulated the ER stress-induced autophagy in auditory cells. PMID- 28667326 TI - Quantitative Proteomics Analysis of Plasmodium vivax Induced Alterations in Human Serum during the Acute and Convalescent Phases of Infection. AB - The radial distribution of Plasmodium vivax malaria burden has evoked enormous concern among the global research community. In this study, we have investigated the serum proteome alterations in non-severe vivax malaria patients before and during patient recuperation starting from the early febrile to the defervescence and convalescent stages of the infection. We have also performed an extensive quantitative proteomics analysis to compare the serum proteome profiles of vivax malaria patients with low (LPVM) and moderately-high (MPVM) parasitemia with healthy community controls. Interestingly, some of the serum proteins such as Serum amyloid A, Apolipoprotein A1, C-reactive protein, Titin and Haptoglobin, were found to be sequentially altered with respect to increased parasite counts. Analysis of a longitudinal cohort of malaria patients indicated reversible alterations in serum levels of some proteins such as Haptoglobin, Apolipoprotein E, Apolipoprotein A1, Carbonic anhydrase 1, and Hemoglobin subunit alpha upon treatment; however, the levels of a few other proteins did not return to the baseline even during the convalescent phase of the infection. Here we present the first comprehensive serum proteomics analysis of vivax malaria patients with different levels of parasitemia and during the acute and convalescent phases of the infection. PMID- 28667327 TI - Intermolecular steric inhibition of Ephexin4 is relieved by Elmo1. AB - Ephexin4, a guanine nucleotide-exchange factor for RhoG, promotes engulfment of apoptotic cells and cancer cell migration in a RhoG-dependent manner, which is synergistically augmented by Elmo1, an Ephexin4-interacting protein. However, the underlying molecular mechanism remains elusive. Here, we report a mechanism by which Elmo1 cooperates with Ephexin4 to activate RhoG. We found that Ephexin4 activity was increased by elimination of its SH3 domain which intermolecularly interacts with the N20 region of Ephexin4. This interaction prevented RhoG from binding to Ephexin4 and thus inhibited RhoG activation. Moreover, we also found that Elmo1 associated with the SH3 domain as well as the N20 region and competed with the SH3 domain for binding to the N20 region, interrupting the interaction of the SH3 domain with the N20 region and thereby promoting RhoG binding to Ephexin4. In addition, the activity of Ephexin4 lacking the SH3 domain was comparable to that of Ephexin4 with Elmo1. Taken together, the data suggest that Elmo1 relieves the steric hindrance of Ephexin4 generated by the intermolecular interaction of the SH3 domain and makes Ephexin4 more accessible to RhoG. PMID- 28667328 TI - EEG correlates of sensorimotor processing: independent components involved in sensory and motor processing. AB - Sensorimotor processing is a critical function of the human brain with multiple cortical areas specialised for sensory recognition or motor execution. Although there has been considerable research into sensorimotor control in humans, the steps between sensory recognition and motor execution are not fully understood. To provide insight into brain areas responsible for sensorimotor computation, we used complex categorization-response tasks (variations of a Stroop task requiring recognition, decision-making, and motor responses) to test the hypothesis that some functional modules are participating in both sensory as well as motor processing. We operationalize functional modules as independent components (ICs) yielded by an independent component analysis (ICA) of EEG data and measured event related responses by means of inter-trial coherence (ITC). Our results consistently found ICs with event-related ITC responses related to both sensory stimulation and motor response onsets (on average 5.8 ICs per session). These findings reveal EEG correlates of tightly coupled sensorimotor processing in the human brain, and support frameworks like embodied cognition, common coding, and sensorimotor contingency that do not sequentially separate sensory and motor brain processes. PMID- 28667329 TI - Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells. AB - Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre clinical development for targeting high risk AML. PMID- 28667330 TI - Co-fermentation using Recombinant Saccharomyces cerevisiae Yeast Strains Hyper secreting Different Cellulases for the Production of Cellulosic Bioethanol. AB - To realize the economical production of ethanol and other bio-based chemicals from lignocellulosic biomass by consolidated bioprocessing (CBP), various cellulases from different sources were tested to improve the level of cellulase secretion in the yeast Saccharomyces cerevisiae by screening an optimal translational fusion partner (TFP) as both a secretion signal and fusion partner. Among them, four indispensable cellulases for cellulose hydrolysis, including Chaetomium thermophilum cellobiohydrolase (CtCBH1), Chrysosporium lucknowense cellobiohydrolase (ClCBH2), Trichoderma reesei endoglucanase (TrEGL2), and Saccharomycopsis fibuligera beta-glucosidase (SfBGL1), were identified to be highly secreted in active form in yeast. Despite variability in the enzyme levels produced, each recombinant yeast could secrete approximately 0.6-2.0 g/L of cellulases into the fermentation broth. The synergistic effect of the mixed culture of the four strains expressing the essential cellulases with the insoluble substrate Avicel and several types of cellulosic biomass was demonstrated to be effective. Co-fermentation of these yeast strains produced approximately 14 g/L ethanol from the pre-treated rice straw containing 35 g/L glucan with 3-fold higher productivity than that of wild type yeast using a reduced amount of commercial cellulases. This process will contribute to the cost effective production of bioenergy such as bioethanol and biochemicals from cellulosic biomass. PMID- 28667331 TI - A new, exceptionally preserved juvenile specimen of Eusaurosphargis dalsassoi (Diapsida) and implications for Mesozoic marine diapsid phylogeny. AB - Recently it was suggested that the phylogenetic clustering of Mesozoic marine reptile lineages, such as thalattosaurs, the very successful fish-shaped ichthyosaurs and sauropterygians (including plesiosaurs), among others, in a so called 'superclade' is an artefact linked to convergent evolution of morphological characters associated with a shared marine lifestyle. Accordingly, partial 'un-scoring' of the problematic phylogenetic characters was proposed. Here we report a new, exceptionally preserved and mostly articulated juvenile skeleton of the diapsid reptile, Eusaurosphargis dalsassoi, a species previously recovered within the marine reptile 'superclade', for which we now provide a revised diagnosis. Using micro-computed tomography, we show that besides having a deep skull with a short and broad rostrum, the most outstanding feature of the new specimen is extensive, complex body armour, mostly preserved in situ, along its vertebrae, ribs, and forelimbs, as well as a row of flat, keeled ventrolateral osteoderms associated with the gastralia. As a whole, the anatomical features support an essentially terrestrial lifestyle of the animal. A review of the proposed partial character 'un-scoring' using three published data matrices indicate that this approach is flawed and should be avoided, and that within the marine reptile 'superclade' E. dalsassoi potentially is the sister taxon of Sauropterygia. PMID- 28667333 TI - Post-secretional activation of Protease IV by quorum sensing in Pseudomonas aeruginosa. AB - Protease IV (PIV), a key virulence factor of Pseudomonas aeruginosa is a secreted lysyl-endopeptidase whose expression is induced by quorum sensing (QS). We found that PIV expressed in QS mutant has severe reduction of activity in culture supernatant (CS), even though it is overexpressed to high level. PIV purified from the QS mutant (M-PIV) had much lower activity than the PIV purified from wild type (P-PIV). We found that the propeptide cleaved from prepro-PIV was co purified with M-PIV, but never with P-PIV. Since the activity of M-PIV was restored by adding the CS of QS-positive and PIV-deficient strain, we hypothesized that the propeptide binds to and inhibits PIV, and is degraded to activate PIV by a QS-dependent factor. In fact, the CS of the QS-positive and PIV deficient strain was able to degrade the propeptide. Since the responsible factor should be a QS-dependently expressed extracellular protease, we tested QS dependent proteases of P. aeruginosa and found that LasB (elastase) can degrade the propeptide and activate M-PIV. We purified the propeptide of PIV and confirmed that the propeptide can bind to and inhibit PIV. We suggest that PIV is post-secretionally activated through the extracellular degradation of the propeptide by LasB, a QS-dependent protease. PMID- 28667332 TI - Viperin is an important host restriction factor in control of Zika virus infection. AB - Zika virus (ZIKV) infection has emerged as a global health threat and infection of pregnant women causes intrauterine growth restriction, spontaneous abortion and microcephaly in newborns. Here we show using biologically relevant cells of neural and placental origin that following ZIKV infection, there is attenuation of the cellular innate response characterised by reduced expression of IFN-beta and associated interferon stimulated genes (ISGs). One such ISG is viperin that has well documented antiviral activity against a wide range of viruses. Expression of viperin in cultured cells resulted in significant impairment of ZIKV replication, while MEFs derived from CRISPR/Cas9 derived viperin-/- mice replicated ZIKV to higher titers compared to their WT counterparts. These results suggest that ZIKV can attenuate ISG expression to avoid the cellular antiviral innate response, thus allowing the virus to replicate unchecked. Moreover, we have identified that the ISG viperin has significant anti-ZIKV activity. Further understanding of how ZIKV perturbs the ISG response and the molecular mechanisms utilised by viperin to suppress ZIKV replication will aid in our understanding of ZIKV biology, pathogenesis and possible design of novel antiviral strategies. PMID- 28667334 TI - 3'UTR polymorphisms of carbonic anhydrase IX determine the miR-34a targeting efficiency and prognosis of hepatocellular carcinoma. AB - Carbonic anhydrase IX (CA9) expression level has been considered as a poor prognostic factor in hepatocellular carcinoma (HCC) patients. However, the judging criteria of CA9 level is hard to define for potential clinical applications. Unlike CA9 expression level, CA9 polymorphism is poorly documented in HCC. Here, we found that people carry A allele at CA9 rs1048638, a 3'UTR SNP, has higher risk of HCC. rs1048638-CA correlates with advanced stages, larger tumor sizes, more vascular invasion, and shorter survival of HCC patients. A allele at CA9 rs1048638 impairs miR-34a, a tumor suppressor miRNA in HCC, binding to CA9 3'UTR and desensitizes CA9 mRNA to miR-34a-dependent RNA degradation. CA9 expression levels were also correlated with miR-34a levels and rs1048638 genotypes in HCC patients. rs1048638 influences HCC risk and progression through effects on miR-34a-targeted CA9 expression in HCC. In conclusion, genetic variations of the CA9 3'UTR play important roles in regulating CA9 expression and cancer progression, which is a novel determinant and target for HCC metastasis and prognosis. PMID- 28667336 TI - Eigen-analysis reveals components supporting super-resolution imaging of blinking fluorophores. AB - This paper presents eigen-analysis of image stack of blinking fluorophores to identify the components that enable super-resolved imaging of blinking fluorophores. Eigen-analysis reveals that the contributions of spatial distribution of fluorophores and their temporal photon emission characteristics can be completely separated. While cross-emitter cross-pixel information of spatial distribution that permits super-resolution is encoded in two matrices, temporal statistics weigh the contribution of these matrices to the measured data. The properties and conditions of exploitation of these matrices are investigated. Con-temporary super-resolution imaging methods that use blinking for super-resolution are studied in the context of the presented analysis. Besides providing insight into the capabilities and limitations of existing super resolution methods, the analysis shall help in designing better super-resolution techniques that directly exploit these matrices. PMID- 28667335 TI - The importance of Rydberg orbitals in dissociative ionization of small hydrocarbon molecules in intense laser fields. AB - Much of our intuition about strong-field processes is built upon studies of diatomic molecules, which typically have electronic states that are relatively well separated in energy. In polyatomic molecules, however, the electronic states are closer together, leading to more complex interactions. A combined experimental and theoretical investigation of strong-field ionization followed by hydrogen elimination in the hydrocarbon series C2D2, C2D4 and C2D6 reveals that the photofragment angular distributions can only be understood when the field dressed orbitals rather than the field-free orbitals are considered. Our measured angular distributions and intensity dependence show that these field-dressed orbitals can have strong Rydberg character for certain orientations of the molecule relative to the laser polarization and that they may contribute significantly to the hydrogen elimination dissociative ionization yield. These findings suggest that Rydberg contributions to field-dressed orbitals should be routinely considered when studying polyatomic molecules in intense laser fields. PMID- 28667337 TI - Contrasting dynamics of leaf potential and gas exchange during progressive drought cycles and recovery in Amorpha fruticosa and Robinia pseudoacacia. AB - Leaf gas exchange is closely associated with water relations; however, less attention has been given to this relationship over successive drought events. Dynamic changes in gas exchange and water potential in the seedlings of two woody species, Amorpha fruticosa and Robinia pseudoacacia, were monitored during recurrent drought. The pre-dawn leaf water potential declined in parallel with gas exchange in both species, and sharp declines in gas exchange occurred with decreasing water potential. A significant correlation between pre-dawn water potential and gas exchange was observed in both species and showed a right shift in R. pseudoacacia in the second drought. The results suggested that stomatal closure in early drought was mediated mainly by elevated foliar abscisic acid (ABA) in R. pseudoacacia, while a shift from ABA-regulated to leaf-water potential-driven stomatal closure was observed in A. fruticosa. After re watering, the pre-dawn water potential recovered quickly, whereas stomatal conductance did not fully recover from drought in R. pseudoacacia, which affected the ability to tightly control transpiration post-drought. The dynamics of recovery from drought suggest that stomatal behavior post-drought may be restricted mainly by hydraulic factors, but non-hydraulic factors may also be involved in R. pseudoacacia. PMID- 28667338 TI - Accurate strain sensing based on super-mode interference in strongly coupled multi-core optical fibres. AB - We report on the use of a multi-core fibre (MCF) comprising strongly-coupled cores for accurate strain sensing. Our MCF is designed to mode match a standard single mode optical fibre. This allows us to fabricate simple MCF interferometers whose interrogation is carried out with light sources, detectors and fibre components readily available from the optical communications tool box. Our MCF interferometers were used for sensing strain. The sensor calibration was carried out in a high-fidelity aerospace test laboratory. In addition, a packaged MCF interferometer was transferred into field trials to validate its performance under deployment conditions, specifically the sensors were installed in a historical iron bridge. Our results suggest that the MCF strain sensors here proposed are likely to reach the readiness level to compete with other mature sensor technologies, hence to find commercial application. An important advantage of our MCF interferometers is their capability to operate at very high temperatures. PMID- 28667340 TI - ANKRD22 promotes progression of non-small cell lung cancer through transcriptional up-regulation of E2F1. AB - Lung cancer is the leading cause of death among all malignancies due to rapid tumor progression and relapse; however, the underlying molecular mechanisms of tumor progression are unclear. In the present study, we identified ANKRD22 as a novel tumor-associated gene in non-small cell lung cancer (NSCLC). According to the clinical correlation analysis, ANKRD22 was highly expressed in primary cancerous tissue compared with adjacent cancerous tissue, and high expression levels of ANKRD22 were significantly correlated with relapse and short overall survival time. Knockdown and overexpression analysis revealed that ANKRD22 promoted tumor progression by increasing cell proliferation. In xenograft assays, knockdown of ANKRD22 or in vivo treatment with ANKRD22 siRNA inhibited tumor growth. Furthermore, ANKRD22 was shown to participate in the transcriptional regulation of E2F1, and ANKRD22 promoted cell proliferation by up-regulating the expression of E2F1 which enhanced cell cycle progression. Therefore, our studies indicated that ANKRD22 up-regulated the transcription of E2F1 and promoted the progression of NSCLC by enhancing cell proliferation. These findings suggest that ANKRD22 could potentially act as a novel therapeutic target for NSCLC. PMID- 28667341 TI - [Locked retrograde fibula nail for the surgical treatment of unstable ankle fractures]. AB - OBJECTIVE: Minimally invasive surgical stabilization of ankle fractures allowing postoperative full weight bearing. INDICATIONS: Unstable ankle fractures type Weber B and C in the geriatric patients or with a critical soft tissue situation. CONTRAINDICATIONS: Ankle fractures in young patients and patients with high demands (relative contraindication). SURGICAL TECHNIQUE: Closed reduction, retrograde insertion of the intramedullary nail into the fibula via a small incision, insertion of up to four locking screws using an aiming device and small incisions. POSTOPERATIVE MANAGEMENT: Full weight bearing in an ankle joint orthosis. RESULTS: In 34 patients who were treated with a retrograde fibula nail, a 6-month follow-up was possible in 18 patients. Osseous consolidation was achieved without any soft tissue complications or infections in all 18 cases. The patients regained their preoperative level of mobility (Parker Mobility Score 4.2 preoperative vs 4.3 postoperative). PMID- 28667339 TI - Differential Membrane Dipolar Orientation Induced by Acute and Chronic Cholesterol Depletion. AB - Cholesterol plays a crucial role in cell membrane organization, dynamics and function. Depletion of cholesterol represents a popular approach to explore cholesterol-sensitivity of membrane proteins. An emerging body of literature shows that the consequence of membrane cholesterol depletion often depends on the actual process (acute or chronic), although the molecular mechanism underlying the difference is not clear. Acute depletion, using cyclodextrin-type carriers, is faster relative to chronic depletion, in which inhibitors of cholesterol biosynthesis are used. With the overall goal of addressing molecular differences underlying these processes, we monitored membrane dipole potential under conditions of acute and chronic cholesterol depletion in CHO-K1 cells, using a voltage-sensitive fluorescent dye in dual wavelength ratiometric mode. Our results show that the observed membrane dipole potential exhibits difference under acute and chronic cholesterol depletion conditions, even when cholesterol content was identical. To the best of our knowledge, these results provide, for the first time, molecular insight highlighting differences in dipolar reorganization in these processes. A comprehensive understanding of processes in which membrane cholesterol gets modulated would provide novel insight in its interaction with membrane proteins and receptors, thereby allowing us to understand the role of cholesterol in cellular physiology associated with health and disease. PMID- 28667343 TI - Interfacial fluid instabilities and Kapitsa pendula. AB - The onset and development of instabilities is one of the central problems in fluid mechanics. Here we develop a connection between instabilities of free fluid interfaces and inverted pendula. When acted upon solely by the gravitational force, the inverted pendulum is unstable. This position can be stabilized by the Kapitsa phenomenon, in which high-frequency low-amplitude vertical vibrations of the base creates a fictitious force which opposes the gravitational force. By transforming the dynamical equations governing a fluid interface into an appropriate pendulum-type equation, we demonstrate how stability can be induced in fluid systems by properly tuned vibrations. We construct a "dictionary"-type relationship between various pendula and the classical Rayleigh-Taylor, Kelvin Helmholtz, Rayleigh-Plateau and the self-gravitational instabilities. This makes several results in control theory and dynamical systems directly applicable to the study of tunable fluid instabilities, where the critical wavelength depends on the external forces or the instability is suppressed entirely. We suggest some applications and instances of the effect ranging in scale from microns to the radius of a galaxy. PMID- 28667342 TI - Ictal postural phantom limb sensation is associated with impaired mental imagery of body parts. PMID- 28667344 TI - [Current EAU guidelines, practice-relevant knowledge, and not a discussion of scientific hypotheses]. PMID- 28667345 TI - [Adjuvant radiotherapy for lymph-node-positive prostate cancer with low tumor load after radical prostatectomy : Multicenter randomized phase III study of the effect of adjuvant radiotherapy in patients with prostate cancer with or without a positive margin after radical prostatectomy (RP) and lymph node metastasis with low tumor load (micrometastases, <= 2 lymph node macrometastases). ART-2 - study AP 61/10 of the AUO]. PMID- 28667346 TI - [Comments on the therapy and prevention of urinary tract infections in children]. PMID- 28667347 TI - Clinical Analysis of Diabetic Combined Pulmonary Mucormycosis. AB - OBJECTIVE: To improve the understanding of diabetic combined pulmonary mucormycosis. METHODS AND RESULTS: The clinical data of twelve patients diagnosed as diabetic combined pulmonary mucormycosis were analyzed by the clinical manifestations, imaging features, diagnosis, treatment and prognosis of this disease. Patients from January 1999 to June 2015 in our hospital had poor blood glucose control and varying degrees of diabetic chronic complications with an on average of diabetes 8.6 +/- 3.5 years. The clinical symptoms of diabetic combined pulmonary mucormycosis included different degrees of fever, cough, sputum and dyspnea. The numbers of white blood cells and neutrophils were significantly elevated in patients, and Mucor had been checked in sputum culture for three times. In addition, although the liver and kidney functions were normal, the patients had hypoxemia and decreased diffusion capacity, lung capacity and carbon dioxide binding force. Imaging manifestations revealed small patchy shadows with nodular shadows and pneumonia in the lung of the patients. Twelve patients took oral hypoglycemic drugs for improving glucose combined with subcutaneous injection of insulin. One patient with intravenous injection of fluconazole was died of respiratory failure at 1 week. There were two of seven cases with amphotericin B liposome died of haemoptysis and respiratory failure, respectively, and the other five were cured. Moreover, four cases who took more than two drugs were cured. CONCLUSION: Diabetic with pulmonary mucormycosis is a rare but fatal fungal infection disease. Diagnosis and treatment early are essential to improve the prognosis of the patients. PMID- 28667348 TI - Cryptococcosis in HIV-negative Patients with Renal Dialysis: A Retrospective Analysis of Pooled Cases. AB - Cryptococcosis is a lethal fungal infection mainly caused by Cryptococcus neoformans/C. gattii species. Currently, our understanding of cryptococcosis episodes in HIV-negative patients during renal dialysis remains scarce and fragmented. Here, we performed an analysis of pooled cases to systemically summarize the epidemiology and clinical characteristics of cryptococcosis among HIV-negative patients with renal dialysis. Using pooled data from our hospital and studies identified in four medical databases, 18 cases were identified and analyzed. The median duration time of renal dialysis for peritoneal renal dialysis and hemodialysis cases was 8 months and 36 months, respectively. Several non-neoformans/gattii species were identified among the renal dialysis recipients with cryptococcosis, particularly Cryptococcus laurentii and Cryptococcus albidus, which share similar clinical manifestations as those caused by C. neoformans and C. gattii. Our analyses suggest that physicians should consider the possibility of the occurrence of cryptococcosis among renal dialysis recipients even when cryptococcal antigen test result is negative. The timely removal of the catheter is crucial for peritoneal dialysis patients with cryptococcosis. In addition, there is a need for optimized antifungal treatment strategy in renal dialysis recipients with cryptococcal infections. PMID- 28667350 TI - Strain and plastic composite support (PCS) selection for vitamin K (Menaquinone 7) production in biofilm reactors. AB - Menaquinone-7 (MK-7), a subtype of vitamin K, has received a significant attention due to its effect on improving bone and cardiovascular health. Current fermentation strategies, which involve static fermentation without aeration or agitation, are associated with low productivity and scale-up issues and hardly justify the commercial production needs of this vitamin. Previous studies indicate that static fermentation is associated with pellicle and biofilm formations, which are critical for MK-7 secretion while posing significant operational issues. Therefore, the present study is undertaken to evaluate the possibility of using a biofilm reactor as a new strategy for MK-7 fermentation. Bacillus species, namely, Bacillus subtilis natto, Bacillus licheniformis, and Bacillus amyloliquifaciens as well as plastic composite, supports (PCS) were investigated in terms of MK-7 production and biofilm formation. Results show the possibility of using a biofilm reactor for MK-7 biosynthesis. Bacillus subtilis natto and soybean flour yeast extract PCS in glucose medium were found as the most potent combination for production of MK-7 as high as 35.5 mg/L, which includes both intracellular and extracellular MK-7. PMID- 28667349 TI - Pediatric 320-row cardiac computed tomography using electrocardiogram-gated model based full iterative reconstruction. AB - BACKGROUND: Full iterative reconstruction algorithm is available, but its diagnostic quality in pediatric cardiac CT is unknown. OBJECTIVE: To compare the imaging quality of two algorithms, full and hybrid iterative reconstruction, in pediatric cardiac CT. MATERIALS AND METHODS: We included 49 children with congenital cardiac anomalies who underwent cardiac CT. We compared quality of images reconstructed using the two algorithms (full and hybrid iterative reconstruction) based on a 3-point scale for the delineation of the following anatomical structures: atrial septum, ventricular septum, right atrium, right ventricle, left atrium, left ventricle, main pulmonary artery, ascending aorta, aortic arch including the patent ductus arteriosus, descending aorta, right coronary artery and left main trunk. We evaluated beam-hardening artifacts from contrast-enhancement material using a 3-point scale, and we evaluated the overall image quality using a 5-point scale. We also compared image noise, signal-to noise ratio and contrast-to-noise ratio between the algorithms. RESULTS: The overall image quality was significantly higher with full iterative reconstruction than with hybrid iterative reconstruction (3.67+/-0.79 vs. 3.31+/-0.89, P=0.0072). The evaluation scores for most of the gross structures were higher with full iterative reconstruction than with hybrid iterative reconstruction. There was no significant difference between full and hybrid iterative reconstruction for the presence of beam-hardening artifacts. Image noise was significantly lower in full iterative reconstruction, while signal-to-noise ratio and contrast-to-noise ratio were significantly higher in full iterative reconstruction. CONCLUSION: The diagnostic quality was superior in images with cardiac CT reconstructed with electrocardiogram-gated full iterative reconstruction. PMID- 28667351 TI - Efficacy and safety of eltrombopag in persistent and newly diagnosed ITP in clinical practice. AB - Eltrombopag is safe and effective in primary chronic ITP. However, lack of clinical trials avoids a clear demonstration of its utility in newly diagnosed and persistent ITP. Our aim here is to report Spanish results for this type of patients. We retrospectively evaluated 220 adult primary ITP patients. According to standard definition, patients were allocated to newly diagnosed (n = 30), persistent (n = 30), and chronic (n = 160) ITP. Groups were homogenous regarding most relevant parameters. 180 (90%) of 220 patients achieved a platelet response (R) with 167 (75.9%) complete responses (CR) after a 15-month follow-up. No statistical significant differences among groups but a trend towards a greater efficacy in newly diagnosed ITP were observed (93.3% of responses with 86.7% of CR). Efficacy in persistent ITP (83.3% of responses with 80.0% of CR) and chronic ITP (79.4% of responses with 73.1% of CR) was similar. 70 patients (31.8%) experienced adverse events. 15 of them were grade 3-4. Most common adverse effects were headache and hepatobiliary laboratory abnormalities (HBLAs). One persistent ITP had a venous thrombosis and one chronic ITP had grade II myelofibrosis. We consider Eltrombopag use for the early stage ITP as effective and safe as it is in chronic ITP. PMID- 28667353 TI - The use of handheld nasal spirometry to predict the presence of obstructive sleep apnea. AB - OBJECTIVE: Nasal obstruction and oral breathing may play an important role in the pathophysiology of obstructive sleep apnea (OSA). This study aims to better understand the link between oral breathing, nasal obstruction, and the spectrum of sleep-disordered breathing. STUDY DESIGN: Prospective study. METHODS AND MATERIALS: Prospective study of patients who presented to the Otolaryngology clinic and underwent polysomnogram (PSG) from 2015 to 2016. Patients were divided into two groups based on the severity of their OSA as defined by PSG results. Both apnea-hypopnea index (AHI) and supine and REM AHI (SUP-REMe AHI), a parameter that takes into account both sleep position and sleep stage, were recorded. The primary outcome was awake nasal-oral forced expiratory volume in 1 s (FEV1) ratio as measured by handheld spirometry. RESULTS: A total of 21 patients were included in the study. We found that nasal-oral FEV1 ratio was significantly different between patients with minimal and substantial OSA as stratified by SUP-REMe AHI, while not significant when stratified by AHI. CONCLUSION: Patients with substantial OSA as determined by SUP-REMe AHI are more likely to have decreased awake nasal airflow as measured by nasal-oral FEV1. SUP REMe AHI may represent an improved metric of OSA severity by taking into account sleep position and sleep stage. Handheld spirometers have the potential to become an important office tool by allowing for easy and reliable measurement of nasal airflow. PMID- 28667352 TI - Endothelium-derived fibronectin regulates neonatal vascular morphogenesis in an autocrine fashion. AB - Fibronectin containing alternatively spliced EIIIA and EIIIB domains is largely absent from mature quiescent vessels in adults, but is highly expressed around blood vessels during developmental and pathological angiogenesis. The precise functions of fibronectin and its splice variants during developmental angiogenesis however remain unclear due to the presence of cardiac, somitic, mesodermal and neural defects in existing global fibronectin KO mouse models. Using a rare family of surviving EIIIA EIIIB double KO mice, as well as inducible endothelial-specific fibronectin-deficient mutant mice, we show that vascular development in the neonatal retina is regulated in an autocrine manner by endothelium-derived fibronectin, and requires both EIIIA and EIIIB domains and the RGD-binding alpha5 and alphav integrins for its function. Exogenous sources of fibronectin do not fully substitute for the autocrine function of endothelial fibronectin, demonstrating that fibronectins from different sources contribute differentially to specific aspects of angiogenesis. PMID- 28667354 TI - Dose individualization of sunitinib in metastatic renal cell cancer: toxicity adjusted dose or therapeutic drug monitoring. AB - PURPOSE: Dose individualization of sunitinib has been proposed using therapeutic drug monitoring (TDM) or toxicity-adjusted dose (TAD). We prospectively studied aspects of TDM and TAD to inform future trials, namely (1) intrapatient variability (CV) of sunitinib and (2) feasibility of a TAD protocol. METHODS: Sunitinib dose was adjusted to ensure grade 1 or 2 toxicity on 10-20 days of each 42-day cycle. Total trough levels (TTL) C min of sunitinib and its active metabolite were measured every 6 weeks. RESULTS: In 45 patients with mRCC, 283 TTL samples were assayed over a median 30 weeks (6-108 weeks). Fifteen patients (33%) had an intrapatient CV of >25% in TTL. Ninety-one percent achieved target toxicity with a final sunitinib dose of 25 mg (18%), 37.5 mg (27%), 50 mg (50%), and 62.5 or 75 mg (7%). TTL C min was <50, 50-100, and >100 ng/mL in 7 (15%), 31 (69%), and 7 patients (15.5%), respectively. The median overall survival was 32 months. CONCLUSIONS: Sunitinib level has minimal variability in the majority of patients on stable dose. A subset of patients had a significant intrapatient variation, so we recommend two samples 4 to 6 months apart. TAD is feasible for dosing sunitinib and showed a favourable outcome. PMID- 28667355 TI - Visfatin mediates doxorubicin resistance in human colorectal cancer cells via up regulation of multidrug resistance 1 (MDR1). AB - Colorectal cancer (CRC) is one of the prevalent and deadly cancers worldwide. Chemotherapy resistance is one of the most challenging problems for CRC and other cancer treatments. Recent studies indicated that increasing levels of visfatin are correlated with worse clinical prognosis of CRC patients, while the effects and mechanisms of visfatin on progression of CRC remain unclear. Our present study established doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (named HCT-116 Dox/R and SW480 Dox/R). The expression of visfatin, while not IL-6, IL-8, or TGF-beta, in CRC Dox-resistant cells was significantly greater than that in their parental cells, while knockdown of visfatin by its specific siRNAs can elevate Dox sensitivity of CRC-resistant cells. In addition, si-visfatin can significantly down regulate the expression of multidrug resistance 1 (MDR1), while not multidrug resistance-associated protein 1 or lung resistance-related protein, in both HCT-116 Dox/R and SW480 Dox/R cells. Visfatin can regulate the transcription of MDR1 via modulating its promoter activities. Si-visfatin can also decrease the activation and nuclear localization of p65, one of the most important transcription factors for the expression of MDR1. Chromatin immunoprecipitation (ChIP) indicated that si-visfatin can suppress the binding between p65 and MDR1 promoter. Collectively, our present study revealed that visfatin mediates the Dox resistance of CRC cells via up regulation of MDR1. It indicated that targeted inhibition of visfatin might be helpful for overcoming Dox resistance of CRC therapy. PMID- 28667357 TI - ? PMID- 28667358 TI - ? PMID- 28667356 TI - Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice. AB - While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces "aging-like" effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire. PMID- 28667359 TI - Sensitivity of susceptibility-weighted imaging in detecting developmental venous anomalies and associated cavernomas and microhemorrhages in children. AB - PURPOSE: Developmental venous anomalies (DVA) are common neuroimaging abnormalities that are traditionally diagnosed by contrast-enhanced T1-weighted images as the gold standard. We aimed to evaluate the sensitivity of SWI in detecting DVA and associated cavernous malformations (CM) and microhemorrhages in children in order to determine if SWI may replace contrast-enhanced MRI sequences. METHODS: Contrast-enhanced T1-weighted images were used as diagnostic gold standard for DVA. The presence of DVA was qualitatively assessed on axial SWI and T2-weighted images by an experienced pediatric neuroradiologist. In addition, the presence of CM and microhemorrhages was evaluated on SWI and contrast-enhanced T1-weighted images. RESULTS: Fifty-seven children with DVA (34 males, mean age at neuroimaging 11.2 years, range 1 month to 17.9 years) were included in this study. Forty-nine out of 57 DVA were identified on SWI (sensitivity of 86%) and 16 out of 57 DVA were detected on T2-weighted images (sensitivity of 28.1%). General anesthesia-related changes in brain hemodynamics and oxygenation were most likely responsible for the majority of SWI false negative. CM were detected in 12 patients on axial SWI, but only in six on contrast-enhanced T1-weighted images. Associated microhemorrhages could be identified in four patients on both axial SWI and contrast-enhanced T1-weighted images, although more numerous and conspicuous on SWI. CONCLUSION: SWI can identify DVA and associated cavernous malformations and microhemorrhages with high sensitivity, obviating the need for contrast-enhanced MRI sequences. PMID- 28667360 TI - Cortical venous disease severity in MELAS syndrome correlates with brain lesion development. AB - PURPOSE: MELAS syndrome is a mitochondrial disorder typified by recurrent stroke like episodes, seizures, and progressive brain injury. Abnormal mitochondria have been found in arterial walls implicating a vasculogenic etiology. We have observed abnormal cortical vein T2/FLAIR signal in MELAS patients, potentially representing wall thickening and sluggish flow. We sought to examine the relationship of hyperintense veins and brain lesions in MELAS. METHODS: Imaging databases at two children's hospitals were searched for brain MRIs from MELAS patients. Artifact, sedated exams, and lack of 2D-T2/FLAIR sequences were exclusion criteria. Each exam was assigned a venous score based on number of T2/FLAIR hyperintense veins: 1 = <10, 2 = 10 to 20, 3 = >20. Cumulative brain lesions and venous score in MELAS and aged-matched normal exams were compared by Mann-Whitney test. RESULTS: A total of 106 exams from 14 unique MELAS patients (mean 16 +/- 3 years) and 30 exams from normal aged-matched patients (mean 15 +/- 3 years) were evaluated. Median venous score between MELAS and control patients significantly differed (3 versus 1; p < 0.001). In the MELAS group, venous score correlated with presence (median = 3) or absence (median = 1) of cumulative brain lesions. In all 8 MELAS patients who developed lesions, venous hyperintensity was present prior to, during, and after lesion onset. Venous score did not correlate with brain lesion acuity. CONCLUSION: Abnormal venous signal correlates with cumulative brain lesion severity in MELAS syndrome. Cortical venous stenosis, congestion, and venous ischemia may be mechanisms of brain injury. Identification of cortical venous pathology may aid in diagnosis and could be predictive of lesion development. PMID- 28667361 TI - [International relationships in ophthalmology in the German Democratic Republic (GDR)]. AB - International relationships in ophthalmology in the former German Democratic Republic (GDR) were directed by the government and predominantly promoted relationships to socialist countries in Eastern Europe. The lack of freedom of travel, restrictions of import for scientific journals and general prevention of contacts by the State security service led to a stagnation in daily practice and in research, mainly from 1961 until 1989. PMID- 28667362 TI - Quantitative contrast-enhanced CT attenuation evaluation of osseous metastases following chemotherapy. AB - PURPOSE: Osseous metastases often undergo an osteoblastic healing response following chemotherapy. The purpose of our study was to demonstrate the quantitative CT changes in attenuation of osseous metastases before and after chemotherapy. MATERIALS AND METHODS: Our study was IRB approved and HIPAA compliant. Our cohort consisted of 86 consecutive cancer patients with contrast enhanced CTs before and 14 +/- 2 (12-25) months after initiation of chemotherapy (60 +/- 11 years, 36 males, 50 females). The average and maximum metastasis attenuations were measured in Hounsfield units (HU) by two readers. Treatment effects were assessed using paired t-tests and Fisher exact tests. Intraclass correlation coefficients (ICCs) were calculated. Patient records were reviewed to determine the patient's clinical status (worse, unchanged, or improved) at the time of follow-up CT. RESULTS: The distribution of lesion types was as follows: lytic (30/86, 35%), blastic (43/86, 50%), and mixed lytic-blastic (13/86, 15%). There was a significant increase in average and maximum CT attenuation of metastases following chemotherapy for all patients, which remained statistically significant when stratified by lesion type, clinical status (worsening or improving/stable), cancer type (breast, lung), and radiation therapy (P < 0.05). In a subgroup of patients whose osseous metastases decreased in average attenuation (14/86, 16%), more patients had a worse clinical status (11/14, 79%) (P = 0.02). ICC was almost perfect for average attenuation and substantial for maximum attenuation. CONCLUSION: Quantitative assessment of osseous metastatic disease using CT attenuation measurements demonstrated a statistically significant increase in attenuation more than 12 months after initiation of chemotherapy. PMID- 28667364 TI - Erratum to: In Vivo Model of Small Intestine. PMID- 28667363 TI - Which patient-reported factors predict referral to spinal surgery? A cohort study among 4987 chronic low back pain patients. AB - PURPOSE: It is unknown which chronic low back pain (CLBP) patients are typically referred to spinal surgery. The present study, therefore, aimed to explore which patient-reported factors are predictive of spinal surgery referral among CLBP patients. METHODS: CLBP patients were consecutively recruited from a Dutch orthopedic hospital specialized in spine care (n = 4987). The outcome of this study was referral to spinal surgery (yes/no), and was assessed using hospital records. Possible predictive factors were assessed using a screening questionnaire. A prediction model was constructed using logistic regression, with backwards selection and p < 0.10 for keeping variables in the model. The model was internally validated and evaluated using discrimination and calibration measures. RESULTS: Female gender, previous back surgery, high intensity leg pain, somatization, and positive treatment expectations increased the odds of being referred to spinal surgery, while being obese, having comorbidities, pain in the thoracic spine, increased walking distance, and consultation location decreased the odds. The model's fit was good (X 2 = 10.5; p = 0.23), its discriminative ability was poor (AUC = 0.671), and its explained variance was low (5.5%). A post hoc analysis indicated that consultation location was significantly associated with spinal surgery referral, even after correcting for case-mix variables. CONCLUSION: Some patient-reported factors could be identified that are predictive of spinal surgery referral. Although the identified factors are known as common predictive factors of surgery outcome, they could only partly predict spinal surgery referral. PMID- 28667365 TI - A high-urgency stroke code reduces in-hospital delays in acute ischemic stroke: a single-centre experience. AB - Timely treatment is essential in acute ischemic stroke as the chances of recovery diminish over time, so efforts are necessary to streamline in-hospital pathways and reduce delays. Here, we analyse the interventions to reduce door-to-needle time in stroke patients suitable for intravenous thrombolysis at the Emergency Department of San Carlo Borromeo Hospital, Milan, Italy. All stroke patients consecutively treated with intravenous thrombolysis at our centre from January 1, 2013 to December 31, 2015 were included in this analysis. The main interventions adopted were (1) continuous education of personnel, (2) reconsideration of blood tests and identify the ones really affecting treatment decision, (3) approval of a new high-urgency Stroke Code activated as soon as the triage nurse comes to know of a potential thrombolysis candidate. Median door-to-needle time progressively decreased from 103 min (iqr 78-120) in 2013, to 92 min (iqr 72-112) in 2014, and to 37 min (iqr 27-58) with the new Stroke Code (p < 0.001) in 2015. Simultaneously, median onset-to-treatment time decreased from 177 min (iqr 142 188) in 2013, to 155 min (iqr 141-198) in 2014, and to 114 min (iqr 86-160) with the new Stroke Code (p < 0.001 and p 0.005, respectively). We did not observe any significant difference in bleeding risks or deaths, whereas the likelihood of favourable outcome (mRS 0-2) increased. Streamlining in-hospital pathways with progressive interventions significantly decreases door-to-needle time and onset to-treatment time and may contribute to improve stroke outcomes. PMID- 28667366 TI - Normal platelet function. AB - Platelets play an important role in the vessel. Following their formation from megakaryocytes, platelets exist in circulation for 5-7 days and primarily function as regulators of hemostasis and thrombosis. Following vascular insult or injury, platelets become activated in the blood resulting in adhesion to the exposed extracellular matrix underlying the endothelium, formation of a platelet plug, and finally formation and consolidation of a thrombus consisting of both a core and shell. In pathological conditions, platelets are essential for formation of occlusive thrombus formation and as a result are the primary target for prevention of arterial thrombus formation. In addition to regulation of hemostasis in the vessel, platelets have also been shown to play an important role in innate immunity as well as regulation of tumor growth and extravasations in the vessel. These primary functions of the platelet represent its normal function and versatility in circulation. PMID- 28667367 TI - Platelets, circulating tumor cells, and the circulome. AB - Platelets are cytoplasmic fragments generated by megakaryocytes in the bone marrow and do not possess a nucleus. They contribute to the "Circulome" consisting of all circulating cells, factors and macromolecules such as cfDNA. Their primary function is to recognize vascular lesions and initiate thrombus formation that ceases bleeding. This distinctive characteristic of platelets also contributes to cancer and its progression. The ability of platelets to recognize and interact with other cells and neighboring platelets enables them to interact with tumor cells in the circulation. Receptor recognition and factor mediated crosstalk between tumor cells and platelets stimulate platelet activation, release of factors, and aggregation that promotes tumor cell survival and cancer progression. This review describes platelet: (i) contributions to the "Circulome" (ii) their importance as diagnostic tools in predicting cancer risk and (iii) therapies targeting platelet activation in inhibiting tumor progression and metastasis. PMID- 28667368 TI - [Puberty is a major factor in pilonidal sinus disease : Gender-specific investigations of case number development in Germany from 2007 until 2015]. AB - BACKGROUND: Pilonidal sinus disease is an acute abscess-forming or chronic subacute inflammation, characterized by a fistula system with typical ostia. Treatment is primarily surgical. OBJECTIVE: This study aimed to investigate and evaluate the evolution of pilonidal sinus disease in Germany on the basis of data provided by the Federal Statistical Office in Germany (Statistisches Bundesamt). MATERIAL AND METHODS: From the diagnosis data of hospital inpatients generated by the Federal Statistical Office in Germany the data on the International Classification of Diseases (ICD) code L05 for pilonidal sinus from 2007 to 2015 were extracted and processed. RESULTS AND DISCUSSION: The number of cases increased from 25,835 cases in 2007 to 31,033 cases in 2011, followed by a decrease to 30,235 cases in 2015. Considering the number of patients under 20 years of age, there was also an increase from 40 cases per 100,000 population in 2007 to 50 cases per 100,000 population in 2013. Ever since, the case numbers have remained relatively constant and have reached a plateau. The maximum number of case numbers was in the age group of 20-24 years. The female age group 10-14 years old is the only group among all investigated age groups with more cases than the respective male age group. The investigated data did not permit any epidemiological conclusions for pilonidal sinus disease because outpatient cases have not been included. The higher incidence in the female age group 10-14 years old could be explained by the earlier onset of adolescence. Thus, adolescence appears to have a major impact on the development of pilonidal sinus disease. PMID- 28667370 TI - Structure-Photoproperties Relationship Investigation of the Singlet Oxygen Formation in Porphyrin-Fullerene Dyads. AB - A systematic structure-photoproperties relationship study of the interactions of porphyrin-fullerene dyads with molecular oxygen was conducted on a set of three porphyrin-fullerene dyads, as this approach of related applications - oxygen sensitivity and photo-induced singlet oxygen generation - of such dyads remained to be endeavoured. To promote energy transfers between the porphyrin and fullerene units and limit undesired charge separation, a particular attention was devoted to the choice of the solvents for the photoproperties determination. Toluene, in which in addition the compounds investigated are not aggregated, was selected accordingly. The molecular orbital levels and energy gaps of the dyads were determined by electrochemistry and theoretical calculations. Their ground state absorption, steady-state fluorescence-based oxygen sensitivity and photo induced singlet oxygen generation were determined. The dyads were designed to benefit from a facilitated synthetic porphyrin-fullerene coupling thanks to an easy access to formyl-functionalized porphyrins. The effect of two structural parameters was investigated: the presence of electron-donating hexyloxy chains at the para position of the meso-phenyl, and the presence of a phenylacetylene spacer. This latest factor appeared to have the most predominant effect on all these properties. PMID- 28667369 TI - DFT studies of the substituent effects of dimethylamino on non-heme active oxidizing species: iron(V)-oxo species or iron(IV)-oxo acetate aminopyridine cation radical species? AB - Through the introduction of dimethylamino (Me2N) substituent at the pyridine ring of 2-((R)-2-[(R)-1-(pyridine-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1 ylmethyl)pyridine (PDP) ligand, the non-heme FeII(Me2NPDP)/H2O2/AcOH catalyst system was found to exhibit significant higher catalytic activity and enantioselectivity than the non-substituent one in the asymmetric epoxidation experiments. The mechanistic origin of the remarkable substituent effects in these oxidation reactions has not been well established. To ascertain the potent oxidant and the related reaction mechanism, a detailed DFT calculation was performed. Interestingly, a novel Fe(IV)-oxo Me2NPDP cation radical species, [(Me2NPDP)+.FeIV(O)(OAc)]2+ ( Me2N 5), with about one spin spreading over the non heme Me2NPDP ligand was formed via a carboxylic-acid-assisted O-O bond heterolysis, which is reminiscent of Compound I (an Fe(IV)(O)(porphyrin cation radical) species) in cytochrome P450 chemistry. Me2N 5 is energetically comparable with the cyclic ferric peracetate species Me2N 6, while in the pristine Fe(PDP) catalyst system, H 6 is more stable than H 5. Comparison of the activation energy for the ethylene epoxidation promoted by Me2N 5 and Me2N 6, Me2N 5 is supposed as the true oxidant triggering the epoxidation of olefins. In addition, a systematic research on the substituent effects varied from the electron-donating substituent (dMM, the substituents at sites 3, 4, and 5 of the pyridine ring: methyl, methoxyl, and methyl) to the electron-withdrawing one (CF3, 2,6-bis(trifluoromethyl)phenyl) on the electronic structure of the reaction intermediates has also been investigated. An alternative cyclic ferric peracetate complex is obtained, indicating that the substituents at the pyridine ring of PDP ligands have significant impacts on the electronic structure of the oxidants. PMID- 28667371 TI - Surface Engineered Ho3+ Incorporated Fluorescent Dye-Doped Bifunctional Silica Nanoparticles for Receptor Targeted Fluorescence Imaging and Potential Magnetic Resonance Imaging. AB - The authors report Ho3+ ion incorporated and fluorescent dye-doped silica nanoparticles which are engineered to enable the imaging modalities of receptor targeted fluorescence imaging (FI) and magnetic resonance imaging (MRI). The silica nanoparticles synthesized through a modified Stober method is luminomagnetic by virtue of the luminescence of organic dye fluorophore (FITC) and magnetism of Ho3+. The doping concentration of Ho3+ is estimated by inductively coupled plasma mass spectrometry (ICP-MS) as 0.97%. The presence of Ho3+ has a little effect on the luminescence intensity but impart strong paramagnetism of 27.217 emu/g at room temperature. The relaxivity measurements shown that the nanoparticles exhibit a longitudinal relaxivity (r1) of 0.12 s-1 mM-1 and transverse relaxivity (r2) of 26.96 s-1 mM-1, which makes the system potentially suitable for developing T2 MRI contrast agents based on holmium. The luminomagnetic nanoparticles were surface engineered through aminization and conjugated with folic acid (FA) to address the folate receptor targeted imaging of the cancer cells. The biocompatibility studies revealed no apparent toxicity even at higher doses of 750 MUg/mL and at 48 h of incubation. The as prepared nanoparticles were demonstrated as a bioimaging probe in the in vitro receptor targeted fluorescence imaging of HeLa cells. The luminescence and magnetism together with biocompatibility enables the adaptability of the present system as a nano platform for potential bimodal imaging. Graphical Abstract ?. PMID- 28667372 TI - What can be observed in real time PCR and when does it show? AB - Real time, or quantitative, PCR typically starts from a very low concentration of initial DNA strands. During iterations the numbers increase, first essentially by doubling, later predominantly in a linear way. Observation of the number of DNA molecules in the experiment becomes possible only when it is substantially larger than initial numbers, and then possibly affected by the randomness in individual replication. Can the initial copy number still be determined? This is a classical problem and, indeed, a concrete special case of the general problem of determining the number of ancestors, mutants or invaders, of a population observed only later. We approach it through a generalised version of the branching process model introduced in Jagers and Klebaner (J Theor Biol 224(3):299-304, 2003. doi: 10.1016/S0022-5193(03)00166-8 ), and based on Michaelis-Menten type enzyme kinetical considerations from Schnell and Mendoza (J Theor Biol 184(4):433-440, 1997). A crucial role is played by the Michaelis Menten constant being large, as compared to initial copy numbers. In a strange way, determination of the initial number turns out to be completely possible if the initial rate v is one, i.e all DNA strands replicate, but only partly so when [Formula: see text], and thus the initial rate or probability of succesful replication is lower than one. Then, the starting molecule number becomes hidden behind a "veil of uncertainty". This is a special case, of a hitherto unobserved general phenomenon in population growth processes, which will be adressed elsewhere. PMID- 28667375 TI - Different patterns of gray matter density in early- and middle-late-onset Parkinson's disease: a voxel-based morphometry study. AB - Early-onset Parkinson's disease (EOPD) has a clinical course and characteristics distinct from middle-late-onset Parkinson's disease (M-LOPD). Although many studies have investigated these differences, the neural mechanisms of these characteristics remain unclear. This study aimed to investigate the morphological differences, and their related clinical significance, between EOPD and M-LOPD patients. We recruited two groups of patients, 28 EOPD patients and 37 M-LOPD patients, and two age- and sex-matched control groups (23 controls in each group). The voxel-based morphometry (VBM) technique was used to examine changes in gray matter (GM) density between patients and their corresponding controls. Compared with controls, EOPD patients had lower GM density in the left putamen, inferior frontal gyrus and insula, and higher GM density in the right occipital lobe and bilateral cerebellum posterior lobes. M-LOPD patients had lower GM density in the left cerebellum posterior lobe, occipital lobe and right supplementary motor area (SMA), and higher GM density in the left middle temporal gyrus. Correlation analyses showed that GM density values in the right cerebellum posterior lobe positively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and the Hoehn-Yahr stages in EOPD patients. Our results reveal different patterns of structural changes in EOPD and M-LOPD patients. A probable compensatory effect of the cerebellum was observed and may partly explain the slower decline of motor function in EOPD patients. PMID- 28667373 TI - The Stress-Responding miR-132-3p Shows Evolutionarily Conserved Pathway Interactions. AB - MicroRNAs (miRNAs) are small non-coding RNA chains that can each interact with the 3'-untranslated region of multiple target transcripts in various organisms, humans included. MiRNAs tune entire biological pathways, spanning stress reactions, by regulating the stability and/or translation of their targets. MiRNA genes are often subject to co-evolutionary changes together with their target transcripts, which may be reflected by differences between paralog mouse and primate miRNA/mRNA pairs. However, whether such evolution occurred in stress related miRNAs remained largely unknown. Here, we report that the stress-induced evolutionarily conserved miR-132-3p, its target transcripts and its regulated pathways provide an intriguing example to exceptionally robust conservation. Mice and human miR-132-3p share six experimentally validated targets and 18 predicted targets with a common miRNA response element. Enrichment analysis and mining in house and web-available experimental data identified co-regulation by miR-132 in mice and humans of stress-related, inflammatory, metabolic, and neuronal growth pathways. Our findings demonstrate pan-mammalian preservation of miR-132's neuronal roles, and call for further exploring the corresponding stress-related implications. PMID- 28667374 TI - Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein. AB - Spinocerebellar ataxia 3 (SCA3), which is a progressive neurodegenerative disease, is currently incurable. Emerging studies have reported that human umbilical cord mesenchymal stem cells (HUC-MSCs) transplantation could be a promising therapeutic strategy for cerebellar ataxias. However, few studies have evaluated the effects of HUC-MSCs on SCA3 transgenic mouse. Thus, we investigated the effects of HUC-MSCs on SCA3 mice and the underlying mechanisms in this study. SCA3 transgenic mice received systematic administration of 2 * 106 HUC-MSCs once per week for 12 continuous weeks. Motor coordination was measured blindly by open field tests and footprint tests. Immunohistochemistry and Nissl staining were applied to detect neuropathological alternations. Neurotrophic factors in the cerebellum were assessed by ELISA. We used western blotting to detect the alternations of heat shock protein 70 (HSP70), IGF-1, mutant ataxin-3, and apoptosis-associated proteins. Tunel staining was also used to detect apoptosis of affected cells. The distribution and differentiation of HUC-MSCs were determined by immunofluorescence. Our results exhibited that HUC-MSCs transplantation significantly alleviated motor impairments, corresponding to a reduction of cerebellar atrophy, preservation of neurons, decreased expression of mutant ataxin-3, and increased expression of HSP70. Implanted HUC-MSCs were mainly distributed in the cerebellum and pons with no obvious differentiation, and the expressions of IGF-1, VEGF, and NGF in the cerebellum were significantly elevated. Furthermore, with the use of HSP70 analogy quercetin injection, it demonstrated that HSP70 is involved in mutant ataxin-3 reduction. These results showed that HUC-MSCs implantation is a potential treatment for SCA3, likely through upregulating the IGF-1/HSP70 pathway and subsequently inhibiting mutant ataxin-3 toxicity. PMID- 28667376 TI - Sexually divergent effect of COMT Val/met genotype on subcortical volumes in schizophrenia. AB - Structural and functional alterations of subcortical areas have been observed in schizophrenia. COMT Val108/158Met has been associated with schizophrenia and implicated in different cognitive and neurofunctional alterations. Recent studies suggested that COMT genotype influences neuronal growth. Genetic variations in COMT were associated with sexually dimorphic effects on enzymatic activity, brain anatomy and behavior suggesting that gender might be crucial in interpreting COMT dependent effects. Based on these data, we investigated possible effects of the interaction between COMT Val108/158Met genotype and gender on subcortical volumes among 79 patients with schizophrenia. All patients were genotyped for COMT Val108/158Met polymorphism and underwent 3 T-MRI. Volumetric segmentation of subcortical structures was performed with Freesurfer 5.3. The general linear model yielded no significant effect of COMT genotype alone, thus revealing a significant interaction of gender and COMT gene on subcortical volumes. The overall significance of the interaction was driven by significant effects in the right caudate, and bilaterally in putamen, pallidum, and nucleus accumbens. Post hoc analyses showed that female Met/Met patients had smaller volumes, whereas male subjects homozygous for the Met allele showed higher or not different subcortical volumes compared to the other groups. This study reports a sexually divergent effect of COMT polymorphism on subcortical structures in schizophrenia. These results support the hypothesis of a sexually dimorphic effect of COMT genetic variations on brain morphology. PMID- 28667377 TI - Intramolecular versus intermolecular hydrogen bonds in a novel conjugated dimethylamino-benzylidene-amino-2-naphthoic acid Schiff base. AB - A new compound based on the D-pi-A concept, where D = dimethylamino-phenyl and A = naphthoic acid, separated by an imine motif, was designed, synthesized and characterized. The spectral, energetics, and structural characteristics of the compound were studied thoroughly theoretically by density functional theory (DFT) in the gas and aqueous phases and experimentally (steady-state absorption) in aqueous media with various degrees of polarity and hydrogen bonding ability. This compound shows high sensitivity to the polarity, basicity and proton affinity of the environment. Based on DFT, TD-DFT and NBO analysis, the compound exists in the ground-state with both intermolecular and intramolecular hydrogen bond conformations in association with the -COOH, with latter isomer calculated to be more stable. Furthermore, structural changes via intermolecular solute-solvent interactions, dictate electronic modifications and spectral changes. Graphical abstract Acidic and basic sites in DMAMN involved in protonation/deprotonation. PMID- 28667378 TI - Perturbation of hydrogen bonding in hydrated pyrrole-2-carboxaldehyde complexes. AB - The interaction of external water molecules with hydrated pyrrole-2 carboxaldehyde PCL/(H2O) n complexes was investigated. The work was supported by both theoretical [DFT/TD-DFT methods using 6-311G++(d,p) basis set in the ground (S0) and excited (S1, S2, S3)states] and experimental [UV-Vis, FTIR and Raman] verification. The focus of the present work was on the weak intermolecular O-H?O, N-H?O-H hydrogen bonded interaction (IerHB) between PCL and external water molecules, and the influence of increasing the number of water molecules to form hydrated PCL/(H2O)n complexes. Effects were observed on different vibrational normal modes and on electronic transition levels. A hydrogen-bonded network of water induces a shift to higher energy in certain normal modes of PCL to form stable PCL/(H2O)n complexes by lowering the barrier energy. Potential energy distribution (PED) analysis indicates a significant charge transfer from PCL to water by creating a water bridge. Hydrogen bonding effects account for the substantial red shift and broadness in nuNH, nuCO vibrational modes. Water rearrangement turns out to be the main driving force for hydrated complex formation. Graphical abstract Stability of PCL/(H2O)4 hydarted complex. PMID- 28667379 TI - Calcium levels on admission and before discharge are associated with mortality risk in hospitalized patients. AB - AIM: Investigate the association of calcium levels on admission and change in levels during hospitalization with hospitalization outcomes. METHODS: Historical prospective data of patients hospitalized to units of internal medicine between 2011 and 2013. Albumin-corrected-calcium levels were classified to marked hypocalcemia (<7.5 mg/dL), mild hypocalcemia (7.5-8.5 mg/dL), normal calcium (8.5 10.5 mg/dL), mild hypercalcemia (10.5-11.5 mg/dL), marked hypercalcemia (>11.5 mg/dL). Main outcomes were length-of-hospitalization, in-hospital and long-term mortality. RESULTS: Cohort included 30,813 patients (mean age 67 +/- 18 years, 51% male). Follow-up (median +/- standard deviation) was 1668 +/- 325 days. Most patients had normal calcium on admission (93%), 3% had hypocalcemia, 3% had hypercalcemia. Common causes for marked hypercalcemia were malignancy (56%) and hyperparathyroidism (22%). Last calcium levels before discharge or death were normal in 94%, with similar rates of hypercalcemia or hypocalcemia (3% each). Compared to in-hospital mortality with normal calcium on admission (6%), mortality was higher with mild (8%) and marked hypocalcemia (11%), and highest with mild (18%) and marked hypercalcemia (22%). Mortality rate at the end of follow-up was 48% with normal calcium or mild hypocalcemia, 51% with marked hypocalcemia, 68 and 79% with mild and marked hypercalcemia, respectively. Patients with normal calcium on admission and before discharge had the best prognosis. Hypercalcemia on admission or before discharge was associated with a 70% mortality risk at the end of follow-up. Normalization of admission hypercalcemia had no effect on long-term mortality risk. CONCLUSIONS: Abnormal calcium on admission is associated with increased short-term and long-term mortality. The excess mortality risk is higher with hypercalcemia than hypocalcemia. Calcium normalization before discharge had no effect on mortality. PMID- 28667380 TI - Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia. AB - Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) severe bacterial infection at least once during the patient's follow-up. The absence of the haplotype [Del]-T-[n >= 17] (Hap7) in homozygocity protected against subphenotype (B), in a statistically significant association, resisting correction for multiple testing. For the individual loci, the same association tendencies were observed as in the haplotype, including a deleterious association between the SNP rs4696480 T allele and subphenotype (A), whereas the A/A genotype was protective, and a deleterious effect of the A/T genotype with subphenotype (B), as well as including the protective effect of 196 to -174 insert (Ins) and deleterious effect of the deletion (Del) in homozygocity, against subphenotype (B). Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyurea treatment), and 3.7-kb alpha thalassemia. Interestingly, differences between the effects of the two latter covariables favoring a reduction in the incidence rate of subphenotype (B) contrast with a resulting increase in relation to subphenotype (A). These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients. PMID- 28667381 TI - Differential Treatment Response to Insulin Intensification Therapy: A Post Hoc Analysis of a Randomized Trial Comparing Premixed and Basal-Bolus Insulin Regimens. AB - INTRODUCTION: Identification of subgroups of patients that may benefit most from certain treatment is important because individual treatment response varies due to multiple contributing factors. The present study used the subgroup identification based on the differential effect search (SIDES) algorithm to identify subgroups with different treatment responses to insulin intensification therapies. METHODS: This was a post hoc analysis of a 24-week, multicenter, open label, randomized, parallel study comparing prandial premixed therapy (PPT) to basal-bolus therapy (BBT). Patients with type 2 diabetes mellitus were randomized to PPT (insulin lispro mix 50/50 thrice daily with meals) or BBT (glargine at bedtime plus mealtime insulin lispro) insulin intensification therapies. The SIDES algorithm was used to identify the subgroups from at-goal patients [glycated hemoglobin (HbA1c) <7.0% (53.0 mmol/mol) at the end of 24 weeks; n = 182] who could have benefitted from insulin intensification therapies. RESULTS: Baseline characteristics of overall at-goal patients were comparable between PPT and BBT groups. The SIDES algorithm identified patients with race other than Caucasian (i.e., African-American, Asian, and Hispanic) and baseline fasting blood glucose (FBG) <8.89 mmol/L as a subgroup that could respond better to PPT relative to BBT than the overall at-goal patient population. In this identified subgroup population, the HbA1c mean (standard deviation) changes from baseline to endpoint in PPT and BBT groups were -2.27 (0.88)% versus -2.05 (0.75)%; p = 0.40, respectively; while in the overall at-goal patients, the HbA1c changes were -2.17 (0.79)% versus -2.34 (1.00)%; p = 0.19, respectively. CONCLUSIONS: The preliminary results showed that the subgroup of patients with race other than Caucasian and FBG <8.89 mmol/L may respond better to premixed intensification therapy. This result provides some preliminary information for further investigation in prospective studies. FUNDING: Eli Lilly and Company. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov ID number: NCT00110370. PMID- 28667383 TI - Comparison of fixed-bearing and mobile-bearing total knee arthroplasty after high tibial osteotomy. AB - PURPOSE: There is no information comparing the results of fixed-bearing total knee replacement and mobile-bearing total knee replacement in the same patients previously treated by high tibial osteotomy. The purpose was therefore to compare fixed-bearing and mobile-bearing total knee replacements in patients treated with previous high tibial osteotomy. METHODS: We compared the results of 57 patients with osteoarthritis who had received a fixed-bearing prosthesis after high tibial osteotomy with the results of 41 matched patients who had received a rotating platform after high tibial osteotomy. The match was made for length of follow-up period. The mean follow-up was 17 years (range, 15-20 years). The patients were assessed clinically and radiographically. RESULTS: The pre-operative knee scores had no statistically significant differences between the two groups. So was the case with the intra-operative releases, blood loss, thromboembolic complications and infection rates in either group. There was significant improvement in both groups of knees, and no significant difference was observed between the groups (i.e., fixed-bearing and mobile-bearing knees) for the mean Knee Society knee clinical score (95 and 92 points, respectively), or the Knee Society knee functional score (82 and 83 points, respectively) at the latest follow-up. However, the mean post-operative knee motion was higher for the fixed-bearing group (117 degrees versus 110 degrees ). In the fixed-bearing group, one knee was revised because of periprosthetic fracture. In the rotating platform mobile bearing group, one knee was revised because of aseptic loosening of the tibial component. The Kaplan-Meier survivorship for revision at ten years of follow-up was 95.2% for the fixed bearing prosthesis and 91.1% for the rotating platform mobile-bearing prosthesis. CONCLUSIONS: Although we did manage to detect significant differences mainly in clinical and radiographic results between the two groups, we found no superiority or inferiority of the mobile-bearing total knee prosthesis over the fixed-bearing total knee prosthesis for patients previously operated by high tibial osteotomy. PMID- 28667382 TI - Magnetic Resonance Imaging and Clinical Features in Acute and Subacute Myelopathies. AB - Differential diagnosis of acute and subacute transverse myelopathy includes inflammatory, infectious, vascular, metabolic and paraneoplastic etiologies. Information on the diagnostic approach to transverse myelopathy with regard to daily clinical practice is provided. The differentiation between five lesion patterns on magnetic resonance imaging (MRI) in myelitis may be helpful: (1) longitudinal extensive transverse myelitis, (2) short segment ovoid or peripherally located, (3) "polio-like", (4) granulomatous and (5) segmental with rash. A correlation with these imaging features is supported if the clinical course and neurological symptoms are known. Although the mean interval from onset to nadir of symptoms in spinal cord infarction is 1 h, an overlap with a fulminant course of myelitis is possible, and impaired diffusion may also occur in acute inflammatory processes. As a result, laboratory testing, including aquaporin-4 antibodies and cerebrospinal fluid analysis, is crucial for the correct interpretation of imaging findings. Moreover, the discrimination of acute complete and acute partial transverse myelitis is advantageous in order to identify diverse entities, the latter often being a precursor to multiple sclerosis. Additional brain imaging is mandatory in suspected demyelinating, infectious, neoplastic and systemic autoimmune disease. A symmetrical lesion pattern restricted to individual tracts or dorsal columns indicates subacute combined degeneration of the spinal cord and, in addition to deficiency syndromes, a paraneoplastic etiology should be considered. PMID- 28667384 TI - Effectiveness and Safety of Switching from Innovator Infliximab to Biosimilar CT P13 in Inflammatory Rheumatic Diseases: A Real-World Case Study. AB - OBJECTIVE: CT-P13 is a biosimilar with comparable pharmacokinetics, efficacy and safety to its reference product (RP), infliximab. Studies have shown that switching from RP to CT-P13 does not reduce the effectiveness or safety of treatment. METHODS: In this retrospective real-world study, patients with inflammatory diseases treated with RP were switched to CT-P13 (n = 7) or continued on RP (n = 6). Clinical outcomes were compared between groups after four treatment cycles. RESULTS: CT-P13 demonstrated comparable effectiveness to its RP. All patients who switched to the biosimilar maintained or improved their clinical response, including two who remained in remission and three who moved into remission. In the RP group, five patients maintained their clinical response, with one achieving remission. Safety profiles were similar between groups. CONCLUSIONS: CT-P13 was equally effective as infliximab RP in this real world study. CT-P13 is a valid, lower-cost alternative for patients currently receiving RP. PMID- 28667385 TI - Potential application of SERS for arsenic speciation in biological matrices. AB - Speciation of arsenic is usually carried out using chromatography-based methods coupled with spectroscopic determination; however, the inevitable procedures involving sample preparation and separation could potentially alter the integrity of the arsenic metabolites present in biological samples. Surface-enhanced Raman spectroscopy (SERS) could be a promising alternative for providing a reliable arsenic analysis under the influence of a cellular matrix. A method for arsenic speciation using SERS in cellular matrix was developed in this study and four arsenicals were selected, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV). Silver nanoparticles in the form of colliodal suspension with different surface charges, i.e., coated with citrate (AgNPs-Citrate) and spermine (AgNPs-Spermine) were employed as SERS substrates. Adsorption of arsenicals on nanoparticles in colloidal suspensions and the cellular matrix and the pH, size, and zeta potential of the colloidal suspensions were investigated for a better understanding of the SERS signal response of arsenicals in the colloidal suspensions or under the influence of cellular matrix. Arsenicals showed substantially different SERS responses in the two colloidal suspensions, mainly because of the distinct difference in the interaction between the arsenicals and the nanoparticles. Arsenic speciation in cell lysate could be successfully carried out in AgNPs-Spermine suspension, while AgNPs-Citrate could not yield significant SERS signals under the experimental conditions. This study proved that AgNPs-Spermine colloidal suspension could be a promising SERS substrate for studying arsenic metabolism in a biological matrix, reducing the bias caused by traditional techniques that involve sample extraction and pretreatment. PMID- 28667386 TI - A label-free electrochemical biosensor based on tubulin immobilized on gold nanoparticle/glassy carbon electrode for the determination of vinblastine. AB - Vinblastine (VLB) is prescribed for a wide variety of cancers. Therefore, development of sensitive methods for early diagnosis is urgently required. In this work, a highly sensitive and label-free impedimetric biosensor was fabricated for the electrochemical detection of VLB. First, the gold nanoparticles (AuNPs) were electrodeposited on the surface of a glassy carbon electrode (GCE). 3-Mercaptopropionic acid (MPA) was self-assembled over the AuNPs. Then, tubulin (TUB), as a receptor, was covalently immobilized at the AuNPs/GCE surface via carbodiimide coupling reaction using N-(3 dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) and N-hydroxy succinimide (NHS). The step-by-step modification process was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) in the presence of a redox probe [Fe(CN)6]3-/4-. The VLB concentration was measured through the increase of impedance values in the corresponding specific binding of VLB and TUB. The increased electron-transfer resistance (R et) values were proportional to the value of VLB concentrations in the range of 0.4 to 65.0 nmol L-1 with a detection limit of 8.4 * 10-2 nmol L-1 (SN-1 = 3). The practical analytical performance of the proposed method was demonstrated by determination of VLB in plant extracts and human serum samples with satisfactory recoveries. PMID- 28667387 TI - [Rare cervical soft tissue tumor]. PMID- 28667388 TI - Tufted angiomas of the head and neck. AB - BACKGROUND: Tufted angiomas (TAs) are uncommon benign vascular tumors mostly located cutaneously or subcutaneously in the skin of the neck and upper trunk, which appear during childhood and grow slowly. TAs are a variant of lobular capillary hemangiomas. This is the first study to provide an overview of the current literature in combination with the authors' own clinical experience on this rare entity in the head and neck area with non-dermatological localization. METHODS: A selective Medline and Google Scholar database search was performed. Additionally, we conducted an ICD-10-based database search on hemangiomas (D18.0) in the Charite SAP patient records. RESULTS: We identified 13 reports in the literature consisting of 16 cases of TA of the head and neck. Males were predominantly affected by TAs (70.6%). The mean age of the patients at the time of surgery was 31.5 years; the mean maximum diameter of the tumors was 16.3 mm. Additionally, we report on one case of TA in our Department of Head and Neck Surgery. A male patient presented with swelling and redness of the left upper eyelid. Radiological examination with computed tomography showed a suprabulbar tumor with a diameter of 13 mm. The tumor was surgically removed via a transcutaneous blepharoplasty approach with the patient under general anesthesia. DISCUSSION: There is only one other case report on the surgical excision of an intra-orbital TA described to date. Here, we present an epidemiological overview, therapeutic considerations, and differential diagnoses. PMID- 28667389 TI - Unmonitored use of herbal medicine by patients with breast cancer: reframing expectations. AB - PURPOSE: To identify the unmonitored use of herbal medicine by female patients with breast cancer, examining the impact of an integrative physician (IP) consultation on this practice. METHODS: The files of 269 female patients with breast cancer following an IP consultation were surveyed retrospectively for use of herbal medicine for cancer-related goals. Expectations from the IP consultation and adherence to the IP-guided treatments were examined as well. RESULTS: Among the cohort, 111 (41.3%) reported using herbal medicine for cancer related goals, unmonitored by their oncology healthcare professional. Factors predicting herbal medicine use were the adoption of dietary changes (odds ratio = 13.6, p < 0.001, CI 7.16-26.0) and the expectation that the IP consultation and treatments would address cancer-related goals (odds ratio = 3.29, p = 0.001, CI 1.64-6.6). Patients with metastatic disease were more likely to be using herbal medicine than non-users (34.5 vs. 22.8%; p = 0.088), as were those who had consulted with a complementary/alternative medicine practitioner (54.9 vs. 20.8%; p = 0.005). The IP advised 17 patients (15.3%) to stop taking specific herbal products due to safety-related concerns; and 10 patients to take dietary supplements for relief of specific symptoms. Herbal medicine users were less likely than non-users to adhere to the IP-recommended treatment program (34.7 vs. 48.3%; p = 0.037). CONCLUSIONS: Unmonitored use of herbal medicine by patients with breast cancer is more frequent among those adopting dietary changes for cancer-related goals. Integrative physicians provide evidence-based guidance on the safe and effective use of herbal products, and reframe patient expectations from cancer-related goals to reducing symptoms and improving quality of life. PMID- 28667391 TI - [Tumors of the sellar region]. AB - METHODICAL ISSUE: The anatomy of the sellar region is complex and tumors of the sellar region are very variable because they arise from the many different tissue types in the sellar region, ranging from benign to life-threatening. Despite this variety, approximately 80% of sellar region tumors are due to the 5 most common lesions: adenomas, meningiomas, aneurysms, astrocytomas and craniopharyngiomas. STANDARD RADIOLOGICAL METHODS: In addition to clinical and laboratory results, the magnetic resonance imaging (MRI) and computed tomography (CT) results including the exact anatomical position and the proliferation pattern of the lesion are decisive for the diagnosis. The gold standard for diagnostic imaging is multiplanar, thin section, contrast-enhanced MRI with soft tissue contrast. Vessel imaging and CT are complementary modalities in selected cases and often for preoperative planning. METHODICAL INNOVATIONS: Whereas most sellar region tumors can be well visualized with multiplanar, contrast-enhanced MRI, for very small intrapituitary microadenomas dynamic contrast-enhanced T1-weighted sequences can be necessary. Microadenomas can often only be clearly demarcated from the rest of the pituitary tissue due to the different perfusion pattern. Optimized diffusion-weighted images can also be useful for narrowing down the differential diagnoses of sellar region tumors. PERFORMANCE AND ACHIEVEMENTS: Tumors of the sellar region can be subdivided in intrahypophysial and extrahypophysial lesions as well as intrinsic skull base lesions. The most common sellar tumors are adenomas of the pituitary gland, which can be subdivided into microadenoma and macroadenoma and into secretory and non-secretory. PRACTICAL RECOMMENDATIONS: If there is suspicion of a sellar region lesion due to clinical or laboratory results, multiplanar contrast enhanced thin section MRI of the sellar region should be used as the primary imaging modality. The keys to the diagnosis are the precise anatomical location of the lesion and the proliferation pattern. The most common lesions in the sellar region are pituitary gland adenomas, which can be small and often secretory or larger and often non secretory. PMID- 28667390 TI - Novel PSCA targeting scFv-fusion proteins for diagnosis and immunotherapy of prostate cancer. AB - PURPOSE: Despite great progress in the diagnosis and treatment of localized prostate cancer (PCa), there remains a need for new diagnostic markers that can accurately distinguish indolent and aggressive variants. One promising approach is the antibody-based targeting of prostate stem cell antigen (PSCA), which is frequently overexpressed in PCa. Here, we show the construction of a molecular imaging probe comprising a humanized scFv fragment recognizing PSCA genetically fused to an engineered version of the human DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT), the SNAP-tag, enabling specific covalent coupling to various fluorophores for diagnosis of PCa. Furthermore, the recombinant immunotoxin (IT) PSCA(scFv)-ETA' comprising the PSCA(scFv) and a truncated version of Pseudomonas exotoxin A (PE, ETA') was generated. METHODS: We analyzed the specific binding and internalization behavior of the molecular imaging probe PSCA(scFv)-SNAP in vitro by flow cytometry and live cell imaging, compared to the corresponding IT PSCA(scFv)-ETA'. The cytotoxic activity of PSCA(scFv)-ETA' was tested using cell viability assays. Specific binding was confirmed on formalin fixed paraffin-embedded tissue specimen of early and advanced PCa. RESULTS: Alexa Fluor(r) 647 labeling of PSCA(scFv)-SNAP confirmed selective binding to PSCA, leading to rapid internalization into the target cells. The recombinant IT PSCA(scFv)-ETA' showed selective binding leading to internalization and efficient elimination of target cells. CONCLUSIONS: Our data demonstrate, for the first time, the specific binding, internalization, and cytotoxicity of a scFv-based fusion protein targeting PSCA. Immunohistochemical staining confirmed the specific ex vivo binding to primary PCa material. PMID- 28667393 TI - [Interventional treatment of benign prostatic hyperplasia : Embolization of the testicular vein]. AB - CLINICAL/METHODICAL ISSUE: Embolization of the testicular veins (Gat-Goren technique) is an interventional procedure for the treatment of benign prostatic hyperplasia (BPH). STANDARD RADIOLOGICAL METHODS: In addition to standard urological procedures, such as transurethral resection of the prostate (TUR-P), arterial embolization of the prostate is considered as the interventional radiological method of choice. METHODICAL INNOVATIONS: Embolization of the testicular veins is technically identical to the embolization of varicoceles in infertile men and represents a less invasive treatment. PERFORMANCE: Embolization of the testicular veins can be performed as a low-risk intervention with low side effects. Variants of the venous anatomy can make the procedure more difficult. In current studies a good reduction of symptoms could be achieved in intermediate term follow-up. ACHIEVEMENTS: The medium-term results are promising but data on long-term results and comparisons with alternative treatments are missing. PRACTICAL RECOMMENDATIONS: Embolization of the testicular veins is a minimally invasive method for the treatment of BPH. The procedure can be performed in an outpatient setting. In the intermediate course up to 6 months after treatment, promising results were demonstrated in recent studies. Randomized studies, data on long-term results and comparisons to alternative methods (e. g. arterial prostatic embolization and surgical procedures) are missing. PMID- 28667392 TI - [Multiparametric MRI of the prostate : Important radiological findings for urologists]. AB - CLINICAL/METHODICAL ISSUE: High prevalence of prostate cancer with multifocality and biological heterogeneity. Insufficient conventional urological diagnostics. Discrimination between significant and insignificant cancer needed. STANDARD DIAGNOSTIC METHODS: Digital rectal examination, prostate-specific antigen (PSA) serum level, systematic transrectal ultrasound (TRUS)-guided prostate biopsy. METHODICAL INNOVATIONS: Multiparametric magnetic resonance imaging (mpMRI) including T2-weighted (T2w), diffusion-weighted and dynamic contrast-enhanced MRI according to the prostate imaging reporting and data system (PIRADS), MR-targeted biopsy, most frequently MR/TRUS image fusion biopsy. FINDINGS AND PERFORMANCE: Prostate cancer is characterized by low signal intensity on T2w MRI, restricted water diffusion and pronounced and early uptake of contrast enhancement. Sensitivity and specificity according to the current literature are ca. 80% and 90%, respectively. PRACTICAL RECOMMENDATIONS: In cases of suspected prostate cancer, most accurate are mpMRI according to PIRADS and in cases of positive findings, MRI-targeted biopsy, most frequently as MRI/TRUS image fusion biopsy. PMID- 28667394 TI - [Pain in the ankle and forefoot : Not always a traumatic cause]. PMID- 28667395 TI - [Intra-axial brain tumors in adults : On the basis of the 2016 WHO classification]. AB - CLINICAL/METHODICAL ISSUE: The influence of the World Health Organization (WHO) classification from 2016 on the radiological diagnosis for tumors of the central nervous system (CNS) in adults. STANDARD RADIOLOGICAL METHODS: Computed tomography (CT), magnetic resonance imaging (MRI) and MR spectroscopy. PRACTICAL RECOMMENDATIONS: In order to come as close as possible to the correct diagnosis of CNS tumors, MRI is the long-standing accepted method of choice that can in some cases be supported by the use of CT to demonstrate calcification or bone destruction. In individual cases MRI spectroscopy can be helpful for the differentiation between neoplasms and inflammatory lesions or surveillance of tumor therapy, just as perfusion, which is not discussed in this article. PMID- 28667396 TI - Biomechanics and indications for application of the method of BDSF. Answer to manuscript draft number AOTS-D- 17-00378, Letter to the Editor concerning ''Femoral neck fracture osteosynthesis by the biplane double-supported screw fixation method (BDSF) reduces the risk of fixation failure: clinical outcomes in 207 patients'' by Filipov O, Sommer C, et al. (2017) Arch Orthop Trauma Surg. Apr 8. [Epub ahead of print]. PMID- 28667397 TI - Delayed union of humeral shaft fractures: comparison of autograft with and without platelet-rich plasma treatment: a randomized, single blinded clinical trial. AB - INTRODUCTION: Despite an adequate orthopedic treatment with functional bracing, some patients develop a delayed union in humeral shaft fractures. The objective of the present study was to determine the bone consolidation time among patients with delayed union of diaphyseal humeral fractures who were managed with locking compression plate (LCP) fixation combined with an iliac crest autograft using platelet-rich plasma (PRP) as a co-adjuvant. MATERIALS AND METHODS: This study was a controlled, randomized, experimental, longitudinal, comparative, prospective, blind clinical trial. Patients diagnosed with delayed union of a diaphyseal humeral fracture with at least 4 months of evolution were treated with an open reduction and LCP osteosynthesis combined with an iliac crest autograft. The experimental group also received PRP. The patients were assessed radiographically until 36 weeks of evolution. RESULTS: A total of 16 patients were included. Both groups had similar demographic characteristics. The patients treated with PRP had an earlier beginning of bone consolidation. Furthermore, these same patients exhibited bone consolidation at 19.9 weeks, on average, in contrast to 25.4 weeks in the control group. CONCLUSIONS: The use of PRP promotes earlier bone consolidation in patients with delayed union of the humeral shaft. PMID- 28667398 TI - Caries progression as a risk factor for increase in the negative impact on OHRQOL a longitudinal study. AB - OBJECTIVES: The aim of this study is to evaluate the association between caries lesions progression and oral health-related quality of life (OHRQoL) among Brazilian preschools, after 2 years. MATERIALS AND METHODS: At baseline, 163 children (3-4 years old) enrolled in 12 public primary care services in Porto Alegre/RS-Brazil were evaluated. After 2 years, 119 children were re-evaluated. Calibrated examiners employing the ICDAS criteria conducted clinical examinations. A socio-demographic questionnaire and the Brazilian version of the Early Childhood Oral Health Impact Scale were applied to the parents of the children at baseline and 2-year follow-up. Data analysis was performed using a hierarchical approach based in a conceptual framework testing by Poisson regression. RESULTS: The number of surfaces that progressed from baseline to 2 year follow-up was associated with an increased negative impact on OHRQoL. CONCLUSIONS: Caries progression increased the negative impact on OHRQoL. CLINICAL RELEVANCE: The progression of caries lesions could negative impact on OHRQoL in Brazilian preschoolers. PMID- 28667399 TI - Chemical composition and morphology study of bovine enamel submitted to different sterilization methods. AB - OBJECTIVES: The morphology and chemical composition of enamel submitted to different sterilization methods was studied. METHODS: X-ray photoelectron spectroscopy (XPS), field emission gun scanning electron microscopy (FEG-SEM), and energy-dispersive X-ray spectroscopy (EDS) were performed to evaluate 50 bovine enamel specimens sterilized using four methods: microwaving (MI), gamma irradiation (GI), ethylene oxide (EO), and steam autoclave (SA). Non-sterilized specimens were used as control. RESULTS: XPS indicated that the concentration of P (phosphorus), CO3 (carbonate), and CO3/P was not changed in all groups. GI produced no significant change on elemental composition. SA produced the major decrease in calcium (Ca), Ca/P ratio, and increase in N (nitrogen). MI was found to decrease Ca, Ca/P ratio and O (oxygen), and increase in C (carbon) and N. EO produced decrease in Ca and O with increased C concentration. FEG-SEM revealed surface and in-depth morphological changes on SA specimens. Minor surface alterations were observed for EO and for MI groups, and no alteration was observed on GI group. EDS indicated no difference on elemental composition of enamel bulk among groups. CONCLUSIONS: SA produced mineral loss and morphological alterations on surface and in depth. MI and EO sterilization caused mineral loss showing only slight alteration on enamel surface. GI sterilization preserves the morphological characteristics of enamel. The sterilization methods could be classified from lower to high damage as GI < MI < EO < SA. CLINICAL RELEVANCE: This is a comprehensive comparative study where different methods for enamel sterilization were investigated in terms of chemical changes. The results presented here may help researchers to choose the most appropriate method for their research setting and purpose. PMID- 28667400 TI - Microfluidic device flow field characterization around tumor spheroids with tunable necrosis produced in an optimized off-chip process. AB - Tumor spheroids are a 3-D tumor model that holds promise for testing cancer therapies in vitro using microfluidic devices. Tailoring the properties of a tumor spheroid is critical for evaluating therapies over a broad range of possible indications. Using human colon cancer cells (HCT-116), we demonstrate controlled tumor spheroid growth rates by varying the number of cells initially seeded into microwell chambers. The presence of a necrotic core in the spheroids could be controlled by changing the glucose concentration of the incubation medium. This manipulation had no effect on the size of the tumor spheroids or hypoxia in the spheroid core, which has been predicted by a mathematical model in computer simulations of spheroid growth. Control over the presence of a necrotic core while maintaining other physical parameters of the spheroid presents an opportunity to assess the impact of core necrosis on therapy efficacy. Using micro-particle imaging velocimetry (micro-PIV), we characterize the hydrodynamics and mass transport of nanoparticles in tumor spheroids in a microfluidic device. We observe a geometrical dependence on the flow rate experienced by the tumor spheroid in the device, such that the "front" of the spheroid experiences a higher flow velocity than the "back" of the spheroid. Using fluorescent nanoparticles, we demonstrate a heterogeneous accumulation of nanoparticles at the tumor interface that correlates with the observed flow velocities. The penetration depth of these nanoparticles into the tumor spheroid depends on nanoparticle diameter, consistent with reports in the literature. PMID- 28667402 TI - Phylogenetic, structural, and functional characterization of AMT3;1, an ammonium transporter induced by mycorrhization among model grasses. AB - In the arbuscular mycorrhizal (AM) symbiosis, plants satisfy part of their nitrogen (N) requirement through the AM pathway. In sorghum, the ammonium transporters (AMT) AMT3;1, and to a lesser extent AMT4, are induced in cells containing developing arbuscules. Here, we have characterized orthologs of AMT3;1 and AMT4 in four other grasses in addition to sorghum. AMT3;1 and AMT4 orthologous genes are induced in AM roots, suggesting that in the common ancestor of these five plant species, both AMT3;1 and AMT4 were already present and upregulated upon AM colonization. An artificial microRNA approach was successfully used to downregulate either AMT3;1 or AMT4 in rice. Mycorrhizal root colonization and hyphal length density of knockdown plants were not affected at that time, indicating that the manipulation did not modify the establishment of the AM symbiosis and the interaction between both partners. However, expression of the fungal phosphate transporter FmPT was significantly reduced in knockdown plants, indicating a reduction of the nutrient fluxes from the AM fungus to the plant. The AMT3;1 knockdown plants (but not the AMT4 knockdown plants) were significantly less stimulated in growth by AM fungal colonization, and uptake of both 15N and 33P from the AM fungal network was reduced. This confirms that N and phosphorus nutrition through the mycorrhizal pathway are closely linked. But most importantly, it indicates that AMT3;1 is the prime plant transporter involved in the mycorrhizal ammonium transfer and that its function during uptake of N cannot be performed by AMT4. PMID- 28667403 TI - Molecular and FISH analyses of a 53-kbp intact DNA fragment inserted by biolistics in wheat (Triticum aestivum L.) genome. AB - KEY MESSAGE: A large, 53-kbp, intact DNA fragment was inserted into the wheat ( Triticum aestivum L.) genome. FISH analyses of individual transgenic events revealed multiple insertions of intact fragments. Transferring large intact DNA fragments containing clusters of resistance genes or complete metabolic pathways into the wheat genome remains a challenge. In a previous work, we showed that the use of dephosphorylated cassettes for wheat transformation enabled the production of simple integration patterns. Here, we used the same technology to produce a cassette containing a 44-kb Arabidopsis thaliana BAC, flanked by one selection gene and one reporter gene. This 53-kb linear cassette was integrated in the bread wheat (Triticum aestivum L.) genome by biolistic transformation. Our results showed that transgenic plants harboring the entire cassette were generated. The inheritability of the cassette was demonstrated in the T1 and T2 generation. Surprisingly, FISH analysis performed on T1 progeny of independent events identified double genomic insertions of intact fragments in non homoeologous positions. Inheritability of these double insertions was demonstrated by FISH analysis of the T1 generation. Relative conclusions that can be drawn from molecular or FISH analysis are discussed along with future prospects of the engineering of large fragments for wheat transformation or genome editing. PMID- 28667404 TI - Identification of critical genes associated with lignin biosynthesis in radish (Raphanus sativus L.) by de novo transcriptome sequencing. AB - Radish is an important root vegetable crop with high nutritional, economic, and medicinal value. Lignin is an important secondary metabolite possessing a great effect on plant growth and product quality. To date, lignin biosynthesis-related genes have been identified in some important plant species. However, little information on characterization of critical genes involved in plant lignin biosynthesis is available in radish. In this study, a total of 71,148 transcripts sequences were obtained from radish root, of which 66 assembled unigenes and ten candidate genes were identified to be involved in lignin monolignol biosynthesis. Full-length cDNA sequences of seven randomly selected genes were isolated and sequenced from radish root, and the assembled unigenes covered more than 80% of their corresponding cDNA sequences. Moreover, the lignin content gradually accumulated in leaf during the developmental stages, and it increased from pre cortex to cortex splitting stage, followed by a decrease at thickening stage and then increased at mature stage in root. RT-qPCR analysis revealed that all these genes except RsF5H exhibited relatively low expression level in root at thickening stage. The expression profiles of Rs4CL5, RsCCoAOMT1, and RsCOMT genes were consistent with the changes of root lignin content, implying that these candidate genes may play important roles in lignin formation in radish root. These findings would provide valuable information for identification of lignin biosynthesis-related genes and facilitate dissection of molecular mechanism underlying lignin biosynthesis in radish and other root vegetable crops. PMID- 28667405 TI - Utilizing Hybrid Techniques to Maximize Clinical Outcomes in Congenital Heart Disease. AB - PURPOSE OF REVIEW: The past couple of decades have brought tremendous advances to the field of pediatric and adult congenital cardiology. Recent collaborations between interventional cardiologists and cardiac surgeons have sparked novel innovative hybrid procedures that provide potentially safer, faster, and less invasive alternatives to the management of many diseases. This paper will review the most recent advances in hybrid interventions in the field of pediatric and adult congenital cardiology. RECENT FINDINGS: The earliest experiences with hybrid interventions included intraoperative stenting of pulmonary arteries and perventricular device closure of ventricular septal defects. Newer hybrid interventions have focused on a hybrid approach to stage 1 palliation for infants with hypoplastic left heart syndrome and hybrid approaches to transcatheter pulmonary valve replacement in patients of all ages. Hybrid approaches to complex congenital heart disease are important in the management of congenital heart disease offering a less invasive approach, and novel hybrid procedures will likely be a focus of future research in this field. PMID- 28667407 TI - Invertebrate-Based Water Quality Impairments and Associated Stressors Identified through the US Clean Water Act. AB - Macroinvertebrate community assessment is used in most US states to evaluate stream health under the Clean Water Act. While water quality assessment and impairment determinations are reported to the US Environmental Protection Agency, there is no national summary of biological assessment findings. The objective of this work was to determine the national extent of invertebrate-based impairments and to identify pollutants primarily responsible for those impairments. Evaluation of state data in the US Environmental Protection Agency's Assessment and Total Maximum Daily Load Tracking and Implementation System database revealed considerable differences in reporting approaches and terminologies including differences in if and how states report specific biological assessment findings. Only 15% of waters impaired for aquatic life could be identified as having impairments determined by biological assessments (e.g., invertebrates, fish, periphyton); approximately one-third of these were associated with macroinvertebrate bioassessment. Nearly 650 invertebrate-impaired waters were identified nationwide, and sediment was the most common pollutant in bedded (63%) and suspended (9%) forms. This finding is not unexpected, given previous work on the negative impacts of sediment on aquatic life, and highlights the need to more specifically identify the mechanisms driving sediment impairments in order to design effective remediation plans. It also reinforces the importance of efforts to derive sediment-specific biological indices and numerical sediment quality guidelines. Standardization of state reporting approaches and terminology would significantly increase the potential application of water quality assessment data, reveal national trends, and encourage sharing of best practices to facilitate the attainment of water quality goals. PMID- 28667406 TI - Biochemical indicators of root damage in rice (Oryza sativa) genotypes under zinc deficiency stress. AB - Zn deficiency is one of the major soil constraints currently limiting rice production. Although recent studies demonstrated that higher antioxidant activity in leaf tissue effectively protects against Zn deficiency stress, little is known about whether similar tolerance mechanisms operate in root tissue. In this study we explored root-specific responses of different rice genotypes to Zn deficiency. Root solute leakage and biomass reduction, antioxidant activity, and metabolic changes were measured using plants grown in Zn-deficient soil and hydroponics. Solute leakage from roots was higher in sensitive genotypes and linked to membrane damage caused by Zn deficiency-induced oxidative stress. However, total root antioxidant activity was four-fold lower than in leaves and did not differ between sensitive and tolerant genotypes. Root metabolite analysis using gas chromatography-mass spectrometry and high performance liquid chromatography indicated that Zn deficiency triggered the accumulation of glycerol-3-phosphate and acetate in sensitive genotypes, while less or no accumulation was seen in tolerant genotypes. We suggest that these metabolites may serve as biochemical indicators of root damage under Zn deficiency. PMID- 28667409 TI - Integrating Mental Health Services into Primary Care. PMID- 28667408 TI - Randomized phase II study of daily and alternate-day administration of S-1 for advanced gastric cancer (JFMC43-1003). AB - PURPOSE: Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. METHODS: 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. RESULTS: The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15-2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97-2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). CONCLUSION: The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer. PMID- 28667410 TI - Pollen wall ontogeny in Polemonium caeruleum (Polemoniaceae) and suggested underlying mechanisms of development. AB - By a detailed ontogenetic study of Polemonium caeruleum pollen, tracing each stage of development at high TEM resolution, we aim to understand the establishment of the pollen wall and to unravel the mechanisms underlying sporoderm development. The main steps of exine ontogeny in Polemonium caeruleum, observed in the microspore periplasmic space, are spherical units, gradually transforming into columns, then to rod-like units (procolumellae), the appearance of the initial tectum, growth of columellae in height and tectum in thickness and initial sporopollenin accumulation on them, the appearance of the endexine lamellae and of dark-contrasted particles on the tectum, the appearance of a sponge-like layer and of the intine in aperture sites, the appearance of the foot layer on the base of the sponge-like layer and of spinules on the tectum, and massive sporopollenin accumulation. This sequence of developmental events fits well to the sequence of self-assembling micellar mesophases. This gives (together with earlier findings and experimental exine simulations) strong evidence that genome and self-assembly probably share control of exine formation. It is highly probable that self-assembly is an intrinsic instrument of evolution. PMID- 28667411 TI - Symbiotic microorganisms in Puto superbus (Leonardi, 1907) (Insecta, Hemiptera, Coccomorpha: Putoidae). AB - The scale insect Puto superbus (Putoidae) lives in mutualistic symbiotic association with bacteria. Molecular phylogenetic analyses have revealed that symbionts of P. superbus belong to the gammaproteobacterial genus Sodalis. In the adult females, symbionts occur both in the bacteriocytes constituting compact bacteriomes and in individual bacteriocytes, which are dispersed among ovarioles. The bacteriocytes also house a few small, rod-shaped Wolbachia bacteria in addition to the numerous large, elongated Sodalis-allied bacteria. The symbiotic microorganisms are transovarially transmitted from generation to generation. In adult females which have choriogenic oocytes in the ovarioles, the bacteriocytes gather around the basal part of the tropharium. Next, the entire bacteriocytes pass through the follicular epithelium surrounding the neck region of the ovariole and enter the space between oocyte and follicular epithelium (perivitelline space). In the perivitelline space, the bacteriocytes assemble extracellularly in the deep depression of the oolemma at the anterior pole of the oocyte, forming a "symbiont ball". PMID- 28667412 TI - Exogenous salicylic acid-mediated modulation of arsenic stress tolerance with enhanced accumulation of secondary metabolites and improved size of glandular trichomes in Artemisia annua L. AB - The present study was undertaken to find out individual and interactive effects of arsenic (As) and salicylic acid (SA) on an important medicinal plant, Artemisia annua. As uptake and its accumulation was detected and found to be maximum in roots at higher As concentration (150 MUM). Under As treatments, H2O2 and MDA content were induced. Biomass and chlorophyll content were negatively affected under As treatments. Furthermore, enzymatic (SOD, CAT, APX, and GR) and non-enzymatic antioxidants were also enhanced under As treatments. Exogenous application of SA reduced the extent of H2O2 and O2- generation and lipid peroxidation, while reverted biomass and chlorophyll content to overcome oxidative stress. Simultaneous application of SA with As increased endogenous SA level, artemisinin, and dihydroartemisinic acid as compared with individual As treatment and pre-application of SA with As treatments. The expression of four key artemisinin biosynthetic pathway genes, i.e., ADS, CYP71AV1, DBR2, and ALDH1 were upregulated at a maximum in plants simultaneously treated with SA and As. Similar pattern of artemisinin accumulation and glandular trichome size was observed which attest that SA has a stimulatory impact on artemisinin biosynthesis under As stress. Our study suggests that exogenous application of SA and As together induced more tolerance in A. annua than a comparable dose of SA pre-treatment. The study may provide a platform with dual benefits by developing As-tolerant plants to be used for phytoremediation of arsenic from As contaminated soil and obtaining high artemisinin-producing A. annua plants. PMID- 28667413 TI - Management of toxic cyanobacteria for drinking water production of Ain Zada Dam. AB - Blooms of toxic cyanobacteria in Algerian reservoirs represent a potential health problem, mainly from drinking water that supplies the local population of Ain Zada (Bordj Bou Arreridj). The objective of this study is to monitor, detect, and identify the existence of cyanobacteria and microcystins during blooming times. Samples were taken in 2013 from eight stations. The results show that three potentially toxic cyanobacterial genera with the species Planktothrix agardhii were dominant. Cyanobacterial biomass, phycocyanin (PC) concentrations, and microcystin (MC) concentrations were high in the surface layer and at 14 m depth; these values were also high in the treated water. On 11 May 2013, MC concentrations were 6.3 MUg/L in MC-LR equivalent in the drinking water. This study shows for the first time the presence of cyanotoxins in raw and treated waters, highlighting that regular monitoring of cyanobacteria and cyanotoxins must be undertaken to avoid potential health problems. PMID- 28667414 TI - Indoor airborne fungal pollution in newborn units in Turkey. AB - Pathogenic and/or opportunistic fungal species are major causes of nosocomial infections, especially in controlled environments where immunocompromised patients are hospitalized. Indoor fungal contamination in hospital air is associated with a wide range of adverse health effects. Regular determination of fungal spore counts in controlled hospital environments may help reduce the risk of fungal infections. Because infants have inchoate immune systems, they are given immunocompromised patient status. The aim of the present study was to evaluate culturable airborne fungi in the air of hospital newborn units in the Thrace, Marmara, Aegean, and Central Anatolia regions of Turkey. A total of 108 air samples were collected seasonally from newborn units in July 2012, October 2012, January 2013, and April 2013 by using an air sampler and dichloran 18% glycerol agar (DG18) as isolation media. We obtained 2593 fungal colonies comprising 370 fungal isolates representing 109 species of 28 genera, which were identified through multi-loci gene sequencing. Penicillium, Aspergillus, Cladosporium, Talaromyces, and Alternaria were the most abundant genera identified (35.14, 25.40, 17.57, 2.70, and 6.22% of the total, respectively). PMID- 28667415 TI - Determination of selected steroid hormones in some surface water around animal farms in Cape Town using HPLC-DAD. AB - In this study, a method for the simultaneous determination of two steroid hormones, 17beta-estradiol (E2) and estriol (E3), and a hormone mimicking polycarbonate, bisphenol-A (BPA), was developed and validated. This was thereafter used for the determination of the levels of the hormones in surface water collected around some livestock farms. The sensitivity of the method allowed the LODs and LOQs of the hormones and mimic hormone in the range 1.14 2.510 and 3.42-7.53 MUg/L, respectively. The results revealed wide variability in the concentrations of E2 and E3, while BPA was not detected at any of the sampling stations. The concentration of E3 ranged between <1.14 and 45.5 MUg/L (N = 120) in station 2 water. The highest concentration of E2 (15.7 MUg/L, N = 80) was observed in water from station 1. The varied concentrations may be connected with the nature and sources of release, inconsistencies in analyte distribution due to dynamics of water flow pattern and the physical/chemical properties of the receiving water bodies. PMID- 28667416 TI - SATB2 suppresses non-small cell lung cancer invasiveness by G9a. AB - Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor, which plays an important role in transcriptional regulation and chromatin recombinant by combining with matrix attachment regions. More evidence shows that SATB2 is involved in progression of breast cancer, head and neck squamous cell carcinomas and osteosarcoma. However, the role of SATB2 in cancer initiation and progression is still not well understood. Our study identified that decreased expression of SATB2 was correlated with tumor progression and poor prognosis in non-small cell lung cancer (NSCLC) patients. Furthermore, SATB2 suppressed lung cancer cell invasion and metastasis and regulated the expression of EMT-related proteins and histone methylation by G9a. In summary, SATB2 may act as a tumor suppressor gene in NSCLC. PMID- 28667417 TI - Enhanced biomass and oxidative stress tolerance of Synechococcus elongatus PCC 7942 overexpressing the DHAR gene from Brassica juncea. AB - OBJECTIVES: To improve the oxidative stress tolerance, biomass yield, and ascorbate/dehydroascorbate (AsA/DHA) ratio of Synechococcus elongatus PCC 7942 in the presence of H2O2, by heterologous expression of the dehydroascorbate reductase (DHAR) gene from Brassica juncea (BrDHAR). RESULTS: Under H2O2 stress, overexpression of BrDHAR in the transgenic strain (BrD) of S. elongatus greatly increased the AsA/DHA ratio. As part of the AsA recycling system, the oxidative stress response induced by reactive oxygen species was enhanced, and intracellular H2O2 level decreased. In addition, under H2O2 stress conditions, the BrD strain displayed increased growth rate and biomass, as well as higher chlorophyll content and deeper pigmentation than did wild-type and control strains. CONCLUSION: By maintaining the AsA pool and redox homeostasis, the heterologous expression of BrDHAR increased S. elongatus tolerance to H2O2 stress, improving the biomass yield under these conditions. The results suggest that the BrD strain of S. elongatus, with its ability to attenuate the deleterious effects of ROS caused by environmental stressors, could be a promising platform for the generation of biofuels and other valuable bioproducts. PMID- 28667418 TI - Diabetic nephropathy: serum miR-9 confers a poor prognosis in and is associated with level changes of vascular endothelial growth factor and pigment epithelium derived factor. AB - OBJECTIVE: To investigate the relationship between the serum level of miR-9 and the progression of diabetic nephropathy (DN) and related molecular mechanisms. RESULTS: Thirty-five healthy subjects and 140 DN patients were divided into five groups: control, DN I-II, DN III, DN IV and DN V. Serum level of miR-9 was measured by real-time qPCR. Serum levels of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF) lipids, fasting glucose, insulin, hemoglobin A1c (HBA1c), creatinine, fibrinogen and insulin resistance (HOMA-IR) were also measured. The results show that the levels of miR-9, PEDF and VEGF are increased with DN progression (P < 0.05). miR-9, VEGF and PEDF are independent risk factors of DN (R2 = 0.430). Spearman rank correlation analysis showed that miR-9 level is positively related to the levels of VEGF, PEDF, cholesterol, triglyceride, fasting glucose, fasting insulin, HBA1c, creatinine, fibrinogen and HOMA-IR (P < 0.05). CONCLUSIONS: Serum miR-9 is a potential marker for conferring a poor prognosis in DN and associated with the levels of VEGF, PEDF and biochemical indices. PMID- 28667419 TI - Regulation of DNA methylation on EEF1D and RPL8 expression in cattle. AB - Dynamic changes to the epigenome play a critical role in a variety of biology processes and complex traits. Many important candidate genes have been identified through our previous genome wide association study (GWAS) on milk production traits in dairy cattle. However, the underlying mechanism of candidate genes have not yet been clearly understood. In this study, we analyzed the methylation variation of the candidate genes, EEF1D and RPL8, which were identified to be strongly associated with milk production traits in dairy cattle in our previous studies, and its effect on protein and mRNA expression. We compared DNA methylation profiles and gene expression levels of EEF1D and RPL8 in five different tissues (heart, liver, mammary gland, ovary and muscle) of three cows. Both genes showed the highest expression level in mammary gland. For RPL8, there was no difference in the DNA methylation pattern in the five tissues, suggesting no effect of DNA methylation on gene expression. For EEF1D, the DNA methylation levels of its first CpG island differed in the five tissues and were negatively correlated with the gene expression levels. To further investigate the function of DNA methylation on the expression of EEF1D, we collected blood samples of three cows at early stage of lactation and in dry period and analyzed its expression and the methylation status of the first CpG island in blood. As a result, the mRNA expression of EEF1D in the dry period was higher than that at the early stage of lactation, while the DNA methylation level in the dry period was lower than that at the early stage of lactation. Our result suggests that the DNA methylation of EEF1D plays an important role in the spatial and temporal regulation of its expression and possibly have an effect on the milk production traits. PMID- 28667420 TI - [Choosing wisely in anesthesia : An important step in quality optimization]. PMID- 28667423 TI - Endosulfan, Short-Chain Chlorinated Paraffins (SCCPs) and Octachlorostyrene in Wildlife from Greenland: Levels, Trends and Methodological Challenges. AB - Besides globally banned "legacy" persistent organic pollutants, other compounds might be present in Arctic wildlife, for which regulation was introduced recently (the insecticide endosulfan), is considered (short-chain chlorinated paraffins, SCCPs) or does not exist (octachlorostyrene, OCS, a byproduct of manufacturing and combustion processes involving chlorine). The purpose of this study was to analyze the time trend of endosulfan (1986-2012) in ringed seals and to address the levels of SCCPs and OCS in wildlife species from Greenland (black guillemot, glaucous gull, ringed seal, polar bear), while taking a critical standpoint to analytical methods typically applied. The metabolite endosulfan sulfate was the only endosulfan compound consistently above detection limits, with a median concentration of 0.23 ng/g lipid weight (lw) and a significant annual decrease of -5.6%. The low-resolution mass spectrometry (LRMS) method appeared accurate and sufficiently precise; however, the gel permeation chromatography had to balance lipid removal and analyte loss. SCCPs and OCS were present in all samples. OCS median concentrations were between 2.8 (ringed seal blubber) and 29 (glaucous gull liver) ng/g lw, determined by a straightforward dual column electron capture detection method. SCCPs were analyzed by LRMS, following removal of potential interferences, and had median concentrations of several 100 ng/g wet weight. While the method showed good precision and recovery rates as well as acceptable accuracy in control samples, the Greenland samples had high concentrations in an Arctic context, possibly indicating limited selectivity of the LRMS method. PMID- 28667421 TI - [Intensive care studies from 2016/2017]. PMID- 28667424 TI - Evaluating retinal vessel diameter with optical coherence tomography in normal tension glaucoma patients. AB - PURPOSE: To investigate a novel optical coherence tomography (OCT)-derived variable, circumpapillary mean retinal shadow width (cpMRSW), and to elucidate its association with normal-tension glaucoma (NTG). METHODS: For the purpose of validation, we measured retinal vascular calibers in 68 arterioles and 100 venules of 12 NTG patients and 12 healthy subjects and compared the width of the visible retinal shadows in spectral-domain OCT images and the caliber of retinal vessels in retinal photographs. Then we calculated cpMRSW in 78 NTG eyes and 25 age-matched healthy control eyes. Additionally, we divided the patients into early (mean deviation: MD > -6 dB), moderate (MD -6 to -12 dB), and severe (MD < 12 dB) NTG groups, and compared cpMRSW in these groups. Finally, we calculated the area under the receiver operating characteristic (ROC) curve in order to determine the power of mean retinal shadow width to distinguish the groups. RESULTS: OCT retinal shadow width was significantly correlated with photography measured retinal caliber (r = 0.82, P < 0.001). CpMRSW was significantly different between the control and NTG patients (control: 107.3 +/- 7.0 um, mild: 99.4 +/- 8.6 um, moderate: 99.7 +/- 9.5 um, severe: 90.5 +/- 12.0 um, P < 0.001), despite similar distributions in systemic variables. An ROC analysis revealed that cpMRSW could differentiate NTGs from normal eyes (area under the ROC curve: 0.81). CONCLUSIONS: Our new software for measuring mean retinal shadow width in OCT images may be a valuable tool for detecting NTG and diagnosing its severity. PMID- 28667425 TI - Effectiveness of catheter directed thrombolysis and stent implantation on iliofemoral vein thrombosis caused by iliac vein compression. AB - The purpose of this study was to objectively assess the morbidity of post thrombotic syndrome (PTS) in iliofemoral vein thrombosis treated with catheter directed thrombolysis (CDT) and stenting under the protection of inferior vena cava (IVC) filter. All patients with an unprovoked episode of iliofemoral vein thrombosis combined with iliac vein compression syndrome (IVCS) during January 2011 and January 2015 were enrolled. Clinical records of all patients were evaluated. Firstly, cox regression was performed to find out the factors impacted the incidence of PTS. Then, Kaplan Meier analysis was conducted to verify the roles of these factors in PTS. A total of 247 patients who underwent CDT and IVC filter insertion for iliofemoral vein thrombosis and were found stenosis in the iliac vein after CDT were included in this study. Among them, 74 patients suffered PTS diagnosed via Villalta scale. Comparison with patients without stent implantation and filter withdrawal, patients with stent implantation and filter withdrawal had a less risk of PTS, but patients with a lesion in the left or bilateral proximal deep vein had a more risk of PTS. Cox regression found that stent implantation was a preventive measure to prevent PTS (OR 0.541, 95% CI 0.334-0.876, p = 0.012). The Kaplan-Meier curve found that patients with stent implantation had a less ratio of PTS occurrence (P = 0.008). In patients with iliofemoral vein thrombosis and IVCS, stent implantation to solve the residual obstruction after CDT might play an important role in preventing PTS. PMID- 28667426 TI - Maternal depressive symptoms during pregnancy are associated with amygdala hyperresponsivity in children. AB - Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child's brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6-9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology. PMID- 28667427 TI - Variation of Synechococcus Pigment Genetic Diversity Along Two Turbidity Gradients in the China Seas. AB - Synechococcus are important and widely distributed picocyanobacteria that encompass a high pigment diversity. In this study, we developed a primer set (peBF/peAR) for amplifying the cpeBA operon sequence from Synechococcus genomic DNA to study Synechococcus pigment diversity along two turbidity gradients in the China seas. Our data revealed that all previously reported pigment types occurred in the South (SCS) and East (ECS) China Seas. In addition, a novel pigment genetic type (type 3f), represented by the high phycourobilin Synechococcus sp. strain KORDI-100 (Exc495:545 = 2.35), was detected. This pigment genetic type differs from the 3c/3d types not only for a very high PUB/PEB ratio but also for a different intergenic spacer sequence and gene organization of the phycobilisome. Synechococcus of different pigment types exhibited clear niche differentiation. Type 2 dominated in the coastal waters, whereas type 3c/3d and 3f were predominant in oceanic waters of the SCS in summer. In the ECS, however, type 3a was the major pigment type throughout the transect. We suggest that in marine environment, various pigment types often co-occur but with one type dominant and PUB/PEB ratio is related to geographic distribution of Synechococcus pigment types. The two marginal seas of China have markedly different Synechococcus pigment compositions. PMID- 28667428 TI - The Secretory Leukocyte Protease Inhibitor mRNA expression is involved with inflammatory control after downhill exercise in the triceps brachii intermediary head in Wistar rats. AB - After severe skeletal muscle damage, communication between inflammatory macrophages, myogenic cells, and modulatory secretion factors is essential to induce re-establishment of skeletal muscle structure. To analyze when characteristic gene expression of macrophages, myogenic cells, and SLPI are modulated after an exercise-induced muscle damage (EIMD) downhill protocol. Twenty-six rats were exposed to an experimental protocol of exercise and euthanized before (CTRL), immediately after (G0), and 24 (G24) and 48 (G48) hours after the exercise. After euthanasia, the Triceps brachii were dissected and analyzed by enzyme-linked immunosorbent assay and real time polymerase chain reaction. The CD68 expression was higher in the G24 when compared with all groups (p value < 0.05), whereas the CD163 was inhibited compared with G0 (p value < 0.05). MyoD and Myogenin were higher in the G24 when compared with G0 and G48 (p value < 0.05). The mRNA Secretory Leukocyte Protease Inhibitor (SLPI) was higher in the G48 when compared with the CTRL and G0 (p value < 0.05). IL-6 and TNF alpha cytokines did not significantly change, but IL-10 presented a trend to be lower in the G0 when compared with G24 (p value = 0.054). A significant negative correlation was observed between CD68/CD163 (C.C = -0.71) and positive correlations between CD68/Myogenin (C.C = 0.65); MyoD/Myogenin (C.C = 0.72); IL 10/MyoD (C.C = 0.46), IL-10/MYOGENIN (C.C = 0.59); and IL-6/IL-10 (C.C = 0.64). A higher expression of CD68, concomitant with an elevation in MyoD and Myogenin 24 h after exercise, along with some correlations, suggests macrophage communication with myogenic cells independent of CD163 elevation. Additionally, the reestablishment of IL-10 in 24 h with the SLPI increased until 48 h indicate that these molecules are involved with anti-inflammatory transition after downhill exercise in the TBIH of Wistar rats. PMID- 28667429 TI - Long-Term Clinical Outcomes After Switching from Remicade(r) to Biosimilar CT-P13 in Inflammatory Bowel Disease. AB - BACKGROUND: Limited data are available on long-term clinical outcomes regarding the switch from Remicade(r) to the infliximab biosimilar CT-P13 in inflammatory bowel disease (IBD) patients. AIMS: To investigate long-term efficacy, safety, pharmacokinetic profile, and immunogenicity. METHODS: We performed a single center prospective observational cohort study following an elective switch from Remicade(r) to CT-P13 in IBD patients. RESULTS: Eighty-three patients were included (57 Crohn's disease, 24 ulcerative colitis, and 2 IBD unclassified), and 68 patients completed one-year follow-up. Disease activity (Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index) as well as inflammatory markers (CRP, fecal calprotectin) did not change significantly during the 1-year follow-up. In total, 7 out of 83 patients (8%) demonstrated detectable antidrug antibodies during follow-up, and 5 out of 7 antidrug antibody titers were already detectable at baseline prior to switching. Six patients (7%) discontinued CT-P13 due to adverse events. CONCLUSIONS: Following a switch from Remicade(r) to CT-P13, 82% of IBD patients continued treatment through 1 year. Disease activity scores and inflammatory markers remained unchanged during follow-up, and no CT-P13-related serious adverse events occurred. These 1-year data suggest that switching to CT P13 in Remicade(r)-treated IBD patients is safe and feasible. PMID- 28667431 TI - Increase in Hospital Discharges for Inflammatory Bowel Diseases in Chile Between 2001 and 2012. AB - AIM: To determine the number of annual hospital discharges for inflammatory bowel diseases in Chile. The hypothesis is that there is a significant increase in the hospital discharges due to this disease from 2001 to 2012. MATERIALS AND METHODS: This is a descriptive study. Data were obtained from the Web site of the Department of Health Statistics. All hospital discharges from 2001 to 2012 were included. The following variables were analyzed: length of stay, hospital mortality, and eventual surgical procedure. Data are presented as descriptive statistics. The B-coefficient was calculated to establish the significance of the annual trend. RESULTS: There were 13,001 hospital discharges with the diagnosis of ulcerative colitis or Crohn's disease, corresponding to 0.067% of all hospital discharges in the whole period. Within these discharges, 31.2% were Crohn's disease and 68.8% were ulcerative colitis. At least one surgical procedure was performed in 12.9% of the hospitalizations. There was a significant increase in the annual rate of hospital discharges from 5.25 in 2001 to 8.64 per 100 thousand inhabitants in 2012. This increase was from 1.68 to 3.11 in Crohn's disease and from 3.58 to 5.53 in ulcerative colitis. However, a decrease was observed in length of stay, need of surgical treatment and in-hospital mortality. CONCLUSION: From 2001 until 2012, there has been a significant increase in hospital discharges for inflammatory bowel diseases in Chile, associated with a decrease in length of stay, need of surgery and in-hospital mortality. PMID- 28667430 TI - Attenuated GABAergic Signaling in Intestinal Epithelium Contributes to Pathogenesis of Ulcerative Colitis. AB - BACKGROUND: Neuromediators produced by enteric nervous system regulate inflammatory processes via interacting with enteric immune system. Role of gamma aminobutyric acid (GABA), which is also a neuromediator, has been implicated in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, where they modulate the immune responses. However, its role in ulcerative colitis (UC) has not been defined. AIMS: This study was carried out to investigate the role of GABA and its signaling components in pathogenesis of UC. METHODS: Peripheral blood, colon mucosal biopsy, and fecal specimens were collected from UC and control groups. Quantification of GABA was done using ELISA. Expression of GABAergic signal system components was analyzed through RT PCR analysis. Enumeration of GABA-producing bacteria was done by qPCR analysis. Activity of p38 MAPK and expression of proinflammatory cytokines were determined by immunohistochemistry and RT-PCR analysis, respectively. RESULTS: GABA levels were significantly reduced in patients with UC as compared to control group when measured in serum and colon biopsy. Altered expression of GABAergic signal system was observed in UC patients. Reduced abundance of selected GABA-producing bacteria was detected in stool samples of UC patients as compared to control. p38 MAPK activity and expression of its downstream effector cytokines were found to be increased in UC patients as compared to control. CONCLUSIONS: Reduced levels of GABA were observed in patients with UC, and this leads to hyperactivation of p38 MAPK and overexpression of downstream effector cytokines suggesting a role of GABA in pathogenesis of UC. PMID- 28667432 TI - Evaluation of the International Consensus Guidelines for the Surgical Resection of Intraductal Papillary Mucinous Neoplasms. AB - BACKGROUND: International consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) were revised in 2012. AIMS: We aimed to evaluate the clinical utility of each predictor in the 2006 and 2012 guidelines and validate the diagnostic value and surgical indications. METHODS: Forty-two patients with surgically resected IPMNs were included. Each predictor was applied to evaluate its diagnostic value. RESULTS: The 2012 guidelines had greater accuracy for invasive carcinoma than the 2006 guidelines (64.3 vs. 31.0%). Moreover, the accuracy for high-grade dysplasia was also increased (48.6 vs. 77.1%). When the main pancreatic duct (MPD) size >=8 mm was substituted for MPD size >=10 mm in the 2012 guidelines, the accuracy for high-grade dysplasia was 80.0%. CONCLUSIONS: The 2012 guidelines exhibited increased diagnostic accuracy for invasive IPMN. It is important to consider surgical resection prior to invasive carcinoma, and high-risk stigmata might be a useful diagnostic criterion. Furthermore, MPD size >=8 mm may be predictive of high-grade dysplasia. PMID- 28667433 TI - Craniofacial features affecting mandibular asymmetries in skeletal Class II patients. AB - OBJECTIVES: The aim of this study was to evaluate the characteristics affecting different intensities of mandibular asymmetry in skeletal Class II adults using three-dimensional images. This study is clinically relevant since it allows professionals to evaluate the morphological components related to these deformities and more carefully obtain correct diagnosis and treatment plan for such patients. METHODS: Cone-beam computed tomography data of 120 Class II patients (40 with relative symmetry, 40 with moderate asymmetry, and 40 with severe asymmetry) were imported to SimPlant Ortho Pro(r) 2.0 software (Dental Materialise, Leuven, Belgium). Three reference planes were established and linear measurements were performed from specific landmarks to these planes, comparing the deviated side and the contralateral side in each group, as well as the differences between groups. The correlation between midline mandibular asymmetry and other variables was also evaluated. Statistical analyses considered a significance level of 5%. RESULTS: Comparing the values obtained on the deviated side and on the contralateral side, there were significant differences for patients with moderate asymmetry and severe asymmetry. However, differences were seen more often in severe mandibular asymmetries. In those patients, there was a significant correlation of the gnathion deviation with lower dental midline deviation, difference in the lateral gonion positions, difference in the mandibular rami heights, and difference in the jugale vertical displacements. CONCLUSIONS: For skeletal Class II patients with mandibular asymmetry, some craniofacial features are related to chin deviation and require proper evaluation, including the bilateral differences in the ramus height, mandibular body length, transverse and vertical positioning of the gonion and jugale points. PMID- 28667434 TI - The Pitfalls of Left Trisectionectomy or Central Bisectionectomy for Biliary Cancer: Anatomical Classification Based on the Ventral Branches of Segment VI Portal Vein Relative to the Right Hepatic Vein. AB - BACKGROUNDS: Some patients have P6a running on the ventral side (Ventral-P6a), relative to the right hepatic vein (RHV). STUDY DESIGN: Forty-one patients who underwent left trisectionectomy or central bisectionectomy for biliary cancer were enrolled. We compared the anatomical features using 3D images and surgical outcomes between patients with Ventral-P6a (n = 17) and those with P6a running on the dorsal side relative to the RHV (Dorsal-P6a; n = 25). Moreover, the liver volume by hand-tracing 2D axial images was compared to the volume calculated using the 3D images. RESULTS: The frequency of complete exposure of RHV on the transection plane was less in Ventral-P6a (12 vs. 76%; p < 0.001), and the frequency of supraportal type of right posterior hepatic artery (RPHA, 29 vs. 4%, p = 0.020), the presence of inferior RHV (47 vs. 12%, p = 0.011), and the angle between the transection plane of segment VI and VII (S6-S7angle, 29.0 degrees vs. 4.9 degrees ; p < 0.001) were greater in Ventral-P6a than in Dorsal-P6a. In Dorsal-P6a, the volume of posterior section calculated using 2D images was greater than that calculated using 3D images (404 vs. 370 mL; p = 0.004). The incidence of daily diuretic administration in Dorsal-P6a was greater than in Ventral-P6a (88 vs. 54%, p = 0.035). CONCLUSION AND RELEVANCE: In Ventral-P6a, the complete exposure of RHV was rare in left trisectionectomy or central bisectionectomy. Surgeons should preoperatively recognize the course of RPHA, the presence of inferior RHV, and the S6-S7angle. In Dorsal-P6a, the volume of posterior section, which tended to be overestimated using 2D images, was smaller than that in Ventral-P6a. PMID- 28667435 TI - Using Osteoporosis Therapies in Combination. AB - PURPOSE OF REVIEW: The objective of this review is to update evidence regarding the use of osteoporosis drugs in sequence or in combination to optimize increases in bone mass and strength. RECENT FINDINGS: Simultaneous use of denosumab plus teriparatide produces larger increases in BMD than does monotherapy. The use of bisphosphonates or denosumab after teriparatide results in progressive gains in BMD. When switching from bisphosphonates and especially denosumab to teriparatide, an overlap of 6-12 months may prevent the transient loss of BMD in cortical sites. Phase 3 trials document fracture risk reduction with anabolic therapy for 12-18 months followed by an anti-remodeling drug. With the exception of adding teriparatide to ongoing denosumab therapy, there is little evidence to support the use of more than one osteoporosis drug at a time. In contrast, sequential therapy regimens of anabolic drugs followed by potent anti-remodeling agents will be the new standard for treating patients at imminent risk of fracture. PMID- 28667436 TI - Comparison of quality of life among community-dwelling older adults with the frailty phenotype. AB - PURPOSE: To compare the perception of the quality of life (QOL) of community dwelling older adults with the phenotype of frailty. METHODS: Cross-sectional analysis of baseline data of the "Cohort of Obesity, Sarcopenia and Frailty of Mexican Older Adults" (COSFOMA). Operationalization of frailty was carried out using the phenotype as follows: weight loss, self-report of exhaustion, low physical activity, slow gait, and weakness. QOL was measured using two scales: World Health Organization Quality of Life of Older Adults (WHOQOL-OLD), which is a specific instrument for the elderly population, and Short Form-36 Health Survey (SF-36), a generic instrument to evaluate the QOL related to health. One-way analyses of variance were conducted to assess the differences among the three phenotypes of frailty and QOL perception. RESULTS: There were 1252 older adult participants who were analyzed; 11.2% (n = 140) had frailty, 50.3% (n = 630) pre frailty and 38.5% (n = 482) were not frail. The mean (+/-SD) total score of the WHOQOL-OLD according to the phenotype of frailty was 60.3 (13.9) for those with frailty, 67.4 (12.7) pre-frailty and 72.4 (11.2) not frail (ANOVA, p < 0.001). The mean (+/-SD) of the SF-36 of the physical and mental component measures the sum, 38.9 (9.9) and 41.9 (11.3) with frailty, 45.7 (9.1) and 46.6 (9.8) pre frailty, and 49.6 (7.3) and 49.4 (7.9) not frail, respectively (ANOVA, p < 0.001). CONCLUSIONS: Frailty is observed in 1/10 community-dwelling older adults. Those with frailty and pre-frailty had a lower perception of QOL compared with those who were not frail. PMID- 28667437 TI - An Elf2-like transcription factor acts as repressor of the mouse ecto-5' nucleotidase gene expression in hepatic myofibroblasts. AB - Hepatic fibrosis represents a pathological wound healing and tissue repair process triggered in response to chronic liver injury. A heterogeneous population of activated non-parenchymal liver cells, known as liver myofibroblasts, functions as the effector cells in hepatic fibrosis. Upon activation, liver myofibroblasts become fibrogenic, acquiring contractile properties and increasing collagen production capacity, while developing enhanced sensitivity to endogenous molecules and factors released in the local microenvironment. Hepatic extracellular adenosine is a bioactive small molecule, increasingly recognized as an important regulator of liver myofibroblast functions, and an important mediator in the pathogenesis of liver fibrosis overall. Remarkably, ecto-5' nucleotidase/Nt5e/Cd73 enzyme, which accounts for the dominant adenosine generating activity in the extracellular medium, is expressed by activated liver myofibroblasts. However, the molecular signals regulating Nt5e gene expression in liver myofibroblasts remain poorly understood. Here, we show that activated mouse liver myofibroblasts express Nt5e gene products and characterize the putative Nt5e minimal promoter in the mouse species. We describe the existence of an enhancer sequence upstream of the mouse Nt5e minimal promoter and establish that the mouse Nt5e minimal promoter transcriptional activity is negatively regulated by an Elf2-like Ets-related transcription factor in activated mouse liver myofibroblasts. PMID- 28667438 TI - Phospholipases Dzeta1 and Dzeta2 have distinct roles in growth and antioxidant systems in Arabidopsis thaliana responding to salt stress. AB - MAIN CONCLUSION: Phospholipases Dzeta play different roles in Arabidopsis salt tolerance affecting the regulation of ion transport and antioxidant responses. Lipid signalling mediated by phospholipase D (PLD) plays essential roles in plant growth including stress and hormonal responses. Here we show that PLDzeta1 and PLDzeta2 have distinct effects on Arabidopsis responses to salinity. A transcriptome analysis of a double pldzeta1pldzeta2 mutant revealed a cluster of genes involved in abiotic and biotic stresses, such as the high salt-stress responsive genes DDF1 and RD29A. Another cluster of genes with a common expression pattern included ROS detoxification genes involved in electron transport and biotic and abiotic stress responses. Total superoxide dismutase (SOD) activity was induced early in the shoots and roots of all pldzeta mutants exposed to mild or severe salinity with the highest SOD activity measured in pldzeta2 at 14 days. Lipid peroxidation in shoots and roots was higher in the pldzeta1 mutant upon salt treatment and pldzeta1 accumulated H2O2 earlier than other genotypes in response to salt. Salinity caused less deleterious effects on K+ accumulation in shoots and roots of the pldzeta2 mutant than of wild type, causing only a slight variation in Na+/K+ ratio. Relative growth rates of wild type plants, pldzeta1, pldzeta2 and pldzeta1pldzeta2 mutants were similar in control conditions, but strongly affected by salt in WT and pldzeta1. The efficiency of photosystem II, estimated by measuring the ratio of chlorophyll fluorescence (F v/F m ratio), was strongly decreased in pldzeta1 under salt stress. In conclusion, PLDzeta2 plays a key role in determining Arabidopsis sensitivity to salt stress allowing ion transport and antioxidant responses to be finely regulated. PMID- 28667439 TI - Left hepatectomy after right paramedian sectoriectomy. AB - Repeat hepatectomy is beneficial for selected patients with recurrence of liver malignancies. However, the operative procedure becomes technically demanding when the previous hepatectomy was complex, with hepatic veins and stump of portal pedicles exposed on the liver transection surface. We performed left hepatectomy after right paramedian sectoriectomy (RPMS) for three patients. Here, we describe our surgical technique and the postoperative outcomes achieved. This procedure allowed for safe adhesiolysis between the middle and right hepatic veins by following a fibrous plane. The mean operative time was 8.7 h, including 4.9 h of adhesiolysis. The mean remnant liver volume (right lateral sector and the caudate lobe) was calculated as 704 ml, being 62% of total liver volume. There was no postoperative liver failure or mortality. In conclusion, left hepatectomy after RPMS is a feasible procedure for patients with sufficient remnant liver volume, even though the middle and right hepatic veins run side by side after liver regeneration. PMID- 28667440 TI - [Surgical treatment of aortic valve stenosis]. AB - Surgical aortic valve replacement still represents the gold standard in patients with severe symptomatic aortic valve stenosis. In addition to conventional aortic valve replacement by mechanical or biological prostheses via a median sternotomy, novel approaches including minimally invasive strategies and new devices, such as so-called rapid deployment prostheses, are becoming increasingly more established. Autologous replacement strategies including the Ross and the Ozaki procedures have evolved into reliable options at selected centers of excellence. These novel treatment approaches in aortic valve surgery result in excellent short and long-term outcomes with a reduction of procedure-related complications. Taken together, these modern surgical replacement strategies enable a personalized surgical treatment in patients with aortic valve stenosis, which are tailored to the individual patient. PMID- 28667441 TI - Lifespan-extending and stress resistance properties of brazilin from Caesalpinia sappan in Caenorhabditis elegans. AB - This study contributes to the continual discovery of lifespan-extending compounds from plants, using the Caenorhabditis elegans model system. An ethyl acetate soluble fraction of methanol extract from the heartwood of Caesalpinia sappan showed a significant lifespan-extending activity. Subsequent activity-guided chromatography of the ethyl acetate-soluble fraction led to the isolation of brazilin. Brazilin showed potent 2,2-diphenyl-1-picrylhydrazyl radical scavenging and superoxide anion quenching activities and also revealed a lifespan-extending activity in C. elegans under normal culture conditions. Brazilin also exhibited the protective effects against thermal, oxidative and osmotic stress conditions to improve the survival rate of the nematode. Furthermore, brazilin elevated superoxide dismutase (SOD) activity and decreased intracellular reactive oxygen species accumulation in C. elegans. Further studies showed that brazilin-mediated increased stress tolerance of worms could be due to increased expressions of stress resistance proteins such as heat shock protein (HSP-16.2) and superoxide dismutase (SOD-3). Besides, there were no significant, brazilin-induced changes in aging-related factors, including progeny production, food intake, and growth, indicating brazilin influences longevity activity independent of affecting these factors. Brazilin increased the body movement of aged worms, indicating brazilin affects the healthspan and lifespan of nematode. These results suggest that brazilin contributes to the lifespan of C. elegans under both normal and stress conditions by increasing the expressions of stress resistance proteins. PMID- 28667442 TI - Detection of mimivirus genome and neutralizing antibodies in humans from Brazil. AB - In recent years, giant viruses belonging to the family Mimiviridae have been proposed to be infectious agents in humans. In this work we provide evidence of mimivirus genome and neutralizing antibodies detection in humans. PMID- 28667443 TI - First genetic characterization of peste des petits ruminants virus from Mongolia. AB - Between August and September 2016 pathological samples were collected from sheep and goats following suspected peste des petits ruminants (PPR) outbreaks in western Mongolia. RT-PCR followed by sequencing and phylogenetic analysis of the samples confirmed the presence of a PPR virus belonging to lineage IV. A full genome analysis of the viral RNA from one of the samples revealed a high similarity (99.0-99.5%) with PPR viruses currently circulating in China (2013 2015) indicating a common origin. This is the first genetic characterization of PPR virus in Mongolia and the data generated will have important implications for control and management of the disease in the region. PMID- 28667444 TI - An "earthworm" in the superior vena cava and right atrium. PMID- 28667445 TI - The clinical picture of severe leptospirosis in critically ill patients. PMID- 28667446 TI - Diagnostic performance of flexible sigmoidoscopy combined with fecal immunochemical test in colorectal cancer screening: meta-analysis and modeling. AB - Once-only flexible sigmoidoscopy (FS), which reliably detects neoplasms in the distal colon and rectum but not in the proximal colon, has been shown to reduce incidence and mortality of distal colorectal cancer (CRC). Fecal immunochemical tests (FITs) detect the majority of CRCs and some proportion of adenomas also in the proximal colon. We assessed the expected diagnostic performance of combined application of FS and FIT. We systematically reviewed screening studies conducted in an average risk population that reported specificities and site-specific sensitivities of FITs for detection of CRC or advanced adenoma (AA). Only studies that conducted colonoscopy in all subjects were included. PubMed and Web of Science were searched until May 13, 2016. Reference lists of eligible studies were also screened. Sensitivity of FS was derived from colonoscopy results, assuming the same sensitivity as colonoscopy for left-sided neoplasms and follow up colonoscopy after detection of distal adenomas. Bivariate meta-analyses were used to derive summary estimates of overall sensitivity and specificity of individual and joint application of both tests. Ten eligible studies were identified. Summary estimates (95% confidence intervals) of overall sensitivity for detecting CRC and AA were 65% (56-74%) and 27% (23-31%) for FIT alone, 67% (58-75%) and 67% (59-75%) for FS alone, and 89% (83-92%) and 75% (68-80%), respectively, for the combination of both tests. The pooled specificity (95% CI) of FIT was 92% (90-95%). Adding a FIT to a once-only screening FS would substantially increase sensitivity of CRC screening at a modest loss in specificity. PMID- 28667447 TI - The association between leisure-time physical activity, low HDL-cholesterol and mortality in a pooled analysis of nine population-based cohorts. AB - The objective of this study was to investigate associations between leisure-time physical activity, low high-density lipoprotein cholesterol (HDL-C) and mortality. Self-reported leisure-time physical activity, HDL-C concentration, and mortality were assessed in 37,059 adults in Health Survey for England and Scottish Health Survey. Meeting physical activity guidelines was defined as >=150 min wk-1 of moderate-intensity activity, >=75 min wk-1 of vigorous-intensity activity, or equivalent combinations. Low HDL-C was defined as <1.03 mmol L-1. Cox proportional hazard models were adjusted for age, sex, smoking, total cholesterol, systolic blood pressure, body mass index, longstanding illness, and socioeconomic status. There were 2250 deaths during 326,016 person-years of follow-up. Compared with those who met physical activity guidelines and whose HDL C was normal (reference group), all-cause mortality risk was not elevated in those who met physical activity guidelines and whose HDL-C concentration was low (hazard ratio: 1.07; 95% confidence interval: 0.75, 1.53). Compared with the reference group, all-cause mortality risk was elevated in those who did not meet physical activity guidelines and whose HDL-C was normal (1.37; 1.16, 1.61), and in those who did not meet physical activity guidelines and whose HDL-C was low (1.65; 1.37, 1.98). Cardiovascular disease mortality hazard ratios were similar, although confidence intervals were wider. There was no statistically significant evidence of biological interaction between physical inactivity and low HDL-C. This novel study supports the notion that leisure-time physical activity be recommended in those with low HDL-C concentration who may be resistant to the HDL raising effect of exercise training. PMID- 28667449 TI - Patient preferences: a Trojan horse for evidence-based medicine? AB - The evidence-based medicine (EBM) movement has long acknowledged the relevance of patient preferences and values. According to EBM, clinicians first clarify the medical evidence about the benefits and burdens of the treatment in question and then, as a second step, elicit values and preferences from patients. Importantly, however, values are placed on patient-relevant outcomes. Surrogate endpoints are only used if their validity is proven. This article shows that some recent patient-preference studies attribute value to surrogate endpoints even when there is no improvement in patient-relevant outcomes. The article points out their foundation in neoclassical economics and discusses their clash with principles of EBM and medical ethics. PMID- 28667448 TI - Adjuvant versus salvage radiotherapy in prostate cancer: multi-institutional retrospective analysis of the Spanish RECAP database. AB - PURPOSE: To compare adjuvant radiotherapy (ART) to salvage radiotherapy (SRT) after radical prostatectomy (RP) in a cohort of prostate cancer (PCa) patients. The primary aim was to comparatively assess 2- and 5-year biochemical relapse free survival (BRFS). A secondary aim was to identify predictors of survival. PATIENTS AND METHODS: Data were acquired from the RECAP database, a population based prostate cancer registry in Spain. Inclusion criteria included RP (with or without lymphadenectomy) followed by ART or SRT. A total of 702 patients were analyzed. Pre-RT PSA values (>0.5 vs. <=0.5 ng/ml), pathological stage (T1-2 vs. T3-4), post-surgical Gleason score (<=7 vs. 8-10), margin status (positive vs. negative), hormonal treatment (yes vs. no), and RT dose (<=66 Gy vs. >66 Gy) were evaluated to assess their impact on BRFS. RESULTS: The mean patient age in the ART and SRT groups, respectively, was 64 years (range 42-82) and 64.8 years (range 42-82). Median follow-up after RT in the whole sample was 34 months (range 3-141). A total of 702 patients were included: 223 (31.8%) received ART and 479 (68.2%) SRT. BRFS rates (95% CI) in the ART and SRT groups at months 24 and 60 were, respectively: 98.1% (95.9-100.0%) vs. 91.2% (88.2-94.2%) and 84.5% (76.4 92.6%) vs. 74.0% (67.4-80.7%) (p = 0.004). No significant differences in OS were observed (p = 0.053). The following variables were significant predictors of biochemical recurrence in the SRT group: (1) positive surgical margin status (p = 0.049); (2) no hormonotherapy (p = 0.03); (3) total prostate dose <=66 Gy (p = 0.004); and pre-RT PSA >=0.5 ng/ml (p = 0.013). CONCLUSIONS: This is the first nationwide study in Spain to evaluate a large cohort of PCa patients treated with RP followed by postoperative RT. ART yielded better 2- and 5-year BRFS rates, although OS was equivalent. These findings are consistent with most other published studies and support ART in patients with adverse prognostic characteristics after radical prostatectomy. Prospective trials are needed to compare immediate ART to early SRT to better determine their relative benefits. PMID- 28667450 TI - Review of stochastic hybrid systems with applications in biological systems modeling and analysis. AB - Stochastic hybrid systems (SHS) have attracted a lot of research interests in recent years. In this paper, we review some of the recent applications of SHS to biological systems modeling and analysis. Due to the nature of molecular interactions, many biological processes can be conveniently described as a mixture of continuous and discrete phenomena employing SHS models. With the advancement of SHS theory, it is expected that insights can be obtained about biological processes such as drug effects on gene regulation. Furthermore, combining with advanced experimental methods, in silico simulations using SHS modeling techniques can be carried out for massive and rapid verification or falsification of biological hypotheses. The hope is to substitute costly and time consuming in vitro or in vivo experiments or provide guidance for those experiments and generate better hypotheses. PMID- 28667451 TI - Pretransplant diabetes mellitus predicts worse outcomes of liver transplantation: evidence from meta-analysis. AB - BACKGROUND: It has been demonstrated that the prognosis of liver transplantation (LT) is significantly influenced by pretransplant factors, such as diabetes mellitus (DM). However, inconsistent observations are obtained. METHODS: We comprehensively searched PubMed, Embase and Web of Science to identify eligible cohort studies to evaluate the impact of preexisting DM on LT prognosis. Overall mortality and graft loss, as the most frequently observed parameters, were used to evaluate the outcomes of LT. Hazard ratios (HRs) with their 95% confidence intervals (CIs) were pooled to assess the effect of DM. RESULTS: 15,768 diabetic LT recipients and 60,176 non-diabetic LT recipients from 13 populations were included in this meta-analysis. Preexisting DM increased the risk for overall death of LT by 40% (95% CI 1.22-1.61), compared with DM-free patients. In addition, the risk for graft loss was also elevated by pretransplant DM (HR 1.28, 95% CI 1.07-1.54). Both analyses showed high heterogeneities (I 2 = 85.2 and 93.2%, respectively) and their sources were not identified by meta-regression analyses. In terms of the additive effect of hepatitis C virus (HCV) infection on poor outcomes of diabetic LT recipients, stratified meta-analyses were conducted. It was demonstrated that HCV infection increased the risk for mortality by 73% (95% CI 1.64-1.83), relatively higher than non-HCV recipients (HR 1.32, 95% CI 1.25-1.39) and general population (HR 1.40, 95% CI 1.22-1.61). CONCLUSION: Preexisting DM predicts worse patient and graft survivals of LT. Concomitant HCV infection would further deteriorate this unfavorable impact. Given the high heterogeneities and the insufficient evidences, more studies are still warranted to support these observations. PMID- 28667453 TI - The long way to dose reduction in myocardial perfusion imaging. PMID- 28667452 TI - Role of contrast-enhanced ultrasound to define prognosis and predict response to biotherapy in pancreatic neuroendocrine tumors. AB - PURPOSE: The incidence of neuroendocrine tumors (NETs) is progressively increasing. Most cases arise from the digestive system, where ileum, rectum and pancreas represent the commonest site of origin. Liver metastases are frequently detected at diagnosis or during the follow-up. Contrast-enhanced ultrasound (CEUS) is used in patients with pancreatic NETs (P-NETs) and liver metastases from P-NET but its role has not been standardized. The aim of this retrospective study was to investigate CEUS in patients with P-NETs and liver metastases from P NET both as prognostic factor and predictor of response to therapy with somatostatin analogues (SSAs). METHODS: CEUS was performed at the diagnosis of NET and 3, 6 and 12 months after the beginning of SSAs. CEUS pattern was compared with contrast-enhanced computed tomography (CT) pattern. RESULTS: There was a significant association between CEUS and CT pattern (X 2 = 79.0; p < 0.0001). A significant association was found between CEUS pattern and Ki-67 index (X 2 = 24.6; p < 0.0001). The hypervascular homogeneous CEUS typical pattern was associated with low tumor grading (G1 or G2) (X 2 = 24.0; p < 0.0001). CEUS pattern changed from hypervascular homogeneous in baseline to hypovascular/hypervascular inhomogeneous after SSA therapy, with a significant association between tumor response at CT scan and appearance of hypervascular inhomogeneous pattern at CEUS evaluation (6 months: X 2 = 57.0; p < 0.0001; 12 months: X 2 = 49.8; p < 0.0001). CONCLUSIONS: In patients with P-NET, CEUS pattern correlates with tumor grading, being homogeneous in G1-G2 but not in G3 tumors. After therapy with SSAs, CEUS is predictive of response to SSAs. These findings seem to support a role of CEUS as prognostic and predictive factor of response. PMID- 28667454 TI - Effects of cardiac resynchronization therapy on right ventricular function during rest and exercise, as assessed by radionuclide angiography, and on NT-proBNP levels. AB - AIM: We carried out this study to investigate mid-term effects of cardiac resynchronization therapy (CRT) on right ventricular (RV) function and neurohormonal response, expressed by N-terminal pro-brain natriuretic peptide (NT proBNP), in heart failure patients stratified by baseline RV ejection fraction (RVEF). METHODS AND RESULTS: Thirty-six patients with nonischemic dilated cardiomyopathy underwent technetium-99m radionuclide angiography with bicycle exercise immediately after CRT implantation (during spontaneous rhythm and after CRT activation) and 3 months later. Plasma NT proBNP was assessed before implantation and after 3 months. At baseline, RVEF was impaired (<=35%) in 14 patients, preserved (>35%) in 22. At 3 months, RVEF improved during rest and exercise (P = .02) in patients with impaired RV function, while remaining unchanged in patients with preserved RV function. Rest and exercise RV dyssynchrony decreased in both groups at follow-up (P < .05). A similar mid-term improvement in left ventricular (LV) function and NT-proBNP was observed in patients with impaired and preserved RVEF. In the former, the decrease in NT proBNP correlated with the improvements both in LV and RV dyssynchrony and functions. CONCLUSION: CRT may improve RV performance, during rest and exercise, and neurohormonal response in heart failure patients with nonischemic dilated cardiomyopathy and baseline RV dysfunction. RV dysfunction should not be considered per se a primary criterion for excluding candidacy to CRT. PMID- 28667455 TI - Response Letter. PMID- 28667456 TI - From clinical trials to clinical practice: outcome of NSABP-B27 neoadjuvant chemotherapy regimen for high-risk early-stage breast cancer. AB - PURPOSE: Majority of Jordanian breast cancer patients present at a relatively young age and with locally advanced disease highlight the importance of neoadjuvant chemotherapy. This study evaluated the efficacy and safety of NSABP B27 regimen in high-risk patients in daily clinical practice. METHODS: Patients' medical records and hospital database were searched for all consecutive patients treated at our institution for breast cancer using neoadjuvant NSABP-B27 chemotherapy regimen. Chemotherapy was given at standard doses and schedule as originally reported in the NSABP-B27. RESULTS: 346 female patients (median age 51 years) were treated using this regimen. Majority had high-risk features including larger tumor size (>4 cm in 68.5%), positive axillary lymph nodes (78.3%), and Grade III disease (47.4%). While most patients tolerated and completed planned chemotherapy, 41 (11.8%) patients failed to complete all four cycles of docetaxel. Following neoadjuvant chemotherapy, complete pathological response (pCR) was achieved in 84 (25.0%) evaluable patients; pCR was higher in hormone receptor-negative disease (40.0 vs. 22.1%, p = 0.002), in patient with tumor size <=4 cm (28.3 vs. 23.5%, p = 0.024) and in patients with node-negative disease (41.2 vs. 20.7%, p = 0.002). Age (<50 vs. >=50) had no effect, with pCR of 24.2 and 26.4%, respectively (p = 0.607). Breast-conserving surgery was performed in 85 (24.6%). CONCLUSIONS: NSABP-B27 is an effective neoadjuvant regimen. Despite including higher risk patients, pCR is similar to the original NSABP-B27 and many other anthracycline-taxane-based regimens. Tumor size, LN status, hormone receptors status, but not age, were significant factors in achieving pCR. PMID- 28667457 TI - The dietary form of choline during lactation affects maternal immune function in rats. AB - PURPOSE: The present study was designed to determine the effects of both choline form and availability on maternal immune function during lactation. METHODS: Sprague-Dawley rats were randomized to one of the three diets 24-48 h before parturition and fed ad libitum until 21 days postnatal: 1 g/kg choline as free choline (C, n = 11), the current form, and amount of choline in commercial diets; 1 g/kg choline as phosphatidylcholine (PC1, n = 11); or 2.5 g/kg choline as PC (PC2.5, n = 8). Choline metabolites in offspring stomach contents were quantified. At 21 days, lymphocytes from mothers' mesenteric lymph nodes and spleens were isolated and phenotypes and ex vivo cytokine production after mitogen exposure were determined. RESULTS: There was a higher proportion of choline and a lower proportion of lyso-PC in stomach contents (representing dam's milk) of C pups compared to PC1. In the mesenteric lymph nodes, feeding PC1 compared to C led to a higher IL-2 production after Concanavalin A (ConA) stimulation and a higher proportion of T cells (CD3+) and a lower proportion of B cells [immunoglobulin (Ig)kappa, CD45RA+, and IgM+; P < 0.05]. Splenocytes from the PC1 group produced more IL-6 and TNF-alpha after lipopolysaccharides stimulation compared to C (P < 0.05). Splenocytes from the PC2.5 group produced more IL-2 and IL-6 after ConA stimulation compared to PC1 (P < 0.05). CONCLUSIONS: Feeding choline as PC in the maternal diet improved the ability of immune cells to respond ex vivo to mitogens and increasing the amount of PC in the diet further improved T cell proliferation. PMID- 28667459 TI - Clinical Pharmacokinetics and Pharmacodynamics of Panobinostat. AB - Histone deacetylase (HDAC) inhibitors cause an increase in acetylation that leads to an increase in DNA transcription and accumulation of different proteins, reducing cell proliferation and inducing cell death. Panobinostat is a first-in line HDAC inhibitor approved for treating multiple myeloma in combination with bortezomib and dexamethasone. It is a pan-deacetylase inhibitor and therefore inhibits not only HDAC but also other deacetylases. The main mechanism of action of panobinostat is to inhibit HDAC, which causes cell cycle arrest and apoptosis, leading to it being an antineoplastic drug. Pooled data of multiple-dose studies show that an oral dose of panobinostat 20 mg resulted in a maximum plasma concentration (C max) of 21.6 ng/mL approximately 1 h after administration, while doses between 10 and 30 mg resulted in dose proportional plasma levels. The absolute bioavailability of panobinostat is 21.4%, and it is moderately bound to plasma proteins. Renal impairment does not influence the intrinsic pharmacokinetics of panobinostat, however hepatic impairment causes an increase in the plasma concentrations of this drug. Therefore, starting treatment at lower doses could be considered in patients with mild to moderate hepatic impairment. Different ethnic backgrounds have an influence on the pharmacokinetics of panobinostat; however, due to major interindividual variability, no dose adjustment is recommended. The area under the concentration-time curve of panobinostat changes significantly under cytochrome P450 (CYP) 3A4 inhibitors, CYP3A4 and CYP2D6 inducers, and P-glycoprotein inhibitors. Panobinostat itself is a CYP2D6 inhibitor, which influences the plasma levels of the CYP2D6 substrate dexamethasone. The main side effects of panobinostat are diarrhea, peripheral neuropathy, asthenia and fatigue; hematologic side effects include neutropenia, thrombocytopenia, and lymphocytopenia. PMID- 28667458 TI - Variability in measures of mineral metabolism in children on hemodialysis: impact on clinical decision-making. AB - BACKGROUND: Variability in measures of mineral metabolism has not been studied in pediatric end stage kidney disease. We sought to determine the intra-individual variability in measures of mineral metabolism in children on hemodialysis (HD) and its impact on clinical decision-making. METHODS: We conducted a prospective single-center study of children (3.6-17.3 years old) on chronic HD. Serial twice weekly measures of serum calcium, phosphate and intact parathyroid hormone (PTH), as well as weekly measures of fibroblast growth factor 23 (FGF23) and vitamin D metabolites, were obtained over a 12-week period in 10 children. Samples (n = 226) were assayed in a single batch at the end of the study. RESULTS: The median intra-individual coefficient of variation (CV) calculated by 4-week blocks was 5.1-6.5% for calcium, 9.5-14.9% for phosphate and 32.7-33.4% for PTH. The median overall CV for FGF23 was 44.4%. Using the first value of each block as a reference, subsequent values would dictate a discrepant management decision 33 56%, 19-28%, and 30-33% of the time for calcium, phosphate, and PTH, respectively. Adjusting for sex and age, most of the variability in phosphate and PTH was attributable to within-participant variability. For calcium, 49% of the variability was attributable to day of blood collection (Monday vs. Friday). The median (range) of an individual participant's values within clinical target ranges was 55% (26-86%) for calcium, 58% (0-96%) for phosphate, and 21% (0-64%) for PTH. CONCLUSIONS: There is considerable intra-individual variability in measures of mineral metabolism that serve as surrogate markers for bone health in children on HD. Within a 4-week period, at least 20-30% of measures would dictate a discrepant decision from the referent measure of that month. These findings have important implications for clinical decision-making and underscore the need to base therapeutic decisions on trends rather than single measurements. PMID- 28667460 TI - Prediction of the Effect of Renal Impairment on the Pharmacokinetics of New Drugs. AB - INTRODUCTION: Renal impairment may have a significant impact on the pharmacokinetics of drugs. Ad hoc studies in subjects with renal impairment are required by the regulatory authorities to propose dose adjustments in these subjects, to find a dosing regimen able to provide a systemic exposure similar to those in subjects with a normal renal function given the relevant clinical dose. METHODS: To evaluate the main descriptors and establish a predictive model of the effect of renal impairment on the exposure of new drugs, we considered 73 marketed drugs, for which studies in subjects with different degrees of renal impairment were available in the literature. Multivariate analysis was performed using the main pharmacokinetic parameters. Other approaches, including data mining and machine learning techniques, were tested to propose models based on a categorical definition of the exposure changes. RESULTS: Stepwise multivariate regression analyses revealed, as expected, that the fraction of dose excreted unchanged in urine and plasma protein binding were the factors primarily related to the change in exposure between subjects with normal and impaired renal function. Data mining techniques provided similar results. DISCUSSION: The pharmacokinetic predictions were however not always satisfactory, especially for drugs which, despite the negligible renal excretion, are characterized by significant increases in the systemic exposure in subjects with renal impairment. This phenomenon, interpreted considering the accumulation of endogenous metabolism inhibitors in subjects with moderate and severe renal disease (uremic toxins), cannot be fully captured and described, likely owing to an incomplete understanding of the pathophysiological phenomena and to some limitations of the available database of clinical studies. PMID- 28667461 TI - Tissue banking, biovigilance and the notify library. AB - This issue is dedicated to the contributions of Professor Glyn O. Phillips to the field of tissue banking and the advancement of science in general. The use of ionizing radiation to sterilize medical products drew the interest of the International Atomic Energy Agency (IAEA). A meeting in 1976 in Athens Greece to present work on the effects of sterilizing radiation doses upon the antigenic properties of proteins and biologic tissues was my first introduction of Professor Phillips and the role that he was to play in Tissue Banking (Friedlaender, in Phillips GO, Tallentine AN (eds) Radiation sterilization. Irradiated tissues and their potential clinical use. The North E. Wales Institute, Clwyd, p 128, 1978). The IAEA sponsored subsequent meetings in the Republic of Korea, Czechoslovakia and Rangoon, the later including a visit to the tissue bank by Professor Phillips. His advocacy resulted in multiple workshops and teaching opportunities in a variety of countries, one of which led to the establishment of the Asia Pacific Surgical Tissue Banking Association in 1989 (Phillips and Strong, in Phillips GO, Strong DM, von Versen R, Nather A (eds) Advances in tissue banking, vol 3. World Scientific, Singapore, pp 403-417, 1999). PMID- 28667462 TI - The evaluation of cartilage differentiations using transforming growth factor beta3 alone and with combination of bone morphogenetic protein-6 on adult stem cells. AB - In our quest to standardize our formula for a clinical trial, transforming growth factor-beta3 (TGF-beta3) alone and in combination with bone morphogenetic protein 6 (BMP-6) were evaluated for their effectiveness in cartilage differentiation. Bone Marrow Stem Cells (BMSCs) and Adipose Derived Stem Cells (ADSCs) were induced to chondrogenic lineage using two different media. Native chondrocytes served as positive control. ADSCs and BMSCs proved multipotency by tri-lineage differentiations. ADSC has significantly higher growth kinetics compare to Chondrocyte only p <= 0.05. Using TGF-beta3 alone, BMSC revealed higher expressions for hyaline cartilage genes compare to ADSCs. Chondrocyte has significantly higher early chondrogenic markers expression to ADSCs and BMSCs, while BMSCs was only higher to ADSC at chondroadherin, p <= 0.0001. On mature chondrogenic markers, chondrocytes were significantly higher to ADSCs and BMSCs for aggrecan, collagen IX, sry (sex determining region y)-box9, collagen II and fibromodullin; and only to ADSC for collagen XI. BMSC was higher to ADSC for aggrecan and collagen IX, p <= 0.0001. The combination of TGF-beta3 + BMP-6 revealed increased gene expressions on both BMSCs and ADSCs for early and mature chondrogenic markers, but no significance difference. For dedifferentiation markers, ADSC was significantly higher to chondrocyte for collagen I. Glycosaminoglycan evaluations with both formulas revealed that chondrocytes were significantly higher to ADSCs and BMSCs, but none was significant to each other, p <= 0.0001. Combination of 10 ng TGF-beta3 with 10 ng of BMP-6 enhanced chondrogenic potentials of BMSCs and ADSCs compare to TGF-beta3 alone. This could be the ideal cocktail for either cell's chondrogenic induction. PMID- 28667463 TI - [Noninvasive ventilation after extubation : "Go ahead" in patients with chronic respiratory disorders]. PMID- 28667464 TI - Can Neurochemical Changes of Mood Disorders Explain the Increase Risk of Epilepsy or its Worse Seizure Control? AB - The existence of a bidirectional relation between mood disorders and epilepsy has been suggested by six population-based studies. Furthermore, three studies have associated a higher risk of treatment-resistant epilepsy with a history of depression preceding the onset of epilepsy. Common pathogenic mechanisms operant in depression and epilepsy may provide a possible explanation of these observations. This article reviews some of the leading pathogenic mechanisms of depression with respect to potential proconvulsant properties that may provide explanations for these phenomena. PMID- 28667466 TI - Safety, pharmacokinetic, and clinical activity profiles of ramucirumab in combination with three platinum/fluoropyrimidine doublets in Japanese patients with chemotherapy-naive metastatic gastric/gastroesophageal junction cancer. AB - BACKGROUND: We evaluated the safety, tolerability, pharmacokinetics, and tumor response of ramucirumab in combination with one of three platinum/fluoropyrimidine regimens in Japanese patients with chemotherapy-naive metastatic gastric/gastroesophageal junction cancer. METHODS: In this phase 1b study, patients received 8 mg/kg ramucirumab on days 1 and 8 every 3 weeks, following one of three regimens: capecitabine + cisplatin, XP; S-1 + cisplatin, SP; or S-1 + oxaliplatin, SOX. The primary objective was to assess safety and tolerability; the secondary objectives were to evaluate pharmacokinetics and tumor response. RESULTS: Six patients were treated in each cohort. All regimens were generally well tolerated, although 1 patient in SOX was associated with grade 3 enterocolitis, which was considered a dose-limiting toxicity. Common grade 3 or higher adverse events included neutropenia (1 in XP, 3 in SP, and 2 in SOX), decreased appetite (1 in SP), and hypertension (2 in XP). The mean trough ramucirumab concentrations were consistent across all cohorts, and those of most patients exceeded target levels, which were estimated from previous studies of the approved ramucirumab dose (8 mg/kg every 2 weeks). Among the 11 patients with measurable disease, overall response rate and disease control rate were 45.5% and 100.0%, respectively. Median progression-free survival (95% CI) was 7.6 months (6.0 to not estimable). CONCLUSION: Ramucirumab 8 mg/kg on days 1 and 8 every 3 weeks in combination with XP, SP, or SOX was generally well tolerated and demonstrated preliminary anti-tumor activity in chemotherapy-naive Japanese metastatic gastric/gastroesophageal junction cancer patients. PMID- 28667468 TI - Surveillance Among Men Who have Sex with Men in the United States: A Comparison of Web-Based and Venue-Based Samples. AB - Although men who have sex with men (MSM) recruited through web-based and venue based sampling methods have been compared, no large web-based and venue-based samples using similar survey instruments have been examined in the U.S. This study describes the differences in sociodemographic characteristics and risk behaviors between the 2012 Web-based HIV Behavioral Survey (n = 3221) and 2011 National HIV Behavioral Surveillance (n = 9256). Compared with participants in the venue-based sample, participants in the web-based sample were older, less likely to be black or Hispanic, more likely to have higher socioeconomic status, and more likely to have anal sex without a condom with their last male sex partner. Web-based participants were less likely to have multiple male sex partners, ever injected drugs, been tested for HIV in the past 12 months, and received free condoms than venue-based participants. The method for sampling MSM into a behavioral survey should consider the sub-population of MSM to be reached. PMID- 28667467 TI - The Gut Bacterial Community Composition of Wild Cervus albirostris (White-Lipped Deer) Detected by the 16S Ribosomal RNA Gene Sequencing. AB - Cervus albirostris (white-lipped deer) is an endemic species in China. As the name implies, C. albirostris has a characteristic pure white marking around their mouth and on the underside of the throat. The animal is a typical alpine species normally living at the height of 3500-4300 m. In this study, by pyrosequencing the 16S rRNA gene sequences, we for the first time analyzed the gut bacterial community composition in eight feces samples of wild C. albirostris. From a total of 243,634 high-quality sequences, we identified 186 genera, included in 17 prokaryotic phyla in the feces. The relative proportions of Firmicutes and Bacteroidetes were highly consistent in each individual sample. The most frequently detected genus was Ruminococcaceae UCG-005, ranging from 6.70 to 21.00%, displaying positively connections with the Rikenellaceae RC9 gut group. The bacterial communities associated with C. albirostris provide the basic knowledge for further microbiological studies and facilitates the conservation efforts of this vulnerable deer species. PMID- 28667465 TI - The role of vitamin D in male fertility: A focus on the testis. AB - In the last decade, vitamin D has emerged as a pleiotropic molecule with a multitude of autocrine, paracrine and endocrine functions, mediated by classical genomic as well as non-classical non-genomic actions, on multiple target organs and systems. The expression of vitamin D receptor and vitamin D metabolizing enzymes in male reproductive system, particularly in the testis, suggests the occurrence of vitamin D synthesis and regulation as well as function in the testis. The role of vitamin D in the modulation of testis functions, including hormone production and spermatogenesis, has been investigated in animals and humans. Experimental studies support a beneficial effect of vitamin D on male fertility, by modulating hormone production through genomic and non-genomic actions, and, particularly, by improving semen quality essentially through non genomic actions. However, clinical studies in humans are controversial. Indeed, vitamin D seems to contribute to the modulation of the bioavailable rather than total testosterone. Moreover, although an increased prevalence or risk for testosterone deficiency was reported in men with vitamin D deficiency in observational studies, the majority of interventional studies demonstrated the lack of effect of vitamin D supplementation on circulating levels of testosterone. The most consistent effect of vitamin D was reported on semen quality. Indeed, vitamin D was shown to be positively associated to sperm motility, and to exert direct actions on spermatozoa, including non-genomic driven modulation of intracellular calcium homeostasis and activation of molecular pathways involved in sperm motility, capacitation and acrosome reaction. The current review provides a summary of current knowledge on the role of vitamin D in male fertility, by reporting clinical and experimental studies in humans and animals addressing the relationship between vitamin D and testis function. PMID- 28667469 TI - Reliability, Validity, and Factor Structure of the Hopkins Symptom Checklist-25: Population-Based Study of Persons Living with HIV in Rural Uganda. AB - Depression and anxiety are highly comorbid among people living with HIV (PLHIV), but few instruments for screening or measurement have been validated for use in sub-Saharan Africa. The objective of this study was to determine the reliability, validity, and factor structure of the 25-item Hopkins Symptom Checklist (HSCL) in a population-based sample of PLHIV in rural Uganda. This study was nested within an ongoing population-based cohort of all residents living in Nyakabare Parish, Mbarara District, Uganda. All participants who identified as HIV-positive by self report were included in this analysis. We performed parallel analysis on the scale items and estimated the internal consistency of the identified sub-scales using ordinal alpha. To assess construct validity we correlated the sub-scales with related constructs, including subjective well being (happiness), food insecurity, and health status. Of 1814 eligible adults in the population, 158 (8.7%) self-reported being HIV positive. The mean age was 41 years, and 68% were women. Mean HSCL-25 scores were higher among women compared with men (1.71 vs. 1.44; t = 3.6, P < 0.001). Parallel analysis revealed a three-factor structure that explained 83% of the variance: depression (7 items), anxiety (5 items), and somatic symptoms (7 items). The ordinal alpha statistics for the sub-scales ranged from 0.83 to 0.91. Depending on the sub-scale, between 27 and 41% of the sample met criteria for caseness. Strong evidence of construct validity was shown in the estimated correlations between sub-scale scores and happiness, food insecurity, and self-reported overall health. The HSCL-25 is a reliable and valid measure of mental health among PLHIV in rural Uganda. In cultural contexts where somatic complaints are commonly elicited when screening for symptoms of depression, it may be undesirable to exclude somatic items from depression symptom checklists administered to PLHIV. PMID- 28667470 TI - [30-day mortality after systemic anticancer treatment : Population-based observational study on breast and lung cancer]. PMID- 28667471 TI - Topical application of Dermatophagoides farinae or oxazolone induces symptoms of atopic dermatitis in the rabbit ear. AB - Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of the epidermis, and dermal infiltration of inflammatory cells. Appropriate animal models that recapitulate human AD and allow the analysis of disease processes in a reliable manner are essential to the study of AD. In this study, we established two AD models in rabbits by applying an allergen, Dermatophagoides farinae (Der f), or a hapten, oxazolone (OXZ). Application of the allergen or hapten induced a rapid onset and a chronically sustained AD-like skin lesion. The clinical symptoms, which include skin erythema, scaling, papula and edema, of AD-like rabbit skin were similar to those in human AD. Histological analysis showed that allergen- or hapten-treated rabbit skin showed increased epidermal thickening and inflammatory cell infiltration. Furthermore, PCNA and keratin 10 (K10) staining revealed excessive proliferation and insufficient differentiation of the epidermis in the rabbit AD-like skin. Western blot analysis showed decreased expression of thymic stromal lymphopoietin (TSLP), an AD cytokine, in the rabbit AD-like skin. Our results suggest that the allergen- or hapten-induced rabbit AD models have pathological features of human AD-like symptoms and will be useful for evaluating both pathogenic mechanisms and potential therapeutic agents for human AD. PMID- 28667472 TI - Erratum to: Combined effect of pulse density and grid cell size on predicting and mapping aboveground carbon in fast-growing Eucalyptus forest plantation using airborne LiDAR data. PMID- 28667473 TI - Differences in functional traits between invasive and native Amaranthus species under different forms of N deposition. AB - Differences in functional traits between invasive and native plant species are believed to determine the invasion success of the former. Increasing amounts of anthropogenic nitrogen (N) are continually deposited into natural ecosystems, which may change the relative occurrence of the different N deposition forms (such as NH4-N, NO3-N, and CO(NH2)2-N) naturally deposited. Under high N deposition scenarios, some invasive species may grow faster, gaining advantage over native species. In a greenhouse experiment, we grew invasive and native Amaranthus species from seed both alone and in competition under simulated N enriched environments with different forms of N over 3 months. Then, we measured different leaf traits (i.e., plant height, leaf length, leaf width, leaf shape index, specific leaf area (SLA), and leaf chlorophyll and N concentrations). Results showed that the competition intensity between A. retroflexus and A. tricolor decreased under N deposition. This may be due to the large functional divergence between A. retroflexus and A. tricolor under simulated N deposition. Phenotypic plasticity of SLA and leaf chlorophyll concentration of A. retroflexus were significantly lower than in A. tricolor. The lower range of phenotypic plasticity of SLA and leaf chlorophyll concentration of A. retroflexus may indicate a fitness cost for plastic functional traits under adverse environments. The restricted phenotypic plasticity of SLA and leaf chlorophyll concentration of A. retroflexus may also stabilize leaf construction costs and the growth rate. Meanwhile, the two Amaranthus species possessed greater plasticity in leaf N concentration under NO3-N fertilization, which enhanced their competitiveness. PMID- 28667474 TI - RETRACTED ARTICLE: Development and In Vitro-In Vivo Characterization of Chronomodulated Pulsatile Delivery Formulation of Terbutaline Sulphate by Box Behnken Statistical Design. PMID- 28667475 TI - Smoking and Religion: Untangling Associations Using English Survey Data. AB - While factors affecting smoking are well documented, the role of religion has received little attention. This national study aims to assess the extent to which religious affiliation is associated with current-smoking and ever-smoking, controlling for age, sex, ethnicity and socio-economic status. Variations between adult and youth populations are examined using secondary analysis of individual level data from 5 years of the Health Survey for England for adult (aged >20, n = 39,837) and youth (aged 16-20, n = 2355) samples. Crude prevalence statistics are contrasted with binary logistic models for current-smoking and ever-smoking in the adult and youth samples. Analyses suggest that Muslims smoke substantially less than Christians. Highest levels of smoking characterise people not professing any religion. Associations between smoking and the Muslim religion attenuate to statistical insignificance in the face of ethnic and socio-economic factors. An association between smoking and the absence of a religious affiliation is sustained. An understanding of the association between smoking and religion is essential to the development of tobacco control programmes. PMID- 28667476 TI - 3D Homology Model of Sigma1 Receptor. AB - This chapter presents the three-dimensional (3D) model of the Sigma1 receptor protein as obtained from homology modeling techniques. We show the applicability of this structure to docking-based virtual screening and discuss combined in silico/in vitro mutagenesis studies performed to validate the structural features of the Sigma1 receptor model and to qualify/quantify the prominent role of specific amino acid residues in ligand binding. The validation of the virtual 3D Sigma1 receptor model and its reliable applicability to docking-based virtual screening is of significance for rational ligand design, even in light of the recently reported crystal structure for the Sigma1 receptor. PMID- 28667477 TI - Allosteric Modulation of Opioid G-Protein Coupled Receptors by Sigma1 Receptors. AB - Since their proposal in 1976, the concept of sigma1 receptors has been continually evolving. Initially thought to be a member of the opioid receptor family, molecular studies have now identified its genes and established its structure crystallographically. Much effort has now revealed its importance as a chaperone in the endoplasmic reticulum, but its functions extend beyond this. Sigma1 receptors have been associated with a host of signaling systems. Evidence over the past 20 years has established the modulatory effects of sigma1 ligands on opioid systems. Despite their inability to bind directly to opioid receptors, sigma1 ligands can modulate opioid analgesia in vivo and signal transduction mechanisms in vitro. Furthermore, sigma1 receptors can physically associate with GPCRs. Together, these findings show that sigma1 ligands can function as allosteric modulators of GPCR function through their association with the sigma1 receptors, which are in direct physical association with opioid receptors, members of the G-protein coupled family of receptors. PMID- 28667478 TI - Pulmonary hypertension nosography: are all patients classifiable? PMID- 28667480 TI - MRI surveillance for the detection of local recurrence in rectal cancer after transanal endoscopic microsurgery. AB - OBJECTIVES: To evaluate diagnostic performance of follow-up MRI for detection of local recurrence of rectal cancer after transanal endoscopic microsurgery (TEM). METHODS: Between January 2006 and February 2014, 81 patients who underwent TEM were included. Two expert readers (R1 and R2), independently evaluated T2 weighted (T2W) MRI and diffusion-weighted (DWI) MRI for the detection of local recurrence, retrospectively, and recorded confidence on a five-point scale. Diagnostic performance of follow-up MRI was assessed using ROC-curve analysis and kappa statistics for the reproducibility between readers. RESULTS: 293 MRIs were performed, 203 included DWI. 18 (22%) patients developed a local recurrence: luminal 11, nodal two and both five. Areas under the curve (AUCs) for local recurrence detection were 0.72 (R1) and 0.80 (R2) for T2W-MRI. For DWI, AUCs were 0.70 (R1) and 0.89 (R2). For nodal recurrence AUCs were 0.72 (R1) and 0.80 (R2) for T2W-MRI. Reproducibility was good for T2W-MRI (kappa0.68 for luminal and kappa0.71 for nodal recurrence) and moderate for DWI (kappa0.57). AUCs and reproducibility for recurrence detection increased during follow-up. CONCLUSIONS: Follow-up with MRI after TEM for rectal cancer is feasible. Postoperative changes can be confusing at the first postoperative MRI, but during follow-up diagnostic performance and reproducibility increase. KEY POINTS: * Follow-up with MRI is feasible for follow-up after TEM for rectal cancer. * DWI-MRI is a useful addition to detect recurrences after TEM. * Postoperative changes can be confusing and can lead to underestimation of recurrence. * Appearance of intermediate signal at T2W-MRI is suspicious for recurrence. * Nodal staging remains challenging. PMID- 28667479 TI - Combining Human and Rodent Genetics to Identify New Analgesics. AB - Most attempts at rational development of new analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacologically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design: the use of controlled inhibition of peripheral tetrahydrobiopterin (BH4) synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially identified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype (present in 25% of Caucasians) of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 (GCH1). Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, targeting the last enzyme of the BH4 synthesis pathway, sepiapterin reductase (SPR), allows reduction of pathological BH4 production without completely blocking physiological BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhibited, sepiapterin serves as a reliable biomarker of target engagement, allowing potential quantification of drug efficacy. The emerging development of therapeutics that target BH4 synthesis to treat chronic pain illustrates the power of combining human and mouse genetics: human genetic studies for clinical selection of relevant targets, coupled with causality studies in mice, allowing the rational engineering of new analgesics. PMID- 28667481 TI - Disrupted topological organization of brain structural network associated with prior overt hepatic encephalopathy in cirrhotic patients. AB - OBJECTIVES: To investigate structural brain connectome alterations in cirrhotic patients with prior overt hepatic encephalopathy (OHE). METHODS: Seventeen cirrhotic patients with prior OHE (prior-OHE), 18 cirrhotic patients without prior OHE (non-prior-OHE) and 18 healthy controls (HC) underwent diffusion tensor imaging. Neurocognitive functioning was assessed with Psychometric Hepatic Encephalopathy Score (PHES). Using a probabilistic fibre tracking approach, we depicted the whole-brain structural network as a connectivity matrix of 90 regions (derived from the Automated Anatomic Labeling atlas). Graph theory-based analyses were performed to analyse topological properties of the brain network. RESULTS: The analysis of variance showed significant group effects on several topological properties, including network strength, global efficiency and local efficiency. A progressive decrease trend for these metrics was found from non prior-OHE to prior-OHE, compared with HC. Among the three groups, the regions with altered nodal efficiency were mainly distributed in the frontal and occipital cortices, paralimbic system and subcortical regions. The topological metrics, such as network strength and global efficiency, were correlated with PHES among cirrhotic patients. CONCLUSIONS: The cirrhotic patients developed structural brain connectome alterations; this is aggravated by prior OHE episode. Disrupted topological organization of the brain structural network may account for cognitive impairments related to prior OHE. KEY POINTS: * Altered structural brain connectome is found in cirrhotic patients. * Structural brain connectome alterations could be aggravated by prior-OHE episode. * Altered structural brain connectome may account for cognitive impairments associated with prior OHE. PMID- 28667482 TI - Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS. AB - OBJECTIVE: To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. PATIENTS AND METHODS: We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. RESULTS: MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow up showed association with clinical disability in NMO. CONCLUSION: Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. KEY POINTS: * Spinal cord atrophy progression was observed in NMO. * Spinal cord atrophy changes were associated with disability progression in NMO. * Brain lesion and atrophy were related to disability progression in MS. PMID- 28667484 TI - Encouraging results of 25G+ minimally invasive vitrectomy surgery for diabetic tractional retinal detachment. PMID- 28667483 TI - Is ellipsoid zone integrity essential for visual recovery in myopic neovascularization after anti-VEGF therapy? AB - PURPOSE: To evaluate functional prognostic factors and neuroretinal changes after anti-vascular endothelial growth factor (VEGF) treatment in patients with naive, recent myopic neovascularization (mCNV), as assessed by spectral-domain optical coherence tomography (SD-OCT). METHODS: Specific changes in tomographic features between baseline and final follow-up were retrospectively evaluated by two examiners independently. Imaging was obtained by a multi-modal imaging system which combines fluorescein angiography and SD-OCT. RESULTS: Twenty-two eyes (male, six; female, 16; mean age, 65 +/- 14 years) were considered. Mean follow up was 21.5 +/- 14 months. Best-corrected visual acuity (BCVA) improved from 0.38 +/- 0.26 to 0.16 +/- 0.20 logMAR (p < 0.001). The ellipsoid zone and the external limiting membrane (ELM) were disrupted in 21 (95.5%) and 15 (68.2%) eyes at baseline, and in 16 (72.7%) and nine (40.9%) eyes after therapy respectively. The ellipsoid zone and ELM were typically intact at lesion margins in 13 (59.1%) and 19 eyes (86.5%) respectively at baseline. The inner retina was intact in 20 eyes (91%). Six eyes (27.3%) exhibited complete regression without fibrosis. Absence of hemorrhage and integrity of lesion-adjacent ELM and of lesion-adjacent ellipsoid zone at baseline were factors for better final BCVA (p <= 0.05) CONCLUSION: Vision gain might occur despite ellipsoid zone or ELM restoration. Hemorrhage could be considered a negative prognostic factor, integrity of lesion adjacent ELM and of lesion-adjacent ellipsoid zone as positive prognostic factors. Myopic CNV can also resolve completely without fibrosis. PMID- 28667485 TI - Income inequality among American states and the conditional risk of post traumatic stress disorder. AB - PURPOSE: Vulnerability to post-traumatic disorder (PTSD) following a traumatic event can be influenced by individual-level as well as contextual factors. Characteristics of the social and economic environment might increase the odds for PTSD after traumatic events occur. One example that has been identified as a potential environmental determinant is income inequality. The purpose of this study is to investigate the association between State-level income inequality and PTSD among adults who have been exposed to trauma. METHODS: We used data from the National Epidemiologic Survey on Alcohol and Related Conditions (n = 34,653). Structured diagnostic interviews were administered at baseline (2001-2002) and follow-up (2004-2005). Weighted multi-level logistic regression was used to determine if US State-level income inequality, as measured by the Gini coefficient, was associated with incident episodes of PTSD during the study's 3 year follow-up period adjusting for individual and state-level covariates. RESULTS: The mean Gini coefficient across states in the NESARC was 0.44 (SD = 0.02) and ranged from 0.39 to 0.53. Of the respondents, 27,638 reported exposure to a traumatic event. Of this sample, 6.9 and 2.3% experienced persistent or recurrent and incident PTSD, respectively. State-level inequality was not associated with increased odds for persistent or recurrent PTSD (OR = 1.02; 95% CI 0.85, 1.22), but was associated with incident PTSD (OR = 1.30, 95% CI 1.04, 1.63). CONCLUSION: The degree of income inequality in one's state of residence is associated with vulnerability to PTSD among individuals exposed to traumatic events. Additional work is needed to determine if this association is causal (or alternatively, is explained by other socio-contextual factors associated with income inequality), and if so, what anxiogenic mechanisms explain it. PMID- 28667486 TI - A cluster randomised controlled trial of a staff-training intervention in residential units for people with long-term mental illness in Portugal: the PromQual trial. AB - PURPOSE: This study aimed to assess the efficacy of a staff-training intervention to improve service users' engagement in activities and quality of care, by means of a cluster randomised controlled trial. METHOD: All residential units with at least 12-h a day staff support (n = 23) were invited to participate. Quality of care was assessed with the Quality Indicator for Rehabilitative Care (QuIRC) filled online by the unit's manager. Half the units (n = 12) were randomly assigned to continue providing treatment as usual, and half (n = 11) received a staff-training intervention that focused on skills for engaging service users in activities, with trainers working alongside staff to embed this learning in the service. The primary outcome was service users' level of activity (measured with the Time Use Diary), reassessed at 4 and 8 months. Secondary outcomes were the quality of care provided (QuIRC), and service users' quality of life (Manchester Short Assessment of Quality of Life) reassessed at 8 months. Generalized linear mixed effect models were used to assess the difference in outcomes between units in the two trial arms. The trial was registered with Current Controlled Trials (Ref NCT02366117). RESULTS: Knowledge acquired by the staff during the initial workshops increased significantly (p <= 0.01). However, the intervention and comparison units did not differ significantly in primary and secondary outcomes at either follow-up. CONCLUSIONS: The intervention increased the level of knowledge of staff without leading to an improvement in service users' engagement in activities, quality of life, or quality of care in the units. PMID- 28667488 TI - Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b. AB - DNA relaxation is an important step in DNA replication. DNA topoisomerases play a major role in DNA relaxation. Hence these enzymes are important targets for cancer drugs. DNA topoisomerase inhibitors bind to the transient enzyme-DNA complex and inhibit DNA replication. Various inhibitors of topoisomerase I and II are prescribed as drugs. Topoisomerase II is considered as an important target for the development of anticancer drugs. In this study we have demonstrated molecular docking of thirteen fluoroquinolines with human DNA topoisomerase II alpha (a) and beta (b). Fluoroquinolines are broad spectrum antibacterial antibiotics and it is highly effective against various bacterial infections. Some of the fluoroquinolines like moxifloxacin exert antifungal as well as anti-cancer activity. It forms complexes with topoisomerase II a and are responsible for stoppage DNA replication. Molecular docking studies showed that fluoroquinolines has shown formation of hydrogen bond and good binding affinity with human Topo2a and Topo2b. Hence FQs may inhibit the activity of enzyme topoisomerase by binding at its active site. Ofloxacin, sparafloxacin, ciprofloxacin and moxifloxacin are predicted to be the most potent inhibitors among the thirteen FQs docked. GLN773, ASN770, LYS723 and TRP931 amino acid residues of Topo2a are involved in binding with FQs while ASP479, SER480, ARG820, ARG503, LYS456 and GLN778 amino acid residues of Topo2b are involved in binding with FQs. Our in silico study suggests that fluoroquinolines could be repositioned as DNA topoisomerase II inhibitors hence can be used as anticancer drugs. In vitro and in vivo experiments need to be done to confirm their efficacy. PMID- 28667487 TI - Tibolone Preserves Mitochondrial Functionality and Cell Morphology in Astrocytic Cells Treated with Palmitic Acid. AB - Obesity has been associated with increased chronic neuroinflammation and augmented risk of neurodegeneration. This is worsened during the normal aging process when the levels of endogenous gonadal hormones are reduced. In this study, we have assessed the protective actions of tibolone, a synthetic steroid with estrogenic actions, on T98G human astrocytic cells exposed to palmitic acid, a saturated fatty acid used to mimic obesity in vitro. Tibolone improved cell survival, and preserved mitochondrial membrane potential in palmitic acid-treated astrocytic cells. Although we did not find significant actions of tibolone on free radical production, it modulated astrocytic morphology after treatment with palmitic acid. These data suggest that tibolone protects astrocytic cells by preserving both mitochondrial functionality and morphological complexity. PMID- 28667489 TI - In vivo visualization of braid-like appearance in Kawasaki disease: insights from multi-modality imaging. AB - A 42-year-old gentleman with Kawasaki disease was referred for silent cardiac ischemia at inferior myocardial region. Coronary angiography showed braid-like appearance in the right coronary artery. Several channels at the segment with braid-like appearance were visualized by multi-slice computed tomography and intravascular ultrasound. Interestingly in particular, optical coherence tomography visualized the presence of multiple micro-vessels which were not detectable on other modalities. This case further elucidates distinct morphological features of braid-like lesion which potentially influences blood supply and causing cardiac ischemia. PMID- 28667490 TI - Biomarkers in Sleep Apnea and Heart Failure. AB - PURPOSE OF REVIEW: Sleep-disordered breathing (SDB) is highly prevalent in heart failure (HF) and may confer significant stress to the cardiovascular system and increases the risk for future cardiovascular events. The present review will provide updates on the current understanding of the relationship of SDB and common HF biomarkers and the effect of positive airway pressure therapy on these biomarkers, with particular emphasis in patients with coexisting SDB and HF. RECENT FINDINGS: Prior studies have examined the relationship between HF biomarkers and SDB, and the effect of SDB treatment on these biomarkers, with less data available in the context of coexisting SDB and HF. Overall, however, the association of SDB and circulating biomarkers has been inconsistent. Further research is needed to elucidate the relationship between biomarkers and SDB in HF, to evaluate the clinical utility of biomarkers over standard methods in large, prospective studies and also to assess the impact of treatment of SDB on these biomarkers in HF via interventional studies. PMID- 28667491 TI - SGLT-2 Inhibitors in Heart Failure: Implications for the Kidneys. AB - PURPOSE OF REVIEW: This review aims to summarize the renal effects of sodium glucose transporter-2 (SGLT-2) inhibitors and their potential implications in heart failure pathophysiology. RECENT FINDINGS: In patients with diabetes and established atherosclerosis, the SGLT-2 inhibitor empagliflozin versus placebo significantly reduced the rate of heart failure admissions with 35%. Moreover, empagliflozin slowed kidney disease progression and reduced the need for renal replacement therapy. SGLT-2 inhibitors inhibit proximal tubular sodium and chloride reabsorption, leading to increased nephron flux throughout the distal renal tubules, most notably at the level of the macula densa. Afferent arteriolar vasoconstriction is promoted through tubulo-glomerular feedback and reduces glomerular capillary hydrostatic pressure, relieving podocyte stress and explaining renal preservation. Further, plasma volume is contracted and natriuresis promoted without inducing neurohumoral activation. Finally, SGLT-2 inhibitors may improve endothelial function and energy metabolism efficiency. Together, these promising features place them as a potential novel treatment for heart failure. PMID- 28667493 TI - MiR-16-1 Targeted Silences Far Upstream Element Binding Protein 1 to Advance the Chemosensitivity to Adriamycin in Gastric Cancer. AB - Chemotherapy can prevent metastasis and recurrence of gastric cancer (GC), and is a well supplement for operation. But, chemotherapy resistance has severely restricted the application of chemotherapy. This study aimed to investigate the regulatory roles and molecular mechanism of miR-16-1 to the chemosensitivity to adriamycin in GC. In this study, the expression of miR-16-1 and FUBP1 was down regulated and up-regulated respectively in adriamycin-resistant GC tissues and cell lines, and represented a negative relationship between them. MiR-16-1 could silence FUBP1 directly and specifically, FUBP1 was a target gene of miR-16-1. Silence of FUBP1 inhibited the half maximal inhibitory concentration (IC50) of SGC7901/AR cell line to adriamycin, chemosensitivity enhanced significantly. Moreover, FUBP1 silence in SGC7901/AR cell line also inhibited proliferation and invasion, and advanced cell apoptosis. To sum up, the expression of miR-16-1 was positively related with the chemosensitivity of GC to adriamycin, and miR-16-1 could targeted silence FUBP1 to advance the chemosensitivity to adriamycin in GC, which might be a novel potential therapeutic target for GC. PMID- 28667494 TI - Single-Nucleotide Polymorphisms of the MSH2 and MLH1 Genes, Potential Molecular Markers for Susceptibility to the Development of Basal Cell Carcinoma in the Brazilian Population. AB - Basal cell carcinoma - BCC is considered a multifactorial neoplasm involving genetic, epigenetic and environmental factors. Where UVB radiation is considered the main physical agent involved in BCC carcinogenesis. The Brazil and state of Paraiba are exposed to high levels of UVB rays. The mismatch repair - MMR is important DNA repair mechanisms to maintain replication fidelity. Therefore, single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in MMR may be potential molecular markers of susceptibility to BCC. The objective of this study was to evaluate and describe for the first time the SNPs rs560246973, rs2303425 and rs565410865 and risk of developing BCC. The present study analyzed 100 samples of paraffin-embedded tissue from patients with histopathological diagnosis of BCC and 100 control samples. The results were obtained by genotyping method, Dideoxy Unique Allele Specific - PCR (DSASP). The SNPs rs2303425 were not associated with Basal Cell Carcinoma. However, the SNPs rs560246973 and rs565410865 was shown to be associated with the development of BCC when compared to control samples (P < 0.0001). The SNPs rs565410865 was also statistical significance between the genotypes of and the age group (p = 0.0027) and tumor location (p = 0,0191). The result suggests that SNPs rs2303425 and rs565410865 are associated with susceptibility to the development of BCC in the Brazilian population and may be considered as potential molecular markers for BCC. PMID- 28667492 TI - Inflammation - Cause or Consequence of Heart Failure or Both? AB - PURPOSE OF REVIEW: With the intention to summarize the currently available evidence on the pathophysiological relevance of inflammation in heart failure, this review addresses the question whether inflammation is a cause or consequence of heart failure, or both. RECENT FINDINGS: This review discusses the diversity (sterile, para-inflammation, chronic inflammation) and sources of inflammation and gives an overview of how inflammation (local versus systemic) can trigger heart failure. On the other hand, the review is outlined how heart failure associated wall stress and signals released by stressed, malfunctioning, or dead cells (DAMPs: e.g., mitochondrial DNA, ATP, S100A8, matricellular proteins) induce cardiac sterile inflammation and how heart failure provokes inflammation in various peripheral tissues in a direct (inflammatory) and indirect (hemodynamic) manner. The crosstalk between the heart and peripheral organs (bone marrow, spleen, gut, adipose tissue) is outlined and the importance of neurohormonal mechanisms including the renin angiotensin aldosteron system and the beta-adrenergic nervous system in inflammation and heart failure is discussed. Inflammation and heart failure are strongly interconnected and mutually reinforce each other. This indicates the difficulty to counteract inflammation and heart failure once this chronic vicious circle has started and points out the need to control the inflammatory process at an early stage avoiding chronic inflammation and heart failure. The diversity of inflammation further addresses the need for a tailored characterization of inflammation enabling differentiation of inflammation and subsequent target-specific strategies. It is expected that the characterization of the systemic and/or cardiac immune profile will be part of precision medicine in the future of cardiology. PMID- 28667495 TI - Synthesis and antiproliferative activity of amino-substituted benzimidazo[1,2 alpha]quinolines as mesylate salts designed by 3D-QSAR analysis. AB - An experimental search for new benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D QSAR models were derived on an available database of compounds with previously measured activities. Our QSAR analysis revealed that an increase of the antiproliferative activities towards H460, HCT 116, MCF-7 and SW 620 cells will be obtained if new compounds are charged at a pH range from 5 to 7 and if their hydrophobicity is increased compared to the dataset compounds. Novel benzimidazo[1,2-a]quinolines bearing quarternary amino groups with corresponding aliphatic chains were designed, and their antiproliferative activities were computationally predicted. Using uncatalysed microwave-assisted amination reactions, 14 novel compounds were obtained to assess their antiproliferative activities towards H460, HCT 116, MCF-7, and SW 620 tumour cell lines in vitro. Novel compounds showed antiproliferative activities at micromolar and submicromolar inhibition concentrations. Experimental measurements of antiproliferative activities validation the QSAR models showing very good agreement between experimentally measured activities and computational predictions. In an attempt to elucidate the mode of action through which benzimidazole derivatives accomplish their antiproliferative activities, thermal denaturation experiments were performed to test their DNA-binding properties. PMID- 28667496 TI - Skin Health Connected to the Use of Absorbent Hygiene Products: A Review. AB - Over the past 50 years, absorbent hygiene products such as baby diapers and incontinence products have become essential features of modern day life. Through innovation and enhanced technology, their design, composition and performance have been dramatically upgraded from their early forms, and they have transformed the lives of millions of people, improving their quality of life. Skin health related to the use of absorbent hygiene products has accordingly also greatly improved. Still, the wearing of absorbent hygiene products will affect the skin, and for some users the changes in microclimate, mechanical interactions and the exposure to urine and faeces may result in irritant contact dermatitis, i.e. diaper dermatitis (DD) or incontinence-associated dermatitis (IAD). Babies with developing skin and the elderly with deteriorating skin functions who are the most frequent users of absorbent hygiene products are more vulnerable to the causal factors. Although irritant reactions are the most common, allergic contact dermatitis should be considered if a DD/IAD fails to improve by recommended actions. There is also a connection between IAD and pressure ulcer development of which it is important to be aware. A holistic approach of using high-quality absorbent hygiene products in combination with appropriate skin care will help maintaining good skin health. PMID- 28667498 TI - Colorectal cancer surgery in the very elderly patient: a systematic review of laparoscopic versus open colorectal resection. AB - INTRODUCTION: Colorectal cancer is the second most common cause of death from neoplastic disease in men and third in women of all ages. Globally, life expectancy is increasing, and consequently, an increasing number of operations are being performed on more elderly patients with the trend set to continue. Elderly patients are more likely to have cardiovascular and pulmonary comorbidities that are associated with increased peri-operative risk. They further tend to present with more locally advanced disease, more likely to obstruct or have disseminated disease. The aim of this review was to investigate the feasibility of laparoscopic colorectal resection in very elderly patients, and whether there are benefits over open surgery for colorectal cancer. METHODS: A systematic literature search was performed on Medline, Pubmed, Embase and Google Scholar. All comparative studies evaluating patients undergoing laparoscopic versus open surgery for colorectal cancer in the patients population over 85 were included. The primary outcomes were 30-day mortality and 30-day overall morbidity. Secondary outcomes were operating time, time to oral diet, number of retrieved lymph nodes, blood loss and 5-year survival. RESULTS: The search provided 1507 citations. Sixty-nine articles were retrieved for full text analysis, and only six retrospective studies met the inclusion criteria. Overall mortality for elective laparoscopic resection was 2.92% and morbidity 23%. No single study showed a significant difference between laparoscopic and open surgery for morbidity or mortality, but pooled data analysis demonstrated reduced morbidity in the laparoscopic group (p = 0.032). Patients undergoing laparoscopic surgery are more likely to have a shorter hospital stay and a shorter time to oral diet. CONCLUSION: Elective laparoscopic resection for colorectal cancer in the over 85 age group is feasible and safe and offers similar advantages over open surgery to those demonstrated in patients of younger ages. PMID- 28667500 TI - Safety Pin as a Chest Tube Clamp - Cause of Iatrogenic Pneumothorax. PMID- 28667499 TI - Two-stage Turnbull-Cutait pull-through coloanal anastomosis versus coloanal anastomosis with protective loop ileostomy for low rectal cancer. Protocol for a randomized controlled trial (Turnbull-BCN). AB - PURPOSE: The aim of this study was to determine whether patients that underwent ultra-low rectal resection for cancer can benefit from the recently reintroduced two-stage Turnbull-Cutait abdominoperineal pull-through procedure. METHODS: Patients with low rectal tumors undergoing radical sphincter-sparing resection are eligible for inclusion in a randomized multicenter study. Whether two-stage Turnbull-Cutait coloanal anastomosis provides significant benefits over hand-sewn coloanal anastomosis and associated lateral ileostomy in terms of postoperative morbidity is the primary endpoint. In addition, the study aims to assess secondary endpoints such as quality of life, fecal incontinence, and locoregional recurrence of the neoplasm. Patients with adenocarcinoma of the lower rectum diagnosed by rigid proctoscopy, with histological confirmation of malignancy, and who are candidates of rectal removal and coloanal anastomosis will be included in a randomized controlled and multicenter trial. Postoperative morbidity is defined as complications that occur within 30 days of the data of the second surgical procedure of the last patient included in the trial. Patients will be followed for a minimum period of 3 years. CONCLUSIONS: The two-stage Turnbull-Cutait coloanal anastomosis may constitute an effective surgical alternative in the current approach to the treatment of low rectal cancer without the need of a temporary loop colostomy, preventing the wide range of complications related to stoma surgery. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (trial number: NCT01766661). This trial is registered in January 10, 2013. PMID- 28667501 TI - A Review of Hip Hop-Based Interventions for Health Literacy, Health Behaviors, and Mental Health. AB - OBJECTIVE: African-American children and adolescents experience an undue burden of disease for many health outcomes compared to their White peers. More research needs to be completed for this priority population to improve their health outcomes and ameliorate health disparities. Integrating hip hop music or hip hop dance into interventions may help engage African-American youth in health interventions and improve their health outcomes. We conducted a review of the literature to characterize hip hop interventions and determine their potential to improve health. METHODS: We searched Web of Science, Scopus, PsycINFO, and EMBASE to identify studies that assessed hip hop interventions. To be included, studies had to (1) be focused on a psychosocial or physical health intervention that included hip hop and (2) present quantitative data assessing intervention outcomes. Twenty-three articles were identified as meeting all inclusion criteria and were coded by two reviewers. Articles were assessed with regards to sample characteristics, study design, analysis, intervention components, and results. RESULTS: Hip hop interventions have been developed to improve health literacy, health behavior, and mental health. The interventions were primarily targeted to African-American and Latino children and adolescents. Many of the health literacy and mental health studies used non-experimental study designs. Among the 12 (of 14) health behavior studies that used experimental designs, the association between hip hop interventions and positive health outcomes was inconsistent. CONCLUSIONS: The number of experimental hip hop intervention studies is limited. Future research is required to determine if hip hop interventions can promote health. PMID- 28667502 TI - Lysophosphatidic Acid Protects Against Endotoxin-Induced Acute Kidney Injury. AB - Septic shock is the most common cause of acute kidney injury (AKI), but the underlying mechanisms remain unclear and no targeted therapies exist. Lysophosphatidic acid (LPA) is a bioactive lipid which in vivo administration was reported to mitigate inflammation and injuries caused by bacterial endotoxemia in the liver and lung. The objective of the present study was to determine whether LPA can protect against sepsis-associated AKI. C57BL/6 mice were treated with LPA 18:1 (5 mg/kg, i.p.) 1 h before being injected with the endotoxin lipopolysaccharide (LPS), and AKI was evaluated after 24 h. LPA significantly decreased the elevation of plasma urea and creatinine caused by LPS. In the kidney, LPA pretreatment significantly reduced the upregulation of inflammatory cytokines (IL-6, TNFalpha, monocyte chemoattractant protein-1 (MCP-1)), and completely prevented downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and upregulation of heme oxygenase-1 caused by LPS. LPA also prevented LPS-mediated alterations of the renal mitochondrial ultrastructure. In vitro pretreatment with LPA 18:1 significantly attenuated LPS induced upregulation of the inflammatory cytokines (TNFalpha and MCP-1) in RAW264 macrophages. Moreover, in vivo LPS treatment lowered urinary LPA concentration and reduced LPA anabolic enzymes (autotaxin and acylglycerol kinase), and increased the LPA catalytic enzyme (lipid phosphate phosphatase 2) expression in the kidney cortex. In conclusion, exogenous LPA exerted a protective action against renal inflammation and injuries caused by bacterial endotoxemia. Moreover, LPS reduces the renal production of LPA suggesting that sepsis associated AKI could be mediated, at least in part, by alleviation of the protective action of endogenous LPA. PMID- 28667503 TI - Antipyretic Effects of Citral and Possible Mechanisms of Action. AB - Citral is a mixture of the two monoterpenoid isomers (neral and geranial) widely used as a health-promoting food additive safe for human and animal (approved by the US Food and Drug Administration). In vitro studies have reported on the capability of citral to reduce inflammation. Here, we report antipyretic effects of citral in vivo using the most well-accepted model of sickness syndrome, i.e., systemic administration of lipopolysaccharide ( LPS ) to rats. Citral given by gavage caused no change in control euthermic rats (treated with saline) but blunted most of the assessed parameters related to the sickness syndrome [fever (hallmark of infection), plasma cytokines (IL-1beta, IL-6, and TNF-alpha) release, and prostaglandin E2 (PGE2) synthesis (both peripherally and hypothalamic)]. Moreover, LPS caused a sharp increase in plasma corticosterone levels that was unaltered by citral. These data are consistent with the notion that citral has a corticosterone-independent potent antipyretic effect, acting on the peripheral febrigenic signaling (plasma levels of IL-1beta, IL-6, TNF-alpha, and PGE2), eventually down-modulating hypothalamic PGE2 production. PMID- 28667504 TI - Controversies in Thrombolysis. AB - PURPOSE OF REVIEW: The purpose of the review is to examine recent evidence on the effects of intravenous thrombolysis and identify the remaining uncertainties. RECENT FINDINGS: We review the results of two large trials (the third International Stroke Trial (IST-3) and The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)) and the publications from the individual patient data analyses of the trials of alteplase conducted by the Stroke Thrombolysis Trialists Collaboration. Despite about a 2% risk of fatal intracerebral haemorrhage, on average, adult patients of all ages treated with 0.9 mg/kg alteplase within 4.5 h will have better long-term functional outcome. The use of a lower dose of alteplase (0.6 mg/kg) is associated with a lower risk of haemorrhage but its effect on functional outcome has not been proven to be non inferior to standard dose therapy. Some clinicians feel confident to treat selected patients who present beyond 4.5 h or have unknown time of onset, but many also agree that the current trials and other research is needed to reliably define the optimum imaging methods and treatment eligibility criteria. PMID- 28667506 TI - A rare presentation of nephrotic syndrome. AB - Nephrotic syndrome usually presents with oedema due to fluid accumulation in subcutaneous space. Renal subcapsular fluid accumulation is a rare presentation. We present a rare case of membranoproliferative glomerulonephritis which presented with bilateral subcapsular fluid collection and was successfully managed by percutaneous drainage and treating the underline pathology. PMID- 28667505 TI - Dissection of Cervical and Cerebral Arteries. AB - PURPOSE OF REVIEW: We aimed to summarize recent findings in cervical (CeAD) and intracranial artery dissection (IAD) research. RECENT FINDINGS: Considered a disease of the young- and middle-aged, an analysis on the largest CeAD-population to date (n = 2391) revealed that about 1 of 14 CeAD-patients was aged >=60 years. Distinct genetic variants were associated with CeAD. However, in clinical practice, genetic investigations are not helpful due to the small effect size. Despite the paucity of data from randomized-controlled trials in CeAD-stroke patients, both intravenous thrombolysis and endovascular treatment should be considered as acute treatment in such patients. Future research is needed to clarify which patients benefit most from each treatment modality. Whether to use antiplatelets or anticoagulants in stroke prevention in CeAD-patients is still a matter of debate. One randomized-controlled feasibility trial has been published, and another trial designed to show non-inferiority of aspirin to vitamin-K antagonists is underway and will be terminated in late 2018. Non-vitamin-K-oral anticoagulants should not be used in CeAD outside a properly designed trial, as experience with these drugs in CeAD-patients is limited. With many IAD patients developing intracranial hemorrhage, antithrombotic therapy should be used with caution. Knowledge about CeAD and IAD has advanced substantially. Nevertheless, further research is mandatory, in particular regarding pathophysiology, acute treatment, and stroke-preventive therapy, as well as long-term outcome and prognosis. PMID- 28667507 TI - Endoluminal Nd:YAG laser application in ex vivo biliary porcine tissue. AB - Adequate biliary drainage with endoscopic or percutaneous placement of self expandable metal stents represents the goal of palliation in patients with inoperable malignant obstruction of the biliary tree. As an adjunct to stenting, various tissue ablation treatments have been proposed with conflicting results. The aim of this study was to test the effect on biliary tissue of a new ablation technique based on Nd:YAG laser light delivery. The study was conducted on ex vivo specimens of 18 healthy farm pigs, using cystic ducts that are the simplest biliary structures to isolate and cannulate ex vivo. A 22G cannula was positioned into the cystic duct and a quartz optical fibre, with a prototypal cooling system, was inserted into the cannula. Nd:YAG laser output powers of 10, 12, and 15 W were tested, with a total delivered energy of 1000 J in continuous mode in each case. After laser treatment, histological analysis was performed. At macroscopical examination, no lesions of the external wall of the cystic ducts were detected. At histopathological examination, a coagulative necrosis involving the entire mucosa up to the muscolaris propria without significant changes of periductal tissues was observed in all specimens. This study shows the possibility of using Nd:YAG laser on ex vivo porcine biliary ducts with the effect of obtaining a coagulative necrosis involving the whole mucosa. PMID- 28667508 TI - Laser irradiation promotes the proliferation of mouse pre-osteoblast cell line MC3T3-E1 through hedgehog signaling pathway. AB - Low-level laser could promote osteoblast proliferation, and it has been applied in clinical practice to promote wound healing and tissue regeneration. However, the mechanism related to laser irradiation remains unclear. This study aimed to investigate the effects of low-level laser irradiation on the cell proliferation and the expressions of hedgehog signaling molecules Indian hedgehog (Ihh), Ptch, and Gli in vitro. In our present study, the MTT method was used to evaluate the effect on cell proliferation of laser irradiation on MC3T3-E1 cells. And cell cycle was examined by flow cytometry. Gene and protein expressions of hedgehog signaling molecules, including Ihh, Ptch, Smoothened (Smo), and Gli, were examined by qRT-PCR and western blot analysis. The results showed that laser irradiation at dosage of 3.75 J/cm2 enhances the proliferation of MC3T3-E1 cells compared with control groups (p = 0.00). Moreover, laser irradiation (3.75 J/cm2) increased the cell amount at S phase (p = 0.00). In addition, the expressions of Ihh, Ptch, Smo, and Gli were significantly increased compared to the control during laser irradiation (3.75 J/cm2)-induced MC3T3-E1 osteoblast proliferation. After adding the hedgehog signaling inhibitor CY (cyclopamine), cell proliferation and Ihh, Ptch, Smo, and Gli expressions were inhibited (p = 0.00), and the cell amount at S phase was reduced compared with combination groups (p = 0.00). These results indicated that laser irradiation promotes proliferation of MC3T3-E1 cells through hedgehog signaling pathway. Our findings provide insights into the mechanistic link between laser irradiation-induced osteogenesis and hedgehog signaling pathway. PMID- 28667511 TI - The Patients' Perspective Is the Missing Link in Current Bariatric Surgical Practice. PMID- 28667509 TI - Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling. AB - RATIONALE: Cocaine addiction is a chronic psychiatric disorder characterized by pathological motivation to obtain cocaine and behavioral and neurochemical hypersensitivity to cocaine-associated cues. These features of cocaine addiction are thought to be driven by aberrant phasic dopamine signaling. We previously demonstrated that blockade of the hypocretin receptor 1 (HCRTr1) attenuates cocaine self-administration and reduces cocaine-induced enhancement of dopamine signaling. Despite this evidence, the effects of HCRTr1 blockade on endogenous phasic dopamine release are unknown. OBJECTIVE: In the current studies, we assessed whether blockade of HCRTr1 alters spontaneous and cue-evoked dopamine release in the nucleus accumbens core of freely moving rats. METHODS: We first validated the behavioral and neurochemical effects of the novel, highly selective, HCRTr1 antagonist RTIOX-276 using cocaine self-administration and fast scan cyclic voltammetry (FSCV) in anesthetized rats. We then used FSCV in freely moving rats to examine whether RTIOX-276 impacts spontaneous and cue-evoked dopamine release. Finally, we used ex vivo slice FSCV to determine whether the effects of RTIOX-276 on dopamine signaling involve dopamine terminal adaptations. RESULTS: Doses of RTIOX-276 that attenuate the motivation for cocaine reduce spontaneous dopamine transient amplitude and cue-evoked dopamine release. Further, these doses attenuated cocaine-induced dopamine uptake inhibition at the level of dopamine terminals. CONCLUSION: Our results provide support for the standing hypothesis that HCRTr1 blockade suppresses endogenous phasic dopamine signals, likely via actions at dopamine cell bodies. These results also elucidate a second process through which HCRTr1 blockade attenuates the effects of cocaine by reducing cocaine sensitivity at dopamine terminals. PMID- 28667510 TI - A randomized controlled trial of ganaxolone in posttraumatic stress disorder. AB - Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated ganaxolone (a synthetic 3beta-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open label 6-week extension phase, the initial ganaxolone group continued ganaxolone, while the placebo group crossed over to ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and ganaxolone was generally well tolerated. Trough blood levels of ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of ganaxolone to out-perform placebo. Future investigations of ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689. PMID- 28667512 TI - The Inequity of Bariatric Surgery: Publicly Insured Patients Undergo Lower Rates of Bariatric Surgery with Worse Outcomes. AB - OBJECTIVE: Bariatric surgery has been shown to be the most effective method of achieving weight loss and alleviating obesity-related comorbidities. Yet, it is not being used equitably. This study seeks to identify if there is a disparity in payer status of patients undergoing bariatric surgery and what factors are associated with this disparity. METHODS: We performed a case-control analysis of National Inpatient Sample. We identified adults with body mass index (BMI) greater than or equal to 25 kg/m2 who underwent bariatric surgery and matched them with overweight inpatient adult controls not undergoing surgery. The sample was analyzed using multivariate logistic regression. RESULTS: We identified 132,342 cases, in which the majority had private insurance (72.8%). Bariatric patients were significantly more likely to be privately insured than any other payer status; Medicare- and Medicaid-covered patients accounted for a low percentage of cases (Medicare 5.1%, OR 0.33, 95% CI 0.29-0.37, p < 0.001; Medicaid 8.7%, OR 0.21, 95% CI 0.18-0.25, p < 0.001). Medicare (OR 1.54, 95% CI 1.33-1.78, p < 0.001) and Medicaid (OR 1.31, 95% CI 1.08-1.60, p = 0.007) patients undergoing bariatric surgery had an increased risk of complications compared to privately insured patients. CONCLUSIONS: Publicly insured patients are significantly less likely to undergo bariatric surgery. As a group, these patients experience higher rates of obesity and related complications and thus are most in need of bariatric surgery. PMID- 28667513 TI - Assessment of the Bioaccessibility of Trace Elements in Cat's Claw Teas by In Vitro Simulated Gastrointestinal Digestion Using FAAS. AB - The aim of this study was to evaluate the bioaccessibility of Ca, Fe, Mg, Mn, and Zn in cat's claw plant teas through in vitro gastrointestinal digestion with gastric and intestinal juice solutions. The total concentrations and bioaccessible fractions of Ca, Fe, Mg, Mn, and Zn were measured by flame atomic absorption spectrometry (FAAS). The results obtained showed that Zn was the most bioaccessible element in the teas, contributing a mean of 57.9% by infusion and 62.5% by decoction. Among macroelements, the Ca was less bioaccessible with 17.4% recovery. The bioavailability assessment revealed that daily intake of 200 ml of cat's claw teas cover about 1.0% of manganese RDA. PMID- 28667514 TI - Comparison of Different Invasive Hemodynamic Measurements as a Prediction Tool for Mortality after Transcatheter Aortic Valve Replacement in Men: A Retrospective Observational Study. AB - INTRODUCTION: Hemodynamic measurements can assess for paravalvular aortic regurgitation after transcatheter aortic valve replacement (TAVR). This study compared the utility of different invasive hemodynamic measures in providing prognostic information. METHODS: This retrospective observational study of TAVR patients at a Veterans Hospital assessed aortic regurgitation index, diastolic delta, pulse pressure, and heart rate adjusted diastolic delta obtained at valve implantation. The primary outcome was total mortality. RESULTS: Overall, 151 patients underwent TAVR. Immediately after implantation, mean aortic regurgitation index was 31 +/- 8.6, mean diastolic delta was 38 +/- 9.8 mmHg, mean pulse pressure was 67 +/- 18 mmHg, and mean heart rate adjusted diastolic delta was 47 +/- 14.3 mmHg/beats per minute. Two percent of patients had >= moderate paravalvular aortic regurgitation by postoperative transthoracic echocardiography. Total mortality was 15.2% at a mean follow-up of 12.7 +/- 9.2 months. Aortic regurgitation index <25 vs. >=25, diastolic delta <19 vs. >=19 mmHg, and pulse pressure >60 vs. <=60 mmHg were not associated with total mortality. However, total mortality was 50% for heart rate adjusted diastolic delta <25 mmHg/beats per minute vs. 12.6% for heart rate adjusted diastolic delta >=25 mmHg/beats per minute (p = 0.017). In a multivariate Cox regression analysis, heart rate adjusted diastolic delta <25 mmHg/beats per minute vs. heart rate adjusted diastolic delta >=25 mmHg/beats per minute was associated with total mortality (hazard ratio 9.4, 95% confidence interval 2.0-44, p = 0.004). CONCLUSIONS: Among a cohort of TAVR patients, the only invasive hemodynamic test independently associated with total mortality was heart rate adjusted diastolic delta. PMID- 28667515 TI - Tumor necrosis factor alpha accelerates Hep-2 cells proliferation by suppressing TRPP2 expression. AB - TRPP2, a Ca2+-permeable non-selective cation channel, has been shown to negatively regulate cell cycle, but the mechanism underlying this regulation is unknown. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine extensively involved in immune system regulation, cell proliferation and cell survival. However, the effects and mechanisms for the role of TNF-alpha in laryngeal cancer remain unclear. Here, we demonstrated using western blot analyses and intracellular Ca2+ concentration measurements that TNF-alpha treatment suppressed both TRPP2 expression and ATP-induced Ca2+ release in a laryngeal cancer cell line (Hep-2). Knockdown of TRPP2 by a specific siRNA significantly decreased ATP-induced Ca2+ release and abolished the effect of TNF alpha on the ATP-induced Ca2+ release. TNF-alpha treatment also enhanced Hep-2 cell proliferation and growth, as determined using cell counting and flow cytometry cell cycle assays. Moreover, TNF-alpha treatment down-regulated phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK) and phosphorylated eukaryotic translation initiation factor (p-eIF2alpha) expression levels, without affecting PERK and eIF2alpha expression levels in Hep-2 cells. We concluded that suppressing TRPP2 expression and TRPP2-mediated Ca2+ signaling may be one mechanism underlying TNF-alpha-enhanced Hep-2 cell proliferation. These results offer new insights into the mechanisms of TNF-alpha-mediated laryngeal cancer cell proliferation, and provide evidences showing a potential role of TNF alpha in the development of laryngeal cancer. PMID- 28667516 TI - Atomic force microscopy studies on cellular elastic and viscoelastic properties. AB - In this work, a method based on atomic force microscopy (AFM) approach-reside retract experiments was established to simultaneously quantify the elastic and viscoelastic properties of single cells. First, the elastic and viscoelastic properties of normal breast cells and cancerous breast cells were measured, showing significant differences in Young's modulus and relaxation times between normal and cancerous breast cells. Remarkable differences in cellular topography between normal and cancerous breast cells were also revealed by AFM imaging. Next, the elastic and viscoelasitc properties of three other types of cell lines and primary normal B lymphocytes were measured; results demonstrated the potential of cellular viscoelastic properties in complementing cellular Young's modulus for discerning different states of cells. This research provides a novel way to quantify the mechanical properties of cells by AFM, which allows investigation of the biomechanical behaviors of single cells from multiple aspects. PMID- 28667517 TI - Differential expression of Kindlin-1 and Kindlin-2 correlates with esophageal cancer progression and epidemiology. AB - Esophageal cancer (EC) is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry (IHC) and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin-1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC. PMID- 28667518 TI - Screening cytokine/chemokine profiles in serum and organs from an endotoxic shock mouse model by LiquiChip. AB - Studying the cytokine profiles in animal models or patients with sepsis provides an experimental basis for the identification of diagnostic biomarkers and therapeutic targets. In this study, we used a liquid protein chip (LiquiChip), also known as flexible multi-analyte profiling technology, to perform quantitative analyses of several cytokines and chemokines (e.g., IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-alpha, IFN-gamma, granulocyte-macrophage colony-stimulating factor, keratinocyte chemoattractant, monocyte chemoattractant protein, monokine induced by gamma interferon, IFN-gamma-inducible protein 10, and macrophage inflammatory protein 1 alpha). The levels of these cytokines and chemokines were determined both in the blood and in tissues, including the lung, liver, heart, kidney, spleen, brain, stomach, intestine and muscle, of mice challenged with LPS. Our data showed variable production levels of LPS-induced cytokines in different mouse organs, and the cytokine in the blood did not correlate with those in the organs. We also showed that the levels of most cytokines peaked within 1 to 6 h and decreased rapidly afterward. A variety of inflammatory cytokines might be related to the damage in different organs during septic shock. Our data also suggest that the spleen might be an important target organ in the development of systemic inflammatory response syndrome and sepsis. PMID- 28667519 TI - Retinoic acid ameliorates high-fat diet-induced liver steatosis through sirt1. AB - In this study, treatment of C57BL/6J (wild type, WT) mice fed a high-fat diet (HFD) with retinoic acid (RA) decreased body weight and subcutaneous and visceral fat content, reversed the apparent hepatosteatosis, and reduced hepatic intracellular triglyceride and serum alanine transaminase (ALT) and aspartate aminotransferase (AST) concentrations. Moreover, RA treatment improved glucose tolerance and insulin sensitivity in WT mice fed a HFD. However, these RA-induced effects in WT mice fed a HFD were alleviated in liver specific Sirtuin 1 (Sirt1) deficient (LKO) mice fed a HFD. Furthermore, RA also could not improve glucose tolerance and insulin sensitivity in LKO mice fed a HFD. The mechanism studies indicated that RA indeed increased the expression of hepatic Sirt1 and superoxide dismutase 2 (Sod2), and inhibited the expression of sterol regulatory element binding protein 1c (Srebp-1c) in WT mice in vivo and in vitro. RA decreased mitochondrial reactive oxygen species (ROS) production in WT primary hepatocytes and increased mitochondrial DNA (mtDNA) copy number in WT mice liver. However, these RA-mediated molecular effects were also abolished in the liver and primary hepatocytes from LKO mice. In summary, RA protected against HFD-induced hepatosteatosis by decreasing Srebp-1c expression and improving antioxidant capacity through a Sirt1-mediated mechanism. PMID- 28667520 TI - Structure of parasites community in Chaetobranchopsis orbicularis (Cichlidae), a host from the Amazon River system in northern Brazil. AB - The aim of this paper was to investigate the component communities of parasites in Chaetobranchopsis orbicularis from a tributary of the Amazon River system, in Northern Brazil. In 32 fish examined, 902,551 parasites were collected, including Ichthyophthirius multifiliis, Piscinoodinium pillulare, Sciadicleithrum geophagi, Posthodiplostomum sp., Clinostomum marginatum, Echinorhynchus paranensis, Neoechinorhynchus pterodoridis, and Dolops longicauda. I. multifiliis was the dominant and abundant parasite species. The ectoparasites presented aggregate dispersion, but the endoparasites showed random dispersion pattern. Mean species richness was 4.0 +/- 1.5 parasites, mean Brillouin diversity (HB) was 0.33 +/- 0.28, mean evenness was 0.15 +/- 0.13, and Berger-Parker dominance (d) was 0.85 +/- 0.17. The species richness of parasites and HB were positively correlated with the length of hosts. There was positive correlation between the abundance of P. pillulare and length and weight, between the abundance of I. multifiliis and weight, as well as between the abundance of E. paranensis and N. pterodoridis and the length of hosts. Body condition of the hosts was not affected by moderate parasitism. The low diversity of endoparasites indicates that C. orbicularis is a host with low position in the food web. This is the first record of all these parasites for C. orbicularis. PMID- 28667521 TI - Influence of preservative and mounting media on the size and shape of monogenean sclerites. AB - Based on Cichlidogyrus sp. (Monogenea, Ancyrocephalidae) specimens from Hemichromis sp. hosts, we tested the influence of different methods to fix/preserve samples/specimens [frozen material, alcohol or formalin preserved, museum process for fish preservation (fixed in formalin and preserved in alcohol)] and different media used to mount the slides [tap water, glycerin ammonium picrate (GAP), Hoyer's one (HM)] on the size/shape of sclerotized parts of monogenean specimens. The results show that the use of HM significantly increases the size of haptoral sclerites [marginal hooks I, II, IV, V, and VI; dorsal bar length, width, distance between auricles and auricle length, ventral bar length and width], and changes their shape [angle opening between shaft and guard (outer and inner roots) in both ventral and dorsal anchors, ventral bar much wider, dorsal one less curved]. This influence seems to be reduced when specimens/samples are fixed in formalin. The systematics of Monogenea being based on the size and shape of their sclerotized parts, to prevent misidentifications or description of invalid new species, we recommend the use of GAP as mounting medium; Hoyer's one should be restricted to monogenean specimens fixed for a long time which are more shrunken. PMID- 28667522 TI - The Toxoplasma gondii inhibitor-2 regulates protein phosphatase 1 activity through multiple motifs. AB - Toxoplasma gondii has a complex life cycle characterized by multiple differentiation steps that are essential for its survival in both human and definitive feline host. Several studies have demonstrated the importance of phosphorylations by protein kinases during the life cycle of T. gondii. However, very little is known about protein phosphatases and their regulators in the parasite. We report the molecular and functional characterization of the T. gondii ortholog of the inhibitor-2 protein, designated TgI2. We show that TgI2 encompasses conserved motifs involved in the interaction and modulation of the phosphatase activity of T. gondii protein phosphatase 1, named TgPP1. We show that a specific combination of motifs is involved in binding and/or inhibition of the TgPP1 activity. We show here that the TgI2 protein is a potent inhibitor of TgPP1 phosphatase activity. TgI2 SILK and RVxF motifs are critical for regulating the activity of TgPP1, a feature that is common with the higher eukaryotes inhibitor-2 protein. PMID- 28667525 TI - Natural Antibodies: Next Steps Toward Translational Investigation. AB - Natural antibodies have diverse functions in maintaining immune homeostasis and in the regulation of autoimmune response. Yet there might be other important functions of natural antibodies for human medicine such as the ability of natural antibodies to shape and induce antibody immune responses. I propose that natural antibodies, present in IVIG, could be used to prevent autoimmune reactions and to enhance the immune response to vaccination. PMID- 28667523 TI - Development and evaluation of a rapid diagnostic immunochromatographic device to detect antibodies in sera from intestinal capillariasis cases. AB - Intestinal capillariasis, a fish-borne nematodiasis, is an important emerging zoonotic disease. Patients present clinical symptoms of borborygmus chronic diarrhea, intermittent abdominal pain, weight loss, and several degrees of painless lower-leg edema. Death may occur in cases of misdiagnosis and improper treatment. Diagnosis is difficult because of the atypical clinical symptoms and diagnostic confusion with diarrhea caused by gastrointestinal cancer, opportunistic infections in human immunodeficiency virus patients, and hyperthyroidism. In addition, parasite eggs are not always found in stool examination. Serology can provide a supportive diagnostic tool. We have produced a rapid and simple immunochromatographic test (ICT) kit for diagnosis of intestinal capillariasis by detection of diagnostic antibodies in human sera. Serum samples from healthy volunteers and patients with proven intestinal capillariasis and other parasitic diseases were evaluated with the Trichinella spiralis larval extract antigen absorbed ICT strips. The diagnostic sensitivity, specificity, and positive and negative predictive values were 100, 96.6, 90.2, and 100%, respectively. The ICT kit is simple and rapid to use and can supplement stool examination in clinical diagnosis of intestinal capillariasis. The test can be completed in 15 min without a need for any sophisticated instruments or reagents. PMID- 28667524 TI - Low evaluation rate for osteoporosis among patients presenting with a rib fracture. AB - : This study in a regional hospital setting found a low evaluation rate for osteoporosis among patients presenting with a rib fracture. Increased emphasis or education for osteoporosis evaluation may be necessary in case of rib fractures. INTRODUCTION: Rib fractures from a low-energy trauma are common in the elderly, and a history of rib fracture has been reported to increase the risk for a subsequent osteoporotic fracture. The purpose of this study was to evaluate how many of the patients presenting with an isolated rib fracture were being evaluated for osteoporosis and the risk for a subsequent fracture. METHODS: We retrospectively reviewed all patients aged 50 years or older who were diagnosed with a rib fracture between January 2011 and April 2016 at a regional tertiary care university hospital near Seoul, South Korea. We excluded those who had been treated for osteoporosis or those with other concomitant fractures or fractures from a motor vehicle accident or cancer. We evaluated the frequency of dual energy X-ray absorptiometry (DXA) scan examinations in these patients. RESULTS: There were 231 patients with isolated rib fractures (132 men and 99 women). The mean age was 65 years. Rib fractures were most commonly diagnosed at the emergency department and most of the patients were referred to the department of thoracic surgery for follow-up evaluations. Of these 231 patients, 29 (12%) had DXA examinations after the injury, and only 9 (4%) of them did so within 6 months. Physicians specializing in orthopedic surgery, family medicine, internal medicine, rehabilitation medicine, and emergency medicine were ordering the examination. CONCLUSIONS: This study in a regional hospital setting found a low evaluation rate for osteoporosis among patients presenting with a rib fracture. This study suggests that increased emphasis or education for osteoporosis evaluation may be necessary for physicians who are often referred to for care of rib fractures. PMID- 28667526 TI - Isolation of Natural Anti-FcepsilonRIalpha Autoantibodies from Healthy Donors. AB - Natural antibodies are defined as antibodies detected in a healthy individual without active immunization. These antibodies are specific for exoantigens, as well as for autoantigens, mostly without any pathogenic role. Most of the studies conducted with natural (auto-) antibodies have been performed using affinity purified antibodies from individual sera or polyclonal Ig-preparations such as Intravenous Ig (IVIg). For in-depth analysis of such autoantibodies affinity purified Ig-preparations from healthy individuals are of no use, as they are oligoclonal or polyclonal. Thus, there is a need of human monoclonal autoantibodies. Human monoclonal autoantibodies can be produced from B cells isolated from humans; however, this requires the screening of a large number of antibodies to identify one among them specific to an antigen. Using the phage display technology we generated such autoantibodies against the alpha subunit of the high-affinity IgE receptor (FcepsilonRIalpha). Here we describe the step-by step protocol for the generation of such libraries and the isolation of autoantibodies by affinity panning. PMID- 28667527 TI - Isolation of Antibodies from Human Plasma, Saliva, Breast Milk, and Gastrointestinal Fluid. AB - Different protocols are required for the collection and isolation of antibodies from various body sites. For the sample collection factors to be considered include anatomic or physiological particularities. Secretory fluids such as saliva, gastrointestinal fluid, or breast milk may contain degrading enzymes that potentially affect the integrity of isolated antibodies. While the isolation of IgG from plasma is a common and often-described procedure, here we focus on methodological approaches to isolate antibodies immunoglobulin A (IgA) or IgM from plasma or secretory fluids. These protocols shall facilitate research on natural and induced antibodies. PMID- 28667528 TI - Purification of Natural Antibodies Against Tau Protein by Affinity Chromatography. AB - Natural antibodies are now widely studied for their therapeutical potential. Therefore, their isolation and subsequent characterization is desired. Here, we describe an isolation method for natural anti-tau antibodies from human plasma by utilization of affinity chromatography with epoxy-activated copolymer resin. The evalution of isolation efficiency and avidity of isolated antibodies is decribed by modified indirect ELISA assay. PMID- 28667529 TI - Unbiased RACE-Based Massive Parallel Surveys of Human IgA Antibody Repertoires. AB - For investigations of human B-cell receptor (BCR) repertoires, we have developed a protocol for large-scale surveys of human antibody heavy chain (VH) rearrangements. Here we study IgA repertoires, as more IgA antibodies are synthesized in the human body on a daily level than all other isotypes combined. In fact, IgA is secreted at all mucosal surfaces, and it is also secreted in the perspiration that coats our cutaneous surfaces. In these studies we can characterize the IgA clonal diversity of B-cell populations obtained from any donor. To recover representative repertoire libraries, we make our libraries from antibody gene transcript templates (i.e., cDNA), as these are closer reflections of the immune repertoire expressed at the antibody protein level. To avoid biases potentially introduced by upstream oligonucleotide primers that hybridize to variable region framework regions, our approach also uses rapid amplification of cDNA ends (RACE) of antibody transcripts. For exploration of human IgA responses, we have designed a duplexing antisense constant region primer that efficiently amplifies, side-by-side, heavy chain transcripts of both the IgA1 and IgA2 subclasses. By these methods we have begun to define the molecular differences in the IgA1 and IgA2 responses occurring simultaneously in different donors. These methods will be used to investigate the effects of microbial virulence factors on host defenses, during autoimmune responses, and in B-cell malignancies. PMID- 28667530 TI - Analysis of Signaling Events in B-1a Cells. AB - B-1a cells are a unique subset of B cells that are phenotypically and functionally distinguishable from conventional (B-2) cells. Here we detail methods to analyze signaling events in B-1a cells. We demonstrate by flow cytometry and Western blot that mouse peritoneal B-1a but not splenic B-2 cells have constitutive activation of signal transducers and activators of transcription-3 (Stat3) and extracellular signal-regulated kinase (Erk). PMID- 28667531 TI - Exploring the Role of Microbiota in the Limiting of B1 and MZ B-Cell Numbers by Naturally Secreted Immunoglobulins. AB - Immunoglobulins (Igs)-or antibodies (Ab)-are important to combat foreign pathogens but also to the immune system homeostasis. We developed the AID-/-MUS-/ mouse model devoid of total soluble Igs and suitable to monitor the role of Igs on immune homeostasis. We used this experimental system to uncover a negative feedback control of marginal zone (MZ) and B1 B cells numbers by naturally secreted Igs. We raised AID-/-MUS-/- mice in germ-free conditions demonstrating that this effect of natural secreted Igs is independent of the microbiota. Herein, we provide a comprehensive description of the protocols to establish and use the AID-/-MUS-/- mice to study the role of total secreted Igs or of different Ig classes. This study involves Igs injections to AID-/-MUS-/- mice or establishment of AID-/-MUS-/- mixed bone marrow chimeras that provide a powerful system to study AID-/-MUS-/- B cells in the presence of stable concentrations of different Ig classes. While we describe flow cytometric and histological methods to analyze MZ and B1 B cell subsets, AID-/-MUS-/- mice can be used to study the effects of natural Igs on other B cell subsets or immune cells. PMID- 28667532 TI - Assessment of Anti-Tumor Cytotoxic Activity of Naturally Occurring Antibodies in Human Serum or Plasma. AB - A small percentage of the Western population carries antibodies in the peripheral blood, which are able to kill human tumors such as neuroblastoma or melanoma. Several observations indicate that these antibodies, preferentially of IgM isotype, belong to the class of naturally occurring antibodies. Here, we describe two screening methods for the detection and quantification of such antibodies in human blood samples: a cellular ELISA technique and a flow cytometric assay, based on intercalation of fluorescent propidium iodide into the DNA of dying or dead cells. PMID- 28667533 TI - Hydrolysis and Dissolution of Amyloids by Catabodies. AB - Catalytic antibodies (catabodies) hold potential for superior immunotherapy because of their turnover capability and no or minimal induction of inflammatory responses. Catabodies neutralize and remove target antigens more potently than conventional antibodies. Depending on the catalytic rate constant, a single catabody molecule degrades thousands to millions of target molecules over its useful lifespan, whereas conventional antibodies only form reversibly associated, stoichiometric complexes with the target. Thus, removal of the antibody-bound target requires accessory phagocytic cells that ingest the immune complexes, which is usually accompanied by release of inflammatory mediators. In comparison, catabodies bind the target only transiently, and the rapid and direct target destruction reduces the concentration of immune complexes that can activate inflammatory processes. These features are especially pertinent when large target amounts at anatomically vulnerable sites must be removed, e.g., amyloids. We reported specific catabodies to misfolded transthyretin (misTTR) amyloid and amyloid beta peptide (Abeta). Accumulation of the oligomeric and fibrillized amyloid TTR forms causes diverse systemic pathologies, including cardiomyopathy, polyneuropathy, and skeletal diseases. Brain Abeta aggregates are thought to cause central nervous system degenerative disease, chiefly Alzheimer's disease. We describe methods for testing catabody-mediated degradation and dissolution of Abeta and TTR. PMID- 28667534 TI - Methods for Posttranslational Induction of Polyreactivity of Antibodies. AB - An antibody molecule that recognizes multiple unrelated antigens is defined as polyreactive. Polyreactivity is an intrinsic characteristic of immune repertoires. Degenerated antigen binding diversifies the repertoire of specificities, thus contributing to immune defense and immune regulation. Immune repertoire contains also a fraction of immunoglobulins, which acquire polyreactivity only following contact with various protein-destabilizing or pro oxidative substances. Posttranslational induction of the antibody polyreactivity may have important repercussion for laboratory practice, as well as in cases of pathological conditions accompanied by liberation of large quantities of pro oxidative substances such as heme, labile iron, or reactive oxygen species. Antibodies with induced polyreactivity have been demonstrated to exert pathogen neutralization and immune regulatory potential in inflammatory conditions, suggesting that this phenomenon may be exploited for design of therapeutic strategies. In this article, we provide description of the basic procedures for uncovering of the cryptic polyreactivity of antibodies by heme, ferrous ions, and acid pH solution. PMID- 28667535 TI - Characterization of Natural IgM Antibodies Recognizing Oxidation-Specific Epitopes on Circulating Microvesicles. AB - Natural IgM antibodies specific for oxidation-specific epitopes (OSEs) have been found to bind to circulating microvesicles (MVs), also known as microparticles. This chapter describes how endogenous natural IgM antibodies bound to circulating MV subsets can be characterized on the one hand, and how monoclonal natural IgM antibodies can be used to characterize subsets of circulating MVs on the other hand. PMID- 28667536 TI - Natural Monoclonal Antibody to Oxidized Low-Density Lipoprotein and Aggregatibacter actinomycetemcomitans. AB - Natural antibodies are produced by B lymphocytes without exogenous antigenic exposure and are present at the time of birth. They usually bind to conserved epitopes on antigens of different chemical compositions. We cloned and characterized a natural mouse monoclonal IgM antibody (Aa_Mab) by selecting the binding to malondialdehyde acetaldehyde (MAA) adducts on low-density lipoprotein (LDL). The data showed that the Aa_Mab cross-reacted with Aggregatibacter actinomycetemcomitans (Aa) bacteria, an important oral pathogen in periodontitis associated with atherosclerosis. Surprisingly, the binding molecule of Aa bacteria to the Aa_Mab was Aa chaperonin 60 or HSP60, a protein that is not only responsible for maintaining cellular proteins conformation, but also functions as a potent virulence factor prompting bone resorption in periodontitis and as a putative pathogenic factor in atherosclerosis. PMID- 28667537 TI - Detection of Natural Antibodies and Serological Diagnosis of Pneumococcal Pneumonia Using a Bead-Based High-Throughput Assay. AB - Surface-exposed proteins of pathogenic bacteria play a critical role during infections . The vast majority of these molecules are able to trigger strong immune responses. Measuring the humoral immune response against pathogenic bacteria through less-time consuming tests is necessary to reduce the window time for the diagnosis of diseases that may be associated with high morbidity and mortality rates. Due to the multiplex setup, Luminex xMAP(r) technology allows analysis of immune responses against many antigens in a single assay. Therefore, less volumes of sera samples are needed and inter assay coefficient of variation is much lower in comparison with other immunoassays. With this methodology, the carboxyl groups on the surface of the polystyrene microspheres must first be activated with a carbodiimide derivative prior to coupling antigens . After the antigen is coupled to a microsphere , different microspheres (all having a unique color) can be combined whereafter the presence of specific antibodies directed against the different antigens in sera can be determined simultaneously. The platform here described can also be useful for epidemiological surveillance programs and vaccine studies. PMID- 28667538 TI - Detection of Naturally Occurring Human Antibodies Against Gangliosides by ELISA. AB - Gangliosides are sialic acid-containing glycolipids that have been considered attractive targets for cancer immunotherapy, based on the qualitative and quantitative changes they suffer during malignant transformation and due to their importance for tumor biology. Natural antibodies against gangliosides have been detected not only in cancer patients but also in healthy donors. The presence of these antibodies can be used as diagnostic or prognostic factor. However, these responses are difficult to detect because anti-ganglioside antibodies are usually of IgM isotype and low affinity. Enzyme Linked Immunosorbent Assay (ELISA) is an immunoassay based on the specific binding of antibodies to antigens bound to a solid phase. These antigens can be glycolipids like gangliosides. An enzyme linked to the last reactant allows the detection of specific binding through the development of color after the addition of a suitable substrate. ELISA combines the specificity of antibodies with the sensitivity of enzyme reactions. The ELISA method described herein can be used to detect antibody responses against gangliosides not only related to cancer but also to autoimmune diseases and infections, both in healthy donors, and patients, untreated or receiving specific immunotherapy. PMID- 28667539 TI - Evaluating the Impact of Natural IgM on Adenovirus Type 5 Gene Therapy Vectors. AB - Natural IgM antibodies have an innate ability to recognize many viruses and viral based gene therapy vectors. Naive mice have natural IgM antibodies that bind to adenoviruses, and these antibodies can profoundly affect the biodistribution and efficiency of gene delivery by adenovirus type 5 vectors. Here, we present protocols for isolating IgM from mouse serum, for assaying the concentration and adenoviral reactivity of mouse IgM, and for evaluating how natural antibodies and complement can synergize to neutralize adenovirus vectors. PMID- 28667540 TI - Trait compassion is associated with the neural substrate of empathy. AB - Individual differences in the personality trait Agreeableness underlie humans' ability to interpret social cues and coordinate effectively with others. However, previous investigations of the neural basis of Agreeableness have yielded largely inconsistent results. Recent evidence has demonstrated that Agreeableness can be divided into two, correlated subdimensions. Compassion reflects tendencies toward empathy, sympathy, and concern for others, while Politeness reflects tendencies toward compliance and refraining from aggression and exploitation. The present study seeks to clarify the neural substrates of Agreeableness by examining whether structural differences in the brain show distinct associations with Compassion and Politeness. Results of a meta-analysis of fMRI studies examining empathy were used to generate hypotheses about the brain regions and networks that underlie trait Compassion. Results of a large-scale structural neuroimaging investigation (N = 275) were largely consistent with the meta-analysis: Compassion was positively correlated with gray matter volume in the bilateral anterior cingulate cortex (ACC) and anterior insula (AI). Further, these differences appear to be associated with Compassion specifically, as opposed to Politeness, suggesting that these two traits have at least partially distinct neuroanatomical substrates. PMID- 28667541 TI - Serotonergic medications, herbal supplements, and perioperative serotonin syndrome. AB - PURPOSE: Perioperative use of serotonergic agents increases the risk of serotonin syndrome. We describe the occurrence of serotonin syndrome after fentanyl use in two patients taking multiple serotonergic agents. CLINICAL FEATURES: Two patients who had been taking multiple serotonergic medications or herbal supplements (one patient taking fluoxetine, turmeric supplement, and acyclovir; the other taking fluoxetine and trazodone) developed serotonin syndrome perioperatively when undergoing outpatient procedures. Both experienced acute loss of consciousness and generalized myoclonus after receiving fentanyl. In one patient, the serotonin syndrome promptly resolved after naloxone administration. In the other patient, the onset of serotonin syndrome was delayed and manifested after discharge, most likely attributed to the intraoperative use of midazolam for sedation. CONCLUSION: Even small doses of fentanyl administered to patients taking multiple serotonergic medications and herbal supplements may trigger serotonin syndrome. Prompt reversal of serotonin toxicity in one patient by naloxone illustrates the likely opioid-mediated pathogenesis of serotonin syndrome in this case. It also highlights that taking serotonergic agents concomitantly can produce the compounding effect that causes serotonin syndrome. The delayed presentation of serotonin syndrome in the patient who received a large dose of midazolam suggests that outpatients taking multiple serotonergic drugs who receive benzodiazepines may require longer postprocedural monitoring. PMID- 28667542 TI - Application of multivariate statistical approach to identify trace elements sources in surface waters: a case study of Kowalskie and Stare Miasto reservoirs, Poland. AB - The paper reports the results of measurements of trace elements concentrations in surface water samples collected at the lowland retention reservoirs of Stare Miasto and Kowalskie (Poland). The samples were collected once a month from October 2011 to November 2012. Al, As, Cd, Co, Cr, Cu, Li, Mn, Ni, Pb, Sb, V, and Zn were determined in water samples using the inductively coupled plasma with mass detection (ICP-QQQ). To assess the chemical composition of surface water, multivariate statistical methods of data analysis were used, viz. cluster analysis (CA), principal components analysis (PCA), and discriminant analysis (DA). They made it possible to observe similarities and differences in the chemical composition of water in the points of water samples collection, to uncover hidden factors accounting for the structure of the data, and to assess the impact of natural and anthropogenic sources on the content of trace elements in the water of retention reservoirs. The conducted statistical analyses made it possible to distinguish groups of trace elements allowing for the analysis of time and spatial variation of water in the studied reservoirs. PMID- 28667543 TI - A new method for modeling dissolved phosphorus transport with the use of WaTEM/SEDEM. AB - This paper presents a newly-derived method for directly determining the amount of transported dissolved phosphorus by water erosion. The results of the method are compared to prediction based on enrichment ratio (as proposed by Sharpley) and average share of dissolved phosphorus (DP) in total transported phosphorus (5%) that is widely used in the Czech Republic. Four study areas (catchments of dozens of sq. kilometer) were chosen for their different characteristics (land use, average slope, average elevation, phosphorus concentration in the soil) which influence their rainfall-runoff behavior. The modeled results are compared with data measured in situ. The two methods provide similar results in intensively agriculturally used regions. Agreement among the methods was observed for three study areas with significant erosion intensity (above 4 t/ha/year). In the catchment with significantly lower erosion intensity (0.5 t/ha/year), the indirect method (Sharpley) underestimates the amount of DP transported in the watercourses. The sum of transports of suspended solids into watercourses and the average available phosphorus content in the soil determined by the Mehlich 3 method (PM3) are the main factors influencing the results provided by the two methods. An analysis of the impact of these factors on the difference between the results of the methods was provided. Transport of suspended solids is related to the method difference (R range from 0.37 to 0.71). However, no significant relationship was found between the difference in the results and the average PM3 content in the soil (R range from 0.15 to 0.36). PMID- 28667544 TI - Analysis of transport eco-efficiency scenarios to support sustainability assessment: a study on Dhaka City, Bangladesh. AB - The study focused to assess the level of efficiency (of both emissions and service quality) that can be achieved for the transport system in Dhaka City, Bangladesh. The assessment technique attempted to quantify the extent of eco efficiency achievable for the system modifications due to planning or strategy. The eco-efficiency analysis was facilitated with a detailed survey data on Dhaka City transport system, which was conducted for 9 months in 2012-2013. Line source modelling (CALINE4) was incorporated to estimate the on-road emission concentration. The eco-efficiency of the transport systems was assessed with the 'multi-criteria analysis' (MCA) technique that enabled the valuation of systems' qualitative and quantitative parameters. As per the analysis, driving indiscipline on road can alone promise about 47% reductions in emissions, which along with the number of private vehicles were the important stressors that restrict achieving eco-efficiency in Dhaka City. Detailed analysis of the transport system together with the potential transport system scenarios can offer a checklist to the policy makers enabling to identify the possible actions needed that can offer greater services to the dwellers against lesser emissions, which in turn can bring sustainability of the system. PMID- 28667545 TI - What is the Role of the Oncology Nurse in Fertility Preservation Counseling and Education for Young Patients? AB - Oncology nurses are uniquely positioned to offer fertility preservation counseling and education for cancer patients of reproductive age, yet there is a dearth of research that focuses on current practice and perceptions of nursing role. In 2013, the American Society of Clinical Oncology extended the duties of fertility preservation counseling among patients of reproductive age undergoing cancer treatment to include registered nurses and other allied health professionals as active partners in the counseling and education process. This study used a cross-sectional descriptive survey to assess current practices, role perceptions, and barriers to fertility preservation counseling among registered nurses working in an academic care setting with outpatient and inpatient services. There were significant gaps in current practices and perceptions of roles regarding fertility preservation counseling. Many nurses expressed the perception that fertility preservation counseling was important, but it was outside the scope of their practice to perform this education. This preliminary work defined need for an interdisciplinary fertility preservation team, communication surrounding educational practice norms, and designated oncofertility navigator. PMID- 28667546 TI - Assessment of Robotic Console Skills (ARCS): construct validity of a novel global rating scale for technical skills in robotically assisted surgery. AB - BACKGROUND: Skill assessment during robotically assisted surgery remains challenging. While the popularity of the Global Evaluative Assessment of Robotics Skills (GEARS) has grown, its lack of discrimination between independent console skills limits its usefulness. The purpose of this study was to evaluate construct validity and interrater reliability of a novel assessment designed to overcome this limitation. METHODS: We created the Assessment of Robotic Console Skills (ARCS), a global rating scale with six console skill domains. Fifteen volunteers who were console surgeons for 0 ("novice"), 1-100 ("intermediate"), or >100 ("experienced") robotically assisted procedures performed three standardized tasks. Three blinded raters scored the task videos using ARCS, with a 5-point Likert scale for each skill domain. Scores were analyzed for evidence of construct validity and interrater reliability. RESULTS: Group demographics were indistinguishable except for the number of robotically assisted procedures performed (p = 0.001). The mean scores of experienced subjects exceeded those of novices in dexterity (3.8 > 1.4, p < 0.001), field of view (4.1 > 1.8, p < 0.001), instrument visualization (3.9 > 2.2, p < 0.001), manipulator workspace (3.6 > 1.9, p = 0.001), and force sensitivity (4.3 > 2.6, p < 0.001). The mean scores of intermediate subjects exceeded those of novices in dexterity (2.8 > 1.4, p = 0.002), field of view (2.8 > 1.8, p = 0.021), instrument visualization (3.2 > 2.2, p = 0.045), manipulator workspace (3.1 > 1.9, p = 0.004), and force sensitivity (3.7 > 2.6, p = 0.033). The mean scores of experienced subjects exceeded those of intermediates in dexterity (3.8 > 2.8, p = 0.003), field of view (4.1 > 2.8, p < 0.001), and instrument visualization (3.9 > 3.2, p = 0.044). Rater agreement in each domain demonstrated statistically significant concordance (p < 0.05). CONCLUSIONS: We present strong evidence for construct validity and interrater reliability of ARCS. Our study shows that learning curves for some console skills plateau faster than others. Therefore, ARCS may be more useful than GEARS to evaluate distinct console skills. Future studies will examine why some domains did not adequately differentiate between subjects and applications for intraoperative use. PMID- 28667547 TI - Transversus abdominis plane (TAP) block versus thoracic epidural analgesia (TEA) in laparoscopic colon surgery in the ERAS program. AB - AIM: The enhanced recovery after surgery (ERAS) pathway and laparoscopic approach had been proven beneficial for patients and should now be considered as a standard of care in colorectal surgery. Multimodal analgesia is the gold standard in the ERAS program with the use of thoracic epidural analgesia (TEA). Few data are available on Transversus abdominis plane (TAP) blocks in laparoscopic colorectal surgery and ERAS pathway. The aim of this study is to evaluate the efficacy of TAP block compared to TEA in the management of postoperative pain and the impact on the recurrence of postoperative nausea, vomiting and ileus in laparoscopic colorectal surgery in the ERAS program. METHOD: From October 2014 to October 2016, 182 patients underwent elective colon surgical interventions in enhanced recovery after surgery pathway. The patients were divided into two groups: Group 1 (n = 92) and Group 2 (n = 91) who received TEA and TAP block, respectively, with a standardized postoperative analgesic regimen consisting of regular 1 g of paracetamol every 8 h and a rescue dose with intravenous non steroidal anti-inflammatory drugs infusion for both groups. RESULTS: No differences were observed in baseline patient characteristics, clinical variables and surgical procedures between the two groups, as well as in the postoperative complications rate (p = 0.515) in accordance with Clavien-Dindo classification, 90-day mortality (p = 0.319), hospital stay (p = 0.469) and 30-day readmission rate (p = 0.711). Patients in the TAP block group showed lower postoperative nausea and vomiting rates (p = 0.025), as well as lower ileus (p = 0.031) and paraesthesia rates (p = 0.024). No differences were found in urinary retention (p = 0.157). Despite the "opioid-free" analgesia protocol in the TAP block group, pain intensity was comparable between the two groups (p = 0.651). CONCLUSION: TAP block combined with an opioid-sparing analgesia in the setting of the laparoscopic colorectal surgery and ERAS program is feasible and effective in postoperative pain control. PMID- 28667549 TI - Exploring the influence of context on feedback at medical school: a video ethnography study. AB - Feedback in medical education is complicated by the multiple contexts within which learning occurs. However, feedback research in medical education has typically focused on information provided by tutors to students with limited exploration of the influence of context. This research seeks to address this gap by exploring the influence of multiple contexts upon feedback processes. Employing video-ethnography methodology we explored feedback in two common contexts for medical student learning: the simulated clinical environment and the medical workplace. Learning and teaching sessions were filmed in each of these contexts, capturing diverse feedback processes. Data were analysed for key themes using a Framework Analysis approach and similarities and differences between the two contexts identified. In total 239 distinct feedback episodes across 28 different teaching and learning sessions were captured, with feedback processes relating to the patient, practice, educational and institutional contexts observed. In this paper, we concentrate on key similarities and differences in feedback processes between the two contexts with respect to six themes: feedback interlocutors, interlocutor positioning, feedback types, feedback foci, feedback styles and feedback milieu. We argue that feedback is inextricably linked to the multiple contexts in which feedback is enacted. It is only by exploring these contextual influences that feedback can be understood more fully. With such understanding we should be better placed to develop interventions capable of improving the long elusive experience of successful feedback. PMID- 28667548 TI - Synthetic Co-Attractants of the Aggregation Pheromone of the Date Palm Root Borer Oryctes agamemnon. AB - Laboratory and field investigations to identify and evaluate plant co-attractants of the aggregation pheromone of the date palm pest Oryctes agamemnon are reported. Volatiles emitted by freshly cut palm core and palm core with feeding males, were collected, analyzed by gas chromatography coupled to mass spectrometry and evaluated in olfactometers alone or combined with synthetic pheromone. A collection of palm odor without male effluvia was attractive alone and enhanced attraction to synthetic pheromone in an olfactometer similar to that to a collection of palm odor emitted with feeding males and containing natural pheromone. Behavioral responses to collections of palm volatiles were correlated to the amount of volatiles material in them. Enhancement of the attractiveness of the pheromone was not correlated to chemicals specific to beetle feeding. The chemicals common to the active collections extracts were benzoate esters, mostly ethyl benzoate, anisole derivatives and sesquiterpenes. Blends of the most abundant components of the extracts were evaluated for enhancement of the attractiveness of pheromone (1 MUg) in olfactometers at 1 or 10 MUg doses. The mixtures were further evaluated by field trapping in Tunisia at 3-10 mg/day using reference (6 mg/day) or experimental pheromone formulations. A mixture of ethyl benzoate, 4-methylanisole and farnesol (1:1:1 w/w at 6.5 mg/day) enhanced captures in pheromone baited traps in 2014 and 2015 and this mixture was as active as the natural palm bait. The practical prospect of the result for the management for O. agamemnon, and other palm beetles is discussed. PMID- 28667551 TI - The Role of the Immune System Beyond the Fight Against Infection. AB - The immune system was identified as a protective factor during infectious diseases over a century ago. Current definitions and textbook information are still largely influenced by these early observations, and the immune system is commonly presented as a defence machinery. However, host defence is only one manifestation of the immune system's overall function in the maintenance of tissue homeostasis and system integrity. In fact, the immune system is integral part of fundamental physiological processes such as development, reproduction and wound healing, and a close crosstalk between the immune system and other body systems such as metabolism, the central nervous system and the cardiovascular system is evident. Research and medical professionals in an expanding range of areas start to recognise the implications of the immune system in their respective fields.This chapter provides a brief historical perspective on how our understanding of the immune system has evolved from a defence system to an overarching surveillance machinery to maintain tissue integrity. Current perspectives on the non-defence functions of classical immune cells and factors will also be discussed. PMID- 28667550 TI - Onabotulinumtoxin A for the management of chronic migraine in current clinical practice: results of a survey of sixty-three Italian headache centers. AB - BACKGROUND: Chronic migraine is a complex clinical condition often undertreated. Onabotulinumtoxin A (OBT-A) was approved in Italy in 2013 for symptom relief in patients with chronic migraine who have failed, or do not tolerate, oral prophylactic treatments. However, the impact of OBT-A in clinical practice remains to be defined. METHODS: To investigate the current management of chronic migraine with OBT-A in clinical practice, a web-based survey was conducted among clinicians working in third-level headache centers across Italy. A 26-item questionnaire was designed and developed by a group of 10 Italian headache specialists to address the following issues: treatment paradigm and OBT-A injection intervals, frequency of treatment and retreatment, definition of responders/non-responders, satisfaction with treatment potential impact of early treatment with OBT-A. Ninety-six headache centers were selected and contacted via e-mail. The online survey was anonymous and carried out using a secure website. RESULTS: Overall, 64 of the 96 centers (66.7%) completed the questionnaire. Most centers (98.4%) had been using OBT-A for >1 year. OBT-A was administered according to the PREEMPT paradigm in most centers (88.9%). While during the first year of prophylaxis with OBT-A most clinicians (93.6%) repeated OBT-A treatment every 3 months, as recommended, in the following years interval duration was variable. Response to OBT-A was defined as a >= 50% reduction in the headache days by 58.7% of the clinicians, and as a >= 30% reduction by 25.4% of them. Almost 60% of the clinicians considered OBT-A as a long-lasting therapy, while for one-third of them treatment could be discontinued in patients showing a benefit for >=6 months. According to 80% of the clinicians, early administration of OBT-A after the onset of chronic migraine was associated with better outcomes, and 47.6% felt that OBT-A should be recommended as a first-line option. CONCLUSIONS: This survey indicates that in third-level headache centers in Italy OBT-A is used in good compliance with current recommendations. There is agreement about the definition of response as a reduction in headache days by 30% to 50%. Additional effort is required to define response to OBT-A and to establish optimal treatment duration. PMID- 28667552 TI - Paying for the Tolls: The High Cost of the Innate Immune System for the Cardiac Myocyte. AB - The cardiac myocyte differs strikingly from the specialized cells of the immune system, which has two different responses to invading organisms and tissue damage. Adaptive or acquired immunity generates highly specific antibodies in response to threats and is an essential component of immunity; however, adaptive immunity can take 4-7 days to mobilize, and a more primitive response, innate immunity, fills the gap. Innate immunity is expressed in complex and in primitive life forms. Specialized receptors, Toll-like receptors (TLRs), which are widely distributed throughout different tissues recognize danger signals and rapidly respond with the release of noxious substances, such as TNFalpha. The problem is that many endogenous molecules have been found to act as ligands for specific TLRs, and when these molecules are released into the extracellular environment, they can cause problems by activating innate immunity and an inflammatory response. In cardiac myocytes heat shock protein (HSP)60 can activate TLR4, as can HMGB1, and this type of response can amplify the response to ischemia/reperfusion leading to increased cell and tissue injury. Activation of TLRs can potentially amplify chronic, inflammatory diseases, such as ischemic heart failure. Thus, it is important to understand the regulation of the TLRs and their downstream effects. This chapter will focus on the TLRs and cardiac myocytes. PMID- 28667553 TI - Properties and Immune Function of Cardiac Fibroblasts. AB - This chapter will discuss the role of cardiac fibroblasts as a target of various immunological inputs as well as an immunomodulatory hub of the heart through interaction with immune cell types and chemokine or cytokine signaling. While the purpose of this chapter is to explore the immunomodulatory properties of cardiac fibroblasts, it is important to note that cardiac fibroblasts are not a homogeneous cell type, but have a unique embryological origin and molecular identity. Specific properties of cardiac fibroblasts may influence the way they interact with the heart microenvironment to promote healthy homeostatic function or respond to pathological insults. Therefore, we will briefly discuss these aspects of cardiac fibroblast biology and then focus on their immunomodulatory role in the heart. PMID- 28667554 TI - Endothelial Cells. AB - Endothelial cells are a constitutive part of the heart and vasculature and form a crucial link between the cardiovascular system and the immune system. Besides their commonly accepted roles in angiogenesis, hemostasis, and the regulation of vascular tone, they are an essential and active component of immune responses. Expression of a range of innate pattern recognition receptors allows them to respond to inflammatory stimulation, and they control immune cell recruitment and extravasation into target tissues throughout the body.In this chapter, I will therefore summarize classical endothelial cell properties and functions and their cross talk with the immune system as well as the operational immunological role of endothelial cells in facilitating immune responses. PMID- 28667555 TI - Immune Functions and Properties of Resident Cells in the Heart and Cardiovascular System: Pericytes. AB - This chapter provides an introduction to pericyte physiology. Pericytes are smooth muscle-like cells that wrap around vessels and arterioles. Here, we discuss their structure, function, contractility and interaction with other cells including immune cells and finally their role in pathological processes. Additionally, we discuss recent studies describing pericyte populations in the heart and their potential as targets for future cardiac therapeutic interventions. PMID- 28667556 TI - The Role of Cardiac Tissue Macrophages in Homeostasis and Disease. AB - Macrophages are principally recognized as an important cell type for removal of tissue debris and as sentinels for tissue damage and foreign antigens. However, macrophages also participate in a diverse range of biological processes including angiogenesis, fibrosis, immune modulation, cell survival, and stem cell mobilization. Cardiac tissue macrophages (cTMs) are a heterogeneous population of phagocytic cells with distinct ontogenetic, phenotypic, and functional characteristics. While our understanding of cTMs has increased substantially over the last 5 years, large gaps in our knowledge regarding the cell biology of cTMs exist, in particular, the development of their unique phenotype and their roles in cardiac homeostasis and tissue stress. This review aims to discuss the current knowledge regarding cTMs and identify key questions that must be addressed to gain a better understanding of the role of cTMs in tissue development, homeostasis, and disease. PMID- 28667557 TI - Atherosclerosis. AB - In this chapter, we discuss the manner through which the immune system regulates the cardiovascular system in health and disease. We define the cardiovascular system and elements of atherosclerotic disease, the main focus in this chapter. Herein we elaborate on the disease process that can result in myocardial infarction (heart attack), ischaemic stroke and peripheral arterial disease. We have discussed broadly the homeostatic mechanisms in place that help autoregulate the cardiovascular system including the vital role of cholesterol and lipid clearance as well as the role lipid homeostasis plays in cardiovascular disease in the context of atherosclerosis. We then elaborate on the role played by the immune system in this setting, namely, major players from the innate and adaptive immune system, as well as discussing in greater detail specifically the role played by monocytes and macrophages.This chapter should represent an overview of the role played by the immune system in cardiovascular homeostasis; however further reading of the references cited can expand the reader's knowledge of the detail, and we point readers to many excellent reviews which summarise individual immune systems and their role in cardiovascular disease. PMID- 28667558 TI - Immune-Mediated Heart Disease. AB - The heart involvement in systemic autoimmune diseases represents a growing burden for patients and health systems. Cardiac function can be impaired as a consequence of systemic conditions and manifests with threatening clinical pictures or chronic myocardial damage. Direct injuries are mediated by the presence of inflammatory infiltrate which, even though unusual, is one of the most danger manifestations requiring prompt recognition and treatment. On the other hand, a not well-managed inflammatory status leads to accelerated atherosclerosis that precipitates ischemic disease. All cardiac structures may be damaged with different grades of intensity; moreover, lesions can appear simultaneously or more frequently at a short distance from each other leading to the onset of varied clinical pictures. The pathogenesis of heart damages in systemic autoimmune conditions is not yet completely understood for the great part of situations, even if several mechanisms have been investigated. The principal biochemical circuits refer to the damaging role of autoantibodies on cardiac tissues and the precipitation of immune complexes on endocardium. These events are finally responsible of inflammatory infiltration which leads to subsequent worsening of the previous damage. For these reasons, it appears of paramount importance a regular and deepened cardiovascular assessment to prevent a progressive evolution toward heart failure in patient affected by autoimmune diseases. PMID- 28667559 TI - Vasculitis in the Central Nervous System. AB - Central nervous system (CNS) vasculitides are a heterogeneous group of disorders characterized by an inflammatory cell infiltration and necrosis of blood vessel walls in the brain, spinal cord, and the meninges. The CNS complications are likely to be fatal without judicious use of immunosuppression; thus, early diagnosis may prevent from damage and disability. This chapter updates our knowledge on CNS vasculitis-related immunological mechanisms, neurological complications, diagnosis, and management. PMID- 28667561 TI - Lymphocytes at the Heart of Wound Healing. AB - The adult mammalian heart displays negligible regenerative capacity. Therefore, myocardial infarction (MI) often results in an irreversible loss of contractile tissue, leading to a collagenous scar formation, progressive remodelling and heart failure (HF). Over the past few years, emerging evidences indicate that a myocardial ischemic injury mobilizes not only sterile unspecific inflammation but also lymphocyte-mediated immune responses to cardiac auto-antigens. In the current chapter, we depict the infarcted heart as a "wounded" tissue and focus on the dynamic events leading to myocardial repair, with special emphasis on the role played by lymphocytes in this process. PMID- 28667562 TI - The Innate Immune Response in Myocardial Infarction, Repair, and Regeneration. AB - Following myocardial infarction (MI), resident innate immune cells such as macrophages, innate lymphoid cells, and mast cells rapidly coordinate their function to contain inflammation by removing dying cells and promoting cardiomyocyte replenishment. To sustain local tissue repair functions, hematopoietic progenitors are mobilized from the bone marrow to the spleen to generate subsequent myeloid cells such as monocytes and neutrophils, which are rapidly recruited at the site of MI. A finely tuned balance between local adaptation and recruitment controls the overall outcome of the cardiac tissue regeneration versus repair and scar formation.In this chapter, the (potential) roles of the innate immune system residing in the heart are discussed in the context of recent findings about macrophage ontogeny and their homeostasis with circulating monocytes during cardiac tissue growth and after myocardial infarction. Their interactions with other members of the innate immune system are also discussed with a particular emphasis on the potential involvement of mast cells and innate lymphoid cells during MI, largely underestimated until recently. Understanding the development and the functions of the different protagonists responding to MI as well as their potential cross talk could help design new strategies for regenerative medicine intervention. PMID- 28667560 TI - Cardiac Autoimmunity: Myocarditis. AB - Myocarditis is the inflammation of the muscle tissues of the heart (myocardium). After a pathologic cardiac-specific inflammatory process, it may progress to chronic damage and dilated cardiomyopathy. The latter is characterized by systolic dysfunction, whose clinical correlate is heart failure. Nevertheless, other acute complications may arise as consequence of tissue damage and electrophysiologic disturbances. Different etiologies are involved in triggering myocarditis. In some cases, such as giant cell myocarditis or eosinophilic necrotizing myocarditis, it is an autoimmune process. Several factors predispose the development of autoimmune myocarditis such as systemic/local primary autoimmunity, viral infection, HLA and gender bias, exposure of cryptic antigens, mimicry, and deficient thymic training/Treg induction. Once the anti-myocardium autoimmune process is triggered, several components of the immune response orchestrate a sustained attack toward myocardial tissues with particular timing and immunopathogenic features. Innate response mediated by monocytes/macrophages, neutrophils, and eosinophils parallels the adaptive response, playing a final effector role and not only a priming function. Stromal cells like fibroblast are also involved in the process through specific cytokines. Furthermore, adaptive T cell responses have anti-paradigmatic features, as Th17 response is dispensable for acute myocarditis but is the main driver of the process leading to dilated cardiomyopathy. Humoral response, thought to be a bystander, is important in the appearance of late-stage hemodynamic complications. The complexity of that process, as well as the unspecific and variable clinical presentation, had generated difficulties for diagnosis and treatment, which remain suboptimal. In this chapter, we will discuss the most relevant immunopathogenic findings from a basic science and clinical perspective. PMID- 28667563 TI - Resistance training as supportive measure in advanced cancer patients undergoing TKI therapy-a controlled feasibility trial. AB - PURPOSE: While there is growing evidence for positive effects of progressive resistance training in curatively treated cancer patients, data on advanced cancer patients are scarce. This pilot study aimed at investigating for the first time feasibility and effects of progressive resistance training in advanced cancer patients undergoing tyrosine kinase inhibitor (TKI) therapy. METHODS: Patients starting a TKI-based anti-tumor therapy were assigned to a resistance training group (RT, 12 weeks of progressive machine-based resistance training 2*/week) or a control group (CON, treatment as usual) until 10 patients had finished in each group (RT 80% males, 90% renal cell carcinoma, 65 +/- 11 years, CON 80% males, 70% renal cell carcinoma, 61 +/- 6 years). Primary endpoint was feasibility. Furthermore, fatigue (MFI), quality of life (QoL, EORTC QLQC30), and muscle strength were assessed. Testing occurred at baseline and after 12 weeks. RESULTS: Training was feasible in 9 out of 10 participants and no serious adverse events occurred. It had beneficial effects on muscle strength (maximum voluntary isometric contraction of the quadriceps: RT +11 +/- 9 Nm, CON -13 +/- 25 Nm, p = 0.005), but not on fatigue (general fatigue score RT +0.3 +/- 4.1, CON -1.5 +/- 3.0, p = 0.223) or QoL (global QoL score RT -5.6 +/- 16.1, CON -2.0 +/- 18.2, p = 0.617). CONCLUSIONS: Progressive machine-based resistance training appears feasible in the majority of advanced cancer patients undergoing TKI therapy. However, its positive effects on muscle strength do not seem to be associated with positive effects on fatigue or quality of life. Future studies should therefore compare whether home-based training is more beneficial for patient reported outcomes. TRIAL REGISTRATION: NCT01645150. PMID- 28667564 TI - The influence of unmet supportive care needs on anxiety and depression during cancer treatment and beyond: a longitudinal study of survivors of haematological cancers. AB - OBJECTIVES: This paper aims to examine the cross-sectional and longitudinal associations between patient-reported unmet needs and anxiety and depression for survivors of diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM). METHODS: In a longitudinal study design, self-reported data were collected through telephone interviews at two time points approximately 7 (T1) and 15 (T2) months post-diagnosis. The sample was recruited through the population-based Victorian Cancer Registry. At T1 and T2, the study outcomes, anxiety and depression, were assessed using the Hospital Anxiety and Depression Scale (HADS) and unmet needs were measured using the Supportive Care Needs Survey (SCNS-SF34). Questions related to social/family problems, relationship problems and financial problems were also asked. A three-step multivariable hierarchical logistic regression analysis examined the relative role of T1 anxiety and depression, T1 and T2 unmet needs and other psychosocial factors with T2 anxiety and depression. RESULTS: Both cross-sectional and longitudinal associations were observed between unmet needs and psychological distress. T2 anxiety was associated with T1 anxiety (OR 4.75, 95% CI 1.86-11.09), T2 psychological needs (OR 1.68, 95% CI 1.34-2.11) and with T1 social problems (OR 2.33, 95% CI 1.03-5.05) in multivariate analysis. T2 depression was associated with both T1 (OR 1.28, 95% CI 1.06-1.57) and T2 psychological needs (OR 1.35, 95% CI 1.06-1.70), T2 physical needs (OR 1.89, 95% CI 1.27-2.81) and T1 depression (OR 4.52, 95% CI 1.88-10.86). CONCLUSIONS: Unmet needs that manifest following diagnosis and treatment may persist into early survivorship and contribute to psychological distress. Addressing these needs during treatment may diminish the risk of current and future anxiety and depression. PMID- 28667565 TI - Is Low FMR1 CGG Repeat Length in Males Correlated with Family History of BRCA Associated Cancers? An Exploratory Analysis of Medical Records. AB - The FMR1 gene has been studied extensively with regard to expansions and premutations, but much less research has focused on potential effects of low CGG repeat length. Previous studies have demonstrated that BRCA1/2 positive women are more likely to have an FMR1 genotype with one low CGG allele, and that women with both FMR1 alleles in the low CGG repeat range are more likely to have had breast cancer compared to women with normal numbers of CGG repeats. However, there has been no research as to whether low CGG repeat length impacts cancer risks in men. Therefore, this study aimed to examine cancer incidence and related risk factors in men with low CGG repeat length in the FMR1 gene. We utilized subject data from the Marshfield Personalized Medicine Research Project to compare cancer-related diagnoses between 878 males with low CGG repeat length (< 24 repeats) and 368 male controls with CGG repeats in the normal range (24 to 40 repeats). We utilized ICD-9 codes to examine various cancer diagnoses, family histories of cancer, other non-malignant neoplasms, cancer surveillance, and genetic susceptibility. Men with low CGG repeats were identified to have significantly higher rates of family history of any cancer type (p = 0.011), family history of any BRCA-associated cancer (p = 0.002), and specifically, family history of prostate cancer (p = 0.007). The mean number of BRCA-associated cancer diagnoses (breast, prostate, pancreatic, and melanoma) per individual in the low CGG group was slightly higher than that of the control group, with this difference trending toward significance (p = 0.091). Additionally, men with low CGG repeats had significantly higher rates of connective/soft tissue neoplasms (p = 0.026). Additional research is needed to replicate the observations reported in this preliminary exploratory study, particularly including verification of ICD-9 codes and family history by a genetic counselor. PMID- 28667566 TI - Connecting Gaucher and Parkinson Disease: Considerations for Clinical and Research Genetic Counseling Settings. AB - There are multiple autosomal recessive disorders in which carriers may be at risk for other diseases. This observation calls into question the previous understanding that carriers of autosomal recessive disorders escape clinical consequences. We also know that childhood genetic conditions may have adult disease counterparts (Zimran et al., The Israel Medical Association Journal: IMAJ, 16(11), 723-724, 2014). Individuals who have Gaucher disease and carriers of the disorder are at increased risk for a seemingly unrelated and complex neurological condition, Parkinson disease. Parkinson disease is, in part, caused by the same mutations in the GBA gene that lead to Gaucher disease, and the two conditions are thought to have shared pathophysiology. Briefly reviewed are how these two diseases historically became linked, where their paths cross, potential problems and considerations in disclosure of the link, and current guidelines and research in this area. Genetic counseling experience with a large Parkinson disease cohort is used as a starting point to question the state of clinical and nonclinical practice in disclosing this unusual connection We conclude that more research and discussion are needed to inform practice regarding the crossroads of Gaucher and Parkinson disease. PMID- 28667567 TI - Women's Experience with Non-Invasive Prenatal Testing and Emotional Well-being and Satisfaction after Test-Results. AB - Increasingly, high-risk pregnant women opt for non-invasive prenatal testing (NIPT) instead of invasive diagnostic testing. Since NIPT is less accurate than invasive testing, a normal NIPT result might leave women less reassured. A questionnaire study was performed among pregnant women with elevated risk for fetal aneuploidy based on first-trimester combined test (risk >=1:200) or medical history, who were offered NIPT in the nationwide Dutch TRIDENT study. Pre- and post-test questionnaires (n = 682) included measures on: experiences with NIPT procedure, feelings of reassurance, anxiety (State-Trait Anxiety Inventory, STAI), child-related anxiety (PRAQ-R), and satisfaction. The majority (96.1%) were glad to have been offered NIPT. Most (68.5%) perceived the waiting time for NIPT results (mean: 15 days, range 5-32) as (much) too long. Most women with a normal NIPT result felt reassured (80.9%) or somewhat reassured (15.7%). Levels of anxiety and child-related anxiety were significantly lower after receiving a normal NIPT result as compared to the moment of intake (p < 0.001). Women with inadequate health literacy or a medical history (e.g. previous child with trisomy) experienced significantly higher post-test-result anxiety (Mean (M) STAI = 31.6 and 30.0, respectively) compared to those with adequate health literacy (M = 28.6) and no medical history (M = 28.6), indicating these women might benefit from extra information and/or guidance when communicating NIPT test-results. Introducing NIPT as an alternative to invasive testing, led to an offer that satisfied and largely reassured high-risk pregnant women. PMID- 28667568 TI - Family Communication, Risk Perception and Cancer Knowledge of Young Adults from BRCA1/2 Families: a Systematic Review. AB - Understanding challenges in familial communication of cancer risk has informed genetic service delivery. Parent-child interactions have received considerable attention, but few studies focus on young adulthood experiences within BRCA1/2 families. Young adults are approaching, or at a life stage where awareness of hereditary cancer risk is vital for informed choice of risk management options. This review assesses family communication, risk perception and cancer knowledge held by 18-40 year old individuals who have a parent with a BRCA1/2 gene mutation or carry the gene mutation themselves. Thirteen papers met the inclusion criteria. One utilized a 'mixed methods' methodology and the remaining used a qualitative approach. Findings were synthesized into themes and reported narratively. In general, parents are communicating openly about genetic risk with young adult offspring, but there is evidence that some young adults are withholding information from their parents about their own test results. Risk perception is influenced by a family history of cancer, childbearing plans and health providers' advice. Misconceptions about genetic risk appear to be common and gaps in hereditary cancer knowledge are evident. It is unclear whether incorrect knowledge was passed from parents to offspring. Health providers need to provide developmentally appropriate services for emerging adults (18-25 years old), with particular support in navigating through risk management options. PMID- 28667569 TI - Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management. OBJECTIVES: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD. METHODS: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale. RESULTS: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by >=5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m2 (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a >=30% or >=50% reduction from baseline in ADHD-RS IV total score, respectively. CONCLUSIONS: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756. PMID- 28667570 TI - Molecular Cloning, Expression and Characterization of Oenococcus oeni Priming Glycosyltransferases. AB - Oenococcus oeni is the main bacterial species that drives malolactic fermentation in wine. Most O. oeni strains produce capsular exopolysaccharides (EPS) that may contribute to protect them in the wine hostile environment. In O. oeni genome sequences, several genes are predicted to encode priming glycosyltransferases (pGTs). These enzymes are essential for EPS formation as they catalyze the first biosynthetic step through the formation of a phosphoanhydride bond between a hexose-1-phosphate and a lipid carrier undecaprenyl phosphate. In many microorganisms, mutations abolishing the pGT activity also abolish the EPS formation. We first made an in silico analysis of all the genes encoding putative pGT over 50 distinct O. oeni genome sequences. Two polyisoprenyl-phosphate-hexose 1-phosphate transferases, WoaA and WobA, and a glycosyltransferase (It3) were particularly examined for their topology and amino acid sequence. Several isoforms of these enzymes were then expressed in E. coli, and their substrate specificity was examined in vitro. The substrate specificity varied depending on the protein isoform examined, and several mutations were shown to abolish WobA activity but not EPS synthesis. Further analysis of woaA and wobA gene expression levels suggests that WoaA could replace the deficient WobA and maintain EPS formation. PMID- 28667571 TI - Extracellular Secretion of Phytase from Transgenic Wheat Roots Allows Utilization of Phytate for Enhanced Phosphorus Uptake. AB - A significant portion of organic phosphorus comprises of phytates which are not available to wheat for uptake. Hence for enabling wheat to utilize organic phosphorus in form of phytate, transgenic wheat expressing phytase from Aspergillus japonicus under barley root-specific promoter was developed. Transgenic events were initially screened via selection media containing BASTA, followed by PCR and BASTA leaf paint assay after hardening. Out of 138 successfully regenerated To events, only 12 had complete constructs and thus further analyzed. Positive T1 transgenic plants, grown in sand, exhibited 0.08 1.77, 0.02-0.67 and 0.44-2.14 fold increase in phytase activity in root extracts, intact roots and external root solution, respectively, after 4 weeks of phosphorus stress. Based on these results, T2 generation of four best transgenic events was further analyzed which showed up to 1.32, 56.89, and 15.40 fold increase in phytase activity in root extracts, intact roots and external root solution, respectively, while in case of real-time PCR, maximum fold increase of 19.8 in gene expression was observed. Transgenic lines showed 0.01-1.18 fold increase in phosphorus efficiency along with higher phosphorus content when supplied phytate or inorganic phosphorus than control plants. Thus, this transgenic wheat may aid in reducing fertilizer utilization and enhancing wheat yield. PMID- 28667572 TI - The Role of Practice Research Networks (PRN) in the Development and Implementation of Evidence: The Northern Improving Access to Psychological Therapies PRN Case Study. AB - Practice research networks (PRNs) can support the implementation of evidence based practice in routine services and generate practice based evidence. This paper describes the structure, processes and learning from a new PRN in the Improving Access to Psychological Therapies programme in England, in relation to an implementation framework and using one study as a case example. Challenges related to: ethics and governance processes; communications with multiple stakeholders; competing time pressures and linking outcome data. Enablers included: early tangible outputs and impact; a collaborative approach; engaging with local research leads; clarity of processes; effective dissemination; and committed leadership. PMID- 28667573 TI - Urologic Dermatology: a Review. AB - PURPOSE OF REVIEW: Genital dermatology represents a challenge to many providers. Though dermatologic lesions involving the genitalia may present to any of a number of practices, ranging from primary care to urology, gynecology, and dermatology, few training programs provide significant training regarding the diagnosis and management of genital dermatologic lesions. The purpose of this review is to provide urologists with an overview of common genital dermatological lesions that may be encountered in a clinic. The review also provides a guide to how to approach these conditions. RECENT FINDINGS: This manuscript summarizes the most common categories of genital dermatologic lesions, starting with normal variants and progressing to a review of contagious conditions, premalignant lesions, and malignant lesions. In cases in which a lesion does not definitively belong to one of these categories, an algorithmic approach to making a diagnosis may be helpful to narrow the differential diagnosis. The most common benign genital growths include cysts, syringomas, seborrheic keratosis, pearly papules, and Fordyce spots. Contagious lesions, such as herpes, syphilis, scabies, or molluscum contagiosum, should be treated immediately before complications or transmission can occur. Inflammatory genital lesions are very diverse in etiology and presentation but are the most common genital lesions in urological clinical practice. This category of lesions can be approached by dividing them into non erythematous and erythematous (scaling and non-scaling) lesions. Given the potential evolution of the challenging category of premalignant genital lesions, proper recognition and early biopsy play an important role. Premalignant lesions can be broadly classified into two categories: those not related to HPV infection and those that are related to HPV, including erythroplasia of Queyrat (EQ), Bowen's disease, Bowenoid papulosis, vulvar intraepithelial neoplasia (VIN), and giant condyloma. Herein, contemporary nomenclature and proper evaluation and management of premalignant lesions are reviewed which provide safe and efficacious outcomes for patients. Finally, malignant genital lesions, though rare, must be recognized early and addressed correctly. Squamous cell carcinoma represents 95% of penile and approximately 90% of vulvar and vaginal malignancies, and diagnosis and management can be challenging and require proper referral to an oncologist. Genital dermatology is a challenging field marked by diagnostic difficulty and management challenges. This manuscript provides an overview of genitourinary dermatologic lesions in an effort to provide clinicians with a framework with which to approach the evaluation of these various conditions that will facilitate proper consideration of the differential diagnoses and help the urologist distinguish between normal, benign, premalignant, and malignant lesions. PMID- 28667574 TI - Reproducibility of 24-h heart rate variability in children. AB - BACKGROUND: Over the last decades, time domain heart rate (HR) variability analysis has been explored in different pediatric clinical settings to obtain information on the cardiac autonomic tone. However, the consistency over time of 24 h time domain HRV measurements in children is not well-known. METHODS: We investigated the reproducibility of 24 h HRV time-domain indices (1 day apart), from 39 healthy children (9.5 +/- 5.3 years, 56.4% girls). The parameters analysed included: standard deviation of all the adjacent NN intervals, standard deviation of the averages of NN intervals (the intervals between normal R-peaks) in all 5-min segments, and square root of the mean of the sum of the squares of the differences between adjacent NN intervals, uncorrected and corrected for HR. Reproducibility between two 24-h ECG recordings was evaluated by intraclass correlation coefficients, standard error of measurement, coefficients of variation and Bland-Altman plots. RESULTS: For the analyzed time-domain indices, standard deviation of all the adjacent NN intervals corrected for HR showed best reproducibility with the highest intraclass correlation coefficient (0.987), the lowest coefficients of variation (5.5%) and the best level of agreement between two recordings as assessed by Bland-Altman plots. CONCLUSIONS: Our results indicate that the standard deviation of all the adjacent NN intervals corrected for the HR parameter obtained from 24-h ambulatory recordings in children is consistent and reproducible over time, thus allowing reliable identification of cardiac autonomic tone in this age group. PMID- 28667575 TI - Animal and cellular models of familial dysautonomia. AB - Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60 years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders. PMID- 28667576 TI - Can syncope cause convulsive seizures in adults? AB - PURPOSE: Convulsive epileptic seizures triggered by transient cerebral hypoperfusion 'reflex anoxic seizures' are well-described in children but are not commonly recognized in adults. METHODS: We report a case series of 12 adults who presented acutely after generalized tonic-clonic seizures with a clear syncopal phase before the convulsion. We describe the aetiology, semiology and natural history of these events. RESULTS: Four patients (33.3%) had relevant risk factors for development of seizures/active epilepsy. Five patients (41.7%) had recurrent events prior to initial review by an epileptologist, but when anti-syncope measures were instituted there were no seizure recurrences over a median follow up period of 34.5 (interquartile range 29.3-41.8) months. CONCLUSIONS: Syncope may be an under-recognized trigger for convulsive acute symptomatic seizures. Avoidance of syncope may be more effective than anti-seizure medications in preventing reflex anoxic seizures. PMID- 28667577 TI - The Role of BEAMing and Digital PCR for Multiplexed Analysis in Molecular Oncology in the Era of Next-Generation Sequencing. AB - BEAMing polymerase chain reaction (PCR) and digital PCR (dPCR) are used for robust and accurate quantification of nucleic acids. These methods are particularly well suited for the identification of very small fractions (<1%) of variant copies such as the presence of mutant genes in a predominantly wild-type background. BEAMing and dPCR are increasingly used in diverse fields including bacteriology, virology, non-invasive prenatal testing, and oncology, in particular for the molecular analysis of liquid biopsies. In this review, we present the principles of BEAMing and dPCR as well as the trends of future technical development, focusing on the possibility of developing multiplexed mutation analysis. Finally, we will discuss why such techniques will remain useful despite the ever-decreasing costs and increased automatization of next generation sequencing (NGS), using molecular characterization of cancer cells as an example. PMID- 28667578 TI - [Who benefits from the night clinic? - Value of a part-time treatment facility]. AB - BACKGROUND: The night clinic which is part of the psychiatric department of the University of Zurich is a part-time treatment option with psychiatric treatment and support in the evening. This study aimed to characterize the patients and detect different functions of the treatment setting. METHODS: Data of 253 patients covering a six-year period from 2008 up to 2013 were retrospectively assessed using descriptive methods. Subgroups according to the situation before admission and after discharge were compared. RESULTS: Patients admitted from home differed considerably from those who were transferred from a psychiatric ward concerning sociodemographic and clinical factors. They were more frequently single, unemployed, received disability funds and suffered from a psychotic disorder. They were also more likely to be discharged in a supported housing condition. CONCLUSIONS: The night clinic serves as an alternative to full inpatient treatment for individuals who have work as well as a rehabilitative option for homeless patients with severe mental illness. It contributes to a reduction of avoidance of inpatients stays for those groups of patients. PMID- 28667579 TI - The impact of fish oil and wheat germ oil combination on mineral-bone and inflammatory markers in maintenance hemodialysis patients: a randomized, double blind, placebo-controlled clinical trial. AB - PURPOSE: This study aimed to examine the impact of combined supplementation of fish oil (FO) with antioxidants like wheat germ oil (WGO) on mineral-bone and inflammatory markers in maintenance HD patients. METHODS: This randomized, double blind, placebo-controlled trial involved 46 HD patients who were randomly assigned into two groups to receive daily 3000 mg of FO [1053 mg omega-3 fatty acids (omega-3 FAs)] plus 300 mg of WGO [0.765 mg vitamin E] or placebo for 4 months. Blood concentrations of hemoglobin (Hgb), white blood cells, mineral-bone parameters including serum calcium (Ca), phosphorus, calcium-phosphorus product, parathyroid hormone, alkaline phosphatase, and osteoprotegerin and serum concentrations of inflammatory markers including high-sensitivity C-reactive protein, ferritin, and uric acid were measured before and after the intervention. RESULTS: Eighty-seven percentage of patients in each group completed the study. The mean serum Ca levels increased significantly in the supplemented group at the end of study (p = 0.0016), and this increment was also significant as compared to placebo group (p = 0.0418). No significant alterations were observed in the other measured parameters within each group during the study (as p values were >0.05). CONCLUSION: FO plus WGO supplementation showed beneficial effect on serum Ca levels of HD patients without any statistically significant effect on other mineral-bone and inflammatory markers. Further investigations are required to confirm it. PMID- 28667580 TI - Assessing the Therapeutic Utility of Professional Continuous Glucose Monitoring in Type 2 Diabetes Across Various Therapies: A Retrospective Evaluation. AB - BACKGROUND: There have been few large studies that have analyzed the effect of professional (masked) continuous glucose monitoring (P-CGM) on glycemic control in patients with type 2 diabetes (T2DM) who were on a broad spectrum of baseline therapies. METHODS: We performed a retrospective, blinded evaluation of glycemic control in 296 T2DM adults for 6 months following a 6- to 7-day study of their glycemic profile using masked P-CGM. At baseline, 91% of the patients were on some form of insulin treatment with oral hypoglycemic agents (OHA), while 7% were on one or more OHAs without insulin, and the remaining 2% were on GLP-1RAs. On the basis of the masked CGM profile, patients were counselled on diet and exercise change(s) in their baseline diabetes therapy by our professionally trained diabetes team. They also continued to receive regular treatment advice and dose titrations through our Diabetes Tele-Management System (DTMS(r)). The baseline changes in hemoglobin A1C (A1C) observed in these patients after 6 months of undergoing P-CGM was compared to a matched control group. RESULTS: P CGM revealed that the predominant pattern of hyperglycemia was postprandial while previously unknown hypoglycemia was found in 38% of the patients; over half of the cases of hypoglycemia were nocturnal. The mean A1C of the P-CGM group dropped from 7.5 +/- 1.4% at baseline vs. 7.0 +/- 0.9% at 6 months (p < 0.0001). The frequency of performing self-monitoring of blood glucose (SMBG) was also found to be significantly increased in these patients from the baseline. Meanwhile, no significant improvement in A1C was noted in the control group during the same time frame (7.7 +/- 1.1% at baseline vs. 7.4 +/- 1.1% at 6 months; p = 0.0663) and frequency of SMBG remained almost unchanged. CONCLUSIONS: P-CGM can provide actionable data and motivate patients for diabetes self-care practices, resulting in an improvement in glycemic control over a wide range of baseline therapies. PMID- 28667581 TI - Intracameral Dexamethasone Injection as Adjuvant Therapy in Endothelial Immune Reaction After Penetrating and Posterior Lamellar Keratoplasty: A Retrospective Clinical Observation. AB - INTRODUCTION: The aim of this observational study is to evaluate the effectiveness of an adjuvant intracameral corticosteroid injection (ICI) in cases of severe endothelial immune reaction (SEIR) (anterior chamber cells and flare, retrocorneal precipitates, Descemet's folds, and corneal edema) after penetrating keratoplasty and posterior lamellar keratoplasty. METHODS: In this retrospective study, 24 subjects treated between November 2011 and September 2014 were divided into two groups. The control group received topical and systemic steroid therapy while the study group received additionally ICI (400 ug dexamethasone). Outcome measures included changes in best corrected visual acuity (BCVA), central corneal thickness (CCT, Pentacam), endothelial cell count (ECC), and intraocular pressure (IOP). The follow-up examinations were conducted after a period of 6 weeks and 3 months. Results were compared using the Wilcoxon signed-rank test. RESULTS: BCVA of the patients in the study group increased from logMAR 1.5 +/- 0.77 at baseline to 0.99 +/- 0.44 (p = 0.009) at 6 weeks and to 0.78 +/- 0.45 (p = 0.017) at 3 months following the ICI. The CCT decreased from 835 +/- 211 um at baseline to 609 +/- 63 um (p = 0.005) after 3 months. ECC showed a significant reduction 12 weeks after treatment in both groups (p = 0.012 in the control group and p = 0.005 in the study group). This reflects a mean ECC loss of 17% and 19% due to the immune reaction in the control and study group, respectively. A significant temporary increase in the IOP was documented only in the control group (p = 0.005). CONCLUSION: The ICI seems to be a safe adjuvant approach, which improves therapeutic efficacy of SEIR after keratoplasty. PMID- 28667582 TI - Recent trends for the removal of colored particles in industrial wastewaters. PMID- 28667583 TI - Phytoremediation of cadmium-polluted soil by Chlorophytum laxum combined with chitosan-immobilized cadmium-resistant bacteria. AB - This study examined the performance of the chitosan-immobilized cadmium-resistant bacteria Arthrobacter sp. and Micrococcus sp. on cadmium phytoremediation by Chlorophytum laxum in cadmium-polluted soil. These immobilized cadmium-resistant bacteria can survive in cadmium-contaminated soil and significantly increased soil cadmium solubility, but the ability of chitosan-immobilized cells to increase cadmium solubility was lower than that of free cells. A pot experiment demonstrated that chitosan-immobilized Micrococcus sp. promoted the growth of C. laxum planted in cadmium-contaminated soil. A significant increase in the cadmium concentration in the roots and aboveground parts of C. laxum was found in plants inoculated with free and chitosan-immobilized cells of these bacteria. The performance of Arthrobacter sp. free cells to augment cadmium accumulation in C. laxum was a little bit better than that of chitosan-immobilized Arthrobacter sp., except at 9 weeks after planting. The phytoextraction coefficient, bioaccumulation factor, and translocation factor of C. laxum inoculated with free and chitosan-immobilized cells of cadmium-resistant bacteria were higher than those of the uninoculated control and increased with time. Our findings suggest that chitosan-immobilized cells can be exploited to enhance the efficiency of cadmium phytoremediation by C. laxum. PMID- 28667584 TI - Evaluating the performance and intellectual structure of construction and demolition waste research during 2000-2016. AB - Construction and demolition (C&D) waste diminishes scarce land resources and endangers human health and the surrounding environment. Quantitative and visualized analysis was conducted to evaluate worldwide scientific research output on C&D waste from 2000 to 2016. The related information of 857 publications was collected from SCI-Expanded database and statistically analyzed. The number of documents about C&D waste presented a general growth during the last 17 years. Construction and Building Materials publication ranked first in the most productive journals. China and Spain acted as dominated roles comparing to other countries, and Hong Kong Polytechnic University was the institution with the largest amount of C&D waste research. Recycled aggregates, sustainable C&D waste management, and the rewarding program and commerce system were the hottest topics during 2000-2016 and in the near future according to the intellectual structure analysis. PMID- 28667585 TI - Effects of low doses of glyphosate on DNA damage, cell proliferation and oxidative stress in the HepG2 cell line. AB - We studied the toxic effects of glyphosate in vitro on HepG2 cells exposed for 4 and 24 h to low glyphosate concentrations likely to be encountered in occupational and residential exposures [the acceptable daily intake (ADI; 0.5 MUg/mL), residential exposure level (REL; 2.91 MUg/mL) and occupational exposure level (OEL; 3.5 MUg/mL)]. The assessments were performed using biomarkers of oxidative stress, CCK-8 colorimetric assay for cell proliferation, alkaline comet assay and cytokinesis-block micronucleus (CBMN) cytome assay. The results obtained indicated effects on cell proliferation, both at 4 and 24 h. The levels of primary DNA damage after 4-h exposure were lower in treated vs. control samples, but were not significantly changed after 24 h. Using the CBMN assay, we found a significantly higher number of MN and nuclear buds at ADI and REL after 4 h and a lower number of MN after 24 h. The obtained results revealed significant oxidative damage. Four-hour exposure resulted in significant decrease at ADI [lipid peroxidation and glutathione peroxidase (GSH-Px)] and OEL [lipid peroxidation and level of total antioxidant capacity (TAC)], and 24-h exposure in significant decrease at OEL (TAC and GSH-Px). No significant effects were observed for the level of reactive oxygen species (ROS) and glutathione (GSH) for both treatment, and for 24 h for lipid peroxidation. Taken together, the elevated levels of cytogenetic damage found by the CBMN assay and the mechanisms of primary DNA damage should be further clarified, considering that the comet assay results indicate possible cross-linking or DNA adduct formation. PMID- 28667586 TI - Occurrence, distribution, and risk assessment of antibiotics in the Songhua River in China. AB - The occurrence, distribution, and risk assessment of antibiotics in freshwater systems are receiving global attention, because of their impact on the environment and human health. However, few studies have focused on this topic in Northeast China and its Songhua River, the third-largest river in China. This study investigated the occurrence and distribution of 12 antibiotics, including three cephalosporins (cefazolin, cefmetazole, cefotaxime), three macrolides (azithromycin, clarithromycin, roxithromycin), three fluoroquinolones (ofloxacin, norfloxacin, flumequine), and three sulfonamides (sulfadiazine, sulfapyridine, sulfamethoxazole) in the mainstream and tributaries of the Songhua River. A total of 152 surface water samples were collected in January, May, July, and October 2016. These samples were analyzed using solid-phase extraction (SPE) and ultra high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The results indicated the wide use of all 12 antibiotics in the mainstream of the Songhua River. Sulfamethoxazole and cefazolin were the dominant antibiotics, with maximum concentrations of 73.1 and 65.4 ng L-1, respectively. Other antibiotics were present at mean concentrations below 15 ng L-1, except cefmetazole, present at a mean concentration of 35.6 ng L-1. The spatial distribution of antibiotics showed that unbalanced regional development may lead to the distribution pattern of the antibiotics in the tributaries and the mainstream. Thus study also assessed the seasonal variation of antibiotics in urban surface water; cephalosporin, sulfonamide, fluoroquinolone, and macrolide concentrations were significantly higher during the icebound season than during non-icebound season. This may be due to the low temperature and water flow of the river in winter. Risk assessment showed that azithromycin, clarithromycin, roxithromycin, flumequine, and sulfamethoxazole posed a low or median risk to the aquatic organisms in the mainstream. The potential risks created by antibiotics to the aquatic environment should not be neglected in the Songhua River. The potential risks created by antibiotics to the aquatic environment should not be neglected in the Songhua River. PMID- 28667587 TI - Insulin Glargine/Lixisenatide: A Review in Type 2 Diabetes. AB - Subcutaneous insulin glargine/lixisenatide (SuliquaTM) is a titratable, fixed ratio combination of a long-acting basal insulin analogue and a glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of adult patients with inadequately controlled type 2 diabetes. Once-daily insulin glargine/lixisenatide, in combination with metformin, provided effective glycaemic control and was generally well tolerated in the 30-week, multinational, phase 3 LixiLan-O and LixiLan-L trials in insulin-naive and -experienced adult patients with inadequately controlled type 2 diabetes. Although long-term clinical experience with this fixed-ratio combination is currently lacking, given its convenient once-daily regimen and beneficial effects on glycaemic control and bodyweight loss in the absence of an increase in the incidence of hypoglycaemia, insulin glargine/lixisenatide is an emerging option for the treatment of adult patients with type 2 diabetes to improve glycaemic control when this has not been provided by metformin alone or metformin combined with another OAD or basal insulin. PMID- 28667588 TI - Post-injury stretch promotes recovery in a rat model of muscle damage induced by lengthening contractions. AB - We investigated the cellular mechanisms and therapeutic effect of post-injury stretch on the recovery process from muscle injury induced by lengthening contractions (LC). One day after LC, a single 15-min bout of muscle stretch was applied at an intensity of 3 mNm. The maximal isometric torque was measured before and at 2-21 days after LC. The myofiber size was analyzed at 21 days after LC. Developmental myosin heavy chain-immunoreactive (dMHC-ir) cells, a marker of regenerating myofibers, were observed in the early recovery stage (2-5 days after LC). We observed that LC-induced injury markedly decreased isometric torque and myofiber size, which recovered faster in rats that underwent stretch than in rats that did not. Regenerating myofiber with dMHC-ir cells was observed earlier in rats that underwent stretch. These results indicate that post-injury stretch may facilitate the regeneration and early formation of new myofibers, thereby promoting structural and functional recovery from LC-induced muscle injury. PMID- 28667589 TI - Design and evaluation of safety operation VR training system for robotic catheter surgery. AB - A number of remote robotic catheter systems have been developed to protect physicians from X-ray exposure in endovascular surgery. However, the teleoperation prevents the physicians sensing the force directly which may easily result in healthy vessels injured. To realize the safe operation, a tissue protection-based VR training system has been developed in this paper to prevent collateral damage by collision. The integrated VR simulator cannot only remind the novice possible collisions by visual signs, but also cooperate with the newly designed tissue protection mechanism to remit collision trauma beforehand. Such mechanism exploits the diameter variable pulley in order to implement the safe interaction between catheter and vasculature. To testify the effectiveness of the tissue protection in training system, we invited four non-medical students to participate the successive 5 days training session. The evaluation results show that the average impingement distance (representing tissue damage) to vascular wall has been reduced to 0.6 mm, and the collision frequency is greatly decreased which implies the realization of relative safe catheterization. PMID- 28667590 TI - Using nonlinear finite element models to analyse stress distribution during subluxation and torque required for dislocation of newly developed total hip structure after prosthetic impingement. AB - Dislocation is a serious potential complication of total hip replacement. Previous studies have proposed a newly developed total hip structure that meets the required oscillation angle of 120 degrees , for which the chamfer on the acetabular liner rim was designed to enable the neck to impinge on the chamfer over a large area after impingement occurs. This study adopted the finite element method to further analyse the torque limits leading to dislocation and the contact stresses at the impingement and egress sites of the liner during subluxation. The compressive stress-strain curve for ultra-high molecular weight polyethylene is nonlinear. The results reveal that an adequate chamfer angle of the acetabular cup liner can significantly increase dislocation torque and decrease contact stress on the liner rim. By means of the new design, when the head-neck ratio (HNR) is 2.5 or 3.0, the maximum torque value that a 36-mm head can withstand is 1.38 (8.7 Nm/6.3 Nm) or 1.47 (8.4 Nm/5.7 Nm) times that of a 22 mm head, while the maximum stress of a 36-mm head is 0.41 (14.58 MPa/35.73 MPa) or 0.70 (33.71 MPa/47.90 MPa) times that of a 22-mm head. When the head diameters are identical, the dislocation torque of the HNR = 2.5 structure is slightly greater than that of the HNR = 3.0 structure (3.3-10.5%); thus, the newly developed structure can disperse contact stress, and the structure of a large head with a low HNR exhibits a higher dislocation torque value and lower stress. PMID- 28667592 TI - Intracranial granulocytic sarcoma as the first presentation of chronic myeloid leukemia in chronic phase. PMID- 28667591 TI - Classification of upper limb disability levels of children with spastic unilateral cerebral palsy using K-means algorithm. AB - Treatment for cerebral palsy depends upon the severity of the child's condition and requires knowledge about upper limb disability. The aim of this study was to develop a systematic quantitative classification method of the upper limb disability levels for children with spastic unilateral cerebral palsy based on upper limb movements and muscle activation. Thirteen children with spastic unilateral cerebral palsy and six typically developing children participated in this study. Patients were matched on age and manual ability classification system levels I to III. Twenty-three kinematic and electromyographic variables were collected from two tasks. Discriminative analysis and K-means clustering algorithm were applied using 23 kinematic and EMG variables of each participant. Among the 23 kinematic and electromyographic variables, only two variables containing the most relevant information for the prediction of the four levels of severity of spastic unilateral cerebral palsy, which are fixed by manual ability classification system, were identified by discriminant analysis: (1) the Falconer index (CAI E ) which represents the ratio of biceps to triceps brachii activity during extension and (2) the maximal angle extension (theta Extension,max). A good correlation (Kendall Rank correlation coefficient = -0.53, p = 0.01) was found between levels fixed by manual ability classification system and the obtained classes. These findings suggest that the cost and effort needed to assess and characterize the disability level of a child can be further reduced. PMID- 28667593 TI - Significant response of pituitary carcinoma to carboplatin, leucovorin and fluorouracil chemotherapy: a pediatric case report and review of the literature. PMID- 28667594 TI - Do race and age vary in non-malignant central nervous system tumor incidences in the United States? AB - Epidemiological analyses of many cancers have demonstrated differences in incidence and outcome for patients from different racial backgrounds. The aim of this study was to determine the incidence of non-malignant CNS tumors by race and age to identify incidence variance. Data from the Central Brain Tumor Registry of the United States (CBTRUS) from 2009 to 2013 were used to calculate age-adjusted incidence rates (IR) per 100,000 population and 95% confidence intervals for selected tumors overall, by race, age group, and race stratified by age group. In those aged 0-14 years, Whites had significantly greater IR of neuronal and mixed neuronal-glial tumors (IR = 0.37) compared to Others (IR = 0.26) and Blacks (IR = 0.24). In those 15-39 years, Blacks had significantly greater IR of tumors of the pituitary (IR = 3.80) than Others (IR = 3.29) and Whites (IR = 3.15), and significantly greater IR of grade I meningioma (IR = 1.93) than Whites (IR = 1.59) and Others (IR = 1.21). In those 40 years and older, Blacks had significantly greater IR of grade I meningioma (IR = 19.16) compared to Whites (IR = 15.77) and Others (IR = 15.32), and significantly greater IR of tumors of the pituitary (IR = 10.47) than Others (IR = 5.85) and Whites (IR = 4.99). Others had significantly greater IR of nerve sheath tumors (IR = 4.00) compared to Whites (IR = 3.46) and Blacks (IR = 1.64). The incidence of non-malignant CNS tumors differs significantly by race and age in the USA. These differences may contribute to previously-described health outcome disparities. PMID- 28667595 TI - Optimizing bevacizumab dosing in glioblastoma: less is more. AB - Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10 mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (>=grade 3) when the administered dose was (<3 mg/kg/week), compared to a 21% incidence in those who received higher doses (>=3 mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified. PMID- 28667596 TI - Natural history of intramedullary spinal cord ependymoma in patients preferring nonoperative treatment. AB - Surgical resection of intramedullary spinal cord ependymoma still remains the standard of care but is challenging and occasionally associated with poor outcome. The aim of this study is therefore to provide additional information regarding the natural history of conservatively treated symptomatic intramedullary spinal cord ependymoma. Retrospective, single center review of all patients with intramedullary spinal cord ependymoma treated conservatively (wait and see) between 1980 and 2016. The neurological outcomes at first presentation, as well as in long-term follow-up, were assessed using the modified McCormick Disability Scale and modified Rankin Scale. Thirteen of 41 patients were managed conservatively and were included in the study. Mean age at the admission was 49 years. There were seven women and six men. All patients were symptomatic at the time of presentation. The mean follow-up from admission to the last neurological examination was 47.9 months. The mean modified McCormick score in conservatively treated patients was 1.3 at admission and 1.6 (p = 0.3) at last follow-up. There was no significant neurological detoriation over time in conservatively managed patients as assessed by the modified Rankin Scale at first presentation and last follow-up (mRS scores of 0-2, 100 vs 92%; p = 0.9). This cohort of conservatively managed patients with symptomatic intramedullary spinal cord ependymoma was clinically stable throughout the follow-up period. Our data provide additional information for counseling patients with intramedullary spinal cord tumors who chose a nonoperative treatment. PMID- 28667597 TI - Stereotactic radiotherapy as primary definitive or postoperative treatment of intracranial meningioma of WHO grade II and III leads to better disease control than stereotactic radiotherapy of recurrent meningioma. AB - The aim of this study was to evaluate long-term clinical outcome, prognostic factors and quality of life after adjuvant or definitive fractionated stereotactic radiotherapy (SRT) of meningioma WHO grade II and III or at recurrence. 131 patients with 138 meningioma (64 WHO grade II, 16 WHO grade III, 58 without histology) of the skull base, falx and convexity were treated between 01/2002 and 01/2015 at the Erlangen University Hospital by fractionated stereotactic radiotherapy (SRT) as primary treatment (adjuvant or definitive) and at recurrence. 53% (n = 53) lesions of patients with primary tumour received postoperative SRT and 47% (n = 47) as definitive treatment (without surgery). All 38 lesions (100%) of recurrent meningioma underwent surgery followed by SRT. SRT was mostly given in 28, 30 or 25 fractions to a median dose of 54.0 Gy in the reference point. Progression-free-survival at 8 years for patients with meningioma at primary treatment were significantly better with 100% for patients with definitive SRT (p = 0.008) or 85% for patients with adjuvant SRT (p = 0.009) compared to 42% after treatment (surgery + SRT) of recurrence. Progression-free survival at 8 years for patients with SRT as adjuvant treatment after gross total resection of WHO grade II meningioma were significantly better at 83% (p = 0.016) compared to 46% after adjuvant SRT of recurrence. In 31% of patients after primary treatment and in 38.5% after recurrence treatment an improvement of pain symptoms was achieved. The favourable prognostic factor for better PFS at recurrence treatment was tumor location (skull base or convexity better compared to the falx). Postoperative SRT of WHO grade II meningioma after gross total resection (GTR) can effectively reduce recurrence risk. PMID- 28667598 TI - Comparison of two bacterial DNA extraction methods from non-polluted and polluted soils. AB - DNA extraction from soil samples is a critical step for molecular biology analyses. The present study compared the efficiency of two DNA isolation methods from non-polluted and polluted soils with or without the presence of a plant. Both applied methods used chemical and physical lyses, but method 1 had an additional physical disruption. The main difference between these two methods was the humic acid purification technique as it was carried out during cell lysis for method 1 and after cell lysis for method 2. Samples were assessed on the basis of their yield and DNA purity as well as their bacterial quantity and diversity. Based on our results, method 1 proved to be more effective at removing protein and RNA, whereas method 2 proved to be more effective at removing humic acids. Although no differences were obtained in terms of the DNA yield, both the bacterial quantity and community structure were affected by the method used. Method 1 allowed for the recovery of more information than method 2, and polluted soil was more sensitive to the DNA extraction procedure. We recommend carefully selecting the DNA extraction method, especially when soil is disturbed. PMID- 28667599 TI - Identification of Protein Secretion Systems in Bacterial Genomes Using MacSyFinder. AB - Protein secretion systems are complex molecular machineries that translocate proteins through the outer membrane, and sometimes through multiple other barriers. They have evolved by co-option of components from other envelope associated cellular machineries, making them sometimes difficult to identify and discriminate. Here, we describe how to identify protein secretion systems in bacterial genomes using MacSyFinder. This flexible computational tool uses the knowledge stemming from experimental studies to identify homologous systems in genome data. It can be used with a set of predefined models-"TXSScan"-to identify all major secretion systems of diderm bacteria (i.e., with inner and with LPS containing outer membranes). For this, it identifies and clusters colocalized components of secretion systems using sequence similarity searches with hidden Markov model protein profiles. Finally, it checks whether the genetic content and organization of clusters satisfy the constraints of the model. TXSScan models can be customized to search for variants of known systems. The models can also be built from scratch to identify novel systems. In this chapter, we describe a complete pipeline of analysis, including the identification of a reference set of experimentally studied systems, the identification of components and the construction of their protein profiles, the definition of the models, their optimization, and, finally, their use as tools to search genomic data. PMID- 28667600 TI - Protein Sorting Prediction. AB - Many computational methods are available for predicting protein sorting in bacteria. When comparing them, it is important to know that they can be grouped into three fundamentally different approaches: signal-based, global-property based and homology-based prediction. In this chapter, the strengths and drawbacks of each of these approaches is described through many examples of methods that predict secretion, integration into membranes, or subcellular locations in general. The aim of this chapter is to provide a user-level introduction to the field with a minimum of computational theory. PMID- 28667601 TI - Cell Fractionation. AB - Protein function is generally dependent on its subcellular localisation. In Gram negative bacteria such as Escherichia coli, a protein can be targeted to five different compartments: the cytoplasm, the inner membrane, the periplasm, the outer membrane and the extracellular medium. Different approaches can be used to determine the protein localisation within a cell such as in silico identification of protein signal sequences and motifs, electron microscopy and immunogold labelling, optical fluorescence microscopy, and biochemical technics. In this chapter, we describe a simple and efficient method to isolate the different compartments of Escherichia coli by a fractionation method and to determine the presence of the protein of interest. For inner membrane proteins we propose a method to discriminate between integral and peripheral membrane proteins. PMID- 28667602 TI - Defining Lipoprotein Localisation by Fluorescence Microscopy. AB - In recent years it has become evident that lipoproteins play crucial roles in the assembly of bacterial envelope-embedded nanomachineries and in the processes of protein export/secretion. In this chapter we describe a method to determine their precise localisation, for example inner versus outer membrane, in Gram-negative bacteria using human opportunistic pathogen Pseudomonas aeruginosa as a model. A fusion protein between a given putative lipoprotein and the red fluorescent protein mCherry must be created and expressed in a strain expressing cytoplasmic green fluorescent protein (GFP). Then the peripheral localisation of the fusion protein in the cell can be examined by treating cells with lysozyme to create spheroplasts and monitoring fluorescence under a confocal microscope. Mutants in the signal peptide can be engineered to study the association with the membrane and efficiency of transport. This protocol can be adapted to monitor lipoprotein localisation in other Gram-negative bacteria. PMID- 28667603 TI - Identification of Lipoproteins Using Globomycin and Radioactive Palmitate. AB - Bacterial lipoproteins are characterized by fatty acids that are covalently attached to their amino terminus via posttranslational modification in the cytoplasmic membrane. Three enzymatic steps are involved in the synthesis of mature triacylated lipoprotein: prolipoprotein converts into diacylglyceryl prolipoprotein that in turn converts into apolipoprotein, which is finally converted into mature triacylated lipoprotein. Here we describe the detection of one of these intermediate forms of lipoprotein, diacylglyceryl-prolipoprotein, using 3H-palmitate labeling and inhibition by globomycin and detection by fluorography. PMID- 28667604 TI - Defining Membrane Protein Localization by Isopycnic Density Gradients. AB - In many bacteria, membrane proteins account for around one-third of the proteome and can represent much more than half of the mass of a membrane. Classic techniques in cell biology can be applied to characterise bacterial membranes and their membrane protein constituents. Here we describe a protocol for the purification of outer and inner membranes from Escherichia coli. The procedure can be applied with minor modifications to other bacterial species, including those carrying capsular polysaccharide attached to the outer membrane. PMID- 28667605 TI - Cell Surface Exposure. AB - Surface-exposed proteins of Gram-negative bacteria are represented by integral outer membrane beta-barrel proteins and lipoproteins. No computational methods exist for predicting surface-exposed lipoproteins, and therefore lipoprotein topology must be experimentally tested. This chapter describes three distinct but complementary methods for the detection of surface-exposed proteins: cell surface protein labeling, accessibility to extracellular protease and antibodies. PMID- 28667606 TI - Probing Inner Membrane Protein Topology by Proteolysis. AB - Inner membrane proteins are inserted into the membrane via alpha-helices. These helices do not only constitute membrane anchors but may mediate specific interactions with membrane protein partners or participate in energetic processes. The number, location, and orientation of these helices is referred to as topology. Bitopic membrane proteins that consist of a single membrane-embedded domain connecting two soluble domains are distinguished from polytopic ones that consist of multiple membrane-spanning helices connected by extramembrane domains. Defining inner membrane protein topology could be achieved by different methods. Here we describe a protease accessibility assay that makes it possible to define topology based on digestion profiles. PMID- 28667607 TI - Mapping of Membrane Protein Topology by Substituted Cysteine Accessibility Method (SCAMTM). AB - A described simple and advanced protocol for the substituted-cysteine accessibility method as applied to transmembrane (TM) orientation (SCAMTM) permits a topology analysis of proteins in their native state and can be universally adapted to any membrane system to either systematically map an uniform topology or identify and quantify the degree of mixed topology. In this approach, noncritical individual amino acids that are thought to reside in the putative extracellular or intracellular loops of a membrane protein are replaced one at a time by cysteine residue, and the orientation with respect to the membrane is evaluated using a pair of membrane-impermeable nondetectable and detectable thiol-reactive labeling reagents. PMID- 28667608 TI - Defining Membrane Protein Topology Using pho-lac Reporter Fusions. AB - Experimental determination of membrane protein topology can be achieved using various techniques. Here we present the pho-lac dual reporter system, a simple, convenient, and reliable tool to analyze the topology of membrane proteins in vivo. The system is based on the use of two topological markers with complementary properties, the Escherichia coli beta-galactosidase LacZ, which is active in the cytoplasm, and the E. coli alkaline phosphatase PhoA, which is active in the bacterial periplasm. Specifically, in this pho-lac gene system, the reporter molecule is a chimera composed of the mature PhoA that is in frame with the beta-galactosidase alpha-peptide, LacZalpha. Hence, when targeted to the periplasm, the PhoA-LacZalpha dual reporter displays high alkaline phosphatase activity but no beta-galactosidase activity. Conversely, when located in the cytoplasm, PhoA-LacZalpha has no phosphatase activity but exhibits high beta galactosidase activity in E. coli cells expressing the omega fragment of LacZ, LacZomega (via the alpha-complementation phenomenon). The dual nature of the PhoA LacZalpha reporter allows a simple way to normalize both enzymatic activities to obtain readily interpretable information about the subcellular location of the fusion site between the membrane protein under study and the reporter. In addition, the PhoA-LacZalpha reporter permits utilization of dual-indicator agar plates to easily discriminate between colonies bearing cytoplasmic fusions, periplasmic fusions, or out-of-frame fusions. In total, the phoA-lacZalpha fusion reporter approach is a straightforward and rather inexpensive method of characterizing the topology of membrane proteins in vivo. PMID- 28667609 TI - In Vivo and In Vitro Protein-Peptidoglycan Interactions. AB - Bacteria have developed a number of trans-envelope systems to transport molecules or assemble organelles across bacterial envelopes. However, bacterial envelopes contain a rigid netlike peptidoglycan structure that protects cells from osmotic lysis. Trans-envelope systems thus must interact with the peptidoglycan barrier to generate gaps or anchor structures to the peptidoglycan scaffold. Here we describe methods to use in vivo cross-linking and in vitro co-sedimentation to study protein-peptidoglycan interactions in Gram-negative bacteria. In particular, we address important considerations to ensure the specificity of the interactions in question. PMID- 28667610 TI - Measure of Peptidoglycan Hydrolase Activity. AB - Most gene clusters encoding multiprotein complexes of the bacterial cell envelope, such as conjugation and secretion systems, Type IV pili, and flagella, bear a gene encoding an enzyme with peptidoglycan hydrolase activity. These enzymes are usually glycoside hydrolases that cleave the glycan chains of the peptidoglycan. Their activities are spatially controlled to avoid cell lysis and to create localized rearrangement of the cell wall. This is assured by interaction with the structural subunits of the apparatus. Here we describe protocols to test the peptidoglycan hydrolase activity of these proteins in vitro and in solution. PMID- 28667611 TI - Protein-Protein Interaction: Bacterial Two-Hybrid. AB - The bacterial two-hybrid (BACTH, for "Bacterial Adenylate Cyclase-Based Two Hybrid") system is a simple and fast genetic approach to detecting and characterizing protein-protein interactions in vivo. This system is based on the interaction-mediated reconstitution of a cyclic adenosine monophosphate (cAMP) signaling cascade in Escherichia coli. As BACTH uses a diffusible cAMP messenger molecule, the physical association between the two interacting chimeric proteins can be spatially separated from the transcription activation readout, and therefore it is possible to analyze protein-protein interactions that occur either in the cytosol or at the inner membrane level as well as those that involve DNA-binding proteins. Moreover, proteins of bacterial origin can be studied in an environment similar (or identical) to their native one. The BACTH system may thus permit a simultaneous functional analysis of proteins of interest provided the hybrid proteins retain their activity and their association state. This chapter describes the principle of the BACTH genetic system and the general procedures to study protein-protein interactions in vivo in E. coli. PMID- 28667612 TI - Protein-Protein Interactions: Yeast Two-Hybrid System. AB - The yeast two-hybrid system is a powerful and commonly used genetic tool to investigate interactions between artificial fusion proteins inside the nucleus of yeast. Here we describe how to use the Matchmaker GAL4-based yeast two-hybrid system to detect the interaction of the Agrobacterium type VI secretion system (T6SS) sheath components TssB and TssC41. The bait and prey gene are expressed as a fusion to the GAL4 DNA-binding domain (DNA-BD) and GAL4 activation domain (AD, prey/library fusion protein) respectively. When bait and prey fusion proteins interact in yeast nucleus, the DNA-BD and AD are brought into proximity, thereby activating the transcription of reporter genes. This technology can be widely used to identify interacting partners, confirm suspected interactions, and define interacting domains. PMID- 28667613 TI - Protein-Protein Interactions: Cytology Two-Hybrid. AB - Identifying protein-protein interactions between the machine components of bacterial secretion systems and their cognate substrates is essential. Establishing which component and substrate interactions are direct or indirect further facilitates (1) advancing the architecture and assembly of the machines and (2) understanding the substrates' translocation mechanistics. Currently, though biochemical means exist for identifying such direct interactions, they primarily remain in vitro and are quite labor intensive. Thus, adopting genetic approaches to help visualize these interactions in vivo is quick and advantageous. Here I describe bimolecular fluorescence complementation and cytology-based two-hybrid assays that could easily be adopted to understand the bacterial secretions systems. PMID- 28667614 TI - Fusion Reporter Approaches to Monitoring Transmembrane Helix Interactions in Bacterial Membranes. AB - In transenvelope multiprotein machines such as bacterial secretion systems, protein-protein interactions not only occur between soluble domains but might also be mediated by helix-helix contacts in the inner membrane. Here we describe genetic assays commonly used to test interactions between transmembrane alpha helices in their native membrane environment. These assays are based on the reconstitution of dimeric regulators allowing the control of expression of reporter genes. We provide detailed protocols for the TOXCAT and GALLEX assays used to monitor homotypic and heterotypic transmembrane helix-helix interactions. PMID- 28667615 TI - Protein-Protein Interactions: Co-Immunoprecipitation. AB - Proteins often do not function as single substances but rather as team players in a dynamic network. Growing evidence shows that protein-protein interactions are crucial in many biological processes in living cells. Genetic (such as yeast two hybrid, Y2H) and biochemical (such as co-immunoprecipitation, co-IP) methods are the methods commonly used at the beginning of a study to identify the interacting proteins. Immunoprecipitation (IP), a method using a target protein-specific antibody in conjunction with Protein A/G affinity beads, is a powerful tool to identify molecules that interact with specific proteins. Therefore, co-IP is considered to be one of the standard methods of identifying or confirming the occurrence of protein-protein interaction events in vivo. Co-IP experiments can identify proteins via direct or indirect interactions or in a protein complex. Here, we use Agrobacterium type VI secretion system (T6SS) sheath components TssB TssC41 interaction as an example to describe the principle, procedure, and experimental problems of co-IP. PMID- 28667616 TI - Protein-Protein Interaction: Tandem Affinity Purification in Bacteria. AB - The discovery of protein-protein interaction networks can lead to the unveiling of protein complex(es) forming cellular machinerie(s) or reveal component proteins of a specific cellular pathway. Deciphering protein-protein interaction networks therefore contributes to a deeper understanding of how cells function. Here we describe the protocol to perform tandem affinity purification (TAP) in bacteria, which enables the identification of the partners of a bait protein under native conditions. This method consists in two sequential steps of affinity purification using two different tags. For that purpose, the bait protein is translationally fused to the TAP tag, which consists of a calmodulin binding peptide (CBP) and two immunoglobulin G (IgG) binding domains of Staphylococcus aureus protein A (ProtA) that are separated by the tobacco etch virus (TEV) protease cleavage site. After the first round of purification based on the binding of ProtA to IgG coated beads, TEV protease cleavage releases CBP-tagged bait-protein along with its partners for a second round of purification on calmodulin affinity resin and leaves behind protein contaminants bound to IgG. Creating the TAP-tag translational fusion at the chromosomal locus allows detection of protein interactions occurring in physiological conditions. PMID- 28667617 TI - Site-Directed and Time-Resolved Photocrosslinking in Cells Metabolically Labeled with Radioisotopes. AB - To efficiently transport proteins into and across cellular membranes, specialized transport machineries engage in recognition events with different domains of their client proteins, forming sequential intermediate complexes. The short-lived nature of these interactions poses a big challenge in the identification of the key factors involved in transport reactions and their mechanism of action. Site directed photocrosslinking is a powerful method for the detection and accurate mapping of interacting protein domains. This chapter describes a protocol that combines site-directed photocrosslinking to metabolic labeling of proteins and lipids as a method to characterize, with temporal and spatial resolution, the interactions of a secretory protein as it transverses the bacterial envelope. PMID- 28667618 TI - Protein-Protein Interactions: Pull-Down Assays. AB - Determining protein partners is an essential step toward understanding protein function and identifying relevant biological pathways. Many methods exist for investigating protein-protein interactions. The pull-down assay is an in vitro technique used to detect physical interactions between two or more proteins and an invaluable tool for confirming a predicted protein-protein interaction or identifying novel interacting partners. This method typically involves the use of affinity purification with various wash and elution steps. In this chapter, we describe how an interaction between two purified bacterial proteins or between bacterial and eukaryotic proteins can be detected by pull-down experiments. PMID- 28667619 TI - Protein-Protein Interactions: Surface Plasmon Resonance. AB - Surface plasmon resonance (SPR) is one of the most commonly used techniques to study protein-protein interactions. The main advantage of SPR is it gives on the ability to measure the binding affinities and association/dissociation kinetics of complexes in real time, in a label-free environment, and using relatively small quantities of materials. The method is based on the immobilization of one of the binding partners, called the ligand, on a dedicated sensor surface. Immobilization is followed by the injection of the other partner, called the analyte, over the surface containing the ligand. The binding is monitored by subsequent changes in the refractive index of the medium close to the sensor surface upon injection of the analyte. During the last 10 years, SPR has been intensively used in the study of secretion systems because of its ability to detect highly dynamic complexes that are difficult to investigate using other techniques. This chapter will guide users in the setup of SPR experiments in order to identify protein complexes and to assess their binding affinity or kinetics. It will include detailed protocols for (i) the immobilization of proteins with the amine coupling capture method, (ii) analyte-binding analysis, (iii) affinity/kinetic measurements, and (iv) data analysis.Secretion systems are multiprotein complexes allowing the transport of a large number of effectors from the inside to the outside of bacterial cells. The assembly of these supramolecular machineries is ensured by the formation of protein complexes with extremely different times of stability, from transitory to stable interactions. To understand the function of these machineries as well as their modes of association, it is important to study their building blocks by identifying the different interacting partners and assessing their relative affinities and association/dissociation kinetics. For that purpose, scientists combine genetic, biochemical, and biophysical tools. During the last decade, the use of surface plasmon resonance (SPR) in the study of secretion systems has increased spectacularly [1-12]. This in vitro approach is the method of choice to study such dynamic systems owing to its ability to detect both weak and strong interactions ranging from the millimolar to the nanomolar range [13, 14]. SPR can be used as a primary tool to screen interacting partners or as a validation tool for interactions previously identified by other methods (e.g., bacterial two hybrid, co-immunoprecipitation, chemical crosslinking). The determination of the affinity or kinetics of an interaction, as can be done by SPR, is fundamental to understanding the nature of binding at the cellular level. PMID- 28667620 TI - Assessing Energy-Dependent Protein Conformational Changes in the TonB System. AB - Changes in conformation can alter a protein's vulnerability to proteolysis. Thus, in vivo differential proteinase sensitivity provides a means for identifying conformational changes that mark discrete states in the activity cycle of a protein. The ability to detect a specific conformational state allows for experiments to address specific protein-protein interactions and other physiological components that potentially contribute to the function of the protein. This chapter presents the application of this technique to the TonB dependent energy transduction system of Gram-negative bacteria, a strategy that has refined our understanding of how the TonB protein is coupled to the ion electrochemical gradient of the cytoplasmic membrane. PMID- 28667621 TI - Defining Assembly Pathways by Fluorescence Microscopy. AB - Bacterial secretion systems are among the largest protein complexes in prokaryotes and display remarkably complex architectures. Their assembly often follows clearly defined pathways. Deciphering these pathways not only reveals how bacteria accomplish building these large functional complexes but can provide crucial information on the interactions and subcomplexes within secretion systems, their distribution within bacteria, and even functional insights. The emergence of fluorescent proteins has provided a new powerful tool for biological imaging, and the use of fluorescently labeled components presents an interesting method to accurately define the biogenesis of macromolecular complexes. Here we describe the use of this method to decipher the assembly pathway of bacterial secretion systems. PMID- 28667622 TI - Large Complexes: Cloning Strategy, Production, and Purification. AB - Membrane proteins can assemble and form complexes in the cell envelope. In Gram negative bacteria, a number of multiprotein complexes, including secretion systems, efflux pumps, molecular motors, and pilus assembly machines, comprise proteins from the inner and outer membranes. Besides the structures of isolated soluble domains, only a few atomic structures of these assembled molecular machines have been elucidated. To better understand the function and to solve the structure of protein complexes, it is thus necessary to design dedicated production and purification processes. Here we present cloning procedures to overproduce membrane proteins into Escherichia coli cells and describe the cloning and purification strategy for the Type VI secretion TssJLM membrane complex. PMID- 28667623 TI - Shearing and Enrichment of Extracellular Type IV Pili. AB - Pili are widespread among bacteria. Type IVa pili (T4aP) are associated with a variety of bacterial functions, including adhesion, motility, natural transformation, biofilm formation, and force-dependent signaling. In pathogenic bacteria, T4aP play a crucial role during infection and have been the subject of hundreds of studies. Methods for the isolation and purification of T4aP were first described in the 1970s. Purified pili have been used for studies of filament protein content, morphology, immunogenicity, post-translational modifications, and X-ray crystallography. We detail a tried-and-true method of isolating large amounts of native T4aP from bacterial surfaces. The method requires supplies and equipment that are available in most microbiology labs. PMID- 28667624 TI - Blue Native PAGE Analysis of Bacterial Secretion Complexes. AB - Bacterial protein secretion systems serve to translocate substrate proteins across up to three biological membranes, a task accomplished by hydrophobic, membrane-spanning macromolecular complexes. The overexpression, purification, and biochemical characterization of these complexes is often difficult, impeding progress in understanding the structure and function of these systems. Blue native (BN) polyacrylamide gel electrophoresis (PAGE) allows for the investigation of these transmembrane complexes right from their originating membranes, without the need for long preparative steps, and is amenable to the parallel characterization of a number of samples under near-native conditions. Here we present protocols for sample preparation, one-dimensional BN PAGE and two dimensional BN/sodium dodecyl sulfate (SDS)-PAGE, as well as for downstream analysis by staining, immunoblotting, and mass spectrometry on the example of the type III secretion system encoded on Salmonella pathogenicity island 1. PMID- 28667625 TI - In Situ Imaging of Bacterial Secretion Systems by Electron Cryotomography. AB - The unique property of electron cryotomography (ECT) is its capability to resolve the structure of macromolecular machines in their cellular context. The integration of ECT data with high-resolution structures of purified subcomplexes and live-cell fluorescence light microscopy can generate pseudo-atomic models that lead to a mechanistic understanding across size and time scales. Recent advances in electron detection, sample thinning, data acquisition, and data processing have significantly enhanced the applicability and performance of ECT. Here we describe a detailed workflow for an ECT experiment, including cell culture, vitrification, data acquisition, data reconstruction, tomogram analysis, and subtomogram averaging. This protocol provides an entry point to the technique for students and researchers and indicates the many possible variations arising from specific target properties and the available instrumentation. PMID- 28667626 TI - Structural Analysis of Protein Complexes by Cryo Electron Microscopy. AB - Structural studies of biocomplexes using single-particle cryo-electron microscopy (cryo-EM) is now a well-established technique in structural biology and has become competitive with X-ray crystallography. The latest advances in EM enable us to determine structures of protein complexes at 3-5 A resolution for an extremely broad range of sizes from ~200 kDa up to hundreds of megadaltons (Bartesaghi et al., Science 348(6239):1147-1151, 2051; Bai et al., Nature 525(7568):212-217, 2015; Vinothkumar et al., Nature 515(7525):80-84, 2014; Grigorieff and Harrison, Curr Opin Struct Biol 21(2):265-273, 2011). The majority of biocomplexes comprise a number of different components and are not amenable to crystallisation. Secretion systems are typical examples of such multi-protein complexes, and structural studies of them are extremely challenging. The only feasible approach to revealing their spatial organisation and functional modification is cryo-EM. The development of systems for digital registration of images and algorithms for the fast and efficient processing of recorded images and subsequent analysis facilitated the determination of structures at near atomic resolution. In this review we will describe sample preparation for cryo EM, how data are collected by new detectors, and the logistics of image analysis through the basic steps required for reconstructions of both small and large biological complexes and their refinement to nearly atomic resolution. The processing workflow is illustrated using examples of EM analysis of a Type IV Secretion System. PMID- 28667627 TI - Bacterial Filamentous Appendages Investigated by Solid-State NMR Spectroscopy. AB - The assembly of filamentous appendages at the surface of bacteria is essential in many infection mechanisms. The extent of mechanical, dynamical, and functional properties of such appendages is very diverse, ranging from a structural scaffold of the pathogen-host cell interaction to cell motility, surface adhesion, or the export of virulence effectors. In particular, the architectures of several bacterial secretion systems have revealed the presence of filamentous architectures, known as pili, fimbriae, andneedles. At the macroscopic level, filamentous bacterial appendages appear as thin extracellular filaments of several nanometers in diameter and up to several microns in length. The structural characterization of these appendages at atomic-scale resolution represents an extremely challenging task because of their inherent noncrystallinity and very poor solubility. Here, we describe protocols based on recent advances in solid-state NMR spectroscopy to investigate the secondary structure, subunit-subunit protein interactions, symmetry parameters, and atomic architecture of bacterial filaments. PMID- 28667628 TI - Energy Requirements for Protein Secretion via the Flagellar Type III Secretion System. AB - Protein transport across the cytoplasmic membrane is coupled to energy derived from adenosine triphosphate hydrolysis or the protein motive force (pmf). A sophisticated, multi-component type III secretion system exports substrate proteins of both the bacterial flagellum and virulence-associated injectisome system of many Gram-negative pathogens. The type-III secretion system is primarily a pmf-driven protein exporter. Here, I describe methods to investigate the export of substrate proteins into the culture supernatant under conditions that manipulate the pmf. PMID- 28667629 TI - Identification of Effectors: Precipitation of Supernatant Material. AB - Bacterial secretion systems allow the transport of proteins, called effectors, as well as external machine components in the extracellular medium or directly into target cells. Comparison of the secretome, i.e. the proteins released in the culture medium, of wild-type and mutant cells provides information on the secretion profile. In addition, mass spectrometry analyses of the culture supernatant of bacteria grown in liquid culture under secreting conditions allows the identification of secretion system substrates. Upon identification of the substrates, the secretion profile serves as a tool to test the functionality of secretion systems. Here we present a classical method used to concentrate the culture supernatant, based on trichloroacetic acid precipitation. PMID- 28667630 TI - Screening for Secretion of the Type VI Secretion System Protein Hcp by Enzyme Linked Immunosorbent Assay and Colony Blot. AB - The bacterial type VI secretion system (T6SS) is a secretory apparatus encoded by many Gram-negative bacteria. The T6SS facilitates the secretion and injection of toxic effector proteins into host cells, providing a competitive advantage to bacteria encoding this machinery. The activity of the T6SS can be monitored by probing for the conserved tubule component Hcp, which is secreted to the supernatants by the T6SS. Detection of Hcp in culture supernatants is indicative of an active T6SS, but this secretion system is often tightly regulated or inactive under laboratory conditions and different bacterial strains display differing Hcp secretion phenotypes. Herein, we describe an enzyme-linked immunosorbent assay (ELISA) and colony blot methods to facilitate large-scale screening of isolates for Hcp secretion and, thus, T6SS activity. PMID- 28667631 TI - Effector Translocation: Cya Reporter Assay. AB - An accurate and complete roster of the Type III effector (T3E) proteins translocated by the P. syringae Type III secretion system (T3SS) into host cells is critical to understanding the pathogen's interactions with plants. The adenylate cyclase (Cya) reporter offers a highly sensitive and robust assay for monitoring the translocation of T3Es. T3Es are fused to the calmodulin-dependent adenylate-cyclase domain of CyaA. The T3E targets Cya for translocation through the T3SS into the host cell at which point it is activated by calmodulin and converts adenosine triphosphate into cyclic adenosine monophosphate (cAMP). The T3SS translocation-dependent increase in cAMP concentration in plant cells is then measured with an enzyme-linked immunosorbent assay kit. The Cya reporter can be used to determine whether a candidate protein is translocated by T3SS or to measure relative levels of T3SS translocation in a semiquantitative manner. PMID- 28667632 TI - Monitoring Effector Translocation using the TEM-1 Beta-Lactamase Reporter System. AB - Among the bacterial secretion systems, the Type III, IV, and VI secretion systems enable bacteria to secrete proteins directly into a target cell. This specific form of secretion, referred to as translocation, is essential for a number of pathogens to alter or kill targeted cells. The translocated proteins, called effector proteins, can directly interfere with the normal processes of the targeted cells, preventing elimination of pathogens and promoting their multiplication. The function of effector proteins varies greatly depending on the considered pathogen and the targeted cell. In addition, there is often no magic bullet, and the number of effector proteins can range from a handful to hundreds, with, for instance, a substrate of over 300 effector proteins of the Icm/Dot Type IV secretion system in the human pathogen Legionella pneumophila. Identifying, detecting, and monitoring the translocation of each of the effector proteins represents an active field of research and is key to understanding the bacterial molecular weaponry. Translational fusion of an effector with a reporter protein of known activity remains the best method to monitor effector translocation. The development of a fluorescent substrate for the TEM-1 beta-lactamase has turned this antibiotic-resistant protein into a highly versatile reporter system for investigating protein transfer events associated with microbial infection of host cells. Here we describe a simple protocol to assay the translocation of an effector protein by the Icm/Dot system of the human pathogen Legionella pneumophila. PMID- 28667633 TI - Effector Translocation Assay: Differential Solubilization. AB - The identification of effector proteins delivered into mammalian host cells by bacterial pathogens possessing syringelike nanomachines is an important step toward understanding the mechanisms underlying the virulence of these pathogens. In this chapter, we describe a method based on mammalian tissue culture infection models where incubation with a nonionic detergent (Triton X-100) enables solubilization of host cell membranes but not of bacterial membranes. This allows the isolation of a Triton-soluble fraction lacking bacteria but enriched in proteins present in the host cell cytoplasm and plasma membrane. Using appropriate controls, this fraction can be probed by immunoblotting for the presence of bacterial effector proteins delivered into host cells. PMID- 28667634 TI - Quantitative Determination of Anti-bacterial Activity During Bacterial Co culture. AB - Anti-bacterial activity assays are an important tool in the assessment of the ability of one bacterium to kill or inhibit the growth of another, for example during the study of the Type VI secretion system (T6SS) and the anti-bacterial toxins it secretes. The method we describe here can detect the ability of a bacterial strain to kill or inhibit other bacterial cells in a contact-dependent manner when co-cultured on an agar surface. It is particularly useful since it enumerates the recovery of viable target cells and thus enables quantification of the anti-bacterial activity. We provide a detailed description of how to measure the T6SS-dependent anti-bacterial activity of a bacterium such as Serratia marcescens against a competitor prokaryotic organism, Escherichia coli, and also describe possible variations in the method to allow adaptation to other attacker and target organisms. PMID- 28667636 TI - Assessment of phytoremediation ability of Coriander sativum for soil and water co contaminated with lead and arsenic: a small-scale study. AB - A study was conducted to access the phytoremediation potential of Coriandrum sativum for lead (Pb) and Arsenic (As). Metal tolerance index and pot experiment were conducted. Viable seeds were spread on filter paper and planted in soil placed in pots. The amount of Pb and As in control and in tailing soil was 0.27, 0.141, 1.77, and 0.35 ppm. The study was carried out in triplicates for a period of 4 weeks under natural conditions. The physico-chemical properties of soil were determined using the standard methods. Germination of seeds of Coriander sativum was inhibited more rigorously in filter paper as compared to soil medium. Shoot height and root length were significantly reduced in filter paper medium under Pb and As stress. These were inhibited by 33 and 40%, respectively, from the first to fourth weeks. Seedling growth was less affected in soil medium while greatly reduced in filter paper medium. Soil sustained almost equal stress in the fourth week as compared to the third week in filter paper medium. Shoot height was enormously affected by Pb and As compared to root length in filter paper medium, whereas slight inhibition of growth was observed in soil medium. Coriander sativum grown in pots was effective in removing Pb and As from control and tailing soils in comparison with seeds grown on filter paper. On this basis, it could be used in restoring soil polluted with Pb and As. PMID- 28667635 TI - Genetically modified phytase crops role in sustainable plant and animal nutrition and ecological development: a review. AB - Globally, plant-derivatives especially cereals and legumes are the major staple food sources for animals. The seeds of these crops comprise of phytic acid, the major repository form of the phosphorus, which is not digestible by simple stomached animals. However, it is the most important factor responsible for impeding the absorption of minerals by plants that eventually results in less use of fertilizers that ultimately cause eutrophication in water bodies. Although abundant phosphorus (P) exists in the soils, plants cannot absorb most of the P due to its conversion to unavailable forms. Hence, additional P supplementation is indispensable to the soil to promote crop yields which not only leads to soil infertility but also rapid depletion of non-renewable P reservoirs. Phytase/phosphatase enzyme is essential to liberate P from soils by plants and from seeds by monogastric animals. Phytases are kind of phosphatases which can hydrolyse the indigestible phytate into inorganic Phosphate (Pi) and lower myo inositol. There are several approaches to mitigate the problems associated with phytate indigestibility. One of the best possible solutions is engineering crops to produce heterologous phytase to improve P utilization by monogastric animals, plant nutrition and sustainable ecological developments. Previously published reviews were focused on either soil phytate or seed-phytate, related issues, but this review will address both the problems as well as phytate related ecological problems. This review summarizes the overall view of engineered phytase crops and their role in sustainable agriculture, animal nutrition and ecological development. PMID- 28667637 TI - Proteomic approaches in microalgae: perspectives and applications. AB - Biofuels are the promising sources which are produced by various microalgae or in the form of metabolic by-products from organic or food waste products. Microalgae have been widely reported for the production of biofuels since these have a high storage of lipids as triacylglycerides, which can mainly be converted into biofuels. Recently, products such as biodiesel, bioethanol and biogas have renewed the interest toward the microalgae. The proteomics alone will not pave the way toward finding an ideal alga which will fulfill the current energy demands, but a combined approach of proteomics, genomics and bioinformatics can be pivotal for a sustainable solution. The present review emphasizes various technologies currently involved in algal proteomics for the efficient production of biofuels. PMID- 28667638 TI - Organic carbon and nitrogen availability determine bacterial community composition in paddy fields of the Indo-Gangetic plain. AB - Soil quality is an important factor and maintained by inhabited microorganisms. Soil physicochemical characteristics determine indigenous microbial population and rice provides food security to major population of the world. Therefore, this study aimed to assess the impact of physicochemical variables on bacterial community composition and diversity in conventional paddy fields which could reflect a real picture of the bacterial communities operating in the paddy agro ecosystem. To fulfill the objective; soil physicochemical characterization, bacterial community composition and diversity analysis was carried out using culture-independent PCR-DGGE method from twenty soils distributed across eight districts. Bacterial communities were grouped into three clusters based on UPGMA cluster analysis of DGGE banding pattern. The linkage of measured physicochemical variables with bacterial community composition was analyzed by canonical correspondence analysis (CCA). CCA ordination biplot results were similar to UPGMA cluster analysis. High levels of species-environment correlations (0.989 and 0.959) were observed and the largest proportion of species data variability was explained by total organic carbon (TOC), available nitrogen, total nitrogen and pH. Thus, results suggest that TOC and nitrogen are key regulators of bacterial community composition in the conventional paddy fields. Further, high diversity indices and evenness values demonstrated heterogeneity and co-abundance of the bacterial communities. PMID- 28667639 TI - Flavonoid-rich agro-industrial residues for enhanced bacterial laccase production by submerged and solid-state fermentation. AB - Laccases have potential applications in industrial, biotechnological, and environmental set ups. Development of cost effective and efficient production technologies has gained significant attention in recent years. To enhance the laccase production from Rheinheimera sp. (Gram negative) using submerged fermentation (SmF) and from Lysinibacillus sp. (Gram positive) using solid-state fermentation (SSF), the inducing effect of various flavonoid-rich agro-industrial residues was investigated. Peels of citrus fruits, soybean meal, tofu dreg, lignin monomers, and lingo-cellulosic waste, used tea leaves and peels of onion and kiwi, paper, and dying industry effluents were tested as inducers. In SmF, 0.1% of soybean meal, tofu dreg, and powdered orange peel were best, enhancing the laccase production 2.57-, 2.11-, and 2.05-fold, respectively. In SSF, 10 mg (w/w) of used tata acti green tea leaves per 5 g of wheat bran, 1% pulp and paper industry effluent (agro based), and 1% wine made from Sygium cumini enhanced the laccase production 2.69-, 2.61-, and 2.09-fold, respectively. These results suggest the utilization of these flavonoid and phenolic-rich waste materials to be potential enhancers of industrially important laccase production. PMID- 28667640 TI - Comparative adsorption of amylase, protease and lipase on ZnFe2O4: kinetics, isothermal and thermodynamics studies. AB - The role of enzyme engineering in biotechnology, biological and pharmaceutical process cannot be over emphasized. This study compared the adsorption of digestives enzymes; amylase, protease and lipase on to Zn-ferrite (ZnFe2O4). The metal ferrite was synthesized via a sol-gel technique and characterized with scanning electron microscopy (SEM), X-ray diffraction (XRD), Electron paramagnetic resonance (EPR) and Fourier transform infrared spectroscopy (FTIR). The adsorption was studied in a batch process and the data were subjected to kinetics and isotherm models. Characterization shows that the particle has a nanoporous structure, with pore sizes of about 5.4 nm and good magnetic properties. The FTIR data showed the presence of M-O bond, which is a characteristic of metal ferrites. The adsorption of the amylase, lipase and protease on ZnFe2O4 follow first-order kinetic model with rate constants increasing with concentration. The maximum adsorption capacities as revealed by the generalized adsorption isotherms are 7.20, 42.90 and 22.24 mg g-1 for amylase, lipase and protease, respectively, with cooperative binding. The Dubinin Radushkevich model gave the maximum adsorption energies, E of 3.74 kJ mol-1 for amylase, 2.01 kJ mol-1 for lipase and 1.51 kJ mol-1 for the protease adsorption, showing that the process is physisorption dominated. The isotherms fit the adsorption data in the order of Freundlinch > Generalized > Guggenheim-Anderson de Boer > Tempkin isotherm > Dubinin-Radushkevich. Thermodynamic study revealed a spontaneous adsorption process with increased entropy. ZnFe2O4, therefore, is a very good adsorbent for the purification of enzymes and can be used as a supporter for enzymatic process that required immobilization of the enzymes. PMID- 28667641 TI - Optimization of pectinase-assisted and tri-solvent-mediated extraction and recovery of lycopene from waste tomato peels. AB - In the present work, optimization of pectinase-assisted and tri-solvent-mediated extraction of lycopene from waste tomato peels was carried out. The optimized parameters for enzymatic pre-treatment were 2% pectinase concentration, pH 5.5, 4 h incubation, 45 degrees C and 150 rpm. Maximum recovery of lycopene from tomato peels using optimized tri-solvent extraction was achieved at 45 degrees C, 120 min incubation and 200 rpm. The extracted lycopene was confirmed through functional and characteristic peaks in UV-Vis and FTIR spectra and with retention time in HPLC. The radical scavenging activity was 72.30 +/- 2.70 and 43.40 +/- 2.01 ug ascorbic acid equivalents (AAE)/ml for 1,1-diphenyl-2-picrylhydrzyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals, respectively. The optimized method resulted in 7.38, 4.65 and 1.59 times enhancement in lycopene extraction and recovery in correlation with single solvent, enzyme-treated and tri-solvent extraction methods, respectively. PMID- 28667642 TI - Optimization of nutritional components of medium by response surface methodology for enhanced production of lactase. AB - Lactase has excellent applications in dairy industry and commercially this enzyme is produced from bacterial sources but not in high yields. In this work, the production of lactase was improved by designing of nutrient components in fermentation medium by one factor at a time. Lactose and yeast extract were selected as preferable carbon and nitrogen sources for lactase production with tryptophan and MgSO4 showing enhanced production. Statistical analysis proved to be a useful and powerful tool in developing optimum fermentation conditions. The individual and interactive role of lactose, yeast extract, magnesium sulfate, and tryptophan concentration on lactase production was examined by central composite design. Submerged fermentation with Bacillus subtilis strain VUVD001 produced lactase activity of 63.54 U/ml in optimized medium. The activity was threefold higher in comparison to an unoptimized medium. This result confirmed that the designed medium was useful for producing higher yields of lactase. PMID- 28667643 TI - Upscale production of a recombinant cyclodextrin glycosyltransferase from Paenibacillus macerans in Escherichia coli. AB - Cyclodextrin glucanotransferase (CGTase) is an important enzyme with multiple functions in starch utilization. In the present study, a fermentation process for the production of CGTase from Escherichia coli harboring the recombinant plasmid pET28b(+)-CGTase was investigated and optimized. The optimal fermentation and expression conditions were 10.0 g/L glycerol, 20.0 g/L tryptone, and 10.0 g/L yeast extract with an initial pH of 7.0, an IPTG concentration of 0.1 mM and an induction temperature of 28 degrees C for 10 h. The resulting CGTase activity reached up to 36.4 U/L and was 2.1-fold higher than before optimization. Under these optimal fermentation conditions, the up-scaled fermentation was carried out in a 500-L fermentor, and a CGTase activity of 45.2 U/L was achieved. This study provides a foundation for the industrial production of CGTase. PMID- 28667644 TI - Somatic embryogenesis in guava (Psidium guajava L.): current status and future perspectives. AB - Guava (Psidium guajava L.) is a highly perishable fruit crop comparable to mango owing to its high medicinal value and intense aroma. The presence of high genetic variability limits the chances of further expansion of guava improvement using biotechnological interventions. Conventional methods of guava improvement encountered with restricted achievement in progress of disease resistant varieties because of existing high genetic variability in the germplasm. There is a considerable demand for the establishment of successful and efficient regeneration protocols via somatic embryogenesis. Plants regenerated through somatic embryogenesis could be more useful than plants obtained through organogenesis because, in most cases, somatic embryos are of single-cell origin, and have a low frequency of chimeras and a high number of regenerations. This review is a snapshot of the recent status of somatic embryogenesis as a basis for expanding genetic improvement in guava for quality traits and future perspectives using advanced technologies. PMID- 28667645 TI - Recombinant production of Aspergillus Flavus uricase and investigation of its thermal stability in the presence of raffinose and lactose. AB - Aspergillus flavus uricase (Rasburicase) with a molecular mass of 135 kDa is currently used for the treatment of gout and hyperuricemia occurring in tumor lysis syndrome. To characterize the effects of raffinose and lactose osmolytes on the uricase structure, its coding sequence was cloned, expressed in E. coli BL21, and purified by Ni-NTA agarose affinity chromatography. Thermal inactivation studies at 40 degrees C showed that nearly 15% of UOX activity was preserved, while the presence of raffinose and lactose reduced its activity to 35 and 45% of its original activity, respectively. Investigation of UOX thermal stability at 40 degrees C in the course of time showed that the enzyme relatively lost almost 60% of its original activity after 40 min, whereas more than 50% of UOX activity is preserved in the presence of lactose. Estimation of thermal inactivation rate constant, k in, showed that the UOX k in and UOX k in in the presence of raffinose was unchanged (0.018 min-1), whereas for the presence of lactose, it was 0.015 min-1. Half-life and T m analysis showed that UOX half-life is almost 38 min and addition of raffinose did not change the half-life, whereas the presence of lactose had remarkable impact on UOX half-life (46 min). The presence of raffinose increased UOX T m to a lesser extent, whereas lactose notably enhanced the T m from 27 to 37 degrees C. Overall, our findings show that lactose has protective effects on UOX stability, while for raffinose, it is relatively compromised. PMID- 28667646 TI - qPCR and HRM-based diagnosis of SNPs on growth differentiation factor 9 (GDF9), a gene associated with sheep (Ovis aries) prolificacy. AB - Prolificacy is a desirable trait for genetic improvement of sheep flocks, since it holds the potential to improve productivity. Animals carrying single nucleotide polymorphisms (SNPs) in genes associated with this trait can be identified and employed to increase prolificacy in flocks. In this study, we report a diagnostic method based on quantitative PCR and high-resolution melting curves to detect different SNPs in the prolificacy-associated gene growth differentiation factor 9 (GDF9). The diagnostic method was validated using artificial sequences representing known SNPs in GDF9, then applied to a real flock comprising four breeds and admixed animals (n = 306). Five different SNPs were identified in this flock, as was a low or null frequency of occurrence of SNPs positively associated with prolificacy. This indicates a need to implement a breeding strategy for recovering or reintroducing such SNPs. Our method provides a genotyping strategy for identifying individuals with SNPs of interest for prolificacy, which will help producers plan a breeding strategy for this trait. This method can be adapted and expanded for the diagnosis of other traits of interest. PMID- 28667647 TI - Elucidating stress proteins in rice (Oryza sativa L.) genotype under elevated temperature: a proteomic approach to understand heat stress response. AB - Rice is one of the widely consumed staple foods among the world's human population. Its production is adversely affected by high temperature and is more pronounced at flowering stage. Elucidating elevated temperature stress-related proteins as well as associated mechanisms is inevitable for improving heat tolerance in rice. In the present study, a proteomic analysis of heat-sensitive rice genotype, IET 21405 was conducted. Two-dimensional electrophoresis (2-DE) and MALDI-TOF/MS-based proteomics approaches revealed a total of 73 protein spots in rice leaf. The protein profiles clearly indicated variations in protein expression between the control and heat treated rice genotypes. Functional assessment of 73 expressed proteins revealed several mechanisms thought to be involved in high temperature including their putative role in metabolism, energy, protein synthesis, protein transport/storage, etc. Besides these, some proteins are expected to involve in photosynthesis, tricarboxylic acid (TCA) cycle, glycolysis and other proteins for energy production. The proteins identified in the present study provide a strong basis to elucidate gene function of these proteins and to explain further the molecular mechanisms underlying the adaptation of rice to high temperature stress. PMID- 28667648 TI - Combination of DNA isolation and RP-HPLC analysis method for bark samples of Saraca asoca and its adulterant. AB - DNA fingerprinting singly or in combination with phytochemical analysis is ideal for quality control of crude plant-based drugs. However, when the source material is tannin rich stem bark, extraction of DNA by conventional methods becomes challenging. In such cases, phytochemical profiling serves as very useful tool for its identification. The work herein described a method for simultaneous DNA isolation and phytochemical extraction for downstream analysis and applications from dried bark powder of Saraca asoca and commercial samples of this crude drug as well as from those of Polyalthia longifolia, its most common adulterant. It is a modified CTAB-based method which involves a pre-extraction step by soaking samples overnight in de-ionized water followed by filtration. The residues in the filter paper were used for DNA isolation and dried filtrate was used for Reverse Phase-High-Performance Liquid Chromatography analysis. Results revealed that genomic DNA isolated was PCR amplifiable with Inter Simple Sequence Repeat and Start Codon Targeted markers. Phenolic compounds of catechin, epicatechin, and gallic acid were detected from the above dried filtrate. The method is simple, reliable and it requires small amount of sample with an option of integrating both phytochemical and DNA-based profiling, from the same starting material. Therefore, the present method could be useful for further potential applications such as quality control assessment of S. asoca products. PMID- 28667649 TI - Analysis of transcription factors among differentially expressed genes induced by drought stress in Populus davidiana. AB - Populus davidiana is native to the Korean Peninsula and is one of the most dominant and abundantly growing forest trees in eastern Asia. Compared to other Populus species such as P. trichocarpa, P. euphratica, and P. tremula, relatively little is known about P. davidiana. Here, we performed transcriptomic analysis of P. davidiana under drought stress induced by 10% polyethylene glycol. A total of 12,403 and 12,414 differentially expressed genes (DEGs) were successfully annotated with the P. trichocarpa reference genome after 6 and 12 h of treatment, respectively. Of these, a total of 404 genes (238 up-regulated and 166 down regulated) after 6 h and 359 genes (187 up-regulated and 172 down-regulated) after 12 h of treatment were identified as transcription factors. Transcription factors known to be key genes for drought stress response, such as AP2-EREB, WRKY, C2H2, and NAC, were identified. This results suggesting that early induction of these genes affected initiation of transcriptional regulation in response to drought stress. Quantitative real-time PCR results of selected genes showed highly significant (R = 0.93) correlation with RNA-Seq data. Interestingly, the expression pattern of some transcription factors was P. davidiana specific. The sequence of P. davidiana ortholog of P. trichocarpa gene POPTR_0018s10230, which plays an important role in plant response to drought, was further analyzed as our RNA-Seq results showed highly significant changes in the expression of this gene following the stress treatment. Sequence of the gene was compared to P. trichocarpa gene sequence using cloning-based sequencing. Additionally, we generated a predicted 3D protein structure for the gene product. Results indicated that the amino acid sequence of P. davidiana-specific POPTR_0018s10230 is different at six different positions compared to P. trichocarpa, resulting in a significantly different structure of the protein. Identifying the transcription factors expressed in P. davidiana under drought stress will not only offer clues for understanding the underlying mechanisms involved in drought stress physiology but also serve as a basis for future molecular studies on this species. PMID- 28667650 TI - Bacopaside N1 biosynthetic potential of endophytic Aspergillus sp. BmF 16 isolated from Bacopa monnieri. AB - Chemically unique environment of endophytes makes them to have various adaptive mechanisms for survival. One of such mechanisms involves the production of pharmacologically significant plant-specific metabolites. In the present study, 26 endophytic fungi were isolated from stem of Bacopa monnieri (L.) Wettst. plants. All the isolates were screened for bacopaside production property by HPLC. Among these, the fungal isolate BmF 16 which was identified as Aspergillus sp. was confirmed for bacopaside N1 production (m/z 796) by LC-MS/MS analysis. As the extract of BMF16 used in the study was prepared from the fifth generation of culture, the obtained result can be confirmed as due to fungal production of bacopaside. In addition, this property was identified only for one among the 26 fungi screened. As bacopaside N1 production in fungi has not yet been reported, the results of the study are novel. PMID- 28667651 TI - Degradation and conversion of endosulfan by newly isolated Pseudomonas mendocina ZAM1 strain. AB - Endosulfan contamination is one of the major concerns of soil ecosystem, which causes detrimental effects not only to humans but also to animals and plants. Therefore, the aim of this study was to isolate and identify a novel bacterial strain capable of degrading endosulfan in agriculture contaminated soils. A novel bacterial strain was isolated from the sugarcane field contaminated with endosulfan, and was named as ZAM1 strain. The ZAM1 bacterial strain was further identified as Pseudomonas mendocina based on the biochemical and molecular analysis. 16sRNA sequence analysis of ZAM1 strain shows maximum similarity with known endosulfan-degrading bacteria (Pseudomonas putida), respectively. Enrichment was carried out using the endosulfan as sole sulfur source. The ZAM1 strain was able to use alpha and beta endosulfan as a sole sulfur source. Our results showed that ZAM1 strain degrades endosulfan >64.5% (50 mg/l) after 12 days of incubation. The residues were analyzed by GC-MS analysis and confirmed the formation of metabolites of dieldrin, 2 heptanone, methyl propionate, and endosulfan lactone compounds. Hence, these results indicate that the ZAM1 strain is a promising bacterial source for detoxification of endosulfan residues in the environment. PMID- 28667652 TI - Biomineralisation of fipronil and its major metabolite, fipronil sulfone, by Aspergillus glaucus strain AJAG1 with enzymes studies and bioformulation. AB - Fipronil is a phenylpryazole insecticide which is extensively used for the protection of agricultural yields. However, this insecticide poses various threats to the environment. Therefore it is essential to develop an effective method to degrade or eliminate this pollutant from the environment. In this present study, a fungal strain AJAG1 capable of degrading fipronil and its metabolite, fipronil sulfone, was isolated through enrichment technique. Isolated fungal strain was identified as Aspergillus glaucus based upon its morphological, and 18S rRNA sequence analysis. Strain AJAG1 could degrade 900 mg L-1 of fipronil efficiently in both aqueous medium and soil. In addition, fipronil degradation was tested with various kinetic models and the results revealed that biodegradation in aqueous medium and soil was ascertained by pseudo-first order and zero order rate kinetics, respectively. The infrared spectrum of fipronil degraded sample confirmed the formation of esters, nitro, and alkanes groups. A tentative degradation pathway of fipronil by strain AJAG1 has been proposed on the basis of gas chromatography-mass spectrometry (GC-MS) analysis. The lignolytic enzymes activities were studied during fipronil degradation by strain AJAG1. Further, scanning electron microscopy (SEM) was used to examine the surface morphology of strain AJAG1 after fipronil degradation. In the present investigation, bioformulation of strain AJAG1 was developed using low cost materials such as groundnut shell powder, molasses, and fly ash to remediate the fipronil from agricultural field. These results highlight A. glaucus strain AJAG1 may have potential for use in bioremediation of fipronil-contaminated environment. PMID- 28667653 TI - Occurrence of bronchial anthracofibrosis in respiratory symptomatics with exposure to biomass fuel smoke. AB - INTRODUCTION: Bronchial anthracofibrosis (BAF), confirmed bronchoscopically, is characterised by bluish-black mucosal pigmentation and distortion/narrowing of the bronchus. We investigated the occurrence of BAF in respiratory symptomatics with biomass fuel smoke exposure and evaluated its clinico-radiological attributes and impact on functional status. MATERIAL AND METHODS: Of the eighty subjects evaluated, 60 consented for fiberoptic bronchoscopy (FOB). All 60 subjects also underwent chest radiography, high resolution computed tomography (HRCT) of the thorax, complete pulmonary function testing including diffusion capacity and six-minute-walk test. Information regarding cardinal respiratory symptoms and duration of biomass fuel smoke exposure was documented. FOB evaluation revealed that 24 patients had BAF (Group 1), 17 had bronchial anthracosis (Group 2) and 19 had normal appearance (Group 3). RESULTS: Group 1 patients had significantly higher biomass fuel smoke exposure (p < 0.0001), lower mean post bronchodilator FEV1/FVC values (P = 0.02) and lower walk distance (p = 0.003) with greater desaturation. On HRCT, segmental collapse and consolidation were significantly higher in Group 1 while fibrotic lesions were the predominantly seen in Groups 2 and 3. A significant inverse correlation in Group 1 was seen between exposure index, six-minute-walk distance and spirometric parameters. In Group 1, the right middle lobe (RML) bronchus was most commonly involved (15/24 [62.5%]). In Group 2, RML and left upper lobe bronchi were affected in 8/17 (47.1%) patients each. CONCLUSIONS: All patients in our study were females. Those with BAF had poorer lung functions and functional status as compared to those with anthracosis only. On imaging, multifocal bronchial narrowing was specific to BAF. . PMID- 28667654 TI - Idiopathic pulmonary fibrosis (IPF) - common practice in Poland before the "antifibrotic drugs era". AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and debilitating lung disease with a median survival time of 3-5 years. For now, pirfenidone (PIR) and nintedanib (NTB) are the only drugs that can slow down the disease's progression. In Poland, these drugs, although registered for legal use, had not been reimbursed for IPF patients until the end of the year 2016. Aim of the study was to assess what was common practice in terms of diagnosis and treatment in the period before antifibrotic drugs became available for IPF patients in Poland. MATERIAL AND METHODS: We performed a survey among participants of two nationwide pulmonological congresses held in 2016. RESULTS: One hundred and fifty physicians took part in the study. Only 55% of respondents would reach their final diagnosis in collaboration with a radiologist. Just 40% of those sending patients for surgical lung biopsy (SLB) would discuss the case directly with a pathologist. 22% would never refer the patient suspected of having IPF for SLB. 85% believed that bronchoalveolar lavage (BAL) may be useful for diagnosis. 41% of respiratory professionals would not use any drug for the treatment of IPF patients. 23% of physicians would prescribe corticosteroids in high doses (CS), either in monotherapy or in combination with other drugs. Only 43% of respondents would use antacid drugs in case of symptomatic gastro oesophageal reflux disease (GERD), and only 11% would prescribe these drugs regardless of GERD diagnosis. CONCLUSIONS: The majority of Polish pulmonologists were not supported by radiologists and pathologists in the diagnostic process. Treatment standards were unsatisfactory, mostly due to a lacking of reimbursement regulations. Further education is necessary to improve management of IPF patients in Poland. PMID- 28667655 TI - Public spirometry campaign in chronic obstructive pulmonary disease screening - hope or hype? AB - INTRODUCTION: Underdiagnosis of COPD seems to be a relevant clinical and social problem. We hypothesized that active public spirometry campaign may help identify subjects with airflow limitation consistent with COPD. The aim of the study was (1) to evaluate the willingness of random smokers to undergo public spirometry, (2) to assess the ability to obtain an acceptable quality spirometry during a public campaign, and (3) to assess the relationships between the presence and severity of respiratory symptoms and readiness to undergo spirometry. MATERIAL AND METHODS: Pedestrians aged > 40 years and a smoking history >10 pack-years were recruited by medical students to fill a questionnaire and perform spirometry. Those with obstructive or borderline ventilatory insuffciency were invited and encouraged to undergo stationary spirometry in a pulmonary outpatient department. RESULTS: Nine hundred and five subjects meeting the inclusion criteria were invited to the study. Only 178 subjects agreed to complete the questionnaire and undergo spirometry. Airway obstruction and borderline spirometry result (classified as possible airway obstruction) were found in 22 and 37 subjects, respectively. Of these, only 15 patients attended follow-up visit to verify public spirometry results. Extrapolation of the limited data showed the incidence of newly diagnosed airway obstruction as 10.7%. CONCLUSION: Public spirometry campaign does not seem to be an effective way of COPD screening. Smokers are reluctant to undergo complimentary spirometry even in the presence of pronounced respiratory symptoms. Our observations may be helpful in elaborating future screening programs for COPD. PMID- 28667656 TI - A rare case of community acquired serratia lung abscess in a patient with cardiac bronchus. AB - The incidence of lung abscess caused by Serratia marcescens is extremely low and is only reported in the immunocompromised population. We present a previously healthy woman with Serratia lung abscess in close proximity with an accessory cardiac bronchus. The patient was treated with appropriate antibiotics which led to complete resolution of the lesion. Our case highlights that individuals without medical co-morbidities may develop atypical lung infections like Serratia when associated with anatomic anomalies. PMID- 28667657 TI - Tracheal bronchus presenting with recurrent haemoptysis in an adult female. AB - Abnormal bronchus arising directly from the trachea or the main bronchus is a rare developmental anomaly of the tracheobronchial tree. In general, tracheal bronchus has been reported in less than 1% of adult patients undergoing bronchoscopy with a male predominance. Tracheal bronchus is classified as - 'displaced' and 'supernumerary', the former being the most common type reported. Most patients are asymptomatic; however, cases presenting with cough, haemoptysis or recurrent lung infections are not uncommon. The diagnosis is usually made through computed tomography or bronchoscopy. Awareness of this anomaly may help in timely identification or prevention of perioperative complications during general anaesthesia or resectional thoracic surgery. Herein we report a case of right-sided displaced tracheal bronchus in an adult female presenting with recurrent haemoptysis. PMID- 28667658 TI - Tracheobronchopathia osteochondroplastica - a 61-year-old female with middle lobe syndrome. AB - The authors present a case of a 61-year-old female patient suffering from tracheobronchopathia osteochondroplastica (TBO). Etiology of this unit is uncertain. TBO is characterised by presence of multiple nodules of various size, situated in the submucosa of the trachea and major bronchi. The course is usually benign, until lesion obstructs the bronchial lumen. In the presented case, occluded middle lobe bronchi resulted in peripheral atelectasis of the lung. PMID- 28667659 TI - Respiratory system involvement in inflammatory bowel diseases. AB - Inflammatory bowel diseases are systemic disorders that can manifest in any location. The problem of respiratory system involvement is very important form clinical point of view. In the article we try to systematize the current knowledge on this topic. PMID- 28667660 TI - Signaling pathways and their miRNA regulators involved in the etiopathology of idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP). AB - Idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) belong to heterogenic group of interstitial lung diseases (ILD). For the reason that this group of diseases present with complex clinical non-specific features, they represent a diagnostic and therapeutic challenge. In this review we focus on several crucial signaling pathways participating in inflammation, fibrosis and EMT processes, so important in the course of ILD: TNF-alpha/NFkappabeta, TGF beta/SMAD, Wnt-beta-catenin and PI3K-Akt signaling. Moreover, this review summarizes the role of selected signaling pathways and some miRNAs which are their regulators during development and progression of IPF and HP. Recent advances indicate the potential role of miRNAs as a molecular markers differentiating clinical course of ILD. PMID- 28667661 TI - Recovery and immune priming modulate the evolutionary trajectory of infection induced reproductive strategies. AB - In response to parasite exposure, organisms from a variety of taxa undergo a shift in reproductive investment that may trade off with other life-history traits including survival and immunity. By suppressing reproduction in favour of somatic and immunological maintenance, hosts can enhance the probability of survival and recovery from infection. By plastically enhancing reproduction through terminal investment, on the other hand, hosts under the threat of disease induced mortality could enhance their lifetime reproductive fitness through reproduction rather than survival. However, we know little about the evolution of these strategies, particularly when hosts can recover and even bequeath protection to their offspring. In this study, we develop a stochastic agent-based model that competes somatic maintenance and terminal investment strategies as they trade off differentially with lifespan, parasite resistance, recovery and transgenerational immune priming. Our results suggest that a trade-off between reproduction and recovery can drive directional selection for either terminal investment or somatic maintenance, depending on the cost of reproduction to lifespan. However, some conditions, such as low virulence with a high cost of reproduction to lifespan, can favour diversifying selection for the coexistence of both strategies. The introduction of transgenerational priming into the model favours terminal investment when all strategies are equally likely to produce primed offspring, but favours somatic maintenance if it confers even a slight priming advantage over terminal investment. Our results suggest that both immune priming and recovery may modulate the evolution of reproductive shift diversity and magnitude upon exposure to parasites. PMID- 28667662 TI - Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor. AB - A series of thiazole-based inhibitors selectively targeting DNA-binding domain of the androgen receptor (AR) were synthesized and evaluated, and the SAR data were summarized. We identified a novel compound SKLB-C2807 that effectively inhibited the human prostate cancer cell line LNCaP/AR with the IC50 value of 0.38 MUm without significant antiproliferative effects on other cell lines PC-3 (AR negative), SW620, MCF-7 (ER-positive), and L-O2 (non-cancerous). This compound also considerably decreased the expression of prostate-specific antigen. Its binding mode to the AR-DBD was studied. These efforts lay the foundation for developing the next generation of anti-androgens. PMID- 28667663 TI - Neuromuscular ultrasound findings in distal acquired demyelinating symmetric variant of chronic inflammatory demyelinating polyneuropathy. PMID- 28667664 TI - Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants. AB - The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo-interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC-C0 target at 1-year 6-10 ng/ml) and reduced MMF dose (500 mg bid at 1-year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC-C0 (target 3-7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC C0 in the early (OR: 0.75, 95% CI: 0.61-0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50-0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83-0.98; P = 0.0101) and with low TAC-C0 in late biopsies (OR: 0.77, 95% CI: 0.61-0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC-C0 or MMF dose in the multivariate analysis. Our data suggest that in TAC- and MMF-based regimens, TAC-C0 levels are associated with subclinical inflammation in patients receiving reduced MMF dose. PMID- 28667665 TI - Relationship between portopulmonary hypertension and splenectomy: Mayo Clinic experience and review of published works. AB - AIM: Portopulmonary hypertension is a serious complication of portal hypertension that can lead to right heart failure and death. To our knowledge, an association between portopulmonary hypertension and prior splenectomy has not been described previously. The goals of this study were to describe the frequency of splenectomy in portopulmonary hypertension and compare selected parameters between portopulmonary hypertension subgroups. METHODS: This is a retrospective analysis of patients diagnosed with portopulmonary hypertension between 1 January 1988 and 30 June 2015 at Mayo Clinic (Rochester, MN, USA). We compared age, sex, right ventricle systolic pressure by echocardiography, and right heart catheterization measurements/calculations among subgroups of portopulmonary hypertension patients with splenectomy and/or autoimmune liver disease (autoimmune hepatitis/primary biliary cirrhosis/primary sclerosing cholangitis). RESULTS: The cohort consisted of 141 patients, of whom 8 (6%) had a history of splenectomy prior to the development of portopulmonary hypertension. Twenty-seven (19%) portopulmonary hypertension patients had autoimmune liver disease, and 5 of 8 (62.5%) splenectomized portopulmonary hypertension patients had autoimmune liver disease. No significant difference was noted in right heart catheterization measurements/calculations between splenectomized and non-splenectomized portopulmonary hypertension patients. Right ventricle systolic pressure by echocardiography was significantly higher in those splenectomized. CONCLUSIONS: Prior history of splenectomy in portopulmonary hypertension was 6% in this cohort. The combination of autoimmune liver disease and splenectomy in portopulmonary hypertension was not uncommon. History of splenectomy in patients with portal hypertension and/or autoimmune liver disease may have clinical implications. PMID- 28667667 TI - Theoretical study on selectivity trends in (N-heterocyclic carbene)-Pd catalyzed mizoroki-heck reactions: Exploring density functionals methods and molecular models. AB - The regioselectivity of the NHC-Pd catalyzed Heck coupling reaction between phenyl bromide and styrene has been investigated using the density functional theory, wave-function (WF)-based methods and two different sizes of model ligands. In addition to the WF methods, the TPSS-D3, omega B97X-D, BP86-D3, and M06-L density functionals were reliable approaches to be applied, independently of the basis set. Moreover, the NCI analysis showed that weak interactions are important forces to be taken into account when exploring the regioselectivity of this reaction, mainly when a crowded NHC ligand is present. (c) 2017 Wiley Periodicals, Inc. PMID- 28667668 TI - Assessment of arterial function in pregnancy: recommendations of the International Working Group on Maternal Hemodynamics. AB - There is strong evidence supporting the role of maternal arterial dysfunction in pregnancy-specific disorders such as pre-eclampsia and intrauterine growth restriction. As more work is focused towards this field, it is important that methods and interpretation of arterial function assessment are applied appropriately. Here, we summarize techniques and devices commonly used in maternal health studies, with consideration of their technical application in pregnant cohorts. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28667670 TI - Preparation, characterization, and in vitro evaluation of isoniazid and rifampicin-loaded archaeosomes. AB - The ability of Archaea to adapt their membrane lipid compositions to extreme environments has brought in archaeosomes into consideration for the development of drug delivery systems overcoming the physical, biological blockades that the body exhibits against drug therapies. In this study, we prepared unilamellar archaeosomes, from the polar lipid fraction extracted from Haloarcula 2TK2 strain, and explored its potential as a drug delivery vehicle. Rifampicin and isoniazid which are conventional drugs in tuberculosis medication were loaded separately and together in the same archaeosome formulation for the benefits of the combined therapy. Particle size and zeta potential of archaeosomes were measured by photon correlation spectroscopy, and the morphology was assessed by with an atomic force microscope. Encapsulation efficiency and loading capacities of the drugs were determined, and in vitro drug releases were monitored spectrophotometrically. Our study demonstrates that rifampicin and isoniazid could be successfully loaded separately and together in archaeosomes with reasonable drug-loading and desired vesicle-specific characters. Both of the drugs had greater affinity for archaeosomes than a conventional liposome formulation. The results imply that archaeosomes prepared from extremely halophilic archaeon were compatible with the liposomes for the development of stable and sustained release of antituberculosis drugs. PMID- 28667666 TI - Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies. AB - The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proved to be resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the National Institute of Mental Health Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia and Research Domain Criteria initiatives) are an important step towards standardization of outcome measures that can be used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc. PMID- 28667669 TI - Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice. AB - Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Abeta) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreERT2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams). We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 * ArcCreERT2 * channelrhodopsin (ChR2) enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control (Ctrl) mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD. PMID- 28667671 TI - Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors. AB - The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short-term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2 3, dentate gyrus (DG)-CA4, stratum radiatum-lacunosum-moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale-third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG CA4, CA1, CA2-3, and stratum radiatum-lacunosum-moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG-CA4, CA1, and stratum radiatum-lacunosum-moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood. PMID- 28667672 TI - Is cystic artery lymph node excision during laparoscopic cholecystectomy a marker of technique? AB - BACKGROUND: In order to minimize bile duct injury, experts suggest that dissection during laparoscopic cholecystectomy (LC) should be performed lateral to the lymph node (LN). This study aims to determine whether the frequency of excision of the LN is related to patient factors, disease severity or surgical difficulty. METHODS: All LCs performed or supervised by one surgeon were identified from a prospective database. The presence of LN was retrospectively determined by reviewing the gallbladder histology report. RESULTS: The LN was identified in 10.4% of 1332 cholecystectomies. The American Society of Anesthesiologists class 3 was associated with a lower rate of LN excision compared with class 1 (odds ratio: 0.36; P = 0.049) as was the presence of a senior surgical trainee (odds ratio: 0.18; P < 0.001). Rate of LN excision was independent of patient demographic and clinical characteristics, including indication for cholecystectomy, conversion to open, gallbladder perforation, cholangiography, bile duct exploration and overall surgical difficulty. CONCLUSIONS: The frequency with which the LN is excised during LC by the one surgeon is independent of the majority of clinical and surgical factors and may represent a surrogate marker of surgical technique. Whether this is related to the rate of bile duct injury remains to be determined. PMID- 28667673 TI - On the Presence of the Patella in Frogs. AB - The patella is one of the most studied sesamoids. Historically, the patella is described as a big sesamoid embedded in the tendon of the quadriceps femoris muscle. This sesamoid is studied from developmental, functional, clinical, and anatomical perspectives. The presence of a patella is reported in squamatans, birds, and mammals. Lissamphibians are identified as the major lineage that fail to develop a patella. However, this sesamoid is reported at least once in anurans, but without detailed anatomical discussions. Through anatomical and histological studies we examined the topography and tissue composition of two structures that we identify as the proximal and distal patellae in several anuran species. We explored the evolution of these sesamoids through ancestral state reconstruction, finding that they are ancestral for amphibians and possibly tetrapods as a whole. The presence of these patellae in anurans would roll back their origin to the last common ancestor of tetrapods. From a functional perspective, the overwhelming evidence of fibrocartilage as a clear response to compression suggests that the fibrocartilaginous patellae could also withstand the mechanical stress generated on the knee undergoing compression during limb extension. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1747 1755, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28667674 TI - Micro-CT assessment of the shaping ability of four root canal instrumentation systems in oval-shaped canals. AB - AIM: To compare the shaping ability of four root canal instrumentation systems in oval-shaped canals using micro-computed tomographic analysis. METHODOLOGY: Forty anatomically matched mandibular incisors were scanned and assigned to four groups (n = 10), according to the canal preparation protocol: BioRace, Reciproc, Self Adjusting File (SAF) and TRUShape systems. After canal instrumentation, the specimens were rescanned, and the registered pre- and postoperative datasets were examined to evaluate the percentages of accumulated hard-tissue debris, untouched canal walls and dentine removed. Kruskal-Wallis and Mann-Whitney U-tests with Bonferroni correction were used to compare the variables in the groups (alpha = 5%). RESULTS: The preparation techniques did not affect the percentage of accumulated hard-tissue debris (P = 0.126). The percentage of untouched canal areas was significantly higher for BioRace (32.38%)compared to Reciproc (18.95%) and SAF (16.08%) systems (P < 0.05). Reciproc removed significantly more dentine (4.18%) than BioRace (2.21%) and SAF (2.56%) (P < 0.05). The TRUShape system had intermediate results for both untouched canal walls (19.20%) and dentine removed (3.77%), with no significant difference compared to BioRace, Reciproc and SAF systems. CONCLUSIONS: The preparation techniques resulted in the same level of accumulated hard-tissue debris. Compared to the other tested systems, BioRace was associated with more untouched canal walls and Reciproc produced the greatest amount of removed dentine. Although it touched more of the root canal walls, the SAF system removed less dentine, whereas TRUShape had intermediate results for these same parameters. None of the systems tested were able to provide optimal shaping ability in oval-shaped canals. PMID- 28667675 TI - D-512, a novel dopamine D2/3 receptor agonist, demonstrates greater anti Parkinsonian efficacy than ropinirole in Parkinsonian rats. AB - BACKGROUND AND PURPOSE: Symptoms of Parkinson's disease are commonly managed using selective dopamine D2/3 receptor agonists, including ropinirole. While D2/3 agonists are useful in early-stage Parkinson's disease, they tend to lose efficacy in later disease stages and do not appear to modify disease progression. We have recently developed a novel 'multifunctional' compound, D-512: a high affinity D2/3 receptor agonist with antioxidant and other neuroprotective properties that may limit Parkinson's disease progression. This study sought to compare the anti-Parkinsonian properties of the clinically used compound, ropinirole, with those of the novel compound, D-512. EXPERIMENTAL APPROACH: A rat model of Parkinson's disease was created by unilaterally infusing 6 hydroxydopamine, a dopamine neurotoxin, into the medial forebrain bundle. D-512 was compared with ropinirole for ability to stimulate spontaneous motor activity and reverse Parkinsonian akinesia. These beneficial effects were compared against each drug's liability to provoke dyskinesia, a common motor side effect. KEY RESULTS: Both compounds increased spontaneous movement, but D-512 showed a longer duration of action. Only D-512 was able to significantly reverse forelimb akinesia. Drug-induced dyskinesia was similar for equivalent doses. CONCLUSIONS AND IMPLICATIONS: Compared with ropinirole, D-512 showed greater peak-dose efficacy and a longer duration of action, despite a similar side-effect profile. Our results add to earlier data showing that D-512 is superior to available D2/3 agonists and could merit clinical investigation. PMID- 28667677 TI - Resting heart rate, guilt, and sympathy: A developmental psychophysiological study of physical aggression. AB - Although low resting heart rate has been linked to frequent aggressive conduct in childhood, little is known about the interaction of this biological risk with social emotions that protect against aggression across development. With a sample of 5-, 8-, and 12-year-olds (N = 110), we tested whether the negative link between resting heart rate and physical aggression was offset by high guilt and sympathy. Caregivers reported their children's physical aggression and sympathy. Children's electrocardiogram data were collected while they viewed a nondescript video, after which they reported their guilt-or lack thereof-in response to vignettes depicting social transgressions. Lower resting heart rate was significantly associated with higher physical aggression in 5-year-olds who reported low-but not medium and high-levels of guilt, and in 8-year-olds with low but not medium and high-ratings of sympathy. Neither guilt nor sympathy moderated the resting heart rate-physical aggression link in 12-year-olds. We discuss how social emotions may help children with low resting heart rates navigate social conflicts and avoid aggressive physical confrontations. PMID- 28667676 TI - Cannabinoids prevent the differential long-term effects of exposure to severe stress on hippocampal- and amygdala-dependent memory and plasticity. AB - Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light-dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long term potentiation (LTP) in the CA1, (iii) impaired hippocampal-dependent short term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala-dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55-212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal- and amygdala-dependent processes. Moreover, the effects of WIN55-212,2 and URB597 on Ext and acoustic startle were prevented by co-administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55-212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala. PMID- 28667678 TI - Effects of photodynamic therapy in periodontal treatment: A randomized, controlled clinical trial. AB - AIM: To evaluate the effects of photodynamic therapy (PDT) in the nonsurgical treatment of chronic periodontitis. MATERIALS AND METHODS: A randomized, single blind, controlled, parallel-group clinical trial was performed. Sixty patients were enrolled: 20 healthy controls and 40 patients with periodontitis. The 40 patients were randomized for scaling and root planing (SRP) or SRP + PDT. Periodontal (plaque index, probing depth, clinical recession, clinical attachment level, bleeding on probing and gingival crevicular fluid volume, corresponding to 381 versus 428 critical sites), microbiological (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia and Campylobacter rectus presence, 18 versus 19 samples) and biochemical (interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)-alpha, receptor activator of nuclear factor-kappaB ligand (RANK-L) and osteoprotegerin (OPG) levels, 18 versus 19 samples) parameters were recorded. RESULTS: Within each group, significant improvements were found for clinical parameters, though without significant differences between groups. RANK-L was significantly decreased at week 13 in the SRP + PDT group compared with the SRP group. SRP + PDT, but not SRP alone, significantly reduced the abundance of A. actinomycetemcomitans. CONCLUSIONS: Except for a significant decrease in the pathogenic burden of A. actinomycetemcomitans, coadjuvant PDT resulted in no additional improvement compared with SRP alone in patients diagnosed with moderate-to-advanced chronic periodontitis. PMID- 28667679 TI - An interaction potential to study the thermal structure evolution of a thermoelectric material: beta-Cu2 Se. AB - An interaction potential model has been developed, for the first time, for beta Cu2 Se using the ab initio derived data. The structure and elastic constants of beta-Cu2 Se using the derived force-field are within a few percent of DFT derived structure and elastic constants and reported experimental structure. The derived force-field also shows remarkable ability to reproduce temperature dependent behavior of the specific heat and thermal expansion coefficient. The thermal structure evolution of the beta-Cu2 Se is studied by performing the molecular dynamic simulations using the derived force-field. The simulation results demonstrate that the Cu ions moves around the equilibrium lattice position within the temperature range of 500-800 K. However, at a temperature > 800 K, the Cu ions starts diffusing within the material, while the Se ions remains in their lattice position. The evaluated thermodynamic properties such as free energy and excess entropy, show that the increased Cu-Se interaction with the temperature makes the system more thermodynamically stable. (c) 2017 Wiley Periodicals, Inc. PMID- 28667680 TI - Fast and comprehensive characterization of chemical ingredients in traditional Chinese herbal medicines by extractive atmospheric pressure photoionization (EAPPI) mass spectrometry. AB - RATIONALE: The goal of this work is to employ extractive atmospheric pressure photoionization mass spectrometry (EAPPI-MS) to characterize the constituents in traditional Chinese herbal medicine (TCHM) directly without chromatographic separation. METHODS: Sample was placed in 4 mL of methanol/water (v/v, 3:1) in the nebulization cell, and then the ultrasonic nebulizer was switched on. The ultrasonic nebulization system allows the simultaneous sample extraction and introduction of extract aerosols. The extract aerosols were vaporized in a transfer tube. Mixed with a gaseous dopant, vaporized analytes were ionized through ambient photon-induced ion-molecule reactions, and were mass-analyzed by high-resolution time-of-flight mass spectrometry (TOF-MS). RESULTS: The major ingredients including alkaloids, flavonoids, amino acids, saccarides, ginsenosides, lignans and terpenoids were readily detected. Compared with electrospray ionization (ESI), EAPPI allowed the ionization of a wider range of compounds, which is desirable for the integral characterization of TCHMs containing numerous constituents. The significant discrepancies for both alkaloids and terpenoids in tripterygium glycoside tablets from two different manufacturers could be simultaneously reflected from EAPPI mass spectra. CONCLUSIONS: Our results demonstrate that EAPPI-MS can be regarded as a supplementary ambient method for the fast and comprehensive analysis of TCHMs, which is important for the quality control and safety assurance of these products. PMID- 28667681 TI - Escapees from Rhombomeric Lineage Restriction: Extensive Migration Rostral to the r4/r5 Border of Hox-a3 Expression. AB - The rhombomeric compartments of the hindbrain are characterized by lineage restriction; cells born in one compartment generally remain there and do not migrate to neighboring rhombomeres. Two well-known exceptions are the substantial migrations of the pontine nuclei and the mammalian facial nucleus. In this study we used Hoxa3-Cre lineage to permanently mark cells that originate in rhombomeres caudal to r4. We found that cells born caudal to the r4/r5 border migrate forwards to a number of different locations in rhombomeres 1-4; the final locations include the interfascicular trigeminal nucleus, the principal trigeminal nucleus, the pontine nuclei, the reticulotegmental nucleus, the ventral nucleus of the lateral lemniscus, and the lateral and medial vestibular nuclei. We suggest that there are numerous exceptions to the principle of rhombomeric lineage restriction that have previously gone unnoticed. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1838-1846, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28667682 TI - Dedifferentiated carcinoma with clear cell carcinoma of the endometrium: A case report. AB - Endometrial dedifferentiated carcinoma consists of a combination of undifferentiated and differentiated carcinomas. To date, clear cell carcinoma components in endometrial dedifferentiated carcinoma have not been reported. We report the first case of endometrial dedifferentiated carcinoma with clear cell carcinoma in a 58-year-old woman. The uterine corpus was completely replaced and enlarged by a heterogeneous mass. The endometrial cut surface showed a yellowish papillary growing mass involving endometrium and deeper myometrium. Microscopically, the three components (endometrioid carcinoma, FIGO grade 1, clear cell carcinoma and undifferentiated carcinoma) were noted with differentiated carcinoma components lining the endometrial cavity, while undifferentiated carcinoma components were identified in deeper endometrium and myometrium. Our histologic diagnosis was supported by the pattern of immunoreactivity. Tumor cells showed loss of expression of MLH1/PMS2 protein and displayed high microsatellite-instability in all three components. Furthermore, all three components including clear cell carcinoma had loss of PTEN and ARID1A expression. Our observations suggest that the three components derived from a monoclonal origin, as the three components had in common specific genetic alterations. PMID- 28667683 TI - Pouch failures following ileal pouch-anal anastomosis for ulcerative colitis. AB - AIM: Ileal pouch-anal anastomosis is a procedure offered to patients with ulcerative colitis who opt for restoration of bowel continuity. The aim of this study was to determine the risk of pouch failure and ascertain the risk factors associated with failure. METHOD: The study included 1991 patients with ulcerative colitis who underwent ileal pouch-anal anastomosis in Denmark in the period 1980 2013. Pouch failure was defined as excision of the pouch or presence of an unreversed stoma within 1 year after its creation. We used Cox proportional hazards regression to explore the association between pouch failure and age, gender, synchronous colectomy, primary faecal diversion, annual hospital volume (very low, 1-5 cases per year; low, 6-10; intermediate 11-20; high > 20), calendar year, laparoscopy and primary sclerosing cholangitis. RESULTS: Over a median 11.4 years, 295 failures occurred, corresponding to 5-, 10- and 20-year cumulative risks of 9.1%, 12.1% and 18.2%, respectively. The risk of failure was higher for women [adjusted hazard ratio (aHR) 1.39, 95% CI 1.10-1.75]. Primary non-diversion (aHR 1.63, 95% CI 1.11-2.41) and a low hospital volume (aHR, very low volume vs high volume 2.30, 95% CI 1.26-4.20) were also associated with a higher risk of failure. The risk of failure was not associated with calendar year, primary sclerosing cholangitis, synchronous colectomy or laparoscopy. CONCLUSION: In a cohort of patients from Denmark (where pouch surgery is centralized) with ulcerative colitis and ileal pouch-anal anastomosis, women had a higher risk of pouch failure. Of modifiable factors, low hospital volume and non-diversion were associated with a higher risk of pouch failure. PMID- 28667684 TI - Molecular electrostatic potential and "atoms-in-molecules" analyses of the interplay between pi-hole and lone pair...pi/X-H...pi/metal...pi interactions. AB - Using ab initio calculations, we analyze the interplay between pi-hole interactions involving the nitro group of 1,4-dinitrobenzene and lone pair...pi (lp...pi), C-H...pi or metal(M)...pi noncovalent interactions. Moreover, we have also used 1,4-phenylenebis(phosphine dioxide) for comparison purposes. Interesting cooperativity effects are found when pi-hole (F...N,P) and lp...pi/C H...pi/M...pi interactions coexist in the same supramolecular assembly. These effects are studied theoretically in terms of energetic and geometric features of the complexes, which are computed by ab initio methods (RI-MP2/def2-TZVP). A charge density analysis using the Bader's theory of "atoms in molecules" is carried out to characterize the interactions and to analyze their strengthening or weakening depending on the variation of charge density at critical points. The importance of electrostatic effects on the mutual influence of the interaction is studied by means of molecular electrostatic potential calculations. By taking advantage of these computational tools, the present study examines interplay of these interactions. (c) 2017 Wiley Periodicals, Inc. PMID- 28667685 TI - Faecaloma causing large bowel obstruction: a case report and review of literature. PMID- 28667686 TI - Pulsatile crizotinib treatment for brain metastasis in a patient with non-small cell lung cancer. AB - WHAT IS KNOWN AND OBJECTIVE: Anaplastic lymphoma kinase (ALK)-rearranged non small-cell lung cancer (NSCLC) is a distinct subtype with patients showing peculiar clinicopathological features and dramatic responses to the ALK tyrosine kinase inhibitor crizotinib. Patients with this cancer variant have a dismal prognosis and limited treatment options when it has progressed to intracranial metastasis because of inadequate drug penetration into the central nervous system (CNS). Factors associated with response to TKI therapy have been reported to include pharmacokinetic and biodynamic resistance phenomena. CASE DESCRIPTION: In our NSCLC patient with multiple intracranial metastases, we administered high dose pulsatile crizotinib therapy (1000 mg/d) on a one-day-on/one-day-off basis. A significant central nervous system (CNS) response was achieved, and time to neurological progression was prolonged to 6 months. WHAT IS NEW AND CONCLUSION: High-dose pulsatile therapy may be an effective dosing strategy for crizotinib in NSCLC showing progression to metastasis in the brain. PMID- 28667687 TI - Obstetric rectovaginal fistula: should there be a different treatment paradigm? PMID- 28667688 TI - Robotic right colectomy with complete mesocolic excision: bottom-to-up suprapubic approach - a video vignette. PMID- 28667689 TI - Cluster size convergence for the energetics of the oxygen evolving complex in PSII. AB - Density functional theory calculations have been made to investigate the stability of the energetics for the oxygen evolving complex of photosystem II. Results published elsewhere have given excellent agreement with experiments for both energetics and structures, where many of the experimental results were obtained several years after the calculations were done. The computational results were obtained after a careful extension from small models to a size of about 200 atoms, where stability of the results was demonstrated. However, recently results were published by Isobe et al., suggesting that very different results could be obtained if the model was extended from 200 to 340 atoms. The present study aims at understanding where this difference comes from. (c) 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 28667690 TI - Sympathetic and parasympathetic cardiac responses to phobia-relevant and disgust specific emotion provocation in blood-injection-injury phobia with and without fainting history. AB - The autonomic regulation in blood-injection-injury (BII) phobia has received particular attention due to the unique link between fear and fainting in this anxiety disorder. However, systematic exploration of sympathetic and parasympathetic cardiac activity during exposure to phobia-relevant emotional stimuli has remained rare and inconclusive, including with regard to disgust, a frequent response to BII stimuli. Existing studies using respiratory sinus arrhythmia (RSA) as a noninvasive index of parasympathetic cardiac activity also have not accounted sufficiently for effects of respiration. We compared 60 participants with BII phobia (27 with and 33 without history of loss of consciousness) and 20 healthy controls during emotion induction with films, including a disgust and a BII-relevant surgery film. Cardiorespiratory activity was measured continuously, with RSA (controlled for respiration) and T-wave amplitude (TWA; as a noninvasive index of sympathetic cardiac activity) extracted. Significant increases in RSA during the surgery film were observed for participants with a history of loss of consciousness compared to others, but controlling for respiration eliminated these differences. Sympathetic effects with heart rate accelerations, which were most pronounced for the disgust film, did not differentiate groups. However, substantial increases in RSA and TWA, suggesting parasympathetic excitation and sympathetic withdrawal, were observed in five participants that became presyncopal during the surgery film. Thus, parasympathetic excitation and sympathetic withdrawal appear to be cardinal autonomic features in BII phobia, but larger studies of participants reaching presyncopal states in BII-relevant stimulus exposure are needed to consolidate these findings. PMID- 28667691 TI - Subacute demyelinating peripheral neuropathy as a novel presentation of late infantile metachromatic leukodystrophy. PMID- 28667692 TI - Hybrid TiO2 -Ruthenium Nano-photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions. AB - Photodynamic therapy (PDT) is widely used to treat diverse diseases, but its dependence on oxygen to produce cytotoxic reactive oxygen species (ROS) diminishes the therapeutic effect in a hypoxic environment, such as solid tumors. Herein, we developed a ROS-producing hybrid nanoparticle-based photosensitizer capable of maintaining high levels of ROS under both normoxic and hypoxic conditions. Conjugation of a ruthenium complex (N3) to a TiO2 nanoparticle afforded TiO2 -N3. Upon exposure of TiO2 -N3 to light, the N3 injected electrons into TiO2 to produce three- and four-fold more hydroxyl radicals and hydrogen peroxide, respectively, than TiO2 at 160 mmHg. TiO2 -N3 maintained three-fold higher hydroxyl radicals than TiO2 under hypoxic conditions via N3-facilitated electron-hole reduction of adsorbed water molecules. The incorporation of N3 transformed TiO2 from a dual type I and II PDT agent to a predominantly type I photosensitizer, irrespective of the oxygen content. PMID- 28667693 TI - In vitro and in vivo gene delivery using chitosan/hyaluronic acid nanoparticles: Influences of molecular mass of hyaluronic acid and lyophilization on transfection efficiency. AB - BACKGROUND: Lyophilization is an effective method for preserving nonviral gene vectors. To improve the stability and transgene expression of lyophilized plasmid DNA (pDNA) complexes, we coated the surfaces of pDNA/chitosan complexes with hyaluronic acid (HA) of varying molecular masses. The transgene expression of pDNA/chitosan/HA ternary complexes was characterized in vitro and in vivo. METHODS: pDNA complexes were lyophilized overnight and the resultant products with spongy, porous consistencies were stored at -30, 4 or 25 degrees C for 2 weeks. Rehydrated complexes were characterized using gel retardation assays, aiming to confirm complex formation, measure particle size and evaluate zeta potential, as well as conduct luciferase gene reporter assays. The anti-tumor effects of pDNA ternary complexes were evaluated using suicide gene (pTK) coding thymidine kinase in Huh7-implanted mice. RESULTS: Transfection efficiencies of pDNA/chitosan/HA ternary complexes were dependent on the average molecular masses of HA. The coating of pDNA/chitosan complexes with HA maintained the cellular transfection efficiencies of lyophilized pDNA ternary complexes. Furthermore, intratumoral injection of lyophilized, rehydrated pDNA ternary complexes into tumor-bearing mice showed a significant suppression of tumor growth. CONCLUSIONS: The coating of pDNA/chitosan complexes with high-molecular-weight HA augmented the stability and cellular transfection ability of the complexes after lyophilization-rehydration. PMID- 28667694 TI - Accelerated growth of B16BL6 tumor in mice through efficient uptake of their own exosomes by B16BL6 cells. AB - Exosomes are extracellular vesicles released by various cell types and play roles in cell-cell communication. Several studies indicate that cancer cell-derived exosomes play important pathophysiological roles in tumor progression. Biodistribution of cancer cell-derived exosomes in tumor tissue is an important factor for determining their role in tumor proliferation; however, limited studies have assessed the biodistribution of exosomes in tumor tissues. In the present study, we examined the effect of cancer-cell derived exosomes on tumor growth by analyzing their biodistribution. Murine melanoma B16BL6-derived exosomes increased the proliferation and inhibited the apoptosis of B16BL6 cells, which was associated with an increase and decrease in the levels of proliferation and apoptosis-related proteins, respectively. GW4869-induced inhibition of exosome secretion decreased the proliferation of B16BL6 cells, and treatment of GW4869-treated cells with B16BL6-derived exosomes restored their proliferation. Next, we treated B16BL6 tumors in mice with B16BL6-derived exosomes and examined the biodistribution and cellular uptake of these exosomes. After the intratumoral injection of radiolabeled B16BL6-derived exosomes, most radioactivity was detected within the tumor tissues of mice. Fractionation of cells present in the tumor tissue showed that fluorescently labeled exosomes were mainly taken up by B16BL6 cells. Moreover, intratumoral injection of B16BL6-derived exosomes promoted tumor growth, whereas intratumoral injection of GW4869 suppressed tumor growth. These results indicate that B16BL6 cells secrete and take up their own exosomes to induce their proliferation and inhibit their apoptosis, which promotes tumor progression. PMID- 28667695 TI - Recognition memory: Cellular evidence of a massive contribution of the LEC to familiarity and a lack of involvement of the hippocampal subfields CA1 and CA3. AB - A highly debated issue in memory research is whether familiarity is supported by the parahippocampal region, especially the lateral (LEC) and the perirhinal (PER) cortices, or whether it is supported by the same brain structure as recollection: the hippocampus. One reason for this is that conflicting results have emerged regarding the contribution of the hippocampus to familiarity. This might stem from the lack of dissociation between hippocampal subfields CA1 and CA3 as these areas are involved to a different extent in processes which are pertinent to familiarity. Another reason is that empirical evidence for a contribution of the LEC is still missing. Furthermore, it is unclear whether the superficial and the deep layers of the LEC would equally contribute to this process as these layers are differentially recruited during memory retrieval which partly relies on familiarity. To identify the specific contribution of the LEC, CA1, and CA3, we imaged with cellular resolution activity in the brain of rats performing a version of a standard human memory task adapted to rats that yields judgments based on familiarity. Using this translational approach, we report that in striking contrast to CA1 and CA3, the LEC is recruited for familiarity-judgments and that its contribution is comparable to that of the PER. These results show for the first time that the LEC, specifically its deep layers, contributes to familiarity and constitute the first cellular evidence that the hippocampus does not, thus establishing that familiarity does not share the same neural substrate as recollection. PMID- 28667696 TI - Phylogenetic convergence and multiple shell shape optima for gliding scallops (Bivalvia: Pectinidae). AB - An important question in evolutionary biology is how often, and to what extent, do similar ecologies elicit distantly related taxa to evolve towards the same phenotype? In some scenarios, the repeated evolution of particular phenotypes may be expected, for instance when species are exposed to common selective forces that result from strong functional demands. In bivalved scallops (Pectinidae), some species exhibit a distinct swimming behaviour (gliding), which requires specific biomechanical attributes to generate lift and reduce drag during locomotive events. Further, a phylogenetic analysis revealed that gliding behaviour has independently evolved at least four times, which raises the question as to whether these independent lineages have also converged on a similar phenotype. Here, we test the hypothesis that gliding scallops display shell shape convergence using a combination of geometric morphometrics and phylogenetic comparative methods that evaluate patterns of multivariate trait evolution. Our findings reveal that the gliding species display less morphological disparity and significant evolutionary convergence in morphospace, relative to expectations under a neutral model of Brownian motion for evolutionary phenotypic change. Intriguingly, the phylomorphospace patterns indicate that gliding lineages follow similar evolutionary trajectories to not one, but two regions of morphological space, and subsequent analyses identified significant differences in their biomechanical parameters, suggesting that these two groups of scallops accomplish gliding in different ways. Thus, whereas there is a clear gliding morphotype that has evolved convergently across the phylogeny, functionally distinct morphological subforms are apparent, suggesting that there may be two optima for the gliding phenotype in the Pectinidae. PMID- 28667697 TI - Sexual and Regional Differences in Myosin Heavy Chain Expression in the Rat External Urethral Sphincter. AB - The external urethral sphincter is a unique striated muscle surrounding the urethra that plays a crucial role in urinary continence, and a comprehensive understanding of its morphology is needed to determine the pathophysiology underlying urinary incontinence and find suitable therapies. Differences between the sexes and among species regarding the fiber types present remain controversial. This study used triple immunofluorescence labeling to visualize one slow (Type 1) and two fast (Types 2A and 2B) myosin isoforms in rat external urethral sphincters from both sexes. Type 2A fibers predominated throughout the sphincter and Type 2B fibers were restricted to the proximal one-third of the external urethral sphincter in the female rats. Type 1 fibers were present adluminally and were concentrated in the proximal and distal segments of the sphincter. While most of the male external urethral sphincter comprised Type 2B fibers, Type 2A fibers intermingled among these fibers in the proximal one-third of the sphincter, and a few Type 1 fibers were present that were restricted to the adluminal region of the proximal segment. The fiber-type compositions and their areal densities changed in both sexes after gonadectomy. The areal density of the Type 1 fibers increased significantly in the ovariectomized females, especially in the distal segment. In the orchidectomized males, the areal densities of the Types 1 and 2A fibers increased significantly, but that of the Type 2B fibers decreased. These results indicate that myosin heavy chain expression in the rat external urethral sphincter is sexually dimorphic and shows regional differences. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:2058-2069, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28667698 TI - Evidenced-based clinical practice guideline for prostate cancer (summary: Japanese Urological Association, 2016 edition). AB - These guidelines cover a wide range of topics from prostate cancer epidemiology to palliative care. Questions arising in daily clinical practice have been extracted and formulated as clinical questions. In the 4 years since the previous edition, there have been major changes - for example, robot-assisted prostatectomy has rapidly come into widespread use, and new hormones and anticancer drugs have been developed for castration-resistant prostate cancer. In response to these developments, the number of fields included in this guideline was increased from 11 in the 2012 edition to 16, and the number of clinical questions was increased from 63 to 70. The number of papers identified in searches of the existing literature increased from 4662 in the first edition, published in 2006, to 10 490 in the 2012 edition. The number of references has reached 29 448 just during this review period, indicating the exponential increase in research on the topic of prostate cancer. Clinical answers have been prepared based on the latest evidence. Recommendation grades for the clinical answers were determined by radiologists, pathologists, and other specialists in addition to urologists in order to reflect the recent advances and diversity of prostate cancer treatment. Here, we present a short English version of the original guideline, and overview its key clinical issues. PMID- 28667699 TI - Influence of EGCG on alpha-synuclein (alphaS) aggregation and identification of their possible binding mode: A computational study using molecular dynamics simulation. AB - The accumulation of intrinsically disordered alpha-synuclein (alphaS) protein that can form beta-sheet-rich fibrils is linked to Parkinson's disease. (-) Epigallocatechin-3-gallate (EGCG) is the most abundant active component in green tea and can inhibit the fibrillation of alphaS. The elucidation of this molecular mechanism will be helpful to understand the inhibition mechanism of EGCG to the fibrillation of alphaS and also to find more potential small molecules that can inhibit the aggregation of alphaS. In this work, to study the influence of EGCG on the structure of beta-sheet-rich fibrils of alphaS and identification of their possible binding mode, molecular dynamics simulations of pentamer and decamer aggregates of alphaS in complex with EGCG were performed. The obtained results indicate that EGCG can remodel the alphaS fibrils and break the initial ordered pattern by reducing the beta-sheet content. EGCG can also break the Greek conformation of alphaS by the disappeared H-bond in the secondary structure of turn. The results from our study can not only reveal the specific interaction between EGCG and beta-sheet-rich fibrils of alphaS, but also provide the useful guidance for the discovery of other potential inhibitors. PMID- 28667700 TI - Decoding Nucleation and Growth of Zeolitic Imidazolate Framework Thin Films with Atomic Force Microscopy and Vibrational Spectroscopy. AB - The synthesis of metal-organic framework (MOF) thin films has garnered significant attention during the past decade. By better understanding the parameters governing the nucleation and growth of such thin films, their properties can be rationally tuned, empowering their application as (reactive) membranes. Here, a combined AFM-vibrational spectroscopy research strategy is employed to detail the chemistries governing the nucleation and growth of zeolitic imidazolate framework (ZIF) thin films, in particular isostructural Co ZIF-67 and Zn-ZIF-8. First, a single step direct synthesis approach is used to investigate the influence of different synthesis parameters -metal/linker ratio, temperature, and metal type- on the thin film nucleation and growth behaviour. While the metal/linker ratio has a pronounced effect on the thin film nucleation rate, the temperature mainly influences the growth kinetics of nuclei forming the thin film. In addition, the nucleation and growth of ZIF thin films is shown to be highly dependent on the electronegativity of the metal type. Thin-film thickness control can be achieved by using a multistep synthesis strategy, implying repetitive applications of single step deposition under identical synthesis conditions, for which a growth mechanism is proposed. This study provides insight into the influence of synthesis parameters on the ZIF thin film properties, using tools at hand to rationally tune MOF thin film properties. PMID- 28667702 TI - Tuberous sclerosis complex: Recent advances in manifestations and therapy. AB - Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex. PMID- 28667701 TI - The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma. AB - The genetic aetiology of sporadic neuroblastoma is still largely unknown. We have identified diverse neuroblastoma susceptibility loci by genomewide association studies (GWASs); however, additional SNPs that likely contribute to neuroblastoma susceptibility prompted this investigation for identification of additional variants that are likely hidden among signals discarded by the multiple testing corrections used in the analysis of genomewide data. There is evidence suggesting the CDKN1B, coding for the cycle inhibitor p27Kip1, is involved in neuroblastoma. We thus assess whether genetic variants of CDKN1B are associated with neuroblastoma. We imputed all possible genotypes across CDKN1B locus on a discovery case series of 2101 neuroblastoma patients and 4202 genetically matched controls of European ancestry. The most significantly associated rs34330 was analysed in an independent Italian cohort of 311 cases and 709 controls. In vitro functional analysis was carried out in HEK293T and in neuroblastoma cell line SHEP-2, both transfected with pGL3-CDKN1B-CC or pGL3-CDKN1B-TT constructs. We identified an association of the rs34330 T allele (-79C/T) with the neuroblastoma risk (Pcombined = 0.002; OR = 1.17). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P < 0.05). Three independent sets of neuroblastoma tumours carrying -79TT genotype showed a tendency towards lower CDKN1B mRNA levels. Our study shows that a functional variant, associated with a reduced CDKN1B gene transcription, influences neuroblastoma susceptibility. PMID- 28667703 TI - Hippocampal gamma-slow oscillation coupling in macaques during sedation and sleep. AB - Behavioral and neurophysiological evidence suggests that the slow (<=1 Hz) oscillation (SO) during sleep plays a role in consolidating hippocampal (HIPP) dependent memories. The effects of the SO on HIPP activity have been studied in rodents and cats both during natural sleep and during anesthetic administration titrated to mimic sleep-like slow rhythms. In this study, we sought to document these effects in primates. First, HIPP field potentials were recorded during ketamine-dexmedetomidine sedation and during natural sleep in three rhesus macaques. Sedation produced regionally-specific slow and gamma (~40 Hz) oscillations with strong coupling between the SO phase and gamma amplitude. These same features were seen in slow-wave sleep (SWS), but the coupling was weaker and the coupled gamma oscillation had a higher frequency (~70 Hz) during SWS. Second, electrical stimuli were delivered to HIPP afferents in the parahippocampal gyrus (PHG) during sedation to assess the effects of sleep-like SO on excitability. Gamma bursts after the peak of SO cycles corresponded to periods of increased gain of monosynaptic connections between the PHG and HIPP. However, the two PHG HIPP connectivity gains during sedation were both substantially lower than when the animal was awake. We conclude that the SO is correlated with rhythmic excitation and inhibition of the PHG-HIPP network, modulating connectivity and gamma generators intrinsic to this network. Ketamine-dexmedetomidine sedation produces a similar effect, but with a decreased contribution of the PHG to HIPP activity and gamma generation. PMID- 28667704 TI - Growth and Development at the Sphenoethmoidal Junction in Perinatal Primates. AB - Integration of the sphenoid and ethmoid bones during early postnatal development is poorly described in the literature. A uniquely prolonged patency of sphenoethmoidal synchondrosis or prespheno-septal synchondrosis (PSept) has been attributed to humans. However, the sphenoethmoidal junction has not been studied using a comparative primate sample. Here, we examined development of the sphenoethmoidal interface using ontogenetic samples of Old and New World monkeys, strepsirrhine primates (lemurs and lorises), and a comparative sample of other mammals. Specimens ranging from late fetal to 1 month postnatal age were studied using histology, immunohistochemistry, and micro-computed tomography methods. Our results demonstrate that humans are not unique in anterior cranial base growth at PSept, as it is patent in all newborn primates. We found two distinctions within our sample. First, nearly all primates exhibit an earlier breakdown of the nasal capsule cartilage that abuts the orbitosphenoid when compared to nonprimates. This may facilitate earlier postnatal integration of the basicranium and midface and may enhance morphological plasticity in the region. Second, the PSept exhibits a basic dichotomy between strepsirrhines and monkeys. In strepsirrhines, the PSept has proliferating chondrocytes that are primarily oriented in a longitudinal plane, as in other mammals. In contrast, monkeys have a convex anterior end of the presphenoid with a radial boundary of cartilaginous growth at PSept. Our findings suggest that the PSept acts as a "pacemaker" of longitudinal facial growth in mammals with relatively long snouts, but may also contribute to facial height and produce a relatively taller midface in anthropoid primates. Anat Rec, 300:2115-2137, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28667705 TI - Effects of prior mental effort on picture processing: An ERP investigation. AB - The current study examined the aftereffects of mental effort on the processing of picture stimuli using neural measures. Ninety-seven healthy young adults were randomly assigned to exercise more versus less mental effort on a writing task. Then participants viewed positive, negative, and neutral affective images while P1, N1, P2, N2, P3, and late positive potential (LPP) magnitudes to the images were assessed. We found that performing the more (versus less) effortful writing task caused more negative N2 amplitudes to all images. In addition, and consistent with past research, emotional (versus neutral) images elicited more positive amplitudes on the N2, P3, and LPP components. Thus, prior mental effort appeared to reduce early attentional engagement with visual stimuli but did not diminish later attention modulation by emotional content. These findings suggest novel implications for understanding the behavioral aftereffects of mental effort and self-control. PMID- 28667706 TI - An autopsy case of non-traumatic fat embolism syndrome. AB - Fat embolism syndrome (FES) occurs after long bone fractures and the symptoms appear 24-72 h after the initial trauma. Fat emboli can affect both the pulmonary and systemic circulation. Apart from the most common type of FES that originates from bone fracture, non-traumatic FES has been also reported. We have experienced an autopsy case of non-traumatic FES. An 81-year-old man with hepatocellular carcinoma associated with alcoholic liver cirrhosis suddenly lost consciousness before transcatheter arterial chemoembolization treatment for his disease and died 5 h after the episode. At autopsy, numerous fat droplets were detected in the alveolar capillaries of the lung and glomerular capillaries of the kidney. Lipid analysis of lung autopsy specimens by thin-layer chromatography showed that the emboli were composed mainly of tristearin. Free fatty acids (FFA) has been considered to be the main component of fat emboli and can be a cause of acute respiratory distress syndrome (ARDS). However, in the present case, the lung specimen contained tristearin and ARDS did not occur. This is the first report of non-traumatic FES in which lipid analysis of human autopsy specimens has been conducted. PMID- 28667707 TI - A Nanosized Gly-Decorated Praseodymium-Stabilized Selenotungstate Cluster: Synthesis, Structure, and Oxidation Catalysis. AB - A flexible one-pot strategy with pyramidal SeIV heteroatoms was employed for the assembly of the praseodymium-containing gly-decorated polyoxotungstate [{Pr3 (H2 O)10 [Se2 W22 O76 (gly)2 ]}2 (Se2 W7 O30 H2 )]18- (1 a), which is constructed from one {Se2 W7 O30 H2 } unit and two identical {Pr3 (H2 O)10 [Se2 W22 O76 (gly)2 ]} units. Furthermore, the catalytic performance of Cs2 Na4 H12 [{Pr3 (H2 O)10 [Se2 W22 O76 (gly)2 ]}2 (Se2 W7 O30 H2 )]?25 H2 O (1) for alkene epoxidation with hydrogen peroxide was investigated under mild reaction conditions, and the experimental results suggested that compound 1 exhibits good catalytic performance for the epoxidation of cyclooctene. PMID- 28667708 TI - Acute painful autoimmune neuropathy: A variant of Guillain-Barre syndrome. AB - INTRODUCTION: We present a painful small-fiber neuropathy variant of Guillain Barre syndrome characterized by antecedent infectious symptoms, hyporeflexia, and albuminocytologic dissociation. METHODS: Two patients received intravenous immunoglobulin, one corticosteroids. RESULTS: The patients subsequently improved. Immunoglobulin G (IgG) antibodies in their acute phase sera strongly bound to murine small nerve fibers, and the binding disappeared during the convalescent phase. Serum transfer to a murine nociceptive model induced transient alteration in thermal pain responses. DISCUSSION: Our case series suggest that an acute transient immune response can be directed against small nerve fibers, and that patients so affected can exhibit features of Guillain-Barre syndrome. Muscle Nerve 57: 320-324, 2018. PMID- 28667709 TI - Relationship between expression level of hygromycin B-resistant gene and Agrobacterium tumefaciens-mediated transformation efficiency in Beauveria bassiana JEF-007. AB - AIMS: Agrobacterium tumefaciens-mediated transformation (AtMT) is an effective method for generation of entomopathogenic Beauveria bassiana transformants. However, some strains grow on the selective medium containing hygromycin B (HygB), which reduces the selection efficiency of the putative transformants. In this work, a relationship between HygB resistance gene promoter and AtMT efficiency was investigated to improve the transformant selection. METHODS AND RESULTS: Ten B. bassiana isolates were grown on 800 MUg ml-1 HygB medium, but only JEF-006, -007 and -013 showed susceptibility to the antibiotics. Particularly, JEF-007 showed the most dose-dependent susceptibility. Two different Ti-Plasmids, pCeg (gpdA promoter based) and pCambia-egfp (CaMV 35S promoter based), were constructed to evaluate the promoters on the expression of HygB resistance gene (hph) at 100, 150 and 200 MUg ml-1 HygB medium. Eight days after the transformation, wild type, AtMT/pCeg and AtMT/pCambia-egfp colonies were observed on 100 MUg ml-1 HygB, but significantly larger numbers of colonies were counted on AtMT/pCeg plates. At higher HygB concentration (150 MUg ml-1 ), only AtMT/pCeg colonies were further observed, but very few colonies were observed on the wild type and AtMT/pCambia-egfp plates. Putative transformants were subjected to PCR, RT-PCR and qRT-PCR to investigate the T-DNA insertion rate and gene expression level. Consequently, >80% of colonies showed successful AtMT transformation, and the hph expression level in AtMT/pCeg colonies was higher than that of AtMT/pCambia-egfp colonies. CONCLUSIONS: In the HygB-susceptible B. bassianaJEF-007, gpdA promoter works better than CaMV 35S promoter in the expression of HygB resistance gene at 150 MUg ml-1 HygB, consequently improving the selection efficiency of putative transformants. SIGNIFICANCE AND IMPACT OF THE STUDY: These results provide useful information for determining AtMT effectiveness in B. bassiana isolates, particularly antibiotic susceptibility and the role of promoters. PMID- 28667710 TI - Determination of Nitrite in Milk- and Soy-Based Nutritional Ingredients by Derivatization with 2,3-Diaminonaphthalene and Fluorescence Spectrometry. AB - Nitrite (NO2-) is an inorganic anion that can be found in various powdered milk- and soy-based nutritional ingredients as an incidental contaminant. Reliable determination of NO2- in nutritional ingredients is of paramount importance to ensure the safety of finished products. The derivatization reaction of NO2- with 2,3-diaminonaphthalene with the formation of fluorescent 2,3-naphtotriazole has been adapted to milk- and soy-based nutritional ingredients. The sample preparation consisted of protein precipitation with Carrez solution, simple pass through cleanup of extracts utilizing a carbon black-based cartridge and derivatization, followed by batch fluorometry. The method was validated in six representative ingredient matrixes-i.e., whole-milk powder, nonfat dry milk, milk protein concentrate, whey protein concentrate, sodium caseinate, and soy protein isolate. Recovery values were 82-109%, whereas within-day and intermediate precision were 0.6-5.2 and 3.6-11% (RSDs), respectively. The method LOQ was 0.1 or 0.2 ug/g sodium nitrite (NaNO2), depending on the ingredient matrix. Surveyed NO2- concentration levels in 25 lots of 10 types of nutritional ingredients ranged from between less than 0.1 to 29 ug/g NaNO2. This method is proposed as a more sensitive and rugged alternative to the widely used ion chromatographic and colorimetric approaches. PMID- 28667711 TI - Pneumococcal Conjugate Vaccine Introduction in India's Universal Immunization Program. PMID- 28667712 TI - Ethical Off-label Drug use: Need for a Rethink? AB - Off-label drug use is unavoidable, especially in children. Legal justice originates from ethical justice; therefore, ethical off-label drug use can be considered legal. We share our successful experiences with this issue in China, which may provide a reference to Indian healthcare professionals, to develop a common executable standard to be applied to evaluate the off-label drug use in clinical practice. PMID- 28667713 TI - Quality, Equity and Dignity for Preterm Infants Through Family-centered Care. PMID- 28667714 TI - Size at Birth and Later "Metabesity". PMID- 28667715 TI - Family-Centered Care to Complement Care of Sick Newborns: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the impact of family-centered care in delivery of care to sick newborns, on nosocomial infection rate. DESIGN: Randomized controlled trial. SETTING: Tertiary referral nursery (October 2010 to March 2012). PARTICIPANTS: 295 neonates randomized at the time of hospitalization in neonatal intensive care unit. INTERVENTION: Parent-attendant of intervention group were trained using an indigenously developed and pretested, culturally sensitive, simple audio-video tool that covered domains of personal hygiene, hand washing, danger signs recognition and feeding of sick neonate. Control group received routine care by nurses and doctors. OUTCOME MEASURE: Primary: culture positive nosocomial infection rate. Secondary: culture negative nosocomial infection rate, duration of hospitalization, mortality and breastfeeding rate. RESULTS: Two-thirds of family caregivers were fathers/ mothers and about 20% were grandparents. About 60% of family care givers were either illiterate (25%) or primary/middle pass (34%). Incidence of nosocomial episodes of sepsis was not different between groups (incidence rate difference 0.74, 95 % CI -4.21, 5.6, P = 0.76). Pre discharge exclusive breastfeeding rates were significantly higher in intervention group [80.4% vs 66.7% (P=0.007)]. CONCLUSION: There was no significant difference in nosocomial infection rate between the two groups. Translating and adapting principles of family-centered care was feasible, and improved the pre-discharge exclusive breastfeeding rates. PMID- 28667716 TI - Components of Metabolic Syndrome at 22 years of Age - Findings From Pune Low Birth Weight Study. AB - BACKGROUND: To study the early markers of Metabolic syndrome in a cohort of low birth weight (LBW) children followed up since birth, at the age of 22 years. DESIGN: Prospective cohort study. SETTING: Tertiary-care hospital. PARTICIPANTS: Neonates weighing less than 2000 g discharged from a neonatal special care unit were followed up prospectively; 153 cases and 77 controls were assessed at 22 years of age. METHODS: Fasting, 30 minute and 120 minute glucose and insulin after a bolus of 75g of glucose was determined. Insulin resistance was calculated. A lipid profile was also done. Anthropometric measurements were taken and abdominal fat was determined by magnetic resonance imaging. MAIN OUTCOME: Prevalence of the five components of Metabolic Syndrome as described by the International Diabetic Federation (IDF). RESULTS: 65.1% of the cohort was born small for gestational age. All three components of Metabolic syndrome were present in only three cases and none of the controls. However, two components were present in 25 (16.4%) cases and 5 (6%) controls (P=0.039). Cases in the lowest quartile of birthweight who became big at 22 years had significantly higher fasting insulin (P=0.001), Homeostatic Model Assessment - Insulin Resistance (Homa-IR) (P=0.001) and higher systolic blood pressure. Sum of skinfold thickness at 4 sites correlated significantly with fasting insulin and HOMA-IR, and was a stronger correlate compared to BMI, waist circumference and MRI fat. There was no difference in the biochemical parameters between appropriate for gestational age and small for gestational age infants. CONCLUSION: Prevelence of three or more components of Metabolic syndrome was low in LBW children at 22 years, but of two components was high. Those 'Small at birth and big at 22 years' had high insulin resistance. PMID- 28667717 TI - Clinical and Molecular Characterization of Children with Neonatal Diabetes Mellitus at a Tertiary Care Center in Northern India. AB - OBJECTIVE: To study the genetic mutations and clinical profile in children with neonatal diabetes mellitus. METHODS: Genetic evaluation, clinical management and follow-up of infants with neonatal diabetes. RESULTS: Eleven infants were studied of which eight had permanent neonatal diabetes. Median age at presentation was 8 weeks and mean (SD) birth weight was 2.4 (0.5) kg. Pathogenic genetic mutations were identified in 7 (63.6%) children; 3 infants with mutations in KCNJ11 gene and 1 in ABCC8 were switched to oral sulfonylureas; 2 infants had mutations in INS and 1 in ZFP57. CONCLUSION: Neonatal diabetes mellitus is a heterogeneous disorder. Identification of genetic cause guides clinical management. PMID- 28667718 TI - Acquired Methemoglobinemia - A Sporadic Holi Disaster. AB - OBJECTIVE: To study clinical profile and outcome in patients with methemoglobinemia following exposure to toxic colors during Holi festival. METHODS: This retrospective study included 112 children (5 to 12 years) admitted with methemoglobinemia after playing Holi. Clinical and treatment details were reviewed. RESULTS: The common symptoms were giddiness, vomiting and headache. Treatment included thorough skin wash, intravenous fluid and methylene blue in 111 children. Age 7-9 and > 11 years, vomiting, giddiness, cyanosis, PaO2 < 80 mm Hg and oxygen saturation < 95% were associated with higher need for methylene blue. All children had a good outcome. CONCLUSION: Timely diagnosis and management of acquired methemoglobinemia can save lives. PMID- 28667719 TI - Screening for Hypoglycemia in Exclusively Breastfed High-risk Neonates. AB - OBJECTIVE: To determine incidence of hypoglycemia in exclusively breastfed, high risk but healthy newborns, and risk factors for its development. METHODS: This observational study enrolled 407 exclusively breastfed high-risk (low birth weight newborns (1800-2499 g), late preterms, small-for-gestation, large-for gestation and infant of diabetic mother), who did not require admission to neonatal intensive care unit and were kept in postnatal wards with mother. Hypoglycemia was defined as blood glucose L46 mg/dL (2.6 mmol/L). Blood glucose was monitored till 48 hours of life. RESULTS: 27% of the screened newborns developed hypoglycemia in first 48 hours. 31 (7.6%) developed recurrent (>2) episodes, 28 (6.8%) had moderate (<37mg/dL) while 8 (1.9%) developed symptomatic hypoglycemia. With increase in birthweight, risk of hypoglycemia reduced significantly (P=0.003). Hypoglycemia was observed more frequently in first 2 hours as compared to next 48 hours (P=0.0001). Low birth- weight, preterm gestation and male gender was significantly associated with increased risk of hypoglycemia. CONCLUSION: Healthy, high-risk exclusively breastfed newborns in postnatal wards need close monitoring for hypoglycemia in first 24 hrs of life. PMID- 28667720 TI - Randomized Controlled Trial Evaluating Probiotics in Children with Severe Acute Malnutrition: Evidence-based Medicine Viewpoint. PMID- 28667721 TI - Randomized Controlled Trial Evaluating Probiotics in Children with Severe Acute Malnutrition: Pediatrician's Viewpoint. PMID- 28667722 TI - Randomized Controlled Trial Evaluating Probiotics in Children with Severe Acute Malnutrition: Pediatric Gastroenterologist's Viewpoint. PMID- 28667723 TI - Kyphoscolitic Type of Ehlers-Danlos Syndrome with Prenatal Stroke. AB - BACKGROUND: The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS type VIA) is an autosomal recessive disorder characterized by connective tissue dysplasia. CASE CHARACTERISTICS: We report two children with perinatal stroke; accompanied by neonatal joint hypermobility, hypotonia; and early development of kyphoscoliosis. OUTCOME: Molecular analysis revealed a PLOD1 gene mutation. Our definitive diagnosis was a EDS VIA. MESSAGE: Prenatal brain stroke is a rare clinical feature of EDSVIA. PMID- 28667724 TI - An Indian Family with Tyrosine Hydroxylase Deficiency. AB - BACKGROUND: Tyrosine Hydroxylase deficiency is a rare neurotransmitter disorder. CASE CHARACTERISTICS: An Indian family with the disorder. OBSERVATIONS: Phenotypic variation, elevated serum prolactin, genetic confirmation, and partial treatment-responsiveness. MESSAGE: Tyrosine Hydroxylase deficiency is a treatable inborn error of metabolism and serum prolactin assists in diagnosis. PMID- 28667725 TI - Right Atrial Diverticulosis and Early-onset Arrhythmia: Rare Cause of Incessant Neonatal Arrhythmia. AB - BACKGROUND: Atrial flutter not responding to medications could be secondary to structural malformations of heart. CASE CHARACTERISTICS: A 5-year-old child with resistant arrhythmia, with onset in neonatal period. OBSERVATIONS: Multiple right atrial diverticuli were detected on CT angiography and cardiac catheterization. Patient reverted to sinus rhythm following surgical excision of diverticuli. MESSAGE: In cases of intractable supraventricular tachycardia, structural anomalies of atrium should be suspected. PMID- 28667726 TI - Dengue: Differently Conceptualized. PMID- 28667727 TI - Coagulation abnormalities in children with Celiac disease. AB - We prospectively analyzed the coagulation abnormalities in 111 children with Celiac disease at diagnosis and its association with histology grade on duodenal biopsy; 27% had deranged prothrombin time. There was an increasing proportion of coagulopathy with progression of Marsh Grade on duodenal histology. PMID- 28667728 TI - Glomerular Filtration Rate Estimation by Serum Creatinine or Serum Cystatin C in Preterm (<31 Weeks) Neonates. AB - Glomerular filtration rate (GFR) was estimated by serum creatinine (Schwartz's equation) and serum cystatin C (Filler's equation) in preterm neonates (24-31 weeks of gestation) in a prospective cohort study. Serum creatinine and cystatin C was obtained at birth and then every two weeks during the first month. We found a poor fit between two methods, and a steadier GFR assessment by cystatin C. PMID- 28667729 TI - Going Solar is Good but Caution Needed! PMID- 28667730 TI - Going Solar is Good but Caution Needed!: Authors' Reply. PMID- 28667731 TI - Congenital Junctional Ectopic Tachycardia in a Neonate. PMID- 28667732 TI - Sunlight Exposure and Vitamin D Status in Breastfed Infant. PMID- 28667734 TI - Life-threatening Child Abuse: Penetrating Injury of Abdomen with Sewing Needles. PMID- 28667733 TI - Sunlight Exposure and Vitamin D Status in Breastfed Infant: Authors' Reply. PMID- 28667735 TI - Hepatitis A with Superadded Salmonella paratyphi A Infection Presenting with Exudative Pleural Effusion and Acalculous Cholecystitis. PMID- 28667736 TI - Infantile Tumoral Calcinosis. PMID- 28667737 TI - Periostin as a marker of mucosal remodelling in chronic rhinosinusitis. AB - BACKGROUND: Although extracellular matrix (ECM) proteins are associated with irreversible lower airway changes, the relationship with upper airway remodelling which occurs during chronic rhinosinusitis (CRS) is poorly understood. This study assessed the expression of ECM proteins periostin, fibulin-1, fibronectin and collagenIV in nasal mucosa of patients with and without histologic features of remodelling. METHODS: A cross-sectional study of sinonasal mucosal biopsies taken from patients, undergoing surgery for CRS was performed, where patients were grouped according to remodelling, defined by basement membrane thickening (BMT over 7.5 micrometer) and subepithelial fibrosis. An overall view and three random fields of immunostained tissue sections that included epithelium, basement membrane and submucosa, were imaged using Zeiss Zen software. The area and intensity of positive staining were scored by two blinded observers, using a 12 point ordinal scale of weak to strong. RESULTS: 65 patients (47.6 +/- 13.4years, 44.6% female) were assessed. Patients were grouped as controls 26.2%, BMT/no fibrosis 38.5% or BMT and fibrosis 33.8%. Stronger grade of periostin expression was associated with remodelling changes and tissue eosinophilia over 10/HPF. Fibulin-1, fibronectin and collagenIV did not differ. CONCLUSION: Periostin expression was associated with the presence of BMT, fibrosis and tissue eosinophilia and may identify patients undergoing remodelling changes. PMID- 28667738 TI - Developing global regression models for metabolite concentration prediction regardless of cell line. AB - Following the Process Analytical Technology (PAT) of the Food and Drug Administration (FDA), drug manufacturers are encouraged to develop innovative techniques in order to monitor and understand their processes in a better way. Within this framework, it has been demonstrated that Raman spectroscopy coupled with chemometric tools allow to predict critical parameters of mammalian cell cultures in-line and in real time. However, the development of robust and predictive regression models clearly requires many batches in order to take into account inter-batch variability and enhance models accuracy. Nevertheless, this heavy procedure has to be repeated for every new line of cell culture involving many resources. This is why we propose in this paper to develop global regression models taking into account different cell lines. Such models are finally transferred to any culture of the cells involved. This article first demonstrates the feasibility of developing regression models, not only for mammalian cell lines (CHO and HeLa cell cultures), but also for insect cell lines (Sf9 cell cultures). Then global regression models are generated, based on CHO cells, HeLa cells, and Sf9 cells. Finally, these models are evaluated considering a fourth cell line(HEK cells). In addition to suitable predictions of glucose and lactate concentration of HEK cell cultures, we expose that by adding a single HEK-cell culture to the calibration set, the predictive ability of the regression models are substantially increased. In this way, we demonstrate that using global models, it is not necessary to consider many cultures of a new cell line in order to obtain accurate models. Biotechnol. Bioeng. 2017;114: 2550-2559. (c) 2017 Wiley Periodicals, Inc. PMID- 28667739 TI - Patient preferences for the attributes of a noninvasive treatment for superficial basal cell carcinoma: a discrete choice experiment. PMID- 28667740 TI - Functional melanoma-risk variant IRF4 rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas. PMID- 28667741 TI - Coronal advanced flap in combination with a connective tissue graft. Is the thickness of the flap a predictor for root coverage? A prospective clinical study. AB - AIM: Evaluate if there is any relationship between the flap thickness (FT) and the presence of complete root coverage (CRC) when performing coronally advanced flaps in combination with a connective tissue graft (CTG). MATERIALS AND METHODS: Prospective clinical study, in which multiple Miller class I and II recessions were treated with a coronally advanced flap and a CTG standardized at 1 mm of thickness. Individual stents permitted repeated measurements of conventional periodontal parameters at the same point. The primary outcome variable was CRC. Secondary outcomes were recession reduction, gingival thickness and width of keratinized tissue (KT) achieved at 6 months post-surgery. RESULTS: Forty-five recessions (2.4 +/- 0.75 mm) were treated in 20 patients. Mean root coverage was 93.4 +/- 10.98%; 65% achieved CRC. The mean FT was 1.01 mm +/- 0.64 mm and 1.01 +/- 0.61 mm at 2 and 5 mm from the gingival margin, respectively. No relationship could be found between FT and CRC (p > .05). Statistical significant changes (p < .05) were observed for recession depth, clinical attachment level, KT and soft tissue thickness at the end of the study. CONCLUSIONS: Flap thickness seems not to be a predictor for CRC when performing a coronally advanced flap plus a CTG. This technique may be of choice when treating thin biotypes. PMID- 28667742 TI - Gingival bleeding, a possible "serious" adverse drug reaction: An observational study in the French PharmacoVigilance Database. AB - INTRODUCTION: Antithrombotic drugs are known to increase the risk of gingival bleeding because they affect coagulation. However, other drugs could also be involved in gingival bleeding. AIM: We performed a pharmacoepidemiological study to identify the drugs most frequently "suspected" in the occurrence of gingival bleeding. MATERIAL AND METHODS: We selected reports of "gingival bleeding" from 1 January 1985 to 30 September 2014 in the French PharmacoVigilance Database. RESULTS: Among 523,808 reports of adverse drug reactions, we identified 454 reports of gingival bleeding (0.09%). Most of them were "serious" (58.4%) and occurred in females (54.6%). The frequency of gingival bleeding increased with age. The most frequently "suspected" drugs were antithrombotics (67.8%), particularly fluindione. Other drugs frequently involved were furosemide followed by paracetamol, amiodarone, amoxicillin, paroxetine, ketoprofen, zolpidem, enalapril and ramipril. Thirty-nine reports involved a drug-drug interaction with antithrombotics, mainly with anti-infectives. CONCLUSION: Gingival bleeding can be an adverse drug reaction, often "serious" and rarely fatal. Patients older than 50 years and women are particularly at risk. Among drugs known to increase the risk of gingival bleeding, the most frequently involved were fluindione, furosemide, paracetamol, amiodarone, amoxicillin, paroxetine or ketoprofen. We also identified signal for drugs not usually known to be involved in bleeding, like zolpidem, enalapril or ramipril. PMID- 28667743 TI - Hidradenitis suppurativa and electrocardiographic changes: a cross-sectional population study. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease, recently associated with metabolic syndrome, subclinical atherosclerosis and increased risk of cardiovascular disease. OBJECTIVES: To investigate the hitherto unknown electrocardiographic (ECG) changes associated with HS, which have recently been associated with significant cardiovascular burden. METHODS: Data were obtained from the cross-sectional Danish General Population Study (GESUS). HS diagnosis was based on a validated self-reported questionnaire; 404 individuals met the HS diagnosis criteria and 19 001 controls without HS were identified. Severity of HS was staged according to a modified Hurley score. The ECG parameters of heart rate (HR), PR interval, QRS duration, JTc interval and QTc interval were obtained from 12-lead resting ECGs. We investigated the difference in means by unpaired t-test or anova. RESULTS: HR was significantly higher [mean difference 2.3 beats per min (bpm), 95% confidence interval (CI) 1.2 3.4; P < 0.01] when adjusting for age and sex, but when adjusting for multivariates, there was no significant difference (0.3 bpm, 95% CI -0.7 to 1.4; P = 0.52). Severe HS was significantly associated with increased HR across all models (2.9 bpm, 95% CI 0.7-5.1; P = 0.01). Mean QRS duration was significantly shorter in the group with mild HS but not in the groups with moderate and severe HS. CONCLUSIONS: Mean resting HR in patients with severe HS was significantly higher compared with controls. Given that resting HR is associated with increased risk of all-cause and cardiovascular mortality, and that patients with HS have increased risk of cardiovascular events, this finding is potentially important, easily testable and intervenable. PMID- 28667744 TI - European Heart Systemic Coronary Risk Evaluation may underestimate cardiovascular risk after assessing cardiovascular disease with carotid ultrasound in hidradenitis suppurativa. PMID- 28667745 TI - A hyaluronic acid-based microneedle patch to treat psoriatic plaques: a pilot open trial. PMID- 28667747 TI - Lack of response to intravenous sodium thiosulfate in three cases of extensive connective tissue disease-associated calcinosis cutis. AB - Dystrophic calcinosis cutis is a debilitating condition of calcium salt deposition in the skin often occurring in association with connective tissue disease (CTD). Available treatments for calcinosis cutis are unsatisfactory, but given the recent use of topical and intralesional sodium thiosulfate (STS) to treat calcifying disorders, we sought to describe the use of intravenous (IV) STS for CTD-associated dystrophic calcinosis cutis. We report three patients with long-standing and extensive CTD-associated calcinosis cutis treated with IV STS after having failed multiple prior therapies. All three patients experienced fatigue and nausea with STS infusions, and none of the patients had notable clinical or symptomatic improvement of calcinosis. It remains to be seen whether the administration of IV STS earlier in the onset of calcinosis might be of benefit given that these patients all had long-standing and refractory CTD associated calcinosis. Given the small number of patients in this series, further investigation into the use of IV STS in calcinosis cutis is warranted. PMID- 28667746 TI - Integrated gut/liver microphysiological systems elucidates inflammatory inter tissue crosstalk. AB - A capability for analyzing complex cellular communication among tissues is important in drug discovery and development, and in vitro technologies for doing so are required for human applications. A prominent instance is communication between the gut and the liver, whereby perturbations of one tissue can influence behavior of the other. Here, we present a study on human gut-liver tissue interactions under normal and inflammatory contexts, via an integrative multi organ platform comprising human liver (hepatocytes and Kupffer cells), and intestinal (enterocytes, goblet cells, and dendritic cells) models. Our results demonstrated long-term (>2 weeks) maintenance of intestinal (e.g., barrier integrity) and hepatic (e.g., albumin) functions in baseline interaction. Gene expression data comparing liver in interaction with gut, versus isolation, revealed modulation of bile acid metabolism. Intestinal FGF19 secretion and associated inhibition of hepatic CYP7A1 expression provided evidence of physiologically relevant gut-liver crosstalk. Moreover, significant non-linear modulation of cytokine responses was observed under inflammatory gut-liver interaction; for example, production of CXCR3 ligands (CXCL9,10,11) was synergistically enhanced. RNA-seq analysis revealed significant upregulation of IFNalpha/beta/gamma signaling during inflammatory gut-liver crosstalk, with these pathways implicated in the synergistic CXCR3 chemokine production. Exacerbated inflammatory response in gut-liver interaction also negatively affected tissue specific functions (e.g., liver metabolism). These findings illustrate how an integrated multi-tissue platform can generate insights useful for understanding complex pathophysiological processes such as inflammatory organ crosstalk. Biotechnol. Bioeng. 2017;114: 2648-2659. (c) 2017 Wiley Periodicals, Inc. PMID- 28667748 TI - Combined Catalase and ADH Inhibition Ameliorates Ethanol-Induced Myocardial Dysfunction Despite Causing Oxidative Stress in Conscious Female Rats. AB - BACKGROUND: Ethanol (EtOH)-evoked oxidative stress, which contributes to myocardial dysfunction in proestrus rats, is mediated by increases in NADPH oxidase (Nox) activity, malondialdehyde (MDA), and ERK1/2 phosphorylation. Whether these biochemical responses, which are triggered by alcohol-derived acetaldehyde in noncardiac tissues, occur in proestrus rats' hearts remains unknown. Therefore, we elucidated the roles of alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), and catalase, which catalyze alcohol oxidation to acetaldehyde, in these alcohol-evoked biochemical and hemodynamic responses in proestrus rats. METHODS: Conscious proestrus rats prepared for measurements of left ventricular (LV) function and blood pressure (BP) received EtOH (1.5 g/kg, intravenous [i.v.] infusion over 30 minutes) or saline 30 minutes after an ADH and CYP2E1 inhibitor, 4-methylpyrazole (4-MP) (82 mg/kg, intraperitoneal), a catalase inhibitor, 3-AT (0.5 g/kg, i.v.), their combination, or vehicle. LV function and BP were monitored for additional 60 minutes after EtOH or saline infusion before collecting the hearts for ex vivo measurements of LV reactive oxygen species (ROS), Nox activity, MDA, and ERK1/2 phosphorylation. RESULTS: EtOH reduced LV function (dP/dtmax and LV developed pressure) and BP, and increased cardiac Nox activity, ROS and MDA levels, and ERK1/2 phosphorylation. Either inhibitor partially, and their combination significantly, attenuated these responses despite the substantially higher blood EtOH level, and the increased cardiac oxidative stress and reduced BP caused by 3-AT alone or with 4-MP. The inhibitors reduced cardiac MDA level and reversed EtOH effect on cardiac and plasma MDA. CONCLUSIONS: EtOH oxidative metabolism plays a pivotal role in the EtOH-evoked LV oxidative stress and dysfunction in proestrus rats. Notably, catalase inhibition (3-AT) caused cardiac oxidative stress and hypotension. PMID- 28667751 TI - A supplement-free osteoclast-osteoblast co-culture for pre-clinical application. AB - There is increasing demand for efficient and physiological in vitro cell culture systems suitable for testing new pharmaceutical drugs or for evaluating materials for tissue regeneration. In particular, co-cultures of two or more tissue relevant cell types have the advantage to study the response of cells on diverse parameters in a more natural environment with respect to physiological complexity. We developed a direct bone cell co-culture system using human peripheral blood monocytes (hPBMC) and human bone marrow stromal cells (hBMSC) as osteoclast/osteoblast precursor cells, respectively, strictly avoiding external supplements for the induction of differentiation. The sophisticated direct hPBMC/hBMSC co-culture was characterized focusing on osteoclast function and was compared with two indirect approaches. Only in the direct co-culture, hPBMC were triggered by hBMSC into osteoclastogenesis and became active resorbing osteoclasts. Bisphosphonates and sulfated glycosaminoglycans were used to examine the suitability of the co-culture system for evaluating the influence of certain effectors on bone healing and bone regeneration and the contribution of each cell type thereby. The results show that the investigated substances had more pronounced effects on both osteoblasts and osteoclasts in the co-culture system than in respective monocultures. PMID- 28667749 TI - Empirical modeling of T cell activation predicts interplay of host cytokines and bacterial indole. AB - Adoptive transfer of anti-inflammatory FOXP3+ Tregs has gained attention as a new therapeutic strategy for auto-inflammatory disorders such as Inflammatory Bowel Disease. The isolated cells are conditioned in vitro to obtain a sufficient number of anti-inflammatory FOXP3+ Tregs that can be reintroduced into the patient to potentially reduce the pathologic inflammatory response. Previous evidence suggests that microbiota metabolites can potentially condition cells during the in vitro expansion/differentiation step. However, the number of combinations of cytokines and metabolites that can be varied is large, preventing a purely experimental investigation which would determine optimal cell therapeutic outcomes. To address this problem, a combined experimental and modeling approached is investigated here: an artificial neural network model was trained to predict the steady-state T cell population phenotype after differentiation with a variety of host cytokines and the microbial metabolite indole. This artificial neural network model was able to both reliably predict the phenotype of these T cell populations and also uncover unexpected conditions for optimal Treg differentiation that were subsequently verified experimentally. Biotechnol. Bioeng. 2017;114: 2660-2667. (c) 2017 Wiley Periodicals, Inc. PMID- 28667750 TI - Flt3 ligand-eGFP-reporter expression characterizes functionally distinct subpopulations of CD150+ long-term repopulating murine hematopoietic stem cells. AB - The pool of hematopoietic stem cells (HSCs) in the bone marrow is a mixture of resting, proliferating, and differentiating cells. Long-term repopulating HSCs (LT-HSC) are routinely enriched as Lin- Sca1+ c-Kit+ CD34- Flt3- CD150+ CD48- cells. The Flt3 ligand (Flt3L) and its receptor Flt3 are important regulators of HSC maintenance, expansion and differentiation. Using Flt3L-eGFP reporter mice, we show that endogenous Flt3L-eGFP-reporter RNA expression correlates with eGFP protein expression. This Flt3L-eGFP-reporter expression distinguishes two LT-HSC populations with differences in gene expressions and reconstituting potential. Thus, Flt3L-eGFP-reporterlow cells are identified as predominantly resting HSCs with long-term repopulating capacities. In contrast, Flt3L-eGFP-reporterhigh cells are in majority proliferating HSCs with only short-term repopulating capacities. Flt3L-eGFP-reporterlow cells express hypoxia, autophagy-inducing, and the LT-HSC-associated genes HoxB5 and Fgd5, while Flt3L-eGFP-reporterhigh HSCs upregulate genes involved in HSC differentiation. Flt3L-eGFP-reporterlow cells develop to Flt3L-eGFP-reporterhigh cells in vitro, although Flt3L-eGFP reporterhigh cells remain Flt3L-eGFP-reporterhigh . CD150+ Flt3L-eGFP-reporterlow cells express either endothelial protein C receptor (EPCR) or CD41, while Flt3L eGFP-reporterhigh cells do express EPCR but not CD41. Thus, FACS-enrichment of Flt3/ Flt3L-eGFP-reporter negative, Lin- CD150+ CD48- EPCR+ CD41+ HSCs allows a further 5-fold enrichment of functional LT-HSCs. PMID- 28667753 TI - Invasive dermatophyte infection with Trichophyton interdigitale is associated with prurigo-induced pseudoperforation and a signal transducer and activator of transcription 3 mutation. AB - Invasive dermatophyte infection, with extension beyond the dermis, in immunocompetent hosts is exceptionally rare. Dermatophytes are keratinophilic and are usually confined to the stratum corneum, hair and nails. Susceptibility to dermatophyte infections is incompletely understood, but inherited mutations in key signalling pathways of the innate immune system have been identified. We report the first case of an invasive dermatophyte infection associated with abrupt onset of a prurigo-induced pseudoperforation and a loss-of-function mutation in signal transducer and activator of transcription 3 (STAT3). PMID- 28667752 TI - In vitro analysis of 4-methylumbelliferone as a sole carbon source for Lactobacillus helveticus 2126. AB - : In the recent years, 4-methylumbelliferone (4-MU) has been gaining importance, both as an anti-cancer agent and as a dietary supplement. The aim of this study was to determine the effectiveness of 4-MU as a carbon source for potential probiotic bacteria Lactobacillus helveticus 2126. For this purpose, a series of plate assays and infrared spectroscopy (FTIR) were used for 4-MU before and after the treatment with L. helveticus 2126. The plate assays indicated an initial inhibition followed by utilization of 4-MU that stimulated bacterial growth. A significant shift was observed in the FTIR peaks, which also have suggested possible extracellular activity of the bacteria for 4-MU utilization. SIGNIFICANCE AND IMPACT OF THE STUDY: 4-Methylumbelliferone (4-MU) is a widely used chloretic and is currently under research for treating colon cancer. Preliminary studies suggest that it has the potential to be used as an effective and sustainable prebiotic for the human microbiome, as it can be naturally obtained from plants. This manuscript describes the effectiveness of 4-MU as a carbon source for the probiotic bacteria Lactobacillus helveticus. Our study also suggests the role of bacterial superoxide dismutase in transforming 4-MU as a possible prebiotic for the human microbiome. PMID- 28667754 TI - MTA-induced Notch activation enhances the proliferation of human dental pulp cells by inhibiting autophagic flux. AB - AIM: To determine the roles of autophagy and Notch signalling in mineral trioxide aggregate (MTA)-mediated proliferation and differentiation of human dental pulp cells (hDPCs). METHODOLOGY: hDPCs were separated from human healthy molar teeth using collagenase I/dispase II digestion and then cultured in alpha-MEM medium with 15% foetal bovine serum. hDPCs were seeded in 96-well plates, and cell counting kit assays were carried out to test their viability. Real-time quantitative polymerase chain reaction (qPCR) was used to evaluate ALP, Runx2, Notch1, Hes1 and Hey1 mRNA levels. Notch1, hes1, LC3 and p62 protein levels were quantified by Western blotting. Colocalization of LC3 and Notch1 was measured by immunofluorescence. Two-tailed Student's t-tests were used for statistical analysis. RESULTS: Autophagic flux was significantly (P < 0.05) inhibited by MTA extracts, causing Notch degradation arrest. This resulted in the promotion of cell proliferation and inhibition of differentiation during the logarithmic phase of cell growth. CONCLUSION: MTA extract promoted the proliferation of hDPCs in part by activating Notch signalling through inhibition of autophagic flux during the early stage and, thus, might potentially induce rapid restoration of injured pulps. PMID- 28667756 TI - Prognosis and predictors of hepatocellular carcinoma in elderly patients infected with hepatitis B virus. AB - With rapidly aging population in the world, many elderly patients present with hepatitis B virus (HBV) infection. We conducted a retrospective cohort study involving 359 untreated HBV patients aged 60 and older who were free of hepatocellular carcinoma (HCC) and acute hepatitis at the initial visit, and examined the incidence of HCC and liver-related mortality rate. During the follow up period of 7.9 years (range, 0-25 years), 26 patients (7.2% of patients) developed HCC, 20 patients died from liver-related diseases (61% of total deaths), including HCC, liver failure, and gastrointestinal bleeding. The cumulative rates of HCC at years 5, 10, and 15 were 6.5%, 15.6%, and 15.6%, respectively. The cumulative rates of mortality from liver-related diseases at years 5, 10, 15 were 3.3%, 12.3%, and 15.7%, respectively. Multivariate analysis identified HBV DNA (>=5.0 Log IU/mL), male gender, and FIB4-Index (>=3.6) as significant independent risk factors for HCC, and alpha-fetoprotein (>=10 ng/mL) as significant independent predictors of liver-related mortality. We conclude that high levels of HBV DNA, progression of liver fibrosis, and male gender are independent risk factors of HCC in untreated patients infected with HBV aged 60 and older. PMID- 28667755 TI - Incidence and risk factors for human papillomavirus infections in young female online daters. AB - Risk factors for incident human papillomavirus (HPV) infections are undefined in young women who use internet dating Web sites. From 2010-2012 we followed 18- to 24-year-old female internet daters (N = 164) triannually for a mean of 1 year. Women collected and returned self-collected vaginal samples for HPV genotyping and health and behavior questionnaires. We used Kaplan-Meier methods to estimate incidence of clinically relevant HPV infection (high-risk HPV, HPV-6, or HPV-11) and generalized estimating equations and Firth logistic regression to identify associated risk factors. At enrollment, women reported a median lifetime number of six male sex partners, and 36% reported a history of HPV vaccination. The 12 month cumulative incidence of clinically relevant HPV was 32.9% (95%CI: 26.0 41.0%). Reporting a recent male sex partner met via the internet versus not was not significantly associated with incident HPV (odds ratio [OR] = 0.91, 95%CI: 0.53-1.55). In multivariate analysis adjusted for lifetime number of partners, reporting new and/or multiple partners in the past 6 months was positively associated with incident HPV (OR = 6.38, 95%CI: 1.56-26.02, compared to reporting no recent partners). In a separate model, self-reporting >=1 dose of HPV vaccine was inversely associated with vaccine-type HPV (6/11/16/18) (OR = 0.21, 95%CI: 0.05-0.86), but the association was attenuated and not statistically significant after adjusting for sexual history (OR = 0.36, 95%CI: 0.09-1.43). While recent high-risk sexual behavior was associated with incident HPV, sex with partners met via the internet was not associated with increased HPV risk in young female internet daters. Although not statistically significant after adjusting for sexual history, HPV vaccination showed substantial protection against vaccine type HPV infection. PMID- 28667757 TI - Intracellular characterization of Gag VLP production by transient transfection of HEK 293 cells. AB - Transient transfection is a fast, flexible, and cost-effective approach to produce biological products. Despite the continued interest in transient transfection, little is known regarding the transfection process at the intracellular level, particularly for complex products, such as virus-like particles (VLPs). The kinetics of PEI-mediated transfection following an established in-house protocol is reported in this work with the aim of characterizing and understanding the complete process leading to VLP generation and identifying important events driving process improvement. For this purpose, DNA/PEI polyplexes' internalization in cells was tracked using Cy3 DNA staining. The production of a fluorescently labeled Gag polyprotein (a Gag-GFP fusion construct that forms fluorescent Gag-VLPs) was monitored by flow cytometry and confocal microscopy, and the VLP concentration in supernatants was measured by fluorometry. DNA/PEI polyplexes interact with the cell membrane immediately after polyplex addition to the cell culture. A linear increase in the number of cells expressing the protein is observed during the first 60 min of contact between the cells and polyplexes. No additional improvement in the number of cells expressing the protein (up to 60%) or VLP production (up to 1 * 1010 VLPs/mL) is observed with additional contact time between the cells and polyplexes. Polyplexes can be detected in the cytoplasm of transfected cells as early as 1.5 h post transfection (hpt) and reach the nucleus approximately 4 hpt. GFP fluorescence is observed homogeneously in the cytoplasm of transfected cells 24 hpt, but generalized VLP budding is not observed by microscopy until 48 hpt. Although all cells have internalized a polyplex soon after transfection, only a fraction of cells (60%) express the fluorescent Gag protein. VLP production kinetics was also studied. Fluorescence in the supernatant (enveloped VLPs) is 40% less than total fluorescence, supernatant plus pellet (total Gag-GFP), indicating that there is a fraction of Gag that remains inside the cells. The maximum VLP concentration in the cell culture supernatant with cell viability >89% was observed at 72 hpt, which was determined to be the optimal harvest time. Biotechnol. Bioeng. 2017;114: 2507-2517. (c) 2017 Wiley Periodicals, Inc. PMID- 28667758 TI - TGF-beta and Th17 cells related injuries in patients with sulfur mustard exposure. AB - Sulfur mustard (SM) is a vesicating agent that has been employed as a chemical warfare agent. High-dose exposure to sulfur mustard may lead to the damage of rapidly proliferating cells of bone marrow and, therefore, suppression of the immune system. This may be continued as dysfunction of the immune system, and ultimately result in secondary immune disorders. Studies have suggested a role for T cells in SM-induced lung injury. Moreover, observations from animal studies indicate a delayed-type hypersensitivity (DTH) response after skin exposure to SM, providing an understanding that SM can stimulate specific T cell-mediated immune responses. On the other hand, T helper (Th) 17 cells, which are a subset of CD4+ T cells, have recently been reported to be involved in a number of inflammatory, autoimmune, and chronic fibrotic lung diseases. Furthermore, a strong association has been established between the overproduction of profibrotic cytokines like transforming growth factor (TGF)-beta and Th17 cell number. In this review, we aimed to go through the new findings about the involvement and interactions of TGF-beta and Th17 in SM-related injuries. PMID- 28667759 TI - Experiences of rosacea and its treatment: an interpretative phenomenological analysis. AB - BACKGROUND: While rosacea is a chronic skin condition, it can often have a large psychosocial impact on the individual. There is therefore a need to understand the experience of living with rosacea from the patient perspective. OBJECTIVES: To examine the experience of living with rosacea and the experience of seeking and receiving treatment. METHODS: Nine participants took part in semistructured interviews, which were analysed using interpretative phenomenological analysis. RESULTS: Three superordinate themes were identified within the data: 'self consciousness', which focused on the fear of others assigning blame to participants for having caused symptoms; 'avoidance, concealment and hiding emotions', referring to the coping strategies participants employed in response to rosacea; and 'inconsistencies in general practitioner treatment and guidance', which focused on the need for medical professionals to assess the psychosocial well-being of patients with rosacea. CONCLUSIONS: Rosacea can have a negative impact on the daily life of people with the condition, contributing to lowered self-esteem, embarrassment and feelings of shame. Engaging in emotion-focused and behavioural/avoidant-focused coping strategies increased participants' confidence and reduced their avoidance of social situations. However, such strategies might still serve to maintain underlying unhelpful cognitive processes. Consequently, it is important for medical professionals to assess for the presence of cognitive factors that might contribute to maintaining distress in patients with rosacea, and where unhelpful thoughts or beliefs are reported, patients may need to be referred for psychological support. PMID- 28667760 TI - AGREE II assessments of recent acne treatment guidelines: how well do they reveal trustworthiness as defined by the U.S. Institute of Medicine criteria? AB - BACKGROUND: Up-to-date, trustworthy guidelines are a widely relied upon means of promoting excellent patient care. OBJECTIVES: To determine the quality of recently published acne treatment guidelines by utilizing the Appraisal of Guidelines for Research and Evaluation (AGREE) II Reporting Checklist, the U.S. Institute of Medicine's (IOM) criteria of trustworthiness, the red flags of Lenzer et al. and CheckUp. METHODS: Systematic searches were conducted in bibliographic databases, guideline depositories and using Google to identify acne treatment guidelines published since 2013. Six assessors independently scored each guideline using the AGREE II Reporting Checklist. Guidelines were concomitantly assessed for trustworthiness using the IOM criteria and for the red flags of Lenzer et al., indicative of potential bias. Updates were screened using CheckUp. RESULTS: Eight guidelines were identified, two of which were updates. Lowest scoring AGREE II domains across all guidelines were applicability (six poor, one fair, one average) and rigour (four poor, one fair, three average). Two of the three highest-scoring guidelines were developed using AGREE II. No guideline fully met each IOM criterion and all raised at least one red flag indicative of potential bias. One updated guideline did not address seven of 16 items on CheckUp and the other did not address four. Patient involvement in guideline development was minimal. CONCLUSIONS: Use of the AGREE II instrument during guideline development did not have as great an effect on guideline quality as might be expected. There is considerable room for improvement in acne treatment guidelines in order to satisfy the IOM trustworthiness criteria and avoid bias. PMID- 28667761 TI - Persistent accumulation of gut macrophages with impaired phagocytic function correlates with SIV disease progression in macaques. AB - The contribution of macrophages in the gastrointestinal tract to disease control or progression in HIV infection remains unclear. To address this question, we analyzed CD163+ macrophages in ileum and mesenteric lymph nodes (LN) from SIV infected rhesus macaques with dichotomous expression of controlling MHC class I alleles predicted to be SIV controllers or progressors. Infection induced accumulation of macrophages into gut mucosa in the acute phase that persisted in progressors but was resolved in controllers. In contrast, macrophage recruitment to mesenteric LNs occurred only transiently in acute infection irrespective of disease outcome. Persistent gut macrophage accumulation was associated with CD163 expression on alpha4beta7+ CD16+ blood monocytes and correlated with epithelial damage. Macrophages isolated from intestine of progressors had reduced phagocytic function relative to controllers and uninfected macaques, and the proportion of phagocytic macrophages negatively correlated with mucosal epithelial breach, lamina propria Escherichia coli density, and plasma virus burden. Macrophages in intestine produced low levels of cytokines regardless of disease course, while mesenteric LN macrophages from progressors became increasingly responsive as infection advanced. These data indicate that noninflammatory CD163+ macrophages accumulate in gut mucosa in progressive SIV infection in response to intestinal damage but fail to adequately phagocytose debris, potentially perpetuating their recruitment. PMID- 28667762 TI - Enhanced isoprenoid production from xylose by engineered Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae has limited capabilities for producing fuels and chemicals derived from acetyl-CoA, such as isoprenoids, due to a rigid flux partition toward ethanol during glucose metabolism. Despite numerous efforts, xylose fermentation by engineered yeast harboring heterologous xylose metabolic pathways was not as efficient as glucose fermentation for producing ethanol. Therefore, we hypothesized that xylose metabolism by engineered yeast might be a better fit for producing non-ethanol metabolites. We indeed found that engineered S. cerevisiae on xylose showed higher expression levels of the enzymes involved in ethanol assimilation and cytosolic acetyl-CoA synthesis than on glucose. When genetic perturbations necessary for overproducing squalene and amorphadiene were introduced into engineered S. cerevisiae capable of fermenting xylose, we observed higher titers and yields of isoprenoids under xylose than glucose conditions. Specifically, co-overexpression of a truncated HMG1 (tHMG1) and ERG10 led to substantially higher squalene accumulation under xylose than glucose conditions. In contrast to glucose utilization producing massive amounts of ethanol regardless of aeration, xylose utilization allowed much less amounts of ethanol accumulation, indicating ethanol is simultaneously re-assimilated with xylose consumption and utilized for the biosynthesis of cytosolic acetyl-CoA. In addition, xylose utilization by engineered yeast with overexpression of tHMG1, ERG10, and ADS coding for amorphadiene synthase, and the down-regulation of ERG9 resulted in enhanced amorphadiene production as compared to glucose utilization. These results suggest that the problem of the rigid flux partition toward ethanol production in yeast during the production of isoprenoids and other acetyl-CoA derived chemicals can be bypassed by using xylose instead of glucose as a carbon source. Biotechnol. Bioeng. 2017;114: 2581-2591. (c) 2017 Wiley Periodicals, Inc. PMID- 28667763 TI - Greater Prevalence of Proposed ICD-11 Alcohol and Cannabis Dependence Compared to ICD-10, DSM-IV, and DSM-5 in Treated Adolescents. AB - BACKGROUND: Proposed International Classification of Diseases, 11th edition (ICD 11), criteria for substance use disorder (SUD) radically simplify the algorithm used to diagnose substance dependence. Major differences in case identification across DSM and ICD impact determinations of treatment need and conceptualizations of substance dependence. This study compared the draft algorithm for ICD-11 SUD against DSM-IV, DSM-5, and ICD-10, for alcohol and cannabis. METHODS: Adolescents (n = 339, ages 14 to 18) admitted to intensive outpatient addictions treatment completed, as part of a research study, a Structured Clinical Interview for DSM SUDs adapted for use with adolescents and which has been used to assess DSM and ICD SUD diagnoses. Analyses examined prevalence across classification systems, diagnostic concordance, and sources of diagnostic disagreement. RESULTS: Prevalence of any past-year proposed ICD-11 alcohol or cannabis use disorder was significantly lower compared to DSM-IV and DSM-5 (ps < 0.01). However, prevalence of proposed ICD-11 alcohol and cannabis dependence diagnoses was significantly higher compared to DSM-IV, DSM-5, and ICD-10 (ps < 0.01). ICD-11 and DSM-5 SUD diagnoses showed only moderate concordance. For both alcohol and cannabis, youth typically met criteria for an ICD-11 dependence diagnosis by reporting tolerance and much time spent using or recovering from the substance, rather than symptoms indicating impaired control over use. CONCLUSIONS: The proposed ICD-11 dependence algorithm appears to "overdiagnose" dependence on alcohol and cannabis relative to DSM-IV and ICD-10 dependence, and DSM-5 moderate/severe use disorder, generating potential "false-positive" cases of dependence. Among youth who met criteria for proposed ICD-11 dependence, few reported impaired control over substance use, highlighting ongoing issues in the conceptualization and diagnosis of SUD. PMID- 28667764 TI - Human polyomavirus 9 in immunocompromised patients in the University Hospital in Hradec Kralove, Czech Republic. AB - Human polyomaviruses such as JC polyomavirus and BK polyomavirus have long been well known pathogens of immunocompromised patients. Several new members of this viral family have been described during the last decade. Human polyomavirus 9 seems to be a novel pathogen of transplanted patients according to some studies. The aim of our study was to determine the presence of human polyomavirus 9 in patients after kidney or stem cell transplantation (SCT) at the University Hospital in Hradec Kralove, Czech Republic. Overall 100 patients, 65 after kidney transplantation and 35 after SCT, were included into the study. At least three follow-up samples from each patient were examined for human polyomavirus 9 DNA presentation with the two previously described in-house PCR protocols. Despite the frequent reactivation of human CMV (14.3% in kidney transplantation and 63.3% after SCT) or BK polyomavirus in our patient group, there was no positivity for human polyomavirus 9 either in blood samples or urine samples. One of the possible reasons for this discrepancy versus previous published studies could be a relatively low proportion of patients treated by induction therapy before kidney transplantation in our study cohort. PMID- 28667766 TI - Shared decision-making, value pluralism and the zone of parental discretion. PMID- 28667765 TI - The effects of 2-hydroxyethyl methacrylate on matrix metalloproteinases 2 and 9 in human pulp cells and odontoblast-like cells in vitro. AB - AIM: To assess the effects of 2-hydroxyethyl methacrylate (HEMA) on proliferation and migration of human pulp cells, as well as on matrix metalloproteinase (MMP-2 and MMP-9) expression in human odontoblast-like cells, contributing to the goal of determining the relationship between resin materials and MMP activity in pulp dentine complexes. METHODOLOGY: Dental pulp cell cultures were established from pulp tissue of human teeth extracted for orthodontic purposes. Pulp cell differentiation was characterized in the presence of dentine sialophosphoprotein, bone sialoprotein and alkaline phosphatase by reverse transcription polymerase chain reaction. MMP activity was assessed by gelatine zymography with media containing HEMA. Cell viability was evaluated using methyl thiazolyl tetrazolium assay for 24-72 h. Cell migration was tested using Transwell migration assay. Western blotting was used to visualize MMP expression with the nontoxic HEMA concentrations (0-400 MUg mL-1 ) for 48 h. RESULTS: Pulp cell proliferation decreased with HEMA exposure in a time- and concentration-dependent manner. HEMA concentrations <=400 MUg mL-1 did not induce changes in cell viability at 48 h (P < 0.05). Pulp cells were induced to differentiate into odontoblast-like cells in media containing 5 mg mL-1 ascorbic acid and 10 mmol L-1 beta-sodium glycerophosphate for 3-4 weeks. After incubation with HEMA, dose-dependent inhibition was observed; HEMA had a strong inhibitory effect on MMP activity. Compared with the control group, cell migration and MMP expression were inhibited significantly with increasing HEMA concentration at noncytotoxic doses (P < 0.05). CONCLUSIONS: Cell viability was not affected at HEMA concentrations <=400 MUg mL-1 . Within this range, HEMA inhibited MMP-2 and MMP-9 expression and activity, which may protect against type I collagen degradation effectively during dentine adhesive procedures. PMID- 28667767 TI - Equine meniscal degeneration is associated with medial femorotibial osteoarthritis. AB - BACKGROUND: There is limited information available concerning normal equine meniscal morphology, its degeneration and role in osteoarthritis (OA). OBJECTIVES: To characterise normal equine meniscal morphology and lesions and to explore the relationship between equine meniscal degeneration and femorotibial OA. STUDY DESIGN: Ex vivo cadaveric study. METHODS: Menisci were harvested from 7 normal joints (n = 14 menisci) and 15 joints with OA (n = 30 menisci). A macroscopic femorotibial OA score (cartilage degeneration and osteophytosis) was employed to measure disease severity in each compartment. The femoral and tibial meniscal surfaces were scored for macroscopic fibrillation and tears (1-4). Histological sections (regions: cranial and caudal horn; body) were also scored for microscopic fibrillation and tears (0-3) and inner border degeneration (0-3). RESULTS: Partial meniscal tears were present on both femoral and tibial surfaces in all 3 regions and most frequently identified on the femoral surface of the cranial horn of the medial meniscus and body of the lateral meniscus. There was a significantly positive correlation between the global medial meniscal macroscopic scores and osteophyte (r = 0.7, P = 0.002) or cartilage degeneration (r = 0.5, P = 0.03) scores within the medial femorotibial joint. The global medial meniscal macroscopic score was greater (P = 0.004) in the advanced OA joints compared with control joints. MAIN LIMITATIONS: The menisci were principally from abattoir specimens without a known clinical history because of the challenge in obtaining a large number of specimens with a clinical diagnosis of femorotibial OA. CONCLUSIONS: This study is the first to describe normal equine meniscal morphology and lesions. Meniscal lesions were identified in all segments and on both articular surfaces. Meniscal degeneration significantly correlated with OA severity in the equine medial femorotibial joint. The relationship between OA and meniscal pathology remains to be elucidated. PMID- 28667768 TI - Chronic toxicity of aluminum, at a pH of 6, to freshwater organisms: Empirical data for the development of international regulatory standards/criteria. AB - The chemistry, bioavailability, and toxicity of aluminum (Al) in the aquatic environment are complex and affected by a wide range of water quality characteristics (including pH, hardness, and dissolved organic carbon). Data gaps in Al ecotoxicology exist for pH ranges representative of natural surface waters (pH 6-8). To address these gaps, a series of chronic toxicity tests were performed at pH 6 with 8 freshwater species, including 2 fish (Pimephales promelas and Danio rerio), an oligochaete (Aeolosoma sp.), a rotifer (Brachionus calyciflorus), a snail (Lymnaea stagnalis), an amphipod (Hyalella azteca), a midge (Chironomus riparius), and an aquatic plant (Lemna minor). The 10% effect concentrations (EC10s) ranged from 98 MUg total Al/L for D. rerio to 2175 MUg total Al/L for L. minor. From these data and additional published data, species sensitivity distributions (SSDs) were developed to derive concentrations protective of 95% of tested species (i.e., 50% lower confidence limit of a 5th percentile hazard concentration [HC5-50]). A generic HC5-50 (not adjusted for bioavailability) of 74.4 MUg total Al/L was estimated using the SSD. An Al specific biotic ligand model (BLM) was used to develop SSDs normalized for bioavailability based on site-specific water quality characteristics. Normalized HC5-50s ranged from 93.7 to 534 MUg total Al/L for waters representing a range of European ecoregions, whereas a chronic HC5 calculated using US Environmental Protection Agency aquatic life criteria methods (i.e., a continuous criterion concentration [CCC]) was 125 MUg total Al/L when normalized to Lake Superior water in the United States. The HC5-50 and CCC values for site-specific waters other than those in the present study can be obtained using the Al BLM. Environ Toxicol Chem 2018;37:36-48. (c) 2017 SETAC. PMID- 28667769 TI - Resistance to RHD virus in wild Australian rabbits: Comparison of susceptible and resistant individuals using a genomewide approach. AB - Deciphering the genes involved in disease resistance is essential if we are to understand host-pathogen coevolutionary processes. The rabbit haemorrhagic disease virus (RHDV) was imported into Australia in 1995 as a biocontrol agent to manage one of the most successful and devastating invasive species, the European rabbit (Oryctolagus cuniculus). During the first outbreaks of the disease, RHDV caused mortality rates of up to 97%. Recently, however, increased genetic resistance to RHDV has been reported. Here, we have aimed to identify genomic differences between rabbits that survived a natural infection with RHDV and those that died in the field using a genomewide next-generation sequencing (NGS) approach. We detected 72 SNPs corresponding to 133 genes associated with survival of a RHD infection. Most of the identified genes have known functions in virus infections and replication, immune responses or apoptosis, or have previously been found to be regulated during RHD. Some of the genes identified in experimental studies, however, did not seem to play a role under natural selection regimes, highlighting the importance of field studies to complement the genomic background of wildlife diseases. Our study provides a set of candidate markers as a tool for the future scanning of wild rabbits for their resistance to RHDV. This is important both for wild rabbit populations in southern Europe where RHD is regarded as a serious problem decimating the prey of endangered predator species and for assessing the success of currently planned RHDV variant biocontrol releases in Australia. PMID- 28667770 TI - Professionals' positive perceptions of fathers are associated with more favourable attitudes towards including them in family interventions. AB - AIM: This Universite du Quebec en Outaouais study examined professionals' attitudes towards fathers, their perceived self-efficacy when working with them and their perceptions of the importance of including fathers in family interventions. METHODS: Professionals in Quebec, Canada, working in childcare fields such as education, social services, health, community services and management answered a self-report questionnaire between 2013 and 2015. The 296 respondents (90% females) had a mean age of 39 (20-65), were from urban, semi urban and rural settings and provided services to families with children up to five years of age. RESULTS: Social service professionals perceived fathers more negatively than did other professionals. Even though male professionals perceived fathers more negatively, they felt more confident working with them than did their female counterparts. Positive perceptions of fathers were associated with more favourable attitudes towards including them in family interventions, and this association was mediated by the professionals' perceptions of their own self efficacy. CONCLUSION: The most negative attitudes were reported by social service professionals. Male professionals viewed fathers more negatively but were more confident working with them than were female colleagues. Improving professionals' perceptions of fathers could help to promote their inclusion in family interventions. PMID- 28667771 TI - Long-Term Effects of Severe Burn Injury on Bone Turnover and Microarchitecture. AB - Severe burn injury triggers massive alterations in stress hormone levels with a dose-dependent hypermetabolic status including increased bone resorption. This study evaluated bone microarchitecture measured by noninvasive high-resolution peripheral quantitative computed tomography (HR-pQCT). Changes of serum bone turnover markers (BTM) as well as regulators of bone signaling pathways involved in skeletal health were assessed. Standardized effect sizes as a quantitative measure regarding the impact of serum changes and the prediction of these changes on bone microarchitecture were investigated. In total, 32 male patients with a severe burn injury (median total body surface area [TBSA], 40.5%; median age 40.5 years) and 28 matched male controls (median age 38.3 years) over a period of 24 months were included. In patients who had sustained a thermal injury, trabecular and cortical bone microstructure showed a continuous decline, whereas cortical porosity (Ct.Po) and pore volume increased. Initially, elevated levels of BTM and C-reactive protein (CRP) continuously decreased over time but remained elevated. In contrast, levels of soluble receptor activator of NF-kappaB ligand (sRANKL) increased over time. Osteocalcin, bone-specific alkaline phosphatase (BALP), intact N-terminal type 1 procollagen propeptide (P1NP), and cross-linked C telopeptide (CTX) acutely reflected the increase of Ct.Po at the radius (R2 = 0.41), followed by the reduction of trabecular thickness at the tibia (R2 = 0.28). In adult male patients, early and sustained changes of markers of bone resorption, formation and regulators of bone signaling pathways, prolonged inflammatory cytokine activities in conjunction with muscle catabolism, and vitamin D insufficiency were observed. These alterations are directly linked to a prolonged deterioration of bone microstructure. The probably increased risk of fragility fractures should be of clinical concern and subject to future interventional studies with bone-protective agents. (c) 2017 American Society for Bone and Mineral Research. PMID- 28667772 TI - Genotypic diversity in root-endophytic fungi reflects efficient dispersal and environmental adaptation. AB - Studying community structure and dynamics of plant-associated fungi is the basis for unravelling their interactions with hosts and ecosystem functions. A recent sampling revealed that only a few fungal groups, as defined by internal transcribed spacer region (ITS) sequence similarity, dominate culturable root endophytic communities of nonmycorrhizal Microthlaspi spp. plants across Europe. Strains of these fungi display a broad phenotypic and functional diversity, which suggests a genetic variability masked by ITS clustering into operational taxonomic units (OTUs). The aims of this study were to identify how genetic similarity patterns of these fungi change across environments and to evaluate their ability to disperse and adapt to ecological conditions. A first ITS-based haplotype analysis of ten widespread OTUs mostly showed a low to moderate genotypic differentiation, with the exception of a group identified as Cadophora sp. that was highly diverse. A multilocus phylogeny based on additional genetic loci (partial translation elongation factor 1alpha, beta-tubulin and actin) and amplified fragment length polymorphism profiling of 185 strains representative of the five dominant OTUs revealed a weak association of genetic differences with geography and environmental conditions, including bioclimatic and soil factors. Our findings suggest that dominant culturable root endophytic fungi have efficient dispersal capabilities, and that their distribution is little affected by environmental filtering. Other processes, such as inter- and intraspecific biotic interactions, may be more important for the local assembly of their communities. PMID- 28667774 TI - When sperm meets egg: the spark of new life. PMID- 28667773 TI - Short stature homeobox-containing gene duplications in 3.7% of girls with tall stature and normal karyotypes. AB - AIM: The short stature homeobox-containing gene (SHOX) plays an important role in short stature, but has not been explored in detail in a tall stature population before. This study explored the prevalence of SHOX aberrations in girls diagnosed with idiopathic tall stature with a normal karyotype. METHODS: We studied SHOX aberrations in 81 girls with a median age of 10.43 (7.17-12.73) years diagnosed with tall stature who were referred to our clinic at Copenhagen University Hospital, Denmark, between 2003 and 2013. SHOX copy variations were analysed by quantitative polymerase chain reaction, and aberrations were confirmed by multiplex ligation probe-dependent amplification. RESULTS: One extra SHOX copy was found in three (3.7%) of the 81 girls with tall stature, and their heights were 2.87, 3.71 and 3.98 standard deviation scores (SDS) and above the median height SDS of the girls with two SHOX copies. Their sitting height/height ratios (-3.08, -2.00 and -2.18 SDS) were all lower than the population mean. Despite these SHOX duplications, the three girls were clinically and biochemically comparable to the 78 girls with two SHOX copies. CONCLUSION: This study was the first to demonstrate SHOX duplications in three girls with tall stature and normal karyotypes. PMID- 28667775 TI - A one-step immune-chromatographic Helicobacter pylori stool antigen test for children was quick, consistent, reliable and specific. AB - AIM: This French study assessed a quick, noninvasive, immuno-chromatographic, Helicobacter pylori (H. pylori) stool antigen test for detecting infections in children. METHODS: We enrolled 158 children, with a median age of 8.5 years (range eight months to 17 years), with digestive symptoms suggesting upper gastrointestinal tract disease. Upper digestive endoscopy was performed with gastric biopsy specimens for histology, a rapid urease test, culture test and quantitative real-time polymerase chain reaction. The H. pylori stool antigen test was performed twice for each child and the results were compared to the reference method. RESULTS: The reference methods showed that 23 (14.6%) of the 158 children tested were H. pylori positive. The H. pylori stool antigen test showed 91.3% sensitivity, with a 95% confidence interval (95% CI) of 86.9-95.6 and 97% specificity (95% CI 94.3-99.6), 30.84 positive likelihood ratio and 0.09 negative likelihood ratio. The test accuracy was 96.2% (95% CI 93.2-99.1). The two blinded independent observers produced identical H. pylori stool antigen test results and the Kappa coefficient for the H. pylori stool antigen test was one. CONCLUSION: The H. pylori stool antigen test was found to be a consistent, reliable, quick and specific test for detecting the H. pylori infection in children. PMID- 28667777 TI - Review of phase III trial data on IL-23 inhibitors tildrakizumab and guselkumab for psoriasis. AB - The development of monoclonal antibodies targeting IL-12 and IL-23 has enhanced the therapeutic options available for psoriasis patients. Recent research suggests that IL-23 alone plays a role in the pathogenesis of psoriasis. The objective was to review the phase III clinical trial data for the anti-IL-23 agents to evaluate the safety and efficacy profile of each agent. We reviewed the results of the phase III clinical trials for the anti-IL-23 agents tildrakizumab and guselkumab. The results of phase III trials on risankizumab have not yet been reported. By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was >60% among the most efficacious dose of each agent. The percentage of patients achieving PASI 90 at week 16 was the primary endpoint for the phase III trials for guselkumab, which was above 70%. The safety profiles of the agents were comparable, with the most commonly reported adverse events of nasopharyngitis and upper respiratory tract infections. The anti-IL-23 agents demonstrated a rapid clinical improvement that is similar or superior to the improvement seen with currently marketed IL-17 inhibitors with a favourable short term safety profile. The results of the phase III trials support the notion that IL-23 is a potential target in psoriasis treatment. PMID- 28667776 TI - Preservation of truncal genomic alterations in clear cell and papillary renal cell carcinomas with sarcomatoid features: An intra- and intertumoral, multifocal fluorescence in situ hybridization analysis reveals limited genetic heterogeneity. AB - Understanding tumor genomic heterogeneity may offer vital information in an age of targeted therapy for renal cell carcinoma. We sought to investigate hallmark truncal chromosomal alterations between conventional, sarcomatoid, and matched metastatic tumor foci in clear cell and papillary renal cell carcinomas. A retrospective review identified 58 cases including clear cell (CCRCC) and papillary renal cell carcinomas (PRCC). All cases contained sarcomatoid transformation. Additionally, 10 of 58 patients had matched metastatic disease available for analysis. Three separate foci of conventional and sarcomatoid morphologies were analyzed in each tumor using dual color interphase fluorescence in situ hybridization. In the CCRCC cohort, hallmark chromosome 3p deletion was identified in 71% of cases (37/52). Complete concordance of chromosomal status between intratumoral foci in sarcomatoid and conventional foci was 89% and 86%, respectively. Overall chromosome 3p status between matched conventional and sarcomatoid morphologies was identified in 98% of cases (51/52). Hallmark 3p deletion was present in 91% of CCRCC metastatic samples (10/11) and was concordant with the matched primary CCRCC tumor in 91% (10/11). In the PRCC cohort, trisomy 7 and 17 was identified in all six cases (6/6). Complete concordance between intratumoral foci of trisomy 7 and 17 was 83% (5/6). Trisomy 7 and 17 were identified in all metastatic PRCC samples with 100% concordance with the matched primary tumor. These data show the relative preservation of truncal chromosomal abnormalities between conventional and sarcomatoid morphologic as well as matched metastatic settings. PMID- 28667778 TI - Organ donation following euthanasia starting at home. PMID- 28667779 TI - Suberoylanilide hydroxamic acid induces thioredoxin1-mediated apoptosis in lung cancer cells via up-regulation of miR-129-5p. AB - Histone deacetylase (HDAC) inhibitors, especially suberoylanilide hydroxamic acid (SAHA) induce apoptosis in various cancer cells. Here, we investigated the effect of SAHA on apoptosis in lung cancer cells and addressed the role of reactive oxygen species (ROS), glutathione (GSH), and thioredoxin1 (Trx1) levels in this process. We also identified the miRNAs that down-regulate Trx1 expression at RNA level and thereby influence apoptotic cell death of SAHA increased intracellular ROS levels and promoted apoptotic cell death in cancerous cells but not in non cancerous normal lung cells. Likewise, SAHA induced GSH depletion specifically in cancerous cells. While N-acetyl cysteine (NAC) reduced ROS level and reversed the effect of SAHA on cell death, L-buthionine sulfoximine (BSO) further enhanced GSH depletion, and promoted cell death. SAHA decreased the mRNA and protein levels of Trx1 in lung cancer cells. Knockdown/suppression of Trx1 intensified apoptosis in SAHA-treated lung cancer cells whereas overexpression of Trx1 prevented the cell death in these cells. SAHA up-regulated the level of miR-129-5p, which binds to 3' untranslated region (3'UTR) of Trx1 and down-regulates Trx1 expression. Down regulation of Trx1 led to activation of apoptosis-signal regulating kinase (ASK), which induced apoptotic cell death by triggering ASK-JNK or ASK-p38 kinase pathway. In conclusion, changes in ROS and GSH levels in SAHA-treated lung cancer cells partially co-related with cell death. SAHA induced apoptosis via the down regulation of Trx1, which was regulated by miR-129-5p. PMID- 28667780 TI - Gene flow and selection interact to promote adaptive divergence in regions of low recombination. AB - Adaptation to new environments often occurs in the face of gene flow. Under these conditions, gene flow and recombination can impede adaptation by breaking down linkage disequilibrium between locally adapted alleles. Theory predicts that this decay can be halted or slowed if adaptive alleles are tightly linked in regions of low recombination, potentially favouring divergence and adaptive evolution in these regions over others. Here, we compiled a global genomic data set of over 1,300 individual threespine stickleback from 52 populations and compared the tendency for adaptive alleles to occur in regions of low recombination between populations that diverged with or without gene flow. In support of theory, we found that putatively adaptive alleles (FST and dXY outliers) tend to occur more often in regions of low recombination in populations where divergent selection and gene flow have jointly occurred. This result remained significant when we employed different genomic window sizes, controlled for the effects of mutation rate and gene density, controlled for overall genetic differentiation, varied the genetic map used to estimate recombination and used a continuous (rather than discrete) measure of geographic distance as proxy for gene flow/shared ancestry. We argue that our study provides the first statistical evidence that the interaction of gene flow and selection biases divergence toward regions of low recombination. PMID- 28667782 TI - Elevated HbA1c in donor organs from patients without a diagnosis of diabetes portends worse liver allograft survival. AB - Recipients of liver allografts from diabetic donors have decreased graft survival. However, limited data exist on the effects of donor HbA1c. We hypothesized that allografts from nondiabetic donors with elevated HbA1c would be associated with decreased survival. Liver transplant recipients from the UNOS database from nondiabetic donors were stratified into two groups: euglycemic (HbA1c<6.5) and hyperglycemic (HbA1c>=6.5). Propensity score matching (10:1) was used to adjust for donor and recipient characteristics. Kaplan-Meier analysis was used to assess survival. Donors of hyperglycemic allografts were older (49 vs 36, P<.001), were more likely to be non-white, had a higher BMI (29.8 vs 26.2, P<.001), were more likely to engage in heavy cigarette use (1.5% vs 1.3%, P=.004), had higher serum creatinine levels (1.3 vs 1.0, P=.002), and were more likely to be an expanded-criteria donor (35.8% vs 14.4%, P<.001). After propensity matching to account for these differences, allograft survival was significantly decreased in the recipients of hyperglycemic allografts (P=.049), and patient survival showed a trend toward reduction (P=.082). These findings suggest that HbA1c may be a simple and inexpensive test with potential utility for better organ risk stratification. PMID- 28667781 TI - Translocator protein (18 kDa): an update on its function in steroidogenesis. AB - Translocator protein (18 kDa) (TSPO) is a ubiquitous mitochondrial protein. Studies of its responses to drug and endogenous ligands have shown TSPO to be involved either directly or indirectly in numerous biological functions, including mitochondrial cholesterol transport and steroid hormone biosynthesis, porphyrin transport and heme synthesis, apoptosis, cell proliferation, and anion transport. Localised to the outer mitochondrial membrane of steroidogenic cells, TSPO has been shown to associate with cytosolic and mitochondrial proteins as part of a large multiprotein complex involved in mitochondrial cholesterol transport, the rate-limiting step in steroidogenesis. There is general agreement as to the structure and pharmacology of TSPO. Stimulation of TSPO has been shown to have therapeutic use as anxiolytics by inducing allopregnanolone production in the brain, and also potentially for re-establishing androgen levels in hypogonadal ageing animals. Until recently, there has been general agreement regarding the role of TSPO in steroidogenesis. However, recent studies involving genetic depletion of TSPO in mice have created controversy about the role of this protein in steroid and heme synthesis. We review the data on the structure and function of TSPO, as well as the recent results obtained using various genetic animal models. Taken together, these studies suggest that TSPO is a unique mitochondrial pharmacological target for diseases that involve increased mitochondrial activity, including steroidogenesis. Although there is no known mammalian species that lacks TSPO, it is likely that, because of the importance of this ancient protein in evolution and mitochondrial function, redundant mechanisms may exist to replace it under circumstances when it is removed. PMID- 28667783 TI - Prussian Blue-Derived Synthesis of Hollow Porous Iron Pyrite Nanoparticles as Platinum-Free Counter Electrodes for Highly Efficient Dye-Sensitized Solar Cells. AB - Iron pyrite has long been an attractive material for environmental and energy applications, but is hampered by a lack of control over morphology and purity. Hollow porous iron pyrite nanoparticles were synthesized by a direct sulfurization of iron oxide derived from Prussian blue. The high efficiencies of these hollow porous iron pyrite nanoparticles as effective dye-sensitized solar cell counter electrodes were demonstrated, with an efficiency of 7.31 %. PMID- 28667785 TI - Reply to: Osteoporosis: An Independent Determinant of Bone Erosions in Rheumatoid Arthritis? PMID- 28667784 TI - Transcription factor-microRNA associations and their impact on colorectal cancer survival. AB - MicroRNAs (miRNAs) and Transcription Factors (TFs) both influence messenger RNA (mRNA) expression, disrupting biological pathways involved in carcinogenesis and prognosis. As many miRNAs target multiple mRNAs, thus influencing a multitude of biological pathways, deciphering which miRNAs are important for cancer development and survival is difficult. In this study, we (i) determine associations between TF and survival (N = 168 colon cancer cases); (ii) identify miRNAs associated with TFs related to survival; and (iii) determine if factors derived from TF-specific miRNA principal component analysis (PCA) influence survival. Cox Proportional hazard models were run for each PCA factor to determine Hazard Ratios (HR) and 95% Confidence Intervals (CI) adjusting for age, center, and AJCC stage. Thirty TFs improved survival when differential expression increased; 27 of these were associated significantly with normal colonic mucosa expression of 65 unique miRNAs when an FDR q-value of <0.05 was applied. Five factors, comprising 21 miRNAs, altered survival in rectal cancer subjects; four of these five factors improved survival and one factor reduced survival. One factor comprising four miRNAs reduced survival in colon cancer subjects. In summary, our data suggest that expression of TFs and their related miRNAs influence survival after diagnosis with colorectal cancer. PMID- 28667786 TI - Association Between Vertebral Cross-sectional Area and Vertebral Wedging in Children and Adolescents: A Cross-sectional Analysis. AB - A small vertebral cross-sectional area (CSA) imparts a mechanical disadvantage that escalates the risk for vertebral fractures in elderly populations. We examined whether a small vertebral CSA is also associated with a greater degree of vertebral wedging in children. Measurements of vertebral CSA, lumbar lordosis (LL) or thoracic scoliosis angle, and vertebral wedging were obtained in 100 healthy adolescents (50 boys and 50 girls) and 25 girls with adolescent idiopathic scoliosis (AIS) using magnetic resonance imaging. Vertebral CSA of the lumbar vertebrae negatively correlated to the degree of posteroanterior vertebral wedging at L5 (r = -0.49; p < 0.0001); this was true whether all subjects were analyzed together or boys and girls independently. In contrast, we found a positive correlation between the degree of LL and vertebral wedging (r = 0.57; p < 0.0001). Multiple regression analysis showed that the association between vertebral CSA and wedging was independent of age and body mass index. In girls with AIS, vertebral CSA negatively correlated to the degree of lateral thoracic vertebral wedging (r = -0.66; p = 0.0004), an association that persisted even after accounting for age and body mass index. Additionally, Cobb angle positively correlated to lateral thoracic vertebral wedging (r = 0.46; p = 0.021). Our cross sectional results support the hypothesis that smaller vertebral CSA is associated with greater vertebral deformity during growth, as in adulthood. (c) 2017 American Society for Bone and Mineral Research. PMID- 28667787 TI - Global Trends in Aspirin Resistance-Related Research from 1990 to 2015: A Bibliometric Analysis. AB - Aspirin resistance can be defined as the inability of the usual dose of aspirin medication to produce its antithrombotic effect. Patients with diabetes or cardiovascular disease are at higher risk of stroke, myocardial infarction or cardiovascular death due to aspirin resistance. The aim of this bibliometric study was to identify and analyse the status and trends of aspirin resistance research production at global level through publications indexed in the Scopus database; this will shed new light on future research trends and help researchers predict dynamic direction of research. Literature search using the Scopus database was conducted to assess publications related to aspirin resistance. The selected publications included the terms related to aspirin resistance in the title, abstract or keywords. The searching was accomplished on 20 March 2016 and can be considered to include all publications up to 31 December 2015. Global cumulative publication output on aspirin resistance consists of 986 papers during 1990-2015. Among the 986 documents, 19 (1.9%) were published before 2000, 567 (57.5%) were published from 2000 to 2009 and 400 (40.6%) were published from 2010 to 2015, with peak of publications on this topic in 2008. The leading country in the field of aspirin resistance was the United States, which had the greatest counts of independent articles (165) and international collaboration articles (44). Turkey was in the second rank with 78 articles, followed by Italy (68), the UK (62) and Poland (60). The total number of citations for all documents was 26,342, and the average citations per document were 26.7. The h-index for all aspirin resistance publications was 82. This study presents the results of the first bibliometric study (including quantitative and qualitative analysis) of scientific publications in the field of aspirin renitence at global level. Aspirin resistance-related researches have notably increased in the last years, especially from 2000 to 2015. The United States is the most prolific country, not only in research quantity but also in quality. Furthermore, Turkey and European countries provided more research related to aspirin resistance than other regions such as the developing countries. PMID- 28667788 TI - Altered beta2 -glycoprotein I expression on microparticles in the presence of antiphospholipid antibodies. AB - Essentials beta2 glycoprotein-I (beta2 GPI) is a scavenger molecule that binds to microparticles (MPs). beta2 GPI expression on MPs was measured in systemic lupus erythematosus (SLE) patients and controls. beta2 GPI positive MPs is depressed among SLE patients positive for antiphospholipid antibodies. Complex formation between beta2 GPI on MPs and patients own anti-beta2 GPI may disturb MP clearance. Click to hear an ISTH Academy presentation on antiphospholipid antibody syndrome by Drs de Laat and Bertolaccini SUMMARY: Background Antiphospholipid antibodies (aPLs) together with thrombosis and/or pregnancy morbidities characterize the antiphospholipid syndrome. beta2 -Glycoprotein I (beta2 GPI), the most important antigen for aPLs, is a scavenger molecule that specifically binds to phosphatidylserine (PS) expressed on microparticles (MPs). Objectives To evaluate beta2 GPI-expressing MPs in patients with systemic lupus erythematosus (SLE) stratified for aPL status, and in healthy controls. Patients/Methods We investigated 18 aPL/anti-beta2 GPI-positive and 22 aPL negative patients from a large SLE cohort and 19 healthy controls. beta2 GPI positive MPs and IgG-positive MPs were detected by flow cytometry. We measured plasma levels of beta2 GPI, and performed in vitro experiments to investigate the binding properties of beta2 GPI on MPs. Results SLE patients had more MPs and IgG positive MPs than controls. We observed fewer beta2 GPI-positive MPs in aPL/anti beta2 GPI-positive patients than in aPL/anti-beta2 GPI-negative patients and controls (approximately two-fold). beta2 GPI levels in plasma did not differ with aPL/anti-beta2 GPI status in patients; however, controls had slightly higher levels of beta2 GPI than aPL/anti-beta2 GPI-positive patients. In vitro experiments revealed that beta2 GPI preferentially binds to PS-positive MPs. Conclusions Despite abundant total MPs and MPs in immune complexes, beta2 GPI positive MPs were depleted in SLE patients, and the levels were especially low in aPL/anti-beta2 GPI-positive patients. We suggest that anti-beta2 GPI antibodies bind to beta2 GPI-PS complexes expressed on MPs. Consequent loss of beta2 GPI-PS expression on MPs may impair scavenging and contribute to the accumulation of circulating PS-negative MPs, a possible source of autoantigens. Autoantibodies delaying MP clearance may thus constitute an important mechanism underlying autoimmunity. PMID- 28667789 TI - Efficacy of oral methylcobalamin in treatment of vitamin B12 deficiency anemia in children. AB - To demonstrate the efficacy of oral methylcobalamin in treating vitamin B12 (vitB12) deficiency anemia, our prospective observational study enrolled 28 children with both macrocytic anemia and low holotranscobalamin (HoloTC) levels. Their hematological and biochemical parameters pre- and posttreatment at 1 month were compared. Hemoglobin showed mean increase of 2.89 g/dl (P < 0.001), rising above 10 g/dl in 24 patients (85.7%). Reticulocytes peaked at 1 week. Mean fall in mean corpuscular volume of 24.83 fl (P < 0.001) and mean improvement in platelets of 122,100/MUl (P = 0.001) were noted, and mean rise in HoloTC and vitB12 were 111.36 pmol/l (P < 0.001) and 918.34 pg/ml (P < 0.001), respectively. Thus, initial responses to oral methylcobalamin in children with vitB12 deficiency anemia were adequate. PMID- 28667790 TI - Modeling the impacts of two age-related portfolio effects on recruitment variability with and without a marine reserve. AB - Many rockfish species are long-lived and thought to be susceptible to being overfished. Hypotheses about the importance of older female rockfish to population persistence have led to arguments that marine reserves are needed to ensure the sustainability of rockfish populations. However, the implications of these hypotheses for rockfish population dynamics are still unclear. We modeled two mechanisms by which reducing the proportion of older fish in a population has been hypothesized to influence sustainability, and explored whether these mechanisms influenced mean population dynamics and recruitment variability. We explored whether populations with these mechanisms could be managed more sustainably with a marine reserve in addition to a constant fishing mortality rate (F) than with a constant F alone. Both hypotheses can be seen as portfolio effects whereby risk of recruitment failure is spread over a "portfolio" of maternal ages. First, we modeled a spawning window effect whereby mothers of different ages spawned in different times or locations (windows) with local environmental conditions. Second, we modeled an offspring size effect whereby older mothers produced larger offspring than younger mothers, where length of a starvation period over which offspring could survive increased with maternal age. Recruitment variability resulting from both models was 55-65% lower than for models without maternal age-related portfolio effects in the absence of fishing and increased with increases in Fs for both models. An offspring size effect caused lower output reproductive rates such that the specified reproductive rate input as a model parameter was no longer the realized rate measured as the reproductive rate observed in model results; this quirk is not addressed in previous analyses of offspring size effects. We conducted a standardization such that offspring size effect and control models had the same observed reproductive rates. A comparison of long-term catch, the probability of falling below a biomass threshold, and recruitment variability over a range of exploitation rates for models with an age-related portfolio effect showed no benefit of a marine reserve implemented in addition to a constant F (as compared to a constant F alone) for populations with sedentary adults and sedentary or mobile larvae. PMID- 28667791 TI - A matter of perception: Perceived socio-economic status and cortisol on the island of Utila, Honduras. AB - OBJECTIVES: Numerous studies link low objective and subjective socioeconomic status (SES) to chronic activation of the hypothalamic pituitary adrenal (HPA) axis. Here, we examine associations between objective and subjective SES and diurnal salivary cortisol, a primary HPA component, as well as demographic and ecological predictors associated with SES perceptions and changes in diurnal cortisol. METHODS: Participants were residents (age 18-79, n = 61) of Utila, a Honduran island where economic disparities are overt and geographically contained. Objective SES was measured as a composite of income, education, and occupation. Subjective SES was measured with a MacArthur ladder and a perceived lifestyle discrepancy (PLD) scale. Salivary cortisol was collected three times per day for two days. Questions addressing demographic, social, and household characteristics were assessed as predictors of PLD. RESULTS: Assessed independently, objective SES (P = .06) and PLD (P = .003) were associated with the steepness of diurnal cortisol changes, while PLD was also associated with higher cortisol area under the curve (AUC) (P = .036). Modeled together, only PLD predicted diurnal slope and AUC. PLD was associated with household sanitation, immigration status, food scarcity, objective SES, and owing money. Only access to sanitation and owing money had direct associations with cortisol that were not mediated by PLD. CONCLUSIONS: For adults on Utila, perceptions of unmet need outweigh other social and economic status factors in predicting cortisol AUC and slope. In addition, the unmediated effects of access to sanitation and owing money on cortisol suggest that these distinct aspects of inequality are important to consider when seeking to understand how inequality can impact HPA function. PMID- 28667793 TI - Physiological mechanisms through which heat stress compromises reproduction in pigs. AB - Seasonal variations in environmental temperatures impose added stress on domestic species bred for economically important production traits. These heat-mediated stressors vary on a seasonal, daily, or spatial scale, and negatively impact behavior and reduce feed intake and growth rate, which inevitably lead to reduced herd productivity. The seasonal infertility observed in domestic swine is primarily characterized by depressed reproductive performance, which manifests as delayed puberty onset, reduced farrowing rates, and extended weaning-to-estrus intervals. Understanding the effects of heat stress at the organismal, cellular, and molecular level is a prerequisite to identifying mitigation strategies that should reduce the economic burden of compromised reproduction. In this review, we discuss the effect of heat stress on an animal's ability to maintain homeostasis in multiple systems via several hypothalamic-pituitary-end organ axes. Additionally, we discuss our understanding of epigenetic programming and how hyperthermia experienced in utero influences industry-relevant postnatal phenotypes. Further, we highlight the recent recognized mechanisms by which distant tissues and organs may molecularly communicate via extracellular vesicles, a potentially novel mechanism contributing to the heat-stress response. PMID- 28667792 TI - Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer. AB - Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854. PMID- 28667794 TI - Oral Administration of Polaprezinc Attenuates Fluorouracil-induced Intestinal Mucositis in a Mouse Model. AB - 5-Fluorouracil (5-FU) has broadly been applied to treat colorectal cancer as one of the most effective chemotherapeutic agents. However, it frequently causes intestinal mucosal injury and related side effects, such as abdominal pain and diarrhoea, which limit the use of 5-FU in a clinic setting. Polaprezinc has gradually become known as a mucosal protective agent for the management of gastric ulcer. This study aimed to investigate the prophylactic efficacy of Polaprezinc administered orally against intestinal mucositis induced by 5-FU in mice on the condition that the antitumour effect could not be compromised. We induced intestinal mucositis in SPF-grade ICR mice with 5-FU, and evaluated intestinal damage in the absence or presence of Polaprezinc. We examined the score of diarrhoea and the loss of weight after the 5-FU treatment and assessed the integrity of villus and the proliferation of small intestine crypt cells by haematoxylin and eosin staining and PCNA immunohistochemical detection. The antitumour effect of 5-FU on colorectal cancer was assessed with or without Polaprezinc in a xenograft model. The result showed that Polaprezinc significantly reduced the elevated diarrhoea score and the body-weight loss caused by 5-FU abolished histological abnormality and crypt cell hypoproliferation in a dose-dependent manner, without affecting 5-FU efficacy on colon xenograft tumour in mice. We conclude that Polaprezinc could inhibit 5-FU induced diarrhoea and alleviate the weight loss during 5-FU chemotherapy, as a possible candidate for treatment and prevention of intestinal mucositis, through protecting intestinal mucosa and improving the quality of life after chemotherapy. PMID- 28667796 TI - When new human-modified habitats favour the expansion of an amphibian pioneer species: Evolutionary history of the natterjack toad (Bufo calamita) in a coal basin. AB - Human activities affect microevolutionary dynamics by inducing environmental changes. In particular, land cover conversion and loss of native habitats decrease genetic diversity and jeopardize the adaptive ability of populations. Nonetheless, new anthropogenic habitats can also promote the successful establishment of emblematic pioneer species. We investigated this issue by examining the population genetic features and evolutionary history of the natterjack toad (Bufo [Epidalea] calamita) in northern France, where populations can be found in native coastal habitats and coalfield habitats shaped by European industrial history, along with an additional set of European populations located outside this focal area. We predicted contrasting patterns of genetic structure, with newly settled coalfield populations departing from migration-drift equilibrium. As expected, coalfield populations showed a mosaic of genetically divergent populations with short-range patterns of gene flow, and native coastal populations indicated an equilibrium state with an isolation-by-distance pattern suggestive of postglacial range expansion. However, coalfield populations exhibited (i) high levels of genetic diversity, (ii) no evidence of local inbreeding or reduced effective population size and (iii) multiple maternal mitochondrial lineages, a genetic footprint depicting independent colonization events. Furthermore, approximate Bayesian computations suggested several evolutionary trajectories from ancient isolation in glacial refugia during the Pleistocene, with biogeographical signatures of recent expansion probably confounded by human-mediated mixing of different lineages. From an evolutionary and conservation perspective, this study highlights the ecological value of industrial areas, provided that ongoing regional gene flow is ensured within the existing lineage boundaries. PMID- 28667795 TI - Dietary intake habits and the prevalence of nocturia in Japanese patients with type 2 diabetes mellitus. AB - AIMS/INTRODUCTION: No reports have been published on the association between dietary intake habits and nocturia in the diabetes population. We therefore evaluated this issue among Japanese patients with diabetes mellitus. MATERIALS AND METHODS: Study participants in the present study were 785 Japanese patients with type 2 diabetes mellitus. Self-administered questionnaires were used to assess each type of dietary intake habit. Vegetable intake habit was assessed by the following question: "Do you have vegetables or seaweed every day?" We used the following two outcomes: (i) nocturia: >=2 voids per night; and (ii) severe nocturia: >=3 voids per night. Adjustment was made for age, sex, body mass index, glycated hemoglobin, hypertension, dyslipidemia, smoking, drinking, exercise habit, stroke, ischemic artery disease, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy. RESULTS: The prevalence of nocturia, severe nocturia, and vegetable intake habit was 39.9%, 14.4% and 67.3%, respectively. After adjusting for confounding factors, vegetable intake habit was independently inversely associated with nocturia and severe nocturia: the adjusted odds ratios were 0.67 (95% confidence interval [CI] 0.48-0.94) and 0.46 (95% CI 0.30-0.71), respectively. Among male patients, vegetable intake habit was independently inversely associated with severe nocturia, but not nocturia: the adjusted OR was 0.51 (95% CI 0.29-0.88). Among female patients, vegetable intake habit was independently inversely associated with nocturia and severe nocturia: the adjusted ORs were 0.44 (95% CI 0.24-0.79) and 0.34 (95% CI 0.15-0.78), respectively. CONCLUSIONS: We found an inverse association between vegetable intake habit and nocturia in Japanese patients with type 2 diabetes mellitus. PMID- 28667797 TI - Differential growth costs and nitrogen fixation in Cytisus multiflorus (L'Her.) Sweet and Cytisus scoparius (L.) Link are mediated by sources of inorganic N. AB - Shrubby legumes in Mediterranean-type ecosystems face strong nutrient limitations that worsen in summer, when water is absent. Nitrogen-fixing legumes are likely to be able to switch between soil N and atmospheric N (N2 ) sources to adjust the C costs of N acquisition in different seasons. We investigated the utilisation of different inorganic N sources by two indigenous shrubby legumes (Cytisus multiflorus and Cytisus scoparius). Plant performance in terms of photosynthesis and biomass production was also analysed. Plants were cultivated in sterile river sand supplied with Hoagland nutrient solution, grown in N-free nutrient solution and inoculated with effective rhizobial strains from nodules of adult plants of the same species. A second treatment consisted of plants given 500 MUm NH4 NO3 added into the nutrient solution. In a third treatment, plants were watered with another source of N (500 MUm NH4 NO3 ) as well as being inoculated with effective rhizobial strains. The application of NH4 NO3 to the legumes resulted in a larger increase in plant dry matter. Carbon construction costs were higher in plants supplied with mineral and symbiotic N sources and always higher in the endemic C. multiflorus. Differences in photosynthesis rates were only observed between species, regardless of the N source. Non-fertilised inoculated plants had more effective root nodules and a clear dependence on N2 fixation. We propose that the ability of C. scoparius to change N source makes it a plastic species, which would account for its broader distribution in nature. PMID- 28667798 TI - A genomic investigation of ecological differentiation between free-living and Drosophila-associated bacteria. AB - Various bacterial taxa have been identified both in association with animals and in the external environment, but the extent to which related bacteria from the two habitat types are ecologically and evolutionarily distinct is largely unknown. This study investigated the scale and pattern of genetic differentiation between bacteria of the family Acetobacteraceae isolated from the guts of Drosophila fruit flies, plant material and industrial fermentations. Genome-scale analysis of the phylogenetic relationships and predicted functions was conducted on 44 Acetobacteraceae isolates, including newly sequenced genomes from 18 isolates from wild and laboratory Drosophila. Isolates from the external environment and Drosophila could not be assigned to distinct phylogenetic groups, nor are their genomes enriched for any different sets of genes or category of predicted gene functions. In contrast, analysis of bacteria from laboratory Drosophila showed they were genetically distinct in their universal capacity to degrade uric acid (a major nitrogenous waste product of Drosophila) and absence of flagellar motility, while these traits vary among wild Drosophila isolates. Analysis of the competitive fitness of Acetobacter discordant for these traits revealed a significant fitness deficit for bacteria that cannot degrade uric acid in culture with Drosophila. We propose that, for wild populations, frequent cycling of Acetobacter between Drosophila and the external environment prevents genetic differentiation by maintaining selection for traits adaptive in both the gut and external habitats. However, laboratory isolates bear the signs of adaptation to persistent association with the Drosophila host under tightly defined environmental conditions. PMID- 28667799 TI - Reduced bone loss in a murine model of postmenopausal osteoporosis lacking complement component 3. AB - The growing field of osteoimmunology seeks to unravel the complex interdependence of the skeletal and immune systems. Notably, we and others have demonstrated that complement signaling influences the differentiation of osteoblasts and osteoclasts, the two primary cell types responsible for maintaining bone homeostasis. However, the net effect of complement on bone homeostasis in vivo was unknown. Our published in vitro mechanistic work led us to hypothesize that absence of complement component 3 (C3), a central protein in the complement activation cascade, protects against bone loss in the ovariectomy-based model of postmenopausal osteoporosis. Indeed, we report here that, when compared to their C57BL/6J (WT) counterparts, ovariectomized C3 deficient mice experienced reduced bone loss at multiple sites and increased stiffness at the femoral neck, the latter potentially improving mechanical function. WT and B6;129S4-C3tm1Crr /J (C3 /- ) mice were either ovariectomized or sham-operated at 6 weeks of age and euthanized at 12 weeks. MicroCT on harvested bones revealed that the trabecular bone volume fraction in the metaphyses of both the proximal tibiae and distal femora of ovariectomized C3-/- mice is significantly greater than that of their WT counterparts. Lumbar vertebrae showed significantly greater osteoid content and mineral apposition rates. Mechanical testing demonstrated significantly greater stiffness in the femoral necks of ovariectomized C3-/- mice. These results demonstrate that C3 deficiency reduces bone loss at ovariectomy and may improve mechanical properties. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:118-128, 2018. PMID- 28667800 TI - Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non-small cell lung cancer patients. AB - Lasp2, as well as Lasp1, is a member of the LIM-protein subfamily of the nebulin group characterized by the combined presence of LIM and SH3 domains. Lasp1 and Lasp2 are highly conserved in their LIM, nebulin-like, and SH3 domains but differ significantly at their linker regions. Lasp1 had been described as an oncogenic protein that was highly expressed in diverse cancer types and facilitated tumor proliferation, invasion, and metastasis process. However, unlike Lasp1, little is known about the functions of Lasp2. In the present study, using immunohistochemistry, we found that Lasp2 expression was significantly correlated with histological type (P = 0.012), advanced TNM stage (P = 0.024), positive regional lymph node metastasis (P = 0.035), and poor overall survival (P = 0.001). Would healing assay and transwell assay results indicated that Lasp2 promoted tumor migration and invasion in NSCLC cells. Furthermore, Lasp2 facilitated Snail expression and inhibited Zo-1. The levels of phosphorylated FAK (Tyr397 and Tyr925) were obviously increased after overexpressing Lasp2 and were downregulated by transfecting Lasp2-siRNA. FAK inhibitor counteracted upregulating Snail expression and downregulating of Zo-1 expression induced by Lasp2 overexpression. Taken together, Lasp2 may facilitate tumor migration and invasion of NSCLCs through FAK-Snail/Zo-1 signaling pathway. Lasp2 may be a potential prognostic predictor of NSCLC patients. PMID- 28667801 TI - A study of selected factors affecting efficacy of compost tea against several fungal pathogens of potato. AB - AIM: To investigate selected factors of two nonaerated compost teas (NCT) and mechanisms that influence the restriction of several fungal potato pathogens. METHODS AND RESULTS: Two NCTs, made from either commercial compost, (CCT) or vineyard compost (VCT), were tested for their ability to suppress potato pathogens. The VCT was more suppressive than CCT to mycelial growth of Alternaria solani and Rhizoctonia solani isolate 299, but not for R. solani isolate 422. Metagenomic studies of microbial diversity revealed that the CCT had higher fungal and bacterial diversity and richness than the VCT. Use of CCT significantly reduced lesion area of Alternaria alternata on detached leaves, however, a gum adjuvant did not lead to significantly greater control. Scanning microscopy showed that the spatial distribution of microbes from the CCT was altered with gum addition, to resemble what may have been a microbial biofilm. CONCLUSION: We confirmed that each NCT could suppress the mycelial growth of selected potato pathogens in culture, and CCT reduced A. alternata lesions on detached leaves. Factors including concentration, microbial communities and physio-chemical properties could not be consistently linked to NCT efficacy. SIGNIFICANCE AND IMPACT OF THE STUDY: This study particularly highlights the application of scanning microscopy to study the interaction between pathogens and putative NCT microbes on foliar surfaces. This adds insight to mechanisms of NCT efficacy, along with physico-chemical and microbial characterization of the teas. This study shows the potential for the use of NCTs as a crop protection tool of low-cost which could be of particular benefit in smallholder agriculture. PMID- 28667802 TI - Reply to: Vincristine toxicity with coadministration of fluconazole long-term concerns. PMID- 28667803 TI - Abdominal obesity in adolescents: Development of age-specific waist circumference cut-offs linked to adult IDF criteria. AB - OBJECTIVES: The purpose of this study was to develop age- and sex-specific waist circumference (WC) cut-off points, linked to older adolescent and adult criteria for abdominal obesity, to be applied to children in the clinical setting. METHODS: A total of 16,788 adolescents aged 10 to 16 years were assessed for WC. Smoothed age and sex-specific WC curves were obtained using Cole's LMS method. RESULTS: Percentiles that corresponded to the International Diabetes Federation (IDF) recommendations used for older adolescents and adults (16+ years old) were the 97th percentile for boys and the 87th percentile for girls. Using these cutoffs, a total of 368 boys and 1138 girls were categorized as abdominally obese, in contrast to 1654 boys and 987 girls that were identified using the current IDF pediatric criteria (90th percentile). CONCLUSIONS: We provide age- and sex-specific cut-off points that can be used to identify abdominal obesity in adolescents. The present findings provide a tool that can be used in the clinical setting for the early detection and prevention of adult obesity. Population specific cutoffs may be required for pediatric ages to diagnose children at risk. PMID- 28667804 TI - Balloon-Assisted Tracking Use Reduces Radial Artery Access Failure in an Experienced Radial Center and is Feasible During Primary PCI for STEMI. AB - OBJECTIVE: This prospective study assesses balloon-assisted tracking (BAT) in reducing radial access failure during percutaneous coronary intervention (PCI). BACKGROUND: Arterial spasm prevents PCI from the radial artery in a small percentage of cases. METHODS: A total of 2223 consecutive patients undergoing PCI from the radial approach were analyzed. Radial access failure mode and requirement for crossover to femoral access during a 12-month run-in period were compared with the following 14-month period with routine BAT usage. RESULTS: During the 14-month study period, 1334 radial PCIs were attempted. Twenty-six patients switched to femoral at an early stage, while 76 encountered radial spasm and underwent successful BAT in 69 cases (91%), giving a total crossover rate to femoral of 33/1334 (2.5%). Utilizing BAT rather than a femoral puncture reduced our institution's radial-femoral crossover rate from 7.6% to 2.5% (P<.01), which is also significantly lower than the radial-femoral crossover rate in the 12 months before BAT implementation (6.1%; P<.01). Mean procedure times were similar for those requiring BAT compared with conventional radial access (51.3 +/- 21.3 min vs 47.9 +/- 23.7 min; P=.23), and those crossing straight to femoral (BAT not attempted) (60.7 +/- 31.9 min; P=.10). Mean first device/balloon time for the BAT assisted primary PCI cases (22.6 +/- 9.4 min) was similar to cases that had radial difficulties and converted to femoral without attempting BAT (25.8 +/- 13.4 min; P=.54). CONCLUSION: BAT allowed catheter passage despite radial spasm in 91% of cases, significantly reducing the institution's rate of femoral crossover. During radial spasm in primary PCI, using BAT did not delay reperfusion compared with femoral crossover. PMID- 28667805 TI - The Compleat Radialist. PMID- 28667806 TI - Abdominal Infrarenal Aortic Stenosis Approached Through a Full Transradial Approach: A Case Series. AB - Six consecutive patients (3 men; mean age, 63 +/- 14 years; age range, 38-81 years) with infrarenal abdominal aortic stenosis underwent unilateral or bilateral transradial approach for stenting of the aortic lesion. In 4 cases, isolated aortic stenting was performed through single transradial approach (in 2 cases with precise alignment to the proximal end of previously deployed iliac stents), whereas in the other 2 cases bilateral transradial approach was used for aortic stenting followed by bilateral stenting of the proximal iliac arteries. Either a "bare-on-the-wire" or a "support-catheter" technique was used, according to patient anatomy and technical requirements. The median follow-up was 14.3 months, at which time all patients had relief of symptoms without thromboembolic or bleeding complications. In this performance and safety evaluation, full transradial approach was effective and safe for treating infrarenal aortic stenosis that is isolated or associated with iliac disease. PMID- 28667807 TI - Improved Algorithm for Ostium Size Assessment in Watchman Left Atrial Appendage Occlusion Using Three-Dimensional Echocardiography. AB - AIMS: Correct sizing of the ostium is a crucial step in left atrial appendage (LAA) occlusion procedures. However, unfavorable anatomy of the ostium often complicates the assessment of the true ostium diameter. We hypothesized that area derived diameter (ADD) and perimeter-derived diameter (PDD) from three dimensional transesophageal echocardiogram (3D-TEE) can facilitate this step of the procedure as compared with two-dimensional (2D) measurements. METHODS AND RESULTS: For 55 patients within the ALSTER-LAA registry, retrospective analysis of PDD and ADD was correlated with 2D measurements used during the procedure to ascertain correct size of the Watchman device (Boston Scientific). The observed data were put into relation to the calculated area of the device with 10%-30% compression and the clinical outcome after 30 days. 3D area and perimeter measurements of the LAA ostium matched the calculated range of the different device sizes. Recapture during implantation, gaps <5 mm, and device size changes were more often observed when ADDs would also have suggested the use of a larger device. CONCLUSION: 3D ADDs and PDDs are feasible to use in device size decisions. Employing these measurements may allow operators to further reduce intraprocedural recapture maneuvers, peridevice leakage, and device size changes. PMID- 28667808 TI - Coronary Artery Aneurysm After Bioresorbable Scaffold Implantation in a Woman With an Acute Coronary Syndrome. AB - We herein report the case of an ST-elevation myocardial infarction due to bioresorbable vascular scaffold (BRS) failure. Optical coherence tomography (OCT) revealed the exact mechanism of late BRS stent thrombosis due to an acquired coronary aneurysm related to BRS. A drug eluting OCT-guided stenting over a failed BRS in the context of an acute coronary syndrome, with the simultaneous presence of a BRS thrombosis and coronary artery aneurysm, proved to be effective. PMID- 28667809 TI - Coronary Artery Aneurysm After Bioresorbable Scaffold Implantation. AB - The clinical course of coronary artery aneurysms after drug-eluting stent implantation is variable. Some aneurysms naturally resolve, but some can lead to complications such as stent thrombosis. In order to avoid such complications, it is important to reduce as much as possible the chance of exposing causal factors, and intravascular imaging may be needed in order to accurately assess the results of stent deployment and apposition. In the presented case, intravascular imaging was shown to be useful in accurately assessing the results of bioresorbable stent deployment and apposition. PMID- 28667810 TI - Coronary Artery Aneurysm After Mini-Crush Drug-Eluting Stent Technique in a Chronic Total Occlusion. AB - A 53-year-old man underwent percutaneous coronary intervention of a chronic total occlusion of the circumflex artery. A mini-crush stent technique with two drug eluting stents was performed. To the best of our knowledge, this is the first case of coronary artery aneurysm affecting a bifurcated chronic total occlusion treated with a two-stent technique. PMID- 28667811 TI - Premature Ventricular Contractions Producing Brockenbrough-Braunwald Sign in Obstructive Cardiomyopathy. AB - Increased dynamic flow in hypertrophic obstructive cardiomyopathy depicts a classic sign on invasive pressure tracings of the aorta and left ventricle, simultaneously known as the Brockenbrough-Braunwald sign, which is demonstrated in the presented case. PMID- 28667812 TI - Utility of 3D-OCT Imaging With Angiographic Co-Registration in Acute Coronary Syndrome With Normal or Near-Normal Coronary Arteries. AB - The OPTIS integrated system (St. Jude Medical) is a new technology allowing the online co-registration of optical coherence tomography (OCT) images with the angiogram in the catheterization laboratory. Additionally, 3D navigation can be performed. This integration of OCT information on an angiographic roadmap could find broad application in the characterization of substrates causing acute coronary syndromes with normal or near-normal coronary arteries. The utility of OCT with co-registration for the guidance of percutaneous coronary intervention could be considerable in the management of patients with acute coronary syndromes. PMID- 28667813 TI - Twin Hearts in Identical Twins. AB - Cardiac manifestations and angiographic characteristics of coronary artery disease in identical twins have been previously dealt with in a handful of case reports and series; yet, the results were highly controversial. Our rare case demonstrates striking similarities in both the timing and type of clinical manifestation, as well as in the underlying anatomy and the distribution of coronary artery disease. When premature coronary artery disease is found in one of a monozygotic twin pair, evaluating the other twin is a reasonable approach. PMID- 28667814 TI - Preface to special issue on 'The hormone FGF21: a paramount actor of endocrine metabolic regulation, and even more'. PMID- 28667815 TI - Pulmonary thromboembolism in an emergency hospital: Are our patients different? AB - INTRODUCTION: Pulmonary thromboembolism (PTE) represents a medical emergency and is the third most common cause of mortality after myocardial infarction and stroke. The purpose of this study was to describe the characteristics and management of patients with PTE admitted in a referral emergency hospital in Romania. MATERIAL AND METHODS: We retrospectively reviewed all cases of PTE diagnosed in one of the largest emergency hospitals in Bucharest during a 2-year period (January 2014 - December 2016). Patients with acute PTE were identified by a database search of the diagnostic codes of all discharge diagnoses. Demographic, clinical and paraclinical tests data was retrieved from medical records. RESULTS: 221 patients (48.87% male, mean age 61.76 years (range 21-94 years)) were diagnosed with PTE in our hospital (0.31% of all hospitalizations). Dyspnea was the most frequent symptom reported (78.9%), followed by pleuritic chest pain (23.9%) and unilateral leg pain (15.8%). Upon presentation, 12.6% of patients had high-risk PTE. Up to 72.8% of patients had at least one thrombotic risk factor, while cancer (14%) was the most frequent amongst them. The mean length of hospitalization was 10.3 +/- 4.6 days. Unfractioned heparin (UFH) was the preferred anticoagulant during hospital stay (73.7%, p < 0.001). Vitamin K antagonists (AVK) were the preferred anticoagulant (71.7%, p < 0.001) after discharge, whereas non-antivitamin K oral anticoagulants (NOAC) were recommended in 26.3% of patients. Thrombolysis was used in 18 (8.4%) cases. Mortality was 0.9%. Younger patients more frequently associated thrombophilia or a previous thromboembolic event and clinical signs of DVT at presentation. Older patients associated more frequently a history of hospitalization for heart failure or atrial fibrillation during the previous 3 months and a history of cancer. The clinical presentation in older patients was more severe, with higher PESI scores (103.6 +/- 33.4 vs. 55.5 +/- 17.9, p<0.001) and a longer hospital stay (10.7 +/- 4.7 vs. 9.2 +/- 3.9, p = 0.03). The type of anticoagulant treatment did not differ depending on age. CONCLUSION: In our emergency hospital, PTE is a relatively rare cause of hospitalization; the rate is, however, comparable with other major hospitals. Dyspnea and pleuritic chest pain was the clinical presentation dyad. UFH was the preferred anticoagulant for in-hospital treatment while AVK was the preferred option for long term treatment and recurrence prophylaxis; however an increasing number of patients are prescribed NOAC. In older patients clinical severity was higher upon presentation, hospitalization duration was increased and cancer was more frequently associated. Younger patients associated more frequently a primary hypercoagulable state and recurrent thromboembolism. Mortality rate was low during hospitalization, comparable with that seen in other studied populations. PMID- 28667816 TI - Significance of Pretreatment Red Blood Cell Distribution Width in Patients with Newly Diagnosed Glioblastoma. AB - BACKGROUND Red blood cell distribution width (RDW) is a parameter of the complete blood count (CBC) test. Recent evidence suggests that pretreatment RDW is associated with patient survival in various malignant tumors. We explored the association of pretreatment RDW and other red blood cell (RBC) parameters with clinical parameters and assessed their prognostic impact on overall survival (OS) in patients with glioblastoma (GBM). MATERIAL AND METHODS In total, 109 patients with newly diagnosed GBM were retrospectively reviewed. The Cox proportional hazards regression model and Kaplan-Meier method were used to examine the survival function of pretreatment RDW, mean cell volume (MCV), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RBC count, and hematocrit (HCT) values in patients with newly diagnosed GBM. RESULTS Univariate analysis showed that MCV, MCHC, and RDW were associated with overall survival (OS). However, only RDW remained significant in multivariate analysis. The Kaplan-Meier survival curves showed that patients belonging to the high-RDW group had a worse median OS (293 days versus 375 days, P=0.023) than those belonging to the low-RDW group. CONCLUSIONS The present study showed that pretreatment RDW was superior to MCV and MCHC as a prognostic predictor of clinical outcome in patients newly diagnosed with GBM. Pretreatment RDW was derived directly from the CBC test, which can be easily performed in clinical practice. Therefore, pretreatment RDW values can provide additional prognostic information for patients with GBM. Further larger and prospective studies are needed to confirm these findings and to investigate the mechanism by which of RDW is associated with prognosis in patients with GBM. PMID- 28667817 TI - Solanum dulcamara's response to eggs of an insect herbivore comprises ovicidal hydrogen peroxide production. AB - Plants can respond to insect oviposition, but little is known about which responses directly target the insect eggs and how. Here, we reveal a mechanism by which the bittersweet nightshade Solanum dulcamara kills the eggs of a generalist noctuid herbivore. The plant responded at the site of oviposition by Spodoptera exigua with formation of neoplasms and chlorotic tissue, accumulation of reactive oxygen species and induction of defence genes and proteins. Transcriptome analysis revealed that these responses were reflected in the transcriptional reprogramming of the egg-laden leaf. The plant-mediated egg mortality on S. dulcamara was not present on a genotype lacking chlorotic leaf tissue at the oviposition sites on which the eggs are exposed to less hydrogen peroxide. As exposure to hydrogen peroxide increased egg mortality, while catalase supplementation prevented the plants from killing the eggs, our results suggest that reactive oxygen species formation directly acts as an ovicidal plant response of S. dulcamara. PMID- 28667819 TI - Airborne signals from Trichoderma fungi stimulate iron uptake responses in roots resulting in priming of jasmonic acid-dependent defences in shoots of Arabidopsis thaliana and Solanum lycopersicum. AB - Root colonization by Trichoderma fungi can trigger induced systemic resistance (ISR). In Arabidopsis, Trichoderma-ISR relies on the transcription factor MYB72, which plays a dual role in the onset of ISR and the activation of Fe uptake responses. Volatile compounds (VCs) from rhizobacteria are important elicitors of MYB72 in Arabidopsis roots. Here, we investigated the mode of action of VCs from Trichoderma fungi in the onset of ISR and Fe uptake responses. VCs from Trichoderma asperellum and Trichoderma harzianum were applied in an in vitro split-plate system with Arabidopsis or tomato seedlings. Locally, Trichoderma-VCs triggered MYB72 expression and molecular, physiological and morphological Fe uptake mechanisms in Arabidopsis roots. In leaves, Trichoderma-VCs primed jasmonic acid-dependent defences, leading to an enhanced resistance against Botrytis cinerea. By using Arabidopsis micrografts of VCs-exposed rootstocks and non-exposed scions, we demonstrated that perception of Trichoderma-VCs by the roots leads to a systemic signal that primes shoots for enhanced defences. Trichoderma-VCs also elicited Fe deficiency responses and shoot immunity in tomato, suggesting that this phenomenon is expressed in different plant species. Our results indicate that Trichoderma-VCs trigger locally a readjustment of Fe homeostasis in roots, which links to systemic elicitation of ISR by priming of jasmonic acid-dependent defences. PMID- 28667818 TI - Hospitalization rates during potentially inappropriate medication use in a large population-based cohort of older adults. AB - BACKGROUND AND AIMS: The temporal relationship between potentially inappropriate medication (PIM) use and hospitalization remains uncertain. We examined whether current PIM use increases the rate of hospitalization and estimated the rate of hospitalization during exposure to individual PIMs. METHODS: A retrospective population-based cohort study of 1 480 137 older adults was conducted using the 2003-2013 Italian Emilia-Romagna Regional administrative healthcare database (~4.5 million residents), which includes demographic, hospital and outpatient prescription information. Each day of follow-up was defined as exposed/unexposed to PIMs that 'should always be avoided', according to the Maio criteria, an Italian modified version of the Beers criteria. The study outcome was all-cause hospitalizations. Crude PIM-related hospitalization rates were calculated for individual PIMs. Repeated-events Cox proportional hazards models with time dependent covariates estimated adjusted hazard ratios for hospitalization during PIM exposure, as defined by three versions of the Maio criteria (v2007, v2011, v2014). RESULTS: During >10 million person-years of follow-up, 54.2% of individuals used >=1 PIM and 10.9% of all person-time was exposed to v2014 PIMs. Among 1 604 901 hospitalizations, 15.6% occurred during v2014 PIM exposure. Crude hospitalization rates during v2014 PIM-exposed and unexposed person-time were 228.1 and 152.1 per 1000 person-years, respectively. The PIM with the highest rate of hospitalization was ketorolac, while nonsteroidal anti-inflammatory drugs had the most exposure time. The hazard of hospitalization was 16% greater (hazard ratio = 1.16; 95% confidence interval 1.14, 1.18) among patients exposed to v2014 PIMs. The v2007 and v2011 estimates were similar. CONCLUSIONS: In this large population-based cohort of older adults, we found a 16% increased hospitalization risk associated with PIM exposure. PMID- 28667820 TI - Human Umbilical Cord-Derived Mesenchymal Stem Cells Conditioned Medium Attenuate Interstitial Fibrosis and Stimulate the Repair of Tubular Epithelial Cells in an Irreversible Model of Unilateral Ureteral Obstruction. AB - AIM: The growing number of patients suffering from chronic renal disease (CKD) is a challenge for the development of innovative therapies. Researchers have studied the therapeutic effects of cell therapy in acute kidney injury (AKI). However, the therapeutical effect of conditional medium (CM) in the CKD models have been rarely reported. Here, we examined the effects of umbilical cord derived mesenchymal stem cells (hUC-MSCs) CM on renal fibrosis in a rat model of unilateral ureteral obstruction (UUO). METHODS: We randomly divided the animals into three groups: sham-operated, UUO, UUO + CM. CM was administered via the left renal artery after total ligation of the left ureter. Rats were killed after 14 days of obstruction. Histological changes and oxidative stress parameters were assessed. Western blotting and immunohistochemistry analysis were used to measure epithelial-mesenchymal transition (EMT) markers, including epithelial cadherin (E cadherin), alpha-smooth muscle actin (alpha-SMA), tumor necrosis factor-alpha (TNF-alpha), Collagen-I, and transforming growth factor beta1 (TGF-beta1). Proliferation and apoptosis of renal tubular epithelial cells (RTEs) were also measured. RESULTS: HucMSC-CM significantly reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and increased the activity of glutathione (GSH) induced by UUO. Moreover, CM significantly reduced the expression of TGF-beta1, alpha-SMA, TNF-alpha and Collagen-I in UUO kidney, promoted the proliferation of RTEs and inhibited its apoptosis. In addition, the increased expression of E-cadherin also reflects the effective improvement of renal interstitial fibrosis. CONCLUSION: This study shows that CM protects UUO induced kidney damage and therefore could be a potential tool to prevent CKD progression. PMID- 28667821 TI - An apple CIPK protein kinase targets a novel residue of AREB transcription factor for ABA-dependent phosphorylation. AB - Phytohormone abscisic acid (ABA) regulates many important processes in plants. It is a major molecule facilitating signal transduction during the abiotic stress response. In this study, an ABA-inducible transcription factor gene, MdAREB2, was identified in apple. Transgenic analysis was performed to characterize its function in ABA sensitivity. Overexpression of the MdAREB2 gene increased ABA sensitivity in the transgenic apple compared with the wild-type (WT) control. In addition, it was found that the protein MdAREB2 was phosphorylated at a novel site Thr411 in response to ABA. A yeast two-hybridization screen of an apple cDNA library demonstrated that a protein kinase, MdCIPK22, interacted with MdAREB2. Their interaction was further verified with Pull Down and Co-IP assays. A series of transgenic analyses in apple calli and plantlets showed that MdCIPK22 was required for ABA-induced phosphorylation at Thr411 of the MdAREB2 protein and enhanced its stability and transcriptional activity. Finally, it was found that MdCIPK22 increased ABA sensitivity in an MdAREB2-dependent manner. Our findings indicate a novel phosphorylation site in CIPK-AREB regulatory module for the ABA signalling pathway, which would be helpful for researchers to identify the functions of uncharacterized homologs in the future. PMID- 28667822 TI - Effects of comorbid substance use disorders on outcomes in a Housing First intervention for homeless people with mental illness. AB - BACKGROUND AND AIMS: Evidence supports the effectiveness of Housing First (HF) programmes for people who are experiencing homelessness and mental illness; however, questions remain about its use in people with comorbid substance use disorders (SUD). The aim of this project was to test whether SUD modifies the effectiveness of an HF intervention. DESIGN: Secondary analysis of data from a randomized controlled trial of HF versus treatment-as-usual (TAU) with 24-month follow-up, comparing those with and without SUD at trial entry. SETTING: Vancouver, Toronto, Winnipeg, Moncton and Montreal, Canada. PARTICIPANTS: A total of 2154 participants recruited from 2009 to 2013 and randomized to HF versus TAU (67% male, mean age 40.8 +/- 11.2, 25% ethno-cultural minority). All were homeless and had a mental disorder at baseline; 35% reported symptoms consistent with SUD. INTERVENTION: Housing paired with Intensive Case Management or Assertive Community Treatment. MEASUREMENTS: Primary outcomes were days housed and community functioning. Secondary outcomes were general and health-related quality of life and mental health symptoms. Predictors were SUD status crossed with intervention group (HF versus TAU). FINDINGS: People with SUD in both the HF and TAU groups spent less time in stable housing, but the effect of HF did not vary by SUD status [odds ratio (OR) = 1.17, 95% confidence interval (CI) = -0.77, 1.76]. Similarly, there was no difference between those with and without SUD in the effect of HF (over TAU) on community functioning (b = 0.75, 95% CI = -0.36, 1.87), quality of life (b = -1.27, 95% CI = -4.17, 1.63), health-related quality of life (b = -0.01, 95% CI = -0.03, 0.02) or mental health symptoms (b = 0.43, 95% CI = -0.99, 1.86). CONCLUSIONS: Housing First programs in Canada are equally effective in people with and without comorbid substance use disorder (SUD). Overall, the intervention appears to be able to engage people with SUD and is reasonably successful at housing them, without housing being contingent upon abstinence or treatment. PMID- 28667823 TI - Bordered pits in xylem of vesselless angiosperms and their possible misinterpretation as perforation plates. AB - Vesselless wood represents a rare phenomenon within the angiosperms, characterizing Amborellaceae, Trochodendraceae and Winteraceae. Anatomical observations of bordered pits and their pit membranes based on light, scanning and transmission electron microscopy (SEM and TEM) are required to understand functional questions surrounding vesselless angiosperms and the potential occurrence of cryptic vessels. Interconduit pit membranes in 11 vesselless species showed a similar ultrastructure as mesophytic vessel-bearing angiosperms, with a mean thickness of 245 nm (+/- 53, SD; n = six species). Shrunken, damaged and aspirated pit membranes, which were 52% thinner than pit membranes in fresh samples (n = four species), occurred in all dried-and-rehydrated samples, and in fresh latewood of Tetracentron sinense and Trochodendron aralioides. SEM demonstrated that shrunken pit membranes showed artificially enlarged, > 100 nm wide pores. Moreover, perfusion experiments with stem segments of Drimys winteri showed that 20 and 50 nm colloidal gold particles only passed through 2 cm long dried-and-rehydrated segments, but not through similar sized fresh ones. These results indicate that pit membrane shrinkage is irreversible and associated with a considerable increase in pore size. Moreover, our findings suggest that pit membrane damage, which may occur in planta, could explain earlier records of vessels in vesselless angiosperms. PMID- 28667824 TI - The association between personal income and smoking among adolescents: a study in six European cities. AB - AIMS: This study investigates the link between personal income and smoking among adolescents, and aims to answer the following questions: (i) to what extent is personal income related to smoking, independent of family socio-economic status (SES) and (ii) does the association between personal income and smoking apply to different subpopulations? DESIGN: Cross-sectional study. SETTING: Six cities from European countries (Amersfoort, the Netherlands; Coimbra, Portugal; Hannover, Germany; Latina, Italy; Namur, Belgium; Tampere, Finland) in 2013. PARTICIPANTS: A school-based sample of 10 794 adolescents aged 14-17 years. MEASUREMENTS: We modelled smoking experimentation, weekly smoking, daily smoking and (among daily smokers) smoking intensity as function of personal income, adjusting for age, sex, family SES, parental smoking and country. We tested interactions between personal income and covariates. Stratification analyses were performed for the variables for which interactions were significant. FINDINGS: Adolescents in the highest income quintile were more likely to be smoking experimenters [odds ratio (OR) = 1.87; P < 0.01], weekly smokers (OR = 3.51; P < 0.01) and daily smokers (OR = 4.55; P < 0.01) than those in the lowest quintile. They also consumed more cigarettes per month (beta = 0.79; P < 0.01). Adjusting for family SES did not modify the significance of relationships, and increased the magnitude of the association for daily smoking. None of the interactions between covariates and personal income was significant for smoking measures. For the intensity of smoking, the interaction was significant for SES. The stratified analysis showed a non-significant association between smoking intensity and personal income among the oldest adolescents and those with the lowest SES background, while significant among younger and higher SES backgrounds. CONCLUSION: In the Netherlands, Portugal, Germany, Italy, Belgium and Finland, adolescents' personal income is related positively to smoking behaviours independent of family socio economic status (SES). However, among low socio-economic status adolescent daily smokers, the association between the intensity of smoking and personal income is weaker. PMID- 28667825 TI - Heavy alcohol consumption increases the risk of active tuberculosis in Taiwanese adults: a nation-wide population-based cohort study. AB - AIMS: To investigate the impact of alcohol exposure on tuberculosis (TB) development in Taiwanese adults. DESIGN: Participants from the Taiwan National Health Interview Survey. Alcohol consumption and other covariates were collected by in-person interviews at baseline. Incident cases of active TB were identified from the National Health Insurance database. A multivariable Cox regression model was used to estimate the association between alcohol consumption and active TB, with adjustment for age, sex, smoking, socio-economic status and other covariates. SETTING: Taiwan National Health Interview Survey. PARTICIPANTS: A total of 46 196 adult participants aged >= 18 years from three rounds (2001, 2005, 2009) of the Taiwan National Health Interview Survey. MEASUREMENTS: Alcohol consumption was classified into never, social, regular or heavy alcohol use. Heavy alcohol consumption was defined as intoxication at least once/week. FINDINGS: Of the 46 196 study subjects, 61.8, 24.2, 13.5 and 0.5% were classified as never, social, regular and heavy alcohol users, respectively. During the 398 443 person-years of follow-up, 279 (0.60%) subjects developed new-onset active TB. After adjusting for the subject demographics and comorbidities, heavy [hazard ratio (HR) = 5.27; 95% confidence interval (CI) = 2.51-11.09] and regular alcohol users (HR = 1.80; 95% CI = 1.32-2.45) had increased risks of incident TB compared to never users. Moreover, a positive trend between increasing levels of alcohol consumption and the risk of active TB was noted (P < 0.001). CONCLUSIONS: In Taiwan, heavy and regular alcohol consumption are associated with higher risks of active tuberculosis. PMID- 28667826 TI - Effectiveness of intensive practice nurse counselling versus brief general practitioner advice, both combined with varenicline, for smoking cessation: a randomized pragmatic trial in primary care. AB - AIMS: To study the effectiveness of intensive counselling by a practice nurse (PN) versus brief advice by a general practitioner (GP), each combined with pharmacotherapy, for 6 months' tobacco abstinence (primary outcome). Secondary outcomes included 12-month abstinence, medication adherence and incremental costs per life-year gained. DESIGN: A multi-site (n = 10), two-group, parallel, pragmatic randomized controlled trial. SETTING: A network of primary health-care centres in the Netherlands. PARTICIPANTS: A total of 295 adult daily smokers (mean age = 48 years; mean cigarettes/day = 19). INTERVENTION AND COMPARATOR: Patients were randomized to receive individual counselling by a practice nurse (PN) (n = 149) or brief advice by a general practitioner (GP) (146). All patients received 12 weeks of open-label varenicline. MEASUREMENTS: The primary outcome was prolonged biochemically validated abstinence from weeks 9 to 26 after treatment initiation. Secondary outcomes included abstinence from weeks 9 to 52, good dosing adherence (> 80% days taken) and incremental costs per life-year gained. FINDINGS: Abstinence rates in the PN versus GP groups were 32.2% (n = 48) versus 39.0% [n = 57; odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.44 1.16] from weeks 9 to 26 and 25.5% (n = 38) versus 28.8% (n = 42; OR = 0.84, 95% CI = 0.50-1.43) from weeks 9 to 52, respectively. Values of the Bayes factor indicated that the PN and GP were equally effective. Good dosing adherence was significantly lower in the PN (45.5%, n = 56/123) than in the GP group (62.0%, n = 75/121; OR = 0.45, 95% CI = 0.26-0.77), and the incremental costs per life-year gained were -?416.10. CONCLUSIONS: Among people seeking help to stop smoking from their general practice, one-off brief advice from a general practitioner appears to be as effective as several sessions of behavioural support from a practice nurse when smoking cessation medication is provided. PMID- 28667827 TI - The identification of new candidate genes Triticum aestivum FLOWERING LOCUS T3-B1 (TaFT3-B1) and TARGET OF EAT1 (TaTOE1-B1) controlling the short-day photoperiod response in bread wheat. AB - Perception of photoperiod changes enables plants to flower under optimum conditions for survival. We used doubled haploid populations of crosses among Avalon * Cadenza, Charger * Badger and Spark * Rialto and identified short-day flowering time response quantitative trait loci (QTL) on wheat chromosomes 1BS and 1BL. We used synteny between Brachypodium distachyon and wheat to identify potential candidates for both QTL. The 1BL QTL peak coincided with TaFT3-B1, a homologue of the barley gene HvFT3, the most likely candidate gene. The 1BS QTL peak coincided with homologues of Arabidopsis thaliana SENSITIVITY TO RED LIGHT REDUCED 1, WUSCHEL-like and RAP2.7, which is also known as Zea mays TARGET OF EAT1, named TaSRR1-B1, TaWUSCHELL-B1 and TaTOE1-B1, respectively. Gene expression assays suggest that TaTOE1-B1 and TaFT3-B1 are expressed more during short days. We identified four alleles of TaFT3-B1 and three alleles of TaTOE1-B1. We studied the effect of these alleles in the Watkins and GEDIFLUX diversity panels by using 936 and 431 accessions, respectively. Loss of TaFT3-B1 by deletion was associated with late flowering. Increased TaFT3-B1 copy number was associated with early flowering, suggesting that TaFT3-B1 promotes flowering. Significant association was observed in the GEDIFLUX collection for TaTOE1-B1, a putative flowering repressor. PMID- 28667828 TI - The relationship between gambling expenditure, socio-demographics, health-related correlates and gambling behaviour-a cross-sectional population-based survey in Finland. AB - AIMS: To investigate gambling expenditure and its relationship with socio demographics, health-related correlates and past-year gambling behaviour. DESIGN: Cross-sectional population survey. SETTING: Population-based survey in Finland. PARTICIPANTS: Finnish people aged 15-74 years drawn randomly from the Population Information System. The participants in this study were past-year gamblers with gambling expenditure data available (n = 3251, 1418 women and 1833 men). MEASUREMENTS: Expenditure shares, means of weekly gambling expenditure (WGE, ?) and monthly gambling expenditure as a percentage of net income (MGE/NI, %) were calculated. The correlates used were perceived health, smoking, mental health [Mental Health Inventory (MHI)-5], alcohol use [Alcohol Use Disorders Identification Test (AUDIT)-C], game types, gambling frequency, gambling mode and gambling severity [South Oaks Gambling Screen (SOGS)]. FINDINGS: Gender (men versus women) was found to be associated significantly with gambling expenditure, with exp(beta) = 1.40, 95% confidence interval (CI) = 1.29, 1.52 and P < 0.005 for WGE, and exp(beta) = 1.39, 95% CI = 1.27, 1.51 and P < 0.005 for MGE/NI. All gambling behaviour correlates were associated significantly with WGE and MGE/NI: gambling frequency (several times a week versus once a month/less than monthly, exp(beta) = 30.75, 95% CI = 26.89, 35.17 and P < 0.005 for WGE, and exp(beta) = 31.43, 95% CI = 27.41, 36.03 and P < 0.005 for MGE/NI), gambling severity (probable pathological gamblers versus non-problem gamblers, exp(beta) = 2.83, 95% CI = 2.12, 3.77 and P < 0.005 for WGE, and exp(beta) = 2.67, 95% CI = 2.00, 3.57 and P < 0.005 for MGE/NI) and on-line gambling (on-line and land-based versus land-based only, exp(beta) = 1.35, 95% CI = 1.24, 1.47 and P < 0.005 for WGE, and exp(beta) = 1.35, 95% CI = 1.24, 1.47 and P < 0.005 for MGE/NI). CONCLUSIONS: In Finland, male gender is associated significantly with both weekly gambling expenditure and monthly gambling expenditure related to net income. People in Finland with lower incomes contribute proportionally more of their income to gambling compared with middle- and high-income groups. PMID- 28667829 TI - Rapid and simple flow injection analysis tandem mass spectrometric method for the quantification of melphalan in a lipid-based drug delivery system. AB - RATIONALE: The use of the anticancer drug melphalan is limited due to its poor water solubility. To address this limitation, it is incorporated within a novel delivery system using beta-cyclodextrin-gemini surfactants (18:1betaCDg). METHODS: Herein, two fast and simple flow injection analysis/tandem mass spectrometric (FIA-MS/MS) methods are developed for the quantification of melphalan (Mel) within the drug delivery system so that the solubilization efficiency of the system can be assessed. FIA-MS/MS methods are developed using a triple quadrupole linear ion trap mass spectrometer, equipped with electrospray ionization (ESI) in the positive ion mode. A deuterated form of melphalan (melphalan-d8) was used as an internal standard (IS). The methods were validated according to the FDA guidance. RESULTS: A linearity in the range of 2-100 ng/mL and accuracy and precision below 15% were observed for all standard points and quality control samples. The intra- and inter-day variations and freeze-thaw stability were within the acceptable range according to the criteria set by regulatory guidelines. On the other hand, other stability measures, such as room temperature stability and long-term stability, did not meet the required guidelines in some cases, indicating the need for quick sample analysis upon preparation. Such a fact could have been overlooked if full method validation had not been performed. CONCLUSIONS: The developed methods were applied to determine the encapsulation/solubilization of the [18:1betaCDg/Mel] delivery system. 18:1betaCDg enhances the aqueous solubility of melphalan without the need for co solvent. The highest melphalan solubility was observed at a melphalan18:1betaCDg/Mel complex molar ratio of 2:1. This study demonstrated that a fast analysis for the purpose of quantifying a chemically unstable drug, such as melphalan, is feasible and important for the development of commercial dosage forms. PMID- 28667831 TI - Systematic Review of Immigrant Women's Experiences With Perinatal Care in North America. AB - OBJECTIVE: To understand the perinatal care experiences of pregnant immigrant women in North America. DATA SOURCES: We searched five electronic databases: MEDLINE, PsycINFO, SocINDEX, CINAHL, and Social Work Abstracts. Two categories of search terms, pregnancy and immigrant, were used to conduct a title/abstract and subject heading search. We manually searched the reference lists of all relevant articles to identify additional articles. STUDY SELECTION: Inclusion criteria were qualitative or mixed methods study design, focus on immigrant women's experiences of accessing perinatal care, and data collection in North America. Two reviewers were involved in a three-stage selection process: title/abstract screen, full text review, and data extraction and quality appraisal. DATA EXTRACTION: Data on authors, date, location, methodology, sample characteristics, data collection, and themes or topics were extracted from 19 articles. DATA SYNTHESIS: We followed the Thomas and Harden (2008) thematic synthesis methodology, which involved a three-stage data analysis approach: free line-by line coding, organization of free codes into descriptive themes, and construction of analytical themes. We developed three meta-themes from the 19 articles included in our review: Expectations of Pregnancy as Derived From Home, Reality of Pregnancy in the Host Health Care System, and Support. CONCLUSION: Immigration is a relevant issue in North America, and pregnancy can be an entry point into the health care system for immigrant women. We provide relevant information for health care providers, policy makers, program planners, and researchers about opportunities to explain models of health care delivery, improve communication, and facilitate social support to improve the experiences of immigrant women who interact with the health care system during pregnancy. PMID- 28667830 TI - Predictors of comorbid eating disorders and association with other obsessive compulsive spectrum disorders in trichotillomania. AB - Trichotillomania (TTM) and eating disorders (ED) share many phenomenological similarities, including ritualized compulsive behaviors. Given this, and that comorbid EDs may represent additional functional burden to hair pullers, we sought to identify factors that predict diagnosis of an ED in a TTM population. Subjects included 555 adult females (age range 18-65) with DSM-IV-TR TTM or chronic hair pullers recruited from multiple sites. 7.2% (N=40) of our TTM subjects met criteria for an ED in their lifetime. In univariable regression analysis, obsessive-compulsive disorder (OCD), Yale-Brown Obsessive Compulsive Scale (Y-BOCS) worst-ever compulsion and total scores, certain obsessive compulsive spectrum disorders, anxiety disorder, attention-deficit/hyperactivity disorder (ADHD), and substance disorder all met the pre-specified criteria for inclusion in the multivariable analysis. In the final multivariable model, diagnosis of OCD (OR: 5.68, 95% CI: 2.2-15.0) and diagnosis of an additional body focused repetitive behavior disorder (BFRB) (OR: 2.69, 95% CI: 1.1-6.8) were both associated with increased risk of ED in TTM. Overall, our results provide further support of the relatedness between ED and TTM. This finding highlights the importance of assessing for comorbid OCD and additional BFRBs in those with TTM. Future research is needed to identify additional predictors of comorbid disorders and to better understand the complex relationships between BFRBs, OCD and EDs. PMID- 28667833 TI - Treatment of Temporomandibular Joint Disorders: The Unwanted Stepchild. PMID- 28667832 TI - Effect of Previous Posttraumatic Stress in the Perinatal Period. AB - OBJECTIVE: To review the extant literature on the effect of traumatic experiences that pre-date conception, pregnancy, and the postpartum period (perinatal period) and present a thematic overview of current issues in this relatively new area of inquiry. DATA SOURCES: Electronic databases Cochrane, CINAHL, PsychINFO, and PubMed were searched. Manual searches of reference lists supplemented the electronic search. STUDY SELECTION: Peer-reviewed articles written in English on the role of posttraumatic stress disorder during the perinatal period were included. DATA EXTRACTION: Key findings relevant to perinatal posttraumatic stress that were reported in primary sources and meta-analyses were organized according to themes, including The Role of Childbirth, Comorbidity With Depression and Anxiety, Risk Factors for Perinatal PTSD, High-Risk Health Behaviors, and Association With Adverse Health Outcomes. DATA SYNTHESIS: Across studies, antenatal posttraumatic stress disorder (PTSD) rates were estimated between 2.3% and 24%, and observed prevalence rates during the postnatal period ranged from 1% to 20%; however, many researchers failed to assess PTSD that existed before or during pregnancy, and when preexisting PTSD is a controlled variable, postpartum rates drop to 2% to 4.7%. In addition to prenatal depression and anxiety and pre-pregnancy history of psychiatric disorders, history of sexual trauma, childhood sexual abuse, intimate partner violence, and psychosocial attributes are risk factors for development or exacerbation of perinatal PTSD. CONCLUSION: Women's health care providers should evaluate for PTSD in routine mental health assessments during and after pregnancy, especially with a reported history of trauma or the presence of a mood or anxiety disorder. Such screening will allow women to receive needed treatment and referrals and mitigate the potentially negative sequelae of PTSD. Future investigators must recognize the importance of subsyndromal posttraumatic stress symptoms and individual differences in responses to trauma. PMID- 28667834 TI - Black-white metropolitan segregation and self-rated health: Investigating the role of neighborhood poverty. AB - While black-white segregation has been consistently linked to detrimental health outcomes for blacks, whether segregation is necessarily a zero-sum arrangement in which some groups accrue health advantages at the expense of other groups and whether metropolitan segregation impacts the health of racial groups uniformly within the metropolitan area, remains unclear. Using nationally representative data from the 2008-2013 National Health Interview Survey linked to Census data, we investigate whether the association between metropolitan segregation and health is invariant within the metropolitan area or whether it is modified by neighborhood poverty for black and white Americans. In doing so, we assess the extent to which segregation involves direct health tradeoffs between blacks and whites. We conduct race-stratified multinomial and logistic regression models to assess the relationship between 1) segregation and level of neighborhood poverty and 2) segregation, neighborhood poverty, and poor health, respectively. We find that, for blacks, segregation was associated with a higher likelihood of residing in high poverty neighborhoods, net of individual-level socioeconomic characteristics. Segregation was positively associated with poor health for blacks in high poverty neighborhoods, but not for those in lower poverty neighborhoods. Hence, the self-rated health of blacks clearly suffers as a result of black-white segregation - both directly, and indirectly through exposure to high poverty neighborhoods. We do not find consistent evidence for a direct relationship between segregation and poor health for whites. However, we find some suggestive evidence that segregation may indirectly benefit whites through decreasing their exposure to high poverty environments. These findings underscore the critical role of concentrated disadvantage in the complex interconnection between metropolitan segregation and health. Weakening the link between racial segregation and concentrated poverty via local policy and planning has the potential for broad population-based health improvements and significant reductions in black-white health disparities. PMID- 28667835 TI - Monocytes Promote Crescent Formation in Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis. AB - Neutrophils and monocytes express anti-neutrophil cytoplasmic antibody (ANCA) antigens, and activation of these cells by ANCA is central to ANCA-associated vasculitis and necrotizing crescentic glomerulonephritis (NCGN). The importance of neutrophils is established; however, any role of monocytes is less clear. We tested the hypothesis that depletion of CCR2+ inflammatory monocytes and their derivatives would abrogate anti-myeloperoxidase (MPO) antibody-induced NCGN in a mouse model. We used passive anti-MPO antibody transfer for NCGN induction in wild-type mice or mice expressing the CCR2 promoter-controlled diphtheria toxin receptor. Both mouse strains showed similar circulating Ly6Chi and Ly6Clo monocytes and neutrophils at baseline. Diphtheria toxin robustly depleted circulating monocytes only in CCR2 promoter-controlled diphtheria toxin receptor mice, whereas neutrophil numbers were similar. Anti-MPO antibody transfer resulted in nephritic urine by dipstick and albuminuria by enzyme-linked immunosorbent assay, and monocyte depletion had no effect. However, monocyte depletion significantly reduced glomerular necrosis and crescent formation and abrogated monocyte, macrophage, and dendritic cell increase in the affected kidneys, whereas renal neutrophil numbers were not affected. Soluble CD163 increased in serum, but not in urine, with anti-MPO antibody treatment and was completely abolished with monocyte depletion. Our findings establish an important role of monocytes/macrophages for glomerular necrosis and crescent formation in a renal ANCA-associated vasculitis model. PMID- 28667836 TI - Adenosine A2a Receptor Blockade Diminishes Wnt/beta-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis. AB - Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/beta-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/beta-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/beta-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of beta-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated beta-catenin or beta-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated beta-catenin and beta-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A2aR inhibits the WNT/beta-catenin signaling pathway, contributing to its capacity to inhibit dermal fibrosis in diseases such as scleroderma. PMID- 28667837 TI - A high sensitive visible light-driven photoelectrochemical aptasensor for shrimp allergen tropomyosin detection using graphitic carbon nitride-TiO2 nanocomposite. AB - Herein, for the first time a visible-light-driven photoelectrochemical (PEC) aptasensor for shrimp tropomyosin determination was fabricated by using graphitic carbon nitride (g-C3N4) and titanium dioxide (TiO2) as photoactive nanomaterials, ascorbic acid (AA) as electron donor and ruthenium (III) hexaammine (Ru(NH3)63+) as signal enhancer. The surface of an ITO electrode was first modified with g C3N4, TiO2, and polyethyleneimine (PEI) and then the amine terminal aptamerTROP probe was attached to PEI by the use of glutaraldehyde (GA) as cross-linker. After that, Ru(NH3)63+ was adsorbed on aptamer to enhance the photocurrent signal. The principle of proposed PEC aptasensor is based on the formation of a selective complex between tropomyosin and immobilized aptamerTROP probe on the surface of ITO/g-C3N4-TiO2/PEI/aptamerTROP-Ru(NH3)6+3. After the incubation of tropomyosin with TROP aptamer probe, the photocurrent signal decreased due to releasing adsorbed Ru(NH3)63+ on aptamer and preventing AA from scavenging photogenerated holes to the photoactive modified electrode. Under the optimized conditions, the fabricated PEC aptasensor was used for the determination of shrimp tropomyosin in the concentration range of 1-400ngmL-1 with a limit of detection of 0.23ngmL-1. The proposed PEC aptasensor exhibited high selectivity, sensitivity, and good stability. PMID- 28667838 TI - Quantitative ratiometric phosphorescence hypoxia-sensing nanoprobes based on quantum dots/Ir(III) glycerol monoolein cubic-phase nanoparticles. AB - A novel protocol is developed to prepare quantum dot (QD)/Ir(III) complex glycerol monoolein (GMO) cubic-phase nanoparticles (Qd/Ir GMCPNPs) as hypoxia nanoprobes, in which hypoxia probe Tris [1-phenylisoquinoline-C2, N] Iridium(III) [Ir(piq)3] and the reference QDs are separately loaded at hydrophilic and hydrophobic channels to avoid interference. Qd/Ir GMCPNPs were nearly spherical in shape, with an average size of 20-30nm. Their phosphorescence spectra showed that nanoprobes have a wide excited wave length range of 360-500nm, which is suitable for different types of measurement instruments. When the oxygen content decreased from 21% to 1%, the luminescent intensity ratio of Qd/Ir GMCPNPs in the solution and cells increased 4-fold and 2.8-fold, respectively, with an acceptable linear relationship. Particularly, extensive preliminary quantitative ratiometric oxygen sensing and long tumor imaging monitoring can be achieved with these nanoprobes. PMID- 28667839 TI - Multiple amplified enzyme-free electrochemical immunosensor based on G quadruplex/hemin functionalized mesoporous silica with redox-active intercalators for microcystin-LR detection. AB - A novel multiple amplified enzyme-free immunosensor was developed for competitive immunoassay of microcystin-LR (MC-LR). Classical electrochemical immunosensors usually employ enzymes as biocatalysts to afford amplified signals, but the proteolytic degradation and poor stability are still crucial problem. Herein, monodisperse core-shell mesoporous silica (SiO2@MSN)-functionalized DNAzyme concatamers were synthesized to load hemin and methylene blue (MB) as the mimic enzyme. Firstly, the surface of SiO2@MSN was conjugated with secondary antibody as the recognition of MC-LR antibody and with a DNA strand as the initiator. Two auxiliary DNA strands were then selected for the in-situ propagation to form a double-helix DNA through hybridization chain reaction (HCR), forming numerous DNAzymes (G-quadruplex/hemin) after the addition of hemin. Secondly, MB was inserted into the formed double-helix DNA, and also loaded in the brush-like structure of mesoporous SiO2@MSN. The molecular docking study showed that electrons can transfer more effectively with pi-pi stack of hemin/G-quadruplex and intercalation of MB/DNA, thus the catalytic ability of DNAzymes can be greatly improved. With the aid of MB, DNAzymes can catalyze the reduction of H2O2 to produce the electrochemical signal. This enzyme-free electrochemical immunosensor can successfully detect MC-LR in a range of 0.5ng/L and 25MUg/L with a detection limit of 0.3ng/L. This stable, sensitive and selective nonenzymatic electrochemical immunoassay shows promise for applications in food and environmental monitoring. PMID- 28667840 TI - Thermal pyrolysis characteristics of macroalgae Cladophora glomerata. AB - The Cladophora glomerata (C. glomerata) is a kind of widely distributed macroalgae in the freshwater ecosystems. It primarily consists of carbohydrates that can be converted into biofuel by pyrolysis. In this study, thermogravimetric analysis (TGA) was used to investigate the thermal behavior and kinetics of C. glomerata during the pyrolysis process. The results showed that heating rates slightly affect the decomposition properties of C. glomerata; with the heating rates increasing, the maximum peak of weight loss rate shifted to higher temperatures. The activation energies of C. glomerata pyrolysis reaction were 244.25 and 238.07kJ/mol, respectively, as calculated by Friedman and Kissinger Akahira-Sunose (KAS) methods. The pre-exponential factor and reaction order were determined by Coats-Redfern model, and applied to simulate the pyrolysis process of C. glomerata. The model calculated data and experimental data were consistent. This study could provide theoretical supports for designing C. glomerata conversion processes. PMID- 28667841 TI - Integrating multisensor satellite data merging and image reconstruction in support of machine learning for better water quality management. AB - Monitoring water quality changes in lakes, reservoirs, estuaries, and coastal waters is critical in response to the needs for sustainable development. This study develops a remote sensing-based multiscale modeling system by integrating multi-sensor satellite data merging and image reconstruction algorithms in support of feature extraction with machine learning leading to automate continuous water quality monitoring in environmentally sensitive regions. This new Earth observation platform, termed "cross-mission data merging and image reconstruction with machine learning" (CDMIM), is capable of merging multiple satellite imageries to provide daily water quality monitoring through a series of image processing, enhancement, reconstruction, and data mining/machine learning techniques. Two existing key algorithms, including Spectral Information Adaptation and Synthesis Scheme (SIASS) and SMart Information Reconstruction (SMIR), are highlighted to support feature extraction and content-based mapping. Whereas SIASS can support various data merging efforts to merge images collected from cross-mission satellite sensors, SMIR can overcome data gaps by reconstructing the information of value-missing pixels due to impacts such as cloud obstruction. Practical implementation of CDMIM was assessed by predicting the water quality over seasons in terms of the concentrations of nutrients and chlorophyll-a, as well as water clarity in Lake Nicaragua, providing synergistic efforts to better monitor the aquatic environment and offer insightful lake watershed management strategies. PMID- 28667842 TI - Proactive modeling of water quality impacts of extreme precipitation events in a drinking water reservoir. AB - Extreme precipitation events are of concern to managers of drinking water sources because these occurrences can affect both water supply quantity and quality. However, little is known about how these low probability events impact organic matter and nutrient loads to surface water sources and how these loads may impact raw water quality. This study describes a method for evaluating the sensitivity of a water body of interest from watershed input simulations under extreme precipitation events. An example application of the method is illustrated using the Wachusett Reservoir, an oligo-mesotrophic surface water reservoir in central Massachusetts and a major drinking water supply to metropolitan Boston. Extreme precipitation event simulations during the spring and summer resulted in total organic carbon, UV-254 (a surrogate measurement for reactive organic matter), and total algae concentrations at the drinking water intake that exceeded recorded maximums. Nutrient concentrations after storm events were less likely to exceed recorded historical maximums. For this particular reservoir, increasing inter reservoir transfers of water with lower organic matter content after a large precipitation event has been shown in practice and in model simulations to decrease organic matter levels at the drinking water intake, therefore decreasing treatment associated oxidant demand, energy for UV disinfection, and the potential for formation of disinfection byproducts. PMID- 28667843 TI - The impact of multimorbidity on grip strength in adults age 50 and older: Data from the health and retirement survey (HRS). AB - BACKGROUND: Multimorbidity, the presence of two or more chronic diseases, is a public health concern. The measurement of grip strength has been proposed as a measure of overall body strength and is reliable and easy to measure. The purpose of this study was to investigate the relationship between the number of chronic diseases and common co-occurring chronic diseases with grip strength. METHODS: A cross-sectional analysis was conducted of 5877 respondents (2744=male, 3103=female) from the 2008 Health and Retirement Study (HRS) who completed grip strength measurements (kg). RESULTS: As the number of chronic diseases increased, an incremental decrease in grip strength occurred and became more pronounced with >=3 chronic diseases present (b=3.1, 95% CI=2.3-3.9, p<0.001). No statistically significant relationship was identified between specific chronic diseases (except for stroke) and grip strength. CONCLUSION: Multimorbidity has a statistically significant negative relationship on grip strength. Grip strength should be considered as a physical performance measure to incorporate into the care of patients with multimorbidity. PMID- 28667844 TI - Elevated plasma vitamin B12 levels and risk of venous thromboembolism among cancer patients: A population-based cohort study. AB - INTRODUCTION: Both venous thromboembolism (VTE) and high plasma vitamin B12 levels (cobalamin, Cbl) are markers of occult cancer and aggressive cancer with a poor prognosis. In this population-based cohort study, we assessed VTE risk among cancer patients with high plasma Cbl levels. MATERIALS AND METHODS: We used Danish health registries to identify a Cb1 cohort of 25,310 cancer patients with a plasma Cbl measurement prior to cancer diagnosis. The cohort was subdivided according to Cbl levels (pmol/L): 200-600 (population reference range), 601-800 and >800. All VTE events were considered provoked and categorised as either cancer-associated if no other provoking factors were present before VTE or provoked by other risk factors (surgery, trauma, or pregnancy). We calculated cumulative incidence proportions and adjusted hazard ratios computed from Cox regression analysis (reference: plasma Cbl of 200-600pmol/L) for the risk of VTE before and after the cancer diagnosis date (index date). RESULTS: The risk of cancer-associated VTE 30days after index date increased with higher Cbl levels. The cumulative incidence (95% CI) by Cbl levels was: 200-600pmol/L: 0.24 (0.18 0.31); 601-800pmol/L: 0.63 (0.34-1.09); >800pmol/L: 0.86 (0.49-1.40). Adjusted hazard ratios (95% CI) were: 601-800 vs. 200-600: 2.55 (1.32-4.92); >800 vs. 200 600: 2.36 (1.19-4.71). We found similar results for VTE provoked by other risk factors and for VTE occurring before index date, but scarcity of events produced uncertain risk estimates. CONCLUSION: We demonstrated an association between high plasma Cbl levels and risk of VTE in cancer patients. Any clinical implications warrant further study. PMID- 28667845 TI - Observation of SOA tracers at a mountainous site in Hong Kong: Chemical characteristics, origins and implication on particle growth. AB - Secondary organic aerosol (SOA) is an important constituent of airborne fine particles. PM2.5 (particles with aerodynamic diameters<=2.5MUm) samples were collected at a mountainous site in Hong Kong in autumn of 2010, and analyzed for SOA tracers. Results indicated that the concentrations of isoprene SOA tracers (54.7+/-22.7ng/m3) and aromatics SOA tracers (2.1+/-1.6ng/m3) were on relatively high levels in Hong Kong. Secondary organic carbon (SOC) derived from isoprene, monoterpenes, sesquiterpenes and aromatics was estimated with the SOA tracer based approach, which constituted 0.35+/-0.15MUg/m3 (40.6+/-5.7%), 0.20+/ 0.03MUg/m3 (30.4+/-5.5%), 0.05+/-0.02MUg/m3 (5.6+/-1.7%) and 0.26+/-0.20MUg/m3 (21.3+/-8.2%) of the total estimated SOC. Biogenic SOC (0.60+/-0.18MUg/m3) dominated over anthropogenic SOC (0.26+/-0.20MUg/m3) at this site. In addition to the total estimated SOC (17.8+/-4.6% of organic carbon (OC) in PM2.5), primary organic carbon (POC) emitted from biomass burning also accounted for a considerable proportion of OC (11.6+/-3.2%). Insight into the OC origins found that regional transport significantly (p<0.05) elevated SOC from 0.37+/-0.17 to 1.04+/-0.39MUg/m3. Besides, SOC load could also increase significantly if there was influence from local ship emission. Biomass burning related POC in regional air masses (0.81+/-0.24MUg/m3) was also higher (p<0.05) than that in samples affected by local air (0.29+/-0.35MUg/m3). Evidences indicated that SOA formation was closely related to new particle formation and the growth of nucleation mode particles, while biomass burning was responsible for some particle burst events in Hong Kong. This is the first SOA study in afforested areas of Hong Kong. PMID- 28667846 TI - The use of Sn(II) oxy-hydroxides for the effective removal of Cr(VI) from water: Optimization of synthesis parameters. AB - The development of a novel adsorbent based on Sn(II) oxy-hydroxide nanoparticles and the optimization of main synthesis parameters was examined for the efficient removal of hexavalent chromium at low residual concentration levels. The aqueous hydrolysis of Sn(II) salts in a continuous-flow process was evaluated as an effective method to synthesize an appropriate material able to operate both as an electron donor for Cr(VI) reduction, and provide a suitable crystal structure that favors strong complexation with the formed Cr(III) species. Experimental results revealed that the main hydrolysis parameters, such as pH value and tin origin/source, can be used to determine the chemical formula of the produced materials and thereby, eventually improve their uptake capacity for Cr(VI). Among the tested sorbent materials, the synthetic nanostructured hydroromarchite, Sn6O4(OH)4, prepared by the hydrolysis of SnCl2 in a highly acidic environment (pH2), was deemed the best sorbent material and it was further investigated for its Cr(VI) uptake performance under reliable conditions (column experiments) for drinking water treatment. Specifically, Rapid Small-Scale (laboratory) Column Tests indicated that aggregates of the Sn6O4(OH)4 nanomaterial can achieve a maximum uptake capacity of around 19mg/g, keeping the levels of outflow Cr(VI) below 10MUg/L during the treatment of natural-like water at pH7. The high efficiency is mainly attributed to the stabilization of Sn(II) content in nanoparticles, as well as the improved surface charge density, reaching 1.0mmol[OH-]/g, whereas the obtained thermodynamic data indicate a combined reduction-sorption process. The latter aspect was further verified by XPS, showing that even in the highly-loaded sorbent materials with adsorbed chromium, its trivalent form is the predominant one. These specific characteristics suggest that the product is a more favorable candidate for wider applications in water treatment units, regarding Cr(VI) removal, compared to other examined sorbent materials. PMID- 28667847 TI - Unraveling of permafrost hydrological variabilities on Central Qinghai-Tibet Plateau using stable isotopic technique. AB - Permafrost degradation on the Qinghai-Tibet Plateau (QTP) will substantially alter the surface runoff discharge and generation, which changes the recharge processes and influences the hydrological cycle on the QTP. Hydrological connections between different water bodies and the influence of thawing permafrost (ground ice) are not well understood on the QTP. This study applied water stable isotopic method to investigate the permafrost hydrological variabilities in Beiluhe Basin (BLB) on Central QTP. Isotopic variations of precipitation, river flow, thermokarst lake, and near-surface ground ice were identified to figure out the moisture source of them, and to elaborate the hydrological connections in permafrost region. Results suggested that isotopic seasonalities in precipitation is evident, it is showing more positive values in summer seasons, and negative values in winter seasons. Stable isotopes of river flow are mainly distributed in the range of precipitation which is indicative of important replenishment from precipitation. delta18O, deltaD of thermokarst lakes are more positive than precipitation, indicating of basin-scale evaporation of lake water. Comparison of deltaI values in different water bodies shows that hydrology of thermokarst lakes was related to thawing of permafrost (ground ice) and precipitation. Near-surface ground ice in BLB exhibits different isotopic characteristics, and generates a special deltaD-delta18O relationship (freezing line): deltaD=5.81delta18O-23.02, which reflects typical freezing of liquid water. From isotopic analysis, it is inferred that near-surface ground ice was mainly recharged by precipitation and active layer water. Stable isotopic and conceptual model is suggestive of striking hydrological connections between precipitation, river flow, thermokarst lake, and ground ice under degrading permafrost. This research provides fundamental comprehensions into the hydrological processes in permafrost regions on QTP, which should be considered in investigating the influence of thawing permafrost on the hydrological cycle on QTP. PMID- 28667848 TI - Prediction of the bioavailability of potentially toxic elements in freshwaters. Comparison between speciation models and passive samplers. AB - The aim of this work is to predict the bioavailability of the Potentially Toxic Elements (PTEs) Cd, Pb, Hg, Ni, Cu, Zn, As, Cr and Se in 6 sites within the Ebro River basin. In situ Diffusive gradient in thin-films (DGTs) and classical sampling have been used and compared. The potentially bioavailable fractions of each PTE was estimated by modelling their chemical speciation using three programs (WHAM 7.0, Visual MINTEQ 3.1 and Bio-met), following the suggestions published in recent European regulations. Results of the equilibrium-based models WHAM 7.0 and Visual MINTEQ 3.1 indicate that As, Cd, Ni, Se and Zn, predominate as free metals ions or forming inorganic soluble complexes. Copper, Pb and Hg bioavailability is conditioned by their affinity to dissolved humic substances. According to Visual MINTEQ 3.1, Cr is subjected to redox reactions, being Cr (VI) present (at low concentrations) in the studied rivers. According to Bio-met model, the bioavailability of Cu and Zn is highly influenced by soluble organic matter and water hardness, respectively. For most PTEs, the bioavailability estimated by deploying DGTs in river waters tends to be slightly lower than the estimation obtained with speciation models, since in real conditions more environmental factors take place comparing to the finite number of parameters considered in models. PMID- 28667849 TI - Contributions of climate change and human activities to runoff change in seven typical catchments across China. AB - Climate change and human activities are two major factors affecting water resource change. It is important to understand the roles of the major factors in affecting runoff change in different basins for watershed management. Here, we investigated the trends in climate and runoff in seven typical catchments in seven basins across China from 1961 to 2014. Then we attributed the runoff change to climate change and human activities in each catchment and in three time periods (1980s, 1990s and 2000s), using the VIC model and long-term runoff observation data. During 1961-2014, temperature increased significantly, while the trends in precipitation were insignificant in most of the catchments and inconsistent among the catchments. The runoff in most of the catchments showed a decreasing trend except the Yingluoxia catchment in the northwestern China. The contributions of climate change and human activities to runoff change varied in different catchments and time periods. In the 1980s, climate change contributed more to runoff change than human activities, which was 84%, 59%, -66%, -50%, 59%, 94%, and -59% in the Nianzishan, Yingluoxia, Xiahui, Yangjiaping, Sanjiangkou, Xixian, and Changle catchment, respectively. After that, human activities had played a more essential role in runoff change. In the 1990s and 2000s, human activities contributed more to runoff change than in the 1980s. The contribution by human activities accounted for 84%, -68%, and 67% in the Yingluoxia, Xiahui, and Sanjiangkou catchment, respectively, in the 1990s; and -96%, -67%, -94%, and 142% in the Nianzishan, Yangjiaping, Xixian, and Changle catchment, respectively, in the 2000s. It is also noted that after 2000 human activities caused decrease in runoff in all catchments except the Yingluoxia. Our findings highlight that the effects of human activities, such as increase in water withdrawal, land use/cover change, operation of dams and reservoirs, should be well managed. PMID- 28667850 TI - Correlation of trace element concentrations between epidermis and internal organ tissues in Indo-Pacific humpback dolphins (Sousa chinensis). AB - Trace element accumulation in the epidermis of cetaceans has been less studied. This study explored the feasibility of using epidermis as a surrogate tissue to evaluate internal contaminant burdens in Indo-Pacific humpback dolphin (Sousa chinensis). Eleven trace elements were analyzed in the epidermis, muscle and liver tissues from 46 individuals of dolphins stranded along the Pearl River Estuary (PRE) coast between 2007 and 2013. Trace elemental concentrations varied among the three tissues, generally with the highest concentrations found in liver tissues and lowest in the epidermis (except Zn, As, and Pb). Zn concentration in the epidermis was the highest among all tissues, indicating that Zn could be an important element for the epidermis physiology. High concentrations of Hg and Cr in liver were likely due to an excessive intake by dolphins which consumed high Hg and Cr contaminated fishes in the PRE. Hg concentrations in epidermis and muscle tissues were significantly higher in the females than in males. Concentrations of V and Pb in liver, Se and Cd in both muscle and liver, and As and Hg in all tissue samples showed significantly positive relationships with body length. Hepatic Cu concentrations were significantly negatively correlated with the body length. Hg and As concentrations in epidermis showed significantly positive correlations with those in liver tissues. Thus this study proposed that epidermis could be used as a non-invasive monitoring tissue to evaluate Hg and As bioaccumulation in internal tissues of Indo-Pacific humpback dolphins populations. PMID- 28667851 TI - Natural disasters and climate change call for the urgent decentralization of urban water systems. AB - Lima is gradually upgrading its urban water cycle to comply with improved sanitation standards, with the aim of treating the entire flow of water and wastewater that it creates. However, this paper examines the basic characteristics of the main treatment systems that are currently in operation in the Peruvian capital, highlighting the myopic and inefficient nature of these investments. It digs deep in the debate between centralized and decentralized water management systems in a city that is exposed to numerous hydro meteorological and geological hazards. Previous errors that have occurred in the developed world throughout the evolution process of the urban water cycle should be taken into consideration prior to any infrastructure development in emerging countries. For the particular case of Lima, special emphasis should be given to the resilience of its urban water system in order to guarantee rapid recovery after disaster events. PMID- 28667852 TI - Associations of prenatal and early childhood mercury exposure with autistic behaviors at 5years of age: The Mothers and Children's Environmental Health (MOCEH) study. AB - BACKGROUND: Although mercury is an established neurotoxin, only few longitudinal studies have investigated the association between prenatal and early childhood mercury exposure and autistic behaviors. METHODS: We conducted a longitudinal cohort study using an ongoing prospective birth cohort initiated in 2006, wherein blood mercury levels were measured at early and late pregnancy; in cord blood; and at 2 and 3years of age. We analyzed 458 mother-child pairs. Autistic behaviors were assessed using the Social Responsiveness Scale (SRS) at 5years of age. Both continuous SRS T-scores and T-scores dichotomized by a score of >=60 or <60 were used as outcomes. RESULTS: The geometric mean of mercury concentrations in cord blood was 5.52MUg/L. In adjusted models, a doubling of blood mercury levels at late pregnancy (beta=1.84, 95% confidence interval [CI]: 0.39, 3.29), in cord blood (beta=2.24, 95% CI: 0.22, 4.27), and at 2years (beta=2.12, 95% CI: 0.54, 3.70) and 3years (beta=2.80, 95% CI: 0.89, 4.72) of age was positively associated with the SRS T-scores. When the SRS T-scores were dichotomized, we observed positive associations with mercury levels at late pregnancy (relative risk [RR]=1.31, 95% CI: 1.08, 1.60) and in cord blood (RR=1.28, 95% CI: 1.01, 1.63). CONCLUSION: We found that blood mercury levels at late pregnancy and early childhood were associated with more autistic behaviors in children at 5years of age. Further study on the long-term effects of mercury exposure is recommended. PMID- 28667853 TI - Greenhouse gas emission quantification from wastewater treatment plants, using a tracer gas dispersion method. AB - Plant-integrated methane (CH4) and nitrous oxide (N2O) emission quantifications were performed at five Scandinavian wastewater treatment plants, using a ground based remote sensing approach that combines a controlled release of tracer gas from the plant with downwind concentration measurements. CH4 emission factors were between 1 and 21% of CH4 production, and between 0.2 and 3.2% of COD influent. The main CH4 emitting sources at the five plants were sludge treatment and energy production units. The lowest CH4 emission factors were obtained at plants with enclosed sludge treatment and storage units. N2O emission factors ranged from <0.1 to 5.2% of TN influent, and from <0.1 to 5.9% of TN removed. In general, measurement-based, site-specific CH4 and N2O emission factors for the five studied plants were in the upper range of the literature values and default emission factors applied in international guidelines. This study showed that measured CH4 and N2O emission rates from wastewater treatment plants were plant specific and that emission rates estimated using models in current guidelines, mainly meant for reporting emissions on the country scale, were unsuitable for Scandinavian plant-specific emission reporting. PMID- 28667854 TI - Spatio-temporal shifts in the archaeal community of a constructed wetland treating river water. AB - The distribution of archaeal community and the associated environmental variables in constructed wetland (CW), especially in free water surface flow CW (FWSF-CW), remain poorly understood. The present study explored the spatial and temporal dynamics of archaeal community in an FWSF-CW used for surface water treatment and evaluated the driving environmental variables. The archaeal density varied considerably among sites and seasons, ranging from 3.37*108 to 3.59*109 16S rRNA gene copies per gram dry sediment/soil. The archaeal population density was adversely affected by high temperatures and tended to be lower during summer than during spring and winter. Moreover, considerable spatio-temporal variations of archaeal richness, diversity and community structure also occurred in the FWSF CW. Higher nutrient contents correlated with a lower archaeal richness and diversity. Nitrate and carbon/nitrogen ratio were found to play important roles in shaping the overall archaeal community structure. Euryarchaeota and Bathyarchaeota were the dominant archaeal phyla in wetland sediments, while Thaumarchaeota tended to be dominant in wetland soils. In addition, the wetland archaeal community was related to vegetation type. PMID- 28667855 TI - Validating novel air pollution sensors to improve exposure estimates for epidemiological analyses and citizen science. AB - Low cost, personal air pollution sensors may reduce exposure measurement errors in epidemiological investigations and contribute to citizen science initiatives. Here we assess the validity of a low cost personal air pollution sensor. Study participants were drawn from two ongoing epidemiological projects in Barcelona, Spain. Participants repeatedly wore the pollution sensor - which measured carbon monoxide (CO), nitric oxide (NO), and nitrogen dioxide (NO2). We also compared personal sensor measurements to those from more expensive instruments. Our personal sensors had moderate to high correlations with government monitors with averaging times of 1-h and 30-min epochs (r ~ 0.38-0.8) for NO and CO, but had low to moderate correlations with NO2 (~0.04-0.67). Correlations between the personal sensors and more expensive research instruments were higher than with the government monitors. The sensors were able to detect high and low air pollution levels in agreement with expectations (e.g., high levels on or near busy roadways and lower levels in background residential areas and parks). Our findings suggest that the low cost, personal sensors have potential to reduce exposure measurement error in epidemiological studies and provide valid data for citizen science studies. PMID- 28667856 TI - Interaction between Y chromosome haplogroup O3* and 4-n-octylphenol exposure reduces the susceptibility to spermatogenic impairment in Han Chinese. AB - Certain genetic background (mainly Y chromosome haplogroups, Y-hg) may modify the susceptibility of certain environmental exposure to some diseases. Compared with respective main effects of genetic background or environmental exposure, interactions between them reflect more realistic combined effects on the susceptibility to a disease. To identify the interactions on spermatogenic impairment, we performed Y chromosome haplotyping and measurement of 9 urinary phenols concentrations in 774 infertile males and 520 healthy controls in a Han Chinese population, and likelihood ratio tests were used to examine the interactions between Y-hgs and phenols. Originally, we observed that Y-hg C and Y hg F* might modify the susceptibility to male infertility with urinary 4-n octylphenol (4-n-OP) level (Pinter = 0.005 and 0.019, respectively). Subsequently, based on our results, two panels were tested to identify the possible protective sub-branches of Y-hg F* to 4-n-OP exposure, and Y-hg O3* was uncovered to interact with 4-n-OP (Pinter = 0.019). In conclusion, while 4-n-OP shows an adverse effect on spermatogenesis, Y-hg O3* makes individuals more adaptive to such an effect for maintaining basic reproductive capacity. PMID- 28667857 TI - The potential acute and chronic toxicity of cyfluthrin on the soil model organism, Eisenia fetida. AB - In this study, the acute (72h and 14 d) and chronic (28 d and 8 weeks) effects of cyfluthrin on earthworms were evaluated across different endpoints, which are mortality, growth, reproduction and enzyme activities. Cyfluthrin was rated as moderately toxic in 72-h filter paper test and low toxic in 14-day soil test. The exposure of earthworms to cyfluthrin-polluted soil for 8 weeks showed that growth of earthworms was inhibited by cyfluthrin, cocoon production and hatching were inhibited by 20-60mg/kg cyfluthrin. Moreover, 28-day soil test on the responses of enzymes associated with antioxidation and detoxification showed that the activities of catalase (CAT) and glutathione S- transferase (GST) were initially increased by cyfluthrin at 5-20mg/kg, but reduced at 30-60mg/kg, peroxidase (POD) was increased by 26-102% by cyfluthrin in the early period, except 5mg/kg on day 7, and ethoxyresorufin-O-deethylase (EROD) was increased by 29-335% by cyfluthrin after 3 days. Cyfluthrin degraded with a half-life of 24.8-34.8 d, showing the inconsistency between the continuous toxic responses of earthworms and degradation of cyfluthrin in soil. The variable responses of these indexes indicated that different level endpoints should be jointly considered for better evaluation of the environmental risk of contaminants in soil. PMID- 28667858 TI - Pollution and ecological risk assessment of heavy metals in the soil-plant system and the sediment-water column around a former Pb/Zn-mining area in NE Morocco. AB - This study discussed the environmental fate and ecological hazards of heavy metals in the soil-plant system and sediment-water column around the former Pb-Zn mining Zeida district, in Northeastern Morocco. Spatial distribution, pollution indices, and cluster analysis were applied for assessing Pb, Zn, As, Cu and Cd pollution levels and risks. The geo-accumulation index (Igeo) was determined using two different geochemical backgrounds: i) the commonly used upper crust values, ii) local geochemical background calculated with exploratory data analysis. The soils in the vicinity of the tailings, as well as the sediments downstream of the latter, displayed much higher metal concentrations, Igeo, and potential ecology risk coefficient values than other sites, classifying these sites as highly contaminated and severely hazardous. The concentrations of Pb in contaminated sediment samples also exceeded the PEC limits and are expected to cause harmful effects on sediment-dwelling organisms. Based on the comparison with the toxicity limits, the most contaminated plant samples were found around the tailings piles. The metal concentrations in both raw and filtrated water samples were overall below the drinking water standards in samples upstream and downstream of the mining center, indicating that heavy metals levels in the Moulouya River surface waters were not affected by the tailings spill. Cluster analysis suggest that: i) Pb and Zn in sediments were derived from the abandoned tailings and are mainly stored and transported as particle-bound to the bedload, ii) Pb, Zn, and Cu in the soil-plant system were related to the dispersion of tailings materials while As and Cd originated primarily from natural geological background in both the soil-plant and the water-sediment systems. PMID- 28667859 TI - Global concentration additivity and prediction of mixture toxicities, taking nitrobenzene derivatives as an example. AB - The toxicity of a mixture depends not only on the mixture concentration level but also on the mixture ratio. For a multiple-component mixture (MCM) system with a definite chemical composition, the mixture toxicity can be predicted only if the global concentration additivity (GCA) is validated. The so-called GCA means that the toxicity of any mixture in the MCM system is the concentration additive, regardless of what its mixture ratio and concentration level. However, many mixture toxicity reports have usually employed one mixture ratio (such as the EC50 ratio), the equivalent effect concentration ratio (EECR) design, to specify several mixtures. EECR mixtures cannot simulate the concentration diversity and mixture ratio diversity of mixtures in the real environment, and it is impossible to validate the GCA. Therefore, in this paper, the uniform design ray (UD-Ray) was used to select nine mixture ratios (rays) in the mixture system of five nitrobenzene derivatives (NBDs). The representative UD-Ray mixtures can effectively and rationally describe the diversity in the NBD mixture system. The toxicities of the mixtures to Vibrio qinghaiensis sp.-Q67 were determined by the microplate toxicity analysis (MTA). For each UD-Ray mixture, the concentration addition (CA) model was used to validate whether the mixture toxicity is additive. All of the UD-Ray mixtures of five NBDs are global concentration additive. Afterwards, the CA is employed to predict the toxicities of the external mixtures from three EECR mixture rays with the NOEC, EC30, and EC70 ratios. The predictive toxicities are in good agreement with the experimental toxicities, which testifies to the predictability of the mixture toxicity of the NBDs. PMID- 28667860 TI - Poplar response to cadmium and lead soil contamination. AB - An outdoor pot experiment was designed to study the potential of poplar (Populus nigra 'Italica') in phytoremediation of cadmium (Cd) and lead (Pb). Poplar was treated with a combination of different concentrations of Cd (w = 10, 25, 50mgkg 1 soil) and Pb (400, 800, 1200mgkg-1 soil) and several physiological and biochemical parameters were monitored including the accumulation and distribution of metals in different plant parts (leaf, stem, root). Simultaneously, the changes in the antioxidant system in roots and leaves were monitored to be able to follow synergistic effects of both heavy metals. Moreover, a statistical analysis based on the Random Forests Analysis (RFA) was performed in order to determine the most important predictors affecting growth and antioxidative machinery activities of poplar under heavy metal stress. The study demonstrated that tested poplar could be a good candidate for phytoextraction processes of Cd in moderately contaminated soils, while in heavily contaminated soil it could be only considered as a phytostabilisator. For Pb remediation only phytostabilisation process could be considered. By using RFA we pointed out that it is important to conduct the experiments in an outdoor space and include environmental conditions in order to study more realistic changes of growth parameters and accumulation and distribution of heavy metals. Also, to be able to better understand the interactions among previously mentioned parameters, it is important to conduct the experiments during prolonged time exposure., This is especially important for the long life cycle woody species. PMID- 28667861 TI - Cyanidin-3-rutinoside increases glucose uptake by activating the PI3K/Akt pathway in 3T3-L1 adipocytes. AB - In this study, the effect of cyanidin-3-rutinoside (C3R) on glucose uptake by 3T3 L1 adipocytes was studied. C3R significantly increased glucose uptake, which was associated with enhanced plasma membrane glucose transporter type 4 (PM-GLUT4) expression in 3T3-L1 adipocytes. The potentiating effect of C3R on glucose uptake and PM-GLUT4 expression was related to enhanced phosphorylation of insulin receptor substrate 1 (IRS-1) and Akt, as well as augmented activation of phosphatidylinositol-3-kinase (PI3K) in the insulin signaling pathway. C3R induced glucose uptake was inhibited only by the PI3K inhibitor, but not by an AMPK inhibitor in 3T3-L1 adipocytes. Therefore, C3R likely up-regulates glucose uptake and PM-GLUT4 expression in 3T3-L1 adipocytes by activating the PI3K/Akt pathways. PMID- 28667862 TI - Icariin exerts inhibitory effects on the growth and metastasis of KYSE70 human esophageal carcinoma cells via PI3K/AKT and STAT3 pathways. AB - Esophageal cancer is one of the leading causes of cancer related mortality across the globe. The current treatment options are insufficient and are associated with number of side effects. Therefore there is a pressing need to develop effective and more efficient strategies for the treatment of esophageal cancer. Consistently, natural products are considered potential candidates for develop of cancer chemotherapy. Icariin is a naturally occurring flavonol glucoside and has been reported to possess tremendous pharmacological potential ranging from neuroprotection to anticancer activity. However, the pharmacological role of icariin in esophageal cancer is still largely unclear. Here in the present study, icariin was evaluated for its anticancer activity against KYSE70 esophageal cancer cells and the possible underlying mechanism was determined. Icariin induced cytotoxicity with an IC50 of 40MUM in esophageal cancer cells. These inhibitory effects were due to apoptosis through reactive oxygen species (ROS) mediated alterations in mitochondrial membrane potential (MMP). The results indicated that icariin enhanced the accretion of ROS upto 260% and reduced the MMP upto 48% at 100MUM. Icariin also induced G2/M cell cycle arrest as evident from the significant increase in the G2 cell populations of KYSE70 esophageal cancer cells. Additionally, icariin inhibited esophageal cancer cell migration, invasion and metastasis by regulating the expression of epithelial to mesenchymal transition (EMT) markers. Results also indicated that icariin reduced cell viability and migration in part through suppression of the PI3K/AKT and STAT3 pathways. Taken together, our results indicate that icariin may prove a potential natural anticancer molecule against esophageal cancer. PMID- 28667863 TI - A phylogenetic approach for haplotype analysis of sequence data from complex mitochondrial mixtures. AB - Massively parallel (next-generation) sequencing provides a powerful method to analyze DNA from many different sources, including degraded and trace samples. A common challenge, however, is that many forensic samples are often known or suspected mixtures of DNA from multiple individuals. Haploid lineage markers, such as mitochondrial (mt) DNA, are useful for analysis of mixtures because, unlike nuclear genetic markers, each individual contributes a single sequence to the mixture. Deconvolution of these mixtures into the constituent mitochondrial haplotypes is challenging as typical sequence read lengths are too short to reconstruct the distinct haplotypes completely. We present a powerful computational approach for determining the constituent haplotypes in massively parallel sequencing data from potentially mixed samples. At the heart of our approach is an expectation maximization based algorithm that co-estimates the overall mixture proportions and the source haplogroup for each read individually. This approach, implemented in the software package mixemt, correctly identifies haplogroups from mixed samples across a range of mixture proportions. Furthermore, our method can separate fragments in a mixed sample by the most likely originating contributor and generate reconstructions of the constituent haplotypes based on known patterns of mtDNA diversity. PMID- 28667864 TI - An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy. AB - Diets that increase production of ketone bodies to provide alternative fuel for the brain are evolving from the classic ketogenic diet for epilepsy devised nearly a century ago. The classic ketogenic diet and its more recent variants all appear to have similar efficacy with approximately 50% of users showing a greater than 50% seizure reduction. They all require significant medical and dietetic support, and there are tolerability issues. A review suggests that low-grade chronic metabolic acidosis associated with ketosis is likely to be an important contributor to the short term and long term adverse effects of ketogenic diets. Recent studies, particularly with the characterization of the acid sensing ion channels, suggest that chronic metabolic acidosis may increase the propensity for seizures. It is also known that low-grade chronic metabolic acidosis has a broad range of negative health effects and an increased risk of early mortality in the general population. The modified ketogenic dietary treatment we propose is formulated to limit acidosis by measures that include monitoring protein intake and maximizing consumption of alkaline mineral-rich, low carbohydrate green vegetables. We hypothesize that this acidosis-sparing ketogenic diet is expected to be associated with less adverse effects and improved efficacy. A case history of life-long intractable epilepsy shows this diet to be a successful long-term strategy but, clearly, clinical studies are needed. PMID- 28667865 TI - Engineering cell identity: establishing new gene regulatory and chromatin landscapes. AB - Cellular reprogramming can be achieved by ectopically expressing transcription factors that directly convert one differentiated cell type into another, bypassing embryonic states. A number of different cell types have been generated by such 'direct lineage reprogramming' methods, but their practical utility has been limited because, in most protocols, the resulting populations are often partially differentiated or incompletely specified. Here, we review mechanisms of lineage reprogramming by pioneer transcription factors, a unique class of transcriptional regulators that has the capacity to engage with silent chromatin to activate target gene regulatory networks. We assess the possible barriers to successful reprogramming in the context of higher-order chromatin landscape, considering how the mechanistic relationship between nuclear organization and cell identity will be crucial to unlocking the full potential of cell fate engineering. PMID- 28667866 TI - A case that illustrates the challenges of managing pregnant patients with antithrombin deficiency: More questions than answers. AB - Using an illustrative case of a patient with antithrombin (AT) deficiency who developed a recurrent venous thromboembolism (VTE) in pregnancy despite therapeutic low-molecular-weight heparin (LMWH), we highlight what is known in the literature and address areas of controversy through a series of questions around the case. The questions we address include the role of anti-Xa monitoring for patients with past VTE on antepartum LMWH, what treatment regimen is recommended for pregnant patients who develop a recurrent VTE while on therapeutic anticoagulation, the role of antepartum AT concentrate prophylaxis, and the management of labor/delivery, epidural anesthesia and postpartum anticoagulation. We also describe practical considerations for use of AT concentrate, including teaching our patient to self-infuse AT concentrate at home with support of a hemophilia treatment center (HTC), and the direct and indirect costs of AT concentrate for secondary prophylaxis. PMID- 28667867 TI - Autophagy-related protein expression was associated with BRAF V600E mutation in epilepsy associated glioneuronal tumors. AB - PURPOSE: The aim of this study was to explore the expression level of autophagy related proteins in epileptic patients with glioneuronal tumors (GNTs) and evaluate the association with clinicopathological features. MATERIALS AND METHODS: We obtained the brain specimens from 33 patients with GNTs, including 22 gangliogliomas (GGs) and 11 dysembryoplastic neuroepithelial tumors (DNTs). The expression of two autophagy-related proteins (LC3B and Beclin-1) was evaluated by immunohistochemistry, and BRAF V600E mutation was examined by DNA sequencing. RESULTS: Among 33 epileptic patients with GNTs, the frequency of high expression of LC3B was 36.4% (12/33), and that of Beclin-1 was 39.4% (13/33). High expression of LC3B and Beclin-1 proteins was significantly associated with BRAF V600E mutation in GNTs (P=0.008; P=0.018), and LC3B overexpression was also correlated with temporal location of GNTs (P=0.002). In GGs alone, high expression of LC3B revealed significant correlation with BRAF V600E mutation and temporal location (P=0.020; P=0.015), while Beclin-1 showed no correlation with them (P>0.05). Furthermore, autophagy-related proteins did not show any association with other studied clinicopathological features, such as gender, age at seizure onset, epilepsy duration and postoperative seizure outcome. CONCLUSIONS: Our observations demonstrated that impaired autophagy may be associated with BRAF V600E mutation. However, large sample studies with long-term follow-up were required. PMID- 28667868 TI - Social support and breast cancer: A comparatory study of breast cancer survivors, women with mental depression, women with hypertension and healthy female controls. AB - OBJECTIVES: Among breast cancer (BC) survivors, inadequate social support (SS) is associated with a significant increase in cancer-related mortality and reduction in quality of life (QoL). The aim of the study was to explore perceived SS during BC trajectory by comparing BC survivors, women with depression, women with arterial hypertension, and healthy female controls to each other, and to compare perceived balance of receiving and providing SS. MATERIAL AND METHODS: The data of ongoing prospective postal survey was linked with national health registries. Respondents with BC (n = 64), depression (n = 471), arterial hypertension (n = 841) and healthy controls (n = 6274) formed the study population. SS was measured by a Sarason's 6-item shortened version of the Social Support Questionnaire (SSQ). The modified Antonucci's (1986) social support convoy model of the network of individuals was used to measure the dominating direction of SS. RESULTS: The main provider of SS for all participants combined was the spouse or partner (94.3%), close relative (12.0%) and friends (5.4%). In all groups, particularly in the BC and arterial hypertension group, spouse or partner was seen as the most important supporter. The group suffering from depression reported significantly less SS in each domain of appraisal (p < 0.001). In total, 24.6% of all respondents reported receipt dominance of SS. CONCLUSION: SS is a well-known determinant of wellbeing. Our study lends support to the spouse's or the partner's central role during the recovery phase of BC. Identification of factors improving the overall QoL of BC survivors is an important public health challenge. PMID- 28667869 TI - Dynamic modeling of trolling-mode AFM: Considering effects of cantilever torsion, nanoneedle flexibility and liquid-nanoneedle interactions. AB - Trolling mode atomic force microscope (TR-Mode AFM) significantly reduces the hydrodynamic drag generated during operation in liquid environments. This is achieved by utilizing a long nanoneedle and keeping the cantilever out of liquid. In this research, a continuous mathematical model is developed to study TR-Mode AFM dynamics near a sample submerged in the liquid. Effects of cantilever torsion, nanoneedle flexibility, and liquid-nanoneedle interactions are considered in the model. In order to derive the equations of motion, Hamilton's principle and assumed mode method are used. System operation in dynamic mode is numerically simulated and the accuracy of the results is verified by comparison with the results of the finite element method. Displacements of different components of the system are also compared with each other and the dominant displacements are determined. PMID- 28667870 TI - Anti-radical flavonol glycosides from the aerial parts of Cleome chelidonii L.f. AB - Eleven previously undescribed flavonoid glycosides, named cleomesides C-M, along with five known compounds, were isolated from the aerial parts of Cleome chelidonii L.f. (Cleomaceae). All flavonol glycosides were esterified derivatives of 3,7-O-diglycosides of quercetin or kaempferol. Their structures were elucidated by analysis of the 1D and 2D NMR spectra, HR-ESI-MS data, UV spectra, optical rotation and by comparison with literature data. The DPPH radical scavenging properties of the flavonoid glycosides were studied in order to appreciate the effect of the glycoside parts and of the ester groups on this activity compared with the quercetin and kaempferol aglycones. An acetate at position 3 of rhamnose linked to C-7 of flavonol, gave compounds with the strongest antiradical activity. An aromatic ester group at position 6 of terminal glucose of diglycoside chain linked to C-3 of flavonol did not seem to influence the antiradical activity. PMID- 28667871 TI - Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety. AB - A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC50 = 56 nM) and 9n against MOLT-4 (IC50 = 80 nM), more potent than monastrol (IC50 = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining. PMID- 28667872 TI - Polysubstituted 2-aminoimidazoles as anti-biofilm and antiproliferative agents: Discovery of potent lead. AB - Most of the human bacterial infections are associated with the biofilm formation and the natural tolerance of biofilms to antibiotics challenges treatment. Because of their low immunity, cancer patients are especially susceptible to bacterial infections. Compounds with anti-biofilm activity could therefore become a useful adjunct to chemotherapy, in particular if they also show antiproliferative activities. Taking this into consideration and as a result of our continuous interest in 2-aminoimidazole derivatives, we have designed and synthesized a series of novel polysubstituted 2-aminoimidazoles (20a-x). The compounds were evaluated against a panel of three bacterial strains for their biofilm and planktonic growth inhibitory activity and most of them show promising results. Furthermore, the synthesized compounds were evaluated against various cancer cell lines and almost all the compounds were found to possess potent antiproliferative activity. The substitution pattern at the C-4 position and the aryl carboxamide ring at the N-1 position have major effects on the biofilm inhibitory and antiproliferative activity. Especially, the introduction of a p methyl group at the carboxamide ring remarkably enhances both the anti-biofilm and antiproliferative activity. The two most potent compounds (20i &20r) were further studied for their antiproliferative activity and a flow cytometer-based cell cycle experiment was performed, which revealed their capability to induce G2/M phase cell cycle arrest. Based on these results, these two new compounds having potential to target both cancer proliferation and microbial biofilms might be used in single drug monotherapy. PMID- 28667873 TI - New arylpyrazoline-coumarins: Synthesis and anti-inflammatory activity. AB - To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives (4a~4m) were designed and synthesized. Compounds 4a and 4b were determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-alpha and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-alpha, NO through NF kappaB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints. PMID- 28667874 TI - Recent developments in biological activities of indanones. AB - Indanone is one of the privileged structures in medicinal chemistry and it's commonly associated with various pharmacologically active compounds. The indanone moiety is found in several natural compounds and also, it can be used as intermediate in the synthesis of many different types of medicinally important molecules. Among the medicinally important indanones, the most significant drug probably is donepezil (IV), an acetylcholinesterase (AChE) inhibitor, which has been approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Along with donepezil, the indanone moiety can be seen in a number of other pre-clinical and clinical candidates which belong to different categories with diverse therapeutic activities. In summary, the present review article encompasses the recent biological applications such as antialzheimer, anticancer, antimicrobial and antiviral activity of various indanone derivatives. PMID- 28667875 TI - Discovery of potent IDO1 inhibitors derived from tryptophan using scaffold hopping and structure-based design approaches. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells. Treatment with these three compounds promoted the proliferation of T lymphocyte and led to the dramatic decrease of regulatory T cells in the B16F1 cells and naive T cells co-culture system. Subsequent spectroscopic experiments suggested that these benzoxazolinones formed a coordinate bond with the heme iron to stabilize the complex. This study suggested that the benzoxazolinone was an interesting scaffold for discovering novel IDO1 inhibitors, and these compounds are attractive candidates for further development. PMID- 28667876 TI - A novel structural class of coumarin-chalcone fibrates as PPARalpha/gamma agonists with potent antioxidant activities: Design, synthesis, biological evaluation and molecular docking studies. AB - A series of structurally interesting coumarin-chalcone fibrates were synthesized and evaluated for their PPARalpha/gamma agonist activities and antioxidant activities. Among these compounds, compounds 5a, 5d, and 7a were identified as potent PPARalpha and gamma dual agonists, and their PPARalpha agonist activities were found to be more potent than that of Fenofibrate. Furthermore, the results of antioxidant investigations revealed that compounds 5d and 6a-6d had greater potency than Trolox with IC50 values ranging from 9.40 MUM to 18.63 MUM. The structure-activity relationship revealed that the electron-withdrawing nitro group substituted at the C6' position of the benzopyran moiety increased the PPARalpha and gamma agonist efficacy. Moreover, the presence of a double bond on the benzopyran moiety was essential for PPARalpha and gamma agonist efficacy. The agonist activity of PPARalpha exhibited by compound 5d was examined by molecular docking studies. Taken together, the results we obtained showed that compound 5d had the potential to be a lead compound for further research. PMID- 28667877 TI - Effect of humic acid on uranium(VI) retention and transport through quartz columns with varying pH and anion type. AB - Humic acid (HA)1 is ubiquitous in the environment and is an important factor in the migration behavior of U(VI) in the geological medium. The present work investigated the effect of HA on the migration behavior of U(VI) using quartz column experiments at different pH values and in the presence of various anions. The U(VI) adsorption characteristics and speciation were also studied to illuminate further the migration behavior of U(VI). Our results indicated that, at pH 6.0, HA slightly increased the migration velocity of U(VI) during the initial phase and reduced the quantity of eluted U(VI) because of the formation of HA-U(VI). The relative concentration (c/c0) of U(VI)was higher in the HA-U system at pH 8.0 than that at pH 5.0 because of the higher solubility of HA in basic solutions and the difference in charge of HA-U(VI). In the U-HA-anion system at pH 6.0, the breakthrough pore volumes (PVs2) of U(VI) in electrolytes containing Cl- and SO42- anions (PV = 8) are much higher than for solutions containing phosphate (PV = 3), while the HA migration behavior was not significantly affected by the type of anion. Thus, the fast migration of U(VI) under HA and phosphate was attributed to phosphate rather than HA. This result suggests that phosphate should be given more attention in predictions of U(VI) migration, especially in regions with high groundwater phosphate content. PMID- 28667878 TI - Are dispensaries indispensable? Patient experiences of access to cannabis from medical cannabis dispensaries in Canada. AB - BACKGROUND: In 2001, Canada established a federal program for cannabis for therapeutic purposes (CTP). Medical cannabis dispensaries (dispensaries) are widely accessed as a source of CTP despite storefront sales of cannabis being illegal. The discrepancy between legal status and social practice has fuelled active debate regarding the role of dispensaries. The present study aims to inform this debate by analysing CTP user experiences with different CTP sources, and comparing dispensary users to those accessing CTP from other sources. METHODS: We compared sociodemographic characteristics, health related factors and patterns of cannabis use of 445 respondents, 215 who accessed CTP from dispensaries with 230 who accessed other sources. We compared patients' ratings of CTP sources (dispensaries, Health Canada's supplier, self-production, other producer, friend or acquaintance, street dealer) for quality and availability of product, safety and efficiency of access, cost, and feeling respected while accessing. RESULTS: Patients using dispensaries were older, more likely to have arthritis and HIV/AIDS, and less likely to have mental health conditions than those not using dispensaries. Those accessing dispensaries used larger quantities of cannabis, placed greater value on access to specific strains, and were more likely to have legal authorization for CTP. Dispensaries were rated equally to or more favourably than other sources of CTP for quality, safety, availability, efficiency and feeling respected, and less favourably than self-production and other producer for cost. CONCLUSION: Given the high endorsement of dispensaries by patients, future regulations should consider including dispensaries as a source of CTP and address known barriers to access such as cost and health care provider support. Further research should assess the impact of the addition of licensed producers on the role and perceived value of dispensaries within the Canadian medical cannabis system. PMID- 28667879 TI - Process evaluation of the implementation of scorecard-based antenatal risk assessment, care pathways and interdisciplinary consultation: the Healthy Pregnancy 4 All study. AB - OBJECTIVE: To evaluate the implementation of a complex intervention in the antenatal healthcare field in 14 Dutch municipalities. The intervention consisted of the implementation of a systematic scorecard-based risk assessment in pregnancy, subsequent patient-tailored care pathways, and consultations of professionals from different medical and social disciplines. METHODS: Saunders's seven-step method was used for the development of a programme implementation monitoring plan, with specific attention to the setting and context of the programme. Data were triangulated from multiple sources, and prespecified criteria were applied to examine the evidence for implementation. RESULTS: Six out of 11 municipalities (54%) met the implementation criteria for the entire risk assessment programme, whereas three municipalities (27%) met the criteria if the three components of implementation were analysed separately. CONCLUSIONS: A process evaluation of implementation of a complex intervention is possible. The results can be used to improve understanding of the associations between specific programme elements and programme outcomes on effectiveness of the intervention. Additionally, the results are important for formative purposes to assess how future implementation of antenatal risk assessment can be improved in comparable contexts. PMID- 28667880 TI - How does the use of multiple needles/syringes per injecting episode impact on the measurement of individual level needle and syringe program coverage? AB - BACKGROUND: Recent work by McCormack et al. (2016) showed that the inclusion of syringe stockpiling improves the measurement of individual-level syringe coverage. We explored whether including the use of a new parameter, multiple sterile syringes per injecting episode, further improves coverage measures. METHODS: Data comes from 838 people who inject drugs, interviewed as part of the 2015 Illicit Drug Reporting System. Along with syringe coverage questions, the survey recorded the number of sterile syringes used on average per injecting episode. We constructed three measures of coverage: one adapted from Bluthenthal et al. (2007), the McCormack et al. measure, and a new coverage measure that included use of multiple syringes. Predictors of multiple syringe use and insufficient coverage (<100% of injecting episodes using a sterile syringe) using the new measure, were tested in logistic regression and the ability of the measures to discriminate key risk behaviours was compared using ROC curve analysis. RESULTS: 134 (16%) participants reported needing multiple syringes per injecting episode. Women showed significantly increased odds of multiple syringe use, as did those reporting injection related injuries/diseases and injecting of opioid substitution drugs or pharmaceutical opioids. Levels of insufficient coverage across the three measures were substantial (20%-28%). ROC curve analysis suggested that our new measure was no better at discriminating injecting risk behaviours than the existing measures. CONCLUSION: Based on our findings, there appears to be little need for adding a multiple syringe use parameter to existing coverage formulae. Hence, we recommend that multiple syringe use is not included in the measurement of individual-level syringe coverage. PMID- 28667881 TI - Grey matter density changes of structures involved in Posttraumatic Stress Disorder (PTSD) after recovery following Eye Movement Desensitization and Reprocessing (EMDR) therapy. AB - Recovery of stress-induced structural alterations in Posttraumatic Stress Disorder (PTSD) remains largely unexplored. This study aimed to determine whether symptoms improvement is associated with grey matter (GM) density changes of brain structures involved in PTSD. Two groups of PTSD patients were involved in this study. The first group was treated with Eye Movement Desensitization and Reprocessing (EMDR) therapy and recovered from their symptoms (recovery group) (n = 11); Patients were scanned prior to therapy (T1), one week (T2) and five months after the end of therapy (T3). The second group included patients which followed a supportive therapy and remained symptomatic (wait-list group) (n = 7). They were scanned at three time-steps mimicking the same inter-scan intervals. Voxel based morphometry (VBM) was used to characterize GM density evolution. GM density values showed a significant group-by-time interaction effect between T1 and T3 in prefrontal cortex areas. These interaction effects were driven by a GM density increase in the recovery group with respect to the wait-list group. Symptoms removal goes hand-in-hand with GM density enhancement of structures involved in emotional regulation. PMID- 28667882 TI - Reactive oxygen species accumulation and homeostasis are involved in plant immunity to an opportunistic fungal pathogen. AB - Alternaria blight is a major and destructive disease of potato worldwide. In recent years, A. tenuissima is recognized as the most prevalent species of this phytopathogenic fungus in potato fields of Asian countries, which causes high yield losses every year. Any potato cultivar with complete resistance to this disease is not recognized, so far. Therefore, screening resistance levels of potatoes and identification of plant defense mechanisms against this fungus might be important for designing novel and effective disease management strategies for controlling the disease. In this research, the role of reactive oxygen species, antioxidants, lignin and phenolics in potato basal resistance to A. tenuissima was compared in the partially resistant Ramus and susceptible Bamba cultivars. Priming O2- and H2O2 production and enhanced activity of peroxidase (POX) and catalase (CAT) during interaction with A. tenuissima were observed in Ramus cultivar. Application of ROS generating systems and scavengers revealed critical role of O2- and H2O2 in potato defense, which was associated with lignification and phenolics production. More OH- and lipid peroxidation in the susceptible Bamba compared to Ramus cultivar showed their negative effects on resistance. Priming the POX and CAT activity, in correlation with upregulation of the corresponding genes was observed in Ramus. The POX and CAT inhibitors increased disease progress, which was related with decreased lignification. This assay demonstrated not only POX-dependency of lignification, but also its dependence on CAT. However, POX had more importance than CAT in potato defense and in lignification. These findings highlight the function of ROS accumulation and homeostasis in potato resistance against A. tenuissima. PMID- 28667883 TI - Study of phytohormone profile and oxidative metabolism as key process to identification of salinity response in tomato commercial genotypes. AB - Climatic change, intensive agriculture, and worsening water quality induce abiotic stress conditions for plants. Among these factors, salinity stress is a limit factor for plant growth. Therefore, the purpose of this study was to analyze the phytohormones role and oxidative metabolism in response to salt stress of two genotypes of tomato cv. Grand Brix and cv. Marmande RAF, the crops were carried out in a growth chamber. Salinity stress reduces biomass and relative growth rate (RGR) in both genotypes, this effect being greater in cv. Marmande RAF. These results, together with main stress indicator response, the O2.-, indicate that cv. Marmande RAF is more sensitive to Saline stress. Grand Brix showed less oxidative stress, because it presented greater detoxification of the O2-, due to SOD enzyme activity induction and greater antioxidant capacity. Furthermore, Grand Brix has a better hormonal profile adapted to salt stress resistance, the accumulation of IAA, GA4 and CKs and their beneficial role against oxidative stress could make the difference between resistance and sensitivity to salt stress. On the other hand, a lower ACC concentration, ethylene precursor, combined with a greater O2.- detoxification in the cv. Grand Brix could play a fundamental role in tolerance to saline stress. Besides, an increase in ABA levels promotes better stomatal closure, better photosynthesis control and a lower rate of water loss. This data could be essential to select plants with greater resistance to saline stress. PMID- 28667885 TI - Activation of murine macrophages by G1-4A, a polysaccharide from Tinospora cordifolia, in TLR4/MyD88 dependent manner. AB - Macrophages are centrally placed in the innate immune system and their activation is crucial to the generation of appropriate immune response in the event of any pathogenic invasion, tumorigenesis or other human diseases. Many plant derived polysaccharides are known to activate macrophages. In the present study, effects of G1-4A, a polysaccharide derived from Tinospora cordifolia, on the activation of macrophages were investigated. Our data demonstrated the up regulation of expression of TNF-alpha, IL-beta, IL-6, IL-12, IL-10 and IFN-gamma in RAW 264.7 cell line and peritoneal macrophages after G-14A treatment. Nitric oxide levels were also enhanced along with up-regulation of NOS2 expression in murine macrophages post G1-4A treatment. Further, G1-4A treatment up-regulated the surface expression of MHC-II and CD-86 in macrophages. Using siRNA against TLR4, MyD88 and anti-TLR4 blocking antibodies, we established that G1-4A activated macrophages by classical pathway in TLR4-MyD88 dependent manner. Additionally, G1 4A treatment activated p38, ERK and JNK MAPKs in macrophages. Using pharmaceutical inhibitors of above MAPKs we concluded that G1-4A activates the macrophages by activation of p38, ERK and JNK MAPKs in RAW264.7 macrophages. Thus our data suggests the activation of macrophages by classical pathway after treatment of G1-4A. PMID- 28667884 TI - Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy. AB - OBJECTIVE: The development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with ABL1 kinase domain (KD) mutations, but only around half of TKI non-responders have detectable ABL1 KD mutations. METHOD: We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without ABL1 KD mutations using whole-exome sequencing. RESULTS: In 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, and TP63. We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as DNMT3A and ASXL1 seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of ABL1 KD mutations. CONCLUSION: This study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking ABL1 KD mutations. PMID- 28667886 TI - Direct effects of interleukin-8 on growth and functional activity of T lymphocytes. AB - CD3+ T-lymphocytes were isolated from the normal donors by positive magnetic separation. Activation of the T cells with particles conjugated with antibodies to CD3, SD28 and SD2 molecules led to a marked increase in T-cell production of interleukine-8 (IL-8). We present evidence that IL-8 receptor alpha-chain (CXCR1, CD181) is expressed on the cell surface of 13.3% T cells. Activation of T lymphocytes resulted in significant enhancement of CD181+ cells both in naive CD4+ T cell and terminally differentiated effector CD4+ T cell compartments with concomitant reduction of CD181+ cells in effector memory CD4+ T cell subset. The level of T cell activation was assessed judging from the surface expression of CD25 (IL-2 receptor alpha-chain). We demonstrate that IL-8 treatment (0.01 10.0ng/ml concentration range) reduced the activation status of both CD4- and CD4+ effector memory T cells, as well as terminally differentiated effector T cells, without significantly affecting the activation of naive T cells or central memory T cells. In addition, IL-8 up-regulated IL-2 and down-regulated IL-10 production by activated T cells, with no effect on interferon-gamma (IFN-gamma) and IL-4 production. Data obtained suggests the importance of IL-8 in the direct regulation of adaptive T cell reactivity. PMID- 28667887 TI - Feasibility, safety, and preliminary efficacy of Low Amplitude Seizure Therapy (LAP-ST): A proof of concept clinical trial in man. AB - BACKGROUND: Current pulse amplitude used in clinical ECT may be higher than needed. Reducing pulse amplitude may improve focality of the electric field and thus cognitive adverse effects. Here we examine the feasibility, safety, and whether Low Pulse Amplitude Seizure Therapy (LAP-ST, 0.5-0.6A) minimizes cognitive adverse effects while retaining efficacy. METHODS: Patients with treatment-resistant primary mood (depressive episodes) or psychotic disorders who were clinically indicated to undergo ECT were offered to be enrolled in an open label study. The study consisted of a full acute course of LAP-ST under standard anesthesia and muscle relaxation. The primary outcome was feasibility of seizure induction. Clinical outcome measures were: time to reorientation (TRO), Mini Mental State Examination, Montgomery Aberg Depression Scale, and Brief Psychiatric Rating Scale, and Clinical Global Impression Scale. RESULTS: Twenty two patients consented for enrollment in the study. LAP-ST was feasible, and all patients had seizures in the first session. Participants had a quick orientation with median TRO of 4.5min. Treatment was efficacious for both depressive and psychotic symptoms. LIMITATIONS: Relatively small sample size, non-blinded, and no randomization was performed in this initial proof of concept study. CONCLUSIONS: This first human preliminary data of a full course of focal LAP-ST demonstrates that seizure induction is feasible. These results, although preliminary, suggest that the LAP-ST compared to the standard ECT techniques may result in less cognitive side effects, but comparable efficacy. Larger studies are needed to replicate these findings. PMID- 28667889 TI - Major depression with seasonal pattern: Reply to Winkler, et al. PMID- 28667888 TI - Cognitive impairment as measured by the THINC-integrated tool (THINC-it): Association with psychosocial function in major depressive disorder. AB - BACKGROUND: Psychosocial impairment represents an important treatment target in major depressive disorder (MDD). The majority of patients with MDD do not regain premorbid levels of psychosocial functioning despite the resolution of core depressive symptoms. This study aimed to investigate the respective effects of cognitive function and depression severity on impaired psychosocial function in MDD. METHODS: Adults aged 18-65 with moderate-to-severe MDD (n = 100) and age-, sex-, and education-matched healthy controls participated in a cross-sectional study validating the THINC-integrated tool (THINC-it), a cognitive screening tool comprised of objective and subjective measures of cognitive function. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale and psychosocial function was assessed using the Sheehan Disability Scale (SDS). RESULTS: Subjects with MDD reported greater impairment in psychosocial function than healthy controls, with significant differences in SDS total and domain scores (ps < .01) after controlling for age, sex, and education. Generalized linear models indicated that subjective cognitive function was most strongly associated with SDS total score (RR = .14, p = .01) and SDS domains of work/school (RR = .15, p = .03), family and home responsibilities (RR = .15, p = .02), and economic days lost (RR = .18, p =.03). Depression severity was most strongly associated with SDS social life (RR = .08, p < .01) and economic days underproductive (RR = .07, p < .01). Objective cognitive function was not significantly associated with any SDS outcomes. LIMITATIONS: The cross-sectional, observational study design limits temporal inferences. The self-report nature of measures included may have influenced associations observed. Potential medication effects are not noted. CONCLUSIONS: Cognitive deficits, as measured by the THINC it, are associated with significant psychosocial impairment in MDD. These results provide empirical support for the assessment of both subjective and objective measures of cognition, as they are not associated with each other and have differential effects on functional trajectory. PMID- 28667890 TI - Subcortical structural volumes in recently remitted first episode mania. AB - BACKGROUND: Magnetic resonance imaging (MRI) studies have yielded inconsistent findings with regard to subcortical volumetric abnormalities in patients with bipolar I disorder. Duration of illness and long term medication intake could have confounded the findings. METHOD: Volumes of nine subcortical structures were compared between 63 patients who recently remitted from their first manic episode and 77 healthy volunteers. The volumetric segmentation was performed with the automated segmentation algorithm Freesurfer version 5.1. RESULTS: There were no significant volumetric differences between the two groups in any of the structures examined including caudate, putamen, globus pallidum, nucleus accumbens, amygdala, thalamus, cerebellum, hippocampus and lateral ventricles (q > 0.05-false discovery rate corrected). LIMITATIONS: All patients were on psychotropic medications at the time of scanning, which might have confounded the results. Sample size may not be large enough to detect small volumetric changes. CONCLUSIONS: Patients with bipolar I disorder do not appear to have any significant subcortical volumetric abnormalities during the early stage of the disease. Thus, early stage bipolar disorder may present an opportunity for intervention to arrest neuroprogression of the disease. PMID- 28667891 TI - Anomalous prefrontal-limbic activation and connectivity in youth at high-risk for bipolar disorder. AB - OBJECTIVE: Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD. METHODS: We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene. RESULTS: While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortex CONCLUSIONS: Similar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD. PMID- 28667893 TI - Amphipathic dextran-doxorubicin prodrug micelles for solid tumor therapy. AB - A group of micelles self-assembled from deoxycholic acid-doxorubicin-conjugated dextran (denoted as Dex-DCA-DOX) prodrugs were designed and prepared for pH triggered drug release and cancer chemotherapy. These prodrugs could be successfully produced by chemically coupling hydrophobic deoxycholic acid (DCA) to dextran hydrazine (denoted as Dex-NHNH2) and hydrazone linker formation between doxorubicin (DOX) and Dex-NHNH2. These Dex-DCA-DOX prodrugs self assembled to form micelles under physiological conditions with varied particle sizes depending on molecular weight of dextran, degree of substitution (DS) of DCA and DOX. After optimization, Dex10k-DCA9-DOX5.5 conjugate comprising dextran of 10kDa, DCA of DS 9 and DOX loading content of 5.5wt%, formed the micelles with the smallest size (110nm). These prodrug micelles could slowly liberate DOX under physiological conditions but efficiently released the drug at an acidified endosomal pH by the hydrolysis of acid-labile hydrazone linker. In vitro cytotoxicity experiment indicated that Dex10k-DCA9-DOX5.5 micelles exerted marked antitumor activity against MCF-7 and SKOV-3 cancer cells. Besides, intravenous administration of the micelles afforded growth inhibition of SKOV-3 tumor bearing in nude mice at a dosage of 2.5mg per kg with anti-cancer efficacy comparable to free DOX-chemotherapy but low systemic toxicity. This study highlights the feasibility of bio-safe and efficient dextran-based prodrug micelles designed for cancer chemotherapy. PMID- 28667892 TI - Normal aging and Parkinson's disease are associated with the functional decline of distinct frontal-striatal circuits. AB - Impaired ability to shift attention between stimuli (i.e. shifting attentional 'set') is a well-established part of the dysexecutive syndrome in Parkinson's Disease (PD), nevertheless cognitive and neural bases of this deficit remain unclear. In this study, an fMRI-optimised variant of a classic paradigm for assessing attentional control (Hampshire and Owen 2006) was used to contrast activity in dissociable executive circuits in early-stage PD patients and controls. The results demonstrated that the neural basis of the executive performance impairments in PD is accompanied by hypoactivation within the striatum, anterior cingulate cortex (vACC), and inferior frontal sulcus (IFS) regions. By contrast, in aging it is associated with hypoactivation of the anterior insula/inferior frontal operculum (AI/FO) and the pre-supplementary motor area (preSMA). Between group behavioural differences were also observed; whereas normally aging individuals exhibited routine-problem solving deficits, PD patients demonstrated more global task learning deficits. These findings concur with recent research demonstrating model-based reinforcement learning deficits in PD and provide evidence that the AI/FO and IFS circuits are differentially impacted by PD and normal aging. PMID- 28667894 TI - Examining how different measurement approaches impact safety outcomes in child pedestrian research: Implications for research and prevention. AB - There has been a great deal of research aimed at understanding the causes of child pedestrian injury. Many different methods have been employed with the goal of designing simulations that produce rigorous assessment of children's behaviors without putting children at risk of actual pedestrian injury. Most research has assessed children's pre-crossing decision making and extrapolated crossing outcome measures from estimates of mean walking speed. This study explores the nature and extent of measurement bias that is introduced when average walking speed is used to produce estimates of outcomes versus measuring actual in-road behavior directly. Using a within-subjects design and a fully immersive virtual reality pedestrian simulator, both measures were taken. Comparisons based on regression models revealed the extent of differences in results produced by measurement bias. Results indicated that measurement bias is produced when average walking speed is used such that hits and high risk crossings are overestimated and missed opportunities are underestimated, resulting in an overall overestimate of children's risk for pedestrian injury. The discussion highlights how these two measurement approaches emphasize different underlying processes as determinants of child pedestrian injury risk. PMID- 28667895 TI - SIRT1 Regulates the Chemoresistance and Invasiveness of Ovarian Carcinoma Cells. AB - BACKGROUND: SIRT1 is a longevity gene that forestalls aging and age-related diseases including cancer, and has recently attracted widespread attention due to its overexpression in some cancers. We previously identified the overexpression of SIRT1 in ovarian carcinoma (OvCa) as a poor prognostic factor. However, mechanistic insights into the function of SIRT1 in OvCa have yet to be elucidated. METHODS: Quantitative real-time reverse PCR (qRT-PCR) and Western blotting were employed to examine the expression of SIRT1 in a panel of human OvCa cell lines. si-RNA or sh-RNA and cDNA technologies were utilized to knockdown or overexpress SIRT1, respectively. The effects of SIRT1 on proliferation and chemoresistance were examined using a WST-1 assay, and the underlying mechanisms were confirmed using an apoptotic assay, and the quantification of glutathione (GSH), and reactive oxygen species (ROS). The aggressiveness of SIRT1 was analyzed using in vitro invasion and migration assays. RESULTS: SIRT1 was more strongly expressed in OvCa cell lines than in the immortalized ovarian epithelium at the gene and protein levels. Stress up regulated the expression of SIRT1 in dose- and time-dependent manners. SIRT1 significantly enhanced the proliferation (P<.05), chemoresistance (P<.05), and aggressiveness of OvCa cells by up-regulating multiple antioxidant pathways to inhibit oxidative stress. Further study into the overexpression of SIRT1 demonstrated the up-regulation of several stemness-associated genes and enrichment of CD44v9 via an as-yet-unidentified pathway. CONCLUSIONS: Our results suggest that SIRT1 plays a role in the acquisition of aggressiveness and chemoresistance by OvCa, and has potential as a therapeutic target for OvCa. PMID- 28667896 TI - Preliminary evidence for snail deformation from a Eutrophic lake. AB - The incidence of deformities in snails Bellamya aeruginosa was investigated in a typical eutrophicated lake - Taihu Lake. A total of 15 105 specimens were collected, and 0.18-0.93% of the snails exhibited abnormal tentacle bifurcations. Abnormally developed snails were all female and were found in regions with relatively high Chlorophyll a levels (12.40+/-7.23MUg/L). As tentacles are sexually dimorphic in B. aeruginosa, we postulated that factors associated with eutrophication might be responsible for the partial masculinization of tentacles in females. Differential gene expression analyses revealed that a number of unigenes were significantly up-regulated or down-regulated in snails sampled from three locations having high Chlorophyll a levels compared with snails sampled from the region with lower Chlorophyll a level (2.95MUg/L). Thus, transcriptomic profiling revealed potential molecular signal of eutrophication that can lead to developmental abnormalities in this species. PMID- 28667897 TI - Rate of force development and muscle activation of trunk muscles in women with and without low back pain: A case-control study. AB - OBJECTIVE: To evaluate the rate of force development (RFD) and the rate of electromyography rise (RER) of global and local trunk muscles in women with and without low back pain. DESIGN: Cross-sectional study. SETTING: Laboratory setting. PARTICIPANTS: Twenty-eight women divided into low back pain (LBP, n = 14) and control groups (CG, n = 14) participated in this study. MAIN OUTCOME MEASURES: Subjects performed isometric contractions of trunk using an isokinetic dynamometer, and simultaneously the electromyography (EMG) signals were collected for global (rectus abdominis and longissimus thoracic) and local (internal oblique and multifidus) muscles. All variables were calculated using Matlab software. RESULTS: Symptomatic subjects showed lower RFD during trunk extension and it was correlated to a reduced RER mainly in the trunk extensor musculature (p < 0.05). During trunk flexion, LBP exhibited a delayed time to reach peak RFD (p < 0.05) compared to CG. RER for global anterior muscle was higher than for local muscle (p < 0.05) and it was more persistent in asymptomatic women. CG also presented greater activation amplitude for both agonist and antagonist trunk muscles, mainly the global ones. CONCLUSION: Symptomatic women showed lower RFD and it was correlated to a reduced capacity of rapid muscle activation mainly in the trunk extensor musculature. PMID- 28667898 TI - Experiential avoidance and dysfunctional beliefs in the prediction of body image disturbance in a nonclinical sample of women. AB - Body image disturbance (BID) refers to persistent dissatisfaction, distress, and dysfunction related to some aspect(s) of one's physical appearance. Cognitive models of BID highlight the importance of dysfunctional beliefs in maintaining BID. Relational Frame Theory (RFT), in contrast, posits that psychological distress is sustained by the unwillingness to experience aversive internal experiences (i.e., experiential avoidance [EA]). The present study tested the hypothesis that both dysfunctional beliefs and EA uniquely predict BID even after accounting for general distress. A nonclinical female sample (N=100) completed measures of general distress, dysfunctional beliefs about appearance, EA, and BID in addition to providing in vivo anxiety ratings after looking at their most dissatisfactory facial feature in a vanity mirror. Linear regression analyses showed that dysfunctional beliefs, but not EA, accounted for significant unique variance in BID outcomes. Implications for understanding, assessing, and treating clinically significant BID are discussed. PMID- 28667899 TI - Sensitivity to antitubulin chemotherapeutics is potentiated by a photoactivable nanoliposome. AB - Anti-microtubule therapy represents one of the most strategic cancer therapeutics. Tublin inhibitor such as paclitaxel (PTX) is well known to disturb the dynamic nature of microtubules, being considered as the first-line drug for various malignancies. However, PTX does not show favorable clinical outcomes due to serious systemic toxicities and low selectivity. The development of PTX delivery systems and combinational therapies has been conducted to enhance PTX efficacy with poorly defined mechanisms. Herein, we introduced a reactive oxygen species producible composite liposome based on a new photosensitizer sinoporphyrin sodium (DVDMS) to enhance the therapeutic effect of PTX through photochemical stimulation, and more importantly, the pivotal molecular regulation mechanisms were specifically explored. Compared with DVDMS-liposome (DL) or PTX liposome (PL), the composite liposome DVDMS-PTX-liposome (PDL) exhibited a superior anti-tumor advantage following laser irradiation against MCF-7 breast cancer. The localized PTX release after PDL administration greatly decreased the drug dosage and laser power required, leading to much higher safety and lower costs. In vitro, the combined treatment significantly suppressed cell viability and potentiated cell apoptosis. The apoptotic central regulator Mcl-1 as a favorable target, was evaluated in association with photochemically enhanced sensitivity to anti-tubulin chemotherapeutics. Phosphorylation of Mcl-1 led to its direct degradation with the proteasome system, making it relatively unstable and potentiating cell death resulting from photochemical synergy via PDL plus laser irradiation. Further, a decrease in ATP production and glycolysis after PDL plus laser would prevent the possible energy-switch and apoptosis-escape by PTX alone treatment, thereby resulted in increased cell death in combinational therapy. Systemic administration of PDL followed by in vivo photochemotherapy achieved significantly improved therapeutic effects compared to either alone. And, the intrinsic fluorescence of DVDMS facilitated real-time imaging of PDL in tumors. Therefore, the present strategy with details at the molecular regulation could be a promising platform for antitublin chemotherapeutics. PMID- 28667901 TI - Fibrous scaffolds potentiate the paracrine function of mesenchymal stem cells: A new dimension in cell-material interaction. AB - While the studies on the material interaction with mesenchymal stem cells (MSCs) have been mainly focused on the ability of materials to provide environment to regulate cell viability, proliferation or differentiation, the therapeutic effects of MSC-material constructs may result from the secretion of immunomodulatory and angiogenic cytokines from MSCs. Here, electrospun scaffolds composed of fibers in random, aligned and mesh-like patterns were fabricated, and the paracrine behavior of adipose-derived MSCs (Ad-MSCs) on the scaffolds were investigated in comparison to the cell culture via conventional microplates. It was found that the Ad-MSCs on the electrospun fibers produced significantly higher levels of anti-inflammatory and pro-angiogenic cytokines compared to those cultured on microplates. The enhanced modulatory effects of the secreted products of Ad-MSCs on fibrous electrospun scaffolds were also proven in the cultures of endothelial cells and the LPS-stimulated macrophages, with three types of scaffolds showing distinct influences on the paracrine function of Ad-MSCs. In a skin excisional wound-healing model in rat, the conditioned medium collected from the MSC-scaffold system accelerated the wound closure, promoted the macrophage recruitment and enhanced the polarization of macrophages toward the pro-healing phenotype in the wound bed. Our study demonstrates that the fibrous topography of scaffolds is a key material property that modulates the paracrine function of cells. The discovery elucidates a new aspect of material functions, laying the foundation for developing scaffold materials to promote tissue regeneration/repair through guiding the paracrine signaling network. PMID- 28667900 TI - Improving in vivo outcomes of decellularized vascular grafts via incorporation of a novel extracellular matrix. AB - Each year, hundreds of thousands coronary bypass procedures are performed in the US, yet there currently exists no off-the-shelf alternative to autologous vessel transplant. In the present study, we investigated the use of mouse thrombospondin 2 knockout (TSP2 KO) cells, which secrete a non-thrombogenic and pro-migratory extracellular matrix (TSP2 KO ECM), to modify small diameter vascular grafts. To accomplish this, we first optimized the incorporation of TSP2 KO ECM on decellularized rat aortas. Because MMP levels are known to be elevated in TSP2 KO cell culture, it was necessary to probe the effect of the modification process on the graft's mechanical properties. However, no differences were found in suture retention, Young's modulus, or ultimate tensile strength between modified and unmodified grafts. Platelet studies were then performed to determine the time point at which the TSP2 KO ECM sufficiently reduced thrombogenicity. Finally, grafts modified by either TSP2 KO or WT cells or unmodified grafts, were implanted in an abdominal aortic interposition model in rats. After 4 weeks, grafts with incorporated TSP2 KO ECM showed improved endothelial and mural cell recruitment, and a decreased failure rate compared to control grafts. Therefore, our studies show that TSP2 KO ECM could enable the production of off-the-shelf vascular grafts while promoting reconstruction of native vessels. PMID- 28667902 TI - Cognitive-motor interference in multiple sclerosis: What happens when the gait speed is fixed? AB - During the last decade, numerous studies have confirmed a coupling between walking performance and cognition in people with multiple sclerosis (PwMS). Our aim was to provide new insights into a walking-cognitive dual-task (DT) in PwMS. We tested the DT phenomenon by controlling the walking speed using an instrumented treadmill. Thirty PwMS (20 women) with a mean age 40.1 (SD=12.0) participated in the study. Twenty-one healthy subjects served as controls. Each subject completed a sequence of tests: a) Normal walking (ST) - the participant walked on the instrumented treadmill at a comfortable walking speed for 1min; b) Cognitive evaluation (ST) - subjects performed two cognitive tests while seated; c) DT cognitive tests performed while walking on the treadmill at the identical speed performed during normal walking. Outcome measures were spatio-temporal parameters of gait (mean and variability), the Word List Generation Test (WLG) and the Serial-3 Subtraction Test. MS participants significantly decreased their cadence while increasing their stride length during the DT condition compared to the ST condition. Non-significant differences were observed for the WLG and Serial-3 Subtraction Cognitive Tests between the ST condition and the DT condition in both the MS and healthy groups. In terms of gait variability parameters, MS subjects demonstrated a 2 to 3-fold greater gait variability compared to the healthy controls. Non-significant differences in gait variability parameters were observed between the ST and DT conditions in both the MS and control groups. This study provides new insights into the DT phenomenon in the MS population. PMID- 28667903 TI - Gait parameter and event estimation using smartphones. AB - BACKGROUND AND OBJECTIVES: The use of smartphones can greatly help for gait parameters estimation during daily living, but its accuracy needs a deeper evaluation against a gold standard. The objective of the paper is a step-by-step assessment of smartphone performance in heel strike, step count, step period, and step length estimation. The influence of smartphone placement and orientation on estimation performance is evaluated as well. METHODS: This work relies on a smartphone app developed to acquire, process, and store inertial sensor data and rotation matrices about device position. Smartphone alignment was evaluated by expressing the acceleration vector in three reference frames. Two smartphone placements were tested. Three methods for heel strike detection were considered. On the basis of estimated heel strikes, step count is performed, step period is obtained, and the inverted pendulum model is applied for step length estimation. Pearson correlation coefficient, absolute and relative errors, ANOVA, and Bland Altman limits of agreement were used to compare smartphone estimation with stereophotogrammetry on eleven healthy subjects. RESULTS: High correlations were found between smartphone and stereophotogrammetric measures: up to 0.93 for step count, to 0.99 for heel strike, 0.96 for step period, and 0.92 for step length. Error ranges are comparable to those in the literature. Smartphone placement did not affect the performance. The major influence of acceleration reference frames and heel strike detection method was found in step count. CONCLUSION: This study provides detailed information about expected accuracy when smartphone is used as a gait monitoring tool. The obtained results encourage real life applications. PMID- 28667904 TI - Somatosensory impairment and its association with balance limitation in people with multiple sclerosis. AB - BACKGROUND: Somatosensory impairments are common in multiple sclerosis. However, little data are available to characterize the nature and frequency of these problems in people with multiple sclerosis. OBJECTIVE: To investigate the frequency of somatosensory impairments and identify any association with balance limitations in people with multiple sclerosis. METHODS: The design was a prospective cross-sectional study, involving 82 people with multiple sclerosis and 30 healthy controls. Tactile and proprioceptive sensory acuity were measured using the Rivermead Assessment of Somatosensory Performance. Vibration duration was assessed using a tuning fork. Duration for the Timed Up and Go Test and reaching distance of the Functional Reach Test were measured to assess balance limitations. The normative range of sensory modalities was defined using cut-off points in the healthy participants. The multivariate linear regression was used to identify the significant predictors of balance in people with multiple sclerosis. RESULTS: Proprioceptive impairments (66.7%) were more common than tactile (60.8%) and vibration impairments (44.9%). Somatosensory impairments were more frequent in the lower limb (78.2%) than the upper limb (64.1%). All sensory modalities were significantly associated with the Timed Up and Go and Functional Reach tests (p<0.05). The Timed Up and Go test was independently predicted by the severity of the neurological lesion, Body Mass Index, ataxia, and tactile sensation (R2=0.58), whereas the Functional Reach test was predicted by the severity of the neurological lesion, lower limb strength, and vibration sense (R2=0.49). CONCLUSIONS: Somatosensory impairments are very common in people with multiple sclerosis. These impairments are independent predictors of balance limitation. PMID- 28667905 TI - Spatial and temporal postural analysis in children born prematurely. AB - The aim of this study was to compare postural stability in a group of preterm born children aged 4-6 years old and in a group of age-matched full-term control children by exploring both spatial and temporal analysis of the Center of Pressure (CoP). Twenty-nine children born prematurely (mean age: 5.38+/-0.17) and twenty-nine age-matched full-term control children participated in this study. Postural control was tested on both a stable and an unstable platform (from Framiral(r)) in three different visual conditions: eyes open fixating a target, eyes closed, and with vision perturbed by optokinetic stimulation. We observed a significant increase of both surface area and mean velocity of the CoP in pre term children compared to full-term control children, particularly in an unstable postural condition. The spectral power indices increased significantly in pre term children with respect to full-term control children, while the cancelling time was not different between the two groups of children tested. We suggested that poor postural stability observed in preterm children could be due to immaturity of the cortical processes (the occipital parietal prefrontal cortex) involved in motor control. Preterm children could have an inappropriate compensation of sensory inputs when they are tested in difficult postural and/or visual conditions. PMID- 28667906 TI - The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. AB - Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance(r)), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, beta-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF-Leprfa/fa and 16 ZDF-Lepr+/+ controls). Empagliflozin (10 and 30mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial). PMID- 28667907 TI - Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers. AB - Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver. PMID- 28667909 TI - Graphical review: The redox dark side of e-cigarettes; exposure to oxidants and public health concerns. AB - Since the initial marketing in 2005, the use of e-cigarettes has increased exponentially. Nonetheless, accumulating evidence has demonstrated the ineffectiveness of e-cigarettes in leading to smoking cessation, and decreasing the adverse health impacts of cigarette smoking. The number of adolescents adapted to e-cigarettes has been increasing substantially each year, and this adaptation has promoted openness to tobacco smoking. The present review discusses controversies regarding the smoking cessation effects of e-cigarettes, recent governmental policies and regulations of e-cigarette use, toxic components and vaporization products of e-cigarettes, and the novel molecular mechanisms underlying the adverse health impacts of e-cigarettes leading to oxidative stress in target tissues, and consequent development of cardiopulmonary diseases (i.e. COPD), neurodegenerative disorders (i.e. Alzheimer's' disease), and cancer. Health warning signs on the packaging and professional consultation to avoid adaptation in risk groups might be helpful solutions to control negative impacts of e-cigarettes. It is also recommended to further expand basic and clinical investigations to reveal more detailed oxidative stress mechanisms of e-cigarette induced damages, which would ultimately result in more effective protective strategies. PMID- 28667910 TI - Anxiety and depression in people with epilepsy: The contribution of metacognitive beliefs. AB - PURPOSE: Anxiety and depressive disorders frequently occur in people with epilepsy (PWE). An information processing model of psychopathology, the Self Regulatory Executive Function (S-REF) model specifies that maladaptive metacognitive beliefs and processes play a fundamental role in the development and maintenance of anxiety and depression. This study explored whether metacognitive beliefs would explain additional variance in anxiety and depression after accounting for demographics, physical and/or psychiatric illnesses, epilepsy characteristics and medication issues. The mediational relationships between metacognitive beliefs, worry and anxiety and depression, predicted by the metacognitive model were also explored, METHODS: Three hundred and forty-nine PWE participated in an online survey and completed self-report questionnaires measuring anxiety, depression, metacognitive beliefs and worry. Participants also provided information on epilepsy characteristics, demographics, comorbid physical and/or psychiatric illnesses, number of, and perceived side effects of, anti epileptic medication. RESULTS: Regression analysis showed that metacognitive beliefs were associated with symptoms of anxiety, depression, and explained additional variance in these outcomes after accounting for the control variables. Furthermore, the fundamental tenet of the metacognitive model was supported; the relationship between negative metacognitive beliefs about uncontrollability and danger of worry and anxious and depressive symptoms was partially mediated by worry. CONCLUSION: This is the first study to demonstrate that metacognitive beliefs and processes contribute to anxiety and depression beyond variables often associated with emotional distress in PWE. Further research is required to test if modification of metacognitive beliefs and processes using metacognitive therapy would effectively alleviate anxiety and depression in PWE. PMID- 28667908 TI - Transcription factor NRF2 controls the fate of neural stem cells in the subgranular zone of the hippocampus. AB - Neural stem/progenitor cells (NSPCs) located at the subgranular zone (SGZ) of the hippocampus participate in the maintenance of synaptic networks that ensure cognitive functions during life. Although it is known that this neurogenic niche losses activity with oxidative stress and ageing, the molecular events involved in its regulation are largely unknown. Here, we studied the role of transcription factor Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) in the control of NSPCs destinies in the SGZ. We first describe that NRF2-knockout (Nrf2-/-) mice exhibit impaired long term potentiation, a function that requires integrity of the SGZ, therefore suggesting a cognitive deficit that might be linked to hippocampal neurogenesis. Then, we found a reduction in NSCs from birth to adulthood that was exacerbated in Nrf2-/- vs. Nrf2+/+ mice. The clonogenic and proliferative capacity of SGZ-derived NSPCs from newborn and 3-month-old Nrf2-/- mice was severely reduced as determined in neurosphere cultures. Nrf2-deficiency also impaired neuronal differentiation both the SGZ, and in neurosphere differentiation assays, leading to an abnormal production of astrocytes and oligodendrocytes vs. neurons. Rescue of Nrf2-/- NSPCs by ectopic expression of NRF2 attenuated the alterations in clonogenic, proliferative and differentiating capacity of hippocampal NSPCs. In turn, knockdown of the NRF2 gene in wild type NSPCs reproduced the data obtained with Nrf2-/- NSPCs. Our findings demonstrate the importance of NRF2 in the maintenance of proper proliferation and differentiation rates of hippocampal NSPCs and suggest that interventions to up regulate NRF2 might provide a mechanism to preserve the neurogenic functionality of the hippocampus. PMID- 28667911 TI - Metabolomics analysis of TiO2 nanoparticles induced toxicological effects on rice (Oryza sativa L.). AB - The wide occurrence and high environmental concentration of titanium dioxide nanoparticles (nano-TiO2) have raised concerns about their potential toxic effects on crops. In this study, we employed a GC-MS-based metabolomic approach to investigate the potential toxicity of nano-TiO2 on hydroponically-cultured rice (Oryza sativa L.) after exposed to 0, 100, 250 or 500 mg/L of nano-TiO2 for fourteen days. Results showed that the biomass of rice was significantly decreased and the antioxidant defense system was significantly disturbed after exposure to nano-TiO2. One hundred and five identified metabolites showed significant difference compared to the control, among which the concentrations of glucose-6-phosphate, glucose-1-phosphate, succinic and isocitric acid were increased most, while the concentrations of sucrose, isomaltulose, and glyoxylic acid were decreased most. Basic energy-generating ways including tricarboxylic acid cycle and the pentose phosphate pathway, were elevated significantly while the carbohydrate synthesis metabolism including starch and sucrose metabolism, and glyoxylate and dicarboxylate metabolism were inhibited. However, the biosynthetic formation of most of the identified fatty acids, amino acids and secondary metabolites which correlated to crop quality, were increased. The results suggest that the metabolism of rice plants is distinctly disturbed after exposure to nano-TiO2, and nano-TiO2 would have a mixed effect on the yield and quality of rice. PMID- 28667912 TI - Organochlorine pesticide, antibiotic and heavy metal residues in mussel, crayfish and fish species from a reservoir on the Euphrates River, Turkey. AB - This study investigated the residues of 19 organochlorine pesticides, 37 antibiotics and 5 heavy metals in biota samples (one mussel species, one crayfish species, six wild fish species and one farmed fish species) from the Keban Dam Reservoir on the Euphrates River, Turkey. Among monitored OCPs, only p,p'-DDE was detected in biota samples. It was found only in mussel, fish muscle and fish gill samples. The highest concentration of p,p'-DDE (0.032 mg/kg ww) was determined in the gill of common carp, which was found to be below the maximum residue limit (MRL). Only sulfadimethoxine was detected among antibiotics in biota samples. Its maximum concentration (0.0044 mg/kg ww) did not exceed the MRL of 0.1 mg/kg. Sulfadimethoxine was found only in muscle and gill of common carp collected from site S6, where there are many rainbow trout cage farms. However, no detectable residue of sulfadimethoxine was found in farmed rainbow trout. The highest concentrations of As, Cd and Pb were detected in mussels, while the highest concentrations Cu and Zn were determined in crayfish. Metal concentrations in biota samples did not exceed the maximum permissible levels. According to these results, the consumption of biota samples from the Keban Dam Reservoir is safe for human health. PMID- 28667913 TI - Lead and cadmium exposure, higher thyroid antibodies and thyroid dysfunction in Chinese women. AB - BACKGROUND: Exposure to lead(Pb) or cadmium(Cd) has been related to decreasing thyroxine in many previous studies. The underlying mechanisms have not been clarified. Heavy metal-induced thyroid autoimmunity in pregnant women has been found, despite having been rarely explored in the general population. OBJECTIVES: We aimed to determine whether the blood levels of lead(BPb) or cadmium(BCd) related to the levels of sera antibodies to thyroid proteins and thyroid dysfunction in the general population. METHODS: Our study included 5628 Chinese adults and was based on the 2014 SPECT-China study. Thyroid dysfunction and subclinical thyroid dysfunction were defined by total triiodothyronine (TT3), total thyroxine(TT4) and thyroid stimulating hormone (TSH).Thyroid peroxidase antibody (TPOAb), thyroglobulin antibodies (TGAb), TT3, TT4, and TSH were measured by immunochemiluminometric assays. BPb and BCd levels were tested by atomic absorption spectrometry. Linear and logistic regression models were used to analyze the associations. RESULTS: After adjustment for age, body mass index, smoking status (men only) and drinking status, the natural log(ln) BPb was positively related to the lnTPOAb (B = 0.062, P < 0.05) and to the lnTSH (B = 0.047, P < 0.01) in women. The lnBCd in women was positively related to the lnTGAb (B = 0.046, P < 0.05). In the adjusted logistic regression models, the BCd of women was positively related to their hypothyroid status and TGAb tertiles. The ORs of women in the middle and higher TPOAb tertiles were 1.38 (P < 0.001) and 1.35 (P < 0.001) times greater for every ln-unit increase in BPb, respectively. In men, no continuous correlation was found among variables. CONCLUSIONS: In women, BPb and BCd levels were related to higher TSH and hypothyroid status, respectively, suggesting a Pb and Cd induction of sex-biased thyroid autoimmunity. PMID- 28667914 TI - In vivo wound healing and in vitro antioxidant activities of Bletilla striata phenolic extracts. AB - Bletilla striata has attracted extensive research interest due to the potential uses for its extracts to treat skin burns and inflammatory disorders in a clinical setting. My current research focuses on Bletilla striata polysaccharides (BSP), and often ignores the residues that remain after polysaccharide extraction. It also remains unclear whether the residues have medical value related its traditional clinic function. During this work, we firstly identified the contents of the post-extraction residue by UPLC-Q-Exactive Orbitrap-MS and evaluated its in vivo wound healing and in vitro antioxidant activity. The wound healing activity of the ointment containing residue was assessed for 15days the scald model was used in mice, followed by histopathology and histomorphological analysis. The in vitro antioxidant effect of Bletilla residue was researched using DPPH, ABTS, Hydroxyl radical scavenging, superoxideanion radical scavenging, and reducing power assays. AUPLC-Q-Exactive Orbitrap-MS analysis identified 6 phenolic compounds: protocatechuic acid, p-hydroxybenzoic acid, caffeic acid, p-hydroxybenzaldehyde, 3-Hydroxycinnamic acid, and ferulic acid. Animals treated with "mixed ointment" experienced inflammatory infiltration, which was lower than that of other groups. Both "BSPG ointment" and "Bletilla phenolic ointment" demonstrated superior tissue repair compared to the control. This study was the first to confirm that the residual liquid after polysaccharide extraction has excellent antioxidant and wound healing activities. In addition to Bletilla striata polysaccharides, the residual liquid can improve skin regeneration after burns and reduce inflammatory marker levels. These results have implications that the residual liquid has potential wound healing medicinal value. PMID- 28667915 TI - Knockdown of TNF receptor-associated factor 2 (TRAF2) modulates in vitro growth of TRAIL-treated prostate cancer cells. AB - TNF receptor-associated factor 2 (TRAF2) is documented to regulate tumor development and progression. Currently, the effect of TRAF2 on growth of androgen refractory prostate cancer in response to TRAIL and the molecular mechanisms are not well understood. Here, we aim to investigate the effect of TRAF2 on in vitro growth of human androgen-insensitive prostate cancer DU-145 cells in the presence of TRAIL. Bioinformatics analysis of the Cancer Genome Atlas (TCGA) data was performed to examine TRAF2 expression and the prognostic value in prostate cancer. Microarray data of GSE21032 dataset were downloaded from Gene Expression Omnibus (GEO) to explore TRAF2 expression in metastatic prostate cancer. Bioinformatics analysis was further conducted to investigate the association of TRAF2 expression with recurrence-free survival in prostate cancer patients. Colony formation, cell viability, and Annexin V/PI apoptosis assays were performed to investigate the effect of TRAF2 on in vitro growth and apoptosis in TRAIL-treated DU-145 cells. The expression levels of mRNA and protein were detected by quantitative RT-PCR and immunoblotting assays. Bioinformatics analysis indicated that TRAF2 expression is significantly upregulated in prostate cancer patients with high Gleason scores (GS>7) compared with those with low Gleason scores (GS<=7). Upregulation of TRAF2 expression is significantly associated with recurrence-free survival in patients. In addition, TRAF2 knockdown can enhance apoptosis and downregulate SIRT1 expression in TRAIL treated DU-145 cells. In vitro experiments further showed that SIRT1 knockdown can inhibit growth, and promote apoptosis in TRAIL-treated DU-145 cells. Overall, TRAF2 can influence in vitro growth of TRAIL-treated DU-145 cells at least partially via regulating SIRT1 expression, and may be a potentially valuable biomarker predicting recurrence-free survival in prostate cancer patients. PMID- 28667916 TI - MiR-210 facilitates ECM degradation by suppressing autophagy via silencing of ATG7 in human degenerated NP cells. AB - Intervertebral disc degeneration (IDD) is thought to be the most common cause of low back pain. Dysregulation of microRNAs (miRNAs) is involved in the development of IDD. The aim of this study was to explore the influence of miR-210 on type II collagen (Col II) and aggrecan expression and possible mechanisms in human degenerated nucleus pulposus (NP) cells. Our results showed that miR-210 levels were significantly increased in degenerated NP tissues compared with healthy controls, and positively correlated with disc degeneration grade. By gain-of function and loss-of-function studies in human degenerated NP cells, miR-210 was shown to inhibit autophagy and then upregulate MMP-3 and MMP-13 expression, leading to increased degradation of Col II and aggrecan. Autophagy-related gene 7 (ATG7) was identified as a direct target of miR-210. Knockdown of ATG7 by small interfering RNA (siRNA) abrogated the effects of miR-210 inhibitor on MMP-3, MMP 13, Col II and aggrecan expression. Taken together, these results suggest that miR-210 inhibits autophagy via silencing of ATG7, leading to increased Col II and aggrecan degradation in human degenerated NP cells. PMID- 28667917 TI - Identification of peptide-mediated interactions between human PTTG and SH3 domains in pALL gene expression profile. AB - Human pituitary tumor-transforming gene (PTTG) plays an essential role in the development and progression of pediatric acute lymphoblastic leukemia (pALL). PTTG has two SH3-binding peptide motifs that can be recognized by a variety of SH3-containing proteins in the pALL through peptide-mediated interactions. In this study, the gene expression profile of pALL was examined in detail by integrating computational modeling and experimental assay, aiming to identify those potential partner proteins of human PTTG. The binding potency of domain candidates to peptide motifs was ranked using knowledge-based scoring and fluorescence titration. A number of SH3 domains found in a variety of pALL proteins were identified as potent binders with moderate or high affinity for PTTG. It is revealed that the PTTG peptide motifs show different affinity profiles for various candidate proteins, indicating that the PTTG selectivity is optimized across pALL gene expression space. The PTTG peptides were then mutated rationally to target the SH3 domains of identified partner proteins by competing with the native peptide motifs. PMID- 28667918 TI - The inverse association of HDL-cholesterol with future risk of hypertension is not modified by its antioxidant constituent, paraoxonase-1: The PREVEND prospective cohort study. AB - BACKGROUND AND AIMS: High-density lipoprotein cholesterol (HDL-C), an established risk marker for atherosclerotic cardiovascular disease (CVD), has been shown to be inversely and independently associated with incident hypertension. Paraoxonase 1 (PON-1) is an HDL-bound esterase enzyme associated with CVD, but its relationship with incident hypertension has not been previously investigated. We aimed at evaluating the prospective association between PON-1 and hypertension risk. METHODS: PON-1 arylesterase activity was measured in serum at baseline in 3988 participants without pre-existing hypertension in the Prevention of Renal and Vascular End-stage Disease (PREVEND) prospective population-based study. During a median follow-up of 10.7 years, 1206 participants developed hypertension. RESULTS: In age- and sex-adjusted analysis, the hazard ratio (95% CI) for incident hypertension per 1 standard deviation increase in PON-1 was 1.01 (0.96-1.07; p = 0.656), which remained non-significant after adjustment for several established hypertension risk factors and other potential confounders (0.99, 0.93 to 1.05; p = 0.764). The association was also non-existent on further adjustment for HDL-C (1.00 (0.94-1.06; p = 0.936)) and did not importantly vary across several clinical subgroups. In analyses in the same set of participants, HDL-C was continuously inversely and independently associated with hypertension risk; the association persisted after further adjustment for PON-1 activity and was not modified by PON-1 activity. CONCLUSIONS: In this Caucasian cohort of men and women, HDL-C, but not its anti-oxidant constituent - PON-1, is inversely, continuously and independently associated with future risk of hypertension. The association is independent of and not modified by PON-1. PMID- 28667919 TI - A rare case report of bilateral choanal atresia in an adult. AB - INTRODUCTION: Adult choanal atresia is a rare congenital malformation of the nasal cavity characterized by the complete obliteration of the posterior choanae, only ninth cases are reported in the literature, we present in our observation the tenth case of adult bilateral choanal atresia. PRESENTATION OF CASE: A 18 year-old man presented at our department with complaints of nasal obstruction, nasal discharge, snoring, anosmia, and mouth breathing since childhood. Endoscopic examination and paranasal sinus tomography revealed bilateral choanal atresia. An endoscopic choanoplasty was performed. Follow-up evaluation at postoperative 12th month showed that his symptoms improved significantly and, on endoscopic examination, both choanae remained patent. DISCUSSION AND CONCLUSION: Adult bilateral choanal atresia is a rare entity. The revelation in adulthood of congenital bilateral atresia remains exceptional. Nasal endoscopy and preoperative computed tomography scan help in planning surgery. Endoscopic transnasal choanoplasty is the criterion standard treatment. The exact role of the postoperative stent and use of mitomycin C is controversial. PMID- 28667920 TI - Mandibular metastasis revealed papillary thyroid carcinoma: Rare case. AB - INTRODUCTION: Papillary carcinoma is the most frequent differentiated malignant thyroid neoplasm, Metastasis occurs frequently in regional lymph nodes and mandibular metastasis are very rare and most are secondary to follicular carcinomas due to their blood diffusion, The mandibular metastasis of papillary carcinoma is exceptional. CASE REPORT: We report a rare case of mandibular metastasis revealing papillary thyroid carcinoma in a 52-year-old patient, with a review of the literature on clinical features, radiological aspect, and treatment options. DISCUSSION CONCLUSION: Mandibular metastasis of thyroid cancer are rare and the initial metastases revealing papillary carcinoma are exceptional, few cases are reported in the literature, and due to their rarities and relative lack of data on their management, There is no clearly defined processing algorithm. PMID- 28667921 TI - Primary and isolated thyroid Hodgkin's lymphoma: A case report. AB - INTRODUCTION: Hodgkin's lymphoma rarely involves the thyroid gland. It is typically presented as a fast growing neck mass that is sometimes accompanied by respiratory compression symptoms. CASE REPORT: We report one of the few (the seventeenth) case of primary and isolated Hodgkin's thyroid lymphoma presented by a 65 years old man, consulting for a fast growing neck mass with Hodgkin's symptoms. The patient had total thyroidectomy and short courses of chemotherapy, then total resolution of symptomatology. CONCLUSION: Most thyroid Hodgkin's lymphoma are presented by women, rarely man, isolated and primary. Since 1962, we only found sixteen cases described in the literature. Hodgkin's lymphoma should be considered in the differential diagnosis of patients with a thyroid mass for rapid management. PMID- 28667922 TI - Combination of hydroxyapatite, platelet rich fibrin and amnion membrane as a novel therapeutic option in regenerative periapical endodontic surgery: Case series. AB - INTRODUCTION: Periapical surgery is the last resort in the arsenal of an endodontist to effectively deal with periapical lesions that result from necrosis of the pulp. Bone grafts, growth factors and membranes form an array of regenerative materials that influence the healing outcome of periapical surgery. PRESENTATION OF CASE: The main purpose of the two cases reported here was to assess the potential benefits of a combination of bone graft, platelet-rich fibrin (PRF) and amnion membrane in terms of reduced post-operative discomfort, radiographic evidence of accelerated periapical bone healing and present a novel therapeutic option in the management of large periapical lesions. Two cases of radicular cysts were treated through a combined regenerative approachof Bio-Gen mix(r), PRF and amnion membrane. The patients were assessed for discomfort immediate post-operatively and after a week. The patients were recalled every month for the next 6 months for radiographic assessment of the periapical healing. DISCUSSION: Literature is replete with articles that have substantiated the role of demineralized bone matrix comprising a mixture of cancellous and cortical bone graft particles in enhancing regeneration. To the best of our knowledge, there has been no evidence related to the application of a human placental membrane in periapical surgery. Hence, the rationale of using a combined approach of Bio-Gen mix(r), PRF and amnion membrane was to combine the individual advantages of these materials to enhance clinical and radiographic healing outcomes. Our present case reports provide an insight into this novel therapeutic option. CONCLUSION: The results of this case seriessubstantiatesthe credibility of using a combination ofamnion membrane with a bone graft and PRF to enhance radiographic healing outcome with decreased post-operative discomfort and present a viable regenerative treatment modality in periapical surgery. PMID- 28667923 TI - Selective and sensitive determination of lactose in low-lactose dairy products with HPAEC-PAD. AB - The demand for low lactose dairy products is increasing and more different lactose free food is commercially available. The level of lactose in these products decreased during the last years and nowadays a concentration of <0.01% is generally accepted as "lactose free". For the determination of the lactose concentrations in these dairy products a sensitive analysis method is needed. We developed a method for the determination of low concentrations of lactose in a wide range of dairy products. A simple sample preparation with dilution, centrifugation and ultrafiltration is efficient for the isolation of lactose from the sample matrix. In this paper, a new HPAEC-PAD analysis on a CarboPac PA100 column gives a good separation of lactose from the other saccharides. This separation in combination with the PAD detector yields a selective and sensitive method for the quantification at the desired concentrations of lactose in low lactose dairy products. PMID- 28667924 TI - LC-MS/MS quantification of free and Fab-bound colchicine in plasma, urine and organs following colchicine administration and colchicine-specific Fab fragments treatment in Gottingen minipigs. AB - Clinical evaluation of a colchicine specific antigen-binding fragment (Fab) in order to treat colchicine poisoning required the development of an accurate method allowing quantification of free and Fab-bound colchicine in plasma and urine, and free colchicine in tissues, to measure colchicine redistribution after Fab administration. Three methods have been developed for this purpose, and validated in plasma, urine and liver: total colchicine was determined after denaturation of Fab by dilution in water and heating; free colchicine was separated from Fab-bound colchicine by filtration with 30KDa micro-filters; tissues were homogenized in a tissue mixer. Deuterated colchicine was used as internal standard. Samples were extracted by liquid-liquid extraction and analyzed with a LC-MS/MS. LOQ were 0.5ng/mL in plasma and urine for free and total colchicine and 5pg/mg in tissues. The methods were linear in the 0.5 100ng/mL range in plasma and urine, and 5-300pg/mg in tissues with determination coefficients>0.99. Precision and accuracy of QC samples presented a CV<9.4%. The methods require only 200MUL of sample and allow a high throughput due to short analytical run (2min). These methods were successfully applied to a pig intoxicated with colchicine and treated with colchicine specific Fab fragments. PMID- 28667925 TI - Serum fibroblast growth factor 23 concentrations in dogs with chronic kidney disease. AB - The aim of this study was to determine if serum fibroblast growth factor (FGF23) concentrations were increased in dogs with chronic kidney disease (CKD). Serum samples submitted to a commercial laboratory were collected over a 15-month period, 14 samples were from dogs with a history of polyuria/polydipsia, azotaemia and low urine specific gravity, 20 samples were from non-azotaemic dogs. Serum FGF23, parathyroid hormone, total calcium and phosphorus, urea and creatinine were measured. Mann-Whitney test was used to determine differences between non-azotaemic and CKD groups; a one-way ANOVA with Tukey pairwise comparisons was used to determine any differences between International Renal Interest Society stages; and regression models were used to determine predictors of International Renal Interest Society stage, serum phosphorus and FGF23 concentrations. The median serum FGF23 concentration of dogs with CKD was 5194.6pg/mL, which was significantly greater (P<0.001) than the median serum FGF23 concentration of non-azotaemic dogs (259.2pg/mL). Log serum FGF23 and age were significantly associated with IRIS stage (P=0.027 and P=0.032 respectively), while log serum phosphorus concentration (P<0.001) was significantly associated with log serum FGF23 concentration. In summary, serum FGF23 concentration is increased in dogs with CKD, and is associated with serum phosphorus concentration. This phosphatonin pathway may be a useful target for the development of future treatments to control plasma phosphorus concentrations in chronic kidney disease. PMID- 28667926 TI - Momentary emotion identification in female adolescents with and without anorexia nervosa. AB - Individuals with anorexia nervosa (AN) often report difficulties in identifying emotions, which have been mostly studied as an alexithymia trait. In a controlled two-day ecological momentary assessment, we studied the influence of time of day and aversive tension on self-reported momentary emotion identification. Analysis on an aggregated level revealed a significant lower mean emotion identification in the AN group. In a mixed model analysis, the AN group showed lower emotion identification than the control group (HC). Both a general and a group effect of time of day were found, indicating that emotion identification improved during the day in HC, whereas a negligible decrease of the emotion identification over time was observed in the AN group. Age was associated positively with emotion identification in general, but no specific effect on a group level was found. No effect of aversive tension was found. Our results indicate that an improvement during the day might be a natural process of emotion identification, which is hindered in AN. Future research should focus on temporal relations between emotion identification and disordered eating behavior to further evaluate the clinical relevance of emotion identification difficulties in AN. PMID- 28667927 TI - The prevalence and outcomes of exposure to potentially traumatic stressful life events compared across patients with bipolar disorder and unipolar depression. AB - This study examined the profile of stressful life experiences in patients with unipolar depression (UP) compared to bipolar disorder (BP), including their subsequent psychological impact and affirmation of post-traumatic stress symptoms. We studied 747 tertiary patients diagnosed with either a UP (n = 413) or BP condition (n = 334) according to a structured research interview and psychiatrist assessment. An online assessment collected additional study variables. Results showed that despite being younger in age, the BP group were more likely to have experienced 8 of the stressful life events, including childhood and adulthood abuse. However, both groups judged the consequential 'impact' of those events similarly. The BP group was significantly more likely than the UP group (45% vs. 36%) to affirm exposure to an extremely stressful event across their lifetime, resulting in 26.3% of the BP and 14.5% of the UP group affirming DSM-IV criteria for lifetime PTSD. The onset of DSM-IV-defined post-traumatic symptoms tended to occur in adulthood for both groups, with trauma often following the onset of the mood disorder. Thus, BP patients displayed greater vulnerability toward traumatic experiences and anxiety disorders, but reported a similar psychological impact in response to each stressor, compared with the UP group. PMID- 28667928 TI - Affective and cognitive theory of mind abilities in youth with borderline personality disorder or major depressive disorder. AB - BACKGROUND: Theory of mind (ToM) is an important social cognitive ability that has been investigated in BPD, with inconsistent findings indicating impaired, comparable, and enhanced ToM in BPD. This study aimed to clarify and extend previous findings by investigating affective and cognitive ToM abilities in youth early in the course of BPD, by including a clinical comparison group of youth with major depressive disorder (MDD). METHODS: Female participants aged 15-24 years diagnosed with BPD (n = 41) or MDD (n = 37) completed the Reading the Mind in the Eyes Test (RMET) and Happe's Cartoon Task, measures of affective and cognitive dimensions of ToM, respectively. RESULTS: The BPD group performed significantly worse than the MDD group on the affective ToM task, even after controlling for age, intelligence and depressive symptoms. Results for cognitive ToM were not significantly different. CONCLUSIONS: Finding of poorer performance on a measure of affective ToM, in BPD youth, relative to youth with MDD early in the course of BPD suggest a developmental failure of sociocognitive abilities needed for mentalising and which are theorised as giving rise to core features of BPD. Future research should employ more naturalistic paradigms to study social cognition and should assess individuals even earlier in the course of BPD. PMID- 28667929 TI - Using lexical analysis to identify emotional distress in psychometric schizotypy. AB - Through the use of lexical analysis software, researchers have demonstrated a greater frequency of negative affect word use in those with schizophrenia and schizotypy compared to the general population. In addition, those with schizotypy endorse greater emotional distress than healthy controls. In this study, our aim was to expand on previous findings in schizotypy to determine whether negative affect word use could be linked to emotional distress. Schizotypy (n=33) and non schizotypy groups (n=33) completed an open-ended, semi-structured interview and negative affect word use was analyzed using a validated lexical analysis instrument. Emotional distress was assessed using subjective questionnaires of depression and psychological quality of life (QOL). When groups were compared, those with schizotypy used significantly more negative affect words; endorsed greater depression; and reported lower QOL. Within schizotypy, a trend level association between depression and negative affect word use was observed; QOL and negative affect word use showed a significant inverse association. Our findings offer preliminary evidence of the potential effectiveness of lexical analysis as an objective, behavior-based method for identifying emotional distress throughout the schizophrenia-spectrum. Utilizing lexical analysis in schizotypy offers promise for providing researchers with an assessment capable of objectively detecting emotional distress. PMID- 28667930 TI - Transected sciatic nerve repair by diode laser protein soldering. AB - BACKGROUND AND OBJECTIVE: Despite advances in microsurgical techniques, repair of peripheral nerve injuries (PNI) is still a major challenge in regenerative medicine. The standard treatment for PNI includes suturing and anasthomosis of the transected nerve. The objective of this study was to compare neurorraphy (nerve repair) using standard suturingto diode laser protein soldering on the functional recovery of transected sciatic nerves. STUDY DESIGN/MATERIALS AND METHODS: Thirty adult male Fischer-344 Wistar rats were randomly assigned to 3 groups: 1. The control group, no repair, 2. the standard of care suture group, and 3. The laser/protein solder group. For all three groups, the sciatic nerve was transected and the repair was done immediately. For the suture repair group, 10.0 prolene suture was used and for the laser/protein solder group a diode laser (500mW output power) in combination with bovine serum albumen and indocyanine green dye was used. Behavioral assessment by sciatic functional index was done on all rats biweekly. At 12weeks post-surgery, EMG recordings were done on all the rats and the rats were euthanized for histological evaluation of the sciatic nerves. The one-way ANOVA test was used for statistical analysis. RESULTS: The average time required to perform the surgery was significantly shorter for the laser-assisted nerve repair group compared to the suture group. The EMG evaluation revealed no difference between the two groups. Based on the sciatic function index the laser group was significantly better than the suture group after 12weeks (p<0.05). Histopathologic evaluation indicated that the epineurium recovery was better in the laser group (p<0.05). There was no difference in the inflammation between the suture and laser groups. CONCLUSION: Based on this evidence, laser/protein nerve soldering is a more efficient and efficacious method for repair of nerve injury compared to neurorraphy using standard suturing methods. PMID- 28667931 TI - The impact of high-dose narrowband ultraviolet A1 on dermal thickness, collagen and matrix-metalloproteinases in animal model of scleroderma. AB - OBJECTIVE: The main purpose of the present study was to define the impact of high dose of 365+/-5nm ultraviolet A1 (UVA1) on dermal fibrosis in the pre established, bleomycin-induced mouse model of scleroderma. METHODS: DBA/2 strain mice with the pre-established, bleomycin-induced scleroderma were irradiated with cumulative UVA1 dose of 1200J/cm2 and in parallel were challenged with prolonged administration of bleomycin. Non-treated groups served as the control. Light source emitting a narrow band UVA1 light of 365+/-5nm and 21mW/cm2 power density was used in the study. Histological analysis was performed for the evaluation of dermal thickness. The expressions of matrix-metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3), collagen types I and III were evaluated by immunohistochemical analyses. The Mann - Whitney U test was used for statistical analysis. RESULTS: Dermal thickness in mice injected with bleomycin during all the experiment (8weeks) and irradiated with UVA1 for the last 5weeks was significantly lower than that in mice challenged only with bleomycin for 8weeks (253.96+/-31.83MUm and 497.43+/-57.83MUm, respectively; P=0.002). The dermal thickness after phototherapy was lower as compared with the pre-existing fibrotic changes observed after 3weeks of bleomycin injections (253.96+/-31.83MUm and 443.87+/-41.76MUm, respectively; P=0.002). High-dose of UVA1 induced the 5.8- and 5.2-fold increase in MMP-1 and MMP-3 expressions, respectively, and the 1.2- and 1.4-fold decrease in collagen type I and collagen type III expressions in the pre established, bleomycin-induced scleroderma model as compared to that in the control non-irradiated mice (P=0.002). CONCLUSIONS: Our study has demonstrated that a cumulative 365+/-5nm UVA1 radiation dosage of 1200J/cm2 not only prevents the progression of dermal fibrosis, but also induces a regression of pre-existing fibrotic changes. PMID- 28667932 TI - Combined effects of water stress and pollution on macroinvertebrate and fish assemblages in a Mediterranean intermittent river. AB - Water stress is a key stressor in Mediterranean intermittent rivers exacerbating the negative effects of other stressors, such as pollutants, with multiple effects on different river biota. The current study aimed to determine the response of macroinvertebrate and fish assemblages to instream habitat and water chemistry, at the microhabitat scale and at different levels of water stress and pollution, in an intermittent Mediterranean river. Sampling was conducted at high and low summer discharge, at two consecutive years, and included four reaches that were targeted for their different levels of water stress and pollution. Overall, the macroinvertebrate fauna of Evrotas River indicated high resilience to intermittency, however, variation in community structure and composition occurred under acute water stress, due to habitat alteration and change in water physico-chemistry, i.e. water temperature increase. The combined effects of pollution and high water stress had, however, pronounced effects on species richness, abundance and community structure in the pollution impacted reach, where pollution sensitive taxa were almost extirpated. Fish response to drought, in reaches free of pollution, consisted of an increase in the abundance of the two small limnophilic species, coupled with their shift to faster flowing riffle habitats, and a reduction in the abundance of the larger, rheophilic species. In the pollution impacted reach, however, the combination of pollution and high water stress led to hypoxic conditions assumed to be the leading cause of the almost complete elimination of the fish assemblage. In contrast, the perennial Evrotas reaches with relatively stable physicochemical conditions, though affected hydrologically by drought, appear to function as refugia for fish during high water stress. When comparing the response of the two biotic groups to combined acute water stress and pollution, it is evident that macroinvertebrates were negatively impacted, but fish were virtually eliminated under the two combined stressors. PMID- 28667933 TI - Contrasting results of tests of peripheral vestibular function in patients with bilateral large vestibular aqueduct syndrome. AB - OBJECTIVE: To analyze and summarize the effect of bilateral large vestibular aqueducts in peripheral vestibular organ function. METHODS: Eighteen patients with bilateral large vestibular aqueduct syndrome (LVAS; Study Group) and 18 healthy volunteers (Control Group) were investigated using audiometry, caloric test, sensory organization test (SOT), and vestibular-evoked myogenic potential (VEMP) tests. RESULTS: All 18 patients (36 ears) exhibited sensorineural hearing loss. For cervical VEMP (cVEMP), the Study Group showed lower thresholds (Study Group vs. CONTROL GROUP: 71.4vs. 75.3dBnHL; p=0.006), N1 latencies (24.1vs. 25.2ms; p=0.026) and shorter P1 (15.3vs. 16.6ms; p=0.003), and higher amplitudes (400.7vs. 247.2uV; p<0.001) than the Control Group. For ocular VEMP (oVEMP), the Study Group had lower thresholds (79.3vs. 81.8dBnHL; p=0.046) and higher amplitudes (40.6vs. 14.4uV; p<0.001) than the Control Group. Fourteen of 16 patients (87.5%) who completed caloric tests had abnormal results, and 10 of 18 patients (55.6%) exhibited abnormal results in SOTs. CONCLUSIONS: The hyperfunction of vestibular test in otolithic organs and the hypofunction of vestibular test in semicircular canals, as well as the dysfunction in the balance test were demonstrated in patients with LVAS. SIGNIFICANCE: Our findings can help clinicians gain a better understanding of the characteristics of vestibular organ function in patients with LVAS, which can facilitate optimal targeted treatment. PMID- 28667934 TI - HIT and brain reward function: A case of mistaken identity (theory). AB - This paper employs a case study from the history of neuroscience-brain reward function-to scrutinize the inductive argument for the so-called 'Heuristic Identity Theory' (HIT). The case fails to support HIT, illustrating why other case studies previously thought to provide empirical support for HIT also fold under scrutiny. After distinguishing two different ways of understanding the types of identity claims presupposed by HIT and considering other conceptual problems, we conclude that HIT is not an alternative to the traditional identity theory so much as a relabeling of previously discussed strategies for mechanistic discovery. PMID- 28667935 TI - Internalization of Listeria monocytogenes in cantaloupes during dump tank washing and hydrocooling. AB - Recent listeriosis outbreaks and recalls associated with cantaloupes urge for studies to understand the mechanisms of cantaloupe contamination by Listeria monocytogenes. Postharvest practices such as washing and hydrocooling were suggested to facilitate the contamination of fresh fruits by human pathogens. This study assessed the potential of L. monocytogenes internalization into cantaloupes during dump tank washing and immersion-type hydrocooling in water contaminated with L. monocytogenes. The effect of cantaloupe cultivar, water temperature, and harvesting technique on L. monocytogenes internalization was also evaluated. Full slip (cantaloupe without any residual stem) Western and Eastern cultivar cantaloupes were pre-warmed to 42 degrees C (to imitate peak high field temperatures of freshly harvested cantaloupes) and then immersed in water at 6 degrees C and 18 degrees C containing 4 and 6logCFU/ml of L. monocytogenes. Clipped (cantaloupe with short stem residues obtained by clipping the stem at harvest) Western and Eastern cantaloupes were pre-warmed to 42 degrees C and then immersed in water at 6 degrees C containing 6logCFU/ml of L. monocytogenes. Additionally, full slip and clipped Western cantaloupes were equilibrated to 18 degrees C and then immersed in water at 18 degrees C containing 6logCFU/ml of L. monocytogenes (isothermal immersion without temperature differential). Water containing L. monocytogenes infiltrated both full slip and clipped cantaloupes through the stems/stem scars and was then distributed along the vascular system in hypodermal mesocarp reaching the calyx area of the fruit. The current study demonstrated that, under experimental conditions, L. monocytogenes can internalize into cantaloupes during immersion in water contaminated by L. monocytogenes, both in the presence and absence of temperature differential, and that temperature differential moderately enhanced the internalization of L. monocytogenes. The incidence and levels of L. monocytogenes internalized in the middle-mesocarp were significantly affected by harvesting technique but not by cantaloupe cultivar. PMID- 28667936 TI - Rapid screening of non-steroidal anti-inflammatory drugs illegally added in anti rheumatic herbal supplements and herbal remedies by portable ion mobility spectrometry. AB - In this work, for the first time, a high-performance ion mobility spectrometry with electrospray ionization (ESI-HPIMS) method has been employed as a rapid screening tool for the detection of acetaminophen, ibuprofen, naproxen, diclofenac sodium and indomethacin illegally added in anti-rheumatic herbal supplements and herbal remedies. Samples were dissolved and filtered through a 0.45MUm microporous membrane, then the filtrate was directly injected into the high-performance ion mobility spectrometry for analysis. Using this approach, the screening of illegal additions can be accomplished in as rapid as two to three minutes with no pretreatment required. The proposed method provided a LOD of 0.06 0.33MUgmL-1, as well as a good seperation of the five NSAIDs. The precision of the method was 0.1-0.4% (repeatability, n=6) and 0.9-3.3% (reproducibility, n=3). The proposed method appeared to be simple, rapid and highly specific, thus could be effective for the in-situ screening of NSAIDs in anti-rheumatic herbal supplements and herbal remedies. PMID- 28667937 TI - Metabolic profiling of the traditional Chinese medicine formulation Yu Ping Feng San for the identification of constituents relevant for effects on expression of TNF-alpha, IFN-gamma, IL-1beta and IL-4 in U937 cells. AB - Yu Ping Feng San (YPFS) is a classical TCM formulation which has been traditionally used for treatment of immune system related diseases such as chronic bronchitis, allergic rhinitis and asthma. The formula is a mixture of Radix Saposhnikoviae (Fangfeng), Radix Astragali (Huangqi), and Rhizoma Atractylodis macrocephalae (Baizhu). TLC- and LC-DAD-ESI-MS/MS methods have been developed for the analysis of the metabolic profiles of the single herbs and of the formula. Decoctions and ASE extracts were analyzed in order to trace components of the individual herbs in YPFS. Nine constituents of Radix Saposhnikoviae, ten constituents of Radix Astragali and five constituents of Rhizoma Atractylodis macrocephalae have been assigned in the chemical profiles of the formula, which now allow the standardisation of YPFS. The pharmacological testing showed that all extracts significantly inhibited expression of TNF-alpha, IFN-gamma, and IL-1beta in U937 cells, while the inhibition of IL-4 was consistently low. Compared to conventional analyses which are focused on a limited set of compounds, metabolomics approaches, together with novel data processing tools, enable a more holistic comparison of the herbal extracts. In order to identify the constituents which are relevant for the immunomodulatory effects of the formula, metabolomics studies (PCA, OPLS-DA) have been performed using UPLC/QTOF MS data. PMID- 28667939 TI - Validation of a novel nonlinear black box Wiener System model for arterial pulse transmission. AB - Numerous linear dynamic models exist for describing the arterial pulse transmission phenomenon. We introduce a novel Wiener system based model in which a linear filter representing large arteries is coupled with a hysteresis-free nonlinear function representing complex wave transmission of branching arteries and the periphery. Experimental datasets (n = 7) are used to first estimate the Wiener model with linear, quadratic and cubic function for the aorta to radial artery pulse transmission and aorta to femoral artery pulse transmission. To model the nonlinear memoryless monotonic function in the Wiener System model, a correlation study is performed for linear finite impulse response (FIR) filter simulated peripheral pressure vs. measured peripheral pressure waveform. Each of this correlation curves were fitted to linear, quadratic and cubic polynomial equation. Wiener model is then simulated for aortic-to-radial artery as well as aortic-to-femoral artery to reconstruct radial and femoral pressure waveform. It was found that Wiener model with 3rd order polynomial function yielded better modeling accuracy (with average RMSE = 2.187 mmHg for radial and 4.281 mmHg for femoral pressure) than that from 2nd order polynomial function (with average RMSE = 2.242 mmHg for radial and 4.355 mmHg for femoral pressure) which in turn was better than mere linear FIR filter (with average RMSE = 2.604 mmHg for radial and 4.810 mmHg for femoral pressure). PMID- 28667938 TI - Altered stress system reactivity after pediatric injury: Relation with post traumatic stress symptoms. AB - Injury is the leading cause of death and disability in childhood. Injured children are at high risk for developing alterations in stress response systems and post-traumatic stress symptoms (PTSS) that may compromise long-term physical and psychological health. In a prospective, observational cohort study, we examined individual differences in, and correlates of, stress-reactivity of the hypothalamic-pituitary-adrenal axis (HPA; salivary cortisol) and autonomic nervous system (ANS; salivary alpha amylase, sAA) following pediatric injury. Participants were 8-15 years of age and hospitalized for traumatic brain injury (TBI; n=55; M age=13.9 yrs; 40 males) or extracranial injury (EI; n=29; M age 12.3 yrs, 20 males) following vehicular accidents. Six months post-injury, saliva was collected before and after the Trier Social Stress Test and later assayed for cortisol and sAA. Relative to a healthy non-injured comparison group (n=33; M age=12.5 yrs, 16 males), injured children (ages 8-12 years), but not adolescents (ages 13-15 yrs), had higher cortisol levels; regardless of age, injured participants showed dampened cortisol reactivity to social evaluative threat. Compared to participants with EI, children with TBI had elevated cortisol and adolescents had elevated sAA. With respect to PTSS, individual differences in sAA were negatively correlated with avoidance in the TBI group and positively correlated with emotional numbing within the EI group. Importantly, psychological and neurobiological sequelae were weakly related to injury severity. Given the high prevalence of pediatric injury, these sequelae affect many children and represent a significant public health concern. Consequently, surveillance of post traumatic sequelae should include the full spectrum of injury severity. Monitoring the activity, reactivity, and regulation of biological systems sensitive to environmental insults may advance our understanding of individual differences in sequelae and adaptation following traumatic pediatric injury. PMID- 28667940 TI - Growth hormone-specific induction of the nuclear localization of porcine growth hormone receptor in porcine hepatocytes. AB - The phenomenon of nuclear translocation of growth hormone receptor (GHR) in human, rat, and fish has been reported. To date, this phenomenon has not been described in a domestic animal (such as pig). In addition, the molecular mechanisms of GHR nuclear translocation have not been thoroughly elucidated. To this end, porcine hepatocytes were isolated and used as a cell model. We observed that porcine growth hormone (pGH) can induce porcine GHR's nuclear localization in porcine hepatocytes. Subsequently, the dynamics of pGH-induced pGHR's nuclear localization were analyzed and demonstrated that pGHR's nuclear localization occurs in a time-dependent manner. Next, we explored the mechanism of pGHR nuclear localization using different pGHR ligands, and we demonstrated that pGHR's nuclear translocation is GH(s)-dependent. We also observed that pGHR translocates into cell nuclei in a pGH dimerization-dependent fashion, whereas further experiments indicated that IMPalpha/beta is involved in the nuclear translocation of the pGH-pGHR dimer. The pGH-pGHR dimer may form a pGH-GHR-JAK2 multiple complex in cell nuclei, which would suggest that similar to its function in the cell membrane, the nuclear-localized pGH-pGHR dimer might still have the ability to signal. PMID- 28667942 TI - Effects of parental alcohol rules on risky drinking and related problems in adolescence: Systematic review and meta-analysis. AB - BACKGROUND: It is unclear what effect parents' rules about their children's alcohol use have on drinking in adolescence. This review and meta-analysis investigated associations between prospectively measured parental alcohol rules and later adolescent risky drinking. METHODS: Using the PRISMA guidelines, we searched eight electronic databases for a variety of terms up to 10 September 2016. We imposed no restrictions on publication year. We assessed the risk of bias and conducted a meta-analysis. RESULTS: We identified 13 eligible studies in four groups of specific exposures for meta-analysis. The pooled overall estimate showed that when parents set rules concerning alcohol, their children were less likely to develop risky drinking and related problems (OR=0.64, 95% CI=0.48, 0.86). Pooled estimates illustrate that parental alcohol rules were significantly negatively associated with adolescent risky drinking and related problems (OR=0.73, 95% CI=0.53, 0.99), as was parental approval of alcohol use (inverse OR=0.41, 95% CI=0.34, 0.50). Neither parental permissiveness (inverse OR=0.83, 95% CI=0.59, 1.19) nor parental disapproval of alcohol use (OR=0.49, 95% CI=0.20, 1.20) was significantly associated with alcohol-related problems. However, the small number of studies and variability in the point estimates in these latter two groups of studies limits inferences. CONCLUSIONS: Parents' restrictiveness of their children's drinking was associated with lower risky drinking, but the risk of bias in the existing literature precludes strong inferences about the association. Further longitudinal studies with prospective measurement of parent behaviour, low attrition, and control for likely confounders, are needed. PMID- 28667941 TI - Trajectories of alcohol, marijuana, and illicit drug use in a diverse sample of young men who have sex with men. AB - INTRODUCTION: Cross-sectional research has found that young men who have sex with men (YMSM) are more likely to engage in heavy drinking and to have higher rates of marijuana and other illicit drug use compared to their heterosexual peers, but considerably less is known about their patterns of substance use over time. METHODS: In this study, we combined two longitudinal samples of racially diverse YMSM (N=552) and modeled their substance use trajectories from late-adolescence to young adulthood, including their frequency of alcohol use, frequency of marijuana use, and poly-drug use, using piecewise latent curve growth modeling to model change from ages 17-21 and change from ages 22-24. RESULTS: We found that all three substance use behaviors increased linearly over the adolescent-to-adult transition. The trajectories for all three substance use behaviors were significantly correlated from ages 17-21. Black YMSM had significantly lower growth from ages 17-21 in alcohol, marijuana, and poly-drug use compared to White YMSM. Hispanic/Latino YMSM had significantly higher growth from ages 22-24 in alcohol use but significantly lower growth in poly-drug use compared to White YMSM. YMSM with higher alcohol frequency slopes and YMSM with higher marijuana use slopes were more likely to have alcohol-related and marijuana-related problems, respectively, at the last wave of the study. CONCLUSIONS: The results of the present study suggest that the transition from adolescence to adulthood for YMSM is a time of increasing and co-varying substance use and may be a critical period for substance use behaviors to grow into substance use problems. PMID- 28667943 TI - Seed soaking in I and Se solutions increases concentrations of both elements and changes morphological and some physiological parameters of pea sprouts. AB - Pea (Pisum sativum L., cv. 'Petit Provencal') seeds were soaked in solutions of different iodine (I) and selenium (Se) forms (1000 mg I L-1 and 10 mg Se L-1). Iodine and selenium content in different parts of pea sprouts, as well as morphological, biochemical and physiological characteristics were measured in sprouts. The results showed increased concentrations of both elements in sprouts grown from treated seeds. Soaking influenced the biomass and height of the sprouts. Significant differences between plants grown from treated seeds in comparison with control plants were also observed for electron transport system activity and concentrations of tocopherol and glutathione. On the other hand, the content of photosynthetic pigments and anthocyanins remained similar as in control plants. Potential photochemical efficiency of photosystem II was close to theoretical maximum 0.8 in all samples. From the pattern of changes of stress indicators we suppose that plants adapted to the stress earlier in the experiment, i.e. before they were sampled for physiological measurements. PMID- 28667944 TI - Cavity resonator for dielectric measurements of high-epsilon, low loss materials, demonstrated with barium strontium zirconium titanate ceramics. AB - A resonant cavity method is presented which can measure loss tangents and dielectric constants for materials with dielectric constant from 150 to 10 000 and above. This practical and accurate technique is demonstrated by measuring barium strontium zirconium titanate bulk ferroelectric ceramic blocks. Above the Curie temperature, in the paraelectric state, barium strontium zirconium titanate has a sufficiently low loss that a series of resonant modes are supported in the cavity. At each mode frequency, the dielectric constant and loss tangent are obtained. The results are consistent with low frequency measurements and computer simulations. A quick method of analyzing the raw data using the 2D static electromagnetic modeling code SuperFish and an estimate of uncertainties are presented. PMID- 28667945 TI - Two-probe atomic-force microscope manipulator and its applications. AB - We report on a manipulator based on a two-probe atomic force microscope (AFM) with an individual feedback system for each probe. This manipulator works under an upright optical microscope with 3 mm focal distance. The design of the microscope helps us tomanipulate nanowires using the microscope probes as a two prong fork. The AFM feedback is realized based on the dynamic full-time contact mode. The applications of the manipulator and advantages of its two-probe design are presented. PMID- 28667946 TI - Position error correction of large-aperture aspherical in-position measurement. AB - An improved mathematical model of aspherical in-position measurement calibration is proposed in this paper, including hardware and software methods. The hardware method is used in rough calibration, but it is not precise enough. Then, the software method is chosen to further reduce the error. Simulation experiments are performed to demonstrate the effectiveness of this improved approach. Lastly, the model is verified through the testing of a concave aspheric surface. The experiment results show that the measurement errors of mirror after data processing can be reduced about 2 MUm. PMID- 28667947 TI - Note: Laser-cut molybdenum grids for a retarding field energy analyzer. AB - A retarding field energy analyzer (RFEA) with grids created by laser-cutting a honeycomb mesh in a 50 MUm thick molybdenum foil is presented. The flat grids span an area of 1 cm2 and have high transmission (20 MUm wide walls between 150 MUm wide meshes). The molybdenum grids were tested in a 3-grid RFEA configuration with an analyzer depth of 0.87 mm. PMID- 28667948 TI - Chamber for mechanical testing in H2 with observation by neutron scattering. AB - A gas-pressure chamber has been designed, constructed, and tested at a moderate pressure (3.4 MPa, 500 psi) and has the capability of mechanical loading of steel specimens for neutron scattering measurements. The chamber will allow a variety of in situ neutron scattering measurements: in particular, diffraction, quasielastic scattering, inelastic scattering, and imaging. The chamber is compatible with load frames available at the user facilities at the NIST Center for Neutron Research and Oak Ridge National Laboratory Spallation Neutron Source. A demonstration of neutron Bragg edge imaging using the chamber is presented. PMID- 28667949 TI - Edge-illumination x-ray phase contrast imaging with Pt-based metallic glass masks. AB - Edge-illumination x-ray phase contrast imaging (EI XPCI) is a non-interferometric phase-sensitive method where two absorption masks are employed. These masks are fabricated through a photolithography process followed by electroplating which is challenging in terms of yield as well as time- and cost-effectiveness. We report on the first implementation of EI XPCI with Pt-based metallic glass masks fabricated by an imprinting method. The new tested alloy exhibits good characteristics including high workability beside high x-ray attenuation. The fabrication process is easy and cheap, and can produce large-size masks for high x-ray energies within minutes. Imaging experiments show a good quality phase image, which confirms the potential of these masks to make the EI XPCI technique widely available and affordable. PMID- 28667950 TI - A novel large thrust-weight ratio V-shaped linear ultrasonic motor with a flexible joint. AB - A novel large thrust-weight ratio V-shaped linear ultrasonic motor with a flexible joint is proposed in this paper. The motor is comprised of a V-shaped transducer, a slider, a clamp, and a base. The V-shaped transducer consists of two piezoelectric beams connected through a flexible joint to form an appropriate coupling angle. The V-shaped motor is operated in the coupled longitudinal bending mode. Longitudinal and bending movements are transferred by the flexible joint between the two beams. Compared with the coupled longitudinal-bending mode of the single piezoelectric beam or the symmetrical and asymmetrical modes of the previous V-shaped transducer, the coupled longitudinal-bending mode of the V shaped transducer with a flexible joint provides higher vibration efficiency and more convenient mode conformance adjustment. A finite element model of the V shaped transducer is created to numerically study the influence of geometrical parameters and to determine the final geometrical parameters. In this paper, three prototypes were then fabricated and experimentally investigated. The modal test results match well with the finite element analysis. The motor mechanical output characteristics of three different coupling angles theta indicate that V 90 (theta = 90 degrees ) is the optimal angle. The mechanical output experiments conducted using the V-90 prototype (Size: 59.4 mm * 30.7 mm * 4 mm) demonstrate that the maximum unloaded speed is 1.2 m/s under a voltage of 350 Vpp, and the maximum output force is 15 N under a voltage of 300 Vpp. The proposed novel V shaped linear ultrasonic motor has a compact size and a simple structure with a large thrust-weight ratio (0.75 N/g) and high speed. PMID- 28667951 TI - Generation and application of LET calibration curve for neutron dosimetry using CR-39 detector and microwave induced chemical etching. AB - Microwave induced chemical etching (MICE) has been established as a faster and improved technique compared to other contemporary etching techniques for the development of tracks in a CR-39 detector. However, the methodology could not be applied for LET (linear energy transfer) spectrometry due to lack of a calibration curve using this method. For this purpose, a new LET calibration curve in the range of 12 keV/MUm-799 keV/MUm was generated considering different ions such as H, Li, C, O, and F on CR-39 having different LETs in water. An empirical relation was established from the obtained calibration curve for determining the value of LET (in water) from the value of V, the ratio of track etch rate to bulk etch rate. For application of this calibration curve in neutron dosimetry, CR-39 detectors were irradiated to neutrons generated from 120 and 142 MeV 16O+27Al systems followed by a similar MICE procedure. The absorbed dose (DLET) and the dose equivalent (HLET) were obtained from the LET spectra and were found to be 13% and 10% higher for 142 MeV 16O+27Al system than those for 120 MeV 16O+27Al system, respectively. The outcome of the study demonstrates the possibility of using the MICE technique for neutron dose estimation by CR-39 via LET spectrometry. PMID- 28667952 TI - Simultaneous measurement of thermal conductivity and heat capacity by flash thermal imaging methods. AB - Thermal properties are important for material applications involved with temperature. Although many measurement methods are available, they may not be convenient to use or have not been demonstrated suitable for testing of a wide range of materials. To address this issue, we developed a new method for the nondestructive measurement of the thermal effusivity of bulk materials with uniform property. This method is based on the pulsed thermal imaging-multilayer analysis (PTI-MLA) method that has been commonly used for testing of coating materials. Because the test sample for PTI-MLA has to be in a two-layer configuration, we have found a commonly used commercial tape to construct such test samples with the tape as the first-layer material and the bulk material as the substrate. This method was evaluated for testing of six selected solid materials with a wide range of thermal properties covering most engineering materials. To determine both thermal conductivity and heat capacity, we also measured the thermal diffusivity of these six materials by the well-established flash method using the same experimental instruments with a different system setup. This paper provides a description of these methods, presents detailed experimental tests and data analyses, and discusses measurement results and their comparison with literature values. PMID- 28667953 TI - Estimating two-point statistics from derivatives of a signal containing noise: Application to auto-correlation functions of turbulent Lagrangian tracks. AB - This article describes a method for calculating moments and correlation functions of signal derivatives, which were rid of experimental noise without the use of filtering operations. The method is based on the computation of the ensemble average of different time (or spatial) increments of the signal. The hypotheses are that the noise is white and not correlated with the signal; however, the method is also shown to work with colored noise. The method is first developed, considering white noise, and benchmarked with synthetic trajectories containing noise with variable signal-to-noise ratios. It is then tested on experimental trajectories in the context of Lagrangian tracking of particles in turbulent flows, either containing a short-correlated noise or a colored noise. PMID- 28667954 TI - Radioactive ion beams of 111In using ECR plasma sputtering method. AB - Radioactive ion beams of 111In (indium-111, half-life 2.8 days) have been produced using the plasma sputtering method in an electron cyclotron resonance (ECR) ion source at the Variable Energy Cyclotron Centre RIB facility. Indium isotopes were first produced by bombarding a natural silver target with a 32 MeV, 40 MUA alpha particle beam from the K-130 cyclotron. After radio-chemical separation, about 25 mCi In-chloride was deposited on an aluminum electrode and inserted in the plasma chamber of the ECR. Indium ions produced by ion induced sputtering in the plasma were extracted from the ion source, isotopically separated, and a pure 111In beam was measured at the focal plane of the separator. The measured 111In beam intensity was 2.67 * 105 particles/s for a beam energy of 5 keV. PMID- 28667955 TI - A pulse-to-pulse timing jitter measurement between two synchronized amplified laser beams for TTX. AB - In China, Tsinghua Thomson Scattering X-ray Source (TTX) is the dedicated hard X ray source based on the Thomson scattering between a terawatt ultrashort laser and a relativistic electron beam. In the TTX, two synchronized Ti: sapphire laser systems generate the terawatt ultrashort infrared scattering laser and the ultraviolet driving laser for the photocathode RF gun to produce the electron beam; measuring the timing jitter between the electron beam and the laser beam is an essential task for the X-ray source. In the present study, we report on a single shot, non-collinear cross correlator with fs resolution and measured the timing jitter between the two synchronized laser systems with a pulse-to-pulse method, which is beneficial to estimate the jitter of the X-ray yield in the TTX system. Although it is more important to synchronize the scattering laser to the electron beam and not of the driving laser, the laser-laser jitter measurement would be a good first step towards that goal, and the result generated can be considered as the error signal for the potential feedback stabilization. PMID- 28667956 TI - First demonstration of simultaneous measurement of beam current, beam position, and beam tilt on induction linac using combined B-dot monitor. AB - The authors previously reported that the axial B-dots can be used to directly measure the beam tilt and demonstrated that the axial B-dots are applicable to a coaxial calibration stand. In this study, a combined B-dot monitor composed of four axial B-dot loops and four azimuthal ones is tested for the simultaneous measurement of the time-varying beam current, beam offset, and beam tilt at the output of the injector of the DRAGON-I induction linac. In the experiments, the beam offset and beam tilt at the position of the monitor are proportionally adjusted using a pair of steering coils. Eight waveforms acquired from the B-dot monitor are analyzed to reconstruct the time-varying beam current, beam offset, and beam tilt. The original signals of both the azimuthal B-dot and the axial B dot ports change significantly with respect to the current applied to the steering coils. The measured beam tilt is linearly dependent on the current applied to the steering coils and agrees well with the measured beam offset. PMID- 28667957 TI - Sample exchange by beam scanning with applications to noncollinear pump-probe spectroscopy at kilohertz repetition rates. AB - In laser spectroscopy, high photon flux can perturb the sample away from thermal equilibrium, altering its spectroscopic properties. Here, we describe an optical beam scanning apparatus that minimizes repetitive sample excitation while providing shot-to-shot sample exchange for samples such as cryostats, films, and air-tight cuvettes. In this apparatus, the beam crossing point is moved within the focal plane inside the sample by scanning both tilt angles of a flat mirror. A space-filling spiral scan pattern was designed that efficiently utilizes the sample area and mirror scanning bandwidth. Scanning beams along a spiral path is shown to increase the average number of laser shots that can be sampled before a spot on the sample cell is resampled by the laser to ~1700 (out of the maximum possible 2500 for the sample area and laser spot size) while ensuring minimal shot-to-shot spatial overlap. Both an all-refractive version and an all reflective version of the apparatus are demonstrated. The beam scanning apparatus does not measurably alter the time delay (less than the 0.4 fs measurement uncertainty), the laser focal spot size (less than the 2 MUm measurement uncertainty), or the beam overlap (less than the 3.3% measurement uncertainty), leading to pump-probe and autocorrelation signal transients that accurately characterize the equilibrium sample. PMID- 28667958 TI - In situ chamber built for clarifying the relationship between methane hydrate crystal morphology and gas permeability in a thin glass micromodel cell. AB - We developed a novel in situ chamber to investigate the relationship between gas hydrate crystal morphology and gas permeability in a glass micromodel that mimics marine sediment. This high-pressure experimental chamber was able to use a thin glass cell without high pressure resistance. The formation of methane hydrate (MH) in the glass micromodel was observed in situ. We investigated the relationship between the MH growth rate and the degree of super cooling DeltaT. In addition, we successfully performed the in situ observation of both hydrate morphology and gas permeability measurement simultaneously. PMID- 28667959 TI - Note: Development of a wideband amplifier for cryogenic scanning tunneling microscopy. AB - A wideband cryogenic amplifier has been developed for low temperature scanning tunneling microscopy. The amplifier consisting of a wideband complementary metal oxide semiconductor field effect transistors operational amplifier together with a feedback resistor of 100 kOmega and a capacitor is mounted within a 4 K Dewar. This amplifier has a wide bandwidth and is successfully applied to scanning tunneling microscopy applications at low temperatures down to ~7 K. The quality of the designed amplifier is validated by high resolution imaging. More importantly, the amplifier has also proved to be capable of performing scanning tunneling spectroscopy measurements, showing the detection of the Shockley surface state of the Au(111) surface and the superconducting gap of Nb(110). PMID- 28667960 TI - A model combustor for studying a reacting jet in an oscillating crossflow. AB - This paper discusses a novel model combustion experiment that was built for studying the structure and dynamics of a reacting jet in an unsteady crossflow. A natural-gas-fired dump combustor is used to generate and sustain an acoustically oscillating vitiated flow that serves as the crossflow for transverse jet injection. Unlike most other techniques that are limited in operating pressure or acoustic amplitude, this method of generating an unsteady flow field is demonstrated at a pressure of 10 atm with peak-to-peak oscillation amplitudes approaching 20% of the mean pressure. An optically accessible test section designed for these conditions provides access for advanced laser and optical diagnostic measurements. Detailed measurements provide insight into the complex acoustic-hydrodynamic-combustion coupling processes and offer high-quality, high resolution validation data for numerical simulations. Careful instrumentation port design considerations for the higher amplitude acoustics are detailed. As a whole, this paper focuses on select representative segments of the experiment operational space that highlight our strategy of providing an oscillatory flowfield. This includes presenting the acoustic operational space such as acoustic amplitudes, frequencies, and mode shapes. Select imaging results are then reported to support our strategies capability to produce high-fidelity measurements. PMID- 28667961 TI - Novel design of high voltage pulse source for efficient dielectric barrier discharge generation by using silicon diodes for alternating current. AB - This work focuses on design, construction, and optimization of configuration of a novel high voltage pulse power source for large-scale dielectric barrier discharge (DBD) generation. The pulses were generated by using the high-speed switching characteristic of an inexpensive device called silicon diodes for alternating current and the self-terminated characteristic of DBD. The operation started to be powered by a primary DC low voltage power supply flexibly equipped with a commercial DC power supply, or a battery, or DC output of an independent photovoltaic system without transformer employment. This flexible connection to different types of primary power supply could provide a promising solution for the application of DBD, especially in the area without power grid connection. The simple modular structure, non-control requirement, transformer elimination, and a minimum number of levels in voltage conversion could lead to a reduction in size, weight, simple maintenance, low cost of installation, and high scalability of a DBD generator. The performance of this pulse source has been validated by a load of resistor. A good agreement between theoretically estimated and experimentally measured responses has been achieved. The pulse source has also been successfully applied for an efficient DBD plasma generation. PMID- 28667962 TI - Development of multi-channel apparatus for electron-atom Compton scattering to study the momentum distribution of atoms in a molecule. AB - We have developed multi-channel apparatus for electron-atom Compton scattering to study the momentum distribution of atoms in a molecule. It combines the features of both a spherical electron energy analyzer and a large-area position sensitive detector, thereby having an ability to cover almost completely the azimuthal angle range available for quasi-elastic electron Rutherford backscattering at an angle of 135 degrees . Details and performance of the apparatus are reported, together with experimental results measured for Xe and CH4 at an incident electron energy of 2 keV. In particular, it is shown that the instrumental sensitivity is remarkably high, which has increased the signal count rate by nearly three orders of magnitude compared to existing setups. This technical progress would be useful for advancing atomic momentum spectroscopy studies. PMID- 28667963 TI - Cryogenic loading of argon pressure medium in diamond anvil high pressure cells with in situ pressure determination. AB - A versatile system for cryogenic loading of argon pressure medium into the sample space of a diamond anvil cell has been developed. The system has been designed such that, with suitable adaptors, a wide range of diamond anvil cell designs can be pressurized. The pressure in the cell can be monitored during pressurization using the ruby fluorescence method via optical fiber access into the loading chamber. This enables the precise and accurate setting of the loading pressure in the cell. PMID- 28667964 TI - A high-resolution programmable Vernier delay generator based on carry chains in FPGA. AB - This paper presents an architecture of a high-resolution delay generator implemented in a single field programmable gate array chip by exploiting the method of utilizing dedicated carry chains. It serves as the core component in various physical instruments. The proposed delay generator contains the coarse delay step and the fine delay step to guarantee both large dynamic range and high resolution. The carry chains are organized in the Vernier delay loop style to fulfill the fine delay step with high precision and high linearity. The delay generator was implemented in the EP3SE110F1152I3 Stratix III device from Altera on a self-designed test board. Test results show that the obtained resolution is 38.6 ps, and the differential nonlinearity/integral nonlinearity is in the range of [-0.18 least significant bit (LSB), 0.24 LSB]/(-0.02 LSB, 0.01 LSB) under the nominal supply voltage of 1100 mV and environmental temperature of 20 degrees C. The delay generator is rather efficient concerning resource cost, which uses only 668 look-up tables and 146 registers in total. PMID- 28667965 TI - Coaxial CVD diamond detector for neutron diagnostics at ShenGuang III laser facility. AB - A coaxial, high performance diamond detector has been developed for neutron diagnostics of inertial confinement fusion at ShenGuangIII laser facility. A Phi10 mm * 1 mm "optical grade" chemical-vapor deposition diamond wafer is assembled in coaxial-designing housing, and the signal is linked to a SubMiniature A connector by the cathode cone. The coaxial diamond detector performs excellently for neutron measurement with the full width at half maximum of response time to be 444 ps for a 50 Omega measurement system. The average sensitivity is 0.677 MUV ns/n for 14 MeV (DT fusion) neutrons at an electric field of 1000 V/mm, and the linear dynamic range is beyond three orders of magnitude. The ion temperature results fluctuate widely from the neutron time-of flight scintillator detector results because of the short flight length. These characteristics of small size, large linear dynamic range, and insensitive to x ray make the diamond detector suitable to measure the neutron yield, ion temperature, and neutron emission time. PMID- 28667966 TI - Three-dimensional characterization of tightly focused fields for various polarization incident beams. AB - Tightly focused vectorial optical beams have found extensive applications in variety of technical fields like single-molecule detection, optical tweezers, and super-resolution optical microscopy. Such applications require an accurate measurement and manipulation of focal optical fields. We have developed a compact instrument (with dimensions of 35 * 35 * 30 cm3) to rapidly measure the intensity distribution in three dimensions of the focused fields of vectorial beams and any other incident beams. This instrument employs a fluorescent nanoparticle as a probe to scan the focal region to obtain a high spatial resolution of intensity distribution. It integrates a liquid-crystal spatial light modulator to allow for tailoring the point spread function of the optical system, making it a useful tool for multi-purpose and flexible research. The robust applicability of the instrument is verified by measuring the 3D intensity distributions of focal fields of various polarization and wavefront modulated incident beams focused by a high NA (=1.25) objective lens. The minimal data acquisition time achievable in the experiment is about 8 s for a scanning region of 3.2 * 3.2 MUm2 (512 * 512 pixels). The measured results are in good agreement with those predicted by the vectorial diffraction theory. PMID- 28667967 TI - Experimental helium liquefier with a GM cryocooler. AB - A helium liquefier has been developed with a Gifford-McMahon cryocooler using the cold enthalpy available at the first stage, the inter-stage, and the second stage of the cryocooler. Most of the enthalpy of the helium gas at 300 K is absorbed in the first stage by a coaxial heat exchanger and inter-stage region of the cryocooler. Pre-cooled helium gas is liquefied at the second stage heat exchanger where the final cooldown and condensation happens. The measured production capacity of the liquefier is 17.4 l/day at atmospheric pressure. The whole setup has been designed to work in a coaxial configuration where the two heat exchangers, the cryostat, and the dewar are symmetrically placed around the central axis. PMID- 28667968 TI - Fast x-ray detector system with simultaneous measurement of timing and energy for a single photon. AB - We developed a fast X-ray detector system for nuclear resonant scattering (NRS) experiments. Our system employs silicon avalanche photo-diode (Si-APD) as a fast X-ray sensor. The system is able to acquire both timing and energy of a single X ray photon simultaneously in a high rate condition, 106 counts per second for one Si-APD. The performance of the system was investigated in SPring-8, a synchrotron radiation facility in Japan. Good time resolution of 120 ps (FWHM) was achieved with a slight tail distribution in the time spectrum by a level of 10-9 at 1 ns apart from the peak. Using this system, we successfully observed the NRS from the 26.27-keV level of mercury-201, which has a half-life of 630(50) ps. We also demonstrated the reduction of background events caused by radioactive decays in a radioactive sample by discriminating photon energy. PMID- 28667969 TI - Direct measurements of safety factor profiles with motional Stark effect for KSTAR tokamak discharges with internal transport barriers. AB - The safety factor profile evolutions have been measured from the plasma discharges with the external current drive mechanism such as the multi-ion-source neutral beam injection for the Korea Superconducting Tokamak Advanced Research (KSTAR) for the first time. This measurement has been possible by the newly installed motional Stark effect (MSE) diagnostic system that utilizes the polarized Balmer-alpha emission from the energetic neutral deuterium atoms induced by the Stark effect under the Lorentz electric field. The 25-channel KSTAR MSE diagnostic is based on the conventional photoelastic modulator approach with the spatial and temporal resolutions less than 2 cm (for the most of the channels except 2 to 3 channels inside the magnetic axis) and about 10 ms, respectively. The strong Faraday rotation imposed on the optical elements in the diagnostic system is calibrated out from a separate and well-designed polarization measurement procedure using an in-vessel reference polarizer during the toroidal-field ramp-up phase before the plasma experiment starts. The combination of the non-inductive current drive during the ramp-up and shape control enables the formation of the internal transport barrier where the pitch angle profiles indicate flat or slightly hollow profiles in the safety factor. PMID- 28667970 TI - Adaptive pseudo-color enhancement method of weld radiographic images based on HSI color space and self-transformation of pixels. AB - The radiographic testing (RT) image of a steam turbine manufacturing enterprise has the characteristics of low gray level, low contrast, and blurriness, which lead to a substandard image quality. Moreover, it is not conducive for human eyes to detect and evaluate defects. This study proposes an adaptive pseudo-color enhancement method for weld radiographic images based on the hue, saturation, and intensity (HSI) color space and the self-transformation of pixels to solve these problems. First, the pixel's self-transformation is performed to the pixel value of the original RT image. The function value after the pixel's self transformation is assigned to the HSI components in the HSI color space. Thereafter, the average intensity of the enhanced image is adaptively adjusted to 0.5 according to the intensity of the original image. Moreover, the hue range and interval can be adjusted according to personal habits. Finally, the HSI components after the adaptive adjustment can be transformed to display in the red, green, and blue color space. Numerous weld radiographic images from a steam turbine manufacturing enterprise are used to validate the proposed method. The experimental results show that the proposed pseudo-color enhancement method can improve image definition and make the target and background areas distinct in weld radiographic images. The enhanced images will be more conducive for defect recognition. Moreover, the image enhanced using the proposed method conforms to the human eye visual properties, and the effectiveness of defect recognition and evaluation can be ensured. PMID- 28667971 TI - Controllable picoliter pipetting using hydrophobic microfluidic valves. AB - A picoliter pipetting technique using the microfluidic method is presented. Utilizing the hydrophobic self-assembled monolayer films patterned in microchannels as pressure-controlled valves, a small volume of liquid can be separated by a designed channel trap and then ejected from the channel end at a higher pressure. The liquid trap section is composed of a T-shaped channel junction and a hydrophobic patch. The liquid volume can be precisely controlled by varying the distance of the hydrophobic patch from the T-junction. By this means, liquid less than 100 pl can be separated and pipetted. The developed device is potentially useful for sample dispensing in biological, medical, and chemical applications. PMID- 28667972 TI - Note: Current induced fluctuations in the orientation of the beam diffracted by a liquid crystal spatial light modulator. AB - In this paper, we report a peculiar movement of the beam cross sections associated with both the diffracted and undiffracted laser beams from a liquid crystal spatial light modulator (LCSLM). The beam movement becomes noticeable when the beam position is monitored continuously for several hours. We perform experiments to show that the beam movement is non-mechanical in nature and is connected with the power on/off instants of the LCSLM as well as the heat conductivity of the mounting slab which acts as the rigid support to the LCSLM panel. We also present a detailed analysis of the experimental findings to ascertain the possible cause of the beam fluctuations. PMID- 28667973 TI - Highly efficient angularly resolving x-ray spectrometer optimized for absorption measurements with collimated sources. AB - Highly collimated betatron radiation from a laser wakefield accelerator is a promising tool for spectroscopic measurements. Therefore, there is a requirement to create spectrometers suited to the unique properties of such a source. We demonstrate a spectrometer which achieves an energy resolution of <5 eV at 9 keV (E/DeltaE>1800) and is angularly resolving the x-ray emission allowing the reference and spectrum to be recorded at the same time. The single photon analysis is used to significantly reduce the background noise. Theoretical performance of various configurations of the spectrometer is calculated by a ray tracing algorithm. The properties and performance of the spectrometer including the angular and spectral resolution are demonstrated experimentally on absorption above the K-edge of a Cu foil backlit by a laser-produced betatron radiation x ray beam. PMID- 28667974 TI - Implementation and modeling of a femtosecond laser-activated streak camera. AB - A laser-activated streak camera was built to measure the duration of femtosecond electron pulses. The streak velocity of the device is 1.89 mrad/ps, which corresponds to a sensitivity of 34.9 fs/pixels. The streak camera also measures changes in the relative time of arrival between the laser and electron pulses with a resolution of 70 fs RMS. A full circuit analysis of the structure is presented to describe the streaking field and the general behavior of the device. We have developed a general mathematical model to analyze the streaked images. The model provides an accurate method to extract the pulse duration based on the changes of the electron beam profile when the streaking field is applied. PMID- 28667975 TI - Note: Fabrication of roughened tips for liquid metal ion sources. AB - In a liquid metal ion source (LMIS), the radius and the surface texture of the LMIS needle tip are demonstrated to have great effect on the I-V characteristics and the threshold voltages. In this paper, the dependence of the AC electrochemical etching parameters on the radius and the surface texture of the needle tip is investigated experimentally. A new method for fabricating the needle tip with the designed radius and texture for the LMIS is proposed. In this method, the roughening of a needle tip consists of two processes: a short time high AC voltage etching process and a long time low AC voltage etching process. The performances of the presented method are validated by a number of experiments. PMID- 28667976 TI - Note: A novel cantilever beam for low-frequency high performance piezoelectric geophone. AB - A multilayer spiral-corrugated cantilever beam was developed as an improvement for a conventional single-layer flat cantilever beam to improve the performance of a piezoelectric geophone adopting polyvinylidene fluoride film for low frequency seismic vibration measurement. The proposed structure is longer and has less stiffness compared with the conventional beam, so the piezoelectric geophone adopting the developed cantilever beam has a lower natural frequency. To confirm the validity of the design, the finite element analysis was conducted and the results showed that the natural frequency of the geophone with the multilayer spiral-corrugated cantilever beam is much lower and the corrugated structure can improve the sensitivity of the geophone. PMID- 28667978 TI - VISdish: A new tool for canting and shape-measuring solar-dish facets. AB - Solar dishes allow us to obtain highly concentrated solar fluxes used to produce electricity or feed thermal processes/storage. For practical reasons, the reflecting surface is composed by a number of facets. After the dish assembly, facet-canting is an important task for improving the concentration of solar radiation around the focus-point, as well as the capture ratio at the receiver placed there. Finally, flux profile should be measured or evaluated to verify the concentration quality. All these tasks can be achieved by the new tool we developed at ENEA, named VISdish. The instrument is based on the visual inspection system (VIS) approach and can work in two functionalities: canting and shape-measurement. The shape data are entered in a simulation software for evaluating the flux profile and concentration quality. With respect to prior methods, VISdish offers several advantages: (i) simpler data processing, because light point-source and its reflections are univocally related, (ii) higher accuracy. The instrument functionality is illustrated through the preliminary experimental results obtained on the dish recently installed in ENEA-Casaccia in the framework of the E.U. project OMSoP. PMID- 28667977 TI - High-precision, accurate optical frequency reference using a Fabry-Perot diode laser. AB - We show that the optical output of a temperature and current-tuned Fabry-Perot diode laser system, with no external optical feedback and in which the frequency is locked to Doppler-free hyperfine resonances of the 87Rb D2 line, can achieve high frequency stability and accuracy. Experimental results are presented for the spectral linewidth, frequency stability, and frequency accuracy of the source. Although our optical source is limited by a short-term spectral linewidth greater than 2 MHz, beat signal measurements from two such sources demonstrate a frequency stability of 1.1 kHz, or minimum Allan deviation of 4*10-12, at an integration time tau=15 s and with a frequency accuracy of 60 kHz at tau=300 s. We demonstrate the use of the optical source for the precision measurement of hyperfine level frequency spacings in the 5P3/2 excited state of 87Rb and provide an accurate frequency scale for optical spectroscopy. PMID- 28667979 TI - Optical derotator alignment using image-processing algorithm for tracking laser vibrometer measurements of rotating objects. AB - An optical component called a Dove prism is used to rotate the laser beam of a laser-scanning vibrometer (LSV). This is called a derotator and is used for measuring the vibration of rotating objects. The main advantage of a derotator is that it works independently from an LSV. However, this device requires very specific alignment, in which the axis of the Dove prism must coincide with the rotational axis of the object. If the derotator is misaligned with the rotating object, the results of the vibration measurement are imprecise, owing to the alteration of the laser beam on the surface of the rotating object. In this study, a method is proposed for aligning a derotator with a rotating object through an image-processing algorithm that obtains the trajectory of a landmark attached to the object. After the trajectory of the landmark is mathematically modeled, the amount of derotator misalignment with respect to the object is calculated. The accuracy of the proposed method for aligning the derotator with the rotating object is experimentally tested. PMID- 28667980 TI - Noise characterization of analog to digital converters for amplitude and phase noise measurements. AB - Improvements on electronic technology in recent years have allowed the application of digital techniques in phase noise metrology, where low noise and high accuracy are required, yielding flexibility in system implementation and setup. This results in measurement systems with extended capabilities, additional functionalities, and ease of use. In most digital schemes, the Analog to Digital Converters (ADCs) set the ultimate performance of the system; therefore the proper selection of this component is a critical issue. Currently, the information available in the literature describes in depth the ADC features only at frequency offsets far from the carrier. However, the performance close to the carrier is a more important concern. As a consequence, the ADC noise is, in general, analyzed on the implemented phase measurement setup. We propose a noise model for ADCs and a method to estimate its parameters. The method retrieves the phase modulation and amplitude modulation noise by sampling around zero and maximum amplitude, a test sine-wave synchronous with the ADC clock. The model allows discriminating the ADC noise sources and obtaining the phase noise and amplitude noise power spectral densities from 10 Hz to one half of the sampling frequency. This approach reduces the data processing, allowing an efficient ADC evaluation in terms of hardware complexity and computational cost. PMID- 28667981 TI - Full area covered 3D profile measurement of special-shaped optics based on a new prototype non-contact profiler. AB - A new prototype non-contact profiler based on surface tracking has been specially developed. Surface tracking is carried out by a specially designed dual stage probe system with the aid of a four-Degree Of Freedom high-precision motion platform. The dual stage probe system keeps a short-range optical probe constantly tracking the surface by a self-developed voice coil motor servo, by which a wide measuring range of up to 10 mm is realized. The system performance evaluation including resolution, repeatability, and scanning speed proved the good capability of the new prototype non-contact profiler. To realize a full area covered 3D profile measurement of special-shaped optics within one scanning procedure, a signal intensity monitor integrated in the surface tracking controller is specially developed. In the experiment, a snip-single-corner rectangular-shaped freeform surface was successfully measured over full area by the new non-contact profiler. This work provides an effective solution for 3D profile measurement of special-shaped optical surfaces over full reflecting area. Experimental results demonstrate that the proposed measuring system is of great significance in quality evaluation of optical surfaces. PMID- 28667982 TI - A gyro-stabilized platform leveling loop for marine gravimeter. AB - An ultra-low-frequency platform leveling loop based on a mixed sensitivity Hinfinity approach, which considers both the system bandwidth and response speed, was designed and applied to a prototype, two-axis gyro-stabilized platform marine gravimeter CHZ-II. The instrument was developed for regional surveys in deep ocean areas where high-resolution gravity measurements with accuracy 1 mGal are required. Horizontal accelerations in the surge and sway directions are suppressed about 60 dB in the frequency range 0.05 to 0.5 Hz. This typically improves the quality of the gravity data before any processing corrections. The time required for stabilizing the platform at the beginning of a survey line or course change is about 3 min, which improves the data collection efficiency. In May 2015, the first test was conducted in open sea conditions aboard the Chinese State Oceanic Administration's R/V Xiangyanghong 10. Sixteen traverses were run in the South China Sea to evaluate the loop performance. Platform motion tracks and gravity data from the survey were of satisfactory quality. According to analyses of 16 sets of calculated errors, the root mean square repeatability of the pitch and roll off-level angles were less than 10 and 20 arc sec, respectively, with a horizontal acceleration of about 50 Gal. Errors derived from the inability of the platform to maintain perfect sensor leveling during the survey cruise were less than 0.3 mGal. PMID- 28667983 TI - Note: Coaxial-heater hollow cathode. AB - The design and tests of a LaB6 hollow cathode with a novel heater are presented. In the new design, the heater wire is completely encapsulated around the cathode tube and a coaxial return electrode, thereby eliminating hot spots on the heater wire due to the free hanging regions. Since the new heater confines the Joule heating to the region of interest, where the LaB6 emitter is placed, the heater terminals are further secured from overheating. The cathode with the presented heater design has been successfully tested and is able to deliver currents in the 0.5-15 A range. PMID- 28667984 TI - Ion mass and energy selective hyperthermal ion-beam assisted deposition setup. AB - For the synthesis of high-quality thin films, ion-beam assisted deposition (IBAD) is a frequently used technique providing precise control over several substantial film properties. IBAD typically relies on the use of a broad-beam ion source. Such ion sources suffer from the limitation that they deliver a blend of ions with different ion masses, each of them possessing a certain distribution of kinetic energy. In this paper, a compact experimental setup is presented that enables the separate control of ion mass and ion kinetic energy in the region of hyperthermal energies (few 1 eV - few 100 eV). This ion energy region is of increasing interest not only for ion-assisted film growth but also for the wide field of preparative mass spectrometry. The setup consists of a constricted glow discharge plasma beam source and a tailor-made, compact quadrupole system equipped with entry and exit ion optics. It is demonstrated that the separation of monoatomic and polyatomic nitrogen ions (N+ and N2+) is accomplished. For both ion species, the kinetic energy is shown to be selectable in the region of hyperthermal energies. At the sample position, ion current densities are found to be in the order of 1 MUA/cm2 and the full width at half maximum of the ion beam profile is in the order of 10 mm. Thus, the requirements for homogeneous deposition processes in sufficiently short periods of time are fulfilled. Finally, employing the described setup, for the first time in practice epitaxial GaN films were deposited. This opens up the opportunity to fundamentally study the influence of the simultaneous irradiation with hyperthermal ions on the thin film growth in IBAD processes and to increase the flexibility of the technique. PMID- 28667985 TI - CCD camera as feasible large-area-size x-ray detector for x-ray fluorescence spectroscopy and imaging. AB - As X-ray fluorescence radiation isotropically spreads from the sample, one of the most important requirements for spectrometers for many years has been a large solid angle. Charge-coupled device (CCD) cameras are quite promising options because they have a fairly large area size, usually larger than 150 mm2. The present work has examined the feasibility of a commercially available camera with an ordinary CCD chip (1024 * 1024 pixels, the size of one pixel is 13 MUm * 13 MUm, designed for visible light) as an X-ray fluorescence detector. As X-ray photons create charges in the CCD chip, reading very quickly the amount is the key for this method. It is very simple if the charges always go into one pixel. As the charges quite often spread to several pixels, and sometimes can be lost, it is important to recover the information by filtering out the unsuccessful events. For this, a simple, versatile, and reliable scheme has been proposed. It has been demonstrated that the energy resolution of the present camera is 150 eV at Mn Kalpha, and also that its overall achievement in seeing minor elements is almost compatible with conventional X-ray fluorescence detectors. When the CCD camera is combined with a micro-pinhole collimator, full field X-ray fluorescence imaging with a spatial resolution of 20 MUm becomes possible. Further feasibility in practical X-ray fluorescence analysis is discussed. PMID- 28667986 TI - A novel sensor for two-degree-of-freedom motion measurement of linear nanopositioning stage using knife edge displacement sensing technique. AB - This paper presents a novel method for measuring two-degree-of-freedom (DOF) motion of flexure-based nanopositioning systems based on optical knife-edge sensing (OKES) technology, which utilizes the interference of two superimposed waves: a geometrical wave from the primary source of light and a boundary diffraction wave from the secondary source. This technique allows for two-DOF motion measurement of the linear and pitch motions of nanopositioning systems. Two capacitive sensors (CSs) are used for a baseline comparison with the proposed sensor by simultaneously measuring the motions of the nanopositioning system. The experimental results show that the proposed sensor closely agrees with the fundamental linear motion of the CS. However, the two-DOF OKES technology was shown to be approximately three times more sensitive to the pitch motion than the CS. The discrepancy in the two sensor outputs is discussed in terms of measuring principle, linearity, bandwidth, control effectiveness, and resolution. PMID- 28667987 TI - Electrostatic simulation of a complete cluster deposition apparatus. AB - A complete electrostatic model of a cluster deposition apparatus is presented using SIMION. It consists of fifteen different ion optical components including a quadrupole mass filter and a quadrupole ion deflector. The accuracy of the model was tested by comparing calculated cationic cluster transmissions with experimental ion currents by varying the electrostatic potential of different components. Considering the negatively charged particles produced by the magnetron cluster source as a charged background with a density of 5?10-7 cm-3, the influence of the first components on cluster transmission is well reproduced in comparison to the experimental results. This background was included by increasing the charge of the clusters from zero to an elementary charge using a sigmoidal function. The inflection point of this function was found to depend on the first components' electrostatic potential but in good approximation, not on later ones. All of the calculated transmissions represent the experimental data quite well; therefore, the simulation is validated and helps us to understand the influence of the electrostatic components on cluster transmission and improve the target efficiency. Furthermore, this understanding opens the possibility for a global optimization scheme to be employed in the ion optics' geometries. PMID- 28667988 TI - An oil-free compact X-pinch plasma radiation source: Design and radiation performance. AB - This paper describes a new, high-current, X-pinch radiation source recently developed and tested at Idaho State University. Our design is based on two linear transformer driver (LTD) bricks arranged in side-by-side geometry and directly coupled with an X-pinch load. The salient features of our 2-LTD-bricks are its simplicity, compactness, and portability: there is no oil, no water, and no SF6. It can be easily relocated to any place where a compact X-pinch radiation source is wanted. The driver can store up to 2.8 kJ of initial energy and can deliver more than 200-kA peak-current with less than 200-ns, 10%-90%, rise time into a short-circuit load. When the driver is coupled with an X-pinch load, it generates a very fast and bright radiation pulse. Source size measurements indicate that this radiation originates from a very small dense plasma, known as a "hot spot." PMID- 28667990 TI - Note: A new optical method for the detection of bubble nucleation in superheated droplet detector. AB - A superheated droplet detector (SDD) consists of a large number of micron-sized superheated liquid drops suspended in a gel medium. The vaporization of a superheated drop is associated with the emission of an acoustic signal. A novel optical method is developed for the detection of this acoustic signal. In this method, a probe-bubble picks up the acoustic signal, and the oscillation of the probe-bubble is detected by employing a laser and phototransistor. The method can detect vaporization of an individual superheated drop in real-time and can be used for studying the response of SDDs to ionizing radiations. PMID- 28667991 TI - Erratum: "A piezoelectric cryogenic heat switch" [Rev. Sci. Instrum. 85, 065118 (2014)]. PMID- 28667992 TI - Anti-saturation system for surface nuclear magnetic resonance in efficient groundwater detection. AB - Compared to other geophysical techniques, the surface nuclear magnetic resonance (SNMR) method could provide unique insights into the hydrologic properties of groundwater in the subsurface. However, the SNMR signal is in the order of nanovolts (10-9 V), and the complex environmental noise, i.e., the spike and the harmony noise (10-4 V), can reach up to 105 times the signal amplitude. Saturation of the amplifier is therefore a serious problem in current SNMR systems. In this study, we propose an anti-saturation method based on an instantaneous floating-point amplifier. The gain of a programmable amplifier is controlled by the value of the input signal. A regulating speed of 50 kS/s is thus achieved to satisfy the self-adaptive adjustment of the real-time SNMR system, which replaces the original man-made setting gain. A large dynamic range of 192.65 dB with a 24-bit high speed analog-digital converter module is then implemented. Compared to traditional SNMR instruments, whose magnification factor is fixed during the experiment, our system can effectively inhibit the distortion of the SNMR signal in both laboratory and field settings. Furthermore, an improved SNR, which is realized by the real-time SNMR system, enables the accurate inversion of the aquifer. Our study broadens the applicability of SNMR systems to use in and around developed areas. PMID- 28667993 TI - Experimental percolation studies of random networks. AB - This report establishes an experimental method of studying electrically percolating networks at a higher resolution than previously implemented. This method measures the current across a conductive sheet as a function of time as elliptical pores are cut into the sheet. This is done utilizing a Universal Laser System X2-600 100 W CO2 laser system with a 76 * 46 cm2 field and 394 dpc (dots/cm) resolution. This laser can cut a random system of elliptical pores into a conductive sheet with a potential voltage applied across it and measures the current versus time. This allows for experimental verification of a percolation threshold as a function of the ellipse's aspect ratio (minor/major diameter). We show that as an ellipse's aspect ratio approaches zero, the percolation threshold approaches one. The benefit of this method is that it can experimentally measure the effect of removing small pores, as well as pores with complex geometries, such as an asterisk from a conductive sheet. PMID- 28667994 TI - VIS-NIR multispectral synchronous imaging pyrometer for high-temperature measurements. AB - A visible-infrared multispectral synchronous imaging pyrometer was developed for simultaneous, multispectral, two-dimensional high temperature measurements. The multispectral image pyrometer uses prism separation construction in the spectrum range of 650-950 nm and multi-sensor fusion of three CCD sensors for high temperature measurements. The pyrometer had 650-750 nm, 750-850 nm, and 850-950 nm channels all with the same optical path. The wavelength choice for each channel is flexible with three center wavelengths (700 nm, 810 nm, and 920 nm) with a full width at half maximum of the spectrum of 3 nm used here. The three image sensors were precisely aligned to avoid spectrum artifacts by micro mechanical adjustments of the sensors relative to each other to position them within a quarter pixel of each other. The pyrometer was calibrated with the standard blackbody source, and the temperature measurement uncertainty was within 0.21 degrees C-0.99 degrees C in the temperatures of 600 degrees C-1800 degrees C for the blackbody measurements. The pyrometer was then used to measure the leading edge temperatures of a ceramics model exposed to high-enthalpy plasma aerodynamic heating environment to verify the system applicability. The measured temperature ranges are 701-991 degrees C, 701-1134 degrees C, and 701-834 degrees C at the heating transient, steady state, and cooling transient times. A significant temperature gradient (170 degrees C/mm) was observed away from the leading edge facing the plasma jet during the steady state heating time. The temperature non-uniformity on the surface occurs during the entire aerodynamic heating process. However, the temperature distribution becomes more uniform after the heater is shut down and the experimental model is naturally cooled. This result shows that the multispectral simultaneous image measurement mode provides a wider temperature range for one imaging measurement of high spatial temperature gradients in transient applications. PMID- 28667995 TI - Developments on a SEM-based X-ray tomography system: Stabilization scheme and performance evaluation. AB - Recent improvements in a SEM-based X-ray tomography system are described. In this type of equipment, X-rays are generated through the interaction between a highly focused electron-beam and a geometrically confined anode target. Unwanted long term drifts of the e-beam can lead to loss of X-ray flux or decrease of spatial resolution in images. To circumvent this issue, a closed-loop control using FFT based image correlation is integrated to the acquisition routine, in order to provide an in-line drift correction. The X-ray detection system consists of a state-of-the-art scientific CMOS camera (indirect detection), featuring high quantum efficiency (~60%) and low read-out noise (~1.2 electrons). The system performance is evaluated in terms of resolution, detectability, and scanning times for applications covering three different scientific fields: microelectronics, technical textile, and material science. PMID- 28667996 TI - The free electron gas primary thermometer using an ordinary bipolar junction transistor approaches ppm accuracy. AB - In this paper, it is demonstrated that the free electron gas primary thermometer based on a bipolar junction transistor is able to provide the temperature with an accuracy of a few parts per million. Its simple functioning principle exploits the behavior of the collector current when properly biased to extract the temperature. Using general purpose silicon transistors at the water triple point (273.16 K) and gallium melting point (302.9146), an accuracy of a few parts per million has been reached, constituting the simplest and the easiest to operate primary thermometer, that might be considered even for the redefinition of Kelvin. PMID- 28667997 TI - A new torsion pendulum for gravitational reference sensor technology development. AB - We report on the design and sensitivity of a new torsion pendulum for measuring the performance of ultra-precise inertial sensors and for the development of associated technologies for space-based gravitational wave observatories and geodesy missions. The apparatus comprises a 1 m-long, 50 MUm-diameter tungsten fiber that supports an inertial member inside a vacuum system. The inertial member is an aluminum crossbar with four hollow cubic test masses at each end. This structure converts the rotation of the torsion pendulum into translation of the test masses. Two test masses are enclosed in capacitive sensors which provide readout and actuation. These test masses are electrically insulated from the rest of the crossbar and their electrical charge is controlled by photoemission using fiber-coupled ultraviolet light emitting diodes. The capacitive readout measures the test mass displacement with a broadband sensitivity of 30 nm/Hz and is complemented by a laser interferometer with a sensitivity of about 0.5 nm/Hz. The performance of the pendulum, as determined by the measured residual torque noise and expressed in terms of equivalent force acting on a single test mass, is roughly 200 fN/Hz around 2 mHz, which is about a factor of 20 above the thermal noise limit of the fiber. PMID- 28667998 TI - A convenient method for large-scale STM mapping of freestanding atomically thin conductive membranes. AB - Two-dimensional atomically flat sheets with a high flexibility are very attractive as ultrathin membranes but are also inherently challenging for microscopic investigations. We report on a method using Scanning Tunneling Microscopy (STM) under ultra-high vacuum conditions for large-scale mapping of several-micrometer-sized freestanding single and multilayer graphene membranes. This is achieved by operating the STM at unusual parameters. We found that large scale scanning on atomically thin membranes delivers valuable results using very high tip-scan speeds combined with high feedback-loop gain and low tunneling currents. The method ultimately relies on the particular behavior of the freestanding membrane in the STM which is much different from that of a solid substrate. PMID- 28667999 TI - A compact linear accelerator based on a scalable microelectromechanical-system RF structure. AB - A new approach for a compact radio-frequency (RF) accelerator structure is presented. The new accelerator architecture is based on the Multiple Electrostatic Quadrupole Array Linear Accelerator (MEQALAC) structure that was first developed in the 1980s. The MEQALAC utilized RF resonators producing the accelerating fields and providing for higher beam currents through parallel beamlets focused using arrays of electrostatic quadrupoles (ESQs). While the early work obtained ESQs with lateral dimensions on the order of a few centimeters, using a printed circuit board (PCB), we reduce the characteristic dimension to the millimeter regime, while massively scaling up the potential number of parallel beamlets. Using Microelectromechanical systems scalable fabrication approaches, we are working on further reducing the characteristic dimension to the sub-millimeter regime. The technology is based on RF acceleration components and ESQs implemented in the PCB or silicon wafers where each beamlet passes through beam apertures in the wafer. The complete accelerator is then assembled by stacking these wafers. This approach has the potential for fast and inexpensive batch fabrication of the components and flexibility in system design for application specific beam energies and currents. For prototyping the accelerator architecture, the components have been fabricated using the PCB. In this paper, we present proof of concept results of the principal components using the PCB: RF acceleration and ESQ focusing. Ongoing developments on implementing components in silicon and scaling of the accelerator technology to high currents and beam energies are discussed. PMID- 28668000 TI - A micromachined piezoelectric microgripper for manipulation of micro/nanomaterials. AB - Micro/nanomaterials and devices have attracted great interest in recent years because of their extensive application prospects in almost all kinds of fields. However, the manipulations of the material at the micro/nanoscale, such as the separation or transfer of a micro/nano-object in the process of assembling micro/nanodevices, are quite difficult. In this paper, we present a micromachined micro-gripper made of photoresist material (SU-8) and driven by piezoelectric Pb(Mg,Nb)O3-PbTiO3 single crystal pieces. In order to keep two grasping jaws of the micro-gripper operating in the same plane at the micro/nanometer scale, a fine circular flexure hinge was fabricated for elastically connecting them together. After introducing the interface effect, the relationship between the opening stroke of two jaws and the applied voltage was developed and then confirmed by finite element simulation. The micro-gripper was finally installed on a six degree of freedom stage for performing a pick-up, release, and transfer manipulation of a 2 MUm ZnO micro-fiber. The presented piezoelectric micro gripper shows a great potential for the precise manipulation of a single piece of micro/nanomaterial for micro/nanodevices' assembling. PMID- 28668001 TI - SPINS-IND: Pellet injector for fuelling of magnetically confined fusion systems. AB - Using a Gifford-McMahon cycle cryocooler based refrigeration system, a single barrel hydrogen pellet injection (SPINS-IND) system is indigenously developed at Institute for Plasma Research, India. The injector is based on a pipe gun concept, where a pellet formed in situ in the gun barrel is accelerated to high speed using high pressure light propellant gas. The pellet size is decided by considering the Greenwald density limit and its speed is decided by considering a neutral gas shielding model based scaling law. The pellet shape is cylindrical of dimension (1.6 mm l * 1.8 mm phi). For pellet ejection and acceleration, a fast opening valve of short opening duration is installed at the breech of the barrel. A three-stage differential pumping system is used to restrict the flow of the propellant gas into the plasma vacuum vessel. Diagnostic systems such as light gate and fast imaging camera (240 000 frames/s) are employed to measure the pellet speed and size, respectively. A trigger circuit and a programmable logic controller based integrated control system developed on LabVIEW enables to control the pellet injector remotely. Using helium as a propellant gas, the pellet speed is varied in the range 650 m/s-800 m/s. The reliability of pellet formation and ejection is found to be more than 95%. This paper describes the details of SPINS-IND and its test results. PMID- 28668002 TI - First simultaneous measurements of Reynolds stress with ball-pen and Langmuir probes. AB - A new multi-pin probe head was installed and tested at the COMPASS tokamak. The probe head consists of several ball-pen and Langmuir probes in similar geometric configurations, which enables fast, simultaneous measurements of the radial and poloidal electric field components from differences of plasma or floating potentials using appropriately positioned ball-pen or Langmuir probes, respectively. The fast measurements of the radial electric field are compared with other methods of measuring selected frequency components of the radial electric field. The radial profiles of the Reynolds stress calculated from correlations of electric field fluctuations obtained by either probe type are compared along with their spectral composition. Lower Reynolds stress values are found for Langmuir probes in comparison to ball-pen probes due to negative contributions from higher frequency fluctuations possibly associated with electron temperature fluctuations. PMID- 28668003 TI - Continuous reading SQUID magnetometer and its applications. AB - We show a continuous reading superconducting quantum interference detector magnetometer used to measure the magnetic moment of small samples of materials as a function of an applied magnetic field, temperature, and time. A sample is held stationary while the magnetic field and sample temperature may be varied continuously in an arbitrary way, determined by the user. The applied field range is +/-25 mT and the temperature range is 4.2-150 K. The advantage of a stationary sample technique is that the sample is not exposed to variations in the magnetic field or temperature, which may set in when the sample is moving. An evaluation of the measurements is not bound by the dipolar magnetic moment of the sample. High linearity of the detection system, low harmonic distortion of the applied time-varying magnetic field, and precise sample temperature control make this device suitable for studies of phase transitions, hysteretic phenomena, and nonlinear phenomena in magnetic materials and superconductors. The magnetometer's sensitivity (noise floor), i.e., magnetic moment noise spectral density, is 10 pA m2 Hz-1/2 in the white noise region. PMID- 28668004 TI - A compact two-way power divider based on five-port structure. AB - A novel compact five-port waveguide power divider based on the single-ridge waveguide and three-ridge waveguide structure is proposed. It is realized by the coupling of the TE10 and TE30 modes. At the central coupling section, the single ridge and three-ridge waveguides are used to constitute the conventional rectangular waveguide to reduce the sectional sizes. It consists of one input port, two output ports, and two isolated ports. For validation, a compact five port power divider is designed, fabricated, and measured. The measured results show that, from 8 to 9 GHz, the return loss of the input port and output ports is higher than 18 dB, the isolation between the output ports is higher than 15 dB, the insertion loss is less than 0.3 dB, and the amplitude and the phase imbalance between the output ports are less than +/-0.05 dB and +/-1 degrees , respectively. The simulated results basically agree with the simulations. Its sectional sizes are 1.1 lambda * 0.4 lambda which are more compact than most of the two-way isolated waveguide power dividers. PMID- 28668005 TI - Cryogenic mount for mirror and piezoelectric actuator for an optical cavity. AB - We present the development of a mount that accommodates a mirror and a piezoelectric actuator with emphasis on physical needs for low temperature operation. The design uses a monolithic construction with flexure features that allow it to steadily hold the mirror and the piezoelectric actuator without glue and accommodate differential thermal contraction. The mount is small and lightweight, adding little heat capacity and inertia. It provides a pre-loading of the piezoelectric actuator as well as a good thermal connection to the mirror and a thermal short across the piezoelectric actuator. The performance of the assemblies has been tested by thermally cycling from room temperature down to 3 K more than a dozen times and over one hundred times to 77 K, without showing any derating. Such mounts are proposed for the cryogenic optical enhancement cavities of the ALPHA experiment at CERN for laser spectroscopy of antihydrogen and for hydrogen spectroscopy in our laboratory at UFRJ. PMID- 28668006 TI - Hyperspectral sensing data analysis based on quasiconformal mapping-based multiple kernels learning machine. AB - Hyperspectral remote sensing has a strong ability of object information expression, so it provides better support for object classification. Many methods are proposed for the hyperspectral data classification. The spectrum classification is a classical nonlinear problem, and a kernel-based machine is feasible to classify the spectrum data. In the nonlinear kernel-based space, the spectrum data are more discriminative. The kernel functions determine the data distribution in the feature space. In this paper, we propose the quasiconformal multiple kernels-based machine learning for the hyperspectral data classification. In the framework, the structure of hyperspectral data is adaptively adjusted for classification. The multiple kernels extract the multiple features of hyperspectral data for classification. Multiple features-based machine learning exhibits a great potential on the classification of hyperspectral data. Two public datasets, India Pines dataset and Pavia University dataset, are used to test the proposed algorithm. Experimental results demonstrate that the proposed quasiconformal multiple kernels-based hyperspectral data classification method can show competitive performance. PMID- 28668007 TI - A novel measurand independent of the distance between the source and detector for continuous wave near-infrared spectroscopy. AB - A new measurand is proposed for use in continuous wave near-infrared spectroscopy (cw-NIRS). The conventional measurand of cw-NIRS is l?c, which is the product of the change in the hemoglobin concentration (?c) and the partial path lengh (l), which depends on the source-detector (SD) distance (d). The SD distance must remain constant during cw-NIRS measurements, and we cannot compare the l?c value with that obtained using a different SD distance. In addition, the conventional measurand obtained using the standard measurement style sometimes includes a contribution from the human scalp. The SD distance independent (SID) measurand obtained using multi-SD distances is proportional to the product of the change in hemoglobin concentration and the derivative of the partial path length for the deep region with no scalp contribution under the assumption of a layer model. The principle of SID was validated by the layered phantom study. In order to check the limitation of assumption, a human study was conducted. The value of the SID measurand for the left side of the forehead during working memory task was approximately independent of the SD distance between 16 and 32 mm. The SID measurand and the standardized optode arrangement using flexible SD distances in a head coordinate system must be helpful for comparing the data in a population study. PMID- 28668008 TI - Two-color monochromatic x-ray imaging with a single short-pulse laser. AB - Simultaneous monochromatic crystal imaging at 4.5 and 8.0 keV with x-rays produced by a single short-pulse laser is presented. A layered target consisting of thin foils of titanium and copper glued together is irradiated by the 50 TW Leopard short-pulse laser housed at the Nevada Terawatt Facility. Laser accelerated MeV fast electrons transmitting through the target induce Kalpha fluorescence from both foils. Two energy-selective curved crystals in the imaging diagnostic form separate monochromatic images on a single imaging detector. The experiment demonstrates simultaneous two-color monochromatic imaging of the foils on a single detector as well as Kalpha x-ray production at two different photon energies with a single laser beam. Application of the diagnostic technique to x ray radiography of a high density plasma is also presented. PMID- 28668009 TI - Plasma fireball: A unique tool to fabricate patterned nanodots. AB - A large plasma fireball is formed using a reverse biased planar sputter magnetron source. The magnetic field considerably reduces the contact area of the anode with the plasma and results in the formation of the fireball. Ions are extracted from the fireball using a large voltage cathode sheath of the grounded sample holder. The physical mechanism for the extraction of the ions from the fireball along with the effect of the sample holder on the fireball and the discharge current is discussed. The device is shown as a novel tool for developing nanodot patterns on a GaSb substrate without the use of additional ion source or power supplies. Variable nanodot patterns produced simply by the alteration of discharge conditions demonstrate unique surface wettability and reflection properties. PMID- 28668010 TI - Upgrade of a commercial four-probe scanning tunneling microscopy system. AB - Upgrade of a commercial ultra-high vacuum four-probe scanning tunneling microscopy system for atomic resolution capability and thermal stability is reported. To improve the mechanical and thermal performance of the system, we introduced extra vibration isolation, magnetic damping, and double thermal shielding, and we redesigned the scanning structure and thermal links. The success of the upgrade is characterized by its atomically resolved imaging, steady cooling down cycles with high efficiency, and standard transport measurement capability. Our design may provide a feasible way for the upgrade of similar commercial systems. PMID- 28668011 TI - Uniform coating of Ta2O5 on vertically aligned substrate: A prelude to forced flow atomic layer deposition. AB - Uniform tantalum oxide thin films, with a growth rate of 0.6 A/cycle, were fabricated on vertically aligned, 10 cm-long, silicon substrates using an innovative atomic layer deposition (ALD) design. The ALD system, with a reaction chamber depth of 13.3 cm and 18 vertical enclosed channels (inner diameter 1.3 cm), was coupled with a shower-head type precursor conduit plate bearing 6 radial channels. This design enabled deposition on 6 silicon substrates at a time. The degrees of non-uniformity of deposits along the length of the silicon wafer and across different positions in the ALD chamber were found to be 1.77%-6.21% and 3.27%-5.45%, respectively. A further advantage of the design is that the conduit plate may be modified and the number of channels increased to process 18 substrates simultaneously, thus moving toward efficient and expedited ALD systems. PMID- 28668012 TI - Note: Measuring instrument of singlet oxygen quantum yield in photodynamic effects. AB - Using diphenylisobenzofuran (C20H14O) as a singlet oxygen (1O2) reporter, a comparison method, which can be used to measure the singlet oxygen quantum yield (PhiDelta) of the photosensitizer quantitatively, is presented in this paper. Based on this method, an automatic measuring instrument of singlet oxygen quantum yield is developed. The singlet oxygen quantum yield of the photosensitizer hermimether and aloe-emodin is measured. It is found that the measuring results are identical to the existing ones, which verifies the validity of the measuring instrument. PMID- 28668013 TI - Geometric factors affecting capillary discharge jet length in atmospheric pressure air. AB - The capillary discharge triggered by a pulse source can produce a certain length of plasma jet. In this paper, the physical process of the capillary discharge jet is analyzed, and it is pointed out that the capillary plasma-jet length is significantly affected by the expansion pressure caused by the arc discharge in the capillary chamber. The greater the pressure in the capillary chamber is, the longer the jet length. The experimental setup of the capillary discharge is established in atmospheric pressure air. The influence of the surface distance along the capillary wall, the diameter of the capillary cathode, and the length of the cathode tip on the plasma-jet length is studied under a specific trigger pulse. The experimental results show that the greater the deposited energy density in the capillary chamber is, the longer the plasma jet length. As the surface distance increases, the energy deposited in the arc channel increases first and then tends to be saturated. There is an optimum surface distance to maximize the energy density in the capillary chamber, while the plasma jet length is the longest. PMID- 28668014 TI - Note: Setup for chemical atmospheric control during in situ grazing incidence X ray scattering of printed thin films. AB - In order to tailor the assembling of polymers and organic molecules, a deeper understanding of the kinetics involved in thin film production is necessary. While post-production characterization only provides insight on the final film structure, more sophisticated experimental setups are needed to probe the structure formation processes in situ during deposition. The drying kinetics of a deposited organic thin film strongly influences the assembling process on the nanometer scale. This work presents an experimental setup that enables fine control of the atmosphere composition surrounding the sample during slot die coating, while simultaneously probing the film formation kinetics using in situ grazing incidence X-ray scattering and spectroscopy. PMID- 28668015 TI - High resolution quantum cascade laser spectroscopy of the simplest Criegee intermediate, CH2OO, between 1273 cm-1 and 1290 cm-1. AB - The region 1273-1290 cm-1 of the nu4 fundamental of the simplest Criegee intermediate, CH2OO, has been measured using a quantum cascade laser transient absorption spectrometer, which offers greater sensitivity and spectral resolution (<0.004 cm-1) than previous works based on thermal light sources. Gas phase CH2OO was generated from the reaction of CH2I + O2 at 298 K and 4 Torr. The analysis of the absorption spectrum has provided precise values for the vibrational frequency and the rotational constants, with fitting errors of a few MHz. The determined ratios of the rotational constants, A'/A" = 0.9986, B'/B" = 0.9974, and C'/C" = 1.0010, and the relative intensities of the a- and b-type transitions, 90:10, are in good agreement with literature values from a theoretical calculation using the MULTIMODE approach, based on a high-level ab initio potential energy surface. The low-K (=Ka) lines can be fitted extremely well, but rotational perturbations by other vibrational modes disrupt the structure for K = 4 and K >= 6. Not only the spectral resolution but also the detection sensitivity of CH2OO IR transitions has been greatly improved in this work, allowing for unambiguous monitoring of CH2OO in kinetic studies at low concentrations. PMID- 28668016 TI - Dehydrogenation of methanol on Cu2O(100) and (111). AB - Adsorption and desorption of methanol on the (111) and (100) surfaces of Cu2O have been studied using high-resolution photoelectron spectroscopy in the temperature range 120-620 K, in combination with density functional theory calculations and sum frequency generation spectroscopy. The bare (100) surface exhibits a (3,0; 1,1) reconstruction but restructures during the adsorption process into a Cu-dimer geometry stabilized by methoxy and hydrogen binding in Cu bridge sites. During the restructuring process, oxygen atoms from the bulk that can host hydrogen appear on the surface. Heating transforms methoxy to formaldehyde, but further dehydrogenation is limited by the stability of the surface and the limited access to surface oxygen. The (?3 * ?3)R30 degrees reconstructed (111) surface is based on ordered surface oxygen and copper ions and vacancies, which offers a palette of adsorption and reaction sites. Already at 140 K, a mixed layer of methoxy, formaldehyde, and CHxOy is formed. Heating to room temperature leaves OCH and CHx. Thus both CH-bond breaking and CO-scission are active on this surface at low temperature. The higher ability to dehydrogenate methanol on (111) compared to (100) is explained by the multitude of adsorption sites and, in particular, the availability of surface oxygen. PMID- 28668017 TI - Vibration and vibration-torsion levels of the S1 state of para-fluorotoluene in the 580-830 cm-1 range: Interactions and coincidences. AB - A study of the vibration and vibration-torsion levels of para-fluorotoluene in the 580-830 cm-1 region is presented, where a number of features are located whose identity is complicated by interactions and overlap. We examine this region with a view to ascertaining the assignments of the bands; in particular, identifying those that arise from interactions involving various zero-order states (ZOSs) involving both vibrations and torsions. Resonance-enhanced multiphoton ionization (REMPI) is employed to identify the wavenumbers of the relevant transitions, and subsequently zero-kinetic-energy (ZEKE) spectra are recorded to assign the various eigenstates. In some cases, a set of ZEKE spectra are recorded across the wavenumber range of a REMPI feature, and we construct what we term a two-dimensional ZEKE (2D-ZEKE) spectrum, which allows the changing ZOS contributions to the eigenstates to be ascertained. Assignment of the observed bands is aided by quantum chemical calculations and all b1 and a2 symmetry vibrational wavenumbers are now determined in the S1 state and cation, as well as those of the D10 vibration. We also compare to the activity seen in the corresponding S1 <- S0 spectrum of para-difluorobenzene. PMID- 28668018 TI - Application of the spectral element method to the solution of the multichannel Schrodinger equation. AB - We apply the spectral element method to the determination of scattering and bound states of the multichannel Schrodinger equation. In our approach, the reaction coordinate is discretized on a grid of points whereas the internal coordinates are described by either purely diabatic or locally diabatic (diabatic-by-sector) bases. Bound levels and scattering matrix elements are determined with spectral accuracy using relatively small number of points. The scattering problem is cast as a linear system solved using state-of-the-art sparse matrix non-iterative packages. Boundary conditions can be imposed so as to compute a single column of the matrix solution. A comparison with log-derivative propagators customarily used in molecular physics is performed. The same discretization scheme can also be applied to bound levels that are computed using direct scalable sparse-matrix solvers. PMID- 28668019 TI - Note: Deep UV-pump THz-probe spectroscopy of the excess electron in water. AB - In the work of Savolainen et al. [Nat. Chem. 6, 697 (2014)], we studied the excess (hydrated) electron in water with the help of transient THz spectroscopy, which is a sensitive probe of its delocalization length. In that work, we used laser pulses at 800 nm, 400 nm, and 267 nm for photoionization. While the detachment mechanism for 400 nm and 267 nm is complicated and requires a concerted nuclear rearrangement, we provided evidence that 800 nm pumping excites the excess electron directly and vertically into the conduction band, despite a highly nonlinear field-ionization process. In the present note, we extend that work to 200 nm pumping, which provides a much cleaner way to reach the conduction band. We show that the detachment pathways upon 200 nm and 800 nm pumping are in essence the same, as indicated by the same initial size of the electron wavefunction and the same time scales for the collapse of the wavefunction and geminate recombination. PMID- 28668020 TI - Adsorption and encapsulation of flexible polyelectrolytes in charged spherical vesicles. AB - We present a theory of adsorption of flexible polyelectrolytes on the interior and exterior surfaces of a charged vesicle in an electrolyte solution. The criteria for adsorption and the density profiles of the adsorbed polymer chain are derived in terms of various characteristics of the polymer, vesicle, and medium, such as the charge density and length of the polymer, charge density and size of the vesicle, electrolyte concentration and dielectric constant of the medium. For adsorption inside the vesicle, the competition between the loss of conformational entropy and gain in adsorption energy results in two kinds of encapsulated states, depending on the strength of the polymer-vesicle interaction. By considering also the adsorption from outside the vesicle, we derive the entropic and energy contributions to the free energy change to transfer an adsorbed chain in the interior to an adsorbed chain on the exterior. In this paper, we have used the Wentzel-Kramers-Brillouin (WKB) method to solve the equation for the probability distribution function of the chain. The present WKB results are compared with the previous results based on variational methods. The WKB and variational results are in good agreement for both the interior and exterior states of adsorption, except in the zero-salt limit for adsorption in the exterior region. The adsorption criteria and density profiles for both the interior and exterior states are presented in terms of various experimentally controllable variables. Calculation of the dependencies of free energy change to transfer an adsorbed chain from the interior to the exterior surface on salt concentration and vesicle radius shows that the free energy penalty to expel a chain from a vesicle is only of the order of thermal energy. PMID- 28668021 TI - Photoelectron angular distribution from free SiO2 nanoparticles as a probe of elastic electron scattering. AB - In order to gain quantitative information on the surface composition of nanoparticles from X-ray photoelectron spectroscopy, a detailed understanding of photoelectron transport phenomena in these samples is needed. Theoretical results on the elastic and inelastic scattering have been reported, but a rigorous experimental verification is lacking. We report in this work on the photoelectron angular distribution from free SiO2 nanoparticles (d = 122 +/- 9 nm) after ionization by soft X-rays above the Si 2p and O 1s absorption edges, which gives insight into the relative importance of elastic and inelastic scattering channels in the sample particles. The photoelectron angular anisotropy is found to be lower for photoemission from SiO2 nanoparticles than that expected from the theoretical values for the isolated Si and O atoms in the photoelectron kinetic energy range 20-380 eV. The reduced angular anisotropy is explained by elastic scattering of the outgoing photoelectrons from neighboring atoms, smearing out the atomic distribution. Photoelectron angular distributions yield detailed information on photoelectron elastic scattering processes allowing for a quantification of the number of elastic scattering events the photoelectrons have undergone prior to leaving the sample. The interpretation of the experimental photoelectron angular distributions is complemented by Monte Carlo simulations, which take inelastic and elastic photoelectron scattering into account using theoretical values for the scattering cross sections. The results of the simulations reproduce the experimental photoelectron angular distributions and provide further support for the assignment that elastic and inelastic electron scattering processes need to be considered. PMID- 28668022 TI - Time-dependent N-electron valence perturbation theory with matrix product state reference wavefunctions for large active spaces and basis sets: Applications to the chromium dimer and all-trans polyenes. AB - In earlier work [A. Y. Sokolov and G. K.-L. Chan, J. Chem. Phys. 144, 064102 (2016)], we introduced a time-dependent formulation of the second-order N electron valence perturbation theory (t-NEVPT2) which (i) had a lower computational scaling than the usual internally contracted perturbation formulation and (ii) yielded the fully uncontracted NEVPT2 energy. Here, we present a combination of t-NEVPT2 with a matrix product state (MPS) reference wavefunction (t-MPS-NEVPT2) that allows us to compute uncontracted dynamic correlation energies for large active spaces and basis sets, using the time dependent density matrix renormalization group algorithm. In addition, we report a low-scaling MPS-based implementation of strongly contracted NEVPT2 (sc-MPS NEVPT2) that avoids computation of the four-particle reduced density matrix. We use these new methods to compute the dissociation energy of the chromium dimer and to study the low-lying excited states in all-trans polyenes (C4H6 to C24H26), incorporating dynamic correlation for reference wavefunctions with up to 24 active electrons and orbitals. PMID- 28668023 TI - Resonant energy transfer under the influence of the evanescent field from the metal. AB - We present a quantum framework based on a density matrix of a dimer system to investigate the quantum dynamics of excitation energy transfer (EET) in the presence of the evanescent field from the metal and the phonon bath. Due to the spatial correlation of the electric field in the vicinity of the metal, the spectral density of the evanescent field is similar to that of a shared phonon bath. However, the EET dynamics under the influence of the evanescent field is an open and a new problem. Here we use a thin metallic film to investigate the effect of the evanescent field on the excitation energy transfer in a dimer system based on a density matrix approach. Our results indicate that a thin metallic film enhances the energy transfer rate at the expense of absorbing energy during the process. Since the spectral density of the evanescent field is affected by the geometry of the medium and the distance of a dimer system from the medium, our results demonstrate the possibility to tune EET based on material geometry and distances. Our model also serves as an expansion to quantum heat engine models and provides a framework to investigate the EET in light harvesting molecular networks under the influence of the evanescent field. PMID- 28668024 TI - Using force-based adaptive resolution simulations to calculate solvation free energies of amino acid sidechain analogues. AB - The calculation of free energy differences is a crucial step in the characterization and understanding of the physical properties of biological molecules. In the development of efficient methods to compute these quantities, a promising strategy is that of employing a dual-resolution representation of the solvent, specifically using an accurate model in the proximity of a molecule of interest and a simplified description elsewhere. One such concurrent multi resolution simulation method is the Adaptive Resolution Scheme (AdResS), in which particles smoothly change their resolution on-the-fly as they move between different subregions. Before using this approach in the context of free energy calculations, however, it is necessary to make sure that the dual-resolution treatment of the solvent does not cause undesired effects on the computed quantities. Here, we show how AdResS can be used to calculate solvation free energies of small polar solutes using Thermodynamic Integration (TI). We discuss how the potential-energy-based TI approach combines with the force-based AdResS methodology, in which no global Hamiltonian is defined. The AdResS free energy values agree with those calculated from fully atomistic simulations to within a fraction of kBT. This is true even for small atomistic regions whose size is on the order of the correlation length, or when the properties of the coarse-grained region are extremely different from those of the atomistic region. These accurate free energy calculations are possible because AdResS allows the sampling of solvation shell configurations which are equivalent to those of fully atomistic simulations. The results of the present work thus demonstrate the viability of the use of adaptive resolution simulation methods to perform free energy calculations and pave the way for large-scale applications where a substantial computational gain can be attained. PMID- 28668025 TI - Erratum: "Electrokinetic detection for x-ray spectra of weakly interacting liquids: n-decane and n-nonane" [J. Chem. Phys. 140, 234202 (2014)]. PMID- 28668026 TI - Diffusion and interactions of point defects in hard-sphere crystals. AB - Using computer simulations, we study the diffusion, interactions, and strain fields of point defects in a face-centered-cubic crystal of hard spheres. We show that the vacancy diffusion decreases rapidly as the density is increased, while the interstitial diffusion exhibits a much weaker density-dependence. Additionally, we predict the free-energy barriers associated with vacancy hopping and find that the increasing height of the free-energy barrier is solely responsible for the slowing down of vacancy diffusion. Moreover, we find that the shape of the barriers is independent of the density. The interactions between vacancies are shown to be weakly attractive and short-ranged, while the interactions between interstitials are found to be strongly attractive and are felt over long distances. As such, we find that vacancies do not form vacancy clusters, while interstitials do form long-lived interstitial clusters. Considering the strain field of vacancies and interstitials, we argue that vacancies will hardly feel each other, as they do not substantially perturb the crystal, and as such exhibit weak interactions. Two interstitials, on the other hand, interact with each other over long distances and start to interact (attractively) when their strain fields start to overlap. PMID- 28668027 TI - Density matrices in full configuration interaction quantum Monte Carlo: Excited states, transition dipole moments, and parallel distribution. AB - We present developments in the calculation of reduced density matrices (RDMs) in the full configuration interaction quantum Monte Carlo (FCIQMC) method. An efficient scheme is described to allow storage of RDMs across distributed memory, thereby allowing their calculation and storage in large basis sets. We demonstrate the calculation of RDMs for general states by using the recently introduced excited-state FCIQMC approach [N. S. Blunt et al., J. Chem. Phys. 143, 134117 (2015)] and further introduce calculation of transition density matrices in the method. These approaches are combined to calculate excited-state dipole and transition dipole moments for heteronuclear diatomic molecules, including LiH, BH, and MgO, and initiator error is investigated in these quantities. PMID- 28668028 TI - Accelerating self-consistent field theory of block polymers in a variable unit cell. AB - Self-consistent field theory (SCFT) is one of the most widely used tools to study the equilibrium phase behavior of block polymers. We have extended an existing version of the Anderson-mixing iteration scheme to solve the highly nonlinear SCFT equations while simultaneously optimizing the unit-cell dimensions. This improved scheme substantially increases the computational efficiency compared to existing schemes. PMID- 28668029 TI - Stiffness-guided motion of a droplet on a solid substrate. AB - A range of technologies require the directed motion of nanoscale droplets on solid substrates. A way of realizing this effect is durotaxis, whereby a stiffness gradient of a substrate can induce directional motion without requiring an energy source. Here, we report on the results of extensive molecular dynamics investigations of droplets on a surface with varying stiffness. We find that durotaxis is enhanced by increasing the stiffness gradient and, also, by increased wettability of the substrate, in particular, when the droplet size decreases. We anticipate that our study will provide further insights into the mechanisms of nanoscale directional motion. PMID- 28668030 TI - Sine-squared shifted pulses for recoupling interactions in solid-state NMR. AB - Rotational-Echo DOuble-Resonance (REDOR) is a versatile experiment for measuring internuclear distance between two heteronuclear spins in solid-state NMR. At slow to intermediate magic-angle spinning (MAS) frequencies, the measurement of distances between strongly coupled spins is challenging due to rapid dephasing of magnetisation. This problem can be remedied by employing the pulse-shifted version of REDOR known as Shifted-REDOR (S-REDOR) that scales down the recoupled dipolar coupling. In this study, we propose a new variant of the REDOR sequence where the positions of the pi pulses are determined by a sine-squared function. This new variant has scaling properties similar to S-REDOR. We use theory, numerical simulations, and experiments to compare the dipolar recoupling efficiencies and the experimental robustness of the three REDOR schemes. The proposed variant has advantages in terms of radiofrequency field requirements at fast MAS frequencies. PMID- 28668031 TI - Ultrafast proton migration and Coulomb explosion of methyl chloride in intense laser fields. AB - We investigated the ultrafast proton migration and the Coulomb explosion (CE) dynamics of methyl chloride (CH3Cl) in intense femtosecond laser fields at the wavelengths of 800 nm (5.5 * 1014 W/cm2) and 400 nm (4 * 1014 W/cm2), respectively. Various fragment channels from molecular dication and trication were observed by coincidence momentum imaging through the measurement of their kinetic energy releases (KERs). The proton migration from different charged parent ions was analyzed from the obtained KER distributions. For the direct CE channel of CH3+ + Cl+ and CH3+ + Cl2+, the contribution of multiply excited electronic states and multicharged states is identified. In addition, the measurements of relative yields of the fragmentation channel at different laser wavelengths provide a selective control of proton migration for CH3Cl molecules in intense laser fields. PMID- 28668032 TI - Parallel O(N) Stokes' solver towards scalable Brownian dynamics of hydrodynamically interacting objects in general geometries. AB - An efficient parallel Stokes' solver has been developed for complete description of hydrodynamic interactions between Brownian particles in bulk and confined geometries. A Langevin description of the particle dynamics is adopted, where the long-range interactions are included using a Green's function formalism. A scalable parallel computational approach is presented, where the general geometry Stokeslet is calculated following a matrix-free algorithm using the general geometry Ewald-like method. Our approach employs a highly efficient iterative finite-element Stokes' solver for the accurate treatment of long-range hydrodynamic interactions in arbitrary confined geometries. A combination of mid point time integration of the Brownian stochastic differential equation, the parallel Stokes' solver, and a Chebyshev polynomial approximation for the fluctuation-dissipation theorem leads to an O(N) parallel algorithm. We illustrate the new algorithm in the context of the dynamics of confined polymer solutions under equilibrium and non-equilibrium conditions. The method is then extended to treat suspended finite size particles of arbitrary shape in any geometry using an immersed boundary approach. PMID- 28668033 TI - Channel interference in multiphoton absorption. AB - We extend the theory of channel interference to higher-order multiphoton absorption processes. We derive an explicit expression for channel interference in a three-photon absorption process and propose a general scheme for deriving such expressions for multiphoton absorption processes of any order. Based on this general scheme, we derive and analyze the simplest few-state models for multiphoton absorption in centrosymmetric molecules and discuss the criteria for maximizing the corresponding multiphoton absorption strengths. PMID- 28668034 TI - Predicting vapor-liquid phase equilibria with augmented ab initio interatomic potentials. AB - The ability of ab initio interatomic potentials to accurately predict vapor liquid phase equilibria is investigated. Monte Carlo simulations are reported for the vapor-liquid equilibria of argon and krypton using recently developed accurate ab initio interatomic potentials. Seventeen interatomic potentials are studied, formulated from different combinations of two-body plus three-body terms. The simulation results are compared to either experimental or reference data for conditions ranging from the triple point to the critical point. It is demonstrated that the use of ab initio potentials enables systematic improvements to the accuracy of predictions via the addition of theoretically based terms. The contribution of three-body interactions is accounted for using the Axilrod-Teller Muto plus other multipole contributions and the effective Marcelli-Wang-Sadus potentials. The results indicate that the predictive ability of recent interatomic potentials, obtained from quantum chemical calculations, is comparable to that of accurate empirical models. It is demonstrated that the Marcelli-Wang-Sadus potential can be used in combination with accurate two-body ab initio models for the computationally inexpensive and accurate estimation of vapor-liquid phase equilibria. PMID- 28668035 TI - A jellium model of a catalyst particle in carbon nanotube growth. AB - We show how a jellium model can represent a catalyst particle within the density functional theory based approaches to the growth mechanism of carbon nanotubes (CNTs). The advantage of jellium is an abridged, less computationally taxing description of the multi-atom metal particle, while at the same time in avoiding the uncertainty of selecting a particular atomic geometry of either a solid or ever-changing liquid catalyst particle. A careful choice of jellium sphere size and its electron density as a descriptive parameter allows one to calculate the CNT-metal interface energies close to explicit full atomistic models. Further, we show that using jellium permits computing and comparing the formation of topological defects (sole pentagons or heptagons, the culprits of growth termination) as well as pentagon-heptagon pairs 5|7 (known as chirality-switching dislocation). PMID- 28668036 TI - Quantifying uncertainty in the chemical master equation. AB - We describe a novel approach to quantifying the uncertainty inherent in the chemical kinetic master equation with stochastic coefficients. A stochastic collocation method is coupled to an analytical expansion of the master equation to analyze the effects of both extrinsic and intrinsic noise. The method consists of an analytical moment-closure method resulting in a large set of differential equations with stochastic coefficients that are in turn solved via a Smolyak sparse grid collocation method. We discuss the error of the method relative to the dimension of the model and clarify which methods are most suitable for the problem. We apply the method to two typical problems arising in chemical kinetics with time-independent extrinsic noise. Additionally, we show agreement with classical Monte Carlo simulations and calculate the variance over time as the sum of two expectations. The method presented here has better convergence properties for low to moderate dimensions than standard Monte Carlo methods and is therefore a superior alternative in this regime. PMID- 28668037 TI - Multiband Monte Carlo modeling of upconversion emission in sub 10 nm beta NaGdF4:Yb3+, Er3+ nanocrystals-Effect of Yb3+ content. AB - In this work, we report the results of theoretical modeling supported and confirmed by experimentally measured emission, emission decay curves, and power dependent emission spectra for sub 10 nm beta-NaGdF4:Er3+,Yb3+ nanocrystals with different Yb3+ content (0.5%-15%). For the theoretical analysis, we develop a stochastic Monte Carlo model which is based on two components: (i) formation of clusters composed of Er3+ ion and Yb3+ neighbors, which gives insight into the role of local parameters and (ii) a simplified kinetic model of excitation and relaxation phenomena in pairs of Er3+and Yb3+ ions. The quantitative agreement between experimental data and modeling was obtained for the relative emission ratio of upconversion luminescence in green, red, and blue spectral ranges. Theoretical predictions of impact of excitation pulse duration and pumping light power on upconversion luminescence are presented. PMID- 28668038 TI - Hydrogen bonding characterization in water and small molecules. AB - The prototypical hydrogen bond in water dimer and hydrogen bonds in the protonated water dimer, in other small molecules, in water cyclic clusters, and in ice, covering a wide range of bond strengths, are theoretically investigated by first-principles calculations based on density functional theory, considering not only a standard generalized gradient approximation functional but also, for the water dimer, hybrid and van der Waals corrected functionals. We compute structural, energetic, and electrostatic (induced molecular dipole moments) properties. In particular, hydrogen bonds are characterized in terms of differential electron density distributions and profiles, and of the shifts of the centres of maximally localized Wannier functions. The information from the latter quantities can be conveyed to a single geometric bonding parameter that appears to be correlated with the Mayer bond order parameter and can be taken as an estimate of the covalent contribution to the hydrogen bond. By considering the water trimer, the cyclic water hexamer, and the hexagonal phase of ice, we also elucidate the importance of cooperative/anticooperative effects in hydrogen bonding formation. PMID- 28668039 TI - Time-dependent analysis of the mixed-field orientation of molecules without rotational symmetry. AB - We present a theoretical study of the mixed-field orientation of molecules without rotational symmetry. The time-dependent one-dimensional and three dimensional orientation of a thermal ensemble of 6-chloropyridazine-3 carbonitrile molecules in combined linearly or elliptically polarized laser fields and tilted dc electric fields is computed. The results are in good agreement with recent experimental results of one-dimensional orientation for weak dc electric fields [J. L. Hansen, J. Chem. Phys. 139, 234313 (2013)]. Moreover, they predict that using elliptically polarized laser fields or strong dc fields, three-dimensional orientation is obtained. The field-dressed dynamics of excited rotational states is characterized by highly non-adiabatic effects. We analyze the sources of these non-adiabatic effects and investigate their impact on the mixed-field orientation for different field configurations in mixed-field orientation experiments. PMID- 28668040 TI - The excess proton at the air-water interface: The role of instantaneous liquid interfaces. AB - The magnitude of the pH of the surface of water continues to be a contentious topic in the physical chemistry of aqueous interfaces. Recent theoretical studies have shown little or no preference for the proton to be at the surface compared to the bulk. Using ab initio molecular dynamics simulations, we revisit the propensity of the excess proton for the air-water interface with a particular focus on the role of instantaneous liquid interfaces. We find a more pronounced presence for the proton to be at the air-water interface. The enhanced water structuring around the proton results in the presence of proton wires that run parallel to the surface as well as a hydrophobic environment made up of under coordinated topological defect water molecules, both of which create favorable conditions for proton confinement at the surface. The Grotthuss mechanism within the structured water layer involves a mixture of both concerted and closely spaced stepwise proton hops. The proton makes excursions within the first solvation layer either in proximity to or along the instantaneous interface. PMID- 28668041 TI - Analysis of shear viscosity and viscoelastic relaxation of liquid methanol based on molecular dynamics simulation and mode-coupling theory. AB - The role of the prepeak structure of liquid methanol in determining its shear viscosity was studied by means of molecular dynamics (MD) simulation and mode coupling theory (MCT). The autocorrelation function of the shear stress and the intermediate scattering functions at both the prepeak and the main peak were calculated from the MD trajectories. Their comparison based on MCT suggests that the viscoelastic relaxation in the ps regime is affected by the slow structural dynamics at the prepeak. On the other hand, the MCT for molecular liquids based on the interaction-site model (site-site MCT) fails to describe the coupling between the prepeak dynamics and shear stress. The direct evaluation of the coupling between the two-body density and the shear stress reveals that the viscoelastic relaxation is actually affected by the prepeak dynamics, although the coupling is not captured by the site-site MCT. The site-site MCT works well for a model methanol without partial charges, suggesting that the failure of the site-site MCT originates from the existence of a hydrogen-bonding network structure. PMID- 28668042 TI - On the computations of interatomic Coulombic decay widths with R-matrix method. AB - Interatomic Coulombic Decay (ICD) is a general mechanism in which an excited atom can transfer its excess energy to a neighbor which is thus ionized. ICD belongs to the family of Feshbach resonance processes, and, as such, states undergoing ICD are characterized by their energy width. In this work, we investigate the computations of ICD widths using the R-matrix method as implemented in the UKRmol package. Helium dimer is used here as a benchmark system. The results are compared with those obtained with the well established Fano-Algebraic Diagrammatic Construction method. It is shown that the R-matrix method in its present implementation provides accurate total and partial widths if the kinetic energy of the ICD electron is lower than 10 eV. Advantages and limitations of the R-matrix method on the computations of ICD widths are discussed. PMID- 28668043 TI - Luminescent tunable polydots: Charge effects in confined geometry. AB - Long-lived soft nanoparticles, formed by conjugated polymers, constitute a new class of far-from-equilibrium responsive structures for nano-medicine. Tethering ionizable groups to the polymers enables functionality. However concurrently, the ionic groups perturb the delicate balance of interactions that governs these particles. Using fully atomistic molecular dynamics simulations, this study probed the effects of charged groups tethered to poly para phenylene ethynylene substituted by alkyl groups on the polymer conformation and dynamics in confined geometry. We find that the ionizable groups affect the entire shape of the polydots and impact the conformation and dynamics of the polymer. PMID- 28668044 TI - How good is the generalized Langevin equation to describe the dynamics of photo induced electron transfer in fluid solution? AB - The dynamics of unimolecular photo-triggered reactions can be strongly affected by the surrounding medium for which a large number of theoretical descriptions have been used in the past. An accurate description of these reactions requires knowing the potential energy surface and the friction felt by the reactants. Most of these theories start from the Langevin equation to derive the dynamics, but there are few examples comparing it with experiments. Here we explore the applicability of a Generalized Langevin Equation (GLE) with an arbitrary potential and a non-Markovian friction. To this end, we have performed broadband fluorescence measurements with sub-picosecond time resolution of a covalently linked organic electron donor-acceptor system in solvents of changing viscosity and dielectric permittivity. In order to establish the free energy surface (FES) of the reaction, we resort to stationary electronic spectroscopy. On the other hand, the dynamics of a non-reacting substance, Coumarin 153, provide the calibrating tool for the non-Markovian friction over the FES, which is assumed to be solute independent. A simpler and computationally faster approach uses the Generalized Smoluchowski Equation (GSE), which can be derived from the GLE for pure harmonic potentials. Both approaches reproduce the measurements in most of the solvents reasonably well. At long times, some differences arise from the errors inherited from the analysis of the stationary solvatochromism and at short times from the excess excitation energy. However, whenever the dynamics become slow, the GSE shows larger deviations than the GLE, the results of which always agree qualitatively with the measured dynamics, regardless of the solvent viscosity or dielectric properties. The method applied here can be used to predict the dynamics of any other reacting system, given the FES parameters and solvent dynamics are provided. Thus no fitting parameters enter the GLE simulations, within the applicability limits found for the model in this work. PMID- 28668045 TI - Probing the global potential energy minimum of (CH2O)2: THz absorption spectrum of (CH2O)2 in solid neon and para-hydrogen. AB - The true global potential energy minimum configuration of the formaldehyde dimer (CH2O)2, including the presence of a single or a double weak intermolecular CH?O hydrogen bond motif, has been a long-standing subject among both experimentalists and theoreticians as two different energy minima conformations of Cs and C2h symmetry have almost identical energies. The present work demonstrates how the class of large-amplitude hydrogen bond vibrational motion probed in the THz region provides excellent direct spectroscopic observables for these weak intermolecular CH?O hydrogen bond motifs. The combination of concentration dependency measurements, observed isotopic spectral shifts associated with H/D substitutions and dedicated annealing procedures, enables the unambiguous assignment of three large-amplitude infrared active hydrogen bond vibrational modes for the non-planar Cs configuration of (CH2O)2 embedded in cryogenic neon and enriched para-hydrogen matrices. A (semi)-empirical value for the change of vibrational zero-point energy of 5.5 +/- 0.3 kJ mol-1 is proposed for the dimerization process. These THz spectroscopic observations are complemented by CCSD(T)-F12/aug-cc-pV5Z (electronic energies) and MP2/aug-cc-pVQZ (force fields) electronic structure calculations yielding a (semi)-empirical value of 13.7 +/- 0.3 kJ mol-1 for the dissociation energy D0 of this global potential energy minimum. PMID- 28668046 TI - Model of ultrafast demagnetization driven by spin-orbit coupling in a photoexcited antiferromagnetic insulator Cr2O3. AB - We theoretically study the dynamic time evolution following laser pulse pumping in an antiferromagnetic insulator Cr2O3. From the photoexcited high-spin quartet states to the long-lived low-spin doublet states, the ultrafast demagnetization processes are investigated by solving the dissipative Schrodinger equation. We find that the demagnetization times are of the order of hundreds of femtoseconds, in good agreement with recent experiments. The switching times could be strongly reduced by properly tuning the energy gaps between the multiplet energy levels of Cr3+. Furthermore, the relaxation times also depend on the hybridization of atomic orbitals in the first photoexcited state. Our results suggest that the selective manipulation of the electronic structure by engineering stress-strain or chemical substitution allows effective control of the magnetic state switching in photoexcited insulating transition-metal oxides. PMID- 28668047 TI - Substituents' effect in electron attachment to epigenetic modifications of cytosine. AB - Epigenetic modifications of cytosine have been found to influence differently in many processes in biological systems. In order to investigate the differences in electron attachment to different epigenetic modifications of cytosine, we reported the A" component of the integral cross section of electron scattering by cytosine (C) and its epigenetic modifications 5-methylcytosine (5mC), 5 hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Our results were obtained with the Schwinger multichannel method with pseudopotentials in the static-exchange (SE) and static-exchange plus polarization (SEP) approximations. In addition to the scattering results, we present electron attachment energies obtained through an empirical scaling relation for the five molecules. We observed three pi* resonances for C, 5mC, and 5hmC and four for 5fC and 5caC, in both SE and SEP approximations. The cross sections show that the pi* resonances of 5mC and 5hmC are located at higher energies than the resonances of C, while the resonances of 5fC and 5caC are located at lower energies. In order to investigate this shift in the resonances' positions, we analyzed the pi* lowest-lying orbitals and the electronic density over the molecules. Using the inductive and mesomeric effects, we were able to analyze the influence of each substituent over the molecule and on the resonances' positions. PMID- 28668048 TI - Mass density fluctuations in quantum and classical descriptions of liquid water. AB - First principles molecular dynamics simulation protocol is established using revised functional of Perdew-Burke-Ernzerhof (revPBE) in conjunction with Grimme's third generation of dispersion (D3) correction to describe the properties of water at ambient conditions. This study also demonstrates the consistency of the structure of water across both isobaric (NpT) and isothermal (NVT) ensembles. Going beyond the standard structural benchmarks for liquid water, we compute properties that are connected to both local structure and mass density fluctuations that are related to concepts of solvation and hydrophobicity. We directly compare our revPBE results to the Becke-Lee-Yang-Parr (BLYP) plus Grimme dispersion corrections (D2) and both the empirical fixed charged model (SPC/E) and many body interaction potential model (MB-pol) to further our understanding of how the computed properties herein depend on the form of the interaction potential. PMID- 28668049 TI - Diblock copolymer bilayers as model for polymersomes: A coarse grain approach. AB - This paper presents a new model for polymersomes developed using a poly(ethylene oxide)-poly(butadiene) diblock copolymer bilayer. The model is based on a coarse grained approach using the MARTINI force field. Since no MARTINI parameters exist for poly(butadiene), we have refined these parameters using quantum mechanical calculations and molecular dynamics simulations. The model has been validated using extensive molecular dynamics simulations in systems with several hundred polymer units and reaching up to 6 MUs. These simulations show that the copolymer coarse grain model self-assemble into bilayers and that NPT and NPNgammaT ensemble runs reproduce key structural and mechanical experimental properties for different copolymer length chains with a similar hydrophilic weight fraction. PMID- 28668050 TI - Ionization of pyridine: Interplay of orbital relaxation and electron correlation. AB - The valence shell ionization spectrum of pyridine was studied using the third order algebraic-diagrammatic construction approximation scheme for the one particle Green's function and the outer-valence Green's function method. The results were used to interpret angle resolved photoelectron spectra recorded with synchrotron radiation in the photon energy range of 17-120 eV. The lowest four states of the pyridine radical cation, namely, 2A2(1a2-1), 2A1(7a1-1), 2B1(2b1 1), and 2B2(5b2-1), were studied in detail using various high-level electronic structure calculation methods. The vertical ionization energies were established using the equation-of-motion coupled-cluster approach with single, double, and triple excitations (EOM-IP-CCSDT) and the complete basis set extrapolation technique. Further interpretation of the electronic structure results was accomplished using Dyson orbitals, electron density difference plots, and a second-order perturbation theory treatment for the relaxation energy. Strong orbital relaxation and electron correlation effects were shown to accompany ionization of the 7a1 orbital, which formally represents the nonbonding sigma type nitrogen lone-pair (nsigma) orbital. The theoretical work establishes the important roles of the pi-system (pi-pi* excitations) in the screening of the nsigma-hole and of the relaxation of the molecular orbitals in the formation of the 7a1(nsigma)-1 state. Equilibrium geometric parameters were computed using the MP2 (second-order Moller-Plesset perturbation theory) and CCSD methods, and the harmonic vibrational frequencies were obtained at the MP2 level of theory for the lowest three cation states. The results were used to estimate the adiabatic 0-0 ionization energies, which were then compared to the available experimental and theoretical data. Photoelectron anisotropy parameters and photoionization partial cross sections, derived from the experimental spectra, were compared to predictions obtained with the continuum multiple scattering approach. PMID- 28668051 TI - Algorithm based on the Thomson problem for determination of equilibrium structures of metal nanoclusters. AB - A new algorithm for the determination of equilibrium structures suitable for metal nanoclusters is proposed. The algorithm performs a stochastic search of the minima associated with the nuclear potential energy function restricted to a sphere (similar to the Thomson problem), in order to guess configurations of the nuclear positions. Subsequently, the guessed configurations are further optimized driven by the total energy function using the conventional gradient descent method. This methodology is equivalent to using the valence shell electron pair repulsion model in guessing initial configurations in the traditional molecular quantum chemistry. The framework is illustrated in several clusters of increasing complexity: Cu7, Cu9, and Cu11 as benchmark systems, and Cu38 and Ni9 as novel systems. New equilibrium structures for Cu9, Cu11, Cu38, and Ni9 are reported. PMID- 28668052 TI - First principles crystal engineering of nonlinear optical materials. I. Prototypical case of urea. AB - The crystalline materials with nonlinear optical (NLO) properties are critically important for several technological applications, including nanophotonic and second harmonic generation devices. Urea is often considered to be a standard NLO material, due to the combination of non-centrosymmetric crystal packing and capacity for intramolecular charge transfer. Various approaches to crystal engineering of non-centrosymmetric molecular materials were reported in the literature. Here we propose using global lattice energy minimization to predict the crystal packing from the first principles. We developed a methodology that includes the following: (1) parameter derivation for polarizable force field AMOEBA; (2) local minimizations of crystal structures with these parameters, combined with the evolutionary algorithm for a global minimum search, implemented in program USPEX; (3) filtering out duplicate polymorphs produced; (4) reoptimization and final ranking based on density functional theory (DFT) with many-body dispersion (MBD) correction; and (5) prediction of the second-order susceptibility tensor by finite field approach. This methodology was applied to predict virtual urea polymorphs. After filtering based on packing similarity, only two distinct packing modes were predicted: one experimental and one hypothetical. DFT + MBD ranking established non-centrosymmetric crystal packing as the global minimum, in agreement with the experiment. Finite field approach was used to predict nonlinear susceptibility, and H-bonding was found to account for a 2.5-fold increase in molecular hyperpolarizability to the bulk value. PMID- 28668053 TI - Magnitude of pseudopotential localization errors in fixed node diffusion quantum Monte Carlo. AB - Growth in computational resources has lead to the application of real space diffusion quantum Monte Carlo to increasingly heavy elements. Although generally assumed to be small, we find that when using standard techniques, the pseudopotential localization error can be large, on the order of an electron volt for an isolated cerium atom. We formally show that the localization error can be reduced to zero with improvements to the Jastrow factor alone, and we define a metric of Jastrow sensitivity that may be useful in the design of pseudopotentials. We employ an extrapolation scheme to extract the bare fixed node energy and estimate the localization error in both the locality approximation and the T-moves schemes for the Ce atom in charge states 3+ and 4+. The locality approximation exhibits the lowest Jastrow sensitivity and generally smaller localization errors than T-moves although the locality approximation energy approaches the localization free limit from above/below for the 3+/4+ charge state. We find that energy minimized Jastrow factors including three-body electron-electron-ion terms are the most effective at reducing the localization error for both the locality approximation and T-moves for the case of the Ce atom. Less complex or variance minimized Jastrows are generally less effective. Our results suggest that further improvements to Jastrow factors and trial wavefunction forms may be needed to reduce localization errors to chemical accuracy when medium core pseudopotentials are applied to heavy elements such as Ce. PMID- 28668054 TI - Local structural ordering in surface-confined liquid crystals. AB - The effect of the interplay between attractive nonlocal surface interactions and attractive pair long-range intermolecular couplings on molecular structures of liquid crystals confined in thin cells with flat solid surfaces has been studied. Extending the McMillan mean field theory to include finite systems, it has been shown that confining surfaces can induce complex orientational and translational ordering of molecules. Typically, local smectic A, nematic, and isotropic phases have been shown to coexist in certain temperature ranges, provided that confining cells are sufficiently thick, albeit finite. Due to the nonlocality of surface interactions, the spatial arrangement of these local phases can display, in general, an unexpected complexity along the surface normal direction. In particular, molecules located in the vicinity of surfaces can still be organized in smectic layers, even though nematic and/or isotropic order can simultaneously appear in the interior of cells. The resulting surface freezing of smectic layers has been confirmed to occur even for rather weak surface interactions. The surface interactions cannot, however, prevent smectic layers from melting relatively close to system boundaries, even when molecules are still arranged in layers within the central region of the system. The internal interfaces, separating individual liquid-crystal phases, are demonstrated here to form fronts of local finite-size transitions that move across cells under temperature changes. Although the complex molecular ordering in surface confined liquid crystal systems can essentially be controlled by temperature variations, specific thermal properties of these systems, especially the nature of the local transitions, are argued to be strongly conditioned to the degree of molecular packing. PMID- 28668055 TI - Nonequilibrium molecular dynamics simulations of nanoconfined fluids at solid liquid interfaces. AB - We investigate the hydrodynamic properties of a Lennard-Jones fluid confined to a nanochannel using molecular dynamics simulations. For channels of different widths and hydrophilic-hydrophobic surface wetting properties, profiles of the fluid density, stress, and viscosity across the channel are obtained and analysed. In particular, we propose a linear relationship between the density and viscosity in confined and strongly inhomogeneous nanofluidic flows. The range of validity of this relationship is explored in the context of coarse grained models such as dynamic density functional-theory. PMID- 28668056 TI - Girsanov reweighting for path ensembles and Markov state models. AB - The sensitivity of molecular dynamics on changes in the potential energy function plays an important role in understanding the dynamics and function of complex molecules. We present a method to obtain path ensemble averages of a perturbed dynamics from a set of paths generated by a reference dynamics. It is based on the concept of path probability measure and the Girsanov theorem, a result from stochastic analysis to estimate a change of measure of a path ensemble. Since Markov state models (MSMs) of the molecular dynamics can be formulated as a combined phase-space and path ensemble average, the method can be extended to reweight MSMs by combining it with a reweighting of the Boltzmann distribution. We demonstrate how to efficiently implement the Girsanov reweighting in a molecular dynamics simulation program by calculating parts of the reweighting factor "on the fly" during the simulation, and we benchmark the method on test systems ranging from a two-dimensional diffusion process and an artificial many body system to alanine dipeptide and valine dipeptide in implicit and explicit water. The method can be used to study the sensitivity of molecular dynamics on external perturbations as well as to reweight trajectories generated by enhanced sampling schemes to the original dynamics. PMID- 28668057 TI - Observation of promoted C-O bond weakening on the heterometallic nickel-silver: Photoelectron velocity-map imaging spectroscopy of AgNi(CO)n. AB - We report a joint experimental and theoretical study on heterodinuclear silver nickel carbonyl clusters: AgNi(CO)n- and AgNi(CO)n (n = 2, 3). The photoelectron spectra and photoelectron angular distribution provide information on the electronic structures and geometries of these complexes. Electron affinities of AgNi(CO)2 and AgNi(CO)3 are measured from the photoelectron velocity-map imaging spectra to be 2.29 +/- 0.03 and 2.32 +/- 0.03 eV, respectively. The complementary theoretical calculations at the B3LYP level and Franck-Condon simulations are performed to establish their geometrical structures. The C-O stretching modes are activated upon photodetachment and determined to be 2024 and 2028 cm-1 for AgNi(CO)2 and AgNi(CO)3, respectively, which are notably red-shifted with respect to those of corresponding unsaturated binary nickel carbonyls. These findings will shed light on the promoted C-O bond weakening by the introduction of a foreign atom to binary unsaturated TM carbonyl complexes. PMID- 28668058 TI - Erratum: "Erratum: Study of SF6 adsorption on graphite using infrared spectroscopy" [J. Chem. Phys. 145, 249901 (2016)]. PMID- 28668059 TI - Planarizing cytosine: The S1 state structure, vibrations, and nonradiative dynamics of jet-cooled 5,6-trimethylenecytosine. AB - We measure the S0 -> S1 spectrum and time-resolved S1 state nonradiative dynamics of the "clamped" cytosine derivative 5,6-trimethylenecytosine (TMCyt) in a supersonic jet, using two-color resonant two-photon ionization (R2PI), UV/UV holeburning, and ns time-resolved pump/delayed ionization. The experiments are complemented with spin-component scaled second-order approximate coupled cluster (SCS-CC2), time-dependent density functional theory, and multi-state second-order perturbation-theory (MS-CASPT2) ab initio calculations. While the R2PI spectrum of cytosine breaks off ~500 cm-1 above its 000 band, that of TMCyt extends up to +4400 cm-1 higher, with over a hundred resolved vibronic bands. Thus, clamping the cytosine C5-C6 bond allows us to explore the S1 state vibrations and S0 -> S1 geometry changes in detail. The TMCyt S1 state out-of-plane vibrations nu1', nu3', and nu5' lie below 420 cm-1, and the in-plane nu11', nu12', and nu23' vibrational fundamentals appear at 450, 470, and 944 cm-1. S0 -> S1 vibronic simulations based on SCS-CC2 calculations agree well with experiment if the calculated nu1', nu3', and nu5' frequencies are reduced by a factor of 2-3. MS CASPT2 calculations predict that the ethylene-type S1 ? S0 conical intersection (CI) increases from +366 cm-1 in cytosine to >6000 cm-1 in TMCyt, explaining the long lifetime and extended S0 -> S1 spectrum. The lowest-energy S1 ? S0 CI of TMCyt is the "amino out-of-plane" (OPX) intersection, calculated at +4190 cm-1. The experimental S1 ? S0 internal conversion rate constant at the S1(v'=0) level is kIC=0.98-2.2?108 s-1, which is ~10 times smaller than in 1-methylcytosine and cytosine. The S1(v'=0) level relaxes into the T1(3pipi*) state by intersystem crossing with kISC=0.41-1.6?108 s-1. The T1 state energy is measured to lie 24 580+/-560 cm-1 above the S0 state. The S1(v'=0) lifetime is tau=2.9 ns, resulting in an estimated fluorescence quantum yield of Phifl=24%. Intense two-color R2PI spectra of the TMCyt amino-enol tautomers appear above 36 000 cm-1. A sharp S1 ionization threshold is observed for amino-keto TMCyt, yielding an adiabatic ionization energy of 8.114+/-0.002 eV. PMID- 28668060 TI - Improving proton conduction pathways in di- and triblock copolymer membranes: Branched versus linear side chains. AB - Phase separation within a series of polymer membranes in the presence of water is studied by dissipative particle dynamics. Each polymer contains hydrophobic A beads and hydrophilic C beads. Three parent architectures are constructed from a backbone composed of connected hydrophobic A beads to which short ([C]), long ([A3C]), or symmetrically branched A5[AC][AC] side chains spring off. Three di block copolymer derivatives are constructed by covalently bonding an A30 block to each parent architecture. Also three tri-blocks with A15 blocks attached to both ends of each parent architecture are modeled. Monte Carlo tracer diffusion calculations through the water containing pores for 1226 morphologies reveal that water diffusion for parent architectures is slowest and diffusion through the di blocks is fastest. Furthermore, diffusion increases with side chain length and is highest for branched side chains. This is explained by the increase of water pore size with , which is the average number of bonds that A beads are separated from a nearest C bead. Optimization of within the amphiphilic parent architecture is expected to be essential in improving proton conduction in polymer electrolyte membranes. PMID- 28668061 TI - Polyamorphism of D-mannitol. AB - Polymorphism is common in the crystalline state but rare and even controversial in the liquid or glassy state. Among molecular substances, only two are major contenders for materials that exhibit the phenomenon, including the famous case of water with its low- and high-density amorphous (LDA and HDA) ices . We report that the same phenomenon exists in another extensively hydrogen-bonded system, D mannitol. Under the ambient pressure, D-mannitol's supercooled liquid spontaneously transforms to another amorphous phase of lower energy, larger volume (2.1%), and stronger hydrogen bonds. This transition is similar to water's HDA to LDA transition and shows the same anomaly of heat release coupled with volume expansion. In both systems, polyamorphism appears to arise from the competing demands of hydrogen bonds (loose packing) and van der Waals forces (close packing). D-mannitol is expected to play an important role as a new system for investigating polyamorphic transitions and suggests a more general occurrence of the phenomenon than the current literature indicates in systems with extensive hydrogen bonds (network bonds in general). PMID- 28668062 TI - Structure-based sampling and self-correcting machine learning for accurate calculations of potential energy surfaces and vibrational levels. AB - We present an efficient approach for generating highly accurate molecular potential energy surfaces (PESs) using self-correcting, kernel ridge regression (KRR) based machine learning (ML). We introduce structure-based sampling to automatically assign nuclear configurations from a pre-defined grid to the training and prediction sets, respectively. Accurate high-level ab initio energies are required only for the points in the training set, while the energies for the remaining points are provided by the ML model with negligible computational cost. The proposed sampling procedure is shown to be superior to random sampling and also eliminates the need for training several ML models. Self correcting machine learning has been implemented such that each additional layer corrects errors from the previous layer. The performance of our approach is demonstrated in a case study on a published high-level ab initio PES of methyl chloride with 44 819 points. The ML model is trained on sets of different sizes and then used to predict the energies for tens of thousands of nuclear configurations within seconds. The resulting datasets are utilized in variational calculations of the vibrational energy levels of CH3Cl. By using both structure based sampling and self-correction, the size of the training set can be kept small (e.g., 10% of the points) without any significant loss of accuracy. In ab initio rovibrational spectroscopy, it is thus possible to reduce the number of computationally costly electronic structure calculations through structure-based sampling and self-correcting KRR-based machine learning by up to 90%. PMID- 28668063 TI - Highly accurate intensity factors of pure CO2 lines near 2 MUm. AB - Line intensities for carbon dioxide are measured with a novel spectroscopic approach, assisted by an optical frequency comb synthesizer for frequency calibration purposes. The main feature of the spectrometer consists in the exploitation of optical feedback from a V-shaped high-finesse optical resonator to effectively narrow a distributed feedback diode laser at the wavelength of 2 MUm. Laser-gas interaction takes place inside an isothermal cell, which is placed on the transmission from the cavity. High quality, self-calibrated, absorption spectra are observed in pure CO2 samples at different gas pressures, in coincidence with three lines of the R-branch of the nu1 + 2nu2 + nu3 band. Line intensities are determined using a global fitting approach in which a manifold of spectra are simultaneously analyzed across the range of pressures between 5 and 100 Torr, sharing a restricted number of unknown parameters. Various sources of uncertainty have been identified and carefully quantified, thus leading to an overall uncertainty ranging between 0.17% and 0.23%. The measured values are in a very good agreement with recent ab initio predictions. PMID- 28668065 TI - Thermodynamics of star polymer solutions: A coarse-grained study. AB - We consider a coarse-grained (CG) model with pairwise interactions, suitable to describe low-density solutions of star-branched polymers of functionality f. Each macromolecule is represented by a CG molecule with (f + 1) interaction sites, which captures the star topology. Potentials are obtained by requiring the CG model to reproduce a set of distribution functions computed in the microscopic model in the zero-density limit. Explicit results are given for f = 6, 12, and 40. We use the CG model to compute the osmotic equation of state of the solution for concentrations c such that Phip=c/c*?1, where c* is the overlap concentration. We also investigate in detail the phase diagram for f = 40, identifying the boundaries of the solid intermediate phase. Finally, we investigate how the polymer size changes with c. For Phip?0.3, polymers become harder as f increases at fixed reduced concentration c/c*. On the other hand, for Phip?0.3, polymers show the opposite behavior: At fixed Phip, the larger the value of f, the larger their size reduction is. PMID- 28668064 TI - Optimizing symmetry-based recoupling sequences in solid-state NMR by pulse transient compensation and asynchronous implementation. AB - Pulse imperfections like pulse transients and radio-frequency field maladjustment or inhomogeneity are the main sources of performance degradation and limited reproducibility in solid-state nuclear magnetic resonance experiments. We quantitatively analyze the influence of such imperfections on the performance of symmetry-based pulse sequences and describe how they can be compensated. Based on a triple-mode Floquet analysis, we develop a theoretical description of symmetry based dipolar recoupling sequences, in particular, R26411, calculating first- and second-order effective Hamiltonians using real pulse shapes. We discuss the various origins of effective fields, namely, pulse transients, deviation from the ideal flip angle, and fictitious fields, and develop strategies to counteract them for the restoration of full transfer efficiency. We compare experimental applications of transient-compensated pulses and an asynchronous implementation of the sequence to a supercycle, SR26, which is known to be efficient in compensating higher-order error terms. We are able to show the superiority of R26 compared to the supercycle, SR26, given the ability to reduce experimental error on the pulse sequence by pulse-transient compensation and a complete theoretical understanding of the sequence. PMID- 28668066 TI - Localized diabatization applied to excitons in molecular crystals. AB - Traditional ab initio electronic structure calculations of periodic systems yield delocalized eigenstates that should be understood as adiabatic states. For example, excitons are bands of extended states which superimpose localized excitations on every lattice site. However, in general, in order to study the effects of nuclear motion on exciton transport, it is standard to work with a localized description of excitons, especially in a hopping regime; even in a band regime, a localized description can be helpful. To extract localized excitons from a band requires essentially a diabatization procedure. In this paper, three distinct methods are proposed for such localized diabatization: (i) a simple projection method, (ii) a more general Pipek-Mezey localization scheme, and (iii) a variant of Boys diabatization. Approaches (i) and (ii) require localized, single-particle Wannier orbitals, while approach (iii) has no such dependence. These methods should be very useful for studying energy transfer through solids with ab initio calculations. PMID- 28668067 TI - An experimental study of OH(A2Sigma+) + H2: Electronic quenching, rotational energy transfer, and collisional depolarization. AB - Zeeman quantum beat spectroscopy has been used to determine the thermal (300 K) rate constants for electronic quenching, rotational energy transfer, and collisional depolarization of OH(A2Sigma+) by H2. Cross sections for both the collisional disorientation and collisional disalignment of the angular momentum in the OH(A2Sigma+) radical are reported. The experimental results for OH(A2Sigma+) + H2 are compared to previous work on the OH(A2Sigma+) + He and Ar systems. Further comparisons are also made to the OH(A2Sigma+) + Kr system, which has been shown to display significant non-adiabatic dynamics. The OH(A2Sigma+) + H2 experimental data reveal that collisions that survive the electronic quenching process are highly depolarizing, reflecting the deep potential energy wells that exist on the excited electronic state surface. PMID- 28668068 TI - Repetition and pair-interaction of string-like hopping motions in glassy polymers. AB - The dynamics of many glassy systems are known to exhibit string-like hopping motions each consisting of a line of particles displacing one another. By using the molecular dynamics simulations of glassy polymers, we show that these motions become highly repetitive back-and-forth motions as temperature decreases and do not necessarily contribute to net displacements. Particle hops which constitute string-like motions are reversed with a high probability, reaching 73% and beyond at low temperature. The structural relaxation rate is then dictated not by a simple particle hopping rate but instead by the rate at which particles break away from hopping repetitions. We propose that disruption of string repetitions and hence also structural relaxations are brought about by pair-interactions between strings. PMID- 28668069 TI - Revealing isomerism in sodium-water clusters: Photoionization spectra of Na(H2O)n (n = 2-90). AB - Soft ionization of sodium tagged polar clusters is increasingly used as a powerful technique for sizing and characterization of small aerosols with possible application, e.g., in atmospheric chemistry or combustion science. Understanding the structure and photoionization of the sodium doped clusters is critical for such applications. In this work, we report on measurements of photoionization spectra for sodium doped water clusters containing 2-90 water molecules. While most of the previous studies focused on the ionization threshold of the Na(H2O)n clusters, we provide for the first time full photoionization spectra, including the high-energy region, which are used as reference for a comparison with theory. As reported in previous work, we have seen an initial drop of the appearance ionization energy with cluster size to values of about 3.2 eV for n<5. In the size range from n = 5 to n = 15, broad ion yield curves emerge; for larger clusters, a constant range between signal appearance (~2.8 eV) and signal saturation (~4.1 eV) has been observed. The measurements are interpreted with ab initio calculations and ab initio molecular dynamics simulations for selected cluster sizes (n<= 15). The simulations revealed theory shortfalls when aiming at quantitative agreement but allowed us identifying structural motifs consistent with the observed ionization energy distributions. We found a decrease in the ionization energy with increasing coordination of the Na atom and increasing delocalization of the Na 3s electron cloud. The appearance ionization energy is determined by isomers with fully solvated sodium and a highly delocalized electron cloud, while both fully and incompletely solvated isomers with localized electron clouds can contribute to the high energy part of the photoionization spectrum. Simulations at elevated temperatures show an increased abundance of isomers with low ionization energies, an entropic effect enabling size selective infrared action spectroscopy, based on near threshold photoionization of Na(H2O)n clusters. In addition, simulations of the sodium pick up process were carried out to study the gradual formation of the hydrated electron which is the basis of the sodium-tagging sizing. PMID- 28668070 TI - beta-NMR measurements of molecular-scale lithium-ion dynamics in poly(ethylene oxide)-lithium-salt thin films. AB - beta-detected NMR (beta-NMR) has been used to study the molecular-scale dynamics of lithium ions in thin films of poly(ethylene oxide) (PEO) containing either lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) or lithium trifluoroacetate (LiTFA) salts at monomer-to-salt ratios (EO/Li) of 8.3. The results are compared with previous beta-NMR measurements on pure PEO and PEO with lithium triflate (LiOTf) at the same loading [McKenzie et al., J. Am. Chem. Soc. 136, 7833 (2014)]. Activated hopping of 8Li+ was observed in all of the films above ~250 K, with the hopping parameters strongly correlated with the ionicity of the lithium salt rather than the polymer glass transition temperature. The pre-exponential factor increases exponentially with ionicity, while the activation energy for hopping increases approximately linearly, going from 6.3+/-0.2 kJ mol-1 in PEO:LiTFA to 17.8+/-0.2 kJ mol-1 in PEO:LiTFSI. The more rapid increase in the pre-exponential factor outweighs the effect of the larger activation energy and results in 8Li+ hopping being fastest in PEO followed by PEO:LiTFSI, PEO:LiOTf, and PEO:LiTFA. PMID- 28668071 TI - Facing the challenge of predicting the standard formation enthalpies of n-butyl phosphate species with ab initio methods. AB - Tributyl-phosphate (TBP), a ligand used in the PUREX liquid-liquid separation process of spent nuclear fuel, can form an explosive mixture in contact with nitric acid that might lead to a violent explosive thermal runaway. In the context of safety of a nuclear reprocessing plant facility, it is crucial to predict the stability of TBP at elevated temperatures. So far, only the enthalpies of formation of TBP are available in the literature with rather large uncertainties, while those of its degradation products, di-(HDBP) and mono (H2MBP), are unknown. In this goal, we have used state-of-the art quantum chemical methods to compute the formation enthalpies and entropies of TBP and its degradation products di-(HDBP) and mono-(H2MBP) in gas and liquid phases. Comparisons of levels of quantum chemical theory revealed that there are significant effects of correlation on their electronic structures, pushing for the need of not only high level of electronic correlation treatment, namely, local coupled cluster with single and double excitation operators and perturbative treatment of triple excitations, but also extrapolations to the complete basis to produce reliable and accurate thermodynamics data. Solvation enthalpies were computed with the conductor-like screening model for real solvents [COSMO-RS], for which we observe errors not exceeding 22 kJ mol-1. We thus propose with final uncertainty of about 20 kJ mol-1 standard enthalpies of formation of TBP, HDBP, and H2MBP which amounts to -1281.7 +/- 24.4, -1229.4 +/- 19.6, and -1176.7 +/- 14.8 kJ mol-1, respectively, in the gas phase. In the liquid phase, the predicted values are -1367.3 +/- 24.4, -1348.7 +/- 19.6, and 1323.8+/- 14.8 kJ mol-1, to which we may add about -22 kJ mol-1 error from the COSMO-RS solvent model. From these data, the complete hydrolysis of TBP is predicted as an exothermic phenomena but showing a slightly endergonic process. PMID- 28668072 TI - High resolution jet-cooled infrared absorption spectra of (HCOOH)2, (HCOOD)2, and HCOOH-HCOOD complexes in 7.2 MUm region. AB - The rotationally resolved infrared spectra of (HCOOH)2, (HCOOD)2, and HCOOH-HCOOD complexes have been measured in 7.2 MUm region by using a segmented rapid-scan distributed-feedback quantum cascade laser absorption spectrometer to probe a slit supersonic jet expansion. The observed spectra are assigned to the v21 (H C/O-H in-plane bending) fundamental band of (HCOOH)2, the v15 (H-C/O-D in-plane bending) fundamental band of HCOOH-HCOOD, and the v20 (H-C-O in-plane bending) fundamental band of (HCOOD)2. Strong local perturbations caused by the rotation tunneling coupling between two tunneling components are observed in (HCOOH)2. The v21 fundamental band of (HCOOH)2 and the previously measured v22 fundamental and v12 + v14 combination bands [K. G. Goroya et al., J. Chem. Phys. 140, 164311 (2014)] are analyzed together, yielding a more precise tunneling splitting in the ground state, 0.011 367(92) cm-1. The band-origin of the v21 band of (HCOOH)2 is 1371.776 74(8) cm-1, and the tunneling splitting decreases to 0.000 38(18) cm-1 upon the vibrational excitation. The vibrational energy is 1386.755 49(16) cm-1 for the v15 vibrational mode of HCOOH-HCOOD and 1391.084 39(17) cm-1 for the v20 vibrational mode of (HCOOD)2. No apparent spectral splittings are resolved for HCOOH-HCOOD and (HCOOD)2 under our experimental conditions. The tunneling splitting in the ground state of HCOOH-HCOOD is estimated to be 0.001 13 cm-1 from its average linewidth. PMID- 28668073 TI - Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08). AB - BACKGROUND: Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013-08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. METHODS: The BOOG 2013-08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1-2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. DISCUSSION: If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. TRIAL REGISTRATION: The BOOG 2013-08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828. PMID- 28668074 TI - Evidence of lower oxygen reserves during labour in the growth restricted human foetus: a retrospective study. AB - BACKGROUND: The aim of the present study is to test the hypothesis that Growth Restricted foetuses (FGR) have the tendency to develop more pathological cardiotocograpic tracings during labour than do appropriate for gestational age foetuses and that there is a shorter time lapse from the beginning of labour and the advent of a pathological cardiotocograpic tracing. METHODS: The study was carried out at the Maternal-Foetal Medicine Unit of the Sant'Anna University Hospital, Turin, Italy. A total of 930 foetuses born at term between January and December 2012 were analysed: 355 small for gestational age (SGA) comprising both constitutional small for gestational age and growth restricted foetuses (cases group) and 575 Appropriate for Gestational Age (AGA) foetuses (control group). Tracings were evaluated independently by two obstetric consultants, according to the International Federation of Gynaecology and Obstetrics (FIGO) classification. The main outcomes considered were the incidence of pathological cardiotocograpic tracings and the time interval between the beginning of labour and the advent of pathological cardiotocograpic tracing. The Student's t-test, chi-square test and ANOVA were used for comparisons between cases and controls and amongst groups. Significance was set at <0.05. Univariate and multivariate odds-ratios were calculated. RESULTS: Foetuses with birthweight <3rd centile (growth restricted foetuses) more frequently presented pathological cardiotocograpic tracings in labour than did controls (43.8% vs. 21.6%; p < 0.001). Pathological cardiotocograpic tracing developed faster in the foetuses with birthweight <3rd centile group (53', 0'-277') than it did in the control group (170.5', 0'-550'; p < 0.05). A higher induction rate was observed in the cases (29.6%) than in the control group (17%), with statistical significance p < 0.001. To correct for this possible confounding factor a multivariate logistic regression analysis was performed. It confirmed a statistically significant increased risk of pathological cardiotocographic tracings in the FGR group (OR 1.63; CI 1.30-2.05). CONCLUSION: The results confirm the hypothesis that Growth Restricted foetuses (FGR) have fewer oxygen reserves to deal with labour. Our results underscore the importance of the prenatal detection of these foetuses and of their continuous cardiotocographic monitoring during labour. PMID- 28668075 TI - miRNome landscape analysis reveals a 30 miRNA core in retinoblastoma. AB - BACKGROUND: miRNAs exert their effect through a negative regulatory mechanism silencing expression upon hybridizing to their target mRNA, and have a prominent position in the control of many cellular processes including carcinogenesis. Previous miRNA studies on retinoblastoma (Rb) have been limited to specific miRNAs reported in other tumors or to medium density arrays. Here we report expression analysis of the whole miRNome on 12 retinoblastoma tumor samples using a high throughput microarray platform including 2578 mature miRNAs. METHODS: Twelve retinoblastoma tumor samples were analyzed using an Affymetrix platform including 2578 mature miRNAs. We applied RMA analysis to normalize raw data, obtained categorical data from detection call values, and also used signal intensity derived expression data. We used Diana-Tools-microT-CDS to find miRNA targets and ChromDraw to map miRNAs in chromosomes. RESULTS: We discovered a core cluster of 30 miRNAs that were highly expressed in all the cases and a cluster of 993 miRNAs that were uniformly absent in all cases. Another 1022 miRNA were variably present in the samples reflecting heterogeneity between tumors. We explored mRNA targets, pathways and biological processes affected by some of these miRNAs. We propose that the core-cluster of 30 miRs represent miRNA machinery common to all Rb, and affecting most pathways considered hallmarks of cancer. In this core, we identified miR-3613 as a potential and critical down regulatory hub, because it is highly expressed in all the samples and its potential mRNA targets include at least 36 tumor suppressor genes, including RB1. In the variably expressed miRNA, 36 were differentially expressed between males and females. Some of the potential pathways targeted by these 36 miRNAs were associated with hormonal production. CONCLUSION: These findings indicate that Rb tumor samples share a common miRNA expression profile regardless of tumor heterogeneity, and shed light on potential novel therapeutic targets such as mir 3613 This is the first work to delineate the miRNA landscape in retinoblastoma tumor samples using an unbiased approach. PMID- 28668076 TI - Ex vivo expanded natural killer cells from breast cancer patients and healthy donors are highly cytotoxic against breast cancer cell lines and patient-derived tumours. AB - BACKGROUND: Natural killer (NK) cells play a critical role in cancer immunosurveillance. Recent developments in NK cell ex-vivo expansion makes it possible to generate millions of activated NK cells from a small volume of peripheral blood. We tested the functionality of ex vivo expanded NK cells in vitro against breast cancer cell lines and in vivo using a xenograft mouse model. The study aim was to assess functionality and phenotype of expanded NK cells from breast cancer patients against breast cancer cell lines and autologous primary tumours. METHODS: We used a well-established NK cell co-culture system to expand NK cells ex vivo from healthy donors and breast cancer patients and examined their surface marker expression. Moreover, we tested the ability of expanded NK cells to lyse the triple negative breast cancer and HER2-positive breast cancer cell lines MDA-MB-231 and MDA-MB-453, respectively. We also tested their ability to prevent tumour growth in vivo using a xenograft mouse model. Finally, we tested the cytotoxicity of expanded NK cells against autologous and allogeneic primary breast cancer tumours in vitro. RESULTS: After 3 weeks of culture we observed over 1000-fold expansion of NK cells isolated from either breast cancer patients or healthy donors. We also showed that the phenotype of expanded NK cells is comparable between those from healthy donors and cancer patients. Moreover, our results confirm the ability of ex vivo expanded NK cells to lyse tumour cell lines in vitro. While the cell lines examined had differential sensitivity to NK cell killing we found this was correlated with level of major histocompatibility complex (MHC) class I expression. In our in vivo model, NK cells prevented tumour establishment and growth in immunocompromised mice. Finally, we showed that NK cells expanded from the peripheral blood of breast cancer patients show high cytotoxicity against allogeneic and autologous patient derived tumour cells in vitro. CONCLUSION: NK cells from breast cancer patients can be expanded similarly to those from healthy donors, have a high cytotoxic ability against breast cancer cell lines and patient-derived tumour cells, and can be compatible with current cancer treatments to restore NK cell function in cancer patients. PMID- 28668077 TI - Variation of mutant allele frequency in NRAS Q61 mutated melanomas. AB - BACKGROUND: Somatic mutations of BRAF or NRAS activating the MAP kinase cell signaling pathway are present in 70% of cutaneous melanomas. The mutant allele frequency of BRAF V600E (M%BRAF) was recently shown to be highly heterogeneous in melanomas. The present study focuses on the NRAS Q61 mutant allele frequency (M%NRAS). METHODS: Retrospective quantitative analyze of 104 NRAS mutated melanomas was performed using pyrosequencing. Mechanisms of M%NRAS imbalance were studied by fluorescence in situ hybridization (FISH) and microsatellite analysis. RESULTS: M%NRAS was increased in 27.9% of cases. FISH revealed that chromosome 1 instability was the predominant mechanism of M%NRAS increase, with chromosome 1 polysomy observed in 28.6% of cases and intra-tumor cellular heterogeneity with copy number variations of chromosome 1/NRAS in 23.8%. Acquired copy-neutral loss of heterozygosity (LOH) was less frequent (19%). However, most samples with high M%NRAS had only one copy of NRAS locus surrounding regions suggesting a WT allele loss. Clinical characteristics and survival of patients with either <60% or >=60% of M%NRAS were not different. CONCLUSION: As recently shown for M%BRAF, M%NRAS is highly heterogeneous. The clinical impacts of high M%NRAS should be investigated in a larger series of patients. PMID- 28668078 TI - Population genetic structure in Sabatieria (Nematoda) reveals intermediary gene flow and admixture between distant cold seeps from the Mediterranean Sea. AB - BACKGROUND: There is a general lack of information on the dispersal and genetic structuring for populations of small-sized deep-water taxa, including free-living nematodes which inhabit and dominate the seafloor sediments. This is also true for unique and scattered deep-sea habitats such as cold seeps. Given the limited dispersal capacity of marine nematodes, genetic differentiation between such geographically isolated habitat patches is expected to be high. Against this background, we examined genetic variation in both mitochondrial (COI) and nuclear (18S and 28S ribosomal) DNA markers of 333 individuals of the genus Sabatieria, abundantly present in reduced cold-seep sediments. Samples originated from four Eastern Mediterranean cold seeps, separated by hundreds of kilometers, and one seep in the Southeast Atlantic. RESULTS: Individuals from the Mediterranean and Atlantic were divided into two separate but closely-related species clades. Within the Eastern Mediterranean, all specimens belonged to a single species, but with a strong population genetic structure (PhiST = 0.149). The haplotype network of COI contained 19 haplotypes with the most abundant haplotype (52% of the specimens) shared between all four seeps. The number of private haplotypes was high (15), but the number of mutations between haplotypes was low (1-8). These results indicate intermediary gene flow among the Mediterranean Sabatieria populations with no evidence of long-term barriers to gene flow. CONCLUSIONS: The presence of shared haplotypes and multiple admixture events indicate that Sabatieria populations from disjunct cold seeps are not completely isolated, with gene flow most likely facilitated through water current transportation of individuals and/or eggs. Genetic structure and molecular diversity indices are comparable to those of epiphytic shallow-water marine nematodes, while no evidence of sympatric cryptic species was found for the cold-seep Sabatieria. PMID- 28668080 TI - Psychometric evaluation of the canine brief pain inventory in a Swedish sample of dogs with pain related to osteoarthritis. AB - BACKGROUND: To evaluate intervention, implement evidence-based practice and enhance the welfare of dogs with naturally occurring osteoarthritis (OA), access to valid, reliable and clinically relevant outcome measures is crucial for researchers, veterinarians and rehabilitation practitioners. The objectives of the present study were to translate and evaluate psychometric properties, in terms of internal consistency and construct validity, of the owner-reported measure canine brief pain inventory (CBPI) in a Swedish sample of dogs with pain related to OA. RESULTS: Twenty-one owners of clinically sound dogs and 58 owners of dogs with pain related to OA were included in this observational and cross sectional study. After being translated according to the guidelines for patient reported outcome measures, the CBPI was completed by the canine owners. Construct validity was assessed by confirmatory factor analysis, by repeating the principal component analysis and by assessing for differences between clinically sound dogs and dogs with pain related to OA. Internal consistency was estimated by Cronbach's alpha. Confirmatory factor analysis was not able to confirm the factor structure models tested in our sample. Principal component analysis showed a two component structure, pain severity and pain interference of function. Two components accounted for 76.8% of the total variance, suggesting an acceptable fit of a two-component structure. The ratings from the clinically sound dogs differed from OA dogs and showed significantly lower CBPI total sum. Cronbach's alpha was 0.94 for the total CBPI, 0.91 for the pain severity and 0.91 for the pain interference of function. CONCLUSIONS: The results indicate that the translated version of the CBPI is valid for use in the Swedish language. The findings suggest satisfying psychometric properties in terms of high internal consistencies and ability to discriminate clinically sound dogs from OA dogs. However, based on the confirmatory factor analysis, the original factor structure in the CBPI is not ideally suited to measure pain related to OA in our sample and the hypothesis of the presented two-factor structure was rejected. Further research needs to be conducted to determine whether the original psychometric results from CBPI can be replicated across different target groups and particularly with larger sample size. PMID- 28668079 TI - Effects of Bu Shen Yi sui capsule on NogoA/NgR and its signaling pathways RhoA/ROCK in mice with experimental autoimmune encephalomyelitis. AB - BACKGROUND: Axon growth inhibitory factors NogoA/Nogo receptor (NgR) and its signaling pathways RhoA/Rho kinase (ROCK) play a critical role in the repair of nerve damage in multiple sclerosis (MS). Bu Shen Yi Sui Capsule (BSYSC) is an effective Chinese formula utilized to treat MS in clinical setting and noted for its potent neuroprotective effects. In this study, we focus on the effects of BSYSC on promoting nerve repair and the underlying mechanisms in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. METHODS: The EAE mouse model was induced by injecting subcutaneously with myelin oligodendrocyte glycoprotein (MOG) 35-55 supplemented with pertussis toxin. BSYSC was orally administrated at dose of 3.0 g/kg once a day for 40 days. The levels of protein gene product (PGP) 9.5, p-Tau, growth associated protein (GAP) -43, KI67 and Nestin in the brain or spinal cord on 20 and 40 day post-induction (dpi) were detected via immunofluorescence and Western blot analysis. Furthermore, NogoA/NgR and RhoA/ROCK signaling molecules were studied by qRT-PCR and Western blot analysis. RESULTS: Twenty or 40 days of treatment with BSYSC increased markedly PGP9.5 and GAP-43 levels, reduced p-Tau in the brain or spinal cord of mice with EAE. In addition, BSYSC elevated significantly the expression of KI67 and Nestin in the spinal cord 40 dpi. Further study showed that the activation of NogoA/NgR and RhoA/ROCK were suppressed by the presence of BSYSC. CONCLUSIONS: BSYSC could attenuate axonal injury and promote repair of axonal damage in EAE mice in part through the down-regulation of NogoA/NgR and RhoA/ROCK signaling pathways. PMID- 28668081 TI - Comparing trends in mortality from cardiovascular disease and cancer in the United Kingdom, 1983-2013: joinpoint regression analysis. AB - BACKGROUND: We aimed to study the time trends underlying a change from cardiovascular disease (CVD) to cancer as the most common cause of age standardized mortality in the UK between 1983 and 2013. METHODS: A retrospective trend analysis of the World Health Organization mortality database for mortality from all cancers, all CVDs, and their three most common types, by sex and age. Age-standardized mortality rates were adjusted to the 2013 European Standard Population and analyzed using joinpoint regression analysis for annual percent changes. RESULTS: The difference in mortality rate between total CVD and cancer narrowed over the study period as age-standardized mortality from CVD decreased more steeply than cancer in both sexes. We observed higher overall rates for both diseases in men compared to women, with high mortality rates from ischemic heart disease and lung cancer in men. Joinpoint regression analysis indicated that trends of decreasing rates of CVD have increased over time while decreasing trends in cancer mortality rates have slowed down since the 1990s. The lowest improvements in mortality rates were for cancer in those over 75 years of age and lung cancer in women. CONCLUSIONS: In 2011, the age-standardized mortality rate for cancer exceeded that of CVD in both sexes in the UK. These changing trends in mortality may support evidence for changes in policy and resource allocation in the UK. PMID- 28668082 TI - Genetic diversity, population structure and marker-trait associations for agronomic and grain traits in wild diploid wheat Triticum urartu. AB - BACKGROUND: Wild diploid wheat, Triticum urartu (T. urartu) is the progenitor of bread wheat, and understanding its genetic diversity and genome function will provide considerable reference for dissecting genomic information of common wheat. RESULTS: In this study, we investigated the morphological and genetic diversity and population structure of 238 T. urartu accessions collected from different geographic regions. This collection had 19.37 alleles per SSR locus and its polymorphic information content (PIC) value was 0.76, and the PIC and Nei's gene diversity (GD) of high-molecular-weight glutenin subunits (HMW-GSs) were 0.86 and 0.88, respectively. UPGMA clustering analysis indicated that the 238 T. urartu accessions could be classified into two subpopulations, of which Cluster I contained accessions from Eastern Mediterranean coast and those from Mesopotamia and Transcaucasia belonged to Cluster II. The wide range of genetic diversity along with the manageable number of accessions makes it one of the best collections for mining valuable genes based on marker-trait association. Significant associations were observed between simple sequence repeats (SSR) or HMW-GSs and six morphological traits: heading date (HD), plant height (PH), spike length (SPL), spikelet number per spike (SPLN), tiller angle (TA) and grain length (GL). CONCLUSIONS: Our data demonstrated that SSRs and HMW-GSs were useful markers for identification of beneficial genes controlling important traits in T. urartu, and subsequently for their conservation and future utilization, which may be useful for genetic improvement of the cultivated hexaploid wheat. PMID- 28668083 TI - Increasing family planning in Myanmar: the role of the private sector and social franchise programs. AB - BACKGROUND: This study examines the influence of clinical social franchise program on modern contraceptive use. METHODS: This was a cross-sectional survey of contraceptive use among 2390 currently married women across 25 townships in Myanmar in 2014. Social franchise program measures were from programmatic records. RESULTS: Multivariable models show that women who lived in communities with at least 1-5 years of a clinical social franchise intrauterine device (IUD) program had 4.770 higher odds of using a modern contraceptive method compared to women living in communities with no IUD program [CI: 3.739-6.084]. Townships where the reproductive health program had existed for at least 10 years had 1.428 higher odds of reporting modern method use compared to women living in townships where the programs had existed for less than 10 years [CI: 1.016-2.008]. CONCLUSIONS: This study found consistent and robust evidence for an increase in family planning methods over program duration as well as intensity of social franchise programs. PMID- 28668085 TI - Utility of somatosensory evoked potentials in the assessment of response to IVIG in a long-lasting case of chronic immune sensory polyradiculopathy. AB - BACKGROUND: Chronic immune sensory polyradiculopathy (CISP) identifies a progressive acquired peripheral dysimmune neuropathy recognized as a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) variant. We describe a young woman with a thirteen-year history of CISP with a belated variable response to intravenous immunoglobulin (IVIG) and an almost erratic anticipation of symptoms between IVIG cycles. The association of IVIG and corticosteroids, immunosuppressants, plasmapheresis, did not lead to clinical improvement and was characterized by significant side effects. We evaluated a combined clinical and somatosensory evoked potentials (SSEPs) approach aimed to identify possible predictive parameters concerning the effect and duration of each IVIG administration. Neurologic disability was evaluated using INCAT - Overall Disability Sum Score (INCAT-ODSS). CASE PRESENTATION: A 30-year-old woman presented on 2004 for the subacute onset of asymmetric paresthesias in the lower limbs over the previous six months. The symptoms had been relapsing-remitting during the first four months, followed by a slow progression, resulting in limbs ataxia and a progressive gait disturbance requiring Canadian crutches. Motor and sensory nerve conduction studies and electromyographic evaluation were into normal limits. Median SSEPs were normal, while tibial SSEPs were characterised by the bilateral absence of both lumbar and cortical responses. Cerebrospinal fluid detected an increased protein concentration, while spinal MRI showed a pronounced thickening of the sacral nerve roots, together with a tube-shaped enlargement. These findings led to the diagnosis of CISP and the patient was treated with IVIG reaching a stable remission over the following 9 years. In early 2014, the patient began to show a variable response to treatment with erratic anticipation of sensory disturbances, and a more pronounced walking disability: corticosteroids, plasmapheresis, mycophenolate mofetil and cyclophosphamide were uneffective and burdened by relevant side effects. To better assess the response to IVIG in terms of time-effect, consistency and duration, we have combined a scheduled clinical and SSEPs evaluation during and after each IVIG cycle. CONCLUSIONS: The correlation between the neurophysiological data and the INCAT ODSS scores has allowed the modulation of IVIG cycles with a significant reduction of the clinical fluctuations and disability. SSEPs may therefore represent an useful and recommended additional aid for the treatment schedule of this rare clinical form. PMID- 28668084 TI - Factors influencing the ownership and utilization of long-lasting insecticidal nets for malaria prevention in Ethiopia. AB - BACKGROUND: Utilization of long-lasting insecticidal nets (LLINs) is regarded as key malaria prevention and control strategy. However, studies have reported a large gap in terms of both ownership and utilization particularly in the sub Saharan Africa (SSA). With continual efforts to improve the use of LLIN and to progress malaria elimination, examining the factors influencing the ownership and usage of LLIN is of high importance. Therefore, the current study was conducted to examine the level of ownership and use of LLIN along with identification of associated factors at household level. METHODS: A cross-sectional study was conducted in Mirab Abaya District, Southern Ethiopia in June and July 2014. A total of 540 households, with an estimated 2690 members, were selected in four kebeles of the district known to have high incidence of malaria. Trained data collectors interviewed household heads to collect information on the knowledge, ownership and utilization of LLINs, which was complemented by direct observation on the conditions and use of the nets through house-to-house visit. Bivariate and multivariable logistic regression analyses were used to determine factors associated to LLIN use. RESULTS: Of 540 households intended to be included in the survey, 507 responded to the study (94.24% response rate), covering the homes of 2759 people. More than 58% of the households had family size >5 (the regional average), and 60.2% of them had at least one child below the age of 5 years. The ownership of at least one LLIN among households surveyed was 89.9%, and using at least one LLIN during the night prior to the survey among net owners was 85.1% (n = 456). Only 36.7% (186) mentioned at least as the mean of correct scores of all participants for 14 possible malaria symptoms and 32.7% (166) knew at least as the mean of correct scores of all participants for possible preventive methods. Over 30% of nets owned by the households were out of use. After controlling for confounding factors, having two or more sleeping places (adjusted odds ratio [aOR] = 2.58, 95% CI 1.17, 5.73), knowledge that LLIN prevents malaria (aOR = 2.51, 95% CI 1.17, 5.37), the presence of hanging bed nets (aOR = 19.24, 95% CI 9.24, 40.07) and walls of the house plastered or painted >12 months ago (aOR = 0.09, 95% CI 0.01, 0.71) were important predictors of LLIN utilization. CONCLUSIONS: This study found a higher proportion of LLIN ownership and utilization by households than had previously been found in similar studies in Ethiopia, and in many studies in SSA. However, poor knowledge of the transmission mechanisms and the symptoms of malaria, and vector control measures to prevent malaria were evident. Moderate proportions of nets were found to be out of use or in poor repair. Efforts should be in place to maintain the current rate of utilization of LLIN in the district and improve on the identified gaps in order to support the elimination of malaria. PMID- 28668086 TI - The (Mis)appropriation of HIV/AIDS advocacy strategies in Global Mental Health: towards a more nuanced approach. AB - BACKGROUND: Mental health is increasingly finding a place on global health and international development agendas. Advocates for Global Mental Health (GMH), and international organizations such as the World Health Organization (WHO) and the World Bank, argue that treatments available in high-income countries should also be made available in low- and middle-income countries. Such arguments are often made by comparing mental health to infectious diseases, including the relative disease and economic burdens they impose, and pointing to the applicability of the right to access treatment for mental health, not only infectious diseases. HIV/AIDS advocacy in particular has been held up by GMH advocates as offering an appropriate strategy for generating global commitment. DISCUSSION: There is a need to assess how health issues are framed not only in relation to social goods outside of health (such as human rights, security or development), but also in relation to other health or disease models, and how health policy and practice is shaped as a result. The article debates the merits and consequences of likening mental health to HIV/AIDS, and identifies four major problems with the model for GMH advocacy being developed through these analogies: 1. An inappropriately universalizing global approach to context-specific problems; 2. A conception of human rights that focuses on the right to access treatment at the expense of the right to refuse it; 3. A tendency to treat poverty as a psychiatric issue, rather than recognizing that mental distress can be the result of poverty and other forms of inequality; 4. The prioritization of destigmatization of disease over social justice models. CONCLUSION: There are significant problems with the wholesale adoption of an (often simplified) version of HIV/AIDS advocacy as a model for GMH. Yet critical engagement with the important and nuanced differences between HIV/AIDS and mental health may nevertheless point to some possibilities for productive engagement and cross-fertilisation between advocates, activists and scholars in both fields. PMID- 28668087 TI - Inhibition of HDAC6 activity through interaction with RanBPM and its associated CTLH complex. AB - BACKGROUND: Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase that promotes many cellular processes that lead to cell transformation and tumour development. We previously documented an interaction between Ran-Binding Protein M (RanBPM) and HDAC6 and found that RanBPM expression inhibits HDAC6 activity. RanBPM is part of a putative E3 ubiquitin ligase complex, termed the C-terminal to LisH (CTLH) complex. Here, we investigated the involvement of the CTLH complex on HDAC6 inhibition and assessed the outcome of this regulation on the cellular motility induced by HDAC6. METHODS: Cell lines (Hela, HEK293 and immortalized mouse embryonic fibroblasts) stably or transiently downregulated for several components of the CTLH complex were employed for the assays used in this study. Interactions of HDAC6, RanBPM and muskelin were assessed by co immunoprecipitations. Quantifications of western blot analyses were employed to evaluate acetylated alpha-tubulin levels. Confocal microscopy analyses were used to determine microtubule association of HDAC6 and CTLH complex members. Cell migration was evaluated using wound healing assays. RESULTS: We demonstrate that RanBPM-mediated inhibition of HDAC6 is dependent on its association with HDAC6. We show that, while HDAC6 does not require RanBPM to associate with microtubules, RanBPM association with microtubules requires HDAC6. Additionally, we show that Twa1 (Two-hybrid-associated protein 1 with RanBPM) and MAEA (Macrophage Erythroblast Attacher), two CTLH complex members, also associate with alpha tubulin and that muskelin, another component of the CTLH complex, is able to associate with HDAC6. Downregulation of CTLH complex members muskelin and Rmnd5A (Required for meiotic nuclear division homolog A) resulted in decreased acetylation of HDAC6 substrate alpha-tubulin. Finally, we demonstrate that the increased cell migration resulting from downregulation of RanBPM is due to the relief in inhibition of HDAC6 alpha-tubulin deacetylase activity. CONCLUSIONS: Our work shows that RanBPM, together with the CTLH complex, associates with HDAC6 and restricts cell migration through inhibition of HDAC6 activity. This study uncovers a novel function for the CTLH complex and suggests that it could have a tumour suppressive role in restricting HDAC6 oncogenic properties. PMID- 28668089 TI - Patient experience and overall satisfaction after emergency abdominal surgery. AB - BACKGROUND: There is a growing recognition of the importance of patient experience in healthcare, however little is known in the context of emergency abdominal surgery. This study sought to quantify the association between patient experience and overall satisfaction. METHODS: Patient demographics, operation details and 30-day clinical outcome data of consecutive patients undergoing emergency abdominal surgery were collected. Data was collected using validated Patient Reported Experience Measures (PREMs) questionnaires. Categorical data were tested using Mann Whitney U test. Multivariable regression was used to determine independent factors associated with satisfaction. RESULTS: In a well fitting multivariable analysis (R2 = 0.71), variables significantly associated with a higher global satisfaction score were "sufficient information given about treatment" (beta = 0.86, 95% CI 0.01-1.70, p = 0.047), "sufficient explanation of risks and benefits of surgery" (beta = 1.26, 95% CI 0.18-2.34, p = 0.020), "absence of night-time noise" (beta = 1.35, 95% CI 0.56-2.14, p = 0.001) and "confidence and trust in nurses" (beta = 1.51, 95% CI 0.54-2.49, p = 0.003). CONCLUSIONS: Overall patient satisfaction was strongly associated with perceptions of good communication and transfer of information. Confidence and trust in the clinical team is an important determinant of patient experience. Improving the ward environment by reducing noise at night may also improve the overall experience and satisfaction in emergency surgery. PMID- 28668088 TI - Transforming growth factor activating kinase 1 regulates extracellular matrix degrading enzymes and pain-related molecule expression following tumor necrosis factor-alpha stimulation of synovial cells: an in vitro study. AB - BACKGROUND: Recent studies have suggested that the tumor necrosis factor-alpha (TNF-alpha) pathway is a potential target for the management of osteoarthritis (OA). Transforming growth factor (TGF)-beta-activated kinase 1 (TAK1) is essential in several cytokine-mediated cascades, including the TNF-alpha, interleukin-1 (IL-1), and TGF-beta pathways. The role of TAK1 in synovial tissue in OA is not fully understood. Using synovial cells harvested from OA patients during surgery, we investigated whether TAK1 inhibition suppresses production of TNF-alpha-induced extracellular matrix degrading enzymes and expression of pain related molecules. METHODS: Synovial tissues were harvested from ten subjects with radiographic evidence of osteoarthritis (OA) during total knee arthroplasty. Synovial cells were cultured and stimulated with control (culture media), 10 ng/mL human recombinant TNF-alpha, or 10 ng/mL TNF-alpha and 10 MUM of the TAK1 inhibitor (5Z)-7-oxozeaenol for 24 h. Real-time polymerase chain reaction (PCR) analysis was used to monitor expression of mRNA of the extracellular matrix degrading enzymes matrix metalloproteinase-3 (MMP-3) and a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 4 (ADAMTS-4); and of the pain-related molecules cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), and nerve growth factor (NGF). MMP-3 and NGF protein concentrations in cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). COX-2, mPGES-1 and ADAMTS-4 protein expression was also evaluated by western blotting. RESULTS: TNF-alpha stimulated increases in ADAMTS-4 and MMP3 mRNA (2.0-fold and 1.6-fold, respectively, p < 0.05) and protein expression (21.5-fold and 2.0-fold, respectively). Treatment with the TAK1 inihibitor (5Z)-7-oxozeaenol reduced ADAMTS-4 and MMP3 mRNA (0.5-fold and 0.6-fold, respectively) and protein expression (1.4-fold and 0.5-fold, respectively) in OA synovial cells. COX-2, mPGES-1 and NGF mRNA (11.2-fold, 3.1 fold and 2.7-fold, respectively) and protein expression (3.0-fold, 2.7-fold and 2.2-fold, respectively) were increased by TNF-alpha. (5Z)-7-oxozeaenol treatment reduced mPGES1 and NGF mRNA (1.5-fold and 0.8-fold, respectively) and protein (1.5-fold and 0.5-fold, respectively). CONCLUSION: TAK1 plays an important role in the regulation of TNF-alpha induced extracellular matrix degrading enzymes and pain-related molecule expression. TAK1 may be a potential target for therapeutic strategies aimed at preventing osteoarthritis progression and pain. PMID- 28668090 TI - Informal caregivers experience of supplemental oxygen in pulmonary fibrosis. AB - BACKGROUND: Patients prescribed supplemental oxygen (O2) therapy face challenges as they adjust to being constantly "tethered" to an oxygen delivery device. Informal caregivers (ICs) of patients with pulmonary fibrosis (PF) face their own, often overlooked hardships when O2 is brought into their home and added to their lives. Our aim was to understand the multiple effects of supplemental oxygen therapy on ICs of patients with PF. METHODS: We conducted single, semi structured telephone interviews with twenty ICs of patients with PF who were using O2 for at least 8 months. We performed a qualitative, content analysis based in grounded theory to examine data across subjects. RESULTS: ICs initially reacted to O2 with trepidation and sadness as they came to recognize the changes it would cause in the lives of their patient-loved one (PLO). ICs recognized both beneficial and negative effects of O2 on their PLOs. ICs also realized that O2 created significant changes in their own lives, including introducing new roles and responsibilities for them, altering their home environments and significantly impacting their relationships with their PLOs. Although O2 was a tangible and constant reminder of disease progression, over time ICs were able to adapt and accept their new lives with O2. CONCLUSION: ICs of patients with PF experience many life changes when their PLO is prescribed O2. Having O2 prescribers anticipate and recognize these challenges provides an opportunity to give support and guidance to ICs of PF patients who require O2 in the hopes of limiting the negative impact of O2 on their lives. TRIAL REGISTRATION: Clinicaltrials.gov , registration number NCT01961362 . Registered 9 October 2013. PMID- 28668091 TI - Amplification and propagation of interleukin-1beta signaling by murine brain endothelial and glial cells. AB - BACKGROUND: During acute infections and chronic illnesses, the pro-inflammatory cytokine interleukin-1beta (IL-1beta) acts within the brain to elicit metabolic derangements and sickness behaviors. It is unknown which cells in the brain are the proximal targets for IL-1beta with respect to the generation of these illness responses. We performed a series of in vitro experiments to (1) investigate which brain cell populations exhibit inflammatory responses to IL-1beta and (2) examine the interactions between different IL-1beta-responsive cell types in various co culture combinations. METHODS: We treated primary cultures of murine brain microvessel endothelial cells (BMEC), astrocytes, and microglia with PBS or IL 1beta, and then performed qPCR to measure inflammatory gene expression or immunocytochemistry to evaluate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation. To evaluate whether astrocytes and/or BMEC propagate inflammatory signals to microglia, we exposed microglia to astrocyte-conditioned media and co-cultured endothelial cells and glia in transwells. Treatment groups were compared by Student's t tests or by ANOVA followed by Bonferroni-corrected t tests. RESULTS: IL-1beta increased inflammatory gene expression and NF-kappaB activation in primary murine-mixed glia, enriched astrocyte, and BMEC cultures. Although IL-1beta elicited minimal changes in inflammatory gene expression and did not induce the nuclear translocation of NF-kappaB in isolated microglia, these cells were more robustly activated by IL-1beta when co-cultured with astrocytes and/or BMEC. We observed a polarized endothelial response to IL-1beta, because the application of IL-1beta to the abluminal endothelial surface produced a more complex microglial inflammatory response than that which occurred following luminal IL-1beta exposure. CONCLUSIONS: Inflammatory signals are detected, amplified, and propagated through the CNS via a sequential and reverberating signaling cascade involving communication between brain endothelial cells and glia. We propose that the brain's innate immune response differs depending upon which side of the blood brain barrier the inflammatory stimulus arises, thus allowing the brain to respond differently to central vs. peripheral inflammatory insults. PMID- 28668092 TI - Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer's disease. AB - BACKGROUND: Given multiple studies of brain microRNA (miRNA) in relation to Alzheimer's disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimer's disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region. METHODS: We report analyses of expression profiling of miRNA (n = 700 subjects) and lincRNA (n = 540 subjects) from the dorsolateral prefrontal cortex of individuals participating in two longitudinal cohort studies of aging. RESULTS: We confirm the association of two well-established miRNA (miR-132, miR 129) with pathologic AD in our dataset and then further characterize this association in terms of its component neuritic beta-amyloid plaques and neurofibrillary tangle pathologies. Additionally, we identify one new miRNA (miR 99) and four lincRNA that are associated with these traits. Many other previously reported associations of microRNA with AD are associated with the confounders quantified in our longitudinal cohort. Finally, by performing analyses integrating both miRNA and RNA sequence data from the same individuals (525 samples), we characterize the impact of AD associated miRNA on human brain expression: we show that the effects of miR-132 and miR-129-5b converge on certain genes such as EP300 and find a role for miR200 and its target genes in AD using an integrated miRNA/mRNA analysis. CONCLUSIONS: Overall, miRNAs play a modest role in human AD, but we observe robust evidence that a small number of miRNAs are responsible for specific alterations in the cortical transcriptome that are associated with AD. PMID- 28668093 TI - Serum cytokine profile in pediatric Sweet's syndrome: a case report. AB - BACKGROUND: Sweet's syndrome is characterized by fever, leukocytosis, and tender erythematous papules or nodules. It is a rare condition, particularly in the pediatric population, and has recently been proposed to be an autoinflammatory disease that occurs due to innate immune system dysfunction, involving several cytokines, which causes abnormally increased inflammation. To the best of our knowledge, no report has documented the cytokine profile in a pediatric patient with Sweet's syndrome. CASE PRESENTATION: A previously healthy 34-month-old Japanese girl was hospitalized because of remittent fever and pain in her right lower extremity with erythematous nodules. A skin biopsy of the eruption revealed dermal perivascular neutrophilic infiltration with no evidence of vasculitis, which led to the diagnosis of Sweet's syndrome. She was prescribed with orally administered prednisolone and a prompt response was observed; then, the prednisolone dose was tapered. During treatment she developed upper and lower urinary tract infections, after which her cutaneous symptoms failed to improve despite increasing the prednisolone dosage. To avoid long-term use of systemic corticosteroids, orally administered potassium iodide was initiated, but it was unsuccessful. However, orally administered colchicine along with prednisolone effectively ameliorated her symptoms, and prednisolone dosage was reduced again. We analyzed the circulating levels of interleukin-1beta, interleukin-6, interleukin-18, neopterin, and soluble tumor necrosis factor receptors I and II, in order to clarify the pathogenesis of Sweet's syndrome. Of these cytokines, only interleukin-6 levels were elevated prior to orally administered prednisolone therapy. Following therapy, the elevated interleukin-6 levels gradually diminished to almost normal levels; interleukin-1beta and interleukin-18 stayed within normal ranges throughout the treatment. Neopterin became marginally elevated after the start of treatment. Both soluble tumor necrosis factor receptor I and soluble tumor necrosis factor receptor II levels increased shortly after the onset of urinary tract infections. CONCLUSIONS: This is the first case report of pediatric Sweet's syndrome in which serum cytokine levels were investigated. Future studies should gather more evidence to elucidate the pathophysiology of Sweet's syndrome. PMID- 28668096 TI - Research Abstracts Dental Emergencies. PMID- 28668094 TI - Genome-wide organization and expression profiling of the R2R3-MYB transcription factor family in pineapple (Ananas comosus). AB - BACKGROUND: The MYB proteins comprise one of the largest families of plant transcription factors, which are involved in various plant physiological and biochemical processes. Pineapple (Ananas comosus) is one of three most important tropical fruits worldwide. The completion of pineapple genome sequencing provides a great opportunity to investigate the organization and evolutionary traits of pineapple MYB genes at the genome-wide level. RESULTS: In the present study, a total of 94 pineapple R2R3-MYB genes were identified and further phylogenetically classified into 26 subfamilies, as supported by the conserved gene structures and motif composition. Collinearity analysis indicated that the segmental duplication events played a crucial role in the expansion of pineapple MYB gene family. Further comparative phylogenetic analysis suggested that there have been functional divergences of MYB gene family during plant evolution. RNA-seq data from different tissues and developmental stages revealed distinct temporal and spatial expression profiles of the AcMYB genes. Further quantitative expression analysis showed the specific expression patterns of the selected putative stress related AcMYB genes in response to distinct abiotic stress and hormonal treatments. The comprehensive expression analysis of the pineapple MYB genes, especially the tissue-preferential and stress-responsive genes, could provide valuable clues for further function characterization. CONCLUSIONS: In this work, we systematically identified AcMYB genes by analyzing the pineapple genome sequence using a set of bioinformatics approaches. Our findings provide a global insight into the organization, phylogeny and expression patterns of the pineapple R2R3-MYB genes, and hence contribute to the greater understanding of their biological roles in pineapple. PMID- 28668097 TI - Medico-Legal Considerations in Providing Emergency Dental Care in Practice. AB - The unpredictability of unscheduled emergency dental care carries its own clinical, communication and management challenges with associated medico-legal risks. Providing emergency dental treatment for unfamiliar patients in an unfamiliar environment amplifies the hidden pitfalls which failure to avoid can create potentially damaging critical incidents in a practitioner's professional life. These are preferably avoided through consistent attention to best practice and risk management. Day to day processes, such as excellent record-keeping, valid consent and effective communication are under the spotlight in the event that a patient complains, raises a concern with a regulator or seeks compensation following alleged negligent care. This paper aims to highlight the dento-legal pitfalls that may be pertinent in such a challenging situation. PMID- 28668098 TI - The Role of Mouthguards in Preventing and Reducing Sports-related Trauma. AB - a mouthguard, also known as a gumshield, mouth protector or sports guard is an appliance that covers the teeth and surrounding mucosa with the aim of preventing or reducing trauma to the teeth, gingival tissue, lips and jaws. The device is usually worn on the maxillary arch and works by separating the maxillary and mandibular dentition, protecting the teeth from the surrounding soft tissue, absorbing or redistributing shock and/or stabilising the mandible during traumatic jaw closure. They may also play a role in preventing and reducing concussion by absorbing impact forces that would otherwise be transmitted through the base of the skull to the brain, although the evidence for this is less conclusive. A mouthguard will usually fall into one of three categories: stock mouthguards (which are made ready to use and are believed to give the least protection), the mouth-formed or 'boil and bite' type (which are heated in hot water, placed in the mouth and moulded to the teeth) and custom-made mouthguards (which are usually made on a stone model of the maxillary teeth and surrounding tissue and are thought to give the most protection). These devices can be made from various materials but ethylene-vinyl acetate is by far the most popular material, probably because of the ease with which it can be used for the production of custom-made mouthguards. This paper gives a review of the role of mouthguards in preventing and reducing sports-related trauma and examines the materials that are used to fabricate them. PMID- 28668099 TI - The Emergency Treatment of Traumatised Permanent Anterior Teeth in Children and Adolescents. AB - This article aims to provide a practical clinician's guide to assessing and diagnosing dental trauma involving permanent teeth in children and young people, and for carrying out appropriate, guideline supported acute management. Timely referral to specialist paediatric dental services is crucial in more complex trauma presentations and will lead to improved outcomes for the dentition. Appropriate acute management by the primary clinician optimises the prognosis of any traumatised tooth and this article will focus on the emergency treatment of the traumatised permanent tooth. PMID- 28668095 TI - CSPG4: a prototype oncoantigen for translational immunotherapy studies. AB - Thanks to striking progress in both the understanding of anti-tumor immune response and the characterization of several tumor associated antigens (TAA), a more rational design and more sophisticated strategies for anti-tumor vaccination have been possible. However, the effectiveness of cancer vaccines in clinical trial is still partial, indicating that additional studies are needed to optimize their design and their pre-clinical testing. Indeed, anti-tumor vaccination success relies on the choice of the best TAA to be targeted and on the translational power of the pre-clinical model used to assess its efficacy. The chondroitin sulfate proteoglycan-4 (CSPG4) is a cell surface proteoglycan overexpressed in a huge range of human and canine neoplastic lesions by tumor cells, tumor microenvironment and cancer initiating cells. CSPG4 plays a central role in the oncogenic pathways required for malignant progression and metastatization. Thanks to these features and to its poor expression in adult healthy tissues, CSPG4 represents an ideal oncoantigen and thus an attractive target for anti-tumor immunotherapy. In this review we explore the potential of CSPG4 immune-targeting. Moreover, since it has been clearly demonstrated that spontaneous canine tumors mimic the progression of human malignancies better than any other pre-clinical model available so far, we reported also our results indicating that CSPG4 DNA vaccination is safe and effective in significantly increasing the survival of canine melanoma patients. Therefore, anti-CSPG4 vaccination strategy could have a substantial impact for the treatment of the wider population of spontaneous CSPG4-positive tumor affected dogs with a priceless translational value and a revolutionary implication for human oncological patients. PMID- 28668100 TI - Periodontal Emergencies in General Practice. AB - Diagnosing and managing periodontal emergencies is a common part of general dental practice. This article summarises the presentation, aetiology and management of the key periodontal emergencies, including gingival abscess, periodontal abscess, peri-coronitis/peri-coronal abscess, perio-endo lesion/ abscess, necrotising gingivitis and periodontitis, acute herpetic gingivostomatitis, acute physical/chemical/thermal injury and subgingival root fracture. PMID- 28668101 TI - The Emergency Dental Appointment: Restorative Emergencies Part 1 - Tooth Related Problems. AB - Dental emergencies affect a large proportion of the population. While there is ample information in the literature on how to manage medical emergencies in dental practice, there is little information on common dental emergencies and how to manage them. In the UK, the 2009 Adult Dental Health Survey reported 9% of dentate adults reporting pain at their clinical examination. 1 The prevalence of non-pain related restorative dental emergencies is estimated to be higher, and will be a common presenting situation in the dental clinic. Often these unplanned events cause difficulties for dental practitioners, who are already constrained by time, to fit in these patients and manage them. Over and above this, the increasing life spans, retention of teeth into later life and finite life of dental restorations all add to the challenges encountered by the dental practitioner. Prompt and effective management of these conditions often leads to optimising patient experience, but also offers better outcomes. This two-part series provides an overview of the more common dental emergencies encountered by the dental practitioner and their management. Paper 1 focuses on the management of common tooth-related emergencies and includes non-odontogenic and odontogenic pain. Paper 2 focuses on the management of osseointegrated dental implant related emergencies. PMID- 28668102 TI - The Emergency Dental Appointment: Restorative Emergencies Part 2 - Dental Implant Related Problems. AB - This is the second paper in a two-part series discussing the management of common restorative dental emergencies. The first paper focussed upon problems relating to conventional fixed and removable restorations, and this paper discusses the management of common dental implant related emergencies. With dental implant treatment becoming an increasingly popular method of replacing missing teeth, it is very likely that dentists working in general practice will routinely come across patients who have previously undergone this form of treatment, even if they themselves are not directly involved in placing or restoring dental implants. This paper is aimed at general dental practitioners (GDPs) who have some experience in managing dental implants, and those who want to gain further insight into how such situations may be managed. PMID- 28668103 TI - Key Factors in Treating the Emergency Patient. PMID- 28668104 TI - A call to arms of specialty societies to review the WHO International Classification of Diseases, Eleventh Revision terms appropriate for the diseases they manage: The example of the Joint Allergy Academies. PMID- 28668105 TI - The atopic disorders and atopy ... "strange diseases" now better defined! PMID- 28668106 TI - Atopic dermatitis treatment: Current state of the art and emerging therapies. AB - BACKGROUND: Atopic dermatitis (AD) can be debilitating and often requires the use of combination topical and systemic therapy to achieve adequate disease control. METHODS: A non-systematic review was performed of current state of the art and emerging therapies for AD. RESULTS: There are a number of topical agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of AD and multiple nonapproved systemic agents that are used off label for the treatment of AD. All of these have limitations of efficacy and/or safety, which leads to a number of unmet disease-treatment needs. Recent insight has identified a number of novel pathways as treatment targets for AD, including the T-helper type 2 cytokines, interleukins (IL) 4, IL-13, IL-33, phosphodiesterase E 4, and Janus kinase signaling. Dupilumab is a monoclonal antibody that inhibits interleukin 4 and 13 signaling and was recently approved by the FDA for the treatment of moderate-severe AD in adults. DISCUSSION: There are a number of current treatment approaches and emerging therapies for AD. PMID- 28668107 TI - Asthma in older people hospitalized with influenza in Spain: A case-control study. AB - BACKGROUND: Influenza infection is an exacerbating factor for asthma, and its prevention is critical in older patients with asthma. OBJECTIVE: This study investigated the association between asthma and influenza-related hospitalization, in Spain, of patients ages >= 65 years and their clinical evolution. METHODS: A multicenter case-control study was carried out in 20 Spanish hospitals during the 2013-2014 and 2014-2015 influenza seasons. Patients ages >= 65 years hospitalized with laboratory-confirmed influenza with and without asthma were matched with controls according to the presence of asthma, sex, age, hospital, and date of hospitalization. RESULTS: A total of 561 patients with influenza (15.9% with asthma) and 1258 patients without influenza (8.0% with asthma) were included as cases and controls, respectively. The adjusted risk of influenza for patients with asthma was calculated by multivariate conditional logistic regression. The adjustment variables were the following: smoker/nonsmoker, pneumonia in the 2 years before hospital admission, previous oral treatment with corticosteroids, influenza vaccination during the seasonal campaign, Barthel index (ordinal scale used to measure performance in activities of daily living), level of education, obesity, and the presence of other comorbidities. Patients with asthma presented a great risk of influenza (adjusted odds ratio 2.64 [95% confidence interval, 1.77-3.94]). Compared with patients without asthma, patients with asthma had more symptoms, and these had been present for longer before admission but presented a lower hospital or postdischarge mortality. CONCLUSION: This study indicated that asthma was associated with hospitalization from influenza A infection. Although patients with asthma and with influenza had more symptoms, hospital or postdischarge mortality was lower, probably due to a better response to medical treatment. PMID- 28668108 TI - Prevalence and triggers of anaphylactic events in schools. AB - BACKGROUND: Prevention and management of anaphylaxis in schools is an area of active interest as allergy and asthma rates in children continue to increase. A greater understanding of the prevalence and characteristics of anaphylaxis can help guide preventive and management strategies both within and outside of the school setting, with the goal of reducing morbidity and mortality. OBJECTIVE: This study was performed to elucidate the epidemiology of and management strategies for anaphylaxis in the school setting. METHODS: A cross-sectional, Web based survey was administered to schools that participated in an initiative that provides stock epinephrine autoinjectors (EAIs) to qualifying U.S. schools. Representatives from participating schools completed a questionnaire regarding anaphylactic reactions that occurred during the 2014-2015 school year. Weighted analyses were performed to account for differential responses between schools that completed the survey and those that did not. RESULTS: A total of 12,275 of the 45,819 invited schools responded to the survey. The occurrence of one or more anaphylactic events was reported by 1358 schools. Most events (89.8% [1803/2008]) occurred in students. High school students accounted for the largest proportion of anaphylactic reactions among students (40.1% [723/1802]). Food was the most commonly identified anaphylaxis trigger across grade levels, seasons, and geographic regions. The trigger was unknown to the individual who experienced anaphylaxis in 21.8% of the events (436/1998). No known history of allergy or asthma was present in 24.5% (491/2001) and 51.3% (1026/2000) of affected individuals, respectively. Transportation to the hospital or clinic for further treatment and/or management was reported for 72.6% of the individuals with anaphylactic events (1450/1997). Results from the weighted analyses were similar to those of the unweighted analyses. CONCLUSION: Anaphylaxis occurred across grade levels and in individuals with or without known risk factors, which reinforced the need for school preparedness in both management of anaphylaxis and stocking of EAIs. PMID- 28668109 TI - Seasonal variation and monthly patterns of skin symptoms in Korean children with atopic eczema/dermatitis syndrome. AB - BACKGROUND: There have been controversies about the seasonality in aggravation of atopic eczema/dermatitis syndrome (AEDS) symptoms, although understanding the seasonal patterns of AEDS symptoms is an important step in preventing exacerbation through proactive management. OBJECTIVE: The aim of this study was to evaluate whether there are seasonal variations or monthly patterns of symptoms in children with AEDS. METHODS: A total of 590 children with AEDS (median age, 21 months) were enrolled and were followed up for at least 1 year between August 2012 and March 2015. Daily symptom scores that described the extent of itching, sleep disturbance, erythema, dryness, oozing, and edema were recorded on a scale of 0 to 4. The baseline score for each patient was defined as the 20th percentile of each individual's total score. The symptom score difference of each patient was expressed relative to the baseline level. The seasonal or monthly variation in symptom score differences was analyzed through generalized estimating equation analysis. RESULTS: Based on the AEDS symptom records from 87,879 person-days, the mean symptom score difference from baseline in patients with AEDS increased significantly in spring, autumn, and winter relative to the reference season (summer): by 0.62 (95% confidence interval [CI], 0.44-0.81) in spring, by 0.45 (95% CI, 0.24-0.67) in winter, and by 0.18 (95% CI, 0.02-0.36) in autumn. The mean symptom score difference from baseline increased significantly in January, February, March, April, May, June, October, November, and December relative to the reference month of August. CONCLUSION: Skin symptoms in children with AEDS were worse in spring, winter, and autumn than in summer. In terms of monthly patterns, the skin symptoms were the worst in April. PMID- 28668110 TI - Association of maternal depression and allergic diseases in Korean children. AB - PURPOSE: An association between childhood allergic disease and parental psychological disorders has been reported. However, little is known about the relationship between childhood allergic disease and maternal depression. This study was performed to determine if there is an association between childhood allergic disease and maternal depression. METHODS: Data were acquired from 13,782 subjects (8091 mothers) ages < 18 years who participated in the Korea National Health and Nutrition Examination Surveys, which was conducted from 2007 to 2014. The presence of allergic disease (asthma or atopic dermatitis) and depression was based on self-reported physician diagnosis in the health interview surveys. RESULTS: Logistic regression analyses showed maternal depression was significantly associated with single marital status (separated or divorced, adjusted odds ratio [aOR] 2.204 [95% confidence interval {CI},1.256-3.867]), less than middle school graduated level (aOR 2.959 [95% CI, 1.514-5.781]), middle school graduated educational level (aOR 2.420 [95% CI, 1.355-4.319]), being a current smoker (aOR 2.257 [95% CI, 1.481-3.438]), being an ex-smoker (aOR 2.533 [95% CI, 1.506-4.260]), maternal asthma (aOR 2.786 [95% CI, 1.453-5.344]), and maternal hypertension (aOR 1.942 [95% CI, 1.106-3.408]). Maternal depression was significantly associated with children's asthma (aOR 2.028 [95% CI, 1.234-3.335]) and children's atopic dermatitis (aOR 1.755 [95% CI, 1.183-2.602]). CONCLUSION: The present study showed maternal depression might be a risk factor for the clinical diagnosis of asthma and atopic dermatitis in Korean children. PMID- 28668111 TI - A 10-year experience of a novel and safe modified environmental rush immunotherapy protocol. AB - BACKGROUND: Allergen immunotherapy (AIT) is an effective treatment option for allergic rhinitis. Although conventional AIT takes 6 months to reach maintenance dosing, rush AIT accelerates the build-up period and reaches the maintenance dose months earlier. However, accelerated schedules of AIT carry an increased risk of systemic reactions (SR). OBJECTIVE: We aimed to describe a novel 1-day, eight step modified environmental rush immunotherapy (MERIT) protocol, characteristics of the patients who underwent this therapy, and the safety of this procedure. We also compared distinguishing features of those patients with SRs. METHODS: We retrospectively analyzed demographic and clinical data of 362 adult patients seen in an outpatient university allergy clinic, from January 2005 to January 2015, and who underwent MERIT protocol treatment for allergic rhinitis. RESULTS: In a univariate analysis, the factors significantly associated with SR were lower body mass index (BMI); younger age; a higher number of allergens in the extracts; and the presence of cat, dust mite, and certain weed pollens. In a multivariate analysis, cat, dust mite, and mugwort were significantly associated with SRs. Over the 10-year period, 50 patients experienced SRs (13.81%), with a total number of 68 SRs. Only 4.7% of the SRs occurred on the MERIT day. Most SRs occurred >30 minutes and were mild. Our MERIT protocol continuation rate for all the patients was 49.2% and did not seem to be influenced by having an SR versus no SR. CONCLUSION: We present a modified rush AIT protocol that seems to be effective and safe. Most patients tolerated therapy, and only a minority of patients developed SRs, which generally were mild. We identified novel risk factors for SRs that may help determine optimal dosing to decrease the risk of SRs. Ultimately, future studies will be needed to compare the safety of our MERIT protocol with traditional AIT. PMID- 28668112 TI - Pearls and pitfalls: Autoimmune lymphoproliferative syndrome and autoimmune lymphoproliferative syndrome-like disease. AB - A case of autoimmune lymphoproliferative syndrome (ALPS) was presented, followed by a discussion of the clinical characteristics, pathophysiology, diagnosis, and management of this disease. Clinical pearls and pitfalls are emphasized for the use of the practicing allergist and the fellow in-training. The diagnosis of ALPS was guided by published criteria. A careful history and workup were needed to exclude other possible etiologies for the patient's symptoms and physical findings. ALPS often carries significant morbidity and is best managed through a multidisciplinary approach. PMID- 28668113 TI - A 28-year-old woman with fever, rash, and pancytopenia. AB - A 28-year-old Hispanic woman was admitted to the hospital with fever, sore throat, arthralgia, and a generalized rash of 2 weeks' duration. Her medical history was significant for various food and medication allergies. Multiple antibiotics were given for suspected infection, and she subsequently developed a new skin rash, acute liver injury, eosinophilia, and pancytopenia. Additional studies showed hypertriglyceridemia; elevated interleukin-2 receptor levels; absent natural killer cell activity; and hemophagocytosis in skin, liver, and bone marrow biopsy specimens. Treatment with intravenous immunoglobulin and steroids resulted in complete remission. PMID- 28668114 TI - For the Patient: Prevalence and triggers of anaphylactic events in schools. PMID- 28668116 TI - MacroBac: New Technologies for Robust and Efficient Large-Scale Production of Recombinant Multiprotein Complexes. AB - Recombinant expression of large, multiprotein complexes is essential and often rate limiting for determining structural, biophysical, and biochemical properties of DNA repair, replication, transcription, and other key cellular processes. Baculovirus-infected insect cell expression systems are especially well suited for producing large, human proteins recombinantly, and multigene baculovirus systems have facilitated studies of multiprotein complexes. In this chapter, we describe a multigene baculovirus system called MacroBac that uses a Biobricks type assembly method based on restriction and ligation (Series 11) or ligation independent cloning (Series 438). MacroBac cloning and assembly is efficient and equally well suited for either single subcloning reactions or high-throughput cloning using 96-well plates and liquid handling robotics. MacroBac vectors are polypromoter with each gene flanked by a strong polyhedrin promoter and an SV40 poly(A) termination signal that minimize gene order expression level effects seen in many polycistronic assemblies. Large assemblies are robustly achievable, and we have successfully assembled as many as 10 genes into a single MacroBac vector. Importantly, we have observed significant increases in expression levels and quality of large, multiprotein complexes using a single, multigene, polypromoter virus rather than coinfection with multiple, single-gene viruses. Given the importance of characterizing functional complexes, we believe that MacroBac provides a critical enabling technology that may change the way that structural, biophysical, and biochemical research is done. PMID- 28668118 TI - Structural Studies of RNases H2 as an Example of Crystal Structure Determination of Protein-Nucleic Acid Complexes. AB - RNases H2 are nucleases that cleave nucleic acids that comprise both RNA and DNA. They specifically recognize and cleave junctions between RNA and DNA using an intricate mechanism that involves substrate-assisted catalysis. Archaeal and eukaryotic RNases H2 also cleave the RNA strands of RNA/DNA hybrids. RNases H2 use their activity to maintain the integrity of genetic information. Particularly important is their ability to initiate the removal of single ribonucleotides from genomic DNA. Single ribonucleotides are very common in replicating cells and pose a serious threat to the stability of genomic DNA. The only known pathway for the error-free removal of single ribonucleotides begins with their recognition and cleavage by RNases H2. The importance of these enzymes is further underscored by the fact that mutations in the human enzyme lead to a severe autoimmune disease, Aicardi-Goutieres syndrome. This review summarizes methods for the overproduction and purification of bacterial and human RNases H2. We also describe methods for testing the enzymatic activity of these nucleases and their crystallization both in unliganded form and in complex with nucleic acid substrates. We use these studies to describe general principles of the crystallization and structure determination of protein-nucleic acid complexes, particularly for nucleases. As illustrated by the structural studies of RNases H2, such complex structures can reveal intricate and fascinating aspects of the molecular mechanisms of nucleic acid enzymes. PMID- 28668117 TI - Expression and Structural Analyses of Human DNA Polymerase theta (POLQ). AB - DNA polymerase theta (pol theta) is an evolutionarily conserved protein encoded by the POLQ gene in mammalian genomes. Pol theta is the defining enzyme for a pathway of DSB repair termed "alternative end-joining" (altEJ) or "theta-mediated end-joining." This pathway contributes significantly to the radiation resistance of mammalian cells. It also modulates accuracy in repair of breaks that occur at stalled DNA replication forks, during diversification steps of the mammalian immune system, during repair of CRISPR-Cas9, and in many DNA integration events. Pol theta is a potentially important clinical target, particularly for cancers deficient in other break repair strategies. The enzyme is uniquely able to mediate joining of single-stranded 3' ends. Because of these unusual biochemical properties and its therapeutic importance, it is essential to study structures of pol theta bound to DNA. However, challenges for expression and purification are presented by the large size of pol theta (2590 residues in humans) and unusual juxtaposition of domains (a helicase-like domain and distinct DNA polymerase, separated by a region predicted to be largely disordered). Here we summarize work on the expression and purification of the full-length protein, and then focus on the design, expression, and purification of an active C-terminal polymerase fragment. The generation of this active construct was nontrivial and time consuming. Almost all published biochemical work to date has been performed with this domain fragment. Strategies to obtain and improve crystals of a ternary pol theta complex (enzyme:DNA:nucleotide) are also presented, along with key elements of the structure. PMID- 28668119 TI - DNA-PKcs, Allostery, and DNA Double-Strand Break Repair: Defining the Structure and Setting the Stage. AB - DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is central to the regulation of the DNA damage response and repair through nonhomologous end joining. The structure has proved challenging due to its large size and multiple HEAT repeats. We have recently reported crystals of selenomethionine-labeled DNA PKcs complexed with native KU80ct194 (KU80 residues 539-732) diffracting to 4.3A resolution. The novel use of crystals of selenomethionine-labeled protein expressed in HeLa cells has facilitated the use of single anomalous X-ray scattering of this 4128 amino acid, multiple HEAT-repeat structure. The monitoring of the selenomethionines in the anomalous-difference density map has allowed the checking of the amino acid residue registration in the electron density, and the labeling of the Ku-C-terminal moiety with selenomethionine has further allowed its identification in the structure of the complex with DNA-PKcs. The crystal structure defines a stage on which many of the components assemble and regulate the kinase activity through modulating the conformation and allosteric regulation of kinase activity. PMID- 28668120 TI - Single-Particle Electron Microscopy Analysis of DNA Repair Complexes. AB - DNA repair complexes play crucial roles in maintaining genome integrity, which is essential for the survival of an organism. The understanding of their modes of action is often obscure due to limited structural knowledge. Structural characterizations of these complexes are often challenging due to a poor protein production yield, a conformational flexibility, and a relatively high molecular mass. Single-particle electron microscopy (EM) has been successfully applied to study some of these complexes as it requires low amount of samples, is not limited by the high molecular mass of a protein or a complex, and can separate heterogeneous assemblies. Recently, near-atomic resolution structures have been obtained with EM owing to the advances in technology and image processing algorithms. In this chapter, we review the EM methodology of obtaining three dimensional reconstructions of macromolecular complexes and provide a workflow that can be applied to DNA repair complex assemblies. PMID- 28668121 TI - Using Atomic Force Microscopy to Characterize the Conformational Properties of Proteins and Protein-DNA Complexes That Carry Out DNA Repair. AB - Atomic force microscopy (AFM) is a scanning probe technique that allows visualization of single biomolecules and complexes deposited on a surface with nanometer resolution. AFM is a powerful tool for characterizing protein-protein and protein-DNA interactions. It can be used to capture snapshots of protein-DNA solution dynamics, which in turn, enables the characterization of the conformational properties of transient protein-protein and protein-DNA interactions. With AFM, it is possible to determine the stoichiometries and binding affinities of protein-protein and protein-DNA associations, the specificity of proteins binding to specific sites on DNA, and the conformations of the complexes. We describe methods to prepare and deposit samples, including surface treatments for optimal depositions, and how to quantitatively analyze images. We also discuss a new electrostatic force imaging technique called DREEM, which allows the visualization of the path of DNA within proteins in protein-DNA complexes. Collectively, these methods facilitate the development of comprehensive models of DNA repair and provide a broader understanding of all protein-protein and protein-nucleic acid interactions. The structural details gleaned from analysis of AFM images coupled with biochemistry provide vital information toward establishing the structure-function relationships that govern DNA repair processes. PMID- 28668122 TI - Single-Molecule Methods for Nucleotide Excision Repair: Building a System to Watch Repair in Real Time. AB - Single-molecule approaches to solving biophysical problems are powerful tools that allow static and dynamic real-time observations of specific molecular interactions of interest in the absence of ensemble-averaging effects. Here, we provide detailed protocols for building an experimental system that employs atomic force microscopy and a single-molecule DNA tightrope assay based on oblique angle illumination fluorescence microscopy. Together with approaches for engineering site-specific lesions into DNA substrates, these complementary biophysical techniques are well suited for investigating protein-DNA interactions that involve target-specific DNA-binding proteins, such as those engaged in a variety of DNA repair pathways. In this chapter, we demonstrate the utility of the platform by applying these techniques in the studies of proteins participating in nucleotide excision repair. PMID- 28668123 TI - Next-Generation DNA Curtains for Single-Molecule Studies of Homologous Recombination. AB - Homologous recombination (HR) is a universally conserved DNA double-strand break repair pathway. Single-molecule fluorescence imaging approaches have revealed new mechanistic insights into nearly all aspects of HR. These methods are especially suited for studying protein complexes because multicolor fluorescent imaging can parse out subassemblies and transient intermediates that associate with the DNA substrates on the millisecond to hour timescales. However, acquiring single molecule datasets remains challenging because most of these approaches are designed to measure one molecular reaction at a time. The DNA curtains platform facilitates high-throughput single-molecule imaging by organizing arrays of DNA molecules on the surface of a microfluidic flowcell. Here, we describe a second generation UV lithography-based protocol for fabricating flowcells for DNA curtains. This protocol greatly reduces the challenges associated with assembling DNA curtains and paves the way for the rapid acquisition of large datasets from individual single-molecule experiments. Drawing on our recent studies of human HR, we also provide an overview of how DNA curtains can be used for observing facilitated protein diffusion, processive enzyme translocation, and nucleoprotein filament dynamics on single-stranded DNA. Together, these protocols and case studies form a comprehensive introduction for other researchers that may want to adapt DNA curtains for high-throughput single-molecule studies of DNA replication, transcription, and repair. PMID- 28668124 TI - Production and Assay of Recombinant Multisubunit Chromatin Remodeling Complexes. AB - We have developed a novel system to facilitate the rapid and easy cloning of multiple genes (>10) in under a week. Using this system we have been able to successfully clone, overexpress, and purify a number of large multimeric proteins from insect cells, including the chromatin remodeling complexes SWR1 and INO80. Using Forster resonance energy transfer (FRET)-based assays we have demonstrated that our overexpressed enzymes have activities comparable to those purified from sources where the proteins are expressed under their endogenous promoters. PMID- 28668126 TI - Analyzing the Catalytic Activities and Interactions of Eukaryotic Translesion Synthesis Polymerases. AB - Translesion synthesis is the process by which nonclassical DNA polymerases bypass DNA damage during DNA replication. Cells possess a variety of nonclassical polymerases, each one is specific for incorporating nucleotides opposite to one or more closely related DNA lesions, called its cognate lesions. In this chapter, we discuss a variety of approaches for probing the catalytic activities and the protein-protein interactions of nonclassical polymerases. With respect to their catalytic activities, we discuss polymerase assays, steady-state kinetics, and presteady-state kinetics. With respect to their interactions, we discuss qualitative binding assays such as enzyme-linked immunosorbent assays and coimmunoprecipitation; quantitative binding assays such as isothermal titration calorimetry, surface plasmon resonance, and nuclear magnetic resonance spectroscopy; and single-molecule binding assays such as total internal reflection fluorescence microscopy. We focus on how nonclassical polymerases accommodate their cognate lesions during nucleotide incorporation and how the most appropriate nonclassical polymerase is selected for bypassing a given lesion. PMID- 28668125 TI - Detection of Reaction Intermediates in Mg2+-Dependent DNA Synthesis and RNA Degradation by Time-Resolved X-Ray Crystallography. AB - Structures of enzyme-substrate/product complexes have been studied for over four decades but have been limited to either before or after a chemical reaction. Recently using in crystallo catalysis combined with X-ray diffraction, we have discovered that many enzymatic reactions in nucleic acid metabolism require additional metal ion cofactors that are not present in the substrate or product state. By controlling metal ions essential for catalysis, the in crystallo approach has revealed unprecedented details of reaction intermediates. Here we present protocols used for successful studies of Mg2+-dependent DNA polymerases and ribonucleases that are applicable to analyses of a variety of metal ion dependent reactions. PMID- 28668127 TI - Kinetic Methods for Studying DNA Glycosylases Functioning in Base Excision Repair. AB - Base excision repair (BER) is a conserved and ubiquitous pathway that is initiated by DNA glycosylases, which recognize and remove damaged or mismatched nucleobases, setting the stage for restoration of the correct DNA sequence by follow-on BER enzymes. DNA glycosylases employ a nucleotide-flipping step prior to cleavage of the N-glycosyl bond, and most exhibit slow release of the abasic DNA product and/or strong product inhibition. As such, studying the catalytic mechanism of these enzymes requires care in the design, execution, and interpretation of single- and multiple-turnover kinetics experiments, which is the topic of this chapter. PMID- 28668128 TI - Transient Kinetic Methods for Mechanistic Characterization of DNA Binding and Nucleotide Flipping. AB - Enzymes that modify nucleobases in double-stranded genomic DNA, either as part of a DNA repair pathway or as an epigenetic modifying pathway, adopt a multistep pathway to locate target sites and reconfigure the DNA to gain access. Work on several different enzymes has shown that in almost all cases base flipping, also known as nucleotide flipping, is a key feature of specific site recognition. In this chapter, we discuss some of the strategies that can be used to perform a kinetic characterization for DNA binding and nucleotide flipping. The resulting kinetic and thermodynamic framework provides a platform for understanding substrate specificity, mechanisms of inhibition, and the roles of important amino acids. We use a human DNA repair glycosylase called alkyladenine DNA glycosylase as a case study, because this is one of the best-characterized nucleotide flipping enzymes. However, the approaches that are described can be readily adapted to study other enzymes, and future studies are needed to understand the mechanism of substrate recognition in each individual case. As more enzymes are characterized, we can hope to uncover which features of DNA searching and nucleotide flipping are fundamental features shared by many different families of DNA modifying enzymes, and which features are specific to a particular enzyme. Such an understanding provides reasonable models for less characterized enzymes that are important for epigenetic DNA modification and DNA repair pathways. PMID- 28668130 TI - Analysis of Functional Dynamics of Modular Multidomain Proteins by SAXS and NMR. AB - Multiprotein machines drive virtually all primary cellular processes. Modular multidomain proteins are widely distributed within these dynamic complexes because they provide the flexibility needed to remodel structure as well as rapidly assemble and disassemble components of the machinery. Understanding the functional dynamics of modular multidomain proteins is a major challenge confronting structural biology today because their structure is not fixed in time. Small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy have proven particularly useful for the analysis of the structural dynamics of modular multidomain proteins because they provide highly complementary information for characterizing the architectural landscape accessible to these proteins. SAXS provides a global snapshot of all architectural space sampled by a molecule in solution. Furthermore, SAXS is sensitive to conformational changes, organization and oligomeric states of protein assemblies, and the existence of flexibility between globular domains in multiprotein complexes. The power of NMR to characterize dynamics provides uniquely complementary information to the global snapshot of the architectural ensemble provided by SAXS because it can directly measure domain motion. In particular, NMR parameters can be used to define the diffusion of domains within modular multidomain proteins, connecting the amplitude of interdomain motion to the architectural ensemble derived from SAXS. Our laboratory has been studying the roles of modular multidomain proteins involved in human DNA replication using SAXS and NMR. Here, we present the procedure for acquiring and analyzing SAXS and NMR data, using DNA primase and replication protein A as examples. PMID- 28668131 TI - Use of Single-Cysteine Variants for Trapping Transient States in DNA Mismatch Repair. AB - DNA mismatch repair (MMR) is necessary to prevent incorporation of polymerase errors into the newly synthesized DNA strand, as they would be mutagenic. In humans, errors in MMR cause a predisposition to cancer, called Lynch syndrome. The MMR process is performed by a set of ATPases that transmit, validate, and couple information to identify which DNA strand requires repair. To understand the individual steps in the repair process, it is useful to be able to study these large molecular machines structurally and functionally. However, the steps and states are highly transient; therefore, the methods to capture and enrich them are essential. Here, we describe how single-cysteine variants can be used for specific cross-linking and labeling approaches that allow trapping of relevant transient states. Analysis of these defined states in functional and structural studies is instrumental to elucidate the molecular mechanism of this important DNA MMR process. PMID- 28668132 TI - Preface. PMID- 28668133 TI - Retraction notice to "Dysregulated glutamate and dopamine transporters in postmortem frontal cortex from bipolar and schizophrenic patients" [JAD 136/1-2 (2012) 63 - 71]. PMID- 28668129 TI - What Combined Measurements From Structures and Imaging Tell Us About DNA Damage Responses. AB - DNA damage outcomes depend upon the efficiency and fidelity of DNA damage responses (DDRs) for different cells and damage. As such, DDRs represent tightly regulated prototypical systems for linking nanoscale biomolecular structure and assembly to the biology of genomic regulation and cell signaling. However, the dynamic and multifunctional nature of DDR assemblies can render elusive the correlation between the structures of DDR factors and specific biological disruptions to the DDR when these structures are altered. In this chapter, we discuss concepts and strategies for combining structural, biophysical, and imaging techniques to investigate DDR recognition and regulation, and thus bridge sequence-level structural biochemistry to quantitative biological outcomes visualized in cells. We focus on representative DDR responses from PARP/PARG/AIF damage signaling in DNA single-strand break repair and nonhomologous end joining complexes in double-strand break repair. Methods with exemplary experimental results are considered with a focus on strategies for probing flexibility, conformational changes, and assembly processes that shape a predictive understanding of DDR mechanisms in a cellular context. Integration of structural and imaging measurements promises to provide foundational knowledge to rationally control and optimize DNA damage outcomes for synthetic lethality and for immune activation with resulting insights for biology and cancer interventions. PMID- 28668134 TI - APIC 2017: Reaching new heights in infection prevention. PMID- 28668135 TI - Can education influence stethoscope hygiene? AB - The importance of stethoscope hygiene has been demonstrated in prior studies, and is acknowledged by guidelines, yet it is rarely done. We implemented a pilot project consisting of provider education, reminder flyers and provision of cleaning supplies at the start of clinical rotations for housestaff, medical students, and attending physicians. Hand hygiene rates did not change significantly with rates between 58% and 63% while stethoscope hygiene remained at zero. PMID- 28668136 TI - Code Lavender: Cultivating Intentional Acts of Kindness in Response to Stressful Work Situations. AB - CONTEXT: Providing healthcare can be stressful. Gone unchecked, clinicians may experience decreased compassion, and increased burnout or secondary traumatic stress. Code Lavender is designed to increase acts of kindness after stressful workplace events occur. OBJECTIVE/INTERVENTION: To test the feasibility of providing Code Lavender. HYPOTHESES: After stressful events in the workplace, staff will provide, receive, and recommend Code Lavender to others. The provision of Code Lavender will improve Professional Quality of Life Scale (ProQoL) scores, general job satisfaction, and feeling cared for in the workplace. METHOD/SAMPLE: Pilot program testing and evaluation. Staff and physicians on four hospital units were informed of the Code Lavender kit availability, which includes words of comfort, chocolate, lavender essential oil, and employee health referral information. Feasibility data and ProQoL scores were collected at baseline and three months. RESULTS: At baseline, 48% (n = 164) reported a stressful event at work in the last three months. Post-intervention, 51% reported experiencing a stressful workplace event, with 32% receiving a Code Lavender kit from their co workers as a result (n = 83). Of those who received the Code Lavender intervention; 100% found it helpful, and 84% would recommend it to others. No significant changes were demonstrated before and after the intervention in ProQoL scores or job satisfaction, however the emotion of feeling cared-for improved. CONCLUSIONS: Results warrant continuation and further dissemination of Code Lavender. Investigators have received requests to expand the program implying positive reception of the intervention. Additional interventions are needed to overcome workplace stressors. A more intense peer support program is being tested. PMID- 28668138 TI - Erratum to "Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary" [Arch Bronconeumol. 2017;53:128-49]. PMID- 28668139 TI - Hair Transplant: Added Value When Performed by a Dermatologist. PMID- 28668140 TI - Clinical Features, Diagnosis, and Management of Patients With Anderson-Fabry Cardiomyopathy. AB - Anderson-Fabry disease (AFD) is an X-linked recessive, multisystem disease of lysosomal storage. A mutation in the gene encoding the hydrolase enzyme alpha galactosidase A results in its deficiency, or complete absence of activity. Subsequent progressive intracellular accumulation of glycosphingolipids, predominantly globotriaosylceramide, in various tissues, results in progressive organ dysfunction and failure, most commonly affecting the kidneys, nervous system, skin, eyes, vascular endothelium, and the heart. Cardiac involvement in AFD represents a leading cause of morbidity and mortality. Globotriaosylceramide accumulation affects cardiomyocytes, smooth muscle cells, vascular endothelial cells, and fibroblasts leading to various pathologies including valvular regurgitation, conduction disease and arrhythmias, coronary microvascular dysfunction, and right and left ventricular hypertrophy (LVH) leading to early diastolic dysfunction and late-stage systolic impairment. Diagnosis is on the basis of decreased plasma alpha-galactosidase activity in men and positive genetic testing in women. Contemporary large-scale screening studies have revealed a prevalence of 1%-5% in patients with unexplained LVH in multiple cohorts. Cardiac magnetic resonance imaging, with its unique tissue characterization capabilities, is the most important imaging modality to assess for cardiomyopathy in patients with AFD. Enzyme replacement therapy is indicated in AFD patients with significant organ involvement, and has been shown to clear sphingolipids from endothelial cells in other organs, as well as to reduce left ventricular mass as early as 6 months after starting treatment. There is increasing evidence that enzyme replacement therapy might be more effective if given at earlier stages of disease, before the development of LVH and myocardial fibrosis. PMID- 28668141 TI - High-Sensitivity Cardiac Troponin Risk Cutoffs for Acute Cardiac Outcomes at Emergency Department Presentation. AB - The optimal high-sensitivity cardiac troponin (hs-cTn) cutoffs for determining risk in patients who present with acute coronary syndrome symptoms are unknown. In 1137 emergency department patients we calculated adjusted relative risks for a composite outcome (myocardial infarction, unstable angina, heart failure, ventricular arrhythmia, or cardiovascular death) within 7 days for the presentation of hs-cTnT (Roche) and hs-cTnI (Abbott) assay concentrations on the basis of literature cutoffs. Patients with hs-cTn concentrations >= 14 ng/L had an adjusted relative risk of 4.9 for the composite outcome, with different hs cTnT/hs-cTnI concentration ranges yielding higher risks. A common low-risk cutoff of 14 ng/L may be used for hs-cTn with higher cutoffs identifying high-risk patients. PMID- 28668142 TI - Left Atrial Phasic Function and Its Association With Atrial Fibrillation in Patients After Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Left atrial (LA) size is a marker of prognosis in severe aortic stenosis (AS). The aims of this retrospective study were to assess the impact of transcatheter aortic valve implantation (TAVI) on the recovery of LA phasic function and to assess the relationship between LA function and new-onset atrial fibrillation (NAF) after TAVI. METHODS: In this retrospective cohort study, LA function was measured using biplane volumes and 2-dimensional (2D) speckle tracking echocardiography (STE) in 52 patients (median age, 81 years) with severe AS before TAVI and at midterm follow-up. Twenty healthy individuals >= 75 years were used as controls. RESULTS: Before TAVI, the 3 phasic volumetric emptying fractions and all STE-derived parameters of LA function were significantly reduced. At 5 +/- 3 months after TAVI, there was an improvement in LA reservoir and contractile function. However, LA phasic volumes and emptying fractions showed minimal changes. Fourteen patients had NAF in the early postprocedural period after TAVI. These patients experienced longer hospitalization (11 days vs 6 days; P = 0.002). By bivariable logistic regression analysis, the use of a transapical approach and the LA early diastolic strain rate (SR) before TAVI were significantly associated with NAF immediately after TAVI. CONCLUSIONS: Severe AS is associated with LA dysfunction. Intrinsic LA compliance and LA contractile properties by STE improved at midterm follow-up after TAVI. Preprocedural LA early diastolic SR may predict the development of NAF after TAVI pending confirmation by larger prospective evaluations. PMID- 28668143 TI - Prognosis Impact of Frailty Assessed by the Edmonton Frail Scale in the Setting of Acute Coronary Syndrome in the Elderly. AB - BACKGROUND: Elderly patients represent a large proportion of patients admitted for acute coronary syndrome (ACS). Whether frailty-defined as a biological syndrome that reflects a state of decreased physiological reserve and vulnerability to stressors-may impact the clinical outcomes in this population remains unclear. We aimed to determine the prevalence of frailty and its impact on mortality in patients aged >= 80 years admitted for ACS. METHODS: This prospective observational study was conducted in patients aged 80 years or older admitted to a tertiary hospital for ACS. Frailty was assessed using the Edmonton Frail Scale (EFS), which provides a score ranging from 0 (not frail) to 17 (very frail). The population was divided into 3 classes: EFS score 0-3, EFS score 4-6; and EFS score >7. RESULTS: Two hundred thirty-six patients were included, with a mean follow-up duration of 470 days. The mean age was 85.9 years. Seventy-five patients died during the follow-up period. One hundred nineteen patients (50.4%) had an EFS score of 0-3, 68 patients (28.8%) had an EFS score of 4-6, and 49 patients (20.8%) had an EFS score >= 7. The all-cause mortality rate was 17.7% in the EFS 0-3 group, 35.3% in the EFS 4-6 group, and 61.2% in the EFS >= 7 group (P < 0.001). After multivariate analysis, frailty status remained associated with all-cause mortality: the hazard ratio (HR) was 1.53 (95% confidence interval [CI], 0.74-3.16) in the EFS 4-6 group, and the HR was 3.60 (95% CI, 1.70-7.63) in the EFS >= 7 group. CONCLUSIONS: Frailty is a strong and independent prognostic factor for midterm all-cause mortality in elderly patients presenting with ACS. PMID- 28668144 TI - A Practical Guide to the Use of Glucose-Lowering Agents With Cardiovascular Benefit or Proven Safety. AB - Patients with type 2 diabetes continue to have a high residual risk for cardiovascular events despite intensive risk factor modification. Recent clinical trials have shown that the antihyperglycemic agents empagliflozin and liraglutide reduce cardiovascular events. Other drugs have been shown to have cardiovascular safety. With glucose-lowering agents proven to reduce adverse cardiovascular outcomes, many cardiologists have begun to prescribe or recommend glucose lowering agents. Other cardiologists are not yet comfortable with this role because they are not accustomed to initiating these drugs. This document provides updated details of glucose-lowering agents associated with either proven cardiovascular benefit or safety, to help cardiologists to safely prescribe and monitor their patients with diabetes. PMID- 28668145 TI - Modifiable Risk Factors in Atrial Fibrillation: The Role of Alcohol, Obesity, and Sleep Apnea. AB - Atrial fibrillation (AF) is a common arrhythmia affecting a growing number of Canadians. Traditional risk factors, such as hypertension, diabetes, and valvular disease, are often present in older patients with AF. Modifiable risk factors should also be sought in patients presenting with new-onset AF. Obesity is a rapidly growing epidemic in Canada. Emerging evidence is linking obesity and the often coexistent obstructive sleep apnea with an increased incidence of AF. Alcohol intake can also predispose to the development of AF. The purpose of this article is to review recent evidence looking at these modifiable risk factors and how intervention can mitigate these increased risks. PMID- 28668146 TI - A Rare Case of Cardiac Melanoma Mimicking Hypertrophic Cardiomyopathy. AB - A 40-year-old female patient with a remote history of a malignant melanoma treated with curative intent presented with the diagnosis of hypertrophic cardiomyopathy (HCM) made at another hospital. Further diagnostic workup included positron emission tomography/computed tomography, which revealed that the HCM phenotype was produced by cardiac involvement of metastatic melanoma. For this reason, the primary diagnosis of HCM had to be retracted and melanoma-specific antineoplastic treatment was initiated. PMID- 28668147 TI - Acute Myocardial Infarction in a Young Girl with Nephrotic Syndrome: A Case Report and Literature Review. AB - Acute myocardial infarction is not a very rare complication of nephrotic syndrome. The pathogenesis of ischemic heart disease among patients with nephrosis is commonly thrombosis, whereas atherosclerosis is rare, especially in young individuals. In this case report, we present a 15-year-old girl with nephrotic syndrome who had acute non-ST-elevation myocardial infarction secondary to atherosclerosis of the 3 coronary arteries. PMID- 28668148 TI - Large Left Ventricular Aneurysm and Multifocal Myocardial Involvement in a Patient With Systemic Sclerosis. AB - A 43-year-old man with systemic sclerosis and chest pain had negative T waves in precordial electrocardiographic leads. The echocardiogram showed a large left ventricular apical accessory chamber. The coronary arteries were normal. Cardiac magnetic resonance imaging (MRI) showed a large fibrotic aneurysm and a small patch of midwall late enhancement in the septum. The aneurysm was surgically removed. At the 8-month follow-up, cardiac MRI showed the appearance of a new nodular lesion in the anterior wall, causing a localized wall motion abnormality. Myocardial involvement in patients with systemic sclerosis can be severe, and cardiac MRI evaluation is fundamental. PMID- 28668149 TI - A Novel Technique for Prosthetic Valve Retrieval After Transcatheter Aortic Valve Embolization. AB - Although the rate of procedural complications during transcatheter aortic valve implantation has decreased because of technological advancement and increased operator experience, device embolization remains a rare but potentially fatal complication, even with new generation devices. We report, to our knowledge, the first case of Portico valve (St Jude Medical, Minneapolis, MN) migration despite apparent optimal initial implantation depth, which was retrieved using a novel strategy after failure of a traditional retrieval technique. We also describe a mechanism of left coronary artery systolic perfusion with diastolic backflow, which led to myocardial ischemia. PMID- 28668151 TI - Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. AB - Repeated implantation failure (RIF) is an intriguing, massive failure of reproductive treatment in otherwise healthy women leading to the introduction of empirical adjuvant interventions that are costly, inefficient, and frustrating for our patients. In this article, we will try to convince the readers that RIF is neither a stigma nor a mysterious pathology but rather our failure to diagnose and properly synchronize the euploid blastocyst with the patient's personalized window of implantation. PMID- 28668150 TI - Reevaluating response and failure of medical treatment of endometriosis: a systematic review. AB - OBJECTIVE: To assess patient response rates to medical therapies used to treat endometriosis-associated pain. DESIGN: A systematic review with the use of Medline and Embase. SETTING: Not applicable. PATIENT(S): Women receiving medical therapy to treat endometriosis. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The proportions of patients who: experienced no reduction in endometriosis associated pain symptoms; had pain symptoms remaining at the end of the treatment period; had pain recurrence after treatment cessation; experienced an increase or no change in disease score during the study; were satisfied with treatment; and discontinued therapy owing to adverse events or lack of efficacy. The change in pain symptom severity experienced during and after treatment, as measured on the visual analog scale, was also assessed. RESULT(S): In total, 58 articles describing 125 treatment arms met the inclusion criteria. Data for the response of endometriosis-associated pain symptoms to treatment were presented in only 29 articles. The median proportions of women with no reduction in pain were 11%-19%; at the end of treatment, 5%-59% had pain remaining; and after follow-up, 17%-34% had experienced recurrence of pain symptoms after treatment cessation. After median study durations of 2-24 months, the median discontinuation rates due to adverse events or lack of efficacy were 5%-16%. CONCLUSION(S): Few studies of medical therapies for endometriosis report outcomes that are relevant to patients, and many women gain only limited or intermittent benefit from treatment. PMID- 28668152 TI - Endometrial receptivity in eutopic endometrium in patients with endometriosis: it is not affected, and let me show you why. AB - Many women with endometriosis experience compromised fertility. This disease clearly exerts quantitative damage on the ovaries, and perhaps, also qualitative damage. However, it remains controversial whether endometrial receptivity is compromised. Here we review the evidence from basic transcriptomic signature data to clinical data from an oocyte donation model and find support for the concept that endometrial receptivity is not impaired in women with endometriosis when healthy embryos reach the endometrial cavity. PMID- 28668153 TI - Corrigendum to "Drug-protein binding mechanism of juglone for early pharmacokinetic profiling: Insights from ultrafiltration, multi-spectroscopic and molecular docking methods" [J. Pharm. Biomed. Anal., 141 (2017) 262-269]. PMID- 28668154 TI - MR Imaging of the Female Perineum: Clitoris, Labia, and Introitus. AB - The female perineum has a complex anatomy and can be involved by a wide range of pathologies. In this article, we specifically focus on the clitoris, labia, and introitus. We discuss the normal anatomy of these structures, the MR imaging techniques to optimize their evaluation, and several common and uncommon entities that may affect them, including benign and malignant tumors, as well as infectious and inflammatory, vascular, iatrogenic, and developmental entities. PMID- 28668155 TI - MR Imaging of the Pelvic Floor. AB - Pelvic floor dysfunction is a term used to describe a broad set of conditions including pelvic organ prolapse, urinary or fecal incontinence, defecatory dysfunction, and chronic pelvic pain that frequently affects multiple compartments of the pelvic floor. Imaging is important, because physical examination may not be adequate as the only means of evaluating pelvic floor disorders. This article reviews pertinent pelvic floor anatomy as well as the technique for performing, interpreting, and reporting abnormalities seen on MR defecography examinations in the anterior, middle, and posterior compartments. PMID- 28668156 TI - MR Imaging of Vulvar and Vaginal Cancer. AB - Vulvar and vaginal cancer are uncommon gynecologic malignancies, most frequently diagnosed clinically. MR imaging is a powerful tool for local staging of these tumors and to detect posttreatment complications and recurrent disease. This review presents anatomic delineation of the female pelvis, pathology and staging of vulvar and vaginal cancer, MR imaging techniques of the pelvis, MR features of vulvar and vaginal cancer, and the differential diagnosis of potential mimickers. PMID- 28668157 TI - MR Imaging of Pelvic Emergencies in Women. AB - MR imaging is a useful adjunct imaging modality for evaluating women presenting with acute lower abdominal/pelvic pain who have negative or inconclusive sonographic findings. In pregnant women, although obstetric complications are of prime concern, gastrointestinal pathologies also warrant careful attention, and MR imaging is often useful in refining the diagnosis. In nonpregnant women, gynecologic pathologies and gastrointestinal pathologies are of major concern, and may necessitate evaluation with MR imaging. Knowledge of imaging features in the appropriate clinical setting helps in early and accurate diagnosis, enabling timely management for better clinical outcomes. PMID- 28668158 TI - MR Imaging for Incidental Adnexal Mass Characterization. AB - Incidentally detected adnexal masses are common, and the overwhelming majority of them are benign. As many of these adnexal masses are considered indeterminate at CT or US, a large number of benign oophorectomies occur. Of the malignant adnexal masses, high-grade primary ovarian neoplasms with fast doubling times and early dissemination are the most common. Due to their aggressive behavior, diagnosis of malignancy by interval growth on surveillance imaging represents an undesirable option. Immediate MR characterization allows for a decreased rate of benign oophorectomies and expedited triage of patients to definitive treatment when malignancy is suspected. PMID- 28668159 TI - MR Imaging-Pathologic Correlation in Ovarian Cancer. AB - There are many ovarian cancer subtypes, giving rise to a range of appearances at gross pathology and magnetic resonance (MR) imaging. Certain fundamental concepts at MR, arising from underlying tissue characteristics, can provide guidance to radiologists in suggesting a diagnosis. The ability of multiparametric MR to risk stratify ovarian masses can contribute substantially to clinical decision making and patient management. PMID- 28668160 TI - MR Imaging of Mullerian Fusion Anomalies. AB - Mullerian duct anomalies, also called congenital uterine anomalies, are developmental structural disorders of the female genital tract. These anomalies are clinically relevant in patients with a history of infertility and pregnancy related complications. The American Society for Reproductive Medicine classification system is the most well known, although newer systems, such as from the European Society of Human Reproduction and Embryology/European Society for Gynaecological Endoscopy, are becoming more widely accepted. MR imaging remains the optimal imaging modality due to its superior multiplanar capability and spatial resolution. This review article describes the typical MR appearance of congenital uterine anomalies. PMID- 28668161 TI - Benign Gynecologic Conditions of the Uterus. AB - In this article, the authors review the anatomy, pathophysiology, MR imaging features, and diagnostic criteria for benign uterine conditions, including adenomyosis, uterine leiomyomas, retained products of conception, and uterine arteriovenous malformations. Pearls, pitfalls, and variants are discussed for each entity as well as important imaging features that can affect management decisions. PMID- 28668162 TI - MR Imaging of Abnormal Placentation. AB - Morbidly adherent placenta (MAP) encompasses a spectrum of conditions characterized by abnormal adherence of the placenta to the implantation site. Classification of MAP is based on the degree of trophoblastic invasion through myometrium and uterine serosa and includes accrete, when the villi are attached to the myometrium but do not invade the muscle; increta, when the placenta invades partially through the myometrium; and percreta, when it invades up to and beyond the uterine serosa. Knowledge of the common findings of MAP on MR imaging is important to be able to provide an accurate diagnosis. PMID- 28668163 TI - From Staging to Prognostication: Achievements and Challenges of MR Imaging in the Assessment of Endometrial Cancer. AB - Endometrial cancer is the most common gynecologic malignancy in the United States, with recent increasing incidence mostly owing to obesity. Preoperative MR imaging is essential to stratify patients according to their risk of recurrence and to guide surgical management. In the combination of T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast enhancement, MR imaging provides a "one-stop shop" approach for patient-specific accurate staging including the evaluation of the depth of myometrial invasion, cervical stromal invasion, extrauterine extension, and lymph node status. PMID- 28668164 TI - MR Imaging of Cervical Cancer. AB - Cervical cancer is a significant cause of morbidity and mortality worldwide despite advances in screening and prevention. Although cervical cancer remains clinically staged, the 2009 International Federation of Gynecology and Obstetrics committee has encouraged the use of advanced imaging modalities, including MR imaging, where available, to increase the accuracy of staging, guide treatment, and detect recurrence. Understanding the multiple roles of advanced imaging in the evaluation of cervical cancer will help radiologists provide an accurate and useful report to the referring clinicians. PMID- 28668165 TI - MR Imaging in Gynecologic Brachytherapy. AB - Magnetic resonance-based image-guided adaptive brachytherapy is gaining popularity in the United States in the setting of gynecologic malignancies. This technique improves local control, increases overall survival, and minimizes toxicity to the adjacent organs at risk. The purpose of this article is to familiarize radiologists with image-guided adaptive brachytherapy by describing its history, detailing MR imaging techniques, describing treatment considerations, and reviewing image interpretation. PMID- 28668166 TI - PET/MR Imaging in Gynecologic Oncology. AB - MR imaging and PET using 2-Deoxy-2-[18F]fluoroglucose (FDG) are both useful in the evaluation of gynecologic malignancies. MR imaging is superior for local staging of disease whereas fludeoxyglucose FDG PET is superior for detecting distant metastases. Integrated PET/MR imaging scanners have great promise for gynecologic malignancies by combining the advantages of each modality into a single scan. This article reviews the technology behind PET/MR imaging acquisitions and technical challenges relevant to imaging the pelvis. A dedicated PET/MR imaging protocol; the roles of PET and MR imaging in cervical, endometrial, and ovarian cancers; and future directions for PET/MR imaging are discussed. PMID- 28668167 TI - Foreword. PMID- 28668168 TI - Be an Advocate for Women's Health: Get a Pelvic MRI. PMID- 28668169 TI - Perforated inguinal hernia with extensive emphysema in thigh. PMID- 28668170 TI - Aortic stenosis. Indications and results of percutaneous aortic valve implantation (TAVI). AB - Aortic stenosis (AS) is the most common valvular heart disease in developed countries. Its prevalence increases progressively due the aging of the population. Transcatheter aortic valve implantation (TAVI), however, has revolutionised the treatment of AS. With the current data, we can confirm that TAVI is the treatment of choice for patients with severe symptomatic AS considered inoperable or with high surgical risk. In recent years, the use of TAVI has grown exponentially and is spreading to patients of intermediate surgical risk due to the procedure's good results, the reduced number of complications and the low incidence of prosthetic degeneration. The results appear to indicate that, in the medium term, TAVI will progressively substitute conventional surgery for treating most patients with severe AS. PMID- 28668172 TI - Update concept of the dual blocking of the renin-angiotensin-aldosteron system. A new therapeutic option? PMID- 28668171 TI - Emerging nanotechnology based strategies for diagnosis and therapeutics of urinary tract infections: A review. AB - At present, various diagnostic and therapeutic approaches are available for urinary tract infections. But, still the quest for development of more rapid, accurate and reliable approach is an unending process. The pathogens, especially uropathogens are adapting to new environments and antibiotics day by day rapidly. Therefore, urinary tract infections are evolving as hectic and difficult to eradicate, increasing the economic burden to the society. The technological advances should be able to compete the adaptability characteristics of microorganisms to combat their growth in new environments and thereby preventing their infections. Nanotechnology is at present an extensively developing area of immense scientific interest since it has diverse potential applications in biomedical field. Nanotechnology may be combined with cellular therapy approaches to overcome the limitations caused by conventional therapeutics. Nanoantibiotics and drug delivery using nanotechnology are currently growing areas of research in biomedical field. Recently, various categories of antibacterial nanoparticles and nanocarriers for drug delivery have shown their potential in the treatment of infectious diseases. Nanoparticles, compared to conventional antibiotics, are more beneficial in terms of decreasing toxicity, prevailing over resistance and lessening costs. Nanoparticles present long term therapeutic effects since they are retained in body for relatively longer periods. This review focuses on recent advances in the field of nanotechnology, principally emphasizing diagnostics and therapeutics of urinary tract infections. PMID- 28668173 TI - Mapping urban air quality in near real-time using observations from low-cost sensors and model information. AB - The recent emergence of low-cost microsensors measuring various air pollutants has significant potential for carrying out high-resolution mapping of air quality in the urban environment. However, the data obtained by such sensors are generally less reliable than that from standard equipment and they are subject to significant data gaps in both space and time. In order to overcome this issue, we present here a data fusion method based on geostatistics that allows for merging observations of air quality from a network of low-cost sensors with spatial information from an urban-scale air quality model. The performance of the methodology is evaluated for nitrogen dioxide in Oslo, Norway, using both simulated datasets and real-world measurements from a low-cost sensor network for January 2016. The results indicate that the method is capable of producing realistic hourly concentration fields of urban nitrogen dioxide that inherit the spatial patterns from the model and adjust the prior values using the information from the sensor network. The accuracy of the data fusion method is dependent on various factors including the total number of observations, their spatial distribution, their uncertainty (both in terms of systematic biases and random errors), as well as the ability of the model to provide realistic spatial patterns of urban air pollution. A validation against official data from air quality monitoring stations equipped with reference instrumentation indicates that the data fusion method is capable of reproducing city-wide averaged official values with an R2 of 0.89 and a root mean squared error of 14.3 MUg m-3. It is further capable of reproducing the typical daily cycles of nitrogen dioxide. Overall, the results indicate that the method provides a robust way of extracting useful information from uncertain sensor data using only a time-invariant model dataset and the knowledge contained within an entire sensor network. PMID- 28668174 TI - Paraneoplastic thrombocytosis is associated with increased mortality and increased rate of lymph node metastasis in oesophageal adenocarcinoma. AB - Paraneoplastic thrombocytosis has been associated with adverse outcomes in several cancers, but has not been described in oesophageal adenocarcinoma. The aim of our study was to examine the prognostic value of platelet counts in patients with oesophageal adenocarcinoma. A cohort of 584 patients who underwent oesophagectomy for oesophageal adenocarcinoma was identified. Platelet counts, history of neoadjuvant chemoradiation, and clinicopathological factors such as T and N stage, and overall survival were recorded. Patients with elevated platelet count (>450,000/MUL) had a higher mortality rate than patients with normal platelet count (150,000-450,000/MUL) (hazard ratio = 2.60, p = 0.0013). This effect was seen in patients with and without neoadjuvant chemoradiation therapy. Paraneoplastic thrombocytosis was also associated with increased likelihood of lymph node metastasis compared to normal platelet count (69% versus 31%, p < 0.01). Paraneoplastic thrombocytosis is associated with increased rate of lymph node metastasis and mortality in oesophageal adenocarcinoma. Further studies are needed to examine the mechanisms behind this phenomenon. PMID- 28668176 TI - Predictive factors of complicated appendicitis in children. PMID- 28668175 TI - Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches. AB - Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing. PMID- 28668177 TI - A brief assessment of capacity to consent instrument in acutely intoxicated emergency department patients. AB - OBJECTIVE: The aim of this study was to determine to what extent acute alcohol intoxication effects capacity to assent, consent, or refuse research participation. METHODS: This was a prospective, observation study performed at our inner city, county hospital with >100,000 annual emergency department visits. Non-pregnant, English speaking patients older than 18 with evidence of acute alcohol intoxication were considered eligible. After medical screening, a trained research associate presented the study version of the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) tool. The primary outcome was the number of patients able to correctly respond to all 10 questions. RESULTS: Of 642 screened patients, 415 patients were enrolled and completed the tool. The mean alcohol concentration was 227mg/dL (range 25-500mg/dL). Sixteen patients (3.9%) answered all 10 questions correctly; by definition of the UBACC, these patients were deemed to possess capacity to consent. Mean alcohol concentrations in the capacity group were lower than in those lacking capacity; 182mg/dL (SD 6.7) versus 229mg/dL, (SD 7.9). Of the 287 patients who were interviewed upon sobriety at discharge, 182 patients (63.4%) did not recall completing the questionnaire. CONCLUSIONS: While intoxicated emergency department patients are able to complete the questionnaire, the majority do not possess capacity to provide informed consent to research. A minority of participants remember involvement once they have achieved sobriety, exception from informed consent protocols are needed to perform emergency research in this population. PMID- 28668179 TI - Does VideoStylet improve the effectiveness of endotracheal intubation during cardiopulmonary resuscitation? PMID- 28668178 TI - Cholinergic symptoms and QTc prolongation following donepezil overdose. AB - Donepezil is the most commonly prescribed acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, an ailment that affects millions of older adult patients. By inhibiting the breakdown of acetylcholine in the central nervous system, donepezil has been shown to slow cognitive decline and improve patients' functional status. While donepezil is well-tolerated and generally considered safe at therapeutic doses, taking more than the prescribed dose could result in adverse cholinergic effects that range from mild gastrointestinal distress to serious cardiac dysrhythmias. We present a case of an 84-year-old man who developed gastrointestinal and cardiac disturbances after ingesting seven-times his daily dose of donepezil. As no specific antidote is available for donepezil overdose, this case highlights the importance of supportive care with particular attention to the management of cardiac dysrhythmias in patients displaying signs of toxicity. PMID- 28668180 TI - Reducing risk and increasing confidence of decision making at a lower cost: In situ pXRF assessment of metal-contaminated sites. AB - This study evaluates the in-situ use of field portable X-ray Fluorescence (pXRF) for metal-contaminated site assessments, and assesses the advantages of increased sampling to reduce risk, and increase confidence of decision making at a lower cost. Five metal-contaminated sites were assessed using both in-situ pXRF and ex situ inductively coupled plasma mass spectrometry (ICP-MS) analyses at various sampling resolutions. Twenty second in-situ pXRF measurements of Mn, Zn and Pb were corrected using a subset of parallel ICP-MS measurements taken at each site. Field and analytical duplicates revealed sampling as the major contributor (>95% variation) to measurement uncertainties. This study shows that increased sampling led to several benefits including more representative site characterisation, higher soil-metal mapping resolution, reduced uncertainty around the site mean, and reduced sampling uncertainty. Real time pXRF data enabled efficient, on-site decision making for further judgemental sampling, without the need to return to the site. Additionally, in-situ pXRF was more cost effective than the current approach of ex-situ sampling and ICP-MS analysis, even with higher sampling at each site. Lastly, a probabilistic site assessment approach was applied to demonstrate the advantages of integrating estimated measurement uncertainties into site reporting. PMID- 28668181 TI - Arthroscopic Joint Preservation in Severe Glenohumeral Arthritis Using Interpositional Human Dermal Allograft. AB - PURPOSE: To investigate the outcomes of arthroscopic glenoid resurfacing (AGR) for severe glenohumeral arthritis at short- to medium-term follow-up. METHODS: We performed a multicenter retrospective review of consecutive patients undergoing AGR (2005-2013) with a minimum of 2 years' follow-up or until revision. Patients lost to follow-up and those included in a prior study were excluded. The indications for AGR were severe primary shoulder osteoarthritis without significant bone loss in younger, higher-demand patients. Outcome measures included revision, pain and American Shoulder and Elbow Surgeons (ASES) scores, and range of motion. Exact logistic regression was used to assess preoperative risk factors for revision. RESULTS: Forty-three shoulders with an average of 60 months' clinical follow-up underwent AGR. The rate of revision to prosthetic arthroplasty was 23% (95% confidence interval [CI], 12%-39%) after a mean of 45 months. The visual analog scale pain score (0-10) improved from a median of 7 to 2 (median difference [Delta], 4 [95% CI, 3-6]; P < .0001), representing pain relief similar to total shoulder arthroplasty in young patients. Improvements in the median ASES score (from 47 to 76; Delta, 28 [95% CI, 17-40]; P < .0001), active forward elevation (from 110 degrees to 140 degrees ; Delta, 20 degrees [95% CI, 10 degrees -35 degrees ]; P < .0001), and active external rotation (from 0 degrees to 20 degrees ; Delta, 10 degrees [95% CI, 5 degrees -20 degrees ]; P < .0001) were noted. The mean age of revised shoulders (60 years [95% CI, 54-66 years]) was higher than that of surviving shoulders (53 years [95% CI, 50-57 years], P = .005). The preoperative ASES score of revised shoulders (34 [95% CI, 27-42]) was lower than that of surviving shoulders (47 [95% CI, 43-51], P = .006). No complications were noted. CONCLUSIONS: AGR with dermal allograft is a safe option for joint preservation in selected patients, provides pain relief, and has an acceptable rate of revision to prosthetic arthroplasty at short-term to midterm follow-up. Increased age and lower preoperative ASES score were risk factors for failure of AGR. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28668182 TI - Preparing for an ageing HIV epidemic. PMID- 28668183 TI - Social change and HIV in Iran: reaching hidden populations. PMID- 28668184 TI - Correction to Lancet HIV 2017; 4: e240. PMID- 28668185 TI - An automated method to morph finite element whole-body human models with a wide range of stature and body shape for both men and women. AB - Field data analyses have shown that small female, obese, and/or older occupants are at increased risks of death and serious injury in motor-vehicle crashes compared with mid-size young men. The current adult finite element (FE) human models represent occupants in the same three body sizes (large male, mid-size male, and small female) as those for the contemporary adult crash dummies. Further, the time needed to develop an FE human model using the traditional method is measured in months or even years. In the current study, an improved regional mesh morphing method based on landmark-based radial basis function (RBF) interpolation was developed to rapidly morph a mid-size male FE human model into different geometry targets. A total of 100 human models with a wide range of human attributes were generated. A pendulum chest impact condition was applied to each model as an initial assessment of the resulting variability in response. The morphed models demonstrated mesh quality similar to the baseline model. The peak impact forces and chest deflections in the chest pendulum impacts varied substantially with different models, supportive of consideration of population variation in evaluating the occupant injury risks. The method developed in this study will enable future safety design optimizations targeting at various vulnerable populations that cannot be considered with the current models. PMID- 28668186 TI - An active balance board system with real-time control of stiffness and time-delay to assess mechanisms of postural stability. AB - Increased time-delay in the neuromuscular system caused by neurological disorders, concussions, or advancing age is an important factor contributing to balance loss (Chagdes et al., 2013, 2016a,b). We present the design and fabrication of an active balance board system that allows for a systematic study of stiffness and time-delay induced instabilities in standing posture. Although current commercial balance boards allow for variable stiffness, they do not allow for manipulation of time-delay. Having two controllable parameters can more accurately determine the cause of balance deficiencies, and allows us to induce instabilities even in healthy populations. An inverted pendulum model of human posture on such an active balance board predicts that reduced board rotational stiffness destabilizes upright posture through board tipping, and limit cycle oscillations about the upright position emerge as feedback time-delay is increased. We validate these two mechanisms of instability on the designed balance board, showing that rotational stiffness and board time-delay induced the predicted postural instabilities in healthy, young adults. Although current commercial balance boards utilize control of rotational stiffness, real-time control of both stiffness and time-delay on an active balance board is a novel and innovative manipulation to reveal balance deficiencies and potentially improve individualized balance training by targeting multiple dimensions contributing to standing balance. PMID- 28668187 TI - Experimental validation of finite element predicted bone strain in the human metatarsal. AB - Metatarsal stress fracture is a common injury observed in athletes and military personnel. Mechanical fatigue is believed to play an important role in the etiology of stress fracture, which is highly dependent on the resulting bone strain from the applied load. The purpose of this study was to validate a subject specific finite element (FE) modeling routine for bone strain prediction in the human metatarsal. Strain gauge measurements were performed on 33 metatarsals from seven human cadaveric feet subject to cantilever bending, and subject-specific FE models were generated from computed tomography images. Material properties for the FE models were assigned using a published density-modulus relationship as well as density-modulus relationships developed from optimization techniques. The optimized relationships were developed with a 'training set' of metatarsals (n=17) and cross-validated with a 'test set' (n=16). The published and optimized density elasticity equations provided FE-predicted strains that were highly correlated with experimental measurements for both the training (r2>=0.95) and test (r2>=0.94) sets; however, the optimized equations reduced the maximum error by 10% to 20% relative to the published equation, and resulted in an X=Y type of relationship between experimental measurements and FE predictions. Using a separate optimized density-modulus equation for trabecular and cortical bone did not improve strain predictions when compared to a single equation that spanned the entire bone density range. We believe that the FE models with optimized material property assignment have a level of accuracy necessary to investigate potential interventions to minimize metatarsal strain in an effort to prevent the occurrence of stress fracture. PMID- 28668188 TI - The need for better legislation for generic drug manufacturers. PMID- 28668189 TI - Unrelated cord blood transplantation for non-malignant diseases: every HLA allele counts. PMID- 28668190 TI - Do big numbers assure high-quality of data? PMID- 28668192 TI - Intraoperative processing and epicardial transplantation of autologous atrial tissue for cardiac repair. PMID- 28668191 TI - Monoclonal B-cell lymphocytosis in a hospital-based UK population and a rural Ugandan population: a cross-sectional study. AB - BACKGROUND: Reported incidence of B-cell malignancies shows substantial geographical variation, being more common in the Americas and Europe than in Africa. This variation might reflect differences in diagnostic capability, inherited susceptibility, and infectious exposures. Monoclonal B-cell lymphocytosis (MBL) is a precursor lesion that can be screened for in apparently healthy people, allowing comparison of prevalence across different populations independently of health-care provision. We aimed to compare the prevalence and phenotypic characteristics of MBL in age-and-sex-matched populations from rural Uganda and the UK. METHODS: In this cross-sectional study, we recruited volunteers aged at least 45 years who were seronegative for HIV-1 from the established Ugandan General Population Cohort and obtained their whole-blood samples. We also obtained blood samples from anonymised waste material of age-and sex-matched individuals (aged >45 years, with a normal blood count and no history of cancer) in the UK. We used flow cytometry to determine the presence of MBL, defined according to standard diagnostic criteria, in the samples and compared differences in the proportion of cases with chronic lymphocytic leukaemia (CLL) phenotype MBL and CD5-negative MBL, as well as differences in absolute monoclonal B-cell count between the two cohorts. FINDINGS: Between Jan 15 and Dec 18, 2012, we obtained samples from 302 Ugandan volunteers and 302 UK individuals who were matched by age and sex to the Ugandan population. Overall MBL prevalence was higher in the Ugandan participants (42 [14%] individuals) than in the UK cohort (25 [8%]; p=0.038). CLL-phenotype MBL was detected in three (1%) Ugandan participants and 21 (7%) UK participants (p=0.00021); all three Ugandan participants had absolute monoclonal B-cell count below one cell per MUL, whereas the 21 UK participants had a median absolute number of circulating neoplastic cells of 4.6 (IQR 2-12) cells per MUL. The prevalence of CD5-negative MBL was higher in the Ugandan cohort (41 [14%], of whom two [5%] also had CLL-phenotype MBL) than in the UK cohort (six [2%], of whom two [33%] also had CLL-phenotype MBL; p<0.0001), but the median absolute B-cell count was similar (227 [IQR 152 345] cells per MUL in the Ugandan cohort vs 135 [105-177] cells per MUL in the UK cohort; p=0.13). INTERPRETATION: MBL is common in both Uganda and the UK, but the substantial phenotypic differences might reflect fundamental differences in the pathogenesis of B-cell lymphoproliferative disorders. FUNDING: UK Medical Research Council and UK Department for International Development. PMID- 28668193 TI - Diaminopimelic acid (DAP) analogs bearing isoxazoline moiety as selective inhibitors against meso-diaminopimelate dehydrogenase (m-Ddh) from Porphyromonas gingivalis. AB - Two diastereomeric analogs (1 and 2) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso-diaminopimelate dehydrogenase (m-Ddh) from the periodontal pathogen, Porphyromonas gingivalis. Compound 2 showed promising inhibitory activity against m-Ddh with an IC50 value of 14.9uM at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773uM and 1.875mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases. PMID- 28668195 TI - Selected Abstracts From the 2017 SPN Conference. PMID- 28668194 TI - Discovery of novel dengue virus entry inhibitors via a structure-based approach. AB - Dengue is a mosquito-borne virus that has become a major public health concern worldwide in recent years. However, the current treatment for dengue disease is only supportive therapy, and no specific antivirals are available to control the infections. Therefore, the need for safe and effective antiviral drugs against this virus is of utmost importance. Entry of the dengue virus (DENV) into a host cell is mediated by its major envelope protein, E. The crystal structure of the E protein reveals a hydrophobic pocket occupied by the detergent n-octyl-beta-d glucoside (beta-OG) lying at a hinge region between domains I and II, which is important for the low-pH-triggered conformational rearrangement required for fusion. Thus, the E protein is an attractive target for the development of antiviral agents. In this work, we performed prospective docking-based virtual screening to identify small molecules that likely bind to the beta-OG binding site. Twenty-three structurally different compounds were identified and two of them had an EC50 value in the low micromolar range. In particular, compound 2 (EC50=3.1MUM) showed marked antiviral activity with a good therapeutic index. Molecular dynamics simulations were used in an attempt to characterize the interaction of 2 with protein E, thus paving the way for future ligand optimization endeavors. These studies highlight the possibility of using a new class of DENV inhibitors against dengue. PMID- 28668196 TI - Erratum to "The activity of a Spanish bone densitometry unit revisited under the point of view of FRAX" <[Reumatol Clin 8 (2012) 179-183]>. PMID- 28668197 TI - Improving healthcare value through clinical community and supply chain collaboration. AB - BACKGROUND: We hypothesized that integrating supply chain with clinical communities would allow for clinician-led supply cost reduction and improved value in an academic health system. METHODS: Three clinical communities (spine, joint, blood management) and one clinical community-like physician led team of surgeon stakeholders partnered with the supply chain team on specific supply cost initiatives. The teams reviewed their specific utilization and cost data, and the physicians led consensus-building conversations over a series of team meetings to agree to standard supply utilization. RESULTS: The spine and joint clinical communities each agreed upon a vendor capping model that led to cost savings of $3 million dollars and $1.5 million dollars respectively. The blood management decreased blood product utilization and achieved $1.2 million dollars savings. $5.6 million dollars in savings was achieved by a clinical community-like group of surgeon stakeholders through standardization of sutures and endomechanicals. CONCLUSIONS: Physician led clinical teams empowered to lead change achieved substantial supply chain cost savings in an academic health system. The model of combining clinical communities with supply chain offers hope for an effective, practical, and scalable approach to improving value and engaging physicians in other academic health systems. IMPLICATIONS: This clinician led model could benefit both private and academic health systems engaging in value optimization efforts. LEVEL OF EVIDENCE: N/A. PMID- 28668198 TI - Academic physicians' views on low-value services and the choosing wisely campaign: A qualitative study. AB - BACKGROUND: In 2012, the American Board of Internal Medicine (ABIM) Foundation launched a campaign called Choosing Wisely which was intended to start a national dialogue on services that are not medically necessary. More research is needed on the in-depth reasons why doctors overuse low-value services, their views on Choosing Wisely specifically, and ways to help them change their practice patterns. METHODS: We performed a qualitative study of focus groups with physicians to explore their views on the problem of overuse of low-value services, the reasons why they overuse, and ways that they think could be effective at curbing overuse. Participants were attendings in the fields of emergency medicine, internal medicine, hospital medicine, and cardiology. RESULTS: All physicians felt that overuse of low-value services was a significant problem. Physicians frequently cited that patient expectations drove the use of low-value services and lack of time was the most cited reason why behavior change was difficult. Facilitators that could promote behavior change included decision support through the electronic medical record, motivation to maintain their reputation among their colleagues, internal motivation to be a good doctor, objective data showing their rates of overuse, alignment of institutional goals, and forums to discuss evidence and new research. CONCLUSIONS AND IMPLICATIONS: In focus groups with physicians, we found that physicians perceived that overuse of low-value services was a problem. Participants cited many barriers to behavior change. Methods that help address patient expectations, physician time, and social norms may help physicians reduce their use of low-value services. PMID- 28668199 TI - Chronic respiratory failure: Utilization of a pediatric specialty integrated care program. AB - OBJECTIVE: Describe utilization and satisfaction in a specialty integrated care program for children with severe, chronic respiratory insufficiency (CRI). SUBJECTS: Enrollees of the Critical Care, Anesthesia, Perioperative Extension (CAPE) and Home Ventilation Program. METHODS: Children with CRI received home visits, care coordination, and "on-demand" 24/7 access to physicians. Program activity and outcomes were recorded for 3 years using an adapted Care Coordination Measurement Tool(c) version. Parents completed the Consumer Assessment of Healthcare Providers and Systems (CAHPS). Patient characteristics, program activity, clinical outcomes, utilization, and satisfaction were summarized using descriptive statistics. RESULTS: CAPE provided care for 320 patients from 2012 to 2014 with a median of 7 encounters per year. Neuromuscular (n=132, 41%), chronic lung disease (n=37, 12%), and congenital heart disease (n=13, 4%) represented the majority of underlying conditions. Services included 905 home, 504 clinic, and 3633 telephone encounters, of which 43.6% included a care coordination activity. CAHPS (n=102) revealed that 92.1% (n=93) of children had at least one non-urgent (i.e., routine) visit and nearly two-thirds (64.7%, n=66) reported the need for urgent or emergency care. Overall, parents were highly satisfied with CAPE, with a mean satisfaction rating of 9.3 (+/-1.3) out of 10. Most parents reported that the CAPE team understood the child's (96.0%, n=95) and family's day-to-day life (86.9%, n=86). CONCLUSIONS: When given open access to an intregated care program, children in our highly complex population required a median of 7 encounters per year. We believe that this experience is scalable and may inform other organizations contemplating similar services. PMID- 28668200 TI - Adopting SCAN-ECHO: The providers' experiences. AB - A qualitative descriptive analysis of providers' (primary care providers and specialists) experiences adopting SCAN-ECHO identifies perceived challenges, benefits, effects on patient care, and engagement factors. PMID- 28668201 TI - Using behavioral economics in provider payment to motivate improved quality, outcomes & cost: The Alternative Quality Contract. PMID- 28668202 TI - Home infusion: Safe, clinically effective, patient preferred, and cost saving. AB - BACKGROUND: As the U.S. healthcare payment system shifts from volume to value, identifying care approaches that improve outcomes while lowering costs are essential. We sought to understand the utility of home infusion versus medical setting infusion as a mechanism to affect the three-part aim: better care, better health outcomes, and lower costs. STUDY DESIGN: Systematic review. METHODS: We searched MEDLINE, EMBASE, and Science Citation Index for articles related to the safety, clinical effectiveness, quality of life and satisfaction, and/or costs of home infusion as compared with infusion in an outpatient medical facility or hospital. RESULTS: Of 253 potentially relevant articles, 13 met all inclusion criteria. Study design, disease state, and outcomes varied considerably. As compared to medical setting infusion patients, home infusion patients were no more likely to experience adverse drug events or side effects (all p>0.05). Clinical outcomes were as good or better, e.g., for patients with hemophilia, a 40% (0.50-0.70) reduced likelihood of hospitalization for bleeding complications. Patients overwhelmingly preferred home infusion, reporting significantly better physical and mental well being and less disruption of family and personal responsibilities. Home infusion costs were significantly lower than medical setting infusion costs, with savings between $1928 and $2974 per treatment course. CONCLUSIONS: Home infusion care can provide safe, clinically effective care improve patients' quality of life and reduce healthcare costs. As the overhaul of the healthcare payment system gains momentum, the home infusion care delivery model offers strong promise as one in a set of approaches that can improve care and lower costs. PMID- 28668203 TI - Principles for provider incentives in CMS's alternative payment models. PMID- 28668204 TI - Randomized Phase III Study of Cisplatin With Pemetrexed and Cisplatin With Vinorelbine for Completely Resected Nonsquamous Non-Small-Cell Lung Cancer: The JIPANG Study Protocol. AB - This trial report describes the background and design for the Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous Non Small-Cell Lung Cancer (JIPANG) study (University Hospital Medical Information Network database: UMIN000006737). Various randomized trials have shown the efficacy of postoperative adjuvant chemotherapy regimens that include cisplatin for resected non-small-cell lung cancer (NSCLC), but the optimal regimen is not known. The JIPANG study is a randomized study comparing cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) with cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2, days 1 and 8) for nonsquamous NSCLC as postoperative adjuvant chemotherapy. A total of 804 patients with pathological stage II to IIIA completely resected nonsquamous NSCLC were enrolled in this study between March 2012 and August 2016. These patients have been randomized in a 1:1 ratio and stratified according to sex (female vs. male), age (< 70 years vs. >= 70 years), pathologic stage (II vs. IIIA), mutation of the epidermal growth factor receptor (mutant vs. wild) and institution. Each treatment will be undertaken every 3 weeks until 4 cycles have been completed. The primary endpoint is overall survival and the secondary endpoints are disease-free survival, rate of treatment completion, and incidence of adverse events. This design has 80% power to detect overall survival with a hazard ratio of 0.786 (alpha = 1-sided 0.05) with 5-year follow-up after registration of the final patient. This study will show a superior regimen for completely resected nonsquamous NSCLC. Biomarker analyses of the JIPANG study are ongoing. PMID- 28668205 TI - An Evolving Algorithm to Select and Sequence Therapies in EGFR Mutation-positive NSCLC: A Strategic Approach. AB - The optimal treatment sequence for patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive (EGFR-M+) non-small-cell lung cancer (NSCLC) continues to evolve, related largely to an increasing number of breakthroughs and studies in the field. The efficacy of tyrosine kinase inhibitors in the treatment of these patients is well established; however, the treatment decision-making process is becoming more complex as our knowledge of EGFR mutations and resistance pathways grows and more treatment options become available. Thus, treating physicians must consider an increasing number of factors. We present a stepwise approach to personalizing the treatment of patients with EGFR-M+ NSCLC, emphasizing some of the real world challenges faced by treating physicians. We reviewed the decision criteria for selecting the best first-line therapy, highlighted the importance of repeat biopsy on disease progression to determine the most appropriate next-line therapy, and discussed the options for third-line therapy and beyond. We also present an algorithm designed to optimize the sequencing strategies for prolonging survival and maintaining quality of life in our patients with EGFR-M+ NSCLC. PMID- 28668206 TI - Editorial Comment: Predictors of Post-Traumatic Stress Disorder in Acutely Traumatized Older Adults. PMID- 28668207 TI - 2017 American Association for Geriatric Psychiatry (AAGP) Annual Meeting Presidential Plenary Address: The Cultural Diversity Amongst Us (Members of the AAGP) and Our Patients-Our Challenge and Our Strength. PMID- 28668208 TI - 10 workshops on Immunology of preeclampsia. AB - For the 10th issue of the " island workshops ", now the Reunion Workshops, organised by Pierre Yves Robillard since the first one in Tahiti challenging the "vascular disease only" theory of pre eclampsia and introducing the primipaternity concept, we examined the reasons for considering an Immunological approach to the disease. This (brief) overview thus examines several important topics in an Immunological framework. I have chosen to present here the evolution of the main themes rather than a purely chronological vision. PMID- 28668209 TI - Impact of preoperative visceral fat proportion on type 2 diabetes in patients with low body mass index after gastrectomy. AB - BACKGROUND: Metabolic surgery is an effective option for treatment of type 2 diabetes. Although body mass index (BMI) has several limitations in differentiating the metabolic risks of the same weight of muscle and fat, it is used as the basis of indication for metabolic surgery. OBJECTIVES: Since visceral fat is highly associated with metabolic disease, we evaluated the effectiveness of visceral fat proportion (VFP) for predicting metabolic risk preoperatively. SETTING: University hospital. METHODS: Fifty-two type 2 diabetes patients with BMI<=35 kg/cm2 who underwent gastrectomy for gastric cancer were included. Pre- and postoperative VFPs were measured using abdominal computed tomography. Multivariate logistic regression analysis was performed to estimate the effect of VFP on type 2 diabetes. Receiver operating curve analysis was used to estimate the effectiveness of VFP as a predictor of type 2 diabetes improvement. RESULTS: Thirty-three of the 52 patients (63%) showed improved type 2 diabetes postoperatively. Low preoperative VFP (odds ratio [OR] = .913; 95% confidence interval [CI] = .835-.999; P = .048) and low glycated hemoglobin level (OR = .357; 95% CI = .172-.742; P = .006) were associated with type 2 diabetes improvement 2 years after gastrectomy. The area under the curve was 70.2%, indicating moderate accuracy. CONCLUSIONS: Preoperative VFP might be a reasonable predictive factor for type 2 diabetes improvement after gastrectomy for patients with a BMI<=35 kg/cm2. High-quality studies of visceral fat for metabolic function are needed in the future. PMID- 28668210 TI - Associative Learning Should Go Deep. AB - Conditioning, how animals learn to associate two or more events, is one of the most influential paradigms in learning theory. It is nevertheless unclear how current models of associative learning can accommodate complex phenomena without ad hoc representational assumptions. We propose to embrace deep neural networks to negotiate this problem. PMID- 28668211 TI - Survivorship of Total Hip Joint Replacements Following Isolated Liner Exchange for Wear. AB - BACKGROUND: Liner exchange for articular component wear in total hip joint replacements (THJRs) is a common procedure, often thought to be benign with reliable outcomes. Recent studies, however, suggest high failure rates of liner exchange revisions with significant complications. The primary aim of this study was, therefore, to analyze the survivorship of isolated liner exchange for articular component wear, and secondarily to assess the influence of patient demographics (gender, age, and American Society of Anaesthesiologists [ASA] ratings) on rerevisions following isolated liner exchange for wear. METHODS: A retrospective review of the 15-year New Zealand Joint Registry (1999-2014) was performed, analyzing the outcomes of isolated liner exchange for articular component wear. The survivorship as defined as rerevision with component exchange was determined and 10-year Kaplan-Meier survivorship curves were constructed. These revision rates were compared to age, gender, and ASA rating groups using a log-rank test. RESULTS: The 10-year survivorship of THJR following liner exchange revision for liner wear was 75.3%. If a rerevision was required, the median time to rerevision was 1.33 years with a rerevision rate of 3.33 per 100 component years (95% confidence interval 2.68-4.08/100 component years). The principle reasons for rerevision were dislocation (48.4%) and acetabular component loosening (20.9%). There was no statistically significant difference in rerevision rates based on gender, age categories, or ASA scores. CONCLUSION: THJR isolated liner exchange for liner wear is not a benign procedure with a survivorship of 75.3% at 10 years. Surgeons contemplating liner exchange revisions should be cognisant of this risk and should adequately assess component position and stability preoperatively. PMID- 28668212 TI - Fretting and Corrosion Damage in Taper Adapter Sleeves for Ceramic Heads: A Retrieval Study. AB - BACKGROUND: During revision surgery with a well-fixed stem, a titanium sleeve can be used in conjunction with a ceramic head to achieve better stress distribution across the taper surface. In vitro testing suggests that corrosion is not a concern in sleeved ceramic heads; however, little is known about the in vivo fretting corrosion of the sleeves. The purpose of this study was to investigate fretting corrosion in sleeved ceramic heads in retrieved total hip arthroplasties. METHODS: Thirty-seven sleeved ceramic heads were collected during revision. The femoral heads and sleeves were implanted 0.0-3.3 years. The implants were revised predominantly for instability, infection, and loosening. Fifty percent of the retrievals were implanted during a primary surgery. Fretting corrosion was assessed using the Goldberg-Higgs semiquantitative scoring system. RESULTS: Mild-to-moderate fretting corrosion scores (score = 2-3) were observed in 92% of internal tapers, 19% of external tapers, and 78% of the stems. Severe fretting corrosion was observed in 1 stem trunnion that was previously retained during revision surgery and none of the retrieved sleeves. There was no difference in corrosion damage of sleeves used in primary or revision surgery. CONCLUSION: The fretting corrosion scores in this study were predominantly mild and lower than reported fretting scores of cobalt-chrome heads in metal-on polyethylene bearings. Although intended for use in revisions, we found that the short-term in vivo corrosion behavior of the sleeves was similar in both primary and revision surgery applications. From an in vivo corrosion perspective, sleeves are a reasonable solution for restoring the stem taper during revision surgery. PMID- 28668213 TI - Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy. AB - TAM receptors (Tyro3, Axl, and Mer) have been implicated in innate immunity. Circulating TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in urine, identifying the kidney as a source of sTAM. PMID- 28668214 TI - The Youth Anxiety Measure for DSM-5 (YAM-5): Correlations with anxiety, fear, and depression scales in non-clinical children. AB - The Youth Anxiety Measure for DSM-5 (YAM-5) is a newly developed rating scale for assessing anxiety disorder symptoms of children and adolescents in terms of the contemporary classification system. In the present study, 187 children aged 8-12 years completed the new measure as well as the trait version of the State-Trait Anxiety Inventory for Children (STAIC), the Short Form of the Fear Survey Schedule for Children-Revised (FSSC-R-SF), the Spence Children's Anxiety Scale (SCAS), the Selective Mutism Questionnaire (SMQ), and the Children's Depression Inventory (CDI). Results indicated that part one of the YAM-5, which measures symptoms of the major anxiety disorders, was most substantially linked with the trait anxiety scale of the STAIC, whereas part two, which measures phobic symptoms, was most clearly associated with the FSSC-R-SF. The correlation between the YAM-5 and the SCAS was also robust, and particularly strong correlations were found between subscales of both questionnaires that assessed similar symptoms. Further, the selective mutism subscale of the YAM-5 was most clearly linked to the SMQ. Finally, the YAM-5 was also significantly correlated with depression symptoms as indexed by the CDI. These findings provide further support for the concurrent validity of the YAM-5. PMID- 28668215 TI - [Social cognition in children with neurogenetic syndromes: A literature review]. AB - Social cognitive impairments may largely contribute to reduced social skills and adaptive problems in individuals with microdeletion syndromes associated with behavioral and psychiatric phenotypes. Understanding the role of social information processing deficits in the emergence of psychotic disorders is a crucial challenge in the management of these patients. Each neurogenetic disorder is characterized by a specific social cognition phenotype. Clarifying the social ability profile of each population may help adjust patient care according to their key strengths and weaknesses. The main objective of this article is to review the social cognitive skills of various neurogenetic disorders and shed light on the specific mechanisms that may underlie these skills in each syndrome. After detailing the different processes unified under the generic term "social cognition", we present these processes in the most frequent microdeletion syndromes presenting with social interaction deficits: 22q11.2 deletion syndrome, Angelman syndrome, fragile X syndrome, Klinefelter syndrome, Prader-Willi syndrome, Rett syndrome, Smith-Magenis syndrome, Turner syndrome, and Williams syndrome. Finally, we highlight future approaches that may have a significant influence on the development of adapted therapeutic interventions, such as cognitive remediation therapies. The importance of connecting neurocognitive and social cognition remediations is also emphasized. PMID- 28668216 TI - [Drugs news]. PMID- 28668217 TI - [Non invasive ventilation and pediatric palliative care. A French survey]. AB - OBJECTIVES: The benefits of non-invasive ventilation (NIV) have been clearly demonstrated in pediatrics. In palliative care, NIV can improve the level of comfort and quality of life and can decrease dyspnea. The objective was to survey pediatricians' opinions and practices regarding NIV in palliative care in France. DESIGN: A mail survey was conducted among pediatric pneumologists, intensivists and palliative medicine consultants from February 2015 to March 2015. RESULTS: In case of acute respiratory failure, 84% of the responding practitioners found NIV appropriate in do-not-intubate (DNI) children, while only 35% of them found it appropriate in comfort-measures-only (CMO) children (P<0.0001). In case of progressive respiratory failure, 68% of the responders found NIV appropriate in DNI children, while only 30% in CMO children (P<0.05). The major criterion for initiating NIV in pediatric palliative care was the presence of dyspnea. In pediatric palliative care, the efficacy of NIV was evaluated primarily clinically in terms of the improvement of the child's comfort level, as well as the child's and family's satisfaction. Hypercapnia and desaturation were rarely measured to initiate NIV or to assess its efficacy. Sixty percent of the responding practitioners indicated that referral to NIV was anticipated with children and family before acute events or end-of-life occurred. CONCLUSION: French pediatricians habitually use NIV for management of acute or progressive respiratory symptoms in DNI children. In CMO children, a majority of responding practitioners find NIV inappropriate. In palliative care, the indications for and efficacy of NIV are evaluated based on clinical criteria and rarely on gasometric criteria. PMID- 28668218 TI - [Severe nutritional rickets in young children: Resurgence of an old disease]. AB - Nutritional rickets remains a significant public health issue for children worldwide. Although it has almost disappeared in industrialized countries following routine vitamin D supplementation, recent evidence suggests an increasing incidence, especially in young children. In addition to the classical clinical consequences on bone and the growth plate, rickets may also be associated with life-threatening neurological and cardiac complications in the most severe forms. Consequently, early screening and treatment are required. Here, we report the case of a 2-year-old child who presented with severe nutritional rickets associated with seizure and cardiomyopathy. Family screening revealed rickets in all the siblings. This case report emphasizes the importance of being aware of this disease, notably in population with sociocultural risk factors. PMID- 28668219 TI - Three-Dimensional Correction of Complex Ankle Deformities With Computer-Assisted Planning and Patient-Specific Surgical Guides. AB - Three-dimensional computer-assisted preoperative planning, combined with patient specific surgical guides, has become an effective technique for treating complex extra- and intraarticular bone malunions by corrective osteotomy. The feasibility and accuracy of such a technique has not yet been evaluated for ankle deformities. Four surgical cases of varying complexity and location were selected for evaluation. Three-dimensional bone models of the affected and contralateral healthy lower limb were generated from computed tomography scans. The preoperative planning software permitted quantification of the deformity in 3 dimensions and subsequent simulation of reduction, yielding a precise surgical plan. Patient-specific surgical guides were designed, manufactured, and finally applied during surgery to reproduce the preoperative plan. Evaluation of the postoperative computed tomography scans indicated adequate reduction accuracy with residual translational and rotational errors of <3 mm and <6 degrees , respectively. Two patients required revision surgery owing to anterior osseous impingement or delayed union of the osteotomy. All patients were satisfied with the postoperative course and were pain free at a mean follow-up period of 2.5 (range 1 to 4) years. These promising results require confirmation in a clinical study with a larger sample size. PMID- 28668220 TI - Modulation of protein function in membrane mimetics: Characterization of P. denitrificans cNOR in nanodiscs or liposomes. AB - For detailed functional characterization, membrane proteins are usually studied in detergent. However, it is becoming clear that detergent micelles are often poor mimics of the lipid environment in which these proteins function. In this work we compared the catalytic properties of the membrane-embedded cytochrome c dependent nitric oxide reductase (cNOR) from Paracoccus (P.) denitrificans in detergent, lipid/protein nanodiscs, and proteoliposomes. We used two different lipid mixtures, an extract of soybean lipids and a defined mix of synthetic lipids mimicking the original P. denitrificans membrane. We show that the catalytic activity of detergent-solubilized cNOR increased threefold upon reconstitution from detergent into proteoliposomes with the P. denitrificans lipid mixture, and above two-fold when soybean lipids were used. In contrast, there was only a small activity increase in nanodiscs. We further show that binding of the gaseous ligands CO and O2 are affected differently by reconstitution. In proteoliposomes the turnover rates are affected much more than in nanodiscs, but CO-binding is more significantly accelerated in liposomes with soybean lipids, while O2-binding is faster with the P. denitrificans lipid mix. We also investigated proton-coupled electron transfer during the reaction between fully reduced cNOR and O2, and found that the pKa of the internal proton donor was increased in proteoliposomes but not in nanodiscs. Taking our results together, the liposome-reconstituted enzyme shows significant differences to detergent-solubilized protein. Nanodiscs show much more subtle effects, presumably because of their much lower lipid to protein ratio. Which of these two membrane-mimetic systems best mimics the native membrane is discussed. PMID- 28668221 TI - Human neuroimaging reveals the subcomponents of grasping, reaching and pointing actions. AB - Although the neural underpinnings of visually guided grasping and reaching have been well delineated within lateral and medial fronto-parietal networks (respectively), the contributions of subcomponents of visuomotor actions have not been explored in detail. Using careful subtraction logic, here we investigated which aspects of grasping, reaching, and pointing movements drive activation across key areas within visuomotor networks implicated in hand actions. For grasping tasks, we find activation differences based on the precision required (fine > coarse grip: anterior intraparietal sulcus, aIPS), the requirement to lift the object (grip + lift > grip: aIPS; dorsal premotor cortex, PMd; and supplementary motor area, SMA), and the number of digits employed (3-/5- vs. 2 digit grasps: ventral premotor cortex, PMv; motor cortex, M1, and somatosensory cortex, S1). For reaching/pointing tasks, we find activation differences based on whether the task required arm transport ((reach-to-point with index finger and reach-to-touch with knuckles) vs. point-without-reach; anterior superior parietal lobule, aSPL) and whether it required pointing to the object centre ((point without-reach and reach-to-point) vs. reach-to-touch: anterior superior parieto occipital cortex, aSPOC). For point-without-reach, in which the index finger is oriented towards the object centre but from a distance (point-without-reach > (reach-to-point and reach-to-touch)), we find activation differences that may be related to the communicative nature of the task (temporo-parietal junction, TPJ) and the need to precisely locate the target (lateral occipito-temporal cortex, LOTC). The present findings elucidate the different subcomponents of hand actions and the roles of specific brain regions in their computation. PMID- 28668222 TI - The SELFIE framework for integrated care for multi-morbidity: Development and description. AB - BACKGROUND: The rise of multi-morbidity constitutes a serious challenge in health and social care organisation that requires a shift from disease- towards person centred integrated care. The aim of the current study was to develop a conceptual framework that can aid the development, implementation, description, and evaluation of integrated care programmes for multi-morbidity. METHODS: A scoping review and expert discussions were used to identify and structure concepts for integrated care for multi-morbidity. A search of scientific and grey literature was conducted. DISCUSSION: meetings were organised within the SELFIE research project with representatives of five stakeholder groups (5Ps): patients, partners, professionals, payers, and policy makers. RESULTS: In the scientific literature 11,641 publications were identified, 92 were included for data extraction. A draft framework was constructed that was adapted after discussion with SELFIE partners from 8 EU countries and 5P representatives. The core of the framework is the holistic understanding of the person with multi-morbidity in his or her environment. Around the core, concepts were grouped into adapted WHO components of health systems: service delivery, leadership & governance, workforce, financing, technologies & medical products, and information & research. Within each component micro, meso, and macro levels are distinguished. CONCLUSION: The framework structures relevant concepts in integrated care for multi-morbidity and can be applied by different stakeholders to guide development, implementation, description, and evaluation. PMID- 28668223 TI - An Overview of Novel Adjuvants Designed for Improving Vaccine Efficacy. AB - Adjuvants incorporated in prophylactic and/or therapeutic vaccine formulations impact vaccine efficacy by enhancing, modulating, and/or prolonging the immune response. In addition, they reduce antigen concentration and the number of immunizations required for protective efficacy, therefore contributing to making vaccines more cost effective. Our better understanding of the molecular mechanisms of immune recognition and protection has led research efforts to develop new adjuvants that are currently at various stages of development or clinical evaluation. In this review, we focus mainly on several of these promising adjuvants, and summarize recent work conducted in various laboratories to develop novel lipid-containing adjuvants. PMID- 28668224 TI - The Future of Cysteine Cathepsins in Disease Management. AB - Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody-drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions. PMID- 28668225 TI - Autoinflammatory keratinization diseases. PMID- 28668226 TI - Sustained Chronic Maternal Hyperoxygenation Increases Myocardial Deformation in Fetuses with a Small Aortic Isthmus at Risk for Coarctation. AB - BACKGROUND: We aimed to assess differences in myocardial deformation in fetuses at risk for coarctation (CoA) and the effects of maternal hyperoxygenation on deformation. METHODS: Fetal echocardiography and velocity vector imaging were performed prospectively and serially in 48 fetuses with a small aortic isthmus and 48 gestation age-matched normal fetuses. Fetuses with a small aortic isthmus were randomly divided into two groups: one group with and the other group without maternal supplemental oxygen administration. The strain (S) and strain rate (SR) in the left ventricle (LV) and right ventricle (RV) were measured and compared between the groups. Regression analyses were performed to identify potential factors associated with myocardial deformation. RESULTS: Compared with normal fetuses, fetuses with a small aortic isthmus exhibited a lower S and SR at baseline. A negative correlation was found between aortic isthmus velocity-time integrals and S and SR at baseline (P < .05). In the group that received supplemental oxygen therapy, the S and SR in both the LV and RV increased as a function of time, especially 4 weeks after the initiation of oxygen therapy (P < .05). The duration of oxygen therapy and increased combined cardiac index were associated with increased myocardial deformation (P < .05). CONCLUSIONS: Myocardial deformation appears abnormal in those at risk for CoA beginning in utero, and chronic oxygen therapy appears to increase deformation measures. These findings may improve patient counseling and perinatal management. PMID- 28668227 TI - Psychometric properties and predictive validity of a police version of a violence risk screen - A pilot study. AB - The Violence Risk Screening - Police Version (V-RISK-POL) is a seven-item screening tool for use at police stations by police officers and law enforcement officials to assist in the process of decision making regarding release, restrictive measures or arrest for apprehended individuals where the risk of future violence must be considered. The screen is based on the V-RISK-10, originally developed for emergency psychiatry. We examined psychometric properties and the prospective predictive validity of future violent convictions for the V-RISK-POL in a sample of 111 persons arrested for suspicion of violent crimes. Seventeen persons were convicted for a new violent crime committed during the 24-40months follow-up. The V-RISK-POL demonstrated good internal consistency; Cronbach's alpha=0.81 (95% CI=0.75-0.86) and moderate predictive validity; the area under the curve of the receiving operator characteristics (AUC)=0.753 (95% CI=0.644-0.843). Further research on larger and more heterogeneous samples is necessary to examine whether the screen may be useful in the police context. PMID- 28668228 TI - Initial development of the Psychopathic Processing and Personality Assessment (PAPA) across populations. AB - Three studies describe development of the Psychopathic Processing and Personality Assessment (PAPA). Study one outlines a literature review and Expert Delphi (n=32) to develop the initial PAPA. Study two validates the PAPA with 431 participants (121 male prisoners and 310 university students: 154 men, 156 women), also using the Levenson Self Report Psychopathy scale and a measure of cognitive schema and affect. Study three refined the PAPA, employing it with 50 male students and 40 male forensic psychiatric patients using clinical (interview) assessments of psychopathy: the Psychopathy Checklist - Screening Version and the Affect, Cognitive and Lifestyle assessment. The PAPA comprised four factors; dissocial tendencies; emotional detachment; disregard for others; and lack of sensitivity to emotion. It positively correlated with existing psychopathy measures. Variations across PAPA subscales were noted across samples when associated with clinical measures of psychopathy. Support for the validity of the PAPA was indicated across samples. Directions for research and application are outlined. PMID- 28668229 TI - The impact of oral probiotics on vaginal Group B Streptococcal colonisation rates in pregnant women: A pilot randomised control study. AB - OBJECTIVE: To perform a pilot project to determine if this research design was appropriate to explore potential causal relationships between oral probiotic use and vaginal Group B Streptococcal (GBS) colonisation rates in pregnant women. METHOD: Thirty-four GBS-positive women at 36 weeks pregnant were recruited. The participants were randomly allocated to the control group, who received standard antenatal care, or to the intervention group, who received standard antenatal care and a daily oral dose of probiotics for three weeks or until they gave birth. A vaginal GBS swab was collected three weeks post consent or during labour. FINDINGS: No significant difference was found in vaginal GBS rates between the control and intervention groups. Only seven of 21 women in the intervention group completed the entire 21days of probiotics. A subgroup analysis, including only those who had completed 14days or more of probiotics (n=16), also showed no significant difference in vaginal GBS when compared to the control. The findings did show significantly more vaginal commensals in the probiotics group (p=0.048). DISCUSSION: Five possible reasons for the lack of significant results are: the length of the intervention was too short; the dosage of the probiotics was too low; the wrong strains of probiotics were used; the sample size was inadequate; or oral probiotics are ineffective in impacting vaginal GBS. IMPLICATIONS: The finding of a significant increase of vaginal commensals in women who completed 14days or more of probiotics supports the potential of probiotics to impact vaginal GBS in pregnancy. PMID- 28668231 TI - Inequalities in investment in malaria research in sub-Saharan Africa: are they inequities? PMID- 28668230 TI - Global funding trends for malaria research in sub-Saharan Africa: a systematic analysis. AB - BACKGROUND: Total domestic and international funding for malaria is inadequate to achieve WHO global targets in burden reduction by 2030. We describe the trends of investments in malaria-related research in sub-Saharan Africa and compare investment with national disease burden to identify areas of funding strength and potentially neglected populations. We also considered funding for malaria control. METHODS: Research funding data related to malaria for 1997-2013 were sourced from existing datasets, from 13 major public and philanthropic global health funders, and from funding databases. Investments (reported in US$) were considered by geographical area and compared with data on parasite prevalence and populations at risk in sub-Saharan Africa. 45 sub-Saharan African countries were ranked by amount of research funding received. FINDINGS: We found 333 research awards totalling US$814.4 million. Public health research covered $308.1 million (37.8%) and clinical trials covered $275.2 million (33.8%). Tanzania ($107.8 million [13.2%]), Uganda ($97.9 million [12.0%]), and Kenya ($92.9 million [11.4%]) received the highest sum of research investment and the most research awards. Malawi, Tanzania, and Uganda remained highly ranked after adjusting for national gross domestic product. Countries with a reasonably high malaria burden that received little research investment or funding for malaria control included Central African Republic (ranked 40th) and Sierra Leone (ranked 35th). Congo (Brazzaville) and Guinea had reasonably high malaria mortality, yet Congo (Brazzaville) ranked 38th and Guinea ranked 25th, thus receiving little investment. INTERPRETATION: Some countries receive reasonably large investments in malaria-related research (Tanzania, Kenya, Uganda), whereas others receive little or no investments (Sierra Leone, Central African Republic). Research investments are typically highest in countries where funding for malaria control is also high. Investment strategies should consider more equitable research and operational investments across countries to include currently neglected and susceptible populations. FUNDING: Royal Society of Tropical Medicine and Hygiene and Bill & Melinda Gates Foundation. PMID- 28668232 TI - Effect of Salbutamol on Respiratory Muscle Strength in Spinal Muscular Atrophy. AB - BACKGROUND: Oral salbutamol has shown clinical benefits in spinal muscular atrophy (SMA). We studied its effect on the respiratory muscle strength in children with different types of SMA. METHODS: Lung and respiratory muscle functions were assessed in children receiving daily oral salbutamol for at least one year. The respiratory data of age-matched SMA II historical control subjects were compared with data of SMA II patients receiving salbutamol. RESULTS: Seven children (6.4 +/- 2.0 years old, range four to ten; one SMA I, five SMA II, and one SMA III) treated with salbutamol (duration 23 +/- 8 months) were assessed. Maximal static inspiratory pressure, sniff nasal inspiratory pressure, and slow vital capacity were significantly better in the salbutamol-treated SMA II group compared with control subjects (P < 0.05). CONCLUSIONS: Long-term oral salbutamol showed benefits in respiratory function in children with SMA and appeared to increase the strength of the inspiratory muscles in a small cohort of SMA II patients. PMID- 28668233 TI - Incidence and Demographics of Pediatric Intracranial Hypertension. AB - OBJECTIVE: We analyzed the incidence and demographic features of pediatric intracranial hypertension. METHODS: Inpatient and outpatient encounters of children aged 18 years or younger who were diagnosed with primary (idiopathic) or secondary intracranial hypertension between January 2010 and December 2013 were identified. Data were collected from a subspecialty clinic devoted to intracranial hypertension and the sole children's hospital in a large Midwestern city of the United States. Estimated incidence rates were calculated based on the number of newly diagnosed patients in our hospital's primary service area, which includes seven central Ohio counties. Sex, race, body mass index, socioeconomic status, and geographic distribution were also noted. RESULTS: A total of 74 pediatric patients were diagnosed with intracranial hypertension (49 primary/idiopathic and 25 secondary) between January 2010 and December 2013. Using census data, we determined the pediatric population in our service area during the four-year period. The Ohio Hospital Association's database indicated that 92.3% of patients aged 0 to 17 years residing in the region sought care at our institution. By combining these data, we calculated an annual incidence of primary and secondary intracranial hypertension of 0.63 and 0.32 per 100,000 children, respectively. CONCLUSIONS: The estimated annual incidence of pediatric primary intracranial hypertension in our seven county service area in central Ohio is similar to previous pediatric reports from other countries and is 67% of that reported in the US adult population. PMID- 28668234 TI - Reply to the letter: "A case of Guillain-Barre syndrome with meningeal irritation". PMID- 28668235 TI - Severe hypotonia and postnatal growth impairment in a girl with a missense mutation in COL1A1: Implication of expanded phenotypic spectrum of type I collagenopathy. AB - BACKGROUND: It is known that type I collagenopathy has a broad-spectrum phenotypic variability. Here, we report a case of a Korean girl with a heterozygous COL1A1 mutation who had an atypical presentation. CASE PRESENTATION: A 26-month-old girl presented with delayed motor development and failure to thrive. She had severe growth retardation. She exhibited right-sided plagiocephaly, blue sclerae, and facial dysmorphism, including a small pointed chin, frontal bossing, and a triangular face, but had microcephaly. Whole-exome sequencing revealed a novel de novo heterozygous sequence variant in COL1A1 (p.Gly1127Asp), which was validated by Sanger sequencing. Radiological finding showed generalized osteoporosis with progressive scoliosis of the spine without evidence of platyspondyly related to fractures and bowing of the long bones, and markedly delayed carpal bone age. Muscle pathology showed a marked size variation of myofibers and selective type 1 atrophy. CONCLUSIONS: This study expanded the clinical and genetic spectrum of type I collagenopathy with a COL1A1 variant. Therefore, we suggest that type I collagenopathy should be considered in the patients who have some features of osteogenesis imperfecta simultaneously with atypical features such as facial dysmorphism. PMID- 28668236 TI - Mammalian raw materials used to produce allergen extracts. AB - OBJECTIVE: To provide information about the complexity of skin-derived mammalian allergen extracts and recent advances made in their characterization and production. DATA SOURCES: Original and review articles (involving nonfood allergy to mammals) published in indexed journals were searched in the PubMed database. STUDY SELECTIONS: Studies were selected with the following criteria: novelty, species of the study, and date of publication. RESULTS: The information provided will help in the understanding and the selection of the appropriate allergen source materials for the preparation of extracts for the diagnosis and treatment of allergic respiratory diseases induced by the inhalation of skin-derived mammalian allergens. The data presented herein suggest the presence of cross reactive and species-specific allergens in extracts prepared from different mammalian dander. Dander should be strongly considered in the preparation of allergenic extracts not only of cats and dogs but also of other mammalian species. CONCLUSION: New methods should be developed to estimate the relative quantities of specific allergens in the extracts. The current knowledge illustrates the complexity of these extracts, and more efforts should be undertaken to fully understand the wide spectrum of mammalian allergens. PMID- 28668237 TI - Point-of-care blood eosinophil count in a severe asthma clinic setting. AB - BACKGROUND: One of the main severe asthma phenotypes is severe eosinophilic or eosinophilic refractory asthma for which novel biologic agents are emerging as therapeutic options. In this context, blood eosinophil counts are one of the most reliable biomarkers. OBJECTIVE: To evaluate the performance of a point-of-care peripheral blood counter in a patients with severe asthma. METHODS: The blood eosinophil counts of 76 patients with severe asthma were evaluated by point-of care and standard analyzers. RESULTS: A significant correlation between blood eosinophils assessed by the 2 devices was found (R2 = 0.854, P < .001); similar correlations were found also for white blood cells, neutrophils, and lymphocytes. The point-of-care device had the ability to predict blood eosinophil cutoffs used to select patients for biologic treatments for severe eosinophilic asthma and the ELEN index, a composite score useful to predict sputum eosinophilia. CONCLUSION: The results of our study contribute to the validation of a point-of-care device to assess blood eosinophils and open the possibility of using this device for the management of severe asthma management. PMID- 28668238 TI - Genetic variants and risk of asthma in an American Indian population. AB - BACKGROUND: Asthma is recognized as a complex, multifactorial disease with a genetic component that is well recognized. Certain genetic variants are associated with asthma in a number of populations. OBJECTIVE: To determine whether the same variants increase the risk of asthma among American Indian children. METHODS: The electronic medical records of an Indian Health Service facility identified all children between 6 and 17 years of age with case-defining criteria for asthma (n = 108). Control children (n = 216), matched for age, were also identified. Real-time polymerase chain reaction assays were used to genotype 10 single-nucleotide polymorphisms (SNPs) at 6 genetic loci. Genotypic distributions among cases and controls were evaluated by chi2 and logistic regression methods. RESULTS: A variant at 5q22.1 revealed a statistically significant imbalance in the distribution of genotypes between case-control pairs (rs10056340, P < .001). In logistic regression analyses, the same variant at 5q22.1 and a variant at 17q21 were associated with asthma at P < .05 (rs10056340 and rs9303277). Inclusions of age, body mass index, and atopy in multivariate models revealed significant associations between rs10056340 (odds ratio, 2.020; 95% confidence interval, 1.283-3.180; P = .002) and all 5 17q21 SNPs and asthma in this population. In analyses restricted to atopic individuals, the association of rs10056340 was essentially unchanged, whereas among nonatopic individuals the trend was in the same direction but nonsignificant. The reverse was true for the 17q21 SNPs. CONCLUSION: These findings demonstrate that many variants commonly associated with asthma in other populations also accompany this condition among American Indian children. American Indian children also appear to have an increased risk of asthma associated with obesity. PMID- 28668239 TI - Association of altered gut microbiota composition with chronic urticaria. AB - BACKGROUND: An altered gut microbiota composition has recently been linked to some types of allergies. OBJECTIVE: To compare the relative amounts of Akkermansia muciniphila, Clostridium leptum, Faecalibacterium prausnitzii, and Enterobacteriaceae as members of gut microbiota among patients with chronic urticaria (CU) and healthy controls. METHODS: A total of 20 patients with CU and 20 healthy individuals matched by age and sex participated in the study. Fresh fecal samples were collected, and DNA extracted from stool samples was analyzed by real-time polymerase chain reaction for the qualitative and quantitative assays of the so-called bacteria. RESULTS: The frequencies of A muciniphila, C leptum, and F prausnitzii in healthy controls' stool samples were significantly more than those of patients with CU (P < .001, P < .01, and P < .05, respectively), whereas the Enterobacteriaceae family was detected in all patients and healthy controls' stool samples. The relative amounts of A muciniphila in healthy control positive samples were significantly higher than those of samples from patients with CU (P < .001). Furthermore, there was a corresponding increase of relative amounts of C leptum and F prausnitzii in healthy control positive samples compared with those of patients with CU (P = .09 and P = .08, respectively). The mean of the relative amounts of Enterobacteriaceae family in the stool samples from patients with CU was more than that of healthy controls; however, the difference was nearly significant (P = .12). CONCLUSION: The results reveal a change of frequency and relative amounts of A muciniphila, C leptum, and F prausnitzii in patients with CU compared with healthy controls. This is the first study, to our knowledge, to show the change of microbiota composition in patients with CU. PMID- 28668240 TI - Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5. AB - BACKGROUND: In the past few decades, the prevalence of allergic diseases has increased rapidly worldwide. At the same time, the overuse of antibiotics has been observed, especially in Japan. OBJECTIVE: To elucidate the association of early childhood antibiotic use with allergic diseases in later childhood at 5 years of age. METHODS: Relevant data were extracted from the hospital-based birth cohort study, the Tokyo Children's Health, Illness and Development Study. To identify signs of asthma and allergic diseases in children, the International Study of Asthma and Allergies in Childhood questionnaire was used. Logistic regression models were applied to estimate the effect of antibiotic use on outcomes in later life. RESULTS: Antibiotic exposure in children within the first 2 years of life was associated with current asthma (adjusted odds ratio [aOR] 1.72, 95% confidence interval [CI] 1.10-2.70), current atopic dermatitis (aOR 1.40, 95% CI 1.01-1.94), and current allergic rhinitis (aOR 1.65, 95% CI 1. 05 2.58) at 5 years of age. Analysis of the associations by type of antibiotics showed that cephem was associated with current asthma (aOR 1.97, 95% CI 1.23 3.16) and current rhinitis (aOR 1.82, 95% CI 1.12-2.93), and macrolide was associated with current atopic dermatitis (aOR 1.58, 95% CI 1.07-2.33). CONCLUSION: Our findings suggest that antibiotic use within the first 2 years of life was a risk factor for current asthma, current atopic dermatitis, and current allergic rhinitis in 5-year-old children. PMID- 28668241 TI - Patient satisfaction and experience with intravenously administered C1-inhibitor concentrates in the United States. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder with substantial morbidity and mortality. Despite expanded choices for effective acute treatment, prophylactic options are more limited. Intravenous C1 esterase inhibitor (C1-INH[IV]) is licensed and used to prevent HAE symptoms. OBJECTIVE: To better understand patient experiences with using C1-INH(IV), including level of satisfaction and types and frequency of complications. METHODS: Fifty adult members (>=18 years of age) of the US HAE Association who had HAE type I or II completed a self-administered internet survey. Eligible participants were experiencing at least 1 HAE attack per month and must have been receiving treatment with C1-INH(IV) as prophylaxis or acute therapy. RESULTS: Almost all respondents (n = 47; 94%) were using C1-INH(IV) for HAE prophylaxis. Most patients reported administration of C1-INH(IV) through a peripheral vein (n = 34) and 19 were currently (n = 17) or previously (n = 2) using a central venous port. Most respondents (62%) who used a peripheral vein to administer treatment reported having difficulty finding a usable vein or getting the infusion to work properly at least some of the time. Issues accessing veins, exhausted veins, and frequency of attacks were the main reasons physicians recommended ports to respondents. Although ports allow easier administration of therapy, 47% of respondents with ports experienced problems such as occlusion, thrombosis, and infection. Respondents using C1-INH prophylaxis reported a mean of 2.3 attacks per month during the previous 6 months. CONCLUSION: The survey results identified clinical challenges with IV HAE medication use, including venous access issues and ongoing monthly attack occurrence despite prophylactic C1-INH(IV) administration. PMID- 28668243 TI - Effect of misoprostol on patients with aspirin-exacerbated respiratory disease undergoing aspirin challenge and desensitization. AB - BACKGROUND: Prostaglandin E2 (PGE2) is an anti-inflammatory compound that inhibits 5-lipoxygenase activity. Diminished PGE2 regulation in aspirin exacerbated respiratory disease (AERD) leads to respiratory reactions on cyclooxygenase 1 inhibition. In vitro studies have found that exogenous PGE2 stabilizes inflammatory mediator release. OBJECTIVE: To examine whether misoprostol (oral prostaglandin E1 analogue) use during aspirin challenge and desensitization might decrease the severity of aspirin-induced symptoms and make desensitization safer for patients with AERD. METHODS: Forty-five patients undergoing aspirin challenge and/or desensitization were randomized to misoprostol (n = 30) or placebo (n = 15) and compared with a group of historical controls (n = 31). Misoprostol (200 MUg) was administered at 30 minutes, 90 minutes, and 4 hours after the first dose of nasal ketorolac. Measured end points included change in forced expiratory volume in 1 second (FEV1), peak nasal inspiratory flow rate (PNIF), number of treatments received for induced reactions, and adverse gastrointestinal effects. RESULTS: A difference in FEV1 and PNIF reduction was detected between misoprostol and placebo (P = .03) and misoprostol and historical controls (P = .01), respectively, during nasal ketorolac challenge. No difference was detected among aspirin reactors. Among all reactors, no difference in magnitude was found for FEV1 (P = .13) or PNIF (P = .07) reduction across all 3 groups. Total treatment requirement was similar (P = .14). Patients receiving misoprostol were more likely to report adverse gastrointestinal effects (P = .02). CONCLUSION: The addition of misoprostol to current aspirin challenge and/or desensitization protocols reveals no protective effect in reducing the intensity of nonsteroidal anti-inflammatory drug-induced symptoms and is not recommended based on the findings in this study. PMID- 28668242 TI - Cockroach allergen exposure and plasma cytokines among children in a tropical environment. AB - BACKGROUND: Little is known about the effects of socioeconomic status or cockroach allergen on immune responses in school-age children, particularly in tropical environments. OBJECTIVE: To examine whether cockroach allergen and/or socioeconomic status is associated with plasma cytokine levels in Puerto Rican children. METHODS: This was a cross-sectional study of 532 children (6-14 years old) with (n = 272) and without (n = 260) asthma in San Juan (Puerto Rico). House dust allergens (cockroach [Bla g 2], dust mite [Der p 1], cat dander [Fel d 1], dog dander [Can f 1], and mouse urinary protein [Mus m 1]) were quantified using monoclonal antibody arrays. A panel of 14 cytokines (interleukin [IL]-1beta, IL 4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon-gamma, and tumor necrosis factor-alpha) was measured in plasma samples. Low household income was defined as less than $15,000 per year (below the median income for Puerto Rico in 2008-2009). Linear regression was used for the analysis of cockroach allergen and plasma cytokines. RESULTS: In a multivariable analysis adjusting for low income and other allergen levels, cockroach allergen was significantly associated with decreased IL-17A and with increased levels of 8 cytokines (IL-4, IL-10, IL-17F, IL-21, IL-25, IL-31, interferon-gamma, and tumor necrosis factor-alpha). After stratifying this analysis by cockroach allergy (ie, having a cockroach positive immunoglobulin E reaction), our findings remained largely unchanged for children sensitized to cockroach but became weaker and statistically nonsignificant for non-sensitized children. CONCLUSION: Cockroach allergen has broad effects on adaptive immune responses in school-age children in a tropical environment, particularly in those sensitized to cockroach. PMID- 28668245 TI - Drug eruption caused by memantine. PMID- 28668244 TI - Prolonged effect of allergen sublingual immunotherapy for house dust mites in elderly patients. AB - BACKGROUND: The prolonged effect of allergen immunotherapy is unknown, especially in older patients. OBJECTIVE: To analyze the 3-year effect of sublingual allergen specific immunotherapy (SLIT) to house dust mites in elderly patients with allergic rhinitis. METHODS: Forty-seven elderly patients (65.78 +/- 4.89 years old) underwent SLIT to house dust mites and were monitored for 3 years and compared with a placebo group. SLIT was performed with the use of oral Staloral 300 SR Der p and Der f 50/50% extract (Stallergens Greer, London, United Kingdom) or placebo. Symptoms and medication score, represented by the average adjusted symptom score (AAdSS), serum level of immunoglobulin (Ig) G4 to Dermatophagoides pteronyssinus, Dermatophagoides farinae, Der p 1, and Der p 2, and quality of life, were assessed immediately after SLIT and 3 years later. RESULTS: The AAdSS was significantly decreased after SLIT, and the level remained low during the 3 years after SLIT compared with placebo. Serum-specific IgG4 against D pteronyssinus, D farinae, Der p 1, and Der p 2 increased during the SLIT trial in the study group. For the 3 years of observation after SLIT, there were no significant changes of specific IgG4 levels against the analyzed allergens compared with results just after SLIT. Quality of life based on the Rhinoconjunctivitis Quality of Life Questionnaire score was significantly decreased in patients who received SLIT, from 1.48 (95% confidence interval 1.33 1.79) to 0.98 (95% confidence interval 0.67-1.07; P < .05) compared with 0.94 (95% confidence interval 0.55-1.04) 3 years after SLIT. CONCLUSION: The prolonged positive effect after SLIT to house dust mites was observed in elderly patients with allergic rhinitis. Further trials are needed to confirm this effect. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01605760. PMID- 28668246 TI - Desensitization to protein kinase inhibitors: A systematic review. PMID- 28668247 TI - Grasshopper anaphylaxis in patients allergic to dust mite, cockroach, and crustaceans: Is tropomyosin the cause? PMID- 28668248 TI - Modern challenges of allergic bronchopulmonary aspergillosis diagnosis and management: Finding from a case study with a history of rituximab use. PMID- 28668249 TI - Vitamin D and asthma: A Mendelian randomization study. PMID- 28668250 TI - Erratum. PMID- 28668252 TI - Nanotechnology as a potential therapeutic alternative for schistosomiasis. AB - Schistosomiasis is a neglected disease that affects millions of people worldwide, recognized as the most important human helminth infection in terms of morbidity and mortality. The treatment of choice presents low bioavailability and water solubility, in addition to the induction of parasite resistance. In this context, researchers have been conducting studies seeking to develop new drugs to ensure safety, quality, and efficacy against this parasitosis. In this scenario, nanotechnology arises including the drug delivery systems in nanoscale: nanoemulsions, liposomes and nanoparticles. These drug delivery systems have been extensively applied for in vitro and in vivo studies against Schistosoma spp. with promising results. This review pointed out the most relevant development scenarios regarding the treatment of schistosomiasis as well as the application of nanotechnology as a vaccine, highlighting the use of nanotechnology as an alternative therapy for both the repositioning of drugs and the use of new pharmaceutical products, with promising results regarding the aforementioned disease. PMID- 28668251 TI - Bicycle Trains, Cycling, and Physical Activity: A Pilot Cluster RCT. AB - INTRODUCTION: Increasing children's cycling to school and physical activity are national health goals. The objective was to conduct an RCT of a bicycle train program to assess impact on students' school travel mode and moderate-to-vigorous physical activity (MVPA). STUDY DESIGN: Pilot cluster RCT with randomization at the school level and N=54 participants. SETTING/PARTICIPANTS: Fourth-fifth graders from four public schools serving low-income families in Seattle, WA in 2014 with analyses in 2015-2016. All participants were provided and fitted with bicycles, safety equipment (helmets, locks, and lights), and a 2- to 3-hour bicycle safety course. INTERVENTION: The intervention was a bicycle train offered daily (i.e., students volunteered to cycle with study staff to and from school). MAIN OUTCOME MEASURES: Time 1 assessments occurred prior to randomization. Time 2 assessments occurred after 3-5 weeks of the intervention (i.e., during Weeks 4-6 of the intervention period). The primary outcome was the percentage of daily commutes to school by cycling measured by validated survey. MVPA, measured by accelerometry and GPS units and processed by machine learning algorithms, was a secondary outcome. RESULTS: For two separate adjusted repeated measures linear mixed effects models in which students (N=54) were nested within schools (N=4), intervention participants had: (1) an absolute increase in mean percentage of daily commutes by cycling of 44.9%, (95% CI=26.8, 63.0) and (2) an increase in mean MVPA of 21.6 minutes/day, (95% CI=8.7, 34.6) from Time 1 to Time 2 compared with controls. CONCLUSIONS: A pilot bicycle train intervention increased cycling to school and daily MVPA in the short term among diverse, inner-city elementary school students. The bicycle train intervention appears promising and warrants further experimental trials among large, diverse samples with longer follow-up. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT02006186. PMID- 28668253 TI - Expression and secretion of the Giardia duodenalis variant surface protein 9B10A by transfected trophozoites causes damage to epithelial cell monolayers mediated by protease activity. AB - Giardia duodenalis is the protozoan parasite responsible for most cases of parasitic diarrhea worldwide. The pathogenic mechanisms of giardiasis have not yet been fully characterized. In this context parasite's excretory/secretory products have been related to the damage induced by the parasite on enterocytes. Among these is the Variable Surface Proteins (VSPs) family involved in antigenic variation and in the induction of protective response. In proteomic analyses carried out to identify the proteases with high molecular weight secreted by Giardia trophozoites during the initial phase of interaction with IEC-6 cell monolayers we identified the VSP9B10A protein. In silico bioinformatics analyses predicted a central region in residues 324-684 displaying the catalytic triad and the substrate binding pocket of cysteine proteases. The analysis of the effect of the VSP9B10A protein on epithelial cell monolayers using trophozoites that were transfected with a plasmid carrying the vsp9b10a gene sequence under the control of a constitutive promoter showed that transfected trophozoites expressing the VSP9B10A protein caused cytotoxic damages on IEC-6 and MDCK cell monolayers. This was characterized by loss of cell-cell contacts and cell detachment from the substrate while no damage was observed with trophozoites that did not express the VSP9B10A protein. The same cytotoxic effect was detected when IEC-6 cell monolayers were incubated only with supernatants from co-cultures of IEC-6 cell monolayers with VSP9B10A transfected trophozoites and this effect was not observed when transfected trophozoites were incubated with a monospecific polyclonal antibody anti-VSP9B10A previous to interaction with IEC-6 monolayers. These results demonstrate that the VSP9B10A protein secreted upon interaction with epithelial cells caused damage in these cells. Thus this protein might be considered as a conditional virulence factor candidate. To our knowledge this is the first report on the proteolytic activity from a Giardia VSP opening new research lines on these proteins. PMID- 28668254 TI - Corrigendum to "MALDI-TOF MS is more accurate than VITEK II ANC card and API Rapid ID 32 A system for the identification of Clostridium species" [Anaerobe 40 (2016) 73-75]. PMID- 28668255 TI - Hemocytes and hemocytic responses in the mole crab Emerita emeritus (Linnaeus 1767). AB - The mole crab, Emerita emeritus, collected from the sandy shores of a Chennai beach, was investigated for cellular immune responses based on the morphology and defensive reactions of the circulating haemocytes. Three haemocyte morphotypes were identified using light and electron microscopy, and separated in a discontinuous percoll gradient. A phagocytosis study using human B erythrocyte as a target cell under phase-contrast optics showed that granular and semi-granular haemocytes were phagocytic, and this response was enhanced by using serum (opsonin)-coated human B erythrocyte in unfractionated and fractionated haemocytes. Observation of TEM image of phagocytosis revealed that the initial recognition and binding of the target cell was restricted to granular and semigranular haemocytes, which were lacking with hyaline cells. However, the encapsulation of DEAE Sepharose CL 6B beads, either untreated or coated with serum (opsonin), was restricted to hyaline cells. This suggests the occurrence of two cell lines in haemocytes, based on the differences observed in the response of haemocytes to bind target cells for phagocytosis or encapsulation. The present study also differentiated the activation of PO in the plasma, serum, and haemocyte lysate supernatant (HLS). PMID- 28668256 TI - UV-B radiation-related effects on conidial inactivation and virulence against Ceratitis capitata (Wiedemann) (Diptera; Tephritidae) of phylloplane and soil Metarhizium sp. strains. AB - Recent studies have demonstrated the presence of Metarhizium species on the epigeal areas of weeds and woody plants in various Mediterranean ecosystems, and the question arises whether isolates from the phylloplane, which experiences greater exposure to environmental UV-B radiation than soil isolates do, could have better UV-B radiation tolerance. The in vitro response of 18 Metarhizium strains isolated from phylloplane and soil of several Mediterranean ecosystems to UV-B radiation and the in vitro and in vivo effects of UV-B radiation on the viability and virulence of a selected M. brunneum strain against C. capitata were determined. The conidial germination, culturability and colony growth of these strains exposed to 1200mWm-2 for 2, 4 or 6h were evaluated. Germination rates below 30% and poor conidia recovery rates were observed for all strains. However, no relationship between the Metarhizium species or isolation habitat and the effect of UV-B radiation was found. Strain EAMa 01/58-Su, which showed a high tolerance to UV-B inactivation in terms of relative germination, was subsequently selected to investigate the UV-B related effects on virulence toward C. capitata adults. In a series of bioassays, the virulence and viability was determined using pure dry conidia, which were irradiated with 1200mWm-2 for 6h prior or after adult flies were inoculated, which resulted in a significant 84.7-86.4% decrease in conidial viability but only a slightly significant reduction of virulence, with 100.0% and 91.4% adult mortality rates and 4.6 and 5.9days average survival time for the no UV-B and UV-B treatments, respectively. A second series of experiments was performed to determine whether the UV-B effects on strain EAMa 01/58-Su were dose- or exposure time-dependent. Adult flies were inoculated with five doses (1.0*104-1.0*108conidiaml-1) and then irradiated at 1200mWm-2 for 6h, and similar LC50 values, 3.8*107 and 4.3*107conidiaml-1, were determined for the UV-B and no UV-B treatments, respectively. However, the LT50 values for flies inoculated with 1.0*108conidiaml-1 and with1.0*107conidiaml-1 were 15.1% and 30.8% longer for UV-B treatments than no UV-B treatments, respectively. Next, adult flies were treated with 1.0*108conidiaml-1 and then exposed to 1200mWm-2 for 0, 6, 12, 24, 36 and 48h, and the relationships among exposure time and conidia viability and fly mortality losses were determined. The exposure time for adult flies at 1200mWm-2 to achieve a 50% reduction in fly mortality was 47.2h, which was longer than that of 5.6h required for a 50% reduction in conidia viability. Our results show that the UV-B radiation significantly affected the virulence of EAMa 01/58-Su strain against C. capitata adults, with this effect being dependent on the exposure time but not related to fungal dosage. PMID- 28668257 TI - Comparative proteomic analysis of differentially expressed proteins in the Bombyx mori fat body during the microsporidia Nosema bombycis infection. AB - Nosema bombycis is an obligate intracellular parasite, which can cause pebrine disease. To investigate the effects of N. bombycis infection, 5th-instar silkworms were challenged with N. bombycis isolate CQ1, and two-dimensional gel electrophoresis analysis was performed to analyze the differentially expressed proteins in infected and uninfected silkworm fat bodies 1, 2, 4, 6 and 8days post infection (dpi). 46 differentially expressed proteins were identified at the 5 time points using MALDI-TOF/TOF MS. The changed proteins mainly involved in immune response, energy metabolism, and molecular synthesis. Overall, the identified proteins may provide important insights into the mechanisms of the silkworm response to N. bombycis infection. PMID- 28668258 TI - Infection by Streptococcus pneumoniae in children with or without radiologically confirmed pneumonia. AB - OBJECTIVE: Community-acquired pneumonia is an important cause of morbidity in childhood, but the detection of its causative agent remains a diagnostic challenge. The authors aimed to evaluate the role of the chest radiograph to identify cases of community-aquired pneumonia caused by typical bacteria. METHODS: The frequency of infection by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis was compared in non-hospitalized children with clinical diagnosis of community acquired pneumonia aged 2-59 months with or without radiological confirmation (n=249 and 366, respectively). Infection by S. pneumoniae was diagnosed by the detection of a serological response against at least one of eight pneumococcal proteins (defined as an increase >=2-fold in the IgG levels against Ply, CbpA, PspA1 and PspA2, PhtD, StkP-C, and PcsB-N, or an increase >=1.5-fold against PcpA). Infection by H. influenzae and M. catarrhalis was defined as an increase >=2-fold on the levels of microbe-specific IgG. RESULTS: Children with radiologically confirmed pneumonia had higher rates of infection by S. pneumoniae. The presence of pneumococcal infection increased the odds of having radiologically confirmed pneumonia by 2.8 times (95% CI: 1.8-4.3). The negative predictive value of the normal chest radiograph for infection by S. pneumoniae was 86.3% (95% CI: 82.4-89.7%). There was no difference on the rates of infection by H. influenzae and M. catarrhalis between children with community acquired pneumonia with and without radiological confirmation. CONCLUSIONS: Among children with clinical diagnosis of community-acquired pneumonia submitted to chest radiograph, those with radiologically confirmed pneumonia present a higher rate of infection by S. pneumoniae when compared with those with a normal chest radiograph. PMID- 28668259 TI - Ayurvedic anti-diabetic formulation Lodhrasavam inhibits alpha-amylase, alpha glucosidase and suppresses adipogenic activity in vitro. AB - BACKGROUND: The patho-physiological cross-talk between diabetes and obesity is well established. However, the choices of drugs suitable for combined treatment of diabetes and obesity are limited. Integration of complementary and alternative medicines (CAMs), like Ayurveda, with modern medicine would be a promising strategy to fill this gap. The diagnostic principles of Ayurveda define obesity as one of the predisposing factors of Madhumeha (correlated as diabetes) and recommends specific formulations for managing obese-diabetes. Lodhrasavam is one such poly-herbal formulation prescribed for obese-diabetic patients. OBJECTIVES: The present study is an attempt to demonstrate the possible modes of action of Lodhrasavam, built on the hypothesis that the formulation can exert both anti diabetic and anti-obesity actions. MATERIALS AND METHODS: Lodhrasavam, following simulated gastro-intestinal digestion, was monitored for inhibition of alpha amylase, alpha-glucosidase (key digestive enzyme targets of anti-diabetic drugs) and adipogenesis using standard in vitro model systems. RESULTS: Lodhrasavam digest inhibited alpha-amylase (90%) and alpha-glucosidase (78%) activity as well as reduced the differentiation of 3T3-L1 fibroblasts to adipocytes. Upon fractionation, the enzyme inhibitory activity and anti-adipogenic activity of the digest were found distributed in different solvent fractions. This partly indicates a potential pharmacological networking of chemically and functionally diverse bioactive molecules in Lodhrasavam. CONCLUSION: The study provides a possible mode of action and an experimental support for the Ayurvedic use of Lodhrasavam for managing obese-diabetes. Generating scientific evidences and understanding the modes of action, in contemporary scientific language, would essentially help in expanding global acceptance of potentials of CAMs in the management of life style disorders. PMID- 28668260 TI - [Amyopathic dermatomyositis (DM) with anti-MDA5 antibodies, associated with bullous pemphigoid, Sjogren syndrome and gastric MALT lymphoma]. AB - BACKGROUND: The inflammatory myopathies are a heterogeneous group of muscle diseases and comprise polymyositis, dermatomyositis (DM), myopathies associated with cancers, necrotising myositis and inclusion body myositis. DM occasionally exhibits few or no muscular signs: i.e. hypomyopathic/amyopathic DM. Anti-MDA5 dermatomyositis (DM) is a rare form of dermatomyositis that is frequently amyopathic; the prognosis is linked mainly to pulmonary involvement. PATIENTS AND METHODS: A 69-year-old woman treated for mucosa-associated lymphoid tissue (MALT) gastric lymphoma was referred for a bullous eruption. Based on the investigations performed, a diagnosis was made of bullous pemphigoid. At the same time, amyopathic dermatomyositis was discovered together with interstitial lung disease. Systemic steroids were introduced in combination with rituximab. A favourable outcome was achieved. DISCUSSION: Anti-MDA5 dermatomyositis must be considered systematically in all cases of pulmonary involvement associated with cutaneous signs of dermatomyositis, in which no muscular involvement is generally seen. This condition accounts for up to 7% of DM and carries a severe prognosis due to pulmonary involvement. PMID- 28668261 TI - [Contribution of reflectance confocal microscopy and optical coherence tomography in the diagnosis of gouty tophus: First reported case]. PMID- 28668262 TI - [Contribution of reflectance confocal microscopy in the diagnosis of uterine cervix melanoma: First case report]. PMID- 28668263 TI - Meta-analysis of Predictors of Early Severe Bleeding in Patients Who Underwent Transcatheter Aortic Valve Implantation. AB - Severe bleeding (SB) in patients who underwent transcatheter aortic valve implantation (TAVI) could be fatal. Although multiple independent predictors of bleeding post-TAVI have been identified, the definitions of bleeding and predictors vary across studies. This study aimed to provide summary effect estimates for predictors of SB within 30 days post-TAVI. A systematic review of studies that reported the incidence of bleeding post-TAVI with raw data for predictors of interest was performed. Data on characteristics of study, patient, and procedure were extracted. Crude risk ratios (RRs) and 95% confidence intervals were calculated using random-effect model. Fifteen predictors on 65,209 patients from 47 studies were analyzed. The median rate of SB was 11% across studies. Seven factors (3 patient related and 4 procedure related) were recognized as predictors of early SB post-TAVI. Age >=90 years (RR 1.17; p = 0.008), female (RR 1.13; p = 0.01), and sheath diameter >19 Fr (RR 1.19; p = 0.04) were weak predictors. Chronic kidney disease (RR 1.94; p <0.001) and transapical (TA) (RR 1.82; p <0.001) were moderate predictors that were almost associated with twofold risk. Vascular complication (RR 2.97; p <0.001) and circulatory support (RR 3.39; p <0.001) were strong predictors that were nearly associated with threefold risk. In conclusion, age, gender, chronic kidney disease, TA, sheath diameter, vascular complication, and circulatory support were all predictors of early SB post-TAVI in this meta-analysis, which provided possible guidance for prevention and management of SB related to TAVI. PMID- 28668264 TI - Rotation of the EZ Blocker After Unilateral Cuff Rupture. PMID- 28668265 TI - Hemoptysis in a Patient With Persistent Left Upper Lobe Consolidation. PMID- 28668266 TI - Zika Virus and Anesthesiologists. PMID- 28668267 TI - Measurement of phase resetting curves using optogenetic barrage stimuli. AB - BACKGROUND: The phase resetting curve (PRC) is a primary measure of a rhythmically firing neuron's responses to synaptic input, quantifying the change in phase of the firing oscillation as a function of the input phase. PRCs provide information about whether neurons will synchronize due to synaptic coupling or shared input. However, PRC estimation has been limited to in vitro preparations where stable intracellular recordings can be obtained and background activity is minimal, and new methods are required for in vivo applications. NEW METHOD: We estimated PRCs using dense optogenetic stimuli and extracellular spike recording. Autonomously firing neurons in substantia nigra pars reticulata (SNr) of Thy1 channelrhodopsin 2 (ChR2) transgenic mice were stimulated with random barrages of light pulses, and PRCs were determined using multiple linear regression. RESULTS: The PRCs obtained were type-I, showing only phase advances in response to depolarizing input, and generally sloped upward from early to late phases. Secondary PRCs, indicating the effect on the subsequent ISI, showed phase delays primarily for stimuli arriving at late phases. Phase models constructed from the optogenetic PRCs accounted for a large fraction of the variance in ISI length and provided a good approximation of the spike-triggered average stimulus. COMPARISON WITH EXISTING METHODS: Compared to methods based on intracellular current injection, the new method sacrifices some temporal resolution. However, it should be much more widely applicable in vivo, because only extracellular recording and optogenetic stimulation are required. CONCLUSIONS: These results demonstrate PRC estimation using methods suitable for in vivo applications. PMID- 28668268 TI - Fix the problem - A practical guide to whole-mount immunohistochemistry of teased nerve fibres. AB - BACKGROUND: Immunohistochemical staining of entire nerve fibres allows for studying the molecular composition of functional fibre subunits and may add to the diagnostic value of nerve fibre teasing. NEW METHOD: In this study, we established a sealed-slide method for reproducible immunostaining of deep axoplasmic proteins in permanently straightened nerve fibres. RESULTS: Immunostaining of teased nerve fibres very much is facilitated by tip-fixation with biocompatible glass adhesives. Antibody penetration in fresh nerves can be achieved by thermic and chemical permeabilisation while enzymatic digestion allows for sufficient permeability after aldehyde fixation. COMPARISON WITH EXISTING METHODS: The methods recommended herein are easy to perform and represent a reliable and reproducible way to whole mount immunostaining. CONCLUSIONS: Sealed-slide immunostaining of tip-fixed and permeabilised nerve biopsies will help to validate neurophysiological abnormalities and to screen for target molecules and predictive markers of peripheral nerve disorders such as in inherited neuropathies and Guillain-Barre syndrome. PMID- 28668269 TI - Valproic acid alters the content and function of the cell-free DNA released by hepatocellular carcinoma (HepG2) cells in vitro. AB - BACKGROUND: It has long been believed that cell-free DNA (cfDNA) actively released into circulation can serve as intercellular messengers, and their involvement in processes such as the bystander effect strongly support this. However, this intercellular messaging function of cfDNA may have clinical implications that have not yet been considered. METHODS: CfDNA was isolated from the growth medium of HepG2 cells treated with valproic acid (VPA). This cfDNA was then administered to untreated cells and cellular metabolic activity was measured. RESULTS: VPA altered the characteristics of cfDNA released by treated HepG2 cells in vitro. When administered to untreated cells, the cfDNA from cells treated with VPA resulted in the dose-dependent induction of glycolytic activity within 36 min of administration, but little to no alterations in oxidative phosphorylation. The glycolytic activity lasted for 4-6 h, whereas changes in subsequent cfDNA release and characteristics were found to remain persistent after two 24 h treatments. Fragmented genomic DNA from VPA-treated cells did not induce the effects observed for cfDNA obtained VPA-treated cells. CONCLUSIONS: It is possible for cfDNA to, under in vitro conditions, transfer pharmaceutically induced effects to untreated recipient cells. Further investigation regarding this occurrence under in vivo conditions is, therefore, strongly encouraged. GENERAL SIGNIFICANCE: The intercellular messaging functions of cfDNA present in donated biological fluids has potential clinical implications that require urgent attention. These implications may, however, also have potential as new forms of treatment that can circumvent pharmacological barriers. PMID- 28668271 TI - Molecular analysis of sentinel lymph node in colon carcinomas by one-step nucleic acid amplification (OSNA) reduces time to adjuvant chemotherapy interval. AB - BACKGROUND: The interval between surgery and adjuvant chemotherapy (AC) is a predictive factor of survival in high-risk colon cancer (CC). This study aimed to evaluate the impact of intraoperative sentinel lymph node (SLN) analysis using the one-step nucleic acid amplification (OSNA) technique on the time interval between surgery and AC. METHODS: We performed a prospective study analyzing 56 consecutive patients who had surgery for CC between July 2012 and October 2014, including 20 patients needing AC. SLN status was determined intraoperatively in 17 patients in the OSNA group; when positive, a portacath (PAC) was placed during the procedure for upcoming AC. In the remaining patients, we proceeded without SLN status determination and the PAC was installed after definitive histopathological analysis of the specimen if needed. RESULTS: There was no difference between the groups regarding cancer staging, duration of hospitalization (7.5days in the OSNA group and 10days in the control group, p=0.43) and major complications (20% vs 30% respectively, p=0.55). The time interval between surgery and adjuvant chemotherapy was significantly shorter in the OSNA group at 35 (+/-8) days vs 67 (+/-36) days (p=0.021). CONCLUSION: SLN status determination by the OSNA technique is safe, feasible and could significantly reduce time between surgery and adjuvant chemotherapy in a pilot study. PMID- 28668270 TI - Exogenous fatty acid metabolism in bacteria. AB - Bacterial type II fatty acid synthesis (FASII) is a target for novel antibiotic development. All bacteria encode for mechanisms to incorporate exogenous fatty acids, and some bacteria can use exogenous fatty acids to bypass FASII inhibition. Bacteria encode three different mechanisms for activating exogenous fatty acids for incorporation into phospholipid synthesis. Exogenous fatty acids are converted into acyl-CoA in Gammaproteobacteria such as E. coli. Acyl-CoA molecules constitute a separate pool from endogenously synthesized acyl-ACP. Acyl CoA can be used for phospholipid synthesis or broken down by beta-oxidation, but cannot be used for lipopolysaccharide synthesis. Exogenous fatty acids are converted into acyl-ACP in some Gram-negative bacteria. The resulting acyl-ACP undergoes the same fates as endogenously synthesized acyl-ACP. Exogenous fatty acids are converted into acyl-phosphates in Gram-positive bacteria, and can be used for phospholipid synthesis or become acyl-ACP. Only the order Lactobacillales can use exogenous fatty acids to bypass FASII inhibition. FASII shuts down completely in presence of exogenous fatty acids in Lactobacillales, allowing Lactobacillales to synthesize phospholipids entirely from exogenous fatty acids. Inhibition of FASII cannot be bypassed in other bacteria because FASII is only partially down-regulated in presence of exogenous fatty acid or FASII is required to synthesize essential metabolites such as beta-hydroxyacyl ACP. Certain selective pressures such as FASII inhibition or growth in biofilms can select for naturally occurring one step mutations that attenuate endogenous fatty acid synthesis. Although attempts have been made to estimate the natural prevalence of these mutants, culture-independent metagenomic methods would provide a better estimate. PMID- 28668272 TI - In-vitro construction of endometrial-like epithelium using CD146+ mesenchymal cells derived from human endometrium. AB - Endometrial CD146+ cells were purified, using magnetic activated cell sorting, and then embedded and cultured in a collagen-matrigel scaffold on top of myometrial smooth muscle cells for 10 days. At the end of culture period, the differentiation and formation of the epithelial-like cells were confirmed by morphological and ultrastructural evaluations, and analysis by reverse transcription polymerase chain reaction of the specific expression of genes: osteopontin (SPP1), matrix metalloproteinase 2, zonula occludens 1, laminin alpha 2 and collagen type IV; and by western blotting of CD9 protein. The results showed that the human endometrial mesenchymal CD146+ cells were able to produce endometrial glandular tube-like structures in vitro. Ultrastructural observation revealed some projections on the apical surfaces, appearance of basal lamina-like structures on the basal surface, and tight junctions and desmosomes on the lateral surfaces of the epithelial-like cells. The expression of studied genes at RNA level and CD9 at protein level confirmed the formation of endometrial epithelial-like cells. This culture system may have potential applications in cell therapy and in studies on human embryo implantation. PMID- 28668273 TI - Effect of unilateral tubal abnormalities on the results of intrauterine inseminations. AB - A total of 101 patients with one normal tube were compared with 117 patients with two normal tubes to assess the effect of unilateral tubal abnormalities on the results of intrauterine inseminations. The clinical pregnancy and live birth rates seemed to reduce by one-half in almost all types of abnormality, suggesting that these patients should be preferentially treated with IVF. PMID- 28668274 TI - Impact of Time Between Diagnosis and SLNB on Outcomes in Cutaneous Melanoma. AB - BACKGROUND: Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response. Available data are conflicting about the effect of SLNB delay on patient survival. Our objective was to determine whether delay between initial diagnosis and SLNB affects outcomes in patients with cutaneous melanoma. STUDY DESIGN: We performed query and analysis of a large prospectively maintained database of patients with primary cutaneous melanomas undergoing SLNB. An independent dataset from MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was used for validation. Primary outcomes included disease-free survival and melanoma-specific survival. RESULTS: Early and delayed SLNB were defined as less than 30 and 30 or more days from initial diagnosis, respectively. There were 2,483 patients that met inclusion criteria. Positive sentinel lymph nodes were identified in 17.4% (n = 432). Among all patients, 42% had SLNB 30 or more days after diagnosis and 37% of positive sentinel lymph nodes were at 30 or more days. No differences in sex, anatomic site, or histopathologic features were identified between the 2 groups. There was no difference in melanoma-specific survival or disease-free survival between those undergoing early or delayed SLNB. Examination of MSLT-1 trial data similarly demonstrated no difference in survival outcomes. CONCLUSIONS: This, the largest study on this subject to date, found no adverse impact on long-term clinical outcomes of patients due to delay of SLNB beyond 30 days. The MSLT-1 data confirm this result. Patients can be reassured that if the operation is performed 30 or more days after diagnosis, it will not cause harm. PMID- 28668275 TI - Midterm outcomes and evolution of gutter area after endovascular aneurysm repair with the chimney graft procedure. AB - OBJECTIVE: The objective of this study was to describe our experience with endovascular aneurysm repair (EVAR) with the use of chimney grafts for branch vessel preservation. METHODS: Patients treated with a chimney graft procedure between October 2009 and May 2015 were included for analysis. Patients who were not considered eligible for open surgical repair or for conventional, branched, or fenestrated endovascular repair were selected. A standardized operating procedure with left brachial or axillary artery cutdown access for the chimney grafts and bilateral femoral artery cutdown access for the aortic main device was used. Outcomes were noted according to the Society for Vascular Surgery reporting standards. In addition, evolution of gutter area over time was determined. Estimated rates of survival, freedom from aneurysm growth, and clinical success at 24 months of follow-up were calculated. RESULTS: Thirty-three patients (mean age, 77.6 +/- 6.8 years; 87.9% male) with a mean preoperative maximum aneurysm diameter of 71.7 +/- 13.5 mm were included. A total of 54 of an intended 54 chimney grafts were deployed. Primary technical success and 30-day secondary clinical success rates were 87.9% and 84.8%, respectively. The early mortality rate was 6.1% (n = 2). The early type IA endoleak rate was 6.1% (n = 2), and the chimney graft occlusion rate was 6.1% (n = 2). Median follow-up duration was 26 months (interquartile range, 14.8-37.3 months). The estimated 2-year actuarial survival rate was 78.1% (standard error, +/-7.4%). Late complications included type IA endoleak (n = 1), chimney graft occlusion (n = 2), type II endoleak with aneurysm growth (n = 4), and distal stent graft limb kinking and occlusion (n = 1). Late reinterventions included coil or glue embolization (n = 3), distal limb extension (n = 2), open endoleak ligation (n = 2), Palmaz stent placement (n = 1), repeated EVAR (n = 1), and femorofemoral bypass graft (n = 1). At 2 years, the estimated secondary clinical success and freedom from aneurysm growth rates were 80.5% (+/-7.2%) and 84.4% (+/-7.2%). Gutter size showed a small but significant decrease over time at the level of the proximal markers and at 10 mm distal from the markers. CONCLUSIONS: Midterm results show that a standardized procedure for EVAR using chimney grafts for branch vessel preservation is an acceptable option for high-risk patients with large, complex aneurysms who are unfit for open repair and who have been excluded from fenestrated EVAR. Gutter size decreases over time, but the rate of branch vessel loss and reinterventions demonstrate that this approach should remain reserved for those who are at truly prohibitive risk for open or fenestrated stent graft repair. PMID- 28668276 TI - A Walking Intervention Among Men With Prostate Cancer: A Pilot Study. AB - BACKGROUND: Men diagnosed with prostate cancer have increased risk for disease progression, cardiovascular events, and impairments in quality of life. This pilot study evaluated the feasibility of a randomized walking group intervention to improve quality of life, circulating biomarkers, and morbidity among men with newly diagnosed prostate cancer. METHODS: Men were recruited at Orebro University Hospital, Sweden, and randomized to an 11-week walking group intervention (n = 21) or usual care (n = 20). The intervention included weekly 1-hour walking group sessions and maintenance of 10,000 steps/day. Outcomes were changes in body composition, clinical factors, biomarkers of cardiovascular health, and quality of life between baseline and end of study. Analysis of covariance was used to compare outcomes in each group adjusted for baseline values. RESULTS: All 41 men randomized completed the 11-week trial. Men assigned to the intervention walked on average 10,644 steps/day, and 92% reported missing 2 or fewer sessions. Both groups experienced similar weight loss at 11 weeks. Men in the intervention had a significant adjusted mean change in high-density lipoprotein of 0.14 mmol/L (95% confidence interval [CI], 0.01-0.27; P = .04), and suggestive adjusted mean changes in low-density lipoprotein of -0.22 mmol/L (95% CI, -0.47 to 0.03; P = .08) and in systolic blood pressure of -8.5 mm Hg (95% CI, -21.2 to 4.2; P = .18), compared with the usual care group. CONCLUSIONS: A walking group intervention among men with recent diagnosis of prostate cancer is feasible and potentially effective in improving cardiovascular health. A larger randomized trial of longer duration is required to elucidate its potential for improvement in longer term outcomes. PMID- 28668277 TI - A Phase II Trial of AEZS-108 in Castration- and Taxane-Resistant Prostate Cancer. AB - BACKGROUND: AEZS-108 (zoptarelin doxorubicin) is a cytotoxic hybrid molecule consisting of doxorubicin covalently coupled with a luteinizing hormone-releasing hormone (LHRH) analogue, which selectively targets doxorubicin to tumor cells expressing LHRH receptors. We report the clinical efficacy of AEZS-108 in a phase II trial in men with metastatic castrate-resistant prostate cancer who had disease progression after taxane-based chemotherapy. PATIENTS AND METHODS: Patients received AEZS-108 210 mg/m2 intravenously every 3 weeks. The primary end point was clinical benefit defined as nonprogression at 12 weeks with no dose limiting toxicities (DLTs) or other toxicities requiring termination of treatment. Secondary end points included response rate, pain response, progression-free survival (PFS), and overall survival (OS). Circulating tumor cells (CTCs) were captured and tested for LHRH receptors, as well as for internalization of AEZS-108 using autofluorescence. RESULTS: Twenty-five patients were enrolled; 20 patients had at least 1 measurable lesion at baseline. Patients received a median of 5 cycles (range, 1-9) and 44% of patients received at least 6 cycles with 2 patients who completed >= 8 cycles. Considering clinical benefits, 13 patients (52%) remained progression-free at 12 weeks with no DLT or other toxicities requiring termination of treatment. For clinical response according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, 1 patient (4%) experienced a confirmed partial response (PR) within 12 weeks, 14 patients (56%) had stable disease (SD), and 8 patients (32%) had disease progression. For maximal prostate-specific antigen (PSA) response, 1 patient (4%) experienced a confirmed PR within 12 weeks, 21 patients (84%) had SD, and 3 patients (12%) had disease progression as denoted by their best PSA response. Pain improved in 13 (59%) patients. The median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4), and median OS was 6.0 months (95% CI, 4.2-10.1) with a median follow-up of 16.1 months (range, 3.2-36.1). Baseline CTC enumeration was an independent predictor of OS but not PFS. CONCLUSION: AEZS-108 showed activity in patients who were pretreated, a subset typically very difficult to treat, and maintained an acceptable safety profile. PMID- 28668278 TI - Synthetic scale-up of a novel fluorescent probe and its biological evaluation for surface detection of Staphylococcus aureus. AB - This paper reports on the LGX fluorometric test for enzymatic MRSA/MSSA detection. It highlights the reasons rhodamines have been overlooked and also strategies to improve the synthesis of rhodamine-peptide conjugates. Evaluation of the LGX test for detection of MRSA/MSSA on surfaces is undertaken in the presence of potentially confounding E. coli and S. epidermidis for the first time. PMID- 28668280 TI - Classification of somatosensory cortex activities using fNIRS. AB - The ability of the somatosensory cortex in differentiating various tactile sensations is very important for a person to perceive the surrounding environment. In this study, we utilize a lab-made multi-channel functional near infrared spectroscopy (fNIRS) to discriminate the hemodynamic responses (HRs) of four different tactile stimulations (handshake, ball grasp, poking, and cold temperature) applied to the right hand of eight healthy male subjects. The activated brain areas per stimulation are identified with the t-values between the measured data and the desired hemodynamic response function. Linear discriminant analysis is utilized to classify the acquired data into four classes based on three features (mean, peak value, and skewness) of the associated oxy hemoglobin (HbO) signals. The HRs evoked by the handshake and poking stimulations showed higher peak values in HbO than the ball grasp and cold temperature stimulations. For comparison purposes, additional two-class classifications of poking vs. temperature and handshake vs. ball grasp were performed. The attained classification accuracies were higher than the corresponding chance levels. Our results indicate that fNIRS can be used as an objective measure discriminating different tactile stimulations from the somatosensory cortex of human brain. PMID- 28668279 TI - The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning. AB - Brain-derived neurotrophic factor (BDNF) has been directly related to exercise enhanced motor performance in the neurologically injured animal model; however literature concerning the role of BDNF in the enhancement of motor learning in the human population is limited. Previous studies in healthy subjects have examined the relationship between intensity of an acute bout of exercise, increases in peripheral BDNF and motor learning of a simple isometric upper extremity task. The current study examined the role of high intensity exercise on upregulation of peripheral BDNF levels as well as the role of high intensity exercise in mediation of motor learning and retention of a novel locomotor task in neurologically intact adults. In addition, the impact of a single nucleotide polymorphism in the BDNF gene (Val66Met) in moderating the relationship between exercise and motor learning was explored. It was hypothesized that participation in high intensity exercise prior to practicing a novel walking task (split-belt treadmill walking) would elicit increases in peripheral BDNF as well as promote an increased rate and magnitude of within session learning and retention on a second day of exposure to the walking task. Within session learning and retention would be moderated by the presence or absence of Val66Met polymorphism. Fifty four neurologically intact participants participated in two sessions of split belt treadmill walking. Step length and limb phase were measured to assess learning of spatial and temporal parameters of walking. Serum BDNF was collected prior to and immediately following either high intensity exercise or 5min of quiet rest. The results demonstrated that high intensity exercise provides limited additional benefit to learning of a novel locomotor pattern in neurologically intact adults, despite increases in circulating BDNF. In addition, presence of a single nucleotide polymorphism on the BDNF gene did not moderate the magnitude of serum BDNF increases with high intensity exercise, nor did it moderate the relationship between high intensity exercise and locomotor learning. PMID- 28668281 TI - Disruption of GluA2 phosphorylation potentiates stress responsivity. AB - Cocaine addiction is characterized by persistent craving and addicts frequently relapse even after long periods of abstinence. Exposure to stress can precipitate relapse in humans and rodents. Stress and drug use can lead to common alterations in synaptic plasticity and these commonalities may contribute to the ability of stress to elicit relapse. These common changes in synaptic plasticity are mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors. Exposure to both cocaine and stress can lead to alterations in protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and thus alter the trafficking of GluA2-containing AMPARs. However, it is not clear what role AMPAR trafficking plays in the interactions between stress and cocaine. The current study utilized a mouse with a point mutation within the GluA2 subunit c-terminus resulting in a disruption of PKC-mediated GluA2 phosphorylation to examine stress responsivity. Although no differences were seen in the response to a forced swim stress in naive mice, GluA2 K882A knock-in mice exhibited an increased stress response following cocaine self-administration. Furthermore, we demonstrated that disrupting GluA2 phosphorylation increases vulnerability to stress-induced reinstatement of both cocaine seeking and cocaine-conditioned reward. Finally, GluA2 K882A knock-in mice exhibit an increased vulnerability to social defeat as indicated by increased social avoidance. Taken together these results indicate that disrupting GluA2 phosphorylation leads to increased responsivity to acute stress following cocaine exposure and increased vulnerability to chronic stress. These results highlight the GluA2 phosphorylation site as a novel target for the stress-related disorders. PMID- 28668282 TI - Brain infusion of alpha-synuclein oligomers induces motor and non-motor Parkinson's disease-like symptoms in mice. AB - Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of alpha-synuclein (alpha-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of alpha-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of alpha-syn oligomers (alpha-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that alpha-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). alpha- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of alpha-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of alpha-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of alpha-SYOs recapitulated some of PD-associated non motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, alpha-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to alpha-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening. PMID- 28668283 TI - Association of Hypertriglyceridemia With the Incidence and Progression of Chronic Kidney Disease and Modification of the Association by Daily Alcohol Consumption. AB - OBJECTIVE: The association of serum triglycerides (TGs) and alcohol consumption with chronic kidney disease (CKD) is unclear. The purpose of this study was to investigate the association of serum TG and daily alcohol consumption with CKD in the general population. DESIGN: The design of the study was longitudinal cohort study. SUBJECTS: Male (n = 47,737) and female (n = 69,542) participants were grouped into quartiles based on serum TG levels. MAIN OUTCOME MEASURES: We examined the associations of serum TG with annual changes in estimated glomerular filtration rate (eGFR) in all participants, the incident CKD in participants without CKD, and the progression of CKD in participants with CKD. We also examined the association of alcohol consumption with these factors and whether daily alcohol consumption alters the association of serum TG with renal prognosis. RESULTS: The higher quartile of serum TG at baseline was significantly associated with a greater decline in eGFR during the 2-year study period in all participants, even after adjustment for confounding factors. Serum TG was also significantly associated with the incidence and progression of CKD after 2 years in participants with and without CKD at baseline, respectively. Moreover, daily alcohol consumption was protectively associated with these outcomes. Stratified analysis according to the alcohol consumption status revealed that daily alcohol consumption modified the association of high TG with eGFR and CKD. CONCLUSION(S): Elevated serum TG was associated with the decline in eGFR and the incidence and progression of CKD. In addition, these associations were modified by daily alcohol consumption in this Japanese population. PMID- 28668284 TI - Is There a Role for Diaphoresis Therapy for Advanced Chronic Kidney Disease Patients? AB - Diaphoresis therapy to remove water and solutes for the treatment of advanced chronic kidney disease (CKD) and chronic dialysis patients is an inadequately characterized treatment that was first reported over 50 years ago. Intensive diaphoresis, induced by heat treatment with saunas (dry heat) or hot baths (wet heat), can substantially increase cutaneous losses of water, urea, sodium, potassium, chloride, lactate, and possibly other solutes. How effectively diaphoresis therapy might remove many uremic toxins is not known. Diaphoresis therapy is not sufficiently effective to replace dialysis treatments, but theoretically it might be used to delay the start of chronic dialysis, supplement infrequent dialysis therapy, or augment chronic dialysis treatment perhaps especially for dialysis patients with excessive salt and water intake. Diaphoresis might be helpful for managing edema resistant states. Because it is inexpensive, diaphoresis may be particularly valuable in lower income countries where some patients may need to pay for dialysis. Diaphoresis might enhance some aspects of dietary treatment. The short-term and long-term effectiveness, safety, and patient acceptance of diaphoretic therapy need to be more carefully investigated. PMID- 28668285 TI - Bronchopulmonary dysplasia as a risk factor for asthma in school children and adolescents: A systematic review. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that mainly affects extremely pre-term infants, and remains the most common complication of prematurity. Several studies have shown that prematurity predisposes to the development of asthma in school children and adolescents. Nevertheless, it is not clear to what extent a history of BPD involves an additional risk. METHODS: A systematic review of studies assessing the association between BPD and asthma in school-children and adolescents was made. A literature search was carried out in the MEDLINE and EMBASE databases to retrieve articles published between 1 January 2000 and 31 August 2016. RESULTS: A total of 17 studies comprising 7433 patients were included in the review. There was considerable heterogeneity in the definitions of BPD and asthma among studies. Overall, the prevalence of asthma was higher in children and adolescents with a history of prematurity and BPD compared with those who did not develop BPD. However, in only one of the studies did this difference reach statistical significance. The main limitation of this review was potential bias due to the lack of adjustment for confounding factors between exposure (BPD) and outcome (asthma) in most of the studies. CONCLUSION: Based on the studies reviewed, it cannot be argued that BPD, as an independent factor of prematurity, increases the risk of asthma defined by clinical parameters in school-children and adolescents. Further studies of greater methodological quality and homogeneous diagnostic criteria of BPD and asthma are needed for improved assessment of this association. PMID- 28668286 TI - Three modalities on management of choledocholithiasis: A prospective cohort study. AB - BACKGROUND: Choledocholithiasis can be managed by endoscopic retrograde cholangiopancreaticography/endoscopic sphincterotomy (ERCP/EST) or laparoscopic common bile duct (CBD) exploration by transcystic (TC) or transductal (TD) stone extraction. OBJECTIVE: The aim of this study was to evaluate the safety and effectiveness of common bile duct stones extraction by ERCP/EST, TC approach and TD approach for choledocholithiasis, with specific emphasis on ERCP/EST, TC approach versus TD approach. METHODS: Between January 2011 and June 2014, a total of 161 patients were scheduled for two-stage (preoperative ERCP/EST followed by cholecystectomy, ERCP group, n = 52)or single-stage (laparoscopic exploration of the CBD combined with cholecystectomy, n = 109) treatment for choledocholithiasis with concomitant cholecystitis. Laparoscopic common bile duct exploration was performed by TC approach (TC group, n = 63)or TD approach (TD group, n = 46). T tube insertion was performed in selected patients. Patients were regularly followed up at bimonthly intervals or more frequently in presence of any symptom. Primary outcomes measures included length of hospital stay, successful bile duct clearance, postoperative/procedural morbidity and mortality. RESULTS: Successful bile duct clearance was 100.0% in TD group, 93.7% in TC group and 92.3% in ERCP group. 4 cases in the TC group and 4 cases in the ERCP group required an extra choledocholithotomy due to impacted stones. 9 patients underwent T-tube drainage in TD group comparing to 1 case in ERCP group and no cases in TC group. Comparing to TC group, there was more postoperative morbidity in TD and ERCP group. Bile leaks were more frequent in TD group (8.7%) than TC (3.2%) and ERCP group (3.8%), which prolonged hospitalization in TD group than TC and ERCP group. 2 patients in ERCP group suffered duodenal perforation and one of them died because of the complication. However, total procedural morbidity was 0% in TC and TD group. CONCLUSION: TD stone extraction has a higher stone clearance but with a higher risk of bile leaks. Procedural morbidity is more often happened in ERCP/EST, which may result in serious consequences. TC stone extraction, which seems an effective approach with lower complication rates, is accessible techniques simplifying the operation procedure by avoiding choledocholithotomy and subsequent T-tube insertion. PMID- 28668287 TI - Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma. AB - PURPOSE: We investigated the prognostic value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: Tissue microarrays of 423 patients treated with extirpative surgery for high grade upper tract urothelial carcinoma from the International Upper Tract Urothelial Carcinoma collaboration were stained for PD-1 and PD-L1 using antibodies, including Cell MarqueTM NAT105 diluted 1:250 and prediluted E1L3N(r) via immunohistochemistry. A 1% or greater staining rate of tumor infiltrating lymphocytes (PD-1) and tumor cells (PD-L1) was considered positive. Univariate and multivariate analyses were performed to assess independent prognosticators of survival outcomes. RESULTS: Median patient age was 70.0 years and median followup was 37.0 months. PD-1 and PD-L1 were positive in 37.2% and 26.2% of patients, respectively. PD-1 positivity was significantly associated with adverse pathological characteristics while PD-L1 positivity was associated with favorable pT stage. On univariate analysis PD-1 expression was associated with worse recurrence-free, cancer specific and overall survival. On multivariate analysis PD-1 expression was an independent prognosticator of cancer specific survival (HR 1.7, 95% CI 1.03-2.66, p = 0.039) and overall survival (HR 1.5, 95% CI 1.05-2.24, p = 0.029) but not recurrence-free survival (HR 1.4, 95% CI 0.9-2.16, p = 0.139). On univariate analysis PD-L1 expression was not significantly associated with survival outcomes. However, on multivariate analysis in patients with organ confined disease (pT2 or less, pN0/x and cM0), PD-L1 positivity was an independent prognosticator of recurrence-free survival (HR 0.2, 95% CI 0.06-0.98, p = 0.046) and overall survival (HR 0.3, 95% CI 0.11-0.63, p = 0.003). CONCLUSIONS: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and independent prognostication of worse survival outcomes. PD-L1 positivity of tumor cells was an independent prognosticator of favorable survival outcomes in cases of organ confined disease. PMID- 28668288 TI - Oral misoprostol for induction of labour in hypertensive pregnancies. PMID- 28668290 TI - Beyond Th2, more than ILC2. PMID- 28668289 TI - Foley catheterisation versus oral misoprostol for induction of labour in hypertensive women in India (INFORM): a multicentre, open-label, randomised controlled trial. AB - BACKGROUND: Between 62 000 and 77 000 women die annually from pre-eclampsia and eclampsia. Prompt delivery, preferably by the vaginal route, is vital for good maternal and neonatal outcomes. Two low-cost interventions-low-dose oral misoprostol tablets and transcervical Foley catheterisation-are already used in low-resource settings. We aimed to compare the relative risks and benefits of these interventions. METHODS: We undertook this multicentre, open-label, randomised controlled trial in two public hospitals in Nagpur, India. Women (aged >=18 years) who were at 20 weeks' gestation or later with a live fetus and required delivery as a result of pre-eclampsia or hypertension were randomly assigned (1:1), via computer-generated block randomisation (block sizes of four, six, and eight) with concealment by use of opaque, sequentially numbered, sealed envelopes, to receive labour induction with either oral misoprostol 25 MUg every 2 h (maximum of 12 doses) or a transcervical Foley catheter (silicone, size 18 F with 30 mL balloon). Randomisation was stratified by study centre. The catheter remained in place until active labour started, the catheter fell out, or 12 h had elapsed. If the catheter did not fall out within 12 h, induction continued with artificial membrane rupture and oxytocin, administered through a micro-drip gravity infusion set. Fetal monitoring was by intermittent auscultation. The primary outcome was vaginal birth within 24 h. Due to the nature of the interventions, masking of participants, study investigators, and care providers to group allocation was not possible. We analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01801410. FINDINGS: Between Dec 20, 2013, and June 29, 2015, we randomly assigned 602 women to induction with misoprostol (n=302) or the Foley catheter (n=300; intention-to treat population). Vaginal birth within 24 h was more common in women in the misoprostol group than in the Foley catheter group (172 [57.0%] vs 141 [47.0%] women; absolute risk difference 10.0%, 95% CI 2.0-17.9; p=0.0136). Rates of uterine hyperstimulation were low in both the misoprostol and Foley catheter groups (two [0.7%] vs one [0.3%] cases; absolute risk difference 0.3%, 95% CI 0.8 to 1.5; p=0.566) and neonatal deaths did not differ significantly between groups (six [2.0%] vs three [1.0%] neonatal deaths; 1.0, -1.04 to 2.97; p=0.322). 17 serious adverse events (3%) were reported during the study: one case of intrapartum convulsion and one case of disseminated intravascular coagulation (both in the Foley group); ten perinatal deaths, including two stillbirths (both in the Foley catheter group) and eight neonatal deaths (n=5 in the misoprostol group and n=3 in the Foley catheter group); and five of neonatal morbidity, comprising birth asphyxia (n=3), septicaemia (n=1), and neonatal convulsion (n=1). INTERPRETATION: Oral misoprostol was more effective than transcervical Foley catheterisation for induction of labour in women with pre-eclampsia or hypertension. Future studies are required to assess whether oxytocin augmentation following misoprostol can be replaced by regular doses of oral misoprostol tablets. FUNDING: Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials Scheme. PMID- 28668291 TI - Comparison of simulation-based assessments and faculty ratings for general surgery resident milestone evaluation: Are they telling the same story? AB - BACKGROUND: The goal of this article is to examine the role of simulation in documenting resident nontechnical competencies outlined by the general surgery milestones, and compare those assessments to faculty ratings. METHODS: Trainees completed a multiphasic simulation scenario to assess ability to obtain informed consent, lead a preoperative time out, crisis management, communication, and delivering bad news. Assessments from this scenario were compared with ratings of these same competencies collected from clinical rotations. RESULTS: Twenty-six PGY1 trainees participated in the training program. Results revealed no significant correlations between simulation performance and faculty rotation ratings for any of the 5 competencies. With the exception of communication in the operating room, faculty reported an overall inability to reliably observe these competencies 26% to 41% of the time. CONCLUSIONS: This work suggests that traditional end-of-rotation evaluations may not be the most feasible and valid method to evaluate resident nontechnical skills for milestone assessment. Simulation-based assessments should be considered to fill this gap. PMID- 28668292 TI - A longitudinal study of diurnal cortisol patterns and associated factors in breast cancer patients from the transition stage of the end of active cancer treatment to post-treatment survivorship. AB - OBJECTIVES: The aim of this study was to examine the changes in diurnal cortisol patterns and its associated factors among breast cancer patients over a 14-month follow up period. MATERIALS AND METHODS: A total of 85 breast cancer patients were recruited to participate in this study. Assessments were performed at baseline (T0), T1 (the 2nd month), T2 (the 5th month), T3 (the 8th month), and T4 (the 14th month). Salivary cortisol was measured and the following questionnaires were administered: BDI-II depression scale, European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its breast cancer-specific complementary measure (EORTC QLQ-BR23). Patients were grouped into flat and steep groups, according to the median of the diurnal cortisol slopes at the time of the transition period. RESULTS: Breast cancer patients in the flatter slope group at transition period demonstrated steeper slopes over the course of recovery from treatment and those in the steeper slope group at transition period continued with steeper slopes over the course of recovery. The greater breast cancer-related symptoms (side-effects, symptoms relating to breast and arm, and hair loss) were associated with the changes in flatter diurnal cortisol slopes during14-month follow up period. CONCLUSION: Diurnal cortisol patterns in flatter slope group at the transition period appear to have a trend of recovery with the passage of time over the course of recovery from treatment. Management of breast cancer symptoms could improve dysregulation of diurnal cortisol patterns among survivors. PMID- 28668293 TI - Mechanisms of resistance of chemotherapy in early-stage triple negative breast cancer (TNBC). AB - Triple negative breast cancer (TNBC) a clinically aggressive subtype of breast cancer with poor outcomes. Chromosomal instability is a hallmark of many TNBCs, and likely underlies its ability to adapt and rapidly become resistant to chemotherapy. A study of residual disease after neoadjuvant chemotherapy have identified biological mechanisms driving this resistance to chemotherapy. Copy number amplifications such as MCL1, MYC and JAK2, as well as PTEN deletions or mutations have all been identified at a higher frequency in residual disease, suggesting they may play a role in de novo or acquired chemotherapy resistance. Increased copy number and expression of the PIM1 proto-oncogene in TNBC has also been identified as a new target of chemotherapy resistance. However, given the genomic instability and subclonal nature of driver mutations in TNBC, single agent targeted therapy is unlikely to be effective. Lately immune evasion has also been identified as another key characteristic of poor prognostic and chemo resistant primary TNBCs. Combinations of checkpoint inhibition with targeted therapy and/or chemotherapy are currently being investigated. PMID- 28668294 TI - Aclarubicin, an anthracycline anti-cancer drug, fluorescently contrasts mitochondria and reduces the oxygen consumption rate in living human cells. AB - Aclarubicin (Acla), an effective anthracycline chemotherapeutic agent for hematologic cancers and solid tumors, is documented to perturb chromatin function via histone eviction and DNA topoisomerase inhibition in the nucleus, but much less attention has been paid to cytotoxic function in the cytoplasm. Here, we showed that Acla emitted fluorescence and that human cervical cancer HeLa cells exposed to Acla exhibited bright fluorescence signals in the cytoplasm when fluorescence microscopy was performed using the red filter (excitation 530 550nm/emission 575nm). Intriguingly, most of the signals appeared to be partitioned and enriched in entangled tubule-like structures; moreover, these signals merged with the mitochondria-specific MitoTracker signals. Notably, analysis of mitochondrial respiratory activity revealed that the oxygen consumption rate was decreased in Acla-treated cells. These findings suggest that Acla accumulates efficiently in the mitochondria of living human cells and leads to mitochondrial dysfunction, implying a previously overlooked cytotoxicity of Acla in the cytoplasm and adding mechanistic insight of the anti-cancer activity, as well as the side effects, of Acla/anthracycline-based chemotherapy. PMID- 28668295 TI - Chemometrics-assisted solid-state characterization of pharmaceutically relevant materials. Polymorphic substances. AB - Current regulations command to properly characterize pharmaceutically relevant solid systems. Chemometrics comprise a range of valuable tools, suitable to process large amounts of data and extract valuable information hidden in their structure. This review aims to detail the results of the fruitful association between analytical techniques and chemometrics methods, focusing on those which help to gain insight into the characteristics of drug polymorphism as an important aspect of the solid state of bulk drugs and drug products. Hence, the combination of Raman, terahertz, mid- and near- infrared spectroscopies, as well as instrumental signals resulting from X-ray powder diffraction, 13C solid state nuclear magnetic resonance spectroscopy and thermal methods with quali-and quantitative chemometrics methodologies are examined. The main issues reviewed, concerning pharmaceutical drug polymorphism, include the use of chemometrics based approaches to perform polymorph classification and assignment of polymorphic identity, as well as the determination of given polymorphs in simple mixtures and complex systems. Aspects such as the solvation/desolvation of solids, phase transformation, crystallinity and the recrystallization from the amorphous state are also discussed. A brief perspective of the field for the next future is provided, based on the developments of the last decade and the current state of the art of analytical instrumentation and chemometrics methodologies. PMID- 28668296 TI - IgG glycan patterns are associated with type 2 diabetes in independent European populations. AB - BACKGROUND: Type 2 diabetes results from interplay between genetic and acquired factors. Glycans on proteins reflect genetic, metabolic and environmental factors. However, associations of IgG glycans with type 2 diabetes have not been described. We compared IgG N-glycan patterns in type 2 diabetes with healthy subjects. METHODS: In the DiaGene study, a population-based case-control study, (1886 cases and 854 controls) 58 IgG glycan traits were analyzed. Findings were replicated in the population-based CROATIA-Korcula-CROATIA-Vis-ORCADES studies (162 cases and 3162 controls), and meta-analyzed. AUCs of ROC-curves were calculated using 10-fold cross-validation for clinical characteristics, IgG glycans and their combination. RESULTS: After correction for extensive clinical covariates, 5 IgG glycans and 13 derived traits significantly associated with type 2 diabetes in meta-analysis (after Bonferroni correction). Adding IgG glycans to age and sex increased the AUC from 0.542 to 0.734. Adding them to the extensive model did not substantially improve the AUC. The AUC for IgG glycans alone was 0.729. CONCLUSIONS: Several IgG glycans and traits firmly associate with type 2 diabetes, reflecting a pro-inflammatory and biologically-aged state. IgG glycans showed limited improvement of AUCs. However, IgG glycans showed good prediction alone, indicating they may capture information of combined covariates. The associations found may yield insights in type 2 diabetes pathophysiology. GENERAL SIGNIFICANCE: This work shows that IgG glycomic changes have biomarker potential and may yield important insights into pathophysiology of complex public health diseases, illustrated here for the first time in type 2 diabetes. PMID- 28668297 TI - Conductive polymer-based bioelectrochemical assembly for in vitro cytotoxicity evaluation: Renoprotective assessment of Salvia officinalis against carbon tetrachloride induced nephrotoxicity. AB - BACKGROUND: The rise of organic electronics represents one of the most prominent technological developments of the last two decades, with its interface with biological systems highlighting new directions of research. The "soft" nature of conducting polymers renders them unique platforms for cell-based microdevices, allowing their implementation in drug discovery, pharmaceutical effect analysis, environmental pollutant testing etc. METHODS: Cellular adhesion, proliferation and viability experiments were carried out to verify the biocompatibility of a PEDOT conductive polymer surface. Cyclic voltammetry was employed for estimating the electrocatalytic activity of the renal cell/electrode interface. The nephrotoxicity agent CCl4 and the medicinal plant Salvia officinalis were used on the proposed assembly. Renal cell viability was also assayed through the MTT assay. RESULTS: Renal cells were able to adhere and proliferate on the conducting polymer surface. Electrochemical responses of the polymer exhibited good correlation with cell number and CCl4 concentration. Amelioration of the CCl4 induced renotoxicity by co-incubation with Salvia officinalis extract was demonstrated by both the MTT assay and the electrode's capacitance. CONCLUSIONS: A conducting polymer-based bioelectrochemical assembly was established for in vitro mammalian cytotoxicity/cytoprotection assessment, employing renal cell monolayers as the primary transducers for signal generation and biological sensing. GENERAL SIGNIFICANCE: The knowledge on PEDOT mammalian cell biocompatibility and possible applications was expanded. The proposed interdisciplinary approach connects soft electronics with biology and could provide a useful tool for preliminary crude drug screening and bioactivity studies of natural products or plant extracts in vitro. PMID- 28668298 TI - Interstitial fluid flow-induced growth potential and hyaluronan synthesis of fibroblasts in a fibroblast-populated stretched collagen gel culture. AB - BACKGROUND: Tensioned collagen gels with dermal fibroblasts (DFs) as a dermis model are usually utilized in a static culture (SC) that lacks medium flowing. To make the model closer to its in vivo state, we created a device to perfuse the model with media flowing at a physiological velocity and examined the effects of medium flow (MF) on the cultures. METHODS: We constructed a medium perfusion device for human DF-embedded stretched collagen gels (human dermis model), exposed the model to media that flows upwardly at ~1mL/day, and examined water retention of the gels, cells' growth ability, metabolic activity, expression profiles of nine extracellular matrix (ECM)-related genes. The obtained data were compared with those from the model in SC. RESULTS: MF increases the gels' water retention and cells' growth potential but had little effect on their metabolic activities. MF robustly enhanced hyaluronan synthase 2 (HAS2) and matrix metalloprotease 1 (MMP1) gene expressions but not of the other genes (MMP2, HYAL1, HYAL2, HYAL3, COL1A1, COL3A1, and CD44). MF significantly increased the amounts of cellular hyaluronan and adenosine triphosphate. CONCLUSIONS: The MF at a physiological speed significantly influences the nature of ECMs and their resident fibroblasts and remodels ECMs by regulating hyaluronan metabolism. GENERAL SIGNIFICANCE: Fibroblasts in tensioned collagen gels altered their phenotypes in a MF rate-dependent manner. Collagen gel culture with tension and MF could be utilized as an appropriate in vitro model of interstitial connective tissues to evaluate the pathophysiological significance of mechanosignals generated by fluid flow and cellular/extracellular tension. PMID- 28668299 TI - Head & neck reconstruction: Predictors of readmission. AB - Unplanned hospital readmission following head and neck cancer surgery is common and associated with significant negative consequences. Because of the vital role that microvascular free tissue transfer plays in the management of head and neck oncologic defects, its relationship to unplanned hospital readmission requires attention. In this review, the incidence of, risk factors for, and reasons for unplanned readmission in patients undergoing free flap reconstruction for head and neck cancer are analyzed. The role of free flap reconstruction as a separate risk factor for unplanned readmission in patients with head and neck cancer is described. Limitations of the existing literature, strategies to decrease unplanned readmissions, and direction for future research are addressed. PMID- 28668300 TI - Lipid droplet growth and adipocyte development: mechanistically distinct processes connected by phospholipids. AB - The differentiation of preadipocytes into mature adipocytes is accompanied by the growth and formation of a giant, unilocular lipid droplet (LD). Mechanistically however, LD growth and adipogenesis are two different processes. Recent studies have uncovered a number of proteins that are able to regulate both LD dynamics and adipogenesis, such as SEIPIN, LIPIN and CDP-Diacylglycerol Synthases. It appears that phospholipids, phosphatidic acid in particular, play a critical role in both LD budding/growth and adipocyte development. This review summarizes recent advances, and aims to provide a better understanding of LD growth as well as adipogenesis, two critical aspects in mammalian fat storage. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28668301 TI - The Significance of Epidermal Lipid Metabolism in Whole-Body Physiology. AB - The skin is the largest sensory organ of the human body. The skin not only prevents loss of water and other components of the body, but also is involved in regulation of body temperature and serves as an essential barrier, protecting mammals from both routine and extreme environments. Given the importance of the skin in temperature regulation, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with systemic physiological responses. Despite that impaired lipid metabolism in the skin often impairs the epidermal permeability barrier and insulation properties of the skin, its role in regulating systemic physiology and metabolism is yet to be recognized. PMID- 28668302 TI - Role of CaMKII in free fatty acid/hyperlipidemia-induced cardiac remodeling both in vitro and in vivo. AB - RATIONALE: The cellular mechanisms of obesity/hyperlipidemia-induced cardiac remodeling are many and not completely elucidated. Ca2+/calmodulin-dependent protein kinase II (CaMKII), a multifunctional serine/threonine kinase, has been reported to be involved in a variety of cardiovascular diseases. However, its role in obesity/hyperlipidemia-induced cardiac remodeling is still unknown. OBJECTIVE: The objective of this study was to demonstrate the role of CaMKII in the pathogenesis of obesity/hyperlipidemia-induced cardiac remodeling both in vitro and in vivo. METHODS AND RESULTS: In cardiac-derived H9C2 cells, palmitate treatment induced cell apoptosis coupled with activation of the mitochondrial apoptotic pathway, and cell hypertrophic and fibrotic responses. All of these alterations were inhibited by pharmacological inhibition of CaMKII with either of two specific inhibitors, Myr-AIP and KN93. In addition, an increased inflammatory response coupled with activation of the MAPKs and NF-kappaB signaling pathway, exaggerated oxidative stress, ER stress and autophagy were also observed in palmitate-treated H9C2 cells, while pretreatment with CaMKII inhibitors decreased these pathological signals. Furthermore, we also demonstrated that TLR4 is upstream signal of CaMKII in palmitate-treated H9C2 cells. In APOE-/- mice fed a high-fat diet (HFD) for 16weeks, serum lipid profiles (FFAs, TG, TC) and blood glucose levels were significantly increased compared with mice fed a normal diet. In addition, apparent cardiac hypertrophy, fibrosis and apoptosis associated with increased inflammation, ER stress, and autophagy were also observed in the hearts of HFD-fed mice. However, all these changes were reversed by 8-weeks of KN93 peritoneal injections. KN93 also increased antioxidant defense as evidenced by increased expression of the Nrf2 system in the hearts of HFD-fed mice. CONCLUSIONS: Taken together, our results demonstrate a critical role of CaMKII in the pathogenesis of obesity/hyperlipidemia-induced cardiac remodeling. Also, TLR4 may be an upstream signal of cardiac CaMKII under hyperlipidemia conditions. These results suggest that CaMKII has the potential to be a therapeutic target in the prevention of obesity/hyperlipidemia-induced cardiac remodeling. PMID- 28668304 TI - Toll-like receptor-4 signaling pathway in aorta aging and diseases: "its double nature". AB - Recent advances in the field of innate immunity have revealed a complex role of innate immune signaling pathways in both tissue homeostasis and disease. Among them, the Toll-like receptor 4 (TLR-4) pathways has been linked to various pathophysiological conditions, such as cardiovascular diseases (CVDs). This has been interrogated by developing multiple laboratory tools that have shown in animal models and clinical conditions, the involvement of the TLR-4 signaling pathway in the pathophysiology of different CVDs, such as atherosclerosis, ischemic heart disease, heart failure, ischemia-reperfusion injury and aorta aneurysm. Among these, aorta aneurysm, a very complex pathological condition with uncertain etiology and fatal complications (i.e. dissection and rupture), has been associated with the occurrence of high risk cardiovascular conditions, including thrombosis and embolism. In this review, we discuss the possible role of TLR-4 signaling pathway in the development of aorta aneurysm, considering the emerging evidence from ongoing investigations. Our message is that emphasizing the role of TLR-4 signaling pathway in aorta aneurysm may serve as a starting point for future studies, leading to a better understanding of the pathophysiological basis and perhaps the effective treatment of this difficult human disease. PMID- 28668303 TI - Ca2+-activated Cl- current is antiarrhythmic by reducing both spatial and temporal heterogeneity of cardiac repolarization. AB - The role of Ca2+-activated Cl- current (ICl(Ca)) in cardiac arrhythmias is still controversial. It can generate delayed afterdepolarizations in Ca2+-overloaded cells while in other studies incidence of early afterdepolarization (EAD) was reduced by ICl(Ca). Therefore our goal was to examine the role of ICl(Ca) in spatial and temporal heterogeneity of cardiac repolarization and EAD formation. Experiments were performed on isolated canine cardiomyocytes originating from various regions of the left ventricle; subepicardial, midmyocardial and subendocardial cells, as well as apical and basal cells of the midmyocardium. ICl(Ca) was blocked by 0.5mmol/L 9-anthracene carboxylic acid (9-AC). Action potential (AP) changes were tested with sharp microelectrode recording. Whole cell 9-AC-sensitive current was measured with either square pulse voltage-clamp or AP voltage-clamp (APVC). Protein expression of TMEM16A and Bestrophin-3, ion channel proteins mediating ICl(Ca), was detected by Western blot. 9-AC reduced phase-1 repolarization in every tested cell. 9-AC also increased AP duration in a reverse rate-dependent manner in all cell types except for subepicardial cells. Neither ICl(Ca) density recorded with square pulses nor the normalized expressions of TMEM16A and Bestrophin-3 proteins differed significantly among the examined groups of cells. The early outward component of ICl(Ca) was significantly larger in subepicardial than in subendocardial cells in APVC setting. Applying a typical subepicardial AP as a command pulse resulted in a significantly larger early outward component in both subepicardial and subendocardial cells, compared to experiments when a typical subendocardial AP was applied. Inhibiting ICl(Ca) by 9-AC generated EADs at low stimulation rates and their incidence increased upon beta-adrenergic stimulation. 9-AC increased the short-term variability of repolarization also. We suggest a protective role for ICl(Ca) against risk of arrhythmias by reducing spatial and temporal heterogeneity of cardiac repolarization and EAD formation. PMID- 28668305 TI - Detrimental role of lysyl oxidase in cardiac remodeling. AB - A key feature of heart failure is adverse extracellular matrix (ECM) remodeling, which is associated with increases in the collagen cross-linking enzyme, lysyl oxidase (LOX). In this study, we assess the progression of cardiovascular remodeling from the compensatory to decompensatory phase, with a focus on the change in LOX expression and activity as it relates to alterations in ECM composition and changes in cardiac function. Adult male Sprague-Dawley rats were studied after 4, 14, or 21weeks of aortocaval fistula-induced volume overload (VO). Progressive increases in the left and right ventricular mass indicated biventricular hypertrophy. Echocardiography revealed significant increases in the posterior wall thickness and internal diameter of the left ventricle as early as 3weeks, which persisted until the 21week endpoint. There were also significant decreases in eccentric index and fractional shortening in VO animals. Hemodynamic measurements showed progressive decreases in contractility, indicative of systolic dysfunction. There were progressive VO-induced increases in LOX expression and activity, collagen, and collagen cross-linking during the course of these experiments. We observed a negative correlation between LOX activity and cardiac function. Additional rats were treated with an inhibitor of LOX activity starting at 2weeks post-surgery and continued to 14weeks. LOX inhibition prevented the cardiac dysfunction and collagen accumulation caused by VO. Overall these data suggest a detrimental role for the chronic increase of cardiac LOX expression and activity in the transition from compensated remodeling to decompensated failure. PMID- 28668306 TI - Periodontal status in 18-year-old Lithuanian adolescents: An epidemiological study. AB - OBJECTIVE: The aim of this study was to investigate the periodontal and oral hygiene status of 18-year-old Lithuanian adolescents. MATERIALS AND METHODS: Cross-sectional data were collected by a multistage sampling approach that was used to draw a representative sample of 1063 adolescents attending schools. In total, 20 schools from the alphabetical list of educational institutions in Lithuania agreed to participate. Periodontal status was evaluated using the Periodontal Screening and Recording (PSR) index. The oral hygiene status was assessed using the Silness-Loe plaque index. RESULTS: The analysis of the PSR index showed that 77.1% of the study population exhibited gum bleeding on probing, had supragingival and/or subgingival calculus, and shallow pockets. Analysis of the composition of the PSR index revealed that in children whose parents had low education levels (18.6%), gum bleeding was more common than in those whose parents had medium education levels (9.5%) (P<0.05). Our data showed that in 40.0% of the study participants, oral hygiene status was satisfactory, with a statistically significant difference between boys (46.9%) and girls (35.3%) (P<0.001). CONCLUSIONS: The results of our study showed that the periodontal and oral hygiene status of 18-year-old Lithuanian population could be characterized as poor. In total, 77.1% of the study participants were found to have periodontal conditions such as gum bleeding, dental calculus, and shallow pockets. The anterior teeth of the mandible were most frequently affected. PMID- 28668307 TI - Influence of light and temperature on the development and denitrification potential of periphytic biofilms. AB - Periphytic biofilms are microbial aggregates commonly present in submerged aquatic environments and play a significant role in nutrient cycling. In recent years, utilization of natural periphytic biofilms in wastewater treatment and water restoration attracts growing research interests. Light and temperature are two important environmental factors known to affect the development of periphytic biofilms and can be manipulated for the regulation of the biofilm properties. In this work, effects of light and temperature on the development and function (denitrification potential) of periphytic biofilms were investigated using a microcosm experiment. Results showed that thicker periphytic biofilms with higher Chlorophyll a, extracellular polymeric substances (EPS), and total phosphorus contents were developed under higher temperature. Whereas, biomass accumulation was more rapid for periphytic biofilms under higher irradiance. The denitrification potential rate was negatively associated with irradiance, which can be linked to the influence of irradiance on biofilm structure and microbial composition. A relatively lower irradiance is recommended when using periphytic biofilms in nitrogen removal from wastewater. PMID- 28668308 TI - Corrigendum to "Synthetic fibers as microplastics in the marine environment: A review from textile perspective with a focus on domestic washings" [Sci. Total Environ. 598 (2017) 1116-1129]. PMID- 28668309 TI - A Niche Indication for Intra-Aortic Balloon Pump Counterpulsation: Aortic Valve Opening in a Surgically Vented Left Ventricle on Venoarterial ECMO. PMID- 28668310 TI - Aortoarteritis With Chronic Total Occlusion of All Neck Vessels: Percutaneous Stenting to Salvage Intractable Syncope. PMID- 28668311 TI - Full Metal Jacket With Drug-Eluting Stents for Coronary Chronic Total Occlusion. AB - OBJECTIVES: The aim of this study was to evaluate the long-term outcomes and predictors of adverse events following successful "full metal jacket" (FMJ) (stent length >=60 mm without gap) procedures using drug-eluting stents to treat coronary chronic total occlusions (CTOs). BACKGROUND: The FMJ stenting procedure is often required to treat CTOs, but its clinical efficacy and safety remain unknown. METHODS: In total, 1,126 successful CTO procedures (1,107 consecutive patients) performed between May 2003 and March 2015 were studied. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel related myocardial infarction, or target lesion revascularization or reocclusion. RESULTS: Overall, 406 patients (36.7%) underwent the FMJ procedure, increasing in frequency over time (28.5% from 2003 to 2006 and 41.7% after 2011). The mean stent length was 76.8 +/- 14.6 mm (range 60 to 122 mm), and the average number of stent overlaps was 2.5 +/- 0.6 (range 2 to 4). A total of 127 patients (31.3%) had persistent luminal narrowing at the distal reference segment after stenting. During the median follow-up period of 5.1 years, target lesion failure occurred in 16.0% of patients. There were 17 cases of total reocclusion and 5 cases of stent thrombosis. Multivariate analysis confirmed that the number of implanted stents (hazard ratio: 1.72; 95% confidence interval: 1.16 to 2.54; p = 0.006) and persistent distal luminal narrowing (hazard ratio: 2.73; 95% confidence interval: 1.66 to 4.47; p < 0.001) were predictors of increased risk for target lesion failure. CONCLUSIONS: The FMJ procedure using drug-eluting stents for CTOs provides acceptable long-term clinical results. Persistent distal luminal narrowing increases the future likelihood of adverse events despite procedural success. PMID- 28668312 TI - Ultrasound-Assisted Catheter-Directed Thrombolysis in Pulmonary Embolism in Transit. PMID- 28668313 TI - In-Stent Catheter-Induced Neointimal Dissection Assessed by Optical Coherence Tomography. PMID- 28668314 TI - Percutaneous Closure of a Delayed Left Ventricular Pseudoaneurysm After Transseptal Transcatheter Mitral Valve Replacement. PMID- 28668315 TI - Full Metal Jacket: Is it En Vogue? PMID- 28668316 TI - Ontogenetic development of the inner ear saccule and utricle in the Lusitanian toadfish: Potential implications for auditory sensitivity. AB - Studies addressing structure-function relationships of the fish auditory system during development are sparse compared to other taxa. The Batrachoididae has become an important group to investigate mechanisms of auditory plasticity and evolution of auditory-vocal systems. A recent study reported ontogenetic improvements in the inner ear saccule sensitivity of the Lusitanian toadfish, Halobatrachus didactylus, but whether this results from changes in the sensory morphology remains unknown. We investigated how the macula and organization of auditory receptors in the saccule and utricle change during growth in this species. Inner ear sensory epithelia were removed from the end organs of previously PFA-fixed specimens, from non-vocal posthatch fry (<1.4 cm, standard length) to adults (>23 cm). Epithelia were phalloidin-stained and analysed for area, shape, number and orientation patterns of hair cells (HC), and number and size of saccular supporting cells (SC). Saccular macula area expanded 41x in total, and significantly more (relative to body length) among vocal juveniles (2.3-2.9 cm). Saccular HC number increased 25x but HC density decreased, suggesting that HC addition is slower relative to epithelial growth. While SC density decreased, SC apical area increased, contributing to the epithelial expansion. The utricule revealed increased HC density (striolar region) and less epithelial expansion (5x) with growth, contrasting with the saccule that may have a different developmental pattern due to its larger size and main auditory functions. Both macula shape and HC orientation patterns were already established in the posthatch fry and retained throughout growth in both end organs. We suggest that previously reported ontogenetic improvements in saccular sensitivity might be associated with changes in HC number (not density), size and/or molecular mechanisms controlling HC sensitivity. This is one of the first studies investigating the ontogenetic development of the saccule and utricle in a vocal fish and how it potentially relates to auditory enhancement for acoustic communication. PMID- 28668317 TI - Assessment and management of cervico-mediastinal goiter. AB - Cervico-mediastinal goiter is a particular entity from the point of view of thyroid surgery. Its volume, hardness and intrathoracic extension require the surgeon to adapt technique and perform a painstaking preoperative work-up, so as to draw up fully-fledged plan. CT is now indispensable, to anticipate risks and determine whether sternotomy is needed. Surgery seems to induce more postoperative complications than in conventional surgery, although they can be reduced by retrograde dissection of the inferior laryngeal nerve and downward dissection of the posterior side of the lobe to optimize control of adjacent structures. This surgery requires optimal teamwork between all of the specialties involved in patient management: medical, radiological, anesthesiological and surgical. PMID- 28668318 TI - Hamartoma of the tongue. PMID- 28668319 TI - Fluctuating neck mass: Letter to the editor and review of the literature on anterior jugular phlebectasia. PMID- 28668321 TI - Corrigendum to: "A flexible multi-stimuli in-situ (S)TEM: Concept and optical performance" [Ultramicroscopy 151 (2015) 31-36]. PMID- 28668322 TI - Wingless is a positive regulator of eyespot color patterns in Bicyclus anynana butterflies. AB - Eyespot patterns of nymphalid butterflies are an example of a novel trait yet, the developmental origin of eyespots is still not well understood. Several genes have been associated with eyespot development but few have been tested for function. One of these genes is the signaling ligand, wingless, which is expressed in the eyespot centers during early pupation and may function in eyespot signaling and color ring differentiation. Here we tested the function of wingless in wing and eyespot development by down-regulating it in transgenic Bicyclus anynana butterflies via RNAi driven by an inducible heat-shock promoter. Heat-shocks applied during larval and early pupal development led to significant decreases in wingless mRNA levels and to decreases in eyespot size and wing size in adult butterflies. We conclude that wingless is a positive regulator of eyespot and wing development in B. anynana butterflies. PMID- 28668320 TI - Engineering Natural Killer Cells for Cancer Immunotherapy. AB - The past several years have seen tremendous advances in the engineering of immune effector cells as therapy for cancer. While chimeric antigen receptors (CARs) have been used extensively to redirect the specificity of autologous T cells against hematological malignancies with striking clinical results, studies of CAR modified natural killer (NK) cells have been largely preclinical. In this review, we focus on recent advances in NK cell engineering, particularly on preclinical evidence suggesting that NK cells may be as effective as T cells in recognizing and killing targets after genetic modification. We will discuss strategies to introduce CARs into both primary NK cells and NK cell lines in an effort to provide antigen specificity, the challenges of manufacturing engineered NK cells, and evidence supporting the effectiveness of this approach from preclinical and early-phase clinical studies using CAR-engineered NK cells. CAR-NK cells hold great promise as a novel cellular immunotherapy against refractory malignancies. Notably, NK cells can provide an "off-the-shelf" product, eliminating the need for a personalized and patient-specific product that plagues current CAR-T cell therapies. The ability to more potently direct NK cell-mediated cytotoxicity against refractory tumors through the expression of CAR is likely to contribute to the recent paradigm shift in cancer treatment. PMID- 28668323 TI - Cestode parasites release extracellular vesicles with microRNAs and immunodiagnostic protein cargo. AB - Intercellular communication is crucial in multiple aspects of cell biology. This interaction can be mediated by several mechanisms including extracellular vesicle (EV) transfer. EV secretion by parasites has been reported in protozoans, trematodes and nematodes. Here we report that this mechanism is present in three different species of cestodes, Taenia crassiceps, Mesocestoides corti and Echinococcus multilocularis. To confirm this we determined, in vitro, the presence of EVs in culture supernatants by transmission electron microscopy. Interestingly, while T. crassiceps and M. corti metacestodes secrete membranous structures into the culture media, similar vesicles were observed in the interface of the germinal and laminated layers of E. multilocularis metacestodes and were hardly detected in culture supernatants. We then determined the protein cargo in the EV-enriched secreted fractions of T. crassiceps and M. corti conditioned media by LC-MS/MS. Among the identified proteins, eukaryotic vesicle enriched proteins were identified as expected, but also proteins used for cestode disease diagnosis, proteins related to neurotransmission, lipid binding proteins as well as host immunoglobulins and complement factors. Finally, we confirmed by capillary electrophoresis the presence of intravesicular RNA for both parasites and detected microRNAs by reverse transcription-PCR. This is the first report of EV secretion in cestode parasites and of an RNA secretion mechanism. These findings will provide valuable data not only for basic cestode biology but also for the rational search for new diagnostic targets. PMID- 28668324 TI - Population genetic analysis informs the invasion history of the emerging trematode Dicrocoelium dendriticum into Canada. AB - Parasite distributions are constantly changing due to climate change, local and global movement of animals and humans, as well as land use and habitat change. The trematode Dicrocoelium dendriticum is a relatively recent invader of Canada, being first reported in eastern Canada in the 1930s and western Canada in the 1970s. However, historical records are scarce and its emergence is poorly understood. The establishment of this parasite in Canada provides an interesting opportunity to explore the use of population genetic approaches to help elucidate the invasion history of a relatively recently established helminth parasite. In this study, we compare the genetic diversity and population structure of a number of D. dendriticum populations from western and eastern Canada, and compare these with much longer established European populations. Two independent genetic marker systems were used; a microsatellite marker panel and a cytochrome c oxidase 1 (cox1) mitochondrial (mt)DNA sequence marker. We found distinct differences in both genetic diversity and population structure of the different Canadian populations that provide insights into their invasion histories compared with the European populations. Two populations from British Columbia, Canada - Salt Spring and Vancouver Islands - are of low diversity, show evidence of a population bottleneck and are closely related to each other, suggesting a shared recent history of establishment. These west coast populations are otherwise most closely related to those from eastern Canada and western Europe, and in contrast are genetically divergent from those in Cypress Hills, Alberta, Canada. Although the Alberta parasite population is the most recently reported in Canada, being first identified there in the early 1990s, it was the most genetically diverse of those examined and showed a strong pattern of admixture of genotypes present in western and eastern Europe. Overall, our results are consistent with a model in which western Europe is likely the source of flukes on the east coast of Canada, which were then subsequently translocated to the west coast of Canada. The most recently reported D. dendriticum population in Canada appears to have a different history and likely has multiple origins. PMID- 28668325 TI - IgG opsonization of merozoites: multiple immune mechanisms for malaria vaccine development. AB - Global eradication of the human-infecting malaria parasite Plasmodium falciparum, the major cause of malaria mortality, is unlikely to be achieved without an effective vaccine. However, our limited understanding of how protective immune responses target malaria parasites in humans, and how to best elicit these immune responses through vaccination, has hampered vaccine development. The red blood cell invading stage of the parasite lifecycle (merozoite) displays antigens that are attractive vaccine candidates as they are accessible to antibodies and raise high antibody titres in naturally immune individuals. The number of merozoite antigens that elicit an immune response, and their structural and functional diversity, has led to a large number of lead antigens being pursued as vaccine candidates. Despite being seemingly spoilt for choice in terms of vaccine candidates, there is still a lack of consensus on exactly how merozoite antibodies reduce parasitemia and malaria disease. In this review we describe the various immune mechanisms that can result from IgG opsonization of merozoites, and highlight recent developments that support a role for these functional antibodies in naturally acquired and vaccine-induced immunity. PMID- 28668326 TI - Influences of climate change on the potential distribution of Lutzomyia longipalpis sensu lato (Psychodidae: Phlebotominae). AB - This study explores the present day distribution of Lutzomyia longipalpis in relation to climate, and transfers the knowledge gained to likely future climatic conditions to predict changes in the species' potential distribution. We used ecological niche models calibrated based on occurrences of the species complex from across its known geographic range. Anticipated distributional changes varied by region, from stability to expansion or decline. Overall, models indicated no significant north-south expansion beyond present boundaries. However, some areas suitable both at present and in the future (e.g., Pacific coast of Ecuador and Peru) may offer opportunities for distributional expansion. Our models anticipated potential range expansion in southern Brazil and Argentina, but were variably successful in anticipating specific cases. The most significant climate related change anticipated in the species' range was with regard to range continuity in the Amazon Basin, which is likely to increase in coming decades. Rather than making detailed forecasts of actual locations where Lu. longipalpis will appear in coming years, our models make interesting and potentially important predictions of broader-scale distributional tendencies that can inform heath policy and mitigation efforts. PMID- 28668328 TI - Reply by Authors. PMID- 28668327 TI - An Updated Translation. PMID- 28668329 TI - Editorial Comment. PMID- 28668330 TI - Molecular and functional characterisation of two elovl4 elongases involved in the biosynthesis of very long-chain (>C24) polyunsaturated fatty acids in black seabream Acanthopagrus schlegelii. AB - Elongation of very long-chain fatty acid (Elovl) 4 proteins are important fatty acyl elongases that participate in the biosynthesis of long-chain (C20-24) and very long-chain (?C24) polyunsaturated fatty acids (LC-PUFA and VLC-PUFA, respectively) in teleost fish, especially in marine species. Moreover, knowledge of Elovl4 and other elongases such as Elovl2 has contributed to an advanced understanding of the LC-PUFA biosynthetic pathway in marine fish. In the present study, elovl4a and elovl4b were cloned from black seabream Acanthopagrus schlegelii and functionally characterised using recombinant expression in yeast. The elovl4a and elovl4b cDNA sequences included open reading frames (ORF) of 969 and 918 base pairs (bp), encoding proteins of 322 and 315 amino acids (aa), respectively. The functional characterisation of A. schlegelii Elovl4 proteins showed they were able to utilise all assayed C18-22 PUFA substrates except 22:6n 3. Moreover, it was particularly noteworthy that both A. schlegelii Elovl4a and Elovl4b proteins had the ability to elongate 20:5n-3 and 22:5n-3 to 24:5n-3, which can be potentially desaturated and beta-oxidised to 22:6n-3. Tissue transcript abundance analysis showed the highest expression of elovl4a and elovl4b in brain and eye, respectively, suggesting these tissues were major sites for VLC-PUFA biosynthesis in black seabream. The functions of the A. schlegelii Elovl4-like elongases, Elovl4a and Elovl4b, characterised in the present study, along with those of the Elovl5 and fatty acyl desaturase (Fads2) proteins of A. schlegelii characterised previously, provided evidence of the biosynthetic pathways of LC-PUFA and VLC-PUFA in this teleost species. PMID- 28668332 TI - Ethanol-induced PGE2 up-regulates Abeta production through PKA/CREB signaling pathway. AB - Ethanol abuse aggravates dementia-associated cognitive defects through the progression of Alzheimer's disease (AD) pathophysiology. Beta-site APP-cleaving enzyme 1 (BACE1) has been considered as a key regulator of AD pathogenesis by controlling amyloid beta peptide (Abeta) accumulation. In addition, previous studies reported that endoplasmic reticulum (ER) stress and neuroinflammation have been proposed in ethanol-induced neurodegeneration. Thus, we investigated the role of ER stress and PGE2, a neuroinflammation mediator, in the ethanol stimulated BACE1 expression and Abeta production. Using the human-derived neuroblastoma cell line SK-N-MC, the results show that ethanol up-regulated BACE1 expression in a dose-dependent manner. Ethanol stimulated reactive oxygen species (ROS) production, which induced CHOP expression and eIF2alpha phosphorylation. PBA (an ER stress inhibitor) attenuated the ethanol-increased cyclooxygenase-2 (COX-2) expression and PGE2 production. By using salubrinal (an eIF2alpha dephosphorylation inhibitor) or EIF2A siRNA, we found that eIF2alpha phosphorylation mediated the ethanol-induced COX-2 expression. In addition, COX-2 induced BACE1 up-regulation was abolished by NS-398 (a selective COX-2 inhibitor). And, PF-04418948 (an EP-2 receptor inhibitor) pretreatment reduced ethanol-induced PKA activation and CREB phosphorylation as well as ethanol stimulated Abeta production. Furthermore, 14-22 amide (a PKA inhibitor) pretreatment or CREB1 siRNA transfection suppressed the ethanol-induced BACE1 expression. In conclusion, ethanol-induced eIF2alpha phosphorylation stimulates COX-2 expression and PGE2 production which induces the BACE1 expression and Abeta production via EP-2 receptor-dependent PKA/CREB pathway. PMID- 28668331 TI - Total abdominal irradiation exposure impairs cognitive function involving miR-34a 5p/BDNF axis. AB - Radiotherapy is often employed to treat abdominal and pelvic malignancies, but is frequently accompanied by diverse acute and chronic local injuries. It was previously unknown whether abdominal and pelvic radiotherapy impairs distant cognitive dysfunction. In the present study, we demonstrated that total abdominal irradiation (TAI) exposure caused cognitive deficits in mouse models. Mechanically, microarray assay analysis revealed that TAI elevated the expression level of miR-34a-5p in small intestine tissues and peripheral blood (PD), which targeted the 3'UTR of Brain-derived neurotrophic factor (Bdnf) mRNA in hippocampus to mediate cognitive dysfunction. Tail intravenous injection of miR 34a-5p antagomir immediately after TAI exposure rescued TAI-mediated cognitive impairment via blocking the up-regulation of miR-34a-5p in PD, resulting in restoring the Bdnf expression in the hippocampus. More importantly, high throughput sequencing validated that the gut bacterial composition of mice was shifted after TAI exposure, which was retained by miR-34a-5p antagomir injection. Thus, our findings provide new insights into pathogenic mechanism underlying abdominal and pelvic radiotherapy-mediated distant cognitive impairment. PMID- 28668334 TI - A retrospective analysis of in vivo eye irritation, skin irritation and skin sensitisation studies with agrochemical formulations: Setting the scene for development of alternative strategies. AB - Analysis of the prevalence of health effects in large scale databases is key in defining testing strategies within the context of Integrated Approaches on Testing and Assessment (IATA), and is relevant to drive policy changes in existing regulatory toxicology frameworks towards non-animal approaches. A retrospective analysis of existing results from in vivo skin irritation, eye irritation, and skin sensitisation studies on a database of 223 agrochemical formulations is herein published. For skin or eye effects, high prevalence of mild to non-irritant formulations (i.e. per GHS, CLP or EPA classification) would generally suggest a bottom-up approach. Severity of erythema or corneal opacity, for skinor eye effects respectively, were the key drivers for classification, consistent with existing literature. The reciprocal predictivity of skin versus eye irritation and the good negative predictivity of the GHS additivity calculation approach (>85%) provided valuable non-testing evidence for irritation endpoints. For dermal sensitisation, concordance on data from three different methods confirmed the high false negative rate for the Buehler method in this product class. These results have been reviewed together with existing literature on the use of in vitro alternatives for agrochemical formulations, to propose improvements to current regulatory strategies and to identify further research needs. PMID- 28668333 TI - Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs). AB - Schizophrenia is a chronic disabling mental disorder that affects about 1% population world-wide, for which there is a desperate need to develop more effective treatments. In this minireview, we summarize the findings from recent studies using induced pluripotent stem cells to model the developmental pathogenesis of schizophrenia and discuss what we have learned from these studies. We also discuss what are the important next steps and key issues to be addressed to move the field forward. PMID- 28668335 TI - Unravelling HIV-1 Latency, One Cell at a Time. AB - A single virus is capable of infecting and replicating in a single cell. Recent advances across single-cell omics technologies - genomics, epigenomics, transcriptomics, epitranscriptomics, proteomics, and metabolomics - will offer unprecedented opportunities to gain more insights into the various aspects of the life cycle of viruses and their impact on the host cell. Here, using the human immunodeficiency virus type 1 (HIV-1) as an example, we summarize the current knowledge and the future potential of single-cell omics in the investigation of an important aspect of the life cycle of HIV-1 that represents a major hurdle in achieving viral eradication, HIV-1 latency. PMID- 28668337 TI - Modeling the synergistic elimination of bacteria by phage and the innate immune system. AB - Phage therapy has been viewed as a potential treatment for bacterial infections for over a century. Yet, the year 2016 marks one of the first phase I/II human trials of a phage therapeutic - to treat burn wound patients in Europe. The slow progress in realizing clinical therapeutics is matched by a similar dearth in principled understanding of phage therapy. Theoretical models and in vitro experiments find that combining phage and bacteria often leads to coexistence of both phage and bacteria or phage elimination altogether. Both outcomes stand in contrast to the stated goals of phage therapy. A potential resolution to the gap between models, experiments, and therapeutic use of phage is the hypothesis that the combined effect of phage and host immune system can synergistically eliminate bacterial pathogens. Here, we propose a phage therapy model that considers the nonlinear dynamics arising from interactions between bacteria, phage and the host innate immune system. The model builds upon earlier efforts by incorporating a maximum capacity of the immune response and density-dependent immune evasion by bacteria. We analytically identify a synergistic regime in this model in which phage and the innate immune response jointly contribute to the elimination of the target bacteria. Crucially, we find that in this synergistic regime, neither phage alone nor the innate immune system alone can eliminate the bacteria. We confirm these findings using numerical simulations in biologically plausible scenarios. We utilize our numerical simulations to explore the synergistic effect and its significance for guiding the use of phage therapy in clinically relevant applications. PMID- 28668336 TI - The NOD2-Smoking Interaction in Crohn's Disease is likely Specific to the 1007fs Mutation and may be Explained by Age at Diagnosis: A Meta-Analysis and Case-Only Study. AB - BACKGROUND: NOD2 and smoking are risk factors for Crohn's disease. We meta analyzed NOD2-smoking interactions in Crohn's disease (Phase 1), then explored the effect of age at diagnosis on NOD2-smoking interactions (Phase 2). METHODS: Phase 1: MEDLINE and EMBASE were searched for studies (n=18) providing data on NOD2 and smoking in Crohn's disease. NOD2-smoking interactions were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) calculated using random effects models. Phase 2: A case-only study compared the proportion of smokers and carriers of the 1007fs variant across ages at diagnosis (<=16, 17-40, >40years). FINDINGS: Phase 1: Having ever smoked was less common among carriers of the 1007fs variant of NOD2 (OR 0.74, 95%CI:0.66-0.83). There was no interaction between smoking and the G908R (OR 0.96, 95%CI:0.82-1.13) or the R702W variant (OR 0.89, 95%CI:0.76-1.05). Phase 2: The proportion of patients (n=627) carrying the 1007fs variant decreased with age at diagnosis (<=16years: 15%; 17 40: 12%; >40: 3%; p=0.003). Smoking was more common in older patients (<=16years: 4%; 17-40: 48%; >40: 71%; p<0.001). INTERPRETATION: The negative NOD2-smoking interaction in Crohn's disease is specific to the 1007fs variant. However, opposing rates of this variant and smoking across age at diagnosis may explain this negative interaction. PMID- 28668338 TI - [Analysis of prenatal abuse in catalonia between the years 2011 and 2014]. AB - INTRODUCTION: Foetal abuse is that intentional or negligent act that causes a harmful effect to the foetus. It is a type of abuse difficult to diagnose and handle. Some indicators of suspicion are the absence of gestational control, the maternal consumption of toxic substances, or the problematic maternal social environment. OBJECTIVE: To analyse the cases of foetal abuse registered in Catalonia between 2011 and 2014 to identify the risk profile. METHODS: A cross sectional descriptive study was conducted on a sample of 222 cases of prenatal abuse registered in Catalonia between 2011 and 2014. RESULTS: The mean maternal age was 28.11 years, with 63% of Spanish nationality, 76% were unemployed, 60% had not followed correct gestational control, 76% had previous pregnancy interruptions, 20% reported to have been mistreated by the partner, had history of social problems (76% social intervention, 30.5% previous child retention, 13% custody of the mother by the administration, 7% deprivation of liberty), with high rates of mother-to-child transmission of infection (HIV 4.95%, HCV 9%, HIV+HCV co-infection 1.8%), and 73% reported toxic use (in order of frequency, cannabis, cocaine and heroin). In newborns, the rate of prematurity (26.3%) is highlighted, as well as the diagnosis of withdrawal syndrome in 34 cases. Just over half (51.6%) of the infants are currently with their mother. CONCLUSIONS: In our reference population with a diagnosis of prenatal abuse, there are high rates of maternal toxic consumption, HIV-HCV infection, unemployment, history of previous social intervention, and poor gestational control. PMID- 28668339 TI - [Ten years experience with the first approved biosimilar recombinant human growth hormone drug in normal clinical practice]. AB - INTRODUCTION: Recombinant human growth hormone (rhGH) is the first biosimilar drug approved by the European Medicines Agency in 2006, using the biosimilar registration process. It was authorised for the treatment of growth hormone deficiency, and growth disorders associated with Turner's syndrome, chronic renal failure, Prader-Willi syndrome, and growth disorders in children/adolescents born small for gestational age, and replacement therapy in adults with pronounced growth hormone deficiency. MATERIALS AND METHODS: This review is focused on the scientific evidence published about this drug in the last ten years, including the clinical trials on which the approval of the regulatory authority is based, and the most relevant studies evaluating the clinical impact of the drug in clinical practice. RESULTS: The equivalence between biosimilar and original product has been confirmed in the clinical trials published by Romer et al. and Lopez-Siguero et al. Furthermore, studies carried out in real-life conditions confirm its long-term efficacy and safety, as well as the absence of clinical impact by switching treatment from the original to the biosimilar product. CONCLUSION: The number of patients receiving this medication has continuously increased since its approval. Its equivalence with the original product has been verified. Preliminary data from the post-authorisation PATRO study confirm the efficacy and safety of the biosimilar product in comparison with data from clinical trials. However, final results must be evaluated at the end of the study, which will provide additional information about the long-term efficacy and safety of the biosimilar drug. PMID- 28668340 TI - A Formulation Development Approach to Identify and Select Stable Ultra-High Concentration Monoclonal Antibody Formulations With Reduced Viscosities. AB - High protein concentration formulations are required for low-volume administration of therapeutic antibodies targeted for subcutaneous, self administration by patients. Ultra-high concentrations (>=150 mg/mL) can lead to dramatically increased solution viscosities, which in turn can lead to stability, manufacturing, and delivery challenges. In this study, various categories and individual types of pharmaceutical excipients and other additives (56 in total) were screened for their viscosity reducing effects on 2 different mAbs. The physicochemical stability profile, as well as viscosity ranges, of several candidate antibody formulations, identified and designed based on the results of the excipient screening, were evaluated over a 6-month time period under accelerated and real-time storage conditions. In addition to reducing the solution viscosities to acceptable levels for parenteral administration (using currently available and acceptable delivery devices), the candidate formulations did not result in notable losses of physicochemical stability of the 2 antibodies on storage for 6 months at 25 degrees C. The experiments described here demonstrate the feasibility of a formulation development and selection approach to identify candidate high-concentration antibody formulations with viscosities within pharmaceutically acceptable ranges that do not adversely affect their physicochemical storage stability. PMID- 28668341 TI - Exposure assessment using human biomonitoring for glyphosate and fluroxypyr users in amenity horticulture. AB - BACKGROUND: Pesticides and their potential adverse health effects are of great concern and there is a dearth of knowledge regarding occupational exposure to pesticides among amenity horticulturalists. OBJECTIVE: This study aims to measure occupational exposures to amenity horticuturalists using pesticides containing the active ingredients, glyphosate and fluroxypyr by urinary biomonitoring. METHODS: A total of 40 work tasks involving glyphosate and fluroxypyr were surveyed over the period of June - October 2015. Workers used a variety of pesticide application methods; manual knapsack sprayers, controlled droplet applicators, pressurised lance applicators and boom sprayers. Pesticide concentrations were measured in urine samples collected pre and post work tasks using liquid chromatography tandem mass spectrometry (LC-MS/MS). Differences in pesticide urinary concentrations pre and post work task, and across applications methods were analysed using paired t-tests and linear regression. RESULTS: Pesticide urinary concentrations were higher than those reported for environmental exposures and comparable to those reported in some agricultural studies. Log-transformed pesticide concentrations were statistically significantly higher in post-work samples compared to those in pre-work samples (paired t-test, p<0.001; for both MUgL-1 and MUmol/mol creatinine). Urinary pesticide concentrations in post-work samples had a geometric mean (geometric standard deviation) of 0.66 (1.11) MUgL-1 for glyphosate and 0.29 (1.69) MUgL-1 for fluroxypyr. Linear regression revealed a statistically significant positive association to exist between the time-interval between samples and the log transformed adjusted (i.e. post- minus pre-task) pesticide urinary concentrations (beta=0.0039; p<0.0001). CONCLUSION: Amenity horticulturists can be exposed to pesticides during tasks involving these products. Further research is required to evaluate routes of exposure among this occupational group. PMID- 28668342 TI - Animal house: University risk environments and the regulation of students' alcohol use. AB - BACKGROUND: This article extends the risk environment framework to understand the factors that universities identify as influencing university students' risky drinking behaviours and universities attempts at managing risky alcohol use on their campuses. METHODS: This article examines data collected as part of qualitative fieldwork on university corporate security services, and others involved in university alcohol policy implementation (e.g., residence services), conducted at five Canadian universities. Interviews (n=56), fieldnotes from 246h of observations of university corporate security personnel, and university policy documents (i.e., codes of student behaviour, residence policies) were analysed to understand the influence of risk environments on high-risk alcohol use. RESULTS: We identify three risk environments on university campuses in relation to the use and regulation of alcohol: the physical, social, and policy environments. Residence buildings and abutting spaces (physical risk environment) and the university "party" culture (social risk environment) are principal contributors to risk within their risk environments. University policies and practices (policy risk environment) attempt to modify these environments in order to manage risky alcohol use. CONCLUSION: We suggest current approaches to regulating student alcohol use may not be the best approach to preventing harms (e.g., health problems, legal troubles) to students. Given university policies and practices have the potential to shape and influence risky alcohol use and associated harms we argue it is necessary for university administrators to adopt the best practices of "harm reduction" and seek new ways to address on-campus alcohol use. PMID- 28668343 TI - Changes in arterial cerebral blood volume during lower body negative pressure measured with MRI. AB - Cerebral Autoregulation (CA), defined as the ability of the cerebral vasculature to maintain stable levels of blood flow despite changes in systemic blood pressure, is a critical factor in neurophysiological health. Magnetic resonance imaging (MRI) is a powerful technique for investigating cerebrovascular function, offering high spatial resolution and wide fields of view (FOV), yet it is relatively underutilized as a tool for assessment of CA. The aim of this study was to demonstrate the potential of using MRI to measure changes in cerebrovascular resistance in response to lower body negative pressure (LBNP). A Pulsed Arterial Spin Labeling (PASL) approach with short inversion times (TI) was used to estimate cerebral arterial blood volume (CBVa) in eight healthy subjects at baseline and -40mmHg LBNP. We estimated group mean CBVa values of 3.13 +/- 1.00 and 2.70 +/- 0.38 for baseline and lbnp respectively, which were the result of a differential change in CBVa during -40mmHg LBNP that was dependent on baseline CBVa. These data suggest that the PASL CBVa estimates are sensitive to the complex cerebrovascular response that occurs during the moderate orthostatic challenge delivered by LBNP, which we speculatively propose may involve differential changes in vascular tone within different segments of the arterial vasculature. These novel data provide invaluable insight into the mechanisms that regulate perfusion of the brain, and establishes the use of MRI as a tool for studying CA in more detail. PMID- 28668344 TI - Maternal thyroid hormone trajectories during pregnancy and child behavioral problems. AB - There is ample evidence demonstrating the importance of maternal thyroid hormones, assessed at single trimesters in pregnancy, for child cognition. Less is known, however, about the course of maternal thyroid hormone concentrations during pregnancy in relation to child behavioral development. Child sex might be an important moderator, because there are sex differences in externalizing and internalizing behavioral problems. The current study examined the associations between maternal thyroid hormone trajectories versus thyroid assessments at separate trimesters of pregnancy and child behavioral problems, as well as sex differences in these associations. In 442 pregnant mothers, serum levels of TSH and free T4 (fT4) were measured at 12, 24, and 36weeks gestation. Both mothers and fathers reported on their children's behavioral problems, between 23 and 60months of age. Latent growth mixture modeling was used to determine the number of different thyroid hormone trajectories. Three trajectory groups were discerned: 1) highest and non-increasing TSH with lowest fT4 that decreased least of the three trajectories; 2) increasing TSH and decreasing fT4 at intermediate levels; 3) lowest and increasing TSH with highest and decreasing fT4. Children of mothers with the most flattened thyroid hormone trajectories (trajectory 1) showed the most anxiety/depression symptoms. The following trimester-specific associations were found: 1) lower first-trimester fT4 was associated with more child anxiety/depression, 2) higher first-trimester TSH levels were related to more attention problems in boys only. A flattened course of maternal thyroid hormone concentrations during pregnancy was a better predictor of child anxiety/depression than first-trimester fT4 levels. PMID- 28668345 TI - Scriptaid cause histone deacetylase inhibition and cell cycle arrest in HeLa cancer cells: A study on structural and functional aspects. AB - Scriptaid (SCR), a well-known histone deacetylase inhibitor, cause various cellular effects such as cell growth inhibition and apoptosis. In this study, we have evaluated the anti-cancer effects of Scriptaid in HeLa cells, IMR-32 and HepG2 cells. Scriptaid inhibited the growth of HeLa cells with IC50 of 2MUM at 48h in a dose-dependent manner. Flow-cytometric analysis indicated that SCR induced apoptosis. Scriptaid was found to inhibit HDAC-8 effectively than other HDAC inhibitor such as TSA as observed by HDAC-8 assay, Western blotting and modelling study. This observation was further strengthened by an artificial neuronal network (ANN) model. PMID- 28668346 TI - Identification and characterization of vp7 gene in Bombyx mori cytoplasmic polyhedrosis virus. AB - The genome of Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) contains 10 double stranded RNA segments (S1-S10). The segment 7 (S7) encodes 50kDa protein which is considered as a structural protein. The expression pattern and function of p50 in the virus life cycle are still unclear. In this study, the viral structural protein 7 (VP7) polyclonal antibody was prepared with immunized mouse to explore the presence of small VP7 gene-encoded proteins in Bombyx mori cytoplasmic polyhedrosis virus. The expression pattern of vp7 gene was investigated by its overexpression in BmN cells. In addition to VP7, supplementary band was identified with western blotting technique. The virion, BmCPV infected cells and midguts were also examined using western blotting technique. 4, 2 and 5 bands were detected in the corresponding samples, respectively. The replication of BmCPV genome in the cultured cells and midgut of silkworm was decreased by reducing the expression level of vp7 gene using RNA interference. In immunoprecipitation experiments, using a polyclonal antiserum directed against the VP7, one additional shorter band in BmCPV infected midguts was detected, and then the band was analyzed with mass spectrum (MS), the MS results showed thatone candidate interacted protein (VP7 voltage-dependent anion selective channel-like isoform, VDAC) was identified from silkworm. We concluded that the novel viral product was generated with a leaky scanning mechanism and the VDAC may be an interacted protein with VP7. PMID- 28668347 TI - Managing hazards in place: The risks of residual risks. AB - Managing hazards in place (MHP) is a policy instrument in environmental health that allows less than complete removal, abatement, or remediation of environmental hazards. The practice of minimizing exposure to hazards rather than removing them is widely recognized as part of the toolbox of environmental protection for human and ecosystem health. The concept of managing hazards in place is embedded in several environmental statutes and regulations in the US notably the waste management regulations, as well as in the Safe Drinking Water Act and the Clean Water Act. While this commentary focuses largely on applications of MHP in the US, this policy is also utilized by agencies in many other countries for managing hazardous waste sites, lead in housing and drinking water systems, and environmental contamination of rivers and estuaries. The rationale for this concept is not difficult to understand: MHP policies can reduce the costs of meeting environmental goals; it can provide opportunities for access to resources that have been contaminated by past actions such as waste disposal, and it can enhance land and property values as well as tax revenues all of which are important to home owners and communities. The concerns related to this concept are also not difficult to understand: an incompletely abated or contained hazard may present future exposure risks to humans and environmental biota. Further, the compromise implicit in MHP is the assurance of indefinite oversight and monitoring to detect any releases. To that extent, MHP involves both sociology as well as toxicology and the exposure sciences. Because of the prevalence of managing hazards in place, this commentary suggests that evaluation of its performance is needed. PMID- 28668348 TI - Resurgence of response duration in human participants. AB - Previously reinforced responses can reappear when reinforcement is withdrawn from current responding. This is known as resurgence. Although resurgence of response topography, spacing, and patterns over time has been demonstrated, there is no evidence of resurgence of response duration. This experiment explored resurgence of response duration in humans. In Phase 1 a multiple schedule of reinforcement with two components was used. In each component a chained variable-interval 30s, variable-ratio 3 schedule was implemented. In the terminal link of the chained schedule, response durations between 0.1 and 0.5s were reinforced during one component, and between 2 and 8s in the other component. In Phase 2, response requirement during the terminal link of the chained schedule was inverted between components relative to Phase 1. In Phase 3 the chained schedule was changed to a variable-interval 30-s, extinction 30s. Resurgence of the durations trained during Phase 1 was observed. It was concluded that duration is a response dimension that reappears during extinction. PMID- 28668349 TI - Bilateral inner ear damage after electrical injury: A case report. AB - Electrical injury occurs as a result of direct contact with an electrical source. We present the case of a 62-year-old male patient, an electrician by profession, who was hit by a high-voltage electrical current while working with cables in proximity to a wet floor. The patient suffered from immediate loss of consciousness and five days later he started complaining of slight hearing loss, persistent vertigo, instability and bilateral tinnitus. A thorough audiological and vestibular examination revealed an extensive bilateral vestibulocochlear dysfunction. The exact pathogenetic mechanisms of inner ear dysfunction after electrical injury have not been fully elucidated, although it is believed that there is significant improvement with time. Long-term follow-up, medical assistance and psychological support are crucial factors for the patient management. PMID- 28668350 TI - Unlocking the potential of anti-CD33 therapy in adult and childhood acute myeloid leukemia. AB - Acute myeloid leukemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a clinically, morphologically, and genetically heterogeneous disease, and biological differences between adult and childhood AML have been identified. AML comprises 15%-20% of all children <15 years of age diagnosed with acute leukemia. Relapse occurs in up to 40% of children with AML and is the most common cause of death. Relapse arises from leukemic stem cells (LSCs) that persist after conventional chemotherapy. The treatment of AML is challenging, and new strategies to target LSCs are required. The cell surface marker CD33 has been identified as a therapeutic target, and novel anti-CD33 immunotherapies are promising new agents in the treatment of AML. This review summarizes recent developments emphasizing the genetic differences in adult and childhood AML and highlights the rationale for CD33 as a target for therapy in all age groups. PMID- 28668351 TI - Utility of CRISPR/Cas9 systems in hematology research. AB - Since the end of the 20th century, novel approaches have emerged to manipulate experimental models of hematological disorders so that they more accurately mirror what is observed in the clinical setting. Despite these technological advances, the characterization of crucial genes for benign or malignant hematological disorders remains challenging, given the dynamic nature of the hematopoietic system and the genetic heterogeneity of these disorders. To overcome this limitation, genome-editing technologies have been developed to manipulate the genome specifically via deletion, insertion, or modification of targeted loci. These technologies have progressed swiftly, allowing their common use to investigate genetic function in experimental hematology. Among them, homologous-recombination-mediated targeting technologies have facilitated the manipulation of specific loci by generating knock-out and knock-in models. Despite promoting significant advances in our understanding of the molecular mechanisms involved in hematology, these inefficient, time-consuming, and labor intensive approaches did not permit the development of cellular or animal models, recapitulating the complexity of hematological disorders. On October 26, 2016, Drs. Ben Ebert and Chad Cowan shared their knowledge of and experience with the utilization of CRISPR for models of myeloid malignancy, disease, and novel therapeutics in an International Society for Experimental Hematology webinar titled "Utility of CRISPR/Cas9 Systems in Hematology Research." Here, we provide an overview of the topics they covered, including their insights into the novel applications of the technique and its strengths and limitations. PMID- 28668353 TI - SALSA-A dance on a slippery floor with changing partners. AB - It is becoming increasingly clear that the connections between our immune system and the microbiota colonizing us have a tremendous impact on human health. A number of innate molecular defence mechanisms cooperate to selectively target unwanted microorganisms at the mucosal surfaces. Amongst others these include the complement system, IgA and the SALSA molecule. The salivary scavenger and agglutinin (SALSA), also known as deleted in malignant brain tumors 1 (DMBT1), salivary agglutinin (SAG) or gp340 is a multifunctional molecule with important functions in innate immunity, inflammation and epithelial homeostasis. The SALSA protein is expressed at most mucosal surfaces, where it is one of the most abundant proteins. In the fetal meconium and infant intestine it may constitute even up to 10% of the total protein amount. SALSA is found either directly associated with the epithelial surface or secreted into the lining fluids. In the fluid-phase SALSA interacts with a number of bacterial and viral organisms, as well as with endogenous ligands, including IgA, lactoferrin, surfactant proteins and complement components. While complement has been shown to impact the mucosal environment, this remains an area of limited research. The multiple interactions of the SALSA molecule provide a scaffold, where this potent defence system may engage in cooperative microbial clearance together with corresponding mucosal host ligands. With its high abundance, and multiple effects on both host and microbes, the SALSA molecule is a key player in maintaining the immunological balance at the mucosal surfaces. This is further supported by observations linking the expression of different SALSA isoforms to the development of chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. This review describes the latest advances in understanding functions of SALSA and its different isoforms. Recently recognized functions are related to complement activation and regulation, endothelial development and epithelial homeostasis. In addition, we suggest mechanisms how SALSA regulates inflammation at the mucosal surfaces. PMID- 28668354 TI - The use of metabolomic quantitative trait locus mapping and osmotic adjustment traits for the improvement of crop yields under environmental stresses. AB - The sustainable production of food to feed an increasing world population is a major challenge for plant scientists, especially due to the unpredictable and dynamic nature of global climatic conditions. Heat waves, drought, increased soil salinity, unseasonal cold and flooding are all becoming more common climate related causes of stress for crop plants, and are already affecting yields and the geographical distributions of optimal growing regions for many crops. Therefore, the development and application of multi-faceted strategies, including sustainable agricultural practices and the development and cultivation of new varieties containing genetic traits associated with abiotic stress tolerance, will either alone or together be essential to sustainably grow high-yielding crops under increasingly stressful environmental conditions. The development of abiotic stress-resilient crops requires an in-depth knowledge of plant development and of the biological processes that enable plants to survive in stressful environments, and this knowledge can be obtained from "omic" studies, such as bioinformatics, genomics, transcriptomics, proteomics and metabolomics. The plant metabolome can provide a snapshot of the physiological and biochemical status of a plant cell under normal or stressful conditions, and thus it is closely related to the plant phenotypes. Analysis of the metabolomes of plants grown under stressful conditions can be used to identify stress resistance associated metabolites or biomarkers, which can then be used by plant breeders as selective markers to help identify the phenotypes, resulted from the complex interactions between genotype and environment. Osmotic adjustment is an important metabolic adaptation mechanism which helps plants survive abiotic stress and can support higher crop yield under stressful environmental conditions. This review highlights the recent advances in our understanding of the functions of abiotic stress-responsive metabolites, with an emphasis on the use of metabolomic quantitative trait locus mapping and osmotic adjustment agronomic traits, for the improvement of crop yields under environmental stresses. PMID- 28668355 TI - Cell biology of microbes and pharmacology of antimicrobial drugs explored by Atomic Force Microscopy. AB - Antimicrobial molecules have been used for more than 50 years now and are the basis of modern medicine. No surgery can nowdays be imagined to be performed without antibiotics; dreadful diseases like tuberculosis, leprosis, siphilys, and more broadly all microbial induced diseases, can be cured only through the use of antimicrobial treatments. However, the situation is becoming more and more complex because of the ability of microbes to adapt, develop, acquire, and share mechanisms of resistance to antimicrobial agents. We choose to introduce this review by briefly drawing the panorama of antimicrobial discovery and development, but also of the emergence of microbial resistance. Then we describe how Atomic Force Microscopy (AFM) can be used to provide a better understanding of the mechanisms of action of these drugs at the nanoscale level on microbial interfaces. In this section, we will address these questions: (1) how does drug treatment affect the morphology of single microbes?; (2) do antimicrobial molecules modify the nanomechanical properties of microbes, or do the nanomechanical properties of microbes play a role in antimicrobial activity and efficiency?; and (3) how are the adhesive abilitites of microbes affected by antimicrobial drugs treatment? Finally, in a second part of this review we focus on recent studies aimed at changing the paradigm of the single molecule/cell technology that AFM typically represents. Recent work dealing with the creation of a microbe array which can be explored by AFM will be presented, as these developments constitute the first steps toward transforming AFM into a higher throughput technology. We also discuss papers using AFM as NanoMechnanicalSensors (NEMS), and demonstrate the interest of such approaches in clinical microbiology to detect quickly and with high accuracy microbial resistance. PMID- 28668357 TI - COPD exacerbator phenotype: time for reassessment? PMID- 28668352 TI - The chick eye in vision research: An excellent model for the study of ocular disease. AB - The domestic chicken, Gallus gallus, serves as an excellent model for the study of a wide range of ocular diseases and conditions. The purpose of this manuscript is to outline some anatomic, physiologic, and genetic features of this organism as a robust animal model for vision research, particularly for modeling human retinal disease. Advantages include a sequenced genome, a large eye, relative ease of handling and maintenance, and ready availability. Relevant similarities and differences to humans are highlighted for ocular structures as well as for general physiologic processes. Current research applications for various ocular diseases and conditions, including ocular imaging with spectral domain optical coherence tomography, are discussed. Several genetic and non-genetic ocular disease models are outlined, including for pathologic myopia, keratoconus, glaucoma, retinal detachment, retinal degeneration, ocular albinism, and ocular tumors. Finally, the use of stem cell technology to study the repair of damaged tissues in the chick eye is discussed. Overall, the chick model provides opportunities for high-throughput translational studies to more effectively prevent or treat blinding ocular diseases. PMID- 28668358 TI - A new algebraic method for quantitative proton density mapping using multi channel coil data. AB - A difficult problem in quantitative MRI is the accurate determination of the proton density, which is an important quantity in measuring brain tissue organization. Recent progress in estimating proton density in vivo has been based on using the inverse linear relationship between the longitudinal relaxation rate T1 and proton density. In this study, the same type of relationship is being used, however, in a more general framework by constructing 3D basis functions to model the receiver bias field. The novelty of this method is that the basis functions developed are suitable to cover an entire range of inverse linearities between T1 and proton density. The method is applied by parcellating the human brain into small cubes with size 30mm x 30mm x 30mm. In each cube the optimal set of basis functions is determined to model the receiver coil sensitivities using multi-channel (32 element) coil data. For validation, we use arbitrary data from a numerical phantom where the data satisfy the conventional MR signal equations. Using added noise of different magnitude and realizations, we show that the proton densities obtained have a bias close to zero and also low noise sensitivity. The obtained root-mean-square-error rate is less than 0.2% for the estimated proton density in a realistic 3D simulation. As an application, the method is used in a small cohort of MS patients, and proton density values for specific brain structures are determined. PMID- 28668359 TI - The balance between induction and inhibition of mevalonate pathway regulates cancer suppression by statins: A review of molecular mechanisms. AB - Statins are widely used drugs for their role in decreasing cholesterol in hypercholesterolemic patients. Statins through inhibition of Hydroxy Methyl Glutaryl-CoA Reductase (HMGCR), the main enzyme of the cholesterol biosynthesis pathway, inhibit mevalonate pathway that provides isoprenoids for prenylation of different proteins such as Ras superfamily which has an essential role in cancer developing. Inhibition of the mevalonate/isoprenoid pathway is the cause of the cholesterol independent effects of statins or pleotropic effects. Depending on their penetrance into the extra-hepatic cells, statins have different effects on mevalonate/isoprenoid pathway. Lipophilic statins diffuse into all cells and hydrophilic ones use a variety of membrane transporters to gain access to cells other than hepatocytes. It has been suggested that the lower accessibility of statins for extra-hepatic tissues may result in the compensatory induction of mevalonate/isoprenoid pathway and so cancer developing. However, most of the population-based studies have demonstrated that statins have no effect on cancer developing, even decrease the risk of different types of cancer. In this review we focus on the cancer developing "potentials" and the anti-cancer "activities" of statins regarding the effects of statins on mevalonate/isoprenoid pathway in the liver and extra-hepatic tissues. PMID- 28668356 TI - Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. AB - BACKGROUND: Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. METHODS: In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post bronchodilator FEV1. Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. FINDINGS: 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (>=1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations. INTERPRETATION: Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations. FUNDING: National Institutes of Health, and National Heart, Lung, and Blood Institute. PMID- 28668360 TI - Reproductive Coercion in High School-Aged Girls: Associations with Reproductive Health Risk and Intimate Partner Violence. AB - STUDY OBJECTIVE: To determine the prevalence of reproductive coercion, a form of intimate partner violence (IPV) including contraceptive sabotage and pregnancy pressure, among urban high school-aged girls and to examine its associations with reproductive health risks. DESIGN AND SETTING: A self-administered survey completed by high school-aged girls living in high-poverty neighborhoods while awaiting medical care in a pediatric emergency room, inpatient service, school based, and hospital-based clinic. PARTICIPANTS: One hundred forty-nine sexually active girls aged 14-17 years. INTERVENTIONS AND MAIN OUTCOME MEASURES: To determine the prevalence of reproductive coercion and to examine associations with unprotected sex, sexually transmitted infections, physical IPV, and risk factors for abusive relationships. RESULTS: Twenty-nine of 149 (19%) of girls reported reproductive coercion, most frequently that a romantic or sexual partner had ever: "told them not to use any birth control" (n = 23; 79%); "took off a condom during sex so they would get pregnant" (n = 12; 43%); and "said he would leave them if they didn't get pregnant" (n = 6; 21%). Girls reporting reproductive coercion were nearly 3 times more likely than those not coerced to have had chlamydia (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.01 7.19) and nearly 5 times more likely to report IPV (OR, 4.8; 95% CI, 2.0-11.8). In addition, girls reporting coercion were less likely to have high recognition of abusive behaviors (OR, 0.10; 95% CI, 0.01-0.8) and less likely to have high comfort communicating with their sexual partners (OR, 0.32; 95% CI, 0.1-0.7) than girls not reporting coercion. CONCLUSION: Reproductive coercion is experienced by 1 in 5 high school-aged girls in a high-poverty community and is associated with chlamydia infection and IPV. Awareness of the high prevalence and health risks of coercion might allow for intervention. PMID- 28668361 TI - Synthesis and evaluation of (E)-2-(5-phenylpent-2-en-4-ynamido)cyclohex-1-ene-1 carboxylate derivatives as HCA2 receptor agonists. AB - Novel series of compounds consisting of 2-amidocyclohex-1-ene carboxylate and phenyl parts which are connected by enyne (compounds 2a-f), but-1-yne (compounds 4a-j), and phenylethylene (compounds 5a-f) linkers as HCA2 full agonists were designed and their functional activity using cAMP assay and binding affinity using radioligand (3H-niacin) binding assay were evaluated. In general, compounds of all three series exhibit similar HCA2 binding and activation profile. However, the activity is strongly dependent on the substituent at the aromatic part of the structure. Among the structures evaluated, the highest affinity and potency in all series were exhibited by compounds containing 4-hydroxy and/or 2-chloro or 2 fluoro substituents. The most active compounds in the enyne and but-1-yne series in the cAMP assay are 2-fluoro,4-hydroxy and 2-chloro,4-hydroxy phenyl derivatives 2f, 4f, and 4g showing potency similar to the previously described 4 hydroxy-biphenyl analogue 5c. PMID- 28668362 TI - [Food protein-induced enterocolitis syndrome (FPIES)]. PMID- 28668363 TI - [Antiplatelet therapy in patient undergoing angioplasty for peripheral artery disease]. AB - Antiplatelet therapy in patients undergoing PTA/Stenting for PAD relies on low quality evidences. Most interventionists provide a loading dose of clopidogrel in addition to aspirin followed by dual antiplatelet therapy for a duration of 1 to 3 months after PTA. The rational of this strategy relies mostly on the results of studies dedicated to coronary angioplasty. Ongoing trials with direct oral anticoagulants will perhaps provide new data in order to improve the practice. PMID- 28668365 TI - Recurrent neural networks as versatile tools of neuroscience research. AB - Recurrent neural networks (RNNs) are a class of computational models that are often used as a tool to explain neurobiological phenomena, considering anatomical, electrophysiological and computational constraints. RNNs can either be designed to implement a certain dynamical principle, or they can be trained by input-output examples. Recently, there has been large progress in utilizing trained RNNs both for computational tasks, and as explanations of neural phenomena. I will review how combining trained RNNs with reverse engineering can provide an alternative framework for modeling in neuroscience, potentially serving as a powerful hypothesis generation tool. Despite the recent progress and potential benefits, there are many fundamental gaps towards a theory of these networks. I will discuss these challenges and possible methods to attack them. PMID- 28668364 TI - [Health benefits of aerobic training programs in adults aged 70 or over: A systematic review]. AB - CONTEXT: Seniors represent the population where sedentary is the highest. OBJECTIVE: To evaluate of the exact health benefits of regular aerobic training (AT) in seniors aged 70 years or older. DOCUMENTARY SOURCE: Systematic review in CINAHL Plus, Embase, Medline, PubMed Central, ScienceDirect, Scopus, Sport Discus and Web of Science with a keyword search. SELECTION OF STUDIES: Two independent readers have selected randomized controlled and quasi-controlled studies and observational cohort studies published in English. RESULTS: Of 3515 articles identified, 87 studies were included in the systematic review and categorized according to the analysed outcomes. The benefits of AT are clearly demonstrated on total mortality, coronary and neurovascular disease, glucose metabolism and type 2 diabetes, blood lipid profile, body composition, blood pressure, cardiorespiratory performances, muscle strength and functional capacity, and quality of life among senior aged 70 years or more. More recently, it has shown benefits for primary and tertiary prevention of cancer and primary and secondary prevention of cognitive decline. The benefits on bone health and the risk of falling are yet to confirm. LIMITATION OF THE WORK: The data of benefits result from studies published in English only. CONCLUSION: The AT is an important determinant of health and quality of life in seniors. Its promotion in this population should be part of the continuity of efforts undertaken among younger population. Thus, seniors should be more actively encouraged to engage in training programs. PMID- 28668366 TI - Understanding and manipulating the separation in hydrophilic interaction liquid chromatography. AB - Hydrophilic interaction liquid chromatography (HILIC) has emerged as a valuable complimentary technique to reversed-phase (RP), being especially suited for the analysis of polar and ionised solutes, which are difficult to retain in RP. For solutes amenable to both separation mechanisms, HILIC provides a different selectivity to RP, and also offers possibilities as an orthogonal mechanism for 2 dimensional LC when combined with RP. HILIC has further advantages of lower column back pressures, and increased sensitivity with mobile phase evaporative detectors such as electrospray mass spectrometry. This review covers progress in our understanding of the HILIC technique, principally over the last ten years, including the classification of columns, the factors that control retention and selectivity, and attempts to model the separation process and its kinetics. PMID- 28668367 TI - Determination of aflatoxin M1 in milk and dairy products using high performance liquid chromatography-fluorescence with post column photochemical derivatization. AB - The determination of aflatoxin M1 in milk using high performance liquid chromatography with photochemical post-column derivatization and fluorescence detection is described. The samples were first extracted and clean-up using the immunoaffinity AFLATEST column originally targeted for aflatoxins B1, B2, G1 and G2. The separation of aflatoxin M1 were performed using C18 Hypersil gold (150mm*4.6mm, 5MUm) column at 40 degrees C under isocratic elution. Fluorescence detector (FLD) was set at 360nm and 440nm as excitation and emission, respectively. The use of methanol to replace acetonitrile as the mobile phase resulted in ~67% peak area enhancement of AFM1. The limit of detection (LOD) and quantification (LOQ) of the analytical method after post-column derivatization without evaporation/reconstitution with mobile phase was 0.0085MUgL-1 and 0.025MUgL-1 respectively. However, LOD and LOQ improved to 0.002 and 0.004MUgL-1 respectively with the addition of evaporation/reconstitution step. The method was statistically validated, showing linear response (R2>0.999), good recoveries (85.2-107.0%) and relative standard deviations (RSD) were found to be <=7%. The proposed method was applied to determine AFM1 contamination in various types of milk and milk products. Only 2 samples were contaminated with aflatoxin M1 (10% incidence). However, the contamination level is below the Malaysian and European legislation limits. PMID- 28668368 TI - High-throughput investigation of single and binary protein adsorption isotherms in anion exchange chromatography employing multivariate analysis. AB - The combination of multi-well plates and automated liquid handling is well suited to the rapid measurement of the adsorption isotherms of proteins. Here, single and binary adsorption isotherms are reported for BSA, ovalbumin and conalbumin on a strong anion exchanger over a range of pH and salt levels. The impact of the main experimental factors at play on the accuracy and precision of the adsorbed protein concentrations is quantified theoretically and experimentally. In addition to the standard measurement of liquid concentrations before and after adsorption, the amounts eluted from the wells are measured directly. This additional measurement corroborates the calculation based on liquid concentration data, and improves precision especially under conditions of weak or moderate interaction strength. The traditional measurement of multicomponent isotherms is limited by the speed of HPLC analysis; this analytical bottleneck is alleviated by careful multivariate analysis of UV spectra. PMID- 28668369 TI - Evaluation of a multiresidue capillary electrophoresis-quadrupole-time-of-flight mass spectrometry method for the determination of antibiotics in milk samples. AB - A selective and rapid method has been developed to determine 15 antibiotic residues (eight tetracyclines and seven quinolones) in milk samples by capillary zone electrophoresis coupled with quadrupole time-of-flight mass spectrometry (CZE-Q-TOF-MS). The use of this hybrid mass spectrometer allowed obtaining full scan and full MS/MS spectra for quantification/confirmation purposes in a single run. In addition, solid phase extraction (SPE) using the new Oasis PRiME HLB cartridge was proposed for the extraction, achieving excellent results in terms of sample throughput. The proposed method was validated using whole cow milk as representative matrix. Good linearity was obtained (R2>0.99) for all the studied compounds. The precision, expressed as relative standard deviation (%, RSD), at two concentration levels (50 and 100MUgkg-1) was below 13%. Recoveries obtained from goat milk, whole cow milk and semi-skimmed cow milk, at two concentration levels, ranged from 76 to 106%, while limits of quantification ranged from 1.5 to 9.6MUgkg-1, being lower than the established maximum residue limits in the European legislation. Matrix effect was negligible in all cases, showing that with this new SPE sorbent cleanest extracts were obtained with a minimum number of steps in the sample treatment. Thus, the proposed SPE-CZE-Q-TOF-MS method is suitable for multiclass multiresidue monitoring in different types of milk samples. PMID- 28668370 TI - Development of a conductivity-based photothermal absorbance detection microchip using polyelectrolytic gel electrodes. AB - The development and application of polyelectrolytic gel electrodes (PGEs) for a microfluidic photothermal absorbance detection system is described. The PGEs are used to measure changes in conductivity based on heat generation by analytes absorbing light and changing the solution viscosity. The PGEs are suitable for direct contact conductivity measurements since they do not degrade with exposure to high electric fields. Both a 2-electrode system with DC voltages and a 3 electrode system with AC voltages were investigated. Experimental factors including excitation voltage, excitation frequency, laser modulation frequency, laser power, and path length were tested. The limits of detection for the 3 electrode and 2-electrode systems are 500nM and 0.55nM for DABSYL-tagged glucosamine, respectively. In addition, an electrokinetic separation of a potassium, DABSYL-tagged glucosamine, Rhodamine 6G, and Rhodamine B mixture was demonstrated. PMID- 28668371 TI - The versatility of heart-cutting and comprehensive two-dimensional liquid chromatography in monoclonal antibody clone selection. AB - In recent years, two-dimensional liquid chromatography (2D-LC) has seen an enormous evolution and one of the fields where it is being widely adopted is in the analysis of therapeutic monoclonal antibodies (mAbs). We here further add to the many flavours of this powerful technology. Workflows based on heart-cutting (LC-LC) and comprehensive (LC*LC) 2D-LC are described that allow to guide the clone selection process in mAb and biosimilar development. Combining Protein A affinity chromatography in the first dimension with size exclusion (SEC), cation exchange (CEX) or reversed-phase liquid chromatography-mass spectrometry (RPLC MS) in the second dimension simultaneously allows to assess mAb titer and critical structural aspects such as aggregation, fragmentation, charge heterogeneity, molecular weight (MW), amino acid sequence and glycosylation. Complementing the LC-LC measurements at intact protein level with LC*LC based peptide mapping provides the necessary information to make clear decisions on which clones to take further into development. PMID- 28668373 TI - Corrections. PMID- 28668372 TI - [Two cases of myeloid sarcomas with review of literature]. AB - INTRODUCTION: Myeloid sarcomas are uncommon proliferations of immature myeloid cells occurring in any extramedullary organ. We report here two cases of myeloid sarcomas in patients with, respectively, a polycythemia vera and a myelodysplastic syndrome. CASE REPORTS: The first is an 81-year-old woman who presented with osteolytic lesions. Diagnosis has been highlighted using anatomopathological study after bone marrow biopsy, but it was delayed because of a very localized basin lesion and few positive myeloid markers. The second patient is an 86-year-old man who presented with pancytopenia and several lymph nodes. Lymph node cytology failed because of the rarity of blast cells. Diagnosis was done after anatomopathological study on lymph node biopsy which revealed a localized form of myeloid sarcoma. CONCLUSION: The diagnosis of myeloid sarcoma must be considered when unusual tumors occur in patients with a chronic myeloid disease. In that case, therapeutic options are those of an acute myeloid leukemia. PMID- 28668374 TI - A new non-surgical approach for deep-brain stimulation. PMID- 28668375 TI - Transient receptor potential melastatin 2 channels (TRPM2) mediate neonatal hypoxic-ischemic brain injury in mice. AB - Transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non selective cation channel, is reported to mediate brain damage following ischemic insults in adult mice. However, the role of TRPM2 channels in neonatal hypoxic ischemic brain injury remains unknown. We hypothesize that TRPM2+/- and TRPM2-/- neonatal mice have reduced hypoxic-ischemic brain injury. To study the effect of TRPM2 on neonatal brain damage, we used 2,3,5-triphenyltetrazolium chloride (TTC) staining to assess the infarct volume and whole brain imaging to assess morphological changes in the brain. In addition, we also evaluated neurobehavioral outcomes for sensorimotor function 7days following hypoxic ischemic brain injury. We report that the infarct volumes were significantly smaller and behavioral outcomes were improved in both TRPM2+/- and TRPM2-/- mice compared to that of wildtype mice. Next, we found that TRPM2-null mice showed reduced dephosphorylation of GSK-3beta following hypoxic ischemic injury unlike sham mice. TRPM2+/- and TRPM2-/- mice also had reduced activation of astrocytes and microglia in ipsilateral hemispheres, compared to wildtype mice. These findings suggest that TRPM2 channels play an essential role in mediating hypoxic ischemic brain injury in neonatal mice. Genetically eliminating TRPM2 channels can provide neuroprotection against hypoxic-ischemic brain injury and this effect is elicited in part through regulation of GSK-3beta. PMID- 28668376 TI - Clinical characteristics, beta-cell dysfunction and treatment outcomes in patients with A-beta+ Ketosis-Prone Diabetes (KPD): The first identified cohort amongst Asian Indians. AB - OBJECTIVE: Ketosis-prone diabetes (KPD), an atypical form of diabetes, has emerged as a heterogeneous syndrome in multiple ethnic groups. The objectives of this study were to look into the clinical characteristics of adult Asian Indian patients with recently diagnosed, antibody negative diabetes presenting with unprovoked ketoacidosis (A-beta+ KPD) and to determine the natural course of recovery of beta-cell functions on serial follow-up over one year. RESEARCH DESIGN AND METHODS: Newly diagnosed adult diabetes patients (n=11) with suspected KPD (A-beta+) were prospectively studied over a period of 1-year with serial evaluations of clinical, biochemical and beta-cell secretion characteristics. These were compared with a control group (n=23) of KPD (A+beta-) (classical Type 1A diabetes) with similar presentation. Beta-cell secretion was assessed by fasting and stimulated C-peptide values after a standard mixed meal challenge. Glycaemic control and treatment outcomes were also documented. RESULTS: In comparison to the A+beta- KPD controls, the A-beta+ KPD patients had a significantly older age, higher BMI, stronger family history of type 2 diabetes, more severe ketoacidosis and higher fasting and stimulated C-peptide level at presentation. On serial follow-up, the patients with KPD achieved complete recovery of their beta-cell function with remission from insulin-dependence within 3-4months without further recurrences of DKA. CONCLUSIONS: This is the first reported series of A-beta+ KPD from India. The phenotype of Indian A-beta+ KPD patients differs from their Western counterparts in that they are relatively younger and leaner, though the male preponderance and natural history of recovery of beta-cell dysfunction bears similarity. PMID- 28668377 TI - Priorities for Broadening the Malaria Vector Control Tool Kit. AB - Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) have contributed substantially to reductions in the burden of malaria in the past 15 years. Building on this foundation, the goal is now to drive malaria towards elimination. Vector control remains central to this goal, but there are limitations to what is achievable with the current tools. Here we highlight how a broader appreciation of adult mosquito behavior is yielding a number of supplementary approaches to bolster the vector-control tool kit. We emphasize tools that offer new modes of control and could realistically contribute to operational control in the next 5 years. Promoting complementary tools that are close to field-ready is a priority for achieving the global malaria-control targets. PMID- 28668378 TI - 3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release. AB - A hot melt 3D inkjet printing method with the potential to manufacture formulations in complex and adaptable geometries for the controlled loading and release of medicines is presented. This first use of a precisely controlled solvent free inkjet printing to produce drug loaded solid dosage forms is demonstrated using a naturally derived FDA approved material (beeswax) as the drug carrier and fenofibrate as the drug. Tablets with bespoke geometries (honeycomb architecture) were fabricated. The honeycomb architecture was modified by control of the honeycomb cell size, and hence surface area to enable control of drug release profiles without the need to alter the formulation. Analysis of the formed tablets showed the drug to be evenly distributed within the beeswax at the bulk scale with evidence of some localization at the micron scale. An analytical model utilizing a Fickian description of diffusion was developed to allow the prediction of drug release. A comparison of experimental and predicted drug release data revealed that in addition to surface area, other factors such as the cell diameter in the case of the honeycomb geometry and material wettability must be considered in practical dosage form design. This information when combined with the range of achievable geometries could allow the bespoke production of optimized personalised medicines for a variety of delivery vehicles in addition to tablets, such as medical devices for example. PMID- 28668379 TI - Design and optimization of PLGA microparticles for controlled and local delivery of Neuregulin-1 in traumatic spinal cord injury. AB - Spinal cord injury (SCI) results in significant tissue damage that underlies functional impairments. Pharmacological interventions to confer neuroprotection and promote cell replacement are essential for SCI repair. We previously reported that Neuregulin-1 (Nrg-1) is acutely and permanently downregulated after SCI. Nrg 1 is a critical growth factor for differentiation of neural precursor cells (NPCs) into myelinating oligodendrocytes. We showed that intrathecal delivery of Nrg-1 enhances oligodendrocyte replacement following SCI. While an effective delivery system, intrathecal and systemic administration of growth factors with diverse biological targets may pose adverse off-target effects. Here, we have developed and optimized an injectable biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles system for sustained and prolonged intraspinal delivery of Nrg-1 in SCI. Recombinant human Nrg-1beta1 peptide was encapsulated into PLGA microparticles. Optimal Nrg-1 release rate and duration were achieved by manipulating the porosity and size of PLGA particles. Our in vitro analysis showed a direct correlation between particle size and porosity with Nrg-1 release rate, while Nrg-1 loading efficiency in PLGA microparticles was inversely correlated with particle porosity. In SCI, local intraspinal injection of PLGA Nrg-1 microparticles maintained significantly higher tissue levels of Nrg-1 for a long-term duration compared to Nrg-1 delivered intrathecally by osmotic pumps. Bioactivity of Nrg-1 in PLGA microparticles was verified by promoting oligodendrocyte differentiation of NPCs in vitro, and preservation of oligodendrocytes and axons in SCI. PLGA-Nrg-1 also attenuated neuroinflammation and glial scarring following SCI. We show, for the first time, the feasibility, efficacy and safety of PLGA microparticle system for local and controlled administration of Nrg-1 in SCI. PMID- 28668380 TI - Sleep deprivation induces changes in 5-HT actions and 5-HT1A receptor expression in the rat hippocampus. AB - A 12h sleep deprivation enhances the expression of 5-hydroxytryptamine (5-HT) 1A receptors in rat hippocampus that recedes with 48h sleep recovery. The depressant effect of applied 5-HT on the field excitatory postsynaptic potentials recorded in the CA1 area, is also enhanced in hippocampi of SD rats. Following a 24 or 48h sleep recovery, the increase in the 5-HT effect subsided. These results have implications for therapeutics treating clinical depression. PMID- 28668381 TI - Imaging empathy and prosocial emotions. AB - Empathy is a multi-faceted construct with important implications for social behavior. Based on a selective review of the neuroscientific evidence collected in humans, the present paper discusses the neural representations underlying affect sharing, its relation to mentalizing, the importance of self-other distinction, the distinction between empathy, sympathy and compassion, and how these phenomena are linked to prosocial behavior. Apart from reviewing the literature, we also highlight open questions and how they might be addressed by a research approach that tries to integrate across these diverse constructs. PMID- 28668382 TI - Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders? AB - Experimental evidence supports an intricate association between inflammation and mitochondrial dysfunction as main contributors of neurological diseases. Inflammatory mediators produced by activated microglia and infiltrated immune cells trigger intracellular signalling cascades that can alter cellular mitochondrial metabolism. Cytokines, particularly tumor necrosis factor-alpha, impede mitochondrial oxidative phosphorylation and associated ATP production and instigate mitochondrial reactive oxygen species production. This culminates in mitochondrial membrane permeabilization, altered mitochondrial dynamics and might ultimately result in cell death. When severely injured mitochondria are not appropriately removed by mitophagy they can release their contents into the cytosol and extracellular environment and thereby amplify the inflammatory process. Here we provide a comprehensive overview on how inflammatory mediators impair mitochondrial metabolism and discuss how defective mitochondria can elicit and potentiate an inflammatory response. PMID- 28668383 TI - The neuroprotective effects of Berberine against amyloid beta-protein-induced apoptosis in primary cultured hippocampal neurons via mitochondria-related caspase pathway. AB - BACKGROUND AND PURPOSE: Neuronal cell apoptosis is an important pathological change in Alzheimer's disease (AD). Berberine, an isoquinoline alkaloid isolated and extracted from Coptidis and rhizome and Cortex phellodendri, has a wide range of pharmacological effects. In this study, we investigated the neuroprotective effects of Berberine against neuronal insults induced by Abeta25-35 in primary cultured hippocampal neurons. METHODS: Primary neuron cells have been isolated from hippocampus of C57BL/6 newborn mice. We investigated effect of Berberine against neuronal insults induced by Abeta25-35 in primary cultured hippocampal neurons. TdT-mediated dUTP nick-end labeling, MTT, Propidium iodide, MMP, Caspase activity measurement, Western blot. RESULT: These neurons explosure to the beta25 35 protein resulted in a loss in cell viability and a surge in apoptosis. However, the presence of Berberine significantly reversed the effects induced by Abeta25-35. Through decreasing viability and caspase activity in neurons, the pretreatment with Berberine attenuated the cytotoxic effect of the Abeta25-35. Furthermore, it's found that expression of cytochrome C, as well as the restoration of Bcl-2/Bax and Bcl-xl/Bax ratio in the presence of Berberine, led to a decline in the apoptotic rate. CONCLUSION: The neuroprotective effects of Berberine against Abeta25-35-induced neuronal apoptosis, suggesting that this may be a promising therapeutics against AD. PMID- 28668384 TI - Mitochondria in neuroinflammation - Multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS. AB - Mitochondrial dysfunction is associated with neuroinflammation and neurodegenerative disease, but its role as a driver in these processes is uncertain. Understanding the pathogenesis of inherited mitochondrial disorders may help us to uncover mechanisms involved during acquired mitochondrial dysfunction. We review the mechanisms of mitochondrial dysfunction in Leber's hereditary optic neuropathy and multiple sclerosis and discuss shared clinical and molecular features in both conditions. Targeting mitochondrial pathways involved in inflammation or apoptosis may be a possible therapeutic approach in multiple sclerosis. PMID- 28668385 TI - Driving to Cancer on a Four-Lane Expressway. AB - Recent findings from a prospective clinical study involving multiregion whole exome sequencing suggest that driver mutations in cancer-relevant genes including EGFR and TP53 are often clonal and precede whole-genome duplication events in early lung carcinogenesis. This paves an expressway to extensive subclonal diversification, elevated intratumoral heterogeneity, and dismal disease outcome. PMID- 28668387 TI - Rac1 signalling coordinates epiboly movement by differential regulation of actin cytoskeleton in zebrafish. AB - Dynamic cytoskeleton organization is essential for polarized cell behaviours in a wide variety of morphogenetic events. In zebrafish, epiboly involves coordinated cell shape changes and expansion of cell layers to close the blastopore, but many important regulatory aspects are still unclear. Especially, the spatio-temporal regulation and function of actin structures remain to be determined for a better understanding of the mechanisms that coordinate epiboly movement. Here we show that Rac1 signalling, likely functions downstream of phosphatiditylinositol-3 kinase, is required for F-actin organization during epiboly progression in zebtafish. Using a dominant negative mutant of Rac1 and specific inhibitors to block the activation of this pathway, we find that marginal contractile actin ring is sensitive to inhibition of Rac1 signalling. In particular, we identify a novel function for this actin structure in retaining the external yolk syncytial nuclei within the margin of enveloping layer for coordinated movement toward the vegetal pole. Furthermore, we find that F-actin bundles, progressively formed in the vegetal cortex of the yolk cell, act in concert with marginal actin ring and play an active role in pulling external yolk syncytial nuclei toward the vegetal pole direction. This study uncovers novel roles of different actin structures in orchestrating epiboly movement. It helps to provide insight into the mechanisms regulating cellular polarization during early development. PMID- 28668386 TI - Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. AB - BACKGROUND: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 * 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R CHOP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 on day 1, plus oral prednisone 100 mg on days 1 5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m2 and doxorubicin 70 mg/m2) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m2 and dexamethasone 4 mg/m2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m2 on day -7, intravenous cytarabine 200 mg/m2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m2 twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m2 on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005 002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018. FINDINGS: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0.65 [95% CI 0.47 0.91]; stratified log-rank test p=0.012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71 83]; HR 0.98 [0.65-1.48]; stratified log-rank test p=0.91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group. INTERPRETATION: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis. FUNDING: Fondazione Italiana Linfomi. PMID- 28668388 TI - AMPKalpha1 deficiency suppresses brown adipogenesis in favor of fibrogenesis during brown adipose tissue development. AB - Brown adipose tissue (BAT) dissipates energy for thermogenesis which reduces or prevents obesity and metabolic dysfunction. AMP-activated protein kinase (AMPK) is a master regulator of energy metabolism and its activity is inhibited in the developing BAT due to obesity. We previously found that AMPK is required for brown fat development and thermogenic function, but the non-brown adipogenic differentiation of progenitor cells due to AMPKalpha1 deficiency has not been defined. We found that, in vivo, the thermogenic capacity and morphology of BAT were compromised due to AMPK deficiency, which was correlated with decreased progenitor density in BAT. In addition, the expression of fibrogenic markers was higher in AMPK deficient compared to wild-type mice. Furthermore, we transplanted AMPKalpha1 wild-type (WT) and floxed BAT into the same recipient mice; following tamoxifen induced AMPKalpha1 knockout in floxed BAT, the fibrogenesis was enhanced compared to WT mice. Taken together, our data demonstrated that AMPKalpha1 deficiency suppressed brown adipogenesis in favor of fibrogenesis during BAT development. PMID- 28668389 TI - Inducible liver-specific overexpression of gankyrin in zebrafish results in spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma formation. AB - Liver cancer is the second leading cause of death worldwide. As such, establishing animal models of the disease is important for both basic and translational studies that move toward developing new therapies. Gankyrin is a critical oncoprotein in the genetic control of liver pathology. In order to evaluate the oncogenic role of gankyrin without cancer cell inoculation and drug treatment, we overexpressed gankyrin under the control of the fabp10a promoter. A Tet-Off system was used to drive expression in hepatocytes. At seven to twelve months of age, gankyrin transgenic fish spontaneously incurred persistent hepatocyte damage, steatosis, cholestasis, cholangitis, fibrosis and hepatic tumors. The tumors were both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). ICC is the second most frequent primary liver cancer in human patients and the first to develop in this tumor model. We further investigated the role of complement C3, a central molecule of the complement system, and found the expression levels of both in mRNA and protein are decreased during tumorigenesis. Together, these findings suggest that gankyrin can promote malignant transformation of liver cells in the context of persistent liver injury. This transformation may be related to compensatory proliferation and the inflammatory microenvironment. The observed decrease in complement C3 may allow transforming cells to escape coordinated induction of the immune response. Herein, we demonstrate an excellent zebrafish model for liver cancers that will be useful for studying the molecular mechanisms of tumorgenesis. PMID- 28668390 TI - Ser-261 phospho-regulation is involved in pS256 and pS269-mediated aquaporin-2 apical translocation. AB - Vasopressin catalyzes aquaporin-2 phosphorylation at several serine sites in the C-terminal region. Compared with Ser-256 and Ser-269 phosphorylation, the role of Ser-261 phospho-regulation on vasopressin-regulated AQP2 apical translocation is largely unknown. In addition, recent discovery of transcytotic apical delivery of AQP2 made the concept of its intracellular trafficking even more complicated. In this study, we evaluated how intact phospho-AQP2 signals fit with the transcytosis trafficking model in Madin-Darby canine kidney cells. PS256 and pS269 signals were intracellularly detectable in wild-type AQP2 at the beginning of forskolin stimulation (1 min). These phospho-signals were detectable in basolateral membranes even after 10 min of stimulation. AQP2 stably inserted in the apical membrane increased pS269 and decreased pS261 signals. In an NDI causing mutant P262L-AQP2, in which Ser-261 phospho-regulation is impaired, the pS256 and pS269 signals were detectable in the basolateral membranes with increased pS261 signals after forskolin stimulation. These results suggest that Ser-261 phospho-regulation is involved in pS256- and pS269-mediated AQP2 apical translocation. PMID- 28668391 TI - Tyro3 carboxyl terminal region confers stability and contains the autophosphorylation sites. AB - Tyro3, a member of TAM receptor tyrosine kinase family has been suggested to be autophosphorylated upon activation. In the current study we mapped the autophosphorylation sites of murine Tyro3 to tyrosine 723 and 756, with K540 being required for its kinase activity. Knockdown of Axl significantly decreases the tyrosyl-phosphorylation of Tyro3 in fibroblasts NR6WT, suggesting an interaction among the TAM family members. Interestingly, the carboxyl terminal region of Tyro3 is required for its stability in cells with a minimal length of 1 778 amino acids which is not conserved in murine Axl, a member of TAM. These data suggest that the autophosphorylation sites of TAM RTK members are unique although they share high similarity in amino acids within their carboxyl kinase domain. PMID- 28668392 TI - A novel conformation of the LC3-interacting region motif revealed by the structure of a complex between LC3B and RavZ. AB - LC3-family member proteins play a critical role in autophagy, a cellular process responsible for the degradation of massive cellular components including intracellular pathogens. A variety of molecules involved in the autophagic pathway engage in specific interactions with a unique sequence motif referred to as the LIR (LC3-interacting region) motif. Although identification of conserved structural features of LIR motifs in complex with LC3-family members has established a canonical LIR motif, atypical conformations of LIR motifs have recently been revealed. Here, we determined the three-dimensional crystal structures of LC3B in complex with three different LIR motifs of RavZ from Legionella pneumophila, an intracellular pathogen that can manipulate the host autophagy system. The tandem LIR motifs located in the N-terminal region of RavZ adopt a novel beta-sheet conformation and thus provide specific ionic interactions with LC3B in addition to canonical hydrophobic plugged-in interactions. Consequently, these motifs possess higher binding affinity to LC3 family members than canonical LIR motifs, although the tandem repeats can only bind to one LC3 molecule. These findings broaden our understanding of the functional repertoire of LIR motifs in autophagy. PMID- 28668394 TI - Colonization by the endophyte Piriformospora indica leads to early flowering in Arabidopsis thaliana likely by triggering gibberellin biosynthesis. AB - Piriformospora indica is an endophytic fungus colonizing roots of a wide variety of plants. Previous studies showed that P. indica promotes early flowering and plant growth in the medicinal plant Coleus forskohlii. To determine the impact of P. indica on flowering time in Arabidopsis, we co-cultivated the plants with P. indica under long day condition. P. indica inoculated Arabidopsis plants displayed significant early flowering phenotype. qRT-PCR analysis of colonized plants revealed an up-regulation of flowering regulatory (FLOWERING LOCUS T, LEAFY, and APETALA1) and gibberellin biosynthetic (Gibberellin 20-Oxidase2, Gibberellin 3-Oxidase1 and Gibberellin requiring1) genes, while the flowering repressing gene FLOWERING LOCUS C was down regulated. Quantification of gibberellins content showed that the colonization with P. indica caused an increase in GA4 content. Compared to wild-type plants, inoculation of the Arabidopsis ga5 mutant affected in gibberellin biosynthetic gene led to less pronounced changes in the expression of genes regulating flowering and to a lower increase in GA4 content. Taken together, our data indicate that P. indica promotes early flowering in Arabidopsis likely by increasing gibberellin content. PMID- 28668393 TI - Skin changes in streptozotocin-induced diabetic rats. AB - Diabetes can cause serious health complications, which can affect every organ of the body, including the skin. The molecular etiology has not yet been clarified for all diabetic skin conditions. Thus, this study aimed to investigate the changes of diabetes in skin compared to non-diabetic skin in rats. Fifteen days after establishing the diabetic status, skin samples from the dorsum-cervical region were harvested for subsequent analysis of alterations caused by diabetes. Our results demonstrate that diabetes stimulated higher inflammation and oxidative stress in skin, but antioxidant defense levels were lower compared to the non-diabetic group (p < 0.05). This could have been related to a decreased number of blood vessels and low expression of VEGF, eNOS and TGF-beta1. Finally, insulin signaling proteins IRS, Akt, Shc and ERK showed a low expression in the diabetic group. Thus, our study shows that the pathology of diabetes induced immunohistopathological and biochemical skin changes compared to non-diabetic skin in rats. PMID- 28668395 TI - GC-MS based metabolomics of CSF and blood serum: Metabolic phenotype for a rat model of cefoperazone-induced disulfiram-like reaction. AB - Cefoperazone is most popularly used in the treatment of complicated infections clinically. Concomitant ingestion of ethnaol and cefoperazone may cause a disulfiram-like reaction. However, very little is known about the possible interactions between cefoperazone treatment and an alcohol with regard to the induction of disulfiram-like reaction. Study of the metabolic impact of cotreatment with cefoperazone and alcohol on animals can facilitate the identification of markers relevant to disulfiram-like reaction. In this study, the serum and cerebrospinal fluid (CSF) metabolites from Sprague-Dawley rats were profiled using gas chromatography mass spectrometry. Serum levels of valine, leucine, glycine, palmitelaidic acid, and 2-hydroxyisobutyrate in combination application group were significantly higher than those in the control; while alanine and pyruvate deceased in cotreatment group. Most TCA intermediates, glutamate and aspartate had lower CSF level in combination application group, except citrate. In addition, most carbohydrates, ethylmalonate and N acetylaspartate had higher level compared with control group. These results highlight concomitant ingestion of alcohol and cefoperazone generated disulfiram like reaction by way of disrupting normal metabolic pathway. Cefoperazone magnifes ethanol-induced impairment of TCA cycle and aspartate metabolism, thereby affects energy metabolism and neural transmission. PMID- 28668396 TI - Omega-3 fatty acids promote fatty acid utilization and production of pro resolving lipid mediators in alternatively activated adipose tissue macrophages. AB - It is becoming increasingly apparent that mutual interactions between adipocytes and immune cells are key to the integrated control of adipose tissue inflammation and lipid metabolism in obesity, but little is known about the non-inflammatory functions of adipose tissue macrophages (ATMs) and how they might be impacted by neighboring adipocytes. In the current study we used metabolipidomic analysis to examine the adaptations to lipid overload of M1 or M2 polarized macrophages co incubated with adipocytes and explored potential benefits of omega-3 polyunsaturated fatty acids (PUFA). Macrophages adjust their metabolism to process excess lipids and M2 macrophages in turn modulate lipolysis and fatty acids (FA) re-esterification of adipocytes. While M1 macrophages tend to store surplus FA as triacylglycerols and cholesteryl esters in lipid droplets, M2 macrophages channel FA toward re-esterification and beta-oxidation. Dietary omega 3 PUFA enhance beta-oxidation in both M1 and M2. Our data document that ATMs contribute to lipid trafficking in adipose tissue and that omega-3 PUFA could modulate FA metabolism of ATMs. PMID- 28668397 TI - Interleukin-6, C/EBP-beta and PPAR-gamma expression correlates with intramuscular liposarcoma growth in mice: The impact of voluntary physical activity levels. AB - IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited ~6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-alpha/beta and PPAR-gamma expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-beta and PPAR-gamma exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses. PMID- 28668399 TI - Impact of statin therapy intensity on endothelial progenitor cells after percutaneous coronary intervention in diabetic patients. The REMEDY-EPC late study. AB - BACKGROUND: A low number (that is, <=0.0038 per 100 peripheral mononuclear cells) of circulating endothelial progenitor cells (EPC) is common in diabetic patients. Statins increase EPC levels. It is unclear whether intensity of statin therapy has a different impact on EPC levels. METHODS: Diabetic patients undergoing drug eluting stent (DES) implantation were randomized to 1) High intensity statin therapy (atorvastatin 80mg/day; n=66) or 2) Moderate intensity statin therapy (atorvastatin 20mg/day; n=64). EPC levels were assessed at baseline, 24h and 3months. Endpoints assessed at 3months were 1) changes in the proportion of patients with low EPC levels, and 2) uncovered struts rate and neointima growth evaluated by optical coherence tomography. RESULTS: Low EPC levels rate significantly decreased in the High intensity statin therapy group (from 31.7% to 12.7%; p=0.017) but not in the Moderate intensity statin therapy group (from 25.5% to 21.8%; p=0.81). Uncovered struts rate was similar in the 2 groups (2.4+/ 2.6% vs 2.3+/-2.2%; p=0.82), whereas mean neointima area and volume were lower in the High intensity statin therapy group (0.68+/-0.69 vs 1.22+/-1.29mm2; p=0.001; and, respectively, 13.10+/-5.77 vs 20.19+/-24.08mm3; p=0.042). CONCLUSIONS: In diabetic patients, a high intensity statin therapy 1) significantly increases EPC levels and decreases in-stent neointima area and volume, and 2) does not have an impact on the degree of stent re-endothelialization at 3months after DES implantation. PMID- 28668398 TI - Differences in endothelial dysfunction induced by paroxysmal and persistent atrial fibrillation: Insights from restoration of sinus rhythm by catheter ablation. AB - BACKGROUND: Atrial fibrillation (AF) is associated with endothelial dysfunction. Studies have shown the incidence of cardiovascular events to be greater in patients with persistent AF (PeAF) than paroxysmal AF (PAF). OBJECTIVE: The aim of this study was to investigate whether endothelial dysfunction and the impact of catheter ablation on the endothelial function differs between PAF and PeAF. METHODS: We prospectively measured the endothelial function by reactive hyperemia peripheral arterial tonometry (RH-PAT) in 103 PAF, 75 PeAF, and 51 control patients at baseline, with follow-up in the AF patients at 6 and 12months after the catheter ablation. RESULTS: The log-transformed RH-PAT index (ln RHI) was the highest in the control group, followed by the PAF and PeAF (0.67+/-0.23, 0.57+/ 0.29, and 0.45+/-0.3, respectively, p<0.001) groups. PeAF was determined to be an independent factor of endothelial dysfunction (ln RHI <0.55) even after adjustment for the conventional cardiovascular risk factors. For 12months after the catheter ablation, 102 (99%) PAF and 72 (96%) PeAF patients maintained sinus rhythm. On average, the ln RHI in the PAF group did not change during the follow up, but it significantly increased in the PeAF group to a level comparable to that of the PAF patients 6months after the catheter ablation (0.53+/-0.28, p=0.034), and maintained the same level at 12months after the catheter ablation. CONCLUSIONS: The persistent form of AF may independently contribute to endothelial dysfunction. In addition, by catheter ablation, the maintenance of sinus rhythm may protect against exacerbations of endothelial dysfunction. PMID- 28668400 TI - Idiopathic pulmonary fibrosis in the era of antifibrotic therapy: Searching for new opportunities grounded in evidence. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that up to now has been associated with a poor prognosis. However, the results of the INPULSIS and ASCEND trials and the approval of nintedanib and pirfenidone have marked the beginning of a new era for IPF patients. Questions remain, however. Should these drugs be used earlier? What effect will they have on more severe disease? Will their effects last beyond the trial period? This manuscript is the outcome of a multidisciplinary meeting between pulmonology, radiology, and pathology clinicians on the use of antifibrotic agents in IPF. In our opinion, the existing data show that pirfenidone and nintedanib slow functional decline in early stages of disease. These drugs also appear to result in therapeutic benefits when administered to patients with advanced disease at diagnosis and maintain effective over time. The data also suggest that continuing antifibrotic therapy after disease progression may confer benefits, but more evidence is needed. Early diagnosis and treatment are crucial for reducing functional decline, slowing disease progression, and improving quality of life. PMID- 28668401 TI - Quantification of aortic annulus in computed tomography angiography: Validation of a fully automatic methodology. AB - BACKGROUND: Automatic accurate measuring of the aortic annulus and determination of the optimal angulation of X-ray projection are important for the trans catheter aortic valve replacement (TAVR) procedure. The objective of this study was to present a novel fully automatic methodology for the quantification of the aortic annulus in computed tomography angiography (CTA) images. METHODS: CTA datasets of 26 patients were analyzed retrospectively with the proposed methodology, which consists of a knowledge-based segmentation of the aortic root and detection of the orientation and size of the aortic annulus. The accuracy of the methodology was determined by comparing the automatically derived results with the reference standard obtained by semi-automatic delineation of the aortic root and manual definition of the annulus plane. RESULTS: The difference between the automatic annulus diameter and the reference standard by observer 1 was 0.2+/ 1.0mm, with an inter-observer variability of 1.2+/-0.6mm. The Pearson correlation coefficient for the diameter was good (0.92 for observer 1). For the first time, a fully automatic tool to assess the optimal projection curves was presented and validated. The mean difference between the optimal projection curves calculated based on the automatically defined annulus plane and the reference standard was 6.4 degrees in the cranial/caudal (CRA/CAU) direction. The mean computation time was short with around 60s per dataset. CONCLUSION: The new fully automatic and fast methodology described in this manuscript not only provided precise measurements about the aortic annulus size with results comparable to experienced observers, but also predicted optimal X-ray projection curves from CTA images. PMID- 28668402 TI - Comparative study of post-transplant outcomes in hepatocellular carcinoma patients treated with chemoembolization or radioembolization. AB - PURPOSE: To analyze long-term outcomes in patients bridged/downstaged to orthotopic liver transplantation (OLT) by transarterial chemoembolization (TACE) or yttrium-90 radioembolization (Y90) for hepatocellular carcinoma (HCC). METHODS: 172 HCC patients who underwent OLT after being treated with transarterial liver-directed therapies (LDTs) (Y90: 93; TACE: 79) were identified. Pre-LDT and pre-OLT clinical/imaging/laboratory characteristics including United Network for Organ Sharing (UNOS) staging and alpha-fetoprotein values (AFP) were tabulated. Post-OLT HCC recurrence was assessed by imaging follow-up per standard of care. Recurrence-free (RFS) and overall survival (OS) were calculated. Uni/multivariate and sub-stratification analyses were performed. RESULTS: Time-to-OLT was longer in the Y90 group (Y90: 6.5 months; TACE: 4.8 months; p=0.02). With a median post-OLT follow-up of 26.1 months (IQR: 11.1 49.7), tumor recurrence was found in 6/79 (8%) TACE and 8/93 (9%) Y90 patients. Time-to-recurrence was 26.6 (CI: 7.0-49.5) and 15.9 months (CI: 7.8-46.8) for TACE and Y90, respectively (p=0.48). RFS (Y90: 79 months; TACE: 77 months; p=0.84) and OS (Y90: 57% alive at 100 months; TACE: 84.2 months; p=0.57) were similar. 54/155 patients (Y90: 29; TACE: 25) were downstaged to UNOS T2 or less. RFS hazard ratios for patients downstaged to <=T2 versus those that were not were 0.6 (CI: 0.33-1.1) and 1.7 (CI: 0.9-3.1) respectively (p=0.13). 17/155 patients (Y90: 8; TACE: 9) that were >T2 were downstaged to UNOS T2 or less (within transplant criteria). Distribution (unilobar/bilobar), AFP, and pre-transplant UNOS stage affected RFS on univariate analyses. CONCLUSION: Despite longer time to-OLT for Y90 patients, post-OLT outcomes were similar between patients bridged or downstaged by TACE or Y90. A trend towards improved RFS for downstaged patients was identified. PMID- 28668403 TI - F-18 FDG PET/CT metabolic tumor volume predicts overall survival in patients with disseminated epithelial ovarian cancer. AB - OBJECTIVE: We evaluated the prognostic impact of quantitative assessment by maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG) on [F-18] FDG PET/CT for patients with peritoneal carcinomatosis from epithelial ovarian cancer (EOC). METHODS: Thirty-one patients with EOC underwent PET/CT for an early restaging after cytoreductive surgery, having been diagnosed with carcinomatosis (before chemotherapy). The SUVmax, MTV (cm3; 42% threshold) and TLG (g) were registered on residual peritoneal lesions. The patients were followed up 20+/-12months thereafter. The PET/CT results were compared to overall survival (OS). RESULTS: The Kaplan-Meier survival analysis for the SUVmax did not reveal significant differences in OS (p=0.48). The MTV survival analysis showed a significant higher OS in patients presenting with a higher tumour burden than those with less tumour burden (p=0.01; 26 vs. 14 months), whereas TLG exhibited a similar trend though not significant (p=0.06). Apart from chemo-resistance, the higher the MTV, the better will be the response to chemotherapy. CONCLUSIONS: Quantitative assessment by MTV rather than by SUVmax and TLG on PET/CT may be helpful for stratifying patients who present with peritoneal carcinomatosis from EOC, in order to implement the appropriate therapeutic regimen. PMID- 28668404 TI - Differentiation and diagnosis of benign and malignant testicular lesions using 18F-FDG PET/CT. AB - OBJECTIVES: The purpose of this study was to evaluate the differential diagnostic value of 18F-fluorodeoxy glucose positron emission tomography/computed tomography (18F-FDG PET/CT) for benign and malignant testicular lesions. METHODS: The PET/CT scans of 53 patients with testicular lesions confirmed by biopsy or surgical pathology were retrospectively analyzed. There were 32 cases of malignant tumors and 21 cases of benign lesions. Differences in the maximum standardized uptake value (SUVmax) measurements and the SUVmax lesion/background ratios between benign and malignant lesions were analyzed. The diagnostic value of this PET/CT modality for the differential diagnosis of benign versus malignant testicular lesions was calculated. RESULTS: The differences in the SUVmax measurements and the SUVmax lesion/background ratios between benign and malignant lesions were statistically significant (SUVmax: Z=-4.295, p=0.000; SUVmax lesion/background ratio: Z=-5.219, p=0.000); specifically, both of these indicators were higher in malignant lesions compared to benign lesions. An SUVmax of 3.75 was the optimal cutoff value to differentiate between benign and malignant testicular lesions. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of this PET/CT modality in the differential diagnosis of benign versus malignant testicular lesions were 90.6%, 80.9%, 86.8%, 87.9%, and 85.0%, respectively. CONCLUSIONS: 18F-FDG PET/CT can accurately identify benign and malignant testicular lesions. PMID- 28668405 TI - Local breast density assessment using reacquired mammographic images. AB - PURPOSE: The aim of this paper is to evaluate the spatial glandular volumetric tissue distribution as well as the density measures provided by VolparaTM using a dataset composed of repeated pairs of mammograms, where each pair was acquired in a short time frame and in a slightly changed position of the breast. MATERIALS AND METHODS: We conducted a retrospective analysis of 99 pairs of repeatedly acquired full-field digital mammograms from 99 different patients. The commercial software VolparaTM Density Maps (Volpara Solutions, Wellington, New Zealand) is used to estimate both the global and the local glandular tissue distribution in each image. The global measures provided by VolparaTM, such as breast volume, volume of glandular tissue, and volumetric breast density are compared between the two acquisitions. The evaluation of the local glandular information is performed using histogram similarity metrics, such as intersection and correlation, and local measures, such as statistics from the difference image and local gradient correlation measures. RESULTS: Global measures showed a high correlation (breast volume R=0.99, volume of glandular tissue R=0.94, and volumetric breast density R=0.96) regardless the anode/filter material. Similarly, histogram intersection and correlation metric showed that, for each pair, the images share a high degree of information. Regarding the local distribution of glandular tissue, small changes in the angle of view do not yield significant differences in the glandular pattern, whilst changes in the breast thickness between both acquisition affect the spatial parenchymal distribution. CONCLUSIONS: This study indicates that VolparaTM Density Maps is reliable in estimating the local glandular tissue distribution and can be used for its assessment and follow-up. VolparaTM Density Maps is robust to small variations of the acquisition angle and to the beam energy, although divergences arise due to different breast compression conditions. PMID- 28668406 TI - Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients. AB - PURPOSE: Main symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before. MATERIAL AND METHODS: MRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90 degrees and 130 degrees in the vessel course was defined as tortuosity, less than 90 degrees as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS. RESULTS: The deflection angle [ degrees ] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132+/-24 vs. 177+/-6, BA/VA transition 113+/-21 vs. 152+/-13, right VA 108+/-23 vs. 156+/-13, left VA 110+/- 22 vs. 157+/-14 (all p<0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27+/-4 vs. 21+/-2, right VA 20+/-6 vs. 10+/-1, left VA 18+/-5 vs. 11+/-2 (all p<0.005). CONCLUSION: MPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events. PMID- 28668408 TI - Metal artifact reduction by dual-layer computed tomography using virtual monoenergetic images. AB - OBJECTIVE: The aim of the study was to investigate the performance and diagnostic value of metal artifact reduction in virtual monoenergetic images generated from dual-layer computed tomography (DLCT). METHODS: 35 patients that received a DLCT at the University Hospital Cologne and had an orthopedic implant in the examined region were included in this study. For each DLCT virtual monoenergetic images of different energy levels (64keV, 70keV, 105keV, 140keV, 200keV and an optimized photon energy) were reconstructed and analyzed by three blinded observers. Images were analyzed with regard to subjective criteria (extent of artifacts, diagnostic image quality) and objective criteria (width and density of artifacts). RESULTS: 21 patients had implants in the spine, 8 in the pelvis and 6 patients in the extremities. Diagnostic image quality improved significantly at high photon energies from a Likert-score of 4.3 (+/-0.83) to 2.3 (+/-1.02) and artifacts decreased significantly from a score of 4.3 (+/-0.66) to 2.6 (+/-2.57). The average optimized photon energy was 149.2+/-39.4keV. The density as well as the width of the most pronounced artifacts decreased from-374.6+/-251.89HU to -12.5+/ 205.84HU and from 14.5+/-8.74mm to 6.4+/-10.76mm, respectively. CONCLUSION: Using virtual monoenergetic images valuable improvements of diagnostic image quality can be achieved by reduction of artifacts associated with metal implants. As preset for virtual monoenergetic images, 140keV appear to provide optimal artifact reduction. In 20% of the patients, individually optimized keV can lead to a further improvement of image quality compared to 140keV. PMID- 28668407 TI - Current and cutting-edge interventions for the treatment of obese patients. AB - The number of people classified as obese, defined by the World Health Organization as having a body mass index >=30, has been rising since the 1980s. Obesity is associated with comorbidities such as hypertension, diabetes mellitus, and nonalcoholic fatty liver disease. The current treatment paradigm emphasizes lifestyle modifications, including diet and exercise; however this approach produces only modest weight loss for many patients. When lifestyle modifications fail, the current "gold standard" therapy for obesity is bariatric surgery, including Roux-en-Y gastric bypass, sleeve gastrectomy, duodenal switch, and placement of an adjustable gastric band. Though effective, bariatric surgery can have severe short- and long-term complications. To fill the major gap in invasiveness between lifestyle modification and surgery, researchers have been developing pharmacotherapies and minimally invasive endoscopic techniques to treat obesity. Recently, interventional radiologists developed a percutaneous transarterial catheter-directed therapy targeting the hormonal function of the stomach. This review describes the current standard obesity treatments (including diet, exercise, and surgery), as well as newer endoscopic bariatric procedures and pharmacotherapies to help patients lose weight. We present data from two ongoing human trials of a new interventional radiology procedure for weight loss, bariatric embolization. PMID- 28668409 TI - A BMI-adjusted ultra-low-dose CT angiography protocol for the peripheral arteries Image quality, diagnostic accuracy and radiation exposure. AB - OBJECTIVES: To investigate radiation exposure, objective image quality, and the diagnostic accuracy of a BMI-adjusted ultra-low-dose CT angiography (CTA) protocol for the assessment of peripheral arterial disease (PAD), with digital subtraction angiography (DSA) as the standard of reference. METHODS: In this prospective, IRB-approved study, 40 PAD patients (30 male, mean age 72 years) underwent CTA on a dual-source CT scanner at 80kV tube voltage. The reference amplitude for tube current modulation was personalized based on the body mass index (BMI) with 120 mAs for [BMI<=25] or 150 mAs for [2570%) was assessed by two readers independently and compared to subsequent DSA. Radiation exposure was assessed with the computed tomography dose index (CTDIvol) and the dosis-length product (DLP). Objective image quality was assessed via contrast- and signal-to-noise ratio (CNR and SNR) measurements. Radiation exposure and image quality were compared between the BMI groups and between the BMI-adjusted ultra-low-dose protocol and the low-dose institutional standard protocol (ISP). RESULTS: The BMI-adjusted ultra-low-dose protocol reached high diagnostic accuracy values of 94% for Reader 1 and 93% for Reader 2. Moreover, in comparison to the ISP, it showed significantly (p<0.001) lower CTDIvol (1.97+/-0.55mGy vs. 4.18+/-0.62 mGy) and DLP (256+/-81mGy x cm vs. 544+/-83mGy x cm) but similar image quality (p=0.37 for CNR). Furthermore, image quality was similar between BMI groups (p=0.86 for CNR). CONCLUSIONS: A CT protocol that incorporates low kV settings with a personalized (BMI-adjusted) reference amplitude for tube current modulation and iterative reconstruction enables very low radiation exposure CTA, while maintaining good image quality and high diagnostic accuracy in the assessment of PAD. PMID- 28668410 TI - Focal lesions in cirrhosis: Not always HCC. AB - Even though most hepatocellular carcinomas (HCC) develop in the setting of cirrhosis, numerous other focal liver lesions and pseudolesions may be encountered. The role of the radiologist is therefore to differentiate these lesions from HCC to avoid under- and overdiagnosis. There are several ways of classifying these lesions: those which predate the development of fibrosis and cirrhosis (cystic lesions, hemangioma), those related to or a consequence of cirrhosis (regenerative nodules, dysplastic nodules, focal fibrosis, peribiliary cysts, shunts, or even cholangiocarcinoma), and those related to the underlying cause of chronic liver disease (lymphoma). Finally, some may develop independently (liver metastases). From an imaging point of view, it is important to remember that the imaging features of pre-existing lesions are not dramatically changed by cirrhosis. Differentiating non-HCC from HCC requires not only an understanding of the multi-step process of hepatocarcinogenesis, but also the importance of medical history, and of complimentary imaging modalities, namely computed tomography (CT) and magnetic resonance imaging (MRI). This review article gives an overview of the imaging features of benign and malignant non-HCC focal liver lesions in the setting of cirrhosis, with a focus on CT and MR imaging. PMID- 28668411 TI - Functional and structural changes in gray matter of parkinson's disease patients with mild cognitive impairment. AB - BACKGROUND AND PURPOSE: Cognitive impairment is a common non-motor complication of Parkinson's disease (PD). To investigate cognitive-related changes of gray matter (GM) structure and function in PD using voxel-based morphometry (VBM) and resting state functional connectivity (RSFC). MATERIALS AND METHODS: Resting state functional magnetic resonance imaging (rs-fMRI) and 3D-T1-weighted MRI scans were obtained from 21 PD patients with mild cognitive impairment (PD-MCI), 11 PD patients with normal cognitive function (PD-NC), and 21 healthy controls (HC). Functional connectivity (FC) was analyzed by defining the posterior cingulated cortex (PCC) as the seed region. VBM was performed to assess patterns of GM atrophy. RESULTS: In PD-NC versus HC, results indicated decreased PCC-FC in the right temporal gyrus(TG) and increased PCC-FC in the left medial temporal lobe(MTL), bilateral precuneus(Pcu), and parieto-occipital junction(POJ), as well as GM atrophy in the bilateral prefrontal-striatal circuit(pFTSC), TG and Pcu. In PD-MCI versus PD-NC, decreased PCC-FC was found in the bilateral prefrontal cortex(PFC), left POJ, and right TG. In addition, PCC-FC of the bilateral Pcu and GM volume of the left MTL, bilateral TG, and PFC were positively associated with cognitive score. CONCLUSIONS: Structural and functional damage of the PFC and temporal lobe are associated with subtle cognitive decline in PD, while functional enhancement of the MTL and POJ is involved in normal cognitive function of PD. In addition, the combined application of rs-fMRI and VBM analysis might become an effective means to investigate cognitive impairment-related GM abnormalities in PD-MCI patients prior to development of dementia. PMID- 28668412 TI - Impact on mortality of coronary and non-coronary cardiovascular findings in non gated thoracic CT by malignancy status. AB - PURPOSE: The prognostic value of coronary artery calcification (CAC) assessed on non-gated thoracic CT scans has only been explored in population-based studies. We explored the impact of the presence and extension of CAC, as well as of non coronary atherosclerosis cardiovascular findings (NCACVF) in survival of patients with and without malignancies undergoing clinically indicated non-gated thoracic computed tomography (CT) scans. MATERIALS AND METHODS: Between August and December 2012, a total of 1.901 patients aged between 35 and 74 years underwent clinically indicated non-gated, non-enhanced thoracic CT scans and followed for mortality through September 2016. RESULTS: Three hundred and thirty two (17.5%), 250 (13.2%), and 329 (17.3%) patients showed CAC in 1, 2, and 3 vessels, respectively, and the remaining had no CAC. Two hundred and fifty five (13.4%) patients had evidence of extensive calcification (CACSIS>5). Only 62 (3.3%) had major NCACVF whereas 1635 (86%) had none or minimal NCACVF. After a median follow up of 3.7 (3.5-3.9) years, 217 (11.4%) deaths occurred. Age [HR 1.03 (95% CI 1.01 1.05), p=0.001], a history of malignancy [HR 8.04 (95% CI 5.95-10.9), p<0.0001], and the NCACVF class [HR 1.79 (95% CI 1.45-2.19), p<0.0001] were identified as independent predictors of death. CACSIS was found an independent predictor of death only among patients without malignancy (HR 1.10 (95% CI 1.02-1.20), p=0.019). CONCLUSIONS: In this study including clinically indicated non-gated standard thoracic CT scans, survival rates were associated to the CAC extension among patients without malignancy, and to the NCACVF class independent from the malignancy status. PMID- 28668413 TI - Comparison of 3D bone models of the knee joint derived from CT and 3T MR imaging. AB - PURPOSE: To examine whether magnetic resonance (MR) imaging can offer a viable alternative to computed tomography (CT) based 3D bone modeling. METHODS: CT and MR (SPACE, TrueFISP, VIBE) images were acquired from the left knee joint of a fresh-frozen cadaver. The distal femur, proximal tibia, proximal fibula and patella were manually segmented from the MR and CT examinations. The MR bone models obtained from manual segmentations of all three sequences were compared to CT models using a similarity measure based on absolute mesh differences. RESULTS: The average absolute distance between the CT and the various MR-based bone models were all below 1mm across all bones. The VIBE sequence provided the best agreement with the CT model, followed by the SPACE, then the TrueFISP data. The most notable difference was for the proximal tibia (VIBE 0.45mm, SPACE 0.82mm, TrueFISP 0.83mm). CONCLUSIONS: The study indicates that 3D MR bone models may offer a feasible alternative to traditional CT-based modeling. A single radiological examination using the MR imaging would allow simultaneous assessment of both bones and soft-tissues, providing anatomically comprehensive joint models for clinical evaluation, without the ionizing radiation of CT imaging. PMID- 28668414 TI - Extra-adrenal myelolipoma and extramedullary hematopoiesis: Imaging features of two similar benign fat-containing presacral masses that may mimic liposarcoma. AB - OBJECTIVE: To describe the imaging characteristics of extra-adrenal myelolipoma and mass-forming extramedullary hematopoiesis (EMH) occurring in the presacral region. MATERIALS AND METHODS: Retrospective review between 1980 and 2015 revealed 11 patients with biopsy-proven presacral extra-adrenal myelolipoma and 11 patients with presacral EMH and radiologic imaging studies. RESULTS: All cases of both myelolipoma and EMH directly abutted the anterior sacrum and were centered on the midline. Myelolipomas were round or bilobed (8/11), or were multilobulated in appearance (3/11). On CT, margins could be smooth or ill defined. On MRI, all masses were well-marginated with evidence of a "capsule". All myelolipomas showed evidence of macroscopic fat on both CT and MRI with scattered hazy and nodular soft tissue components. On MRI, all cases showed areas of high T1 signal intermixed with areas of intermediate T1 signal. On T2, all cases showed areas of low and high T2 signal. Enhancement was usually minimal or mild. Most EMH cases had a well-defined round, bilobed or macro-lobulated presacral mass (9/11); 2/11 cases were ill-defined. On CT, when a dominant fatty component was present, the soft tissue components had hazy and nodular features, similar to myelolipoma. On MRI, the masses demonstrated intermediate T1 signal, isointense to skeletal muscle with varying amounts of hyperintense T1 signal. On T2-weighted images, 3 of 4 cases showed areas of mildly hyperintense T2 signal with varying amounts of dark signal. All patients with clinically or biopsy proven EMH had a hematologic or myeloid disorder. CONCLUSION: Presacral myelolipoma and presacral EMH are two benign fat-containing masses that can present as discrete, often encapsulated, lipomatous masses with varying amounts of non-lipomatous soft tissue components and should be considered in the differential diagnosis of a well-defined fat-containing presacral mass. PMID- 28668415 TI - Bronchocele density in cystic fibrosis as an indicator of allergic broncho pulmonary aspergillosis: A preliminary study. AB - OBJECTIVE: Allergic broncho-pulmonary aspergillosis (ABPA) is a severe and under diagnosed complication of cystic fibrosis (CF). The aim of the study was to determine whether the mucus content of bronchoceles in cystic fibrosis complicated with ABPA reveals a higher density than the mucus content of non-ABPA cystic fibrosis. MATERIALS AND METHODS: We studied retrospectively 43 computed tomography scans (CT scans) of a pediatric population of cystic fibrosis patients. We measured the mucus attenuation in Hounsfield Units (HU) of all bronchoceles >5mm in diameter. RESULTS: We found bronchoceles >5mm in 13/43 patients. 5/13 patients had a positive diagnosis of ABPA. The median HU value of bronchoceles was higher in patients with than without ABPA [98 HU (26-135) vs 28 HU (10-36); P=0,02]. Moreover, all patients with a bronchocele density >36HU were ABPA positive. CONCLUSIONS: CF complicated with ABPA shows higher attenuation bronchoceles on CT scans of the chest. Systematic density measurements of bronchoceles could help to raise the difficult diagnosis of ABPA in patients suffering from cystic fibrosis. Larger series could confirm a threshold in HU which could become a new imaging criterion for the diagnosis of ABPA. PMID- 28668416 TI - Complex US adnexal masses during pregnancy: Is pelvic MR imaging accurate for characterization? AB - OBJECTIVE: To retrospectively evaluate the accuracy of pelvic magnetic resonance (MR) imaging for the characterization of complex sonographic adnexal masses discovered in women during pregnancy. STUDY DESIGN: The study population comprised 31 pregnant women (median age: 32 years (range: 19-42); mean gestation age of 16 weeks) referred to our institution for MR imaging for characterization of an adnexal mass discovered incidentally during routine ultrasound (US) for other indications. The population comprised of 31 women, with 36 adnexal lesions (mean size: 103mm [range: 20-290]), of which 27 were benign and 9 were malignant masses. Prospective US and MR reports were reviewed to determine the presence of a benign or malignant lesion. Two radiologists (R1 and R2) blinded to the final outcome, retrospectively evaluated the MR images using the criteria based on the ADNEXMR-SCORE and classified the lesion as benign or malignant. The reference standard was surgical pathology or at least a 1-year imaging follow-up. RESULTS: Prospective US and MR imaging correctly identified the diagnosis in 27/36 (75%) (95% confidence interval (CI): 58.9%-86.2%) and in 32/36 (88.9%) (95% CI: 74.6% 95.6%) of lesions, respectively. MR imaging with ADNEXMR-SCORE allowed a correct diagnosis in 32/36 (88.9%) (95% CI: 74.6%-95.6%) of lesions for R1 and in 30/36 (83.3%) (95% CI: 68.1%-92.1%) of lesions for R2. The sensitivities and specificities of MR imaging using the MR ADNEXMR-SCORE were 100% (95% CI: 70.1% 1000%) for both readers and 85.1% (95% CI: 67.5%-94%) and 77.7% (95% CI: 59.2% 89.4%) for R1 and R2, respectively. No malignancy was classified as benign using MR criteria. The reproducibility between the two readers was almost perfect, with a kappa of 0.914. CONCLUSION: MR imaging is highly accurate for the characterization of complex adnexal masses incidentally discovered during pregnancy. CLINICAL RELEVANCE: MR imaging can accurately characterize adnexal masses in pregnancy and could be useful in opting for expectant management until delivery. PMID- 28668417 TI - MR Enterography in paediatric patients with obscure gastrointestinal bleeding. AB - OBJECTIVES: To evaluate the performance of Magnetic Resonance enterography (MRE) in the diagnostic work-up of children presenting with obscure gastrointestinal bleeding (OGIB). MATERIALS AND METHODS: From January 2014 to January 2016, a single-centre prospective study was performed on all children between 0 and 16 years of age referred to the radiology department for OGIB. Each child underwent MRE examination after negative oesophagogastroduodenoscopy and ileocolonoscopy. MRE results were recorded. All patients proceeded to the related gold standard for diagnostic confirmation. RESULTS: 25 patients (mean age 10.8+/-4.5 years, range 4 months to 16 years) were included. MRE was diagnostic in 76% (19 of 25). The most frequent diagnoses were intestinal polyp (28%) and Meckel's diverticulum (16%). Sensitivity and specificity of MRE were 86% and 100% respectively. There were no reported complications during any of the examinations. CONCLUSION: MRE is a safe and accurate imaging modality in the evaluation of paediatric OGIB. Its diagnostic capability is comparable to current evidence for capsule endoscopy in this patient group. Further research with larger sample sizes and standardized control groups is warranted to improve our understanding of MRE in this application. PMID- 28668418 TI - Benign biliary diseases. AB - Benign biliary diseases include a large spectrum of congenital and acquired disorders, which have different prognosis and require different treatment management. The diagnosis may be challenging since some benign disorders may mimic malignancy. Imaging has an important role in the diagnostic process, for treatment decision and planning and in patient follow up. Magnetic resonance (MR) with magnetic resonance cholangiopancreatography (MRCP) sequences is the imaging modality of choice for biliary diseases and has demonstrated high diagnostic accuracy. Moreover, the use of a hepato-specific MR contrast agent allows morphological and functional assessment of the liver and the biliary tree improving the diagnostic performance. PMID- 28668419 TI - Dose reduction techniques in coronary calcium scoring: The effect of iterative reconstruction combined with low tube voltage on calcium scores in a thoracic phantom. AB - OBJECTIVES: To define a dose-reduced coronary calcium CT protocol that provides similar calcium score values as a conventional 120kVp protocol. METHODS: A thorax phantom containing 100 calcifications was scanned with the reference protocol (120kVp, 90 ref mAs, FBP) and 30 dose-reduced protocols (70-110kVp, 90 ref mAs, FBP and iterative reconstruction (IR) levels 1-5) with 3rd generation dual-source CT. For protocols that yielded similar detectability and calcium scores as the reference protocol, additional scans were acquired at reduced ref mAs. Kendall's taub and independent-samples-median test were used to determine trends and differences in contrast/signal-to-noise ratio (CNR and SNR), dose and calcium scores. RESULTS: The detectability and calcium scores decreased at increasing IR levels (taub<-0.825, p<0.001) and increasing tube voltage (taub<-0.679, p<0.001). For 90kVp-IR3 and 100kVp-IR1, similar detectability and calcium score was found compared to the reference protocol (p>0.206). For these protocols, lower tube currents did not affect the detectability and Agatston score (p>0.206), while CNR and SNR were similar/higher compared to the reference protocol (0.0080.05). However, none of the DTI parameters correlated with age and disease duration (P>0.05). CONCLUSIONS: Our study has demonstrated that rFOV-DTI could provide information of optic nerve damage in chronic LHON, and can serve as technique for detecting and evaluating pathological changes in the optic nerve in LHON. PMID- 28668422 TI - Effects of pure and hybrid iterative reconstruction algorithms on high-resolution computed tomography in the evaluation of interstitial lung disease. AB - OBJECTIVES: To compare image quality characteristics of high-resolution computed tomography (HRCT) in the evaluation of interstitial lung disease using three different reconstruction methods: model-based iterative reconstruction (MBIR), adaptive statistical iterative reconstruction (ASIR), and filtered back projection (FBP). METHODS: Eighty-nine consecutive patients with interstitial lung disease underwent standard-of-care chest CT with 64-row multi-detector CT. HRCT images were reconstructed in 0.625-mm contiguous axial slices using FBP, ASIR, and MBIR. Two radiologists independently assessed the images in a blinded manner for subjective image noise, streak artifacts, and visualization of normal and pathologic structures. Objective image noise was measured in the lung parenchyma. Spatial resolution was assessed by measuring the modulation transfer function (MTF). RESULTS: MBIR offered significantly lower objective image noise (22.24+/-4.53, P<0.01 among all pairs, Student's t-test) compared with ASIR (39.76+/-7.41) and FBP (51.91+/-9.71). MTF (spatial resolution) was increased using MBIR compared with ASIR and FBP. MBIR showed improvements in visualization of normal and pathologic structures over ASIR and FBP, while ASIR was rated quite similarly to FBP. MBIR significantly improved subjective image noise (P<0.01 among all pairs, the sign test), and streak artifacts (P<0.01 each for MBIR vs. the other 2 image data sets). CONCLUSION: MBIR provides high-quality HRCT images for interstitial lung disease by reducing image noise and streak artifacts and improving spatial resolution compared with ASIR and FBP. PMID- 28668423 TI - The breast lesion excision system (BLES) under stereotactic guidance cannot be used as a therapeutic tool in the excision of small areas of microcalcifications in the breast. AB - OBJECTIVE: The breast lesion excision system (BLES) is a new, automatic percutaneous breast biopsy device that excises single large specimens using radiofrequency cutting. The aim of this study was to determine whether BLES, under stereotactic guidance, can be used as a therapeutic tool in the assessment of small areas of microcalcifications in the breast by providing samples with clear margins. MATERIAL AND METHODS: In this retrospective study, 149 patients with suspicious (BIRADS 4 or 5) small areas of microcalcifications underwent stereotactic-guided BLES. Of these, 34 patients (22.8%) with microcalcifications that had a diameter smaller than the basket size (<=15mm) underwent both BLES and subsequent surgery. Histopathology findings from BLES and subsequent surgery were compared. Identical, underestimation and total excision findings were assessed. RESULTS: BLES revealed fourteen (41.1%) high-risk lesions, ten (29.4%) ductal carcinomas in situ, and ten (29.4%) invasive cancers. Identical results between BLES and surgery were seen in 17/34 (50%) lesions. Surgery confirmed total excision of BLES in 15/34 (44.1%) lesions. Underestimation was seen in 2/34 (5.8%) lesions. CONCLUSION: BLES allows accurate diagnosis of small areas of microcalcifications, with few underestimates. BLES is a diagnostic, but cannot be considered to be a therapeutic tool in the case of suspicious microcalcifications because total excision was seen in only 44.1% of these lesions. Studies are needed to address the therapeutic benefit of this procedure in solid lesions. PMID- 28668424 TI - Digital breast tomosynthesis versus full-field digital mammography-Which modality provides more accurate prediction of margin status in specimen radiography? AB - OBJECTIVES: To evaluate the reliability of tumor margin assessment in specimen radiography (SR) using digital breast tomosynthesis (DBT) and full-field digital mammography (FFDM) in comparison to postoperative histopathology margin status as the gold standard. METHODS: After ethics committee approval, 102 consecutive patients who underwent breast conservative surgery for nonpalpable proven breast cancer were prospectively included. All patients underwent ultrasound/mammography guided wire localization of their lesions. After excision, each specimen was marked for orientation and imaged using FFDM and DBT. Two blinded radiologists (R1, R2) independently analyzed images acquired with both modalities. Readers identified in which direction the lesion was closest to the specimen margin and to measure the margin width. Their findings were compared with the final histopathological analysis. True positive margin status was defined as a margin measuring <1mm for invasive cancer and 5mm for ductal carcinoma in situ (DCIS) at imaging and pathology. RESULTS: For FFDM, correct margin direction was identified in 45 cases (44%) by R1 and in 37 cases (36%) by R2. For DBT, 69 cases (68%) were correctly identified by R1 and 70 cases (69%) by R2. Overall accuracy was 40% for FFDM and 69% for DBT; the difference was statistically significant (p<0.0001). Sensitivity in terms of correct assessment of margin status was significantly better for DBT than FFDM (77% versus 62%). CONCLUSION: SR using DBT is significantly superior to FFDM regarding identification of the closest margin and sensitivity in assessment of margin status. PMID- 28668425 TI - Early liver metastases in resectable periampullary cancer: Incidence and risk factors. AB - PURPOSE: The aim of the present study was to estimate the incidence of very early hepatic metastases (HMs) (<6 months) and their imaging patterns after cephalic duodenopancreatectomy (CDP) for periampullary carcinoma (excluding duodenal carcinoma) and to identify their associated risk factors. METHODS: From January 2003 to June 2016, all patients who underwent surgical treatment for periampullary carcinoma by CDP at our institution and with adequate pre- and postoperative CT scans were included. Univariate and multivariate logistic regressions were performed to determine factors associated with very early HM and recurrence. RESULTS: Of the 132 patients included retrospectively, 27 (20.5%) patients developed HMs. The mean time to diagnosis of HM was 103.9+/-55.2days. HMs were multiple in 81.4% of cases and bilobar in 59.3% of cases; their mean maximum size was 16.7+/-12.7mm. In univariate logistic analysis, lymphovascular emboli were significantly associated with HM (p=0.02). No independent risk factors for HM were found in multivariate analysis. In multivariate logistic analysis, two independent risk factors were identified for the occurrence of early recurrence: tumor size >23mm on preoperative CT scan (OR: 3.3; 95% CI: [1.2 9.3]; p=0.02) and tumor differentiation (poor vs. good: OR 15.5; 95 CI [1.5 158.3]; moderate vs. good: OR: 17.1; 95% CI: [1.9-154.4]; p=0.04). CONCLUSIONS: Nearly one in five patients developed HM after CDP within 6 months with a highly consistent pattern. A thorough preoperative assessment, combining CT scan and MRI with a delay of less than three weeks before surgery, appears essential. A routine systematic postoperative CT scan at 8 weeks is also required prior to initiating adjuvant chemotherapy. The type of surgical intervention does not seem to be a risk factor, although the risk of HM occurrence appears to be related to the lymphovascular invasion of the tumor and maybe its degree of differentiation, elements not assessable by imaging. PMID- 28668426 TI - Fetal MRI of the central nervous system: State-of-the-art. AB - Prenatal ultrasonographic (US) examination is considered as the first tool in the assessment of fetal abnormalities. However, several large-scale studies point out that some malformations, in particular central nervous system (CNS) anomalies, are not well characterized through US. Therefore, the actual malformation severity is not always related to prenatal ultrasound (US) findings. Over the past 20 years, ultrafast Magnetic Resonance Imaging (MRI) has progressively increased as a prenatal 3rd level diagnostic technique with a good sensitivity, particularly for the study of fetal CNS malformations. In fact, CNS anomalies are the most common clinical indications for fetal MRI, representing about 80% of the total examinations. This review covers the recent literature on fetal brain MRI, with emphasis on techniques, safety and indications. PMID- 28668427 TI - Typical MR imaging findings of perianal infections in patients with hematologic malignancies. AB - OBJECTIVE: We aimed to investigate the MR imaging findings of patients with hematologic malignancies who have symptoms suggesting perianal infection and to demonstrate the importance of imaging. SUBJECTS AND METHODS: The study included 36 patients with hematologic malignancies who underwent anorectal MR imaging in our department between September 2011-May 2016. Two radiologists experienced in abdominal radiology viewed the MR images in consensus. Abscesses, fistulous or sinus tracts, signal alterations and contrast enhancement in keeping with an inflammation and edema in the perianal region were recorded. RESULTS: Perianal abscess was found in 16 of the 36 patients. In 10 of these 16 patients there was also extensive inflammatory signal alterations in perianal and/or perineal soft tissues. In six of the 36 patients perianal fistula was detected. A sinus tract was seen at the level of subcutaneous external anal sphincter in one patient. Inflammatory signal alterations in the surrounding soft tissues were present in three of these seven patients. There were abscesses in labium majus in two patients and in one patient there were perineal abscesses with accompanying inflammatory signal alterations. In six of the 36 patients no abscess or fistula/sinus tract was seen. There were only inflammatory signal alterations with contrast enhancement in perianal or subcutaneous tissues. In two patients presenting with perianal pain and hemorrhoids, minimal inflammatory changes were detected on MR images. There were two patients with normal MR imaging findings. CONCLUSION: As digital examination of the anorectum and rectoscopy are avoided in neutropenic patients, MR imaging, which clearly demonstrates the perianal pathology should be preferential. PMID- 28668428 TI - Liver MRI: From basic protocol to advanced techniques. AB - Liver MR is a well-established modality with multiparametric capabilities. However, to take advantage of its full capacity, it is mandatory to master the technique and optimize imaging protocols, apply advanced imaging concepts and understand the use of different contrast media. Physiologic artefacts although inherent to upper abdominal studies can be minimized using triggering techniques and new strategies for motion control. For standardization, the liver MR protocol should include motion-resistant T2-w sequences, in-op phase GRE T1 and T2-w fast spin echo sequences with fat suppression. Diffusion-weighted imaging (DWI) is mandatory, especially for detection of sub-centimetre metastases. Contrast enhanced MR is the cornerstone of liver MR, especially for lesion characterization. Although extracellular agents are the most extensively used contrast agents, hepatobiliary contrast media can provide an extra-layer of functional diagnostic information adding to the diagnostic value of liver MR. The use of high field strength (3T) increases SNR but is more challenging especially concerning artefact control. Quantitative MR belongs to the new and evolving field of radiomics where the use of emerging biomarkers such as perfusion or DWI can derive new information regarding disease detection, prognostication and evaluation of tumour response. This information can overcome some of the limitations of current tests, especially when using vascular disruptive agents for oncologic treatment assessment. MR is, today, a robust, mature, multiparametric imaging modality where clinical applications have greatly expanded from morphology to advanced imaging. This new concept should be acknowledged by all those involved in producing high quality, high-end liver MR studies. PMID- 28668429 TI - Diagnosis of lower gastrointestinal bleeding by multi-slice CT angiography: A meta-analysis. AB - PURPOSE: To estimate the diagnostic value of multi-slice spiral CT angiography (CTA) in lower gastrointestinal bleeding by a meta-analysis. METHODS: The relevant clinical studies on the diagnostic value of CTA were searched on PubMed, Embase and other electronic documents databases with the deadline of 2016 September. Language was limited to English. A diagnostic meta-analysis was performed by using Meta-DiSc software. The effect sizes included sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) and 95% confidence interval (CI). The Cochran-Q test and I2 statistic based on chi2 test were used for estimation of the heterogeneity. Meta-regression was performed to explore the source of heterogeneity. SROC curve was established. RESULTS: A total of 14 articles including 549 patients with lower gastrointestinal bleeding were enrolled in the meta-analysis. The combined PLR, NLR and DOR were respectively 8.149, 0.158 and 56.213. There were significant heterogeneities in all estimations but we could not find the sources by meta-regression based on study design, study location, CT slices and sample size. The AUC and Q index under the fixed effect model was respectively 0.9463 and 0.8856. CONCLUSIONS: The multi-slice CTA has high diagnostic value for lower gastrointestinal bleeding. PMID- 28668430 TI - Pixel-wise derivation of pulmonary regurgitation index could influence clinical decision: A phase-contrast MR imaging study on patients with repaired tetralogy of Fallot. AB - PURPOSE: Regurgitant fraction (RF) measured from 2D phase-contrast MRI has been used as a standard to quantitate the degree of pulmonary regurgitation and serves as a determinant indicator of prognosis for tetralogy of Fallot after surgical repair. This study demonstrated the potential underestimate of RF using the conventional definition and its impact on clinical decision when backward flow occurred during systolic periods. METHODS: Quantitative flow parameters, including forward flow volume (FFV), backward flow volume (BFV), and RF were estimated by two approaches: One derived from conventional ROI-averaged curve (bulk quantity) and the other in a pixel-wise manner to spatially reflect inhomogeneous flow profile (pixel-wise quantity). Eccentricity at systolic peak (Eccsys) was adopted as an index reflecting spatial flow inhomogeneity. RESULTS: Flow parameters derived from ROI-averaged curves on main pulmonary artery were significantly smaller than that of pixel-wise measurement (P<0.001). Difference between RFbulk and RFpx for the group of Eccsys > 0.3 appears greater compared to the group with Eccsys < 0.3. Thirteen out of 68 RF values (19%) were underrated while using bulk analysis. CONCLUSIONS: The spatial-related flow parameters showed more consistency with the qualitative flow profile pattern for pulmonary arteries, and could be a decisive complement for diagnostic classification. PMID- 28668431 TI - Image quality evaluation of dual-layer spectral detector CT of the chest and comparison with conventional CT imaging. AB - OBJECTIVES: To evaluate image quality parameters of virtual mono-energetic (MonoE) and conventional (CR) imaging derived from a dual-layer spectral detector CT (DLCT) in oncological follow-up venous phase imaging of the chest and comparison with conventional multi-detector CT (CRMDCT) imaging. MATERIALS AND METHODS: A total of 55 patients who had oncologic staging with conventional CT and DLCT of the chest in venous phase were included in this study. Established image quality parameters were derived from all datasets in defined thoracic landmarks. Attenuation, image noise, and signal-/contrast- to noise ratios (SNR, CNR) were compared between CRDLCT and MonoE as well as CRMDCT imaging. Two readers performed subjective image analysis. RESULTS: CRMDCT showed significant lower attenuation values compared to CRDLCT and MonoE at 40-70keV (p<=0.05). Moreover, MonoE at 40-70keV revealed significantly higher attenuations values compared to CRDLCT (p<0.001). Noise was statistically lower in CRMDCT compared with CRDLCT and MonoE at 40keV (11.4+/-2.3 HU vs. 12.0+/-3.1 HU vs. 11.7+/-5.2 HU; p<0.001). In contrast, all MonoE levels showed significantly lower noise levels compared to CRDLCT (p<0.001). SNR was not significantly different between CRMDCT and CRDLCT (13.5+/-3.7 vs. 14.4+/-5.3; p>0.99). SNR values were significantly increased for MonoE at 40-80keV compared to CRMDCT and CRDLCT (p<0.001). CRDLCT and MonoE (40-70keV) from DLCT revealed significantly higher CNR values than CRMDCT (p<0.001). In subjective analysis, MonoE at 40keV surpassed all other image reconstructions except for noise in MonoE at 70 keV. CONCLUSION: In dual-layer spectral detector CT, MonoE at low keV showed superior image quality compared to conventional images derived from the same system and may therefore be added to clinical routine imaging protocols. Whether MonoE reconstructions yield additional diagnostic information is still unknown. PMID- 28668433 TI - Scan time adapted contrast agent injection protocols with low volume for low-tube voltage CT angiography: An in vitro study. AB - PURPOSE: The aims of this study were twofold. First, we investigated the extent of changes in arterial peak enhancement and changes in the duration of a diagnostic arterial enhancement when small amounts of CA volumes (<=30mL) were administered at varying tube voltages. Second, we investigated how to optimize CA injection protocols for CT-angiography with long scan times at various tube voltages to achieve optimal vascular enhancement at the lowest reasonable CA dose. MATERIALS AND METHODS: Measurements were performed with a custom-made dynamic flow phantom. For CTA protocols with a short scan time, we investigated the effect of various tube voltages (70-120kVp) on the arterial enhancement profile with very small CA volumes (20 and 30mL of Iobitridol 350mg I/mL) at a flow rate of 5mL/s. For CTA protocols with a long scan time, we utilized an optimized multi-bolus technique switching rapidly between 13 "micro-boli" of CA (total, 60mL) and saline (total, 24mL) at a flow rate of 4mL/s. The peak arterial enhancement (PAE) and the time period of diagnostic aortic enhancement >=200 HU (T200) were analyzed. RESULTS: For the short scan time protocols, a diagnostic peak enhancement was achieved using 20mL of CA at 70 and 80kVp (PAE: 327+/-10 and 255+/-15 HU, respectively) or 30mL of CA at 70, 80 and 100kVp (PAE 451+/-10, 367+/-9, and 253+/-15 HU). For the long scan time, the optimized multi-bolus injection protocol extended T200 at 100kVp by 6s (40%) compared to a linear injection protocol (21+/-1s and 15+/-1s, respectively; p<0.001). CONCLUSION: Optimized CTA protocols comprising alternations of tube voltage and the CA injection protocol can save radiation doses and CA volumes at the same time. PMID- 28668432 TI - Treatment of multiple test readers in diagnostic accuracy systematic reviews-meta analyses of imaging studies. AB - OBJECTIVE: To evaluate the handling of multiple readers in imaging diagnostic accuracy systematic reviews-meta-analyses. METHODS: Search was performed for imaging diagnostic accuracy systematic reviews that performed meta-analysis from 2005-2015. Handling of multiple readers was classified as: 1) averaged; 2) 'best' reader; 3) 'most experienced' reader; 4) each reader counted individually; 5) random; 6) other; 7) not specified. Incidence and reporting of multiple reader data was assessed in primary diagnostic accuracy studies that were included in a random sample of reviews. RESULTS: Only 28/296 (9.5%) meta-analyses specified how multiple readers were handled: 7/28 averaged results, 2/28 included the best reader, 14/28 treated each reader as a separate data set, 1/28 randomly selected a reader, 4/28 used other methods. Sample of 27/268 'not specified' reviews generated 442 primary studies. 270/442 (61%) primary studies had multiple readers: 164/442 (37%) reported consensus reading, 87/442 (20%) reported inter observer variability, 9/442 (2%) reported independent datasets for each reader. 26/27 (96%) meta-analyses contained at least one primary study with multiple readers. CONCLUSIONS: Reporting how multiple readers were treated in imaging systematic reviews-meta-analyses is uncommon and method used varied widely. This may result from a lack of guidance, unavailability of appropriate statistical methods for handling multiple readers in meta-analysis, and sub-optimal primary study reporting. PMID- 28668434 TI - Clinical evaluation of whole-body oncologic PET with time-of-flight and point spread function for the hybrid PET/MR system. AB - PURPOSE: Hybrid positron emission tomography/magnetic resonance (PET/MR) imaging is a new multimodality imaging technology that can provide structural and functional information simultaneously. The aim of this study was to investigate the effects of the time-of-flight (TOF) and point-spread function (PSF) on small lesions observed in PET/MR images from clinical patient image sets. MATERIALS AND METHODS: This study evaluated 54 small lesions in 14 patients who had undergone 18F-fluorodeoxyglucose (FDG) PET/MR. Lesions up to 30mm in diameter were included. The PET data were reconstructed with a baseline ordered-subsets expectation-maximization (OSEM) algorithm, OSEM+PSF, OSEM+TOF and OSEM+TOF+PSF. PET image quality and small lesions were visually evaluated and scored by a 3 point scale. A quantitative analysis was then performed using the mean and maximum standardized uptake value (SUV) of the small lesions (SUVmean and SUVmax). The lesions were divided into two groups according to the long-axis diameter and the location respectively and evaluated with each reconstruction algorithm. We also evaluated the background signal by analyzing the SUVliver. RESULTS: OSEM+TOF+PSF provided the highest value and OSEM+TOF or PSF showed a higher value than OSEM for the visual assessment and quantitative analysis. The combination of TOF and PSF increased the SUVmean by 26.6% and the SUVmax by 30.0%. The SUVliverwas not influenced by PSF or TOF. For the OSEM+TOF+PSF model, the change in SUVmean and SUVmax for lesions <10mm in diameter was 31.9% and 35.8%, and 24.5% and 27.6% for lesions 10-30mm in diameter, respectively. The abdominal lesions obtained the higher SUV than those of chest on the images with TOF and/or PSF. CONCLUSION: Application of TOF and PSF significantly increased the SUV of small lesions in hybrid PET/MR images, potentially improving small lesion detectability. PMID- 28668435 TI - Magnetic resonance imaging in tubal and non-tubal ectopic pregnancy. AB - Ectopic pregnancy is the leading cause of pregnancy-related death in the first trimester. Ectopic pregnancy is usually diagnosed by clinical, laboratory, and sonographic findings, with implantation most commonly located in the ampullary part of the fallopian tube. However, pregnancies that develop at unusual implantation sites, such as angular, interstitial, cornual, cervical, ovarian, cesarean scar, and abdominal cavity pregnancies, may rarely occur. Although ultrasound is considered the primary pregnancy-related imaging modality, it may not be able to illustrate the implantation site in certain types of pregnancy. Magnetic resonance imaging (MRI) has gained popularity as an imaging tool for evaluating pregnant patients, and it is used as a problem-solving tool in special circumstances, including ectopic pregnancy. MRI can confirm abnormal implantation site, and distinguish rupture from nonrupture cases before management. Other benefits include absence of ionizing radiation, superb soft tissue contrast, and sensitivity sufficient for identifying hemorrhage and its stages. This article summarizes imaging findings in tubal and non-tubal ectopic pregnancy with an emphasis on the roles and protocols of MRI, key MRI features, and differential diagnosis. PMID- 28668436 TI - Diagnostic performance and reproducibility of T2w based and diffusion weighted imaging (DWI) based PI-RADSv2 lexicon descriptors for prostate MRI. AB - PURPOSE: To examine the diagnostic performance of PI-RADSv2 T2w and diffusion weighted imaging (DWI) based lexicon descriptors, inter-observer agreement for descriptor assignment and diagnostic accuracy of the PI-RADSv2 assessment categories for multiparametric prostate MRI. MATERIALS AND METHODS: 176 lesions in 79 consecutive patients are analyzed, lesions are histopathologically verified by MRI-ultrasound fusion biopsy. All lesions are rated according to the PI-RADSv2 lexicon, descriptors for T2w and DWI sequences and resulting assessment categories are assigned by two independent blinded radiologists. We perform receiver-operating-characteristic analysis using the assessment categories. To analyze inter-observer agreement, we calculate weighted kappa values for assessment category assignment and unweighted kappa values for descriptor assignment. RESULTS: PI-RADSv2 assessment categories yield an area under the curve of 0.76/0.74 (radiologist 1/radiologist 2), P >0.05. Weighted kappa for agreement is 0.601 in the peripheral zone and 0.580 in the transition zone. We detect a difference in the cancer rate for PI-RADSv2 category 3 between peripheral zone (32%) and transition zone (12%), P <0.05. We obtain moderate agreement at most for descriptor assignment with kappa values ranging from 0.082 (T2w shape in the transition zone) to 0.407 (T2w signal intensity in the peripheral zone) and 0.493 (ADC pattern in the peripheral zone). Our analysis corroborates typical descriptors for benign/malignant lesions, but also reveals insights into potential pitfalls - T2w wedge shaped lesions in the peripheral zone have a considerable cancer rate, despite being labelled category 2 in the lexicon. CONCLUSION: Agreement for descriptor assignment in the PI-RADSv2 lexicon is at most moderate in our study. Typical descriptors for benign and malignant lesions are validated, whereas the discriminatory power of some descriptors is challenged. The difference in the cancer rate for PI-RADSv2 category 3 between peripheral zone and transition zone should be considered when management recommendations are linked to assessment categories in the future. PMID- 28668437 TI - Usefulness of conventional and low-dose hydro-CT in the diagnosis of gastric tumors in comparison to endoscopy. AB - PURPOSE: The aim of this retrospective study was to evaluate the usefulness of hydro-CT in the diagnosis of gastric tumors in comparison to endoscopy. MATERIAL AND METHODS: The study involved 40 patients with a diagnosis of gastric tumor established by histopathology who underwent endoscopy and conventional or low dose hydro-CT. Hydro-CT images were retrospectively analyzed based on the consensus of two radiologists who were blinded to the endoscopy findings. The diagnostic accuracy of hydro-CT and endoscopy for the diagnosis of gastric tumors was evaluated using the results of the histopathological examination as the reference standard. RESULTS: Histopathology confirmed the presence of gastric cancer in 28 patients (70%), while gastrointestinal stromal tumors (GISTs) were recognized in the remaining 12 cases (30%). Correct diagnoses of the type of gastric tumor in hydro-CT were obtained in 37 patients (92.5%). This was not significantly different from the 85% accuracy of endoscopy. Further analysis showed that the correctness of GIST diagnosis in endoscopy and hydro-CT also did not differ significantly (91.7% and 100% respectively). The percentage of correctly diagnosed malignant lesions in hydro-CT was lower than for GISTs at 89.29%, while in endoscopy it was insignificantly lower (82.14%). The diagnostic accuracy of conventional and low-dose hydro-CT in the diagnosis of gastric tumors (95% and 90% respectively) was not significantly different. CONCLUSIONS: Conventional and low-dose hydro-CT may be a valuable non-invasive diagnostic method in the diagnosis of gastric tumors for patients who have contraindications to endoscopy or who are unable to undergo gastric biopsy. PMID- 28668438 TI - Lumbar plexus in patients with chronic inflammatory demyelinating polyneuropathy: Evaluation with 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (3D SHINKEI). AB - PURPOSE: To evaluate whether 3D SHINKEI in the lumbar plexus could identify patients with chronic inflammatory demyelinating polyneuropathy (CIDP). MATERIALS AND METHODS: Twenty-one patients with CIDP and 15 non-CIDP patients were studied in this retrospective study. The SNR, contrast-to-noise ratio (CNR), contrast ratio (CR) and the size of the lumbar ganglions and roots were measured. Statistical analyses were performed with Mann-Whitney U test and receiver operating characteristics (ROC) analysis. RESULTS: The SNRs of the ganglions and roots were larger in patients with CIDP (8.30+/-4.87 and 8.24+/-4.92) than in non CIDP patients (4.95+/-2.05 and 5.08+/-1.97, P<0.0001, respectively). The CNRs of the ganglions and roots were larger in patients with CIDP (40.79+/-43.19 and 37.16+/-48.31) than in non-CIDP patients (25.90+/-10.41 and 18.37+/-32.83, P<0.0001, respectively). The CRs of the ganglions and roots were larger in patients with CIDP (0.74+/-0.13 and 0.66+/-0.17) than in non-CIDP patients (0.72+/-0.12 and 0.50+/-0.17, P=0.004 and P<0.0001, respectively). The sizes of the ganglions and the roots were larger in patients with CIDP (6.62+/-1.81mm and 5.76+/-3.24mm) than in non-CIDP patients (5.23+/-1.17mm and 4.24+/-1.11mm, P<0.0001, respectively). ROC analysis showed the best diagnostic performance with the CNR of the roots. CONCLUSION: Patients with CIDP could be distinguished from controls on 3D SHINKEI. PMID- 28668439 TI - Brief rTMS delivered by H-Coil to a healthy volunteer induced delayed, transient hypomanic symptoms: A case report. PMID- 28668440 TI - State of the art on nailfold capillaroscopy in dermatomyositis and polymyositis. AB - OBJECTIVES: To provide an overview of the main nailfold capillaroscopy (NFC) changes described in dermatomyositis (DM) and polymyositis (PM) and to discuss the current evidence supporting its clinical relevance and applications in daily practice. METHODS: All relevant literature in the field of NFC and DM and PM published in the last 30 years has been systematically reviewed. A systematic research was performed in the electronic databases PubMed and EMBASE. RESULTS: A total of 540 publications were identified according to the proposed filters and 27 were included for the review. The articles have been critically analyzed with a focus on technical aspects, examined anatomical areas, main pathological capillaroscopy findings ,and the relationship between NFC alterations and critical parameters of DM and PM. CONCLUSIONS: The overview confirms that NFC is a safe and noninvasive tool able to help the clinician in the diagnosis of DM and PM and to better characterize the phase of disease activity of these patients. PMID- 28668441 TI - Reply to letter to the editor. PMID- 28668443 TI - Erratum to "Validation of a novel claims-based stroke severity index in patients with intracerebral hemorrhage" [J Epidemiol 27 (1) (2017) 24-29]. PMID- 28668442 TI - Resveratrol has anti-thyroid effects both in vitro and in vivo. AB - Resveratrol is a natural polyphenol with antioxidant, anti-inflammatory, and antiproliferative properties. We have shown previously that resveratrol decreases sodium/iodide symporter expression and iodide uptake in thyrocytes, both in vitro and in vivo. In the present study, we further investigated the effects of resveratrol, with evaluation of the expression of additional thyroid-specific genes in the FRTL-5 rat thyroid cell line: thyroglobulin, thyroid peroxidase, TSH receptor, Nkx2-1, Foxe1 and Pax8. We observed decreased expression of these genes in FRTL-5 cells treated with 10 MUM resveratrol. The effects of resveratrol was further evaluated in vivo using Sprague-Dawley rats treated with resveratrol 25 mg/kg body weight intraperitoneally, for 60 days. No clinical signs of hypothyroidism were seen, although the treated rats showed significant increase in thyroid size. Serum TSH and thyroid hormone levels were in the normal range, with significantly higher TSH seen in resveratrol-treated rats, compared with control rats. Histological and immunohistochemical analyses confirmed increased proliferative activity in the thyroid from resveratrol-treated rats. These data suggest that resveratrol acts as a thyroid disruptor and a goitrogen, which indicates the need for caution as a supplement and for therapeutic uses. PMID- 28668444 TI - The effect of circadian blood pressure pattern on presence of fragmented QRS complexes in hypertensive subjects. AB - The association of deteriorated circadian blood pressure (BP) variability with presence of fragmented QRS (fQRS) on electrocardiography (ECG) is not clear. The present study aims to evaluate the relationship of BP patterns with presence of fQRS on ECG. A total of 338 consecutive newly diagnosed and never treated hypertensive patients who are without left ventricular hypertrophy and underwent 24-hour ambulatory BP monitoring were enrolled. Patients were classified as dippers, nondippers, and reverse dippers according to ambulatory BP monitoring results. The groups were compared regarding frequency of fQRS on ECG. The frequency of fQRS was significantly higher in reverse dippers compared with dippers (37.7% vs. 20.6%, P = .013). In multivariate logistic regression analysis, nighttime systolic BP was found to be an independent predictor of fQRS on ECG (P < .001, 95% confidence interval = 0.901-0.955). Other predictors of fQRS were daytime diastolic BP and age. Furthermore, fQRS was found to be an independent predictor of reverse dipping BP pattern in hypertensive patients (P = .004, odds ratio: 2.416, 95% confidence interval = 1.327-4.396). In conclusion, as a marker of fibrosis and higher fibrotic burden within myocardium, fQRS may be useful to determine the high-risk hypertensive patients in the absence of left ventricular hypertrophy. PMID- 28668445 TI - Comparison of four measures in reducing length of stay in burns: An Asian centre's evolved multimodal burns protocol. AB - INTRODUCTION: Multidisciplinary burns care is constantly evolving to improve outcomes given the numerous modalities available. We examine the use of Biobrane, micrografting, early renal replacement therapy and a strict target time of surgery within 24h of burns on improving outcomes of length of stay, duration of surgery, mean number of surgeries and number of positive tissue cultures in a tertiary burns centre. METHODS: A post-implementation prospective cohort of inpatient burns patients from 2014 to 2015 (n=137) was compared against a similar pre-implementation cohort from 2013 to 2014 (n=93) using REDCAP, an electronic database. RESULTS: There was no statistically significant difference for comorbidities, age and percentage (%) TBSA between the new protocol and control groups. The protocol group had shorter mean time to surgery (23.5-38.5h) (p<0.002), 0.63 fewer operative sessions, shorter mean length of stay (11.8-16.8 days) (p<0.04), less positive tissue cultures (0.59-1.28) (p<0.03). DISCUSSION/CONCLUSION: The 4 measures of the new burns protocol improved burns care and validated the collective effort of a multi-disciplinary, multipronged burns management supported by surgeons, anesthetists, renal physicians, emergency physicians, nurses, and allied healthcare providers. Biobrane, single stage onlay micrograft/allograft, early CRRT and surgery within 24h were successfully introduced. These are useful adjuncts in the armamentarium to be considered for any burns centre. PMID- 28668446 TI - Influenza vaccine effectiveness in adults based on the rapid influenza diagnostic test results, during the 2015/16 season. AB - We assessed the influenza vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine in adult patients, in our test-negative case control design study based on the results of a rapid influenza diagnostic test. During the 2015/16 season in Japan, influenza A(H1N1)pdm09 virus and influenza B virus were epidemic. The overall adjusted VE was 44% (95% confidence interval [CI]: 13.6%-63.7%). The adjusted VE was 52.9% (95%CI: 20%-72.3%) against any influenza virus among those < 65 years of age and -5% (95%CI: 136%-53.5%) among the elderly ? 65 years of age. The adjusted VE against influenza A was 49.1% (95%CI: 13.9%-69.9%). Although the VE was 55.5% (95%CI: 14.8%-76.8%) among those <65 years of age, it was only 15.3% (95%CI: 120%-67.4%) among the elderly ? 65 years of age. The adjusted VE against influenza B was 33.8% (95%CI: 25%-64.8%) among adult patients (?16 years of age) and 46.8% (95%CI: 13%-75%) among those < 65 years of age, the VE against influenza B could not be estimated in those ?65 years of age because of the low number of elderly patients with that virus. PMID- 28668447 TI - Effect of cryopreservation on viability and growth efficiency of stromal epithelial cells derived from neonatal human thymus. AB - The thymus is the major site of T lymphocyte generation and so is critical for a functional adaptive immune system. Since, thymectomy is a component of neonatal surgery for congenital heart diseases, it provides great potential for collection and storage of thymic tissue for autologous transplantation. However, specific investigation into the optimum parameters for thymic tissue cryopreservation have not been conducted. In this research, we evaluated the effect of different cryoprotective media compositions, which included penetrating (Me2SO, glycerol) and non-penetrating (dextran-40, sucrose, hydroxyethyl starch) components, on the viability and functionality of frozen-thawed human thymic samples to select an optimal cryoprotective medium suitable for long-term storage of thymic tissue and a stromal-epithelial enriched population. Our primary focus was on receiving, low temperature storage, culturing and evaluation of thymic tissue samples from newborns and infants with congenital heart diseases, who had undergone thymectomy as a part of standard surgical procedure. Thus, this work builds the platform for autologous clinical intervention into the thymus-deficient patients with congenital heart diseases. From our data, we conclude that although there were no significant differences in efficiency of tested cryoprotective media compositions, the combination of Me2SO and dextran-40 compounds was the most suitable for long-term storage both thymic cell suspensions and thymic fragments based on the viability of CD326+ epithelial cells and stromal-epithelial cell monolayer formation. PMID- 28668448 TI - In quest of epinephrine's optimal route and dose in neonatal cardiopulmonary resuscitation-are we there yet? PMID- 28668449 TI - Outcome Evidence for Structured Pediatric to Adult Health Care Transition Interventions: A Systematic Review. AB - OBJECTIVE: To identify statistically significant positive outcomes in pediatric to-adult transition studies using the triple aim framework of population health, consumer experience, and utilization and costs of care. STUDY DESIGN: Studies published between January 1995 and April 2016 were identified using the CINAHL, Ovid MEDLINE, PubMed, Scopus, and Web of Science databases. Included studies evaluated pre-evaluation and postevaluation data, intervention and comparison groups, and randomized clinic trials. The methodological strength of each study was assessed using the Effective Public Health Practice Project Quality Assessment Tool. RESULTS: Out of a total of 3844 articles, 43 met our inclusion criteria. Statistically significant positive outcomes were found in 28 studies, most often related to population health (20 studies), followed by consumer experience (8 studies), and service utilization (9 studies). Among studies with moderate to strong quality assessment ratings, the most common positive outcomes were adherence to care and utilization of ambulatory care in adult settings. CONCLUSIONS: Structured transition interventions often resulted in positive outcomes. Future evaluations should consider aligning with professional transition guidance; incorporating detailed intervention descriptions about transition planning, transfer, and integration into adult care; and measuring the triple aims of population health, experience, and costs of care. PMID- 28668450 TI - Gastric Lesion in a Patient With Lynch Syndrome. PMID- 28668451 TI - A Rarissime Case of Abnormally Appearing Appendix. PMID- 28668452 TI - Toasted: The Perils of Home Remedy. PMID- 28668453 TI - Achalasia: It's Not All About the Lower Esophageal Sphincter. PMID- 28668454 TI - Rifaximin in Prevention of Intestinal Lesions Associated With Nonsteroidal Anti Inflammatory Drugs: Good Idea Needing Confirmation. PMID- 28668456 TI - Discussion. PMID- 28668457 TI - Surgical management of adult endocardial fibroelastosis. PMID- 28668455 TI - Polymorphisms in DENND1B gene are associated with asthma and atopy phenotypes in Brazilian children. AB - Asthma is a heterogeneous disease associated with a complex basis involving environmental factors and individual variabilities. The DENN Domain Containing 1B (DENND1B) gene has an important role on T cell receptor (TCR) down-regulation on Th2 cells and studies have shown that mutations or loss of this factor can be associated with increased Th2 responses and asthma. The aim of this work is to evaluate the association of polymorphisms in the DENND1B with asthma and allergy markers phenotypes in Brazilian children. Genotyping was performed using a commercial panel from Illumina (2.5 Human Omni bead chip) in 1309 participants of SCAALA (Social Change, Asthma, Allergy in Latin American) program. Logistic regressions for asthma and atopy markers were performed using PLINK software 1.9. The analyzes were adjusted for sex, age, helminth infections and ancestry markers. The DENND1B gene was associated with different phenotypes such as severe asthma and atopic markers (specific IgE production, skin prick test and IL-13 production). Among the 166 SNPs analyzed, 72 were associated with asthma and/or allergy markers. In conclusion, polymorphisms in the DENND1B are significantly associated with development of asthma and atopy and these polymorphisms can influence DENND1B expression and consequently, asthma. PMID- 28668459 TI - Are outcomes of thoracoabdominal aortic aneurysm repair different in men versus women? A propensity-matched comparison. AB - OBJECTIVE: Women fare worse than men after many cardiovascular operations, including coronary artery bypass grafting and valve surgery. We sought to determine whether sex affects outcomes after open thoracoabdominal aortic aneurysm repair. METHODS: We evaluated data on 3353 consecutive patients (1281 women, 38.2%) who underwent open thoracoabdominal aortic aneurysm repair between October 1986 and July 2015. We compared preoperative characteristics, surgical variables, and outcomes between men and women in the overall group. A propensity matching analysis was performed to adjust for preoperative and intraoperative differences. A multivariable analysis was conducted to identify predictors of poor outcomes using relevant preoperative and intraoperative factors. RESULTS: Men had a significantly higher prevalence of comorbid conditions, including coronary artery disease, and presented more often with dissection; women were slightly older than men (median age, 69 [62-74] years vs 67 [57-73] years; P < .001) and more often symptomatic. Men underwent extent II and IV repairs more often, whereas women more often had extent I and III repairs. The propensity analysis resulted in 958 matched pairs. Overall, women and men had similar early mortality (7.9% vs 7.2%, P = .5) and adverse event rates (14.8% vs 14.1%, P = .6), which were similar in propensity-matched groups. Multivariable analysis showed that predictors of operative death and adverse event differed between the sexes. Survival and freedom from repair failure were similar between the overall and matched groups. CONCLUSIONS: Men and women who undergo thoracoabdominal aortic aneurysm repair have similar outcomes, but there are important differences in several perioperative factors and predictors of poor outcomes. PMID- 28668458 TI - Prognostic significance of early aortic remodeling in acute uncomplicated type B aortic dissection and intramural hematoma. AB - BACKGROUND: Patients with Stanford type B aortic dissections (ADs) are at risk of long-term disease progression and late complications. The aim of this study was to evaluate the natural course and evolution of acute type B AD and intramural hematomas (IMHs) in patients who presented without complications during their initial hospital admission and who were treated with optimal medical management (MM). METHODS: Databases from 2 aortic centers in Europe and the United States were used to identify 136 patients with acute type B AD (n = 92) and acute type B IMH (n = 44) who presented without complications during their index admission and were treated with MM. Computed tomography angiography scans were available at onset (<=14 days) and during follow-up for those patients. Relevant data, including evidence of adverse events during follow-up (AE; defined according to current guidelines), were retrieved from medical records and by reviewing computed tomography scan images. Aortic diameters were measured with dedicated 3 dimensional software. RESULTS: The 1-, 2-, and 5-year event-free survival rates of patients with type B AD were 84.3% (95% confidence interval [CI], 74.4-90.6), 75.4% (95% CI, 64.0-83.7), and 62.6% (95% CI, 68.9-73.6), respectively. Corresponding estimates for IMH were 76.5% (95% CI, 57.8-87.8), 76.5% (95% CI, 57.8-87.8), and 68.9% (95% CI, 45.2-83.9), respectively. In patients with type B AD, risk of an AE increased with aortic growth within the first 6 months after onset. A diameter increase of 5 mm in the first half year was associated with a relative risk for AE of 2.29 (95% CI, 1.70-3.09) compared with the median 6 months' growth of 2.4 mm. In approximately 60% of patients with IMH, the abnormality resolved within 12 months and in the patients with nonresolving IMH, risk of an adverse event was greatest in the first year after onset and remained stable thereafter. CONCLUSIONS: More than one third of patients with initially uncomplicated type B AD suffer an AE under MM within 5 years of initial diagnosis. In patients with nonresolving IMH, most adverse events are observed in the first year after onset. In patients with type B AD an early aortic growth is associated with a greater risk of AE. PMID- 28668460 TI - It could work! PMID- 28668461 TI - Lateral cervical approach for supracricoid partial laryngectomy. AB - INTRODUCTION: The supracricoid partial laryngectomy has been described for the treatment of T3 laryngeal glottic and supraglottic tumors as well as upfront and salvage surgery. Good oncological and functional outcomes are expected, while the post-operative rehabilitation can be quite difficult for the patient. Early and late complications can occur especially in salvage surgery. Neck dissection according to the T stage is often associated with the resection of the primary tumor. OBJECTIVE: To verify the feasibility of a minimally invasive procedure for supracricoid partial laryngectomy by adopting the lateral cervical approach. METHODS/RESULTS: A 61-year old man affected by a cT3N0 glottic cancer already treated 10years prior with radiotherapy for oropharyngeal cancer underwent supracricoid laryngectomy using the lateral approach. The key point of the procedure was a subfascial dissection with the harvesting of anterior cervical flap including skin, fat, platysma, fascia superficialis, anterior jugular veins, homo- and sterno-hyoid muscles. CONCLUSION: Supracricoid laryngectomy by a lateral approach is feasible and safe; it allows to perform a simultaneous neck dissection and the removal of the entire laryngeal specimen preserving ample healthy tissue compared to the classic anterior approach. PMID- 28668462 TI - How is Europe positioned for a re-emergence of Schmallenberg virus? AB - Schmallenberg virus (SBV) caused a large scale epidemic in Europe from 2011 to 2013, infecting ruminants and causing foetal deformities after infection of pregnant animals. The main impact of the virus was financial loss due to restrictions on trade of animals, meat and semen. Although effective vaccines were produced, their uptake was never high. Along with the subsequent decline in new SBV infections and natural replacement of previously exposed livestock, this has resulted in a decrease in the number of protected animals. Recent surveillance has shown that a large population of naive animals is currently present in Europe and that the virus is circulating at a low level. These changes in animal status, in combination with favourable conditions for insect vectors, may open the door to the re-emergence of SBV and another large scale outbreak in Europe. This review details the potential and preparedness for SBV re-emergence in Europe, discusses possible co-ordinated sentinel monitoring programmes for ruminant seroconversion and the presence of SBV in the insect vectors, and provides an overview of the economic impact associated with diagnosis, control and the effects of non-vaccination. PMID- 28668463 TI - Valuing Science. PMID- 28668464 TI - Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells. AB - Mercury (Hg) has been implicated as a factor contributing to autoimmune disease in animal models and humans. However the mechanism by which this occurs has remained elusive. Since the discovery of B cells it has been appreciated by immunologists that during the normal course of B cell development, some immature B cells must be generated that produce immunoglobulin reactive to self-antigens (auto-antibodies). However in the course of normal development, the vast majority of immature auto-reactive B cells are prevented from maturing by processes collectively known as tolerance. Autoimmune disease arises when these mechanisms of tolerance are disrupted. In the B cell compartment, it is firmly established that tolerance depends in part upon negative selection of self-reactive immature (transitional type 1) B cells. In these cells negative selection depends upon signals generated by the B Cell Receptor (BCR), in the sense that those T1 B cells who's BCRs most strongly bind to, and so generate the strongest signals to self-antigens are neutralized. In this report we have utilized multicolor phosphoflow cytometry to show that in immature T1 B cells Hg attenuates signal generation by the BCR through mechanisms that may involve Lyn, a key tyrosine kinase in the BCR signal transduction pathway. We suggest that exposure to low, environmentally relevant levels of Hg, disrupts tolerance by interfering with BCR signaling in immature B cells, potentially leading to the appearance of mature auto-reactive B cells which have the ability to contribute to auto-immune disease. PMID- 28668465 TI - Screening, monitoring, prevention, prophylaxis and therapy for hepatitis B virus reactivation in patients with haematologic malignancies and patients who underwent haematologic stem cell transplantation: a systematic review. AB - BACKGROUND: The growth of new therapeutic options and practices increases the risk of hepatitis B virus (HBV) reactivation in patients with haematologic malignancies and/or patients undergoing haematologic stem cell transplantation (HSCT). OBJECTIVES: To provide a systematic review supporting recommendations for prevention, monitoring, prophylaxis and therapy of HBV reactivation in patients with haematologic malignancies and HSCT. DATA SOURCES: The systematic review was based on a strategy using PubMed and the Cochrane Library searching literature published from 1991 to December 31, 2016. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were followed. SELECTION CRITERIA: Randomized control trials, prospective and retrospective cohort studies. RISK-OF-BIAS ASSESSMENT: Cochrane Risk of Bias Tool and Newcastle Ottawa Quality Assessment Scale. RESULTS: Forty-two studies of fair or good quality were included in this systematic review. The following main results were obtained: haematologic patients should be screened for HBV before chemotherapy; HBV DNA levels should be monthly monitored in all HBV-positive patients not receiving prophylaxis; hepatitis B surface antigen (HBsAg)-positive haematologic patients and patients undergoing HSCT should receive prophylaxis and third-generation HBV drugs should be provided; and anti-hepatitis B core protein-positive lymphoma patients and patients who underwent HSCT should receive antiviral prophylaxis. CONCLUSIONS: A higher quality of evidence is needed. However, the level of evidence was sufficient to support the recommendations published in this issue of the journal. PMID- 28668466 TI - Recommendations for screening, monitoring, prevention, prophylaxis and therapy of hepatitis B virus reactivation in patients with haematologic malignancies and patients who underwent haematologic stem cell transplantation-a position paper. AB - SCOPE: Hepatitis B virus (HBV) infection reactivation is associated with high morbidity and mortality in patients with haematologic malignancy and/or haematopoietic stem cell transplantation (HSCT). However, information on this issue is limited. The scope of this position paper is to provide recommendations on HBV screening, monitoring, prophylaxis, treatment and vaccination in the patients described above. METHODS: These recommendations were developed from one meeting of experts attended by different Italian scientific societies as well as from a systematic literature review (of articles published through December 31, 2016) on HBV infection in haematologic patients and in patients who underwent haematopoietic stem cell transplantation published in the same issue of the journal. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess each recommendation's quality. QUESTIONS ADDRESSED: These recommendations provide the answers to the following questions: (a) HBV screening and monitoring: Who should be screened before chemotherapy? Which screening tests should be used? Should HBV-DNA detection be used to monitor HBV reactivation before starting antivirals? What is the best timeline to monitor HBV reactivation? (b) Prophylaxis in HBsAg-positive patients: Which antiviral drugs should be used to treat HBsAg-positive patients? How long should antiviral prophylaxis be provided to HBsAg-positive patients? (c) Prophylaxis in patients with resolved HBV infection: Which patients with resolved HBV infection should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (d) HBV infection management strategy in autologous (auto-HSCT) and allogeneic HSCT (allo-HSCT): Which HSCT recipients should receive antiviral prophylaxis? Which antiviral drug should be used? How long should antiviral prophylaxis be provided? (e) Choice of antiviral drugs in the treatment of HBV reactivation: Should third-generation anti-HBV drugs be preferred to first- or second-generation antiviral drugs in the treatment of HBV reactivation with or without hepatitis flare in haematologic patients? (f) Immunization against HBV in patients with haematologic malignancies and/or patients who underwent HSCT: Should these patients be vaccinated? Which HBV vaccination schedule should be adopted? RECOMMENDATIONS: Haematologic patients should be screened for hepatitis B surface antigen (HBsAg) plus anti-hepatitis B core protein (HBc), and HBV DNA before chemotherapy. HBV DNA levels should be monitored monthly in all HBV-positive patients who do not receive prophylaxis. HBsAg-positive haematologic patients and those undergoing HSCT should receive third-generation antiviral therapy as prophylaxis. Anti-HBc-positive lymphoma patients and those receiving HSCT should receive antiviral prophylaxis. All HBV negative haematologic patients should be vaccinated for HBV. The acquisition of data from well-designed studies is desirable in the near future. PMID- 28668467 TI - Identification of a PVL-negative SCCmec-IVa sublineage of the methicillin resistant Staphylococcus aureus CC80 lineage: understanding the clonal origin of CA-MRSA. AB - OBJECTIVES: Community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) isolates belonging to clonal complex 80 (CC80) are recognized as the European CA-MRSA. The prevailing European CA-MRSA clone carries a type IVc staphylococcal cassette chromosome mec (SCCmec) and expresses Panton-Valentine leukocidin (PVL). Recently, a significant increase of PVL-negative CC80 MRSA has been observed in Denmark. The aim of this study was to examine their genetics and epidemiology, and to compare them to the European CA-MRSA clone in order to understand the emergence of PVL-negative CC80 MRSA. METHODS: Phylogenetic analysis of the CC80 S. aureus lineage was conducted from whole-genome sequences of 217 isolates (23 methicillin-susceptible S. aureus and 194 MRSA) from 22 countries. All isolates were further genetically characterized in regard to resistance determinants and PVL carriage, and epidemiologic data were obtained for selected isolates. RESULTS: Phylogenetic analysis revealed the existence of three distinct clades of the CC80 lineage: (a) an methicillin-susceptible S. aureus clade encompassing Sub-Saharan African isolates (n = 13); (b) a derived clade encompassing the European CA-MRSA SCCmec-IVc clone (n = 185); and (c) a novel and genetically distinct clade encompassing MRSA SCCmec-IVa isolates (n = 19). All isolates in the novel clade were PVL negative, but carried remnant parts (8-12 kb) of the PVL-encoding prophage PhiSa2 and were susceptible to fusidic acid and kanamycin/amikacin. Geospatial mapping could link these isolates to regions in the Middle East, Asia and South Pacific. CONCLUSIONS: This study reports the emergence of a novel CC80 CA-MRSA sublineage, showing that the CC80 lineage is more diverse than previously assumed. PMID- 28668468 TI - Standardization of automated 25-hydroxyvitamin D assays: How successful is it? AB - OBJECTIVES: Multiple 25(OH)D assays have recently been aligned to improve comparibility. In this study we investigated the performance of these assays using both native single-donor sera with target values certified by a reference method as well as single donor sera from a heterogeneous patient population. DESIGN & METHODS: 25(OH)D levels were measured in twenty reference samples (Ref!25OHD; Labquality, Finland) using five automated methods (Lumipulse, Liaison, Cobas, iSYS and Access) and one aligned ID-XLC-MS/MS method (slope: 1,00; intercept: 0,00; R=0,996). Furthermore, 25(OH)D concentrations measured in 50 pregnant women and 52 random patients using the 5 automated assays were compared to the ID-XLC-MS/MS. In addition, Vitamin D binding protein (DBP) was measured. RESULTS: Most automated assays showed significant differences in 25(OH)D levels measured in reference samples. Slopes varied from 1,00 to 1,33, intercepts from -5.48 to -15,81nmol/L and the R from 0,971 to 0,997. This inaccuracy was even more prominent in a heterogeneous patient population. Slopes varied from 0,75 to 1,35, intercepts from -9.02 to 11,51nmol/L and the R from 0,840 to 0,949. For most assays the deviation in 25(OH)D concentration increased with elevating DBP concentrations suggesting that DBP might be one of the factors contributing to the inaccuracy in currently used automated 25(OH)D methods. CONCLUSIONS: Despite the use of standardized assays, we observed significant differences in 25(OH)D concentrations in some automated methods using reference material obtained from healthy single donor sera. In sera of a patient population this inaccuracy was even worse which is highly concerning as patient samples are being investigated in clinical laboratories. PMID- 28668469 TI - The role of elevated serum procalcitonin in neuroendocrine neoplasms of digestive system. AB - INTRODUCTION: Elevated serum procalcitonin (PCT) was reported in patients with certain type of neuroendocrine neoplasms (NENs). OBJECTIVE: The aim of this study was to assess the role of elevated serum PCT in NENs from digestive system. PATIENTS AND METHODS: Serum PCT and serum CgA level were measured in 155 patients with NENs from digestive system. RESULTS: Elevated serum PCT was found in 63 patients (40.6%). Grade 3 disease was a significant factor associated with elevated serum PCT (OR, 9.24; 95%CI, 3.04-28.08; P<0.001). Serum PCT level was significantly decreased after treatment both in patients with stable disease (P=0.003) and patients with partial remission (P=0.001). In these patients, serum PCT level significantly increased again at the time of progression disease (P=0.001). Elevated serum PCT was a significant factor of worse survival (HR, 2.86; 95%CI, 1.36-6.03; P=0.006). Compared with patients with normal serum PCT and CgA level, patients with either PCT or CgA elevated and patients with both PCT and CgA elevated had progressively worse survival. Additionally, PCT expression in tumor cells was found in 24.0% of patients but did not correlate with other clinicopathological factors, including serum PCT. CONCLUSIONS: Serum PCT is elevated in part of patients with NENs of digestive system, especially in patients with grade 3 disease. Serum PCT level can help evaluate treatment response and its elevation indicates poor prognosis. Combination of serum PCT and CgA can improve outcome prediction. PMID- 28668470 TI - Estimating the solute transport parameters of the spatial fractional advection dispersion equation using Bees Algorithm. AB - This study represents the first attempt to estimate the solute transport parameters of the spatial fractional advection-dispersion equation using Bees Algorithm. The numerical studies as well as the experimental studies were performed to certify the integrity of Bees Algorithm. The experimental ones were conducted in a sandbox for homogeneous and heterogeneous soils. A detailed comparative study was carried out between the results obtained from Bees Algorithm and those from Genetic Algorithm and LSQNONLIN routines in FracFit toolbox. The results indicated that, in general, the Bees Algorithm much more accurately appraised the sFADE parameters in comparison with Genetic Algorithm and LSQNONLIN, especially in the heterogeneous soil and for alpha values near to 1 in the numerical study. Also, the results obtained from Bees Algorithm were more reliable than those from Genetic Algorithm. The Bees Algorithm showed the relative similar performances for all cases, while the Genetic Algorithm and the LSQNONLIN yielded different performances for various cases. The performance of LSQNONLIN strongly depends on the initial guess values so that, compared to the Genetic Algorithm, it can more accurately estimate the sFADE parameters by taking into consideration the suitable initial guess values. To sum up, the Bees Algorithm was found to be very simple, robust and accurate approach to estimate the transport parameters of the spatial fractional advection-dispersion equation. PMID- 28668471 TI - The broad spectrum of signaling pathways regulated by unfolded protein response in neuronal homeostasis. AB - The protein folding capabilities in the endoplasmic reticulum (ER) are disturbed by alternations in the cellular homeostasis such as the disruption of calcium ion homeostasis, the expression of mutated proteins and oxidative stress. In response to these ER dysfunctions, eukaryotic cells activate canonical branches of signal transduction cascades to restore the protein folding capacity and avoid irreversible damages, collectively termed the unfolded protein response (UPR). Prolonged ER dysfunctions and the downregulation of UPR signaling pathways have been accepted as a crucial trigger for the pathogenesis of various neurodegenerative diseases. Furthermore, recent studies have revealed that the UPR has a wide spectrum of signaling pathways for unique physiological roles in the diverse developmental, differential and lipidomic processes. A developed and intricate ER network exists in the neurites of neurons. Neuronal ER functions and ER-derived signaling mediate efficient communication between cell soma and distal sites through local protein synthesis, sorting and lipogenesis. However, relevant of ER-derived UPR signaling pathways in the elaborate mechanisms regulating neuronal activities, synaptic functions and protective responses against injury is not fully elucidated. In this review, we summarized our current understanding of how the UPR functions provide the appropriate signals for neuronal capabilities. We also reviewed how UPR dysfunctions lead to the pathogenesis of neurodegenerative diseases, and the possibilities ameliorating their toxic effects by targeting UPR components. PMID- 28668472 TI - Phase I dose escalation study of concurrent palliative radiation therapy with sorafenib in three anatomical cohorts (Thorax, Abdomen, Pelvis): The TAP study. AB - BACKGROUND AND PURPOSE: To evaluate the tolerability and maximum tolerated dose (MTD) of sorafenib administered concurrently with palliative radiotherapy. MATERIAL AND METHODS: In patients with incurable cancer, sorafenib was escalated independently in three cohorts based on irradiation site: thorax, abdomen or pelvis. Sorafenib was administered days 1-28 and radiotherapy (30Gy in 10 fractions) was delivered days 8-12 and 15-19. Dose-limiting toxicities (DLT) were acute grade 3+ toxicities attributable to radiotherapy. RESULTS: For the thorax, abdomen and pelvis cohorts, 14, 16 and 4 patients were recruited, and Dose Levels 3, 3 and 2 were reached, respectively. Sorafenib-related systemic toxicity led to significant sorafenib interruption in 10 patients. There were 3 DLTs in total, one per cohort: grade 3 oesophagitis (thoracic), transaminase elevation (abdominal) and grade 5 bowel perforation (pelvic; patient with tumour invading bowel). Grade 2 radiation dermatitis developed in 12 patients. The trial was terminated early as slow accrual and sorafenib-related systemic toxicity prevented efficient evaluation of RT-related DLTs. CONCLUSIONS: The MTD of sorafenib when used with 30Gy in 10 fractions was not established due to sorafenib-related systemic toxicity. Severe radiotherapy-related toxicities were also observed. These events suggest this concurrent combination does not warrant further study. PMID- 28668473 TI - Multiple recurrences require long-term follow-up in patients diagnosed with spindle cell oncocytoma of the sella turcica. AB - Spindle cell oncocytoma (SCO) of the sella turcica is characterized as a WHO grade I non-endocrine neoplasm of the sella turcica. Histologically, these tumors contain spindled and variably oncocytic cellular processes. Although SCOs lack immunoreactivity for neuroendocrine markers and pituitary hormones, they are clinically indistinguishable from non-functioning pituitary adenomas. In contrast to the initially described benign clinical course, several reports have subsequently illustrated cases with multiple recurrences with or without histological features of anaplasia in the form of nuclear pleomorphism, frequent mitoses, high Ki-67 index, and/or necrosis. With a follow-up of 14years, we report a case of SCO with multiple recurrences along with an exhaustive clinico pathological review of all 41 cases of SCO reported in the literature, of which recurrence has been described in 11 cases. Collectively, this report highlights the importance of long-term follow-up and the possible need for adjuvant radiotherapy in patients diagnosed with a sellar SCO and provides a comprehensive review of this rare nonadenomatous sellar tumor. PMID- 28668475 TI - Recent progress in theranostic applications of hybrid gold nanoparticles. AB - A significant area of research is theranostic applications of nanoparticles, which involves efforts to improve delivery and reduce side effects. Accordingly, the introduction of a safe, effective, and, most importantly, renewable strategy to target, deliver and image disease cells is important. This state-of-the-art review focuses on studies done from 2013 to 2016 regarding the development of hybrid gold nanoparticles as theranostic agents in the diagnosis and treatment of cancer and infectious disease. Several syntheses (chemical and green) methods of gold nanoparticles and their applications in imaging, targeting, and delivery are reviewed; their photothermal efficiency is discussed as is the toxicity of gold nanoparticles. Owing to the unique characterizations of hybrid gold nanoparticles and their potential to be developed as multifunctional, we predict they will present an undeniable role in clinical studies and provide treatment platforms for various diseases. Thus, their clearance and interactions with extra- and intra-cellular molecules need to be considered in future projects. PMID- 28668474 TI - Dermal Blimp1 Acts Downstream of Epidermal TGFbeta and Wnt/beta-Catenin to Regulate Hair Follicle Formation and Growth. AB - B-lymphocyte-induced maturation protein 1 (Blimp1) is a transcriptional repressor that regulates cell growth and differentiation in multiple tissues, including skin. Although in the epidermis Blimp1 is important for keratinocyte and sebocyte differentiation, its role in dermal fibroblasts is unclear. Here we show that Blimp1 is dynamically regulated in dermal papilla cells during hair follicle (HF) morphogenesis and the postnatal hair cycle, preceding dermal Wnt/beta-catenin activation. Blimp1 ablation in E12.5 mouse dermal fibroblasts delayed HF morphogenesis and growth and prevented new HF formation after wounding. By combining targeted quantitative PCR screens with bioinformatic analysis and experimental validation we demonstrated that Blimp1 is both a target and a mediator of key dermal papilla inductive signaling pathways including transforming growth factor-beta and Wnt/beta-catenin. Epidermal overexpression of stabilized beta-catenin was able to override the HF defects in Blimp1 mutant mice, underlining the close reciprocal relationship between the dermal papilla and adjacent HF epithelial cells. Overall, our study reveals the functional role of Blimp1 in promoting the dermal papilla inductive signaling cascade that initiates HF growth. PMID- 28668476 TI - Conventional and microwave-assisted synthesis of new 1H-benzimidazole thiazolidinedione derivatives: A potential anticancer scaffold. AB - A series of new benzimidazole bearing thiazolidinedione derivatives has been designed, synthesized by using conventional as well as microwave-assisted methods. Microwave-assisted synthesis caused a significant reduction in the reaction times and improvement in the yields of all the derivatives. All the new synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines of breast (MDAMB-231), prostate (PC-3), cervical (HeLa), lung (A549) and bone (HT1080) along with a normal kidney cells (HeK-293T). The compounds 17n, 17p and 17q were found to be potent cytotoxic with IC50 values in the range of 0.096-0.63 MUM on PC-3, HeLa, A549 and HT1080 cancer cells. Most of the compounds have found to be safe on normal HeK-293T kidney cells in comparison to cancer cells. The treatment of cells with 17p and 17q showed the typical apoptotic morphological features like fragmentation and shrinkage of nuclei. Further, test compounds resulted in inhibition of cell migration through disruption of F-actin protein assembly. Hoechst, DCFH-DA staining, mitochondrial membrane and annexin binding assays revealed that the cancer cell proliferation was inhibited through induction of apoptosis in A549 cells. PMID- 28668477 TI - Cyclometalated iridium(III)-guanidinium complexes as mitochondria-targeted anticancer agents. AB - Guanidinium-functionalized molecules are commonly studied for their use as pharmaceutically active compounds and drugs carriers. Herein, four cyclometalated iridium(III) complexes containing guanidinium ligands have been synthesized and characterized as potential anticancer agents. These complexes exhibit moderate antitumor activity in HeLa, MCF-7, HepG2, CNE-2, and A549 human tumor cells. Interestingly, all complexes showed higher cytotoxicity than cisplatin against a cisplatin-resistant cell line A549R, and less cytotoxicity on the nontumorigenic LO2 cells. Intracellular distribution studies suggest that these complexes are selectively localized in the mitochondria. Mechanism studies indicate that these complexes arrested the cell cycle in the G0/G1 phase and can influence mitochondrial integrity, inducing cancer cell death through reactive oxygen species (ROS)-dependent pathways. PMID- 28668478 TI - Preliminary evidence of polymorphisms of cell cycle regulatory genes and their roles in urinary tract urothelial cancer susceptibility and prognosis in a Taiwan population. AB - OBJECTIVE: Our aims were to investigate the correlations between polymorphisms in the cell cycle regulatory genes (aurora kinase A [AURKA], survivin, p21, and p53) and UC risk and prognosis. PATIENTS AND METHODS: This study recruited 185 patients with UTUC, 46 patients with bladder cancer, and 188 hospital controls. Demographic data and possible confounding factors were collected using a standardized questionnaire. Genotyping was determined by real-time polymerase chain reaction and TaqMan probe methods. RESULTS: Compared to the UTUC group, the control group had significantly more alcohol drinkers and coffee drinkers but not cigarette smokers. Statistical analyses showed that UTUC risk correlated with AURKA rs2273535 (adjusted odds ratio = 2.51, 95% CI = 1.07-6.15) and with survivin rs9904341 (adjusted odds ratio = 1.82, 95% CI = 1.03-3.26) polymorphisms but not with p21 and p53 polymorphisms. The bladder cancer risk showed no significant correlations with the 4 polymorphisms. In both the UTUC and UC groups, disease-free survival and overall survival were significantly longer in patients with the rs1801270CC genotype compared to those with CA+AA genotypes. Poor prognosis did not correlate with polymorphisms in AURKA, survivin, and p53 genes. CONCLUSION: These results suggest that cell cycle regulatory gene polymorphisms rs2273535 and rs9904341 may contribute to UTUC susceptibility; gene polymorphism rs1801270 may contribute to prognosis of UTUC and prognosis of UC. The p53 polymorphisms may not correlate with UTUC susceptibility and prognosis of UTUC or UC. Further well-designed, large-scale studies are needed to clarify these findings. PMID- 28668479 TI - Sex determination based on a thoracic vertebra and ribs evaluation using clinical chest radiography. AB - Our aim was to investigate whether sex can be determined from a combination of geometric features obtained from the 10th thoracic vertebra, 6th rib, and 7th rib. Six hundred chest radiographs (300 males and 300 females) were randomly selected to include patients of six age groups (20s, 30s, 40s, 50s, 60s, and 70s). Each group included 100 images (50 males and 50 females). A total of 14 features, including 7 lengths, 5 indices for the vertebra, and 2 types of widths for ribs, were utilized and analyzed for sex determination. Dominant features contributing to sex determination were selected by stepwise discriminant analysis after checking the variance inflation factors for multicollinearity. The accuracy of sex determination using a combination of the vertebra and ribs was evaluated from the selected features by the stepwise discriminant analysis. The accuracies in each age group were also evaluated in this study. The accuracy of sex determination based on a combination of features of the vertebra and ribs was 88.8% (533/600). This performance was superior to that of the vertebra or ribs only. Moreover, sex determination of subjects in their 20s demonstrated the highest accuracy (96.0%, 96/100). The features selected in the stepwise discriminant analysis included some features in both the vertebra and ribs. These results indicate the usefulness of combined information obtained from the vertebra and ribs for sex determination. We conclude that a combination of geometric characteristics obtained from the vertebra and ribs could be useful for determining sex. PMID- 28668480 TI - A new challenge in forensic toxicology exemplified by a case of murder under the influence of a synthetic cannabinoid - AM-2201. AB - Among new psychoactive substances (NPS) available on the narcotic market, a significant number consists of synthetic cannabinoids commonly known as smokable herbal "spice" and "K2", and which are legally treated as a legal alternative to marijuana. The dearth of information on the pharmacology of these intoxicants as they are introduced into the market has created the urgent need among healthcare providers for case studies on the substances belonging to this group, both in terms of the consequences of using such intoxicants, and in methods of detection. The subject of the present report is a multi-parameter analysis of a criminal case of an 18-year-old male who was charged with murder of his female relative and attempted murder of two other victims by stabbing. The defendant pleaded guilty, but he claimed that he had been acting without volition, because he was under the influence of the synthetic cannabinoid AM-2201, which had been purchased from a dealer as a 10g package labelled "Mr Green - No bad trip". Analytical methods including gas chromatography - electron ionization - quadrupole ion trap mass spectrometry (GC-EI-QIT/MS) and liquid chromatography, electrospray ionization, tandem mass spectrometry (LC-ESI-MS-MS) were developed to determine the presence of AM-2201 in the Mr Green - No Bad Trip, and in the blood of the perpetrator, respectively. Toxicological findings are discussed in the context of psychoactive and adverse physical effects resulting from the presence of AM-2201 in the human body; the observations were also analyzed in conjunction with data from the literature. PMID- 28668481 TI - Life-extending dietary restriction and ovariectomy each increase leucine oxidation and alter leucine allocation in grasshoppers. AB - Reduced reproduction and dietary restriction each extend lifespan in many animal models, but possible contributions of nutrient oxidation and allocation are largely unknown. Ovariectomy and eating 70% of ad libitum-feeding each extend lifespan in lubber grasshoppers. When feeding levels between the two groups are matched, ovariectomy increases fat and protein storage while dietary restriction reduces fat storage. Because of these disparities in nutrient investment, metabolism may differ between these two life-extending treatments. Therefore, we examined the allocation and organismal oxidation of one representative of each macronutrient class: leucine, oleic acid, and glucose. Ovariectomy and dietary restriction each increased oxidation of dietary leucine. Dietary leucine may play a special role in aging because amino acids stimulate cellular growth. Speeding oxidation of leucine may attenuate cellular growth. Allocation of leucine to muscle was the clearest difference between ovariectomy and dietary restriction in this study. Ovariectomy reduced allocation of leucine to femur muscle, whereas dietary restriction increased allocation of leucine to femur muscle. This allocation likely corresponds to muscle maintenance for locomotion, suggesting dietary restriction increases support for locomotion, perhaps to search for food. Last, ovariectomy decreased oxidation of dietary oleic acid and glucose, perhaps to save them for storage, but the site of storage is unclear. This study suggests that the oxidation of branched-chain amino acids may be an underappreciated mechanism underlying lifespan extension. PMID- 28668482 TI - New and cost-effective way of retracting orbital contents during repair of the orbital floor. PMID- 28668484 TI - A new genus and species of scorpion from Burma [Myanmar] (Scorpiones: Scorpiopidae): Implications for the taxonomy of the family. AB - Plethoscorpiops profusus gen. n., sp. n., belonging to the family Scorpiopidae Kraepelin, 1905 is described on the basis of two specimens, one adult female and one male juvenile collected in the Saddan Cave, in Kayin State, Hpa-An, Burma (Myanmar). This new scorpion taxon most certainly represents an endemic element for the fauna of Burma and seems to be strictly distributed inside the cave system. The new genus is characterized by a previously unknown and totally unique plethotaxic trichobothrial pattern within the family Scorpiopidae. PMID- 28668485 TI - Edwardsiella piscicida lacking the cyclic AMP receptor protein (Crp) is avirulent and immunogenic in fish. AB - Edwardsiella piscicida is a Gram-negative pathogen that generally causes lethal septicemia in marine and freshwater fish. We generated a E. piscicida CK216 Deltacrp mutant to investigate various biological roles related to this organism, including pathogenesis. Lack of Crp in CK216 was demonstrated by immunoblotting using a Crp-specific antibody. Compared to the parental strain, the mutant exhibited changes in three biochemical phenotypes, including ornithine decarboxylation, citrate utilization, and H2S production. Complementation of crp deletion in trans rescued the phenotype of the parental strain. This study proved that hemolytic activity in E. piscicida is controlled by Crp. In addition, significantly reduced motility of E. piscicida CK216 was observed, which resulted from a lack of flagella synthesis. To examine the virulence in fish, E. piscicida cells were injected into the goldfish (Carassius auratus) via intraperitoneal route. The LD50 of CK216 was 9.25 * 108 CFU, while that of the CK108 parental strain was 9.24 * 105 CFU, attenuated 1000 fold in goldfish. Fish immunized with CK216 elicited IgM responses. Moreover, 80% of goldfish immunized with 1 * 106 CFU survived after administration of a lethal dose (1 * 107 CFU) of virulent E. piscicida CK41, suggesting the potential for E. piscicida CK216 to serve as a live attenuated vaccine in aquaculture. PMID- 28668483 TI - Advances in keratinocyte delivery in burn wound care. AB - This review gives an updated overview on keratinocyte transplantation in burn wounds concentrating on application methods and future therapeutic cell delivery options with a special interest in hydrogels and spray devices for cell delivery. To achieve faster re-epithelialisation of burn wounds, the original autologous keratinocyte culture and transplantation technique was introduced over 3 decades ago. Application types of keratinocytes transplantation have improved from cell sheets to single-cell solutions delivered with a spray system. However, further enhancement of cell culture, cell viability and function in vivo, cell carrier and cell delivery systems remain themes of interest. Hydrogels such as chitosan, alginate, fibrin and collagen are frequently used in burn wound care and have advantageous characteristics as cell carriers. Future approaches of keratinocyte transplantation involve spray devices, but optimisation of application technique and carrier type is necessary. PMID- 28668486 TI - Glycogenolysis, an Astrocyte-Specific Reaction, is Essential for Both Astrocytic and Neuronal Activities Involved in Learning. AB - In brain glycogen, formed from glucose, is degraded (glycogenolysis) in astrocytes but not in neurons. Although most of the degradation follows the same pathway as glucose, its breakdown product, l-lactate, is released from astrocytes in larger amounts than glucose when glycogenolysis is activated by noradrenaline. However, this is not the case when glycogenolysis is activated by high potassium ion (K+) concentrations - possibly because noradrenaline in contrast to high K+ stimulates glycogenolysis by an increase not only in free cytosolic Ca2+ concentration ([Ca2+]i) but also in cyclic AMP (c-AMP), which may increase the expression of the monocarboxylate transporter through which it is released. Several transmitters activate glycogenolysis in astrocytes and do so at different time points after training. This stimulation is essential for memory consolidation because glycogenolysis is necessary for uptake of K+ and stimulates formation of glutamate from glucose, and therefore is needed both for removal of increased extracellular K+ following neuronal excitation (which initially occurs into astrocytes) and for formation of transmitter glutamate and GABA. In addition the released l-lactate has effects on neurons which are essential for learning and for learning-related long-term potentiation (LTP), including induction of the neuronal gene Arc/Arg3.1 and activation of gene cascades mediated by CREB and cofilin. Inhibition of glycogenolysis blocks learning, LTP and all related molecular events, but all changes can be reversed by injection of l-lactate. The effect of extracellular l-lactate is due to both astrocyte-mediated signaling which activates noradrenergic activity on all brain cells and to a minor uptake, possibly into dendritic spines. PMID- 28668487 TI - STDP Allows Close-to-Optimal Spatiotemporal Spike Pattern Detection by Single Coincidence Detector Neurons. AB - Repeating spatiotemporal spike patterns exist and carry information. How this information is extracted by downstream neurons is unclear. Here we theoretically investigate to what extent a single cell could detect a given spike pattern and what the optimal parameters to do so are, in particular the membrane time constant tau. Using a leaky integrate-and-fire (LIF) neuron with homogeneous Poisson input, we computed this optimum analytically. We found that a relatively small tau (at most a few tens of ms) is usually optimal, even when the pattern is much longer. This is somewhat counter-intuitive as the resulting detector ignores most of the pattern, due to its fast memory decay. Next, we wondered if spike timing-dependent plasticity (STDP) could enable a neuron to reach the theoretical optimum. We simulated a LIF equipped with additive STDP, and repeatedly exposed it to a given input spike pattern. As in previous studies, the LIF progressively became selective to the repeating pattern with no supervision, even when the pattern was embedded in Poisson activity. Here we show that, using certain STDP parameters, the resulting pattern detector is optimal. These mechanisms may explain how humans learn repeating sensory sequences. Long sequences could be recognized thanks to coincidence detectors working at a much shorter timescale. This is consistent with the fact that recognition is still possible if a sound sequence is compressed, played backward, or scrambled using 10-ms bins. Coincidence detection is a simple yet powerful mechanism, which could be the main function of neurons in the brain. PMID- 28668488 TI - Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice. AB - Acetaminophen (APAP) is a widely used antipyretic and analgesic drug, which is safe and effective at the therapeutic dose. Unfortunately, excessive dosage of APAP could cause severe liver injury due to lack of effective therapy. Successful therapeutic strategies are urgently requested in clinic. Glycyrrhetinic acid (GA), derived from a traditional medicine licorice, has been shown to exert anti inflammatory and antioxidant actions. In this study, the effect and the underlying mechanism of GA on APAP-induced hepatotoxicity were explored. Our results showed that pretreatment with GA significantly reduced serum ALT and AST activities, alleviated hepatic pathological damages with hepatocellular apoptosis, down-regulated expression of CYP2E1 mRNA and protein, increased GSH levels, and reduced reactive oxygen species (ROS) productions in the liver of APAP-exposed mice. Furthermore, GA obviously inhibited APAP-induced HMGB1-TLR4 signal activation, as evaluated by reduced hepatic HMGB1 release, p-IRAK1, p-MAPK and p-IkappaB expression as well as the productions of TNF-alpha and IL-1beta. In addition, GA attenuated hepatic neutrophils recruitment and macrophages infiltration caused by APAP. These findings reflected that GA could alleviate APAP-induced hepatotoxicity, the possible mechanism is associated with down regulation of CYP2E1 expression and deactivation of HMGB1-TLR4 signal pathway. PMID- 28668489 TI - Pulmonary Clinicopathological Correlation after Allogeneic Hematopoietic Stem Cell Transplantation: An Autopsy Series. AB - Pulmonary complications are a significant cause of morbidity, mortality, and resource utilization after hematopoietic stem cell transplantation (HSCT). The objective of this study was to compare antemortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. All patients who underwent allogeneic HSCT at our institution (n = 1854) between January 1, 2000 and June 30, 2010 were reviewed and patients who died of any cause greater than 1 year after HSCT and had an unrestricted autopsy available for analysis were included. Presence of pulmonary graft-versus-host disease (GVHD) was assessed by a pathologist blinded to the autopsy report, as previously described by Yousem (1995). A total of 35 (1.9%) patients had autopsies available for review. Airway disease, vascular disease, and interstitial disease were all clinically under recognized compared with the pathological findings on autopsy. Varying degrees of pathological changes were detected, including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno occlusive disease (PVOD). Pulmonary manifestations of chronic GVHD, particularly BO and PVOD, were clinically under-recognized in our cohort. Our results suggest that PVOD, which has traditionally been considered a rare complication, may be clinically and histologically under-recognized. PMID- 28668490 TI - Co-Infections by Double-Stranded DNA Viruses after Ex Vivo T Cell-Depleted, CD34+ Selected Hematopoietic Cell Transplantation. AB - Recipients of ex vivo T cell-depleted (TCD) hematopoietic cell transplantation (HCT) are at risk of infection by double-stranded (ds) DNA viruses. We report rates of dsDNA viremia, end-organ disease (EOD), infection-related mortality, and overall survival (OS) in a contemporary cohort of adult TCD HCT recipients routinely monitored for cytomegalovirus (CMV), adenovirus (ADV), human herpesvirus 6 (HHV6), and Epstein-Barr virus (EBV). Healthcare utilization in the first 6 months post-HCT was compared between patients with dsDNA viremia versus no viremia. This was an observational study of adult patients with acute leukemia and myelodysplastic syndrome who received CD34+ selected, peripheral blood HCT at Memorial Sloan Kettering Cancer Center from March 2012 through December 2014. Patients were prospectively monitored by quantitative PCR assays for CMV, ADV, HHV6, and EBV in whole blood or plasma. The cumulative incidence of viremia(s) at day +180, EOD at 1 year, and OS at 1 year were estimated by the Kaplan-Meier method and compared by the log-rank test among patient with and without viremia/EOD. Standardized incidence ratios were used to compare overall length of hospital stay (LOS), number of readmissions after HCT, and length of readmissions through day +180. Of 156 patients, 96 (62%) were CMV recipient seropositive. Forty-two patients received grafts from matched related (27%), 86 from matched unrelated (55%), and 28 from mismatched (18%) donors. Overall, 132 patients (85%) had >=1 viremia and 52 (33%) >=2 viremias by day +180. The cumulative incidences for CMV, HHV6, ADV, and EBV viremia were 44%, 61%, 7%, and 16%, respectively, with median times of onset 28 days (interquartile range [IQR], 25 to 33), 33 days (IQR, 25 to 47), 60 days (IQR, 19 to 84), and 79 days (IQR, 54 to 106) post-HCT, respectively. Twenty-eight patients (18%) developed EOD by dsDNA viruses at 1 year post-HCT. Treatment for CMV accounted for 91% total antiviral treatment days. Compared with patients with no viremia, patients with CMV viremia, HHV6 viremia, or >=2 viremias experienced longer LOS (P <.001) and a higher number of readmissions (P <.001) by day +180. OS rate at 1 year was 79% and was similar between patients with or without dsDNA viremias. EOD was associated with lower 1 year OS rates (63.4%) versus without EOD (81.1%) (P = .02). Of 33 patients who died, 10 died due to infection, and 7 of these infection-related deaths were due to dsDNA viruses. Viremia by dsDNA viruses occurred in 85% of TCD HCT recipients by day +100 and 33% of patients experienced >=2 viremias by day +180. CMV accounted for most antiviral use. CMV, HHV6, or >=2 viremias were associated with more readmissions and longer LOS. One year OS rate was 78%. EOD by dsDNA viruses was associated with decreased 1-year OS. Infections by dsDNA viruses pose a substantial burden after TCD HCT. PMID- 28668491 TI - Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation. AB - The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score >= 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT. PMID- 28668492 TI - Epidemiology and Risk Factors for Invasive Fungal Diseases among Allogeneic Hematopoietic Stem Cell Transplant Recipients in Korea: Results of "RISK" Study. AB - Incidence, epidemiology, and risk factors of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients can vary from different cohorts and countries. Therefore, we performed a nationwide study to establish a proper antifungal prophylaxis strategies based on risk stratifications of IFDs after all-HSCT in Korea (RISK study). This was a multicenter, retrospective, and observational study in Korea. All consecutive adult patients who received allo-HSCT in 2013 were included. The 12-month cumulative incidence of proven/probable IFDs (PP-IFDs) was calculated during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT. Cox proportional hazard regression analysis was performed to identify risk factors for PP-IFDs at each phase. A total 521 allo-HSCT cases in 518 patients were analyzed. Overall cumulative incidence of PP-IFDs were 4.09% (95% confidence interval [CI], 2.38 to 5.81), 7.38% (95% CI, 5.09 to 9.67), and 15.36% (95% CI, 12.04 to 18.68) at the early, late and very phases, respectively. In multiple Cox regression analysis, variables were associated with PP-IFDs in each period were identified. Variables associated with early phase include underlying pulmonary diseases, underlying nonmalignant stable or chronic disease at allo-HSCT, unrelated or family mismatched donor, and prolonged neutropenia. Variables associated with the late phase include high ferritin level at the time point of allo-HSCT, use of secondary immunosuppressive agents due to refractory graft-versus-host disease (GVHD), and cytomegalovirus reactivation. For the very late phase, variables were secondary neutropenia, severe chronic GVHD, and use of TNF-alpha inhibitor for refractory GVHD. This study revealed the high cumulative incidence of IFDs in Korean allo-HSCT recipients, which have distinct risk factors in each phase after allo-HSCT. Our findings indicate that tailored antifungal prophylaxis is necessary for high-risk patients. Clinicians should consider using mold-active antifungal prophylaxis in allo-HSCT recipients who have high risks at different treatment period. PMID- 28668493 TI - Uncovering the flocculating potential of extracellular polymeric substances produced by periphytic biofilms. AB - The aim of this work was to study the characteristics and flocculating properties of extracellular polymeric substances (EPS) extracted from periphytic biofilms. The periphytic EPS, with an extracted yield of 491.8mg/g, were mainly composed of hetero-polysaccharides and proteins, and the elements C1s, N1s, and O1s. Polysaccharides represented 53.28% of the periphytic EPS. Proteins constituted 20.26% of the EPS, and contributed to at least 34.65% of the total flocculating activity. The periphytic EPS showed high turbidity removal capacity (86.76+/ 1.52%, 10min) and efficient aniline blue (AB) removal capacity (56.46+/-1.41%, 30min). The mechanism of AB removal by the periphytic EPS seemed to be a combined technique of "adsorption-flocculation". This study reveals the flocculating capability of periphytic EPS, and suggests that periphytic biofilms are novel sources for bioflocculants preparation. PMID- 28668494 TI - Lung metastasis in primary cutaneous adenoid cystic carcinoma - Clinicopathological evaluation of a rare case with review of literature. AB - Primary cutaneous adenoid cystic carcinoma (ACC) is an extremely rare and indolent cutaneous malignancy with very infrequent distant metastasis. We present a case of primary cutaneous ACC with bilateral lung metastases in a 57-year-old male along with literature review. To the best of our knowledge this is the tenth case of primary cutaneous ACC reported presenting with distant metastasis. PMID- 28668495 TI - Toward standardization of laparoscopic resection for colorectal cancer in developing countries: A step by step module. AB - BACKGROUND: Despite the proven benefits, laparoscopic colorectal surgery is still underutilized among surgeons especially in developing countries. Also a steep learning is one of the causes of its limited adoption. OBJECTIVE: To explore the learning curve of single surgeon experience in laparoscopic colectomy and feasibility of implementing a well standardized step by step operative technique to overcome the beginning technical obstacles. PATIENTS AND METHODS: This prospective study included 50 patients with carcinoma of the left colon and rectum recruited from the department of surgical oncology at National Cancer Institute, Cairo University in the period 2012-2016. All the procedures were performed through laparoscopic approach. Intra and post-operative data were recorded and analyzed. RESULTS: The mean age was 49.7+/-10.6years (range: 33 74years). They were 29 males and 21 females. The mean operation time was 180min (range 100-370min), and the mean blood loss was 350ml (60-600ml). Six patients (12%) were converted to a laparotomy. The median lymph nodes harvest was 12 (range 7-25). The mean time of passing flatus after surgery was 2days (1-4days) and the mean time of passing stools was 3.3days (2-5) days. The median hospitalization period after surgery was 4days (3-12). 5 patients (10%) had postoperative morbidity, major morbidity occurred in one patient. CONCLUSION: Laparoscopic colorectal surgery for colorectal cancer is safe and oncologically sound, standardized well-structured laparoscopic technique masters the procedure even in early learning curve setting. PMID- 28668496 TI - Generation of Nanobodies against SlyD and development of tools to eliminate this bacterial contaminant from recombinant proteins. AB - The gene for a protein domain, derived from a tumor marker, fused to His tag codons and under control of a T7 promotor was expressed in E. coli strain BL21 (DE3). The recombinant protein was purified from cell lysates through immobilized metal affinity chromatography and size-exclusion chromatography. A contaminating bacterial protein was consistently co-purified, even using stringent washing solutions containing 50 or 100 mM imidazole. Immunization of a dromedary with this contaminated protein preparation, and the subsequent generation and panning of the immune Nanobody library yielded several Nanobodies of which 2/3 were directed against the bacterial contaminant, reflecting the immunodominance of this protein to steer the dromedary immune response. Affinity adsorption of this contaminant using one of our specific Nanobodies followed by mass spectrometry identified the bacterial contaminant as FKBP-type peptidyl-prolyl cis-trans isomerase (SlyD) from E. coli. This SlyD protein contains in its C-terminal region 14 histidines in a stretch of 31 amino acids, which explains its co purification on Ni-NTA resin. This protein is most likely present to varying extents in all recombinant protein preparations after immobilized metal affinity chromatography. Using our SlyD-specific Nb 5 we generated an immune-complex that could be removed either by immunocapturing or by size exclusion chromatography. Both methods allow us to prepare a recombinant protein sample where the SlyD contaminant was quantitatively eliminated. PMID- 28668497 TI - A fusion protein of the synthetic IgG-binding domain and aequorin: Expression and purification from E. coli cells and its application. AB - Aequorin is a Ca2+-binding photoprotein that is a complex of apoaequorin (apoAQ) and 2-peroxycoelenterazine. In this study, the fusion protein (ZZ-apoAQ) composed of the synthetic IgG-binding domain (ZZ domain) derived from Staphylococcus aureus protein A and apoAQ was expressed into the periplasmic space of Escherichia coli cells. ZZ-apoAQ was highly purified using Ni-chelate affinity chromatography followed by IgG affinity chromatography. ZZ-AQ was prepared from purified ZZ-apoAQ by incubation with coelenterazine and was characterized, including its luminescence properties. ZZ-AQ could be used as a reporter for detecting IgG and the measurable range of IgG coated on a 96-well plate was 1 1000 ng/mL. PMID- 28668498 TI - How to reverse first time donors to become regular donors? A questionnaire survey in Estonia. AB - BACKGROUND: Donating blood in Estonia is non-remunerated and voluntary. Estonian Blood Service system has four independent regional blood centres that are responsible for blood collection, processing, screening and distribution of blood components to hospitals for clinical use. STUDY DESIGN: This research was carried out as a questionnaire survey. A questionnaire was developed to study lapsing first time donors' (FTD) blood donation experience, intention and willingness to donate again. METHODS: A thousand five hundred and forty-six questionnaires were posted to donors who had one successful donation in 2010 and who had not returned to second donation till the year 2012. For data analysis routine statistical methods were used. To evaluate the most appropriate number of classes, based on previous experience and future expectations, latent class analysis was used. RESULTS: There were 453 respondents (29.3%). For the majority of aspects of blood donation experience the emotions were positive. Results of the study suggested that blood collection agencies should intervene to bolster donors' attitudes, perceived control, and identity as a donor during this crucial post-first donation period. CONCLUSION: First blood donation seems to have been a positive experience. Reasons leading to stopping blood donation should be studied further. Establishing a donor registry for Estonia would be essential to keep track of donors. PMID- 28668499 TI - The difficulty with correlations: Energy expenditure and brain mass in bats. AB - Brain mass has been suggested to determine a mammal's energy expenditure. This potential dependence is examined in 48 species of bats. A correlation between characters may be direct or derived from shared correlations with intervening factors without a direct interaction. Basal rate of metabolism in these bats increases with brain mass: large brains are more expensive than small brains, and both brain mass and basal rate increase with body mass. Basal rate and brain mass also correlate with food habits in bats. Mass-independent basal rate weakly correlates with mass-independent brain mass, the correlation only accounting for 12% of the variation in basal rate, which disappears when the combined effects of body mass and food habits are deleted. The correlation between basal rate and brain mass seen in this and other studies usually accounts for <10% of the variation in basal rate and often <4%, even when statistically significant, a minimalist explanation for the level the basal rate. This correlation probably reflects the intermediacy of secondary factors, as occurred with food habits in bats. Most biological correlations are complicated and must be examined in detail before assurance can be given as to their bases. PMID- 28668500 TI - Toll-like receptor-4/p38 MAPK signaling in the dorsal horn contributes to P2X4 receptor activation and BDNF over-secretion in cancer induced bone pain. AB - Our previous research suggested that the P2X4 receptor (P2X4R) expression in microglia was involved in the activation of toll-like receptor-4 (TLR4) in the dorsal horn in the rat model of cancer induced bone pain (CIBP). In this study, we focused on whether TLR4- mitogen-activated protein kinases, p38 (p38 MAPK) contributes to P2X4R activation and brain-derived neurotrophic factor (BDNF) over secretion in CIBP. In in vitro experiment, the results showed that BDNF expression evoked by ATP stimulation was dependent on TLR4-p38. In in vivo experiment, the results demonstrated that an intrathecal injection of TLR4 siRNA alleviated nociception induced by lipopolysaccharide (LPS) plus ATP or CIBP with decreased expression of P2X4R, TLR4, BDNF, interleukin-6 (IL-6) and phosphorylated-p38 MAPK (p-p38 MAPK). Moreover, injection with p38MAPK inhibitor SB203580 resulted in an identical pattern compared with treatment with TLR4 siRNA. Our results demonstrate that the activation of TLR4-p38MAPK-P2X4R signaling in microglial possibility plays an important role in the process of nociceptive transmission in CIBP, suggesting new mechanism and potential therapeutic targets for CIBP. PMID- 28668501 TI - A potential contribution of tenascin-X to blood vessel formation in peripheral nerves. AB - Tenascin-X (TNX), an extracellular matrix protein, is abundantly expressed in peripheral nerves. However, the physiological role of TNX in peripheral nerves remains unknown. In this study, we found that actin levels in sciatic nerves of TNX-deficient mice were markedly decreased. Since actin was highly expressed in endothelial cells in wild-type sciatic nerves, we assessed morphological alterations of blood vessels in TNX-null sciatic nerves. The density of blood vessels was significantly decreased and the size of blood vessels was larger than those in wild-type sciatic nerves. Immunofluorescence showed that TNX was expressed by Schwann cells and fibroblasts in sciatic nerves. The results suggest that TNX secreted from Schwann cells and/or fibroblasts is involved in blood vessel formation in peripheral nerves. PMID- 28668502 TI - BDNF as a possible modulator of EEG oscillatory response at the parietal cortex during visuo-tactile integration processes using a rubber hand. AB - Multisensory integration of visuo-tactile information presented on the body or a dummy body has a strong impact on body image. Previous researches show that alteration of body image induced by visuo-tactile integration is closely related to the activation of the parietal cortex, a sensory association area. The expression of brain-derived neurotrophic factor (BDNF) in the parietal area of macaque monkeys is thought to modulate the activation of the parietal cortex and alter the extension of body image during tool-use learning. However, the relationship between parietal cortex activation related to body image alterations and BDNF levels in humans remains unclear. We investigated the relationship between human serum BDNF levels and electroencephalography responses during a visuo-tactile integration task involving a rubber hand. We found cortical oscillatory components in the high frequency (gamma) band in the left parietal cortex. Moreover, the power values of these oscillations were positively correlated (p<0.05) with serum BDNF levels. Our results suggest that serum BDNF could play a role in modulating the cortical activity in response to visuo tactile integration processes related to body image alteration in humans. PMID- 28668503 TI - Spatial analysis of Leptospira infection in muskrats in Lower Saxony, Germany, and the association with human leptospirosis. AB - Leptospirosis has been reported as an emerging zoonosis and the most widespread zoonotic disease in the world. Muskrats (Ondatra zibethicus) have been known to carry Leptospira serovars, which have been linked to Weil's disease - a serious and life threatening disease in humans. In this study, muskrats were sampled across 43 regions of Lower Saxony, Germany, during 2007 to 2009 and were tested for leptospirosis using Polymerase Chain Reaction (PCR). Circular and flexibly shaped spatial scan tests were applied and detected two leptospirosis clusters in Lower Saxony, Germany. Several predictor variables were investigated using spatial Poisson rate regression analysis; however, only maximum regional temperature was associated with the incidence rate of leptospirosis in muskrats. For every 5 degrees C increase in temperature, the incidence rate of leptospirosis in muskrats decreased 0.97 times. The association between the smoothed muskrat leptospirosis prevalence and the rate of human leptospirosis was also investigated using a Poisson rate regression model and revealed no relationship. Although no relationship was found at the level investigated in this study, recent human leptospirosis outbreaks have been linked to muskrats, so muskrats as a risk factor for human leptospirosis should not be ruled out. Overall, leptospirosis clusters were found within the muskrat population in Lower Saxony, Germany and temperature was confirmed as a risk factor. PMID- 28668504 TI - Mirtazapine attenuates the expression of nicotine-induced locomotor sensitization in rats. AB - Nicotine is the primary psychoactive component of tobacco. Many addictive nicotinic actions are mediated by an increase in the activity of the serotonin (5 HT) system. Some studies show that the 5-HT2A, 5-HT2C, and 5-HT3 receptors have a central role in the induction and expression of nicotine-induced locomotor sensitization. Mirtazapine, an antagonist of the alpha2-adrenergic receptors, the 5-HT2A/C, and the 5-HT3 receptors, has proven effective in reducing behavioral effects induced by drugs like cocaine and methamphetamines in human and animal. In this study, we evaluated the effect of mirtazapine on the locomotor activity and on the expression of nicotine-induced locomotor sensitization. We used the nicotine locomotor sensitization paradigm to assess the effects of mirtazapine on nicotine-induced locomotor activity and locomotor sensitization. Mirtazapine (30mg/kg, i.p.) was administered during extinction. Our study found that mirtazapine attenuated the expression of locomotor sensitization induced by different nicotine doses, decreased the duration of locomotor effects and locomotor activity induced by binge administration of nicotine. In addition, our study revealed that treatment with mirtazapine for 60 days produced an enhanced attenuation of nicotine-induced locomotor activity during the expression phase of behavioral sensitization, compared to that obtained when mirtazapine was administered for 30 days. This suggests that use of mirtazapine in controlled clinical trials may be a useful therapy to maintain abstinence for long periods. PMID- 28668505 TI - Regulation of allergic airway inflammation by adoptive transfer of CD4+ T cells preferentially producing IL-10. AB - Anti-inflammatory pharmacotherapy for asthma has mainly depended on the inhalation of glucocorticoids, which non-specifically suppress immune responses. If the anti-inflammatory cytokine interleukin (IL)-10 can be induced by a specific antigen, asthmatic airway inflammation could be suppressed when individuals are exposed to the antigen. The purpose of this study was to develop cellular immunotherapeutics for atopic diseases using IL-10-producing CD4+ T cells. Spleen cells isolated from ovalbumin (OVA)-sensitized mice were cultured with the antigen, OVA and growth factors, IL-21, IL-27 and TGF-beta for 7 days. After the 7-day culture, the CD4+ T cells were purified using a murine CD4 magnetic beads system. When the induced CD4+ T cells were stimulated by OVA in the presence of antigen-presenting cells, IL-10 was preferentially produced in vitro. When CD4+ T cells were adoptively transferred to OVA-sensitized mice followed by intratracheal OVA challenges, IL-10 was preferentially produced in the serum and bronchoalveolar lavage fluid in vivo. IL-10 production coincided with the inhibition of eosinophilic airway inflammation and epithelial mucus plugging. Most of the IL-10-producing CD4+ T cells were negative for Foxp3 and GATA-3, transcription factors of naturally occurring regulatory T cells and Th2 cells, respectively, but double positive for LAG-3 and CD49b, surface markers of inducible regulatory T cells, Tr1 cells. Collectively, most of the induced IL-10 producing CD4+ T cells could be Tr1 cells, which respond to the antigen to produce IL-10, and effectively suppressed allergic airway inflammation. The induced Tr1 cells may be useful for antigen-specific cellular immunotherapy for atopic diseases. PMID- 28668506 TI - Interleukin-33 signaling contributes to renal fibrosis following ischemia reperfusion. AB - Acute kidney injury caused by ischemia-reperfusion injury (IRI) is a major risk factor for chronic kidney disease, which is characterized by renal interstitial fibrosis. However, the molecular mechanisms underlying renal fibrosis induced by IRI are not fully understood. Our results showed that interleukin (IL)-33 was induced markedly after IRI insult, and the kidneys of mice following IRI plus IL 33 treatment presented more severe renal fibrosis compared with mice treated with IRI alone. Therefore, we investigated whether inhibition of IL-33 protects against IRI-induced renal fibrosis. Mice were administrated with soluble ST2 (sST2), a decoy receptor that neutralizes IL-33 activity, or vehicle by intraperitoneal injection for 14 days after IRI challenge. We revealed that mice treated with sST2 exhibited less severe renal dysfunction and fibrosis in response to IRI compared with vehicle-treated mice. Inhibition of IL-33 suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidneys after IRI stress, which was associated with less expression of extracellular matrix proteins. Furthermore, inhibition of IL-33 also showed a significant reduction of F4/80+ macrophages and CD3+ T cells in the kidneys of mice after IRI treatment. Finally, Treatment with IL-33 inhibitor reduced proinflammatory cytokine and chemokine levels in the kidneys of mice following IRI insult. Taken together, our findings indicate that IL-33 signaling plays a critical role in the pathogenesis of IRI-induced renal fibrosis through regulating myeloid fibroblast accumulation, inflammation cell infiltration, and the expression of proinflammatory cytokines and chemokines. PMID- 28668507 TI - Synthetic peptide TEKKRRETVEREKE derived from ezrin induces differentiation of NIH/3T3 fibroblasts. AB - Synthetic 14 AA peptide (Gepon) derived from the hinge region of ezrin, a protein that links cell surface molecules to intracellular actin filaments, accelerates and facilitates wound and ulcer healing in clinical applications. However, the molecular mechanisms underlying this phenomenon and involved in enhanced healing of wounds with Gepon are not yet understood. The purpose of current study was to investigate intracellular signaling pathways involved in the effect of this peptide on wild type and genetically modified (CD44 KO) NIH/3T3 embryonic mouse fibroblasts. Gepon treatment of NIH/3T3 cells resulted in morphological and biochemical changes, characteristic of differentiated fibroblasts. While treatment of NIH/3T3 cells with TGF-beta1 triggered the activation of both canonical and non-canonical signaling pathways, exposure of fibroblasts to Gepon activated only the ERK1/2 dependent pathway without modulating SMAD dependent signaling pathway. Knocking out hyaluronic acid CD44 receptor did not change Gepon or TGF-beta1 dependent activation of intracellular signaling pathways and assembling of alpha-SMA-positive filaments. Gepon dependent differentiation of NIH/3T3 fibroblasts is based on activation of ERK1/2 kinase, non-canonical intracellular signaling pathway. Our data suggest that the treatment of fibroblasts with Gepon triggers activation of the non-canonical (SMAD independent) intracellular signaling pathway that involves ERK1/2kinase phosphorylation. Activation of the MAPK signaling pathway and the increase in formation of alpha-SMA containing stress filaments induced by Gepon were independent on presence of CD44 receptor in NIH/3T3 fibroblasts. Thus, our observation designates the significance and sufficiency of MAPK pathway mediated activation of fibroblasts with Gepon for healing of erosion, ulcers and wounds. PMID- 28668508 TI - Covalent modifications of the amyloid beta peptide by hydroxynonenal: Effects on metal ion binding by monomers and insights into the fibril topology. AB - Amyloid beta peptides (Abeta) and metal ions are associated with oxidative stress in Alzheimer's disease (AD). Oxidative stress, acting on omega-6 polyunsaturated fatty acyl chains, produces diverse products, including 4-hydroxy-2-nonenal (HNE), which can covalently modify the Abeta that helped to produce it. To examine possible feedback mechanisms involving Abeta, metal ions and HNE production, the effects of HNE modification and fibril formation on metal ion binding was investigated. Results indicate that copper(II) generally inhibits the modification of His side chains in Abeta by HNE, but that once modified, copper(II) still binds to Abeta with high affinity. Fibril formation protects only one of the three His residues in Abeta from HNE modification, and this protection is consistent with proposed models of fibril structure. These results provide insight into a network of biochemical reactions that may be operating as a consequence of oxidative stress in AD, or as part of the pathogenic process. PMID- 28668509 TI - Quantitatively Understanding Plant Signaling: Novel Theoretical-Experimental Approaches. AB - With the need to respond to and integrate a multitude of external and internal stimuli, plant signaling is highly complex, exhibiting signaling component redundancy and high interconnectedness between individual pathways. We review here novel theoretical-experimental approaches in manipulating plant signaling towards the goal of a comprehensive understanding and targeted quantitative control of plant processes. We highlight approaches taken in the field of synthetic biology used in other systems and discuss their applicability in plants. Finally, we introduce existing tools for the quantitative analysis and monitoring of plant signaling and the integration of experimentally obtained quantitative data into mathematical models. Incorporating principles of synthetic biology into plant sciences more widely will lead this field forward in both fundamental and applied research. PMID- 28668510 TI - Plant SAM-Domain Proteins Start to Reveal Their Roles. AB - Proteins often act in complexes assembled via protein-protein interaction domains. The sterile alpha motif (SAM) domain is one of the most prominent interaction domains in animals and is present in proteins of diverse functions. This domain allows head-to-tail closed oligomerisation or polymer formation resulting in homo- and/or heterocomplexes that have been shown to be important for proper protein localisation and function. In plants this domain is also present but has been poorly studied except for recent studies on the LEAFY floral regulator and the tRNA import component (TRIC)1/2 proteins. Here we catalogue SAM domain-containing proteins from arabidopsis (Arabidopsis thaliana), compare plant and other eukaryotic SAM domains, and perform homology modelling to probe plant SAM domain interaction capabilities. PMID- 28668511 TI - Voltage-sensitive potassium channels expressed after 20-Hydroxyecdysone treatment of a mosquito cell line. AB - The goal of this research was to express receptors and ion channels in hormone treated insect cell lines. Treatment of Anopheles gambiae Sua1B cells with 20 hydroxyecdysone showed an inhibition of cell growth over a time course of three days, with no change in cellular morphology. The effect of 20-hydroxyecdysone was enhanced in the presence of the potassium channel blocker 4-aminopyridine, but not tetraethylammonium. Concentration-response curves of 4-aminopyridine in the presence of 42 MUM (1 mg/ml) 20-hydroxyecdysone showed similar IC50 values (6-10 MUM) across 3 day exposures. Whole cell patch clamp confirmed the expression of delayed-rectifier (Kv2) potassium channels in hormone-supplemented Sua1B cells, whereas untreated Sua1B cells showed no evidence of Kv2 expression. The hormone induced expression of Kv2 channels occurred in as little as 4 h after treatment, but were not observed after 24 h of exposure to 20-hydroxyecdysone, suggesting they played a role in cell death. The expressed channels had current-voltage relationships diagnostic for the Kv2 subtype, and were inhibited with an IC50 = 13 mM of tetraethylammonium. Overall, these parameters were similar to Anopheles gambiae Kv2 potassium channels expressed in HEK-293 cells. The induced presence of ion channels (and possibly receptors) in these cells has potential utility for high throughput screening and basic neuroscience research. PMID- 28668512 TI - H. pylori infection increases gastric mucosal COX2 and mTOR expression in chronic gastritis: Implications for cancer progression? AB - BACKGROUND: Helicobacter Pylori is a Gram-negative bacterium that infects the human stomach and plays an important role in the pathogenesis of chronic gastritis. H. pylori associated chronic gastritis affects various molecular markers related to gastric cancer development. The aim of this study to assess the effect of H. pylori infection on gastric mucosa and to explore its role in gastric carcinogenesis via COX2 and mTOR mucosal expression. MATERIALS AND METHODS: This study comprised archival blocks from 60 dyspeptic patients who underwent gastric endoscopic biopsies for histopathological examination. The blocks were cut at 4 MUm thicknesses, stained with hematoxylin and eosin to score, using updated Sydney system, and subjected to Giemsa stain to assess H. pylori infection. Then, immunohistochemical method was carried out to determine the expression of COX2 and mTOR. RESULTS: Increased H. pylori colonization was significantly correlated with increased severity of inflammation, activity, atrophy, intestinal metaplasia, and the presence of high-grade dysplasia. Also, studied molecular markers were significantly associated with increased H. pylori colonization and presence of severe metaplasia, atrophy, and dysplasia. CONCLUSION: These findings suggest that there is a positive feedback loop between H. pylori infection and the pathogenesis of gastric mucosal changes. Also, mTOR and COX2 over expression cause premalignant changes and subsequent tumor occurrence. This may help in providing innovative approaches for the detection of patients-with a higher chance of cancer development, and in trying to introduce effective therapy preventing tumor occurrence, or even using these molecular markers as potential targets for tumors treatment strategies. PMID- 28668513 TI - Toll-like receptors, NF-kappaB, and IL-27 mediate adenosine A2A receptor signaling in BTBR T+ Itpr3tf/J mice. AB - Autism is a predominant neurodevelopmental disorder characterized by impaired communication, social deficits, and repetitive behaviors. Recent research has proposed that the impairment of innate immunity may play an important role in autism. Toll-like receptors (TLRs) are potential therapeutic targets against neuroinflammation. The BTBR T+ Itpr3tf/J (BTBR) mouse is a well-known model of autism, showing repetitive behaviors such as cognitive inflexibility and increased grooming as compared to C57BL/6 (B6) mice. Adenosine A2A receptor (A2AR) signaling is involved in inflammation, brain injury, and lymphocyte infiltration into the CNS, but the role of A2AR in autism remains unknown. We investigated the effect of A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on the expression levels of TLRs, IL-27, NF-kappaB p65, and IkappaBalpha in BTBR mice. Treatment of BTBR mice with SCH increased the percentage of splenic CD14+TLR2+ cells, CD14+TLR3+ cells, CD14+TLR4+ cells, and decreased the percentage of CD14+IL-27+ cells, as compared to the untreated BTBR mice. Our results reveal that BTBR mice treated with CGS had reversal of SCH-induced immunological responses. Moreover, mRNA and protein expression analyses confirmed increased expression of TLR2, TLR3, TLR4, and NF-kappaB p65 in brain tissue, and decreased IL-27 and IkappaBalpha expression following SCH treatment, as compared to the untreated-BTBR and CGS-treated BTBR mice. Together, these results suggest that the A2AR agonist corrects neuroimmune dysfunction observed in BTBR mice, and thus has the potential as a therapeutic approach in autism. PMID- 28668514 TI - Photocatalytic study and superparamagnetic nature of Zn-doped MgFe2O4 colloidal size nanocrystals prepared by solvothermal reflux method. AB - Biocompatible Mg1-xZnxFe2O4 (x=0.2, 0.4, 0.5, 0.6 & 0.8) nanoparticles were synthesized by solvothermal reflux method. All compounds were crystallized in cubic spinel structure with slightly enhance of lattice parameter with biocompatible substituent Zn2+ concentration. All compounds were shown spherical geometry with average particle diameter is around 12nm (colloidal size). The spinel structure formation was confirmed by X-ray diffraction,electron diffraction, infrared, Raman shift measurements. Infrared analysis shows oleic acid coating on the surface of nanoparticles and TGA analysis shows that oleic acid desorbs from nanoparticle by decomposition at around 400 degrees C. UV-Vis NIR spectra show all the compounds show energy band gap in the semiconductor range (~ 1.9eV). All compounds show superparamagnetic characteristics at room temperature with enhanced saturated mass magnetization (Ms) with Zn2+ concentration up to x=0.5 and then reduces with further enhance of x up to 0.8. The Ms changes were ascribed to occupation of Zn2+ at tetrahedral sites and proportional enhance of Fe3+ at octahedral sites. The enhanced Fe3+ concentration at octahedral sublattice leads to formation Fe3+-O2--Fe3+ networks which favor antiferromagnetic interactions due to superexchange phenomenon. Photocatalytic activity of all compounds were studied through methylene blue (MB) degradation analysis. All compounds show ~ 96% degradation of MB upon 70min irradiation of light on photoreactor vessel. In addition, photocatalytic activity (degradation efficiency) enhances with Zn2+ concentration in MgFe2O4. The Zn2+ substitution enhances both Ms and photocatalytic activity biocompatible of MgFe2O4 nanoparticles. PMID- 28668515 TI - Elucidation of photocatalysis, photoluminescence and antibacterial studies of ZnO thin films by spin coating method. AB - The ZnO thin films have been prepared by spin coating followed by annealing at different temperatures like 300 degrees C, 350 degrees C, 400 degrees C, 450 degrees C, 500 degrees C & 550 degrees C and ZnO nanoparticles have been used for photocatalytic and antibacterial applications. The morphological investigation and phase analysis of synthesized thin films well characterized by X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), Photoluminescence (PL), Transmission Electron Microscopy (TEM) and Raman studies. The luminescence peaks detected in the noticeable region between 350nm to 550nm for all synthesized nanosamples are associated to the existence of defects of oxygen sites. The luminescence emission bands are observed at 487nm (blue emission), and 530nm (green emission) at the RT. It is observed that there are no modification positions of PL peaks in all ZnO nanoparticles. In the current attempt, the synthesized ZnO particles have been used photocatalytic and antibacterial applications. The antibacterial activity of characterized samples was regulated using different concentrations of synthesized ZnO particles (100MUg/ml, 200MUg/ml, 300MUg/ml, 400MUg/ml, 500MUg/ml and 600MUg/ml) against gram positive and gram negative bacteria (S. pnemoniae, S. aureus, E. coli and E. hermannii) using agar well diffusion assay. The increase in concentration, decrease in zone of inhibition. The prepared ZnO morphologies showed photocatalytic activity under the sunlight enhancing the degradation rate of Rhodamine-B (RhB), which is one of the common water pollutant released by textile and paper industries. PMID- 28668516 TI - Effect of monochromatic light on circadian rhythmic expression of clock genes in the hypothalamus of chick. AB - To clarify the effect of monochromatic light on circadian clock gene expression in chick hypothalamus, a total 240 newly hatched chickens were reared under blue light (BL), green light (GL), red light (RL) and white light (WL), respectively. On the post-hatched day 14, 24-h profiles of seven core clock genes (cClock, cBmal1, cBmal2, cCry1, cCry2, cPer2 and cPer3) were measured at six time points (CT 0, CT 4, CT 8, CT 12, CT 16, CT 20, circadian time). We found all these clock genes expressed with a significant rhythmicity in different light wavelength groups. Meanwhile, cClock and cBmal1 showed a high level under GL, and followed a corresponding high expression of cCry1. However, RL decreased the expression levels of these genes. Be consistent with the mRNA level, CLOCK and BMAL1 proteins also showed a high level under GL. The CLOCK-like immunoreactive neurons were observed not only in the SCN, but also in the non-SCN brain region such as the nucleus anterior medialis hypothalami, the periventricularis nucleus, the paraventricular nucleus and the median eminence. All these results are consistent with the auto-regulatory circadian feedback loop, and indicate that GL may play an important role on the circadian time generation and development in the chick hypothalamus. Our results also suggest that the circadian clock in the chick hypothalamus such as non-SCN brain region were involved in the regulation of photo information. PMID- 28668517 TI - Interaction of a bioactive pyrazole derivative with calf thymus DNA: Deciphering the mode of binding by multi-spectroscopic and molecular docking investigations. AB - Deoxyribonuclic acid (DNA) is the most relevant intracellular target for a wide variety of anticancer and antibiotic drugs. Elucidating the binding interaction of small bioactive molecules with DNA provides a structural guideline for designing new drugs with improved selectivity and superior clinical efficacy. In the present work interaction of a newly synthesized biologically relevant fluorophore, namely, (E)-1,5-diphenyl-3-styryl-4,5-dihydro-1H-pyrazole (DSDP) with calf thymus DNA (ctDNA) has been investigated vividly through a number of in vitro studies. Noteworthy modifications in the UV-Vis absorption and emission spectra reveal the formation of the probe-ctDNA complex. Several other spectroscopic experiments such as circular dichromism (CD), iodide induced quenching, competitive binding assay with known groove binder probe, 3 hydroxyflavone (3HF), time resolved fluorescence decay measurements, thermometric experiment in connection with the helix melting of ctDNA etc. unequivocally ascertain the groove binding interaction of DSDP with ctDNA. Determination of the thermodynamic parameters through temperature variation study implies the dominant role of hydrophobic interaction in the probe-DNA binding process. Inappreciable change in the CD spectrum of ctDNA with the addition of DSDP suggests that binding of the probe with the DNA does not lead to a significant modification in the DNA conformation. In-silico molecular docking simulation corroborates the experimental findings and depicts that DSDP favorably binds to the minor groove region of the biomacromolecule. PMID- 28668518 TI - Cytotoxic effect of TDZ on human cervical cancer cells. AB - The present study investigates the anticancer activity of Thidiazuron (TDZ). Anticancer activity of TDZ was evaluated in cervical carcinoma cells (HeLa cells). Sulforhodamine-B (SRB) assay indicates that TDZ was about 100 times more toxic to the cancer cell than normal cells. TUNEL assay showed TDZ induced DNA damage in tumor cells. The loss of mitochondrial membrane potential (MMP) in cancer cells was observed following TDZ treatment. The Bax and bcl-2 gene expression ratio are highly responsible for the regulation of MMP balance, and these ratio was significantly altered following TDZ treatment. The p53 and caspase-3 expressions were increased in cancer cells following treatment. Caspase 3 activation is the key factor for apoptosis. Cytotoxicity of TDZ on HeLa cells was 100 times higher than normal kidney cell (MDCK cells). Moreover, the anticancer activity of TDZ was tested by DNA damage, mitochondrial dysfunction, some gene expression and caspase-3 inhibition in silico. TDZ detected has higher ability on early apoptosis of cancer cell through DNA damage. Additionally, cancer cellular MMP was significantly reduced under inoculation of TDZ. In silico assay confirmed that TDZ was able to bind with the active site of the capase-3 protein. Therefore, taking all these data together it is suggested that the TDZ may be a potential agent to act against cervical cancer cells. PMID- 28668519 TI - Natural alkaloid Luotonin A and its affixed acceptor molecules: Serum albumin binding studies. AB - Effective interaction of natural alkaloid Luotonin A (L) and its affixed acceptor molecules 1 and 2 with donor molecule as Bovine serum albumin (BSA) at various pH (4.0, 7.4 and 10.0) medium have been demonstrated using various conventional spectroscopic techniques. These analyses provide some valuable features on the interaction between BSA and acceptor molecules (L, 1 and 2). From the absorption and fluorescence spectral titration studies, the formation of ground-state complexes between the acceptor molecules (L, 1 and 2) and the BSA have been confirmed. The results of the afore titrations analysis reveal that, the strong binding of receptor 1 with BSA (Kapp 5.68*104M-1; KSV 1.86*106Lmol-1; Ka 6.42*105Lmol-1; Kass 8.09*106M-1; DeltaG -33.35kJ/mol) at physiological pH medium (7.4) than other receptor molecules 2 and L. The Forster resonance energy transfer (FRET) efficiency between the tryptophan (Trp) residues of BSA and acceptor molecules L, 1 and 2 during the interaction, are 28.85, 85.24 and 53.25 % respectively. The superior binding efficacy of acceptor 1 at physiological pH condition has been further confirmed by FT-IR and Raman spectral analysis methods. Moreover, theoretical docking studies of acceptors L, 1 and 2 towards HSA have been demonstrated to differentiate their binding behaviours. It reveals that, acceptor 1 has the strongest binding ability with HSA through two hydrogen bonding and the Atomic contact energy (ACE) value of -483.96kcal/mol. PMID- 28668520 TI - 24-h personal monitoring of exposure to Power Frequency Magnetic Fields in adolescents - Results of a National Survey. AB - OBJECTIVES: The aim of this exposure assessment study was to gain information about the exposure levels of adolescents in Israel to power frequency (50Hz) magnetic fields (MF) through personal monitoring, and to provide reliable data for national policy development. METHODS: 84 adolescents, 6-10th grade students, carried an EMDEX II meter attached to their body for 24h. The meter recorded the MF every 1.5s. The students documented their activities and microenvironments, such as apartment (awake or asleep), school, transportation, open public areas and other indoor environments. RESULTS: The geometric mean (GM) of the daily time weighted average (TWA) of all the participants was 0.059 MUT (STD = 1.83). This result is similar to those of personal exposure surveys conducted in the UK (GM 0.042-0.054MUT), but lower than levels found in the US (GM 0.089 - 0.134MUT). The arithmetic mean was 0.073MUT, 23% higher than the GM. Fields were lowest at school (GM 0.033MUT), and average outdoor exposures were higher than indoor ones. 3.6% of the participants were exposed to daily TWA above 0.2MUT. The typical time spent above 0.2MUT ranged from few minutes to few hours. The time spent above 0.4MUT and 1MUT were much shorter, around 1-15min and from few seconds to 2min, respectively. Momentary peaks ever recorded were in the range of 0.35-23.6MUT CONCLUSIONS: Exposure of adolescents in Israel is similar to data reported in other countries, being below 0.1MUT for the vast majority, with very few average exposures above 0.2MUT. Analysis of the different microenvironments allows for a cost-effective and equitable policy development. PMID- 28668522 TI - The traumatic bone: trauma-induced heterotopic ossification. AB - Heterotopic ossification (HO) is a common occurrence after multiple forms of extensive trauma. These include arthroplasties, traumatic brain and spinal cord injuries, extensive burns in the civilian setting, and combat-related extremity injuries in the battlefield. Irrespective of the form of trauma, heterotopic bone is typically endochondral in structure and is laid down via a cartilaginous matrix. Once formed, the heterotopic bone typically needs to be excised surgically, which may result in wound healing complications, in addition to a risk of recurrence. Refinements of existing diagnostic modalities, like micro- and nano-CT are being adapted toward early intervention. Trauma-induced HO is a consequence of aberrant wound healing, systemic and local immune system activation, infections, extensive vascularization, and innervation. This intricate molecular crosstalk culminates in activation of stem cells that initiate heterotopic endochondral ossification. Development of animal models recapitulating the unique traumatic injuries has greatly facilitated the mechanistic understanding of trauma-induced HO. These same models also serve as powerful tools to test the efficacy of small molecules which specifically target the molecular pathways underlying ectopic ossification. This review summarizes the recent advances in the molecular understanding, diagnostic and treatment modalities in the field of trauma-induced HO. PMID- 28668521 TI - Lipidomics in translational research and the clinical significance of lipid-based biomarkers. AB - Lipidomics is a rapidly developing field of study that focuses on the identification and quantitation of various lipid species in the lipidome. Lipidomics has now emerged in the forefront of scientific research due to the importance of lipids in metabolism, cancer, and disease. Using both targeted and untargeted mass spectrometry as a tool for analysis, progress in the field has rapidly progressed in the last decade. Having the ability to assess these small molecules in vivo has led to better understanding of several lipid-driven mechanisms and the identification of lipid-based biomarkers in neurodegenerative disease, cancer, sepsis, wound healing, and pre-eclampsia. Biomarker identification and mechanistic understanding of specific lipid pathways linked to a disease's pathologies can form the foundation in the development of novel therapeutics in hopes of curing human disease. PMID- 28668523 TI - How to deal with hepatic artery injury during pancreaticoduodenectomy. A systematic review. AB - BACKGROUND: Operative injury to the hepatic artery is a serious complication of pancreaticoduodenectomy and guidelines to manage this complication are lacking. METHODS: A systematic search performed in PubMed database identified eleven studies overall including 20 patients having sustained injury to the hepatic artery during pancreaticoduodenectomy (n=18) or total pancreatectomy (n=2). One further unpublished personal observation following pancreaticoduodenectomy was also included. RESULTS: Sixteen of 21 patients (76%) experienced serious complications including liver necrosis/abscess (n=14), acute liver failure (n=3), and biliary anastomotic dehiscence (n=6). Eleven patients (52%) were reoperated and 5 patients died (24%). Arterial injury was recognized and repaired immediately in five patients, four recovering uneventfully and one dying from acute liver failure (20%). In contrast delayed or conservative treatment in 16 patients was associated with serious early morbidity in 15 patients (94%), leading to death in 4 patients and late biliary complications in four others. CONCLUSIONS: Accidental interruption of arterial flow to the liver during pancreaticoduodenectomy often results in serious short and long-term consequences. Immediate restoration of arterial flow is indicated whenever technically feasible and may prevent early life-threatening complications as well as late biliary stenosis. PMID- 28668524 TI - Effects of dexmedetomidine on CD42a+/CD14+, HLADR+/CD14+ and inflammatory cytokine levels in patients undergoing multilevel spinal fusion. AB - OBJECTIVE: To assess the effects of dexmedetomidine (Dex) on CD42a+/CD14+,HLADR+/CD14+ and inflammatory cytokine levels in patients undergoing multilevel spinal fusion. Patients and methods Forty ASA I-II patients undergoing multilevel spinal fusion were randomly divided into Dex and control groups (n=20). A continuous intravenous infusion of Dex (0.5MUg/kg/h) or normal saline was started 10min prior to induction and was stopped 15min before operation completion. Serum levels of CD42a+/CD14+, HLADR+/CD14+, WBC, PLT, CRP, IL-6, IL 10, and TNF-alpha were measured before induction (T1), 30min (T2) after operation initiation, and 60min (T3), 1d (T4), 3d (T5), and 5d (T6) post-operation. VAS values were obtained at T3, T4, T5 and T6, as well as hospital days. RESULTS: Treatment with Dex significantly decreased CD42a+/CD14+ at T2, T3, and T4, and markedly increased HLADR+/CD14+ at T4 and T5 when compared with controls. CRP and WBC were markedly decreased at T2, T3, T4 and T5 (P<0.01 or P<0.05). Serum IL-6 and TNF-alpha level in Dex group was significantly increased at T3 and T4 (P<0.05), and IL-6 and TNF-alpha level in control group was significantly increased at T2, T3, T4 and T5 (P<0.05) when compared with their respective preoperative levels (T1). IL-6 and TNF-alpha levels at T2, T3, T4 and T5 in Dex group were significantly lower than those in control group (P<0.05). There were no significant differences in operation time, hospital days or VAS values between the two groups (P>0.05). CONCLUSION: Dex can inhibit the inflammatory response and reduce immunosuppression in patients undergoing multilevel spinal fusion. PMID- 28668525 TI - Dynamics of putative sex pheromone components during heat periods in estrus induced cows. AB - Determination of the optimal insemination time in dairy cows is vital for fertilization success and is a challenging task due to silent or weak signs of estrus shown by some cows. This can be overcome by combining several estrus detection methods, leading to higher detection rates. However, an efficient, noninvasive method for detecting estrus in cows is still needed. Chemical cues released by the cow during estrus have been proposed to have pheromonal properties and signal readiness to mate to the bull. Such cues could be used in an industrial setting to detect cows in estrus. However, no conclusive published data show temporal changes in putative sex pheromone levels during estrus. The goal of this study was to determine the temporal pattern of putative sex pheromone components during estrus and to assess the reproducibility of changes in pheromone concentration with respect to ovulation time. Two injections of the hormone PGF2alpha were administered over a 2-wk interval to induce and synchronize the estrous cycles of 6 Holstein cows. The precise time of ovulation was determined by means of an ultrasound technique, and estrus was determined by visual observation. Using solid-phase microextraction gas chromatography-mass spectrometry techniques, we showed that acetic and propionic acids, which have been proposed to be putative sex pheromone components in cows, were present in the headspaces of all estrous and diestrous fecal samples, whereas 1-iodoundecane was not detected by solid-phase microextraction or by solvent extraction with diethyl ether. Low levels of acids were observed until 1 d before ovulation, at which point their concentrations increased, peaking around 0.5 d before ovulation. The application of labeled synthetic standards revealed that during the peak of release, 36 +/- 8 ng (average +/- SD) of acetic acid and 10 +/- 3 ng of propionic acid were present in 0.5-g samples of estrous-phase fecal matter compared with 19 +/- 5 and 2.3 +/- 1 ng of acetic and propionic acids, respectively, in the control diestrous samples. After the peak, the amounts of the compounds decreased sharply to match those of the control samples and afterward returned to the baseline readings. This decrease in the amounts of putative pheromone components was registered about 12 h before ovulation, indicating that acetic and propionic acids could be used as biomarkers for the electronic detection of ovulation. PMID- 28668526 TI - Effect of supplemental concentrate during the dry period or early lactation on rumen epithelium gene and protein expression in dairy cattle during the transition period. AB - We previously reported 2 experiments with rumen-cannulated Holstein-Friesian dairy cows showing that during the transition period, rumen papillae surface area, and fractional absorption rate of volatile fatty acids (VFA) increase after calving. However, supplemental concentrate during the dry period and rate of increase of concentrate allowance during lactation affected papillae surface area, but not VFA absorption. Here we report the changes in gene and protein expression in rumen papillae related to tissue growth and VFA utilization. The lactation experiment treatment consisted of a rapid [RAP; 1.0 kg of dry matter (DM)/d; n = 6] or gradual (GRAD; 0.25 kg of DM/d; n = 6) increase of concentrate allowance (up to 10.9 kg of DM/d), starting at 4 d postpartum (pp). The dry period experiment treatment consisted of 3.0 kg of DM/d of concentrate (n = 4) or no concentrate (n = 5) during the last 28 d of the dry period. Real-time quantitative PCR analysis of rumen papillae showed that the expression of apoptosis-related genes was neither affected by day nor its interaction with treatment for both experiments. Expression of epithelial transporter genes was not affected by day or treatment in the lactation experiment, except for NBC1. In the dry period experiment, expression of MCT1, NBC1, DRA, NHE2, NHE3, and UT-B generally decreased after calving. A day and treatment interaction was observed for ATP1A1 in the dry period experiment, with greater expression at 18 and 8 d antepartum for concentrate than no concentrate. Generally, expression of VFA metabolism-related genes was not affected by day or its interaction with treatment. In the lactation experiment, immunoblotting of 5 selected genes showed that protein expression of DRA and PCCA was greater at 16 d pp compared with 3 and 44 d pp. Expression of NHE2 was greater, and that of ATP1A1 lower, at 16 and 44 d pp compared with 3 d pp, suggesting alterations in intracellular pH regulation and sodium homeostasis. Both MCT1 and PCCA protein were upregulated by RAP from 3 to 16 d pp, indicating modulations in VFA metabolism. Our data suggests that VFA absorption and metabolic capacity changed little per unit of surface area during the transition period, and suggests that a change in mitosis rate rather than apoptosis rate is associated with the increased ruminal VFA production, resulting in tissue growth. A significant but weak correlation between the examined gene and protein expression levels was observed only for PCCA, indicating that care must be taken when interpreting results obtained at either level. PMID- 28668527 TI - Effectiveness of collective treatments in the prevention and treatment of bovine digital dermatitis lesions: A systematic review. AB - The collective treatment (CT) of an affected herd is commonly advised to control bovine digital dermatitis (DD). Several CT are commercialized, frequently without major evidence supporting their effectiveness. The objective of this systematic review was to evaluate the published evidence that supports CT in the treatment and prevention of DD lesions in dairy herds. Across the evidence, the main limitations in the studies design were identified and the possible sources of inconsistency were investigated. An extensive literature search of publications through electronic databases and gray literature was conducted between July 2015 and January 2016. Studies that did not include an untreated or placebo control group were excluded from the review. The literature search and screening process identified 13 publications with 24 treatment trial comparisons and 18 prevention trial comparisons. The published evidence included studies mostly considered to have a low or unclear risk of bias. Descriptive analyses were performed according to the prevention and treatment outcomes, and case and success definitions were identified for each study and summarized in odds ratios (OR). Pairwise meta analyses were conducted according to the prevention and treatment outcomes, comparing directly the intervention used in each study, and ignoring any other differences in the intervention characteristics. The results of the meta-analyses indicated a low degree of heterogeneity across the evidence for the prevention outcome [I2 = 0%, 95% CI: 0 to 37.2%, 95% prediction interval (PI): 0.72 to 1.74)] and a moderate degree for the treatment outcome (I2 = 25.3%, 95% CI: 0 to 63%, 95% PI: 0.39 to 3.73). Similarly, appraisal of the graphical L'Abbe plot suggested a considerable degree of heterogeneity across the evidence for the treatment outcome. For both outcomes, the frequent small sample sizes of the trials indicate imprecision across the included studies. Additionally, for the treatment and prevention outcomes, an asymmetric funnel plot suggested possible publication bias. The overall quality of the evidence, for both outcomes (prevention and treatment), was therefore considered to be low, indicating that the true effect of CT may be substantially different from that estimated across the included studies. Consequently, this review and meta-analysis does not support an association between the CT considered in the review and a beneficial effect in the prevention and treatment of DD lesions. The effectiveness of CT therefore remains uncertain, and the epidemiological circumstances in which it can be useful must be investigated. These findings highlight the importance of developing high quality, controlled trials to evaluate the effectiveness of CT for DD control. PMID- 28668528 TI - Effect of stocking rate and animal genotype on dry matter intake, milk production, body weight, and body condition score in spring-calving, grass-fed dairy cows. AB - The objective of the experiment was to quantify the effect of stocking rate (SR) and animal genotype on milk production, dry matter intake (DMI), energy balance, and production efficiency across 2 consecutive grazing seasons (2014 and 2015). A total of 753 records from 177 dairy cows were available for analysis: 68 Holstein Friesian and 71 Jersey * Holstein-Friesian (JxHF) cows each year of the experiment under a pasture-based seasonal production system. Animals within each breed group were randomly allocated to 1 of 3 whole-farm SR treatments defined in terms of body weight per hectare (kg of body weight/ha): low (1,200 kg of body weight/ha), medium (1,400 kg of body weight/ha), and high (1,600 kg of body weight/ha), and animals remained in the same SR treatments for the duration of the experiment. Individual animal DMI was estimated 3 times per year at grass using the n-alkane technique: March (spring), June (summer), and September (autumn), corresponding to 45, 111, and 209 d in milk, respectively. The effects of SR, animal genotype, season, and their interactions were analyzed using mixed models. Milk production, body weight, and production efficiency per cow decreased significantly as SR increased due to reduced herbage availability per cow and increased grazing severity. As a percentage of body weight, JxHF cows had higher feed conversion efficiency, higher DMI and milk solids (i.e., kg of fat + kg of protein) production, and also required less energy intake to produce 1 kg of milk solids. The increased production efficiency of JxHF cows at a similar body weight per hectare in the current analysis suggests that factors other than individual cow body weight contribute to the improved efficiency within intensive grazing systems. The results highlight the superior productive efficiency of high genetic potential crossbred dairy cows within intensive pasture-based milk production systems at higher SR where feed availability is restricted. PMID- 28668529 TI - Ruminal bacteria and protozoa composition, digestibility, and amino acid profile determined by multiple hydrolysis times. AB - Microbial samples from 4 independent experiments in lactating dairy cattle were obtained and analyzed for nutrient composition, AA digestibility, and AA profile after multiple hydrolysis times ranging from 2 to 168 h. Similar bacterial and protozoal isolation techniques were used for all isolations. Omasal bacteria and protozoa samples were analyzed for AA digestibility using a new in vitro technique. Multiple time point hydrolysis and least squares nonlinear regression were used to determine the AA content of omasal bacteria and protozoa, and equivalency comparisons were made against single time point hydrolysis. Formalin was used in 1 experiment, which negatively affected AA digestibility and likely limited the complete release of AA during acid hydrolysis. The mean AA digestibility was 87.8 and 81.6% for non-formalin-treated bacteria and protozoa, respectively. Preservation of microbe samples in formalin likely decreased recovery of several individual AA. Results from the multiple time point hydrolysis indicated that Ile, Val, and Met hydrolyzed at a slower rate compared with other essential AA. Singe time point hydrolysis was found to be nonequivalent to multiple time point hydrolysis when considering biologically important changes in estimated microbial AA profiles. Several AA, including Met, Ile, and Val, were underpredicted using AA determination after a single 24-h hydrolysis. Models for predicting postruminal supply of AA might need to consider potential bias present in postruminal AA flow literature when AA determinations are performed after single time point hydrolysis and when using formalin as a preservative for microbial samples. PMID- 28668530 TI - Development of a rapid mitochondrial DNA extraction method for species identification in milk and milk products. AB - Isolation of mitochondrial DNA (mtDNA) from milk offers an effective way to monitor aspects of quality control and traceability to ensure food safety. A few methods of DNA isolation from milk have been reported, but many of them are time consuming and expensive. Here, we report a rapid, simple, and efficient method of mtDNA extraction from raw and processed milk (pasteurized, retorted, and UHT milk) to generate substrate for analysis using any PCR analysis platform. Various techniques used for the separation of mitochondria were explored and combined with a sodium dodecyl sulfate method for mtDNA extraction from raw and processed milk. The optimized protocol supports the efficient amplification of mtDNA independent of sample origin and is sufficiently straightforward to allow its widespread adoption by industry. PMID- 28668531 TI - Short communication: Neonatal calves coagulate first-milking colostrum and produce a large curd for efficient absorption of immunoglobulins after first ingestion. AB - Calves are fed milk and milk replacer for their growth until approximately 2 mo after birth. During this period, their abomasa produce curd and whey from milk. It has been thought that curd formation is important for digestion and absorption of milk nutrients and immune substances in calves. However, no study has been done observing abomasal contents in neonatal calves after first ingestion of first milking colostrum. Here we report curd formation in neonatal calves and its physiological function with a focus on immunoglobulin absorption. We first examined curd formation by ultrasonography in 3 neonatal calves after first ingestion of first-milking colostrum. Between 0.5 and 8 h after colostrum ingestion, a curd was visualized as a large echogenic image with a clear outline, which was surrounded by an anechoic image corresponding to whey. We next compared serum IgG and IgA concentrations in 10 calves fed the pooled colostrum and 7 calves fed the whey solution that did not coagulate into curds. Serum from 1 calf in the pooled colostrum sample set was excluded due to incomplete curd formation in that the whole colostrum did not coagulate into a large mass of curd and a portion of the colostrum remained as its residue caseins detectable from the abomasal fluid. Serum IgG and IgA concentrations were significantly higher in the 9 calves fed the colostrum than the 7 calves fed the whey solution. One calf exhibiting incomplete curd formation showed low levels of serum IgG and IgA after ingestion, similar to the calves fed the whey solution. These results indicate that curd formation is associated with IgG and IgA absorption in neonatal calves after first ingestion of colostrum. PMID- 28668532 TI - Thermal and chemical inactivation of Lactobacillus virulent bacteriophage. AB - The effect of thermal treatments and several biocides on the viability of Lactobacillus virulent phage P1 was evaluated. Times to achieve 99% inactivation (T99) of phage at different treatment conditions were calculated. The thermal treatments applied were 63, 72, and 90 degrees C in 3 suspension media (de Man, Rogosa, Sharpe broth, reconstituted skim milk, and Tris magnesium gelatin buffer). Phage P1 was completely inactivated in 5 and 10 min at 90 and 72 degrees C, respectively; however, reconstituted skim milk provided better thermal protection at 63 degrees C. When phage P1 was treated with various biocides, 800 mg/L of sodium hypochlorite was required for total inactivation (~7.3 log reduction) within 60 min, whereas treatment with 100% ethanol resulted in only a ~4.7 log reduction, and 100% isopropanol resulted in a 5.2-log reduction. Peracetic acid (peroxyacetic acid) at the highest concentration used (0.45%) resulted in only a ~4.-log reduction of phage within 60 min. The results of this study provide additional information on effective treatments for the eradication of potential phage infections in dairy plants. PMID- 28668533 TI - Resynchronization of ovulation protocols for dairy cows including or not including gonadotropin-releasing hormone to induce a new follicular wave: Effects on re-insemination pattern, ovarian responses, and pregnancy outcomes. AB - Our objectives were to evaluate the pattern of re-insemination, ovarian responses, and pregnancy per artificial insemination (P/AI) of cows submitted to different resynchronization of ovulation protocols. The base protocol started at 25 +/- 3 d after artificial insemination (AI) and was as follows: GnRH, 7 and 8 d later PGF2alpha, GnRH 32 h after second PGF2alpha, and fixed timed AI (TAI) 16 to 18 h after GnRH. At 18 +/- 3 d after AI, cows were randomly assigned to the G25 (n = 1,100) or NoG25 (n = 1,098) treatments. The protocol for G25 and NoG25 was the same, except that cows in NoG25 did not receive GnRH 25 +/- 3 d after AI. At nonpregnancy diagnosis (NPD), 32 +/- 3 d after AI, cows from G25 and NoG25 with a corpus luteum (CL) >=15 mm in diameter and a follicle >=10 mm completed the protocol (G25 CL = 272, NoG25 CL = 194), whereas cows from both treatments that did not meet these criteria received a modified Ovsynch protocol with P4 supplementation [controlled internal drug release insert plus GnRH, controlled internal drug release insert removal, and PGF2alpha 7 and 8 d later, GnRH 32 h after second PGF2alpha, and TAI 16 to 18 h after GnRH (G25 NoCL = 53, NoG25 NoCL = 78)]. Serum concentrations of progesterone (P4) were determined and ovarian ultrasonography was performed thrice weekly from 18 +/- 3 d after AI until 1 d after TAI (G25 = 46, NoG25 = 44 cows). A greater percentage of NoG25 cows were re inseminated at detected estrus (NoG25 = 53.5%, G25 = 44.6%), whereas more cows had a CL at NPD in G25 than NoG25 (83.7 and 71.3%). At 32 d after AI, P/AI was similar for G25 and NoG25 for inseminations at detected estrus (38.4 and 42.9%), TAI services for cows with no CL (40.4 and 36.7%), and for all services combined (39.6 and 39.0%). However, P/AI were greater for cows with a CL in G25 than NoG25 (40.6 and 32.8%) that received TAI. More cows ovulated spontaneously or in response to GnRH for the G25 than the NoG25 treatment (70 and 36%) but a similar proportion had an active follicle at NPD (G25 = 91% and NoG25 = 96%). The largest follicle diameter at NPD (G25 = 15.0 +/- 0.4 mm, NoG25 = 16.5 +/- 0.6 mm) and days since it reached >=10 mm (G25 = 4.0 +/- 0.3 d, NoG25 = 5.8 +/- 0.6 d) were greater for the NoG25 than G25 treatment. For cows with a CL at NPD, CL regression after NPD, ovulation after TAI, and ovulatory follicle diameter did not differ. In conclusion, removing the first GnRH of a modified Resynch-25 protocol for cows with a CL at NPD and a modified Ovsynch protocol with P4 supplementation for cows without a CL at NPD resulted in a greater percentage of cows re-inseminated at detected estrus and a similar proportion of cows pregnant in spite of reduced P/AI for cows with a CL at NPD. PMID- 28668534 TI - Short communication: Prediction of milk coagulation and acidity traits in Mediterranean buffalo milk using Fourier-transform mid-infrared spectroscopy. AB - Milk coagulation and acidity traits are important factors to inform the cheesemaking process. Those traits have been deeply studied in bovine milk, whereas scarce information is available for buffalo milk. However, the dairy industry is interested in a method to determine milk coagulation and acidity features quickly and in a cost-effective manner, which could be provided by Fourier-transform mid-infrared (FT-MIR) spectroscopy. The aim of this study was to evaluate the potential of FT-MIR to predict coagulation and acidity traits of Mediterranean buffalo milk. A total of 654 records from 36 herds located in central Italy with information on milk yield, somatic cell score, milk chemical composition, milk acidity [pH, titratable acidity (TA)], and milk coagulation properties (rennet coagulation time, curd firming time, and curd firmness) were available for statistical analysis. Reference measures of milk acidity and coagulation properties were matched with milk spectral information, and FT-MIR prediction models were built using partial least squares regression. The data set was divided into a calibration set (75%) and a validation set (25%). The capacity of FT-MIR spectroscopy to correctly classify milk samples based on their renneting ability was evaluated by a canonical discriminant analysis. Average values for milk coagulation traits were 13.32 min, 3.24 min, and 39.27 mm for rennet coagulation time, curd firming time, and curd firmness, respectively. Milk acidity traits averaged 6.66 (pH) and 7.22 Soxhlet-Henkel degrees/100 mL (TA). All milk coagulation and acidity traits, except for pH, had high variability (17 to 46%). Prediction models of coagulation traits were moderately to scarcely accurate, whereas the coefficients of determination of external validation were 0.76 and 0.66 for pH and TA, respectively. Canonical discriminant analysis indicated that information on milk coagulating ability is present in the MIR spectra, and the model correctly classified as noncoagulating the 91.57 and 67.86% of milk samples in the calibration and validation sets, respectively. In conclusion, our results can be relevant to the dairy industry to classify buffalo milk samples before processing. PMID- 28668535 TI - Insights into the mechanism of the formation of the most stable crystal polymorph of milk fat in model protein matrices. AB - The effect of incorporation and presence of various ingredients in a model sodium caseinate-based imitation cheese matrix on the polymorphism of milk fat was comprehensively described using powder x-ray diffraction, differential scanning calorimetry, and microscopy. With anhydrous milk fat (AMF) in bulk used as control, the embedding of AMF as droplets in a protein matrix was found to result in a greater extent of formation of the beta polymorph than AMF alone and AMF homogenized with water and salts solution. The use of other protein matrices such as soy and whey protein isolate gels revealed that the nature of the protein and other factors associated with it (i.e., hydrophobicity and molecular structure) do not seem to play a role in the formation of the beta polymorph. These results indicated that the most important factor in the formation of the beta polymorph is the physical constraints imposed by a solid protein matrix, which forces the triacylglycerols in milk fat to arrange themselves in the most stable crystal polymorph. Characterization of the crystal structure of milk fat or fats in general within a food matrix could provide insights into the complex thermal and rheological behavior of foods with added fats. PMID- 28668537 TI - Reply. PMID- 28668536 TI - High urea and pregnancy or conception in dairy cows: A meta-analysis to define the appropriate urea threshold. AB - Dietary proteins play an important role in reproduction, and increased dietary crude proteins, increased degradability of dietary proteins, and elevated blood or milk urea have been associated with decreased conception and pregnancy in many studies. The aim of this work was to provide a meta-analysis on the relationship between high milk or blood urea and pregnancy or conception, with a focus on defining the appropriate urea threshold associated with this issue. The meta analysis included 61 different models from 21 papers. The thresholds of urea tested in the various models were built by steps of 1 mM urea. This constructed variable reduced heterogeneity by 61% in the meta-regression. The meta-analysis showed 43% lower odds of pregnancy or conception (odds ratio = 0.57; 95% confidence interval = 0.45-0.73) in cases where urea was >=7.0 mM in the blood (plasma urea nitrogen = 19.3 mg/dL) or where urea was >=420 mg/L in the milk compared with where urea values were lower. This threshold is the most suitable with regard to pregnancy or conception success, even if a threshold of 6.5 mM cannot be excluded with certainty. The results also highlighted the possibility of a stronger association between high urea concentrations and pregnancy or conception when high nitrogen exposure occurs before artificial insemination compared with after artificial insemination, but this possibility needs to be further studied. Whether the present results also apply to extensively pasture based countries remains to be determined. PMID- 28668538 TI - Community Practice Implementation of a Self-administered Version of PREMM1,2,6 to Assess Risk for Lynch Syndrome. AB - BACKGROUND & AIMS: Lynch syndrome is a genetic disorder that greatly increases risk for colorectal and other cancers, although it is underdiagnosed. Prediction of MLH1, MSH2, and MSH6 (PREMM1,2,6) is a web-based tool that analyzes individuals' personal/family histories of cancer to quantify their likelihood of carrying a germline mutation associated with Lynch syndrome. We investigated the feasibility of systematic risk assessment for Lynch syndrome in a community gastroenterology practice using a patient-completed version of PREMM1,2,6. METHODS: PREMM1,2,6 was adapted into a computer tablet version designed for self administration by patients. Individuals presenting to a community gastroenterology office and endoscopy facility in California completed the PREMM1,2,6 assessment before their visit (n = 3134). The total study duration (8 months) comprised a 2-month initiation period (May 1-June 30, 2013) and a 6-month study period (July 1-December 31, 2013). Genetic counseling and germline analysis for mutations in genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM) were offered to individuals with PREMM1,2,6 scores of 5% or higher. Patients and providers completed surveys to evaluate the feasibility and satisfaction with the process. RESULTS: Of the 3134 individuals assessed by PREMM1,2,6 during the 6-month study period, 177 individuals (5.6%) had scores of 5% or higher. Of these, 146 individuals underwent genetic testing, along with 28 additional participants recruited nonconsecutively during the initiation period. Mutations associated with Lynch syndrome were detected in 3 of the 146 individuals (2.1%) with PREMM1,2,6 scores of 5% or higher who underwent germline testing, and 3 of the 28 patients (10.7%) recruited during study initiation with PREMM1,2,6 scores of 5% or higher. Of the participants who underwent genetic analysis, 98.6% stated that they understood the information provided to them. All of the surveyed providers stated that they were satisfied with the incorporation of PREMM1,2,6 into their clinical practice, and that they would continue using it to assess risk for Lynch syndrome. CONCLUSIONS: A patient self-administered version of the PREMM1,2,6 Lynch syndrome risk assessment model can be used systematically in community-based gastroenterology and endoscopy practices. PMID- 28668539 TI - A Diet Low in Fermentable Oligo-, Di-, and Monosaccharides and Polyols Improves Quality of Life and Reduces Activity Impairment in Patients With Irritable Bowel Syndrome and Diarrhea. AB - BACKGROUND & AIMS: We investigated the effects of a diet low in fermentable oligo , di-, and monosaccharides and polyols (FODMAPs) vs traditional dietary recommendations on health-related quality of life (QOL), anxiety and depression, work productivity, and sleep quality in patients with irritable bowel syndrome and diarrhea (IBS-D). METHODS: We conducted a prospective, single-center, single blind trial of 92 adult patients with IBS-D (65 women; median age, 42.6 years) randomly assigned to groups placed on a diet low in FODMAPs or a modified diet recommended by the National Institute for Health and Care Excellence (mNICE) for 4 weeks. IBS-associated QOL (IBS-QOL), psychosocial distress (based on the Hospital Anxiety and Depression Scale), work productivity (based on the Work Productivity and Activity Impairment), and sleep quality were assessed before and after diet periods. RESULTS: Eighty-four patients completed the study (45 in the low-FODMAP group and 39 in the mNICE group). At 4 weeks, patients on the diet low in FODMAPs had a larger mean increase in IBS-QOL score than did patients on the mNICE diet (15.0 vs 5.0; 95% CI, -17.4 to -4.3). A significantly higher proportion of patients in the low-FODMAP diet group had a meaningful clinical response, based on IBS-QOL score, than in the mNICE group (52% vs 21%; 95% CI, 0.52 to -0.08). Anxiety scores decreased in the low-FODMAP diet group compared with the mNICE group (95% CI, 0.46-2.80). Activity impairment was significantly reduced with the low-FODMAP diet (-22.89) compared with the mNICE diet (-9.44; 95% CI, 2.72-24.20). CONCLUSIONS: In a randomized, controlled trial, a diet low in FODMAPs led to significantly greater improvements in health-related QOL, anxiety, and activity impairment compared with a diet based on traditional recommendations for patients with IBS-D. ClinicalTrials.gov, number NCT01624610. PMID- 28668540 TI - Budesonide Versus Acetazolamide for Prevention of Acute Mountain Sickness. AB - BACKGROUND: Inhaled budesonide has been suggested as a novel prevention for acute mountain sickness. However, efficacy has not been compared with the standard acute mountain sickness prevention medication acetazolamide. METHODS: This double blind, randomized, placebo-controlled trial compared inhaled budesonide versus oral acetazolamide versus placebo, starting the morning of ascent from 1240 m (4100 ft) to 3810 m (12,570 ft) over 4 hours. The primary outcome was acute mountain sickness incidence (headache and Lake Louise Questionnaire >=3 and another symptom). RESULTS: A total of 103 participants were enrolled and completed the study; 33 (32%) received budesonide, 35 (34%) acetazolamide, and 35 (34%) placebo. Demographics were not different between the groups (P > .09). Acute mountain sickness prevalence was 73%, with severe acute mountain sickness of 47%. Fewer participants in the acetazolamide group (n = 15, 43%) developed acute mountain sickness compared with both budesonide (n = 24, 73%) (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.3-10.1) and placebo (n = 22, 63%) (OR 0.5, 95% CI 0.2-1.2). Severe acute mountain sickness was reduced with acetazolamide (n = 11, 31%) compared with both budesonide (n = 18, 55%) (OR 2.6, 95% CI 1-7.2) and placebo (n = 19, 54%) (OR 0.4, 95% CI 0.1-1), with a number needed to treat of 4. CONCLUSION: Budesonide was ineffective for the prevention of acute mountain sickness, and acetazolamide was preventive of severe acute mountain sickness taken just before rapid ascent. PMID- 28668541 TI - Non-linear optical microscopy as a novel quantitative and label-free imaging modality to improve the assessment of tissue-engineered cartilage. AB - OBJECTIVE: Current systems to evaluate outcomes from tissue-engineered cartilage (TEC) are sub-optimal. The main purpose of our study was to demonstrate the use of second harmonic generation (SHG) microscopy as a novel quantitative approach to assess collagen deposition in laboratory made cartilage constructs. METHODS: Scaffold-free cartilage constructs were obtained by condensation of in vitro expanded Hoffa's fat pad derived stromal cells (HFPSCs), incubated in the presence or absence of chondrogenic growth factors (GF) during a period of 21 d. Cartilage-like features in constructs were assessed by Alcian blue staining, transmission electron microscopy (TEM), SHG and two-photon excited fluorescence microscopy. A new scoring system, using second harmonic generation microscopy (SHGM) index for collagen density and distribution, was adapted to the existing "Bern score" in order to evaluate in vitro TEC. RESULTS: Spheroids with GF gave a relative high Bern score value due to appropriate cell morphology, cell density, tissue-like features and proteoglycan content, whereas spheroids without GF did not. However, both TEM and SHGM revealed striking differences between the collagen framework in the spheroids and native cartilage. Spheroids required a four-fold increase in laser power to visualize the collagen matrix by SHGM compared to native cartilage. Additionally, collagen distribution, determined as the area of tissue generating SHG signal, was higher in spheroids with GF than without GF, but lower than in native cartilage. CONCLUSION: SHG represents a reliable quantitative approach to assess collagen deposition in laboratory engineered cartilage, and may be applied to improve currently established scoring systems. PMID- 28668542 TI - CD56+/CD16- Natural Killer cells expressing the inflammatory protease granzyme A are enriched in synovial fluid from patients with osteoarthritis. AB - OBJECTIVE: Natural killer (NK) cells have been involved in the pathology of different inflammatory and autoimmune disorders. Inflammation is an important regulator of osteoarthritis (OA), but the molecular and cellular mechanisms regulating this process are not well defined. DESIGN: To understand the role of NK cells in OA, we have compared the phenotype (CD56 subsets and perforin and granzyme expression) and cytotoxic function of NK cells in peripheral blood and synovial fluid from patients with OA undergoing total knee arthroplasty. RESULTS: In contrast to peripheral blood lymphocytes (PBLs), the majority of NK cells from the synovial fluid were CD56brightCD16(-) cells. As expected the expression of the cytolytic mediators perforin and granzyme B in CD56brightCD16(-) cells was low and correlated with a poor cytotoxic potential against K562 sensitive target cells. Surprisingly, this low cytotoxic NK cell subset expressed high levels of granzyme A (a protease recently characterized as a key modulator of inflammation in mouse models) in synovial fluid but not in peripheral blood. The presence of the CD56(+)brightCD16(-) cells expressing granzyme A correlated with increased levels of pro-inflammatory cytokines in synovial fluid from OA patients. CONCLUSION: Our results indicate that NK cells from the synovium of patients with OA, which present an immunoregulatory non-cytotoxic phenotype, show different phenotype comparing with NK cells from peripheral blood, especially expressing granzyme A, a pro-inflammatory molecule which may contribute to the establishment of chronic articular inflammation in this type of patients. PMID- 28668543 TI - Decreasing Opioid Utilization in Rehabilitation Patients Using a Clinical Nurse Specialist Pain Consultant Program. AB - OBJECTIVE: To investigate whether access to a clinical nurse specialist (CNS) with expertise in pain management will result in more rapid decline in opioid use across the rehabilitation hospitalization. DESIGN: Retrospective chart review of patients discharged during 6 months prior to and 6 months after introduction of the CNS role. SETTING: Not-for-profit 98-bed community inpatient rehabilitation hospital. PARTICIPANTS: Two population-based samples of adult, inpatient rehabilitation patients (N=72) with daily opioid use >=30mg morphine equivalent dose (MED) per day on admission and length of stay >=24 days. INTERVENTIONS: Implementation of a CNS pain consult program. MAIN OUTCOME MEASURES: Change in average daily opioid use (milligrams of MED per day), measured at admission, week 1, week 2, and week 3. RESULTS: Linear mixed modeling was used to estimate individual and group average opioid trajectories, including individual patient intercepts (opioid use at admission) and slopes (change in opioid use over time). There was a significant interaction between group and time (b=5.75, t=2.52, P<.01), indicating faster change in opioid use for the CNS group (quadratic slope, -5.91) compared with the no CNS group (quadratic slope, -.16). Quadratic change in the CNS group reflected an initial increase in opioid use from admission to week 1, followed by a steady decline. Conversely, there was virtually no change in the no CNS group. Random effects revealed considerable variability in opioid trajectories across patients. CONCLUSIONS: Addition of a CNS pain consultant program to an inpatient rehabilitation hospital supported a distinct pattern of opioid tapering that promoted more rapid titration of daily opioid use across the rehabilitation hospitalization. PMID- 28668545 TI - Increased production of TGF-beta1 from sputum cells of COPD: Relationship with airway obstruction. AB - Chronic obstructive pulmonary disease (COPD) is a chronic airway disease characterized by a profound airway remodelling that leads to airway obstruction. A role for transforming growth factor-beta1 (TGF-beta1) has been proposed in airway remodelling of COPD. Regarding the TGF-beta1 production at local level, the results seemed to be controversial. In this study, an original model of sputum cell culture thought to maintain important cells interactions, was used. We investigated the production of TGF-beta1 from sputum cell culture in 33 COPD encompassing the whole severity spectrum and compared the results with those found in 39 healthy controls. Sputum was induced by inhalation of saline, the cellular fraction cultured for 24 h and the spontaneous production of total TGF beta1 was assessed by ELISA. Using, a TGF-beta1 reporter cell assay, we also compared the levels of active and total TGF-beta1 in the sputum cell culture supernatants of COPD and controls. Moreover, as a combination of tumor necrosis factor-alpha (TNF-alpha) and TGF-beta1 have been shown to have a cumulative impact on the severity of airflow limitation in COPD, the TNF-alpha release was also measured in a representative subgroup of patients. Our results indicated that the use of sputum cell culture was a reliable and reproducible method to assess TGF-beta1 production at airway level. Sputum cells from COPD produced greater amount of total TGF-beta1 than those of healthy controls (p<0.001). This result was confirmed using the cell reporter assay which also showed a higher level of active TGF-beta1 in the COPD group compared to controls. In addition, total TGF-beta1 production was increased according to GOLD stage and was inversely related to FEV1/FVC ratio (p<0.05). By contrast, the production of this growth factor was not correlated with the functional markers of emphysema nor with demographic characteristics such as age, BMI or smoking status. Interestingly, the production of total TGF-beta1 was inversely related to that of TNF-alpha (r=-0.53, p<0.05) which was decreased in COPD. In summary, COPD patients displayed a raised production of total and active TGF-beta1 from their airway cells. Total TGF-beta1 correlates with the severity of airway obstruction without evidence of a link with emphysema. . PMID- 28668544 TI - The potential impact of cannabis legalization on the development of cannabis use disorders. AB - Specific provisions of legal cannabis legislation and regulation could influence cannabis initiation, frequency and quantity of use, and progression to cannabis use disorder. This brief essay highlights scientifically based principles and risk factors that underlie substance use and addiction that can be leveraged to inform policies that might mitigate the development and consequences of cannabis use disorder. Specifically, pharmacologic, access/availability, and environmental factors are discussed in relation to their influence on substance use disorders to illustrate how regulatory provisions can differentially affect these factors and risk for addiction. Relevant knowledge from research and experience with alcohol and tobacco regulation are also considered. Research designed to inform regulatory policy and to evaluate the impact of cannabis legislation on cannabis use and problems is progressing. However, definitive findings will come slowly, and more concerted efforts and resources are needed to expedite this process. In the meantime, policymakers should take advantage of the large body of scientific literature on substance use to foster empirically-guided, common sense approaches to cannabis policy that focus on prevention of addiction. PMID- 28668546 TI - Effectiveness of montelukast in overweight and obese atopic asthmatics. PMID- 28668547 TI - Associations of self-reported allergic diseases and musculoskeletal problems in children: A US population-based study. AB - BACKGROUND: Previous studies have found increased rates of musculoskeletal problems in adults with allergic disease, but whether this association holds true for children is unknown. OBJECTIVE: To investigate the association of bone, joint, and muscle problems in children with a history of allergic disease. METHODS: Data were obtained from the 2007 Child and Adolescent Health Measurement Initiative. Univariable and multivariable logistic regression models accounting for the sampling design were used to evaluate associations of bone, joint, and muscle problems with allergic diseases, such as asthma, hay fever, food allergies, and eczema. Associations were summarized with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The survey included 91,642 individuals aged 0 to 17 years. Multivariable modeling found statistically significant associations between the number of allergic diseases and bone, joint, and muscle problems (1 allergic disease: adjusted OR, 1.28; 95% CI, 1.04-1.56; P = .02; 2 allergic diseases: adjusted OR, 2.55; 95% CI, 1.92-3.39; P < .001; 3 allergic diseases: adjusted OR, 2.70; 95% CI, 1.88-3.86; P < .001; and 4 allergic diseases: adjusted OR, 4.35; 95% CI, 2.46-7.69; P < .001). Severe eczema (but not mild eczema) was associated with bone, joint, and muscle problems (adjusted OR, 2.81; 95% CI, 1.64-4.81; P < .001) and with bone problems (adjusted OR, 6.08; 95% CI, 1.94-19.12; P = .002). CONCLUSION: Self-reported allergic diseases in children were associated with bone, joint, and muscle problems, and associations strengthened with allergic disease severity and number of allergic diseases. Severe eczema may be associated with bone problems in children. Bone, joint, and muscle problems must be considered in children with severe allergic disease, and prospective studies are necessary to define this association. PMID- 28668549 TI - Design and Implementation of a Robotic Surgery Training Experience Logging System. AB - PURPOSE: Residents currently log robotic cases in the ACGME system as a "surgeon" if they performed any critical step of the procedure on the surgeon console. There is no standardization as to which steps or how much of the procedure should be performed by the resident. It was our objective to establish a tool for logging the true operative experience in robotic surgery to aid in assessing surgical competency as well as curriculum development. MATERIALS AND METHODS: We propose a tool to log surgical skill progression, experience, and feedback for robotic cases. A web-based robotic experience logging system (RoboLog) was developed with procedures deconstructed to their major steps. Trainees may request the supervising attending review their performance. RoboLog provides automated summary reports to both residents and attendings. RESULTS: RoboLog was successfully developed and piloted with a total of 310 cases logged over 1 year. A reporting structure was developed where residents could view statistics on several data points such as step-specific involvement and feedback from attending staff. Detailed data on resident experience were obtained. For instance, 82% of the 151 robotic prostatectomies were logged as "surgeon", yet urethral transection had <35% resident involvement. CONCLUSIONS: Our current system for logging robotic experience is lacking given the fact that resident involvement on the surgical console is variable. Widespread usage of a logging system with more insight into step-specific involvement is needed. RoboLog fills this need and can be used to track robotic training progress and aid in development of a standardized curriculum. PMID- 28668548 TI - Association of prenatal and early childhood stress with reduced lung function in 7-year-olds. AB - BACKGROUND: No prior study has examined associations between prenatal and early life stress on childhood lung function or identified critical windows of exposure. OBJECTIVE: To prospectively examine associations between prenatal and early-life stress and childhood lung function. METHODS: Stress was indexed by a maternal negative life events (NLEs) score ascertained during pregnancy and between 1 and 2 years post partum. Spirometry was performed when children were a mean (SD) of 6.99 (0.89) years old. Associations of prenatal and early postnatal stress with spirometry z scores were examined in 199 children using linear regression. Effect modification by child sex was explored. RESULTS: Most mothers were minorities (65% Hispanic, 21% African American), had 12 years or less of education (67%), and did not smoke prenatally (78%). The highest level of prenatal stress (>=5 NLEs) was associated with lower levels of forced expiratory volume in 1 second (FEV1) (z score = -0.53, P = .03), forced vital capacity (FVC) (z score = -0.49, P = .04), and forced expiratory flow between 25% and 75% (FEF25%-75%) (z score = -0.68, P = .01) after covariate adjustment; effects were similar for postnatal stress considered separately. In sex-stratified analyses, high postnatal stress (>=5 NLEs) was associated with lower FEV1 (z score = -0.76, P = .01), FVC (z score = -0.77, P = .01), and FEF25%-75% (z score = -0.67, P = .02) in boys but not girls, although the interaction term was not significant (P for interaction >.10). CONCLUSION: These are the first prospective data that link perinatal stress with reduced child lung function. High levels of stress in the prenatal and postnatal periods were associated with symmetric reductions in FEV1 and FVC consistent with impaired lung growth. Given that lung function growth patterns are established by 7 years of age, these findings have lifelong implications. PMID- 28668550 TI - Impact of audio-visual storytelling in simulation learning experiences of undergraduate nursing students. AB - BACKGROUND: Use of high fidelity simulation has become increasingly popular in nursing education to the extent that it is now an integral component of most nursing programs. Anecdotal evidence suggests that students have difficulty engaging with simulation manikins due to their unrealistic appearance. Introduction of the manikin as a 'real patient' with the use of an audio-visual narrative may engage students in the simulated learning experience and impact on their learning. A paucity of literature currently exists on the use of audio visual narratives to enhance simulated learning experiences. OBJECTIVE: This study aimed to determine if viewing an audio-visual narrative during a simulation pre-brief altered undergraduate nursing student perceptions of the learning experience. DESIGN: A quasi-experimental post-test design was utilised. PARTICIPANTS: A convenience sample of final year baccalaureate nursing students at a large metropolitan university. METHODS: Participants completed a modified version of the Student Satisfaction with Simulation Experiences survey. This 12 item questionnaire contained questions relating to the ability to transfer skills learned in simulation to the real clinical world, the realism of the simulation and the overall value of the learning experience. Descriptive statistics were used to summarise demographic information. Two tailed, independent group t-tests were used to determine statistical differences within the categories. RESULTS: Findings indicated that students reported high levels of value, realism and transferability in relation to the viewing of an audio-visual narrative. Statistically significant results (t=2.38, p<0.02) were evident in the subscale of transferability of learning from simulation to clinical practice. The subgroups of age and gender although not significant indicated some interesting results. CONCLUSIONS: High satisfaction with simulation was indicated by all students in relation to value and realism. There was a significant finding in relation to transferability on knowledge and this is vital to quality educational outcomes. PMID- 28668551 TI - Crossing the "line": College students and academic integrity in nursing. AB - BACKGROUND: Researchers have shown a relationship between academic integrity in the classroom and acts of dishonest behavior in the clinical setting which is concerning for nursing faculty and the health care field. OBJECTIVES: The purpose of this study was to compare the attitudes toward academic integrity and the frequency of behaviors related to academic dishonesty in nursing and non-nursing students at a religiously affiliated institution. DESIGN: A cross-sectional, descriptive design was used to collect data regarding the knowledge, behavior, perceptions, and attitudes related to academic integrity via an online survey. SETTINGS AND PARTICIPANTS: Nursing students and non-nursing students who attended a religiously affiliated (Jesuit) University in the United States were surveyed for this study. RESULTS: Results of the study suggest upper division and second degree nursing students are less tolerant and more condemnatory of cheating than younger students. Frequent dishonest classroom behaviors include asking and telling other students what was on the exam while the most frequent dishonest clinical behaviors included documenting findings that were not assessed or findings that were false. CONCLUSION: Recommendations for nursing faculty include frequent and timely discussion of expected behaviors and values of nurses in order to support students' development of honesty and integrity beyond the classroom and into the clinical setting. PMID- 28668552 TI - The effect of an 8-week stabilization exercise program on the lumbopelvic rhythm and flexion-relaxation phenomenon. AB - BACKGROUND: Lumbar stabilization exercise programs should normalize the aberrant movements patterns often observed in patients with low back pain. This study aimed to determine the effect of an 8-week lumbar stabilization program on EMG/kinematics measures of the aberrant movement patterns in such patients. A secondary goal was to assess the 8-week test-retest reliability of these measures. METHODS: The patients followed an 8-week lumbar stabilization program while no intervention was carried out on the controls. Before and after this period, kinematics of the spine along with the EMG of paraspinal muscles were recorded during trunk maximal flexion-extension. ANOVAs tested the effect of the intervention in the patients, relative to the controls. Within the patients, correlation of the EMG/kinematics measures with the change in disability and pain following the intervention was investigated. FINDINGS: A significant reduction in pain (Hedges's g effect size=2.31) and improvement in function (g=1.74) was reported in the patients. While EMG/kinematics measures disclosed impairments in the patients at baseline compared to the controls, no change was observed over the intervention. Nevertheless, the change of lumbar range of motion was positively correlated (r=0.42; P=0.015) with the change in disability. INTERPRETATION: Although pain and disability decreased following the intervention, the EMG/kinematics measures did not change concomitantly suggesting that the patients learned to stiffen the lumbar spine during the treatment, and this technique was applied even if pain and disability unequivocally decreased after the treatment, which would not necessarily be beneficial to the patient. PMID- 28668553 TI - The recovery response to a novel unannounced laboratory-induced slip: The "first trial effect" in older adults. AB - BACKGROUND: After a single slip, older adults rapidly make adaptive changes to avoid or eliminate further backward loss of balance or a fall. This rapid adaptation has been termed the "single trial effect". The purpose of this study was to explore the relationship between the motor errors subjects experienced upon a novel slip and the selection and execution of corrective response by which they modified their ongoing gait pattern and turned it into a protective step. METHODS: A forward slip was induced in the laboratory among 145 community-living older (>=65year old) adults who were protected by an overhead full body harness system. An eight-camera motion analysis system recorded subjects' kinematics, which was used to compute their instability (motor error), recovery step placement (response selection), and stability gain (motor correction). FINDINGS: A linear relationship was found between the stability errors at recovery foot liftoff and the distance between the recovery foot and slipping foot at the time of its touchdown, reflecting an appropriate selection of response that was proportionate to the motor error. A linear relationship was also found between this step modification and resulting stability gain, indicating that greater step modification resulted in greater stability gain. This learning behavior was surprisingly consistent regardless whether the outcome was a recovery or a fall. INTERPRETATIONS: These results suggest that fallers and non-fallers all have an intact motor learning foundation that has enabled them to rapidly improve their stability in subsequent exposures. PMID- 28668554 TI - ERK pathway activation contributes to the tumor-promoting effects of hepatic stellate cells in hepatocellular carcinoma. AB - BACKGROUND: Activated hepatic stellate cell (aHSC) play a critical role in hepatocellular carcinoma (HCC) progression crosstalking with cancer cell via various signaling pathways. The aim of our study is to explore the tumor promoting effects of aHSCs on HCC via ERK pathway. METHODS: alpha-SMA, p-ERK and p-JNK expression levels in tumoral and peritumoral tissues of HCC were assessed by immunohistochemical and western blotting. The protein and mRNA expression levels in human hepatoma cell treated with aHSC conditioned medium (CM) were determined by western blotting and real-time quantitative PCR, respectively. Cell migration and invasion abilities were assessed using transwell assays. The proliferation ability of HCC cells induced by aHSCs-CM was detected by CCK-8 assay and cell cycle analysis. RESULTS: We found that aHSC number was positively correlated with p-ERK expression levels in tumoral tissues and aHSC-CM could time dependently promote PCNA, p-ERK expression in HCC cells. Moreover, aHSC-CM enhanced HCC cells proliferation via ERK. Additionally, aHSC upregulated c-jun and cyclinD1 expression levels, accelerating the transition from G1 to the S phase of HCC cells, and this effect could be arrested by inhibiting ERK pathway. Furthermore, aHSC-CM promoted migration and invasion of HCC cells via ERK. Epithelial-mesenchymal transitions (EMT) phenomenon could be reversed by ERK suppression. CONCLUSION: High expression of p-ERK and aHSCs may be associated with the aggressive behavior of HCC cells. Secretions from aHSCs could promote proliferation and EMT of HCC cells via ERK1/2/c-jun/cyclinD1 axis or ERK pathway. PMID- 28668555 TI - The obesity paradox: An analysis of pre-procedure weight trajectory on survival outcomes in patients undergoing transcatheter aortic valve implantation. AB - INTRODUCTION: Increased mortality has been observed in those with cardiovascular diseases who are of normal body mass index (BMI) compared to the overweight and the obese. A similar association has been demonstrated in patients undergoing transcatheter aortic valve (TAVI) implantation. However, it still remains unclear whether low or normal BMI itself is unfavourable or whether this is merely a reflection of cardiac cachexia due to severe aortic stenosis. The hypothesis for the study was that weight change prior to TAVI may be associated with increased mortality following the procedure. SUBJECTS, MATERIALS AND METHODS: Single centre retrospective analysis using the SWEDEHEART registry, national mortality statistics and local hospital database. Body mass index was used as the anthropomorphic measurement and patients grouped by WHO categories and weight change trajectory before and at TAVI. Kaplan-Meier survival was constructed and a Cox proportional hazard model used to evaluate predictors of outcome. RESULTS: Consecutive data on 493 patients with three year follow-up between 2008-2015 were evaluated. Overweight and obese body mass index categories (BMI>25) were associated with improved mortality compared to normal and underweight patients (BMI<25) (log rank p=0.02), hazard ratio of 0.68 (0.50-0.93). Weight loss trajectory was associated with increased mortality compared to stable weight (log rank p=0.01), hazard ratio 1.64 p=0.025. CONCLUSION: The pre-procedural weight trajectory of patients undergoing TAVI is an important predictor of clinical outcome after TAVI. Patients with stable weight trajectories are associated with improved mortality outcome compared to those with decreasing weight. PMID- 28668556 TI - 1,2,3,4,6-Penta-O-galloyl-beta-D-glucose, a bioactive compound in Elaeocarpus sylvestris extract, inhibits varicella-zoster virus replication. AB - The aim of this study was to establish the effect of a 70% ethanol extract of Elaeocarpus sylvestris (ESE) on varicella-zoster virus (VZV) replication and identify the specific bioactive component(s) underlying its activity. ESE induced a significant reduction in replication of the clinical strain of VZV. Activity guided fractionation indicated that the ethyl acetate (EtOAc) fraction of ESE contains the active compound(s) inhibiting VZV replication. High-Performance Liquid Chromatography coupled to Electrospray Ionization Quadrupole Time-of Flight Mass Spectrometry (HPLC-Q-TOF-MS/MS) analysis of the EtOAc fraction of ESE facilitated the identification of 13 chemical components. Among these, 1,2,3,4,6 penta-O-galloyl-beta-D-glucose (PGG) markedly suppressed VZV-induced c-Jun N terminal kinase (JNK) activation, expression of viral immediate-early 62 (IE62) protein and VZV replication. Our results collectively support the utility of PGG as a potential candidate anti-viral drug to treat VZV-associated diseases. PMID- 28668558 TI - Early rehabilitation after lumbar disc surgery is not effective or cost-effective compared to no referral: a randomised trial and economic evaluation. AB - QUESTION: Is referral for early rehabilitation after lumbar disc surgery effective and cost-effective compared to no referral? DESIGN: Multicentre, randomised, controlled trial, and economic evaluation with concealed allocation and intention-to-treat-analysis. PARTICIPANTS: Adults who underwent discectomy for a herniated lumbar disc, confirmed by magnetic resonance imaging, and signs of nerve root compression corresponding to the herniation level. INTERVENTION: Early rehabilitation (exercise therapy) for 6 to 8 weeks, versus no referral, immediately after discharge. OUTCOME MEASURES: In line with the recommended core outcome set, the co-primary outcomes were: functional status (Oswestry Disability Index); leg and back pain (numerical rating scale 0 to 10); global perceived recovery (7-point Likert scale); and general physical and mental health (SF12), assessed 3, 6, 9, 12 and 26 weeks after surgery. The outcomes for the economic evaluation were quality of life and costs, measured at 6, 12 and 26 weeks after surgery. RESULTS: There were no clinically relevant or statistically significant overall mean differences between rehabilitation and control for any outcome adjusted for baseline characteristics: global perceived recovery (OR 1.0, 95% CI 0.6 to 1.7), functional status (MD 1.5, 95% CI -3.6 to 6.7), leg pain (MD 0.1, 95% CI -0.7 to 0.8), back pain (MD 0.3, 95% CI -0.3 to 0.9), physical health (MD 3.5, 95% CI -11.3 to 4.3), and mental health (MD -4.1, 95% CI -9.4 to 1.3). After 26 weeks, there were no significant differences in quality-adjusted life years (MD 0.01, 95% CI -0.02 to 0.04 points) and societal costs (MD -?527, 95% CI -2846 to 1506). The maximum probability for the intervention to be cost-effective was 0.75 at a willingness-to-pay of ?32 000/quality-adjusted life year. CONCLUSION: Early rehabilitation after lumbar disc surgery was neither more effective nor more cost-effective than no referral. TRIAL REGISTRATION: Netherlands Trial Register NTR3156. [Oosterhuis T, Ostelo RW, van Dongen JM, Peul WC, de Boer MR, Bosmans JE, Vleggeert-Lankamp CL, Arts MP, van Tulder MW (2017) Early rehabilitation after lumbar disc surgery is not effective or cost-effective compared to no referral: a randomised trial and economic evaluation. Journal of Physiotherapy 63: 144-153]. PMID- 28668559 TI - Characterization of a novel canine T-cell line established from a dog with cutaneous T-cell lymphoma. PMID- 28668557 TI - Adiposity moderates links from early adversity and depressive symptoms to inflammatory reactivity to acute stress during late adolescence. AB - Both early adversity and depression are associated with heightened inflammation. However, few studies have focused on inflammatory reactivity to psychosocial stress and examined adiposity as a potential moderator. Yet, repeated heightened inflammatory reactivity over time is thought to contribute to low-grade chronic inflammation and adipose tissue is a key source of pro-inflammatory cytokines. The purpose of the present study was to examine whether early adversity and depressive symptoms were related to stress-induced inflammation and whether these associations varied by total body and abdominal adiposity as measured by body mass index (BMI) and waist circumference (WC) in a sample of late adolescents. Participants reported on their early family environment and current depressive symptoms, had their height, weight, and WC assessed for adiposity markers, and provided blood samples for IL-6 assessment before and after a standardized laboratory stress task. No main effect of early adversity on IL-6 reactivity to acute stress was observed. However, significant interactions between early adversity and BMI and WC emerged. Greater exposure to early adversity was associated with greater IL-6 responses only among adolescents with higher BMI or WC. The same pattern of findings was observed for depressive symptoms. Additionally, moderated mediation analyses indicated that among adolescents with greater adiposity, early adversity indirectly influenced IL-6 reactivity via current depressive symptoms. These findings contribute to our understanding of vulnerability factors that may amplify the associations between early adversity and depressive symptoms and inflammation during relatively early stages of life. PMID- 28668560 TI - Performance evaluation and microbial community dynamics in a novel AnMBR for treating antibiotic solvent wastewater. AB - This study aims at evaluating the performance and microbial community dynamics of anaerobic membrane bioreactor (AnMBR) treating antibiotic solvent wastewater at improved influent quality period. The whole process was divided into five phases according to the influent COD concentration with a fluctuated volume loading rate (VLR) ranging from 3.9 to 12.7kgCOD/(m3.d). After 249days of operation, the average COD and THF removal efficiency were 93.6% and 98.7%, respectively. The accumulation of VFA, relatively low pH, decline of biogas production and methane content were discovered at higher VLR (>10kgCOD/(m3.d)). Methanomicrobiales are the major population throughout the whole running period. Methanosaetaceae showed a minor relative abundance compared both of them, while Methanobacteriales remained a minimum value. Results showed that the reactor performed an excellent pollutants removal effect because of the function of membranes even at high VLR conditions. PMID- 28668561 TI - Effect of zinc oxide nanoparticles on nitrogen removal, microbial activity and microbial community of CANON process in a membrane bioreactor. AB - In this study, a membrane bioreactor (MBR) was adopted for completely autotrophic nitrogen removal over nitrite (CANON) process. Zinc oxide nanoparticles (ZnO NPs) was step-wise increased to analyze the influence on nitrogen removal, microbial activity and microbial communities. Finally ZnO NPs was removed to study its recovery capability. The bioactivities of ammonia-oxidizing bacteria (AOB), anaerobic ammonia-oxidizing bacteria (AAOB) and nitrite-oxidizing bacteria (NOB) were detected by batch experiments. Results showed that the ZnO NPs with low concentration (<=5mgL-1) was profitable for nitrogen removal while the high concentration performed inhibition, and it lowered the abundance of both AOB and NOB while enhanced that of AAOB. ZnO NPs with high concentration (>=10mgL-1) suppressed both AOB and AAOB, and long-term exposure within ZnO NPs led to microbial diversity decrease. The inhibition threshold of ZnO NPs on CANON process was 10mgL-1, and the profitable concentration was 1mgL-1. PMID- 28668562 TI - Origin and characterization of small membranous vesicles present in the venom of Crotalus durissus terrificus. AB - Small membranous vesicles are small closed fragments of membrane. They are released from multivesicular bodies (exosomes) or shed from the surface membrane (microvesicles). They contains various bioactive molecules and their molecular composition varies depending on their cellular origin. Small membranous vesicles have been identified in snake venoms, but the origin of these small membranous vesicles in the venom is controversial. The aim of this study was to verify the origin of the small membranous vesicles in venom of Crotalus durissus terrificus by morphological analyses using electron microscopy. In addition, the protein composition of the vesicles was analyzed by using a proteome approach. The small membranous vesicles present in the venom were microvesicles, since they originated from microvilli on the apical membrane of secretory cells. They contained cytoplasmic proteins, and proteins from the plasma membrane, endoplasmic reticulum (ER), and Golgi membrane. The release of microvesicles may be a mechanism to control the size of the cell membrane of the secretory cells after intense exocytosis. Microvesicle components that may have a role in envenoming include ecto-5'-nucleotidase, a cell membrane protein that releases adenosine, and aminopeptidase N, a cell membrane protein that may modulate the action of many peptides. PMID- 28668563 TI - Production of a bisdemethylated microcystin variant by Planktothrix rubescens. AB - Reservoir samples from a bloom of Planktothrix rubescens were analyzed by ELISA and LC-MS/MS. The comparison of the results of both methods points to the presence of a microcystin variant not yet available as analytical standard and therefore, not detectable by LC-MS/MS analysis. It is proposed that the unknown cyanotoxin variant is a bisdemethylated microcystin variant, presumably [Asp3,Dha7]-microcystin-RR. [Asp3,Dha7]-MC-RR has not been described for a bloom of P. rubescens before. PMID- 28668564 TI - Serum periostin concentrations and outcomes after severe traumatic brain injury. AB - BACKGROUND: Periostin, a neurite outgrowth-promoting factor, is increasingly expressed in rat brain tissues after cerebral ischemia or subarachnoid hemorrhage. However, periostin concentrations are undetermined in peripheral blood from patients with traumatic brain injury (TBI). METHODS: In this prospective, observational study, serum periostin concentrations were measured in 130 controls and 130 severe TBI patients. We investigated its association with trauma severity reflected by Glasgow Coma Scale (GCS) score and prognosis (i.e., 30-day mortality and 30-day overall survival). RESULTS: As compared with the controls, serum periostin concentrations were significantly increased in the patients [(median, 246.5ng/ml; interquartile range, 164.5-328.6ng/ml) vs. (median, 61.8ng/ml; interquartile range, 37.9-77.9ng/ml), P<0.001]. Periostin concentrations independently correlated with GCS scores (t=-6.199, P<0.001). Serum periostin concentrations higher than 308.2ng/ml predicted 30-day mortality with a sensitivity of 72.4% and a specificity of 78.2% [area under curve, 815; 95% confidence interval (CI), 0.737-0.878]. Periostin concentrations higher than 246.5ng/ml were independently related to 30-day mortality and 30-day overall survival with odds ratio value of 3.829 (95% CI, 1.104-13.281) and hazard ratio value of 5.667 (95% CI, 1.953-16.443) respectively. CONCLUSIONS: Increased serum periostin concentrations clearly reflect trauma severity and mortality following TBI. PMID- 28668565 TI - M2SR, a novel live influenza vaccine, protects mice and ferrets against highly pathogenic avian influenza. AB - The emergence of highly pathogenic avian influenza H5N1 viruses has heightened global concern about the threat posed by pandemic influenza. To address the need for a highly effective universal influenza vaccine, we developed a novel M2 deficient single replication (M2SR) influenza vaccine virus and previously reported that it provided strong heterosubtypic protection against seasonal influenza viruses in mice. In the current study, we assessed M2SR induced protection against H5N1 influenza in mice and ferrets. Mice were intranasally inoculated with M2SR viruses containing the HA and NA from A/Vietnam/1203/2004 (M2SR H5N1) or A/California/07/2009 (M2SR H1N1). All M2SR vaccinated mice survived lethal challenge with influenza A/Vietnam/1203/2004 (H5N1), whereas 40% of mice vaccinated with recombinant H5 HA and none of the naive controls survived. M2SR H5N1 provided sterile immunity, whereas low levels of virus were detected in the lungs of some M2SR H1N1 vaccinated mice. In contrast, recombinant H5 HA vaccinated mice and naive controls showed systemic infection. M2SR H5N1 induced strong serum and mucosal antibody responses (IgG and IgA classes) against H5 HA, with high hemagglutination inhibition (HAI) titers. In contrast, while M2SR H1N1 elicited cross-reactive antibodies recognizing the H5 HA2 stalk region or the neuraminidase, no HAI activity against H5N1 virus was detected after M2SR H1N1 immunization. Both M2SR H5N1 and H1N1 also protected ferrets against lethal challenge with A/Vietnam/1203/2004. A prime-boost regimen provided optimal protection with no virus detected in the respiratory tract or brain after challenge. As in the mouse model, only the M2SR H5N1 vaccine induced HAI antibodies against the challenge virus in ferrets, while the M2SR H1N1 was able to provide protection without the induction of HAI antibodies. In summary, effective protection against highly pathogenic H5N1 influenza virus was provided by both homologous H5N1 M2SR and heterologous H1N1 M2SR demonstrating the cross protective attributes of the M2SR platform. PMID- 28668566 TI - Vaccination of horses with Lyme vaccines for dogs induces short-lasting antibody responses. AB - Borrelia burgdorferi can induce Lyme disease. Approved Lyme vaccines for horses are currently not available. In an effort to protect horses, veterinarians are using Lyme vaccines licensed for dogs. However, data to assess the response of horses to, or determine the efficacy of this off-label vaccine use are missing. Here, antibodies against outer surface protein A (OspA), OspC, and OspF were quantified in diagnostic serum submissions from horses with a history of vaccination with canine Lyme vaccines. The results suggested that many horses respond with low and often short-lasting antibody responses. Subsequently, four experimental vaccination trials were performed. First, we investigated antibody responses to three canine vaccines in B. burgdorferi-naive horses. One killed bacterin vaccine induced antibodies against OspC. OspA antibodies were low for all three vaccines and lasted less than 16weeks. The second trial tested the impact of the vaccine dose using the OspA/OspC inducing bacterin vaccine in horses. A 2mL dose produced higher OspA and OspC antibody values than a 1mL dose. However, the antibody response again quickly declined, independent of dose. Third, the horses were vaccinated with 2 doses of a recombinant OspA vaccine. Previous vaccination and/or environmental exposure enhanced the magnitude and longevity of the OspA antibody response to about 20weeks. Last, the influence of intramuscular versus subcutaneous vaccine administration was investigated for the recombinant OspA vaccine. OspA antibody responses were not influenced by injection route. The current work highlights that commercial Lyme vaccines for dogs induce only transient antibody responses in horses which can also be of low magnitude. Protection from infection with B. burgdorferi should not be automatically assumed after vaccinating horses with Lyme vaccines for dogs. PMID- 28668567 TI - 10-valent pneumococcal conjugate vaccine (PCV10) decreases metabolic activity but not nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae. AB - BACKGROUND: The effect of pneumococcal vaccination is widely variable when measured by nasopharyngeal carriage of vaccine and non-vaccine targets. The aim of this study was to compare the carriage rates and metabolic activity of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis among children who were or were not vaccinated with PCV10. METHODS: We included children with acute respiratory infection aged 6-23months from a cross-sectional study (CHIADO-IVAS). Nasopharyngeal aspirates were collected and respiratory pathogens were quantified by nCounter digital transcriptomics (Nanostring) and metagenomic sequencing of 16S ribosomal RNA (Illumina). The metabolic rate was calculated by the ratio between RNA transcripts and 16S DNA reads. RESULTS: Out of the 80 patients in this study, 53 were vaccinated with PCV10 and 27 were unvaccinated. There was no difference in nasopharyngeal carriage rates of S. pneumoniae, S. aureus, H. influenzae or M. catarrhalis by either transcriptomic analysis or 16S metagenomics. However, unvaccinated children presented a higher metabolic rate for S. pneumoniae compared to PCV10-vaccinated children (Median [25-75th percentiles]: 126 [22.75 218.41] vs. 0[0-47.83], p=0.004). Furthermore, unvaccinated children presented a positive correlation between mRNA counts and 16S DNA reads for S. pneumoniae (r=0.707; p<0.001) and H. influenzae (r=0.525; p=0.005), in contrast to vaccinated children. No such effect was observed for S. aureus and M. catarrhalis. CONCLUSIONS: Vaccination by PCV10 exerts a pathogen-specific effect on pneumococcal metabolic rate. Pathogen RNA/DNA ratio might represent a more sensitive readout for vaccine follow-up, as compared to nasopharyngeal carriage. PMID- 28668568 TI - Norovirus vaccines under development. AB - Noroviruses (NoVs) are one of the leading causes of acute gastroenteritis, including both outbreaks and endemic infections. The development of preventive strategies, including vaccines, for the most susceptible groups (children <5years of age, the elderly and individuals suffering crowding, such as military personnel and travelers) is desirable. However, NoV vaccine development has faced many difficulties, including genetic/antigenic diversity, limited knowledge on NoV immunology and viral cycle, lack of a permissive cell line for cultivation and lack of a widely available and successful animal model. Vaccine candidates rely on inoculation of virus-like particles (VLPs) formed by the main capsid protein VP1, subviral particles made from the protruding domain of VP1 (P particles) or viral vectors with a NoV capsid gene insert produced by bioengineering technologies. Polivalent vaccines including multiple NoV genotypes and/or other viruses acquired by the enteric route have been developed. A VLP vaccine candidate has reached phase II clinical trials and several others are in pre-clinical stages of development. In this article we discuss the main challenges facing the development of a NoV vaccine and the current status of prevailing candidates. PMID- 28668569 TI - Increasing seasonal influenza vaccination among high risk groups in China: Do community healthcare workers have a role to play? AB - BACKGROUND: Seasonal influenza vaccine uptake in China is low. This study aims to assess the role of community healthcare workers (HCWs) in increasing vaccination among high risk groups in China. METHODS: We analyzed data from four knowledge, attitude and practice (KAP) studies on seasonal influenza vaccination in China targeting guardians of young children, pregnant women, adults aged >=60years, and HCWs from 2012 to 2014. RESULTS: Thirty-one percent of pregnant women and 78% adults aged >=60years reported willingness to follow HCWs' recommendations for influenza vaccination. Guardians were more likely to vaccinate their children if they received HCWs' recommendations (35% vs. 17%, p<0.001). Community HCWs were more likely to recommend seasonal influenza vaccination than hospital HCWs (58% vs. 28%, p<0.001). CONCLUSION: Study results suggest the value of incorporating community HCWs' recommendation for seasonal influenza vaccination into existing primary public health programs to increase vaccination coverage among high risk groups in China. PMID- 28668570 TI - Changes in pathogens and pneumococcal serotypes causing community-acquired pneumonia in The Netherlands. AB - BACKGROUND: In 2006 a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the immunisation programme for infants in The Netherlands and replaced by PCV10 in 2011. Limited data exist about the impact of PCV on the aetiology of CAP as a whole. The aim of the present study is to describe the overall changes in microbial aetiology, pneumococcal burden (including non bacteraemic pneumococcal pneumonia) and its serotypes in adult community-acquired pneumonia (CAP) after the introduction of these PCVs. METHODS: Hospitalised adult CAP patients who participated in three consecutive trials were studied (2004-2006 (n=201), 2007-2009 (n=304) and 2012-2016 (n=300) and considered as pre-PCV7, PCV7 and PCV10 period). Extensive conventional microbiological testing was applied for all patients. In addition, patients with a serotype-specific pneumococcal antibody response were diagnosed with pneumococcal CAP. Changes in proportions of causative pathogens and distributions of pneumococcal serotypes were calculated. RESULTS: The proportion of pneumococcal CAP decreased from 37% (n=74/201) to 26% (n=77/300) comparing the pre-PCV7 period with the PCV10 period (p=0.01). For other pathogens, including Legionella spp., Mycoplasma pneumoniae, S. aureus, H. influenzae, and respiratory viruses, no sustained shifts were observed in their relative contribution to the aetiology of CAP. Within the pneumococcal CAP patients, we observed a decrease in PCV7 and an increase in non-PCV10 serotype disease. PCV10-extra type disease did not decrease significantly comparing the PCV10 period with the pre-PCV7 and PCV7 period, respectively. Notably, PCV7 type disease decreased both in bacteraemic and non-bacteraemic patients. CONCLUSIONS: Our findings confirm that PCV introduction in infants impact the microbial aetiology of adult CAP and suggest herd effects in adults with CAP after introduction of PCVs in children. PMID- 28668571 TI - Hepatitis B vaccine birth dose coverage correlates worldwide with rates of institutional deliveries and skilled attendance at birth. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection occurs in 90% of infants infected perinatally but is prevented when a hepatitis B vaccine is given within 24h of birth (HepB-BD), followed by 2-3 additional doses. METHODS: Using Spearman's rho correlation coefficients (rho), we analyzed global and regional data to assess correlations between HepB-BD coverage, institutional delivery rates (IDR), skilled birth attendance (SBA) rates, and other potential co variates. RESULTS: Significant correlations were observed worldwide between HepB BD and SBA rates (rho=0.44, p<0.001), IDR (rho=0.42, p<0.001), adult literacy rate (rho=0.37, p=0.003), total health expenditure per capita (rho=0.24, p=0.03) and live births (rho=-0.27, p=0.014). HepB-BD, IDR, and SBA rates were significantly correlated in the World Health Organization African, South-East Asia and Western Pacific Regions. CONCLUSIONS: Increasing IDR and SBA rates, training and supervising staff, increasing community awareness, and using HepB-BD outside the cold chain where needed would increase HepB-BD coverage and prevent chronic infections. PMID- 28668572 TI - Characteristics of pediatric invasive pneumococcal diseases and the pneumococcal isolates in Suzhou, China before introduction of PCV13. AB - BACKGROUND: Data on characteristics of invasive pneumococcal diseases (IPD) is limited in China. We aimed to understand the clinical features and explore the molecular characteristics of the pneumococcal isolates in China. METHODS: Since 2010, we prospectively collected the pneumococcal isolates and the IPD patients' demographic and clinical information in Suzhou University Affiliated Children's Hospital (SCH). The antibiotic susceptibility, serotypes, genotypes of Streptococcus pneumoniae strains were identified by E-test, quellung reaction and/or multiplex PCR, and multi-locus sequence typing, respectively. RESULTS: During the period from January 2010 to December 2015, a total of 80 IPD patients were identified. They were diagnosed as meningitis (31.3%), septicemia (27.5%), pneumonia (21.3%) and others (20.0%). About half of them required vancomycin treatment, 42.5% were admitted to ICUs, 36.2% had complications and 6.2% were hospitalized for over 1year. The most common serotypes of the pneumococcal isolates were serotypes 6B and 14, the coverage of PCV13 was 92.5%, and CC236s and CC199s were the most common clone complexes. CONCLUSIONS: Pediatric IPD patients had severe clinical symptoms, demanded intensive treatment, suffered poor prognosis and substantial burden. The pneumococcal isolates' serotype coverage of PCV13 vaccine was high, which leads to implication of PCV vaccine usage among children in China. PMID- 28668573 TI - Safety and immunogenicity of an inactivated cell culture-derived H7N9 influenza vaccine in healthy adults: A phase I/II, prospective, randomized, open-label trial. AB - BACKGROUND: We conducted a phase I/II clinical trial to evaluate the safety and immunogenicity of a Madin-Darby canine kidney (MDCK) cell-grown inactivated H7N9 influenza vaccine for pandemic preparedness purposes. METHODS: Between April 7, 2015 and May 27, 2016, healthy adults aged 20-60years were enrolled sequentially in phase I (n=40) and phase II (n=160) from three hospitals in Taiwan and randomized to receive 2 doses of whole-virus H7N9 vaccine (15 or 30MUg hemagglutinin antigen (HA) with or without an aluminum hydroxide adjuvant) at 21 day intervals. Safety up to 180days and changes in hemagglutinin inhibition (HI) titers at 21days after each vaccination were determined. RESULTS: Of the 200 randomized subjects, 193 (96.5%) received 2 doses of the study vaccine and were included in the intention-to-treat analysis for safety, and 190 (95%) were included in the per-protocol analysis for immunogenicity. Most adverse events were mild and transient; no death or vaccine-related serious adverse events were reported. Overall, higher immune responses were observed in the groups administered with 30MUgHA formulation than in the other two groups administered with 15MUgHA formulation. The highest immune response was observed in subjects who received 2 doses of the adjuvanted vaccine containing 30MUgHA with HI titer, seroprotection rate, seroconversion rate, and seroconversion factor of 36.2, 64.6%, 64.6% and 5.7, respectively. CONCLUSIONS: Our study demonstrated that the H7N9 influenza vaccine containing 30ugHA with aluminum hydroxide adjuvant was immunogenic and safe in adults aged 20-60years. CLINICALTRIALS.GOV identifier: NCT02436928. PMID- 28668574 TI - Heterologous prime-boost immunization of Newcastle disease virus vectored vaccines protected broiler chickens against highly pathogenic avian influenza and Newcastle disease viruses. AB - Avian Influenza virus (AIV) is an important pathogen for both human and animal health. There is a great need to develop a safe and effective vaccine for AI infections in the field. Live-attenuated Newcastle disease virus (NDV) vectored AI vaccines have shown to be effective, but preexisting antibodies to the vaccine vector can affect the protective efficacy of the vaccine in the field. To improve the efficacy of AI vaccine, we generated a novel vectored vaccine by using a chimeric NDV vector that is serologically distant from NDV. In this study, the protective efficacy of our vaccines was evaluated by using H5N1 highly pathogenic avian influenza virus (HPAIV) strain A/Vietnam/1203/2004, a prototype strain for vaccine development. The vaccine viruses were three chimeric NDVs expressing the hemagglutinin (HA) protein in combination with the neuraminidase (NA) protein, matrix 1 protein, or nonstructural 1 protein. Comparison of their protective efficacy between a single and prime-boost immunizations indicated that prime immunization of 1-day-old SPF chicks with our vaccine viruses followed by boosting with the conventional NDV vector strain LaSota expressing the HA protein provided complete protection of chickens against mortality, clinical signs and virus shedding. Further verification of our heterologous prime-boost immunization using commercial broiler chickens suggested that a sequential immunization of chickens with chimeric NDV vector expressing the HA and NA proteins following the boost with NDV vector expressing the HA protein can be a promising strategy for the field vaccination against HPAIVs and against highly virulent NDVs. PMID- 28668575 TI - Meningococcal serogroup C immunogenicity, antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial. AB - BACKGROUND: Adolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster. METHODS: Healthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year. RESULTS: Of 501 participants, 464 (92.6%) were included in the 'according to protocol' cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds. CONCLUSION: Both MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease in the long term. PMID- 28668577 TI - A mitochondrial protein increases glycolytic flux. AB - The purpose of this study was to determine the role of mitochondria in postmortem muscle metabolism. Isolated mitochondria were incorporated into a reaction buffer that mimics postmortem glycolysis with or without mitochondrial electron transport chain inhibitors. Addition of mitochondria lowered pH values at 240 and 1440min regardless of inhibitors. Reduction in pH was accompanied by enhanced glycogen degradation and lactate accumulation. To explore the mechanism responsible for this exaggerated metabolism, mitochondrial preparations were mechanically disrupted and centrifuged. Resulting supernatants and pellets each were added to the in vitro model. Mitochondrial supernatants produced similar effects as those including intact mitochondria. To narrow further our target of investigation, mitochondrial supernatants were deproteinized with perchloric acid. The effect of mitochondrial supernatant was lost after perchloric acid treatment. These data indicate that a mitochondrial-based protein is capable of increasing glycolytic flux in an in vitro model and may partially explain acid meat development in highly oxidative AMPKgamma3R200Q mutated pigs. PMID- 28668578 TI - Computer-assisted three-dimensional tracking of sensory innervation in the murine bladder mucosa with two-photon microscopy. AB - A strong association between functional bladder disorders and bladder sensation is well-known, with a relationship between malfunctioning detrusor muscle and abnormal sensation arising from the sub-urothelium and the lamina propria (LP), has been suggested. However, the exact underlying pathophysiology of these bladder disorders is not completely understood. Therefore, it is important to gain knowledge on sensory innervation of the urinary bladder in order to understand the neural network function in healthy and diseased bladder. In the present study we aim at the development of a computer-assisted method for 3D tracking of sensory innervation in the murine bladder mucosa using two-photon laser scanning microscopy (TPLSM). TPLSM was performed on 10 fixed, stained (CGRP) bladder samples in both the trigone and dome. Nerve tracking was performed in subvolumes (6.3+/-2.9106MUm3; median+/-IQR) of 22 stacks with determining total nerve length, nerve segment lengths, curviness, straightness, and locations of branching and ending points in the lamina propria (LP). The results show that the highest concentration of afferent fibres was found at the urothelium-LP interface. Nerve curviness, a presumed indicator of nerve activity, showed an equal value throughout the complete LP. We found a significantly higher median nerve segment length in the LP of the trigone and significantly more curved nerves in the dome of the bladder. This indicates an adaptation to, or an involvement in the detection of, bladder volume changes. Conclusively, we successfully developed a computer-assisted method for 3D tracking of sensory nerve fibres in the LP of the murine bladder wall. PMID- 28668576 TI - Functional outcomes following lesions in visual cortex: Implications for plasticity of high-level vision. AB - Understanding the nature and extent of neural plasticity in humans remains a key challenge for neuroscience. Importantly, however, a precise characterization of plasticity and its underlying mechanism has the potential to enable new approaches for enhancing reorganization of cortical function. Investigations of the impairment and subsequent recovery of cognitive and perceptual functions following early-onset cortical lesions in humans provide a unique opportunity to elucidate how the brain changes, adapts, and reorganizes. Specifically, here, we focus on restitution of visual function, and we review the findings on plasticity and re-organization of the ventral occipital temporal cortex (VOTC) in published reports of 46 patients with a lesion to or resection of the visual cortex early in life. Findings reveal that a lesion to the VOTC results in a deficit that affects the visual recognition of more than one category of stimuli (faces, objects and words). In addition, the majority of pediatric patients show limited recovery over time, especially those in whom deficits in low-level vision also persist. Last, given that neither the equipotentiality nor the modularity view on plasticity was clearly supported, we suggest some intermediate possibilities in which some plasticity may be evident but that this might depend on the area that was affected, its maturational trajectory as well as its structural and functional connectivity constraints. Finally, we offer suggestions for future research that can elucidate plasticity further. PMID- 28668579 TI - A Candidate Imaging Marker for Early Detection of Charcot Neuroarthropathy. AB - Inflammation-mediated foot osteopenia may play a pivotal role in the etiogenesis, pathogenesis, and therapeutic outcomes in individuals with diabetes mellitus (DM), peripheral neuropathy (PN), and Charcot neuroarthropathy (CN). Our objective was to establish a volumetric quantitative computed tomography-derived foot bone measurement as a candidate prognostic imaging marker to identify individuals with DMPN who were at risk of developing CN. We studied 3 groups: 16 young controls (27 +/- 5 years), 20 with DMPN (57 +/- 11 years), and 20 with DMPN and CN (55 +/- 9 years). Computed tomography image analysis was used to measure metatarsal and tarsal bone mineral density in both feet. The mean of 12 right (7 tarsals and 5 metatarsals) and 12 left foot bone mineral densities, maximum percent difference in bone mineral density between paired bones of the right and the left feet, and the mean difference of the 12 right and the 12 left bone mineral density measurements were used as input variables in different classification analysis methods to determine the best classifier. Classification tree analysis produced no misclassification of the young controls and individuals with DMPN and CN. The tree classifier found 7 of 20 (35%) individuals with DMPN to be classified as CN (1 participant developed CN during follow-up) and 13 (65%) to be classified as healthy. These results indicate that a decision tree employing 3 measurements derived from volumetric quantitative computed tomography foot bone mineral density defines a candidate prognostic imaging marker to identify individuals with diabetes and PN who are at risk of developing CN. PMID- 28668580 TI - Elevated levels of circulating osteopontin are associated with a poor survival after resection of cholangiocarcinoma. AB - BACKGROUND & AIMS: Cholangiocarcinoma (CCA) represents a primary hepatic malignancy with incidence and mortality rising globally. Surgical treatment has remained the only potentially curative treatment option, but it is still unclear which patients benefit most from extended liver surgery, highlighting the need for new pre-operative stratification strategies. Osteopontin is a secreted extracellular glyco-phosphoprotein that has been associated with inflammation, metabolic disorders and cancer. Here, we examined the potential of circulating osteopontin serum levels as a diagnostic or prognostic biomarker in patients with CCA undergoing extended liver surgery. METHODS: Osteopontin expression levels were analysed in human and murine CCA tumour samples, using semi-quantitative reverse transcriptase PCR and immunohistochemistry. Osteopontin serum concentrations were measured by enzyme-linked immunosorbent assay in 107 patients with CCA undergoing elective tumour resection as well as 55 healthy controls. Results were correlated with clinical data. RESULTS: Correlating with an upregulation in CCA tumour cells and the tumour stroma, serum levels of osteopontin were elevated in patients with cholangiocarcinoma compared to healthy controls and patients with primary sclerosing cholangitis. Importantly, pre- and postoperative elevations of osteopontin showed a striking association with poor postoperative survival. CONCLUSIONS: Serum osteopontin concentrations represent a promising prognostic biomarker in patients resectable CCA which could help to guide preoperative treatment decisions and to identify patients that will particularly benefit from extended liver surgery. Lay summary: Extended liver surgery is the only potentially curative treatment for patients with cholangiocarcinoma (CCA/biliary cancer), but it is currently unclear which patients benefit most from surgery. Detecting serum levels of osteopontin - a specific secreted glycoprotein involved in multiple human diseases - in CCA patients might help to identify those patients that particularly benefit from tumour resection. PMID- 28668581 TI - Sorting of nuclear-encoded chloroplast membrane proteins. AB - Among the many organelles in eukaryotic cells, chloroplasts have the most complex structure, with multiple suborganellar membranes, making protein targeting to chloroplasts, particularly to various suborganellar membranes, highly challenging. Multiple mechanisms function in the biogenesis of chloroplast membrane proteins. Nuclear-encoded nascent proteins can be targeted to the outer envelope membrane directly from the cytosol after translation, but their targeting to the inner envelope and thylakoid membranes requires multiple steps, including cytosolic sorting, translocation across the envelope membranes, sorting in the stroma, and insertion into their target membranes. In this review, we discuss the current knowledge about the sorting mechanisms of proteins to the two envelope membranes and the thylakoid membrane, along with perspectives for future research. PMID- 28668582 TI - Selective laser sintering (SLS) 3D printing of medicines. AB - Selective laser sintering (SLS) 3-dimensional printing is currently used for industrial manufacturing of plastic, metallic and ceramic objects. To date there have been no reports on the use of SLS to fabricate oral drug loaded products; therefore, the aim of this work was to explore the suitability of SLS printing for manufacturing medicines. Two thermoplastic pharmaceutical grade polymers, Kollicoat IR (75% polyvinyl alcohol and 25% polyethylene glycol copolymer) and Eudragit L100-55 (50% methacrylic acid and 50% ethyl acrylate copolymer), with immediate and modified release characteristics respectively, were selected to investigate the versatility of a SLS printer. Each polymer was investigated with three different drug loadings of paracetamol (acetaminophen) (5, 20 and 35%). To aid the sintering process, 3% Candurin(r) gold sheen was added to each of the powdered formulations. In total, six solid formulations were successfully printed; the printlets (3D printed tablets) were robust, and no evidence of drug degradation was observed. In biorelevant bicarbonate dissolution media, the Kollicoat formulations showed pH-independent release characteristics, with the release rate dependent on the drug content. In the case of the Eudragit formulations, these showed pH-dependent, modified-release profiles independent of drug loading, with complete release being achieved over 12h. In conclusion, this work has demonstrated that SLS is a versatile and practical 3D printing technology which can be applied to the pharmaceutical field, thus widening the armamentarium of 3D printing technologies available for the manufacture of modern medicines. PMID- 28668583 TI - Pharmaceutical versatility of cationic niosomes derived from amino acid-based surfactants: Skin penetration behavior and controlled drug release. AB - The natural capability shown by cationic vesicles in interacting with negatively charged surfaces or biomolecules has recently attracted increased interest. Important pharmacological advantages include the selective targeting of the tumour vasculature, the promotion of permeation across cell membranes, as well as the influence of cationic vesicles on drug delivery. Accordingly, cationic amphiphiles derived from amino acids may represent an alternative to traditional synthetic cationic surfactants due to their lower cytotoxicity. The importance of a synthesized lysine-based gemini surfactant (labelledC6(LL)2) was evaluated in drug delivery by designing cationic niosomes as usable pharmaceutical tools of chemotherapeutics and antibiotics, respectively like methotrexate and tetracycline. The influence of formulation factors on the vesicles' physical chemical properties, drug entrapment efficiency, in vitro release and ex-vivo skin permeation were investigated. A niosomal gel containing the gemini surfactant was also tested as a viable multi-component topical formulation. Results indicate that in the presence of cholesterol, C6(LL)2 was able to form stable and nanosized niosomes, loading hydrophilic or hydrophobic molecules. Furthermore, in vitro release studies and ex-vivo permeation profiles showed that C6(LL)2-based vesicles behave as sustained and controlled delivery systems in the case of parenteral administration, and as drug percutaneous permeation enhancers after topical application. Finally, cationic C6(LL)2 acts as a carrier constituent, conferring peculiar and interesting functionality to the final formulation. PMID- 28668584 TI - The biotechnology and bioeconomy landscape in Malaysia. AB - Since 1990s Malaysia aspired to make biotechnology and bioeconomy as her engines of economic growth to utlise the abundance of natural resources and biodiversity. The public sector plays an integral role in developing the sector and various incentives are in place for the private sector to be actively involved and to forge collaboration with the public sector. The country launched its National Biotechnology Policy in 2005 and later launched its National Bioeconomy Programme in 2010 to become the first country in South East Asia and second in Asia after China to have such an initiative. Malaysia is also very proactive in its biosafety law and regulations and has most of the related legal instrument in place. A lot of success has been recorded since the inception of the National Biotechnology Policy in terms of job creation, contribution to GDP through biobusinesses and investment from foreign companies, but the sector is not spared from challenges too. Due to the nature of the discipline that is multidisciplinary and that requires huge amount of investment, expertise and political will, there are a lot of barriers before the country emerges as a bioeconomy player. This paper discusses the public policies, initiatives and funding mechanisms in place in Malaysia that drive its research, development and commercialisation in the area of biotechnology and bioeconomy. The authors also discuss the challenges faced in Malaysia in implementing the policies. PMID- 28668585 TI - A competitively designed version of the point subtraction aggression paradigm is related to proactive aggressive and psychopathic traits in males. AB - The Point Subtraction Aggression Paradigm (PSAP) is a well-validated and frequently applied behavioral paradigm for provocation and quantification of reactive aggressive behavior in laboratory settings. Here, we design and test a newly developed PSAP version in its ability to quantify proactive aggressive behavior. A group of 119 male volunteers was allocated to the conventional PSAP and two other variants of the PSAP. The first PSAP adaptation intended to abet proactive aggression by monetary reward for aggressive actions. In the second variant, a highly competitive situation was created. In addition, two sets of aggression questionnaires, related to proactive and reactive aggressive and psychopathic traits, were used (Reactive-Proactive Aggression Questionnaire (RPQ), Psychopathic Personality Inventory-Revised (PPI-R)). Our results showed strong positive correlations among RPQ/PPI-R and aggressive behavior only for the new competitive version of the PSAP. In contrast, the scores of these scales showed weak and non-significant correlations with observed aggression in the two PSAP variants. The scores for reactive aggression were not significantly associated with any of the PSAP versions. These data indicate that aggression on the newly developed competitive PSAP design is mainly driven by proactive aggressive mechanisms. PMID- 28668586 TI - The art of preceptorship. A qualitative study. AB - In the clinical nursing practice preceptorship is a widespread method to improve patient care by assisting nurses in developing the right clinical skills. However, little is known about how preceptorship should be practiced to achieve a positive learning outcome. The aim of the study was to investigate how preceptorship can be used in clinical practice to create learning and facilitate competence development. A qualitative study guided by a hermeneutic phenomenological approach and inspired by ethnographic fieldwork included 28 participant observations and 58 interviews. Data were analysed according to Steinar Kvale's three interpretation contexts. The findings showed three themes: Being together: Preceptee and preceptor were physically present in the same room optimising the learning situation with focus on complexity, use of senses and patient safety. Doing together: Preceptee and preceptor performed nursing together to obtain skills focusing on independence, practical skills and communication. Getting along together: Preceptee and preceptor together focused on the patient, relation, comfort and managing how to keep the balance between a professional and a personal relation. Precepetorship is situated learning where knowledge and skills are generated through participation in clinical practice. In this way, nurses develop clinical judgement and independence. PMID- 28668587 TI - Studying structure and function of spliceosomal helicases. AB - The splicing of eukaryotic precursor mRNAs requires the activity of at least three DEAD-box helicases, one Ski2-like helicase and four DEAH-box helicases. High resolution structures for five of these spliceosomal helicases were obtained by means of X-ray crystallography. Additional low resolution structural information could be derived from single particle cryo electron microscopy and small angle X-ray scattering. The functional characterization includes biochemical methods to measure the ATPase and helicase activities. This review gives an overview on the techniques used to gain insights in to the structure and function of spliceosomal helicases. PMID- 28668588 TI - Optimized FISH methods for visualizing RNA localization properties in Drosophila and human tissues and cultured cells. AB - Eukaryotic gene expression is orchestrated by a large number of regulatory steps to modulate the synthesis, maturation and fate of various families of protein coding and non-coding RNA molecules. Defining the subcellular localization properties of an RNA molecule is thus of considerable importance for gleaning its function(s) and for elucidating post-transcriptional gene regulation pathways. For decades, fluorescent In Situ hybridization (FISH) has constituted the gold standard technique for assessing RNA expression and distribution properties in cultured cells, tissue specimens, and whole mount organisms. Recently, several attempts aimed at advancing multiplex RNA-FISH experiments have been published. However, these procedures are both financially demanding and technically challenging, while their full potential remains unexploited. Here we describe an optimized RNA-FISH method employing the Tyramide Signal Amplification system that robustly enhances resolution and sensitivity needed for exploring RNA localization in Drosophila embryos, tissues and commonly cultured human and insect cell lines. Methodological details and key parameters are outlined for high-throughput analyses conducted in 96-well plate format. PMID- 28668589 TI - Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome. AB - Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis characterized by autoimmune features and lymphoproliferation. Heterozygous germline or somatic FAS mutations associated with preserved protein expression have been described. Very rare cases of homozygous germline FAS mutations causing severe autosomal recessive form of ALPS with a complete defect of Fas expression have been reported. We report two unrelated patients from highly inbred North African population showing a severe ALPS phenotype and an undetectable Fas surface expression. Two novel homozygous mutations have been identified underlying rare splicing defects mechanisms. The first mutation breaks a branch point sequence and the second alters a regulatory exonic splicing site. These splicing defects induce the skipping of exon 6 encoding the transmembrane domain of CD95. Our findings highlight the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing and illustrate the importance of such studies in highly consanguineous populations. PMID- 28668590 TI - Mapping the relationship between anxiety, anhedonia, and depression. AB - INTRODUCTION: Anxiety and depression are often comorbid conditions, but there is uncertainty as to how this comorbidity develops. Thus, in three studies, we attempted to discern whether anhedonia may be a key linking factor between anxiety and depression. METHODS: Three studies asked participants about their symptoms of anxiety and depression: in Study 1, 109 participants completed measures of anxiety, depression, activity avoidance, and perceived enjoyability and importance of avoided activities; in Study 2, 747 participants completed measures of anhedonia, anxiety, depression, and defensiveness; in Study 3, 216 participants completed measures assessing the same constructs as in Study 2 at four time-points (ranging 11 months in span). RESULTS: In Study 1, symptoms of anxiety and depression were positively related only in individuals who relinquished potential enjoyment due to their anxiety-related avoidance; in Study 2, the indirect effect of anhedonia helped explained how anxiety symptoms imparted risk onto depressive symptoms; and in Study 3, anxiety led to anhedonia and then depression over time and anhedonia led to anxiety and then depression at both 5 and 11 months. LIMITATIONS: The manuscript is limited by the use of a student sample in study 2, cross-sectional methods in studies 1 and 2, and reliance on self-ratings. CONCLUSIONS: Anxiety may devolve into depression through anhedonia, such that anxious individuals begin to lose pleasure in anxiety-provoking activities, which results in the development of other depressive symptoms. PMID- 28668591 TI - Alteration of cortico-limbic-striatal neural system in major depressive disorder and bipolar disorder. AB - BACKGROUND: It is often difficult to differentiate major depressive disorder (MDD) and bipolar disorder (BD) merely according to clinical symptoms. Similarities and differences in neural activity between the two disorders remain unclear. In current study, we use amplitude of low-frequency fluctuations (ALFF) to compare neural activation changes between MDD and BD patients. METHODS: One hundred and eighty-three adolescents and young adults (57 MDD, 46 BD and 80 healthy controls, HC) were scanned during resting state. The ALFF for each participant was calculated, and were then compared among all groups using voxel based analysis. RESULTS: There was a significant effect of diagnosis in the core regions of cortico-limbic-striatal neural system. Furthermore, MDD showed left sided abnormal neural activity while BD showed a bilateral abnormality in this neural system. LIMITATIONS: This study was underpowered to consider medications, mood states and neural developmental effects on the neural activation. CONCLUSIONS: Differences in lateralization of ALFF alterations were found. Alterations predominated in the left hemisphere for MDD, whereas alterations were bilateral for BD. PMID- 28668592 TI - Physiologic musculofascial compliance following reinforcement with electrospun polycaprolactone-ureidopyrimidinone mesh in a rat model. AB - PURPOSE: Electrospun meshes may be considered as substitutes to textile polypropylene implants. We compared the host response and biomechanical properties of the rat abdominal wall following reinforcement with either polycaprolactone (PCL) modified with ureidopyrimidinone-motifs (UPy) or polypropylene mesh. METHODS: First we measured the response to cyclic uniaxial load within the physiological range both dry (room temperature) and wet (body temperature). 36 rats underwent primary repair of a full-thickness abdominal wall defect with a polypropylene suture (native tissue repair), or reinforced with either UPy-PCL or ultra-light weight polypropylene mesh (n = 12/group). Sacrifice was at 7 and 42 days. Outcomes were compliance of explants, mesh dimensions, graft related complications and semi-quantitative assessment of inflammatory cell (sub) types, neovascularization and remodeling. RESULTS: Dry UPy-PCL implants are less stiff than polypropylene, both are more compliant in wet conditions. Polypropylene loses stiffness on cyclic loading. Both implant types were well incorporated without clinically obvious degradation or herniation. Exposure rates were similar (n = 2/12) as well as mesh contraction. There was no reinforcement at low loads, while, at higher tension, polypropylene explants were much stiffer than UPy-PCL. The latter was initially weaker yet by 42 days it had a compliance similar to native abdominal wall. There were eventually more foreign body giant cells around UPy-PCL fibers yet the amount of M1 subtype macrophages was higher than in polypropylene explants. There were less neovascularization and collagen deposition. CONCLUSION: Abdominal wall reconstruction with electrospun UPy-PCL mesh does not compromise physiologic tissue biomechanical properties, yet provokes a vivid inflammatory reaction. PMID- 28668593 TI - Mechanical characterization and finite element implementation of the soft materials used in a novel anthropometric test device for simulating underbody blast loading. AB - Soft materials (e.g. polymers) are widely used in biomechanical devices to represent the nonlinear viscoelastic properties inherent in biological soft tissues. Knowledge of their mechanical properties is used to inform design choices and develop accurate finite element (FE) models of human surrogates. The goal of this study was to characterize the behavior of eight polymeric materials used in the design of a novel anthropomorphic test device (ATD) and implement these materials in an FE model of the ATD. Tensile and compressive tests at strain rates ranging from 0.01s-1 to 1000s-1 were conducted on specimens from each material. Stress-strain relationships at discrete strain rates were used to define strain rate-dependent hyper-elastic material models in a commercial finite element solver. Then, the material models were implemented into an FE model of the ATD. The performance of the material models in the FE model was evaluated by simulating experiments that were conducted on the ATD lower limb. The material characterization tests revealed viscoelastic strain rate-dependent properties in the flesh and compliant elements of the ATD. Higher modulus polymers exhibited rate-dependent, strain-hardening properties. A strong agreement was seen between the material model simulations and corresponding experiments. In component simulations, the materials performed well and the model reasonably predicted the forces observed in experiments. PMID- 28668594 TI - The role of tailored biochar in increasing plant growth, and reducing bioavailability, phytotoxicity, and uptake of heavy metals in contaminated soil. AB - Microwave-assisted catalytic pyrolysis was investigated using K3PO4 and clinoptilolite to enhance biochar sorption affinity for heavy metals. The performance of resulting biochar samples was characterized through their effects on plant growth, bioavailability, phytotoxicity, and uptake of heavy metals in a sandy soil contaminated with Pb, Ni, and Co. The produced biochars have high cation-exchange capacity (CEC) and surface area, and rich in plant nutrients, which not only reduced heavy metals (Pb, Ni, and Co), bioavailability and phytotoxicity, but also increased plant growth rate by up to 145%. The effectiveness of biochar in terms of reduced phytotoxicity and plant uptake of heavy metals was further improved by mixing K3PO4 and clinoptilolite with biomass through microwave pyrolysis. This may be due to the predominance of different mechanisms as 10KP/10Clino biochar has the highest micropore surface area (405 m2/g), high concentrations of K (206 g/kg), Ca (26.5 g/kg), Mg (6.2 g/kg) and Fe (11.9 g/kg) for ion-exchange and high phosphorus content (79.8 g/kg) for forming insoluble compounds with heavy metals. The largest wheat shoot length (143 mm) and lowest extracted amounts of Pb (107 mg/kg), Ni (2.4 mg/kg) and Co (63.9 mg/kg) were also obtained by using 10KP/10Clino biochar at 2 wt% load; while the smallest shoot length (68 mm) and highest extracted amounts of heavy metals (Pb 408 mg/kg, Ni 15 mg/kg and Co 148 mg/kg) for the samples treated with biochars were observed for soils mixed with 1 wt% 10Clino biochar. Strong negative correlations were also observed between biochar micropore surface area, CEC and the extracted amounts of heavy metals. Microwave-assisted catalytic pyrolysis of biomass has a great potential for producing biochar with high sorption affinity for heavy metals and rich nutrient contents using properly selected catalysts/additives that can increase microwave heating rate and improve biochar and bio-oil properties. PMID- 28668595 TI - Diagnosing ozone stress and differential tolerance in rice (Oryza sativa L.) with ethylenediurea (EDU). AB - Rising tropospheric ozone concentrations in Asia necessitate the breeding of adapted rice varieties to ensure food security. However, breeding requires field based evaluation of ample plant material, which can be technically challenging or very costly when using ozone fumigation facilities. The chemical ethylenediurea (EDU) has been proposed for estimating the effects of ozone in large-scale field applications, but controlled experiments investigating constitutive effects on rice or its suitability to detect genotypic differences in ozone tolerance are missing. This study comprised a controlled open top chamber experiment with four treatments (i) control (average ozone concentration 16 ppb), (ii) control with EDU application, (iii) ozone stress (average 77 ppb for 7 h daily throughout the season), and (iv) ozone stress with EDU application. Three contrasting rice genotypes were tested, i.e. the tolerant line L81 and the sensitive Nipponbare and BR28. The ozone treatment had significant negative effects on plant growth (height and tillering), stomatal conductance, SPAD value, spectral reflectance indices such as the normalized difference vegetation index (NDVI), lipid peroxidation, as well as biomass and grain yields. These negative effects were more pronounced in the a priori sensitive varieties, especially the widely grown Bangladeshi variety BR28, which showed grain yield reductions by 37 percent. EDU application had almost no effects on plants in the absence of ozone, but partly mitigated ozone effects on foliar symptoms, lipid peroxidation, SPAD value, stomatal conductance, several spectral reflectance parameters, panicle number, grain yield, and spikelet sterility. EDU responses were more pronounced in sensitive genotypes than in the tolerant L81. In conclusion, EDU had no constitutive effects on rice and partly offset negative ozone effects, especially in sensitive varieties. It can thus be used to diagnose ozone damage in field grown rice and for distinguishing tolerant (less EDU-responsive) and sensitive (more EDU-responsive) genotypes. PMID- 28668596 TI - Testing the time-scale dependence of delayed interactions: A heat wave during the egg stage shapes how a pesticide interacts with a successive heat wave in the larval stage. AB - Under global change organisms are exposed to multiple, potentially interacting stressors. Especially interactions between successive stressors are poorly understood and recently suggested to depend on their timing of exposure. We particularly need studies assessing the impact of exposure to relevant stressors at various life stages and how these interact. We investigated the single and combined impacts of a heat wave (mild [25 degrees C] and extreme [30 degrees C]) during the egg stage, followed by successive exposure to esfenvalerate (ESF) and a heat wave during the larval stage in damselflies. Each stressor caused mortality. The egg heat wave and larval ESF exposure had delayed effects on survival, growth and lipid peroxidation (MDA). This resulted in deviations from the prediction that stressors separated by a long time interval would not interact: the egg heat wave modulated the interaction between the stressors in the larval stage. Firstly, ESF caused delayed mortality only in larvae that had been exposed to the extreme egg heat wave and this strongly depended upon the larval heat wave treatment. Secondly, ESF only increased MDA in larvae not exposed to the egg heat wave. We found little support for the prediction that when there is limited time between stressors, synergistic interactions should occur. The intermediate ESF concentration only caused delayed mortality when combined with the larval heat wave, and the lowest ESF concentrations only increased oxidative damage when followed by the mild larval heat wave. Survival selection mitigated the interaction patterns between successive stressors that are individually lethal, and therefore should be included in a predictive framework for the time-scale dependence of the outcome of multistressor studies with pollutants. The egg heat wave shaping the interaction pattern between successive pesticide exposure and a larval heat wave highlights the connectivity between the concepts of 'heat-induced pesticide sensitivity' and 'pesticide induced heat sensitivity'. PMID- 28668597 TI - Mechano-sensitivity of mitochondrial function in mouse cardiac myocytes. AB - Mitochondria are an important source of reactive oxygen species (ROS). Although it has been reported that myocardial stretch increases cellular ROS production by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), referred to as X-ROS signalling, the involvement of mitochondria in X-ROS is not clear. Mitochondria are organelles that generate adenosine triphosphate (ATP) for cellular energy needs, which are mechanical-load-dependent. Therefore, it would not be surprising if these organelles had mechano-sensitive functions associated with stretch-induced ROS production. In the present study, we investigated the relation between X-ROS and mitochondrial stretch-sensitive responses in isolated mouse cardiac myocytes. The cells were subjected to 10% axial stretch using computer-controlled, piezo-manipulated carbon fibres attached to both cell ends. Cellular ROS production and mitochondrial membrane potential (Deltapsim) were assessed optically by confocal microscopy. The axial stretch increased ROS production and hyperpolarised Deltapsim. Treatment with a mitochondrial metabolic uncoupler, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), at 0.5 MUM did not suppress stretch-induced ROS production, whereas treatment with a respiratory Complex III inhibitor, antimycin A (5 MUM), blunted the response. Although NOX inhibition by apocynin abrogated the stretch-induced ROS production, it did not suppress stretch-induced hyperpolarisation of Deltapsim. These results suggest that stretch causes activation of the respiratory chain to hyperpolarise Deltapsim, followed by NOX activation, which increases ROS production. PMID- 28668598 TI - Successful treatment of Pseudomonas aeruginosa osteomyelitis with antibiotic monotherapy of limited duration. AB - OBJECTIVES: The aim of this study was to present a 15-year experience and provide a comprehensive analysis of a large cohort of patients with Pseudomonas aeruginosa osteomyelitis. METHODS: We reviewed the medical records of patients admitted to a large French university hospital for P. aeruginosa osteomyelitis over a 15-year period. Patient outcome was assessed at follow-up after at least six months. RESULTS: Sixty-seven patients were included, comprising 57% with chronic osteomyelitis. Polymicrobial infection was predominant (63%), and an infected device was involved in 39% patients. The overall treatment success rate was 79.1%. All but one patient were treated with a combination of surgery and antibiotic therapy. The antibiotic treatment had a mean duration of 45 days (range, 21-90 days). Single-antibiotic therapy was preferred in nearly all cases. Treatment failure was reported for 14 (21%) patients and was due to the persistence of P. aeruginosa in four cases. No significant risk factor for treatment failure was identified, especially when treatment strategies were compared. CONCLUSIONS: We advocate optimal surgical debridement combined with initial parenteral antibiotics for a maximum of 15 days, followed by an oral fluoroquinolone. Total treatment duration should not exceed six weeks, and antibiotic treatment with two-drug combinations does not seem necessary. PMID- 28668599 TI - Enhancing anaerobic digestion of food waste through biochemical methane potential assays at different substrate: inoculum ratios. AB - Food waste has a high energy potential that can be converted into useful energy in the form of methane via anaerobic digestion. Biochemical Methane Potential assays (BMPs) were conducted to quantify the impacts on methane production of different ratios of food waste. Anaerobic digester sludge (ADS) was used as the inoculum, and BMPs were performed at food waste:inoculum ratios of 0.42, 1.42, and 3.0g chemical oxygen demand/g volatile solids (VS). The 1.42 ratio had the highest CH4-COD recovery: 90% of the initial total chemical oxygen demand (TCOD) was from food waste, followed by ratios 0.42 and 3.0 at 69% and 57%, respectively. Addition of food waste above 0.42 caused a lag time for CH4 production that increased with higher ratios, which highlighted the negative impacts of overloading with food waste. The Gompertz equation was able to represent the results well, and it gave lag times of 0, 3.6 and 30days and maximum methane productions of 370, 910, and 1950mL for ratios 0.42, 1.42 and 3.0, respectively. While ratio 3.0 endured a long lag phase and low VSS destruction, ratio 1.42 achieved satisfactory results for all performance criteria. These results provide practical guidance on food-waste-to-inoculum ratios that can lead to optimizing methanogenic yield. PMID- 28668600 TI - Evaluating opinions, behaviours and motivations of the users of a MSW separate collection centre in the town of Baronissi, Southern Italy. AB - This paper presents the results of a survey regarding customer satisfaction as well as other aspects relating to the frequency and motivations of citizens going to a separate collection centre (SCC) for recyclables in a Southern Italian town. The study was carried out in 2015 to verify whether there were significant changes in the behaviours and opinions of the SCC's users, who had been interviewed in 2013, in the light of the change of the local administration. The majority of the respondents (60.4%) coupled going to the SCC with other tasks, with 58.6% of them going to a supermarket. Therefore, future SCCs should localized near shopping centres (it would be preferable to have small and numerous SCCs). Chi-square and Fisher's exact tests showed how SCC's users of the town under study behaved as a community. The percentage of respondents that declared to 'agree' or 'strongly agree' with the idea that only putrescibles and residue could be collected at their home, with all the other materials being collected at the SCC, increased from 56.6%, in 2013, up to 59.0%, in 2015. The percentage of respondents that declared going to the SCC due to environmental motivations was unanimous. Moreover, the saving of money for the community became the second preferred option, with a significant improvement (from 65.6%, in 2013, up to 93.2%, in 2015). Therefore, the community's interests over the individual's were privileged. The SCC's users confirmed their attention to environmental issues even though the local administration changed. It is probable that this could be the result of maintaining high standard of service as well as a good job in terms of communication, continuous involvment of citizens and the adoption of good environmental practices. PMID- 28668601 TI - Application of high temperature phase change materials for improved efficiency in waste-to-energy plants. AB - This study reports the thermal analysis of a novel thermal energy storage based on high temperature phase change material (PCM) used to improve efficiency in waste-to-energy plants. Current waste-to-energy plants efficiency is limited by the steam generation cycle which is carried out with boilers composed by water walls (i.e. radiant evaporators), evaporators, economizers and superheaters. Although being well established, this technology is subjected to limitations related with high temperature corrosion and fluctuation in steam production due to the non-homogenous composition of solid waste; this leads to increased maintenance costs and limited plants availability and electrical efficiency. The proposed solution in this paper consists of replacing the typical refractory brick installed in the combustion chamber with a PCM-based refractory brick capable of storing a variable heat flux and to release it on demand as a steady heat flux. By means of this technology it is possible to mitigate steam production fluctuation, to increase temperature of superheated steam over current corrosion limits (450 degrees C) without using coated superheaters and to increase the electrical efficiency beyond 34%. In the current paper a detailed thermo-mechanical analysis has been carried out in order to compare the performance of the PCM-based refractory brick against the traditional alumina refractory bricks. The PCM considered in this paper is aluminium (and its alloys) whereas its container consists of high density ceramics (such as Al2O3, AlN and Si3N4); the different coefficient of linear thermal expansion for the different materials requires a detailed thermo-mechanical analysis to be carried out to ascertain the feasibility of the proposed technology. PMID- 28668602 TI - Biochemical, hydrological and mechanical behaviors of high food waste content MSW landfill: Liquid-gas interactions observed from a large-scale experiment. AB - The high food waste content (HFWC) MSW at a landfill has the characteristics of rapid hydrolysis process, large leachate production rate and fast gas generation. The liquid-gas interactions at HFWC-MSW landfills are prominent and complex, and still remain significant challenges. This paper focuses on the liquid-gas interactions of HFWC-MSW observed from a large-scale bioreactor landfill experiment (5m*5m*7.5m). Based on the connected and quantitative analyses on the experimental observations, the following findings were obtained: (1) The high leachate level observed at Chinese landfills was attributed to the combined contribution from the great quantity of self-released leachate, waste compression and gas entrapped underwater. The contribution from gas entrapped underwater was estimated to be 21-28% of the total leachate level. (2) The gas entrapped underwater resulted in a reduction of hydraulic conductivity, decreasing by one order with an increase in gas content from 13% to 21%. (3) The "breakthrough value" in the gas accumulation zone was up to 11kPa greater than the pore liquid pressure. The increase of the breakthrough value was associated with the decrease of void porosity induced by surcharge loading. (4) The self-released leachate from HFWC-MSW was estimated to contribute to over 30% of the leachate production at landfills in Southern China. The drainage of leachate with a high organic loading in the rapid hydrolysis stage would lead to a loss of landfill gas (LFG) potential of 13%. Based on the above findings, an improved method considering the quantity of self-released leachate was proposed for the prediction of leachate production at HFWC-MSW landfills. In addition, a three-dimensional drainage system was proposed to drawdown the high leachate level and hence to improve the slope stability of a landfill, reduce the hydraulic head on a bottom liner and increase the collection efficiency for LFG. PMID- 28668603 TI - The effects of temperament and character traits on perceived social support and quality of life in patients with epilepsy. AB - OBJECTIVES: This study aimed to investigate the effect of temperament and character traits on perceived social support and quality of life in patients with epilepsy (PWE). METHODS: Fifty-two PWE and 54 healthy controls were included in this study. Demographics and clinical data were recorded. Temperament and Character traits were investigated using Temperament and Character Inventory (TCI), Perceived Social Support was evaluated by Multidimensional Scale of Perceived Social Support Scale (MSPSS), and quality of life was assessed using a 36-Item Short-Form Health Survey (SF-36). Participants also completed the Hospital Anxiety Depression Scale (HADS). RESULTS: TCI and MSPSS scores showed no significant difference between the groups (p>0.05). Mental and physical subscales of SF-36 were significantly lower in PWE than the controls (p=0.012, p=0.020, respectively). Multiple linear regression analysis indicated that Reward Dependence and Cooperativeness were independent predictors for perceived social support, and Persistence score was an independent predictor for the physical subscale of SF-36 even after adjustment for confounding background variables (p<0.05, for all). CONCLUSION: Temperament and character traits may affect perceived social support and quality of life in PWE. Thus, an evaluation of temperament and character traits may play a significant role in preventing negative effects on perceived social support and quality of life in PWE. PMID- 28668604 TI - Antifungal activity and expression patterns of extracellular chitinase and beta 1,3-glucanase in Wickerhamomyces anomalus EG2 treated with chitin and glucan. AB - In this study, the expression patterns of extracellular chitinase and beta-1,3 glucanase from cultured Wickerhamomyces anomalus EG2 treated with chitin, glucan, and chemical chitinase inhibitors (kinetin, caffeine, and acetazolamide) were investigated using SDS-PAGE. Relationship between enzyme expression and antifungal activity from yeast plays a very important role for biocontrol of phytopathoges. To determine antifungal activity against phytopathogens, W. anomalus EG2 was shown to strongly inhibit hyphal growth of Fusarium oxysporum KACC 40032 and Rhizoctonia solani KACC 40111. Slight chitinase activity was observed 12 h after incubation in both PDB and YPD medium without colloidal chitin. The molecular weight of chitinase was approximately 124 kDa beta-1,3 Glucanase isoenzyme (GN1 and GN2) was observed distinctly on SDS-PAGE gels when laminarin was used as a substrate. beta-1,3-Glucanase isoenzyme was not observed when using glucan-containing high polymer complex (GHPC) as a substrate. Production of chitinase from W. anomalus EG2 was inhibited slightly by acetazolamide. Abnormal and cluster-shaped cells of W. anomalus EG2 were observed in both PDB and YPD medium treated with colloidal chitin. These results indicated that W. anomalus EG2 could be applied commercially as a biological control agent of phytopathogens and as a bioinhibitor of yeast cell growth. PMID- 28668605 TI - Study on spoilage capability and VBNC state formation and recovery of Lactobacillus plantarum. AB - OBJECTIVE: The present study aimed at investigating the capability of L. plantarum strain BM-LP14723 to enter into and recover from the viable but nonculturable (VBNC) state and to cause beer spoilage. METHODS: VBNC state was induced by incubating in beer with subculturing or low temperature treatment. Culturable, total, and viable cells numbers were assessed by MRS agar plate counting, acridine orange direct counting, and Live/Dead BacLight bacterial viability kit, respectively. Organic acids concentrations were measured by reversed-phase high performance liquid chromatography. RESULTS: VBNC L. plantarum cells were detected after 189 +/- 1.9 days low temperature treatment or 29 +/- 0.7 subcultures in beer. The VBNC L. plantarum retained spoilage capability. Addition of catalase is an effective method for the recovery of the VBNC L. plantarum cells. CONCLUSION: L. plantarum strain BM-LP14723 is capable of entering into and recovery from the VBNC state and maintained spoilage capability. The current study presented that beer-spoilage L. plantarum can hide both in breweries and during transporting and marketing process and thus lead to beer-spoilage incidents. PMID- 28668606 TI - A preliminary study on the proinflammatory mechanisms of Treponema pallidum outer membrane protein Tp92 in human macrophages and HMEC-1 cells. AB - AIMS: To determine proinflammatory mechanisms of Treponema pallidum outer membrane protein Tp92 in the early syphilis infection in human macrophages and HMEC-1 cells. METHODS: Recombinant Tp92 protein was used to stimulate target human macrophages and HMEC-1 cells. PDTC (Pyrrolidinedithiocarbamic acid), SB202190 and Z-YVAD-FMK were used to block the MyD88/NF-kappaB, MAPKs/p38 and NLRP3/Caspase-1 pathway, respectively. TNF-alpha, IL-1beta, IL-6, IL-8,NLRP3, casepase-1 were detected by ELISA or Western blot. Lactate dehydrogenase (LDH) activity was measured. RESULTS: Tp92 protein could significantly induced the secretion of proinflammatory cytokines TNF-alpha, IL-1beta, IL-6 and IL-8 in HMEC 1 cells, but not in macrophages except IL-8. When MyD88/NF-kappaB pathway was blocked, differences in the secretion of TNF-alpha, IL-6 and IL-1beta levels and LDH enzyme activity between Tp92 group and Tp92 + PDTC group were not significant (P > 0.05) in HMEC-1 cells and macrophages except IL-8(P < 0.05). When MAPKs/p38 pathway was blocked, differences in the secretion of TNF-alpha, IL-1beta, IL-6 and IL-8 and LDH enzyme activity both Tp92 group and Tp92 + SB2010190 group were not significant (P > 0.05) in HMEC-1 cells and macrophages. In contrast, when NLRP3/Caspase-1 pathway was blocked with Z-YVAD-FMK, TNF-alpha, IL-6 and IL-1beta levels, LDH enzyme activity, and Caspase-1 and NLRP3 protein levels were significantly declined (P < 0.05) in HMEC-1 cells except IL-8(P > 0.05). The LDH enzyme activity in macrophages was decreased before and after Z-YVAD-FMK blocking (P < 0.05),however, differences in the secretion of TNF-alpha, IL-1beta, IL-6 and IL-8 between Tp92 group and Tp92+Z-YVAD-FMK group in macrophages were not significant (P > 0.05). CONCLUSIONS: Tp92 protein may promote proinflammatory cytokines TNF-alpha, IL-1beta, IL-6 secretion of HMEC-1 cells, but not in macrophages, and increase the LDH enzyme activity of HMEC-1 cells and macrophages through NLRP3/Caspase-1 pathway. However, Tp92 protein may promote IL-8 secretion of HMEC-1 cells and macrophages through MyD88/NF-kappaB pathway. PMID- 28668607 TI - Characterization and serotype distribution of Aggregatibacter actinomycetemcomitans: Relationship of serotypes to herpesvirus and periodontal status in Indian subjects. AB - BACKGROUND: The virulence of Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) in any individual depends on the type of strain of this bacterium. To our knowledge, there have been no studies reported in Indian subjects about A. actinomycetemcomitans serotype occurrence, co-existence with herpes virus and the possible influence of such co-existence on periodontal pathology. METHODS: Subjects for this study were a subset of a larger study to identify the prevalence of A. actinomycetemcomitans in chronic periodontitis. A total of 63 subjects (12 periodontally healthy and 51 with chronic periodontitis) who were positive for A. actinomycetemcomitans were serotyped for strain-level identification. The presence of Human Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) was tested in subgingival plaque samples by polymerase chain reaction. RESULTS: All five serotypes a to e were detected. Of the samples analyzed 38.09% harbored a single serotype, 36.5% had two serotypes, 6.3% demonstrated three and 4.7% demonstrated four serotypes. None of the samples showed presence of JP2 strain. Serotypes b, c, and e were most frequently identified in these individuals (46.03%, 36.5% and 38.09% respectively). Presence of serotypes b and c and absence of serotype d was associated with increased PD and CAL. Among 63 samples analyzed, 11 samples had CMV, four samples had EBV and nine samples had both these viruses. The PD and CAL were significantly higher (p = 0.04) when a combination of CMV and one of the serotypes was present indicating a pathological role of the coexistence. CONCLUSION: Multiple serotypes are associated with chronic periodontitis in Indians, however, JP2 strains are not detectable in this cohort. Presence of multiple serotypes and a combination of any serotype with herpesvirus is associated with greater severity of the disease. PMID- 28668608 TI - Babesia bovis BOV57, a Theileria parva P67 homolog, is an invasion-related, neutralization-sensitive antigen. AB - Babesia bovis BOV57, which is a homolog of the Theileria parva vaccine candidate antigen P67, is expressed in both the tick and blood stages of the life cycle of this parasite. However, the vaccine potential of BOV57 remained to be investigated. In the present study, we generated recombinant BOV57 (rBOV57) and prepared polyclonal antibodies against rBOV57 in mice and rabbits. Indirect immunofluorescence assays conducted with the mouse anti-rBOV57 antibody demonstrated that BOV57 localized at the apical end of paired merozoites in infected bovine red blood cells, whereas the antigen was found in the parasite membrane around the apical end of intraerythrocytic single and extracellular merozoites. In an invasion-inhibition assay, the rabbit anti-rBOV57 antibody potentially inhibited RBC invasion of B. bovis merozoites in vitro. In addition, the invasion inhibition mediated by rabbit anti-rBOV57 antibody resulted in a reduced growth rate of B. bovis in the in vitro culture. These findings indicated that B. bovis BOV57 plays a critical role in the invasion of merozoites into red blood cells, suggesting its potential as a subunit vaccine candidate against B. bovis infection in cattle. Furthermore, we analyzed the genetic diversity of bov57 gene sequences isolated from Sri Lanka, Mongolia, the Philippines, and Vietnam. The bov57 gene sequences derived from Mongolia, the Philippines, and Vietnam were conserved, whereas insertion and/or deletion mutations resulted in sequence diversity among the Sri Lankan samples. In summary, BOV57 is an invasion related, neutralization-sensitive antigen encoded by the bov57 gene, which displays higher sequence diversity than previously reported. PMID- 28668610 TI - Formulation and characterization of chitosan encapsulated phytoconstituents of curcumin and rutin nanoparticles. AB - Curcumin and Rutin are natural polyphenolic molecules exhibits several pharmacological actives like antibacterial, anticancer, antioxidant, chemo preventive and anti-inflammatory properties. However till date, no studies have been reported on their combination efficacy, especially in treating multi-drug resistance of cancers because of their poor solubility and bioavailability. Hence in the present study, an attempt has been made to load both these drugs into a single nanoparticlulate system to enhance their bioavailability and efficacy. This novel formulation was prepared by solvent evaporation technique and was evaluated for particle size and shape using Zeta Sizer, Scanning Electron Microscopy (SEM) and Fourier Transform Infra Red (FT-IR) Spectroscopy. The optimized formulation was further subjected to in vitro and in vivo evaluations. The prepared nanoparticles were in the size range of 25-100nm and the release profile was found to be Non -Fickian transport. In-vivo pharmacokinetic studies were carried in rabbits and the pharmacokinetic profile was studied. The results indicate that oral bioavailability of Curcumin and Rutin has been increased to 3.06 and 4.24 folds respectively when compared to their pure drugs. This data suggest that the present novel nanoparticles loaded with these combinational drugs may have better therapeutic potential in treating drug resistant cancers. PMID- 28668611 TI - Implications of recovery procedures on structural and rheological properties of schizophyllan produced from date syrup. AB - This study investigates the effects of different recovery procedures on high molar mass schizophyllan produced by Schizophyllum commune using low value agricultural residues. Recovered extracellular polysaccharides (EPSs) were compared in terms of purity, sugar composition, degree of branching, molecular weight, and rheological properties. Performing different recovery methods, such as re-dissolving in water and re-precipitation with ethanol on produced EPS, provided schizophyllan with purity similar to the commercial grade. Besides, Freeze-thawing cycles allowed the fractionation of schizophyllan based on branching degree and solubility. The EPSs with higher purity and lower degree of branching (less conformational flexibility) showed higher viscosity. This study evidences the possibility of producing EPSs with excellent rheological properties using low value agricultural side products. Furthermore, our results demonstrate the importance of recovery methods for tailoring the purity, molecular structure and macroscopic properties of the produced polysaccharides for specific applications. PMID- 28668609 TI - Near infrared-assisted Fenton reaction for tumor-specific and mitochondrial DNA targeted photochemotherapy. AB - The strong dependence on oxygen level, low ultraviolet/visible (UV/vis) light penetration depth and the extremely short lifetime of reactive oxygen species (ROS) are the major challenges of photodynamic therapy (PDT) for tumors. Fenton reaction can produce abundant ROS such as reactive hydroxyl radicals (OH) with significantly higher oxidation performance than singlet oxygen (1O2), which, however, has been rarely used in biomedical fields due to strict reaction conditions (favorably in pH range of 3-4, mostly under UV/vis light catalysis). Herein we propose and demonstrate a photochemotherapy (PCT) strategy of cancer therapy using near-infrared (NIR)-assisted tumor-specific Fenton reactions. NIR light-upconverted UV/vis light by upconversion nanoparticles (UCNPs) catalyze the intra-mitochondrial Fenton reaction between the delivered Fe2+ and H2O2 species over-expressed in cancer cell's mitochondria to in-situ kill the cancer cells. The intra-mitochondrial ROS generation of enabled by directly targeting the mitochondrial DNA (mtDNA) helix minimized the distance between the ROS and mtDNA molecules, thus the present PCT strategy showed much enhanced and tumor-specific therapeutic efficacy, as demonstrated by the intratumoral-accelerated OH burst and elevated cytotoxicity. Following the direct intratumoral injection, the PCT revealed marked tumor regression effect in vivo. This constructed PCT-agent is the first paradigm of NIR-upconversion catalyzed intra-mitochondrial Fenton reaction in response to tumoral microenvironment, establishing a novel photochemotherapy strategy for efficient cancer therapy. PMID- 28668612 TI - Controlled release of Doxycycline from gum acacia/poly(sodium acrylate) microparticles for oral drug delivery. AB - In the present work, Doxycycline loaded gum acacia (GA)/poly(sodium acrylate) (SA) hydrogels were prepared for the oral drug delivery of model drug Doxycycline. The hydrogels were characterized by X-ray diffraction analysis (XRD), Fourier transform infrared spectroscopy (FTIR) scanning electron microscopy (SEM) and Zeta potential. The dynamic release of Doxycycline was investigated in the physiological fluids at 37 degrees C. Various kinetic models such as Power function model, Schott model and Higuchi model were applied to interpret the release data. Schott model was found to be most fitted. The Doxycycline loaded hydrogels were tested for their antibacterial action against E. coli. PMID- 28668613 TI - beta-Chitin and chitosan from squid gladius: Biological activities of chitosan and its application as clarifying agent for apple juice. AB - Chitin is the second most abundant polysaccharide in biomass after cellulose and the term chitosan usually refers to a family of polymers obtained after chitin deacetylation. The aim of this work was the preparation and the characterization of chitin and chitosan from the gladius (pen) of the European squid (Loligo vulgaris). A high level of deproteinization (more than 80%) was recorded using Alcalase(r) with an enzyme/protein ratio of 10U/mg. The demineralization of the gladius was completely achieved within 8h at room temperature in HCl. 13C NMR, FTIR, and XRD diffractograms of prepared chitin and chitosan were taken and then degree of deacetylation of chitosan was calculated using 13C CP/MAS-NMR Spectroscopic. Further, in vitro antioxidant capacity of chitosan was evaluated on 1,1-diphenyl-2-picrylhydrazyl method (IC50=3.2mgmL-1) and the beta-carotene bleaching assay (IC50=3.3mgmL-1). Antimicrobial activity was also investigated and assays indicated that prepared chitosan exhibited marked inhibitory activity against all microbial strains tested. Additionally, chitosan was tested such as clarifying agent for apple juice and showed powerful clarification capability, without affecting nutritional value. Furthermore, the results suggested that prepared chitosan could be used as alternative additive in pharmaceutical preparations and food industry. PMID- 28668614 TI - Solution and microwave assisted synthesis of beta-Cyclodextrin grafted polyacrylamide: Water treatment and In-vitro drug release study. AB - The present article reports the application of beta-cyclodextrin grafted polyacrylamides synthesized through solution and microwave assisted polymerization techniques as flocculants and then the employment of partially hydrolyzed products of best grade of each technique in-vitro drug release study of diclofenac sodium. Five different grades of beta-cyclodextrin grafted polyacrylamides by each of solution and microwave assisted polymerization techniques have been synthesized, by varying the monomer concentration. The synthesized polymers have been well characterized and their flocculation performances have been evaluated in kaolin suspension through settling and jar test methods Then the best performing grades of both the techniques have been partially hydrolyzed to prepare three different grades each technique by varying the concentration aqueous NaOH solution. Flocculation efficiencies of these polymers have been investigated in kaolin suspension. Thus best grades of partially hydrolyzed grafted polymers of each technique have been chosen for further study of drug delivery. In-vitro drug release study has been done using diclofenac sodium loaded microbeads prepared by ionic gelation method with two partially hydrolyzed grafted polymers (one from each technique) in phosphate buffer solution (PBS) at 37+/-0.5 ?C and pH 7.4. The drug load and release have been analyzed by UV-vis spectroscopy. PMID- 28668615 TI - Incorporation of zinc oxide nanoparticles into chitosan-collagen 3D porous scaffolds: Effect on morphology, mechanical properties and cytocompatibility of 3D porous scaffolds. AB - The zinc oxide nanoparticles (particles size <50nm) incorporated into chitosan collagen 3D porous scaffolds and investigated the effect of zinc oxide nanoparticles incorporation on microstructure, mechanical properties, biodegradation and cytocompatibility of 3D porous scaffolds. The 0.5%, 1.0%, 2.0% and 4.0% zinc oxide nanoparticles chitosan-collagen 3D porous scaffolds were fabricated via freeze-drying technique. The zinc oxide nanoparticles incorporation effects consisting in chitosan-collagen 3D porous scaffolds were investigated by mechanical and swelling tests, and effect on the morphology of scaffolds examined microscopically. The biodegradation and cytocompatibility tests were used to investigate the effects of zinc oxide nanoparticles incorporation on the ability of scaffolds to use for tissue engineering application. The mean pore size and swelling ratio of scaffolds were decreased upon incorporation of zinc oxide nanoparticles however, the porosity, tensile modulus and biodegradation rate were increased upon incorporation of zinc oxide nanoparticles. In vitro culture of human fibroblasts and keratinocytes showed that the zinc oxide nanoparticles facilitated cell adhesion, proliferation and infiltration of chitosan-collagen 3D porous scaffolds. It was found that the zinc oxide nanoparticles incorporation enhanced porosity, tensile modulus and cytocompatibility of chitosan-collagen 3D porous scaffolds. PMID- 28668616 TI - Influence of flavonols and quercetin derivative compounds on MA-10 Leydig cells steroidogenic genes expressions. AB - Androgen are mainly synthesized and secreted from testicular Leydig cells and play critical roles in testis development, normal masculinization, spermatogenesis, and male fertility. The rate-limiting step in testosterone biosynthesis involves the import of cholesterol inside mitochondria by the steroidogenic acute regulatory (Star) protein. Cholesterol is then converted to pregnenolone by the steroidogenic enzyme Cyp11a1, followed by a chemical transformation to testosterone using other steroidogenic enzymes. Interestingly, levels of Star protein within adult Leydig cells decrease during aging, resulting in defective mitochondrial cholesterol transfer and reduced testosterone production. Such decline may be delayed by increasing Star and/or Cyp11a1 gene expressions using supplementation with flavonoids, a group of the polyphenolic compounds widely distributed in fruits and vegetables. In this study, we examined whether the distribution of hydroxyl groups and/or acetylation or methylation of flavonols could influence their potency to stimulate steroidogenesis within Leydig cells. Low levels of quercetin, myricetin and pentaacetylquercetin (10MUM) stimulated cAMP-dependent Star, Cyp11a1 and Fdx1 promoters' activations and may increase steroidogenesis within Leydig cells. Indeed, pentaacetylquercetin successfully increased cAMP-dependent accumulation of progesterone from MA-10 Leydig cells, possibly through activation of Star and Cyp11a1 transcriptions. Thus, dietary supplementation of pentaacetylquercetin could be potentially effective to maintain testosterone production within aging males. PMID- 28668617 TI - Atorvastatin mitigates testicular injuries induced by ionizing radiation in mice. AB - BACKGROUND: Radiotherapy in patients with pelvis malignancy causes testes irradiation and resulted in testicular damages. Atorvastatin (ATV) in the low dose is considered as antioxidant and anti-inflammatory properties. OBJECTIVE: This experimental study was investigated protective effects of ATV on irradiation induced testicular injury. MATERIAL AND METHODS: Sixty male balb/c mice were randomly divided into 6 groups: 1: control, 2: irradiated (IR), 3, 4 and 5: IR plus ATV (10, 20 and 50mg/kg), 6: only ATV (50mg/kg). The ATV treated groups were received ATV for 7days via oral gavage before IR. Irradiated groups exposed to 2Gy whole body X-ray on day 8. Biochemical, histological and immunohistological parameters were evaluated for radioprotective effect of ATV. RESULTS: In the ATV pretreatment in irradiated mice, MDA levels were significantly decreased compared with the IR group. The effect of all three doses of ATV caused reduced MDA level, but ATV to dose of 50mg/kg had more effect than other doses of ATV. Significant decrease in the concentration of testosterone was observed in only irradiated mice compared with the ATV plus irradiated. In addition, the histological examination showed Johnsen Score in the IR group was lower compared to ATV pretreated groups. ATV significantly reduced caspase-3 immunoreactivity induced by irradiation. CONCLUSION: The results from this study suggest that ATV at low dose has a protective effect against irradiation-induced testicular damage. This result provides a new indication of ATV for protection of testis during radiation therapy in treatment of cancer patients. PMID- 28668618 TI - Mammalian nonapeptides activate territorial behavior in an amphibian. AB - Arginine vasopressin (VP) and oxytocin (OT) are two nonapeptides present in mammals and execute a wide array of physiological and behavioral functions. In amphibians arginine vasotocin (VT) is hypothesized as a homologous nonapeptide for VP and also performs physiological and behavioral tasks. Studies have demonstrated that the structural and functional relationships between VP, OT, and VT receptor families are similar; however, little behavioral data has complimented these studies. The objective of this investigation was to determine if the mammalian nonapeptides VP and OT would activate behavioral manifestations naturally activated by VT. Frogs are particularly attractive for such an investigation because it is well documented that VT activates advertisement calling and territorial behavior. This investigation was a large sample size field study that utilized the territorial frog, Eleutherodactylus coqui. Fieldwork occurred on the Islands of Puerto Rico and Hawai'i and focused on territorial (calling) and non-territorial (silent) males. Frogs were administered exogenous injections of VP, OT, VT (positive control), or saline (control) in the field, placed back in their original locations, and were observed for behaviors. Exogenous injections of VP and OT significantly activated silent males to emit advertisement calls and exhibit territorial behavior. Additionally, silent males moved into new areas prior to calling whereas territorial males remained in their own territories. Control (saline) males displayed normal behaviors. This is the first study to demonstrate that mammalian nonapeptides activate calling and territorial behaviors in frogs and corroborates the close evolutionary relationships within the nonapeptide family. PMID- 28668619 TI - Internal training load and its longitudinal relationship with seasonal player wellness in elite professional soccer. AB - Monitoring internal training load has been extensively used and described within team sport environments, however when compared to internal physiological measures such as heart rate (HR) and rating of perceived exertion (RPE), the literature is sparse. The primary aim of this investigation study was to assess differences of playing position on ITL, session-RPE and wellness across two different training microcycles (1 vs. 2 competitive games), in addition with examining the relationship between ITL and Hooper's Index across an entire season. Thirty-five professional soccer players from the Portuguese premier league participated in the study (25.7+/-5.0years; 182.3+/-6.4cm; 79.1+/-7.0kg). Analysis of variance revealed higher values of DOMS (Means(M): 3.33 vs. 3.10; p=0.001; effect Size (ES)=0.087), fatigue (M: 3.18 vs. 2.99; p=0.001; ES=0.060) and HI (M: 11.85 vs. 11.56; p=0.045; ES=0.034) in 2-game weeks compared with 1-game weeks. Correlation between ITL and HI levels found significant negative correlations between ITL and DOMS (rho=-0.156), ITL and sleep (rho=-0.109), ITL and fatigue (rho=-0.225), ITL and stress (rho=-0.188), and ITL and HI (rho=-0.238) in 2-game weeks. Results from 1-game microcycle only highlighted negative correlations between ITL and stress (rho=-0.080). It was concluded from the study that greater fatigue potential, muscle soreness, stress and ITL was significantly more apparent within a 2-game microcycle. As a result, care should be taken when planning the lead into and out of a 2-game fixture microcycle highlighting key specific recovery strategies to damped the increased stress effect. Additionally, the potential utilization of squad rotation strategies may be a positive approach with aim of managing the fatigue effect. PMID- 28668620 TI - Effect of load carriage and natural terrain conditions on cognitive performance in desert environments. AB - BACKGROUND: Correct decision making is a critical component of cognitive performance of a soldier, which may be influenced by the load carriage and terrain conditions during their deployment in desert environment. PURPOSE: The present study was aimed to investigate the effects of loads and terrain conditions on the cognitive performance in a group of twelve healthy heat acclimatized infantry soldiers under natural desert environment. METHODS: The soldiers participated in a 10min walking trial during carrying no load and also carrying 10.7, 21.4 and 30kg at two terrain conditions viz., sandy and hard. We studied attention, memory and executive function, which are having immense functional importance in military operations. Standardized cognitive test battery was applied to the participants after carrying each magnitude of load at each terrain. Baseline cognitive performance was recorded on a separate day and was compared with the performances recorded after the load carriage trials. An attempt was made to reveal the relationship between physiological workload (relative workload) and cognitive performance at the point of completion of load carriage trials. RESULTS: Load, terrains and load*terrain interaction did not produce any significant effect (p>0.05) on the cognitive performance. Attention and relative workload were found significantly correlated at hard terrain under no load, 21.4kg and 30kg. Significant correlation was found between executive function and relative workload at hard terrain under no load. CONCLUSION: Carrying upto 30kg load for 10min at 3.5-4kmph walking speed resulted in improvement in attention at sandy terrain, decrement in memory at both sandy and hard terrains and improvement in executive function at sandy terrain. PMID- 28668621 TI - Circadian disruption affects initial learning but not cognitive flexibility in an automated set-shifting task in adult Long-Evans rats. AB - A sizeable percent of adults are subject to circadian disturbances such as shift work, which involves misalignment of time of light exposure, activity periods, sleep, and eating. Chronic adherence to disruptive circadian schedules can negatively impact cognitive functioning. Developing preclinical models of circadian disruption allow investigation of the relationship and underlying mechanisms between circadian disruption and cognitive functioning. We placed adult Long-Evans rats of both sexes on a 12:12h light:dark schedule in which rats performed an automated operant-behavior task for 3months, with daily testing occurring either 4h after lights-on or lights-off. At the end of this period, rats were tested on an automated set-shifting task to compare the effects of the 2 testing schedules on cognitive flexibility, which is the focus of this report. Over the initial 3-month period, day-tested rats shifted to a diurnal activity schedule, with males shifting more effectively than females, while night-tested rats remained nocturnal. Upon beginning the set-shifting task, night-tested rats took longer to reach criterion performance in the initial, visual-cue detection stage as compared to day-tested rats. The groups did not differ in performance on subsequent egocentric-cue based and reversal phases. Sex-related differences in task performance unrelated to testing schedule, particularly longer latencies to lever press in females, were also detected. One possible explanation for our findings is that the night-tested rats also experienced a form of circadian disruption when they were exposed to ambient light during the daily testing sessions, and that the form they experienced was more detrimental to initial acquisition of the task than testing during the light phase. Subsequent experiments will incorporate a night-tested group that is not exposed to ambient light in order to better understand the effect seen in the night-tested rats in the current study. PMID- 28668622 TI - Uncontrollable chronic stress reduces growth disparities in farmed Atlantic salmon. AB - Individual variation in behavior and physiological traits in a wide variety of animals has been the focus of numerous studies in recent years. In this context, early life experiences shape responses that individuals have to subsequent environments, i.e. developmental plasticity. In this experiment, we subjected 10 month old fish to an unpredictable chronic stress (UCS) regime or no stress (control) for 3weeks. These individuals then underwent the parr-smolt transformation, when salmonids become adapted for the seawater environment, and were subsequently transferred into seawater before the final sampling. Biometric data was collected at the end of each period. Sampling on the final day was conducted in order to analyze basal monoaminergic activity in the brain stem and hypothalamus, as well as gene expression of target genes in the telencephalon. We found that post-hoc sorting of individuals by their serotonergic activity (high and low) resulted in the elucidation of growth and gene expression differences. UCS groups were found to have less growth disparities throughout the experiment, compared to control fish. Furthermore, we found brain serotonergic signaling and corticotropic releasing factor binding protein expression were positively associated with brain stem serotonergic activity, which is consistent with fish showing a stress reactivity neurophysiological profile. In conclusion, we here submit evidence that sorting individuals by their basal serotonergic activity levels may be a useful tool in the study of developmental plasticity. These results may thus apply directly to improving husbandry practices in aquaculture and elucidating neural mechanisms for coping behavior. PMID- 28668624 TI - How to map and ablate papillary muscle ventricular arrhythmias. PMID- 28668623 TI - Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3'K pathways. AB - BACKGROUND: The limited regenerative capacity of cardiac tissue has long been an obstacle to treating damaged myocardium. Cell-based therapy offers an enormous potential to the current treatment paradigms. However, the efficacy of regenerative therapies remains limited by inefficient delivery and engraftment. Electrotaxis (electrically guided cell movement) has been clinically used to improve recovery in a number of tissues but has not been investigated for treating myocardial damage. OBJECTIVE: The purpose of this study was to test the electrotactic behaviors of several types of cardiac cells. METHODS: Cardiac progenitor cells (CPCs), cardiac fibroblasts (CFs), and human induced pluripotent stem cell-derived cardiac progenitor cells (hiPSC-CPCs) were used. RESULTS: CPCs and CFs electrotax toward the anode of a direct current electric field, whereas hiPSC-CPCs electrotax toward the cathode. The voltage-dependent electrotaxis of CPCs and CFs requires the presence of serum in the media. Addition of soluble vascular cell adhesion molecule to serum-free media restores directed migration. We provide evidence that CPC and CF electrotaxis is mediated through phosphatidylinositide 3-kinase signaling. In addition, very late antigen-4, an integrin and growth factor receptor, is required for electrotaxis and localizes to the anodal edge of CPCs in response to direct current electric field. The hiPSC-derived CPCs do not express very late antigen-4, migrate toward the cathode in a voltage-dependent manner, and, similar to CPCs and CFs, require media serum and phosphatidylinositide 3-kinase activity for electrotaxis. CONCLUSION: The electrotactic behaviors of these therapeutic cardiac cells may be used to improve cell-based therapy for recovering function in damaged myocardium. PMID- 28668625 TI - Plasma activated coating immobilizes apolipoprotein A-I to stainless steel surfaces in its bioactive form and enhances biocompatibility. AB - We utilized a plasma activated coating (PAC) to covalently bind the active component of high density lipoproteins (HDL), apolipoprotein (apo) A-I, to stainless steel (SS) surfaces. ApoA-I suppresses restenosis and thrombosis and may therefore improve SS stent biocompatibility. PAC-coated SS significantly increased the covalent attachment of apoA-I, compared to SS alone. In static and dynamic flow thrombosis assays, PAC+apoA-I inhibited thrombosis and reduced platelet activation marker p-selectin. PAC+apoA-I reduced smooth muscle cell attachment and proliferation, and augmented EC attachment to PAC. We then coated PAC onto murine SS stents and found it did not peel or delaminate following crimping/expansion. ApoA-I was immobilized onto PAC-SS stents and was retained as a monolayer when exposed to pulsatile flow in vivo in a murine stent model. In conclusion, ApoA-I immobilized on PAC withstands pulsatile flow in vivo and retains its bioactivity, exhibiting anti-thrombotic and anti-restenotic properties, demonstrating the potential to improve stent biocompatibility. PMID- 28668626 TI - MicroRNA-mediated signaling and regulation of nutrient transport and utilization. AB - MicroRNAs (miRNAs), a group of small-RNA regulators, control diverse developmental processes and stress responses. Recent studies of nutrient responsive miRNAs have offered novel insights into how plants regulate gene expression to coordinate endogenous demand and external availability of nutrients. Here, we review the mechanisms mediated by miRNAs to facilitate nutrient transport and utilization and show that miRNAs: first, control nutrient uptake and translocation by targeting nutrient transporters or their regulators; second, adjust nutrient metabolism by redistributing nutrients for biosynthesis of more essential compounds; and third, modulate root development and microbial symbiosis to exploit soil nutrients. We also highlight the long-distance movement of miRNAs in maintaining whole-plant nutrient homeostasis and propose several directions for future research. PMID- 28668627 TI - Vigabatrin Lacks Proarrhythmic Potential: Results from a Thorough QT/QTc Study in Healthy Volunteers. AB - PURPOSE: A thorough QT study was performed to assess the proarrhythmic potential of vigabatrin, an antiepileptic drug approved in the United States for the treatment of infantile spasms and refractory complex partial seizures. METHODS: In this Phase I, randomized, double-blind, placebo- and active-controlled (moxifloxacin), 4-sequence, crossover study conducted at a single center, healthy participants received 1 of 4 randomly assigned treatments: 3.0g vigabatrin solution (therapeutic dose) and 1 moxifloxacin placebo tablet; 6.0g vigabatrin solution (supratherapeutic dose) and 1 moxifloxacin placebo tablet; 400 mg moxifloxacin and vigabatrin placebo solution; moxifloxacin placebo tablet and vigabatrin placebo solution. FINDINGS: Mean changes from baseline in placebo corrected QTcF, QTcB, and QTcI with vigabatrin 3.0 g and 6.0 g indicated no signal for any QTc effect relative to baseline. All 1-sided upper 95% confidence intervals for the differences between each vigabatrin dose and placebo were <10 ms at all time points. QTcF was unaffected by increasing plasma vigabatrin concentrations; no arrhythmias were observed in any treatment group. Low rates of first-degree atrioventricular block, sinus tachycardia, and sinus bradycardia occurred in all treatment groups. Most adverse events were mild. IMPLICATIONS: The findings from this thorough QT study are consistent with existing clinical data and confirm a lack of proarrhythmic potential of vigabatrin. PMID- 28668628 TI - Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation and Venous Thromboembolism: A Systematic Review and Meta analyses. AB - PURPOSE: The findings from the observational studies comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban). METHODS: The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance-weighted random effects models. FINDINGS: A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57-1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83-1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67-0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59-1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66-0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77-1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40 1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59-1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding. IMPLICATIONS: Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested. PMID- 28668629 TI - Cooccurrence and potential role of nitrite- and nitrate-dependent methanotrophs in freshwater marsh sediments. AB - Nitrite- and nitrate-dependent anaerobic methane oxidation are mediated by the NC10 bacteria closely related to "Candidatus Methylomirabilis oxyfera" (M. oxyfera) and the ANME-2d archaea closely related to "Candidatus Methanoperedens nitroreducens" (M. nitroreducens), respectively. Here, we investigated the occurrence and activity of both M. oxyfera-like bacteria and M. nitroreducens like archaea in the sediment of freshwater marshes in Eastern China. The presence of diverse M. oxyfera-like bacteria (>87% identity to M. oxyfera) and M. nitroreducens-like archaea (>96% identity to M. nitroreducens) was confirmed by using Illumina-based total bacterial and archaeal 16S rRNA gene sequencing, respectively. The recovered M. oxyfera-like bacterial sequences accounted for 1.6 4.3% of the total bacterial 16S rRNA pool, and M. nitroreducens-like archaeal sequences accounted for 0.2-1.8% of the total archaeal 16S rRNA pool. The detected numbers of OTUs of the 16S rRNA genes of M. oxyfera-like bacteria and M. nitroreducens-like archaea were 78 and 72, respectively, based on 3% sequence difference. Quantitative PCR showed that the 16S rRNA gene abundance of M. oxyfera-like bacteria (6.1 * 106-3.2 * 107 copies g-1 sediment) was 2-4 orders of magnitude higher than that of M. nitroreducens-like archaea (1.4 * 103-3.2 * 104 copies g-1 sediment). Stable isotope experiments showed that the addition of both nitrite and nitrate stimulated the anaerobic methane oxidation, while the stimulation by nitrite is more significant than nitrate. Our results provide the first evidence that the M. oxyfera-like bacteria play a more important role than the M. nitroreducens-like archaea in methane cycling in wetland systems. PMID- 28668630 TI - Evaluation of physical and chemical properties and their interactions in fat, oil, and grease (FOG) deposits. AB - Fat, oil and grease (FOG) blockages in sewer systems are a substantial problem in the United States. It has been estimated that over 50% of sewer overflows are a result of FOG blockages. In this work, a thorough laboratory study was undertaken to examine key variables that contribute to FOG deposit formation under controlled conditions. Physical and chemical properties and their interactions were evaluated and conditions that generated deposits that mimicked field FOG deposits were identified. It was found that 96 of the of 128 reaction conditions tested in the laboratory formed FOG deposits with similar physical and chemical characteristics as field FOG deposits. It was also found that FOG deposits can be created through fatty acid crystallization and not just saponification. Furthermore FOG deposits were found to be more complex than previously documented and contain free fatty acids, fatty acid metal salts, triacylglycerol's, diacylglycerol's and, monoacylglycerol's. Lastly it was found that FOG deposits that only contained saturated fatty acids were on average 2.1 times higher yield strength than deposits that contained unsaturated fatty acids. PMID- 28668631 TI - Enhanced adsorption of arsenic through the oxidative treatment of reduced aquifer solids. AB - Arsenic (As) contamination in drinking water is an epidemic in many areas of the world, especially Eastern Asian countries. Developing affordable and efficient procedures to remove arsenic from drinking water is critical to protect human health. In this study, the oxidation of aquifer solids through the use of sodium permanganate (NaMnO4), hydrogen peroxide (H2O2), and exposure to air, enhanced the adsorption of arsenic to the aquifer material resulting in treatment of the water. NaMnO4 was more effective than H2O2. NaMnO4 was tested at different loading rates (0.5, 1.5, 2.4, 3.4, and 4.9 g NaMnO4/kg aquifer material), and after 30 days contact time, arsenic removal ([As+3]INITIAL = 610 MUg/L) was 77%, 88%, 93%, 95%, 97%, respectively, relative to un-oxidized aquifer material. Arsenic removal increased with increasing contact time (30, 60, 90 days) suggesting removal was not reversible under the conditions of these experiments. Oxidative treatment by exposing the aquifer solids to air for 68 days resulted in >99% removal of Arsenic ([As+3]INITIAL = 550 MUg/L). Less arsenic removal (38.2%) was measured in the un-oxidized aquifer material. In-situ oxidation of aquifer materials using NaMnO4, or ex-situ oxidation of aquifer materials through exposure to air could be effective in the removal of arsenic in ground water and a potential treatment method to protect human health. PMID- 28668632 TI - Urban sewage lipids in the suspended particulate matter of a coral reef under river influence in the South West Gulf of Mexico. AB - Nutritional quality of suspended particulate matter (SPM) and the degree of human fecal pollution in the largest coral reef system in the southwest Gulf of Mexico were evaluated using lipid classes, fatty acids (FA) and sterols in the dry and rainy seasons. High proportions of triacylglycerols and saturated and monounsaturated FA were detected in the SPM however it was considered poor quality because it had low proportions of highly unsaturated FA which can be used to determine production of marine biogenic material of dietary value to pelagic and benthic organisms. Urban sewage organic carbon was traced with coprostanol. The reference value of coprostanol from the point source of pollution was set using two samples from a sewage treatment plant processing waste from >140,000 people near the coral reef system, and it was contrasted with one river station and nine marine stations including six coral reefs. The concentration of coprostanol in the SPM was 3621 +/- 98 ng L-1 comprising 26% of total sterols. During the dry season, the river was contaminated upstream with human feces as evidenced by coprostanol at 1823 ng L-1, the 5beta-coprostanol: cholesterol ratio at 0.5, and 5beta-coprostanol: [5alpha-cholestanol+5beta-coprostanol] at 0.7. In contrast, marine stations had concentrations of coprostanol lower than a suggested regulation limit for tropical marine coastal waters (30 ng L-1), ranging between 6 and 28 ng L-1. During the rainy season a dilution effect was detected in the river, however significantly higher concentrations of coprostanol in the marine stations were detected ranging between 15 and 215 ng L-1, higher than the tentative tropical regulation range (30-100 ng L-1). Among the reefs, the nearshore one, 14.3 km from the treatment plant, was more exposed to human fecal pollution, and offshore reefs, >17.3 km from the plant, had a lower degree of contamination. Finally, only three stations were clearly uncontaminated during both seasons including two reefs in the south located 21.8 and 35.6 km from the plant, with no presence of coprostanol. Contamination in the rainy season likely comes from a village with untreated sewage located 9.3-32 km from the reefs, and from the second largest Mexican river flowing into the Gulf of Mexico which has a watershed covering three states with lower than average sewage treatment. Inclusion of coprostanol monitoring could be a key factor in the management of this coral reef system. PMID- 28668633 TI - Distinct and diverse anaerobic respiration of methanogenic community in response to MnO2 nanoparticles in anaerobic digester sludge. AB - Recently, the influence of metal oxide nanoparticles (NPs) on methanogenesis in anaerobic digestion has drawn much attention, however, the changes in NPs and functioning consortia within the methanogenic community are usually not investigated. Therefore, the methanogenesis performance, NPs transformation and methanogenic community development in anaerobic digester sludge under MnO2 NP supplementation were demonstrated in this study. MnO2 NPs (400 mg/gVSS) stimulated the methane (CH4) yield by 42% for a final CH4 proportion of 81.8% of the total gas production. Meanwhile, the coenzyme F420 and INT-electron transport system activities showed positive correlation with MnO2 concentration. Microbial Mn reduction and oxidation occurred in conjunction with methanogenesis, resulting in transformation of the shape of the MnO2 NPs from wire-like to globular particles. Microbial community analysis indicated that the relative abundances of genera Methanobacterium, Methanosaeta, and Methanosarcina were higher in the presence of MnO2 NPs. Moreover, a new and different crucial synergy within the methanogenic community was formed with low-abundance consortia driving Mn respiration coupled to methanogenesis in anaerobic digestion. To our knowledge, this is the first report on transformation of metal oxides NPs combined with syntrophic community development in studies focusing on methanogenesis in response to NPs. PMID- 28668634 TI - Let's talk about empathy! AB - BACKGROUND: Research faces a challenge to find a shared, adequate and scientific definition of empathy. OBJECTIVE: Our work aimed to analyze what clinical empathy is in the specific context of cancer care and to identify the effect of empathy in it. METHOD: This study gives voice to physicians with extensive experience in cancer care. This original research combines qualitative data collection and quantitative data analysis. Semi-structured individual interviews were conducted with 25 physicians. The content of the interviews was analyzed according to the Content Analysis Technique. RESULTS: Empathy is described according to six dimensions that give a strong role to interpersonal and cognitive skills. This description integrates previous and various conceptualizations of clinical empathy. Physicians detail the beneficial effects of clinical empathy on patients' outcomes and well-being as well as physicians' practices. Physician interviews also revealed the relationship between empathic concerns and physicians' emotional difficulties. CONCLUSION: Empathy in cancer care is a complex process and a multicomponent competence. PRACTICE IMPLICATIONS: This operational description of clinical empathy has three main implications: to draw up a training program for physicians, to detail recommendations for physicians' work-related quality of life and to develop new tools to measure empathy. PMID- 28668635 TI - Reprogramming human cells to naive pluripotency: how close are we? AB - Pluripotent stem cells (PSCs) have the potential to revolutionise biomedical science; however, while it is simple to reproducibly obtain comparable, stable cell lines in mouse, those produced from human material typically show significant variability both within and between cell lines. This is likely due to differences in the cell identity of conventional mouse and human PSCs. It is hoped that recently identified conditions to reprogram human cells to a naive like state will produce better PSCs resulting in reproducible experimental outcomes and more consistent differentiation protocols. In this review we discuss the latest literature on the discovery of human naive-like stem cells and examine how similar they are to both mouse naive cells and the preimplantation human epiblast. PMID- 28668636 TI - Optimizing Sensitivity of Ultrasound Contrast-Enhanced Super-Resolution Imaging by Tailoring Size Distribution of Microbubble Contrast Agent. AB - Ultrasound contrast-enhanced super-resolution imaging has recently attracted attention because of its extraordinary ability to image vascular features much smaller than the ultrasound diffraction limit. This method requires sensitive detection of separable microbubble events despite a noisy tissue background to indicate the microvasculature, and any approach that could improve the sensitivity of the ultrasound system to individual microbubbles would be highly beneficial. In this study, we evaluated the effect of varying microbubble size on super-resolution imaging sensitivity. Microbubble preparations were size sorted into different mean diameters and then were imaged at equal concentrations. Commercially manufactured Definity and Optison were also imaged for comparison. Both in vitro experiments in phantom vessels and in vivo experiments imaging rat tumors revealed that the sensitivity of contrast-enhanced super-resolution imaging can be improved by using microbubbles with a larger diameter. PMID- 28668637 TI - Molecular differences between human liver fatty acid binding protein and its T94A variant in their unbound and lipid-bound states. AB - Liver fatty acid binding protein (L-FABP) is an abundant cytosolic protein playing a central role in intracellular lipid trafficking. The L-FABP T94A variant, originating from one of the most common polymorphisms in the FABP family, is associated with several lipid-related disorders. However, the molecular factors that determine the observed functional differences are currently unknown. In our work, we performed a high resolution comparative molecular analysis of L-FABP T94T and L-FABP T94A in their unbound states and in the presence of representative ligands of the fatty acid and bile acid classes. We collected residue-resolved NMR spectral fingerprints of the two variants, and compared secondary structures, backbone dynamics, side chain arrangements, binding site occupation, and intermolecular contacts. We found that threonine to alanine replacement did not result in strongly perturbed structural and dynamic features, although differences in oleic acid binding by the two variants were detected. Based on chemical shift perturbations at sites distant from position 94 and on differences in intermolecular contacts, we suggest that long-range communication networks in L-FABP propagate the effect of amino acid substitution at sites relevant for ligand binding or biomolecular recognition. PMID- 28668638 TI - Crystal structure and DNA-binding property of the ATPase domain of bacterial mismatch repair endonuclease MutL from Aquifex aeolicus. AB - DNA mismatch repair (MMR) system corrects mismatched bases that are generated mainly by DNA replication errors. The repair system excises the error-containing single-stranded region and enables the re-synthesis of the strand. In the early reactions of MMR, MutL endonuclease incises the newly-synthesized/error containing strand of the duplex to initiate the downstream excision reaction. MutL endonuclease consists of the N-terminal ATPase and C-terminal endonuclease domains. In this study, we report the crystal structure of the ATPase domain of MutL endonuclease from Aquifex aeolicus. The overall structure of the domain was similar to those of human MutL homologs and Escherichia coli MutL, although E. coli MutL has no endonuclease activity. The ATPase domain was comprised of two subdomains: the N-terminal ATP-binding subdomain and the C-terminal alpha-beta sandwich subdomain. Site-directed mutagenesis experiment identified DNA interacting eight basic amino acid residues, which were distributed across both the two subdomains and formed a DNA-binding cleft. Docking simulation between the structures of the ATPase and endonuclease domains generated a reliable model structure for the full-length A. aeolicus MutL, which satisfies our previous result of small-angle X-ray scattering analysis. On the basis of the model structure and further experimental results, we concluded that the two separate DNA-binding sites in the full-length A. aeolicus MutL simultaneously bind a dsDNA molecule. PMID- 28668639 TI - Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is a novel biomarker of myxofibrosarcoma invasion identified by global protein expression profiling. AB - Myxofibrosarcoma (MFS) is a mesenchymal malignancy characterized by frequent recurrence even after radical wide resection. To optimize therapy for MFS patients, we aimed to identify candidate tissue biomarkers of MFS invasion potential. Invasion characteristics of MFS were evaluated by magnetic resonance imaging and protein expression profiling of primary tumor tissues performed using two-dimensional difference gel electrophoresis (2D-DIGE). Protein expression profiles were compared between invasive and non-invasive tumors surgically resected from 11 patients. Among the 3453 protein spots observed, 59 demonstrated statistically significant difference in intensity (>=2-fold) between invasive and non-invasive tumors (p<0.01 by Wilkoxon test), and were identified by mass spectrometry as 47 individual proteins. Among them, we further focused on discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2), a receptor tyrosine kinase with aberrant expression in malignant tumors. Immunohistochemistry analysis of 21 additional MFS cases revealed that higher DCBLD2 expression was significantly associated with invasive properties of tumor cells. DCBLD2 sensitivity and specificity, and positive and negative predictive values for MFS invasion were 69.2%, 87.5%, 90%, and 63.6%, respectively. The expression level of DCBLD2 was consistent in different portions of tumor tissues. Thus, DCBLD2 expression can be a useful biomarker to evaluate invasive properties of MFS. Further validation studies based on multi-institutional collaboration and comprehensive analysis of DCBLD2 biological functions in MFS are required to confirm its prognostic utility for clinical application. PMID- 28668641 TI - Glycosylation of human vaspin (SERPINA12) and its impact on serpin activity, heparin binding and thermal stability. AB - Vaspin is a glycoprotein with three predicted glycosylation sites at asparagine residues located in proximity to the reactive center loop and close to domains that play important roles in conformational changes underlying serpin function. In this study, we have investigated the glycosylation of human vaspin and its effects on biochemical properties relevant to vaspin function. We show that vaspin is modified at all three sites and biochemical data demonstrate that glycosylation does not hinder inhibition of the target protease kallikrein 7. Although binding affinity to heparin is slightly decreased, the protease inhibition reaction is still significantly accelerated in the presence of heparin. Glycosylation did not affect thermal stability. PMID- 28668642 TI - Thank you letters from patients in an intensive care unit: From the expression of gratitude to an applied ethic of care. AB - INTRODUCTION: Patients' perception of an intensive care unit stay can lead to a better understanding of the expectations and needs of patients hospitalised in intensive care so that care for critically ill patients can be adapted and improved. Thank you letters are sources of original information which come directly and spontaneously from patients. OBJECTIVE: The objective of this study was to analyse the thank you letters from patients who required intensive care treatment and to identify messages that could be intended for the intensive care unit team. DESIGN: We conducted a qualitative study according to a thematic analysis. The body of research consisted of 17 letters from patients hospitalised in intensive care unit. SETTING: The study took place in the medical-surgical intensive care unit of a French general hospital. The intensive care unit is made up of 16 resuscitation beds and four continuous monitoring beds. FINDINGS: Two main themes emerged: (i) expression of gratitude through a description of the caregivers' behaviour (humanity and professionalism) and recognition for surviving (ii) the narrative of the intensive care unit experience. CONCLUSION: Thank you letters give a rich insight into how the patients perceived their stay in intensive care unit. Letters from patients give direct feedback on the quality of care provided, contribute to give meaning to work and raise the question of what the core values of care should be for all concerned in the healthcare providers-patients relationship. PMID- 28668643 TI - 'She didn't have a word of English; we didn't have a word of Vietnamese': Exploring parent experiences of communication with toddlers who were adopted internationally. AB - The purpose of this study was to explore in detail parents' experiences of communicating with toddlers who were adopted internationally. Often, there is a mismatch between parents and children in terms of language, particularly in the early post-adoption period. There is a gap in the literature regarding parent experiences of this phase of their lives. Changing patterns in international adoption have led to an increase in adoptions of toddlers and older children. Due to institutional care, these toddlers and older children often lack exposure to their native language which may lead to language delay. When they are brought home, they are immersed in English. As well beginning to acquire English, these children are also forming an attachment with their parents. While research has investigated speech and language skills in this population, there is a lack of literature exploring the experiences of parents regarding communicating with toddlers who are adopted internationally in the early months following adoption. This is a qualitative study where interviews and thematic analysis were used to explore the experiences of 12 parents of 12 toddlers who were adopted internationally. Three main themes: 'Getting ready', 'Support', and 'Challenges' emerged from the data. The results highlight the ways in which adoptive parents facilitated communication with their toddlers, supporting their acquisition of English. The results also reveal gaps in service provision for this population. Results also illustrate the proactive way in which parents dealt with challenges, even in the presence of limited support services. Gaps in service provision where intense focus pre-adoption was followed by a lack of support post-adoption were identified by parents. The dual needs of developing attachment and common language development strategies were also described by parents. The study demonstrates the need for pre- and post-adoptive speech and language services for this client group. It highlights the importance of the role of speech and language pathology in working with parents of toddlers and children who were adopted internationally. This role is in health promotion and prevention, as well as providing a service to this population as part of a multidisciplinary team, post-adoption. PMID- 28668644 TI - An inner nuclear membrane protein induces rapid differentiation of human induced pluripotent stem cells. AB - The ability of iPSCs (induced pluripotent stem cells) to generate any cell type in the body makes them valuable tools for cell replacement therapies. However, differentiation of iPSCs can be demanding, slow and variable. During differentiation chromatin is re-organized and silent dense heterochromatin becomes tethered to the nuclear periphery by processes involving the nuclear lamina and proteins of the INM (inner nuclear membrane). The INM protein, Samp1 (Spindle Associated Membrane Protein 1) interacts with Lamin A/C and the INM protein Emerin, which has a chromatin binding LEM (Lap2-Emerin-Man1)-domain. In this paper we investigate if Samp1 can play a role in the differentiation of iPSCs. Samp1 levels increased as differentiating iPSCs started to express Lamin A/C. Interestingly, even under pluripotent culturing conditions, ectopic expression of Samp1 induced a rapid differentiation of iPSCs, of which some expressed the neuronal marker betaIII-tubulin already after 6days. This suggests that Samp1 is involved in early differentiation of iPSCs and could potentially be explored as a tool to promote progression of the differentiation process. PMID- 28668645 TI - Herbal medicinal products - Evidence and tradition from a historical perspective. AB - BACKGROUND: Aside from the fully licensed herbal medicines there are products on the European pharmaceutical market which are registered by virtue of their longstanding traditional use. The normal registration procedure does not apply to them because presently they do not meet the legal requirements for a full license as set out in the relevant European Union Directive. One of these requirements, "proof of tradition", has so far been dealt with in different ways and fails to meet the criteria of good practice. METHOD: This analysis is based on a selective literature search in PubMed and in databases of medical and pharmaceutical history, interviews with licensing experts, a consensus meeting attended by researchers with a background in general medicine, phytotherapy, medical and pharmaceutical history, biometry, ethnopharmacology, pharmacognosy and the pharmaceutical industry. RESULTS AND DISCUSSION: The 2004 EU Directive, which governs the registration of Traditional Herbal Medicinal Products and demands proof of tradition, is a regulatory construct and, above all, the outcome of a political process that has ended in a pragmatic compromise. The concept of tradition applied in the Directive does not sufficiently reflect the semantic breadth of the term. The only condition defined is that a specific commercial preparation needs to have been on the market for 30 years (15 of them inside the EU). Such an approach does not make full scientific use of the evidence available because the information excerpted from historical sources, if adequately processed, may yield valuable insights. This applies to indications, modes of application, efficacy and product safety (innocuousness). Such criteria should enter in full into the benefit-risk-analysis of applied preparations, in the registration process as well as in the therapeutic practice. CONCLUSION: When registering Traditional Herbal Medicinal Products the criterion of evidence-based medicine will only be met if all the facts available are assessed and evaluated, over and above the formally stipulated regulatory provisions (30 years, product reference). To this end, the scientific methods (from among the natural, life or cultural sciences), which are recognized as authoritative in each case, must be applied. PMID- 28668646 TI - Systematic review and technological overview of the antimicrobial activity of Tagetes minuta and future perspectives. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The antimicrobial potential of Tagetes minuta was correlated with its traditional use as antibacterial, insecticidal, biocide, disinfectant, anthelminthic, antifungal, and antiseptic agent as well as its use in urinary tract infections. AIM OF THE STUDY: This study aimed to systematically review articles and patents regarding the antimicrobial activity of T. minuta and give rise to perspectives on this plant as a potential antimicrobial agent. MATERIALS AND METHODS: A literature search of studies published between 1997 and 2015 was conducted over five databases: MedLine (PubMed), Web of Science, Scopus, Google Scholar, Portal de Periodicos Capes and SciFinder, grey literature was explored using the System for Information on Dissertations database, and theses were searched using the ProQuest Dissertations and Theses Full text database and the Periodicos Capes Theses database. Additionally, the following databases for patents were analysed: United States Patent and Trademark Office (USPTO), Google Patents, National Institute of Industrial Property (INPI) and Espacenet patent search (EPO). The data were tabulated and analysed using Microsoft Office Excel 2010. RESULTS: After title screening, 51 studies remained and this number decreased to 26 after careful examinations of the abstracts. The full texts of these 26 studies were assessed to check if they were eligible. Among them, 3 were excluded for not having full text access, and 11 were excluded because they did not fit the inclusion criteria, which left 10 articles for this systematic review. The same process was conducted for the patent search, resulting in 4 patents being included in this study. CONCLUSION: Recent advances highlighted by this review may shed light on future directions of studies concerning T. minuta as a novel antimicrobial agent, which should be repeatedly proven in future animal and clinical studies. Although more evidence on its specificity and clinical efficacy are necessary to support its clinical use, T. minuta is expected to be a highly effective, safe and affordable treatment for infectious diseases. PMID- 28668647 TI - Toxicological evaluation of the aqueous whole plant extract of Aerva lanata (l.) Juss. ex Schult (Amaranthaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aerva lanata (L.) of the family Amaranthaceae is a Nigerian medicinal plant used traditionally for the management of lithiasis, headache, renal disorder, haematemesis, bronchitis, nasal bleeding, cough, scorpion stings, fractures and spermatorrhoea. Studies that show the pharmacological basis for some of such uses have been reported. There is, however, no scientific report on its toxicity profile to the best of our knowledge. AIM OF THE STUDY: This study was therefore aimed at investigating the toxicity profile of the aqueous extract of Aerva lanata. MATERIALS AND METHODS: Acute toxicity tests for the extract administered orally at 1-30g/kg and intraperitoneally at 0.1-2g/kg were carried out in albino mice; while a sub chronic toxicity test was done by daily oral administration of the extract at 40 1000mg/kg to albino rats for 90 days. Anthropometric, biochemical and haematological parameters' assessments as well as vital organs histological examinations were performed in the sub-chronic toxicity study. RESULTS: The LD50 of the extract for oral and intraperitoneal acute toxicity tests were 22.62g/kg and 0.432g/kg respectively. The extract produced apparent changes in body weights of both male and female rats and significantly (p < 0.05) increased the weights of lungs, brain and pancreas of female rats while reducing the weight of testes in male rats. Haematological parameters were also altered with total leukocytes significantly (p < 0.05) increased and platelets significantly (p < 0.05) reduced in female rats; while neutrophils significantly (p < 0.05) increased in male rats. The extract (40-1000mg/kg) produced significant (p < 0.05) reduction of serum alanine transaminase concentration in both male and female rats. Aspartate transaminases and albumin were also significantly (p < 0.05) reduced in both male (at 1000mg/kg) and female (at 200mg/kg) rats. Alkaline phosphatase was also significantly (p < 0.05) reduced in female rats at 200mg/kg of the extract. Substantial alterations of creatinine, urea and uric acid were also observed. Triglyceride and cholesterol concentrations were significantly increased in male rats but decreased in female rats. At 1000mg/kg, the extract significantly elevated catalase and superoxide dismutase levels with no effect on malondialdehyde levels. It also reduced sperm count and motility of male rats. Mild to moderate cellular changes in the brain, kidney, liver, lungs, spleen and testes of treated rats were observed on histological examinations. Significant changes in biochemical and haematological parameters were also noted in treated animals when compared to control animals 30 days after cessation of treatment. CONCLUSION: The overall findings of this study suggest that the aqueous extract of A. lanata is relatively safe on acute oral exposure, moderately toxic on acute intraperitoneal administration and is relatively safe with antioxidant actions on prolonged exposure. It however shows potentials for toxic effects such as cellular damage to organs, dyslipidaemia and reduction in male reproductive capacity. Caution must therefore be applied in its use on a long term basis. PMID- 28668640 TI - Spectroscopic studies of the cytochrome P450 reaction mechanisms. AB - The cytochrome P450 monooxygenases (P450s) are thiolate heme proteins that can, often under physiological conditions, catalyze many distinct oxidative transformations on a wide variety of molecules, including relatively simple alkanes or fatty acids, as well as more complex compounds such as steroids and exogenous pollutants. They perform such impressive chemistry utilizing a sophisticated catalytic cycle that involves a series of consecutive chemical transformations of heme prosthetic group. Each of these steps provides a unique spectral signature that reflects changes in oxidation or spin states, deformation of the porphyrin ring or alteration of dioxygen moieties. For a long time, the focus of cytochrome P450 research was to understand the underlying reaction mechanism of each enzymatic step, with the biggest challenge being identification and characterization of the powerful oxidizing intermediates. Spectroscopic methods, such as electronic absorption (UV-Vis), electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electron nuclear double resonance (ENDOR), Mossbauer, X-ray absorption (XAS), and resonance Raman (rR), have been useful tools in providing multifaceted and detailed mechanistic insights into the biophysics and biochemistry of these fascinating enzymes. The combination of spectroscopic techniques with novel approaches, such as cryoreduction and Nanodisc technology, allowed for generation, trapping and characterizing long sought transient intermediates, a task that has been difficult to achieve using other methods. Results obtained from the UV-Vis, rR and EPR spectroscopies are the main focus of this review, while the remaining spectroscopic techniques are briefly summarized. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28668648 TI - Familial digit ratio (2D:4D) associations in a general population sample from Wales. AB - BACKGROUND: The relative length of the second and fourth fingers (2D:4D) may be a sex-linked correlate of prenatal androgen exposure. However, the nature of the sex-linkage is controversial, with evidence for both X- and Y-linkage of the 2D:4D phenotype. AIMS: To examine transgenerational effects relating to sex linkage. In addition, assortative mating on 2D:4D was considered, as well as associations between 2D:4D and age and sex. STUDY DESIGN: A family study was conducted. Parents and offspring completed a demographic questionnaire, and digit ratios were calculated from photocopies of participants' hands. SUBJECTS: We recruited and phenotyped 585 individuals attending a cultural festival in Wales. 2D:4D information was available for 47 mother-son dyads, 70 mother-daughter dyads, 31 father-son dyads and 30 father-daughter dyads. OUTCOME MEASURES: Correlations between 2D:4D of parents and children, as well as between mothers and fathers were conducted. 2D:4D was also examined in relation to age and sex. RESULTS AND CONCLUSIONS: There was a sex difference in 2D:4D (males=1.3MUg/mL in most of the children (99.4%). The carriage rate of S. pneumoniae was 39%, and the Binax NOW(r)Sp test was positive in 26% of children. There was no significant variation between the means of IgG concentrations against pneumococcal polysaccharides as related to vaccination status, age and nasopharyngeal carriage of S. pneumoniae. However, there was a weak positive correlation between age and level of IgG (r=0.08; p=0.021), and there was a significant variation (p=0.038) of the IgG level according to presence of S. pneumoniae antigen in urine. The presence of S. pneumoniae antigen in urine is significantly (p<=0.01) higher in children with nasopharyngeal carriage of S. pneumoniae (40%) than non-carriers (20%). This study shows that S. pneumoniae has high circulation in children under the age of five years either through infection or carriage. PMID- 28668655 TI - Seasonal variations of respiratory viruses detected from children with respiratory tract infections in Riyadh, Saudi Arabia. AB - ARTIs have a huge impact in health systems in which 20-30% of all hospital admissions and 30-60% of practitioner visits are related to respiratory tract infections. The aim of this study is to determine the prevalence, age distribution, and seasonal variation of respiratory viruses. This study was descriptive retrospective study in which all patients 14 years of age and below who presented with signs and symptoms of ARTIs between January 2013 and December 2014 and had respiratory specimen tested by direct immunofluorescence assays for viruses identification were included in the study. During that period, a total of 4611 patients who presented with ARTIs from January 2013 to December 2014 were investigated, viruses were detected in 1115 (24%). RSV was associated with 97.4% of the total viral pathogens. Viruses were detected throughout all the two years with a peak in winter; Dec (n: 265), Jan (n: 418), Feb (n: 218), and Mar (n: 109). Viral pathogens are very important cause of ARTIs in our region. RSV was the most common virus detected with the highest detection rate in children who are two years old and below. A multi-center surveillance with more sensitive detection methods like PCR may help to provide a comprehensive understanding of virus distribution in our area, which may contribute implant an effective prevention approach for each virus. PMID- 28668656 TI - Epidemiology, management, and outcome of carbapenem-resistant Klebsiella pneumoniae bloodstream infections in hospitals within the same endemic metropolitan area. AB - In the last decade, carbapenem-resistant Klebsiella pneumoniae (CR-Kp) has become endemic in several countries, including Italy. In the present study, we assessed the differences in epidemiology, management, and mortality of CR-Kp bloodstream infection (BSI) in the three main adult acute-care hospitals of the metropolitan area of Genoa, Italy. From January 2013 to December 2014, all patients with CR-Kp BSI were identified through the computerized microbiology laboratory databases of the three hospitals. The primary endpoints of the study were incidence and characteristics of CR-Kp BSI in hospitals within the same endemic metropolitan area. Secondary endpoints were characteristics of CR-Kp BSI in hospitals with and without internal infectious diseases consultants (IDCs) and 15-day mortality. During the study period, the incidence of healthcare-associated CR-Kp BSI in the entire study population was 1.35 episodes per 10,000 patient-days, with substantial differences between the three hospitals. Patients admitted to the two hospital with internal IDCs were more likely to receive post-susceptibility test combined therapy including carbapenems (77% vs. 26%, p<0.001), adequate post susceptibility test therapies (86% vs. 52%, p<0.001), and post-susceptibility therapies prescribed by an infectious diseases specialist (84% vs. 14%, p<0.001). Overall, the crude 15-days mortality was 26%. In the final multivariable model, only septic shock at BSI presentation was unfavorably and independently associated with 15-days mortality (odds ratio [OR] 6.7, 95% confidence intervals [CI] 2.6-17.6, p<0.001), while a protective effect was observed for post susceptibility test combined therapies including a carbapenem (OR 0.11, 95% CI 0.03-0.43, p=0.002). Mortality of CR-Kp remains high. Differences in the incidence of CR-Kp BSI were detected between acute-care centers within the same endemic metropolitan area. Efforts should be made to improve the collaboration and coordination between centers, to prevent further diffusion of CR-Kp. PMID- 28668657 TI - Knowledge and beliefs about HPV among college students in Vietnam and the United States. AB - Any sexually active person has the possibility of contracting the human papillomavirus (HPV) sometime in their lifetime. HPV vaccines are effective in preventing HPV if obtained prior to viral exposure. Research on knowledge and beliefs of HPV and HPV vaccination among college students in Vietnam is significantly scarce. The purpose of this study is to examine the knowledge and beliefs about HPV among college students in Vietnam compared to college students in the US. This cross-cultural comparison will fill a void in current research on this subject. Over 900 college students (N=932: n=495 in Vietnam and n=437 in the US) participated in a self-administered survey on the knowledge and beliefs about HPV in September and October 2016. Vietnamese participants reported lower levels of knowledge and experiences with the HPV virus and vaccines (p<0.01). Additionally, Vietnamese participants also exhibited more barriers in obtaining the vaccination, as well as, HPV risk denial (p<0.01). The level of knowledge is an important predictor of barriers (p<0.01; etap2=0.022) and risk denial (p<0.01; etap2=0.116). On average, both Vietnamese and US participants could correctly answer less than half of the survey questions regarding HPV knowledge. Additionally, provider recommendations are potentially more important than informal connections (e.g. friends, family) to reduce barriers to HPV vaccination (p<0.01; etap2=0.035) and denial of HPV risks (p<0.05; etap2=0.008). The increase of knowledge about HPV prevention, including and vaccination, has the potential to be improved through provider interventions. Vietnam could take action toward promoting HPV vaccinations not only at an individual level but also at a national or local level. Further research may examine the effects of a lack of knowledge on HPV-related health outcomes. PMID- 28668658 TI - Evaluation of enzyme linked immunosorbent assay for stool antigen detection for the diagnosis of cryptosporidiosis among HIV negative immunocompromised patients in a tertiary care hospital of northern India. AB - The diagnosis of cryptosporidiosis among HIV positive patients has been the focus of many studies worldwide. However, there is a paucity of data on HIV negative immunocompromised patients like post-renal transplant recipients and those with haematological malignancies. Stool microscopy, the conventional method of diagnosis, is fraught with difficulties like cumbersome sample processing and subjective interpretation. Enzyme linked immunosorbent assay (ELISA), on the other hand, is quicker and easier. The present study was conducted in a tertiary care and super speciality hospital of north India. Stool specimens from HIV negative immunocompromised patients were subjected to both modified acid fast staining for oocysts of Cryptosporidium and ELISA for detection of Cryptosporidium copro-antigen, over a period of six years. Of the 637 specimens evaluated, 97 (15.23%) samples were positive for Cryptosporidium by both techniques; 25 (3.92%) specimens were positive by ELISA and negative by microscopy, 14 (2.20%) specimens were positive by microscopy but negative by ELISA, while 501 (78.65%) specimens were negative for Cryptosporidium by both techniques. Significant correlation was observed as a measure of agreement (Kappa test value 0.795) between modified ZN stained microscopy and ELISA for the detection of Cryptosporidium oocysts. The sensitivity, specificity, positive and negative predictive value of ELISA, keeping stool microscopy as gold standard were 87.38%, 95.25%, 87.39% and 97.28% respectively. We conclude that ELISA may be used as a reliable substitute for microscopy in setups where the case load is higher or expertise in special staining techniques is not available. The cost of the kit can be justified if the sample load is sufficiently high or if immunocompromised patients form a significant patient population. PMID- 28668659 TI - Morbidity and mortality amongst Indian Hajj pilgrims: A 3-year experience of Indian Hajj medical mission in mass-gathering medicine. AB - The Hajj, a mass-gathering of over 3.5-million pilgrims, faces challenges to global health-security, housing, food, water, transportation, communication, sanitation, crowd-control and security. The Indian Medical Mission extended health-security to approximately 140,000 pilgrims, through outreach medical teams, primary-care clinics, tent-clinics, secondary-care hospitals and evacuation capabilities. Data on medical attendance, bed-occupancy, investigations, referrals, medication usage and deaths was compared. Outpatient attendance was 374,475 in static-clinics, 5135 in tent-clinics and 13,473 through task-forces. 585 (62.90%) in-patients were hospitalized amongst 930 secondary care referrals. Secondary-care bed-days were 2106 with average bed-occupancy being 77.78%. 495 patients were institutionalized in tertiary-care Saudi-Arabian hospitals. Infectious diseases were most commonly (53.26%) encountered due to overwhelming respiratory-infections, followed by trauma (24.40%). Analgesics (66.38/100 patients) and antibacterials (48.34/100 patients) were frequently prescribed. Crude mortality amongst Indian pilgrims was 11.99/10,000. Risk factors associated with high morbidity were old-age and pre-existing comorbidities. Overwhelming surge of patients facilitates transmission of communicable infections and leads to stress induced physical, mental and compassion fatigue amongst healthcare personnel. Respiratory infections are highly prevalent and easily transmissible during Hajj leading to significant morbidity, increased burden to existing health facilities, overwhelming costs on health systems and globalization of multiresistant pathogens. Diabetic patients should avoid heat exposure and use protective footwear during Hajj rituals. Mass gathering medicine at Hajj can be optimized by improving patient knowledge on performing Hajj at a younger age, medicine compliance, avoiding self-medication, self-monitoring of hypertension, blood glucose, and preventive health measures; screening of pre-existing comorbidities; and resource augmentation with telemedicine networks and decision-support systems. PMID- 28668660 TI - Accelerating deep neural network training with inconsistent stochastic gradient descent. AB - Stochastic Gradient Descent (SGD) updates Convolutional Neural Network (CNN) with a noisy gradient computed from a random batch, and each batch evenly updates the network once in an epoch. This model applies the same training effort to each batch, but it overlooks the fact that the gradient variance, induced by Sampling Bias and Intrinsic Image Difference, renders different training dynamics on batches. In this paper, we develop a new training strategy for SGD, referred to as Inconsistent Stochastic Gradient Descent (ISGD) to address this problem. The core concept of ISGD is the inconsistent training, which dynamically adjusts the training effort w.r.t the loss. ISGD models the training as a stochastic process that gradually reduces down the mean of batch's loss, and it utilizes a dynamic upper control limit to identify a large loss batch on the fly. ISGD stays on the identified batch to accelerate the training with additional gradient updates, and it also has a constraint to penalize drastic parameter changes. ISGD is straightforward, computationally efficient and without requiring auxiliary memories. A series of empirical evaluations on real world datasets and networks demonstrate the promising performance of inconsistent training. PMID- 28668661 TI - Reviewing the impact of lipid synthetic flux on Th17 function. AB - CD4+ T helper 17 cells (Th17) acquire specific effector functions in response to activation and instructional signals. Accumulating evidence indicates that specific cellular lipid metabolic pathways play essential roles in regulating the differentiation and function of Th17 cells. Mechanistic studies reveal that metabolic fluxes through both the cholesterol and long chain fatty acid biosynthetic pathways are important in controlling RORgamma transcriptional activity through their ability to generate lipid ligands of RORgamma. Genetic and pharmacologic studies demonstrate that altering the flux through these lipid biosynthetic pathways impacts the generation of IL-17 as well as the balance of Th17 and CD4+ regulatory T cells (Tregs). In this mini-review, we briefly introduce the mechanics of cholesterol and long chain fatty acid biosynthesis. We also discuss the evidence underlying the unique role that these lipid metabolic pathways play in intrinsically regulating the fate and function of Th17 cells under normal and pathogenic conditions. PMID- 28668662 TI - The Dutch Move Beyond the Concept of Nursing Home Physician Specialists. PMID- 28668663 TI - Prevalence and Determinants of Poor Food Intake of Residents Living in Long-Term Care. AB - OBJECTIVE: Poor food intake is known to lead to malnutrition in long-term care homes (LTCH), yet multilevel determinants of food intake are not fully understood, hampering development of interventions that can maintain the nutritional status of residents. This study measures energy and protein intake of LTCH residents, describes prevalence of diverse covariates, and the association of covariates with food intake. DESIGN: Multisite cross-sectional study. SETTING: Thirty-two nursing homes from 4 provinces in Canada. PARTICIPANTS: From a sample of 639 residents (20 randomly selected per home), 628 with complete data were included in analyses. MEASUREMENTS: Three days of weighed food intake (main plate, estimated beverages and side dishes, snacks) were completed to measure energy and protein intake. Health records were reviewed for diagnoses, medications, and diet prescription. Mini-Nutritional Assessment-SF was used to determine nutritional risk. Oral health and dysphagia risk were assessed with standardized protocols. The Edinburgh-Feeding Questionnaire (Ed-FED) was used to identify eating challenges; mealtime interactions with staff were assessed with the Mealtime Relational Care Checklist. Mealtime observations recorded duration of meals and assistance received. Dining environments were assessed for physical features using the Dining Environment Audit Protocol, and the Mealtime Scan was used to record mealtime experience and ambiance. Staff completed the Person Directed Care questionnaire, and managers completed a survey describing features of the home and food services. Hierarchical multivariate regression determined predictors of energy and protein intake adjusted for other covariates. RESULTS: Average age of participants was 86.3 +/- 7.8 years and 69% were female. Median energy intake was 1571.9 +/- 411.93 kcal and protein 58.4 +/- 18.02 g/d. There was a significant interaction between being prescribed a pureed/liquidized diet and eating challenges for energy intake. Age, number of eating challenges, pureed/liquidized diet, and sometimes requiring eating assistance were negatively associated with energy and protein intake. Being male, a higher Mini-Nutritional Assessment-Short Form score, often requiring eating assistance, and being on a dementia care unit were positively associated with energy and protein intake. Energy intake alone was negatively associated with homelikeness scores but positively associated with person-centered care practices, whereas protein intake was positively associated with more dietitian time. CONCLUSION: This is the first study to consider resident, unit, staff, and home variables that are associated with food intake. Findings indicate that interventions focused on pureed food, restorative dining, eating assistance, and person-centered care practices may support improved food intake and should be the target for further research. PMID- 28668664 TI - A Pilot Randomized Trial of a Companion Robot for People With Dementia Living in the Community. AB - OBJECTIVES: To investigate the affective, social, behavioral, and physiological effects of the companion robot Paro for people with dementia in both a day care center and a home setting. DESIGN: A pilot block randomized controlled trial over 12 weeks. Participants were randomized to the intervention (Paro) or control condition (standard care). SETTING: Two dementia day care centers and participants' homes in Auckland, New Zealand. PARTICIPANTS: Thirty dyads (consisting of a care recipient with dementia and their caregiver) took part in this study. All care recipients attended dementia day care centers at Selwyn Foundation and had a formal diagnosis of dementia. INTERVENTION: Thirty-minute unstructured group sessions with Paro at the day care center were run 2 to 3 times a week for 6 weeks. Participants also had Paro at home for 6 weeks. MEASUREMENTS: At the day care centers, observations of the care recipients' behavior, affect, and social responses were recorded using a time sampling method. Observations of interactions with Paro for participants in the intervention were also recorded. Blood pressure and salivary cortisol were collected from care recipients before and after sessions at day care. In the home setting, level of cognition, depressive symptoms, neuropsychiatric symptoms, behavioral agitation, and blood pressure were measured at baseline, 6 weeks, and 12 weeks. Hair cortisol measures were collected at baseline and at 6 weeks. RESULTS: Observations showed that Paro significantly improved facial expressions (affect) and communication with staff (social interaction) at the day care centers. Subanalyses showed that care recipients with less cognitive impairment responded significantly better to Paro. There were no significant differences in care recipient dementia symptoms, nor physiological measures between the intervention and control group. CONCLUSION: Paro shows promise in enhancing affective and social outcomes for certain individuals with dementia in a community context. Larger randomized controlled trials in community settings, with longer time frames, are needed to further specify the contexts and characteristics for which Paro is most beneficial. PMID- 28668665 TI - The Quality of POLST Completion to Guide Treatment: A 2-State Study. AB - OBJECTIVES: Physician Orders for Life-Sustaining Treatment (POLST) need to be complete and consistent to allow health care personnel to honor patient preferences in a time of emergency. The purpose of our study was to evaluate the quality of POLST completion to guide treatment for level of medical intervention. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study combined data from the Oregon and West Virginia POLST registries for the study period January 1, 2010, through December 31, 2016. All POLST form resuscitation (section A) and level of medical intervention (section B) orders were reviewed. MEASUREMENTS: Percent of POLST form orders in sections A and B with and without contradictions. RESULTS: During the study period, there were 268,386 POLST forms in the Oregon POLST Registry and 10,122 forms in the West Virginia e-Directive Registry. Of the forms, 99.2% in Oregon and 96.6% in West Virginia contained orders in both sections A and B. There were contradictions on 0.11% of forms from Oregon and 2.53% from West Virginia. CONCLUSIONS: The quality of POLST form completion in the Oregon and West Virginia registries is good with less than 10% of forms lacking orders in sections A and B and containing contradictory orders. This study indicates what type of results are possible with statewide education, likely through POLST Paradigm Programs. Further research is needed to determine the quality of POLST form completion in other states and other factors that contribute to their quality. PMID- 28668666 TI - GHB levels in breast milk of women with narcolepsy with cataplexy treated with sodium oxybate. AB - OBJECTIVE: To determine GHB levels in breast milk of women taking sodium oxybate (Xyrem) for treatment of narcolepsy and cataplexy. METHODS: Two women with narcolepsy and cataplexy treated with sodium oxybate before pregnancy collected breast milk for analysis of GHB concentration after resuming sodium oxybate postpartum. One woman collected samples across two consecutive nights (doses: 3.0 gm and 4.5 gm twice per night) five months after delivering her first child; the other collected samples on three separate days (doses: 2.25 gm and 3.0 gm twice per night) nine months after the births of her first two children. GHB concentration was determined by gas chromatography/mass spectrometry. RESULTS: Milk GHB levels before sodium oxybate ranged from 5.81 to 7.60 MUM. Levels were 2 4 times higher four hours after the first sodium oxybate dose (10.44-23.58 MUM) and 3-5 times higher four hours after the second dose (ie, eight hours after first dose; 14.60-34.01 MUM). GHB levels returned to endogenous levels 6-10 h following the second dose, however variability was observed between patients and pregnancies. Higher breast milk GHB levels were observed with higher doses for both patients. CONCLUSIONS: Sodium oxybate is transmitted to breast milk. Despite its short half-life, GHB concentrations remained two-to-five times higher than endogenous levels four hours after both nighttime doses. To avoid excess GHB exposure, breastfeeding mothers who take sodium oxybate should consider expressing and discarding their morning milk. Future work should examine milk GHB levels after chronic sodium oxybate and determine whether levels change as milk composition changes across the postpartum period. PMID- 28668667 TI - Factors influencing codon usage of mitochondrial ND1 gene in pisces, aves and mammals. AB - Animal mitochondrial genome harbours 13 protein coding genes which regulate the process of respiration. The mitochondrial NADH dehydrogenase 1 (MT-ND1) gene, one of the 13 protein-coding genes, encodes the NADH dehydrogenase 1 enzyme of the respiratory chain. Analysis of codon usage bias (CUB) acquires importance for better understanding of the molecular biology, new gene discovery, design of transgenes and gene evolution. The MT-ND1 gene seems to be a good candidate for analyzing codon usage pattern, since no work has yet been reported. Moreover, it is still not clear which factors significantly influence the codon usage pattern. In the present study, comparative analysis of codon usage pattern, expression level and influencing factors for MT-ND1 gene from 100 different species each of pisces, aves and mammals were used for CUB analysis. Our result suggests that the gene is AT rich in pisces, aves and mammals and most of the nucleotides significantly differ among them as revealed from t-test. CUB was not remarkable as reflected by high value of effective number of codons and it also significantly differs among pisces, aves and mammals. Although we found that CUB is mainly influenced by natural selection and mutation pressure for MT-ND1 gene as suggested by correlation and correspondence analysis but neutrality plot further revealed that natural selection played a major role and mutation pressure played a minor role in codon usage pattern. Additionally, t-test analysis showed that the MT-ND1 gene has a wide significant discrepancy in codon choices in pisces, aves and mammals. This study has contributed to boost our understanding about the mechanism of distribution of the codons and the factors that may influence the evolution of the MT-ND1 gene. PMID- 28668668 TI - Postoperative stereotactic radiosurgery for resected brain metastases: A comparison of outcomes for large resection cavities. AB - PURPOSE: Although historical trials have established the role of surgical resection followed by whole brain irradiation (WBRT) for brain metastases, WBRT has recently been shown to cause significant neurocognitive decline. Many practitioners have employed postoperative stereotactic radiosurgery (SRS) to tumor resection cavities to increase local control without causing significant neurocognitive sequelae. However, studies analyzing outcomes of large brain metastases treated with resection and postoperative SRS are lacking. Here we compare outcomes in patients with large brain metastases >4 cm to those with smaller metastases <=4 cm treated with surgical resection followed by SRS to the resection cavity. METHODS AND MATERIALS: Consecutive patients with brain metastases treated at our institution with surgical resection and postoperative SRS were retrospectively reviewed. Patients were stratified into <=4 cm and >4 cm cohorts based on preoperative maximal tumor dimension. Cumulative incidence of local failure, radiation necrosis, and death were analyzed for the 2 cohorts using a competing-risk model, defined as the time from SRS treatment date to the measured event, death, or last follow-up. RESULTS: A total of 117 consecutive cases were identified. Of these patients, 90 (77%) had preoperative tumors <=4 cm, and 27 (23%) >4 cm in greatest dimension. The only significant baseline difference between the 2 groups was a higher proportion of patients who underwent gross total resection in the <=4 cm compared with the >4 cm cohort, 76% versus 48%, respectively (P <.01). The 1-year rates of local failure, radiation necrosis, and overall survival for the <=4 cm and >4 cm cohorts were 12.3% and 16.0%, 26.9% and 28.4%, and 80.6% and 67.6%, respectively (all P >.05). The rates of local failure and radiation necrosis were not statistically different on multivariable analysis based on tumor size. CONCLUSIONS: Brain metastases >4 cm in largest dimension managed by resection and radiosurgery to the tumor cavity have promising local control rates without a significant increase in radiation necrosis on our retrospective review. PMID- 28668669 TI - Practical workflow for rapid prototyping of radiation therapy positioning devices. PMID- 28668670 TI - A new class of VMAT-2 inhibitors for tardive dyskinesia. PMID- 28668671 TI - Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. AB - BACKGROUND: Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia. METHODS: We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (>=3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score >=6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861. FINDINGS: Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3.3 points (SE 0.42) in the deutetrabenazine 36 mg/day group, -3.2 points (0.45) in the 24 mg/day group, and -2.1 points (0.42) in the 12 mg/day group, with a treatment difference of -1.9 points (SE 0.58, 95% CI -3.09 to -0.79; p=0.001), -1.8 points (0.60, -3.00 to -0.63; p=0.003), and -0.7 points (0.57, 1.84 to 0.42; p=0.217), respectively, versus -1.4 points (0.41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor. INTERPRETATION: Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability. FUNDING: Teva Pharmaceutical Industries. PMID- 28668672 TI - Amiodarone and itraconazole improve the activity of pentavalent antimonial in the treatment of experimental cutaneous leishmaniasis. AB - Leishmaniasis affect millions of people, causing morbidity and mortality, especially in developing tropical and subtropical countries. Unfortunately, the possibilities of treatment for these infections are still quite limited and most of the available drugs present serious side effects. The objective of this paper was to evaluate the therapeutic role of amiodarone and itraconazole in the treatment of cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis. In order to perform this evaluation, hamsters were infected with 1 * 106 metaciclic promastigotes of the parasite in the hind footpad and, after the onset of the lesions, were treated with glucantime, amiodarone, itraconazole, glucantime and amiodarone, glucantime and itraconazole or amiodarone and itraconazole. The treatments' efficacy was evaluated per analysis of the size of the cutaneous lesions and by parasitic investigation of the infected foot (by histopathological examination and PCR) and possible side effects were analyzed taking into account the weight of the animals and some biochemical and metabolic parameters (glucose, urea, creatinine, AST, ALT and ALP). The results have shown that, in hamsters, amiodarone and itraconazole, either used isolated or in combination, are unable to stop the development of cutaneous lesions caused by L. (L.) amazonensis, but improve the activity of glucantime in the treatment of these lesions and seem to present no evident side effects. More studies are necessary in order to investigate the clinical potential of these combinations, so there can be the possibility of broadening the therapeutic options available, especially in resistant cases. PMID- 28668673 TI - The chemotherapeutic potential of chalcones against leishmaniases: a review. AB - Leishmaniases are endemic diseases in tropical and sub-tropical regions of the world and are considered by the World Health Organization (WHO) to be among the six most important neglected tropical diseases. The current therapeutic arsenal against the disease is associated with a series of chemotherapeutic setbacks. However, since the early 1990s, naturally occurring chalcones with promising antileishmanial effects have been reported, and several other synthetic chalcones and chalcone-hybrid molecules have been confirmed to possess potent activity against various Leishmania species. This paper is a comprehensive review covering the antileishmanial activity of 34 naturally occurring chalcones, 224 synthetic/semisynthetic chalcones and 54 chalcone-hybrid molecules. Several chalcones in the synthetic/semisynthetic category had IC50 values < 5 uM, with very good selectivity against parasites, and the structure-activity relationships as well as the proposed mechanism of action are discussed. We identified knowledge-gaps with the hope of providing future direction for the discovery of novel antileishmanial drugs from chalcones. PMID- 28668674 TI - 16-membered macrolide antibiotics: a review. AB - The 16-membered macrolide antibiotics (e.g. tylosin A and josamycin) are mainly used in veterinary medicine, and are much less studied than their 14- and 15 membered erythromycin-based cousins. Although these antibiotics have similar antibacterial profiles, with activity primarily against Gram-positive and a limited range of Gram-negative organisms, the 16-membered macrolides show some advantages. These include better gastrointestinal tolerance, lack of drug-drug interactions, and activity against certain resistant bacterial strains by extension of the peptide tunnel reach allowing additional interactions. In addition to antibacterial activity, the most famous representative of the class, tylosin A, as well as some derivatives of desmycosin (tylosin B), have shown antimalarial activity. Such activity has also been observed in the 14-membered macrolide antibiotics, azithromycin, solithromycin and clindamycin. This antimalarial activity provides the opportunity to investigate these drugs as cheap and effective antimalarials. This is an overview of the latest research on biosynthesis, structure, chemical properties and mode of action of 16-membered macrolides, with special emphasis on their most explored members: tylosin A and josamycin. PMID- 28668675 TI - Effect of residual doxycycline concentrations on resistance selection and transfer in porcine commensal Escherichia coli. AB - Pig feed may contain various levels of antimicrobial residues due to cross contamination. A previous study showed that a 3% carry-over level of doxycycline (DOX) in the feed results in porcine faecal concentrations of approximately 4 mg/L. The aim of this study was to determine the effect of residual DOX concentrations (1 and 4 mg/L) in vitro on selection of DOX-resistant porcine commensal Escherichia coli and transfer of their resistance plasmids. Three different DOX-resistant porcine commensal E. coli strains and their plasmids were characterised. These strains were each brought in competition with a susceptible strain in a medium containing 0, 1 and 4 mg/L DOX. Resistant bacteria, susceptible bacteria and transconjugants were enumerated after 24 h and 48 h. The tet(A)-carrying plasmids showed genetic backbones that are also present among human E. coli isolates. Ratios of resistant to susceptible bacteria were significantly higher at 1 and 4 mg/L DOX compared with the blank control, but there was no significant difference between 1 and 4 mg/L. Plasmid transfer frequencies were affected by 1 or 4 mg/L DOX in the medium for only one of the resistance plasmids. In conclusion, DOX concentrations of 1 and 4 mg/L can select for resistant E. coli in vitro. Further research is needed to determine the effect of these concentrations in the complex environment of the porcine intestinal microbiota. PMID- 28668676 TI - Comparison of the therapeutic efficacy of fluoroquinolone and non-fluoroquinolone treatment in patients with Elizabethkingia meningoseptica bacteraemia. AB - Elizabethkingia meningoseptica is a non-fermentative Gram-negative bacillus that has emerged as an important pathogen in nosocomial infections and is usually associated with high mortality. E. meningoseptica is inherently resistant to many broad-spectrum antibiotics, and appropriate antibiotic selection is crucial for survival. Data about the therapeutic efficacy of fluoroquinolone in E. meningoseptica bacteraemia are limited. We retrospectively enrolled patients with E. meningoseptica bacteraemia who were treated with a single antimicrobial agent with in vitro activity against E. meningoseptica for at least 48 hours in a Taiwanese medical centre between January 2011 and June 2016. We compared the therapeutic efficacy of fluoroquinolone and non-fluoroquinolone treatment. A logistic regression and a propensity score-adjusted model were used to evaluate the risk factors for 14-day mortality. A total of 66 patients were identified, 24 who received fluoroquinolone treatment (ciprofloxacin, n = 9; levofloxacin, n = 15) and 42 who received non-fluoroquinolone treatment (piperacillin/tazobactam, n = 26; trimethoprim/sulfamethoxazole, n = 15; minocycline, n = 1). The fluoroquinolone group had significantly lower 14-day mortality than the non fluoroquinolone group (8.3% vs. 33.3%, P = 0.023). The APACHE II score was significantly higher in the non-fluoroquinolone group than in the fluoroquinolone group. In a propensity-adjusted analysis, fluoroquinolone use was an independent factor associated with 14-day survival. After stratification using the APACHE II score, treatment with fluoroquinolone was associated with 14-day survival, but did not reach statistical significance in both groups with greater and lesser severity. Therefore, fluoroquinolone is a suitable antimicrobial agent for treating E. meningoseptica bacteraemia. PMID- 28668677 TI - Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy. AB - Malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials, including chloroquine (CQ), new drugs are urgently needed. Here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ resistant (Dd2) strain of Plasmodium falciparum. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of >=50% were further examined in vitro to determine the 50% inhibitory concentration (IC50) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium berghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo prolonged the survival of treated versus untreated mice, four of which afforded >=60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ-resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines. PMID- 28668678 TI - Moxifloxacin plus rifampin as an alternative for levofloxacin plus rifampin in the treatment of a prosthetic joint infection with Staphylococcus aureus. AB - OBJECTIVES: The combination of a fluoroquinolone with rifampin is one of the cornerstones in the treatment of prosthetic joint infections (PJI) caused by staphylococci. Moxifloxacin is highly active against methicillin-susceptible Staphylococcus aureus (MSSA) and, therefore, is an attractive agent to use. However, several studies reported a lowering in serum moxifloxacin levels when combined with rifampin. The clinical relevance remains unclear. We determined the outcome of patients with early acute PJI caused by MSSA treated with either moxifloxacin/rifampin or levofloxacin/rifampin. METHODS: Medical files of patients treated with moxifloxacin/rifampin (University Medical Centre Groningen) or levofloxacin/rifampin (Hospital Clinic Barcelona) were retrospectively reviewed (2005-2015). Treatment failure was defined as the need for revision surgery and/or suppressive therapy, death by infection or a relapse of infection during follow-up. RESULTS: Differences in baseline characteristics between the two cohorts were observed, but prognostic parameters for failure, as defined by the KLIC-score (Kidney failure, Liver cirrhosis, Index surgery, C-reactive protein and Cemented prosthesis), were similar in the two groups (2.9 [1.5 SD] for the moxifloxacin group vs. 2.2 [1.2 SD] for the levofloxacin group [P = 0.16]). With a mean follow-up of 50 months (36 SD) in the moxifloxacin group, and 67 months (50 SD) in the levofloxacin group (P = 0.36), treatment was successful in 89% vs. 87.5%, respectively (P = 0.89). None of the failures in the moxifloxacin group were due to rifampin- or moxifloxacin-resistant S. aureus strains. CONCLUSION: Our data indicate that moxifloxacin combined with rifampin is as clinically effective as levofloxacin/rifampin for early acute PJI caused by MSSA. PMID- 28668679 TI - Novel application of published risk factors for methicillin-resistant S. aureus in acute bacterial skin and skin structure infections. AB - Methicillin-resistant Staphylococcus aureus acute bacterial skin and skin structure infections (MRSA ABSSSIs) are associated with a significant clinical and economic burden; however, rapid identification of MRSA remains a clinical challenge. This study aimed to use a novel method of predictive modeling to determine those at highest risk of MRSA ABSSSIs. Risk factors for MRSA ABSSSI were derived from a combination of previously published literature and multivariable logistic regression of individual patient data (IPD) using the 'adaptation method.' A risk-scoring tool was derived from weight-proportional integer-adjusted coefficients of the predictive model. Likelihood ratios were used to adjust posterior probability of MRSA. Risk factors were identified from 12 previously published studies and adapted based on IPD (n = 231). Risk factors were: history of diabetes with obesity (adapted odds ratio [aOR] = 1.1), prior antibiotics (90 days) (aOR = 2.6), chronic kidney disease/hemodialysis (aOR = 1.4), intravenous drug use (aOR = 2.8), previous MRSA exposure/infection (12 months) (aOR = 2.8), previous hospitalization (12 months) (aOR = 7.5), and HIV/AIDS (aOR = 4.0). Baseline prevalence of MRSA was 42.7%. Scores ranged from 0 - 8 points. Post-test probability of MRSA: score 0 = 35.0%; score 1 - 2 = 45.0%; score 3 = 63.0%. The newly derived risk-scoring tool is proof-of-concept of the adaptation method. This study is hypothesis generating and such a tool remains to be validated for clinical use. PMID- 28668680 TI - Antimicrobial activities of LCB10-0200, a novel siderophore cephalosporin, against the clinical isolates of Pseudomonas aeruginosa and other pathogens. AB - Infections caused by multidrug-resistant bacteria, including Pseudomonas aeruginosa, are threatening public health worldwide. Therefore, a novel antibacterial agent is needed to treat these infections. Here, we investigated the in vitro and in vivo activities of a novel siderophore-conjugated cephalosporin, LCB10-0200, against the clinical isolates of Gram-negative bacteria, including multidrug-resistant P. aeruginosa. In vitro susceptibility to LCB10-0200 was assessed by performing a two-fold agar dilution method, as described by the Clinical and Laboratory Standards Institute. LCB10-0200 showed the most potent antibacterial activity against P. aeruginosa clinical isolates, including beta-lactamase-producing strains. Moreover, LCB10-0200 showed better antibacterial activity against recently isolated clinical isolates than its comparators, except colistin. The in vivo activity of LCB10-0200 was examined using four mouse models of systemic, thigh, respiratory tract, and urinary tract infections. LCB10-0200 was more effective than ceftazidime in treating systemic, thigh, respiratory tract, and urinary tract infections caused by drug-susceptible and drug-resistant P. aeruginosa strains in these mouse models. Thus, the potent in vitro and in vivo activities of LCB10-0200 observed in the present study indicate that it has the potential for treating infections caused by Gram negative bacteria, including P. aeruginosa. PMID- 28668681 TI - Targeting the active sites of malarial proteases for antimalarial drug discovery: approaches, progress and challenges. AB - Malaria is an infectious disease causing vast mortality and morbidity worldwide. Although antimalarial drugs are effective in several parts of the world, there is a serious threat to malaria control as malaria parasites are continuously developing widespread resistance against currently available antimalarial drugs, including artemisinin. Such widespread antimalarial drug resistance confirms the need to improve the efficacy of existing or new drugs as well as to develop alternative treatments through the identification of novel drug targets and the development of candidate drugs. Similar to proteases in other parasitic diseases such as leishmaniasis, schistosomiasis, Chagas disease and African sleeping sickness, malarial proteases constitute the major virulence factors in malaria. Malarial proteases belong to several classes and many of them have been targeted for the design and discovery of antimalarial agents. This review summarises the approaches, progress and challenges in the design of small-molecule inhibitors as antimalarial drugs targeting the inhibition of various malarial proteases. PMID- 28668682 TI - Inhibition of herpes simplex virus 1 (HSV-1) and poliovirus (PV-1) by bacteriocins from lactococcus lactis subsp. lactis and enterococcus durans strains isolated from goat milk. AB - Bacteriocins have unusual inhibitory activity, including antiviral properties, and this can be exploited to give alternative applications. Semi-purified bacteriocins of six lactic acid bacteria (LAB) strains isolated from goat milk (two Lactococcus lactis: GLc03 and GLc05, and four Enterococcus durans: GEn09, GEn12, GEn14 and GEn17) were tested for cytotoxicity in Vero cells (50% Cytotoxicity Concentration: CC50), and for their antiviral activities against herpes simplex virus 1 (HVS-1) and poliovirus (PV-1). Semi-purified bacteriocins presented low cytotoxicity, with CC50 varying from 256.2 ug/mL (GLc05) to 1084.5 ug/mL (GEn14). CC10 was determined for all isolates (GLc03: 36.9 ug/mL; GLc05: 51.2 ug/mL; GEn09: 88.1 ug/mL; GEn12: 99.9 ug/mL; GEn14: 275 ug/mL; and GEn17: 62.2 ug/mL) and considered for antiviral activity assays. Antiviral activity before virus adsorption was recorded against PV-1 for GLc05 (4.9%), GEn09 (3.4%), GEn12 (24.7%) and GEn17 (23.5%), and against HSV-1 for GEn12 (27.9%), GEn14 (58.7%) and GEn17 (39.2%). Antiviral activity after virus adsorption was identified against PV-1 for GLc05 (32.7%), GEn09 (91.0%), GEn12 (93.7%) and GEn17 (57.2%), and against HSV-1 for GEn17 (71.6%). The results obtained indicate the potential of some bacteriocins, particularly those produced by E. durans strains investigated in the present study, in viral inhibition and their application as new antiviral agents. PMID- 28668683 TI - Defining the impact of severity of illness on time above the MIC threshold for cefepime in Gram-negative bacteraemia: a 'Goldilocks' window. AB - The quantitative impact of severity of illness on pharmacodynamic thresholds is poorly defined. We used a robust cefepime outcomes cohort and previously identified pharmacodynamic breakpoints of 68% [pharmacokinetic (PK) model 1] and 74% (PK model 2) to probe interactions and relationships with modified Acute Physiology and Chronic Health Evaluation (mAPACHE) II scores. When the time that serum concentration remains above the minimum inhibitory concentration during the dosing interval (fT>MIC) was optimised, mortality was improved between mAPACHE II scores of 9-23 and 9-22 in models 1 and 2, respectively. No significant interactions were identified. These results suggest that mAPACHE II scores of 9 22 may fall within a 'Goldilocks' window in which hospital survival is improved among patients achieving goal fT>MIC thresholds. PMID- 28668684 TI - High incidence of fluoroquinolone resistance and effect of efflux pump inhibitors on moxifloxacin resistance among Mycobacterium tuberculosis isolates causing urinary tract infection in Taiwan. AB - This study explored the prevalence of urinary tract tuberculosis (UTB) and whether efflux pump activation accounts for resistance to moxifloxacin in Taiwan. Of 3034 patients with culture-confirmed TB from 2005-2012, 47 patients (1.5%) with UTB were included in this study. Minimum inhibitory concentrations (MICs) of moxifloxacin were determined in the presence and absence of efflux pump inhibitors (EPIs), including verapamil, reserpine and carbonyl cyanide 3 chlorophenylhydrazone (CCCP). EPI responders were defined as isolates with at least a four-fold reduction in MICs in the presence of EPIs. Among the 47 isolates, 24 (51.1%) were resistant to ofloxacin and 22 (46.8%) were resistant to moxifloxacin by the agar proportion method. Among the 22 moxifloxacin-resistant isolates, 19 (86.4%) had low-level resistance (MIC = 1.0-2.0 mg/L). Patients with prior exposure to fluoroquinolones were more likely than non-exposed patients to have moxifloxacin-resistant isolates [14/22 (63.6%) vs. 8/25 (32.0%); P = 0.030]. All 3 isolates with high-level moxifloxacin resistance (MIC >= 4.0 mg/L) had mutations in the gyrA or gyrB genes; however, among the 19 isolates with low level resistance, only 1 (5.3%) had a mutation in the gyrA gene. Among the 19 isolates with low-level moxifloxacin resistance, 16 isolates (84.2%) were EPIs responders, but none of the high-level resistant isolates were EPIs responders. Approximately one-half (46.8%) of the isolates from patients with UTB were resistant to moxifloxacin, and activation of efflux pumps accounted for most low level moxifloxacin-resistant isolates. PMID- 28668685 TI - Effect of administration route and dose alteration on sulfadiazine-trimethoprim plasma and intestinal concentrations in pigs. AB - Potentiated sulfonamides, such as sulfadiazine-trimethoprim (SDZ-TRIM), are frequently used antimicrobials in both human and veterinary medicine. To optimise their use in relation to the emerging problem of resistance selection, this paper studied the impact of dose and administration route of SDZ-TRIM on the exposure of the gut microbiota to these antimicrobials. An animal experiment was conducted with 36 pigs, divided into six different treatment groups (n = 6). Three different administration routes were outlined: oral (PO) gavage, intramuscular (IM) injection and medicated feed, with 5-day therapy duration. Conventional dosing (30 mg SDZ-TRIM/kg bodyweight [BW]) and half dosing (15 mg SDZ-TRIM/kg BW) was performed for the oral routes in two applications per day. For the IM route, a conventional dose of 15 mg SDZ-TRIM/kg BW or a double dose of 30 mg SDZ-TRIM/kg BW was administered once daily. After daily collection of blood and faeces, the intestinal content of all animals was sampled in different gastrointestinal tract (GIT) segments, and SDZ and TRIM were quantified. Remarkably, SDZ accumulated in distal GIT segments, independently of the administration route. High concentrations (mean +/- standard deviation) up to 26.93 +/- 8.36 ug/g, 11.15 +/- 3.78 ug/g and 19.36 +/- 1.86 ug/g after PO gavage, IM administration and medicated feed, respectively, were measured for SDZ. In contrast, TRIM concentrations decreased from proximal to distal segments and were mostly below the limit of quantification (0.025 ug/g). The high oral bioavailability of SDZ indicates gastrointestinal secretion is a substantial elimination route for SDZ. PMID- 28668687 TI - Lack of experimental evidence to support mcr-1-positive Escherichia coli strain selection during oral administration of colistin at recommended and higher dose given by gavage in weaned piglets. AB - In this study, we assessed the selective effect of colistin administered orally to healthy weaned piglets harbouring an intestinal mcr-1-positive Escherichia coli strain. Maximum recommended dose and a higher dose often used in European pig farms were given by gavage. No selection of the mcr-1-positive strain was observed in our controlled conditions, irrespective of the dose. Further investigations in real farming conditions seem necessary. PMID- 28668686 TI - Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial. AB - The impact of early ART initiation (versus deferring) on kidney function has not been studied. START was a randomised comparison of immediate versus deferred ART initiation among HIV-positive persons with CD4+ (cells/mm3) counts >500. Serum creatinine and urine dipstick protein were measured at Months 0, 1, 4, 8 and 12, and annually thereafter. The two arms were compared for changes in eGFR (mL/min/1.73 m2, calculated by CKD-EPI equation), over time using longitudinal mixed models. Of 4685 START participants, 4629 (2294 in immediate and 2335 deferred arm) were included. Median baseline CD4+ and eGFR were 651 and 111.5, respectively. ART was initiated in 2271 participants (99.0%) in the immediate and 1127 (48.3%) in the deferred arm, accounting for >94% and >19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over 2.1 years median follow-up, mean eGFR was 0.56 (95% CI 0.003-1.11) higher in the immediate versus deferred arm, which was more prominent after adjustment for current tenofovir or bPI use (1.85, 95% CI 1.21-2.50) and in Black participants (30.1% overall) (3.90, 95% CI 2.84-4.97) versus non-Blacks (1.05, 95% CI 0.33 1.77) (P < 0.001 for interaction). Relative risk for proteinuria in the immediate versus deferred arm was 0.74 (95% CI 0.55-1.00) (P = 0.049). In the short-term, immediate ART initiation was associated with a modestly higher eGFR and lower proteinuria risk versus deferring ART (more pronounced in Black participants). Whether this early benefit translates into a lower risk of CKD requires further follow-up. PMID- 28668688 TI - Massive misuse of antibiotics by university students in all regions of China: implications for national policy. AB - Antimicrobial resistance (AMR) is one of the greatest threats to global health this century. The primary cause of AMR is antibiotic misuse, especially routine use of antibiotics for self-limiting illnesses. This study aimed to explore behaviours related to antibiotic use in university students across China. An electronic questionnaire was distributed at a major university in each of the six regions. A cluster random sampling method was adopted. The chi2 test and logistic regression were used to assess the relationship between knowledge and behaviour. A total of 11,192 students completed the questionnaire. In the past month, 3337 students (29.8%) reported a self-limiting illness, of whom 913 (27.3%) saw a doctor, 600 (65.7%) of whom were prescribed antibiotics [190 (31.7%) by infusion]; 136 students (22.7%) asked for and received antibiotics. Of the 1711 students (51.3%) who treated themselves, 507 (29.6%) self-medicated with antibiotics. In the past year, 23.0% of students had used antibiotics as prophylaxis, 63.1% kept a personal stock of antibiotics and 56.0% had bought antibiotics at a drugstore (two-thirds without a prescription). Students with lower knowledge scores about antibiotics were significantly more likely to see a doctor, be prescribed with antibiotics, self-medicate with antibiotics, and use antibiotics prophylactically. This massive misuse of antibiotics for self limiting illnesses by well-educated young adults is a serious concern. A national campaign is urgently required to address rational prescribing of antibiotics by doctors, enforce existing restrictions on over-the-counter sale of antibiotics, and educate the general public about antibiotics and the management of self limiting illnesses. PMID- 28668689 TI - Suppressive antibiotic therapy with oral doxycycline for Staphylococcus aureus prosthetic joint infection: a retrospective study of 39 patients. AB - The aim of this study was to describe the use of oral doxycycline as suppressive antibiotic therapy (SAT) in patients with Staphylococcus aureus periprosthetic (hip or knee) joint infections. The medical charts of all patients with surgical revisions for S. aureus hip or knee prosthetic joint infections (PJIs) who were given doxycycline-based SAT because of a high risk of failure of various origins were reviewed. Data regarding tolerability and effectiveness of doxycycline-based SAT were analysed. A total of 39 patients (mean age 66.1 +/- 16.3 years) received doxycycline-base SAT in the period from January 2006 to January 2014. PJIs involved the hip in 23 patients (59.0%) and the knee in 16 (41.0%), and were qualified as early in 15 patients (38.5%). Methicillin-resistant S. aureus (MRSA) accounted for 22% of the total number of bacterial strains identified. All patients included in the study had surgery, which consisted of debridement and implant retention in 32 (82.1%). Adverse events likely attributable to SAT were reported in six patients (15.4%), leading to discontinuation of SAT in three (7.7%). A total of 29 patients (74.4%) remained event-free and 10 (25.6%) failed, including 8 (20.5%) relapses and 2 (5.1%) superinfections. Overall, 8 of the 10 failure cases were related to a doxycycline-susceptible pathogen. These results suggest that oral doxycycline used as SAT in patients treated for S. aureus hip or knee PJIs has an acceptable tolerability and effectiveness and appears to be a reasonable option in this setting. PMID- 28668690 TI - In vivo development of tigecycline resistance in Klebsiella pneumoniae owing to deletion of the ramR ribosomal binding site. AB - Tigecycline resistance is emerging among Klebsiella pneumoniae, but knowledge regarding in vivo development of tigecycline resistance is limited. Here we report a new mechanism of tigecycline resistance in K. pneumoniae that evolved during tigecycline therapy. Klebsiella pneumoniae isolates were consecutively obtained from urine samples of a patient with scrotal abscess and urinary tract infection before and during tigecycline treatment. Two tigecycline-resistant K. pneumoniae strains (KP-3R and KP-4R; MIC = 8 ug/mL) were isolated after 41 days and 47 days of tigecycline therapy. These isolates had the same sequence type (ST11) and PFGE patterns as tigecycline-susceptible strains (KP-1S and KP-2S; MIC = 2 ug/mL) initially isolated from the patient. Compared with KP-1S and KP-2S, KP 3R and KP-4R exhibited higher expression of efflux pump AcrAB. Sequence comparison of the repressor gene ramR did not find any mutation within the open reading frame that exist frequently in tigecycline-resistant K. pneumoniae. Instead, a 12-bp deletion of ramR upstream region including the ribosomal binding site (RBS) TGAGG was observed in KP-3R and KP-4R. qRT-PCR and immunoblotting analyses showed that KP-3R and KP-4R did not have impaired ramR transcription but had abolished RamR protein production. Furthermore, xylE reporter assay demonstrated that KP-3R and KP-4R had a defect in RamR translation caused by the 12-bp deletion. Complementing KP-3R and KP-4R with functional ramR suppressed expression of acrAB and consequently restored tigecycline susceptibility. This is the first report identifying deletion of the ramR RBS as a mechanism of in vivo tigecycline resistance in K. pneumoniae developing during tigecycline therapy. PMID- 28668691 TI - Colistin resistance gene mcr-1 in gut flora of children. AB - The aim of this study was to determine the prevalence and transmission mechanism(s) of mcr-1 in the gut flora of children. Faecal samples (n = 173) were obtained from non-diarrhoea patients at the Children's Hospital of Zhejiang University (Hangzhou, China). PCR-based analysis indicated that 17 isolates from 9.8% of the samples were positive for mcr-1, comprising 16 Escherichia coli and 1 Citrobacter freundii. Nine mcr-1-bearing isolates co-expressed extended-spectrum beta-lactamase (ESBL) genes, but plasmid-mediated quinolone resistance (PMQR) genes were not detected. Transconjugation followed by Southern hybridisation analysis revealed that 14 of the E. coli isolates were able to transfer their colistin-resistant phenotype to E. coli EC600. All 14 of these E. coli strains contained a major mcr-1-containing conjugative plasmid with a size of ca. 33 kb or 55 kb. All but two of the E. coli isolates presented distinct pulsed-field gel electrophoresis (PFGE) patterns. Multilocus sequence typing (MLST) analysis revealed 11 sequence types (STs) among the E. coli 16 isolates, with ST117 being the most common. The finding of a high prevalence of mcr-1 in the intestinal flora of children, with the majority of mcr-1-positive isolates being E. coli, highlights the need for more rational use of polymyxins to prevent polymyxin resistance from becoming disseminated among different microbial pathogens. Given the high detection rate of mcr-1 in children, we recommend that polymyxin is no longer used as a last-resort antimicrobial agent and that alternative strategies are developed to treat infections caused by such pathogens. PMID- 28668692 TI - Wastewater is a reservoir for clinically relevant carbapenemase- and 16s rRNA methylase-producing Enterobacteriaceae. AB - The aim of this study was to evaluate wastewater for carbapenemase-producing Enterobacteriaceae (CPE) and 16S rRNA methylase-producing Gram-negative bacteria (MPB) and to assess their occurrence following wastewater treatment. Wastewater samples were collected between June 2015 and March 2016 in the sewage network of the city of Basel (Switzerland) from sites located before and after influx of wastewater from the hospital into the sewage network. Samples were also obtained from the influent and effluent of the receiving wastewater treatment plant. Samples were screened for CPE and MPB using selective media. Escherichia coli and Klebsiella pneumoniae were typed by multilocus sequence typing (MLST). Carbapenemase and 16S rRNA methylase genes were identified by PCR and sequencing. Resistance profiles were determined by the disk diffusion test and Etest. The occurrence of CPE and MPB was increased downstream of hospital wastewater influx. Of 49 CPE isolates, 9 belonged to OXA-48-producing E. coli clone D:ST38, 7 were OXA-48-producing Citrobacter freundii, and 6 were KPC-2- or OXA-48-producing K. pneumoniae belonging to clonal complex 258. NDM (NDM-1, -5 and -9) and VIM (VIM 1) producers were detected sporadically. MPB included ArmA- and RmtB-producing E. coli and Citrobacter spp. Isolates corresponding to strains from wastewater were detected in the effluent of the treatment plant. Conclusively, CPE and MPB, predominantly OXA-48-producing Enterobacteriaceae, are readily detected in wastewater, survive wastewater treatment and are released into the aquatic environment. OXA-48-producers may represent an emerging threat to public health and environmental integrity. PMID- 28668693 TI - Molecular epidemiology of colistin-resistant Enterobacteriaceae in inpatient and avian isolates from China: high prevalence of mcr-negative Klebsiella pneumoniae. AB - Whether chromosomal and transmissible mechanisms contribute simultaneously to colistin resistance in Klebsiella pneumoniae and Escherichia coli remains unknown. This study aims to identify the underlying mechanisms of colistin resistance in inpatient and avian K. pneumoniae and E. coli in China. We retrospectively screened 2353 Enterobacteriaceae isolates from inpatients at multiple centers during 2011-2014, and 168 avian isolates from one slaughterhouse in 2013 for the presence of MCR-1/MCR-2. Mutations and transcriptional levels of the chromosomal RamA, PhoPQ, and PmrAB genes were determined by PCR and RT-qPCR. The transferability and genetic characteristics of the underlying colistin resistance genes were detected by conjugation and whole-genome sequencing. The MIC90 for colistin in colistin-resistant K. pneumoniae (ColRKP, 128 mg/L, N = 17) was 16-fold higher than in colistin-resistant E. coli (ColREC, 8 mg/L, N = 33). The dominant sequence types of ColRKP were ST2018 and ST37, whereas ColREC displayed diversity. The chromosomal genes ramA, pmrB, and phoQ were not associated with colistin resistance in ColRKP. The transcriptional levels of PmrB in ColREC were 7.5-fold greater than in colistin-susceptible isolates. The carrying rates of MCR-1 in ColREC and ColRKP were 100% (33/33) and 23.5% (4/17), respectively. Plasmid IncI2 (~60 kb) carrying MCR-1 could be transferred to recipient E. coli EC600 with frequencies ranging from 8.74 * 10-6 to 1.31 * 10-4. No transferable genes were identified in mcr-1-negative ColRKP. MCR-1 combined with upregulated PmrB was associated with low-level colistin resistance in ColREC. However, two-thirds of the ColRKP isolates were mcr-negative and need to be studied further. PMID- 28668694 TI - Population pharmacokinetics of cefepime in febrile neutropenia: implications for dose-dependent susceptibility and contemporary dosing regimens. AB - Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4-8 ug/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CLCr) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3-8 g/day infused over 0.5-24 h, replaced every 6-24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two compartment PK model with BSA- and CLCr-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 +/- 1.1 L/h), intercompartmental clearance (6.9 +/- 2.8 L/h), and central (14.8 +/- 3.8 L) and peripheral (10.9 +/ 4.6 L) distribution volumes were all estimated with <50% CV. Simulated dosing regimens of 3-4 g/day administered as continuous infusions and doses of 2 g administered q6h (0-5 h infusion) to q8h (4-h infusion) achieved >=90% PTA at MICs up to 8 ug/mL. Simulated regimens of 1 g q8h (4-h infusion) or 1 g q6h (0.5 h infusion) achieved >=90% PTA only against MICs up to 4 ug/mL. High-dose prolonged infusion or more frequent cefepime regimens may be necessary to treat FN organisms with SDD MICs. PMID- 28668695 TI - "What constitutes a 'problem'?" Producing 'alcohol problems' through online counselling encounters. AB - Typically, health policy, practice and research views alcohol and other drug (AOD) 'problems' as objective things waiting to be detected, diagnosed and treated. However, this approach to policy development and treatment downplays the role of clinical practices, tools, discourses, and systems in shaping how AOD use is constituted as a 'problem'. For instance, people might present to AOD treatment with multiple psycho-social concerns, but usually only a singular AOD associated 'problem' is considered serviceable. As the assumed nature of 'the serviceable problem' influences what treatment responses people receive, and how they may come to be enacted as 'addicted' or 'normal' subjects, it is important to subject clinical practices of problem formulation to critical analysis. Given that the reach of AOD treatment has expanded via the online medium, in this article we examine how 'problems' are produced in online alcohol counselling encounters involving people aged 55 and over. Drawing on poststructural approaches to problematisation, we not only trace how and what 'problems' are produced, but also what effects these give rise to. We discuss three approaches to problem formulation: (1) Addiction discourses at work; (2) Moving between concerns and alcohol 'problems'; (3) Making 'problems' complex and multiple. On the basis of this analysis, we argue that online AOD counselling does not just respond to pre-existing 'AOD problems'. Rather, through the social and clinical practices of formulation at work in clinical encounters, online counselling also produces them. Thus, given a different set of circumstances, practices and relations, 'problems' might be defined or emerge differently-perhaps not as 'problems' at all or perhaps as different kinds of concerns. We conclude by highlighting the need for a critical reflexivity in AOD treatment and policy in order to open up possibilities for different ways of engaging with, and responding to, people's needs in their complexity. PMID- 28668696 TI - Reducing Fluoroquinolone Use Is a Key Step in Controlling the Burden of Clostridium difficile Infection. PMID- 28668697 TI - Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as long-acting hypoglycemic and insulinotropic agents with significant therapeutic potential. AB - We here report the discovery and therapeutic efficacy of a novel series of glucagon-like peptide-1 (GLP-1) receptor agonists derived from Xenopus GLP-1. First, five amino acid-mutated Xenopus GLP-1s were synthesized, and xGLP-3 with the best acute and long-acting hypoglycemic activity was selected for further modification. Next, PEGylation of xGLP-3 was performed at specific sites, which were determined using cysteine mutagenesis scanning. Twelve PEGylated conjugates tethered with Mal-PEGs of 1, 2, and 5kDa were synthesized. Conjugates 7b and 7c, which exhibited comparable hypoglycemic and insulinotropic effects to Gly8-GLP-1, were selected for in-depth evaluation. It was found that 7b and 7c exhibited prolonged in vivo half-life and improved pharmacokinetic behaviors. The long-term hypoglycemic effects of 7b and 7c were further confirmed by pre-OGTT and multiple OGTT. Importantly, long-term administration of 7b or 7c in db/db mice achieved beneficial effects on body weight loss, food intake and HbA1c reduction, and glucose tolerance normalization. These preclinical studies indicate the promising role of 7b and 7c as long-acting type 2 diabetes therapeutics. In addition, our research demonstrated the feasibility of developing novel antidiabetic agents based on Xenopus GLP-1. PMID- 28668698 TI - Aggregatibacter actinomycetemcomitans serotype prevalence and antibiotic resistance in a UK population with periodontitis. AB - OBJECTIVES: Aggregatibacter actinomycetemcomitans is a recognised pathogen involved in aggressive periodontitis. Seven serotypes of A. actinomycetemcomitans exist with a range of virulence and distribution dependent on ethnicity and geography. The ability of A. actinomycetemcomitans to invade soft tissue can necessitate the use of systemic antibiotics for treatment, however variations in its antibiotic susceptibility exist dependent on geographical location. METHODS: Serotypes of A. actinomycetemcomitans isolates from a UK cohort of 50 patients with aggressive periodontitis were determined by PCR. Resistance of the isolates to eight antibiotics [penicillin (1U), amoxicillin (2MUg), amoxicillin/clavulanic acid (30MUg), metronidazole (5MUg), clindamycin (2MUg), tetracycline (10MUg), ciprofloxacin (5MUg) and ceftazidime (30MUg)] were determined by disk diffusion according to BSAC guidelines. RESULTS: Prevalences of serotypes a, c, b, e and mixed serotypes were 48%, 22%, 2%, 2% and 12%, respectively. The serotype of isolates from seven patients (14%) could not be deduced by PCR. Of the 56 isolates tested, 100% were resistant to penicillin and metronidazole, 87.5% to clindamycin, 83.9% to amoxicillin and 76.8% to ceftazidime. Low rates of resistance to tetracycline (8.9% resistant) and amoxicillin/clavulanic acid (14.3% resistant) were observed, whereas no isolates were resistant to ciprofloxacin. CONCLUSIONS: As in a number of publications the suggested treatment of aggressive periodontitis includes the combined use of amoxicillin with metronidazole, these results highlight the need for culture and antimicrobial susceptibility investigations in patients with aggressive periodontitis prior to systemic use of antibiotics concomitantly to periodontal therapy. PMID- 28668699 TI - CXCR2 +1208 CT genotype may predict earlier clinical stage at diagnosis in patients with prostate cancer. AB - : Interleukin-8 (IL-8) is an angiogenic CXC chemokine that plays an important role in both the development and progression of several human malignancies including prostate cancer (PC). A single nucleotide polymorphism (SNP) at -251 upstream of the transcriptional start site of the IL-8 gene has been shown to influence its production. The effects of IL-8 are mediated by two highly related chemokine receptors, CXCR1 and CXCR2. The present study investigated the influence of the IL-8 and CXCR2 gene variation on susceptibility and clinicopathological characteristics of PC in a group of Brazilian subjects. METHODS: Two hundred and one patients and 185 healthy controls were enrolled in a case-control study. Blood was collected for DNA extraction; typing of IL-8 -251 T/A and CXCR2 +1208 C/T genes was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP), followed by agarose gel electrophoresis. Risk association between the genotypes, PC susceptibility and tumor characteristics was estimated by odds ratio (OR) and 95% confidence intervals (95% CI) using logistic regression analysis, after adjusting for age at diagnosis. RESULTS: A significant association was found between the heterozygous CXCR2 +1208 CT genotype and stage of PC. The CXCR2 +1208 CT genotype was significantly less frequent in patients with clinical stage T3-T4 compared to T1 T2 (56.7 versus 80.5%). Our findings suggest that carriers of the CXCR2 +1208 CT genotype had a protective effect for advanced PC (CT versus CC: adjusted OR=0.25; P=0.02). No association was observed between the SNP for IL-8 -251 T/A and clinicopathological parameters of PC. CONCLUSION: These results indicated that the CXCR2 +1208 CT genotype is less frequent in advanced stages of PC, suggesting that this chemokine receptor plays a role in the pathogenesis of this disease. PMID- 28668700 TI - Comparison of brain computed tomography and diffusion-weighted magnetic resonance imaging to predict early neurologic outcome before target temperature management comatose cardiac arrest survivors. AB - AIM: We previously reported that diffusion-weighted magnetic resonance imaging (DW-MRI) could be used to predict neurologic outcomes before targeted temperature management (TTM) after return of spontaneous circulation (ROSC) from cardiac arrest (CA). We compared the efficacy of brain computed tomography (CT) and DW MRI to predict neurologic outcome before TTM in comatose cardiac arrest survivors. METHODS: We performed a retrospective study of CA patients treated with TTM. The brain CT and DW-MRI were both obtained before TTM. We analysed the grey matter to white matter ratio (GWR) on the brain CT and the presence of high signal intensity on DW-MRI, alone or in combination, to predict poor neurologic outcome (CPC 3-5). RESULTS: Of 47 comatose CA patients treated with TTM, 39 patients with brain CT and DW-MRI data were included. Median time from the ROSC to the brain CT and DW-MRI was 90min (52-150) and 175min (118-240), respectively. There was no significant difference in predicting poor neurologic outcome between average GWR (area under the curve [AUC] 0.891, sensitivity/specificity 78.8%/100%) and DW-MRI (AUC 0.894, sensitivity/specificity 75.8%/100%) (p=0.963). The combination of average GWR and DW-MRI (AUC 0.939, sensitivity/specificity 87.9%/100%) improved the prediction of poor neurologic outcome rather than each one alone and in other combinations. CONCLUSION: Our preliminary finding suggests that DW-MRI is potentially useful for early prediction of neurologic outcome (i.e., before TTM) in CA patients. The combination of GWR on brain CT and that on DW-MRI, rather than on each modality alone, appears to improve the sensitivity for predicting neurologic outcome after ROSC from CA. Large prospective multicenter studies should be conducted to confirm these results. PMID- 28668701 TI - Cardiopulmonary resuscitation by trained responders versus lay persons and outcomes of out-of-hospital cardiac arrest: A community observational study. AB - OBJECTIVES: The study aims to compare bystander processes of care (cardiopulmonary resuscitation (CPR) and defibrillation) and outcomes for witnessed presumed cardiac etiology in OHCA patients in whom initial resuscitation was provided by dedicated trained responder (TR) versus lay person (LP) bystanders. METHODS: Data on witnessed and presumed cardiac OHCA in adults (15 years or older) from 2011 to 2015 in a metropolitan city with 10 million persons were collected, excluding cases in which the information on TRs, bystander CPR, defibrillation, and clinical outcomes was unknown. Exposure variables were TRs who were legally designated with CPR education and response and LPs who were bystanders who witnessed the OHCA by chance. The primary/secondary/tertiary outcomes were a good cerebral performance category (CPC) of 1 or 2, survival to discharge, and bystander defibrillation. A multivariable logistic regression analysis was used to calculate the adjusted odds ratio (AOR) with 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Of 20,984 OHCA events, 6475 cases were ultimately analyzed. The TR group constituted 6.4% of the cases, and the patients showed significantly better survival and a good CPC. From the multivariable logistic regression analysis of the outcomes, by comparing the TR group with the LP group, the AOR (95% CIs) was 1.49 (1.04-2.15) for a good CPC, 1.59 (1.20-2.11) for survival to discharge, and 10.02 (7.04-14.26) for bystander defibrillation. CONCLUSION: The TR group witnessed a relatively low proportion of OHCA but was associated with better survival outcomes and good neurological recovery through higher CPR rates and defibrillation of adults older than 15 years with witnessed OHCA in a metropolitan city. PMID- 28668702 TI - Differential expression of novel microRNAs in response to the infection of a TMV mutant with an internal poly(A) tract in N. benthamiana. AB - We first constructed small RNA libraries of TMV- and TMV-43A-infected N. benthamiana for high throughput sequencing. A total number of 181 novel microRNAs (miRNAs) were identified through an improved miRNAs analysis pipeline. We were able to identify consistent miRNA expression changes induced in TMV and TMV-43A infected plants, as well as differences associated with the UPD substitution in the TMV-43A viral genome. Virally induced miRNAs are associated with distinct processes and functions of predicted mRNA targets, including relation to host target defense. This study suggests an approach for functional genomics miRNAs in incompletely assembled genomes. These findings provide valuable information for further characterization of miRNAs by two genomic similar viruses, and provide clues to the study of TMV-UPD to find potential defense-related host genes targeted by miRNAs (126 words). PMID- 28668703 TI - DNA damage and repair, oxidative stress and metabolism biomarker responses in lungs of rats exposed to ambient atmospheric 1-nitropyrene. AB - 1-Nitropyrene (1-NP) is a mutagenic and carcinogenic pollutant very widespread in the environment. However, the relative investigations on genotoxicity, oxidative stress and metabolic enzymes in lungs of mammalian caused by 1-NP have not been fully established. In this study, the 1-NP solutions at 3 dosages (1.0*10-5, 4.0*10-5 and 1.6*10-4mg/kg body weight) were respectively given to rats by the intratracheal instillation. The responses of 1-NP on DNA damage and repair, oxidative stress and metabolism biomarkers in rat lungs after exposure to 1-NP were measured. The results showed 1-NP at three dosages induced obvious DNA strand breaks, 8-OH-dG formation and DNA-protein cross-link in rat lungs compared with the control. Higher dosage 1-NP (4.0*10-5 and 1.6*10-4mg/kg body weight) greatly activated DNA repair gene OGG1 and inhibited MTH1 and XRCC1 expressions, and they significantly elevated the levels of GADD153, heme oxygenase-1 and malondialdehyde and decreased SOD activity, accompanied by the increases of CYP450, CYP1A1, CYP1A2 and GST levels. These results suggested the genotoxicity of 1-NP might rely on 1-NP-caused DNA damage and its combined effects on the suppression of DNA repair and the enhancement of oxidative stress and metabolic enzyme activity. PMID- 28668704 TI - Effects of 1,4-naphthoquinone aged carbon black particles on the cell membrane of human bronchial epithelium. AB - Black carbon (BC) and polycyclic aromatic hydrocarbons (PAHs), which are major atmospheric pollutants in China, are hazardous to humans following inhalation. BC can be oxidized by PAHs forming secondary particles of which the health effects are unknown. In this study, carbon black (CB) was used to simulate BC to reveal the adverse effects of 1,4-naphthoquinone aged carbon black (CB/1,4-NQ) particles on the membrane of human bronchial epithelial (16HBE) cells. It was showed that, the cell viability, cell membrane fluidity, membrane potential and mitochondrial membrane potential were significantly decreased after 16HBE cells were treated with CB, 1,4-NQ or CB/1,4-NQ. Meanwhile, the cell membrane permeability and intracellular Ca2+ concentration were increased. CB/1,4-NQ could induce more adverse effects on cell membrane than single CB treated, while less than 1,4-NQ. The results indicated that CB/1,4-NQ particles in the atmosphere may cause more damage to health, and the effects on cell membrane can be used to evaluate the early health effects of the particulate matter exposure. PMID- 28668705 TI - The research of genetic toxicity of beta-phellandrene. AB - beta-Phellandrene, a plant extract, can be used as natural pesticides and synthetic materials. As a factor that human may be exposed to, the toxicity information about beta-phellandrene is scared at present. This study focused on the genetic toxicity of beta-phellandrene. The genetic toxicity of beta phellandrene was evaluated by micronucleus test, comet assay, Ames test, and chromosomal aberration test. In this study, 2850, 1425, 712.5mg/kg beta phellandrene were used in vivo experiments (comet assay and micronucleus test). For Ames test, pure beta-phellandrene and different concentrations were used in the experiment. According to the results of cell viability assay (MTT test), the concentration of chromosomal aberration test was formulated. The result of comet assay showed that beta-phellandrene can significantly induce DNA damage at the dosage of 1425 and 2850mg/kg. While the results of Micronucleus test and chromosome aberration test showed that beta-phellandrene does not lead to apparently genetic toxicity on chromosome level. Ames tests suggest that beta phellandrene had the ability to increase gene mutation with or without S9 mixture. So, it could be drawn that beta-phellandrene would have certain genetic toxicity, and the toxicity is reflected as DNA strand breaks and mutation. This study filled the lack of genetic toxicity study of beta-phellandrene, and enriched information for risk assessment for beta-phellandrene. PMID- 28668706 TI - Destructive effect of non-enzymatic glycation on catalase and remediation via curcumin. AB - Non-enzymatic glycation of proteins is a post-translational modification that is produced by a covalent binding between reducing sugars and amino groups of lysine and arginine residues. In this paper the effect of pathological conditions, derived from hyperglycemia on bovine liver catalase (BLC) as a model protein was considered by measuring enzyme activity, reactive oxygen species (ROS) generation, and changes in catalase conformational properties. We observed that in the presence of glucose, the catalase activity gradually decreased. ROS generation was also involved in the glycation process. Thus, decreased BLC activity was partly considered as a result of ROS generation through glycation. However, in the presence of curcumin the amount of ROS was reduced resulting in increased activity of the glycated catalase. The effect of high glucose level and the potential inhibitory effect of curcumin on aggregation and structural changes of catalase were also investigated. Molecular dynamic simulations also showed that interaction of catalase with curcumin resulted in changes in accessible surface area (ASA) and pKa, two effective parameters of glycation, in potential glycation lysine residues. Thus, the decrease in ASA and increase in pKa of important lysine residues were considered as predominant factors in decreased glycation of BLC by curcumin. PMID- 28668707 TI - Dose-response effects of dietary pequi oil on fermentation characteristics and microbial population using a rumen simulation technique (Rusitec). AB - The effect of increasing the concentration of commercial pequi (Caryocar brasiliense) oil on fermentation characteristics and abundance of methanogens and fibrolityc bacteria was evaluated using the rumen simulation technique (Rusitec). In vitro incubation was performed over 15 days using a basal diet consisting of ryegrass, maize silage and concentrate in equal proportions. Treatments consisted of control diet (no pequi oil inclusion, 0 g/kg DM), pequi dose 1 (45 g/kg DM), and pequi dose 2 (91 g/kg DM). After a 7 day adaptation period, samples for fermentation parameters (total gas, methane, and VFA production) were taken on a daily basis. Quantitative real time PCR (q-PCR) was used to evaluate the abundance of the main rumen cellulolytic bacteria, as well as abundance of methanogens. Supplementation with pequi oil did not reduce overall methane production (P = 0.97), however a tendency (P = 0.06) to decrease proportion of methane in overall microbial gas was observed. Increasing addition of pequi oil was associated with a linear decrease (P < 0.01) in dry matter disappearance of maize silage. The abundance of total methanogens was unchanged by the addition of pequi oil, but numbers of those belonging to Methanomassiliicoccaceae decreased in liquid-associated microbes (LAM) samples (P < 0.01) and solid-associated microbes (SAM) samples (P = 0.09) respectively, while Methanobrevibacter spp. increased (P < 0.01) only in SAM samples. Fibrobacter succinogenes decreased (P < 0.01) in both LAM and SAM samples when substrates were supplemented with pequi oil. In conclusion, pequi oil was ineffective in mitigating methane emissions and had some adverse effects on digestibility and selected fibrolytic bacteria. PMID- 28668708 TI - A case of severe empyema with acute respiratory distress syndrome caused by Slackia exigua requiring veno-venous extracorporeal membrane oxygenation. AB - Slackia exigua (S. exigua) is an obligatory anaerobic coccobacillus under the family of Coriobacteriaceae. It is a rare cause of pyogenic extraoral infections. We report a 58-year-old lady with good past health presented with fulminant community-acquired pneumonia causing acute respiratory distress syndrome caused by S. exigua requiring veno-venous extra-corporeal membrane oxygenation (VV ECMO). Bacterial identification can be challenging and often require 16 S rRNA and MALDI-TOF MS. The patient was treated with amoxicillin-clavulanic acid according to sensitivity and made significant recovery. PMID- 28668709 TI - Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice. AB - High fat diet (HFD)-induced alterations in gut microbiota and resultant 'leaky gut' phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-alpha, and IL-1beta) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods. PMID- 28668710 TI - Accurate virus quantitation using a Scanning Transmission Electron Microscopy (STEM) detector in a scanning electron microscope. AB - A method for accurate quantitation of virus particles has long been sought, but a perfect method still eludes the scientific community. Electron Microscopy (EM) quantitation is a valuable technique because it provides direct morphology information and counts of all viral particles, whether or not they are infectious. In the past, EM negative stain quantitation methods have been cited as inaccurate, non-reproducible, and with detection limits that were too high to be useful. To improve accuracy and reproducibility, we have developed a method termed Scanning Transmission Electron Microscopy - Virus Quantitation (STEM-VQ), which simplifies sample preparation and uses a high throughput STEM detector in a Scanning Electron Microscope (SEM) coupled with commercially available software. In this paper, we demonstrate STEM-VQ with an alphavirus stock preparation to present the method's accuracy and reproducibility, including a comparison of STEM VQ to viral plaque assay and the ViroCyt Virus Counter. PMID- 28668711 TI - DHEA and DHEA-S levels in posttraumatic stress disorder: A meta-analytic review. AB - Differences in hypothalamic-pituitary-adrenocortical (HPA) functioning between patients with posttraumatic stress disorder (PTSD) and controls are among the most consistent neurobiological findings in PTSD. HPA-axis activation results in the output of various steroid hormones including dehydroepiandrosterone (DHEA), which is then converted into dehydroepiandrosterone sulfate (DHEA-S), with anti glucocorticoid actions among its pleiotropic effects. To investigate whether there is evidence for consistent differences in basal DHEA and DHEA-s levels between individuals with and without PTSD, we performed random-effect meta analyses aggregating findings of previously published studies. Nine studies reporting on DHEA levels (486 participants) and 8 studies reporting on DHEA-S levels (501 participants) were included. No significant differences in DHEA or DHEA-S levels between PTSD and control groups were found. Exploratory subgroup analyses were performed to distinguish between effects of PTSD and trauma exposure. A trend for higher DHEA levels was found in PTSD patients compared to non-trauma-exposed controls (NTC) (k=3, SMD=1.12 95% CI -0.03-2.52, Z=1.91, p=0.06). Significantly higher DHEA-S levels were observed in PTSD patients compared to NTC (k=2, SMD=0.76, 95% CI 0.38-1.13, Z=3.94, p<0.001). Additionally, significantly higher DHEA levels were observed in trauma-exposed controls (TC) compared to NTC (k=3, SMD=0.66, 95% CI 0.33-0.99, Z=3.88, p<0.001, I2=86%) this suggests that trauma exposure, irrespective of further PTSD development, might increase basal DHEA and DHEA-S levels. PMID- 28668712 TI - A meta-analysis of adjuvant group-interventions in psychiatric care for patients with bipolar disorders. AB - BACKGROUND: Bipolar disorders are ranked amongst the top ten causes of global disability and cause high health care costs. Previous studies have showed that mood stabilizing drug therapy combined with psychological treatments lead to significantly fewer relapses and a reduction in hospitalization rates. However, there is a wide spectrum of psychosocial intervention methods for individuals and groups which have been insufficiently examined on a scientific basis. METHODS: Studies published between 2003 and 2015 on different types of adjuvant psychosocial group interventions in the MESH database were reviewed and evaluated for their efficacy on patients with bipolar disorder related to the relapse ratio by a meta-analysis. RESULTS: The meta-analysis included 24 intervention groups and showed that 75% of treated groups under medication and psychosocial therapy had a lower risk of a relapse than the control groups which only received medication therapy. LIMITATIONS: The meta-analysis includes a number of trials with participants in different phases of disease course and study designs, the number of studies in each analyzed intervention group was not balanced and many studies focused on recovery and recurrence of episodes, precluding identification of the impact on subsyndromal symptoms CONCLUSIONS: Adjuvant psychosocial interventions seem to be indispensable for patients, their relations as well as for saving costs in the health care system. Nevertheless, an evaluation of effectiveness and impact factors of different psychosocial intervention methods needs further research. PMID- 28668713 TI - The association between the hypothalamic pituitary adrenal axis and tryptophan metabolism in persons with recurrent major depressive disorder and healthy controls. AB - OBJECTIVES: Persistent changes in serotonergic and hypothalamic pituitary adrenal (HPA) axis functioning are implicated in recurrent types of major depressive disorder (MDD). Systemic tryptophan levels, which influence the rate of serotonin synthesis, are regulated by glucocorticoids produced along the HPA axis. We investigated tryptophan metabolism and its association with HPA axis functioning in single episode MDD, recurrent MDD and non-depressed individuals. METHODS: We included depressed individuals (n = 1320) and controls (n = 406) from the Netherlands Study of Depression and Anxiety (NESDA). The kynurenine to tryptophan ratio (kyn/trp ratio) was established using serum kynurenine and tryptophan levels. Several HPA axis parameters were calculated using salivary cortisol samples. We adjusted the regression analyses for a wide range of potential confounders and differentiated between single episode MDD, recurrent MDD and control. RESULTS: Tryptophan, kynurenine and the kyn/trp ratio did not differ between controls and depressed individuals. Increased evening cortisol levels were associated with a decreased kyn/trp ratio in the total sample (Crude: beta = -.102, p < .001; Adjusted: beta = -.083, p < .001). This association was found to be restricted to recurrently depressed individuals (Crude: beta = -.196, p < .001; Adjusted: beta = -.145, p = .001). Antidepressant treatment did not affect this association. CONCLUSIONS: Our results suggest that an imbalance between HPA axis function and tryptophan metabolism could be involved in recurrent depression. PMID- 28668714 TI - Corrigendum to "Music therapy as an adjunct to standard treatment for obsessive compulsive disorder and co-morbid anxiety and depression: A randomized clinical trial" [J. Affect. Disord. 184 (2015) 13-17]. PMID- 28668715 TI - Depression burden in luxembourg: Individual risk factors, geographic variations and the role of migration, 2013-2015 European Health Examination Survey. AB - BACKGROUND: Depression is a complex mental disorder that affects an increasing proportion of the worldwide population. This study aims to estimate the prevalence of depressive symptoms in Luxembourg, associated risk factors and geographic variations. Additionally, it aims to assess whether first and second generation immigrants are at higher risk for depressive symptoms compared to non immigrants. METHODS: Representative cross-sectional data from 1499 residents of Luxembourg, aged 25-64 years, were collected from the Luxembourg European Health Survey (EHES-LUX). Depressive symptoms were defined as a score of >=5 on the Patient Health Questionnaire for depression (PHQ-9) (i.e. mild, moderate or severe). Standard and Bayesian regression models were used to examine associations between depressive symptoms, immigration status and geographic distribution across Luxembourg. RESULTS: The prevalence of depressive symptoms was 21.55% (15.54% mild, 3.54% moderate, and 2.49% moderately severe to severe). The odds of having depressive symptoms was higher among second generation immigrants compared to non-immigrants (OR: 1.58, 95% CI: 1.04, 2.41), independent of socioeconomic and behavioral characteristics. Healthier diet, higher social support and good health perception were protective towards experiencing depressive symptoms. One of the highest likelihoods of reporting depressive symptoms was observed in the South-West of the country with a positive effect at 80% credible region [CR] (1.42 [0.92, 2.73]). LIMITATIONS: The participation rate was low (26.7%). The cross-sectional nature of the study does not allow us to establish causality. CONCLUSIONS: Depression constitutes an important public health challenge in Luxembourg due to the impact on the overall health of the population. Social programs of health promotion should be developed to improve mental wellbeing in immigrants, especially those of second generation. PMID- 28668716 TI - Replication of rs300774, a genetic biomarker near ACP1, associated with suicide attempts in patients with schizophrenia: Relation to brain cholesterol biosynthesis. AB - The aim of this study was to determine if three biomarkers for suicide attempts previously identified and replicated in a genome-wide association (GWAS) study of bipolar disorder (BD) suicide attempters also predicted suicide attempts in patients prospectively diagnosed with schizophrenia (SCZ) or schizoaffective disorder (SAD). 162 genetically-verified Caucasian patients with SCZ or SAD were phenotyped for presence (45.7%) or absence of a lifetime suicide attempt. Three single nucleotide polymorphisms (SNPs) were genotyped or partially imputed from a GWAS dataset. After controlling for genetic architecture and gender, we replicated rs300774 (p = 0.012), near ACP1 (acid phosphatase 1), the top predictor of suicide attempts in the BD study. The result of Willour et al. (2012) was replicated in males (p = 0.046) but not in females (p = 0.205). The other two SNPs, rs7296262, and rs10437629, were not associated with suicide attempts in this study. rs300774 could be a cis-eQTL for ACP1, with minor allele carriers having lower expression levels (p = 0.002). This SNP also functioned as a trans-eQTL for genes related to cholesterol biosynthesis and the wnt-beta catenin pathway (p <= 0.0001). Further, co-expression analysis of candidate genes in brain suggested ACP1 is important to the regulation of a number of brain mechanisms linked to suicide, including cholesterol synthesis, beta-catenin mediated signaling pathway, serotonin, GABA, and the stress response via ARHGAP35 (p190rhogap), a repressor of glucocorticoid receptor (NR3C1) transcription. This study provides an additional validation of rs300774 as a potential transdiagnostic biomarker for suicide attempts and evidence that ACP1 may have an important role in regulation of the multiple systems associated with suicide. PMID- 28668718 TI - All-cause and cardiovascular mortality in a consecutive series of patients with diabetic foot osteomyelitis. AB - BACKGROUND: Mortality in patients with type 2 diabetes and diabetic foot osteomyelitis (DFO) have been explored in few small studies with a short follow up. Aim of the present study is to assess all-cause and cardiovascular mortality and predictors of mortality in a consecutive series of patients with DFO. RESEARCH DESIGN AND METHODS: Patients with a diagnosis of DFO, attending the Diabetic Foot Unit of San Donato Hospital in Arezzo between January 1st, 2012 and December 31st, 2013, were included in this retrospective study. Information on all-cause mortality up to December 1st, 2016, was obtained from the registry of the Local Health Unit of Arezzo, which contains updated records of all persons living in Tuscany. RESULTS: One hundred ninety-four patients were included in the study. During a mean period of observation of 2.8+/-1.4years, 73 (37.6%) died, with a yearly rate of 13.2%. Of the 73 deaths, 59 were attributable to cardiovascular causes. After adjusting for possible confounders in a Cox analysis, site of osteomyelitis (hindfoot vs mid/forefoot) was associated with a higher mortality, and surgical treatment with a lower mortality. CONCLUSIONS: Mortality in patients with DFO appears to be much higher than that reported in clinical series of patients with diabetic foot ulcers, particularly when hindfoot is affected. PMID- 28668719 TI - Evaluation of the timing and coordination of prandial insulin administration in the hospital. AB - AIMS: The objective of this study was to examine the relationship between measures of coordinated insulin delivery and capillary blood glucose (CBG) levels among hospitalized patients and to assess nurse perceptions of insulin administration. METHODS: Hospitalized patients (n=451) receiving rapid acting insulin analog (RAIA) using carbohydrate counting were retrospectively analyzed. Nurses (n=35) were asked to complete an 18-item anonymous survey assessing perception of RAIA dosing. RESULTS: The median time from breakfast CBG to RAIA dose was 93 (IQR 57-138) min. There was no association between timeliness measures and mean CBG at lunch or dinner. Hypoglycemia was rare (N=2). More than half (54%) of nurses were confident all of the time in determining the correct dose of RAIA, though none were confident in administering it on time. The majority of nurses perceived an electronic dosing calculator and a patient reminder to notify the nurse at the end of the meal favorably. CONCLUSIONS: The data demonstrate suboptimal coordination of CBG monitoring and insulin doses using a flexible meal insulin dosing strategy, though there was minimal impact on glycemic control. Nurses reported high confidence in the ability to calculate the correct insulin dose but not in the ability to administer it on time. PMID- 28668717 TI - Predictors of rapid high weight gain in schizophrenia: Longitudinal analysis of the French FACE-SZ cohort. AB - Metabolic syndrome (MetS) is highly prevalent in schizophrenia. However very little is known about the time course of MetS and its components. The few longitudinal studies that have been carried out had small sample sizes and a short follow-up. The aim of our study was to evaluate the prevalence of MetS and its components, at baseline and one year later, and to investigate predictors of weight gain (WG) in a cohort of individuals with schizophrenia. We followed 167 schizophrenia patients from the FACE-SZ cohort for one year. The Structured Clinical Interview for DSM-IV (SCID) was used to confirm the diagnosis of schizophrenia. Data on socio-demographic and clinical characteristics, antipsychotic treatment, and comorbidities were collected, and a blood sample was drawn. We found that the prevalence of MetS increased from 21.0% to 26.6% after one year. Patients with baseline depressive symptoms had a 4.5-fold higher risk of WG at the one-year follow-up (p = 0.02) than those without depressive symptoms, after adjusting for confounding variables. WG also correlated with high levels of metabolic parameters and peripheral inflammation. These findings highlight the need to systematically diagnose depression in Schizophrenia. Future studies should determine whether specific pharmacological and non-pharmacological interventions for depression in SZ subjects are effective in preventing rapid high weight gain. PMID- 28668721 TI - PDE2 at the crossway between cAMP and cGMP signalling in the heart. AB - The cyclic nucleotides cAMP and cGMP are central second messengers in cardiac cells and critical regulators of cardiac physiology as well as pathophysiology. Consequently, subcellular compartmentalization allows for spatiotemporal control of cAMP/cGMP metabolism and subsequent regulation of their respective effector kinases PKA or PKG is most important for cardiac function in health and disease. While acute cAMP-mediated signalling is a mandatory prerequisite for the physiological fight-or-flight response, sustained activation of this pathway may lead to the progression of heart failure. In contrast, acute as well as sustained cGMP-mediated signalling can foster beneficial features, e.g. anti-hypertrophic and vasodilatory effects. These two signalling pathways seem to be intuitively counteracting and there is increasing evidence for a functionally relevant crosstalk between cAMP and cGMP signalling pathways on the level of cyclic nucleotide hydrolysing phosphodiesterases (PDEs). Among this diverse group of enzymes, PDE2 may fulfill a unique integrator role. Equipped with dual substrate specificity for cAMP as well as for cGMP, it is the only cAMP hydrolysing PDE, which is allosterically activated by cGMP. Recent studies have revealed strongly remodelled cAMP/cGMP microdomains and subcellular concentration profiles in different cardiac pathologies, leading to a putatively enhanced involvement of PDE2 in cAMP/cGMP breakdown and crosstalk compared to the other cardiac PDEs. This review sums up the current knowledge about molecular properties and regulation of PDE2 and explains the complex signalling network encompassing PDE2 in order to better understand the functional role of PDE2 in distinct cell types in cardiac health and disease. Moreover, this review gives an outlook in which way PDE2 may serve as a therapeutic target to treat cardiac disease. PMID- 28668720 TI - Inhibition of CRISPR-Cas systems by mobile genetic elements. AB - Clustered, regularly interspaced, short, palindromic repeats (CRISPR) loci, together with their CRISPR-associated (Cas) proteins, provide bacteria and archaea with adaptive immunity against invasion by bacteriophages, plasmids, and other mobile genetic elements. These host defenses impart selective pressure on phages and mobile elements to evolve countermeasures against CRISPR immunity. As a consequence of this pressure, phages and mobile elements have evolved 'anti CRISPR' proteins that function as direct inhibitors of diverse CRISPR-Cas effector complexes. Some of these CRISPR-Cas complexes can be deployed as genome engineering platforms, and anti-CRISPRs could therefore be useful in exerting spatial, temporal, or conditional control over genome editing and related applications. Here we describe the discovery of anti-CRISPRs, the range of CRISPR Cas systems that they inhibit, their mechanisms of action, and their potential utility in biotechnology. PMID- 28668722 TI - The tyrosine Y2502.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled. AB - Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y2502.39) in the intracellular loop 1 (IL1) of human FZD4. We have found Y2502.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y2502.39F, impaired in DVL2 binding, was defective in both beta-catenin-dependent and beta-catenin independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Galpha12 and Galpha13 and was able to mediate WNT-induced G protein dissociation and G protein dependent YAP/TAZ signaling. We conclude from modeling and dynamics simulation efforts that Y2502.39 is important for the structural integrity of the FZD-DVL, but not for the FZD-G protein interface and hypothesize that the interaction network of Y2502.39 and H3484.46 plays a role in specifying downstream signaling pathways induced by the receptor. PMID- 28668723 TI - The impact of antiangiogenic therapy combined with Transarterial Chemoembolization on enhancement based quantitative tumor response assessment in patients with hepatocellular carcinoma. AB - PURPOSE: To investigate whether bevacizumab compromises early response assessment after Transarterial Chemoembolization (TACE) in patients with hepatocellular carcinoma by 3D quantitative European Association for the Study of the Liver (qEASL) criteria in comparison to other imaging-based criteria. MATERIALS AND METHODS: Each of 14 patients receiving TACE and bevacizumab was matched with two patients receiving TACE alone. Baseline and Follow-up MRI was retrospectively analyzed regarding qEASL and other imaging-based criteria. RESULTS: Percentage based qEASL achieved significant separation in both therapy arms (p=0.046 and p=0.015). Response and Overall Survival showed similar association among treatment groups (p=0.749). CONCLUSIONS: Anti-angiogenic therapy with bevacizumab does not impede early response assessment by qEASL. PMID- 28668724 TI - Integrating Education and Service in Pediatric Residency Training: Results of a National Survey. AB - OBJECTIVE: The definition and proper role of service, as it relates to education, in the residency training experience has been long debated. In this study we aimed to develop definitions for service and education, delineate how each is perceived to contribute value to training, and to measure respondents' ratings of service and education using case vignettes. METHODS: We conducted a multisite cohort survey study of pediatric residents (n = 797) and program directors (PDs; n = 37) using a region-stratified sample of 2 to 3 participating pediatric residency programs per region. RESULTS: Surveys were completed by 34 PDs (92%) and 359 trainees (45%). PDs and residents agree that service can, in the absence of formal teaching, be considered educational. When asked how often rotations provide an appropriate balance between education and service, 94% of PDs responded 'extremely/very often' whereas only 68% of residents agreed (P = .005). Residents were significantly more likely than PDs to endorse definitions for service that included volunteer work (82% vs 59%; P = .002), going above and beyond for a patient (91% vs 78%; P = .017), and routine patient care activities (91% vs 72%; P < .001). For 6 of 12 case vignettes, trainees gave median service ratings that were significantly higher than PDs (P = .03). CONCLUSIONS: Medical educators and pediatric residents hold mismatched impressions of their training programs' balance of service obligations with clinical education. Specifically, residents more frequently report an overabundance of service. Both groups acknowledge that service activities can be educationally valuable although the groups' definitions of service are not fully aligned. PMID- 28668725 TI - Patterns of cellular phone use among young people in 12 countries: Implications for RF exposure. AB - Characterizing exposure to radiofrequency (RF) fields from wireless telecommunications technologies during childhood and adolescence is a research priority in investigating the health effects of RF. The Mobi-Expo study aimed to describe characteristics and determinants of cellular phone use in 534 young people (10-24years) in 12 countries. The study used a specifically designed software application installed on smartphones to collect data on the use of wireless telecommunications devices within this age group. The role of gender, age, maternal education, calendar period, and country was evaluated through multivariate models mutually adjusting for all variables. Call number and duration were higher among females compared to males (geometric mean (GM) ratio 1.17 and 1.42, respectively), among 20-24year olds compared to 10-14year olds (GM ratio 2.09 and 4.40, respectively), and among lowest compared to highest social classes (GM ratio 1.52 and 1.58, respectively). The number of SMS was higher in females (GM ratio 1.46) and the middle age group (15-19year olds: GM ratio 2.21 compared to 10-14year olds) and decreased over time. Data use was highest in the oldest age group, whereas Wi-Fi use was highest in the middle age group. Both data and Wi-Fi use increased over time. Large differences in the number and duration of calls, SMS, and data/Wi-Fi use were seen by country, with country and age accounting for up to 50% of the variance. Hands-free and laterality of use did not show significant differences by sex, age, education, study period, or country. Although limited by a convenience sample, these results provide valuable insights to the design, analysis, and interpretation of future epidemiological studies concerning the health effects of exposure resulting from cellular phone use in young people. In addition, the information provided by this research may be used to design strategies to minimize RF exposure. PMID- 28668726 TI - Prudence, pleasure, and cognitive ageing: Configurations of the uses and users of brain training games within UK media, 2005-2015. AB - The use of 'brain training' games is often regarded as relating to wider ideals of self-improvement and youthfulness. Hence, use is intertwined with discourses of 'active' ageing. This paper analyzes how the use and users of brain training games were configured in the UK media, from 2005 to 2015, and examines how notions of active ageing relate to these representations. Game users were rarely constructed solely as gamers, and were more often presented as prudent individuals focused on a serious goal. This configuration related to assumed and enjoined motivations for brain training; specifically, users were commonly framed as seeking to enhance cognition and limit/delay cognitive decline. Scientific evidence about brain training was often deployed to explain how games might work; sometimes, however, it was used to undermine the utility of games and assert the significance and cognitive health-benefits of other activities. A minority of texts explicitly critiqued ideals of self-improvement, arguing that game playing was important for its own sake. Yet, even the pleasure associated with gaming was occasionally instrumentalized as a mechanism for ensuring prudent life choices. The analysis casts fresh light on how debates around health, ageing, and science correspond to configurations of technology uses and users. It presents evidence of the widespread cultural circulation of enjoiners regarding self-care and healthy ageing within British society. However, the paper also provides indications of the limits to such imperatives: discourses of pleasure co-exist with and perhaps supplant logics of prudence in (accounts of) practices ostensibly aimed at ageing 'well'. PMID- 28668728 TI - Influence of Torulaspora delbrueckii in varietal thiol (3-SH and 4-MSP) release in wine sequential fermentations. AB - In last years, non-Saccharomyces yeasts have emerged as innovative tools to improve wine quality, being able to modify the concentration of sensory-impact compounds. Among them, varietal thiols released by yeasts, play a key role in the distinctive aroma of certain white wines. In this context, Torulaspora delbrueckii is in the spotlight because of its positive contribution to several wine quality parameters. This work studies the physiological properties of an industrial T. delbrueckii strain, for the production of wines with increased thiol concentrations. IRC7 gene, previously described in S. cerevisiae, has been identified in T. delbrueckii, establishing the genetics basis of its thiol releasing capability. Fermentations involving T. delbrueckii showed improvements on several parameters (such as glycerol content, ethanol index, and major volatile compounds composition), but especially on thiols release. These results confirm the potential of T. delbrueckii on wine improvement, describing new metabolic features regarding the release of cysteinylated aroma precursors. PMID- 28668727 TI - Inactivation of viruses and bacteria on strawberries using a levulinic acid plus sodium dodecyl sulfate based sanitizer, taking sensorial and chemical food safety aspects into account. AB - The efficacy of levulinic acid (LVA) in combination with sodium dodecyl sulfate (SDS) in removal of foodborne viruses, enteric bacterial pathogens and their surrogates on fresh strawberries was investigated. Inoculated strawberries were treated with potable water, sodium hypochlorite solution (50ppm), 0.5% LVA plus 0.5% SDS solution, and 5% LVA plus 2% SDS solution respectively for 2min, followed by spray-rinsing with potable water. Water washing removed at least 1.0 log of the tested viral and bacterial strains from the strawberries' surfaces. The 50ppm chlorine wash induced 3.4, 1.5 and 2.1-log reductions for hepatitis A virus (HAV), murine norovirus-1 (MNV-1) and MS2 bacteriophage, respectively. In comparison, the tested bacterial strains showed uniform reductions around 1.6-log CFU/ml. The 0.5% LVA plus 0.5% SDS wash induced 2.7, 1.4 and 2.4-log reductions for HAV, MNV-1 and MS2, which were comparable with the reductions induced by chlorine (P>0.05). For bacteria, over 2.0-log reductions were obtained for Enterococcus faecium, Listeria monocytogenes and Salmonella, while Escherichia coli O157:H7 and Escherichia coli P1 showed reductions of 1.9 and 1.8-log CFU/ml. Higher concentration of LVA plus SDS showed no significantly higher reductions (P>0.05). Sensory tests of washed strawberries and chemical residue analysis of LVA on strawberries after washing were also performed. In conclusion, this study demonstrates good performance of 0.5% LVA plus 0.5% SDS to reduce the levels of enteric pathogens if present on strawberries without altering taste and introducing chemical safety issues. PMID- 28668729 TI - Characterization of antibiotic resistant and pathogenic Escherichia coli in irrigation water and vegetables in household farms. AB - This study aimed to characterize Escherichia coli present in irrigation water and vegetables from 16 household farms. Isolates were obtained from 50% of water (n=210 isolates) and 38% of vegetable samples (n=239). Phylogroups B1 (56% of isolates) and A (22%) were the most prevalent both in water and vegetables. Diarrheagenic strains were detected in vegetables. Irrespective of the source (i.e. water or vegetables), the most common antibiotic resistance was against streptomycin (89% resistant isolates) and tetracycline (24%). Common acquired genes (e.g. blaTEM, tetA, tetB) were found in isolates from both sources. Class I integrons were detected in water (arrays dfrA1-aadA1 and dfr16-blaP1b-aadA2-ereA) and vegetables (unknown arrays). intI2 was detected in water (dfrA1-sat2-aadA1). Plasmids were detected in 14 isolates (IncFIC, IncFIB, IncFrep, IncI1 in both samples; IncY in vegetables). Plasmids from seven isolates were transferrable by conjugation, conferring resistance to antibiotics to the recipient strain. Multidrug-resistant (MDR) strains were isolated from water (12% of the unique isolates) and vegetables (21%). Predominant sequence types (STs) among MDR isolates were ST10, ST297 and ST2522. In some cases, the same STs and identical clones (as showed by rep-PCR typing) were detected in water and vegetables, suggesting cross-contamination. This study identified several risk factors in E. coli isolates from vegetables and irrigation water, raising health concerns. Also, results suggest that irrigation groundwater constitutes a source of E. coli that may enter the food chain through vegetables ingestion. PMID- 28668730 TI - A general method for determining molecular interfaces and layers. AB - A general and direct computational scheme to locate the surface separating arbitrarily shaped domains made up of molecules (or any other particles) has been developed and is described and illustrated for several, both artificial and physical examples. The proposed scheme consists of two modules: (i) triangulation and (ii) assignment of simplices to domains. Three different triangulation methods are employed, viz., the Delaunay triangulation, regular triangulation, and quasi-triangulation. In the triangulated system, the assignment step is carried out in two different ways, one based on the characteristic metric of a particular triangulation procedure and the other on the concept of a touching sphere. Some of the combinations of the triangulation and assignment steps lead to methods already used by others to find interfacial or surface molecules, namely the alpha-shape-based method of Usabiaga nad Duque [Phys. Rev. E 79 (2009) 046709] and GITIM of Sega et al. [J. Chem. Phys. 138 (2013) 044110]. The resulting surface is defined not only as a discrete set of particles, but it is build up of facets of the triangulation forming a broken line in two dimensions or a polyhedral surface in three dimensions. Individual molecular layers are identified in a very straightforward manner, starting with the interfacial layer itself and proceeding into the interior of the phase. The proposed scheme is illustrated first by identifying border molecules of pre-sampled domains of several shapes in a plane and then applied to five physically meaningful examples: thin films, near critical water, liquid water slab in an electric field, liquid water at a solid wall, and water at condition of electric-field induced jetting. Performance of the considered methods is critically assessed. Treatment of domains forming percolating clusters through periodic boundary conditions is also described along with the determination of their periodicity and dimensionality. PMID- 28668731 TI - Determination of thorium (IV) using isophthalaldehyde-tetrapyrrole as probe by resonance light scattering, second-order scattering and frequency-doubling scattering spectra. AB - The coordination reaction of thorium (IV) with a ditopic bidentate ligand to form supramolecular polymer was studied by resonance light scattering (RLS) spectra, second-order scattering (SOS) spectra and frequency-doubling scattering (FDS) spectra, respectively. The ditopic bidentate ligand is isophthalaldehyde tetrapyrrole (IPTP). It was synthesized through a condensation reaction of isophthalaldehyde with pyrrole. The formation of supramolecular polymer results in remarkable intensity enhancements of the three light scattering signals. The maximum scattering wavelengths of RLS, FDS and SOS were 290, 568 and 340nm, respectively. The reaction was used to establish new light scattering methods for the determination of thorium (IV) by using IPTP as probe. Under optimum conditions, the intensity enhancements of RLS, SOS and FDS were directly proportional to the concentration of thorium (IV) in the ranges of 0.01 to 1.2MUgmL-1, 0.05 to 1.2MUgmL-1 and 0.05 to 1.2MUgmL-1, respectively. The detection limits were 0.003MUgmL-1, 0.012MUgmL-1 and 0.021MUgmL-1, respectively. The methods were suitable for analyzing thorium (IV) in actual samples. The results show acceptable recoveries and precision compared with a reference method. PMID- 28668732 TI - Evolution of Bovine viral diarrhea virus in Canada from 1997 to 2013. AB - Bovine viral diarrhea virus (BVDV) is a rapidly evolving, single-stranded RNA virus and a production limiting pathogen of cattle worldwide. 79 viral isolates collected between 1997 and 2013 in Canada were subjected to next-generation sequencing. Bayesian phylogenetics was used to assess the evolution of this virus. A mean substitution rate of 1.4*10-3 substitutions/site/year was found across both BVDV1 and BVDV2. Evolutionary rates in the E2 gene were slightly faster than other regions. We also identified population structures below the sub genotype level that likely have phenotypic implications. Two distinct clusters within BVDV2a are present and can be differentiated, in part, by a tyrosine to isoleucine mutation at position 963 in the E2 protein, a position implicated in the antigenicity of BVDV1 isolates. Distinct clustering within all sub-genotypes, particularly BVDV2a, is apparent and could lead to new levels of genotypic classification. Continuous monitoring of emerging variants is therefore necessary. PMID- 28668733 TI - Challenging abdominal incisional hernia repaired with platelet-rich plasma and bone marrow-derived mesenchymal stromal cells. A case report. AB - INTRODUCTION: The necessity to develop new treatment options for challenging procedures in hernia surgery is becoming even more evident and tissue engineering and biological technologies offer even newer strategies to improve fascial healing. The present case reports a patient-tailored surgical technique performed to repair a grade IV abdominal incisional hernia, with a combined use of platelet rich plasma and bone marrow-derived mesenchymal stromal cells, implanted on a biological mesh. PRESENTATION OF THE CASE: A 71 year-old female patient complained of an abdominal incisional hernia, complicated by enterocutaneous fistula, four-months following laparostomy. Contrast enhanced computed tomography showed an incisional hernia defect of 15.5*20cm, with a subcutaneous abscess and an intestinal loop adherent to the anterior abdominal wall, with a concomitant enterocutaneous fistula. Surgery involved abdominal wall standardized technique closure, with in addition platelet-rich plasma and bone marrow-derived mesenchymal stromal cells implanted on a biological mesh. Two years follow up showed no recurrences of incisional hernia. DISCUSSION: Coating surgical meshes with patient's own cells may improve biocompatibility, by reducing inflammation and adhesion formation. Moreover, platelet-rich plasma is a good source of growth factors for wound healing, as well as a good medium for bone marrow multinucleate cells introduction into fascial repair. CONCLUSION: This approach is likely to improve abdominal wall repair in high grade (IV) incisional hernia, with the real possibility of improving prosthetic compatibility and reducing future recurrences. The authors agree with the necessity of further studies and trials to assure the safety profile and superiority of this procedure. PMID- 28668734 TI - Can digital dermatitis be detected in the milking parlor without washing cows' feet? AB - Scoring digital dermatitis (DD) in the milking parlor after washing the hind feet of cows has been recommended. However, farmers might be reluctant to perform this washing due to compromised udder hygiene. The objective of this study was to evaluate if DD prevalence can be determined without the washing procedure. A total of 4510 cows from 22 dairy herds were scored for DD in the milking parlor without and with washing their hind feet. In all DD infected herds, DD prevalence was higher when scored with washing. The two methods were highly correlated (r=0.987, P<0.001). Scoring with washing resulted in a median of 32% more detected DD cases with a large variation between herds. Overall, DD measurements without washing the feet of cows should be interpreted with caution. PMID- 28668735 TI - Characteristics of patients with fibromyalgia. AB - BACKGROUND: Fibromyalgia is characterised by generalized pain. A search of the available literature found no previous reports describing the specific characteristics of patients with fibromyalgia. OBJECTIVES: To describe characteristics of patients with fibromyalgia. MATERIAL AND METHODS: Case-control study including 50 patients with fibromyalgia and 50 gender and age-matched controls. After obtaining written informed consent for the study, demographic data were collected and pain in the leg, ankle and foot area was measured using a visual analogue scale (VAS). A general physical examination to test mobility and rigidity of the foot joints was also performed. Patients were also asked about their shoe utilisation habits. RESULTS: The results confirm that patients with fibromyalgia experience significantly more pain in the whole leg, ankle and foot areas than the control subjects. For this reason they use significantly more pain killing drugs than the control subjects. However, this increase in pain is not associated with stiffness or mobility abnormalities in this series. In addition, patients with fibromyalgia show no increase in the rate of hyperkeratosis or other foot lesions. CONCLUSIONS: Patients with fibromyalgia do not seem to show a higher rate of foot lesions or a peculiar pattern of foot involvement compared to age and gender-matched controls. PMID- 28668736 TI - Toward an accurate quantification in atom probe tomography reconstruction by correlative electron tomography approach on nanoporous materials. AB - In this contribution, we propose a protocol for analysis and accurate reconstruction of nanoporous materials by atom probe tomography (APT). The existence of several holes in porous materials makes both the direct APT analysis and reconstruction almost inaccessible. In the past, a solution has been proposed by filling pores with electron beam-induced deposition. Here, we present an alternative solution using an electro-chemical method allowing to fill even small and dense pores, making APT analysis possible. Concerning the 3D reconstruction, the microstructural features observed by electron tomography are used to finely calibrate the APT reconstruction parameters. PMID- 28668737 TI - Lower limb kinematics during the swing phase in patients with knee osteoarthritis measured using an inertial sensor. AB - BACKGROUND: During gait, the swing limb requires flexible control to adapt to ever changing environmental circumstances. However, few studies have focused on the mechanics of swing limb control in patients with knee osteoarthritis (OA). Investigating the variability of swing limb kinematics, which can be represented by variables such as the peak shank angular velocity during the swing phase obtained from an inertial sensor, provides insights into the adaptability of swing limb control. The purpose of this study was to investigate how patients with knee OA control the swing limb and whether the degree of impairment and disability due to knee OA affects swing limb control. METHODS: Twelve subjects diagnosed with knee OA and 11 healthy control subjects participated in this study. Subjects walked on a treadmill for 10min. The mean, coefficient of variation, and fractal scaling exponent alpha of the peak shank angular velocity during the swing phase were calculated. FINDINGS: There were no significant differences between the groups for any of the kinematic parameters. The Knee Injury and Osteoarthritis Outcome Score (KOOS) activities of daily living (ADL) subsection correlated with the coefficient of variation (r=-0.677, p=0.016) and the scaling exponent alpha (r=0.604, p=0.037) of the peak shank angular velocity. INTERPRETATION: Control of the swing limb was associated with the degree of impairment and disability. Larger and more random variability of peak shank angular velocity may indicate decreased ADL ability in patients with knee OA. PMID- 28668738 TI - Correlation of the torsion values measured by rotational profile, kinematics, and CT study in CP patients. AB - BACKGROUND: The purpose of study was to analyze correlations between bony torsions measured by Staheli's rotation profile, computed tomography (CT) torsional study, and gait analysis in patients with cerebral palsy (CP). MATERIALS & METHOD: The study group comprised of 26 children with CP (spastic diplegia, Gross Motor Function Classification System (GMFCS) 1-2, mean age 12.6 years) with torsional deformities. All subjects were assessed by examining: 1) rotational profile [internal rotation (IR) and external rotation (ER)], 2) CT torsional profile [femoral anteversion (FAV) and tibial torsion (TT)], and 3) gait analysis [mean hip rotation (HR) and mean knee rotation (KR)]. Statistical analysis was performed using the Pearson correlation test. RESULTS: In the femur, there was good correlation between FAV and Staheli's rotational profile of IR and ER (Pearson correlation coefficient (PC=0.69, 0.52, p<0.05)). ER correlated very strongly with mean HR during gait (PC=0.8, p<0.05). There was, however, poor correlation between HR and IR (p>0.05), and between HR and FAV (p>0.05). In the tibia, mean KR correlated well with thigh-foot angle (TFA) (PC=0.72) and CT tibia torsion (TT) (PC=0.62). TT also correlated with TFA (PC=0.62). CONCLUSION: Gait analysis and Staheli's rotational profile reflect both static and dynamic factors of gait abnormalities. However, CT study reflect static factor primarily. Dynamic factors tend to influence the measurements of the femoral torsion only due to large rotational arc of hip joint. In surgical planning, it must be considered that HR sometimes does not correlate with CT anteversion angle. Similarly, it must also be considered that KR correlates well with TFA and CT TT angle. PMID- 28668739 TI - Spatial prediction of water quality variables along a main river channel, in presence of pollution hotspots. AB - In order to treat and evaluate the available data of water quality and fully exploit monitoring results (e.g. characterize regional patterns, optimize monitoring networks, infer conditions at unmonitored locations, etc.), it is crucial to develop improved and efficient methodologies. Accordingly, estimation of water quality along fluvial ecosystems is a frequent task in environment studies. In this work, a particular case of this problem is examined, namely, the estimation of water quality along a main stem of a large basin (where most anthropic activity takes place), from observational data measured along this river channel. We adapted topological kriging to this case, where each watershed contains all the watersheds of the upstream observed data ("nested support effect"). Data analysis was additionally extended by taking into account the upstream distance to the closest contamination hotspot as an external drift. We propose choosing the best estimation method by cross-validation. The methodological approach in spatial variability modeling may be used for optimizing the water quality monitoring of a given watercourse. The methodology presented is applied to 28 water quality variables measured along the Santiago River in Western Mexico. PMID- 28668740 TI - Bacterial diversity and population shifts driven by spotlight wastewater micropollutants in low-temperature highly nitrifying activated sludge. AB - In this study the influence of low-temperature (8 degrees C), sludge retention time (SRT) and loading of spotlight wastewater micropollutants (MPs) on bacterial community of activated sludge was investigated with a special focus on nitrification. Two Sequencing batch reactors (SBR) and two membrane bioreactors (MBR) were operated with synthetic municipal-like wastewater receiving and not receiving ibuprofen, diclofenac, estrone and 17alpha-ethynylestradiol (EE2). Bacterial population studies were related to removal efficiencies of studied MPs. The results showed that studied bacterial communities significantly differed from all previously published nitrifying activated sludge communities. Exceptionally low concentration of autotrophic nitrifying bacteria were found (<0.5%) as well as no common heterotrophic nitrifies were presenting in activated sludge and therefore could not be related to the MPs removal. Additionally SRT had a spacious effect on the diversity of bacteria and bacterial population shifts under pressure of MPs. Growth of Firmicutes was suppressed by presence of MPs in all the reactors. Increase of MPs concentrations in wastewater improved the removal of EE2. Abundance of Delta- and Gammaproteobacteria showed positive correlation with diclofenac removal. PMID- 28668741 TI - Cost-benefit analysis of copper recovery in remediation projects: A case study from Sweden. AB - Contamination resulting from past industrial activity is a problem throughout the world and many sites are severely contaminated by metals. Advances in research in recent years have resulted in the development of technologies for recovering metal from metal-rich materials within the framework of remediation projects. Using cost-benefit analysis (CBA), and explicitly taking uncertainties into account, this paper evaluates the potential social profitability of copper recovery as part of four remediation alternatives at a Swedish site. One alternative involves delivery of copper-rich ash to a metal production company for refining. The other three alternatives involve metal leaching from materials and sale of the resulting metal sludge for its further processing at a metal production company using metallurgical methods. All the alternatives are evaluated relative to the conventional excavation and disposal method. Metal recovery from the ash, metal sludge sale, and disposal of the contaminated soil and the ash residue at the local landfill site, was found to be the best remediation alternative. However, given the present conditions, its economic potential is low relative to the conventional excavation and disposal method but higher than direct disposal of the copper-rich ash for refining. Volatile copper prices, the high cost of processing equipment, the highly uncertain cost of the metal leaching and washing process, coupled with the substantial project risks, contribute most to the uncertainties in the CBA results for the alternatives involving metal leaching prior to refining. However, investment in processing equipment within the framework of a long-term investment project, production of safe, reusable soil residue, and higher copper prices on the metal market, can make metal recovery technology socially profitable. PMID- 28668742 TI - Degradation of chlortetracycline using immobilized laccase on Polyacrylonitrile biochar composite nanofibrous membrane. AB - The continuous release of antibiotic compounds through wastewater effluent into environment has raised concerns about their potential problems for different organisms. Enzymatic degradation with laccase is a green option for removal of pharmaceutical compounds from aqueous media. In this study, laccase was immobilized onto homemade Polyacrylonitrile-biochar composite nanofibrous membrane and the obtained biocatalyst was employed for removal of chlortetracycline, a widely used antibiotic, from aqueous media in continuous mode. The results showed that the immobilized laccase has improved storage, temperature and pH stability compared to free laccase. Also, it retained more than 50% of its initial activity after 7cycles of ABTS oxidation which indicated improved enzyme reusability. Finally, while using immobilized laccase for degradation of chlortetracycline in continuous mode exhibited 58.3%, 40.7% and 22.6% chlortetracycline removal efficiency at flux rates of 1, 2 and 3mL/h?cm2. PMID- 28668743 TI - Uptake of the veterinary antibiotics chlortetracycline, enrofloxacin, and sulphathiazole from soil by radish. AB - Veterinary antibiotics are available for uptake by the plants through sources such as manure, irrigation, and atmospheric interaction. The present study was conducted to estimate the half-lives of three veterinary antibiotics, chlortetracycline (CTC), enrofloxacin (ENR), and sulphathiazole (STZ), in soil and experimentally explore their uptake from contaminated soil to radish roots and leaves. Samples were extracted using a modified citrate-buffered version of the quick, easy, cheap, effective, rugged, and safe "QuEChERS" method followed by liquid chromatography coupled with tandem mass spectrometric analysis (LC-MS/MS) in the positive ion mode. Good linearity was observed for the three tested antibiotics in soil and plants (roots and leaves) with high coefficients of determination (R2>=0.9922). The average recovery rates at two spiking levels with three replicates per level ranged between 77.1 and 114.8%, with a relative standard deviation (RSD)<=19.9% for all tested drugs. In a batch incubation experiment (in vitro study), the half-lives of CTC, ENR, and STZ ranged from 2.0 6.1, 2.2-4.5, and 1.1-2.2days, respectively. Under greenhouse conditions, the half-lives of the three target antibiotics in soil with and without radishes were 2.5-6.9 and 2.7-7.4; 4.7-16.7 and 10.3-14.6; and 4.4-4.9 and 2.5-2.8days, respectively. Trace amounts of the target antibiotics (CTC, ENR, and STZ) were taken up from soil via roots and entered the leaves of radishes. The concentration of CTC was lower than 2.73%, ENR was 0.08-3.90%, and <1.64% STZ was uptaken. In conclusion, the concentrations of the tested antibiotics decreased with time and consequently lower residues were observed in the radishes. The rapid degradation of the tested antibiotics in the present study might have only little impact on soil microorganisms, fauna, and plants. PMID- 28668744 TI - Long-term phosphorus addition enhances the biodegradability of dissolved organic carbon in a nitrogen-limited temperate freshwater wetland. AB - Phosphorus (P) enrichment is expected to strongly influence dissolved organic carbon (DOC) biodegradation. However, the relationship between P availability and DOC biodegradation is largely unknown in nitrogen (N)-limited ecosystems. Here, we investigated the changes in the ratio of DOC to dissolved total nitrogen (DTN), specific UV absorbance at 254nm (SUVA254), and DOC biodegradation in surface water and soil pore water (0-15cm depth) following eight years of multi level P addition (0, 1.2, 4.8, and 9.6gPm-2year-1) in an N-limited freshwater marsh in Northeast China. We found that P addition caused an increase in DOC biodegradation in surface water and soil pore water, irrespective of the P addition levels. Compared with the control treatment, the P addition rates of 1.2, 4.8, and 9.6gPm-2year-1 increased DOC biodegradation by 20.7%, 15.2%, and 14.5% in surface waters, and 11.3%, 9.4%, and 12.0% in soil pore waters, respectively. The DOC biodegradation was separately negatively correlated with the DOC:DTN ratio and SUVA254, indicating that the positive effect of P addition on DOC biodegradation was caused by the elevated N concentration and the reduced DOC aromaticity. Our findings suggest that P enrichment enhances the biodegradability of DOC through increased N availability and altered DOC chemical composition, which would accelerate DOC loss from the waters and alter ecosystem C balance in N-limited temperate wetlands. PMID- 28668745 TI - Temporal and spatial distribution of PM2.5 chemical composition in a coastal city of Southeast China. AB - Rapid economic development and urbanization in China has been concentrated in coastal cities, resulting in haze and photochemical smog issues, especially in the densely-populated Yangtze River Delta. In this study, we explore particulate matter (specifically PM2.5) pollution in a city in Zhejiang Province (Ningbo), chosen to represent a typical, densely-populated urban city with residential and industrial sections. PM2.5 samples were collected at five sites in four seasons from Dec. 2012 to Nov. 2013. The annual average PM2.5 mass concentration was 53.2+/-30.4MUg/m3, with the highest concentration in winter and lowest in summer. Among the five sites, PM2.5 concentration was highest in an urban residential site and lowest in a suburban site, due to effects of urbanization and the anthropogenic influences. The chemical components of PM2.5 show significant seasonal variation. In addition, secondary transformation was high in Ningbo, with the highest proportion of secondary components found at a suburban site and the lowest at the industrial sites. Ningbo is controlled by five major air masses originating from inland China, from the Bohai Sea, offshore from the southeast, the Yellow Sea, and off the east coast of Korea. The relative contributions of these air masses differ, by season, with the Bohai Sea air mass dominating in winter and spring, the maritime southeast air mass in summer, and the Yellow Sea and coastal Korean air masses dominating in autumn. The continental air mass is associated with a high PM2.5 concentration, indicating that it is primarily transports primary emissions. In contrast, the concentration ratios among secondary formed pollutants were higher in the maritime air masses, which suggests that sea breezes control temporal and spatial variations of air pollution over coastal cities. PMID- 28668746 TI - The abolition of war as a goal of environmental policy. AB - Since the 1950s, select military and political leaders have had the capacity to kill all or nearly all human life on Earth. The number of people entrusted with this power grows each year through proliferation and the rise of new political leaders. If humans continue to maintain and develop nuclear weapons, it is highly probable that a nuclear exchange will occur again at some point in the future. This nuclear exchange may or may not annihilate the human species, but it will cause catastrophic effects on the biosphere. The international community has attempted to resolve this existential problem via treaties that control and potentially eliminate nuclear weapons, however, these treaties target only nuclear weapons, leaving the use of war as a normalized means for settling conflict. As long as war exists as a probable future, nations will be under pressure to develop more powerful weapons. Thus, we argue that the elimination of nuclear weapons alone is not a stable, long-term strategy. A far more secure strategy would be the elimination of war as a means of settling international disputes. Therefore, those concerned about environmental sustainability or the survival of the biosphere should work to abolish war. PMID- 28668747 TI - Phosphorus adsorption onto clay minerals and iron oxide with consideration of heterogeneous particle morphology. AB - Particle morphology plays an important role in solid-water interface adsorption, which affects the fate and behavior of phosphorus (P) in rivers and lakes and the resulting eutrophication. In this paper, three minerals including kaolinite, montmorillonite and hematite were considered to investigate the contributions of particle morphology to P adsorption using adsorption experiments and microscopic examinations. The Taylor expansion method is applied to quantitatively characterize the heterogeneity of surface morphology. The results reveal that local concave or convex micro-morphology characterized by the second order term of Taylor expansion F2, can affect the local adsorption capacity due to its effect on the distribution of surface charge and reactive sites. Moreover, the adsorbed P at different F2 here fits to a Weibull distribution, which can further define the representative average adsorption onto individual particles. A weighted average morphology factor F2a is derived to characterize the surface heterogeneity, and correlated with average P adsorption of particular mineral particles. In addition, the Sips model can successfully fit the experimental data of different minerals, and the heterogeneity parameters gamma and adsorption capacity Qm in the model are proved to be functions with the basic mineral properties, including particle size, surface site density and morphology characterization as well. It is concluded that the complex surface morphology plays a significant role in particle adsorption and the morphological role need to be considered in the adsorption model in order to better describe the adsorption in system with heterogeneous solid surface. PMID- 28668748 TI - Effect of ciprofloxacin on biological nitrogen and phosphorus removal from wastewater. AB - In this work, both short-term and long-term experiments were therefore conducted to assess the effects of ciprofloxacin (0.2 and 2mg.L-1) on wastewater nutrient removal. The results showed that both levels of ciprofloxacin had no acute and chronic adverse effects on the surface integrity and viability of activated sludge. Short-term exposure to all the ciprofloxacin levels induced negligible influences on wastewater nutrient removal. However, the prolonged exposure to ciprofloxacin decreased total phosphorus and nitrogen removal efficiencies from 96.8, 95.8% (control) to 91.7, 84.9% (0.2mg.L-1) and 90.5%, 80.2% (2mg.L-1), respectively. The mechanism study showed that ciprofloxacin exposure suppressed denitrification and phosphorus uptake processes. It was also found that ciprofloxacin affected the transformations of intracellular polyhydroxyalkanoates and glycogen in the oxic and anoxic stages. Moreover the activities of nitrite reductase and polyphosphate kinase were inhibited by the presence of ciprofloxacin. Further analysis with high-throughput sequencing revealed that compared with the control, the abundances of polyphosphate accumulating organisms, glycogen accumulating organisms and denitrifying bacteria in ciprofloxacin exposure reactors reduced, which were consistent with the decreased nutrient removal performance measured in these reactors. PMID- 28668749 TI - Spruce-fir forest changes during a 30-year nitrogen saturation experiment. AB - A field experiment was established in a high elevation red spruce (Picea rubens Sarg.) - balsam fir (Abies balsamea) forest on Mount Ascutney Vermont, USA in 1988 to test the nitrogen (N) saturation hypothesis, and to better understand the mechanisms causing forest decline at the time. The study established replicate control, low and high dose nitrogen addition plots (i.e., 0, 15.7 and 31.4kgNH4Cl Nha-1yr-1). The treatments began in 1988 and continued annually until 2010, but monitoring has continued to present. During the fertilization period, forest floor C:N, net in situ N mineralization, spruce foliar Ca%, and live spruce basal area decreased with increasing N addition, while foliar spruce N% and forest floor net nitrification increased with increasing N addition. The control plots aggraded forest floor N at a rate equal to the sum of the net in situ N mineralization plus average ambient deposition. Conversely, N addition plots lost forest floor N. Following the termination of N additions in 2010, the measured tree components returned to pre-treatment levels, but forest floor processes were slower to respond. During the 30year study, site surface air temperature has increased by 0.5 degrees C per decade, and total N deposition has decreased 5.5 to 4.0kgNha-1yr-1. There have also been three significant drought years and at least one freeze injury year after which much of the forest mortality on the N addition plots occurred. Given that there was no control for the air temperature increase, discussion of the interactive impacts of climate and change and N addition is only subjective. Predicted changes in climate, N deposition and other stressors suggest that even in the absence of N saturation, regeneration of the spruce-fir ecosystem into the next century seems unlikely despite recent region wide growth increases. PMID- 28668750 TI - Arsenic contamination in irrigation water, agricultural soil and maize crop from an abandoned smelter site in Matehuala, Mexico. AB - Mobility of Arsenic (As) from metallurgical wastes in Matehuala, Mexico has been accounted for ultra-high concentration of As in water (4.8-158mg/L) that is used for recreational purposes as well as cultivation of maize. In this study, we (i) measured As concentrations in soils irrigated with this water, (ii) investigated the geochemical controls of available As, and (iii) measured bioaccumulation of As in maize. Water, soil, and maize plant samples were collected from 3 different plots to determine As in environmental matrices as well as water soluble As in soils. Soil mineralogy was determined by X-ray diffraction analysis. Bioaccumulation of As in maize plants was estimated from the bioconcentration and translocation factors. We recorded As built-up in agricultural soils to the extent of 172mg/kg, and noted that this As is highly soluble in water (30% on average). Maize crops presented high bioaccumulation, up to 2.5 times of bioconcentration and 45% of translocation. Furthermore, we found that water extractable As was higher in soils rich in calcite, while it was lower in soils containing high levels of gypsum, but As bioconcentration showed opposite trend. Results from this study show that irrigation with As rich water represents a significant risk to the population consuming contaminated crops. PMID- 28668751 TI - Coupling biological assays with diffusive gradients in thin-films technique to study the biological responses of Eisenia fetida to cadmium in soil. AB - This work sets out to investigate biological responses of Eisenia fetida to Cd, based on the bioavailable rather than total concentration of Cd, in soils. E. fetida was cultured for 14d in three selected Chinese soils amended with 0.1 40mgkg-1 Cd. Potentially bioavailable concentrations of Cd were measured in soil solution, in extractions using CaCl2 and HAc solutions, and using the technique of diffusive gradients in thin-films (DGT). Antioxidant system responses in E. fetida to Cd were measured as biological endpoints. Biological responses were more highly correlated with Cd concentrations evaluated using bioavailable methods than with total concentrations. Cd concentration measured using DGT and CaCl2 extraction provided the narrowest ranges of lowest observed effect concentration (LOEC) values based on biological responses, indicating the potential use of these measurements in management of soil quality and setting soil remediation standards. The LOEC values obtained from 15 field soils contaminated by Cd were similar to those from the three Cd-amended soils and suggested that DGT in particular can be a good tool to predict stress responses of E. fetida to Cd in soils. The study shows the potential of combining biological response and DGT measurements in risk assessment. PMID- 28668752 TI - Effects of humic acid concentration on the microbially-mediated reductive solubilization of Pu(IV) polymers. AB - The role of humic acid concentration in the microbially-mediated reductive solubilization of Pu(IV) polymers remains unclear until now. The effects of humic concentration (0-150.5mg/L) on the rate and extent of reduction of polymeric Pu(IV) were studied under anaerobic and pH 7.2 conditions. The results show that Shewanella putrefaciens, secreting flavins as endogenous electron shuttles, cannot notably stimulate the reduction of polymeric Pu(IV). In the presence of humic acids, the reduction rate of polymeric Pu(IV) increased with increasing humic concentrations (0-15.0mg/L): e.g., a 102-fold increase from 4.1*10-15 (HA=0) to 4.2*10-13mol Pu(III)aq/h (HA=15.0mg/L). The bioreduced humic acids by S. putrefaciens facilitated the extracellular electron transfer to Pu(IV) polymers and thus the reduction of polymeric Pu(IV) to Pu(III)aq became thermodynamically favorable. However, the reduction rate did not increase but decrease with increasing humic concentrations from 15.0 to 150.5mg/L. Humic coatings formed on the polymer surfaces at relatively high humic concentrations limited the electron transfer to the polymers and thus decreased the reduction rate. The finding of the dynamic role of humic acids in the bioreductive solubilization may be helpful in evaluating Pu mobility in the geosphere. PMID- 28668753 TI - Precipitation, adsorption and rhizosphere effect: The mechanisms for Phosphate induced Pb immobilization in soils-A review. AB - Lead (Pb) is one of the most toxic heavy metals that pose a direct threat to organisms and it can not been degraded through microbial activities or chemical reaction. Bioavaibility and eco-toxicity of Pb which mostly depend on Pb chemical speciation play an important role in the remediation of Pb-contaminated soils. Phosphate (P) amendments which could transfer Pb from unstable fraction to stable fraction are commonly used to immobilize Pb in soils and have been extensively studied by researchers during decades. Based on the previous study, it can be concluded that three principal mechanisms may be responsible for P-induced Pb immobilization: 1) the precipitation of Pb-phosphates, including direct precipitation, ion-exchange (or substitution) effect and liming effect; 2) the adsorption of Pb, including the direct adsorption and the adsorption of Pb to iron (hydr)oxides; 3) the rhizosphere effect, including acidification effect and mycorrhizae effect. In this review, these mechanisms have been completely discussed and the internal relationships among them were summarized to give a better understanding of P-induced Pb immobilization in soils and promote the development of P-based remediation technology. PMID- 28668754 TI - Thiol-ethylene bridged PMO: A high capacity regenerable mercury adsorbent via intrapore mercury thiolate crystal formation. AB - Highly ordered thiol-ethylene bridged Periodic Mesoporous Organosilicas were synthesized directly from a homemade thiol-functionalized bis-silane precursor. These high surface area materials contain up to 4.3mmol/g sulfur functions in the walls and can adsorb up to 1183mg/g mercury ions. Raman spectroscopy reveals the existence of thiol and disulfide moieties. These groups have been evaluated by a combination of Raman spectroscopy, Ellman's reagent and elemental analysis. The adsorption of mercury ions was evidenced by different techniques, including Raman, XPS and porosimetry, which indicate that thiol groups are highly accessible to mercury. Scanning transmission electron microscopy combined with EDX showed an even homogenous distribution of the sulfur atoms throughout the structure, and have revealed for the first time that a fraction of the adsorbed mercury is forming thiolate nanocrystals in the pores. The adsorbent is highly selective for mercury and can be regenerated and reused multiple times, maintaining its structure and functionalities and showing only a marginal loss of adsorption capacity after several runs. PMID- 28668755 TI - Compost-derived humic acids as regulators for reductive degradation of nitrobenzene. AB - Nitrobenzene (NB) is a major class of contaminants in soil and groundwater. The current methods involved in the reductive degradation of NB suffer either cost ineffective or slow conversion rate. Here, we investigated the mechanisms regarding compost-derived humic acids (HAs) as cost-effective regulators to enhance the reduction of NB to aniline (AN). Our results show that the compost derived HAs, which have been reduced by a Pd-H2 catalytic system, were able to reduce NB to AN, and their redox properties were the main factors governing the reduction of NB to AN. The decreasing reduction of NB was mainly caused by the decreasing phenol content of compost-derived HAs during composting. In addition, the results reveal that the increase in the generation content of AN was mainly attributed to the increase in the quinones, aromaticity and humic-like components of compost-derived HAs. The findings demonstrate that the HAs derived from compost are effective regulators to enhance the reduction of NB to AN, and that they exert a bright application prospect for the remediation of the NB contaminated soil. PMID- 28668756 TI - Crude oil contamination of plastic and copper drinking water pipes. AB - This study was conducted to determine the susceptibility of plastic (i.e., PEX, HDPE and CPVC) and copper pipes to short-term contamination by crude oil. Pipes were exposed to highly and slightly contaminated drinking water for the typical duration of Do Not Use drinking water orders. PEX pipes sorbed and desorbed the greatest amount of monoaromatic hydrocarbons (MAHs), whereas copper pipes were less susceptible to contamination. For benzene, toluene, ethylbenzene, and xylenes (BTEX) quantified in water, only benzene exceeded its health based maximum contaminant level (MCL). The MCL was exceeded for copper pipe on day 3, for CPVC pipe through day 9, and PEX and HDPE pipes through day 15. The BTEX compound concentration in water after the pipes were returned to service depended on the initial crude oil concentration, material type, and exposure duration. Total organic carbon (TOC) measurement was not helpful in detecting oil contaminated water. Except BTEX, trimethylbenzene isomers and a couple of polycyclic aromatic hydrocarbons (PAHs) with and without MCLs were also detected desorbing from PEX-A pipe. Oil contaminated water must be thoroughly characterized and pipe type will influence the ability of drinking water levels to return to safe limits. PMID- 28668757 TI - Determination of LongR3-IGF-I, R3-IGF-I, Des1-3 IGF-I and their metabolites in human plasma samples by means of LC-MS. AB - According to the regulations of the World Anti-Doping Agency (WADA), growth promoting peptides such as the insulin-like growth factor-I (IGF-I) and its synthetic analogues belong to the class of prohibited compounds. While several assays to quantify endogenous IGF-I have been established, the potential misuse of synthetic analogues such as LongR3-IGF-I, R3-IGF-I and Des1-3-IGF-I remains a challenge and superior pharmacokinetic properties have been described for these analogues. Within the present study, it was demonstrated that the target peptides can be successfully detected in plasma samples by means of magnetic beads-based immunoaffinity purification and subsequent nanoscale liquid chromatographic separation with high resolution mass spectrometric detection. Noteworthy, the usage of a specific antibody for LongR3-IGF-I enables the determination in low ng/mL levels despite the presence of an enormous excess of endogenous human IGF I. In addition, different metabolism studies (in-vitro and in-vivo) were performed using sophisticated strategies such as incubation with skin tissue microsomes, degradation in biological fluids (for all analogues), and administration to rats (for LongR3-IGF-I). Herewith, several C-and N-terminally truncated metabolites were identified and their relevancy was additionally confirmed by in-vivo experiments with rodents. Especially for LongR3-IGF-I, a metabolite ((Des1-11)-LongR3-IGF-I) was identified that prolonged the detectability in-vivo by a factor of approximately 2. The method was validated for qualitative interpretation considering the parameters specificity, identification capability, recovery (26-60%), limit of detection (0.5ng/mL), imprecision (<25%), linearity, stability, and matrix effects. A stable isotope labelled (15N)-IGF-I was used as internal standard to control all sample preparation steps. PMID- 28668758 TI - Gender differences and stage-specific influence of parent-adolescent conflicts on adolescent suicidal ideation. AB - This study examined familial and peer related factors as predictors of suicidal ideation in school students. Total 2896 participants were included from Taiwan Youth Project released data, a longitudinal survey of adolescent suicidal ideation at ages 15, 18, and 20. Logistic regression analysis risk factors associated with adolescent suicidal ideation reveled differences during the developmental stages. After adjusted for psychological symptoms, effect of quarrels with parents on suicidal ideation lasts in early and middle stages; in the late adolescent stage, only cigarette or alcohol use remained significant. Girls who reported quarrels with parents had the highest level of suicidal ideation before age 18. Stage- and gender-specific differences may provide appropriate intervention strategies for parents and teachers preventing adolescent suicidal ideation. PMID- 28668759 TI - Adverse childhood experiences among youth reported to child welfare: Results from the national survey of child & adolescent wellbeing. AB - The negative influence of adverse childhood experiences (ACEs) on social, emotional, and behavioral (SEB) outcomes are well documented. However, no research to date has examined the effect of ACEs on SEB outcomes in youth who received mental health services after reporting to the child welfare system. This study's analyses of data from the National Survey of Child and Adolescent Well Being II revealed that the most prevalent ACEs included hospitalization for a medical condition, neglect, and exposures to domestic and community violence. Logistic regression of this data showed that the odds of being diagnosed with internalizing problems increased with age and when sexual abuse was reported. The results also showed that compared to Caucasian youth, Latinos were less likely to be diagnosed with externalizing behaviors, even when sexual abuse had been reported. Contrary to one of this study's hypotheses, mental health service use within the past 18 months increased the odds of being diagnosed with SEB problems. These findings highlight the persistence of SEB problems despite receipt of mental health services. Future research should assess the impact of interventions that aim to mitigate poor SEB outcomes due to ACEs, especially sexual abuse. PMID- 28668760 TI - Effect of contaminants of emerging concern on liver mitochondrial function in Chinook salmon. AB - We previously reported the bioaccumulation of contaminants of emerging concern (CECs), including pharmaceuticals and personal care products (PPCPs) and perfluorinated compounds, in field-collected juvenile Chinook salmon from urban estuaries of Puget Sound, WA (Meador et al., 2016). Although the toxicological impacts of CECs on salmon are poorly understood, several of the detected contaminants disrupt mitochondrial function in other species. Here, we sought to determine whether environmental exposures to CECs are associated with hepatic mitochondrial dysfunction in juvenile Chinook. Fish were exposed in the laboratory to a dietary mixture of 16 analytes representative of the predominant CECs detected in our field study. Liver mitochondrial content was reduced in fish exposed to CECs, which occurred concomitantly with a 24-32% reduction in expression of peroxisome proliferator-activated receptor (PPAR) Y coactivator-1a (pgc-1alpha), a positive transcriptional regulator of mitochondrial biogenesis. The laboratory exposures also caused a 40-70% elevation of state 4 respiration per unit mitochondria, which drove a 29-38% reduction of efficiency of oxidative phosphorylation relative to controls. The mixture-induced elevation of respiration was associated with increased oxidative injury as evidenced by increased mitochondrial protein carbonyls, elevated expression of glutathione (GSH) peroxidase 4 (gpx4), a mitochondrial-associated GSH peroxidase that protects against lipid peroxidation, and reduction of mitochondrial GSH. Juvenile Chinook sampled in a WWTP effluent-impacted estuary with demonstrated releases of CECs showed similar trends toward reduced liver mitochondrial content and elevated respiratory activity per mitochondria (including state 3 and uncoupled respiration). However, respiratory control ratios were greater in fish from the contaminated site relative to fish from a minimally-polluted reference site, which may have been due to differences in the timing of exposure to CECs under laboratory and field conditions. Our results indicate that exposure to CECs can affect both mitochondrial quality and content, and support the analysis of mitochondrial function as an indicator of the sublethal effects of CECs in wild fish. PMID- 28668761 TI - Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma. AB - Increased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib; hence, it is a promising target in MM patients. Hypoxia is known to mediate tumor progression and drug resistance (including bortezomib resistance) in MM cells. In this study, we tested the effects of selinexor alone or in combination with bortezomib in normoxia and hypoxia on MM cell survival and apoptosis in vitro and in vivo. In vitro, selinexor alone decreased survival and increased apoptosis, resensitizing MM cells to bortezomib. In vivo, we examined the effects of selinexor alone on tumor initiation and tumor progression, as well as selinexor in combination with bortezomib, on tumor growth in a bortezomib-resistant MM xenograft mouse model. Selinexor, used as a single agent, delayed tumor initiation and tumor progression, prolonging mice survival. In bortezomib resistant xenografts, selinexor overcame drug resistance, significantly decreasing tumor burden and extending mice survival when combined with bortezomib. PMID- 28668762 TI - Mangafodipir a Selective Cytoprotectant - with Special Reference to Oxaliplatin and Its Association to Chemotherapy-Induced Peripheral Neuropathy (CIPN). AB - Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has increased survival substantially in stage III colorectal cancer and prolonged life in stage IV patients, but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral neuropathy (CIPN) is the most problematic dose limiting toxicity of oxaliplatin. Oncologists included for years calcium and magnesium infusion as part of clinical practice for preventing CIPN. Results from a phase III prospective study published in 2014, however, overturned this practice. No other treatments have been clinically proven to prevent this toxicity. There is a body of evidence that CIPN is caused by cellular oxidative stress. Clinical and preclinical data suggest that the manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) is an efficacious inhibitor of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy. MnPLED, the metabolite of MnDPDP, attacks cellular oxidative stress at several critical levels. Firstly, MnPLED catalyzes dismutation of superoxide (O2*-), and secondly, having a tremendous high affinity for iron (and copper), PLED binds and disarms redox active iron/copper, which is involved in several detrimental oxidative steps. A case report from 2009 and a recent feasibility study suggest that MnDPDP may prevent or even cure oxaliplatin-induced CIPN. Preliminary results from a phase II study (PLIANT) suggest efficacy also of calmangafodipir, but these results are according to available data obscured by a surprisingly low number of adverse events and a seemingly lower than expected efficacy of FOLFOX. PMID- 28668764 TI - Spatio-temporal distribution of perchlorate and its toxicity in Hydrilla verticillata. AB - The spatio-temporal distribution of perchlorate in water sources around an ammonium perchlorate production unit and its toxicity response on a dominant aquatic plant, Hydrilla verticillata are reported in this study. Samples (n=453) from ground water (open well) and surface water sources within 5km from the production unit over a period of 12 months (2014, June - 2015, May) were screened for ClO4-. During the period, ClO4-concentration in ground water samples close to the production unit increased to >40,000MUg/L, and ClO4- was detected at 1740MUg/L in well water 1.6km away from the production unit. A community pond in the area also showed an increase in ClO4- level up to 29,000MUg/L. In all water sources, ClO4- level was maximum during the rainy season (July, monsoon). A natural degradation of ClO4- was not observed in the area as evident from its persistent level and spreading to more areas. H. verticillata, the dominant vegetation in the pond exhibited severe toxic response like massive decay and loss of photosynthetic pigments such as chlorophyll and carotene due to ClO4- exposure. The plant accumulated ClO4- up to 60+/-0.8mg/kg wet weight with a Bio Concentration Factor 2.06+/-0.005. This is the first report on spatio-temporal distribution of ClO4- at higher levels in a natural environment and its toxicity response to plants under natural condition. PMID- 28668763 TI - Vascular Mimicry: A Novel Neovascularization Mechanism Driving Anti-Angiogenic Therapy (AAT) Resistance in Glioblastoma. AB - Glioblastoma (GBM) is a hypervascular neoplasia of the central nervous system with an extremely high rate of mortality. Owing to its hypervascularity, anti angiogenic therapies (AAT) have been used as an adjuvant to the traditional surgical resection, chemotherapy, and radiation. The benefits of AAT have been transient and the tumors were shown to relapse faster and demonstrated particularly high rates of AAT therapy resistance. Alternative neovascularization mechanisms were shown to be at work in these resilient tumors to counter the AAT therapy insult. Vascular Mimicry (VM) is the uncanny ability of tumor cells to acquire endothelial-like properties and lay down vascular patterned networks reminiscent of host endothelial blood vessels. The VM channels served as an irrigation system for the tumors to meet with the increasing metabolic and nutrient demands of the tumor in the event of the ensuing hypoxia resulting from AAT. In our previous studies, we have demonstrated that AAT accelerates VM in GBM. In this review, we will focus on the origins of VM, visualizing VM in AAT treated tumors and the development of VM as a resistance mechanism to AAT. PMID- 28668765 TI - Topical application of ointment containing 0.5% green tea catechins suppresses tongue oxidative stress in 5-fluorouracil administered rats. AB - OBJECTIVE: The purpose of this study was to investigate the preventive effects of topical application of green tea catechins on tongue oxidative stress induced by 5-fluorouracil (5-FU) administration in rats. DESIGN: Male Wistar rats (n=28, 8 weeks old) were divided into four groups of seven rats each: a negative control group (saline administration and application of ointment without green tea catechins), a positive control group (5-FU administration and application of ointment without green tea catechins), and two experimental groups (5-FU administration and application of ointment containing 0.1% or 0.5% green tea catechins). Topical application of each ointment to the ventral surface of the tongue was performed once a day for 5days. The level of 8-hydroxydeoxyguanosine (8-OHdG) was determined to evaluate oxidative stress. Fluorescence staining was also performed to confirm nuclear factor erythroid 2-related factor 2 (Nrf2) translocation to the nucleus. RESULTS: After the experimental period, the ratios of 8-OHdG-positive cells in the ventral tongue tissue were higher in the positive control group than in the negative control group (P<0.05). On the other hand, those in the 0.5% green tea catechin group, but not in the 0.1% green tea catechin group, were lower than the positive control group (P<0.05). In addition, Nrf2 translocation to the nucleus was greater in the 0.5% green tea catechin group than in the positive control group (P<0.05). CONCLUSIONS: Topical application of ointment containing 0.5% green tea catechins could prevent tongue oxidative stress in 5-FU administered rats, via up-regulation of the Nrf2 signaling pathway. PMID- 28668766 TI - Effect of arginine on the growth and biofilm formation of oral bacteria. AB - BACKGROUND: Alkali production via arginine deiminase system (ADS) of oral bacteria plays a significant role in oral ecology, pH homeostasis and inhibition of dental caries. ADS activity in dental plaque varies greatly between individuals, which may profoundly affect their susceptibility to caries. OBJECTIVE: To investigate the effect of arginine on the growth and biofilm formation of oral bacteria. METHODS AND RESULTS: Polymicrobial dental biofilms derived from saliva were formed in a high-throughput active attachment biofilm model and l-arginine (Arg) was shown to reduce the colony forming units (CFU) counts of such biofilms grown for various periods or biofilms derived from saliva of subjects with different caries status. Arg hardly disturbed bacterial growth of Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinis and Streptococcus gordonii in BHI medium, but only inhibited biofilm formation of S. mutans. Scanning electron microscope (SEM) showed S. mutans biofilms harboured fewer cells grown with Arg than that without Arg, even in the initial 2h and 8h phase. Confocal laser scanning microscope (CLSM) images of poly-microbial dental and S. mutans biofilms revealed the biofilms grown with Arg had lower exopolysaccharide (EPS)/bacteria ratios than those without Arg (P=0.004, 0.002, respectively). Arg could significantly reduce the production of water-insoluble EPS in S. mutans biofilms (P<0.001); however, quantitative real-time PCR (qRT PCR) did not show significantly influence in gene expression of gtfB, gtfC or gtfD (P=0.32, 0.06, 0.44 respectively). CONCLUSIONS: Arg could reduce the biomass of poly-microbial dental biofilms and S. mutans biofilms, which may be due to the impact of Arg on water-insoluble EPS. Considering the contribution to pH homeostasis in dental biofilms, Arg may serve as an important agent keeping oral biofilms healthy thus prevent dental caries. PMID- 28668767 TI - Dynamic changes of plasma metabolites in pigs with GalN-induced acute liver failure using GC-MS and UPLC-MS. AB - Metabolomics facilitates investigation of the mechanisms of disease and screening for biomarkers. Here, a gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics approach was employed to identify plasma biomarkers of acute liver failure (ALF) in pigs. Blood was collected from pigs at 12h intervals during ALF. Hepatic injury was quantified by determining liver function and histopathology. Based on a multivariate data matrix and pattern recognition, two upregulated metabolites, namely, amino acids and conjugated bile acids, and two downregulated metabolites, lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs), were identified. All of these metabolites showed a strong relationship with the extent of liver injury. Amino acids were biomarkers of the severity of liver impairment, conjugated bile acids were predictive of early stage liver damage, and LPCs and PCs were related to the prognosis of liver injury. In conclusion, our results demonstrated the occurrence of marked metabolic disturbances during ALF and that integrated metabolomics analysis facilitates identification of biomarkers of disease. PMID- 28668768 TI - Low brain tissue oxygenation contributes to the development of delirium in critically ill patients: A prospective observational study. AB - PURPOSE: To test the hypothesis that poor brain tissue oxygenation (BtO2) during the first 24h of critical illness correlates with the proportion of time spent delirious. We also sought to define the physiological determinants of BtO2. MATERIALS AND METHODS: Adult patients admitted to the ICU within the previous 24h were considered eligible for enrollment if they required mechanical ventilation, and/or vasopressor support. BtO2 was measured using near-infrared spectroscopy, for 24h after enrollment. Hourly vital signs and clinically ordered arterial and central venous blood gases were collected throughout BtO2 monitoring. Patients were screened daily for delirium with the confusion assessment method for the intensive care unit (CAM-ICU). RESULTS: BtO2 and the proportion of time spent delirious did not result in a significant correlation (p=0.168). However, critically ill patients who spent the majority of their ICU stay delirious had significantly lower mean BtO2 compared to non-delirious patients, (p=0.017). BtO2 correlated positively with central venous pO2 (p=0.00003) and hemoglobin concentration (p=0.001). Logistic regression indicated that lower BtO2, higher narcotic doses and a history of alcohol abuse were independent risk factors for delirium. CONCLUSIONS: Poor cerebral oxygenation during the first 24 hours of critical illness contributes to the development of delirium. TRIAL REGISTRATION: This trial is registered on clinicaltrials.gov (Identifier: NCT02344043), retrospectively registered January 8, 2015. PMID- 28668769 TI - Microbial influence on Drosophila biology. AB - Commensal bacteria profoundly affect the biology of their animal partners. Drosophila melanogaster has been broadly used to study microbiota effects on invertebrates, whose findings are frequently applicable to translational studies. The beneficial role of commensal microbes on Drosophila biology is extensively described, ranging from growth to metabolism, immunity and even behaviour. However, the mechanisms underlying these effects are not well understood. Studies continue to discover new layers of complexity in the host-bacteria partnership that constantly changes depending on a plethora of different variables. This review discusses the latest advances in understanding the molecular bases of microbiota impact on Drosophila physiology and behaviour, emphasizing its broad influence and the intricate interdependence of the two partners in shaping their biology. PMID- 28668770 TI - Efficacy of imagery rescripting and imaginal exposure for nightmares: A randomized wait-list controlled trial. AB - Nightmares can be effectively treated with cognitive-behavioral therapies. Though it remains elusive which therapeutic elements are responsible for the beneficial effects on nightmare symptoms, imagery rescripting (IR) and imaginal exposure (IE) are commonly identified as active treatment components of nightmare therapies. With this randomized controlled trial, we compared IR and IE as individual treatments to a wait-list (WL) condition to determine whether these particular therapeutic elements ameliorate nightmare symptoms. For this purpose, 104 patients with a primary DSM-5 diagnosis of nightmare disorder were randomly assigned to three weekly individual sessions of either IR or IE, or WL. Results showed that compared to WL, both interventions effectively reduced nightmare frequency (DeltadIR-WL = 0.74; DeltadIE-WL = 0.70) and distress (DeltadIR-WL = 0.98; DeltadIE-WL = 1.35) in a sample that predominantly consisted of idiopathic nightmare sufferers. The effects of IR and IE were comparable to those observed for other psychological nightmare treatments. Initial effects at post-treatment were sustained at 3- and 6-months follow-up, indicating that IR and IE both seem to be efficacious treatment components of nightmare therapies. Additional research is needed to directly compare IR and IE among both idiographic and posttraumatic nightmare sufferers with respect to treatment expectancy, acceptability, and effectiveness. PMID- 28668771 TI - Label-free electrochemiluminescence assay for aqueous Hg2+ through oligonucleotide mediated assembly of gold nanoparticles. AB - Development of ultrasensitive method for Hg2+ analysis is important for human health protection and environment monitoring. In this work, we present a highly sensitive and selective electrochemiluminescence (ECL) assay in a "turn-on" mode for the detection of Hg2+ through selective assembly of gold nanoparticles (AuNPs) on the surface of indium tin oxide (ITO) electrode. In the absence of Hg2+, the nonthiolated ssDNA could protected AuNPs against its assembly on ITO surface, producing rather low ECL emission for Ru(bpy)32+/TPA system. Conversely, binding of Hg2+ with the Hg2+-specific oligonucleotide through thymine-Hg2+ thymine coordination formed the double-stranded structure, which could not effectively adsorb to AuNPs in solution. The assembly of free-state AuNPs is achieved, which well preserves electronical conductivity. The presence of AuNPs can catalyze the electro-oxidation of TPA, producing significantly enhanced ECL signal. Through detecting the ECL signal mediated by assembly of AuNPs, the proposed method was able to ensure substantial signal amplification and a low background. It was demonstrated that the ECL intensity was correlated with the ssDNA-based recognition reaction, enabling quantitative analysis of Hg2+ over the range of 8pM to 2nM, with a detection limit of 2pM. ECL intensity of the system were extremely specific for Hg2+ even in the presence of 1000-fold higher concentrations of other metal ions. Analytical results of Hg2+ spiked into water samples by the proposed ECL method were in good agreement with that obtained by atomic fluorescent spectrometry or mass spectrometry data. PMID- 28668772 TI - Field-effect transition sensor for KI detection based on self-assembled calixtube monolayers. AB - A series of novel calixarene-based tubes comprising different numbers of silatrane anchoring groups was synthesized. For the first time, a self-assembled monolayer (SAM) derived from calixtubes was formed on a SiO2 surface. The formation of the SAM was confirmed by X-ray photoelectron spectroscopy, scanning electron microscopy-energy dispersive X-ray analysis, and contact angle measurements. Modification of the sensitive surface of a conventional ion selective field effect transistor (ISFET) with the afforded SAM resulted in the production of a KI-sensitive sensor. This sensor selectively determined KI compare to different alkali metal iodides: NaI, RbI, CsI; also investigation of different potassium salts (acetate, iodide, nitrate, chloride, dihydrophosphate, perchlorate) showed the highest response to KI. This sensor was successfully employed to determine the presence of KI in artificial saliva with a limit of detection of ~3 * 10-8 M. In addition, it was found that the detection limit of the sensor could be increased by combining the sensor with a microfluidic system. Due to the obtained sensor sensitivity and its ability to detect KI in artificial saliva, we could conclude that this sensor shows great potential for application in the determination of KI in different media, such as the human body and in biological liquids, such as saliva or urine. PMID- 28668773 TI - Fluorescent carbon nanoparticle-based lateral flow biosensor for ultrasensitive detection of DNA. AB - We report a fluorescent carbon nanoparticle (FCN)-based lateral flow biosensor for ultrasensitive detection of DNA. Fluorescent carbon nanoparticle with a diameter of around 15nm was used as a tag to label a detection DNA probe, which was complementary with the part of target DNA. A capture DNA probe was immobilized on the test zone of the lateral flow biosensor. Sandwich-type hybridization reactions among the FCN-labeled DNA probe, target DNA and capture DNA probe were performed on the lateral flow biosensor. In the presence of target DNA, FCNs were captured on the test zone of the biosensor and the fluorescent intensity of the captured FCNs was measured with a portable fluorescent reader. After systematic optimizations of experimental parameters (the components of running buffers, the concentration of detection DNA probe used in the preparation of FCN-DNA conjugates, the amount of FCN-DNA dispensed on the conjugate pad and the dispensing cycles of the capture DNA probes on the test-zone), the biosensor could detect a minimum concentration of 0.4 fM DNA. This study provides a rapid and low-cost approach for DNA detection with high sensitivity, showing great promise for clinical application and biomedical diagnosis. PMID- 28668774 TI - Clinical predictors of early death from sepsis. AB - PURPOSE: Patients with severe sepsis who experience rapid, early deterioration and death are of particular concern. Our objective was to identify predictors of early death in Emergency Department (ED) patients with severe sepsis. METHODS: Secondary analysis of two prospective studies of adult ED patients with severe sepsis. The primary outcome was early death, defined as death within 24h of triage. RESULTS: Out of 410 severe sepsis admissions, 20 patients experienced early death. These patients demonstrated significantly higher initial lactate (7.3 versus 3.3mmol/L, p<0.001) and modified SOFA (mSOFA) scores (10 vs 6, p<0.001), were less likely to normalize their lactate (p<0.001), had lower initial pH (p<0.001), and more frequently had early positive blood cultures (p=0.021). Multivariable logistic regression identified initial serum lactate level (OR 1.19, 95% CI 1.06-1.35) and mSOFA score (OR 1.17, 95% CI 1.00-1.36) as independent predictors of early death. A repeat lactate>=5mmol/L had a sensitivity of 55% and specificity of 89% for early death. There were no significant treatment differences between groups. CONCLUSION: Initial serum lactate and mSOFA score were independent predictors of mortality within 24h of ED admission in patients with severe sepsis. PMID- 28668775 TI - Towards an early clinical diagnosis of sporadic CJD VV2 (ataxic type). AB - INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) includes a broad spectrum of clinical-pathological subtypes, which complicates the clinical differential diagnosis with other rapidly progressive neurological syndromes. AIM: To provide a better characterisation of clinical features and results of diagnostic investigations, especially at an early disease stage, in patients with sCJDVV2, the second most common sCJD subtype. METHODS: We evaluated neurological symptoms/signs, and results of brain diffusion-weighted resonance imaging (DW MRI), electroencephalographic recordings (EEG) and cerebrospinal fluid (CSF) biomarker studies in 120 patients with a definite (n=93) or probable (n=27) diagnosis of sCJDVV2. RESULTS: All patients presented with prominent cerebellar signs, which were often associated with memory loss and/or oculomotor, visual or peripheral/spinal cord signs. In contrast, dementia was invariably a late finding. All CSF samples were positive for the 14-3-3 protein assay and had total tau protein levels above 1250 pg/mL. Brain DW-MRI showed hyperintensity of basal ganglia, thalamus and cerebral cortex, respectively in 91.5%, 57.4% and 19.1% of cases. EEG revealed periodic sharp-wave complexes in only 17.8% of cases. CONCLUSIONS: sCJDVV2 should be considered in any patient presenting with a rapidly progressive ataxia, especially when associated with oculomotor, visual or peripheral/spinal cord signs, even in the absence of dementia or myoclonus. CSF assays and brain DW-MRI represent sensitive diagnostic tests, even at an early stage. These data strongly suggest that sCJDVV2 can be clinically diagnosed early and accurately based on clinical data, DW-MRI, CSF assays and codon 129 genotyping and provide the basis for improved and subtype-specific diagnostic criteria of sCJD. PMID- 28668776 TI - GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS. PMID- 28668778 TI - Solitary fibrous tumour of the pleura presenting as a giant intrathoracic mass. AB - Solitary fibrous tumours (SFTs) are relatively rare neoplasms thought to originate from the submesothelial connective tissue. SFTs have been described in a variety of sites, including the pleura, orbit, lower respiratory tract, peritoneal cavity and heart. These neoplasms are usually benign, though locally aggressive, and metastatic behaviour has been observed in some cases. We describe a case of a 61-year-old man presenting with weight loss, poor appetite, malaise, worsening dyspnoea on exertion and lower extremity oedema, who was found to have a gigantic-21*21 cm-tumour occupying the entire right hemithorax causing compression and displacement of the mediastinum and liver. Transthoracic CT guided biopsy revealed SFT of the pleura. The patient underwent preoperative angiography and embolisation of the tumour followed by successful surgical resection via thoracotomy. PMID- 28668780 TI - ADEA Mission, Strategic Directions, and Key Priorities, 2015-18. PMID- 28668779 TI - Bylaws of the American Dental Education Association: (With changes approved by the 2017 House of Delegates). PMID- 28668790 TI - ADEA Foundation Knowledge and Skills for the New General Dentist: (As approved by the 2011 ADEA House of Delegates). PMID- 28668777 TI - Translating Divergent Environmental Stresses into a Common Proteome Response through the Histidine Kinase 33 (Hik33) in a Model Cyanobacterium. AB - The histidine kinase Hik33 plays important roles in mediating cyanobacterial response to divergent types of abiotic stresses including cold, salt, high light (HL), and osmotic stresses. However, how these functions are regulated by Hik33 remains to be addressed. Using a hik33-deficient strain (Deltahik33) of Synechocystis sp. PCC 6803 (Synechocystis) and quantitative proteomics, we found that Hik33 depletion induces differential protein expression highly like that induced by divergent types of stresses. This typically includes downregulation of proteins in photosynthesis and carbon assimilation that are necessary for cell propagation, and upregulation of heat shock proteins, chaperons, and proteases that are important for cell survival. This observation indicates that depletion of Hik33 alone mimics divergent types of abiotic stresses, and that Hik33 could be important for preventing abnormal stress response in the normal condition. Moreover, we found most proteins of plasmid origin were significantly upregulated in Deltahik33, though their biological significance remains to be addressed. Together, the systematically characterized Hik33-regulated cyanobacterial proteome, which is largely involved in stress responses, builds the molecular basis for Hik33 as a general regulator of stress responses. PMID- 28668789 TI - ADEA Competencies for the New General Dentist: (As approved by the 2008 ADEA House of Delegates). PMID- 28668792 TI - ADEA Core Competencies for Graduate Dental Hygiene Education: (As approved by the 2011 ADEA House of Delegates). PMID- 28668793 TI - Exhibit 10: ADEA Principles for Accreditation in Dental Education: (As approved by the 1997 ADEA House of Delegates). PMID- 28668791 TI - ADEA Competencies for Entry into the Allied Dental Professions: (As approved by the 2011 ADEA House of Delegates). PMID- 28668795 TI - ADEA Policy Statements: Recommendations and Guidelines for Academic Dental Institutions: (With changes approved by the 2015 ADEA House of Delegates). PMID- 28668794 TI - Exhibit 11: ADEA Policy Statements. PMID- 28668797 TI - ADEA Statement on Professionalism in Dental Education: (As approved by the 2009 ADEA House of Delegates). PMID- 28668796 TI - ADEA Policy Statement on Health Care Reform: Oral Health Care: Essential to Health Care Reform (As approved by the 2009 ADEA House of Delegates). PMID- 28668798 TI - ADEA Guiding Principles for the Education of Oral Health Professionals in Emerging Workforce Models: (As approved by the 2011 ADEA House of Delegates). PMID- 28668799 TI - Statement of ADEA Policy on Diversity and Inclusion: (As approved by the 2016 ADEA House of Delegates). PMID- 28668800 TI - Exhibit 12: ADEA Position Papers. PMID- 28668802 TI - Anticyclic Citrullinated Peptide Antibodies and Rheumatoid Factor as Risk Factors for 10-year Cardiovascular Morbidity in Patients with Rheumatoid Arthritis: A Large Inception Cohort Study. AB - OBJECTIVE: To determine whether anticyclic citrullinated peptide antibodies (anti CCP) and rheumatoid factor (RF) are risk factors for 10-year cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). METHODS: Analyses were performed using data from the Nijmegen early RA inception cohort, in which patients with newly diagnosed RA, consecutively included since 1985, were regularly followed up. Anti-CCP and RF were determined at baseline (diagnosis). Outcome was the first cardiovascular disease (CVD) event [ischemic heart disease, nonhemorrhagic cerebrovascular accident (CVA), or peripheral artery disease (PAD)] after baseline as retrieved from physician diagnosis. Fatality was checked against death certificates. Cox regression including correction for baseline confounders was performed to estimate the effect of anti-CCP, RF, and their interaction on 10-year CVD-free survival. RESULTS: Of 929 patients included, 628 were anti-CCP-positive and 697 were RF-positive. During followup, with a median of 7.5 years, 162 CV events were observed (101 ischemic heart disease, 45 CVA, and 16 PAD), of which 15 were fatal. The HRadjusted for anti-CCP was 1.17 (95% CI 0.82-1.67) and the HRadjusted for RF was 1.52 (95% CI 1.00-2.30). The association of RF positivity with CVD was even stronger in the anti-CCP-negative patients: HRadjusted 2.09 (95% CI 1.18-3.71). There was no significant interaction (p = 0.098) between anti-CCP and RF. CONCLUSION: Rather than anti-CCP, presence of RF was associated with CVD in this cohort of patients with RA. PMID- 28668803 TI - Longterm Data on Disease Flares in Patients with Proliferative Lupus Nephritis in Recent Years. AB - OBJECTIVE: To examine the disease flare rate in lupus nephritis (LN), focusing on renal flares, and the factors associated with relapse risk in recent years. METHODS: We analyzed data on 139 Chinese patients with class III/IV +/- V LN diagnosed from January 1983 to December 2013. We also compared data before and after 1998, when maintenance immunosuppression was changed from azathioprine (AZA) to mycophenolic acid (MPA). RESULTS: Over 112.5 +/- 88.4 months, 135 episodes of renal flare occurred, giving a flare rate of 0.108 episodes per patient-year. The renal relapse-free survival rate was 96%, 90%, 86%, 80%, 69%, and 57% after 1, 2, 3, 4, 5, and 10 years, respectively, calculated from the start of induction treatment. Reduced risk of flare was associated with MPA maintenance (OR 0.314, 95% CI 0.099-0.994, p = 0.049), complete remission after induction immunosuppression (OR 0.329, 95% CI 0.133-0.810, p = 0.016), and diagnosis after 1998 (OR 0.305, 95% CI 0.133-0.700, p = 0.005). Relapse-free survival was significantly better in patients treated with prednisolone and MPA as maintenance immunosuppression (91% after 5 yrs and 83% after 10 yrs, respectively) compared with prednisolone and AZA (70% and 52%, respectively, p = 0.044). LN diagnosed in 1998-2013 showed 5-year and 10-year relapse-free survival rates of 93% and 86%, respectively, compared with 81% and 66%, respectively (p = 0.017) for LN that presented in 1983-1997. CONCLUSION: Our data show a relatively low flare rate for LN in the more recent era, attributed to effective induction of immunosuppression and MPA as maintenance treatment. PMID- 28668804 TI - Validation of a Knowledge Transfer Tool According to the OMERACT Filter: Does Web based Real-time Iterative Calibration Enhance the Evaluation of Bone Marrow Lesions in Hip Osteoarthritis? AB - OBJECTIVE: To assess reliability and feasibility of using a Web-based interface and interactive online calibration tool for magnetic resonance imaging (MRI) scoring of bone marrow lesions (BML) in osteoarthritis (OA), applied to the Hip MR Inflammation Scoring System (HIMRISS). METHODS: Seven readers new to HIMRISS (3 radiologists, 4 rheumatologists) scored coronal short-tau inversion recovery MRI from a hip OA observational study obtained pre- and 8-week poststeroid injection (n = 40 * 2 scans * 2 hips = 160 hips). By crossover design, Group B (4 readers) scored 20 patients (40 hips) using conventional spreadsheet-based methods and then another 20 using a Web-based interface and an online real-time iterative calibration (RETIC) training module. Group A (3 readers) reversed the order, scoring the first 20 subjects by the new method and the final 20 conventionally. Outcomes included ICC and reader survey. RESULTS: Interobserver reliability for BML status was high by both spreadsheet and Web-based methods (0.84-0.90), regardless of the order in which scoring was performed. Reliability of change scores was moderate and improved with training. Improvement was greater in readers who began with the spreadsheet method and then used the Web-based method than in those who began with the Web-based method, especially at the acetabulum. Readers found Web-based/RETIC scoring more user-friendly and nearly 50% faster than traditional spreadsheet methods. CONCLUSION: HIMRISS offers reliable BML scoring in OA, whether by conventional spreadsheet-based scoring or by a Web-based interface with interactive feedback. The new method allowed faster readings, provided a consistent training environment that helped inexperienced readers achieve reliability equivalent to that of conventional methods, and was preferred by the readers. PMID- 28668805 TI - "Rheum to Improve": Quality Improvement in Outpatient Rheumatology. AB - The commitment to improve care processes and patient outcomes is a professional mandate for clinicians and is also seen as an operational priority for institutions. Quality improvement now figures in the accreditation of training programs, specialty examinations, and hospital scorecards. Rheumatologists have traditionally focused primarily on quality problems such as guideline adherence; however, improvement goals should also include other aspects of care that are helpful to patients and are professionally rewarding for practitioners. This review makes use of improvement projects in outlining tangible tools rheumatologists can use to resolve quality concerns in their practices. PMID- 28668807 TI - Sex and Gender Interactions in the Lives of Patients with Spondyloarthritis in Spain: A Quantitative-qualitative Study. AB - OBJECTIVE: To illustrate the experiences and contextual support perceived by men and women with spondyloarthritis (SpA) in relation to their demanding productive and reproductive roles. METHODS: A quantitative-qualitative study of 96 men and 54 women with SpA was conducted at the Alicante University General Hospital, in a Spanish Mediterranean city, from March 2013 to February 2014. Descriptive and qualitative content analyses compared working lives and family/partner relationships of male and female patients. RESULTS: Working life: both women (55.6%) and men (51.04%) were similarly affected, but women had worse disease activity (5.4 vs 4.0, p = 0.01) and less antitumor necrosis factor-alpha therapy (56.7% vs 77.6%, p < 0.05). Different patterns were found by gender: women mostly practiced presenteeism whereas men practiced absenteeism, women took antiinflammatories prior to work and men after work, employers suggested more frequently the beneficial actions for men, and some women withdrew permanently from the labor market. Family/partner relationships: women were more affected (57.4%) than men (41.7%), with worse results for diagnostic delay (11.2 vs 6.4 yrs, p = 0.02), disease activity (5.8 vs 3.6, p < 0.001), and physical function (5.2 vs 3.8, p = 0.02). Gender role conflicts emerged, with women developing strategies to face compulsory housework whereas men avoided them; women regretted neglecting their children and men not sharing leisure activities with them. CONCLUSION: Our study highlights the vital complexity in which patients with SpA are immersed, especially for women in a country where a mix of new and traditional gender roles coexist. Awareness of its existence is crucial when professionals strive to provide healthcare focused on their well-being in addition to medical therapy. PMID- 28668808 TI - Defining Flare in Osteoarthritis of the Hip and Knee: A Systematic Literature Review - OMERACT Virtual Special Interest Group. AB - OBJECTIVE: Beyond the exacerbation of pain in describing a flare in osteoarthritis (OA), patients and health professionals add other elements that deserve to be fully elucidated, such as effusion, swelling, and mobility limitation. To define and conceptualize the construct flare in OA, the objective was to identify the key variables, or symptoms, that worsen, and to clarify how these variables are described in the literature by patients and clinicians. METHODS: A systematic review of the literature was conducted in Medline and PsychINFO. In brief, the search terms used were "osteoarthritis," "knee," "hip," and "flare." Specific characteristics of included studies were identified, including the type of study design, type of flare assessed, how the flare developed, and what definition of flare was used, including whether the definition was based on qualitative or quantitative analysis. RESULTS: Pain was the major factor in the definition of flare within these studies. Four components of flare were identified: pain, other factors, composite criteria, and global assessment. While the majority of studies reported flare as an increase in pain using standardized outcome measures, only 1 study reported the antecedents and consequences of a pain flare using qualitative methods. CONCLUSION: The use of flare as an outcome or inclusion criterion in rheumatology trials is a common occurrence; however, this review highlights the wide variation in the definitions of OA flare currently in use and the emphasis on the measurement of pain. This variation in definition does not allow for direct comparison between trials and limits interpretation of evidence. PMID- 28668806 TI - Patient-reported Outcomes as Predictors of Change in Disease Activity and Disability in Early Rheumatoid Arthritis: Results from the Yorkshire Early Arthritis Register. AB - OBJECTIVE: To assess patient-reported variables as predictors of change in disease activity and disability in early rheumatoid arthritis (RA). METHODS: Cases were recruited to the Yorkshire Early Arthritis Register (YEAR) between 1997 and 2009 (n = 1415). Predictors of the 28-joint Disease Activity Score (DAS28) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline and change over 12 months were identified using multilevel models. Baseline predictors were sex, age, symptom duration, autoantibody status, pain and fatigue visual analog scales (VAS), duration of early morning stiffness (EMS), DAS28, and HAQ-DI. RESULTS: Rates of change were slower in women than men: DAS28 fell by 0.19 and 0.17 units/month, and HAQ-DI by 0.028 and 0.023 units/month in men and women, respectively. Baseline pain and EMS had small effects on rates of change, whereas fatigue VAS was only associated with DAS28 and HAQ-DI at baseline. In patients recruited up to 2002, DAS28 reduced more quickly in those with greater pain at baseline (by 0.01 units/mo of DAS28 per cm pain VAS, p = 0.024); in patients recruited after 2002, the effect for pain was stronger (by 0.01 units/mo, p = 0.087). DAS28 reduction was greater with longer EMS. In both cohorts, fall in HAQ-DI (p = 0.006) was greater in patients with longer EMS duration, but pain and fatigue were not significant predictors of change in HAQ-DI. CONCLUSION: Patient-reported fatigue, pain, and stiffness at baseline are of limited value for the prediction of RA change in disease activity (DAS28) and activity limitation (HAQ-DI). PMID- 28668809 TI - Adherence to Antitumor Necrosis Factor Use Recommendations in Spondyloarthritis: Measurement and Effect in the DESIR Cohort. AB - OBJECTIVE: To evaluate a classification system to define adherence to axial spondyloarthritis (axSpA) anti-tumor necrosis factor (anti-TNF) use recommendations and examine the effect of adherence on outcomes in the DESIR cohort (Devenir des Spondylarthropathies Indifferenciees Recentes). METHODS: Using alternate definitions of adherence, patients were classified as adherent "timely" anti-TNF users, nonadherent "late" anti-TNF users, adherent nonusers ("no anti-TNF need"), non-adherent nonusers ("unmet anti-TNF need"). Multivariate models were fitted to examine the effect of adherence on quality-adjusted life years (QALY), total costs, and nonbiologic costs 1 year following an index date. Generalized linear regression models assuming a gamma-distribution with log link were used for costs outcomes and linear regression models for QALY outcomes. RESULTS: Using the main definition of adherence, there were no significant differences between late anti-TNF users and timely anti-TNF users in total costs (RR 0.86, 95% CI 0.54-1.36, p = 0.516) or nonbiologic costs (RR 0.72, 95% CI 0.44 1.18, p = 0.187). However, in the sensitivity analysis, late anti-TNF users had significantly increased nonbiologic costs compared with timely users (RR 1.58, 95% CI 1.06-2.36, p = 0.026). In the main analysis, there were no significant differences in QALY between timely anti-TNF users and late anti-TNF users, or between timely users and patients with unmet anti-TNF need. In the sensitivity analysis, patients with unmet anti-TNF need had significantly lower QALY than timely anti-TNF users (-0.04, 95% CI -0.07 to -0.01, p = 0.016). CONCLUSION: The effect of adherence to anti-TNF recommendations on outcomes was sensitive to the definition of adherence used, highlighting the need to validate methods to measure adherence. PMID- 28668811 TI - The Effect of Anterior Uveitis and Previously Undiagnosed Spondyloarthritis: Results from the DUET Cohort. AB - OBJECTIVE: Anterior uveitis (AU) is an intraocular inflammatory condition closely linked to spondyloarthritis (SpA). Clinical disease variables may often underestimate the true effect of the disease on patient's quality of life. This study examines AU and associated undiagnosed SpA using established quality-of life tools to inform clinicians of the effect of these diseases. METHODS: The Dublin Uveitis Evaluation Tool (DUET) algorithm was developed and validated in a cohort of consecutive patients with AU who were all screened by a rheumatologist for the presence of SpA. This same cohort completed vision-related [Vision Core Measure 1 (VCM1)] and general health [Medical Outcomes Study Short Form-36 (SF 36)] questionnaires when AU was active and resolved. RESULTS: VCM1 scores improved with AU resolution. VCM1 did not correlate with vision at baseline, but did on resolution of inflammation. Physical SF-36 scores were reduced during AU episodes and improved on resolution remaining below those of population norms. Subanalysis revealed that SpA scores were more affected than the idiopathic AU group. CONCLUSION: AU affects physical aspects of quality of life more than is appreciated by clinical variables, especially in those with pre-existing, undiagnosed SpA. This study is unique in examining the effect of SpA on patients prior to diagnosis. These results highlight the role of the ophthalmologist in identifying patients with SpA who present with AU using the DUET algorithm. PMID- 28668810 TI - An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc. PMID- 28668812 TI - Cost-effectiveness of Biological Disease-modifying Antirheumatic Drugs for the Treatment of Rheumatoid Arthritis: Implications for Clinical Practice. PMID- 28668813 TI - The Herpes Zoster Vaccine in Rheumatic Diseases: Duration of Response. PMID- 28668814 TI - Weathering a Macrophage Storm. PMID- 28668815 TI - Adie Pupil as the Initial Presentation of Localized En Coup de Sabre Scleroderma. PMID- 28668816 TI - PET/CT Imaging in Fever of Unknown Origin: A Case of Relapsing Polychondritis. PMID- 28668817 TI - Gottron Sign with Ulceration Is Not a Poor Prognostic Factor in Patients with Dermatomyositis and Interstitial Lung Disease. PMID- 28668818 TI - Drs. Cao and Zheng reply. PMID- 28668819 TI - Calcium Pyrophosphate Crystal Inflammatory Arthritis (Pseudogout) with Myelodysplastic Syndrome: A New Paraneoplastic Syndrome? PMID- 28668821 TI - Preimplantation genetic diagnosis for mitochondrial DNA mutations: analysis of one blastomere suffices. AB - BACKGROUND: Preimplantation genetic diagnosis (PGD) is a reproductive strategy for mitochondrial DNA (mtDNA) mutation carriers, strongly reducing their risk of affected offspring. Embryos either without the mutation or with mutation load below the phenotypic threshold are transferred to the uterus. Because of incidental heteroplasmy deviations in single blastomere and the relatively limited data available, we so far preferred relying on two blastomeres rather than one. Considering the negative effect of a two-blastomere biopsy protocol compared with a single-blastomere biopsy protocol on live birth delivery rate, we re-evaluated the error rate in our current dataset. METHODS: For the m.3243A>G mutation, sufficient embryos/blastomeres were available for a powerful analysis. The diagnostic error rate, defined as a potential false-negative result, based on a threshold of 15%, was determined in 294 single blastomeres analysed in 73 embryos of 9 female m.3243A>G mutation carriers. RESULTS: Only one out of 294 single blastomeres (0.34%) would have resulted in a false-negative diagnosis. False-positive diagnoses were not detected. CONCLUSION: Our findings support a single-blastomere biopsy PGD protocol for the m.3243A>G mutation as the diagnostic error rate is very low. As in the early preimplantation embryo no mtDNA replication seems to occur and the mtDNA is divided randomly among the daughter cells, we conclude this result to be independent of the specific mutation and therefore applicable to all mtDNA mutations. PMID- 28668822 TI - When cancer patients suddenly have a positive pregnancy test. AB - We present the case of non-small cell lung cancer (NSCLC) in a 48-year-old woman with an active history of smoking. The patient initially presented to her general practitioner with a progressive swelling on the neck. Further investigations diagnosed a metastatic lung tumour, and palliative chemotherapy was started. After 5 months of treatment, by newly reported amenorrhoea, cautiously before a restaging CT scan of the abdomen, a pregnancy test was performed and was positive. Both the gynaecological examination and the hormonal panel yielded no signs of pregnancy. Immunohistochemically, staining of the tumour was strongly positive for beta-subunit of human chorionic gonadotropin (beta-hCG) suggesting that the tumour was responsible for high beta-hCG levels.Paraneoplastic beta-hCG secretion from adenocarcinomas is rare. In the literature, only a few such cases have been reported. Previous studies suggested that the ability to secrete beta hCG in tumours may correlate to some extent to chemoresistance and thus, to a worse prognosis. PMID- 28668823 TI - Desmoid Tumors in Familial Adenomatous Polyposis. AB - Familial adenomatous polyposis (FAP) is a cancer syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene. It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation. Among associated lesions in FAP, desmoid tumors represent a common possible life-threatening condition that requires special attention. They are rare tumors occurring with a particularly high incidence in FAP, especially after surgery. In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids. Several lines of evidence show that germline mutations affect the functional domains of the APC gene that are responsible for interactions of the transcript with beta-catenin, whereas somatic second mutations involve the downstream region of the gene. Hence, an understanding of the molecular pathways underlying desmoid progression in FAP could be important for research and a valid resource for the early prevention and tailored treatment of this disease. In this review, we provide an updated insight into desmoids in FAP syndrome, from molecular pathogenesis to the main issues in management, with special attention given to genetic and molecular features of these tumors. PMID- 28668820 TI - Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women. AB - BACKGROUND: Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. METHODS AND RESULTS: We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community based study of existing ("parent") cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12-lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea-hypopnea index (OAHI). CSA was defined by a central apnea index >=5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow-up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2- to 3-fold increased odds of developing AF (central apnea index >=5 odds ratio [OR], 3.00, 1.40-6.44; Cheyne-Stokes respiration OR, 1.83, 0.95-3.54; CSA or Cheyne-Stokes respiration OR, 2.00, 1.16 3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91-1.03; OAHI 5 to <15 OR, 0.84, 0.59-1.17; OAHI 15 to <30 OR, 0.93, 0.60-1.45; OAHI >=30 OR, 0.76, 0.42-1.36). CONCLUSIONS: In a prospective, community-based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors. PMID- 28668824 TI - Application of Cancer Cell Reprogramming Technology to Human Cancer Research. AB - The cancer stem cell (CSC) hypothesis is an evolving concept of oncogenesis that has recently gained wide acceptance. By definition, CSCs exhibit continuous proliferation and self-renewal, and they have been proposed to play significant roles in oncogenesis, tumor growth, metastasis, chemoresistance, and cancer recurrence. The reprogramming of cancer cells using induced pluripotent stem cell (iPSC) technology is a potential strategy for the identification of CSC-related oncogenes and tumor-suppressor genes. This technology has some advantages for studying the interactions between CSC-related genes and the cancer microenvironment. This approach may also provide a useful platform for studying the mechanisms of CSCs underlying cancer initiation and progression. The present review summarizes the recent advances in cancer cell reprogramming using iPSC technology and discusses its potential clinical use and related drug screening. PMID- 28668825 TI - Clinical Implications of Augmenter of Liver Regeneration in Cancer: A Systematic Review. AB - BACKGROUND/AIM: Hepatocellular carcinoma is a substantial healthcare burden with high prevalence and poor prognosis. As such, efforts are continually made to uncover molecules relevant in cancer biology, that are exploitable as targets for therapy. The mitochondrion is the powerhouse of the cell and exhibits altered functionality in the malignant state, including aberrant regulation of apoptosis and cellular respiration. Augmenter of liver regeneration (ALR) is a multifunctional mitochondrial protein that demonstrates anti-oxidative and anti apoptotic properties and plays a key role in liver regeneration. MATERIALS AND METHODS: The present study systematically reviews the available literature on the role of ALR in cancer. RESULTS: Systematic search of PubMed resulted in 12 studies discussing ALR in multiple types of cancer. More specifically, ALR appears to be up-regulated in malignant cells and tissues. Furthermore, treatment of cells with exogenous ALR shows an anti-apoptotic effect while silencing or inhibiting ALR decreases cell and tumor survival. CONCLUSION: ALR clearly plays a role in cancer biology and demonstrates potential as a therapeutic target. PMID- 28668826 TI - Inhibition of ERG Activity in Patient-derived Prostate Cancer Xenografts by YK-4 279. AB - BACKGROUND/AIM: The aim of the current study was to determine the effects of the ERG small-molecule inhibitor YK-4-279 on ERG+ prostate cancer patient-derived xenografts (PDX). MATERIALS AND METHODS: ERG activity was blocked using YK-4-279 in three subcutaneously-implanted ERG+ (LuCaP 23.1, 86.2 and 35) and one ERG- (LuCaP 96) PDX. Treated animals tumor volume (TV), body weight (BW) and serum prostate-specific antigen (PSA) were compared to vehicle-treated control animals. Gene expression, proliferation, apoptosis, microvessel density and ERG expression were also assessed. RESULTS: Administration of YK-4-279 decreased TV (p=0.026), proliferation (p=0.0038) and PSA (p=0.022) in Severe Combined Immunodeficiency (SCID) mice bearing LuCaP 23.1 tumors. LuCaP 86.2, LuCaP 35 and LuCaP 96 showed no significant changes in TV, or PSA. Mineralocorticoid receptor (MR) and MR direct target genes were up-regulated in treatment-resistant LuCaP 86.2 and LuCaP 35 PDX. CONCLUSION: YK-4-279 decreased ERG+ LuCaP 23.1 tumor growth, but not LuCaP 86.2 and LuCaP 35 ERG+ tumor growth. PMID- 28668827 TI - A Novel mTOR Inhibitor; Anthracimycin for the Treatment of Human Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Anthracimycin, a secondary metabolite of Streptomyces, has been shown to inhibit the invasion of certain cancer cell lines. MATERIALS AND METHODS: In this study we evaluated the effect of anthracimycin on cell growth and signaling pathways in hepatocellular carcinoma (HCC). RESULTS: Anthracimycin suppressed cell proliferation and motility and induced apoptosis in human HCC cell lines. Furthermore, anthracimycin had no effect on the enrichment of EpCAM high liver cancer stem cells (CSCs), while fluorouracil dramatically enriched the CSCs with activation of the stemness-related genes EPCAM and SOX9 in HuH7 cells. Mechanistically, anthracimycin suppressed mammalian target of rapamycin (mTOR) signaling, and was most effective at inhibiting HCC cell proliferation with mTOR activation. CONCLUSION: Anthracimycin is a novel mTOR inhibitor capable of suppressing the proliferation of CSCs and non-CSCs equally well in HCC, and it is suggested that anthracimycin could be effective in the eradication of HCC associated with mTOR-signaling activation. PMID- 28668828 TI - Patient-derived Xenografts from Colorectal Carcinoma: A Temporal and Hierarchical Study of Murine Stromal Cell Replacement. AB - BACKGROUND/AIM: Patient-derived xenografting (PDX) of human colorectal cancer (CRC) is the preferred experimental model to study tumor response to therapeutic agents. Gradually, human stromal cells are replaced by mouse stromal cells; however, the exact timing of the replacement of human with murine stromal cells in human CRC xenograft has not been fully elucidated. We hypothesize that orthologous murine transcripts functionally substitutes for the loss due to replacement of human stromal genes. MATERIALS AND METHODS: Human CRC were implanted in athymic nude mice in replicates and followed-up over time. Using next-generation sequencing, we determined the temporal kinetics of human stromal cell replacement with the orthologous murine transcripts. RESULTS: CRC cell induced re-organization of the normal, quiescent murine stromal cells into a protumorigenic phenotype supporting human CRC growth occurs at initial implantation. CONCLUSION: Murine cell replacement occurs in a time- and size dependent manner. PMID- 28668829 TI - Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide. AB - BACKGROUND/AIM: Since temozolomide (TMZ) is activated under alkaline conditions, we expected lonidamine (LND) to have no effect or perhaps diminish its activity, but initial results suggest it may actually enhance either or both short- and long-term activity of TMZ in melanoma xenografts. MATERIALS AND METHODS: Cohorts of 5 mice with subcutaneous xenografts ~5 mm in diameter were treated with saline (control (CTRL)), LND only, TMZ only or LND followed by TMZ at t=40 min (time required for maximal tumor acidification). RESULTS: Mean tumor volume for LND+TMZ for the period between 6 and 26 days was reduced compared to TMZ alone (repeated measures ANOVA F (1, 8), p=0.006), suggesting a pronounced impact of LND on this phenomenon. TMZ and LND+TMZ produced median growth delays of 82 and 106 days, respectively. CONCLUSION: The use of TMZ alone and in combination with LND deserves further investigation in treatment of melanoma and other malignancies. PMID- 28668830 TI - Increased Nicotinamide Phosphoribosyltransferase and Cystathionine-beta-Synthase in Renal Oncocytomas, Renal Urothelial Carcinoma, and Renal Clear Cell Carcinoma. AB - BACKGROUND: Renal oncocytomas (ROs), and clear cell (RCC) and urothelial carcinomas (UC), are common renal neoplasms. Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of NAD+ synthesis and its expression is increased in several tumors. Nampt concomitantly regulates hydrogen sulfide (H2S)-synthesizing enzyme levels, including cystathionine-beta-synthase (CBS). MATERIALS AND METHODS: We used tissue microarrays to examine Nampt and the H2S-synthesizing enzyme CBS protein levels in benign kidney, RCC, UC and ROs. RESULTS: Compared to benign kidney, all three neoplasms showed increased Nampt and CBS protein levels, with the levels increasing in RCC at higher Fuhrman grades. CONCLUSION: H2S is known to ameliorate chronic renal failure but, as yet, no role for H2S in renal neoplasia has been demonstrated. Here, we showed, for the first time, that Nampt, CBS and, likely, H2S likely play a role in malignant and benign neoplastic renal disease. PMID- 28668831 TI - Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment. AB - BACKGROUND/AIM: Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. MATERIALS AND METHODS: C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. RESULTS: Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. CONCLUSION: The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. PMID- 28668833 TI - Overexpression of Activin Receptor-like Kinase 7 in Breast Cancer Cells Is Associated with Decreased Cell Growth and Adhesion. AB - AIM: To examine the expression and function of activin receptor-like kinase 7 (ALK7) in breast cancer, its association with disease prognosis, and its impact on breast cancer cell function. PATIENTS AND METHODS: A cohort of patients with breast cancer were examined for ALK7 expression in association with pathological and clinical aspects. In vitro cell assays of ALK7 were investigated using an expression plasmid. RESULTS: Overall higher levels of ALK7 transcripts were seen in the breast cancer samples vs. normal tissue. However, within the cancer cohort, lower levels of ALK7 transcript were associated with poor prognosis. Patients with lower expression of ALK7 also had shorter survival. Overexpression of ALK7 reduced proliferation and adhesion of breast cancer cells in vitro. We found that overexpressed ALK7 had complex effects on the MCF-7 cell sensitivity to chemotherapy drugs. CONCLUSION: Decreased expression of ALK7 in breast cancer is correlated with poor prognosis. ALK7 is a negative regulator of adhesion and proliferation of breast cancer cells. This suggests that ALK7 is a potential tumor suppressor in breast cancer. PMID- 28668834 TI - Effects of Pulsed Electromagnetic Fields on Breast Cancer Cell Line MCF 7 Using Absorption Spectroscopy. AB - We present an analysis of the effects of pulsed electromagnetic fields (PEMF) with 3.3 MHz carrier frequency and modulated by audio resonant frequencies on the MCF-7 breast cancer cell line in vitro using absorption spectroscopy. This involves a fluorescence dye called PrestoBlueTM Cell Viability Reagent and a spectrophotometry to test the viability of MCF-7 breast cancer cells under different PEMF treatment conditions in terms of the cell absorption values. The DNA molecule of the MCF-7 breast cancer cells has an electric dipole property that renders it sensitive and reactive to applied electromagnetic fields. Resonant frequencies derived from four genes mutated in MCF-7 breast cancer cells [rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR), peroxisome proliferator-activated receptor (PPARG), Nijmegen breakage syndrome 1 (NBN) and checkpoint kinase 2 (CHEK2)] were applied in generating square pulsed electromagnetic waves. Effects were monitored through measurement of absorption of the samples with PrestoBlueTM, and the significance of the treatment was determined using the t-test. There was a significant effect on MCF-7 cells after treatment with PEMF at the resonant frequencies of the following genes for specific durations of exposure: RICTOR for 10 min, PPARG for 10 min, NBN for 15 min, and CHEK2 for 5 min. PMID- 28668832 TI - Imaging the Role of Multinucleate Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in Peritoneal Metastasis in Mouse Models. AB - BACKGROUND/AIM: The interaction between pancreatic-cancer cells and stromal cells in the tumor microenvironment (TME) is of particular importance in cancer progression and metastasis. The present report demonstrates the role of cancer associated fibroblasts (CAFs) and multinucleate pancreatic-cancer cells in peritoneal metastasis. MATERIALS AND METHODS: An orthotopic mouse model of pancreatic cancer was established with the human pancreatic cancer cell line BxPC3, which stably expresses green fluorescent protein (GFP). RESULTS: BxPC3-GFP cells formed peritoneal metastases by week 18 after orthotopic implantation. Using an Olympus FV1000 confocal microscope, multi-nucleated cancer cells were frequently observed in the peritoneal metastases. The primary pancreatic tumor and peritoneal-metastases were harvested, cultured and then transplanted subcutaneously. Subcutaneous tumors established from peritoneal-metastatic cells were larger than subcutaneous tumors established from primary-tumor cells. Subcutaneous tumors of each type were subsequently cultured in vitro. CAFs were observed growing out from the tumors established from peritoneal-metastatic cells, but not the tumors established from the primary cancer. CONCLUSION: The results of the present study suggest that multi-nucleated cancer cells and CAFs were related to peritoneal metastasis of pancreatic cancer. PMID- 28668835 TI - Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas. AB - BACKGROUND/AIM: Tumor-associated macrophages (TAMs), together with splenic CD11b+ cells, help maintain the tumor microenvironment. The immunomodulatory compound imiquimod (IQM) stimulates innate immune cells, including macrophages, to induce antitumor effects. In order to elucidate the effects of IQM on the tumor microenvironment, we investigated the immunomodulatory effect of IQM during melanoma growth by using the B16F10 melanoma model. MATERIALS AND METHODS: To elucidate the immunomodulatory effects of IQM on the tumor microenvironment, we isolated CD11b+ TAMs and splenic CD11b+ cells and evaluated the immunomodulatory effects of IQM, using the B16F10 melanoma model. RESULTS: IQM suppressed B16F10 melanoma growth in parallel with reduction of Foxp3+ regulatory T cells (Tregs) at the tumor site, caused by the down-regulation of CCL22 production by tumor derived and splenic CD11b+ cells. Subsequently, we investigated the antitumor or tumor-loading effects of splenic CD11b+ cells on B16F10 melanoma growth in vivo. B16F10 melanoma growth was accelerated by splenic CD11b+ cells from untreated mice, but was inhibited by splenic CD11b+ cells from IQM-treated mice. Consistent with these results, Foxp3+ Tregs were significantly decreased in tumors of mice implanted with both melanoma and splenic CD11b+ cells from topical IQM-treated mice. Furthermore, intratumoral administration of anti-CCL22 antibody inhibited B16F10 melanoma growth by decreasing Treg recruitment at the tumor site. CONCLUSION: Our results suggest a possible mechanism for the antitumor immune response induced by IQM through tumor-associated macrophages. PMID- 28668836 TI - MicroRNA Profiling and Target Genes Related to Metastasis of Salivary Adenoid Cystic Carcinoma. AB - BACKGROUND/AIM: Perineural invasion and distant metastasis lead to a poor prognosis of adenoid cystic carcinoma and there is no effective therapy available. MicroRNAs (miRNAs) are small non-coding RNAs that regulate target gene expression, which can be biomarkers or therapeutic targets for certain cancer types. We aimed to identify miRNAs and their target genes possibly involved in metastasis of salivary gland adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: Using Nanostring nCounter analysis, we examined miRNA expression in two SACC cell lines: SACC-83 and SACC-LM, with low and high lung metastasis rates, respectively. We then verified the differentially expressed miRNAs with real-time polymerase chain reaction in the cell lines and in tumor samples from patients with SACC. miRNA target-gene expression was also analyzed. RESULTS: SACC-83 showed higher gene expression of miR-130a, miR-342, and miR-205; SACC-LM showed higher gene expression of miR-99a and miR-155. In human tissue, miR-205 was highly expressed in the primary SACC, while miR-155 and miR-342 were highly expressed in recurrent SACC. Six predicted target genes of miRNA-155 and miR-99a linked to tumorigenesis were further analyzed and RNA expression of ubiquitin like modifier activating enzyme 2 (UBA2) was higher in SACC than normal salivary gland tissue, and higher in primary compared to recurrent SACC (p<0.05). RNA expression of retinoic acid receptors (RARS) was higher in tissue from primary than recurrent SACC and normal salivary gland (p<0.05), but that in recurrent SACC was not significantly higher than normal salivary gland tissue. RNA expression of minichromosome maintenance 8 homologous recombination repair factor (MCM8) and 24-dehydrocholesterol reductase (DHCR24) was higher in primary SACC than normal salivary gland tissue (p<0.05). CONCLUSION: miR-99a, miR-155, miR 130a, miR-342, and miR-205 may play a role in metastasis of SACC. MiR-155 may be involved in SACC metastasis through UBA2 pathways, and UBA2 may function as a biomarker/mediator of SACC metastasis. PMID- 28668837 TI - Distribution and Metabolism of LipocurcTM (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance. AB - BACKGROUND/AIM: The aim of this study was to investigate the distribution of curcumin (in the form of LipocurcTM) and its major metabolite tetrahydrocurcumin (THC) in Beagle dog and human red blood cells, peripheral blood mononuclear cells (PBMC) and hepatocytes. MATERIALS AND METHODS: LipocurcTM was used as the source of curcumin for the cell distribution assays. In vitro findings with red blood cells were also compared to in vivo pharmacokinetic data available from preclinical studies in dogs and phase I clinical studies in humans. RESULTS: High levels of curcumin were measured in PBMCs (625.5 ng/g w.w. cell pellet or 7,297 pg/106 cells in dog and 353.7 ng/g w.w. cell pellet or 6,809 pg/106 cells in human) and in hepatocytes (414.5 ng/g w.w. cell pellet or 14,005 pg/106 cells in dog and 813.5 ng/g w.w. cell pellet or 13,780 pg/106 cells in human). Lower curcumin levels were measured in red blood cells (dog: 78.4 ng/g w.w. cell pellet or 7.2 pg/106 cells, human: 201.5 ng/g w.w. cell pellet or 18.6 pg/106 cells). A decrease in the medium concentration of curcumin was observed in red blood cells and hepatocytes, but not in PBMCs. Red blood cell levels of THC were ~5-fold higher in dog compared to human and similar between dog and human for hepatocytes and PBMCs. The ratio of THC to curcumin found in the red blood cell medium following incubation was 6.3 for dog compared to 0.006 for human, while for PBMCs and hepatocytes the ratio of THC to curcumin in the medium did not display such marked species differences. CONCLUSION: There was an excellent correlation between the in vitro disposition of curcumin and THC following incubation with red blood cells and in vivo plasma levels of curcumin and THC in dog and human following intravenous infusion. The disposition of curcumin in blood cells is, therefore, species-dependent and of pharmacokinetic relevance. PMID- 28668838 TI - Down-regulation of the Tumor Suppressor CYLD Enhances the Transformed Phenotype of Human Breast Cancer Cells. AB - BACKGROUND/AIM: The cylindromatosis tumor suppressor (CYLD) has been implicated in the inhibition of human breast cancer development by virtue of the poor prognosis of patients with down-regulated CYLD expression. In order to investigate the mechanism of breast cancer suppression by CYLD, in the present study, cellular and molecular aspects of CYLD-dependent phenotypic regulation of different types of human breast cancer cell lines were analyzed. MATERIALS AND METHODS: CYLD expression was down-regulated by RNA interference in human breast cancer cell lines. Parental and CYLD-deficient cell lines were evaluated for their viability, migratory capacity, anchorage-independent growth and chemoresistance. Wild-type and mutated forms of CYLD were also evaluated for their ability to suppress the clonogenic potential of breast cancer cells. RESULTS: CYLD down-regulation enhanced the survival and migratory properties of basal and luminal breast cancer cell lines. In addition, down-regulation of CYLD expression enhanced the ability of human breast cancer cells to grow in an anchorage-independent manner and could be associated with resistance to chemotherapeutic drugs. The growth-suppressive properties of CYLD on breast cancer cell lines were dependent on its de-ubiquitinating activity and its amino terminal cytoskeleton-interacting region. CONCLUSION: Our results establish a broad range of tumor-suppressive properties that are conferred by CYLD in basal and luminal human breast cancer cells and support the significance of targeted de ubiquitination by CYLD in breast cancer cell growth suppression. PMID- 28668839 TI - Evaluation of Natriuretic Peptide in Non-small Cell Lung Cancer Patients Treated with Bevacizumab Together with Carboplatin-Paclitaxel: A Prospective Study. AB - AIM: To identify predictive markers for efficacy of combination bevacizumab and carboplatin-paclitaxel treatment in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty patients received carboplatin (area under the concentration-time curve (AUC) 6 mg/ml*min) and paclitaxel (200 mg/m2) with bevacizumab (15 mg/kg) on day 1 of a 21-day cycle. After four cycles of induction therapy, patients received bevacizumab maintenance therapy until disease progression or unacceptable toxicity occurred. Plasma and serum samples (baseline, day 8 and before cycle 2) were analyzed for natriuretic peptide content. RESULTS: Plasma brain natriuretic peptide (BNP) levels were significantly decreased at day 8 (20.1+/-4.0 pg/ml vs. 9.1+/-1.8 pg/ml, p=0.0002). Patients whose plasma BNP level was reduced to <50% of the baseline at day 8 had a longer progression-free survival (PFS) than those with a less decrease (9.73 versus 2.63 months, p=0.00013). In multivariate Cox analysis, decrease of plasma BNP concentration was associated with a longer PFS (p=0.0022). CONCLUSION: Decrease of plasma BNP concentration correlated with PFS after a treatment of combination bevacizumab plus carboplatin-paclitaxel. PMID- 28668840 TI - In Vitro Apoptosis Induction by Fenofibrate in Lymphoma and Multiple Myeloma. AB - BACKGROUND/AIM: Recent innovations in the treatment of multiple myeloma have enriched our therapeutic repertoire regarding the treatment of multiple myeloma during the last decades. However, despite today's therapies many multiple myeloma (MM) patients experience relapse of disease and eventually remain incurable. Wnt/beta-catenin signaling has been demonstrated in lymphoma and MM, rendering related signaling molecules promising therapeutic targets. Fenofibrate, an extensively scrutinized and widely used drug for primary hypercholesterolemia or mixed dyslipidemia, has proven anticarcinogenic properties mediated by peroxisome proliferator-activated receptor-alpha (PPARalpha) agonism, thereby also influencing WNT-associated signaling molecules. MATERIALS AND METHODS: The antitumor apoptotic effect of fenofibrate at doses ranging from 0.1-200 MUM was investigated on a total of seven human, two murine myeloma/lymphoma cell lines and two healthy control cell lines, as determined by 3'3-Dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry. RESULTS: Fenofibrate significantly reduced viability due to apoptosis induction in all investigated myeloma and lymphoma cell lines in a dose-dependent manner, whereas healthy control cells were less sensitive. CONCLUSION: Our results provide a rationale for future in vitro and in vivo studies with fenofibrate as a safe and well-tolerated agent in MM and lymphoma treatment. PMID- 28668841 TI - Itraconazole Modulates Hedgehog, WNT/beta-catenin, as well as Akt Signalling, and Inhibits Proliferation of Cervical Cancer Cells. AB - BACKGROUND/AIM: Repurposing itraconazole as an anticancer agent has been evaluated in several studies. The present study investigated whether itraconazole exerts an anticancer effect on cervical cancer cells. MATERIALS AND METHODS: CaSki and HeLa cells were cultured in itraconazole and vehicle after which colony forming and cell viability assays were performed. Transcription and protein expression were assessed by cDNA microarray analysis and immunoblotting, respectively. RESULTS: Itraconazole suppressed proliferation of CaSki and HeLa cells in a dose- and time-dependent manner. Furthermore, CaSki cells were more significantly affected by itraconazole than HeLa cells. The microarray analysis showed an 8-fold down-regulation in the expression of GLI1, WNT4 and WNT10A among itraconazole-treated CaSki cells. Moreover, the transcription of sterol carrier protein-2 and ATP-binding cassette transporter-1 was unaffected by itraconazole. Immunoblots showed suppression in beta-catenin expression and Akt phosphorylation. CONCLUSION: Itraconazole is a multi-targeting anticancer agent and a promising therapeutic agent for cervical cancer. PMID- 28668842 TI - Diagnostic Value of Systemic Cholesteryl Ester/Free Cholesterol Ratio in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) most commonly occurs in the setting of liver cirrhosis which is characterized by low serum lipids. We hypothesized that composition of lipoproteins and consequently lipid species ratios are mostly unchanged in patients with cirrhosis compared to controls. This approach may be appropriate to identify lipid ratios altered in HCC irrespective of liver dysfunction. PATIENTS AND METHODS: Lipids were measured in serum of 21 patients with HCC, 41 patients with liver cirrhosis and 22 controls. Ratios of lipids known to be changed in HCC tissues were calculated. RESULTS: Ratios of polyunsaturated to mono-unsaturated lysophosphatidylcholine, ceramide/sphingomyelin and cholesteryl ester/free cholesterol were changed in HCC compared to both control cohorts. The latter was most suited to diagnosing HCC. Systemic ratios of these lipid classes were not associated with fibrosis, staging or grade in patients with HCC. CONCLUSION: The cholesteryl ester/free cholesterol ratio is comparable in controls and patients with cirrhosis, but is specifically increased in patients with HCC. PMID- 28668843 TI - The Diagnostic Significance of Serum Alcohol Dehydrogenase Isoenzymes and Aldehyde Dehydrogenase Activity in Urinary Bladder Cancer Patients. AB - BACKGROUND: The aim of this study was to investigate a potential role of alcohol dehydrogenase and aldehyde dehydrogenase as tumor markers for urinary bladder cancer. MATERIALS AND METHODS: Serum samples were obtained from 41 patients with bladder cancer and 52 healthy individuals. Class III and IV of ADH and total ADH activity were measured by the photometric method. For measurement of class I and II ADH and ALDH activity, the fluorometric method was employed. RESULTS: Significantly higher total activity of ADH was found in sera of both, low-grade and high-grade bladder cancer patients. The diagnostic sensitivity for total ADH activity was 81.5%, specificity 98.1%, positive (PPV) and negative (NPV) predictive values were 97.4% and 92.3% respectively. Area under ROC curve for total ADH activity was 0.848. CONCLUSION: A potential role of total ADH activity as a marker for bladder cancer, is herein proposed. PMID- 28668844 TI - The Effect of Afatinib Treatment in Non-small Cell Lung Cancer Cells. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is a very aggressive and histologically heterogeneous type of lung cancer. The main problem in the treatment of NSCLC is chemoresistance and metastasis. Compared to other malignant tumors, many molecular mechanisms are dysfunctional in NSCLC. Epidermal growth factor receptor (EGFR) is one of the most frequently mutated genes in NSCLC. MATERIALS AND METHODS: We investigated the effect of afatinib the against A549 NSCLC cell line, because it is active against mutated EGFR. Moreover, we aimed to investigate the mRNA level of HSPA5 (one of the heat shock proteins that can contribute in the down-regulation of the EGF-signaling pathway) before and after afatinib treatment. RESULTS: Afatinib treatment induced apoptosis and decreased levels of HSPA5 mRNA in cancer cells. CONCLUSION: Advanced analysis, might be helpful in understanding the mechanisms of relations between tyrosine kinase inhibition of EGFR and HSPA5 in lung cancer cells. PMID- 28668845 TI - Correlation Between Thrombospondin-1 Expression in Non-cancer Tissue and Gastric Carcinogenesis. AB - BACKGROUND/AIM: Thrombospondin-1 (TSP1) is correlated with carcinogenesis occurring in cases of intestinal inflammation. The aim of this study was to clarify the role of TSP1 in gastric carcinogenesis. MATERIALS AND METHODS: A total of 39 patients with gastric cancer who had undergone gastrectomy were enrolled. The expression of TSP1 mRNA in non-cancer tissues was determined. Furthermore, the expression of CD36, STAT3 and TGFbetaR2 mRNA in non-cancer tissues in two expression groups, the TSP1 high- and low-expression groups, were examined. RESULTS: The expression of TSP1 was high in the mucosal-atrophy group and tended to be high in the Helicobacter pylori (H. pylori) (+) and multiple cancer groups. The levels of CD36, STAT3 and TGFbetaR2 mRNA were significantly higher in the TSP1-high group. TSP1 signaling pathway was induced in multiple cancer or atrophy (+) or H. pylori (+) compared to cases with single cancer, atrophy (-) and H. pylori (-). Expression of proteins involved in the TSP1 signaling pathway in non-cancer tissues with multiple gastric cancers were higher than that with single gastric cancer. CONCLUSION: Expression of TSP1 in non cancer tissue correlated with gastric carcinogenesis. PMID- 28668846 TI - Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility. AB - BACKGROUND/AIM: Inhibitory effects of extracellular nucleotides have been investigated in many types of cancers. Herein, we aimed to determine the effects of ATP and adenosine and their receptor profile on cholangiocarcinoma (CCA) cells. MATERIALS AND METHODS: Two CCA and one immortalized cholangiocyte cell line were used. The effects of ATP and adenosine on cell proliferation and motility were examined by MTT and wound-healing/trans-well invasion assays, respectively. Purinergic receptor profiling was carried out by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: ATP and adenosine induced proliferation-inhibitory and motility-inhibitory effects in all cell lines tested. However, immortalized cholangiocytes showed resistance in proliferation inhibition. Several P2 receptors were commonly expressed in all cells, whereas no adenosine receptor was expressed. Furthermore, no synergistic effects of ATP and adenosine were observed in CCA cells. CONCLUSION: ATP and adenosine had anti-proliferative and anti-motility effects in CCA cells, while there was a smaller effect on normal cholangiocytes. These data indicate the potential use of ATP and odenosine as a novel therapy for CCA. PMID- 28668847 TI - The Contribution of MMP-8 Promoter Polymorphisms in Lung Cancer. AB - BACKGROUND/AIM: Accumulated evidence has supported the hypothesis that the functional polymorphisms of matrix metalloproteinases (MMP) were associated with the risk of various types of cancer. However, few reports have studied the contribution of MMP-8 genotypes to either diagnostic or prognostic potential in lung cancer. In this study, we focused on the contribution of a polymorphism in the promoter region of MMP-8 (C-799T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to lung cancer risk. PATIENTS AND METHODS: Genomic DNA was isolated from peripheral blood of 358 patients with lung cancer and 716 non cancer healthy individuals. MMP-8 C-799T (rs11225395), Val436Ala (rs34009635) and Lys460Thr (rs35866072) polymorphic genotypes of each subject were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). RESULTS: The results showed that the three polymorphisms were not significantly associated with increased risk of lung cancer in the overall investigated population. Furthermore, when the analyses were stratified according to age, sex, status of smoking and drinking, pack-years of smoking and family history of lung cancer, there was also no significant association between these genotypes and increased lung cancer risk. CONCLUSION: The polymorphisms MMP-8 C 799T, Val436Ala and Lys460Thr may not play a major role in mediating personal susceptibility to lung cancer in Taiwan. PMID- 28668848 TI - A Novel Small-molecule WNT Inhibitor, IC-2, Has the Potential to Suppress Liver Cancer Stem Cells. AB - BACKGROUND/AIM: The presence of cancer stem cells (CSCs) contributes to metastasis, recurrence, and resistance to chemo/radiotherapy in hepatocellular carcinoma (HCC). The WNT signaling pathway is reportedly linked to the maintenance of stemness of CSCs. In the present study, in order to eliminate liver CSCs and improve the prognosis of patients with HCC, we explored whether small-molecule compounds targeting WNT signaling pathway suppress liver CSCs. MATERIALS AND METHODS: The screening was performed using cell proliferation assay and reporter assay. We next investigated whether these compounds suppress liver CSC properties by using flow cytometric analysis and sphere-formation assays. A mouse xenograft model transplanted with CD44-positive HuH7 cells was used to examine the in vivo antitumor effect of IC-2. RESULTS: In HuH7 human HCC cells, 10 small-molecule compounds including novel derivatives, IC-2 and PN-3-13, suppressed cell viability and WNT signaling activity. Among them, IC-2 significantly reduced the CD44-positive population, also known as liver CSCs, and dramatically reduced the sphere-forming ability of both CD44-positive and CD44 negative HuH7 cells. Moreover, CSC marker-positive populations, namely CD90 positive HLF cells, CD133-positive HepG2 cells, and epithelial cell adhesion molecule-positive cells, were also reduced by IC-2 treatment. Finally, suppressive effects of IC-2 on liver CSCs were also observed in a xenograft model using CD44-positive HuH7 cells. CONCLUSION: The novel derivative of small molecule WNT inhibitor, IC-2, has the potential to suppress liver CSCs and can serve as a promising therapeutic agent to improve the prognosis of patients with HCC. PMID- 28668849 TI - Impact of Physical Training on Sex Hormones and Their Receptors During N-Methyl-N nitrosourea-induced Carcinogenesis in Rats. AB - BACKGROUND/AIM: The risk of breast cancer is related to duration of exposure to sex hormones, especially estrogen. The aim of this study was to assess the impact of physical training (PT) on estrogen and progesterone levels and expression of their receptors during carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in rats. MATERIALS AND METHODS: Fifty female Sprague-Dawley rats were intraperitoneally administered MNU and divided into four groups: low-, moderate-, and high-intensity PT, and no PT (control). Plasma levels of sex hormones and tissue expression of their receptors were quantified and statistically analyzed. RESULTS: In the group of rats subjected to PT, a significantly higher progesterone level was observed. The highest progesterone level was noted in the low-intensity PT group. An increase in apoptosis of MNU-induced tumor cells was also demonstrated in the PT groups. CONCLUSION: PT stimulates apoptosis of tumor cells without an increase in their proliferative activity. The increase in apoptosis of tumor cells correlates positively with the progesterone level. PMID- 28668850 TI - Nimotuzumab Inhibits Cholangiocarcinoma Cell Metastasis via Suppression of the Epithelial-Mesenchymal Transition Process. AB - BACKGROUND/AIM: Changes in epidermal growth factor receptor (EGFR) are commonly found in cancer progression, signaling a poor outcome in patients. In the present study, we aimed to investigate whether nimotuzumab could be of benefit for cholangiocarcinoma (CCA) treatment. MATERIALS AND METHODS: The expression of EGFR was explored using immunohistochemical staining in cases divided into groups with low and high expression. The effect of nimotuzumab on CCA cell growth, metastasis and the molecular mechanisms by which nimotuzumab inhibits CCA cell metastasis were evaluated. RESULTS: The expression of EGFR was high in 55% of patients with CCA. This was significantly correlated with a shorter survival of patients. CCA cells treated with nimotuzumab showed inhibited cell growth. Moreover, nimotuzumab inhibited CCA cell metastasis via induction of E-cadherin and suppression of zinc finger protein SNAI1 (SNAIL1), vimentin and matrix metalloproteinase 9 (MMP9) expression. CONCLUSION: Nimotuzumab appears to inhibit cell metastasis via suppression of the epithelial-mesenchymal transition process. Therefore, nimotuzumab should be considered as a potential therapeutic agent against CCA. PMID- 28668851 TI - A Tumor-targeting Adenovirus with High Gene-transduction Efficiency for Primary Pancreatic Cancer and Ascites Cells. AB - BACKGROUND: Optimizing targeting strategies for vectors in order to enhance antitumor activity and secure patient safety is important for cancer gene therapy. We previously identified two pancreatic cancer-targeting ligands (PFWSGAV: PFW and SYENFSA: SYE) by screening an adenovirus library in vivo and in vitro, respectively. MATERIALS AND METHODS: To examine clinical usefulness, we assessed gene-transduction efficiency using surgically-resected pancreatic cancer specimens and ascites cells. RESULTS: For surgical specimens, vectors displaying PFW and SYE improved transduction efficiency by 4.4- and 4.3-fold, respectively. The SYE-displaying vector was >2-fold more efficient for all seven cases, whereas the PFW-displaying vector increased efficiency in two out of four cases. For ascites samples, both vectors increased gene-transduction efficiency of epithelial cell adhesion molecule (EpCAM)-positive ascites cells by >2-fold in two out of five cases. CONCLUSION: Both vectors enhanced adenovirus infectivity of pancreatic cancer cells and have potential for gene therapy of pancreatic cancer; therefore they should be further evaluated in clinical studies. PMID- 28668852 TI - Sphingosine-1-Phosphate-Receptor 1 as a Marker for Endothelial Cells in Mouse Xenograft Models of Human Cancer. AB - BACKGROUND/AIM: The sphingosine-1-phosphate (S1P) 1 receptor (S1P1R) is an important receptor for the modulation of endothelial cell function. We, therefore, wanted to investigate its expression as a blood vessel marker. MATERIALS AND METHODS: The expression of the S1P receptor 1 (S1P1R) in mouse blood vessel endothelium was investigated immunohistochemically in normal blood vessel endothelium and blood vessel endothelium of xenografted human tumors. RESULTS: The S1P1 receptor was expressed in the endothelium of most mouse organs. Endothelia of the intestinal tract and of adipose tissue showed the strongest immunoreactivity. However, a difference in staining between larger vessels and fenestrated endothelium was observed, whereas fenestrated endothelium expressed a weaker staining. In addition to normal endothelia, most tumor blood vessel endothelia expressed S1P1R. A particularly strong expression in the endothelium was detected in primary pancreatic and prostate cancer xenografts. In both xenograft tumor entities, no significant difference in staining intensities of the endothelium between arteries, veins and capillaries was observed. CONCLUSION: As S1P1R is expressed in most blood vessel endothelia and in the tumor blood vessel endothelia, it is an ideal blood vessel marker. PMID- 28668853 TI - Neocarzinostatin, Aptamer Conjugates for Targeting EpCAM-positive Tumor Cells. AB - BACKGROUND/AIM: The aim of this study was to investigate the role of Neocarzinostatin (NCS) conjugated with epithelial cell adhesion molecule (EpCAM) aptamer in EpCAM-positive cancer cells. NCS is an antitumor antibiotic protein chromophore that has the ability to cleave double stranded DNA and can be used as a potential drug for the treatment of EpCAM-positive cancers. EpCAM aptamer is an oligonucleotide ligand that binds specifically to EpCAM, a protein overexpressed in tumor cells. MATERIALS AND METHODS: NCS was conjugated with EpCAM aptamer using Sulfo-Succinimidyl 6-(3-(2-pyridyldithio) - propionamide hexanoate) LC (SPDP) cross-linker to deliver it to EpCAM-positive tumor cells. The conjugates were characterized using polyacrylamide gel electrophoresis (PAGE) and high performance liquid chromatography (HPLC). Flow cytometry was used to study the binding efficiency of the aptamer and the conjugates in cancer cells. The effect of the conjugate on cancer cells was studied using propidium iodide (PI) to analyze the cell cycle phase changes. The apoptosis assay was performed using the IC50 concentration of NCS. Microarrays were performed to study the gene level changes in cancer cells upon treatment with NCS and the conjugate. RESULTS: Flow cytometry revealed significant binding of aptamer and conjugate in the MCF-7 and WERI-Rb1 cell lines. Briefly, 62% in MCF and 30% in WERI-Rb1 cells with conjugate treated cells (p<0.005). The cell-cycle analysis indicated G2 phase arrest in MCF 7 cells and S phase arrest in WERI-Rb1 cells (p<0.005). Microarray analysis showed differentially expressed genes involved in cell cycle, DNA damage, and apoptosis. The BrDU assay and the apoptosis assay showed that the expression of BrDU was reduced in conjugate-treated cells and the PARP levels were increased confirming the double stranded DNA breaks (p<0.005). In MCF-7 and WERI-Rb1 cells, most of the cells underwent necrosis (p<0.005). CONCLUSION: The EpCAM aptamer conjugated NCS showed specificity to EpCAM-positive cells. The effect of the conjugates on cancer cells were impressive as the conjugate arrested the cell cycle and promoted apoptosis and necrosis. The high levels of PARP expression confirmed the DNA breaks upon conjugate treatment. Our study demonstrates that the NCS conjugated with EpCAM can be targeted to cancer cells sparing normal cells. PMID- 28668854 TI - PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade. AB - BACKGROUND/AIM: Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells. MATERIALS AND METHODS: In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR+ cells and VCaP cells (representing CRPC), PCA3 was silenced using siRNA oligonucleotides. Gene expression and cell viability was assessed in PCA3 silenced and/or AR-blocked cells. RESULTS: PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR+ cells. Furthermore, PCA3 silencing sensitized PCa cells to enzalutamide-induced loss of cell growth. CONCLUSION: PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists. PMID- 28668855 TI - Slow-release L-Cysteine (Acetium(r)) Lozenge Is an Effective New Method in Smoking Cessation. A Randomized, Double-blind, Placebo-controlled Intervention. AB - BACKGROUND/AIM: Because of the major health problems and annual economic burden caused by cigarette smoking, effective new tools for smoking intervention are urgently needed. Our previous randomized controlled trial (RCT) provided promising results on the efficacy of slow-release L-cysteine lozenge in smoking intervention, but the study was not adequately powered. To confirm in an adequately-powered study the results of the previous RCT implicating that effective elimination of acetaldehyde in saliva by slow-release L-cysteine (Acetium(r) lozenge, Biohit Oyj, Helsinki), would assist in smoking cessation by reducing acetaldehyde-enhanced nicotine addiction. On this matter, we undertook a double-blind, randomized, placebo-controlled trial comparing Acetium(r) lozenge and placebo in smoking intervention. MATERIALS AND METHODS: A cohort of 1,998 cigarette smokers were randomly allocated to intervention (n=996) and placebo arms (n=1,002). At baseline, smoking history was recorded by a questionnaire, with nicotine dependence testing according to the Fagerstrom scale (FTND). The subjects used smoking diary recording the daily numbers of cigarettes, lozenges and subjective sensations of smoking. The data were analysed separately for point prevalence of abstinence (PPA) and prolonged abstinence (PA) endpoints. RESULTS: Altogether, 753 study subjects completed the trial per protocol (PP), 944 with violations (mITT), and the rest (n=301) were lost to follow-up (LTF). During the 6-month intervention, 331 subjects stopped smoking; 181 (18.2%) in the intervention arm and 150 (15.0%) in the placebo arm (OR=1.43; 95%CI=1.09-1.88); p=0.010). In the PP group, 170 (45.3%) quitted smoking in the intervention arm compared to 134 (35.4%) in the placebo arm (OR=1.51, 95%CI=1.12-2.02; p=0.006). In multivariate (Poisson regression) model, decreased level of smoking pleasure (p=0.010) and "smoking sensations changed" were powerful independent predictors of quit events (IRR=12.01; 95%CI=1.5-95.6). CONCLUSION: Acetium(r) lozenge, herein confirmed in an adequately powered study to be an effective means to aid smoking quit, represents a major breakthrough in the development of smoking intervention methods, because slow-release L-cysteine is non-toxic, with no side effects or limitations of use. PMID- 28668856 TI - Cancer Antigen 72-4 for the Monitoring of Advanced Tumors of the Gastrointestinal Tract, Lung, Breast and Ovaries. AB - BACKGROUND: Cancer antigen CA72-4 is a tumor marker found to be elevated in a variety of human adenocarcinomas. Using the DRG TM-CA72-4, we quantified the elevation of CA72-4 compared to current United States Food And Drug Administration-approved tumor markers in various cancer types. MATERIALS AND METHODS: We conducted a prospective, single-center study enrolling 96 patients between March 2013 and August 2016 with different locally advanced, unresectable or metastatic cancer known to express CA72-4. Quantification of CA72-4 was performed according to the manufacturer's instructions using the DRG TM-CA72-4 enzyme-linked immunosorbent assay kit and the positivity rates were calculated. RESULTS: CA72-4 expression varied with tumoral site of origin, with the highest positivity rates found in pancreatic and ovarian malignancies. Correlation with clinical activity was also noted in some patients. CONCLUSION: CA72-4 may have a potential role as an adjunct to conventional biomarkers in disease monitoring of pancreatic, ovarian and colorectal carcinomas. PMID- 28668857 TI - Self-Efficacy for Coping with Cancer Enhances the Effect of Reiki Treatments During the Pre-Surgery Phase of Breast Cancer Patients. AB - BACKGROUND/AIM: Self-efficacy for coping with cancer plays a critical role in influencing psychological cancer-related outcomes, some studies suggested its role in enhancing or reducing the effects of psychological interventions in cancer patients. Reiki has recently been included among the efficacious complementary therapeutic intervention for cancer patients. PATIENTS AND METHODS: The present study evaluated the role of self-efficacy for coping with cancer as buffer of the Reiki treatment effects on cancer-related symptoms in a randomized controlled trial (intervention versus control group) of breast cancer patients (N=110) during the pre-surgery phase. RESULTS: Results showed that self-efficacy for coping with cancer can influence the effect of a Reiki treatment. Higher efficacious patients showed a more powerful effect of the Reiki intervention on both anxiety and mood than the low efficacious patients. CONCLUSION: From a practical perspective, the study provides insightful results for healthcare professionals. PMID- 28668858 TI - Evaluation of Bone Turnover / Quality Markers and Bone Mineral Density in Prostate Cancer Patients Receiving Androgen Deprivation Therapy with or without Denosumab. AB - BACKGROUND/AIM: Androgen deprivation therapy (ADT) is a mainstay therapy for prostate cancer (PCa). ADT induces bone loss and increases the risk of osteoporosis and fractures. Recently, loss of bone quality has received attention as a factor that causes loss of bone strength independent of bone mineral density (BMD). Pentosidine has been identified as a surrogate marker of bone quality. Therefore, bone quality markers were evaluated retrospectively in PCa patients receiving ADT with or without denosumab. PATIENTS AND METHODS: This study included 46 PCa patients. Twenty patients received denosumab. We measured pentosidine as bone quality marker and TRACP-5b as bone turnover marker. Pre- and 12-month BMD was measured in the lumbar spine and femoral neck. RESULTS: In the denosumab group (D+), BMD at the lumbar spine was increased by 6.7% compared with the group that did not receive denosumab (D-) at 12 months (p=0.0015). BMD at the femoral neck was increased by 3.1% at 12 months (p=0.0076). The mean value of TRAP-5b was lower in the D+ group than the D- group at 12 months (p<0.001). The mean serum levels of pentosidine in the D+ group were decreased by -39.6% compared with the D- group at 12 months (p=0.0036). CONCLUSION: Denosumab increased BMD during ADT for PCa and inhibited the increasing levels of serum pentosidine in PCa patients undergoing ADT. PMID- 28668860 TI - Gastrocutaneous Fistula in a Patient with Locally Recurrent MSI-High Colorectal Cancer: Local Complications Arising from Therapeutic Response to Immune Checkpoint Blockade. AB - Colorectal cancers with high microsatellite instability (MSI-H) have distinct clinical features in terms of their prognosis, recurrence patterns, and sensitivity to immunotherapeutic agents. We present the case of a woman with a left-sided MSI-H colon cancer who had repeated recurrences concentrated exclusively in the left upper quadrant of the abdomen, including gastric involvement. Despite multiple surgical resections, radiation, and several lines of chemotherapy, her disease eventually eroded through the chest wall. Treatment with an immune checkpoint inhibitor produced a rapid clinical response with significant tumor necrosis; however, this necessitated surgical debridement that ultimately led to a large gastrocutaneous fistula. This case highlights the importance of recognizing locoregional tumor-associated complications that may result from robust therapeutic responses to immuno-oncology drugs, which are increasingly being used in clinical practice today. PMID- 28668859 TI - Inflammatory and Nutritional Serum Markers as Predictors of Peri-operative Morbidity and Survival in Ovarian Cancer. AB - AIM: To identify preoperative nutritional and inflammatory markers that predict perioperative outcomes in patients with ovarian cancer (OC). PATIENTS AND METHODS: Fifty patients who underwent primary debulking for advanced (stage III/IV) OC were selected from a cohort of patients who underwent surgery between 2002 and 2009. We analyzed C-reactive protein (CRP), interleukin-6 (IL6) and albumin and their impact on mortality and surgical outcomes. RESULTS: Two patients were excluded since they did not have adequate measurements of CRP and IL6. Among the remaining patients, 25 (52%) were >=70 years old. Nine (19%), 12 (25%) and 12 (25%) patients had low serum albumin (<3.0 g/dl), elevated CRP (>=70 mg/l) and elevated IL6 (>=24 pg/ml), respectively. Age was a significant predictor of non-home discharge (p=0.01). Low serum albumin (<3.0 g/dl) was a predictor of death within 6 month (p=0.03). Elevated CRP (>=70 mg/l) was a predictor of non-home discharge (p=0.02), death within 6 months (p=0.02), death within 12 months (p=0.04), and longer hospital stay (p=0.01). Elevated IL6 (>=24 pg/ml) was a predictor of non-home discharge (p=0.002) and surgical complications (p=0.02), and also associated with longer hospital stay (p=0.03). CONCLUSION: Poor nutrition and high inflammatory status negatively influence surgical and oncological outcomes of patients with OC. These preoperative markers can be used for selection of patients for neoadjuvant chemotherapy at high risk of short survival, non-home discharge and long hospital stay. PMID- 28668861 TI - Prognostic Factors and Recurrence Pattern of Far-advanced Gastric Cancer with Pathologically-positive Para-aortic Lymph Nodes. AB - BACKGROUND: The role of para-aortic lymph node (PALN) dissection for far-advanced gastric cancer is controversial in patients with clinical PALN positivity who have responded to chemotherapy. MATERIALS AND METHODS: We retrospectively analyzed long-term outcomes of patients with pathologically-positive PALNs who underwent radical gastrectomy. RESULTS: The 3- and 5-year overall survival (OS) rates of 65 pathologically PALN-positive patients who underwent PALN dissection (n=704) were 33.8% and 21.2%, respectively. Multivariable analysis revealed the following poor prognostic factors: nodal involvement around the celiac axis (hazard ratio (HR)=4.04, 95% confidence interval (CI)=1.55-9.63), tumor diameter of >=120 mm (HR=3.37; 95% CI=1.18-9.63) and >=3 PALNs involved (HR=2.24; 95% CI=1.21-4.15). Patients with none of these factors survived significantly longer than those with any of these factors (5-year OS=87.5% versus 9.3%, respectively; p<0.001). CONCLUSION: Pathologically PALN-positive patients achieve long survival; however, the indications for PALN dissection should be carefully considered. PMID- 28668862 TI - Clinicopathological Characteristics of Metaplastic Papillary Tumor of the Fallopian Tube. AB - Metaplastic papillary tumor (MPT) of the fallopian tube is a very uncommon lesion, displaying papillary growth of bland-appearing cells with abundant, eosinophilic cytoplasm and mucinous metaplasia. It is difficult for pathologists to determine whether to categorize this lesion as a metaplastic proliferative lesion or a true neoplasm. We recently experienced a case of tubal MPT and initiated a comprehensive review of previously published cases with thorough analysis of clinicopathological characteristics. MPT is typically related to pregnancy, but we describe the first case of pregnancy-unrelated, incidentally detected tubal MPT in a 51-year-old woman who underwent surgery for endometrial cancer. The MPT consisted of small papillary formations with epithelium consisting of nonciliated, columnar cells with abundant eosinophilic cytoplasm arranged as either a single layer or pseudostratified layer. The stroma had a myxoid appearance. Intraluminal and extracellular mucin and floating papillary tufts were observed. Nuclei of the epithelial lining cells were centrally located, rounded or oval, and displayed intranuclear pseudoinclusions or grooves. The MPT cells were positive for paired box 8, epithelial membrane antigen, and cytokeratin. Interestingly, Wilms tumor 1 (WT1) protein was localized within the cytoplasm of MPT cells. Furthermore, the MPT cells did not express phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In summary, MPT of the fallopian tube is a very unusual, distinctive entity displaying unique histopathological features and immunophenotype. Our observation of cytoplasmic WT1 expression and loss of PTEN expression in tubal MPT suggests its neoplastic nature and raises the possibility of WT1 or PTEN involvement in the development of MPT. PMID- 28668863 TI - Phase I Study of Neoadjuvant Chemotherapy with Capecitabine and Oxaliplatin for Locally Advanced Gastric Cancer. AB - AIM: To determine the recommended dose of neoadjuvant chemotherapy of combined capecitabine and oxalipatin (G-XELOX) for locally advanced gastric cancer. PATIENTS AND METHODS: Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1 and capecitabine (2,000 mg/m2/day, b.i.d.) on days 1 14, repeated every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph-node dissection followed by adjuvant therapy with S-1 for 1 year. De escalation of oxaliplatin dose was planned (starting at level 1, oxalipatin 130 mg/m2). RESULTS: Six patients were enrolled. The maximum tolerated dose was not reached at level 1. Oxaliplatin at 130 mg/m2 combined with capecitabine at 2,000 mg/m2/day, b.i.d. had acceptable toxicity. No treatment-related death occurred. Most frequent drug-related adverse events during neoadjuvant G-XELOX were nausea and peripheral sensory neuropathy. One patient declined surgical resection, leaving five undergoing resection with curative intent, of whom four achieved pathological down-staging after neoadjuvant G-XELOX. CONCLUSION: Neoadjuvant G XELOX was feasible in patients with locally advanced gastric cancer. PMID- 28668864 TI - Axitinib for Gemcitabine-refractory Advanced Biliary Tract Cancer: Report of 5 Cases. AB - BACKGROUND/AIM: Vascular endothelial growth factor receptor (VEGFR) has been identified as a treatment target for biliary tract cancer (BTC) and axitinib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3. This study was conducted as a preliminary evaluation of the safety and efficacy of axitinib for patients with advanced BTC. PATIENTS AND METHODS: Patients refractory to gemcitabine-based regimens were administered axitinib at the dose of 5 mg twice daily. RESULTS: Five patients (3 male and 2 female) with a median age of 68 years were enrolled. Although 3 patients developed treatment-related grade 3/4 adverse events (AEs), none of these patients required discontinuation of the protocol treatment due to the AEs. Partial response (PR) was achieved in 1 patient, with a 67% reduction. The response was classified as stable disease (SD) in 3 patients and as progressive disease (PD) in 1 patient. Overall survival (OS) and progression-free survival (PFS) ranged from 2.0 to 19.9 months and 1.5 to 7.4 months, respectively. CONCLUSION: This preliminary study suggested that axitinib is well-tolerated and might exert promising activity in patients with BTC. PMID- 28668865 TI - Combining Abiraterone and Radiotherapy in Prostate Cancer Patients Who Progressed During Abiraterone Therapy. AB - BACKGROUND/AIM: This multicenter, retrospective, 'field-practice' study investigated treatment outcomes of ongoing abiraterone therapy with the addition of radiotherapy (RT) - initiated for oligoprogression or with a palliative intent. PATIENTS AND METHODS: Consecutive patients affected by metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate were considered if they had received RT after the initiation of abiraterone treatment. RESULTS: A total of 32 patients were enrolled in the study. Median duration of abiraterone treatment was 13.0 months (range=3.8-40.9 months). Median duration of abiraterone treatment before RT was 5.9 months (range=0.4-40.0 months), and 7.2 months after RT (range=0.1-29.7 months). Median progression-free survival (PFS) was 12.6 months (95%CI=10.5-14.7) from the initiation of abiraterone treatment. From RT administration, PFS was 9.6 months (95%CI=6.4 12.9). Median overall survival (OS) since abiraterone initiation was 18.9 months (95%CI=4.7-33.0). CONCLUSION: RT prolongs abiraterone treatment in mCRPC patients leading to better clinical outcomes with this molecule. PMID- 28668866 TI - Histology-based Combination Induction Chemotherapy for Elderly Patients with Clinical Stage III Non-small Cell Lung Cancer. AB - AIM: To explore the feasibility and activity of a histology-based induction combination chemotherapy for elderly patients with clinical stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients aged >=70 years with stage IIIA and IIIB lung squamous cell carcinoma (SCC) or adenocarcinoma were treated with three cycles of carboplatin and gemcitabine or pemetrexed, respectively, followed by definitive radiotherapy or surgery. The primary endpoint was the overall response rate (ORR) following induction. RESULTS: Twenty seven patients, with a median age of 74 years (range=70-80 years) were treated for adenocarcinoma in 14 (52%) and SCC in 13 (48%), clinical stage IIIA in eight (30%) and IIIB in 19 (70%). Grade 3 or 4 toxicity was reported for five patients (18.5%). The ORR was 46% in 12 (partial responses) out of 26 assessable patients. CONCLUSION: Histology-based induction combination chemotherapy is active and feasible in elderly patients with stage III NSCLC. PMID- 28668867 TI - Radiosurgery with a Rotating Gamma System: A Very Effective Treatment for Symptomatic Cerebral Cavernomas. AB - AIM: To evaluate the value of radiosurgery with a rotating gamma-system (RGS) for cerebral cavernomas. PATIENTS AND METHODS: Seventy-nine patients with symptomatic cerebral cavernomas underwent RGS radiosurgery at the Bach Mai Hospital, Hanoi, Vietnam. Median dose (single fraction) was 20 Gy (range=14-26 Gy). Endpoints included effect on headache, seizures and tumor size. RESULTS: Of 60 patients with headache, 17% had complete response, 82% partial response and 2% stable disease (best response). Of 39 patients with seizures, 31% had complete response, 64% partial response and 5% stable disease. Four patients developed recurrent seizures after 1 year. Regarding the size of cavernoma at 15 months, complete response was observed in 6%, partial response in 75%, stable disease in 15%, progression in 1% and pseudo-progression in 3% of patients. Bleeding within 2 years after RGS radiosurgery occurred in only five patients (6%). RGS dose had no significant impact on outcomes. CONCLUSION: RGS radiosurgery provided very high rates of symptom relief in patients with cerebral cavernomas. PMID- 28668868 TI - Evaluation of a New Technique for iFOBT Utilising a New Sample Collection Device with Increased Buffer Stability. AB - AIMS: The aims of the present study were: (i) Evaluate specificity and sensitivity of Hb Smart enzyme-linked immunosorbent assay (ELISA) (ScheBo Biotech) compared to colonoscopy results and (ii) assess stability of a new sample collection device containing a newly formulated buffer to extract haemoglobin using buffer and stool samples spiked with defined concentrations of haemoglobin. MATERIALS AND METHODS: Stool samples were quantified with the ELISA method. The stability of haemoglobin in the extraction buffer and in native stool samples, respectively, was determined daily by ELISA during storage for 5 days at 4 degrees C and at room temperature after addition of haemoglobin. RESULTS: Haemoglobin ELISA had a sensitivity of 78.4% for detection of CRC with a specificity of 98%. Haemoglobin extracted in corresponding extraction buffer demonstrated stability throughout storage for 5 days at 4 degrees C and at room temperature. CONCLUSION: Hb Smart represents a very promising tool for large scale screening of CRC with regard to sample handling, stability and analysis of haemoglobin in faeces. PMID- 28668869 TI - Clinical Outcomes of Resectable Esophageal Cancer with Supraclavicular Lymph Node Metastases Treated with Curative Intent. AB - BACKGROUND: In the seventh edition of the Union for International Cancer Control (UICC) TNM classification, supraclavicular lymph node (SCLN) in regard to thoracic esophageal cancer (EC) is regarded as a distant organ, therefore, if resectable, SCLN metastasis is considered a candidate for systemic chemotherapy. The purpose of this study was to clarify the survival outcome in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated with curative intent. PATIENTS AND METHODS: Clinical outcomes in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated by esophagectomy or definitive chemoradiotherapy (dCRT) were retrospectively analyzed. RESULTS: A total of 102 patients were divided in three groups: Surgery with perioperative therapy, n=45; surgery alone, n=19; and dCRT, n=38. Overall, median progression-free survival and median survival time were 9.3 and 26.7 months, respectively. The median survival time was 27.5 months in the group treated with surgery with perioperative treatment, 50.6 months in those treated with surgery alone, and 22 months in the dCRT group. No significant survival difference was seen among the three groups. CONCLUSION: Over 30% of patients with resectable M1LYM treated with curative intent achieved long-term survival. PMID- 28668870 TI - Left Ventricular Ejection Fraction Screening and Clinical Decision-making in Metastatic HER2-positive Breast Cancer. AB - BACKGROUND: Antibodies against human epidermal growth factor receptor 2 (HER2) affect metastatic breast cancer cells and cardiac myocytes. Guidelines recommend evaluation of cardiac ejection fraction (EF) every 3 months despite little supporting evidence for this need. We assessed the impact of EF screening on clinical practice. PATIENTS AND METHODS: We carried out retrospective analysis of patients with HER2-positive metastatic breast cancer receiving HER2-directed therapy to assess the impact of aggressive cardiac screening on management decisions. RESULTS: Data for 128 patients were analyzed. The median number of EF screenings in the first year of therapy was 3 (range=1-8). A total of 29 patients had an asymptomatic decrease in EF. These patients had more EF screenings, more exposure to anthracyclines or left-sided radiation, were more likely to receive a cardiology consult and have an angiotensin converting enzyme inhibitor added to their therapy. Ninety patients underwent aggressive screening; this was not associated with cessation of HER2 therapy (p=0.92). CONCLUSION: Routine EF screening did not have an impact on decisions regarding HER2 therapy in patients with metastatic breast cancer. Given the known benefit of HER2 treatment, reducing the frequency of cardiac screening may be reasonable. PMID- 28668871 TI - The Sentinel Node with Isolated Breast Tumor Cells or Micrometastases. Benefits and Risks of Axillary Dissection. AB - BACKGROUND/AIM: Sentinel lymph node (SLN) biopsy has become the standard procedure to identify metastases in axillary nodes in breast cancer. Even after careful SLN examination additional micrometastases and isolated tumor cells (ITCs) are sometimes found, resulting in a need for delayed axillary lymph node dissection (ALND). This study was undertaken to assess prognostic factors identifying additional axillary lymph node (ALN) metastases at delayed ALND. PATIENTS AND METHODS: To define the impact of late ALND regarding their outcome, 162 breast cancer patients with 169 operated breasts treated between 2010 and 2012 were evaluated, with follow-up through 2016. Data were collected on the patients, histology and biologic profile of the cancer, lymph node involvement, recurrence of breast cancer and adverse effects of ALND. RESULTS: With thorough examination and immunohistochemical stainings twenty-nine of 168 SLN biopsies (28 patients, 17% of the patients) showed micrometastases or ITC, and a full ALND was performed at a later time. During these ALNDs 13 to 31 lymph nodes were removed. Additional ALN metastases were found in three (10%) patients. Two (7%) of the 28 patients with triple-negative cancer deceased of metastatic breast cancer. Three patients (11%) reported adverse effects of ALND requiring physiotherapy due to pain, stiffness, swelling or arm oedema. Tumor factors such as molecular subtype (p=0.002), tumor size (p=0.004), and proliferation index (Ki-67) (p=0.003) correlated with higher numbers of ALN metastases. CONCLUSION: Since most patients with micrometastases found in the primary operation showed no additional positive lymph nodes, completion ALND may not be required in patients with micrometastases or ITCs in the SLN. In our study, the predictive factors for additional ALN metastases were tumur size, molecular subtype and proliferation index. It is conceivable that the features of the primary tumor, rather than the amount of cancer cells in the SLN, might serve to identify patients in whom ALDN can be avoided. PMID- 28668872 TI - Impact and Prediction of Lymph Node Involvement in Patients with Intrahepatic Cholangiocarcinoma After Curative Resection. AB - BACKGROUND: The aim of this study was to identify the preoperative predictors of prognosis in patients with intrahepatic cholangiocarcinoma (ICC) undergoing resection. PATIENTS AND METHODS: We enrolled 90 patients with ICC who underwent surgical resection, including 59 in whom surgery was considered curative, and measured the overall survival (OS), recurrence-free survival (RFS), and other outcomes and potential prognostic factors. RESULTS: Multivariate Cox proportional hazards analysis showed that tumor in the resection margins (R>0) independently predicted long-term OS in the whole cohort. In the curatively-resected group (R0), lymph node involvement was the only independent predictor of long-term OS. Multiple tumors, perihilar tumor location and serum carcinoembryonic antigen (CEA) concentration >2.2 ng/ml were independent predictors of lymph node involvement before curative resection. CONCLUSION: Patients with ICC with multiple tumors, perihilar tumors and serum CEA concentration >2.2 ng/ml in association with lymph node involvement may need additional preoperative chemotherapy. PMID- 28668873 TI - Weekly High-dose 5-Fluorouracil as 24-hour Infusion Combined with Sodium Folinic Acid (AIO regimen) Plus Irinotecan in Second-line and Sequential Therapy of Metastatic Colorectal Cancer (CRC). AB - BACKGROUND/AIM: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) combined with sodium folinic acid (FA) (AIO-regimen) plus irinotecan (Iri.) after pretreatment with AIO-regimen plus oxaliplatin (L-OHP). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous progression of first-line treatment in accordance with the AIO regimen plus oxaliplatin. On an outpatient basis, the patients received a treatment regimen comprising of weekly 80 mg/m2 irinotecan in the form of a 1 hour i.v. infusion and 2,000 mg/m2 5-FU combined with 500 mg/m2 sodium folinic acid administered as a 24-h infusion i.v. once weekly. RESULTS: During second line treatment, a total of 59 patients received 520 chemotherapy applications. As the main higher-grade symptom of toxicity, diarrhea (NCI-CTC-toxicity grade 3) presented in 8 patients (13.6%, 95%CI=5.1-23.7), followed by leukocytopenia (CTC grade 3) in 3 patients (5.1%, 95%CI=0-11.9), followed by thrombocytopenia (CTC grade 3) in 1 patient (1.7%, 95%CI=0-5.1). Fifty-nine patients were evaluable for treatment response. The remission data can be summarized as follows: complete remission (CR); n=0; partial remission (PR); n=6 (10%; 95%CI=3.4-18.6); stable disease (SD); n=31 (53%; 95%CI=39.0-64.4); progressive disease (PD); n=19 (33%; 95%CI=20.3-44.1). The median progression-free survival (PFS) rate (n=59) was 4.2 months (range=3.8-5.8 months). The median survival time counted from the start of second-line treatment (n=59) 14.2 months (range 8.2-17.3 months) and the median survival time counted from the start of first-line therapy (n=59) 25 months (range 19-27 months). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus irinotecan offers both a favourable toxicity profile and promising efficacy in second-line and palliative sequential therapy. PMID- 28668874 TI - Immunological Status May Predict Response to Nivolumab in Non-small Cell Lung Cancer without Driver Mutations. AB - BACKGROUND/AIM: It remains challenging to select patients with non-small cell carcinoma (NSCLC) for nivolumab monotherapy. We evaluated whether early termination of nivolumab monotherapy correlated with pretreatment neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI). PATIENTS AND METHODS: Twenty patients received nivolumab monotherapy for NSCLC with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) during 2016. Early termination and continued therapy were defined as <=5 and >=6 cycles of monotherapy, respectively. RESULTS: Early termination and continued therapy groups included 9 and 11 patients, respectively. High pretreatment NLR and low pretreatment PNI were significantly associated with early termination of nivolumab, both in an overall analysis (p<0.001 and p=0.016) and in subgroup analyses of patients with performance scores of 0-1 and >=30 days of pretreatment drug holidays. CONCLUSION: High NLR and low PNI were associated with early termination of nivolumab monotherapy, suggesting they might be useful biomarkers for treatment selection. PMID- 28668875 TI - Neck Dissection and Thoracoscopic Esophagectomy in Esophageal Cancer with Aberrant Subclavian Artery. AB - We report a case of esophageal cancer with a non-recurrent inferior laryngeal nerve associated with aberrant right subclavian artery treated with neck dissection followed by thoracoscopic esophagectomy. A 60-year-old man experienced esophageal cancer, hoarseness, and left supraclavicular lymph node swelling was noted on endoscopy. Computed tomography revealed an aberrant right subclavian artery between the esophagus and vertebrae. We administered neo-adjuvant chemotherapy and performed thoracoscopic esophagectomy. During the neck dissection, we confirmed a non-recurrent inferior laryngeal nerve along the inferior thyroid artery. After the neck dissection, we performed thoracoscopic esophagectomy. We confirmed an aberrant right subclavian artery arising from the aortic arch, and resected the left recurrent nerve due to cancer invasion. No postoperative complication was observed, and the patient was discharged 17 days after surgery. Thus, we recommend prior neck dissection in cases involving aberrant right subclavian artery during esophagectomy. PMID- 28668876 TI - Hepatitis B Reactivation in a Patient Receiving Chemotherapy for Breast Cancer: A Case Report. AB - Hepatitis B virus (HBV) reactivation is a known complication of immunosuppressive therapy. While patients who are undergoing treatment with anti-CD20 agents or stem cell transplantation are commonly screened for chronic HBV infection prior to treatment, there are no consensus guidelines regarding HBV screening for patients undergoing chemotherapy for solid tumors. We present a rare case of fulminant liver failure due to HBV reactivation in a patient receiving chemotherapy for breast cancer. Our case highlights the importance of developing definitive guidelines regarding HBV screening in patients receiving chemotherapy for solid tumors and raises the question of the need for universal screening. PMID- 28668877 TI - KLF9 Is a Prognostic Indicator in Human Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: The aim of this study was to investigate the expression of Kruppel like factor 9 (KLF9) and its clinicopathological significance and prognostic value in pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: A total of 149 patients diagnosed with pancreatic ductal adenocarcinoma who underwent curative surgery were enrolled in this study. The expression of KLF9 was examined immunohistochemically. The correlation of KLF9 with clinicopathological parameters and overall survival rate of patients were analyzed. RESULTS: Low expression of KLF9 was observed in 62.82% of tumors, which was related to poor differentiation (p=0.036) and vascular invasion (p=0.017). Furthermore, the overall survival of patients with low KLF9 expression was significantly shorter than that of those with high KLF9 expression (p=0.001). Multivariate analysis confirmed KLF9 as an independent prognostic factor (p=0.000). CONCLUSION: KLF9 expression was found to be a valuable prognostic factor for patients with pancreatic ductal adenocarcinoma. PMID- 28668878 TI - Prognostic Importance of Vitamins A, E and Retinol-binding Protein 4 in Renal Cell Carcinoma Patients. AB - AIM: To assess the prognostic importance of serum levels of retinol, retinol binding protein 4 (RBP4) and vitamin E at the time of diagnosis in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: In this prospective study, in a cohort of 102 renal cell carcinoma patients, relationships between serum levels of the aforementioned markers and recurrence-free survival (RFS), overall survival (OS), as well as cancer-specific survival (CSS), were evaluated. The vitamin A and vitamin E levels were determined by high-performance liquid chromatography (HPLC), while the RBP4 level by enzyme-linked immunosorbent assay (ELISA). RESULTS: The median follow-up period was 39 months. Renal cell carcinoma recurred in 9 patients; 23 patients died with 12 of them from RCC. The preoperative vitamin E level was associated to RFS (p=0.02). We found a significant relationship between OS and the level of RBP4 (p=0.002), retinol (p=0.037) and vitamin E (p=0.007). The CSS period was significantly associated with the level of RBP4 (p=0.0001) and retinol (p=0.0003). Patients with an RBP4 level less than 21.0 mg/l at the time of diagnosis had a 13.5-times higher risk of death due to RCC progression; this risk was up to 7.7-times higher with vitamin A levels under 0.52 mg/l. CONCLUSION: Low levels of vitamin A, E and RBP4 at the time of RCC diagnosis are associated with a poorer prognosis after surgery. PMID- 28668879 TI - Correlation Between Minimum Apparent Diffusion Coefficient (ADCmin) and Tumor Cellularity: A Meta-analysis. AB - BACKGROUND/AIM: Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique based on measure of water diffusion that can provide information about tissue microstructure, especially about cell count. Increase of cell density induces restriction of water diffusion and decreases apparent diffusion coefficient (ADC). ADC can be divided into three sub-parameters: ADC minimum or ADCmin, mean ADC or ADCmean and ADC maximum or ADCmax Some studies have suggested that ADCmin shows stronger correlations with cell count in comparison to other ADC fractions and may be used as a parameter for estimation of tumor cellularity. The aim of the present meta-analysis was to summarize correlation coefficients between ADCmin and cellularity in different tumors based on large patient data. PATIENTS AND METHODS: For this analysis, MEDLINE database was screened for associations between ADC and cell count in different tumors up to September 2016. For this work, only data regarding ADCmin were included. Overall, 12 publications with 317 patients were identified. Spearman's correlation coefficient was used to analyze associations between ADCmin and cellularity. The reported Pearson correlation coefficients in some publications were converted into Spearman correlation coefficients. RESULTS: The pooled correlation coefficient for all included studies was rho=-0.59 (95% confidence interval (CI)=-0.72 to -0.45), heterogeneity Tau2=0.04 (p<0.0001), I2=73%, test for overall effect Z=8.67 (p<0.00001). CONCLUSION: ADCmin correlated moderately with tumor cellularity. The calculated correlation coefficient is not stronger in comparison to the reported coefficient for ADCmean and, therefore, ADCmin does not represent a better means to reflect cellularity. PMID- 28668880 TI - Factors Influencing Disease Progression in Patients with Head and Neck Melanoma. AB - BACKGROUND: Histological parameters as well as the status of sentinel lymph node are known to be strong prognostic factors in patients with melanoma. PATIENTS AND METHODS: In this study, we retrospectively analyzed 1,384 patients who were diagnosed with head and neck melanoma between 1976 and 2010 regarding prognostic factors [tumor thickness, level of invasion, sentinel lymph node (SLN) status, ulceration, histological subtype, localization, and gender], overall survival, and disease-free survival. RESULTS: Patients who developed metastases had a significantly thicker tumor than patients without metastases. Additionally, a thicker tumor was often associated with a higher level of invasion (Clark level). There was no overall survival benefit in patients who underwent SLN dissection when compared to patients who did not (p=0.07). Compared to SLN-negative patients, patients with SLN involvement had a significantly shorter disease-free period (p<0.001) and shorter overall survival time (p<0.001). CONCLUSION: In summary, tumor thickness is the most important prognostic factor. SLN dissection does not affect the overall survival of patients with melanoma. However, a positive SLN is a marker for a worse outcome in these patients. PMID- 28668881 TI - Clinicopathological and Corresponding Genetic Features of Colorectal Signet Ring Cell Carcinoma. AB - Europe and the United States have high morbidity rates of colorectal cancer, it being the third most common new cancer among both men and women each year. Colorectal cancer morbidity is also high in Japan. Advances in surgery, chemotherapy, and molecular targeted drugs have extended the prognosis of colorectal cancer, although the effects of these treatments remain poor in some patients. Colorectal cancer almost always presents as differentiated adenocarcinoma, although one tissue type, signet-ring cell carcinoma, occurs rarely. Overall, colorectal signet-ring cell carcinoma is very infrequent among cases of colorectal cancer, however, its prognosis is reported as being extremely poor. Several reports have addressed its clinicopathological and typical genetic characteristics, such as mutation of viral oncogene Kirsten rat sarcoma (KRAS) gene, but there have been few comprehensive investigations of its characteristics and genetic background. In this review, we examine features of colorectal signet ring cell carcinoma by summarizing its clinical and genetic characteristics. PMID- 28668882 TI - HB-EGF Is a Promising Therapeutic Target for Lung Cancer with Secondary Mutation of EGFRT790M. AB - Advanced lung cancer is one of the most lethal malignancies. Many anticancer agents have been developed for lung cancer with epidermal growth factor receptor (EGFR) mutations, but its prognosis remains extremely poor. The development of molecularly-targeted therapies is required for patients with lung cancer with secondary mutation of the EGFR gene. In this study, in order to assess the validity of heparin-binding EGF-like growth factor (HB-EGF) as a therapeutic target for lung cancer with EGFR mutation, we examined the antitumor effects of a specific inhibitor (cross-reacting material 197; CRM197) on lung cancer cells with EGFR mutation. HB-EGF was the most predominantly expressed EGFR ligand in lung cancer cells with EGFR mutation. CRM197 induced significant cell apoptosis and marked suppression of tumorigenicity in lung cancer cells with single or double mutation of EGFR. These results suggest that HB-EGF is a rational target for the treatment of lung cancer with EGFR mutation. PMID- 28668883 TI - Apremilast Induces Apoptosis of Human Colorectal Cancer Cells with Mutant KRAS. AB - BACKGROUND/AIM: We previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 (PDE4B2) expression in human colorectal cancer (CRC) HCT116 cells in a three-dimensional culture (3DC). Here, we evaluated the effects of apremilast, a selective PDE4 inhibitor, on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type (wt)PDE4B2 (HKe3-wtPDE4B2), mutant (mt)PDE4B2 (kinase dead) (HKe3-wtKRAS), wtKRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS). MATERIALS AND METHODS: Apoptosis was detected by immunofluorescence using confocal laser scanning microscopy or western blot in HKe3-wtPDE4B2, HKe3 mtPDE4B2, HKe3-wtKRAS and mtKRAS cells treated with or without apremilast in 3DC. Tumourigenicity was assessed in nude mice assay using these cells. RESULTS: Apremilast did not inhibit the proliferation of HKe3-wtPDE4B2 cells or HKe3 mtKRAS in two-dimensional cultures, whereas the number of apoptotic HKe3-wtPDE4B2 cells and HKe3-mtKRAS cells increased after apremilast treatment in 3DC, leading to formation of a luminal cavity. Tumour growth in nude mice was dramatically reduced by intraperitoneal injection of apremilast. Notably, a decreased level of caspase-1 expression was observed in HKe3-wtPDE4B2 and HKe3-mtKRAS cells. CONCLUSION: Apremilast induces tumour regression in nude mice, possibly by inducing caspase-1 expression. PMID- 28668884 TI - Loss of Tyrosine Kinase 2 Does Not Affect the Severity of Jak2V617F-induced Murine Myeloproliferative Neoplasm. AB - BACKGROUND/AIM: In myeloproliferative neoplasms (MPN), Janus kinase 2 (JAK2) is activated by mutations including JAK2V617F (JAK2VF). It is unclear whether JAK kinases [i.e. JAK1, JAK2, JAK3, or tyrosine kinase 2 (TYK2)] other than JAK2 have cooperative actions such as enhancement or suppression of JAK2. If other kinases enhance activation, therapies that co-target them could have a therapeutic efficacy. We examined the role of TYK2 in Jak2VF-induced murine MPN. MATERIALS AND METHODS: We crossed Jak2VF transgenic mice and Tyk2-knockout (Tyk2KO) mice to generate Jak2VF/Tyk2KO mice. The disease severity and treatment effect with a JAK2 inhibitor was compared between Jak2VF and Jak2VF/Tyk2KO mice. RESULTS: Both types of mice developed MPN, and there were no differences in peripheral blood counts, spleen weight, or survival period. Upon JAK2 inhibitor therapy, both types of mice had equally improved leukocytosis and splenomegaly. CONCLUSION: TYK2 does not have cooperative effects with JAK2VF upon MPN onset nor in the presence of a JAK2 inhibitor. PMID- 28668885 TI - Interactive Analysis of TX-1123 with Cyclo-oxygenase: Design of COX2 Selective TX Analogs. AB - BACKGROUND: To date, two cyclo-oxygenase (COX) isoforms, COX1 and COX2, have been identified. In the present study, the COX-inhibitory activities of TX-1123 derivatives with the 2-hydroxyarylidene-4-cyclopentene-1,3-dione structure were examined, and the binding profiles of TX-1123 to COXs were analyzed using docking simulations. MATERIALS AND METHODS: X-Ray data on COX1 [protein data bank (PDB) ID=1PGG] and COX2 (PDB ID=3LN1) were used for molecular interactive simulations. The interactive profiles of TX-1123 derivatives with COXs were examined using a molecular simulation technique with Molegro Virtual Docker (CLC bio, Aarhus, Denmark). RESULTS: TX-1123 exhibited COX1-inhibitory activity [half-maximal inhibitory concentration (IC50)=1.57*10-5 M]. The COX2 inhibitory activity of TX 1123 was potent (IC50=1.16*10-6 M), and the ratio of COX1/COX2 inhibition was 13.5. TX-1123 bound to the COX2 molecule, and the oxygen atom of the 4 cyclopentene-1,3-dione region of TX-1123 interacted with Cys26 and Gln447 of COX2. CONCLUSION: The TX-1123-binding pocket of COX2 differs from that of the COX2-selective celecoxib-binding pocket. TX-1123 exhibited a different COX2 interactive mechanism from that of celecoxib. PMID- 28668886 TI - An Alpha-kinase 2 Gene Variant Disrupts Filamentous Actin Localization in the Surface Cells of Colorectal Cancer Spheroids. AB - BACKGROUND/AIM: Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene down-regulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. MATERIALS AND METHODS: Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). RESULTS: We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95% confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. CONCLUSION: The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function. PMID- 28668887 TI - Frequency of Myeloid-derived Suppressor Cells in the Peripheral Blood Reflects the Status of Tumor Recurrence. AB - BACKGROUND: Malignant tumors inhibit antitumor immune responses, which are driven by T-regulatory cells or myeloid-derived suppressor cells (MDSCs). Since MDSCs are involved in invasion, migration, and metastasis of tumor cells, we hypothesized that MDSCs are also involved in tumor recurrence after surgical resection. MATERIALS AND METHODS: C57BL/6 mice were subcutaneously inoculated with B16F10 melanoma cells in the right flank. In some experiments, established tumors were surgically resected. Peripheral blood was drawn over time, and immune cells and cytokines were evaluated using flow cytometry. RESULTS: MDSCs and relevant pro-inflammatory cytokines increased in the peripheral blood of tumor bearing mice. Moreover, the frequency of MDSCs rapidly increased in mice with tumor recurrence. CONCLUSION: The frequency of MDSCs in the peripheral blood of tumor-bearing mice reflects the status of tumor progression as well as tumor recurrence. Continuous monitoring of MDSCs in the peripheral blood might be a useful indicator of tumor recurrence. PMID- 28668888 TI - Efficacy of Combination Therapy with MET and VEGF Inhibitors for MET overexpressing Glioblastoma. AB - BACKGROUND: Glioblastoma multiforme (GBM) is a malignant brain tumor with an extremely poor prognosis. GBM tissues frequently express mesenchymal-epithelial transition factor (MET), which induces cell division, growth and migration. In addition, angiogenesis is a significant feature of GBM, attributable to the overexpression of vascular endothelial growth factor (VEGF). Although the VEGF inhibitor bevacizumab was recently highlighted as the second-line drug for GBM treatment, GBMs often recur even with bevacizumab therapy. Based on these findings, we hypothesized that inhibition of both MET and VEGF would exhibit a synergistic effect on MET-overexpressing GBM. MATERIALS AND METHODS: As we observed MET expression at high levels in some patients with GBM, we designed GL261 murine glioma-based experiments. GL261 cells were transfected with siRNAs specific for MET and VEGF in vitro, and the cell growth ratios were evaluated. Simultaneously, transfected GL261 cells were transplanted into the brain of C57BL/6 mice, and their survival was monitored. RESULTS: GBM tissues frequently overexpressed MET protein at high levels compared with lower-grade gliomas. These GBMs at first responded to bevacizumab, but often eventually recurred. When GL261 cells were co-transfected with both MET-specific siRNA and VEGF-specific siRNA, the in vitro tumor cell growth significantly decelerated compared to single siRNA transfection. Consistently, when mice were transplanted with co-transfected GL261 cells, their survival was significantly prolonged compared to those given cells transfected with single siRNA. CONCLUSION: The current data indicate that the inhibition of both MET and VEGF exhibits efficient therapeutic effects of GBM bearing hosts. PMID- 28668889 TI - Design and Synthesis of Novel Anti-metastatic Hypoxic Cytotoxin TX-2137 Targeting AKT Kinase. AB - BACKGROUND: The hypoxic microenvironment plays a crucial role in the malignant progression of tumor cells. Moreover, AKT, a serine/threonine kinase, is activated by various extracellular growth factors and is important for cell growth, survival, and motility of leukocytes, fibroblasts, endothelial cells, and tumor cells. Therefore, we aimed to design an anti-metastatic hypoxic cytotoxin which has inhibitory effects on AKT. RESULTS: TX-2137 was designed and synthesized based on the structural similarity of a preexisting AKT1/2 kinase inhibitor and a hypoxic cytotoxin tirapazamine. TX-2137 effectively reduced the expression of phosphorylated AKT and matrix metalloproteinase 9 (MMP9) and showed strong inhibition of the proliferation of B16-F10, HT-1080, and MKN-45 cells. In addition, TX-2137 exhibited hypoxia-selective cytotoxicity towards A549 cells and inhibited liver metastasis of B16-F10 cells in a xenograft chick embryo model in the same way as doxorubicin. CONCLUSION: TX-2137 may be a potent lead compound in the development of a novel anti-metastatic AKT kinase inhibitor. PMID- 28668890 TI - Discordance of MCM7 mRNA and its Intronic MicroRNA Levels Under Hypoxia. AB - BACKGROUND: Intronic microRNAs (miRNAs) are considered to be transcribed using their host gene promoter. However, about one third of intronic miRNAs are predicted to have independent promoter elements. MATERIALS AND METHODS: Human breast cancer cells were cultured under normoxia or hypoxia, and expression levels of intronic miR-106b-25 cluster miRNAs and their host gene minichromosome maintenance complex component 7 (MCM7) transcripts were analyzed by semi quantitative polymerase chain reaction. The putative promoter element of miR-106b 25 cluster was analyzed by chromatin immunoprecipitation and luciferase assays. RESULTS: Exposure to hypoxia reduced the expression of MCM7 mRNA and a primary transcript of miR-106b-25 cluster, but did not affect that of mature miRNAs. The putative promoter element of miR-106b-25 cluster was not bound by hypoxia inducible factor 1-alpha (HIF1-alpha), and was not activated under hypoxia. CONCLUSION: Maintenance of miR-106b-25 cluster miRNA levels under hypoxia was not caused by the activation of an independent promoter element. PMID- 28668891 TI - Antitumour Effects of Intravenous Administration of BK-UM, a Novel Inhibitor of HB-EGF, in Ovarian Cancer Therapy. AB - BACKGROUND: Patients with ovarian cancer with high levels of heparin-binding epidermal growth factor-like growth factor have a poor prognosis. Here we assessed the pharmacokinetics and tumour-inhibiting effects of cross-reacting material 197, produced commercially as BK-UM, and examined the efficacy and safety of its intravenous (i.v.) administration. MATERIALS AND METHODS: BK-UM was administered to rats, and its serum levels were measured. Ovarian cancer cell lines were either intraperitoneally (i.p.) or subcutaneously administered into mice, to establish a mouse model of ovarian cancer. BK-UM was then administered i.p. or i.v., and its tumour-inhibiting effects were examined. RESULTS: Higher maximum serum concentration (Cmax) values resulted from i.v. administration, whereas longer time to maximum serum (Tmax) values resulted from i.p. administration. In the peritoneal dissemination model, i.p. administration inhibited tumour growth and increased survival rate, whereas in the subcutaneous model, i.v. administration significantly inhibited tumour growth compared to i.p. administration. CONCLUSION: Administration of BK-UM by i.v. is both efficacious and safe. PMID- 28668892 TI - Measurement of the Phagocytic Activity of Human Peripheral Blood Using a Highly Sensitive Fluorometric Detection Device Without Hemolysis. AB - BACKGROUND/AIM: Phagocytes recognize pathogens that enter the body as well as other abnormal and foreign materials that may exist within an organism (such as dead cells, oxidized lipids, and denatured proteins), and phagocytose and eliminate them to maintain a healthy state. In a previous study a simple prototype device was used, under development by Hamamatsu Photonics (Prototype), that detects fluorescence to determine the phagocytic activity of the murine macrophage cell line J774.1. The present study aimed to determine whether it was possible to detect phagocytic activity in a slight amount of human peripheral blood without using hemolysis. MATERIALS AND METHODS: Three microliters of human peripheral blood was drawn from the fingertip and mixed with 30 MUg of pH sensitive fluorescent particles. The fluorescence intensity of the human peripheral blood sample was then measured using the Prototype in development, cultured for 2 h at 37 degrees C, and then re-measured. The phagocytes were observed under fluorescence microscopy and the phagocytosis rate of CD11b positive cells was verified with a flow cytometer. RESULT: The phagocytic activity of non-hemolyzed human peripheral blood was measured using the Prototype under development; fluorescence after phagocytosis was detected. Furthermore, this was confirmed by both fluorescence microscopy and flow cytometry. The precision of the measurements of human peripheral blood phagocytic activity was verified with the Prototype using samples from three healthy individuals. The relationship between blood sugar levels and phagocytic activity before and after meal times was determined. Concerning exercise, phagocytic activity tended to decrease, although salivary amylase level increased in the healthy individual examined after exercise. CONCLUSION: The simple Prototype can measure phagocytic activity in a small amount of peripheral blood without hemolysis. The device allows for rapid and minimally-invasive detection of changes in phagocytic activity, which has conventionally been difficult. These findings provide promising evidence that assessment of individual phagocytic capacity can be made easier using this novel device. PMID- 28668893 TI - Expression of N-Acetylgalactosaminyltransferase-6 Is Related to Expression of Cell Adhesion Molecules in Endometrial Cancer. AB - BACKGROUND: The aberrant glycosylation of mucin type O-glycans is thought to be associated with functional alteration of cancer cells, including adhesive properties, as well as their potential for invasion and metastasis. Positive expression of N-acetylgalactosaminyltransferase-6 (GalNAc-T6) may also be a marker for aberrant O-glycans in carcinogenesis. We previously reported that over expression of GalNAc-T6 had a strong association with endometrial cell invasion ability in vitro. MATERIALS AND METHODS: This study investigated the relationship between GalNAc-T6 expression and cell adhesion molecules in 218 endometrial carcinomas by immunohistochemistry. RESULTS: Expression of GalNAc-T6 was found to be significantly related to expression of E-cadherin. Positive expression of GalNAc-T6 was significantly associated with better histological grade and good clinical prognosis of patients, but positive E-cadherin and beta-catenin expression were not significantly associated with improved overall survival. CONCLUSION: GalNAc-T6 might be related to cell-cell adhesion in the early phase of cancer invasion in endometrial carcinoma. PMID- 28668894 TI - Expression of Polypeptide N-Acetylgalactosaminyltransferase-6 in Epithelial Ovarian Carcinoma. AB - BACKGROUND: The family of polypeptide N-acetylgalactosanimyltransferases (GalNAc Ts) are important factors in glycosylation in carcinomas. The purpose of this study was to investigate the clinical significance of GalNAc-T6 and its correlation with the prognosis of epithelial ovarian carcinoma. MATERIALS AND METHODS: A total of 150 patients with epithelial ovarian carcinoma were enrolled and the relationship between GalNAc-T6 expression by immunohistochemistry and long-term survival was evaluated. RESULTS: The expression of GalNAc-T6 was positive in 57.6% (34/59) of those with serous carcinoma, 85.3% (29/34) in mucinous carcinoma, 15.6% (5/27) in clear cell carcinoma, and 44% (14/25) in endometrioid carcinoma. In a Kaplan-Meier analysis of patients with grade 1 or 2 serous carcinoma, the 10-year overall survival rates were 47.4% in the GalNAc-T6 positive and 9.1% in the GalNAc-T6-negative groups (p=0.047). CONCLUSION: GalNAc T6 expression in epithelial ovarian carcinoma was different according to pathological type. In low-grade serous carcinoma, GalNAc-T6 expression may contribute to improved long-term survival. PMID- 28668895 TI - Lipopolysaccharides Derived from Pantoea agglomerans Can Promote the Phagocytic Activity of Amyloid beta in Mouse Microglial Cells. AB - BACKGROUND/AIM: Recent studies reported that lipopolysaccharide (LPS) exhibits beneficial effects on prevention of immune-related diseases by activating macrophages. We previously demonstrated that pre-treatment with LPS derived from Pantoea agglomerans (LPSp) activated amyloid beta (Abeta) phagocytosis in mouse primary microglia. In the present study, we further examined the promotory effect on phagocytosis of phagocytic particles in the C8-B4 microglia cell line. MATERIALS AND METHODS: Phagocytic analysis of C8-B4 cells was evaluated using phagocytic particles (latex beads or HiLyteTM Fluor 488-conjugated Abeta1-42). RESULTS: The phagocytic activity of latex beads was dependent on the concentration of beads and incubation time. LPSp, at as low as 100 pg/ml, significantly increased phagocytosis against the beads. In the experiment of Abeta1-42 phagocytosis, LPSp significantly increased Abeta phagocytic activity. CONCLUSION: LPSp treatment was confirmed to enhance Abeta1-42 phagocytosis by mouse microglia. It is suggested that the use of LPSp may be a potential promising candidate for the prevention of Alzheimer's disease. PMID- 28668896 TI - Systemic Intravenous Adoptive Transfer of Autologous Lymphokine-activated alphabeta T-Cells Improves Temozolomide-induced Lymphopenia in Patients with Glioma. AB - In this clinical study, we investigated the safety and clinical usefulness of systemic adoptive immunotherapy using autologous lymphokine-activated alphabeta T cells (alphabeta T-cells), combined with standard therapies, in patients with malignant brain tumors. Twenty-three patients with different malignant brain tumors, consisting of 14 treated with temozolomide (TMZ group) and 9 treated without temozolomide (non-TMZ group), received systemic intravenous injections of alphabeta T-cells (mean=10.4 injections/patient for the TMZ group, and 4.78 for the non-TMZ group). No significant adverse effects associated with the alphabeta T-cell injection were observed, and the total lymphocyte count (TLC) improved significantly in the TMZ group after five injections. Furthermore, CD8-positive or T-cell receptor V gamma -positive cells were increased with TLC in three patients with glioblastoma multiforme. These findings suggest that systemic alphabeta T-cell immunotherapy is well tolerated, and may help restore an impaired and imbalanced T-cell immune status, and temozolomide- and/or radiotherapy-induced lymphopenia. Future prospective study is needed to clarify the clinical merits of this immunotherapy. PMID- 28668897 TI - Hepatectomy for Liver Metastases of Colorectal Cancer After Adoptive Chemoimmunotherapy Using Activated alphabeta T-cells. AB - BACKGROUND/AIM: Various types of chemoimmunotherapies for malignant tumors have been reported. However, there are few reports on hepatectomy after chemoimmunotherapy. We evaluated the safety and efficacy of hepatectomy for patients with stage IV colorectal liver metastases (CLM) after chemoimmunotherapy using activated alphabeta T-cells. PATIENTS AND METHODS: From June 2012 to December 2016, five patients who underwent hepatectomy after receiving capecitabine and oxaliplatin (XELOX) plus bevacizumab and ex vivo-expanded alphabeta T-lymphocytes as first-line chemoimmunotherapy were included. RESULTS: The median age of the five patients (two men, three women) was 61.4 (range=56-75) years. The surgical procedure was partial hepatectomy in two, laparoscopic partial hepatectomy in two, and one case of partial hepatectomy with subsegmentectomy. There was no postoperative complication of Clavien-Dindo grade 3A or higher. One patient had multiple lung metastases. CONCLUSION: Hepatectomy after chemoimmunotherapy using activated alphabeta T-cells for CLM can be performed safely. PMID- 28668898 TI - Clinical Study on the Medical Value of Combination Therapy Involving Adoptive Immunotherapy and Chemotherapy for Stage IV Colorectal Cancer (COMVI Study). AB - BACKGROUND: Adoptive immunotherapy for cancer has evolved through development of novel technologies for generating a large number of activated killer cells, such as alphabeta T-cells, gammadelta T-cells, and natural killer cells. There has been no prospective trial of combination therapy involving adoptive immunotherapy and first-line chemotherapy for stage IV colorectal cancer. The present pilot study aimed to evaluate the safety and feasibility of combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer (COMVI study). PATIENTS AND METHODS: The COMVI study was a prospective, single arm pilot trial. Therapy in each 21-day treatment cycle involved XELOX (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1 14), bevacizumab (7.5 mg/kg on day 1), and alphabeta T-lymphocytes (over 5*109 on day 18) cultured ex vivo with an immobilized antibody to CD3 and interleukin-2. RESULTS: The study included six patients (two men and four women) between June 2013 and September 2014. The median patient age was 68 years (range=55-75 years). The overall response rate was 83.3% [complete response in two (33.3%); partial response in three (50.0%); stable disease in one (16.7%); no cases of progressive disease]. The tumor volume reduction rate was 53% (range=38.0-100%). The median progression-free and overall survival durations were 567 and 966 days, respectively. Most adverse events were mild-to-moderate in intensity, and no grade 4 adverse events occurred in the six patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study. CONCLUSION: Combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are needed to confirm the safety and efficacy of such chemoimmunotherapy. PMID- 28668899 TI - Efficacy of Adoptive Immune-cell Therapy in Patients with Advanced Gastric Cancer: A Retrospective Study. AB - BACKGROUND: Conventional therapy for advanced gastric cancer (GC) has limited survival benefits. In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy, using in vitro-activated T-lymphocytes with and without dendritic cells (DCs), in combination with standard therapies in terms of the survival of patients with advanced GC. PATIENTS AND METHODS: A total of 242 patients who were diagnosed as having stage-IV GC were enrolled in this study to receive immune-cell therapy with or without standard therapies, such as chemotherapy, surgery, or radiation therapy. Overall survival was analyzed by the Kaplan-Meier with log-rank test and Cox regression methods. RESULTS: Immune-cell therapy increased median survival time (21.5 months) in patients with advanced GC. The patients who underwent surgery with or without chemotherapy as a prior treatment showed better prognosis than those who received other therapies (p<0.001). Patients who showed stable disease or a partial response to immune cell therapy had a better prognosis than those with progressive disease (p<0.001). Multivariate analysis revealed that performance status, the type of immune-cell therapy, and prior treatment were independent prognostic factors for patients with GC. No serious adverse event was reported in immune-cell therapy. CONCLUSION: Immune-cell therapy might extend the survival of patients with advanced GC. PMID- 28668900 TI - Serum Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) as a Biomarker for Primary Ovarian Cancer. AB - Ovarian cancer is the most lethal malignancy among gynaecological cancers. Although many anticancer agents have been developed for the treatment of ovarian cancer, it continues to have an extremely poor prognosis. Heparin-binding epidermal growth factor-like grown factor (HB-EGF) has been reported to be a rational therapeutic target for ovarian cancer. Here, we evaluated the clinical significance of serum HB-EGF by examining the association between prognosis and serum HB-EGF levels in patients with primary ovarian cancer. We found that high serum HB-EGF concentrations were significantly associated with poor prognosis in a combined cohort of patients with all stages of ovarian cancer, as well as in a subset of patients with advanced disease. In addition, serum HB-EGF levels increased as the cancer advanced. These data suggest that serum HB-EGF may be a target for the design of novel therapies for ovarian cancer. PMID- 28668901 TI - Perineural Invasion Is a Prognostic Factor and Treatment Indicator in Patients with Rectal Cancer Undergoing Curative Surgery: 2000-2011 Data from a Single center Study. AB - BACKGROUND/AIM: The aim of the present study was to investigate whether perineural invasion (PNI) was a prognostic index for patients who underwent curative surgery for Dukes' grade B and C rectal cancer. PATIENTS AND METHODS: A total of 645 patients with rectal cancer between January 2000 and December 2011; 363 with Dukes' B or C stages who did not undergo chemoradiotherapy were reviewed. RESULTS: Of 363 patients, 83 (22.9%) were PNI-positive. The 5-year overall survival and disease-specific survival rates were significantly worse for patients with PNI-positive Dukes' B or C disease compared to those with PNI negative disease. There was no significant difference in the recurrence pattern (hematogenous or lymphatic spread), but patients with PNI-positive disease had a significantly higher rate of recurrence compared to those with PNI-negative disease (p<0.001). CONCLUSION: PNI was a significant prognostic factor in rectal cancer, and the PNI status in primary rectal cancer pathology specimens should be considered for therapy stratification. PMID- 28668902 TI - Analysis of Evolving Clinicopathological Features of Metastatic Brain Tumors Over 30 Years of Surgical Management. AB - We reviewed 232 cases, in which patients underwent surgical resection and histopathological diagnosis of metastatic brain tumor between 1985 and 2014. We analyzed trends in clinicopathological changes present over three decades in a single institution. The most frequent site of metastatic tumors was the frontal lobe. The average patient age and the percentage of female patients increased over the 30-year study period. The most frequent primary cancer was lung cancer, followed by breast cancer; these were the top two primary cancer types over the three decades. However, use of chemotherapy and radiotherapy as standard treatments for postoperative treatment of metastatic brain tumors has increased over the past 20 years. Development of novel, targeted treatments for these cancer types have created new tools for use in the clinical care of patients with metastatic brain tumors. Incorporation of these tools in a multimodal approach is critical in contemporary management of metastatic brain tumors. PMID- 28668904 TI - Errata. PMID- 28668903 TI - Laparoscopically Removed Streak Gonad Revealed Gonadoblastoma in Frasier Syndrome. AB - BACKGROUND: Frasier syndrome (FS) is characterized by gonadal dysgenesis and progressive nephropathy caused by mutation in the Wilm's tumor gene (WT1). We report a case of FS in which diagnosis was based on amenorrhea with nephropathy, and laparoscopically-removed streak gonad which revealed gonadoblastoma. CASE REPORT: At the age of 3 years, the patient developed nephrotic syndrome. This later became steroid-resistant and, by the age of 16 years, had progressed to end stage renal failure with peritoneal dialysis. At the age of 17 years, the patient presented primary amenorrhea and was referred to our department. Physical examination was consistent with Tanner 1 development and external genitalia were female phenotype. Speculum examination showed uterine cervix and uterine body and bilateral ovaries were not palpable on pelvic examination. Multi-sliced computed tomography of abdomen and pelvis revealed streaked structure along the bilateral external iliac artery at pelvic wall and hypoplastic uterus. Serum testing revealed primary hypogonadism pattern, elevated follicle-stimulating hormone and luteinizing hormone with low concentrations of estradiol and testosterone. The patient underwent genetic counseling with her parents. Chromosomal status was 46XY karyotype and DNA sequencing confirmed FS due to a heterozygous WT1 mutation (IVS9+5G>A). Elective laparoscopic bilateral salpingo-oophorectomy was performed to avoid increased risk for gonadoblastoma. Pathological examination revealed gonadoblastoma in the right gonad. CONCLUSION: Although a rare disease, the diagnosis of FS should be considered in the case of primary amenorrhea with nephropathy. Prophylatic gonadectomy is recommended due to the high risk of gonadoblastoma in the dysgenetic gonad. PMID- 28668906 TI - A current approach to heart failure in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a genetic, progressive neuromuscular condition that is marked by the long-term muscle deterioration with significant implications of pulmonary and cardiac dysfunction. As such, end-stage heart failure (HF) in DMD is increasingly becoming the main cause of death in this population. The early detection of cardiomyopathy is often challenging, due to a long subclinical phase of ventricular dysfunction and difficulties in assessment of cardiovascular symptomatology in these patients who usually loose ambulation during the early adolescence. However, an early diagnosis of cardiovascular disease in patients with DMD is decisive since it allows a timely initiation of cardioprotective therapies that can mitigate HF symptoms and delay detrimental heart muscle remodelling. Echocardiography and ECG are standardly used for screening and detection of cardiovascular abnormalities in these patients, although these tools are not always adequate to detect an early, clinically asymptomatic phases of disease progression. In this regard, cardiovascular magnetic resonance (CMR) with late gadolinium enhancement is emerging as a promising method for the detection of early cardiac involvement in patients with DMD. The early detection of cardiac dysfunction allows the therapeutic institution of various classes of drugs such as corticosteroids, beta-blockers, ACE inhibitors, antimineralocorticoid diuretics and novel pharmacological and surgical solutions in the multimodal and multidisciplinary care for this group of patients. This review will focus on these challenges and available options for HF in patients with DMD. PMID- 28668907 TI - Rigor and Reproducibility in Critical Care Research. PMID- 28668908 TI - Bacteriuria and Risk Factors for Bacteremia. PMID- 28668909 TI - Response. PMID- 28668911 TI - Recognizing the Ordinary as Extraordinary: Insight Into the "Way We Work" to Improve Patient Safety Outcomes. AB - The Institute of Medicine (now National Academy of Medicine) reports "To Err is Human" and "Crossing the Chasm" made explicit 3 previously unappreciated realities: (1) Medical errors are common and result in serious, preventable adverse events; (2) The majority of medical errors are the result of system versus human failures; and (3) It would be impossible for any system to prevent all errors. With these realities, the role of the nurse in the "near miss" process and as the final safety net for the patient is of paramount importance. The nurse's role in patient safety is described from both a systems perspective and a human factors perspective. Critical care nurses use specific strategies to identify, interrupt, and correct medical errors. Strategies to identify errors include knowing the patient, knowing the plan of care, double-checking, and surveillance. Nursing strategies to interrupt errors include offering assistance, clarifying, and verbally interrupting. Nurses correct errors by persevering, being physically present, reviewing/confirming the plan of care, or involving another nurse or physician. Each of these strategies has implications for education, practice, and research. Surveillance is a key nursing strategy for identifying medical errors and reducing adverse events. Eye-tracking technology is a novel approach for evaluating the surveillance process during common, high risk processes such as blood transfusion and medication administration. Eye tracking has also been used to examine the impact of interruptions to care caused by bedside alarms as well as by other health care personnel. Findings from this safety-related eye-tracking research provide new insight into effective bedside surveillance and interruption management strategies. PMID- 28668913 TI - Helping Patients Sleep. PMID- 28668912 TI - Factors Influencing Patients' Sleep in the Intensive Care Unit: Perceptions of Patients and Clinical Staff. AB - BACKGROUND: Multiple factors are believed to contribute to disruption of patients' sleep and negatively affect clinical outcomes in the intensive care unit. Achieving restorative sleep for critically ill patients remains a challenge. OBJECTIVES: To explore the perceptions and beliefs of staff, patients, and surrogates regarding the environmental and nonenvironmental factors in the medical intensive care unit that affect patients' sleep. METHODS: This qualitative study included 24 medical intensive care unit staff (7 physicians, 5 respiratory therapists, 10 nurses, and 2 patient-care assistants), 8 patients, and 6 patient surrogates. Semistructured interviews were conducted, and qualitative analysis of content was used to code, categorize, and identify interview themes. RESULTS: Interview responses revealed 4 themes with related subthemes: (1) The overnight medical intensive care unit environment does affect sleep, (2) nonenvironmental factors such as difficult emotions and anxiety also affect sleep, (3) respondents' perceptions about sleep quality in the medical intensive care unit were highly variable, and (4) suggestions for sleep improvement included reassuring patients and care-clustering strategies. CONCLUSIONS: Results of this study suggest that environment is not the only factor influencing patients' sleep. Decreases in environmental sources of disturbance are necessary but not sufficient for sleep improvement. Guideline recommended clustered care is needed to provide adequate sleep opportunity, but patients' emotions and anxiety also must be addressed. PMID- 28668914 TI - Safety and Acceptability of Patient-Administered Sedatives During Mechanical Ventilation. AB - BACKGROUND: Safety and acceptability of sedative self-administration by patients receiving mechanical ventilation is unknown. OBJECTIVES: To determine if self administration of dexmedetomidine by patients is safe and acceptable for self management of anxiety during ventilatory support. METHODS: In a pilot trial in 3 intensive care units, 17 intubated patients were randomly assigned to dexmedetomidine and 20 to usual care. Dexmedetomidine was administered via standard pumps for patient-controlled analgesia, with a basal infusion (0.1-0.7 MUg/kg per hour) titrated by the number of patient-triggered doses (0.25 MUg/kg per dose). Safety goals were heart rate greater than 40/min, systolic blood pressure greater than 80 mm Hg, and diastolic blood pressure greater than 50 mm Hg. Acceptability was based on patients' self-reported satisfaction and ability to administer the sedative. A 100-mm visual analog scale was used daily to assess patients' anxiety. RESULTS: The sample was 59% male and 89% white. Mean values were age, 50.6 years; score on the Acute Physiology and Chronic Health Evaluation, 60.1; and protocol duration, 3.4 days. Five dexmedetomidine patients had blood pressure and/or heart rate lower than safety parameters, necessitating short-term treatment. Nurses' adherence to reporting of safety parameters was 100%; adherence to the dexmedetomidine titration algorithm was 73%. Overall baseline anxiety score was 38.4 and did not change significantly (betaday = 2.1; SE, 2.5; P = .40). Most dexmedetomidine patients (92%) were satisfied or very satisfied with their ability to self-administer medication. CONCLUSIONS: For select patients, self-administration of dexmedetomidine is safe and acceptable. PMID- 28668915 TI - Mechanical Ventilation and Cytopathological Changes in the Oral Mucosa. AB - BACKGROUND: The oral mucosa is an important defense barrier to penetration of microorganisms. Thus, changes in the oral epithelium might indicate risk for infection in intensive care patients receiving mechanical ventilation. OBJECTIVE: To evaluate the oral mucosa of intensive care patients who did or did not receive mechanical ventilation by using liquid-base exfoliative cytology. METHODS: The sample consisted of 3 groups: 27 patients admitted to intensive care during a 7- to 14-day period who received mechanical ventilation, 29 patients admitted during the same period who did not receive mechanical ventilation, and 27 healthy patients who had no lesions in the mouth. For all 3 groups, samples were collected from the buccal mucosa by using cytology brushes. Smears were applied to glass slides before Papanicolaou staining and were codified for blind analyses by a cytopathologist. Kruskal-Wallis and Dunn tests were used to analyze the results. RESULTS: Patients receiving mechanical ventilation had higher prevalence and intensity of karyomegaly, perinuclear halos, cell keratinization, deep cells, and leukocyte infiltrates than did patients in the other 2 groups (P < .05). No significant differences were observed between the control group and the group who did not receive mechanical ventilation. CONCLUSIONS: Liquid-base exfoliative cytology can be used to detect preclinical alterations in the oral mucosa. Patients treated with mechanical ventilation are vulnerable to infections, and oral care may be valuable in their prognosis. PMID- 28668916 TI - Improving Family Meetings in Intensive Care Units: A Quality Improvement Curriculum. AB - BACKGROUND: Family meetings in the intensive care unit are associated with beneficial outcomes for patients, their families, and health care systems, yet these meetings often do not occur in a timely, effective, reliable way. OBJECTIVE: The Department of Veterans Affairs Comprehensive End-of-Life Care Implementation Center sponsored a national initiative to improve family meetings in Veterans Affairs intensive care units across the United States. Process measures of success for the initiative were identified, including development of a curriculum to support facility-based quality improvement projects to implement high-quality family meetings. METHODS: Identified curriculum requirements included suitability for distance learning and applicability to many clinical intensive care units. Curriculum modules were cross-mapped to the "Plan-Do-Study Act" model to aid in planning quality improvement projects. A questionnaire was e mailed to users to evaluate the curriculum's effectiveness. RESULTS: Users rated the curriculum's effectiveness in supporting and achieving aims of the initiative as 3.6 on a scale of 0 (not effective) to 4 (very effective). Users adapted the curriculum to meet local needs. The number of users increased from 6 to 17 quality improvement teams in 2 years. All but 3 teams progressed to implementation of an action plan. CONCLUSION: Users were satisfied with the effectiveness and adaptability of a family-meeting quality improvement curriculum to support implementation of a quality improvement project in Veterans Affairs intensive care units. This tool may be useful in facilitating projects to improve the quality of family meetings in other intensive care units. PMID- 28668917 TI - Recovery, Risks, and Adverse Health Outcomes in Year 1 After Extracorporeal Membrane Oxygenation. AB - BACKGROUND: Cross-sectional studies suggest that patients treated with extracorporeal membrane oxygenation (ECMO) have adverse health outcomes and high risk for mental health problems after discharge. OBJECTIVES: To describe the recovery of discharged patients during the first year after ECMO. METHODS: In a prospective cohort study, data were collected 3, 6, and 12 months after discontinuation of ECMO and discharge. Postal surveys included the 36-Item Short Form Health Survey, the EuroQol-5-Dimensions-5-Levels health questionnaire, the Hospital Anxiety and Depression Scale, and the Impact of Event Scale-Revised. Telephone interviews were used to track adverse physical outcomes. The Telephone Interview for Cognitive Status questionnaire was administered at the end of each call. RESULTS: Patients in the study experienced more physical than mental adverse health outcomes, and the risk for mental problems was 2 or 3 times the rate expected. Adverse physical outcomes were common. One-quarter of patients remained significantly restricted; some had severe neurological impairments of the lower extremities. On cognitive tests, about half scored inconclusive or mildly impaired. Patients were often admitted to the hospital. CONCLUSIONS: Physical health was more severely impaired than was mental health, and both types improved over time. The EuroQol-5-Dimensions-5-Levels instrument was useful for detecting neurological problems of the lower extremities early and may qualify as a core outcome measure for patients treated with ECMO. PMID- 28668918 TI - Pediatric Skin Failure. AB - BACKGROUND: The phenomenon of skin failure as distinct from pressure ulcers has been documented in the adult literature. However, in the pediatric population, skin injury continues to be grouped indiscriminately as various types of pressure ulcers. OBJECTIVE: To identify and describe the phenomenon of skin failure in critically ill children. METHODS: Retrospective chart review of 19 patients who had serious skin injuries develop. Organ dysfunction scores, medications, pressure ulcer prevention techniques used, and laboratory values in the 7 days leading up to the development of a skin lesion were evaluated. RESULTS: At the start of the evaluation period, all patients (N = 19) had pressure ulcer prevention measures in place before the development of a serious skin injury. All of the skin lesions were full-thickness injuries on the day they were identified (as opposed to the more gradual progression from simple to complex skin injuries typically seen in pressure ulcers). As predicted, 18 of 19 patients had multiple organ dysfunction syndrome (MODS) in the week leading up to the skin injury. All patients with MODS had at least 2 dysfunctional systems, and 12 patients had 4 or more dysfunctional systems. Of the 19 patients, 8 (42%) progressed to death, compared with 1.8% in our general pediatric intensive care unit population. CONCLUSION: Although the traditional paradigm is that pressure ulcers are preventable, a subset of pressure ulcers in critically ill children may actually represent acute skin failure as a consequence of MODS. PMID- 28668919 TI - Feasibility of Continuous Actigraphy in Patients in a Medical Intensive Care Unit. AB - BACKGROUND: Poor sleep and immobility are common in patients in the medical intensive care unit (MICU) and are associated with adverse outcomes. Interventions to promote sleep and mobilization in the MICU are gaining popularity, but feasible instruments to measure their effectiveness are lacking. Actigraphy may be useful for large-scale, continuous measurement of sleep and activity, but its feasibility in MICU patients has not been rigorously evaluated. OBJECTIVE: To evaluate the feasibility of continuous actigraphy measurement in consecutive MICU patients. METHODS: Wrist and ankle actigraphy data were collected for 48 hours in consenting MICU patients. Actigraphy-based measures of estimated sleep and activity were summarized by using descriptive statistics. Agreement between wrist and ankle measurements was evaluated using Cohen kappa statistics (for sleep quantity) and intraclass correlation coefficients (for activity). RESULTS: Overall, 35 of 48 (73%) eligible patients were enrolled, including 10 requiring mechanical ventilation. Of these patients, 34 (97%) completed the 48-hour actigraphy period; 20 (57%) found the devices comfortable. Wrist devices logged a mean (SD) of 33.4 (8.8) hours of estimated sleep (72% [19%] of recording period) and 19.6 (17.2) movements per 30-second epoch. Ankle devices recorded 43.2 (4.1) hours of estimated sleep (93% [7%] of recording period) and 5.1 (6.0) movements per 30 seconds. CONCLUSIONS: Uninterrupted actigraphy is feasible and generally well tolerated by MICU patients and may be considered for future large-scale studies. Wrist and ankle actigraphy measurements of sleep and activity in this setting agree poorly and cannot be used interchangeably. PMID- 28668920 TI - Communication and Decision-Making About End-of-Life Care in the Intensive Care Unit. AB - BACKGROUND: Clinicians in the intensive care unit commonly face decisions involving withholding or withdrawing life-sustaining therapy, which present many clinical and ethical challenges. Communication and shared decision-making are key aspects relating to the transition from active treatment to end-of-life care. OBJECTIVES: To explore the experiences and perspectives of nurses and physicians when initiating end-of-life care in the intensive care unit. METHODS: The study was conducted in a 24-bed intensive care unit in Melbourne, Australia. An interpretative, qualitative inquiry was used, with focus groups as the data collection method. Intensive care nurses and physicians were recruited to participate in a discipline-specific focus group. Focus group discussions were audio-recorded, transcribed, and subjected to thematic data analysis. RESULTS: Five focus groups were conducted; 17 nurses and 11 physicians participated. The key aspects discussed included communication and shared decision-making. Themes related to communication included the timing of end-of-life care discussions and conducting difficult conversations. Implementation and multidisciplinary acceptance of end-of-life care plans and collaborative decisions involving patients and families were themes related to shared decision-making. CONCLUSIONS: Effective communication and decision-making practices regarding initiating end-of life care in the intensive care unit are important. Multidisciplinary implementation and acceptance of end-of-life care plans in the intensive care unit need improvement. Clear organizational processes that support the introduction of nurse and physician end-of-life care leaders are essential to optimize outcomes for patients, family members, and clinicians. PMID- 28668921 TI - Evidence-Based Review and Discussion Points. PMID- 28668922 TI - The Role of Mindfulness in Enhancing Self-Care for Nurses. PMID- 28668923 TI - Sources of QRS Couplets. PMID- 28668926 TI - Consequences of Moral Distress in the Intensive Care Unit: A Qualitative Study. AB - BACKGROUND: Moral distress is common among personnel in the intensive care unit, but the consequences of this distress are not well characterized. OBJECTIVE: To examine the consequences of moral distress in personnel in community and tertiary intensive care units in Vancouver, Canada. METHODS: Data for this study were obtained from focus groups and analysis of transcripts by themes and sub-themes in 2 tertiary care intensive care units and 1 community intensive care unit. RESULTS: According to input from 19 staff nurses (3 focus groups), 4 clinical nurse leaders (1 focus group), 13 physicians (3 focus groups), and 20 other health professionals (3 focus groups), the most commonly reported emotion associated with moral distress was frustration. Negative impact on patient care due to moral distress was reported 26 times, whereas positive impact on patient care was reported 11 times and no impact on patient care was reported 10 times. Having thoughts about quitting working in the ICU was reported 16 times, and having no thoughts about quitting was reported 14 times. CONCLUSION: In response to moral distress, health care providers experience negative emotional consequences, patient care is perceived to be negatively affected, and nurses and other health care professionals are prone to consider quitting working in the intensive care unit. PMID- 28668925 TI - Perceptions of Workload Burden and Adherence to ABCDE Bundle Among Intensive Care Providers. AB - BACKGROUND: Use of the interprofessional Awakening and Breathing Coordination, Delirium Monitoring and Management, and Early Mobility (ABCDE) bundle is recommended practice in intensive care, but its adoption remains limited. OBJECTIVE: To examine the relationship between intensive care unit provider attitudes regarding the ABCDE bundle and ABCDE bundle adherence. METHODS: A 1 time survey of 268 care providers in 10 intensive care units across the country who had worked at least 4 shifts per month to examine their attitudes toward workload burden, difficulty carrying out the bundle, perceived safety, confidence, and perceived strength of evidence. Logistic regression models were used to examine the relationship of unit-level provider attitudes with ABCDE bundle adherence in 101 patients, adjusted for patients' age, severity of illness, and comorbidity. RESULTS: For every unit increase in workload burden, adherence to the ABCDE bundle decreased 53% (odds ratio [OR], 0.47; 95% CI, 0.28 0.79; P = .004). Bundle difficulty (OR, 0.29; 95% CI, 0.08-1.07), perceived safety (OR, 0.51; 95% CI, 0.10-2.65), confidence (OR, 0.37, 95% CI, 0.10-1.35), and perceived strength of evidence (OR, 0.69; 95% CI, 0.14-3.35) were not associated with ABCDE bundle adherence. For every unit increase in perceived difficulty carrying out the bundle, adherence with early mobility was reduced 59% (OR, 0.41; 95% CI, 0.19-0.90; P = .03). In addition, ABCDE bundle adherence (ie, ventilator bundle) was less than DE bundle adherence (ie, ventilator-free bundle) (97% vs 72%, z = 5.47; P < .001). CONCLUSIONS: Focusing interventions on workload burden and factors influencing bundle difficulty may facilitate ABCDE bundle adherence. PMID- 28668927 TI - Delirium After Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Postoperative delirium is associated with increased mortality. Patients undergoing transcatheter aortic valve replacement are at risk for delirium because of comorbid conditions. OBJECTIVE: To compare the incidence, odds, and mortality implications of delirium between patients undergoing transcatheter replacement and patients undergoing surgical replacement. METHODS: The Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the Intensive Care Unit were used to assess arousal level and delirium prospectively in all patients with severe aortic stenosis who had transcatheter or surgical aortic valve replacement at an academic medical center. Multivariable logistic regression was used to determine the relationship between procedure type and occurrence of delirium. Cox regression was used to assess the association between postoperative delirium and 6-month mortality. RESULTS: A total of 105 patients had transcatheter replacement and 121 had surgical replacement. Patients in the transcatheter group were older (median age, 81 vs 68 years; P < .001) and had more comorbid conditions (median Charlson Comorbidity Index, 3 vs 2; P < .001). Patients in the transcatheter group also had lower incidence (19% vs 21%; P = .65) and odds of delirium developing (odds ratio, 0.4; 95% CI, 0.2-0.9; P = .03). Delirium was independently associated with a 3-fold higher mortality by 6 months (hazard ratio, 3.4; 95% CI, 1.3-8.8; P = .01). CONCLUSIONS: Delirium occurs in at least 1 in 5 patients after transcatheter or surgical aortic valve replacement. Delirium is less likely to develop in the transcatheter group but is associated with higher mortality in both groups. PMID- 28668931 TI - Lamins in the nuclear interior - life outside the lamina. AB - Nuclear lamins are components of the peripheral lamina that define the mechanical properties of nuclei and tether heterochromatin to the periphery. A-type lamins localize also to the nuclear interior, but the regulation and specific functions of this nucleoplasmic lamin pool are poorly understood. In this Commentary, we summarize known pathways that are potentially involved in the localization and dynamic behavior of intranuclear lamins, including their post-translational modifications and interactions with nucleoplasmic proteins, such as lamina associated polypeptide 2alpha (LAP2alpha; encoded by TMPO). In addition, new data suggest that lamins in the nuclear interior have an important role in chromatin regulation and gene expression through dynamic binding to both hetero- and euchromatic genomic regions and promoter subdomains, thereby affecting epigenetic pathways and chromatin accessibility. Nucleoplasmic lamins also have a role in spatial chromatin organization and may be involved in mechanosignaling. In view of this newly emerging concept, we propose that the previously reported cellular phenotypes in lamin-linked diseases are, at least in part, rooted in an impaired regulation and/or function of the nucleoplasmic lamin A/C pool. PMID- 28668932 TI - Molecular mechanisms of kinesin-14 motors in spindle assembly and chromosome segregation. AB - During eukaryote cell division, molecular motors are crucial regulators of microtubule organization, spindle assembly, chromosome segregation and intracellular transport. The kinesin-14 motors are evolutionarily conserved minus end-directed kinesin motors that occur in diverse organisms from simple yeasts to higher eukaryotes. Members of the kinesin-14 motor family can bind to, crosslink or slide microtubules and, thus, regulate microtubule organization and spindle assembly. In this Commentary, we present the common subthemes that have emerged from studies of the molecular kinetics and mechanics of kinesin-14 motors, particularly with regard to their non-processive movement, their ability to crosslink microtubules and interact with the minus- and plus-ends of microtubules, and with microtubule-organizing center proteins. In particular, counteracting forces between minus-end-directed kinesin-14 and plus-end-directed kinesin-5 motors have recently been implicated in the regulation of microtubule nucleation. We also discuss recent progress in our current understanding of the multiple and fundamental functions that kinesin-14 motors family members have in important aspects of cell division, including the spindle pole, spindle organization and chromosome segregation. PMID- 28668933 TI - Correction: Shot and Patronin polarise microtubules to direct membrane traffic and biogenesis of microvilli in epithelia. PMID- 28668940 TI - 50 Weeks to Our 50th. PMID- 28668941 TI - Effects of Photodynamic Therapy on the Clinical and Biomechanical Efficiency of Mini-Implants: A Randomized Controlled Trial. PMID- 28668942 TI - Spring-Assisted Molar Intrusion in Clear-Aligner Treatment. PMID- 28668943 TI - Targeted Mechanics for Treatment of Patients with Severe Short-Root Anomaly. PMID- 28668944 TI - Miniscrew-Supported Orthodontic Pseudo-Ankylosis for Mesialization of a Lower Third Molar. PMID- 28668945 TI - Measuring Bonded Lingual Retainers. PMID- 28668946 TI - Simultaneous Phase I Expansion and Ectopic Molar Correction with a Hyrax Halterman Appliance. PMID- 28668947 TI - Perioperative Systemic Inflammatory Response following Robot-Assisted Laparoscopic Cystectomy vs. Open Mini-Laparotomy Cystectomy: A Prospective Study. AB - INTRODUCTION: Surgeries, such as radical cystectomy (RC), induce a systemic inflammatory response (SIR). SIR plays an important role in controlling the human immune system. This study aims at comparing the SIR in robot-assisted laparoscopic cystectomy (RALC) to open mini-laparotomy cystectomy (OMC) with a urinary diversion (UD). Comparison was based on immunologic markers of SIR, thus quantifying the degree of tissue trauma. MATERIALS AND METHODS: Forty-two male patients underwent RC with an ileal conduit. Either OMC RC (OMC; n = 20), RALC with extracorporeal UD (RALC-EUD; n = 13), or RALC with intracorporeal UD (RALC IUD; n = 9) was performed. Blood samples were obtained preoperatively (PREOP), immediately after surgery (POD0), 24 (POD1) and 48 h (POD2) postoperatively. Clinical parameters were collected from medical records. RESULTS: Estimated blood loss and blood transfusion volume was higher in OMC (p's < 0.001). The operative time was longer in RALC groups (p < 0.001). On POD0, interleukin (IL)-6 showed significant lower level in RALC-IUD compared to OMC (p = 0.016). IL-10 level was higher at POD0 (p = 0.029) and POD1 (p = 0.038) in OMC vs. RALC-EUD. MCP-1 levels for RALC-IUD were significantly lower compared to RALC-EUD (p = 0.027). CONCLUSIONS: This study found that postoperative SIR was overall less pronounced in RALC, thus depicting reduced tissue trauma. No major clinical differences between RALC-IUD and -EUD were found. PMID- 28668948 TI - Limited Role of Random Skin Biopsy in the Diagnosis of Intravascular Lymphoma in Adult Patients with Hemophagocytic Lymphohistiocytosis. AB - BACKGROUND/AIMS: This study examined the role of random normal skin biopsy in the diagnosis of intravascular lymphoma (IVL) in adult Western patients with clinically diagnosed hemophagocytic lymphohistiocytosis (HLH). METHODS: In a retrospective chart review study, we analyzed a total of 59 skin biopsies that were performed to diagnose IVL in 21 adult patients with HLH seen at Stanford Hospital between 2004 and 2016. RESULTS: Out of the 59 skin biopsies, 42 were taken from clinically normal-appearing skin and 17 from clinically abnormal appearing skin. None of the 59 biopsies revealed a diagnosis of primary or metastatic malignancy, regardless of the malignancy history, clinical presentation, and biopsy and histopathologic characteristics. A review of 8 positive IVL cases at Stanford Hospital including 1 case associated with HLH showed 1 positive diagnosis by a targeted skin biopsy and other positive diagnoses by bone marrow (n = 4), lung (n = 2), brain (n = 2), muscle (n = 1), and nerve (n = 1). CONCLUSION: Random skin biopsies have a limited role in diagnosing IVL in adult patients with HLH, in the setting of a single academic institution in the USA. A review of the literature emphasizes the role of a full body skin exam with a selective skin biopsy in these patients. PMID- 28668949 TI - Naringin Reverses Neurobehavioral and Biochemical Alterations in Intracerebroventricular Collagenase-Induced Intracerebral Hemorrhage in Rats. AB - Intracerebral hemorrhage (ICH) contributes to 10-15% of all strokes and is a high risk factor for morbidity and mortality as compared to other subtypes of stroke, that is, cerebral ischemia and subarachnoid hemorrhage. Oxidative stress (OS) induced neuroinflammation and neuronal cell death contribute towards the hallmarks of ICH. Spared antioxidant levels, increased inflammatory cytokines and free radicals in ICH lead to neuronal death and exaggerate the hallmarks of ICH. Intracerebroventricular (ICV) collagenase (COL-induced neuronal cell damage and cognitive deficits form a widely recognized experimental model for ICH. Naringin (NGN), a natural antioxidant bioflavonoid, has shown potent neuroprotective effects in different neurodegenerative diseases. However, its potential is least explored in pathological conditions, such as hemorrhagic stroke. This study is aimed at exploring the protective effects of NGN against ICV-COL induced behavioral, neurological and memory deficits in rats. ICV-ICH was induced by single, unilateral intrastriatal injection of COL (1 IU in 2 uL, ICV) over 10 min. From 2nd day onwards, NGN was administered in three different doses (10, 20, and 40 mg/kg; p.o.). Animals were subjected to a battery of behavioral tests to assess behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Selitto and von Frey. Poststroke depression and memory deficits were estimated using forced swim test and Morris water maze test, respectively. Poststroke depression, neurological and cognitive deficits were mitigated dose dependently by NGN administration. NGN administration also attenuated the nitro-OS and restored tumor necrosis factor-alpha and endogenous antioxidant levels. Our research demonstrates that NGN has a protective effect against ICH-induced neurocognitive deficits, along with mitigation of oxido nitrosative and inflammatory stress. PMID- 28668950 TI - Histamine Induces Bovine Rumen Epithelial Cell Inflammatory Response via NF kappaB Pathway. AB - BACKGROUND/AIMS: Subacute ruminal acidosis (SARA) is a common disease in high producing lactating cows. Rumenitis is the initial insult of SARA and is associated with the high concentrations of histamine produced in the rumen of dairy cows during SARA. However, the exact mechanism remains unclear. The objective of the current study is to investigate whether histamine induces inflammation of rumen epithelial cells and the underlying mechanism of this process. METHODS: Bovine rumen epithelial cells were cultured and treated with different concentrations of histamine and pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor) cultured in different pH medium (pH 7.2 or 5.5). qRT-PCR, Western-blotting, ELISA and immunocytofluorescence were used to evaluate whether histamine activated the NF-kappaB pathway and inflammatory cytokines. RESULTS: The results showed that histamine significantly increased the activity of IKK beta and the phosphorylation levels of IkappaB alpha, as well as upregulated the mRNA and protein expression levels of NF-kappaB p65 in the rumen epithelial cells cultured in neutral (pH=7.2) and acidic (pH=5.5) medium. Furthermore, histamine treatment also significantly increased the transcriptional activity of NF-kappaB p65. High expression and transcriptional activity of NF-kappaB p65 significantly increased the mRNA expressions and concentrations of inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 1 beta (IL-1beta), thereby inducing the inflammatory response in bovine rumen epithelial cells. However, inhibition of NF-kappaB p65 by PDTC significantly decreased the expressions and concentrations of the inflammatory cytokines induced by histamine in the rumen epithelial cells cultured in the neutral and acidic medium. CONCLUSION: The present data indicate that histamine induces the inflammatory response of bovine rumen epithelial cells through the NF-kappaB pathway. PMID- 28668951 TI - The Relationship between Age, Common Bile Duct Diameter and Diagnostic Probability in Suspected Choledocholithiasis. AB - BACKGROUND: Aging has been associated with increasing common bile duct (CBD) diameter and reported as independently predictive of the likelihood of choledocolithiasis. These associations are controversial with uncertain diagnostic utility in patients presenting with symptomatic disease. The current study examined the relationship between age, CBD size, and the diagnostic probability of choledocolithiasis. METHODS: Symptomatic patients undergoing evaluation for suspected choledocolithiasis from January 2008 to February 2011 were reviewed. In the cohort without choledocolithiasis, the relationship between aging and CBD size was examined as a continuous variable and by comparing mean CBD size across stratified age groups. Multivariate analysis examined the relationship between increasing age and diagnostic probability of choledocolithiasis in all patients. RESULTS: Choledocolithasis was diagnosed by MR cholangiopancreatography (MRCP) or endoscopic retrograde (ERCP) in 496 of 1,000 patients reviewed. Mean CBD was 6.0 mm (+/-2.8 mm) in the 504 of 1,000 patients without choledocolithiasis on ERCP/MRCP. Increasing age had no correlation with CBD size as a continuous variable (r2 = 0.011, p = 0.811). No difference occurred across age groups (Kruskal-Wallis, p = 0.157). Age had no association with diagnostic likelihood of choledocolithiasis (AOR [95% CI] 0.99 [0.98-1.01], adjusted-p = 0.335). CONCLUSION: In a large population undergoing investigation for biliary disease, increasing age was neither associated with increasing CBD diameter nor predictive of the likelihood of choledocolithiasis. PMID- 28668953 TI - IgA Enhances IGF-1 Mitogenic Activity Via Receptor Modulation in Glomerular Mesangial Cells: Implications for IgA-Induced Nephropathy. AB - BACKGROUND/AIM: Glomerulonephritis due to mesangial proliferation is responsible for renal dysfunction in IgA nephropathy (IgAN), however molecular mechanisms of pathogenesis are not well known. We examined the effect of IgA on Insulin-like Growth Factor-1 (IGF-1) activity, a potent mitogen with vital role in growth and development of children, and IGF-1 receptor (IGF-1R) in cultures of glomerular mesangial cells (GMC). METHODS: GMC were isolated from rat kidneys using sieving and enzymatic digestion of tissue homogenates, and cultured in RPMI 1640 medium. GMC cultures were treated with IgA (0-10 ug/ml) in the presence or absence of IGF 1 and fetal bovine serum (FBS), and BrdU incorporation was measured. IGF-1 levels were assayed along with real-time PCR quantification of IGF-1R mRNA. RESULTS: Treatment of GMC with IgA (5 -10 ug/ml) significantly (p < 0.01) increased the BrdU incorporation in the presence or absence of FBS or IGF-1. IgA-mediated effects were more pronounced in IGF-1 treated cells that were significantly (p < 0.01) blocked by pretreatment of cells with IGF-1 receptor antibody or genistein. IgA significantly increased the levels of IGF-1 in culture supernatants and GMC homogenates. IGF-1R mRNA was significantly (p < 0.01) increased in IgA treated cells particularly by co-treatment with IGF-1. CONCLUSION: These findings show that IgA enhances the IGF-1 activity in GMC via stimulation of IGF-1R gene transcription and suggest a role for IGF-1 in pathogenesis of IgAN. PMID- 28668952 TI - Myeloperoxidase Levels and Its Product 3-Chlorotyrosine Predict Chronic Kidney Disease Severity and Associated Coronary Artery Disease. AB - BACKGROUND: The role of myeloperoxidase in chronic kidney disease (CKD) and its association with coronary artery disease (CAD) is controversial. In this study, we compared myeloperoxidase and protein-bound 3-chlorotyrosine (ClY) levels in subjects with varying degrees of CKD and tested their associations with CAD. METHODS: From Clinical Phenotyping Resource and Biobank Core, 111 patients were selected from CKD stages 1 to 5. Plasma myeloperoxidase level was measured using enzyme-linked-immunosorbent assay. Plasma protein-bound 3-ClY, a specific product of hypochlorous acid generated by myeloperoxidase was measured by liquid chromatography mass spectrometry. RESULTS: We selected 29, 20, 24, 22, and 16 patients from stages 1 to 5 CKD, respectively. In a sex-adjusted general linear model, mean +/- SD of myeloperoxidase levels decreased from 18.1 +/- 12.3 pmol in stage 1 to 10.9 +/- 4.7 pmol in stage 5 (p = 0.011). In patients with and without CAD, the levels were 19.1 +/- 10.1 and 14.8 +/- 8.7 pmol (p = 0.036). There was an increase in 3-ClY mean from 0.81 +/- 0.36 mmol/mol-tyrosine in stage 1 to 1.42 +/- 0.41 mmol/mol-tyrosine in stage 5 (p < 0.001). The mean 3-ClY levels in patients with and without CAD were 1.25 +/- 0.44 and 1.04 +/- 0.42 mmol/mol tyrosine (p = 0.023), respectively. C-statistic of ClY when added to myeloperoxidase level to predict CKD stage 5 was 0.86, compared to 0.79 for the myeloperoxidase level alone (p = 0.0097). CONCLUSION: The myeloperoxidase levels decrease from stages 1 to 5, whereas activity increases. In contrast, both myeloperoxidase and ClY levels rise in the presence of CAD at various stages of CKD. Measuring both plasma myeloperoxidase and 3-CLY levels provide added value to determine the burden of myeloperoxidase-mediated oxidative stress. PMID- 28668954 TI - Lipoencephalocele in a Child: An Uncommon Swelling in the Occipital Region. AB - Neural tube defects are common congenital malformations of the central nervous system. The 3 most common neural tube defects are anencephaly, myelomeningocele, and encephalocele. Lipoencephalocele is an extremely uncommon entity with sporadic reports in the literature. We treated a 4-year-old gild with occipital lipoencephalocele. This report presents the clinical presentation and management of the patient along with a review of the relevant literature. PMID- 28668955 TI - Influence of Sex and Age on Posterior Semicircular Canal Thickness. AB - OBJECTIVE: The aim of this study is to determine whether sex and age influence posterior semicircular canal (PSC) thickness. METHODS: This observational study was conducted in 3 tertiary hospitals. The minimal distance between the PSC and the posterior cranial fossa (PSC thickness) was estimated by thin-section multidetector row computed axial tomography (CAT) scan of the temporal bones. Nonselected consecutive patients of all ages (607 temporal bones) were considered. RESULTS: A significant effect was only detected for sex (F = 5.418, p = 0.020); PSC thickness showed a higher mean value in women (mean difference +/- SE: 0.224 +/- 0.096 mm). A significant and negative r value was detected for males aged >45 years (-0.173, p = 0.026); in that group of patients, PSC thickness decreased as age increased (0.018 +/- 0.008 mm/year). For females aged <=45 years, a significant and positive r value was found (0.198, p = 0.022); in that group, PSC thickness increased as age increased (0.020 +/- 0.008 mm/year). CONCLUSIONS: PSC thickness did not significantly evolve with age in young males (<=45 years) but it decreased from age 45 years onwards. On the other hand, PCS thickness increased with age in women until the age of 45 years and it did not significantly change in older females. PMID- 28668956 TI - Inhibition of the lncRNA Mirt1 Attenuates Acute Myocardial Infarction by Suppressing NF-kappaB Activation. AB - BACKGROUND/AIMS: The expression of a novel lncRNA, myocardial infarction associated transcript 1(Mirt1), has been shown to be upregulated in acute myocardial infarction (AMI). However, the role of Mirt1 in AMI is not clear. METHODS: In this study, we analyzed the level of Mirt1 in cardiomyocytes and cardiac fibroblasts in AMI mice. Moreover, adenovirus mediated knockdown of Mirt1 was employed to clarify its roles in AMI mice or cultured cardiac fibroblasts. The cardiac functions and infarct size of AMI mice were examined, and tissues and cultured cells were collected and processed for histology and biochemical examination. RESULTS: We demonstrated that Mirt1 was mainly expressed in cardiac fibroblasts, and that knockdown of Mirt1 improved cardiac functions, decreased cardiomyocytes apoptosis and attenuated inflammatory cell infiltration in vivo. Furthermore, knockdown of Mirt1 in cardiac fibroblasts not only attenuated the apoptosis of cardiomyocytes, but also suppressed the migration of macrophages under hypoxia in vitro. NF-kappaB signaling pathway, activated under hypoxia, was also inhibited by Mirt1 knockdown in fibroblasts. CONCLUSIONS: Knockdown of Mirt1 attenuates AMI injury presumably by decreasing cardiomyocytes apoptosis and reducing inflammatory cell infiltration. These effects could be attributed, at least partly, to inhibition of the NF-kappaB pathway, resulting in decreased expression of inflammatory factors. PMID- 28668957 TI - Pure Testicular Seminoma with Non-Pathologic Elevation of Alpha Fetoprotein: A Case Series. AB - BACKGROUND: Pure testicular seminoma does not express alpha fetoprotein (AFP). However, seminoma patients with mildly elevated serum AFP levels are increasingly reported. As this finding may prompt unwarranted treatment measures, we reviewed our experience with AFP levels in seminoma. PATIENTS AND METHODS: We retrospectively registered AFP levels in 254 consecutive seminoma patients, and in 196 male controls with non-malignant diseases. In those with elevated AFP levels, we re-examined the orchiectomy specimens histologically. We reviewed the clinical course and looked for hepatic disorders. RESULTS: Elevated AFP levels were found in 5 patients (1.97%, 95% CI 0.19-3.68) and in 4 controls (2.04%, 95% CI 0.06-4.02). The elevations were modest and kept elevated throughout the clinical course. No hepatic disorders were recorded. Histologically, pure seminoma was confirmed. CONCLUSION: Unspecific AFP elevations occur in about 2% of seminoma patients. Care-givers should be aware of this particular subgroup of seminoma patients to avoid unwarranted treatment burden. PMID- 28668958 TI - Spectrin and Other Membrane-Skeletal Components in Human Red Blood Cells of Different Age. AB - BACKGROUND: Old human red blood cells (RBCs) have a reduced surface area with respect to young RBCs. If this decrease occurred through the release of vesicles similar to the spectrin-free vesicles that are shed in vitro under different experimental conditions or during storage, there would be no decrease of membrane skeleton, but only of lipid bilayer surface area, during RBC ageing in vivo. However, we observed a decrease in spectrin and other membrane-skeletal proteins in old RBCs. Because RBCs contain components of the ubiquitin-proteasome system and other hydrolytic systems for protein degradation, we asked whether increased membrane-skeleton fragments could be detected in older RBCs. METHODS: Four different anti-spectrin antibodies and an antibody anti-ubiquitin conjugates were used to analyse, by Western blotting, fragments of spectrin and other proteins in RBCs of different age separated in density gradients and characterized for their protein 4.1a/4.1b ratio as a cell age parameter. RESULTS: spectrin fragments do exist in RBCs of all ages, they represent a minute fraction of all spectrin, are membrane-bound and not cytoplasmic and do not increase with cell age. Besides spectrin, other membrane-skeletal components decrease with cell age. CONCLUSION: Observed results challenge the commonly accepted view that decrease in cell membrane throughout RBC life in vivo occurs via the release of spectrin-free vesicles. PMID- 28668959 TI - Contribution of Next-Generation Sequencing to Aquatic and Fish Virology. AB - The recent technological advances in nucleic acid sequencing, called next generation sequencing (NGS), have revolutionized the field of genomics and have also influenced viral research. Aquatic viruses, and especially those infecting fish, have also greatly benefited from NGS technologies, which provide a huge amount of molecular information at a low cost in a relatively short period of time. Here, we review the use of the current high-throughput sequencing platforms with a special focus on the associated challenges (regarding sample preparation and bioinformatics) in their applications to the field of aquatic virology, especially for: (i) discovering novel viruses that may be associated with fish mortalities, (ii) elucidating the mechanisms of pathogenesis, and finally (iii) studying the molecular epidemiology of these pathogens. PMID- 28668960 TI - Genetic Heterogeneity in Chronic Lymphocytic Leukemia: What Can Conventional Cytogenetics Add? PMID- 28668961 TI - Single Nucleotide Polymorphism in the Aetiology of Caries: Systematic Literature Review. AB - Recent progress in the field of molecular biology and techniques of DNA sequence analysis allowed determining the meaning of hereditary factors of many common human diseases. Studies of genetic mechanisms in the aetiology of caries encompass, primarily, 4 main groups of genes responsible for (1) the development of enamel, (2) formation and composition of saliva, (3) immunological responses, and (4) carbohydrate metabolism. The aim of this study was to present current knowledge about the influence of single nucleotide polymorphism (SNP) genetic variants on the occurrence of dental caries. PubMed/Medline, Embase, and Cochrane Library databases were searched for papers on the influence of genetic factors connected with SNP on the occurrence of dental caries in children, teenagers, and adults. Thirty original papers written in English were included in this review. Study groups ranged from 30 to 13,000 subjects. SNPs were observed in 30 genes. Results of the majority of studies confirm the participation of hereditary factors in the aetiology of caries. Three genes, AMELX, AQP5, and ESRRB, have the most promising evidence based on multiple replications and data, supporting a role of these genes in caries. The review of the literature proves that SNP is linked with the aetiology of dental caries. PMID- 28668962 TI - Acute Exercise Stimulates Carnitine Biosynthesis and OCTN2 Expression in Mouse Kidney. AB - BACKGROUND/AIMS: Carnitine is essential for the transport of long-chain FAs (FA) into the mitochondria for energy production. During acute exercise, the increased demand for FAs results in a state of free carnitine deficiency in plasma. The role of kidney in carnitine homeostasis after exercise is not known. METHODS: Swiss Webster mice were sacrificed immediately after a 1-hour moderate intensity treadmill run, and at 4-hours and 8-hours into recovery. Non-exercising mice served as controls. Plasma was analyzed for carnitine using acetyltransferase and [14C] acetyl-CoA. Kidney was removed for gene and protein expression of butyrobetaine hydroxylase (gamma-BBH), organic cation transporter (OCTN2), and peroxisome proliferator-activated receptor (PPARalpha), a regulator of fatty acid oxidation activated by FAs. RESULTS: Acute exercise caused a decrease in plasma free carnitine levels. Rapid return of free carnitine to control levels during recovery was associated with increased gamma-BBH expression. Both mRNA and protein levels of OCTN2 were detected in kidney after exercise and during recovery, suggesting renal transport mechanisms were stimulated. These changes were accompanied with a reciprocal increase in PPARalpha protein expression. CONCLUSIONS: Our results show that the decrease in free carnitine after exercise rapidly activates carnitine biosynthesis and renal transport mechanism in kidney to establish carnitine homeostasis. PMID- 28668963 TI - Metformin-Associated Lactic Acidosis Undergoing Renal Replacement Therapy in Intensive Care Units: A Five-Million Population-Based Study in the North-West of Italy. AB - BACKGROUND: Metformin-associated lactic acidosis (MALA) is a severe complication of drug administration with significant morbidity and mortality. So far no study in large population areas have examined the incidence, clinical profile and outcome of acute kidney injury (AKI)-MALA patients admitted in intensive care units (ICUs) and treated by renal replacement therapy (MALA-RRT). METHODS: Retrospective analysis over a 6-year period (2010-2015) in Piedmont and Aosta Valley regions (5,305,940 inhabitants, 141,174 diabetics treated with metformin) of all MALA-RRT cases. RESULTS: One hundred and seventeen cases of AKI-MALA-RRT were observed (12.04/100,000 metformin treated diabetics, 1.45% of all RRT-ICU patients). Survival rate was 78.3%. The average duration of RRT was 4.0 days at mean dialysis effluent of 977 mL/kg/day. At admission most patients were dehydrated, and experienced shock and oliguria. CONCLUSION: Our data showed that MALA-RRT is a common complication, needing more prevention. Adopted policy of early, extended, continuous and high efficiency dialysis could contribute to an observed high survival rate. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=471917. PMID- 28668964 TI - GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis. AB - BACKGROUND/AIMS: The aim of this study was to determine the direct role of liraglutide (LG) in adipogenesis and lipid metabolism. METHODS: Lipid accumulation was evaluated by oil red O staining, quantitative real-time PCR (qPCR) was performed to determine glucagon-like peptide 1 receptor (GLP-1R), fatty acid synthase (FASN) and adipose triglyceride lipase (ATGL) expression in 3T3-L1 preadipocytes, differentiated adipocytes and in adipose tissues from mice. The effects of LG on 3T3-L1 adipogenesis and lipid metabolism were analyzed with qPCR, Western Blotting, oil red O staining, immunohistochemistry (IHC) and immunofluorescence (IF). All measurements were performed at least three times. RESULTS: LG increased the expression of differentiation marker genes and lipid accumulation during preadipocyte differentiation. In differentiated adipocytes, LG decreased FASN expression, and simultaneously led to CREB phosphorylation and ERK1/2 activation which were abolished by a GLP-1R antagonist, exendin (9-39). LG induced-FASN down-regulation was partially reversed by PKA and ERK1/2 inhibitors. Consistent with above in vitro findings, LG treatment significantly reduced FASN expression in visceral adipose tissues of ob/ob mice, and reduced body weight gain. CONCLUSION: LG promotes preadipocytes differentiation, and inhibits FASN expression in adipocytes. LG induced down-regulation of FASN is at least partially mediated by PKA and MAPK signaling pathways. PMID- 28668965 TI - Membrane Remodelling and Vesicle Formation During Ageing of Human Red Blood Cells. AB - BACKGROUND/AIMS: A high surface-to-volume ratio and a spectrin membrane-skeleton (MS) confer to the mammalian red blood cells (RBCs) their characteristic deformability, mechanical strength and structural stability. During their 120 days of circulatory life in humans, RBCs decrease in size, while remaining biconcave disks, owing to a coordinated decrease in membrane surface area and cell water. It is generally believed that part of the membrane is lost with the shedding of spectrin-free vesicles of the same type that can be obtained in vitro by different treatments. If this were true, an excess of MS would arise in old RBCs, with respect to the lipid bilayer. Aim of this paper was to investigate this aspect. METHODS: Quantification of spectrin by electrophoretic methods was carried out in RBCs of different age. RESULTS: Spectrin decreases, on a per cell basis, with RBC ageing. On the other hand, the membrane raft protein marker flotillin-2, while decreasing in the membrane of old cells, was found to be strongly depleted in the membrane of in vitro-induced vesicles. CONCLUSION: Part of the membrane-skeleton is probably lost together with part of the lipid bilayer in a balanced way. These findings point to a mechanism for the in vivo release of membrane that is different from that which is known to occur in vitro. PMID- 28668966 TI - Long Non-Coding RNA MALAT1 Decreases the Sensitivity of Resistant Glioblastoma Cell Lines to Temozolomide. AB - BACKGROUND/AIM: Multidrug resistance (MDR) is largely responsible for the failure of chemotherapy. The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript (MALAT1) has been reported to be closely related to tumor biology. In the present study, whether MALAT1 contributes to the resistance of glioblastoma cell lines to temozolomide (TMZ) was investigated. METHODS: The glioblastoma cell lines U251 and U87 were exposed to increasing concentrations of TMZ to generate TMZ-resistant colonies (the U251/TMZ and U87/TMZ cell lines). The expression levels of MALAT1 and proteins related to epithelial-mesenchymal transition (EMT) were detected by real-time PCR and western blot, respectively. After the transfection of si-MALAT1 or pcDNA-MALAT1, cell viability, mRNA expression of MDR-associated proteins (MDR1, MRP5 and LRP1), and protein expression of EMT related proteins (ZEB1, Snail and SLUG) were evaluated. RESULTS: The expression of MALAT1 was upregulated in the U251/TMZ and U87/TMZ cell lines compared to that in U251 and U87 cell lines, respectively. The treatment of si-MALAT1 decreased MDR1, MRP5, and LRP1 expression, enhanced cell sensitivity to TMZ, and downregulated ZEB1 protein expression, whereas pcDNA MALAT1 had the opposite effects. However, the effects of si-MALAT1 on MDR associated protein expression, cell viability, and EMT status were reversed by the transfection of pcDNA-ZEB1, and the effects of pcDNA-MALAT1 were reversed by the transfection of si-ZEB1. In vivo, MALAT1 overexpression enhanced tumors' TMZ resistance and upregulated ZEB1 expression. CONCLUSION: MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by regulating ZEB1. PMID- 28668967 TI - Anatomy Revisited: Hemodialysis Catheter Malposition in the Left Ascending Lumbar Vein. AB - In selected cases, cuffed tunneled catheters via the iliac vein are implanted as a last resort access for hemodialysis. To monitor the correct position, sonography of the inferior vena cava (IVC) is sufficient in most cases. Position control using an X-ray of the abdomen is not routinely recommended when femoral catheters are implanted. In this report, we describe the case of a 59-year-old patient on chronic hemodialysis due to granulomatosis with polyangiitis and complex shunt history with multiple shunt occlusions and revisions. The implantation of an iliac-cuffed tunneled catheter led to complications because the catheter was malpositioned into the left ascending lumbar vein (ALV). It is important to be aware of potential incorrect positioning of dialysis catheters into the ALV. Due to the anatomical relation to the IVC, this happens more frequently on the left side than on the right side. In case of doubt, the correct placement of large-bore catheters via iliac access route should be verified by means of appropriate imaging before hemodialysis is performed. PMID- 28668968 TI - Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction. AB - BACKGROUND Endothelial dysfunction is an important pathophysiologic feature in many smoke-related diseases. Endothelial progenitor cells (EPCs) are the precursors of endothelial cells and play a fundamental role in the maintenance of endothelial integrity and function. Endothelial nitric oxide synthase (eNOS) is the dominant NOS isoform in the vasculature and plays a central role in the maintenance of endothelial homeostasis. p16(INK4a) is a cyclin-dependent kinase inhibitor and could be regarded as a major dominant senescence gene. The present study aimed to determine whether the expression of eNOS and p16(INK4a) in EPCs is related to EPCs function and the possible epigenetic mechanism, if any. MATERIAL AND METHODS We investigated EPCs capacity for proliferation, adhesion, and secretion, and the expression of eNOS and p16(INK4a) in EPCs which were altered by cigarette smoke extract (CSE) in vitro. Furthermore, Decitabine (Dec), an agent of demethylation, was used to examine whether it could alter the changes induced by CSE. RESULTS The present study demonstrated that EPCs altered by CSE in vitro displayed decreased capacities of proliferation, adhesion, and secretion, which was accompanied by decreased eNOS expression and increased p16(INK4a) expression in EPCs. Furthermore, Dec could alleviate the changes in the expression of eNOS and p16(INK4a), and protect against the EPCs dysfunction caused by CSE. CONCLUSIONS The decreased eNOS expression and increased p16(INK4a) expression was associated with dysfunction of EPCs caused by CSE. The mechanism of methylation, one of the most common epigenetic mechanism, may be involved in the EPCs dysfunction caused by CSE. PMID- 28668969 TI - Food for thought ... the first ten years. PMID- 28668970 TI - Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis. AB - PURPOSE AND HYPOTHESIS: Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles tendon rupture (ATR) has been shown to reduce the risk of deep venous thrombosis. The purpose of this study was to investigate whether IPC can also promote tendon healing. METHODS: One hundred and fifty patients with surgical repair of acute ATR were post-operatively leg immobilized and prospectively randomized. Patients were allocated for 2 weeks of either adjuvant IPC treatment (n = 74) or treatment-as-usual (n = 74) in a plaster cast without IPC. The IPC group received 6 h daily bilateral calf IPC applied under an orthosis on the injured side. At 2 weeks post-operatively, tendon healing was assessed using microdialysis followed by enzymatic quantification of tendon callus production, procollagen type I (PINP) and type III (PIIINP) N-terminal propeptide, and total protein content. 14 IPC and 19 cast patients (control group) consented to undergo microdialysis. During weeks 3-6, all subjects were leg-immobilized in an orthosis without IPC. At 3 and 12 months, patient-reported outcome was assessed using reliable questionnaires (ATRS and EQ 5D). At 12 months, functional outcome was measured using the validated heel-rise test. RESULTS: At 2 weeks post-rupture, the IPC-treated patients exhibited 69% higher levels of PINP in the ruptured Achilles tendon (AT) compared to the control group (p = 0.001). Interestingly, the IPC-treated contralateral, intact AT also demonstrated 49% higher concentrations of PINP compared to the non treated intact AT of the plaster cast group (p = 0.002). There were no adverse events observed associated with IPC. At 3 and 12 months, no significant (n.s.) differences between the two treatments were observed using patient-reported and functional outcome measures. CONCLUSIONS: Adjuvant IPC during limb immobilization in patients with ATR seems to effectively enhance the early healing response by upregulation of collagen type I synthesis, without any adverse effects. Whether prolonged IPC application during the whole immobilization period can also lead to improved long-term clinical healing response should be further investigated. The healing process during leg immobilization in patients with Achilles tendon rupture can be improved through adjuvant IPC therapy, which additionally prevents deep venous thrombosis. LEVEL OF EVIDENCE: Randomized controlled trial, Level I. PMID- 28668971 TI - Arthroscopic arthrolysis provides good clinical outcome in post-traumatic and degenerative elbow stiffness. AB - PURPOSE AND HYPOTHESIS: The purpose of this retrospective study was to report on the functional outcome after arthroscopic arthrolysis in patients with post traumatic or degenerative elbow stiffness. It was hypothesized that this operative procedure leads to improved range of motion (ROM) and improved functional outcome in both groups. METHODS: Patients who underwent arthroscopic arthrolysis of the elbow between 2010 and 2015 were included in this study. Forty two patients with an average age of 41.0 +/- 13.5 years were available for evaluation. The mean follow-up was 28.3 +/- 14.9 months. With regard to aetiology of elbow contractures, patients were divided into post-traumatic (group A) and degenerative (group B) cohort. General patients' data, previous surgical treatment and ROM were recorded. At follow-up evaluation, the clinical outcome was assessed by the ROM, visual analogue scale (VAS) for pain assessment and the Elbow Self-Assessment Score (ESAS). RESULTS: The mean arc of motion of group A (n = 20) increased from preoperatively 74.3 degrees to 120.5 degrees postoperatively (p < 0.001); group B (n = 22) showed an improvement of 104.6 degrees preoperatively to 123.4 degrees after surgery (p = 0.002). Mean improvement was 46.3 degrees +/- 27.5 degrees in group A and 16.4 degrees +/- 19.4 degrees in group B. Mean post-operative VAS was 0.9 +/- 1.5 in group A and 1.3 +/- 2.2 in group B. 92.9% of patients achieved a functional arc of elbow motion >100 degrees . The ESAS indicated good to excellent clinical outcome showing 88.8 +/- 10.0 points in group A and 84.1 +/- 21.4 points in group B. Thirty-six patients (85.7%) returned to their previous work level after surgery. CONCLUSIONS: Arthroscopic arthrolysis is an effective treatment option for patients with restriction in elbow motion reasoned by post-traumatic or degenerative changes. Both groups showed a significant improvement of ROM and comparable outcome scores. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 28668972 TI - A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis. AB - Alpha-1-antitrypsin deficiency (AATD) is a genetic condition caused by SERPINA1 mutations, which culminates into lower protease inhibitor activity in the serum and predisposes to emphysema. Clinical manifestations of AATD are often associated to ZZ (p.Glu342Lys) and SZ (p.Glu264Val) genotypes and less frequently to rare deficiency or null alleles in heterozygous and homozygous states. We report a case of a 52-year-old woman with bronchiectasis without other potential causes other than an electrophoresis that showed a decrease of alpha-1 globin band and AAT levels below the normal value (78 mg/dl; v.n. 90-200 mg/dl). No S or Z mutation was identified, but sequencing analysis found a novel missense variant Ile74Asn (c.221T > A) in heterozygous state on an M3 allele (Glu400Asp) in the exon 2 of the SERPINA-1gene, probably leading to a dysfunctional protein. This mutation has never been previously identified, and it is interesting to note the association with bronchiectasis in the absence of emphysema. PMID- 28668973 TI - Trends in the perceived body size of adolescent males and females in Scotland, 1990-2014: changing associations with mental well-being. AB - OBJECTIVES: This paper explores trends in Scottish adolescents' body size perceptions and associated mental well-being outcomes. METHODS: Data were collected on Scottish 11-, 13-, and 15-year-olds by the Health Behaviour in School-aged Children study between 1990 and 2014 (n = 42,312). Logistic regression was used to examine changes in the prevalence of over- and underweight perceptions. Ordinal and linear regressions were used to examine changes in the association between body perception and mental well-being. RESULTS: Little change was observed in over- or underweight perceptions. However, relative to those perceiving their body as 'about right', those perceiving themselves as overweight reported decreasing confidence (all groups), decreasing happiness (11- and 13 year-old girls), and increasing psychological health symptoms (all girls and 15 year-old boys). Perceived underweight is associated with poor well-being, especially in males, but we present little evidence that this is a recent phenomenon. CONCLUSIONS: We present evidence suggesting that the association between body size perception and poor mental health in adolescence is changing over time. This may play a role in the recently observed worsening of mental well being in Scottish adolescents. PMID- 28668974 TI - Rickettsiosis: a rare challenge in ICU. PMID- 28668975 TI - Marker-assisted introgression of resistance to fusarium wilt race 2 in Pusa 256, an elite cultivar of desi chickpea. AB - Fusarium wilt caused by F. oxysporum f. sp. ciceris causes extensive damage to chickpea (Cicer arietinum L.) in many parts of the world. In the central part of India, pathogen race 2 (Foc 2) causes severe yield losses. We initiated molecular marker-assisted backcrossing (MABC) using desi cultivar, Vijay, as a donor to introgress resistance to this race (Foc2) in Pusa 256, another elite desi cultivar of chickpea. To confirm introgression of resistance for this race, foreground selection was undertaken using two SSR markers (TA 37 and TA110), with background selection to observe the recovery of recurrent parent genome using 45 SSRs accommodated in 8 multiplexes. F1 plants were confirmed with molecular markers and backcrossed with Pusa 256, followed by cycles of foreground and background selection at each stage to generate 161 plants in BC3F2 during the period 2009-2013. Similarly, 46 BC3F1 plants were also generated in another set during the same period. On the basis of foreground selection, 46 plants were found homozygotes in BC3F2. Among them, 17 plants recorded >91% background recovery with the highest recovery percentage of 96%. In BC3F1 also, 14 hybrid plants recorded a background recovery of >85% with the highest background recovery percentage of >94%. The identified plants were selfed to obtain 1341 BC3F3 and 2198 BC3F2 seeds which were screened phenotypically for resistance to fusarium wilt (race 2) besides doing marker analysis. Finally, 17 BC3F4 and 11 BC3F3 lines were obtained which led to identification of 5 highly resistant lines of Pusa 256 with Foc 2 gene introgressed in them. Development of these lines will help in horizontal as well as vertical expansion of chickpea in central part of India. PMID- 28668976 TI - Abscisic acid-regulated protein degradation causes osmotic stress-induced accumulation of branched-chain amino acids in Arabidopsis thaliana. AB - MAIN CONCLUSION: Whereas proline accumulates through de novo biosynthesis in plants subjected to osmotic stress, leucine, isoleucine, and valine accumulation in drought-stressed Arabidopsis thaliana is caused by abscisic acid-regulated protein degradation. In response to several kinds of abiotic stress, plants greatly increase their accumulation of free amino acids. Although stress-induced proline increases have been studied the most extensively, the fold-increase of other amino acids, in particular branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), is often higher than that of proline. In Arabidopsis thaliana (Arabidopsis), BCAAs accumulate in response to drought, salt, mannitol, polyethylene glycol, herbicide treatment, and nitrogen starvation. Plants that are deficient in abscisic acid signaling accumulate lower amounts of BCAAs, but not proline and most other amino acids. Previous bioinformatic studies had suggested that amino acid synthesis, rather than protein degradation, is responsible for the observed BCAA increase in osmotically stressed Arabidopsis. However, whereas treatment with the protease inhibitor MG132 decreased drought induced BCAA accumulation, inhibition of BCAA biosynthesis with the acetolactate synthase inhibitors chlorsulfuron and imazapyr did not. Additionally, overexpression of BRANCHED-CHAIN AMINO ACID TRANSFERASE2 (BCAT2), which is upregulated in response to osmotic stress and functions in BCAA degradation, decreased drought-induced BCAA accumulation. Together, these results demonstrate that BCAA accumulation in osmotically stressed Arabidopsis is primarily the result of protein degradation. After relief of the osmotic stress, BCAA homeostasis is restored over time by amino acid degradation involving BCAT2. Thus, drought-induced BCAA accumulation is different from that of proline, which is accumulated due to de novo synthesis in an abscisic acid-independent manner and remains elevated for a more prolonged period of time after removal of the osmotic stress. PMID- 28668977 TI - Organization and evolution of four differentially amplified tandem repeats in the Cucumis hystrix genome. AB - MAIN CONCLUSION: Three subtelomeric satellites and one interstitial 5S rDNA were characterized in Cucumis hystrix, and the pericentromeric signals of two C. hystrix subtelomeric satellites along C. sativus chromosomes supported the hypothesis of chromosome fusion in Cucumis. Tandem repeats are chromosome structural fractions consisting of highly repetitive sequences organized in large tandem arrays in most eukaryotes. Differentiation of tandem repeats directly affects the chromosome structure, which contributes to species formation and evolution. Cucumis hystrix (2n = 2x = 24) is the only wild Cucumis species grouped into the same subgenus with C. sativus (2n = 2x = 14), hence its phylogenetic position confers a vital role for C. hystrix to understand the chromosome evolution in Cucumis. However, our knowledge of C. hystrix tandem repeats is insufficient for a detailed understanding of the chromosome evolution in Cucumis. Based on de novo tandem repeat characterization using bioinformatics and in situ hybridization (ISH), we identified and characterized four differentially amplified tandem repeats, Cucumis hystrix satellite 1-3 (CuhySat1 CuhySat3) located at the subtelomeric regions of all chromosomes, and Cucumis hystrix 5S (Cuhy5S) located at the interstitial regions of one single chromosome pair. Comparative ISH mapping using CuhySat1-3 and Cuhy5S revealed high homology of tandem repeats between C. hystrix and C. sativus. Intriguingly, we found signal distribution variations of CuhySat2 and CuhySat3 on C. sativus chromosomes. In comparison to their subtelomeric signal distribution on C. hystrix chromosomes, CuhySat3 showed a pericentromeric signal distribution and CuhySat2 showed both subtelomeric and pericentromeric signal distributions on C. sativus chromosomes. This detailed characterization of four C. hystrix tandem repeats significantly widens our knowledge of the C. hystrix chromosome structure, and the observed signal distribution variations will be helpful for understanding the chromosome evolution of Cucumis. PMID- 28668978 TI - Prognostic value of tricuspid regurgitation velocity and probability of pulmonary hypertension in patients undergoing transcatheter aortic valve implantation. AB - Pulmonary hypertension (PH) is associated with adverse clinical outcomes after transcatheter aortic valve implantation (TAVI). We sought to investigate the effects of tricuspid regurgitant velocity (TRV) and echocardiographic probability of PH on clinical outcomes of patients undergoing TAVI. A total of 148 consecutive patients undergoing TAVI were included and stratified as having "low" (TRV <=2.8 m/s), "intermediate" (TRV 2.9-3.4 m/s), and "high" (TRV >3.4 m/s) probability of PH. Only the patients from the "high" probability group were considered as patients with PH. All-cause mortality, complications rate and quality of life (QoL) were assessed according to VARC-2 recommendations. Of 148 patients, 65 (43.9%) were considered as patients with PH. These presented with higher NYHA class at baseline (p = 0.027) and had more frequently a history of previous stroke/transient ischemic attack (p = 0.019). A difference in all-cause mortality was noted at 12 months [PH (-) vs. PH (+): 9.6 vs. 21.5%; p = 0.043]; however, it was no longer significant after adjustment for age and gender (OR 2.39, 95% CI 0.91-6.24; p = 0.08). Unadjusted and adjusted rates of all-cause death at maximal follow-up of 13.3 (6.0-31.1) months were higher in patients with PH. However, the presence of PH was not identified as an independent predictor of all-cause mortality at follow-up. No difference in other complications rates and QoL were noted. The presence of TRV >3.4 m/s indicating "high" probability of PH may predict impaired clinical outcomes after TAVI. No impact of PH on QoL outcomes was confirmed. PMID- 28668979 TI - Comparison of systemic right ventricular function in transposition of the great arteries after atrial switch and congenitally corrected transposition of the great arteries. AB - In patients with transposition of the great arteries corrected by interatrial baffle (TGA) and those with congenitally corrected transposition of the great arteries (ccTGA) the right ventricle (RV) is subjected to systemic pressure and fails prematurely. Previous studies have demonstrated RV dysfunction may be more pronounced in patients with TGA. The present study sought to compare patients with TGA and ccTGA using three-dimensional (3D) techniques to comprehensively analyze the shape, volume, global and regional function in the systemic RV. We compared RV size, shape, and regional and global function in 25 patients with TGA, 17 patients with ccTGA, and 9 normal subjects. The RVs were reconstructed from cardiac Magnetic Resonance Images for 3D analyses. Compared to normal, the RV in TGA and ccTGA was dilated, rounded, and reduced in function. Compared to each other, TGA and ccTGA patients had similar RV size and shape. Global RV function was lower in TGA than ccTGA when assessed from ejection fraction (EF) (30 +/- 7 vs. 35 +/- 7, p = 0.02) and from normalized tricuspid annular systolic plane excursion (TAPSE) (0.10 +/- 0.04 vs. 0.18 +/- 0.04, p < 0.01). Basilar RV function was poorer in the TGA patients when compared to ccTGA. The systemic RVs in both TGA and ccTGA are dilated, spherical, and poorly functioning. Compared to ccTGA, TGA RVs have reduced TAPSE and worse basilar hypokinesis. PMID- 28668980 TI - One-Year Prospective Study on Passion and Gambling Problems in Poker Players. AB - The concept of passion is relevant to understanding gambling behaviours and gambling problems. Longitudinal studies are useful to better understand the absence and development of gambling problems; however, only one study has specifically considered poker players. Using a longitudinal design, this study aims to determine the influence, 1 year later, of two forms of passion-harmonious and obsessive-on gambling problems in poker players. A total of 116 poker players was recruited from across Quebec, Canada. The outcome variable of interest was participants' category on the Canadian Pathological Gambling Index, and the predictive variable was the Gambling Passion Scale. Multiple logistic regression analyses were conducted to identify independent risk factors of at-risk poker players 1 year later. Obsessive passion at baseline doubled the risk of gambling problems 1 year later (p < 0.01); for harmonious passion, there was no association. Number of gambling activities, drug problems, and impulsivity were also associated with at-risk gambling. This study highlights the links between obsessive passion and at-risk behaviours among poker players. It is therefore important to prevent the development of obsessive passion among poker players. PMID- 28668981 TI - Implicit Valuation of the Near-Miss is Dependent on Outcome Context. AB - Gambling studies have described a "near-miss effect" wherein the experience of almost winning increases gambling persistence. The near-miss has been proposed to inflate the value of preceding actions through its perceptual similarity to wins. We demonstrate here, however, that it acts as a conditioned stimulus to positively or negatively influence valuation, dependent on reward expectation and cognitive engagement. When subjects are asked to choose between two simulated slot machines, near-misses increase valuation of machines with a low payout rate, whereas they decrease valuation of high payout machines. This contextual effect impairs decisions and persists regardless of manipulations to outcome feedback or financial incentive provided for good performance. It is consistent with proposals that near-misses cause frustration when wins are expected, and we propose that it increases choice stochasticity and overrides avoidance of low valued options. Intriguingly, the near-miss effect disappears when subjects are required to explicitly value machines by placing bets, rather than choosing between them. We propose that this task increases cognitive engagement and recruits participation of brain regions involved in cognitive processing, causing inhibition of otherwise dominant systems of decision-making. Our results reveal that only implicit, rather than explicit strategies of decision-making are affected by near-misses, and that the brain can fluidly shift between these strategies according to task demands. PMID- 28668982 TI - Community structure of helminth parasites in two closely related South African rodents differing in sociality and spatial behaviour. AB - To understand the effect of social and spatial behaviour of a host on parasite community organization, we studied species co-occurrence and nestedness of assemblages of gastrointestinal helminths in two closely related rodents, solitary and mobile Rhabdomys dilectus and social and territorially conservative Rhabdomys pumilio, and asked whether helminth communities of the two hosts are characterized by a non-random pattern and whether the occurrence or degree of this non-randomness (a) differs between hosts and (b) is associated with abundance, prevalence and diversity of helminths. We found that although the general pattern of helminth co-occurrence was similar in the two hosts, helminth infracommunities of R. dilectus and R. pumilio differed in the relative frequency of positive and negative pairwise species co-occurrences (only positive in the former and both positive and negative in the latter). Nestedness-related patterns in helminth infracommunities were found in R. pumilio (predominantly anti-nested) but not R. dilectus (predominantly non-nested), whereas the opposite was the case for their component communities (non-nested versus nested, respectively). The level of infection was generally associated with the manifestation of non randomness in helminth assemblages. Different infection parameters affected different structure patterns in the two hosts. We concluded that community structure of helminths in Rhabdomys spp. results from complex interactions between parasite- and host-associated factors. PMID- 28668983 TI - The role of Blastocystis sp. and Dientamoeba fragilis in irritable bowel syndrome: a systematic review and meta-analysis. AB - Irritable bowel syndrome (IBS) is globally one of the most prevalent gastrointestinal disorders with a negative impact on quality of life and socio economic status of patients. Recently, controversial evidences suggest that Blastocystis sp. and Dientamoeba fragilis infections may be implicated in the development of IBS. We performed a systematic review and meta-analysis to examine the possible association regarding this issue. PubMed, ScienceDirect, Scopus, Web of Science, and Cochrane electronic databases were searched (up to February 2017) to identify the relevant studies. Pooled odds ratio (OR) and 95% confidence intervals were estimated using a random effects meta-analysis model on data from included studies. A total of 17 studies including 5882 participants (2527 patients and 3310 controls) met the eligibility criteria. Individuals with Blastocystis infection were found to have a positive association with IBS (OR, 2.19; 95% CI, 1.54-3.13), while this association was not observed for D. fragilis infection (OR, 1.13; 95% CI, 0.22-5.72). In subgroup analysis for Blastocystis infection, the pooled ORs were OR 2.29, 95% CI 1.55-3.41; OR 1.70, 95% CI 0.83 3.44; and OR 3.83, 95% CI 2.34-6.27 for hospital-based, healthy volunteers, and combined controls, respectively. Considering the subtypes, meta-analysis result demonstrated significant positive ORs for ST1 (OR, 4.40; 95% CI, 2.81-6.90) and ST3 (OR, 1.94; 95% CI, 1.36-2.77) to be potential risk factors for IBS. Our results support the existence of a positive association between Blastocystis sp. and IBS. Further studies with more sample size should be performed to better investigate the real impact of these parasites on the occurrence of IBS. PMID- 28668984 TI - Intra-individual changes in haemosporidian infections over the nesting period in great tit females. AB - Prevalence of haemosporidian parasites in bird populations varies temporally both between years and within a year. In contrast to variation at the population level, relatively little is known about variation in infection attributes at the individual level, especially in non-migratory species. We examined intra individual changes in the presence and identity of haemosporidian parasites (genera Plasmodium and Haemoproteus) over the course of the nesting period in females of great tits (Parus major)-a species considered to be resident over much of its distribution range. Birds were sampled during two stages of the nesting period: nest building and nestling rearing. The mean time interval between sampling occasions was 43 days. Between the first and second samplings, 30.6% of females gained at least one parasite lineage and 18.5% lost the lineage. Haemoproteus gains were over three times more common than Plasmodium gains. The probability of the lineage gain decreased with the date of the first sampling, was higher in individuals in better body condition and differed between years, but was not associated with the host age. The probability of the lineage loss was not explained by any of the considered parameters except for year. These results indicate that in a large proportion of a population, infection attributes (presence/absence and/or parasite identity) may change over the nesting period and the occurrence of such changes may be associated with the individual quality. Consequently, this phenomenon should be taken into account to correctly interpret parasite-mediated effects. PMID- 28668986 TI - A rebus to say goodbye: a suicide note on a bedsheet. PMID- 28668985 TI - Toxoplasma genotyping in congenital toxoplasmosis in Upper Egypt: evidence of type I strain. AB - Toxoplasma gondii has subpopulation structures in different geographical regions caused by less frequent sexual recombination, population sweeps, and biogeography. The majority of strains isolated in North America and Europe fall into one of three clonal lineages, referred to as types I, II, and III. So far, little is known about genetics of Toxoplasma strains in Africa. The present study aimed to determine the genotype of Toxoplasma strains obtained directly from trophoblastic/placental tissues of 29 complicated pregnant women using multilocus nested-PCR-RFLP technique depending on four independent genetic loci (5' SAG2 and 3' SAG2), SAG3, GRA6, and BTUB genes. All samples gave positive amplicons at 5' 3' SAG2 and SAG3 genes. Meanwhile, no amplification products were observed in 12 (41.37%) and 10 (34.48%) samples with GRA6 and BTUB genes, respectively. The restriction pattern revealed the presence of genotype I in all samples, except one sample, which revealed atypical genotype with unusual restriction pattern at 3' SAG2 gene. The negative amplifications in some samples could be due to presence of mutations or polymorphisms in the primer binding sites of these isolates, raising the possibility of mixed or recombinant genotypes. To the best of our knowledge, this is the first time to perform genotype analysis study based on Multiplex nPCR-RFLP technique for genetic characterization of T. gondii in Egypt. Besides, it is the first time to prove that the most prevalent strain of T. gondii, responsible for congenital toxoplasmosis in Upper Egypt, is the highly virulent type I. Atypical genotype was detected as well. PMID- 28668987 TI - A case of fatal idiosyncratic reaction to the designer drug 3,4 methylenedioxypyrovalerone (MDPV) and review of the literature. AB - The stimulant designer drug 3,4-methylenedioxypyrovalerone (MDPV) was first synthesized by Boehringer Ingelheim in 1969 and introduced on the black market in 2006. Only a small number of fatal intoxication cases have been reported in the literature, all with significant blood MDPV concentrations. In this report, we describe one fatality attributed to an idiosyncratic reaction to MDPV. The victim displayed agitation, violent behavior and delirium followed by cardiac arrest. Hyperthermia was observed at the hospital. The MDPV cardiac and femoral blood concentrations were 6 ng/mL. The presence of excited delirium syndrome and MDPV, a drug with a pharmacology similar to cocaine, leads to the conclusion that the victim suffered a fatal adverse reaction to MDPV. This is the first published case of idiosyncratic reaction to MDPV. PMID- 28668988 TI - Blowfly puparia in a hermetic container: survival under decreasing oxygen conditions. AB - Despite widely accepted standards for sampling and preservation of insect evidence, unrepresentative samples or improperly preserved evidence are encountered frequently in forensic investigations. Here, we report the results of laboratory studies on the survival of Lucilia sericata and Calliphora vomitoria (Diptera: Calliphoridae) intra-puparial forms in hermetic containers, which were stimulated by a recent case. It is demonstrated that the survival of blowfly intra-puparial forms inside airtight containers is dependent on container volume, number of puparia inside, and their age. The survival in both species was found to increase with an increase in the volume of air per 1 mg of puparium per day of development in a hermetic container. Below 0.05 ml of air, no insect survived, and above 0.2 ml of air per 1 mg of puparium per day, survival reached its maximum. These results suggest that blowflies reveal a single, general pattern of survival under decreasing oxygen conditions and that this pattern is a product of number of developing insects, their age and the initial amount of available air. Implications for forensic entomology are discussed. PMID- 28668989 TI - Sudden unexplained death in alcohol misuse (SUDAM) patients have different characteristics to those who died from sudden arrhythmic death syndrome (SADS). AB - There is growing awareness of sudden unexplained death in alcohol misuse (SUDAM) in which there is no obvious cause of death, no evidence of acute alcohol toxicity or alcoholic ketoacidosis, and the heart is morphologically normal. This study describes the characteristics of a cohort with SUDAM from a tertiary cardiovascular referral center and compares the findings with those of individuals who died from sudden arrhythmic death syndrome (SADS). Cases in this retrospective cross-sectional study were identified from a database of referrals to our center spanning approximately 40 years. Cases with recorded heavy use of alcohol and non-alcohol users were selected, then limited to those with SUDAM or SADS aged 16 to 64 years. 62 cases of SUDAM and 41 cases of SADS were identified. The SUDAM group were older than the SADS group; mean age 35.8 years and 27.7 years respectively (P=0.0002). There was also a higher incidence of significant psychiatric illness in SUDAM (19.7%) than SADS (2.4%) cases. Post mortem liver examination was more likely to reveal heavy livers in SUDAM than SADS (2196.1g and 1572.4g respectively; P=0.0033) and more fatty liver change (24.2% and 2.4%). SUDAM tends to occur in individuals who are older and have heavier livers than those with SADS. Psychiatric illness is also more common. SADS, unlike SUDAM, is often associated with heritable channelopathies that may affect surviving family members. Therefore, differentiating between SUDAM and SADS identifies families likely to benefit from screening for these mutations, thus preventing further sudden arrhythmic deaths. PMID- 28668990 TI - Improving binding mode and binding affinity predictions of docking by ligand based search of protein conformations: evaluation in D3R grand challenge 2015. AB - The growing number of protein-ligand complex structures, particularly the structures of proteins co-bound with different ligands, in the Protein Data Bank helps us tackle two major challenges in molecular docking studies: the protein flexibility and the scoring function. Here, we introduced a systematic strategy by using the information embedded in the known protein-ligand complex structures to improve both binding mode and binding affinity predictions. Specifically, a ligand similarity calculation method was employed to search a receptor structure with a bound ligand sharing high similarity with the query ligand for the docking use. The strategy was applied to the two datasets (HSP90 and MAP4K4) in recent D3R Grand Challenge 2015. In addition, for the HSP90 dataset, a system-specific scoring function (ITScore2_hsp90) was generated by recalibrating our statistical potential-based scoring function (ITScore2) using the known protein-ligand complex structures and the statistical mechanics-based iterative method. For the HSP90 dataset, better performances were achieved for both binding mode and binding affinity predictions comparing with the original ITScore2 and with ensemble docking. For the MAP4K4 dataset, although there were only eight known protein-ligand complex structures, our docking strategy achieved a comparable performance with ensemble docking. Our method for receptor conformational selection and iterative method for the development of system-specific statistical potential-based scoring functions can be easily applied to other protein targets that have a number of protein-ligand complex structures available to improve predictions on binding. PMID- 28668991 TI - Effect of metalimnetic gradient on phytoplankton and zooplankton (Rotifera, Crustacea) communities in different trophic conditions. AB - Theory predicts and recent study revealed that depth of the thermocline can strongly influence the nutrient availability and composition of plankton communities. We are focused on the effect of metalimnetic gradients on water chemistry and plankton communities in three stratified lakes with different trophic conditions. Vertical changes in water chemistry revealed significant increase of macroelement concentrations in the metalimnion of all studied lakes. However, there was no significant increase of nutrient concentrations in the thermocline of lakes with smoother metalimnetic gradient, whereas sharp and deep thermocline zone caused higher concentration of orthophosphates and dissolved inorganic nitrogen in the metalimnion. The maximum concentrations of phytoplankton were observed just below the thermocline and were caused mostly by the abundance of diatoms and cryptophytes. Vertical distribution of the crustacean zooplankton was similar to the distribution of phytoplankton. Especially, Daphnia cucullata was strongly related with the phytoplankton distribution and reached maximum densities in deep layers with high chlorophyll concentrations, and, conversely, smaller crustacean species and rotifers were not affected by the vertical distribution of phytoplankton. PMID- 28668992 TI - Cervical Cancer Knowledge, Self-Efficacy, and Health Literacy Levels of Married Women. AB - The purpose of this descriptive and relational study is to investigate the relationship between cervical cancer knowledge and self-efficacy and health literacy levels of married women aged 18-65 years. The study sample consisted of 400 married women (18-65 years old) who presented to a family health center. Independent variables were sociodemographic characteristics; dependent variables were cancer knowledge, self-efficacy, and health literacy level. Of the participants, 67% had a Pap smear. The participants' median knowledge score was 13 (min-max = 1-21). As the age increased, so did the knowledge score (p = 0.001). The secondary school graduates had the lowest knowledge level (p = 0.009). The participants' self-efficacy level was moderate (83.18 +/- 7.70). As the educational status increased, so did their self-efficacy. Of the participants, 55.2% had a health literacy level of 7th-8th grade. The health literacy level was lower among the literate, primary school graduate, and advanced-age participants (p = 0.000). Increases in the self-efficacy and health literacy levels of the participants positively affected their knowledge status. The participants' cervical cancer and Pap smear screening knowledge levels increased as their self-efficacy levels increased. The literate or primary school graduate participants had the self-efficacy and health literacy levels. PMID- 28668993 TI - Trauma related admissions to the PICU at Chris Hani Baragwanath Academic Hospital, Johannesburg. AB - BACKGROUND: Paediatric trauma is a major cause of morbidity and mortality in low and middle income countries. Data from these regions are scant. We aimed to describe the demographic and injury profile, treatment modality and outcome of trauma admissions to the paediatric intensive care unit at Chris Hani Baragwanath Academic Hospital (CHBAH). METHODS: A retrospective record review of trauma cases admitted to the PICU at CHBAH from 2011 to 2013 was performed. RESULTS: One-fifth of admissions were due to trauma. 58% of admissions were male. Weekends accounted for 49% of admissions. Road traffic injuries (RTI) (66%) and toxin ingestion (TI) (17%) contributed the majority of admissions. Children aged 0-4 years accounted for 45%, 5-9 years 39%, and 10-15 years 16% of admissions. The mortality rate was 9.0% with RTI accounting for 64%. 64% of mortalities occurred in the 0-4 year cohort. Mean age of survivors (5.8 years) was significantly higher than non survivors (3.4 years) (p < 0.05). 89% of all children required invasive ventilation on PICU admission. Mean length of ventilation in non-survivors (10.2 days) was significantly longer than survivors (4.5 days) (p < 0.05). CONCLUSIONS: RTI accounted for the majority of trauma admissions to our PICU. RTI, female gender and age less than 4 years were all associated with an increased risk for mortality in our study. PMID- 28668994 TI - Validation of FRAX and the impact of self-reported falls among elderly in a general population: the HUNT study, Norway. AB - : Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD) for hip fracture prediction was validated in a Norwegian population 50-90 years. Fracture risk increased with higher FRAX score, and the observed number of hip fractures agreed well with the predicted number, except for the youngest and oldest men. Self-reported fall was an independent risk factor for fracture in women. INTRODUCTION: The primary aim was to validate FRAX without BMD for hip fracture prediction in a Norwegian population of men and women 50-90 years. Secondary, to study whether information of falls could improve prediction of fractures in the subgroup aged 70-90 years. METHODS: Data were obtained from the third survey of the Nord-Trondelag Health Study (HUNT3), the fracture registry in Nord-Trondelag, and the Norwegian Prescription Database (NorPD), including 15,432 women and 13,585 men. FRAX hip without BMD was calculated, and hip fractures were registered for a median follow-up of 5.2 years. The number of estimated and observed fractures was assessed, ROC curves with area under the curve (AUC), and Cox regression analyses. For the group aged 70-90 years, self-reported falls the last year before HUNT3 were included in the Cox regression model. RESULTS: The risk of fracture increased with higher FRAX score. When FRAX groups were categorized in a 10-year percentage risk for hip fracture as follows, <4, 4-7.9, 8-11.9, and >=12%, the hazard ratio (HR) for hip fracture between the lowest and the highest group was 17.80 (95% CI: 12.86-24.65) among women and 23.40 (13.93 39.30) in men. Observed number of hip fractures agreed quite well with the predicted number, except for the youngest and oldest men. AUC was 0.81 (0.78 0.83) for women and 0.79 (0.76-0.83) for men. Self-reported fall was an independent risk factor for fracture in women (HR 1.64, 1.20-2.24), and among men, this was not significant (1.09, 0.65-1.83). CONCLUSIONS: FRAX without BMD predicted hip fracture reasonably well. In the age group 70-90 years, falls seemed to imply an additional risk among women. PMID- 28668995 TI - Partial structure and immunological properties of lipopolysaccharide from marine derived Pseudomonas stutzeri KMM 226. AB - The partial structure and immunology of the lipopolysaccharide (LPS) of Pseudomonas stutzeri KMM 226, a bacterium isolated from a seawater sample collected at a depth of 2000 m, was characterised. The O-polysaccharide was built up of disaccharide repeating units constituted by L-Rhap and D-GlcpNAc: ->2) alpha-L-Rhap-(1->3)-alpha-D-GlcpNAc-(1->. The structural analysis of the lipid A showed a mixture of different species. The major species were hexa-acylated and penta-acylated lipids A, bearing the 12:0(3-OH) in amide linkage and 10:0(3-OH) in ester linkage, while the secondary fatty acids were present only as 12:0. The presence of 12:0(2-OH) was not detected. The immunology experiments demonstrated that P. stutzeri KMM 226 LPS displayed a low ability to induce TNF-alpha, IL 1beta, IL-6, IL-8 and IL-10 cytokine production and acted as an antagonist of hexa-acylated Escherichia coli LPS in human blood in vitro. PMID- 28668996 TI - Dietary L-arginine accelerates pupation and promotes high protein levels but induces oxidative stress and reduces fecundity and life span in Drosophila melanogaster. AB - L-Arginine, a precursor of many amino acids and of nitric oxide, plays multiple important roles in nutrient metabolism and regulation of physiological functions. In this study, the effects of L-arginine-enriched diets on selected physiological responses and metabolic processes were assessed in Drosophila melanogaster. Dietary L-arginine at concentrations 5-20 mM accelerated larval development and increased body mass, and total protein concentrations in third instar larvae, but did not affect these parameters when diets contained 100 mM arginine. Young (2 days old) adult flies of both sexes reared on food supplemented with 20 and 100 mM L-arginine possessed higher total protein concentrations and lower glucose and triacylglycerol concentrations than controls. Additionally, flies fed 20 mM L arginine had higher proline and uric acid concentrations. L-Arginine concentration in the diet also affected oxidative stress intensity in adult flies. Food with 20 mM L-arginine promoted lower protein thiol concentrations and higher catalase activity in flies of both sexes and higher concentrations of low molecular mass thiols in males. When flies were fed on a diet with 100 mM L arginine, lower catalase activities and concentrations of protein thiols were found in both sexes as well as lower low molecular mass thiols in females. L Arginine-fed males demonstrated higher climbing activity, whereas females showed higher cold tolerance and lower fecundity, compared with controls. Food containing 20 mM L-arginine shortened life span in both males and females. The results suggest that dietary L-arginine shows certain beneficial effects at the larval stage and in young adults. However, the long-term consumption of L arginine-enriched food had unfavorable effects on D. melanogaster due to decreasing fecundity and life span. PMID- 28668997 TI - Chemical Constituents of Carbonaceous and Nitrogen Aerosols over Thumba Region, Trivandrum, India. AB - Aerosol filter samples collected at a tropical coastal site Thumba over Indian region were analysed for water-soluble ions, total carbon and nitrogen, organic carbon (OC), elemental carbon (EC), and water-soluble organic carbon/nitrogen and their sources for different seasons of the year. For the entire study period, the order of abundance of ions showed the dominance of secondary ions, such as SO42-, NO3-, and NH4+. On average, Mg2+ (56%), K+ (11%), SO42- (8.8%), and Ca2+ (8.1%) contributions were from maritime influence. There was significant chloride depletion due to enhanced levels of inorganic acids, such as SO42- and NO3-. Total carbon contributed 21% of the aerosol total suspended particulate matter in which 85% is organic carbon. Primary combustion-generated carbonaceous aerosols contributed 41% of aerosol mass for the entire study period. High average ratios of OC/EC (5.5 +/- 1.8) and WSOC/OC (0.38 +/- 0.11) suggest that organic aerosols are predominantly comprised of secondary species. In our samples, major fraction (89 +/- 9%) was found to be inorganic nitrate in total nitrogen (TN). Good correlations (R 2 >= 0.82) were observed between TN with NO3- plus NH4+, indicating that nitrate and ammonium ions account for a significant portion of TN. The temporal variations in the specific carbonaceous aerosols and air mass trajectories demonstrated that several pollutants and/or their precursor compounds are likely transported from north western India and the oceanic regions. PMID- 28668998 TI - Magnesium-Zinc-Calcium-Vitamin D Co-supplementation Improves Hormonal Profiles, Biomarkers of Inflammation and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial. AB - Data on the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress among women with polycystic ovary syndrome (PCOS) are scarce. The objective of this study was to assess the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress in women with PCOS. Sixty PCOS women were randomized into two groups and treated with 100 mg magnesium, 4 mg zinc, 400 mg calcium plus 200 IU vitamin D supplements (n = 30), or placebo (n = 30) twice a day for 12 weeks. Hormonal profiles, biomarkers of inflammation, and oxidative stress were assessed at baseline and at end-of treatment. After the 12-week intervention, compared with the placebo, magnesium zinc-calcium-vitamin D co-supplementation resulted in significant reductions in hirsutism (-2.4 +/- 1.2 vs. -0.1 +/- 0.4, P < 0.001), serum high sensitivity C reactive protein (-0.7 +/- 0.8 vs. +0.2 +/- 1.8 mg/L, P < 0.001), and plasma malondialdehyde (-0.4 +/- 0.3 vs. +0.2 +/- 1.0 MUmol/L, P = 0.01), and a significant increase in plasma total antioxidant capacity concentrations (+46.6 +/- 66.5 vs. -7.7 +/- 130.1 mmol/L, P = 0.04). We failed to find any significant effect of magnesium-zinc-calcium-vitamin D co-supplementation on free androgen index, and other biomarkers of inflammation and oxidative stress. Overall, magnesium-zinc-calcium-vitamin D co-supplementation for 12 weeks among PCOS women had beneficial effects on hormonal profiles, biomarkers of inflammation, and oxidative stress. PMID- 28668999 TI - Heterozygous deletion of the OPA1 gene in patients with dominant optic atrophy. AB - PURPOSE: Several OPA1 variants cause dominant optic atrophy (DOA), the most common hereditary optic atrophy. Here, we describe a newly discovered OPA1 deletion in 3 patients with DOA. METHODS: A female proband, her brother, and her mother underwent complete ophthalmologic examinations that included optical coherence tomography and visual field assessments using a Humphrey Field Analyzer with both standard automated perimetry (SAP) and short-wavelength automated perimetry (SWAP). Genomic DNA from each patient was examined to detect genomic rearrangements involving OPA1; the genetic analysis involved both multiplex ligation probe amplification and conventional Sanger sequencing. RESULTS: Each patient had temporal optic disc pallor and significant thinning of the retinal nerve fiber layer in both eyes, although there was phenotypic variability among the patients that ranged from asymptomatic to moderately decreased visual acuity. For the affected brother and mother, the mean deviation values from SAP were within the normal range, whereas those from SWAP were significantly below the normal range (P < .05). The genetic analysis identified a newly discovered heterozygous deletion that encompasses exons 9-14 and revealed a breakpoint junction that directly connects intron 8 to intron 14. CONCLUSIONS: This newly described deletion is likely to lead to loss of function in the functionally important GTPase domain encoded by exons 9-16, and the heterozygosity suggested that haploinsufficiency caused the phenotypes. The deletion may be associated with mild DOA phenotypes ranging from asymptomatic to moderately decreased visual acuity. PMID- 28669001 TI - Long-term deer exclosure alters soil properties, plant traits, understory plant community and insect herbivory, but not the functional relationships among them. AB - Evidence of the indirect effects of increasing global deer populations on other trophic levels is increasing. However, it remains unknown if excluding deer alters ecosystem functional relationships. We investigated how sika deer exclosure after 18 years changed soil conditions, the understory plant community, the traits of a dominant understory plant (Sasa palmata), herbivory by three insect-feeding guilds, and the functional relationships between these properties. Deer absence decreased understory plant diversity, but increased soil organic matter and ammonium concentrations. When deer were absent, S. palmata plants grew taller, with more, larger, and tougher leaves with higher polyphenol concentrations. Deer absence led to higher leaf area consumed by all insect guilds, but lower insect herbivory per plant due to increased resource abundance (i.e., a dilution effect). This indicates that deer presence strengthened insect herbivory per plant, while in deer absence plants compensated losses with growth. Because plant defenses increased in the absence of deer, higher insect abundances in deer absence may have outweighed lower consumption rates. A path model revealed that the functional relationships between the measured properties were similar between deer absence versus presence. Taken together, deer altered the abiotic and biotic environment, thereby changing insect herbivory, which might impact upon nutrient cycling and primary productivity. These results provide evidence that deer can alter interactions between trophic levels, but that functional relationships between certain ecosystem components may remain constant. These findings highlight the need to consider how increasing global deer populations can have cascade effects that might alter ecosystem dynamics. PMID- 28669000 TI - Towards Holistic Heart Failure Management-How to Tackle the Iron Deficiency Epidemic? AB - PURPOSE OF REVIEW: Heart failure (HF) is a common, costly, disabling, and deadly clinical syndrome and often associated with one or several co-morbidities complicating its treatment or worsening its symptoms. During the last decade, iron deficiency (ID) got recognized as a frequent, debilitating yet easily treatable co-morbidity in HF. In this review, we focus on new evidence that emerged during the last 5 years and discuss the epidemiology, the causes, and the clinical consequences of ID in HF. RECENT FINDINGS: Apart from replenishing iron stores, intravenous iron improves patients' symptoms, perceived quality of life (QoL), exercise capacity, and hospitalization rates. These beneficial effects cannot be attributed to oral iron, as increased hepcidin levels, typical in inflammatory states such as HF, preclude resorption of iron from the gut. Intravenous iron is the only valid treatment option for ID in HF. However, there are several burning research questions and gaps in evidence remaining in this research field. PMID- 28669002 TI - Embryonic learning and developmental carry-over effects in an invasive anuran. AB - Carry-over effects influence trait responses in later life stages as a result of early experience with environmental cues. Predation risk is an influential stressor and selection exists for early recognition of threats. In particular, invasive species may benefit from carry-over effects by preemptively recognizing and responding to novel predators via latent developmental changes and embryonic learning. In a factorial experiment, we conditioned invasive American bullfrog embryos (Lithobates catesbeianus) to the odor of a novel fish predator, largemouth bass (Micropterus salmoides) alone or in combination with injured conspecific cues. We quantified developmental carryover in the larval life stage and found that individuals conditioned to the highest risk (fish and injured conspecific cues) grew into longer bodied larvae relative to larvae from lower risk treatments. We also assessed embryonic learning, a behavioral carry-over effect, and found an interaction between embryonic conditioning and larval exposure. Behavioral responses were only found in scenarios when predation risk varied in intensity across life history stages, thus requiring a more flexible antipredator strategy. This indicates a potential trade-off between the two strategies in larval growth and development rates, and time until metamorphosis. Our results suggest that early predator exposure and carry-over effects have significant impacts on life history trajectories for American bullfrogs. This research contributes to our understanding of a potentially important invasion mechanism in an anuran species of conservation concern. PMID- 28669003 TI - Aggression, interference, and the functional response of coral-feeding butterflyfishes. AB - Functional responses describing how foraging rates change with respect to resource density are central to our understanding of interspecific interactions. Competitive interactions are an important determinant of foraging rates; however, the relationship between the exploitation and interference components of competition has received little empirical or theoretical consideration. Moreover, little is known about the relationship between aggressive behavioural interactions and interference competition. Using a natural gradient of consumer and resource densities, we empirically examine how aggressiveness relates to consumer-consumer encounter rates and foraging for four species of Chaetodon reef fish spanning a range of dietary niche breadths. The probability of aggression was most strongly associated with both total consumer and resource densities. In contrast, total encounter rates were best predicted by conspecific consumer density, and were highest for the most specialised consumer (Chaetodon trifascialis), not the most aggressive (Chaetodon baronessa). The most specialised consumer, not the most aggressive, also exhibited the largest reduction in foraging rates with increasing consumer density. Our results support the idea of a positive link between the exploitation and interference components of competition for the most specialised consumer. Moreover, our results caution against inferring the presence of ecological interactions (competition) from observations of behaviour (aggression and agonism) alone. PMID- 28669004 TI - An update: Epstein-Barr virus and immune evasion via microRNA regulation. AB - Epstein-Barr virus (EBV) is an oncogenic virus that ubiquitously establishes life long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that microRNAs (miRNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes miRNAs for immune evasion. EBV encodes miRNAs targeting both viral and host genes involved in the immune response. The miRNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4+ and CD8+ T cell response of infected cells. These reports strongly indicate that EBV miRNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host miRNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated miRNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment. During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of miRNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases. PMID- 28669006 TI - An Investigation of Unmet Socio-Economic Needs Among Arab American Breast Cancer Patients Compared with Other Immigrant and Migrant Patients. AB - Although Arabs are a growing population in the United States, they are a hidden minority when compared to larger, more studied groups like Latinos and Caribbean immigrants of African descent (CIAD). There is limited research pertaining to patients' unmet socioeconomic and supportive care needs when undergoing breast cancer treatment, particularly among immigrants and migrants. This is a comparative study of a nested cohort of 36 Arabs, 145 Latinos and 128 CIAD breast cancer patients participating in the Integrated Cancer Care Access Network and their areas of needed assistance. The patients were recruited from eleven community cancer clinics in New York City and through community based organizations. Patients most commonly reported needing financial, transportation, and food assistance. Arabs were more likely than their CIAD and Latino counterparts to have health insurance and legal aid needs. Arabs also has the highest proportion of patients unaware of their own cancer stage, at odds with their report of lower information needs than the other groups. Additional culturally tailored Arabic language interventions are needed to educate Arabic speaking breast cancer patients to help facilitate access to available services. PMID- 28669005 TI - Phylogenetic analysis based on mitochondrial DNA sequences of wild rats, and the relationship with Seoul virus infection in Hubei, China. AB - Seoul virus (SEOV), which is predominantly carried by Rattus norvegicus, is one of the major causes of hemorrhagic fever with renal syndrome (HFRS) in China. Hubei province, located in the central south of China, has experienced some of the most severe epidemics of HFRS. To investigate the mitochondrial DNA (mtDNA) based phylogenetics of wild rats in Hubei, and the relationship with SEOV infection, 664 wild rats were captured from five trapping sites in Hubei from 2000-2009 and 2014-2015. Using reverse-transcription (RT)-PCR, 41 (6.17%) rats were found to be positive for SEOV infection. The SEOV-positive percentage in Yichang was significantly lower than that in other areas. The mtDNA D-loop and cytochrome b (cyt-b) genes of 103 rats were sequenced. Among these animals, 37 were SEOV-positive. The reconstruction of the phylogenetic relationship (based on the complete D-loop and cyt-b sequences) allowed the rats to be categorized into two lineages, R. norvegicus and Rattus nitidus, with the former including the majority of the rats. For both the D-loop and cyt-b genes, 18 haplotypes were identified. The geographic distributions of the different haplotypes were significantly different. There were no significant differences in the SEOVpositive percentages between different haplotypes. There were three sub lineages for the D-loop, and two for cyt-b. The SEOV-positive percentages for each of the sub-lineages did not significantly differ. This indicates that the SEOV-positive percentage is not related to the mtDNA D-loop or cyt-b haplotype or the sub-lineage of rats from Hubei. PMID- 28669007 TI - Nephrocalcinosis in a young male with anorexia nervosa. AB - Nephrocalcinosis (NC) has been described as a long-term complication of anorexia nervosa (AN). This is the first report of this complication in an adolescent male patient. We describe the case of a 12-year-old male with AN who presented with acute food restriction and excessive exercising leading to three inpatient admissions. The patient experienced an isolated episode of dysuria and hematuria while on calcium and vitamin D supplementation. Investigations revealed hypophosphatemia, hypercalciuria and mild NC. Follow-up confirmed the presence of NC and possible nephrolithiasis (NL). We discuss the pathophysiology and risk factors of NC and NL in the context of an early presentation of AN. We suggest fluid intake should be liberalized under observation and calcium and vitamin D supplementation should be initiated with caution in patients presenting with AN and risk factors for NC and NL. PMID- 28669008 TI - The influence of rituximab-containing chemotherapy on HCV load in patients with HCV-associated non-Hodgkin's lymphomas. AB - Efficacy and safety of rituximab treatment in patients with Hepatitis C virus (HCV) infection associated non-Hodgkin's lymphoma (NHL) are still disputable. The aim of this study was to evaluate the influence of rituximab-containing chemotherapy on HCV load. Fifty-four patients with both HCV infection and NHL were identified between 2000 and 2016 at our institution. We retrospectively analyzed patients' demographic characteristics, treatment, and kinetics of HCV load before and after treatment with rituximab-containing chemotherapy. In the total group of 54 patients, 29 (54%) received rituximab. Both HCV load pre rituximab and maximal HCV load post rituximab were available in 16 patients. Overall, we observed no significant difference between HCV load pre rituximab and the maximal HCV load post rituximab (P = 0.19). In a patient who was treated simultaneously with direct-acting antivirals (DAAs) and rituximab-containing chemotherapy, HCV load decreased below the sensitivity level (<=12 IU/ml) during treatment. When regarding the influence of rituximab-containing chemotherapy alone on HCV load, we observed a significant elevation of HCV load (P = 0.04). Rituximab-containing chemotherapy may lead to an increase of HCV load in patients with HCV-associated NHL. However, this finding is based on small patient cohort and should be confirmed in larger clinical trials. PMID- 28669009 TI - Neuroprotective effects of AT1 receptor antagonists after experimental ischemic stroke: what is important? AB - The present study conducted in rats defines the requirements for neuroprotective effects of systemically administered AT1 receptor blockers (ARBs) in acute ischaemic stroke. The inhibition of central effects to angiotensin II (ANG II) after intravenous (i.v.) treatment with candesartan (0.3 and 3 mg/kg) or irbesartan and losartan (3 and 30 mg/kg) was employed to study the penetration of these ARBs across the blood-brain barrier. Verapamil and probenecid were used to assess the role of the transporters, P-glycoprotein and the multidrug resistance related protein 2, in the entry of losartan and irbesartan into the brain. Neuroprotective effects of i.v. treatment with the ARBs were investigated after transient middle cerebral artery occlusion (MCAO) for 90 min. The treatment with the ARBs was initiated 3 h after the onset of MCAO and continued for two consecutive days. Blood pressure was continuously recorded before and during MCAO until 5.5 h after the onset of reperfusion. The higher dose of candesartan completely abolished, and the lower dose of candesartan and higher doses of irbesartan and losartan partially inhibited the drinking response to intracerebroventricular ANG II. Only 0.3 mg/kg candesartan improved the recovery from ischaemic stroke, and 3 mg/kg candesartan did not exert neuroprotective effects due to marked blood pressure reduction during reperfusion. Both doses of irbesartan and losartan had not any effect on the stroke outcome. An effective, long-lasting blockade of brain AT1 receptors after systemic treatment with ARBs without extensive blood pressure reductions is the prerequisite for neuroprotective effects in ischaemic stroke. PMID- 28669010 TI - A cross sectional analysis from a single institution's experience of psychosocial distress and health-related quality of life in the primary brain tumor population. AB - Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke's The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network's Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score >=4 (moderate/severe distress). Women reported DT >= 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT >= 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p < 0.001). Primary brain tumor patients experience memory dysfunction, fatigue, nervousness, worry, and financial concerns, which have a negative effect on the patient's HRQoL. By identifying and addressing these stressors, it may be possible to improve patient HRQoL. PMID- 28669011 TI - Extent of resection and Carmustine wafer implantation safely improve survival in patients with a newly diagnosed glioblastoma: a single center experience of the current practice. AB - For newly diagnosed glioblastomas treated with resection in association with the standard combined chemoradiotherapy, the impact of Carmustine wafer implantation remains debated regarding postoperative infections, quality of life, and feasibility of adjuvant oncological treatments. To assess together safety, tolerance and efficacy of Carmustine wafer implantation and of extent of resection for glioblastoma patients in real-life experience. Observational retrospective monocentric study including 340 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent surgical resection with (n = 123) or without (n = 217) Carmustine wafer implantation as first-line oncological treatment. Carmustine wafer implantation and extent of resection did not significantly increase postoperative complications, including postoperative infections (p = 0.269, and p = 0.446, respectively). Carmustine wafer implantation and extent of resection did not significantly increase adverse events during adjuvant oncological therapies (p = 0.968, and p = 0.571, respectively). Carmustine wafer implantation did not significantly alter the early postoperative Karnofsky performance status (p = 0.402) or the Karnofsky performance status after oncological treatment (p = 0.636) but a subtotal or total surgical resection significantly improved those scores (p < 0.001, and p < 0.001, respectively). Carmustine wafer implantation, subtotal and total resection, and standard combined chemoradiotherapy were independently associated with longer event-free survival (adjusted Hazard Ratio (aHR), 0.74 [95% CI 0.55 0.99], p = 0.043; aHR, 0.70 [95% CI 0.54-0.91], p = 0.009; aHR, 0.40 [95% CI 0.29 0.55], p < 0.001, respectively) and with longer overall survival (aHR, 0.69 [95% CI 0.49-0.96], p = 0.029; aHR, 0.52 [95% CI 0.38-0.70], p < 0.001; aHR, 0.58 [95% CI 0.42-0.81], p = 0.002, respectively). Carmustine wafer implantation in combination with maximal resection, followed by standard combined chemoradiotherapy is safe, efficient, and well-tolerated in newly diagnosed supratentorial glioblastomas in adults. PMID- 28669012 TI - Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study. AB - Epidermal growth factor receptor (EGFR) mutations are commonly observed in Glioblastoma (GBM) and have long posed as a target for new therapies. Trials involving erlotinib have shown mixed results, likely owing to a mechanism of the mutation that may instead favor other EGFR inhibitors, such as lapatinib. We aimed to determine whether or not pulse high-dose lapatinib was a safe and tolerable regimen in addition to standard therapy. We recruited adult patients with newly-diagnosed GBM who had Karnofsky Performance Status >=60, normal baseline hematological, hepatic, and renal function tests, and no prior history of radiation or treatment with EGFR inhibitor. Lapatinib was administered at 2500 mg twice daily for two consecutive days per week on a weekly basis throughout concomitant and adjuvant standard therapy. The primary endpoints were tolerability and safety. 12 patients were enrolled in this study over 2 years. Of the non-hematological adverse events, there were 2 grade 3 events, fatigue and post-radiation cystic brain necrosis. The most common adverse events in general were fatigue, rashes, and diarrhea. Of the hematological adverse events, there were 13 grade 3 events, all of which were due to lymphopenia and affected 6 of 12 patients. Pulse high-dose lapatinib in addition to standard therapy for newly diagnosed GBM is a tolerable and safe regimen, but higher rates of lymphopenia should be noted. However, further investigations will be required to evaluate the efficacy of this combination for the treatments of GBM. Trial registration ClinicalTrials.gov Identifier: NCT01591577. PMID- 28669013 TI - Narrative Medicine perspectives on patient identity and integrative care in neuro oncology. AB - Narrative Medicine sessions can encourage patients to rediscover personal identity and meaning by telling or writing their stories. We explored this process to improve care and quality of life for brain cancer patients in an academic neuro-oncology program. Brain cancer and its treatments may threaten a patient's quality of life and sense of self in many ways, including impaired cognitive skills, loss of memory, reduced coordination, and limited capacity for self-expression. The impact of symptoms and side effects on quality of life must be evaluated in terms of each patient's identity and may be understood in terms of each patient's story. Insights from Narrative Medicine visits may also be helpful for the treatment team as they seek to assess patient needs, attitudes, and abilities. We provide case-based histories demonstrating applications of Narrative Medicine in the care of patients with brain tumors whose sense of self and quality of life are challenged. The cases include managing frontal lobe syndrome of loss of initiative and pervasive emotional apathy with his wife and young children, regaining a meaningful activity in a patient, re-establishing self-identity in a young woman with ependymoma, and improving spells with coexistent epilepsy and psychogenic non-epileptic seizures (PNES). PMID- 28669014 TI - Temporal evolution of perfusion parameters in brain metastases treated with stereotactic radiosurgery: comparison of intravoxel incoherent motion and dynamic contrast enhanced MRI. AB - Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) technique that is seeing increasing use in neuro-oncology and offers an alternative to contrast-enhanced perfusion techniques for evaluation of tumor blood volume after stereotactic radiosurgery (SRS). To date, IVIM has not been validated against contrast enhanced techniques for brain metastases after SRS. In the present study, we measure blood volume for 20 brain metastases (15 patients) at baseline, 1 week and 1 month after SRS using IVIM and dynamic contrast enhanced (DCE)-MRI. Correlation between blood volume measurements made with IVIM and DCE-MRI show poor correlation at baseline, 1 week, and 1 month post SRS (r = 0.33, 0.14 and 0.30 respectively). At 1 week after treatment, no significant change in tumor blood volume was found using IVIM or DCE-MRI (p = 0.81 and 0.41 respectively). At 1 month, DCE-MRI showed a significant decrease in blood volume (p = 0.0002). IVIM, on the other hand, demonstrated the opposite effect and showed a significant increase in blood volume at 1 month (p = 0.03). The results of this study indicate that blood volume measured with IVIM and DCE-MRI are not equivalent. While this may relate to differences in the type of perfusion information each technique is providing, it could also reflect a limitation of tumor blood volume measurements made with IVIM after SRS. IVIM measurements of tumor blood volume in the month after SRS should therefore be interpreted with caution. PMID- 28669016 TI - Co-infection of Pseudomonas aeruginosa and Stenotrophomonas maltophilia in hospitalised pneumonia patients has a synergic and significant impact on clinical outcomes. AB - Ventilator-acquired pneumonia and hospital community-acquired pneumonia are frequently caused by Gram-negative and -positive bacteria. We noted that pneumonia patients with co-infection of Pseudomonas aeruginosa and Stenotrophomonas maltophilia had a poor clinical outcome. To verify this, we retrospectively reviewed pneumonia cases at Hebei General Hospital from 2010 to 2015. These cases were grouped into four categories: (1) co-infection with P. aeruginosa and S. maltophilia, (2) infection with P. aeruginosa, (3) infection with S. maltophilia and (4) infection with none of the known pneumonia-causing pathogens. The numbers of cases in each group were 50, 40, 41 and 33, with mortality rates of 64.0%, 12.5%, 14.6% and 6.1%, respectively. The analysed results indicated that a co-infection of P. aeruginosa and S. maltophilia had a synergic impact on the mortality of pneumonia patients. Therefore, future research is needed to develop treatment strategies for the co-infected patients to reduce the rate of mortality. PMID- 28669015 TI - Present status of laboratory diagnosis of human taeniosis/cysticercosis in Europe. AB - Human cysticercosis (CC) is a parasitic zoonosis caused by the larval stage (cyst) of the Taenia solium. Cysts can establish in the human central nervous system (neurocysticercosis, NCC) and other organs and tissues; they also develop in pigs, the natural intermediate host. Human taeniosis may be caused by T. solium, Taenia saginata and Taenia asiatica tapeworms; these infections are usually asymptomatic, but show a significant relevance as they perpetuate the parasites' life cycle, and, in the case of T. solium, they are the origin of (N)CC. In European Union (EU) member states and associated countries, the occurrence of autochthonous T. solium cases is debated, and imported cases have significantly increased lately; the status of T. asiatica has been never reported, whereas T. saginata is prevalent and causes an economic impact due to condemned carcasses. Based on their effects on the EU society, the specific diagnosis of these pathologies is relevant for their prevention and control. The aims of this study were to know the diagnostic tests used in European laboratories for human taeniosis/cysticercosis by means of a questionnaire, to determine potential gaps in their detection, and to obtain preliminary data on the number of diagnosed taeniosis/CC cases. PMID- 28669017 TI - Bartonella henselae is usually not viable in lymph nodes of patients with cat scratch disease. AB - Bartonella henselae, the agent of cat scratch disease (CSD), appears to be a common organism responsible for lymphadenitis in both adults and children. There is a very low isolation rate for B. henselae from lymph nodes of patients with CSD. Our objective was to evaluate B. henselae viability in a large series of lymph nodes from patients with CSD. From January to November 2016, we analyzed lymph node biopsy samples from patients diagnosed with CSD. We used reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to detect B. henselae RNA, as well as cultures, histological analyses, and fluorescence in situ hybridization (FISH). We tested 87 lymph nodes positive for B. henselae DNA but only 8 (9%) presented with B. henselae RNA. We did not find a significant difference for the pap threshold cycle (CT) values between RNA-positive and RNA negative lymph nodes (p = 0.5). Cultures, histological analyses, and FISH were negative for all the tested samples. We provide evidence that B. henselae are not or are rarely viable in most cases in the lymph nodes of patients with CSD. PMID- 28669018 TI - Revision knee arthroplasty using a distal femoral replacement prosthesis for periprosthetic fractures in elderly patients. AB - PURPOSE: Distal femoral periprosthetic fractures above a total knee replacement in elderly patients are technically challenging to treat. Bone quality is often poor, the fractures comminuted, and post-operative mobilisation is difficult. This study assesses the clinical, radiological and functional outcome of revision knee distal femoral replacement (DFR) in these fractures. METHODS: We identified 14 patients over 70 years of age (70-94) who underwent DFR for periprosthetic fractures above a knee replacement. All the 14 fractures were classified as Su type III. Clinical and radiological records were retrospectively reviewed. The mean of clinical follow-up was 27 months (8-46). Functional outcome was assessed using Oxford Knee Score and EQ-5D (UK English Version) score at a mean time of 35 months (20-65). The Knee Society patient category score was also evaluated. RESULTS: The median post-operative knee flexion was 100 degrees (range 90 degrees -135 degrees ). Nine patients (64%) returned to their pre-fracture level of mobility or better. The median post-operative Oxford Knee Score was 27 (range 4-40). The median EQ-5D was 11 (range 6-12). Cognitive impairment negatively impacted the functional outcome in four patients. One patient died early post operatively, and two patients had complications. CONCLUSIONS: DFR led to satisfactory outcome in our patients with a relatively low complication rate. In our experience, revision knee distal femoral replacement is an appropriate method to treat elderly patients who sustained periprosthetic Su et al. type III distal femoral fractures in association with poor bone stock, caused by osteoporosis and/or comminution. PMID- 28669019 TI - Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome. AB - The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome. PMID- 28669020 TI - Expanding the 'Digital Protologue' Database (DPD) to 'Current Microbiology': An Offer to Scientists and Science. PMID- 28669021 TI - New, Occasional, and Frequent Use of Zolpidem or Zopiclone (Alone and in Combination) and the Risk of Injurious Road Traffic Crashes in Older Adult Drivers: A Population-Based Case-Control and Case-Crossover Study. AB - BACKGROUND: Previous studies on the effect of zolpidem or zopiclone use on the risk of road traffic crashes (RTCs) have shown mixed results. OBJECTIVE: Our objective was to determine the association between zolpidem or zopiclone use (as separate drugs or combined) and the occurrence of injurious RTCs among older adult drivers. METHODS: This was a population-based matched case-control and case crossover study based on secondary data linked together from Swedish national registers. Cases were drivers aged 50-80 years involved in a vehicle crash resulting in injuries between January 2006 and December 2009 for the case-control study (n = 27,096) and from February 2006 to December 2009 for the case-crossover study (n = 26,586). For the first design, four controls were matched to each case by sex, age, and residential area, and exposure was categorized into new, occasional, and frequent use of zolpidem only, zopiclone only, and combined zolpidem and zopiclone. For the case-crossover study, newly dispensed zolpidem or zopiclone users were assessed during the 28 days prior to the crash and compared with an equally long control period using a 12-week washout period. Matched adjusted odds ratios (OR) were computed using conditional logistic regression. RESULTS: Increased ORs for all users were observed. In the case-control study, the highest odds were seen among newly initiated zolpidem-only users involved in single-vehicle crashes (adjusted OR 2.27; 95% confidence interval [CI] 1.21 4.24), followed by frequent combined zolpidem and zopiclone users [adjusted OR 2.20; CI 1.21-4.00]. In the case-crossover, newly initiated treatment with zolpidem or zopiclone showed an increased risk that was highest in the 2 weeks after the start of the treatment (OR 2.66; 95% CI 1.04-6.81). CONCLUSIONS: These results provide more compelling evidence for the role of zolpidem or zopiclone in the occurrence of RTCs among older adults, not only in frequent users, but also at the beginning of treatment. PMID- 28669022 TI - Pharmacological Treatment of Bipolar Disorder with Comorbid Alcohol Use Disorder. AB - Bipolar disorder (BD) spectrum and alcohol use disorders (AUDs) commonly occur together. Comorbidity between the two conditions predisposes patients to elevated risks of adverse outcomes, including hospitalization and suicide, compared with either condition alone. Despite the consistent relationship observed between BD and AUD, the underlying cause remains incompletely characterized. Few trials conducted have been able to identify promising interventions for patients with these disease states. The antipsychotic quetiapine has been evaluated most commonly as a therapeutic agent for patients with BD and AUD followed by naltrexone and acamprosate. Randomized controlled trials of quetiapine have consistently reported a lack of efficacy for the treatment of patients with BD and AUD. Trials of acamprosate have also been negative but small in size. Results of the sole randomized controlled trial of naltrexone have found large treatment effect sizes, but no statistically significant difference between treatment groups. Other agents including the antipsychotic aripiprazole, mood stabilizing agents including lamotrigine, lithium, and divalproex, and the antiepileptic agent topiramate have also been evaluated for the treatment of BD and AUD with mixed findings. The lone statistically significant treatment effect was observed in a randomized, placebo-controlled trial of divalproex added on to lithium which demonstrated a reduction in alcohol use. This review summarizes the available clinical evidence and current guideline recommendations for the treatment of comorbid BD and AUD, and provides discussion and recommendations based on the current literature. PMID- 28669023 TI - Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility: A Single-Institution Experience. AB - BACKGROUND: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. OBJECTIVE: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). PATIENTS AND METHODS: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). RESULTS: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63 3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06). CONCLUSIONS: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment. PMID- 28669025 TI - Effects of GSH1 and GSH2 Gene Mutation on Glutathione Synthetases Activity of Saccharomyces cerevisiae. AB - In this paper, three mutants from wild Saccharomyces cerevisiae HBU2.558, called U2.558, UN2.558, and UNA2.558, were screened by UV, sodium nitrite, Atmospheric and room temperature plasma, respectively. Glutathione production of the three mutants increased by 41.86, 72.09 and 56.76%, respectively. We detected the activity of glutathione synthetases and found that its activity was improved. Amino acid sequences of three mutant colonies were compared with HBU2.558. Four mutants: Leu51->Pro51 (L51P), Glu62->Val62 (E62V), Ala332->Glu332 (A332E) and Ser653->Gly653 (S653G) were found in the analysis of gamma-glutamylcysteine ligase. L51 is located adjacently to the two active sites of GCL/E/Mg2+/ADP complex in the overall GCL structure. L51P mutant spread distortion on the beta sheet due to the fact that the phi was changed from -50.4 degrees to -40.2 degrees . A mutant Leu54->Pro54 (L54P) was found in the analysis of glutathione synthetase, and L54 was an amino acid located between an alpha-helix and a beta sheet. The results confirm that introduction of proline located at the middle of the beta-sheet or at the N- or C-terminal between alpha-helix and beta-sheet or, i.e., L51P and L54P, changed the phi, rigidity, hydrophobicity and conformational entropy, thus increased protein stability and improved the enzyme activity. PMID- 28669024 TI - Substance Use Disorders, Violence, Mental Health, and HIV: Differentiating a Syndemic Factor by Gender and Sexuality. AB - This paper measures syndemic substance use disorder, violence, and mental health and compares the syndemic among HIV-infected heterosexual men, heterosexual women, and men who have sex with men (MSM). Data were from a sample of high needs substance-using, HIV-infected people in South Florida between 2010 and 2012 (n = 481). We used confirmatory factor analysis to measure a syndemic latent variable and applied measurement invariance models to identify group differences in the data structure of syndemic co-morbidities among heterosexual men, heterosexual women, and MSM. We found that variables used to measure the syndemic fit each sub group, supporting that substance use disorder, violence, and mental health coincide in HIV-infected individuals. Heterosexual men and MSM demonstrated similar syndemic latent variable factor loadings, but significantly different item intercepts, indicating that heterosexual men had larger mean values on substance use disorder, anxiety, and depression than MSM. Heterosexual men and heterosexual women demonstrated significantly different syndemic variable factor loadings, indicating that anxiety and depression contribute more (and substance use contributes less) to the syndemic in heterosexual men compared to heterosexual women. MSM and heterosexual women demonstrated similar syndemic latent variable factor loadings and intercepts, but had significantly different factor residual variances indicating more variance in violent victimization and depression for MSM and more variance in stress for heterosexual women than what is captured by the observed syndemic indicators. Furthermore, heterosexual women had a larger syndemic factor mean than MSM, indicating that the syndemic burden is greater among heterosexual women than MSM. Our findings support that measurement invariance can elucidate differences in the syndemic to tailor interventions to sub-group needs. PMID- 28669026 TI - A Pilot Study on Ocular Safety and Efficacy of Infliximab as an Antifibrotic Agent After Experimental Glaucoma Filtration Surgery. AB - INTRODUCTION: Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional, proinflammatory cytokine that mediates pleiotropic biological functions, especially inflammation and immunoregulation. We hypothesized that blocking TNF alpha with a monoclonal antibody would decrease inflammation and subconjunctival scarring in an animal model of experimental filtration surgery. METHODS: In a randomized, prospective, masked-observer study, 30 New Zealand albino rabbits underwent glaucoma filtration surgery. The animals were allocated to receive either intraoperative application of infliximab (group A) or mitomycin C (MMC) at a concentration of 0.2 mg/ml (group B) or balanced salt solution (BSS, control) (group C). Different infliximab doses, namely 1.0, 2.0, 3.0, 4.0, 5.0 mg in 0.1 ml, were applied. Bleb survival and characteristics were evaluated over a 30-day period. The animals were killed on postoperative day 15 or 30. Histology of the operated eyes was performed to evaluate and grade the amount of scarring in each group. Cellular density was evaluated in each case. RESULTS: Infliximab did not appear to improve outcomes in this model of glaucoma filtration surgery. Bleb survival was significantly higher in the MMC group compared to the other groups (p < 0.001 for both comparisons). Vascularity was also significantly lower in the MMC group compared to the other groups (p = 0.018 for both comparisons). There was a significant decrease in cellular density in the MMC group compared to the control (p = 0.0352) and the infliximab group (p < 001). CONCLUSION: Our results have shown that trabeculectomies in the infliximab group failed faster and displayed more scarring, compared to the control and MMC groups. This outcome suggests that the infliximab doses used in this pilot study resulted in a subconjunctival TNF-alpha concentration, which acted as a stimulator to fibroblasts. PMID- 28669027 TI - The impact of structural biology in medicine illustrated with four case studies. AB - The contributions of structural biology to drug discovery have expanded over the last 20 years from structure-based ligand optimization to a broad range of clinically relevant topics including the understanding of disease, target discovery, screening for new types of ligands, discovery of new modes of action, addressing clinical challenges such as side effects or resistance, and providing data to support drug registration. This expansion of scope is due to breakthroughs in the technology, which allow structural information to be obtained rapidly and for more complex molecular systems, but also due to the combination of different technologies such as X-ray, NMR, and other biophysical methods, which allows one to get a more complete molecular understanding of disease and ways to treat it. In this review, we provide examples of the types of impact molecular structure information can have in the clinic for both low molecular weight and biologic drug discovery and describe several case studies from our own work to illustrate some of these contributions. PMID- 28669028 TI - The excitatory/inhibitory input to orexin/hypocretin neuron soma undergoes day/night reorganization. AB - Orexin (OX)/hypocretin-containing neurons are main regulators of wakefulness stability, arousal, and energy homeostasis. Their activity varies in relation to the animal's behavioral state. We here tested whether such variation is subserved by synaptic plasticity phenomena in basal conditions. Mice were sacrificed during day or night, at times when sleep or wake, respectively, predominates, as assessed by electroencephalography in matched mice. Triple immunofluorescence was used to visualize OX-A perikarya and varicosities containing the vesicular glutamate transporter (VGluT)2 or the vesicular GABA transporter (VGAT) combined with synaptophysin (Syn) as a presynaptic marker. Appositions on OX-A+ somata were quantitatively analyzed in pairs of sections in epifluorescence and confocal microscopy. The combined total number of glutamatergic (Syn+/VGluT2+) and GABAergic (Syn+/VGAT+) varicosities apposed to OX-A somata was similar during day and night. However, glutamatergic varicosities were significantly more numerous at night, whereas GABAergic varicosities prevailed in the day. Triple immunofluorescence in confocal microscopy was employed to visualize synapse scaffold proteins as postsynaptic markers and confirmed the nighttime prevalence of VGluT2+ together with postsynaptic density protein 95+ excitatory contacts, and daytime prevalence of VGAT+ together with gephyrin+ inhibitory contacts, while also showing that they formed synapses on OX-A+ cell bodies. The findings reveal a daily reorganization of axosomatic synapses in orexinergic neurons, with a switch from a prevalence of excitatory innervation at a time corresponding to wakefulness to a prevalence of inhibitory innervations in the antiphase, at a time corresponding to sleep. This reorganization could represent a key mechanism of plasticity of the orexinergic network in basal conditions. PMID- 28669029 TI - Slc11a1 (Nramp-1) gene modulates immune-inflammation genes in macrophages during pristane-induced arthritis in mice. AB - OBJECTIVE AND DESIGN: Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA. TREATMENT: Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60 day intervals. Arthritis development was accompanied for 180 days. RESULTS: AIRmax SS mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of H2O2, NO, IL-1beta, IL-6, TNF-alpha, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development. CONCLUSION: Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines. PMID- 28669030 TI - Vgamma9Vdelta2 T cell activation by strongly agonistic nucleotidic phosphoantigens. AB - Human Vgamma9Vdelta2 T cells can sense through their TCR tumor cells producing the weak endogenous phosphorylated antigen isopentenyl pyrophosphate (IPP), or bacterially infected cells producing the strong agonist hydroxyl dimethylallyl pyrophosphate (HDMAPP). The recognition of the phosphoantigen is dependent on its binding to the intracellular B30.2 domain of butyrophilin BTN3A1. Most studies have focused on pyrophosphate phosphoantigens. As triphosphate nucleotide derivatives are naturally co-produced with IPP and HDMAPP, we analyzed their specific properties using synthetic nucleotides derived from HDMAPP. The adenylated, thymidylated and uridylated triphosphate derivatives were found to activate directly Vgamma9Vdelta2 cell lines as efficiently as HDMAPP in the absence of accessory cells. These antigens were inherently resistant to terminal phosphatases, but apyrase, when added during a direct stimulation of Vgamma9Vdelta2 cells, abrogated their stimulating activity, indicating that their activity required transformation into strong pyrophosphate agonists by a nucleotide pyrophosphatase activity which is present in serum. Tumor cells can be sensitized with nucleotide phosphoantigens in the presence of apyrase to become stimulatory, showing that this can occur before their hydrolysis into pyrophosphates. Whereas tumors sensitized with HDMAPP rapidly lost their stimulatory activity, sensitization with nucleotide derivatives, in particular with the thymidine derivative, induced long-lasting stimulating ability. Using isothermal titration calorimetry, binding of some nucleotide derivatives to BTN3A1 intracellular domain was found to occur with an affinity similar to that of IPP, but much lower than that of HDMAPP. Thus, nucleotide phosphoantigens are precursors of pyrophosphate antigens which can deliver strong agonists intracellularly resulting in prolonged and strengthened activity. PMID- 28669031 TI - Experimental design and reporting standards for metabolomics studies of mammalian cell lines. AB - Metabolomics is an analytical technique that investigates the small biochemical molecules present within a biological sample isolated from a plant, animal, or cultured cells. It can be an extremely powerful tool in elucidating the specific metabolic changes within a biological system in response to an environmental challenge such as disease, infection, drugs, or toxins. A historically difficult step in the metabolomics pipeline is in data interpretation to a meaningful biological context, for such high-variability biological samples and in untargeted metabolomics studies that are hypothesis-generating by design. One way to achieve stronger biological context of metabolomic data is via the use of cultured cell models, particularly for mammalian biological systems. The benefits of in vitro metabolomics include a much greater control of external variables and no ethical concerns. The current concerns are with inconsistencies in experimental procedures and level of reporting standards between different studies. This review discusses some of these discrepancies between recent studies, such as metabolite extraction and data normalisation. The aim of this review is to highlight the importance of a standardised experimental approach to any cultured cell metabolomics study and suggests an example procedure fully inclusive of information that should be disclosed in regard to the cell type/s used and their culture conditions. Metabolomics of cultured cells has the potential to uncover previously unknown information about cell biology, functions and response mechanisms, and so the accurate biological interpretation of the data produced and its ability to be compared to other studies should be considered vitally important. PMID- 28669032 TI - Immunosenescence: the Role of Aging in the Predisposition to Neuro-Infectious Complications Arising from the Treatment of Multiple Sclerosis. AB - PURPOSE OF REVIEW: This review highlights some of the important changes in the immune system that occur in the process of normal aging. Immunosenescence as a concept is directly relevant to the world of neuro-inflammation, as it may be a contributing factor to the risks associated with some of the current immunosuppressive and immunomodulatory therapies used in treating multiple sclerosis (MS) and other inflammatory disorders. RECENT FINDINGS: Profound qualitative and quantitative changes occur in the adaptive and innate immunity compartments during aging. These changes may explain why patients of older age are at an increased risk of infections and infection-associated mortality. Immunosenescence-associated changes may be additive or synergistic with the effects produced by immunomodulatory and immunosuppressive medications. Clinicians should exercise a high level of vigilance in monitoring the risk of infections in older patients on these treatments. PMID- 28669033 TI - Monitoring the Brain After Cardiac Arrest: a New Era. AB - PURPOSE OF REVIEW: Of the approximately 350,000 out-of-hospital, and 750,000 after in-hospital cardiac arrest (CA) events in the US annually approximately 5 9% and 20% respectively may achieve return of spontaneous circulation (ROSC) after attempted cardiopulmonary resuscitation (CPR). Up to 2/3 of these initial survivors may go on die in the subsequent 24-72 hours after ROSC due to a combination of (1) on-going cerebral injury, (2) myocardial dysfunction and (3) massive systemic inflammatory response. In order to successfully manage patients more effectively, monitoring methods are needed to aid clinicians in the detection and quantification of intra-cardiac arrest and post-resuscitation pathophysiological cerebral injury processes in the intensive care unit. RECENT FINDINGS: Over the last few years many modalities have been used for cerebral monitoring during and after CA, these include quantitative pupillometry, transcranial doppler sonography, optic nerve sheath diameter measurements, microdialysis, tissue oxygenation monitoring, intra-cranial pressure monitoring, and electroencephalography. Current studies indicate that these modalities may be used for the purpose of neurological monitoring during cardiac arrest resuscitation as well as in the post-resuscitation period. Multiple overlapping processes, including alterations in cerebral blood flow (CBF), raised intracerebralpressure, disorders of metabolism, imbalanced oxygen delivery and reperfusion injury contribute to cell death during the post-resuscitation period has led to the birth of post-resuscitation management strategies in the 21st century. This review provides a succinct overview of currently available bedside invasive and non-invasive neuro-monitoring methods after CA. PMID- 28669035 TI - The longitudinal association between multiple job holding and long-term sickness absence among Danish employees: an explorative study using register-based data. AB - PURPOSE: Multiple job holding (MJH) is common in many countries, but little is known about its (health) consequences. Our aim is to explore the longitudinal association between MJH and long-term sickness absence (LTSA) among Danish employees. METHODS: We included employees (N = 8968) who participated in the Danish Work Environment Cohort Study (DWECS), based on a representative sample of the Danish working population. Three dichotomous independent variables were created: MJH in general, combination MJH (i.e. second job as employee) and hybrid MJH (i.e. self-employed in second job). LTSA (>=5 weeks) was measured using the Danish Register for Evaluation of Marginalization during 78 weeks of follow-up. Potential confounders included demographics, health, and work characteristics. Logistic regression analyses were performed to study whether LTSA was associated with MJH in general, combination MJH, and hybrid MJH. Interaction effects for gender, age, total working hours per week (<=37 or >37 h a week), and shift work were tested. RESULTS: In total, 11.7% (N = 1048) of the respondents reported having multiple jobs and 7.6% (N = 678) experienced LTSA during follow-up. After adjustment for confounders, no significant association between LTSA and MJH in general (OR = 0.82), combination MJH (OR = 0.81), or hybrid MJH (OR = 0.83) was found. Among employees working more than 37 h per week, combination MJH was associated with a higher likelihood of LTSA (OR = 1.50). CONCLUSIONS: We did not find evidence for an increased likelihood of LTSA among multiple job holders. Future research should study the likelihood of LTSA among subgroups of multiple job holders, e.g. those working long hours. PMID- 28669034 TI - Cannabinoid reward and aversion effects in the posterior ventral tegmental area are mediated through dissociable opiate receptor subtypes and separate amygdalar and accumbal dopamine receptor substrates. AB - RATIONALE: The ventral tegmental area (VTA) and its projections to the basolateral amygdala (BLA) and nucleus accumbens (NAc) are critical for cannabinoid-related motivational effects. Cannabinoid CB1 receptor (CB1R) transmission modulates VTA dopamine (DA) neuron activity and previous reports demonstrate anatomically segregated effects of CB1R transmission in the VTA. However, the underlying pharmacological and anatomical regions responsible for these effects are currently unknown. OBJECTIVES: The objective of the study is to characterize the motivational effects of localized anterior vs. posterior intra VTA activation vs. blockade of CB1R transmission and the potential role of intra BLA and intra-NAc DA transmission in these phenomena. METHODS: Using a conditioned place preference (CPP) procedure, we administered a CB1 agonist (WIN 55,212-2) or antagonist (AM 251) into the posterior VTA (pVTA) or anterior VTA (aVTA) of rats, combined with intra-BLA or intra-NAc DA receptor blockade and intra-VTA co-administration of selective mu vs. kappa opiate-receptor antagonists. RESULTS: Intra-pVTA CB1R activation produced robust rewarding effects through a mu-opiate receptor mechanism whereas CB1R blockade produced conditioned place aversions (CPA) through a kappa-opiate receptor substrate. In contrast, modulation of aVTA CB1R transmission produced no observable effects. Intra-BLA DA receptor blockade prevented the rewarding effects of pVTA CB1R activation, but had no effects on CB1R blockade-induced aversions. In contrast, intra-NAc DA receptor blockade selectively blocked the aversive effects of pVTA CB1R antagonism. CONCLUSIONS: Activation vs. blockade of CB1R transmission in the posterior VTA produces bivalent rewarding or aversive effects through separate mu vs. kappa-opiate receptor substrates. These dissociable effects depend on separate DA receptor transmission substrates in the BLA or NAc, respectively. PMID- 28669036 TI - Genomic and antigenic relationships between two 'HoBi'-like strains and other members of the Pestivirus genus. AB - 'HoBi'-like viruses comprise a putative new species within the genus Pestivirus of the family Flaviviridae. 'HoBi'-like viruses have been detected worldwide in batches of fetal calf serum, in surveillance programs for bovine pestiviruses and from animals presenting clinical signs resembling bovine viral diarrhea virus (BVDV)-associated diseases. To date, few complete genome sequences of 'HoBi'-like viruses are available in public databases. Moreover, detailed analyses of such genomes are still scarce. In an attempt to expand data on the genetic diversity and biology of pestiviruses, two genomes of 'HoBi'-like viruses recovered from Brazilian cattle were described and characterized in this study. Analysis of the whole genome and antigenic properties of these two new 'HoBi'-like isolates suggest that these viruses are genetically close to recognized pestiviruses. The present data provide evidence that 'HoBi'-like viruses are members of the genus Pestivirus and should be formally recognized as a novel species. PMID- 28669037 TI - In vitro study of Zika virus infection in boar semen. AB - Zika virus (ZIKV) is an important arbovirus that is capable of directly infecting neuronal cells. Infection can cause microcephaly in fetuses and Guillain-Barre syndrome in adults. Recent epidemiological studies have shown that ZIKV is sexually transmitted, especially from infected males to uninfected females. This study aimed to investigate the transmission pattern of ZIKV in semen using boar semen. Experiments were performed ex vivo using semen from healthy boar. The samples were infected with ZIKV, and viral RNA was detected and cell morphology was examined at different time points postinfection. ZIKV infection was confirmed by transmission electron microscopy. Viral RNA levels were found to markedly decrease as the time postinfection increased, without any evidence of virus replication. The sperm showed no significant changes in morphology. Transmission electron microscopy revealed the presence of virus-free sperm, suggesting that ZIKV cannot replicate in boar semen. We suggest three possible reasons underlying this phenomenon. First, the spermatozoa of boar might not be the target of ZIKV associated with sexual transmission. Second, the effect of the external environment on spermatozoa may affect ZIKV replication. Third, ZIKV may not be tropic for spermatozoa. This ex vivo study might be used as a platform to study the association of sexual transmission with ZIKV in other longer-lasting cells, such as Leydig or Sertoli cells. PMID- 28669038 TI - Asymmetrical Priming Effects: An Exploration of Trilingual German-English-French Lexico-Semantic Memory. AB - The growing number of multilingual speakers poses an interesting question as to the way in which three or more languages are represented in the memory of a language user. The Revised Hierarchical Model (Kroll and Stewart in J Mem Lang 33: 149-174, 1994) or the Sense Model (Finkbeiner et al. in J Mem Lang 51(1), 1 22, 2004) skillfully capture the prediction regarding two languages, with the lexical level being separate and the conceptual one being unified or distributed to a varying degree. In this set of experiments, we employed primed animacy decision tasks to address the lexico-semantic representation of trilingual German English-French speakers. The comparison of reaction times has revealed priming effects from L1 to L2 and from L2 to L1, both with prime duration of 100 and 50 ms; a priming asymmetry effect between the L2 and L3 language directions; and no interaction between L1 and L3. The aggregated findings point to a hybrid representation, with both compound and coordinate representations being possible. PMID- 28669039 TI - Blockade of MMP-2 and MMP-9 inhibits corneal lymphangiogenesis. AB - PURPOSE: To investigate the roles of a selective MMP-2 and -9 inhibitor (SB-3CT) in corneal inflammatory lymphangiogenesis. METHODS: The expression of MMP-2 and 9 in the cornea after suture inplacement, treated with SB-3CT or negative control, was detected by real-time polymerase chain reaction (PCR). Inflammatory corneal neovascularization (NV) was induced by corneal suture placement. Mice were treated with SB-3CT eye drops (twice daily for 1 week, 5 MUL per drop; 50, 100, or 200 MUM). The outgrowth of blood and lymphatic vessels, and macrophage recruitment were analyzed by immunofluorescence assay. The expressions of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were tested by real-time PCR. RESULTS: MMP-2 and -9 expression were suppressed significantly by treatment with SB-3CT. The data demonstrated, for the first time, that SB-3CT strongly reduced corneal lymphangiogenesis and macrophage infiltration during inflammation. Furthermore, expressions of VEGF-C and its receptor VEGFR-3 were significantly inhibited by SB-3CT during corneal lymphangiogenesis. CONCLUSIONS: These novel findings indicated that blockade of MMP-2 and -9 could inhibit lymphangiogenesis. Further investigation of this factor may provide novel therapies for transplant rejection and other lymphatic disorders. PMID- 28669040 TI - OCT angiography in idiopathic macular holes, some methodological concerns. PMID- 28669041 TI - Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy. AB - PURPOSE: To evaluate the effects of aflibercept therapy using a treat-and-extend regimen on treatment-naive polypoidal choroidal vasculopathy (PCV). METHODS: In a retrospective interventional case series of 58 eyes of 58 patients with PCV, we assessed best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and number of injections for 2 years. Polypoidal lesions were also evaluated before treatment and after the loading phase by indocyanine green angiography. RESULTS: BCVA significantly improved after the loading phase and was maintained in the maintenance phase. CMT and CCT significantly reduced after the loading phase and were maintained throughout the follow-up period. The number of injections averaged 7.72 in the first year and 4.67 in the second year. The average number of polypoidal lesions per patient was 2.43 before treatment. In 32 patients (55.2%), polypoidal lesions regressed completely after the loading phase; these patients also needed significantly fewer injections compared to other patients. CCT at baseline was positively correlated with the decreased amount of CCT after 2 years and negatively correlated with the number of injections for 2 years. CONCLUSIONS: Treat-and extend intravitreal therapy with aflibercept may be effective for improving BCVA and exudative change in eyes with PCV. The regression of polypoidal lesions after the loading phase and thicker choroid at baseline might lead to fewer total number of intravitreal injections of aflibercept. PMID- 28669042 TI - Paravascular inner retinal abnormalities in healthy eyes. AB - PURPOSE: To investigate the prevalence and characteristics of paravascular inner retinal abnormalities in healthy eyes. MATERIALS AND METHODS: In this prospective observational case series, we included 178 healthy eyes (178 patients) with no ocular diseases. Eyes with co-existing ocular diseases, e.g., epiretinal membrane, glaucoma, or high myopia, were excluded from the current study. The posterior pole and paravascular areas of the temporal arcade vessels were comprehensively examined by dense radial scanning of optical coherence tomography (OCT) with the extended field imaging technique. RESULTS: On fundus photography, no inner retinal abnormalities were detected along the temporal arcade vessels. On OCT sections, paravascular inner retinal abnormalities were seen in 77 (43.3%) eyes. In 71 (39.9%) eyes, inner retinal cystoid or fissure-like spaces that had no connection to the vitreous cavity were seen adjacent to the temporal arcade vessels. Most of these lesions were detected only on several consecutive OCT sections. In four (2.2%) eyes, inner retinal cleavages with openings to the vitreous cavity were seen adjacent to the temporal arcade vessels. These lesions were more frequently detected in the inferior hemisphere and along the major retinal veins. No eyes showed typical broad defects of the inner retinal tissue. There were no significant differences in age, gender, visual acuity, refractive error, or axial length between eyes with or without paravascular inner retinal abnormalities. CONCLUSIONS: Paravascular cystoid or fissure-like spaces were frequently seen in the inner retina of healthy eyes. However, we detected no typical paravascular inner retinal defects in healthy eyes. PMID- 28669043 TI - The XprESS Multi-Sinus Dilation System for the Treatment of Chronic Sinusitis: A NICE Medical Technology Guidance. AB - The XprESS multi-sinus dilation system (XprESS) is a minimally invasive alternative to functional endoscopic sinus surgery (FESS) used in the treatment of people with chronic or recurrent acute sinusitis refractory to medical treatment. The manufacturer of XprESS, Entellus Medical, claims the technology is as effective as FESS in improving quality of life and is associated with quicker recovery times and reduced costs. The Medical Technologies Advisory Committee (MTAC) at the National Institute for Health and Care Excellence (NICE) selected XprESS for evaluation. Nine trials published in 13 papers were correctly identified by the company as relevant to the decision problem, including one randomised controlled trial (REMODEL study). From this evidence, the company concluded that XprESS is as beneficial as FESS for a range of clinical endpoints. The External Assessment Centre (EAC) agreed with the company's conclusion in a subgroup of patients, but judged that the evidence did not generalise to patients within the NHS fully. The company constructed a de novo costing model. XprESS generated cost-savings of L1302 per patient compared with FESS. The EAC critiqued and updated the model's inputs, with differences in results driven by changes in assumptions on procedure duration, length of hospital stay and the proportion of procedures undertaken in an outpatient setting under local anaesthetic. Although cost-incurring in the base case, XprESS generated cost savings under certain scenarios. The MTAC reviewed the evidence and supported the case for adoption, issuing positive draft recommendations. After public consultation NICE published this as Medical Technologies Guidance 30. PMID- 28669044 TI - Genotoxicity and cytotoxicity response to environmentally relevant complex metal mixture (Zn, Cu, Ni, Cr, Pb, Cd) accumulated in Atlantic salmon (Salmo salar). Part I: importance of exposure time and tissue dependence. AB - Health impact of metal mixture at environment realistic concentrations are difficult to predict especially for long-term effects where cause-and-effect relationships may not be directly obvious. This study was aimed to evaluate metal mixture (Zn-0.1, Cu-0.01, Ni-0.01, Cr-0.01, Pb-0.005 and Cd-0.005 mg/L, respectively for 1, 2, 4, 7, 14 and 28 days at concentrations accepted for the inland waters in EU) genotoxicity (micronuclei, nuclear buds, nuclear buds on filament), cytotoxicity (8-shaped nuclei, fragmented-apoptotic erythrocytes), bioaccumulation, steady-state and the reference level of geno-cytotoxicity in hatchery-reared Atlantic salmon tissues. Metals accumulated mostly in gills and kidneys, to the lesser extent in the muscle. Uptake of metals from an entire mixture in the fish for 14 days is sufficient to reach steady-state Cr, Pb concentrations in all tissues; Zn, Cu-in kidneys and muscle, Ni-in liver, kidneys, muscle and Cd-in muscle. Treatment with metal mixture significantly increased summed genotoxicity levels at 7 days of exposure in peripheral blood and liver erythrocytes, at 14 days of exposure in gills and kidney erythrocytes. Significant elevation of cytotoxicity was detected after 2 and 14 days of exposure in gills erythrocytes and after 28 days-in peripheral blood erythrocytes. The amount of Cu, Cr, Pb and Cd accumulated in tissues was dependent upon duration of exposure; nuclear buds, 8-shaped nuclei frequencies also were dependent upon duration of exposure. This study indicates that metals at low levels when existing in mixture causes significant geno-cytotoxicity responses and metals bioaccumulation in salmon. PMID- 28669045 TI - Development of a procedure for determining the mixing ratios in ecotoxicological experiments and its application in binary salt mixture experiments. AB - Although a plethora of models exist to describe the characteristics and risk assessment of chemical mixtures in ecotoxicology, there is no specific procedure to decide on the mixing ratios (i.e. proportions of the individual chemical substances that form the mixture) at any desired level of concentration in an ecotoxicological mixture experiment. In this study, an attempt was made to develop a procedure for determining the mixing ratios in ecotoxicological experiments. In brief, from a single salt exposure test, the relative toxic fractions, which represent the toxic effect exerted by the individual salts, are determined. Thereafter, the proportions of each individual salt at any level of concentration in the mixture are estimated by multiplying the desired concentration with the relative toxic fraction of that particular salt. The procedure was applied to ecotoxicological experiments involving four binary salt mixtures (MgCl2 + MgSO4, NaCl + Na2SO4, MgCl2 + Na2SO4 and NaCl + MgSO4) and Caridina nilotica, an indigenous South African freshwater shrimp. It is hoped that the application of this developed procedure will ensure administering the correct proportions of individual chemical substances in chemical mixtures in order to obtain the desired levels of concentration in aquatic ecotoxicological mixture experiments. PMID- 28669046 TI - Anticoagulant rodenticide exposure and toxicosis in four species of birds of prey in Massachusetts, USA, 2012-2016, in relation to use of rodenticides by pest management professionals. AB - Restrictions on second-generation anticoagulant rodenticides (SGARs) in the United States, which were partially implemented in 2011, prohibit the sale of SGAR products through general consumer outlets to minimize use by non professional or non-agricultural applicators. This study analyzed liver tissue from four species of birds of prey admitted to a wildlife clinic in Massachusetts, USA, from 2012-2016 for residues of anticoagulant rodenticides (ARs). Ninety-four birds were analyzed; 16 were symptomatic for AR toxicosis, and 78 asymptomatic. Ninety-six percent of all birds tested were positive for SGARs: 100% of those diagnosed with AR toxicosis ante-mortem and/or post-mortem and 95% of subclinically exposed birds. Brodifacoum was found in 95% of all birds. Sixty six percent of all birds contained residues of two or more SGARs. A significant increase in exposures to multiple SGARs occurred in later years in the study. Pesticide use reports (PURs) filed with the Massachusetts Department of Agricultural Resources were reviewed to determine the frequency of use of different ARs by pest management professionals (PMPs) across five years. This study finds that the three SGARs favored by PMPs-bromadiolone, difethialone, brodifacoum-were present in combination in the majority of birds, with increases in multiple exposures driven by increased detections of bromadiolone and difethialone. Continued monitoring of AR residues in nontarget species following full implementation of sales and packaging restrictions in the US is needed in order to elucidate the role of PMP use of SGARs in wildlife exposures and to evaluate the effectiveness of current mitigation measures. PMID- 28669047 TI - Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca2+]c/VDAC-[Ca2+]m axis by activation of MAPK/ERK signaling pathway. AB - The cardiac microvascular reperfusion injury is characterized by the microvascular endothelial cells (CMECs) oxidative damage which is responsible for the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. This study aimed to explore the mechanism by which oxidative stress induced CMECs death and the beneficial actions of melatonin on CMECs survival, with a special focused on IP3R-[Ca2+]c/VDAC-[Ca2+]m damage axis and the MAPK/ERK survival signaling. We found that oxidative stress induced by H2O2 significantly activated cAMP response element binding protein (CREB) that enhanced IP3R and VDAC transcription and expression, leading to [Ca2+]c and [Ca2+]m overload. High concentration of [Ca2+]m suppressed DeltaPsim, opened mPTP, and released cyt-c into cytoplasm where it activated mitochondria-dependent death pathway. However, melatonin could protect CMECs against oxidative stress injury via stimulation of MAPK/ERK that inactivated CREB and therefore blocked IP3R/VDAC upregulation and [Ca2+]c/[Ca2+]m overload, sustaining mitochondrial structural and function integrity and ultimately blockading mitochondrial mediated cellular death. In summary, these findings confirmed the mechanisms by which oxidative injury induced CMECs mitochondrial-involved death and provided an attractive and effective way to enhance CMECs survival. PMID- 28669048 TI - Severity of community acquired hypernatremia is an independent predictor of mortality: a matter of water balance and rate of correction. PMID- 28669049 TI - Endoscopic versus microscopic type 1 tympanoplasty in the same patients: a prospective randomized controlled trial. AB - The aim of this study was to compare the audiologic outcomes of the patients who underwent endoscopy on one ear and microscopic tympanoplasty on the other, and to investigate the operative time, graft success, postoperative pain and health status. This prospective randomized controlled study was carried out in Ege University ENT Department between February 2015 and September 2016. The patients who had bilateral chronic otitis media, normal middle ear mucosa and a hearing loss difference of 10 dB or less between the two ears randomly underwent microscopic tympanoplasty in one ear and endoscopic tympanoplasty in the contralateral ear, with 6-month intervals. 13 patients were included in the study with a mean age of 36.17 +/- 3.61 years (range 17-53 years, 7 female, 6 male). The improvement in air-bone gap for groups 1 (endoscopic) and 2 (microscopic) was 9.48 +/- 5.23 and 9.89 +/- 2.79 dB, respectively. The duration of the surgery in group 1 was significantly lower than that in group 2 (p < 0.01). VAS scores were 2.15 +/- 0.37 and 3.76 +/- 1.64 cm for groups 1 and 2, respectively (p = 0.006). The endoscopic approach for type 1 tympanoplasty offers shorter surgery time, better health status and lower postoperative pain than microscopic surgery. In addition, endoscopic surgery offers comparable improvement in air-bone gap and similar graft success. The endoscopic approach has comparable audiological and morphological graft outcomes with the microscopic one. The endoscopic approach yielded better health and pain status for the same patients. Level of evidence This is an individual randomized controlled trial. The level of evidence is 1b. PMID- 28669050 TI - The presence of aberrant p53 pattern is a negative prognostic predictor in squamous cell carcinoma of the nasal vestibule. AB - The aim of this study was to analyze the role of Ki-67, p53, and the "aberrant p53 pattern" in squamous cell carcinomas of the nasal vestibule. Patients between 1995 and 2014 were included. Baseline characteristics and outcome were analyzed with respect to immunohistochemical staining of Ki-67 and p53. "Aberrant p53 pattern" was represented by a moderate or strong staining of at least 60% of the tumor cells or a complete absence of immunoreactivity. Forty-six patients were included of whom 31 (67.4%) were available for Ki-67 and 32 (69.9%) for p53 immunohistochemistry. The "aberrant pattern" of p53 was present in 50% of the patients. While immunoreactivity for both Ki-67 and p53 was not related to each other or outcome, the "aberrant p53 pattern" was associated with a worse disease free survival (p = 0.014). The "aberrant p53 pattern" is a negative prognostic factor in squamous cell carcinoma of the nasal vestibule and might enable a patient-tailored treatment. PMID- 28669051 TI - Antioxidant Response in Duckweed After Exposure to Secondary Effluent from Municipal Wastewater Treatment Plant, Elazig, Turkey. AB - The aim of this study is to evaluate the effects of the effluent of Elazig Municipality Wastewater Treatment Plant on the oxidative defense capacity of aquatic plants (Lemna minor L. and Lemna gibba L.). For this purpose, malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), vitamin A (retinol), vitamin E (alpha-tocopherol), and vitamin C (Ascorbic acid) levels were determined by the HPLC (high performance liquid chromatography) in the control groups and the groups adapting to reactors fed with discharge water. The depletion of vitamins (A, E, and C), decrease of GSH/GSSG ratio, and increase of MDA that reflect a precarious state of the cell in L. minor L. and L. gibba L. were observed after exposure to wastewater. It can be suggested that the selected biomarkers are useful in understanding the biochemical mechanisms of the secondary effluents from wastewater treatment plant in L. minor L. and L. gibba L. as early warning indicators. PMID- 28669052 TI - The combination of preoperative PET/CT and sentinel lymph node biopsy in the surgical management of early-stage cervical cancer. AB - INTRODUCTION: The aim of the study was to evaluate the use of PET/CT and/or SLN mapping alone or in combination in cervical cancer patients. MATERIALS AND METHODS: Data on stage IA1-IIA cervical cancer patients undergoing PET/CT and SLN mapping were retrospectively collected. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT and SLN mapping, alone or in combination, in identifying cervical cancer patients with lymph node metastases were calculated. RESULTS: Sixty patients met the inclusion criteria. PET/CT showed a sensitivity of 68%, a specificity of 84%, a PPV of 61% and a NPV of 88% in detecting lymph nodal metastases. SLN mapping showed a sensitivity of 93%, a specificity of 100%, a PPV of 100% and a NPV of 97%. The combination of PET/CT and SLN mapping showed a sensitivity of 100%, a specificity of 86%, a PPV of 72% and a NPV of 100%. For patients with tumors of >2 cm in diameter, the PET/CT showed a sensitivity of 68%, a specificity of 72%, a PPV of 61% and a NPV of 86%. SLN mapping showed a sensitivity of 93%, a specificity of 100%, a PPV of 100% and a NPV of 95%. The combination of PET/CT and SLN mapping showed a sensitivity of 100%, a specificity of 76%, a PPV of 72% and a NPV of 100%. CONCLUSION: PET/CT represents a "safety net" that helps the surgeon in identifying metastatic lymph nodes, especially in patients with larger tumors. PMID- 28669053 TI - Efficient targeting of CD13 on cancer cells by the immunotoxin scFv13-ETA' and the bispecific scFv [13xds16]. AB - PURPOSE: Treatment of cancer using standard chemotherapy still offers a poor prognosis combined with severe side effects. Novel antibody-based therapies have been shown to overcome low efficiency and lack of selectivity by targeting cancer associated antigens, such as aminopeptidase CD13. METHODS: We isolated a high affinity CD13-specific single-chain fragment variable (scFv13) from a phage display library of V-genes from mice immunized with soluble antigen. An immunotoxin comprising the scFv13 and a truncated version of the exotoxin A of Pseudomonas aeruginosa (ETA', scFv13-ETA') and a bispecific scFv targeting CD13 and CD16 simultaneously (bsscFv[13xds16]) was generated and investigated for their therapeutic potential. RESULTS: Both fusion proteins bound specifically to target cells with high affinity. Furthermore, scFv13-ETA' inhibited the proliferation of human cancer cell lines efficiently at low concentrations (IC50 values of 408 pM-7 nM) and induced apoptosis (40-85% of target cells). The bsscFv triggered dose-dependent antibody-dependent cell-mediated cytotoxicity, resulting in the lysis of up to 23.9% A2058 cells, 18.0% MDA-MB-468 cells and 19.1% HL-60 cells. CONCLUSION: The provided data demonstrate potent therapeutic activity of the scFv13-ETA' and the bsscFv[13xds16]. The CD13-specific scFv is therefore suitable for the direct and specific delivery of both cytotoxic agents and effector cells to cancer-derived cells, making it ideal for further therapeutic evaluation. PMID- 28669055 TI - Long-term hormonal contraceptive use is associated with a reversible suppression of antral follicle count and a break from hormonal contraception may improve oocyte yield. AB - PURPOSE: Unlike infertility, patients presenting for fertility preservation (FP) are often using combined hormonal contraceptives (CHC). We studied whether long term (>=6 months) CHC use is associated with reversible suppression of antral follicle count (AFC). METHODS: This is a longitudinal study of FP cycles from 2012 to 2016. We studied three groups: those without CHC exposure (NO CHC), those with CHC usage with a CHC break (BREAK), and without a break (NO BREAK) prior to ovarian stimulation. We assessed ovarian reserve by AFC at initial consultation and discussed the possibility of CHC suppression of AFC. Patients chose between ovarian stimulation with no CHC break versus ovarian stimulation after a CHC break. AFC was measured serially in the BREAK group. We assessed whether AFC suppression was reversed in the BREAK group. Total oocyte yield was compared among the NO CHC, BREAK, and NO BREAK groups. T tests, ANOVA, and linear/logistic regressions were used. RESULTS: Seven hundred forty-three women underwent FP. Twenty-one percent (n = 154) were taking long-term CHC (>=6 months). AFC suppression was more likely with CHC use (OR 1.6, 95% CI 1.1-2.4, P = 0.011). The BREAK group (n = 79) stopped CHC for an average of 4 months. AFC improvement started at 1 month and plateaued at approximately 6- to 7-month break. The BREAK group had approximately twice as many oocytes per initial AFC as NO BREAK (2.8 +/ 3.8 vs. 1.4 +/- 0.9, P < 0.001). CONCLUSIONS: When women present for FP on CHC, AFC may be suppressed. A CHC break of several months is associated with an increase in AFC and a potential improvement in overall egg yield. PMID- 28669054 TI - Trichomonas vaginalis infection and risk of prostate cancer: associations by disease aggressiveness and race/ethnicity in the PLCO Trial. AB - PURPOSE: Results from previous sero-epidemiologic studies of Trichomonas vaginalis infection and prostate cancer (PCa) support a positive association between this sexually transmitted infection and aggressive PCa. However, findings from previous studies are not entirely consistent, and only one has investigated the possible relation between T. vaginalis seropositivity and PCa in African American men who are at highest risk of both infection and PCa. Therefore, we examined this possible relation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, including separate analyses for aggressive PCa and African-American men. METHODS: We included a sample of participants from a previous nested case-control study of PCa, as well as all additional Caucasian, aggressive, and African-American cases diagnosed since the previous study (total n = 438 Gleason 7 Caucasian cases, 487 more advanced Caucasian cases (>=Gleason 8 or stage III/IV), 201 African-American cases, and 1216 controls). We tested baseline sera for T. vaginalis antibodies. RESULTS: No associations were observed for risk of Gleason 7 (odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.55 1.37) or more advanced (OR = 0.90, 95% CI 0.58-1.38) PCa in Caucasian men, or for risk of any PCa (OR = 1.06, 95% CI 0.67-1.68) in African-American men. CONCLUSIONS: Our findings do not support an association between T. vaginalis infection and PCa. PMID- 28669056 TI - Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. AB - PURPOSE: To study the levels of pathogenic and non-pathogenic Th17 and Th22 cells in autoimmune thyroid disorders patients. Although Th17 cells seem to play an important role in the pathogenesis of thyroid autoimmune disorders, the specific subsets of these lymphocytes have not been analyzed in this condition. METHODS: We assessed the levels of Th17 (pathogenic and non-pathogenic) and Th22 cells in peripheral blood and thyroid glands of autoimmune thyroid disorders patients (n = 26, 16 with Graves' disease and 10 with Hashimoto's thyroiditis) and 15 healthy controls by multi-parametric flow cytometry and immunofluorescence microscopy. RESULTS: We found increased levels of pathogenic Th17 lymphocytes and Th22 cells in peripheral blood from autoimmune thyroid disorders patients. In addition, these cells were detected in thyroid glands from HT patients. Furthermore, we found significant correlations between the levels of these cells and disease activity, disease duration, and the presence of ophthalmopathy. CONCLUSIONS: The increased levels of pathogenic Th17 lymphocytes and Th22 cells in autoimmune thyroid disorders suggest their involvement in the pathogenesis of this condition. PMID- 28669057 TI - A Combination of Stable Isotope Probing, Illumina Sequencing, and Co-occurrence Network to Investigate Thermophilic Acetate- and Lactate-Utilizing Bacteria. AB - Anaerobic digestion is a complicated microbiological process that involves a wide diversity of microorganisms. Acetate is one of the most important intermediates, and interactions between acetate-oxidizing bacteria and archaea could play an important role in the formation of methane in anoxic environments. Anaerobic digestion at thermophilic temperatures is known to increase methane production, but the effects on the microbial community are largely unknown. In the current study, stable isotope probing was used to characterize acetate- and lactate oxidizing bacteria in thermophilic anaerobic digestion. In microcosms fed 13C acetate, bacteria related to members of Clostridium, Hydrogenophaga, Fervidobacterium, Spirochaeta, Limnohabitans, and Rhodococcus demonstrated elevated abundances of 13C-DNA fractions, suggesting their activities in acetate oxidation. In the treatments fed 13C-lactate, Anaeromyxobacter, Desulfobulbus, Syntrophus, Cystobacterineae, and Azospira were found to be the potential thermophilic lactate utilizers. PICRUSt predicted that enzymes related to nitrate and nitrite reduction would be enriched in 13C-DNA fractions, suggesting that the acetate and lactate oxidation may be coupled with nitrate and/or nitrite reduction. Co-occurrence network analysis indicated bacterial taxa not enriched in 13C-DNA fractions that may also play a critical role in thermophilic anaerobic digestion. PMID- 28669058 TI - Improved Neuroimaging Atlas of the Dentate Nucleus. AB - The dentate nucleus (DN) of the cerebellum is the major output nucleus of the cerebellum and is rich in iron. Quantitative susceptibility mapping (QSM) provides better iron-sensitive MRI contrast to delineate the boundary of the DN than either T2-weighted images or susceptibility-weighted images. Prior DN atlases used T2-weighted or susceptibility-weighted images to create DN atlases. Here, we employ QSM images to develop an improved dentate nucleus atlas for use in imaging studies. The DN was segmented in QSM images from 38 healthy volunteers. The resulting DN masks were transformed to a common space and averaged to generate the DN atlas. The center of mass of the left and right sides of the QSM-based DN atlas in the Montreal Neurological Institute space was -13.8, -55.8, and -36.4 mm, and 13.8, -55.7, and -36.4 mm, respectively. The maximal probability and mean probability of the DN atlas with the individually segmented DNs in this cohort were 100 and 39.3%, respectively, in contrast to the maximum probability of approximately 75% and the mean probability of 23.4 to 33.7% with earlier DN atlases. Using QSM, which provides superior iron-sensitive MRI contrast for delineating iron-rich structures, an improved atlas for the dentate nucleus has been generated. The atlas can be applied to investigate the role of the DN in both normal cortico-cerebellar physiology and the variety of disease states in which it is implicated. PMID- 28669060 TI - Anti-Mullerian hormone (AMH) and embryo quality assessed by time-lapse imaging (TLI): a cross-sectional observational study. AB - PURPOSE: Serum anti-Mullerian hormone shows a strong positive correlation to the quantitative ovarian reserve but its correlation to embryo quality is unclear. This study assessed the association between serum AMH as a marker of ovarian reserve and embryo quality, using the technology of time-lapse imaging of the embryos in women undergoing in vitro fertilisation (IVF) treatment. METHODS: 304 embryos from 198 women undergoing IVF were included in the study. Serum AMH was assessed for all women. Embryo quality was assessed with the known implantation data (KID) score generated by the time-lapse imaging system. RESULTS: There was no statistically significant difference in mean serum AMH among different KID score categories (p = 0.135). This remained non-significant after controlling for confounding variables (p = 0.305). CONCLUSIONS: The results of our study show no significant association between serum AMH and embryo quality in women undergoing IVF treatment when embryo quality was assessed using the KID scores generated by time-lapse imaging which is a better method of embryo assessment rather than conventional morphological assessment. PMID- 28669059 TI - Reemergence of translocation t(11;19)(q23;p13.1) in the absence of clinically overt leukemia. AB - We report the case of a 10-year-old female with acute myeloid leukemia (AML) FAB M0 carrying a novel t(11;19)(q23;p13.1) MLL-ELL variant, in which intron 8 of MLL is fused to exon 6 of ELL. Complete remission, judged by morphology and cytogenetic analysis, was achieved after the conventional chemotherapy. Eight months after completion of therapy, the level of WT-1 in peripheral blood and the number of cells with the MLL-ELL fusion transcript resurged. However, the patient remained overtly healthy and the morphology in the bone-marrow smear was innocuous, with no sign of relapse or secondary leukemia. Without any evidence of relapse, the patient has been closely observed without any therapeutic intervention. For approximately 2 years after the completion of therapy, despite clonal proliferation of pre-leukemic cells with an MLL-ELL fusion gene, she has maintained complete remission. In this case, the rare variant form of MLL-ELL fusion that has been identified may be related to diminished leukemogenic capacity, resulting in the persistence of pre-leukemic status; an additional genetic abnormality may thus be necessary for full transformation of pre-leukemic cells. PMID- 28669062 TI - Comparative efficacy of oestrus synchronization protocols in buffalo (Bubalus bubalis). AB - This study was conducted to test the efficacy of gonadotropic hormone (GnRH) based synchronization protocols (Ovsynch, Heatsynch, and Ovsynch Plus) in buffaloes under field condition. Based on anamnesis and transrectal palpation twice at 10-day interval and serum progesterone (P4) concentration, 150 anoestrous buffaloes and delayed pubertal heifers were selected to induce oestrus using GnRH-based protocols. These selected animals were randomly divided into three groups: group I: Ovsynch (n = 50), group II: Heatsynch (n = 50), and group III: Ovsynch Plus (n = 50) regimen. Before treatment initiation, blood samples were collected for P4, beta-hydroxy butyric acid (beta-OHB), and mineral estimation, in addition to the monitoring of oestrus signs. In this investigation, no significant difference (P > 0.05) in oestrus signs was deduced among three groups. Oestrus induction rate (OIR) was comparable (P > 0.05) among the groups (Ovsynch 82%, Heatsynch 86%, and Ovsynch Plus 88%). Conception rate (CR) following fixed time artificial insemination (FTAI) was slightly higher with Ovsynch Plus group (28%) as compared to Ovsynch (24%) and Heatsynch (18%) groups, though non-significant. Furthermore, serum glucose, beta-OHB, macrominerals (calcium, potassium, and magnesium), and trace minerals (copper, zinc, and iron) remained comparable (P > 0.05) among the groups. In conclusion, all the protocols (Ovsynch, Heatsynch, and Ovsynch Plus) are efficient in oestrus induction in anoestrous buffaloes under field condition with Ovsynch Plus protocol resulting in higher CR as compared to other protocols. PMID- 28669061 TI - Male patients affected by mosaic PCDH19 mutations: five new cases. AB - Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years). PMID- 28669063 TI - Maternal undernutrition during the pre- and post-conception periods in twin bearing hairsheep ewes: effects on fetal and placental development at mid gestation. AB - To evaluate the effects of pre- and post-conception undernutrition (UN) on fetal and placental development at mid-gestation, 28 Katahdin * Pelibuey multiparous ewes were blocked by weight and assigned to the following four dietary treatments (n = 7 each): ewes fed 100% (control) or 60% of their nutritional requirements 30 days before mating (UNPre), 50 days after mating (UNPost) or during both periods (UNB). Four twin-bearing ewes were selected per treatment at day 50 post conception and then slaughtered at day 75 of gestation to analyze their fetuses. Control fetuses were heavier (P < 0.05) than UNPost and UNB fetuses in 14.6 and 9.4%, respectively. Organ weights as percentage of the fetal weight (except for liver) and morphometric measurements (except for abdominal girth) were similar between control and UN fetuses (UNPre, UNPost, and UNB). Placental mass was heavier (P < 0.05) in control ewes than UNB ewes, but not relative to ewes of other treatments. The number of placentomes per ewe and placental efficiency were unaffected by UN treatments. Compared to control, only UNB ewes exhibited variations (P < 0.05) in the proportion of placentomes, specifically for type A (+13.8%) and B (-12.6%). Placentomes of type A and B had lower weight, length, and width of placentas in UNPost and UNB ewes than placentas of control ewes (P < 0.05). Overall results indicate that fetal and placental development of ewes carrying twins is mainly altered when nutritional restriction occurs simultaneously before conception and during the first third of pregnancy. PMID- 28669064 TI - Apparent diffusion coefficient as it relates to histopathology findings in post chemotherapy nephroblastoma: a feasibility study. AB - BACKGROUND: Nephroblastomas represent a group of heterogeneous tumours with variable proportions of distinct histopathological components. OBJECTIVE: The purpose of this study was to investigate whether direct comparison of apparent diffusion coefficient (ADC) measurements with post-resection histopathology subtypes is feasible and whether ADC metrics are related to histopathological components. MATERIALS AND METHODS: Twenty-three children were eligible for inclusion in this retrospective study. All children had MRI including diffusion weighted imaging (DWI) after preoperative chemotherapy, just before tumour resection. A pathologist and radiologist identified corresponding slices at MRI and postoperative specimens using tumour morphology, the upper/lower calyx and hilar vessels as reference points. An experienced reader performed ADC measurements, excluding non-enhancing areas. A pathologist reviewed the corresponding postoperative slides according to the international standard guidelines. We tested potential associations with the Spearman rank test. RESULTS: Side-by-side comparison of MRI-DWI with corresponding histopathology slides was feasible in 15 transverse slices in 9 lesions in 8 patients. Most exclusions were related to extensive areas of necrosis/haemorrhage. In one lesion correlation was not possible because of the different orientation of sectioning of the specimen and MRI slices. The 25% ADC showed a strong relationship with percentage of blastema (Spearman rho=-0.71, P=0.003), whereas median ADC was strongly related to the percentage stroma (Spearman rho=0.74, P=0.002) at histopathology. CONCLUSION: Side-by-side comparison of MRI-DWI and histopathology is feasible in the majority of patients who do not have massive necrosis and hemorrhage. Blastemal and stromal components have a strong linear relationship with ADC markers. PMID- 28669065 TI - Consolidation hyperthermic intraperitoneal chemotherapy for the treatment of advanced stage ovarian carcinoma: a 3 year experience. AB - PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) potentially confers significant survival benefits in the management of ovarian cancer although the long-term data remain scant. We sought to compare the survival rates of advanced stage ovarian cancer patients who were treated with primary induction therapy alone or in conjunction with consolidation HIPEC. METHODS: 69 ovarian cancer patients who underwent surgery and completed their primary induction chemotherapy were treated with consolidation carboplatin (AUC 10) based HIPEC and compared to a historical cohort that received surgery and primary chemotherapy alone (n = 69). The demographic and clinical characteristics on which we were primarily focused, included patient age, body mass index, surgery and pathology data, chemotherapy regimen, toxicity, and progression free/overall survival. RESULTS: The two patient groups' demographic and clinical characteristics were similar (P > 0.05). Progression-free survival was significantly more pronounced in the HIPEC (25.1 months) patients compared to the control group (20 months) (P = 0.024) and there was a decreased risk of disease progression accorded to the patients treated with HIPEC (HR 2.1028; 95% CI 1.2941-3.4167; P = 0.0027). However, we did not discern any HIPEC related overall survival advantages (P = 0.29). CONCLUSIONS: The results from our ovarian cancer study suggest that adjunctive HIPEC proffers a significant progression-free survival advantage and a decreased risk for disease progression. There was, however, no overall survival advantage discerned by the HIPEC group. We also recognize that HIPEC remains controversial, and thus randomized studies evaluating HIPEC compared to standard chemotherapy in the management of ovarian cancer are warranted. PMID- 28669066 TI - Hypertension Survey in Italy: Novel Findings from the Campania Salute Network. AB - The "Campania Salute" (CS) is a network system aimed at improving the management of essential hypertension by integrating the activity of general practitioners (GPs) with that of the hypertension specialists. It involves 23 outpatient hypertensive clinics distributed in different community hospitals of the Napoli's metropolitan area, 60 randomly selected GPs homogeneously distributed in the same area, and the Hypertension Clinic of the Federico II University in Naples (co ordinating centre). Through the CS system it is possible to share clinical data collected during each visit at peripheral units (general practitioners and community hospitals hypertensive clinics), which manage low-risk hypertensive patients, and the co-ordinating centre, which mainly manages high-risk hypertensive patients. The co-ordinating centre works in co-operation with the peripheral units in the treatment and follow-up of all hypertensive patients. Since the first reports on the CS network activity, it has been evident the effectiveness of this network in ameliorating the clinical management of the hypertensive disease. CS network is also a large prospective registry that generated several scientific reports based on the longitudinal assessment of hypertensive patients during their treatment. Nowadays, as observed in the Health Search Database, the rate of BP control in Campania was 69.5%, almost reaching the "Objective 70%", a result that could be in part linked to the activity of the CS network. PMID- 28669067 TI - Determining the optimal dose of 1940-nm thulium fiber laser for assisting the endodontic treatment. AB - Insufficient cleaning, the complex anatomy of the root canal system, inaccessible accessory canals, and inadequate penetration of irrigants through dentinal tubules minimizes the success of the conventional endodontic treatment. Laser assisted endodontic treatment enhances the quality of conventional treatment, but each laser wavelength has its own its own limitations. The optimal parameters for the antibacterial efficiency of a new wavelength, 1940-nm Thulium Fiber Laser, were firstly investigated in this study. This paper comprises of two preliminary analyses and one main experimental study, presents data about thermal effects of 1940-nm laser application on root canal tissue, effective sterilization parameters for bacteria, Enterococcus faecalis, and finally the antibacterial effectiveness of this 1940-nm Thulium Fiber Laser irradiation in single root canal. Based on these results, the optimal parameter range for safe laser assisted root canal treatment was investigated in the main experiments. Comparing the antibacterial effects of four laser powers on an E. faecalis bacteria culture in vitro in 96-well plates showed that the most effective group was the one irradiated with 1 W of laser power (antibacterial effect corresponding to a log kill of 3). After the optimal laser power was determined, varying irradiation durations (15, 30, and 60 s) were compared in disinfecting E. faecalis. Laser application caused significant reduction in colony-forming unit values (CFU) compared with control samples in the 17% ethylenediaminetetraacetic acid (EDTA) group. The results of bacteria counts showed that 1 W with 30 s of irradiation with a 1940-nm thulium fiber laser was the optimal dose for safely achieving maximal bactericidal effect. PMID- 28669068 TI - Evaluation of laser fluorescence in monitoring non-cavitated caries lesion progression on smooth surfaces in vitro. AB - The aim of this study was to evaluate the performance of a pen-type laser fluorescence (LF) device (LFpen: DIAGNOdent pen) to detect and monitor the progression of caries-like lesions on smooth surfaces. Fifty-two bovine enamel blocks were submitted to three different demineralisation cycles for caries-like lesion induction using Streptococcus mutans, Lactobacillus casei and Actinomyces naeslundii. At baseline and after each cycle, the enamel blocks were analysed under Knoop surface micro-hardness (SMH) and an LFpen. One enamel block after each cycle was randomly chosen for Raman spectroscopy analysis. Cross-sectional micro-hardness (CSMH) was performed at different depths (20, 40, 60, 80 and 100 MUm) in 26 enamel blocks after the second cycle and 26 enamel blocks after the third cycle. Average values of SMH (+/- standard deviation (SD)) were 319.3 (+/- 21.5), 80.5 (+/- 31.9), 39.8 (+/- 12.7), and 29.77 (+/- 10.34) at baseline and after the first, second and third cycles, respectively. Statistical significant difference was found among all periods (p < 0.01). The LFpen values were 4.3 (+/- 1.5), 7.5 (+/- 9.4), 7.1 (+/- 7.1) and 5.10 (+/- 3.58) at baseline and after the first, second, and third cycles, respectively, among all periods (p < 0.05). The CSMH values after the second and third cycles at 20, 40, 60, 80 and 100 MUm were 182.8 (+/- 69.8), 226.1 (+/- 79.6), 247.20 (+/- 69.36), 262.35 (+/- 66.36) and 268.45 (+/- 65.49), and for the third cycle were 193.7 (+/- 73.4), 239.5 (+/- 81.5), 262.64 (+/- 82.46), 287.10 (+/- 78.44) and 284.79 (+/- 72.63) (n = 24 and 23), respectively. No correlation was observed between the LFpen and SMH values (p > 0.05). One sample of each cycle was characterised through Raman spectroscopy analysis. It can be concluded that LF was effective in detecting the first demineralisation on enamel; however, the method did not show any effect in monitoring lesion progression after three cycles of in vitro demineralisation. PMID- 28669069 TI - Cyanobacterial and rhizobial inoculation modulates the plant physiological attributes and nodule microbial communities of chickpea. AB - The present investigation aimed to understand the influence of two plant growth promoting cyanobacterial formulations (Anabaena-Mesorhizobium ciceri biofilm and Anabaena laxa), along with Mesorhizobium ciceri, on the symbiotic performance of five each of desi- and kabuli-chickpea cultivars. Inoculation with cyanobacterial formulations led to significant interactions with different cultivars, in terms of fresh weight and number of nodules, the concentration of nodular leghemoglobin, and the number of pods. The inoculant A. laxa alone was superior in its performance, recording 30-50% higher values than uninoculated control, and led to significantly higher nodule number per plant and fresh root weight, relative to the M. ciceri alone. Highest nodule numbers were recorded in the kabuli cultivars BG256 and BG1003. The kabuli cultivar BG1108 treated with the biofilmed Anabaena-M. ciceri inoculant recorded the highest concentration of leghemoglobin in nodules. These inoculants also stimulated the elicitation of defense- and pathogenesis-related enzymes in both the desi and kabuli cultivars, by two to threefolds. The analyses of Denaturing Gradient Gel Electrophoresis (DGGE) profiles revealed that microbial communities in nodules were highly diverse, with about 23 archaeal, 9 bacterial, and 13 cyanobacterial predominant phylotypes observed in both desi and kabuli cultivars, and influenced by the inoculants. Our findings illustrate that the performance of the chickpea plants may be significantly modulated by the microbial communities in the nodule, which may contribute towards improved plant growth and metabolic activity of nodules. This emphasizes the promise of cyanobacterial inoculants in improving the symbiotic performance of chickpea. PMID- 28669070 TI - Patients' Expectations are Important for Success in Bariatric Surgery. PMID- 28669071 TI - Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials. AB - BACKGROUND: We aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L). METHODS: This post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or <=30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated. RESULTS: The mean ALT change at 12 weeks was -10.3 +/- 11.7 and -3.2 +/- 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P < 0.0001). The mean change in ALT at 52 weeks was -16.0 +/- 18.8 U/L in the high ALT subgroup (P < 0.0001, Study 2). The incidence of AEs or serious AEs in the high ALT subgroup in the canagliflozin group was similar to that in the placebo group (Study 1) or low ALT subgroup (Studies 1 and 2). CONCLUSIONS: In T2DM patients with impaired liver function, canagliflozin may improve liver function, reduce HbA1c and body weight, and be well tolerated. PMID- 28669072 TI - Free and immobilized Aspergillus oryzae SBS50 producing protease-resistant and thermostable phytase. AB - Optimization for enhanced phytase production by Aspergillus oryzae SBS50 in submerged fermentation was investigated using Taguchi design. In first step design, starch, beef extract, magnesium sulphate, ferrous sulphate and Tween 80 were identified as significant factors affecting phytase production. These significant factors were further optimized at four different levels using a second Taguchi design and were observed that 1% starch, 2% beef extact, 3% Tween 80, 0.1% magnesium sulphate and 0.225% ferrous sulphate supported maximum phytase production (47,432 U/L). The use of Taguchi designed experiments resulted in 14.9 fold enhancement in phytase production compared to the medium optimized by 'one variable at a time' approach. Furthermore, 4% agar immobilized conidiospores of A. oryzae supported high phytase production compared with free cells and other matrices. Agar-immobilized conidiospores resulted in sustained phytase production up to eight repeated batch cycles followed by a decrease in enzyme titres. PMID- 28669073 TI - Improvement of abiotic stress adaptive traits in mulberry (Morus spp.): an update on biotechnological interventions. AB - Mulberry (Morus spp.), being an economically important tree, is cultivated in China, India, Thailand, Brazil, Uzbekistan and other Countries across the globe, for its leaves to feed monophagous mulberry silkworm (Bombyx mori). The sustainability of silk industry is directly correlated with the production and continuous supply of high-quality mulberry leaves. In India, it is cultivated on large scale in tropical, sub-tropical and temperate regions under irrigated conditions for silkworm rearing. Drought, low temperature, high salinity and alkalinity, being experienced in widespread areas, are the major abiotic stresses, causing reduction in its potential foliage yield and quality. Further, climate change effects may worsen the productivity of mulberry in near future, not only in India but also across the globe. Although traditional breeding methods contributed immensely towards the development of abiotic stress-tolerant mulberry varieties, still there is lot of scope for implementation of modern genomic and molecular biology tools for accelerating mulberry genetic improvement programmes. This review discusses omics approaches, molecular breeding, plant tissue culture and genetic engineering techniques exploited for mulberry genetic improvement for abiotic stress tolerance. However, high-throughput biotechnological tools such as RNA interference, virus-induced gene silencing, epigenomics and genome editing tools need to be utilized in mulberry to accelerate the progress of functional genomics. The application of genomic tools such as genetic engineering, marker-assisted selection and genomic selection in breeding programmes can hasten the development of climate resilient and productive mulberry varieties leading to the vertical and horizontal expansion for quality silk production. PMID- 28669074 TI - A comparative study of utilization of single and mixed phenolic compounds by individual and mixed culture. AB - Three bacterial strains; Pseudomonas sp. TRMK1, Stenotrophomonas sp. TRMK2 and Xanthomonas sp. TRMK3 were isolated from agro-industrial waste by enrichment culture technique that are capable of utilizing phenolic acids as sole source of carbon and energy. These strains were found to utilize p-coumaric, ferulic and caffeic acid. The individual strains utilized 5 mM of mixed phenolic acids within 20 h of incubation. The bacterial consortium composing these strains was prepared and studied the efficient degradation of phenolic compounds. The bacterial consortium showed the enhanced utilization of 30 mM individual and 25 mM mixed phenolic acids within 32 and 40 h of incubation, respectively. The degradation efficiency of these strains in all the above experiments was above 90%. The prepared bacterial consortium serves as a suitable method for the in situ application of sites contaminated with wide range of phenolic compounds. PMID- 28669075 TI - Origin and evolution of group XI secretory phospholipase A2 from flax (Linum usitatissimum) based on phylogenetic analysis of conserved domains. AB - Phospholipase A2 (PLA2) belongs to class of lipolytic enzymes (EC 3.1.1.4). Lysophosphatidic acid (LPA) and free fatty acids (FFAs) are the products of PLA2 catalyzed hydrolysis of phosphoglycerides at sn-2 position. LPA and FFA that act as second mediators involved in the development and maturation of plants and animals. Mining of flax genome identified two phospholipase A2 encoding genes, viz., LusPLA 2 I and LusPLA 2 II (Linum usitatissimum secretory phospholipase A2). Molecular simulation of LusPLA2s with already characterized plant sPLA2s revealed the presence of conserved motifs and signature domains necessary to classify them as secretory phospholipase A2. Phylogenetic analysis of flax sPLA2 with representative sPLA2s from other organisms revealed that they evolved rapidly via gene duplication/deletion events and shares a common ancestor. Our study is the first report of detailed phylogenetic analysis for secretory phospholipase A2 in flax. Comparative genomic analysis of two LusPLA2s with earlier reported plant sPLA2s, based on their gene architectures, sequence similarities, and domain structures are presented elucidating the uniqueness of flax sPLA2. PMID- 28669076 TI - Isolation, identification, optimization, and metabolite profiling of Streptomyces sparsus VSM-30. AB - Deep sea sediment samples of Bay of Bengal (Visakhapatnam) have been analyzed for actinomycetes as an elite source to screen for the production of bioactive metabolites. The actinomycetes strain VSM-30 has an exciting bioactivity profile and was isolated during our systemic screening of marine actinomycetes. It was identified as Streptomyces sparsus based on morphological, physiological, biochemical, and molecular approaches. Response surface methodology regression analysis was carried out to fit the experimental data of each response by the second-order polynomial. The results have proven right interaction among process variables at optimized values of incubation time at 12 days, pH at 8, temperature at 30 degrees C, concentrations of starch at 1%, and tryptone at 1% and the data have been adequately fitted into the second-order polynomial models. Under these conditions, the responses (zones of inhibition) of plant pathogenic fungi Aspergillus niger, Aspergillus flavus, Fusarium oxysporum, Fusarium solani, and Penicillium citrinum were also matched with experimental and predicted results. Chemotypic analysis of ethyl acetate extract of the strain was done using LC-Q TOF-MS revealed the presence of bioactive compounds including tryptophan dehydrobutyrine diketopiperazine, maculosin, 7-o-demethyl albocycline, albocycline M-2, and 7-o-demethoxy-7-oxo albocycline in a negative ion mode. The ethyl acetate extract of actinobacterium has been subjected to gas chromatography and mass spectroscopy (GC-MS) revealed the presence of diverse compounds such as dotriacontane, tetracosane 11-decyl-, diheptyl phthalate, 1-hexadecanesulfonyl chloride, L-alanyl-L-tryptophan, phthalic acid ethyl pentyl ester, 4 trifluoroacetoxyhexadecane, and 1H-imidazole 4,5-dihydro-2,4-dimethyl. Hence, the ethyl acetate extract of Streptomyces sparsus VSM-30 may have antibacterial, antifungal, and antioxidant activities due to the presence of secondary metabolites in ethyl acetate extract. The study also supports marine sediment samples of Bay of Bengal, a promising marine ecosystem remained to be explored for new bioactive compounds. PMID- 28669078 TI - The incidence of life threatening iatrogenic vessel injury following closed or open reduction and internal fixation of intertrochanteric femoral factures. AB - AIM OF THE STUDY: Bleeding due to a vascular injury is a possible life threatening complication of intertrochanteric femoral fracture internal fixation. Our goals were to find the current incidence of these events, and to describe the reasons, the presentation, and the treatment options. METHOD: We conducted a retrospective record review of 1,469 patients who were operated upon at our institution due to AO31A femoral fractures from 2011 through 2015 and were treated with closed reduction and internal fixation. RESULTS: Three patients were diagnosed with iatrogenic vascular bleeding, which constitute an incidence of 0.2%. The vascular injuries were detected as deep femoral artery bleeding adjacent to the distal locking screws. The patients were treated with ultrasound guided thrombin injection, endovascular coil embolization or with no endovascular intervention. DISCUSSION: Vascular injuries are caused mainly by perforating a vessel while drilling the distal locking screw holes. A high level of suspicion and immediate imaging work-up are mandatory. CONCLUSIONS: A vascular injury due to internal fixation of a proximal AO31A femoral fracture is a rare complication. PMID- 28669077 TI - Lung as a Niche for Hematopoietic Progenitors. AB - Platelets are released from megakaryocytes. The bone marrow has been proposed to be the major site where this process occurs. Lefrancais et al. (2017) using state of-the-art techniques including two-photon microscopy, in vivo lineage-tracing technologies, and sophisticated lung transplants reveal that the lung is also a primary site for platelet biogenesis. Strikingly, lung megakaryocytes can completely reconstitute platelet counts in the blood in mice with thrombocytopenia. This study also shows that hematopoietic progenitors, with capacity to repopulate the bone marrow after irradiation, are present in the lungs. This work brings a novel unexpected role for the lung as a niche for hematopoiesis. The emerging knowledge from this research may be important for the treatment of several disorders. PMID- 28669079 TI - Immunohistochemical Analysis of Foxp3+, CD4+, CD8+ Cell Infiltrates and PD-L1 in Oral Squamous Cell Carcinoma. AB - The immunoexpression of the PD-L1 and the number of immune infiltrating cells have been shown to be a significant prognostic factors in various human cancers. Immunohistochemical method was used to examine the immunoexpression of PD-L1 and number of Foxp3+, CD4+, CD8+ cells in 78 cases of oral squamous cell carcinomas (OSCCs): with better prognosis - OSCCBP (n = 37), and with poorer prognosis - OSCCPP (n = 41), and 18 cases of normal mucosa as a control. The immunoexpression of PD-L1 and the mean number of Foxp3+ cells was significantly increased in OSCCPP group in comparison to OSCCBP and control groups. The mean number of CD4+ cells was significantly increased in OSCCPP group in comparison to OSCCBP and control groups. CD8+ cells were significantly more numerous in OSCCBP group in comparison to OSCCPP and control group. In both OSCCPP and OSCCBP groups there were positive significant correlations between number of Foxp3+ and CD4+ cells. We found positive correlations between the immunoexpression of PD-L1 and numbers of Foxp3+ cells, and negative correlation between the immunoexpression of PD-L1 and numbers of CD8+ cells in both OSCCPP and OSCCBP groups. We found also significant positive correlation between immunoexpression of PD-L1 and the number of CD4+ cells in OSCCPP group. In conclusion, our findings support the hypothesis of involvement of Tregs and PD-L1 in OSCC development and progression. PMID- 28669080 TI - Identification of Potential Gene Network Associated with HCV-Related Hepatocellular Carcinoma Using Microarray Analysis. AB - In order to identify potential specific gene networks of Hepatitis C virus (HCV) related hepatocellular carcinoma (HCC), weighted gene co-expression network analysis (WGCNA) was performed, which may provide an insight into the potential mechanism of the HCC development. HCV-related HCC and normal sample data were downloaded from GEO, T test of limma package was used to screen different expression genes (DEGs); KEGG pathway was used to analyze related biochemical pathways, and WGCNA was used to construct clustering trees and screen hub genes in the HCC-specific modules. A total of 1151 DEGs were authenticated between the HCC and normal liver tissue samples, including 433 upregulated and 718 downregulated genes. Among these genes, three specific modules of HCC were constructed, including Tan, Yellow and Cyan, but only Yellow module had a significant enrichment score in substance combination module with three hub genes: SLA2547, EFNA4 and MME. Although Tan and Cyan separately had four and three hub genes, but the bio-functions of them did not have significant enrichment scores (score < 2). SLA2547, EFNA4 and MME may play important roles in the substance combination of HCV-related HCC, so studying the function of this gene network may provide us a deeper understanding of HCV-related HCC. PMID- 28669081 TI - Distribution of Vascular Patterns in Different Subtypes of Renal Cell Carcinoma. A Morphometric Study in Two Distinct Types of Blood Vessels. AB - To analyze the presence of mature and immature vessels as a prognostic factor in patients with renal cell carcinoma and propose a classification of renal cancer tumor blood vessels according to morphometric parameters. Tissue samples were obtained from 121 renal cell carcinoma patients who underwent radical nephrectomy. Staining with CD31 and CD34 was used to differentiate between immature (CD31+) and mature (CD34+) blood vessels. We quantified the microvascular density, microvascular area and different morphometric parameters: maximum diameter, minimum diameter, major axis, minor axis, perimeter, radius ratio and roundness. We found that the microvascular density was higher in CD31+ than CD34+ vessels, but CD34+ vessels were larger than CD31+ vessels, as well as being strongly correlated with the ISUP tumor grade. We also identified four vascular patterns: pseudoacinar, fascicular, reticular and diffuse. Pseudoacinar and fascicular patterns were more frequent in clear cell renal cell carcinoma (37.62 and 35.64% respectively), followed by reticular pattern (21.78%), while in chromophobe tumors the reticular pattern predominated (90%). The isolated pattern was present in all papillary tumors (100%). In healthy renal tissue, the pseudoacinar and isolated patterns were differentially found in the renal cortex and medulla respectively. We defined four distinct vascular patterns significantly related with the ISUP tumor grade in renal cell carcinomas. Further studies in larger series are needed in order to validate these results. Analysis of both mature and immature vessels (CD34+ and CD31+) provides additional information when evaluating microvascular density. PMID- 28669082 TI - Accompanying migrainous features in pediatric migraine patients with restless legs syndrome. AB - The present study aimed to examine the frequency of restless legs syndrome (RLS) in pediatric patients with migraine and tension-type headache (TTH) and to investigate accompanying migrainous symptoms, sleep characteristics, as well as levels of serum ferritin between the pediatric migraine patients with RLS and those without RLS. We included 65 consecutive patients diagnosed with migraine, 20 patients with TTH, and 97 headache-free children in our study. Demographic, clinical, and laboratory data were noted. The presence of a primary headache was diagnosed using the ICHD-II criteria, and RLS was determined with face-to-face interviews conducted by an experienced neurologist based on the revised International RLS Study Group criteria for pediatrics. The frequency of RLS in pediatric migraine and TTH patients was significantly higher than in the controls (p = 0.0001 and p = 0.025, respectively). The frequencies of allodynia, vertigo/dizziness, and self-reported frequent arousals were significantly higher, and serum ferritin levels were significantly lower in migraine patients with RLS compared to those without RLS (p = 0.05, p = 0.028, p = 0.02, and p = 0.038, respectively). Our study suggests that the frequency of RLS is higher in pediatric migraine and TTH patients compared to controls. Therefore, pediatric headache patients should be questioned about the presence of RLS, as this co occurrence may lead to more frequent accompanying migrainous symptoms and sleep disturbances. PMID- 28669084 TI - Painful Peripheral Neuropathy and Cancer. AB - Peripheral neuropathy (PN) is very prevalent in cancer patients and a leading cause of pain related to cancer. However, the underlying pathophysiological mechanisms vary significantly. Peripheral neuropathy can be a direct or an indirect complication of cancer or cancer-related treatment, or a pre-existing comorbidity not related to cancer. PN might also occur as a paraneoplastic neurological syndrome. Such syndromes are immune-mediated manifestations that usually precede the diagnosis of cancer or cancer's relapse. Pain is very prevalent in paraneoplastic peripheral neuropathies and, therefore, merits attention. PMID- 28669083 TI - Quenching of chlorophyll triplet states by carotenoids in algal light-harvesting complexes related to fucoxanthin-chlorophyll protein. AB - We have used time-resolved absorption and fluorescence spectroscopy with nanosecond resolution to study triplet energy transfer from chlorophylls to carotenoids in a protective process that prevents the formation of reactive singlet oxygen. The light-harvesting complexes studied were isolated from Chromera velia, belonging to a group Alveolata, and Xanthonema debile and Nannochloropsis oceanica, both from Stramenopiles. All three light-harvesting complexes are related to fucoxanthin-chlorophyll protein, but contain only chlorophyll a and no chlorophyll c. In addition, they differ in the carotenoid content. This composition of the complexes allowed us to study the quenching of chlorophyll a triplet states by different carotenoids in a comparable environment. The triplet states of chlorophylls bound to the light-harvesting complexes were quenched by carotenoids with an efficiency close to 100%. Carotenoid triplet states were observed to rise with a ~5 ns lifetime and were spectrally and kinetically homogeneous. The triplet states were formed predominantly on the red-most chlorophylls and were quenched by carotenoids which were further identified or at least spectrally characterized. PMID- 28669085 TI - Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Paraneoplastic neurological syndromes (PNS) consist of a heterogeneous group of neurological disorders triggered by cancer. The aim of this systematic review is to estimate the reported prevalence of pain in patients with paraneoplastic peripheral neuropathy (PPN). METHODS: A systematic computer based literature search was conducted on PubMed database. RESULTS: Our search strategy resulted in the identification of 126 articles. After the eligibility assessment, 45 papers met the inclusion criteria. Full clinical and neurophysiological data were further extracted and involved 92 patients with PPN (54.5% males, mean age 60.0 +/- 12.2 years). The commonest first manifestation of PPN is sensory loss (67.4%), followed by pain (41.3%), weakness (22.8%), and sensory ataxia (20.7%). In 13.0% of the cases, pain was the sole first manifestation of the PPN. During the course of the PPN, 57.6% of the patients may experience pain secondary to the neuropathy. CONCLUSIONS: Pain is very prevalent within PPN. Pain specialists should be aware of this. Detailed history-taking, full clinical examination, and requesting nerve conduction studies might lead to an earlier diagnosis of an underlying malignancy. PMID- 28669086 TI - Why is it so difficult to measure glucagon-like peptide-1 in a mouse? AB - AIMS/HYPOTHESIS: In humans, glucagon-like peptide-1 (GLP-1) is rapidly degraded by dipeptidyl peptidase-4 to a relatively stable metabolite, GLP-1(9-36)NH2, which allows measurement of GLP-1 secretion. However, little is known about the kinetics of the GLP-1 metabolite in mice. We hypothesised that the GLP-1 metabolite is rapidly degraded in this species by neutral endopeptidase(s) (NEP[s]). METHODS: We administered glucose, mixed meal or water orally to 256 mice, and took blood samples before and 2, 6, 10, 20, 30, 60 or 90 min after stimulation. To study the metabolism of the GLP-1 metabolite, i.v. GLP-1(9-36)NH2 (800 fmol) or saline (154 mmol/l NaCl) was administered to 160 mice, some of which had a prior injection of a selective NEP 24.11 +/- inhibitor (candoxatril, 5 mg/kg) or saline. Blood was collected before and 1, 2, 4 and 12 min after GLP 1/saline injection. Plasma GLP-1 levels were analysed using a customised single site C-terminal ELISA, two different two-site ELISAs and MS. RESULTS: GLP-1 secretion profiles after oral glucose administration differed markedly when assayed by C-terminal ELISA compared with sandwich ELISAs, with the former showing a far higher peak value and AUC. In mice injected with GLP-1(9-36)NH2, immunoreactive GLP-1 plasma levels peaked at approximately 75 pmol/l at 1 min when measured with sandwich ELISAs, returning to baseline (~20 pmol/l) after 12 min, but remained elevated using the C-terminal ELISA (~90 pmol/l at 12 min). NEP 24.11 inhibition by candoxatril significantly attenuated GLP-1(9-36)NH2 degradation in vivo and in vitro. MS identified GLP-1 fragments consistent with NEP 24.11 degradation. CONCLUSIONS/INTERPRETATION: In mice, the GLP-1 metabolite is eliminated within a few minutes owing to endoproteolytic cleavage by NEP 24.11. Therefore, accurate measurement of GLP-1 secretion in mice requires assays for NEP 24.11 metabolites. Conventional sandwich ELISAs are inadequate because of endoproteolytic cleavage of the dipeptidyl peptidase-4-generated metabolite. PMID- 28669088 TI - Vasovagal syncope with asystole: the role of cardiac pacing. AB - Whereas cardiac pacing has a very limited role overall in patients with vasovagal syncope (VVS), there are three reasons which support pacing efficacy in tilt induced asystolic VVS. These are: (1) contrary to mixed and vasodepressor forms, an asystolic tilt response is specific, i.e., diagnostic, of VVS and is unlikely to occur in control patients without history of syncope and in patients with cardiac syncope; (2) contrary to mixed and vasodepressor forms, an asystolic tilt response predicts a similar asystolic event during prolonged ECG monitoring with a positive predictive value of 86%; (3) the available evidence from trials supports the efficacy of dual-chamber pacing with a low recurrence rate of syncope after pacing ranging from 6% up to 23% during 3 years of follow-up. The latter results should be confirmed by an ongoing double-blind randomized controlled trial before cardiac pacing becomes an established indication. It is commonly believed that the most frequent cause of recurrence of syncope in patients treated with a pacemaker is an associated hypotensive reflex. In these cases additional measures should be used to counteract hypotension. Recognizing prodromal symptoms, avoiding triggers, and performing counterpressure maneuvers are the well-known first steps. There are two additional useful measures when these fail: stopping/reducing hypotensive drugs and (in selected cases) adding fludrocortisone. PMID- 28669087 TI - Typical vasovagal syncope as a "defense mechanism" for the heart by contrasting sympathetic overactivity. AB - Many observations suggest that typical (emotional or orthostatic) vasovagal syncope (VVS) is not a disease, but rather a manifestation of a non-pathological trait. Some authors have hypothesized this type of syncope as a "defense mechanism" for the organism and a few theories have been postulated. Under the human violent conflicts theory, the VVS evolved during the Paleolithic era only in the human lineage. In this evolutionary period, a predominant cause of death was wounding by a sharp object. This theory could explain the occurrence of emotional VVS, but not of the orthostatic one. The clot production theory suggests that the vasovagal reflex is a defense mechanism against hemorrhage in mammals. This theory could explain orthostatic VVS, but not emotional VVS. The brain self-preservation theory is mainly based on the observation that during tilt testing a decrease in cerebral blood flow often precedes the drop in blood pressure and heart rate. The faint causes the body to take on a gravitationally neutral position, and thereby provides a better chance of restoring brain blood supply. However, a decrease in cerebral blood flow has not been demonstrated during negative emotions, which trigger emotional VVS. Under the heart defense theory, the vasovagal reflex seems to be a protective mechanism against sympathetic overactivity and the heart is the most vulnerable organ during this condition. This appears to be the only unifying theory able to explain the occurrence of the vasovagal reflex and its associated selective advantage, during both orthostatic and emotional stress. PMID- 28669089 TI - Patient experience in the pediatric emergency department: do parents and children feel the same? AB - : The objectives are to describe the experience of children and parents in a pediatric emergency service (PED) and to determine whether there are differences of opinion between the two groups. This was a descriptive study. A questionnaire was designed based on the Picker questionnaire on the patient experience. From July through December 2015, a survey was made of the children aged 8-18 treated in the PED, as well as of their parents. The proportion of dissatisfaction was determined. A total of 514 questionnaires (257 children, 257 parents) were completed. The most poorly rated aspects according to the children and parents were the entertainment activities (43.2%), the waiting time (23.7%), and the treatment for pain (10.5%). Differences were detected in the experiences of the children and the parents regarding the overlong waiting time (28.0% children vs 19.5% parents; p = 0.023), inadequate explanations (7.0 vs 1.6%, p = 0.002), inadequate treatment for pain (14.4 vs 6.6%; p = 0.004), and insufficient privacy (11.7 vs 2.7%; p < 0.001). CONCLUSION: The entertainment activities during the wait and the waiting time are the two elements viewed most negatively by the children and the parents. The children tend to evaluate certain aspects of their experience as patients more negatively, which needs to be borne in mind in order to improve the attention provided. What is Known: * Studying the experience of patients is a key point in patient-centered medicine. * The experience of the pediatric patient has been little studied to date. The experience of the children is often inferred from that of their parents. Nevertheless, the experience of the children as patients might be different. What is New: * Overall, the experience of children and parents in the pediatric emergency department in the study is positive. Some aspects of the experience in emergency are poorly rated by the children, such as the waiting time, the information provided, treatment for pain, and privacy during the visit. * The experience of the children (and not merely that of their parents) needs to be studied in order to improve those areas that are rated poorly do as to enrich the experience in the emergency department. PMID- 28669090 TI - Field crops (Ipomoea aquatica Forsk. and Brassica chinensis L.) for phytoremediation of cadmium and nitrate co-contaminated soils via rotation with Sedum alfredii Hance. AB - Phytoremediation coupled with crop rotation (PCC) is a feasible strategy for remediation of contaminated soil without interrupting crop production. The objective of this study was to develop a PCC technology system for greenhouse fields co-contaminated with Cd and nitrate using hyperaccumulator Sedum alfredii. In this system, endophytic bacterium M002 inoculation, CO2 fertilization, and fermentation residue were continuously applied to improve the growth of S. alfredii, and low-accumulator Ipomoea aquatica and low-accumulator Brassica chinensis were rotated under reasonable water management. These comprehensive management practices were shown to increase S. alfredii biomass and Cd uptake and reduce Cd and nitrate concentration in I. aquatica and B. chinensis. This crop rotating system could remove 56.5% total Cd, 62.3% DTPA extractable Cd, and 65.4% nitrate, respectively, from the co-contaminated soil in 2 years of phytoremediation, and is an effective way of remediating moderately co contaminated soil by Cd and nitrate. PMID- 28669091 TI - The use of saline aquaculture effluent for production of Enterolobium contortisiliquum seedlings. AB - The use of aquaculture effluent for irrigation of field crops has been suggested as the most appropriate biological method for treatment of this effluent. However, using it for irrigation of tree species in seedling nurseries might be a better alternative to avoid soil salinization and groundwater contamination in agricultural fields. This paper aimed at assessing the production of Enterolobium contortisiliquum seedlings under irrigation with saline aquaculture effluent. The experiment was carried out in a randomized complete block design with four replicates and four seedlings per experimental unit. Each replicate was daily irrigated with five solutions containing different concentrations of saline aquaculture effluent diluted with freshwater (0, 25, 50, 75 and 100% effluent). Despite increasing substrate salinity, the dilution of saline aquaculture effluent in the irrigation water promoted greater shoot growth and higher total dry weight in E. contortisiliquum. Moreover, seedlings treated with low concentrations of this effluent increased their leaf area expansion and chlorophyll content. Therefore, the use of solutions containing 25 and 50% effluent allowed the production of high-quality seedlings. These results suggest that saline aquaculture effluent can be reused to irrigate tree species, enabling a successful integration of aquaculture and agriculture and reducing environmental impacts of improper effluent disposal. PMID- 28669092 TI - Release of polyester and cotton fibers from textiles in machine washings. AB - Microplastics are widely spread in the environment, which along with still increasing production have aroused concern of their impacts on environmental health. The objective of this study is to quantify the number and mass of two most common textile fibers discharged from sequential machine washings to sewers. The number and mass of microfibers released from polyester and cotton textiles in the first wash varied in the range 2.1 * 105 to 1.3 * 107 and 0.12 to 0.33% w/w, respectively. Amounts of released microfibers showed a decreasing trend in sequential washes. The annual emission of polyester and cotton microfibers from household washing machines was estimated to be 154,000 (1.0 * 1014) and 411,000 kg (4.9 * 1014) in Finland (population 5.5 * 106). Due to the high emission values and sorption capacities, the polyester and cotton microfibers may play an important role in the transport and fate of chemical pollutants in the aquatic environment. PMID- 28669093 TI - Influence of environmental factors on absorption characteristics of suspended particulate matter and CDOM in Liaohe River watershed, northeast China. AB - Absorption characteristics of optically active substances, including non-algal particles, phytoplankton, and chromophoric dissolved organic matter (CDOM), were measured in conjunction with environmental factors in five rivers within the Liaohe River watershed. Spectral absorption of non-algal particles [a NAP(lambda)] was similar to that of total particles for most samples, suggesting that the absorption of the total particles [a p(lambda)] was dominated by a NAP(lambda). The CDOM absorption spectra [a CDOM(lambda)] of West Liaohe and Taizihe rivers were easily distinguished from those of Hunhe, Liaohe, and East Liaohe rivers. Redundancy analysis indicated that absorption by optically active substances and anthropogenic nutrient disturbances probably resulted in the diversity of water quality parameters. The environmental variables including dissolved organic carbon, total alkalinity (TAlk), and total nitrogen (TN) had a significant correlation with CDOM absorption at 440 nm [a CDOM(440)]. There was almost no correlation between a p(lambda) and chlorophyll a, TN, total phosphorus, and TAlk. Moreover, total copper ion concentration and mercury ion concentration had a strong correlation with a p(440), a p(675), a NAP(440), and a NAP(675). The concentration of total aluminum ions exhibited a positive correlation with a p(675) and a NAP(675) (p < 0.05), and a significant correlation was observed between total arsenic concentration and a CDOM(440). Furthermore, the interaction between metal ions and optically active substances provided an insight into particulates and CDOM properties linked to water quality characteristics for rivers in semiarid areas. PMID- 28669094 TI - Ecotoxicity of 1,3-dichloropropene, metam sodium, and dazomet on the earthworm Eisenia fetida with modified artificial soil test and natural soil test. AB - 1,3-Dichloropropene (1,3-D), metam sodium (MS), and dazomet (DZ) are widely used as preplant soil fumigants to solve soilborne problems. To provide a more scientific and accurate evaluation of 1,3-D, MS, and DZ toxicity to the earthworm Eisenia fetida, modified artificial soil test and natural soil test were studied. The suitable soil moisture to maintain over 90% survival of the earthworms after 4 weeks of treatment in an enclosed system for modified artificial soil test and natural soil test were 26.9 to 86.4% of water-holding capacity (WHC) and 66.2 to 84.3% of WHC, respectively. The optimal soil moisture levels for modified artificial soil test and natural soil test (75 and 55% of WHC, respectively) were finally used to evaluate the toxicity of 1,3-D, MS, and DZ on earthworms. Each desiccator with 10 earthworms and natural or artificial soil was stored at 20 +/- 1 degrees C under constant light of 400 to 800 lx for 2 weeks. The modified artificial soil test showed LC50 values for 1,3-D, MS, and DZ of 3.60, 1.69, and 5.41 mg a.i. kg-1 soil, respectively. The modified natural soil test of the fumigants showed similar LC50 values of 2.77 and 0.65 mg a.i. kg-1 soil, except for DZ at 0.98 mg a.i. kg-1 soil. The present study confirms that both modified artificial soil test and modified natural soil test offer standard methods for acute toxicity test of 1,3-D, MS, and DZ on the earthworms and scientific evidences for assessing the effects of soil fumigants on non-target organisms in the soils. Graphical Abstract Two novel acute toxicity test methods for soil fumigants on the earthworm Eisenia fetida. PMID- 28669095 TI - Simultaneous effect of dissolved organic carbon, surfactant, and organic acid on the desorption of pesticides investigated by response surface methodology. AB - Desorption of pesticides (fenobucarb, endosulfan, and dichlorodiphenyltrichloroethane (DDT)) from soil to aqueous solution with the simultaneous presence of dissolved organic carbon (DOC), sodium dodecyl sulfate (SDS), and sodium oxalate (Oxa) was investigated in batch test by applying a full factorial design and the Box-Behnken response surface methodology (RSM). Five concentration levels of DOC (8 to 92 mg L-1), SDS (0 to 6.4 critical micelle concentration (CMC)), and Oxa (0 to 0.15 M) were used for the experiments with a rice field topsoil. The results of RSM analysis and analysis of variance (ANOVA) have shown that the experimental data could be well described by quadratic regression equations with determination coefficients (R 2) of 0.990, 0.976, and 0.984 for desorption of fenobucarb, endosulfan, and DDT, respectively. The individual effects and interaction of DOC, SDS, and Oxa were evaluated through quadratic regression equations. When the aqueous solution includes 50 mg L-1 DOC, 3.75 CMC SDS, and 0.1 M Oxa, the maximum desorption concentrations of fenobucarb, endosulfan, and DDT were 96, 80, and 75 MUg L-1, respectively. The lowest concentration of SDS, DOC, and Oxa caused the minimum desorption. This point at conditions of concern for flooding water is high content of organic compounds causing potentially high contamination by desorption, and the remarkably lower desorption at organic matter-free conditions. The suspended organic matter is one of the common characteristics of flooding and irrigation water in rice fields, and surfactants from pollution increase the problem with desorption of legacy pesticides in the rice fields. PMID- 28669096 TI - Suppressive effects of thermal-treated oyster shells on cadmium and copper translocation in maize plants. AB - The effect of varied concentrations of thermal-treated oyster shells (TOS) on the suppression of cadmium (Cd) and copper (Cu) uptake and translocation into the shoots of maize plants was examined. Maize plants were grown in Cd- and Cu contaminated Andosol for 70 days. The concentration of mobile Cd (extracted with 1 M NH4NO3) decreased with increasing TOS applications, whereas an increase in the concentration of mobile Cu in soil resulted from cumulative TOS additions. The addition of 2% TOS had no prohibitive effects on Cd uptake in maize shoots, but the 4 and 8% TOS treatments decreased Cd accumulation in shoots by 41 and 59%, respectively. The possible mechanisms underlying Cd suppression in maize shoots were the enhanced Cd adsorption caused by pH-induced increases in the negative charge of the soil and the antagonistic effects of Ca resulting from competition for exchange sites at the root surface. Cu accumulation in maize shoots increased by 34, 51, and 53% with the addition of 2, 4, and 8% TOS, respectively, but this increase was not observed for Cd accumulation. These results suggested that, in multi-metal-contaminated soils, attention should be paid to the potential mobility of target metals and the pH of the contaminated soil. From a plant physiological perspective, contaminated soils slightly reduced photosynthetic performance. However, the addition of TOS to the soil at levels higher than 4% substantially decreased photosynthetic performance, indicating that CaO-based suppressants at critical loads might damage the net photosynthetic rates of sensitive maize plants. PMID- 28669097 TI - Medical education in pharmacogenomics-results from a survey on pharmacogenetic knowledge in healthcare professionals within the European pharmacogenomics clinical implementation project Ubiquitous Pharmacogenomics (U-PGx). AB - PURPOSE: Due to the diversity within Europe, the implementation of pharmacogenomic testing in clinical practice faces specific challenges. In the context of the European pharmacogenomics implementation project "Ubiquitous Pharmacogenomics" (U-PGx; funded by the European Commission), we studied the current educational background. METHODS: We developed a questionnaire including 29 questions. It was spread out to healthcare professionals working at the future implementation sites (in Austria, Greece, Italy, Netherlands, Slovenia, Spain and Great Britain) of the U-PGx project in preparation of an educational programme. Aim of the survey was to analyse the current educational situation at the implementation sites. RESULTS: In total, 70 healthcare professionals participated in the survey. Of participants, 84.3% found pharmacogenomics relevant to their current practice, but experience was still rare. More than two-thirds (65.7%) did not order nor recommend a pharmacogenomic test in the past year. This was mainly attributed to not having enough knowledge on pharmacogenomics (40.0%). Needs were identified in application of pharmacogenomics (identifying drugs 41.4%, interpreting test results 37.2%) as well as in underlining mechanisms (better knowledge on drug metabolism 67.1%, better knowledge on basic principles of pharmacogenomics 60.0%). CONCLUSIONS: This study analysed the specific attitudes, experience and education on pharmacogenomics of future users. There was a general positive attitude and interest towards pharmacogenomic testing. However, the grade of own experience, and knowledge about application and interpretation of pharmacogenomics caused uncertainty. Thus, education and training programmes may be helpful for implementation of pharmacogenomics at a homogenous level within Europe. PMID- 28669098 TI - Associations between treatment, scoliosis, pulmonary function, and physical performance in long-term survivors of sarcoma. AB - PURPOSE: Longer survival for children with sarcoma has led to the recognition of chronic health conditions related to prior therapy. We sought to study the association of sarcoma therapy with the development of scoliosis. METHODS: We reviewed patient demographics, treatment exposures, and functional outcomes for patients surviving >10 years after treatment for sarcoma between 1964 and 2002 at our institution. The diagnosis of scoliosis was determined by imaging. Functional performance and standardized questionnaires were completed in a long-term follow up clinic. RESULTS: We identified 367 patients, with median age at follow-up of 33.1 years. Scoliosis was identified in 100 (27.2%) patients. Chest radiation (relative risk (RR), 1.88 (95% confidence interval (CI), 1.21-2.92), p < 0.005) and rib resection (RR, 2.64 (CI, 1.79-3.89), p < 0.0001) were associated with an increased incidence of scoliosis; thoracotomy without rib resection was not. Of 21 patients who underwent rib resection, 16 (80.8%) had the apex of scoliosis towards the surgical side. Scoliosis was associated with worse pulmonary function (RR, 1.74 (CI, 1.14-2.66), p < 0.01) and self-reported health outcomes, including functional impairment (RR, 1.60 (CI, 1.07-2.38), p < 0.05) and cancer-related pain (RR, 1.55 (CI, 1.11-2.16), p < 0.01). Interestingly, pulmonary function was not associated with performance on the 6-min walk test in this young population. CONCLUSIONS: Children with sarcoma are at risk of developing scoliosis when treatment regimens include chest radiation or rib resection. Identification of these risk factors may allow for early intervention designed to prevent adverse long-term outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors at risk of developing scoliosis may benefit from monitoring of pulmonary status and early physical therapy. PMID- 28669099 TI - Bilateral simultaneous acute angle closure attack triggered by an over-the counter flu medication. AB - Most of the rare bilateral acute angle closure (AAC) cases are precipitated by systemic factors, such as drug intake, snake bite or general anaesthesia. We present a case of simultaneous bilateral AAC in a middle-aged male, precipitated by the use of medication for flu, containing an alpha-1 adrenergic receptor agonist and an anticholinergic agent. In our case, axial length was shorter, anterior chamber depth was narrower, and the lens was thicker than normal, including the patient within the risk group for AAC. In this circumstance, drugs acted as triggers. Case description and evolution following treatment are completed with the discussion of mechanisms involved in triggering bilateral AAC in predisposed patients, as emerging from literature. This case report brings up the risk of bilateral AAC in patients at risk, of which ophthalmologists, physicians of other specialties and patients should be aware of. PMID- 28669100 TI - Long-term evaluation of refractive changes in eyes of preterm children: a 6-year follow-up study. AB - PURPOSE: To investigate the longitudinal changes in refractive errors in preterm children with and without retinopathy of prematurity (ROP) in the first 6 years of life. METHODS: We included 226 preterm children with a gestational age of <=34 weeks: 222 eyes with no ROP, 73 eyes with mild ROP and 145 eyes with severe ROP. Longitudinal cycloplegic refraction data were collected initially and yearly thereafter until 6 years of age. RESULTS: Eyes in the severe ROP group showed an increase in myopia values between the 1- and 3-year examinations (p = 0.005), with little change thereafter. However, the mild/no ROP group demonstrated a nonsignificant increasing myopia values throughout the 6-year follow-up (p = 0.073). Both the mild/no ROP and severe ROP groups were found to have increasing mean astigmatism values with increasing age, albeit nonsignificantly (p = 0.418, p = 0.384, respectively). Likewise, the stable mean values of anisometropia increased nonsignificantly during the first 6 years of life in both the mild/no ROP and severe ROP groups (p = 0.246, p = 0.073, respectively). Severe ROP group had higher values regarding myopia, astigmatism, and anisometropia parameters than the mild/no ROP group for all ages during the follow-up. CONCLUSIONS: Preterm children with severe ROP should be closely monitored, and also those with mild/no ROP should be carefully followed up for not overlooking possible increases in refractive conditions. PMID- 28669101 TI - Characterisation of MHC class I genes in the koala. AB - Koala (Phascolarctos cinereus) populations are on the decline across the majority of Australia's mainland. Two major diseases threatening the long-term survival of affected koala populations are caused by obligate intracellular pathogens: Chlamydia and koala retrovirus (KoRV). To improve our understanding of the koala immune system, we characterised their major histocompatibility complex (MHC) class I genes, which are centrally involved in presenting foreign peptides derived from intracellular pathogens to cytotoxic T cells. A total of 11 class I genes were identified in the koala genome. Three genes, Phci-UA, UB and UC, showed relatively high genetic variability and were expressed in all 12 examined tissues, whereas the other eight genes had tissue-specific expression and limited polymorphism. Evidence of diversifying selection was detected in Phci-UA and UC, while gene conversion may have played a role in creating new alleles at Phci-UB. We propose that Phci-UA, UB and UC are likely classical MHC genes of koalas, and further research is needed to understand their role in koala chlamydial and KoRV infections. PMID- 28669102 TI - Femoral revision with primary cementless stems: a systematic review of the literature. AB - The use of primary cementless stems in femoral revision has gained popularity, but no clear consensus about the correct indication is still present. The aim of our systematic review is to: (1) summarize the available literature focused on the use of cementless primary stem in revision total hip arthroplasty (THA); (2) evaluate whether the use of cementless primary stems could represent a feasible option in hip revision; (3) define the proper indication of this surgical approach. A systematic literature review was performed about the use of cementless primary stems in revision THA. The PRISMA 2009 checklist was considered to edit our review. A total of nine articles were included. The current evidence is primarily Level IV. A total of 439 patients (454 hips) underwent THA revision with primary cementless stem. Partial cementless porous coated stems were used in 246 hips (54.2%). The majority of patients were affected by type I or II Paprosky femoral defects. The mean stem-related survival rate is 95.6% +/- 3.8 with a mean follow-up of 4.7 years +/- 1.3. Poor standardization of methodological analysis was observed. Current literature shows lacking evidence about primary cementless stems in revision THA. Despite these limitations, we can affirm that primary cementless stems in femoral revision surgery represent a viable option in selected patients. The proper indication is a patient with femoral Paprosky defect types I or II, with low number of previous surgeries and a previous cementless stem. PMID- 28669103 TI - Disease-modifying anti-rheumatic drug effect of denosumab on radiographic progression in rheumatoid arthritis: a systematic review of the literature. AB - The aim of this study was to evaluate the structural effect of denosumab on patients with rheumatoid arthritis (RA). We performed a systematic review of the literature in the following databases: PubMed, Cochrane, Web of Science, ClinicalTrials.gov , and the WHO International Clinical Trials Registry Platform. All studies evaluating the structural effect of denosumab on RA and meeting predefined criteria were included. Data regarding disease activity, progression of joint damage, joint space narrowing, and safety were recorded. Among 168 studies identified, only 4 were finally included in this review, involving a total of 687 patients. These 4 studies showed that denosumab is effective on joint damage at 6 and 12 months as compared to placebo, alendronate, and biological disease-modifying anti-rheumatic drugs (bDMARDs) alone. No effect was observed in terms of joint space narrowing, and DAS28 and HAQ scores remained unchanged. No case of osteonecrosis of the jaw or atypical fracture was recorded, and safety was similar in both denosumab and control groups. Denosumab appears to be effective on joint erosion at 6 and 12 months in patients with RA meeting the ACR criteria, treated or not by a biologic, with excellent safety. PMID- 28669104 TI - The prognostic significance of preoperatively assessed AST/ALT (De Ritis) ratio on survival in patients underwent radical cystectomy. AB - PURPOSES: We aimed to evaluate prognostic significance of preoperatively assessed aspartate aminotransaminase (AST)/alanine aminotransferase (ALT) (De Ritis) ratio on survival in bladder cancer (BC) patients underwent radical cystectomy (RC). METHODS: We, respectively, analysed clinical and pathological data of 153 patients who underwent RC for BC between February 2006 and December 2016 at a tertiary level hospital. The potential prognostic value of De Ritis ratio was assessed by using ROC curve analysis. The effect of the De Ritis ratio was analysed by the Kaplan-Meier method and Cox regression hazard models for patients' disease-specific survival (DSS) and overall survival (OAS). RESULTS: We had 149 BC patients, in total. Mean age was 61.65 +/- 9.13 years. One hundred and thirty-nine (93.3%) of the patients were men. According to ROC analysis, optimal threshold of De Ritis ratio for DSS was 1.30. In Kaplan-Meier analyses, the high De Ritis ratio group showed worse progression in DSS and OAS (all parameters, p < 0.001). On Cox regression models of clinical and pathological parameters to predict DSS, De Ritis ratio (HR 5.79, 95% CI 2.25-15.13), pathological T stage (HR 15.89, 95% CI 3.92-64.33, in all p < 0.001); and to predict OAS, De Ritis ratio (HR 2.61, 95% CI 1.49-4.56; p < 0.001), pathological T stage (HR 5.42, 95% CI 2.63-11.64; p < 0.001) and age (HR 1.05, 95% CI 1.02-1.08; p = 0.001) were determined as independent prognostic factors. CONCLUSIONS: Preoperative elevated De Ritis ratio could be an independent prognostic factor in BC patients underwent RC. Our results should be confirmed by large and properly designed prospective, randomized trials. PMID- 28669105 TI - Effect of root canal preparation techniques on chlorhexidine substantivity on human dentin: a chemical analysis. AB - OBJECTIVES: Chlorhexidine binds to dentine to provide sustained action. The aim of the present study was to evaluate and compare the substantivity of chlorhexidine using manual, rotary, and reciprocating systems for root canal preparation. METHODS: Forty-five extracted human single-rooted teeth were used for this study. The samples were divided into three groups (n = 15) according to the instrumentation technique used: manual instrumentation (K-File), rotary instrumentation (ProTaper), and reciprocating instrumentation (Reciproc R25). Chlorhexidine gel (2%) was used as auxiliary chemical substance during root canal preparation. Longitudinal grooves were carved on the free surfaces of the roots, providing two halves of each root and resulting in 30 samples per group. Each group was randomly divided into three subgroups (n = 10), and substantivity was evaluated after 48 h, 7 days, and 30 days of incubation. The amount of CHX (in mg/mL) was measured through reverse-phase high-performance liquid chromatography. Statistical analysis was performed by analysis of variance and the Tukey test for post hoc comparisons (alpha = 0.05). RESULTS: The manual did not show a statistical significant difference with rotary instrumentation (P > 0.05), but higher CHX substantivity was recorded in all periods of observation when compared to reciprocating instrumentation (P < 0.05). CONCLUSIONS: The CHX substantivity on human dentine is lowest when using reciprocating compared to manual and rotary instrumentation. CLINICAL SIGNIFICANCE: Using chemical analysis, this study showed that a manual and rotary multi-instrument system results in greater chlorhexidine substantivity on human dentin than a reciprocating single instrument system. PMID- 28669106 TI - Oral shedding of human herpesviruses in renal transplant recipients. AB - OBJECTIVE: To describe the shedding profile of human herpesviruses in the saliva of renal transplant recipients. METHODS: This is a prospective case-control study of 50 renal transplant recipients and control group of 50 individuals (non transplanted and immunocompetent). Mouthwash samples were collected via oral rinse and then submitted to screening for the presence of eight types of herpesviruses by using multiplex PCR. Fisher's exact, chi-square, and Student t tests were used for statistical analysis, and the significance level was set at 5%. RESULTS: The mean age of the study group was 49.42 +/- 12.94 years, 28/50 (56%) were female, and the time elapsed after transplantation was 68.20 +/- 67.19 months. Herpes simplex virus 1 (HSV-1) (P = 0.025) and Epstein-Barr virus (EBV) (P = 0.024) were, statistically, more excreted in the saliva of renal transplant recipients compared to control group. Gender (P = 1.00) and age (P = 0.563) did not influence the salivary shedding of herpesviruses in renal transplant recipients. Individuals who excreted varicella-zoster virus in saliva had a shorter mean time of transplantation (22:00 + 2.82 months) (P < 0.001). CONCLUSION: Renal transplant recipients excreted herpesviruses more often than controls, especially HSV-1 and EBV, with salivary shedding of herpesviruses being more frequent in patients with recent kidney transplantation. CLINICAL RELEVANCE: The present findings support other longitudinal studies evaluating the relationship between oral shedding of human herpesviruses and clinical presence of active infection and renal transplant failure. PMID- 28669107 TI - Outcomes and Costs of Cardiac Surgery in Adults with Congenital Heart Disease. AB - Advances in pediatric cardiac surgical and medical care have led to increased survival of patients with congenital heart disease (CHD). Consequently, many CHD patients survive long enough to require cardiac surgery as adults. Using the 2013 Nationwide Inpatient Sample (NIS) database, we compared costs and outcomes for adult patients undergoing surgery for treatment of CHD to a reference population of adults undergoing CABG. Patients were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) procedure codes. We recorded the demographic characteristics, gender, ethnicity, hospital bed size, hospital length of stay, in-hospital mortality, and comorbidities. Patients with ACHD have higher incidences of in-hospital mortality (2.6 vs. 1.8%), and complication rates including neurologic complications (2.6 vs. 0.9%), thromboembolic complications (3.9 vs. 1.4%), arrhythmias (51.6 vs. 29.8%), hepatic failure (4.44 vs. 2.03%), and sepsis (7.24 vs. 4.61%) (all p < 0.001). In addition, cost is higher in patients with CHD (Coefficient = 0.116, 95% CI, 0.105-0.128; p < 0.001), Elixhauser score >= 7 (Coefficient = 0.114, 95% CI, 0.108-0.121; p < 0.001), neurologic complications (Coefficient = 0.169, 95% CI, 0.143-0.196; p < 0.001), thrombotic complications (Coefficient = 0.243, 95% CI, 0.222-0.265; p < 0.001), sepsis (Coefficient = 0.198, 95% CI, 0.185-0.211; p < 0.001), acute kidney injury (Coefficient = 0.056, 95% CI, 0.041-0.063; p < 0.001), elective cases (Coefficient = 0.047, 95% CI, 0.041-0.053; p < 0.001), and length of stay > 6 days (Coefficient = 0.703, 95% CI, 0.697-0.710; p < 0.001). This study shows that ACHD patients undergoing cardiac surgery experience higher hospital costs and poorer outcomes than a reference population of adult CABG patients. Recognition and treatment of comorbidities in ACHD patients undergoing cardiac surgery may provide an opportunity to improve perioperative outcomes in this growing patient population. PMID- 28669108 TI - Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death. AB - Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G>A(p.Arg173Gln)] and BAG3 [BAG3 c.785C>T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood. PMID- 28669109 TI - Perception of Candomble Practitioners About Herbal Medicine and Health Promotion in Ceara, Brazil. AB - Candomble, a Brazilian religion of African origin that worships Orishas, promotes "healing" assistance during its worship rituals using therapy with plants and beliefs. From its ancestry tradition, the respect and beware with nature are expressed. Therefore, the aim of this study is to investigate the perception of ethnoecology and health promotion among Candomble practitioners from a Candomble temple in the state of Ceara, Brazil. The ethnography was designed to allow greater immersion into the current mystique. This immersion results in the breaking of existing prejudices and admiration for their worldview. Thus, it can be observed that people seek Candomble to get rid of "bad" health difficulties, such as insomnia, depression, eyesight problems among others, which are commonly treated with herbal preparations, baths, and teas, using plants native to the region; however, their indications are not always in accordance with scientific evidence. In parallel with biomedicine, their hospitable and healthcare practices are considered by most as the equivalent to traditional healthcare actions, but greater recognition of biomedicine is necessary. Based on this perspective, the use of native plants in Candomble is examples of memory, hospitality, and humanization for the community wellness. PMID- 28669110 TI - Near-Death Experiences in a Multi-religious Hospital Population in Sri Lanka. AB - Near-death experiences (NDEs) are a wide range of experiences that occur in association with impending death. There are no published studies on NDEs in general hospital populations, and studies have been mainly conducted on critically ill patients. We assessed the prevalence of NDEs and its associations in a multi-religious population in a general hospital in Sri Lanka. A randomised sample of patients admitted to the Colombo North Teaching Hospital was assessed using the Greyson NDE scale and clinical assessment. Out of total 826 participants, NDEs were described by 3%. Compared to the NDE-negative participants, the NDE-positive group had a significantly higher mean for age and a ratio of men. Women reported deeper NDEs. Patients of theistic religions (Christianity, Islam and Hinduism) reported significantly more NDEs compared to patients from the non-theistic religious group (Buddhism). NDE-positive patient group had significantly higher reporting of a feeling 'that they are about to die', the presence of loss of consciousness and a higher percentage of internal medical patients. This is the first time that NDEs are assessed in a general hospital population and NDEs being reported from Sri Lanka. We also note for the first time that persons with theistic religious beliefs reported more NDEs than those with non-theistic religious beliefs. Medical professionals need to be aware of these phenomena to be able to give an empathic hearing to patients who have NDE. PMID- 28669111 TI - Iopamidol as an oral contrast media for computed tomography: a taste comparison to iohexol, diatrizoate sodium, and barium sulfate. AB - OBJECTIVES: The objective of this study is to compare the palatability of iopamidol and iohexol. METHODS: This was a blinded and randomized trial in which fifty healthy subjects taste tested iopamidol (Isovue, Bracco Diagnostics), iohexol (Omnipaque, GE Healthcare), diatrizoate meglumine and diatrizoate sodium solution (Gastrografin, Bracco Diagnostics), and barium sulfate suspension 2.1% w/v, 2.0% w/w (READI-CAT2, E-Z-EM). Participants scored palatability on a continuous scale from 0 to 40 (0 = intolerable, 10 = unpleasant but tolerable, 20 = neutral, 30 = kind of like, 40 = strongly like). RESULTS: Mean scores (SD/SEM) for the contrast agents (n = 50) were iopamidol = 21.0 (8.4/1.2); iohexol = 21.8 (7.1/1.0); Gastrografin = 16.8 (9.6/1.4); and barium = 23.7 (9.1/1.3). One-way ANOVA equality of means test shows rejection of the hypothesis that the means are equal (F* = 6.550, p = .000). Post hoc testing demonstrates Gastrografin to be significantly less preferred to barium (p = .000) and iohexol (p = .012). No difference was found between iopamidol and iohexol (p = .959). One-way ANOVA equality of means test of just iopamidol, iohexol, and barium does not reject the hypothesis that means are equal (F* = 1.778 and p = .174). CONCLUSION: There is no significant difference in palatability between iopamidol and iohexol, supporting the use of iopamidol as a viable alternative to iohexol as an oral contrast agent. PMID- 28669113 TI - Efficient Heritable Gene Expression Readily Evolves in RNA Pools. AB - Heritable gene expression arises readily in a simple non-genetic system employing known small-RNA biochemistry. Pooled cross-templating ribonucleotides show varied chemical competence on which selection acts, even calculating only minimal effects. Evolution can be quick-computed progress toward encoded gene expression can require only days or weeks for two millimolar, partly activated complementary 5' ribonucleotides. After only one product selection cycle, early templating can become prevailing pool behavior. Subsequently, a selected templated product is efficiently amplified as a pool ages, frequently accumulated in the same order of concentration as incoming nucleotides. Pools spontaneously favor templating because sporadic nucleotide accumulations increase it-and selection increases templating in pools of all ages. Nonetheless, templated chemical competence appears most easily in young pools. Pool history is critical-pools can perish from periodic hazards (like tides), or alternatively, from hazards roughly constant in time (like rainfall). Selection is greatly enhanced in constant hazard pools-more effective if pools have varied ages. Stronger selection is disproportionately more effective. Selected evolutionary change has an uncomplicated molecular basis-progress from chemical product synthesis to templated, proto-genetic inheritance exploits identity between templating and entropic catalysis. Though discovered by computation, selection of an elevated product of template catalysis is plausible, independent of any chemical or mathematical assumption. Selected chemical variation before genetics (chance utility) therefore inaugurates inheritance, even when hindered by unstable, dilute nucleotides, erratically supplied in undependable quantities. Remarkably, such uncontrolled conditions are not necessarily hostile, but can instead accelerate appearance of primordial gene-like behavior. PMID- 28669112 TI - Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. AB - There has been a resurgence in gene therapy efforts that is partly fueled by the identification and understanding of new gene delivery vectors. Adeno-associated virus (AAV) is a non-enveloped virus that can be engineered to deliver DNA to target cells, and has attracted a significant amount of attention in the field, especially in clinical-stage experimental therapeutic strategies. The ability to generate recombinant AAV particles lacking any viral genes and containing DNA sequences of interest for various therapeutic applications has thus far proven to be one of the safest strategies for gene therapies. This review will provide an overview of some important factors to consider in the use of AAV as a vector for gene therapy. PMID- 28669114 TI - Sure enough: efficient Bayesian learning and choice. AB - Probabilistic decision-making is a general phenomenon in animal behavior, and has often been interpreted to reflect the relative certainty of animals' beliefs. Extensive neurological and behavioral results increasingly suggest that animal beliefs may be represented as probability distributions, with explicit accounting of uncertainty. Accordingly, we develop a model that describes decision-making in a manner consistent with this understanding of neuronal function in learning and conditioning. This first-order Markov, recursive Bayesian algorithm is as parsimonious as its minimalist point-estimate, Rescorla-Wagner analogue. We show that the Bayesian algorithm can reproduce naturalistic patterns of probabilistic foraging, in simulations of an experiment in bumblebees. We go on to show that the Bayesian algorithm can efficiently describe the behavior of several heuristic models of decision-making, and is consistent with the ubiquitous variation in choice that we observe within and between individuals in implementing heuristic decision-making. By describing learning and decision-making in a single Bayesian framework, we believe we can realistically unify descriptions of behavior across contexts and organisms. A unified cognitive model of this kind may facilitate descriptions of behavioral evolution. PMID- 28669115 TI - Rats know when they remember: transfer of metacognitive responding across odor based delayed match-to-sample tests. AB - Metamemory entails cognitively assessing the strength of one's memories. We tested the ability of nine Long-Evans rats to distinguish between remembering and forgetting by presenting a decline option that allowed a four-choice odor-based delayed match to sample (DMTS) tests to be by-passed. Rats performed significantly better on tests they chose to take than on tests they were forced to take, indicating metacognitive responding. However, rather than control by internal mnemonic cues, one alternative explanation is that decline use is based on external test-specific cues that become associated with increased rewards overtime. To examine this possibility, we tested rats on three generalization tests in which external contingencies were inconsistent and therefore could not serve as discriminative cues. Rats transferred adaptive use of the decline response in tests that eliminated memory by presenting no sample, increased memory by presenting multiple samples, and both weakened and strengthened memory by varying the retention interval. Further, subjects chose to take or decline the test before encountering the memory test, providing evidence that rats based their metacognitive responding on internal cues rather than external ones. To our knowledge, this is the first robust evidence for metamemory in rats using the DMTS decline-test paradigm in which several possible sources of external stimulus control can be ruled out. PMID- 28669116 TI - Validation of ApneaLinkTM Plus for the diagnosis of sleep apnea. AB - PURPOSE: The aim of this study is to evaluate the validation of ApneaLinkTM Plus (ALP) based on a large number of subjects in a prospective design. METHOD: We recommended enrolling of 200 consecutive patients who had been referred because of habitual snoring or witnessed apnea during sleep. If consent was obtained, patients underwent standard polysomnography (PSG) and ALP evaluation simultaneously at the hospital (ALPlab), and repeated ALP at home (ALPhome) within 1 month. The parameters of ALP were scored based on three different systems, Manual, Auto AASM, and Auto scoring systems. RESULT: Among the 200 patients who were recommended for enrollment, 149 completed the study. Sensitivity was good for all three scoring systems, while specificity was poor for the Auto scoring system. The area under curve was highest for the manual scoring system and lowest for the auto scoring system, and increased as the apnea hypopnea index (AHI) cutoff value increased from 5 to 30. Regarding agreement with PSG, the manual scoring system was most superior, followed by the Auto AASM, and Auto scoring systems. The degree of agreement between PSG and ALP was affected by sleep efficiency and the arousal index. Moderate agreement between PSG and ALP based on central apnea index was observed. CONCLUSION: ALP is an accurate and reliable device for the diagnosis of OSA. Manual scoring is recommended; however, Auto AASM is also acceptable. ALP detects central sleep apnea to a certain degree. Both sleep efficiency and the arousal index affect the results of ALP. PMID- 28669117 TI - Comparison of patient satisfaction with mini-implant versus standard diameter implant overdentures: a systematic review and meta-analysis of randomized controlled trials. AB - Mini-implants have certain advantages over standard size implants which are being tested in various randomized controlled trials. This systematic review and meta analysis aims to compare conventional implant overdentures to mini-implant retained overdentures as regards to patient satisfaction. Electronic databases were searched for eligible studies data required were extracted. The extracted data were analyzed using non-Cochrane mode in RevMan 5.0 software. The heterogeneity between the studies was assessed using Forest plot, I 2 statistics, and chi-square test with a statistical P value of less than 0.10 to indicate statistical significance. Random-effect models were used in case of moderate heterogeneity. Four studies were included for the review and two for meta analysis. Two studies in 177 patients comparing quality of life with mini or standard diameter implants showed a pooled result of -4.76 [-6.48, -3.04] favoring the use of mini-implants. The results for other outcomes were incomputable due to inadequate studies. GRADE approach was used for quality of life, and the strength of evidence was observed to be "low". Mini-implant supported overdentures had better patient satisfaction levels compared to standard diameter implant overdenture. There is definite lack of evidence to support the use of mini-implants for overdentures. PMID- 28669118 TI - Quantifying fat replacement of muscle by quantitative MRI in muscular dystrophy. AB - The muscular dystrophies are rare orphan diseases, characterized by progressive muscle weakness: the most common and well known is Duchenne muscular dystrophy which affects young boys and progresses quickly during childhood. However, over 70 distinct variants have been identified to date, with different rates of progression, implications for morbidity, mortality, and quality of life. There are presently no curative therapies for these diseases, but a range of potential therapies are presently reaching the stage of multi-centre, multi-national first in-man clinical trials. There is a need for sensitive, objective end-points to assess the efficacy of the proposed therapies. Present clinical measurements are often too dependent on patient effort or motivation, and lack sensitivity to small changes, or are invasive. Quantitative MRI to measure the fat replacement of skeletal muscle by either chemical shift imaging methods (Dixon or IDEAL) or spectroscopy has been demonstrated to provide such a sensitive, objective end point in a number of studies. This review considers the importance of the outcome measures, discusses the considerations required to make robust measurements and appropriate quality assurance measures, and draws together the existing literature for cross-sectional and longitudinal cohort studies using these methods in muscular dystrophy. PMID- 28669119 TI - MRI volumetric morphometry in vascular parkinsonism. AB - Vascular parkinsonism is a difficult clinical differential diagnosis in elderly subjects. We aimed at identifying morphometric markers in the brain of elderly patients with vascular parkinsonism (VP) compared with age-matched patients with Parkinson's disease (PD) and healthy controls. In this multicenter prospective study, 46 patients (80 +/- 5 years old; male 32) with parkinsonism (32 PD and 14 VP) and 29 controls (mean age 78 +/- 3 years; male 21) underwent brain MRI on a 3 T scanner including T1 MPRAGE and FLAIR sequences. Volumetric morphometry was obtained using Morphobox software and compared between patients and controls. Receiver operating characteristics curve analysis with computation of area under the curve (AUC) was used to compare diagnostic values. Caudate nucleus and white matter hyperintense lesions (WMHL) volumes appeared significantly higher in patients with VP. Normalized caudate volume of at least 0.67% and normalized WMHL of at least 1.11% identified patients with VP from patients with PD and controls with similar performances (p > 0.25). Caudate nucleus and WMHL volumes were positively correlated (rho = 0.74, p < 0.0001), suggesting vascular disease related remodelling in elderly subjects. Caudate nucleus and WMHL MRI volumes might be used as additional markers to help identify patients with VP in the initial workup of elderly subjects with parkinsonian symptoms. PMID- 28669121 TI - Development of national system performance metrics for tissue donation, production, and distribution activity. AB - Canada's federal, provincial, and territorial governments gave Canadian Blood Services a mandate for organ and tissue donation and transplantation, including system performance, data and analytics. In 2012 Canadian Blood Services facilitated an eye and tissue banking workshop focused on standardized specifications and practices. At the workshop, the Canadian tissue community directed Canadian Blood Services to facilitate the development and implementation of a national data stream and analytics. Prior to this no national data was prospectively collected or collated on tissue donation, production or distribution activity. An eye and tissue data committee was formed with representation from eye and tissue banks in all Canadian jurisdictions. A minimum data set, standardized definitions, a data submission form and a quality assurance process was developed. Training was provided to data personal identified by each eye and tissue bank. Data collection was initiated January 1, 2013; with quarterly data submitted to Canadian Blood Services via excel spreadsheet. Data was submitted by sixteen Canadian eye and tissue banks, located in eight of Canada's thirteen provinces and territories, representing a census of activity. Annual data reports, with trend analysis, are generated and distributed to the tissue community to inform operational strategy and system performance improvement. This report provides an overview of the data process and provides visibility to the Canadian tissue donation, production and distribution activities for 3 years; January 1, 2013 to December 31, 2015. PMID- 28669120 TI - The protection of novel 2-arylethenylquinoline derivatives against impairment of associative learning memory induced by neural Abeta in C. elegans Alzheimer's disease model. AB - Cerebral deposition of amyloid beta-peptide (Abeta), a fundamental feature of Alzheimer's disease (AD), damages the neurocytes and impairs the cognition functions and associative learning memory of AD patients. A series of novel 2 arylethenylquinoline derivatives were synthesized and evaluated in our previous study, which inhibited Abeta aggregation in vitro effectively at the concentration of 20 MUmol/L and exhibited high antioxidant activity. In order to verify the capacity of anti-AD in vivo, the transgenic Caenorhabditis elegans (C. elegans) strain CL2355 expressing neural Abeta was employed as the AD model to investigate the neuroprotective activity of seven high-potential compounds (4a1, 4a2, 4b1, 4b2, 4c1, 4c2, 4c3) selected from those derivatives. Learning memory associated chemotaxis assay was performed to evaluate the neural repairment capacity. The underlying mechanism was investigated by mRNA analysis of Abeta gene and heat shock protein genes (hsp-16.1 and hsp-16.2) and Western blot of Abeta. Our data indicated that among seven tested compound, 4b1 and 4c2 reduced Abeta-induced stress, suppressed the expression of neural Abeta monomers and toxic oligomers, and recovered the damaged associative learning memory in C. elegans AD model. These findings further confirmed their potentials to become valuable agents for AD therapy. PMID- 28669122 TI - Validation of a DICE Simulation Against a Discrete Event Simulation Implemented Entirely in Code. AB - BACKGROUND: Modeling is an essential tool for health technology assessment, and various techniques for conceptualizing and implementing such models have been described. Recently, a new method has been proposed-the discretely integrated condition event or DICE simulation-that enables frequently employed approaches to be specified using a common, simple structure that can be entirely contained and executed within widely available spreadsheet software. To assess if a DICE simulation provides equivalent results to an existing discrete event simulation, a comparison was undertaken. METHODS: A model of osteoporosis and its management programmed entirely in Visual Basic for Applications and made public by the National Institute for Health and Care Excellence (NICE) Decision Support Unit was downloaded and used to guide construction of its DICE version in Microsoft Excel(r). The DICE model was then run using the same inputs and settings, and the results were compared. RESULTS: The DICE version produced results that are nearly identical to the original ones, with differences that would not affect the decision direction of the incremental cost-effectiveness ratios (<1% discrepancy), despite the stochastic nature of the models. LIMITATION: The main limitation of the simple DICE version is its slow execution speed. CONCLUSIONS: DICE simulation did not alter the results and, thus, should provide a valid way to design and implement decision-analytic models without requiring specialized software or custom programming. Additional efforts need to be made to speed up execution. PMID- 28669123 TI - Retraction Note to: The Crucial Role of Cyclin-Dependent Kinase-5-Ataxia Telangiectasia Mutated Axis in ICH-Induced Neuronal Injury of Rat Model. PMID- 28669124 TI - Erratum to: The Development of Translational Biomarkers as a Tool for Improving the Understanding, Diagnosis and Treatment of Chronic Neuropathic Pain. PMID- 28669125 TI - Development of In Vivo Imaging Tools for Investigating Astrocyte Activation in Epileptogenesis. AB - Insights into the dynamic changes in molecular processes occurring in the brain during epileptogenesis can substantially improve our understanding of their pathogenetic relevance. In this context, neuroinflammation is a potential mechanism of epileptogenesis which has recently been investigated in animal models by MRI or PET molecular imaging. Here, we developed an alternative and complementary molecular imaging strategy by designing a serotype 8 recombinant adeno-associated virus (AAV8) harboring promoter fragments of the GFAP or IL 1beta promoter and a luciferase reporter gene. Mice were injected intrahippocampally with rAAV8 and treated with intracortical kainic acid to induce status epilepticus (SE) and hence epileptogenesis. In vivo bioluminescence imaging combined with immunohistochemistry revealed a significant activation of the GFAP promoter 24 h and 3 days after kainate-induced SE. For IL-1beta, we identified the promoter region required for studying cell-specific induction of the promoter in longitudinal studies. We conclude that the GFAP promoter fragment represents a useful tool for monitoring the in vivo activation of astrocytes with an inflammatory phenotype during epileptogenesis, or under other pathophysiological conditions. PMID- 28669126 TI - Hardness maximization or equalization? New insights and quantitative relations between hardness increase and bond dissociation energy. AB - It has been overlooked that the change of hardness, eta, upon bonding is intimately connected to thermochemical cycles, which determine whether hardness is increased according to Pearson's "maximum hardness principle" (MHP) or equalized, as expected by Datta's "hardness equalization principle" (HEP). So far the performances of these likely incompatible "structural principles" have not been compared. Computational validations have been inconclusive because the hardness values and even their qualitative trends change drastically and unsystematically at different levels of theory. Here I elucidate the physical basis of both rules, and shed new light on them from an elementary experimental source. The difference, Deltaeta = eta mol - , of the molecular hardness, eta mol, and the averaged atomic hardness, , is determined by thermochemical cycles involving the bond dissociation energies D of the molecule, D + of its cation, and D - of its anion. Whether the hardness is increased, equalized or even reduced is strongly influenced by DeltaD = 2D - D + - D -. Quantitative expressions for Deltaeta are obtained, and the principles are tested on 90 molecules and the association reactions forming them. The Wigner-Witmer symmetry constraints on bonding require the valence state (VS) hardness, eta VS, instead of the conventional ground state (GS) hardness, eta GS. Many intriguingly "unpredictable" failures and systematic shortcomings of said "principles" are understood and overcome for the first time, including failures involving exotic and/or challenging molecules, such as Be2, B2, O3, and transition metal compounds. New linear relationships are discovered between the MHP hardness increase Deltaeta VS and the intrinsic bond dissociation energy D i . For bond formations, MHP and HEP are not compatible, and HEP does not qualify as an ordering rule. PMID- 28669127 TI - Ensemble-based virtual screening: identification of a potential allosteric inhibitor of Bcr-Abl. AB - Ensemble-based virtual screening using different conformations of a target protein is gaining popularity, as it can leverage information from target flexibility for effective lead identification. In this paper, molecular dynamics simulation followed by RMSD-based clustering was employed to generate and choose distinct conformations of Bcr-Abl. Three representative structures from the most populated clusters along with the crystal structure conformation (PDBID: 3K5V) were used to perform docking-based virtual screening of 14,400 compounds (in the Maybridge database) in order to identify potential allosteric site binders. Seven compounds found as hits in at least three of the four virtual screenings had higher Glide docking scores than the co-crystallized allosteric inhibitor GNF-2. Detailed computational analyses of the seven hits identified SEW02675 (DeltaG bind = -164.92 kJ/mol with the wild-type (wt) Bcr-Abl and -167.37 kJ/mol with the T334I Bcr-Abl mutant) as a better allosteric site binder with both the wt and the mutant Bcr-Abl protein than the reference allosteric inhibitor GNF-2 (DeltaG bind = -103.12 with wt and -142.96 kJ/mol with T334I). Moreover, the presence of SEW02675 in the allosteric site enhanced the binding of imatinib (DeltaG bind = 367.58 with wt and -294.56 kJ/mol with T334I) to the ATP sites of the wt and the mutant Bcr-Abl. However, when GNF-2 was present in the allosteric site, the binding of imatinib (DeltaG bind = -351.76 with wt and -273.94 kJ/mol with T334I) to the ATP site was weaker. The in silico findings suggest that SEW02675 could be used in combination with imatinib to treat chronic myeloid leukemia, and that it could help to overcome resistance due to T334I Bcr-Abl mutation. Graphical abstract Virtual screening strategy to identify allosteric inhbitors of Bcr-Abl for the treatment of Chronic myeloid leukemia. PMID- 28669128 TI - Phenomenology of pregnancy and the ethics of abortion. AB - In this article I investigate the ways in which phenomenology could guide our views on the rights and/or wrongs of abortion. To my knowledge very few phenomenologists have directed their attention toward this issue, although quite a few have strived to better understand and articulate the strongly related themes of pregnancy and birth, most often in the context of feminist philosophy. After introducing the ethical and political contemporary debate concerning abortion, I introduce phenomenology in the context of medicine and the way phenomenologists have understood the human body to be lived and experienced by its owner. I then turn to the issue of pregnancy and discuss how the embryo or foetus could appear for us, particularly from the perspective of the pregnant woman, and what such showing up may mean from an ethical perspective. The way medical technology has changed the experience of pregnancy-for the pregnant woman as well as for the father and/or other close ones-is discussed, particularly the implementation of early obstetric ultra-sound screening and blood tests (NIPT) for Down's syndrome and other medical defects. I conclude the article by suggesting that phenomenology can help us to negotiate an upper time limit for legal abortion and, also, provide ways to determine what embryo-foetus defects to look for and in which cases these should be looked upon as good reasons for performing an abortion. PMID- 28669129 TI - Assumptions and moral understanding of the wish to hasten death: a philosophical review of qualitative studies. AB - It is not uncommon for patients with advanced disease to express a wish to hasten death (WTHD). Qualitative studies of the WTHD have found that such a wish may have different meanings, none of which can be understood outside of the patient's personal and sociocultural background, or which necessarily imply taking concrete steps to ending one's life. The starting point for the present study was a previous systematic review of qualitative studies of the WTHD in advanced patients. Here we analyse in greater detail the statements made by patients included in that review in order to examine their moral understandings and representations of illness, the dying process and death. We identify and discuss four classes of assumptions: (1) assumptions related to patients' moral understandings in terms of dignity, autonomy and authenticity; (2) assumptions related to social interactions; (3) assumptions related to the value of life; and (4) assumptions related to medicalisation as an overarching context within which the WTHD is expressed. Our analysis shows how a philosophical perspective can add to an understanding of the WTHD by taking into account cultural and anthropological aspects of the phenomenon. We conclude that the knowledge gained through exploring patients' experience and moral understandings in the end-of life context may serve as the basis for care plans and interventions that can help them experience their final days as a meaningful period of life, restoring some sense of personal dignity in those patients who feel this has been lost. PMID- 28669131 TI - Congenital Muscular Dystrophies and Myopathies: An Overview and Update. PMID- 28669130 TI - Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. AB - Alemtuzumab is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells. Alemtuzumab is registered for the treatment of multiple sclerosis (MS) and is also used in chronic lymphocytic leukemia (CLL). Alemtuzumab is used off-label in kidney transplantation as induction and anti-rejection therapy. The objective of this review is to present a review of the pharmacokinetics, pharmacodynamics, and use of alemtuzumab in kidney transplantation. A systematic literature search was conducted using Ovid Medline, Embase, and Cochrane Central Register of controlled trials. No pharmacokinetic or dose-finding studies of alemtuzumab have been performed in kidney transplantation. Although such studies were conducted in patients with CLL and MS, these findings cannot be directly extrapolated to transplant recipients, because CLL patients have a much higher load of CD52-positive cells and, therefore, target-mediated clearance will differ between these two indications. Alemtuzumab used as induction therapy in kidney transplantation results in a lower incidence of acute rejection compared to basiliximab therapy and comparable results as compared with rabbit anti-thymocyte globulin (rATG). Alemtuzumab used as anti-rejection therapy results in a comparable graft survival rate compared with rATG, although infusion-related side effects appear to be less. There is a need for pharmacokinetic and dose-finding studies of alemtuzumab in kidney transplant recipients to establish the optimal balance between efficacy and toxicity. Furthermore, randomized controlled trials with sufficient follow-up are necessary to provide further evidence for the treatment of severe kidney transplant rejection. PMID- 28669132 TI - The Role of Muscle Imaging in the Diagnosis and Assessment of Children with Genetic Muscle Disease. PMID- 28669133 TI - Management of Polypoid Gallbladder Lesions in Children: A Multicenter Study. AB - INTRODUCTION: Polypoid lesions of the gallbladder (PLG) are relatively common in adults, while they are very rare in children. The use of high-quality ultrasonography leads to increased detection of PLG, although less than 20 pediatric cases of primary PLG have been reported in the literature. The aim of this study was to address the experience of PLG management in children. MATERIALS AND METHODS: A retrospective multicenter review of children with ultrasonographically defined PLG between 2006 and 2016 was performed. The data from 12 pediatric surgery centers were compiled for this purpose. RESULTS: Eighteen patients (mean age: 10.4 +/- 4.1 years) were included and managed according to each center's protocols. Cholecystectomy was performed for nine symptomatic patients. Histopathology conclusively revealed four tubular and five papillary adenomas, with a median size of 12 mm (ranging from 3 to 35 mm). Nine asymptomatic children were monitored by sonography over a 24-month (ranging from 12 to 66 months) follow-up period. The median PLG size was 7 mm (ranging from 3 to 9 mm). Two lesions disappeared after 1 and 2 years of follow-up, respectively. None of the patients developed symptoms or malignant transformation. CONCLUSION: This report confirms appropriate use of a conservative approach with annual clinical and ultrasound follow-up for small-sized and isolated PLG in children given the absence of malignancy and potential vanishing entities. Surgical treatment should be considered in case of lesions larger than 10 mm in size or when they are associated with symptoms. PMID- 28669134 TI - Cephalic vein thrombosis. AB - An 83-year-old male patient presented to the outpatient clinic with complaint of swelling at right antecubital area. Ultrasonographic examination of the right upper extremity revealed a mass lesion within the right cephalic vein, which was consistent with thrombus. A computed tomography (CT) venography showed contrast enhancement in cephalic vein at distal arm and an aneurysmatic thrombus area displaying regular borders with a size of 28*30 mm; there was no contrast enhancement at more proximal levels at the cephalic vein. PMID- 28669135 TI - Changes over the last 15 years in the psychopharmacological management of persons with borderline personality disorder. AB - OBJECTIVE: To describe the pharmacological management of borderline personality disorder (BPD) in Spain from 2001 through 2016, the factors associated with prescriptions, and changes in pharmacotherapy over this time period. METHODS: Retrospective, cross-sectional, observational study conducted in a sample of 457 patients with BPD consecutively admitted to a specialist BPD Program between January 2001 and November 2016. Data on sociodemographic and clinical variables, as well as pharmacological treatment upon the admission to the programme, were used to describe pharmacological prescriptions, the factors associated with these medications, and changes in prescription over the last 15 years. RESULTS: Most (88.4%) patients were on pharmacological treatment, with 53.8% of persons taking >=3 medications. No significant changes in these percentages were observed over the study period. The use of tricyclic antidepressants and benzodiazepines decreased, while the use of atypical antipsychotics increased. Axis I comorbidity was the main factor associated with pharmacological treatment and polypharmacy. CONCLUSIONS: This study provides further evidence confirming the worldwide overuse of prescription medications for BPD and shows that there has been a shift in the prescription pattern in the last 15 years. These results suggest that real clinical practice only partially adheres to clinical treatment guidelines. PMID- 28669136 TI - Left ventricular diverticulum mimicking cardiac tumor. AB - Left ventricular (LV) diverticulum represents a rare and frequently asymptomatic congenital anomaly, which is incidentally discovered during routine transthoracic echocardiography. We present a case of a 66-year-old female patient who was admitted to the cardiology department due to incidental finding of a tumor-like mass associated with the posterior mitral leaflet. Preliminary echocardiographic evaluation revealed a solid structure, suspected of mitral annulus calcification or LV malignancy. However, cardiac contrast-enhanced computed tomography confirmed the presence of LV diverticulum, partially filled with calcified thrombus. Conservative management was recommended. This case underscores the importance of multimodality imaging for differentiation of LV tumor-like structures. PMID- 28669137 TI - Effects of Benazepril on Survival of Dogs with Chronic Kidney Disease: A Multicenter, Randomized, Blinded, Placebo-Controlled Clinical Trial. AB - BACKGROUND: Chronic kidney disease (CKD) is an important cause of morbidity and mortality in dogs. OBJECTIVE: To evaluate the efficacy in prolonging survival and safety of benazepril administration to dogs with CKD. ANIMALS: Forty-nine client owned dogs with CKD. METHODS: Dogs were randomized to benazepril (0.25 to <0.5 mg/kg) or placebo once daily for up to 2 years in a prospective, multicenter, blinded clinical trial. The primary endpoint variable was the renal survival time, defined as the time from inclusion in the study to the treatment failure endpoint of death or euthanasia or need for administration of parenteral fluids related to renal failure. RESULTS: No benefit of benazepril versus placebo was detected for renal survival time in all dogs; median (95% confidence interval (CI)) survival times were 305 (53-575) days in the benazepril group and 287 (152 not available) in the placebo group (P = .53). Renal survival times were not significantly longer with benazepril compared to placebo for subgroups: hazard ratios (95% CI) were 0.50 (0.21-1.22) with P = .12 for initial urine protein-to creatinine ratio (UPC) >0.5, and 0.38 (0.12-1.19) with P = .080 for initial UPC >0.5 plus plasma creatinine <=440 MUmol/L. Proteinuria, assessed from the UPC, was significantly (P = .0032) lower after treatment with benazepril compared to placebo. There were no significant differences between groups for clinical signs or frequencies of adverse events. CONCLUSIONS AND CLINICAL RELEVANCE: Benazepril significantly reduced proteinuria in dogs with CKD. Insufficient numbers of dogs were recruited to allow conclusions on survival time. PMID- 28669138 TI - Feedbacks between plant N demand and rhizosphere priming depend on type of mycorrhizal association. AB - Ecosystem carbon (C) balance is hypothesised to be sensitive to the mycorrhizal strategies that plants use to acquire nutrients. To test this idea, we coupled an optimality-based plant nitrogen (N) acquisition model with a microbe-focused soil organic matter (SOM) model. The model accurately predicted rhizosphere processes and C-N dynamics across a gradient of stands varying in their relative abundance of arbuscular mycorrhizal (AM) and ectomycorrhizal (ECM) trees. When mycorrhizal dominance was switched - ECM trees dominating plots previously occupied by AM trees, and vice versa - legacy effects were apparent, with consequences for both C and N stocks in soil. Under elevated productivity, ECM trees enhanced decomposition more than AM trees via microbial priming of unprotected SOM. Collectively, our results show that ecosystem responses to global change may hinge on the balance between rhizosphere priming and SOM protection, and highlight the importance of dynamically linking plants and microbes in terrestrial biosphere models. PMID- 28669139 TI - Is alanine aminotransferase flare-up in nucleos(t)ide analogue treatment of chronic hepatitis B a promising, rather than a devastating, sign? PMID- 28669140 TI - Can metronomic chemotherapy be an alternative to sorafenib in advanced hepatocellular carcinoma? PMID- 28669141 TI - Development of a new lactic acid bacterial inoculant for fresh rice straw silage. AB - OBJECTIVE: Effects of newly isolated Lactobacillus plantarum on the fermentation and chemical composition of fresh rice straw silage was evaluated in this study. METHODS: Lactic acid bacteria (LAB) from good crop silage were screened by growing them in MRS broth and a minimal medium with low carbohydrate content. Selected LAB (LAB 1821) were Gram-positive, rods, catalase negative, and were identified to be Lactobacillus plantarum based on their biochemical characteristics and a 16S rRNA analysis. Fresh rice straw was ensiled with two isolated LAB (1821 and 1841), two commercial inoculants (HM/F and P1132) and no additive as a control. RESULTS: After 2 months of storage at ambient temperature, rice straw silages treated with additives were well-preserved, the pH values and butyric and acetic acid contents were lower, and the lactic acid content and lactic/acetic acid ratio were higher than those in the control (p<0.05). Acidity (pH) was lowest, and lactic acid highest, in 1821-treated silage (p<0.05). The NH3-N content decreased significantly in inoculant-treated silage (p<0.05) and the NH3-N content in 1821-treated silage was lowest among the treatments. The dry matter (DM) content of the control silage was lower than that of fresh rice straw (p<0.05), while that of the 1841- and p1174-inoculant-treated silages was significantly higher than that of HM/F-treated silage. Microbial additives did not have any significant (p>0.05) effect on acid detergent fiber or neutral detergent fiber contents. Crude protein (CP) content and in vitro DM digestibility (IVDMD) increased after inoculation of LAB 1821 (p<0.05). CONCLUSION: LAB 1821 increased the CP, IVDMD, lactic acid content and ratio of lactic acid to acetic acid in rice straw silage and decreased the pH, acetic acid, NH3-N, and butyric acid contents. Therefore, adding LAB 1821 improved the fermentation quality and feed value of rice straw silage. PMID- 28669142 TI - Polymorphism in the intron 20 of porcine O-linked N-acetylglucosamine transferase. AB - OBJECTIVE: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) catalyzes the addition of O-GlcNAc and GlcNAcylation has extensive crosstalk with phosphorylation to regulate signaling and transcription. Pig OGT is located near the region of chromosome X that affects follicle stimulating hormone level and testes size. The objective of this study was to find the variations of OGT between European and Chinese pigs. METHODS: Pigs were tested initially for polymorphism in OGT among European and Chinese pigs by polymerase chain reaction and sequencing at the U.S. Meat Animal Research Center (USMARC). The polymorphism was also determined in an independent population of pigs including European and Chinese Meishan (ME) breeds at the National Institute of Animal Science (NIAS, RDA, Korea). RESULTS: The intron 20 of OGT from European and Chinese pigs was 514 and 233 bp, respectively, in the pigs tested initially. They included 1 White composite (WC) boar and 7 sows (2 Minzu*WC, 2 Duroc [DU]*WC, 2 ME*WC, 1 Fengzing*WC) at USMARC. The 281-bp difference was due to an inserted 276-bp element and GACTT in European pigs. When additional WC and ME boars, the grandparents that were used to generate the 1/2ME*1/2WC parents, and the 84 boars of 16 litters from mating of 1/2ME*1/2WC parents were analyzed, the breeds of origin of X chromosome quantitative trait locus (QTL) were confirmed. The polymorphism was determined in an independent population of pigs including DU, Landrace, Yorkshire, and ME breeds at NIAS. OGT was placed at position 67 cM on the chromosome X of the USMARC swine linkage map. CONCLUSION: There was complete concordance with the insertion in European pigs at USMARC and NIAS. This polymorphism could be a useful marker to identify the breed of origin of X chromosome QTL in pigs produced by crossbreeding Chinese and European pigs. PMID- 28669143 TI - Effects of feeding system on growth performance, plasma biochemical components and hormones, and carcass characteristics in Hanwoo steers. AB - OBJECTIVE: This study was conducted to compare growth performance, blood components and carcass traits by two feeding systems (concentrate with roughage separately [CON] vs total mixed ration [TMR]) in Hanwoo steers, and to learn the relationship between blood components during fattening or finishing phases and carcass traits in Hanwoo steers. METHODS: Sixty steers aged 8 months were allotted to two feeding systems and fed similar amounts of average dry matter and total digestible nutrient throughout whole experimental period according to each feeding program. Steers were weighed monthly, taken blood at the end of growing, fattening and finishing periods, and slaughtered at 30 month of age. RESULTS: Growing performance was higher (p<0.05) in the CON group compared to the TMR group during fattening and finishing periods. The CON group was lower (p<0.05) in blood aspartic acid transaminase, blood urea nitrogen and retinol levels during growing period, but higher in triglyceride and cholesterol levels during fattening and finishing periods compared to the TMR group. The CON group was greater (p<0.05) in rib-eye area, and lighter (p<0.05) red in meat color compared to the TMR group. In the correlation coefficients between blood components of steers and carcass traits, retinol had a negative (p<0.05) correlation with marbling score and rib-eye area. Leptin had a positive (p<0.05) correlation with back fat thickness. Blood cholesterol and triglyceride were positively (p<0.05) correlated with carcass weight and rib-eye area. CONCLUSION: Growth performance, carcass ribeye area and meat color showed a more desirable result in the CON compared to the TMR in Hanwoo steers. Assessing the accumulated data of carcass traits with blood components including hormones-particularly retinol, cholesterol, triglyceride, and leptin-during the fattening or finishing phases, it may be possible to find a biomarker for determining beef quality in living animals. PMID- 28669144 TI - Cross-validation of the Student Perceptions of Team-Based Learning Scale in the United States. AB - PURPOSE: The purpose of this study was to cross-validate the factor structure of the previously developed Student Perceptions of Team-Based Learning (TBL) Scale among students in an entry-level doctor of physical therapy (DPT) program in the United States. METHODS: Toward the end of the semester in 2 patient/client management courses taught using TBL, 115 DPT students completed the Student Perceptions of TBL Scale, with a response rate of 87%. Principal component analysis (PCA) and confirmatory factor analysis (CFA) were conducted to replicate and confirm the underlying factor structure of the scale. RESULTS: Based on the PCA for the validation sample, the original 2-factor structure (preference for TBL and preference for teamwork) of the Student Perceptions of TBL Scale was replicated. The overall goodness-of-fit indices from the CFA suggested that the original 2-factor structure for the 15 items of the scale demonstrated a good model fit (comparative fit index, 0.95; non-normed fit index/Tucker-Lewis index, 0.93; root mean square error of approximation, 0.06; and standardized root mean square residual, 0.07). The 2 factors demonstrated high internal consistency (alpha= 0.83 and 0.88, respectively). DPT students taught using TBL viewed the factor of preference for teamwork more favorably than preference for TBL. CONCLUSION: Our findings provide evidence supporting the replicability of the internal structure of the Student Perceptions of TBL Scale when assessing perceptions of TBL among DPT students in patient/client management courses. PMID- 28669145 TI - Junior doctors' preparedness to prescribe, monitor, and treat patients with the antibiotic vancomycin in an Australian teaching hospital. AB - PURPOSE: We aimed to assess the preparedness of junior doctors to use vancomycin, and to determine whether attending an educational session and being provided pocket guidelines were associated with self-reported confidence and objective knowledge. METHODS: This was a 2-component cross-sectional study. A 60-minute educational session was implemented and pocket guidelines were provided. Preparedness was evaluated by a self-reported confidence survey in the early and late stages of each training year, and by continuing medical education (CME) knowledge scores. RESULTS: Self-confidence was higher among those later in the training year (n=75) than in those earlier (n=120) in the year for all questions. In the late group, vancomycin education was associated with higher self confidence regarding the frequency of therapeutic drug monitoring (P=0.02) and dose amendment (P=0.05); however, the confidence for initial monitoring was lower (P<0.05). Those with pocket guidelines were more confident treating patients with vancomycin (P<0.001), choosing initial (P=0.01) and maintenance doses (P<0.001), and knowing the monitoring frequency (P=0.03). The 85 respondents who completed the knowledge assessment scored a mean+/-standard deviation of 8.55+/-1.55 on 10 questions, and the interventions had no significant effect. CONCLUSION: Attending an educational session and possessing pocket guidelines were associated with preparedness, as measured by higher self-reported confidence using vancomycin. High knowledge scores were attained following CME; however attending an educational session or possessing pocket guidelines did not significantly increase the knowledge scores. Our findings support providing educational sessions and pocket guidelines to increase self-confidence in prescribing vancomycin, yet also highlight the importance of evaluating content, format, and delivery when seeking to improve preparedness to use vancomycin through education. PMID- 28669146 TI - Development of the Clinical Teaching Effectiveness Questionnaire in the United States. AB - PURPOSE: The purpose of this study was to develop a valid measure for assessing clinical teaching effectiveness within the field of physical therapy. METHODS: The Clinical Teaching Effectiveness Questionnaire (CTEQ) was developed via a 4 stage process, including (1) initial content development, (2) content analysis with 8 clinical instructors with over 5 years of clinical teaching experience, (3) pilot testing with 205 clinical instructors from 2 universities in the Northeast of the United States, and (4) psychometric evaluation, including principal component analysis. RESULTS: The scale development process resulted in a 30-item questionnaire with 4 sections that relate to clinical teaching: learning experiences, learning environment, communication, and evaluation. CONCLUSION: The CTEQ provides a preliminary valid measure for assessing clinical teaching effectiveness in physical therapy practice. PMID- 28669147 TI - Proposal for improving the system of physical therapy education and the Korean physical therapist licensing examination based on a comparison of the systems in World Confederation for Physical Therapy member countries. PMID- 28669148 TI - The Impact of Patient Education with a Smartphone Application on the Quality of Bowel Preparation for Screening Colonoscopy. AB - BACKGROUND/AIMS: Few studies have evaluated the use of a smartphone application (app) for educating people undergoing colonoscopy and optimizing bowel preparation. Therefore, this study was designed to develop a smartphone app for people to use as a preparation guide and to evaluate the efficacy of this app when used prior to colonoscopy. METHODS: In total, 142 patients (male:female=84:58, mean age=43.5+/-9.3 years), who were scheduled to undergo a colonoscopy at Myongji Hospital, were enrolled in this study. Seventy-one patients were asked to use a smartphone app that we had recently developed to prepare for the colonoscopy, while the 71 patients of the sex and age-matched control group were educated via written and verbal instructions. RESULTS: The quality of bowel cleansing, evaluated using the Boston Bowel Preparation Scale, was significantly higher in the smartphone app group than in the control group (7.70+/-1.1 vs. 7.24+/-0.8, respectively, p=0.007 by t-test). No significant differences were found between the two groups regarding work-up time and the number of patients with polyps. CONCLUSIONS: In this study, targeting young adults (<=50 years), the bowel preparation achieved by patients using the smartphone app showed significantly better quality than that of the control group. PMID- 28669151 TI - New Insight of OCT2 Regulation as Mediator for Cisplatin- Induced Nephrotoxicity PMID- 28669149 TI - Current Treatment Options for Bilateral Vocal Fold Paralysis: A State-of-the-Art Review. AB - Vocal fold paralysis (VFP) refers to neurological causes of reduced or absent movement of one or both vocal folds. Bilateral VFP (BVFP) is characterized by inspiratory dyspnea due to narrowing of the airway at the glottic level with both vocal folds assuming a paramedian position. The primary objective of intervention for BVFP is to relieve patients' dyspnea. Common clinical options for management include tracheostomy, arytenoidectomy and cordotomy. Other options that have been used with varying success include reinnervation techniques and botulinum toxin (Botox) injections into the vocal fold adductors. More recently, research has focused on neuromodulation, laryngeal pacing, gene therapy, and stem cell therapy. These newer approaches have the potential advantage of avoiding damage to the voicing mechanism of the larynx with an added goal of restoring some physiologic movement of the affected vocal folds. However, clinical data are scarce for these new treatment options (i.e., reinnervation and pacing), so more investigative work is needed. These areas of research are expected to provide dramatic improvements in the treatment of BVFP. PMID- 28669152 TI - Cervical Cancer Screening in Resource-Constrained Countries: Current Status and Future Directions AB - Cervical cancer continues to be a major public health problem affecting large numbers of women in many developingcountries. Limitations of various screening modalities and the lack of ready availability of a cost-effective point-of carescreening tool have hindered the efficient implementation of population-based screening programs in these settings. Ithas not proved possible for many countries to adopt cytology as a screening modality due to inadequate infrastructureand trained manpower. However, recent developments, notably design and testing of a low-cost HPV test kit andinitiatives by countries like India in developing and putting into operation a framework for large-scale screening ofwomen, have raised hopes that cervical cancer control may be possible even in resource-constrained locations. Withthe advent of HPV vaccination, primary prevention of cervical cancer also seems a distinct possibility. However, wideavailability and acceptability of vaccination is still an unresolved issue for developing countries. The possible futureeffects of vaccination on test characteristics of various screening strategies also need to be evaluated. This review gathersinformation on the current status of cervical cancer screening with a special focus on low resource settings. It revisitsthe strengths and limitations of the available screening modalities for cervical cancer viz. cytology, visual methods andHPV testing, in the context of their applicability in developing countries. In addition, the role of newer HPV-detectionmethods, for instance DNA, RNA and protein-based techniques, in triage of screen-positive women is discussed. Thecontemporary issue of impact of HPV vaccination on cervical cancer screening is also addressed briefly. The mainhighlight of the review is the reference to 'operational framework guidelines' for population based cervical cancerscreening, which have recently been formulated and are in the process of being implemented in India. The guidelinesmay serve as a model for other similar low-resource settings where implementation of cancer screening is desired. PMID- 28669150 TI - Prevalence, Pathogenesis, Diagnosis, and Management of Microscopic Colitis. AB - Microscopic colitis (MC), which is comprised of lymphocytic colitis and collagenous colitis, is a clinicopathological diagnosis that is commonly encountered in clinical practice during the evaluation and management of chronic diarrhea. With an incidence approaching the incidence of inflammatory bowel disease, physician awareness is necessary, as diagnostic delays result in a poor quality of life and increased health care costs. The physician faces multiple challenges in the diagnosis and management of MC, as these patients frequently relapse after successful treatment. This review article outlines the risk factors associated with MC, the clinical presentation, diagnosis and histologic findings, as well as a proposed treatment algorithm. Prospective studies are required to better understand the natural history and to develop validated histologic endpoints that may be used as end points in future clinical trials and serve to guide patient management. PMID- 28669153 TI - Cholangiocarcinoma: New Insights AB - Cholangiocarcinoma is a malignant neoplasm originating from biliary epithelial cells. The incidence and mortalityof this cancer are rising in the world. Currently, cholangiocarcinoma is accepted as a stem cell disease with many riskfactors. Diagnosis is relatively simple but therapy is extremely difficult. Surgery is the mainstay of treatment for earlystage patients. Endobiliary approaches, chemotherapy and radiotherapy are other therapeutic approaches. PMID- 28669154 TI - Anti-Genotoxicity Evaluation of Cratoxylum Formosum Dyer Leaves by Comet Assay and Micronucleus Test AB - Cratoxylum formosum Dyer is the Thai vegetable which commonly consumed a fresh leaves. In this study, weextracted Cratoxylum formosum with water and tested the extract for genotoxicity and anti-genotoxicity effects. Wecarried out the experiment using micronucleus test and comet assay in TK6 cells. In micronucleus experiment, we usedcytokinesis-block proliferation technique to stop cell division which produced a cell at binucleated (BNC) stage. Thecomet assay was carried out after pre-treatment the cell with C. formosum for 18 h. The results revealed not increasedthe micronucleus frequency of C. formosum at concentration ranging from 50-150 MUg/ml. In contract, it showed thatthe combination between C. formosum at various concentrations (25, 50, 75, 100, 150 and 200 MUg/ml) and mitomycinC could decrease significantly in frequency of micronuclei. The mean of micronucleus frequency in the sample were23.17 +/-3.33, 23.33 +/-4.72, 21.00 +/ 3.61, 11.33 +/-3.21, 16.67 +/-2.08, and 23.33+/-1.53 MN/ 1,000 BNC, respectively whereasthe MMC-treated group was 33.67 +/- 8.96 MN/ 1,000 BNC. The comet assay result showed that pre-treatment withCratoxylum formosum (25, 50, 100, 200 MUg/ml) could inhibit the hydrogen peroxide induced DNA damage by 6.95,12.99, 17.61, and 26.39 respectively. PMID- 28669155 TI - Disease Mapping for Stomach Cancer in Libya Based on Besag- York- Mollie (BYM) Model AB - Globally, Cancer is the ever-increasing health problem and most common cause of medical deaths. In Libya, it is animportant health concern, especially in the setting of an aging population and limited healthcare facilities. Therefore,the goal of this research is to map of the county' cancer incidence rate using the Bayesian method and identify thehigh-risk regions (for the first time in a decade). In the field of disease mapping, very little has been done to addressthe issue of analyzing sparse cancer diseases in Libya. Standardized Morbidity Ratio or SMR is known as a traditionalapproach to measure the relative risk of the disease, which is the ratio of observed and expected number of accountsin a region that has the greatest uncertainty if the disease is rare or small geographical region. Therefore, to solvesome of SMR's problems, we used statistical smoothing or Bayesian models to estimate the relative risk for stomachcancer incidence in Libya in 2007 based on the BYM model. This research begins with a short offer of the SMR andBayesian model with BYM model, which we applied to stomach cancer incidence in Libya. We compared all of theresults using maps and tables. We found that BYM model is potentially beneficial, because it gives better relative riskestimates compared to SMR method. As well as, it has can overcome the classical method problem when there is noobserved stomach cancer in a region. PMID- 28669156 TI - Cancer Incidence and Mortality: District Cancer Registry, Trivandrum, South India AB - Background: Cancer is emerging as a major cause of morbidity and mortality in low and middle-income countries.Cancer registry figures help for planning and delivery of health services. This paper provided the first results of cancerincidence and mortality [Crude (CR) and age-standardized (ASR)] rates (world-standard population) of Trivandrumdistrict, South India and compared with other registries under the network of National Cancer Registry Programme(NCRP), Government of India. Materials and Methods: Trivandrum district cancer registry encompasses a populationof 3.3 million, compiles data from nearly 75 sources (hospitals and diagnostic laboratories) and included under theNCRP in 2012. During 2012-2014, registry recorded 15,649 incident cases and 5667 deaths. Proportion of microscopicdiagnosis was 85% and 'Death certificate only' was 8%. Results: Total cancer incidence (CRs) rates were 161 and 154(ASR: 142.2 and 126) and mortality rates were 66 and 49 (ASR: 54 and 37) per 105 males and females respectively.Common cancers in males were lung (ASR:19), oral cavity (ASR:15), colo-rectum (ASR:11.2), prostate (ASR:10.2)and lymphoma (ASR:7) and in females, breast (ASR:36), thyroid (ASR:13.4), cervix-uteri (ASR:7.3), ovary (ASR:7)and colo-rectum (ASR:7). Nationally, the highest CRs for breast, prostate, colo rectum, corpus-uteri and urinarybladder cancers and low incidence of cervix-uteri cancer were observed in Trivandrum. Conclusion: Cancer incidence(CR) in Trivandrum was the highest in both genders in India (except Aizwal). This is mainly due to the highest lifeexpectancyin Kerala. Also, an epidemiologic transition in cancer pattern is taking place and is changing to more similarto "western" jurisdictions. PMID- 28669157 TI - Cancer Survival Estimates Due to Non-Uniform Loss to Follow-Up and Non Proportional Hazards AB - Background: Cancer survival depends on loss to follow-up (LFU) and non proportional hazards (non-PH). If LFUis high, survival will be over-estimated. If hazard is non-PH, rank tests will provide biased inference and Cox-modelwill provide biased hazard-ratio. We assessed the bias due to LFU and non-PH factor in cancer survival and providedalternate methods for unbiased inference and hazard ratio. Materials and Methods: Kaplan-Meier survival wereplotted using a realistic breast cancer (BC) data-set, with >40%, 5-year LFU and compared it using another BCdata-set with <15%, 5-year LFU to assess the bias in survival due to high LFU. Age at diagnosis of the latter dataset was used to illustrate the bias due to a non-PH factor. Log-rank test was employed to assess the bias in p-valueand Cox model was used to assess the bias in hazard-ratio for the non-PH factor. Schoenfeld statistic was used to testthe non-PH of age. For the non-PH factor, we employed Renyi statistic for inference and time dependent Cox-modelfor hazard ratio. Results: Five-year BC survival was 69% (SE: 1.1%) vs. 90% (SE: 0.7%) for data with low vs. highLFU respectively. Age (<45, 46-54 & >54 years) was a non-PH factor (p-value: 0.036). However, survival by age wassignificant (log-rank p value: 0.026), but not significant using Renyi statistic (p=0.067). Hazard ratio (HR) for ageusing Cox-model was 1.012 (95%CI: 1.004 -1.019) and the same using time-dependent Cox-model was in the otherdirection (HR: 0.997; 95% CI: 0.997- 0.998). Conclusion: Over-estimated survival was observed for cancer with highLFU. Log-rank statistic and Cox-model provided biased results for non-PH factor. For data with non-PH factors, Renyistatistic and time dependent Cox-model can be used as alternate methods to obtain unbiased inference and estimates. PMID- 28669158 TI - Reliability and Validity of the Malay Version of a Modified Smoking Self-Efficacy Questionnaire among Bruneian Secondary Students AB - Introduction: The 12-items Smoking Self-Efficacy Questionnaire (SEQ-12) has been shown to be a valid andreliable instrument to assess confidence in one's ability to refrain from smoking. However, although such measureshave been validated worldwide, most of them have not been culturally and linguistically adapted for use among Malaycommunities. The objective of this study was therefore to modify the SEQ-12 according to the Bruneian context forcultural adaptation for use among Bruneian adolescents, and assess the validity and reliability of the Malay translatedversion among secondary students. Methods: The original English version of the SEQ-12 was modified accordingto Bruneian context, translated and back translated into and from the Malay language. The Malay version was thenpre-tested and finally distributed to 40 purposively selected students in two secondary schools in Bandar Seri Begawan,Brunei Darussalam. Reliability was determined using Cronbach's alpha for internal consistency, while to assess theconstruct validity, an exploratory principle component factor analysis with varimax rotation was applied. Test-retestreliability was assessed with the students and tested using the intraclass correlation coefficient (ICC). Results: In total,31 students participated with the initial questionnaire and the test-retest reliability. Exploratory factor analysis revealedtwo factors, representing two constructs as in the original questionnaire. Cronbach's alpha co-efficients for the first andsecond factors were 0.87 and 0.92, respectively. The test-retest reliability test showed an ICC of 0.98 (95%CI: 0.96,0.99). Conclusions: The Malay version of the M-SEQ-12 is a valid and reliable scale, with potential applications inboth research and clinical settings. It is a useful instrument for measuring self-efficacy regarding avoidance of smokingamong Bruneian secondary students. Further analysis is necessary to assess the concurrent validity of the M-SEQ-12. PMID- 28669159 TI - Simplified Techniques for Killing the Carcinogenic, Opisthorchis Viverrini Metacercariae in Cyprinid Fish AB - Consumption of fluke-free fish is the most important factor in controlling Opisthorchis viverrini (OV) infectionin endemic areas such as northeast Thailand and thereby reducing the risk of cholangiocarcinoma. Cooking fish isthe best way to avoid infection; however, the cultural practice of eating raw or fermented fish is difficult to change.We investigated the food preparation process, using freezing, heating and fermentation to kill OV metacercariae infish. Uncooked cyprinid fish infected with OV were divided into three groups: refrigerated at 4 oC for 24, 48 or 72 h(control group); frozen at -20 oC for 24, 48 or 72 h; or heated by microwaving (at 400 or 800 W) or boiling at 90 oCfor 1, 5 or 10 min. Moreover, pickled (fermented) fish were divided into two groups: refrigerated at 4 oC (control) orfrozen at -20 oC for 24 or 48 h. The infectivity of recovered metacercariae was confirmed by infecting hamsters withOV and then evaluating the recovery of adult worms after 1 month. We found that a heating process, by boiling ormicrowaving at 400 or 800 W for at least 5 min, could kill OV metacercariae, and freezing pickled fish at -20 oC for 48h could kill OV metacercariae in all sizes of fish. The present study found that heating and freezing processes, as wellas the fermentation process under optimal conditions, could kill OV metacercariae in a timely manner. This knowledgeis valuable for implementation in endemic areas to control OV infection and cholangiocarcinoma. PMID- 28669160 TI - Expression of Radioresistant Gene PEG10 in OSCC Patients and Its Prognostic Significance AB - Background: Oral squamous cell carcinoma (OSCC) is one of the most common forms of cancer occurringworldwide. PEG10 is well known as a paternally expressed gene from a newly recognized imprinted region at humanchromosome 7q21. Previous study had demonstrated that the significant expression of PEG10 was found in radioresistantOSCC cell line and its expression was significantly associated with poor survival in several cancers. Therefore it hasbeen evaluated as a potential marker in OSCC patients undergoing radiotherapy. Objective: This study was conductedto analyze the mRNA expression of PEG10 in OSCC and its expression in relation to clinicpathological features,radiotherapy treatment response and survival. Methods: This study included tissue specimens obtained via biopsy of118 patients with OSCC who were recommended for radiotherapy treatment and 80 healthy control tissues analysisof mRNA expression of PEG10 was done by real-time quantitative reverse transcriptase-polymerase chain reaction(qRT-PCR). Patients were treated with 70 Gy of radiation dose by shrinking field technique using Cobalt-60 teletherapymachine. Results: Significantly higher mRNA expression of PEG10 was found in OSCC patients when compared withmatched controls. High level of PEG10 mRNA expression showed a significant correlation with lymph node metastasis(p = 0.0047) and tumor stage (p = 0.0499). Multivariate Cox regression analysis revealed that high level of mRNAexpression of PEG10 was significantly associated with poor survival (p < 0.05). Our research demonstrated that theexpression of PEG10 was higher in radioresistant tumor. Conclusion: We observed significantly increased expressionof PEG10 in context of lymph node status, advanced stage and poor survival in our study. Thus PEG10 gene can beused as potential predictive and prognostic biomarker in OSCC patients undergoing radiotherapy. PMID- 28669161 TI - Overweight: Is It a Prognostic Factor in Women with Triple-Negative Breast Cancer? AB - Background: Obesity is associated with poor outcomes in patients with breast cancer expressing hormonereceptors, but this association is not well established for triple-negative breast cancer. In this study, we investigatedthe influence of body mass index (BMI) in triple-negative breast cancer outcomes. Methods: This is a descriptiveand analytical retrospective cohort study at the Regional Oncology Center Hassan II-Oujda. We identified 115 patientswith triple-negative breast cancer, met the criteria for inclusion, treated between January 2009 and December 2011.The clinicopathological characteristics were collected to assess the association between BMI and overall survival anddisease-free survival at 5 years, using the Kaplan-Meier and Cox model. Results: Data analysis focused on 115 patients,34 patients (28.7%) were normal weight (BMI < 25) and 82 patients (71.3%) were overweight (BMI >= 25). The rates ofoverall mortality and progression at 5 years were 37.4% and 69.6% respectively. After adjusting for clinicopathologicalvariables and menopausal status, overweight was associated with OS (HR: 2.903, 95% CI: 1.551- 5.432, p = 0.001)and DFS (HR:1.899, 95% IC: 1.05 - 3.433, p=0.034) in all patients with triple-negative breast cancer. When stratifiedby menopausal status, overweight was associated with DFS and OS (HR : 3.242, 95% CI: 1.249 to 8.412, p = 0.016)and (HR : 2.752, 95% CI: 1.267 to 5.978, p = 0.011) respectively in pre-menopausal women. By cons, BMI was notassociated with DFS or OS in postmenopausal women. Conclusions: Overweight is an independent prognostic factorfor OS and DFS at 5 years in all patients with triple-negative breast cancer, and menopausal status may be a mitigatingfactor. Premenopausal women with overweight are at greater risk of death and progression than women with normalweight. Once validated, these results should be considered in the development of prevention programs. PMID- 28669162 TI - Effects of Group Counseling Based on Health Belief Model on Cervical Cancer Screening Beliefs and Performance of Rural Women in Kaboudrahang, Iran AB - Objective: Pap smear test is an appropriate screening method for early diagnosis of cervical cancer and reduction ofmortality. This study targeted effects of group counseling based on the Health Belief Model on cervical cancer screeningpractices of Iranian rural women. Method: This quasi-experimental study was conducted on 80 rural women undercoverage of the health care centers in rural areas in the city of Kabudrahang, Iran, in 2015. The data collection toolwas a researcher-made questionnaire covering demographic information, Health Belief Model (HBM) constructs andscreening performance. Data were collected using a multi-stage sampling method. Group counseling was conductedbased on the Health Belief Model and the GATHER steps in three sessions for the intervention group. Counselingincluded an introduction to cervical cancer, disease symptoms, warning signs and prevention approaches. Pap smeartesting in both intervention and control groups was evaluated two months after the group counseling. Results: Beforethe intervention, there was no significant difference between both groups in the HBM constructs and performance. Afterthe intervention, a significant difference was seen in the perceived susceptibility (P<0.001), severity (P=006), benefits(P=012), barriers (P<0.001), and self-efficacy (P=002). Two months after the intervention, 17 patients (42.5%) in theintervention group, and 4 patients (10%) in the control group had undergone a Pap smear test (P<0.001). Conclusion:Design and implementation of counseling programs based on the HBM can modify the beliefs of rural women regardingcervical cancer screening and increase their performance. PMID- 28669163 TI - Analyzing a Lung Cancer Patient Dataset with the Focus on Predicting Survival Rate One Year after Thoracic Surgery AB - Background: Data mining, a new concept introduced in the mid-1990s, can help researchers to gain new, profoundinsights and facilitate access to unanticipated knowledge sources in biomedical datasets. Many issues in the medicalfield are concerned with the diagnosis of diseases based on tests conducted on individuals at risk. Early diagnosisand treatment can provide a better outcome regarding the survival of lung cancer patients. Researchers can use datamining techniques to create effective diagnostic models. The aim of this study was to evaluate patterns existing in riskfactor data of for mortality one year after thoracic surgery for lung cancer. Methods: The dataset used in this studycontained 470 records and 17 features. First, the most important variables involved in the incidence of lung cancerwere extracted using knowledge discovery and datamining algorithms such as naive Bayes, maximum expectationand then, using a regression analysis algorithm, a questionnaire was developed to predict the risk of death one yearafter lung surgery. Outliers in the data were excluded and reported using the clustering algorithm. Finally, a calculatorwas designed to estimate the risk for one-year post-operative mortality based on a scorecard algorithm. Results: Theresults revealed the most important factor involved in increased mortality to be large tumor size. Roles for type IIdiabetes and preoperative dyspnea in lower survival were also identified. The greatest commonality in classificationof patients was Forced expiratory volume in first second (FEV1), based on levels of which patients could be classifiedinto different categories. Conclusion: Development of a questionnaire based on calculations to diagnose disease canbe used to identify and fill knowledge gaps in clinical practice guidelines. PMID- 28669164 TI - Application of the Weibull Distribution with a Non-Constant Shape Parameter for Identifying Risk Factors in Pharyngeal Cancer Patients AB - Background: In its standard form, the parametric survival model assumes that the shape parameter is constantand the scaling parameter is not. This article focuses on how a model with a non-constant shape parameter couldmake differences in oncology studies and lead to more precise results. Materials and Methods: Online data for partof a large clinical trial conducted by the Radiation Oncology Group in the United States available online on UMassAmherst's website were employed. The full study included patients with squamous cell carcinoma from fifteen sites inthe mouth and throat, although only data on three sites in the oropharynx reported by the six largest institutions wereconsidered here. To identify clinical, pathological and biological characteristics of patients which might have had aneffect on their survival, we compared Weibull distributions once with a constant shape parameter and again with anon-constant shape parameter. Analyzes were performed using SAS university edition. The level of significance wasset at P <= 0.05. Results: Based on the model with a constant shape parameter only the patient status was identified asa risk factor and the AIC of this model was 2152.4, but based on the model with a non-constant shape parameter, sex,patient status, stage of the tumor and the institute at which the patient had been treated were significant, with an AICof 2150.1. Conclusion: On the basis of the AIC, the second model with a non-constant shape parameter was suggestedto be more accurate for identifying risk factors, leading to more precise results. PMID- 28669165 TI - Prevalence of Human Papillomavirus subtypes 16 and 18 among Yemeni Patients with Cervical Cancer AB - Background: The Human Papillomavirus (HPV) is a DNA tumor virus that causes epithelial proliferation. Thereare more than 100 HPV subtypes, of which 13 subtypes are regarded as high risk subtypes that can cause cancers ofepithelial mucosal surfaces. High risk human papilloma viruses (HR-HPV) subtypes 16 and 18 plays a major role inthe etiology of cervical cancer worldwide. Therefore, the aim of this study was to screen for the existence of HPV16and HPV18 among Yemeni women with cervical lesions. Methodology: Formalin fixed paraffin wax processed tissueblocks were retrieved for 200 patients (150 were previously diagnosed with cervical cancer and the remaining 50 werediagnosed with different benign conditions). Results: Of the 200 cervical cancer tissue specimens, HR-HPV 16 wasidentified in 74/200 (37%) samples and couldn't be recognized in 126/200(63%) tissue samples. HR-HPV 18 wasidentified in 32/200 (16%) specimens and couldn't be recognized in 168/200(84%) tissue specimens. Conclusion:HR-HPV subtypes were prevalent among Yemeni women with cervical cancer, with significant increase of HR-HPVsubtype 16 over the HR-HPV subtype 18. PMID- 28669166 TI - Managerial Self-Efficacy for Chemotherapy-Related Symptoms and Related Risk Factors in Women with Breast Cancer AB - Background: Breast cancer is one of the most important diseases affecting physical, psychological and social healthof women. This study aimed to determine managerial self-efficacy regarding chemotherapy-related symptoms andrelated risk factors in Iranian patients. Materials and methods: This descriptive-analytical cross-sectional study wasconducted on 150 patients with breast cancer referred to medical centers of Urmia in 2016 with a convenience samplingmethod . The data collection instrument was the symptom-management self-efficacy scale-breast cancer (SMSES-BC)questionnaire whose validity and reliability was evaluated for the first time for Iranians. Data were analyzed using SPSSsoftware version 20. Results: Most of the patients were in the age range of 41-49 years. Lowest scores were in the areasof emotional and interpersonal disorders and the highest scores in the area of managing chemotherapy-related symptoms.The mean score of self efficacy chemotherapy-related symptoms was 168.0+/-25.4. There were significant relationshipsbetween age, education, economic status, marital status and life status and self-efficacy chemotherapy-related symptoms.In addition, a positive significant correlation for each of the subscales. Conclusion: It should be noted that interventionalefforts for improving managerial self-efficacy of symptoms, especially management of interpersonal and emotionaldisorders in these patients are necessary. PMID- 28669167 TI - The Prognostic Value of Pre-Treatment Leukocytosis in Patients with Previously Treated, Stage IIIB/IV Non-Small Cell Lung Cancer Treated with the IGF-1R Pathway Modulator AXL1717 or Docetaxel; a Retrospective Analysis of a Phase II Trial AB - Background: The aim of the present study was to investigate any prognostic value of pre-treatment anemia,leukocytosis and thrombocytosis in patients with advanced pretreated NSCLC. Methods: A randomized, multicenterphase II study comparing the IGF-1R modulator AXL with standard docetaxel in the treatment of previously treatedstage IIIB or IV NSCLC patients was conducted in 2011-2013. Clinical and laboratory data were collected, includingserum values for hemoglobin (Hgb), white blood cells (WBC) and platelets (Plt) at baseline. These hematologicalparameters were studied in relation to overall survival using Kaplan-Meier product-limit estimates and multivariate Coxproportional hazards regression models. Results: The median overall survival for all patients was 8.9 months. Patientswith leukocytosis (WBC > 9 x 109/L) had a significantly shorter median overall survival (4.2 months) as comparedwith those with a WBC <= 9 x 109/L at baseline (12.3 months) with a corresponding of HR 2.10 (95% CI: 1.29-3.43).Patients with anemia (Hgb < 110 g/L) had a non-significant (p = 0.097) shorter median overall survival (6.1 months) ascompared with their counterparts with Hgb >= 110 g/L at baseline (9.4 months). As for thrombocytosis (Plt > 350 x 109/L),there was no statistically significant impact on overall survival. Leukocytosis retained its prognostic significancein a multivariate model where other clinical factors such as age, sex and WHO performance status were taken intoconsideration (HR: 1.83, 95% CI: 1.06-3.13, p = 0.029). Conclusion: Pre-treatment leukocytosis is a strong andindependent prognostic marker for shorter overall survival in previously treated stage IIIB or IV NSCLC patientsreceiving docetaxel or AXL1717. Combined use of pre-treatment leukocytosis assessments together with establishedprognostic factors such as performance status could be of help when making treatment decisions in this clinical setting. PMID- 28669168 TI - The -160 (C>A) CDH1 Gene Promoter Polymorphism and Its Relationship with Survival of Patients with Gastric Cancer inKurdistan PMID- 28669169 TI - Metastasis and its Related Factors in Female Breast Cancer Patients in Kerman, Iran AB - Background: Metastasis is important in survival and the quality of life of female breast cancer patients. This studywas run in order to investigate metastasis and its related factors in female breast cancer patients in Kerman province from2005 to 2015. The aim of this study was to investigate the factors associated with secondary metastasis in female breastcancer patients in the largest province of Iran (Kerman). Materials and Methods: In this case-control study, medicalrecords of women diagnosed with breast cancer between the years of 2005 to 2015 were studied. Among them, 200breast cancer patients with secondary metastasis were randomly selected as cases and 400 patients without metastasiswere selected as the control group. Backward logistic regression, chi-square test, t-test and Mann Whitney-U test wereperformed for comparing the two groups in SPSS 22. Results: Disease stage at diagnosis was significantly associatedwith secondary metastasis (p<0.001). Female patients with stage III breast cancer at the time of diagnosis had a higherchance OR=9.11 (CI 95%=2.99-27.76) of metastasis than women with stage 0 and 1 at diagnosis. Also, patients fromrural areas had a higher chance for metastasis OR=1.89 (CI 95%=1.04-3.41). Other factors such as age, tumor size,tumor grade at diagnosis, hormone receptor status of estrogen and progesterone and Her-2 showed no significantassociation with metastasis (p>0.05). Conclusion: Stage at diagnosis and the residential location of patients were themost important factors related to secondary metastasis. These results emphasize the importance of early diagnosis,adequate education and awareness for breast cancer screening. PMID- 28669170 TI - Knowledge about Human Papillomavirus and Cervical Cancer: Predictors of HPV Vaccination among Dental Students AB - Background: The objective of this study is to determine the influence of dental students' knowledge and attituderegarding human papillomavirus infection of cervical cancer on willingness to pay for vaccination. Basic researchdesign: A convenience sampling method was used. The minimal sample size of 136 was calculated using the Raosoftcalculator with a 5 % margin of error and 95% confidence level. Participants: The study population were all finalyear dental students from the School of Dentistry. Methods: A self-administered questionnaire was used to measureknowledge levels and attitudes regarding human papillomavirus vaccination. Contingent valuation was conductedfor willingness to pay for vaccination. Main outcome measures: The Center for Disease Control and Prevention hasstated that human papillomavirus are associated with oropharynx cancer and the American Dental Association insist onexpanding public awareness of the oncogenic potential of some HPV infections. Thus, as future dental practitioners,dental students should be aware of human papillomavirus and their links with cancer and the benefits of vaccination.Results: Knowledge on HPV and cervical cancer did not impact on attitudes towards vaccines. However, significantcorrelation existed between knowledge and willingness to pay for vaccination. Conclusions: Dental students' knowledgeon HPV and cervical cancer has no influence on their attitude towards HPV vaccines. However, their willingness topay for HPV vaccination is influenced by their knowledge of cervical cancer and HPV vaccination. PMID- 28669171 TI - HOTAIR Long Noncoding RNA is not a Biomarker for Acute Myeloid Leukemia (AML) in Iranian Patients AB - Accumulating evidence indicates that lncRNAs may have potential as new biomarkers to predict prognosis of differenthuman cancers. HOTAIR lncRNA, transcribed from the human HOX locus, has been suggested to regulate gene expressionof important target genes and up-regulation has been noted in malignancies. The role of HOX transcript antisense RNAin acute myeloid leukemia (AML) was investigated in the present case control study. HOTAIR expression was evaluatedin blood samples of twenty five de novo AML patients and fifty healthy controls using real-time quantitative reversetranscription-PCR (qRT-PCR). Our results demonstrated no significant differences in HOTAIR lncRNA expressionlevel between AML patients and healthy individuals. The obtained data indicate that HOTAIR is not an informativeand reliable biomarker for AML diagnosis, although our results should be confirmed in further studies. PMID- 28669172 TI - Differential Association of the Lifestyle-Related Risk Factors Smoking and Obesity with Triple Negative Breast Cancer in a Brazilian Population AB - Background: A longer lifespan and changing lifestyle-related and reproductive risk factors have led to an increasedincidence of breast cancer in Brazil. There have been few studies about associations of specific risk factors withmolecular subtypes of the disease. The aim of the present study was to identify factors that modulate the risk of triplenegative breast cancer. Materials and Methods: A case-case analysis was performed. Data for 236 breast cancerpatients from two reference centres in North-eastern Brazil were applied to assess the association of risk factors withtriple negative breast cancer relative to the luminal A subtype. Molecular subtypes were defined by expression statusof hormone receptors and amplification of HER2. Nominal logistic regression was used to estimate odds ratios and togenerate a model of independent variables. Results: Smoking and body mass index were differentially associated withlikelihood of triple negative breast cancer compared to the Luminal A subtype (p= 0.013; p= 0.004): Women who eversmoked some time in their lives were 4.016 (OR= 0.249; CI 95%: 0.09- 0.71) times less likely to have triple negativebreast cancer. Obese and overweight patients, respectively, were 4.489 (CI 95%: 1.32- 15.28) and 1.340 (CI 95%:0.38- 4.69) times more likely to have triple negative breast cancer. Conclusions: Case case analysis with the LuminalA subtype as the reference group indicated that smoking and body mass index are differentially associated with riskof triple negative breast cancer. PMID- 28669173 TI - Flow Cytometric Analysis of DNA Ploidy in Liquid Based Cytology for Cervical Pre Cancer and Cancer AB - Background: DNA ploidy analysis of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer samples byflow cytometry (FCM) has been established as an aid to prognostic assessment. Liquid based cytology (LBC) increasesdiagnostic specificity by using ancillary techniques that provide information beyond morphology. The present study wasundertaken to assess DNA ploidy in LBC samples as an adjunct for early detection of cervical pre-cancer and cancer.Methods: DNA ploidy assessment was performed on LBC samples of 50 cases and 31 controls. Cell pellets wereobtained by centrifugation and stained with Telford reagent. At least 20,000 R1 gate (G0-G1) events were acquired ona BD FACSCalibur by using a 575+/ 10 nm filter. Results: Mean diploid G1 values were lowered significantly (p<0.01)while diploid S values were significantly elevated (p<0.01) in both high grade squamous intraepithelial lesions (HSILs)and squamous cell carcinomas (SCCs) as compared to controls. Receiver operating curve (ROC) analysis of the diploidG1 value was found to have significant diagnostic potential (AUC=0.682, Z=2.00, p=0.046) for distinction betweencontrol and low grade squamous intraepithelial lesion (LSIL) at a cut off value of <=91.6 with a sensitivity and specificityof 50.0 and 87.1%, respectively. Conclusions: ROC analysis of diploid G1 and diploid S values allows discriminationbetween LSIL and HSIL with sensitivities and specificities of 65 and 100% and 70 and100%, respectively, and betweenLSIL and SCC cases with values of 71.4 and 100% and 64.3 and 100%, respectively. PMID- 28669174 TI - Influence of ultrasound contrast agents on spectral Doppler analysis in recipients of liver transplantation. AB - BACKGROUND/AIMS: Clinical validation is required to determine whether Doppler measurements are comparable before and after administering ultrasound contrast agent (USCA). The purpose of this study is to explore whether the use of USCA affects spectral Doppler analysis in recipients of liver transplantation (LT). METHODS: For this study, 36 patients were examined using Doppler ultrasonography (US) along with a contrast-enhanced US for surveillance of vascular complications after LT. The following spectral Doppler US parameters were measured before and after administration of USCA: peak systolic velocity, end-diastolic velocity, resistive index, and systolic acceleration time of the graft hepatic artery; peak flow velocity of the graft portal vein; and peak flow velocity and venous pulsatility index of the graft hepatic vein. RESULTS: The mean peak systolic and end-diastolic velocities of the hepatic artery and the peak flow velocity of the portal and hepatic veins were increased after intravenously administration of the USCA, ranging from 10% to 13%. However, the changes were not statistically significant (P=0.097, 0.103, 0.128, and 0.190, respectively). There were no significant differences in other measured parameters, including the resistive index (P=0.205) and systolic acceleration time (P=0.489) of the hepatic artery and venous pulsatility index (P=0.494) of the hepatic vein. CONCLUSIONS: The measured velocities of graft hepatic vessels tended to increase after administration of USCA, but without statistical significance. The comparison of serial Doppler parameters with or without injection of USCA is valid during Doppler surveillance in recipients of LT. PMID- 28669176 TI - Factors Associated with Delayed Diagnosis of Lymphomas: Experience with Patients from Hematology Centers in Morocco AB - Background: Moroccan cancer patients usually have to go through several steps before they are diagnosed. Itis important to assess factors associated with diagnosis delay for lymphomas, which might have significant effectson survival. The aim of this study was to determine factors leading to late diagnosis of lymphomas. Methods: Across-sectional study was conducted with three hematology centers in Morocco in 2008, to analyze the impact ofsociodemographic and clinical factors on delay-time from symptoms to diagnosis. Results: A total of 151 patients wereincluded in the study. Late delay was significantly associated with gender, (for men compared to women: OR=2.46; 95%CI: 1.06-5.74), to marital status (not married: OR=2.50; 95% CI: 1.06-5.92) and low socioeconomic level (OR=5.82;95% CI: 2.23-15.17). Late medical delay was significantly associated with having three or more medical visits beforediagnosis (Adjusted OR=5.67; 95% CI: 2.55-12.59). Late total delay was observed for patients with three children or less(adjusted OR=4.39; 95% CI: 1.32-14.56), those who were non-married (adjusted OR=2.49; 95% CI: 1.07-5.81), had anon Hodgkin's lymphoma (Adjusted OR=2.08; 95% CI: 1.06-4.00) or featuring three or more medical visits before thediagnosis (Adjusted OR=2.13; 95% CI: 0.99-5.88). Conclusion: This analysis provides a basis for understanding thesources, extent, and root causes of lymphoma diagnostic delays. The findings appear crucial for system-wide interventionsaimed to facilitate clinical management of patients with lymphoma and to improve prognosis and quality of life. PMID- 28669175 TI - Efficacy of tenofovir-based rescue therapy for chronic hepatitis B patients with resistance to lamivudine and entecavir. AB - BACKGROUND/AIMS: Tenofovir disoproxil fumarate (TDF) monotherapy for 48 weeks provided a virological response comparable to that of TDF and entecavir (ETV) combination therapy in patients infected with ETV-resistant hepatitis B virus (HBV). Little long-term data in routine clinical practice are available regarding the optimal treatment of patients with ETV-resistant HBV. METHODS: We investigated the long-term antiviral efficacy of combination therapy of TDF+lamivudine (LAM) or TDF+ETV compared to that of TDF monotherapy in 73 patients with resistance to both LAM and ETV. RESULTS: Patients were treated with TDF monotherapy (n=12), TDF+LAM (n=19), or TDF+ETV (n=42) for more than 6 months. The median duration of TDF-based rescue therapy was 37 months. Virologic response (VR) was found in 63 patients (86.3%). The rates of VR among the three groups (TDF monotherapy, TDF+LAM, and TDF+ETV) were not statistically different (log rank P=0.200) at 12 months (59.3%, 78.9%, and 51.8%, respectively) or at 24 months (88.4%, 94.7%, and 84.2%). In addition, treatment efficacy of TDF-based combination or TDF monotherapy was not statistically different with ETV-resistant strains or exposure to other antiviral agents. In multivariate analysis, only lower baseline HBV DNA level was an independent predictor for VR (hazard ratio, 0.723; 95% confidence interval, 0.627-0.834; P<0.001). CONCLUSIONS: TDF monotherapy was as effective as combination therapy of TDF+LAM or TDF+ETV in maintaining long-term viral suppression in chronic hepatitis B patients with resistance to both LAM and ETV. HBV DNA level at the start of TDF rescue therapy was the only independent predictor of subsequent VR. PMID- 28669177 TI - High-Throughput in Situ Pressure Analysis of Lithium-Ion Batteries. AB - Many degradation processes in lithium-ion batteries are accompanied by gas evolution and therefore lead to an increase in internal cell pressure. This causes serious safety concerns for state-of-the-art lithium-ion batteries, calling for a thorough investigation of the origin and the magnitude of such processes. Herein we introduce a multichannel in situ pressure measurement system that allows for the high-throughput quantification of gas evolution under realistic battery conditions. The capability of the system was demonstrated through its application on Li4Ti5O12 half cells. The pressure changes could be divided into an irreversible and a reversible part, where the latter is caused by the deposition and dissolution of elemental lithium during cycling. Comparison of the measured and the theoretical reversible pressure changes showed a close match, indicating the high accuracy of the system. Additionally, the irreversible part observed in the pressure changes was attributed to gas evolution, as confirmed by complementary measurements using differential electrochemical mass spectrometry. To show the practicality of the system, the temperature dependence of gas evolution in Li1+xNi0.6Co0.2Mn0.2O2 full cells was investigated. Enhanced gas evolution was observed at elevated temperature, which is partly attributed to the thermal decomposition of the conducting salt LiPF6. PMID- 28669178 TI - Determination of Carbon Content in Steels Using Laser-Induced Breakdown Spectroscopy Assisted with Laser-Induced Radical Fluorescence. AB - Carbon is a key element for steel properties but hard to be determined by laser induced breakdown spectroscopy (LIBS). Utilizing the combination of carbon in analytes and nitrogen in ambient gas to generate carbon-nitrogen (CN) radicals, LIBS assisted with laser-induced radical fluorescence (LIBS-LIRF) was proposed to resonantly excite radicals instead of atoms in plasmas. The CN radicals in the B2Sigma-A2Pi band were stimulated by a 421.60 nm laser wavelength and emitted 388.34 nm fluorescence. The results show that the spectral intensity of the CN radicals was enhanced by 2 orders of magnitude using LIBS-LIRF. Then carbon content in steels was accurately and sensitively determined without spectral interference. The limits of detection (LoDs) were 0.039 and 0.013 wt % in air and nitrogen gas, respectively. The limits of quantification (LoQs) were 0.130 and 0.043 wt % in air and nitrogen gas, respectively. This work demonstrated the feasibility of LIBS to realize reliable carbon determination in steel industry. PMID- 28669179 TI - Novel Fluoroalkylated Surfactants in Soils Following Firefighting Foam Deployment During the Lac-Megantic Railway Accident. AB - The derailment of an unmanned train carrying crude oil and subsequent fire in the town of Lac-Megantic, Quebec, led to the use of 33 000 L of aqueous film forming foam (AFFF) concentrate. While it is known that per- and polyfluoroalkyl substances (PFASs) contained in AFFFs pose a potential environmental and health risk, critical knowledge gaps remain as regards to their environmental fate after release. The accident in Lac-Megantic provided valuable information regarding the identity and concentration of PFASs present in the soil after the AFFF deployment, as well as their possible transformation over time. The current study analyzed four sets of samples from Lac-Megantic: soil collected days after the accident from a heavily impacted area, soil sampled two years later from the treatment biopiles, soil collected two years after the accident from downtown Lac Megantic, and nonimpacted soil from a nearby area. A total of 33 PFASs were quantified in the soils. The highest observed concentrations correspond to those of 6:2 fluorotelomer sulfonamidoalkyl betaine, 6:2 and 8:2 fluorotelomer sulfonates, and short chain perfluorocarboxylic acids. The soils collected in Lac Megantic two years after the accident show a total PFAS concentration that is ~50 times lower than soils collected in 2013, while the proportion of perfluoroalkyl acids in those samples shows an increase. Qualitative analysis revealed the presence in soil of 55 additional PFASs that had been previously identified in AFFF formulations. The present study highlights the need to perform detailed analysis of AFFF impacted sites, instead of focusing solely on perfluoroalkyl acids. PMID- 28669180 TI - Polysaccharides and Oligosaccharides Produced on Malvar Wines Elaborated with Torulaspora delbrueckii CLI 918 and Saccharomyces cerevisiae CLI 889 Native Yeasts from D.O. "Vinos de Madrid". AB - Polysaccharides and oligosaccharides released into Malvar white wines elaborated through pure, mixed, and sequential cultures with Torulaspora delbrueckii CLI 918 and Saccharomyces cerevisiae CLI 889 native yeasts from D.O. "Vinos de Madrid" were studied. Both fractions from different white wines were separated by high resolution size-exclusion chromatography. Glycosyl composition and wine polysaccharide linkages were determined by GC-EI-MS chromatography. Molar-mass distributions were determined by SEC-MALLS, and intrinsic viscosity was determined by differential viscometer. Yeast species and type of inoculation have a significant impact on wine carbohydrate composition and structure. Mannose residues from mannoproteins were significantly predominant in those cultures where T. delbrueckii was present in the fermentation process in comparison with when pure cultures of S. cerevisiae were present in the fermenation process. Galactose residues from polysaccharides rich in arabinose and galactose presented greater values in pure cultures of S. cerevisiae, indicating that S. cerevisiae released fewer mannoproteins than T. delbrueckii. Moreover, we reported structural differences between mannoproteins released by T. delbrueckii CLI 918 and those released by S. cerevisiae CLI 889. These findings help to provide important information about the polysaccharides and oligosaccharides released from the cell walls of Malvar grapes and the carbohydrates released from each yeast species. PMID- 28669181 TI - Controlling Cooperative CO2 Adsorption in Diamine-Appended Mg2(dobpdc) Metal Organic Frameworks. AB - In the transition to a clean-energy future, CO2 separations will play a critical role in mitigating current greenhouse gas emissions and facilitating conversion to cleaner-burning and renewable fuels. New materials with high selectivities for CO2 adsorption, large CO2 removal capacities, and low regeneration energies are needed to achieve these separations efficiently at scale. Here, we present a detailed investigation of nine diamine-appended variants of the metal-organic framework Mg2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) that feature step-shaped CO2 adsorption isotherms resulting from cooperative and reversible insertion of CO2 into metal-amine bonds to form ammonium carbamate chains. Small modifications to the diamine structure are found to shift the threshold pressure for cooperative CO2 adsorption by over 4 orders of magnitude at a given temperature, and the observed trends are rationalized on the basis of crystal structures of the isostructural zinc frameworks obtained from in situ single-crystal X-ray diffraction experiments. The structure-activity relationships derived from these results can be leveraged to tailor adsorbents to the conditions of a given CO2 separation process. The unparalleled versatility of these materials, coupled with their high CO2 capacities and low projected energy costs, highlights their potential as next-generation adsorbents for a wide array of CO2 separations. PMID- 28669182 TI - AF4-ICPMS with the 300 Da Membrane To Resolve Metal-Bearing "Colloids" < 1 kDa: Optimization, Fractogram Deconvolution, and Advanced Quality Control. AB - The smallest colloids exert a disproportionately large influence on colloidal systems owing to their greater surface area; however, the challenges of working in the smaller size range have limited most field-flow fractionation-ICPMS analyses to sizes > ca. 1 kDa. We discuss considerations and present solutions for overcoming these challenges, including high pressures associated with using the 300-Da membrane, calibration in this small size range, accounting for drifting LODs and separation conditions during membrane aging, and optimizing the compromise between resolution and recovery. Necessary flow program ranges for observing pressure limits are discussed, and calibration is conducted using a combination of bromophenol blue and polystyrene size standards. The impact of membrane drift on size is demonstrated and effectively corrected by routine calibration. Separation conditions are optimized by monitoring the recovery and resolution of several trace metals. A precise, high-resolution separation is achieved using fractogram deconvolution to fully resolve overlapping peaks. Method effectiveness and precision are demonstrated through triplicate analyses of three natural water samples: Mp = 2.89 +/- 0.04, 3.20 +/- 0.03 and 3.50 +/- 0.12 kDa for DOM-associated Fe in the three samples (+/-95% CI). A primarily inorganic Fe fraction with Mp = 14.7 +/- 0.5 kDa was also resolved from the DOM associated fraction. Quality control methods and considerations for optimizing flow conditions are detailed in the Supporting Information as a guide for researchers seeking to analyze colloids in this smallest size range using AF4 ICPMS with the 300-Da membrane. PMID- 28669183 TI - Ionic Conductivity and Potential Application for Fuel Cell of a Modified Imine Based Covalent Organic Framework. AB - We present the novel potential application of imine-based covalent organic frameworks (COFs), formed by the direct Schiff reaction between 1,3,5-tris(4 aminophenyl)benzene and 1,3,5-benzenetricarbaldehyde building blocks in m-cresol or acetic acid, named RT-COF-1 or RT-COF-1Ac/RT-COF-1AcB. The post-synthetic treatment of RT-COF-1 with LiCl leads to the formation of LiCl@RT-COF-1. The ionic conductivity of this series of polyimine COFs has been characterized at variable temperature and humidity, using electrochemical impedance spectroscopy. LiCl@RT-COF-1 exhibits a conductivity value of 6.45 * 10-3 S cm-1 (at 313 K and 100% relative humidity) which is among the highest values so far reported in proton conduction for COFs. The mechanism of conduction has been determined using 1H and 7Li solid-state nuclear magnetic resonance spectroscopy. Interestingly, these materials, in the presence of controlled amounts of acetic acid and under pressure, show a remarkable processability that gives rise to quasi-transparent and flexible films showing in-plane structural order as confirmed by X-ray crystallography. Finally, we prove that these films are useful for the construction of proton exchange membrane fuel cells (PEMFC) reaching values up to 12.95 mW cm-2 and 53.1 mA cm-2 for maximum power and current density at 323 K, respectively. PMID- 28669184 TI - Singlet Fission Reaction of Light-Exposed beta-Carotene Bound to Bovine Serum Albumin. A Novel Mechanism in Protection of Light-Exposed Tissue by Dietary Carotenoids. AB - We have attempted to investigate the role of carotenoids (Car) in protecting pigment-protein complexes against light-induced degradation. Upon direct photoexcitation of beta-carotene (beta-Car), nanosecond flash photolysis and femtosecond time-resolved spectroscopy detected a substantial population of triplet states for beta-Car aggregates associated with bovine serum albumin (BSA) or dispersed in aqueous phase with 10% tetrahydrofuran (THF), but none were observed for monomeric beta-Car in neat THF. The direct photogeneration of triplet states was on the time scale of <1 ps, indicating that the underlying reaction mechanism was singlet fission (SF). Efficient triplet-triplet annihilation in the time regime from picoseconds to microseconds resulted in a <1 MUs triplet lifetime for beta-Car aggregates, in contrast to a 20 MUs lifetime for monomeric beta-Car as determined by anthracene-sensitized flash photolysis. The short-lived triplet excitations of beta-Car aggregates associated with BSA or dispersed in aqueous phase were found to be insensitive to the presence of oxygen, which are considered to be important for the protection of both protein and carotenoid against light-induced degradation via reaction with oxidative species. PMID- 28669186 TI - Volatile Compound and Gene Expression Analyses Reveal Temporal and Spatial Production of LOX-Derived Volatiles in Pepino (Solanum muricatum Aiton) Fruit and LOX Specificity. AB - Lipoxygenase (LOX) is an important contributor to aroma compounds in most fresh produce; however, little is known about the LOX pathway in pepino (Solanum muricatum Aiton) fruit. We explored the LOX aroma compounds produced by the flesh and the peel and identified eight putative LOX genes expressed in both tissues during fruit growth and development during two consecutive seasons. This study shows that pepino produces C5, C6, and C9 LOX-derived compounds. Odorant C9 volatiles were produced during immature stages with a concomitant decrease when the fruit ripens, whereas C5 and C6 compounds were formed throughout ripening. trans-2-Hexenal and its alcohol were produced in the peel, but not detected in the flesh. The expression of three genes, SmLOXD (putative 13-LOX), SmLOXB, and SmLOX5-like1 (putative 9-LOXs), increased during fruit ripening. These genes may account for aroma volatiles in pepino. Here, we discuss the possible roles of individual LOX genes in pepino. PMID- 28669185 TI - Supramolecular Low-Molecular-Weight Hydrogelator Stabilization of SERS-Active Aggregated Nanoparticles for Solution and Gas Sensing. AB - The potential of surface-enhanced Raman scattering (SERS) spectroscopy in both laboratory and field analyses depends on the reliable formation of so-called SERS hot spots, such as those formed during gold or silver nanoparticle aggregation. Unfortunately such aggregates are not stable in solution because they typically grow until they precipitate. Here we describe the use of low-molecular-weight hydrogels formed through pH-triggered self-assembly that occurs at a rate that well matches the rates of aggregation of Au or Ag colloids, allowing them to be trapped at the SERS-active point in the aggregation process. We show that the colloid-containing gels give SERS signals similar to the parent colloid but are stable over several months. Moreover, lyophilized gels can be stored as dry powders for subsequent use in the analyses of gases and dissolved analytes by contact with either solutions or vapors. The present system shows how the combination of pH-switchable low-molecular-weight gelators and pH-induced colloid aggregation can be combined to make a highly stable, low-cost SERS platform for the detection of volatile organic compounds and the microvolume analysis of solutions. PMID- 28669187 TI - The Discovery of Citral-Like Thiophenes in Fried Chicken. AB - The isomers of 3,7-dimethyl-2,6-octadienal, more commonly known together as citral, are two of the most notable natural compounds in the flavor and fragrance industry. However, both isomers are inherently unstable, limiting their potential use in various applications. To identify molecules in nature that can impart the fresh lemon character of citral while demonstrating stability under acidic and thermal conditions has been a major challenge and goal for the flavor and fragrance industry. In the study of fried chicken, several alkyl thiophenecarbaldehydes were identified by gas chromatography-mass spectrometry and gas chromatography-olfactometry that provided a similar citral-like aroma. The potential mechanism of formation in fried chicken is discussed. Furthermore, in order to explore the organoleptic properties of this structural backbone, a total of 35 thiophenecarbaldehyde derivatives were synthesized or purchased for evaluation by odor and taste. Certain organoleptic trends were observed as the length of the alkyl or alkenyl chain increased or when the chain was moved to different positions on the thiophene backbone. The 3-substituted alkyl thiophenecarbaldehydes, specifically 3-butyl-2-thiophenecarbaldehyde and 3-(3 methylbut-2-en-1-yl)-2-thiophenecarbaldehyde, exhibited strong citrus and citral like notes. Several alkyl thiophenecarbaldehydes were tested in high acid stability trials (4 degrees C vs 38 degrees C) and outperformed citral both in terms of maintaining freshness over time and minimizing off-notes. Additional measurements were completed to calculate the odor thresholds for a select group of thiophenecarbaldehydes, which were found to be between 4.7-215.0 ng/L in air. PMID- 28669188 TI - Enhanced Cooperativity in Supported Spin-Crossover Metal-Organic Frameworks. AB - The impact of surface deposition on cooperativity is explored in Au(111) supported self-assembled metal-organic frameworks (MOFs) based on Fe(II) ions. Using a thermodynamic model, we first demonstrate that dimensionality reduction combined with deposition on a metal surface is likely to deeply enhance the spin crossover cooperativity, going from gamma3D = 16 K for the bulk material to gamma2Dsupp = 386 K for its 2D supported derivative. On the basis of density functional theory, we then elucidate the electronic structure of a promising Fe based MOF. A chemical strategy is proposed to turn a weakly interacting magnetic system into a strongly cooperative spin-crossover monolayer with gammaMOFAu(111) = 83 K. These results open a promising route to the fabrication of cooperative materials based on SCO Fe(II) platforms. PMID- 28669189 TI - Unique Approach To Develop Carbon Dot-Based Nanohybrid Near-Infrared Ratiometric Fluorescent Sensor for the Detection of Mercury Ions. AB - The ratiometric fluorescence assay, which can eliminate the external effects, has attracted great attention. In this work, a carbon dot (CD)-based nanohybrid dual emission system was simply prepared by a unique approach of solvothermal treating corn bract and used as a ratiometric fluorescent sensor for Hg2+ detection. Under a single excitation, the obtained nanohybrid sensor had two emission bands around 470 and 678 nm, which may originate from the intrinsic structure of CDs and chlorophyll-derived porphyrins, respectively. In the presence of Hg2+, the fluorescence at 678 nm could be remarkably quenched, while the fluorescence intensity at 470 nm was only slightly altered. The fluorescence intensity ratio at 470 and 678 nm exhibited a good linear relationship in the Hg2+ concentration range from 0 to 40 MUM with a detection limit of about 9.0 nM. It also had a satisfying assay performance in serum and river water samples. The prepared CD based nanohybrid sensor here may hold the further potential applications in biomedicine study, environmental protection, and food safety. PMID- 28669190 TI - Temperature and Size Dependence of Characteristic Hydrogen-Bonded Network Structures with Ion Core Switching in Protonated (Methanol)6-10-(Water)1 Mixed Clusters: A Revisit. AB - Hydrogen-bonded network structures and preferential ion core in the protonated methanol-water mixed clusters, H+(methanol)n-(water)1 (n = 6-10), were explored by a combination of infrared spectroscopy and theoretical calculations. Infrared spectra of the OH stretch region of the clusters were measured at the two different temperature ranges by using Ar-tagging. Stable isomer structures of the clusters were searched by the multiscale modeling approach and temperature dependent infrared spectra were simulated based on the statistical populations of the isomers. The combined experimental and theoretical studies revealed that the characteristic multiring structures begin to form at n = 7 under the low temperature condition and they are preferential at the wide temperature range in n >= 8. It was also demonstrated that the preferential ion core type changes from methanol (MeOH2+) to water (H3O+) with increasing cluster size. In n <= 8, the observed infrared spectral features partly depend on the monitoring vibrational predissociation channel, and weak correlations between the hydrogen-bonded network structure and preferential dissociation channels were suggested. However, the ion core type does not necessarily correlate to the preferential dissociation channel. This implies that large rearrangement of the hydrogen-bonded network structure occurs prior to the dissociation. PMID- 28669191 TI - Two-Dimensional Electrochemiluminescence: Light Emission Confined at the Oil Water Interface in Emulsions Stabilized by Luminophore-Grafted Microgels. AB - We describe a method to confine electrochemiluminescence (ECL) at the oil-water interface of emulsion droplets that are stabilized by luminophore-grafted microgels. These hydrogel nanoparticles incorporating covalently bound Ru(bpy)32+ as the luminophore are irreversibly adsorbed at the interface of micrometric oil droplets dispersed in a continuous aqueous phase. We study the electrochemical and ECL properties of this multiscale system, composed of a collection of droplets in close contact in the presence of two types of model coreactants. ECL emission is observed upon oxidation of the coreactant and of the luminophore. ECL imaging confirms that light is emitted at the surface of oil droplets. Interestingly, light emission is observed more than 100 MUm far from the electrode. It is possibly due to the interconnection between redox-active microgels, making an entangled two-dimensional network at the dodecane-water interface and/or to some optical effects related to the light propagation and refraction at different interfaces in this multiphasic system. Confining ECL in such an inhomogeneous medium should find promising applications in the study of compartmentalized systems, interfacial phenomena, sensors, and analysis of single oil droplets. PMID- 28669192 TI - Pathways and Controls of N2O Production in Nitritation-Anammox Biomass. AB - Nitrous oxide (N2O) is an unwanted byproduct during biological nitrogen removal processes in wastewater. To establish strategies for N2O mitigation, a better understanding of production mechanisms and their controls is required. A novel stable isotope labeling approach using 15N and 18O was applied to investigate pathways and controls of N2O production by biomass taken from a full-scale nitritation-anammox reactor. The experiments showed that heterotrophic denitrification was a negligible source of N2O under oxic conditions (>=0.2 mg O2 L-1). Both hydroxylamine oxidation and nitrifier denitrification contributed substantially to N2O accumulation across a wide range of conditions with varying concentrations of O2, NH4+, and NO2-. The O2 concentration exerted the strongest control on net N2O production with both production pathways stimulated by low O2, independent of NO2- concentrations. The stimulation of N2O production from hydroxylamine oxidation at low O2 was unexpected and suggests that more than one enzymatic pathway may be involved in this process. N2O production by hydroxylamine oxidation was further stimulated by NH4+, whereas nitrifier denitrification at low O2 levels was stimulated by NO2- at levels as low as 0.2 mM. Our study shows that 15N and 18O isotope labeling is a useful approach for direct quantification of N2O production pathways applicable to diverse environments. PMID- 28669193 TI - Foams Stabilized by Surfactant Precipitates: Criteria for Ultrastability. AB - Foams are ultrastable when all the aging processes arrest. We make such foams by precipitating sodium dodecyl sulfate with potassium chloride during the foaming process. The precipitate crystals adsorb onto the bubble surfaces to arrest coarsening and stop drainage by blocking in the interstices around the bubbles. However, if the concentration of SDS is too high, the foams are no longer ultrastable. The transition is sudden and corresponds to the point at which significant dodecyl sulfate remains in solution. The presence of the noncrystallized surfactant allows the foam to coarsen leading to the eventual disappearance of the foams, even if the crystals in the continuous phase can still block drainage. The transition occurs as the concentration of nonsolubilized KCl becomes higher than the concentration of SDS, giving us a linear stability boundary. The system offers an interesting alternative to other types of particles because the surfactant crystals break and reform as the temperature is cycled, which makes for reusable solutions and stimulable foams. PMID- 28669194 TI - Nanoparticle properties for delivery to cartilage: the implications of disease state, synovial fluid, and off-target uptake. AB - A major hurdle limiting the ability to treat and cure osteoarthritis, a common and debilitating disease, is rapid joint clearance and limited cartilage targeting of intra-articular therapies. Nano-scale drug carriers have the potential to improve therapeutic targeting and retention in the joint after direct injection, however, there still lacks a fundamental understanding of how the physiochemical properties of nanoparticles (NPs) influence localization to the degenerating cartilage and how joint conditions such as disease state and synovial fluid impact NP biodistribution. The goal of this study was to assess how physicochemical properties of NPs influence their interactions with joint tissues and, ultimately, cartilage localization. Ex vivo models of joint tissues were used to study how poly(lactide-co-glycolide) (PLGA) and polystyrene (PS) NP size, charge, and surface chemistry influence cartilage retention under normal and disease-mimicking conditions. Of the particles investigated, PLGA NPs surface modified with a quaternary ammonium cation had the greatest retention within cartilage explants, however, retention was diminished 2 to 2.9-fold in arthritic tissue and in the presence of synovial fluid. Interactions with synovial fluid induced changes to NP surface properties and colloidal stability in vitro. The impact of NP charge on "off-target" synoviocyte uptake was also dependent on synovial fluid interactions. The results suggest that the design of nanocarriers for targeted drug delivery within the joint cannot be based on a single parameter such as zeta potential or size, and that the fate of injected delivery systems will likely be influenced by the disease state of the joint and the presence of synovial fluid. PMID- 28669195 TI - Anomalous Structural Disorder in Supported Pt Nanoparticles. AB - Supported Pt nanocatalysts generally exhibit anomalous behavior, including negative thermal expansion and large structural disorder. Finite temperature DFT/MD simulations reproduce these properties, showing that they are largely explained by a combination of thermal vibrations and low-frequency disorder. We show here that a full interpretation is more complex and that the DFT/MD mean square relative displacements (MSRD) can be further separated into vibrational disorder, "dynamic structural disorder" (DSD), and long-time equilibrium fluctuations of the structure dubbed "anomalous structural disorder" (ASD). We find that the vibrational and DSD components behave normally, increasing linearly with temperature while the ASD decreases, reflecting the evolution of mean nanoparticle geometry. As a consequence the usual procedure of fitting the MSRD to normal vibrations plus temperature-independent static disorder results in unphysical bond strengths and Gruneisen parameters. PMID- 28669196 TI - Correlates of Successful Aging in South Korean Older Adults: A Meta-Analytic Review. AB - The purpose of this study was to examine the factors contributing to achieving successful aging (SA) among the Korean older population and identified the strength of each factor's contribution to SA. We extensively searched 4 Korean and 3 English online databases, extracting a total of 64 studies for the analysis. Finally, 42 associated factors and 347 correlation coefficients were found, which were then categorized into 5 domains: functional, psychological, familial, social, and demographic. The psychological domain had the highest effect size. This was followed, in descending order, by the social, functional and familial, and demographic domains. Importantly, the familial domain, which has not been explored in many existing SA models, emerged as a notable predictor. This study is meaningful in terms of understanding one of the minority older populations more deeply and providing stronger evidence for developing evidence based intervention programs for Korean older adults. PMID- 28669197 TI - Prevalence and correlates of everyday discrimination among black Caribbeans in the United States: the impact of nativity and country of origin. AB - OBJECTIVES: Black Caribbeans in the United States have been the victims of major discrimination (e.g. unfairly fired, denied a promotion, denied housing). What is not known is the degree to which they also experience more routine forms of everyday discrimination such as receiving poor restaurant service, being perceived as dishonest, and being followed in stores. This paper investigates the distribution and correlates of everyday discrimination among a national sample of black Caribbeans in the U.S. DESIGN: This analysis used the black Caribbean sub sample (n = 1,621) of the National Survey of American Life. Demographic and immigration status correlates of ten items from the Everyday Discrimination Scale were investigated: being treated with less courtesy, treated with less respect, receiving poor restaurant service, being perceived as not smart, being perceived as dishonest, being perceived as not as good as others, and being feared, insulted, harassed, or followed in stores. RESULTS: Roughly one out of ten black Caribbeans reported that, on a weekly basis, they were treated with less courtesy and other people acted as if they were better than them, were afraid of them, and as if they were not as smart. Everyday discrimination was more frequent for black Caribbeans who were male, never married, divorced/separated, earned higher incomes, and who were second or third generation immigrants. Black Caribbeans attributed the majority of the discrimination they experienced to their race. CONCLUSION: To our knowledge, this is the first study to provide an in-depth investigation of everyday discrimination among the black Caribbean population. It provides the frequency, types and correlates of everyday discrimination reported by black Caribbeans in the United States. Understanding the frequency and types of discrimination is important because of the documented negative impacts of everyday discrimination on physical and mental health. PMID- 28669198 TI - Pathological and microbiological investigations into cases of bacterial chondronecrosis and osteomyelitis in broiler poultry. AB - Bacterial chondronecrosis and osteomyelitis (BCO) is increasingly recognized as a major cause of lameness in commercial broilers chickens worldwide, but the pathogenesis of the condition is incompletely understood. This was a longitudinal study of 20 commercial broiler farms in Victoria, Australia, to investigate the aetiology and pathology of BCO. Thorough postmortem examination was performed on culled and dead birds (n = 325) from 20 different flocks at either 1 week, 4 weeks or 5 weeks of age and samples were analysed by conventional bacteriology, molecular identification of infectious organisms detected, serology and histopathology. BCO occurs throughout the life of broiler flocks at a very high rate, with lesions detected in 28% (95% CI 23-34%) of the mortalities and culls. The condition occurs with similar prevalence in both the femur and tibiotarsus. BCO is an infectious process that appears to result from bacteraemia and haematological spread of bacterial pathogens, especially Escherichia coli, to the bones, with 65.3% bacterial isolates from histologically confirmed BCO identified as E. coli, 11.5% as Staphylococcus and the remainder composed of mixed infections or a range of other minor isolates. We observed that almost all E. coli isolated from cases of BCO are avian pathogenic E. coli, suggesting that preventative measures should be directed at this organism. PMID- 28669199 TI - Physical activity and obesity: is there a difference in association between the Asian- and African- Surinamese adult population? AB - OBJECTIVE: The role of different physical activity (PA) characteristics, i.e. domain, duration and intensity in obesity prevention still requires investigation. Furthermore, ethnicity can modify the effect of PA on body composition. Therefore, we aim to describe the association between obesity and PA characteristics across the Asian- and African-Surinamese population, living in the capital of Suriname. DESIGN: Between February 2013 and July 2015, we included 1157 healthy subjects, 18-70 years, from the Healthy Life in Suriname (HELISUR) study. We measured height, weight, hip and waist circumference and defined general and central obesity according to World Health Organization (WHO) recommendations. The International Physical Activity Questionnaire was used to assess PA and to calculate the duration (minutes/week) and the total volume (METs minutes/week) of activity. Ethnicity was self-reported. RESULTS: Out of 1157 participants we included 1079 (42.6% Asian-Surinamese, 40.1% African-Surinamese and 17.3% of other ethnicity), mean age 42.6 +/- 13.6 years for analysis. Obesity prevalence ratio (PR) was significantly lower in participants meeting WHO PA recommendations [PR= 0.81 (0.68-0.97)], especially within the commuting [PR= 0.66 (0.47-0.91)] and leisure time domains [PR= 0.67 (0.47-0.94)], compared to participants that did not meet the recommendations. Active minutes/week and total volume of activity were inversely associated with obesity and waist circumference, in the overall (p < 0.05) and in the African-Surinamese population (p < 0.05), but not in the Asian-Surinamese population. CONCLUSION: Meeting PA recommendations, particularly within the commuting and leisure time domains, is associated with lower obesity prevalence in the total population. Among the African-Surinamese population, PA within the leisure time domain, more active minutes/week and higher levels of total volume are associated with a lower obesity prevalence. This is not found in the Asian-Surinamese population. PMID- 28669200 TI - Are there adverse effects associated with mindfulness? PMID- 28669201 TI - Australian adolescents' understanding of confidentiality in mental health. PMID- 28669202 TI - A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders. PMID- 28669203 TI - Vagus Nerve Stimulation: Back to the Future. PMID- 28669204 TI - Psychiatric Complications of Primary Hyperparathyroidism and Mild Hypercalcemia. PMID- 28669205 TI - Reports to the Membership. AB - The following are edited/abbreviated versions of the annual reports of the APA Secretary, Treasurer, CEO and Medical Director, Speaker, and Speaker-Elect and the chairpersons of the APA Committee on Bylaws, Membership Committee, Committee of Tellers, and Elections Committee. The full reports were presented at the APA Annual Business Meeting in San Diego, May 21, 2017. PMID- 28669206 TI - Friends. PMID- 28669208 TI - DREAMers Living in the United States: A Contextual Perspective and Clinical Implications. PMID- 28669209 TI - The Neural Correlates of Transdiagnostic Dimensions of Psychopathology. PMID- 28669210 TI - High Placebo Response Rates Hamper the Discovery of Antidepressants for Depression in Children and Adolescents. PMID- 28669212 TI - Vincent Van Gogh (1853-1890): Experiencing Madness. PMID- 28669213 TI - Harnessing the Power of Gaze Through Music. PMID- 28669214 TI - Diabetes and Schizophrenia-New Findings for an Old Puzzle. PMID- 28669217 TI - Risky sexual behaviors among Malay adolescents: a comparison with Chinese adolescents in Singapore. AB - OBJECTIVE: Malays, with majority of the individuals being Muslim, form the largest ethnic group in Southeast Asia. This region is experiencing a rising incidence of HIV infections. Due to circumcision and prohibition of sex outside marriage, being Muslim was argued to be a protective factor against sexually transmitted infections (STI) and Human Immunodeficiency Virus (HIV). However, Malay adolescents were found to be more likely to contract chlamydia and gonorrhea than non-Malay adolescents in Singapore. DESIGN: Using a cross sectional survey, we examined and compared safer sex knowledge, attitudes and self-efficacy, and sexual behaviors of 248 sexually active Malay adolescents with 384 Chinese adolescents aged 16-19 years in Singapore. Poisson regression, adjusted for socio-demographic characteristics, was used for modeling each dependent variable. Adjusted prevalence ratios (aPR) with 95% confidence intervals (CI) were obtained. RESULTS: On multivariate analysis, Malay adolescents were more likely to report marginally unfavorable attitude towards condom use (aPR 1.21 CI 1.00-1.48) and significantly lower confidence in using condoms correctly (aPR 1.24 CI 1.05-1.47) than Chinese adolescents. They were also more likely to report significantly younger first sex age (aPR 0.98 CI 0.96 1.00), never use of condoms for vaginal sex (aPR 1.32 CI 1.16-1.49) and anal sex (aPR 1.75 CI 1.11-2.76) and non-use of contraceptives at last sex (aPR 1.30 CI 1.17-1.45) than Chinese respondents. Malay males were less likely to buy sex (aPR 0.56 CI 0.37-0.85), but they reported higher likelihood of inconsistent condom use with female sex workers (aPR 2.24 CI 1.30-3.87). CONCLUSION: Malay ethnicity was associated with unfavorable condom use attitude and lower self-efficacy in using condoms, which was consistent with risky sexual behaviors such as non-use of condoms. Future research should use mixed methods to explore and identify cultural influences to these behaviors. PMID- 28669216 TI - Considerations and treatment options for patients with comorbid atrial fibrillation and diabetes mellitus. AB - INTRODUCTION: Atrial fibrillation (AF) and diabetes mellitus (DM) are common worldwide and their incidence is increasing, representing a significant public health and economic burden as well as an increase in individual increased morbidity and mortality risk profiles. Both conditions are closely related, as patients with DM are at increased risk of incident AF, and AF patients with DM are at higher risk of cardiovascular events compared to non-AF patients. Areas covered: This review article aims to provide an overview of the current evidence linking DM and AF, as well as the impact of obesity, weight loss and stroke on these coexisting conditions. Second, the effects of new oral anti hyperglycaemic medications on cardiovascular risk will be considered. Expert opinion: In conclusion, coexisting AF and DM represent a high risk population of patients requiring aggressive risk factor identification and treatment optimisation. The multifactorial interplay between these conditions requires individual assessment of patient risk profiles with the aim of minimising the impact of each modifiable risk factor. PMID- 28669218 TI - Protective effect of Nigella sativa oil against acetamiprid induced reproductive toxicity in male rats. AB - The present study was designed to investigate the adverse reproductive effects of acetamiprid, besides the possible protective role of Nigella sativa oil (NSO), as a potential antioxidant agent. Thirty-two male Wistar rats were allocated into four equal groups of eight, control (CRL), acetamiprid (ACMP, 27 mg/kg), Nigella sativa oil (NSO, 0.5 ml/kg) and in combination (ACMP + NSO). The experimental animals were dosed by gavage (5 days per week) for 45 consecutive days. Body weight gain, reproductive organs weights, sperm characteristics, testosterone, and thiobarbutiric acid-reactive substances (TBARS) levels were investigated. The obtained results showed that ACMP decreased significantly (p < 0.001) the body weight gain and the absolute weights of reproductive organs (testes, epididymis, and seminal vesicles). Furthermore, significant alterations at least (p < 0.01) in semen characteristics were noted in ACMP group as evidenced by a decline in spermatids number, sperm count, sperm motility, and testosterone level with an increase in abnormal and dead sperm and TBARS level. Treatment with NSO alone may stimulate spermatogenesis, increased significantly (p < 0.001) spermatids number and the weight of seminal vesicles. On the other hand, the co-administration of NSO along with ACMP can mitigate more efficiently and modulate in certain cases the adverse effects induced by ACMP on reproductive organs weights, semen quality, testosterone, and TBARS levels (at least p < 0.001). This obvious protective role of NSO against ACMP induced reproductive toxicity may be due to its antioxidant properties and ability to reduce TBARS levels as shown in this work. PMID- 28669219 TI - The prevalence of non-classic congenital adrenal hyperplasia due to 21 hydroxylase deficiency in Russian women with hyperandrogenism. AB - The aim of the study was to determine the prevalence of non-classic congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase (21-OH) deficiency among hyperandrogenic women in a Russian population and to evaluate diagnostic value of basal serum 17-hydroxyprogesterone (17-OHP) level to diagnose this disease. A total of 800 consecutive Caucasian women presenting with elevation of at least one serum androgen and/or manifestation of one of the clinical androgenic symptoms were prospectively recruited and evaluated by basal 17-OHP. The diagnosis of NCAH due to 21-OH deficiency was considered in patients when basal level exceeded 5.0 nmol/L and CYP21A2 gene mutation analysis was performed in this case. Eight (1.0%) of the patients had NCAH due to 21-OH deficiency confirmed by genotyping. These women had a V281L mutation: five homozygous and three compound heterozygous with genotypes V281L/P453S, V281L/I2splice and V281L/I2splice. One patient was diagnosed with NCAH (genotype V281L/I2splice) before the study and was excluded from the analysis. Thus, the unbiased prevalence of NCAH was 0.9%. The 17-OHP basal level ranges from 16.8 to 17.7 nmol/L predicted NCAH with 100% sensitivity and 100% specificity. PMID- 28669220 TI - Effects of octenidine mouth rinse on apoptosis and necrosis of human fibroblasts and epithelial cells - an in vitro study. AB - This study aimed at comparing the cytotoxicity of a new octenidine mouth rinse (MR) on gingival fibroblasts and epithelial cells using different established MRs. Octenidol (OCT), Chlorhexidine 0.2% (CHX), Meridol (MER), Oral B (OB), and control (PBS only) were used. Human primary gingival fibroblasts (HGFIBs) and human primary nasal epithelial cells (HNEPCs) were cultivated in cell-specific media (2 * 105 cells/well) and treated with a MR or PBS for 1, 5, and 15 min. All tests were performed in duplicate and repeated 12 times. The apoptosis and necrosis were determined using a Caspase-3/7 assay and LDH assay, respectively. The data were analyzed using two-way analysis of variance with subsequent Mann Whitney U-test. No significant differences could be found between the incubation times of the MR, neither for apoptosis nor necrosis (p > 0.05). Regarding apoptosis of HGFIBs, MRs had no influence at all. In HNEPCs, OCT induced relevantly lower apoptosis than CHX (p = 0.01). Considering necrosis, MER showed the lowest numbers of necrotic HGFIBs and HNEPCs, whereas OB induced the highest number of necrotic cells. The differences between both MR were statistically relevant (p < 0.01). OCT did neither differ from the other MRs nor from the control (PBS) in induction of necrosis in both cell types. In conclusion, the slightly negative effect of OCT considering apoptosis and necrosis of HGFIBs and HNEPCs is nearly the same or even lower compared to the established MRs included in this study. The results confirm that OCT is a potential alternative to CHX. PMID- 28669221 TI - Maternal chromium restriction modulates miRNA profiles related to lipid metabolism disorder in mice offspring. AB - Increasing evidence shows that maternal nutrition status has a vital effect on offspring susceptibility to obesity. MicroRNAs are related to lipid metabolism processes. This study aimed to evaluate whether maternal chromium restriction could affect miRNA expression involved in lipid metabolism in offspring. Weaning C57BL/6J mice born from mothers fed with normal control diet or chromium restricted diet were fed for 13 weeks. The adipose miRNA expression profile was analyzed by miRNA array analysis. At 16 weeks old, pups from dams fed with chromium-restricted diet exhibit higher body weight, fat weight, and serum TC, TG levels. Six miRNAs were identified as upregulated in the RC group compared with the CC group, whereas eight miRNAs were lower than the threshold level set in the RC group. In the validated target genes of these differentially expressed miRNA, the MAPK signaling pathway serves an important role in the influence of early life chromium-restricted diet on lipid metabolism through miRNA. Long-term programming on various specific miRNA and MAPK signaling pathway may be involved in maternal chromium restriction in the adipose of female offspring. Impact statement For the first time, our study demonstrates important miRNA differences in the effect of maternal chromium restriction in offspring. These miRNAs may serve as "bridges" between the mother and the offspring by affecting the MAPK pathway. PMID- 28669222 TI - Comparison of serological assessments in the diagnosis of liver fibrosis in bile duct ligation mice. AB - Liver fibrosis assessment is essential to make a prognosis and to determine the appropriate anti-fibrosis treatment. Non-invasive serum markers are widely studied in patients to assess liver fibrosis due to the limitations of liver biopsy. When using animal models to study the mechanism and intervention of hepatic fibrosis, serum markers might be useful for the continuous assessment of liver fibrosis in individual animals, which could avoid the influence of biological differences between individuals. However, it is unclear whether serum markers can assess hepatic fibrosis in the animal model. In the present study, we evaluated and compared the ability of four serum markers to assess liver fibrosis in bile duct ligation mice. According to the stages of liver fibrosis assessed by pathological changes, mice in this study were divided into five groups (F0, F1, F2, F3, and F4). Subsequently, four serum markers, aspartate aminotransferase-to alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), and Forns Index, were calculated for each group. Furthermore, the correlations between serum markers and pathological stages and the ability of serological markers to evaluate liver fibrosis were analyzed. AAR, APRI, FIB-4, and Forns Index could significantly distinguish F0-2 from F3-4 mice. APRI, FIB-4, and Forns Index could detect F0-3 from F4 mice. Among these four markers, FIB-4 was the best able to distinguish >=F2 and >=F3, with area under the curve values of 0.882 and 0.92, respectively. Forns Index was best for diagnosing F4 with area under the curve value of 0.879. These results demonstrated that serum markers could be used for assessing liver fibrosis in bile duct ligation mice, and therefore, these markers might lead to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals. Impact statement The assessment of liver fibrosis is essential for making a prognosis and determining the appropriate anti fibrosis treatment. In studies focusing on the mechanism and treatment of liver fibrosis using animal models, it would be more accurate to continuously evaluate liver fibrosis in a single animal to avoid individual biological differences. Unfortunately, it is difficult to perform continuous assessment through liver biopsy in the most commonly used rodent models. It is unclear whether serum markers, which have been used in hepatic fibrosis patients, could be used in animal models. Our results demonstrate that serum markers could be used for assessing liver fibrosis in bile duct ligation mice. This study might contribute to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals. PMID- 28669223 TI - Salicylaldehyde and dihydroisobenzofuran derivatives from the marine fungus Zopfiella marina. AB - Two salicylaldehyde derivatives (1 and 2), a hydroxymethylphenol (3), five dihydroisobenzofuran (4-8) derivatives, and a 5-chloro-3-deoxyisoochracinic acid (9), together with a known 3-deoxyisoochracinic acid (10) were isolated from the marine fungus Zopfiella marina BCC 18240 (or NBRC 30420). The structures of these compounds were elucidated by extensive spectroscopic analysis. Compound 1 showed weak antituberculous activity against Mycobacterium tuberculosis H37Ra, and antibacterial activity against Bacillus cereus with MIC values of 25 and 12.5 MUg/mL, respectively. PMID- 28669224 TI - Development and field testing of a smartphone "App" for tinnitus management. AB - OBJECTIVE: This study's objective was to develop and test a smartphone app that supports learning and using coping skills for managing tinnitus. DESIGN: The app's content was based on coping skills that are taught as a part of progressive tinnitus management (PTM). The study involved three phases: (1) develop a prototype app and conduct usability testing; (2) conduct two focus groups to obtain initial feedback from individuals representing potential users; and (3) conduct a field study to evaluate the app, with three successive groups of participants. STUDY SAMPLE: Participants were adults with bothersome tinnitus. For Phase 2, two focus groups were attended by a total of 17 participants. Phase 3 involved three consecutive rounds of participants: five from the focus groups followed by two rounds with 10 participants each who had not seen the app previously. RESULTS: In both the focus groups and field studies, participants responded favourably to the content. Certain features, however, were deemed too complex. CONCLUSION: Completion of this project resulted in the development and testing of the delivery of PTM coping skills via a smartphone app. This new approach has the potential to improve access to coping skills for those with bothersome tinnitus. PMID- 28669225 TI - Cochrane Corner: interventions to improve hearing aid use in adult auditory rehabilitation. AB - This "Cochrane Corner" will be a recurring feature in the journal that highlights systematic reviews relevant to audiology, with invited commentary to aid clinical decision making. This first instalment features the Cochrane review "Interventions to Improve Hearing Aid Use in Adult Auditory Rehabilitation," published in 2016. In their review, Barker et al identified 37 randomised controlled trials (RCTs) and concluded that there is low-quality evidence using self-management support and complex interventions (support plus delivery system design) in adult auditory rehabilitation. The review highlights the need for well conducted studies in this area. PMID- 28669226 TI - Usage of healthcare services and preference for mental healthcare among older Somali immigrants in Finland. AB - OBJECTIVES: The aims of the study were, first, to describe and analyze healthcare services utilization patterns of older immigrants in Finland, and particularly to compare the availability and accessibility of health services between older Somalis and Finns. The second aim was to examine the preferences for mental healthcare within the group of Somalis. The third aim was to test the existence of a service usage gap expected to be characteristic of the Somali group, in which high levels of mental health problems occur alongside simultaneous low levels of mental health service usage. DESIGN: The participants were 256 men and women between the ages of 50-85; half were Somali migrants and the other half Finnish matched pairs. The participants were surveyed regarding their usage of somatic, mental, and preventive health services, as well as symptoms of depression, general distress, and somatization. The Somali participants were also surveyed regarding their usage of traditional healing methods and preferences for mental healthcare. RESULTS: The Somali group had significantly lower access to personal/family doctors at healthcare centers as well as a lower availability of private doctors and occupational health services than the Finns. Instead, they used more nursing services than Finnish patients. The Somali participants attended fewer age-salient preventive check-ups than the Finns. The majority of the Somalis preferred traditional care, most commonly religious healing, for mental health problems. The hypothesized service gap was not substantiated, as a high level of depressive symptoms was not associated with a low usage of health services among the Somalis, but it was found unexpectedly among the Finns. CONCLUSION: Our findings call for culturally appropriate general and mental health services for older immigrants, which requires awareness of clients' preferences, needs, and alternative healing practices. Somali participants encountered institutional barriers in accessing healthcare, and they preferred informal mental healthcare, especially religious healing instead of Western practices. PMID- 28669227 TI - Understanding untreated hypertension from patients' point of view: A qualitative study in rural Yogyakarta province, Indonesia. AB - Objectives This study aimed to explore perspectives about hypertension from patients who do not take anti-hypertensive medications. Factors that shape their perspectives as well as patients' expectations were also canvassed. Method Individual, face-to-face interviews were conducted with 30 people (>=45 years old) living in rural villages, diagnosed with hypertension, who had not taken any anti-hypertensive medications for at least one year. Interviews were audiotaped, transcribed verbatim and thematically analysed. Results Four themes emerged: (1) alternative medicines for managing high blood pressure; (2) accessing health care services; (3) the need for anti-hypertensive medications; and (4) existing support and patients' expectations. Reluctance to take anti-hypertensive medications was influenced by patients' beliefs in personal health threats and the effectiveness of anti-hypertensive medications, high self-efficacy for taking alternative medicines, the lack of recommendation regarding hypertension treatment, and barriers to accessing supplies of medicines. Conclusion Despite their awareness of being diagnosed with hypertension, patients undervalued visiting a health professional to control their high blood pressure. Health strategies need to consider patients' beliefs, concerns and expectations. Providing an accessible, affordable and adequate supply of hypertension medication is also key to any programs designed to optimise hypertension management. PMID- 28669228 TI - Open defecation explains differences in nutritional status between Bengali and tribal children in the Chittagong Hill Tracts of Bangladesh. AB - OBJECTIVE: We describe differences in linear growth as measured by height-for-age z-score (HAZ) between children from Bengali and tribal populations in the Chittagong Hill Tracts of Bangladesh and examine factors associated with HAZ in both groups. DESIGN: We used nutritional surveillance data collected in Bangladesh from 2003 to 2006 to analyze HAZ among 12,006 children aged 6-23 months and conducted multivariate linear regression and Blinder-Oaxaca decomposition to quantify the relative contribution of independent variables to differences in HAZ between Bengali and tribal children. RESULTS: Mean HAZ was stable for Bengali children (-1.88 in 2003 to -1.90 in 2006) but improved for tribal children (-1.87 in 2003 to -1.68 in 2006). The difference between groups was significant across the study period (p = 0.008). Among Bengali children, HAZ was positively associated with father's schooling (beta = 0.221; 95% CI: 0.079 0.363). Among tribal children, HAZ was positively associated with consumption of animal source foods (beta = 0.073; 95% CI: 0.051-0.096) and goat ownership (beta = 0.240; 95% CI: 0.025-0.454). Results of a likelihood ratio test indicated that distance to a health center was inversely associated with HAZ among tribal children (p < 0.001). Blinder-Oaxaca decomposition demonstrated a difference in pooled coefficients between groups (p = 0.004), explained primarily by differences in coefficients for paternal education (p = 0.001) and village-level prevalence of open defecation (p = 0.004). CONCLUSIONS: Different responses among Bengali and tribal children to village-level open defecation are an explanatory factor for the difference in HAZ between Bengali and tribal populations. Open defecation may also act a proxy for unmeasured factors such as household environmental conditions and food hygiene. ABBREVIATIONS: Chittagong Hill Tracts (CHT); height-for-age z-scores (HAZ); Nutrition Surveillance Project (NSP); World Health Organization (WHO). PMID- 28669229 TI - Cytotoxic activity of alkyl benzoate and fatty acids from the red sea sponge Hyrtios erectus. AB - The chemical investigation of the methylene chloride fraction of marine sponge Hyrtios erectus led to the isolation of the known oxysterol (2) along with a new alkyl benzoate compound identified by spectroscopic methods (NMR and MS) as 4' methylheptyl benzoate (1), whilst the n-butanol fraction afforded the known indole 3-carbaldehyde and beta-carboline derivatives. Moreover, the hexane fraction was analysed by GC-MS for their fatty acids (FAs). A total of 17 FAs with chain lengths between 14 and 25 carbons were identified. Methyl-branched FAs are predominated suggesting the presence of bacterial symbionts in the H. erectus sponge. Furthermore, compounds 1 and 2 displayed significant cytotoxicity against breast adenocarcinoma (MCF-7) with IC50 values of 2.4 and 3.8 MUM, respectively, since compound 2 was also shown to have potent cytotoxic effect against hepatocellular carcinoma cells (HepG 2) with IC50 value of 1.3 MUM. PMID- 28669230 TI - Factors associated with participation by African Americans in a study of the genetics of glaucoma. AB - OBJECTIVE: African Americans have been historically underrepresented in research studies. Our aim was to evaluate factors influencing enrollment in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. DESIGN: Patients approached to enroll in the POAAGG study were asked to complete a 15-item survey addressing demographic characteristics, knowledge of genetics and glaucoma, and opinions on human research. Survey responses were compared between subjects who enrolled (Enrollers) and did not enroll (Decliners) in the POAAGG study. RESULTS: Enrollers (N = 190) were 3.7 years younger (P = 0.007) and had similar gender, education, and income level to Decliners (N = 117). Knowledge about genetics and glaucoma was similar between groups. Enrollers were more comfortable providing DNA for research studies (93.1% vs 54.1%; P < 0.001) and more likely to have participated in prior studies (P = 0.003) and consider participating in future studies (P < 0.001). Among Decliners, lack of time was the primary reason given for not enrolling. CONCLUSION: To increase participation of African Americans in genetic research studies, efforts should be made to raise comfort with DNA donation. PMID- 28669231 TI - In vitro antioxidant/prooxidant effects of combined use of flavonoids. AB - The present study was undertaken to investigate the individual and combined antioxidant or prooxidant effects of genistein, daidzein and quercetin in human erythrocytes and rat microsomes in vitro. Their reducing potential against oxidation of a redox sensitive fluorescent probe, their protective effect against H2O2-induced membrane lipid peroxidation and their inhibitory effect on AAPH induced hemolysis were evaluated. Genistein and daidzein were prooxidant in erythrocytes but antioxidant in microsomes where their metabolites might have been formed which suggests the importance of metabolic capacity in in vitro models to predict the physiological situation. Quercetin showed antioxidant effects in all models and conditions. Prooxidant effect of 'genistein-daidzein mixture', at their concentrations reflecting the real life, was suppressed by addition of quercetin to the mixture. Our study shows that flavonoids can exert prooxidant effects depending on the conditions, but the mixture effect should be considered while assessing their effects and safety in humans. PMID- 28669232 TI - Phytochemical study of leaves of Ocotea caudata from Colombia. AB - This first phytochemical study of leaves of Ocotea caudata led to the isolation of ten isoquinoline alkaloids, one of them previously unreported, S-(+)-9-O demethylnorpreocoteine (1), three known flavonoids, two phenols, two eudesmane type sesquiterpenoids, one proline derivative, one fatty alcohol and a phytosterol. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic analyses including HSQC, HMBC, 1H-1H COSY, NOESY, as well as HRESIMS data in addition to comparison with reports in the literature. PMID- 28669233 TI - The Graying of Rural America: Community Engagement and Health Promotion Challenges. AB - BACKGROUND: Although social participation has been linked to positive physical and mental health outcomes, elderly people in rural areas remain highly disengaged. Also, few studies have examined community residents' perceptions of the barriers and opportunities for the elderly to participate in community activities. PURPOSE: This article highlights the perceptions of rural community residents regarding their understanding of the following: (1) community leadership, (2) barriers and opportunities for the elderly to engage in leadership, and (3) potential community-based solutions for promoting more social participation. METHOD: Individual interviews were conducted with 16 community members. Content analysis was used to analyze the data. Researchers immersed and familiarized themselves with the data prior to developing codes. Coding was initially done manually and later using NVivo. FINDINGS: Four major themes emerged: conceptions of community leadership, elderly resource inventory, barriers to elderly engagement, and potential solutions. Themes collectively illustrated that residents have a clear understanding of the role of community leadership, of available resources for the elderly, and of the barriers encountered when using these resources. CONCLUSION: Our findings highlight a need for health promotion strategies that are informed by community needs and foster healthy lifestyles for all community residents. PMID- 28669234 TI - How 'healthy' are healthcare organizations? Exploring employee healthcare utilization rates among Dutch healthcare organizations. AB - Occupational health and safety research rarely makes use of data on employee healthcare utilization to gain insight into the physical and mental health of healthcare staff. This paper aims to fill this gap by examining the prevalence of two relevant types of healthcare utilization among staff working in healthcare organizations: physical therapy and mental healthcare utilization. The paper furthermore explores what role employee and organizational characteristics play in explaining differences in healthcare utilization between organizations. A Dutch healthcare insurance company provided healthcare utilization records for a sample of 417 organizations employing 136,804 healthcare workers in the Netherlands. The results showed that there are large differences between and within healthcare industries when it comes to employee healthcare utilization. Multivariate regression analyses revealed that employee characteristics such as age and gender distributions, and healthcare industry, explain some of the variance between healthcare organizations. Nevertheless, the results of the analyses showed that for all healthcare utilization indicators there is still a large amount of unexplained variance. Further research into the subject of organizational differences in employee healthcare utilization is needed, as finding possibilities to influence employee health and subsequent healthcare utilization is beneficial to employees, employers and society as a whole. PMID- 28669235 TI - Social stress, obesity, and depression among women: clarifying the role of physical activity. AB - OBJECTIVE: This study examined the role of stress in the association among physical activity, obesity, and depression among women. The extent to which physical activity moderated these relationships was also examined. DESIGN: Data from the National Survey of American Life (N = 3235) and multivariable regression analyses were used to examine the effects of chronic stress, material hardship, racial discrimination, and physical activity on obesity and depression among African American, Caribbean Black and White women. RESULTS: Stress was not related to body mass index (BMI) for African American or White women, but chronic stress was associated with higher BMI for Caribbean Black women. Stress was associated with depressive symptoms, but there was variation by the type of stressor under consideration. Physical activity was associated with fewer depressive symptoms and lower BMI, but the relationships varied by type of stressor and race/ethnicity. Physical activity moderated the effect of chronic stress on depressive symptoms and BMI, but only for African American women who reported high levels of chronic stress. Among White women, physical activity moderated the effect of racial discrimination on BMI for those who reported experiencing both high and low levels of discrimination. CONCLUSION: This study was the first to document physical activity as a moderator in the relationship among stress, depression, and obesity using a nationally representative sample of racially/ethnically diverse women. Findings provide insight into the role of stress in relation to depression and obesity while highlighting heterogeneity among Black Americans. PMID- 28669236 TI - Differences in nativity, age and gender may impact health behavior and perspectives among Asian Indians. AB - OBJECTIVE: Identify health perspectives among Asian Indians in greater Houston area, to guide a tailored community wide survey. DESIGN: Four focus groups of different ages, gender, and nativity were conducted at which participants were asked for their opinions about specific health topics. Key informant interviews were conducted with ten community leaders to validate focus group responses. Recordings from focus groups and key informant interviews were transcribed and analyzed. RESULTS: Diabetes, cancer, and hypertension were primary health concerns. Common themes were sedentary lifestyle and poor health literacy. Older participants were more accepting of having familial hypertension and high cholesterol. Women were more concerned about health of family members and dietary habits. Perspectives differed on eating habits, physical activity, use of Western medicine, and smoking based on nativity. Responses from key informant interviews validated focus group findings. CONCLUSION: Perspectives on health may differ among Asian Indians depending on gender, age, and nativity. PMID- 28669237 TI - Nutritional anemia predominant form of anemia in educated young Thai women. AB - OBJECTIVE: Anaemia is one of the most common health problems worldwide, with a high prevalence in Africa and South East Asia, including Thailand. Thai women of childbearing age have an increased risk of anaemia due to several factors including underlying health problems, lifestyles and poor diet. Therefore, we investigated the prevalence of anaemia among female students of Chulalongkorn University (aged 18-22) and categorized causes of the anaemia. DESIGN: 400 Thai female student-volunteers, without known underlying diseases were subjected to blood tests; complete blood count, Haemoglobin typing and serum ferritin level. Bloods, having haemoglobin under 12 g/dl and hematocrit under 36%, were designated as anaemia. Then causes of anaemia are categorized into 3 groups; Iron deficiency, Thalassemia and Others. RESULTS: We found that 21% of the volunteers were anaemic. In 85 anaemic volunteers, they were classified as Iron deficiency anaemia (IDA); with low serum ferritin levels 42.4%, Thalassemia; total of 6 types 25.9%, IDA and Thalassemia 2.3% and Others 29.4% in which haemoglobin typing and serum ferritin level were normal. CONCLUSION: Iron deficiency anaemia (IDA) is the major cause of anaemia in Thai female students in our study. Several students were gradually developing anaemia where their haematocrit (Hct) and haemaglobin (Hb) were within reference range but mean corpuscular volume (MCV), mean corpuscular haemaglobin (MCH) and serum ferritin fell below reference range, indicating latent iron deficiency. A few volunteers had both IDA and Thalassemia and also Thalassemia with iron overloaded where health can be deteriorated without knowledge of having these conditions or proper health care. To improve their health, universities or public organizations should provide education and/or screen for anaemia. With the knowledge and understanding of their health issues or underling diseases, students themselves can prevent serious health conditions, improve university performances, and improve their quality of life. PMID- 28669238 TI - Stress across generations: A qualitative study of stress, coping, and caregiving among Mexican immigrant mothers. AB - OBJECTIVE: Hispanic immigrants represent the largest and fastest growing ethnic minority within the US, justifying increased attention to identify factors that influence declining immigrant health across generations. This study investigates the range of psychosocial stress exposures and coping mechanisms of Mexican immigrant mothers, and implications for the health of their US-born children. DESIGN: We conducted 10 focus groups with 1st generation Mexican-born immigrant mothers (n = 32 women) in Nashville, TN, in the summer of 2014. Focus groups elicited challenges and benefits of life as an immigrant mother. Data were analyzed using a modified grounded theory approach. RESULTS: We identified four themes that indicate how maternal stressors could impact children's health: (1) work-family tradeoff, (2) limited freedom/mobility, (3) reduction of social networks, and (4) transmission of anxiety and fears to children. Women in our study also engage in a range of coping mechanisms, including the creation of new social networks, seeking support in religion, and seeking help from community resources. CONCLUSION: These results highlight the importance of developing new questionnaires to elicit stress exposures for Mexican immigrant mothers. Findings also suggest the value of intervention strategies and social policies that would ultimately improve maternal and child health in this marginalized population. PMID- 28669239 TI - Understanding of cardiovascular disease risk factors among Bangladeshi immigrants in New York City. AB - OBJECTIVES: Among all South Asians, Bangladeshis have the highest prevalence of cardiovascular disease (CVD). The purpose of our study was to compare the understanding of CVD risk factors among Bangladeshi immigrants to the general Caucasian population in the U.S. DESIGN: We surveyed Bangladeshi immigrants in Queens, New York using a CVD risk factor knowledge instrument used in the Coronary Artery Risk Development in Young Adults (CARDIA) study to assess awareness of risk factors. Using multivariate regression modeling, we compared scores on the knowledge instrument between Bangladeshis we surveyed and Caucasians from the CARDIA study, controlling for potential confounders. We subsequently examined the frequency of mentioning each risk factor to understand what was driving the difference in the overall score. RESULTS: The proportion of Bangladeshis scoring low on the knowledge assessment was 0.53, where as the proportion of whites scoring low in the CARDIA study was 0.32 (p value < .001). Whites were 34% more likely to score high than Bangladeshis (adjusted odds ratio [aOR] 1.34, 95% confidence interval [CI] 1.19-1.52). Bangladeshis were more likely to mention diet and cholesterol as risk factors and less likely to mention lack of exercise, being overweight, and smoking as risk factors. CONCLUSION: Understanding of cardiovascular disease risk factors was lower among Bangladeshis than whites. This was driven by Bangladeshis having less awareness regarding how exercise and being overweight contribute to CVD. Community based interventions and community health partnerships should target these behavioral risk factors in the Bangladeshi population. PMID- 28669240 TI - Antibiotic activity of Emerimicin IV isolated from Emericellopsis minima from Talcahuano Bay, Chile. AB - Due to the increasing emergence of resistance of bacterial pathogens to current antibiotics, we have examined the marine fungi present in sea sediments obtained 200 m offshore to discover new antibacterial compounds active against multidrug resistant bacteria. One strain, identified as Emericellopsis minima, was isolated from sediments of Talcahuano Bay (Chile). From the liquid culture of E. minima, we isolated Emerimicin IV, a unique fungal peptaibol that exhibited antibacterial activity. The structure of this compound was assigned by interpretation of 1H NMR and HR-LCMS data. Emerimicin IV showed bacteriostatic activity against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis with MIC values ranging between 100 and 12.5 MUg/mL. PMID- 28669241 TI - Reality Versus Grant Application Research "Plans". AB - This article describes the implementation of the American Indian mHealth Smoking Dependence Study focusing on the differences between what was written in the grant application compared to what happened in reality. The study was designed to evaluate a multicomponent intervention involving 256 participants randomly assigned to one of 15 groups. Participants received either a minimal or an intense level of four intervention components: (1) nicotine replacement therapy, (2) precessation counseling, (3) cessation counseling, and (4) mHealth text messaging. The project team met via biweekly webinars as well as one to two in person meetings per year throughout the study. The project team openly shared progress and challenges and collaborated to find proactive solutions to address challenges as compared to what was planned in the original grant application. The project team used multiple strategies to overcome unanticipated intervention issues: (1) cell phone challenges, (2) making difficult staffing decisions, (3) survey lessons, (4) nicotine replacement therapy, (5) mHealth text messages, (6) motivational interviewing counseling sessions, and (7) use of e-cigarettes. Smoking cessation studies should be designed based on the grant plans. However, on the ground reality issues needed to be addressed to assure the scientific rigor and innovativeness of this study. PMID- 28669242 TI - Understanding the Experiences of Low-Income Individuals Receiving Farmers' Market Incentives in the United States: A Qualitative Study. AB - OBJECTIVE: The objective of this study was to identify benefits and barriers to using a farmers' market (FM) incentive program among program participants. DESIGN: In qualitative semistructured interviews, participants were asked about their experiences with shopping at FM, using FM incentives, barriers to fruit and vegetable (F&V) intake, and changes in dietary intake. Interviews were recorded and transcribed. Inductive content analysis was used to code, categorize, and develop themes based on the transcriptions. SETTING: A FM in Northern Utah. SUBJECTS: A convenience sample of participants ( n = 14) completed a 45- to 60 minute interview after receiving FM incentives for an 8-week intervention period. RESULTS: FM incentives reduced barriers associated with shopping at FM such as cost and accessibility among program participants. Incentives provided participants with greater spending flexibility, allowing parents to provide children with F&V that previously did not fit into their food budget. Participants reported greater family and community involvement when shopping at FM. However, the limited hours and days of operation were factors that reduced the use of FM among participants, even when incentives were provided. CONCLUSIONS: The perceived benefits and barriers to shopping at FM and receiving FM incentives should be considered by future programmers and funding agencies. PMID- 28669243 TI - Anti-Escherichia coli activity of extracts from Schinus terebinthifolius fruits and leaves. AB - Ethanol extracts obtained from Schinus terebinthifolius Raddi fruits and leaves were active against Escherichia coli with MIC of 78 MUg mL-1 for both extracts. Phytochemical analyses revealed a major presence of phenolic acids, tannins, fatty acids and acid triterpenes in the leaves and phenolic acids, fatty acids, acid triterpenes and biflavonoids in the fruits. Major compounds isolated from the plant, such as the acid triterpene schinol, the phenolic acid derivative ethyl gallate and the biflavonoids agathisflavone and tetrahydroamentoflavone, showed very little activity against E. coli. Bioautography of the ethanol extracts on silica gel plate showed inhibition zones for E. coli. They were removed from the plate and the compounds identified as a mixture of myristic, pentadecanoic, palmitic, heptadecanoic, stearic, nonadecanoic, eicosanoic, heneicosanoic and behenic fatty acids. PMID- 28669244 TI - Automated Detector of High Frequency Oscillations in Epilepsy Based on Maximum Distributed Peak Points. AB - High frequency oscillations (HFOs) are considered as biomarker for epileptogenicity. Reliable automation of HFOs detection is necessary for rapid and objective analysis, and is determined by accurate computation of the baseline. Although most existing automated detectors measure baseline accurately in channels with rare HFOs, they lose accuracy in channels with frequent HFOs. Here, we proposed a novel algorithm using the maximum distributed peak points method to improve baseline determination accuracy in channels with wide HFOs activity ranges and calculate a dynamic baseline. Interictal ripples (80 200[Formula: see text]Hz), fast ripples (FRs, 200-500[Formula: see text]Hz) and baselines in intracerebral EEGs from seven patients with intractable epilepsy were identified by experienced reviewers and by our computer-automated program, and the results were compared. We also compared the performance of our detector to four well-known detectors integrated in RIPPLELAB. The sensitivity and specificity of our detector were, respectively, 71% and 75% for ripples and 66% and 84% for FRs. Spearman's rank correlation coefficient comparing automated and manual detection was [Formula: see text] for ripples and [Formula: see text] for FRs ([Formula: see text]). In comparison to other detectors, our detector had a relatively higher sensitivity and specificity. In conclusion, our automated detector is able to accurately calculate a dynamic iEEG baseline in different HFO activity channels using the maximum distributed peak points method, resulting in higher sensitivity and specificity than other available HFO detectors. PMID- 28669245 TI - Do Visually Impaired People Develop Superior Smell Ability? AB - It is well known that visually impaired people perform better in orientation by sound than sighted individuals, but it is not clear whether this enhanced awareness also extends to other senses. Therefore, the aim of this study was to observe whether visually impaired subjects develop superior abilities in olfactory perception to compensate for their lack of vision. We investigated the odor perception of visually impaired individuals aged 7 to 89 ( n = 99; 52 women, 47 men) and compared them with subjects of a control group aged 8 to 82 years ( n = 100; 45 women, 55 men) without any visual impairment. The participants were evaluated by Sniffin' Sticks odor identification and discrimination test. Identification ability was assessed for 16 common odors presented in felt-tip pens. In the odor discrimination task, subjects had to determine which of three pens in 16 triplets had a different odor. The median number of correctly identified odorant pens in both groups was the same, 13 of the offered 16. In the discrimination test, there was also no significant difference observed. Gender did not influence results. Age-related changes were observed in both groups with olfactory perception decreasing after the age of 51. We could not confirm that visually impaired people were better in smell identification and discrimination ability than sighted individuals. PMID- 28669246 TI - Calculating theoretical base rates of score differences. AB - OBJECTIVE: In this study, we developed new methods to calculate theoretical base rates of score differences when more than two test scores are involved in score comparisons. The study compares the results of theoretical and observed base rates, and then explores whether these methods can be used in practice. METHODS: We proposed the formulas and the Monte Carlo methods calculating theoretical base rates of score differences between a single test score and a mean of several test scores by overall sample and subsamples. We also compared observed and theoretical base rates of score differences in the Wechsler Intelligence Scale for Children (5th ed.). using the normative sample data. RESULTS: The theoretical base rates obtained from the new methods were close to the observed base rates. CONCLUSIONS: The new methods can derive reasonable theoretical base rates and are usable practically. PMID- 28669247 TI - Prediction of venous wound healing with laser speckle imaging. AB - Introduction Laser speckle imaging is used for noninvasive assessment of blood flow of cutaneous wounds. The aim of this study was to assess if laser speckle imaging can be used as a predictor of venous ulcer healing. Methods After generating the flux speckle images, three regions of interest (ROI) were identified to measure the flow. Sensitivity, specificity, negative predictive value, and positive predictive value for ulcer healing were calculated. Results In total, 17 limbs were included. A sensitivity of 92.3%, specificity of 75.0%, PPV of 80.0%, and NPV 75.0% were found in predicting wound healing based on laser speckle images. Mean flux values were lowest in the center (ROI I) and showed an increase at the wound edge (ROI II, p = 0.03). Conclusion Laser speckle imaging shows acceptable sensitivity and specificity rates in predicting venous ulcer healing. The wound edge proved to be the best probability for the prediction of wound healing. PMID- 28669248 TI - Mid-term results in the treatment of varicose veins with N-butyl cyanoacrylate. AB - Aim To present mid-term results of patients with varicose veins treated with N butyl cyanoacrylate (VariClose(r)), a nontumescent endovenous ablation technique. Patients and method Endovenous ablation was performed on 180 patients with saphenous vein incompetence between May and October 2014. One hundred sixty-eight subjects capable of being followed-up for 30 months were included. Patients' pre- and postoperative data were recorded. Results Procedures were performed on the great saphenous vein in 159 patients and on the small saphenous vein in nine patients. Saphenous vein diameters ranged between 5.5 mm and 14 mm. Full ablation was achieved in all patients following the procedure. No complications were encountered. Patients were monitored for 30 months. Ablation rates were 100% at the 3rd month, 98.3% at the 6th month, 96.6% at 1 year, and 94.1% at 30 months. Mean venous clinical severity score was 10.2 before procedures, decreasing to 3.9 at 3 months, 4.2 at 6 months, 2.9 at 12 months, and 2.7 at 30 months ( p = 0.000). Conclusion Due to its high success rate, absence of complications, no tumescent anesthesia requirement and high patient satisfaction, endovenous ablation with N-butyl cyanoacrylate is a good method. However, long-term follow up results are now needed. PMID- 28669249 TI - Human papillomavirus and p16 protein expression as prognostic biomarkers in mobile tongue cancer. AB - OBJECTIVES: The objectives were to determine the prevalence of human papillomavirus (HPV) in mobile tongue cancer (MTC) and evaluate associations and survival. MATERIALS AND METHODS: Patients who underwent surgical resection as primary treatment for MTC (n = 127) were retrospectively evaluated. Formalin fixed paraffin-embedded (FFPE) specimens were assessed for p16 and p53 by immunohistochemistry; for HPV DNA by nested multiplex polymerase chain reaction (PCR) using two pairs of consensus primers (MY09-MY11 and GP5+-GP6+); and for E6 and E7 oncogenes from 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, 66, and 68) by real-time reverse transcription PCR (RT-PCR). RESULTS: There were 18 (14.2%) p16-positive, 45 (35.4%) p53-positive, 9 (7.1%) HPV DNA positive, and 7 (5.5%) E6 and/or E7 mRNA-positive tumors, but the correlation of all pairs was poor. There was no demographic or histopathologic association with HPV status. Cause-specific survival was significantly better with p16-positive than with p16-negative tumors (p = .037). CONCLUSIONS: The prevalence of HPV and p16 positivity was relatively low and p16 status was a poor surrogate marker for HPV status. The results showed the importance of p16 expression in prognosticating mobile tongue cancer. PMID- 28669250 TI - Primary CNS Nonamyloidogenic Light Chain Deposition Disease: Case Report and Brief Review. AB - The true incidence of light chain deposition disease (LCDD) restricted to the central nervous system (CNS) is unknown. To our knowledge only 7 cases of LCDD restricted to the brain have been previously reported. We herein describe an unusual example. A 44-year-old man presented with a history of ischemic retinopathy in 2004 and left lower extremity hypoesthesia in 2007 that progressed gradually to left-sided weakness and numbness in the 2 years prior to his hospitalization in 2015. A stereotactic brain biopsy was performed, displaying nonspecific hyaline deposits of amorphous "amyloid-like" material involving deep brain white matter and vessels. These were Congo red negative and were accompanied by a sparse lymphoplasmacytic infiltrate. Plasma cells demonstrated kappa light chain class restriction by chromogenic in situ hybridization (CISH). There was patchy reactivity with kappa immunohistochemistry in the amorphous deposits. A diagnosis of light chain deposition disease was made. Subsequent systemic myeloma and lymphoma workups were negative. Previously reported cases have included men and women, spanning the ages of 19 and 72 years, often presenting with hemiparesis, hypoesthesia, or seizures. Deposits have been reported in the cerebrum and cerebellum. T2/FLAIR (fluid attenuation inversion recovery) changes are usual, but lesions may or may not produce contrast enhancement. The light chain deposition may be of kappa or lambda class. Most lesions have been accompanied by local lymphoid and/or plasma cell infiltrates exhibiting light chain restriction of the same class as the deposits. In summary, LCDD limited to the CNS is a rare lesion consisting of deposition of amyloid like, but Congo red-negative monotypic light chain usually produced by local lymphoplasmacytic infiltrates. PMID- 28669251 TI - An algorithmic approach for the management of hand deformities in dystrophic epidermolysis bullosa. AB - Treatment of hand deformities in epidermolysis bullosa patients represents a challenging field in hand surgery practice, thus a systematic approach by a team is mandatory for a successful result. A simple and practical algorithm for the surgical treatment of hand deformities in EB was employed by the authors where the deformities of each digit in EB patients was categorized according to pseudosyndactyly and interphalangeal joint contracture severity for guidance during the surgical treatment. The current study retrospectively reviewed the medical records and photographic data of 13 EB patients followed in our department, for whom a systematic approach to the management and treatment was used. Mild cases were treated by surgical release and secondary healing with non adhesive dressing while moderate cases were treated with autologous dermal grafts harvested with a special technique that were fixed on denuded areas on the proximal interphalageal joints after release. The remaining areas were treated similarly to the mild group. Additional K-wires were applied for two weeks in severe cases. A total of 21 procedures were performed on 13 EB patients with hand deformities according to the proposed treatment strategy. Functional recovery was satisfactory for each patient and the outcomes were dependent upon the severity of deformity. A multidisciplinary and conscious approach followed by an algorithmic surgical treatment protocol described in the study has been beneficial in providing consistent and successful long-term results for these patients. PMID- 28669252 TI - Parents' Experience of Hope When Their Child Has Cancer: Perceived Meaning and the Influence of Health Care Professionals. AB - OBJECTIVE: This study examined the role and importance of hopefulness for parents of children with cancer, how hope relates to parents' experience with the diagnosis, and the influence nurses and other health care professionals have on parents' hope. METHOD: Using an interview format, 50 parents of children diagnosed with cancer were given the Reaction to Diagnosis Interview, and asked 5 open-ended questions about hope. Answers were analyzed using content analysis. Parents' adaptation to their child's diagnosis was compared with answers to the hope questions. RESULTS: Parents defined hope as a knowing, belief, or wish regarding their child's health. They emphasized the importance of hope over the course of their child's treatment. Staff increased parents' hope by providing care to children and families, educating parents, and by connecting with and providing a positive outlook for families. Most parents felt there was nothing staff did to decrease their hope. CONCLUSION: Understanding parents' experiences validates the quality care and connections we make with children and families, and encourages us to consider the effects of our interactions. This underscores the importance of education and support as a means of instilling hope in parents, who are valued, critical members of their child's health care team. PMID- 28669253 TI - Unaltered emotional experience in Parkinson's disease: Pupillometry and behavioral evidence. AB - INTRODUCTION: Recognizing emotions in others is a pivotal part of socioemotional functioning and plays a central role in social interactions. It has been shown that individuals suffering from Parkinson's disease (PD) are less accurate at identifying basic emotions such as fear, sadness, and happiness; however, previous studies have predominantly assessed emotion processing using unimodal stimuli (e.g., pictures) that do not reflect the complexity of real-world processing demands. Dynamic, naturalistic stimuli (e.g., movies) have been shown to elicit stronger subjective emotional experiences than unimodal stimuli and can facilitate emotion recognition. METHOD: In this experiment, pupil measurements of PD patients and matched healthy controls (HC) were recorded while they watched short film clips. Participants' task was to identify the emotion elicited by each clip and rate the intensity of their emotional response. We explored (a) how PD affects subjective emotional experience in response to dynamic, ecologically valid film stimuli, and (b) whether there are PD-related changes in pupillary response, which may contribute to the differences in emotion processing reported in the literature. RESULTS: Behavioral results showed that identification of the felt emotion as well as perceived intensity varies by emotion, but no significant group effect was found. Pupil measurements revealed differences in dilation depending on the emotion evoked by the film clips (happy, tender, sadness, fear, and neutral) for both groups. CONCLUSIONS: Our results suggest that differences in emotional response may be negligible when PD patients and healthy controls are presented with dynamic, ecologically valid emotional stimuli. Given the limited data available on pupil response in PD, this study provides new evidence to suggest that the PD-related deficits in emotion processing reported in the literature may not translate to real-world differences in physiological or subjective emotion processing in early-stage PD patients. PMID- 28669254 TI - Papillary Renal Cell Carcinoma With Osteosarcomatous Heterologous Differentiation: A Case Report With Molecular Genetic Analysis and Review of the Literature. AB - Sarcomatoid differentiation can occur in all subtypes of renal cell carcinoma (RCC). In rare cases, heterologous differentiation has been described. We present a case of heterologous osteosarcomatous differentiation in association with sarcomatoid papillary RCC including an analysis of chromosomal copy number alteration. This is the first case to identify heterologous differentiation in association with papillary RCC. The patient was a 70-year-old man who had a mass in the right kidney. Speckled calcification was seen on computed tomography scan. Histological assessment demonstrated papillary RCC merging with areas of sarcomatoid change and malignant bone formation simulating osteosarcoma. Cytogenetic evaluation demonstrated additional copies of chromosome 7 in both epithelial and osteosarcomatous components. A literature review identified 33 previous cases of heterologous differentiation in association with RCC. Of the 14 cases that reported an epithelial subtype, 13 cases were reported to be chromophobe RCC and 1 case was reported to be clear cell RCC. PMID- 28669255 TI - A simple and inexpensive way to document simple husbandry in animal care facilities using QR code scanning. AB - Record keeping within research animal care facilities is a key part of the guidelines set forth by national regulatory bodies and mandated by federal laws. Research facilities must maintain records of animal health issues, procedures and usage. Facilities are also required to maintain records regarding regular husbandry such as general animal checks, feeding and watering. The level of record keeping has the potential to generate excessive amounts of paper which must be retained in a fashion as to be accessible. In addition it is preferable not to retain within administrative areas any paper records which may have been in contact with animal rooms. Here, we present a flexible, simple and inexpensive process for the generation and storage of electronic animal husbandry records using smartphone technology over a WiFi or cellular network. PMID- 28669256 TI - Pediatric coblation total tonsillectomy: intracapsular or extracapsular? AB - OBJECTIVES: To compare the results of coblation intracapsular total tonsillectomy (CITT) with those of conventional coblation extracapsular total tonsillectomy (CETT) in the treatment of tonsillar hypertrophy in children with regards to efficacy and complications. METHODS: Ninety children with adenotonsillar hyperplasia underwent tonsillectomy +/- adenoidectomy (48 CITT and 42 CETT). Intraoperative situation was observed and recorded. Patients were reexamined regarding recovery condition and tonsil regrowth, and were followed for at least one year. RESULTS: Significant differences were observed in four clinical features when the CITT group was compared with the CETT group: intraoperative bleeding score, intraoperative tonsillar fossa score, color of white membrane one day postoperatively, and visual analogue scale (VAS) value one week postoperatively (p < .05). There were statistical correlations between intraoperative bleeding score and age, course of disease, surgery method, number of acute tonsillitis attacks per year, and intraoperative tonsillar fossae score (p < .05). Two significant differences were noted when the tonsil hypertrophy group was compared with the chronic tonsillitis group: color of white membrane at one day and one week postoperatively (p < .05). No regrowth of tonsil was found. CONCLUSIONS: Compared with conventional extracapsular tonsillectomy, CITT has the advantages of decreased pain and bleeding, and promote healing of wounds. No tonsillar regrowth was observed after at least one year of follow-up. PMID- 28669257 TI - Disease modification in advanced MS: Focus on upper limb function. PMID- 28669258 TI - Titanium dioxide nanoparticles prime a specific activation state of macrophages. AB - Titanium dioxide nanoparticles (TiO2 NPs) are widely used in foods, cosmetics, and medicine. Although the inhalation toxicity of TiO2 NPs has been studied, the potential adverse effects of oral exposure of low-dose TiO2 NPs are largely unclear. Herein, with macrophage cell lines, primary cells, and mouse models, we show that TiO2 NPs prime macrophages into a specific activation state characterized by excessive inflammation and suppressed innate immune function. After a month of dietary exposure in mice or exposure in vitro to TiO2 NPs (10 and 50 nm), the expressions of pro-inflammatory genes in macrophages were increased, and the expressions of anti-inflammatory genes were decreased. In addition, for macrophages exposed to TiO2 NPs in vitro and in vivo, their chemotactic, phagocytic, and bactericidal activities were lower. This imbalance in the immune system could enhance the susceptibility to infections. In mice, after a month of dietary exposure to low doses of TiO2 NPs, an aggravated septic shock occurred in response to lipopolysaccharide challenge, leading to elevated levels of inflammatory cytokines in serum and reduced overall survival. Moreover, TLR4-deficient mice and primary macrophages, or TLR4-independent stimuli, showed less response to TiO2 NPs. These results demonstrate that TiO2 NPs induce an abnormal state of macrophages characterized by excessive inflammation and suppressed innate immune function in a TLR4-dependent manner, which may suggest a potential health risk, particularly for those with additional complications, such as bacterial infections. PMID- 28669259 TI - Correction of inverted nipples with the double-track sun-cross running suture technique. AB - Various techniques have been reported for correcting inverted nipples; however, problems such as incomplete correction, recurrence, scarring and nerve or duct injury persist. To minimise the recurrence rate and reliably attain a well projected nipple, we developed a technique involving a single suture that runs through both the periphery and the core of the nipple. After the dissection and release of fibrotic connective tissue, an absorbable monofilament suture was passed through the periphery and core to leave double tracks of the suture at all locations, creating the final shape of a cross inside a circle (resembling the sun-cross symbol). Finally, the suture was tied in a purse-string manner to push the nipple outward. We performed this surgery on 34 congenital cases, comprising 29 patients with bilateral inverted nipples, 5 patients with a unilateral inverted nipple and 12 patients with an acquired deformity. During a mean follow up period of 22.4 months, all of the corrected nipples remained everted without reinvagination. We successfully corrected inverted nipples with the double-track sun-cross running suture technique, which provided long-lasting eversion and created an aesthetically pleasing nipple contour. PMID- 28669260 TI - Andrographolide attenuates microglia-mediated Abeta neurotoxicity partially through inhibiting NF-kappaB and JNK MAPK signaling pathway. AB - Neuroinflammation plays a critical role in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD). Microglial cells after activated play critical roles in development of neuroinflammation, and may accelerate the progression of AD. Andrographolide (ANDRO), a potent naturally extracted substance, has been demonstrated to exert suppressive effects on LPS induced inflammation by modulating macrophage and microglia overactivation. Whereas in AD, beta-amyloid (Abeta) peptides have been considered as a potent activator of neuroinflammation, the effect of ANDRO on Abeta-induced neuroinflammation has not been examined. In this study, we investigated the effects of ANDRO on Abeta(1-42)-induced neuroinflammation. We found that ANDRO significantly protected neuronal cells against microglia-mediated Abeta(1-42) toxicity and attenuated the release of preinflammatory productions such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), nitric oxide (NO), and prostaglandin E2 (PGE2). It also downregulated the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. Further the involved mechanism study demonstrated that ANDRO inhibited the nuclear translocation of nuclear factor-kappaB (NF-kappaB) by affecting IkappaB phosphorylation, and attenuated Abeta(1-42)-induced JNK-MAPK overactivation. In summary, this study, for the first time, revealed ANDRO reduced inflammation mediated neuronal damage by blocking inflammatory responses of microglial cells to Abeta(1-42), suggesting ANDRO may be an effective agent in modulating neuroinflammatory process in AD. PMID- 28669261 TI - Dupuytren's disease: my personal view. AB - Dupuytren's disease is a heterogenous condition for which a palette of treatment options is required. Randomized control trial evidence is sparse; design challenges, such as validated outcome measures, blinding, equipoise, funding and assessment of recurrence, may limit further data accrual. Recurrence has different significance with different treatments and so rates are not directly comparable. The risk of any treatment is a function of both the chance of a complication and the clinical sequelae of that complication. The patient must be intimately involved in choosing treatment and is often trading rapid recovery for a higher chance of recurrence. Health economies are strained and as custodians of healthcare, surgeons should consider whether many patients even need treatment. To minimize the chance of complex, hazardous and expensive revision surgery, a low threshold for primary skin grafting should be applied, especially for those who are young, have dense disease or vulnerable genes. PMID- 28669262 TI - The paramedian supracerebellar-transtentorial approach to remove a posterior fusiform gyrus arteriovenous malformation. AB - This is the case of a 14-year-old female who presented with headache and seizures. Cranial magnetic resonance imaging revealed an arteriovenous malformation (AVM) located at the posterior portion of the right-sided fusiform gyrus. Cerebral angiography showed that the AVM was fed mainly by branches from the inferior temporal trunk of the posterior cerebral artery. The main venous drainage was to the right transverse sinus through the tentorial vein. The AVM was totally excised through the paramedian supracerebellar-transtentorial approach with the patient in a semisitting position. Postoperative MRI and cerebral angiography confirmed the total resection. The patient was discharged on the 5th postoperative day without neurological deficit. The video can be found here: https://youtu.be/QPrUl8AP7G8 . PMID- 28669263 TI - Microsurgical treatment for arteriovenous malformation of the corpus callosum and choroidal fissure. AB - The management of arteriovenous malformations (AVMs) of the corpus callosum and choroidal fissure is challenging because they commonly receive arterial feeders from the anterior and posterior circulation, and drain to deep veins. In this video the authors present the case of a 20-year-old man who presented with acute onset of headache, loss of consciousness, and nuchal rigidity. Computed tomography, MRI, and cerebral angiography performed in tandem revealed a ruptured, large, Grade IV AVM of the corpus callosum and choroidal fissure with two groups of arterial feeders: one from the pericallosal artery and the other from the medial and lateral posterior choroidal arteries. The treatment strategy included two stages. The first stage involved preoperative embolization of the arterial feeders from the posterior circulation, which promoted reduction of the nidus flow of the AVM. The second involved a microsurgical resection, using the interhemispheric approach, with the patient in the prone position, which allowed accessing the anterior circulation feeders and the complete resection of the AVM, without associated morbidity. The video can be found here: https://youtu.be/5wcYKhcJtls . PMID- 28669264 TI - Surgical treatment of a complex Grade III Spetzler-Martin posterior temporal arteriovenous malformation. AB - Grade III Spetzler-Martin arteriovenous malformations (AVMs) are a distinct subgroup of brain AVMs. Their variety in terms of location, type of venous drainage, and size makes them the most heterogenous group in the AVM classification. The surgical risk of treatment is also variable depending on the specifics of a given Grade III AVM. In this video illustration, the authors describe the technical nuances of surgical resection of a very complex Grade III left posterior temporal AVM. According to supplementary grading, the unruptured aspect and patient age give this lesion a Grade III; therefore, the combined grading gives the patient a score of 6, which puts him at moderate risk of morbidity for surgery. The indication for surgery was based on the patient's young age, lifetime risk of hemorrhage, and the location of the AVM in the left inferior/posterior temporal gyrus. The patient underwent 2 sessions of preoperative embolization of the posterior cerebral artery and the external carotid artery feeders prior to craniotomy. The day after the second embolization, the patient was operated on via a posterior temporobasal craniotomy. The dural supply attached to the draining vein was left intact during the dural exposure. The detail of the AVM resection is described in the video clip. A total resection was achieved, and the patient's neurological examination was intact after the procedure. The video can be found here: https://youtu.be/fj5Cxw3kpXQ . PMID- 28669265 TI - Contralateral transcallosal resection of a ventricular body arteriovenous malformation: 3D operative video. AB - A 46-year-old male presented with an incidentally discovered left ventricular body arteriovenous malformation (AVM). It measured 2 cm in diameter and had drainage via an atrial vein into the internal cerebral vein (Spetzler-Martin Grade III, Supplementary Grade 4). Preoperative embolization of the posterior medial choroidal artery reduced nidus size by 50%. Subsequently, he underwent a right-sided craniotomy for a contralateral transcallosal approach to resect the AVM. This case demonstrates strategic circumferential disconnection of feeding arteries (FAs) to the nidus, the use of aneurysm clips to control large FAs, and the use of dynamic retraction and importance of a generous callosotomy. Postoperatively, he was neurologically intact, and angiogram confirmed complete resection. The video can be found here: https://youtu.be/j0778LfS3MI . PMID- 28669266 TI - Navigation-guided transsylvian approach and microsurgical resection of a deep left temporal low-grade arteriovenous malformation. AB - This video demonstrates stereotactic-guided resection of a ruptured diffuse left temporal arteriovenous malformation (AVM) in an adolescent male who presented with headache and speech difficulties. The diffuse nidus of the AVM, 25 mm in size, was located in the posterior superior temporal gyrus, with drainage into the sylvian veins (Spetzler-Martin Grade II). The AVM was located stereotactically, and resection was performed through a small corticectomy. The clot cavity was evacuated. Feeding branches to the AVM were identified during careful dissection, and parent M1 and M2 branches were preserved. The patient recovered well, with no residual speech deficit. Postoperative angiogram demonstrated complete AVM removal. The video can be found here: https://youtu.be/Sttc86H8jCw . PMID- 28669267 TI - Microsurgical resection of a high-grade occipital arteriovenous malformation after staged embolization. AB - The authors demonstrate the case of a 16-year-old girl with a large symptomatic occipital arteriovenous malformation (AVM). The staged embolization was performed to downgrade the AVM from Spetzler-Martin (S-M) Grade IV (Supplementary S-M Grade 7) to Grade III (Supplementary S-M Grade 5). The patient developed a subacute progressive visual field defect after the final time of embolization. MRI revealed an enlarged draining venous ectasia of the AVM compressing the visual cortex. Postoperatively, good radiological results were achieved, and the patient reported an improvement in her symptoms. The detailed operative technique and surgical nuances (including the surgical features of the AVM postembolization) of the marginal dissection and removal are illustrated in this video atlas. The video can be found here: https://youtu.be/2MZq5patcJI . PMID- 28669268 TI - Introduction to the supratentorial cerebral arteriovenous malformation video supplement. AB - It is with great pleasure that we present this Neurosurgical Focus video supplement on supratentorial cerebral arteriovenous malformations (AVMs). We were privileged to view a remarkable number of outstanding videos demonstrating current state-of-the-art management of brain AVMs using endovascular and microsurgical modalities. Careful and critical review was required to narrow down the submitted videos to a workable volume for this supplement, which reflects the excellent work being done at multiple centers with these lesions. This issue consists of videos that represent modern microsurgical and neuroendovascular techniques for the treatment of supratentorial cerebral AVMs. The videos demonstrate cutting-edge therapies as well as standard ones, which will be valuable to both novice and expert neurointerventionists and neurosurgeons. We are honored to be involved with this project and proud of its content and expert authors. We believe you will enjoy the video content of this supplement and hope that it will raise the collective expertise of our community of AVM surgeons. PMID- 28669269 TI - Microsurgical management of a high-grade brain arteriovenous malformation in the central lobe after unsuccessful radiosurgery. AB - The recommendation for the great majority of high-grade brain arteriovenous malformations (bAVMs) is observation, except for those patients with recurrent hemorrhages, progressive neurological deficits, steal-related symptoms, or AVM related aneurysms, for whom intervention should be considered. These are general recommendations, and the decision should be made on an individual basis. Surgical resection of an AVM in the central lobe may cause postoperative sensorimotor deficits since this anatomical region includes the pre- and postcentral gyri on the lateral surface and the paracentral lobule on the medial surface. The authors present a patient with a ruptured high-grade bAVM in the central lobe who underwent previous surgery for hematoma evacuation and previous radiosurgery, and whose indication for reoperation was proposed based on progressive hemiparesis. Microsurgical resection was possible after a wide frontoparietal craniotomy, which made all the nidus borders accessible. This case illustrates the anatomy and surgical technique for large nidus AVMs in eloquent areas, showing that complete microsurgical resection is possible with good clinical outcome. The video can be found here: https://youtu.be/Cpd1PK6BLIM . PMID- 28669270 TI - Selective embolization of ruptured feeding artery aneurysm followed by resection of arteriovenous malformation. AB - This is the case of a man in his 40s who suffered sudden collapse into a deep coma as a result of a ruptured arteriovenous malformation (AVM) feeding artery aneurysm within the lateral ventricle. The ruptured aneurysm was successfully treated with Onyx embolization of the feeding pedicle. The AVM and the feeding artery aneurysm were then removed via a transcallosal approach. This case highlights the utility of interrogating the AVM with microcatheterization of the feeding pedicles in order to define the exact anatomical features necessary for treatment planning. It also reviews the anatomy of the choroidal fissure. The video can be found here: https://youtu.be/UeqFzhTRU1Q . PMID- 28669271 TI - Lateral parietal arteriovenous malformation with feeding artery aneurysm. AB - Superficial arteriovenous malformations (AVMs) with favorable Spetzler-Martin grading are amenable to primary surgical resection. Careful preoperative workup including preoperative angiograms is essential to identify feeding artery aneurysms and deep venous drainage. The authors present a 37-year-old female who presented with a Spetzler-Martin Grade II right parietal superficial AVM with a 5 mm feeding artery aneurysm from the posterior cerebral artery. Given the risk of hemorrhage, the AVM was resected completely without any complications. On subsequent postoperative angiograms, the feeding artery aneurysm diminished in caliber. Feeding artery aneurysms may regress spontaneously after resection of an AVM due to flow-related changes. The video can be found here: https://youtu.be/PpwODc9iI3g . PMID- 28669272 TI - Utility of indocyanine green videoangiography in subcortical arteriovenous malformation resection. AB - Subcortical arteriovenous malformations (AVMs) are surgically challenging. Localization is crucial for eloquent areas, and complete resection evaluation is uncertain. Indocyanine green videoangiography (ICG-VA) can assist this surgery. An illustrative video of a subcortical frontoparietal bleeding AVM resection assisted by ICG-VA is presented. A bleeding arterial feeder aneurysm was embolized in the acute phase to protect against rebleeding. ICG-VA helped to detect the AVM's superficial arterialized draining vein, distinguishing it from normal cortical veins. This enabled a customized sulcus approach. ICG-VA showed normalized flow through the previously arterialized vein, confirming the AVM's complete resection. This applies when there is a single drainage remaining. The video can be found here: https://youtu.be/L7yJEE66kV0 . PMID- 28669273 TI - Motor cortex arteriovenous malformation. AB - Supratentorial arteriovenous malformations in eloquent territories can be difficult to resect. This video presents the treatment of a patient with a symptomatic 3-cm arteriovenous malformation in the left motor strip. At the authors' institution, per the surgeon's discretion, preoperative angiography is performed to evaluate the need for preoperative embolization. Multimodality treatment reduced the microsurgical risk by allowing early occlusion of a draining vein, by decreasing overall intraoperative hemorrhage, and by allowing minimal pial dissection in the deep aspect of the arteriovenous malformation that abutted the corticospinal tract. The choice of embolysate was an additional nuance of the embolization. The video can be found here: https://youtu.be/HWZ0RjgPEXg . PMID- 28669274 TI - Resection of complex occipital arteriovenous malformation with giant varix: demonstration of microsurgical technique. AB - The complexity of arteriovenous malformations (AVMs) does not necessarily preclude surgical resection. In this video the authors present a 72-year-old male who was known to have an occipital AVM with a large draining varix for the previous 10 years. The patient had progressively worsening visual and cognitive deficits over several years. Total surgical resection was achieved following single stage preoperative embolization. Although resection of the AVMs is challenging, even in experienced hands, it offers a cure and may improve patient clinical outcome. The video can be found here: https://youtu.be/YI1AwGjJdvo . PMID- 28669275 TI - Early retinal atrophy predicts long-term visual impairment after acute optic neuritis. AB - BACKGROUND: Visual recovery after optic neuritis (ON) used to be defined as good, although patients frequently complain of poor vision. METHODS: We carried out a prospective study on 38 consecutive patients with acute ON followed monthly for 6 months and evaluated high- and low-contrast visual acuity (HCVA and LCVA, respectively), quality of vision (National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25)), visual fields, and retinal thickness by spectral domain optical coherence tomography (OCT). RESULTS: We found significant impaired LCVA and color vision in ON eyes 6 months after acute ON, which impact on quality of life. LCVA and color vision were correlated with the thicknesses of the ganglion cell and inner plexiform layer (GCIPL; 2.5% LCVA r = 0.65 and p = 0.0001; color vision r = 0.75 and p < 0.0001) and that of the peripapillary retinal nerve fiber layer (pRNFL; LCVA r = 0.43 and p = 0.0098; color vision r = 0.62 and p < 0.0001). Linear regression models that included the change in the GCIPL and pRNFL thicknesses from baseline to month 1 after onset explained 47% of the change in 2.5% LCVA and 67% of the change of color vision acuity. When adjusting for the value of visual acuity at baseline, predictors of the change in vision from baseline to month 6 achieved similar performance for all three types of vision (HCVA, LCVA, and color vision). CONCLUSION: Monitoring retinal atrophy by OCT within the first month after ON onset allows individuals at a high risk of residual visual impairment to be identified. PMID- 28669276 TI - 'Natural' and 'Unnatural' medical deaths and coronial law: A UK and international review of the medical literature on natural and unnatural death and how it applies to medical death certification and reporting deaths to coroners: Natural/Unnatural death: A Scientific Review. AB - In the United Kingdom, when people die, either a doctor writes an acceptable natural cause of death medical certificate, or a coroner (fiscal in Scotland) investigates the case, usually with an autopsy. An inquest may or may not follow. The concept of 'natural or unnatural cause' death is not internationally standardized. This article reviews scientific evidence as to what is a natural death or unnatural death and how that relates to the international classification of deaths. Whilst there is some consensus on the definition, its application in considering whether to report to the coroner is more difficult. Depictions of deaths in terminal care, medical emergencies and post-operative care highlight these difficulties. It secondly reviews to what extent natural and unnatural are criteria for notification of deaths in England and Wales and internationally. It concludes with consideration of how medical concepts of unnatural death relate in England and Wales to coroners' legal concepts of what is unnatural. Deaths that appear natural to clinicians and pathologists may be legally unnatural and vice versa. It is argued that the natural/unnatural dichotomy is not a good criterion for reporting deaths under medical care to coroners, but the notification of a medical cause of death, using the International Classification of Disease Codes and the medical professional view as to whether it is scientifically natural, is of great value to the coroner in deciding whether it is legally unnatural. PMID- 28669277 TI - Department of Health consultation on medical examiners and death certification reforms: A commentary on the criteria for notification to be laid down in regulation. AB - The Department of Health has completed its consultation on the nature of the new medical examiner system and supporting regulations. This article considers whether the regulations for death notification to coroners are fit for purpose in the light of the medical literature on unnatural deaths and the experience of a coroner in a jurisdiction with a heavy workload from specialist hospital referrals. It concludes that they are to be welcomed, but that they should not rely on natural/unnatural death as a criterion for notification of deaths during the course of medical treatment, or refer to 'neglect'. Furthermore, they should ensure that sudden-death syndromes, which may be considered by doctors as natural, are still notified. Relying on these changes to reduce coronial investigations would be unwise. If that is the intention, other reforms may be necessary. PMID- 28669278 TI - Effectiveness of Solifenacin for Managing of Bladder Spasms in Patients With Urethroplasty. AB - To evaluate the efficacy and safety of solifenacin in the treatment of bladder spasms after urethroplasty. Patients underwent urethroplasty were randomly assigned to the study group ( n = 165) and the control group ( n = 150). Patients in the study group were treated with solifenacin for 7 days. Patients in the control group were placebo. Each group was further divided into four subgroups: paracentetic suprapubic cystostomy subgroup, traditional suprapubic cystostomy subgroup, former suprapubic cystostomy subgroup, and urethral catheter subgroup. A visual analogue scale (VAS) was used to measure the severity of bladder spasms. The mean duration of spasms, the frequency of spasms, and the incidences of urine extravasation and radiating pain were recorded each day. There were no significant differences in the VAS scores and mean duration of bladder spasms between the study and control groups . However, there was a significantly lower VAS score in the patients taking solifenacin in the paracentetic suprapubic cystostomy subgroup ( p < .05). A similar tendency was noted in the mean duration of bladder spasms in this subgroup. In a comparison of the daily and nightly frequency of spasms within the four subgroups, a significant improvement was noted in the control group within 5 days. A similar difference was not noted within 6 days in the study group. The short-term therapy with solifenacin is an effective and safe method for decreasing the frequency of bladder spasms after urethroplasty. Patients undergoing paracentetic suprapubic cystostomy might be the only subset to benefit from this treatment. PMID- 28669279 TI - Gender differences in symptoms of depression among adolescents in Eastern Norway: Results from a cross-sectional study. AB - AIM: The aim of this study was to compare and describe gender differences and the associations between symptoms of depression and family conflict and economics, lifestyle habits, school satisfaction and the use of health-care services among adolescents. METHODS: Data were retrieved from Ungdata which is a cross-sectional study. Adolescents ( n=8052) from secondary school grades 8, 9 and 10 (age 13-16 years) participated in the study from 41 municipal schools in four counties. RESULTS: Girls reported a higher prevalence of symptoms of depression than boys. Gender differences were seen on all items related to symptoms of depression, family conflict and economics, lifestyle habits, school satisfaction and health care services. Multiple regressions showed that family conflicts and economics contributed to 19.2% of the variance in symptoms of depression in girls and 12.4% in boys. School satisfaction made a strong contribution: 21.5% in girls and 15.4% in boys. The total model explained 49% of the total variance in symptoms of depression in girls and 32.5% in boys. CONCLUSIONS: Gender demonstrated a pattern through a higher proportion of girls reporting symptoms of depression, family conflict and economics, lifestyle habits, school satisfaction and use of health care services. Even though the adolescents reported symptoms of depression, few used the school health-care services and public health nurses. This indicates that they need a person-centered approach for symptoms of depression. The findings may have important implications for planning for adolescents in school health services. PMID- 28669280 TI - The prognostic value of different node staging systems in patients with <=15 lymph nodes following surgery for gastric adenocarcinoma. AB - AIM: Lymph node (LN) status is an important prognostic indicator in patients with gastric cancer (GC). Although American Joint Committee on Cancer/International Union against Cancer (AJCC/UICC) is the most widely used staging system, there is a challenge in predicting survival of patients when the number of total harvested LNs is <=15. Our aim was to investigate the prognostic performances of seventh edition AJCC/UICC, lymph-node ratio (LNR), and log odds of metastatic lymph nodes (LODDS) on the overall survival (OS) of GC patients with <=15 examined LNs after gastric resection. MATERIAL AND METHOD: A total of 74 patients who underwent curative resection for gastric adenocarcinoma and had <=15 LNs at the final histopathological examination were included in the study. The prognostic ability of three node staging models to predict OS was assessed using the area under the curve (AUC). RESULTS: Of the 74 patients, 15 (20.3%) had no LN metastasis whereas 59 (79.7%) had nodal involvement. The median OS was 26 months. When assessed as a continuous variable, LNR was the strongest staging system to stratify GC patients on the basis of LN status. LODDS had superiority on other node staging models when the number of LNs retrieved was modeled as categorical variable. CONCLUSIONS: LNR (continuous) and LODDS (categorical) were the strongest indicators of OS in GC when the number of LN harvested was <=15. Therefore, they may be considered as an alternative nodal staging systems for GC. PMID- 28669281 TI - The global cancer burden and human development: A review. AB - AIMS: This review examines the links between human development and cancer overall and for specific types of cancer, as well as cancer-related risk-factors and outcomes, such as disability and life expectancy. METHODS: To assess human development, the Human Development Index was utilized continuously and according to four levels (low, medium, high, very high), where the low and very high categories include the least and most developed countries, respectively. All studies that assessed aspects of the global cancer burden using this measure were reviewed. RESULTS: Although the present cancer incidence burden is greater in higher Human Development Index countries, a greater proportion of the global mortality burden is observed in less developed countries, with a higher mean fatality rate in the latter countries. Further, the future cancer burden is expected to disproportionally affect less developed regions; in particular, it has been estimated that low and medium Human Development Index countries will experience a 100% and 81% increase in cancer incidence from 2008 to 2030, respectively. Disparities were also observed in risk factors and average health outcomes, such as a greater number of years of life lost prematurely and fewer cancer-related gains in life expectancy observed in lower versus higher Human Development Index settings. CONCLUSIONS: From a global perspective, there remain clear disparities in the cancer burden according to national Human Development Index scores. International efforts are needed to aid countries in social and economic transition in order to efficiently plan, implement and evaluate cancer control initiatives as a means to reduce the widening gap in cancer occurrence and survival worldwide. PMID- 28669282 TI - Use of the ADAPTE Method to Develop a Guideline for the Improvement of Depression Care in Primary Care. AB - Depression is the most frequent psychiatric disorder in primary health care, and the evidence shows that there is suboptimal management by primary care practitioners, perhaps owing to difficulties in decision making. Because clinical guidelines can improve decision making and management, a clinical guideline to manage depression in primary health care was developed in adherence to the ADAPTE method and was implemented in the Malaga Primary Health Care District in Spain. This column reports on the guideline development process, which produced a set of resources to improve the quality of primary health care-based depression care in Spain. PMID- 28669283 TI - Premilitary Trauma as a Correlate of Suicidal Ideation Among Veterans. PMID- 28669284 TI - Ecological Momentary Assessment and Intervention in the Treatment of Psychotic Disorders: A Systematic Review. AB - OBJECTIVE: Ecological momentary assessment (EMA) and ecological momentary intervention (EMI) are technologies used to track fluctuations in experiences and prompt behavioral responses within the context of a person's daily life. Most commonly delivered via smartphone, EMA and EMI have potential to provide simple, cost-effective, and user-led treatment for psychotic disorders. This systematic review aimed to synthesize current research exploring the feasibility, acceptability, and clinical outcomes of EMA and EMI in the treatment of psychotic disorders. METHODS: A systematic search was conducted identifying studies published between 1980 and July 7, 2016, by searching PubMed, PsycINFO, PsycARTICLES, and the Cochrane Central Register of Controlled Trials with combinations of search terms related to mobile devices, EMA and EMI, and psychotic disorders. RESULTS: Of 1,623 studies identified, nine met inclusion criteria for the review. These studies found satisfactory feasibility and acceptability and preliminary evidence of improved clinical outcomes. The interventions, which had a broad array of features, targeted remote monitoring of illness and symptoms, and they also targeted illness self-management by using momentary reminders or instructions for behaviors, including medication adherence, management of symptoms and psychosocial impairments, daily living skills, and goal achievement. CONCLUSIONS: The findings of this review provide preliminary support for the clinical utility of EMA and EMI in the treatment of psychotic disorders. Future research should explore further applications of these technologies with larger sample sizes and controlled designs. PMID- 28669285 TI - Use of Multimodal Technology to Identify Digital Correlates of Violence Among Inpatients With Serious Mental Illness: A Pilot Study. AB - OBJECTIVE: The study examined multimodal technologies to identify correlates of violence among inpatients with serious mental illness. METHODS: Twenty-eight high risk inpatients were provided with smartphones adapted for data collection. Participants recorded their thoughts and behaviors by using self-report software. Sensors embedded in each device (microphone and accelerometers) and throughout the inpatient unit (Bluetooth beacons) captured patients' activity and location. RESULTS: Self-reported delusions were associated with violent ideation (odds ratio [OR]=3.08), damaging property (OR=8.24), and physical aggression (OR=12.39). Alcohol and cigarette cravings were associated with violent ideation (OR=5.20 and OR=6.08, respectively), damaging property (OR=3.71 and OR=4.26, respectively), threatening others (OR=3.62 and OR=3.04, respectively), and physical aggression (OR=6.26, and OR=8.02, respectively). Drug cravings were associated with violent ideation (OR=2.76) and damaging property (OR=5.09). Decreased variability in physical activity and noisy ward conditions were associated with violent ideation (OR=.71 and OR=2.82, respectively). CONCLUSIONS: Identifiable digital correlates may serve as indicators of increased risk of violence. PMID- 28669286 TI - Noncompliance, Nonadherence, and Dropout: Outmoded Terms for Modern Recovery Oriented Mental Health. AB - Discontinuing mental health treatment is traditionally viewed as an adverse event. In this Open Forum the authors explore underlying assumptions that inform this view and encourage reconsideration of the event as a personal choice and of the common tendency to describe people who discontinue treatment as "dropouts." PMID- 28669287 TI - Prevalence of Psychotherapy Surrounding Initiation of Psychotropic Polypharmacy in the Medicaid-Insured Population, 1999-2010. AB - OBJECTIVE: This research aimed to quantify the prevalence of psychotherapy among Medicaid-insured patients within six months of initiating psychotropic medication polypharmacy (PMP). METHODS: Using the Medicaid Analytic eXtract database for 29 states from 1999 to 2010, investigators established ten two-year cohorts of pediatric and adult patients who received two or more psychotropic drugs with a 45-day overlapping days' supply. Among PMP initiators, the prevalence of psychotherapy services, identified from encounter claims via Current Procedural Terminology and Healthcare Common Procedure Coding System codes, was calculated for the six months before and the six months after initiation of PMP. RESULTS: PMP prevalence varied from 21.2% to 27.7% and from 48.5% to 58.0% in pediatric and adult Medicaid-insured patients, respectively. Among pediatric patients who started PMP (N=397,728), the proportion who had received psychotherapy before PMP varied from 21.0% in the 1999-2000 cohort to 40.0% in 2005-2007. After PMP initiation, psychotherapy prevalence was higher, with estimates ranging from 25.4% in 1999-2000 to 44.1% in 2005-2007. Among adults (N=773,205), the prevalence of psychotherapy after PMP initiation ranged from 12.6% in 1999-2001 to 19.25% in 2003-2005. Psychotherapy prevalence prior to PMP initiation varied greatly across states. CONCLUSIONS: Although the prevalence of psychotherapy provided immediately before and after initiation of psychotropic polypharmacy has slightly increased in the past decade, it remains low among Medicaid-insured patients, particularly among adults. Reasons for variation in psychotherapy utilization across states deserve further exploration. PMID- 28669288 TI - Incremental Benefit-Cost of MOMCare: Collaborative Care for Perinatal Depression Among Economically Disadvantaged Women. AB - OBJECTIVE: Effectiveness of collaborative care for perinatal depression has been demonstrated for MOMCare, from early pregnancy up to 15 months postpartum, for Medicaid enrollees in a public health system. MOMCare had a greater impact on reducing depression and improving functioning for women with comorbid posttraumatic stress disorder (PTSD) than for those without PTSD. This study estimated the incremental benefit and cost and the net benefit of MOMCare for women with major depression and PTSD. METHODS: A randomized trial (September 2009 to December 2014) compared the MOMCare collaborative care depression intervention (choice of brief interpersonal psychotherapy or pharmacotherapy or both) with enhanced maternity support services (MSS-Plus) in the public health system of Seattle-King County. Among pregnant women with a probable diagnosis of major depression or dysthymia (N=164), two-thirds (N=106) met criteria for probable PTSD. Blinded assessments at three, six, 12, and 18 months postbaseline included the Symptom Checklist-20 depression scale and the Cornell Services Index. Analyses of covariance estimated gain in depression free days (DFDs) by intervention and PTSD status. RESULTS: When the analysis controlled for baseline depression severity, women with probable depression and PTSD in MOMCare had 68 more depression-free days over 18 months than those in MSS-Plus (p<.05). The additional depression care cost per MOMCare participant with comorbid PTSD was $1,312. The incremental net benefit of MOMCare was positive if a DFD was valued at >=$20. CONCLUSIONS: For women with probable major depression and PTSD, MOMCare had significant clinical benefit over MSS-Plus, with only a moderate increase in health services cost. PMID- 28669289 TI - Outpatient Follow-Up Care and Risk of Hospital Readmission in Schizophrenia and Bipolar Disorder. AB - OBJECTIVE: Although outpatient care within 30 days of mental health hospital discharge is an established quality indicator, little is known about the clinical implications of not receiving such care. This study evaluated whether receipt of outpatient care within 30 days of discharge was associated with a reduced risk of readmission during days 31-120 postdischarge among adult inpatients with schizophrenia or bipolar disorder. METHODS: Retrospective longitudinal cohort analyses were performed with Truven MarketScan Commercial (2010-2014) and Medicaid (2010-2013) databases. Among inpatients with schizophrenia (N=25,401) or bipolar disorder (N=46,375), overall and stratified associations were examined between receipt of an outpatient follow-up visit in the 30 days postdischarge and hospital readmission during days 31-120 postdischarge. RESULTS: Receipt of a follow-up visit within 30 days of discharge was associated with a slightly lower adjusted odds ratio (AOR) of hospital readmission during days 31-120 postdischarge (schizophrenia, AOR=.88, 95% confidence interval [CI]=.81-.96; bipolar disorder, AOR=.91, CI=.85-.98). For patients with schizophrenia, the strongest observed inverse association of follow-up care with readmission risk was among inpatients whose index admissions were 13 to 30 days long (AOR=.73, CI=.61-.89). For patients with bipolar disorder, the strongest corresponding inverse association was among those in the manic phase of illness at the index discharge (AOR=.73, CI=.63-.86). CONCLUSIONS: Outpatient visits during the 30 days after discharge were associated with a lower hospital readmission risk during the following 90 days. Assertive hospital discharge planning to secure outpatient visits after hospital discharge is needed for these patient populations. PMID- 28669291 TI - Association Between Quality Measures and Perceptions of Care Among Patients With Substance Use Disorders. AB - OBJECTIVE: This study evaluated whether eight quality measures assessing care for patients with a substance use disorder were associated with patient perceptions of their care, including perceived improvement and global rating of behavioral health care. METHODS: Secondary data analyses were conducted of administrative and patient survey data collected as part of a national evaluation of Veterans Health Administration (VHA) mental health and substance use services. Data for patients who received care for substance use disorders during October 2006 September 2007 paid for by the VHA and who participated in a telephone interview about their care (N=2,074) were included. Measures of patient perceptions of care included perceived improvement and global rating of behavioral health care. Eight quality measures based on administrative data assessed initiation and engagement in substance use disorder care, receipt of psychotherapy or psychosocial treatment, and follow-up after hospitalization. Regression models were conducted in which each quality measure predicted each outcome, with analyses adjusting for patient characteristics and functioning. RESULTS: Treatment engagement, two measures of psychotherapy receipt, and psychosocial treatment were significantly associated with perceived improvement, whereas treatment initiation and follow-up after hospitalization (seven and 30 days) were not. Psychotherapy receipt and follow-up after hospitalization (seven and 30 days) were significantly associated with global rating of behavioral health care. CONCLUSIONS: Some quality measures assessing care for substance use disorders were significantly associated with patient perceptions of care. Results provide additional support for these quality measures and suggest that patient perceptions of care are an important outcome in assessing care. PMID- 28669290 TI - Cost-Effectiveness of Telemedicine-Based Collaborative Care for Posttraumatic Stress Disorder. AB - OBJECTIVE: The study examined the cost-effectiveness of a telemedicine-based collaborative care model designed to increase rural veterans' engagement in evidence-based treatments for posttraumatic stress disorder (PTSD). METHODS: The Telemedicine Outreach for PTSD (TOP) study used a pragmatic randomized effectiveness trial to examine effects of PTSD care teams located at Veterans Affairs medical centers and supporting primary care providers in satellite clinics. Teams included a nurse care manager, pharmacist, psychologist, and psychiatrist. Effectiveness was estimated with quality-adjusted life years (QALYs) derived from the Short Form Health Survey for Veterans and Quality of Well-Being (QWB) scale. Intervention and health care costs were collected to evaluate the cost-effectiveness of the intervention. RESULTS: The sample (N=265) included mostly rural, unemployed, middle-aged men with a military service connected disability for PTSD randomly assigned to TOP or usual care. Only minor improvements in QWB QALYs were found. The TOP intervention was relatively expensive, with costs totaling $2,029 per patient per year. Intervention costs were not offset by reductions in health care utilization costs, resulting in an incremental cost-effectiveness ratio of $185,565 per QALY (interquartile range $57,675 to $395,743). CONCLUSIONS: Because of the upfront training costs and the resource-intensive nature of this intervention, associated expenses were high. Although PTSD-specific effectiveness measures were significantly improved, these changes did not translate to QALYs in the main analysis. However, analyses focusing on patient subgroups with comorbid mental disorders indicated greater QALY improvement for TOP at lower cost. PMID- 28669292 TI - Service Users' Experiences of Involuntary Hospital Admission Under the Mental Health Act 2001 in the Republic of Ireland. AB - OBJECTIVE: The objective of the study was to explore the experiences of individuals admitted to the hospital involuntarily under the Mental Health Act 2001 in the Republic of Ireland. METHODS: In this qualitative descriptive study, 50 individuals who had been involuntarily admitted to a hospital underwent face to-face semistructured interviews approximately three months after revocation of the involuntary admission order. Data were analyzed by using an inductive thematic process. RESULTS: Participants reported mixed experiences over the course of the admission, with both positive and challenging aspects. Participants reported feeling coerced, disempowered, and unsupported at various stages of the admission and highlighted the long-term deleterious impact on their psychological well-being. However, participants also described encounters with individuals who endeavored to initiate a collaborative, informative, and compassionate approach. Four key themes emerged consistently across the trajectory of participants' involuntary admission experiences: feeling trapped and coerced, feeling disengaged and unsupported, admission-induced distress, and person-centered encounters. CONCLUSIONS: This qualitative study of service users' views across the entire trajectory of their involuntary admission identified a number of factors that should be addressed to reduce the negative impact of involuntary admission. A multifaceted strategy could include ongoing education and training of all stakeholders in the principles and practices of person-centered care, repeated provision of accessible information and emotional support to service users during all stages of involuntary admission, and a shift in culture to one that minimizes the traumatic impact of forced detention on individuals' psychological well-being. PMID- 28669293 TI - Degradation of polyvinyl alcohol by a novel bacterial strain Stenotrophomonas sp. SA21. AB - : In this study, polyvinyl alcohol (PVA)-degrading bacteria were screened from oil sludge using PVA as a sole source of carbon in the culture medium. A novel strain, SA21, was obtained and identified as a member of the Stenotrophomonas genus based on the analysis of a partial 16S rDNA nucleotide sequence, morphological and biochemical characteristics, and phylogenetic analysis. This Stenotrophomonas isolate had not previously been reported as a PVA-degrading bacterium. Stenotrophomonas sp. strain SA21 degraded 90% of the PVA present in the culture medium after 4 days. The effect of nitrogen sources on the production of PVA-degrading enzyme involved in the biodegradation process was significant, and the enzymatic activity reached 82 U/ml when ammonium nitrate or urea was used in the optimized medium. The information obtained in this study will provide a foundation for improving industrial wastewater treatment. ABBREVIATIONS: DCW: dry cell weight; FTIR: Fourier Transform Infrared Spectroscopy; NCBI: National Center for Biotechnology Information; PCR: polymerase chain reaction; PVA: polyvinyl alcohol; SEM: scanning electron microscope. PMID- 28669294 TI - Unilateral thalamic and pallidal deep brain stimulation for idiopathic hemidystonia: results of individual and combined stimulations. Case report. AB - Pallidal stimulation has been the usual surgical treatment for dystonia in the last decades. The continuous investigation of the physiopathology and the motor pathways involved leads to the search for complementary targets to improve results. The authors present the case of a 37-year-old woman who had suffered from idiopathic hemidystonia with hyperkinetic and hypokinetic movements for 11 years, and who was treated with deep brain stimulation. A brief literature review is also provided. The globus pallidus internus and the ventral intermediate/ventral oral posterior complex of the thalamus were stimulated separately and simultaneously for 3 months and compared using the Burke-Fahn Marsden Dystonia Rating Scale and the Global Dystonia Severity Rating Scale, with a 3.5-year follow-up. The synergism of multiple-target stimulation resulted in a complete improvement of the mixed dystonic symptoms. PMID- 28669295 TI - Nerve transfer versus muscle transfer to restore elbow flexion after pan-brachial plexus injury: a cost-effectiveness analysis. AB - OBJECTIVE Pan-brachial plexus injury (PBPI), involving C5-T1, disproportionately affects young males, causing lifelong disability and decreased quality of life. The restoration of elbow flexion remains a surgical priority for these patients. Within the first 6 months of injury, transfer of spinal accessory nerve (SAN) fascicles via a sural nerve graft or intercostal nerve (ICN) fascicles to the musculocutaneous nerve can restore elbow flexion. Beyond 1 year, free-functioning muscle transplantation (FFMT) of the gracilis muscle can be used to restore elbow flexion. The authors present the first cost-effectiveness model to directly compare the different treatment strategies available to a patient with PBPI. This model assesses the quality of life impact, surgical costs, and possible income recovered through restoration of elbow flexion. METHODS A Markov model was constructed to simulate a 25-year-old man with PBPI without signs of recovery 4.5 months after injury. The management options available to the patient were SAN transfer, ICN transfer, delayed FFMT, or no treatment. Probabilities of surgical success rates, quality of life measurements, and disability were derived from the published literature. Cost-effectiveness was defined using incremental cost effectiveness ratios (ICERs) defined by the ratio between costs of a treatment strategy and quality-adjusted life years (QALYs) gained. A strategy was considered cost-effective if it yielded an ICER less than a willingness-to-pay of $50,000/QALY gained. Probabilistic sensitivity analysis (PSA) was performed to address parameter uncertainty. RESULTS The base case model demonstrated a lifetime QALYs of 22.45 in the SAN group, 22.0 in the ICN group, 22.3 in the FFMT group, and 21.3 in the no-treatment group. The lifetime costs of income lost through disability and interventional/rehabilitation costs were $683,400 in the SAN group, $727,400 in the ICN group, $704,900 in the FFMT group, and $783,700 in the no-treatment group. Each of the interventional modalities was able to dramatically improve quality of life and decrease lifelong costs. A Monte Carlo PSA demonstrated that at a willingness-to-pay of $50,000/QALY gained, SAN transfer dominated in 88.5% of iterations, FFMT dominated in 7.5% of iterations, ICN dominated in 3.5% of iterations, and no treatment dominated in 0.5% of iterations. CONCLUSIONS This model demonstrates that nerve transfer surgery and muscle transplantation are cost-effective strategies in the management of PBPI. These reconstructive neurosurgical modalities can improve quality of life and lifelong earnings through decreasing disability. PMID- 28669296 TI - A neurophysiological approach to nerve transfer to restore upper limb function in cervical spinal cord injury. AB - A successful nerve transfer surgery can provide a wealth of benefits to a patient with cervical spinal cord injury. The process of surgical decision making ideally uses all pertinent information to produce the best functional outcome. Reliance on clinical examination and imaging studies alone can miss valuable information on the state of spinal cord health. In this regard, neurophysiological evaluation has the potential to effectively gauge the neurological status of even select pools of anterior horn cells and their axons to small nerve branches in question to determine the potential efficacy of their use in a transfer. If available preoperatively, knowledge gained from such an evaluation could significantly alter the reconstructive surgical plan and avoid poor results. The authors describe their institution's approach to the assessment of patients with cervical spinal cord injury who are being considered for nerve transfer surgery in both the acute and chronic setting and broadly review the neurophysiological techniques used. PMID- 28669297 TI - Establishing reconstructive neurosurgery as a subspecialty. AB - Neurosurgery is experiencing the emergence of a new subspecialty focused on function restoration. New, evolving, and reappraised surgical procedures have provided an opportunity to restore function to many patients with previously undertreated disorders. Candidates for reconstruction were previously limited to those with peripheral nerve and brachial plexus injuries, but this has been expanded to include stroke, spinal cord injury, and a host of other paralyzing disorders affecting both upper and lower motor neurons. Similar to the recent evolution of the well-established subdisciplines of spinal and vascular neurosurgery, reconstructive neurosurgery requires the adaptation of techniques and skills that were not traditionally a part of neurosurgical training. Neurosurgeons-as the specialists who already manage this patient population and possess the requisite surgical skills to master the required techniques-have a unique opportunity to lead the development of this field. The full development of this subspecialty will lay the foundation for the subsequent addition of emerging treatments, such as neuroprosthetics and stem cell-based interventions. As such, reconstructive neurosurgery represents an important aspect of neurosurgical training that can ameliorate many of the deficits encountered in the traditional practice of neurosurgery. PMID- 28669298 TI - Letter to the Editor. Surgical strategy for craniopharyngiomas and the tumor infundibulum relationship. PMID- 28669299 TI - Introduction. Neurosurgical rehabilitation. PMID- 28669301 TI - Editorial. Advancement in brain-machine interfaces for patients with tetraplegia: neurosurgical perspective. PMID- 28669300 TI - Contralateral C-7 transfer: is direct repair really superior to grafting? AB - It is not uncommon for a severe traumatic brachial plexus injury to involve all 5 roots, resulting in a flail upper limb. In such cases, surgical reconstruction is often palliative, providing only rudimentary function. Nerve transfers are the mainstay of reconstructive strategies due to the predominance of root avulsions. Consistent results are obtained only for restoration of shoulder stability and elbow flexion, whereas restoring useful hand function remains a challenge. The transfer of the contralateral C-7 (cC-7) is commonly used in an attempt to restore basic hand function, but results are notoriously unreliable and inconsistent. Shu-feng Wang and colleagues recently proposed a potentially more successful permutation of this procedure. They advocated direct approximation of the cC-7 to the lower trunk on the paralyzed side, thus avoiding the interposition of nerve grafts. This technique involves a lengthy dissection of the cC-7 transfer across the midline via a prespinal route, as well as extensive mobilization of the ipsilateral lower trunk by cutting a subset of its branches, adducting the arm, and (if necessary) shortening the humerus. Each of these steps is indispensable to achieve direct approximation of the nerve ends. Many surgeons have tried to emulate Wang's strategy. However, the technical difficulties involved have forced recourse to interposition of nerve grafts once again. The authors report their observations in the first 22 patients in whom they performed this procedure. Direct cC-7 repair via the prespinal route was performed in 12 patients. Shortening of the humerus was necessary in 9 of these 12 patients. In 10 patients, a direct repair was not feasible and nerve grafting was performed. The median follow-up period was 26 months for the direct coaptation group and 28.5 months for the nerve graft group. In the direct repair group, 10 of the 12 patients regained Medical Research Council Grade 3 flexion of the wrist and of the middle, ring, and little fingers, while the remaining 2 patients had Grade 2 function. Flexion appeared 12-14 months after the operation. At the latest follow up, these patients could activate the wrist and hand without requiring significant augmentation maneuvers in the donor limb. In contrast, repair requiring interposition grafts resulted in Grade 3 strength in only 2 of 10 patients, while 7 had Grade 2 strength, and 1 experienced failure. In all grafted cases, the patient had to forcibly contract the contralateral pectoralis major and triceps muscles to produce the weak movements on the reconstructed side. In this small series, the authors demonstrated a distinct advantage associated with the avoidance of grafts when transferring the cC-7 to restore hand function. The authors conclude that efforts to achieve direct approximation of the donor C-7 and the recipient lower trunk are necessary and justified. PMID- 28669302 TI - The relationship between Vesalius and the Borgarucci family. AB - Two of the four brothers Borgarucci were medical doctors and in one way or another, be it distantly, connected with the great master Vesalius. Giulio Borgarucci was a physician, who became a Calvinist and emigrated to England where he treated many noblemen and friends of Queen Elisabeth I. He was present at a conversation between the Italian writer and traveler Pietro Bizzari and the Venetian jeweler who witnessed Vesalius' death in Zakynthos. Prospero Borgarucci became professor of anatomy and surgery in Padua, some 20 years after Vesalius. He published several treatises on anatomy, pestilential disease, and materia medica. Prospero Borgarucci became physician to Queen Catherine de Medicis in France, and to Archduke Karl II of Habsburg in Graz. His most important work is the so-called Chirurgia Magna of Vesalius. Text and illustrations of this spurious Vesalian work point to the use of passages of the Epitome, surgical college notes and copied Vesalian images in Borgarucci's Chirurgia Magna. PMID- 28669303 TI - Are Drug-Induced Sedation Endoscopy-Based Predictors Better Predictors of Uvulopalatopharyngoplasty Outcomes? PMID- 28669304 TI - Gland Preservation in Patients Undergoing Sialoendoscopy. AB - Objective Sialoendoscopy is a minimally invasive technique for the treatment of obstructive sialadenitis. We aim to describe treatment considerations and report our ultimate rate of gland preservation. Study Design Case series with chart review. Setting Academic tertiary hospital. Subject and Methods A total of 128 consecutive sialoendoscopy cases for obstructive sialadenitis between 2009 and 2015 were evaluated. Procedures included endoscopic stricture dilation, basket assisted stone retrieval, Holmium laser lithotripsy, and combined endoscopic transoral stone excision. Resolution of symptoms, need for additional procedures, and rate of subsequent adenectomy were investigated. Results Sialoendoscopy was completed in 120 of 128 patients (94%). There were 87 parotid gland cases and 41 submandibular gland cases. Endoscopic stricture dilation was attempted in 97 patients and successful in 99%. A sialolith was identified in 31 cases and removed by basket-assisted stone retrieval (10 cases), Holmium:YAG laser stone fragmentation (10 cases), and combined endoscopic transoral stone extraction (4 cases). In 8 cases overall, sialoendoscopy failed, with immediate adenectomy. At a mean follow-up of 18 months, 39 patients (33%) reported recurrence of symptoms, with 90% in the stricture group. For the entire cohort, gland preservation occurred in 112 of 128 patients (88%). Conclusions Sialoendoscopy is an effective technique, with few patients requiring additional procedures. Newer interventional approaches allow for stone retrieval without adenectomy. Patients in the stricture group were more likely to have recurrent symptoms as compared with the sialolithiasis group but often benefit from additional sialoendoscopic procedures, leading to a high overall rate of long-term gland preservation of 91%. PMID- 28669305 TI - Association between Nasal Obstruction and Risk of Depression in Chronic Rhinosinusitis. AB - Objective Chronic rhinosinusitis (CRS) is associated with an increased risk for depression. Since nasal obstruction is a symptom of CRS that is treatable, we sought to characterize its impact on the risk for depression in CRS. Study Design Prospective cross-sectional cohort of 94 patients with CRS. Setting Academic tertiary care rhinology clinic. Subjects and Methods Patients with CRS without vasculitis, cystic fibrosis, sarcoidosis, immunodeficiency, or sinonasal malignancy. Risk for depression was assessed with the 2-item Patient Health Questionnaire (PHQ-2) while nasal obstruction was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) instrument. Multivariate logistic regressions were performed to seek association between NOSE and PHQ-2 scores. Analysis of receiver operating characteristic (ROC) curves defined a NOSE threshold for detecting participants with PHQ-2 greater than 1. Results Of the 94 participants, the mean NOSE score was 47.3, and 29.8% of patients had a PHQ-2 score greater than 1. We found an elevated NOSE score was associated with having a PHQ-2 score greater than 1 (adjusted odds ratio, 1.03; 95% CI, 1.01-1.05; P = .001). Alternatively, a 23-point increase in NOSE score was associated with a 1.5 fold increase in PHQ-2 score (adjusted relative risk, 1.02; 95% CI, 1.01-1.03; P < .001). ROC analysis identified an optimal NOSE threshold of 42.5 for detecting participants with PHQ-2 greater than 1, with 82.1% sensitivity and 50.0% specificity. Conclusions The impact of nasal obstruction is associated with an increased risk for depression in patients with CRS. Assessing for severe nasal obstruction may help to identify those patients with CRS with the highest risk for depression. PMID- 28669307 TI - Multimodality Treatment of Early-Stage Tonsil Cancer. AB - Objective Compare survival outcomes between unimodality and multimodality treatments for early-stage tonsil squamous cell carcinoma (SCC). Study Design and Setting Review of the National Cancer Database. Subjects and Methods Patients were selected if they were <70 years old with clinical stage I-II SCC of the tonsil, as documented in the National Cancer Database from 1998 to 2011. Palliative and nonstandard treatments were excluded. Propensity score matching was performed, controlling for tumor stage, age, race, comorbidity, insurance status, and year of diagnosis. Overall survival (OS) was compared with the Kaplan Meier method and log-rank test. Results We identified 3247 patients. Radiotherapy (RT) was delivered in 1295 patients (39.9%), surgery in 824 (25.4%), and surgery + RT in 1128 (34.7%). Patients treated with surgery + RT had the highest 5-year OS (81.1%), followed by surgery (67.4%) and RT (63.4%; P < .001). In a propensity score-matched subpopulation of 2378 patients, the 5-year OS was 78.8% for surgery + RT, 66.7% for surgery, and 64.5% for RT ( P < .001). Among patients who underwent surgical tonsillectomy plus elective neck dissection and/or adjuvant RT, the 5-year OS was equal ( P = .29), and all were superior to RT alone ( P < .001). Conclusion Multimodality treatment is associated with the greatest survival in early-stage tonsil cancer. The addition of tonsillectomy to RT confers a 20% increase in survival. The current guidelines might not offer the most effective treatment. An up-front surgical approach, followed by appropriately selected adjuvant therapy, may result in improved survival for early-stage tonsil SCC. These findings merit investigation in a prospective clinical trial. PMID- 28669308 TI - The Role of In-Office Ultrasound in the Diagnosis of Neck Masses. AB - To evaluate the efficacy of otolaryngologist-performed in-office ultrasound (US) in the clinical assessment of lateral neck masses, we performed a retrospective review of patients with lateral neck masses who had both a surgeon-performed US and US-guided fine-needle aspiration (USGFNA) at our tertiary academic center from 2012 to 2015. Fifty-nine patients were included. USGFNA results included 32 (54%) malignant lesions, 23 (39%) benign lesions, and 4 (6%) nondiagnostic lesions. USGFNA demonstrated 85% accuracy. In 22 (37%) patients, in-office US revealed additional findings that were not identified on physical examination (eg, nonpalpable lymph nodes or elucidated anatomical structures), which either assisted in surgical planning or altered treatment. In-office US and USGFNA on initial evaluation by the otolaryngologist augment physical examination and have potential value as the primary imaging and diagnostic modality in the workup of lateral neck masses. PMID- 28669309 TI - Outcomes in Adult Sinonasal Rhabdomyosarcoma. AB - Objective To describe patient demographics, histology, treatment modalities, and survival associated with adult sinonasal rhabdomyosarcoma. Study Design Retrospective review of a national database. Setting Tertiary medical center. Subjects and Methods Patient demographics, tumor histology, treatment modalities, and survival trends were examined for patients aged >=18 years who were diagnosed with sinonasal rhabdomyosarcoma between 2004 and 2013 with the National Cancer Database. Kaplan-Meier analysis and the log-rank tests were performed to determine the unadjusted association between overall survival and various patient and disease characteristics. Results A total of 186 patients were identified; 5 year overall survival was 28.4%. Over half of patients were between 18 and 35 years old at diagnosis (53.8%), which was associated with improved 5-year overall survival over patients >35 years old (31.9% vs 24.4%, P = .014). Alveolar sinonasal rhabdomyosarcoma was most common (66.7%). There was no statistical difference in 5-year overall survival between alveolar and embryonal subtypes (30.5% vs 41.6%, P > .05). Metastatic disease was present in 27.7% of patients and was associated with worse 5-year overall survival (14.7% vs 33.9%, P < .0001). The majority of patients were treated with chemotherapy with adjuvant radiation (49.5%). A quarter of patients were treated with surgery plus chemoradiation (25.8%). Conclusion We present the largest analysis of adult sinonasal rhabdomyosarcoma using a standardized national based database. Adult sinonasal rhabdomyosarcoma has a very poor prognosis independent of histologic subtype. The small number of surgical cases limits the ability of the analysis to accurately compare treatment with chemoradiation with and without surgery. PMID- 28669310 TI - Comparing Cancellous Bone Volume of the Manubrium to Iliac Crest in Fresh Cadavers. AB - Objective The iliac crest is the gold standard for cancellous bone grafting. This site is distant from head and neck reconstruction and may lead to significant postoperative morbidity. We propose an alternative harvest site within the head and neck with potentially less mobility deficits, the manubrium. Study Design Fresh-frozen cadaveric study. Setting Gross anatomy laboratory. Subjects and Methods Access to 18 cadavers was granted from the Medical Education and Research Institute in Memphis, Tennessee. The anterior iliac crests were exposed and H type osteotomies performed. The manubrium was accessed through a substernal notch incision and a cortical window created through the anterior manubrium. Cancellous bone was harvested from these sites. Cadaveric demographics and noncompressed and compressed volumes were recorded with statistical comparisons. Results The population was predominantly male (12/18) with a mean age of 69.6 (95% confidence interval [CI], 64.0-75.3) years. The mean body mass index was 22.9 (95% CI, 18.8 27.1) kg/m2 with no sex propensity. Uncompressed volumes did not vary, ranging from 6.4 to 7.5 mL. Compressed volumes (mL) for the right iliac crest (4.3; 95% CI, 3.0-5.6), left iliac crest (3.5; 95% CI, 2.7-4.2), and manubrium (2.4; 95% CI, 1.8-3.0) varied (1-way analysis of variance: F(2, 51) = 4.63; P < .02). Furthermore, there was correlation between compressed volumes taken from either area ( r = 0.58; P < .02). Conclusions The manubrium can be used for cancellous bone grafting. This site affords a proximity to the head and neck rather than the distant iliac crest but with slightly lower yields. Potential applications include reconstructing small mandibular defects, mandible nonunion, or alveolar bone grafting. PMID- 28669311 TI - Description of OPRA: A Danish database designed for the analyses of risk factors associated with 30-day hospital readmission of people aged 65+ years. AB - AIMS: To describe the construction of the Older Person at Risk Assessment (OPRA) database, the ability to link this database with existing data sources obtained from Danish nationwide population-based registries and to discuss its research potential for the analyses of risk factors associated with 30-day hospital readmission. METHODS: We reviewed Danish nationwide registries to obtain information on demographic and social determinants as well as information on health and health care use in a population of hospitalised older people. The sample included all people aged 65+ years discharged from Danish public hospitals in the period from 1 January 2007 to 30 September 2010. We used personal identifiers to link and integrate the data from all events of interest with the outcome measures in the OPRA database. The database contained records of the patients, admissions and variables of interest. RESULTS: The cohort included 1,267,752 admissions for 479,854 unique people. The rate of 30-day all-cause acute readmission was 18.9% ( n=239,077) and the overall 30-day mortality was 5.0% ( n=63,116). CONCLUSIONS: The OPRA database provides the possibility of linking data on health and life events in a population of people moving into retirement and ageing. Construction of the database makes it possible to outline individual life and health trajectories over time, transcending organisational boundaries within health care systems. The OPRA database is multi-component and multi-disciplinary in orientation and has been prepared to be used in a wide range of subgroup analyses, including different outcome measures and statistical methods. PMID- 28669312 TI - Psychological distress among Norwegian adolescents: Changes between 2001 and 2009 and associations with leisure time physical activity and screen-based sedentary behaviour. AB - AIMS: The aim of this work was to examine psychological distress among Norwegian adolescents in relation to changes over time and the associations with leisure time physical activity and screen-based sedentary behaviour. METHODS: This cross sectional study was based on data retrieved from the Norwegian Youth Health Surveys in 2001 and 2009 in Hedmark County. Adolescents aged 15-16 years old completed a questionnaire regarding physical activity, sedentary behaviour, psychological distress and other health and lifestyle variables. The self-report Hopkins Symptom Checklist-10 was used to assess psychological distress. Multinomial logistic regression was used to analyse the associations between psychological distress, physical activity and sedentary behaviour. RESULTS: Self reported psychological distress increased significantly from 2001 to 2009 (from 19.4 to 28.2%), with the proportion of girls reporting psychological distress being twice as large as the proportion of boys. The proportion of adolescents who were physically active for ?11 hours per week increased significantly over the same period (from 6.0 to 10.4%). Sedentary behaviour ?6 hours per school day increased significantly among both sexes between 2001 and 2009. Physical activity (?11 hours) and sedentary behaviour (?6 hours) were both significantly associated with psychological distress. CONCLUSIONS: The association between physical activity, sedentary behaviour and psychological distress was weak; only high amounts of physical activity and high amounts of screen-based sedentary behaviour were associated with psychological distress. Longitudinal studies are needed to provide further insights into these associations and to understand the extent to which these variables might be causally related. PMID- 28669313 TI - Dose-dependent role of novel agents emodin and BTB14431 in colonic cancer treatment in rats. AB - BACKGROUND: BTB14431 is an in silico homolog to emodin. Both were found to possess anti-tumor effects in vitro. The aim of this work was to analyze the tumor suppressing effects of both molecules in an intraperitoneal (ip) and intravenous (iv) treated rat model (WAG-Rij). METHODS: A tumor cell suspension (CC531) was applied at the cecum after laparotomy and at the back. The rats where treated twice a day over 1 week with BTB14431, emodin and isotone sodium chloride solution (control). Treatment was applied iv or ip in a variety of dosages. Peripheral blood samples were taken before tumor application and on day 7. Twenty one days after the last day of therapy animals were euthanized and tumor growth was evaluated. RESULTS: Data showed an insignificant decrease of tumor growth after iv and ip treatment with low doses of BTB14431 and emodin. Differential blood analysis showed apoptosis. Increased doses of emodin clearly raised mortality rate. CONCLUSIONS: Apoptosis was verified but no tumor-suppressing effects could be observed for iv and ip treatment with both agents in contrast to in vitro studies in our model. Establishing a successful ip treatment model for emotion and BTB14331 requires further studies. PMID- 28669314 TI - Understanding heterogeneity in older adults: Latent growth curve modeling of cognitive functioning. AB - BACKGROUND: Clarifying relationships between specific neurocognitive functions in cognitively intact older adults can improve our understanding of mechanisms involved in cognitive decline, which may allow identification of new opportunities for intervention and earlier detection of those at increased risk of dementia. METHOD: The present study employed latent growth curve modeling to longitudinally examine the relationship between executive attention/processing speed, episodic memory, language, and working memory functioning utilizing the neuropsychological test battery from the National Alzheimer's Disease Coordinating Center. A total of 691 relatively healthy older adults (Mage = 69.07, SD = 6.49) were assessed at baseline, and 553 individuals completed three visits spanning a two-year period. RESULTS: Better cognitive performance was concomitantly associated with better functioning across domains. Subtle declines in executive attention/processing speed processes were found, while, on average, memory and language performance improved with repeated testing. Lower executive attention/processing speed performance at baseline predicted less incremental growth rate in memory. In turn, higher initial memory functioning was associated with incremental improvements in language performance. CONCLUSIONS: These results are consistent with the notion that intact executive function and attention processes are important to preserving memory functioning with advanced age, but are also the functions most susceptible to decline with age. These findings also provide further insight into the critical role of practice effects in clinical assessment practice and have implications for pharmaceutical trials. Practice effects should be routinely considered as they may give the appearance of retention of function within the cognitive domains considered to be a hallmark of Alzheimer's disease pathology. PMID- 28669315 TI - The Thermodynamics of Behavioral Health Care. PMID- 28669316 TI - Screening for PTSD symptoms in unaccompanied refugee minors: a test of the CRIES 8 questionnaire in routine care. AB - AIMS: The dramatic increase in the number of refugees in Europe presents a major public health challenge. The limited existing evidence indicates that the mental health needs of refugees are significant; unaccompanied refugee minors (URMs) constitute a particularly vulnerable group. In this study, we aimed to investigate whether a short questionnaire (Children's Revised Impact of Event Scale; CRIES-8) could be used as a screening tool for PTSD symptoms in URMs, 8-18 years old, during their routine health check-up. METHODS: Data were collected at the healthcare centre for asylum-seekers in Uppsala, Sweden. In total, 208 URMs completed the CRIES-8 during their health assessment. RESULTS: The CRIES-8 was feasible to use, showed good internal consistency and its factor structure was confirmed. Children with less than four years of education often had difficulties completing the questionnaire by themselves and needed help reading the questions. Almost all the respondents were male (98%), aged 9-18 years. The majority (81%) came from Afghanistan. About 76% scored above the cut-off and therefore were considered to be at risk of PTSD. The proportion of children who screened positive did not differ based on age, country of origin or current living arrangements. CONCLUSIONS: The CRIES-8 is a useful tool in clinical settings, however, children should be provided with reading support and instructions about how to complete the questionnaire. The high number of children who screened positive for PTSD symptoms indicates the need for a more thorough mental health assessment, and early prevention/intervention programmes to address URMs' mental health issues. PMID- 28669317 TI - Effect of piperine on the bioavailability and pharmacokinetics of rosmarinic acid in rat plasma using UPLC-MS/MS. AB - 1. The purpose of the present study was to investigate the effect of piperine (PP) on the pharmacokinetics of rosmarinic acid (RA) in rat plasma and to determine whether PP could enhance the oral bioavailability of RA via inhibition of its glucuronidation. 2. The pharmacokinetic profiles of RA between oral administration of RA (50 mg/kg) alone and in combination with different oral dose PP (20, 40, 60, and 80 mg/kg) to rats were investigated via a validated UPLC/MS/MS method. 3. The AUC and Cmax of RA were significantly increased in combination with different dose PP dose dependently, especially in the presence of 60 and 80 mg/kg PP (p < 0.01). The relative bioavailability of RA in the presence of 20, 40, 60, and 80 mg/kg PP was 1.24-, 1.32-, 2.02-, and 2.26-folds higher, respectively, compared with the control group given RA alone. Compared with RA, the pharmacokinetic modulations of RA glucuronide were even more apparent, and the glucuronidation of RA was remarkedly inhibited. 4. This study demonstrated that PP significantly improved the in vivo bioavailability of RA partly attributing to the inhibition of gut and hepatic metabolism enzymes of RA. PMID- 28669318 TI - Fronto-subcortical functional connectivity in patients with schizophrenia and bipolar disorder during a verbal fluency task. AB - OBJECTIVES: Impairments in language production are common of schizophrenia (SZ) and bipolar disorder (BD). Identifying distinct functional connectivity (FC) patterns in SZ and BD may provide biomarkers for their diagnoses. METHODS: Forty nine participants (15 SZ, 14 BD and 20 healthy controls (HC)) underwent a verbal fluency task consisting of mentally generating verbs in French, alternated with periods of silence. Functional network allowed identifying activation clusters: the medio-frontal cluster (MFC), the left subcortical cluster (LSCC) and the left fronto-lateral cluster (LFLC). FC was calculated between the average blood oxygen level-dependent signal time series in each cluster. Analyses of covariance were performed to test group differences on FC among the three paired-seed regions. RESULTS: SZ presented a significant reduced FC compared to HC within two paired seed regions between the LFLC and the LSCC and between the MFC and the LSCC while BD were not significantly different from HC. SZ compared to BD exhibited a reduced FC within one paired-seed region between the MFC and the LSCC. There was no group effect between the MFC and the LFLC. CONCLUSIONS: A specific medio prefronto-striato-thalamic functional dysconnectivity may be implicated in the pathophysiology of schizophrenia. This reduced fronto-subcortical FC could be a functional brain biomarker of schizophrenia. PMID- 28669319 TI - Serum inflammatory molecules and markers of neuronal damage in alcohol-dependent subjects after withdrawal. AB - OBJECTIVES: Our aim is to describe changes in serum concentration for the pro inflammatory factors TNF-alpha, IFN-gamma, IL-1beta, IL-8, IL-6, IL-10, IL-12 and MCP-1, for the satiety factor leptin and for factors associated with neuronal changes, neuron-specific enolase (NSE) and glial activation S100-beta protein (S100-beta), and explore their association with abstinence in alcohol-dependent subjects after withdrawal. METHODS: Serum sampling and clinical assessments from 115 alcohol-dependent subjects admitted to a psychiatric hospital for alcohol were repeated during the first 48 h of withdrawal (M0) and 1, 2, 4 and 6 months (M1, M2, M4 and M6) thereafter. Serum factors were determined with Luminex technology or by ELISA. RESULTS: The levels of TNF-alpha, IL-1beta, IL-8, IL-6, IL-12, MCP-1, and leptin decreased after withdrawal and remained low until M6, regardless of alcohol consumption. IFN-gamma levels remained constant and IL-10 levels changed only slightly. NSE levels were not modified, whereas serum S100 beta concentration increased significantly on M1 and then plateaued, regardless of abstinence status at 6 months. CONCLUSIONS: Alcohol-dependent subjects present an inflammatory condition that is not dependent on alcohol consumption. An understanding of the changes in concentration of the various proteins considered here would provide insight into the physiology of withdrawal or dependence. PMID- 28669321 TI - Factors associated with receiving an HIV test among patients admitted through the emergency unit at a Kenyan referral hospital. AB - Despite decreasing incidence, HIV is the leading cause of morbidity and mortality in Kenya. In Kisumu, HIV prevalence is ~19% and incidence is second highest in the country. There is a need to identify HIV-positive persons and link them to care. Universal testing in healthcare facilities is a strategy supported by the Kenyan government to facilitate identification of new HIV cases. The objective was to identify patterns of HIV testing in a hospital in Kisumu, Kenya, a setting where universal testing is recommended. A retrospective chart review of patients seen between January 2014 and December 2014 was conducted. We collected information on 5% of admitted patients older than 18 years of age. Chi square analysis characterized patients and Poisson regression modeling produced the relative risk of being tested. In 2014, 9071 patients were admitted from the emergency unit. From the sample, 24% of patients were recorded to have been tested for HIV. There was no significant difference in testing between genders (p = 0.99). Females with a genitourinary diagnosis were significantly more likely to be tested for HIV than other diagnoses (adjusted relative risk [aRR] = 1.79). Males with an infectious disease were 1.86 times more likely to be tested for HIV than other diagnoses, while females with pregnancy-related diagnoses were 50% less likely to be tested for HIV (aRR = 0.50). While universal testing supports a non-risk-based screening of patients, higher risk diagnoses were more likely to be tested. This study demonstrates that there is still opportunity to further practice and implement universal testing. PMID- 28669320 TI - Social-ecological factors associated with HIV infection among men who have sex with men in Jamaica. AB - In Jamaica, where homosexuality is criminalized, scant research has examined associations between sexual stigma and HIV infection. The study objective was to examine correlates of HIV infection among men who have sex with men (MSM) in Jamaica. We conducted a cross-sectional tablet-based survey with MSM in Jamaica using chain referral sampling. We assessed socio-demographic, individual, social, and structural factors associated with HIV infection. A logit-link model, fit using backwards-stepwise regression, was used to estimate a final multivariable model. Among 498 participants (median age: 24, interquartile range: 22-28), 67 (13.5%) were HIV-positive. In the multivariable model, HIV infection was associated with increased odds of socio-demographic (older age, odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.00-1.10]; residing in Kingston versus Ocho Rios [OR: 6.99, 95% CI 2.54-19.26]), individual (poor/fair versus excellent/good self-rated health [OR: 4.55, 95% CI: 1.81-11.42], sexually transmitted infection [STI] history [OR: 3.67, 95% CI: 1.61-8.38]), and structural (enacted sexual stigma [OR: 1.08, 95% CI: 1.01-1.15], having a health care provider [OR: 2.23, 95% CI: 1.06-4.66]) factors. This is among the first studies to demonstrate associations between sexual stigma and HIV infection in Jamaica. Findings underscore the need to integrate STI testing in the HIV care continuum and to address stigma and regional differences among MSM in Jamaica. PMID- 28669322 TI - Cost-effectiveness of microscopy of urethral smears for asymptomatic Mycoplasma genitalium urethritis in men in England. AB - The objective was to determine whether or not the limited use of urethral microscopy to diagnose asymptomatic and symptomatic non-chlamydial, non gonococcal urethritis (NCNGU) in men is a cost-effective strategy to avert pelvic inflammatory disease (PID), ectopic pregnancy or infertility in female partners. Outputs from a transmission dynamic model of NCNGU in a population of 16-30 year olds in England simulating the number of consultations, PID cases and patients treated over time amongst others, were used along with secondary data to undertake a cost-effectiveness analysis carried out from a health care provider perspective. The main outcome measure was cost per case of PID averted. A secondary outcome measure was cost per major outcome averted, where a major outcome is a case of symptomatic PID, ectopic pregnancy, or infertility. Offering a limited number of asymptomatic men urethral microscopy was more effective than the current practice of no microscopy in terms of reducing the number of cases of PID with an incremental cost-effectiveness ratio of L15,700, meaning that an investment of L15,800 is required to avert one case of PID. For major outcomes averted, offering some asymptomatic men urethral microscopy was again found to be more effective than no microscopy, but here an investment of L49,900 is required to avert one major outcome. Testing asymptomatic men for NCNGU in a small number of genitourinary medicine settings in England is not cost-effective, and thus by maintaining the current practice of not offering this patient group microscopy, this continues to make savings for the health care provider. PMID- 28669323 TI - What impact has tendering had on trainees? Results of a national survey by British Association for Sexual Health and HIV Trainees' Collaborative for audit, research and quality improvement projects. AB - In April 2013, local authorities gained responsibility for commissioning sexual health services in England. With many services going out to tender and resultant change in services or service provider, there is anecdotal evidence that this has impacted on the education, training and morale of genitourinary medicine (GUM) trainees. The aim of this study was to evaluate the impact of tendering on GUM trainees. An electronic survey designed by the British Association for Sexual Health and HIV Trainees' Collaborative for Audit, Research and Quality Improvement Projects (T-CARQ) was distributed to GUM trainees and newly appointed consultants. Eighty-two individuals responded (74% GUM trainees, 25% newly appointed consultants, 1% locum appointed for service). Sixty-three per cent (45/72) had experience of training within a service which was being tendered. Of these, 59% (24/41) felt their training was not considered during the tendering process and 20% (8/41) felt that it was. Forty-four per cent (18/41) felt adequately supported. Thirty per cent (12/40) reported active participation in the tendering process. On a scale of 0 (no impact) to 5 (major impact), the median score for impact of tendering on training was 2. The positive/negative impact of tendering on different training elements was rated: other than management experience the overall impact on all parameters was negative, namely morale, senior support and education. In conclusion, this survey describes the variable impact of service tendering on GUM training. Our recommendations for maintaining training standards despite tendering include actively involving trainees and education partners, inclusion of specialist GUM training in service specifications, development of guidance for commissioners and services for the management of GUM training within tendering. PMID- 28669324 TI - A prospective multicentre study of healthcare provider preference in rapid HIV testing kits: Determine versus INSTI. AB - Rapid HIV testing may circumvent the practical barriers to HIV testing in several settings. User preference of the testing kits available has been relatively underexplored. We examined healthcare provider (HCP) ratings of two validated rapid testing kits in clinical practice. From 1 July to 1 December 2012 we prospectively recruited HCPs (clinic nurses) from three outpatient clinics linked to Lausanne University Hospital, Lausanne, Switzerland. The HCPs had experience in taking blood samples but varying experience in rapid HIV testing. Participating HCPs performed rapid HIV testing using DetermineTM Combo (DETE) or INSTITM (INSTI), according to a predefined randomization sequence, and rated practical aspects of each test using a Likert scale. Seventeen HCPs of 23 approached (74%) were eligible and agreed to participate, performing a total of 336 HIV tests. Globally, the testing procedure was rated as easy or very easy by 97% (DETE) to 99% (INSTI) of tests performed. Among experienced HCPs, DETE was rated easier than INSTI for kit storage (p < 0.001) and blood collection ( P = 0.012) while INSTI was rated easier than DETE for blood application ( P = 0.001) and test interpretation ( P = 0.005). Among less experienced HCPs, both tests performed equally with the exception of test interpretation ( P < 0.001) and overall ease of use ( P = 0.05) in favour of INSTI. Of all HCPs, 94% stated they would recommend INSTI over DETE based on the time to result, ease of test interpretation and overall ease of use. Rapid HIV testing was considered easy to perform, even by inexperienced nursing staff. Whilst both tests were considered easy to use, the HCPs in this study preferred INSTI to DETE overall, due to rapid time to result, ease of test interpretation and general ease of use. PMID- 28669326 TI - Relationships of vertical facial pattern, natural head position and craniocervical posture in young Chinese children. AB - OBJECTIVE: To investigate relationships of vertical facial patterns, natural head position (NHP), and craniocervical posture in young Chinese children with skeletal Class I relationship. METHODS: Ninety-four patients with skeletal Class I relationship were classified into low, average, and high angle groups according to their mandibular plane angle (NSL/ML). Cephalometric radiographs in NHP were taken. Variables representing vertical and sagittal craniofacial morphology, head posture, and craniocervical posture were measured and compared. RESULTS: Inclinations of the mandible to the true vertical and cervical column were smallest in the high angle group and largest in the low angle group. Other variables representing head posture and craniocervical posture were largest in the high angle group, smallest in the low angle group. Inclinations of ramus to cervical column were largest in the high angle group and smallest in the low angle group. DISCUSSION: Subjects with large NSL/ML angles showed extended head and craniocervical posture, while subjects with small NSL/ML angles exhibited flexed head and craniocervical posture. PMID- 28669325 TI - Assessing association between IWantTheKit risk quiz tool and sexually transmitted infection positivity in male users for sexually transmitted infection screening. AB - Our previous pilot study during 2010-2013, based on the IWantTheKit (IWTK) home self-collection program for sexually transmitted infections (STIs), showed that voluntary risk score tool predicted STIs well in female volunteers compared to their male counterparts. Risk score became a required part of the IWTK program in August 2013. We investigated association of IWTK risk score and presence of STI in 592 male participants living in Maryland and Washington DC from August 2013 to April 2015. The risk score quiz includes questions on demographic and sexual risk behavior. Data were analyzed using the Cochran-Armitage test for trend to determine if prevalence of STIs (Chlamydia, gonorrhea, or trichomoniasis) increased with the higher risk score category. Overall, 57% of participants were aged < 30 years (mean: 30.1 +/- 9.3 years); 42% white, 42% black, and 16% other races. The majority (67%) of participants had medium risk scores of 3-6, followed by high scores of 7-10 (22%), and 0-2 (11%). The overall prevalence of STIs was 10.5% (62/592). The prevalence of STIs was 3.1% for users with risk scores of 0 2, 10.4% for those with scores 3-6, and 14.3% for those with scores 7-10 (trend test: p = 0.019). Medium and high IWTK risk scores successfully predicted the probability of STIs in male participants after elimination of potential selection biases. PMID- 28669327 TI - Reproductive factors, lifestyle and dietary habits among pregnant women in Greenland: The ACCEPT sub-study 2013-2015. AB - BACKGROUND: During past decades the formerly active lifestyle in Greenland has become sedentary, and the intake of traditional food has gradually been replaced with imported food. These lifestyle and dietary habits may affect pregnant women. AIM: To describe age and regional differences in reproductive factors, lifestyle and diet among Greenlandic pregnant women in their first trimester. METHODS: A cross-sectional study during 2013-2015 including 373 pregnant women was conducted in five Greenlandic regions (West, Disko Bay, South, North and East). Interview based questionnaires on reproductive factors, lifestyle and dietary habits were compared in relation to two age groups (median age <=28 years and >28 years). RESULTS: In total, 72.4% were Inuit, 46.6% had BMI >25.0 kg/m2, 29.0% were smoking during pregnancy and 54.6% had used hashish. BMI, educational level, personal income, previous pregnancies and planned breastfeeding period were significantly higher in the age group >28 years of age compared to the age group <=28 years of age. In region Disko Bay, 90.9% were Inuit, in region South more had a university degree (37.9%) and region East had the highest number of previous pregnancies, the highest number of smokers during pregnancy and the most frequent intake of sauce with hot meals and fast-food. CONCLUSIONS: Overall a high BMI and a high smoking frequency were found. Age differences were found for BMI and planned breastfeeding period, while regional differences were found for smoking and intake of sauce with hot meals and fast-food. Future recommendations aimed at pregnant women in Greenland should focus on these health issues. PMID- 28669328 TI - Is Nonalcoholic Fatty Liver Disease Indeed the Hepatic Manifestation of Metabolic Syndrome? AB - Metabolic syndrome (MetS) is a cluster of central obesity, dyslipidaemia, insulin resistance and hypertension. MetS frequently co-exists with non-alcoholic fatty liver disease (NAFLD), which is characterized by fat accumulation in the liver in the absence of alcohol abuse, viral hepatitis and other causes of chronic liver diseases. Both MetS and NAFLD are associated with an increased risk for cardiovascular disease and type 2 diabetes mellitus. There are also other associations between MetS and NAFLD. In the present narrative review, we discuss the links between MetS and NAFLD in terms of prevalence, risk factors and treatment (both lifestyle interventions and drug therapy). Such associations highlight the common pathophysiological pathways of these metabolic disorders, although data for an independent association are not robust. Nevertheless, NAFLD may be regarded as a hepatic manifestation of MetS. PMID- 28669329 TI - Effect of Low (5 mg) vs. High (20-40 mg) Rosuvastatin Dose on 24h Arterial Stiffness, Central Haemodynamics, and Non-Alcoholic Fatty Liver Disease in Patients with Optimally Controlled Arterial Hypertension. AB - OBJECTIVE: Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH). METHODS: Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes. RESULTS: Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose. CONCLUSION: Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference. PMID- 28669330 TI - The Quality of Life and Professional Future among Tunisian Workers Suffering from Occupational Asthma. AB - OBJECTIVE: To identify the factors influencing the quality of life and professional future of patients suffering from occupational asthma. METHOD: A cross-sectional study of patients compensated for occupational asthma in Tunisian center during 2004-2011. The study of quality of life was based on the Asthma Quality of Life Questionnaires (AQLQ). Some related patents were also discussed. RESULTS: One hundred twenty-nine patients were compensated and the mean age was 40.8 +/- 7.6 years. The global score of quality of life was 3.65 +/- 0.75. The group of employees having a "bad quality of life" included 82 patients (77.3%), 73 patients kept the same job (56.6%), 20.9% had an occupational reclassification, 13.9% were dismissed, 6.2% abandoned their job and 2.3% were put in disability. The analytical study of the quality of life showed that: - The global score was correlated with the fact of keeping the same job and the application of preventive measures. - The score in the "symptoms" area was correlated with working in the textile sector and the association with an occupational rhinitis. - The score in the "activity limitation" area was correlated with age. The analytical study of the professional future revealed that maintaining the same job was correlated with low rates of permanent partial disability. CONCLUSION: Our study revealed the need to implement early preventive measures and to establish a systematic review of the permanent partial disability rate attributed to workers suffering from occupational asthma before the end of the legal period of five years. PMID- 28669331 TI - Patients with Increased Non-Ceruloplasmin Copper Appear a Distinct Sub-Group of Alzheimer's Disease: A Neuroimaging Study. AB - BACKGROUND: Meta-analyses show that copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in serum is higher in a percentage of Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp Cu cut-off sustains the existence of a copper AD metabolic subtype. OBJECTIVE: In order to find evidence of the existence of a detectable metabolic subtype of AD associated to copper abnormalities, we explore the hypothesis of a neuroimaging pattern heterogeneity in an homogenous and well characterized AD population classified in two groups by the stratification of patients on the basis non-Cp Cu cut-off. METHOD: We assessed levels of copper, ceruloplasmin, non-Cp Cu, cerebrospinal levels of total Tau protein (h-tau), Thr 181 phosphorylated tau protein (P-tau) and beta-amyloid 1-42, and APOE4 genotype in 66 AD patients and compared neuroimaging indices of a visual rating scale of cerebral atrophy and neurovascular burden in AD patients stratified in 'Normal' and 'High' non-Cp Cu groups. RESULTS: The stratification for non-Cp Cu originated AD groups which did not differ for medial temporal lobe atrophy, periventricular hyperintensities, deeper hyperintensities (including frontal, parietooccipital and temporal white matter hyperintensities), infratentorial hyperintensities indices, while they differed for global atrophy. More specifically, AD patients within the high non-Cp Cu group had a less severe burden of global atrophy (p=0.042). CONCLUSION: This neuroimaging heterogeneity between AD groups is suggestive of the existence of a copper metabolic subtype of AD; non-Cp Cu appears a good marker of this copper AD. PMID- 28669332 TI - Biomarkers in Cardiomyopathies and Prediction of Sudden Cardiac Death. AB - BACKGROUND: Cardiomyopathies are a major cause of heart diseases in all age groups leading to heart failure and arrhythmias. Additionally, they are an important cause of sudden cardiac death (SCD) in young people. Major advances have been made in the understanding of the complex and manifold underlying pathomechanisms and their correlating blood measured biomarkers. The aim of this review is to outline the role of such biomarkers in non-ischemic cardiomyopathies and their role in the prediction of SCD. METHODS: A search in bibliographic databases was conducted. Most relevant references focusing on blood measured biomarkers in non-ischemic cardiomyopathies and biomarkers in SCD were reviewed regarding their role in pathophysiology and clinical practice. The references contain prospective and retrospective studies as well as meta-analyses. Current guidelines were analyzed concerning the implementation of biomarkers. RESULTS: Most research on the role of biomarkers in cardiomyopathies is focused on myocardial stress (natriuretic peptides), injury (troponins), inflammation, and remodelling (fibrosis marker). Various studies suggest a potential application of biomarkers in diagnostics, prognosis and treatment response. Further approaches include microRNAs or multimarker approaches. Biomarkers to delineate patients being at risk for SCD have demonstrated predictive ability and could improve risk stratification strategies. CONCLUSION: To improve the prognosis of cardiomyopathies an early onset of treatment is needed. This necessitates further research and a better integration of biomarkers in the diagnostic work-up of cardiomyopathies. Identification of patients being at risk for SCD is mandatory, however, reliable data of biomarkers are still lacking. PMID- 28669333 TI - Biomarkers in Stable Coronary Artery Disease. AB - BACKGROUND: Coronary Artery Disease (CAD) is the most common reason for death in the western hemisphere. Therefore, a well-functioning risk-management has been established over the past decades with uprising interest in 'novel' biomarkers to predict adverse coronary events and detect patients with subclinical CAD. This review will focus on selected biomarkers belonging to the family of inflammatory markers (fibrinogen or hs-CRP) or to the family of lipid-associated markers (Lipoprotein associated PA2 or Lipoprotein a) and organ-specific biomarkers (hs troponin, Cystatin C or NTproBNP). METHODS: This review is based on a pubmed search focusing on the biomarkers fibrinogen, hs-CRP, Lipoprotein associated PA2, Lipoprotein a, hs-troponin, NT-proBNP and Cystatin C. RESULTS: The search retrieved 149 references containing meta-analysis, prospective and retrospective studies concerning the usage of the selected biomarkers in risk prediction and detection of CAD. Despite clinical studies, current guidelines of the European Society of Cardiology (ESC), the American Heart Association (AHA) and the Canadian Cardiovascular Society (CCS) were analyzed regarding their recommendation of the implementation of biomarkers in clinical routine. The review identified promising stand-alone biomarkers and multi-marker risk models for CAD patients. CONCLUSION: Novel biomarkers detect patients at risk beyond established risk scores. However, an ideal biomarker fulfilling all necessary criteria does still not exist. PMID- 28669334 TI - Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer. AB - Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches. PMID- 28669335 TI - Regulation of MicroRNAs by Phytochemicals: A Promising Strategy for Cancer Chemoprevention. AB - A growing body of evidence suggests that phytochemicals are potentially able to affect a variety of cellular processes, including proliferation, apoptosis, cell cycle control, angiogenesis, inflammation, and DNA repair. Phytochemicals may typically play pleiotropic regulatory roles in cancer cells. Chemoprevention, which can be achieved by using these natural agents, has emerged as a helpful strategy to manage a variety of malignancies. With regard to cancer-associated chemopreventive mechanisms, phytochemicals can act by modulating microRNAs (miRNAs) and their target genes. This review aims to present an overview of recent findings on the effects of some wellcharacterized bioactive phytochemicals on miRNA regulation in different cancer types. The potential use of these phytochemicals for the chemoprevention and treatment of cancer is also discussed. PMID- 28669336 TI - The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies. AB - Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac(r), LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors. PMID- 28669337 TI - Synthetic Lethality: From Research to Precision Cancer Nanomedicine. AB - Cancer is an evolutionary disease with multiple genetic alterations, accumulated due to chromosomal instability and/or aneuploidy and it sometimes acquires drug resistant phenotype also. Whole genome sequencing and mutational analysis helped in understanding the differences among persons for predisposition of a disease and its treatment non-responsiveness. Thus, molecular targeted therapies came into existence. Among them, the concept of synthetic lethality have enthralled great attention as it is a pragmatic approach towards exploiting cancer cell specific mutations to specifically kill cancer cells without affecting normal cells and thus enhancing anti-cancer drug therapeutic index. Thus, this approach helped in discovering new therapeutic molecules for development of precision medicine. Nanotechnology helped in delivering these molecules to the target site in an effective concentration thus reducing off target effects of drugs, dose and dosage frequency drugs. Researchers have tried to deliver siRNA targeting synthetic lethal partner for target cancer cell killing by incorporating it in nanoparticles and it has shown efficacy by preventing tumor progression. This review summarizes the brief introduction of synthetic lethality, and synthetic lethal gene interactions, with a major focus on its therapeutic anticancer potential with the application of nanotechnology for development of personalized medicine. PMID- 28669338 TI - MicroRNA Key to Angiogenesis Regulation: MiRNA Biology and Therapy. AB - Angiogenesis is involved in maintaining normal physiological processes like embryonic development, wound healing, inflammation and reproduction. Pathogenesis of various diseases like diabetic retinopathy, rheumatoid arthritis and cancer are associated with imbalanced angiogenesis. Angiogenic stimulators and inhibitors act together for keeping angiogenic switch in balance. Recently, miRNAs have been found to regulate various stages of angiogenesis. miRNAs are 21 23 nucleotides long, single stranded, noncoding RNA molecules generated endogenously. miRNA's ability to target multiple genes within a signaling pathway makes them promising target for the development of second generation anti angiogenesis drugs. This review was conceived with the notion of availability of specific and comprehensive knowledge about AngiomiRs at one place. This will facilitate the research in basic understanding and in the development of new drugs. In this review, we have summarized the biology and therapeutic potential of the miRNAs, which are involved in controlling angiogenesis process. In miRNA biology, we have provided the updated summary of miRNAs in the regulation of endothelial cells, showed role of miRNAs in the signaling pathways of angiogenesis and, discussed the gaps in complete knowledge of mechanism. We have also provided exclusive insights regarding therapeutic potential of these miRNAs, in angiogenesis related disorders. Additionally, we have discussed the challenges in miRNA based drug delivery and updated the current efforts in the development of miRNA delivery methods. Though much research is needed to discover the complete miRNA network regulating angiogenesis but once it is done, targeting miRNA may be considered as a potential candidate for therapeutic invention against angiogenesis related disorders. PMID- 28669339 TI - DNA Fragmentation, Cell Cycle Arrest, and Docking Study of Novel Bis Spiro-cyclic 2-oxindole of Pyrimido[4,5-b]quinoline-4,6-dione Derivatives Against Breast Carcinoma. AB - BACKGROUND: Recently, it is reported that heterocycles containing pyrimidoquinoline moiety show a broad spectrum of medicinal and pharmacological properties including anticancer, anti-microbial, anti-inflammatory activities, analgesic and antiviral. In additions, spirocyclicoxindole containing compounds represent an important class of compounds that exhibit wide range of biological properties. The asymmetric chiral spiro carbon is considered to be the main criteria of the bioactivities. Spirooxindole structures represent the main skeleton for various alkaloids and pharmaceutically important compounds. Among them, the naturally occurring pyrrolidinylespirooxindole alkaloid, horsifiline that exhibits anticancer activity against human brain cancer cell lines. OBJECTIVE: The objective of this study is the synthesis of novel bis spiro-cyclic 2-oxindole of pyrimido[4,5-b]quinoline derivatives and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer. METHOD: An efficient one pot synthesis of bis spiro-cyclic 2 oxindole derivatives of pyrimido[4,5- b]quinoline-4,6-dione using 6-aminouracil, bis-isatin and dimedone has been developed. The cytotoxic effect against different human cell lines MCF7, HCT116 and A549 cell lines was evaluated. The derivative 6a, was found the most encouraging compound in this series and it was selected for molecular studies against MCF7. RESULTS: Our data indicated that compound 6a is an attractive target for breast cancer, as it inhibits proliferation, cell cycle progression and induces apoptosis of tumor cells. This inhibition is mediated by fragmentation of genomic DNA, up-regulation of [caspase 3, tumor suppressor gene p53, and pro-apoptotic gene BAX], and down-regulation of anti-apoptotic BCL2 gene. In additions it caused cell cycle arrest in S phase. This work provides an evidence of the potent effect of the new compound 6a and assists in the progress of new healing agents for cancer. CONCLUSION: We have developed an efficient method for the synthesis of novel bioactive bis spirocyclic 2-oxindole derivatives incorporating pyrimido[4,5-b]quinoline derivatives. Most of our new derivatives give potent cytotoxic effect more than the standard drug Fluorouracil (5-FU) especially, compound 6a which was the most active and promising one in this series against MCF7, HCT116, and A549 cell lines. PMID- 28669340 TI - Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells. AB - BACKGROUND: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system. OBJECTIVE: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVDelta66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVDelta66R/mIL-2. METHODS: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 +/- 4.5 mm3. RESULTS: In cell culture, expression of IL-2 attenuated virus replication of not only TANVDelta66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVDelta66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVDelta66R/mIL-2, compared to wtTANV or TANVDelta66R. CONCLUSION: We conclude that TANVDelta66R/mIL-2 is potentially therapeutic for human melanomas in the absence of T cells, and IL-2 expression resulted in an overall increase of therapeutic efficacy. PMID- 28669341 TI - JQ1, a BET Inhibitor, Synergizes with Cisplatin and Induces Apoptosis in Highly Chemoresistant Malignant Pleural Mesothelioma Cells. AB - BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an asbestos-associated tumor with poor prognosis and few therapeutic options. JQ1, a selective antagonist of BRD4, modulates transcription of oncogenes, including MPM chemoresistance associated c-Myc and Fra-1. OBJECTIVE: We investigated if JQ1 could enhance the efficacy of cisplatin against MPM. METHODS: The antiproliferative activity of cisplatin in combination with JQ1 was assessed on MPM cell lines representative of the cellular phenotypes of this tumor (epithelioid, sarcomatoid and biphasic), and on one cisplatin resistant sub-line. The combination schedule was optimized adopting a 3Dspheroid model. Drug combination effects were correlated with cell cycle distribution and senescence- associated beta-galactosidase positive cells. The expression of c-Myc and Fra-1 proteins and some apoptosis markers was assessed by immunoblotting and RT-qPCR. DNA damage and repair were evaluated by means of alkaline comet assay. RESULTS: JQ1 in combination with cisplatin elicited additive or synergistic (superadditive) antiproliferative effects on MPM cells, depending on the cell line. The combination showed tumor regression on the 3D-spheroid model. It induced increased apoptosis, along with decreased c-Myc and, sometimes, Fra-1 expression. JQ1 decreased cisplatin-induced DNA breaks in all MPM cells and increased senescence even in less proficient cells, thus enhancing the DNA Damage Response (DDR). CONCLUSION: The superadditive effect is due to c-Myc repression. The consequent DDR enhancement triggers to apoptosis induction and/or permanent growth arrest (senescence), depending on the MPM cellular context, leading to tumor regression. Thus, the pharmacological modulation of BET activity could represent a promising tool for future MPM therapy. PMID- 28669342 TI - Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia. AB - BACKGROUND: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. OBJECTIVE: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. METHOD: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. RESULTS: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. CONCLUSION: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia R388 is demonstrated by the CHA derivatives of Valine 1c or 2c. PMID- 28669343 TI - Pharmacoinformatic Approaches to Design Novel Inhibitors of Protein Kinase B Pathways in Cancer. AB - BACKGROUND: Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/ threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBalpha), Akt2 (PKBbeta), and Akt3 (PKBgamma). Besides sharing a similar structural topology, the difference in their physiological functions and tissue distribution makes Akt a cardinal node in diverse signaling pathways involving cell growth, survival, and proliferation. Various immunohistochemical studies have reported that the constitutive hyperactivation of Akt signaling is responsible for several types of human cancer, poor prognosis, as well as chemotherapeutic and radiotherapeutic resistance. Thus, inhibition of Akt activation represents a promising concept to induce cell apoptosis in various cancers and evade chemotherapeutic resistance. However, development of potent and selective inhibitors of Akt kinases as suitable antagonists remained gloomy and thus, only handful of compounds were selected for the clinical investigation but none of them could reach the market for routine clinical usage to circumvent cell proliferation and resistance to chemotherapeutic agents in cancer. Recent reports on achieving isoform selectivity by designing inhibitors against PH domain of Akt, together with availability of crystal structures of the PH domain of Akt1, open the possibility of structurebased design. METHODS: In this article, various biological regulatory networks by which Akt and its substrates regulate cell growth and survival and several SAR and QSAR strategies in combination with molecular docking studies on selective inhibitors of Akt subtypes have been highlighted to further probe the selectivity of ligand-Akt subtypes interactions. RESULTS: Structure-based drug design studies revealed that the interactions of structurally diverse compounds with Glu121, Ala123, Asn171, Asp184, Glu228 and Ala230 amino acid residues in CAT domain and Arg23, Arg25, Lys30, Asn54 and Arg86 amino acid residues within PH domain play an important role in attaining significant inhibitory potency. CONCLUSION: Isoform selective inhibition of Akt might have clinical significance and thus, should be taken into account in future investigations. Moreover, an up to date isoform selective chemical data is required to further validate already reported isoform selective binding hypothesis. PMID- 28669344 TI - p53-Mdm2 Interaction Inhibitors as Novel Nongenotoxic Anticancer Agents. AB - BACKGROUND: Cancer is a major global health problem with high mortality rate. Most of the clinically used anticancer agents induce apoptosis through genotoxic stress at various stages of cell cycle and activation of p53. Acting as a tumor suppressor, p53 plays a vital role in preventing tumor development. Tumor suppressor function of p53 is effectively antagonized by its direct interaction with murine double minute 2 (Mdm2) proteins via multiple mechanisms. Thus, p53 Mdm2 interaction has been found to be an important target for the development of novel anticancer agents. Currently, nutlin, spirooxindole, isoquilinone and piperidinone analogues inhibiting p53-Mdm2 interaction are found to be promising in the treatment of cancer. OBJECTIVE: The current review focused to scrutinize the structural aspects of p53-Mdm2 interaction inhibitors. METHODS: The present study provides a detailed collection of published information on different classes of inhibitors of p53-Mdm2 interaction as potential anticancer agents. The review highlighted the structural aspects of various reported p53-Mdm2 inhibitors for optimization. RESULTS: In the last few years, different classes of inhibitors of p53-Mdm2 have been designed and developed, and seven such compounds are being evaluated in clinical trials as new anticancer drugs. Further, to explore the role of p53 protein as a potential target for anticancer drug development, in this review, the mechanism of Mdm2 mediated inactivation of p53 and recent developments on p53- Mdm2 interactions inhibitors are discussed. CONCLUSION: Agents designed to block the p53-Mdm2 interaction may have a therapeutic potential for the treatment of a subset of human cancers retaining wild-type p53. We review herein the recent advances in the design and development of potent small molecules as p53-Mdm2 inhibitors. PMID- 28669345 TI - Significant Role of MUC1 in Development of Resistance to Currently Existing Anti cancer Therapeutic Agents. AB - As an extensively glycosylated transmembrane protein of epithelium, Mucin1 (MUC1) mostly protects cells from tensions induced by external milieu. Physiologically, during stress condition, MUC1 separates into MUC1-N and MUC1-C moieties, resulting in transduction of inward survival signals, essential for maintaining cell's functionality. Recent studies have proposed a significant correlation between MUC1 overexpression and amplification of cancer cell's proliferation and metastasis through modulation of multiple signaling pathways and cell-cell and cell-matrix interactions. It has been shown that MUC1- Cytoplasmic Domain (MUC1 CD) accelerates development of resistance to several anti-cancer therapeutic agents including bortezomib, trastuzumab and tamoxifen. Furthermore, MUC1-CD is also involved in promoting expression of multi drug resistance (MDR) genes and finally, silencing MUC1 expression was together with resensitization of human epidermal growth factor receptor 2 positive (HER2+) and/or estrogen receptor (ER+) positive breast cancer cells to bortezomib, trastuzumab and tamoxifen respectively. In this review, we briefly describe the role of MUC1 proto-oncogene in cancer cell's survival, tumor progression and metastasis and then continue with mentioning the mechanisms through which MUC1 induce resistance to various currently existing therapeutic agents in market including bortezomib, trastuzumab and tamoxifen. PMID- 28669346 TI - Crizotinib versus chemotherapy on ALK-positive NSCLC :a systematic review of efficacy and safety. AB - Introduction Crizotinib was approved to treat anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. Methods We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcome were the objective response rate (ORR) and disease control rate (DCR). Results Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR(OR: 4.97 , 95%CI: 3.16 to 7.83 ,P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy(OR: 3.42 , 95% CI: 2.33 to 5.01 , P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) were found between crizotinib-treated group and chemotherapy-treated group. Regarding SD(stable disease), chemotherapy treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity. Conclusions This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations. PMID- 28669347 TI - Evaluation of Anti-cancer Activity of Stilbene and Methoxydibenzo[b,f] oxepin Derivatives. AB - BACKGROUND: Stilbenes, 1,2-diphenylethen derivatives, including resveratrol and combretastatins, show anticancer features especially against tumor angiogenesis. Fosbretabulin, CA-4, in combination with carboplatin, is in the last stages of clinical tests as an inhibitor of thyroid cancer. The mode of action of these compounds involves suppression of angiogenesis through interfering with tubulin (de)polymerization. OBJECTIVE: We have previously synthesized five E-2 hydroxystilbenes and seven dibenzo [b,f]oxepins in Z configuration, with methyl or nitro groups at varied positions. The aim of the present work was to evaluate the anticancer activity and molecular mechanism(s) of action of these compounds. RESULTS: Two healthy, EUFA30 and HEK293, and two cancerous, HeLa and U87, cell lines were treated with four newly synthetized stilbenes and seven oxepins. Two of these compounds, JJR5 and JJR6, showed the strongest cytotoxic effect against cancerous cells tested and these two were selected for further investigations. They induced apoptosis with sub-G1 or S cell cycle arrest and PARP cleavage, with no visible activation of caspases 3 and 7. Proteomic differential analysis of stilbene-treated cells led to the identification of proteins involved almost exclusively in cell cycle management, apoptosis, DNA repair and stress response, e.g. oxidative stress. CONCLUSION: Among the newly synthesized stilbene derivatives, we selected two as potent anticancer compounds triggering late apoptosis/necrosis in cancerous cells through sub-G1 phase cell cycle arrest. They changed cyclin expression, induced DNA repair mechanisms, enzymes involved in apoptosis and oxidative stress response. Compounds JJR5 and JJR6 can be a base for structure modification(s) to obtain even more active derivatives. PMID- 28669348 TI - The Structural Bioinformatics analysis of Biophenolic Lignan-Estrogen Receptor interaction. AB - BACKGROUND: Plant lignans have proven efficacious in blocking estrogen receptors of breast cancer cells. However, available studies have mostly dealt with anti cancer effects of groups of lignans in certain foods or plants and the effects of specific lignans, especially from a molecular interaction viewpoint, has been rarely addressed in the literature. OBJECTIVE: We aimed to computationally predict the binding ability and binding strength of pinoresinol, matairesinol, lariciresinol and secoisolariciresinol as potent ligands of estrogen receptor alpha (ER-alpha), in order to study these lignans as drugs. METHODS: Blind Docking method was utilized to predict the binding orientation of lignans to their targets by AutoDock 4.2 software. Docking results of lignan-receptor complexes were compared to tamoxifen-receptor complex separately. Hydrophobic interactions and hydrogen bonds between lignans and ER were perused and the binding energy was calculated. RESULTS: The best binding affinity of tamoxifen, matairesinol, pinoresinol, lariciresinol and secoisolariciresinol were respectively -8.7, -7.5, -6.7, -6.7, -5.8 kcal/mol, and matairesinol showed the minimum binding energy than other studied lignans. Matairesinol showed the most similar interactions with tamoxifen with small molecule-receptor complex in the following residues: Leu:391, Ala:350, Ile:424 and Phe:404. CONCLUSION: Among the studied lignans, matairesinol showed the least binding energy as well as the most similar hydrophobic interactions to tamoxifen suggesting that matairesinol can display more efficacious biological activity to inhibit ER in comparison with pinoresinol, lariciresinol and secoisolariciresinol. Thus, our results introduce matairesinol as a potentially effective anti-ER drug. PMID- 28669349 TI - Recent Updates on the Therapeutic Potential of HER2 Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer. AB - HER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer. PMID- 28669350 TI - Why more research needs to be done on echinococcosis in Pakistan. AB - BACKGROUND: Echinococcosis has a worldwide geographical distribution with endemic foci on every inhabited continent. Due to the frequent outbreaks in different parts of Pakistan in the recent past, echinococcosis is being described as a neglected tropical disease and is considered one of the most neglected parasitic diseases in the country. In endemic regions, predominantly settings with limited resources, there are high numbers of echinococcosis patients, as these communities do not have access to appropriate treatment. In Pakistan, there are limited reports on echinococcosis. The disease is prevalent in human and livestock, but this has not been sufficiently explored yet. Pakistan is an agricultural country and due to the disease's zoonotic mode of transmission, there is a dire need of future research on it. The present paper is an effort to highlight the importance of echinococcosis in Pakistan. DISCUSSION: There is a dire need for future research on echinococcosis in Pakistan as very few investigations had been carried out on this topic thus far. The prevalence of the disease in neighbouring countries highlights that Pakistan might be at severe risk of this zoonotic infection and further supports the need for more research. In Pakistan, the majority of the population lives in rural areas with limited acess to proper hygienic/sanitary facilities. These conditions favour the outbreak of diseases such as echinococcosis. The limited available data could result in higher outbreaks in the future, and thus cause the already weak healthcare system to overburden. The country has a meagre annual budget for health, which is being spent on known infections such as polio, dengue fever and hepatic viral infections. A proper surveillance system for echinococcosis is required across the country as treatment is usually expensive, complicated and may require extensive surgery and/or prolonged drug therapy. Development of new/novel drugs and other treatment modalities receives very little, if any, attention. Prognostic awareness programmes against this infection involve deworming of the infected animals, improved food inspection and slaughterhouse hygiene, and public education campaigns. CONCLUSION: Future research on echinococcosis is anticipated to demonstrate whether the epidemiology, diagnosis and recombinant vaccines/antibodies relating to echinococcosis can meet the quality standards (purity, potency, safety and efficacy) defined by the World Health Organization. Research work should be carried out on the epidemiology and serodiagnosis of echinocossis in the different areas of Pakistan, which will be useful for the proper eradication of echinococcosis in this region. The health department should implement awareness-raising campaigns for the general public in order to reduce the burden of disease. PMID- 28669351 TI - A systematic review of the processes used to link clinical trial registrations to their published results. AB - BACKGROUND: Studies measuring the completeness and consistency of trial registration and reporting rely on linking registries with bibliographic databases. In this systematic review, we quantified the processes used to identify these links. METHODS: PubMed and Embase databases were searched from inception to May 2016 for studies linking trial registries with bibliographic databases. The processes used to establish these links were categorised as automatic when the registration identifier was available in the bibliographic database or publication, or manual when linkage required inference or contacting of trial investigators. The number of links identified by each process was extracted where available. Linear regression was used to determine whether the proportions of links available via automatic processes had increased over time. RESULTS: In 43 studies that examined cohorts of registry entries, 24 used automatic and manual processes to find articles; 3 only automatic; and 11 only manual (5 did not specify). Twelve studies reported results for both manual and automatic processes and showed that a median of 23% (range from 13 to 42%) included automatic links to articles, while 17% (range from 5 to 42%) of registry entries required manual processes to find articles. There was no evidence that the proportion of registry entries with automatic links had increased (R 2 = 0.02, p = 0.36). In 39 studies that examined cohorts of articles, 21 used automatic and manual processes; 9 only automatic; and 2 only manual (7 did not specify). Sixteen studies reported numbers for automatic and manual processes and indicated that a median of 49% (range from 8 to 97%) of articles had automatic links to registry entries, and 10% (range from 0 to 28%) required manual processes to find registry entries. There was no evidence that the proportion of articles with automatic links to registry entries had increased (R 2 = 0.01, p = 0.73). CONCLUSIONS: The linkage of trial registries to their corresponding publications continues to require extensive manual processes. We did not find that the use of automatic linkage has increased over time. Further investigation is needed to inform approaches that will ensure publications are properly linked to trial registrations, thus enabling efficient monitoring of trial reporting. PMID- 28669353 TI - Possible gasoline-induced chronic liver injury due to occupational malpractice in a motor mechanic: a case report. AB - BACKGROUND: Hydrocarbon-induced occupational liver injury is a well-known clinical entity among petroleum industry workers. There are many types of hydrocarbon exposure, with inhalation being the most common. Hydrocarbon-induced occupational liver injury is a rarely suspected and commonly missed etiological agent for liver injury. We report a case of a non-petroleum industry worker with chronic liver disease secondary to hydrocarbon-induced occupational liver injury caused by chronic low-grade hydrocarbon ingestion due to occupational malpractice. CASE PRESENTATION: A 23-year-old Sri Lankan man who was a motor mechanic presented to our hospital with decompensated cirrhosis. He had been chronically exposed to gasoline via inadvertent ingestion due to occupational malpractice. He used to remove gasoline from carburetors by sucking and failed to practice mouth washing thereafter. On evaluation, he had histologically proven established cirrhosis. A comprehensive history and workup ruled out other nonoccupational etiologies for cirrhosis. The patient's long-term occupational gasoline exposure and clinical course led us to a diagnosis of hydrocarbon induced occupational liver injury leading to decompensated cirrhosis. CONCLUSIONS: Hydrocarbon-induced occupational liver injury should be considered as a cause when evaluating a patient with liver injury with possible exposure in relevant occupations. PMID- 28669352 TI - Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. AB - Gout, the most prevalent inflammatory arthritis worldwide, is associated with cardiovascular and renal diseases, and is an independent predictor of premature death. The frequencies of obesity, chronic kidney disease (CKD), hypertension, type 2 diabetes, dyslipidaemias, cardiac diseases (including coronary heart disease, heart failure and atrial fibrillation), stroke and peripheral arterial disease have been repeatedly shown to be increased in gout. Therefore, the screening and care of these comorbidities as well as of cardiovascular risk factors are of outmost importance in patients with gout. Comorbidities, especially CKD, and drugs prescribed for their treatment, also impact gout management. Numerous epidemiological studies have shown the association of asymptomatic hyperuricaemia with the above-mentioned diseases and cardiovascular risk factors. Animal studies have also produced a mechanistic approach to the vascular toxicity of soluble urate. However, causality remains uncertain because confounders, reverse causality or common etiological factors might explain the epidemiological results. Additionally, these uncertainties remain unsolved despite recent studies using Mendelian randomisation or therapeutic approaches. Thus, large randomised placebo-controlled trials are still needed to assess the benefits of treating asymptomatic hyperuricaemia. PMID- 28669354 TI - Epidemic of wild-origin H1NX avian influenza viruses in Anhui, China. AB - BACKGROUND: As the natural hosts of avian influenza viruses (AIVs), aquatic and migratory birds provide a gene pool for genetic transfer among species and across species, forming transient "genome constellations." This work describes the phylogenetic dynamics of H1NX based on the complete molecular characterization of eight genes of viruses that were collected from 2014 to 2015 in Anhui Province, China. METHODS: Hemagglutination and hemagglutination inhibition tests were used to determine the hemagglutination (HA) activity of the HA subtypes. The entire genomes of the viruses were sequenced on an ABI PRISM 3500xl DNA Analyzer. The sequences were genetically analysed to study their genetic evolution using DNASTAR and MEGA 6. The pathogenic effects of the viruses were evaluated using mouse infection models. RESULTS: Seven strains of the H1 subtype avian influenza virus were isolated. Phylogenetic analysis indicated natural recombination of the H1 influenza viruses between the Eurasian lineage and the North American lineage. Some genes had high sequence identity with A/bean goose/Korea/220/2011(H9N2), which is a typical case involving viral reassortment between the Eurasian lineage and the North American lineage. The results of infection experiments in mice showed that the viruses could acquire the ability to multiply in mouse respiratory organs without adaptation. CONCLUSIONS: These findings suggest that continued surveillance of wild birds, particularly migratory birds, is important to provide early warning of possible H1 influenza epidemics and to understand the ecology of the virus. PMID- 28669355 TI - HEALTH TECHNOLOGY DISINVESTMENT WORLDWIDE: OVERVIEW OF PROGRAMS AND POSSIBLE DETERMINANTS. AB - OBJECTIVES: In the past decade, there has been a growing interest in health technology disinvestment. A disinvestment process should involve all relevant stakeholders to identify and deliver the most effective, safe, and cost-effective healthcare interventions. The aim of the present study was to describe the state of the art of health technology disinvestment around the world and to identify parameters that could be associated with the implementation of disinvestment programs. METHODS: A systematic review of the literature was performed from database inception to November 2014, together with the collection of original data on socio-economic indicators from forty countries. RESULTS: Overall, 1,456 records (1,199 from electronic databases and 257 from other sources) were initially retrieved. After analyzing 172 full text articles, 38 papers describing fifteen disinvestment programs/experiences in eight countries were included. The majority (12/15) of disinvestment programs began after 2006. As expected, these programs were more common in developed countries, 63 percent of which had a Beveridge model healthcare system. The univariate analysis showed that countries with disinvestment programs had a significantly higher level of Human Development Index, Gross Domestic Product per capita, public expenditure on health and social services, life expectancy at birth and a lower level of infant mortality rate, and of perceived corruption. The existence of HTA agencies in the country was a strong predictor (p = .034) for the development of disinvestment programs. CONCLUSIONS: The most significant variables in the univariate analysis were connected by a common factor, potentially related to the overall development stage of the country. PMID- 28669357 TI - MBD1 and MeCP2 expression in embryos and placentas from transgenic cloned goats. AB - DNA methylation is an important form of epigenetic regulation in mammalian development. Methyl-CpG-binding domain protein 1 (MBD1) and methyl-CpG-binding domain protein 2 (MeCP2) are two members of the MBD subfamily of proteins that bind methylated CpG to maintain the silencing effect of DNA methylation. Given their important roles in linking DNA methylation with gene silencing, this study characterized the coordinated mRNA expression and protein localization of MBD1 and MeCP2 in embryos and placentas and aimed to analysis the effects of MBD1 and MeCP2 on transgenic cloned goats. Our result showed that MBD1 expression of transgenic cloned embryo increased significantly at the 2-4-cell and 8-16-cell stages (P < 0.05), then decreased at the morula and blastocyst stages (P < 0.05); MeCP2 expression in transgenic cloned embryo was significant decreased at the 2-4 cell stage and increased at the 8-16-cell stage (P < 0.05). Placenta morphology analysis showed that the cotyledon number of deceased transgenic cloned group (DTCG) was significantly lower than that the normal goats (NG) and in the live transgenic cloned goats (LTCG) (P < 0.05). MBD1 and MeCP2 were clearly detectable in the placental trophoblastic binucleate cells by immunohistochemical staining. Moreover, MBD1 and MeCP2 expression in DTCG was significant higher than in the NG and the LTCG (P < 0.05). In summary, aberrant expression of methylation CpG binding proteins MBD1 and MeCP2 was detected in embryonic and placental development, which reflected abnormal transcription regulation and DNA methylation involved in MBD1 and MeCP2. These findings have implications in understanding the low efficiency of transgenic cloning. PMID- 28669356 TI - Prevalence and Predictors of Postdischarge Antibiotic Use Following Mastectomy. AB - OBJECTIVE Survey results suggest that prolonged administration of prophylactic antibiotics is common after mastectomy with reconstruction. We determined utilization, predictors, and outcomes of postdischarge prophylactic antibiotics after mastectomy with or without immediate breast reconstruction. DESIGN Retrospective cohort. PATIENTS Commercially insured women aged 18-64 years coded for mastectomy from January 2004 to December 2011 were included in the study. Women with a preexisting wound complication or septicemia were excluded. METHODS Predictors of prophylactic antibiotics within 5 days after discharge were identified in women with 1 year of prior insurance enrollment; relative risks (RR) were calculated using generalized estimating equations. RESULTS Overall, 12,501 mastectomy procedures were identified; immediate reconstruction was performed in 7,912 of these procedures (63.3%). Postdischarge prophylactic antibiotics were used in 4,439 procedures (56.1%) with immediate reconstruction and 1,053 procedures (22.9%) without immediate reconstruction (P.05). CONCLUSIONS Prophylactic postdischarge antibiotics are commonly prescribed after mastectomy; immediate reconstruction is the strongest predictor. Stewardship efforts in this population to limit continuation of prophylactic antibiotics after discharge are needed to limit antimicrobial resistance. Infect Control Hosp Epidemiol 2017;38:1048-1054. PMID- 28669358 TI - Current status of canine dirofilariosis in an endemic area of western Spain. AB - Since dirofilariosis caused by Dirofilaria immitis is a vector-borne disease, its distribution depends on environmental conditions as well as demographic factors and the management of pets by humans. In the province of Salamanca (west-central Spain) the disease has been known for many years, appearing in an area with extensive irrigated crops along the Tormes river. Because recent demographic changes have occurred in this area, the present study has been carried out with the aim of monitoring the distribution and prevalence of the disease in the canine population of this area. For that purpose, 191 dogs were analysed through antigen and microfilaria tests and geo-referenced in a map. The overall prevalence was 5.8%, although the disease was only present in dogs from municipalities with irrigated crops in which the prevalence was 16.7%. These results indicate that D. immitis continues to be present in the province of Salamanca, and that it is associated with the presence of irrigation, but with a clear decrease in the prevalence. Causes of the decrease in prevalence, as well as the potential zoonotic risk, are discussed. PMID- 28669359 TI - Radiological Growth Patterns of Prolactinomas and Nonfunctioning Adenomas. AB - OBJECTIVES: To compare growth patterns of nonfunctioning and prolactin-producing pituitary macroadenomas, and to find whether their specific growth patterns are associated with clinically significant effects on vision. MATERIALS AND METHODS: From our comprehensive provincial neuropituitary registry, we retrospectively identified 35 randomly selected patients each with nonfunctioning adenomas and prolactinomas >10 mm in any dimension. MRI scans were analyzed to determine the superior and inferior growth, volume, and maximum craniocaudal height of the adenomas. Patients underwent visual field testing at diagnosis. Continuous variables were compared using Student's t test, the Mann-Whitney U test, and ANOVA. Categorical variables were compared using the chi-square test. RESULTS: The mean height of prolactinomas (23.2+/-11.3 mm) was similar to nonfunctioning adenomas (22.3+/-9.3 mm, p=0.8), and so were mean tumor volumes (prolactinoma=5.9+/-8 ml vs. nonfunctioning adenoma=4.8+/-5 ml, p=0.47). However, the mean suprasellar growth for prolactinomas was 2.9+/-5.3 mm and 7.3+/-4.7 mm for nonfunctioning adenomas (p<0.001), and the mean infrasellar growth was 10.2+/ 8.0 and 5.0+/-6.6 mm, respectively (p=0.04). The inferior growth pattern of prolactinomas was associated with a significantly lower likelihood of having visual field abnormalities (11.4 vs. 57.1%, p<0.001). CONCLUSIONS: Prolactinomas have predominantly inferior growth compared to nonfunctioning adenomas and are less likely to cause vision changes. PMID- 28669360 TI - Predictors of Treatment Discontinuation During Prolonged Exposure for PTSD. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a highly prevalent and impairing condition for which there are several evidence-based psychotherapies. However, a significant proportion of patients fail to complete a 'sufficient dose' of psychotherapy, potentially limiting treatment gains. AIMS: The present study investigated predictors of premature treatment discontinuation during a trial of prolonged exposure (PE) therapy for PTSD. METHOD: Combat veterans with PTSD were recruited to participate in a randomized clinical trial of PE delivered in person or via telehealth technologies. Of the 150 initial participants, 61 participants discontinued the trial before the completion of eight sessions (of an 8-12 session protocol). Treatment condition (telehealth or in person) and factors identified by prior research (age, combat theatre, social support, PTSD symptoms) were tested as predictors of treatment discontinuation. RESULTS: A Cox proportional hazards model (a subtype of survival analysis) was used to evaluate predictors of treatment discontinuation. Disability status and treatment condition were identified as significant predictors of discontinuation, with a noted disability and use of telehealth demonstrating higher risk. CONCLUSIONS: The present findings highlight the influence of telehealth and disability status on treatment discontinuation, while minimizing the role of the previously identified variables from studies with less sensitive analyses. PMID- 28669361 TI - A systematic review and meta-analysis on the incubation period of Campylobacteriosis. AB - Accurate knowledge of pathogen incubation period is essential to inform public health policies and implement interventions that contribute to the reduction of burden of disease. The incubation period distribution of campylobacteriosis is currently unknown with several sources reporting different times. Variation in the distribution could be expected due to host, transmission vehicle, and organism characteristics, however, the extent of this variation and influencing factors are unclear. The authors have undertaken a systematic review of published literature of outbreak studies with well-defined point source exposures and human experimental studies to estimate the distribution of incubation period and also identify and explain the variation in the distribution between studies. We tested for heterogeneity using I 2 and Kolmogorov-Smirnov tests, regressed incubation period against possible explanatory factors, and used hierarchical clustering analysis to define subgroups of studies without evidence of heterogeneity. The mean incubation period of subgroups ranged from 2.5 to 4.3 days. We observed variation in the distribution of incubation period between studies that was not due to chance. A significant association between the mean incubation period and age distribution was observed with outbreaks involving only children reporting an incubation of 1.29 days longer when compared with outbreaks involving other age groups. PMID- 28669362 TI - Putative germline and pluripotent stem cells in adult mouse ovary and their in vitro differentiation potential into oocyte-like and somatic cells. AB - According to classical knowledge of reproductive biology, in the ovary of female mammals there is a limited number of oocytes and there is no possibility of renewal if the oocytes are lost due to disease or injury. However, in recent years, the results of some studies on renewal and formation of oocytes and follicles in the adult mammalian ovary have led to the questioning of this opinion. The aim of our study is to demonstrate the presence of putative germline and pluripotent stem cells in the adult mouse ovary and their differentiation potential into germ and somatic cells. In ovary tissues and cells harvested from pre-differentiation step, the expression of pluripotent and germline stem cell markers was analysed by reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence staining and western blotting. Embryoid bodies that formed in this step were analysed using immunofluorescence staining and transmission electron microscopy. Ovarian stem cells were induced to differentiate into oocyte, osteoblast, chondrocyte and neural cells. Besides morphological observation, differentiated cells were analysed by RT-PCR, histochemical and immunofluorescence staining. Expression of germline and pluripotent stem cell markers both in mRNA and at the protein level were detected in the pre differentiated cells and ovary tissues. As a result of the differentiation process, the formation of oocyte-like cells, osteoblasts, chondrocytes and neural cells was observed and characteristics of differentiated cells were confirmed using the methods mentioned above. Our study results revealed that the adult mouse ovary contains germline and pluripotent stem cells with the capacity to differentiate into oocyte-like cells, osteoblasts, chondrocytes and neural cells. PMID- 28669363 TI - The Effect of Adding Comorbidities to Current Centers for Disease Control and Prevention Central-Line-Associated Bloodstream Infection Risk-Adjustment Methodology. AB - BACKGROUND Risk adjustment is needed to fairly compare central-line-associated bloodstream infection (CLABSI) rates between hospitals. Until 2017, the Centers for Disease Control and Prevention (CDC) methodology adjusted CLABSI rates only by type of intensive care unit (ICU). The 2017 CDC models also adjust for hospital size and medical school affiliation. We hypothesized that risk adjustment would be improved by including patient demographics and comorbidities from electronically available hospital discharge codes. METHODS Using a cohort design across 22 hospitals, we analyzed data from ICU patients admitted between January 2012 and December 2013. Demographics and International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) discharge codes were obtained for each patient, and CLABSIs were identified by trained infection preventionists. Models adjusting only for ICU type and for ICU type plus patient case mix were built and compared using discrimination and standardized infection ratio (SIR). Hospitals were ranked by SIR for each model to examine and compare the changes in rank. RESULTS Overall, 85,849 ICU patients were analyzed and 162 (0.2%) developed CLABSI. The significant variables added to the ICU model were coagulopathy, paralysis, renal failure, malnutrition, and age. The C statistics were 0.55 (95% CI, 0.51-0.59) for the ICU-type model and 0.64 (95% CI, 0.60-0.69) for the ICU-type plus patient case-mix model. When the hospitals were ranked by adjusted SIRs, 10 hospitals (45%) changed rank when comorbidity was added to the ICU-type model. CONCLUSIONS Our risk-adjustment model for CLABSI using electronically available comorbidities demonstrated better discrimination than did the CDC model. The CDC should strongly consider comorbidity-based risk adjustment to more accurately compare CLABSI rates across hospitals. Infect Control Hosp Epidemiol 2017;38:1019-1024. PMID- 28669364 TI - Expression of markers for germ cells and oocytes in cow dermal fibroblast treated with 5-azacytidine and cultured in differentiation medium containing BMP2, BMP4 or follicular fluid. AB - This study aims to investigate the effect 5-azacytidine (5-Aza) during induction of pluripotency in bovine fibroblasts and to evaluate the effects of BMP2, BMP4 or follicular fluid in the differentiation of reprogrammed fibroblasts in primordial germ cells and oocytes. It also analysis the mRNA levels for OCT4, NANOG, REX, SOX2, VASA, DAZL, cKIT, SCP3, ZPA and GDF9 after culturing 5-Aza treated fibroblasts in the different tested medium. Dermal fibroblasts were cultured and exposed to 0.5, 1.0 or 2.0 MUM of 5-Aza for 18 h, 36 h or 72 h. Then, the cells were cultured in DMEM/F12 supplemented with 10 ng/ml BMP2, 10 ng/ml BMP4 or 5% follicular fluid. After culture, morphological characteristics, viability and gene expression were evaluated by qPCR. Treatment of skin fibroblasts with 2.0 MUM 5-Aza for 72 h significantly increased expression of mRNAs for SOX2, OCT4, NANOG and REX. The culture in medium supplemented with BMP2, BMP4 or follicular fluid for 7 or 14 days induced formation of oocyte-like cells, as well as the expression of markers for germ cells and oocyte. In conclusion, treatment of bovine skin-derived fibroblasts with 2.0 MUM 5-Aza for 72 h induces the expression of pluripotency factors. Culturing these cells in differentiation medium supplemented with BMP2, BMP4 or follicular fluid induces morphological changes and promotes expression of markers for germ cells, meiosis and oocyte. PMID- 28669365 TI - Incidence of pneumonia in nursing home residents with dementia in the Netherlands: an estimation based on three differently designed studies. AB - Pneumonia leads to considerable morbidity and mortality in nursing home residents with dementia. We assessed pneumonia incidence based on data from three different studies: (1) real-time national surveillance of healthcare-associated infections in nursing home residents in 2009-2015; (2) a randomized controlled trial in 2012 2015 to assess effects of a practical guideline in nursing home residents with dementia and pneumonia; and (3) a study in 2007-2010 to assess quality of dying in newly admitted nursing home residents with dementia. In national surveillance data, pneumonia incidence was calculated separately for psychogeriatric and somatic beds, as a proxy for residents with and without dementia. Weekly pneumonia incidence was significantly lower per 1000 psychogeriatric beds (3.9; 95% confidence interval (CI) 3.2-4.6) compared with 1000 somatic beds (5.7; 95% CI 5.1-6.3). Annual incidence per 1000 psychogeriatric beds was similar in national surveillance (range 78.9-117.1) and the trial (range 71.0-94.3), and significantly higher in newly admitted dementia residents (range 267.3-363.2). The incidence was highest during the first months after admission when compared with residents with longer stay. In conclusion, follow-up of pneumonia in newly admitted dementia residents may result in higher incidence, possibly due to higher risk in this population. PMID- 28669366 TI - Effects of Self-Selected Exercise on Strength in Charcot-Marie-Tooth Disease Subtypes. AB - BACKGROUND: Preliminary studies have supported the utility of exercise as a treatment for Charcot-Marie-Tooth disease (CMT) patients. Despite being the most common inherited neuropathy, there remains a paucity of guidelines for CMT management. METHODS: A retrospective chart review was performed on 297 CMT patients. Self-reported exercise and strength results from standardized dynamometer testing were obtained from adult patients' first visits. Values were converted and analyzed based on previously reported age- and sex-matched normative values. RESULTS: Participants with CMT2 had greater strength values than those with CMT1 in hand grip, elbow flexion, and dorsiflexion (p<0.05). Participants with CMT1 and CMT2 who exercised were statistically significantly stronger in elbow flexion and dorsiflexion than those who did not exercise. CONCLUSIONS: These preliminary results suggest that self-directed exercise is associated with greater strength in CMT patients of both CMT1 and CMT2 subtypes. Self-directed exercise may be a convenient, sustainable, and effective method of improving strength and decreasing disability in this population. Future research should explore the type of exercise prescription that best addresses the needs of the CMT population. PMID- 28669367 TI - The Effect of Ultraviolet Light on Clostridium difficile Spore Recovery Versus Bleach Alone. PMID- 28669368 TI - Attitudes of palliative care clinical staff toward prolonged grief disorder diagnosis and grief interventions. AB - : ABSTRACTObjective:The provision of psychological support to caregivers is an important part of the role of the clinical staff working in palliative care. Staff knowledge and attitudes may determine their openness to referring caregivers to a psychological intervention. We recently developed a self-help intervention for grief and psychological distress among caregivers and were interested in exploring the extent to which staff knowledge and attitudes might affect future implementation. The aims of our study were to: (1) examine the acceptability of self-help psychological intervention for caregivers among palliative care clinical staff; (2) examine potential attitudinal barriers toward prolonged grief disorder (PGD) as a diagnosis and interventions for grief; and (3) bolster staff confidence in skills and knowledge in identifying and managing caregiver psychological distress. METHOD: An anonymous survey was distributed among clinical staff at two inpatient units and two community health services that assessed the acceptability of self-help interventions for caregivers, attitudes about PGD diagnosis and grief intervention, and staff confidence in skills and knowledge in assessing caregiver psychological distress. RESULTS: Overall, clinical staff were positively oriented toward self-help for caregivers and intervention for grief. They were also basically confident in their skills and knowledge. While it was positive PGD attitudes that were associated with acceptability of self-help for caregivers, it was both positive and negative PGD attitudes that were associated more specifically with a willingness to refer caregivers to such an intervention. SIGNIFICANCE OF RESULTS: Our findings are useful in highlighting the issues to be considered in the implementation of a self-help intervention within the healthcare service. Clinical staff seemed positively oriented toward engaging with a psychological intervention for caregivers and likely to act as key allies in implementation. PMID- 28669369 TI - Young people's perspectives on open communication between family members when a parent is dying. AB - : ABSTRACTObjective:Living with a parent who is approaching the end of life is profoundly troubling for young people. Research indicates that family communication about life-limiting parental illness can influence how young people manage living with dying. In particular, open communication between family members has been shown to be helpful. This paper reports on a study of young people's experiences of family interaction when a parent is dying and considers the practice of open communication in the context of young people's involvement in giving and receiving family care. METHODS: A narrative approach was employed based on in-depth semistructured interviews with 10 young people (aged 13-21) living with a parent thought to be in the last year of life. RESULTS: Young people's attitudes toward open communication between family members were more ambivalent and ambiguous than previous research suggests. Parental attempts at open communication were sometimes overlooked by young people, indicating that there may be differences between knowledge given and young people's acknowledgment of sensitive information. Some young people valued open communication as a signifier of the close relationships between family members, while others wanted to exercise more control over what they knew, when, and how. Young people's accounts challenged the positioning of young people as passive recipients of information. Young people were active in shaping family communication in their everyday lives, and deliberative acts of speaking or remaining silent were one way in which young people exercised care for themselves and others. SIGNIFICANCE OF RESULTS: This study extends research on communication within families when a parent has a life-limiting illness and suggests that supporting young people's agency in determining how they receive information may be more beneficial than promoting open communication between family members. PMID- 28669370 TI - An isolated outbreak of diphtheria in South Africa, 2015 - Erratum. PMID- 28669371 TI - The following abstracts were presented as posters at the 2016 NEI Psychopharmacology Congress - CORRIGENDUM. PMID- 28669372 TI - Observational Study on Safety of Prehospital BLS CPAP in Dyspnea. AB - : Introduction Continuous positive airway pressure (CPAP) improves outcomes in patients with respiratory distress. Additional benefits are seen with CPAP application in the prehospital setting. Theoretical safety concerns regarding Basic Life Support (BLS) providers using CPAP exist. In Delaware's (USA) two tiered Emergency Medical Service (EMS) system, BLS often arrives before Advanced Life Support (ALS). Hypothesis This study fills a gap in literature by evaluating the safety of CPAP applied by BLS prior to ALS arrival. METHODS: This was a retrospective, observational study using Quality Assurance (QA) data collected from October 2009 through December 2012 throughout a state BLS CPAP pilot program; CPAP training was provided to BLS providers prior to participation. Collected data include pulse-oximetry (spO2), respiratory rate (RR), heart rate (HR), skin color, and Glasgow Coma Score (GCS) before and after CPAP application. Pre-CPAP and post-CPAP values were compared using McNemar's and t-tests. Advanced practitioners evaluated whether CPAP was correctly applied and monitored and whether the patient condition was "improved," "unchanged," or "worsened." RESULTS: Seventy-four patients received CPAP by BLS; CPAP was correctly indicated and applied for all 74 patients. Respiratory status and CPAP were appropriately monitored and documented in the majority of cases (98.6%). A total of 89.2% of patients improved and 4.1% worsened; CPAP significantly reduced the proportion of patients with SpO224, and cyanosis (P<.01). The GCS improved from mean (standard deviation [SD]) 13.9 (SD=1.9) to 14.1 (SD=1.9) after CPAP (mean difference [MD]=0.17; 95% CI, -0.49 to 0.83; P=.59). The HR decreased from 115.7 (SD=53) to 105.1 (SD=37) after CPAP (MD=-10.9; 95% CI, -3.2 to -18.6; P<.01). The SpO2 increased from 80.8% (SD=11.4) to 96.9% (SD=4.2) after CPAP (MD=17.8; 95% CI, 14.2-21.5; P<.01). CONCLUSION: The BLS providers were able to determine patients for whom CPAP was indicated, to apply it correctly, and to appropriately monitor the status of these patients. The majority of patients who received CPAP by BLS providers had improvement in their clinical status and vital signs. The findings suggest that CPAP can be safely used by BLS providers with appropriate training. Sahu N , Matthews P , Groner K , Papas MA , Megargel R . Observational study on safety of prehospital BLS CPAP in dyspnea. Prehosp Disaster Med. 2017;32(6):610 614. PMID- 28669373 TI - On-Scene Rescue Breathing Resulting in Gastric Perforation and Massive Pneumoperitoneum. AB - Rescue breathing performed too vigorously or by untrained individuals may cause gastric distension and perforation. A 26-year-old woman is presented who developed acute abdominal pain and distension after receiving rescue breathing following a heroin overdose. Massive pneumoperitoneum was seen on chest x-ray, and on subsequent laparotomy, a 4cm laceration was found in the lesser curvature of the stomach. Review of the literature suggests that the lesser curvature is particularly susceptible to perforation following over-distension. Emergency personnel should be aware of this rare, but serious, complication. Expansion of community and first responder naloxone use in the proper clinical setting may further diminish utilization of rescue breathing. Butterfield M , Peredy T . On scene rescue breathing resulting in gastric perforation and massive pneumoperitoneum. Prehosp Disaster Med. 2017;32(6):682-683. PMID- 28669374 TI - Reconciling Marriage and Care after Stroke. AB - Most research on stroke's impact on couples has focused on the transition to caregiving/receiving. Despite considerable evidence that marriage is the primary source of support in the face of chronic conditions, little is known about what happens to marriage in the context of care after stroke. To address this gap, we undertook a qualitative grounded-theory study of 18 couples in which one partner had experienced a stroke. Findings revealed two interrelated themes of the couple processes: working out care, which involved discovering and addressing disruptions in day-to-day activities; and rethinking marriage, which involved determining the meaning of their relationship within the new context of care and disability. Three distinct types of marriages evolved from these processes: reconfirmed around their pre-stroke marriage; recalibrated around care; and a parallel relationship, "his" and "her" marriage. Our findings highlight the need to consider relationship dynamics in addition to knowledge about stroke and care. PMID- 28669375 TI - Morphogenesis-related gene-expression profile in porcine oocytes before and after in vitro maturation. AB - Mammalian oocyte maturation is achieved when oocytes reach metaphase II (MII) stage, and accumulate mRNA and proteins in the cytoplasm following fertilization. It has been shown that oocytes investigated before and after in vitro maturation (IVM) differ significantly in transcriptomic and proteomic profiles. Additionally, folliculogenesis and oogenesis is accompanied by morphogenetic changes, which significantly influence further zygote formation and embryo growth. This study aimed to determine new transcriptomic markers of porcine oocyte morphogenesis that are associated with cell maturation competence. An Affymetrix microarray assay was performed on an RNA template isolated from porcine oocytes before (n = 150) and after (n = 150) IVM. The brilliant cresyl blue (BCB) staining test was used for identification of cells with the highest developmental capacity. DAVID (Database for Annotation, Visualization, and Integrated Discovery) software was used for the extraction of the genes belonging to a cell morphogenesis Gene Ontology group. The control group consisted of freshly isolated oocytes. In total, 12,000 different transcripts were analysed, from which 379 genes were downregulated and 40 were upregulated in oocytes following IVM. We found five genes, SOX9, MAP1B, DAB2, FN1, and CXCL12, that were significantly upregulated in oocytes after IVM (in vitro group) compared with oocytes analysed before IVM (in vivo group). In conclusion, we found new transcriptomic markers of oocyte morphogenesis, which may be also recognized as significant mediators of cellular maturation capacity in pigs. Genes SOX9, MAP1B, DAB2, FN1, and CXCL12 may be involved in the regulation of the MII stage oocyte formation and several other processes that are crucial for porcine reproductive competence. PMID- 28669376 TI - Association between pancreatic cancer patients' perception of their care coordination and patient-reported and survival outcomes. AB - OBJECTIVE: People with pancreatic cancer have poor survival, and management is challenging. Pancreatic cancer patients' perceptions of their care coordination and its association with their outcomes have not been well-studied. Our objective was to determine if perception of care coordination is associated with patient reported outcomes or survival. METHODS: People with pancreatic cancer who were 1 8 months postdiagnosis (52 with completed resection and 58 with no resection) completed a patient-reported questionnaire that assessed their perceptions of care coordination, quality of life, anxiety, and depression using validated instruments. Mean scores for 15 care-coordination items were calculated and then ranked from highest (best experience) to lowest (worst experience). Associations between care-coordination scores (including communication and navigation domains) and patient-reported outcomes and survival were investigated using general linear regression and Cox regression, respectively. All analyses were stratified by whether or not the tumor had been resected. RESULTS: In both groups, the highest ranked care-coordination items were: knowing who was responsible for coordinating care, health professionals being informed about their history, and waiting times. The worst-ranked items related to: how often patients were asked about visits with other health professionals and how well they and their family were coping, knowing the symptoms they should monitor, having sufficient emotional help from staff, and access to additional specialist services. For people who had a resection, better communication and navigation scores were significantly associated with higher quality of life and less anxiety and depression. However, these associations were not statistically significant for those with no resection. Perception of cancer care coordination was not associated with survival in either group. SIGNIFICANCE OF RESULTS: Our results suggest that, while many core clinical aspects of care are perceived to be done well for pancreatic cancer patients, improvements in emotional support, referral to specialist services, and self-management education may improve patient-reported outcomes. PMID- 28669377 TI - Data Sharing Statements for Clinical Trials. PMID- 28669378 TI - Night Work and the Risk of Depression. AB - BACKGROUND: Working the night shift interferes with the circadian chronobiological rhythm, causing sleep disturbances, fatigue, and diminished wellbeing, and increases the risk of serious disease. The question whether night work increases the risk of depression has not been adequately studied to date. METHODS: We carried out a systematic, broadly conceived literature search in the PubMed, Scopus, PsycINFO, and PSYNDEX databases and the Medpilot search portal on the topic of nighttime shift work and mental illness. RESULTS: The search yielded 5682 hits, which were narrowed down by predefined selection criteria to 11 high quality longitudinal studies on the relationship between nighttime shift work and depressive illness. Only these 11 studies were subjected to further analysis. 3 of 4 studies on nighttime shift work in the health professions (almost exclusively nursing) revealed no association with depression over an observation period of two years. On the other hand, 5 studies on nighttime shift work in occupations outside the health sector, with observation periods of two or more years, yielded evidence of an elevated risk of depression after several years of nighttime shift work, but not in any uniform pattern. A supplementary meta analysis of 5 of the studies revealed a 42% increase of the risk of depression among persons working the night shift (95% confidence interval [0.92; 2.19]). Psychosocial working conditions that have a negative influence on health partially account for these associations. CONCLUSION: Although there is evidence that nighttime shift work (at least, in occupations outside the health sector) does increase the risk of depression, this evidence is not strong enough to sustain a general medical recommendation against shift work for employees with depressive conditions. It would seem appropriate to address this question on an individual basis, with strong support from physicians and close attention to the deleterious psychosocial factors associated with shift work. PMID- 28669379 TI - The Prevalence of Gestational Diabetes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is defined as a glucose tolerance disorder that arises during pregnancy. Estimates of its prevalence vary widely because of varying threshold values. Screening of all pregnant women with a two step test has been available in Germany since 2012. This study is the first population-based, nationwide analysis of the screening coverage and the resulting one-year prevalence. METHODS: Billing data from the outpatient sector were analyzed for all persons covered by statutory health insurance in the two-year period 2014-2015. A cohort of pregnant women, constructed by using pregnancy care billing data, was studied with respect to the screening coverage. The prevalence of GDM was determined from the use of the corresponding ICD-10-GM codes. RESULTS: 80.8% of 567 191 pregnant women were screened for GDM. Most of them (63.3%) received only the pre-test, and 12.7% received both the pre-test and the diagnostic test. 4.8% received only the diagnostic test. The overall prevalence of GDM was 13.2%. The prevalence rose with age, from 8% to 26% in women aged 45 or older. Younger women more commonly received only the pre-test; the frequency of receiving both tests rose with age. CONCLUSION: Screening for GDM is comprehensively implemented. The analysis of billing data reveals a relatively high prevalence that accords with estimates in other countries, implying that earlier prevalence figures for Germany were probably underestimates. PMID- 28669380 TI - Acute kidney injury in critically-ill adult patients with seasonal influenza infection. AB - BACKGROUND: Acute kidney injury (AKI) occurs in 22.4 - 100% of critically-ill hospitalized patients with influenza infection. In up to 2/3, it is severe enough to necessitate renal replacement therapy. We aimed to document the incidence of AKI among patients with influenza-related critical illness and its relation to clinical outcomes. METHODS: We conducted a retrospective observational study of all adult patients with acute respiratory illness and laboratory-confirmed influenza infection admitted to non-surgical intensive care units at the University Medical Centre Ljubljana between January 1, 2016, and March 31, 2016. RESULT: Our sample consisted of 28 adult patients with mean age in years of 57.5 +/- 20.2. Incidence of AKI was 71.4%. Mortality was 28.6% (35% in patients with AKI and 41.6% in patients who required renal replacement therapy). CONCLUSIONS: Influenza-related critical illness is rare but can cause AKI in a large proportion of affected patients. In this setting, requirement for renal replacement therapy could be associated with increased mortality risk.?. PMID- 28669381 TI - Role of NETs in the difference in host susceptibility to Toxoplasma gondii between sheep and cattle. AB - The main aim of this study was to compare extracellular traps (NETs) formation by polymorphonuclear neutrophils (PMNs) of cattle and sheep when exposed to T. gondii tachyzoites in vitro. The effects of parasite concentrations and different incubation periods on NETs development in cattle and sheep PMNs were studied. The effect of NET structures on host cell invasion by tachyzoites was also studied. This is the first report of NETs development by sheep and cattle PMNs against T. gondii in vitro. T. gondii-induced extracellular DNA production from PMNs was dependent on tachyzoite concentrations and incubation time in both sheep and cattle. Many nuclear and cytoplasmic changes were observed in sheep and cattle PMNs after exposure to T. gondii tachyzoites. The typical appearance of NETs, with MPO, NE and histone (H3) attached to extracellular DNA, was observed. Tachyzoites were entrapped within this structure. Myeloperoxidase (MPO) activity was higher in the cattle PMN-tachyzoite co-cultures than sheep. NETs structures released from sheep PMNs caused mechanical immobilisation of T. gondii tachyzoites, however, NET structures released from cattle PMNs may be lethal to tachyzoites. Bovine MPO may have a lethal effect on T. gondii tachyzoites in vitro during a 3h incubation. Besides other mechanisms that effect on host susceptibility to T. gondii in sheep and cattle, extracellular traps formation as a part of immunological reactions may be play a role in host susceptibility to T. gondii. PMID- 28669382 TI - New wide dynamic range assays for quantification of anti-Leishmania IgG2 and IgA antibodies in canine serum. AB - The aims of this study were (1) to develop and validate time resolved immunofluorometric assays for the detection of anti-Leishmania IgG2 and IgA antibodies in canine serum and (2) to evaluate the ability of these assays to quantify different amounts of anti-Leishmania antibodies in Leishmania seronegative and seropositive dogs, determined by a commercial ELISA assay, and between different clinical stages according to LeishVet guidelines. The analytical validation showed that the assays had a good precision with intra- and inter-assay coefficients of variation lower than 10%. In addition, the assays allowed the quantification of very low concentration of antibodies as well as demonstrated a high level of accuracy, as determined by linearity under dilution (R2=0.99) and recovery tests (>85%). Moreover, no cross-reactions with Ehrlichia canis, Canine Parvovirus Type 2, Anaplasma phagocytophilum, Babesia canis, Dirofilaria immitis and pyometra were found. The assays were able to detect higher values of anti-Leishmania IgG2 and IgA antibodies in seropositive dogs compared with seronegative dogs (p<0.0001), although an overlap between groups existed in the case of IgA. In addition, significantly higher values for both antibodies were detected in LeishVet groups II (p<0.05) and III (p<0.01) when compared with LeishVet group I. From our study, it could be concluded that the immunofluorometric assays developed would be suitable for determination of anti Leishmania IgG2 and IgA antibodies in serum samples with an adequate precision, analytical sensitivity and accuracy. In addition, these assays showed a wider difference in the concentration of both IgG2 and IgA antibodies between seronegative and seropositive dogs and between different clinical stages of CanL than a current commercial ELISA kit. Further studies would be recommended to evaluate the diagnostic sensitivity and specificity of these new assays as well as their application in monitoring CanL. PMID- 28669383 TI - Field performance of six Mycobacterium avium subsp. paratuberculosis antigens in a 20h interferon gamma release assay in Belgium. AB - Paratuberculosis, caused by Mycobacterium avium subsp. paratuberculosis (Map), is a chronic granulomatous enteritis which primarily affects domestic and wild ruminants, resulting in serious economic losses for dairy and beef industry around the world. There is no satisfactory cure or vaccine, and actual diagnostic tests need improvement, particularly for the initial stages of the disease. Map specific cell-mediated immune responses may allow early detection of the infection at subclinical stages. In this study, over a period of 39 months, we collected 548 blood samples in two culture-confirmed Map-infected herds, 95 blood samples in five dairy herds that scored negative during 3 consecutive years of Map serology testing and 79 samples in three culture-confirmed M. bovis infected herds. Based on criteria of bacteriology, serology and ratio of IFN-gamma induced with bovine and avian purified protein derivative of tuberculin (PPD-B/PPD-A), we classified the samples in four groups: 415 samples as Map-exposed/infected (MAP), 58 samples as aspecific reactors (AR), 179 samples as non-responders (NI) and 70 samples as M. bovis infected (TB). Age of the animals influenced the IFN-gamma response in the MAP group, with PPD specific IFN-gamma levels (but not PPD-B/PPD A IFN-gamma ratio) being significantly higher in animals <18 months of age. Map specific antibodies were detected by IDEXX ELISA in 13/415 (3%) sera of the MAP group, whereas fecal culture was positive for only 7/405 (1.7%) samples. Animals in the MAP group could therefore be considered being at the very early stage of Map infection. Six purified, recombinant Map antigens (Ag5, Ag6, MAP1637c, MAP0388, MAP3547c and MAP0586c), previously identified using combined advanced proteomic or reverse genomic approaches, were tested for their diagnostic potential in a 20h IFN-gamma release assay. In the age group >18 months old, Ag5 and MAP0388 were recognized by only 10.1% and 7.7% of the animals in the MAP group, whereas a total of 38.6.%, 29.4%, 25.6% and 39.0% of the animals in the MAP group reacted to Ag6, MAP1637c, MAP3547c and MAP0586c respectively. None of the animals in the TB group reacted to Ag6, MAP1637c or MAP586c. Except for MAP0388, the % of reactors in the MAP group was significantly higher in animals <18 months old: 28.0%, 24.0%, 45.5%, 47.1%, 49.8% and 47.4% respectively. Further studies of these candidates and their combination are needed to confirm their diagnostic potential for the detection of early Map infection. PMID- 28669385 TI - IL-10 suppression of IFN-gamma responses in tuberculin-stimulated whole blood from Mycobacterium bovis infected cattle. AB - The measurement of bovine interferon-gamma (IFN-gamma) forms the basis of a diagnostic test for bovine tuberculosis where Mycobacterium bovis sensitised effector T cells produce IFN-gamma following in vitro stimulation with tuberculin antigens. In cattle infected with M. bovis it is also known that the anti inflammatory IL-10 cytokine can inhibit in vitro production of IFN-gamma leading to a reduced response in the IFN-gamma diagnostic test. In order to investigate this in greater detail, whole blood samples from tuberculin skin test positive and negative cattle were stimulated with bovine and avian tuberculin antigens and in parallel with a neutralising anti-IL-10 monoclonal antibody. The results showed that IFN-gamma protein levels increased when IL-10 activity was suppressed by Anti - IL-10. By using a standard diagnostic interpretation, the elevated levels of IFN-gamma were shown to change the level of agreement between the performance of the single intradermal comparative tuberculin test (SICTT) and IFN gamma assay, depending on the tuberculin treatment. A transcriptomic analysis using RT-qPCR investigated the influence of IL-10 activity on expression of a suite of cytokine genes (IFNG, IL12B, IL10 and CXCL10) associated with antigen stimulated production of IFN-gamma. The IFNG and IL12B genes both experienced significant increases in expression in the presence of Anti-IL-10, while the expression of IL10 and CXCL10 remained unaffected. PMID- 28669384 TI - Differences in expression of genes in the MyD88 and TRIF signalling pathways and methylation of TLR4 and TRIF in Tibetan chickens and DaHeng S03 chickens infected with Salmonella enterica serovar enteritidis. AB - Salmonella enterica serovar (S. enteritidis) is a pathogenic bacterium that can cause symptoms of food poisoning, leading to death of poultry, resulting in serious economic losses. The MyD88 and TRIF signalling pathways play important roles in activating innate and adaptive immunity in chickens infected with S. enteritidis. The objective of the present study was to characterize in vivo mRNA expressions, protein levels and methylation levels of genes in the above two pathways in both Tibetan chickens and DaHeng S03 chickens infected with S. enteritidis. MyD88-dependent and TRIF-dependent signalling pathway were activated by infection, and the MyD88 signalling pathway induced cytokines LITAF and IL-8 played important roles in fighting against the S. enteritidis infection in vivo. The TLR4 methylation might alter expression of genes involved in the MyD88 signalling pathway, and thus different breeds of chickens might show differences in susceptibility to the S. enteritidis. The increased expression of INF beta was activated by S. enteritidis, but its expressions were different in levels of mRNA and protein in Tibetan chickens and DaHeng chickens, suggesting its functions on the resistance to S. enteritidis infection in chickens. This study contributes to the understanding of two pathways activated in response to S. enteritidis infection, and gives indications on the mechanisms underlying resistance of Tibetan chickens and DaHeng chickens to S. enteritidis. PMID- 28669386 TI - Dietary cinnamaldehyde enhances acquisition of specific antibodies following helminth infection in pigs. AB - Dietary phytonutrients such as cinnamaldehyde (CA) may contribute to immune function during pathogen infections, and CA has been reported to have positive effects on gut health when used as feed additive for livestock. Here, we investigated whether CA could enhance antibody production and specific immune responses during infection with an enteric pathogen. We examined the effect of dietary CA on plasma antibody levels in parasite-naive pigs, and subsequently acquisition of humoral immune responses during infection with the parasitic nematode Ascaris suum. Parasite-naive pigs fed diets supplemented with CA had higher levels of total IgA and IgG in plasma, and A. suum-infected pigs fed CA had higher levels of parasite-specific IgM and IgA in plasma 14days post infection. Moreover, dietary CA increased expression of genes encoding the B-cell marker CD19, sodium/glucose co-transporter1 (SCA5L1) and glucose transporter 2 (SLC2A2) in the jejunal mucosa of A.suum-infected pigs. Dietary CA induced only limited changes in the composition of the prokaryotic gut microbiota of A. suum infected pigs, and in vitro experiments showed that CA did not directly induce proliferation or increase secretion of IgG and IgA from lymphocytes. Our results demonstrate that dietary CA can significantly enhance acquisition of specific immune responses in pigs. The underlying mechanism remains obscure, but apparently does not derive simply from direct contact between CA and host lymphocytes and appears to be independent of the gut microbiota. PMID- 28669387 TI - Amplification and selection of PRRSV-activated VDJ repertoires in pigs secreting distinct neutralizing antiboidies. AB - Neutralizing antibodies (nAbs) play an important role in protective immunity against porcine reproductive and respiratory syndrome virus (PRRSV) infection. However, the characterization of PRRSV nAb repertoires is rarely investigated. In this study, we developed a swine VDJ amplification method and selection criteria for the characterization of PRRSV-activated VDJ repertoires. According to clonal expansion theory, two separated aliquots of lymph nodes from pigs producing different PRRSV nAbs were utilized to determine the activated B-cell repertoires. Swine VDJ repertoires from a mock-infected pig and PRRSV-infected pigs secreting no detectable nAbs, only homologous nAbs, and broad nAbs were amplified by a single pair of primers that could detect all seven major VDJ genes. The amplicons were cloned and sequenced to generate 385 VDJ sequences. Sequence alignment showed that the diversification of VDJ genes was mainly due to the variation in complementarity determining regions (CDRs), especially CDR3. Based on selection criteria, shared and abundant sequences were identified in two separated aliquots from PRRSV-infected pigs but not from the mock-infected pig, suggesting they were secreted from PRRSV-activated B cells. Thus, the amplification and selection method provide a potential alternative for the characterization of swine VDJ repertoires. However, additional experiments are required to determine whether the shared and abundant VDJ lineages identified in this study are PRRSV-specific or distinct neutralizing-antibodies-associated. PMID- 28669388 TI - Multivariate analysis of the immune response to a vaccine as an alternative to the repetition of animal challenge studies for vaccines with demonstrated efficacy. AB - The assessment of vaccine combinations, or the evaluation of the impact of minor modifications of one component in well-established vaccines, requires animal challenges in the absence of previously validated correlates of protection. As an alternative, we propose conducting a multivariate analysis of the specific immune response to the vaccine. This approach is consistent with the principles of the 3Rs (Refinement, Reduction and Replacement) and avoids repeating efficacy studies based on infectious challenges in vivo. To validate this approach, a set of nine immunological parameters was selected in order to characterize B and T lymphocyte responses against canine rabies virus and to evaluate the compatibility between two canine vaccines, an inactivated rabies vaccine (RABISIN(r)) and a combined vaccine (EURICAN(r) DAPPi-Lmulti) injected at two different sites in the same animals. The analysis was focused on the magnitude and quality of the immune response. The multi-dimensional picture given by this 'immune fingerprint' was used to assess the impact of the concomitant injection of the combined vaccine on the immunogenicity of the rabies vaccine. A principal component analysis fully discriminated the control group from the groups vaccinated with RABISIN(r) alone or RABISIN(r)+EURICAN(r) DAPPi-Lmulti and confirmed the compatibility between the rabies vaccines. This study suggests that determining the immune fingerprint, combined with a multivariate statistical analysis, is a promising approach to characterizing the immunogenicity of a vaccine with an established record of efficacy. It may also avoid the need to repeat efficacy studies involving challenge infection in case of minor modifications of the vaccine or for compatibility studies. PMID- 28669390 TI - Approaches to self-assembly of colloidal monolayers: A guide for nanotechnologists. AB - Self-assembly of quasi-spherical colloidal particles in two-dimensional (2D) arrangements is essential for a wide range of applications from optoelectronics to surface engineering, from chemical and biological sensing to light harvesting and environmental remediation. Several self-assembly approaches have flourished throughout the years, with specific features in terms of complexity of the implementation, sensitivity to process parameters, characteristics of the final colloidal assembly. Selecting the proper method for a given application amidst the vast literature in this field can be a challenging task. In this review, we present an extensive classification and comparison of the different techniques adopted for 2D self-assembly in order to provide useful guidelines for scientists approaching this field. After an overview of the main applications of 2D colloidal assemblies, we describe the main mechanisms underlying their formation and introduce the mathematical tools commonly used to analyse their final morphology. Subsequently, we examine in detail each class of self-assembly techniques, with an explanation of the physical processes intervening in crystallization and a thorough investigation of the technical peculiarities of the different practical implementations. We point out the specific characteristics of the set-ups and apparatuses developed for self-assembly in terms of complexity, requirements, reproducibility, robustness, sensitivity to process parameters and morphology of the final colloidal pattern. Such an analysis will help the reader to individuate more easily the approach more suitable for a given application and will draw the attention towards the importance of the details of each implementation for the final results. PMID- 28669391 TI - Rates of serum level determinations of antiepileptic drugs in accord with guidelines: A clinical study at a tertiary center. AB - OBJECTIVE: To compare our rates of appropriate therapeutic drug monitoring (TDM) with those defined in the French guidelines for measuring drug levels of antiepileptic drugs (AEDs) during the pre- and post-medical/pharmaceutical interventional periods. METHODS: This study was prospectively carried out at a tertiary center (epilepsy unit of the Pitie-Salpetriere Hospital in Paris) between 2013 and 2016 over three time periods. Criteria for appropriateness were those stated in the current French guidelines. The main outcome measure was the percentage of drug level measurements with an appropriate indication, while a second outcome measure was the impact of education on clinical practice. RESULTS: Of the 698 AED level measurements requested, 84% overall were found to have appropriate indications ranging from 75% to 90%, according to French guideline criteria. Rates of appropriate indications for the three most commonly used individual AEDs-valproate, carbamazepine and lamotrigine-were 79.6%, 77.3% and 90.7%, respectively, whereas the requests considered to not have an appropriate indication involved the majority (63.5%) of cases of routine drug monitoring. In addition, dedicated education seems to substantially increase rates of appropriateness. CONCLUSION: At our center, 84% of AED level determinations had an appropriate indication according to a priori defined and reliable criteria. Moreover, it was noted that a specific educational intervention substantially increased rates of appropriateness. Thus, it appears to be crucial to ensure that medical and paramedical staff are aware of the official recommendations to avoid taking unnecessary drug level measurements. PMID- 28669389 TI - Cathelicidin production and release by mammary epithelial cells during infectious mastitis. AB - Cathelicidins are well-characterized antimicrobial peptides (AMPs) that are present in significant amounts in mastitic milk. Neutrophils are believed to be the main producers of these AMPs, while the role of mammary epithelial cells (MECs) in their production and release is still unclear. In this work, cathelicidin production patterns were investigated in mammary tissues of ewes infected by Staphylococcus aureus, Streptococcus uberis, or Mycoplasma agalactiae, with a combined approach including immunohistochemistry, immune colocalization, and fluorescent in situ hybridization. Our results confirm that MECs produce and release cathelicidins in response to different mastitis pathogens. As opposed to neutrophils, however, MECs do not seem to store the preformed protein precursor in their cytoplasm, but appear to synthesize and release it only upon exposure to the microorganisms. Cathelicidin production by MECs appears to occur before leukocyte influx in the milk, suggesting a role for these cells in the initial response of the mammary epithelium to microbial infection. Once in the milk, infiltrating neutrophils release massive amounts of cathelicidin by degranulation and production of neutrophil extracellular traps, acting as the main contributor for cathelicidin abundance in mastitic milk. Taken together, our results support the active contribution of MECs to cathelicidin production and release, and reinforce the value of cathelicidins as sensitive and pathogen-independent mastitis markers. PMID- 28669392 TI - Strabismus Measurements in Adults Before and After Pupil Dilation. PMID- 28669393 TI - Eryptosis in health and disease: A paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes. AB - During the course of their natural ageing and upon injury, anucleate erythrocytes can undergo an unconventional apoptosis-like cell death, termed eryptosis. Eryptotic erythrocytes display a plethora of morphological alterations including volume reduction, membrane blebbing and breakdown of the membrane phospholipid asymmetry resulting in phosphatidylserine externalization which, in turn, mediates their phagocytic recognition and clearance from the circulation. Overall, the eryptosis machinery is tightly orchestrated by a wide array of endogenous mediators, ion channels, membrane receptors, and a host of intracellular signaling proteins. Enhanced eryptosis shortens the lifespan of circulating erythrocytes and confers a procoagulant phenotype; this phenomenon has been tangibly implicated in the pathogenesis of anemia, deranged microcirculation, and increased prothrombotic risk associated with a multitude of clinical conditions. Herein, we reviewed the molecular mechanisms dictating eryptosis and erythrophagocytosis and critically analyzed the current evidence leading to the pathophysiological ramifications of eryptotic cell death in the context of human disease. PMID- 28669394 TI - Ascending Aortic Dimension Measurements: Apples, Oranges, and Lemons. PMID- 28669395 TI - Afterload Dependence of Right Ventricular Myocardial Strain. AB - BACKGROUND: Right ventricular (RV) free wall strain (RVFWS) is a feasible method for quantitation and follow-up of RV function and may have benefits over traditional markers such as fractional area change. However, like all ejection phase parameters, RVFWS is difficult to assess in the presence of changing afterload. The aim of this study was to compare RVFWS and traditional RV function parameters for tracking progress of RV function in patients with pulmonary arterial hypertension (PAH) over a range of pulmonary artery systolic pressure (PASPs). METHODS: Sequential echocardiograms were collected retrospectively at two time points between 2005 and 2015 in 187 patients (71% women; mean age, 63 +/ 14 years) undergoing pulmonary vasodilator therapy for group 1 PAH. Patients were either studied during PAH therapy (n = 111) or before and after treatment initiation (n = 76). Standard measurements of RV and left ventricular function and PASP were performed, and speckle-tracking strain was used to calculate RVFWS. The linear response of RVFWS to afterload (PASP) was assessed using a standard regression equation. Because it is unclear if the response might be nonlinear, a quadratic association (PASP squared) was also used in the regression model. RESULTS: At visit 1, patients with PAH showed impaired functional capacity (mean 6-min walk distance, 371 +/- 131 m), increased PASP (mean, 54 +/- 26 mm Hg), and borderline RVFWS (mean, 18 +/- 6%). Patients before PAH therapy showed more pronounced reduction in 6-min walk distance (mean, 302 +/- 136 m) and RVFWS (mean, 16 +/- 5%). RVFWS at baseline was associated with PASP (R2 = 0.25, P = .001), RV end-diastolic area (R2 = 0.36, P < .001), and fractional area change (R2 = 0.21, P < .001). Change in RVFWS was more strongly associated with DeltaPASP (std beta = -0.20, P = .02) than DeltaPASP squared (std beta = 0.11, P = .20). RVFWS showed strength over fractional area change for sequential RV assessment over a range of PASP changes. CONCLUSIONS: Afterload changes should be taken into account in the evaluation of RVFWS during PAH follow-up, with the relationship to PASP likely to be linear. PMID- 28669397 TI - Correction. PMID- 28669396 TI - Authors' Reply. PMID- 28669398 TI - Embracing Change. PMID- 28669399 TI - Extending Roles for Allied Health Professionals-How do They Evolve? How are They Implemented Into Practice? PMID- 28669400 TI - Changes Coming to the ASE Councils. PMID- 28669401 TI - A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases. AB - We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian framework. Variant-specific prior information derived from allele frequency databases, consequence prediction algorithms, or genomic datasets can be integrated into the inference. Association models can be fitted to different subsets of variants in a locus and compared using a model selection procedure. This procedure can improve inference if only a particular class of variants confers disease risk and can suggest particular disease etiologies related to that class. We show that our method, called BeviMed, is more powerful and informative than existing rare variant association methods in the context of dominant and recessive disorders. The high computational efficiency of our algorithm makes it feasible to test for associations in the large non-coding fraction of the genome. We have applied BeviMed to whole-genome sequencing data from 6,586 individuals with diverse rare diseases. We show that it can identify multiple loci involved in rare diseases, while correctly inferring the modes of inheritance, the likely pathogenic variants, and the variant classes responsible. PMID- 28669402 TI - SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant Association Studies Using Whole-Genome and Exome Sequence Data. AB - Massively parallel sequencing technologies provide great opportunities for discovering rare susceptibility variants involved in complex disease etiology via large-scale imputation and exome and whole-genome sequence-based association studies. Due to modest effect sizes, large sample sizes of tens to hundreds of thousands of individuals are required for adequately powered studies. Current analytical tools are obsolete when it comes to handling these large datasets. To facilitate the analysis of large-scale sequence-based studies, we developed SEQSpark which implements parallel processing based on Spark to increase the speed and efficiency of performing data quality control, annotation, and association analysis. To demonstrate the versatility and speed of SEQSpark, we analyzed whole-genome sequence data from the UK10K, testing for associations with waist-to-hip ratios. The analysis, which was completed in 1.5 hr, included loading data, annotation, principal component analysis, and single variant and rare variant aggregate association analysis of >9 million variants. For rare variant aggregate analysis, an exome-wide significant association (p < 2.5 * 10 6) was observed with CCDC62 (SKAT-O [p = 6.89 * 10-7], combined multivariate collapsing [p = 1.48 * 10-6], and burden of rare variants [p = 1.48 * 10-6]). SEQSpark was also used to analyze 50,000 simulated exomes and it required 1.75 hr for the analysis of a quantitative trait using several rare variant aggregate association methods. Additionally, the performance of SEQSpark was compared to Variant Association Tools and PLINK/SEQ. SEQSpark was always faster and in some situations computation was reduced to a hundredth of the time. SEQSpark will empower large sequence-based epidemiological studies to quickly elucidate genetic variation involved in the etiology of complex traits. PMID- 28669403 TI - A Genetic Variant Ameliorates beta-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression. AB - A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of beta thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the beta-globin cluster using capture-based next-generation sequencing of 1142 Chinese beta-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for beta-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of beta-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased gamma globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from beta-thalassemia persons. The present study demonstrates that this common rSNP in the proximal Agamma-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of beta-hemoglobinopathy. PMID- 28669404 TI - Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis Associated Mutations throughout Adult Life. AB - Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals >=65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans. PMID- 28669406 TI - RNA Structural Variability and Functional Versatility Challenge RNA Structural Modeling and Design. PMID- 28669405 TI - Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. AB - KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology. PMID- 28669407 TI - Mg2+ Binding Promotes SLV as a Scaffold in Varkud Satellite Ribozyme SLI-SLV Kissing Loop Junction. AB - Though the structure of the substrate stem loop I (SLI)-stem loop V (SLV) kissing loop junction of the Varkud Satellite ribozyme has been experimentally characterized, the dynamics of this Mg2+-dependent loop-loop interaction have been elusive. Specifically, each hairpin loop contains a U-turn motif, but only SLV shows a conformational shift triggered by Mg2+ ion association. Here, we use molecular dynamics simulations to analyze the binding and dynamics of this kissing loop junction. We show that SLV acts as a scaffold, providing stability to the junction. Mg2+ ions associate with SLV when it is part of the junction in a manner similar to when it is unbound, but there is no specificity in Mg2+ binding for the SLI loop. This suggests that the entropic penalty of ordering the larger SLI is too high, allowing SLV to act as a scaffold for multiple substrate loop sequences. PMID- 28669408 TI - Patterns of recurrence/persistence of criptoglandular anal fistula after the LIFT procedure. Long-term observacional study. AB - OBJECTIVE: To study the recurrence/persistence rate of complex cripotoglandular anal fistula after the LIFT procedure and analyse the patterns of recurrence/persistence. PATIENTS AND METHODS: Observational study of patients with transe-sphincteric or supra-sphincteric anal fistula treated using the LIFT procedure from December 2008 to April 2016. Variables studied included clinical characteristics, surgical technique and results. Clinical cure was defined and imaging studies were used in doubtful cases. Wexner's score was used for continence evaluation. The minimum follow-up time was one year. RESULTS: A total of 55 patients were operated on: 53 with a trans-sphincteric fistula and 2 supra sphincteric. There were 16 failures (29%): 7 complete fistulas (original), 6 intersphincteric (downstage), and 3 external residual tracts. A posterior location and complexity of the tract were risk factors for recurrence/persistence. The presence of a seton did not improve results. No case presented decrease of continence (Wexner 0). Nine patients presented minor complications (9%): 4 intersphincteric wounds with delayed closure and one external hemorrhoidal thrombosis. The median time to closure of the external opening was 5 weeks (IR 2-6). Intersphincteric wounds closed in 4-8 weeks. CONCLUSION: In our experience, the LIFT technique is a safe and reproducible procedure with low morbidity, no repercussion on continence and a success rate over 70%. There are 3types of recurrence: the intersphincteric fistula, the original fistulatula (trans- or supra-sphincteric) and the residual external tract. Considering the types of recurrence, only 12,7% of patients need more complex surgery to solve their pathology. The rest of the recurrences/persistence were solved by simple procedures (fistulotomy in intersphincteric forms and legrado in residual tracts). PMID- 28669409 TI - Notch signaling pathway regulates the growth and the expression of inflammatory cytokines in mouse basophils. AB - Basophils (BAs) are the least common granulocytes of all leukocytes, but they play an important role in orchestrating of chronic allergic inflammation. The Notch signaling pathway is a highly conserved pathway that influences cell lineage decisions and differentiation during various stages of development. However, the relationship between Notch signaling and BA remains to be elucidate. Here, we report that several Notch signaling molecules were found to be expressed in BAs. gamma-secretase inhibitor (GSI) treatment increase BAs apoptosis, and suppress BAs proliferation. Furthermore, GSI reduced BAs in the S phase, with a concomitant accumulation in G1 and G2 phases. In addition, GSI also significantly down-regulated mRNA levels of cytokines IL-4, IL-6 and IL-13 induced by A23187, and this effect was dependent on MAPK pathway. Finally, IL-6 inhibition was specifically associated with ERK and IL-13 with JNK. Therefore, Notch signaling regulates BA biological function, at least partially via the modulation of MAPK. PMID- 28669410 TI - Thrombin activatable fibrinolysis inhibitor (TAFI) - A possible link between coagulation and complement activation in the antiphospholipid syndrome (APS). AB - BACKGROUND: Thrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. AIM: To investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls. RESULTS: TAFI (p<0.001), TAFIa (p<0.05) and complement factor C5a (p<0.001) were increased, while fibrin permeability (p<0.01) was decreased and clot lysis time (CLT) was prolonged (p<0.05) in APS patients compared to controls. Furthermore, TAFIa was increased (p<0.01) in samples from APS patients affected by arterial thrombosis compared to other APS-phenotypes. Positive associations were found between TAFI and age, fibrinogen and C5a, and between TAFIa and age, fibrinogen and thrombomodulin. CONCLUSION: TAFI and TAFIa levels were increased in patients with APS as a potential response to complement activation. Interestingly, TAFI activation was associated with arterial thrombotic APS manifestations. Thus, TAFIa may be considered a novel biomarker for arterial thrombosis in APS. PMID- 28669411 TI - A Map of Clinical Dermatology Research Centers in Spain: Results of the MaIND Study. AB - BACKGROUND AND OBJECTIVE: Bibliometric indicators and analyses of clinical research articles can help to quantify the scientific production of hospitals and institutions and identify their main areas of research. The aim of this study was to draw up a bibliometric map of clinical research in dermatology by Spanish hospitals and institutions through an analysis of quantitative, qualitative, and topic-based variables. MATERIAL AND METHOD: Bibliometric study of clinical research articles that met the inclusion criteria and had a definitive publication date between 2005 and 2014 in PubMed or Embase in which the corresponding author's affiliation was a Spanish dermatology department or institution. RESULTS: Barcelona and Madrid were the provinces with the highest number of articles and citations. The centers with the most articles and citations were Hospital Clinic and Instituto Valenciano de Oncologia. Those 2 hospitals also produced the highest number of articles on the most common research topic identified: melanoma. Because the articles were selected on the basis of the affiliation of the corresponding author to a Spanish dermatology center, this analysis does not include collaborative studies or clinical research studies led by nondermatology centers. CONCLUSIONS: We have created a bibliometric map of clinical dermatology research in Spain that shows the distribution of scientific production and the main areas of research by province and hospital/institution. This map could be useful for education and research purposes. PMID- 28669412 TI - Clinical Features of Merkel Cell Carcinoma. PMID- 28669413 TI - Not as Good as it Looks. PMID- 28669414 TI - Evolution of spall-damage in iron caused by repeated plate impacts: Ultrasonic evaluation. AB - This paper focuses on the developed of spall-damage that occurs in pure iron as a result of repeated impact. The employed low-frequency scanning acoustic microscopy (LF-SAM) observations combined with the measurements of ultrasonic wave velocity, attenuation, backscattering intensity and amplitude spectrum of the reflected wave, enabled us to provide a nondestructive evaluation. The spall damage distribution was analyzed in the C-scan images, and we found the spall damage increase with impact stress when the latter exceeds the characteristic spall-threshold stress. Moreover, we recorded the decreased sound velocity, amplitude ratio, and the increase of backscattering intensity, significant attenuation (the high frequency component of the reflected wave) for enhanced impact stress. It was also demonstrated that the tiny cracks generated in iron develop significantly during subsequent impacts either with lower or higher impact stress. Since the presented results concern for the first time the multiple-impact experiments, we contend that the applied ultrasonic investigations constitute the effective method of nondestructive spall-damage evaluation. PMID- 28669415 TI - Global disparities in maternal morbidity and mortality. AB - The disparity in maternal mortality for African American women remains one of the greatest public health inequities in the United States (US). To better understand approaches toward amelioration of these differences, we examine settings with similar disparities in maternal mortality and "near misses" based on race/ethnicity. This global analysis of disparities in maternal mortality/morbidity will focus on middle- and high-income countries (based on World Bank definitions) with multiethnic populations. Many countries with similar histories of slavery and forced migration demonstrate disparities in health outcomes based on social determinants such as race/ethnicity. We highlight comparisons in the Americas between the US and Brazil-two countries with the largest populations of African descent brought to the Americas primarily through the transatlantic slave trade. We also address the need to capture race/ethnicity/country of origin in a meaningful way in order to facilitate transnational comparisons and potential translatable solutions. Race, class, and gender-based inequities are pervasive, global themes. This approach is human rights-based and consistent with the UN Millennium Development Goals (MDG) and post 2015-sustainable development goals' aim to place women's health the context of health equity/women's rights. Solutions to these issues of inequity in maternal mortality are nation-specific and global. PMID- 28669416 TI - The Utility Of Diaphragmatic Ultrasound In The Radiological Diagnosis Of Systemic Lupus Erythymatosus Patients With Shrinking Lung Syndrome. PMID- 28669417 TI - St. George Mivart as Popularizer of Zoology in Britain and America, 1869-1881. AB - Recent scholarly attentions have shifted from key actors within the scientific elite and religious authorities to scientific practitioners and popularizers who used science to pursue a wide variety of cultural purposes. The Roman Catholic zoologist St. George Mivart (1827-1900) has typically been cast as a staunch anti Darwinian ostracized by Darwin's inner circle of scientific naturalists. Understood as a popularizer of science, his position can be re-thought. Mivart did not operate on the periphery of Victorian science. Instead, his notable contributions to the fields of zoology and anatomy and his participation in debates about the origin of the human mind, consciousness, and soul made him a central figure in the changing landscape of late-Victorian scientific culture. Through the popular periodical press and his anatomy textbook for beginners, Mivart secured a reputation as a key spokesman for science and gained authority as a leading critic of agnostic scientific naturalism. PMID- 28669419 TI - Identification of Associated Genes and Diseases in Patients With Congenital Upper Limb Anomalies: A Novel Application of the OMT Classification. AB - PURPOSE: Congenital upper-limb anomalies (CULA) can present as a part of a syndrome or association. There is a wide spectrum of CULA, each of which might be related to different diseases. The structure provided by the Oberg, Manske, and Tonkin (OMT) classification could aid in differential diagnosis formulation in patients with CULA. The aims of this study were to review the Human Phenotype Ontology (HPO) project database for diseases and causative genes related to the CULA described in the OMT classification and to develop a methodology for differential diagnosis formulation based on the observed congenital anomalies, CulaPhen. METHODS: We reviewed the HPO database for all diseases, including causative genes related to CULA. All CULA were classified according to the OMT classification; associated non-hand phenotypes were classified into 12 anatomical groups. We analyzed the contribution of each anatomical group to a given disease and developed a tool for differential diagnosis formulation based on these contributions. We compared our results with cases from the literature and with a current HPO tool, Phenomizer. RESULTS: In total, 514 hand phenotypes were obtained, 384 of which could be classified in the OMT classification. A total of 1,403 diseases could be related to those CULA. A comparison with 10 recently published cases with CULA revealed that the presented phenotype matched the descriptions in our dataset. The differential diagnosis produced using our methodology was more accurate than Phenomizer in 4 of 5 examples. CONCLUSIONS: The OMT classification can be used to describe hand anomalies that may present in over 1,400 diseases. CulaPhen was developed to provide a (hand) phenotype-based differential diagnosis. Differential diagnosis formulation based on the proposed system outperforms the system in current use. CLINICAL RELEVANCE: This study illustrates that the OMT diagnoses, either individually or combined, can be cross referenced with different diseases and syndromes. Therefore, use of the OMT classification can aid differential diagnosis formulation for CULA patients. PMID- 28669418 TI - Checkpoints to Progression: Qualitative Analysis of the Personal and Contextual Factors That Influence Selection of Upper Extremity Reconstruction Among Patients With Tetraplegia. AB - PURPOSE: Patients with tetraplegia consistently rank better use of the upper extremity as their top functional priority. Multiple case series have demonstrated that upper extremity reconstruction (UER) is well-tolerated and can produce substantial functional improvements for appropriate candidates; however, UER remains critically underutilized. The mechanisms that drive differences in provider practice and referral patterns have been studied, but comprehensive examination of the patient factors that influence UER decisions has not been performed for American patients. METHODS: Nineteen patients with C4-8 cervical spinal injuries were selected using purposive sampling: 9 patients had undergone UER, 10 had not undergone UER. Semistructured interviews were conducted and transcripts evaluated using grounded theory methodology. RESULTS: Our study yielded a conceptual model that describes the characteristics common to all patients who undergo UER. Patients who selected reconstruction proceeded stepwise through a shared sequence of steps: (1) functional dissatisfaction, (2) awareness of UER, and (3) acceptance of surgery. Patients' ability to meet these criteria was determined by 3 checkpoints: how well they coped, their access to information, and the acceptability of surgery. Extremely positive or negative coping prevented patients from moving from the Coping to the Information Checkpoint; thus, they remained unaware of UER and did not undergo surgery. A lack of knowledge regarding reconstruction was the strongest barrier to surgery among our participants. CONCLUSIONS: We built a conceptual model that outlines how patients' personal and contextual factors drive their progression to UER. Moving from functional dissatisfaction to understanding that they were candidates for UER was a substantial barrier for participants, particularly those with very high and very low coping skills. CLINICAL RELEVANCE: To improve utilization for all patients, interventions are needed to increase UER awareness. Standardizing introduction to UER during the rehabilitation process or improving e-content may represent key awareness access points. PMID- 28669420 TI - Radial Longitudinal Deficiency: Recent Developments, Controversies, and an Evidence-Based Guide to Treatment. AB - Radial longitudinal deficiency (RLD) is the most common congenital longitudinal deficiency at birth and represents a wide spectrum of upper extremity anomalies, from mild thumb hypoplasia to absent radius. Radial dysplasia may be isolated or associated with an array of systemic anomalies that should be familiar to pediatric hand surgeons. The management of RLD has evolved greatly since its inception in the late 19th century, largely due to decades of innovation that followed the thalidomide catastrophe of the 1960s. Yet controversy still exists regarding many aspects of RLD. Traditional treatments of radial dysplasia (ie, centralization) are unfortunately wrought with poor outcomes and high rates of recurrence, leading some authors to recommend alternative techniques for this condition. Reconstruction of the hypoplastic thumb, although less controversial, is just starting to see long-term outcomes. This article reviews the etiology, classification, and treatment options for RLD, highlighting recent developments and outcomes. PMID- 28669421 TI - Erratum. PMID- 28669422 TI - Slower resting alpha frequency is associated with superior localisation of moving targets. AB - We examined the neurophysiological underpinnings of individual differences in the ability to maintain up-to-date representations of the positions of moving objects. In two experiments similar to the multiple object tracking (MOT) task, we asked observers to monitor continuously one or several targets as they moved unpredictably for a semi-random period. After all objects disappeared, observers were immediately prompted to report the perceived final position of one queried target. Precision of these position reports declined with attentional load, and reports tended to best resemble positions occupied by the queried target between 0 and 30ms in the past. Measurement of event-related potentials showed a contralateral delay activity over occipital scalp, maximal in the right hemisphere. The peak power-spectral frequency of observers' eyes-closed resting occipital alpha oscillations reliably predicted performance, such that lower frequency alpha was associated with superior spatial localisation. Slower resting alpha might be associated with a cognitive style that depends less on memory related processing and instead emphasises attention to changing stimuli. PMID- 28669424 TI - [Current opinion on the therapeutic education of patients with atopic dermatitis]. PMID- 28669423 TI - [Influence of perfusion status on central and mixed venous oxygen saturation in septic patients]. AB - BACKGROUND AND OBJECTIVES: Although there is controversy regarding the role of venous oxygen saturation in the initial resuscitation of septic patients with hypoperfusion, these markers are still widely used. This study aimed to evaluate the correlation and concordance between central (SvcO2) and mixed (SvO2) oxygen saturation in septic shock patients with or without hypoperfusion, in addition to the impact of these differences in patient conduction. METHODS: Patients with septic shock were monitored with pulmonary artery catheter and the following subgroups of hypoperfusion were analyzed: 1) lactate>28mg.dL-1; 2) base excess <= -5mmoL.L-1; 3) venoarterial CO2 gradient>6mmHg; 4) SvO2<65%; 5) SvcO2<70%; 6) lactate>28mg.dL-1 and SvO2<70%; 7) lactate>28mg.dL-1 and SvcO2<75%. RESULTS: Seventy-seven samples from 24 patients were included. There was only a moderate correlation between SvO2 and SvcO2 (r=0.72, p=0.0001) and there was no good concordance between these variables (7.35% bias and 95% concordance limits of 3.0%-17.7%). Subgroup analysis according to the presence of hypoperfusion showed no differences in concordance between variables. There was discordance regarding clinical management in 13.8% (n=9) of the cases. CONCLUSIONS: There is a moderate correlation between SvO2 and SvcO2; however, the concordance between them is inadequate. It was not possible to demonstrate that the presence of hypoperfusion alters the concordance between SvO2 and SvcO2. The use of SvO2 instead of SvcO2 may lead to changes in clinical management in a small but clinically relevant portion of patients. PMID- 28669426 TI - [Pemphigus: Towards a drastic reduction in corticosteroid therapy thanks to rituximab]. PMID- 28669425 TI - [Treatment of Hailey-Hailey disease with botulinic toxin: A retrospective study of 8 cases]. AB - BACKGROUND: Hailey-Hailey disease (HHD) is characterised by episodes of weeping erythematous lesions, particularly in areas subject to friction or maceration. Treatment is complex. The value of botulinum toxin has been demonstrated in several studies and in individual cases. AIM: To report clinical and progressive data for 8 patients treated for HHD with injections of botulinum toxin A (BTX-A), following the failure of several other therapeutic approaches. PATIENTS AND METHODS: Eight patients (three males and five females), of median age 52.5 years (31-80), were included in this retrospective study. Familial history of the disease was noted in 75% of cases. The lesions affected the axillary regions (62% of cases), the sub-mammary region (almost all female patients), the inguinal region (75%) and the genital area (25%). The mean dose injected per site and per session was 300IU of Dysport(r). Clinical evaluation was based on photographs taken before treatment and then after 6 months. RESULTS: Effects on sweating were rapid and occurred as of the fourth day treatment. On average, patient felt the benefits of the injection within 7 days, with subsidence of their erythema and healing of the rhagades. At 6 months, complete clinical response was noted in 80% of the treated zones (12 sites of 15), with partial response in 3 profuse zones (sub-mammary and inguinal). Maintenance sessions were initiated for 6 of the 8 patients due to relapse beyond six months. CONCLUSION: Botulin toxin appears to offer a therapeutic alternative in resistant forms of HHD, either as follow-on treatment or as an adjuvant to more radical forms of therapy such as CO2 laser. These retrospective data, as well as the optimal doses and injection rates, require further refinement by means of prospective studies. PMID- 28669427 TI - [Photography in dermatologic practice. Ethical questions]. PMID- 28669428 TI - Preoperative evaluation of anomalous pulmonary venous connection using dual source computed tomography: Comparison with echocardiography. AB - PURPOSE: To evaluate the image features and diagnostic agreement for anomalous pulmonary venous connection (APVC) by dual-source computed tomography (DSCT) before surgery when compared with trans-thoracic echocardiography (TTE). MATERIALS AND METHODS: A total of one hundred and twenty-three patients were enrolled in this study. The associated malformation was analyzed between 39 total anomalous pulmonary venous connections (TAPVC) and 84 partial anomalous pulmonary venous connections (PAPVC). For 75 patients who received surgical treatment, the diagnostic agreement between the surgical findings of DSCT and TTE was evaluated. The dimensions of the four chambers of the heart were also measured by DSCT and TTE. RESULTS: Atrial septal defect is the most common anomaly associated with APVC (86/123, 69.9%), which has a higher incidence in TAPVC compared to that in PAPVC (100% vs. 56.0%, p<0.001). Of 75 operative patients, discrepancies in diagnostic sensitivity existed between DSCT and TTE for different drainage sites, supracardiac (94.4% vs. 82.2%, p=0.001), cardiac (98.7% vs. 91.1%, p=0.089), and infracardiac (100% vs. 57.1%, p=0.096), respectively, and for different venous origins, right superior pulmonary vein (98.4% vs. 87.1%, p=0.871), right inferior pulmonary vein (100% vs. 87.3%, p=0.006), left superior pulmonary vein (100% vs. 93.1%, p=0.246), left inferior pulmonary vein (100% vs. 95.7%, p=0.500), and atypical pulmonary vein (66.7% vs. 44.4%, p=0.011), respectively. Good agreement was obtained between DSCT and TTE for measurements of left atrium, left ventricle, right atrium, and right ventricle sizes (bias 0.3+/-5.05mm, -0.3+/ 4.50mm, 5.8+/-14.15mm, and 1.1+/-5.95mm, respectively). CONCLUSIONS: DSCT can provide optimal and accurate anatomy details for patients with APVC, and serves as a promising accessary imaging modality after TTE to achieve a better and comprehensive preoperative imaging evaluation. PMID- 28669429 TI - Hybrid Photoacoustic/Ultrasound Tomograph for Real-Time Finger Imaging. AB - We report a target-enclosing, hybrid tomograph with a total of 768 elements based on capacitive micromachined ultrasound transducer technology and providing fast, high-resolution 2-D/3-D photoacoustic and ultrasound tomography tailored to finger imaging. A freely programmable ultrasound beamforming platform sampling data at 80 MHz was developed to realize plane wave transmission under multiple angles. A multiplexing unit enables the connection and control of a large number of elements. Fast image reconstruction is provided by GPU processing. The tomograph is composed of four independent and fully automated movable arc-shaped transducers, allowing imaging of all three finger joints. The system benefits from photoacoustics, yielding high optical contrast and enabling visualization of finger vascularization, and ultrasound provides morphologic information on joints and surrounding tissue. A diode-pumped, Q-switched Nd:YAG laser and an optical parametric oscillator are used to broaden the spectrum of emitted wavelengths to provide multispectral imaging. Custom-made optical fiber bundles enable illumination of the region of interest in the plane of acoustic detection. Precision in positioning of the probe in motion is ensured by use of a motor driven guide slide. The current position of the probe is encoded by the stage and used to relate ultrasound and photoacoustic signals to the corresponding region of interest of the suspicious finger joint. The system is characterized in phantoms and a healthy human finger in vivo. The results obtained promise to provide new opportunities in finger diagnostics and establish photoacoustic/ultrasound-tomography in medical routine. PMID- 28669430 TI - Complications After Gynecologic and Obstetric Procedures: A Pictorial Review. AB - Gynecologic and obstetric procedures require careful dissection in to high real estate regions in the pelvis and abdomen where many structures lie in close proximity: the urinary bladder, ureter, and bowel. Damage to one of these structures can cause significant morbidity. Recognition of the patient who has an acute complication of gynecologic or obstetric surgery on imaging can precipitate quick and effective medical management. Imaging can appropriately diagnose the underlying problem and provide critical information for the clinical team. In this review, we present acute complications of gynecologic and obstetric procedures and their imaging appearances. PMID- 28669431 TI - Radiology Online Patient Education Materials Provided by Major University Hospitals: Do They Conform to NIH and AMA Guidelines? AB - AIMS: The internet creates opportunities for Americans to access medical information about imaging tests and modalities to guide them in their medical decision-making. Owing to health literacy variations in the general population, the American Medical Association and National Institutes of Health recommend patient education resources to be written between the third and seventh grade levels. Our purpose is to quantitatively assess the readability levels of online radiology educational materials, written for the public, in 20 major university hospitals. MATERIALS AND METHODS: In September and October 2016, we identified 20 major university hospitals with radiology residency-affiliated hospital systems. On each hospital's website, we downloaded all radiology-related articles written for patient use. A total of 375 articles were analyzed for readability level using 9 quantitative readability scales that are well validated in the medical literature. RESULTS: The 375 articles from 20 hospital systems were collectively written at an 11.4 +/- 3.0 grade level (range: 8.4-17.1). Only 11 (2.9%) articles were written at the recommended third to seventh grade levels. Overall, 126 (33.6%) were written above a full high-school reading level. University of Washington Medical Center's articles were the most readable with a reading level corresponding to 7.9 +/- 0.9. CONCLUSIONS: The vast majority of websites at major academic hospitals with radiology residencies designed to provide patients with information about imaging were written above the nationally recommended health literacy guidelines to meet the needs of the average American. This may limit the benefit that patients can derive from these educational materials. PMID- 28669432 TI - Cardiorenal Syndrome: Diagnosis and Management. AB - Cardiorenal syndrome (CRS) has not been well characterized in veterinary medicine, yet an accurate appreciation of the kidney and the cardiovascular system and their interactions may have practical clinical implications. A consensus for cardiovascular-renal axis disorders of dogs and cats was recently attempted. The outcome of patients with CRS is likely to improve with the increasing awareness and ability to identify and understand the pathophysiologic characteristics of CRS. The utilization of existing and emerging organ-specific biomarkers with greater sensitivities than conventional diagnostics forecast new opportunities to diagnose and manage cardiac disease. PMID- 28669433 TI - Asymptomatic Canine Degenerative Valve Disease: Current and Future Therapies. AB - Degenerative valve disease (DVD) is the leading cause of heart disease and congestive heart failure (CHF) in the dog. The first published consensus statement provided guidelines for the diagnosis and treatment of DVD. Although treatment was not recommended in stage B1 DVD, consensus was not reached regarding evidence-based recommendations for treatment of stage B2 DVD. This article addresses the impact of new evidence on historical recommendations for stage B DVD and gives the reader a glimpse into possible future therapies. Management of common sequelae of DVD that can result in clinical signs that are not attributable to CHF is also discussed. PMID- 28669434 TI - Real-time Three-dimensional Echocardiography: From Diagnosis to Intervention. AB - Echocardiography is one of the most important diagnostic tools in veterinary cardiology, and one of the greatest recent developments is real-time three dimensional imaging. Real-time three-dimensional echocardiography is a new ultrasonography modality that provides comprehensive views of the cardiac valves and congenital heart defects. The main advantages of this technique, particularly real-time three-dimensional transesophageal echocardiography, are the ability to visualize the catheters, and balloons or other devices, and the ability to image the structure that is undergoing intervention with unprecedented quality. This technique may become one of the main choices for the guidance of interventional cardiology procedures. PMID- 28669435 TI - Durability of tissue valves: Only time will tell? PMID- 28669436 TI - "Be like Mike...". PMID- 28669437 TI - Is the right internal thoracic artery superior to saphenous vein for grafting the right coronary artery? A propensity score-based analysis. AB - OBJECTIVES: Although the use of the right internal thoracic artery (RITA) as second arterial conduit to graft the left coronary system consistently has been shown to provide a survival benefit compared with the saphenous vein graft (SVG), the choice of conduit for the right coronary artery (RCA) system remains controversial. We compared long-term (>15 years) survival in patients who underwent RITA-RCA versus SVG-RCA grafting at a single institution. METHODS: The study population consisted of 7223 patients undergoing coronary artery bypass graft surgery. Of them 245 (3.4%) and 6978 (96.6%) received RITA-RCA and SVG-RCA graft, respectively. Propensity score matching and time-segmented Cox regression were used to compare the 2 groups. RESULTS: Survival probability at 5, 10, and 15 years were 95.9% (95% confidence interval [CI], 93.4-98.4) versus 96.0% (95% CI, 94.3-97.8), 89.8% (95% CI, 85.9-93.7) versus 88.0% (95% CI, 85.0-91.0) and 82.9% (95% CI, 77.6-88.2) versus 76.3 (95% CI, 72.0-80.5) in the RITA-RCA and SVG-RCA group, respectively. Time-segmented Cox regression showed that during the first 9 years, the 2 strategies were associated with comparable risk of death (hazard ratio, 1.13; 95% confidence interval, 0.67-1.90; P = .65) but beyond 9 years, the RITA-RCA was associated with a significantly lower risk of death (hazard ratio, 0.43; 95% confidence interval, 0.22-0.84; P = .01). CONCLUSIONS: Revascularization of the RCA system with the RITA was associated with superior late survival compared with SVG. This supports the view that, the use of RITA to graft the RCA should be encouraged, especially in patients with long life expectancy. PMID- 28669438 TI - Heading toward the future of pediatric heart failure with continuous-flow ventricular assist devices. PMID- 28669439 TI - Biochemistry: On bicuspid aortic valve's aortic service. PMID- 28669440 TI - Electrical storms in patients with apical aneurysms and hypertrophic cardiomyopathy with midventricular obstruction: A case series. PMID- 28669441 TI - Start small, think big. PMID- 28669442 TI - Scar massage for hypertrophic burns scarring-A systematic review. AB - BACKGROUND: Scar massage is used in burn units globally to improve functional and cosmetic outcomes of hypertrophic scarring following a burn, however, the evidence to support this therapy is unknown. OBJECTIVE: To review the literature and assess the efficacy of scar massage in hypertrophic burn scars. METHODS: MEDLINE, PubMed, Embase, CINAHL and the Cochrane Library were searched using the key words "burn", "burn injury", "thermal injury" and "scar", "hypertrophic scar" and "massage", "manipulation", "soft tissue mobilisation", "soft tissue manipulation". The articles were scored by the assessors using the Physiotherapy Evidence Database (PEDro) scale and outcome measures on range of motion (ROM), cosmesis (vascularity, pliability, height), pain scores, pruritus, and psychological measures of depression and anxiety were extracted. RESULTS: Eight publications were included in the review with 258 human participants and 15 animal subjects who received scar massage following a thermal injury resulting in hypertrophic scarring. Outcome measures that demonstrated that scar massage was effective included scar thickness as measured with ultrasonography (p=0.001; g= 0.512); depression (Centre for Epidemiologic Studies - Depression [CES-D]) (p=0.031; g=-0.555); pain as measured with Visual Analogue Scale (VAS) (p=0.000; g=-1.133) and scar characteristics including vascularity (p=0.000; g=-1.837), pliability (p=0.000; g=-1.270) and scar height (p=0.000; g=-2.054). Outcome measures that trended towards significance included a decrease in pruritus (p=0.095; g=-1.157). CONCLUSIONS: It appears that there is preliminary evidence to suggest that scar massage may be effective to decrease scar height, vascularity, pliability, pain, pruritus and depression in hypertrophic burns scaring. This review reflects the poor quality of evidence and lack of consistent and valid scar assessment tools. Controlled, clinical trials are needed to develop evidence-based guidelines for scar massage in hypertrophic burns scarring. PMID- 28669443 TI - I125 brachytherapy guided by individual three-dimensional printed plates for recurrent ameloblastoma of the skull base. AB - Ameloblastoma is one of the most common benign odontogenic tumours of the mandible and the maxilla. Wide excision of the tumour is the first choice for treatment (except for unicystic ones). Patients with invaded margins or unresectable lesions may require radiotherapy. Today, permanent implantation of I125 seeds is widely used in the treatment of cancer of the head and neck. We report a case of recurrent ameloblastoma of the base of the skull that was treated with I125 brachytherapy. The outcome has been encouraging, with total disappearance of the tumour on positron emission tomography 18 months later. PMID- 28669444 TI - Long-term influence of mandibular advancement on the volume of the posterior airway in skeletal Class II-patients: a retrospective analysis. AB - In the past, maxillomandibular advancement has resulted in considerable improvement in the volume of the posterior airway space. The objective of the present study was to find out how mandibular advancement without maxillary involvement would affect the posterior airway space in patients with mandibular retrognathism. Cone-beam computed tomographic (CT) scans were done for 20 patients before, and six months after, mandibular advancement. Cephalometric analysis at both time points included 2-dimensional and 3-dimensional assessment of the upper airway. Eight men and 12 women presented a preoperative mean (SD) Wits value of 7.4 (1.54) mm, with an airway area of 7.11 (1.88) cm2 and a volume of 14.92 (4.46) cm3. Six months postoperatively they showed a Wits value of 2.7 (0.41) mm, an airway area of 11.33 (3.49) cm2, and a volume of 25.7 (6.10) cm3. There was a mean (range) enlargement of 59 (22-82) % of the area and 73 (29-108) % of the volume. A preoperative Wits value of 8mm or more correlated significantly with a larger increase of the posterior airway space (p=0.002). At the same time, an improvement in the Wits value of 4.5mm or more correlated significantly with an increase in volume (p=0.016). The effect of mandibular advancement on the posterior airway space was significant, and the volumetric effect seems to be even more relevant than the two-dimensional changes. PMID- 28669445 TI - Interconvertible geometric isomers of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors exhibit multiple binding modes. AB - Two new tricyclic beta-aminoacrylate derivatives (2e and 3e) have been found to be inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) with Ki 0.037 and 0.15MUM respectively. 1H and 13C NMR spectroscopic data show that these compounds undergo ready cis-trans isomerisation at room temperature in polar solvents. In silico docking studies indicate that for both molecules there is neither conformation nor double bond configuration which bind preferentially to PfDHODH. This flexibility is favourable for inhibitors of this channel that require extensive positioning to reach their binding site. PMID- 28669446 TI - Inflammation and myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPN) include three main entities: Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF). MPN represent a unique model of the relationship between the clonal development of a hematologic malignancy and chronic inflammation. The neoplastic clone is the main driver of this inflammatory reaction as demonstrated by the curative effect of allogeneic stem cell transplantation which leads not only to a complete restore of the hematopoiesis, but also to regression of bone marrow fibrosis. The neoplastic clone and its differentiated progeny are also the main source of an indirect paracrine secretion of inflammatory cytokines released by different normal cells present within the tumor microenvironment. In the end, the cytokine storm within the bone marrow niche leads to fibrosis. In addition, chronic inflammation is responsible of the constitutional symptoms which negatively affect the quality of life of MPN patients and represents a major driver for the development of premature atherosclerosis and disease progression. Here we describe the available data about the link between MPN and chronic inflammation in animal models as well as in clinical studies. We also review the practical value of including acute phase inflammatory proteins such as high sensitivity C-reactive protein (hs-CRP) and pentraxin 3 (PTX-3) in prognostic stratification of MPN patients. Interestingly, the plasma levels of these proteins is often increase in MPN patients and this may be important when considering the well-established link between these two inflammatory proteins and the risk of both arterial and venous thrombosis. Although the available drugs are unable to eradicate the malignant clone, the ability to identify patient with a high inflammatory burden and an adverse molecular profile is important to advise therapy with ruxolitinib or even allogeneic stem cell transplantation that currently represents the only potentially curative option for these diseases. PMID- 28669447 TI - 2017 ACC/AAP/AHA Health Policy Statement on Opportunities and Challenges in Pediatric Drug Development: Learning From Sildenafil. PMID- 28669448 TI - Muscular fitness, adherence to the Southern European Atlantic Diet and cardiometabolic risk factors in adolescents. AB - BACKGROUND AND AIM: Muscular fitness and an adherence to the Southern European Atlantic Diet (SEADiet) have been inversely associated with cardiometabolic risk. Our aim was to assess the independent and combined associations of muscular fitness and adherence to the SEADiet on cardiometabolic risk in adolescents. METHODS AND RESULTS: A total of 467 Portuguese adolescents (275 girls) participated in this cross-sectional study. Sum of the Z-Scores of Curl-Up and Push-Up tests was used to create a muscular fitness score. Adherence to SEADiet was obtained using a food frequency questionnaire. A cardiometabolic risk score was computed from sum of Z-score of triglycerides, systolic blood pressure, total cholesterol/HDL ratio, HOMA-IR and waist circumference. Adolescents with low muscular fitness and low adherence to the SEADiet had the poorest cardiovascular profile F(5, 452) = 5.074 (p < 0.001) and the highest odds of having a high cardiometabolic risk score (OR = 4.5; 95% CI: 2.1-14) when compared to those with High muscular fitness/High adherence to the SEADiet after adjustments for age, sex, pubertal stage, socioeconomic status, total energy intake, low-energy reporter and cardiorespiratory fitness. CONCLUSIONS: Our findings seem suggest that improving muscular fitness as well as an adherence to the SEADiet could be an important strategy to reduce clustered cardiometabolic risk in youth. PMID- 28669449 TI - Neoadjuvant Therapy in Early Breast Cancer: Treatment Considerations and Common Debates in Practice. AB - Neoadjuvant treatment offers a number of benefits for patients with early breast cancer, and is an important option for consideration by multidisciplinary teams. Despite literature showing its efficacy, the use of neoadjuvant therapy varies widely. Here we discuss the clinical evidence supporting the use of neoadjuvant therapy in early stage breast cancer, including patient selection, monitoring response, surgery and radiotherapy considerations, with the aim of assisting multidisciplinary teams to determine patient suitability for neoadjuvant treatment. PMID- 28669450 TI - Pressure and Flow Comparisons Across Vocal Pathologies. AB - OBJECTIVE: The aim of this study was to aid in the distinction among hyperadductive dysphonias by evaluating peak glottal pressure, release burst, and mid and final airflow values across repeated /pa/ syllable trains. METHODS: Sixty subjects were assessed for aerodynamic patterns during onset-offset for the /papapapapa/ task in modal voice. Subject groups included adductory spasmodic dysphonia (AdSD), benign vocal fold lesion, primary muscle tension dysphonia (MTD 1), secondary muscle tension dysphonia with an identifiable primary benign vocal fold lesion (MTD-2), vocal fold paresis or paralysis, and normal controls. RESULTS: Increased peak pressure (PP) was found for AdSD and MTD-2 subjects compared with controls. Release burst and mid airflow were not significantly different among groups. Final airflow was significantly higher for AdSD compared with the other groups. Final airflow was significantly lower for MTD-1. CONCLUSIONS: Significant differences in aerodynamics are seen in subjects with AdSD compared to MTD. AdSD was characterized by higher PP and higher final airflow. MTD-1 was characterized by lower final airflow, whereas MTD-2 was characterized by higher PP. Aerodynamic evaluation may aid in differential diagnosis for those patients in whom distinction among hyperadductive disorders is challenging. PMID- 28669451 TI - Cancer incidence and mortality are associated with human development index and health setups in Africa. AB - BACKGROUND: This study aimed to analyse the correlation between cancer incidence and mortality and the Human Development Index (HDI) in Africa. Furthermore, to analyse the variations in cancer Mortality to Incidence Ratio (MIR) based on health care systems in African countries. MATERIAL AND METHODS: Cancer incidence and mortality data for 53 countries were obtained from GLOBOCAN database. Country wise data on National-HDI were obtained from Human Development Report 2015. Health System Attainment (HSA) data were acquired from World Health Report 2000. The parametric data were analysed by Pearson-correlation and Linear-regression analysis for the effect of HDI and HSA on MIR in African Countries. One-way ANOVA was used to test the differences of MIR in each HDI group. All analyses were performed in SPSS version 20. RESULTS: An inverse correlation was revealed by cancer MIR with both HDI (r=-0.897, p<0.001) and HSA (r=-0.750, p<0.001). A significantly low MIR was reported from high HDI countries compared to medium and low HDI countries by one-way ANOVA analysis (p<0.001). Linear regression analysis also reported a negative effect of MIR with both HDI (adjusted R2=0 0.801, beta= 0.897, p<0.001) and HSA (adjusted R2=0.554, beta=-0.750, p<0.001). CONCLUSIONS: Based on their HDIs, different African countries has different health system attainments, which is the cause of variations in MIR in these countries. To control their cancer burden, these low and medium HDI countries should focus on improvement of their economic status and policies making, regarding the provision of better health systems to the masses. PMID- 28669452 TI - Metaplastic breast carcinoma: Analysis of 31 cases from a single institute. AB - PURPOSE: Metaplastic carcinoma of the breast (MBC) accounts for less than 1% of all mammary tumors. This study aimed at revision of the clinico-pathological features, treatment strategy and outcome for MBC patients presented to the Kuwait Cancer Control Center to define the clinical behavior and prognostic factors of these neoplasms in our population. PATIENT AND METHODS: Thirty-one patients were retrieved from our surgical pathology registry between January 2005 and December 2014. Medical records were revised regarding the clinico-pathological features and treatment outcome. RESULTS: MBC represented 1% of our breast cancer patients. The median age was 50years (32-70years). Two patients presented with metastatic disease. Mastectomy was done for 24 patients and 7 had conservative surgery. The median tumor size at the time of surgery was 5.5cm (1.5-12cm). Axillary nodes were negative in 21 patients (N0), 5 patients were N1, 4 patients were N2 and one Nx. Three histological subtypes were presented: carcinosarcoma (7 cases), squamous cell carcinoma/IDC with squamous differentiation (15 cases), high grade IDC with metaplastic differentiation (9 cases). Immunohistochemically, 26 were negative hormone receptors and all were negative for Her2/neu overexpression. Chemotherapy was used in 28 patients, and adjuvant radiotherapy in 24 patients. The median follow-up was 47months (7-126months), six patients lost follow-up. The 5-year OS was 69% and 5-year PFS was 50%. CONCLUSION: MBC is a rare entity among breast carcinoma in Kuwait. Most of the cases present with poor prognostic indicators and often show lack of expression of ER, PR and Her2/neu. PMID- 28669453 TI - Infant Regulatory Problems and Obesity in Early Childhood. AB - OBJECTIVE: Difficult infant temperament is associated with higher weight status in infancy. However, the association of infant temperament, including regulatory capacities, has not been well studied as a possible predictor of future weight status in early childhood. We examined prospective associations of infant regulatory difficulties with obesity in early childhood in a large, diverse cohort. METHODS: We used data from 5750 children in the Early Childhood Longitudinal Study-Birth Cohort, excluding preterm infants and infants small or large for gestational age. Infant regulatory ability was measured at age 9 months by the Infant Toddler Symptom Checklist (ITSC). We created a multivariable logistic regression model comparing risk of obesity at preschool age in infants with ITSC scores >=6 to infants with scores <6. We further examined the association when stratified by a measure of maternal sensitivity. RESULTS: The cohort of children was 48% non-Hispanic white, and 51% were boys. Twenty-one percent of children with ITSC scores >=6 were obese at preschool age. Infants with ITSC scores >=6 had 32% increased odds of being obese at preschool age (adjusted odds ratio 1.32 [95% confidence interval 1.03, 1.70]). The strongest association existed among children described as demanding attention constantly. There was no difference in the association when comparing mothers with high or low maternal sensitivity. CONCLUSIONS: Infant regulatory difficulties are associated with a higher risk of obesity at preschool age. Helping parents manage and respond to difficult infant behaviors before preschool may serve as a focal point for future interventions. PMID- 28669454 TI - Neurophysiological studies on atypical parkinsonian syndromes. AB - There have been a relatively large number of experimental investigations using neurophysiological techniques in patients with atypical parkinsonian syndromes (APs), including progressive supranuclear palsy, cortico-basal syndrome and multiple system atrophy. Earlier studies focused on the startle, blink and trigemino-cervical reflexes and showed several brainstem abnormalities. Studies using transcranial magnetic stimulation have revealed a number of abnormalities in primary motor cortex and inter-hemispheric connectivity. More recent studies have highlighted the role of cerebellar dysfunction and have reported altered movement kinematics. Neurophysiological abnormalities in APs reflect degeneration or functional changes at multiple brain levels. In the majority of cases, APs share common abnormalities even though some neurophysiological changes differ among the various APs. Evidence of a correlation between neurophysiological abnormalities and clinical signs and symptoms in APs is limited. This paper provides an update on the results of experimental investigations using neurophysiological techniques in APs and also reviews similarities and differences between APs and Parkinson's disease. The potential role of neurophysiological abnormalities in the clinical context of APs is also discussed. PMID- 28669455 TI - Breaking the Silos of Protein Synthesis. AB - Protein synthesis requires factors that are proposed to enhance discrete steps. Eukaryotic initiation factor eIF5A was initially thought to affect initiation; however, it was later shown to facilitate translation elongation at polyproline. Recent work by Schuller et al. demonstrates that eIF5A facilitates both general elongation and termination in yeast, challenging these steps as silos. PMID- 28669456 TI - Biphasic Modeling of Mitochondrial Metabolism Dysregulation during Aging. AB - Organismal aging is classically viewed as a gradual decline of cellular functions and a systemic deterioration of tissues that leads to an increased mortality rate in older individuals. According to the prevailing theory, aging is accompanied by a continuous and progressive decline in mitochondrial metabolic activity in cells. However, the most robust approaches to extending healthy lifespan are frequently linked with reduced energy intake or with lowering of mitochondrial activity. While these observations appear contradictory, recent work and technological advances demonstrate that metabolic deregulation during aging is potentially biphasic. In this Opinion we propose a novel framework where middle age is accompanied by increased mitochondrial activity that subsequently declines at advanced ages. PMID- 28669457 TI - Secondary Partial Thrombosis of a False Lumen Responsible for Acute Mesenteric Embolisation. PMID- 28669459 TI - A Growing Type I TAAA After Treatment With a Multilayer Stent. PMID- 28669458 TI - Mid-term Results of Catheter Directed Foam Sclerotherapy Combined with Tumescent Local Anaesthesia for Treatment of Great Saphenous Vein Incompetence. AB - OBJECTIVES: The purpose of this prospective study was to evaluate the occlusion rate, clinical severity, disease specific health related quality of life (HRQoL), and safety in patients with great saphenous vein (GSV) reflux 3 years after a single treatment session of catheter directed foam sclerotherapy (CDFS) combined with peri-saphenous infiltration of tumescent local anaesthesia (TLA). METHODS: A total of 249 patients with symptomatic unilateral GSV incompetence underwent CDFS combined with TLA and were followed up for 3 years. The primary outcome was complete obliteration of the treated segment of the GSV. Secondary outcomes were changes in Venous Clinical Severity Score (VCSS) and Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ) score, absence of above knee GSV reflux, and safety of treatment. RESULTS: Three years after CDFS, the estimated cumulative proportion of persistently obliterated above knee GSV was 81.5%. Freedom from above knee GSV reflux was demonstrated in 89.6% of patients. Both the VCSS and CIVIQ score improved significantly (p < .0001 and <.0001, respectively). No major adverse events were encountered. Thrombophlebitis, skin pigmentation/matting, and transient scotomata were reported in 2%, 7.8%, and 0.8% of cases, respectively. CONCLUSION: CDFS combined with TLA for treatment of GSV incompetence yields good mid-term results in terms of occlusion rate, clinical severity, patients' QoL, and safety. PMID- 28669460 TI - Boot Camps: Preparing for Residency. AB - Simulation-based boot camps are growing in popularity and are effective in onboarding novice residents with new knowledge, skills, and behaviors. These intensive and immersive courses may be used to train residents and allied health professionals in specific procedures, teamwork, and management of rare clinical scenarios. A needs assessment of learners determines the course curriculum. Boot camps are designed to encourage active and hands-on participation with deliberate practice and immediate feedback. As surgical education shifts toward competency based medical education, there may be an even greater role for simulation-based boot camps as a training and assessment tool. PMID- 28669461 TI - Simulators for Laryngeal and Airway Surgery. AB - There is growing support from the Accreditation Council for Graduate Medical Education and the Joint Commission of Accreditation of Health Care Organizations for a competency-based evaluation of medical and surgical performance. This is part of the quality movement in health care whereby the Centers for Medicare and Medicaid Services and third-party insurance companies have begun to link reimbursement incentives to positive surgical outcomes. Laryngeal and airway surgery require precise technique and significant mastered skill that can be difficult to obtain during otolaryngology residency training. Simulators are useful for developing laryngeal and airway surgery skills ultimately evaluated in a competency-based manner. PMID- 28669462 TI - Advanced Pediatric Airway Simulation. AB - Simulation is an emerging and viable means to increase pediatric airway surgical training. A variety of simulators currently exist that may be used or modified for laryngoscopy, bronchoscopy, and endoscopic intervention, although anatomic realism and utility for complex procedures are limited. There is a need for further development of improved endoscopic and anatomic models. Innovative techniques are enabling small-scale manufacturing of generalizable and patient specific simulators. The high acuity of the pediatric airway patient makes the use of simulation an attractive modality for training, competency maintenance, and patient safety quality-improvement studies. PMID- 28669463 TI - Three-year efficacy and safety of exenatide once weekly: A pooled analysis of three trials. AB - AIMS: To evaluate the 3-year efficacy and safety of exenatide once weekly (QW) for type 2 diabetes (T2D) in a large clinical population. METHODS: This post hoc analysis of three DURATION studies examined pooled efficacy and adverse events with exenatide QW from the 2.5- to 3-year completer populations; insulin glargine (glargine) was a reference (DURATION-3). Patients randomized to exenatide QW during the controlled study periods continued controlled treatment (DURATION-3) or single-arm treatment (DURATION-1; DURATION-2) with exenatide QW for the study duration. RESULTS: In the exenatide QW group (N=329), reductions from baseline in HbA1c, fasting glucose, and body weight were maintained from weeks 4 to 156 (HbA1c: -1.1+/-1.3%; fasting glucose: -1.7+/-2.7mmol/L; body weight: -2.4+/ 5.6kg; P<0.05). Glycemic efficacy with exenatide QW and glargine was similar (HbA1c reduction: -0.8+/-1.0%; N=158); body weight increased with glargine (+2.0+/-4.9kg). Variable reductions in systolic blood pressure and low-density lipoprotein cholesterol occurred with exenatide QW. At week 156, 48.3% and 30.7% of exenatide QW recipients achieved HbA1c goals of <7.0% and <=6.5%, respectively. No new safety or tolerability issues were identified. CONCLUSIONS: Exenatide QW improved glycemic outcomes and was well tolerated in patients with T2D for up to 156weeks. PMID- 28669464 TI - Frailty and sarcopenia - newly emerging and high impact complications of diabetes. AB - Diabetes increases the risk of physical dysfunction and disability. Diabetes related complications and coexisting morbidities partially explain the deterioration in physical function. The decline in muscle mass, strength and function associated with diabetes leads to sarcopenia, frailty and eventually disability. Frailty acts as a mediator in the pathogenesis of disability in older people with diabetes and its measurement in routine daily practice is recommended. Frailty is a dynamic process which progresses from a robust condition to a pre-frail stage then frailty and eventually disability. Therefore, a multimodal intervention which includes adequate nutrition, exercise training, good glycaemic control and the use of appropriate hypoglycemic medications may help delay or prevent the progression to disability. PMID- 28669465 TI - Put Systems in Place to Better Measure Surgical Outcomes. AB - When it comes to interventional medicine, we must put systems in place to better measure outcomes. If surgeons detect poor outcomes, surgeons study and improve. The challenge is detection. Outcome measurement is paramount, and can mitigate against low volume or limited experience. PMID- 28669466 TI - Editorial Commentary: Volume and Outcome: 100 Years of Perspective on Value From E.A. Codman to M.E. Porter. AB - Outcome is the numerator for the value equation, with the denominator being cost; measurement of each is essential to determine the most effective care. With regard to both total shoulder arthroplasty and rotator cuff repair, outcomes of low (vs high) volume providers are associated with longer hospital stay, longer length of operating room time, increased hospital complications, and cost. This suggests that volume thresholds are a key to providing greater value. However, this effect can be modified through systematic efforts to measure outcome and thus improve. To quote Codman, "To effect improvement, the first step is to admit and record the lack of perfection. The next step is to analyze the causes of failure and to determine whether these causes are controllable." Thus, although volume most certainly plays a role in determining outcomes and cost, the more important principle is to measure outcomes and improve with such measurement. PMID- 28669467 TI - Editorial Commentary: Subacromial Decompression Is Unnecessary in Most Routine Rotator Cuff Repairs. AB - There is no need to perform subacromial decompression in partial bursal-sided rotator cuff repairs to obtain a good result. This, paired with the findings of previous studies of full-thickness rotator cuff repairs, suggests that extrinsic factors rarely affect the rotator cuff. PMID- 28669468 TI - Editorial Commentary: When You Have a Hammer, Everything Looks Like a Nail Tenodesis of a Normal Biceps Tendon at the Time of Arthroscopic Rotator Cuff Repair Should Be Avoided. AB - Because of difficulties in diagnosis of pathology of the long head of the biceps tendon and a desire to prevent later complications, there may be a tendency to perform a biceps tenodesis even when pathology is mild. Surprisingly, in this multivariate analysis of a large database, tenodesis of the biceps was associated with increased odds of revision rotator cuff repair. Although the statistical power of these findings must be viewed in light of the limitations of "big data," surgeons must still use all available tools to avoid treatment of normal anatomy. PMID- 28669469 TI - Editorial Commentary: Dry Shoulder Models Are Excellent for Training Shoulder Arthroscopic Skills. AB - Recent research supports the use of arthroscopic simulation using dry models in the training of residents and fellows learning arthroscopic shoulder surgery. PMID- 28669470 TI - Editorial Commentary: The Needle or the Knife? Platelet-Rich Plasma Versus Surgery for Lateral Epicondylitis. AB - The most efficacious treatment for patients with lateral epicondylitis who have not adequately improved despite being treated for extended periods with commonly used nonoperative measures is controversial. Are locally applied platelet-rich plasma (PRP) injections more effective than a surgical procedure, such as arthroscopic lateral epicondylitis debridement, in reducing symptoms for such patients? Level II evidence shows that long-term clinical benefits are much less likely to occur in patients receiving PRP injections. Moreover, in patients treated with PRP injection, progressively worsening pain is more likely to develop during activity at 1 and 2 years of follow-up in contradistinction to arthroscopically managed patients. PMID- 28669471 TI - Editorial Commentary: Adolescents Are Not Small Adults, and Girls Are Not Boys: Arthroscopic Treatment of Hip Labral Tears in Adolescents. AB - In a single-surgeon study of more than 1,400 hip arthroscopies, 102 "adolescents" (aged 13-18) were operated on for labral tears. The authors highlighted significant differences between females and males although the final clinical results in both genders were comparable. In contrast to the nearly equal female to-male ratio seen in most of the adult hip arthroscopy literature, there were >85% females and the authors described several anatomic differences that they stated affected their surgical approach. PMID- 28669472 TI - Editorial Commentary: A Positive "Half Dial Test" Is Seen in Anterior Cruciate Ligament Injury, so Get Out Your Goniometer. AB - Isolated anterior cruciate ligament (ACL)-deficient knees have roughly 7 degrees of increased external rotation at both 30 degrees and 90 degrees of flexion compared with both the contralateral knee and the ACL reconstructed knee. This positive "Half Dial test" may be a new approach to confirming ACL injury but requires confirmation that the posterolateral corner itself is not injured. In the ACL-deficient knee, it is suggested that a greater cutoff (>15 degrees ) for the true Dial test be used to confirm posterolateral corner injuries. Goniometer measurements are reproducible and necessary for confirmation. PMID- 28669473 TI - Editorial Commentary: Ultrasound Barely Beats Magnetic Resonance Imaging in Knee Anterolateral Ligament Evaluation...But Does This Change the Treatment of the Anterior Cruciate Ligament-Deficient Knee? AB - Ultrasound (US) examination of the anterolateral ligament (ALL) in the anterior cruciate ligament-deficient knee betters magnetic resonance imaging analysis with slightly higher identification rate of the entire ALL presumably due to the ability to test in a functional pivot shift configuration. The ALL was injured in 63% of the anterior cruciate ligament-deficient knees and the injury occurred at the tibial insertion in all cases. Although the authors propose US to be the new "gold standard" for diagnosing ALL injuries, there still remains a question of whether there is any necessity for an US diagnosis of ALL injury when the pivot shift test may provide the necessary information, and the consensus for ALL reconstruction or lateral extra-articular tenodesis has yet to be reached. PMID- 28669474 TI - Editorial Commentary: Angle Versus Anatomy: Sacrificing Graft Bending Angle for Anatomic Anterior Cruciate Ligament Reconstruction. AB - Graft bending angle (GBA) is the angle created by the intra-articular anterior cruciate ligament (ACL) graft and the femoral tunnel. By definition then, it is affected by the angle at which the surgeon drills the femoral tunnel. In an attempt to create a more anatomic ACL, different techniques have been described to put the femoral tunnel in the anatomic footprint. If you can get past each author's unique description of GBA, whether they are referring to the graft, the tunnel angle, or using adjectives such as acute or higher GBA, you see that attempting to create more anatomic ACL reconstructions has resulted in a sharper turn for our grafts. The million-dollar question is: what does that mean? For now, the answer is unknown. PMID- 28669475 TI - Editorial Commentary: Robbing Peter to Pay Paul? Is Osteochondral Autograft Transplantation of the Elbow Capitellum Worth the Price? AB - Osteochondritis dissecans (OCD) of the elbow capitellum is a common disorder that causes pain and functional limitation in the athletic adolescent elbow. Many surgical options have been proposed over the years, but none has stood the test of time. A recent well-written systematic review highlights the treatment options and recognizes a growing trend toward osteochondral allograft transplantation as the ideal solution. Unfortunately, the study also underscores the paucity of evidence on which we base our treatment decisions for OCD of the elbow in the young athlete. Although the potential benefits of osteochondral grafting are encouraging, consideration of associated risks such as donor site morbidity is essential. PMID- 28669476 TI - Adsorption of 17 alpha-ethyl estradiol with the competition of bisphenol A on the marine sediment of Hong Kong. AB - The present experimental study was to characterize the adsorption behavior of 17 alpha-ethyl estradiol (EE2) onto marine sediment in both the single and binary solute systems. Stepwise spiking was innovatively performed to better understand the competition effects. Adsorption of EE2 on the marine sediment can be well fitted by the Freundlich model with an affinity coefficient (KF) varying from 15.8 to 39.8L/kg. It was significantly influenced by SOM and the particle properties. Co-presence of BPA brought about a significant competition effect on the adsorption of EE2, leading to a reduced EE2 adsorption. The competitive effect imposed by EE2 to BPA, however, was even more serious owing probably to the large molecular structure and high hydrophobicity of EE2. The sediment sample with the highest SOM and SSA presented a mild competition effect, while the sediment with the lowest SOM and largest particle size exhibited the most serious competition effect. PMID- 28669477 TI - Taiwanese marine microbenthic algal communities remain similar yet chlorophyll a concentrations rise in mesocosms with elevated CO2 and temperature. AB - The effects of increasing CO2 concentrations and temperature on microalgal assemblages were examined in Taiwan using mesocosms that simulate coral reef ecosystem. We assessed changes in abundance and diversity of benthic algae grown at 25 degrees C and 28 degrees C, under ambient (~400MUatm) and at high CO2 conditions (800-1000MUatm). Total alkalinity, pCO2, and the aragonite saturation state, were all significantly different between control and high CO2 treatments in both temperature treatments. Chl a concentration increased significantly in CO2-treated groups at 25 degrees C, but benthic microalgal abundance was not significantly different. The number of microalgal species and the microalgal community structure did not differ between control and CO2-treated groups at both temperatures. Our results suggest that increasing CO2 may boost benthic microalgal primary productivity if sufficient nutrients are available, although site-specific responses are difficult to predict. PMID- 28669478 TI - The marine sedimentary record of natural and anthropogenic contribution from the Sulcis-Iglesiente mining district (Sardinia, Italy). AB - Intensive exploitation of base metal deposits in the Sulcis-Iglesiente district (Sardinia, Italy), lasted from the 1850s to the 1990s, determined a high environmental impact on the coastal area, but the effects on marine environment have never been investigated. A marine sediment core, dated with 14C, was characterized for grain size, chemical and mineralogical composition, in order to reconstruct the sedimentary history of the area and to assess the environmental impact of mining. The comparison of chemical and mineralogical characteristics of recent sediments with those of pre-industrial age allowed discriminating the real anthropogenic impact from the natural metal enrichment. The correspondence, in the upper core, of anthropogenic trace metal enrichment with the presence of mine waste minerals is attributed to the exploiting over industrial scale; the still high metal enrichment in sediment surface levels suggests a still existing impact due to mine dumps and tailings weathering. PMID- 28669479 TI - Petroleum hydrocarbons in a water-sediment system from Yellow River estuary and adjacent coastal area, China: Distribution pattern, risk assessment and sources. AB - Aliphatic hydrocarbons (AHs), biomarker and polycyclic aromatic hydrocarbons (PAHs) concentrations of surface water and sediment samples collected from Yellow River Estuary and adjacent coastal area in China were measured to determine their spatial distributions, analyze their sources and evaluate the ecological risk of PAHs in the water-sediment system. The spatial distributions of n-alkane in sediments are mainly controlled by the mixing inputs of terrigenous and marine components. In comparison with AHs, the total concentrations of Sigma16PAHs in surface sediments from a transect of the offshore area were noticeably higher than that of the riverine and estuary areas. Additionally, the AHs and total PAHs concentrations all indicated an overall pattern of a seaward decrease. The PAHs concentrations during the dry season (mainly in the form of dissolved phase) were higher than that of PAHs (mainly dissolved phase and particulate phase form) in the flooding season. In comparison with global concentration levels of PAHs, the level of PAHs in suspended particulate matter and sediments from the Yellow River Estuary was lower than those from other countries, while the concentration of PAHs in the dissolved phase were in the middle range. Petroleum contamination, mainly from oil exploration and discharge of pollutants from rivers, was the main source of n-alkanes. The PAHs in the river were mostly of petrogenic origin, while those in the estuarial and marine areas originated mainly from pyrogenic sources. The results of the toxicology assessment suggested that the PAHs in sediments from Yellow River Estuary and adjacent coastal area exhibited a low potential eco-toxicological contamination level. PMID- 28669480 TI - Predictive factors for live birth in donor oocyte-recipient cycles. PMID- 28669481 TI - Impact of the opioid system on the reproductive axis. AB - Endogenous opioids, first described more than 40 years ago, have long been recognized for their main role as important neuromodulators within the central nervous system. More recently endogenous opioids and their receptor have been identified in a variety of reproductive and nonreproductive tissues outside the central nervous system. Their role within these tissues and organs, however, is only incompletely understood. In the central nervous system, endogenous opioids inhibit pulsatile GnRH release, in part mediating the stress response within the central nervous-pituitary gonadal axis, resulting in hypothalamic amenorrhea. In the ovary, the presence of endogenous opioids primarily produced by granulosa cells has been demonstrated within the follicular fluid, likely influencing oocyte maturation. In hypothalamic amenorrhea, normal cycles can be restored by the administration of opioid antagonists, such as naltrexone. In polycystic ovarian syndrome, endogenous opioids have found to be elevated and may stimulate insulin secretion from the endocrine pancreas. This effect can be inhibited by opioid antagonists, resulting in a decrease of circulating insulin levels in response to glucose challenge. Endogenous opioids may also play a role in the pathogenesis of ovarian hyperstimulation syndrome. In summary, endogenous opioids exert a wide variety of actions within the reproductive system and are worthy of further scientific study. PMID- 28669482 TI - Creation of a neovagina: what should our focus be when choosing the "right" operative technique? PMID- 28669483 TI - Right ventricular strain in heart failure: Clinical perspective. AB - The number of studies demonstrating the importance of right ventricular remodelling in a wide range of cardiovascular diseases has increased in the past two decades. Speckle-tracking imaging provides new variables that give comprehensive information about right ventricular function and mechanics. In this review, we summarize current knowledge of right ventricular mechanics in heart failure with reduced ejection fraction and preserved ejection fraction. We searched PubMed, MEDLINE, Ovid and Embase databases for studies published from January 2000 to December 2016 in the English language using the following keywords: "right ventricle"; "strain"; "speckle tracking"; "heart failure with reduced ejection fraction"; and "heart failure with preserved ejection fraction". Investigations showed that right ventricular dysfunction is associated with higher cardiovascular and overall mortality in patients with heart failure, irrespective of ejection fraction. The number of studies investigating right ventricular strain in patients with heart failure with reduced ejection fraction is constantly increasing, whereas data on right ventricular mechanics in patients with heart failure with preserved ejection fraction are limited. Given the high feasibility, accuracy and clinical implications of right ventricular strain in the population with heart failure, it is of great importance to try to include the evaluation of right ventricular strain as a regular part of each echocardiographic examination in patients with heart failure. However, further investigations are necessary to establish right ventricular strain as a standard variable for decision-making. PMID- 28669484 TI - Vertebral anomalies in craniofacial microsomia: a systematic review. AB - Craniofacial microsomia (CFM) is characterized by a heterogeneous underdevelopment of the facial structures arising from the first and second branchial arches, but extracraniofacial malformations such as vertebral anomalies also occur. This systematic review provides an overview of the literature on the types and prevalence of vertebral anomalies found in patients with CFM. A systematic search was conducted. Data on the number of patients, patient characteristics, types and prevalence of vertebral anomalies, and other associations between CFM and vertebral anomalies were extracted from the articles identified. Thirty-one articles were included. Seventeen articles described both the prevalence and types of vertebral anomalies in CFM, five articles described solely the types of vertebral anomalies in CFM, and nine articles reported solely the prevalence of vertebral anomalies in CFM. The vertebral anomalies most often reported in CFM are hemivertebrae, block vertebrae, scoliosis/kyphoscoliosis, and spina bifida. These anomalies are mostly present in the cervical and thoracic spine and ribs. The reported prevalence of vertebral anomalies in CFM varies from 8% to 79%. To diagnose vertebral anomalies early in patients with CFM, further research should focus on determining which patients with CFM are at risk of vertebral anomalies. PMID- 28669485 TI - Long-term stability of limiting nasal alar base width changes with a cinch suture following Le Fort I osteotomy with submental intubation. AB - The aim of this study was to assess the effectiveness of the nasal alar base cinch suture following Le Fort I osteotomy at long-term follow-up. One hundred and forty participants (89 female, 51 male) aged between 16 and 51 years underwent Le Fort I osteotomy with submental intubation. Anthropometric measurements of the nose were taken intraoperatively, immediately postoperative, and for up to 3 years postoperative: the maximum lateral convexity of the alae (Al-Al) and the lateral extremity of the alar base curvature at the alar groove (Ac-Ac). The use of a cinch suture was recorded. The results were analysed using a linear mixed-effects model analysis. One hundred and six participants had cinch sutures and 34 had no cinch sutures. Following Le Fort I osteotomy, there were significant increases in Ac-Ac (by 4.29mm) and Al-Al (by 3.70mm) (both P<0.0001). Cinch sutures significantly reduced the widths back to preoperative values (P<0.0001). Alar width remained stable over 3 years, with an increase of 0.36mm for Al-Al (P>0.05) and 1.03mm for Ac-Ac (P<0.05) compared to the postoperative measurement. In conclusion, a cinch suture was helpful in reducing the unwanted alar base width changes, which were found to be relatively stable at 3 years. PMID- 28669486 TI - Method of osteotomy fixation and need for removal following bimaxillary orthognathic, osseous genioplasty, and intranasal surgery: a retrospective cohort study. AB - The purpose of this study was to determine the incidence and causes of fixation hardware removal after bimaxillary orthognathic, osseous genioplasty, and intranasal surgery. A retrospective study was performed, involving subjects with a bimaxillary developmental dentofacial deformity (DFD) and symptomatic chronic obstructive nasal breathing. At a minimum, subjects underwent Le Fort I osteotomy, bilateral sagittal ramus osteotomies (SROs), septoplasty, inferior turbinate reduction, and osseous genioplasty. The primary outcome variable studied was fixation hardware removal. Demographic, anatomical, and surgical predictor variables were assessed. Two hundred sixty-two subjects met the inclusion criteria. Their mean age at operation was 25 years (range 13-63 years); 134 were female (51.1%). Simultaneous removal of a third molar was performed in 39.9% of SROs. Three of 262 Le Fort I procedures (1.1%) and two of 524 SROs (0.4%) required hardware removal. There were four cases of ramus wound dehiscence, four of ramus surgical site infection (SSI), one of chin SSI, two of maxillary sinusitis, and one of lingual nerve injury; none of these subjects underwent hardware removal. A limited need for fixation hardware removal after orthognathic procedures was confirmed. There was no statistical correlation between hardware removal and patient sex, age, pattern of DFD, simultaneous removal of a third molar, or occurrence of wound dehiscence, SSI, or lingual nerve injury. PMID- 28669487 TI - [Functional and aesthetic evaluation of sacrococcygeal teratomas. Not everything ends with surgery]. AB - INTRODUCTION: Sacrococcygeal teratoma is the most common solid neonatal tumour. The improvement in survival has meant that postoperative sequelae can be diagnosed and treated. The aim of this article is to evaluate the long-term outcomes of patients treated in our centre. MATERIAL AND METHODS: Records of patients treated for a sacrococcygeal teratoma in our hospital from 1977 to 2014 were retrospectively reviewed. Personal data was collected and a telephone questionnaire was used to assess long-term bowel and urinary habits, as well as an aesthetic and functional self-assessment. RESULTS: A total of 14 patients were treated during the study period, of whom 11 were females and 3 males, with a mean age at the time of the survey of 17 years (8 months-37 years). Eight patients completed the questionnaire (57.1%). The mean age of the 8 patients was 23 years (4-37 years), of whom 37.5% were operated on due to a sacrococcygeal teratoma type i, 25% type ii, 25% type iii, and 12.5% type iv. Two of them (25%) had constipation, and one (12.5%) had faecal incontinence. Two (25%) patients suffered from recurrent urinary tract infections, and 3 (37.5%) patients had urinary incontinence. Five patients (62.5%) had a perception of being physically impaired, with limitation of their social life. CONCLUSIONS: The incidence of constipation does not differ from that found in the literature. Faecal incontinence is slightly improved compared to what has been published. However, urinary tract infections and incontinence are more prevalent in our series. Five patients out of the eight that responded suffered from psychosocial problems, according to DAS-59 questionnaire. Patients with SCT require urological, bowel, and psychological counselling, until they have a complete functional and emotional development. PMID- 28669488 TI - Prognostic Significance of Discharge Hyponatremia in Heart Failure Patients With Normal Admission Sodium (from the ESCAPE Trial). AB - Hyponatremia in acute decompensated heart failure (HF) is indicative of a poor prognosis and predicts morbidity and mortality. We explored the predictive utility of hyponatremia at the time of hospital discharge among HF patients with normal admission sodium (Na). Characteristics and outcomes of HF patients enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial, who had normal Na on admission, were compared between those who were hyponatremic (Na <135 meq/L) or normonatremic on discharge. Three hundred six patients with normal admission Na had either hyponatremia (n = 86) or normal Na (n = 220) on discharge. Compared with patients with normal Na on discharge, hyponatremic patients were younger (p = 0.004), with lower discharge systolic (p <0.001) and diastolic (p = 0.004) blood pressure, higher discharge blood urea nitrogen (p = 0.011) despite similar creatinine (p = 0.566), lower ejection fraction (p = 0.007), and higher left ventricular end diastolic (p = 0.028) and end-systolic (p = 0.007) dimensions. Despite comparable congestion on hospital admission, patients with discharge hyponatremia had a higher degree of decongestion throughout hospitalization evident in the significantly greater admission to discharge weight loss (p = 0.044) and admission to discharge reduction in inferior vena cava diameter (p = 0.014). Despite longer initial hospitalization (p = 0.004), total duration in hospital at 30 days (p = 0.004) and 6 months (p = 0.045), there were no significant differences between patients with discharge hyponatremia versus normal Na on discharge regarding rehospitalization (p = 0.386), all-cause mortality (p = 0.440), and composite of death, cardiac rehospitalization, and cardiac transplant (p = 0.799), all up to 6-month following randomization. Restricted cubic spline analysis also showed no significant relationships between discharge Na and the aforementioned 3 outcomes. Cox proportional hazards regressions showed that discharge hyponatremia did not significantly predict any of the 3 outcomes after adjustment for imbalances at baseline. Among patients with discharge hyponatremia, a poor outcome was more likely if they were also hyponatremic on admission: the composite end point occurred in 69.2% of those also hyponatremic on admission versus 51.2% of those with normal Na on admission but decreased Na on discharge (p = 0.045). Because the median discharge Na level in the discharge hyponatremia group was 132 meq/L, our findings suggest a benign nature of mild discharge hyponatremia in HF patients with normal admission Na. PMID- 28669489 TI - ERBP guideline on management of patients with diabetes and chronic kidney disease stage 3B or higher. Metformin for all? PMID- 28669491 TI - [Community prioritization in Barcelona Salut als Barris program]. AB - Prioritizing corresponds to the process of selecting and managing health needs identified after diagnosing the community's health needs and assets. Recently, the health needs assessment has been reinforced with the community perspective, providing multiple benefits: it sensitizes and empowers the community about their health, encourages mutual support among its members and promotes their importance by making them responsible for the process of improving their own reality. The objective of this paper is to describe the prioritization of Barcelona Salut als Barris, a community health strategy led by the Barcelona Public Health Agency to promote equity in health in the most disadvantaged neighborhoods of the city. PMID- 28669492 TI - Atropine for the Prevention of Myopia Progression in Children: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To review the published literature on the efficacy of topical atropine for the prevention of myopic progression in children. METHODS: Literature searches were last conducted in December 2016 in the PubMed database with no date restrictions, but were limited to studies published in English, and in the Cochrane Library database without any restrictions. The combined searches yielded 98 citations, 23 of which were reviewed in full text. Of these, 17 articles were deemed appropriate for inclusion in this assessment and subsequently were assigned a level of evidence rating by the panel methodologist. RESULTS: Seventeen level I, II, and III studies were identified. Most of the studies reported less myopic progression in children treated with atropine compared with various control groups. All 8 of the level I and II studies that evaluated primarily myopic progression revealed less myopic progression with atropine (myopic progression ranging from 0.04+/-0.63 to 0.47+/-0.91 diopters (D)/year) compared with control participants (myopic progression ranging from 0.38+/-0.39 to 1.19+/-2.48 D/year). In studies that evaluated myopic progression after cessation of treatment, a rebound effect was noted. Several studies evaluated the optimal dosage of atropine with regard to myopic progression, rebound after treatment cessation, and minimization of side effects. Lower dosages of atropine (0.5%, 0.1%, and 0.01%) were found to be slightly less effective during treatment periods of 1 to 2 years, but they were associated with less rebound myopic progression (for atropine 0.01%, mean myopic progression after treatment cessation of 0.28+/-0.33 D/year, compared with atropine 0.5%, 0.87+/-0.52 D/year), fewer side effects, and similar long-term results for myopic progression after the study period and rebound effect were considered. The most robust and well-designed studies were carried out in Asian populations. Studies involving patients of other ethnic backgrounds failed to provide sufficient evidence of an effect of atropine on myopic progression. CONCLUSIONS: Level I evidence supports the use of atropine to prevent myopic progression. Although there are reports of myopic rebound after treatment is discontinued, this seems to be minimized by using low doses (especially atropine 0.01%). PMID- 28669490 TI - ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma. AB - Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA damaging agents in patients with high-risk MM. PMID- 28669493 TI - Consumer willingness-to-pay for packaging and contents in Asian countries. AB - This study was conducted using a hedonic pricing model to evaluate consumer preference for packaging and contents in five Asian countries: Japan, Indonesia, Singapore, Taiwan, and China. Results revealed that the marginal rate of substitution (MRS) of packaging for contents differs significantly among countries: 17.7 for Singapore, 8.58 for China, 2.71 for Taiwan, 1.65 for Japan and not significant for Indonesia. Share of Willingness-to-pay (WTP) for packaging accounted for 52.8% of the WTP for sales unit of a representative product in Japan and 46.2% in Taiwan, which were significantly higher than the results for Singapore (32.6%) and China (18.2%). Results showed that the higher the share of packaging in the WTP for a product, the higher the relative packaging weight per unit weight of contents. These results suggest that the relative demand for packaging to contents differs among countries. The results underscore the necessity of choosing suitable policy instruments and marketing strategies for different countries. PMID- 28669494 TI - Thermo-Catalytic Reforming of municipal solid waste. AB - Municipal Solid Waste (MSW) refers to a heterogeneous mixture composed of plastics, paper, metal, food and other miscellaneous items. Local authorities commonly dispose of this waste by either landfill or incineration which are both unsustainable practices. Disposing of organic wastes via these routes is also becoming increasingly expensive due to rising landfill taxes and transport costs. The Thermo-Catalytic Reforming (TCR(r)) process, is a proposed valorisation route to transform organic wastes and residues, such as MSW, into sustainable energy vectors including (H2 rich synthesis gas, liquid bio-oil and solid char). The aim herein, was to investigate the conversion of the organic fraction of MSW into fuels and chemicals utilising the TCR technology in a 2kg/h continuous pilot scale reactor. Findings show that MSW was successfully processed with the TCR after carrying out a feedstock pre-treatment step. Approximately, 25wt.% of the feedstock was converted into phase separated liquids, composed of 19wt.% aqueous phase and 6wt.% organic phase bio-oil. The analysis of the bio-oil fraction revealed physical and chemical fuel properties, higher heating value (HHV) of 38MJ/kg, oxygen content <7wt.% and water content <4wt.%. Due to the bio-oil's chemical and physical properties, the bio-oil was found to be directly miscible with fossil diesel when blended at a volume ratio of 50:50. The mass balance closure was 44wt.% synthesis gas, with a H2 content of 36vol% and HHV of 17.23MJ/Nm3, and 31 wt.% char with a HHV of 17MJ/kg. The production of high quantities of H2 gas and highly de-oxygenated organic liquids makes downstream hydrogen separation and subsequent hydro-deoxygenation of the produced bio-oil a promising upgrading step to achieve drop-in transportation fuels from MSW. PMID- 28669495 TI - Use of municipal solid waste incineration bottom ashes in alkali-activated materials, ceramics and granular applications: A review. AB - This paper presents a literature review on the incorporation of municipal solid waste incinerated bottom ash as raw material in several markets, other than those where it is conventionally used, such as geotechnical applications and road pavement construction. The main findings of an ample selection of experimental investigations on the use of the bottom ash as precursor of alkali-activated materials, as an adsorbent material for the removal of hazardous elements from wastewater and landfill gases, as soil replacement in agricultural activities, as partial or complete substitute of raw materials for the manufacture of ceramic based products, as landfill cover and as biogas production enhancer, were gathered, collated and analysed. PMID- 28669496 TI - Using choice architecture to exploit a university Distinct Urban Mine. AB - There are widespread concerns regarding the potential future scarcity of ferrous and non-ferrous materials. However, there are already potentially rich reserves of secondary materials via high ownership of Electrical and Electronic Equipment (EEE) in economically-developed nations. Young people are particularly high consumers of EEE, thus university students and campuses may present an opportunity to harness this potential. University Distinct Urban Mines (DUM) may be used to exemplify how potential reserves of secondary metals may be exploited, and could contribute to the transition from a linear to a circular economy. This study aimed to evaluate small household appliances (SHA) DUM from a UK university, with the objectives to identify and quantify student households' SHA ownership, WEEE recycling, stockpiling and discarding habits amongst student households, assess and evaluate the monetary potential of SHA DUM at UK level, and propose methods to exploit DUM for universities in the UK. To this purpose, a quantitative survey was undertaken to measure students' ownership and discarding behaviour with respect to SHA. The amounts of ferrous and non-ferrous materials were then estimated and converted to monetary values from secondary materials market data to appraise the SHA DUM overall value. Thirty-five per cent of SHA are discarded in the general refuse. Broken personal care appliances (PCA) tend to be discarded due to hygiene and small size factors. When in working order, SHA tend to be equally reused, recycled or stockpiled. We conclude that a total of 189 tonnes of ferrous and non-ferrous materials were available via discarding or being stockpiled at the University of Southampton. Extrapolated to UK higher education level, discarded and stockpiled SHA represent a potential worth ~USD 11 million. To initiate DUM exploitation within Higher Education campuses, we suggest improving users' choice architecture by providing collection methods specific to broken SHA. PMID- 28669497 TI - Simultaneous recovery of Zn and Mn from used batteries in acidic and alkaline mediums: A comparative study. AB - A parallel study of acidic and alkaline leaching for the recovery of Mn and Zn from spent alkaline batteries is outlined. Using H2SO4 as solvent and selecting appropriate conditions of temperature and concentration, all residues were dissolved except carbon. The separation and recovery of the two components were performed by electrodeposition with satisfactory results at pH values above 4 (current efficiency above 70% for Zn and Mn) but rather lower efficiencies as the pH decreased. Most of the Zn was selectively dissolved by alkaline leaching using a 6.5M NaOH solution, and its recovery was examined by means of both electrochemical and chemical processes. The expected formation of pure Zn by electrowinning failed due to the formation of ZnO, the content of which was highly dependent on the electrodeposition time. For short periods, Zn was the main component. For longer periods the electrodeposit consisted of agglomerated microparticles of ZnO with a minor fraction of Zn metal (barely 3% as measured by X-ray diffraction). A chemical reaction of the element with oxygen released at the anode surface might be responsible for its conversion to ZnO. A simple chemical route is described for the first time for the direct conversion of Zn(OH)42- solution to nanostructured ZnO by lowering the pH to values around 12 using 2M HCl solution. PMID- 28669498 TI - Imaging of protein-specific glycosylation by glycan metabolic tagging and in situ proximity ligation. AB - Glycosylation is an important posttranslational modification, which regulates a number of critical biological processes including cell-cell recognition, signal transduction and disease progression. Probing the glycosylation status on a specific protein of interest enables an in-depth understanding of the role of glycosylation on protein structure and function. However, methods for monitoring protein-specific glycosylation are largely lacking. Here we describe a highly sensitive fluorescence imaging strategy to visualize the protein-specific glycosylation by combining glycan metabolic tagging and in situ proximity ligation (termed GPLA). We demonstrate the visualization of sialylation, fucosylation and GalNAcylation on several important membrane proteins. Notably, the high spatial resolution of this method allows subcellular localization of the glycosylated fraction of the proteins. We further show that our strategy can be applied to image the dimerization of endogenous epidermal growth factor receptor. Thus, our study provides a unique tool to monitor the protein-specific glycosylation in a dynamic cellular context. PMID- 28669499 TI - The Impact of Margins on Outcomes After Wedge Resection for Stage I Non-Small Cell Lung Cancer. AB - BACKGROUND: The relationship between margin distance and recurrence and survival for stage I non-small cell lung carcinoma (NSCLC) less than or equal to 2 cm is not clear. METHODS: Patient clinicopathologic data were reviewed from a pooled data set of stage I NSCLC lesions less than or equal to 2 cm resected by wedge resection at Brigham and Women's Hospital (BWH) between 2000 and 2005 and the International Early Lung and Cardiac Action Program (I-ELCAP) between 1999 and 2015. Multivariable models were constructed to evaluate the relationship between margin distance and recurrence and survival, adjusting for patient age, sex, tumor size, and histologic type. Optimal margin distance was determined for recurrence-free and overall survival using maximum chi2 values among survival distributions. RESULTS: Of 182 cases, 138 tumors had margin distance reported (113 BWH and 25 I-ELCAP). The average tumor size was 13.3 mm, and margin distance was 8.3 mm. During a mean follow-up of 49.6 months, there were 33 recurrences and 59 deaths. Increased margin distance was independently associated with lower risk of recurrence (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.83-0.98). Margin distance was also independently associated with longer survival (hazard ratio [HR], 0.94; 95% CI, 0.90-0.98). A margin distance greater than 9 mm was associated with longest recurrence-free survival and a margin distance greater than 11 mm was associated with longest overall survival. CONCLUSIONS: Increased margin distance was independently associated with lower risk of recurrence and longer overall survival in patients undergoing wedge resection for NSCLC tumors less than or equal to 2 cm. These findings suggest that with a minimum appropriate margin distance, wedge resection may yield outcomes comparable to those of lobectomy. PMID- 28669500 TI - One-Year Experience With a Mobile Extracorporeal Life Support Service. AB - BACKGROUND: Severe acute respiratory distress syndrome is associated with a high mortality rate. The International Extracorporeal Membrane Oxygenation Network recommends regionalization of extracorporeal life support (ECLS) to high-volume centers and development of mobile ECLS teams to rescue patients with severe acute respiratory disease. METHODS: A tertiary medical center developed a mobile team and the infrastructure to support a ECLS transport service available 24 hours a day, 7 days a week. We conducted a retrospective study of all consecutive patients presenting for ECLS for severe acute respiratory distress syndrome from outside hospitals through our mobile ECLS program associated with hemodynamic instability from January 1, 2015, until December 31, 2015. RESULTS: During the study period, 106 consultations for ECLS were received, and 36 patients were placed on ECLS. Of these 36 ECLS patients, 11 were deemed stable enough for transport before ECLS, and 21 required mobile ECLS by the mobile ECLS, with a survival of 67% (14 of 21). The other 4 ECLS patients were inhouse patients and therefore received ECLS in a nonmobile fashion. In addition, 28 patients were transferred to our hospital who did not receive ECLS. Patient survival increased significantly with increased experience with the program, as the highest mortality rates were early in the program (p = 0.006), and in conjunction with stricter adherence to our exclusion criteria. CONCLUSIONS: The formation of a mobile ECLS program is a complex undertaking that took 2 years of planning to develop. Development of criteria for ECLS implementation can guide appropriate resources utilization and may prevent their use in patients with little to no chance of survival. PMID- 28669501 TI - Surgical Ablation of Atrial Fibrillation in the United States: Trends and Propensity Matched Outcomes. AB - BACKGROUND: Surgical ablation (SA) for atrial fibrillation (AF) effectively restores sinus rhythm. Incompletely defined risk has previously limited concomitant performance of SA during cardiac operations. The study goals were to define performance trends and risk-adjusted outcomes for contemporary SA. METHODS: From July 2011 to June 2014, 86,941 patients with AF, but without endocarditis, underwent primary nonemergent cardiac operations in The Society of Thoracic Surgeons (STS) database. Cochran-Armitage tests examined performance trends of SA for six operative categories: mitral valve repair or replacement (MVRR) with or without coronary artery bypass graft surgery (CABG), aortic valve replacement (AVR) with or without CABG, CABG, AVR with MVRR, stand-alone SA, and other concomitant operations. The risk of concomitant SA was analyzed by propensity matching 28,739 patient-pairs with and without SA by AF type, primary operation, and STS comorbid risk variables using greedy 1:1 matching algorithms. RESULTS: Among all patients with AF, 48.3% (42,066 of 86,941) underwent SA. Mitral operations had the highest rate of SA (MVRR +/- CABG 68.4% [14,693 of 21,496]; MVRR + AVR 59.1% [1,626 of 2,750]). The AVR +/- CABG and isolated CABG rates were 39.3% (6,816 of 17,349) and 32.8% (9,156 of 27,924), respectively. Nearly half of other concomitant operations underwent SA, 47.6% (6,939 of 14,586). Performance frequency increased throughout the study period. After propensity matching, SA was associated with a reduction in relative risk (RR) of 30-day mortality (RR 0.92, 95% confidence interval [CI]: 0.85 to 0.99) and stroke (RR 0.84, 95% CI: 0.74 to 0.94), but an increase in renal failure (RR 1.12, 95% CI: 1.03 to 1.22) and pacemaker implantation (RR 1.33, 95% CI: 1.24 to 1.43). CONCLUSIONS: Contemporary utilization of SA is increasing across all operative categories. Performance of SA is accompanied by a 30-day reduction in mortality and stroke. These findings further refine our understanding of the role of SA in the treatment of AF. PMID- 28669502 TI - The Impact of 22q11.2 Deletion Syndrome on Surgical Repair Outcomes of Conotruncal Cardiac Anomalies. AB - BACKGROUND: We aim to describe the impact of 22q11.2 deletion syndrome (22q11DS) on clinical characteristics, postoperative course, and early and late outcomes of neonates undergoing surgery for conotruncal anomalies. METHODS: A retrospective review was performed (2002 to 2012) of 224 neonates who underwent surgery for interrupted aortic arch (n = 67), truncus arteriosus (n = 85), or ductal dependent pulmonary atresia and ventricular septal defect (n = 72). Patients were divided into three groups: group 1, n = 119, no genetic syndrome; group 2, n = 64, 22q11DS; and group 3, n = 41, other genetic syndrome. Adjusted analysis to compare outcomes was performed. RESULTS: In comparison with group 1, group 2 had longer mechanical ventilation duration (148 versus 102 hours, p = 0.008), intensive care unit stay (268 versus 159 hours, p < 0.001), and hospital stay (19.3 versus 11.5 days, p < 0.001). On adjusted analysis, there was an insignificant increase in unplanned reoperation (odds ratio [OR] 2.4, 95% confidence interval [CI]: 0.7 to 8.4, p = 0.167) but no increased extracorporeal membrane oxygenation use (OR 1.5, 95% CI: 0.3 to 6.1, p = 0.612), hospital mortality (OR 0.6, 95% CI: 0.1 to 3.3, p = 0.570), or decreased late survival (hazard ratio 0.9, 95% CI: 0.4 to 2.1, p = 0.822). In comparison with group 1, group 3 had longer mechanical ventilation duration (190 versus 102 hours, p < 0.001), intensive care unit stay (236 versus 159 hours, p = 0.007), and hospital stay (21.5 versus 11.5 days, p < 0.001); and increased unplanned reoperation (OR 3.7, 95% CI: 1.1 to 12.5, p = 0.032), extracorporeal membrane oxygenation use (OR 4.4, 95% CI: 1.1 to 17.6, p = 0.038), hospital mortality (OR 4.2, 95% CI: 1.2 to 14.5, p = 0.021), and diminished late survival (hazard ratio 4.0, 95% CI: 2.1 to 8.1, p < 0.001). CONCLUSIONS: In neonates with conotruncal anomalies, 22q11DS is associated with prolonged recovery and increased resource utilization. However, despite a small increase in unplanned reoperation, there is no significant impact on early or late survival. In comparison, other genetic syndromes are associated with increased unplanned reoperation, extracorporeal membrane oxygenation use, hospital mortality, and diminished late survival. These findings are important for family counseling and risk stratification. PMID- 28669503 TI - Impact of Adverse Events and Length of Stay on Patient Experience After Lung Cancer Resection. AB - BACKGROUND: Postoperative adverse events (AEs), prolonged length of stay (PLOS), and patient experience are common quality measures after thoracic surgical procedures. Our objective was to investigate the relationship of postoperative AEs on patient experience and hospital length of stay (LOS) after lung cancer resection. METHODS: AEs (using Thoracic Morbidity and Mortality system based on Clavien-Dindo schema) and LOS were prospectively collected for all patients undergoing lung cancer resection. A 21-item questionnaire, retrospectively asking about patient experience, was mailed to patients twice (October 2015 and January 2016). The impact of AEs on experience was investigated and stratified by hospital LOS, with PLOS defined as the 75th percentile. Univariate analysis used parametric (t test) and nonparametric (Mann-Whitney) tests according to test conditions. RESULTS: Of 288 patients who responded to the survey (70% response rate), 175 (61%) had no AEs, 113 (39%) had experienced at least one AE, and 52 (18%) had experienced PLOS. Lung cancer patients who experienced PLOS showed significantly decreased experience on several questionnaire items, including their impression of comprehensiveness of surgeons information provision during inpatient period (p = 0.008), inpatient recovery from operation (p = 0.001), quality of life 30 days after operation (p = 0.032), follow-up care, (p = 0.022), and satisfaction with outcome 1 year after operation during follow-up care (p = 0.022). The presence of postoperative AEs led only to reduced impression about inpatient recovery from the operation (p = 0.01). CONCLUSIONS: In this cohort, postoperative AEs were minimally associated with negative patient experience. However, patients who experienced PLOS demonstrated a marked reduction in experience after thoracic surgical procedures. PMID- 28669504 TI - Nodal Skip Metastasis in Esophageal Squamous Cell Carcinoma Patients Undergoing Three-Field Lymphadenectomy. AB - BACKGROUND: The clinical and prognostic implications of nodal skip metastasis (NSM) remain unclear in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Patients with pathologically confirmed node metastasis who underwent three-field lymphadenectomy from January 1999 to December 2008 were retrospectively enrolled. The node station is determined based on the classification of the Japanese Society for Esophageal Diseases. NSM is defined as the occurrence of metastases in nodes distant from the primary tumor (station 2 or 3) without the involvement of the adjacent nodes (station 1). To balance the baseline characteristics, a matched cohort was generated by propensity score matching analysis with covariates of age, sex, pathologic status, and treatment. The prognostic implication of NSM was assessed using log-rank tests and Cox regression analyses. RESULTS: In the entire cohort, the NSM rate was 64.0% (657 of 1026); NSM was substantially associated with clinicopathologic variables, including an increased likelihood of middle thoracic tumor location and limited nodal status. Univariate analysis showed similar outcomes between patients with and without NSM (unadjusted hazard ratio [HR] 1.018, 95% confidence interval [CI]: 0.855 to 1.213, p = 0.838). A similar result was obtained in the matched cohort (unadjusted HR 1.057, 95% CI: 0.870 to 1.285, p = 0.578). Although in patients with solitary node metastasis, patients with NSM presented a worse prognosis than patients without (p = 0.043 in log-rank test). CONCLUSIONS: NSM is a common phenomenon in ESCC. Among ESCC patients who underwent three-field lymphadenectomy, NSM is associated with a relatively poor prognosis in individuals with solitary node metastasis. PMID- 28669505 TI - Bioprosthetic Valve Fracture to Facilitate Transcatheter Valve-in-Valve Implantation. AB - BACKGROUND: Valve-in-valve transcatheter aortic valve replacement is less effective in small surgical bioprostheses. We evaluated the feasibility of bioprosthetic valve fracture with a high-pressure balloon to facilitate valve-in valve transcatheter aortic valve replacement. METHODS: In vitro bench testing on aortic tissue valves was performed on 19-mm and 21-mm Mitroflow (Sorin, Milan, Italy), Magna and Magna Ease (Edwards Lifesciences, Irvine, CA), Trifecta and Biocor Epic (St. Jude Medical, Minneapolis, MN), and Hancock II and Mosaic (Medtronic, Minneapolis, MN). High-pressure balloons Tru Dilation, Atlas Gold, and Dorado (C.R. Bard, Murray Hill, NJ) were used to determine which valves could be fractured and at what pressure fracture occurred. RESULTS: Mitroflow, Magna, Magna Ease, Mosaic, and Biocor Epic surgical valves were successfully fractured using high-pressures balloon 1 mm larger than the labeled valve size whereas Trifecta and Hancock II surgical valves could not be fractured. Only the internal valve frame was fractured, and the sewing cuff was never disrupted. Manufacturer's rated burst pressures for balloons were exceeded, with fracture pressures ranging from 8 to 24 atmospheres depending on the surgical valve. Testing further demonstrated that fracture facilitated the expansion of previously constrained, underexpanded transcatheter valves (both balloon and self expanding) to the manufacturer's recommended size. CONCLUSIONS: Bench testing demonstrates that the frame of most, but not all, bioprosthetic surgical aortic valves can be fractured using high-pressure balloons. The safety of bioprosthetic valve fracture to optimize valve-in-valve transcatheter aortic valve replacement in small surgical valves requires further clinical investigation. PMID- 28669506 TI - Risk Factors for Late Aortic Valve Dysfunction After the David V Valve-Sparing Root Replacement. AB - BACKGROUND: Valve-sparing root replacement (VSRR) is an established therapy for aortic root pathology. However, late aortic valve dysfunction requiring reoperation remains a primary concern of this procedure. This study examines risk factors for late aortic insufficiency (AI) and aortic stenosis (AS) after David V VSRR. METHODS: A retrospective review from 2005 to 2015 at a US academic center identified 282 patients who underwent VSRR. Cox proportional hazards regression analysis was used to identify risk factors for late AI and AS after VSRR. RESULTS: The mean age was 46.4 years. Sixty-four patients (22.7%) had bicuspid valves, and 41 patients (14.5%) had Marfan syndrome. The incidence of reoperations was 27 (9.6%), and 42 cases (14.9%) presented with acute type A dissection. Operative mortality was 8 (2.8%). Seven-year survival was 90.9%. Seven-year cumulative incidence of reoperation, greater than 2+ AI and greater than moderate AS were 3.1%, 2.2%, and 0.8%, respectively. Multivariable analysis showed aortic root size 55 mm or larger (hazard ratio 3.44, 95% confidence interval: 1.27 to 9.29, p = 0.01) to be a risk factor for late AI whereas bicuspid valve (hazard ratio 16.07, 95% confidence interval: 3.12 to 82.68, p = 0.001) and cusp repair were found to be risk factors (hazard ratio 5.91, 95% confidence interval: 1.17 to 29.86, p = 0.03) for late AS. CONCLUSIONS: Valve sparing root replacement can be performed with low operative risk and good overall long-term survival even in complex clinical settings. Durable valve function can be expected; however, aortic root size 55 cm or more, bicuspid valve anatomy, and cusp repair represent independent risk factors for late aortic valve dysfunction after these procedures. PMID- 28669507 TI - Motivating factors for dual-method contraceptive use among adolescents and young women: a qualitative investigation. AB - OBJECTIVE: This qualitative study explores how adolescents and young women perceive the need for and describe the use of dual method contraception. STUDY DESIGN: We interviewed 20 sexually active women aged 16-24 who attended an adolescent-focused Title X family-planning clinic and were using a non-barrier contraceptive method. We used a semi-structured interview guide that included domains related to sexual activity, knowledge of and use of contraceptives and condoms, and relationship factors. We coded transcripts using grounded theory techniques and used an iterative process to develop overarching themes. RESULTS: Dual method contraceptive users primarily discussed pregnancy prevention as their motivating factor. Many expressed anxieties over an unplanned pregnancy and reported condom use as "back-up" contraception. Risk perception for pregnancy or STI acquisition did not necessarily change as relationship trust increased, but rather, their anxiety regarding the negativity of such outcomes decreased. Dual method contraception use decreased when participants reported that condoms were not readily available, or when they self-described immaturity. Less frequently, participants reported dual method use for sexually transmitted infection (STI) prevention, and many substituted STI testing for condom use. Contraceptive type (short-acting vs. long-acting) did not influence reported attitudes towards dual method use. CONCLUSION: Health educators and clinicians encourage condom use in young women due to the significant morbidity associated with STI acquisition. Most participants in our study view condoms as a way to improve pregnancy prevention. Acknowledging and addressing this divergence in motivation will allow caregivers to improve strategies for communicating the importance of dual method use. IMPLICATIONS: Young women primarily describe pregnancy prevention as the reason for dual method use, STI protection is less salient. Consideration of this viewpoint by health educators and clinicians will allow us to communicate more effectively to prevent STI morbidity. PMID- 28669509 TI - Out-of-body experience in vestibular disorders - A prospective study of 210 patients with dizziness. AB - Out-of-body experiences (OBEs) are states during which people experience their centre of awareness as located outside of their physical body, along with the sensation of seeing the environment from an elevated viewpoint. OBE is encountered in epilepsy, migraine and depersonalization, and it is not an uncommon experience in the general population. Current neuroscientific models of bodily self-consciousness consider that OBE are related to a failure to integrate visual, somatosensory and vestibular signals. These models have highlighted the importance of visual-vestibular mismatch in OBE. Case reports from older clinical literature suggest that vestibular disorders may precipitate OBE, but we were lacking population-based evidence that OBE is related to vestibular disorders. The present observational, prospective study describes otoneurological, neuropsychological and phenomenological correlates of OBE in the largest sample of patients with dizziness to date (n = 210) compared to a group of age- and gender-matched controls with no history of dizziness (n = 210). We show a significantly higher occurrence of OBE in patients with dizziness (14%) than in healthy participants (5%). Most of the patients experienced OBE only after they started having dizziness for the first time. OBE in patients with dizziness were mainly related to peripheral vestibular disorders. We also identify depersonalization-derealization, depression and anxiety as the main predictors of OBE in patients with dizziness, as well as a contribution of migraine. Depersonalization-derealization was the only significant predictor of OBE in healthy controls. Altogether, our data indicate that OBE in patients with dizziness may arise from a combination of perceptual incoherence evoked by the vestibular dysfunction with psychological factors (depersonalization derealization, depression and anxiety) and neurological factors (migraine). PMID- 28669508 TI - Quinones in the A1 binding site in photosystem I studied using time-resolved FTIR difference spectroscopy. AB - Time-resolved step-scan FTIR difference spectroscopy at low temperature (77 K) has been used to study photosystem I particles with phylloquinone (2-methyl-3 phytyl-1,4-naphthaquinone) and menadione (2-methyl-1,4-naphthaquinone) incorporated into the A1 binding site. By subtracting spectra for PSI with phylloquinone incorporated from spectra for PSI with menadione incorporated a (menadione - phylloquinone) double difference spectrum was constructed. In the double difference spectrum bands associated with protein vibrational modes effectively cancel, and the bands in the spectrum are primarily associated with the neutral and reduced states of the two quinones in the A1 binding site. To aid in the assignment of bands in the experimental double difference spectrum, a double difference spectrum was calculated using three-layer ONIOM methods. The calculated and experimental spectra agree well, allowing unambiguous band assignments to be made. The ONIOM calculations show that both quinones in the A1 binding site are similarly oriented, with only a single hydrogen bond between the C4=O quinone carbonyl group and the backbone NH group of a leucine residue. For the semi-quinone species, but not for the neutral species, this hydrogen bond appears to be very strong. Finally, we have for the first time been able to unmask and identify infrared difference bands associated with neutral naphthoquinone species occupying the A1 binding site in PSI. PMID- 28669510 TI - Word selection processing in Parkinson's disease: When nouns are more difficult than verbs. AB - Patients with Parkinson's disease (PD) are impaired in verb production. Interpretations range from grammatical deficits to semantic-conceptual decay of action representation. The verb production deficit in PD can also be considered a dysexecutive disorder, specifically, a deficit of selection processing during word production, due to corticostriatal damage. Producing verbs is "more difficult" than producing nouns, because verb-forms must be selected from a large set of word-forms which share the verb-root, and the set of possible verb-forms is larger than the set of possible noun-forms when a noun has to be produced. However, if we devise a condition in which a noun must be selected from a set of alternatives larger than the set of alternative forms from which a verb must be selected, we expect an opposite pattern, with nouns becoming more difficult than verbs. We used morphological tasks varying in the number of alternative responses during word production. Fourteen PD patients and 14 healthy Controls participated in the study. Participants performed a noun-from-verb ('observation' from 'to observe') and a noun-from adjective derivation task ('kindness' from 'kind'), and a verb-from-noun ('to observe' from 'observation') and an adjective-from-noun generation task ('kind' from 'kindness'). Input-stimuli were presented singularly on a screen and participants produced the response as fast as possible. Response latencies were longer in derivation tasks (several alternative responses) than in generation tasks (one possible response), irrespective of the grammatical class of the target word, with no difference between groups. PD patients were significantly less accurate than Controls only in the noun-from-verb derivation task, that is, in the task with the highest number of alternative responses (PD: 60%; Controls: 81%). Results suggest that the verb production disorder in PD patients may reflect disturbed selection processes among competitors: the higher the number of alternative responses the more severe the impairment. PMID- 28669511 TI - Illness perceptions in adult congenital heart disease: A multi-center international study. AB - BACKGROUND: Illness perceptions are cognitive frameworks that patients construct to make sense of their illness. Although the importance of these perceptions has been demonstrated in other chronic illness populations, few studies have focused on the illness perceptions of adults with congenital heart disease (CHD). This study examined (1) inter-country variation in illness perceptions, (2) associations between patient characteristics and illness perceptions, and (3) associations between illness perceptions and patient-reported outcomes. METHODS: Our sample, taken from APPROACH-IS, consisted of 3258 adults with CHD from 15 different countries. Patients completed questionnaires on illness perceptions and patient-reported outcomes (i.e., quality of life, perceived health status, and symptoms of depression and anxiety). Patient characteristics included sex, age, marital status, educational level, employment status, CHD complexity, functional class, and ethnicity. Linear mixed models were applied. RESULTS: The inter country variation in illness perceptions was generally small, yet patients from different countries differed in the extent to which they perceived their illness as chronic and worried about their illness. Patient characteristics that were linked to illness perceptions were sex, age, employment status, CHD complexity, functional class, and ethnicity. Higher scores on consequences, identity, and emotional representation, as well as lower scores on illness coherence and personal and treatment control, were associated with poorer patient-reported outcomes. CONCLUSIONS: This study emphasizes that, in order to gain a deeper understanding of patients' functioning, health-care providers should focus not only on objective indicators of illness severity such as the complexity of the heart defect, but also on subjective illness experiences. PMID- 28669512 TI - Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA). AB - BACKGROUND: A family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives. METHODS: Data from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n=378] and T2D (GADA-negative, n=1199), and their matched controls (n=1484). First-degree relatives with disease onset at age<40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes. RESULTS: Both FHD-T1D (OR: 5.8; 95% CI: 3.2 10.3) and FHD-T2D (OR: 1.9; 95% CI: 1.5-2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD-T2D (OR: 2.7; 95% CI: 2.2-3.3), but not FHD-T1D. In LADA patients, FHD-T1D vs FHD-T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low risk HLA genotypes (5.0% vs 28.6%, respectively; P=0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P=0.0576). CONCLUSION: The risk of LADA is substantially increased with FHD-T1D but also, albeit significantly less so, with FHD-T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD-T1D had more T1D-like features, emphasizing the heterogeneity of LADA. PMID- 28669513 TI - High efficacy of screening for diabetes and prediabetes in cardiac rehabilitation after an acute coronary syndrome (ACS). The REHABDIAB study. PMID- 28669514 TI - Identification of urine metabolites associated with 5-year changes in biomarkers of glucose homoeostasis. AB - AIM: Metabolomics provides information on pathogenetic mechanisms and targets for interventions, and may improve risk stratification. During the last decade, metabolomics studies were used to gain deeper insight into the pathogenesis of diabetes mellitus. However, longitudinal metabolomics studies of possible subclinical states of disturbed glucose metabolism are limited. Therefore, the aim of this study was to analyze the associations between baseline urinary metabolites and 5-year changes in continuous markers of glucose homoeostasis, including fasting glucose, HbA1c and homoeostasis model assessment of insulin resistance (HOMA-IR) index values. METHODS: Urine metabolites in 3986 participants at both baseline and 5-year follow-up of the population-based Inter99 study were analyzed by 1H-NMR spectroscopy. Linear regression and analyses of covariance models were used to detect associations between urine metabolites and 5-year changes in markers of glucose homoeostasis. RESULTS: Higher baseline levels of urinary alanine, betaine, N,N-dimethylglycine (DMG), creatinine and trimethylamine were associated with an increase in HbA1c from baseline to follow-up. In contrast, formic acid and trigonelline levels were associated with a decrease in HbA1c over time. Analyses of 5-year changes in fasting glucose and HOMA-IR index showed similar findings, with high baseline levels of lactic acid, beta-d-glucose, creatinine, alanine and 1 methylnicotinamide associated with increases in both parameters. CONCLUSION: Several urine metabolites were found to be associated with detrimental longitudinal changes in biomarkers of glucose homoeostasis. The identified metabolites point to mechanisms involving betaine and coffee metabolism as well as the possible influence of the gut microbiome. PMID- 28669515 TI - Impact of body mass index on the predictive capacity of the COPD-6 device in the detection of airflow obstruction. AB - BACKGROUND AND OBJECTIVE: The portable COPD-6 device has been validated as a screening tool for airflow obstruction through the quantification of the FEV1/FEV6 ratio. To date, however, the impact of body mass index (BMI) on its ability to predict airflow obstruction has not been evaluated. The aim of the study was to assess the predictive ability of COPD-6 to detect airflow obstruction based on the patient's BMI. MATERIAL AND METHOD: A prospective and open cohort study in which 223 subjects who underwent conventional spirometry and COPD-6 were included. The area under the curve ROC (AUC) of FEV1/FEV6 was analysed in the detection of obstruction for all patients in addition to BMI (BMI<30kg/m2 and BMI>=30kg/m2). Sensitivity and specificity, negative and positive predictive value as well as likelihood ratio were calculated to determine the cut-off point of COPD-6 FEV1/FEV6 ratio with greater predictive capacity. RESULTS: The COPD-6 allows ruling out airflow obstruction with AUC of the estimated ROC curve of 88% (95% CI 83-93). The cut-off point FEV1/FEV6 of 0.74-0.76 shows the best predictive capacity. However, this capacity is altered according to BMI with an increase in false positives in subjects with BMI>=30kg/ m2 when using the same cut-off point for the whole sample. CONCLUSION: The choice of cut-off point FEV1/FEV6 for the detection of obstruction should be adjusted to the patient's BMI. PMID- 28669516 TI - Adherence to treatment in patients with systemic lupus erythematosus. AB - BACKGROUND AND OBJECTIVE: Non-adherence to treatment is usually a clinical problem in patients with systemic lupus erythematosus (SLE). Increasing the knowledge of predictors of treatment adherence can be meaningful in the clinical setting. The main objective of the present study was to analyse the influence of sociodemographic, clinical and psychological variables on the degree of treatment adherence in a sample of Spanish women with SLE. PATIENTS AND METHOD: This is an observational-transversal study. All participants were evaluated for the degree of treatment adherence, their clinical status, psychopathological manifestations, the level of perceived stress and self-efficacy. The sample was divided into two groups (adherent vs non-adherent). The factors associated with a lack of adherence in this sample were analysed by means of logistic regression. RESULTS: This study comprises 72 women with SLE (average age=36.72+/-12.2 years). Almost 64% of patients with SLE were non-adherent to treatment. The results showed that a low educational level, being unemployed, living with a partner and alcohol abuse were associated with low treatment adherence. There were significant mean differences between groups in psychopathological subscales of somatisation, obsession-compulsion and general psychopathological indices. There were also mean differences between groups for the level of perceived stress. The use of non steroidal anti-inflammatory drugs, suffering arthrosis and scoring higher in dimensions of psychopathology were significant predictors of treatment adherence, explaining between 35% and 47% of its variability. CONCLUSIONS: Including the clinical and psychopathological manifestations as important aspects in the clinical reasoning of health professionals could improve the adherence to treatment of patients with SLE. PMID- 28669517 TI - Dysbiosis as a determinant factor of systemic and oral pathology: importance of microbiome. AB - Advances in genetic and epigenetic studies modified some concepts of health and disease that had been kept intact for decades. In this respect, in the last few years, microorganisms that have evolved with superior life forms for millions of years have taken an increased prominence. The genes of organisms and their microbiota constitute a microbiome that intervenes in health maintenance. The oral cavity is inhabited by a variety of microorganisms, their control aids in stabilising oral and systemic disease. The objective of this article is to update some concepts related to oral microbiome and its correlation with general and oral health. PMID- 28669518 TI - Impact of Interaction Between PPAR Alpha and PPAR Gamma on Breast Cancer Risk in the Chinese Han Population. AB - BACKGROUND: Several studies have been conducted to investigate the association of the peroxisome proliferator-activated receptor (PPAR) alpha (PPAR A) and PPAR gamma (PPAR G) polymorphism and breast cancer (BC) risk, but the results were inconsistent, and, until now, no study focused on the impact of gene-gene interactions between PPAR A and PPAR G on BC risk; thus, the aim of this study was to investigate the impact of interaction between PPAR A and PPAR G on BC risk in the Chinese Han population. METHODS: A total of 862 participants with a mean age of 63.0 +/- 15.7 years were selected, including 432 patients with BC and 430 controls. A logistic regression model was used to examine the association between single-nucleotide polymorphisms and BC risk. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the gene-gene interaction. RESULTS: Logistic regression analysis showed that BC risk was significantly higher in carriers of G allele of rs1800206 polymorphism than those with CC (CG + GG vs. CC) (adjusted OR, 1.50; 95% CI, 1.20-1.93). In addition, we found that BC risk was also significantly higher in carriers of the G allele of the rs1805192 polymorphism than those with the CC genotype (CG + GG vs. CC) (adjusted OR, 1.78; 95% CI, 1.34-2.26). There was a significant gene-gene interaction between rs1805192 and rs1800206. Overall, the 2-locus models had a cross-validation consistency of 10 of 10, and had a testing accuracy of 60.11%. Patients with CG or GG of rs1805192 and CG or GG of rs1800206 genotype have the highest BC risk, compared with patients with CC of rs1805192 and CC of rs1800206 genotype (OR, 2.59; 95% CI, 1.70-3.48, after covariates adjustment for gender, age, age at menarche, number of children, body mass index, and waist circumference). CONCLUSIONS: The minor allele of rs1800206 and rs1805192 and its interaction were associated with increased BC risk. PMID- 28669520 TI - A rolling stone plugging the colon: Consequence of a cholecystocolonic fistula from gallbladder cancer. PMID- 28669519 TI - Ex-vivo models of the Retinal Pigment Epithelium (RPE) in long-term culture faithfully recapitulate key structural and physiological features of native RPE. AB - The Retinal Pigment Epithelium (RPE) forms the primary site of pathology in several blinding retinopathies. RPE cultures are being continuously refined so that dynamic disease processes in this important monolayer can be faithfully studied outside the eye over longer periods. The RPE substrate, which mimics the supportive Bruch's membrane (BrM), plays a key role in determining how well in vitro cultures recapitulate native RPE cells. Here, we evaluate how two different types of BrM substrates; (1) a commercially-available polyester transwell membrane, and (2) a novel electrospun scaffold developed in our laboratory, could support the generation of realistic RPE tissues in culture. Our findings reveal that both substrates were capable of supporting long-lasting RPE monolayers with structural and functional specialisations of in-situ RPE cells. These cultures were used to study autofluorescence and barrier formation, as well as activities such as outer-segment internalisation/trafficking and directional secretion of key proteins; the impairment of which underlies retinal disease. Hence, both substrates fulfilled important criteria for generating authentic in-vitro cultures and act as powerful tools to study RPE pathophysiology. However, RPE grown on electrospun scaffolds may be better suited to studying complex RPE-BrM interactions such as the formation of drusen-like deposits associated with early retinal disease. PMID- 28669521 TI - Management of delayed hemolytic transfusion reaction in sickle cell disease: Prevention, diagnosis, treatment. AB - Transfusion remains a key treatment of sickle cell disease complications. However, delayed hemolytic transfusion reaction, the most serious complication of transfusion, may be life-threatening if hyperhemolysis develops. This syndrome is generally underdiagnosed because its biological and clinical features resemble those of vaso-occlusive crisis, and red blood cell antibodies are frequently absent. Further transfusions may aggravate the symptoms, leading to severe multiple organ failure and death. It is therefore essential to prevent, diagnose and treat this syndrome efficiently. Prevention is based principally on the attenuation of allo-immunization through the provision of extended-matched RBCs or the use of rituximab. However, such treatment may be insufficient. Early diagnosis might make it possible to implement specific treatments in some cases, thereby avoiding the need for secondary transfusion. Diagnosis is dependent on the knowledge of the medical staff. Finally, many treatments, including steroids, immunoglobulins, erythropoietin and eculizumab, have been used to improve outcome. Improvements in our knowledge of the specific features of DHTR in SCD should facilitate management of this syndrome. PMID- 28669522 TI - In vitro generation of platelets: Where do we stand? AB - Millions of platelets, specialized cells that participate in haemostatic and inflammatory functions, are transfused each year worldwide, but their supply is limited. Platelets are produced by megakaryocytes by extending proplatelets, directly into the bloodstream. Bone marrow structure and extracellular matrix composition together with soluble factors (e.g. Thrombopoietin) are key regulators of megakaryopoiesis by supporting cell differentiation and platelet release. Despite this knowledge, the scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells. PMID- 28669523 TI - [Animal experiment, can we replace?] AB - Animal experiment is a subject of controversies. Some people, defenders of animals, think that it is not acceptable to use for scientific purposes at the risk of making them suffer or assert that the results obtained with animals are not transposable in the human beings. Others, in particular researchers in biology or medicine, think that the animal models are essential for the biomedical search. This confrontation of the opinions bases largely on an evolution of the place of animals in our society. The regulations authorize the use of animals for scientific purposes but oblige to make it under restrictive conditions. The application of 3Rs - replacement, reduction, and refinement - expressed in 1959 by Russel and Burch is an ethical guide to improve the welfare of animals in research. The alternative methods do not allow, in the present state of the knowledge, to answer all the scientific questions in biology and medicine research. They are, most of the time, complementary methods of the in vivo methods. PMID- 28669524 TI - From genetic variability to phenotypic expression of blood group systems. AB - More than 300 red blood cell (RBC) antigens belonging to 36 blood group systems have been officially reported in humans by the International Society of Blood Transfusion (ISBT). Phenotypic variability is directly linked to the expression of the 41 blood group genes. The Rh blood group system, which is composed of 54 antigens, is the most complex and polymorphic system. Many rare genetic variants within the RH (RHD and RHCE) genes, involving various mutational mechanisms (single-nucleotide substitutions, short insertions/deletions, rearrangements, large deletions), have been reported in the literature and reference databases. Expression of the variants induces variable clinical outcomes depending on their nature and impact on antigen structure. Their respective molecular and cellular effects remain however poorly studied. Biological resources to conduct this research are also barely available. We have paid a specific attention to three different classes of single-nucleotide substitutions: 1/ splice site variants in the Rh, Kell, Kidd, Junior and Langereis systems by the minigene splicing assay developed locally; 2/ missense variants in the RhD protein and their effect on intermolecular interaction with its protein partner RhAG, intracellular trafficking and plasma membrane integration; and 3/ synonymous variants in the RHD gene. Overall not only this project has fundamental objectives by analyzing the functional effect of variants in order to make genotype-phenotype correlation, but the aim is also to develop/engineer molecular tools and cell models to carry out those studies. PMID- 28669525 TI - Mechanisms of Skin Toxicity Associated with Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators. AB - Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series. Investigation of a database of chemicals tested in these systems and transcriptional profiling suggested that the mechanism of toxicity may involve modulation of nuclear receptor targets RAR/RXR, and/or VDR with AhR antagonism. The studies reported here demonstrate how phenotypic profiling of preclinical drug candidates using human primary cells can provide insights into the mechanisms of toxicity and inform early drug discovery and development campaigns. PMID- 28669527 TI - Switch on a more efficient pyruvate synthesis pathway based on transcriptome analysis and metabolic evolution. AB - Due to the decrease of intracellular NADH availability, gluconate metabolism is more conducive to pyruvate production than glucose. Transcriptome analysis revealed that the Entner-Doudoroff (ED) pathway was activated by gluconate in Escherichia coli YP211 (MG1655 DeltaldhA DeltapflB Deltapta-ackA DeltapoxB Deltappc DeltafrdBC). To construct a new pyruvate producing strain with glucose metabolism via ED pathway, the genes ppsA, ptsG, pgi and gnd were deleted sequentially to reduce the demand for PEP and block the Embden-Meyerhor-Parnas pathway and Pentose-Phosphate pathway. After nearly 1000 generations of growth based selection, the evolved strain YP404 was isolated and the ED pathway was proved to be activated as the primary glycolytic pathway. Comparing with YP211, the pyruvate concentration and yield increased by 59% and 10.1%, respectively. In fed-batch fermentation, the pyruvate concentration reached 83.5 g l-1 with a volumetric productivity of 2.3 g l-1 h-1. This was the first time to produce pyruvate via ED pathway, and prove that this was a more effective way. PMID- 28669528 TI - Orthogonal partial least squares/projections to latent structures regression based metabolomics approach for identification of gene targets for improvement of 1-butanol production in Escherichia coli. AB - Metabolomics is the comprehensive analysis of metabolites in biological systems that uses multivariate analyses such as principal component analysis (PCA) or partial least squares/projections to latent structures regression (PLSR) to understand the metabolome state and extract important information from biological systems. In this study, orthogonal PLSR (OPLSR) model-based metabolomics approach was applied to 1-butanol producing Escherichia coli to facilitate in strain improvement strategies. Here, metabolite data obtained by liquid chromatography/mass spectrometry (LC/MS) was used to construct an OPLSR model to correlate metabolite changes with 1-butanol production and rationally identify gene targets for strain improvement. Using this approach, acetyl-CoA was determined as the rate-limiting step of the pathway while free CoA was found to be insufficient for 1-butanol production. By resolving the problems addressed by the OPLSR model, higher 1-butanol productivity was achieved. In this study, the usefulness of OPLSR-based metabolomics approach for understanding the whole metabolome state and determining the most relevant metabolites was demonstrated. Moreover, it was able to provide valuable insights for selection of rational gene targets for strain improvement. PMID- 28669529 TI - Development of an in situ evaluation system for neural cells using extracellular matrix-modeled gel culture. AB - Two-dimensional monolayer culture is the most popular cell culture method. However, the cells may not respond as they do in vivo because the culture conditions are different from in vivo conditions. However, hydrogel-embedding culture, which cultures cells in a biocompatible culture substrate, can produce in vivo-like cell responses, but in situ evaluation of cells in a gel is difficult. In this study, we realized an in vivo-like environment in vitro to produce cell responses similar to those in vivo and established an in situ evaluation system for hydrogel-embedded cell responses. The extracellular matrix (ECM)-modeled gel consisted of collagen and heparin (Hep-col) to mimic an in vivo like environment. The Hep-col gel could immobilize growth factors, which is important for ECM functions. Neural stem/progenitor cells cultured in the Hep-col gel grew and differentiated more actively than in collagen, indicating an in vivo like environment in the Hep-col gel. Second, a thin-layered gel culture system was developed to realize in situ evaluation of the gel-embedded cells. Cells in a 200-MUm-thick gel could be evaluated clearly by a phase-contrast microscope and immunofluorescence staining through reduced optical and diffusional effects. Finally, we found that the neural cells cultured in this system had synaptic connections and neuronal action potentials by immunofluorescence staining and Ca2+ imaging. In conclusion, this culture method may be a valuable evaluation system for neurotoxicity testing. PMID- 28669530 TI - "On-Top Plasty" for Radial Polydactyly Reconstruction. AB - PURPOSE: To introduce the "on-top plasty" technique and report our long-term outcomes. METHODS: We evaluated 5 thumbs in 5 patients who underwent radial polydactyly reconstruction using the "on-top plasty" technique between 1998 and 2003. This technique was used when it was felt that neither thumb possessed adequate proximal and distal structures to provide a functional and aesthetically pleasing thumb. Our study group included 1 Flatt type III and 4 Flatt type VII thumbs. The average age at time of surgery was 1.4 years and at final follow-up was 13.5 years. Subjective patient evaluation, objective outcomes values, and validated patient-oriented outcome measures were obtained. RESULTS: There was no soft tissue loss and union was achieved in all thumbs with no further surgery required in any thumb. Mean flexion-extension arc for the metacarpophalangeal joint was 60 degrees (range, 10 degrees extension to 70 degrees flexion) and at the interphalangeal joint was 19 degrees (range, 25 degrees extension to 35 degrees flexion). Mean percentage of age-matched norms for lateral, tripod, and tip pinch were 47.0%, 45.9%, and 47.8%, respectively. Mean grip strength was 54.2% of age-matched norm. The mean Pediatric Quality of Life Inventory (PedsQL) score for parent questionnaires was 89.0 and for teen/child questionnaires was 89.1. The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire revealed a mean score of 4.3. CONCLUSIONS: For patients with radial polydactyly in which neither thumb possesses adequate distal and proximal components, the on top plasty is a reliable method of polydactyly reconstruction with durable results at longer than 10 years' follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 28669531 TI - Mycobacterium marinum and Carpal Tunnel Syndrome: Three Case Reports. AB - Infection with Mycobacterium marinum is often difficult to diagnose. Infection with M. marinum in the upper extremity may involve the tendon sheaths, producing clinical manifestations such as tenosynovitis and symptoms of carpal tunnel syndrome. We report 3 cases of M. marinum infection of the hand associated with carpal tunnel syndrome during an outbreak in New York City's Chinatown. A combination of carpal tunnel release, flexor tenosynovectomy, and appropriate antibiotics yielded complete resolution of symptoms in all cases. PMID- 28669526 TI - Attenuating Staphylococcus aureus Virulence by Targeting Flotillin Protein Scaffold Activity. AB - Scaffold proteins are ubiquitous chaperones that bind proteins and facilitate physical interaction of multi-enzyme complexes. Here we used a biochemical approach to dissect the scaffold activity of the flotillin-homolog protein FloA of the multi-drug-resistant human pathogen Staphylococcus aureus. We show that FloA promotes oligomerization of membrane protein complexes, such as the membrane associated RNase Rny, which forms part of the RNA-degradation machinery called the degradosome. Cells lacking FloA had reduced Rny function and a consequent increase in the targeted sRNA transcripts that negatively regulate S. aureus toxin expression. Small molecules that altered FloA oligomerization also reduced Rny function and decreased the virulence potential of S. aureus in vitro, as well as in vivo, using invertebrate and murine infection models. Our results suggest that flotillin assists in the assembly of protein complexes involved in S. aureus virulence, and could thus be an attractive target for the development of new antimicrobial therapies. PMID- 28669532 TI - Intraoperative cholangiography during cholecystectomy among hospitalized medicare beneficiaries with non-neoplastic biliary disease. AB - BACKGROUND: Prior studies of Medicare beneficiaries with both neoplastic and non neoplastic indications for cholecystectomy demonstrated a reduced risk of common bile duct (CBD) injury when intraoperative cholangiography (IOC) was used. We sought to determine the association between IOC and CBD injury during inpatient cholecystectomy for non-neoplastic biliary disease and compare survival among those with or without CBD injury. METHODS: Retrospective study of patients >=66 who underwent inpatient cholecystectomy (2005-2010) for gallstones, cholecystitis, cholangitis, or gallbladder obstruction. The association between IOC and CBD injury was analyzed using multivariable logistic regression and survival after cholecystectomy was analyzed using multivariable Cox regression. RESULTS: Among 472,367 patients who underwent cholecystectomy, 0.3% had a CBD injury. IOC was associated with increased CBD injury (adjusted OR 1.41[1.27 1.57]). CBD injury was associated with increased hazards of death (adjusted HR 1.37[1.25-1.51]). CONCLUSIONS: IOC in patients with non-neoplastic biliary disease was associated with increased odds of CBD injury. This likely reflects its selective use in patients at higher risk of CBD injury or as a confirmatory test when an injury is suspected. PMID- 28669533 TI - Effects of laparoscopic cholecystectomy in normokinetic biliary dyskinesia. AB - This is the largest single center retrospective study to date looking at response to laparoscopic cholecystectomy in patients with acalculous biliary disease. A chart review was completed on 1116 patients from 2009 to 2014 who had admitting diagnoses related to acalculous cholecystitis and biliary colic. Four hundred and seventy four patients were available for long term follow up (6 months or longer). Multiple factors were studied as related to cholescintigraphy scans with cholecystokinin administration (HIDA with CCK). Hyperkinetic, normokinetic and hypokinetic ejection fractions (EF), as well as reproduction of symptoms with administration of CCK were catagorized. ROME III criteria (Table 1) were used to describe cholecystitis/biliary colic symptoms. (1). It was found that rates of resolution of symptoms after laparoscopic cholecystectomy in normokinetic and hypokinetic were similar. It was also found that reproduction of symptoms after administration of CCK was a better predictor of favorable response to surgery than calculated ejection fraction. PMID- 28669534 TI - Influence of inversion time on endolymphatic hydrops evaluation in 3D-FLAIR imaging. AB - The MRI evaluation of endolymphatic hydrops currently relies on inversion recovery sequences. Signal intensity of such sequences depends on the Inversion Time (TI) parameter. Here, we assessed endolymphatic compartment variation with two 3D-FLAIR sequences, closely similar except for the TI (2300 and 2400ms), in healthy volunteers and patients. We found that the semi-quantitative method of grading was highly dependent on the TI, contrasting with the recently proposed saccular-based grading of endolymphatic hydrops. PMID- 28669535 TI - Ethnic socialization, ethnic identity, life satisfaction and school achievement of Roma ethnic minority youth. AB - This article is part of a Special Issue entitled Explaining Positive Adaptation of Immigrant Youth across Cultures. This study tested a mediation model of ethnic socialization (i.e., parental practices that promote children's knowledge about their history, heritage culture, cultural authenticity, and ethnic bias management) in Roma youth. Roma are the largest ethnic minority group in Europe subjected to severe discrimination, both currently and historically. Participants were 202 Roma youth aged 14 to 19 years old (M = 16.25, 53% females), who provided self-reports on their experience of ethnic socialization, ethnic identity, school achievement, and life satisfaction. Cultural pride reinforcement was related to better school achievement, whereas cultural coping with antagonism was positively related to life satisfaction. The study confirmed the model in that ethnic socialization was positively related to life satisfaction through effects on ethnic identity but negatively associated with school achievement. Findings have implications for adaptive cultural mechanisms promoting positive developmental outcomes among historically disadvantaged groups including those intersecting immigrant and multigenerational ethnic minority group categories. PMID- 28669537 TI - Pneumonia Can Cause Clozapine Intoxication: A Case Report. PMID- 28669538 TI - The Effect of Methylphenidate on the Microstructure of Schedule-Induced Polydipsia in an animal model of ADHD. AB - Schedule-induced polydipsia (SIP) was established in spontaneously hypertensive rats (SHR), Wistar Kyoto rats (WKY), and Wistar rats, using a multiple fixed-time (FT) schedule of food delivery, with 30- and 90-s components. Thereafter, animals were exposed to methylphenidate (MPH; 2.5mg/kg/d) for six consecutive SIP sessions. A test to assess possible sensitization effects was also conducted four days after termination of the drug treatment. At baseline, FT 90-s produced longer and more frequent drinking episodes in SHR than in WKY. An analysis of the distribution of inter-lick intervals revealed that drinking was organized in bouts, which were shorter in SHR than in WKY. Across strains and schedules, MPH shifted drinking episodes towards the beginning of inter-food intervals, which may reflect a stimulant effect on SIP. MPH transiently reduced the frequency of drinking episodes in WKY in FT 30-s, and more permanently reduced the frequency of licking bouts in Wistar rats. MPH also increased the length of licking bouts in Wistar rats. Overall, SHR displayed a hyperactive-like pattern of drinking (frequent but short bouts), which 2.5mg/kg MPH appears to reduce in WKY and Wistar but not in SHR rats. It appears that therapeutic effects of MPH on hyperactive-like SIP require higher doses in SHR relative to control strains. PMID- 28669536 TI - Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13. AB - Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ~100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP. PMID- 28669539 TI - Monte Carlo dosimetric characterization of the Flexisource Co-60 high-dose-rate brachytherapy source using PENELOPE. AB - PURPOSE: 60Co sources have been commercialized as an alternative to 192Ir sources for high-dose-rate (HDR) brachytherapy. One of them is the Flexisource Co-60 HDR source manufactured by Elekta. The only available dosimetric characterization of this source is that of Vijande et al. [J Contemp Brachytherapy 2012; 4:34-44], whose results were not included in the AAPM/ESTRO consensus document. In that work, the dosimetric quantities were calculated as averages of the results obtained with the Geant4 and PENELOPE Monte Carlo (MC) codes, though for other sources, significant differences have been quoted between the values obtained with these two codes. The aim of this work is to perform the dosimetric characterization of the Flexisource Co-60 HDR source using PENELOPE. METHODS AND MATERIALS: The MC simulation code PENELOPE (v. 2014) has been used. Following the recommendations of the AAPM/ESTRO report, the radial dose function, the anisotropy function, the air-kerma strength, the dose rate constant, and the absorbed dose rate in water have been calculated. RESULTS: The results we have obtained exceed those of Vijande et al. In particular, the absorbed dose rate constant is ~0.85% larger. A similar difference is also found in the other dosimetric quantities. The effect of the electrons emitted in the decay of 60Co, usually neglected in this kind of simulations, is significant up to the distances of 0.25 cm from the source. CONCLUSIONS: The systematic and significant differences we have found between PENELOPE results and the average values found by Vijande et al. point out that the dosimetric characterizations carried out with the various MC codes should be provided independently. PMID- 28669540 TI - Successful management of primary atrophic rhinitis by turbinate reconstruction using autologous costal cartilage. AB - Initial management of primary atrophic rhinitis is conservative, with nasal ointments, saline irrigation, and antibiotics prescribed to relieve symptoms. However, in cases that show no improvement, a surgical approach is considered. Recently, many studies have reported successful surgical outcomes using various nasal implants. However, no study has reported implantation of autologous costal cartilage in PAR patients. We report here the case of a 63-year-old woman diagnosed with PAR that was intractable to medical therapy. Under general anesthesia, bilateral inferior turbinate reconstruction with autologous costal cartilage was successfully performed without any complications. One month after surgery, her symptoms improved dramatically. At the 2-year follow-up, her Sinonasal Outcome Test 25 (SNOT-25) score was 6, down from an initial score of 108. Her OMU CT showed improved sinonasal mucosal thickness and disappearance of thick mucosal secretion compared with preoperative CT image. Although this is a single case experience, it is suggested that turbinate reconstruction using autologous costal cartilage can serve as promising surgical modality for management of atrophic rhinitis. PMID- 28669541 TI - Carrier screening for single gene disorders. AB - Screening for genetic disorders began in 1963 with the initiation of newborn screening for phenylketonuria. Advances in molecular technology have made both newborn screening for newborns affected with serious disorders, and carrier screening of individuals at risk for offspring with genetic disorders, more complex and more widely available. Carrier screening today can be performed secondary to family history-based screening, ethnic-based screening, and expanded carrier screening (ECS). ECS is panel-based screening, which analyzes carrier status for hundreds of genetic disorders irrespective of patient race or ethnicity. In this article, we review the historical and current aspects of carrier screening for single gene disorders, including future research directions. PMID- 28669542 TI - Opposite effects of l-dopa and DBS-STN on saccadic eye movements in advanced Parkinson's disease. AB - OBJECTIVE: To assess the effects of l-dopa and deep brain stimulation of the subthalamic nucleus (DBS-STN) on saccadic eye movements in patients with Parkinson's disease (PD). METHODS: Visually and internally guided horizontal saccades were evaluated using a saccadometer in 64 patients with advanced PD and 48 healthy controls. Forty-four pharmacologically treated patients were assessed in their "med-off" (OFF) and "med-on" (ON) status, whereas 20 DBS-STN treated patients were assessed in their "med-off, stim-off" (OFF) and "med-off, stim-on" (ON) status. RESULTS: In all PD patients the saccades in the OFF status were delayed, slower and smaller (p<0.01) than in controls. In pharmacologically treated patients all studied parameters showed tendency to worsen in the ON status as compared to the OFF status. In contrast, activating DBS-STN showed tendency to improve all studied parameters. Comparison of the studied saccade parameters between the ON status of DBS-STN treated patients, ON status of the pharmacologically treated patients and the controls showed that 73% of these parameters in the DBS-STN treated patients were similar as in the controls. While in the pharmacologically treated patients only 26% of these parameters were similar as in the controls. CONCLUSION: This prospective study comparing the influence of l-dopa and DBS-STN on saccades in advanced PD showed contrasting results between these two treatments; the majority of the studied parameters in patients on DBS-STN were similar as in the controls. PMID- 28669543 TI - Fronto-parietal Cortical Circuits Encode Accumulated Evidence with a Diversity of Timescales. AB - Decision-making in dynamic environments often involves accumulation of evidence, in which new information is used to update beliefs and select future actions. Using in vivo cellular resolution imaging in voluntarily head-restrained rats, we examined the responses of neurons in frontal and parietal cortices during a pulse based accumulation of evidence task. Neurons exhibited activity that predicted the animal's upcoming choice, previous choice, and graded responses that reflected the strength of the accumulated evidence. The pulsatile nature of the stimuli enabled characterization of the responses of neurons to a single quantum (pulse) of evidence. Across the population, individual neurons displayed extensive heterogeneity in the dynamics of responses to pulses. The diversity of responses was sufficiently rich to form a temporal basis for accumulated evidence estimated from a latent variable model. These results suggest that heterogeneous, often transient sensory responses distributed across the fronto-parietal cortex may support working memory on behavioral timescales. VIDEO ABSTRACT. PMID- 28669544 TI - TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. AB - Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline. PMID- 28669546 TI - Biased Oxytocinergic Modulation of Midbrain Dopamine Systems. AB - The release of dopamine (DA) regulates rewarding behavior and motor actions through striatum-targeting efferents from ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Here, we map and functionally characterize axonal projections from oxytocin neurons in the hypothalamic paraventricular nucleus to midbrain DA regions. Electrophysiological recordings of DA neurons reveal that both the application of oxytocin and optogenetic stimulation of oxytocinergic terminals suffice to increase DA neuron activity in the VTA but downregulate it in SNc. This biased modulation is mediated by oxytocin and vasopressin G-protein-coupled receptors. Oxytocin release directly activates DA neurons and indirectly inhibits them through local GABA neurons, but the relative magnitudes of the two mechanisms differ in VTA and SNc. Oxytocin-modulated DA neurons give rise to canonical striatal projections. Since hypothalamic oxytocinergic projections also target the striatum, oxytocin is poised to bias the balance of DA tone through multiple sites in vertebrate reward circuits. PMID- 28669545 TI - Retrograde Synaptic Inhibition Is Mediated by alpha-Neurexin Binding to the alpha2delta Subunits of N-Type Calcium Channels. AB - The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here, we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/alpha2delta), decreasing UNC-36 abundance at pre-synaptic elements. Retrograde inhibition is mediated by a soluble form of NRX-1's ectodomain, which is released from the post-synaptic membrane by the SUP 17/ADAM10 protease. Mammalian Neurexin-1alpha binds alpha2delta-3 and decreases CaV2.2 current in transfected cells, whereas Neurexin-1alpha has no effect on CaV2.2 reconstituted with alpha2delta-1 and alpha2delta-2. Collectively, these results suggest that alpha-Neurexin binding to alpha2delta is a conserved mechanism for regulating synaptic transmission. PMID- 28669547 TI - The effects of wrist motion and hand orientation on muscle forces: A physiologic wrist simulator study. AB - Although the orientations of the hand and forearm vary for different wrist rehabilitation protocols, their effect on muscle forces has not been quantified. Physiologic simulators enable a biomechanical evaluation of the joint by recreating functional motions in cadaveric specimens. Control strategies used to actuate joints in physiologic simulators usually employ position or force feedback alone to achieve optimum load distribution across the muscles. After successful tests on a phantom limb, unique combinations of position and force feedback - hybrid control and cascade control - were used to simulate multiple cyclic wrist motions of flexion-extension, radioulnar deviation, dart thrower's motion, and circumduction using six muscles in ten cadaveric specimens. Low kinematic errors and coefficients of variation of muscle forces were observed for planar and complex wrist motions using both novel control strategies. The effect of gravity was most pronounced when the hand was in the horizontal orientation, resulting in higher extensor forces (p<0.017) and higher out-of-plane kinematic errors (p<0.007), as compared to the vertically upward or downward orientations. Muscle forces were also affected by the direction of rotation during circumduction. The peak force of flexor carpi radialis was higher in clockwise circumduction (p=0.017), while that of flexor carpi ulnaris was higher in anticlockwise circumduction (p=0.013). Thus, the physiologic wrist simulator accurately replicated cyclic planar and complex motions in cadaveric specimens. Moreover, the dependence of muscle forces on the hand orientation and the direction of circumduction could be vital in the specification of such parameters during wrist rehabilitation. PMID- 28669548 TI - An effective balancing response to lateral perturbations at pelvis level during slow walking requires control in all three planes of motion. AB - In this study we investigated balancing responses to lateral perturbations during slow walking (0.85m/s). A group of seven healthy individuals walked on an instrumented treadmill while being perturbed at the level of waist at left heel strike in outward and inward lateral directions. Centre of mass (COM) and centre of pressure (COP), rotation of pelvis around vertical axis, step lengths, step widths and step times were assessed. The results have shown that beside control of COP in lateral direction, facilitated by adequate step widths, control of COP in sagittal direction, slowing down movement of COM was present after commencement of lateral perturbations. Sagittal component of COM was significantly retarded as compared to unperturbed walking for both inward (4.32+/ 1.29cm) and outward (9.75+/-2.17cm) perturbations. This was necessary since after an inward perturbation first step length (0.29+/-0.04m compared to 0.52+/-0.02m in unperturbed walking) and step time (0.45+/-0.05s compared to 0.61+/-0.04s in unperturbed walking) were shortened while after an outward perturbation first two step lengths (0.36+/-0.05m and 0.32+/-0.11m compared to 0.52+/-0.03m in unperturbed walking) were shortened that needed to be accommodated by the described modulation of COP in sagittal plane. In addition pronounced pelvis rotation assisted in bringing swing leg to new location. The results of this study show that counteracting lateral perturbations at slow walking requires adequate response in all three planes of motion. PMID- 28669549 TI - Distributed fault-tolerant time-varying formation control for high-order linear multi-agent systems with actuator failures. AB - This paper investigates the fault-tolerant time-varying formation control problems for high-order linear multi-agent systems in the presence of actuator failures. Firstly, a fully distributed formation control protocol is presented to compensate for the influences of both bias fault and loss of effectiveness fault. Using the adaptive online updating strategies, no global knowledge about the communication topology is required and the bounds of actuator failures can be unknown. Then an algorithm is proposed to determine the control parameters of the fault-tolerant formation protocol, where the time-varying formation feasible conditions and an approach to expand the feasible formation set are given. Furthermore, the stability of the proposed algorithm is proven based on the Lyapunov-like theory. Finally, two simulation examples are given to demonstrate the effectiveness of the theoretical results. PMID- 28669550 TI - Sulfasalazine-Induced Crystalluria Causing Severe Acute Kidney Injury. AB - Sulfasalazine is an anti-inflammatory agent commonly used in the treatment of autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine is converted by gut bacteria into sulfapyridine and the clinically active metabolite 5-aminosalicylic acid (5-ASA), and its efficacy is proportional to the 5-ASA concentration within the intestinal lumen. Renal complications are commonly reported for the chemically similar 5-ASA derivative mesalamine, but are not well-known side effects of sulfasalazine therapy. We report a 72-year-old patient with Crohn's disease managed with sulfasalazine for more than 10 years who presented with severe acute kidney injury (serum creatinine, 9.7mg/dL). Renal ultrasound revealed calculi and he subsequently spontaneously voided innumerable stones, which were composed of sulfasalazine metabolites. His renal calculi cleared and serum creatinine concentration improved to 3.1mg/dL after discontinuing sulfasalazine therapy and intravenous fluid hydration. His kidney function eventually returned to baseline. This case demonstrates that renal complications, in particular nephrolithiasis, may be an under-reported but potentially serious phenomenon in patients with inflammatory bowel disease treated with sulfasalazine and that their hydration status may play an important role in this process. PMID- 28669552 TI - Is Bedside Ultrasonography Rapid and Accurate for Confirmation of Central Venous Catheter Position and Exclusion of Pneumothorax Compared With Chest Radiograph? PMID- 28669551 TI - Low Accuracy of Positive qSOFA Criteria for Predicting 28-Day Mortality in Critically Ill Septic Patients During the Early Period After Emergency Department Presentation. AB - STUDY OBJECTIVE: We determine the diagnostic performance of positive Quick Sequential Organ Failure Assessment (qSOFA) scores for predicting 28-day mortality among critically ill septic patients during the early period after emergency department (ED) presentation. METHODS: This was a retrospective cohort study at a tertiary care academic center. We reviewed a registry of adult (>=18 years) patients who received a diagnosis of severe sepsis or septic shock during an ED stay from August 2008 through September 2014. We identified the point at which patients met 2 or more of the 3 qSOFA criteria (indicating a positive qSOFA score) simultaneously during the initial 24 hours. The diagnostic performance of positive qSOFA score for predicting 28-day mortality was assessed (on ED arrival and within 3, 6, and 24 hours after ED presentation). RESULTS: A total of 1,395 patients were included, and the overall 28-day mortality was 15%. For patients with positive qSOFA score, 28-day mortality was 23% (95% confidence interval [CI] 19% to 28%) on ED arrival, 20% (95% CI 17% to 23%) at 3 hours, 20% (95% CI 17% to 22%) at 6 hours, and 17% (95% CI 15% to 20%) at 24 hours. Positive qSOFA score for predicting 28-day mortality had a sensitivity, specificity, and area under the receiver operating curve, respectively, of 39% (95% CI 32% to 46%), 77% (95% CI 75% to 80%), and 0.58 (95% CI 0.55 to 0.62) on ED arrival; 68% (95% CI 62% to 75%), 52% (95% CI 49% to 55%), and 0.60 (95% CI 0.57 to 0.63) within 3 hours; 82% (95% CI 76% to 87%), 41% (95% CI 38% to 44%), and 0.61 (95% CI 0.58 to 0.64) within 6 hours; and 91% (95% CI 86% to 94%), 23% (95% CI 21% to 25%), and 0.57 (95% CI 0.54 to 0.59) within 24 hours. CONCLUSION: The diagnostic performance of positive qSOFA score for predicting 28-day mortality was low in critically ill septic patients, particularly during the early period after ED presentation. The study requires further prospective validation because of limitations with its retrospective design and use of single-center data. PMID- 28669553 TI - Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care. AB - We provide recommendations for stocking of antidotes used in emergency departments (EDs). An expert panel representing diverse perspectives (clinical pharmacology, medical toxicology, critical care medicine, hematology/oncology, hospital pharmacy, emergency medicine, emergency medical services, pediatric emergency medicine, pediatric critical care medicine, poison centers, hospital administration, and public health) was formed to create recommendations for antidote stocking. Using a standardized summary of the medical literature, the primary reviewer for each antidote proposed guidelines for antidote stocking to the full panel. The panel used a formal iterative process to reach their recommendation for both the quantity of antidote that should be stocked and the acceptable timeframe for its delivery. The panel recommended consideration of 45 antidotes; 44 were recommended for stocking, of which 23 should be immediately available. In most hospitals, this timeframe requires that the antidote be stocked in a location that allows immediate availability. Another 14 antidotes were recommended for availability within 1 hour of the decision to administer, allowing the antidote to be stocked in the hospital pharmacy if the hospital has a mechanism for prompt delivery of antidotes. The panel recommended that each hospital perform a formal antidote hazard vulnerability assessment to determine its specific need for antidote stocking. Antidote administration is an important part of emergency care. These expert recommendations provide a tool for hospitals that offer emergency care to provide appropriate care of poisoned patients. PMID- 28669554 TI - A Randomized Controlled Trial on the Effect of a Double Check on the Detection of Medication Errors. AB - STUDY OBJECTIVE: The use of a double check by 2 nurses has been advocated as a key error-prevention strategy. This study aims to determine how often a double check is used for high-alert medications and whether it increases error detection. METHODS: Emergency department and ICU nurses worked in pairs to care for a simulated patient. Nurses were randomized into single- and double-check groups. Errors intentionally introduced into the simulation included weight-based dosage errors and wrong medication vial errors. The evaluator recorded whether a double check was used, whether errors were detected, and observational data about nurse behavior during the simulation. RESULTS: Forty-three pairs of nurses consented to enroll in the study. All nurses randomized to the double-check group used a double check. In the single-check group, 9% of nurses detected the weight based dosage error compared with 33% of nurses in the double-check group (odds ratio 5.0; 95% confidence interval 0.90 to 27.74). Fifty-four percent of nurses in the single-check group detected the wrong vial error compared with 100% of nurses in the double-check group (odds ratio 19.9; 95% confidence interval 1.0 to 408.5). CONCLUSION: Our study demonstrates that nurses use double checks before administering high-alert medications. Use of a double check increases certain error detection rates in some circumstances, but not others. Both techniques missed many errors. In some cases, the second nurse actually dissuaded the first nurse from acting on the error. PMID- 28669555 TI - Variance in the Efficacy of Brief Interventions to Reduce Hazardous and Harmful Alcohol Consumption Between Injury and Noninjury Patients in Emergency Departments: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - STUDY OBJECTIVE: We adopt a comparative framework to measure the extent to which variance in the efficacy of alcohol brief interventions to reduce hazardous and harmful drinking at less than or equal to 5-, 6-, and 12-month follow-up in emergency department settings can be determined by differences between study populations (targeted injury and noninjury specific). METHODS: A systematic review and meta-analysis of randomized controlled trials published before September 2016 was undertaken. Twenty-three high-quality and methodologically similar randomized controlled trials were eligible, with a total number of 15,173 participants included. Primary outcome measure was efficacy of brief intervention compared with a control group in reducing quantity of alcohol consumed. An inverse variance model was applied to measure the effect of treatment in standard mean differences for brief intervention and control groups. RESULTS: At 6-month follow-up, an effect in favor of brief intervention over control was identified for targeted injury studies (standardized mean difference=-0.10; 95% confidence interval [CI] -0.17 to -0.02; I2=0%). For pooled noninjury-specific studies, small benefits of brief intervention were evident at less than or equal to 5 month follow-up (standardized mean difference=-0.15; 95% CI -0.24 to -0.07; I2=0%), at 6-month follow-up (standardized mean difference=-0.08; 95% CI -0.14 to -0.01; I2=1%), and at 12-month follow-up (standardized mean difference=-0.08; 95% CI -0.15 to -0.01; I2=0%). CONCLUSION: Meta-analysis identified noninjury specific studies as associated with better response to brief intervention than targeted injury studies. However, the inclusion of injured patients with noninjured ones in the experimental and control groups of noninjury-specific studies limited the interpretation of this finding. PMID- 28669556 TI - Recombinant influenza vaccine in adults aged 50 years or older. PMID- 28669557 TI - Extreme air pollution in Mongolia's overflowing capital. PMID- 28669558 TI - Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders. AB - Malignancies occur with a higher incidence rate and manifest earlier in life in patients with primary immunodeficiency disorders (PIDs) than in the general population. However, no universal mechanism of malignancy predisposition in patients with PIDs has been determined. Despite strong support for the physiologic role of tumor immunosurveillance and the increasing success of strategies in immunologic tumor therapy, which include checkpoint inhibition, mAbs, and engineered T-cell antigen receptors, the incidence and pattern of malignancies in patients with PIDs do not reflect an increased tumor immune escape per se. In contrast, malignancies appear to be restricted to either (1) tissue types bearing the same molecular defect that underlies the PID, such as syndromes of DNA repair deficiency or immune cell-specific maturation or functional defects that suggest a cell-intrinsic oncogenic basis, or (2) other tissues when they are infected by transforming viruses or chronically inflamed, pointing toward extrinsic causes for transformation that are potentially facilitated by but not predominantly caused by a lack of immunosurveillance. Based on recent studies of pre-existing conditions in patients with malignancies and on malignancies in large PID cohorts, we conclude that a large part of tumor predisposition in patients with PIDs is derived from the same molecular defect as the immunodeficiency itself. The presented concept elucidates diverse pathomechanisms and risks of malignancies in patients with PIDs in light of current tumor immune therapies. PMID- 28669559 TI - Intramural pilot funding and internal grant reviews increase research capacity at a school of nursing. AB - BACKGROUND: Strategies for increasing research capacity such as internal funding mechanisms and internal peer reviews for grants are essential for schools of nursing. Although these are documented in the literature, their processes and outcomes have not been reported. PURPOSE: The purposes of this study were to describe three protocols for building research capacity at a school of nursing intramural pilot grants, Specific Objectives and Aims Reviews, and mock reviews and quantify their outcomes. METHODS: We assessed outcome data on 14 intramural pilot grants and 88 external grant applications from 2012 to 2016. FINDINGS: Pilot grants produced 16 peer-reviewed articles, 33 presentations, and 11 funded grants. For grant applications that underwent any type of internal review, 41.7% (20/48) received funding compared with 20% (8/40) that did not participate, p = .03. Given the resources required to prepare grant applications, internal funding and reviews can enhance return on investment. CONCLUSION: Schools of nursing should consider implementing intramural pilot grants and internal review sessions. PMID- 28669560 TI - Potential of RASSF1A promoter methylation as biomarker for endometrial cancer: A systematic review and meta-analysis. AB - BACKGROUND: An epigenetic approach to explaining endometrial carcinogenesis necessitates good understanding of Ras association domain family 1 isoform A (RASSF1A) promoter methylation data from primary studies. AIMS: Differential magnitude of reported associations between RASSF1A promoter methylation and endometrial cancer (EC) prompted a meta-analysis to obtain more precise estimates. METHODS: Literature search yielded eight included articles. We calculated pooled odds ratios (OR) and 95% confidence intervals and subgrouped the data by race. Sources of heterogeneity were investigated with outlier analysis. RESULTS: The pooled ORs indicated increased risk, mostly significant. The overall effect (OR 11.46) was reflected in the European outcome (OR 15.07). However, both findings were heterogeneous (I2=57-70%) which when subjected to outlier treatment, erased heterogeneity (I2=0%) and retained significance (OR 9.85-12.66). Significance of these pre- and post-outlier outcomes were pegged at P<=0.0001. Only the Asian pre-outlier (OR 6.85) and heterogeneous (I2=82%) outcome was not significant (P=0.12) but when subjected to outlier treatment, erased heterogeneity (I2=0%) and generated significance (OR 23.74, P<=0.0001). CONCLUSIONS: Consistent increased risk associations underpinned by significance and robustness render RASSF1A with good biomarker potential for EC. PMID- 28669561 TI - Effects of icariin on asthma mouse model are associated with regulation of prostaglandin D2 level. AB - BACKGROUND: We aimed to observe the effect of icariin on an asthma mouse model and explore the potential underlying mechanisms. METHODS: The asthma mouse model was established by ovalbumin (OVA) sensitisation and respiratory syncytial virus (RSV) infection and then treated with icariin. Airway resistance was assessed by whole body plethysmograph. In addition, pathological slides were stained with haematoxylin-eosin, and the peribronchial inflammation was observed microscopically. The concentration of prostaglandin D2 (PGD2) in serum and bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immuno sorbent assay (ELISA). The relative level of prostaglandin D2 receptor 2 (CRTH2) mRNA was assessed by real-time quantitative PCR. RESULTS: Compared with the icariin untreated group, there was a significant reduction of Penh in the treated group. Total leucocyte amount and all sorts of leukocytes were lower in the treated group than in the untreated group. HE staining results revealed that a large number of inflammatory cells infiltrated into the peribronchial tissues of untreated group, and the degree of airway inflammation decreased significantly in the treated group. PGD2 in serum and BALF, as well as CRTH2 mRNA level in lung tissues were lower in the treated group than in the untreated group. CONCLUSION: Icariin is a promising therapeutic strategy for asthma, and PGD2 might be a new target for asthma therapy in OVA-induced and RSV-infected asthma model. PMID- 28669562 TI - Clinical safety and professional liability claims in Ophthalmology. AB - INTRODUCTION: Patient safety is an international public health priority. Ophthalmology scientific societies and organisations have intensified their efforts in this field. As a tool to learn from errors, these efforts have been linked to the management of medical professional liability insurance through the analysis of claims. MATERIAL AND METHODS: A review is performed on the improvements in patient safety, as well as professional liability issues in Ophthalmology. RESULTS: There is a high frequency of claims and risk of economic reparation of damage in the event of a claim in Ophthalmology. Special complaints, such as wrong surgery or lack of information, have a high risk of financial compensation and need strong efforts to prevent these potentially avoidable events. Studies focused on pathologies or specific procedures provide information of special interest to sub-specialists. The specialist in Ophthalmology, like any other doctor, is subject to the current legal provisions and appropriate mandatory training in the medical-legal aspects of health care is essential. CONCLUSIONS: Professionals must be aware of the fundamental aspects of medical professional liability, as well as specific aspects, such as defensive medicine and clinical safety. The understanding of these medical-legal aspects in the routine clinical practice can help to pave the way towards a satisfactory and safe professional career, and help in increasing patient safety. The aim of this review is to contribute to this training, for the benefit of professionals and patients. PMID- 28669563 TI - Proteasomal degradation of T. gondii ROP18 requires Derlin2. AB - T. gondii is an obligate intracellular parasite, belonging to the Phylum Apicomplexa, infecting all warm-blooded animals including humans. During host cell invasion, specialized cytoskeletal and secretory organelles play a pivotal role. ROP18, as a member of the ROP2 family, has been identified as a key virulence factor mediating pathogenesis in T. gondii. Here, we identify an ER resident protein, Derlin2, a factor implicated in the removal of misfolded proteins from the ER for cytosolic degradation, as a component of the machinery required for ER-associated protein degradation (ERAD). We identified Derlin2 interacting with ROP18 by yeast two-hybrid screening system. The interaction between ROP18 and Derlin2 was further confirmed through in vitro GST pull-down and in vivo immunoprecipitation assays. By immunofluorescence assay, we found that ROP18 co-localized with Derlin2 in the endoplasmic reticulum. Using overexpression and knockdown approaches, we demonstrated that Derlin2 was required for T. gondii ROP18 degradation. Consistently, cycloheximide chase experiments showed that the degradation of ROP18 relied on the Derlin2, but not Derlin1. These results indicate that interaction between Derlin2 and ROP18 is functionally relevant and leads ultimately to degradation of ROP18. The finding provides the basis for future studies on Derlin2-dependent ERAD of T. gondii ROP18 and subsequent antigen generation. PMID- 28669564 TI - Eriocalyxin B, a novel autophagy inducer, exerts anti-tumor activity through the suppression of Akt/mTOR/p70S6K signaling pathway in breast cancer. AB - Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid presented in the plant Isodon eriocalyx var. laxiflora, has been reported to diminish angiogenesis dependent breast tumor growth. In the present study, the effects of EriB on human breast cancer and its underlying mechanisms were further investigated. The in vitro anti-breast cancer activity of EriB was determined using MCF-7 and MDA-MB 231 cell lines. MDA-MB-231 xenograft model of human breast cancer was also established to explore the anti-tumor effect in vivo. We found that EriB was able to induce apoptosis accompanied by the activation of autophagy, which was evidenced by the increased accumulation of autophagosomes, acidic vesicular organelles formation, the microtubule-associated protein 1A/1B-light chain 3B-II (LC3B-II) conversion from LC3B-I and p62 degradation. Meanwhile, EriB treatment time-dependently decreased the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), leading to the inhibition of Akt/mTOR/p70S6K signaling pathway. Moreover, the blockage of autophagy obviously sensitized EriB-induced cell death, which suggested the cytoprotective function of autophagy in both MCF-7 and MDA-MB-231 cells. Interestingly, the autophagic features and apoptosis induction were prevented by reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine, indicating that ROS played an essential role in the mediation of EriB-induced cell death. Furthermore, in MDA-MB-231 xenograft model, EriB displayed a significant anti tumor effect via the activation of autophagy and apoptosis in breast tumor cells. Taken together, our findings firstly demonstrated that EriB suppressed breast cancer cells growth both in vitro and in vivo, and thus could be developed as a promising anti-breast tumor agent. PMID- 28669565 TI - Helmet Use Among Personal Bicycle Riders and Bike Share Users in Vancouver, BC. AB - INTRODUCTION: Public bike share users have low prevalence of helmet use, and few public bike share systems make helmets available. In summer 2016, a public bike share system launched in Vancouver, BC. Each bicycle is equipped with a free helmet, in response to BC's all-ages compulsory helmet law. This study assessed the prevalence of helmet use among adult cyclists on personal and public bicycles in Vancouver. METHODS: A survey of adult cyclists (age estimated at >=16 years) at five screen line sites and at 15 public bike share docking stations was conducted. Observations were made on fair weather days in 2016. Observers recorded the gender of the rider, bicycle type, helmet use, and helmet type. In 2016, multivariable logistic regression was used to calculate the odds of helmet use by personal and trip characteristics. RESULTS: Observers conducted 87.5 hours of observation and recorded 11,101 cyclists. They observed 10,704 (96.4%) cyclists on personal bicycles and 397 (3.6%) public bicycle users. Overall, the prevalence of helmet use was 78.1% (n=8,670/11,101), higher for personal bicycle riders (78.6%, n=8,416/10,704) than bike share users (64.0%, n=254/397). Helmet use was associated with gender, bicycle facility type, and day and time of travel. CONCLUSIONS: In a city with all-ages helmet legislation, helmet use is high but differs across infrastructure types and cyclist characteristics. Bike share systems could increase helmet use by providing complementary helmets coupled with supportive measures. PMID- 28669566 TI - Recent Patterns in Genetic Testing for Breast and Ovarian Cancer Risk in the U.S. AB - INTRODUCTION: Mutations in BRCA genes are strongly associated with increased risk of breast and ovarian cancer, and it is recommended that women at high risk for these mutations be referred for genetic counseling and testing. The Affordable Care Act (ACA) provision implemented in 2010 eliminated cost sharing for BRCA genetic testing for privately insured women with family history of BRCA-related cancers. METHODS: Using a nationally representative sample from the National Health Interview Survey, this study examined trends in genetic testing for breast and ovarian cancer risk from 2005 to 2015 among women by family history and insurance status. To assess the impact of the ACA provision, a difference-in differences strategy was used to compare changes in genetic testing after ACA implementation between women with a family history of breast or ovarian cancer and those with a family history of other cancers, stratified by insurance type. Analyses were conducted in 2016. RESULTS: Genetic testing for breast and ovarian cancer risk increased among women with private or public insurance, but not among uninsured women. Among privately insured women, those with family history of breast or ovarian cancer experienced a net increase of 2.9 percentage points (p=0.001) over those with a family history of other cancers, but no significant difference was observed among women with public insurance, suggesting a positive effect of the ACA provision. CONCLUSIONS: This study underscores the continued need to improve access to care for all populations. Future work should monitor the impact of policy on genetic testing among the high-risk population. PMID- 28669568 TI - Modeling the Potential Economic Impact of the Medicare Comprehensive Care for Joint Replacement Episode-Based Payment Model. AB - BACKGROUND: The Medicare program has initiated Comprehensive Care for Joint Replacement (CJR), a bundled payment mandate for lower extremity joint replacements. We sought to determine the degree to which hospitals will invest in care redesign in response to CJR, and to project its economic impacts. METHODS: We defined 4 potential hospital management strategies to address CJR: no action, light care management, heavy care management, and heavy care management with contracting. For each of 798 hospitals included in CJR, we used hospital-specific volume, cost, and quality data to determine the hospital's economically dominant strategy. We aggregated data to assess the percentage of hospitals pursuing each strategy; savings to the health care system; and costs and percentages of CJR derived revenues gained or lost for Medicare, hospitals, and postacute care facilities. RESULTS: In the model, 83.1% of hospitals (range 55.0%-100.0%) were expected to take no action in response to CJR, and 16.1% of hospitals (range 0.0% 45.0%) were expected to pursue heavy care management with contracting. Overall, CJR is projected to reduce health care expenditures by 0.5% (range 0.0%-4.1%) or $14 million (range $0-$119 million). Medicare is expected to save 2.2% (range 2.2%-2.2%), hospitals are projected to lose 3.7% (range 4.7% loss to 3.8% gain), and postacute care facilities are expected to lose 6.5% (range 0.0%-12.8%). Hospital administrative costs are projected to increase by $63 million (range $0 $148 million). CONCLUSION: CJR is projected to have a negligible impact on total health care expenditures for lower extremity joint replacements. Further research will be required to assess the actual care management strategies adopted by CJR hospitals. PMID- 28669569 TI - Letter to the Editor on "Weight Gain After Primary Total Knee Arthroplasty Is Associated With Accelerated Time to Revision for Aseptic Loosening". PMID- 28669567 TI - Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2012: General view of the pathogens' antibacterial susceptibility. AB - The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, Japanese association for infectious diseases and Japanese society for Clinical Microbiology in 2012. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January and December in 2012 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standard Institutes. Susceptibility testing was evaluated in 1236 strains (232 Staphylococcus aureus, 225 Streptococcus pneumoniae, 16 Streptococcus pyogenes, 231 Haemophilus influenzae, 147 Moraxella catarrhalis, 167 Klebsiella pneumoniae and 218 Pseudomonas aeruginosa). Ratio of methicillin resistant S. aureus was 51.3%, and those of penicillin-intermediate S. pneumoniae was 0.4%. Among H. influenzae, 5.6% of them were found to be beta-lactamase producing ampicillin-resistant strains, and 37.2% to be beta-lactamase-non producing ampicillin-resistant strains. Extended spectrum beta-lactamase producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo beta lactamase were 4.2% and 3.2%, respectively. Continuous national surveillance is important to determine the actual situation of the resistance shown by bacterial respiratory pathogens to antimicrobial agents. PMID- 28669570 TI - Letter to the Editor on "Physical Activity Promotes Gait Improvement in Patients With Total Knee Arthroplasty". PMID- 28669571 TI - Has Health Care Reform Legislation Reduced the Economic Burden of Hospital Readmissions Following Primary Total Joint Arthroplasty? AB - BACKGROUND: The purpose of this study was to determine whether the cost of readmissions after primary total hip and knee arthroplasty (THA and TKA) has decreased since the introduction of health care reform legislation and what patient, clinical, and hospital factors drive such costs. METHODS: The 100% Medicare inpatient dataset was used to identify 1,654,602 primary THA and TKA procedures between 2010 and 2014. The per-patient cost of readmissions was evaluated in general linear models in which the year of surgery and patient, clinical, and hospital factors were treated as covariates in separate models for THA and TKA. RESULTS: The year-to-year risk of 90-day readmission was reduced by 2% and 4% (P < .001) for THA and TKA, respectively. By contrast, the cost of readmissions did not change significantly over time. The 5 most important variables associated with the cost of 90-day THA readmissions (in rank order) were the nature of the readmission (ie, due to medical or procedure-related reasons), the length of stay, hospital's teaching status, discharge disposition, and hospital's overall total joint arthroplasty volume. The top 5 factors associated with the cost of 90-day TKA readmissions were (in rank order) the length of stay, hospital's teaching status, discharge disposition, patient's gender, and age. CONCLUSION: Although readmission rates declined slightly, the results of this study do not support the hypothesis that readmission costs have decreased since the introduction of health care reform legislation. Instead, we found that clinical and hospital factors were among the most important cost drivers. PMID- 28669572 TI - Enzymatic saccharification of lignocellulosic residues using cellulolytic enzyme extract produced by Penicillium roqueforti ATCC 10110 cultivated on residue of yellow mombin fruit. AB - The aim of this work was to enzymatic saccharification of food waste was performed by crude enzymatic cellulolytic extract produced by P. roqueforti cultivated in yellow mombin residue. The best yield of reducing sugars (259.45mgg 1) was achieved with sugarcane bagasse after 4h; the hydrolysis of corn cob, rice husk and peanut hull resulted in yields around 128-180mgg-1. The addition of 10mmolL-1 of Mn2+ potentiated the saccharification of sugarcane bagasse, in about 86%. The temperature and substrate (sugarcane bagasse) concentration parameters were optimized using a Doehlert Design and, a maximum sugar yield of 662.34+/ 26.72mgg-1 was achieved at 62.40 degrees C, 0.22% (w/v) of substrate, with the addition of Mn2+. Sugar yield was significantly high when compared to previous studies available in scientific literature, suggesting the use of crude cellulolytic supplemented with Mn2+ an alternative and promising process for saccharification of sugarcane bagasse. PMID- 28669573 TI - [The health of the elderly in Spain during the economic crisis]. AB - INTRODUCTION: Numerous studies have shown that economic crises are linked to a worsening of health conditions of the population. During the current economic crisis in Spain, there have been significant cuts in social and health services and a general worsening of the emotional well-being of the population. All these changes could have an impact on the health of the population, especially in the most vulnerable groups like older people. MATERIAL AND METHODS: The evolution of life expectancy and healthy life years in the period 2004-2014 have been examined in order to examine the health status of people aged 65 years and over in Spain during the economic crisis. RESULTS: Changes are observed in the evolution of healthy life years of people aged 65 years and over, particularly in the case of women. CONCLUSIONS: The results do not show that the current economic crisis has had a negative impact on the health conditions of older people in Spain, but there has been a decline in their well-being and quality of life. PMID- 28669574 TI - Could High Mental Demands at Work Offset the Adverse Association Between Social Isolation and Cognitive Functioning? Results of the Population-Based LIFE-Adult Study. AB - OBJECTIVES: The study investigated whether high mental demands at work, which have shown to promote a good cognitive functioning in old age, could offset the adverse association between social isolation and cognitive functioning. METHODS: Based on data from the population-based LIFE-Adult-Study, the association between cognitive functioning (Verbal Fluency Test, Trail Making Test B) and social isolation (Lubben Social Network Scale) as well as mental demands at work (O*NET database) was analyzed via linear regression analyses adjusted for age, sex, education, and sampling weights. RESULTS: Cognitive functioning was significantly lower in socially isolated individuals and in individuals working in low mental demands jobs-even in old age after retirement and even after taking into account the educational level. An interaction effect suggested stronger effects of mental demands at work in socially isolated than nonisolated individuals. CONCLUSIONS: The findings suggest that working in high mental-demand jobs could offset the adverse association between social isolation and cognitive functioning. Further research should evaluate how interventions that target social isolation and enhance mentally demanding activities promote a good cognitive functioning in old age. PMID- 28669575 TI - Targeted Interdisciplinary Model for Evaluation and Treatment of Neuropsychiatric Symptoms: A Cluster Randomized Controlled Trial. AB - OBJECTIVE: To determine the effectiveness of the Targeted Interdisciplinary Model for Evaluation and Treatment of Neuropsychiatric Symptoms (TIME) for treatment of moderate to severe agitation in people with dementia. METHODS: In a single blinded, cluster randomized controlled trial in 33 nursing homes (clusters) from 20 municipalities in Norway, 229 patients (104 patients in 17 nursing homes and 125 patients in 16 nursing homes) were randomized to an intervention or control group, respectively. The intervention group received TIME, and the control group received a brief education-only intervention. TIME is an interdisciplinary multicomponent intervention and consists of a comprehensive assessment of the patient with the goal to create and put into action a tailored treatment plan. The primary outcome was the between-group difference in change at the agitation/aggression item of the Neuropsychiatric Inventory Nursing Home version between baseline and 8 weeks. Secondary outcomes were the between-group difference in change at the agitation/aggression between baseline and 12 weeks in other neuropsychiatric symptoms, quality of life, and use of psychotropic and analgesic medications between baseline and 8 and 12 weeks. RESULTS: A significant between-group difference in reduction of agitation at both 8 weeks (1.1; 95% confidence interval: 0.1-2.1; p = 0.03) and 12 weeks (1.6; 95% confidence interval: 0.6-2.7; p = 0.002) in favor of the TIME intervention was found. CONCLUSION: The implementation of TIME resulted in a significant reduction of agitation among nursing homes patients with dementia. These results should inform training programs for care staff in Norway and internationally. PMID- 28669577 TI - A Hierarchical Convolutional Neural Network for vesicle fusion event classification. AB - Quantitative analysis of vesicle exocytosis and classification of different modes of vesicle fusion from the fluorescence microscopy are of primary importance for biomedical researches. In this paper, we propose a novel Hierarchical Convolutional Neural Network (HCNN) method to automatically identify vesicle fusion events in time-lapse Total Internal Reflection Fluorescence Microscopy (TIRFM) image sequences. Firstly, a detection and tracking method is developed to extract image patch sequences containing potential fusion events. Then, a Gaussian Mixture Model (GMM) is applied on each image patch of the patch sequence with outliers rejected for robust Gaussian fitting. By utilizing the high-level time-series intensity change features introduced by GMM and the visual appearance features embedded in some key moments of the fusion process, the proposed HCNN architecture is able to classify each candidate patch sequence into three classes: full fusion event, partial fusion event and non-fusion event. Finally, we validate the performance of our method on 9 challenging datasets that have been annotated by cell biologists, and our method achieves better performances when comparing with three previous methods. PMID- 28669576 TI - Histone H2A Monoubiquitination in Neurodevelopmental Disorders. AB - Covalent histone modifications play an essential role in gene regulation and cellular specification required for multicellular organism development. Monoubiquitination of histone H2A (H2AUb1) is a reversible transcriptionally repressive mark. Exchange of histone H2A monoubiquitination and deubiquitination reflects the succession of transcriptional profiles during development required to produce cellular diversity from pluripotent cells. Germ-line pathogenic variants in components of the H2AUb1 regulatory axis are being identified as the genetic basis of congenital neurodevelopmental disorders. Here, we review the human genetics findings coalescing on molecular mechanisms that alter the genome wide distribution of this histone modification required for development. PMID- 28669578 TI - Prognostic evaluation of ALIP and CD34 immunostaining in IPSS-R subgroups of myelodysplastic syndromes. AB - In order to evaluate the prognostic value of abnormal localisation of immature precursors (ALIP) and CD34 immunostaining in myelodysplastic syndromes (MDS), bone marrow histopathological features in 187 MDS patients were retrospectively analysed and the prognostic significance of ALIP and CD34 immunostaining on overall survival (OS) and progression to leukaemia-free survival (PFS) in total patients and different Revised-International Prognostic Scoring System (IPSS-R) subgroups were evaluated. In univariate analysis, age >=60, ALIP, >=5% CD34+ cells, CD34+ clusters and IPSS-R subgroups were associated with shorter OS (p = 0.027, p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001, respectively) and PFS (p = 0.029, p = 0.006, p = 0.001, p < 0.0001, p < 0.0001, respectively). Haemoglobin level had a significant impact on OS (p < 0.0001) but not on PFS (p = 0.054). In multivariate analysis, ALIP, haemoglobin level, >=5% CD34+ cells, CD34+ clusters and IPSS-R subgroups had independent influence on OS (p = 0.012, p < 0.0001, p = 0.010, p < 0.0001, p < 0.0001, respectively), while only CD34+ clusters and IPSS R subgroups had independent influence on PFS (p < 0.0001, p = 0.016, respectively). In different IPSS-R subgroups, ALIP could maintain its prognostic impact in lower IPSS-R risk subgroups, while >=5% CD34+ cells and CD34+ clusters had significant prognostic value in both lower and intermediate-higher IPSS-R risk subgroups. Therefore, CD34+ clusters showed more important prognostic impact on survival and progression to leukaemia. PMID- 28669579 TI - Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy. AB - Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied. PMID- 28669581 TI - Efficacy, tolerability, and safety of non-pharmacological therapies for chronic pain: An umbrella review on various CAM approaches. AB - BACKGROUND: Complementary and alternative medicine (CAM) therapies may be used as a non-pharmacological approach to chronic pain management. While hundreds of trials about individual CAM modality have been conducted, a comprehensive overview of their results is currently lacking for pain clinicians and researchers. AIM: This umbrella review synthesized the quality of meta-analytic evidence supporting the efficacy, tolerability and safety of CAM therapies for the management of chronic pain. MATERIALS & METHODS: MEDLINE, EMBASE, CINAHL, and CENTRAL were searched from October 1991 to November 2016. Reviews of clinical trials (randomized and non-randomized) with meta-analysis investigating the utility of any CAM modality for chronic pain were eligible. Pain relief post intervention was the main outcome and secondary outcomes included patients' adherence and incidence of adverse effects during CAM protocol. RESULTS: Twenty six reviews (207 clinical trials, >12,000 participants) about 18 CAM modalities, falling under natural products, mind and body practices or other complementary health approaches were included. Inhaled cannabis, graded motor imagery, and Compound Kushen injection (a form of Chinese medicine) were found the most efficient (with moderate-to-high effect sizes and low heterogeneity) and tolerable (>=80% of adherence to study protocols) for chronic pain relief. When reported, adverse effects related to these CAM were minor. CONCLUSION: Although several CAM were found effective for chronic pain relief, it remains unclear when these modalities are a reasonable choice against or in conjunction with mainstream treatments. In that sense, future research with a clear emphasis on concurrent evaluation of CAM overall efficacy and patient adherence/tolerance is needed. PMID- 28669580 TI - The interplay between inflammation, oxidative stress, DNA damage, DNA repair and mitochondrial dysfunction in depression. AB - A growing body of evidence suggests that inflammation, mitochondrial dysfunction and oxidant-antioxidant imbalance may play a significant role in the development and progression of depression. Elevated levels of reactive oxygen and nitrogen species - a result of oxidant-antioxidant imbalance - may lead to increased damage of biomolecules, including DNA. This was confirmed in depressed patients in a research study conducted by our team and other scientists. 8-oxoguanine - a marker of oxidative DNA damage - was found in the patients' lymphocytes, urine and serum. These results were confirmed using a comet assay on lymphocytes. Furthermore, it was shown that the patients' cells repaired peroxide-induced DNA damage less efficiently than controls' cells and that some single nucleotide polymorphisms (SNP) of the genes involved in oxidative DNA damage repair may modulate the risk of depression. Lastly, less efficient DNA damage repair observed in the patients can be, at least partly, attributed to the presence of specific SNP variants, as it was revealed through a genotype-phenotype analysis. In conclusion, the available literature shows that both oxidative stress and less efficient DNA damage repair may lead to increased DNA damage in depressed patients. A similar mechanism may result in mitochondrial dysfunction, which is observed in depression. PMID- 28669582 TI - Substance-related disorders: A review of prevalence and correlates among patients with chronic pain. AB - Over the past few decades, research has revealed high rates of substance-related disorders among patients with chronic pain. In addition to their potentially deleterious health consequences, substance-related disorders have consistently been associated with negative pain-related outcomes among patients with chronic pain. The goal of this narrative review was to provide an overview of studies that have examined the prevalence and correlates of substance-related disorders among patients with chronic pain. A particular focus was placed on opioids, sedatives/hypnotics, cannabis, tobacco, and alcohol given that these substances have received the bulk of research attention among patients with pain. Research conducted to date suggests that a host of biological and psychological factors are likely to contribute to the elevated rates of substance-related disorders among patients with chronic pain. In this review, in addition to reviewing the prevalence and correlates of substance-related disorders among patients with pain, we briefly discussed the changes that were recently made from the DSM-4 to the DSM-5 in the diagnostic criteria for substance-related disorders, and the implications of these changes for the assessment of patients with chronic pain. We also provided a brief overview of instruments that can be used for the assessment of these disorders in clinical and research settings. PMID- 28669583 TI - Screening and identification of steroidal saponins from Anemarrhena asphodeloides employing UPLC tandem triple quadrupole linear ion trap mass spectrometry. AB - This study presents a practical and valid strategy for the screening and structural characterization of Anemarrhena asphodeloides Bge steroidal saponins (SSs) using ultra-high performance liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry. The whole analytical protocols integrate four-step procedures in the positive mode: (1) rational deduction of mass fragmentation pathways of A. asphodeloides SSs; (2) untargeted screening of potential A. asphodeloides SSs by multiple-ion monitoring-information-dependent acquiring-enhanced product ion (MIM-IDA-EPI) scan through reverse phase liquid chromatography; (3) comprehensive construction of an ammoniated precursor ion database by combining untargeted MIM-IDA-EPI scans and data literature; and (4) structural interpretation of targeted A. asphodeloides SSs using MIM-IDA-EPI and multiple reaction monitoring (MRM)-IDA-EPI with an energy-resolved technique. The protocols were used to analyze SSs in A. asphodeloides; of the 87 detected SSs that were unambiguously characterized or tentatively identified, 19 compounds were the first to be reported from A. asphodeloides and 13 ones were characterized as potential new compounds. Accuracy of the analytical procedure was demonstrated by structural identification of three SSs by NMR spectroscopy. The proposed schemes hold an excellent promise in the structural prediction and interpretation of complex SSs from plant medicines by mass spectrometry. PMID- 28669584 TI - Re "Fertility in disorders of sex development: A review". PMID- 28669585 TI - Commentary to "Attitudes towards 'disorders of sex development' nomenclature among affected". PMID- 28669586 TI - Long-term outcomes of cutaneous vesicostomy in patients with neuropathic bladder caused by spina bifida. AB - OBJECTIVE: To evaluate the outcomes of patients who underwent cutaneous vesicostomy for management of neuropathic bladder secondary to spina bifida. We hypothesize that vesicostomy, in select patients, is beneficial to prevent upper urinary tract deterioration (UTD), reduce febrile urinary tract infections (UTIs), and preserve renal function. STUDY DESIGN: We performed a retrospective chart review on patients with spina bifida who underwent cutaneous vesicostomy at our institution between 2000 and 2016. Demographic information, indication for vesicostomy, pre and postoperative laboratory/radiologic studies, incidence of febrile UTIs, and urodynamic findings were abstracted. RESULTS: A total of 14 patients (eight females and six males) were identified. The indication for vesicostomy was UTD in four, recurrent febrile UTIs in five, parental request in two, both UTD and recurrent febrile UTIs in two, and both UTI and parental request in one patient. Seven patients had a median of three (range one to five) febrile UTI prior to surgery for cutaneous vesicostomy. Median creatinine level before surgery was 0.26 mg/dL (range 0.16-0.97). Either unilateral or bilateral >=SFU Grade 2 hydronephrosis was present in six patients. Median age at vesicostomy creation was 26.5 months (range 4-96). Mean functional bladder capacity assessed during preoperative urodynamic studies was 107 mL (range 20 279), and detrusor sphincter dysynergia was present in all patients. High-grade vesicoureteral reflux (grade >=3) was present in three patients, all with UTD. Mean follow-up after vesicostomy was 62.4 +/- 39.3 months. After vesicostomy, only two of the seven patients with history of febrile UTIs experienced an additional febrile UTI. The median serum creatinine level was 0.36 mg/dL (range 0.2-0.58) at last follow-up. Moreover, 11/14 patients had no hydronephrosis and just two patients had unilateral SFU grade 1 hydronephrosis (Table). DISCUSSION: Worsening UTD, recurrent febrile UTIs, and high-pressure bladder despite maximal medical therapy are several reasons to consider more aggressive management of neuropathic bladders. In young patients, vesicostomy is able to protect the upper urinary tract, decrease rates of febrile UTI, and delay the need for bladder augmentation. CONCLUSION: Vesicostomy is a safe method for temporary diversion of the lower urinary tract in patients with spina bifida who are refractory to conservative and minimally invasive treatments. PMID- 28669587 TI - Therapeutic management of Crimean-Congo haemorrhagic fever. AB - Crimean-Congo haemorrhagic fever has been reported in more than 30 countries in Africa, Asia, the Middle East and Eastern Europe, with an increasing incidence in recent years, especially in Europe. Because no specific treatments have demonstrated efficacy, supportive treatment is essential, as well as the provision of a centre with the appropriate means to guarantee the safety of its healthcare professionals. Laboratory monitoring of thrombocytopenia, severe coagulopathy or liver failure is of critical importance. Patients with Crimean Congo haemorrhagic fever should be admitted to High Level Isolation Units where appropriate biocontainment procedures can prevent nosocomial transmission through infected fluids or accidents with contaminated material. In case of high-risk exposures, early administration of ribavirin should be considered. PMID- 28669588 TI - GH62 arabinofuranosidases: Structure, function and applications. AB - Motivated by industrial demands and ongoing scientific discoveries continuous efforts are made to identify and create improved biocatalysts dedicated to plant biomass conversion. alpha-1,2 and alpha-1,3 arabinofuranosyl specific alpha-l arabinofuranosidases (EC 3.2.1.55) are debranching enzymes catalyzing hydrolytic release of alpha-l-arabinofuranosyl residues, which decorate xylan or arabinan backbones in lignocellulosic and pectin constituents of plant cell walls. The CAZy database classifies alpha-l-arabinofuranosidases in Glycoside Hydrolase (GH) families GH2, GH3, GH43, GH51, GH54 and GH62. Only GH62 contains exclusively alpha-l-arabinofuranosidases and these are of fungal and bacterial origin. Twenty two GH62 enzymes out of 223 entries in the CAZy database have been characterized and very recently new knowledge was acquired with regard to crystal structures, substrate specificities, and phylogenetics, which overall provides novel insights into structure/function relationships of GH62. Overall GH62 alpha-l arabinofuranosidases are believed to play important roles in nature by acting in synergy with several cell wall degrading enzymes and members of GH62 represent promising candidates for biotechnological improvements of biofuel production and in various biorefinery applications. PMID- 28669589 TI - A longitudinal study of cognitive insight and cortical thickness in first-episode psychosis. AB - Among individuals with psychosis, those with poor cognitive insight (lower Self Reflectiveness, higher Self-Certainty) show volumetric reductions in cortical structure. We evaluated whether changes in cognitive insight are associated with progressive changes in cortical structure in first-episode psychosis (FEP) and control subjects. Beck Cognitive Insight Scale ratings and magnetic resonance imaging scans were acquired at baseline for 130 FEP and 52 controls, 59 FEP and 28 controls at 1-year, and 53 FEP and 20 controls at 2-years. Cortical thickness was computed across scans and analyzed with linear mixed models. At baseline, groups did not differ on Self-Reflectiveness or Self-Certainty. At baseline, higher Self-Reflectiveness significantly correlated with thinner right occipital cortex in FEP, and higher Self-Certainty was significantly negatively correlated with cortical thickness in left posterior cingulate in controls. Longitudinal analysis showed that Self-Reflectiveness and Self-Certainty did not change over time in either group. Interestingly, the lack of change in cognitive insight aligned with longitudinal cortical thickness results, where no interaction effects were seen with cortical thickness between time and either Self Reflectiveness or Self-Certainty. Exploratory analyses with a reduced threshold found that in FEP, across all time-points, higher Self-Certainty associated with thinner cortex in left posterior cingulate/precuneus. Results suggest that the posterior cingulate may be a common neural correlate for Self-Certainty in FEP and non-clinical subjects. PMID- 28669590 TI - Tranexamic acid inhibits melanogenesis by activating the autophagy system in cultured melanoma cells. AB - BACKGROUND: As interest in skin beauty increases, the development of new skin whitening agents has attracted substantial attention; however, the action mechanism of the agents developed so far remains largely unknown. Tranexamic acid (TXA) is commonly being used to reduce melanin synthesis in patients with melasma and also used as a raw material for functional whitening cosmetics, although its action mechanism is poorly understood. Autophagy has been well known to be essential for tissue homeostasis, adaptation to starvation, and removal of dysfunctional organelles or pathogens. Recent studies have shown that autophagy regulators might have prominent roles in the initial formation stage of the melanosome, a lysosome-related organelle synthesizing melanin pigments. However, there is still no direct evidence showing a relationship between the activation of the autophagy system and the melanogenesis. OBJECTIVE: To investigate whether TXA can inhibit melanogenesis through the activation of autophagy in a melanoma cell line. METHODS: B16-F1 melanoma cells were treated with TXA and the levels of autophagy- and melanogenesis-related proteins were determined by Western blottings. The direct effect of TXA-mediated autophagy activation on melanin production was further evaluated by transfecting the cells with 60 pmols of small interfering RNAs (siRNAs)-targeting the mechanistic target of rapamycin (mTOR) and the autophagy-related protein 5 (Atg5). RESULTS: The results of Western blottings showed that TXA enhanced the production of autophagy-related proteins such as mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK)1/2, Beclin-1, Atg12, and light chain 3 (LC3) I-II, whereas it decreased the synthesis of the mTOR complex. Confocal microscopy clearly showed that TXA treatment resulted in the formation of autophagosomes in B16-F1 cells, as revealed by immunostaining with an anti-LC3 antibody. The production of melanogenesis-associated proteins, including microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein 1 and 2 (TRP1/2), were clearly downregulated by the treatments with TXA. These results suggest that TXA can mediate a decrease in melanin synthesis by alleviating the production of tyrosinase and TRP1/2, along with lowered MITF protein levels. Furthermore, after treatment with TXA, siRNAs- targeting to mTOR and Atg5 increased melanin synthesis by 20% and 40%, respectively, compared to that in non transfected cells, in a dose-dependent manner. These results further confirmed that TXA can inhibit melanogenesis by activating the autophagy system. CONCLUSION: Collectively, the results demonstrate that TXA can reduce melanin synthesis in melanoma B16-F1 cells by activating the ERK signaling pathway and the autophagy system. PMID- 28669591 TI - Primary biliary cholangitis: Old and novel therapy. AB - Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic liver disease that progresses slowly to end-stage liver disease. The first Food and Drug Administration (FDA)-approved treatment for PBC was ursodeoxycholic acid (UDCA). This treatment slows the progress of the disease, but approximatively 30-40% of patients fail to respond to UDCA. A number of options are under investigation as second line treatment. Obeticholic acid (OCA), a Farnesoid X Receptor agonist, has been approved in May 2017 by FDA for patients non responders or intolerant to UDCA. The results of a randomized, double blind, phase 3 study of OCA (mg or 10mg) compared to placebo, showed that approximatively 50% of patients reached a significant reduction in serum alkaline phosphatase, a marker predictive of disease progression, liver transplantation or death. Other emerging therapies include: agents targeting fibrosis, inflammation, or immunological response. Indeed, after 30years of UDCA therapy as unique choice for PBC patients, a number of targets, derived from a deeper knowledge of the pathophysiology of the disease, has been discovered and they offer different and new therapeutic approaches that are now under evaluation. PMID- 28669592 TI - Personalized microbiome dynamics - Cytometric fingerprints for routine diagnostics. AB - Microbiomes convoy human life in countless ways. They are an essential part of the human body and interact with its host in countless ways. Currently, extensive microbiome analyses assessing the microbiomes' composition and functions based on sequencing information are still far away from being routine analyses due to the complexity of applied techniques and data analysis, their time demand as well as high costs. With the growing demand for on-time community assessment and monitoring of its dynamic behavior with high resolution, alternative high throughput methods such as microbial community flow cytometry come into focus. Our flow cytometric approach provides single-cell based high-dimensional data by using only three parameters but for every cell in a system which is enough to characterize whole communities' attributes with high acuity over time. To interpret such complex cytometric time-series data, novel concepts are required. We provide a workflow which is applicable for easy-to-use handling and measurement of microbiomes. Drawing inspiration from macro-ecology, in which a rich set of concepts has been developed for describing population dynamics, we interpret huge sets of community single cell data in an intuitive and actionable way using a series of bioinformatics tools which we either developed or adapted from sequence based evaluation approaches for the interpretation of single cell data. The developed evaluation pipeline tests for e.g. ecological measures such as community assembly, functioning, and evolution. We also addressed the meta community-concept which is a well acknowledged idea in macro-ecology on how interconnected communities perform. The last concept discusses stability which is a metrics of paramount importance. A fast quantification of stability properties may not only detect disturbances and their impact on the organisms but also allow for on-time microbiome treatment. The workflow's immanent ability to support high temporal sample densities below bacterial generation times provides new insight into the ecology of microbiomes and may also provide access to community control for microbiome based health management. The future developments will facilitate cytometric fingerprinting for human routine diagnostics to be as simple and meaningful as a blood count today. PMID- 28669594 TI - Potential to induce dentinal cracks during retreatment procedures of teeth treated with "Russian red": An ex vivo study. AB - OBJECTIVE: The aim of this study was to compare the impact of treatment procedures on roots previously treated with resorcinol-formaldehyde resin and analyze the effectiveness of dye and magnification for the detection of dentin cracks. MATERIALS AND METHODS: Distal roots of 80 permanent first mandibular molars with a single canal were sectioned at 3mm and 9mm from the anatomical apex. Two groups were formed according to the method used for root canal penetration: group 1 (K-file and Pro Taper instruments) and group 2 (Ultrasound with Pro Ultra and Pro Taper files). Before and after the completion of procedures, photographs of the roots were taken for examination for cracks or/and infraction lines with two levels of magnification and with or without a dye. RESULTS: In groups 1 and 2, either with dye or without it, there were statistically significant differences (P<0.001) with more fractures observed in the coronal than in the apical part of specimens. Statistically significant proportional differences regarding the location of fractures were observed at both magnifications. When the dye was used, there were no statistically significant differences between the two magnifications in the detection of cracks. In the specimens where the dye was not used, differences between the groups were statistically significant at both magnifications with more complete and intra-dental fractures observed in group 2. CONCLUSIONS: Retreatment methods had a damaging effect on the root dentin of teeth previously treated with resorcinol-formaldehyde resin. At magnification *16, the efficacy of using the dye for the detection of cracks was higher than detection without the dye. PMID- 28669593 TI - Pathogen-mimicking vaccine delivery system designed with a bioactive polymer (inulin acetate) for robust humoral and cellular immune responses. AB - New and improved vaccines are needed against challenging diseases such as malaria, tuberculosis, Ebola, influenza, AIDS, and cancer. The majority of existing vaccine adjuvants lack the ability to significantly stimulate the cellular immune response, which is required to prevent the aforementioned diseases. This study designed a novel particulate based pathogen-mimicking vaccine delivery system (PMVDS) to target antigen-presenting-cells (APCs) such as dendritic cells. The uniqueness of PMVDS is that the polymer used to prepare the delivery system, Inulin Acetate (InAc), activates the innate immune system. InAc was synthesized from the plant polysaccharide, inulin. PMVDS provided improved and persistent antigen delivery to APCs as an efficient vaccine delivery system, and simultaneously, activated Toll-Like Receptor-4 (TLR-4) on APCs to release chemokine's/cytokines as an immune-adjuvant. Through this dual mechanism, PMVDS robustly stimulated both the humoral (>32 times of IgG1 levels vs alum) and the cell-mediated immune responses against the encapsulated antigen (ovalbumin) in mice. More importantly, PMVDS stimulated both cytotoxic T cells and natural killer cells of cell-mediated immunity to provide tumor (B16-ova-Melanoma) protection in around 40% of vaccinated mice and significantly delayed tumor progression in rest of the mice. PMVDS is a unique bio-active vaccine delivery technology with broader applications for vaccines against cancer and several intracellular pathogens, where both humoral and cellular immune responses are desired. PMID- 28669595 TI - The effect of educational program based on the precede-proceed model on improving self-care behaviors in a semi-urban population with type 2 diabetes referred to health centers of Bavi, Iran. AB - AIMS: Self-care in patients with diabetes reduces the number of hospital admissions, costs and improves their quality of life so that just by training self-care to them can reduce 80 percent of diabetic complications. Therefore, this study aimed to investigate the effect of educational program based on precede-proceed model on improving self-care behaviors in patients with type 2 diabetes referred to health centers in city Bavi in 2016-2017. MATERIALS AND METHODS: This quasi-experimental study, conducted on 110 patient women with type 2 diabetes referred to health centers in Bavi city in 2016-2017. The training program was designed based on Precede-Proceed Model. Data collection tools included the Precede researcher-made questionnaire and the Glasgow questionnaire. The duration of the training course was three months. After one month, the effect of this program, and the amount of improvement of the patients' self-care behavior were evaluated. Independent t-test, paired t-test, Chi-square and Fisher's exact tests were carried was used for data analysis. RESULTS: After the intervention, the average score of predisposing factors (knowledge, attitude and self-efficacy), reinforcing factors, enabling factors and self-care behaviors, in the intervention group compared to the control group, significantly increased (P<0.05). After the training, the fasting blood sugar (FBS) and body mass index (BMI) decreased in the experimental group, but this reduction was not statistically significant (P>0.05). CONCLUSION: The findings of this research showed that Precede-Proceed Model would be an appropriate framework to educate patients with type 2 diabetes as well as promote self-care behaviors. PMID- 28669596 TI - Role of microglia in mechanical allodynia in the anterior cingulate cortex. AB - Plastic changes that increase nociceptive transmission are observed in several brain regions under conditions of chronic pain. Synaptic plasticity in the anterior cingulate cortex (ACC) is particularly associated with neuropathic pain. Glial cells are considered candidates for the modulation of neural plastic changes in the central nervous system. In this study, we aimed to investigate the role of ACC glial cells in the development of neuropathic pain. First, we examined the expression of glial cells in the ACC of nerve-ligated mice. The expression of astrocytes and microglia was increased in the ACC of nerve-ligated mice, which was reversed by intracerebroventricular (i.c.v) treatment with the microglia inhibitor minocycline. Then, we examined the effect of minocycline on mechanical allodynia in nerve-ligated mice. I.c.v. and intra-ACC treatment with minocycline partially inhibited mechanical allodynia in the nerve-ligated mice. The expression of phosphorylated alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor GluR1 subunit at Ser831, but not at Ser845, was increased in the ACC of the nerve-ligated mice compared to sham operated mice, which was attenuated by minocycline administration. These results suggest that the activation of microglia in the ACC is involved in the development of hyperalgesia in mice with neuropathic pain. PMID- 28669597 TI - Local intra-articular injection of resveratrol delays cartilage degeneration in C57BL/6 mice by inducing autophagy via AMPK/mTOR pathway. AB - Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA) cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM) in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51 like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1alpha, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2alpha, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1alpha and HIF-2alpha expressions and thereby regulating AMPK/mTOR signaling pathway. PMID- 28669598 TI - How Satisfied Are Patients with Arthroscopic Bankart Repair? A 2-Year Follow-up on Quality-of-Life Outcome. AB - PURPOSE: To report general life and health satisfaction after arthroscopic Bankart repair in patients with post-traumatic recurrent anterior glenohumeral instability and to investigate postoperative time lost to return to work at 2 year follow-up. METHODS: Between 2011 and 2013 patients treated with arthroscopic Bankart repair in the beach chair position for acute shoulder instability were included in this study. Questions on Life Satisfaction Modules (FLZM) and the Short Form 12 (SF-12) were used as quality-of-life outcome scales. Oxford Instability Score (OIS), Quick Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH), and self-reported American Shoulder and Elbow Surgeons (ASES) shoulder index were used as functional outcome scales. Return to work (months) was monitored and analyzed depending on physical workload. Data were assessed the day before surgery and prospectively monitored until 24 months postoperatively. Quality-of-life outcome was correlated with functional shoulder outcome and compared with normative age-adjusted data. Paired t-test, Wilcoxon test, Mann-Whitney U-Test, and Spearman's correlation coefficient were used for statistical analysis. RESULTS: Fifty-three patients were prospectively included. The mean age at surgery was 29.4 years. Satisfaction with general life and satisfaction with health (FLZM) as well as physical component scale (SF-12) improved significantly to values above normative data within 6 to 12 months after surgery (each P < .001). OIS, QuickDASH, and ASES improved significantly from baseline until 24 months after surgery (each P < .001). For ASES, improvement above minimal clinically important difference was shown. There was a positive correlation between quality of life and functional outcome scores (P < .05; rho, 0.3-0.4). Mean time to return to work was 2 months (range, 0-10; standard deviation, 1.9), with significantly longer time intervals observed in patients with heavy physical workload (3.1 months; range, 0 to 10; standard deviation, 2.4; P = .002). CONCLUSIONS: Following arthroscopic Bankart repair, quality of life was impaired during early course after surgery and increased significantly above preoperative levels within 6 to 12 months after the procedure. A steady state of excellent quality-of-life and functional outcomes was noted after 12 months of follow-up. Quality-of-life outcome scales correlated significantly with the functional outcome. Heavy physical workload must be considered as a risk factor for prolonged time lost to return to work. LEVEL OF EVIDENCE: Level III, prospective noncomparative therapeutic case series. PMID- 28669599 TI - Inactivation of STAT3 Signaling Impairs Hair Cell Differentiation in the Developing Mouse Cochlea. AB - Although STAT3 signaling is demonstrated to regulate sensory cell differentiation and regeneration in the zebrafish, its exact role is still unclear in mammalian cochleae. Here, we report that STAT3 and its activated form are specifically expressed in hair cells during mouse cochlear development. Importantly, conditional cochlear deletion of Stat3 leads to an inhibition on hair cell differentiation in mice in vivo and in vitro. By cell fate analysis, inactivation of STAT3 signaling shifts the cell division modes from asymmetric to symmetric divisions from supporting cells. Moreover, inhibition of Notch signaling stimulates STAT3 phosphorylation, and inactivation of STAT3 signaling attenuates production of supernumerary hair cells induced by a Notch pathway inhibitor. Our findings highlight an important role of the STAT3 signaling during mouse cochlear hair cell differentiation and may have clinical implications for the recovery of hair cell loss-induced hearing impairment. PMID- 28669600 TI - BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus. AB - BACE1 is validated as Alzheimer's beta-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ). Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development. We show that such neuroblasts are destined to form Prox1-positive granule cells in the dentate granule cell layer, and mainly mature to form excitatory neurons, but not inhibitory neurons. Mechanistically, higher levels of reelin potentially contribute to abnormal neurogenesis and timely migration in BACE1-null SPZ. Altogether, we demonstrate that BACE1 is a critical regulator in forming the dentate granule cell layer through timely maturation and migration of SPZ neuroblasts. PMID- 28669601 TI - Electrical Guidance of Human Stem Cells in the Rat Brain. AB - Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies. PMID- 28669602 TI - The Bile Acid Nuclear Receptor FXRalpha Is a Critical Regulator of Mouse Germ Cell Fate. AB - Spermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRalpha) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied. Here, using a phenotyping approach in Fxralpha-/- mice, we describe unexpected roles of FXRalpha on germ cell physiology independent of its effects on somatic cells. FXRalpha helps establish and maintain an undifferentiated germ cell pool and in turn influences male fertility. FXRalpha regulates the expression of several pluripotency factors. Among these, in vitro approaches show that FXRalpha controls the expression of the pluripotency marker Lin28 in the germ cells. PMID- 28669603 TI - NODAL Secures Pluripotency upon Embryonic Stem Cell Progression from the Ground State. AB - Naive mouse embryonic stem cells (ESCs) can develop multiple fates, but the cellular and molecular processes that enable lineage competence are poorly characterized. Here, we investigated progression from the ESC ground state in defined culture. We utilized downregulation of Rex1::GFPd2 to track the loss of ESC identity. We found that cells that have newly downregulated this reporter have acquired capacity for germline induction. They can also be efficiently specified for different somatic lineages, responding more rapidly than naive cells to inductive cues. Inhibition of autocrine NODAL signaling did not alter kinetics of exit from the ESC state but compromised both germline and somatic lineage specification. Transient inhibition prior to loss of ESC identity was sufficient for this effect. Genetic ablation of Nodal reduced viability during early differentiation, consistent with defective lineage specification. These results suggest that NODAL promotes acquisition of multi-lineage competence in cells departing naive pluripotency. PMID- 28669605 TI - Industrial medicinal chemistry insights: neuroscience hit generation at Janssen. AB - The role of medicinal chemistry has changed over the past 10 years. Chemistry had become one step in a process; funneling the output of high-throughput screening (HTS) on to the next stage. The goal to identify the ideal clinical compound remains, but the means to achieve this have changed. Modern medicinal chemistry is responsible for integrating innovation throughout early drug discovery, including new screening paradigms, computational approaches, novel synthetic chemistry, gene-family screening, investigating routes of delivery, and so on. In this Foundation Review, we show how a successful medicinal chemistry team has a broad impact and requires multidisciplinary expertise in these areas. PMID- 28669604 TI - Redox Homeostasis Plays Important Roles in the Maintenance of the Drosophila Testis Germline Stem Cells. AB - Oxidative stress influences stem cell behavior by promoting the differentiation, proliferation, or apoptosis of stem cells. Thus, characterizing the effects of reactive oxygen species (ROS) on stem cell behavior provides insights into the significance of redox homeostasis in stem cell-associated diseases and efficient stem cell expansion for cellular therapies. We utilized the Drosophila testis as an in vivo model to examine the effects of ROS on germline stem cell (GSC) maintenance. High levels of ROS induced by alteration in Keap1/Nrf2 activity decreased GSC number by promoting precocious GSC differentiation. Notably, high ROS enhanced the transcription of the EGFR ligand spitz and the expression of phospho-Erk1/2, suggesting that high ROS-mediated GSC differentiation is through EGFR signaling. By contrast, testes with low ROS caused by Keap1 inhibition or antioxidant treatment showed an overgrowth of GSC-like cells. These findings suggest that redox homeostasis regulated by Keap1/Nrf2 signaling plays important roles in GSC maintenance. PMID- 28669606 TI - Dose-response Effects of Aerobic Exercise Among Colon Cancer Survivors: A Randomized Phase II Trial. AB - BACKGROUND: Observational studies suggest that higher volumes of physical activity are associated with a lower risk of disease recurrence among survivors of colon cancer. However, the feasibility and safety of prescribing higher volumes of physical activity to survivors of colon cancer are unknown. Furthermore, the pathways through which exercise may reduce disease recurrence are unknown. PATIENTS AND METHODS: Survivors of stage I to III colon cancer were randomized to usual-care control, 150 minutes per week of aerobic exercise (low dose), or 300 minutes per week of aerobic exercise (high-dose). Changes in soluble intercellular adhesion molecule-1 and vascular adhesion molecule-1 prognostic biomarkers were examined. RESULTS: From January 2015 to February 2016, 39 patients were enrolled (n = 13 usual-care control; n = 14 low-dose; n = 12 high-dose), and 38 participants completed the study (97% follow-up). Over 6 months, the low-dose group completed 142 minutes per week (92.8% adherence), and the high-dose group completed 247 minutes per week (89.0% adherence) of exercise. Compared with the control group, changes in soluble intercellular adhesion molecule-1 were -134.9 ng/mL (95% confidence interval, -238.1 to -31.6 ng/mL) in the low-dose group and -114.8 ng/mL (95% confidence interval, -222.5 to -7.1 ng/mL) in the high-dose group (linear Ptrend = .023; nonlinear Ptrend = .044). No changes were observed for soluable vascular adhesion molecule-1 (linear Ptrend = .791; nonlinear Ptrend = .604). Non-serious adverse events occurred at similar rates among randomized groups. No serious adverse events occurred. CONCLUSION: Higher volumes of moderate-intensity aerobic exercise, up to 300 minutes per week, are feasible, safe, and elicit favorable changes in prognostic biomarkers among patients recently treated for stage I to III colon cancer. These data can be used to guide clinical recommendations for patients, and inform future trials. PMID- 28669608 TI - Evaluation of Neonatal Lung Volume Growth by Pulmonary Magnetic Resonance Imaging in Patients with Congenital Diaphragmatic Hernia. AB - OBJECTIVE: To evaluate postnatal lung volume in infants with congenital diaphragmatic hernia (CDH) and determine if a compensatory increase in lung volume occurs during the postnatal period. STUDY DESIGN: Using a novel pulmonary magnetic resonance imaging method for imaging neonatal lungs, the postnatal lung volumes in infants with CDH were determined and compared with prenatal lung volumes obtained via late gestation magnetic resonance imaging. RESULTS: Infants with left-sided CDH (2 mild, 9 moderate, and 1 severe) were evaluated. The total lung volume increased in all infants, with the contralateral lung increasing faster than the ipsilateral lung (mean +/- SD: 4.9 +/- 3.0 mL/week vs 3.4 +/- 2.1 mL/week, P = .005). In contrast to prenatal studies, the volume of lungs of infants with more severe CDH grew faster than the lungs of infants with more mild CDH (Spearman's rho=-0.086, P = .01). Although the contralateral lung volume grew faster in both mild and moderate groups, the majority of total lung volume growth in moderate CDH came from increased volume of the ipsilateral lung (42% of total lung volume increase in the moderate group vs 32% of total lung volume increase in the mild group, P = .09). Analysis of multiple clinical variables suggests that increased weight gain was associated with increased compensatory ipsilateral lung volume growth (rho = 0.57, P = .05). CONCLUSIONS: These results suggest a potential for postnatal catch-up growth in infants with pulmonary hypoplasia and suggest that weight gain may increase the volume growth of the more severely affected lung. PMID- 28669609 TI - The Relationship between High Flow Nasal Cannula Flow Rate and Effort of Breathing in Children. AB - OBJECTIVE: To use an objective metric of effort of breathing to determine optimal high flow nasal cannula (HFNC) flow rates in children <3 years of age. STUDY DESIGN: Single-center prospective trial in a 24-bed pediatric intensive care unit of children <3 years of age on HFNC. We measured the percent change in pressure?rate product (PRP) (an objective measure of effort of breathing) as a function of weight-indexed flow rates of 0.5, 1.0, 1.5, and 2.0 L/kg/minute. For a subgroup of patients, 2 different HFNC delivery systems (Fisher & Paykel [Auckland, New Zealand] and Vapotherm [Exeter, New Hampshire]) were compared. RESULTS: Twenty-one patients (49 titration episodes) were studied. The most common diagnoses were bronchiolitis and pneumonia. Overall, there was a significant difference in the percent change in PRP from baseline (of 0.5 L/kg/minute) with increasing flow rates for the entire cohort (P < .001) with largest change at 2.0 L/kg/min (-21%). Subgroup analyses showed no significant difference in percent change in PRP from baseline when comparing the 2 different HFNC delivery systems (P = .12). Patients <=8 kg experienced a larger percent change in PRP as HFNC flow rates were increased (P = .001) than patients >8 kg. CONCLUSIONS: The optimal HFNC flow rate to reduce effort of breathing in infants and young children is approximately 1.5-2.0 L/kg/minute with more benefit seen in children <=8 kg. PMID- 28669607 TI - The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction? PMID- 28669610 TI - Scrofula. PMID- 28669611 TI - Prevalence of Hypoalbuminemia and Elevated Bilirubin/Albumin Ratios in a Large Cohort of Infants in the Neonatal Intensive Care Unit. AB - OBJECTIVE: To provide descriptive data on serum albumin levels and the bilirubin to albumin (B/A) ratio in neonates admitted to the neonatal intensive care unit, assess the effect of gestational and chronological age on serum albumin and the B/A ratio, and evaluate the association between extreme values and mortality. STUDY DESIGN: Using a retrospective cohort design, we queried the Pediatrix clinical data warehouse for all infants born between 23 and 41 weeks of gestation from 1997 to 2014 who had a report of both a serum albumin and total serum bilirubin (TSB) level on the same day between birth and 14 days of life. RESULTS: There were 382 190 paired albumin and bilirubin levels across 164 401 neonates (15% of the 1 072 682 infants in the clinical data warehouse). Both gestational age and postnatal age were independent factors that influenced the values for serum albumin, TSB, and B/A ratio (ANOVA; P < .0001). TSB and B/A ratios values above birth weight-specific thresholds for exchange transfusions were uncommon (<6% of infants). Hypoalbuminemia (<2.5 mg/dL) was common (29% of infants). Neonates with serum albumin levels <2.5 g/dL or with B/A ratio levels exceeding exchange thresholds were at higher risk of death compared with infants who did not exceed these levels. This association was independent of other risk factors (estimated gestational age, birth weight, sex, and the presence of a major anomaly). CONCLUSION: Both gestational age and postnatal age influence TSB, albumin, and B/A ratios; hypoalbuminemia and extreme B/A ratios are associated with an increased risk of death. PMID- 28669612 TI - Detecting Pharmaceuticals in the Red Blood Cell Inventory of a Hospital Blood Bank. AB - We tested 220 red blood cell units for the presence of pharmaceuticals; 15 units (6.8%) were confirmed to contain low concentrations of opiates, benzodiazepines, stimulants, or barbiturates. Further study is needed to determine whether these drugs, which are not prohibited in donated blood by current Food and Drug Administration standards, could mediate adverse reactions in children. PMID- 28669613 TI - Reply. PMID- 28669614 TI - Safety and effectiveness of Human Papillomavirus (HPV) vaccination: NCI of Milan position statement. PMID- 28669615 TI - Long-term protection after hepatitis B vaccination in people living with HIV. AB - BACKGROUND: Hepatitis B vaccine is important in people living with HIV (PLHIV) since both viruses have the same transmission routes and co-infection has greater morbidity. PLHIV usually have poor response to hepatitis B vaccine. The duration of immunity in PLHIV is unknown. The objective of this study is to evaluate the duration of serological response and clinical protection provided by hepatitis B vaccination in PLHIV. METHODS: Retrospective study of a PLHIV cohort primarily vaccinated for hepatitis B virus (HBV) from 2001 to 2002. Markers of infection and protection from HBV were investigated in those individuals who were still attending the outpatient clinic, in Sao Paulo, Brazil from 2012 to 2014. Three groups were analyzed. Group 1: adults who responded to primary vaccine series. Group 2: non-responders to primary vaccine series. Group 3: subjects from both Groups 1 and 2 who did not receive any booster doses after seroconversion. RESULTS: A cohort of 121 PLHIV was analyzed for seroconversion and persistence of anti-HBs. The majority were female (54.5%) and mean age was 50.1years. After 11years, none of the patients had serologic evidence of HBV infection. Overall, 41/58 (70.7%) of the initial responders (Group 1) had maintained anti HBs>=10mIU/mL. Greater CD4+ values and anti-HBs>100mIU/mL at the time of first vaccine series were associated with persistence of anti-HBs. During the time of evaluation, 35/63 (55.6%) of the initial non-responders (Group 2) successfully seroconverted (anti-HBs>=10mIU/mL) in response to one or more booster doses. From the time of their seroconversion, 70 of the patients did not receive any further booster doses (Group 3). After 10years, 54/70 (77.1%) of these individuals has maintained anti-HBs>=10mIU/mL. CONCLUSIONS: Evaluation of long-term immunity for hepatitis B in PLHIV following vaccination showed a strong persistence of anti HBs and no serologic evidence of HBV infection. Boosters may be effective in PLHIV non-responders to primary vaccination. PMID- 28669616 TI - Clostridium difficile chimeric toxin receptor binding domain vaccine induced protection against different strains in active and passive challenge models. AB - Clostridium difficile is the number one cause of nosocomial antibiotic-associated diarrhea in developed countries. Historically, pathogenesis was attributed two homologous glucosylating toxins, toxin-A (TcdA) and toxin-B (TcdB). Over the past decade, however, highly virulent epidemic strains of C. difficile (B1/NAP1/027) have emerged and are linked to an increase in morbidity and mortality. Increased virulence is attributed to multiple factors including: increased production of A- and B-toxins; production of binary toxin (CDT); and the emergence of more toxic TcdB variants (TcdB(027)). TcdB(027) is more cytotoxicity to cells; causes greater tissue damage and toxicity in animals; and is antigenically distinct from historical TcdB (TcdB(003)). Broadly protective vaccines and therapeutic antibody strategies, therefore, may target TcdA, TcdB variants and CDT. To facilitate the generation of multivalent toxin-based C. difficile vaccines and therapeutic antibodies, we have generated fusion proteins constructed from the receptor binding domains (RBD) of TcdA, TcdB(003), TcdB(027) and CDT. Herein, we describe the development of a trivalent toxin (T-toxin) vaccine (CDTb/TcdB(003)/TcdA) and quadravalent toxin (Q-toxin) vaccine (CDTb/TcB(003)/TcdA/TcdB(027)) fusion proteins that retain the protective toxin neutralizing epitopes. Active immunization of mice or hamsters with T-toxin or Q-toxin fusion protein vaccines elicited the generation of toxin neutralizing antibodies to each of the toxins. Hamsters immunized with the Q-toxin vaccine were broadly protected against spore challenge with historical C. difficile 630 (toxinotype 0/ribotype 003) and epidemic NAP1 (toxinotype III/ribotype 027) strains. Fully human polyclonal antitoxin IgG was produced by immunization of transgenic bovine with these fusion proteins. In passive transfer studies, mice were protected against lethal toxin challenge. Hamsters treated with human antitoxin IgG were completely protected when challenged with historical or epidemic strains of C. difficile. The use of chimeric fusion proteins is an attractive approach to producing multivalent antitoxin vaccines and therapeutic polyclonal antibodies for prevention and treatment of C. difficile infections (CDI). PMID- 28669617 TI - An increasing, potentially measles-susceptible population over time after vaccination in Korea. AB - BACKGROUND: In Korea, measles occurs mainly in infants <12months of age, who are unvaccinated. In addition, vaccine populations, including adolescents and young adults, can become infected though importation. Thus, the question arises whether the current level of herd immunity in Korea is now insufficient for protecting against measles infection. METHODS: Age-specific measles seroprevalence was evaluated by performing enzyme immunoassays and plaque reduction-neutralization tests on 3050 subjects aged 0-50years (birth cohort 1964-2014) and 480 subjects aged 2-30years (birth cohort 1984-2012). RESULTS: The overall seropositivity and measles antibody concentrations were 71.5% and 1366mIU/mL, respectively. Progressive decline in antibody levels and seropositivity were observed over time after vaccination in infants, adolescents, and young adults. The accumulation of potentially susceptible individuals in the population was confirmed by comparing data from 2010 and 2014 seroprevalence surveys. The statistical correlation between measles incidence and measles seronegativity was determined. CONCLUSIONS: Waning levels of measles antibodies with increasing time post-vaccination suggests that measles susceptibility is potentially increasing in Korea. This trend may be related to limitations of vaccine-induced immunity in the absence of natural boosting by the wild virus, compared to naturally acquired immunity triggered by measles infection. This study provides an important view into the current measles herd immunity in Korea. PMID- 28669619 TI - Widespread psoriasis flare following influenza vaccination. PMID- 28669618 TI - Immunization of Zika virus envelope protein domain III induces specific and neutralizing immune responses against Zika virus. AB - In this study, we described the generation and immunogenicity of the Zika Virus (ZIKV) envelope protein (E) domain III (DIII) as a protein subunit vaccine candidate. ZIKV EDIII (zEDIII) was rapidly produced in E. coli in inclusion bodies. ZIKV EDIII was solubilized, refolded and purified to >95% homogeneity with a one-step Ni2+ affinity chromatography process. Further analysis revealed that zEDIII was refolded properly and demonstrated specific binding to an anti zEDIII monoclonal antibody that recognizes a zEDIII conformational epitope. Subcutaneous immunization of mice with 25 and 50MUg of zEDIII was performed over a period of 11weeks. zEDIII evoked ZIKV-specific and neutralizing antibody response with titers that exceed the threshold that correlates with protective immunity against ZIKV. The antigen-specific IgG isotypes were predominantly IgG1 and splenocyte cultures from immunized mice secreted IFN-gamma, IL-4 and IL-6. Notably, zEDIII-elicited antibodies did not enhance the infection of dengue virus in Fc gamma receptor (FcgammaR)-expressing cells. This study provided a proof of principle for the further development of recombinant protein-based subunit vaccines against ZIKV. PMID- 28669620 TI - Prenatal Tdap immunization and risk of maternal and newborn adverse events. AB - Many countries recommend combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis immunization (Tdap) during pregnancy to stimulate transplacental transmission of pertussis antibodies to newborns. The immune system can be altered during pregnancy, potentially resulting in differing immunization risks in pregnant women. The safety of widespread Tdap immunization during pregnancy needs to be established. Our objective was to assess whether prenatal Tdap immunization was associated with adverse birth outcomes, and to evaluate the effect of timing of Tdap administration on these outcomes. We identified pregnancies at delivery in a large insurance claims database (2010 2014). Tdap immunization was categorized as optimal prenatal (27+weeks), early prenatal (<27weeks), postpartum (<=7days post-delivery), or none. Medical claims were searched to identify maternal adverse immunization reactions (e.g. anaphylaxis, fever, Guillian-Barre syndrome [GBS]), adverse birth outcomes (e.g. preeclampsia/eclampsia, premature rupture or membranes, chorioamnionitis) and newborn outcomes (e.g. respiratory distress, pulmonary hypertension, neonatal jaundice). Women with optimal or early prenatal Tdap were compared to those not immunized in pregnancy, using propensity score-weighted log-binomial regression and Cox proportional hazards models to estimate risk ratios (RR) and hazard ratios (HR). We identified 1,079,034 deliveries and 677,075 linked newborns; 11.5% were immunized optimally and 2.3% immunized early. There were 1 case of post-immunization anaphylaxis, and 12 cases of maternal encephalopathy (all post- delivery); there were no cases of GBS. Optimally-timed immunization was associated with small increased relative risks of: chorioamnionitis [RR=1.11, (95% CI: 1.07-1.15), overall risk=2.8%], and postpartum hemorrhage [RR=1.23 (95% DI: 1.18-1.28), overall risk=2.4%]; however, these relative increases corresponded to low absolute risk increases. Tdap was not associated with increased risk of any adverse newborn outcome. Overall, prenatal Tdap immunization was not associated with newborn adverse events, but potential associations with chorioamnionitis consistent with one previous study and postpartum hemorrhage require further investigation. PMID- 28669621 TI - Influenza vaccines effectiveness 2013-14 through 2015-16, a test-negative study in children. AB - BACKGROUND: Trivalent inactivated and live attenuated influenza vaccines (IIV3 and LAIV3) have been reformulated with an extra B strain (IIV4 and LAIV4). They were licensed based on immunogenicity and their effectiveness (VE) still must be empirically tested. METHODS: Children 1-17years tested for influenza during 2013 16 were included and their immunization status verified. They were considered vaccinated if received >=1 dose of an influenza vaccine >=10days before evaluated for a respiratory episode. Age-groups were classified as 1-4years or 5-17years. VE was estimated by comparing vaccination status of influenza-positive versus influenza-negative cases. RESULTS: 6779 children were enrolled in the three seasons. Overall, 27.2% received an influenza vaccine (87.1% IIV3 or IIV4 and 12.9% LAIV4), and 15.6% tested positive for influenza (77.9% A). IIV3 was predominantly used in 2013-14 and IIV4 in 2014-15 and 2015-16. IIV3 and IIV4 had comparable VE over the three seasons (60%, 57% and 53%) and performed similarly against influenza A and B and both age-groups. LAIV4 performed poorly for influenza A (15%, 37% and 48%) but better for influenza B (100%, 56% and 100%), especially among children 5-17years of age with VE=100% (95%CI: 55, 100). CONCLUSIONS: Influenza vaccination showed modest but consistent effectiveness over the years. The switch from IIV3 to IIV4 did not affect VE. LAIV4 did not perform as well as IIVs, yet it improved over the years and was particularly good protecting older children against influenza B. These results emphasize the regional nature of influenza and the need for local surveillance. PMID- 28669622 TI - Smad4 is essential for directional progression from committed neural progenitor cells through neuronal differentiation in the postnatal mouse brain. AB - Signaling by the TGFbeta super-family, consisting of TGFbeta/activin- and bone morphogenetic protein (BMP) branch pathways, is involved in the central nervous system patterning, growth, and differentiation during embryogenesis. Neural progenitor cells are implicated in various pathological conditions, such as brain injury, infarction, Parkinson's disease and Alzheimer's disease. However, the roles of TGFbeta/BMP signaling in the postnatal neural progenitor cells in the brain are still poorly understood. We examined the functional contribution of Smad4, a key integrator of TGFbeta/BMP signaling pathways, to the regulation of neural progenitor cells in the subventricular zone (SVZ). Conditional loss of Smad4 in neural progenitor cells caused an increase in the number of neural stem like cells in the SVZ. Smad4 conditional mutants also exhibited attenuation in neuronal lineage differentiation in the adult brain that led to a deficit in olfactory bulb neurons as well as to a reduction of brain parenchymal volume. SVZ derived neural stem/progenitor cells from the Smad4 mutant brains yielded increased growth of neurospheres, elevated self-renewal capacity and resistance to differentiation. These results indicate that loss of Smad4 in neural progenitor cells causes defects in progression of neural progenitor cell commitment within the SVZ and subsequent neuronal differentiation in the postnatal mouse brain. PMID- 28669623 TI - Dual antibiotherapy of tuberculosis mediated by inhalable locust bean gum microparticles. AB - Despite the existence of effective oral therapy, tuberculosis remains a deadly pathology, namely because of bacterial resistance and incompliance with treatments. Establishing alternative therapeutic approaches is urgently needed and inhalable therapy has a great potential in this regard. As pathogenic bacteria are hosted by alveolar macrophages, the co-localisation of antitubercular drugs and pathogens is thus potentiated by this strategy. This work proposes inhalable therapy of pulmonary tuberculosis mediated by a single locust bean gum (LBG) formulation of microparticles associating both isoniazid and rifabutin, complying with requisites of the World Health Organisation of combined therapy. Microparticles were produced by spray-drying, at LBG/INH/RFB mass ratio of 10/1/0.5. The aerodynamic characterisation of microparticles revealed emitted doses of more than 90% and fine particle fraction of 38%, thus indicating the adequacy of the system to reach the respiratory lung area, thus partially the alveolar region. Cytotoxicity results indicate moderate toxicity (cell viability around 60%), with a concentration-dependent effect. Additionally, rat alveolar macrophages evidenced preferential capture of LBG microparticles, possibly due to chemical composition comprising mannose and galactose units that are specifically recognised by macrophage surface receptors. PMID- 28669624 TI - Reducing agent-free synthesis of curcumin-loaded albumin nanoparticles by self assembly at room temperature. AB - The purpose of this study was to prepare curcumin-loaded bovine serum albumin nanoparticles (CCM-BSA-NPs) by reducing agent-free self-assembly at room temperature. A 24 factorial design approach was used to investigate the CCM-BSA NP preparation process at different pH values, temperatures, dithiothreitol amounts, and CCM/BSA mass ratios. Increasing the ionic strength enabled preparation of CCM-BSA-NPs at 25 degrees C without reducing agent. CCM-BSA-NPs prepared under the optimized conditions at 25 degrees C showed a particle size of 110+/-6nm, yield of 88.5%, and drug loading of 7.1%. The CCM-BSA-NPs showed strong antioxidant activity and neuroprotective effects in glutamate-induced mouse hippocampal neuronal HT22 cells. This study suggests that ionic strength can be a key parameter affecting the preparation of albumin-based NPs. PMID- 28669625 TI - Clinical risk factors predicting genital fungal infections with sodium-glucose cotransporter 2 inhibitor treatment: The ABCD nationwide dapagliflozin audit. AB - INTRODUCTION: Treatment of type 2 diabetes with sodium-glucose cotransporter 2 (SGLT2) inhibitors may result in genital fungal infections. We investigated possible risk factors for developing such infections among patients treated with the SGLT2 inhibitor dapagliflozin. METHODS: The Association of British Clinical Diabetologists (ABCD) collected data on patients treated with dapagliflozin in routine clinical practice from 59 diabetes centres. We assessed possible associations of patient's age, diabetes duration, body mass index, glycated haemoglobin, renal function, patient sex, ethnicity and prior genital fungal infection, urinary tract infection, urinary incontinence or nocturia, with the occurrence of >=1 genital fungal infection within 26 weeks of treatment. RESULTS: 1049 out of 1116 patients (476 women, 573 men) were analysed. Baseline characteristics were, mean+/-SD, age 56.7+/-10.2years, BMI 35.5+/-6.9kg/m2 and HbA1c 9.4+/-1.5%. Only patient sex (13.2% women vs 3.3% men) and prior history of genital fungal infection (21.6% vs 7.3%) were found to be associated with occurrence of genital fungal infections after dapagliflozin treatment, adjusted OR 4.22 [95%CI 2.48,7.19], P<0.001 and adjusted OR 2.41 [95% CI 1.04,5.57], P=0.039, respectively. CONCLUSION: Women and patients with previous genital fungal infections had higher risks of developing genital fungal infections with dapagliflozin treatment. PMID- 28669626 TI - Metabolism and antioxidant effect of malaxinic acid and its corresponding aglycone in rat blood plasma. AB - Malaxinic acid (MA) is a phenolic acid compound, found mainly in pear fruits (Pyrus pyrifolia N.), that is isoprenylated on the C-3 position of benzoic acid. Recently, the effects of prenylated phenolics on health have received much interest owing to their reported potent beneficial biological effects. We conducted a comparative study in rats to determine the metabolism, pharmacokinetics, and antioxidative activities of MA and its corresponding aglycone (MAA). MA and MAA were orally administered to rats (Sprague-Dawley, male, 6 weeks old) and their metabolites in plasma were analyzed. In addition, the MA metabolites in plasma were separated and the structures were confirmed via NMR and HR-MS analyses. The antioxidative activities of MA and MAA were evaluated by measuring their inhibitory effects on the 2,2'-azobis(2 amidinopropane)dihydrochloride- or copper ion-induced lipid peroxidation of rat plasma. MA was not absorbed in the intact form (the glucoside); both MA and MAA were absorbed as MAA and its metabolite form (glucuronide or sulfate). Moreover, the observed metabolite was the glucuronate of MAA rather than the glucuronide or sulfate. Concentrations of the free form of aglycone (MA administration, 4.6 +/- 2.2MUM; MAA administration, 7.2 +/- 2.3MUM) and total MAA (MA administration, 19.6 +/- 4.4MUM; MAA administration, 21.7 +/- 3.3MUM) in plasma reached a maximum at 15min after the oral administration of MA and MAA, respectively. The relative inhibitory effects on the formation of cholesteryl ester hydroperoxides in plasma collected at 15min after the oral administration of MA, MAA, and p-hydroxybenzoic acid (p-HBA) were as follows: MAA > MA >= p-HBA > control. Although the majority of MA and MAA is metabolized to conjugates, the compounds may contribute to the antioxidant defenses in the blood circulation owing to the presence of a phenolic hydroxyl group in the free form. PMID- 28669627 TI - Endogenous hydrogen sulfide-mediated MAPK inhibition preserves endothelial function through TXNIP signaling. AB - Mounting evidence demonstrated deficient cystathionine-gamma-lyase (CSE)/H2S implicated the development of cardiovascular disease. The present study aimed to evaluating the favorable action of CSE derived H2S on endothelial function in CSE /- mice. CSE-/- mice exhibited attenuated endothelium-dependent relaxations, coupled with reduction of endothelial nitric oxide synthase (eNOS) phosphorylation at site of Ser1177, increase of thioredoxin interacting protein (TXNIP) level and MAPK phosphorylation, which were corrected by sodium hydrosulfide chronic treatment for 8 weeks. Impaired relaxations to ACh and upregulated TXNIP of CSE-/- mice aorta were partially corrected by p38 inhibitor, extracellular regulated protein kinase (ERK) inhibitor and c-Jun N-terminal kinase (JNK) inhibitor and totally corrected by combined treatment. Pharmacological inhibition of CSE with DL-propargylglycine (PPG) in vivo and ex vivo induced endothelial dysfunction. PPG stimulated the phosphorylation of p38, JNK and ERK in human umbilical vein endothelial cells (HUVECs). MAPK inhibition by combined treatment of p38, JNK and ERK inhibitors normalized the endothelial changes of eNOS phosphorylation and TXNIP protein level in CSE-/- mice aorta and PPG-treated HUVECs. NaHS offered similar effect with MAKP inhibitors. TXNIP siRNA prevented against endothelial function by PPG and TXNIP overexpression mimics the detrimental effect of PPG treatment on endothelial function, whereas MAPK inhibitor or NaHS has no beneficial effect. In a word, Endogenous CSE/H2S benefits against endothelial dysfunction through suppressing MAPK/TXNIP cascade. CSE deficiency and consequently lowered endogenous H2S level should be considered as risk factors and biomarkers for endothelial dysfunction. PMID- 28669628 TI - Role of oxidative stress in cardiovascular disease outcomes following exposure to ambient air pollution. AB - Exposure to ambient air pollution is associated with adverse cardiovascular outcomes. These are manifested through several, likely overlapping, pathways including at the functional level, endothelial dysfunction, atherosclerosis, pro coagulation and alterations in autonomic nervous system balance and blood pressure. At numerous points within each of these pathways, there is potential for cellular oxidative imbalances to occur. The current review examines epidemiological, occupational and controlled exposure studies and research employing healthy and diseased animal models, isolated organs and cell cultures in assessing the importance of the pro-oxidant potential of air pollution in the development of cardiovascular disease outcomes. The collective body of data provides evidence that oxidative stress (OS) is not only central to eliciting specific cardiac endpoints, but is also implicated in modulating the risk of succumbing to cardiovascular disease, sensitivity to ischemia/reperfusion injury and the onset and progression of metabolic disease following ambient pollution exposure. To add to this large research effort conducted to date, further work is required to provide greater insight into areas such as (a) whether an oxidative imbalance triggers and/or worsens the effect and/or is representative of the consequence of disease progression, (b) OS pathways and cardiac outcomes caused by individual pollutants within air pollution mixtures, or as a consequence of inter-pollutant interactions and (c) potential protection provided by nutritional supplements and/or pharmacological agents with antioxidant properties, in susceptible populations residing in polluted urban cities. PMID- 28669630 TI - Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor. AB - In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC. Unique to Exon19:CIPC, three highly conserved polar residues, Asn341 of CIPC and Gln544 of the two Exon19 helices, are located at the mid-section of the coiled-coil bundle interior and form hydrogen bonds with each other. Combining results from protein database search, sequence analysis, and mutagenesis studies, we discovered for the first time that CLOCK Exon19:CIPC interaction is a conserved transcription regulatory mechanism among mammals, fish, flies, and other invertebrates. PMID- 28669629 TI - The ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cancer death in a Japanese community: The Hisayama Study. AB - BACKGROUND: Whether the intake of eicosapentaenoic acid (EPA) or arachidonic acid (AA) affects the risk of cancer remains unclear, and the association between the serum EPA:AA ratio and cancer risk has not been fully evaluated in general populations. METHODS: A total of 3098 community-dwelling subjects aged >=40 years were followed up for 9.6 years (2002-2012). The levels of the serum EPA:AA ratio were categorized into quartiles (<0.29, 0.29-0.41, 0.42-0.60, and >0.60). The risk estimates were computed using a Cox proportional hazards model. The same analyses were conducted for the serum docosahexaenoic acid to arachidonic acid (DHA:AA) ratio and individual fatty acid concentrations. RESULTS: During the follow-up period, 121 subjects died of cancer. Age- and sex-adjusted cancer mortality increased with lower serum EPA:AA ratio levels (P trend<0.05). In the multivariable-adjusted analysis, the subjects in the first quartile of the serum EPA:AA ratio had a 1.93-fold (95% confidence interval, 1.15-3.22) greater risk of cancer death than those in the fourth quartile. Lower serum EPA concentrations were marginally associated with higher cancer mortality (P trend<0.11), but the serum DHA or AA concentrations and the serum DHA:AA ratio were not (all P trend>0.37). With regard to site-specific cancers, lower serum EPA:AA ratio was associated with a higher risk of death from liver cancer. However, no such associations were detected for deaths from other cancers. CONCLUSIONS: These findings suggest that decreased level of the serum EPA:AA ratio is a significant risk factor for cancer death in the general Japanese population. PMID- 28669631 TI - Structure and Cooperativity of the Cytosolic Domain of the CorA Mg2+ Channel from Escherichia coli. AB - Structures of the Mg2+ bound (closed) and apo (open) states of CorA suggests that channel gating is accomplished by rigid-body motions between symmetric and asymmetric assemblies of the cytosolic portions of the five subunits in response to ligand (Mg2+) binding/unbinding at interfacial sites. Here, we structurally and biochemically characterize the isolated cytosolic domain from Escherichia coli CorA. The data reveal an Mg2+-ligand binding site located in a novel position between each of the five subunits and two Mg2+ ions trapped inside the pore. Soaking experiments show that cobalt hexammine outcompetes Mg2+ at the pore site closest to the membrane. This represents the first structural information of how an analog of hexa-hydrated Mg2+ (and competitive inhibitor of CorA) associates to the CorA pore. Biochemical data on the isolated cytoplasmic domain and full-length protein suggests that gating of the CorA channel is governed cooperatively. PMID- 28669632 TI - Regulation of the Equilibrium between Closed and Open Conformations of Annexin A2 by N-Terminal Phosphorylation and S100A4-Binding. AB - Annexin A2 (ANXA2) has a versatile role in membrane-associated functions including membrane aggregation, endo- and exocytosis, and it is regulated by post translational modifications and protein-protein interactions through the unstructured N-terminal domain (NTD). Our sequence analysis revealed a short motif responsible for clamping the NTD to the C-terminal core domain (CTD). Structural studies indicated that the flexibility of the NTD and CTD are interrelated and oppositely regulated by Tyr24 phosphorylation and Ser26Glu phosphomimicking mutation. The crystal structure of the ANXA2-S100A4 complex showed that asymmetric binding of S100A4 induces dislocation of the NTD from the CTD and, similar to the Ser26Glu mutation, unmasks the concave side of ANXA2. In contrast, pTyr24 anchors the NTD to the CTD and hampers the membrane-bridging function. This inhibition can be restored by S100A4 and S100A10 binding. Based on our results we provide a structural model for regulation of ANXA2-mediated membrane aggregation by NTD phosphorylation and S100 binding. PMID- 28669634 TI - Structure of Phytoene Desaturase Provides Insights into Herbicide Binding and Reaction Mechanisms Involved in Carotene Desaturation. AB - Cyanobacteria and plants synthesize carotenoids via a poly-cis pathway starting with phytoene, a membrane-bound C40 hydrocarbon. Phytoene desaturase (PDS) introduces two double bonds and concomitantly isomerizes two neighboring double bonds from trans to cis. PDS assembles into homo-tetramers that interact monotopically with membranes. A long hydrophobic tunnel is proposed to function in the sequential binding of phytoene and the electron acceptor plastoquinone. The herbicidal inhibitor norflurazon binds at a plastoquinone site thereby blocking reoxidation of FADred. Comparison with the sequence-dissimilar bacterial carotene desaturase CRTI reveals substantial similarities in the overall protein fold, defining both as members of the GR2 family of flavoproteins. However, the PDS active center architecture is unprecedented: no functional groups are found in the immediate flavin vicinity that might participate in dehydrogenation and isomerization. This suggests that the isoalloxazine moiety is sufficient for catalysis. Despite mechanistic differences, an ancient evolutionary relation of PDS and CRTI is apparent. PMID- 28669633 TI - The N-Terminal Region of Fibrillin-1 Mediates a Bipartite Interaction with LTBP1. AB - Fibrillin-1 (FBN1) mutations associated with Marfan syndrome lead to an increase in transforming growth factor beta (TGF-beta) activation in connective tissues resulting in pathogenic changes including aortic dilatation and dissection. Since FBN1 binds latent TGF-beta binding proteins (LTBPs), the major reservoir of TGF beta in the extracellular matrix (ECM), we investigated the structural basis for the FBN1/LTBP1 interaction. We present the structure of a four-domain FBN1 fragment, EGF2-EGF3-Hyb1-cbEGF1 (FBN1E2cbEGF1), which reveals a near-linear domain organization. Binding studies demonstrate a bipartite interaction between a C-terminal LTBP1 fragment and FBN1E2cbEGF1, which lies adjacent to the latency associated propeptide (LAP)/TGF-beta binding site of LTBP1. Modeling of the binding interface suggests that, rather than interacting along the longitudinal axis, LTBP1 anchors itself to FBN1 using two independent epitopes. As part of this mechanism, a flexible pivot adjacent to the FBN1/LTBP1 binding site allows LTBP1 to make contacts with different ECM networks while presumably facilitating a force-induced/traction-based TGF-beta activation mechanism. PMID- 28669635 TI - Neuropsychiatry phenotype in asthma: Psychological stress-induced alterations of the neuroendocrine-immune system in allergic airway inflammation. AB - Since the recognition of asthma as a syndrome with complex pathophysiological signs and symptoms, recent research has sought to classify asthma phenotypes based on its clinical and molecular pathological features. Psychological stress was first recognized as a potential immune system modulator of asthma at the end of the 19th century. The activation of the central nervous system (CNS) upon exposure to psychological stress is integral for the initiation of signal transduction processes. The stress hormones, including glucocorticoids, epinephrine, and norepinephrine, which are secreted following CNS activation, are involved in the immunological alterations involved in psychological stress induced asthma exacerbation. The mechanisms underlying this process may involve a pathological series of events from the brain to the lungs, which is attracting attention as a conceptually advanced phenotype in asthma pathogenesis. This review presents insights into the critical role of psychological stress in the development and exacerbation of allergic asthma, with a special focus on our own data that emphasizes on the continuity from the central sensing of psychological stress to enhanced eosinophilic airway inflammation. PMID- 28669636 TI - Occurrence of oxidative stress in dairy cows seropositives for Brucella abortus. AB - Bovine brucellosis is an important zoonotic disease caused by the bacterium Brucella abortus that leads to economic losses due to animal discard and commercial restrictions. Since positive animals for brucellosis are culled, little is known about the pathogenesis of this disease. Therefore, the aims of this study were to evaluate possible changes in the activity of deaminase adenosine (ADA) and the oxidative stress in cows seropositives for brucellosis (Experiment I), and to evaluate the seroprevalence of B. abortus in dairy cows from the Western state of Santa Catarina, Southern Brazil (Experiment II). The Experiment I evaluated 20 pregnant cows: ten seropositives for B. abortus and ten seronegatives that were used as controls. The ADA activity and markers of oxidative stress (TBARS, catalase (CAT) and superoxide dismutase (SOD)) were evaluated in these animals. A reduction in the activity of ADA and catalase enzymes in seropositive animals was observed (p < 0.001). Conversely, there was an increase in TBARS levels and superoxide dismutase activity in cows infected by B. abortus (p < 0.001). The presence of oxidative stress and a reduction of ADA might be related to the modulation of the inflammatory response. The experiment II was performed due to a high number of herds with restrictions imposed by cases of brucellosis in the state of Santa Catarina in the last two years, and thus, the seroprevalence for B. abortus was evaluated in 1242 serum samples of cows of 69 herds. The serodiagnosis was performed using two tests: buffered acidified antigen and 2-mercaptoethanol. However, none of the serum samples were positive for B. abortus. Although we did not find seropositive animals for brucellosis in our study, the disease still requires continued surveillance, due to its economic impact, and to the oxidative stress caused by it, which may have contributed to cases of abortion in three seropositive cows (Experiment I) in the final third of the gestation. PMID- 28669637 TI - Editorial, IAPC-5 Special Issue. PMID- 28669638 TI - Host Genetics and Gut Microbiome: Challenges and Perspectives. AB - The mammalian gut is colonized by trillions of microorganisms collectively called the microbiome. It is increasingly clear that this microbiome has a critical role of in many aspects of health including metabolism and immunity. While environmental factors such as diet and medications have been shown to influence the microbiome composition, the role of host genetics has only recently emerged in human studies and animal models. In this review, we summarize the current state of microbiome research with an emphasis on the effect of host genetics on the gut microbiome composition. We focus particularly on genetic determinants of the host immune system that help shape the gut microbiome and discuss avenues for future research. PMID- 28669639 TI - Whole blood glycerophospholipids in dried blood spots - a reliable marker for the fatty acid status. AB - BACKGROUND: Whole blood total fatty acid analysis in capillary blood has recently been proposed for fatty acid status determination, but the accuracy of this method is affected by the fast turnover of triaclyglyceride (TAG) fatty acids, the individual hematocrit and postprandial state. METHOD: An established method for the glycerophospholipid (GPL) analysis in plasma was adapted for the analysis of whole blood GPL and tested in a fat challenge test. Blood samples were collected from nine participants after receiving a standardised breakfast containing 42g of sunflower oil. Whole blood GPL fatty acids were compared against whole blood total lipid, plasma TAG and phospholipid fatty acids. RESULTS: All fatty acid concentrations in dried blood samples showed a coefficient of variation <5.7%. The fat challenge test induced a significant increase of TAG fatty acid concentration (mean Delta=42.3%+/-35.7) and whole blood total fatty acid concentration (mean Delta=5.2%+/-3.7) whereas whole blood GPL fatty acids were hardly changed (mean Delta=1.3%+/-1.6). CONCLUSION: Whole blood GPL fatty acids are a robust biological marker for the fatty acid status of fasted and non-fasted subjects. The influence of very recent dietary intake on whole blood GPL is smaller than on whole blood total lipids. PMID- 28669640 TI - Oxysterols and mesenchymal stem cell biology. AB - Oxysterols are oxidized products of cholesterol that play several roles in various pathophysiological processes, including the control of lipid metabolism, immunological processes, and cytotoxicity. Mesenchymal stem cells are multipotent cells with properties of self-renewal and the ability to differentiate into other cell types, including osteoblasts and adipocytes. Here, we review the literature regarding the effects of oxysterols on mesenchymal stem cell differentiation and the main signaling pathways involved in this process. PMID- 28669641 TI - Prognostic significance of extensive necrosis in renal cell carcinoma. AB - Few studies using the current classification of renal cell carcinoma (RCC) have looked at a large number of cases with near total necrosis. We identified 21 cases of resections of RCC with >90% necrosis from the archives of Johns Hopkins Hospital between 2000 and 2015. Patients' mean age was 59 years (43-77) with 16 men (76%); 12 cases (57%) were papillary RCC, 4 clear cell papillary RCC (19%), 4 clear cell RCC (19%), and 1 unclassified with sarcomatoid differentiation (5%). International Society of Urological Pathology (ISUP) nucleolar grade was grade 1 (9 cases) or grade 2 (9 cases). Two cases were ISUP nucleolar grade 3, and 1 case was grade 4. Pathological stage was low (pT1-2) in 20 (95%) with the unclassified RCC with sarcomatoid differentiation RCC stage pT3a. Mean tumor size was 6.3 cm (1.2-17). In 52% (11) of cases, it was difficult to identify viable tumor, requiring multiple sections; 4 cases of papillary RCC were diagnosed in part due to necrotic tumor "ghost" architecture. Follow-up was available in 17 cases (81%) with a mean follow-up of 59 months. Thirteen patients (62%) are alive without disease. The patient with unclassified carcinoma with sarcomatoid differentiation died of cancer, and 2 died due to causes unrelated to cancer. One patient (5%) with low-grade clear cell RCC developed metastases but had a contralateral RCC. In the setting of a low-grade RCC, extensive necrosis does not have an adverse prognosis. In summary, our data, together with a prior study from our institution, comprise one of the largest cohorts of extensively (>90%) necrotic RCCs and suggests that in the setting of a low-grade RCC, it portends a good prognosis (only 2/36 cases showing progression (6%) on follow-up). However, we did identify a single case of high-grade RCC with an adverse prognosis and therefore, careful attention to tumor grade and classification is critical. The presence of tumor necrosis as a prognosticator in RCCs is complex, and despite its well-accepted role as an indicator of poor prognosis, our data would suggest otherwise under specific conditions. Importantly, in diagnosing a renal mass with extensive cystic necrosis, careful and extensive sampling to identify small foci of viable tumor or "ghost" architecture may be necessary for classification. As such, evaluation of its presence should not only be quantitative, but critical attention should be made to tumor grade and stage, whereby in high-grade carcinomas, necrosis likely imparts a worse prognosis; however, in low-grade carcinomas with extensive necrosis, the histological subtype, grade, and stage drive prognosis. PMID- 28669642 TI - Compound posterior cruciate ligament and popliteal artery injury due to dog bite: A case report. AB - Injuries due to dog bites are a common occurrence and are mostly trivial. Severe dog bite injuries requiring hospitalization and complex reconstructive procedures are more common in children. We present the case of a five year old child with popliteal artery thrombosis and compound Posterior Cruciate ligament injury due to a dog bite. The child was managed by immediate thrombectomy, meticulous debridement and knee spanning external fixation followed by Skin Grafting. At one year post surgery range of motion was 10-110 degrees , with no distal neurovascular deficit and no sign of instability. PMID- 28669644 TI - Generalised cowpox virus infection. PMID- 28669643 TI - Saving lives efficiently across sectors: the need for a Congressional cost effectiveness committee. PMID- 28669645 TI - US Senate unveils ACA repeal bill. PMID- 28669646 TI - [Assessment of employment's impact on breastfeeding practices]. AB - OBJECTIVE: Employment is recognized as a weaning factor in many studies. Our aim was to evaluate the impact of employment on women's breastfeeding (BF) with a duration longer than 6 months in a Moroccan population. METHOD: A cross-sectional study was conducted between November 2015 and April 2016 in four hospitals in the region of Rabat-Sale, Morocco. All ages were included with the condition that the woman had at least one living child. A questionnaire-based interview collected data on the duration of BF for each child, breast milk storage practices, woman's opinion on BF, and the perception of work conditions during BF. Factors associated with BF lasting longer than 6 months were analyzed using logistic regression carried out in SPSS 13.0 software. RESULTS: A total of 502 surveyed women were analyzed. The median duration of breastfeeding (exclusive or mixed) in working women was 8 months versus 15 months for those without employment (P<0.001). Only 26 % stored breast milk. For working women, BF practiced due to religious conviction or perceived as mandatory were higher than for unemployed women (18% vs 15% and 11% vs. 7%, respectively; P<0.001). Working conditions during BF were perceived as daunting in 61% of cases. In multivariate analysis, factors correlated with prolonged BF longer than 6 months were: (i) early baby initiation to BF (OR=3; 95% CI [1.9-4.6]), (ii) education level: middle and high school (OR=0.1; 95% CI [0.01-0.5]), and (iii) the social status of working women (OR=0.3; 95% CI [0.1-0.6]). CONCLUSION: Employment has a negative impact on the duration of breastfeeding, work perception, and practices of breastfeeding women. PMID- 28669647 TI - [Children's living conditions influence health and social inequalities in health decades later]. PMID- 28669648 TI - [Teaching pediatrics to residents via conventional lectures in France: A national survey from students]. AB - OBJECTIVE: To assess the point of view of young physicians training in pediatrics in France on their theoretical courses during residency. METHODS: A free-access electronic anonymous survey was sent three times by e-mail to the 1215 residents in pediatrics, from July to October 2015. RESULTS: Fifty-seven percent of French residents in pediatrics responded to the survey. It was established that they took part in six (range, 3-10) half-days of specific theoretical teaching in pediatrics from November 2014 to mid-April 2015. Only 54% participated in more than 75% of regional theoretical training. The main self-declared reason for their absence was that they could not leave their clinical activities. Fifty three per cent of the residents took part in additional training, 45% of them because they found the primary theoretical training insufficient. The overall quality of the theoretical teaching was rated 5 (range, 3-7) out of 10. Eighty five percent of residents expected to be evaluated on their knowledge during their residency. CONCLUSION: In pediatrics, additional training is individually undertaken because they deemed their initial training insufficient during their residency. An evaluation of knowledge is requested by residents. The reform of the national residency program must take into account these results in redesigning the theoretical training in pediatrics, integrating innovative teaching techniques to daily practice, for example. PMID- 28669649 TI - [DRESS syndrome and agranulocytosis, a rare combination]. AB - INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe toxidermia that can lead to death from multivisceral failure. We report a case of DRESS associated with febrile agranulocytosis in a child. OBSERVATION: An 8-year-old child was hospitalized for diffuse maculopapular exanthema with edema of the extremities and face associated with cheilitis and febrile agranulocytosis. This symptomatology began 1month after the introduction of carbamazepine for partial epilepsy. The clinical picture was a multisystemic disease with colitis, interstitial pneumonitis, hepatic cytolysis, and hepatocellular insufficiency. HHV7 viral reactivation and increased eosinophils (20%) in the myelogram were demonstrated, providing the diagnosis of DRESS. The progression was favorable after carbamazepine therapy was stopped and systemic corticosteroids were administered. DISCUSSION: DRESS syndrome is a disorder that is unfamiliar to pediatricians. Its association with agranulocytosis is rare and the absence of hypereosinophilia contributed to diagnostic difficulties in this case. The multisystemic failure, the reactivation of HHV7, the increase of eosinophils in the myelogram, and the favorable progression under systemic corticosteroid therapy contributed greatly to the diagnosis. A cutaneous biopsy was not considered necessary for the diagnosis in the case reported herein. CONCLUSION: DRESS syndrome is rarely associated with agranulocytosis, but its diagnosis must be quickly raised so that the incriminated drug can be interrupted. PMID- 28669650 TI - Next Generation DNA Sequencing of Tissues from Infected Diabetic Foot Ulcers. AB - We used next generation DNA sequencing to profile the microbiome of infected Diabetic Foot Ulcers (DFUs). The microbiota was correlated to clinical parameters and treatment outcomes to determine if directed antimicrobial therapy based on conventional microbiological cultures are relevant based on genomic analysis. Patients>=18years presenting with a new Diabetic Foot Infection (DFI) who had not received topical or oral antimicrobials in the two weeks prior to presentation, were eligible for enrolment. Tissue punch biopsies were obtained from infected DFUs for analysis. Demographics, clinical and laboratory data were collected and correlated against microbiota data. Thirty-nine patients with infected DFUs were recruited over twelve-months. Shorter duration DFUs (=six weeks) were diversely polymicrobial (p<0.01) with an average of 63 (range 19-125) bacterial species. Severe DFIs had complex microbiomes and were distinctly dissimilar to less severe infections (p=0.02), characterised by the presence of low frequency microorganisms. Nineteen patients (49%) during the study period experienced antimicrobial treatment failure, but no overall differences existed in the microbiome of patients who failed therapy and those who experienced treatment success (p=0.2). Our results confirm that short DFUs have a simpler microbiome consisting of pyogenic cocci but chronic DFUs have a highly polymicrobial microbiome. The duration of a DFU may be useful as a guide to directing antimicrobial therapy. PMID- 28669651 TI - Frailty in major oncologic surgery of upper gastrointestinal tract: How to improve postoperative outcomes. AB - INTRODUCTION: Certain surgical interventions, especially those involving upper GI tract remain challenging, due to high morbidity and mortality rates. The study of frailty in the surgical population has allowed the identification of those patients with a higher risk of poor postoperative outcomes. There remains a lack of evidence regarding the possibility of improving these results through a preoperative holistic management of the patients. The aim of this study is to evaluate whether preoperative treatment, in carefully selected patients, can improve the outcome following surgery. PATIENTS AND METHODS: Between March 2015 and February 2016 patients affected by malignant tumors of the upper GI tract were enrolled at our Institution for major oncologic surgery. Amongst them, frail patients (Group 1) were identified using a validated scoring system and underwent a multidisciplinary preoperative management plan, composed of nutritional intervention, physical/respiratory enhancement and optimization of ongoing therapy. Short-term postoperative outcomes were then compared with a control group (Group 2) of patients with comparable frailty features and surgical indications, who had undergone surgery in the period from March 2013 to February 2014. RESULTS: 30-days and 3-months mortality, overall and severe complication rates were found to be significantly lower (p < 0.05) in Group 1 (41 patients) when compared with Group 2 (35 patents). No significant differences were recorded for the following outcomes: length of stay, referral to post-discharge institutionalisation and hospital re-admission. DISCUSSION: This study confirms advantages provided by preoperative treatment in frail patients, suggesting a new pathway for the improvement of postoperative outcomes. PMID- 28669653 TI - Sleep Duration, Sedentary Behavior, Physical Activity, and Quality of Life after Inpatient Stroke Rehabilitation. AB - OBJECTIVE: The aim of this study was to describe accelerometer-derived sleep duration, sedentary behavior, physical activity, and quality of life and their association with demographic and clinical factors within the first month after inpatient stroke rehabilitation. MATERIALS AND METHODS: Thirty people with stroke (mean +/- standard deviation, age: 63.8 +/- 12.3 years, time since stroke: 3.6 +/ 1.1 months) wore an activPAL3 Micro accelerometer (PAL Technologies, Glasgow, Scotland) continuously for 7 days to measure whole-day activity behavior. The Stroke Impact Scale and the Functional Independence Measure were used to assess quality of life and function, respectively. RESULTS: Sleep duration ranged from 6.6 to 11.6 hours/day. Fifteen participants engaged in long sleep greater than 9 hours/day. Participants spent 74.8% of waking hours in sedentary behavior, 17.9% standing, and 7.3% stepping. Of stepping time, only a median of 1.1 (interquartile range: .3-5.8) minutes were spent walking at a moderate-to vigorous intensity (>=100 steps/minute). The time spent sedentary, the stepping time, and the number of steps differed significantly by the hemiparetic side (P < .05), but not by sex or the type of stroke. There were moderate to strong correlations between the stepping time and the number of steps with gait speed (Spearman r = .49 and .61 respectively, P < .01). Correlations between accelerometer-derived variables and age, time since stroke, and cognition were not significant. CONCLUSIONS: People with stroke sleep for longer than the normal duration, spend about three quarters of their waking hours in sedentary behaviors, and engage in minimal walking following stroke rehabilitation. Our findings provide a rationale for the development of behavior change strategies after stroke. PMID- 28669652 TI - Severe Vasospasm of the Middle Cerebral Artery after Mechanical Thrombectomy Due to Infective Endocarditis: An Autopsy Case. AB - Untreated infective endocarditis (IE) often produces infective emboli in major cerebral arteries. We describe a case of middle cerebral artery occlusion due to IE, which caused severe vasospasm and reocclusion after mechanical thrombectomy (MT). We present the pathologic findings of the occluded middle cerebral artery and investigate the precautions to be taken while performing MT due to IE. A 72 year-old man with atrial fibrillation treated with dabigatran presented with right hemiparesis and aphasia. A diffusion-weighted image showed a high-intensity area in the left temporoparietal junction, and magnetic resonance angiography revealed a left M2 occlusion. Because of an elevated activated partial thromboplastin time, the thrombolytic therapy was contraindicated; instead, MT was performed. Just after the withdrawal of a stent retriever, the left M2 segment showed severe vasospasm. The next day, the left M2 segment reoccluded. Transthoracic echocardiogram and blood culture findings revealed IE. On the ninth day, the patient died. According to the autopsy report, the cause of death was pulmonary embolism. Pathologic analysis of the occluded M2 segment revealed fibrin thrombi containing vast amounts of neutrophils and invasion of neutrophils into the internal elastic lamina. Severe vasospasm was thought to have occurred because the vascular injury caused by the stent retriever in the vessel had a marked inflammation background. Our findings suggest that devices that are less invasive to the vascular wall are required for performing MT due to IE. The Penumbra aspiration system is thought to be a suitable device. PMID- 28669654 TI - Hydrogen Gas Inhalation Treatment in Acute Cerebral Infarction: A Randomized Controlled Clinical Study on Safety and Neuroprotection. AB - BACKGROUND: Molecular hydrogen (H2) acts as a therapeutic antioxidant. Inhalation of H2 gas (1-4%) was effective for the improvement of cerebral infarction in multiple animal experiments. Thus, for actual applications, a randomized controlled clinical study is desired to evaluate the effects of inhalation of H2 gas. Here, we evaluate the H2 treatment on acute cerebral infarction. METHODS: Through this randomized controlled clinical study, we assessed the safety and effectiveness of H2 treatment in patients with cerebral infarction in an acute stage with mild- to moderate-severity National Institute of Health Stroke Scale (NIHSS) scores (NIHSS = 2-6). We enrolled 50 patients (25 each in the H2 group and the control group) with a therapeutic time window of 6 to 24 hours. The H2 group inhaled 3% H2 gas (1 hour twice a day), and the control group received conventional intravenous medications for the initial 7 days. The evaluations included daily vital signs, NIHSS scores, physical therapy indices, weekly blood chemistry, and brain magnetic resonance imaging (MRI) scans over the 2-week study period. RESULTS: The H2 group showed no significant adverse effects with improvements in oxygen saturation. The following significant effects were found: the relative signal intensity of MRI, which indicated the severity of the infarction site, NIHSS scores for clinically quantifying stroke severity, and physical therapy evaluation, as judged by the Barthel Index. CONCLUSIONS: H2 treatment was safe and effective in patients with acute cerebral infarction. These results suggested a potential for widespread and general application of H2 gas. PMID- 28669655 TI - IMM-H004, A New Coumarin Derivative, Improved Focal Cerebral Ischemia via Blood Brain Barrier Protection in Rats. AB - OBJECTIVE: IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H chromen-2-one) is a novel coumarin derivative that showed better effect in improving global cerebral ischemia in rats. However, the effects and mechanisms in focal cerebral ischemia were not clear. Blood-brain barrier (BBB) protection is a vital strategy for the treatment of cerebral ischemia. This study is to investigate whether IMM-H004 improves brain ischemia injury via BBB protection. METHODS: Focal brain ischemia model was induced by middle cerebral artery occlusion for 1 hour and reperfusion (MCAO/R) for 24 hours in rats. IMM-H004 (1.5, 3, 6 mg/kg) and edaravone (positive drug, 6 mg/kg) were administered after 5 minutes of occlusion. Neurological score and TTC staining were used to evaluate the effect of IMM-H004. Evans Blue (EB) staining and electron microscopy were used to assess BBB permeability. Western blot, reverse transcription-polymerase chain reaction, and immunohistochemistry were used to detect the expression of BBB structure-related proteins. RESULTS: Compared with the model group, IMM-H004 in the focal brain ischemia model improved neurological function and reduced cerebral infarction size and edema content. IMM-H004 sharply reduced the EB content and alleviated BBB structure. In addition, IMM-H004 increased the level of zonula occludens (ZO-1) and occluding, decreased the level of aquaporin 4 and matrix metalloproteinase 9, either in cortex or in hippocampus. And all of these changed were related to BBB protection. CONCLUSION: IMM-H004 improved cerebral ischemia injury via BBB protection. For a potential therapy drug of cerebral ischemia, IMM-H004 merits further study. PMID- 28669656 TI - Motor Skills Training Enhances alpha-Amino-3-hydroxy-5-methyl-4 isoxazolepropionic Acid Receptor Subunit mRNA Expression in the Ipsilateral Sensorimotor Cortex and Striatum of Rats Following Intracerebral Hemorrhage. AB - BACKGROUND: We investigated the effects of acrobatic training (AT) on expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits in the sensorimotor cortex and striatum after intracerebral hemorrhage (ICH). METHODS: Male Wistar rats were divided into 4 groups: ICH without AT (ICH), ICH with AT (ICH + AT), sham operation without AT (SHAM), and sham operation with AT (SHAM + AT). ICH was induced by collagenase injection into the left striatum. The ICH + AT group performed 5 acrobatic tasks daily on days 4-28 post ICH. Forelimb sensorimotor function was evaluated using the forelimb placing test. On days 14 and 29, mRNA expression levels of AMPAR subunits GluR1-4 were measured by real-time reverse transcription-polymerase chain reaction. RESULTS: Forelimb placing test scores were significantly higher in the ICH + AT group than in the ICH group. Expression levels of all AMPAR subunit mRNAs were significantly higher in the ipsilateral sensorimotor cortex of rats in the ICH + AT group than in that of rats in the ICH group on day 29. GluR3 and GluR4 expression levels were reduced in the ipsilateral striatum of rats in the ICH group compared with that of rats in the SHAM group on day 14. CONCLUSIONS: These changes may play a critical role in motor skills training-induced recovery after ICH. PMID- 28669657 TI - Temporal and Spatial Changes in Cerebral Blood Flow during Management for Preventing Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: Serial Semiquantitative Analysis. AB - BACKGROUND: Delayed cerebral ischemia is a major cause of morbidity after aneurysmal subarachnoid hemorrhage. The management for preventing the delayed cerebral ischemia is clinically difficult because of its multifactorial nature. We tested the hypothesis that spatial and temporal changes of regional cerebral blood flow after subarachnoid hemorrhage might relate to the incidence of the delayed cerebral ischemia and the clinical outcome. METHODS: Eighty-eight patients who underwent single-photon emission computed tomography twice during 14 days after the onset of aneurysmal subarachnoid hemorrhage were retrospectively analyzed. Regional cerebral blood flow was automatically analyzed in statistical imaging analyses using 3-dimensional stereotaxic region of interest template and 3-dimensional stereotaxic surface projection. Ratios were calculated by dividing the regional cerebral blood flow of patients by that of normal volunteers. We assessed the relation of changes in regional cerebral blood flow with the development of the delayed cerebral ischemia and the clinical outcome at 3 months. RESULTS: The regional cerebral blood flow of areas that eventually contained infarction significantly decreased, whereas those with significant increase were associated with transient neurological symptoms during the management for the delayed cerebral ischemia. Patients with both areas of regional cerebral blood flow increasing and decreasing during this period had worse outcomes than patients with a unidirectional change. CONCLUSIONS: Cerebral perfusion may change temporally and spatially during the management for preventing the delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Regional hypoperfusion refractory to the management might exist, which could impact on the clinical outcome. An additional therapeutic approach targeting on such regions may be required. PMID- 28669658 TI - Vascular Risk Factors and Internal Jugular Venous Flow in Transient Global Amnesia: A Study of 165 Japanese Patients. AB - BACKGROUND: The etiology of transient global amnesia (TGA) remains unclear. We studied the pathophysiology of TGA in 165 Japanese patients. SUBJECTS AND METHODS: TGA was diagnosed in hospitalized patients from 2004 to 2015. We analyzed clinical characteristics, magnetic resonance imaging findings, and maximum intima-media thickness of the common carotid artery, and the reflux of internal jugular venous (IJV) flow by ultrasonography, and statistically compared patients with TGA with age-matched and sex-matched patients who have had a transient ischemic attack (TIA), small-vessel occlusion (SVO), and normal controls (each group, N = 165). RESULTS: Patients with TGA showed lower prevalence of vascular risk factors than patients with TIA and SVO did. Eleven patients (6.7%) had 2 episodes of TAG, but specific clinical variables could not be recognized in these patients. The maximum intima-media thickness was significantly thinner in TGA (1.1 +/- .7 mm) than in SVO (1.6 +/- .9 mm; P = .001). The percentages of cases whose IJV flow reflux was increased by Valsalva maneuver showed no difference (P = .573) between TGA (26.0 %) and SVO (29.4%). MR diffusion-weighted imaging yielded small hyperintense signals in the hippocampus in 64 of 90 (71.1%) patients between 24 and 72 hours. Potential precipitating specific factors or events before the attacks could be recognized in 40 cases (24.2%) of 165 patients. CONCLUSION: Arterial ischemia and IJV flow reflux might not contribute to TGA pathophysiology. The vulnerability of the hippocampus to physical or emotional stress might be suspected as an underlying mechanism in some patients with TGA. PMID- 28669660 TI - When Does Assessment for Bile Duct Stones Need to Be Performed Prior to Cholecystectomy for Calculus Gallbladder Disease? PMID- 28669661 TI - Physician Burnout: The Hidden Health Care Crisis. AB - Physician burnout is an under-recognized and under-reported problem. Characterized by a state of mental exhaustion, depersonalization, and a decreased sense of personal accomplishment, burnout may affect more than 60% of family practice providers and at least one third of gastroenterologists. Some studies have shown that younger physicians, physicians performing high-risk procedures, and physicians experiencing work-life conflicts are at greatest risk. If unrecognized, the costs to the physician and to the health care system can be enormous because physician burnout is associated with increased rates of depression, alcohol and drug abuse, divorce, suicide, medical errors, difficult relationships with coworkers, and patient dissatisfaction, as well as physician attrition. If properly recognized, appropriate treatments are available. This article presents a case study of a physician suffering from burnout, reviews how burnout is defined, identifies those providers at greatest risk, discusses root causes, and outlines a treatment program. PMID- 28669659 TI - Variability in the Use of Platelet Transfusion in Patients with Intracerebral Hemorrhage: Observations from the Ethnic/Racial Variations of Intracerebral Hemorrhage Study. AB - BACKGROUND: We examined platelet transfusion (PTx) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, hypothesizing that rates of PTx would vary among hospitals and depend on whether patients were on an antiplatelet therapy or underwent intracerebral hemorrhage (ICH) surgical treatment. METHODS: The ERICH study is a prospective observational study evaluating risk factors for ICH among whites, blacks, and Hispanics. We identified factors associated with PTx, examined practice patterns of PTx across the United States, and explored the association of PTx with mortality and poor outcome (modified Rankin Scale score 4-6). RESULTS: Nineteen centers enrolled 2572 ICH cases; 11.7% received PTx. Factors significantly associated with PTx were antiplatelet use before onset (odds ratio [OR], 5.02; 95% confidence interval [CI], 3.81-6.61, P < .0001), thrombocytopenia (OR, 13.53; 95% CI, 8.43 21.72, P < .0001), and ventriculostomy placement (OR, 1.85; 95% CI, 1.36-2.52, P < .0001). Blacks were less likely (OR, .57; 95% CI, .41-0.80) to receive PTx. Among patients who received PTx, 42.4% were not on an antiplatelet therapy before onset. Twenty-three percent of patients on antiplatelet therapy received PTx, but percentages varied from 0% to 71% across centers. There was no difference in mortality or poor outcome at 3 months between patients receiving PTx and those who did not. CONCLUSIONS: The frequency of PTx for ICH varies across academic centers. Thrombocytopenia, antiplatelet use, vascular risk factors, and ventriculostomy placement were associated with PTx. PTx was not associated with improved outcomes. We anticipate reduced PTx use over time given recent clinical trial data suggesting its use could be harmful; however, the issue of whether surgical management warrants PTx remains. PMID- 28669662 TI - Characterization and functional analysis of the Paralichthys olivaceus prdm1 gene promoter. AB - PR domain containing protein 1 (Prdm1) is a transcriptional repressor identified in various species and plays multiple important roles in immune response and embryonic development. However, little is known about the transcriptional regulation of the prdm1 gene. This study aims to characterize the promoter of Paralichthys olivaceus prdm1 (Po-prdm1) gene and determine the regulatory mechanism of Po-prdm1 expression. A 2000bp-long 5'-flanking region (translation initiation site designated as +1) of the Po-prdm1 gene was isolated and characterized. The regulatory elements in this fragment were then investigated and many putative transcription factor (TF) binding sites involved in immunity and multiple tissue development were identified. A 5'-deletion analysis was then conducted, and the ability of the deletion mutants to promote luciferase and green fluorescent protein (GFP) expression in a flounder gill cell line was examined. The results revealed that the minimal promoter is located in the region between -446 and -13bp, and the region between -1415 and -13bp enhanced the promoter activity. Site-directed mutation analysis was subsequently performed on the putative regulatory elements sites, and the results indicated that FOXP1, MSX and BCL6 binding sites play negative functional roles in the regulation of the Po prdm1 expression in FG cells. In vivo analysis demonstrated that a GFP reporter gene containing 1.4kb-long promoter fragment (-1415/-13) was expressed in the head and trunk muscle fibres of transient transgenic zebrafish embryos. Our study provided the basic information for the exploration of Po-prdm1 regulation and expression. PMID- 28669664 TI - MAPK signaling pathways in eye wounds: Multifunction and cooperation. AB - As is widely distributed in eukaryotic cells, the mitogen-activated protein kinase (MAPK) signaling pathway family plays an inevitable role in diverse cellular processes, being capable of responding to particular physiological reactions induced by multiple extracellular signals or stimuli, such as protean concentrations, ischemia/reperfusion, and inflammation. The physiological reactions mediated by the MAPK signaling pathway contribute to the progression and healing of eye wounds. Meanwhile, several pathways in the MAPK family can cooperate with each other and establish distinct responses to different, or even the same, stimuli and, thus, more attention may be paid to the pathway in future research. PMID- 28669663 TI - 1,25(OH)2 vitamin D(3) contributes to osteoclast-like trans-differentiation of malignant plasma cells. AB - 1,25-dihydroxyvitamin D (1,25(OH)2D) exerts pleiotropic effects including bone turnover and immune system regulation. It inhibits both T and B cell proliferation while decreasing the secretion of inflammatory cytokines and immunoglobulins. 1,25(OH)2D also modulates monocyte-macrophage and osteoclast (OC) maturation. Since we have previously described that malignant plasma cells may trans-differentiate towards the myeloid lineage participating to skeletal devastation in multiple myeloma (MM), we here evaluated in vitro the role of 1,25(OH)2D in this lineage switch. We investigated the gene and protein expression of vitamin D receptor (VDR) in MM cell lines. Thus, after cell treatment with 1,25(OH)2D, we analyzed their morphology and the expression of myeloid and OC markers. Finally, we assessed their bone resorption property on calcium phosphate slices. All MM cells expressed VDR in nuclear and perinuclear sites. Treatment with 1,25(OH)2D altered their morphology from round to fusiform, while inducing paxillin focalization. 1,25(OH)2D administration also up-regulated myeloid and OC genes, including C/EBPalpha, RANK, M-CSFR and V-ATPase, whose promoters contain potential 1,25(OH)2D responsive elements. Finally, 1,25(OH)2D increased MM cell capability to generate pits of erosion on calcium phosphate discs. This data suggest that myeloma cells may undergo a functional trans differentiation into OCs and, under appropriate experimental conditions, 1,25(OH)2D triggers this lineage switch. PMID- 28669665 TI - The FADIR test accuracy for screening cam and pincer morphology in youth ice hockey players. AB - OBJECTIVES: Aim of this study was to evaluate the flexion-adduction-internal rotation (FADIR) test accuracy for screening cam and pincer morphology in youth male ice hockey players without diagnosed hip disorders. DESIGN: Cross-sectional study. METHODS: Seventy-four ice hockey players with a mean age of 16 years (range: 13-20 years) were assessed unilaterally. The presence of cam and pincer morphology was evaluated using the FADIR test and magnetic resonance imaging (MRI) (reference standard). Positive FADIR test consisted of groin pain during the maneuver, while positive MRI findings consisted of (1) pure cam, pure pincer or combined morphology and acetabular labral alterations, or (2) pure cam or combined morphology and acetabular labral alterations. Sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values were calculated. RESULTS: For pure cam, pure pincer or combined morphology as positive MRI findings, the FADIR test demonstrated a sensitivity of 41%, specificity of 47%, positive likelihood ratio of 0.78, negative likelihood ratio of 1.24, positive predictive value of 19% and negative predictive value of 73%. For pure cam or combined morphology as positive MRI findings, the FADIR test showed a sensitivity of 60%, specificity of 52%, positive likelihood ratio of 1.24, negative likelihood ratio of 0.78, positive predictive value of 16% and negative predictive value of 89%. CONCLUSIONS: The FADIR test is inadequate for screening cam and pincer morphology in youth ice hockey players without diagnosed hip disorders because of the large number of false positive test outcomes. PMID- 28669666 TI - A randomized controlled trial on the efficacy of resistant dextrin, as functional food, in women with type 2 diabetes: Targeting the hypothalamic-pituitary-adrenal axis and immune system. AB - OBJECTIVE: The aim of this trial was to determine the efficacy of a resistant dextrin on immune-mediated inflammation and hypothalamic-pituitary-adrenal axis in women with type 2 diabetes mellitus (T2DM). METHODS: Females (n = 55) with T2DM were randomly allocated into intervention group (n = 30) and control group (n = 25), in which they received 10 g/d of Nutriose(r)06 (a resistant dextrin) or maltodextrin for 8 weeks, respectively. Fasting blood samples were taken to measure immune system related parameters like white blood cell count, CD4, CD8, interferon-gamma (IFNgamma), interleukins (IL12, IL4, IL10), cortisol, tryptophan (TRP), ACTH (Adrenocorticotropic hormone), Kynurenine (KYN) and plasma lipopolysaccharide (LPS) at the beginning and end of trial. Mental health was assessed using general health questionnaire (GHQ) and depression, anxiety and stress scale (DASS). RESULTS: Resistant dextrin caused a significant decrease in levels of cortisol, KYN, KYN/TRP ratio, IFNgamma, IL12, IFNgamma/IL10 ratio, LPS, and a significant increase in the monocyte, GHQ, DASS, CD8, IL10, IL4 in the intervention group as compared with baseline. A significant decrease in the level of LPS (-6.20 EU/mL, -17.8%), IFNgamma (-0.6 pg/ml, -26.8%), cortisol (-2.6 MUg/dl, -20.9%), IFNgamma/IL10 ratio (0.01, 10%), GHQ (-5.1, -12.5%), DASS ( 10.4, -38.4%), KYN/TRP ratio (6.8, 29.1%), and a significant increase in levels of CD8 (6.4%, 6.1%) and IL10 (2.6 pg/ml, 21.6%) in the intervention group as compared with the control group (P < 0.05). No significant changes were observed in white blood cell count, CD4, CD4/CD8 ratio, ACTH, KYN, TRP, IL4 and IL12 in the intervention group as compared with the control group (P > 0.05). CONCLUSION: Supplementation of Nutriose(r)06 may have beneficial effects on mental health and the immune system response in women with T2DM. PMID- 28669667 TI - Transhepatic bile acid kinetics in pigs and humans. AB - BACKGROUND & AIMS: Bile acids (BAs) play a key role in lipid uptake and metabolic signalling in different organs including gut, liver, muscle and brown adipose tissue. Portal and peripheral plasma BA concentrations increase after a meal. However, the exact kinetics of postprandial BA metabolism have never been described in great detail. We used a conscious porcine model to investigate postprandial plasma concentrations and transorgan fluxes of BAs, glucose and insulin using the para-aminohippuric acid dilution method. METHODS: Eleven pigs with intravascular catheters received a standard mixed-meal while blood was sampled from different veins such as the portal vein, abdominal aorta and hepatic vein. To translate the data to humans, fasted venous and portal blood was sampled from non-diabetic obese patients during gastric by-pass surgery. RESULTS: The majority of the plasma bile acid pool and postprandial response consisted of glycine-conjugated forms of primary bile acids. Conjugated bile acids were more efficiently cleared by the liver than unconjugated forms. The timing and size of the postprandial response showed large interindividual variability for bile acids compared to glucose and insulin. CONCLUSIONS: The liver selectively extracts most BAs and BAs with highest affinity for the most important metabolic BA receptor, TGR5, are typically low in both porcine and human peripheral circulation. Our findings raise questions about the magnitude of a peripheral TGR5 signal and its ultimate clinical application. PMID- 28669668 TI - Orosensory detection of bitter in fat-taster healthy and obese participants: Genetic polymorphism of CD36 and TAS2R38. AB - BACKGROUND & AIMS: We assessed orosensory detection of a long-chain fatty acid, linoleic acid (LA), and a bitter taste marker, 6-n-propylthiouracil (PROP), and correlated lipid-taster subjects with PROP detection and polymorphism in genes encoding bitter and lipid taste receptors, respectively, TAS2R38 and CD36, in normal weight and obese subjects. DESIGN: The normal weight (n = 52, age = 35.3 +/- 4.10 years, BMI = 23.22 +/- 1.44 kg/m2) and obese (n = 52, age = 35.0 +/- 5.43 years, BMI = 34.29 +/- 5.31 kg/m2) participants were recruited to determine fat and bitter detection thresholds. The genomic DNA was used to determine single nucleotide polymorphism (SNP) of CD36 (rs1761667) and TAS2R38 (rs1726866 and rs10246939). RESULTS: The study included the participants who could detect LA, i.e., lipid-tasters. There was a positive correlation between BMI and detection thresholds for fat and bitter taste in normal weight and obese subjects. Obese participants showed a positive correlation between LA and PROP detection thresholds. PROP detection thresholds were higher for CD36 SNP (rs1761667) and TAS2R38 SNPs (rs1726866 and rs10246939) in obese participants compared to normal weight subjects. LA detection thresholds were not high for CD36 SNP (rs1761667) or TAS2R38 SNP (rs1726866 and rs10246939) in obese participants. CONCLUSIONS: Orosensory detection thresholds for fat and bitter taste are associated with BMI, and CD36 and TAS2R38 genotypes are not always associated with taste phenotypes. PMID- 28669669 TI - Should we recommend reductions in saturated fat intake or in red/processed meat consumption? The SUN prospective cohort study. AB - BACKGROUND & AIMS: While most studies have shown increased mortality associated with excessive red/processed meat consumption, the association of saturated fatty acids (SFA) intake with mortality is less homogeneous. We aimed to prospectively assess the association of both, meat consumption (red, processed, red + processed, and total) and SFA intake, with the risk of all-cause death. METHODS: We assessed 18,540 participants of the SUN (Seguimiento Universidad de Navarra) cohort, followed-up for a mean of 9.5 years. A validated 136-item FFQ was administered at baseline. We used Cox models adjusted for potential confounders. RESULTS: We observed 255 deaths during 176,916 person-years of follow-up. Age modified the association between meat consumption and all-cause mortality (p for interaction = 0.027, 0.075, and 0.013, for red, total, and processed meat, respectively). Among participants aged >45 years the fully-adjusted HRs (95% CIs) for one additional serving/d of red, total, and red + processed meat consumption were 1.47 (1.06, 2.04), 1.23 (1.05, 1.45), and 1.32 (1.05, 1.65), respectively, with significant linear trends (P for trend 0.022, 0.012, and 0.018, respectively). In these participants, SFA intake was non-significantly associated with mortality. However, isocaloric replacement of monounsaturated fat or carbohydrates by SFA resulted in significantly higher mortality risk. Likewise, replacing 100 g of vegetables, fruits & nuts or cereals by 100 g of red meat resulted in higher mortality risk. No association of meat consumption or SFA with all-cause mortality was observed in participants younger than 46 years. CONCLUSIONS: Among highly educated persons, aged >45 years, a high consumption of red, total, and red + processed meat was related to increased all-cause mortality, compared with those with low consumption, whereas no significant associations were found for SFA intake. Dietary guidelines should specifically limit meat consumption and not relying only in limiting SFA intake. PMID- 28669670 TI - Structural adaptations and mechanism of reflex bleeding in the larvae of the myrmecophilous ladybird Diomus thoracicus. AB - Reflex bleeding is an effective defensive mechanism against predators. When attacked, some insects emit hemolymph, which coagulates, quickly entangling their aggressor. Bleeding occurs at weak intersegmental membranes or through dedicated organs, which can be associated or not with glandular cells. Here, we describe the behavior and morphological structures involved in reflex bleeding in the larvae of the ladybird, Diomus thoracicus, which are intranidal parasites of the ant Wasmannia auropunctata. The larvae are tolerated by the ants thanks to odor mimicry, but some rare aggressive ant behaviors were observed that trigger reflex bleeding both at a pair of thoracic tubercles and a pair of posterodorsal abdominal humps. No glandular structure was found in association with these emission points, which suggests that the material emitted was hemolymph only. A 3D reconstruction suggested that reflex bleeding seems to be controlled by muscles whose contraction increases the internal hydrostatic pressure and pushes the hemolymph into a funnel-like structure with an opening to the outside. In D. thoracicus, the morphological structures involved in reflex bleeding are among the most complex and prominent described to date. PMID- 28669671 TI - Viral Replication Complexes Are Targeted by LC3-Guided Interferon-Inducible GTPases. AB - All viruses with positive-sense RNA genomes replicate on membranous structures in the cytoplasm called replication complexes (RCs). RCs provide an advantageous microenvironment for viral replication, but it is unknown how the host immune system counteracts these structures. Here we show that interferon-gamma (IFNG) disrupts the RC of murine norovirus (MNV) via evolutionarily conserved autophagy proteins and the induction of IFN-inducible GTPases, which are known to destroy the membrane of vacuoles containing bacteria, protists, or fungi. The MNV RC was marked by the microtubule-associated-protein-1-light-chain-3 (LC3) conjugation system of autophagy and then targeted by immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs) upon their induction by IFNG. Further, the LC3 conjugation system and the IFN-inducible GTPases were necessary to inhibit MNV replication in mice and human cells. These data suggest that viral RCs can be marked and antagonized by a universal immune defense mechanism targeting diverse pathogens replicating in cytosolic membrane structures. PMID- 28669673 TI - Investigation of pre-XDR Beijing Mycobacterium tuberculosis transmission to a healthcare worker in France, 2016. AB - A case of occupational contamination of a healthcare worker by a pre-extensively drug-resistant (pre-XDR) Beijing strain of Mycobacterium tuberculosis at the University Hospital of Montpellier, France is reported. The index case was identified using genetic fingerprinting of isolates. This report underscores the risk of healthcare-associated contamination by pre-XDR tuberculosis (TB) in low incidence countries and the importance of molecular tools for TB care. It also calls for increased vigilance in the management of multi-drug-resistant/XDR TB patients. PMID- 28669674 TI - Verification of the Cepheid Xpert Carba-R assay for the detection of carbapenemase genes in bacterial isolates cultured on alternative solid culture media. AB - The Xpert Carba-R (Cepheid) is a polymerase chain reaction (PCR) assay for detection and differentiation of five common carbapenemase genes. If used according to manufacturer's instructions, bacterial isolates tested must be cultured on blood or MacConkey agar. This study confirms that the assay performs well against a diverse panel of bacterial isolates with known carbapenemase genes. It also demonstrates that the assay performs well using three solid agar culture media that have not been recommended by the PCR assay's manufacturer: CLED (cystine-, lactose-, and electrolyte-deficient), ChromID CARBA-SMART, and a nutrient slope. By testing isolates directly from any of these media, delays in laboratory reporting can be avoided. PMID- 28669672 TI - Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation. AB - Skin microbiota can impact allergic and autoimmune responses, wound healing, and anti-microbial defense. We investigated the role of skin microbiota in cutaneous leishmaniasis and found that human patients infected with Leishmania braziliensis develop dysbiotic skin microbiota, characterized by increases in the abundance of Staphylococcus and/or Streptococcus. Mice infected with L. major exhibit similar changes depending upon disease severity. Importantly, this dysbiosis is not limited to the lesion site, but is transmissible to normal skin distant from the infection site and to skin from co-housed naive mice. This observation allowed us to test whether a pre-existing dysbiotic skin microbiota influences disease, and we found that challenging dysbiotic naive mice with L. major or testing for contact hypersensitivity results in exacerbated skin inflammatory responses. These findings demonstrate that a dysbiotic skin microbiota is not only a consequence of tissue stress, but also enhances inflammation, which has implications for many inflammatory cutaneous diseases. PMID- 28669675 TI - Timely publishing of experiences and sharing of knowledge. PMID- 28669676 TI - Evaluation of the bactericidal activity of Telavancin against Staphylococcus aureus using revised testing guidelines. AB - The in vitro broth microdilution testing method for telavancin, a lipoglycopeptide active against S. aureus, was revised in 2014 to include polysorbate-80 in the test media. This study evaluates the bactericidal activity of telavancin against S. aureus in media containing polysorbate-80 by in vitro time-kill analysis alongside relevant comparators. PMID- 28669677 TI - Detection of blaVIM-7 in an extensively drug-resistant Pseudomonas aeruginosa isolate belonging to ST1284 in Brazil. AB - We described for the first time an extensively drug-resistant Pseudomonas aeruginosa isolate belonging to ST1284 carrying a plasmid-mediated blaVIM-7 in Brazil. The blaVIM-7 was harbored by an integron that also carried aacA4 and blaOXA-46. Multiple virulence factors were also detected. PMID- 28669678 TI - Virulence and antifungal therapy of murine disseminated infection by Rhodotorula mucilaginosa. AB - Rhodotorula infections have emerged in recent years causing mainly fungemia associated to high mortality. We have evaluated the in vitro activity of nine antifungal drugs against four clinical strains of Rhodotorula mucilaginosa, being amphotericin B, voriconazole and posaconazole the most active compounds. The experimental virulence of this fungus and the efficacy of the three mentioned drugs were evaluated in disseminated infections in neutropenic mice. Infection resulted in a high fungal load in all the organs studied without evident particular tropism. All treated animals showed reduced burden respect to the control in a strain dependent manner being voriconazole slightly superior to posaconazole and amphotericin B. PMID- 28669679 TI - A novel one-step real-time multiplex PCR assay to detect Streptococcus agalactiae presence and serotypes Ia, Ib, and III. AB - Streptococcus agalactiae is the leading cause of early-onset neonatal sepsis. Culture-based screening methods lack the sensitivity of molecular assays and do not indicate serotype; a potentially important virulence marker. We aimed to develop a multiplex PCR to detect S. agalactiae while simultaneously identifying serotypes Ia, Ib, and III; commonly associated with infant disease. Primers were designed to target S. agalactiae serotype-specific cps genes and the dltS gene. The assay was validated with 512 vaginal specimens from pregnant women. 112 (21.9%) were dltS positive, with 14.3%, 0.9%, and 6.3% of these identified as cps Ia, Ib, and III, respectively. Our assay is a specific and sensitive method to simultaneously detect S. agalactiae and serotypes Ia, Ib, and III in a single step. It is of high significance for clinical diagnostic applications and also provides epidemiological data on serotype, information that may be important for vaccine development and other targeted non-antibiotic therapies. PMID- 28669680 TI - Hepatitis C virus core antigen in the management of patients treated with new direct-acting antivirals. AB - We evaluated the utility of Architect core antigen assay(r) Abbott Diagnostics (HCVAg) for monitoring patients with HCV infection and compared to HCV-RNA quantification (Cobas Ampliprep TaqMan-Roche Diagnostics). Samples from 262 patients were studied. Mean baseline HCV RNA and HCVAg levels were similar for responders (6.2 log IU/mL and 3.4 log fmol/L) and non-responders (6.1 log IU/mL and 3.2 log fmol/L), respectively. Only 10 patients failed to achieve SVR12 and all were detected by both assays. To evaluate HCVAg quantification as a tool for the detection of failure to DAAs, we performed a retrospective study of 132 non responder patients. Mean HCV RNA and HCVAg levels at the time of detection of therapeutic failure were 5.88+/-0.97 log IU/mL and 3.19+/-0.79 log fmol/L, respectively. HCVAg (>3 fmol/L) was detected in 130/132 patients (98.5%). HCVAg assay was useful for patient selection and for evaluating virological response to DAAs in the real world. PMID- 28669681 TI - Factors contributing to vancomycin-resistant Enterococcus spp. horizontal transmission events: exploration of the role of antibacterial consumption. AB - BACKGROUND: The relationship between antibiotic consumption and resistance is relatively well defined at the population/ecologic level. Increases in antimicrobial consumption correlate with increased antibiotic resistance for clinical and surveillance isolates. However, the impact of antimicrobial consumption on nosocomial transmission of resistant bacteria is less well defined. This study explores the association between antimicrobial consumption, hand hygiene, and horizontal resistant organism transmission. METHODS: A retrospective cohort pilot study was conducted. Vancomycin-resistant Enterococcus spp. (VRE) horizontal transmission events during a 2-year period were identified. VRE transmission events were defined as isolation of genetically similar VRE strain-types (determined using pulsed field gel electrophoresis) from patients who were temporally and geographically co-localized within our hospital. The Centers for Disease Control and Prevention Antimicrobial Use and Resistance Module was utilized to collect antibacterial consumption data of commonly utilized agents. Hand hygiene was quantified using floor-by-floor peer audit data. Regression techniques were employed to assess population-level relationships between study variables and transmission events. RESULTS: One hundred nineteen transmission events were identified. Hand hygiene estimates were homogeneous and did not correlate with VRE transmission rates. Stepwise multivariate linear regression revealed that aztreonam consumption was associated with a lower rate of transmissions in the medical intensive care unit (P=0.031), and carbapenem consumption was associated with a higher rate of VRE transmission events on one of two oncology floors (P=0.033). DISCUSSION/CONCLUSION: Consumption of aztreonam and carbapenems was associated with VRE horizontal transmission rates. Further studies are necessary to identify other associations and elucidate the full clinical significance of this finding. PMID- 28669682 TI - Differential expression pattern of key regulatory developmental genes in pre implant zona free cloned vs in vitro fertilized goat embryos. AB - The success of Somatic cell nuclear transfer (SCNT) primarily depends on the extent of reprogramming of donor cells genome. The error of reprogramming may lead to inappropriate expression of embryonic genes at any stage of development. Under the present study the relative expression of different genes related to pluripotency (Oct-4 and Nanog), growth factors (IGF-2 and IGF-2R) and DNA methyltransferase gene (Dnmt-1) was evaluated in SCNT embryos at 8-16 cells, morula and blastocyst stages as compared to IVF group. In SCNT, significantly higher degree of relative expression was observed for Oct-4 in morula (1.41) and blastocysts (1.14) as compared to 8-16 cells (referral stage) whereas in IVF, a lower expression was observed at morula (0.82) stage. The expression of Nanog in SCNT embryos was increased significantly in morula (2.23) and decreased subsequently in blastocyst (0.56), whereas it was increased significantly from 8 to 16 cells to morula (1.62) and blastocyst (4.5) of IVF group. The IGF-2 and IGF 2R showed significantly higher expression rates in morula and blastocysts of SCNT (6.56, 5.90 and 1.11, 1.4) and IVF (8.69, 8.25 and 2.96, 3.91) embryos, respectively as compared to referral stage. The expression of Dnmt-1 was significantly higher in SCNT morula (1.29) and blastocyst (1.15) however in IVF, it was similar in 8-16 cells stage and morula but, higher in blastocyst (1.58). The dissimilar pattern of gene expression of SCNT might be a consequence of incomplete reprogramming of donor nucleus which resulted into lower blastocyst rate of SCNT as compared to IVF embryos. PMID- 28669683 TI - Effects of interferon tau on endometrial epithelial cells in caprine in vitro. AB - Embryo attachment, a precondition of ruminant pregnancy, has been recognized to be related to apoptosis in endometrial epithelial cells (EECs). In ruminants, interferon tau (IFNT) is secreted by trophoblast of conceptus and works in a concentration-dependent style. To verify the function of IFNT in caprine embryo attachment, caprine EECs were dealt with IFNT at 0, 1, 10 and 100 ng/ml. In this study, IFNT arrested caprine EEC cell cycle in G2 phase and induced cell apoptosis at 1 ng/ml and 10 ng/ml of IFNT. Interestingly, pro-apoptotic protein FAS and PRbeta together with anti-apoptotic proteins SP1 and IGF1R were all up regulated at 1 ng/ml of IFNT. It demonstrated that IFNT at 1 ng/ml might induce caprine EEC apoptosis and keep a balance between apoptosis and proliferation. Furthermore, regulation of HOXA10, COX-2, PRL, PTEN and STAT3 pathway in caprine EECs was likely to be contributed by IFNT at 1 ng/ml to improve the chances for embryo attachment. PMID- 28669684 TI - Urinary metabolomic analysis of intrahepatic cholestasis of pregnancy based on high performance liquid chromatography/mass spectrometry. AB - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP), a pregnancy-related liver disease, leads to complications for both mothers and fetuses. Metabolomic approach has been applied to maternal-fetal medicine. The global metabolomic alterations that are specific in ICP as yet have not been investigated. METHODS: Based on high performance liquid chromatography/hybrid quadrupole time-of-flight (HPLC/Q-TOF) mass spectrometry, the untargeted metabolomics was used to analyze the changes of urinary metabolites between ICP group and the control group. RESULTS: One hundred nine variables in positive model and 119 variables in negative model were significantly different (p<0.05) between the ICP group and the control group, with the VIP (variable importance in the project) score>1 by the orthogonal partial least squares discriminant analysis (OPLS-DA). 14 metabolites in positive model and 18 metabolites in negative model were selected and identified based on HMDB (human metabolome database). Most of these metabolites were involved in bile acids biosynthesis and metabolism, hormone metabolism and lipid metabolism. A metabolite panel (MG (22:5), LysoPE (22:5), l homocysteine sulfonic acid, glycocholic acid and chenodeoxycholic acid 3-sulfate) was contrusted by the binary logistic regression analysis with high diagnostic accuracy for ICP. The area under the receiver operating characteristic curve was 0.988 with the sensitivity of 90.0% and specificity of 93.3%. CONCLUSIONS: Urinary metabolites allow for the discrimination of ICP from the controls by orthogonal partial least squares discriminant analysis. Therefore, these findings may provide deep insights for the etiopathogenesis of ICP. Moreover, the maternal urinary metabolite panel has the potential to be used as non-invasive biomarkers for the diagnosis of ICP. PMID- 28669685 TI - Association of serum lipid levels over time with survival in incident peritoneal dialysis patients. AB - BACKGROUND: The association of dyslipidemia with mortality has not been fully evaluated in patients on peritoneal dialysis (PD). Moreover, changes in lipids levels over time and associated death risk have not yet been studied in this population. OBJECTIVE: We studied the association of time-updated serum lipid concentrations with all-cause and cardiovascular (CV) mortalities in a 10-year cohort of 749 incident PD patients. METHODS: Association was assessed using time varying Cox proportional hazard regression models with adjustment for multiple variables including statin therapy. RESULTS: During a median follow-up of 36 (interquartile range, 21-61) months, 273 all-cause and 107 CV deaths occurred. Compared with those with total cholesterol (TC) of 180 to <210 or low-density lipoprotein cholesterol (LDL-C) of 100 to <130 mg/dL, hazard ratios (95% confidence interval) of the lowest TC (<150 mg/dL) and LDL-C (<70 mg/dL) were 2.32 (1.61-3.35) and 2.02 (1.45-2.83) for all-cause mortality and 1.87 (1.04 3.37) and 1.92 (1.13-3.26) for CV mortality, respectively. Lower triglyceride (<100 mg/dL) and high-density lipoprotein cholesterol (<30 mg/dL) levels were associated with higher all-cause mortality (1.66 [1.11-2.47] and 1.57 [1.08 2.29]) but not with CV mortality. CONCLUSIONS: Contrary to the general population, lower TC and LDL-C levels over time were significantly associated with both worse survival and increased CV mortality in incident PD patients. Although lower triglyceride and high-density lipoprotein cholesterol concentrations were associated with significantly higher all-cause mortality, they failed to show any clear association with CV mortality. The underlying mechanisms responsible for this apparent paradox await further investigations. PMID- 28669686 TI - Pharmacologic approaches for the management of patients with moderately elevated triglycerides (150-499 mg/dL). AB - Hypertriglyceridemia, defined as serum triglyceride (TG) levels >150 mg/dL, now affects over one-quarter of the US adult population and is associated with an increased risk of atherosclerotic cardiovascular disease. Available guidelines for managing hypertriglyceridemia vary with respect to TG thresholds and severity of disease. Lifestyle modifications and management of secondary causes (eg, diabetes) remain the first step in managing hypertriglyceridemia, with pharmacotherapy reserved to reduce the risk of pancreatitis and/or further reduce TG levels. Several classes of lipid-lowering agents are available with variable TG-lowering efficacy. Although there is no consensus regarding the choice of initial TG-lowering pharmacotherapy, there is general agreement that the decision depends on the degree of hypertriglyceridemia and atherosclerotic cardiovascular disease risk. This review will discuss available and emerging lipid-lowering therapies for the management of moderately elevated TG, defined as TG 150 to 499 mg/dL. PMID- 28669687 TI - Blood lipids profile and lung cancer risk in a meta-analysis of prospective cohort studies. AB - BACKGROUND: Emerging evidence has connected lipid metabolism disturbance with lung diseases, but the relationship between blood lipid profile and lung cancer risk is controversial and inconclusive. OBJECTIVE: We conducted a meta-analysis of prospective cohort studies to evaluate the relationship between blood lipids profile and lung cancer incidence. METHODS: Relevant studies were identified by searching PubMed, Cochrane Library, Web of Science, EBSCO, Ovid, CNKI, VIP, and WANGFANG MED through August 2016. Nine prospective cohort studies were included in the meta-analysis, and fixed or random effects model was used to calculate pooled relative risk (RRs). The RR was calculated using either highest vs lowest categories, or upper quantile vs lowest quantile. The thresholds were determined by the authors of each original publication, based on either predefined cut-offs or the distributions within their study population. RESULTS: Analysis of 18,111 lung cancer cases among 1,832,880 participants showed that serum total cholesterol levels were inverse associated with lung cancer risk (RR = 0.93, 95% confidence interval [CI]: 0.85-1.03). Further analysis considered the lag time and excluded the effects of preclinical cancer, with totally 1,239,948 participants and 14,052 lung cancer cases, found a significantly inverse association between total cholesterol and lung cancer risk (RR = 0.89, 95% CI: 0.83-0.94). Analysis of 3067 lung cancer cases among 59,242 participants found that the high-density lipoprotein cholesterol levels (RR = 0.76, 95% CI: 0.59 0.97) was negatively associated with lung cancer risk and 4673 lung cancer cases among 685,852 participants showed that the total triglyceride (RR = 1.68, 95% CI: 1.44-1.96) was positively associated with lung cancer risk. CONCLUSION: Cholesterol and fatty acid metabolism might present different and specific mechanism on lung cancer etiology and needs further elucidation. PMID- 28669688 TI - Effect of an upstream bulge configuration on film cooling with and without mist injection. AB - To meet the economic requirements of power output, the increased inlet temperature of modern gas turbines is above the melting point of the material. Therefore, high-efficient cooling technology is needed to protect the blades from the hot mainstream. In this study, film cooling was investigated in a simplified channel. A bulge located upstream of the film hole was numerically investigated by analysis of the film cooling effectiveness distribution downstream of the wall. The flow distribution in the plate channel is first presented. Comparing with a case without bulge, different cases with bulge heights of 0.1d, 0.3d and 0.5d were examined with blowing ratios of 0.5 and 1.0. Cases with 1% mist injection were also included in order to obtain better cooling performance. Results show that the bulge configuration located upstream the film hole makes the cooling film more uniform, and enhanceslateral cooling effectiveness. Unlike other cases, the configuration with a 0.3d-height bulge shows a good balance in improving the downstream and lateral cooling effectiveness. Compared with the case without mist at M = 0.5, the 0.3d-height bulge with 1% mist injection increases lateral average effectiveness by 559% at x/d = 55. In addition, a reduction of the thermal stress concentration can be obtained by increasing the height of the bulge configuration. PMID- 28669689 TI - Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Substances that potentially enhance performance (eg, recombinant human erythropoietin [rHuEPO]) are considered doping and are therefore forbidden in sports; however, the scientific evidence behind doping is frequently weak. We aimed to determine the effects of rHuEPO treatment in well trained cyclists on maximal, submaximal, and race performance and on safety, and to present a model clinical study for doping research on other substances. METHODS: We did this double-blind, randomised, placebo-controlled trial at the Centre for Human Drug Research in Leiden (Netherlands). We enrolled healthy, well trained but non professional male cyclists aged 18-50 years and randomly allocated (1:1) them to receive abdominal subcutaneous injections of rHuEPO (epoetin beta; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Randomisation was stratified by age groups (18-34 years and 35-50 years), with a code generated by a statistician who was not masked to the study. The primary outcome was exercise performance, measured as maximal power output (Pmax), maximal oxygen consumption VO2 max, and gross efficiency in maximal exercise tests with 25 W increments per 5 min, as lactate threshold and ventilatory threshold 1 (VT1) and 2 (VT2) at submaximal levels during the maximal exercise test, and as mean power, VO2, and heart rate in the submaximal exercise tests at the highest mean power output for 45 min in a laboratory setting and in a race to the Mont Ventoux (France) summit, using intention-to-treat analyses. The trial is registered with the Dutch Trial Registry (Nederlands Trial Register), number NTR5643. FINDINGS: Between March 7, 2016, and April 13, 2016, we randomly assigned 48 participants to the rHuEPO group (n=24) or the placebo group (n=24). Mean haemoglobin concentration (9.6 mmol/L vs 9.0 mmol/L [estimated difference 0.6, 95% CI 0.4 to 0.8]) and maximal power output (351.55 W vs 341.23 W [10.32, 3.47 to 17.17]), and VO2 max (60.121 mL/min per kg vs 57.415 mL/min per kg [2.707, 0.911 to 4.503]) in a maximal exercise test were higher in the rHuEPO group compared with the placebo group. Submaximal exercise test parameters mean power output (283.18 W vs 277.28 W [5.90, -0.87 to 12.67]) and VO2 (50.288 mL/min per kg vs 49.642 mL/min per kg [0.646, -1.307 to 2.600]) at day 46, and Mont Ventoux race times (1 h 40 min 32 s vs 1 h 40 min 15 s [0.3%, -8.3 to 9.6]) did not differ between groups. All adverse events were grade 1-2 and were similar between both groups. No events of grade 3 or worse were observed. INTERPRETATION: Although rHuEPO treatment improved a laboratory test of maximal exercise, the more clinically relevant submaximal exercise test performance and road race performance were not affected. This study shows that clinical studies with doping substances can be done adequately and safely and are relevant in determining effects of alleged performance-enhancing drugs. FUNDING: Centre for Human Drug Research, Leiden. PMID- 28669690 TI - The relationship of CD34+ dosage and platelet recovery following high dose chemotherapy and autologous CD34+ reinfusion in multiple myeloma. AB - Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for multiple myeloma (MM), yet the impact of transplanted CD34+ cell dose remains unresolved, especially in patients over the age of 65 years. Data was collected from 207 consecutive ASCT patients to determine the relationship between CD34+ infusion count and short-term and long-term platelet recovery. For MM patients under the age of 65 years (n=155), CD34+ dosage correlates with time to platelet engraftment (p<0.001) and platelet count at 30 days (p=0.003), but not with long-term platelet counts at 180 or 360 days from the CD34+ reinfusion. For MM patients aged 65 years or older (n=46), CD34+ dosage did not correlate with time to platelet engraftment, but did correlate with both short-term and long-term platelet counts at 30 (p<0.001), 180 (p=0.021), and 360 days (p=0.005). Exploratory regression analysis was done to explore platelet stability following the current minimum CD34+ dosage reinfusion. For MM patients under the age of 65 years, the minimum standard CD34+ dosage of 2*106cells/kg was sufficient for a timing to platelet engraftment of <21 days and short-term platelets count >=150*109/L at 30 days. Alternatively, for MM patients aged 65 years or older, the CD34+ dosage of 2*106cells/kg was insufficient for platelet counts >=150*109/L at 30 and only marginally attainable at 360 days suggesting that in elderly MM patients a higher CD34+ dosage may be required for platelet recovery and possibly long-term platelet stability. PMID- 28669691 TI - Together We Inspire Smart Eating: A Preschool Curriculum for Obesity Prevention in Low-Income Families. PMID- 28669692 TI - Long-term follow-up indicates unimpaired oral health-related quality of life for people having shortened dental arches. AB - OBJECTIVES: To assess and analyse OHRQoL of people with shortened dental arches (SDA) in a long-term cohort study. METHODS: All participants of a long-term cohort study on SDA who were still attending the university dental clinic and still had an SDA (SDA group) with 3-5 posterior occluding pairs and intact anterior areas, an SDA plus removable dental prosthesis (SDA plus PRDP group) or complete dental arch (CDA group) completed the Dutch version of the Oral Health Impact Profile (OHIP-49NL) and additional questions on satisfaction with their dental status (yes/no). Mann-Whitney tests were performed for OHIP total scores and OHIP domain scores. The chance that the difference in median OHIP scores between the groups was larger than 6 OHIP units, was calculated by a bootstrapping procedure. RESULTS: 10 participants were eligible for SDA group and 11 for CDA group. The SDA plus PRDP group (n=1) was excluded from analyses. Mean follow-up period was 29.3+/-5.5 for SDA group and 36.7+/-5.5years for CDA group. Mean OHIP-49NL score was 13.9+/-10.9 for SDA group and 11.3+/-8.6 for CDA group. Differences in mean total scores and mean scores per domain were not statistically different. The probability that a difference in median OHIP total scores between groups was larger than 6 OHIP units was 0.25. Both groups showed high percentages of satisfaction with dental condition, except for dental appearance. CONCLUSION: OHRQoL of people with a long-term SDA condition was similar to that of people with CDA. CLINICAL SIGNIFICANCE: People having SDA for long periods are expected to report similar OHRQoL and satisfaction levels/oral comfort as people with CDA. PMID- 28669693 TI - Open Access: Concepts, findings, and recommendations for stakeholders in dentistry. AB - OBJECTIVES: Open Access (OA) to the scientific literature, a recent revolution in scientific communication, is now required by an increasing number of funders and institutions. The aims of this narrative review are to raise awareness of OA related concepts and recent research findings among stakeholders in dentistry and to help them make better use of OA and relevant resources. DATA SOURCES: Published journal articles and relevant online materials. STUDY SELECTION/RESULTS: OA-related definitions and research findings, the approaches to OA, as well as its motivating factors, benefits, 'citation advantage', and mandate policies are introduced. Moreover, the phenomenon of predatory publishing and the status quo of OA in dentistry are discussed. Recommendations are made for stakeholders to avoid and address the hazards of predatory publishing, and for dental researchers to make their work OA in an appropriate manner. CONCLUSIONS/CLINICAL SIGNIFICANCE: Knowledge about concepts on OA, associated resources and research findings are important for researchers and other users of dental research to make full, appropriate use of OA, and help reduce the avoidable waste caused by inaccessible research. We need more studies into the use and development of OA in dentistry. In addition, joint efforts are required to eliminate the threat of predatory publishing to the dental profession. PMID- 28669694 TI - Epidemiology of preoperative hematologic assessment of children cared for in a pediatric emergency department. AB - OBJECTIVE: To assess frequency of preoperative hematologic testing in a tertiary care pediatric emergency department (PED) and how often these values predict clinical outcome or change management decisions. METHODS: Single-center retrospective cohort study in a tertiary-care children's hospital PED. Patients 0 18years old, presenting between July 1, 2009-July 1, 2011, ultimately undergoing a surgical procedure within 48h of presentation were included. Patients were defined as having "preoperative" hematologic assessment if these studies were performed solely because the child was going to the operative suite. Patients who met trauma team activation criteria, underwent neurosurgical procedures, or had laboratory studies performed prior to PED arrival were excluded. The primary outcome was the prevalence of preoperative laboratory assessment. RESULTS: 528 children were included, of whom 301 (57%) underwent preoperative hematologic laboratory evaluations. Of these 301 patients, 115 (38%) had abnormal hematologic parameters, and only 3 (1%) of these patients had their perioperative management changed. One additional child had intraoperative bleeding that required blood products but did not undergo preoperative hematologic assessment. All four children had medical histories that would have identified their risk for perioperative bleeding events. CONCLUSION: Preoperative hematologic laboratory assessment occurs frequently in children initially cared for in a tertiary care pediatric emergency department who subsequently undergo operative interventions. Although age-based abnormal hematologic values are often found, rarely are these abnormalities clinically significant. This study suggests that children cared for in a PED without a history concerning for an increased risk of perioperative bleeding does not require preoperative hematologic assessment. PMID- 28669695 TI - Diagnostic accuracy of point-of-care ultrasound in detecting upper and lower extremity fractures: An evidence-based approach. PMID- 28669696 TI - Clevidipine versus sodium nitroprusside in acute aortic dissection: A retrospective chart review. AB - AIM: Intravenous vasodilators are often added to beta-blocking agents to reach blood pressure (BP) goals in aortic dissection. Control of BP using clevidipine has been described in hypertensive emergencies and cardiac surgery but not in aortic dissection. The aim of this study was to compare clevidipine versus sodium nitroprusside (SNP) as adjunct agents to esmolol for BP management in aortic dissection. METHODS: A single-center retrospective chart review evaluated patients diagnosed with aortic dissection. The primary outcome measure was time to reach patient specific systolic blood pressure (SBPPT) goals after initiation of esmolol infusion. Efficacy of clevidipine and SNP was assessed using area under the curve analysis of positive and negative excursions outside of SBPPT goals (AUCSBPe). Cost data was calculated using average wholesale price in U.S. dollars. RESULTS: Fourteen patients were included in final analyses. Median systolic BP immediately prior to initiation of esmolol was 162mm Hg vs 161mm Hg for clevidipine and SNP groups, respectively (p=0.99). Median time to reach SBPPT goal was similar between clevidipine and SNP (1.68 versus 1.03h [p=0.99]). Median AUCSBPe was similar for clevidipine and SNP (206.9 versus 538.9 mm Hg*min*hr-1 [p=0.11]). Cost was significantly reduced using clevidipine versus SNP ($1223.28/day versus $7674.24/day [p<0.001]). CONCLUSIONS: Clevidipine administration during initial medical management of aortic dissection showed similar efficacy compared to SNP when used as adjunct therapy to esmolol. These data suggest clevidipine is a less costly, reasonable alternative to SNP in acute aortic dissection as adjunct therapy to esmolol. Further studies are needed to validate these results. PMID- 28669697 TI - Transfemoral Lotus Valve Implantation for Treatment of Postendocarditis Stentless Prosthesis Degeneration With Pure Aortic Regurgitation. PMID- 28669698 TI - The Curious Incident of Spotty Calcium in Unstable Atherosclerotic Plaque. PMID- 28669699 TI - Coronary Revascularization in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - Concomitant coronary artery disease (CAD) is highly prevalent among patients with severe aortic stenosis (AS). Historically, surgical aortic valve replacement with coronary artery bypass grafting was the only treatment option for patients with severe AS and significant CAD. The rapid expansion of transcatheter aortic valve replacement has led to significant paradigm shifts in the treatment of severe AS and has raised new questions regarding the optimal management of CAD in these patients. We review the evidence regarding management of concomitant CAD in severe AS patients, specifically focusing on issues surrounding transcatheter aortic valve replacement. In the absence of robust evidence supporting specific treatment strategies, decisions regarding coronary revascularization in severe AS should be individualized and made within the context of a multidisciplinary heart team. PMID- 28669700 TI - Cuff Artifact, J Curve, and Application of Hypertension Guidelines in the Elderly. PMID- 28669701 TI - Comparative Evaluation of 2-Hour Rapid Diagnostic Algorithms for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin T. AB - BACKGROUND: Symptoms of acute coronary syndrome account for a large proportion of emergency department (ED) visits and hospitalizations. High-sensitivity troponin can rapidly rule out or rule in acute myocardial infarction (AMI) within a short time of ED arrival. We sought to validate test characteristics and classification performance of 2-hour high-sensitivity troponin T (hsTnT) algorithms for the rapid diagnosis of AMI. METHODS: We included consecutive patients from 4 academic EDs with suspected cardiac chest pain who had hsTnT assays performed 2 hours apart (+/- 30 minutes) as part of routine care. The primary outcome was AMI at 7 days. Secondary outcomes included major adverse cardiac events (mortality, AMI, and revascularization). Test characteristics and classification performance for multiple 2-hour algorithms were quantified. RESULTS: Seven hundred twenty-two patients met inclusion criteria. Seven-day AMI incidence was 10.9% and major adverse cardiac event incidence was 13.7%. A 2-hour rule-out algorithm proposed by Reichlin and colleagues ruled out AMI in 59.4% of patients with 98.7% sensitivity and 99.8% negative predictive value (NPV). The 2-hour rule-out algorithm proposed by the United Kingdom National Institute for Health and Care Excellence ruled out AMI in 50.3% of patients with similar sensitivity and NPV. Other exploratory algorithms had similar sensitivity but marginally better classification performance. According to Reichlin et al., the 2-hour rule-in algorithm ruled in AMI in 16.5% of patients with 92.4% specificity and 58.5% positive predictive value. CONCLUSIONS: Two-hour hsTnT algorithms can rule out AMI with very high sensitivity and NPV. The algorithm developed by Reichlin et al. had superior classification performance. Reichlin and colleagues' 2-hour rule in algorithm had poor positive predictive value and might not be suitable for early rule-in decision-making. PMID- 28669702 TI - Incidence and Prognostic Implications of Late Bleeding After Myocardial Infarction or Unstable Angina According to Treatment Strategy. AB - BACKGROUND: Bleeding complications accompanying coronary revascularization are associated with increased mortality; however, few data are available on subsequent bleeding risk. We used administrative data to assess the incidence of late bleeding events in patients with acute coronary syndrome (ACS) according to treatment allocation. METHODS: The cohort and bleeding events were identified through the Canadian Institute for Health Information discharge abstract database. Crude and adjusted odds ratios (ORs) were calculated for index and postindex admission bleeding up to 1 year after discharge. RESULTS: Of 31,941 patients hospitalized with ACS, 7681 (32.4%) patients were treated with medication alone, 3728 (15.2%) underwent angiography without intervention, and 13,075 (53.4%) underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The overall incidence of readmission with bleeding based on administrative codes was low (3.8% for medically treated patients, 2.8% for patients who underwent angiography alone, 2.6% for patients who underwent CABG, and 1.8% for patients who underwent PCI; P < 0.0001). Bleeding codes were mainly gastrointestinal bleeding (52%), but 7.8% were intracranial episodes of bleeding. Patients who received PCI had significantly lower odds of late bleeding compared with medically treated patients (OR, 0.76; 95% CI, 0.62-0.94). Late bleeding during the first year after ACS was associated with mortality (OR, 4.96; 95% CI, 2.47-9.93). CONCLUSIONS: Patients who underwent revascularization procedures had a relatively low risk for late bleeding events after a hospitalization for ACS. Late bleeding events were associated with an increased risk of death. PMID- 28669703 TI - Design and development of Unani anti-inflammatory cream. AB - Inflammation is the symptom of many diseases like rheumatoid arthritis and osteoarthritis. Many side effects are associated with the Non-Steroidal Anti inflammatory Drugs (NSAIDs) used as conventional treatment for these conditions. In Unani, there are large number of single and compound drugs for inflammatory conditions. One dosage form of Unani system of medicine is named as Zimad in which paste is formed by mixing powder in oil, water, herbal extract. Zimadat is prepared just before application and used in many disease conditions as resolving, styptic, astringent, and antiseptic. As the pre-application procedure is difficult and also complicated for patients, hence, the present study attempted to modify the form of Zimad into cream. Various batches of cream of Zimad Mohallil were prepared by using extracts of the formulation and by adding additives. Various physicochemical parameters of prepared cream were carried and compared with market cream. The optimized cream of Zimad Mohallil (F4) was selected after preliminary tests and evaluated further. The optimized cream showed good results in physicochemical parameters equivalent to market sample. Zimad Mohallil was converted into convenient cream form by adding minimum additives and benefits could be achieved without any hassle and cumbersome work, which is encountered in crude or paste form. The optimized cream was equivalent to standard market cream. PMID- 28669704 TI - Low Pressure Robot-assisted Radical Prostatectomy With the AirSeal System at OLV Hospital: Results From a Prospective Study. AB - BACKGROUND: Limited studies examined effects of pneumoperiotneum during robot assisted radical prostatectomy (RARP) and with AirSeal. The aim of this study was to assess the effect on hemodynamics of a lower pressure pneumoperitoneum (8 mmHg) with AirSeal, during RARP in steep Trendelenburg 45 degrees (ST). MATERIALS AND METHODS: This is an institutional review board-approved, prospective, interventional, single-center study including patients treated with RARP at OLV Hospital by one extremely experienced surgeon (July 2015-February 2016). Intraoperative monitoring included: arterial pressure, central venous pressure, cardiac output, heart rate, stroke volume, systemic vascular resistance, intrathoracic pressure, airways pressures, left ventricular end diastolic and end-systolic areas/volumes and ejection fraction, by transesophageal echocardiography, an esophageal catheter, and FloTrac/Vigileo system. Measurements were performed after induction of anesthesia with patient in horizontal (T0), 5 minutes after 8 mmHg pneumoperitoneum (TP), 5 minutes after ST (TT1) and every 30 minutes thereafter until the end of surgery (TH). Parameters modification at the prespecified times was assessed by Wilcoxon and Friedman tests, as appropriate. All analyses were performed by SPSS v. 23.0. RESULTS: A total of 53 consecutive patients were enrolled. The mean patients age was 62.6 +/ 6.9 years. Comorbidity was relatively limited (51% with Charlson Comorbidity Index as low as 0). Despite the ST, working always at 8 mmHg with AirSeal, only central venous pressure and mean airways pressure showed a statistically significant variation during the operative time. Although other significant hemodynamic/respiratory changes were observed adding pneumoperitoneum and then ST, all variables remained always within limits safely manageable by anesthesiologists. CONCLUSION: The combination of ST, lower pressure pneumoperitoneum and extreme surgeon's experience enables to safely perform RARP. PMID- 28669705 TI - Incubation of cue-induced reinstatement of cocaine, but not sucrose, seeking in C57BL/6J mice. AB - Prior studies have shown that drug-seeking behaviors increase, rather than dissipate, over weeks to months after withdrawal from drug self-administration. This phenomenon - termed incubation - suggests that drug-craving responses elicited by conditioned environmental or discrete cues may intensify over pronged abstinence. While most of this work is conducted in rats with intravenous drug self-administration models, there is less evidence for incubation in mice that have greater utility for molecular genetic analysis and perturbation. We tested whether incubation of cocaine-seeking behavior is evident in C57BL/6J mice following 3weeks (5days/week) of cocaine self-administration in 2h self administration sessions. We compared cocaine-seeking (drug-paired lever) responses 1, 7, or 28days after withdrawal from cocaine self-administration, and over similar times following sucrose pellet self-administration. We found that the initial re-exposure to the self-administration test chambers elicited increased reward-seeking behavior in both sucrose and cocaine self-administering mice, with maximal responses found at 7days compared to 1 or 28days after self administration with either reinforcer. However, following extinction training, reinstatement of cocaine seeking reinforced by response-contingent presentation of reward-associated cues (tone/light) was significantly higher after 28days compared to 1 or 7days following cocaine self-administration. In contrast, cue induced reinstatement of sucrose-paired lever pressing did not increase over this time frame, demonstrating a drug-specific incubation effect not seen with a natural reward. Thus, C57BL/6J mice display incubation of cue-induced reinstatement of cocaine seeking similar to findings with rats, but only show a transient incubation of context-induced cocaine seeking. PMID- 28669706 TI - Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors. AB - PURPOSE: Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR. METHODS AND MATERIALS: We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR. RESULTS: Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity. CONCLUSION: While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies. PMID- 28669707 TI - A multiplex ARMS PCR approach to detection of common beta-globin gene mutations. AB - BACKGROUND: beta-thalassaemia is a group of inherited single-gene disorders worldwide. Each ethnic population has its own common mutations. Heterogeneity of beta-thalassaemia mutations in multi-ethnic population of Surat, makes molecular diagnosis expensive and time consuming. METHODS: Specific primers were used to differentiate four common mutations, IVS I-5 (G->C), Codon 41/42 (- TCTT), 619-bp deletion and FS 8/9 (+G), by a simple PCR involving a multiplex amplification refractory mutation system. RESULTS: Several high prevalence beta-Thalassemia trait groups constituted by Muslims, Patels, Sindhis, ModhBanias, and Mahayavanshi. Four most common mutations detected in them are IVS I-5 (G->C), Codon 41/42 (- TCTT), 619-bp deletion and FS 8/9 (+G). We identified each of these beta-thalassemia mutations in multiplexed ARMS from positive control samples. Our multiplex-ARMS-PCR system was first standardized on positive DNA samples with above known four most common beta-thalassemia mutations, and these positive samples had been diagnosed with beta-thalassemia and also all these samples belonged to Surat ethnic groups. The system was subsequently tested on 110 blood samples from different ethnic backgrounds with unknown beta-thalassemia mutations which were in all specimens. CONCLUSION: The ARMS multiplex system was found reliable, cost effective, fast and most applicable for mutation screening of Thalassemia in Surat populations. PMID- 28669708 TI - A set of enhanced green fluorescent protein concatemers for quantitative determination of nuclear localization signal strength. AB - Regulated transport of proteins between nucleus and cytoplasm is an important process in the eukaryotic cell. In most cases, active nucleo-cytoplasmic protein transport is mediated by nuclear localization signal (NLS) and/or nuclear export signal (NES) motifs. In this study, we developed a set of vectors expressing enhanced GFP (EGFP) concatemers ranging from 2 to 12 subunits (2xEGFP to 12xEGFP) for analysis of NLS strength. As shown by in gel GFP fluorescence analysis and alphaGFP Western blotting, EGFP concatemers are expressed as fluorescent full length proteins in eukaryotic cells. As expected, nuclear localization of concatemeric EGFPs decreases with increasing molecular weight. By oligonucleotide ligation this set of EGFP concatemers can be easily fused to NLS motifs. After determination of intracellular localization of EGFP concatemers alone and fused to different NLS motifs we calculated the size of a hypothetic EGFP concatemer showing a defined distribution of EGFP fluorescence between nucleus and cytoplasm (n/c ratio = 2). Clear differences of the size of the hypothetic EGFP concatemer depending on the fused NLS motif were observed. Therefore, we propose to use the size of this hypothetic concatemer as quantitative indicator for comparing strength of different NLS motifs. PMID- 28669709 TI - A mechanistic insight into curcumin modulation of the IL-1beta secretion and NLRP3 S-glutathionylation induced by needle-like cationic cellulose nanocrystals in myeloid cells. AB - Recently we have demonstrated that needle-like cationic cellulose nanocrystals (CNC-AEMA2) evoke immunological responses through NLRP3 inflammasome/IL-1beta inflammatory pathway. In this study we demonstrated that curcumin, a naturally occurring polyphenolic compound isolated from Curcuma longa (Zingiberaceae), was able to suppress, at least in part, this immunological response, as observed by diminished IL-1beta secretion in CNC-AEMA2-stimulated macrophages primed with LPS. Curcumin is a well-known antioxidant and anti-inflammatory natural compound and in addition to acting as "scavenger" of reactive oxygen species (ROS), it can also upregulates antioxidant enzymes. However, the mechanisms by which this natural compound exerts its protective activity is still under investigation. We hypothesize that curcumin may also affect S-glutathionylation of key proteins involved in the NLRP3 inflammasome/IL-1beta pathway, and therefore impact their protein-protein interactions. The goal of this study was to investigate the effects of curcumin on the S-glutathionylation of NLRP3 induced by CNC-AEMA2 in LPS-primed mouse macrophages (J774A.1), as well as interactions among proteins of the NLRP3 inflammasome complex. Our main finding indicates that the addition of curcumin concomitantly with LPS caused the greatest decrease in NLRP3 S glutathionylation and a respective increase in caspase-1 S-glutathionylation, which appears to favor protein-protein interactions in the NLRP3 complex. Taking together, our results suggest that, at least in part, the anti-inflammatory activity of curcumin is associated with changes in S-glutathionylation of key NLRP3 inflammasome components, and perhaps resulting in sustained complex assembly and suppression of IL-1beta secretion. PMID- 28669710 TI - The genome sequence of Condylorrhiza vestigialis NPV, a novel baculovirus for the control of the Alamo moth on Populus spp. in Brazil. AB - Condylorrhiza vestigialis (Lepidoptera: Cambridae), commonly known as the Brazilian poplar moth or Alamo moth, is a serious defoliating pest of poplar, a crop of great economic importance for the production of wood, fiber, biofuel and other biomaterials as well as its significant ecological and environmental value. The complete genome sequence of a new alphabaculovirus isolated from C. vestigialis was determined and analyzed. Condylorrhiza vestigialis nucleopolyhedrovirus (CoveNPV) has a circular double-stranded DNA genome of 125,767bp with a GC content of 42.9%. One hundred and thirty-eight putative open reading frames were identified and annotated in the CoveNPV genome, including 38 core genes and 9 bros. Four homologous regions (hrs), a feature common to most baculoviruses, and 19 perfect and imperfect direct repeats (drs) were found. Phylogenetic analysis confirmed that CoveNPV is a Group I Alphabaculovirus and is most closely related to Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) and Choristoneura fumiferana DEF multiple nucleopolyhedrovirus CfDEFMNPV. The gp37 gene was not detected in the CoveNPV genome, although this gene is found in many NPVs. Two other common NPV genes, chitinase (v-chiA) and cathepsin (v-cath), that are responsible for host insect liquefaction and melanization, were also absent, where phylogenetic analysis suggests that the loss these genes occurred in the common ancestor of AgMNPV, CfDEFMNPV and CoveNPV, with subsequent reacquisition of these genes by CfDEFMNPV. The molecular biology and genetics of CoveNPV was formerly very little known and our expectation is that the findings presented here should accelerate research on this baculovirus, which will facilitate the use of CoveNPV in integrated pest management programs in Poplar crops. PMID- 28669711 TI - Unlocking the secrets of dopamine in Alzheimer's Disease. PMID- 28669712 TI - Lessons in precision oncology from neoadjuvant endocrine therapy trials in ER+ breast cancer. AB - For post-menopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2.7% or less in the surgical specimen (PEPI = 0) after 16-18 weeks of aromatase inhibitor therapy had a 97% disease free survival after 5.5 years of median follow up. Two approaches are currently underway to extend the PEPI model. The first is to determine whether fulvestrant increases the PEPI-0 rate versus anastrozole, as this would increase the number of patients who could be safely managed without adjuvant chemotherapy. The second is to develop new approaches for tumors that exhibit endocrine therapy resistance identified during NET. Preliminary studies demonstrate that tumors that exhibit AI resistant proliferation in the neoadjuvant setting is often sensitive to palbociclib, a CDK4/6 inhibitor. Serial Ki67 monitoring before surgery is therefore logical approach to tailored use of adjuvant CDK4/6i adjuvant treatment. Finally serial sampling of the tumor inherent in the PEPI approach facilitates the identification of new therapeutic targets, mechanisms of resistance and monitoring of tumor evolution in response to AI therapy. PMID- 28669713 TI - Adjuvant endocrine therapy for premenopausal women: Type and duration. AB - The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis of randomized tamoxifen trials, found that women age <45 years with estrogen receptor-positive (ER+ve) breast cancer, allocated 5 years of adjuvant tamoxifen, have substantial long-term reduction of breast cancer recurrence. Breast cancer mortality was reduced by about one-third through the first 15 years. Increasing the duration of tamoxifen to 10 years can further reduce the risk of recurrence. For women age <45 years allocated 5 years of tamoxifen, the risk of contralateral breast cancer is halved over 15 years. The initial results from the Suppression of Ovarian Function Trial (SOFT) indicate tamoxifen is a suitable therapy for premenopausal women with low risk clinical-pathologic features. For women at sufficient risk to receive chemotherapy who have premenopausal E2 levels within 8 months of completion, the addition of ovarian suppression to tamoxifen for 5 years resulted in some reduction of recurrence. The use of ovarian suppression combined with an aromatase inhibitor exemestane for 5 years, resulted in further reduction of recurrence. The joint analysis of SOFT and Tamoxifen and Exemestane Trial (TEXT) found the combination of ovarian suppression plus exemestane significantly reduced recurrence, compared with ovarian suppression plus tamoxifen. Premenopausal women with ER+ve HER2-negative breast cancer with high risk features can derive a meaningful improvement in 5-year invasive breast cancer-free interval with exemestane plus ovarian suppression, as an alternative to tamoxifen. Very young women under age 35 with ER+ve breast cancer have higher risks of recurrence, and the use of ovarian suppression with oral endocrine therapy should be considered. PMID- 28669714 TI - Parameters Affecting the Enhanced Permeability and Retention Effect: The Need for Patient Selection. AB - The enhanced permeability and retention (EPR) effect constitutes the rationale by which nanotechnologies selectively target drugs to tumors. Despite promising preclinical and clinical results, these technologies have, in our view, underachieved compared to their potential, possibly due to a suboptimal exploitation of the EPR effect. Here, we have systematically analyzed clinical data to identify key parameters affecting the extent of the EPR effect. An analysis of 17 clinical studies showed that the magnitude of the EPR effect was varied and was influenced by tumor type and size. Pancreatic, colon, breast, and stomach cancers showed the highest levels of accumulation of nanomedicines. Tumor size also had an effect on the accumulation of nanomedicines, with large-size tumors having higher accumulation than both medium- and very large-sized tumors. However, medium tumors had the highest percentage of cases (100% of patients) with evidence of the EPR effect. Moreover, tumor perfusion, angiogenesis, inflammation in tumor tissues, and other factors also emerged as additional parameters that might affect the accumulation of nanomedicines into tumors. At the end of the commentary, we propose 2 strategies for identification of suitable patient subpopulations, with respect to the EPR effect, in order to maximize therapeutic outcome. PMID- 28669715 TI - Lead substances selection using GHS approach for the classification of mixtures: Case study of painting in the work environment. AB - We developed a lead substances selection approach based on the concept of mixture classification of UN GHS for the purpose of efficient risk assessment of mixtures consisting of multiple components. Lead substances selection methods are being actively developed in Europe, but these methods are predicated on the regulations and information sources available within Europe and are therefore not readily applicable to countries outside Europe. In this study, the features of the GHS based approach and the risk assessment results for outdoor painting work as a specific utilization example of the GHS-based approach were described. Comparison with the DPD + method and the CCA method proposed in Europe revealed that the GHS based approach resulted in the selection of the safest lead substances. The GHS method, like the DPD + method, is a classification-based approach. We believe that a classification-based approach based on the GHS method can be an appropriate tool to efficiently implement risk assessment of mixtures for countries outside Europe. Some tools for business operators to conduct the management of chemicals using the GHS classification have been established in Japan. We plan to propose the GHS-based approach as a standardized assessment tool. PMID- 28669716 TI - The regulatory and signaling mechanisms of the ASK family. AB - Apoptosis signal-regulating kinase 1 (ASK1) was identified as a MAP3K that activates the JNK and p38 pathways, and subsequent studies have reported ASK2 and ASK3 as members of the ASK family. The ASK family is activated by various intrinsic and extrinsic stresses, including oxidative stress, ER stress and osmotic stress. Numerous lines of evidence have revealed that members of the ASK family are critical for signal transduction systems to control a wide range of stress responses such as cell death, differentiation and cytokine induction. In this review, we focus on the precise signaling mechanisms of the ASK family in response to diverse stressors. PMID- 28669717 TI - miRNAs may regulate GABAergic transmission associated genes in aged rats with anesthetics-induced recognition and working memory dysfunction. AB - BACKGROUND: Isoflurane and sevoflurane are widely used anesthetics in surgery and administration of these anesthetics could lead to postoperative cognitive dysfunction (POCD). However, the mechanisms remain unclear. METHODS: Aged Wistar rats were exposed to isoflurane and sevoflurane for 2 or 4h. Recognition memory and spatial working memory were measured using Novel object recognition (NOR) and Y-maze test, respectively. Apoptotic cells were detected by TUNEL staining. miRNA expression was measured by Real-time PCR while protein expression was measured by Western blot. Dual-Luciferase reporter assay was used to establish the direct relationship between miRNAs and Gabra5 and gephyrin gene expression. RESULTS: Exposure to isoflurane and sevoflurane for 2 or 4h significantly decreased the NOR index in the NOR test and spontaneous alternations in arm entries in the Y maze test in aged rats. TUNEL staining showed that isoflurane and sevoflurane administration significantly induced apoptosis in the mPFC and hippocampus. The protein level of alpha5 GABAA receptor (alpha5GABAAR), gephyrin, and dystrophin were significantly increased, whereas the expression of miR-30a, miR-31, miR 190a, and miR-190b was significantly decreased in the hippocampus and mPFC in aged rats exposed to isoflurane and sevoflurane compared to control rats. The protein levels of alpha5GABAAR, gephyrin, and dystrophin protein in the hippocampus and the mPFC significantly correlated with NOR index and spontaneous alternations. Dual-Luciferase reporter assay showed that miR-30a and miR-190a/b mimics significantly inhibited Gabra5 and gephyrin gene expression, respectively. CONCLUSION: There might be a miRNAs-GABAergic transmission pathway which may be involved in the pathophysiological alteration in anesthetics-induced POCD. PMID- 28669718 TI - Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway. AB - Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that interacts with several intracellular proteins in vivo, including calmodulin and Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt). TRPV1 activation has been reported to exert neuroprotective effects. The aim of this study was to examine the impact of cold stress on the mouse brain and the underlying mechanisms of TRPV1 involvement. Adult male C57BL/6 mice were subjected to cold stress (4 degrees C for 8h per day for 2weeks). The behavioral deficits of the mice were then measured using the Morris water maze. Expression levels of brain injury-related proteins and mRNA were measured by western blot, immunofluorescence or RT-PCR analysis. The mice displayed behavioral deficits, inflammation and changes in brain injury markers following cold stress. As expected, upregulated TRPV1 expression levels and changes in PI3K/Akt expression were found. The TRPV1 inhibitor reduced the levels of brain injury-related proteins and inflammation. These data suggest that cold stress can induce brain injury, possibly through TRPV1 activation and the PI3K/Akt signaling pathway. Suppression of inflammation by inhibition of TRPV1 and the PI3K/Akt pathway may be helpful to prevent cold stress-induced brain injury. PMID- 28669719 TI - Changing similarity: Stable and flexible modulations of psychological dimensions. AB - Successfully categorizing objects requires discriminating between relevant and irrelevant dimensions (e.g., shape, color). Categorization can lead to changes in the visual system that stretch psychological space, making relevant dimensions more distinct and irrelevant dimensions more similar. These changes are known as dimensional modulation (DM) and they can be both stable and flexible in nature. The current study examined the interaction between stable DM and flexible DM, as well as the time course of relative changes in similarity. Using a two dimensional space of cars, participants learned to categorize the space and then completed a target identification task during EEG recording. We found that attention, operationally defined as the selection negativity, was sensitive to category-relevance and appeared to selectively enhance previously irrelevant differences in the service of a target detection task. In contrast, we found that late decisional stages, operationally defined as the P3 b, were less sensitive to relevance and instead more sensitive to the number of morphsteps that separated targets from non-targets. Thus, it appears that relative similarity between targets and non-targets dynamically changed over the time course of individual decisions. Similarity between exemplars was greater along the irrelevant than the relevant dimension early on in the time course but a compensatory allocation of attention led to similarity being optimized among all dimensions for later stages. This finding is important because it 1) provides a new source of converging evidence for stable DM and 2) links a neural measure of attentional modulation with facilitation of an unpracticed, but task-relevant perceptual dimension. PMID- 28669720 TI - Ultra-low friction between boundary layers of hyaluronan-phosphatidylcholine complexes. AB - : The boundary layers coating articular cartilage in synovial joints constitute unique biomaterials, providing lubricity at levels unmatched by any human-made materials. The underlying molecular mechanism of this lubricity, essential to joint function, is not well understood. Here we study the interactions between surfaces bearing attached hyaluronan (hyaluronic acid, or HA) to which different phosphatidylcholine (PC) lipids had been added, in the form of small unilamellar vesicles (SUVs or liposomes), using a surface force balance, to shed light on possible cartilage boundary lubrication by such complexes. Surface-attached HA was complexed with different PC lipids (hydrogenated soy PC (HSPC), 1,2 dimyristoyl-sn-glycero-3-PC (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-PC (POPC)), followed by rinsing. Atomic force microscopy (AFM) and cryo-scanning electron microscopy (Cryo-SEM) were used to image the HA-PC surface complexes following addition of the SUVs. HA-HSPC complexes provide very efficient lubrication, with friction coefficients as low as MU~0.001 at physiological pressures P~150atm, while HA-DMPC and HA-POPC complexes are efficient only at low P (up to 10-20atm). The friction reduction in all cases is attributed to hydration lubrication by highly-hydrated phosphocholine groups exposed by the PC HA complexes. The greater robustness at high P of the HSPC (C16(15%),C18(85%)) complexes relative to the DMPC ((C14)2) or POPC (C16, C18:1) complexes is attributed to the stronger van der Waals attraction between the HSPC acyl tails, relative to the shorter or un-saturated tails of the other two lipids. Our results shed light on possible lubrication mechanisms at the articular cartilage surface in joints. STATEMENT OF SIGNIFICANCE: Can designed biomaterials emulate the unique lubrication ability of articular cartilage, and thus provide potential alleviation to friction-related joint diseases? This is the motivation behind the present study. The principles of cartilage lubrication have attracted considerable attention for decades, and several models have been proposed to elucidate it, however, the mechanism of this ultralow friction is still not clear. In this paper we explore the recent suggestion that its efficient lubrication arises from boundary layers of hyaluronan-lipid complexes at its surface, in particular exploring a range of different phosphatidylcholines (PCs) mimicking the wide range of PCs in synovial joints. The present study suggests a synergistic lubricating behavior of the different lipids in living joints, and potential treatment directions using such biomaterial complexes for widespread cartilage-friction-related diseases such as osteoarthritis. PMID- 28669721 TI - Initial investigation of individual and combined annulus fibrosus and nucleus pulposus repair ex vivo. AB - : Novel tissue engineered and biomaterial approaches to treat intervertebral disc (IVD) degeneration focus on single aspects of the progressive disease and hence are insufficient repair strategies. In this study, annulus fibrosus (AF) and nucleus pulposus (NP) biomaterial repair strategies were used individually and combined to treat IVD degeneration modeled in ex vivo rat-tail motion segments by annulotomy and nucleotomy. An injectable riboflavin cross-linked high-density collagen gel patched defects in the AF, while NP repair consisted of injections of a modified hyaluronic acid (HA) hydrogel. Qualitative imaging showed the annulotomy and nucleotomy successfully herniated NP material, while the HA NP injections restored intact NP morphology and the collagen AF patches sealed AF defects. Assessed by quantitative T2 magnetic resonance imaging, combined repair treatments yielded disc hydration not significantly different than intact hydration, while AF and NP repairs alone only restored ~1/3 of intact hydration. Mechanical testing showed NP injections alone recovered on average ~35% and ~40% of the effective instantaneous and equilibrium moduli. The combined treatment comprising biomaterial AF and NP repair was effective at increasing NP hydration from NP repair alone, however HA injections alone are sufficient to improve mechanical properties. STATEMENT OF SIGNIFICANCE: Intervertebral disc degeneration affects an estimated 90% of individuals throughout their life, and is a candidate pathology for tissue engineered repair. The current standard of clinical care reduces spinal articulation and leads to further degeneration along the spine, hence great interest in a regenerative medicine therapy. Literature studies focused on biomaterial repair strategies for treating degenerated discs have partially restored native disc function, however no studies have reported the use of combined therapies to address multiple aspects of disc degeneration. This initial investigation screened injectable biomaterial repair strategies ex vivo, and through complementary outcome measures showed a combined therapy restores disc function better than individual approaches. This study is the first of its kind to address multiple aspects of disc degeneration, using clinically oriented biomaterials in a well-established animal model. PMID- 28669722 TI - Tacrolimus induces fibroblasts apoptosis and reduces epidural fibrosis by regulating miR-429 and its target of RhoE. AB - Tacrolimus (FK506) has been demonstrated to reduce epidural fibrosis. However, the detailed mechanism of action has not been elucidated. Aberrant miR-429 is involved in many diseases. The aim of this study was to describe the exact mechanism of FK506 induced apoptosis in fibroblasts and the prevention of epidural fibrosis. FK506 induced fibroblast apoptosis was evaluated using CCK-8 assays, flow cytometry, and western blotting. The expression of miR-429 in fibroblasts treated with FK506 was determined by RT-qPCR. Additionally, luciferase activity assays were used to determine the target relationship between miR-429 and RhoE. Flow cytometry and western blot analysis were used to determine the effects of FK506 and miR-429 on fibroblast apoptosis. The effects of FK506 and RhoE on fibroblast apoptosis were determined by CCK-8 assay, flow cytometry, and western blotting. We also evaluate the effects of FK506 and miR-429 on epidural fibrosis in rats by using histological analysis and TUNEL-staining. The results revealed FK506 induces fibroblast apoptosis and significantly downregulates miR-429 expression in fibroblasts. Additionally, miR-429 downregulation caused the apoptosis of fibroblasts. The luciferase activity assay confirmed that RhoE is a direct target of miR-429 and RhoE promotes fibroblast apoptosis. The rat model demonstrated miR-429 inhibition promotes fibroblast apoptosis and epidural fibrosis, which is consistent with the results of FK506 treatment. Our study demonstrates that FK506 induces fibroblast apoptosis and reduces epidural fibrosis by regulating miR-429 expression and its target of RhoE. PMID- 28669723 TI - The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine. AB - P-glycoprotein (P-gp) is overexpressed in cancer cells in order to pump out chemotherapeutic drugs, and is one of the major mechanisms responsible for multidrug resistance (MDR). It is important to identify P-gp inhibitors with low toxicity to normal cells in order to increase the efficacy of anti-cancer drugs. Previously, a JAK2 inhibitor CEP-33779 demonstrated inhibitory actions against P gp and an ability to sensitize drug-resistant cancer cells to treatment. In the present study, we tested another JAK2 inhibitor NVP-BSK805 for P-gp inhibitory activity. In molecular docking simulation modeling, NVP-BSK805 showed higher binding affinity docking scores against a P-gp member (ABCB1) than CEP-33779 did. Furthermore, we found that lower doses of NVP-BSK805 are required to inhibit P-gp in comparison with that of CEP-33779 or verapamil (an established P-gp inhibitor) in KBV20C cells, suggesting that NVP-BSK805 has higher specificity. NVP-BSK805, CEP-33779, and verapamil demonstrated similar abilities to sensitize KBV20C cells to vincristine (VIC) treatment. Our results suggested that the JAK2 inhibitors were able to inhibit P-gp pump-action via a direct binding mechanism, similar to verapamil. However, JAK2 inhibitor-induced sensitization was not observed in VIC treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. FACS, western-blot, and annexin V analyses were used to further investigate the mechanism of action of JAK2 inhibitors in VIC-treated KBV20C cells. Both CEP-33779 and NVP-BSK805 induced the sensitization of KBV20C cells to VIC treatment via the same mechanisms; they each caused a reduction in cell viability, increased G2 arrest, and upregulated expression of the DNA damaging protein pH2AX when used as co-treatments with VIC. These findings indicate that inhibition of JAK2 may be a promising target in the treatment of cancers that are resistant to anti-mitotic drugs. PMID- 28669724 TI - The comprehensive liver transcriptome of two cattle breeds with different intramuscular fat content. AB - Intramuscular fat (IMF) content is an important determinant factor of meat quality in cattle. There is significant difference in IMF content between Jinnan and Simmental cattle. Here, to identify candidate genes and networks associated with IMF deposition, we deeply explored the transcriptome architecture of liver in these two cattle breeds. We sequenced the liver transcriptome of five Jinnan and three Simmental cattle, yielding about 413.9 million sequencing reads. 124 differentially expressed genes (DEGs) were detected, of which 53 were up regulated and 71 were down-regulated in Jinnan cattle. 1282 potentially novel genes were also identified. Gene ontology analysis revealed these DEGs (including CYP21A2, PC, ACACB, APOA1, and FADS2) were significantly enriched in lipid biosynthetic process, regulation of cholesterol esterification, reverse cholesterol transport, and regulation of lipoprotein lipase activity. Genes involved in pyruvate metabolism pathway were also significantly overrepresented. Moreover, we identified an interaction network which related to lipid metabolism, which might be contributed to the IMF deposition in cattle. We concluded that the DEGs involved in the regulation of lipid metabolism could play an important role in IMF deposition. Overall, we proposed a new panel of candidate genes and interaction networks that can be associated with IMF deposition and used as biomarkers in cattle breeding. PMID- 28669725 TI - MiR-21 promotes fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis by activating IL-6 expression. AB - The molecular mechanism underlying the fibrosis of ligamentum flavum(LF) in patients with lumbar spinal canal stenosis(LSCS) remains unknown. MicroRNAs are reported to play important roles in regulating fibrosis in different organs. The present study aimed to identify fibrosis related miR-21 expression profile and investigate the pathological process of miR-21 in the fibrosis of LF hypertrophy and associated regulatory mechanisms. 15 patients with LSCS underwent surgical treatment were enrolled in this study. For the control group, 11 patients with lumbar disc herniation(LDH) was included. The LF thickness was measured on MRI. LF samples were obtained during the surgery. Fibrosis score was assessed by Masson's trichrome staining. The expression of miR-21 in LF tissues were determined by RT-PCR. Correlation among LF thickness, fibrosis score, and miR-21 expression was analyzed. In addition, Lentiviral vectors for miR-21 mimic were constructed and transfected into LF cells to examine the role of miR-21 in LF fibrosis. Types I and III collagen were used as indicators of fibrosis. IL-6 expression in LF cells after transfection was investigated by RT-PCR and ELISA. Patients in two groups showed similar outcomes regarding age, gender, level of LF tissue. The thickness and fibrosis score of LF in the LSCS group were significantly greater than those in LDH group (all P < 0.05). Similarly, the expression of miR-21 in LSCS group was substantially higher than that in LDH group(P < 0.05). Furthermore, the miR-21 expression exhibited positive correlations with the LF thickness (r = 0.595, P < 0.05) and fibrosis score (r = 0.608, P < 0.05). Of note, miR-21 over-expression increased the expression levels of collagen I and III (P < 0.05). Also, IL-6 expression and secretion in LF cells was elevated after transfection of miR-21 mimic. MiR-21 is a fibrosis-associated miRNA and promotes inflammation in LF tissue by activating IL-6 expression, leading to LF fibrosis and hypertrophy. PMID- 28669726 TI - Knockdown of frizzled-7 inhibits cell growth and metastasis and promotes chemosensitivity of esophageal squamous cell carcinoma cells by inhibiting Wnt signaling. AB - A growing body of evidence suggests that frizzled-7 (FZD7) is an important oncogene in multiple human malignancies and is involved in regulating sensitivity to chemotherapeutic drugs. However, little is known about the expression and function of FZD7 in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to investigate the functional significance of FZD7 in ESCC. Here, we found that both mRNA and protein expression levels of FZD7 were highly upregulated in ESCC cell lines. The knockdown of FZD7 inhibited cell growth, induced cell apoptosis, and suppressed cell migration and invasion of ESCC cells in vitro. Furthermore, knockdown of FZD7 promoted chemosensitivity to cisplatin in ESCC cells and suppressed the expression of multidrug resistance protein 1. Moreover, the silencing of FZD7 also significantly impeded the activation of Wnt signaling in ESCC cells. Taken together, our study reveals an oncogenic role of FZD7 in the progression of ESCC and suggests that FZD7 might serve as a potential therapeutic target for treatment of ESCC. PMID- 28669727 TI - Light-chain residue 95 is critical for antigen binding and multispecificity of monoclonal antibody G2. AB - The monoclonal antibody, G2, specifically binds to the immunogen peptide derived from the chicken prion protein, Pep18mer, and two chicken proteins derived peptides, Pep8 and Pep395; G2 binds with equal affinity to Pep18mer. The amino acid sequences of the three peptides are completely different, and so the recognition mechanism of G2 is unique and interesting. We generated a single chain Fv (scFv) antibody of G2, and demonstrated its correct folding with an antigen binding function similar to intact G2 antibody. We also generated a Pro containing mutant of G2 scFv at residue 95 of the light chain, and analyzed its antigen binding using a surface plasmon biosensor. The mutant lost its binding ability to Pep18mer, but remained those to Pep8 and Pep395. The results clearly indicate residue 95 as being critical for multispecific antigen binding of G2 at the site generated from the junctional diversity introduced at the joints between the V and J gene segments. PMID- 28669729 TI - Mangiferin protects osteoblast against oxidative damage by modulation of ERK5/Nrf2 signaling. AB - Oxidative stress has currently been proposed as a risk factor associated with the development and proression of osteoporosis. In this study, we identify the effect of mangiferin (MAN) on apoptosis and differentiation of osteoblast-like MC3T3-E1 cells insulted by H2O2. We firstly found that MAN can promote cell proliferation of MC3T3-E1 cells in a time- and dose-dependent manner and stimulate the phosphorylation of ERK5. Cells were divided as five groups: control, H2O2 (100 MUM, control), H2O2 + MAN (5 MUM), H2O2 + MAN (10 MUM), and H2O2 + MAN (20 MUM). MAN can significantly decrease H2O2-induced apoptosis and elevated ROS level of MC3T3-E1 cells. The expressions of caspase-3, caspase-9 and Bax/Bcl-2 were increased with H2O2 treatment, and MAN can reverse these changes. In addition, Nrf2 and its downstream target effectors (HO1, NQO1) were dramatically attenuated in MC3T3-E cells treatment with H2O2, while MAN can significantly increase the expression of Nrf2, HO1 and NQO1. The expression of ERK5 was down regulated by RNA interference in MC3T3-E1 cells, and we found that MAN (20 MUM) pretreatment didn't make remarkable decrease in cell apoptosis or expressions of apoptosis related proteins in H2O2-insulted siRNA-ERK5 cells. This study indicated that MAN can protect osteoblast against oxidative damage by modulation of ERK5/Nrf2 signaling, which can be new agent for osteoporosis. PMID- 28669728 TI - Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma. AB - Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G2 cell-cycle arrest, followed by apoptosis in a MLN4924 dose-dependent manner. Further mechanistic study revealed that MLN4924 induced apoptosis was mediated by substantial up-regulation of pro-apoptotic NOXA. These findings highlighted the anticancer effects of the neddylation inhibitors (e.g. MLN4924) for the treatment of RCC. PMID- 28669730 TI - ZNF692 promotes proliferation and cell mobility in lung adenocarcinoma. AB - By analyzing The Cancer Genome Atlas (TCGA) datasets, we discovered that the zinc finger protein 692 (ZNF692) were over-expressed in Lung adenocarcinoma (LUAD) tissues compared to adjacent non-tumor tissues (P < 0.0001). In this study, we investigated the function of ZNF692 in the progression of LUAD. We found that ZNF692 knockdown inhibited LUAD cells proliferation, migration, and invasion both in vitro and in vivo. And LUAD cell apoptosis was induced following the down regulation of ZNF692. Our results show that ZNF692 is over-expressed in LUAD tissues compared to adjacent normal tissues, and hyper-expression of ZNF692 in LUAD is an independent risk factor for worse overall survival in LUAD patients (HR: 8.800, 95%CI: 1.082-71.560, P = 0.042) by Tissue Microarray stain assay (TMA). GO analysis indicated that most genes were enriched in metabolic process which were associated highly with ZNF692 levels. Collectively, our results suggested that ZNF692 may serve as a potential oncogene and biomarker in LUAD by influencing cell metabolism. PMID- 28669732 TI - The retention of prion protein in the endoplasmic reticulum prevents N2A cells from proteasome inhibition-induced cytotoxicity. AB - Prion disease is a fatal neurodegenerative disease that may result from the conversion of normal cellular prion protein (PrPC) to the pathogenic scrapie PrP isoform (PrPSc), however, how proliferation of prion leads to neuronal apoptosis is still not clear. In this study, to explore the role of the endoplasmic reticulum (ER) in prion diseases, we engineered the KDEL ER-retention motif to the C-terminus of PrPC and studied its effect on N2A cell toxicity. The KDEL retention signal led to the accumulation of PrP in the ER, and KDEL signal could effectively deplete PrP from the cell surface and trap PrP in the ER/Cis-Golgi compartment. PrPC molecules were delayed in their transit along the early pathway of the secretory compartment, however, they did not aggregate, and were not resistant to Proteinase K (PK) or become detergent-insoluble. Moreover, we found that the ER was not the site where PrP became detergent-insoluble and acquired PK resistance. In addition, an MTT assay indicated cells expressing PrPC/N2A were sensitive to proteasome inhibition, but not N2A cells expressing PrPKDEL. Our findings suggest that the ER is not a compartment in which wild type PrPC is able to initiate aggregation, protease resistance or other scapie-like properties of PrP. PMID- 28669733 TI - BCL11B is frequently downregulated in HTLV-1-infected T-cells through Tax mediated proteasomal degradation. AB - Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia-lymphoma (ATLL). The HTLV-1-encoded protein Tax plays important roles in the proliferation of HTLV-1-infected T-cells by affecting cellular proteins. In this study, we showed that Tax transcriptionally and post-transcriptionally downregulates the expression of the tumor suppressor gene B-cell leukemia/lymphoma 11B (BCL11B), which encodes a lymphoid-related transcription factor. BCL11B expression was downregulated in HTLV-1-infected T-cell lines at the mRNA and protein levels, and forced expression of BCL11B suppressed the proliferation of these cells. The proteasomal inhibitor MG132 increased BCL11B expression in HTLV-1-infected cell lines, and colocalization of Tax with BCL11B was detected in the cytoplasm of HTLV-1-infected T-cells following MG132 treatment. shRNA knock-down of Tax expression also increased the expression of BCL11B in HTLV-1-infected cells. Moreover, we found that Tax physically binds to BCL11B protein and induces the polyubiquitination of BCL11B and proteasome dependent degradation of BCL11B. Thus, inactivation of BCL11B by Tax protein may play an important role in the Tax-mediated leukemogenesis. PMID- 28669731 TI - NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation. AB - Scavenger receptor class B type 1 (SR-B1), an HDL receptor plays a crucial role in cholesterol metabolism in the liver, steroidogenic tissues, and vascular cells including macrophages. SR-B1 is subject to regulation at the transcription, posttranscription and posttranslational levels. We previously provided evidence that PDZ domain containing NHERF1 and NHERF2 regulate SR-B1 protein levels post transcriptionally, although the underlying mechanism(s) by which NHERF1 and NHERF2 regulate SR-B1 protein levels is not well understood. In this study, we demonstrate that SR-B1 is degraded intracellularly via ubiquitin-proteasome pathway and that SR-B1 can be ubiquitinated at K500 and K508 residues. Overexpression of NHERF1 or NHERF2 enhanced SR-B1 ubiquitination and degradation. NHERF1 and NHERF2 promote SR-B1 ubiquitination at sites K508 and K500, respectively. These results suggest that NHERF1 and NHERF2 down-regulated SR-B1 at least in part via the ubiquitin/proteasome pathway. PMID- 28669734 TI - Inhibition of miR-664a interferes with the migration of osteosarcoma cells via modulation of MEG3. AB - Osteosarcoma is the most common primary bone tumor in children and adolescents. Understanding the basic molecular mechanisms in developing cancer can be helpful in developing alternative treatment strategies. The relationship between dysregulated non-coding RNAs' (ncRNA) expression level and osteosarcoma was detected. Among those ncRNAs, the expression levels of miR-664a were detected to be upregulated and MEG3 long non-coding RNA levels were detected to be downregulated in osteosarcoma tissue and cell lines. In this study, miR-664a inhibitor was used in order to investigate the changes in the expression levels of MEG3 gene and miR-664a in osteosarcoma cancer cell line (U2-OS) and human osteoblast cell line (hFOB 1.19). According to our results, the expression level of MEG3 gene was increased while the expression level of miR-664a was decreased, as expected. In addition, changes in expression level of MEG3 and miR-644a interferes with the migration of osteosarcoma cells migration speed of osteosarcoma cells. These results are found to be statistically significant (p < 0.05). As a result of this study, it was shown that the upregulated expression of miR-664a could have an inhibitory effect on MEG3 gene expression and migration of osteosarcoma cells. PMID- 28669735 TI - Prenatal Diagnosis of Caroli Disease Associated With Autosomal Recessive Polycystic Kidney Disease by 3-D Ultrasound and Magnetic Resonance Imaging. AB - BACKGROUND: Caroli disease is a very rare congenital anomaly characterized by non obstructive saccular or fusiform dilatation of the intrahepatic bile ducts. It is associated with bile stagnation and hepatolithiasis, which explain the recurrent cholangitis and portal hypertension as a consequence of congenital liver fibrosis. Although there are several reports of diagnosis in childhood and adult life, the prenatal diagnosis using conventional 2-D ultrasound is rare, with few reports in the literature. CASE: We present a case of a 26-year-old primigravid woman at 24 weeks of gestation which 3-D ultrasound in the rendering mode clearly revealed the enlarged fetal kidneys and the increased abdominal volume, confirming the diagnosis of autosomal recessive polycystic kidney disease. The MRI was essential to the prenatal diagnosis of Caroli disease, identifying the congenital saccular dilations of intrahepatic bile ducts. PMID- 28669736 TI - Midostaurin in FLT3-mutated acute myeloid leukaemia. PMID- 28669737 TI - Savolitinib for MET-driven papillary renal cell carcinoma. PMID- 28669738 TI - Potential biomarker for acute myeloid leukaemia therapy. PMID- 28669740 TI - Oxidative stress and inflammatory biomarkers in normal and preeclamptic pregnancies. PMID- 28669739 TI - An evidence-based recommendation to increase the dosing frequency of buprenorphine during pregnancy. AB - BACKGROUND: Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared with the nonpregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than nonpregnant individuals to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered, but the frequency of dosing is not clearly addressed. Based on buprenorphine's long terminal half-life, once-daily or twice daily dosing has generally been suggested. OBJECTIVE: The objective of the study was to assess the impact of dosing frequency on buprenorphine plasma concentration time course during pregnancy. STUDY DESIGN: We utilized 3 data sources to determine an optimal frequency for dosing of buprenorphine during pregnancy: data from a pharmacokinetic study of 14 pregnant and postpartum women on maintenance buprenorphine in a supervised clinical setting; data from pregnant women attending a buprenorphine clinic; and data from a physiologically based pharmacokinetic modeling of buprenorphine pharmacokinetics in nonpregnant subjects. RESULTS: Among the 14 women participating in the pharmacokinetic study during and after pregnancy, plasma concentrations of buprenorphine were <1 ng/mL (the theoretical concentration required to prevent withdrawal symptoms) for 50 80% of the 12 hour dosing interval while at steady state. Among 62 women followed up in a opioid agonist treatment program, in which dosing frequency is determined in part by patient preference, 10 (16%) were on once-daily dosing, 10 (16%) were on twice-daily dosing, 28 (45%) were on thrice-daily dosing, and 14 (23%) were on four-times-daily dosing. A physiologically based pharmacokinetic model in nonpregnant subjects demonstrated that dosing frequency has an impact on the duration over which the plasma concentrations are below a specified plasma concentration threshold. CONCLUSION: A more frequent dosing interval (ie, three times-daily or four-times-daily dosing) may be required in pregnant women to sustain plasma concentrations above the threshold of 1 ng/mL to prevent withdrawal symptoms and to improve adherence. PMID- 28669741 TI - Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity. AB - Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53-60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC50=14.91MUM, Ki=0.72uM) over COX-1 (IC50>50MUM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC50=13.09MUM, Ki=0.92uM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs. PMID- 28669742 TI - Attribute importance segmentation of Norwegian seafood consumers: The inclusion of salient packaging attributes. AB - The main purpose of this study is to identify consumer segments based on the importance of product attributes when buying seafood for homemade meals on weekdays. There is a particular focus on the relative importance of the packaging attributes of fresh seafood. The results are based on a representative survey of 840 Norwegian consumers between 18 and 80 years of age. This study found that taste, freshness, nutritional value and naturalness are the most important attributes for the home consumption of seafood. Except for the high importance of information about expiration date, most other packaging attributes have only medium importance. Three consumer segments are identified based on the importance of 33 attributes associated with seafood: Perfectionists, Quality Conscious and Careless Consumers. The Quality Conscious consumers feel more self-confident in their evaluation of quality, and are less concerned with packaging, branding, convenience and emotional benefits compared to the Perfectionists. Careless Consumers are important as regular consumers of convenient and pre-packed seafood products and value recipe information on the packaging. The seafood industry may use the results provided in this study to strengthen their positioning of seafood across three different consumer segments. PMID- 28669744 TI - Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy. PMID- 28669743 TI - Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice. AB - Conflicting data in the literature about the function of P2X7R in survival following ischemia necessitates the conductance of in-depth studies. To investigate the impacts of activation vs inhibition of the receptor on neuronal survival as well as the downstream signaling cascades, in addition to optic nerve transection (ONT), 30min and 90min of middle cerebral artery occlusion (MCAo) models were performed in mice. Intracellular calcium levels were assessed in primary cortical neuron cultures. Here, we show that P2X7R antagonist Brilliant Blue G (BBG) decreased DNA fragmentation, infarct volume, brain swelling, neurological deficit scores and activation of microglial cells after focal cerebral ischemia. BBG also significantly increased the number of surviving retinal ganglion cells (RGCs) after ONT and the number of surviving neurons following MCAo. Importantly, receptor agonist BzATP resulted in increased activation of microglial cells and induced phosphorylation of ERK, AKT and JNK. These results indicated that inhibition of P2X7R with BBG promoted neuronal survival, not through the activation of survival kinase pathways, but possibly by improved intracellular Ca2+ overload and decreased the levels of Caspase 1, IL 1beta and Bax proteins. On the other hand, BzATP-mediated increased number of activated microglia and increased survival kinase levels in addition to increased caspase-1 and IL-1beta levels indicate the complex nature of the P2X7 receptor mediated signaling in neuronal injury. PMID- 28669745 TI - The role of mitochondria in amyotrophic lateral sclerosis. AB - Mitochondria are unique organelles that are essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is a prevalent feature of many neurodegenerative diseases including motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption of mitochondrial structure, dynamics, bioenergetics and calcium buffering has been extensively reported in ALS patients and model systems and has been suggested to be directly involved in disease pathogenesis. Here we review the alterations in mitochondrial parameters in ALS and examine the common pathways to dysfunction. PMID- 28669746 TI - Twitter Activity Associated With U.S. News and World Report Reputation Scores for Urology Departments. AB - OBJECTIVE: To analyze the association between US urology department Twitter presence and U.S. News and World Report (USNWR) reputation scores, to examine the content, informational value, and intended audience of these platforms, and to identify objectives for Twitter use. MATERIALS AND METHODS: We identified Twitter accounts for urology departments scored in the 2016-2017 USNWR. Correlation coefficients were calculated between Twitter metrics (number of followers, following, tweets, and Klout influence scores) with USNWR reputation scores. We also performed a detailed content analysis of urology department tweets during a 6-month period to characterize the content. Finally, we distributed a survey to the urology department accounts via Twitter, inquiring who administers the content, and their objectives for Twitter use. RESULTS: Among 42 scored urology departments with Twitter accounts, the median number of followers, following, and tweets were 337, 193, and 115, respectively. All of these Twitter metrics had a statistically significant positive correlation with reputation scores (P <.05). Content analyses revealed that most tweets were about conferences, education, and publications, targeting the general public or urologic community. Survey results revealed that the primary reason for twitter use among urology departments was visibility and reputation, and urologists are considered the most important target audience. CONCLUSION: There is statistically significant correlation between Twitter activity and USNWR reputation scores for urology departments. Our results suggest that Twitter provides a novel mechanism for urology departments to communicate about academic and educational topics, and social media engagement can enhance reputation. PMID- 28669748 TI - Reduction of severe oropharyngeal hemorrhage following transoral robotic surgery. PMID- 28669747 TI - Sexual Satisfaction: An Opportunity to Explore Overall Health in Men. AB - OBJECTIVE: To evaluate the use of sexual dissatisfaction as a marker of poor overall health. Secondary objectives were to assess the effect of age on this measure and the utility of the Brief Sexual Symptom Checklist (BSSC) for general practitioners (GPs) and patients. METHODS: This is a multicenter, cross-sectional study conducted in Spain among men aged >=50 years presenting with mood disorders or cardiovascular comorbidities (hypertension, dyslipidemia, or diabetes) visiting a GP for any reason. A group of men without these comorbidities were also analyzed. The main outcome measures were prevalence of sexual dissatisfaction, based on the comorbidities analyzed (type, number, or their absence) and problems with sexual function in dissatisfied men (overall and in men aged < 60 or >=60 years). RESULTS: Seven hundred eighteen men aged 61.7 +/- 7.1 years who presented the analyzed comorbidities participated, 69.8% of whom were sexually dissatisfied. Men without comorbidities (n = 144) were younger and had lower prevalence of sexual dissatisfaction (54.2%; P = .001). Sexual dissatisfaction increased with age. Having these comorbidities (especially mood disorders) significantly increased the likelihood of sexual dissatisfaction after adjusting for age. Erection problems and lack of interest in sex were the most reported problems, independent of the presence of comorbidities. Differences in the prevalence of these problems were found in men with and without comorbidities after splitting the population into 2 age groups. GPs and dissatisfied patients found the BSSC useful and easy to use. CONCLUSION: Assessment of sexual satisfaction and related sexual problems using the BSSC could help in approaching men's overall health. Further research is needed. PMID- 28669749 TI - Extracellular vesicles in gastrointestinal cancer in conjunction with microbiota: On the border of Kingdoms. AB - Extracellular vesicle (EV) production is a universal feature of metazoan cells as well as prokaryotes (bMVs - bacterial microvesicles). They are small vesicles with phospholipid membrane carrying proteins, DNA and different classes of RNAs and are heavily involved in intercellular communication acting as vectors of information to target cells. For the last decade, the interest in EV research has exponentially increased though thorough studies of their roles in various pathologies that was not previously possible due to technical limitations. This review focuses on research evaluating the role of EV production in gastrointestinal (GI) cancer development in conjunction with GI microbiota and inflammatory diseases. We also discuss recent studies on the promising role of EVs and their content as biomarkers for early diagnosis of GI cancers. The bMVs have also been implicated in the pathogenesis of GI chronic inflammatory diseases, however, possible role of bMVs in tumorigenesis remains underestimated. We propose that EVs from eukaryotic cells as well as from different microbial, fungi, parasitic species and edible plants in GI tract act as mediators of intracellular and inter-species communication, particularly facilitating tumor cell survival and multi-drug resistance. In conclusion, we suggest that matching sequences from EV proteomes (available from public databases) with known protein sequences of microbiome gut bacteria will be useful in identification of antigen mimicry between evolutionary conservative protein sequences. Using this approach we identified Bacteroides spp. pseudokinase with activation loop and homology to PDGFRalpha, providing a proof-of-concept strategy. We speculate that existence of microbial pseudokinase that 'mimics' PDGFRalpha may be related to PDGFRalpha and Bacteroides spp. roles in colorectal carcinogenesis that require further investigation. PMID- 28669750 TI - EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. AB - Reactivation of an embryonic epithelial-to-mesenchymal (EMT) program is commonly accepted as a core component of carcinoma progression. Collectively, EMT and transcription factors (EMT-TFs) of the ZEB, SNAIL and TWIST families are quoted in the same breath for nearly 20years. Recent work on these EMT-TFs has extended their scope, and their typical definition as EMT-inducing factors has become out of-date. New insights have warranted a re-evaluation of these transcription factors and their pleiotropic functions in physiological and pathological conditions, not solely limited to cell invasion and dissemination. PMID- 28669751 TI - Finite element analysis to investigate variability of MR elastography in the human thigh. AB - PURPOSE: To develop finite element analysis (FEA) of magnetic resonance elastography (MRE) in the human thigh and investigate inter-individual variability of measurement of muscle mechanical properties. METHODS: Segmentation was performed on MRI datasets of the human thigh from 5 individuals and FEA models consisting of 12 muscles and surrounding tissue created. The same material properties were applied to each tissue type and a previously developed transient FEA method of simulating MRE using Abaqus was performed at 4 frequencies. Synthetic noise was applied to the simulated data at various levels before inversion was performed using the Elastography Software Pipeline. Maps of material properties were created and visually assessed to determine key features. The coefficient of variation (CoV) was used to assess the variability of measurements in each individual muscle and in the groups of muscles across the subjects. Mean measurements for the set of muscles were ranked in size order and compared with the expected ranking. RESULTS: At noise levels of 2% the CoV in measurements of |G*| ranged from 5.3 to 21.9% and from 7.1 to 36.1% for measurements of phi in the individual muscles. A positive correlation (R2 value 0.80) was attained when the expected and measured |G*| ranking were compared, whilst a negative correlation (R2 value 0.43) was found for phi. CONCLUSIONS: Created elastograms demonstrated good definition of muscle structure and were robust to noise. Variability of measurements across the 5 subjects was dramatically lower for |G*| than it was for phi. This large variability in phi measurements was attributed to artefacts. PMID- 28669752 TI - Novel molecular adaptation in cancer treatment and diagnostics: The importance of molecular, cellular and ethical aspects in an emerging field. PMID- 28669753 TI - Response to the Cochrane systematic review on DAA-based treatment of chronic hepatitis C. PMID- 28669754 TI - The impact of gut hormones on the neural circuit of appetite and satiety: A systematic review. AB - The brain-gut-axis is an interdependent system affecting neural functions and controlling our eating behaviour. In recent decades, neuroimaging techniques have facilitated its investigation. We systematically looked into functional and neurochemical brain imaging studies investigating how key molecules such as ghrelin, glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY), cholecystokinin (CCK), leptin, glucose and insulin influence the function of brain regions regulating appetite and satiety. Of the 349 studies published before July 2016 identified in the database search, 40 were included (27 on healthy and 13 on obese subjects). Our systematic review suggests that the plasma level of ghrelin, the gut hormone promoting appetite, is positively correlated with activation in the pre-frontal cortex (PFC), amygdala and insula and negatively correlated with activation in subcortical areas such as the hypothalamus. In contrast, the plasma levels of glucose, insulin, leptin, PYY, GLP-1 affect the same brain regions conversely. Our study integrates previous investigations of the gut-brain matrix during food-intake and homeostatic regulation and may be of use for future meta-analyses of brain-gut interactions. PMID- 28669755 TI - Y Chromosome Uncovers the Recent Oriental Origin of Modern Stallions. AB - The Y chromosome directly reflects male genealogies, but the extremely low Y chromosome sequence diversity in horses has prevented the reconstruction of stallion genealogies [1, 2]. Here, we resolve the first Y chromosome genealogy of modern horses by screening 1.46 Mb of the male-specific region of the Y chromosome (MSY) in 52 horses from 21 breeds. Based on highly accurate pedigree data, we estimated the de novo mutation rate of the horse MSY and showed that various modern horse Y chromosome lineages split much later than the domestication of the species. Apart from few private northern European haplotypes, all modern horse breeds clustered together in a roughly 700-year-old haplogroup that was transmitted to Europe by the import of Oriental stallions. The Oriental horse group consisted of two major subclades: the Original Arabian lineage and the Turkoman horse lineage. We show that the English Thoroughbred MSY was derived from the Turkoman lineage and that English Thoroughbred sires are largely responsible for the predominance of this haplotype in modern horses. PMID- 28669756 TI - A Splice Variant of Centrosomin Converts Mitochondria to Microtubule-Organizing Centers. AB - Non-centrosomal microtubule organizing centers (MTOCs) direct microtubule (MT) organization to exert diverse cell-type-specific functions. In Drosophila spermatids, the giant mitochondria provide structural platforms for MT reorganization to support elongation of the extremely long sperm. However, the molecular basis for this mitochondrial MTOC and other non-centrosomal MTOCs has not been discerned. Here we report that Drosophila centrosomin (cnn) expresses two major protein variants: the centrosomal form (CnnC) and a non-centrosomal form in testes (CnnT). CnnC is established as essential for functional centrosomes, the major MTOCs in animal cells. We show that CnnT is expressed exclusively in testes by alternative splicing and localizes to giant mitochondria in spermatids. In cell culture, CnnT targets to the mitochondrial surface, recruits the MT nucleator gamma-tubulin ring complex (gamma-TuRC), and is sufficient to convert mitochondria to MTOCs independent of core pericentriolar proteins that regulate MT assembly at centrosomes. We mapped two separate domains in CnnT: one that is necessary and sufficient to target it to mitochondria and another that is necessary and sufficient to recruit gamma-TuRCs and nucleate MTs. In elongating spermatids, CnnT forms speckles on the giant mitochondria that are required to recruit gamma-TuRCs to organize MTs and support spermiogenesis. This molecular characterization of the mitochondrial MTOC defines a minimal molecular requirement for MTOC generation and implicates the potent role of Cnn (or its related) proteins in the direct regulation of MT assembly and organization of non centrosomal MTOCs. PMID- 28669757 TI - A Peptidergic Circuit Links the Circadian Clock to Locomotor Activity. AB - The mechanisms by which clock neurons in the Drosophila brain confer an ~24-hr rhythm onto locomotor activity are unclear, but involve the neuropeptide diuretic hormone 44 (DH44), an ortholog of corticotropin-releasing factor. Here we identified DH44 receptor 1 as the relevant receptor for rest:activity rhythms and mapped its site of action to hugin-expressing neurons in the subesophageal zone (SEZ). We traced a circuit that extends from Dh44-expressing neurons in the pars intercerebralis (PI) through hugin+ SEZ neurons to the ventral nerve cord. Hugin neuropeptide, a neuromedin U ortholog, also regulates behavioral rhythms. The DH44 PI-Hugin SEZ circuit controls circadian locomotor activity in a daily cycle but has minimal effect on feeding rhythms, suggesting that the circadian drive to feed can be separated from circadian locomotion. These findings define a linear peptidergic circuit that links the clock to motor outputs to modulate circadian control of locomotor activity. PMID- 28669758 TI - Muscle Directs Diurnal Energy Homeostasis through a Myokine-Dependent Hormone Module in Drosophila. AB - Inter-tissue communication is critical to control organismal energy homeostasis in response to temporal changes in feeding and activity or external challenges. Muscle is emerging as a key mediator of this homeostatic control through consumption of lipids, carbohydrates, and amino acids, as well as governing systemic signaling networks. However, it remains less clear how energy substrate usage tissues, such as muscle, communicate with energy substrate storage tissues in order to adapt with diurnal changes in energy supply and demand. Using Drosophila, we show here that muscle plays a crucial physiological role in promoting systemic synthesis and accumulation of lipids in fat storage tissues, which subsequently impacts diurnal changes in circulating lipid levels. Our data reveal that the metabolic transcription factor Foxo governs expression of the cytokine unpaired 2 (Upd2) in skeletal muscle, which acts as a myokine to control glucagon-like adipokinetic hormone (AKH) secretion from specialized neuroendocrine cells. Circulating AKH levels in turn regulate lipid homeostasis in fat body/adipose and the intestine. Our data also reveal that this novel myokine-dependent hormone module is critical to maintain diurnal rhythms in circulating lipids. This tissue crosstalk provides a putative mechanism that allows muscle to integrate autonomous energy demand with systemic energy storage and turnover. Together, these findings reveal a diurnal inter-tissue signaling network between muscle and fat storage tissues that constitutes an ancestral mechanism governing systemic energy homeostasis. PMID- 28669760 TI - Eight Millennia of Matrilineal Genetic Continuity in the South Caucasus. AB - The South Caucasus, situated between the Black and Caspian Seas, geographically links Europe with the Near East and has served as a crossroad for human migrations for many millennia [1-7]. Despite a vast archaeological record showing distinct cultural turnovers, the demographic events that shaped the human populations of this region is not known [8, 9]. To shed light on the maternal genetic history of the region, we analyzed the complete mitochondrial genomes of 52 ancient skeletons from present-day Armenia and Artsakh spanning 7,800 years and combined this dataset with 206 mitochondrial genomes of modern Armenians. We also included previously published data of seven neighboring populations (n = 482). Coalescence-based analyses suggest that the population size in this region rapidly increased after the Last Glacial Maximum ca. 18 kya. We find that the lowest genetic distance in this dataset is between modern Armenians and the ancient individuals, as also reflected in both network analyses and discriminant analysis of principal components. We used approximate Bayesian computation to test five different demographic scenarios explaining the formation of the modern Armenian gene pool. Despite well documented cultural shifts in the South Caucasus across this time period, our results strongly favor a genetic continuity model in the maternal gene pool. This has implications for interpreting prehistoric migration dynamics and cultural shifts in this part of the world. PMID- 28669759 TI - SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors. AB - Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well known limitations of tumor-associated macrophages (TAMs). Here, SIRPalpha on macrophages from mouse and human marrow was inhibited to block recognition of its ligand, the "marker of self" CD47 on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted. Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the macrophages engulfed, the more they accumulated within regressing tumors. Human-marrow-derived macrophages engorged on the human tumors, while TAMs were minimally phagocytic, even toward CD47-knockdown tumors. Past studies had opsonized tumors in situ with antibody and/or relied on mouse TAMs but had not injected SIRPalpha-inhibited cells; also, unlike past injections of anti-CD47, blood parameters remained normal and safe. Consistent with tumor-selective engorge-and-accumulate processes in vivo, phagocytosis in vitro inhibited macrophage migration through micropores that mimic features of dense 3D tissue. Accumulation of SIRPalpha-inhibited macrophages in tumors favored tumor regression for 1-2 weeks, but donor macrophages quickly differentiated toward non-phagocytic, high-SIRPalpha TAMs. Analyses of macrophages on soft (like marrow) or stiff (like solid tumors) collagenous gels demonstrated a stiffness-driven, retinoic-acid-modulated upregulation of SIRPalpha and the mechanosensitive nuclear marker lamin-A. Mechanosensitive differentiation was similarly evident in vivo and likely limited the anti-tumor effects, as confirmed by re-initiation of tumor regression by fresh injections of SIRPalpha-inhibited macrophages. Macrophage motility, phagocytosis, and differentiation in vivo are thus coupled. PMID- 28669761 TI - The Origin of Filter Feeding in Whales. AB - As the largest known vertebrates of all time, mysticetes depend on keratinous sieves called baleen to capture enough small prey to sustain their enormous size [1]. The origins of baleen are controversial: one hypothesis suggests that teeth were lost during a suction-feeding stage of mysticete evolution and that baleen evolved thereafter [2-4], whereas another suggests that baleen evolved before teeth were lost [5]. Here we report a new species of toothed mysticete, Coronodon havensteini, from the Oligocene of South Carolina that is transitional between raptorial archaeocete whales and modern mysticetes. Although the morphology and wear on its anterior teeth indicate that it captured large prey, its broad, imbricated, multi-cusped lower molars frame narrow slots that were likely used for filter feeding. Coronodon havensteini is a basal, if not the most basal, mysticete, and our analysis suggests that it is representative of an initial stage of mysticete evolution in which teeth were functional analogs to baleen. In later lineages, the diastema between teeth increased-in some cases, markedly so [6]-and may mark a stage at which the balance of the oral fissure shifted from mostly teeth to mostly baleen. When placed in a phylogenetic context, our new taxon indicates that filter feeding was preceded by raptorial feeding and that suction feeding evolved separately within a clade removed from modern baleen whales. PMID- 28669763 TI - New species in the papaya ringspot virus cluster: Insights into the evolution of the PRSV lineage. AB - The "Papaya ringspot virus (PRSV) cluster" of cucurbit-infecting potyviruses contains five acknowledged species that have similar biological, serological and molecular properties. Additional data suggest there are other uncharacterized species from various locations in the world that likely belong to the PRSV cluster including a new PRSV-like virus reported from Sudan in 2003. Molecular and biological data indicated that the virus from Sudan belongs to a new species, tentatively named wild melon vein banding virus (WMVBV). The complete nucleotide sequence of a second virus from Sudan revealed it was a divergent relative of Moroccan watermelon mosaic virus (MWMV). Based on sequence similarity this virus was determined to be a distinct species and tentatively named Sudan watermelon mosaic virus (SuWMV). Molecular analyses indicate that SuWMV is a recombinant between WMVBV- and MWMV-related viruses. Based on surveys performed in Sudan between 1992 and 2012, SuWMV appeared 10 times more frequent than WMVBV in that country (14.6% vs. 1.5% of the samples tested). The geographic structure and molecular diversity patterns of the putative and acknowledged species suggest that the PRSV-like cluster originated in the Old World about 3600 years ago, with an important diversification in Africa. PMID- 28669762 TI - Space-Specific Deficits in Visual Orientation Discrimination Caused by Lesions in the Midbrain Stimulus Selection Network. AB - Perceptual decisions require both analysis of sensory information and selective routing of relevant information to decision networks. This study explores the contribution of a midbrain network to visual perception in chickens. Analysis of visual orientation information in birds takes place in the forebrain sensory area called the Wulst, as it does in the primary visual cortex (V1) of mammals. In contrast, the midbrain, which receives parallel retinal input, encodes orientation poorly, if at all. We discovered, however, that small electrolytic lesions in the midbrain severely impair a chicken's ability to discriminate orientations. Focal lesions were placed in the optic tectum (OT) and in the nucleus isthmi pars parvocellularis (Ipc)-key nodes in the midbrain stimulus selection network-in chickens trained to perform an orientation discrimination task. A lesion in the OT caused a severe impairment in orientation discrimination specifically for targets at the location in space represented by the lesioned location. Distracting stimuli increased the deficit. A lesion in the Ipc produced similar but more transient effects. We discuss the possibilities that performance deficits were caused by interference with orientation information processing (sensory deficit) versus with the routing of information in the forebrain (agnosia). The data support the proposal that the OT transmits a space-specific signal that is required to gate orientation information from the Wulst into networks that mediate behavioral decisions, analogous to the role of ascending signals from the superior colliculus (SC) in monkeys. Furthermore, our results indicate a critical role for the cholinergic Ipc in this gating process. PMID- 28669765 TI - Independent Validation of the American Joint Committee on Cancer 8th Edition Prostate Cancer Staging Classification. AB - PURPOSE: We sought to independently validate the AJCC (American Joint Committee on Cancer) 8th edition prostate cancer staging classification, which includes the elimination of pT2 subcategories and the reclassification of patients with prostate specific antigen 20 ng/ml or greater and Gleason Grade Group 5 as stage groups III-A and III-C, respectively. MATERIALS AND METHODS: We identified 13,839 men who underwent radical prostatectomy at Mayo Clinic between 1987 and 2011 from our institutional registry. Outcomes included biochemical recurrence-free, metastasis-free and cancer specific survival. Kaplan-Meier analyses and Cox regression models with the c-index were used. RESULTS: Median followup was 10.5 years (IQR 7.1-15.3). Among patients with pT2 prostate cancer the subclassification demonstrated limited discrimination for biochemical recurrence free, metastasis-free and cancer specific survival (c-index 0.531, 0.545 and 0.525, respectively). At the same time patients with 7th edition stage group II prostate cancer and prostate specific antigen 20 ng/ml or greater had significantly worse 15-year biochemical recurrence-free survival (42.2% vs 58.8%), metastasis-free survival (78.2% vs 88.8%) and cancer specific survival (88.0% vs 94.4%, all p <0.001) than patients with 7th edition stage group II prostate cancer and prostate specific antigen less than 20 ng/ml. However, patients with 7th edition stage group II prostate cancer and prostate specific antigen 20 ng/ml or greater had significantly better 15-year biochemical recurrence-free survival (42.2% vs 31.3%, p = 0.007), metastasis-free survival (78.2% vs 68.0%, p <0.001) and cancer specific survival (88.0% vs 83.4%, p = 0.01) than patients with 7th edition stage group III. Also, patients with 7th edition stage group II prostate cancer and Gleason Grade Group 5 had significantly worse 15-year biochemical recurrence-free survival (37.1% vs 57.9%, p <0.001), metastasis-free survival (63.8% vs 88.5%, p <0.001) and cancer specific survival (73.0% vs 94.3%, p <0.001) than patients with 7th edition stage group II prostate cancer and Gleason Grade Group 1-4 as well as worse 15-year cancer specific survival (73.0% vs 83.4%, p = 0.005) than patients with 7th edition stage group III prostate cancer. CONCLUSIONS: Our data support the changes in the new AJCC classification. PMID- 28669764 TI - Isolation and characterization of a highly evolved type 3 vaccine-derived poliovirus in China. AB - In this study, we report the identification and characterization of a highly evolved type 3 vaccine-derived poliovirus (VDPV) strain designated as WIV14, isolated in 2014 from a 4-year-old child suspected of having an enteroviral infection in China. Complete genome sequence of WIV14 revealed multiple nucleotide substitutions when compared with the attenuated poliovirus (PV) Sabin 3, including the reversion of three major attenuation sites to wild type. From the nucleotide divergence for the P1/capsid region, we estimated that the evolution time of WIV14 was more than 7 years, indicating the possible long time of replication. WIV14 strain seemed to have differences in biological characteristics compared with attenuated PV strains, such as being non temperature-sensitive and producing large plaques. The current isolation of a highly divergent type 3 VDPV gives an idea of the risk of emergent VDPV strains, and emphasizes the importance of maintaining high vaccination coverage and herd immunity against PVs in China. PMID- 28669766 TI - Yeast Tok1p channel is a major contributor to membrane potential maintenance under chemical stress. AB - Tok1p is a highly specific yeast plasma membrane potassium channel with strong outward directionality. Its opening is induced by membrane depolarization. Although the biophysical properties of Tok1p are well-described, its potentially important physiological role is currently largely unexplored. To address this issue, we examined the Tok1p activity following chemically-induced depolarization by measuring changes of plasma membrane potential (DeltaPsi) using the diS-C3(3) fluorescence assay in a Tok1p-expressing and a Tok1p-deficient strain. We report that Tok1p channel activity in response to chemical stress does not depend solely on the extent of depolarization, as might have been expected, but may also be negatively influenced by accompanying effects of the used compound. The stressors may interact with the plasma membrane or the channel itself, or cause cytosolic acidification. All of these effects may negatively influence the Tok1p channel opening. While ODDC-induced depolarization exhibits the cleanest Tok1p activation, restoring an astonishing 75% of lost DeltaPsi, higher BAC concentrations reduce Tok1p activity, probably because of direct interactions with the channel and/or its lipid microenvironment. This is not only the first study of the physiological role of Tok1p in DeltaPsi maintenance under chemical stress, but also the first estimate of the extent of depolarization the channel is able to counterbalance. PMID- 28669768 TI - Long-term Outcome of Patients With Tachycardia-induced Cardiomyopathy After Recovery of Left Ventricular Function. PMID- 28669767 TI - Bactericidal activity of cyclotides where phosphatidylethanolamine-lipid selectivity determines antimicrobial spectra. AB - Cyclotides are a family of plant peptides characterized by a cystine knot embedded in a macrocyclic backbone. They bind to and disrupt phospholipid membranes, which explain their lytic activity on cells. In this study, we expose the full antibacterial potency of cyclotides by avoiding its inhibition by rich growth media assay conditions. For that purpose a two-step microdilution assay protocol was developed, using non-growing conditions during initial peptide incubation. A diverse set of cyclotides was tested for antibacterial and antifungal activity, and the results show that most cyclotides are active under these conditions, especially against Gram-negative bacteria. Activity was observed at sub-micromolar concentrations for three of the cyclotides tested, surpassing that of the control peptides LL-37 and melittin. Noteworthy, two anionic cyclotides were active on Pseudomonas aeruginosa at low micromolar concentrations. Broad-spectrum activity was pronounced among cycloviolacin cyclotides, which included activity on Staphylococcus aureus and Candida albicans. The factors influencing their bactericidal spectrum were revealed by correlating antimicrobial activity with membrane permeabilization on various liposome systems and with the physiochemical properties of the cyclotides. Whereas general electrostatic and hydrophobic parameters are more important for broad-spectrum cyclotides; a phospholipid-specific mechanism of membrane permeabilization, through interaction with phosphatidylethanolamine-lipids, is essential for cyclotides active primarily on Gram-negative bacteria. PMID- 28669769 TI - Interview With Thomas Coates, PhD. PMID- 28669770 TI - Feedback on a Multimodal Cognitive Intervention for Adults Aging With HIV: A Focus Group Study. AB - Nearly 50% of adult persons living with HIV (PLWH) experience HIV-associated neurocognitive disorder (HAND), which is associated with deteriorating brain health and cognitive functioning. Multimodal interventions that simultaneously improve physical activity, nutrition, and sleep hygiene may be of value for adult PLWH, especially as they age and become vulnerable to HAND. We used four focus groups of PLWH (N = 30; ages >= 50 years) to solicit feedback about Cognitive Prescriptions, a multimodal cognitive intervention. Lifestyle and health behaviors pertaining to Cognitive Prescriptions were assessed, including: (a) physical activity, (b) mental activity, (c) nutrition, (d) social engagement, (e) emotional health, (f) sleep hygiene, and (g) substance use. When presented a template of the intervention, participants expressed favorable opinions and remarked they would want to work with a clinician, paraprofessional, or peer to implement such a program into their own daily routines. From this, implications for practice and research are provided. PMID- 28669771 TI - Antidiabetic, antioxidant and anti inflammatory properties of water and n-butanol soluble extracts from Saharian Anvillea radiata in high-fat-diet fed mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: According to Saharian traditional medicine, Anvillea radiata Coss. & Dur. (Asteraceae) has been valued for treating a variety of ailments such as gastro-intestinal, liver and pulmonary diseases, and has gained awareness for its beneficial effect on postprandial hyperglycemia. However, to best of our knowledge, no detailed study of the antidiabetic curative effects of this plant has been conducted yet. AIM OF THE STUDY: To determine the hypoglycemic and antidiabetic effect of dietary supplementation with Anvillea radiata extracts on high-fat-diet (HFD)-induced obesity and insulin resistance in C57BL/6J mice in relation with antioxidant, anti-inflammatory, pancreatic beta cells and skeletal muscle protection, and digestive enzyme inhibiting properties. MATERIALS AND METHODS: Six extracts (water soluble and organic) from aerial parts of the plant were analyzed phytochemically (total phenolic and flavonoid content) and screened for in vitro superoxide (by chemiluminescence) and hydroxyl radical (by electron paramagnetic resonance spin-trapping) scavenging, antioxidant (DPPH, TRAP and ORAC assays), xanthine oxidase, metal chelating, alpha-amylase and alpha glucosidase inhibitory property, and protective effects on copper-induced lipoprotein oxidation. Then selected hydroalcoholic and aqueous extracts were assessed for toxicity in normal human lung fibroblasts and A549 cancer cells using FMCA and MTT assays. Two water-soluble extracts having the best overall properties were assessed for their (i) protective effect at 1-15ug/mL on metabolic activity of rat insulinoma-derived INS-1 cells exposed to hyperglycemic medium, and (ii) acute hypoglycemic effect on 16-weeks HFD-induced diabetic mice. Then diabetic mice were administered HFD supplemented by extracts (up to 150mg/kg/day) for 12 additional weeks using standard diet as control and the antidiabetic drug, metformin (150mg/kg), as positive control. Then the antidiabetic, anti-inflammatory and antioxidant activity of extracts were determined. RESULTS: Of the highly efficient polyphenolics-enriched hydroalcoholic and ethyl acetate extracts, the lyophilized aqueous (AQL) and butanol extracts were not toxic in cells (<= 400ug/mL) or when given orally in normal mice (<= 2000mg/kg), exerted a dose-dependent hypoglycemic action in diabetic mice, which was maximal at the dose of 150mg/kg. Upon administering this dose for 12 weeks, both extracts significantly ameliorated body weight control capacity, recovery of plasma glucose and insulin level, reduced oxidative stress in blood, myocardial and skeletal muscles, and improved hyperlipidemic and inflammatory status. Moreover, diabetes-related complications were optimally ameliorated by oral therapy based on halved doses (75mg/kg) of a mixture of AQL and metformin. CONCLUSIONS: Current investigation supports the traditional medicinal usage of Anvillea radiata and suggests that both readily accessible and low-cost bio-extracts have the potency to develop an antihyperglycemic, antihyperlipidemic and protective agent against beta-cells and muscle dysfunction at doses compatible with the common practices of indigenous people for the management of metabolic disorders. PMID- 28669772 TI - Naoxintong inhibits myocardial infarction injury by VEGF/eNOS signaling-mediated neovascularization. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Naoxintong capsules (NXT), a traditional Chinese Medical preparation, are widely used for treatment of cardiovascular diseases, while the mechanism is still unclear. MATERIALS AND METHODS: Myocardial infarction (MI) was induced by ligation of the left coronary artery in mice. Echocardiographic measurements were performed to do physiological assessments of left ventricle (LV) function. Histological and immunohistochemical staining was used to determine infarct size, capillary density, tissue endothelial nitric oxide synthase (eNOS) expression. Bone Marrow Transplantation (BMT) model and flow cytometric (FCM) analyses were applied to assay endothelial progenitor cells (EPCs) mobilization. Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blotting and enzyme-linked immunosorbent assay (ELISA) were performed to detect the expressions of vascular endothelial growth factor (VEGF), kinase domain region (KDR), phosphorylated-Akt (p-Akt), phosphorylated-eNOS (p-eNOS). RESULTS: NXT administration reduced myocardium fibrosis and increased myocardium capillary density in response to MI. NXT increased circulating Sca1+/ Fetal liver kinase 1 (Flk1)+ mononuclear cells (MNCs) and soluble Kit ligand (sKitL) of bone marrow (BM) in response to MI. In mice transplanted with green fluorescent protein (GFP) BM cells, NXT increased the numbers of GFP-positive cells at the border zone of the ischemic region in MI induced mice. NXT increased the numbers of eNOS-expressing BM-derived cells in tissues, which was involved in increased the expressions of VEGF, KDR, p-eNOS, p Akt in the myocardium. CONCLUSION: NXT-mediated recovery in MI-induced mice was involved in mobilization and incorporation of bone marrow-derived EPCs/circulating angiogenic cells (CACs) leading to enhancement of neovascularization via VEGF/eNOS signaling. PMID- 28669773 TI - Development of a methodological approach for the characterization of bioaerosols in exhaust air from pig fattening farms with MALDI-TOF mass spectrometry. AB - In this paper, we evaluated matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) as a cultivation-independent, routinely applicable approach to identify microbial fractions in bioaerosol emission samples. We developed a streamlined protocol in line with the German state-of-the art impingement sampling guideline. Following isokinetic sampling, a fast and reliable pre-treatment methodology involving a series of cascade filtration steps was implemented, which produced fractions for spectrometric measurement devoid of interfering substances. We sampled the exhaust air from eight pig fattening farms around western Germany, which yielded two sets of samples for both method development and validation. For method development, in total 65 bacterial isolates were produced directly from the exhaust air samples, taxonomically classified by 16S rRNA-Gene sequencing, and subjected to MALDI-TOF analysis. In this way, we could assign fingerprint biomarkers to classified bacterial genera or even species to build up a preliminary reference database. For verification of the novel methodology and application of the reference database, we subjected the second set of exhaust air samples to the developed protocol. Here, 18 out of 21 bacterial species deposited in the database were successfully retrieved, including organisms classified in risk group 2, which might be used to evaluate the pathogenic potential of sampled exhaust air. Overall, this study pursues an entirely new approach to rapidly analyze airborne microbial fractions. PMID- 28669774 TI - How well do patients with a first episode of schizophrenia respond to antipsychotics: A systematic review and meta-analysis. AB - It is often stated that first-episode patients tend to respond better to antipsychotics than chronic patients, but the exact numbers and moderators of response in this population are unclear. We, therefore, present the first systematic review on response rates of first episode patients with schizophrenia in randomized trials. We searched multiple databases for randomized-controlled trials of antipsychotics in acutely ill patients with a first episode of schizophrenia (last search: November 17, 2016). The outcomes were response rate based on two criteria, at least 50% PANSS or BPRS total score reduction from baseline and at least 20% reduction. Data were pooled in a single-group summary meta-analysis using Comprehensive Meta-Analysis software. Moreover, several potential moderators of response to antipsychotics were examined by meta regression. We included 17 studies with a total of 3156 participants. On the average, 81.3%/51.9% of the first-episode patients reached an at least 20%/50% PANSS or BPRS reduction from baseline, respectively. Meta-regressions revealed a better treatment response in female patients, in more severely ill patients at baseline, in antipsychotic naive patients, in patients with a shorter illness duration and in open studies. Study duration and dosage were no significant moderators of response. Our finding suggest that more than 80% of first-episode patients achieved 20% PANSS/BPRS reduction from baseline and around 50% achieved a 50% PANSS/BPRS reduction. Several patient characteristics moderated response rates. PMID- 28669775 TI - Investigation of the contribution of RyR target-site mutations in diamide resistance by CRISPR/Cas9 genome modification in Drosophila. AB - Diamide insecticides are used widely against lepidopteran pests, acting as potent activators of insect Ryanodine Receptors (RyRs) and thus inducing muscle contraction and eventually death. However, resistant phenotypes have recently evolved in the field, associated with the emergence of target site resistance mutations (G4946E/V and I4790M). We investigated the frequency of the mutations found in a resistant population of Tuta absoluta from Greece (G4946V ~79% and I4790M ~21%) and the associated diamide resistance profile: there are very high levels of resistance against chlorantraniliprole (9329-fold) and flubendiamide (4969-fold), but moderate levels against cyantraniliprole (191-fold). To further investigate functionally the contribution of each mutation in the resistant phenotype, we used CRISPR/Cas9 to generate genome modified Drosophila carrying alternative allele combinations, and performed toxicity bioassays against all three diamides. Genome modified flies bearing the G4946V mutation exhibited high resistance ratios to flubendiamide (91.3-fold) and chlorantraniliprole (194.7 fold) when compared to cyantraniliprole (5.4-fold). Flies naturally wildtype for the I4790M mutation were moderately resistant to flubendiamide (15.3-fold) but significantly less resistant to chlorantraniliprole (7.5-fold), and cyantraniliprole (2.3-fold). These findings provide in vivo functional genetic confirmation for the role and relative contribution of RyR mutations in diamide resistance and suggest that the mutations confer subtle differences on the relative binding affinities of the three diamides at an overlapping binding site on the RyR protein. PMID- 28669777 TI - Impaired Autoregulation of Blood Flow at the Optic Nerve Head During Vitrectomy in Patients With Type 2 Diabetes. AB - PURPOSE: To determine whether type 2 diabetes mellitus (T2DM) influences autoregulation of optic nerve head (ONH) blood flow during vitrectomy. DESIGN: Cohort study. METHODS: Thirteen eyes of 13 subjects with T2DM and 30 eyes of 30 controls without T2DM undergoing vitrectomy for epiretinal membrane or macular hole were included. Following 25 gauge vitrectomy, we measured the mean blur rate (MBR), an index of ONH blood flow, in the vascular area (vascular MBR) and in the tissue area (tissue MBR) using laser speckle flowgraphy. We performed measurements before and 5 and 10 minutes after intraocular pressure (IOP) elevation of approximately 15 mm Hg; both parameters represent relative values (%, compared with baseline). We calculated the vascular MBR recovery rate as (vascular MBR at 10 min-vascular MBR at 5 min)/(vascular MBR at baseline-vascular MBR at 5 min). RESULTS: Vascular MBR in T2DM subjects was significantly lower than that in controls at 5 and 10 minutes after IOP elevation (P = .0328 and P < .0001, respectively). Tissue MBR was also significantly lower in T2DM subjects than in controls at both time points (P = .0253 and P = .0004, respectively). Vascular MBR recovery rate was significantly lower in the T2DM than in the control group (P = .0090). Furthermore, the vascular MBR recovery rate was significantly negatively correlated with hemoglobin A1c and fasting plasma glucose levels (P = .0284 and P = .0381, respectively). CONCLUSIONS: T2DM is associated with impaired ONH blood flow autoregulation in both vascular and tissue areas when subjected to change in IOP during vitrectomy. PMID- 28669776 TI - Association of Vascular Versus Avascular Subretinal Hyperreflective Material With Aflibercept Response in Age-related Macular Degeneration. AB - PURPOSE: To investigate flow signal within subretinal hyperreflective material (SHRM) using optical coherence tomography angiography (OCTA) and its association with aflibercept treatment responses in treatment-naive neovascular age-related macular degeneration (nAMD). DESIGN: Prospective consecutive interventional case series. METHODS: Forty-four eyes of 44 patients with treatment-naive nAMD manifesting SHRM on OCT were studied. All patients underwent OCTA and received 3 monthly aflibercept injections. The intrinsic flow signals within SHRM were quantitatively analyzed using OCTA, and eyes were classified into the vascular and avascular SHRM groups. RESULTS: Of 44 eyes, 21 (47.7%) and 23 (52.3%) showed vascular SHRM and avascular SHRM, respectively. Compared with eyes with avascular SHRM, eyes with vascular SHRM showed higher rates of external limiting membrane (ELM) disruption owing to SHRM (P = .015), classic choroidal neovascularization (CNV) (85.7% vs 26.1%, P = .87 * 10-4), and intraretinal fluid (P = .008) at baseline. After 3 aflibercept injections, 38 eyes (86.4%) showed dry macula despite persistent SHRM in 24 eyes (54.5%). Compared with the eyes with resolved SHRM, those with persistent SHRM showed higher rate of vascular SHRM (75.0% vs 15.0%, P = .86 * 10-4), classic CNV (P = .032), absence of polypoidal lesion (P = .020), ELM disruption owing to SHRM (P = .042), and intraretinal fluid (P = .008). Dry macula after loading injections was significantly associated with SHRM resolution (P = .025). CONCLUSIONS: In nAMD, SHRM can be categorized as vascular and avascular by quantitative OCTA analysis. Vascular SHRM persisted after treatment and was associated with failure to achieve dry macula, suggesting that vascular SHRM is predictive of lower response to anti-VEGF therapy. PMID- 28669778 TI - Conjunctival Goblet Cell Density Following Cataract Surgery With Diclofenac Versus Diclofenac and Rebamipide: A Randomized Trial. AB - PURPOSE: To determine the effects of topical diclofenac or betamethasone with concomitant application of topical rebamipide on the conjunctival goblet cell density in eyes after cataract surgery. DESIGN: Randomized clinical trial. PARTICIPANTS: Eighty patients who were scheduled for cataract surgery. METHODS: Patients were randomized into 4 groups according to the postoperative topical drugs to be given; Group A, diclofenac alone; Group B, diclofenac and rebamipide; Group C, betamethasone alone; and Group D, betamethasone and rebamipide. Impression cytology was performed before and at 1 month after the surgery, and the mean density of goblet cells was determined. RESULTS: The mean (+/- SD) density of goblet cells before the surgery in Group A was 257.0 +/- 188.7 cells/mm2, and it decreased significantly to 86.5 +/- 76.7 cells/mm2 at 1 month after the surgery (P = .002). In Group B, the goblet cell density was not statistically different between before (238.5 +/- 116.6 cells/mm2) and at 1 month after the surgery (211.3 +/- 184.4 cells/mm2, P = .55). In Groups C and D, the mean density of goblet cells was decreased at 1 month after the surgery, but the decreases were not significant (P = .11 and P = .52, respectively). CONCLUSION: After cataract surgery with postoperative topical diclofenac, the conjunctival goblet cell density was significantly reduced, and this reduction was blocked by the concomitant use of topical rebamipide. These results suggest that the concomitant use of topical rebamipide with nonsteroidal anti-inflammatory drugs is beneficial, especially in cases with postoperative dry eyes. PMID- 28669779 TI - Combined Hamartoma of the Retina and Retinal Pigment Epithelium: An Optical Coherence Tomography-Based Reappraisal. AB - PURPOSE: To analyze the optical coherence tomography (OCT) characteristics of combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) involving the macula. DESIGN: Retrospective, observational case series. METHODS: setting: Single institutional. STUDY POPULATION: Fourteen consecutive patients of CHRRPE were included. OBSERVATION PROCEDURES: The authors analyzed the clinical features, color fundus photography, and swept-source or spectral-domain OCT of all the involved eyes. MAIN OUTCOME MEASURES: OCT characteristics, especially the involvement of the retinal pigment epithelium (RPE). RESULTS: A total of 16 eyes of 5 female and 9 male patients were analyzed. The mean age (+/- SD) was 17.9 +/- 6.4 (range 10-34) years. Mean best-corrected visual acuity (+/- SD) in logMAR was 0.9 +/- 0.5 (20/160 +/- 20/60). The OCT was suggestive of a focal mass-like lesion primarily involving the inner retinal layers limited externally by the outer plexiform layer (OPL) in 15 eyes (93.7%). The OPL appeared to have a saw tooth appearance ("intraretinal peaks") in 12 eyes (75%). The convolutions of the OPL were broader and deeper in some eyes (5 eyes, 31.2%), giving an "omega sign" (omega) appearance. The ellipsoid zone appeared intact in 13 eyes (81.2%). The RPE band appeared intact in all eyes. CONCLUSIONS: Considering the OCT features, available evidence, and embryology, we propose that the true nature of CHRRPE should be reanalyzed. In our series, CHRRPE was noted to be primarily a hamartoma arising from the inner retinal layers. A majority of cases were limited posteriorly by the OPL without any involvement of the outer retinal layers and RPE. PMID- 28669780 TI - Impact of Normal Aging and Progression Definitions on the Specificity of Detecting Retinal Nerve Fiber Layer Thinning. AB - PURPOSE: To evaluate the specificity of current definitions used to identify progressive change of the average peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained on optical coherence tomography (OCT) imaging. DESIGN: Prospective observational cohort study. METHODS: Setting: University of California, San Diego. STUDY POPULATION: Seventy-five eyes from 45 normal participants. OBSERVATION PROCEDURE: Patients were seen at an average of 5.7 visits over 3.2 years, to determine the age-related average RNFL thickness changes and longitudinal measurement variability. Slope and variability estimates were used to reconstruct "real-world" OCT imaging measurements with computer simulations. MAIN OUTCOME MEASURE: False-positive rates for progression in normal eyes using different definitions. RESULTS: The estimated normal average RNFL thickness change over time was -0.54 +/- 0.23 MUm/year (P < .001). Even with a recent definition of progression that appeared to guarantee a high level of specificity by accounting for normal aging (requiring a significant negative slope that was more negative than the 5% lower limit of aging), 18% simulated normal eyes were still falsely identified as having progressed after 5 years of annual testing in a clinical practice scenario. However, this was reduced to 8% and 4% when trend-based analysis of progression was performed after adjustments using the mean and 5% lower limit of normal rates of aging, respectively. CONCLUSIONS: This study highlights how current definitions for detecting RNFL thinning have an unacceptably poor level of specificity, and that more stringent definitions are required to avoid misleading interpretations of progression on OCT imaging in clinical practice. PMID- 28669781 TI - Prevalence of Diabetic Retinopathy and Blindness in Indonesian Adults With Type 2 Diabetes. AB - PURPOSE: To report the prevalence of diabetic retinopathy (DR) and DR-related blindness in an Indonesian population with type 2 diabetes. METHODS: Design: Population-based cross-sectional study. SETTING: Community health centers. STUDY POPULATION: We recruited 1184 people aged older than 30 years with type 2 diabetes residing in Jogjakarta, Indonesia. Multistage, clustered random sampling based on regencies and districts in Jogjakarta was used. OBSERVATION PROCEDURE: Detailed interviews, general and eye examinations, and anthropometric measurement were performed. Disc- and macula-centered retinal photographs were taken to assess DR. The definition of DR followed a modified Airlie House classification system and was categorized into mild, moderate, and vision-threatening DR (VTDR). MAIN OUTCOME MEASURE(S): Prevalence and severity of DR. RESULTS: The median (range) age and diabetes duration of participants was 59 (52-65) and 4 (2-9) years. The prevalence of DR was 43.1% (95% confidence interval 39.6%-46.6%), with mild, moderate, and severe NPDR and PDR to be 9.41%, 7.46%, 11.1%, and 12.1%, respectively. The prevalence of VTDR was 26.3% (23.1%-29.5%). Longer diabetes duration, higher fasting glucose, presence of hypertension, and foot ulcers were associated with DR and VTDR. The prevalence of bilateral blindness was 4% and 7.7% in persons with DR and VTDR. CONCLUSIONS: This study reports a high prevalence of any DR and VTDR among Indonesian adults with type 2 diabetes in urban and rural areas: approximately 1 in 4 adults with diabetes had VTDR and 1 in 12 of those with VTDR was bilaterally blind, suggesting the need for appropriate screening and management of DR among the Indonesian population. PMID- 28669782 TI - The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation. AB - The tribbles (trbl) pseudokinases play important roles in signaling and physiology in multiple contexts, ranging from innate immunity to cancer, suggesting fundamental cellular functions for the trbls' gene products. Despite expression of the trbl pseudokinases in the nervous systems of invertebrate and vertebrate animals, and evidence that they have a function within mouse and human dopamine neurons, there is no clear case for a function of a Trbl protein that influences behavior. Indeed, the first and only evidence for this type of function comes from Drosophila melanogaster, where a mutation of the single trbl gene was identified in a genetic screen for short-term memory mutant flies. The current study tested flies containing multiple trbl mutant alleles and potential transgenic rescue in both operant place memory and classical olfactory memory paradigms. Genetic complementation tests and transgenic rescue of memory phenotypes in both paradigms show that the D. melanogaster trbl pseudokinase is essential for proper memory formation. Expression analysis with a polyclonal antiserum against Trbl shows that the protein is expressed widely in the fly brain, with higher expression in the cellular rind than the neuropil. Rescue of the behavioral phenotype with transgenic expression indicates the trbl function can be localized to a subset of the nervous system. Thus, we provide the first compelling case for the function of a trbl pseudokinase in the regulation of behavior. PMID- 28669783 TI - GABAergic signaling within the Basolateral Amygdala Complex modulates resistance to the labilization/reconsolidation process. AB - It is well known that stress can affect mnemonic processes. In particular, stress before contextual fear conditioning induces a memory which exhibits resistance to being interfered with by Midazolam (MDZ) when applied after memory retrieval. Moreover, stress exposure strongly affects GABAergic transmission within the Basolateral Amygdala Complex (BLA), a brain structure critically involved in fear memory processing. The present study evaluated the involvement of GABAergic signaling within the BLA on the induction of resistance to memory reconsolidation interference. Results showed that MDZ administered intra-BLA before stress prevented the induction of resistance to the interfering effect of systemic administration of both MDZ and Propranolol on fear memory reconsolidation, when both applied after memory retrieval. The blockade of amygdala GABA-A receptors by the antagonist Bicuculline (BIC) before memory encoding induced resistance to interference by post-recall MDZ administration, similarly to that observed with stress exposure. Additionally, the systemic administration of d-cycloserine, a positive allosteric modulator of NMDA receptor, reverted the BIC-induced resistance to the MDZ interfering effect, in the same manner as that reported with stress-induced resistance. In summary, these results suggest that the GABAergic signaling in the BLA at the moment of memory encoding is determinant for the induction of fear memory resistance to the onset of the labilization/reconsolidation process. PMID- 28669784 TI - Neural correlates of prosocial behavior towards persons in pain in healthcare providers. AB - Pain perceived in others can be a stressful signal that elicits personal distress and discomfort that can interfere with prosocial behaviors. Healthcare providers (HCPs) have to be able to regulate these self-oriented feelings to offer optimal help to patients in pain. However, previous studies have documented a tendency in HCPs to underestimate the pain of patients that could interfere with optimal help to these patients. The aim of this study was to compare HCP and control (CTL) participants' prosocial behavior towards persons in pain and their associated brain responses. HCPs and CTL participants took part in a newly developed prosocial task during which they were asked to choose how much time they wanted to offer to help patients in pain. It was shown that compared to CTL participants, HCPs offered more help to persons in pain and reported less trait personal distress when facing suffering in others. Additional evidence was provided by the fMRI results, which indicated that compared to CTL participants, HCP participants showed different pattern of activity in the dorsolateral prefrontal cortex, bilateral precuneus and the posterior cingulate cortex during the prosocial task, suggesting that the underlying mechanisms of the difference in prosocial behaviors could vary according to the degree to which processes such as mentalizing and cognitive control are solicited. PMID- 28669785 TI - Knowledge and attitudes toward vaccination: A survey of Serbian students. AB - Since vaccination coverage in Serbia has been decreasing and health professionals have been identified as the most important factor in making decisions about immunization, vaccination knowledge and attitudes of students, especially medical students, are of particular interest. A cross-sectional survey was carried out on three groups of 509 Belgrade University students (medical, law and engineering students). The data were collected using an on-line questionnaire posted to student groups and included the Vaccine Knowledge Questionnaire and Attitudes Toward Vaccination Scale. This survey also included questions about demographic characteristics and perceived negative experiences. Multiple linear regression analysis was performed. There was a significant difference in the Vaccine Knowledge score (F=40.48, p<0.01) among the three groups of students. Medical students (N=251, Mean=4.47, SD=1.71) had significantly higher mean knowledge scores than did law (N=128, Mean=2.80, SD=1.56) or engineering students (N=130, Mean=3.98, SD=1.81). Compared with the law (Mean=49.77, SD=10.23) and engineering students (Mean=57.62, SD=12.21), medical students (Mean=59.52, SD=9.62) also had significantly higher attitude scores (F=37.56, p<0.01). These findings demonstrate general positive attitudes of Serbian students toward immunization. However, some knowledge gaps were identified. Multivariate analysis showed that those who had better vaccine knowledge, those who studies medicine, those who attended at university for more years, and those who do not know someone who had a negative experience with vaccines were more likely to have positive attitudes toward vaccination. Considering the growing vaccination hesitance in the general population, this is an important result that indicates that medical students are possible important participants in future public health campaigns. A strong association between vaccine knowledge and attitudes implies recommendations to introduce a specialized vaccination curriculum at both the undergraduate and graduate levels of medical study. PMID- 28669786 TI - Postoperative Outcomes among Pediatric and Adolescent Patients Undergoing Minilaparotomy vs Laparoscopy in the Management of Adnexal Lesions. AB - STUDY OBJECTIVE: To compare institutional experience in postoperative recovery in children and adolescents who undergo laparoscopy vs minilaparotomy in the management of benign adnexal cystic lesions. DESIGN: Retrospective cohort study. SETTING: Tertiary care children's hospital. PARTICIPANTS: Patients ages 6-21 years who underwent surgical management for benign adnexal lesions. INTERVENTIONS AND MAIN OUTCOME MEASURES: Comparison of surgery times, size of lesions, pain scores, and patient length of stay after minilaparotomy vs laparoscopy. RESULTS: Forty-four patients were identified. Of those, 59% (n = 26) had a laparoscopic procedure and 41% (n = 18) underwent minilaparotomy. Patients who underwent minilaparotomy were more likely to have a larger adnexal mass than those in the laparoscopy group with a median size of 15.5 cm vs 6.0 cm, respectively (P < .001). Postoperative length of stay and recovery were comparable in both groups. CONCLUSION: Minilaparotomy offers a minimally invasive option for the management of benign adnexal lesions in the pediatric and adolescent age group with recovery comparable to that of laparoscopy. The minilaparotomy approach should be considered when laparoscopy is limited. PMID- 28669787 TI - Ultrasonography in Detection of Vaginal Foreign Bodies in Girls: A Retrospective Study. AB - STUDY OBJECTIVE: In this study we investigated the sonographic features of vaginal foreign bodies in girls and the diagnostic role of combined transperineal and transabdominal ultrasonography in the detection of vaginal foreign bodies in this population. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A retrospective review of the records of 249 girls seen in the outpatient pediatric and adolescent gynecology clinic of our hospital and referred to our department for sonographic evaluation of suspected vaginal foreign bodies between 2013 and 2016 was performed. All patients were transperineally and transabdominally scanned using an ultrasound machine with 3 MHz and 7.5-MHz transducers. The sonographic features of the detected foreign bodies were recorded and reported. All patients also underwent pelvic radiography. The presence of foreign bodies was confirmed using vaginoscopy. RESULTS: Two hundred forty-nine patients were included in this study, and vaginal foreign bodies were detected in 181 patients. Vaginal foreign bodies often present in girls aged from 2 to 12 years old. The most common vaginal foreign bodies were toilet paper, beads, small parts of toys, cap of water color brush, and crayons. The overall sensitivity, specificity, positive and negative predictive values of transperineal/transabdominal sonography in the diagnosis of vaginal foreign bodies were 81%, 53%, 82%, and 51%, respectively. The sensitivity, specificity, and positive and negative predictive values of transabdominal sonography were 33%, 49%, 63%, and 21%, respectively. The sensitivity, specificity, and positive and negative predictive values of transperineal sonography were 64%, 49%, 77%, and 33%, respectively. Abnormal findings were detected using x-ray in only 43 of the 181 cases (23.7%). The sensitivity, specificity, and positive and negative predictive values of x-ray were 24%, 91%, 88%, and 31%, respectively. The size of the foreign bodies ranged from 2 mm to 35 mm. For foreign bodies larger than 5 mm, the rate of sonographic accuracy reached 100%. For foreign bodies smaller than 5 mm, 32 false positive results, and 34 false negative results were identified. One hundred thirty-nine of 181 foreign bodies were less than 2 cm from the vaginal orifice (77%). All foreign bodies were hyperechoic compared with adjacent tissues. Some vaginal foreign bodies had characteristic echo patterns. With the exception of 1 patient with a detained AAA battery that caused vaginal ulceration, the other patients had a full recovery. CONCLUSION: Vaginal foreign bodies were hyperechoic compared with adjacent tissues and often had characteristic echo patterns. The use of combined transperineal and transabdominal ultrasonography might be helpful in diagnosing foreign bodies, especially when the size of the foreign body is larger than 5 mm. Therefore, ultrasonography might be preferred for the initial evaluation of suspected vaginal foreign bodies, because it is a noninvasive, radiation-free, and inexpensive technique. PMID- 28669788 TI - The Effect of Gender on Resident Autonomy in the Operating room. AB - OBJECTIVE: Discrimination against women training in medicine and surgery has been subjectively described for decades. This study objectively documents gender differences in the degree of autonomy given to thoracic surgery trainees in the operating room. DESIGN: Thoracic surgery residents and faculty underwent frame of reference training on the use of the 4-point Zwisch scale to measure operative autonomy. Residents and faculty then submitted evaluations of their perception of autonomy granted for individual operations as well as operative difficulty on a real-time basis using the "Zwisch Me!!" mobile application. Differences in autonomy given to male and female residents were elucidated using chi-square analysis and ordered logistic regression. SETTING: Seven academic medical centers with thoracic surgery training programs. PARTICIPANTS: Volunteer thoracic surgery residents in both integrated and traditional training pathways and their affiliated cardiothoracic faculty. RESULTS: Residents (n = 33, female 18%) submitted a total of 596 evaluations to faculty (n = 48, female 12%). Faculty gave less autonomy to female residents with only 56 of 184 evaluations (30.3%) showing meaningful autonomy (passive help or supervision only) compared to 107 of 292 evaluations (36.7%) at those levels for male residents (p = 0.02). Resident perceptions of autonomy showed even more pronounced differences with female residents receiving only 38 of 197 evaluations (19.3%) with meaningful autonomy compared to 133 of 399 evaluations (33.3%) for male residents (p < 0.001). Potential influencing factors explored included attending gender and specialty, case type and difficulty, and resident level of training. In multivariate analysis, only case difficultly, resident gender, and level of training were significantly related to autonomy granted to residents. CONCLUSIONS: Evaluations of operative autonomy reveal a significant bias against female residents. Faculty education is needed to encourage allowing female residents more operative autonomy. PMID- 28669789 TI - Self-Directed Interactive Video-Based Instruction Versus Instructor-Led Teaching for Myanmar House Surgeons: A Randomized, Noninferiority Trial. AB - OBJECTIVE: To compare self-directed interactive video-based instruction (IVBI) with instructor-led teaching in the acquisition of basic surgical skills by House Surgeons at University of Medicine 1, Yangon. DESIGN: A prospective, 1:1 randomized controlled trial was conducted. Participants were randomized into 2 teaching arms: (1) self-directed IVBI or (2) instructor-led teaching. Self directed IVBI participants were provided with a portable DVD player that could play, fast forward, rewind, and skip through skills modules. Participants in the instructor-led teaching group were taught in small groups by standardized instructors. Pretesting and posttesting of 1-handed knot tie, 2-handed knot tie, vertical mattress suture, and instrument tie was performed using the Objective Structured Assessment of Technical Skills (OSATS). Students randomized to self directed IVBI completed an exit survey to assess satisfaction. Demographic data were collected of all participants. SETTING: University of Medicine 1, Yangon, Myanmar. PARTICIPANTS: Fifty participants were randomly selected from 78 eligible House Surgeons who were enrolled in their basic surgery rotation. RESULTS: Demographic characteristics and baseline skills were comparable in participants randomized to IVBI and instructor-led teaching. Mean OSATS score increased from pretest to posttest in both groups (p < 0.001). The mean posttest OSATS score of the IVBI group was 0.72 points below that of the instructor-led teaching group (90% CI: -3.8 to 5.2), with the 90% CI falling below the a priori noninferiority margin, satisfying criteria for noninferiority. More than 90% of students marked either "agree" or "strongly agree" to the following statements on the exit survey: further expansion of IVBI into other skills modules and integration of IVBI into training curriculum. CONCLUSION: IVBI is noninferior to instructor-led teaching of surgical skills based on OSATS scores. House Surgeons highly rated self-directed IVBI. Self-directed IVBI has the potential to significantly reduce the personnel required for skills teaching and may serve as a long-term learning adjunct in low-resource settings. PMID- 28669790 TI - ESCMID postgraduate education course: applications of MALDI-TOF mass spectrometry in clinical microbiology. PMID- 28669791 TI - Crop Breeding Chips and Genotyping Platforms: Progress, Challenges, and Perspectives. AB - There is a rapidly rising trend in the development and application of molecular marker assays for gene mapping and discovery in field crops and trees. Thus far, more than 50 SNP arrays and 15 different types of genotyping-by-sequencing (GBS) platforms have been developed in over 25 crop species and perennial trees. However, much less effort has been made on developing ultra-high-throughput and cost-effective genotyping platforms for applied breeding programs. In this review, we discuss the scientific bottlenecks in existing SNP arrays and GBS technologies and the strategies to develop targeted platforms for crop molecular breeding. We propose that future practical breeding platforms should adopt automated genotyping technologies, either array or sequencing based, target functional polymorphisms underpinning economic traits, and provide desirable prediction accuracy for quantitative traits, with universal applications under wide genetic backgrounds in crops. The development of such platforms faces serious challenges at both the technological level due to cost ineffectiveness, and the knowledge level due to large genotype-phenotype gaps in crop plants. It is expected that such genotyping platforms will be achieved in the next ten years in major crops in consideration of (a) rapid development in gene discovery of important traits, (b) deepened understanding of quantitative traits through new analytical models and population designs, (c) integration of multi-layer -omics data leading to identification of genes and pathways responsible for important breeding traits, and (d) improvement in cost effectiveness of large-scale genotyping. Crop breeding chips and genotyping platforms will provide unprecedented opportunities to accelerate the development of cultivars with desired yield potential, quality, and enhanced adaptation to mitigate the effects of climate change. PMID- 28669792 TI - Preparation and characterization of bioadhesive system containing hypericin for local photodynamic therapy. AB - Hypericin (Hyp) is a natural photoactive pigment utilized in the treatment of different types of cancer and antimicrobial inactivation using photodynamic therapy (PDT). Hyp is poorly soluble in water leading to problems of administration, getting close contact with the site, and bio-availability. Therefore, this study aimed to develop bioadhesive thermoresponsive system containing Hyp for local PDT. Carbomer 934P, poloxamer 407, and Hyp were used to prepare the thermoresponsive bioadhesive formulations. They were characterized for sol-gel transition temperature, mechanical, mucoadhesive, rheological (continuous flow and oscillatory) and dielectric properties, syringeability, in vitro Hyp release kinetics, ex vivo permeability, and photodynamic activity. The formulations displayed suitable gelation temperature and rheological characteristics. The compressional, mechanical and mucoadhesive properties, as well the syringeability showed the easiness of administration and the permanence of the system adhered to the mucosa or skin. The dielectric analysis helped to understand the Hyp availability, and its release presented an anomalous behavior. The system did not permeate the pig skin nor rat intestine and showed good biological photodynamic activity. Therefore, data obtained from the bioadhesive system indicate a potentially useful role as a platform for local hypericin delivery in PDT, suggesting it is worthy of in vivo evaluation. PMID- 28669794 TI - Climate science, truth, and democracy. AB - This essay was written almost ten years ago when the urgency of America's failure as a nation to respond to the threats of climate change first came to preoccupy me. Although the essay was never published in full, I circulated it informally in an attempt to provoke a more public engagement among my colleagues in the history, philosophy, and sociology of science. In particular, it was written in almost direct response to Philip Kitcher's own book, Science, Truth and Democracy (2001), in an attempt to clarify what was special about Climate Science in its relation to truth and democracy. Kitcher's response was immensely encouraging, and it led to an extended dialogue that resulted, first, in a course we co-taught at Columbia University, and later, to the book The Seasons Alter: How to Save Our Planet in Six Acts (W. W. Norton) published this spring. The book was finished just after the Paris Climate Accord, and it reflects the relative optimism of that moment. Unfortunately events since have begun to evoke, once again, the darker mood of this essay. I am grateful to Greg Radick for suggesting its publication. PMID- 28669793 TI - Comparing clinical effects of photodynamic therapy as a novel method with topical corticosteroid for treatment of Oral Lichen Planus. AB - BACKGROUND: Oral lichen planus is an autoimmune disorder with several challenges in treatment. Photodynamic therapy has been proposed as a new treatment option for the disease. AIM: The present study compared the clinical effects of photodynamic therapy to dexamethasone mouthwash in the treatment of oral lichen planus lesions. MATERIALS AND METHODS: In this randomized clinical trial, 30 patients with oral lichen planus were included.15 patients were treated with 5% methylene blue mediated photodynamic therapy using Fotosan device for 30s (630nm wavelength and 7.2-14.4J/cm2 dose) for 4 sessions in the days 1, 4, 7, 14. In another group, the treatment was done on 15 patients by 0.5mg tab dexamethasone solution in 5cc water, rinsed 4 times in a day within two weeks. The sign score, symptoms scores (pain), clinical severity and treatment efficacy were measured at the days 15, 30, 60, 90 after beginning of the treatment. The results were subjected to Mann-whitney U test in both groups. RESULTS: No significant difference existed between the two modalities regarding the treatment efficacy index, sign score, symptom score and clinical severity on the 15, 30, 60 and 90 post-treatment days. Decreases in patient's symptoms were statistically significant in both groups. CONCLUSION: Photodynamic therapy was as effective as the dexamethasone mouth wash in the treatment of oral lichen planus. It could be used as a safe modality in the treatment of oral lichen planus lesions without identified side effects. PMID- 28669795 TI - Downstream processing of hyperforin from Hypericum perforatum root cultures. AB - Hyperforin is a major metabolite of the medicinal plant Hypericum perforatum (St. John's Wort) and has recently been found in hormone induced root cultures. The objective of this study is to identify a downstream process for the production of a hyperforin-rich extract with maximum extraction efficiency and minimal decomposition. The maximum extraction time was found to be 60min. The comparison of two equipment concepts for the extraction and solvent evaporation was performed employing two different solvents. While the rotary mixer showed better results for the extraction efficiency than a stirred vessel, the latter set-up was able to handle larger volumes but did not meet all process requirements. For the evaporation the prompt evaporation of the extraction agent using nitrogen stripping led to minor decomposition. In a 5L stirred vessel, the highest specific extraction of hyperforin was 4.3mg hyperforin/g dry weight bio material. Parameters for the equipment design for extraction and solvent evaporation were determined based on the experimental data. PMID- 28669796 TI - Alginate hydrogel improves anti-angiogenic bevacizumab activity in cancer therapy. AB - Anti-vascular endothelial growth factor (anti-VEGF) therapy applied to solid tumors is a promising strategy, yet, the challenge to deliver these agents at high drug concentrations together with the maintenance of therapeutic doses locally, at the tumor site, minimizes its benefits. To overcome these obstacles, we propose the development of a bevacizumab-loaded alginate hydrogel by electrostatic interactions to design a delivery system for controlled and anti angiogenic therapy under tumor microenvironmental conditions. The tridimensional hydrogel structure produced provides drug stability and a system able to be introduced as a flowable solution, stablishing a depot after local administration. Biological performance by the chick embryo chorioallantoic membrane (CAM) assay indicated a pH-independent improved anti-angiogenic activity (~50%) compared to commercial available anti-VEGF drug. Moreover, there was a considerable regression in tumor size when treated with this system. Immunohistochemistry highlighted a reduced number and disorganization of microscopic blood vessels resulting from applied therapy. These results suggest that the developed hydrogel is a promising approach to create an innovative delivery system that offers the possibility to treat different solid tumors by intratumoral administration. PMID- 28669797 TI - An examination of changes in maternal neuroimmune function during pregnancy and the postpartum period. AB - There is strong evidence that the immune system changes dramatically during pregnancy in order to prevent the developing fetus from being "attacked" by the maternal immune system. Due to these alterations in peripheral immune function, many women that suffer from autoimmune disorders actually find significant relief from their symptoms throughout pregnancy; however, these changes can also leave the mother more susceptible to infections that would otherwise be mitigated by the inflammatory response (Robinson and Klein, 2012). Only one other study has looked at changes in microglial number and morphology during pregnancy and the postpartum period (Haim et al., 2016), but no one has yet examined the neuroimmune response following an immune challenge during this time. Therefore, in this study, we investigated the impact of an immune challenge during various time-points throughout pregnancy and the postpartum period on the expression of immune molecules in the brain of the mother and fetus. Our results indicate that similar to the peripheral immune suppression measured during pregnancy, we also see significant suppression of the immune response in the maternal brain, particularly during late gestation. In contrast to the peripheral immune system, immune modulation in the maternal brain extends moderately into the postpartum period. Additionally, we found that the fetal immune response in the brain and placenta is also suppressed just before parturition, suggesting that cytokine production in the fetus and placenta are mirroring the peripheral cytokine response of the mother. PMID- 28669798 TI - The pars tuberalis: The site of the circannual clock in mammals? AB - Accurate timing and physiological adaptation to anticipate seasonal changes are an essential requirement for an organism's survival. In contrast to all other environmental cues, photoperiod offers a highly predictive signal that can be reliably used to activate a seasonal adaptive programme at the correct time of year. Coupled to photoperiod sensing, it is apparent that many organisms have evolved innate long-term timekeeping systems, allowing reliable anticipation of forthcoming environmental changes. The fundamental biological processes giving rise to innate long-term timing, with which the photoperiod-sensing pathway engages, are not known for any organism. There is growing evidence that the pars tuberalis (PT) of the pituitary, which acts as a primary transducer of photoperiodic input, may be the site of the innate long-term timer or "circannual clock". Current research has led to the proposition that the PT-specific thyrotroph may act as a seasonal calendar cell, driving both hypothalamic and pituitary endocrine circuits. Based on this research we propose that the mechanistic basis for the circannual rhythm appears to be deeply conserved, driven by a binary switching cell based accumulator, analogous to that proposed for development. We review the apparent conservation of function and pathways to suggest that these broad principles may apply across the vertebrate lineage and even share characteristics with processes driving seasonal adaptation in plants. PMID- 28669799 TI - Comparison of DNA extraction methods used to detect bacterial and yeast DNA from spiked whole blood by real-time PCR. AB - Sepsis is the leading cause of death in intensive care units (ICUs) worldwide and its diagnosis remains a challenge. Blood culturing is the gold standard technique for blood stream infection (BSI) identification. Molecular tests to detect pathogens in whole blood enable early use of antimicrobials and affect clinical outcomes. Here, using real-time PCR, we evaluated DNA extraction using seven manual and three automated commercially available systems with whole blood samples artificially contaminated with Escherichia coli, Staphylococcus aureus, and Candida albicans, microorganisms commonly associated with BSI. Overall, the commercial kits evaluated presented several technical limitations including long turnaround time and low DNA yield and purity. The performance of the kits was comparable for detection of high microorganism loads (106CFU/mL). However, the detection of lower concentrations was variable, despite the addition of pre processing treatment to kits without such steps. Of the evaluated kits, the UMD Universal CE IVD kit generated a higher quantity of DNA with greater nucleic acid purity and afforded the detection of the lowest microbial load in the samples. The inclusion of pre-processing steps with the kit seems to be critical for the detection of microorganism DNA directly from whole blood. In conclusion, future application of molecular techniques will require overcoming major challenges such as the detection of low levels of microorganism nucleic acids amidst the large quantity of human DNA present in samples or differences in the cellular structures of etiological agents that can also prevent high-quality DNA yields. PMID- 28669800 TI - Sensitivity and specificity of Matrix-Associated Laser Desorption/Ionization - Time of Flight Mass Spectrometry (MALDI-TOF MS) in discrimination at species level for Acinetobacter bacteremia. AB - We aimed to establish the role of MALDI-TOF MS on species discrimination of phenotypically indistinguishable A. baumannii, A. pittii and A. nosocomialis. Compared to multiplex PCR, the gold standard, MALDI-TOF MS yielded a high sensitivity for A. baumannii (97.9%) and specificity for A. pittii (98.9%) and A. nosocomialis (100%). PMID- 28669801 TI - Exposure and Engagement With Tobacco- and E-Cigarette-Related Social Media. AB - PURPOSE: Little is known about the nature and extent of adolescents' exposure to tobacco- and e-cigarette-related communications on social media. In this study, we describe the prevalence and correlates of youth exposure and engagement with tobacco- and e-cigarette-related social media. METHODS: Data are from the baseline survey of the Texas Adolescent Tobacco and Marketing Surveillance system, a cross-sectional sample of sixth, eighth, and 10th graders (n = 3907, N = 461,097). Weighted logistic regression models were used to examine associations between demographic characteristics, sensation seeking, tobacco use, and exposure and engagement with tobacco-related social media. RESULTS: Overall, 52.5% of students reported exposure to tobacco-related social media in the past month, whereas < 6% reported engagement. Exposure and some forms of engagement were more common among high school students, girls, those with friends who use tobacco, and high sensation seekers (p < .05). The odds of exposure were significantly higher among students susceptible to combustible tobacco (adjusted odds ratio [AOR] = 1.71, p < .05), e-cigarettes (AOR = 2.10, p < .01), and both combustible tobacco and e-cigarettes (AOR = 2.24, p < .001). The odds of engaging with social media was higher among those who were susceptible to, had ever, or currently use both combustible tobacco and e-cigarettes (AOR = 2.10-3.46, p < .05). CONCLUSIONS: About 1 in every 2 adolescents in Texas are exposed to tobacco-related social media. Adolescents who are susceptible to or use e-cigarettes and/or combustible tobacco are exposed to and engage with tobacco-related social media more than their peers. Social media appears to be an important venue when targeting vulnerable youth in prevention campaigns. PMID- 28669803 TI - Enhancement of antioxidant and antibacterial properties for tannin acid/chitosan/tripolyphosphate nanoparticles filled electrospinning films: Surface modification of sliver nanoparticles. AB - The tannin acid/chitosan/tripolyphosphate nanoparticles were encapsulated in polyvinyl alcohol (PVA)/poly-acrylic acid (PAA) electrospinning films by electrostatic spinning technology. To optimize the prepared condition, properties and morphology of nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). The optimized initial concentration of tannin, chitosan and tripolyphosphate solutions were 1, 1, 0.5mg/ml, respectively, with adding proportion for 5:5:1. The average diameter of tannin acid/chitosan/tripolyphosphate nanoparticles was ~80nm. The electrospinning films showed an excellent water-resistant property with 0.5wt%N,N'-Methylenebisacrylamide (MBA). Due to the antioxidant and antibacterial of tannic acid, the films possessed these properties. The antioxidant and antibacterial of these fibers significantly improved after in situ formation of silver nanoparticles (AgNPs). Electrospun films were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectra (FT-IR), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). PMID- 28669802 TI - The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity. AB - UPF1 is an RNA helicase that orchestrates nonsense-mediated decay and other RNA surveillance pathways. While UPF1 is best known for its basal cytoprotective role in degrading aberrant RNAs, UPF1 also degrades specific, normally occurring mRNAs to regulate diverse cellular processes. Here we describe a role for UPF1 in regulated protein decay, wherein UPF1 acts as an E3 ubiquitin ligase to repress human skeletal muscle differentiation. Suppressing UPF1 accelerates myogenesis, while ectopically increasing UPF1 levels slows myogenesis. UPF1 promotes the decay of MYOD protein, a transcription factor that is a master regulator of myogenesis, while leaving MYOD mRNA stability unaffected. UPF1 acts as an E3 ligase via its RING domain to promote MYOD protein ubiquitination and degradation. Our data characterize a regulatory role for UPF1 in myogenesis, and they demonstrate that UPF1 provides a mechanistic link between the RNA and protein decay machineries in human cells. PMID- 28669804 TI - Adsorptive removal of malachite green from aqueous solutions by almond gum: Kinetic study and equilibrium isotherms. AB - This work aimed at investigating the potential of almond gum as low cost adsorbent for the removal of the cationic dye; malachite green from aqueous solutions. Almond gum was first analyzed by scanning electron microscopy (SEM) and Fourier transforms infrared spectroscopy (FTIR), and then the adsorption behavior was studied in batch system. The effects of the adsorption parameters (adsorbent dose, pH, contact time, particle size, initial dye concentration, temperature and agitation) on the dye removal have been studied. Adsorption equilibrium and isotherms were evaluated depending on temperature using the isotherms of Freundlich, Langmuir, and Tempkin. The obtained result showed that both Langmuir and Freundlich models were adapted to study the dye sorption. The maximum adsorption capacities were equal to 172.41mg/g, 181.81mg/g, and 196.07mg/g at 303.16K, 313.16K, and 323.16K, respectively. The kinetics of sorption were following the pseudo-second order model. The thermodynamic changes in enthalpy (DeltaH), entropy (DeltaS), and free energy (DeltaG) indicated that the adsorption of malachite green at the surface of almond gum is endothermic and occurs spontaneously. Desorption experiments were conducted to regenerate almond gum, showing great desorption capacity when using HCl at pH 2. PMID- 28669805 TI - In vivo diabetic wound healing potential of nanobiocomposites containing bamboo cellulose nanocrystals impregnated with silver nanoparticles. AB - In diabetes, hyperglycemic state immensely hinders the wound healing. Here, nanobiocomposites (NCs) developed by impregnation of in situ prepared silver nanoparticles in the matrix of bamboo cellulose nanocrystals were investigated for their ability to hasten the progress of healing events in streptozotocin induced diabetic mice model. Wounds treated with topically applied NCs (hydrogels) showed full recovery (98-100%) within 18days post wounding in contrast to the various control groups where incomplete healing (88-92%) was noticed. Biochemical estimations documented a marked decrease in the levels of pro-inflammatory cytokines IL-6 and TNF-alpha leading to decreased inflammation in NCs treated mice. Significantly increased expression of collagen and growth factors (FGF, PDGF, VEGF) upon NCs treatment resulted in improved re epithelialization, vasculogenesis and collagen deposition as compared to control groups. Hence, developed nanobiocomposites showcased potential to serve as highly effective and biocompatible wound dressings for diabetic patients. PMID- 28669806 TI - The development of a sensitive droplet digital PCR for quantitative detection of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome (PRRS) is an infectious disease, resulting in important economic losses in pig farming. Prompt detection of PRRS virus (PRRSV) in the field samples is important for effective PRRS control. Droplet digital PCR (ddPCR) is a novel PCR technology, which offers good precision and direct quantification without using calibration curves. In this study, we established a ddPCR system for the sensitive and accurate quantification of PRRSV. Specificity of the assay was determined by the failure of amplification of other relevant viruses. Quantitative linearity, sensitivity and accuracy of ddPCR were compared to those of real time PCR for PRRSV testing. Both methods showed a high degree of linearity (R2=~1) and quantitative correlation, although ddPCR showed somewhat higher sensitivity than real time PCR. Collectively, our findings indicate that ddPCR might offer improved analytical sensitivity and specificity for PRRSV measurements. PMID- 28669807 TI - Transoral lateral oropharyngectomy. AB - Based on a review of the indexed scientific medical literature, the authors document the key technical points, the errors to avoid, the limitations, indications and main oncologic and functional results when performing transoral lateral oropharyngectomy in cancer originating from the tonsillar region. PMID- 28669808 TI - Role of sialendoscopy in juvenile recurrent parotitis (JRP). AB - Juvenile recurrent parotitis (JRP) is a rare disease of childhood occurring between the ages of 3 and 5 years, characterized by recurrent non-suppurative parotitis, spontaneously evolving towards parotid gland dysfunction. Clinically, JRP presents in the form of unilateral or bilateral, usually asynchronous, swelling of the parotid gland. The diagnosis is based on ultrasound characteristics. Widespread use of sialendoscopy has opened up new prospects for the management of this disease. This review of the literature evaluates the role of sialendoscopy in the management of JRP. A Medline search retrieved 68 articles, 18 of which concerned JRP. Standard treatment consists of antibiotics for at least 10 days at the acute phase of the disease. All studies demonstrated the diagnostic value of sialendoscopy by visualizing strictures, hypovascularization and whitish intraductal debris. Sialendoscopy is also useful for treatment, by allowing intraductal lavage and, when possible, dilatation of strictures. Lavage is performed with saline solution, hydrocortisone, antibiotics or a combination of these solutions, with no significant differences in terms of efficacy. The mode of administration with or without sialendoscopy also appears to provide similar results. Sialendoscopy appears to be a diagnostic and therapeutic option, although it has not been shown to be more effective than simple lavage. All lavage solutions appear to be effective. PMID- 28669809 TI - Functional nanosome for enhanced mitochondria-targeted gene delivery and expression. AB - Mitochondria dysfunction plays a role in many human diseases. Therapeutic techniques for these disorders require novel delivery systems that can specifically target and penetrate mitochondria. In this study, we report a novel nanosome composed of dequalinium-DOTAP-DOPE (1,2 dioleoyl-3-trimethylammonium propane-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) (DQA80s) as a potential mitochondria-targeting delivery vector. The functional DQAsome, DQA80s, showed enhanced transfection efficiency compared to a vector DQAsomes in HeLa cells and dermal fibroblasts. In addition, DQA80s/pDNA complexes exhibited rapid escape from the endosome into the cytosol. We observed the delivery of pDNA to mitochondria in living cells using flow cytometry, confocal microscopy, and TME imaging. More specifically, we confirmed our results by co-localization of hmtZsGreen constructs to mitochondria when delivered via DQAsomes and DQA80s in living cells. The mitochondria-targeting DQAsomes and DQA80s induced mitochondrial dysfunction through depolarization of mitochondrial membrane potential. Our data demonstrate that DQA80s show promise for use as a mitochondria-targeted carrier system for treatment of mitochondria diseases in vivo. PMID- 28669810 TI - Relative Validity and Reliability of a 1-Week, Semiquantitative Food Frequency Questionnaire for Women Participating in the Supplemental Nutrition Assistance Program. AB - BACKGROUND: The Supplemental Nutrition Assistance Program (SNAP) plays a critical role in reducing food insecurity by distribution of benefits at a monthly interval to participants. Households that receive assistance from SNAP spend at least three-quarters of benefits within the first 2 weeks of receipt. Because this expenditure pattern may be associated with lower food intake toward the end of the month, it is important to develop a tool that can assess the weekly diets of SNAP participants. OBJECTIVE: The goal of this study was to develop and assess the relative validity and reliability of a semiquantitative 1-week food frequency questionnaire (FFQ) tailored to a population of women participating in SNAP. DESIGN: The FFQ was derived from an existing 195-item FFQ that was based on a reference period of 1 month. This 195-item FFQ has been validated in a population of low-income postpartum women who were recruited from central Texas during 2004. Mean daily servings of each food item in the 195-item FFQ completed by women who took part in the 2004 validation study were calculated to determine the most frequently consumed food items. Emphasis on these items led to the creation of a shorter, 1-week FFQ of only 95 items. This new 1-week instrument was compared with 3-day diet records to evaluate relative validity in a sample of women participating in SNAP. For reliability, the FFQ was administered a second time, separated by a 1-month time interval. PARTICIPANTS/SETTING: The validity study included 70 female SNAP participants who were recruited from the partner agencies of the Central Texas Food Bank from March to June 2015. A subsample of 40 women participated in the reliability study. MAIN OUTCOME MEASURES: Outcome measures were mean nutrient intake values obtained from the two tests of the 95-item FFQ and 3-day diet records. STATISTICAL ANALYSIS PERFORMED: Deattenuated Pearson correlation coefficients examined relationships in nutrient intake between the 95 item FFQ and 3-day diet records, and a paired samples t test determined differences in mean nutrient intake. Weighted Cohen's kappa indicated agreement in quartile classification of study participants by the 95-item FFQ and 3-day diet records, according to nutrient intake. Test-retest reliability was assessed by intraclass correlations and weighted Cohen's kappa. RESULTS: Mean deattenuated Pearson correlation between the FFQ and 3-day diet records was 0.61, and the weighted Cohen's kappa=0.39. Finally, the average test-retest correlation and weighted Cohen's kappa of the FFQ was 0.66 and 0.50, respectively. CONCLUSIONS: These results suggest that the 1-week, 95-item FFQ demonstrated acceptable relative validity and reliability in low-income women participating in SNAP in southwestern United States. PMID- 28669811 TI - Evolutionary persistence of tripartite integrative and conjugative elements. AB - Integrative and conjugative elements (ICEs) are generally regarded as regions of contiguous DNA integrated within a bacterial genome that are capable of excision and horizontal transfer via conjugation. We recently characterized a unique group of ICEs present in Mesorhizobium spp., which exist as three entirely separate but inextricably linked chromosomal regions termed alpha, beta and gamma. These regions occupy three different recombinase attachment (att) sites; however, they do not excise independently. Rather, they recombine the host chromosome to form a single contiguous region prior to excision and conjugative transfer. Like the single-part ICE carried by M. loti R7A (ICEMlSymR7A), these "tripartite" ICEs (ICE3s) are widespread throughout the Mesorhizobium genus and enable strains to form nitrogen-fixing symbioses with a variety of legumes. ICE3s have likely evolved following recombination between three separate ancestral integrative elements, however, the persistence of ICE3 structure in diverse mesorhizobia is perplexing due to its seemingly unnecessary complexity. In this study, examination of ICE3s revealed that most symbiosis genes are carried on the large alpha fragment. Some ICE3-beta and gamma regions also carry genes that potentially contribute to the symbiosis, or to persistence in the soil environment, but these regions have been frequently subjected to recombination events including deletions, insertions and recombination with genes located on other integrative elements. Examination of a new ICE3 in M. ciceri Ca181 revealed it has jettisoned the genetic cargo from its beta region and recruited a serine recombinase gene within its gamma region, resulting in replacement of one of the three ICE3 integration sites. Overall the recombination loci appear to be the only conserved features of the beta and gamma regions, suggesting that the tripartite structure itself provides a selective benefit to the element. We propose the ICE3 structure provides enhanced host range, host stability and resistance to destabilization by tandem insertion of competing integrative elements. Furthermore, we suspect the ICE3 tripartite structure increases the likelihood of gene capture from integrative elements sharing the same attachment sites. PMID- 28669812 TI - A phylogeny of Southern Hemisphere whelks (Gastropoda: Buccinulidae) and concordance with the fossil record. AB - Under current marine snail taxonomy, the majority of whelks from the Southern Hemisphere (Buccinulidae) are hypothesised to represent a monophyletic clade that has evolved independently from Northern Hemisphere taxa (Buccinidae). Phylogenetic analysis of mitochondrial genomic and nuclear ribosomal DNA sequence data indicates that Southern Hemisphere taxa are not monophyletic, and results suggest that dispersal across the equator has occurred in both directions. New Zealand buccinulid whelks, noted for their high endemic diversity, are also found to not be monophyletic. Using independent fossil calibrations, estimated genetic divergence dates show remarkable concordance with the fossil record of the Penion and Kelletia. The divergence dates and the geographic distribution of the genera through time implies that some benthic marine snails are capable of dispersal over long distances, despite varied developmental strategies. Phylogenetic results also indicate that one species, P. benthicolus belongs in Antarctoneptunea. PMID- 28669813 TI - Longamoebia is not monophyletic: Phylogenomic and cytoskeleton analyses provide novel and well-resolved relationships of amoebozoan subclades. AB - Longamoebia is one of the most morphologically diverse member of Amoebozoa. It includes the human pathogen Acanthamoeba, which causes minor skin and serious eye infections as well as fatal central nervous system complications. The taxonomy and phylogeny of Longamoebia is poorly understood partly due to the growing number of molecular studies that report unsuspected affiliations of lineages with extremely different morphotypes in the group. A recent molecular study questioned the monophyly of Longamoebia. In this study, we conducted a more comprehensive phylogenomic analysis including all of putative members of Longamoebia to assess its monophyly. We conducted extensive analyses to see effects of outgroup choice, missing data, and gene and taxon sampling on resulting phylogenies. We also collected morphological characters derived from the cytoskeleton using immunocytochemistry to assess homologies of pseudopodia at a finer scale. Our phylogenomic analysis yielded a well-resolved tree of Amoebozoa and highly supported novel relationships. Discosea is recovered as a monophyletic group with all of its known taxonomic orders. However, its within-group relationships dramatically differed from those originally proposed. Our study strongly demonstrates that Longamoebia sensu Smirnov et al. (2011) is not monophyletic and an invalid taxon. Thecamoebida forms a strongly supported sister group relationship with clade Flabellinea (Dactylopodida and Vannellida), while Dermamoebida (Mayorella+Dermamoeba) form an independent branch basal to other members of Discosea. The remaining groups including members of Centramoebida form a consistently well-supported clade that was shown to form a sister group relationship with Himatismenida. This robust clade shares the unique cytoskeletal features of coiled cytoplasmic microtubule network and F-actin characters. Our analyses demonstrated that placement of unstable taxa in large-scale analysis with varying levels of missing data might be compromised by some confounding factors such as outgroup choice and gene and taxon sampling. PMID- 28669814 TI - Quick 96FASP for high throughput quantitative proteome analysis. AB - : Filter aided sample preparation (FASP) is becoming a central method for proteomic sample cleanup and peptide generation prior to LC-MS analysis. We previously adapted this method to a 96-well filter plate, and applied to prepare protein digests from cell lysate and body fluid samples in a high throughput quantitative manner. While the 96FASP approach is scalable and can handle multiple samples simultaneously, two key advantages compared to single FASP, it is also time-consuming. The centrifugation-based liquid transfer on the filter plate takes 3-5 times longer than single filter. To address this limitation, we now present a quick 96FASP (named q96FASP) approach that, relying on the use of filter membranes with a large MWCO size (~30kDa), significantly reduces centrifugal times. We show that q96FASP allows the generation of protein digests derived from whole cell lysates and body fluids in a quality similar to that of the single FASP method. Processing a sample in multiple wells in parallel, we observed excellent experimental repeatability by label-free quantitation approach. We conclude that the q96FASP approach promises to be a promising cost- and time-effective method for shotgun proteomics and will be particularly useful in large scale biomarker discovery studies. SIGNIFICANCE: High throughput sample processing is of particular interests for quantitative proteomics. The previously developed 96FASP is high throughput and appealing, however it is time-consuming in the context of centrifugation-based liquid transfer (~1.5h per spin). This study presents a truly high throughput sample preparation method based on large cut-off 96-well filter plate, which shortens the spin time to ~20min. To our knowledge, this is the first multi-well method that is entirely comparable with conventional FASP. This study thoroughly examined two types of filter plates and performed side-by-side comparisons with single FASP. Two types of samples, whole cell lysate of a UTI (urinary tract infection)-associated Klebsiella pneumoniae cell and human urine, were tested which demonstrated its capability for quantitative proteomics. The q96FSAP approach makes the filter plate-based approach more appealing for protein biomarker discovery projects, and could be broadly applied to large scale proteomics analysis. PMID- 28669815 TI - Immuno-proteomic discovery of tumor tissue autoantigens identifies olfactomedin 4, CD11b, and integrin alpha-2 as markers of colorectal cancer with liver metastases. AB - : Late-stage colorectal cancer with liver metastasis is common and affords poor prognosis, yet there is a dearth of reliable biomarkers. Cancer is often characterized by an increase in serologic autoantibodies. Hence, we embarked on an immuno-proteomic strategy by using autoantibodies to discover antigens in tumor tissue as potential cancer markers. Matched sets of tissues from primary colon cancer, liver metastases, and adjacent benign tissues were obtained from colon cancer patients. Tissue proteins were extracted, and autoantigens were uncovered by immunoblotting with autoantibodies and sequenced by mass spectrometry. Informatics analyses identified 48 proteins that were found in tumor only but were absent in normal tissue. Five of these were reproducibly found in two independent experiments, including olfactomedin 4 (OLFM4), CD11b, integrin alpha2 (ITGA2), periostin, and thrombospondin-2. Further confirmation with tissue from 43 patients by Western blotting, immunohistochemistry, and tissue microarray deemed OLFM4, CD11b, and ITGA2 to be significantly overexpressed in both primary colon tumors and liver metastases. These tumor tissue autoantigens may serve as promising markers for developing differential diagnostics and immunotherapies for colorectal cancers, in particular, those with tendency to progress to liver metastases. BIOLOGICAL SIGNIFICANCE: Late-stage colorectal cancer with liver metastasis is common and affords poor prognosis, yet there is a dearth of reliable biomarkers. Cancer is often characterized by an increase in serologic autoantibodies. Cancer tissue immunogens - antigens capable of inducing specific antibody production in patients - are promising targets for development of precision diagnostics and immunotherapies. In our manuscript, we describe on an immuno-proteomic strategy by using autoantibodies to discover antigens in tumor tissue as potential cancer markers. Matched sets of tissues from primary colon cancer, liver metastases, and adjacent benign tissues were analyzed. Putative autoantigens were first uncovered by immunoblotting with autoantibodies and sequenced by mass spectrometry. Informatics analyses identified 48 proteins that were found in tumor only but were absent in normal tissue. Using follow-up validation in two independent cohorts, we discovered that OLFM4, CD11b, and ITGA2 are proteins that are overexpressed in both primary colon tumors and liver metastases. We highlight the possible roles of these 3 proteins in carcinogenesis and tumor microenvironment and the implications for autoantigenic immune recognition. More generally, colon cancer biomarkers with autoantigenic properties, like the ones we describe in our manuscript, may open new opportunities for diagnosis, molecular classification, and therapy of colorectal cancer, particularly of aggressive tumors with tendency to progress to liver metastases. The autoantigenic properties of biomarkers are also expected to be of great relevance for immunotherapeutic development. PMID- 28669816 TI - In-depth proteomic analysis of Glycine max seeds during controlled deterioration treatment reveals a shift in seed metabolism. AB - : Seed aging is one of the major events, affecting the overall quality of agricultural seeds. To analyze the effect of seed aging, soybean seeds were exposed to controlled deterioration treatment (CDT) for 3 and 7days, followed by their physiological, biochemical, and proteomic analyses. Seed proteins were subjected to protamine sulfate precipitation for the enrichment of low-abundance proteins and utilized for proteome analysis. A total of 14 differential proteins were identified on 2-DE, whereas label-free quantification resulted in the identification of 1626 non-redundant proteins. Of these identified proteins, 146 showed significant changes in protein abundance, where 5 and 141 had increased and decreased abundances, respectively while 352 proteins were completely degraded during CDT. Gene ontology and KEGG analyses suggested the association of differential proteins with primary metabolism, ROS detoxification, translation elongation and initiation, protein folding, and proteolysis, where most, if not all, had decreased abundance during CDT. Western blotting confirmed reduced level of antioxidant enzymes (DHAR, APx1, MDAR, and SOD) upon CDT. This in-depth integrated study reveals a major downshift in seed metabolism upon CDT. Reported data here serve as a resource for its exploitation to metabolic engineering of seeds for multiple purposes, including increased seed viability, vigor, and quality. BIOLOGICAL SIGNIFICANCE: Controlled deterioration treatment (CDT) is one of the major events that negatively affects the quality and nutrient composition of agricultural seeds. However, the molecular mechanism of CDT is largely unknown. A combination of gel-based and gel-free proteomic approach was utilized to investigate the effects of CDT in soybean seeds. Moreover, we utilized protamine sulfate precipitation method for enrichment of low-abundance proteins, which are generally masked due to the presence of high-abundance seed storage proteins. Reported data here serve as resource for its exploitation to metabolic engineering of seeds for multiple purposes, including increased seed viability, vigor, and quality. PMID- 28669817 TI - Deep ancestry of programmed genome rearrangement in lampreys. AB - In most multicellular organisms, the structure and content of the genome is rigorously maintained over the course of development. However some species have evolved genome biologies that permit, or require, developmentally regulated changes in the physical structure and content of the genome (programmed genome rearrangement: PGR). Relatively few vertebrates are known to undergo PGR, although all agnathans surveyed to date (several hagfish and one lamprey: Petromyzon marinus) show evidence of large scale PGR. To further resolve the ancestry of PGR within vertebrates, we developed probes that allow simultaneous tracking of nearly all sequences eliminated by PGR in P. marinus and a second lamprey species (Entosphenus tridentatus). These comparative analyses reveal conserved subcellular structures (lagging chromatin and micronuclei) associated with PGR and provide the first comparative embryological evidence in support of the idea that PGR represents an ancient and evolutionarily stable strategy for regulating inherent developmental/genetic conflicts between germline and soma. PMID- 28669818 TI - Biophysical regulation of early limb bud morphogenesis. AB - The physical basis of morphogenesis is a fascinating concern that has been a longstanding interest of developmental biologists. In this review, I attempt to incorporate earlier and recent biophysical concepts and data to explain basic features of early limb bud morphogenesis. In particular, I discuss the influence of mesenchymal cohesion and physical properties that might contribute to phase separation of the bud from the lateral plate, the possibility that the early dorsoventral limb bud axis is moulded by the surface ectoderm, and endogenous electric fields that might contribute to oriented cell movements which generate the early limb bud. A combination of quantitative biophysical experimentation and modelling will likely advance this field. PMID- 28669820 TI - Bidirectional factors impact the migration of NK cells to draining lymph node in aged mice during influenza virus infection. AB - Natural killer (NK) cells play an important role in controlling several viral diseases. Our previous studies demonstrated an age-dependent susceptibility to mousepox due to defective NK cell responses and trafficking. However, the mechanisms that underlie the age-related impairment in NK cell migration have yet to be identified. In the present study, we demonstrated that after influenza A virus (IAV) infection, NK cells from aged mice (17-19months old) failed to accumulate in draining lymph node (D-LN). We found that both environmental and intrinsic factors played roles for this defect. After infection, increase of chemokine transcripts, especially CXCL9, 10 and 11, which are important for NK cells homing to D-LN, was significantly lower in the D-LN of aged mice compared with those of young mice. Further, the expression levels of beta2-integrins and beta-actins, which play critical roles in NK cells homing to D-LN failed to be up regulated in NK cells from aged mice. Finally, actin polymerization rates in NK cells from aged mice were also delayed compared to that of the young mice after IAV infection. Taken together, our data indicate that bi-directional factors play essential roles in the defective NK cell trafficking to the D-LN in the aged mice after IAV infection. PMID- 28669819 TI - Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion. AB - Correct cardiac development is essential for fetal and adult life. Disruptions in a variety of signaling pathways result in congenital heart defects, including outflow and inflow tract defects. We previously found that WNT11 regulates outflow tract development. However, tissue specific requirements for WNT11 in this process remain unknown and whether WNT11 is required for inflow tract development has not been addressed. Here we find that germline Wnt11 null mice also show hypoplasia of the dorsal mesenchymal protrusion (DMP), which is required for atrioventricular septation. Ablation of Wnt11 with myocardial cTnTCre recapitulated outflow tract defects observed in germline Wnt11 null mice, but DMP development was unaffected. In contrast, ablation of Wnt11 with Isl1Cre fully recapitulated both outflow tract and DMP defects of Wnt11 germline nulls. DMP hypoplasia in Wnt11 mutants was associated with reduced proliferation within the DMP, but no evident defects in myocardial differentiation of the DMP. Examination of Pitx2-, Axin2-, or Patched-lacZ reporter mice revealed no alterations in reporter expression, suggesting that WNT11 was required downstream of, or in parallel to, these signaling pathways to regulate DMP formation. These studies revealed a previously unappreciated role for WNT11 for DMP formation and distinct tissue-specific requirements for WNT11 in outflow tract and DMP development. PMID- 28669821 TI - Diet enrichment with a specific essential free amino acid mixture improves healing of undressed wounds in aged rats. AB - Chronic wounds are a major, often underestimated, health problem for the elderly. Standard wound care products are not usually manufactured to meet the increased demand of nutrients by skin cells in order to regenerate new tissue and accelerate healing. This work was therefore undertaken to establish whether wound healing could be accelerated by nutritional supplementation with a specific mixture tailored to human need of essential amino acids (EAAs) without topical medication. To this end, using a skin full-thickness excisional model in aged rats, we compared the closure dynamics of undressing wounds in animals fed an EAAs-enriched diet or standard diet. We assessed the degree of fibrosis and inflammation, as well as relevant signaling molecules such as COL1A1, iNOS and TGFbeta1. The results showed wound healing was accelerated in EAAs-fed rats, which was accompanied by reduced inflammation and changes in TGFbeta1 and COL1A1 expression. Collectively, our findings indicate that dietary supplementation with balanced EAAs diet could serve as a strategy to accelerate wound healing without inducing fibrosis and could therefore be a simple but pivotal therapeutic approach in human also. PMID- 28669822 TI - Blood count parameters as a marker for metabolic syndrome in older adults. AB - BACKGROUND AND AIM: Blood count parameters are associated with the metabolic syndrome (MS). However, few studies have evaluated the precision of blood count components to identify MS in older adults. We evaluated the accuracy of blood count components as a screening method and a marker of MS in older adults. METHODS AND RESULTS: A cross-sectional study with 203 older adults of both sexes was conducted. The following variables were used: MS as defined by harmonized criteria, hemoglobin, hematocrit, leukocytes and platelets. Area under the receiver operating characteristic (ROC) curve, sensitivity (sens), specificity (spec) and logistic regression were adjusted for age and sex. Leukocyte count showed the highest Youden's index value for MS screening, with an optimal cut-off point of 7.514103/mm3 (sens: 66.7%; spec: 72.0%) for men and 5.626103/mm3 (sens: 73.1%; spec: 42.4%) for women. Older adults with leukocyte count higher than these cut-off points presented a 2.4 times greater chance of developing MS. CONCLUSION: Leukocyte count can be used as a screening indicator to identify individuals with a higher risk of developing MS. Older adults with high leukocyte count and no associated chronic diseases should receive attention, as they are individuals with a potential risk for MS. PMID- 28669823 TI - Biochemical and Structural Analyses of Two Cryptic Esterases in Bacteroides intestinalis and their Synergistic Activities with Cognate Xylanases. AB - Arabinoxylans are constituents of the human diet. Although not utilizable by the human host, they can be fermented by colonic bacteria. The arabinoxylan backbone is decorated with arabinose side chains that may be substituted with ferulic acid, thus limiting depolymerization to fermentable sugars. We investigated the polypeptides encoded by two genes upregulated during growth of the colonic bacterium Bacteroides intestinalis on wheat arabinoxylan. The recombinant proteins, designated BiFae1A and BiFae1B, were functionally assigned esterase activities. Both enzymes were active on acetylated substrates, although each showed a higher ferulic acid esterase activity on methyl-ferulate. BiFae1A showed a catalytic efficiency of 12mM s-1 on para-nitrophenyl-acetate, and on methyl ferulate, the value was 27 times higher. BiFae1B showed low catalytic efficiencies for both substrates. Furthermore, the two enzymes released ferulic acid from various structural elements, and NMR spectroscopy indicated complete de esterification of arabinoxylan oligosaccharides from wheat bran. BiFae1A is a tetramer based on the crystal structure, whereas BiFae1B is a dimer in solution based on size exclusion chromatography. The structure of BiFae1A was solved to 1.98A resolution, and two tetramers were observed in the asymmetric unit. A flexible loop that may act as a hinge over the active site and likely coordinates critical interactions with the substrate was prominent in BiFae1A. Sequence alignments of the esterase domains in BiFae1B with the feruloyl esterase from Clostridium thermocellum suggest that both domains lack the flexible hinge in BiFae1A, an observation that may partly provide a molecular basis for the differences in activities in the two esterases. PMID- 28669824 TI - Floppy but not sloppy: Interaction mechanism of FG-nucleoporins and nuclear transport receptors. AB - The nuclear pore complex (NPC) forms a permeability barrier between the nucleus and the cytoplasm. Molecules that are able to cross this permeability barrier encounter different disordered phenylalanine glycine rich nucleoporins (FG-Nups) that act as a molecular filter and regulate the selective NPC crossing of biomolecules. In this review, we provide a current overview regarding the interaction mechanism between FG-Nups and the carrier molecules that recognize and enable the transport of cargoes through the NPC aiming to understand the general molecular mechanisms that facilitate the nucleocytoplasmic transport. PMID- 28669825 TI - New multilocus genotypes of Giardia lamblia human isolates. AB - Giardia lamblia is considered a species complex, whose members show little differences in their morphology, but have remarkable genetic variability. The aim of this study was to identify inter- and intra-assemblage genetic variation in G. lamblia among patients in Rio de Janeiro. The parasitological study was performed on faeces, and DNA was extracted from the samples which tested positive for G. lamblia. The genetic assemblages and subtypes were determined via multilocus sequence typing (MLST) using beta-giardin, triose phosphate isomerase and glutamate dehydrogenase gene loci. Fourteen assemblage A samples were successfully genotyped at the three MLST loci (bg/tpi/gdh). Two previously identified multilocus genotypes were found (AII-1 and AII-4), and two novel multilocus genotypes are proposed (AII-8, profile A2/A2/A4; AII-9, profile A3/A2/A2). Sequence analysis showed that assemblage B isolates have a higher nucleotide variation than those from assemblage A. Novel assemblage B sequences are described and most (66.7%) have heterogeneous nucleotides, which prevent the definition of multilocus genotypes. This is the first time that MLST has been used to characterise G. lamblia isolates in human clinical samples from Rio de Janeiro. In addition, MLST has enabled the detection of novel subtypes in both assemblages and the description of two novel multilocus genotypes in assemblage A. This study provides new insights into the genetic diversity of assemblage A and shows that MLST should be used to characterise G. lamblia both in Brazil and globally. PMID- 28669826 TI - Endocrine functions of vitamin D. PMID- 28669827 TI - Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization. AB - Mitochondria are highly dynamic organelles that change size and morphology by fusing together or dividing through fission. In response to cellular cues, signaling cascades may post-translationally modify mitochondria-shaping proteins, which lead to a change in mitochondria morphology. Here we show that nicotinamide (NAM), an inhibitor of sirtuin deacetylases, promotes degradation of mitochondria fusion protein mitofusin 1 (MFN1), suggesting that acetylation status of MFN1 is important for its protein stability. TIP60 but not PCAF acetyltransferase caused a reduction of MFN1 level. Meanwhile, siRNA-mediated knockdown of SIRT1 deacetylase caused a significant reduction of MFN1 whereas over-expression of SIRT1 increased its level in 293T cells. In vitro acetylation experiments showed that TIP60 increased the acetylation of MFN1 that was abolished by co-existence of SIRT1. Notably, MFN1 and SIRT1 levels were accumulated, along with mitochondria elongation under hypoxic conditions. Thus, the data suggest that mitochondria elongation under hypoxic condition is regulated through SIRT1 mediated MFN1 deacetylation and accumulation. The data provide an insight in the maintenance of cellular homeostasis through mitochondria morphological change. PMID- 28669828 TI - First report of OXA-48 carbapenemase-producing Escherichia coli in Taiwan. PMID- 28669829 TI - Meropenem selection induced overproduction of the intrinsic carbapenemase as well as phenotype divergence in Acinetobacter baumannii. AB - Acinetobacter baumannii 37662 is a carbapenem-susceptible isolate with blaOXA-51 like as the sole carbapenemase gene. Following selection with meropenem (MEM) at a subinhibitory concentration, two morphologically different mutants, designated 37662RM1 and 37662RM2, were obtained and characterised. Compared with the parent strain, resistant mutant 37662RM1 grew at a slower rate and had impaired capsule synthesis, whereas 37662RM2 grew fast and abolished capsule synthesis. In addition, the latter resistant mutant also lost pathogenicity but showed significantly enhanced biofilm formation. Transposition of the insertion sequence ISAba1 and formation of ISAba1-blaOXA-51-like was responsible for the upregulated expression of blaOXA-51-like. The blaOXA-51-like gene of A. baumannii 37662 is a close variant of blaOXA-138 and has been designated blaOXA-508. Overproduction of OXA-508 conferred major carbapenem resistance to these two mutants. Overall, these results indicate that a subinhibitory concentration of MEM can induce phenotype divergence together with carbapenem resistance in A. baumannii. PMID- 28669830 TI - Drivers and impact of antifungal therapy in critically ill patients with Aspergillus-positive respiratory tract cultures. AB - Invasive pulmonary aspergillosis (IPA) is an increasingly recognised problem in critically ill patients. Little is known about how intensivists react to an Aspergillus-positive respiratory sample or the efficacy of antifungal therapy (AFT). This study aimed to identify drivers of AFT prescription and diagnostic workup in patients with Aspergillus isolation in respiratory specimens as well as the impact of AFT in these patients. ICU patients with an Aspergillus-positive respiratory sample from the database of a previous observational, multicentre study were analysed. Cases were classified as proven/putative IPA or Aspergillus colonisation. Demographic, microbiological, diagnostic and therapeutic data were collected. Outcome was recorded 12 weeks after Aspergillus isolation. Patients with putative/proven IPA were more likely to receive AFT than colonised patients (78.7% vs. 25.5%; P <0.001). Patients with host factors for invasive fungal disease were more likely to receive AFT (72.5% vs. 37.4%) as were those with multiorgan failure (SOFA score >7) (68.4% vs. 36.9%) (both P <0.001). Once adjusted for disease severity, initiation of AFT did not alter the odds of survival (HR = 1.40, 95% CI 0.89-2.21). Likewise, treatment within 48 h following diagnosis did not change the clinical outcome (75.7% vs. 61.4%; P = 0.63). Treatment decisions appear to be based on diagnostic criteria and underlying disease severity at the time of Aspergillus isolation. IPA in this population has a dire prognosis and AFT is not associated with reduced mortality. This may be explained by delayed diagnosis and an often inevitable death due to advanced multiorgan failure. PMID- 28669831 TI - Epidemiology of antifungal resistance in human pathogenic yeasts: current viewpoint and practical recommendations for management. AB - In this review, we describe the epidemiology and clinical significance of resistance in Candida spp. and other non-Cryptococcus yeasts. The rise in echinocandin resistance, azole resistance and cross-resistance to two or more antifungal classes [multidrug resistance (MDR)] has been a worrisome trend, mainly in US large tertiary and oncology centres, particularly as it relates to Candida glabrata. Candida kefyr is also a concern as it can be resistant to echinocandins and polyenes, especially in patients with haematological malignancies. Lately, Candida auris has drawn a lot of attention: this uncommon Candida spp. is the first globally emerging fungal pathogen that exhibits MDR and strong potential for nosocomial transmission. Its almost simultaneous spread in four continents could be indicative of increasing selection pressures from the use of antifungal agents. Echinocandin non-susceptibility is also common among non-Candida, non-Cryptococcus yeasts. As Candida resistance patterns reflect, in part, institutional practices of antifungal administration, the benefits of antifungal stewardship protocols are increasingly recognised and endorsed in recent guidelines. Development of rapid diagnostic methods for detecting or ruling out the presence of candidaemia and antifungal resistance, as well as discovery of novel antifungals, are key priorities in medical mycology research. PMID- 28669832 TI - Hyperbaric oxygen therapy augments tobramycin efficacy in experimental Staphylococcus aureus endocarditis. AB - Staphylococcus aureus infective endocarditis (IE) is a serious disease with an in hospital mortality of up to 40%. Improvements in the effects of antibiotics and host responses could potentially benefit outcomes. Hyperbaric oxygen therapy (HBOT) represents an adjunctive therapeutic option. In this study, the efficacy of HBOT in combination with tobramycin in S. aureus IE was evaluated. A rat model of S. aureus IE mimicking the bacterial load in humans was used. Infected rats treated subcutaneously with tobramycin were randomised into two groups: (i) HBOT twice daily (n = 13); or (ii) normobaric air breathing (non-HBOT) (n = 17). Quantitative bacteriology, cytokine expression, valve vegetation size and clinical status were assessed 4 days post-infection. Adjunctive HBOT reduced the bacterial load in the aortic valves, myocardium and spleen compared with the non HBOT group (P = 0.004, <0.001 and 0.01, respectively) and improved the clinical score (P <0.0001). Photoplanimetric analysis and weight of valve vegetations showed significantly reduced vegetations in the HBOT group (P <0.001). Key pro inflammatory cytokines [IL-1beta, IL-6, keratinocyte-derived chemokine (KC) and vascular endothelial growth factor (VEGF)] were significantly reduced in valves from the HBOT group compared with the non-HBOT group. In conclusion, HBOT augmented tobramycin efficacy as assessed by several parameters. These findings suggest the potential use of adjunctive therapy in severe S. aureus IE. PMID- 28669833 TI - Pathobiology of Lomentospora prolificans: could this species serve as a model of primary antifungal resistance? AB - The number of fungal isolates resistant to antifungal drugs has increased dramatically over the last few years and has become an important concern for clinicians. Among these isolates, fungi showing multidrug resistance are particularly worrying because of the difficulties associated with their treatment. These factors hamper the successful recovery of patients and drastically raise mortality rates. Antifungal resistance is multifactorial and several mechanisms in different fungi have been described. There is a need to study these mechanisms in depth; however, the study of antifungal drug resistance separately for each individual species makes progress in the field very slow and tedious. The selection of a multiresistant microorganism as a model for understanding resistance mechanisms and extrapolating the results to other species could help in the search for a solution. In this mini-review, we describe the pathobiology of Lomentospora (Scedosporium) prolificans, paying special attention to its intrinsic resistance to all currently available antifungal agents. The characteristics of L. prolificans offer several advantages: the possibility of using a single microorganism for the study of resistance to different drugs, even cases of double and triple resistance; it is biologically safe for society in general as no new genetically-modified strains are needed for the experiments; it is homologous with other fungal species, and there is repetitiveness between different strains. In conclusion, we propose L. prolificans as a candidate for consideration as a fungal model for the study of resistance mechanisms against antifungal agents. PMID- 28669834 TI - Treating influenza with antibiotics. PMID- 28669835 TI - Molecular basis of antifungal drug resistance in yeasts. AB - Besides inherent differences in in vitro susceptibilities, clinically-relevant yeast species may acquire resistance upon exposure to most antifungal drugs used in the clinic. In recent years, major fundamental research studies have been conducted to improve our understanding of the molecular basis of antifungal resistance. This topic is of major interest as antifungal resistance in yeast is clearly evolving and is correlated with clinical failure. This minireview is an overview of the most recent findings about key molecular mechanisms evolving in human pathogenic yeasts, particularly Candida spp., in the context of antifungal drug resistance. Also included are the methods currently available for in vitro antifungal susceptibility testing and for molecular detection of mutations associated with resistance. Finally, the genetic drivers of antifungal resistance are discussed in light of the spectra of multidrug resistance as observed in Candida glabrata. PMID- 28669836 TI - Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: a systematic review and meta-analysis. AB - BACKGROUND: Inhaled colistin is becoming increasingly popular against respiratory tract infections caused by multidrug resistant (MDR) Gram-negative bacteria because it may overcome the problems associated with intravenous (IV) administration. OBJECTIVE: To investigate the effectiveness and safety of inhaled colistin as monotherapy (without concomitant IV administration of colistin) in the treatment of respiratory tract infections caused by MDR or colistin-only susceptible Gram-negative bacteria. METHODS: PubMed and Scopus databases were searched. A systematic review and meta-analysis were conducted. RESULTS: Twelve studies (373 patients receiving inhaled colistin for respiratory tract infection) were included. Ten studies evaluated patients with pneumonia (including 8 studies with ventilator-associated pneumonia) and 2 studies evaluated patients with ventilator-associated tracheobronchitis. Patients with infections due to MDR Acinetobacter baumannii and Pseudomonas aeruginosa were mainly studied. Daily dose of inhaled colistin and treatment duration varied in the individual studies. The pooled all-cause mortality was 33.8% (95% CI 24.6% - 43.6%), clinical success was 70.4% (58.5% - 81.1%) and eradication of Gram-negative bacteria was shown in 71.3% (57.6% - 83.2%) of cases. CONCLUSIONS: Inhaled colistin monotherapy may deserve further consideration as a mode for colistin administration for the treatment of respiratory tract infections caused by MDR A. baumannii and P. aeruginosa. PMID- 28669837 TI - The Microbiological@mind project: a public engagement initiative of Turin University bringing microbiology and health education into primary schools. AB - Despite ongoing global efforts, antimicrobial resistance continues to threaten the treatment of an ever-increasing range of bacterial infections. There is substantial evidence that public education programs that foster microbial literacy amongst young school audiences may improve correct knowledge of specific health issues, such as prevention of microbial infections and responsible use of antibiotics. The aim of the Microbiological@mind project was to engage primary school students with the subject of microbiology, to promote both scientific interest and awareness towards correct behaviors that may ensure a safer lifestyle. Interactive workshops based on a full ''hands-on'' approach were carried out by an expert team from the University of Turin to over 1200 children aged 9-11 years at primary schools in Turin. A questionnaire (pre- and post activity test) on the main topic (i.e. antibiotics) was used to assess project effectiveness. The workshops provided a useful means to strengthen the understanding of basic microbiology concepts amongst students. Students' baseline knowledge of antibiotics was quite low, as low percentages of correct answers on antibiotic action and use (5.0% and 12.1%, respectively) were found in the pre activity tests. A significant increase (P <0.0001) in correct knowledge was observed in the post-activity tests, after implementation of the teaching activity. Our findings support the idea that microbial literacy in early childhood through hands-on educational programs is of great importance to foster children's interest in science learning, and to provide young people with information about general and specific health-related issues, such as prudent antibiotic use, for a more responsible citizenship. PMID- 28669838 TI - Antileishmanial and immunomodulatory activities of lupeol, a triterpene compound isolated from Sterculia villosa. AB - Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis, caused by the protozoan parasite Leishmania donovani. Nowadays there is a growing interest in the therapeutic use of natural products to treat parasitic diseases. Sterculia villosa is an ethnomedicinally important plant. A triterpenoid was isolated from this plant and was screened for its antileishmanial and immunomodulatory activities in vitro and in vivo. Biochemical colour test and spectroscopic data confirmed that the isolated pure compound was lupeol. Lupeol exhibited significant antileishmanial activity, with IC50 values of 65 +/- 0.41 ug/mL and 15 +/- 0.45 ug/mL against promastigote and amastigote forms, respectively. Lupeol caused maximum cytoplasmic membrane damage of L. donovani promastigote at its IC50 dose. It is well known that during infection the Leishmania parasite exerts its pathogenicity in the host by suppressing nitric oxide (NO) production and inhibiting pro-inflammatory responses. It was observed that lupeol induces NO generation in L. donovani-infected macrophages, followed by upregulation of pro-inflammatory cytokines and downregulation of anti inflammatory cytokines. Lupeol was also found to reduce the hepatic and splenic parasite burden through upregulation of the pro-inflammatory response in L. donovani-infected BALB/c mice. Strong binding affinity of lupeol was observed for four major potential drug targets, namely pteridine reductase 1, adenine phosphoribosyltransferase, lipophosphoglycan biosynthetic protein and glycoprotein 63 of L. donovani, which also supported its antileishmanial and immunomodulatory activities. Therefore, the present study highlights the antileishmanial and immunomodulatory activities of lupeol in an in vitro and in vivo model of VL. PMID- 28669839 TI - Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling. AB - Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials. PMID- 28669841 TI - Autochthonous hepatitis E: a common and fatal but neglected emerging disease in France. PMID- 28669840 TI - Characterization of circRNA-Associated-ceRNA Networks in a Senescence-Accelerated Mouse Prone 8 Brain. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Although many researchers have attempted to explain the origins of AD, developing an effective strategy in AD clinical therapy is difficult. Recent studies have revealed a potential link between AD and circRNA-associated-ceRNA networks. However, few genome-wide studies have identified the potential circRNA-associated ceRNA pairs involved in AD. In this study, we systematically explored the circRNA associated-ceRNA mechanism in a 7-month-old senescence-accelerated mouse prone 8 (SAMP8) model brain through deep RNA sequencing. We obtained 235 significantly dysregulated circRNA transcripts, 30 significantly dysregulated miRNAs, and 1,202 significantly dysregulated mRNAs. We then constructed the most comprehensive circRNA-associated-ceRNA networks in SAMP8 brain. GO analysis revealed that these networks were involved in regulating the development of AD from various angles, for instance, axon terminus (GO: 0043679) and synapse (GO: 0045202). Following rigorous selection, we discovered that the circRNA-associated-ceRNA networks in this AD mouse model were mainly involved in the regulation of Abeta clearance (Hmgb2) and myelin function (Dio2). This research is the first to provide a systematic dissection of circRNA-associated-ceRNA profiling in SAMP8 mouse brain. The selected circRNA-associated-ceRNA networks can profoundly affect the diagnosis and therapy of AD in the future. PMID- 28669842 TI - Human Brucella melitensis infections in southern Vietnam. PMID- 28669843 TI - Large outbreak of urogenital schistosomiasis acquired in Southern Corsica, France: monitoring early signs of endemicization? AB - OBJECTIVES: Clustered cases of urogenital schistosomiasis were reported in April 2014 among French and German tourists linked to exposure in the Cavu River, Southern Corsica, France, between 2011 and 2013. We set up national surveillance for autochthonous urogenital schistosomiasis to document the largest possible number of cases in order to identify potential sites of transmission and to determine the extent of the outbreak in France and Corsica. METHODS: The early response consisted mostly of prohibiting swimming in the river, performing a nationwide serologic screening of all persons exposed to the river between 2011 and 2013 and treating confirmed cases. Physicians were asked to report all patients with one or more positive antischistosome serologic test. Cases were defined as occurring in a resident of France with serologic evidence of schistosomiasis or schistosome eggs in urine and no history of contact with freshwater in known endemic areas. We documented symptoms as well as place and time of exposure to freshwater for all subjects. To estimate the outbreak size, we modelled the effect of the 2014 nationwide screening on the 2011-2015 time series of serodiagnosed schistosomiasis cases using log-linear autoregression. RESULTS: In 2014, a total of 106 autochthonous cases were reported, including 35 symptomatic infections. All patients had swum in the Cavu during summer 2013. Over 30 000 persons were likely screened for autochthonous schistosomiasis. The model-estimated outbreak size was 338 cases, including 36 serodiagnosed in 2015. CONCLUSIONS: Besides the 2013 outbreak, there is evidence of small-scale transmission in 2015 in Corsica. Early detection and control of recurrences requires raising community and medical awareness. PMID- 28669844 TI - Prospective multicentre clinical study on inter- and intrapatient genetic variability for antimicrobial resistance of Helicobacter pylori. AB - OBJECTIVES: We report on a large prospective, multicentre clinical investigation on inter- and intrapatient genetic variability for antimicrobial resistance of Helicobacter pylori. METHODS: Therapy-naive patients (n = 2004) who had undergone routine diagnostic gastroscopy were prospectively included from all geographic regions of Austria. Gastric biopsy samples were collected separately from antrum and corpus. Samples were analysed by histopathology and real-time PCR for genotypic resistance to clarithromycin and quinolones. Clinical and demographic information was analysed in relation to resistance patterns. RESULTS: H. pylori infection was detected in 514 (26%) of 2004 patients by histopathology and confirmed in 465 (90%) of 514 patients by real-time PCR. PCR results were discordant for antrum and corpus in 27 (5%) of 514 patients, indicating inhomogeneous infections. Clarithromycin resistance rates were 17% (77/448) and 19% (84/455), and quinolone resistance rates were 12% (37/310) and 10% (32/334) in antrum and corpus samples, respectively. Combination of test results per patient yielded resistance rates of 21% (98/465) and 13% (50/383) for clarithromycin and quinolones, respectively. Overall, infection with both sensitive and resistant H. pylori was detected in 65 (14%) of 465 patients. CONCLUSIONS: Anatomically inhomogeneous infection with different, multiple H. pylori strains is common. Prospective clinical study design, collection of samples from multiple sites and microbiologic methods that allow the detection of coinfections are mandatory for collection of reliable data on antimicrobial resistance patterns in representative patient populations. (ClinicalTrials.gov identifier: NCT02925091). PMID- 28669845 TI - Dioxin-like activity of brominated dioxins as individual compounds or mixtures in in vitro reporter gene assays with rat and mouse hepatoma cell lines. AB - In vitro reporter gene assays detecting dioxin-like compounds have been developed and validated since the middle 1990's, and applied to the determination of dioxin like activities in various samples for their risk management. Data on characterizing the potency of individual brominated dioxins and their activity in mixture with chlorinated dioxins are still limited on the cell-based assay. This study characterized the dioxin-like activities of the 32 brominated dioxins, such as polybrominated dibenzo-p-dioxins, polybrominated dibenzofurans (PBDFs), coplanar polybrominated biphenyls, mixed halogenated dibenzo-p-dioxins and dibenzofurans (PXDFs), as a sole component or in a mixture by DR-CALUX (dioxin responsive chemically activated luciferase expression) using the rat hepatoma H4IIE cell line and XDS-CALUX (xenobiotic detection systems-chemically activated luciferase expression) assays using the mouse hepatoma H1L6.1 cell line. The 2,3,7,8-TCDD-relative potencies (REPs) of most of the brominated dioxins were within a factor of 10 of the WHO toxicity equivalency factor (WHO-TEF) for the chlorinated analogues. The REPs of a few PXDFs were an order of magnitude higher than the corresponding WHO-TEFs, indicating their toxicological importance. Results with reconstituted mixtures suggest that the activity of brominated and chlorinated dioxins in both CALUX assays was dose-additive. Thus, obtained results indicated the applicability of the CALUX assays as screening tools of brominated dioxins together with their chlorinated analogues. PMID- 28669848 TI - Isolated Brain Metastases as the First Relapse After the Curative Surgical Resection in Non-Small-Cell Lung Cancer Patients With an EGFR Mutation. AB - INTRODUCTION: The aim of this study was to clarify the incidence and disease behavior of brain metastases (BM) without extracranial disease (ie, isolated BM) as the first relapse after curative surgery in non-small-cell lung cancer (NSCLC) patients, analyzed according to epidermal growth factor receptor (EGFR) mutation status. PATIENTS AND METHODS: A review of the medical charts of consecutive NSCLC patients diagnosed between 2005 and 2016 with BM as the first relapse after curative surgery was performed. RESULTS: Among 1191 patients evaluated for EGFR mutation status, 28 patients who met the inclusion criteria were divided into 2 groups: EGFR mutation group (16 patients) and wild type group (12 patients). At BM diagnosis, the EGFR-mutation group tended to have more commonly isolated BM compared with that in the wild type group (11 of 16 vs. 3 of 12; P = .054). In the EGFR mutation group, the patients with isolated BM showed longer overall survival than those with non-isolated BM (39.6 vs. 18.7 months; P = .038). Notably, isolated BM in the EGFR mutation group was neurologically asymptomatic in 10 of the 11 patients. With regard to upfront treatment for isolated BM in the EGFR mutation group, 10 of 11 patients were treated with only cranial radiotherapy without EGFR tyrosine kinase inhibitors, but two-thirds of the patients (7 of 11; 64%) developed extracranial disease during the study period. CONCLUSION: In curatively resected NSCLC patients with EGFR mutation, isolated BM would be correlated with better prognosis, but regarded as a precursor to systemic disease. Because isolated BM can be neurologically asymptomatic, it would be important to periodically perform cranial evaluation to detect isolated BM. PMID- 28669847 TI - A review on multiple sequence alignment from the perspective of genetic algorithm. AB - Sequence alignment is an active research area in the field of bioinformatics. It is also a crucial task as it guides many other tasks like phylogenetic analysis, function, and/or structure prediction of biological macromolecules like DNA, RNA, and Protein. Proteins are the building blocks of every living organism. Although protein alignment problem has been studied for several decades, unfortunately, every available method produces alignment results differently for a single alignment problem. Multiple sequence alignment is characterized as a very high computational complex problem. Many stochastic methods, therefore, are considered for improving the accuracy of alignment. Among them, many researchers frequently use Genetic Algorithm. In this study, we have shown different types of the method applied in alignment and the recent trends in the multiobjective genetic algorithm for solving multiple sequence alignment. Many recent studies have demonstrated considerable progress in finding the alignment accuracy. PMID- 28669846 TI - Meibomian glands, meibum, and meibogenesis. AB - Meibum is a lipid-rich secretion that is produced by fully differentiated meibocytes in the holocrine Meibomian glands (MG) of humans and most mammals. The secretion is a part of a defense mechanism that protects the ocular surface from hazardous environmental factors, and from desiccation. Meibomian lipids that have been identified in meibum are very diverse and unique in nature. The lipid composition of meibum is different from virtually any other lipid pool found in the human body. In fact, meibum is quite different from sebum, which is the closest secretion that is produced by anatomically, physiologically, and biochemically related sebaceous glands. However, meibum of mice have been shown to closely resemble that of humans, implying similar biosynthetic mechanisms in MG of both species. By analyzing available genomic, immunohistochemical, and lipidomic data, we have envisioned a unifying network of enzymatic reactions that are responsible for biosynthesis of meibum, which we call meibogenesis. Our current theory is based on an assumption that most of the biosynthetic reactions of meibogenesis are catalyzed by known enzymes. However, the main features that make meibum unique - the ratio of identified classes of lipids, the extreme length of its components, extensive omega-hydroxylation of fatty acids and alcohols, iso- and anteiso-branching of meibomian lipids (e.g. waxes), and the presence of rather unique complex lipids with several ester bonds - make it possible that either the activity of known enzymes is altered in MG, or some unknown enzymes contribute to the processes of meibogenesis, or both. Studies are in progress to elucidate meibogenesis on molecular level. PMID- 28669849 TI - Programmed Death Ligand 1 Expression in Paired Non-Small Cell Lung Cancer Tumor Samples. AB - BACKGROUND: Programmed death ligand 1 (PD-L1) expression may predict response to anti-programmed death 1 (anti-PD-1) or anti-PD-L1 treatment. There is limited information on changes in PD-L1 expression over time in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients with NSCLC who received surgery or underwent biopsy at Samsung Medical Center, Seoul, Republic of Korea, and Aarhus University Hospital, Aarhus, Denmark, between February 2004 and April 2012 were included. PD-L1 expression in paired tumor tissue samples from the same patients at different dates and lesions was measured using a laboratory-developed prototype immunohistochemistry assay (22C3 antibody). PD-L1 positivity was defined as tumor cell membrane positivity in >= 1% of tumor cells (proportion score). Concordance of PD-L1 expression was analyzed by treating proportion score as categoric or continuous variables. RESULTS: Ninety-one patients were included in the analysis. The median interval between the 2 tumor collection dates was 20 months, with 91% of paired samples collected > 3 months apart. The concordance rate for PD-L1 classification between paired samples was 67% (95% confidence interval, 57%-77%). When treating the immunohistochemistry proportional score as a continuous variable, a significant correlation of PD-L1 expression was observed between the paired samples (Pearson correlation coefficient, 0.61; P < .001). CONCLUSION: There are good correlations of PD-L1 expression from paired NSCLC samples. For patients whose PD-L1 status is negative, it may be valuable to obtain additional tissue samples for retesting PD L1 expression when anti-PD-1 immunotherapy is considered. PMID- 28669850 TI - A scoring model predicts hepatitis B e antigen seroconversion in chronic hepatitis B patients treated with nucleos(t)ide analogs: real-world clinical practice. AB - AIM: This study developed and validated a non-invasive scoring model to predict 1 year hepatitis B e antigen (HBeAg) seroconversion in response to nucleos(t)ide analog (NA) treatment in NA-naive patients with HBeAg-positive chronic hepatitis B (CHB). METHODS: Baseline data from 1014 patients visiting the outpatient and inpatient clinics of Beijing Ditan Hospital, Capital Medical University, China between October 2008 and April 2015 were included. These patients received NAs for HBeAg-positive CHB. The patients were assigned randomly to the derivation (n=710) and validation (n=304) cohorts in a 7:3 ratio. A prediction scoring model was established based on univariate and multivariate Cox proportional hazards regression analyses to identify independent prediction factors. In the derivation cohort, the odds ratio of the predictors were converted to integer risk scores by rounding the quotient from dividing the odds ratio, and the final score was the sum of these values. The predictive accuracy of the scoring model was further assessed using Harrell's concordance index (C-index). RESULTS: The 1-year cumulative HBeAg seroconversion rates were 11.83% and 8.55% in the derivation and validation cohorts, respectively. In the derivation cohort, baseline pretreatment alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), globulin (GLO), and quantitative HBeAg (qHBeAg) levels were independently associated with HBeAg seroconversion and were included in the scoring system. The model had good discrimination in the derivation and validation cohorts (C-index=0.750, 95% confidence interval 0.694-0.806 and C-index=0.776, 95% confidence interval 0.698 0.855, respectively). The prediction scores ranged from 0 to 4; scores of 0-1 and 2-4 identified patients with lower and higher levels of HBeAg seroconversion, respectively. Kaplan-Meier analysis was used to determine the 1-year cumulative HBeAg seroconversion rates in the two groups (scores of 0-1 and 2-4) of the primary cohort, and log-rank tests revealed a significant difference (4.87% vs. 20.9%, p<0.0001). CONCLUSIONS: The 1-year prediction scoring model based on baseline levels of ALT, GGT, GLO, and qHBeAg offered a reliable predictive value for the response to NA therapy in a Chinese cohort. PMID- 28669851 TI - Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues. AB - Strategies to minimize the nephrotoxicity of platinated antineoplastics without affecting its antitumour efficacy are strongly necessary to improve the pharmacotoxicological profile of these drugs. The natural flavonoid quercetin has been shown to afford nephroprotection without affecting cisplatin antitumour effect. The purpose of the present study has been to assess the differential mechanisms of action of cisplatin and quercetin on kidney and tumour tissues that could explain these effects. Wistar rats bearing subcutaneous tumours were treated with cisplatin and quercetin (and the appropriate controls). Tumour size and renal function evolution was monitored during 6 days. Platinum and quercetin content were also determined in both tissues. All the parameters studied, including blood supply, inflammation, apoptosis, critical MAPK signaling and oxidative stress in the cisplatin-treated animals are almost normalized by quercetin in the kidneys, but unaffected in the tumours. Our results suggest that in a cancer model in vivo, the protection exerted by quercetin on cisplatin nephrotoxicity is related to its antioxidant, vascular, anti-inflammatory and antiapoptotic effects, but these properties do not affect the mechanisms responsible for the antitumour effect of cisplatin. PMID- 28669852 TI - Dynamin regulates the fusion pore of endo- and exocytotic vesicles as revealed by membrane capacitance measurements. AB - BACKGROUND: Dynamin is a multidomain GTPase exhibiting mechanochemical and catalytic properties involved in vesicle scission from the plasmalemma during endocytosis. New evidence indicates that dynamin is also involved in exocytotic release of catecholamines, suggesting the existence of a dynamin-regulated structure that couples endo- to exocytosis. METHODS: Thus we here employed high resolution cell-attached capacitance measurements and super-resolution structured illumination microscopy to directly examine single vesicle interactions with the plasmalemma in cultured rat astrocytes treated with distinct pharmacological modulators of dynamin activity. Fluorescent dextrans and the lipophilic plasmalemmal marker DiD were utilized to monitor uptake and distribution of vesicles in the peri-plasmalemmal space and in the cell cytosol. RESULTS: Dynamin inhibition with DynoleTM-34-2 and DyngoTM-4a prevented vesicle internalization into the cytosol and decreased fusion pore conductance of vesicles that remained attached to the plasmalemma via a narrow fusion pore that lapsed into a state of repetitive opening and closing - flickering. In contrast, the dynamin activator RyngoTM-1-23 promoted vesicle internalization and favored fusion pore closure by prolonging closed and shortening open fusion pore dwell times. Immunocytochemical staining revealed dextran uptake into dynamin-positive vesicles and increased dextran uptake into Syt4- and VAMP2-positive vesicles after dynamin inhibition, indicating prolonged retention of these vesicles at the plasmalemma. CONCLUSIONS: Our results have provided direct evidence for a role of dynamin in regulation of fusion pore geometry and kinetics of endo- and exocytotic vesicles, indicating that both share a common dynamin-regulated structural intermediate, the fusion pore. PMID- 28669853 TI - Effect of sirolimus on arteriosclerosis induced by advanced glycation end products via inhibition of the ILK/mTOR pathway in kidney transplantation recipients. AB - To investigate the effect and related mechanism of sirolimus (SRL) in arteriosclerosis(AS) induced by advanced glycation end products (AGEs) in kidney transplantation recipients (KTRs). Human kidney tissues from KTRs before and after treatment with SRL were assessed by hematoxylin-eosin and immunohistochemical staining. Rat vascular smooth muscle cells (VSMCs) were treated with AGEs and/or SRL. The expressions of alpha-smooth muscle actin (alpha SMA), osteopontin (OPN), actinin-associated LIM protein (ALP), proliferating cell nuclear antigen (PCNA), integrin-linked kinase (ILK) and the mTOR signaling pathway proteins were examined using western blot assay. Cytosolic calcium present in VSMCs was also measured by the calcium assay kit and von Kossa staining assay. The expression of alpha-SMA was remarkably higher while OPN expression was significantly lower in recipients with AS after they were administered SRL. Rat VSMCs treated with AGEs exhibited significantly lower expression of alpha-SMA and overexpression of OPN, ALP and PCNA than the other groups. In contrast, the expression of alpha-SMA was significantly higher while the expression of OPN, ALP and PCNA was significantly lower in VSMCs treated with both AGEs and SRL. Moreover, the ILK/mTOR signaling pathway was activated in rat VSMCs treated with AGEs, while treatment with AGEs and SRL led to significant inhibition of the ILK/mTOR signaling pathway. AGEs play a critical role in the development and progression of AS after kidney transplantation, but SRL can reverse these effects and therefore slow down the development of AS through inhibition of the ILK/mTOR signaling pathway. PMID- 28669855 TI - The VAO/PCMH flavoprotein family. AB - The VAO/PCMH flavoprotein family consists of structurally homologous flavin dependent enzymes that catalyze a wide range of chemical reactions. Family members share an architecture consisting of a conserved FAD-binding domain and a more variable substrate-binding domain, which enables varying interactions with a range of substrates while maintaining the same cofactor-binding fold. Here, we provide an overview of the current state of our knowledge on the members of the VAO/PCMH family. Based on a phylogenetic analysis, we divide the family into 11 subgroups. We discuss the properties of these subgroups, focusing on recent developments in terms of the discovery of new family members and mechanistic advances. We also highlight open questions that will provide challenges for future research. PMID- 28669854 TI - Uptake of dendrimer-drug by different cell types in the hippocampus after hypoxic ischemic insult in neonatal mice: Effects of injury, microglial activation and hypothermia. AB - Perinatal hypoxic-ischemic encephalopathy (HIE) can result in neurodevelopmental disability, including cerebral palsy. The only treatment, hypothermia, provides incomplete neuroprotection. Hydroxyl polyamidoamine (PAMAM) dendrimers are being explored for targeted delivery of therapy for HIE. Understanding the biodistribution of dendrimer-conjugated drugs into microglia, neurons and astrocytes after brain injury is essential for optimizing drug delivery. We conjugated N-acetyl-L-cysteine to Cy5-labeled PAMAM dendrimer (Cy5-D-NAC) and used a mouse model of perinatal HIE to study effects of timing of administration, hypothermia, brain injury, and microglial activation on uptake. Dendrimer conjugation delivered therapy most effectively to activated microglia but also targeted some astrocytes and injured neurons. Cy5-D-NAC uptake was correlated with brain injury in all cell types and with activated morphology in microglia. Uptake was not inhibited by hypothermia, except in CD68+ microglia. Thus, dendrimer-conjugated drug delivery can target microglia, astrocytes and neurons and can be used in combination with hypothermia for treatment of HIE. PMID- 28669856 TI - Topoisomerase IIbeta and its role in different biological contexts. AB - Topoisomerase IIbeta is a type II DNA topoisomerase that was reported to be expressed in all mammalian cells but abundantly expressed in cells that have undergone terminal differentiation to attain a post mitotic state. Enzymatically it catalyzes ATP-dependent topological changes of double stranded DNA, while as a protein it was reported to be associated with several factors in promoting cell growth, migration, DNA repair and transcription regulation. The cellular roles of topoisomerase IIbeta are very less understood compared to its counterpart topoisomerase IIalpha. This review discusses origin of Topoisomerase II beta, its structure, activities reported in vitro and in vivo along with implications in cellular processes namely transcription, DNA repair, neuronal development, aging, HIV-infection and cancer. PMID- 28669857 TI - Aggregation to promote health in an era of data and value based payment. PMID- 28669858 TI - Pelvic incidence: a fixed value or can you change it? AB - BACKGROUND CONTEXT: There has been renewed interest in the pelvic vertebrae by spinal surgeons recently. Those involved in working with patients with adult spinal deformity focus on the position of the fused spine as it relates to the pelvis, and determine success or failure by specific numbers for given pelvic parameters. The pelvic parameters that are commonly measured for these patients are pelvic tilt, sacral slope, and pelvic incidence (PI). Out of the three, PI has always been considered to be the fixed measurement, whereas pelvic tilt and sacral slope have the capacity to change in relation to external forces. The assumption that the PI does not change has not been proven in a healthy, asymptomatic population. PURPOSE: This study aimed to investigate the differences in PI between three pelvic positions used in common functional activities: resting baseline pelvic posture, maximal anterior pelvic rotation, and maximal posterior pelvic rotation. STUDY DESIGN/SETTING: This was a randomized, prospective study of 50 healthy, asymptomatic, individuals who were recruited from the vicinity of our institution. PATIENT SAMPLE: Fifty patients (16 men with a mean age of 26.5+/-12.1 years; 34 women with a mean age of 27.2+/-10.8 years) were recruited for this study. Initial screening occurred by telephone. The inclusion criteria consisted of participants being between 18 and 79 years of age, no previous history of spine, pelvic, or lower extremity pain which had lasted longer than 48 hours, or history of any disorder in the spine, pelvis, or lower extremity that had required medical care. Female patients could not be pregnant at the time of participation. OUTCOME MEASURES: Changes in PI were assessed by examining the differences between the values of the PI with each change in pelvic position: resting to maximal anterior pelvic rotation and resting to maximal posterior pelvic rotation. Inter-rater reliability was assessed using Cronbach's alpha. METHODS: This study was funded by a Small Exploratory Grant from the Scoliosis Research Society. All subjects had an initial posterior-anterior and lateral radiograph taken in their resting pelvic position. If no spinal deformity was noted, each subject was instructed to maximally rotate their pelvis anteriorly and an immediate lateral radiograph was taken. The subject was then instructed to maximally rotate their pelvis posteriorly and an immediate lateral radiograph was again taken. Radiographic measurements of PI were independently measured by a board-certified, fellowship trained orthopedic spine surgeon and a board-certified musculoskeletal radiologist after defining and agreeing to the specific manner of measurement. RESULTS: Pelvic incidence values changed in 44 of 50 subjects (88%) when they maximally anteriorly rotated their pelvis from the resting pelvic position. The mean change was 2.9 degrees , with 23 of 50 subjects (46%) changing >=3 degrees . Pelvic incidence values changed in 40 of 50 subjects (80%) when they maximally posteriorly rotated their pelvis from the resting position. The mean change was 2.82 degrees with 27 of 50 subjects (54%) changing by >=3 degrees . CONCLUSIONS: This study demonstrated that for a high percentage of the healthy subjects who participated, the PI changed when the subjects varied their pelvic position. This questions the assumption that PI is a fixed parameter and suggests a potential functional motion at the sacroiliac joint. It also supports the idea that intentionally changing one's posture could lead to a change in PI, an idea that could have ramifications in surgical cases. PMID- 28669859 TI - Effect of the upper instrumented vertebral level (upper vs. lower thoracic spine) on gait ability after corrective surgery for adult spinal deformity. AB - BACKGROUND CONTEXT: The relationship between gait pattern and the level of upper instrumented vertebra (UIV) in surgically treated patients with adult spinal deformity (ASD) has not been fully documented. PURPOSE: This study aimed to assess the effect of UIV level for the gait pattern in ASD. STUDY DESIGN/SETTING: A prospective case series was carried out. PATIENT SAMPLE: Thirty surgically treated consecutive female ASD with lumbosacral fusion (age 67.0+/-8.4 years; body mass index 22.7+/-2.4 kg/m2; Cobb angle 49.9 degrees +/-21.3 degrees ; coronal vertical axis 1.5+/-3.6 cm; C7 sagittal vertical axis [C7SVA] 9.3+/-5.3 cm; pelvic incidence-lumbar lordosis 35.4 degrees +/-25.8 degrees ; and lean volume of the lower leg 5.5+/-0.9 kg) were categorized into upper thoracic [UT] group or lower thoracic [LT] group based on the level of UIV (UT; UIV T2-T5, LT; UIV T9-T11), and the gait pattern were compared before and after corrective spine surgery. OUTCOME MEASURES: Scoliosis Research Society Patient Questionnaire, Oswestry Disability Index, and force plate analysis were the outcome measures. METHODS: All subjects underwent gait analysis on a custom-built force plate. Dual energy X-ray absorptiometry. Subjects were followed-up for at least 2 years postoperation. RESULTS: The UT group had larger baseline Cobb angle, whereas the LT group had larger C7SVA (UT vs. LT; Cobb angle: 59.2+/-22.9 vs. 44.6+/-17.4 degrees , p=.03, C7SVA: 10.9+/-8.7 vs. 12.0+/-7.1 cm, p=.03). Preoperatively, no difference was found in gait velocity and stride between UT and LT group, whereas the right and left difference of step length was significantly large in UT group (velocity: 55.0+/-12.5 vs. 53.6+/-9.0 m/min, stride: 99.7+/-13.0 vs. 97.8+/-13.6 cm, step length; 10.4+/-4.9 vs. 5.6%+/-3.3%). Coronal and sagittal alignments were significantly improved in both groups (total; Cobb angle: 19.4 degrees +/ 10.6 degrees , C7SVA: 5.3+/-2.9 cm, PI-LL: 12.1 degrees +/-5.1 degrees ). Gait pattern, stride, and velocity all improved significantly after surgery (total; velocity: 62.3+/-8.9m/min, stride: 106.8+/-12.3 cm, p=.01). The knee angle at the heel contact phase and hip range of motion (ROM) were also significantly improved at postoperation (total; hip ROM: preoperation: 29.2 degrees +/-9.1 degrees , postoperation: 36.2 degrees +/-4.8 degrees , knee angle; preoperation: 10.6 degrees +/-6.6 degrees , postoperation: 4.4 degrees +/-2.8 degrees ). No difference was observed for the pelvis and shoulder rotation on the horizontal plane at postoperation in both groups (total; pelvis rotation; preoperation: 7.4 degrees +/-3.4 degrees , postoperation: 7.9 degrees +/-2.4 degrees , shoulder rotation; preoperation: 7.4 degrees +/-2.9 degrees , postoperation: 8.7 degrees +/-3.6 degrees ). The head vertical deviation was also not changed postoperatively in both groups (preoperation: 3.1+/-0.9 cm, postoperation: 3.1+/ 0.8 cm). CONCLUSIONS: Both UT and LT groups achieved similar improvement of gait ability and pattern after surgery. Additional studies will be needed to further define the effect of UIV for the activity of daily living such as fast walking, stepping the stairs, or standing from the chair in ASDs. PMID- 28669860 TI - Change in pain catastrophizing in patients with lumbar spinal surgery. AB - BACKGROUND CONTEXT: Even though catastrophizing can negatively moderate the outcome of surgery for lumbar spinal stenosis (LSS), it is still unclear whether pain catastrophizing is an enduring stable or a dynamic structure related to pain intensity after spine surgery. PURPOSE: The purpose of this study was to determine whether catastrophizing would change in patients who undergo spinal surgery for LSS. STUDY DESIGN: A prospective observational cohort study was carried out. STUDY SAMPLE: Patients who underwent spine surgery for LSS comprised the study sample. OUTCOME MEASURES: The Visual Analog Pain Scale (VAS) scores for back/leg pain, Oswestry Disability Index (ODI), and Pain Catastrophizing Scale (PCS) were the outcome measures. METHODS: The present observational cohort consisted of 138 patients between the ages of 40 and 80 years who were scheduled to undergo surgery for LSS. Among them, a total of 96 patients underwent a 3-year assessment after surgery. The PCS questionnaire was used for pain catastrophizing assessment before and 3 years after surgery. The VAS for back and leg pain, and ODI were assessed 3 and 6 months, and 1 and 3 years after surgery. The correlations between variables were analyzed before and 3 years after surgery. To clarify the causal relationship, time-series and linear mixed models were also used. RESULTS: At 3 years after surgery, ODI, VAS for back and leg pain, and PCS scores were significantly decreased. The correlation of PCS with VAS and ODI was significant both before and 3 years after surgery. The correlation between change in pain or disability and change in pain catastrophizing from preoperative to 3 years after surgery was also significant. In the causal relationship between pain and catastrophizing, overall changes in pain and disability were significant predictors of overall changes in pain catastrophizing from baseline to 3 year after surgery. CONCLUSION: The present study shows that pain catastrophizing can change in association with the improvement in pain intensity after spine surgery. Therefore, catastrophizing may not be an enduring stable construct, but a dynamic construct. PMID- 28669861 TI - Neurocognitive and behavioral outcomes in a nearly drowned child with cardiac arrest and hypothermia resuscitated after 43min of no flow-time: A case study. PMID- 28669862 TI - Spontaneous and Bite-Evoked Muscle Pain Are Mediated by a Common Nociceptive Pathway With Differential Contribution by TRPV1. AB - : Spontaneous pain and function-associated pain are prevalent symptoms of multiple acute and chronic muscle pathologies. We established mouse models for evaluating spontaneous pain and bite-evoked pain from masseter muscle, and determined the roles of transient receptor potential cation channel subfamily V member 1 (TRPV1) and the contribution of TRPV1- or neurokinin 1 (NK1)-dependent nociceptive pathways. Masseter muscle inflammation increased Mouse Grimace Scale scores and face-wiping behavior, which were attenuated by pharmacological or genetic inhibition of TRPV1. Masseter inflammation led to a significant reduction in bite force. Inhibition of TRPV1 only marginally relieved the inflammation induced reduction of bite force. These results suggest a differential extent of contribution of TRPV1 to the 2 types of muscle pain. However, chemical ablation of TRPV1-expressing nociceptors or chemogenetic silencing of TRPV1-lineage nerve terminals in masseter muscle attenuated inflammation-induced changes in Mouse Grimace Scale scores as well as bite force. Furthermore, ablation of neurons expressing NK1 receptor in trigeminal subnucleus caudalis also prevented both types of muscle pain. Our results suggest that TRPV1 differentially contributes to spontaneous pain and bite-evoked muscle pain, but TRPV1-expressing afferents and NK1-expressing second-order neurons commonly mediate both types of muscle pain. Therefore, manipulation of the nociceptive circuit may provide a novel approach for management of acute or chronic craniofacial muscle pain. PERSPECTIVE: We report the profound contribution of TRPV1 to spontaneous muscle pain but not to bite-evoked muscle pain. These 2 types of muscle pain are transmitted through a common nociceptive pathway. These results may help to develop new strategies to manage multiple modes of muscle pain simultaneously by manipulating pain circuits. PMID- 28669863 TI - Using Screening Tests to Predict Aberrant Use of Opioids in Chronic Pain Patients: Caveat Emptor. AB - : Screening tests represent a critical tool in chronic pain treatment for predicting aberrant opioid use, which has emerged as a significant public health issue. Nevertheless, there remains a significant potential for the misapplication of screeners in this context. The potential difficulties in evaluating the diagnostic efficiency of screeners have been well established, particularly with regard to the effect that the prevalence of a disorder has on predictive value. The wide range in the reported prevalence of aberrant opioid use behaviors makes it difficult to interpret data obtained from popular screeners for assessing the potential for the aberrant use of opioids. Given the prevalence of opioid problems, however, formulating clear clinical guidelines on such screeners appears highly important. The aims of the present report include: 1) providing a review of the salient issues necessary for interpreting diagnostic efficiency statistics of screening tests, 2) identifying the critical differences between sensitivity, specificity, and predictive value, and 3) discussing the characteristic effects that disease prevalence has on statistical prediction. The article also reviews key processes in screening measure development and highlights several key considerations relevant to their appropriate use in clinical decision-making. PERSPECTIVE: This article highlights common metrics for evaluating the clinical utility of screening tests in predicting aberrant opioid use. In addition, it explores a series of considerations key to developing clinical guidelines for interpreting the results of screeners in this context. PMID- 28669864 TI - Is Clostridium difficile infection a risk factor for subsequent bloodstream infection? AB - BACKGROUND: Clostridium difficile infection (CDI) is a common nosocomial diarrheal illness increasingly associated with mortality in United States. The underlying factors and mechanisms behind the recent increases in morbidity from CDI have not been fully elucidated. Murine models suggest a mucosal barrier breakdown leads to bacterial translocation and subsequent bloodstream infection (BSI). This study tests the hypothesis that CDI is associated with subsequent BSI in humans. METHODS: We conducted a retrospective cohort study on 1132 inpatients hospitalized >72 h with available stool test results for toxigenic C. difficile. The primary outcome was BSI following CDI. Secondary outcomes included 30-day mortality, colectomy, readmission, and ICU admission. Unadjusted and adjusted logistic regression models were developed. RESULTS: CDI occurred in 570 of 1132 patients (50.4%). BSI occurred in 86 (7.6%) patients. Enterococcus (14%) and Klebsiella (14%) species were the most common organisms. Patients with BSI had higher comorbidity scores and were more likely to be male, on immunosuppression, critically ill, and have a central venous catheter in place. Of the patients with BSI, 36 (42%) had CDI. CDI was not associated with subsequent BSI (OR 0.69; 95% CI 0.44-1.08; P = 0.103) in unadjusted analysis. In multivariable modeling, CDI appeared protective against subsequent BSI (OR 0.57; 95% CI 0.34-0.96; P = 0.036). Interaction modeling suggests a complicated relationship among CDI, BSI, antibiotic exposure, and central venous catheter use. CONCLUSIONS: In this cohort of inpatients that underwent testing for CDI, CDI was not a risk factor for developing subsequent BSI. PMID- 28669865 TI - Molecular signatures in breast cancer. AB - The use of molecular signatures to add value to standard clinical and pathological parameters has impacted clinical practice in many cancer types, but perhaps most notably in the breast cancer field. This is, in part, due to the considerable complexity of the disease at the clinical, morphological and molecular levels. The adoption of molecular profiling of DNA, RNA and protein continues to reveal important differences in the intrinsic biology between molecular subtypes and has begun to impact the way patients are managed. Several bioinformatic tools have been developed using DNA or RNA-based signatures to stratify the disease into biologically and/or clinically meaningful subgroups. Here, we review the approaches that have been used to develop gene expression signatures into currently available diagnostic assays (e.g., OncotypeDX(r) and Mammaprint(r)), plus we describe the latest work on genome sequencing, the methodologies used in the discovery process of mutational signatures, and the potential of these signatures to impact the clinic. PMID- 28669866 TI - Procedures and applications of long-term intravital microscopy. AB - Intravital microscopy (IVM) is increasingly used in biomedical research to study dynamic processes at cellular and subcellular resolution in their natural environment. Long-term IVM especially can be applied to visualize migration and proliferation over days to months within the same animal without recurrent surgeries. Skin can be repetitively imaged without surgery. To intermittently visualize cells in other organs, such as liver, mammary gland and brain, different imaging windows including the abdominal imaging window (AIW), dermal imaging window (DIW) and cranial imaging window (CIW) have been developed. In this review, we describe the procedure of window implantation and pros and cons of each technique as well as methods to retrace a position of interest over time. In addition, different fluorescent biosensors to facilitate the tracking of cells for different purposes, such as monitoring cell migration and proliferation, are discussed. Finally, we consider new techniques and possibilities of how long-term IVM can be even further improved in the future. PMID- 28669867 TI - Radical probing of spliceosome assembly. AB - Here we describe the synthesis and use of a directed hydroxyl radical probe, tethered to a pre-mRNA substrate, to map the structure of this substrate during the spliceosome assembly process. These studies indicate an early organization and proximation of conserved pre-mRNA sequences during spliceosome assembly. This methodology may be adapted to the synthesis of a wide variety of modified RNAs for use as probes of RNA structure and RNA-protein interaction. PMID- 28669868 TI - Questions about methodological and ethical quality of a vaccine adjuvant critical paper. PMID- 28669869 TI - Intraperitoneal ropivacaine instillation versus no intraperitoneal ropivacaine instillation for laparoscopic cholecystectomy: A systematic review and meta analysis. AB - BACKGROUND: Pain is one of the important reasons for delayed discharge and Enhanced Recovery After Surgery (ERAS) after laparoscopic cholecystectomy. To assess the benefits and disadvantage of intraperitoneal instillation of ropivacaine in people undergoing laparoscopic cholecystectomy. METHODS: We searched the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Science Citation Index Expanded to December 2016 to identify randomised clinical trials of relevance to this review. We analysed the data with Review Manager 5 analysis. MAIN RESULTS: We identified 12 suitable studies. A total of 853 participants were randomised to intraperitoneal ropivacaine instillation (442 participants) versus "no intraperitoneal ropivacaine instillation" (411 participants). The pain scores as measured by the visual analogue scale (VAS) were significantly lower in the ropivacaine instillation group than the control group at 4-8 h (10 trials; 751 participants; MD -0.64 cm; 95% CI -0.86 to -0.43; p < 0.00001) and at 9-24 h (9 trials; 582 participants; MD -0.47 cm; 95% CI -0.66 to -0.28; p < 0.00001).The proportion of people who developed the adverse events were less in the ropivacaine instillation group than the control group(RR 0.60; 95% CI 0.45 to 0.79; p = 0.0002). There was no significant difference in the Post-anesthesia care unit (PACU) stay time between the two groups (3 trials; 197 participants; MD -3.77 min; 95% CI -10.24 to 2.69). The overall quality of evidence was very low. Further trials are necessary. PMID- 28669870 TI - Secretory expression, purification and functional characterization of 17beta hydroxysteroid dehydrogenase type 1 from mammalian HEK293T cells. AB - 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) mainly catalyzes the reduction of estrone into estradiol. The enzymatic conversion is a critical step in estradiol accumulation in breast tissue, which is a valuable prognosis index of breast cancer disease. However, the source of 17beta-HSD1 for inhibitor design is limited. In this study, the fragment encoding human 17beta-HSD1 was successfully cloned and expressed in human embryonic kidney (HEK) 293T mammalian cells. The recombinant protein was purified by immobilized metal ion affinity chromatography yielding above 17 mg of purified 17beta-HSD1 protein per liter of cell culture, with a specific activity of 8.54 MUmoL/min/mg of protein for conversion of estradiol into estrone, with NAD+ as cofactor at pH 9.2. Enzyme characterization studies revealed that the protein has estrogenic activity and the Km value for estrone is about 20 nM. The recombinant protein purified from transfected HEK293T cells had higher specific activity compared to that of the enzyme purified directly from placenta. The present data show that the mammalian cell expression system can provide active 17beta-HSD1 which is functionally identical to its natural counterpart and easy to purify in qualities suitable for its structure-function study. PMID- 28669871 TI - Tissue Expressions of Soluble Human Epoxide Hydrolase-2 Enzyme in Patients with Temporal Lobe Epilepsy. AB - OBJECTIVE: We sought to simply demonstrate how levels of soluble human epoxide hydrolase-2 show changes in both temporal the cortex and hippocampal complex in patients with temporal lobe epilepsy. METHODS: A total of 20 patients underwent anterior temporal lobe resection due to temporal lobe epilepsy. The control group comprised 15 people who died in traffic accidents or by falling from a height, and their autopsy findings were included. Adequately sized temporal cortex and hippocampal samples were removed from each patient during surgery, and the same anatomic structures were removed from the control subjects during the autopsy procedures. Each sample was stored at -80 degrees C as rapidly as possible until the enzyme assay. RESULTS: The temporal cortex in the epilepsy patients had a significantly higher enzyme level than did the temporal cortex of the control group (P = 0.03). Correlation analysis showed that as the enzyme level increases in the temporal cortex, it also increases in the hippocampal complex (r2 = 0.06, P = 0.00001). More important, enzyme tissue levels showed positive correlations with seizure frequency in both the temporal cortex and hippocampal complex in patients (r2 = 0.7, P = 0.00001 and r2 = 0.4, P = 0.003, respectively). The duration of epilepsy was also positively correlated with the hippocampal enzyme level (r2 = 0.06, P = 0.00001). CONCLUSIONS: Soluble human epoxy hydrolase enzyme 2 is increased in both lateral and medial temporal tissues in temporal lobe epilepsy. Further studies should be conducted as inhibition of this enzyme has resulted in a significant decrease in or stopping of seizures and attenuated neuroinflammation in experimental epilepsy models in the current literature. PMID- 28669872 TI - Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Comparison Study Based on End Plate Subsidence and Cystic Change in Individuals Older and Younger than 65 Years. AB - OBJECTIVE: To compare the outcomes between patients older and younger than 65 years who underwent single-level minimally invasive transforaminal interbody fusion (MI-TLIF) surgery. METHODS: This study is a retrospective analysis of 76 patients who underwent MI-TLIF between April 2012 and June 2016. Group A consisted of 35 patients (<65 years) and group B consisted of 41 patients (>=65 years). Intraoperative data were recorded. The evaluation of clinical outcomes was based on the visual analog scale for back and leg pain and the Oswestry Disability Index. Radiologic outcomes including cage subsidence, end plate cyst formation, and fusion rate were assessed. RESULTS: The mean age of the study subjects was 65.3 years, and the mean duration of follow-up was 18.98 months. Group B had a higher rate of comorbidities compared with group A (90.24% vs. 57.14%, respectively; P < 0.05). There was no statistically significant difference in the rate of complications between the groups (group A, 14.29%; group B, 17.07%). Clinical outcomes significantly improved in both groups postoperatively (P < 0.05). Although bony fusion in group A was slightly higher than that in group B, the fusion rate was not statistically different according to age. There were no statistically significant differences in the rates of cage subsidence or positive cyst sign between the groups. CONCLUSIONS: MI-TLIF presented similar safeness and acceptable outcomes and complication rate in both groups. Cyst formation may be aggravated by cage subsidence, because cage subsidence was a useful potential predictor of cyst formation. PMID- 28669873 TI - Endoscopic Endonasal Surgery for Pituitary Apoplexy: Evidence On a 75-Case Series From a Tertiary Care Center. AB - BACKGROUND: The optimal management of pituitary apoplexy (PA) remains debated. The aim of this study was to assess the outcome of the transsphenoidal approach for PA in a large surgical experience. MATERIALS: Each consecutive case of PA consecutively operated by endoscopic endonasal approach from our tertiary care center, from 1998 to 2015, was included in this series. RESULTS: Seventy-five patients (47 male; mean age 52.4 +/- 16.2 years) were included. Mean follow-up was 69.3 +/- 46.7 months. On admission, all patients presented with abrupt severe headache (100%), associated with anterior hypopituitarism in 51 patients (68%), visual disturbances in 55 (73.4%), ophthalmoplegia in 38 (50.7%), and a remarkable reduction of consciousness in 2 (2.6%). Apoplexy proved to be ischemic in 35 patients (46.7%) and hemorrhagic in 40 (53.3%). Patients with hemorrhagic necrosis presented more often with major suprasellar expansion (P = 0.012) Radical removal was achieved in 60 cases (80%). Surgical morbidity consisted in one case of postoperative cerebrospinal fluid leak (1.3%). Anterior hypopituitarism worsened in 15 cases (20%), and diabetes insipidus occurred in 4 cases (5.3%). Ophthalmoplegia improved/normalized in 71% and visual symptoms in 85.5% of the patients, with better results achieved in ischemic forms (P = 0.043). The 2 comatose patients regained normal consciousness. CONCLUSIONS: The endoscopic endonasal approach represents a valid, effective, and safe technique in the management of PA. Favorable outcomes can be achieved by referring patients to dedicated pituitary centers with a multidisciplinary team. Further studies are still needed to define criteria for surgical indication and to identify outcome predictors. PMID- 28669874 TI - Operative Versus Nonoperative Management of Civilian Gunshot Wounds to the Spinal Cord: Novel Use of the Functional Independence Measure for Validated Outcomes. AB - BACKGROUND: Surgery for patients with gunshot wound spinal cord injury (GSCI) remains controversial. Few recent studies provide standardized follow-up and detailed functional outcomes. To our knowledge, the research we present in this study is unique in that we are the first to incorporate Functional Independence Measure (FIM) scores as an outcomes measure for neurologic recovery in patients with GSCI. METHODS: Patients with GSCI were divided into surgical and nonsurgical groups. Neurologic function was measured according to the American Spinal Injury Association impairment scale and defined as either complete or incomplete injury. Outcomes were then analyzed separately for complete and incomplete GSCI groups during hospitalization and rehabilitation. RESULTS: Baseline admissions characteristics were similar between surgical and nonsurgical groups except for a greater median injury severity score in the nonsurgical group (34 vs. 27; P = 0.02). For complete GSCI, total length of stay (LOS) was significantly longer in the surgical group (52 vs. 42 days; P = 0.04), and no difference was observed in overall FIM scores (58 vs. 54; P = 0.7). For incomplete GSCI, rehabilitation LOS was longer (35 vs. 21; P = 0.02) and a trend towards longer total LOS was observed in the surgical group (40 vs. 32; P = 0.07). No difference was observed in overall FIM scores (61 vs. 62; P = 0.9). CONCLUSIONS: Surgery for patients with GSCI is associated with increased LOS and is not associated with improved FIM scores for patients with either complete or incomplete spinal cord injuries. PMID- 28669875 TI - Emergency Trepanation as an Initial Treatment for Acute Subdural Hemorrhage: A Multicenter Retrospective Cohort Study. AB - BACKGROUND: Rapid decompression with trepanation and drainage in an emergency room has been proposed as a potentially effective initial intervention for early stage acute subdural hemorrhage; however, the actual safety and efficacy of the procedure remain unclear. The aim of this study was to evaluate the feasibility of emergency trepanation as an initial treatment for acute subdural hemorrhage. METHODS: We investigated patients with thick subdural hemorrhages who had undergone craniotomy between 2004 and 2015 in Japan using a nationwide trauma registry (the Japan Trauma Data Bank). The endpoint was survival at discharge. We compared patients who underwent trepanation in an emergency room with those who did not undergo trepanation, and adjusted for potential confounders using a multivariate logistic regression model. RESULTS: During the study period, 236,698 patients were registered in the Japan Trauma Data Bank. Of the 1391 patients who were eligible for analysis, 305 had undergone trepanation in an emergency room. The survival rate was 37.7% in patients who had undergone emergency trepanation and 59.3% in those who had not. Performing emergency trepanation was significantly associated with decreased survival even after adjusting for possible confounders (adjusted odds ratio, 0.55; 95% confidence interval, 0.40 0.76; P < 0.001). CONCLUSIONS: Our results indicate that performing trepanation in an emergency room is associated with a decreased survival rate. PMID- 28669876 TI - Changes in Expressions of Major Histocompatibility Complex Class I, Paired Immunoglobulin-Like Receptor B, and Cluster of Differentiation 3zeta in Motor Cortical Representations of the Brachial Plexus After Avulsion in Rats. AB - OBJECTIVE: Major histocompatibility complex class I (MHCI), paired-immunoglobulin like receptor B (PirB), and cluster of differentiation 3zeta (CD3zeta) negatively regulate neuronal plasticity in developing and adult brains. The aim of this study was to evaluate expressive changes of these factors in motor cortical representations of the brachial plexus (MCRBP) after total brachial plexus root avulsion (tBPRA). METHODS: A total of 45 rats were randomly and equally divided into 3 groups for evaluating mRNA and protein expression levels of MHCI, PirB, and CD3zeta: 7 days, 3 months, and control. In the 7-day and 3-month groups, expressions were examined at 7 days and 3 months, respectively, after left tBPRA. In the control group, the brachial plexus was uninjured. Three rats from each group were used for examining expressions of MHCI, PirB, and CD3zeta proteins by immunofluorescence labeling, 6 rats for quantification of MHCI, PirB, and CD3zeta mRNAs by real-time quantitative polymerase chain reaction, and the remaining 6 animals for quantification of MHCI, PirB, and CD3zeta proteins by Western blotting. RESULTS: In the original MCRBP, mRNA and protein expression levels of MHCI, PirB, and CD3zeta were down-regulated 7 days postinjury compared with control (P < 0.01). Interestingly, mRNA and protein expression levels of these factors were up-regulated at 3 months compared with 7 days (P < 0.01), excepting PirB protein, whose expression was not increasing (P > 0.05). Recovery of protein expressions were initiated from near the border region of the original MCRBP. CONCLUSIONS: MHCI, PirB, and CD3zeta may participate in motor cortical reorganization after tBPRA. PMID- 28669877 TI - Intraoperative Near-Infrared Optical Contrast Can Localize Brain Metastases. AB - INTRODUCTION: Approximately 100,000 brain metastases are diagnosed annually in the United States. Our laboratory has pioneered a novel technique, second window indocyanine green (SWIG), which allows for real-time intraoperative visualization of brain metastasis through normal brain parenchyma and intact dura. METHODS: Thirteen patients with intraparenchymal brain metastases were administered indocyanine green (ICG) at 5 mg/kg the day before surgery. A near-infrared (NIR)- capable camera was used intraoperatively to identify the tumor and to inspect surgical margins. Neuropathology was used to assess the accuracy and precision of the fluorescent dye for identifying tumor. RESULTS: ICG was infused at 24.7 +/- 3.45 hours before visualization. All 13 metastases fluoresced with an average signal-to-background ratio (SBR) of 6.62. The SBR with the dura intact was 67.2% of the mean SBR once the dura was opened. The NIR signal could be visualized through normal brain parenchyma up to 7 mm. For the 39 total specimens, the mean SBR for tumor specimens (n = 28) was 6.9, whereas the SBR for nontumor specimens (n = 11) was 3.7. The sensitivity, specificity, positive predictive value, and negative predictive value of NIR imaging for tumor was 96.4%, 27.3%, 77.1%, and 75.0%. DISCUSSION: SWIG relies on the passive accumulation of dye in abnormal tumor tissue via the enhanced permeability and retention effect. It provides strong NIR optical contrast, which can be used to localize tumors before dural opening. The use of SWIG for margin assessment remains limited by its lack of specificity (high false-positive rate); however, ongoing improvements in imaging parameters show great potential to reduce false-positive results. PMID- 28669878 TI - Thresholds for Volume and Expansion in Intraparenchymal Hemorrhage: Predictors of Neurologic Deterioration and Mortality. AB - OBJECTIVE: Spontaneous intraparenchymal hemorrhage (IPH) is a common neurosurgical emergency, with hemorrhage size and expansion associated with poor clinical outcomes. In this study, radiologic risk factors and specific IPH volume thresholds were calculated to identify heightened risk of neurologic deterioration and mortality. METHODS: A consecutive review of all patients with nontraumatic IPH transferred to a tertiary academic neurosurgery service was performed over 2 years. IPH volume, hemorrhage location, presence of intraventricular hemorrhage, hydrocephalus, anticoagulant use, and neurologic status were reviewed. A maximum Youden index was calculated to determine thresholds of initial IPH volume and expansion most predictive of deterioration and mortality. RESULTS: A total of 202 transfers were studied. Both initial IPH volume at the outside hospital and IPH expansion were correlated with neurologic deterioration and death. The most predictive threshold for mortality was 32 mL of initial IPH volume (area under the curve 0.758, P < 0.001, confidence interval 1.012-1.035) and 1 mL of expansion. The threshold for neurologic deterioration was 18 mL of initial volume (area under the curve 0.690, P = 0.004, confidence interval 1.004-1.025) and 1 mL of expansion. Both intraventricular hemorrhage and hydrocephalus were independently associated with elevated risk for deterioration and mortality, while anticoagulant use was associated with neurologic deterioration. CONCLUSIONS: Volume and growth of IPH are significant predictors of neurologic deterioration and death. An initial volume over 32 mL is associated with increased mortality risk, whereas risk of neurologic deterioration appears to peak at a smaller volume of 18 mL. Any measurable IPH expansion suggests elevated risk of deterioration and mortality. PMID- 28669879 TI - Unruptured Paraclinoid Aneurysm Treatment Effects on Visual Function: Systematic Review and Meta-analysis. AB - OBJECTIVE: Postoperative visual outcomes following repair of unruptured paraclinoid aneurysms (UPAs) are not well defined. We aim to investigate the influence of treatment modality on visual function. METHODS: A systematic literature analysis using the Ovid Medline and EMBASE databases was performed, encompassing English language studies (published between 1996 and 2016) reporting treatment outcomes for UPAs. Rates of visual morbidity (new, permanent postoperative deficit, worsening preoperative deficit); angiographic (occlusion, recurrence, retreatment) and clinical outcomes (death, disability, post-treatment subarachnoid hemorrhage) were recorded. Random effects meta-analysis was performed. RESULTS: Twenty-eight studies reported visual outcomes, with data for 1013 endovascular and 691 microsurgical patients. In patients with normal vision undergoing elective repair of UPAs, rates of postoperative visual morbidity were higher following microsurgical (10.8%; 95% confidence interval [CI] 8.5-13.7) than endovascular (2.0%; 95% CI 1.2-3.2) interventions, P < 0.001. In those presenting with preoperative visual impairment, surgery was associated with a modest advantage in visual recovery compared with endovascular therapies (65.2% vs. 48.9%, P < 0.03). There were no differences in visual morbidity following treatment with any of the endovascular modalities. Meta-analysis of comparative studies suggested a trend toward poor visual (ES = 0.42; 95% CI 0.08-2.09) and clinical outcomes (ES = 0.57; 95% CI 0.07-4.44) following microsurgery and a trend toward angiographic recurrence (ES = 2.52; 95% CI 0.80-7.90) and retreatment (ES = 1.62; 95% CI 0.46-5.67) after endovascular interventions. CONCLUSION: In patients with normal vision undergoing repairs for UPAs, there is a positive correlation between visual outcomes and endovascular treatments. When visual compromise is present, surgery provided modest advantage in visual recovery. However, definitive conclusions were not possible due to data heterogeneity. PMID- 28669880 TI - Role of Vitamin D in Amyloid clearance via LRP-1 upregulation in Alzheimer's disease: A potential therapeutic target? AB - Amyloid beta (Abeta) deposition is considered to be one of the primary reason to trigger Alzheimer's disease (AD). Literature clearly suggests decline in Abeta clearance to be accountable for progression of late onset AD as compared to augmented Abeta production. There may be several pathways for Abeta clearance out of which one of the major pathway is the vascular-mediated removal of Abeta from the brain across the blood-brain barrier (BBB) via efflux pumps or receptors. Among Abeta scavenger receptors, low density lipoprotein receptor related protein (LRP-1) has been most extensively studied. LRP-1, is highly expressed in neurons and located on abluminal side of the brain capillaries whose expression decreases in AD patients which give rise to increased cerebral Abeta deposition. Recent evidences reveal that post 1,25-(OH)2D3 treatment, LRP1 expression increases significantly for both in-vivo and in-vitro studies, since Vitamin D receptors (VDR) are broadly expressed in brain. Biological actions of Vitamin D are mediated via its nuclear hormone receptor vitamin D receptor (VDR) and is found to regulate many genes. Several lines of evidence suggest that VDR deficiency/inhibition can be a potential risk factor for AD and sufficient Vitamin D supplementation is beneficial to prevent AD onset/pathology or slow down the progression of disease. The present review establishes a strong correlation between Vitamin D and LRP-1 and their possible involvement in Abeta clearance and thereby emerging as new therapeutic target. PMID- 28669881 TI - An engineering thermodynamic approach to select the electromagnetic wave effective on cell growth. AB - To date, the choice of the characteristics of the extremely low-frequency electromagnetic field beneficial in proliferative disorders is still empirical. In order to make the ELF interaction selective, we applied the thermodynamic and biochemical principles to the analysis of the thermo-chemical output generated by the cell in the environment. The theoretical approach applied an engineering bio thermodynamic approach recently developed in order to obtain a physical mathematical model that calculated the frequency of the field able to maximize the mean entropy changes as a function of cellular parameters. The combined biochemical approach envisioned the changes of entropy as a metabolic shift leading to a reduction of cell growth. The proliferation of six human cancer cell lines was evaluated as the output signal able to confirm the correctness of the mathematical model. By considering the cell as a reactive system able to respond to the unbalancing external stimuli, for the first time we could calculate and validate the frequencies of the field specifically effective on distinct cells. PMID- 28669882 TI - Tumor growth model of ductal carcinoma: from in situ phase to stroma invasion. AB - This paper aims at modeling breast cancer transition from the in situ stage -when the tumor is confined to the duct- to the invasive phase. Such a transition occurs thanks to the degradation of the duct membrane under the action of specific enzymes so-called matrix metalloproteinases (MMPs). The model consists of advection-reaction equations that hold in the duct and in the surrounding tissue, in order to describe the proliferation and the necrosis of the cancer cells in each subdomain. The divergence of the velocity is given by the increase of the cell densities. Darcy law is imposed in order to close the system. The key point of the modeling lies in the description of the transmission conditions across the duct. Nonlinear Kedem-Katchalsky transmission conditions across the membrane describe the discontinuity of the pressure as a linear function of the flux. These transmission conditions make it possible to describe the transition from the in situ stage to the invasive phase at the macroscopic level. More precisely, the membrane permeability increases with respect to the local concentration of MMPs. The cancer cells are no more confined to the duct and the tumor invades the surrounding tissue. The model is enriched by the description of nutrients concentration, tumor necrosis factors, and MMPs production. The mathematical model is implemented in a 3D C++-code, which is based on well adapted finite difference schemes on Cartesian grid. The membrane interface is described by a level-set, and the transmission conditions are precisely approached at the second order thanks to well-suited sharp stencils. Our continuous approach provides new significant insights in the macroscopic modeling of the breast cancer phase transition, due to the membrane degradation by MMP enzymes. PMID- 28669883 TI - High prices for rare species can drive large populations extinct: the anthropogenic Allee effect revisited. AB - Consumer demand for plant and animal products threatens many populations with extinction. The anthropogenic Allee effect (AAE) proposes that such extinctions can be caused by prices for wildlife products increasing with species rarity. This price-rarity relationship creates financial incentives to extract the last remaining individuals of a population, despite higher search and harvest costs. The AAE has become a standard approach for conceptualizing the threat of economic markets on endangered species. Despite its potential importance for conservation, AAE theory is based on a simple graphical model with limited analysis of possible population trajectories. By specifying a general class of functions for price rarity relationships, we show that the classic theory can understate the risk of species extinction. AAE theory proposes that only populations below a critical Allee threshold will go extinct due to increasing price-rarity relationships. Our analysis shows that this threshold can be much higher than the original theory suggests, depending on initial harvest effort. More alarmingly, even species with population sizes above this Allee threshold, for which AAE predicts persistence, can be destined to extinction. Introducing even a minimum price for harvested individuals, close to zero, can cause large populations to cross the classic anthropogenic Allee threshold on a trajectory towards extinction. These results suggest that traditional AAE theory may give a false sense of security when managing large harvested populations. PMID- 28669885 TI - Evaluation of Gastric Microcirculation by Laser Speckle Contrast Imaging During Esophagectomy. AB - BACKGROUND: Thoracic epidural anesthesia (TEA) may provoke hypotension, and that, as well as the use of vasopressors and the surgical technique, could affect splanchnic microcirculation, in which the surgical target organ is of particular interest. This study used laser speckle contrast imaging (LSCI) to monitor gastric microcirculation during esophagectomy. STUDY DESIGN: Forty-five patients undergoing open esophagectomy were randomized to primary activation (EA; 25 patients) or no intraoperative activation (LA; 20 patients) of TEA. Phenylephrine managed intraoperative hypotension and gastric microcirculation was assessed at antrum and corpus area by LSCI. RESULTS: Antrum microcirculation (mean +/- SD) was lower in the EA group at baseline (1,150 +/- 189 laser speckle perfusion units [LSPU] vs LA group: 1,265 +/- 163 LSPU; p = 0.036). In both groups, antrum microcirculation tended to decrease in response to anesthesia, TEA, and surgical procedure (LA: 1,265 +/- 163 to 1,097 +/- 184 LSPU, p = 0.021; EA: 1,150 +/- 189 to 1,064 +/- 177 LSPU, p = 0.093), with no difference between groups during the remaining laparotomy. Corpus microcirculation decreased in both groups from baseline to gastric pull-up in response to anesthesia, TEA, and surgery (LA: 1,081 +/- 236 to 649 +/- 165 LSPU, p < 0.001; EA: 1,011 +/- 208 to 675 +/- 178 LSPU, p < 0.001), but recovered after gastric continuity was re-established (EA to 795 +/- 162 LSPU, p = 0.027; LA to 815 +/- 166 LSPU, p = 0.014), with no significant differences between groups (p > 0.05). The EA group needed continued phenylephrine support to maintain blood pressure (216 +/- 86 vs 58 +/- 91 minutes; p < 0.001). CONCLUSIONS: During esophagectomy, gastric microcirculation can be followed in real-time by LSCI. Flow changes in the stomach seemed related more to surgery than to TEA/vasopressor support. Laser speckle contrast imaging could form basis for directing procedures to maintain the microcirculation. PMID- 28669884 TI - Determining the control networks regulating stem cell lineages in colonic crypts. AB - The question of stem cell control is at the center of our understanding of tissue functioning, both in healthy and cancerous conditions. It is well accepted that cellular fate decisions (such as divisions, differentiation, apoptosis) are orchestrated by a network of regulatory signals emitted by different cell populations in the lineage and the surrounding tissue. The exact regulatory network that governs stem cell lineages in a given tissue is usually unknown. Here we propose an algorithm to identify a set of candidate control networks that are compatible with (a) measured means and variances of cell populations in different compartments, (b) qualitative information on cell population dynamics, such as the existence of local controls and oscillatory reaction of the system to population size perturbations, and (c) statistics of correlations between cell numbers in different compartments. Using the example of human colon crypts, where lineages are comprised of stem cells, transit amplifying cells, and differentiated cells, we start with a theoretically known set of 32 smallest control networks compatible with tissue stability. Utilizing near-equilibrium stochastic calculus of stem cells developed earlier, we apply a series of tests, where we compare the networks' expected behavior with the observations. This allows us to exclude most of the networks, until only three, very similar, candidate networks remain, which are most compatible with the measurements. This work demonstrates how theoretical analysis of control networks combined with only static biological data can shed light onto the inner workings of stem cell lineages, in the absence of direct experimental assessment of regulatory signaling mechanisms. The resulting candidate networks are dominated by negative control loops and possess the following properties: (1) stem cell division decisions are negatively controlled by the stem cell population, (2) stem cell differentiation decisions are negatively controlled by the transit amplifying cell population. PMID- 28669887 TI - Intellectual property rights derived from academic research and their role in the modern bioeconomy-A guide for scientists. PMID- 28669886 TI - Correlation Between Lymphedema Disease Severity and Lymphoscintigraphic Findings: A Clinical-Radiologic Study. AB - BACKGROUND: Lymphoscintigraphy is used to confirm the diagnosis of lymphedema; pathologic findings are abnormal transit time to regional nodes and dermal backflow. A universal protocol for the test does not exist. The purpose of this study was to determine whether the clinical severity of lymphedema correlates with lymphoscintigraphy findings. STUDY DESIGN: Patients treated in our Lymphedema Program between 2009 and 2017 were reviewed. Diagnosis of lymphedema was determined by history, physical examination, and lymphoscintigraphy. Severity was defined by increased volume of the limb as follows: mild (<20%), moderate (20% to 40%), and severe (>40%). Candidate variables included location (arm, leg), age, duration of symptoms, infection history, and lymphedema type (primary, secondary). An association between lymphedema severity and lymphoscintigraphy findings was determined using the Pearson chi-square test and multivariate logistic regression. RESULTS: One hundred and thirty-four patients with 181 affected extremities (24 upper, 157 lower) were included. Clinical severity was as follows: 54% mild, 30% moderate, and 16% severe. Delayed tracer transit to the regional nodes was as follows: 45 minutes (34%), 2 hours (18%), and 4 hours or longer (48%). Thirty-six percent of extremities demonstrated dermal backflow. Abnormal transit time or dermal backflow was identified in 97% of extremities by 45 minutes and in 3% of limbs by 2 hours. Transit time and dermal backflow were not predictive of clinical severity when adjusting for candidate variables (p > 0.1). CONCLUSIONS: Clinical severity of lymphedema is not associated with lymphoscintigraphy findings. A lymphoscintigram should be interpreted as normal or abnormal, and does not need to exceed 2 hours. PMID- 28669888 TI - Outcomes of 84 consecutive open food challenges to extensively heated (baked) milk in the allergy office. PMID- 28669889 TI - Quantitative Assessment of the Safety Benefits Associated with Increasing Clinical Peanut Thresholds Through Immunotherapy. AB - BACKGROUND: Peanut immunotherapy studies are conducted with the aim to decrease the sensitivity of patients to peanut exposure with the outcome evaluated by testing the threshold for allergic response in a double-blind placebo-controlled food challenge. The clinical relevance of increasing this threshold is not well characterized. OBJECTIVE: We aimed to quantify the clinical benefit of an increased threshold for peanut-allergic patients. METHODS: Quantitative risk assessment was performed by matching modeled exposure to peanut protein with individual threshold levels. Exposure was modeled by pairing US consumption data for various food product categories with potential contamination levels of peanut that have been demonstrated to be present on occasion in such food products. Cookies, ice cream, doughnuts/snack cakes, and snack chip mixes were considered in the risk assessment. RESULTS: Increasing the baseline threshold before immunotherapy from 100 mg or less peanut protein to 300 mg peanut protein postimmunotherapy reduces the risk of experiencing an allergic reaction by more than 95% for all 4 food product categories that may contain trace levels of peanut residue. Further increase in the threshold to 1000 mg of peanut protein had an additional quantitative benefit in risk reduction for all patients reacting to 300 mg or less at baseline. CONCLUSIONS: We conclude that achieving thresholds of 300 mg and 1000 mg of peanut protein by peanut immunotherapy is clinically relevant, and that the risk for peanut-allergic patients who have achieved this increased threshold to experience an allergic reaction is reduced in a clinically meaningful way. PMID- 28669890 TI - Detection of anti-glutamic acid decarboxylase antibodies in immunoglobulin products. PMID- 28669891 TI - Skin testing in gadolinium allergy: 2 case reports. PMID- 28669892 TI - Validity of the Asthma Control Test Questionnaire Among Smoking Asthmatics. AB - BACKGROUND: Smoking asthmatics respond worse to existing asthma therapies and have more asthma symptoms and exacerbations. OBJECTIVE: We evaluated the Asthma Control Test (ACT) for assessing asthma control among smokers. METHODS: Adults with asthma who smoked were enrolled and followed for 6 weeks. The statistical properties, validity, and responsiveness of the ACT were evaluated. Physician global assessment (GS) of asthma was the "gold standard." RESULTS: A total of 151 participants were enrolled: 52% female and 48% male. The median (interquartile ranges) was 35 (27, 43) years for age, 11 (7, 18) for pack-years, and 16 (13, 20) for the ACT score. Participants self-identified as African American (49%), non Hispanic whites (38%), and Hispanic whites (11%). Participants were classified as well controlled (24%), not well controlled (42%), or very poorly controlled (34%) at enrollment. Cronbach's alpha (95% confidence interval [CI]) for the ACT at enrollment was 0.81 (0.76, 0.85). The intraclass correlation coefficient (95% CI) for agreement of scores at enrollment and 6 weeks was 0.68 (0.57, 0.78) in participant with stable asthma (n = 93). ACT scores were associated with GS (P < .001). Area under the receiver operating characteristic (ROC) curve (95% CI) for an ACT cutoff score of <=19 (not well controlled) was 0.76 (0.67, 0.84). The ACT score with the maximum area under the ROC curve was 18.6. CONCLUSIONS: The ACT questionnaire was reliable and discriminated between levels of asthma control in smoking asthmatics with similar sensitivity and specificity as nonsmoking asthmatics, which confirms its value as a tool for the management of asthma in this prevalent but understudied subgroup of subjects. PMID- 28669893 TI - Anatomy of the Internal Iliac Vein: Implications for Uterine Transplant. AB - STUDY OBJECTIVE: Uterine transplantation has proven feasible since the first live birth reported in 2014. To enable attachment of the uterus in the recipient, long vascular pedicles of the uterine and internal iliac vessels were obtained during donor hysterectomy, which required a prolonged laparotomy to the living donors. To assist further attempts at uterine transplantation, our video serves to review literature reports of internal iliac vein anatomy and demonstrate a laparoscopic dissection of cadaver pelvic vascular anatomy. DESIGN: Observational (Canadian Task Force Classification III). SETTING: Academic anatomic laboratory. Institutional Review Board ruled that approval was not required for this study. INTERVENTION: Literature review and laparoscopic dissection of cadaveric pelvic vasculature, focusing on the internal iliac vein. MEASUREMENTS AND MAIN RESULTS: Although the internal iliac artery tends to have minimal anatomic variation, its counterpart, the internal iliac vein, shows much variation in published studies [1,2]. Relative to the internal iliac artery, the vein can lie medially or laterally. Normal anatomy is defined as some by meeting 2 criteria: bilateral common iliac vein formed by ipsilateral external and internal iliac vein at a low position and bilateral common iliac vein joining to form a right-sided inferior vena cava [2]. Reports show 79.1% of people have normal internal iliac vein anatomy by these criteria [2]. The cadaver dissection revealed internal iliac vein anatomy meeting criteria for normal anatomy. CONCLUSION: Understanding the complexity and variations of internal iliac vein anatomy can assist future trials of uterine transplantation. PMID- 28669894 TI - Physician Engagement in Improving Operative Supply Chain Efficiency Through Review of Surgeon Preference Cards. AB - STUDY OBJECTIVE: To reduce operative costs involved in the purchase, packing, and transport of unnecessary supplies by improving the accuracy of surgeon preference cards. STUDY DESIGN: Quality improvement study (Canadian Task Force classification II-3). SETTING: Gynecologic surgery suite of an academic medical center. PARTICIPANTS: Twenty-one specialized and generalist gynecologic surgeons. INTERVENTIONS: The preference cards of up to the 5 most frequently performed procedures per surgeon were selected. A total of 81 cards were distributed to 21 surgeons for review. Changes to the cards were communicated to the operating room charge nurse and finalized. MEASUREMENTS AND MAIN RESULTS: Fourteen surgeons returned a total of 48 reviewed cards, 39 of which had changes. A total of 109 disposable supplies were removed from these cards, at a total cost savings of $767.67. The cost per card was reduced by $16 on average for disposables alone. Three reusable instrument trays were also eliminated from the cards, resulting in savings of approximately $925 in processing costs over a 3-month period. Twenty two items were requested by surgeons to be available on request but were not routinely placed in the room at the start of each case, at a total cost of $6,293.54. The rate of return of unused instruments to storage decreased after our intervention, from 10.1 to 9.6 instruments per case. CONCLUSIONS: Surgeon preference cards serve as the basis for economic decision making regarding the purchase, storing, packing, and transport of operative instruments and supplies. A one-time surgeon review of cards resulted in a decrease in the number of disposable and reusable instruments that must be stocked, transported, counted in the operating room, or returned, potentially translating into cost savings. Surgeon involvement in preference card management may reduce waste and provide ongoing cost savings. PMID- 28669895 TI - Algorithm of Transvaginal Ultrasound and/or Hysterosalpingogram for Confirmation Testing at 3 Months after Essure Placement. AB - STUDY OBJECTIVE: To evaluate the algorithm of transvaginal ultrasound (TVU) and/or modified hysterosalpingogram (HSG) confirmation testing 3 months after Essure placement to determine if women can rely on the device for permanent birth control. DESIGN: Interim analysis of an ongoing 10-year, prospective, multicenter, nonrandomized, single-arm, international trial (Canadian Task Force classification II-2). SETTING: Twenty study centers in the United States (n = 12), Canada (n = 1), The Netherlands (n = 6), and Spain (n = 1). PATIENTS: Women undergoing the Essure procedure for permanent birth control. INTERVENTIONS: Based on the algorithm for confirmation testing, women with an uncomplicated Essure procedure underwent TVU as the confirmation test; modified HSG was used for women ineligible for TVU, when TVU findings were abnormal or inconclusive, or based on the physician's discretion. MEASUREMENTS AND MAIN RESULTS: Co-primary endpoints (intention-to-treat [ITT] population) were the reliance rate and the 1-year pregnancy rate. Safety evaluation was based on adverse events. Bilateral insert placement was attempted in 597 women (ITT population) and achieved in 582 of 597 (97.5%). A total of 547 women were told to rely on Essure for permanent birth control. Both co-primary endpoints met prespecified limits: based on Bayesian statistics, the reliance rate was 91.6% (547/597; 95% credible interval, 89.2% 93.6%) and the 1-year pregnancy rate .67% (95% credible interval, .16%-1.53%). Using the algorithm for confirmation testing, of 547 subjects told to rely on Essure, 470 (86%) underwent TVU alone, 30 (6%) had modified HSG alone, and 47 (9%) had TVU followed by modified HSG. Four women became pregnant after being told to rely on Essure. They all had confirmation testing with TVU alone, and each initially read incorrectly as optimal insert locations. In each case postpregnancy follow-up and root cause analysis revealed unsatisfactory insert locations, 2 of which were perforations. Most adverse events were mild and unrelated to Essure. CONCLUSION: The algorithm of TVU and/or modified HSG confirmation testing 3 months after Essure placement can determine that a woman can rely on the device for permanent birth control. The adverse events observed are consistent with the known safety profile of Essure. (clinicaltrials.gov: NCT01327105.). PMID- 28669896 TI - The P3 and the subjective experience of time. AB - Our experience of time is often subject to distortions. For instance, time appears to slow down when unexpected events occur. Previous research has shown that the duration of infrequent stimuli - so-called oddballs - is commonly overestimated, an effect referred to as the temporal oddball effect. Oddballs are also known to cause a posterior P3, an event-related potential elicited by motivationally significant stimuli. Here, we propose that the temporal oddball effect and the posterior P3 share a common mechanism. We hypothesized that the P3 amplitude can be used to predict whether the duration of an oddball will be overestimated or not, even if this P3 precedes the offset of the stimulus. In our task, infrequent red targets were embedded in a series of white standards. All stimuli varied in duration and participants had to estimate the duration of the targets and some of the standards. Our data revealed that the duration of target oddballs, but not of standards, was overestimated and overestimations were associated with larger P3 amplitudes than correct short estimates. Because the P3 peaked before stimulus offset, this effect was independent of actual target oddball duration. Using multivariate pattern analysis, we provided direct evidence that it is indeed the P3 elicited by oddballs that caused this effect. Together, our results suggest that the temporal oddball effect is linked to the posterior P3. Based on these findings and established P3 theories, we propose that the common mechanism underlying both phenomena is a phasic norepinephrine response affecting the subjective experience of time. PMID- 28669897 TI - ERP responses to lexical-semantic processing in typically developing toddlers, in adults, and in toddlers at risk for language and learning impairment. AB - Children begin to establish lexical-semantic representations during their first year of life, resulting in a rapid growth of vocabulary around 18-24 months of age. The neural mechanisms underlying this initial ability to map words onto conceptual representations remain relatively unknown. In the present study, the electrophysiological underpinnings of these mechanisms are explored during the critical phase of lexical acquisition using a picture-word matching paradigm. Event-Related Potentials (ERPs) elicited by words (either congruous or incongruous with the previous picture context) and pseudo-words are investigated in 20-month-old toddlers (N = 20) and compared to those elicited in a sample of adults (N = 20), reflecting the final and efficient system, and a sample of toddlers at familial risk for language and learning impairment (LLI, N = 15). The results suggest that the architecture underlying spoken word representation and processing is constant throughout development, even if some differences between children and adults emerged. Interestingly, children seem to be faster than adults in processing incongruent words, probably because relying on a different and more superficial strategy. This early strategy does not seem to be present in children at risk for LLI. In addition, both groups of children do not show different and specific electrophysiological underpinnings in response to real but incongruent words and unknown words, suggesting that during the critical phase of lexical acquisition any potential word is processed in a similar way. Overall, children at risk for LLI turned out to be sensitive to verbal incongruity of the lexical-semantic context, although some differences from typically developing children emerged, reflecting slower processing and less automatic responses. Taken together, the findings of this study pave the way to further research to investigate these effects in clinical and at-risk populations with the general purpose of disentangling the underlying mechanisms of lexical acquisition, and potentially predicting later language (dis)abilities. PMID- 28669898 TI - Relevance of tissue specific subunit expression in channelopathies. AB - Channelopathies are a diverse group of human disorders that are caused by mutations in genes coding for ion channels or channel-regulating proteins. Several dozen channelopathies have been identified that involve both non excitable cells as well as electrically active tissues like brain, skeletal and smooth muscle or the heart. In this review, we start out from the general question which ion channel genes are expressed tissue-selectively. We mined the human gene expression database Human Protein Atlas (HPA) for tissue-enriched ion channel genes and found 85 genes belonging to the ion channel families. Most of these genes were enriched in brain, testis and muscle and a complete list of the enriched ion channel genes is provided. We further focused on the tissue distribution of voltage-gated calcium channel (VGCC) genes including different brain areas and the retina based on the human gene expression from the FANTOM5 dataset. The expression data is complemented by an overview of the tissue dependent aspects of L-type calcium channel (LTCC) function, dysfunction and pharmacology, as well as of their splice variants. Finally, we focus on the pathology of tissue-restricted LTCC channelopathies and their treatment options. This article is part of the Special Issue entitled 'Channelopathies.' PMID- 28669899 TI - Insights into channel dysfunction from modelling and molecular dynamics simulations. AB - Developments in structural biology mean that the number of different ion channel structures has increased significantly in recent years. Structures of ion channels enable us to rationalize how mutations may lead to channelopathies. However, determining the structures of ion channels is still not trivial, especially as they necessarily exist in many distinct functional states. Therefore, the use of computational modelling can provide complementary information that can refine working hypotheses of both wild type and mutant ion channels. The simplest but still powerful tool is homology modelling. Many structures are available now that can provide suitable templates for many different types of ion channels, allowing a full three-dimensional interpretation of mutational effects. These structural models, and indeed the structures themselves obtained by X-ray crystallography, and more recently cryo-electron microscopy, can be subjected to molecular dynamics simulations, either as a tool to help explore the conformational dynamics in detail or simply as a means to refine the models further. Here we review how these approaches have been used to improve our understanding of how diseases might be linked to specific mutations in ion channel proteins. This article is part of the Special Issue entitled 'Channelopathies.' PMID- 28669900 TI - Transient inhibition of LIMKs significantly attenuated central sensitization and delayed the development of chronic pain. AB - Central sensitization represents a key mechanism mediating chronic pain, a major clinical problem lacking effective treatment options. LIM-domain kinases (LIMKs) selectively regulate several substrates, e.g. cofilin and cAMP response element binding protein (CREB), that profoundly affect neural activities, such as synaptogenesis and gene expression, thus critical in the consolidation of long term synaptic potentiation and memory in the brain. In this study, we demonstrate that LIMK deficiency significantly impaired the development of multiple forms of chronic pain. Mechanistic studies focusing on spared nerve injury (SNI) model reveal a pivotal role of LIMKs in the up-regulation of spontaneous excitatory synaptic transmission and synaptogenesis after pain induction. Depending on the pain induction methods, LIMKs can be transiently activated with distinct time courses. Accordingly, pharmacological inhibition of LIMKs targeting this critical period remarkably attenuated central sensitization in the spinal cord and alleviated pain behaviors. We propose selectively targeting LIMKs during their activation phase as a potential therapeutic strategy for clinical management of chronic pain, especially for chronic pain with predictable onset and development time courses, such as chronic post-surgical pain (PSP). PMID- 28669901 TI - Maternal alcohol binge drinking induces persistent neuroinflammation associated with myelin damage and behavioural dysfunctions in offspring mice. AB - Alcohol binge drinking is on the increase in the young adult population, and consumption during pregnancy can be deleterious for foetal development. Maternal alcohol consumption leads to a wide range of long-lasting morphological and behavioural deficiencies known as foetal alcohol spectrum disorders (FASD), associated with neurodevelopmental disabilities. We sought to test the effects of alcohol on neuroimmune system activation and its potential relation to alcohol induced neurodevelopmental and persistent neurobehavioural effects in offspring after maternal alcohol binge drinking during the prenatal period or in combination with lactation. Pregnant C57BL/6 female mice underwent a procedure for alcohol binge drinking either during gestation or both the gestation and lactation periods. Adult male offspring were assessed for cognitive functions and motor coordination. Early alcohol exposure induced motor coordination impairments in the rotarod test. Object recognition memory was not affected by maternal alcohol binge drinking, but Y-maze performance was impaired in pre- and early postnatal alcohol-exposed mice. Behavioural effects were associated with an upregulation of pro-inflammatory signalling (Toll-like receptor 4, nuclear factor kappa B p65, NOD-like receptor protein 3, caspase-1, and interleukin-1beta), gliosis, neuronal cell death and a reduction in several structural myelin proteins (myelin-associated glycoprotein, myelin basic protein, myelin proteolipid protein and myelin regulatory factor) in both the prefrontal cortex and hippocampus of adult mice exposed to alcohol. Altogether, our results reveal that maternal binge-like alcohol consumption induces neuroinflammation and myelin damage in the brains of offspring and that such effects may underlie the persistent cognitive and behavioural impairments observed in FASD. PMID- 28669903 TI - How to improve parameter estimates in GLM-based fMRI data analysis: cross validated Bayesian model averaging. AB - In functional magnetic resonance imaging (fMRI), model quality of general linear models (GLMs) for first-level analysis is rarely assessed. In recent work (Soch et al., 2016: "How to avoid mismodelling in GLM-based fMRI data analysis: cross validated Bayesian model selection", NeuroImage, vol. 141, pp. 469-489; http://dx.doi.org/10.1016/j.neuroimage.2016.07.047), we have introduced cross validated Bayesian model selection (cvBMS) to infer the best model for a group of subjects and use it to guide second-level analysis. While this is the optimal approach given that the same GLM has to be used for all subjects, there is a much more efficient procedure when model selection only addresses nuisance variables and regressors of interest are included in all candidate models. In this work, we propose cross-validated Bayesian model averaging (cvBMA) to improve parameter estimates for these regressors of interest by combining information from all models using their posterior probabilities. This is particularly useful as different models can lead to different conclusions regarding experimental effects and the most complex model is not necessarily the best choice. We find that cvBMS can prevent not detecting established effects and that cvBMA can be more sensitive to experimental effects than just using even the best model in each subject or the model which is best in a group of subjects. PMID- 28669902 TI - Improved tractography using asymmetric fibre orientation distributions. AB - Diffusion MRI allows us to make inferences on the structural organisation of the brain by mapping water diffusion to white matter microstructure. However, such a mapping is generally ill-defined; for instance, diffusion measurements are antipodally symmetric (diffusion along x and -x are equal), whereas the distribution of fibre orientations within a voxel is generally not symmetric. Therefore, different sub-voxel patterns such as crossing, fanning, or sharp bending, cannot be distinguished by fitting a voxel-wise model to the signal. However, asymmetric fibre patterns can potentially be distinguished once spatial information from neighbouring voxels is taken into account. We propose a neighbourhood-constrained spherical deconvolution approach that is capable of inferring asymmetric fibre orientation distributions (A-fods). Importantly, we further design and implement a tractography algorithm that utilises the estimated A-fods, since the commonly used streamline tractography paradigm cannot directly take advantage of the new information. We assess performance using ultra-high resolution histology data where we can compare true orientation distributions against sub-voxel fibre patterns estimated from down-sampled data. Finally, we explore the benefits of A-fods-based tractography using in vivo data by evaluating agreement of tractography predictions with connectivity estimates made using different in-vivo modalities. The proposed approach can reliably estimate complex fibre patterns such as sharp bending and fanning, which voxel-wise approaches cannot estimate. Moreover, histology-based and in-vivo results show that the new framework allows more accurate tractography and reconstruction of maps quantifying (symmetric and asymmetric) fibre complexity. PMID- 28669904 TI - Functional brain outcomes of L2 speech learning emerge during sensorimotor transformation. AB - Sensorimotor transformation (ST) may be a critical process in mapping perceived speech input onto non-native (L2) phonemes, in support of subsequent speech production. Yet, little is known concerning the role of ST with respect to L2 speech, particularly where learned L2 phones (e.g., vowels) must be produced in more complex lexical contexts (e.g., multi-syllabic words). Here, we charted the behavioral and neural outcomes of producing trained L2 vowels at word level, using a speech imitation paradigm and functional MRI. We asked whether participants would be able to faithfully imitate trained L2 vowels when they occurred in non-words of varying complexity (one or three syllables). Moreover, we related individual differences in imitation success during training to BOLD activation during ST (i.e., pre-imitation listening), and during later imitation. We predicted that superior temporal and peri-Sylvian speech regions would show increased activation as a function of item complexity and non-nativeness of vowels, during ST. We further anticipated that pre-scan acoustic learning performance would predict BOLD activation for non-native (vs. native) speech during ST and imitation. We found individual differences in imitation success for training on the non-native vowel tokens in isolation; these were preserved in a subsequent task, during imitation of mono- and trisyllabic words containing those vowels. fMRI data revealed a widespread network involved in ST, modulated by both vowel nativeness and utterance complexity: superior temporal activation increased monotonically with complexity, showing greater activation for non-native than native vowels when presented in isolation and in trisyllables, but not in monosyllables. Individual differences analyses showed that learning versus lack of improvement on the non-native vowel during pre-scan training predicted increased ST activation for non-native compared with native items, at insular cortex, pre-SMA/SMA, and cerebellum. Our results hold implications for the importance of ST as a process underlying successful imitation of non-native speech. PMID- 28669905 TI - Discovering dynamic brain networks from big data in rest and task. AB - Brain activity is a dynamic combination of the responses to sensory inputs and its own spontaneous processing. Consequently, such brain activity is continuously changing whether or not one is focusing on an externally imposed task. Previously, we have introduced an analysis method that allows us, using Hidden Markov Models (HMM), to model task or rest brain activity as a dynamic sequence of distinct brain networks, overcoming many of the limitations posed by sliding window approaches. Here, we present an advance that enables the HMM to handle very large amounts of data, making possible the inference of very reproducible and interpretable dynamic brain networks in a range of different datasets, including task, rest, MEG and fMRI, with potentially thousands of subjects. We anticipate that the generation of large and publicly available datasets from initiatives such as the Human Connectome Project and UK Biobank, in combination with computational methods that can work at this scale, will bring a breakthrough in our understanding of brain function in both health and disease. PMID- 28669906 TI - Thalamus segmentation using multi-modal feature classification: Validation and pilot study of an age-matched cohort. AB - Automatic segmentation of the thalamus can be used to measure differences and track changes in thalamic volume that may occur due to disease, injury or normal aging. An automatic thalamus segmentation algorithm incorporating features from diffusion tensor imaging (DTI) and thalamus priors constructed from multiple atlases is proposed. Multiple atlases with corresponding manual thalamus segmentations are registered to the target image and averaged to generate the thalamus prior. At each voxel in a region of interest around the thalamus, a multidimensional feature vector that includes the thalamus prior as well as a set of DTI features, including fractional anisotropy, mean diffusivity, and fiber orientation is formed. A random forest is trained to classify each voxel as belonging to the thalamus or background within the region of interest. Using a leave-one-out cross-validation on nine subjects, the proposed algorithm achieves a mean Dice score of 0.878 and 0.890 for the left and right thalami, respectively, which are higher Dice scores than the three state-of-art methods we compared to. We demonstrate the utility of the method with a pilot study exploring the difference in the thalamus fraction between 21 multiple sclerosis (MS) patients and 21 age-matched healthy controls. The left and right thalamic volumes (normalized by intracranial volumes) are larger in healthy controls by 7.6% and 7.3% respectively, compared to MS patients (though neither result is statistically significant). PMID- 28669907 TI - Centre-surround organization of fast sensorimotor integration in human motor hand area. AB - Using the short-latency afferent inhibition (SAI) paradigm, transcranial magnetic stimulation (TMS) of the primary motor hand area (M1HAND) can probe how sensory input from limbs modulates corticomotor output in humans. Here we applied a novel TMS mapping approach to chart the spatial representation of SAI in human hand knob. We hypothesized SAI is somatotopically expressed in M1HAND depending on both the site of peripheral electrical nerve stimulation and the cortical spot targeted by TMS within M1HAND. The left index or little finger was stimulated 23 ms before focal single-pulse TMS of the right M1HAND. Using frameless stereotaxy, we applied biphasic-TMS pulses at seven stimulation positions above right M1HAND and recorded the motor evoked potentials (MEPs) from relaxed left first-dorsal interosseous (FDI) and abductor-digiti-minimi (ADM) muscles. Homotopic stimulation of the finger close to the muscle targeted by TMS revealed a somatotopic expression of afferent inhibition matching the somatotopic representation of unconditioned MEPs (homotopic SAI). Conversely, heterotopic stimulation of a finger distant to the muscle targeted by TMS induced short latency afferent facilitation (SAF) of MEPs in M1HAND. Like homotopic SAI, heterotopic SAF was somatotopically expressed in M1HAND. Together, the results provide first-time evidence that fast sensorimotor integration involves centre inhibition and surround-facilitation in human M1HAND. PMID- 28669908 TI - Modulation of cognitive cerebello-cerebral functional connectivity by lateral cerebellar continuous theta burst stimulation. AB - Network connectivity measured with resting state functional magnetic resonance imaging (rsfMRI) has revealed the contribution of distinct cerebellar lobules to an array of brain wide networks sub-serving motor and cognitive processes. As distinct cerebellar lobules form relatively accessible nodes of different brain networks, this raises the possibility for site-specific modulation of network connectivity using non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS). Continuous theta burst transcranial magnetic stimulation (cTBS) induces long-lasting inhibition of cortical areas. Although previous studies have shown that cTBS of the lateral cerebellum modulates motor cortical excitability and improves symptoms in several movement disorders, the effect on cognitive domains has not been examined. We explored the immediate effects of cTBS in a sham-controlled study on the strength of intrinsic functional connectivity between cerebellar and cortical motor and cognitive regions in 12 participants. Lateral cerebellar cTBS significantly decreased functional connectivity with frontal and parietal cognitive regions, while connectivity with motor regions remained unaltered. Sham stimulation had no effect on either motor or cognitive connectivity. These results show that inhibitory cerebellar stimulation reduces intrinsic functional connectivity between different cortical areas, in keeping with the known connectivity pattern of the cerebellum. The results highlight the plasticity of cerebello-cerebral networks and indicate for the first time that this functional connectivity can be downregulated using an inhibitory neurostimulation paradigm. This may shed light on the pathophysiology of network dysfunction and is a potential treatment for cognitive and movement disorders. PMID- 28669909 TI - Plastic reorganization of neural systems for perception of others in the congenitally blind. AB - Recent evidence suggests that the function of the core system for face perception might extend beyond visual face-perception to a broader role in person perception. To critically test the broader role of core face-system in person perception, we examined the role of the core system during the perception of others in 7 congenitally blind individuals and 15 sighted subjects by measuring their neural responses using fMRI while they listened to voices and performed identity and emotion recognition tasks. We hypothesised that in people who have had no visual experience of faces, core face-system areas may assume a role in the perception of others via voices. Results showed that emotions conveyed by voices can be decoded in homologues of the core face system only in the blind. Moreover, there was a specific enhancement of response to verbal as compared to non-verbal stimuli in bilateral fusiform face areas and the right posterior superior temporal sulcus showing that the core system also assumes some language related functions in the blind. These results indicate that, in individuals with no history of visual experience, areas of the core system for face perception may assume a role in aspects of voice perception that are relevant to social cognition and perception of others' emotions. PMID- 28669910 TI - Vascular density and distribution in neocortex. AB - An amazingly wide range of complex behavior emerges from the cerebral cortex. Much of the information processing that leads to these behaviors is performed in neocortical circuits that span throughout the six layers of the cortex. Maintaining this circuit activity requires substantial quantities of oxygen and energy substrates, which are delivered by the complex yet well-organized and tightly-regulated vascular system. In this review, we provide a detailed characterization of the most relevant anatomical and functional features of the cortical vasculature. This includes a compilation of the available data on laminar variation of vascular density and the topological aspects of the microvascular system. We also review the spatio-temporal dynamics of cortical blood flow regulation and oxygenation, many aspects of which remain poorly understood. Finally, we discuss some of the important implications of vascular density, distribution, oxygenation and blood flow regulation for (laminar) fMRI. PMID- 28669911 TI - Active avoidance and attentive freezing in the face of approaching threat. AB - Defensive behaviors in animals and humans vary dynamically with increasing proximity of a threat and depending upon the behavioral repertoire at hand. The current study investigated physiological and behavioral adjustments and associated brain activation when participants were exposed to dynamically approaching threat that was either inevitable or could be avoided by motor action. When the approaching threat was inevitable, attentive freezing was observed as indicated by fear bradycardia, startle potentiation, and a dynamic increase in activation of the anterior insula and the periaqueductal grey. In preparation for active avoidance a switch in defensive behavior was observed characterized by startle inhibition and heart rate acceleration along with potentiated activation of the amygdala and the periaqueductal grey. Importantly, the modulation of defensive behavior according to threat imminence and the behavioral option at hand was associated with activity changes in the ventromedial prefrontal cortex. These findings improve our understanding of brain mechanisms guiding human behavior during approaching threat depending on available resources. PMID- 28669912 TI - The efficiency of retrospective artifact correction methods in improving the statistical power of between-group differences in spinal cord DTI. AB - Diffusion tensor imaging (DTI) is a promising approach for investigating the white matter microstructure of the spinal cord. However, it suffers from severe susceptibility, physiological, and instrumental artifacts present in the cord. Retrospective correction techniques are popular approaches to reduce these artifacts, because they are widely applicable and do not increase scan time. In this paper, we present a novel outlier rejection approach (reliability masking) which is designed to supplement existing correction approaches by excluding irreversibly corrupted and thus unreliable data points from the DTI index maps. Then, we investigate how chains of retrospective correction techniques including (i) registration, (ii) registration and robust fitting, and (iii) registration, robust fitting, and reliability masking affect the statistical power of a previously reported finding of lower fractional anisotropy values in the posterior column and lateral corticospinal tracts in cervical spondylotic myelopathy (CSM) patients. While established post-processing steps had small effect on the statistical power of the clinical finding (slice-wise registration: -0.5%, robust fitting: +0.6%), adding reliability masking to the post-processing chain increased it by 4.7%. Interestingly, reliability masking and registration affected the t-score metric differently: while the gain in statistical power due to reliability masking was mainly driven by decreased variability in both groups, registration slightly increased variability. In conclusion, reliability masking is particularly attractive for neuroscience and clinical research studies, as it increases statistical power by reducing group variability and thus provides a cost-efficient alternative to increasing the group size. PMID- 28669913 TI - Divergent influences of anterior cingulate cortex GABA concentrations on the emotion circuitry. AB - Neuroimaging research has revealed that emotion processing recruits a widespread neural network including the dorsal anterior cingulate cortex (dACC), hippocampus, and amygdala. Recent studies have started to investigate the role of the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA) on brain function, but little is known about the influences of GABA on this emotion circuitry. Using magnetic resonance spectroscopy, we investigated the role of GABA levels in the dACC on emotion processing by presenting emotional and neutral pictures to 68 healthy male participants during functional magnetic resonance imaging. Results revealed opposing associations of dACC GABA levels and neural activity. GABA levels were positively correlated with blood oxygen level dependent (BOLD) responses to emotional stimuli in the amygdala and to emotional and neutral stimuli in the hippocampus. In contrast, GABA levels were negatively correlated with BOLD responses for the comparison between positive and negative stimuli in the dACC. Our results suggest positive influences of dACC GABA on BOLD responses in the hippocampus and amygdala, and negative influences on BOLD responses in the dACC that are dependent on emotional valence. PMID- 28669914 TI - Neuromagnetic correlates of voice pitch, vowel type, and speaker size in auditory cortex. AB - Vowel recognition is largely immune to differences in speaker size despite the waveform differences associated with variation in speaker size. This has led to the suggestion that voice pitch and mean formant frequency (MFF) are extracted early in the hierarchy of hearing/speech processing and used to normalize the internal representation of vowel sounds. This paper presents a magnetoencephalographic (MEG) experiment designed to locate and compare neuromagnetic activity associated with voice pitch, MFF and vowel type in human auditory cortex. Sequences of six sustained vowels were used to contrast changes in the three components of vowel perception, and MEG responses to the changes were recorded from 25 participants. A staged procedure was employed to fit the MEG data with a source model having one bilateral pair of dipoles for each component of vowel perception. This dipole model showed that the activity associated with the three perceptual changes was functionally separable; the pitch source was located in Heschl's gyrus (bilaterally), while the vowel-type and formant-frequency sources were located (bilaterally) just behind Heschl's gyrus in planum temporale. The results confirm that vowel normalization begins in auditory cortex at an early point in the hierarchy of speech processing. PMID- 28669916 TI - Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats. AB - Manganese in its divalent state (Mn2+) has features that make it a unique tool for tracing neuronal pathways. It is taken up and transported by neurons in an activity-dependent manner and it can cross synapses. It also acts as a contrast agent for magnetic resonance imaging (MRI) enabling visualization of neuronal tracts. However, due to the limited sensitivity of MRI systems relatively high Mn2+ doses are required. This is undesirable, especially in long-term studies, because of the known toxicity of the metal. In order to overcome this limitation, we propose 52Mn as a positron emission tomography (PET) neuronal tract tracer. We used 52Mn for imaging dopaminergic pathways after a unilateral injection into the ventral tegmental area (VTA), as well as the striatonigral pathway after an injection into the dorsal striatum (STR) in rats. Furthermore, we tested potentially noxious effects of the radioactivity dose with a behavioral test and histological staining. 24 h after 52Mn administration, the neuronal tracts were clearly visible in PET images and statistical analysis confirmed the observed distribution of the tracer. We noticed a behavioral impairment in some animals treated with 170 kBq of 52Mn, most likely caused by dysfunction of dopaminergic cells. Moreover, there was a substantial DNA damage in the brain tissue after applying 150 kBq of the tracer. However, all those effects were completely eliminated by reducing the 52Mn dose to 20-30 kBq. Crucially, the reduced dose was still sufficient for PET imaging. PMID- 28669915 TI - Magnetic resonance imaging of odorant activity-dependent migration of neural precursor cells and olfactory bulb growth. AB - Neural progenitors or neuroblasts are produced by precursor cells in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) to the olfactory bulbs (OB) throughout life. In the OB, these adult born neurons either die or replace existing olfactory interneurons, playing a critical role in the stabilization of OB circuitry. Although several aspects of the addition of new neurons into the OB have been studied, it is unclear whether long-distance activity from the OB can regulate the influx of migrating neuroblasts along the RMS. In this study, iron oxide-assisted MRI was used to track the migration of neuroblasts in combination with reversible naris occlusion to manipulate odorant induced activity. It was found that decreasing olfactory activity led to a decrease in the rate of neuroblast migration along the RMS. Removal of the naris occlusion led to an increase in migratory rate back to control levels, indicating that olfactory activity has regulatory function on neuroblast migration in the RMS. Blocking odorant activity also led to an arrest in OB growth and re-opening the block led to a rapid re-growth returning the bulb size to control levels. Furthermore, pharmacogenetic elimination of the neuroblasts demonstrated that they were required for re-growth of the bulb following sensory deprivation. Together, these results show that sensory activity, neural migration and OB growth are tightly coupled in an interdependent manner. PMID- 28669917 TI - Interoceptive signals impact visual processing: Cardiac modulation of visual body perception. AB - Multisensory perception research has largely focused on exteroceptive signals, but recent evidence has revealed the integration of interoceptive signals with exteroceptive information. Such research revealed that heartbeat signals affect sensory (e.g., visual) processing: however, it is unknown how they impact the perception of body images. Here we linked our participants' heartbeat to visual stimuli and investigated the spatio-temporal brain dynamics of cardio-visual stimulation on the processing of human body images. We recorded visual evoked potentials with 64-channel electroencephalography while showing a body or a scrambled-body (control) that appeared at the frequency of the on-line recorded participants' heartbeat or not (not-synchronous, control). Extending earlier studies, we found a body-independent effect, with cardiac signals enhancing visual processing during two time periods (77-130 ms and 145-246 ms). Within the second (later) time-window we detected a second effect characterised by enhanced activity in parietal, temporo-occipital, inferior frontal, and right basal ganglia-insula regions, but only when non-scrambled body images were flashed synchronously with the heartbeat (208-224 ms). In conclusion, our results highlight the role of interoceptive information for the visual processing of human body pictures within a network integrating cardio-visual signals of relevance for perceptual and cognitive aspects of visual body processing. PMID- 28669919 TI - Multiple ginsenosides ratios pattern - A pointer to identify Panax ginseng root extracts adulterated with other plant parts? PMID- 28669918 TI - Estimation of white matter fiber parameters from compressed multiresolution diffusion MRI using sparse Bayesian learning. AB - We present a sparse Bayesian unmixing algorithm BusineX: Bayesian Unmixing for Sparse Inference-based Estimation of Fiber Crossings (X), for estimation of white matter fiber parameters from compressed (under-sampled) diffusion MRI (dMRI) data. BusineX combines compressive sensing with linear unmixing and introduces sparsity to the previously proposed multiresolution data fusion algorithm RubiX, resulting in a method for improved reconstruction, especially from data with lower number of diffusion gradients. We formulate the estimation of fiber parameters as a sparse signal recovery problem and propose a linear unmixing framework with sparse Bayesian learning for the recovery of sparse signals, the fiber orientations and volume fractions. The data is modeled using a parametric spherical deconvolution approach and represented using a dictionary created with the exponential decay components along different possible diffusion directions. Volume fractions of fibers along these directions define the dictionary weights. The proposed sparse inference, which is based on the dictionary representation, considers the sparsity of fiber populations and exploits the spatial redundancy in data representation, thereby facilitating inference from under-sampled q space. The algorithm improves parameter estimation from dMRI through data dependent local learning of hyperparameters, at each voxel and for each possible fiber orientation, that moderate the strength of priors governing the parameter variances. Experimental results on synthetic and in-vivo data show improved accuracy with a lower uncertainty in fiber parameter estimates. BusineX resolves a higher number of second and third fiber crossings. For under-sampled data, the algorithm is also shown to produce more reliable estimates. PMID- 28669920 TI - Revision rate after screw or plate arthrodesis of the glenohumeral joint. AB - INTRODUCTION: Glenohumeral arthrodesis is a rare salvage procedure for selected patients with different shoulder pathologies. Among a variety of surgical techniques, compression screws or plate fixation are most widely used. Minimally invasive screw fixation has become more popular, although it has been shown to be biomechanically inferior to plate arthrodesis. HYPOTHESIS: Screw arthrodesis would lead to a higher revision rate than plate arthrodesis. MATERIAL AND METHODS: Twenty-seven plate and 7 screw arthrodesis of the glenohumeral joint in 19 male and 15 female patients of a mean age of 50years (range, 16-85years) were reviewed in a retrospective multicenter study with at a follow-up of 43months (range, 11-152months) to compare their clinical and radiographic outcome with special focus on revision rate. RESULTS: Constant score did not change, but its subscore for pain significantly improved from 4.5 points (range, 0-15 points) to 11 points (range, 6-15 points). The subjective shoulder value increased significantly from 19% (range, 0-70%) to 41% (range, 10-80%) and 81% of the patients were satisfied. In 14 patients (41%), the arthrodesis had to be revised either for non-union (11) or malunion (3) at a mean of 12months (range, 0 47months). The 2 groups did not differ in terms of demographic data, nor of preoperative and postoperative clinical data. There were more revisions after screw than plate fixation. If revision was performed for non-union, this difference was significant. DISCUSSION/CONCLUSION: In selected patients, glenohumeral arthrodesis can significantly reduce pain and achieve at best a reasonable function and subjective satisfaction rate. Revision rates favor plate over isolated screw fixation. LEVEL OF EVIDENCE: IV retrospective series. PMID- 28669921 TI - Computer-assisted quantification of pre-plus and plus disease in images obtained using Pictor versus video indirect ophthalmoscopy: a pilot study. AB - Subjectivity in the diagnosis of plus disease in retinopathy of prematurity has prompted the creation of computer programs to objectively measure vascular characteristics. ROPtool is a semiautomated computer program that analyzes retinal vascular dilation and tortuosity. To explore its ability to trace images taken with a FDA-approved, portable, handheld noncontact digital fundus camera (Pictor), we compared ROPtool analysis of Pictor still images acquired by nonophthalmologists to video indirect ophthalmoscopy (VIO) still images acquired by ophthalmologists. ROPtool could trace more Pictor versus VIO images. In addition, receiver operating characteristic curves showed that accuracy for diagnosing pre-plus or plus disease was higher using Pictor versus VIO images. PMID- 28669922 TI - Quality of Life after Allogeneic Hematopoietic Cell Transplantation According to Affected Organ and Severity of Chronic Graft-versus-Host Disease. AB - Knowing the impact of chronic graft-versus-host disease (GVHD) on quality of life (QoL) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by GVHD type and severity is critical for providing care to transplant survivors. We conducted a cross-sectional questionnaire study to examine the relationship between patient-reported QoL as measured by the Medical Outcomes Study 36-Item Short-Form Health Survey, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, and visual analogue scale (VAS) and chronic GVHD defined by the National Institutes of Health (NIH) criteria. Recipients of allo-HCT for hematologic disease between 1995 and 2009 aged >= 16 years at transplant and >=20 years at the time of the survey who were relapse-free were eligible. A total of 1140 pairs of patient and physician questionnaires were included in the analysis. By NIH global severity score, QoL scores in all aspects were significantly lower in patients with higher global and organ-specific severity grades, independent of background variables. Compared with patients without GVHD symptoms, those with mild symptoms had impaired physical and general QoL according to global severity score and organ-specific scores except for the genital tract. Mild symptoms in the lungs, gastrointestinal tract, and joints and fascia were associated with clinically meaningful deterioration of physical QoL. VAS scores provided by physicians were generally higher than those provided by patients. Differences between scores reported by patients and physicians were larger for patients with no or mild GVHD symptoms. Our findings based on more than 1000 long-term survivors after HCT enabled us to identify a target of care, informing survivorship care protocols to improve post-transplantation QoL. PMID- 28669923 TI - Hematopoietic Cell Transplantation-Specific Comorbidity Index Predicts Morbidity and Mortality in Autologous Stem Cell Transplantation. AB - The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score is a useful tool to assess the risk for nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation. Although the HCT-CI has been investigated in autologous stem cell transplantation (ASCT), its use is limited. To improve on the current use of the HCT-CI score on the morbidity and mortality after ASCT, we assessed the 100-day morbidity defined as orotracheal intubation (OTI), dialysis or shock (vasopressors need), 100-day NRM, early composite morbidity-mortality (combined endpoint that included any previous endpoints), and long-term NRM. We retrospectively reviewed a cohort of 1730 records of adult patients who received an ASCT in Argentinean center's between October 2002 and August 2016. Median follow-up was 1.15 years, and median age was 53 years. Diseases were multiple myeloma (48%), non-Hodgkin lymphoma (27%), and Hodgkin lymphoma (17%); 51% were in complete or partial remission; and 13% received >= 3 chemotherapy lines before transplant (heavily pretreated). Early NRM (100-day) was 2.7%, 5.4% required OTI, 4.5% required vasopressors, and 2.1% dialysis, with an early composite morbidity-mortality of 6.8%. Long-term (1 and 3 years) NRM was 4% and 5.2% and overall survival 89% and 77%, respectively. High-risk HCT-CI patients had a significant increase in 100-day NRM compared with intermediate and low risk (6.1% versus 3.4% versus 1.8%, respectively; P = .002), OTI (11% versus 6% versus 4%, P = .001), shock (8.7% versus 5.8% versus 3%, P = .001), early composite morbidity-mortality (13% versus 9 % versus 4.7%, P < .001), and long term NRM (1 year, 7.7% versus 4% versus 3.3%; and 3 years, 10.8% versus 4% versus 4.8%, respectively; P = .002). After multivariate analysis these outcomes remained significant: early composite morbidity-mortality (odds ratio [95% confidence interval] compared with low risk: intermediate risk 2.1 [1.3 to 3.5] and high risk 3.3 [1.9 to 5.9]) and NRM (hazard ratio [95% confidence interval] compared with low risk: intermediate risk .97 [.8 to 2.4] and high risk 3.05 [1.3 to 4.5]). No significant impact was observed in overall survival. Other than comorbidities, significant impact was observed for heavily pretreated patients, age >= 55 years, non-Hodgkin lymphoma, and bendamustine-etoposide-citarabine melphalan conditioning. We confirmed that the HCT-CI had a significant impact on NRM after ASCT, and these findings are mainly due to early toxicity express as 100-day NRM and the 3 main morbidity outcomes as well as the composite endpoint. PMID- 28669925 TI - The effect of tomatine on metastasis related matrix metalloproteinase (MMP) activities in breast cancer cell model. AB - Breast cancer is one of the most common malignancies in women and metastasis is the cause of morbidity and mortality in patients. In the development of metastasis, the matrix metalloproteinase (MMP) family has a very important role in tumor development. MMP-2 and MMP-9 work together for extracellular matrix (ECM) cleavage to increase migration. Tomatine is a secondary metabolite that has a natural defense role against plants, fungi, viruses and bacteria that are synthesized from tomato. In addition, tomatine is also known that it breaks down the cell membrane and is a strong inhibitor in human cancer cells. In this study, it was aimed to evaluate the effect of tomatine on cytotoxicity, apoptosis and matrix metalloproteinase inhibition in MCF-7 cell lines. Human breast cancer cell line (MCF-7) was used as a cell line. In MCF-7 cells, the IC50 dose of tomatine was determined to be 7.07MUM. According to the control cells, apoptosis increased 3.4 fold in 48thh. Activation of MMP-2, MMP-9 and MMP-9?NGAL has been shown to decrease significantly in cells treated with tomatine by gelatin zymography compared to the control. As a result, matrix metalloproteinase activity and cell proliferation were suppressed by tomatine and this may provide support in treatment methods. PMID- 28669924 TI - Histone H3 lysine 4 methyltransferase KMT2D. AB - Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells. KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell type specific gene expression during differentiation. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumor suppression. It is frequently mutated in developmental diseases, such as Kabuki syndrome and congenital heart disease, and various forms of cancer. Further understanding of the mechanism through which KMT2D regulates gene expression will reveal why KMT2D mutations are so harmful and may help generate novel therapeutic approaches. PMID- 28669926 TI - Identification of four novel XPC mutations in two xeroderma pigmentosum complementation group C patients and functional study of XPC Q320X mutant. AB - Xeroderma pigmentosum (XP) is a rare, recessive hereditary disease characterized by sunlight hypersensitivity and high incidence of skin cancer with clinical and genetic heterogeneity. We collected two unrelated Chinese patients showing typical symptoms of XPC without neurologic symptoms. Direct sequencing of XPC gene revealed that patient 1 carried IVS1+1G>A and c.958 C>T mutations, and patient 2 carried c.545_546delTA and c.2257_2258insC mutations. All these four mutations introduced premature terminal codons (PTCs) in XPC gene. The nonsense mutation c.958 C>T yielded truncated mutant Q320X, and we studied its function for global genome repair kinetics. Overexpressed Q320X mutant can localize to site of DNA damage, but it is defective in CPD and 6-4PP repair. Readthrough of PTCs is a new approach to treatment of genetic diseases. We found that aminoglycosides could significantly increase the full length protein expression of Q320X mutant, but NER defects were not rescued in vitro. PMID- 28669927 TI - Evaluation of genetic variants in autophagy pathway genes as prognostic biomarkers for breast cancer. AB - Autophagy-related genes (ATGs) play a critical role in the development of various diseases including cancer. However, the role of ATGs in breast cancer survival remains unclear. This study aims to investigate whether genetic variants in core ATGs are correlated with the prognosis of breast cancer. A total of 14 potentially functional variants in core ATGs were genotyped in 790 breast cancer patients. The association of each variant with breast cancer-specific survival was evaluated by log-rank test and Cox regression model. In silico analysis was also performed to evaluate the potential function of selected variants. We found that one variant in ATG7 rs8154 (A>G) was significantly associated with breast cancer-specific survival after adjusted for age and clinical stage (HR=1.61, 95% CI: 1.12-2.31, P=0.010). Stratified analysis showed that the prognostic role of rs8154 was significant in subgroups of elder age, elder menarche age, and postmenopausal status (all P<0.001). Interaction effects were also detected between rs8154 and these grouping variables. In silico analysis revealed that rs8154 was annotated to be expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets (both P<0.05). In addition, upregulated expression of ATG7 in breast cancer tissues was observed and is significantly associated with poorer overall survival (log-rank P=0.015), poorer relapse free survival (log-rank P=0.017), and poorer distant metastasis free survival (log-rank P=0.034) in different datasets. Summarily, ATG7 variant rs8154 represents a novel prognostic marker for breast cancer patients, which may shed light on clinical risk stratification and therapeutic decision making. PMID- 28669928 TI - GATA4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells. AB - Liver sinusoidal endothelial cells (LSEC) represent a unique, organ-specific type of discontinuous endothelial cells. LSEC instruct the hepatic vascular niche by paracrine-acting angiocrine factors. Recently, we have shown that LSEC-specific transcriptional regulator GATA4 induces expression of BMP2 in cultured endothelial cells (EC) in vitro. Furthermore, angiocrine Bmp2 signaling in the liver in vivo was demonstrated to control iron homeostasis. Here, we investigated GATA4-dependent autocrine BMP2 signaling in endothelial cells by gene expression profiling. GATA4 induced a large cluster of inflammatory endothelial response genes in cultured EC, which is similar to previously identified virus-induced and interferon-associated responses. Treating the cells with the BMP2 inhibitor Noggin counter-regulated the GATA4-dependent inflammatory phenotype of EC, indicating that BMP2 is indeed the major driver. In contrast to continuous EC, LSEC were less prone to activation by BMP2. Notably, GATA4-dependent induction of the inflammatory EC response gene cluster was attenuated by over-expression of the LSEC-specific transcriptional modifier LMO3 while hepatocyte activation was fully preserved, indicating conserved BMP2 synthesis. In summary, our data suggest that transcriptional counter-regulation by GATA4 and LMO3 in LSEC prevents autocrine induction of an inflammatory phenotype, while maintaining angiocrine BMP2-mediated cell-cell communication in the liver vascular niche. PMID- 28669929 TI - MiR-126 reverses drug resistance to TRAIL through inhibiting the expression of c FLIP in cervical cancer. AB - TNF-related apoptosis-inducing ligand (TRAIL) represents one potential and ideal anti-tumor drug, because it kills cancer cells specifically without targeting normal cells. However, acquired drug resistance to TRAIL usually impedes the clinical use of TRAIL on cancer patients. In the present study, we established in vitro TRAIL-resistant cervical cancer cell lines through long-term exposure to TRAIL. Interestingly, we observed significant upregulation of c-FLIP in TRAIL resistant Hela and SiHa cells (Hela-TR and SiHa-TR) compared to their parental Hela and SiHa cells. Although Hela-TR and SiHa-TR cells exhibited low-sensitivity to TRAIL treatment, knockdown of c-FLIP significantly increased the cytotoxicity of TRAIL to them. In contrast to high protein level of c-FLIP, expression of miR 126 was significantly downregulated in Hela-TR and SiHa-TR cells. Results of western blot analysis, luciferase assays and bioinformatics proved that c-FLIP was the target of miR-126. Furthermore, as c-FLIP is the cellular antagonist to caspase-8, transfection with miR-126 promoted the activation of caspase-8 induced by TRAIL. As a result, miR-126 increased the TRAIL-induced apoptosis in Hela-TR and SiHa-TR cells. In addition, miR-126 was also able to increase the cytotoxicity of TNF-alpha and FasL (caspase-8 inducers) to Hela-TR and SiHa-TR. We demonstrate that miR-126 impairs drug resistance to TRAIL, TNF-alpha and FasL through inhibiting the expression of c-FLIP in cervical cancer. PMID- 28669930 TI - Systemic analysis of genome-wide expression profiles identified potential therapeutic targets of demethylation drugs for glioblastoma. AB - Glioblastoma represents one of the most aggressive malignant brain tumors with high morbidity and motility. Demethylation drugs have been developed for its treatment with little efficacy has been observed. The purpose of this study was to screen therapeutic targets of demethylation drugs or bioactive molecules for glioblastoma through systemic bioinformatics analysis. We firstly downloaded genome-wide expression profiles from the Gene Expression Omnibus (GEO) and conducted the primary analysis through R software, mainly including preprocessing of raw microarray data, transformation between probe ID and gene symbol and identification of differential expression genes (DEGs). Secondly, functional enrichment analysis was conducted via the Database for Annotation, Visualization and Integrated Discovery (DAVID) to explore biological processes involved in the development of glioblastoma. Thirdly, we constructed protein-protein interaction (PPI) network of interested genes and conducted cross analysis for multi datasets to obtain potential therapeutic targets for glioblastoma. Finally, we further confirmed the therapeutic targets through real-time RT-PCR. As a result, biological processes that related to cancer development, amino metabolism, immune response and etc. were found to be significantly enriched in genes that differential expression in glioblastoma and regulated by 5'aza-dC. Besides, network and cross analysis identified ACAT2, UFC1 and CYB5R1 as novel therapeutic targets of demethylation drugs which also confirmed by real time RT-PCR. In conclusions, our study identified several biological processes and genes that involved in the development of glioblastoma and regulated by 5'aza-dC, which would be helpful for the treatment of glioblastoma. PMID- 28669931 TI - Genome-wide identification, evolution, and expression analysis of GATA transcription factors in apple (Malus*domestica Borkh.). AB - Plant GATA transcription factors are type-IV zinc-finger proteins that play important regulatory roles in plant growth and development. In this study, we identified 35 GATA genes classified into four groups in the whole genome sequence of Malus domestica. A physiochemical property analysis indicated that GATA proteins are largely unstable hydrophilic proteins. An analysis of conserved protein motifs uncovered three highly conserved motifs, in addition to the GATA motif, in all MdGATA proteins. These three motifs, CCT, TIFY, and ASXH, were found to occur in specific GATA groups and may be related to GATA gene function. We identified 10 pairs of putative paralogs, indicating that MdGATA genes have mainly undergone whole genome duplication. Eighteen orthologous gene pairs were also identified between Arabidopsis thaliana and M. domestica. Furthermore, many light-responsive cis-elements were found in MdGATA gene promoters. Tissue specific expression analysis performed by quantitative real-time reverse transcription PCR showed that MdGATA genes were preferentially expressed in flowers, leaves, and buds. Apple seedlings maintained in darkness for 7days exhibited a moderate decline in chlorophyll content along with significant down regulation of most MdGATA genes, suggesting that MdGATA genes may be involved in light-responsive development and chlorophyll-level regulation. The distinctly higher expression levels observed for many MdGATA genes during three stages of floral induction also indicate that MdGATA genes may play a role in the apple flowering transition. The results presented here lay the foundation for further investigation of MdGATA gene family putative functions and improvement of apple yields. PMID- 28669932 TI - Cough and airway disease: The role of ion channels. AB - Cough is the most common reason for patients to visit a primary care physician, yet it remains an unmet medical need. It can be idiopathic in nature but can also be a troublesome symptom across chronic lung diseases such as asthma, COPD and idiopathic pulmonary fibrosis (IPF). Chronic cough affects up to 12% of the population and yet there are no safe and effective therapies. The cough reflex is regulated by vagal, sensory afferent nerves which innervate the airway. The Transient Receptor Potential (TRP) family of ion channels are expressed on sensory nerve terminals, and when activated can evoke cough. This review focuses on the role of 4 TRP channels; TRP Vannilloid 1 (TRPV1), TRP Ankyrin 1 (TRPA1), TRP Vannilloid 4 (TRPV4) and TRP Melastatin 8 (TRPM8) and the purinergic P2X3 receptor and their possible role in chronic cough. We conclude that these ion channels, given their expression profile and their role in the activation of sensory afferents and the cough reflex, may represent excellent therapeutic targets for the treatment of respiratory symptoms in chronic lung disease. PMID- 28669933 TI - Season of Conception, Smoking, and Preeclampsia in Norway. AB - BACKGROUND: Preeclampsia (PE) is a dangerous and unpredictable pregnancy complication. A seasonal pattern of risk would suggest that there are potentially preventable environmental contributors, but prior analyses have not adjusted for confounding by PE risk factors that are associated with season of conception. METHODS: Seasonal effects were modeled and tested by representing each day of the year as an angle on a unit circle and using trigonometric functions of those angles in predictive models, using "harmonic analysis." We applied harmonic Cox regression to model confounder-adjusted effects of the estimated day of the year of conception on risk of PE for births from the Medical Birth Registry of Norway for deliveries between 1999 and 2009. We also examined effect measure modification by parity, latitude (region), fetal sex, and smoking. RESULTS: In adjusted models, PE risk was related to season, with higher risk in spring conceptions and lower risk in autumn conceptions, with a risk amplitude (maximum compared with minimum) of about 20%. The pattern replicated across subpopulations defined by parity, latitude (region), fetal sex, and smoking. CONCLUSIONS: These results suggest that there is a seasonal driver for PE, with effects that are not modified by parity, latitude, fetal sex, or smoking. https://doi.org/10.1289/EHP963. PMID- 28669934 TI - The Joint Effect of Prenatal Exposure to Metal Mixtures on Neurodevelopmental Outcomes at 20-40 Months of Age: Evidence from Rural Bangladesh. AB - BACKGROUND: Exposure to chemical mixtures is recognized as the real-life scenario in all populations, needing new statistical methods that can assess their complex effects. OBJECTIVES: We aimed to assess the joint effect of in utero exposure to arsenic, manganese, and lead on children's neurodevelopment. METHODS: We employed a novel statistical approach, Bayesian kernel machine regression (BKMR), to study the joint effect of coexposure to arsenic, manganese, and lead on neurodevelopment using an adapted Bayley Scale of Infant and Toddler DevelopmentTM. Third Edition, in 825 mother-child pairs recruited into a prospective birth cohort from two clinics in the Pabna and Sirajdikhan districts of Bangladesh. Metals were measured in cord blood using inductively coupled plasma-mass spectrometry. RESULTS: Analyses were stratified by clinic due to differences in exposure profiles. In the Pabna district, which displayed high manganese levels [interquartile range (IQR): 4.8, 18 MUg/dl], we found a statistically significant negative effect of the mixture of arsenic, lead, and manganese on cognitive score when cord blood metals concentrations were all above the 60th percentile (As>=0.7 MUg/dl, Mn>=6.6 MUg/dl, Pb>=4.2 MUg/dl) compared to the median (As=0.5 MUg/dl, Mn=5.8 MUg/dl, Pb=3.1 MUg/dl). Evidence of a nonlinear effect of manganese was found. A change in log manganese from the 25th to the 75th percentile when arsenic and manganese were at the median was associated with a decrease in cognitive score of -0.3 (-0.5, -0.1) standard deviations. Our study suggests that arsenic might be a potentiator of manganese toxicity. CONCLUSIONS: Employing a novel statistical method for the study of the health effects of chemical mixtures, we found evidence of neurotoxicity of the mixture, as well as potential synergism between arsenic and manganese. https://doi.org/10.1289/EHP614. PMID- 28669935 TI - The Exposome Paradigm in Human Health: Lessons from the Emory Exposome Summer Course. AB - The environment plays a major role in human health, yet tools to study the health impacts of complex environmental exposures are lacking. In 2005, Christopher Wild introduced the concept of the exposome, which encompasses environmental exposures and concomitant biological responses throughout the life course. Exposome-based approaches have the potential to enable novel insights into numerous research questions in environmental health sciences. To promote and develop the concept of the exposome, the Health and Exposome Research Center: Understanding Lifetime Exposures (HERCULES) Exposome Research Center at Emory University held the first Emory Exposome Summer Course from 13-17 June 2016. https://doi.org/10.1289/EHP1712. PMID- 28669936 TI - Exposure to Traffic-Related Air Pollution and Serum Inflammatory Cytokines in Children. AB - BACKGROUND: Long-term exposure to ambient air pollution can lead to adverse health effects in children; however, underlying biological mechanisms are not fully understood. OBJECTIVES: We evaluated the effect of air pollution exposure during different time periods on mRNA expression as well as circulating levels of inflammatory cytokines in children. METHODS: We measured a panel of 10 inflammatory markers in peripheral blood samples from 670 8-y-old children in the Barn/Child, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) birth cohort. Outdoor concentrations of nitrogen dioxide (NO2) and particulate matter (PM) with aerodynamic diameter <10 MUm (PM10) from road traffic were estimated for residential, daycare, and school addresses using dispersion modeling. Time weighted average exposures during infancy and at biosampling were linked to serum cytokine levels using linear regression analysis. Furthermore, gene expression data from 16-year-olds in BAMSE (n=238) were used to evaluate links between air pollution exposure and expression of genes coding for the studied inflammatory markers. RESULTS: A 10 MUg/m3 increase of NO2 exposure during infancy was associated with a 13.6% (95% confidence interval (CI): 0.8; 28.1%) increase in interleukin-6 (IL-6) levels, as well as with a 27.8% (95% CI: 4.6, 56.2%) increase in IL-10 levels, the latter limited to children with asthma. However, no clear associations were observed for current exposure. Results were similar using PM10, which showed a high correlation with NO2. The functional analysis identified several differentially expressed genes in response to air pollution exposure during infancy, including IL10, IL13, and TNF;. CONCLUSION: Our results indicate alterations in systemic inflammatory markers in 8-y-old children in relation to early-life exposure to traffic-related air pollution. https://doi.org/10.1289/EHP460. PMID- 28669937 TI - Perfluoroalkyl Substances during Pregnancy and Offspring Weight and Adiposity at Birth: Examining Mediation by Maternal Fasting Glucose in the Healthy Start Study. AB - BACKGROUND: Certain perfluoroalkyl and polyfluoroalkyl substances (PFAS) are widespread, persistent environmental contaminants. Prenatal PFAS exposure has been associated with lower birth weight; however, impacts on body composition and factors responsible for this association are unknown. OBJECTIVES: We aimed to estimate associations between maternal PFAS concentrations and offspring weight and adiposity at birth, and secondarily to estimate associations between PFAS concentrations and maternal glucose and lipids, and to evaluate the potential for these nutrients to mediate associations between PFAS and neonatal outcomes. METHODS: Within the Healthy Start prospective cohort, concentrations of 11 PFAS, fasting glucose, and lipids were measured in maternal mid-pregnancy serum (n=628). Infant body composition was measured using air displacement plethysmography. Associations between PFAS and birth weight and adiposity, and between PFAS and maternal glucose and lipids, were estimated via linear regression. Associations were decomposed into direct and indirect effects. RESULTS: Five PFAS were detectable in >50% of participants. Maternal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) concentrations were inversely associated with birth weight. Adiposity at birth was approximately 10% lower in the highest categories of PFOA, PFNA, and perfluorohexane sulfonate (PFHxS) compared to the lowest categories. PFOA, PFNA, perfluorodecanoate (PFDeA), and PFHxS were inversely associated with maternal glucose. Up to 11.6% of the effect of PFAS on neonatal adiposity was mediated by maternal glucose concentrations. Perfluorooctane sulfonate (PFOS) was not significantly associated with any outcomes studied. CONCLUSIONS: Follow-up of offspring will determine the potential long-term consequences of lower weight and adiposity at birth associated with prenatal PFAS exposure. https://doi.org/10.1289/EHP641. PMID- 28669938 TI - Individual and Joint Effects of Early-Life Ambient Exposure and Maternal Prepregnancy Obesity on Childhood Overweight or Obesity. AB - BACKGROUND: Although previous studies suggest that exposure to traffic-related pollution during childhood increases the risk of childhood overweight or obesity (COWO), the role of early life exposure to fine particulate matter (aerodynamic diameter <2.5 MUm; PM2.5) and its joint effect with the mother's prepregnancy body mass index (MPBMI) on COWO remain unclear. OBJECTIVES: The present study was conducted to examine the individual and joint effects of ambient PM2.5 exposures and MPBMI on the risk of COWO. METHODS: We estimated exposures to ambient PM2.5in utero and during the first 2 y of life (F2YL), using data from the U.S. Environmental Protection Agency's (EPA's) Air Quality System matched to residential address, in 1,446 mother-infant pairs who were recruited at birth from 1998 and followed up prospectively through 2012 at the Boston Medical Center in Massachusetts. We quantified the individual and joint effects of PM2.5 exposure with MPBMI on COWO, defined as the child's age- and sex-specific BMI z score >=85th percentile at the last well-child care visit between 2 and 9 y of age. Additivity was assessed by estimating the reduced excess risk due to interaction. RESULTS: Comparing the highest and lowest quartiles of PM2.5, the adjusted relative risks (RRs) [95% confidence intervals (CIs)] of COWO were 1.3 (95% CI: 1.1, 1.5), 1.2 (95% CI: 1.0, 1.4), 1.2 (95% CI: 1.0, 1.4), 1.3 (95% CI: 1.1, 1.6), 1.3 (95% CI: 1.1, 1.5) and 1.3 (1.1, 1.5) during preconception; the first, second, and third trimesters; the entire period of pregnancy; and F2YL, respectively. Spline regression showed a dose-response relationship between PM2.5 levels and COWO after a threshold near the median exposure (10.46 MUg/m3-10.89 MUg/m3). Compared with their counterparts, children of obese mothers exposed to high levels of PM2.5 had the highest risk of COWO [RR>=2.0, relative excess risk due to interaction (RERI) not significant]. CONCLUSIONS: In the present study, we observed that early life exposure to PM2.5 may play an important role in the early life origins of COWO and may increase the risk of COWO in children of mothers who were overweight or obese before pregnancy beyond the risk that can be attributed to MPBMI alone. Our findings emphasize the clinical and public health policy relevance of early life PM2.5 exposure. https://doi.org/10.1289/EHP261 PMID- 28669939 TI - Major Limitations in Using Element Concentrations in Hair as Biomarkers of Exposure to Toxic and Essential Trace Elements in Children. AB - BACKGROUND: Hair is a commonly used exposure biomarker for metals and other trace elements, but concern has been raised regarding its appropriateness for assessing the internal dose. OBJECTIVES: The aim of the present study was to evaluate children's hair as biomarker of internal dose for toxic (As, Mn, Cd, Pb) and essential elements (Mg, Ca, Fe, Co, Cu, Zn, Se, Mo). METHODS: In 207 children (9 10 years of age), originating from a population-based cohort in rural Bangladesh, we measured concentrations of the selected elements in hair ( closest to the scalp) using ICP-MS. We compared these with previously measured concentrations in erythrocytes, urine, and water. For a subset of children (n=19), we analyzed four consecutive 2 cm pieces of hair. RESULTS: There were strong associations between hair As and the other biomarkers (erythrocytes: rs=0.73, p<0.001; urine: rS=0.66, p<0.001); and water (rs=0.60, p<0.001); and there were significant correlations between Se in hair and erythrocytes (overall rs=0.38, p<0.001), and urine (rs=0.29, p<0.001). Hair Co and Mo showed weak correlations with concentrations in erythrocytes. Hair Mn was not associated with Mn in erythrocytes, urine, or water, and the geometric mean concentration increased almost five times from the 2 cm closest to the head to the 7th-8th cm (p<0.001). Also Mg, Ca, Co, Cd, and Pb increased from the scalp outward (>50% higher in 7th-8th cm compared with 1st-2nd cm, p<0.001). CONCLUSIONS: Hair was found to be a useful exposure biomarker of absorbed As and Se only. Of all measured elements, hair Mn seemed the least reflective of internal dose. https://doi.org/10.1289/EHP1239. PMID- 28669940 TI - Advancing Alternative Analysis: Integration of Decision Science. AB - BACKGROUND: Decision analysis-a systematic approach to solving complex problems offers tools and frameworks to support decision making that are increasingly being applied to environmental challenges. Alternatives analysis is a method used in regulation and product design to identify, compare, and evaluate the safety and viability of potential substitutes for hazardous chemicals. OBJECTIVES: We assessed whether decision science may assist the alternatives analysis decision maker in comparing alternatives across a range of metrics. METHODS: A workshop was convened that included representatives from government, academia, business, and civil society and included experts in toxicology, decision science, alternatives assessment, engineering, and law and policy. Participants were divided into two groups and were prompted with targeted questions. Throughout the workshop, the groups periodically came together in plenary sessions to reflect on other groups' findings. RESULTS: We concluded that the further incorporation of decision science into alternatives analysis would advance the ability of companies and regulators to select alternatives to harmful ingredients and would also advance the science of decision analysis. CONCLUSIONS: We advance four recommendations: a) engaging the systematic development and evaluation of decision approaches and tools; b) using case studies to advance the integration of decision analysis into alternatives analysis; c) supporting transdisciplinary research; and d) supporting education and outreach efforts. https://doi.org/10.1289/EHP483. PMID- 28669942 TI - [Primary lung cancer in Chinese renal transplant recipients: a single-center analysis]. AB - OBJECTIVE: To evaluate the clinical characteristics and the outcomes of primary lung cancer in renal recipients. METHODS: Between January, 1988 and April, 2015, a total of 2793 consecutive patients underwent renal transplantation at our center. Fourteen (0.5%) patients subsequently developed lung cancer, for which 10 (71.4%) received surgical treatment. RESULTS: The mean age of the 14 patients with post-transplant lung cancer was 50.2?8.3 years at transplantation, and 10 of them (71.4%) were former smokers. In 9 (64.3%) of 14 patients, the malignancies were detected incidentally and 5 patients were symptomatic. The average interval from transplantation to cancer diagnosis was 65.7?20.1 months. Eleven patients died from cancer metastasis or organ failure and 3 remained alive with functioning graft. The survival rates of the patients with lung cancer in different stages were statistically different (P=0.001). The overall 5-year survival rate after diagnosis was 17.9% in these 14 patients. CONCLUSION: The risk of primary lung cancer might be higher in renal transplant recipients than in the general Chinese population. Routine chest screening for lung cancer in renal transplant recipients may help in early detection and treatment of the malignancy to improve the prognosis. PMID- 28669941 TI - Maternal Urinary Triclosan Concentration in Relation to Maternal and Neonatal Thyroid Hormone Levels: A Prospective Study. AB - BACKGROUND: Triclosan (TCS) is a synthetic antibacterial chemical widely used in personal care products. TCS exposure has been associated with decreased thyroid hormone levels in animals, but human studies are scarce and controversial. OBJECTIVE: We evaluated the association between maternal TCS exposure and thyroid hormone levels of mothers and newborns. METHODS: TCS was measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in urine samples collected during gestational weeks 38.8+/-1.1 from 398 pregnant women in a prospective birth cohort enrolled in 2012-2013 in Shanghai, China. Maternal serum levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH), and thyroid peroxidase antibody (TPOAb) were obtained from medical records. Cord blood levels of free triiodothyronine (FT3), FT4, TSH, and TPOAb were measured. Multiple linear and logistic regression models were used to examine the relationship between maternal urinary TCS and thyroid hormone levels. RESULTS: TCS was detectable (>=0.1 ng/mL) in 98.24% of maternal urine samples with tertile of urinary TCS levels: low (>0.1-2.75 MUg/g.Cr), medium (2.75-9.78 MUg/g.Cr), and high (9.78-427.38 MUg/g.Cr). With adjustment for potential confounders, cord blood log(FT3)pmol/L concentration was 0.11 lower in newborns of mothers with medium and high urinary TCS levels compared with those with low levels. At third trimester, the high TCS concentration was associated with 0.03 [95% confidence interval (CI) -0.08, -0.02] lower maternal serum log(FT4)pmol/L, whereas the medium TCS concentration was associated with 0.15 (95% CI: -0.28, -0.03) lower serum log(TSH)mIU/L with adjustment for covariates. CONCLUSIONS: Our results suggest significant inverse associations between maternal urinary TCS and cord blood FT3 as well as maternal blood FT4 concentrations at third trimester. https://doi.org/10.1289/EHP500. PMID- 28669943 TI - [A prenatal ultrasound study of cerebral sulci and gyrus development in fetuses with tetralogy of Fallot]. AB - OBJECTIVE: To evaluate the development of the cerebral sulci and gyrus and cerebral blood flow in fetuses with tetralogy of Fallot (ToF) in the second and third trimesters using ultrasound imaging. METHODS: Forty fetuses (23-33+6 weeks) with ToF diagnosed using ultrasound imaging between December, 2015 and September, 2016 were analyzed in this study. The development of the cerebral sulci and gyrus was evaluated by measuring the parietal-occipital fissure (POF) depth, POF angle, sylvian fissure (SF) depth, SF width, uncovered insular width, calcarine fissure (CF) depth, hemisphere depth on the views of POF, SF and CF, uncovered insular ratio, biparietal diameter (BPD), and head circumference (HC). Cerebral hemodynamics were assessed by measuring the umbilical artery resistance index, umbilical artery pulsation index, middle cerebral artery pulsation index (MCA PI), middle cerebral artery resistance index, the cerebral-to-placental resistance ratio, and the cerebroplacental ratio. RESULTS: In ToF fetuses, the POF depth, SF depth, CF depth, BPD, HC and hemisphere depth on the views of parietal-occipital sulcus and calcarine sulcus were significantly smaller than those in the control group (P<0.05). The middle cerebral artery resistance index, middle cerebral artery pulsation index, the cerebral-to-placental resistance ratio and the cerebroplacental ratio were also significantly lower in ToF fetuses than in the control group (P<0.05). CONCLUSION: The cerebral sulci and gyrus in ToF fetuses in second and third trimesters show underdevelopment compared with those in normal fetuses, and the changes in hemodynamics caused by abnormal cardiac structure might be one of the reasons for cerebral sulci and gyrus underdevelopment in fetuses with ToF. PMID- 28669944 TI - [Methyltransferase inhibitor BIX01294 promotes the migration and inhibits decidualization of mouse uterine stromal cells in vitro]. AB - OBJECTIVE: To investigate the effect of BIX01294 (BIX), a methyltransferase inhibitor, on the migration and decidualization of the stromal cells in mouse uterus. METHODS: Mouse endometrial stromal cells were isolated and cultured from the uterus of pregnant mice on day 3.5 of gestation. The migration and decidualization of mouse endometrial stromal cells treated with BIX at different concentrations were observed with wound healing assay and real-time PCR. RESULTS: The migration distance of mouse endometrial stromal cells increased as the BIX concentration increased within the range below 15 umol/L. Compared with the control cells, the cells treated with BIX (15 umol/L) showed significantly increased migration distances, but increasing BIX concentration to 20 umol/L did not further increase the cell migration distance and began to cause cell death. Compared with the control cells, the BIX-treated stromal cells exhibited significantly down-regulated expression of Ehmt2 mRNA, and 15 umol/L BIX caused inhibition of decidualization in the stromal cells. CONCLUSION: Within a defined concentration range, BIX promotes the migration and inhibits decidualization of mouse uterine stromal cells by inhibiting the expression of Ehmt2 mRNA. PMID- 28669945 TI - [Role of epidermal growth factor receptor in house dust mite-induced airway epithelial barrier dysfunction]. AB - OBJECTIVE: To investigate the role of epidermal growth factor receptor (EGFR) signaling pathway in bronchial epithelial actin stress fiber (F-actin) rearrangement induced by house dust mite (HDM). METHODS: Normal human bronchial epithelial cells (16HBE) were stimulated with HDM with or without pretreatment with AG-1478, an EGFR inhibitor. The levels of phospho(p)-EGFR, F-actin, E cadherin and beta-catenin in the cell cultures were detected with Western blotting. The localizations of F-actin, E-cadherin and beta-catenin in the bronchial epithelial cells were determined with immunofluorescence assay, and the transmembrane electrical resistance (TER) and FITC-dextran flux (FITC-DX) in the cells were measured to assess the barrier function of the bronchial epithelia. RESULTS: HDM stimulation of the cells for 10 min resulted in significantly increased p-EGFR expression (P<0.05) without causing obvious changes in the expression of E-cadherin (P>0.05) or beta-catenin (P>0.05). Immunofluorescence assay revealed delocalization of E-cadherin and beta-catenin in HDM-treated 16HBE cells, shown by their diffusion from the cell membrane to the cytoplasm. In HDM treated cells, the TER was significantly decreased to (70.00?4.33)% and the FITC DX was significantly increased to (115.98?4.34)%; Inhibition of EGFR reversed the delocalization of E-cadherin and beta-catenin, improved the TER to (90.00?3.75)% and lowered the FITC-DX to (101.10?2.10)%. HDM induced increased expression and rearrangement of F-actin, which was obviously inhibited by pretreatment of the cells with AG-1478 (P<0.05). CONCLUSION: EGFR signaling pathway mediates HDM induced F-actin rearrangement in human bronchial epithelial cells to contribute to epithelial barrier dysfunction. PMID- 28669946 TI - [Expression of cAMP-dependent protein kinase inhibitor beta in colorectal carcinoma and its clinical significance]. AB - OBJECTIVE: To investigate the expression of cAMP-dependent protein kinase inhibitor beta (PKIB) in colorectal carcinoma (CRC) and its association with the clinicopathological factors of the patients. METHODS: The expression of PKIB mRNA was detected with quantitative real-time PCR in 34 CRC tissues and paired adjacent tissues. Immunohistochemistry was used to detect the expression of PKIB protein in 72 CRC tissue specimens, and the relationship between PKIB protein expression and the clinicopathological features of the patients was analyzed. RESULTS: The expression of PKIB mRNA was significantly higher in CRC tissues than in the paired asjacent tissues (P<0.0001). The expression of PKIB protein in CRC patients was closely related with tumor infiltration (T stage) (P=0.038) but not with age, gender, tumor size, location, lymph node metastasis (N stage) or distant metastasis (M stage) (P>0.05). The survival time of patients with high PKIB expressions was significantly shorter than that of patients with low PKIB expressions (70.532?6.190 vs 93.500?5.847 months, P=0.023). CONCLUSION: A high expression of PKIB in CRC is positively correlated with tumor infiltration (T stage) and a poor prognosis, suggesting an important role of PKIB in the development of CRC and its value as an indicator for prognostic evaluation of CRC patients. PMID- 28669947 TI - [Larvicidal activity of recombinant Escherichia coli expressing scorpion neurotoxin AaIT or B.t.i toxin Cyt2Ba against mosquito larvae and formulations for enhancing the effects]. AB - OBJECTIVE: To assess the larvicidal effects of recombinant Escherichia coli expressing scorpion neurotoxin AaIT or Bacillus thuringiensis subsp israelensis (B.t.i) toxin Cyt2Ba against the second instar larvae of Culex pipiensquinquefasciatus and Aedes albopictus and compare different formulations for their larvicidal effects. METHODS: The AaIT- or Cyt2Ba-coding sequences were cloned into pET28a(+) and the recombinant plasmids were transformed into E. coli BL21(DE3). After induction with IPTG, the recombinant proteins expressed by the recombinant E. coli were detected and identified by SDS-PAGE and Western blotting, respectively. The larvicidal activity of the bacterial suspension was tested at different concentrations against mosquitoes. The effective engineered bacteria were prepared into dry powder with different formulations, and their larvicidal activity was tested. RESULTS: AaIT and Cyt2Ba proteins were successfully expressed in E. coli. The recombinant AaIT protein showed no virulence to the mosquito larvae. The suspension of the recombinant E. coli expressing Cyt2Ba protein exhibited a stronger killing effect on Aedes albopictus larvae than on Culex pipiens quinquefasciatus larvae at 48 h (P<0.001) with LC50 of 3.00*106 cells/mL and 1.25*107 cells/mL, respectively. The dry powder of the engineered bacteria formulated with yeast extract, wheat flour or white pepper powder at the mass ratio of 1:1 showed the strongest killing effect on mosquito larvae (P=0.044), and the formulation with white pepper powder produced a stronger killing effect than formulations with yeast extract or wheat flour (P=0.002). CONCLUSION: The B.t.i Cyt2Ba protein expressed in E. coli BL21(DE3) shows a good larvicidal activity against mosquitoes, and appropriate formulations of the engineered bacteria can enhance its efficiency in mosquito control. PMID- 28669948 TI - [Neural dynamics of cognitive flexibility: spatiotemporal analysis of event related potentials]. AB - OBJECTIVE: To explore the neural dynamics during alternating task switching. METHODS: In an alternating-runs paradigm, 23 healthy volunteers were asked to categorize Arabic numerals displayed on the screen into either even or odd numbers or judge if the number was greater than 5 according its color cues. The color of the numerals were regularly switched every three trials (switch, nested and pre-switch trials). ANOVA of repeated-measure and paired t-test were used for analysis of the behavioral performance and event-related potential (ERP) data of 19 channels, and statistical parametric mapping of F and t values was used to reveal the spatiotemporal patterns of ERP. RESULTS: Significant switch costs (switch versus nested trial) were found in the mean reaction time (123.61?83.84 ms, P<0.05) and the mean accuracy [(1.24?3.30)%, P<0.05]. Statistical parametric mapping of t value of ERP suggested that the switch effects appeared in the right frontal-parietal network and then in the left one. The preparation effects appeared in the right frontal pole followed by the left one, both accompanied by the activation of the posterior regions. CONCLUSIONS: Cognitive flexibility depends on the dynamic activation of the fronto-parietal network. The frontal poles are involved in the pre-switch preparatory process, the dorsal frontal areas are related with the actual switch process, and the left and right frontal regions play different roles. PMID- 28669949 TI - [Three-dimensional bioprinted microstructure promotes proliferation and viability of murine epithelial stem cells in vitro]. AB - OBJECTIVE: To evaluate the effect of different microstructures prepared by three dimensional (3D) bioprinting on proliferation and viability of the murine epithelial stem cells in vitro. METHODS: 3D cell-laden microstructures were constructed using 3 different printing nozzles with diameters of 210, 340, and 420 um. Fluorescence microscopy and the live/dead assay kit were used to observe the proliferation and viability of the murine epithelial stem cells in the microstructures. RESULTS: All the 3D cell-laden micro-structures were capable of promoting the proliferation of murine epithelial stem cells. In the 3 groups of micro-structures, the cell viability decreased significantly with time until 7 days after printing (P<0.01), but at 14 days after the printing, the cell viability increased significantly as compared with that at 7 days (P<0.01). The viability of the cells was significantly higher in the microstructure printed using a 420 um nozzle than in the microstructures printed with 210 um and 340 um nozzles (P<0.01). CONCLUSION: The microstructure printed with a 420 um nozzle can stably promote the proliferation of murine epithelial stem cells and maintain a high level of cell viability, suggesting the feasibility of constructing tissue engineered epidermis and full-thickness skin graft using 3D bioprinting technique. PMID- 28669950 TI - [Screening of biomarkers related with leukocyte responses early after burn injury in mice by differential gene expression profiling]. AB - OBJECTIVE: To screen the genes related with leukocyte responses in mice early after burn injury by bioinformatic analysis of the gene expression profiling data. METHODS: The gene expression profiles were obtained from GEO (GSE7404, Mouse musculus, 25% TBSA, full-thickness) database. T test, fold changes and GO functional enrichment analysis were used to identify the differentially expressed genes (DEGs) related to leukocyte responses to burns; the interacting genes were transferred to STRING to construct the protein-protein interaction (PPI) network. Biological annotation of the sub-networks was executed using the software Cytoscape. Real-time PCR and Western blotting were used to verify the DEGs in mice. RESULTS: In mice at 1 day post-burn, a total of 658 genes were up-regulated and 1167 were down-regulated. PPI network and module analysis suggested that some of the genes (Stat1, Cdk1, Cd19, Lck and Jun) may play critical roles in the PPI network post-burn. Real-time PCR and Western blotting results in mice were consistent with those of bioinformatic analysis of Stat1, Cdk1 and Jun. CONCLUSION: Stat1, Cdk1 and Jun might be critical players in the development of leukocyte response in mice early after burn injury. Our finding provides new insights into the pathogenesis of leukocyte response to burn injury and identifies several biomarkers as potential targets for burn treatment. PMID- 28669951 TI - [Effect of serum restriction on insulin like growth factor-1 expressions and invasiveness in human trophoblast HTR-8/SVneo cells in vitro]. AB - OBJECTIVE: To explore the effect of serum restriction on the invasiveness and expressions of insulin-like growth factor-1 (IGF-1) and matrix metalloproteinase 2 (MMP-2) in human trophoblast HTR-8/SVneo cells in vitro. METHODS: HTR-8/SVneo cells were cultured in the presence of 1%, 5%, or 10% fetal bovine serum (FBS) for 48 h. Fluorescence quantitative PCR and immunofluorescence staining were employed to examine the changes in IGF-1 and MMP-2 expressions at both the mRNA and protein levels in HTR-8/SVneo cells; MTT assay and Transwell invasion assay were used to assess the changes of the cell proliferation and the cell invasion ability, respectively. MMP-2 expression, cell proliferation and invasiveness were also assessed in the cells treated with recombinant human IGF-1. RESULTS: HTR 8/SVneo cells exhibited significantly lowered cell proliferation in cultures containing low concentrations of FBS (P<0.05). The expressions of IGF-1 and MMP-2 at both mRNA and protein levels were significantly down-regulated and the invasiveness was significantly lowered in cells cultured in the medium containing 1% FBS as compared with those of cells cultured in the presence of 5% and 10% FBS (P<0.05). Treatment of the cells with recombinant human IGF-1 significantly up regulated MMP-2 expression (P<0.05) and increased the cell invasiveness (P<0.05). CONCLUSIONS: FBS restriction down-regulates IGF-1 expression in human trophoblast HTR-8/SVneo cells and suppress the cell invasiveness possibly by suppressing MMP 2 expression. Treatment with recombinant human IGF-1 can up-regulate MMP-2 expression and promote the invasiveness of HTR-8/SVneo cells. PMID- 28669952 TI - [Immunomodulatory effects of human amniotic versus bone marrow-derived mesenchymal stem cells on peripheral blood T lymphocytes in vitro]. AB - OBJECTIVE: To compare the immunomodulatory effects of human amniotic mesenchymal stem cell (hAMSCs) and human bone marrow mesenchymal stem cells (hBMSCs) on peripheral blood T lymphocytes in an in vitro co-culture system. METHODS: hAMSCs and hBMSCs isolated using enzymatic digestion and Ficoll-Hypaque density gradient centrifugation, respectively, were culture-expanded in vitro to obtain the 4th generation cells. The two MSCs were co-cultured separately with human peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA-PBMSC) to investigate the changes in T lymphocyte subsets using flow cytomety and the production of interleukin-2 (IL-2) and IL-10 by the T lymphocytes using enzyme linked immunosorbent assay (ELISA). RESULTS: Co-culture with either hAMSCs or hBMSCs significantly increased the proportions of Treg, Th2 and Tc2 and decreased Th1 and Tc1 cell subsets in the PBMCs as compared with the PBMCs cultured alone (P<0.05), and the changes in the PBMCs were similar between the two co-culture systems (P>0.05). In both of the two co-culture systems, IL-2 production by the lymphocytes was significantly lowered (P<0.05) and IL-10 production was significantly increased (P<0.05) as compared with their levels in the PBMCs cultured alone; no significant difference was found in IL-2 or IL-10 levels between the two co-culture systems (P>0.05). CONCLUSION: The MSCs derived from human amnion and bone marrow have similar immunomodulatory effects on the T lymphocytes, suggesting the possibility of using hAMSCs in the treatment of graft versus-host disease after allogeneic hematopoietic stem cell transplantation. PMID- 28669953 TI - [Role of SMU.2055 gene in cariogenic capacity of Streptococcus mutans]. AB - OBJECTIVE: To construct a SMU.2055-dificient mutant strain of Streptococcus mutans (S. mutans) and evaluate its cariogenic capacity in comparison with wild type S. mutans. METHODS: The SMU.2055-dificient mutant strain of S. mutans was constructed using homologous recombination technique and observed with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The absorbance at 600 nm and pH values of the wild-type and mutant strains were monitored to evaluate their growth and acid production. After acid adaption, the two strains were challenged with acid shock and their survival rates were determined. RESULTS: PCR and sequence analyses verified the successful construction of the SMU.2055-dificient mutant strain. Observation with SEM revealed obvious changes in the morphology of the mutant strain, which showed reduced irregular substances between the individual bacteria as compared with the wild-type strain. TEM revealed major alterations in the cellular architecture of the mutant strain with blurry cell membrane and disruption of the membrane integrity. The growth capacity of the mutant strain decreased in both normal and acidic conditions but its acid production capacity remained unaffected. CONCLUSION: SMU.2055 gene is associated with morphology maintenance, growth capacity and acid resistance of S. mutans but is not related to the acid production capacity of the bacterium. PMID- 28669954 TI - [F10 expressions in cervical cancer tissues]. AB - OBJECTIVE: To detect the expression of F10 at both mRNA and protein levels in cervical cancer tissues and explore its role in the occurrence and progression of cervical cancer. METHODS: F10 expressions at mRNA and protein levels were detected in 30 pairs of cervical cancer tissues and adjacent tissues using RT-PCR and immunohistochemistry. RESULTS: The mRNA and protein expressions of F10 were significantly higher in cervical cancer tissues than in the adjacent normal tissues (P<0.05). F10 expression was significantly higher in poorly differentiated cervical cancer than in well differentiated cancer tissues, and was also lower in patients with preoperative chemotherapy than in those without chemotherapy. CONCLUSION: F10 expression level is inversely correlated with the differentiation of cervical cancer and possible plays a role in the tumorigenesis and progression of cervical cancer. PMID- 28669956 TI - [Changes in expressions of sRNA SpR19 and its potential target GroEL in Streptococcus mutans strains with different cariogenicity cultured under different pH conditions]. AB - OBJECTIVE: To investigate the changes in the expression level of sRNA SpR19 and its potential target protein GroEL in clinical isolates of Streptococcus mutans with different cariogenicity exposed to different pH conditions and explore the possibility of using these molecules as biomarkers for assessing the cariogenicity of the bacteria. METHODS: The total RNAs were extracted from the clinical isolates of Streptococcus mutans with high (strain 17) and low cariogenicity (strain 5) for high-throughput sequencing for profiling of the differentially expressed sRNAs. The candidate sRNA, SpR19, was selected for further study on the basis of bioinformatics analysis considering the role of its potential target in the cariogenic process. The differential expression levels of SpR19 in the strains exposed to both pH5.5 and pH7 culture conditions were verified by quantitative real-time PCR. The expression of the potential target of SpR19, GroEL, was also investigated at both the protein and mRNA level using Western blotting and quantitative real-time PCR. RESULTS: Bioinformatic analysis suggested multiple potential target sites of SpR19 both in GroEL mRNA and in the upstream and downstream inter-genic regions. Under different pH conditions, the highly cariogenic strain 17 expressed consistently low levels of SpR19 as compared with the strain 5 with a low cariogenicity; GroEL showed a reverse expression pattern in the 2 strains. An inverse correlation was found between the expressions of SpR19 and GroEL. CONCLUSION: The highly cariogenic strain 17 expressed low levels of SpR19 and high levels of GroEL in both acidic and neutral culture conditions. SpR19 may negatively regulate the cariogenicity of Streptococcus mutants by targeting at GroEL. PMID- 28669955 TI - [Establishment of a modified rabbit model of acute lung injury induced by cardiopulmonary bypass]. AB - OBJECTIVE: To establish an modified rabbit model of the acute lung injury induced by cardiopulmonary bypass (CPB) with ascending aorta and right atrium catheterization and detect the changes in serum tumor necrosis factor-alpha (TNF alpha) level after modeling. METHODS: Ten healthy adult male New Zealand rabbits were randomly selected to establish CPB models. The model establishment was deemed successful if the rabbits survived for over 4 h with stable heart beat after termination of CPB. The vital signs of the rabbits were recorded after anesthesia (T1), before CPB (T2), at 15 after blocking the ascending aorta and pulmonary artery (T3), immediately after re-opening of the ascending aorta and pulmonary artery (T4), and at 1 (T5) and 4 (T6) after CPB. Arterial blood gas (ABG) was monitored at T2, T4 and T6 and the serum levels of TNF-alpha were also detected with ELISA. RESULTS: Nine rabbit models of CPB with acute lung injury were successfully established. During the operation, the MAP was maintained at a level above 55 mmHg, HCT significantly decreased from (30.18?2.88)% at T2 to (17.73?1.95)% at T4 (P<0.05), and plasma lactate level increased significantly from 3.65?1.13 mmol/L at T2 to 9.36?1.28 mmol/L at T4 (P<0.05). The oxygenation index (PaO2/FiO2) at T6 was significantly lower than that at T2 (281.64?55.76 vs 468.36?56.28 mmHg, P<0.05). The serum levels of TNF-alpha were significantly increased (P<0.05) and obvious lung interstitial edema and inflammatory cell infiltration occurred after CPB establishment. CONCLUSION: The modified rabbit model of CPB with acute lung injury is stable and reliable and can be used for studying acute lung injury induced by CPB. PMID- 28669957 TI - [Effects of non-surgical periodontal therapy on serum inflammatory markers and metabolic level in obese rats]. AB - OBJECTIVE: To investigate the effects of non-surgical periodontal therapy on serum inflammatory factors and metabolism levels in obese rats with experimental periodontitis. METHODS: Sixteen obese rats with experimental periodontitis were randomly divided into treatment group and control group with non-surgical periodontal therapy and no treatment, respectively. Oral glucose tolerance test was performed before treatment and 2 weeks after the treatment. All the rats were sacrificed 2 weeks after treatment and the orbital vein blood was taken to detect fasting blood glucose, fasting insulin, and serum level of C-reactive protein (CRP). Results Two weeks after periodontal treatment, fasting blood glucose (t=2.445, P=0.034) and beta cell function index (t=-2.543, P=0.027) were significantly lower in the treatment group than in the control group. Compared with those in the control group, CRP level (t=2.388, P=0.028) and the area under the curve in the oral glucose tolerance test (t=12.053, P=0.000) decreased significantly in the treatment group. CONCLUSION: Non-surgical periodontal treatment can reduce serum CRP level and improve glucose metabolism in obese rats. PMID- 28669958 TI - [Expression of HDAC9 in different brain regions in mice with cerebral ischemic stroke]. AB - OBJECTIVE: To investigate the expression and the subcellular localization of HDAC9 in different brain regions of mice after cerebral ischemic injury and explore the association between HDAC9 and ischemic stroke. METHODS: Twenty-one male C57BL/6 mice were randomly divided into sham-operated group (n=9) and operated group (n=12). In the latter group, the mice with Zea-Longa neurological deficit scores of 2 or 3 following middle cerebral artery occlusion (MCAO) were assigned into MCAO group (n=9). Immunofluorescence was performed to investigate the subcellular localization of HDAC9 in the brain tissues on day 3 after MCAO. Western blotting and qRT-PCR were used to analyze the expression of HDAC9 in different regions of the brain. Results Immunofluorescence showed more intense HDAC9 expressions in the brain tissues around the infarct focus, and in the cells surrounding the infarct, HDAC9 expression was obviously increased in the cytoplasm and reduced in the cell nuclei. Compared with the other brain regions, the ipsilesional cortex with MCAO showed more abundant HDAC9 expressions at both the mRNA and protein levels (P<0.05). CONCLUSION: HDAC9 may be closely related to cerebral ischemic injury and participate in the pathophysiological process of ischemic stroke. PMID- 28669959 TI - [Correlation of blood concentration of tacrolimus with serum cystatin C in renal transplant recipients and effect of tacrolimus on glucose and lipid metabolism]. AB - OBJECTIVE: To investigate the correlation between blood concentrations of tacrolimus (FK506) and cystatin C (Cys C) and the effect of FK506 on glycolipid metabolism in renal transplant recipients. METHODS: A total of 325 patients receiving renal transplantation between August, 2014 and September, 2015 in Nanfang Hospital were divided into 4 groups according to the postoperative time (1 month group, 1-3 months group, 4-6 months group, and 7-12 months group). FK506 blood trough concentration was measured at the time of postoperative follow-up, and creatinine (Scr) and Cys C levels were also detected. Results Plasma FK506 concentration decreased with age in the recipients and showed a positive correlation with Cys C (r=0.985, P=0.015) but no obvious correlation with Scr (r=0.259, P=0.741). FK506 had no effect on blood glucose (5.53-5.59 mmol0.05). CONCLUSION: 3D laparoscopic total thyroidectomy combined with central lymph node dissection is safe and effective and reduces intraoperative blood loss and perioperative adverse reactions without significant influence on inflammatory response in patients with thyroid cancer. PMID- 28669965 TI - [Clinical features of advanced adenoid cystic carcinoma in the nasal cavity and paranasal sinuses: analysis of 21 cases]. AB - OBJECTIVE: To evaluate the clinical characteristics, treatment and prognosis of advanced adenoid cystic carcinoma (ACC) in the nasal cavity and paranasal sinuses. METHODS: Twenty-one patients with advanced ACC in the nasal cavity and paranasal sinuses were treated in our department between February, 2007 and May, 2016. The clinical manifestations, T-stage, N-status, treatment, histological grade, recurrence and distant metastasis of the tumors were analyzed. Univariate survival analysis was performed with Kaplan-Meier method and Log-rank test, and the factors affecting the prognosis of the patients were explored using multivariate analysis with Cox proportional hazard model. RESULTS: Among the 21 patients, 10 (47.6%) had ACC containing less than 30% of solid tumor tissues and their overall survival rates at 1, 3, and 5 years were 100%, 100% and 70%, respectively; in the 11 cases (52.4%) with solid tumor tissues no less than 30%, the overall survival rates at 1, 3, and 5 years were 70%, 40% and 10%, respectively, showing significant differences between the two groups (P=0.02). The Log-rank test and survival analysis using the covariate variable model curve indicated a significant impact of the pathological classification on the patients' prognosis. The patients in T3 stage had slightly better prognosis than those in T4 stage; tumors originating from the maxillary sinus had a slightly better prognosis than those from the sphenoid sinus. Surgery combined with radiotherapy resulted in better outcomes of the patients than surgery or radiotherapy alone. Multiariable Cox regression model analysis showed that the pathological classification (P=0.045) and the disease course (P=0.028) were closely related with the prognosis of the patients. CONCLUSION: ACC in the nasal cavity and paranasal sinuses has a low incidence without specific symptoms. Its early diagnosis can be difficult, and most of the patients are in advanced stage upon diagnosis. We recommend comprehensive treatments combining surgery, postoperative radiotherapy and chemotherapy for these patients. The pathological classification, disease course, lesion site, clinical stage, treatment approache, compromise of the peripheral nerves, status at the edge of resection, and postoperative radiotherapy dose can all be factors affecting the prognosis of patients with advanced ACC. PMID- 28669966 TI - [Effect of intense pulsed light on Trichophyton rubrum growth in vitro]. AB - OBJECTIVE: To investigate the inhibitory effect of 420 nm intense pulsed light on Trichophyton rubrum growth in vitro and explore the mechanism. METHODS: The fungal conidia were divided into treatment group with intense pulse light irradiation and control group without irradiation. The surface areas of the fungal colonies were photographed before irradiation and on the 2nd and 3rd days after irradiation to observe the changes in fungal growth. The viability of the fungus in suspension was detected at 6 h after irradiation using MTT assay. The intracellular reactive oxygen species (ROS) level in the fungus was determined using DCFH-DA fluorescent probe, and the MDA content was detected using TBA method. RESULTS: Intense pulse light (420 nm) irradiation caused obvious injuries in Trichophyton rubrum with the optimal effective light dose of 12 J/cm2 in 12 pulses. At 6 h after the irradiation, the fungus in suspension showed a 30% reduction of viability (P<0.05), and the fungal colonies showed obvious growth arrest without further expansion. Compared to the control group, the irradiated fungus showed significant increases in ROS level and MDA content (P<0.05). CONCLUSION: Intense pulse light (420 nm) irradiation can induce oxidative stress in Trichophyton rubrum to lead to fungal injuries and death. PMID- 28669967 TI - [Synovial chondromatosis in the temporomandibular joint: analysis of 5 cases]. AB - Five patients with synovial chondromatosis in the temporomandibular joint were treated in our hospital between August, 2011 and August, 2014. All the patients underwent preoperative imaging examinations for clinical diagnosis and determining the involvement of the lesions. Surgeries were performed and the lesions were confirmed as synovial chondromatosis by pathological diagnosis. The clinical manifestations, imaging features, diagnosis and treatment results were analyzed. All the 5 patients had pain in the joint region, 3 had limited mouth opening, and 3 had swelling in the joint region. X-ray film showed widening of the joint space in all the 5 cases and radiographic findings showed space occupying lesions in the intra-articular space. Open joint surgeries was performed and completed successfully in all the cases. The postoperative imaging showed no residual lesions in the surgical area. As a rare clinical entity, synovial chondromatosis in the temporomandibular joint was poorly documented without specific clinical manifestations. The diagnosis of synovial chondromatosis relies on imaging, arthroscopic and pathological findings. Corpus liberum is an important feature of the disease occurring frequently in the joint cavity. Surgical intervention is the primary choice for treatment of synovial chondromatosis in the temporomandibular joint, in which the corpus liberum and the affected synovial membrane shall be removed after joint incision. PMID- 28669968 TI - Challenges affecting training in occupational medicine. PMID- 28669971 TI - Girl in the Looking Glass: A Historical Study of the Life of a Deaf Teacher in 19th-century Ireland. AB - The author explicates the life story of Anne Smyth, a deaf teacher in 19th century Ireland. The story was written and published in 1858 by another deaf teacher, Charlotte Mary Kelly, who traced Anne Smyth's life trajectory from her birth to the day she began life in a deaf school until her untimely death at the age of 18 years. The study examines layers of meaning derived from Kelly's narrative, with particular attention to young Anne's practice of going to her bedroom and making up signs in front of a looking glass. The study provides some insight into the meaning of her actions that can inform current understandings of deaf education. The aim is to preserve Anne Smyth's story in order to generate new histories, as well as new discussions in the field of deaf education research. PMID- 28669969 TI - Agreement on what to measure in randomised controlled trials in burn care: study protocol for the development of a core outcome set. AB - INTRODUCTION: In 2004, nearly 11 million severely burn-injured patients required medical care worldwide. Burns cause prolonged hospitalisation and long-term disability. Although mortality has been reduced, morbidity remains significant.Burn care is costly and decision-making is challenging. A range of procedures are performed at different times after injury; new technology is emerging and alternate care pathways are regularly introduced. Data to guide evidence-based decision-making are lacking. Researchers use different outcomes to assess recovery, so it is not possible to combine trial information to draw meaningful conclusions. Early recovery measures include length of hospital stay, healing time and treatment complications. Longer-term outcomes include issues with function, cosmesis and psychological health. Reporting an agreed set of the most important outcomes (core outcome set (COS)) in randomised controlled trials (RCTs) will allow effective evidence synthesis to support clinical decisions. Patient input will ensure relevance. METHODS AND ANALYSIS: The aim is to produce a burn COS for RCT reporting. A long list of outcomes will be identified through systematic reviews of clinical and patient-reported outcomes. Additional outcomes will be identified from interviews with patients over 10 years, parents of children of any age and multidisciplinary professionals. A two-stage modified Delphi exercise will be undertaken to prioritise and condense the list, with patients (n=150) at different stages of recovery. We will also include nursing, therapy (n=100) and medical staff (n=100). A reduced list will be taken to consensus meetings with families and clinical staff to achieve a final COS. ETHICS AND DISSEMINATION: A COS will reduce outcome reporting heterogeneity in burn care research, allowing more effective use of research funding and facilitating evidence synthesis and evidence-based clinical decision-making. Stakeholders will include journal editors, health commissioners, researchers, patients and professionals. The study has ethical approval and is registered with Core Outcome Measures in Effectiveness Trials Initiative (http://www.comet initiative.org/studies/details/798?result=true). PMID- 28669970 TI - What is best practice in sex and relationship education? A synthesis of evidence, including stakeholders' views. AB - OBJECTIVES: Sex and relationship education (SRE) is regarded as vital to improving young people's sexual health, but a third of schools in England lacks good SRE and government guidance is outdated. We aimed to identify what makes SRE programmes effective, acceptable, sustainable and capable of faithful implementation. DESIGN: This is a synthesis of findings from five research packages that we conducted (practitioner interviews, case study investigation, National Survey of Sexual Attitudes and Lifestyles, review of reviews and qualitative synthesis). We also gained feedback on our research from stakeholder consultations. SETTINGS: Primary research and stakeholder consultations were conducted in the UK. Secondary research draws on studies worldwide. RESULTS: Our findings indicate that school-based SRE and school-linked sexual health services can be effective at improving sexual health. We found professional consensus that good programmes start in primary school. Professionals and young people agreed that good programmes are age-appropriate, interactive and take place in a safe environment. Some young women reported preferring single-sex classes, but young men appeared to want mixed classes. Young people and professionals agreed that SRE should take a 'life skills' approach and not focus on abstinence. Young people advocated a 'sex-positive' approach but reported this was lacking. Young people and professionals agreed that SRE should discuss risks, but young people indicated that approaches to risk need revising. Professionals felt teachers should be involved in SRE delivery, but many young people reported disliking having their teachers deliver SRE and we found that key messages could become lost when interpreted by teachers. The divergence between young people and professionals was echoed by stakeholders. We developed criteria for best practice based on the evidence. CONCLUSIONS: We identified key features of effective and acceptable SRE. Our best practice criteria can be used to evaluate existing programmes, contribute to the development of new programmes and inform consultations around statutory SRE. PMID- 28669972 TI - Educational Programs for Deaf Students. PMID- 28669973 TI - University and College Programs for Personnel in Deafness. PMID- 28669975 TI - Advocacy, Support, and Rehabilitation Programs. PMID- 28669974 TI - Programs for Deaf-Blind Youth and Adults. PMID- 28669976 TI - Research on Deafness. PMID- 28669977 TI - An Unusual Triad of Hemophagocytic Syndrome, Lymphoma and Tuberculosis in a Non HIV Patient. AB - BACKGROUND Lymphoma complicated with hemophagocytic syndrome and tuberculosis has been rarely reported. The clinical and radiological presentation of these potentially fatal conditions can be easily confused and there is a potential for misdiagnosis. CASE REPORT We present a 58-year-old Hispanic female who was admitted to the hospital with dizziness and fever. Her initial admission diagnosis was severe sepsis secondary to community acquired pneumonia. She was started on intravenous antibiotics. Due to mediastinal lymphadenopathy, lymphoma was considered as a differential diagnosis for which she underwent bronchoscopy and endobronchial ultrasound-guided sampling of her mediastinal lymph nodes. Lymph node aspirate was suggestive of lymphoma. Initial cultures were negative. Her clinical course was complicated with respiratory failure, cytopenia, and rapidly progressive cervical lymphadenopathy. The patient underwent cervical lymph node excision and bone marrow biopsy. The pathology of the lymph nodes confirmed T cell lymphoma, and bone marrow revealed hemophagocytosis. The patient was started on chemotherapy but she continued to deteriorate and died on day 20 of her hospital admission. Post-mortem results of cultures from a cervical lymph node biopsy and PCR were positive for Mycobacterium tuberculosis. CONCLUSIONS We suggest an aggressive tissue diagnosis with staining for acid-fast bacilli for early diagnosis in patients presenting with hemophagocytic syndrome secondary to lymphoma as coexisting tuberculosis is a consideration. Tuberculosis re activation should be considered in patients from an endemic region who present with lymphoma and a deteriorating clinical condition. PMID- 28669978 TI - Latent Transforming Growth Factor beta Binding Protein 2 (LTBP2) as a Novel Biomarker for the Diagnosis and Prognosis of Pancreatic Carcinoma. AB - BACKGROUND Latent transforming growth factor b binding protein 2 (LTBP2) is proven to be associated with ECM and involved in the advancement of several kinds of cancer. The present study evaluated the diagnosis and prognosis of pancreatic carcinoma (PC) using LTBP2 as a biomarker. MATERIAL AND METHODS Protein levels of LTBP2 were evaluated in 111 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent nontumor tissues via immunohistochemistry. ELISA method was used to quantify the serum concentration of LTBP2. The subjects in this study included 141 PDAC patients, 20 patients with benign pancreatic disease, and 20 healthy volunteers. RESULTS IHC results showed that LTBP2 levels were significantly elevated in the PDAC tissues as compared with the adjacent nontumor tissues (P<0.05). Sixty-one of the 111 (54.9%) PDAC tissues showed high expression of the protein. LTBP2 overexpression was significantly correlated with poor differentiation (P=0.018) and advanced TNM stage (P=0.036). Moreover, Kaplan Meier analysis showed that high levels of LTBP2 predicted worse overall survival (P=0.001) and disease-free survival (P=0.001). Multivariate Cox regression analysis indicated that high expression of LTBP2 was an autonomous prognostic factor for poor overall and disease-free survival (P=0.001; P=0.002). Receiver operating characteristic (ROC) curve analyses of showed that LTBP-2 had an area under the curve (AUC) of 0.846 (95% confidence intervals: 0.757-0.934) and cut off value of 19.12. CONCLUSIONS LTBP2 is a novel biomarker for the diagnosis of PC and may be a potential target for PDAC clinical therapy. PMID- 28669979 TI - Is germinal center selection required for influenza vaccination? PMID- 28669980 TI - Are fat NKT cells born that way? PMID- 28669981 TI - Antimicrobials: Modified sugar compound can clear intestinal colonization by UPEC. PMID- 28669982 TI - Gene expression: Microglia - environment defines identity. PMID- 28669984 TI - Cancer genetics: A 3D view of genome rearrangements. PMID- 28669983 TI - Exploiting induced and natural epigenetic variation for crop improvement. AB - Plant breeding has traditionally relied on combining the genetic diversity present within a species to develop combinations of alleles that provide desired traits. Epigenetic diversity may provide additional sources of variation within a species that could be captured or created for crop improvement. It will be important to understand the sources of epigenetic variation and the stability of newly formed epigenetic variants over generations to fully use the potential of epigenetic variation to improve crops. The development and application of methods for widespread epigenome profiling and engineering may generate new avenues for using the full potential of epigenetics in crop improvement. PMID- 28669985 TI - Translation inhibition and stress granules in the antiviral immune response. AB - Efficient viral gene expression is threatened by cellular stress response programmes that rapidly reprioritize the translation machinery in response to varied environmental assaults, including virus infection. This results in inhibition of bulk synthesis of housekeeping proteins and causes the aggregation of messenger ribonucleoprotein complexes into cytoplasmic foci that are known as stress granules, which can entrap viral mRNAs. There is accumulating evidence for the antiviral nature of stress granules, which is supported by the discovery of many viral factors that interfere with stress granule formation and/or function. This Review focuses on recent advances in our understanding of the role of translation inhibition and stress granules in antiviral immune responses. PMID- 28669990 TI - Chronic kidney disease: Role of suPAR in APOL1-associated kidney disease. PMID- 28669987 TI - Enabling recruitment success in bariatric surgical trials: pilot phase of the By Band-Sleeve study. AB - BACKGROUND: Randomized controlled trials (RCTs) involving surgical procedures are challenging for recruitment and infrequent in the specialty of bariatrics. The pilot phase of the By-Band-Sleeve study (gastric bypass versus gastric band versus sleeve gastrectomy) provided the opportunity for an investigation of recruitment using a qualitative research integrated in trials (QuinteT) recruitment intervention (QRI). PATIENTS/METHODS: The QRI investigated recruitment in two centers in the pilot phase comparing bypass and banding, through the analysis of 12 in-depth staff interviews, 84 audio recordings of patient consultations, 19 non-participant observations of consultations and patient screening data. QRI findings were developed into a plan of action and fed back to centers to improve information provision and recruitment organization. RESULTS: Recruitment proved to be extremely difficult with only two patients recruited during the first 2 months. The pivotal issue in Center A was that an effective and established clinical service could not easily adapt to the needs of the RCT. There was little scope to present RCT details or ensure efficient eligibility assessment, and recruiters struggled to convey equipoise. Following presentation of QRI findings, recruitment in Center A increased from 9% in the first 2 months (2/22) to 40% (26/65) in the 4 months thereafter. Center B, commencing recruitment 3 months after Center A, learnt from the emerging issues in Center A and set up a special clinic for trial recruitment. The trial successfully completed pilot recruitment and progressed to the main phase across 11 centers. CONCLUSIONS: The QRI identified key issues that enabled the integration of the trial into the clinical setting. This contributed to successful recruitment in the By-Band-Sleeve trial-currently the largest in bariatric practice-and offers opportunities to optimize recruitment in other trials in bariatrics. PMID- 28669988 TI - Impairment of body mass reduction-associated activation of brown/beige adipose tissue in patients with type 2 diabetes mellitus. AB - : Backgrounds/Objectives:The activity of brown/beige adipose tissue (B/BAT) is inversely proportional to body adiposity. Studies have shown that obese subjects submitted to distinct approaches aimed at reducing body mass present an increase of B/BAT activation. However, it is unknown if this beneficial effect of body mass reduction applies to patients with type 2 diabetes mellitus. In this study, we evaluated the impact of massive body mass reduction obtained as a consequence of bariatric surgery in the cold-induced activation of B/BAT in obese non diabetic (OND) and obese diabetic (OD) subjects. SUBJECTS/METHODS: This is an observational study. Fourteen OND, 14 OD and 11 subjects were included in the study. All obese subjects were submitted to Roux-in-Y gastric bypass and measurements were performed before and 8 months after surgery. B/BAT was evaluated by (18F)-FDG-PET/CT scan and determination of signature transcript expression in specimens obtained in biopsies. RESULTS: Before surgery, mean B/BAT activity and the expression of signature transcripts were similar between OND and OD groups. Eight months after surgery, body mass reduction was similar between the obese groups. Nevertheless, the activity of B/BAT was increased in OND and unchanged in OD subjects. This effect was correlated with a more pronounced improvement of insulin resistance, as evaluated by the hyperinsulinemic, euglycemic clamp, in OND subjects as compared with OD subjects. CONCLUSIONS: Body mass reduction has a more efficient effect to induce the activation of B/BAT in non-diabetic than in diabetic subjects. This effect is accompanied by more pronounced insulin sensitivity and serine 473 phosphorylation of Akt in B/BAT of non-diabetic than in diabetic subjects. PMID- 28669986 TI - Mitochondrial control of immunity: beyond ATP. AB - Mitochondria are important signalling organelles, and they dictate immunological fate. From T cells to macrophages, mitochondria form the nexus of the various metabolic pathways that define each immune cell subset. In this central position, mitochondria help to control the various metabolic decision points that determine immune cell function. In this Review, we discuss how mitochondrial metabolism varies across different immune cell subsets, how metabolic signalling dictates cell fate and how this signalling could potentially be targeted therapeutically. PMID- 28669989 TI - Exercise training improves fat metabolism independent of total energy expenditure in sedentary overweight men, but does not restore lean metabolic phenotype. AB - BACKGROUND: Obesity is a dietary fat storage disease. Although exercise prevents weight gain, effects of chronic training on dietary fat oxidation remains understudied in overweight adults. OBJECTIVE: We tested whether 2 months of training at current guidelines increase dietary fat oxidation in sedentary overweight adults like in sedentary lean adults. DESIGN: Sedentary lean (n=10) and overweight (n=9) men trained on a cycle ergometer at 50% VO2peak, 1 h day-1, four times per week, for 2 months while energy balance was clamped. Metabolic fate of [d31]palmitate and [1-13C]oleate mixed in standard meals, total substrate use, total energy expenditure (TEE), activity energy expenditure (AEE) and key muscle proteins/enzymes were measured before and at the end of the intervention. RESULTS: Conversely to lean subjects, TEE and AEE did not increase in overweight participants due to a spontaneous decrease in non-training AEE. Despite this compensatory behavior, aerobic fitness, insulin sensitivity and fat oxidation were improved by exercise training. The latter was not explained by changes in dietary fat trafficking but more likely by a coordinated response at the muscle level enhancing fat uptake, acylation and oxidation (FABPpm, CD36, FATP1, ACSL1, CPT1, mtGPAT). ACSL1 fold change positively correlated with total fasting (R2=0.59, P<0.0001) and post-prandial (R2=0.49, P=0.0006) fat oxidation whereas mtGPAT fold change negatively correlated with dietary palmitate oxidation (R2=0.40, P=0.009), suggesting modified fat trafficking between oxidation and storage within the muscle. However, for most of the measured parameters the post training values observed in overweight adults remained lower than the pre training values observed in the lean subjects. CONCLUSION: Independent of energy balance and TEE, exercise training at current recommendations improved fitness and fat oxidation in overweight adults. However the improved metabolic phenotype of overweight adults was not as healthy as the one of their lean counterparts before the 2-month training, likely due to the spontaneous reduction in non training AEE. PMID- 28669991 TI - Polycystic kidney disease: SMYD2 is a novel epigenetic regulator of cyst growth. PMID- 28669994 TI - Cardiovascular disease: PCSK9 inhibition: a new player in cholesterol-lowering therapies? PMID- 28669992 TI - Treatment of membranous nephropathy: time for a paradigm shift. AB - In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition. The anti CD20 monoclonal antibody rituximab is safe and achieves remission of proteinuria in approximately two-thirds of patients with membranous nephropathy. In those with PLA2R-related disease, remission can be predicted by anti-PLA2R antibody depletion and relapse by antibody re-emergence into the circulation. Thus, integrated evaluation of serology and proteinuria could guide identification of affected patients and treatment with individually tailored protocols. Nonspecific and toxic immunosuppressive regimens will fall out of use. B-cell modulation by rituximab and second-generation anti-CD20 antibodies (or plasma cell-targeted therapy in anti-CD20 resistant forms of disease) will lead to a novel therapeutic paradigm for patients with membranous nephropathy. PMID- 28669993 TI - The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2. AB - Lowe syndrome is an X-linked disease that is characterized by congenital cataracts, central hypotonia, intellectual disability and renal Fanconi syndrome. The disease is caused by mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase (OCRL) that acts on phosphoinositides - quantitatively minor constituents of cell membranes that are nonetheless pivotal regulators of intracellular trafficking. In this Review we summarize the considerable progress made over the past decade in understanding the cellular roles of OCRL in regulating phosphoinositide balance along the endolysosomal pathway, a fundamental system for the reabsorption of proteins and solutes by proximal tubular cells. We discuss how studies of OCRL have led to important discoveries about the basic mechanisms of membrane trafficking and describe the key features and limitations of the currently available animal models of Lowe syndrome. Mutations in OCRL can also give rise to a milder pathology, Dent disease 2, which is characterized by renal Fanconi syndrome in the absence of extrarenal pathologies. Understanding how mutations in OCRL give rise to two clinical entities with differing extrarenal manifestations represents an opportunity to identify molecular pathways that could be targeted to develop treatments for these conditions. PMID- 28669997 TI - Effects of early life adversity and sex on dominance in European starlings. AB - Dominance in socially foraging animals may be related to sex and to variation in individual quality. Individual quality may in turn reflect conditions during early development. We studied dominance in a cohort of adult European starlings, Sturnus vulgaris, that had been subject to experimental manipulations of food supply and begging effort when they were nestlings. We measured dominance in two different contexts, contests over a food resource and relative position on a sloping perch, over the course of 3 weeks. Dominance in food contests was extremely stable over the 3 weeks and relative perch position somewhat stable. Males were dominant over females in contests over food and perched in higher positions. These sex differences were not explained by males' greater size or body weight. Food dominance and perch position were uncorrelated. Neither early life food supply nor early life begging effort affected food dominance; nor did an alternative measure of developmental stress, developmental telomere attrition. Birds that had been made to beg more as nestlings perched in higher positions than those that had begged less. Our results did not support the hypothesis that early life adversity leads to lower adult dominance rank in the context of feeding, and we suggest that relative perch position may have measured individual preference rather than competitive ability. PMID- 28669996 TI - Male great tits assort by personality during the breeding season. AB - Animal personalities can influence social interactions among individuals, and thus have major implications for population processes and structure. Few studies have investigated the significance of the social context of animal personalities, and such research has largely focused on the social organization of nonterritorial populations. Here we address the question of whether exploratory behaviour, a well-studied personality trait, is related to the social structure of a wild great tit, Parus major, population during the breeding season. We assayed the exploration behaviour of wild-caught great tits and then established the phenotypic spatial structure of the population over six consecutive breeding seasons. Network analyses of breeding proximity revealed that males, but not females, show positive assortment by behavioural phenotype, with males breeding closer to those of similar personalities. This assortment was detected when we used networks based on nearest neighbours, but not when we used the Thiessen polygon method where neighbours were defined from inferred territory boundaries. Further analysis found no relationship between personality assortment and local environmental conditions, suggesting that social processes may be more important than environmental variation in influencing male territory choice. This social organization during the breeding season has implications for the strength and direction of both natural and sexual selection on personality in wild animal populations. PMID- 28669995 TI - Redefining lupus nephritis: clinical implications of pathophysiologic subtypes. AB - Systemic lupus erythematosus (SLE) is associated with a broad spectrum of clinical and immunologic manifestations, of which lupus nephritis is the most common cause of morbidity and mortality. The development of nephritis in patients with SLE involves multiple pathogenic pathways including aberrant apoptosis, autoantibody production, immune complex deposition and complement activation. The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system for lupus nephritis was widely accepted with high intraobserver and interobserver concordance to guide therapeutic strategy and provide prognostic information. However, this classification system is not based on the underlying disease pathophysiology. Some additional lesions that contribute to disease presentation, including glomerular crescents, podocyte injury, tubulointerstitial lesions and vascular injury, should be recognized. Although outcomes for patients with lupus nephritis have improved over the past 30 years, treatment of this disease remains challenging and is best approached on the basis of the underlying pathogenesis, which is only partially represented by the various pathological phenotypes defined by the ISN/RPS classification. Here, we discuss the heterogeneous mechanisms involved in the pathogenesis of lupus nephritis and how improved understanding of underlying disease mechanisms might help guide therapeutic strategies. PMID- 28669998 TI - On adjustment for auxiliary covariates in additive hazard models for the analysis of randomized experiments. AB - We consider additive hazard models (Aalen, 1989) for the effect of a randomized treatment on a survival outcome, adjusting for auxiliary baseline covariates. We demonstrate that the Aalen least squares estimator of the treatment effect parameter is asymptotically unbiased, even when the hazard's dependence on time or on the auxiliary covariates is misspecified, and even away from the null hypothesis of no treatment effect. We moreover show that adjustment for auxiliary baseline covariates does not change the asymptotic variance of the Aalen least squares estimator of the effect of a randomized treatment. We conclude that, in view of its robustness against model misspecification, Aalen least squares estimation is attractive for evaluating treatment effects on a survival outcome in randomized experiments, and that the primary reasons to consider baseline covariate adjustment in such settings may be the interest in subgroup effects, or the need to adjust for informative censoring or for baseline imbalances. Our results also shed light on the robustness of Aalen least squares estimators against model misspecification in observational studies. PMID- 28669999 TI - Growth of Monolayer Graphene on Nanoscale Copper-Nickel Alloy Thin Films. AB - Growth of high quality and monolayer graphene on copper thin films on silicon wafers is a promising approach to massive and direct graphene device fabrication in spite of the presence of potential dewetting issues in the copper film during graphene growth. Current work demonstrates roles of a nickel adhesion coupled with the copper film resulting in mitigation of dewetting problem as well as uniform monolayer graphene growth over 97 % coverage on films. The feasibility of monolayer graphene growth on Cu-Ni alloy films as thin as 150 nm in total is also demonstrated. During the graphene growth on Cu-Ni films, the nickel adhesion layer uniformly diffuses into the copper thin film resulting in a Cu-Ni alloy, helping to promote graphene nucleation and large area surface coverage. Furthermore, it was found that the use of extremely thin metal catalyst films also constraint the total amount of carbon that can be absorbed into the film during growth, which helps to eliminate adlayer formation and promote monolayer growth regardless of alloying content, thus improving the monolayer fraction of graphene coverage on the thinner films. These results suggest a path forward for the large scale integration of high quality, monolayer graphene into nanoelectronic and nanomechanical devices. PMID- 28670000 TI - A Household Is Not a Person: Consistency of Pro-Environmental Behavior in Adult Couples and the Accuracy of Proxy-Reports. AB - Studies on environmental behavior commonly assume single respondents to represent their entire household or employ proxy-reporting, where participants answer for other household members. It is contested whether these practices yield valid results. Therefore, we interviewed 84 couples, wherein both household members provided self- and proxy-reports for their partner. For use of electrical household appliances, consumption of hot water, space heating, everyday mobility, and environmental values, many variables fail to achieve criteria for validity. Consistency (agreement between self-reports of household members) is higher if behaviors are undertaken jointly or negotiated between partners. Accuracy (agreement of proxy-reports with corresponding self-reports) is higher for routine behaviors and for behaviors easily observable by the partner. Overall, indices perform better than items on single behaviors. We caution against employing individual responses in place of the entire household. Interventions for energy conservation should approach the specific person undertaking the target behavior. PMID- 28670001 TI - Undocumented Latino immigrant men in the United States: Policy and practice considerations. AB - This article presents an exploration of undocumented, Latino male immigrants in the United States, and assesses the impact of new state policies and their implications for social work practice. To meet its aims, we describe the psychosocial risks that they face, and situated these risks within the context of new state policy realities. Implications for practice are presented. PMID- 28670003 TI - Distribution of Cancer by Sex and Site in Nepal AB - Background: Cancer is one of the leading causes of death throughout the world. The indicators of cancer by siteare significant to identify the problem of cancer. The purpose of this retrospective study is to perform the incidenceof all cancers both in males and females over the ten years in Nepal. Methods: The data collected from all the sevenhospital based cancer registries of Nepal have taken for the study. This retrospective study has presented the numberof cases, frequencies, and crude incidence of all cancers by sex and site. Results: A total of 55,931 cancer caseswith known age were registered throughout the hospital based seven cancer registries of Nepal from 2003 to 2012.Throughout the ten years, Lung (incl. trachea and bronchus) cancer (19.08%) was the major cancer in males followedby stomach cancer (7.86%) and Pharynx cancer (5.4%). Similarly, Cervix cancer (21.9%) was the most commoncancer in females followed by breast (15.48%) and Lung (incl. trachea and bronchus) cancer (10.47%) over the tenyears. This retrospective study presented the distribution of the cancer site over the ten years in Nepal. Conclusion:This retrospective study showed that lung cancer is the major cancer in male while in female cervix uteri is the mostcommon cancer ranging from 2003 to 2012. PMID- 28670002 TI - Extreme climate events counteract the effects of climate and land-use changes in Alpine treelines. AB - 1. Climate change and extreme events, such as drought, threaten ecosystems worldwide and in particular mountain ecosystems, where species often live at their environmental tolerance limits. In the European Alps, plant communities are also influenced by land-use abandonment leading to woody encroachment of subalpine and alpine grasslands. 2. In this study, we explored how the forest grassland ecotone of Alpine treelines will respond to gradual climate warming, drought events and land-use change in terms of forest expansion rates, taxonomic diversity and functional composition. We used a previously validated dynamic vegetation model, FATE-HD, parameterised for plant communities in the Ecrins National Park in the French Alps. 3. Our results showed that intense drought counteracted the forest expansion at higher elevations driven by land-use abandonment and climate change, especially when combined with high drought frequency (occurring every 2 or less than 2 years). 4. Furthermore, intense and frequent drought accelerated the rates of taxonomic change and resulted in overall higher taxonomic spatial heterogeneity of the ecotone than would be expected under gradual climate and land-use changes only. 5. Synthesis and applications. The results from our model show that intense and frequent drought counteracts forest expansion driven by climate and land-use changes in the forest grassland ecotone of Alpine treelines. We argue that land-use planning must consider the effects of extreme events, such as drought, as well as climate and land-use changes, since extreme events might interfere with trends predicted under gradual climate warming and agricultural abandonment. PMID- 28670004 TI - Demonstration of AutoDock as an Educational Tool for Drug Discovery. AB - Drug design and discovery remains a popular topic of study to many students interested in visible, real-world applications of the chemical sciences. It is important that laboratory experiments detailing the early stages of drug discovery incorporate both compound design and an exploration of ligand/receptor interactions. Molecular modeling is widely employed in research endeavors seeking to predict the activity of potential compounds prior to synthesis and can therefore be used to illustrate these concepts. The following activity therefore details the use of AutoDock to predict the binding affinity and docked pose of a series of CDK2 inhibitors. Students can then compare their docking output to experimentally determined inhibitory activities and crystal structures. Finally, the AutoDock workflow detailed in this activity can be used in research settings, provided the receptor crystal structure is known. PMID- 28670005 TI - Associations between Methamphetamine Use, Housing Status, and Incarceration Rates among Men Who Have Sex with Men and Transgender Women. AB - The present study examined associations between methamphetamine use and social factors among men who have sex with men (MSM) and transgender women. Over a four year period, 7,419 HIV outreach encounters were conducted with MSM (n=6,243) and transgender women (n=1,176). Logistic and negative binomial regressions estimated associations between sociodemographics, incarceration history, housing status, and methamphetamine use. Incarceration history was associated with marginal housing or homelessness (AOR=3.4) and with increased likelihood (AOR = 6.00) and rate (AIRR = 3.57) of methamphetamine use. African American/Black MSM and transgender women were more likely to report a recent incarceration history compared to non-African American/Black participants (AOR=2.18). Incarceration history was associated with a HIV-positive status (AOR=1.69), and transgender women were 5.2 times more likely to report recent incarceration relative to MSM. Understanding these associations may provide a basis for developing interventions that account for the social factors influencing health outcomes among these high risk populations. PMID- 28670006 TI - Chemical purity using quantitative 1H-nuclear magnetic resonance: a hierarchical Bayesian approach for traceable calibrations. AB - Chemical purity assessment using quantitative 1H-nuclear magnetic resonance spectroscopy is a method based on ratio references of mass and signal intensity of the analyte species to that of chemical standards of known purity. As such, it is an example of a calculation using a known measurement equation with multiple inputs. Though multiple samples are often analyzed during purity evaluations in order to assess measurement repeatability, the uncertainty evaluation must also account for contributions from inputs to the measurement equation. Furthermore, there may be other uncertainty components inherent in the experimental design, such as independent implementation of multiple calibration standards. As such, the uncertainty evaluation is not purely bottom up (based on the measurement equation) or top down (based on the experimental design), but inherently contains elements of both. This hybrid form of uncertainty analysis is readily implemented with Bayesian statistical analysis. In this article we describe this type of analysis in detail and illustrate it using data from an evaluation of chemical purity and its uncertainty for a folic acid material. PMID- 28670007 TI - A Qualitative Exploration of Implementation Factors in a School-Based Mindfulness and Yoga Program: Lessons Learned from Students and Teachers. AB - Identifying factors relevant for successful implementation of school-based interventions is essential to ensure that programs are provided in an effective and engaging manner. The perspectives of two key stakeholders critical for identifying implementation barriers and facilitators - students and their classroom teachers - merit attention in this context and have rarely been explored using qualitative methods. This study reports qualitative perspectives of fifth and sixth grade participants and their teachers of a 16-week school based mindfulness and yoga program in three public schools serving low-income urban communities. Four themes related to program implementation barriers and facilitators emerged: program delivery factors, program buy-in, implementer communication with teachers, and instructor qualities. Feedback from students and teachers is discussed in the context of informing implementation, adaptation, and future development of school-based mindfulness and yoga programming in urban settings. PMID- 28670009 TI - Data sharing statements for clinical trials: a requirement of the International Committee of Medical Journal Editors. PMID- 28670010 TI - Systems science for universal health coverage. PMID- 28670011 TI - Public health round-up. PMID- 28670012 TI - Moving Thailand's mountain of alcohol-related harm. AB - Few low- and middle-income countries have done so much to protect their citizens from alcohol-related harms, but Thailand still faces challenges. Apiradee Treerutkuarkul reports. PMID- 28670013 TI - Patient empowerment can lead to improvements in health-care quality. AB - Frederico C Guanais argues that the expansion of primary care in the Americas is not enough to guarantee quality and effectiveness of health services. He talks to Andreia Azevedo Soares. PMID- 28670014 TI - Implementation research to improve quality of maternal and newborn health care, Malawi. AB - OBJECTIVE: To evaluate the impact of a performance-based financing scheme on maternal and neonatal health service quality in Malawi. METHODS: We conducted a non-randomized controlled before and after study to evaluate the effects of district- and facility-level performance incentives for health workers and management teams. We assessed changes in the facilities' essential drug stocks, equipment maintenance and clinical obstetric care processes. Difference-in difference regression models were used to analyse effects of the scheme on adherence to obstetric care treatment protocols and provision of essential drugs, supplies and equipment. FINDINGS: We observed 33 health facilities, 23 intervention facilities and 10 control facilities and 401 pregnant women across four districts. The scheme improved the availability of both functional equipment and essential drug stocks in the intervention facilities. We observed positive effects in respect to drug procurement and clinical care activities at non intervention facilities, likely in response to improved district management performance. Birth assistants' adherence to clinical protocols improved across all studied facilities as district health managers supervised and coached clinical staff more actively. CONCLUSION: Despite nation-wide stock-outs and extreme health worker shortages, facilities in the study districts managed to improve maternal and neonatal health service quality by overcoming bottlenecks related to supply procurement, equipment maintenance and clinical performance. To strengthen and reform health management structures, performance-based financing may be a promising approach to sustainable improvements in quality of health care. PMID- 28670015 TI - Observations of infection prevention and control practices in primary health care, Kenya. AB - OBJECTIVE: To assess compliance with infection prevention and control practices in primary health care in Kenya. METHODS: We used an observational, patient tracking tool to assess compliance with infection prevention and control practices by 1680 health-care workers during outpatient interactions with 14 328 patients at 935 health-care facilities in 2015. Compliance was assessed in five domains: hand hygiene; protective glove use; injections and blood sampling; disinfection of reusable equipment; and waste segregation. We calculated compliance by dividing the number of correct actions performed by the number of indications and evaluated associations between compliance and the health-care worker's and facility's characteristics. FINDINGS: Across 106 464 observed indications for an infection prevention and control practice, the mean compliance was 0.318 (95% confidence interval, CI: 0.315 to 0.321). The compliance ranged from 0.023 (95% CI: 0.021 to 0.024) for hand hygiene to 0.871 (95% CI: 0.866 to 0.876) for injection and blood sampling safety. Compliance was weakly associated with the facility's characteristics (e.g. public or private, or level of specialization) and the health-care worker's knowledge of, and training in, infection prevention and control practices. CONCLUSION: The observational tool was effective for assessing compliance with infection prevention and control practices across multiple domains in primary health care in a low-income country. Compliance varied widely across infection prevention and control domains. The weak associations observed between compliance and the characteristics of health care workers and facilities, such as knowledge and the availability of supplies, suggest that a broader focus on behavioural change is required. PMID- 28670016 TI - Systematic analysis of protein identity between Zika virus and other arthropod borne viruses. AB - OBJECTIVE: To analyse the proportions of protein identity between Zika virus and dengue, Japanese encephalitis, yellow fever, West Nile and chikungunya viruses as well as polymorphism between different Zika virus strains. METHODS: We used published protein sequences for the Zika virus and obtained protein sequences for the other viruses from the National Center for Biotechnology Information (NCBI) protein database or the NCBI virus variation resource. We used BLASTP to find regions of identity between viruses. We quantified the identity between the Zika virus and each of the other viruses, as well as within-Zika virus polymorphism for all amino acid k-mers across the proteome, with k ranging from 6 to 100. We assessed accessibility of protein fragments by calculating the solvent accessible surface area for the envelope and nonstructural-1 (NS1) proteins. FINDINGS: In total, we identified 294 Zika virus protein fragments with both low proportion of identity with other viruses and low levels of polymorphisms among Zika virus strains. The list includes protein fragments from all Zika virus proteins, except NS3. NS4A has the highest number (190 k-mers) of protein fragments on the list. CONCLUSION: We provide a candidate list of protein fragments that could be used when developing a sensitive and specific serological test to detect previous Zika virus infections. PMID- 28670017 TI - Improving water, sanitation and hygiene in health-care facilities, Liberia. AB - PROBLEM: The lack of proper water and sanitation infrastructures and poor hygiene practices in health-care facilities reduces facilities' preparedness and response to disease outbreaks and decreases the communities' trust in the health services provided. APPROACH: To improve water and sanitation infrastructures and hygiene practices, the Liberian health ministry held multistakeholder meetings to develop a national water, sanitation and hygiene and environmental health package. A national train-the-trainer course was held for county environmental health technicians, which included infection prevention and control focal persons; the focal persons acted as change agents. LOCAL SETTING: In Liberia, only 45% of 701 surveyed health-care facilities had an improved water source in 2015, and only 27% of these health-care facilities had proper disposal for infectious waste. RELEVANT CHANGES: Local ownership, through engagement of local health workers, was introduced to ensure development and refinement of the package. In-county collaborations between health-care facilities, along with multisectoral collaboration, informed national level direction, which led to increased focus on water and sanitation infrastructures and uptake of hygiene practices to improve the overall quality of service delivery. LESSONS LEARNT: National level leadership was important to identify a vision and create an enabling environment for changing the perception of water, sanitation and hygiene in health-care provision. The involvement of health workers was central to address basic infrastructure and hygiene practices in health-care facilities and they also worked as stimulators for sustainable change. Further, developing a long-term implementation plan for national level initiatives is important to ensure sustainability. PMID- 28670018 TI - Proactive community case-finding to facilitate treatment seeking for mental disorders, Nepal. AB - PROBLEM: Underutilization of mental health services is a major barrier to reducing the burden of disease attributable to mental, neurological and substance use disorders. Primary care-based screening to detect people with mental disorders misses people not frequently visiting health-care facilities or who lack access to services. APPROACH: In two districts in Nepal, we trained lay community informants to use a tool to detect people with mental, neurological and substance-use disorders during routine community service. The community informant detection tool consists of vignettes, which are sensitive to the context, and pictures that are easy to understand for low literacy populations. Informants referred people they identified using the tool to health-care facilities. Three weeks after detection, people were interviewed by trained research assistants to assess their help-seeking behaviour and whether they received any treatment. LOCAL SETTING: Decentralized mental health services are scarce in Nepal and few people with mental disorders are seeking care. RELEVANT CHANGES: Out of the 509 people identified through the community informant detection tool, two-thirds (67%; 341) accessed health services and 77% (264) of those individuals initiated mental health treatment. People in the rural Pyuthan district (208 out of 268) were more likely to access health care than those living in Chitwan district (133 out of 241). LESSONS LEARNT: The introduction of the tool increased the utilization of mental health services in a low-income country with few health resources. The tool seems beneficial in rural settings, where communities are close-knit and community informants are familiar with those in need of mental health services. PMID- 28670019 TI - Strengthening health systems for universal health coverage and sustainable development. PMID- 28670020 TI - Should e-cigarette use be included in indoor smoking bans? PMID- 28670021 TI - A global database of abortion laws, policies, health standards and guidelines. PMID- 28670022 TI - Calibrating the prior distribution for a normal model with conjugate prior. AB - For a normal model with a conjugate prior, we provide an in depth examination of the effects of the hyperparameters on the long-run frequentist properties of posterior point and interval estimates. Under an assumed sampling model for the data generating mechanism, we examine how hyperparameter values affect the mean squared error (MSE) of posterior means and the true coverage of credible intervals. We develop two types of hyperparameter optimality. MSE optimal hyperparameters minimize the MSE of posterior point estimates. Credible interval optimal hyperparameters result in credible intervals that have minimum length while still retaining nominal coverage. A poor choice of hyperparameters has a worse consequence on the credible interval coverage than on the MSE of posterior point estimates. We give an example to demonstrate how our results can be used to evaluate the potential consequences of hyperparameter choices. PMID- 28670023 TI - New Contrast Metric for Realistic Display Performance Measure. AB - The contrast ratio (CR) has been used to describe display's performance. However, CR is unbound, ignores the impact of ambient illumination, or viewer's contrast perception. We propose new metric for display's contrast performance based on a modified Weber contrast definition that considers human contrast adaptation and applies for both opaque and see-through displays. PMID- 28670024 TI - Reproducibility of abdominal fat assessment by ultrasound and computed tomography. AB - OBJECTIVE: To test the accuracy and reproducibility of ultrasound and computed tomography (CT) for the quantification of abdominal fat in correlation with the anthropometric, clinical, and biochemical assessments. MATERIALS AND METHODS: Using ultrasound and CT, we determined the thickness of subcutaneous and intra abdominal fat in 101 subjects-of whom 39 (38.6%) were men and 62 (61.4%) were women-with a mean age of 66.3 years (60-80 years). The ultrasound data were correlated with the anthropometric, clinical, and biochemical parameters, as well as with the areas measured by abdominal CT. RESULTS: Intra-abdominal thickness was the variable for which the correlation with the areas of abdominal fat was strongest (i.e., the correlation coefficient was highest). We also tested the reproducibility of ultrasound and CT for the assessment of abdominal fat and found that CT measurements of abdominal fat showed greater reproducibility, having higher intraobserver and interobserver reliability than had the ultrasound measurements. There was a significant correlation between ultrasound and CT, with a correlation coefficient of 0.71. CONCLUSION: In the assessment of abdominal fat, the intraobserver and interobserver reliability were greater for CT than for ultrasound, although both methods showed high accuracy and good reproducibility. PMID- 28670025 TI - High-resolution computed tomography findings in eight patients with hantavirus pulmonary syndrome. AB - OBJECTIVE: The purpose of this study was to describe the high-resolution computed tomography (HRCT) findings in patients with hantavirus pulmonary syndrome (HPS). MATERIALS AND METHODS: We retrospectively reviewed HRCT findings from eight cases of HPS. All patients were men, aged 19-70 (mean, 41.7) years. Diagnoses were established by serological test (enzyme-linked immunosorbent assay) in all patients. Two chest radiologists analyzed the images and reached decisions by consensus. RESULTS: The predominant HRCT findings were ground-glass opacities (GGOs) and smooth inter- and intralobular septal thickening, found in all eight cases; however, the crazy-paving pattern was found in only three cases. Pleural effusion and peribronchovascular thickening were observed in five patients. The abnormalities were bilateral in all patients. CONCLUSION: The predominant HRCT findings in patients with HPS were GGOs and smooth inter- and intralobular septal thickening, which probably correlate with the histopathologic findings of pulmonary edema. PMID- 28670026 TI - Diffusion-weighted imaging of suspicious (BI-RADS 4) breast lesions: stratification based on histopathology. AB - OBJECTIVE: To test the use of diffusion-weighted imaging (DWI) in stratifying suspicious breast lesions (BI-RADS 4), correlating them with histopathology. We also investigated the performance of DWI related to the main enhancement patterns (mass and non-mass) and tested its reproducibility. MATERIALS AND METHODS: Seventy-six patients presented 92 lesions during the sampling period. Two independent examiners reviewed magnetic resonance imaging studies, described the lesions, and determined the apparent diffusion coefficient (ADC) values. Differences among benign, indeterminate- to high-risk, and malignant findings, in terms of the ADCs, were assessed by analysis of variance. Using receiver operating characteristic (ROC) curves, we compared the performance of ADC values in masses and non-mass lesions, and tested the reproducibility of measurements by determining the coefficient of variation and smallest real difference. RESULTS: Among the 92 lesions evaluated, the histopathology showed that 37 were benign, 11 were indeterminate- to high-risk, and 44 were malignant. The mean ADC differed significantly among those histopathological groups, the value obtained for the malignant lesions (1.10 * 10-3 mm2/s) being significantly lower than that obtained for the other groups (p < 0.001). ROC curves demonstrated that DWI performed better when applied to masses than when applied to non-mass lesions (area under the curve, 0.88 vs. 0.67). Reproducibility was good (coefficient of variation, 7.03%; and smallest real difference, +/- 0.242 * 10-3 mm2/s). CONCLUSION: DWI can differentiate between malignant and nonmalignant (benign or indeterminate- to high-risk) lesions, showing better performance for masses. Nevertheless, stratification based on histopathological criteria that are more refined has yet to be achieved. PMID- 28670027 TI - Learning curve of radiology residents during training in fluoroscopy-guided facet joint injections. AB - OBJECTIVE: To develop a simulator for training in fluoroscopy-guided facet joint injections and to evaluate the learning curve for this procedure among radiology residents. MATERIALS AND METHODS: Using a human lumbar spine as a model, we manufactured five lumbar vertebrae made of methacrylate and plaster. These vertebrae were assembled in order to create an anatomical model of the lumbar spine. We used a silicon casing to simulate the paravertebral muscles. The model was placed into the trunk of a plastic mannequin. From a group of radiology residents, we recruited 12 volunteers. During simulation-based training sessions, each student carried out 16 lumbar facet injections. We used three parameters to assess the learning curves: procedure time; fluoroscopy time; and quality of the procedure, as defined by the positioning of the needle. RESULTS: During the training, the learning curves of all the students showed improvement in terms of the procedure and fluoroscopy times. The quality of the procedure parameter also showed improvement, as evidenced by a decrease in the number of inappropriate injections. CONCLUSION: We present a simple, inexpensive simulation model for training in facet joint injections. The learning curves of our trainees using the simulator showed improvement in all of the parameters assessed. PMID- 28670028 TI - Anthropometric study of the knee in patients with osteoarthritis: intraoperative measurement versus magnetic resonance imaging. AB - OBJECTIVE: To compare intraoperative measurements of the knee with those obtained by magnetic resonance imaging, in order to validate the latter method for use in anthropometric studies. MATERIALS AND METHODS: We studied 20 knees in 20 patients with osteoarthritis, all of whom underwent total arthroplasty between August and December of 2013. We took six measurements in the distal femur and two in the proximal tibia. Using the information system of the institution, we made the measurements on magnetic resonance imaging scans that had been obtained in the axial plane. Intraoperative measurements were obtained using a caliper, after the initial cuts made during the arthroplasty. The anatomical parameters determined by magnetic resonance imaging were the same as those determined by intraoperative measurement. The intraclass correlation coefficient was used in order to assess the level of agreement in anthropometric measurements of the knee performed by magnetic resonance imaging and by intraoperative measurement. RESULTS: Statistical analysis revealed a highly significant correlation between the knee anthropometric parameters of the knee determined by intraoperative measurement and those determined by magnetic resonance imaging. CONCLUSION: The dimensions of osteoarthritic knees measured by magnetic resonance imaging were similar to those measured intraoperatively. Therefore, magnetic resonance imaging can be considered a reliable method for use in large-scale anthropometric studies that will allow the available implants to be adapted and improved. PMID- 28670029 TI - Diagnostic performance of magnetic resonance imaging in the assessment of periosteal reactions in bone sarcomas using conventional radiography as the reference. AB - OBJECTIVE: To evaluate the performance of magnetic resonance imaging (MRI) in detecting periosteal reactions and to compare MRI and conventional radiography (CR) in terms of the classification of periosteal reactions. MATERIALS AND METHODS: Retrospective study of 42 consecutive patients (mean age, 22 years; 20 men) with a confirmed diagnosis of osteosarcoma or Ewing's sarcoma, MRI and CR images having been acquired pretreatment. Three blinded radiologists detected periosteal reactions and evaluated each periosteal reaction subtype in CR and MRI images: Codman's triangle; laminated; and spiculated. The CR was used as a benchmark to calculate the diagnostic performance. We used the kappa coefficient to assess interobserver reproducibility. A two-tailed Fisher's exact test was used in order to assess contingency between CR and MRI classifications. RESULTS: In the detection of periosteal reactions, MRI showed high specificity, a high negative predictive value, and low-to-moderate sensitivity. For CR and for MRI, the interobserver agreement for periosteal reaction was almost perfect, whereas, for the classification of different subtypes of periosteal reaction, it was higher for the Codman's triangle subtype and lower for the spiculated subtype. There was no significant difference between MRI and CR in terms of the classifications (p < 0.05). CONCLUSION: We found no difference between MRI and CR in terms of their ability to classify periosteal reactions. MRI showed high specificity and almost perfect interobserver agreement for the detection of periosteal reactions. The interobserver agreement was variable for the different subtypes of periosteal reaction. PMID- 28670030 TI - Coronary artery calcium score: current status. AB - The coronary artery calcium score plays an Important role In cardiovascular risk stratification, showing a significant association with the medium- or long-term occurrence of major cardiovascular events. Here, we discuss the following: protocols for the acquisition and quantification of the coronary artery calcium score by multidetector computed tomography; the role of the coronary artery calcium score in coronary risk stratification and its comparison with other clinical scores; its indications, interpretation, and prognosis in asymptomatic patients; and its use in patients who are symptomatic or have diabetes. PMID- 28670031 TI - Sciatic neuropathy: findings on magnetic resonance neurography. AB - Injuries of the sciatic nerve are common causes of pain and limitation in the lower limbs. Due to its particular anatomy and its long course, the sciatic nerve is often involved in diseases of the pelvis or leg. In recent years, magnetic resonance neurography has become established as an important tool for the study of peripheral nerves and can be widely applied to the study of the sciatic nerve. Therefore, detailed knowledge of its anatomy and of the most prevalent diseases affecting it is essential to maximizing the accuracy of diagnostic imaging. PMID- 28670032 TI - Cesarean scar ectopic pregnancy: invasion of the bladder wall detected by magnetic resonance imaging. AB - Although cesarean scar ectopic pregnancy continues to be the rarest form of ectopic pregnancy, its incidence is increasing because of the worldwide increase in the number of cesarean deliveries. If the diagnosis is delayed, there is a high risk of severe hemorrhage and death, whereas early diagnosis can minimize the complications associated with the condition. Here, we report a case in which invasion of the bladder wall was identified by magnetic resonance imaging. PMID- 28670033 TI - Pheochromocytoma of the urinary bladder. PMID- 28670034 TI - Carpal boss syndrome: os styloideum fused to the trapezoid. PMID- 28670035 TI - Prenatal diagnosis of sirenomelia in the second trimester of pregnancy using two dimensional ultrasound, three-dimensional ultrasound and magnetic resonance imaging. PMID- 28670036 TI - Complementary findings on 18F-FDG PET/CT and 18F-NaF PET/CT in a patient with Erdheim-Chester disease. PMID- 28670037 TI - Clinical and radiological characterization of fibrous hamartoma of infancy. PMID- 28670038 TI - Left renal vein thrombosis secondary to compression by the uncinate process of the pancreas, mimicking the nutcracker syndrome. PMID- 28670040 TI - Self-limiting thoracic aortic dissection during bronchial artery embolization. PMID- 28670039 TI - Atypical presentation of mature cystic teratoma ("floating balls"). PMID- 28670041 TI - Chest computed tomography in bronchiolitis obliterans after bone marrow transplantation. PMID- 28670042 TI - Teleradiology, the Internet, and the development of multidisciplinary professional networks: new times for the specialty? PMID- 28670043 TI - Obesity, adiposopathy, and quantitative imaging biomarkers. PMID- 28670044 TI - High-Speed Monitoring of Multiple Grid-Connected Photovoltaic Array Configurations and Supplementary Weather Station. AB - Three grid-connected monocrystalline silicon photovoltaic arrays have been instrumented with research-grade sensors on the Gaithersburg, MD campus of the National Institute of Standards and Technology (NIST). These arrays range from 73 kW to 271 kW and have different tilts, orientations, and configurations. Irradiance, temperature, wind, and electrical measurements at the arrays are recorded, and images are taken of the arrays to monitor shading and capture any anomalies. A weather station has also been constructed that includes research grade instrumentation to measure all standard meteorological quantities plus additional solar irradiance spectral bands, full spectrum curves, and directional components using multiple irradiance sensor technologies. Reference photovoltaic (PV) modules are also monitored to provide comprehensive baseline measurements for the PV arrays. Images of the whole sky are captured, along with images of the instrumentation and reference modules to document any obstructions or anomalies. Nearly, all measurements at the arrays and weather station are sampled and saved every 1s, with monitoring having started on Aug. 1, 2014. This report describes the instrumentation approach used to monitor the performance of these photovoltaic systems, measure the meteorological quantities, and acquire the images for use in PV performance and weather monitoring and computer model validation. PMID- 28670045 TI - Transition-Metal-Free Formation of C-E Bonds (E = C, N, O, S) and Formation of C M Bonds (M = Mn, Mo) from N-Heterocyclic Carbene Mediated Fluoroalkene C-F Bond Activation. AB - Herein, a recently reported polyfluoroalkenyl imidazolium salt is shown to react with nitrogen-, oxygen- and sulfur-based nucleophiles at the C beta position in a stereoselective and regioselective fashion, without the use of a transition metal. In contrast, reactivity with 1-methylimidazole demonstrates net substitution at C alpha . This product reacts quantitatively with water, affording clean transformation of a difluoromethylene group to give an alpha,beta unsaturated trifluoromethyl ketone. Further reactivity studies demonstrate that the difluoromethyl fragment of an N-heterocyclic fluoroalkene is capable of direct C-C bond formation with NaCp through loss of sodium fluoride and double C F bond activation (Cp = cyclopentadienide). TD-DFT calculations of this product indicate that both the HOMO and LUMO are of mixed pi/pi* character and are delocalized over the N-heterocyclic and Cp fragments, giving rise to a very intense absorption feature in the UV-vis spectrum. Additionally, two carbonylmetalate-substituted fluorovinyl imidazolium complexes featuring Mn and Mo were isolated and fully characterized. PMID- 28670046 TI - Oblique contractional reactivation of inherited heterogeneities: Cause for arcuate orogens. AB - We use lithospheric-scale analog models to study the reactivation of pre-existing heterogeneities under oblique shortening and its relation to the origin of arcuate orogens. Reactivation of inherited rheological heterogeneities is an important mechanism for localization of deformation in compressional settings and consequent initiation of contractional structures during orogenesis. However, the presence of an inherited heterogeneity in the lithosphere is in itself not sufficient for its reactivation once the continental lithosphere is shortened. The heterogeneity orientation is important in determining if reactivation occurs and to which extent. This study aims at giving insights on this process by means of analog experiments in which a linear lithospheric heterogeneity trends with various angles to the shortening direction. In particular, the key parameter investigated is the orientation (angle alpha) of a strong domain (SD) with respect to the shortening direction. Experimental results show that angles alpha >= 75 degrees (high obliquity) allow for reactivation along the entire SD and the development of a linear orogen. For alpha <= 60 degrees (low obliquity) the models are characterized by the development of an arcuate orogen, with the SD remaining partially non-reactivated. These results provide a new mechanism for the origin of some arcuate orogens, in which orocline formation was not driven by indentation or subduction processes, but by oblique shortening of inherited heterogeneities, as exemplified by the Ouachita orogen of the southern U.S. PMID- 28670047 TI - Addressing Barriers to Care Among Hispanic Youth: Telehealth Delivery of Trauma Focused Cognitive Behavioral Therapy. PMID- 28670048 TI - How The Timing of Grade Retention Affects Outcomes: Identification and Estimation of Time-Varying Treatment Effects. AB - In many countries, grade retention is viewed as a useful tool for helping students who fall behind in their achievement. We show how the effect of grade retention varies by abilities, by timing of retention and as time since retention elapses. While existing studies of grade retention also recognize the importance of studying variation by abilities and timing, the existing methods are not well equipped to deal with the possibility that students retained at different grades differ in unobservable abilities (dynamic selection) and the effects of retention also vary by the student's abilities and the time at which the student is retained. We extend existing factor analytic methods for identifying treatment effects to control for dynamic selection in our time-varying treatment effect setting. This approach can be understood as a hybrid between a control function and a generalization of the fixed effects approach. Applying our method to nationally-representative, longitudinal data, we find evidence of dynamic selection into retention and that the treatment effect of retention varies considerably across grades and unobservable abilities of students. Our strategy can be applied more broadly to many time-varying or multiple treatment settings. PMID- 28670049 TI - Examining the relationship between comprehension and production processes in code switched language. AB - We employ code-switching (the alternation of two languages in bilingual communication) to test the hypothesis, derived from experience-based models of processing (e.g., Boland, Tanenhaus, Carlson, & Garnsey, 1989; Gennari & MacDonald, 2009), that bilinguals are sensitive to the combinatorial distributional patterns derived from production and that they use this information to guide processing during the comprehension of code-switched sentences. An analysis of spontaneous bilingual speech confirmed the existence of production asymmetries involving two auxiliary + participle phrases in Spanish English code-switches. A subsequent eye-tracking study with two groups of bilingual code-switchers examined the consequences of the differences in distributional patterns found in the corpus study for comprehension. Participants' comprehension costs mirrored the production patterns found in the corpus study. Findings are discussed in terms of the constraints that may be responsible for the distributional patterns in code-switching production and are situated within recent proposals of the links between production and comprehension. PMID- 28670050 TI - Effects of epidural analgesia on recovery after open colorectal surgery. AB - The use of epidural analgesia (EA) has been suggested as an integral part of an enhanced recovery program for colorectal surgery. However, the effects of EA on postoperative outcomes and hospital length of stay remain controversial. Data from the American College of Surgeons National Surgical Quality Improvement Program database for 2014 and 2015 were queried for adult patients who underwent elective open colorectal surgery. We included only cases with general anesthesia as the main anesthetic. Cases with other types of anesthesia were excluded. A 1:3 matched sample of EA versus non-EA cases was created based on propensity scores. The primary outcome of interest was the occurrence of major cardiopulmonary complications within 7 days of the surgery. Secondary outcome measures were hospital length of stay and 30-day mortality. A total of 24,927 patients were included in the analysis. EA was utilized in 15.02% (n = 3745). The cumulative risk over the study period for major cardiopulmonary complications was 2.52% (n = 627). There were no statistically significant differences in the rate of postoperative complications (relative risk 0.91, 95% CI 0.66-1.27, P = 0.59), length of stay (median [interquartile range], EA 6 [5-9] versus non-EA 6 [4-9] days, P = 0.36), and 30-day mortality rate (relative risk 0.71, 95% CI 0.42-1.20, P = 0.20) between the two propensity-matched cohorts. In conclusion, our study revealed that the benefits of EA in patients undergoing open colorectal surgery are limited, as it does not influence immediate postoperative cardiopulmonary complications or hospital length of stay. PMID- 28670051 TI - Ineffectiveness of magnetic resonance imaging enhancement to predict fibroid volume reduction after uterine artery embolization. AB - Fibroid nonenhancement is considered a relative contraindication to uterine artery embolization (UAE) for symptomatic fibroids. This retrospective study assessed the impact of UAE on nonenhancing fibroids to determine imaging predictors of fibroid shrinkage. All women who underwent UAE for symptomatic fibroids between May 2009 and July 2014 and had follow-up magnetic resonance imaging 6 months after UAE were included. There were 59 fibroids (5 nonenhancing, 54 enhancing) among 18 women aged 40 to 53 (mean 46) years. All fibroids were assessed for size, position, and enhancement on subtraction and apparent diffusion constant (ADC) images. Enhancing fibroids had an average decrease in diameter of 19% +/- 3%, not significantly different than nonenhancing fibroids, which decreased 23% +/- 6% (P = 0.49). Multiple linear regression with percent change in fibroid diameter as the dependent variable and patient age, fibroid position, and pre-UAE fibroid diameter, enhancement, and ADC as independent variables showed that ADC (P = 0.04) and pre-UAE diameter (P = 0.03) were the only significant independent variables. In conclusion, pre-UAE size and ADC, but not contrast enhancement, predicted fibroid diameter reduction. Enhancing and nonenhancing fibroids had a similar size reduction after UAE. Nonenhancement should not be considered a contraindication to UAE. PMID- 28670052 TI - Imaging and clinical predictors of spontaneous bacterial peritonitis diagnosed by ultrasound-guided paracentesis. AB - Spontaneous bacterial peritonitis (SBP) is a potentially life-threatening complication of ascites diagnosed by paracentesis. We determined predictors of SBP to facilitate patient selection. The 301 paracenteses performed in 119 patients (51 women, 68 men) from July to November 2015 were retrospectively reviewed. Presentation, lab data, depth of the deepest ascites pocket on ultrasound, total volume of ascites removed, absolute neutrophil count, and complications were studied. Of 301 paracenteses, 16 (5%) diagnosed SBP. On univariate analysis, SBP was associated negatively with history of cirrhosis and positively with history of cancer, abdominal pain, greater depth of the fluid pocket, prior SBP, and leukocytosis. Multivariate analysis using these variables to predict SBP was significant (P < 0.0001); only depth of the largest fluid pocket (P = 0.008) and complaint of abdominal pain (P = 0.006) were independent predictors. Receiver-operator curve analysis showed that a 5-cm cutoff of pocket depth yielded 100% sensitivity and 32% specificity. Two (0.1%) hemorrhagic complications occurred, one causing death and one necessitating laparotomy. In conclusion, deeper ascites pockets and abdominal pain are independent predictors of SBP. When the largest ascites pocket is <5 cm, the probability of SBP is nearly negligible. Given the potential for hemorrhagic complications, findings may help triage patients for paracentesis. PMID- 28670053 TI - The Everyday Cognition Scale in Parkinson's disease. AB - This brief report describes caregiver ratings on the Everyday Cognition (ECog) scale, a psychometrically robust measure of cognitively driven daily activities that was initially designed for other neurodegenerative conditions, in individuals with Parkinson's disease (PD). In 49 individuals with PD, those with suspected PD dementia had more difficulties across ECog domains than those with normal cognition or mild cognitive impairment. Results from multiple regression analyses revealed that activities captured by the ECog were related to measured cognitive ability, over and above disease duration and demographic factors. The lack of floor and ceiling effects speaks to the potential utility of the instrument in practice and research regarding this population. Preliminary data support the utility of the ECog as a marker of functional impact of cognitive problems in PD, though further research will be required to validate the instrument in this population. PMID- 28670055 TI - Effect of thrombus aspiration on angiography and outcome in patients undergoing primary coronary angioplasty. AB - Thrombus exerts a major impact on the performance and outcome of primary and rescue interventions in acute ST-elevation myocardial infarction. Although the optimal treatment of thrombotic lesions is still controversial, thrombus aspiration provides an effective method to achieve successful reperfusion during primary angioplasty. We compared clinical and angiographic outcomes in 286 patients with acute ST-elevation myocardial infarction undergoing primary percutaneous transluminal coronary angioplasty (PTCA) and thrombus aspiration with those who underwent conventional PTCA without thrombus aspiration. Thrombus aspiration during primary percutaneous coronary intervention in patients with high thrombus burden resulted in better Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the infarct-related artery and helped achieve faster ST-segment resolution on the electrocardiogram compared with conventional angioplasty without thrombus aspiration. PMID- 28670054 TI - Rate of contralateral hip fracture after dynamic hip screw vs intramedullary nail for treatment of pertrochanteric hip fractures. AB - A retrospective, comparative study was performed reviewing the electronic medical records and digital radiographs of patients who underwent treatment for intertrochanteric and pertrochanteric hip fractures with either a hip screw and side plate (HSSP) or intramedullary nail. A total of 430 patients were treated with HSSP, and 725 were managed with a cephalomedullary nail (CMN). Of these, 103 sustained a contralateral hip fracture. Fixation technique was not associated with a significant difference in the rate of contralateral fracture. Among the patients with a contralateral fracture, the median time to contralateral fracture was 119.28 months following HSSP and 81.97 months following CMN. Bisphosphonate use was found to be a significant predictor of contralateral fracture for all patients, but when matching using propensity scores, its use was found to be insignificant. In conclusion, there was no difference in the rate of subsequent contralateral hip fracture when comparing HSSP with CMN. Additionally, the time to second surgery between the two treatment modalities was found to be statistically insignificant. It is unclear if bisphosphonate use increased the odds of having a contralateral fracture, regardless of the surgical intervention. The difference in the bisphosphonate effect using propensity score matching suggests that the results may be due to confounding variables and bias. PMID- 28670056 TI - Clinical experience with machine log file software for volumetric-modulated arc therapy techniques. AB - Mobius FX, an add-on software module from Mobius Medical SystemsTM for intensity modulated radiation therapy (IMRT) quality assurance (QA), uses linac treatment logs to efficiently calculate and verify the 3D dose delivered to patients. An advantage of the Mobius FX module is that it does not require device positioning. In this study, we compared the Mobius FX with another QA option, ArcCheck, as well as with the treatment planning system (TPS) using 30 volumetric-modulated arc therapy (VMAT) plans planned and delivered on a Varian TrueBeam linac. The plans, which involved 6 and 10 MV and consisted of 2 to 3 arcs per plan, were selected to provide a clinically relevant sample. The average gamma value for all plans between Mobius FX and the TPS was 99.96% for the criterion of 3%-3 mm and 98.80% for the criterion of 2%-2 mm. Very similar results were found when comparing Mobius FX and the TPS dose calculations with those acquired by traditional methods (i.e., ArcCheck). As the gamma criterion of the analysis was narrowed, discrepancies between Mobius FX and traditional methods appeared. Profile analysis showed the production of comparable results when using the Mobius FX method or traditional QA methods. In conclusion, the Mobius FX method for pretreatment of patient-specific QA is capable of producing results similar to those obtained by traditional methods. PMID- 28670057 TI - Review of screening studies for atrial fibrillation in rural populations of 11 countries. AB - Atrial fibrillation (AF) is a common cardiac arrhythmia, and pathological burden can be influenced by environmental factors. The rural environment may influence the burden of AF, although no systematic review studies have been conducted to address this issue. We performed a systematic review of AF screening studies conducted in rural global populations to determine the burden, risk factors, and screening methods surrounding AF in these settings. Out of the 1792 articles gathered from a keyword search of medical databases and reference lists, 18 publications from 11 countries were included in our analysis. The pooled prevalence of AF across the studies was 2.05% (95% confidence interval, 1.97% 2.13%) and ranged from 0.3% to 10.87%. Only one study utilized a handheld electrocardiogram to screen AF, while the rest used the 12-lead electrocardiogram. AF risk factors reported across studies varied and included increasing age, male gender, hypertension, diabetes, prior myocardial infarction or stroke, obesity, hyperlipidemia/hypercholesterolemia, alcohol consumption, and heart failure. However, none of the studies assessed all risk factors. We suggest that future research on AF in rural communities examine a complete checklist of AF risk factors to better understand their influence on AF burden and development. This will aid in understanding rural prevention strategies and the management of detected AF cases specific to rural areas. At present, the burden of AF in rural communities is poorly understood and has been underreported. PMID- 28670058 TI - Management of complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is a relatively rare, chronic, and debilitating condition that significantly impacts the patient's quality of life. There is an overall paucity of literature addressing the management of CRPS in immunocompromised patients. We define features of CRPS, outline its treatment options, and describe a course of CRPS management for a 35-year-old patient who had heart transplantation requiring immunosuppressive medications. PMID- 28670059 TI - Management of pelvic floor disorder in a diethylstilbestrol daughter. AB - Between 1947 and 1971, the synthetic estrogen diethylstilbestrol (DES) was prescribed to pregnant women to prevent spontaneous abortions. Many studies have demonstrated adverse consequences of prenatal DES exposure. This report describes a DES daughter treated for uterine cancer who presented with a foreshortened vagina of 4 cm and stage III pelvic organ prolapse. She underwent successful vaginal native tissue reconstructive surgery with uterosacral colpopexy and anterior and posterior repair to lengthen her vagina and treat her prolapse. She then developed stress incontinence and underwent periurethral bulking 5 months later. She has been followed for 2 years with no recurrence of prolapse or incontinence. PMID- 28670060 TI - Deglutition syncope. AB - Deglutition syncope, also known as swallow syncope, is a neurally mediated reflex syndrome. The common intervention of the heart, esophagus, and stomach by the vagus nerve is central to its pathogenesis, whereby swallowing causes inhibition of the cardiac conduction system. It is most commonly associated with disorders of the esophagus, both organic and functional. Herein we describe the case of a 48-year-old man presenting with transient syncopal episodes that occurred while eating caused by an intrathoracic stomach due to a hiatal hernia. PMID- 28670061 TI - Thoracentesis-reverting cardiac tamponade physiology in a patient with myxedema coma and large pleural effusion. AB - A large pleural effusion causing cardiac tamponade physiology and severe hemodynamic compromise is an uncommon event. We report a case of a 53-year-old woman with severe hypothyroidism presenting with myxedema coma and refractory shock. Her hemodynamic status failed to respond to fluid resuscitation and vasopressors. A transthoracic echocardiogram and chest radiograph demonstrated a pericardial fluid accumulation associated with a large left-sided pleural effusion. Thoracostomy tube insertion resulted in prompt improvement of the patient's hemodynamic status. Our finding demonstrates that a large pleural effusion may play an important role in cardiac tamponade physiology. PMID- 28670062 TI - Novel technique of selective stent deployment in complicated thoracic aortic aneurysm. AB - A 72-year-old woman presented with a thoracic aortic aneurysm that was found to have increased from 5.1 cm to 7.1 cm. Due to the increase in size, the aortic aneurysm required endovascular repair. After deployment of a GORE C-TAG stent graft, a distal type 1 endoleak was still present, requiring deployment of another stent to achieve total coverage. The aorta had an angled anatomical variation often associated with type 1 endoleaks causing technical difficulty with conventional deployment of the graft. By employing a novel Parachute technique, the graft was selectively deployed at the distal end, and the position was adjusted to fit the angulation of the aorta, followed by selective deployment of the proximal end. This selective deployment allowed for the adjustment necessary to effectively cover the endoleak. PMID- 28670063 TI - Aorto-right atrial fistula after Bentall repair. AB - We describe a man with the Marfan syndrome and a prior ascending aortic aneurysm resection who presented with knee pain and concern of endocarditis. Transesophageal echocardiogram showed no vegetations, and computed tomography angiogram of the heart showed a possible pseudoaneurysm. Cardiac catheterization and aortogram revealed the diagnosis of an aorto-right atrial fistula, which was then operatively repaired. This case highlights the role that cardiac catheterization with aortogram can play in the detection of aorto-atrial fistula. PMID- 28670064 TI - Coronary arterial aneurysms in previously transplanted (donor) hearts. AB - Described herein is a 57-year-old man who had had a cardiac transplant 5 years earlier (at age 52) and died of a ruptured abdominal aortic aneurysm. The donor heart was found to have a fusiform aneurysm, each filled with thrombus, in 2 major epicardial coronary arteries. PMID- 28670065 TI - Aortic valve perforation secondary to blunt force trauma. AB - Blunt chest trauma has seldom been reported as a cause of rupture of an aortic valve cusp. We report the case of a 63-year-old man who had a motor vehicle collision resulting in transection of the descending thoracic aorta, splenic pseudoaneurysm, and rupture of an aortic valve cusp causing severe aortic regurgitation. Despite replacement of the aortic valve, he died of multiorgan failure. PMID- 28670066 TI - Takotsubo cardiomyopathy with Guillain-Barre syndrome. AB - A 70-year-old woman presented with progressive lower extremity weakness and heaviness accompanied with chest pain. Troponin T was elevated, and an echocardiogram showed a left ventricular ejection fraction of 30% and a hypokinetic left ventricular apex. Neurophysiologic testing was consistent with Guillain-Barre syndrome, which was treated with intravenous immunoglobulin therapy. Repeat echocardiogram showed an improved left ventricular ejection fraction and no left ventricular wall motion abnormalities. Takotsubo cardiomyopathy is a rare complication of Guillain-Barre syndrome; less than 10 cases have been reported. PMID- 28670067 TI - Doxorubicin chronic cardiomyopathy. PMID- 28670068 TI - Spindle-cell sarcoma involving the major pulmonary arteries. AB - Primary pulmonary vasculature tumors are exceptionally rare, with only a few reported cases. Signs and symptoms of such neoplasms vary but include dyspnea, cough, and chest pain. This condition is associated with a high mortality rate and is easily misdiagnosed as a pulmonary artery embolism. We pre-sent a case of pulmonary artery sarcoma that demonstrates the value of cardiac magnetic resonance imaging for accurate diagnosis. PMID- 28670069 TI - Hypertensive crisis secondary to pheochromocytoma. AB - Pheochromocytoma is an uncommon tumor of the adrenal glands that can present with headaches, sweating, palpitations, and paroxysmal hypertension. Pheochromocytoma crisis can lead to cardiomyopathy, pulmonary edema, and even total circulatory collapse. We describe a patient with hypoxic respiratory failure requiring extracorporeal membrane oxygenation to stabilize until the pheochromocytoma was discovered and treated. PMID- 28670070 TI - Two cancers in one: breast carcinoma with underlying melanoma. AB - A 61-year-old woman presented with a diagnosis of metastatic invasive lobular carcinoma of the right breast, and after treatment it had regressed or was stable except for a scalp nodule. When biopsied, the outer edges of the scalp lesion had findings consistent with breast carcinoma; however, the bulk of the tumor's pathology was consistent with melanoma. It appeared that most of the tumor was a highly vascularized melanoma with lobular breast carcinoma noted at its edges. PMID- 28670071 TI - Pleural-based granular cell tumor. AB - Granular cell tumors are rare tumors of Schwann cell origin that arise from tissues of neural crest and mesenchymal origin. We report the clinical, radiographic, and pathological features of a pleural-based granular cell tumor in a 60-year-old African American man. PMID- 28670072 TI - Primary mucoepidermoid carcinoma of the lung with prominent clear cells. AB - Mucoepidermoid carcinoma of the lung is a rare malignancy of salivary gland-type origin. We report a case of a 21-year-old man with a right mainstem bronchus mass composed predominantly of clear cells. This case represents a rare primary pulmonary low-grade mucoepidermoid carcinoma positive for MAML2 rearrangement by fluorescence in situ hybridization with a prominent clear cell component. PMID- 28670073 TI - Ewing's sarcoma of the trachea in an adolescent girl. AB - Primitive neuroectodermal tumors (PNET) are aggressive neoplasms of neuroectodermal origin. Although they are known to arise in a host of locations, involvement of the trachea has rarely been reported. We describe an adolescent girl who presented with stridor and was diagnosed with PNET of the trachea. She is in remission following treatment with combination chemotherapy and local radiotherapy. PMID- 28670074 TI - Persistent hematuria caused by renal cell carcinoma after aortic valve replacement and warfarin therapy. AB - Hematuria is a common finding in renal cell carcinoma, and persistent hematuria, even in those receiving anticoagulation, warrants workup. We present a case of a patient with persistent hematuria who was found to have a renal mass that was not evident on renal ultrasound and computed tomography of the abdomen and pelvis but was seen on magnetic resonance imaging. PMID- 28670075 TI - Malignant thymoma with metastasis associated with paraneoplastic myasthenia gravis. AB - We describe a patient who initially presented with a mixed thymic tumor and developed myasthenia gravis 8 years following thymectomy with recurrence of metastatic disease. Metastasis to the pleura, mediastinum, and cervical spine was identified with a positron emission tomography scan when this patient presented with recurring pneumonias and atrial fibrillation. The presentation and diagnosis were clouded by multiple courses of prednisone and chemotherapy for respiratory complications and metastatic disease, respectively. Classical myasthenia gravis symptoms emerged when his prednisone was tapered. The delayed presentation of paraneoplastic disease and the rare metastatic site make this case particularly unusual. PMID- 28670076 TI - Acute exacerbation of myasthenia gravis with topical imiquimod use. AB - Imiquimod activates the immune system when applied to a local area. We report a patient with a history of well-controlled myasthenia gravis who was prescribed imiquimod for lentigo maligna. Treatment was halted after 2 weeks when the patient reported itching and irritating sensations in his throat, consistent with previous myasthenia exacerbations. The symptoms improved once imiquimod use was discontinued. We advise clinicians to be cautious when prescribing imiquimod to a patient with a history of myasthenia gravis. PMID- 28670077 TI - Mixed phenotypic acute leukemia with leukemia cutis and neuroleukemiosis. AB - Leukemia cutis and neuroleukemiosis are two rare extramedullary manifestations of acute leukemia. We report a 32-year-old woman with multiple skin lesions and painful peripheral neuropathy. Bone marrow biopsy and skin biopsy confirmed the diagnosis of mixed phenotypic acute leukemia. After induction chemotherapy, she attained marrow remission, her skin lesion resolved completely, and her neurologic symptoms significantly improved. PMID- 28670078 TI - B-lymphoblastic lymphoma of the rectum. AB - Lymphoblastic lymphoma is a neoplasm of immature cells committed to the B-cell or T-cell lineage. B-lymphoblastic lymphoma usually involves lymph nodes and extranodal sites, such as the skin, bone, and soft tissue. The rectum is a very rare site of involvement in B-lymphoblastic lymphoma. We describe a 26-year-old man who presented with bleeding per rectum and fecal incontinence. Endoscopy showed a large nodular friable lesion narrowing the entire rectal lumen. Biopsy was diagnostic of B-lymphoblastic lymphoma. He was started on chemotherapy with the Berlin-Frankfurt-Munster protocol and achieved complete remission after induction chemotherapy. This is the first report of B-lymphoblastic lymphoma presenting as a rectal lesion in the world literature. PMID- 28670079 TI - Mantle cell lymphoma of the prostate gland treated with holmium laser enucleation. AB - Mantle cell lymphoma of the prostate is rare and is seldom encountered in general urologic practice. It either arises primarily from the prostate or is a result of metastatic spread from another site. This specific type of lymphoma has an aggressive course and may respond poorly to traditional chemotherapy with frequent relapses. Mantle cell lymphoma occurs in middle age or older, which is also when symptoms of benign prostatic enlargement begin in men. This overlap makes the diagnosis of lymphoma of the prostate difficult and makes the treatment more complex. We describe a case of mantle cell lymphoma of the prostate that caused significant enlargement and bladder outlet obstruction with urinary retention. The obstruction was treated with holmium laser enucleation of the prostate with good functional results. PMID- 28670080 TI - Elastofibroma dorsi. AB - We present a 60-year-old man with biopsy-proven metastatic squamous cell carcinoma of the right inguinal and external iliac lymph nodes with unknown primary. Hypermetabolic soft tissue masses were identified in bilateral subscapular regions on follow-up positron emission tomography (PET)-computed tomography (CT) after completion of chemoradiation. The right subscapular mass was biopsied under CT guidance, and histopathology showed it to be elastofibroma dorsi. Elastofibroma dorsi is a benign tumor with no malignant potential; due to its ill-defined appearance and tracer uptake on PET-CT, it can be misdiagnosed as soft tissue sarcoma. This report describes the typical location and imaging features of this incidental hypermetabolic mass. PMID- 28670081 TI - Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma presenting simultaneously with acquired hemophilia and warm autoimmune hemolytic anemia. AB - Since both acquired factor VIII inhibitor in non-hemophiliac patients and warm autoimmune hemolytic anemia are uncommon disorders with no case-controlled trials, managing these diseases can be challenging. We present a case of a 75 year-old man in whom both diseases were present simultaneously with life threatening bleeding. This case is an example of the successful initial management and long-term treatment of acquired hemophilia A, warm autoimmune hemolytic anemia, and chronic lymphocytic leukemia/small lymphocytic lymphoma with rituximab, prednisone, and cyclophosphamide. PMID- 28670082 TI - Pseudothrombotic microangiopathy and vitamin B12 deficiency in pernicious anemia. AB - Vitamin B12 deficiency may present as pseudothrombotic microangiopathy. Pseudothrombotic microangiopathy is anemia, thrombocytopenia, and schistocytosis caused by vitamin B12 deficiency. Pseudothrombotic microangiopathy may be mistaken for microangiopathic hemolytic anemia, confounding appropriate treatment. Evaluation of lactate dehydrogenase, reticulocyte count, bilirubin, and platelet count are most helpful in differentiating pseudothrombotic microangiopathy from a true microangiopathic hemolytic anemia. A case of pseudothrombotic microangiopathy due to severe vitamin B12 deficiency is presented. PMID- 28670083 TI - Olmesartan-associated enteropathy. AB - Olmesartan, an angiotensin-receptor blocker frequently prescribed for hypertension, has been commercially available since 2002. In 2012, olmesartan associated enteropathy was described, and the Food and Drug Administration now requires a black-box warning for olmesartan regarding severe diarrhea. The disorder can be life-threatening and often requires hospitalization. We present three cases that represent different aspects of this disorder, as well as some unusual features. PMID- 28670084 TI - Medullary angiitis and pauci-immune crescentic glomerulonephritis. AB - Although almost all pathological diagnoses made from a native kidney biopsy come from careful examination of the renal cortex, certain diseases have a characteristic medullary component. Medullary angiitis has histological features of interstitial hemorrhage in the medulla with an associated polymorphonuclear leukocyte infiltrate. These findings are primarily found in the setting of antineutrophil cytoplasmic antibody-associated vasculitis. Medullary angiitis identified in the setting of negative immunofluorescence is most suggestive of pauci-immune crescentic glomerulonephritis, as presented in this case. PMID- 28670085 TI - The case for computed tomographic angiography for initial management of lower gastrointestinal hemorrhage. AB - Lower gastrointestinal hemorrhage remains a common disease, frequently presenting with acute life-threatening symptoms. Although prompt detection and treatment are imperative, it is difficult to diagnose lower gastrointestinal hemorrhage in an accurate and efficient manner. Most available modalities are time consuming. Computed tomographic angiography of the abdomen and pelvis, on the other hand, has the unique capability of rapidly detecting whether life-threatening hemorrhage is occurring and accurately localizing it, thus facilitating definitive treatment. We present a case in which computed tomographic angiography was invaluable in the detection and subsequent empirical transarterial embolization of a lower gastrointestinal hemorrhage and offer evidence as to why it should be a first-line tool in the management of these patients. PMID- 28670086 TI - Posterior reversible leukoencephalopathy syndrome after kratom ingestion. AB - Posterior reversible encephalopathy syndrome has been associated with hypertension, preeclampsia, cancer chemotherapy, and drugs of abuse, such as amphetamine and methamphetamine. We report a young man who suddenly developed severe headache, disorientation, and aphasia following ingestion of kratom and Adderall. Computed tomography and magnetic resonance imaging of his head revealed foci of vasogenic edema in the posterior occipital lobes, frontal lobes, and brainstem. In addition, he had a small area of hemorrhage in the left posterior occipital lobe. Lumbar puncture revealed an increased number of red blood cells but no other abnormalities. His initial blood pressure was elevated but returned to normal during hospitalization. This case suggests that kratom can cause posterior reversible encephalopathy syndrome and needs to be considered when patients present to emergency centers with headaches, confusion, and visual disturbances. PMID- 28670087 TI - Plasmapheresis for recurrent acute pancreatitis from hypertriglyceridemia. AB - Acute pancreatitis is a known complication of severe hypertriglyceridemia. Therapeutic experience with plasmapheresis is less well reported but has been highly successful in life-threatening presentations. We describe a 38-year-old obese Hispanic woman with a previous history of acute pancreatitis from diabetic hypertriglyceridemia who presented to the emergency department with a 2-day history of worsening abdominal pain. Plasmapheresis was initiated with one calculated plasma volume exchange using 5% albumin replacement within 24 hours of admission. Following this treatment, the triglyceride level fell 74%. Another session was performed the following day. The final triglyceride level represented a 93% reduction. This case is novel in that the patient presented twice within the same year with hypertriglyceridemic pancreatitis and responded well to prompt plasmapheresis therapy. PMID- 28670088 TI - Linear IgA bullous dermatosis mimicking oral lichen planus. AB - Linear IgA bullous dermatosis (LABD) is an autoimmune disease characterized by blisters on the skin and mucous membranes. Polycyclic, grouped bullae on cutaneous skin are the most characteristic clinical feature of LABD. Lesions are often indistinguishable from bullous pemphigoid or may resemble dermatitis herpetiformis. Oral lesions may be seen in 5% to 70% of patients with LABD, and in some cases, the oral mucosa may be the only area of involvement. Herein, we report a patient with LABD involving only the oral mucosa clinically. The entity histologically mimicked oral lichen planus, which challenges accurate diagnosis and emphasizes the importance of direct immunofluorescence. PMID- 28670089 TI - Usefulness of positron emission tomography to detect cerebral amyloid as a means to diagnose neurodegenerative disease. AB - Alzheimer's disease is characterized histologically by the accumulation of a subtype of amyloid protein-beta amyloid-in the brain parenchyma in the form of amyloid plaques. In another neurodegenerative disorder, cerebral amyloid angiopathy, the accumulation of beta amyloid occurs within the walls of the cerebral vessels. With recent advances in imaging technology, we can not only image amyloid plaques in the brain parenchyma at an earlier stage of disease, but can also often correlate the presence of Alzheimer's disease with cerebral amyloid angiopathy. We present a case of suspected Alzheimer's disease and discuss the association in this patient between cerebral amyloid angiopathy and Alzheimer's disease, as well as the benefits of a unique nuclear imaging modality, amyloid positron emission tomography, in diagnosing dementia. PMID- 28670090 TI - Neurocysticercosis of the fourth ventricle associated with hydrocephalus. AB - Neurocysticercosis is a parasitic infection of the central nervous system with the cysts of Taenia solium, the pig tapeworm. Infection presents with a pleomorphic picture depending on the stage and location of the infection and the immune response of the infected host. Historically confined to the developing world, neurocysticercosis is no longer limited to endemic regions, as globalization, travel, and immigration permit the spread of the infection. We report a young Hispanic patient who was diagnosed with neurocysticercosis of the fourth ventricle and subsequent hydrocephalus. PMID- 28670091 TI - Metastatic calcinosis cutis in end-stage renal disease. AB - Alterations in calcium and phosphorus levels and joint pain are a common occurrence in end-stage renal disease patients. However, metastatic calcinosis cutis is a rare diagnosis that often combines these two findings, with extensive soft tissue calcification surrounding a large joint being the hallmark of this disease. The exact mechanism behind this clinical entity is unknown. The treatment and complications can be severe and disabling. Here, we discuss the case of a 26-year-old man presenting with unusually advanced skin and joint calcification of the shoulders, neck, hand, and penis. PMID- 28670092 TI - Invited Commentary: Calcinosis cutis and renal disease: an evolving story. PMID- 28670093 TI - Pathognomonic STEW: visible clues to systemic amyloidosis. PMID- 28670094 TI - Humor in medicine: Can laughter help in healing? PMID- 28670095 TI - A great-grandfather's account of the Irish potato famine (1845-1850). AB - My great-grandfather, Rodger Cantwell, and his family managed to survive the Irish famine that began in 1845. Blending what family records we have with Kelly's outstanding 2012 book about the era, the following is an historical fictional account of Rodger's saga. PMID- 28670096 TI - Facts and ideas from anywhere. PMID- 28670097 TI - Word-to-text integration: ERP evidence for semantic and orthographic effects in Chinese. AB - Although writing systems affect reading at the level of word identification, one expects writing system to have minimal effects on comprehension processes. We tested this assumption by recording ERPs while native Chinese speakers read short texts for comprehension in the word-to-text integration (WTI) paradigm to compare with studies of English using this paradigm. Of interest was the ERP on a 2 character word that began the second sentence of the text, with the first sentence varied to manipulate co-reference with the critical word in the second sentence. A paraphrase condition in which the critical word meaning was coreferential with a word in the first sentence showed a reduced N400 reduction. Consistent with results in English, this N400 effect suggests immediate integration of a Chinese 2-character word with the meaning of the text. Chinese allows an additional test of a morpheme effect when one character of a two character word is repeated across the sentence boundary, thus having both orthographic and meaning overlap. This shared morpheme condition showed no effect during the timeframe when orthographic effects are observed (e.g. N200), nor did it show an N400 effect. However, character repetition did produce an N400 reduction on parietal sites regardless it represented the same morpheme or a different one. The results indicate that the WTI integration effect is general across writing systems at the meaning level, but that the orthographic form nonetheless has an effect, and is specifically functional in Chinese reading. PMID- 28670099 TI - Neuropharmacologic Approaches to Cognitive Rehabilitation. PMID- 28670098 TI - A Multifunctional Nanocrystalline CaF2:Tm,Yb@mSiO2 System for Dual-Triggered and Optically Monitored Doxorubicin Delivery. AB - Daunting challenges in investigating the controlled release of drugs in complicated intracellular microenvironments demand the development of stimuli responsive drug delivery systems. Here, a nanoparticle system, CaF2:Tm,Yb@mSiO2, made of a mesoporous silica (mSiO2) nanosphere with CaF2:Tm,Yb upconversion nanoparticles (UCNPs) is developed, filling its mesopores and with its surface modified with polyacrylic acid for binding the anticancer drug molecules (doxorubicin, DOX). The unique design of CaF2:Tm,Yb@mSiO2 enables us to trigger the drug release by two mechanisms. One is the pH-triggered mechanism, where drug molecules are preferentially released from the nanoparticles at acidic conditions unique for the intracellular environment of cancer cells compared to normal cells. Another is the 808 nm near infrared (NIR)-triggered mechanism, where 808 nm NIR induces the heating of the nanoparticles to weaken the electrostatic interaction between drug molecules and nanoparticles. In addition, luminescence resonance energy transfer occurs from the UCNPs (the energy donor) to the DOX drug (the energy acceptor) in the presence of 980 nm NIR irradiation, allowing us to monitor the drug release by detecting the vanishing blue emission from the UCNPs. This study demonstrates a new multifunctional nanosystem for dual triggered and optically monitored drug delivery, which will facilitate the rational design of personalized cancer therapy. PMID- 28670100 TI - The assets-based approach: furthering a neoliberal agenda or rediscovering the old public health? A critical examination of practitioner discourses. AB - The 'assets-based approach' to health and well-being has, on the one hand, been presented as a potentially empowering means to address the social determinants of health while, on the other, been criticised for obscuring structural drivers of inequality and encouraging individualisation and marketisation; in essence, for being a tool of neoliberalism. This study looks at how this apparent contestation plays out in practice through a critical realist-inspired examination of practitioner discourses, specifically of those working within communities to address social vulnerabilities that we know impact upon health. The study finds that practitioners interact with the assets-based policy discourse in interesting ways. Rather than unwitting tools of neoliberalism, they considered their work to be about mitigating the worst effects of poverty and social vulnerability in ways that enhance collectivism and solidarity, concepts that neoliberalism arguably seeks to disrupt. Furthermore, rather than a different, innovative, way of working, they consider the assets-based approach to simply be a re-labelling of what they have been doing anyway, for as long as they can remember. So, for practitioners, rather than a 'new' approach to public health, the assets-based public health movement seems to be a return to recognising and appreciating the role of community within public health policy and practice; ideals that predate neoliberalism by quite some considerable time. PMID- 28670101 TI - Temperament, Parenting, and Moral Development: Specificity of Behavior and Context. AB - This longitudinal study highlights the role of specific parenting behaviors in specific contexts when predicting moral development in children of varying temperament types. A sample of mother-child dyads took part in a competing demands task involving differing "do" and "don't" contextual demands when the child was 2 years of age. Child temperament was also assessed at this time, yielding inhibited, exuberant, and low-reactive temperament groups. Children's moral behavior was assessed at 5.5 years of age. Models examining the interaction of temperament and mother behaviors in each context indicated that mother's reasoning/explanation and ignoring in the "do" context predicted later moral behavior in inhibited children, whereas redirection and commands in the "don't" context predicted moral behavior in exuberant children. PMID- 28670102 TI - Agreement Among Traditional and RTI-based Definitions of Reading-Related Learning Disability with Preschool Children. AB - To investigate approaches for identifying young children who may be at risk for later reading-related learning disabilities, this study compared the use of four contemporary methods of indexing learning disability (LD) with older children (i.e., IQ-achievement discrepancy, low achievement, low growth, and dual discrepancy) to determine risk status with a large sample of 1,011 preschoolers. These children were classified as at risk or not using each method across three early-literacy skills (i.e., language, phonological awareness, print knowledge) and at three levels of severity (i.e., 5th, 10th, 25th percentiles). Chance corrected affected-status agreement (CCASA) indicated poor agreement among methods with rates of agreement generally decreasing with greater levels of severity for both single- and two-measure classification, and agreement rates were lower for two-measure classification than for single-measure classification. These low rates of agreement between conventional methods of identifying children at risk for LD represent a significant impediment for identification and intervention for young children considered at-risk. PMID- 28670103 TI - Computerized Instruction in Translation Strategies for Students in Upper Elementary and Middle School Grades With Persisting Learning Disabilities in Written Language. AB - Students in grades 5 to 9 (ages 10 to 14; 6 girls, 27 boys) who had persisting specific learning disabilities in transcription (handwriting and spelling) completed three kinds of composition tasks requiring translation (thought to written language) on iPads using alternating transcription modes (stylus or keyboard) across every three lessons: personal narratives (6 lessons) and written summaries about read source material (integrated reading-writing) and heard source material (integrated listening-writing) (12 lessons). Before composing summaries, students clicked sequentially one at a time onto translation strategies, which they read and heard through earphones, and could click on again as needed during summary writing: (a) Level I composing of the very next sentence, and (b) Level II composing of a higher-level discourse structure. ANOVAs showed that Level I strategies were used significantly more often than Level II strategies; but the main effect for transcription mode was not significant. Written summaries of read source material had more errors in main ideas and factual details than heard source materials, but not more irrelevant statements. Applications of results are discussed for using computers for writing instruction, not just accommodations, for students with persisting transcription disabilities. PMID- 28670104 TI - Self-consistent gradient flow for shape optimization. AB - We present a model for image segmentation and describe a gradient-descent method for level-set based shape optimization. It is commonly known that gradient descent methods converge slowly due to zig-zag movement. This can also be observed for our problem, especially when sharp edges are present in the image. We interpret this in our specific context to gain a better understanding of the involved difficulties. One way to overcome slow convergence is the use of second order methods. For our situation, they require derivatives of the potentially noisy image data and are thus undesirable. Hence, we propose a new method that can be interpreted as a self-consistent gradient flow and does not need any derivatives of the image data. It works very well in practice and leads to a far more efficient optimization algorithm. A related idea can also be used to describe the mean-curvature flow of a mean-convex surface. For this, we formulate a mean-curvature Eikonal equation, which allows a numerical propagation of the mean-curvature flow of a surface without explicit time stepping. PMID- 28670105 TI - Selection of internal wave beam directions by a geometric constraint provided by topography. AB - Direct numerical simulations are performed to investigate the generation of internal waves in a linearly stratified fluid by oscillating barotropic flows over a model continental shelf-slope topography. The presence of a third wave beam emitted from an abrupt shelf break and transverse to the topography, which has not been adequately interpreted, is now explained in terms of a geometric constraint provided by the topography. This explanation applies to wave beam selection at any abrupt topographic junction point, no matter whether it is convex or concave, or its nearby slope is subcritical or supercritical. One exception is that, at an abrupt concave point with a nearby supercritical slope, the blocking effect leads to the presence of "dead water" (i.e., no flow) and thus no wave beam is emitted. On a critical slope, two beams with opposite directions are emitted from an amphidromic point that has a distinct distance from the shelf break. In addition to the internal wave dispersion relation that restricts possible wave beam directions to form an X-pattern, the geometric constraint proposed in the present work serves as a second selection mechanism that further restricts wave beam directions. The reflective direction of a wave beam incident onto a slope can also be explained by this geometric constraint. The present work provides an updated explanation of internal wave beams emitted at abrupt topographic junction points and unifies the explanation of the wave beam direction for both wave generation and reflection processes. PMID- 28670106 TI - Predicting the refractive outcome and accuracy of IOL power calculation after phacoemulsification using the SRK/T formula with ultrasound biometry in medium axial lengths. AB - PURPOSE: To evaluate the accuracy of the SRK/T formula using ultrasound (US) biometry in predicting a target postoperative refraction of +/-1.00D in eyes with medium axial length (AL) that underwent phacoemulsification. METHODS: The present study was a retrospective analysis, which included 538 eyes with an AL from 22.0 to 24.60 mm that underwent phacoemulsification and foldable intraocular lens (IOL) implantation (six different IOLs) in the bag. Preoperative AL was measured by US biometry and IOL power (IOLp) was calculated with the SRK/T formula. Patients had a complete ophthalmic examination, preoperatively and 1, 7, and 30 days after surgery. The achieved spherical equivalent (SE) and the prediction error (PE) were calculated. The prediction error was defined as the difference between attempted predicted target refraction and the achieved postoperative SE refraction. Statistical analysis was performed with SPSS V21. RESULTS: The mean age of the patients was 66.96+/-9.67 years, the mean AL was 23.29+/-0.62 mm, the mean K1 was 43.62+/-1.49D, the mean K2 was 43.69+/-1.53D, the mean IOL power was 21.066+/-1.464D, the mean attempted (predicted) SE was -0.178+/-0.266D, and the mean achieved SE was -0.252+/-0.562D. The mean PE (difference between predicted and achieved SE) showed a relatively hyperopic shift (mean +/- standard deviation: 0.074+/-0.542D, ranging from -1.855 to 2.170D, P=0.001). A total of 93.87% of eyes were within +/-1.00D of the PE and 92.75% of eyes within +/-1.00D of achieved postoperative refraction. A total of 39 eyes (7.25%) had a refractive surprise. A total of 32 of 39 eyes were more myopic than -1.00D and 7 of them were more hypermetropic than +1.00D. There was no correlation between the mean PE and IOL type, AL, K1, K2, and IOLp. There were a positive statistically significant correlation between PE and age (r=0.095; P=0.028) and a negative statistically significant correlation between achieved SE and AL (Spearman's r= 0.125; P=0.04), and age (r=-0.141; P=0.01). CONCLUSION: The IOLp calculation using the SRK/T formula with US biometry may demonstrate very good postoperative refractive outcomes in medium eyes with a few refractive surprises. PMID- 28670107 TI - Uveitis incidence in Jichi Medical University Hospital, Japan, during 2011-2015. AB - PURPOSE: To investigate uveitis incidence of new patients who visited Jichi Medical University Hospital, Tochigi, north of Tokyo, during 2011-2015, and to compare the results with previously reported data from other facilities. METHODS: We retrospectively analyzed clinical records of new patients with uveitis from April 2011 to March 2015 and compared the uveitis incidence with those from other hospitals. RESULTS: A total of 502 patients were enrolled in the study; definite diagnoses were made in 262 patients (52.2%). The top 4 diseases were sarcoidosis, 47 patients (9.4%); Vogt-Koyanagi-Harada (VKH) disease, 35 patients (7.0%); herpetic iritis, 29 patients (5.8%); and Behcet's disease, 21 patients (4.2%). CONCLUSION: The most commonly diagnosed diseases in our study were sarcoidosis, VKH disease, herpetic iritis, and Behcet's disease. Compared with the latest nationwide survey in Japan, our results showed similar trends. PMID- 28670108 TI - Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials. AB - An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59-0.87; P=<0.0001]) using a 5-point scale to assess [18F] labeled fluorodeoxyglucose metabolic activity in lymphomatous lesions. These results suggest an operationally practical 5-point scale workflow paradigm for potential use in larger clinical trials evaluating lymphoma therapeutics. PMID- 28670109 TI - Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic. AB - Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9-10.1 fold in mice skin and by 1.6-47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration. PMID- 28670110 TI - Cryptotanshinone induces cell cycle arrest and apoptosis through the JAK2/STAT3 and PI3K/Akt/NFkappaB pathways in cholangiocarcinoma cells. AB - BACKGROUND: Cholangiocarcinoma (CCA) is the most common biliary tract malignancy in the world with high resistance to current chemotherapies and extremely poor prognosis. The main objective of this study was to investigate the inhibitory effects of cryptotanshinone (CTS), a natural compound isolated from Salvia miltiorrhiza Bunge, on CCA both in vitro and in vivo and to explore the underlying mechanisms of CTS-induced apoptosis and cell cycle arrest. METHODS: The anti-tumor activity of CTS on HCCC-9810 and RBE cells was assessed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and colony forming assays. Cell cycle changes were detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and Hoechst 33342 staining assays. The efficacy of CTS in vivo was evaluated using a HCCC 9810 xenograft model in athymic nude mice. The expression of key proteins involved in cell apoptosis and signaling pathway in vitro was analyzed by Western blot analysis. RESULTS: CTS induced potent growth inhibition, S-phase arrest, apoptosis, and colony-forming inhibition in HCCC-9810 and RBE cells in a dose dependent manner. Intraperitoneal injection of CTS (0, 10, or 25 mg/kg) for 4 weeks significantly inhibited the growth of HCCC-9810 xenografts in athymic nude mice. CTS treatment induced S-phase arrest with a decrease of cyclin A1 and an increase of cyclin D1 protein level. Bcl-2 expression was downregulated remarkably, while Bax expression was increased after apoptosis occurred. Additionally, the activation of JAK2/STAT3 and PI3K/Akt/NFkappaB was significantly inhibited in CTS-treated CCA cells. CONCLUSION: CTS induced CCA cell apoptosis by suppressing both the JAK2/STAT3 and PI3K/Akt/NFkappaB signaling pathways and altering the expression of Bcl-2/Bax family, which was regulated by these two signaling pathways. CTS may serve as a potential therapeutic agent for CCA. PMID- 28670112 TI - Morusin shows potent antitumor activity for human hepatocellular carcinoma in vitro and in vivo through apoptosis induction and angiogenesis inhibition. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive cancers with high mortality worldwide. Research and development of novel agents for HCC therapy is in demand, urgently. Morusin has been reported to exhibit potential cytotoxic activity in several cancer cell lines. However, whether it has potential antiangiogenic activity especially in HCC remains unclear. In the current study, we found that morusin exerted growth inhibition effects on human HCC cells (HepG2 and Hep3B) in vitro and human HCC cell (HepG2) xenografts in vivo. Moreover, apoptosis induction was observed in a dose-dependent manner after morusin treatment along with an increase in the expression of active caspase-3 and the Bax/Bcl-2 expression ratio. More importantly, morusin inhibited proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and downregulated angiogenic proteins in HCC cells and HUVECs. In vivo, tumor angiogenesis was also attenuated after morusin treatment. In addition, morusin suppressed constitutive as well as IL-6-induced STAT3 phosphorylation in HCC cells and corresponding tumor tissues. Overall, morusin has a potential anticancer effect on human HCC cells in vitro and in vivo by inducing apoptosis and inhibiting anti-angiogenesis. The corresponding mechanism might be associated with the attenuation of the IL-6/STAT3 signaling pathway. Morusin might serve as a promising novel anticancer agent in HCC therapy, and requires further study. PMID- 28670113 TI - Long-term natalizumab treatment is associated with sustained improvements in quality of life in patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) patients experience lower health-related quality of life (HRQoL) than the general population. In clinical trials, natalizumab significantly improved HRQoL and reduced relapse rates and disability progression in patients with relapsing MS. In a 1-year analysis of patients included in the current study, HRQoL improvement occurred within 3 months of natalizumab initiation and continued for 1 year thereafter. However, natalizumab's long-term efficacy in improving HRQoL has not been studied. METHODS: In this longitudinal, observational, single-arm US study, HRQoL and treatment satisfaction were evaluated in MS patients receiving intravenous natalizumab 300 mg every 4 weeks in clinical settings. Patients completed surveys at baseline and every 6 months for 3 years and reported the following measures: Short Form-12 Version 2 (SF-12v2), Multiple Sclerosis Impact Scale (MSIS-29), and Treatment Satisfaction Questionnaire for Medication. RESULTS: In this study, 120 patients completed >=3 years of natalizumab treatment. Significant HRQoL improvements were evident from baseline to year 3 by increases in SF-12v2 Physical Component Summary (PCS) and Mental Component Summary scores (P<0.01) and decreases in MSIS-29 physical and psychological scores (P<0.0001). Patients with less physical disability (baseline Disease Steps [DS] 0-2) had significant improvement from baseline to year 3 in SF-12v2 PCS (P<0.05) and MSIS-29 physical scores (P<0.05). Physical HRQoL outcomes in patients with baseline DS 3-6 remained stable over 3 years. Treatment satisfaction increased significantly from baseline to year 1 (P<0.0001) and was maintained in the following 2 years. CONCLUSION: Patients reported physical and psychological HRQoL improvements over 3 years of natalizumab treatment, supporting the long-term efficacy of natalizumab in real-world settings. Lower baseline disease activity and earlier treatment were related to better outcomes, indicating the importance of starting natalizumab early in the disease course. Treatment satisfaction increased after natalizumab initiation and remained high over 3 years of treatment. PMID- 28670111 TI - Historical development of vaginal microbicides to prevent sexual transmission of HIV in women: from past failures to future hopes. AB - Infection with human immunodeficiency virus (HIV) remains a global public health concern and is particularly serious in low- and middle-income countries. Widespread sexual violence and poverty, among other factors, increase the risk of infection in women, while currently available prevention methods are outside the control of most. This has driven the study of vaginal microbicides to prevent sexual transmission of HIV from men to women in recent decades. The first microbicides evaluated were formulated as gels for daily use and contained different substances such as surfactants, acidifiers and monoclonal antibodies, which failed to demonstrate efficacy in clinical trials. A gel containing the reverse transcriptase inhibitor tenofovir showed protective efficacy in women. However, the lack of adherence by patients led to the search for dosage forms capable of releasing the active principle for longer periods, and hence to the emergence of the vaginal ring loaded with dapivirine, which requires a monthly application and is able to reduce the sexual transmission of HIV. The future of vaginal microbicides will feature the use of alternative dosage forms, nanosystems for drug release and probiotics, which have emerged as potential microbicides but are still in the early stages of development. Protecting women with vaginal microbicide formulations would, therefore, be a valuable tool for avoiding sexual transmission of HIV. PMID- 28670114 TI - Resistance training for activity limitations in older adults with skeletal muscle function deficits: a systematic review. AB - Human aging results in a variety of changes to skeletal muscle. Sarcopenia is the age-associated loss of muscle mass and is one of the main contributors to musculoskeletal impairments in the elderly. Previous research has demonstrated that resistance training can attenuate skeletal muscle function deficits in older adults, however few articles have focused on the effects of resistance training on functional mobility. The purpose of this systematic review was to 1) present the current state of literature regarding the effects of resistance training on functional mobility outcomes for older adults with skeletal muscle function deficits and 2) provide clinicians with practical guidelines that can be used with seniors during resistance training, or to encourage exercise. We set forth evidence that resistance training can attenuate age-related changes in functional mobility, including improvements in gait speed, static and dynamic balance, and fall risk reduction. Older adults should be encouraged to participate in progressive resistance training activities, and should be admonished to move along a continuum of exercise from immobility, toward the recommended daily amounts of activity. PMID- 28670115 TI - The influence of the serotonergic system on the personality and quality of life of postmenopausal women. AB - The aim of this study was to establish the relationship between personality traits of postmenopausal women and the presence of the 44-bp VNTR polymorphism in the serotonin transporter (5-HTT) (SLC6A4) promoter region and the 30-bp VNTR polymorphism in the MAO-A promoter region. The study's aim was also to determine the influence of personality traits on the quality of postmenopausal women's lives. The study involved 214 postmenopausal women from northwest Poland, with an average age of 56.8+/-4.08 years. It was performed using the Temperament and Character Inventory-Revised and the Short Form Health Survey. DNA polymorphisms were identified by means of polymerase chain reaction. Analysis demonstrated that the s/s genotype was significantly more common than the l/l genotype in women with higher fear of uncertainty. In a group with higher enlightened second nature and empathy, the l/s genotype was considerably more common than the l/l genotype. There were statistically significant associations between selected aspects of quality of life and personality traits such as enlightened second nature, transpersonal identification, purposefulness, and self-transcendence. The s/s genotype of the 44-bp VNTR polymorphism in the 5-HTT (SLC6A4) promoter region may increase the tendency to avoid harm within the fear of uncertainty dimension. Carriers of this genotype may have predisposition to anxiety and depressive disorders. The l/s genotype of the 44-bp VNTR polymorphism in the 5-HTT (SLC6A4) promoter region contributes to increased expression of enlightened second nature and empathy. Some personality traits may influence the quality of women's lives. PMID- 28670116 TI - Treatment trends in patients with asthma-COPD overlap syndrome in a COPD cohort: findings from a real-world survey. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is an increasingly recognized phenotype. Few randomized clinical trials have been conducted in patients with ACOS; therefore, scientific evidence concerning ACOS is scarce and a therapeutic approach remains unclear. The aim of this study was to evaluate current treatment trends for patients with ACOS, identified as those with a dual definition of asthma and COPD, in a real-world COPD cohort. METHODS: Data were analyzed from patients with asthma and COPD in the USA, France, Germany, Italy, Spain, and the UK who participated in the 2012 and 2013 Adelphi Respiratory Disease Specific Programmes (DSPs). Patients with ACOS were identified in the COPD population; these patients had a physician confirmed, concomitant asthma diagnosis. Physicians completed a patient record form providing information on patient and disease characteristics including prescribed respiratory treatment. Pairwise comparisons were made between the ACOS, asthma, and COPD populations using chi2 tests. RESULTS: In total, 9,042 patients with asthma-only, 7,119 patients with COPD-only, and 523 patients with ACOS (a dual diagnosis of asthma and COPD) participated in the study. The most commonly prescribed regimens were inhaled corticosteroid/long-acting beta2 agonist (ICS/LABA) + long-acting muscarinic antagonist (LAMA); (ACOS 30%, asthma 1.4%, and COPD 32%), ICS/LABA (19%, 41.5%, and 17%, respectively), and LAMA (6%, 0.4%, and 19%, respectively); 18% of patients with ACOS were not prescribed an ICS. Patients with ACOS had a significantly higher incidence of gastroesophageal reflux disease, diabetes, and obesity and experienced more exacerbations in the past year than those with COPD or asthma. CONCLUSIONS: The majority of patients with ACOS, as defined in this research, were prescribed similar treatment to those with COPD. There is a need, however, for better treatment for patients with ACOS, as indicated by symptoms and exacerbation levels. A clearer therapeutic approach for patients with ACOS is required. PMID- 28670117 TI - Dietary beetroot juice - effects on physical performance in COPD patients: a randomized controlled crossover trial. AB - BACKGROUND AND OBJECTIVE: Dietary beetroot juice (BR) supplementation has been shown to reduce the oxygen (O2) consumption of standardized exercise and reduce resting blood pressure (BP) in healthy individuals. However, the physiological response of BR in chronic obstructive pulmonary disease (COPD) remains controversial. The objective was to test exercise performance in COPD, supplementing with higher doses of BR for a longer duration compared to previous trials in this patient group. METHODS: Fifteen COPD patients consumed concentrated BR (2*70 mL twice daily, each containing 300 mg nitrate) or placebo (PL) (2*70 mL twice daily, nitrate-negligible) in a randomized order for 6 consecutive days. On day 7, participants consumed either BR or PL 150 min before testing. BP was measured before completing 6-minute walk test (6MWT) and two trials of submaximal cycling. The protocol was repeated after a minimum washout of 7 days. RESULTS: Plasma nitrite concentration was higher in the BR condition compared to PL (P<0.01). There was no difference between the BR and PL conditions regarding the covered distance during the 6MWT (mean +/- standard error of the mean: 515+/-35 m (BR) vs 520+/-38 m (PL), P=0.46), O2 consumption of submaximal exercise (trial 1 P=0.31 vs trial 2 P=0.20), physical activity level (P>0.05), or systolic BP (P=0.80). However, diastolic BP (DBP) was reduced after BR ingestion compared to baseline (mean difference: 4.6, 95% CI: 0.1-9.1, P<0.05). CONCLUSION: Seven days of BR ingestion increased plasma nitrite concentrations and lowered DBP in COPD patients. However, BR did not increase functional walking capacity, O2 consumption during submaximal cycling, or physical activity level during the intervention period. PMID- 28670118 TI - Species-specific identification of collagen components in Colla corii asini using a nano-liquid chromatography tandem mass spectrometry proteomics approach. AB - Colla corii asini (CCA) is a protein-based traditional Chinese medicine made from donkey skins. Because it has the ability to nourish blood, its demand is increasing rapidly. The shortage of donkey skins increases the risk of the adulteration of CCA products with other animal skins. To ensure the drug efficacy and safety of CCA products, a proteomics technique was applied to reveal proteins in the skins of donkey, horse, cattle, and pig. Species-specific peptides for each animal species were predicted using bioinformatics, and their presence in the skins and gelatin samples was examined by nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS). One unique marker peptide for each animal species was selected to develop an LC-MS/MS multiple reaction monitoring method. The capability of this method to identify donkey, horse, cattle, and pig materials was demonstrated by analyzing in-house-made donkey gelatins containing different amounts of other animal skins and commercial CCA products. The adulteration of non-donkey species could be sensitively detected at a low level of 0.5%. Hybrid animals, such as mules and hinnies, were also differentiated from donkeys. We provide a practical tool for the quality control of CCA products. The strategy can also be used to study other important traditional Chinese medicines which contain animal proteins. PMID- 28670120 TI - Near-infrared light-triggered theranostics for tumor-specific enhanced multimodal imaging and photothermal therapy. AB - The major challenge in current clinic contrast agents (CAs) and chemotherapy is the poor tumor selectivity and response. Based on the self-quench property of IR820 at high concentrations, and different contrast effect ability of Gd-DOTA between inner and outer of liposome, we developed "bomb-like" light-triggered CAs (LTCAs) for enhanced CT/MRI/FI multimodal imaging, which can improve the signal to-noise ratio of tumor tissue specifically. IR820, Iohexol and Gd-chelates were firstly encapsulated into the thermal-sensitive nanocarrier with a high concentration. This will result in protection and fluorescence quenching. Then, the release of CAs was triggered by near-infrared (NIR) light laser irradiation, which will lead to fluorescence and MRI activation and enable imaging of inflammation. In vitro and in vivo experiments demonstrated that LTCAs with 808 nm laser irradiation have shorter T1 relaxation time in MRI and stronger intensity in FI compared to those without irradiation. Additionally, due to the high photothermal conversion efficiency of IR820, the injection of LTCAs was demonstrated to completely inhibit C6 tumor growth in nude mice up to 17 days after NIR laser irradiation. The results indicate that the LTCAs can serve as a promising platform for NIR-activated multimodal imaging and photothermal therapy. PMID- 28670121 TI - Relapse and hospitalization in patients with schizophrenia and bipolar disorder at the St Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia: a comparative quantitative cross-sectional study. AB - BACKGROUND: Relapse and hospital admission are common among, and carry a heavy burden in, patients with schizophrenia and bipolar disorder. The aim of this study was to assess the risk of relapse and hospitalizations in patients with schizophrenia and bipolar disorder at the St Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia. PATIENTS AND METHODS: A hospital-based comparative cross sectional study was conducted in June 2016. Systematic random sampling technique was used to recruit 521 (260 schizophrenia cases and 261 bipolar disorder cases) study participants. Face-to-face interviews were conducted by trained psychiatry professionals. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria and Structured Clinical Interview of DSM-IV (SCID) were used. RESULTS: The risk of relapse and hospitalizations was slightly higher in patients with bipolar disorder than in patients with schizophrenia. A majority of schizophrenic (213 [81.92%]) and bipolar (215 [82.37%]) patients had a history of hospital admission, and 228 (87.69%) schizophrenic and 230 (88.12%) bipolar patients had a history of relapse. Patients who had a history of hospitalizations also had co-occurring substance use disorders compared to those who had no history of hospitalizations for schizophrenia (81.5% vs 37.9%) and bipolar disorder (82.56% vs 38.2%), respectively. Similarly, those patients who had a history of relapse had high comorbid substance use disorders than those who had no history of relapse for both schizophrenia (87.88% vs 47.37%) and bipolar disorder (88.37% vs 47.19%), respectively. CONCLUSION: It is vital that, in the local context, mental health professionals strengthen their therapeutic relationships with patients and their caregivers. This might enable patients and their caregivers to express their needs and concerns to them, as well as help to plan proper interventions for patients. Attention needs to be given to screening for comorbid substance use disorders in patients with schizophrenia and bipolar disorder, especially in those who have had a history of relapse and hospitalizations. PMID- 28670119 TI - Improved LFIAs for highly sensitive detection of BNP at point-of-care. AB - Heart failure (HF) has become a major cause of morbidity and mortality with a significant global economic burden. Although well-established clinical tests could provide early diagnosis, access to these tests is limited in developing countries, where a relatively higher incidence of HF is present. This has prompted an urgent need for developing a cost-effective, rapid and robust diagnostic tool for point-of-care (POC) detection of HF. Lateral flow immunoassay (LFIA) has found widespread applications in POC diagnostics. However, the low sensitivity of LFIA limits its ability to detect important HF biomarkers (e.g., brain natriuretic peptide [BNP]) that are normally present in low concentration in blood. To address this issue, we developed an improved LFIA by optimizing the gold nanoparticle (GNP)-antibody conjugate conditions (e.g., the conjugate pH and the amount of added antibody), the diameter of GNP and the concentration of antibody embedded on the test line and modifying the structure of test strip. Through these improvements, the proposed test strip enabled the detection of BNP down to 0.1 ng/mL within 10-15 min, presenting ~15-fold sensitivity enhancement over conventional lateral flow assay. We also successfully applied our LFIA in the analysis of BNP in human serum samples, highlighting its potential use for clinical assessment of HF. The developed LFIA for BNP could rapidly rule out HF with the naked eye, offering tremendous potential for POC test and personalized medicine. PMID- 28670122 TI - Burnout and compassion fatigue: prevalence and associations among Israeli burn clinicians. AB - Acute health care environments can be stressful settings with clinicians experiencing deleterious effects of burnout and compassion fatigue affecting their mental health. Subsequently, the quality of patient care and outcomes may be threatened if clinicians experience burnout or compassion fatigue. Therefore, the aim of this descriptive, cross-sectional study was to evaluate the prevalence of burnout and compassion fatigue among burn clinicians in Israel. Fifty-five clinicians from Burns, Plastics and Reconstruction Surgery and Intensive Care completed four validated surveys to assess burnout (Maslach Burnout Inventory), depression (PRIME-MD), health-related quality of life (SF-8), and compassion fatigue (Professional Quality of Life version 5). Burn clinicians were compared with Plastics and Reconstruction Surgery and Intensive Care clinicians. This study identified a high prevalence of burnout (38.2%) among Intensive Care, Plastics and Reconstruction and Burns clinicians, with Burns clinicians having a greatly increased prevalence of burnout compared to Intensive Care clinicians (OR =24.3, P=0.017). Additional factors contributing to compassion fatigue were those without children (P=0.016), divorced (P=0.035), of a younger age (P=0.019), and a registered nurse (P=0.05). Burnout increased clinicians' risk of adverse professional and personal outcomes and correlated with less free time (P<0.001), increased risk of experiencing work-home disputes (P=0.05), increased depression (P=0.001) and decreased career satisfaction (P=0.01). Burnout was also associated with higher physical (mean difference =3.8, P<0.001) and lower mental (mean difference =-3.5, P<0.001) Quality of Life scores. Caring for burn survivors can lead to burnout, compassion fatigue, and vicarious trauma. Identifying strategies to abate these issues is essential to ensure improved clinicial environments and patient outcomes. PMID- 28670123 TI - Intelligence profiles of Chinese school-aged boys with high-functioning ASD and ADHD. AB - PURPOSE: This study aimed to explore the intelligence profiles of Chinese school aged boys with high-functioning autism spectrum disorder (HFASD) and attention deficit/hyperactivity disorder (ADHD). Additionally, differences in intelligence quotient (IQ) between the HFASD group and the ADHD group were examined. PATIENTS AND METHODS: Thirty-two boys with HFASD, 58 boys with ADHD, and 39 typically developing (TD) boys aged 6-16 years participated in this study. The ADHD group was divided into subgroups: ADHD-I (predominantly inattentive) and ADHD-C (combined type). (The ADHD-H [hyperactive] group was excluded because of small sample size). The Wechsler Intelligence Scale for Children-IV Chinese version was administered to every participant, and the FSIQ (Full-Scale IQ) score was used as the measure of IQ. RESULTS: Both boys with HFASD and ADHD (ADHD-I and ADHD-C) showed impairments in Processing Speed Index and FSIQ, as compared to the TD group. Lower Verbal Comprehension Index scores were found in the ASD and ADHD-I groups. Interestingly, Working Memory Index was only impaired in children with ADHD. Additionally, equivalent Perceptual Reasoning Index (PRI) scores were found among the HFASD, ADHD, and TD groups. CONCLUSION: Results indicated that both children with ADHD and HFASD have difficulty in processing speed, which may be explained by these children having neurodevelopmental disorders. These results also indicated that working memory appears to only be impacted by having ADHD. Children with ASD are known to have language difficulties while children with ADHD typically display working memory deficits; thus, these findings were expected. PMID- 28670124 TI - De Ritis ratio (AST/ALT) as an independent predictor of poor outcome in patients with acute ischemic stroke. AB - PURPOSE: The aspartate transaminase/alanine transaminase ratio (De Ritis ratio, AAR) was reported to be associated with patients' prognosis in certain diseases recently. The objective of the current study was to determine the association between the AAR at admission and poor outcome at 3 months in acute ischemic stroke (AIS) patients. PATIENTS AND METHODS: This retrospective cohort study included patients who experienced their first-ever AIS between June 2015 and March 2016. The primary outcome measure was a poor outcome at 3 months (modified Rankin Scale score >2). Multivariate logistic regression models were used to assess the relationship between AAR quartiles and clinical outcomes among the AIS patients. Receiver operating characteristic curve analysis was applied to identify the optimal cutoff for AAR in predicting the prognosis of AIS. RESULTS: In terms of the relationship between poor outcome and AAR, the adjusted odds ratio comparing the highest and lowest AAR quartiles was 2.15 (95% confidence interval =1.14-4.05). An AAR of 1.53 was identified as the optimal cutoff. In a prespecified subgroup analysis according to the time from symptom onset to treatment (>24 vs <=24 hours), there was no significant difference in the effect of AAR >1.53 between the two groups. CONCLUSION: An increased AAR at admission is significantly associated with a poor outcome at 3 months in AIS patients. PMID- 28670125 TI - Risk factors for the existence of attention deficit hyperactivity disorder symptoms in children with autism spectrum disorders. AB - Over the years, several authors have reported symptoms of attention deficit hyperactivity disorder (ADHD) in patients with autism spectrum disorders (ASD); however, studies on the risk factors of ADHD symptoms in children with ASD are lacking. The aim of this cross-sectional study was to identify the risk factors for the development of ADHD symptoms in children with ASD. The sample consisted of 67 children with ASD who were assessed with Conner's Parent Rating Scale Revised (CPRS-R), and with a semi-structured detailed interview administered to parents, to collect a series of clinical data such as coexisting somatic and neuropsychiatric problems and familial and pre/peri/postpartum risk factors. We found that 55% of ASD children exceeded the cut-off of CPRS-R Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), total scale. The univariate analyses showed that children's age (P=0.048), motor delay (P=0.039), enuresis (P=0.014), allergies (P<0.01), comorbid oppositional defiant disorder (P=0.026) and intellectual disabilities comorbidities (P=0.034) were associated to the CPRS-R DSM-IV total score. Some familial predictors such as neuropsychiatric family history of intellectual disabilities (P=0.003) and psychosis (P=0.039) were related to the CPRS-R DSM-IV total score. In particular, a model including allergies (P=0.000) and family history of psychosis (P=0.03) explained 25% (corrected R2=0.25) of the variance of the DSM-IV ADHD score. In conclusion, we identified some risk factors associated with the development of ADHD symptoms in ASD children that need to be studied further. PMID- 28670126 TI - Prognostic value of restless legs syndrome in hemodialysis patients: a systematic review and meta-analysis. AB - BACKGROUND: Previous studies have revealed that restless legs syndrome (RLS) not only is frequently prevalent in dialysis patients but also increases the risk of death in dialysis patients, especially in hemodialysis (HD) patients. However, inconsistent results also still exist, having attracted confusion and discussion. Owing to mixed and inconclusive results, we conducted to perform the comprehensive meta-analysis to evaluate the potential prognostic value of RLS in HD patients. MATERIALS AND METHODS: We conducted a systematic literature search using electronic databases (PubMed, Ovid, Embase and Web of Science) to identify relevant studies reporting on all-cause mortality and cardiovascular (CV) events in HD patients suffering from RLS. We searched the literature published up to December 5, 2016, or earlier. We used both fixed- and random-effects models to calculate the overall effect estimate. An I2>50% indicates at least moderate statistical heterogeneity. A sensitivity analysis and subgroup analysis were performed to find the origin of heterogeneity. RESULTS: A total of four studies including 1,839 patients found that there was no significant association between RLS and all-cause mortality (hazard ratio [HR]: 1.649; 95% confidence interval [CI]: 0.778-3.496) and CV events (HR: 0.863; 95% CI: 0.600-1.127) in HD patients. Heterogeneity among the studies was observed for all-cause mortality (I2=80.7%, P=0.001). CONCLUSION: Our meta-analysis suggests that there was no significant effect of RLS on all-cause mortality and CV events in HD patients. Therefore, large-scale and well-designed studies are needed to validate the association between RLS and the risk of death in HD patients. PMID- 28670127 TI - Suicide and Lyme and associated diseases. AB - PURPOSE: The aim of this paper is to investigate the association between suicide and Lyme and associated diseases (LAD). No journal article has previously performed a comprehensive assessment of this subject. INTRODUCTION: Multiple case reports and other references demonstrate a causal association between suicidal risk and LAD. Suicide risk is greater in outdoor workers and veterans, both with greater LAD exposure. Multiple studies demonstrate many infections and the associated proinflammatory cytokines, inflammatory-mediated metabolic changes, and quinolinic acid and glutamate changes alter neural circuits which increase suicidality. A similar pathophysiology occurs in LAD. METHOD: A retrospective chart review and epidemiological calculations were performed. RESULTS: LAD contributed to suicidality, and sometimes homicidality, in individuals who were not suicidal before infection. A higher level of risk to self and others is associated with multiple symptoms developing after acquiring LAD, in particular, explosive anger, intrusive images, sudden mood swings, paranoia, dissociative episodes, hallucinations, disinhibition, panic disorder, rapid cycling bipolar, depersonalization, social anxiety disorder, substance abuse, hypervigilance, generalized anxiety disorder, genital-urinary symptoms, chronic pain, anhedonia, depression, low frustration tolerance, and posttraumatic stress disorder. Negative attitudes about LAD from family, friends, doctors, and the health care system may also contribute to suicide risk. By indirect calculations, it is estimated there are possibly over 1,200 LAD suicides in the US per year. CONCLUSION: Suicidality seen in LAD contributes to causing a significant number of previously unexplained suicides and is associated with immune-mediated and metabolic changes resulting in psychiatric and other symptoms which are possibly intensified by negative attitudes about LAD from others. Some LAD suicides are associated with being overwhelmed by multiple debilitating symptoms, and others are impulsive, bizarre, and unpredictable. Greater understanding and a direct method of acquiring LAD suicide statistics is needed. It is suggested that medical examiners, the Centers for Disease Control and Prevention, and other epidemiological organizations proactively evaluate the association between LAD and suicide. PMID- 28670128 TI - Clinical features of limbic encephalitis with LGI1 antibody. AB - OBJECTIVE: The objective of this study was to analyze the clinical manifestation, course, evolution, image manifestation, and treatments of LGI1 limbic encephalitis (LE). PATIENTS AND METHODS: Studies confirmed that LE with the complex antibody of voltage-gated potassium channels is LGI1 LE. Since then, LE cases have been reported. In this study, 10 typical LE cases were searched in PubMed. These cases and one additional case, which we reported herein, were retrospectively analyzed. RESULTS: All the patients suffered from recent memory deterioration. The following cases were observed: eight with faciobrachial dystonic seizures (FBDS), six with different kinds of epileptic seizures (four complex partial seizures, one myoclonus seizure, and one generalized tonic-clonic seizure), four with FBDS and different kinds of epileptic seizures at the same time, five with mental disorders (one visual hallucination, one paranoia, one depression, one anxiety, and one dysphoria), five with hyponatremia, and two with sleep disorder. The brain MRI of nine patients revealed abnormalities in the mediotemporal lobe and the hippocampus. The LGI1 antibodies in the blood and/or cerebrospinal fluid (CSF) were positive. The content of the CSF protein of two patients increased slightly. The tumor marker of all the patients was normal, but capitate myxoma was detected in the combined pancreas duct of one patient. Gamma globulin and hormone treatments were administered to nine patients. Of these patients, six received a combination of antiepileptic drugs. The clinical symptoms of all the patients improved. CONCLUSION: LGI1 LE is an autoimmune encephalitis whose clinical manifestations are memory deterioration, FBDS, epileptic seizure, mental disorders, and hyponatremia. Brain MRI shows that this autoimmune disease mainly involves the mediotemporal lobe and the hippocampus. This condition can also be manifested with other autoimmune encephalitis cases but can be rarely associated with tumors. After patients with LGI1 LE receive gamma globulin and hormone treatments, their clinical prognosis is good. PMID- 28670129 TI - Stress reactivity and emotion in premenstrual syndrome. AB - BACKGROUND: Hormone level fluctuation across the menstrual cycle causes women to experience negative emotions and also affects their mood regulation and stress sensitivity. However, the stress reactivity and emotional variations in women with premenstrual syndrome (PMS), who are especially sensitive to the variations in hormone cycles, have not been explained. METHODS: The present study used an electroencephalogram (EEG) stress evaluation test, a physiology stress evaluation test, and the positive affect and negative affect scale (PANAS) to evaluate the stress reactivity pattern and emotional state of women with PMS. RESULTS: The results showed that women with PMS had higher negative affect and lower positive affect compared with controls. Moreover, under stressful conditions, the women with PMS had a higher alpha activity and a lower respiration rate than the controls. The differences in stress reactivity and emotional states between women with PMS and controls were based on a covariant analysis with menstrual cycle (luteal and follicular phases) as the covariate. CONCLUSION: The results demonstrated that, compared with controls, women suffering from PMS have a continuous abnormality in emotional state and stress reactivity, which was independent of the menstrual cycle. PMID- 28670131 TI - Erratum: Comparison of the acute-phase response after laparoscopic versus open aortobifemoral bypass surgery: a substudy of a randomized controlled trial [Erratum]. AB - [This corrects the article on p. 371 in vol. 12, PMID: 27713633.]. PMID- 28670130 TI - Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations. AB - Metachromatic leukodystrophy (MLD) disorder is a rare lysosomal storage disorder that leads to severe neurological symptoms and an early death. MLD occurs due to the deficiency of enzyme arylsulfatase A (ARSA) in leukocytes, and patients with MLD excrete sulfatide in their urine. In this study, the ARSA gene in 12 non consanguineous MLD patients and 40 healthy individuals was examined using polymerase chain reaction sequencing. Furthermore, the structural and functional effects of new mutations on ARSA were analyzed using SIFT (sorting intolerant from tolerant), I-Mutant 2, and PolyPhen bioinformatics software. Here, 4 new pathogenic homozygous mutations c.585G>T, c.661T>A, c.849C>G, and c.911A>G were detected. The consequence of this study has extended the genotypic spectrum of MLD patients, paving way to a more effective method for carrier detection and genetic counseling. PMID- 28670133 TI - Skin toxicity evaluation in patients treated with cetuximab for metastatic colorectal cancer: a new tool for more accurate comprehension of quality of life impacts. AB - OBJECTIVES: The effectiveness of evaluation of the severity of epidermal growth factor receptor inhibitor (EGFRI)-associated dermatological toxicities remains a topic of debate. This study was designed to assess the correlation between quality of life (QoL) and severity of dermatological toxicity, evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and our novel scale, the Eruption Scoring System (ESS), in metastatic colorectal cancer (CRC) patients treated with first-line chemotherapy combined with cetuximab. METHODS: Cutaneous toxicity was evaluated, by oncologists and dermatologists, in patients (n=30) with histologically confirmed metastatic CRC who were scheduled to begin first-line chemotherapy combined with the EGFRI, cetuximab, using the NCI-CTCAE and ESS tools. Health-related QoL (HRQoL) was evaluated using the Skindex-29 and Skindex-17 dermatology-specific instruments. Correlations between QoL and skin toxicity severity were assessed using Spearman's rank tests. Interclass correlation coefficients were used to assess interoperator agreement for ESS and NCI-CTCAE v4.0 scoring. RESULTS: A positive correlation was identified between dermatology HRQoL and the severity of dermatological toxicities assessed using the NCI-CTCAE v4.0 scale for cutaneous papulopustular acneiform rash; however, a stronger correlation was observed between HRQoL and toxicities evaluated using the ESS tool. Both NCI-CTCAE v4.0 and ESS tools demonstrated good interobserver agreement for grading of skin toxicity. CONCLUSION: There is a strong correlation between the scores generated by the ESS and NCI-CTCAE tools to grade cutaneous toxicity related to treatment with the anti-EGFR monoclonal antibody, cetuximab. ESS can be considered a valid instrument for identification and grading of the severity of skin toxicity induced by cetuximab, with some advantages over the standard NCI-CTCAE scoring system. PMID- 28670132 TI - Cost-utility analysis comparing laparoscopic vs open aortobifemoral bypass surgery. AB - OBJECTIVES: Laparoscopic aortobifemoral bypass has become an established treatment option for symptomatic aortoiliac obstructive disease at dedicated centers. Minimally invasive surgical techniques like laparoscopic surgery have often been shown to reduce expenses and increase patients' health-related quality of life. The main objective of our study was to measure quality-adjusted life years (QALYs) and costs after totally laparoscopic and open aortobifemoral bypass. PATIENTS AND METHODS: This was a within trial analysis in a larger ongoing randomized controlled prospective multicenter trial, Norwegian Laparoscopic Aortic Surgery Trial. Fifty consecutive patients suffering from symptomatic aortoiliac occlusive disease suitable for aortobifemoral bypass surgery were randomized to either totally laparoscopic (n=25) or open surgical procedure (n=25). One patient dropped out of the study before surgery. We measured health-related quality of life using the EuroQol (EQ-5D-5L) questionnaire at 4 different time points, before surgery and for 6 months during follow-up. We calculated the QALYs gained by using the area under the curve for both groups. Costs were calculated based on prices for surgical equipment, vascular prosthesis and hospital stay. RESULTS: We found a significantly higher increase in QALYs after laparoscopic vs open aortobifemoral bypass surgery, with a difference of 0.07 QALYs, (p=0.001) in favor of laparoscopic aortobifemoral bypass. The total cost of surgery, equipment and hospital stay after laparoscopic surgery (9,953 ?) was less than open surgery (17,260 ?), (p=0.001). CONCLUSION: Laparoscopic aortobifemoral bypass seems to be cost-effective compared with open surgery, due to an increase in QALYs and lower procedure-related costs. PMID- 28670134 TI - Identification of key genes and molecular mechanisms associated with dedifferentiated liposarcoma based on bioinformatic methods. AB - BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is one of the most deadly types of soft tissue sarcoma. To date, there have been few studies dedicated to elucidating the molecular mechanisms behind the disease; therefore, the molecular mechanisms behind this malignancy remain largely unknown. MATERIALS AND METHODS: Microarray profiles of 46 DDLPS samples and nine normal fat controls were extracted from Gene Expression Omnibus (GEO). Quality control for these microarray profiles was performed before analysis. Hierarchical clustering and principal component analysis were used to distinguish the general differences in gene expression between DDLPS samples and the normal fat controls. Differentially expressed genes (DEGs) were identified using the Limma package in R. Next, the enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were obtained using the online tool DAVID (http://david.abcc.ncifcrf.gov/). A protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software. Furthermore, the hub genes within the PPI network were identified. RESULTS: All 55 microarray profiles were confirmed to be of high quality. The gene expression pattern of DDLPS samples was significantly different from that of normal fat controls. In total, 700 DEGs were identified, and 83 enriched GO terms and three KEGG pathways were obtained. Specifically, within the DEGs of DDLPS samples, several pathways were identified as being significantly enriched, including the PPAR signaling pathway, cell cycle pathway, and pyruvate metabolism pathway. Furthermore, the dysregulated PPI network of DDLPS was constructed, and 14 hub genes were identified. Characteristic of DDLPS, the genes CDK4 and MDM2 were universally found to be up-regulated and amplified in gene copy number. CONCLUSION: This study used bioinformatics to comprehensively mine DDLPS microarray data in order to obtain a deeper understanding of the molecular mechanism of DDLPS. PMID- 28670135 TI - Evaluating asthma websites using the Brief DISCERN instrument. AB - PURPOSE: The primary purpose of this study was to examine the quality of sponsored and unsponsored asthma websites using the Brief DISCERN instrument and to evaluate whether the Health On the Net Code of Conduct (HONcode) logo was present, thereby indicating that the site met the criteria. The Internet is an important source of health information for patients and their families. The primary purpose of this study was to examine the quality of sponsored and unsupported asthma websites. A secondary aim was to determine the readability and reading ease of the materials for each website along with the grade level. METHODS: We queried seven Internet search engines using the keyword "asthma." The websites were evaluated using the six-item Brief DISCERN instrument and by ascertaining whether the HONcode quality label was present. The websites were also evaluated for readability employing Flesch-Kincaid grade level and Flesch reading ease tools using Microsoft Office Word 2013 software. RESULTS: A total of 22 unique websites were included in the study. Approximately 68% of the websites reviewed had a Brief DISCERN cutoff score of >=16. The overall Brief DISCERN scores ranged from 6 to 30, and the mean score was 17.32 (SD =6.71). The Flesch Kincaid grade level scores ranged from 2.9 to 15.4, and the average reading grade score was 9.49 (SD =2.7). The Flesch reading ease scores ranged from 17 to 82.7, with a mean reading ease score of 53.57 (SD =15.03). Sites with a HONcode quality label had significantly higher Brief DISCERN scores than those without one (t=2.3795; df=20; p=0.02). CONCLUSION: Brief DISCERN scores revealed that there is quality asthma information for children and their families available on the Internet. The grade level ranged between 2.9 and 15.4 among the websites. However, the mean grade level scores were 9.3-9.89, which is high for the average consumer. Access to accurate information via the Internet, with appropriate readability, may enable pediatric asthma patients and their caregivers to better control and manage asthma. PMID- 28670136 TI - Sodium-glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions. AB - OBJECTIVE: To evaluate whether adverse event reports to the US Food and Drug Administration on incidents of ketoacidosis from use of sodium glucose cotransport inhibitors (SGLT2 inhibitors) provide insight into ways this new class of drugs is being prescribed with other antihyperglycemic agents; to examine possible mechanisms to explain ketoacidosis. DESIGN AND METHODS: Reports of adverse events concerned to SGLT2 inhibitors, namely, empagliflozin, dapagliflozin, and canagliflozin were obtained under the Freedom of Information Act for 5 years ending in August 31, 2015. The data were evaluated for incidents of ketoacidosis by looking for keywords such as diabetic ketoacidosis, ketoacidosis, lactic acidosis, acidosis, and metabolic acidosis. Results were tabulated individually for empagliflozin (n=260 adverse event reports), dapagliflozin (n=520), and canagliflozin (n=2159). Adverse events were categorized according to age, gender, and insulin use. RESULTS: There were 46, 144, and 450 reports of ketoacidosis concerned with the use of empagliflozin, dapagliflozin, and canagliflozin, respectively. The use of SGLT2 inhibitors was not strictly limited to patients with type 2 diabetes but was cut across categories of insulin use, including a total of 172 cases of SGLT2-related ketoacidosis in individuals above the age of 40 who were not on insulin. CONCLUSION: Further studies should focus to detect pleiotropic effects of SGLT2 inhibitors, particularly with other oral antihyperglycemic drugs or insulin. A review of the literature suggests that patients with type 2 diabetes with low C peptide level may be at increased risk of ketoacidosis, particularly if they are on statins and diuretics due to hypokalemia and impaired release of insulin. More studies are warranted to further clarify these mechanisms. PMID- 28670137 TI - Medication adherence and its associated factors among hypertensive patients attending the Debre Tabor General Hospital, northwest Ethiopia. AB - BACKGROUND: Medication adherence is an important predictor of optimal blood pressure control; hence, it significantly reduces the risk of cardiovascular disease (CVD) and associated deaths. However, studies on medication adherence and its associated factors are scarce. Thus, this study aimed to assess adherence to antihypertensive medications and identify associated factors at Debre Tabor General Hospital, northwest Ethiopia. METHODS: A hospital-based cross-sectional study was conducted. Simple random sampling technique was used to select 346 participants. A structured questionnaire adapted from the World Health Organization (WHO) STEPwise approach was used to collect data. Medication adherence was measured by the four-item Morisky-Green-Levine Scale, with a score >=3 defined as "good adherence". Data were entered using Epi Info version 7 and exported to SPSS version 20 for analysis. Descriptive and summary statistics were used. Bivariate and multivariable analyses were also carried out. RESULTS: A total of 337 hypertensive patients participated in the study. Three-quarters (75.1%) of the participants were found to be adherent to their medication therapy. The multivariable logistic regression analysis showed that urban residence (adjusted odd ratio [AOR]=2.10, 95% confidence interval [CI]: 1.15, 3.85), taking less than two drugs per day (AOR=3.04, 95% CI: 1.53, 6.06), and having knowledge about hypertension (HTN) and its treatment (AOR=8.86, 95% CI: 4.67, 16.82) were positively and significantly associated with medication adherence, while age >60 years (AOR=0.33, 95% CI: 0.11, 0.98) was negatively and significantly associated with good medication adherence. CONCLUSION: A significant proportion of hypertensive patients poorly adhere to antihypertensive medications. Age, residence, pill burden, and knowledge about HTN and its treatment are important predictors of medication adherence. Attention should be given to increase the knowledge of patients about their disease and its treatment, and due emphasis should also be given to older and rural patients. PMID- 28670138 TI - SR-B1-targeted nanodelivery of anti-cancer agents: a promising new approach to treat triple-negative breast cancer. AB - Patients with triple-negative breast cancer (TNBC) have a considerably less favorable prognosis than those with hormone-positive breast cancers. TNBC patients do not respond to current endocrine treatment and have a 5-year survival prognosis of <30%. The research presented here is intended to fill a void toward the much needed development of improved treatment strategies for metastatic TNBC. The overall goal of this research was to evaluate the effectiveness of reconstituted high-density lipoprotein (rHDL) nanoparticles (NPs) as delivery agents for anti-TNBC drugs. Using lapatinib and valrubicin as components of the rHDL/drug complexes resulted in a significantly better performance of the NP transported drugs compared with their free (unencapsulated) counterparts. The enhancement of the therapeutic effect and the protection of normal cells (cardiomyocytes) achieved via the rHDL NPs were likely due to the overexpression of the high-density lipoprotein (HDL) (scavenger receptor class B type 1 [SR-B1]) receptor by the TNBC cells. PMID- 28670139 TI - Younger age is an independent predictor of worse prognosis among Lebanese nonmetastatic breast cancer patients: analysis of a prospective cohort. AB - BACKGROUND: Several retrospective studies have reported that younger age at presentation is associated with a worse prognosis for nonmetastatic breast cancer patients. In this study, we prospectively assessed the association between different baseline characteristics (age, tumor characteristics, mode of treatment, etc) and outcomes among newly diagnosed nonmetastatic Lebanese breast cancer patients. METHODS: We recruited a sample of 123 women newly diagnosed with nonmetastatic breast cancer presenting to American University of Beirut Medical Center. Immunohistochemical, molecular (vitamin D receptor, methylene tetrahydrofolate reductase polymorphisms), and genetic assays were performed. Patient characteristics were compared by age group (<40 and >=40 years). A Cox regression analysis was performed to evaluate the variables affecting the disease free survival (DFS). Outcome data were obtained, and DFS was estimated. RESULTS: Among the 123 patients, 47 were 40 years of age or younger, and 76 were older than 40 years. Median follow-up duration was 58 months. Nine out of 47 patients <40 years (19.1%) experienced disease relapse in contrast to four out of 76 patients >40 years (5.2%). A wide immunohistochemical panel included Ki-67, cyclin B1, p53, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor, and did not reveal any significant difference in these markers between the two age groups. Older patients had a larger percentage of Luminal A than younger patients. On multivariate analysis including age, stage, grade, and subtype, only age <40 and stage were significantly associated with shorter DFS with hazard ratios of 4 (p=0.03, 95% confidence interval [CI]: 1.1 13.5) and 3 (p=0.03, 95% CI: 0.8-14.9), respectively. The estimated 5-year DFS for patients >40 years was 90%, and for patients <40 years was 37%. CONCLUSION: Being <40 years old was an independent risk factor for recurrence in this cohort of patients. PMID- 28670140 TI - Loss of constitutive ABCB1 expression in breast cancer associated with worse prognosis. AB - ABCB1 gene encodes an adenosine 5'-triphosphate-binding cassette transporter, which not only confers multidrug resistance phenotype in malignant cells, but is also present in several nonmalignant tissues. For the last thirty years, ABCB1 expression in breast cancer has been described by many authors, but the extent of expression differs among the studies, and there is no consensus regarding its potential role in carcinogenesis or in the tumor response to antineoplastic drugs. This study aimed to characterize the expression of ABCB1 in breast tumors as a function of genetic, clinical, and histopathological variables. The ABCB1 expression was also evaluated in nonmalignant mammary tissues adjacent to tumors and in benign lesions. The detection of ABCB1 protein was performed by immunohistochemistry in tissue specimens of excised breasts obtained from a prospective cohort of Brazilian women with breast cancer. The association of ABCB1 protein levels with ABCB1 mRNA, gene polymorphisms, and clinical and histopathological variables was also evaluated. The Kaplan-Meier curves and multivariate Cox regression analyses were conducted to identify independent predictors of disease-free survival of patients with breast cancer. ABCB1 was detected in 86.3% (656) of breast tumors, 98.8% (606) of nonmalignant mammary tissue adjacent to tumors, and 100% (28) of benign lesions. Reduced ABCB1 protein levels in breast tumors was associated with triple-negative subtype (adjusted odds ratio [ORadj] =0.24; 95% confidence interval [CI] =0.13-0.45), lymph node status < pN2 (ORadj =0.27; 95% CI =0.10-0.71), tumor size >2 cm (ORadj =0.55; 95% CI =0.32-0.93), and hypertensive status (ORadj =0.42; 95% CI =0.24-0.73), and it was significantly associated with shorter disease-free survival, either for all breast cancer patients (p log-rank =0.012; hazard ratio [HR] =3.46; 95% CI =1.21 9.91) or for those with triple-negative tumors (p log-rank =0.007; HR =11.41; 95% CI =1.29-100.67). The loss of constitutive ABCB1 expression in breast cancer, especially in triple-negative tumors, seems to indicate a subgroup of worse prognosis. PMID- 28670141 TI - High glucose levels promote the proliferation of breast cancer cells through GTPases. AB - Hyperglycemia or diabetes mellitus (DM), which is characterized by high blood glucose levels, has been linked to an increased risk of cancer for years. However, the underlying molecular mechanisms of the pathophysiological link are not yet fully understood. In this study, we demonstrate that high glucose levels promote the proliferation of breast cancer cells by stimulating epidermal growth factor receptor (EGFR) activation and the Rho family GTPase Rac1 and Cdc42 mediate the corresponding signaling induced by high glucose levels. We further show that Cdc42 promotes EGFR phosphorylation by blocking EGFR degradation, which may be mediated by the Cbl proteins, whereas the Rac1-mediated EGFR phosphorylation is independent of EGFR degradation. Our findings elucidate a part of the underlying molecular mechanism of the link between high glucose levels and tumorigenesis in breast cancer and may provide new insights on the therapeutic strategy for cancer patients with diabetes or hyperglycemia. PMID- 28670142 TI - Prevalence of hypercalcemia of malignancy among pediatric cancer patients in the UK Clinical Practice Research Datalink database. AB - BACKGROUND: The reported proportion of cancer patients who experience hypercalcemia of malignancy (HCM) is low, particularly in the pediatric population, ranging between <1% and 5%. HCM can be observed with any type of tumor in children and occurs most commonly with leukemia. While HCM is a potentially fatal condition, the prevalence of HCM is not well understood in pediatric cancer patients. METHODS: Using the UK Clinical Practice Research Datalink, we identified pediatric cancer patients with recorded corrected serum calcium (CSC) from 2003 through 2014. Hypercalcemic patients (CSC >=10.8 mg/dL) were classified into 4 CSC levels. We estimated the annual prevalence of HCM using Byar's method. RESULTS: Among 517 pediatric cancer patients, leukemia, lymphoma, and brain tumors were the most frequent cancer types. The prevalence of HCM overall (grade 1 or higher) ranged from 0.24% to 0.81% between 2003 and 2014. There were too few cases to compare prevalence by type of cancer. CONCLUSION: We provide the first systematic analysis using a UK population-based data source to estimate the number of pediatric cancer patients affected with HCM by grade. Our findings showed that the prevalence of pediatric HCM was very low (0.24%-0.81%) over the 12-year study period, which is consistent with previous study of adult cancer patients in the UK (0.20%-0.67%). PMID- 28670143 TI - Bone marrow mesenchymal stem cell repair of cyclophosphamide-induced ovarian insufficiency in a mouse model. AB - OBJECTIVE: Attempting in vivo healing of cyclophosphamide-induced ovarian insufficiency in a mouse model using bone marrow mesenchymal stem cells (BMMSCs). METHODS: Female BALB/c white mice were used to prepare a model for premature ovarian failure by single intraperitoneal injection of cyclophosphamide (80 mg/kg). Ten mice were injected with BMMSCs and then sacrificed after 21 days for morphometric evaluation of the ovaries. Hormonal profile was evaluated while mice were being sacrificed. Another 10 mice were left for natural breeding with male mice, and 5 of these were injected with BMMSCs. Oocyte-like structures were obtained from 3 mice and were subjected to in vitro fertilization/intracytoplasmic sperm injection. RESULTS: Morphometric analysis of the ovaries demonstrated the presence of newly formed primordial follicles. Contribution of MSCs to the formation of these follicles was proven by a labeling technique. There was a drop in estradiol and rise in follicle-stimulating hormone levels, followed by resumption of the hormonal levels to near normal 21 days after MSCs therapy. The 5 mice that were injected with MSCs became pregnant after natural breeding. Fertilization and further division was reported in 5 oocytes subjected to intracytoplasmic sperm injection, but division did not continue. CONCLUSION: From this proof-of-concept trial, we can say that healing of damaged ovaries after chemotherapy in mice is possible using in vivo therapy with BMMSCs. This should open the gate for a series of animal studies that test the possibility of in vitro maturation of germinal epithelium of the ovary into mature oocytes. PMID- 28670144 TI - Adiposity and hyperleptinemia during the first trimester among pregnant women with preeclampsia. AB - BACKGROUND: Leptin levels start increasing from the early stages of pregnancy, irrespective of the maternal body mass index. Leptin levels are increased in pregnant women with preeclampsia (PE) and may precede the clinical onset of the disease, with peaks occurring around 28 weeks of gestation. This study was aimed at determining whether serum leptin concentration and body fat percentage are significantly altered during the first trimester in pregnancies that subsequently develop PE and whether such changes are useful in predicting the disease. MATERIALS AND METHODS: This was a prospective longitudinal study conducted among pregnant women in Ho municipality. A cohort of 314 pregnant women was monitored from the first antenatal visit to delivery period at the Volta Regional Hospital, Ho, Ghana. Maternal serum leptin and lipid profile were analyzed and body fat percentage determined during first trimester. Body mass index was also calculated. RESULTS: First trimester serum leptin level (P<0.0001) and body fat percentage (P<0.0001) were significantly higher in those who developed PE than those who did not; while triglycerides (P=0.8600), total cholesterol (P=0.5620), high-density lipoprotein (P=0.5880), low-density lipoprotein (P=0.4870) and very low-density lipoprotein (P=0.6540) did not show any significant difference between those with PE and those without PE. CONCLUSION: Leptin levels are increased significantly during the first trimester of pregnancy in obese women with PE, and these increases precede the onset of PE. PMID- 28670145 TI - Anisohypermetropia as a sign of unilateral glaucoma in the pediatric population. AB - Childhood glaucoma poses a diagnostic and therapeutic challenge to ophthalmologists. Difficulty in examination and limitations on ability to perform structural and functional testing of optic nerve make diagnosis and verification of glaucoma control difficult in children. It is well known that an excessive loss of hyperopia is a useful sign in alerting the examining ophthalmologist to the possible diagnosis of glaucoma. We present an interesting case of juvenile onset glaucoma presenting with anisohypermetropic amblyopia in one eye and normal vision in the fellow eye that has glaucoma. It is an unusual case as the left eye with abnormal vision from hypermetropic amblyopia, though by itself requiring treatment, was a red herring for a potentially blinding condition in the fellow eye with normal vision and lower and less amblyogenic hyperopia on examination. We believe that glaucomatous enlargement of the right eye resulted in significant loss of hyperopia in that eye and in turn contributed to anisohypermetropic amblyopia in the left eye. To the best of our knowledge, this is the first reported case of juvenile onset glaucoma presenting with anisohypermetropic amblyopia in one eye and normal vision in the fellow eye that has glaucoma. PMID- 28670146 TI - Prevalence of thrombocytopenia among pregnant women attending antenatal care service at Gondar University Teaching Hospital in 2014, northwest Ethiopia. AB - INTRODUCTION: Thrombocytopenia is a common hematologic abnormality during pregnancy. Pregnant women with thrombocytopenia have a higher risk of bleeding excessively during or after childbirth, particularly if they need to have a cesarean section or other surgical intervention during pregnancy, labor or in the puerperium. The main aim of this study was to determine the prevalence of thrombocytopenia among pregnant women attending antenatal care service at Gondar University Hospital, northwest Ethiopia. MATERIALS AND METHODS: A cross-sectional study was used to assess the prevalence of thrombocytopenia among pregnant women attending antenatal care service at Gondar University Hospital from January to April 2015. A total of 217 pregnant women were included in the study and a structured pretested questionnaire was used to obtain sociodemographic information, nutritional factors, obstetrics and gynecological factors, history and clinical condition. Blood samples were collected for platelet count and other platelet parameters, which were determined by using SysmexKX 21 automation. The data were entered to Epi info version 6 software and analyzed using SPSS version 20 software. Bivariable and multivariable statistical analyses were used to evaluate the effect of independent variable over the dependent variable. A p value of <0.05 was considered as statistically significant. RESULT: A total of 217 women receiving antenatal care service at Gondar University Hospital participated in the study. Thrombocytopenia among 19 pregnant women showed a prevalence of 8.8%. The mean +/- standard deviation platelet count was 238.85*109/L (+/-74.57). Thrombocytopenia was significantly associated with patients who lived rurally (crude odds ratio =4.3, 95% confidence interval 1.48 12.76). CONCLUSION: The prevalence of thrombocytopenia was 8.8% predominantly with mild type of thrombocytopenia. Thrombocytopenia was higher among pregnant women who lived rurally. Therefore, health care providers should screen routinely for thrombocytopenia to avoid excessive bleeding during pregnancy, especially in women who live rurally. PMID- 28670147 TI - Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches? AB - Hemophilia A (HA) is a common bleeding disorder caused by the deficiency of factor VIII (FVIII) with an incidence of ~1 in 5000 male births. Replacement of FVIII is necessary to prevent and treat bleeding episodes. However, with multiple new drugs in addition to old standards, choosing among the different FVIII treatment options is harder than ever. There are FVIII products that are plasma derived or recombinant, FVIII products designed to extend the half-life of FVIII, and the first single-chain FVIII product, recombinant factor VIII single chain (rFVIII-SC). As development of inhibitors to FVIII continues to be a major problem in the care of HA patients, recent studies showing lower rates of inhibitor development with plasma-derived FVIIII products versus recombinant FVIII products have made choosing among the many options now available even more complex. Although still unproven, extended half-life (EHL) products may provide the hope of decreased immunogenicity but need further testing in previously untreated patients (PUPs). This review highlights some of the differences between FVIII products currently available and hopefully assists the clinician to decide which FVIII product to choose for their patients. PMID- 28670149 TI - Use of the National Board of Medical Examiners(r) Comprehensive Basic Science Exam: survey results of US medical schools. AB - PURPOSE: The National Board of Medical Examiners(r) (NBME) Comprehensive Basic Science Exam (CBSE) is a subject exam offered to US medical schools, where it has been used for external validation of student preparedness for the United States Medical Licensing Examination(r) (USMLE) Step 1 in new schools and schools undergoing curricular reform. Information regarding the actual use of the NBME CBSE is limited. Therefore, the aim of the survey was to determine the scope and utilization of the NBME CBSE by US medical schools. METHODS: A survey was sent in May 2016 to curriculum leadership of the 139 US medical schools listed on the Liaison Committee on Medical Education (LCME(r)) website with provisional or full accreditation as of February 29, 2016. Responses were received from 53 schools (38% response rate). A series of different follow-up questions were asked if respondents stated "yes" or "no" to the initial question "Does your institution administer the NBME CBSE prior to the USMLE Step 1?". RESULTS: A total of 37 schools (70%) administered the NBME CBSE. In all, 36 of the 37 schools responded to follow-up questions. Of 36 schools, 13 schools (36%) used the NBME CBSE for curriculum modification. Six schools (17%) used the NBME CBSE for formative assessment for a course, and five schools (14%) used the NBME CBSE for summative assessment for a course. A total of 28 schools (78%) used the NBME CBSE for identifying students performing below expectations and providing targeted intervention strategies. In all, 24 schools (67%) of the 36 responding schools administering the NBME CBSE administered the test once prior to the administration of the USMLE Step 1, whereas 10 (28%) schools administered the NBME CBSE two or more times prior to the administration of the USMLE Step 1. CONCLUSION: Our data suggest that the NBME CBSE is administered by many US medical schools. However, the objective, timing, and number of exams administered vary greatly among schools. PMID- 28670148 TI - Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural History, Diagnosis, and Current Treatment Options. AB - Nonalcoholic fatty liver disease (NAFLD) is on the rise and has become a major etiology for chronic liver disease. It is frequently associated with obesity, insulin resistance, hypertension, and dyslipidemia and is considered the hepatic manifestation of metabolic syndrome. In this review, we present a summary of the epidemiology and pathogenesis of NAFLD, and discuss the clinical evaluation and stratification of NAFLD patients into low, intermediate, and high risk with respect to liver-related outcomes. While diet and exercise are the cornerstone of treatment in all patients, the low rate of adherence and inadequacy of these recommendations necessitate pharmacologic intervention, especially in intermediate- and high-risk patients. We discuss vitamin E and pioglitazone which are often used as first-line therapy by many practitioners, with pentoxifylline and liraglutide as backup agents. Several drugs are in advanced-phase clinical trials and will likely change the landscape for management of NAFLD in the very near future. PMID- 28670150 TI - Predicting United States Medical Licensure Examination Step 2 clinical knowledge scores from previous academic indicators. AB - The use of multiple academic indicators to identify students at risk of experiencing difficulty completing licensure requirements provides an opportunity to increase support services prior to high-stakes licensure examinations, including the United States Medical Licensure Examination (USMLE) Step 2 clinical knowledge (CK). Step 2 CK is becoming increasingly important in decision-making by residency directors because of increasing undergraduate medical enrollment and limited available residency vacancies. We created and validated a regression equation to predict students' Step 2 CK scores from previous academic indicators to identify students at risk, with sufficient time to intervene with additional support services as necessary. Data from three cohorts of students (N=218) with preclinical mean course exam score, National Board of Medical Examination subject examinations, and USMLE Step 1 and Step 2 CK between 2011 and 2013 were used in analyses. The authors created models capable of predicting Step 2 CK scores from academic indicators to identify at-risk students. In model 1, preclinical mean course exam score and Step 1 score accounted for 56% of the variance in Step 2 CK score. The second series of models included mean preclinical course exam score, Step 1 score, and scores on three NBME subject exams, and accounted for 67%-69% of the variance in Step 2 CK score. The authors validated the findings on the most recent cohort of graduating students (N=89) and predicted Step 2 CK score within a mean of four points (SD=8). The authors suggest using the first model as a needs assessment to gauge the level of future support required after completion of preclinical course requirements, and rescreening after three of six clerkships to identify students who might benefit from additional support before taking USMLE Step 2 CK. PMID- 28670151 TI - Dual-Energy CT: New Horizon in Medical Imaging. AB - Dual-energy CT has remained underutilized over the past decade probably due to a cumbersome workflow issue and current technical limitations. Clinical radiologists should be made aware of the potential clinical benefits of dual energy CT over single-energy CT. To accomplish this aim, the basic principle, current acquisition methods with advantages and disadvantages, and various material-specific imaging methods as clinical applications of dual-energy CT should be addressed in detail. Current dual-energy CT acquisition methods include dual tubes with or without beam filtration, rapid voltage switching, dual-layer detector, split filter technique, and sequential scanning. Dual-energy material specific imaging methods include virtual monoenergetic or monochromatic imaging, effective atomic number map, virtual non-contrast or unenhanced imaging, virtual non-calcium imaging, iodine map, inhaled xenon map, uric acid imaging, automatic bone removal, and lung vessels analysis. In this review, we focus on dual-energy CT imaging including related issues of radiation exposure to patients, scanning and post-processing options, and potential clinical benefits mainly to improve the understanding of clinical radiologists and thus, expand the clinical use of dual-energy CT; in addition, we briefly describe the current technical limitations of dual-energy CT and the current developments of photon-counting detector. PMID- 28670152 TI - Deep Learning in Medical Imaging: General Overview. AB - The artificial neural network (ANN)-a machine learning technique inspired by the human neuronal synapse system-was introduced in the 1950s. However, the ANN was previously limited in its ability to solve actual problems, due to the vanishing gradient and overfitting problems with training of deep architecture, lack of computing power, and primarily the absence of sufficient data to train the computer system. Interest in this concept has lately resurfaced, due to the availability of big data, enhanced computing power with the current graphics processing units, and novel algorithms to train the deep neural network. Recent studies on this technology suggest its potentially to perform better than humans in some visual and auditory recognition tasks, which may portend its applications in medicine and healthcare, especially in medical imaging, in the foreseeable future. This review article offers perspectives on the history, development, and applications of deep learning technology, particularly regarding its applications in medical imaging. PMID- 28670153 TI - Influence of B1-Inhomogeneity on Pharmacokinetic Modeling of Dynamic Contrast Enhanced MRI: A Simulation Study. AB - OBJECTIVE: To simulate the B1-inhomogeneity-induced variation of pharmacokinetic parameters on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: B1-inhomogeneity-induced flip angle (FA) variation was estimated in a phantom study. Monte Carlo simulation was performed to assess the FA-deviation-induced measurement error of the pre-contrast R1, contrast enhancement ratio, Gd-concentration, and two-compartment pharmacokinetic parameters (Ktrans, ve, and vp). RESULTS: B1-inhomogeneity resulted in -23-5% fluctuations (95% confidence interval [CI] of % error) of FA. The 95% CIs of FA dependent % errors in the gray matter and blood were as follows: -16.7-61.8% and 16.7-61.8% for the pre-contrast R1, -1.0-0.3% and -5.2-1.3% for the contrast enhancement ratio, and -14.2-58.1% and -14.1-57.8% for the Gd-concentration, respectively. These resulted in -43.1-48.4% error for Ktrans, -32.3-48.6% error for the ve, and -43.2-48.6% error for vp. The pre-contrast R1 was more vulnerable to FA error than the contrast-enhancement ratio, and was therefore a significant cause of the Gd-concentration error. For example, a -10% FA error led to a 23.6% deviation in the pre-contrast R1, -0.4% in the contrast-enhancement ratio, and 23.6% in the Gd-concentration. In a simulated condition with a 3% FA error in a target lesion and a -10% FA error in a feeding vessel, the % errors of the pharmacokinetic parameters were -23.7% for Ktrans, -23.7% for ve, and -23.7% for vp. CONCLUSION: Even a small degree of B1-inhomogeneity can cause a significant error in the measurement of pharmacokinetic parameters on DCE-MRI, while the vulnerability of the pre-contrast R1 calculations to FA deviations is a significant cause of the miscalculation. PMID- 28670155 TI - Ruptured Corpus Luteal Cyst: Prediction of Clinical Outcomes with CT. AB - OBJECTIVE: To evaluate the determinant pretreatment CT findings that can predict surgical intervention for patients suffering from corpus luteal cyst rupture with hemoperitoneum. MATERIALS AND METHODS: From January 2009 to December 2014, a total of 106 female patients (mean age, 26.1 years; range, 17-44 years) who visited the emergency room of our institute for acute abdominal pain and were subsequently diagnosed with ruptured corpus luteal cyst with hemoperitoneum were included in the retrospective study. The analysis of CT findings included cyst size, cyst shape, sentinel clot sign, ring of fire sign, hemoperitoneum depth, active bleeding in portal phase and attenuation of hemoperitoneum. The comparison of CT findings between the surgery and conservative management groups was performed with the Mann-Whitney U test or chi-square test. Logistic regression analysis was used to determine significant CT findings in predicting surgical intervention for a ruptured cyst. RESULTS: Comparative analysis revealed that the presence of active bleeding and the hemoperitoneum depth were significantly different between the surgery and conservative management groups and were confirmed as significant CT findings for predicting surgery, with adjusted odds ratio (ORs) of 3.773 and 1.318, respectively (p < 0.01). On the receiver operating characteristic curve analysis for hemoperitoneum depth, the optimal cut off value was 5.8 cm with 73.7% sensitivity and 58.6% specificity (Az = 0.711, p = 0.004). In cases with a hemoperitoneum depth > 5.8 cm and concurrent active bleeding, the OR for surgery increased to 5.786. CONCLUSION: The presence of active bleeding and the hemoperitoneum depth on a pretreatment CT scan can be predictive warning signs of surgery for a patient with a ruptured corpus luteal cyst with hemoperitoneum. PMID- 28670154 TI - Multiparametric MRI in the Detection of Clinically Significant Prostate Cancer. AB - Prostate cancer is the most common cancer among men aged 50 years and older in developed countries and the third leading cause of cancer-related death in men. Multiparametric prostate MR imaging is currently the most accurate imaging modality to detect, localize, and stage prostate cancer. The role of multi parametric MR imaging in the detection of clinically significant prostate cancer are discussed. In addition, insights are provided in imaging techniques, protocol, and interpretation. PMID- 28670156 TI - Thyroid Radiofrequency Ablation: Updates on Innovative Devices and Techniques. AB - Radiofrequency ablation (RFA) is a well-known, effective, and safe method for treating benign thyroid nodules and recurrent thyroid cancers. Thyroid-dedicated devices and basic techniques for thyroid RFA were introduced by the Korean Society of Thyroid Radiology (KSThR) in 2012. Thyroid RFA has now been adopted worldwide, with subsequent advances in devices and techniques. To optimize the treatment efficacy and patient safety, understanding the basic and advanced RFA techniques and selecting the optimal treatment strategy are critical. The goal of this review is to therefore provide updates and analysis of current devices and advanced techniques for RFA treatment of benign thyroid nodules and recurrent thyroid cancers. PMID- 28670157 TI - Analysis of Participant Factors That Affect the Diagnostic Performance of Screening Mammography: A Report of the Alliance for Breast Cancer Screening in Korea. AB - OBJECTIVE: To analyze participant factors that affect the diagnostic performance of screening mammography. MATERIALS AND METHODS: We enrolled 128756 cases from 10 hospitals between 2005 and 2010. We analyzed recall rate, cancer detection rate (CDR) per 1000 examinations, positive predictive value (PPV), sensitivity, specificity, false positive rate (FPR), and interval cancer rate (ICR) per 1000 negative examinations according to participant factors including age, breast density, and number of visit to the same institution, and adjusted for confounding variables. RESULTS: Increasing age improved recall rates (27.4% in 40's, 17.5% in 50's, 11.1% in 60's, and 8.6% in 70's), CDR (2.7, 3.2, 2.0, and 2.4), PPV (1.0, 1.8, 1.8, and 2.8%), sensitivity (81.3, 88.8, 90.3, and 94.7%), specificity (72.7, 82.7, 89.0, and 91.7%), and FPR (27.3, 17.3, 11.0, and 8.4%) (p < 0.05). Higher breast density impaired recall rates (4.0% in P1, 9.0% in P2, 28.9% in P3, and 27.8% in P4), PPV (3.3, 2.3, 1.2, and 1.3%), specificity (96.1, 91.2, 71.4, and 72.5%), and FPR (3.9, 8.9, 28.6, and 27.6%) (p < 0.001). It also increased CDR (1.3, 2.1, 3.3, and 3.6) and ICR (0.2, 0.3, 0.6, and 1.6) (p < 0.05). Successive visits to the same institution improved recall rates (20.9% for one visit, 10.7% for two visits, 7.7% for more than three visits), PPV (1.6, 2.8, and 2.7%), specificity (79.4, 89.6, and 92.5%), and FPR (20.6, 10.4, and 7.5%) (p < 0.001). CONCLUSION: Young age and dense breasts negatively affected diagnostic performance in mammography screening, whereas successive visits to the same institution had a positive effect. Examinee education for successive visits to the same institution would improve the diagnostic performance. PMID- 28670158 TI - Estimation of Diastolic Filling Pressure with Cardiac CT in Comparison with Echocardiography Using Tissue Doppler Imaging: Determination of Optimal CT Reconstruction Parameters. AB - OBJECTIVE: To determine the optimal CT image reconstruction parameters for the measurement of early transmitral peak velocity (E), early peak mitral septal tissue velocity (E'), and E / E'. MATERIALS AND METHODS: Forty-six patients underwent simultaneous cardiac CT and echocardiography on the same day. Four CT datasets were reconstructed with a slice thickness/interval of 0.9/0.9 mm or 3/3 mm at 10 (10% RR-interval) or 20 (5% RR-interval) RR-intervals. The E was calculated by dividing the peak transmitral flow (mL/s) by the corresponding mitral valve area (cm2). E' was calculated from the changes in the left ventricular length per cardiac phase. E / E' was then estimated and compared with that from echocardiography. RESULTS: For assessment of E / E', CT and echocardiography were more strongly correlated (p < 0.05) with a slice thickness of 0.9 mm and 5% RR-interval (r = 0.77) than with 3 mm or 10% RR-interval. The diagnostic accuracy of predicting elevated filling pressure (E / E' >= 13, n = 14) was better with a slice thickness of 0.9 mm and 5% RR-interval (87.0%) than with 0.9 mm and 10% RR-interval (71.7%) (p = 0.123) and significantly higher than that with a slice thickness of 3 mm with 5% (67.4%) and 10% RR-interval (63.0%), (p < 0.05), respectively. CONCLUSION: Data reconstruction with a slice thickness of 0.9 mm at 5% RR-interval is superior to that with a slice thickness of 3 mm or 10% RR-interval in terms of the correlation of E / E' between CT and echocardiography. Thin slices and frequent sampling also allow for more accurate prediction of elevated filling pressure. PMID- 28670159 TI - Predictive Value of Cardiac Magnetic Resonance Imaging-Derived Myocardial Strain for Poor Outcomes in Patients with Acute Myocarditis. AB - OBJECTIVE: To evaluate the utility of cardiovascular magnetic resonance (CMR) derived myocardial strain measurement for the prediction of poor outcomes in patients with acute myocarditis. MATERIALS AND METHODS: We retrospectively analyzed data from 37 patients with acute myocarditis who underwent CMR. Left ventricular (LV) size, LV mass index, ejection fraction and presence of myocardial late gadolinium enhancement (LGE) were analyzed. LV circumferential strain (EccSAX), radial strain (ErrSAX) from mid-ventricular level short-axis cine views and LV longitudinal strain (EllLV), radial strain (ErrLax) measurements from 2-chamber long-axis views were obtained. In total, 31 of 37 patients (83.8%) underwent follow-up echocardiography. The primary outcome was major adverse cardiovascular event (MACE). Incomplete LV functional recovery was a secondary outcome. RESULTS: During an average follow-up of 41 months, 11 of 37 patients (29.7%) experienced MACE. Multivariable Cox proportional hazard regression analysis, which included LV mass index, LV ejection fraction, the presence of LGE, EccSAX, ErrSAX, EllLV, and ErrLax values, indicated that the presence of LGE (hazard ratio, 42.88; p = 0.014), together with ErrLax (hazard ratio, 0.77 per 1%, p = 0.004), was a significant predictor of MACE. Kaplan-Meier analysis demonstrated worse outcomes in patient with LGE and an ErrLax value <= 9.48%. Multivariable backward regression analysis revealed that ErrLax values were the only significant predictors of LV functional recovery (hazard ratio, 0.54 per 1%; p = 0.042). CONCLUSION: CMR-derived ErrLax values can predict poor outcomes, both MACE and incomplete LV functional recovery, in patients with acute myocarditis, while LGE is only a predictor of MACE. PMID- 28670160 TI - Assessment of Myocardial Bridge by Cardiac CT: Intracoronary Transluminal Attenuation Gradient Derived from Diastolic Phase Predicts Systolic Compression. AB - OBJECTIVE: To study the predictive value of transluminal attenuation gradient (TAG) derived from diastolic phase of coronary computed tomography angiography (CCTA) for identifying systolic compression of myocardial bridge (MB). MATERIALS AND METHODS: Consecutive patients diagnosed with MB based on CCTA findings and without obstructive coronary artery disease were retrospectively enrolled. In total, 143 patients with 144 MBs were included in the study. Patients were classified into three groups: without systolic compression, with systolic compression < 50%, and with systolic compression >= 50%. TAG was defined as the linear regression coefficient between intraluminal attenuation in Hounsfield units (HU) and length from the vessel ostium. Other indices such as the length and depth of the MB were also recorded. RESULTS: TAG was the lowest in MB patients with systolic compression >= 50% (-19.9 +/- 8.7 HU/10 mm). Receiver operating characteristic curve analysis was performed to determine the optimal cutoff values for identifying systolic compression >= 50%. The result indicated an optimal cutoff value of TAG as -18.8 HU/10 mm (area under curve = 0.778, p < 0.001), which yielded higher sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy (54.1, 80.5, 72.8, and 75.0%, respectively). In addition, the TAG of MB with diastolic compression was significantly lower than the TAG of MB without diastolic compression (-21.4 +/- 4.8 HU/10 mm vs. -12.7 +/- 8 HU/10 mm, p < 0.001). CONCLUSION: TAG was a better predictor of MB with systolic compression >= 50%, compared to the length or depth of the MB. The TAG of MB with persistent diastolic compression was significantly lower than the TAG without diastolic compression. PMID- 28670161 TI - Left Ventricular Functional Parameters and Geometric Patterns in Korean Adults on Coronary CT Angiography with a 320-Detector-Row CT Scanner. AB - OBJECTIVE: To assess the normal reference values of left ventricle (LV) functional parameters in Korean adults on coronary CT angiography (CCTA) with a 320-detector-row CT scanner, and to analyze sex-related differences and correlations with various clinical characteristics. MATERIALS AND METHODS: This study retrospectively enrolled 172 subjects (107 men and 65 women; age, 58 +/- 10.9 years; body surface area [BSA], 1.75 +/- 0.2 m2) who underwent CCTA without any prior history of cardiac disease. The following parameters were measured by post-processing the CT data: LV volume, LV functional parameters (ejection fraction, stroke volume, cardiac output, etc.), LV myocardial mass, LV inner diameter, and LV myocardial thickness (including septal wall thickness [SWT], posterior wall thickness [PWT], and relative wall thickness [RWT = 2 * PWT / LV inner diameter]). All of the functional or volumetric parameters were normalized using the BSA. The general characteristics and co-morbidities for the enrolled subjects were recorded, and the correlations between these factors and the LV parameters were then evaluated. RESULTS: The LV myocardial thickness (SWT, 1.08 +/- 0.18 cm vs. 0.90 +/- 0.17 cm, p < 0.001; PWT, 0.91 +/- 0.15 cm vs. 0.78 +/- 0.10 cm, p < 0.001; RWT, 0.38 +/- 0.08 cm vs. 0.33 +/- 0.05 cm, p < 0.001), LV volume (LV end-diastolic volume, 112.9 +/- 26.1 mL vs. 98.2 +/- 21.0 mL, p < 0.001; LV end-systolic volume, 41.7 +/- 14.7 mL vs. 33.7 +/- 12.2 mL, p = 0.001) and mass (145.0 +/- 29.1 g vs. 107.9 +/- 20.0 g, p < 0.001) were significantly greater in men than in women. However, these differences were not significant after normalization using BSA, except for the LV mass (LV mass index, 79.6 +/- 14.0 g/m2 vs. 66.2 +/- 11.0 g/m2, p < 0.001). The cardiac output and ejection fraction were not significantly different between the men and women (cardiac output, 4.3 +/- 1.0 L/min vs. 4.2 +/- 0.9 L/min, p = 0.452; ejection fraction, 63.4 +/- 7.7% vs. 66.4 +/- 7.6%, p = 0.079). Most of the LV parameters were positively correlated with BSA, body weight, and total Agatston score. CONCLUSION: This study provides sex-related reference values and percentiles for LV on cardiac CT and should assist in interpreting results. PMID- 28670162 TI - The Blood Oxygenation T2* Values of Resectable Esophageal Squamous Cell Carcinomas as Measured by 3T Magnetic Resonance Imaging: Association with Tumor Stage. AB - OBJECTIVE: To explore the association between the blood oxygenation T2* values of resectable esophageal squamous cell carcinomas (ESCCs) and tumor stages. MATERIALS AND METHODS: This study included 48 ESCC patients and 20 healthy participants who had undergone esophageal T2*-weighted imaging to obtain T2* values of the tumors and normal esophagi. ESCC patients underwent surgical resections less than one week after imaging. Statistical analyses were performed to identify the association between T2* values of ESCCs and tumor stages. RESULTS: One-way ANOVA and Student-Newman-Keuls tests revealed that the T2* value could differentiate stage T1 ESCCs (17.7 +/- 3.3 ms) from stage T2 and T3 tumors (24.6 +/- 2.7 ms and 27.8 +/- 5.6 ms, respectively; all ps < 0.001). Receiver operating curve (ROC) analysis showed the suitable cutoff T2* value of 21.3 ms for either differentiation. The former statistical tests demonstrated that the T2* value could not differentiate between stages T2 and T3 (24.6 +/- 2.7 ms vs. 27.8 +/- 5.6 ms, respectively, p > 0.05) or between N stages (N1 vs. N2 vs. N3: 24.7 +/- 6.9 ms vs. 25.4 +/- 4.5 ms vs. 26.8 +/- 3.9 ms, respectively; all ps > 0.05). The former tests illustrated that the T2* value could differentiate anatomic stages I and II (18.8 +/- 4.8 ms and 26.9 +/- 5.9 ms, respectively) or stages I and III (27.3 +/- 3.6 ms). ROC analysis depicted the same cutoff T2* value of 21.3 ms for either differentiation. In addition, the Student's t test revealed that the T2* value could determine grouped T stages (T0 vs. T1-3: 17.0 +/- 2.9 ms vs. 25.2 +/- 6.2 ms; T0-1 vs. T2-3: 17.3 +/- 3.0 ms vs. 27.1 +/- 5.3 ms; and T0-2 vs. T3: 18.8 +/- 4.2 ms vs. 27.8 +/- 5.6 ms, all ps < 0.001). ROC analysis indicated that the T2* value could detect ESCCs (cutoff, 20 ms), and discriminate between stages T0-1 and T2-3 (cutoff, 21.3 ms) and between T0-2 and T3 (cutoff, 20.4 ms). CONCLUSION: The T2* value can be an additional quantitative indicator for detecting ESCC except for stage T1 cancer, and can preoperatively discriminate between some T stages and between anatomic stages of this tumor. PMID- 28670163 TI - T2* Mapping from Multi-Echo Dixon Sequence on Gadoxetic Acid-Enhanced Magnetic Resonance Imaging for the Hepatic Fat Quantification: Can It Be Used for Hepatic Function Assessment? AB - OBJECTIVE: To evaluate the diagnostic value of T2* mapping using 3D multi-echo Dixon gradient echo acquisition on gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) as a tool to evaluate hepatic function. MATERIALS AND METHODS: This retrospective study was approved by the IRB and the requirement of informed consent was waived. 242 patients who underwent liver MRIs, including 3D multi-echo Dixon fast gradient-recalled echo (GRE) sequence at 3T, before and after administration of gadoxetic acid, were included. Based on clinico laboratory manifestation, the patients were classified as having normal liver function (NLF, n = 50), mild liver damage (MLD, n = 143), or severe liver damage (SLD, n = 30). The 3D multi-echo Dixon GRE sequence was obtained before, and 10 minutes after, gadoxetic acid administration. Pre- and post-contrast T2* values, as well as T2* reduction rates, were measured from T2* maps, and compared among the three groups. RESULTS: There was a significant difference in T2* reduction rates between the NLF and SLD groups (-0.2 +/- 4.9% vs. 5.0 +/- 6.9%, p = 0.002), and between the MLD and SLD groups (3.2 +/- 6.0% vs. 5.0 +/- 6.9%, p = 0.003). However, there was no significant difference in both the pre- and post-contrast T2* values among different liver function groups (p = 0.735 and 0.131, respectively). A receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve for using T2* reduction rates to differentiate the SLD group from the NLF group was 0.74 (95% confidence interval: 0.63-0.83). CONCLUSION: Incorporation of T2* mapping using 3D multi-echo Dixon GRE sequence in gadoxetic acid-enhanced liver MRI protocol may provide supplemental information for liver function deterioration in patients with SLD. PMID- 28670164 TI - Texture Analysis of Torn Rotator Cuff on Preoperative Magnetic Resonance Arthrography as a Predictor of Postoperative Tendon Status. AB - OBJECTIVE: To evaluate texture data of the torn supraspinatus tendon (SST) on preoperative T2-weighted magnetic resonance arthrography (MRA) using the gray level co-occurrence matrix (GLCM) for prediction of post-operative tendon state. MATERIALS AND METHODS: Fifty patients who underwent arthroscopic rotator cuff repair for full-thickness tears of the SST were included in this retrospective study. Based on 1-year follow-up, magnetic resonance imaging showed that 30 patients had intact SSTs, and 20 had rotator cuff retears. Using GLCM, two radiologists measured independantly the highest signal intensity area of the distal end of the torn SST on preoperative T2-weighted MRA, which were compared between two groups.The relationships with other well-known prognostic factors, including age, tear size (anteroposterior dimension), retraction size (mediolateral tear length), grade of fatty degeneration of the SST and infraspinatus tendon, and arthroscopic fixation technique (single or double row), also were evaluated. RESULTS: Of all the GLCM features, the retear group showed significantly higher entropy (p < 0.001 and p = 0.001), variance (p = 0.030 and 0.011), and contrast (p = 0.033 and 0.012), but lower angular second moment (p < 0.001 and p = 0.002) and inverse difference moment (p = 0.027 and 0.027), as well as larger tear size (p = 0.001) and retraction size (p = 0.002) than the intact group. Retraction size (odds ratio [OR] = 3.053) and entropy (OR = 17.095) were significant predictors. CONCLUSION: Texture analysis of torn SSTs on preoperative T2-weighted MRA using the GLCM may be helpful to predict postoperative tendon state after rotator cuff repair. PMID- 28670165 TI - Efficacy of Maximum Intensity Projection of Contrast-Enhanced 3D Turbo-Spin Echo Imaging with Improved Motion-Sensitized Driven-Equilibrium Preparation in the Detection of Brain Metastases. AB - OBJECTIVE: To evaluate the diagnostic benefits of 5-mm maximum intensity projection of improved motion-sensitized driven-equilibrium prepared contrast enhanced 3D T1-weighted turbo-spin echo imaging (MIP iMSDE-TSE) in the detection of brain metastases. The imaging technique was compared with 1-mm images of iMSDE TSE (non-MIP iMSDE-TSE), 1-mm contrast-enhanced 3D T1-weighted gradient-echo imaging (non-MIP 3D-GRE), and 5-mm MIP 3D-GRE. MATERIALS AND METHODS: From October 2014 to July 2015, 30 patients with 460 enhancing brain metastases (size > 3 mm, n = 150; size <= 3 mm, n = 310) were scanned with non-MIP iMSDE-TSE and non-MIP 3D-GRE. We then performed 5-mm MIP reconstruction of these images. Two independent neuroradiologists reviewed these four sequences. Their diagnostic performance was compared using the following parameters: sensitivity, reading time, and figure of merit (FOM) derived by jackknife alternative free-response receiver operating characteristic analysis. Interobserver agreement was also tested. RESULTS: The mean FOM (all lesions, 0.984; lesions <= 3 mm, 0.980) and sensitivity ([reader 1: all lesions, 97.3%; lesions <= 3 mm, 96.2%], [reader 2: all lesions, 97.0%; lesions <= 3 mm, 95.8%]) of MIP iMSDE-TSE was comparable to the mean FOM (0.985, 0.977) and sensitivity ([reader 1: 96.7, 99.0%], [reader 2: 97, 95.3%]) of non-MIP iMSDE-TSE, but they were superior to those of non-MIP and MIP 3D-GREs (all, p < 0.001). The reading time of MIP iMSDE-TSE (reader 1: 47.7 +/- 35.9 seconds; reader 2: 44.7 +/- 23.6 seconds) was significantly shorter than that of non-MIP iMSDE-TSE (reader 1: 78.8 +/- 43.7 seconds, p = 0.01; reader 2: 82.9 +/- 39.9 seconds, p < 0.001). Interobserver agreement was excellent (kappa > 0.75) for all lesions in both sequences. CONCLUSION: MIP iMSDE-TSE showed high detectability of brain metastases. Its detectability was comparable to that of non-MIP iMSDE-TSE, but it was superior to the detectability of non-MIP/MIP 3D GREs. With a shorter reading time, the false-positive results of MIP iMSDE-TSE were greater. We suggest that MIP iMSDE-TSE can provide high diagnostic performance and low false-positive rates when combined with 1-mm sequences. PMID- 28670166 TI - Splenial Lesions of the Corpus Callosum: Disease Spectrum and MRI Findings. AB - The corpus callosum (CC) is the largest white matter structure in the brain, consisting of more than 200-250 million axons that provide a large connection mainly between homologous cerebral cortical areas in mirror image sites. The posterior end of the CC is the thickest part, which is called the splenium. Various diseases including congenital to acquired lesions including congenital anomalies, traumatic lesions, ischemic diseases, tumors, metabolic, toxic, degenerative, and demyelinating diseases, can involve the splenium of the CC and their clinical symptoms and signs are also variable. Therefore, knowledge of the disease entities and the imaging findings of lesions involving the splenium is valuable in clinical practice. MR imaging is useful for the detection and differential diagnosis of splenial lesions of the CC. In this study, we classify the disease entities and describe imaging findings of lesions involving the splenium of the CC based on our experiences and a review of the literature. PMID- 28670167 TI - Radiation Dose Reduction without Compromise to Image Quality by Alterations of Filtration and Focal Spot Size in Cerebral Angiography. AB - OBJECTIVE: Different angiographic protocols may influence the radiation dose and image quality. In this study, we aimed to investigate the effects of filtration and focal spot size on radiation dose and image quality for diagnostic cerebral angiography using an in-vitro model and in-vivo patient groups. MATERIALS AND METHODS: Radiation dose and image quality were analyzed by varying the filtration and focal spot size on digital subtraction angiography exposure protocols (1, inherent filtration + large focus; 2, inherent + small; 3, copper + large; 4, copper + small). For the in-vitro analysis, a phantom was used for comparison of radiation dose. For the in-vivo analysis, bilateral paired injections, and patient cohort groups were compared for radiation dose and image quality. Image quality analysis was performed in terms of contrast, sharpness, noise, and overall quality. RESULTS: In the in-vitro analysis, the mean air kerma (AK) and dose area product (DAP)/frame were significantly lower with added copper filtration (protocols 3 and 4). In the in-vivo bilateral paired injections, AK and DAP/frame were significantly lower with filtration, without significant difference in image quality. The patient cohort groups with added filtration (protocols 3 and 4) showed significant reduction of total AK and DAP/patient without compromise to the image quality. Variations in focal spot size showed no significant differences in radiation dose and image quality. CONCLUSION: Addition of filtration for angiographic exposure studies can result in significant total radiation dose reduction without loss of image quality. Focal spot size does not influence radiation dose and image quality. The routine angiographic protocol should be judiciously investigated and implemented. PMID- 28670168 TI - Value of Repeat Brain MRI in Children with Focal Epilepsy and Negative Findings on Initial MRI. AB - OBJECTIVE: To evaluate the value of repeat brain magnetic resonance imaging (MRI) in identifying potential epileptogenic lesions in children with initial MRI negative focal epilepsy. MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study and waived the requirement for informed consent. During a 15-year period, 257 children (148 boys and 109 girls) with initial MRI-negative focal epilepsy were included. After re-evaluating both initial and repeat MRIs, positive results at repeat MRI were classified into potential epileptogenic lesions (malformation of cortical development and hippocampal sclerosis) and other abnormalities. Contributing factors for improved lesion conspicuity of the initially overlooked potential epileptogenic lesions were analyzed and classified into lesion factors and imaging factors. RESULTS: Repeat MRI was positive in 21% (55/257) and negative in 79% cases (202/257). Of the positive results, potential epileptogenic lesions comprised 49% (27/55) and other abnormalities comprised 11% of the cases (28/257). Potential epileptogenic lesions included focal cortical dysplasia (n = 11), hippocampal sclerosis (n = 10), polymicrogyria (n = 2), heterotopic gray matter (n = 2), microlissencephaly (n = 1), and cortical tumor (n = 1). Of these, seven patients underwent surgical resection. Contributing factors for new diagnoses were classified as imaging factors alone (n = 6), lesion factors alone (n = 2), both (n = 18), and neither (n = 1). CONCLUSION: Repeat MRI revealed positive results in 21% of the children with initial MRI-negative focal epilepsy, with 50% of the positive results considered as potential epileptogenic lesions. Enhanced MRI techniques or considering the chronological changes of lesions on MRI may improve the diagnostic yield for identification of potential epileptogenic lesions on repeat MRI. PMID- 28670169 TI - CT Quantification of Lungs and Airways in Normal Korean Subjects. AB - OBJECTIVE: To measure and compare the quantitative parameters of the lungs and airways in Korean never-smokers and current or former smokers ("ever-smokers"). MATERIALS AND METHODS: Never-smokers (n = 119) and ever-smokers (n = 45) who had normal spirometry and visually normal chest computed tomography (CT) results were retrospectively enrolled in this study. For quantitative CT analyses, the low attenuation area (LAA) of LAAI-950, LAAE-856, CT attenuation value at the 15th percentile, mean lung attenuation (MLA), bronchial wall thickness of inner perimeter of a 10 mm diameter airway (Pi10), total lung capacity (TLCCT), and functional residual capacity (FRCCT) were calculated based on inspiratory and expiratory CT images. To compare the results between groups according to age, sex, and smoking history, independent t test, one way ANOVA, correlation test, and simple and multiple regression analyses were performed. RESULTS: The values of attenuation parameters and volume on inspiratory and expiratory quantitative computed tomography (QCT) were significantly different between males and females (p < 0.001). The MLA and the 15th percentile value on inspiratory QCT were significantly lower in the ever-smoker group than in the never-smoker group (p < 0.05). On expiratory QCT, all lung attenuation parameters were significantly different according to the age range (p < 0.05). Pi10 in ever-smokers was significantly correlated with forced expiratory volume in 1 second/forced vital capacity (r = -0.455, p = 0.003). In simple and multivariate regression analyses, TLCCT, FRCCT, and age showed significant associations with lung attenuation (p < 0.05), and only TLCCT was significantly associated with inspiratory Pi10. CONCLUSION: In Korean subjects with normal spirometry and visually normal chest CT, there may be significant differences in QCT parameters according to sex, age, and smoking history. PMID- 28670170 TI - RE: Should We Use a Monopolar or Bipolar Mode for Performing No-Touch Radiofrequency Ablation of Liver Tumors? Clinical Practice Might have Already Resolved the Matter Once and for All. PMID- 28670171 TI - How the structure of Wikipedia articles influences user navigation. AB - In this work we study how people navigate the information network of Wikipedia and investigate (i) free-form navigation by studying all clicks within the English Wikipedia over an entire month and (ii) goal-directed Wikipedia navigation by analyzing wikigames, where users are challenged to retrieve articles by following links. To study how the organization of Wikipedia articles in terms of layout and links affects navigation behavior, we first investigate the characteristics of the structural organization and of hyperlinks in Wikipedia and then evaluate link selection models based on article structure and other potential influences in navigation, such as the generality of an article's topic. In free-form Wikipedia navigation, covering all Wikipedia usage scenarios, we find that click choices can be best modeled by a bias towards article structure, such as a tendency to click links located in the lead section. For the goal directed navigation of wikigames, our findings confirm the zoom-out and the homing-in phases identified by previous work, where users are guided by generality at first and textual similarity to the target later. However, our interpretation of the link selection models accentuates that article structure is the best explanation for the navigation paths in all except these initial and final stages. Overall, we find evidence that users more frequently click on links that are located close to the top of an article. The structure of Wikipedia articles, which places links to more general concepts near the top, supports navigation by allowing users to quickly find the better-connected articles that facilitate navigation. Our results highlight the importance of article structure and link position in Wikipedia navigation and suggest that better organization of information can help make information networks more navigable. PMID- 28670173 TI - Beware of Editors Bearing Gifts. PMID- 28670172 TI - New Three-Component Bicyclization Leading to Densely Functionalized Pyrazolo[3,4 d]thiazolo[3,2-a]pyrimidines. AB - A novel three-component bicyclization for the efficient synthesis of densely functionalized pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines has been established from readily accessible aryl aldehydes, alpha-thiocyanate ketones and pyrazol-5 amines. The reaction pathway involves nucleophilic addition/5-exo-trig /6-endo trig bicyclization sequence, resulting in continuous multiple bond-forming events including C-N and C-C bonds to rapidly a molecular complexity. PMID- 28670174 TI - Systematic Review on the Accuracy of Positron Emission Tomography/Computed Tomography and Positron Emission Tomography/Magnetic Resonance Imaging in the Management of Ovarian Cancer: Is Functional Information Really Needed? AB - Ovarian cancer (OC) often presents at an advanced stage with frequent relapses despite optimal treatment; thus, accurate staging and restaging are required for improving treatment outcomes and prognostication. Conventionally, staging of OC is performed using contrast-enhanced computed tomography (CT). Nevertheless, recent advances in the field of hybrid imaging have made positron emission tomography/CT (PET/CT) and PET/magnetic resonance imaging (PET/MRI) as emerging potential noninvasive imaging tools for improved management of OC. Several studies have championed the role of PET/CT for the detection of recurrence and prognostication of OC. We provide a systematic review and meta-analysis of the latest publications regarding the role of molecular imaging in the management of OC. We retrieved 57 original research articles with one article having overlap in both diagnosis and staging; 10 articles (734 patients) regarding the role of PET/CT in diagnosis of OC; 12 articles (604 patients) regarding staging of OC; 22 studies (1429 patients) for detection of recurrence; and 13 articles for prognostication and assessment of treatment response. We calculated pooled sensitivity and specificity of PET/CT performance in various aspects of imaging of OC. We also discussed the emerging role of PET/MRI in the management of OC. We aim to give the readers and objective overview on the role of molecular imaging in the management of OC. PMID- 28670175 TI - A Comparative Study of 68Gallium-Prostate Specific Membrane Antigen Positron Emission Tomography-Computed Tomography and Magnetic Resonance Imaging for Lymph Node Staging in High Risk Prostate Cancer Patients: An Initial Experience. AB - Lymph node staging plays an important role in planning initial management in nonmetastatic prostate cancer. This article compares the role of 68Gallium (68Ga) prostate specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) with magnetic resonance imaging (MRI), which is considered the standard staging modality. Out of 39 high-risk prostate cancer patients who underwent 68Ga-PSMA PET-CT for staging (December 2014-December 2015), 12 patients underwent radical prostatectomy along with ePLND and were included in the analysis. Findings of the PSMA PET and MRI were compared with final histopathology. Sensitivity, specificity, positive predicative value (PPV), negative predicative value (NPV), and accuracy of 68Ga-PSMA PET-CT and MRI were calculated for numbers of patients and pelvic lymph node metastasis. Chi-square test, McNemar's test, and receiver operating characteristic (ROC) analysis were also done. 68Ga-PSMA PET-CT and MRI sensitivity, specificity, PPV, NPV, and accuracy for number of patients detection were 100%, 80%, 87.5%, 100%, 91.67%, and 57.14%, 80%, 80%, 57.4%, 66.67%, respectively. For detection of metastatic lymph node, it was 66.67%, 98.61%, 85.71%, 95.95%, 95.06% and 25.93%, 98.61%, 70%, 91.42%, 90.53%, respectively. Difference of lymph nodal detectability was statistically significant on Chi-square test. On McNemar's test, P value was statistically insignificant for number of patient detection (P = 0.250) but statistically significant for lymph nodal detection (P = 0.001) for 68Ga-PSMA PET CT. In ROC analysis, area under the curve was also significantly high for lymph node detectability by 68Ga-PSMA PET-CT. Our initial experience shows that 68GaPSMA PET-CT is a very promising tracer for N staging in the initial workup of prostate cancer. It has the potential to impact patient's initial management and can up- and down-stage effectively. PMID- 28670176 TI - 18F-Fluorodeoxyglucose-positron Emission Tomography/Computed Tomography Imaging of Metastatic Nasopharyngeal Cancer with Emphasis on the Distribution of Bone Metastases. AB - Distant metastases change the prognosis of patients with nasopharyngeal carcinoma (NPC) which most commonly metastasizes to the bone. 18F-fluorodeoxyglucose (18F FDG) positron emission tomography/computed tomography (PET/CT) is reported as useful in imaging NPC metastases. Our study assesses the incidence and distribution of bone metastases detected by 18F-FDG PET/CT in NPC. 717 18F-FDG PET/CT scan reports of histologically proven NPC patients imaged in Singapore General Hospital, Singapore, between 2003 and 2009 were reviewed for the total number of metastases (scanned from vertex to mid-thigh) and analyzed for distribution. Of the 709 FDG avid metastases in these reports, 357/709 (50.35%) were locoregional nodal metastasis and 352/709 (49.65%) were distant metastases of which 192/709 (27.08%) of total metastases and 54.54% of distant metastases (192/352) were in the bones. The majority of the bone lesions 125/192 (65.1%) were in the axial skeleton with 109/192 (56.77%) in the lower skeleton (thoracolumbar spine, sacrum, and pelvis). The incidence of bone metastases in our study (27.08%) was higher than that reported in other studies, for example, 15% by Liu et al. and 11% (230 patients) by Caglar et al. Bone metastases have been reported in the femurs and the feet and as such some metastases may have been outside the field of view of the scans. In our study, 27% of FDG avid NPC metastases are in the bones. PMID- 28670177 TI - Positron Emission Tomography in Mucosal Melanomas of Head and Neck: Results from a South Asian Tertiary Cancer Care Center. AB - To evaluate the accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in staging and restaging of patients with mucosal melanomas (MM) of head and neck. Patients who underwent PET/CT at our institution, with a biopsy proven diagnosis of MM of the head and neck between March 2006 and December 2013 were included in the study. Nineteen patients with MM of the nasal cavity, paranasal sinuses, and oral cavity were included, of which 12 were for staging and seven for restaging. PET/CT had 100% sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) for detection of the primary. SN of 91.7%, SP of 100%, PPV of 100%, and NPV of 87.5% were seen for nodal metastases. For distant metastases, SN of 85.7%, SP of 100%, PPV of 100%, and NPV of 92.3% were noted. The disease was upstaged from loco-regional to metastatic in 32% leading to treatment change in 25% in the staging group and 43% in the restaging group. PET/CT demonstrates good overall accuracy in evaluation of patients with MM of the head and neck. The main strength of PET/CT lies in detection of distant metastatic disease due to extended whole-body field of view. PMID- 28670178 TI - Association of Preoperative Serum Thyroid-stimulating Hormone Levels with Thyroid Cancer in Patients with Nodular Thyroid Disease. AB - The aim of the current study was to determine the frequency of carcinoma thyroid among patients presenting with goiter and its association with preoperative serum thyroid-stimulating hormone (TSH) levels. A total of 73 (n = 73) adult patients of either gender with solitary solid cold nodule and multinodular goiter with predominant solid cold nodule were analyzed. All surgically resected samples were sent for histopathology. The frequency of thyroid cancer and its subtypes was noted and tested for association with preoperative serum TSH values. Thyroid cancer was diagnosed in 26% (n = 19) of the patients. In patients with thyroid cancer (n = 19), 73.7% (n = 14) were diagnosed with papillary thyroid cancer and 26.3% (n = 5) were diagnosed with follicular thyroid cancer. Presence of thyroid cancer was found to be significantly associated with preoperative higher mean TSH values (P < 0.05). Higher preoperative serum TSH levels may be useful in predicting thyroid cancer in nodular thyroid disease. Further studies are recommended with different cutoff values of serum TSH and its association with the development and progression of thyroid cancer. PMID- 28670179 TI - Evaluation of Diastolic Function in Patients with Normal Perfusion and Type 2 Diabetes Mellitus with Gated Single-photon Emission Computed Tomography. AB - Early identification of diastolic dysfunction of patients with diabetes is important in preventing cardiac events. In this study, we aimed to show that both myocardial perfusion and diastolic function parameters can be evaluated in diabetic patients with possible silent cardiac symptoms using gated single-photon emission computed tomography (G-SPECT). We examined eighty patients: Forty with and forty without diabetes. The patients were compared in terms of systolic and diastolic parameters obtained using G-SPECT. 99mTc-sestamibi was used to obtain 8 frame images in each cardiac cycle, with calculation of the left ventricular ejection fraction (LVEF), peak filling rate (PFR), mean filling rate during the first third of diastolic time (MFR/3), and time to peak filling (TTPF) using the QGS software. G-SPECT results were compared in forty diabetic and forty nondiabetic patients of similar age and sex. Of the diastolic function parameters, PFR was found to be lower in patients with than without diabetes (2.31 +/- 0.68 vs. 2.76 +/- 0.68, respectively; P = 0.004). The TTPF and MFR/3 in both groups were similar. PFR was negatively correlated with end-diastolic volume and end-systolic volume (ESV) and positively correlated with LVEF. This correlation was stronger in patients with diabetes. The diastolic parameter PFR, obtained using G-SPECT, was significantly lower in patients with than without diabetes. We believe that these parameters should be noted for the early diagnosis or prevention of heart disease in patients with a risk of diastolic dysfunction. PMID- 28670180 TI - Demonstration of Ischemia in Myocardial Perfusion Scintigraphy before Coronary Revascularization Decreases Acute Coronary Syndrome-related Hospitalizations. AB - In this study, we compared the patients who underwent coronary angiography (CAG), followed by revascularization by coronary artery stent implantation according to the CAG results without any evidence of ischemia with myocardial perfusion scintigraphy (MPS), and the patients who underwent revascularization by coronary artery stent implantation following the detection of ischemia in MPS before CAG in terms of the mortality and hospitalization due to acute coronary syndrome (ACS). Between January 2009 and January 2016, a total of 407 patients (52% males, 48% females; mean age: 66 +/- 9 years; range: 40-85 years) who underwent CAG following diagnosis of stable angina and underwent coronary artery stenting were retrospectively analyzed. The patients were divided into two groups: Group 1 (n = 200) included those who had MPS before CAG and in whom ischemia was detected and stent was implanted, and Group 2 (n = 207) included those who had stent implantation according to the CAG results without prior MPS. The mean follow-up was 40 +/- 18 months. Although there was no significant difference in the mortality rates between the groups, the rate of hospitalization due to ACS was significantly lower in Group 1 (P = 0.112 vs. P = 0.022, respectively). According to the multivariate Cox-regression analysis, demonstration of ischemia in MPS before revascularization, statin use, clopidogrel use, and higher high-density lipoprotein cholesterol levels were found to be associated with a reduced risk of ACS-related hospitalization, whereas the presence of diabetes mellitus and smoking was found to be associated with an increased risk of ACS-related hospitalization. PMID- 28670181 TI - Transient Ischemic Dilation Ratio in Regadenoson, Single Isotope Gated Single photon Emission Computed Tomography Myocardial Perfusion Imaging. AB - Single isotope 99mTc single-photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) is the most commonly used protocol for nuclear stress testing. Transient ischemic dilation of the left ventricle (TID) has been considered a specific marker of severe coronary artery disease (CAD). Recent publications have questioned the clinical utility of TID, specifically with regadenoson as a stressor and 4DM-SPECT software for TID analysis. These findings have not been demonstrated using other imaging packages. The goal of our study was to establish the TID threshold in the identification of Multi-vessel CAD using Quantitative Perfusion SPECT (QPS) software. Included in this study are 190 patients that had undergone regadenoson-stress, same day, single-isotope 99mTc MPI and had a coronary angiography within a designated 3-month period. QPS (Cedars-Sinai, LA, CA) automated image analysis software was used to calculate TID ratios which were compared across different CAD categories. Coronary angiograms were reviewed to identify both obstructive and nonobstructive CAD. The mean TID for patients with nonobstructive CAD (n = 91) was 1.02 +/- 0.11, and the threshold for TID was 1.24. A receiver operating characteristic curve showed that TID had a poor discriminatory capacity to identify MVD (area under the curve 0.58) with a sensitivity of 3% and a specificity of 97%. In our study with regadenoson MPI in a predominantly African-American population, TID was found to be a poor predictor of MVD using QPS software. The reason is unclear but possibly related to the significant decline in the prevalence of severe CAD in the area where our study took place. PMID- 28670182 TI - 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in Metastatic or Advanced and Inoperable Primary Neuroendocrine Tumors of Rare Sites. AB - The present study aimed at exploring the patient and imaging characteristics of primary neuroendocrine tumors (NETs) of rare sites who presented with metastatic and/or advanced inoperable stages and therefore was considered for peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. A retrospective analysis was undertaken of these patients focusing on the aforementioned aspects. All patients underwent dual-tracer molecular functional imaging with somatostatin receptor (SSTR)-based imaging (with either 99mTc-HYNIC-TOC or 68Ga-DOTATATE) and 18fluorine fludeoxyglucose positron emission tomography-computed tomography as the pretherapy assessment. Based on the qualitative uptake of tracer in SSTR imaging, the lesions were divided into four categories Grade 0-III. The response was assessed post-PRRT by three parameters: (i) symptomatic response, (ii) biochemical response (serum tumor marker), and (iii) objective imaging response. The response profiles under each of these scales were assessed utilizing predefined criteria (detailed in methods). The overall response classification into partial response, stable disease, and progressive disease was done based on documentation of similar scale/category of at least two parameters among the triple parametric assessment. A total of nine patients (7 males, 2 females; age range: 33-59 years) with rare site primary NET were found: The primary sites included ureter (n = 1), sacrococcygeal (n = 1), esophagus (n = 1), thymus (n = 3), and mediastinum (n = 3). Treatment response assessment was undertaken in eight patients who received more than 2 cycles of PRRT with 177Lu-DOTATATE. In this response assessment group (n = 8), the patients received 2-5 cycles and follow-up duration ranged from 5 to 48 months. Symptomatic responses and better quality of life were observed in 4/8 (50%) patients, stable symptomatic disease in 3/8 (37.5%), and progression in 1/8 patients (12.5%). Biochemically, partial response was seen in 3/8 (37.5%), stable values was seen in 3/8 (37.5%), and progression of tumor marker was seen in 2/8 (25%) patients. Morphologically, partial response was seen in 2/8 (25%), stable disease in 5/8 (62.5%), and progressive disease in 1/8 (12.5%) patients. On overall assessment, 2/8 patients (25%) demonstrated partial response, 4/8 stable disease (50%), and 2/8 progressive disease (25%) at the time of assessment. As per the RECIST 1.1, seven patients had stable disease and one patient had progressive disease. No specific correlation could be obtained between dual-tracer molecular imaging features and the response likely due to small population of the study group. Overall, there was evidence of excellent disease stabilization, and symptom palliation with 177Lu-DOTATATE PRRT was documented in these advanced or metastatic NETs of various rare sites. PMID- 28670183 TI - Prostate-Specific Antigen and Prostate-Specific Antigen Kinetics in Predicting 18F-Sodium Fluoride Positron Emission Tomography-Computed Tomography Positivity for First Bone Metastases in Patients with Biochemical Recurrence after Radical Prostatectomy. AB - We evaluated the association between serum prostate specific antigen (PSA) level and kinetics to predict 18F-sodium fluoride positron emission tomography-computed tomography (18F-NaF PET-CT) positivity for first bone metastases in men with biochemical recurrence after radical prostatectomy. All 18F-NaF PET-CT scans that were performed at our institution during 2010-2014 were queried to find patients who demonstrated biochemical recurrence after radical prostatectomy. Records were reviewed to obtain data on PSA levels and kinetics at the time of 18F-NaF PET-CT and pathologic features of the prostatectomy specimen, which were then used for receiver operating characteristic (ROC) analysis to determine predictability for 18F-NaF PET positivity. Thirty-six patients met our inclusion criteria. Of these, 8 (22.2%) had positive 18F-NaF PET-CT scans. Mean values for PSA, PSA doubling time (PSADT), and PSA velocity (PSAV) were 2.02 ng/ml (range: 0.06-11.7 ng/ml), 13.2 months (range: 1.11-60.84), and 1.28 ng/ml/year (range: 0.1-5.28) for 18F NaF PET-CT negative scans, and 4.11 ng/ml (range: 0.04-14.38 ng/ml), 8.9 months (range; 0.7-27.8), and 9.06 ng/ml/year (range: 0.04-50.2) for 18F-NaF PET-CT positive scans, respectively (P = 0.07, 0.47, and 0.02, respectively, for PSA, PSADT, and PSAV). ROC analysis for 18F-NaF PET-CT positivity resulted in area under the curve (AUC) values of 0.634 for PSA, 0.598 for PSADT, and 0.688 for PSAV. ROC analysis with combined models gave AUC values of 0.723 for a combination of PSA and PSADT, 0.689 for a combination of PSA and PSAV, and 0.718 for grouping of PSA, PSADT, and PSAV. There was no significant association between 18F-NaF PET-CT positivity and primary tumor Gleason score, TN staging, and status of surgical margins. 18F-NaF PET-CT detected first-time osseous metastases in 22.2% of our patients with biochemical recurrence after prostatectomy with the PSA level range <=11.7 ng/ml. PSAV was statistically significant in predicting 18F-NaF PET-CT positivity. ROC analysis demonstrated higher AUCs when PSA was combined with PSA kinetics parameters. PMID- 28670184 TI - Unusual Asymptomatic Fluorodeoxyglucose Avid Pheochromocytoma in a Case of Myxoid Liposarcoma of the Extremity on 18-F Fluorodeoxyglucose Positron Emission Tomography-computed Tomography. AB - Sarcomas are a heterogeneous group of rare tumors and arise either from soft tissue or from bone. Soft-tissue sarcomas (STSs) initially metastasize to the lungs. Metastases to extrapulmonary sites such as liver, brain, and soft tissue distant from primary tumor usually develop later. However, cases with isolated adrenal metastasis without disseminated disease have been reported in literature. We present a case of primary myxoid liposarcoma of the lower limb, in which staging 18-F fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan detected a suspicious FDG avid adrenal lesion which eventually on resection was diagnosed as asymptomatic pheochromocytoma. Pheochromocytomas have been reported to demonstrate FDG uptake mimicking metastasis. Hence, while interpreting FDG PET-CT scans in the context of STSs, both the extrapulmonary metastatic potential of aggressive histological subtypes of sarcoma and rare possibility of FDG avid coexistent benign tumor should be taken into consideration. PMID- 28670185 TI - Presentation of Unusual Tracheal Metastasis on Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography after 9 Years in Postnephrectomy Patient of Renal Cell Carcinoma: A Case Report and Review of Literature. AB - Tracheal metastases from renal cell carcinoma (RCC) are extremely rare. Most common primary malignancy metastasizing to this unusual location usually comes from lung region while it is rare to have tracheal metastases from nonpulmonary malignancies such as breast, thyroid, colorectal carcinoma, and melanoma. The lesions detected on fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) scan, especially in the head and neck region, soft tissue, and muscular compartment during follow-up of RCC patients raise the possibility of metastatic lesions in these regions, though rarely encountered. F-18 FDG PET/CT proved to be a valuable noninvasive imaging tool in detecting the very unusual distant metastases and multisystem involvement many years after nephrectomy in RCC in a single session in the present case. PMID- 28670186 TI - Unusual Dipyridamole-induced Aberrant Conduction in the Absence of Myocardial Ischemia. AB - We report two patients referred to 2 day stress-rest single photon emission computed tomography for diagnosis of ischemia who elicited a transient left bundle branch block during dipyridamole intravenous infusion. The conduction disturbance disappeared after aminophyline infusion and became permanent during follow-up. Possible mechanisms underlying this unusual phenomenon in the absence of myocardial ischemia are discussed. PMID- 28670187 TI - Nuclear Protein in Testis Midline Carcinoma Presenting in an Infant as a Pericardial Mass with Staging by 18F-Fluorodeoxyglucose-positron Emission Tomography/Computed Tomography. AB - Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare, aggressive, lethal, epithelioid, poorly differentiated cancer first described in Japan in 1991, unique in that is defined genetically rather than by histological tissue of origin. It usually arises in the body midline and presents as a mass with metastasis. An infant presenting with pneumonia was found to have a pericardial mass, NMC resected, and subsequent staging positron emission tomography (PET) showing residual mediastinal tumor and midline abdominal metastases. Fewer than 100 cases of NMC have been reported in the literature, and PET appears to be the imaging modality of choice in complete staging and evaluation of treatment response. PMID- 28670188 TI - An Uncommon Variant of an Uncommon Disease: A Caucasian Adolescent with Apical Hypertrophic Cardiomyopathy Diagnosed with Myocardial Perfusion Imaging. AB - Apical hypertrophic cardiomyopathy (ApHCM) is a subtype of HCM. This variant is more common in the Asian population when compared to North American patients. Patients may present with arrhythmias, heart failure, myocardial infarction, chest discomfort, fatigue, and presyncope or syncope. Initial evaluation requires electrocardiogram and two-dimensional echocardiogram. T-wave inversion in the precordial leads as well as hypertrophy of the left ventricle is hallmarks of the disease. Cardiac magnetic resonance (CMR) imaging is the most specific and sensitive imaging modality. In patients with contraindications for CMR, myocardial perfusion imaging (MPI) has been described to have diagnostic characteristics for ApHCM. MPI images demonstrating a "solar polar" map pattern and increased apical tracer uptake in single-photon emission computed tomography horizontally and vertical long-axis slices are consistent with the diagnosis of ApHCM. Herein, we present a case of a Caucasian adolescent female who underwent a cardiac screening to rule out hypertrophic obstructive cardiomyopathy. Initially, the patient was unable to undergo CMR, and an MPI was utilized to assist with the diagnosis of ApHCM. PMID- 28670189 TI - ACTH, Cortisol and IL-6 Levels in Athletes following Magnesium Supplementation. AB - BACKGROUND: Physical exercise activates the hypothalamo-pituitary-adrenal (HPA) axis and induces the body's inflammatory response. Due to contemporary dietary habits and increased energy expenditure, athletes are susceptible to depletion of magnesium ions. The aim of our study was to investigate, through assessment of plasma ACTH, serum IL-6, and salivary/serum cortisol levels, if chronic magnesium supplementation might reduce damaging stress effects in amateur rugby players. METHODS: Rugby players (N=23) were randomly assigned to intervention and control group. Basal samples were collected before intervention group started a 4-week long supplementation with magnesium (500 mg Mg/d). Blood and saliva sampling were done a day before the match (Day-1), on the morning of competition (Game), and during a six-day-long recovery period (Day1, Day3 and Day6). ACTH, serum/salivary cortisol, IL-6 and total/differential leukocytes counts were determined at each time point. RESULTS: There was a statistically significant increase in ACTH concentration in intervention group compared to control group, while reductions in cortisol concentrations between the two groups were the greatest at Day-1 (p < 0.01) and at the day of competition (Game) (p < 0.01). Our results revealed that magnesium completely abolished the increase in IL-6 level noted in control group on Day1 and Day3 vs. Day-1 (p < 0.01) and also diminished the rise in neutrophil/lymphocyte ratio in intervention group vs. control group (p < 0.01). CONCLUSIONS: These results suggest the possibly important influence magnesium supplementation might have on the change of parameters of HPA axis activity and reduction of immune response activation following strenuous physical exercise such as a rugby game. PMID- 28670190 TI - Newborn Screening for Thyroid-stimulating Hormone as an Indicator for Assessment of Iodine Status in the Republic of Macedonia. AB - BACKGROUND: Iodine deficiency is associated with goiter and impaired brain function leading to cretinism. An increased frequency of thyroid-stimulating hormone (TSH) measurements above 5 mlU/L on newborn screening points toward an impaired iodine status of the population. METHODS: A 13-year retrospective analysis was performed in 228,266 newborns participating in the national thyroid newborn screening program. The TSH concentration was measured in dry blood spots collected by heel stick on filter paper, 48 hours after birth, using fluoroimmunometric DELFIA method. RESULTS: Out of 236,378 live-born infants, 228,266 (96.6%) have been screened for TSH, of which 198,213 (86.8%) were retrospectively evaluated for TSH levels above 5 mlU/L. Neonates with congenital hypothyroidism, prematurity, and low birth weight were excluded from the evaluation, as well as the inadequately sampled neonates (13.2%). A national prevalence of 3.08% newborns (n=6,105) with TSH > 5 mIU/L was found. Higher percentages were noted in two regions of the country, indicating possible mild iodine deficiency in these regions and shifting the overall average to above 3%. CONCLUSIONS: Our results indicate overall iodine sufficiency in the Macedonian population. Additional assessment of the iodine intake in the regions with suspected mild iodine deficiency is needed to prevent suboptimal cognitive and psychomotor outcomes. PMID- 28670191 TI - Verifying Sarcoidosis Activity: Chitotriosidase versus ACE in Sarcoidosis - a Case-control Study. AB - BACKGROUND: Until now, a proper biomarker(s) to evaluate sarcoidosis activity has not been recognized. The aims of this study were to evaluate the sensitivity and specificity of the two biomarkers of sarcoidosis activity already in use (serum angiotensin converting enzyme - ACE and serum chitotriosidase) in a population of 430 sarcoidosis patients. The activities of these markers were also analyzed in a group of 264 healthy controls. METHODS: Four hundred and thirty biopsy positive sarcoidosis patients were divided into groups with active and inactive disease, and groups with acute or chronic disease. In a subgroup of 55 sarcoidosis patients, activity was also assessed by F-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scanning. Both serum chitotriosidase and ACE levels showed non-normal distribution, so nonparametric tests were used in statistical analysis. RESULTS: Serum chitotriosidase activities were almost 6 times higher in patients with active sarcoidosis than in healthy controls and inactive disease. A serum chitotriosidase value of 100 nmol/mL/h had the sensitivity of .5% and specificity of 70.0%. A serum ACE activity cutoff value of 32.0 U/L had the sensitivity of 66.0% and the specificity of 54%. A statistically significant correlation was obtained between the focal granulomatous activity detected on 18F FDG PET/CT and serum chitotriosidase levels, but no such correlation was found with ACE. The levels of serum chitotriosidase activity significantly correlated with the disease duration (P < 0.0001). Also, serum chitotriosidase significantly correlated with clinical outcome status (COS) categories (rho =0.272, P =0.001). CONCLUSIONS: Serum chitotriosidase proved to be a reliable biomarker of sarcoidosis activity and disease chronicity. PMID- 28670192 TI - The Occurrence of Subclinical Hypercortisolism and Osteoporosis in Patients with Incidentally Discovered Unilateral and Bilateral Adrenal Tumors. AB - BACKGROUND: Adrenal incidentalomas (AI) are clinically silent adrenal masses that are detected incidentally during imaging procedures performed for unrelated diseases. The aim of this study was to investigate the prevalence of sub-clinical hypercortisolism (SH) and associated co-morbidities in patients with unilateral AI (UAI) and bilateral AI (BAI). METHODS: We evaluated 152 patients, 105 (69.1%) with UAI and 47 (30.9%) with BAI. SH was diagnosed in the presence of serum cortisol levels after 1 mg dexamethasone suppression test (DST) or after 2-day low-dose DST (LDDST) > 50 nmol/L with at least one of the following parameters: midnight serum cortisol > 208 nmol/L, 24-h urinary free cortisol > 245 nmol/24 h, or ACTH < 10 ng/L. Bone mineral density (BMD) was measured at lumbar spine (LS) and femoral neck (FN). RESULTS: Age, BMI, and waist circumference were comparable, and diabetes, hypertension and dyslipidemia occurred with similar frequency in both groups. The overall prevalence of SH was 20.5% based on post-1 mg DST, and 20.0% based on post-LDDST cortisol levels, and it was more prevalent in BAI than UAI patients (31.1% vs 15.2%, respectively, p=0.026). LS BMD was lower in BAI than in UAI patients (0.96+/-0.14 vs 0.87+/-0.15, p=0.002). There were no differences in FN BMD. The prevalence of osteoporosis was higher in BAI compared to UAI patients (37.1% vs 15.9%, respectively, p=0.011). CONCLUSIONS: Patients with BAI had higher prevalence of SH and osteoporosis than those with UAI. Frequency of other co-morbidities was similar. This may be due to the higher degree of autonomous cortisol secretion or different tissue-specific sensitivity to glucocorticoids. PMID- 28670193 TI - Serum sdLDL-C and Cellular SREBP2-dependent Cholesterol Levels; is there a Challenge on Targeting PCSK9? AB - BACKGROUND: Serum small dense LDL-cholesterol (sdLDL-C) value is suggested to bean important risk factor for atherosclerosis. Since sdLDL-C changes may be related to PCSK9 and SREBP-2 functions, the aim of this study was to investigate correlations between sdLDL-C, circulating PCSK9, SREBP-2 expression and some lipid parameters in serum and butty coat fraction of healthy subjects. METHODS: One hundred and twenty-four subjects were randomly included in the study. The lipid profile was measured using routine laboratory methods. The serum sdLDL-C level was calculated by a heparin-related precipitation technique. The cellular LDL-C/protein and cholesterol/protein values were measured after lysing of cells with methanol/chloroform binary solvent. The circulating PCSK9 level was measured using ELISA technique. The SREBP-2 expression level was estimated using theRT qPCR technique. RESULTS: Data showed significant correlations between LDL-C, TG and sdLDL-C levels (r=0.34, p=0.001; r=0.2, p=0.04). The circulating PCSK9 level was correlated to LDL-C (r=0.29, p=0.04), but not to sdLDL-C (r=-0.08, p=0.57). Also, cellular LDL-C value was not related to serum LDL-C level (r=-0.12, p=0.39). Furthermore, there was an inverse correlation between cellular LDL C/protein value and estimated de novo cholesterol/protein value (r= -0.5, p=0.001). Similar results were observed for cellular LDL-C/protein value and SREBP-2 expression level (r= -0.52, p=0.004). CONCLUSIONS: We concluded that the serum sdLDL-C value is not related to circulating PCSK9. Furthermore, SREBP-2 regulatory system was able to elevate the cellular cholesterol level after reducing LDL influx. We suggest to investigate the cellular sdLDL fate and lipid synthesis pathways in PCSK9-targeting studies. PMID- 28670194 TI - High Molecular Weight Adiponectin Levels are Neither Influenced by Adiponectin Polymorphisms Nor Associated with Insulin Resistance in Mixed-ancestry Hyperglycemic Subjects from South Africa. AB - BACKGROUND: High molecular weight (HMW) adiponectin has antiatherogenic, antiinflammatory and antidiabetic properties and these effects have been linked to its effect on high density lipoprotein cholesterol (HDL-c). Single nucleotide polymorphisms (SNPs) in the adiponectin gene influence adiponectin levels. We examined the relationship between HMW-adiponectin levels and cardiometabolic traits in normo- and hyperglycemic mixed ancestry South Africans and correlated these levels to two common polymorphisms. METHODS: HMW-adiponectin was determined in 101 subjects from the Cape Town Bellville South community-based study on a mixed ancestry population. Comparisons were made between individuals with normo- and hyperglycemia. Two common SNPs, ADIPOQ SNPs rs17300539 and rs266729, known to affect adiponectin levels were also tested for. Levels of HMW-adiponectin were then correlated with cardiometabolic traits in all groups. RESULTS: Levels of HMW adiponectin were not significantly different in the normo- and hyperglycemic groups (median 11.6 vs. 10.5 MUg/mL, p=0.3060) and in men and women (8.44 vs. 11.34 MUg/mL, p=0.67). ADIPOQ SNPs rs17300539 and rs266729 did not influence levels of HMW-adiponectin. Robust correlation analyses revealed a significant positive correlation between HMW-adiponectin and HDL-c (r=0.45; 95%CI: 0.27 0.59), similarly in normo- and hyperglycemic participants (p > 0.99). This association was substantially attenuated in robust linear regressions adjusted for age, gender and adiposity. CONCLUSIONS: Adiponectin levels in this population were not determined by the commonest SNPs of the adiponectin gene, were unaffected by glycemic status; but were significantly correlated with HDL-c levels. Previous studies have attributed some of the beneficial effects of adiponectin to its effect on HDL-c. PMID- 28670195 TI - Cortisol Response to Low-dose (1 ug) ACTH Stimulation for the Prediction of Outcome in Patients with Systemic Inflammatory Response Syndrome. AB - BACKGROUND: Systemic inflammatory response syndrome (SIRS) changes cortisol dynamics and indicates dissociation between the adrenal cortex and the hypothalamo-pituitary unit. The aim of this study was to assess the cortisol response after stimulation with ACTH1-24 in patients with SIRS at admission to the Respiratory Intensive Care Unit (RICU) and seven days later. METHODS: Fifty four subjects were included in the study, and SIRS was defined according to the Consensus Conference criteria from 1992. Severity of the disease was determined using the APACHE II score, and organ dysfunction using the SOFA score. Low-dose (1, MUg) ACTH test (LDT) was performed in all patients, and cortisol was determined along with basal ACTH. Data were analyzed using parametric and nonparametric tests and regression analysis. The results are presented as mean+/- standard deviation, and P<0.05 was considered statistically significant. RESULTS: There were no differences in cortisol values between the two LDTs. Cortisol increment lower than 250 nmol/L during the LDT was found in 14/54 (25.9%) subjects at the onset of SIRS. Five out of 54 (9.6%)patients died within 7 days from the onset of SIRS. Female sex and maximal cortisol response (? max) on LDT predicted the duration of hospitalization in RICU, while APACHE II and SOFA scores best predicted the duration of hospitalization, mortality outcome as well as overall survival outcome. CONCLUSIONS: A difference was found in A max at the diagnosis of SIRS and seven days later. ? max, and primarily the clinical scores APACHE II and SOFA predicted the outcomes of hospitalization and overall survival. PMID- 28670196 TI - Downregulation of AdipoR1 is Associated with increased Circulating Adiponectin Levels in Serbian Chronic Kidney Disease Patients. AB - BACKGROUND: Since the rise in plasma adiponectin levels in chronic kidney disease (CKD) patients has not yet been elucidated, we sought to investigate if patients on hemodialysis (HD) have altered expression of adiponectin receptors in peripheral blood mononuclear cells (PBMCs) compared to healthy subjects. METHODS: This study included 31 patients with chronic kidney disease on HD and 33 healthy subjects (CG). Circulating adiponectin levels were measured by ELISA while AdipoR1 and AdipoR2 mRNA levels in PBMCs were determined by real-time PCR. RESULTS: Plasma adiponectin levels were significantly higher in patients compared to control group (P=0.036). After adjustment for age, BMI and creatinine, this difference became even more significant (P=0.004). In both groups adiponectin correlated with creatinine (CG: r=-0.472, P=0.006; HD: r=-0.375, P=0.038), triglycerides (CG: r=- 0.490, P=0.004; HD: r=-0.488, P=0.005), insulin (CG: r= 0.386, P=0.038; HD: r=-0.506, P=0.012) and high density lipoprotein cholesterol (HDL-C) (CG: r=-0.672, P<0.001; HD: r=-0.584, P=0.001). Significantly lower expression of PBMCs AdipoR1 mRNA was found in patients compared to CG (P=0.034), while AdipoR2 mRNA levels were similarly expressed in PBMCs in both groups. CONCLUSIONS: Complex pathological processes in CKD cause downregulation of AdipoR1 which could ultimately influence AdipoR1 protein levels leading to a state of ?adiponectin resistance?. PMID- 28670197 TI - High Interleukin 27 Production is Associated with Early Clinical Stage and Localized Disease in Patients with Melanoma. AB - BACKGROUND: The immune response in patients with melanoma is an important focus of research due to the tumor's resistance and immunotherapy possibilities. IL-27 is one of the cytokines with antitumor properties. The role of IL-27 in the pathogenesis of melanoma is still unclear. The aim of this study was to examine the association between serum IL-27 levels and the clinical parameters of melanoma patients. METHODS: The IL-27 concentration was determined by com mercial ELISA in serum samples from melanoma patients (n=72) and healthy control subjects (n=44). Patients were classified according to AJCC clinical stage, TNM stage, the length of progression-free interval (PFI) and the extent of the disease (localized or widespread). RESULTS: Average IL-27 values were increased in patients with early stages of melanoma compared to patients with terminal stages and control values. The highest IL-27 concentration was found in stage IIa. Patients in stages III and IV had significantly lower values of IL-27 compared to control. Patients with localized melanoma and shorter PFI had insignificantly increased IL-27 levels compared to patients with widespread disease and longer PFI. Patients with metastatic disease and stage TNM4 had significantly lower average IL-27 values compared to control. Patients with high production of IL-27 (>1000 pg/mL) were most numerous in IIa AJCC stage, with initial tumor size TNM2 and in the group of patients with localized disease. CONCLUSIONS: High levels of IL-27 in patients with melanoma are associated with the initial stages and lo calized disease. PMID- 28670198 TI - The Importance of Haematological and Biochemical Findings in Patients with West Nile Virus Neuroinvasive Disease. AB - BACKGROUND: West Nile virus neuroinvasive disease (WNND) occurs in less than 1% of infected people. Leukocytosis with lymphocytopenia, mild anaemia, thrombocytopenia, elevated liver and muscle enzymes and hyponatremia are occasionally present in patients with WNND. Cerebrospinal fluid (CSF) findings resemble other viral neuroinfections. The purpose of this study is to pre sent some of the most important laboratory findings of our patients with WNND and to evaluate their correlation with fatal outcome. METHODS: The study included 161 patients with WNND. Their blood and CSF samples were cytobiochemically analysed and the obtained variables were then tested for predictive significance of the disease outcome, or used for differentiation between two clinical syndromes (encephalitis vs meningitis). RESULTS: West Nile encephalitis was present in 127 (78.9%) patients and West Nile meningitis was diagnosed in 34 (21.1%) cases. Leukocytosis was found in 45.9% patients. CRP level higher than 100 mg/L was registered only in those with encephalitis (p=0.020). CSF leukocyte count was 146+/-171 per microlitre, with slight lymphocytic predominance (mean 52%). Hypoglycorrhachia was registered in 9.3% of our patients with WNND. Twenty-eight (17.4%) patients died and all of them had encephalitis. Independent predictors of fatal outcome in WNND were serum CRP > 100 mg/L (p=0.011) and CSF proteins > 1 g/L (p=0.002). CONCLUSIONS: WNND usually affects older males. Prolonged neutrophilic predominance in CSF can occasionally be present, as well as hypoglycorrhachia. Patients with encephalitis, high serum CRP and high CSF protein level have a higher risk of fatal outcome. PMID- 28670199 TI - Crystal alignment of caffeine deposited onto single crystal surfaces via hot-wall epitaxy. AB - Defined crystal growth is highly demanded for technological applications but also fundamental research. Within this work, the crystal growth of the asymmetric molecule caffeine was studied on single crystalline surfaces of muscovite mica, sodium chloride and potassium chloride. While elongated needle-like crystals grow on muscovite mica and sodium chloride, smaller individual "bird-like" structures were observed on potassium chloride. Depending on the surface type and temperature, the disk-shaped caffeine molecules prefer either an edge-on or flat on orientation with respect to the surface, but in each case, a defined crystallographic relation between the surface and caffeine crystallites was determined by using the X-ray pole figure technique. On muscovite mica and sodium chloride, needle-like crystallites with edge-on oriented molecules aligned mainly with the unit cell c-axis (which coincides with the long needle axis) along the [1-10]mica, [100]mica, [110]mica and [110]NaCl, [1-10]NaCl directions, respectively. Crystals consisting of flat-on oriented molecules on KCl showed also defined alignments with respect to the substrate, but due to the altered molecule-substrate contact, the b-axis aligned along [110]KCl and [1-10]KCl. Growth at elevated temperatures enabled changes in the crystal growth whereby more defined structures formed on NaCl. On KCl, the bird-like structures remained very similar, while caffeine on the mica surface at elevated temperatures resulted in even additional texture forming with the caffeine molecules now also favoring a flat-on orientation with respect to the surface. The systematic variation of various system parameters demonstrates how sensitive the growth behavior of caffeine on this variety of substrates is. PMID- 28670200 TI - Fluorescein sodium-guided surgery of parotid gland tumors as a technical advance. AB - BACKGROUND: Complete tumor removal and preservation of the facial nerve are essential in parotid gland surgery. A technical adjunct that potentially enhances the contrast between the facial nerve and the adherent tumor tissue and allows to identify residual tumor tissue could be Fluorescein Sodium. METHODS: Retrospective chart analysis on 7 patients with benign parotid gland lesions that were operated using Fluorescein Sodium intravenously and the application of the YELLOW 560 nm filter of the operating microscope. Safety and feasibility were evaluated. RESULTS: All tumors showed fluorescence and the rating 'contrast enhancing' was assigned in all cases. In 2 patients, satellite nodules were identified and resected meaning that the fluorescence staining of the tumor margins was significantly better than under white light. CONCLUSION: The use of Fluorescein Sodium in parotidectomy is promising. In two cases residual tumor was detected that would have been left behind under white light. Further research in parotid gland surgery and other head and neck tumor procedures is warranted. PMID- 28670201 TI - "Teamwork in hospitals": a quasi-experimental study protocol applying a human factors approach. AB - BACKGROUND: Effective teamwork and sufficient communication are critical components essential to patient safety in today's specialized and complex healthcare services. Team training is important for an improved efficiency in inter-professional teamwork within hospitals, however the scientific rigor of studies must be strengthen and more research is required to compare studies across samples, settings and countries. The aims of the study are to translate and validate teamwork questionnaires and investigate healthcare personnel's perception of teamwork in hospitals (Part 1). Further to explore the impact of an inter-professional teamwork intervention in a surgical ward on structure, process and outcome (Part 2). METHODS: To address the aims, a descriptive, and explorative design (Part 1), and a quasi-experimental interventional design will be applied (Part 2). The study will be carried out in five different hospitals (A E) in three hospital trusts in Norway. Frontline healthcare personnel in Hospitals A and B, from both acute and non-acute departments, will be invited to respond to three Norwegian translated teamwork questionnaires (Part 1). An inter professional teamwork intervention in line with the TeamSTEPPS recommend Model of Change will be implemented in a surgical ward at Hospital C. All physicians, registered nurses and assistant nurses in the intervention ward and two control wards (Hospitals D and E) will be invited to to survey their perception of teamwork, team decision making, safety culture and attitude towards teamwork before intervention and after six and 12 months. Adult patients admitted to the intervention surgical unit will be invited to survey their perception of quality of care during their hospital stay before intervention and after six and 12 month. Moreover, anonymous patient registry data from local registers and data from patients' medical records will be collected (Part 2). DISCUSSION: This study will help to understand the impact of an inter-professional teamwork intervention in a surgical ward and contribute to promote healthcare personnel's team competences with an opportunity to achieve changes in work processes and patient safety. TRIAL REGISTRATION: Trial registration number (TRN) is ISRCTN13997367. The study was registered retrospectively with registration date 30.05.2017. PMID- 28670203 TI - Caregivers' Heart Failure Knowledge is Necessary but not Sufficient to Assure Engagement with Patients in Self-care Maintenance. PMID- 28670202 TI - Conceptualising a model to guide nursing and midwifery in the community guided by an evidence review. AB - BACKGROUND: Successful models of nursing and midwifery in the community delivering healthcare throughout the lifespan and across a health and illness continuum are limited, yet necessary to guide global health services. Primary and community health services are the typical points of access for most people and the location where most care is delivered. The scope of primary healthcare is complex and multifaceted and therefore requires a practice framework with sound conceptual and theoretical underpinnings. The aim of this paper is to present a conceptual model informed by a scoping evidence review of the literature. METHODS: A scoping evidence review of the literature was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Databases included CINAHL, MEDLINE, PsycINFO and SocINDEX using the EBSCO platform and the Cochrane Library using the keywords: model, nursing, midwifery, community, primary care. Grey literature for selected countries was searched using the Google 'advanced' search interface. Data extraction and quality appraisal for both empirical and grey literature were conducted independently by two reviewers. From 127 empirical and 24 non-empirical papers, data extraction parameters, in addition to the usual methodological features, included: the nature of nursing and midwifery; the population group; interventions and main outcomes; components of effective nursing and midwifery outcomes. RESULTS: The evidence was categorised into six broad areas and subsequently synthesised into four themes. These were not mutually exclusive: (1) Integrated and Collaborative Care; (2) Organisation and Delivery of Nursing and Midwifery Care in the Community; (3) Adjuncts to Nursing Care and (4) Overarching Conceptual Model. It is the latter theme that is the focus of this paper. In essence, the model depicts a person/client on a lifespan and preventative curative trajectory. The health related needs of the client, commensurate with their point position, relative to both trajectories, determines the nurse or midwife intervention. Consequently, it is this need, that determines the discipline or speciality of the nurse or midwife with the most appropriate competencies. CONCLUSION: Use of a conceptual model of nursing and midwifery to inform decision-making in primary/community based care ensures clinical outcomes are meaningful and more sustainable. Operationalising this model for nursing and midwifery in the community demands strong leadership and effective clinical governance. PMID- 28670204 TI - Stoichiometric and Non-Stoichiometric Hydrates of Brucine. AB - The complex interplay of temperature and water activity (aw) / relative humidity (RH) on the solid form stability and transformation pathways of three hydrates (HyA, HyB and HyC), an isostructural dehydrate (HyAdehy ), an anhydrate (AH) and amorphous brucine has been elucidated and the transformation enthalpies quantified. The dihydrate (HyA) shows a non-stoichimetric (de)hydration behavior at RH < 40% at 25 degrees C and the removal of the water molecules results in an isomorphic dehydrate structure. The metastable dehydration product converts to AH upon storage at driest conditions or to HyA if exposed to moisture. HyB is a stoichiometric tetrahydrate. The loss of the water molecules causes HyB to collapse to an amorphous phase. Amorphous brucine transforms to AH at RH < 40% RH and a mixture of hydrated phases at higher RH values. The third hyrdate (HyC) is only stable at RH >= 55% at 25 degrees C and contains 3.65 to 3.85 mole equivalent of water. Dehydration of HyC occurs in one step at RH < 55% at 25 degrees C or upon heating and AH is obtained. The AH is the thermodynamically most stable phase of brucine at RH < 40% at 25 degrees C. Depending on the conditions, temperature and aw, each of the three hydrates becomes the thermodynamically most stable form. This study demonstrates the importance of applying complimentary analytical techniques and appropriate approaches for understanding the stability ranges and transition behavior between the solid forms of compounds with multiple hydrates. PMID- 28670205 TI - Why do Hydrates (Solvates) Form in Small Neutral Organic Molecules? Exploring the Crystal Form Landscapes of the Alkaloids Brucine and Strychnine. AB - Computational methods were used to generate and explore the crystal structure landscapes of the two alkaloids strychnine and brucine. The computed structures were analyzed and rationalized by correlating the modelling results to a rich pool of available experimental data. Despite their structural similarity, the two compounds show marked differences in the formation of solid forms. For strychnine only one anhydrous form is reported in the literature and two new solvates from 1,4-dioxane were detected in the course of this work. In contrast, 22 solid forms are so far known to exist for brucine, comprising two anhydrates, four hydrates (HyA - HyC and a 5.25-hydrate), twelve solvates (alcohols and acetone) and four heterosolvates (mixed solvates with water and alcohols). For strychnine it is hard to produce any solid form other than the stable anhydrate while the formation of specific solid state forms of brucine is governed by a complex interplay between temperature and relative humidity/water activity and it is rather a challenging to avoid hydrate formation. Differences in crystal packing and the high tendency for brucine to form hydrates are not intuitive from the molecular structure alone, as both molecules have hydrogen bond acceptor groups but lack hydrogen bond donor groups. Only the evaluation of the crystal energy landscapes, in particular the close-packed crystal structures and high-energy open frameworks containing voids of molecular (water) dimensions, allowed us to unravel the diverse solid state behavior of the two alkaloids at a molecular level. In this study we demonstrate that expanding the analysis of anhydrate crystal energy landscapes to higher energy structures and calculating the solvent accessible volume can be used to estimate non-stoichiometric or channel hydrate (solvate) formation, without explicitly computing the hydrate/solvate crystal energy landscapes. PMID- 28670206 TI - Auto-Tuning and Self-Calibration of High-Sensitivity Radio Frequency Interferometers. AB - We demonstrate a technique that automatically tunes the sensitivity of a radio frequency (RF) interferometer with a tunable liquid attenuator by accurately changing its liquid volume. The obtained effective quality factor (QEFF ) of the interferometer is up to 1*108 at ~5 GHz. The QEFF is ~100 times higher than previously reported results. When material-under-test (MUT), i.e., methanol-water solution in this work, is used for the tuning, a self-calibration and measurement process is demonstrated from 2 GHz to 7.5 GHz at a methanol concentration level down to 5*10-5 mole fraction, which is 100 times lower than previously reported results. Further investigations are needed to achieve better system stability and higher sensitivity. PMID- 28670207 TI - Introducing altmetrics to the Journal of the Medical Library Association. PMID- 28670208 TI - Locating sex- and gender-specific data in health promotion research: evaluating the sensitivity and precision of published filters. AB - OBJECTIVE: This study explored the effectiveness of search filters in identifying sex- and gender-specific data in health promotion studies that are indexed in MEDLINE. METHODS: Literature searches were conducted to identify studies on patient or consumer attitudes and behaviors toward colorectal cancer screening, nutritional labeling, and influenza vaccination. Publications reporting sex- or gender-specific outcome data constituted the gold standards for this study. The sensitivity and precision of previously published gender-specific filters, as well as individual filter component terms, were calculated and compared with values identified in prior studies. RESULTS: The sensitivity and precision of published sex or gender filters varied across topics. Sensitivity values ranged from 14.3% to 92.5%, while precision varied from 17.9% to 51.4%. These filters were less sensitive and less precise in their identification of relevant studies than has been reported in previous studies. Further, while the MEDLINE Medical Subject Headings (MeSH) term "Sex Factors" achieved the greatest average precision (59.3%) of any individual filter term, the MEDLINE check tag "Female" returned the highest average sensitivity (90.1%), with an average precision of 25.0% across topics. CONCLUSIONS: Although search filters can facilitate the identification of research evidence to enable decision making, variability in study abstracting and indexing can limit the generalizability and usability of these filters. This potential for variability should be considered when deciding to incorporate a search filter into any literature search. This research highlights the importance of this awareness when developing strategies for searching the published literature and the potential value of supplementing database searching with other methods of study identification. PMID- 28670209 TI - Surveying hospital nurses to discover educational needs and preferences. AB - OBJECTIVE: The author investigated the educational needs of nurses in an American Nurses Credentialing Center Magnet hospital to determine topics of interest, instruction time and delivery preferences, and interest in a research information skills certificate provided by the library. METHODS: A 9-question survey was distributed to 1,500 nursing staff of the hospital through email. RESULTS: Surveys were completed by 865 respondents, which represented a response rate of 58%. The majority of respondents were registered nurses, licensed practical nurses, and paramedics (81%), and day-shift workers (65%). For education topics, nursing staff placed the highest priority on finding health-related mobile apps for professionals and developing evidence-based research skills. For mode of delivery, respondents expressed a preference for unit-based in-service, computer based tutorials, and hands-on computer training. Most (70%) respondents expressed an interest in participating in a research information skills certificate program. CONCLUSIONS: Our survey results reveal an avenue for reinvigorating and updating the library's educational program to match the needs of nursing staff and may offer valuable insight for other libraries seeking to do the same. PMID- 28670210 TI - Compliance of systematic reviews in veterinary journals with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) literature search reporting guidelines. AB - OBJECTIVE: Complete, accurate reporting of systematic reviews facilitates assessment of how well reviews have been conducted. The primary objective of this study was to examine compliance of systematic reviews in veterinary journals with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for literature search reporting and to examine the completeness, bias, and reproducibility of the searches in these reviews from what was reported. The second objective was to examine reporting of the credentials and contributions of those involved in the search process. METHODS: A sample of systematic reviews or meta-analyses published in veterinary journals between 2011 and 2015 was obtained by searching PubMed. Reporting in the full text of each review was checked against certain PRISMA checklist items. RESULTS: Over one-third of reviews (37%) did not search the CAB Abstracts database, and 9% of reviews searched only 1 database. Over two-thirds of reviews (65%) did not report any search for grey literature or stated that they excluded grey literature. The majority of reviews (95%) did not report a reproducible search strategy. CONCLUSIONS: Most reviews had significant deficiencies in reporting the search process that raise questions about how these searches were conducted and ultimately cast serious doubts on the validity and reliability of reviews based on a potentially biased and incomplete body of literature. These deficiencies also highlight the need for veterinary journal editors and publishers to be more rigorous in requiring adherence to PRISMA guidelines and to encourage veterinary researchers to include librarians or information specialists on systematic review teams to improve the quality and reporting of searches. PMID- 28670211 TI - Trend analysis of journal metrics: a new academic library service? AB - OBJECTIVE: Temporal trends in source normalized impact per paper (SNIP) values for the three top-ranking nursing journals were analyzed and compared to explore whether predicting future SNIP values based on trend analysis could be an innovative service provided by librarians. METHODS: The International Journal of Nursing Studies, Journal of Nursing Scholarship, and Journal of Advanced Nursing were the three top-ranked nursing journals according to 2015 SNIP values. SNIP values for the selected journals were retrieved from the Scopus database, and extracted data were exported to Joinpoint trend analysis software to perform trend analysis. RESULTS: The trend in SNIP values for the International Journal of Nursing Studies was the most stable and positive, whereas the trend in SNIP values for the Journal of Advanced Nursing was the most negative. The annual percentage change of the most recent trend line, which is the best indicator for predicting future SNIP values, was the largest for the International Journal of Nursing Studies. CONCLUSIONS: Predictions of journal metrics based on statistical joinpoint regression may not be completely accurate. Using this technique, however, a librarian can reasonably claim which journal will retain or even improve its prestige in the future and thus safely advise prospective authors on where to publish their research. PMID- 28670212 TI - Native Voices: Native Peoples' Concepts of Health and Illness in New Mexico: opening a local conversation by hosting a national traveling exhibit. AB - BACKGROUND: The University of New Mexico Health Sciences Library and Informatics Center hosted the National Library of Medicine's Native Voices: Native Peoples' Concepts of Health and Illness traveling exhibit. The authors' goal was to promote local interest in the Native Voices exhibit, with an emphasis on making the exhibit content and materials available to American Indian communities throughout rural New Mexico. CASE PRESENTATION: We convened a daylong summit to highlight the exhibit and encourage discussion among 30 American Indian community health educators. The summit prompted the compilation and distribution of descriptions of 23 community projects that promote health and wellness. We also took a scaled-down version of the exhibit to 4 rural college campuses around the state that serve significant Native American student populations. Approximately 140 students and faculty interacted with the exhibit materials, and all 4 sites incorporated the exhibit into curriculum activities. CONCLUSIONS: A hosted national exhibit developed into a multifaceted, funded project that engaged with American Indian communities. We demonstrated successful field deployment of a downsized, portable version of the full traveling exhibit to make meaningful connections with members of our outreach population. PMID- 28670213 TI - Our journey to digital curation of the Jeghers Medical Index. AB - BACKGROUND: Harold Jeghers, a well-known medical educator of the twentieth century, maintained a print collection of about one million medical articles from the late 1800s to the 1990s. This case study discusses how a print collection of these articles was transformed to a digital database. CASE PRESENTATION: Staff in the Jeghers Medical Index, St. Elizabeth Youngstown Hospital, converted paper articles to Adobe portable document format (PDF)/A-1a files. Optical character recognition was used to obtain searchable text. The data were then incorporated into a specialized database. Lastly, articles were matched to PubMed bibliographic metadata through automation and human review. An online database of the collection was ultimately created. The collection was made part of a discovery search service, and semantic technologies have been explored as a method of creating access points. CONCLUSIONS: This case study shows how a small medical library made medical writings of the nineteenth and twentieth centuries available in electronic format for historic or semantic research, highlighting the efficiencies of contemporary information technology. PMID- 28670214 TI - Cultivating a community of practice: the evolution of a health information specialists program for public librarians. AB - BACKGROUND: To help improve the culture of health in Oklahoma-a state that frequently ranks poorly on multiple measures of health and wellness-faculty librarians from an academic health sciences library sought to create a collaborative network of health information professionals in Oklahoma's public libraries through the implementation of the Health Information Specialists Program. CASE PRESENTATION: Health sciences librarians offered a variety of consumer health information courses for public library staff across the state of Oklahoma for three years. Courses were approved by the Medical Library Association for credit toward the Consumer Health Information Specialization. A total of seventy-two participants from public libraries attended the courses, sixty-five achieved a Level I Consumer Health Information Specialization, and nine went on to achieve Level II. CONCLUSIONS: Feedback from participants in the Health Information Specialists Program has indicated a positive impact on the health information expertise of participants, who in turn have used the knowledge that they gained to help their patrons. PMID- 28670216 TI - A competency framework for librarians involved in systematic reviews. AB - OBJECTIVE: The project identified a set of core competencies for librarians who are involved in systematic reviews. METHODS: A team of seven informationists with broad systematic review experience examined existing systematic review standards, conducted a literature search, and used their own expertise to identify core competencies and skills that are necessary to undertake various roles in systematic review projects. RESULTS: The team identified a total of six competencies for librarian involvement in systematic reviews: "Systematic review foundations," "Process management and communication," "Research methodology," "Comprehensive searching," "Data management," and "Reporting." Within each competency are the associated skills and knowledge pieces (indicators). Competence can be measured using an adaptation of Miller's Pyramid for Clinical Assessment, either through self-assessment or identification of formal assessment instruments. CONCLUSIONS: The Systematic Review Competencies Framework provides a standards-based, flexible way for librarians and organizations to identify areas of competence and areas in need of development to build capacity for systematic review integration. The framework can be used to identify or develop appropriate assessment tools and to target skill development opportunities. PMID- 28670215 TI - Using scenario-based training to promote information literacy among on-call consultant pediatricians. AB - BACKGROUND: Traditionally, teaching hospital staff to search for medical information relies heavily on educator-defined search methods. In contrast, the authors describe our experiences using real-time scenarios to teach on-call consultant pediatricians information literacy skills as part of a two-year continuing professional development program. CASE PRESENTATION: Two information searching workshops were held at Sahlgrenska University Hospital in Gothenburg, Sweden. During the workshops, pediatricians were presented with medical scenarios that were closely related to their clinical practice. Participants were initially encouraged to solve the problems using their own preferred search methods, followed by group discussions led by clinical educators and a medical librarian in which search problems were identified and overcome. The workshops were evaluated using questionnaires to assess participant satisfaction and the extent to which participants intended to implement changes in their clinical practice and reported actual change. CONCLUSIONS: A scenario-based approach to teaching clinicians how to search for medical information is an attractive alternative to traditional lectures. The relevance of such an approach was supported by a high level of participant engagement during the workshops and high scores for participant satisfaction, intended changes to clinical practice, and reported benefits in actual clinical practice. PMID- 28670218 TI - Ethics in academic publishing: a timely reminder. PMID- 28670217 TI - Rapid transformation of two libraries using Kotter's Eight Steps of Change. AB - BACKGROUND: Two new directors were each charged by their institutions to catalyze transformational change in their libraries and to develop dynamic and evolving information ecosystems ready for the information challenges of the future. The directors approached this transformational change using a strategic, forward looking approach. RESULTS: This paper presents examples of actions that served as catalysts for change at the two libraries using Kotter's Eight Steps of Change as a framework. Small and large changes are critical for successfully transforming library services, resources, and personnel. CONCLUSIONS: Libraries are faced with incredible pressure to adapt to meet emerging and intensifying information needs on today's academic medical campuses. These pressures offer an opportunity for libraries to accelerate their evolution at the micro and macro levels. This commentary reports the expansion of new services and areas of support, enhancement of professional visibility of the libraries on their campuses, and overall, a more positive and productive environment at the respective institutions. PMID- 28670219 TI - Updating search strategies for systematic reviews using EndNote. PMID- 28670220 TI - History matters...through partnerships that advance research, education, and public service. PMID- 28670221 TI - VetCompanion: response and clarifications. PMID- 28670223 TI - L-Carnitine Supplementation Improves Self-Rating Depression Scale Scores in Uremic Male Patients Undergoing Hemodialysis. AB - BACKGROUND: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. METHODS: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. RESULTS: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyryl carnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). CONCLUSION: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression. PMID- 28670224 TI - Could adalimumab be used safely and effectively in intestinal Behcet's disease refractory to conventional therapy? PMID- 28670222 TI - The impact of growth hormone on proteomic profiles: a review of mouse and adult human studies. AB - Growth hormone (GH) is a protein that is known to stimulate postnatal growth, counter regulate insulin's action and induce expression of insulin-like growth factor-1. GH exerts anabolic or catabolic effects depending upon on the targeted tissue. For instance, GH increases skeletal muscle and decreases adipose tissue mass. Our laboratory has spent the past two decades studying these effects, including the effects of GH excess and depletion, on the proteome of several mouse and human tissues. This review first discusses proteomic techniques that are commonly used for these types of studies. We then examine the proteomic differences found in mice with excess circulating GH (bGH mice) or mice with disruption of the GH receptor gene (GHR-/-). We also describe the effects of increased and decreased GH action on the proteome of adult patients with either acromegaly, GH deficiency or patients after short-term GH treatment. Finally, we explain how these proteomic studies resulted in the discovery of potential biomarkers for GH action, particularly those related with the effects of GH on aging, glucose metabolism and body composition. PMID- 28670227 TI - Optimal diagnosis and disease activity monitoring of intestinal Behcet's disease. AB - Intestinal Behcet's disease (BD), generally accepted as a type of inflammatory bowel disease (IBD), could be diagnosed when patients with BD have objectively documented gastrointestinal symptoms and intestinal ulcerations. Similar to IBD, intestinal BD has an unpredictable disease course with relapse and remission and is often related to a poor prognosis. However, there is no single gold standard for assessment of the disease activity of intestinal BD, and its diagnosis and management depend heavily on expert opinions. The Korean IBD Study Group recently developed novel diagnostic criteria based on colonoscopy findings and clinical manifestations using a modified Delphi process to overcome drawbacks of previously used consensus for the diagnosis of intestinal BD. In addition, the recently developed disease activity index for intestinal BD, consisting of a relatively simple 8-point index, could also help in determining treatment strategies and monitoring therapeutic responses. In this review, the progress in the diagnosis and disease activity measurement of intestinal BD will be discussed. PMID- 28670225 TI - Management of ulcerative colitis in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease. AB - Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic mucosal inflammation of the colon, and the prevalence and incidence of UC have been steadily increasing in Taiwan. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of UC taking into account currently available evidence and the expert opinion of the committee. Accurate diagnosis of UC requires thorough clinical, endoscopic, and histological assessment and careful exclusion of differential diagnoses, particularly infectious colitis. The goals of UC therapy are to induce and maintain remission, reduce the risk of complications, and improve quality of life. As outlined in the recommended treatment algorithm, choice of treatment is dictated by severity, extent, and course of disease. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to immunosuppressive treatment, especially with steroids and biologic agents, and should be regularly monitored for reactivation of latent infection. These consensus statements are also based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of UC in Taiwan. PMID- 28670228 TI - Treatment and outcomes: medical and surgical treatment for intestinal Behcet's disease. AB - Behcet's disease (BD) is a chronic relapsing disease involving multiple organ systems. BD is characterized clinically by oral and genital aphthae, cutaneous lesions, and ophthalmological, neurological, and/or gastrointestinal manifestations. It is widely recognized that the presence of intestinal lesions may be a poor prognostic factor in intestinal BD, increasing the risk of surgery and decreasing the quality of life. Despite this, the management of intestinal BD has not been standardized. Empirical therapies including 5-aminosalicylic acid and corticosteroids have been used anecdotally to treat intestinal BD, but recent studies have provided evidence for the efficacy of anti-tumor necrosis factor alpha monoclonal antibodies. The development of agents targeting tumor necrosis factor alpha continues, it seems likely that they will change the therapeutic strategy and clinical outcomes of intestinal BD and inflammatory bowel disease. Monitoring disease activity such as endoscopic evaluation will become more important to obtain better outcomes. Here, we review current and future perspectives in the treatment and outcomes of intestinal BD. PMID- 28670229 TI - NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases. AB - BACKGROUND/AIMS: Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). METHODS: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. RESULTS: None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (>=8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. CONCLUSIONS: Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD. PMID- 28670226 TI - Management of Crohn's disease in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease. AB - Crohn's disease (CD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. CD is rare in Taiwan and other Asian countries, but its prevalence and incidence have been steadily increasing. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of CD taking into account currently available evidence and the expert opinion of the committee. Thorough clinical, endoscopic, and histological assessments are required for accurate diagnosis of CD. Computed tomography and magnetic resonance imaging are complementary to endoscopic evaluation for disease staging and detecting complications. The goals of CD management are to induce and maintain remission, reduce the risk of complications, and improve quality of life. Corticosteroids are the mainstay for inducing re-mission. Immunomodulating and biologic therapies should be used to maintain remission. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to treatment and receive regular surveillance for cancer. These consensus statements are based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of patients with CD in Taiwan. PMID- 28670230 TI - Impact of inflammatory bowel disease on daily life: an online survey by the Korean Association for the Study of Intestinal Diseases. AB - BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a chronic disabling gastrointestinal disorder that diminishes the quality of life of the affected individuals. Limited data are available regarding the impact of IBD on the daily life of Koreans. METHODS: Self-administered, computer-aided, internet-based questionnaires were distributed to members of a Korean patient organization for IBD from March to April 2013, by the Korean Association for the Study of Intestinal Diseases. RESULTS: A total of 599 patients with IBD (387 with Crohn's disease [CD] and 212 with ulcerative colitis [UC]) were enrolled. The majority of patients (81%) expressed feelings of fatigue, weakness, and being worn out in their daily lives during times of flare; this percentage was reduced to 61% during remission. Respondents were absent from work or school for an average period of 18 days because of illness, within the first 6 months; the majority of respondents (64%) felt stressed about their absence. Forty-six percent of the respondents reported having received unfair comments at work, or having suffered discrimination. Forty-seven percent of the respondents felt that IBD had negatively affected their income and earnings. Compared with patients with UC, those with CD reported a more frequent negative impact of IBD on work, or more economic burden. More than half of the respondents (61%) reported that IBD had prevented them from making or keeping friends. CONCLUSIONS: IBD significantly impacts daily life, including work, education, and social relationships. Treatment that addresses the full spectrum of life of a patient would be more effective. PMID- 28670231 TI - Japanese physicians' attitudes towards enteral nutrition treatment for pediatric patients with Crohn's disease: a questionnaire survey. AB - BACKGROUND/AIMS: Enteral nutrition (EN) is recommended for the treatment of pediatric Crohn's disease (CD) in Japan. However, the indications and treatment protocols for EN vary among hospitals. In the present study, we aimed to determine how EN was administered to pediatric patients and whether physicians followed treatment guidelines in their practices. METHODS: Two types of questionnaires were administered to 32 physicians who were involved in the treatment of pediatric CD. The consensus questionnaire evaluated the physicians' attitudes towards EN, whereas the efficacy questionnaire collected data on patients with CD, aged <17 years, who had undergone induction therapy between 2006 and 2011. RESULTS: A total of 23 physicians responded to the questionnaires. The results of the consensus questionnaire indicated that 82% and 59% of study participants recommended EN treatment for all newly diagnosed pediatric patients with CD and all relapsed patients, respectively. Exclusive EN (EEN) and elemental formula were recommended by 84% and 85% of physicians, respectively. The efficacy questionnaire revealed that 57 of the 58 patients received EN. Elemental formula was used in 39 of 40 patients who were treated with EEN. Of these 40 patients, 27 were treated with EEN alone; of these, 22 (81%) achieved remission without any other treatment. The mean duration of EEN was 15.9 days. CONCLUSIONS: EN is widely recommended by physicians treating pediatric CD in Japan. In contrast to Western countries, clinicians used elemental formula more often and with a shorter EEN treatment duration. PMID- 28670232 TI - Changes in serum levels of lipopolysaccharides and CD26 in patients with Crohn's disease. AB - BACKGROUND/AIMS: Lipopolysaccharide (LPS) is a molecule formed by lipids and polysaccharides and is the major cell wall component of gram-negative bacteria. High LPS levels are known to block CD26 expression by activating Toll-like receptor 4. The aim of this study was to correlate the serum levels of LPS and CD26 in Crohn's disease (CD) patients with serum levels of C-reactive protein (CRP), interleukins, CD activity index, and tumor necrosis factor-alpha (TNF alpha). METHODS: Serum samples were collected from 27 individuals (10 with active CD, 10 with inactive CD, and 7 controls) and the levels of LPS, CD26, TNF-alpha, interleukin-1beta (IL-1beta), IL-6, IL-17, and CRP were determined by enzyme linked immunosorbent assay. The levels of LPS and CD26 were then tested for correlation with TNF-alpha, IL-1beta, IL-6, IL-17, and CRP. RESULTS: Serum levels of LPS were significantly elevated in the active CD group (P=0.003). Levels of IL 1beta (P=0.002), IL-6 (P=0.003), and IL-17 (P<0.001) were lower in the CD groups. Serum TNF-alpha levels were increased in the active CD group. The CRP levels were elevated in the CD groups when compared to controls (P<0.001). The CD26 levels were lower in the CD groups than in the control group (P<0.001). Among the variables analyzed, there was a correlation between LPS and CRP (r=-0.53, P=0.016) in the CD groups. CONCLUSIONS: Individuals with CD exhibited higher serum levels of LPS varying from a 2- to 6-fold increase depending on disease activity, when compared with healthy controls. CD26 levels were lower in the CD groups. Both LPS and CD26 correlated with disease severity and serve as potential CD biomarkers. PMID- 28670233 TI - Comparison of efficacies of once-daily dose multimatrix mesalazine and multiple dose mesalazine for the maintenance of remission in ulcerative colitis: a randomized, double-blind study. AB - BACKGROUND/AIMS: This study compared the efficacy of once-daily administration of multimatrix mesalazine 2.4 g/day with multiple-dose mesalazine for the maintenance of remission. METHODS: In this multicenter, randomized, double-blind study, 203 patients with ulcerative colitis in remission received multimatrix mesalazine 2.4 g/day once-daily or time-dependent (controlled-release) mesalazine 2.25 g/day 3 times-daily for 48 weeks. The primary efficacy endpoint was the proportion of patients without rectal bleeding. RESULTS: The proportion of patients without rectal bleeding during the 48-week treatment period in the per protocol set was 84.8% (84/99) in the multimatrix mesalazine 2.4 g/day group and 78.0% (78/100) in the controlled-release mesalazine 2.25 g/day group. The difference between the 2 treatment groups was 6.8% (two-sided 95% confidence interval, -3.9% to 17.6%). The noninferiority margin of -10% was met in the comparison of multimatrix mesalazine 2.4 g/day once-daily with controlled-release mesalazine 2.25 g/day. Multimatrix mesalazine 2.4 g/day once-daily demonstrated consistent efficacy in all subgroups. There was no difference between the 2 treatment groups with regard to safety. CONCLUSIONS: A once-daily dose of 2 multimatrix mesalazine tablets (2.4 g) was not inferior to controlled-release mesalazine 2.25 g/day 3 times-daily in maintaining absence of rectal bleeding in ulcerative colitis. PMID- 28670234 TI - Comparison of efficacy of multimatrix mesalazine 4.8 g/day once-daily with other high-dose mesalazine in active ulcerative colitis: a randomized, double-blind study. AB - BACKGROUND/AIMS: This study assessed the efficacy and safety of high-dose multimatrix mesalazine once-daily (QD) compared to another form of high-dose mesalazine. METHODS: In this multicenter, randomized, double-blind study, 280 patients with mildly to moderately active ulcerative colitis (UC) received multimatrix mesalazine 4.8 g/day QD or pH-dependent-release mesalazine 3.6 g/day three times daily for 8 weeks. The primary endpoint was the change in the UC Disease Activity Index (UC-DAI) at the end of the treatment period. RESULTS: The change in the UC-DAI (mean+/-standard deviation) in the per-protocol set was 2.6+/-2.47 in the multimatrix mesalazine 4.8 g/day group (n=134) and -1.8+/-2.64 in the pH-dependent-release mesalazine 3.6 g/day group (n=129). The difference in the mean change between the 2 groups was -0.7 (two-sided 95% confidence interval, -1.3 to -0.1). The noninferiority of multimatrix mesalazine 4.8 g/day to pH dependent-release mesalazine 3.6 g/day was verified within the noninferiority margin (1.1). The superiority of multimatrix mesalazine 4.8 g/day to pH-dependent release mesalazine 3.6 g/day was also investigated and confirmed in the full analysis set, according to the study protocol. In subgroup analyses, the effectiveness of multimatrix mesalazine 4.8 g/day was consistent in all subgroups. There was no difference in safety between the 2 treatment groups. CONCLUSIONS: Multimatrix mesalazine 4.8 g/day has higher efficacy and shows no difference in safety in mildly to moderately active UC, in comparison with pH dependent-release mesalazine 3.6 g/day. PMID- 28670235 TI - Ophthalmologic manifestations in patients with inflammatory bowel disease. AB - BACKGROUND/AIMS: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), has been reported to have various ophthalmologic manifestations. The aim of this study was to evaluate the prevalence of ophthalmologic manifestations associated with IBD in Korea. METHODS: Sixty-one patients were examined between May 2013 and October 2014. We performed complete ophthalmologic examinations. RESULTS: Findings included 36 patients with CD and 25 with UC. The mean age of the patients was 34+/-16 years and disease duration was 45.3+/-23.9 months. Ophthalmologic manifestations were positive in 44 cases. Primary complication was diagnosed in 5 cases, as follows; iritis in 2 cases, episcleritis in one case, iritis with optic neuritis in 1 case, and serous retinal detachment in 1 case, without secondary complications. The most common coincidental complication was dry eye syndrome (DES), in 35 patients (57.4%). The prevalence of DES in the control group was 21.3%. The proportion of DES in patients with IBD was significantly higher than in the control group (P=0.002). CONCLUSIONS: Ophthalmologic manifestations were high (72.1%) in IBD patients. Clinically significant primary ocular inflammation occurred in 8.2% of patients. The most common complication was DES. There was a higher rate of DES in patients with IBD compared to the control group. Evaluation of the eye should be a routine component in patients with IBD. PMID- 28670236 TI - Familial aggregation of inflammatory bowel disease in patients with ulcerative colitis. AB - BACKGROUND/AIMS: Familial occurrence of inflammatory bowel disease (IBD) is well documented. Reports from Western countries have shown a higher familial occurrence of ulcerative colitis (UC) in first- and second-degree relatives than that in the Asian UC population. No data are currently available from the Indian subcontinent in this regard. We present our data on the familial aggregation of UC. METHODS: Records of patients with UC followed at the Inflammatory Bowel Disease Clinic at the All India Institute of Medical Sciences, New Delhi from August 2004 to January 2016 were reviewed. Details regarding the prevalence of family history and characteristics of these patients were recorded. Affected family members were contacted and disease characteristics were noted for assessment of familial aggregation. RESULTS: Of the 2,058 UC patients included in the analysis, a positive family history of IBD was confirmed in 31 patients (1.5%), 24 (77.4%) of whom had only first-degree relatives affected. All the affected relatives had UC and none had Crohn's disease. Among first-degree relatives, siblings were found to have the highest prevalence of IBD (53.3%), followed by parents (26.7%). CONCLUSIONS: The probability of occurrence of IBD in family members of affected North Indian UC patients is lower than that reported in Western populations. PMID- 28670237 TI - Long-term safety and efficacy of adalimumab for intestinal Behcet's disease in the open label study following a phase 3 clinical trial. AB - BACKGROUND/AIMS: Intestinal Behcet's disease (BD) is an immune-mediated inflammatory disorder. We followed up the patients and evaluated safety profile and effectiveness of adalimumab for the treatment of intestinal BD through 100 weeks rolled over from the 52 week clinical trial (NCT01243671). METHODS: Patients initiated adalimumab therapy at 160 mg at week 0, followed by 80 mg at week 2, followed by 40 mg every other week until the end of the study. Long-term safety and all adverse events (AEs) were examined. The efficacy was assessed on the basis of marked improvement (MI) and complete remission (CR) using a composite efficacy index, which combined global gastrointestinal symptoms and endoscopic assessments. RESULTS: Twenty patients were enrolled in this study; 15 patients received adalimumab treatment until study completion. The incidence of AEs through week 100 was 544.4 events/100 person-years, which was comparable to the incidence through week 52 (560.4 events/100 person-years). No unexpected trend was observed and adalimumab was well tolerated. At weeks 52 and 100, 60.0% and 40.0% of patients showed MI, respectively, and 20.0% and 15.0% of patients showed CR, respectively. CONCLUSIONS: This report demonstrates 2 years safety and effectiveness of adalimumab in intestinal BD patients. Patients with intestinal BD refractory to conventional treatment receiving up to 2 years of adalimumab treatment demonstrated safety outcomes consistent with the known profile of adalimumab, and the treatment led to sustained reduction of clinical and endoscopic disease activity. PMID- 28670238 TI - Clinical characteristics of patients with serrated polyposis syndrome in Korea: comparison with Western patients. AB - BACKGROUND/AIMS: Serrated polyposis syndrome (SPS) has been shown to increase the risk of colorectal cancer (CRC). However, little is known about the characteristics of Asian patients with SPS. This study aimed to identify the clinicopathological features and risk of CRC in Korean patients with SPS as well as the differences between Korean and Western patients based on a literature review. METHODS: This retrospective study included 30 patients with SPS as defined by World Health Organization classification treated at Samsung Medical Center, Korea, between March 1999 and May 2011. RESULTS: Twenty patients (67%) were male. The median patient age at diagnosis was 56 years (range, 39-76 years). A total of 702 polyps were identified during a median follow-up of 43 months (range, 0-149 months). Serrated polyps were noted more frequently in the distal colon (298/702, 55%). However, large serrated polyps and serrated adenomas were mainly distributed throughout the proximal colon (75% vs. 25% and 81% vs. 19%, respectively); 73.3% had synchronous adenomatous polyps. The incidence of CRC was 10% (3/30 patients), but no interval CRC was detected. A total of 87% of the patients underwent esophagogastroduodenoscopy and 19.2% had significant lesions. CONCLUSIONS: The phenotype of SPS in Korean patients is different from that of Western patients. In Korean patients, SPS is more common in men, there were fewer total numbers of serrated adenoma/polyps, and the incidence of CRC was lower than that in Western patients. Korean patients tend to more frequently have abnormal gastric lesions. However, the prevalence of synchronous adenomatous polyps is high in both Western and Korean patients. PMID- 28670239 TI - Miss rate of colorectal neoplastic polyps and risk factors for missed polyps in consecutive colonoscopies. AB - BACKGROUND/AIMS: Colonoscopic polypectomy is the best diagnostic and therapeutic tool to detect and prevent colorectal neoplasms. However, previous studies have reported that 17% to 28% of colorectal polyps are missed during colonoscopy. We investigated the miss rate of neoplastic polyps and the factors associated with missed polyps from quality-adjusted consecutive colonoscopies. METHODS: We reviewed the medical records of patients who were found to have colorectal polyps at a medical examination center of the Kangbuk Samsung Hospital between March 2012 and February 2013. Patients who were referred to a single tertiary academic medical center and underwent colonoscopic polypectomy on the same day were enrolled in our study. The odds ratios (ORs) associated with polyp-related and patient-related factors were evaluated using logistic regression analyses. RESULTS: A total of 463 patients and 1,294 neoplastic polyps were analyzed. The miss rates for adenomas, advanced adenomas, and carcinomas were 24.1% (312/1,294), 1.2% (15/1,294), and 0% (0/1,294), respectively. Flat/sessile-shaped adenomas (adjusted OR, 3.62; 95% confidence interval [CI], 2.40-5.46) and smaller adenomas (adjusted OR, 5.63; 95% CI, 2.84- 11.15 for <=5 mm; adjusted OR, 3.18; 95% CI, 1.60-6.30 for 6-9 mm, respectively) were more frequently missed than pedunculated/sub-pedunculated adenomas and larger adenomas. In patients with 2 or more polyps compared with only one detected (adjusted OR, 2.37; 95% CI, 1.55-3.61 for 2-4 polyps; adjusted OR, 11.52; 95% CI, 4.61-28.79 for >=5 polyps, respectively) during the first endoscopy, the risk of missing an additional polyp was significantly higher. CONCLUSIONS: One-quarter of neoplastic polyps was missed during colonoscopy. We encourage endoscopists to detect smaller and flat or sessile polyps by using the optimal withdrawal technique. PMID- 28670240 TI - Telmisartan-induced sprue-like enteropathy: a case report and a review of patients using non-olmesartan angiotensin receptor blockers. AB - Recent studies have identified sprue-like illness associated with the use of the antihypertensive agent olmesartan medoxomil. However, whether this condition is specific to the use of olmesartan or is associated with the use of drugs belonging to the class of "sartans" remains to be clarified. A 45-year-old woman with chronic kidney disease along with hypothyroidism and hypertension presented with chronic diarrhea and significant weight loss. Endoscopy of the upper gastrointestinal tract showed scalloping and grooving of the duodenum, and histopathological examination showed subtotal villous atrophy. She was on telmisartan for hypertension, which was discontinued. Subsequently, diarrhea ameliorated dramatically, and she regained weight. To our knowledge, this is the first study to report telmisartan-associated sprue-like enteropathy. Further, we have reviewed the cases of patients with sprue-like enteropathy caused by valsartan, irbesartan, and eprosartan. PMID- 28670241 TI - Behcet's disease with multiple splenic abscesses in a child. AB - We report the case of a 5-year-old male patient with multiple aseptic splenic abscesses associated with Behcet's disease. The patient visited Gachon University Gil Hospital with fever, abdominal pain, and acute watery and bloody diarrhea, and reported a 2-year history of chronic abdominal pain and intermittent watery diarrhea. He was treated with antibiotics at a local clinic for fever and cervical lymph node swelling. Additionally, he had recurrent stomatitis. A colonoscopy showed multiple well-demarcated ulcerations throughout the colon, and abdominal computed tomography showed multiple splenic abscesses. Pathergy and HLA B51 tests were positive. Investigations did not reveal any infectious organisms in the aspirate obtained via ultrasound-guided fine needle aspiration. After steroid treatment, all symptoms and multiple aseptic splenic abscesses resolved. However, oral ulcers, genital ulcers, and abdominal pain recurred after tapering the steroids. Infliximab treatment improved the patient's symptoms. However, 5 months after the treatment, the symptoms recurred. The treatment was changed to include adalimumab. Subsequently, the patient's symptoms resolved and colonoscopic findings improved. No recurrence was noted after 3 months of follow up. PMID- 28670242 TI - Asymptomatic multiple cystic lesions filled with gas in the colon. PMID- 28670243 TI - Peptide Length and Dopa Determine Iron-Mediated Cohesion of Mussel Foot Proteins. AB - Mussel adhesion to mineral surfaces is widely attributed to 3,4 dihydroxyphenylalanine (Dopa) functionalities in the mussel foot proteins (mfps). Several mfps, however, show a broad range (30-100%) of Tyrosine (Tyr) to Dopa conversion suggesting that Dopa is not the only desirable outcome for adhesion. Here, we used a partial recombinant construct of mussel foot protein-1 (rmfp-1) and short decapeptide dimers with and without Dopa and assessed both their cohesive and adhesive properties on mica using a surface forces apparatus (SFA). Our results demonstrate that at low pH, both the unmodified and Dopa-containing rmfp-1s show similar energies for adhesion to mica and self-self interaction. Cohesion between two Dopa-containing rmfp-1 surfaces can be doubled by Fe3+ chelation, but remains unchanged with unmodified rmfp-1. At the same low pH, the Dopa modified short decapeptide dimer did not show any change in cohesive interactions even with Fe3+. Our results suggest that the most probable intermolecular interactions are those arising from electrostatic (i.e., cation pi) and hydrophobic interactions. We also show that Dopa in a peptide sequence does not by itself mediate Fe3+ bridging interactions between peptide films: peptide length is a crucial enabling factor. PMID- 28670244 TI - Design of Multistimuli Responsive Hydrogels Using Integrated Modeling and Genetically Engineered Silk-Elastin-Like Proteins. AB - Elastomeric, robust, and biocompatible hydrogels are rare, while the need for these types of biomaterials in biomedical-related uses remains high. Here, a new family of genetically engineered silk-elastin copolymers (SELPs) with encoded enzymatic crosslinking sites is developed for a new generation of stimuli responsive yet robust hydrogels. Input into the designs is guided by simulation, and realized via genetic engineering strategies. The avoidance of gamma irradiation or chemical crosslinking during gel fabrication, in lieu of an enzymatic process, expands the versatility of these new gels for the incorporation of labile proteins and cells. In the present study, the new SELP hydrogels offers sequence dependent, reversible stimuli-responsive features. Their stiffness covers almost the full range of the elasticity of soft tissues. Further, physical modification of the silk domains provided a secondary control point to fine-tune mechanical stiffness while preserving stimuli-responsive features, with implications for a variety of biomedical materials and device needs. PMID- 28670245 TI - Reviewing putative industrial triggering in pemphigus: cluster of pemphigus in the area near the wastewater treatment plant. AB - A range of pemphigus is relatively rare potentially fatal group of autoimmune blistering dermatoses. Usually, there is no apparent triggering, while in some predisposed patients there are alleged environmental/industrial inducing factors. In a short time period (4 years), we diagnosed 3 novel cases of pemphigus (1 pemphigus vulgaris, 1 pemphigus foliaceus and 1 shift from pemphigus foliaceus into pemphigus vulgaris) at a clinical and laboratory level (ELISA, immunofluorescence studies). We discuss a possible common inducing mechanism as these patients inhabit one estate of the Poznan suburbia (Kozieglowy, population < 12,000), Greater Poland district, Poland, and review literature data on alleged pemphigus triggers. To the best of our knowledge, this is the first report exploring the putative association between pemphigus diseases and wastewater treatment plant waterborne or volatile by-products in the vicinity of such a facility. PMID- 28670246 TI - Relationship of serum levels of interleukin 6, interleukin 8, and C-reactive protein with forced expiratory volume in first second in patients with mustard lung and chronic obstructive pulmonary diseases: systematic review and meta analysis. AB - INTRODUCTION: The chronic systemic inflammation is a result of releasing inflammatory cytokines from the cells relating to the body immunity system and chronic activation of the innate immunity system. AIM: To evaluate the relationship among serum levels of interleukin 6 (IL-6), interleukin 8 (IL-8), C reactive protein (CRP) with forced expiratory volume in 1st s (FEV1) in patients with mustard lung (ML) and chronic obstructive pulmonary diseases (COPD). MATERIAL AND METHODS: A published literature search was performed through SID, web of science, ISI, Science Direct, Scopus, Medline, and PubMed databases for articles published in English. The correlation coefficient (r) and 95% confidence intervals (95% CIs) were calculated using random or fixed effects models. Heterogeneity was assessed using chi2 and I2 statistics. RESULTS: In total, 4 published studies were included in the final analysis. Using the random-effect model, meta-analysis showed that the r was -0.052 (95% CI: -0.14-0.049, p = 0.28) at serum level of IL-8, serum levels of CRP and FEV1 in these results were r = 0.13, p = 0.012, serum levels of tumor necrosis factor (TNF) and FEV1 levels were r = -0.39, p = 0.03 in the conducted studies on mustard lung patients. The IL-6 serum level was explored in COPD patients. The results of the given studies in these patients are r = -0.006, 95% CI: -0.37-0.15, and p = 0.44. CONCLUSIONS: In this meta-analysis, there was evidence that serum levels of CRP and TNF have been significantly increased in chronic obstructive pulmonary diseases compared to the healthy control group, which signifies the presence of systemic inflammation in ML and COPD patients. PMID- 28670247 TI - Differential expression of tumor necrosis factor alpha, interleukin 1beta, nuclear factor kappaB in nasal mucosa among chronic rhinosinusitis patients with and without polyps. AB - INTRODUCTION: The pathogenesis of nasal polyps is still not fully understood. AIM: To analyze the topography and intensity of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), cyclooxygenase 2 (COX-2), nitric oxide synthase 2 (NOS-2), and nuclear factor-kappaB (NF-kappaB) expressions in eosinophilic and neutrophilic polyps and in normal nasal mucosa. MATERIAL AND METHODS: The study included specimens from 20 patients with eosinophilic polyps (more than 10% of eosinophils in inflammatory infiltrate), 20 individuals with neutrophilic polyps (predominance of neutrophils and less than 10% of eosinophils), and samples of normal nasal mucosa from 10 controls. The expressions of studied proteins in vascular endothelial cells, epithelial, stromal and glandular cells were determined immunohistochemically with specific monoclonal antibodies. RESULTS: Irrespective of the cellular type, the intensity of expressions in eosinophilic and neutrophilic polyps was significantly higher than in the normal mucosa. Eosinophilic polyps were characterized by stronger expressions of TNF-alpha (in all cellular types), IL-1beta (in endothelial, glandular and epithelial cells), NF-kappaB (in stromal and epithelial cells), COX 2 (in glandular and stromal cells), and NOS-2 (in endothelial and stromal cells). In contrast, neutrophilic polyps showed significantly stronger expressions of COX 2 (in epithelial and endothelial cells) and NOS-2 (in glandular and epithelial cells). In both phenotypes, the strongest expressions of all studied markers were documented in vascular endothelial cells. CONCLUSIONS: Inflammatory markers are involved in pathogenesis of both eosinophilic and neutrophilic polyps. Endothelial defects can play an important role in the development of nasal polyps. PMID- 28670249 TI - The effect of the training program on the quality of life in patients with asthma based on the Precede model in Ahvaz, Iran. AB - AIM: The aim of the study was to determine the effect of the training program based on the Precede model and its main components on improving the quality of life in patients with asthma. MATERIAL AND METHODS: It was a randomized quasi experimental study done on 120 patients with asthma who were referred to the Imam Khomeini hospital in Ahvaz who were selected using the convenience sampling method and were randomly divided into intervention and control groups. The data collection tool consisted of two questionnaires. The first questionnaire evaluated the quality of life in patients with asthma and the other one was developed by the researcher based on the structures of the Precede model. Training intervention was conducted during four sessions twice a week and each session was carried out for an hour based on the structures of the Precede model. In order to achieve the results, SPSS software, even t-test, and chi2 were used. RESULTS: The results showed that after the training intervention in the experimental group, the mean scores of predisposing factors (p < 0.001), enabling factors, reinforcing factors and behavioral factors were significantly increased (p < 0.001) as compared to the control group. A significant difference was observed in the mean scores of quality of life in two groups after the intervention (p < 0.001), and the quality of life of patients in the experimental group was improved after the training intervention. CONCLUSIONS: The design and implementation of the training program based on the Precede model can have a positive effect on the improvement of quality of life in patients with asthma. PMID- 28670248 TI - Allergic contact dermatitis pattern in Kuwait: nickel leads the pack. In-depth analysis of nickel allergy based on the results from a large prospective patch test series report. AB - INTRODUCTION: Contact dermatitis is a relatively common dermatosis reported among several population groups from all around the globe. However, the data from Kuwait is unavailable. Patch tests are essential for the diagnosis of contact sensitization. AIM: To determine a relative frequency and pattern of sensitizers to different allergens in patients of suspected contact dermatitis in Kuwait and, also to study the role of the commonest sensitizer in detail. MATERIAL AND METHODS: Patch tests were performed in 2461 consecutive patients with a clinical diagnosis of contact dermatitis seen at our hospital between September 1, 2014 and August 31, 2015. Out of the total of 1381 (56.1%) patients with positive patch test results to at least one allergen, 546 (22.2%) patients with a single positive reaction to nickel only (single largest sensitizer) were selected as the study population for further detailed analysis. RESULTS: At least one positive patch test reaction was found in 1381 (56.12%) patients. Nickel was found to be the most common sensitizer seen in 546 (40%) patients. The mean age was 37.3 +/ 13.8 years and the mean duration of disease was 27.3 +/-13.8 months. Most (387/546) patients sensitized were females. The forearms/hands and wrists were the most prevalent sites (52.56% of the participants). In 58.91% of women, dermatitis was more often confined to other sites, mostly ears and the neck due to earrings and necklaces. Just more than half of the number (51.09%) of nickel allergic patients were found in the age group of 15-25 years. Hairdressers/beauticians were the most affected group followed by house workers (housewives, cleaners, housekeepers). CONCLUSIONS: Nickel is the single most common sensitizer found in our patients, and female sex, young age, occupation with long hours of contact to nickel are high risk factors. We recommend that a directive, which limits the release of nickel from products with extended skin contact, be approved in Kuwait. PMID- 28670251 TI - Genetic similarities and differences between discoid and systemic lupus erythematosus patients within the Polish population. AB - INTRODUCTION: Many studies have shown that some SNPs might be a risk factor for systemic lupus erythematosus (SLE), but little is known about potential susceptibility loci of the skin types of the disease. Discoid lupus erythematosus (DLE) is the most common form of the cutaneous lupus erythematosus. Nevertheless, a genetic contribution to DLE is not fully recognized. AIM: We aimed to analyze three SNPs located in the STAT4 (rs7574865), ITGAM (rs1143679) and TNXB (rs1150754) genes in both DLE and SLE patients from Poland. MATERIAL AND METHODS: SNPs were genotyped using real-time polymerase chain reaction (PCR). Statistical significance of the differences between patient and control groups in both allele and genotype frequencies were calculated using two tailed Fisher's exact test. The correction for multiple testing by the Bonferroni adjustment and odds ratio were also calculated. RESULTS: For the first time, we have shown that the polymorphisms located in the STAT4 (rs7574865), but not in the ITGAM (rs1143679) nor the TNXB (rs1150754) genes, might be associated with the development of DLE within the Polish population. The variation of the three investigated SNPs was found to be associated with SLE in our dataset. CONCLUSIONS: The results of our study suggest differences in the molecular background between DLE and SLE within the Polish population. PMID- 28670250 TI - The relationship between severity of disease and vitamin D levels in children with atopic dermatitis. AB - INTRODUCTION: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder. Vitamin D is a liposoluble vitamin synthesized mainly in the skin. Vitamin D has several effects on the skin. AIM: To assess the serum level of vitamin D in children with AD and determine its relation to AD severity. MATERIAL AND METHODS: Sixty patients with AD were enrolled in the study. We evaluated disease severity using the SCORing Atopic Dermatitis (SCORAD) index. The control group consisted of 37 healthy subjects. RESULTS: The mean serum concentration of 25(OH)D3 in patients with AD was not statistically different from control subjects (p = 0.065). The vitamin D level was significantly lower in moderate and severe AD compared with mild AD, and this difference was statistically significant (p = 0.001 and p = 0.004). Vitamin D showed a negative correlation with serum total IgE levels (p = 0.007). There was no significant correlation between total IgE levels and SCORAD scores (p = 0.089). CONCLUSIONS: This study suggests that a low serum vitamin D level is inversely associated with severity of AD in children. Vitamin D has not been included in the routine treatment of AD because of the conflicting results of various studies. Thus, there is a need for more detailed and prospective studies. PMID- 28670253 TI - Renal involvement in leprosy: evaluation of patients in Turkey. AB - INTRODUCTION: Renal involvement in leprosy has previously been described in the literature and can include amyloidosis, glomerulonephritis, nephrosclerosis, tubulointerstitial nephritis, and granulomas. AIM: To evaluate renal involvement in Turkish patients with leprosy. MATERIAL AND METHODS: In total, 32 patients with lepromatous leprosy but without any co-morbidities and 35 healthy control subjects were evaluated for renal involvement at the Elazig Training and Research Hospital in Turkey. The laboratory tests and radiological results concerning renal function were taken from both the patients' medical records and from current examinations. RESULTS: The levels of creatinine, urea, and leukocyturia in the lepromatous leprosy patients were significantly higher than in the controls (p < 0.001, p < 0.001; p = 0.001, p < 0.01; p = 0.036, p < 0.05, respectively). No significant differences in the proteinuria, hematuria, sodium, or potassium levels were found between the leprosy and control groups (p > 0.05). On ultrasonographic examination, the prevalence of renal cortical cysts and renal cortical echogenicity in the leprosy patients was significantly higher than in the controls (p = 0.020, p < 0.05, respectively). There were no significant differences in terms of nephrolithiasis, parapelvic cysts, or hydronephrosis between the leprosy and control groups (p > 0.05). CONCLUSIONS: Evaluating the renal function in all leprosy patients is important to detect abnormalities and to prevent renal failure, which remains a potential cause of death in this disease. PMID- 28670252 TI - CD207+/langerin positive dendritic cells in invasive and in situ cutaneous malignant melanoma. AB - INTRODUCTION: Dendritic cells are crucial for cutaneous immune response. Their role in melanoma progression is however a matter of controversy. MATERIAL AND METHODS: The number of dendritic cells within epidermis and in peri- and intratumoral location was analyzed using CD207 immunostain in 17 cases of in situ and 25 case of invasive melanoma. RESULTS: Average peritumoral CD207+ cells count was 22.88 for all cases, 17.94 for in situ lesions and 26.24 for invasive cases. Average epidermal CD207+ cells count was 164.47 for all cases, 183.00 for in situ lesions and 150.78 - for invasive cases. In case of invasive melanomas, peritumoral CD207+ cells count was positively correlated with Breslow stage (R = 0.59) mitotic activity within the tumor (R = 0.62). Invasive cases with regression showed higher intratumoral and epidermal CD207+ cells count than the ones without (275.00 vs. 95.32 and 173.20 vs. 148.35) but lower peritumoral CD207+ cells count (17.60 vs. 27.26). Invasive cases with ulceration showed higher intratumoral and peritumoral CD207+ cells count than the ones without ulceration (220.08 vs. 55.67 and 44.17 vs. 9.69). CONCLUSIONS: CD207+ cells play a role in both progression and regression of melanoma but their exact role needs further studies. PMID- 28670254 TI - Trichoscopy of scalp dysesthesia. AB - INTRODUCTION: Scalp dysesthesia is characterized by localized pruritus, burning sensations or even pain. AIM: To describe characteristic trichoscopic features of scalp dysesthesia. MATERIAL AND METHODS: The study was a retrospective analysis (2010-2016) of 9 patients (8 females and 1 male; median age: 52 years; range: 38 66 years). A total of 61 trichoscopic images were analyzed by two independent evaluators. RESULTS: In all cases, oval or round areas covered with short hairs: broom hairs (77%; 7/9), block hairs (88%; 8/9), short hairs with trichorrhexis nodosa (78%; 7/9) were found. In 4 of 9 cases these areas were circumscribed by brownish linear discoloration. Background features included: areas lacking hair shafts (44%; 4/9) covered by wavy-shaped scaling, whitish areas with prominent perifollicular yellow discoloration and cloud vessels arranged around follicular openings and around empty follicles (33%, 3/9); focal brownish discoloration with darker wavy lines (78%; 7/9). CONCLUSIONS: Trichoscopy can be helpful in establishing the diagnosis of scalp dysesthesia - broom hairs, block hairs and short hairs with trichorrhexis nodosa covering the alopecia patch, uniform in length, can be considered as characteristic for this condition. PMID- 28670255 TI - 25-hydroxyvitamin D status in patients with alopecia areata. AB - INTRODUCTION: Alopecia areata (AA) is a T cell-mediated autoimmune disease that causes inflammation around anagen-phase hair follicles. Insufficient levels of vitamin D have been implicated in a variety of autoimmune diseases. AIM: To investigate the status of serum 25-hydroxyvitamin D (25(OH)D) in patients with AA, serum 25(OH)D concentrations were compared between AA patients and healthy controls and thus determine if a possible association exists between serum 25(OH)D levels and AA. MATERIAL AND METHODS: The study comprising 41 patients diagnosed with AA and 32 healthy controls was conducted between October 2010 and March 2011. The serum vitamin D levels of the study group were determined by high performance liquid chromatography. Serum levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone were also evaluated. RESULTS: The study was based on 41 patients aged between 20 and 50 (mean: 32.8 +/-7.5). The control group included 32 healthy persons aged between 20 and 51 (mean: 32.7 +/-7.5). Serum 25(OH)D levels in patients with AA ranged from 5.0 to 38.6 ng/ml with a mean of 8.1 ng/ml. Serum 25(OH)D levels in healthy controls ranged from 3.6 to 38.5 ng/ml with a mean of 9.8 ng/ml. There was no statistically significant difference in the serum vitamin D level between AA patients and healthy controls (p > 0.05). CONCLUSIONS: Deficient serum 25(OH)D levels are present in patients with AA. However, considering the high prevalence of vitamin D deficiency in Turkey, no difference was noted between AA patients and controls. PMID- 28670256 TI - Contact allergy in the population of patients with chronic inflammatory dermatoses and contact hypersensitivity to corticosteroids. AB - INTRODUCTION: Clinical studies indicate that contact allergy to glucocorticosteroids (GCS) is not rare and has been increasingly reported over the past decade. Among the risk factors for developing contact hypersensitivity to topical corticosteroids, chronic inflammatory skin diseases and polyvalent contact allergy seem to be most important. AIM: To present the structure of contact allergy in the population of patients with chronic inflammatory dermatoses (CID) and contact hypersensitivity to corticosteroids. MATERIAL AND METHODS: Twenty-seven patients with contact allergy to GCS and chronic inflammatory dermatoses were patch tested with 28 European Baseline Series allergens and 8 corticosteroid allergens. This study group consisted of 5 patients with atopic dermatitis (AD), 15 patients with contact eczema (CE) and 7 with chronic leg eczema (CLE). Nineteen (70.4%) patients were females and 8 (29.6%) were males. RESULTS: In the study group, the most sensitizing non steroidal allergens were nickel sulfate (51.8%), cobalt chloride (33.3%) and balsam of Peru (29.6%). The most sensitizing corticosteroid allergens were budesonide (77.8%), betamethasone valerate and clobetasol propionate (55.5% each). A total of 77.8% of patients allergic to GCS also showed sensitivity to at least one non-steroidal allergen from the European Baseline Series. CONCLUSIONS: The most important risk factors for developing contact allergy to corticosteroids appear to be chronic inflammatory dermatoses, long disease duration, extended on and-off topical corticosteroid use, patients presenting two or more positive patch test results and polyvalent contact allergy to metal salts and to other non steroidal haptens. PMID- 28670257 TI - Changes of Langerhans cells during skin ageing. AB - INTRODUCTION: During the process of skin ageing, changes occur in all skin layers and all cells, including the Langerhans cells. AIM: To assess whether any quantitative difference in the number of CD1a+ LC cells/mm2 and HLA-DR+ LC cells/mm2 as well as in their morphological features can be observed during the course of different types of skin ageing. MATERIAL AND METHODS: The study was conducted in a group of 60 women, which was divided into three independent groups: group I with symptoms of menopausal skin ageing, group II with symptoms of photoageing, group III with symptoms of chronological ageing. Skin biopsy samples were taken from the pre-auricular region from all of the participants. The number of CD1a+ LC cells/mm2 and HLA-DR+ LC cells/mm2 as well as their morphological features were evaluated. RESULTS: The frequency of CD1a+ LC and HLA DR+ LC in all the studied groups was diverse. In groups I and III, the LC with large cell bodies and long, multi-branched processes were the majority. In group II, the LC had small cell bodies and their processes were mainly short and unbranched. CONCLUSIONS: The obtained results indicate the presence of quantitative and morphological changes of the CD1a+ LC and HLA-DR+ LC during the course of different types of skin ageing. PMID- 28670258 TI - Insulin resistance, diabetes mellitus and thyroid dysfunction in patients with palmoplantar pustulosis: a case-controlled study. AB - INTRODUCTION: Palmoplantar pustulosis (PPP) is a chronic pustular inflammatory skin disease; however, its pathogenesis is not well understood. Several factors, such as genetics, tobacco use and autoimmune issues, may contribute to this disease. AIM: This research was conducted to investigate the relationships between insulin resistance, thyroid disease and PPP. MATERIAL AND METHODS: Thirty three patients with PPP and 27 age- and gender-matched controls were analysed for their smoking histories, thyroid function tests, anti-thyroid peroxidase antibody (anti-TPO) levels, fasting glucose, fasting insulin levels and the homeostatic model assessment (HOMA) index for insulin resistance. RESULTS: We found significant differences between the PPP and control groups according to their tobacco use and anti-TPO levels (p = 0.009 and p = 0.009, respectively). The proportion of tobacco use was 90% in the PPP patients and 63% in the controls. Gender and tobacco use were predictive risk factors for PPP in the multivariate analysis (OR = 141.7, p < 0.0001 and OR = 147.6, p = 0.006, respectively). An anti-TPO level > 35 U/ml and the presence of a thyroid abnormality were independent risk factors in the univariate, but not the multivariate analysis (OR = 4.2, p = 0.025 and OR = 5.4, p = 0.004, respectively). A moderate correlation between the gender and anti-TPO level was found (r = 0.361, p = 0.039); however, the fasting glucose, insulin and HOMA index were not significant between the PPP and control groups. CONCLUSIONS: Female gender and smoking were the most important risk factors for PPP; however, the increase in the anti-TPO level may be related to the predominance of females afflicted with this disease. Additional studies are necessary to clarify the relationships between PPP, thyroid disease and diabetes mellitus. PMID- 28670259 TI - Langerhans cell histiocytosis followed by folliculotropic mycosis fungoides. PMID- 28670260 TI - Pityriasis rosea in a patient with retrovirus infection and a history of syphilis and positive results of infection with hepatitis A virus, hepatitis B virus and hepatitis C virus. PMID- 28670261 TI - Anaphylaxis by antihistamine containing bovine gelatin: the utility of the basophil activation test in the diagnostic work-up. PMID- 28670262 TI - Lupus erythematosus panniculitis resistant to standard treatment, complicated with macrophage activation syndrome. PMID- 28670263 TI - Tone Burst Electrocochleography for the Diagnosis of Clinically Certain Meniere's Disease. AB - The technique of transtympanic electrocochleography was initially developed as an objective hearing threshold test by Eggermont. Gibson et al. (1977) claimed that an enlarged direct current component of the action potential (AP) called the summating potential (SP) is an indication of endolymphatic hydrops, later confirmed by Coates who proposed an SP/AP ratio measure. This led to numerous publications using diagnostic ratios of 0.33-0.35. The insensitivity led to an eventual disenchantment with the test as a reliable objective test for Meniere's disease. It was further confused by audiologists employing remote canal or ear drum electrodes which give a response about one-fourth of the magnitude obtained by an electrode in contact with the cochlea. Subsequently Gibson stated that an SP/AP ratio of <0.5 is not diagnostic for hydrops. He then showed that a tone burst stimulus gave the test a significantly higher sensitivity and specificity, which has been supported by others. On MRI inner ear imaging with gadolinium hydrops can be seen, but the quality of images and what is seen may vary according to brand of scanner, settings, mode of gadolinium administration, and the possibility that gadolinium entry may favor the vestibule. Transtympanic tone burst electrocochleography is to date the simplest, cheapest and most sensitive technique for detecting cochlear endolymphatic hydrops to confirm a diagnosis of Meniere's disease. PMID- 28670264 TI - Inter-Rater Reliability of Preprocessing EEG Data: Impact of Subjective Artifact Removal on Associative Memory Task ERP Results. AB - The processing of EEG data routinely involves subjective removal of artifacts during a preprocessing stage. Preprocessing inter-rater reliability (IRR) and how differences in preprocessing may affect outcomes of primary event-related potential (ERP) analyses has not been previously assessed. Three raters independently preprocessed EEG data of 16 cognitively healthy adult participants (ages 18-39 years) who performed a memory task. Using intraclass correlations (ICCs), IRR was assessed for Early-frontal, Late-frontal, and Parietal Old/new memory effects contrasts across eight regions of interest (ROIs). IRR was good to excellent for all ROIs; 22 of 26 ICCs were above 0.80. Raters were highly consistent in preprocessing across ROIs, although the frontal pole ROI (ICC range 0.60-0.90) showed less consistency. Old/new parietal effects had highest ICCs with the lowest variability. Rater preprocessing differences did not alter primary ERP results. IRR for EEG preprocessing was good to excellent, and subjective rater-removal of EEG artifacts did not alter primary memory-task ERP results. Findings provide preliminary support for robustness of cognitive/memory task-related ERP results against significant inter-rater preprocessing variability and suggest reliability of EEG to assess cognitive-neurophysiological processes multiple preprocessors are involved. PMID- 28670266 TI - GSK3alpha and GSK3beta Phosphorylate Arc and Regulate its Degradation. AB - The selective and neuronal activity-dependent degradation of synaptic proteins appears to be crucial for long-term synaptic plasticity. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which regulates the synaptic content of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), excitatory synapse strength and dendritic spine morphology. The levels of Arc protein are tightly regulated, and its removal occurs via proteasome-mediated degradation that requires prior ubiquitination. Glycogen synthase kinases alpha and beta (GSK3alpha, GSKbeta; collectively named GSK3alpha/beta) are serine-threonine kinases with abundant expression in the central nervous system. Both GSK3 isozymes are tonically active under basal conditions, but their activity is regulated by intra- and extracellular factors, intimately involved in neuronal activity. Similar to Arc, GSK3alpha and GSK3beta contribute to synaptic plasticity and the structural plasticity of dendritic spines. The present study identified Arc as a GSK3alpha/beta substrate and showed that GSKbeta promotes Arc degradation under conditions that induce de novo Arc synthesis. We also found that GSK3alpha/beta inhibition potentiated spine head thinning that was caused by the prolonged stimulation of N-methyl-D-aspartate receptors (NMDAR). Furthermore, overexpression of Arc mutants that were resistant to GSK3beta-mediated phosphorylation or ubiquitination resulted in a stronger reduction of dendritic spine width than wildtype Arc overexpression. Thus, GSK3beta terminates Arc expression and limits its effect on dendritic spine morphology. Taken together, the results identify GSK3alpha/beta-catalyzed Arc phosphorylation and degradation as a novel mechanism for controlling the duration of Arc expression and function. PMID- 28670265 TI - The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance. AB - In eukaryotic cells, the endoplasmic reticulum (ER) is the cell compartment involved in secretory protein translocation and quality control of secretory protein folding. Different conditions can alter ER function, resulting in the accumulation of unfolded or misfolded proteins within the ER lumen. Such a condition, known as ER stress, elicits an integrated adaptive response known as the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway. Conversely, in prolonged cell stress or insufficient adaptive response, UPR signaling causes cell death. ER dysfunctions are involved and contribute to neuronal degeneration in several human diseases, including Alzheimer, Parkinson and Huntington disease and amyotrophic lateral sclerosis. The correlations between ER stress and its signal transduction pathway known as the UPR with neuropathological changes are well established. In addition, much evidence suggests that genetic or pharmacological modulation of UPR could represent an effective strategy for minimizing the progressive neuronal loss in neurodegenerative diseases. Here, we review recent results describing the main cellular mechanisms linking ER stress and UPR to neurodegeneration. Furthermore, we provide an up-to-date panoramic view of the currently pursued strategies for ameliorating the toxic effects of protein unfolding in disease by targeting the ER UPR pathway. PMID- 28670268 TI - Serping1/C1 Inhibitor Affects Cortical Development in a Cell Autonomous and Non cell Autonomous Manner. AB - Current knowledge regarding regulation of radial neuronal migration is mainly focused on intracellular molecules. Our unbiased screen aimed at identification of non-cell autonomous mechanisms involved in this process detected differential expression of Serping1 or C1 inhibitor, which is known to inhibit the initiation of the complement cascade. The complement cascade is composed of three pathways; the classical, lectin, and the alternative pathway; the first two are inhibited by C1 inhibitor, and all three converge at the level of C3. Knockdown or knockout of Serping1 affected neuronal stem cell proliferation and impaired neuronal migration in mice. Knockdown of Serping1 by in utero electroporation resulted in a migration delay of the electroporated cells as well as their neighboring cells demonstrating a non-cell autonomous effect. Cellular polarity was also affected. Most importantly, expression of protein components mimicking cleaved C3 rescued the knockdown of Serping1, indicating complement pathway functionality. Furthermore, we propose that this activity is mediated mainly via the complement peptide C5a receptors. Whereas addition of a selective C3a receptor agonist was minimally effective, the addition of a dual C3aR/C5a receptor agonist significantly rescued Serping1 knockdown-mediated neuronal migration defects. Our findings suggest that modulating Serping1 levels in the developing brain may affect the complement pathway in a complex way. Collectively, our findings demonstrate an unorthodox activity for the complement pathway during brain development. PMID- 28670267 TI - Neuronal Polarity in the Embryonic Mammalian Cerebral Cortex. AB - The cerebral cortex is composed of billions of neurons that can grossly be subdivided into two broad classes: inhibitory GABAergic interneurons and excitatory glutamatergic neurons. The majority of cortical neurons in mammals are the excitatory type and they are the main focus of this review article. Like many of the cells in multicellular organisms, fully differentiated neurons are both morphologically and functionally polarized. However, they go through several changes in polarity before reaching this final mature differentiated state. Neurons are derived from polarized neuronal progenitor/stem cells and their commitment to neuronal fate is decided by cellular and molecular asymmetry during their last division in the neurogenic zone. They migrate from their birthplace using so-called multipolar migration, during which they switch direction of movement several times, and repolarize for bipolar migration when the axon is specified. Therefore, neurons have to break their previous symmetry, change their morphology and adequately respond to polarizing signals during migration in order to reach the correct position in the cortex and start making connections. Finally, the dendritic tree is elaborated and the axon/dendrite morphological polarity is set. Here we will describe the function, establishment and maintenance of polarity during the different developmental steps starting from neural stem cell (NSC) division, neuronal migration and axon specification at embryonic developmental stages. PMID- 28670269 TI - Independent Component Analysis and Source Localization on Mobile EEG Data Can Identify Increased Levels of Acute Stress. AB - Mobile electroencephalography (EEG) is a very useful tool to investigate the physiological basis of cognition under real-world conditions. However, as we move experimentation into less-constrained environments, the influence of state changes increases. The influence of stress on cortical activity and cognition is an important example. Monitoring of modulation of cortical activity by EEG measurements is a promising tool for assessing acute stress. In this study, we test this hypothesis and combine EEG with independent component analysis and source localization to identify cortical differences between a control condition and a stressful condition. Subjects performed a stationary shooting task using an airsoft rifle with and without the threat of an experimenter firing a different airsoft rifle in their direction. We observed significantly higher skin conductance responses and salivary cortisol levels (p < 0.05 for both) during the stressful conditions, indicating that we had successfully induced an adequate level of acute stress. We located independent components in five regions throughout the cortex, most notably in the dorsolateral prefrontal cortex, a region previously shown to be affected by increased levels of stress. This area showed a significant decrease in spectral power in the theta and alpha bands less than a second after the subjects pulled the trigger. Overall, our results suggest that EEG with independent component analysis and source localization has the potential of monitoring acute stress in real-world environments. PMID- 28670270 TI - Using MEG to Understand the Progression of Light Sleep and the Emergence and Functional Roles of Spindles and K-Complexes. AB - We used tomographic analysis of MEG signals to characterize regional spectral changes in the brain at sleep onset and during light sleep. We identified two key processes that may causally link to loss of consciousness during the quiet or "core" periods of NREM1. First, active inhibition in the frontal lobe leads to delta and theta spectral power increases. Second, activation suppression leads to sharp drop of spectral power in alpha and higher frequencies in posterior parietal cortex. During NREM2 core periods, the changes identified in NREM1 become more widespread, but focal increases also emerge in alpha and low sigma band power in frontal midline cortical structures, suggesting reemergence of some monitoring of internal and external environment. Just before spindles and K complexes (KCs), the hallmarks of NREM2, we identified focal spectral power changes in pre-frontal cortex, mid cingulate, and areas involved in environmental and internal monitoring, i.e., the rostral and sub-genual anterior cingulate. During both spindles and KCs, alpha and low sigma bands increases. Spindles emerge after further active inhibition (increase in delta power) of the frontal areas responsible for environmental monitoring, while in posterior parietal cortex, power increases in low and high sigma bands. KCs are correlated with increase in alpha power in the monitoring areas. These specific regional changes suggest strong and varied vigilance changes for KCs, but vigilance suppression and sharpening of cognitive processing for spindles. This is consistent with processes designed to ensure accurate and uncorrupted memory consolidation. The changes during KCs suggest a sentinel role: evaluation of the salience of provoking events to decide whether to increase processing and possibly wake up, or to actively inhibit further processing of intruding influences. The regional spectral patterns of NREM1, NREM2, and their dynamic changes just before spindles and KCs reveal an edge effect facilitating the emergence of spindles and KCs and defining the precise loci where they might emerge. In the time domain, the spindles are seen in widespread areas of the cortex just as reported from analysis of intracranial data, consistent with the emerging consensus of a differential topography that depends on the kind of memory stored. PMID- 28670271 TI - White Matter Tract Integrity in Alzheimer's Disease vs. Late Onset Bipolar Disorder and Its Correlation with Systemic Inflammation and Oxidative Stress Biomarkers. AB - Background: Late Onset Bipolar Disorder (LOBD) is the development of Bipolar Disorder (BD) at an age above 50 years old. It is often difficult to differentiate from other aging dementias, such as Alzheimer's Disease (AD), because they share cognitive and behavioral impairment symptoms. Objectives: We look for WM tract voxel clusters showing significant differences when comparing of AD vs. LOBD, and its correlations with systemic blood plasma biomarkers (inflammatory, neurotrophic factors, and oxidative stress). Materials: A sample of healthy controls (HC) (n = 19), AD patients (n = 35), and LOBD patients (n = 24) was recruited at the Alava University Hospital. Blood plasma samples were obtained at recruitment time and analyzed to extract the inflammatory, oxidative stress, and neurotrophic factors. Several modalities of MRI were acquired for each subject, Methods: Fractional anisotropy (FA) coefficients are obtained from diffusion weighted imaging (DWI). Tract based spatial statistics (TBSS) finds FA skeleton clusters of WM tract voxels showing significant differences for all possible contrasts between HC, AD, and LOBD. An ANOVA F-test over all contrasts is carried out. Results of F-test are used to mask TBSS detected clusters for the AD > LOBD and LOBD > AD contrast to select the image clusters used for correlation analysis. Finally, Pearson's correlation coefficients between FA values at cluster sites and systemic blood plasma biomarker values are computed. Results: The TBSS contrasts with by ANOVA F-test has identified strongly significant clusters in the forceps minor, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum gyrus. The correlation analysis of these tract clusters found strong negative correlation of AD with the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) blood biomarkers. Negative correlation of AD and positive correlation of LOBD with inflammation biomarker IL6 was also found. Conclusion: TBSS voxel clusters tract atlas localizations are consistent with greater behavioral impairment and mood disorders in LOBD than in AD. Correlation analysis confirms that neurotrophic factors (i.e., NGF, BDNF) play a great role in AD while are absent in LOBD pathophysiology. Also, correlation results of IL1 and IL6 suggest stronger inflammatory effects in LOBD than in AD. PMID- 28670272 TI - Behavioral and Psychological Symptoms Impact Clinical Competence in Alzheimer's Disease. AB - Decision-making is considered a fundamental aspect of personal autonomy and can be affected in psychiatric and neurologic diseases. It has been shown that cognitive deficits in dementia impact negatively on decision-making. Moreover, studies highlighted impaired clinical competence in neuropsychiatric disorders, such as schizophrenia and bipolar disorder. In this context, the current study explored the relationship between behavioral and psychological symptoms of dementia (BPSD) and clinical competence, especially the capacity to consent to treatment, in Alzheimer's disease (AD). Seventy-one patients with mild to moderate AD participated, completing assessments for capacity to consent to treatment, general cognition and neuropsychiatric disturbances. For each neuropsychiatric symptom, patients with and without the particular disturbance were compared on the different subscales of the MacArthur Competence Tool for Treatment (MacCAT-T; Understanding, Appreciation, Reasoning and Expression). The results showed that patients presenting delusions, as well as apathetic patients, had a lower ability to express a clear treatment choice compared to patients without these symptoms. By contrast, patients with dysphoria/depression had higher scores on this variable. Additionally, AD patients with euphoria had more difficulties discussing consequences of treatment alternatives compared to patients without this disturbance. None of the differences were confounded by global cognition. There were no between-group differences in clinical decision making for patients with hallucinations, agitation/aggression, anxiety, irritability, disinhibition and aberrant motor behavior. These findings highlight the importance of taking BPSD into account when assessing decision-making capacity, especially clinical competence, in AD. Furthermore, reducing BPSD may lead to better clinical competence in patients with AD, as well as to improvements in patients and caregivers' quality of life. PMID- 28670273 TI - Types and Strains: Their Essential Role in Understanding Protein Aggregation in Neurodegenerative Diseases. AB - Protein misfolding and aggregation is a key event in diseases like Alzheimer's disease (AD) or Parkinson's disease (PD) and is associated with neurodegeneration. Factors that initiate protein misfolding and the role of protein aggregation in the pathophysiology of disease pose major challenges to the neuroscientific community. Interestingly, although the accumulation of the same misfolded protein, e.g., alpha-synuclein is detectable in all idiopathic PD patients, the disease spectrum covers a variety of different clinical presentations and disease courses. In a more recent attempt this clinical variance is being explained in analogy to prion diseases by different protein aggregate conformations. In prion diseases a relationship between protein aggregate conformation properties and the clinical disease course was shown by relating different prion types to a dementia and an ataxic disease course in Creutzfeldt-Jakob patients. This principle is currently transferred to AD, PD and other neurodegenerative diseases with protein aggregation. However, differences in protein aggregate conformation are frequently addressed as disease strains. The term "strain" also derives from prion research and evolved by adopting the virus terminology at a time when transmissible spongiform encephalopathies (TSEs; later called prion diseases) were assumed to be caused by a virus. The problem is that in virus taxonomy the term "type" refers to properties of the disease agent itself and the term "strain" refers to host associated factors that interact with the disease agent and may moderately modify the clinical disease presentation. Strain factors can be discovered only after transmission and passaging of the agent in a host of a different species. The incorrect use of the terminology confuses disease agent and host factors and hampers the understanding of the pathophysiology of protein aggregate-associated neurodegenerative diseases. In this review article the discoveries are reviewed that explain how the terms "type" and "strain" emerged for unconventional disease agents. This may help to avoid confusion in the terminology of protein aggregation diseases and to reflect correctly the impact of protein aggregate conformation as well as host factor contribution on different clinical variations of AD, PD and other neurodegenerative diseases. PMID- 28670274 TI - Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation. AB - Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014): on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049), while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05) compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01) and old control mice (p < 0.05). These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes. PMID- 28670275 TI - Results of an Interdisciplinary Day Care Approach for Chronic Tinnitus Treatment: A Prospective Study Introducing the Jena Interdisciplinary Treatment for Tinnitus. AB - Objective: Considering the heterogeneity of the symptoms shown by patients suffering from chronic tinnitus, there are surprisingly few interdisciplinary treatments available, and mostly available only for inpatients. In order to provide an interdisciplinary treatment, we developed a day care concept in which each patient was treated by an ENT doctor, a cognitive behavioral therapist, a specialist for medical rehabilitation and an audiologist (Jena Interdisciplinary Treatment for Tinnitus, JITT). The aim of this study was to observe the changes of tinnitus related distress due to interdisciplinary day care treatment and to determine which factors mediate this change. Subjects and Methods: Tinnitus annoyance was measured using the Tinnitus Questionnaire on 308 patients with chronic tinnitus. They were treated in the day care unit over five consecutive days between July 2013 and December 2014. Data were collected before treatment when screened (T0), at the beginning (T1) and at the end of the 5 day treatment (T2), as well as 20 days (T3) and 6 months after treatment (T4). Results: Overall, tinnitus annoyance improved significantly from the screening day to the beginning of treatment, and to a much larger degree from the beginning to the end of treatment. The treatment outcome remained stable 6 months after treatment. Patients with the following symptoms displayed higher tinnitus annoyance at T0: dizziness at tinnitus onset, tinnitus sound could not be masked with background noise, tinnitus worsening during physical stress, comorbid psychiatric diagnosis, higher age and higher hearing loss. Loudness of tinnitus perceived in the right ear correlated with tinnitus annoyance significantly. Demographic, tinnitus and strain variables could only explain 12.8% of the variance of the change in tinnitus annoyance from T0 to T4. Out of 39 predictors, the only significant ones were "sick leave 6 months before treatment" and "tinnitus annoyance at T0." Conclusion: The newly developed JITT represents a valuable treatment for chronic tinnitus patients with improvement remaining stable for at least 6 months after treatment. Using a large number of variables did not allow predicting treatment outcome which underlines the heterogeneity of tinnitus. PMID- 28670277 TI - Nano-Lazar: Read across Predictions for Nanoparticle Toxicities with Calculated and Measured Properties. AB - The lazar framework for read across predictions was expanded for the prediction of nanoparticle toxicities, and a new methodology for calculating nanoparticle descriptors from core and coating structures was implemented. Nano-lazar provides a flexible and reproducible framework for downloading data and ontologies from the open eNanoMapper infrastructure, developing and validating nanoparticle read across models, open-source code and a free graphical interface for nanoparticle read-across predictions. In this study we compare different nanoparticle descriptor sets and local regression algorithms. Sixty independent crossvalidation experiments were performed for the Net Cell Association endpoint of the Protein Corona dataset. The best RMSE and r2 results originated from models with protein corona descriptors and the weighted random forest algorithm, but their 95% prediction interval is significantly less accurate than for models with simpler descriptor sets (measured and calculated nanoparticle properties). The most accurate prediction intervals were obtained with measured nanoparticle properties (no statistical significant difference (p < 0.05) of RMSE and r2 values compared to protein corona descriptors). Calculated descriptors are interesting for cheap and fast high-throughput screening purposes. RMSE and prediction intervals of random forest models are comparable to protein corona models, but r2 values are significantly lower. PMID- 28670276 TI - Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators. AB - This study was aimed to evaluate the possible protective effects of ursolic acid (UA) against gamma radiation induced damage both in vitro as well as in vivo. It was observed that the exposure to gamma radiation dose- and time-dependently caused a significant decrease in the cell viability, while the treatment of UA attenuated this cytotoxicity. The production of free radicals including reactive oxygen species (ROS) and NO increased significantly post-irradiation and further induced lipid peroxidation and oxidative DNA damage in cells. These deleterious effects could also be effectively blocked by UA treatment. In addition, UA also reversed gamma irradiation induced inflammatory responses, as indicated by the decreased production of TNF-alpha, IL-6, and IL-1beta. NF-kappaB signaling pathway has been reported to be a key mediator involved in gamma radiation induced cellular damage. Our results further demonstrated that gamma radiation dose- and time-dependently enhanced NF-kappaB DNA binding activity, which was significantly attenuated upon UA treatment. The post-irradiation increase in the expression of both phospho-p65, and phospho-IkappaBalpha was also blocked by UA. Moreover, the treatment of UA was found to significantly prolong overall survival in mice exposed to whole body gamma irradiation, and reduce the excessive inflammatory responses. Given its radioprotective efficacy as described here, UA as an antioxidant and NF-kappaB pathway blocker, may function as an important pharmacological agent in protecting against gamma irradiation-induced injury. PMID- 28670278 TI - Rutin Inhibits Streptococcus suis Biofilm Formation by Affecting CPS Biosynthesis. AB - Streptococcus suis (S. suis) form biofilms and causes severe diseases in humans and pigs. Biofilms are communities of microbes embedded in a matrix of extracellular polymeric substances. Eradicating biofilms with the use of antibiotics or biocides is often ineffective and needs replacement with other potential agents. Compared to conventional agents, promising and potential alternatives are biofilm-inhibiting compounds without impairing growth. Here, we screened a S. suis adhesion inhibitor, rutin, derived from Syringa. Rutin, a kind of flavonoids, shows efficient biofilm inhibition of S. suis without impairing its growth. Capsular polysaccharides(CPS) are reported to be involved in its adherence to influence bacterial biofilm formation. We investigated the effect of rutin on S. suis CPS content and structure. The results showed that rutin was beneficial to improve the CPS content of S. suis without changing its structure. We further provided evidence that rutin specifically affected S. suis biofilm susceptibility by affecting CPS biosynthesis in vitro. The study explores the antibiofilm potential of rutin against S. suis which can be used as an adhesion inhibitor for the prevention of S. suis biofilm-related infections. Nevertheless, rutin could be used as a novel natural inhibitor of biolfilm and its molecular mechanism provide basis for its pharmacological and clinical applications. PMID- 28670279 TI - Innovating Chinese Herbal Medicine: From Traditional Health Practice to Scientific Drug Discovery. AB - As one of the major contemporary alternative medicines, traditional Chinese medicine (TCM) continues its influence in Chinese communities and has begun to attract the academic attention in the world of western medicine. This paper aims to examine Chinese herbal medicine (CHM), the essential branch of TCM, from both narrative and scientific perspectives. CHM is a traditional health practice originated from Chinese philosophy and religion, holding the belief of holism and balance in the body. With the development of orthodox medicine and science during the last centuries, CHM also seized the opportunity to change from traditional health practice to scientific drug discovery illustrated in the famous story of the herb-derived drug artemisinin. However, hindered by its culture and founding principles, CHM faces the questions of the research paradigm posed by the convention of science. To address these questions, we discussed two essential questions concerning the relationship of CHM and science, and then upheld the paradigm of methodological reductionism in scientific research. Finally, the contemporary narrative of CHM in the 21st century was discussed in the hope to preserve this medical tradition in tandem with scientific research. PMID- 28670280 TI - Trends and Patterns of Disparities in Oral Cavity and Pharyngeal Cancer in Serbia: Prevalence and Economic Consequences in a Transitional Country. PMID- 28670281 TI - N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization. AB - Resistance of cancer cells to chemotherapy remains a significant problem in oncology. Mechanisms regulating programmed cell death, including apoptosis, autophagy or necrosis, in the treatment of cancers have been extensively investigated over the last few decades. Autophagy is now emerging as an important pathway in regulating cell death or survival in cancer therapy. Recent studies demonstrated variety of natural small-molecules could induce autophagic cell death in apoptosis-resistant cancer cells, therefore, discovery of novel autophagic enhancers from natural products could be a promising strategy for treatment of chemotherapy-resistant cancer. By computational virtual docking analysis, biochemical assays, and advanced live-cell imaging techniques, we have identified N-desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca2+/Calmodulin-dependent protein kinase kinase beta (CaMKKbeta)-AMPK-mTOR signaling cascades, via mobilizing calcium release through inhibition of SERCA, and importantly, lead to autophagic cell death in a panel of cancer cells, apoptosis-defective and apoptosis-resistant cells. Taken together, this study provides detailed insights into the cytotoxic mechanism of a novel autophagic compound that targeting the apoptosis resistant cancer cells, and new implication on drug discovery from natural products for drug resistant cancer therapy. PMID- 28670282 TI - Glycyrrhizin Ameliorate Ischemia Reperfusion Lung Injury through Downregulate TLR2 Signaling Cascade in Alveolar Macrophages. AB - This experiment was conducted to study whether pretreatment with Glycyrrhizin (GL) could ameliorate ischemia-reperfusion (I/R) lung injury and investigate the mechanisms of its protective effects in a mice model. Six-eight weeks male BALB/C mice were randomly assigned to four groups (n = 6): Control, Glycyrrhizin, I/R and I/R+Glycyrrhizin. Lung I/R was achieved by clamping the left hilus pulmonis. GL (200 mg/kg) was injected intraperitoneally 30 min before anesthesia. Measurement of pathohistological lung injury score, pulmonary permeability, isolated alveolar macrophages, inflammatory mediators, TLR2 and its downstream factors (MyD88, NF-kappaB) were performed. The results were as anticipated. Pathohistological evaluation indicated that GL significantly ameliorated I/R induced lung injury, pulmonary permeability and edema. Pretreatment with GL significantly inhibited I/R-induced inflammation in lung tissues and BALF. In addition, GL significantly decreased I/R-induced isolated alveolar macrophages and suppressed I/R-induced expression of TLR2 and its downstream factors in lung tissues and alveolar macrophages. Collectively, our data indicated that pretreatment with GL could ameliorate I/R lung injury. The mechanisms of its protective effects might be inhibit I/R-induced inflammatory response through downregulate TLR2 signaling cascade in alveolar macrophages. PMID- 28670283 TI - Crystal Initiation Structures in Developing Enamel: Possible Implications for Caries Dissolution of Enamel Crystals. AB - Investigations of developing enamel crystals using Atomic and Chemical Force Microscopy (AFM, CFM) have revealed a subunit structure. Subunits were seen in height images as collinear swellings about 30 nM in diameter on crystal surfaces. In friction mode they were visible as positive regions. These were similar in size (30-50 nM) to collinear spherical structures, presumably mineral matrix complexes, seen in developing enamel using a freeze fracturing/freeze etching procedure. More detailed AFM studies on mature enamel suggested that the 30-50 nM structures were composed of smaller units, ~10-15 nM in diameter. These were clustered in hexagonal or perhaps a spiral arrangement. It was suggested that these could be the imprints of initiation sites for mineral precipitation. The investigation aimed at examining original freeze etched images at high resolution to see if the smaller subunits observed using AFM in mature enamel were also present in developing enamel i.e., before loss of the organic matrix. The method used was freeze etching. Briefly samples of developing rat enamel were rapidly frozen, fractured under vacuum, and ice sublimed from the fractured surface. The fractured surface was shadowed with platinum or gold and the metal replica subjected to high resolution TEM. For AFM studies high-resolution tapping mode imaging of human mature enamel sections was performed in air under ambient conditions at a point midway between the cusp and the cervical margin. Both AFM and freeze etch studies showed structures 30-50 nM in diameter. AFM indicated that these may be clusters of somewhat smaller structures ~10-15 nM maybe hexagonally or spirally arranged. High resolution freeze etching images of very early enamel showed ~30-50 nM spherical structures in a disordered arrangement. No smaller units at 10-15 nM were clearly seen. However, when linear arrangements of 30-50 nM units were visible the picture was more complex but also smaller units including ~10-15 nM units could be observed. Conclusions: Structures ~10-15 nM in diameter were detected in developing enamel. While the appearance was complex, these were most evident when the 30-5 nM structures were in linear arrays. Formation of linear arrays of subunits may be associated with the development of mineral initiation sites and attendant processing of matrix proteins. PMID- 28670284 TI - Tensiomyographic Markers Are Not Sensitive for Monitoring Muscle Fatigue in Elite Youth Athletes: A Pilot Study. AB - Objective: Tensiomyography (TMG) is an indirect measure of a muscle's contractile properties and has the potential as a technique for detecting exercise-induced skeletal muscle fatigue. Therefore, the aim of this study was to assess the sensitivity of tensiomyographic markers to identify reduced muscular performance in elite youth athletes. Methods: Fourteen male junior tennis players (age: 14.9 +/- 1.2 years) with an international (International Tennis Federation) ranking position participated in this pre-post single group trial. They completed a 4-day high-intensity interval training (HIT) microcycle, which was composed of seven training sessions. TMG markers; countermovement jump (CMJ) performance (criterion measure of fatigue); delayed onset muscle soreness; and perceived recovery and stress were measured 24 h before and after the training program. The TMG measures included maximal radial deformation of the rectus femoris muscle belly (Dm), contraction time between 10 and 90% Dm (Tc) and the rate of deformation until 10% (V10) and 90% Dm (V90), respectively. Diagnostic characteristics were assessed with a receiver-operating curve (ROC) analysis and a contingency table, in which the area under the curve (AUC), Youden's index, sensitivity, specificity, and the diagnostic effectiveness (DE) of TMG measures were reported. A minimum AUC of 0.70 and a lower confidence interval (CI) >0.50 classified "good" diagnostic markers to assess performance changes. Results: Twenty-four hours after the microcycle, CMJ performance was observed to be significantly (p < 0.001) reduced (Effect Size [ES] = -0.68), and DOMS (ES = 3.62) as well as perceived stress were significantly (p < 0.001) increased. In contrast, Dm (ES = -0.35), Tc (ES = 0.04), V10 (ES = -0.32), and V90 (ES = -0.33) remained unchanged (p > 0.05) throughout the study. ROC analysis and the data derived from the contingency table revealed that none of the tensiomyographic markers were effective diagnostic tools for detecting impaired muscular performance in elite youth athletes (AUC, 95% CI, DE%; Dm: 0.46, 0.15-0.77, 35.7%; Tc: 0.29, 0.03-0.59, 35.7%; V10: 0.71, 0.27-1.00, 35.7%; V90: 0.37, 0.10-0.65, 35.7%). Conclusion: The tensiomyographic parameters that were assessed in this study were not sensitive enough to detect muscular performance changes in elite youth athletes.However, due to the preliminary nature of the study, further research is needed to investigate the sensitivity of TMG in this population. PMID- 28670285 TI - Muscle and Tendon Adaptation in Adolescence: Elite Volleyball Athletes Compared to Untrained Boys and Girls. AB - Though the plasticity of human tendons is well explored in adults, it is still unknown how superimposed mechanical loading by means of athletic training affects the properties of tendons during maturation. Due to the increased responsiveness of muscle to mechanical loading, adolescence is an important phase to investigate the effects of training on the mechanical properties of tendons. Hence, in the present study we compared vastus lateralis (VL) architecture, muscle strength of the knee extensor muscles and patellar tendon mechanical properties of male and female adolescent elite athletes to untrained boys and girls. Twenty-one adolescent volleyball athletes (A; 16.7 +/- 1 years; 12 boys, 9 girls) and 24 similar-aged controls (C; 16.7 +/- 1 years; 12 boys and girls, respectively) performed maximum isometric contractions on a dynamometer for the assessment of muscle strength and, by integrating ultrasound imaging, patellar tendon mechanical properties. Respective joint moments were calculated using an inverse dynamics approach and an electromyography-based estimation of antagonistic contribution. Additionally, the VL pennation angle, fascicle length and muscle thickness were determined in the inactive state by means of ultrasound. Adolescent athletes produced significantly greater knee extension moments (normalized to body mass) compared to controls (A: 4.23 +/- 0.80 Nm/kg, C: 3.57 +/- 0.67 Nm/kg; p = 0.004), and showed greater VL thickness and pennation angle (+38% and +27%; p < 0.001). Tendon stiffness (normalized to rest length) was also significantly higher in athletes (A: 86.0 +/- 27.1 kN/strain, C: 70.2 +/- 18.8 kN/strain; p = 0.04), yet less pronounced compared to tendon force (A: 5785 +/- 1146 N, C: 4335 +/- 1015 N; p < 0.001), which resulted in higher levels of tendon strain during maximum contractions in athletes (A: 8.0 +/- 1.9%, C: 6.4 +/- 1.8%; p = 0.008). We conclude that athletic volleyball training provides a more efficient stimulus for muscle compared to tendon adaptation, which results in an increased demand placed upon the tendon by the working muscle in adolescent volleyball athletes. Besides implications for sport performance, these findings might have important consequences for the risk of tendon overuse injury. PMID- 28670287 TI - Preparative SDS PAGE as an Alternative to His-Tag Purification of Recombinant Amelogenin. AB - Recombinant protein technology provides an invaluable source of proteins for use in structure-function studies, as immunogens, and in the development of therapeutics. Recombinant proteins are typically engineered with "tags" that allow the protein to be purified from crude host cell extracts using affinity based chromatography techniques. Amelogenin is the principal component of the developing enamel matrix and a frequent focus for biomineralization researchers. Several groups have reported the successful production of recombinant amelogenins but the production of recombinant amelogenin free of any tags, and at single band purity on silver stained SDS PAGE is technically challenging. This is important, as rigorous structure-function research frequently demands a high degree of protein purity and fidelity of protein sequence. Our aim was to generate His tagged recombinant amelogenin at single band purity on silver stained SDS PAGE for use in functionality studies after His-tag cleavage. An acetic acid extraction technique (previously reported to produce recombinant amelogenin at 95% purity directly from E. coli) followed by repeated rounds of nickel column affinity chromatography, failed to generate recombinant amelogenin at single band purity. This was because following an initial round of nickel column affinity chromatography, subsequent cleavage of the His-tag was not 100% efficient. A second round of nickel column affinity chromatography, used in attempts to separate the cleaved His-tag free recombinant from uncleaved His-tagged contaminants, was still unsatisfactory as cleaved recombinant amelogenin exhibited significant affinity for the nickel column. To solve this problem, we used preparative SDS PAGE to successfully purify cleaved recombinant amelogenins to single band purity on silver stained SDS PAGE. The resolving power of preparative SDS PAGE was such that His-tag based purification of recombinant amelogenin becomes redundant. We suggest that acetic acid extraction of recombinant amelogenin and subsequent purification using preparative SDS PAGE provides a simple route to highly purified His-tag free amelogenin for use in structure-function experiments and beyond. PMID- 28670286 TI - Short-Term, Low-Volume Training Improves Heat Acclimatization in an Operational Context. AB - Personnel who travel to areas with a hot climate (WBGT > 27 degrees C) may suffer from the heat (physiological strain, thermal discomfort, increased probability of heat illness), making them partially or fully inoperative. Performing physical activities during heat acclimatization is known to improve this process (i.e., improve measures of acclimatization for the same duration of acclimation). However, it is unknown whether such training would be efficient in an operative context, characterized by a high volume of work-related physical activity. Thirty French soldiers (Training group, T) performed a short (5 days), progressive, moderate (from three to five 8-min running sets at 50% of the speed at VO2max for 32-56 min) aerobic training program upon arriving at their base in United Arab Emirates (~40 degrees C and 12% RH). A control group (30 soldiers; No Training, NT) continued to perform their usual outdoor military activities (~6 h.d-1). A field heat stress test (HST; three 8-min running sets at 50% of the speed at VO2max) was performed, before and after the heat acclimatization period, to assess physiological and subjective changes. Rectal temperature, heart rate (HR), thermal discomfort at rest and at the end of exercise, rates of perceived exertion (RPE), and sweat loss and osmolality decreased following heat acclimatization in both groups. However, the decreases in the T group were larger than those in the NT group for HR at the end of exercise (-20 +/- 13 vs. -13 +/- 6 bpm, respectively, p = 0.044), thermal discomfort at rest (-2.6 +/- 2.7 vs. 1.4 +/- 2.1 cm, respectively, p = 0.013) and at the end of exercise (-2.6 +/- 1.9 vs. -1.6 +/- 1.7 cm, respectively, p = 0.037) and RPE (-2.3 +/- 1.8 vs. -1.3 +/- 1.7, respectively, p = 0.035). Thus, we showed that adding short (<60 min), daily, moderate-intensity training sessions during a professional mission in a hot and dry environment accelerated several heat-acclimatization-induced changes at rest and during exercise in only 5 days. PMID- 28670288 TI - Time Course of Metabolic Capacities in Paralarvae of the Common Octopus, Octopus vulgaris, in the First Stages of Life. Searching Biomarkers of Nutritional Imbalance. AB - The culture of the common octopus (Octopus vulgaris) is promising since the species has a relatively short lifecycle, rapid growth, and high food conversion ratios. However, recent attempts at successful paralarvae culture have failed due to slow growth and high mortality rates. Establishing an optimal nutritional regime for the paralarvae seems to be the impeding step in successful culture methods. Gaining a thorough knowledge of food regulation and assimilation is essential for paralarvae survival and longevity under culture conditions. The aim of this study, then, was to elucidate the characteristic metabolic organization of octopus paralarvae throughout an ontogenic period of 12 days post-hatching, as well as assess the effect of diet enrichment with live prey containing abundant marine phospholipids. Our results showed that throughout the ontogenic period studied, an increase in anaerobic metabolism took place largely due to an increased dependence of paralarvae on exogenous food. Our studies showed that this activity was supported by octopine dehydrogenase activity, with a less significant contribution of lactate dehydrogenase activity. Regarding aerobic metabolism, the use of amino acids was maintained for the duration of the experiment. Our studies also showed a significant increase in the rate of oxidation of fatty acids from 6 days after-hatching. A low, although sustained, capacity for de novo synthesis of glucose from amino acids and glycerol was also observed. Regardless of the composition of the food, glycerol kinase activity significantly increased a few days prior to a massive mortality event. This could be related to a metabolic imbalance in the redox state responsible for the high mortality. Thus, glycerol kinase might be used as an effective nutritional and welfare biomarker. The studies in this report also revealed the important finding that feeding larvae with phospholipid-enriched Artemia improved animal viability and welfare, significantly increasing the rate of survival and growth of paralarvae. PMID- 28670290 TI - Sex Differences in the Peripheral Immune System in Patients with Depression. AB - BACKGROUND: Females are twice as likely as males to experience depression. Recent findings indicate a relationship linking inflammation with depression. Whether the higher prevalence of depression in women is sex-specific or if inflammation contributes to a higher prevalence of depression in females is unclear. Thus, the objective was to determine whether depressed females show higher inflammation compared to males in a cross-sectional study. MATERIALS AND METHODS: Two hundred participants were enrolled. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected from all participants to measure inflammatory blood markers. RESULTS: Higher rates of suicidal thoughts, pessimism, and lassitude measured by the MADRS were seen in depressed females compared with depressed males. Among all inflammatory markers measured, there were no significant differences in depressed males vs. male controls. Increased levels of interleukin (IL)-8, interferon gamma, and leptin, and decreased levels of IL-5 and adiponectin were observed in depressed females compared to female controls. Compared with depressed males, IL 6 and leptin levels were significantly elevated in depressed females after controlling for body mass index. Correlation analysis revealed that depression severity negatively correlated with IL-12 in males, and positively correlated with IL-1beta and tumor necrosis factor (TNF)-alpha in females. IL-1beta and TNF alpha correlated with suicidal thoughts, lassitude, and pessimism in depressed females. CONCLUSION: Our findings indicate a sex-specific relationship between inflammation and depression, which may be important in identifying potential psychopathology and suggesting novel immunomodulatory treatments for depressed females. PMID- 28670291 TI - Bayesian Dimensionality Assessment for the Multidimensional Nominal Response Model. AB - This article introduces Bayesian estimation and evaluation procedures for the multidimensional nominal response model. The utility of this model is to perform a nominal factor analysis of items that consist of a finite number of unordered response categories. The key aspect of the model, in comparison with traditional factorial model, is that there is a slope for each response category on the latent dimensions, instead of having slopes associated to the items. The extended parameterization of the multidimensional nominal response model requires large samples for estimation. When sample size is of a moderate or small size, some of these parameters may be weakly empirically identifiable and the estimation algorithm may run into difficulties. We propose a Bayesian MCMC inferential algorithm to estimate the parameters and the number of dimensions underlying the multidimensional nominal response model. Two Bayesian approaches to model evaluation were compared: discrepancy statistics (DIC, WAICC, and LOO) that provide an indication of the relative merit of different models, and the standardized generalized discrepancy measure that requires resampling data and is computationally more involved. A simulation study was conducted to compare these two approaches, and the results show that the standardized generalized discrepancy measure can be used to reliably estimate the dimensionality of the model whereas the discrepancy statistics are questionable. The paper also includes an example with real data in the context of learning styles, in which the model is used to conduct an exploratory factor analysis of nominal data. PMID- 28670289 TI - Non-coding RNA Contribution to Thoracic and Abdominal Aortic Aneurysm Disease Development and Progression. AB - Multiple research groups have started to uncover the complex genetic and epigenetic machinery necessary to maintain cardiovascular homeostasis. In particular, the key contribution of non-coding RNAs (ncRNAs) in regulating gene expression has recently received great attention. Aneurysms in varying locations of the aorta are defined as permanent dilations, predisposing to the fatal consequence of rupture. The characteristic pathology of an aneurysm is characterized by progressive vessel wall dilation, promoted by dying vascular smooth muscle cells and limited proliferation, as well as impaired synthesis and degradation of extracellular matrix components, which at least partially is the result of transmural inflammation and its disruptive effect on vessel wall homeostasis. Currently no conservative pharmacological approach exists that could slow down aneurysm progression and protect from the risk of acute rupture. In the recent past, several non-coding RNAs (mainly microRNAs) have been discovered as being involved in aneurysm progression throughout varying locations of the aorta. Exploring ncRNAs as key regulators and potential therapeutic targets by using antisense oligonucleotide strategies could open up promising opportunities for patients in the near future. Purpose of this current review is to summarize current findings and novel concepts of perspectivly utilizing ncRNAs for future therapeutic and biomarker applications. PMID- 28670292 TI - Decisional Procrastination in Academic Settings: The Role of Metacognitions and Learning Strategies. AB - Nowadays, university students suffer from a broad range of problems, such as educational underachievement or the inability to control themselves, that lead to procrastination as a consequence. The present research aimed at analyzing the determinants of decisional procrastination among undergraduate students and at assessing a path model in which self regulated learning strategies mediated the relationship between metacognitive beliefs about procrastination and decisional procrastination. 273 students from Southern Italy filled out a questionnaire composed by: the socio-demographic section, the Metacognitive Beliefs About Procrastination Questionnaire, the procrastination subscale of the Melbourne Decision Making Questionnaire, and the Anxiety, the Time Management, and the Information Processing subscales of the Learning and Study Strategies Inventory. Results showed that the relationship between negative and positive metacognitive beliefs about procrastination and decisional procrastination was mediated only by time management and anxiety. Such findings underlined the crucial role played by learning strategies in predicting the tendency to delay decisional situations and in mediating the relationship between metacognitive beliefs about procrastination and decisional procrastination. PMID- 28670293 TI - Rapid Estimation of Gustatory Sensitivity Thresholds with SIAM and QUEST. AB - Adaptive methods provide quick and reliable estimates of sensory sensitivity. Yet, these procedures are typically developed for and applied to the non-chemical senses only, i.e., to vision, audition, and somatosensation. The relatively long inter-stimulus-intervals in gustatory studies, which are required to minimize adaptation and habituation, call for time-efficient threshold estimations. We therefore tested the suitability of two adaptive yes-no methods based on SIAM and QUEST for rapid estimation of taste sensitivity by comparing test-retest reliability for sucrose, citric acid, sodium chloride, and quinine hydrochloride thresholds. We show that taste thresholds can be obtained in a time efficient manner with both methods (within only 6.5 min on average using QUEST and ~9.5 min using SIAM). QUEST yielded higher test-retest correlations than SIAM in three of the four tastants. Either method allows for taste threshold estimation with low strain on participants, rendering them particularly advantageous for use in subjects with limited attentional or mnemonic capacities, and for time constrained applications during cohort studies or in the testing of patients and children. PMID- 28670294 TI - Teacher Perceptions of Their Curricular and Pedagogical Shifts: Outcomes of a Project-Based Model of Teacher Professional Development in the Next Generation Science Standards. AB - In this study, we conducted a model of teacher professional development (PD) on the alignment of middle and high school curricula and instruction to the Next Generation Science Standards (NGSSs), and evaluated the impact of the PD on teacher participants' development. The PD model included a 4-day summer academy emphasizing project-based learning (PBL) in the designing of NGSS-aligned curricula and instruction, as well as monthly follow-up Professional Learning Community meetings throughout the year providing numerous opportunities for teachers to develop and implement lesson plans, share results of lesson writing and implementation (successes and challenges), provide mutual feedback, and refine curricula and assessments. Following the summer academy, six female teachers were interviewed about their current conceptualizations of NGSS, the extent of curricular shifts made that are required by NGSS, their self perceptions regarding their level of accomplishment in curriculum writing, and the benefits of the PD in reaching their goals related to NGSS. Interviews were supplemented with an analysis of lesson plans written while participating in the PD program. The interviewed teachers suggested that they had made important conceptual and pedagogical shifts required by NGSS as they participated in the PD, and also noted a variety of challenges as they made this shift. While all teachers were relative novices at NGSS curriculum writing before the PD, most of the teachers interviewed felt that they had achieved the status of an "accomplished novice" following the summer academy. An analysis of their written lessons suggested a great range in the extent to which teachers effectively applied their understanding of NGSS to write lessons aligned to NGSS. Interviewed teachers believed that the PD model was helpful to their development as science teachers, and all reported that there were no aspects of the PD that were not helpful. Even though most teachers obtained a basic understanding and conceptualization of NGSS and PBL, their application of this understanding in their curriculum writing varied. The present study may help to inform future efforts to support teachers to align curricula and instruction to NGSS through teacher PD. PMID- 28670295 TI - Cooperative Behavior in the Ultimatum Game and Prisoner's Dilemma Depends on Players' Contributions. AB - Economic games such as the Ultimatum Game (UG) and Prisoner's Dilemma (PD) are widely used paradigms for studying fairness and cooperation. Monetary versions of these games involve two players splitting an arbitrary sum of money. In real life, however, people's propensity to engage in cooperative behavior depends on their effort and contribution; factors that are well known to affect perceptions of fairness. We therefore sought to explore the impact of relative monetary contributions by players in the UG and PD. Adapted computerized UG and PD games, in which relative contributions from each player were manipulated, were administered to 200 participants aged 18-50 years old (50% female). We found that players' contribution had large effects on cooperative behavior. Specifically, cooperation was greater amongst participants when their opponent had contributed more to joint earnings. This was manifested as higher acceptance rates and higher offers in the UG; and fewer defects in the PD compared to when the participant contributed more. Interestingly, equal contributions elicited the greatest sensitivity to fairness in the UG, and least frequent defection in the PD. Acceptance rates correlated positively with anxiety and sex differences were found in defection behavior. This study highlights the feasibility of computerized games to assess cooperative behavior and the importance of considering cooperation within the context of effortful contribution. PMID- 28670297 TI - Corrigendum: Comparison and Outcome Analysis of Patients with Takotsubo Cardiomyopathy Triggered by Emotional Stress or Physical Stress. AB - [This corrects the article on p. 527 in vol. 8, PMID: 28496419.]. PMID- 28670296 TI - The Evolution of Lateralized Brain Circuits. AB - In the vast clade of animals known as the bilateria, cerebral and behavioral asymmetries emerge against the backdrop of bilateral symmetry, with a functional trade-off between the two. Asymmetries can lead to more efficient processing and packaging of internal structures, but at the expense of efficient adaptation to a natural world without systematic left-right bias. Asymmetries may arise through the fissioning of ancestral structures that are largely symmetrical, creating new circuits. In humans these may include asymmetrical adaptations to language and manufacture, and as one or other hemisphere gains dominance for functions that were previously represented bilaterally. This is best illustrated in the evolution of such functions as language and tool manufacture in humans, which may derive from the mirror-neuron system in primates, but similar principles probably apply to the many other asymmetries now evident in a wide range of animals. Asymmetries arise in largely independent manner with multi-genetic sources, rather than as a single over-riding principle. PMID- 28670298 TI - In Vitro Differentiation of Preosteoblast-Like Cells, MC3T3-E1, to Adipocytes Is Enhanced by 1,25(OH)2 Vitamin D3. AB - Osteoblasts and adipocytes originate from common mesenchymal progenitor cells and are controlled by specific transcription factors. While 1,25-dihydroxyvitamin D3 (vitamin D) is known to be an important factor for osteoblast differentiation, there are conflicting reports regarding its effect on adipogenesis. In this study, we attempted to understand the effect of exposure of preosteoblasts (MC3T3 E1) to adipogenic media with and without vitamin D and determined the expression of adipogenic genes during this process. Our studies show that while transdifferentiation of preosteoblasts occurred on exposure to adipogenic media, the effect of vitamin D treatment was synergistic resulting in several hundred fold increase in adipocyte transcription factors C/EBPalpha and peroxisome proliferator-activated receptor-gamma (P < 0.001) along with an increase in markers of adipogenesis and accumulation of lipid droplets in cells. Vitamin D treatment was also accompanied by 100-fold to 700-fold increases in vitamin D receptor expression during the treatment period (P < 0.001). To determine how the effect of vitamin D might compare to other genetic manipulations that promote adipogenic differentiation, we stably knocked down retinoblastoma expression in MC3T3-E1 cells. Recent studies have suggested retinoblastoma (Rb1) tumor suppressor gene function to be critical to maintain osteoblasts function and inhibit adipocyte differentiation. We exposed MC3T3-E1 cells with reduced Rb1 expression to adipogenic media and found an increase in adipogenic differentiation when compared to cells with a full complement of Rb dosage. However, the extent of the change was not as dramatic as seen with vitamin D. These studies show that preosteoblasts are sensitive and respond to these manipulations that favor the adipocytic phenotype. While vitamin D is not known to directly affect targets in adipogenesis, our observations may have resulted from the malleability of preosteoblast genome in MC3T3-E1 cells, which allowed adipocyte specific gene expression under appropriate stimuli. Why this pathway is influenced and subverted by an anabolic bone factor such as vitamin D remains to be determined. PMID- 28670299 TI - Detection of Diverse N-Acyl-Homoserine Lactones in Vibrio alginolyticus and Regulation of Biofilm Formation by N-(3-Oxodecanoyl) Homoserine Lactone In vitro. AB - Quorum sensing (QS) is a cell-to-cell communication system based on the exchange of small intercellular signal molecules, such as N-Acyl homoserine lactones (AHLs), which act as cell-density mediators of QS gene expression, and are highly variable both in types and amounts in most Gram-negative Proteobacteria. Understanding the regulation of AHLs may contribute to the elucidation of cell density-dependent phenomena, such as biofilm formation. Vibrio alginolyticus is among the most frequently observed marine opportunistic Vibrio pathogens. However, AHL production of this species and its effects on biofilm formation remain to be understood. Here, our study reported the diverse AHL profiles of 47 marine-isolated V. alginolyticus strains and the effects of exogenous 3-oxo-C10 HSL on biofilm formation under different temperature conditions (16 degrees C and 28 degrees C). A total of 11 detected AHLs were produced by the isolates, of which 3-OH-C4-HSL, 3-oxo-C10-HSL and 3-oxo-C14-HSL comprised the largest proportions. We also observed that moderate levels of exogenous 3-oxo-C10-HSL (10 and 20 MUM) could induce or enhance biofilm formation and alter its structure, while high levels (40 and 100 MUM) did not significantly improve and even inhibited biofilm formation in V. alginolyticus. Further, regulation by exogenous 3-oxo-C10-HSL was both concentration- and temperature-dependent in V. alginolyticus. PMID- 28670300 TI - beta-Carotene from Yeasts Enhances Laccase Production of Pleurotus eryngii var. ferulae in Co-culture. AB - Laccase is widely used in several industrial applications and co-culture is a common method for enhancing laccase production in submerged fermentation. In this study, the co-culture of four yeasts with Pleurotus eryngii var. ferulae was found to enhance laccase production. An analysis of sterilization temperatures and extraction conditions revealed that the stimulatory compound in yeasts was temperature-sensitive, and that it was fat-soluble. An LC-MS analysis revealed that the possible stimulatory compound for laccase production in the four yeast extracts was beta-carotene. Moreover, the addition of 4 mg beta-carotene to 150 mL of P. eryngii var. ferulae culture broth improved laccase production by 2.2 fold compared with the control (i.e., a monoculture), and was similar to laccase production in co-culture. In addition, the enhanced laccase production was accompanied by an increase of lac gene transcription, which was 6.2-time higher than the control on the fifth day. Therefore, it was concluded that beta-carotene from the co-cultured yeasts enhanced laccase production in P. eryngii var. ferulae, and strains that produce beta-carotene could be selected to enhance fungal laccase production in a co-culture. Alternatively, beta-carotene or crude extracts of beta-carotene could be used to induce high laccase production in large scale. PMID- 28670301 TI - A Novel Approach for Combating Klebsiella pneumoniae Biofilm Using Histidine Functionalized Silver Nanoparticles. AB - Treating pathogens is becoming challenging because of multidrug resistance and availability of limited alternative therapies which has further confounded this problem. The situation becomes more alarming when multidrug resistant pathogens form a 3D structure known as biofilm. Biofilms are formed in most of the infections especially in chronic infections where it is difficult to eradicate them by conventional antibiotic therapy. Chemically synthesized nanoparticles are known to have antibiofilm activity but in the present study, an attempt was made to use amino acid functionalized silver nanoparticles alone and in combination with gentamicin to eradicate Klebsiella pneumoniae biofilm. Amino acid functionalized silver nanoparticles were not only able to disrupt biofilm in vitro but also led to the lowering of gentamicin dose when used in combination. To the best of our knowledge, this is the first study demonstrating the application of amino acid functionalized silver nanoparticles in the eradication of young and old K. pneumoniae biofilm. PMID- 28670302 TI - Prevalence and Genetic Diversity of Enterococcus faecalis Isolates from Mineral Water and Spring Water in China. AB - Enterococcus faecalis is an important opportunistic pathogen which is frequently detected in mineral water and spring water for human consumption and causes human urinary tract infections, endocarditis and neonatal sepsis. The aim of this study was to determine the prevalence, virulence genes, antimicrobial resistance and genetic diversity of E. faecalis from mineral water and spring water in China. Of 314 water samples collected from January 2013 to January 2014, 48 samples (15.3%) were contaminated E. faecalis. The highest contamination rate occurred in activated carbon filtered water of spring water (34.5%), followed by source water of spring water (32.3%) and source water of mineral water (6.4%). The virulence gene test of 58 E. faecalis isolates showed that the detection rates of asa1, ace, cylA, gelE and hyl were 79.3, 39.7, 0, 100, 0%, respectively. All 58 E. faecalis isolates were not resistant to 12 kinds of antibiotics (penicillin, ampicillin, linezolid, quinupristin/dalfopristin, vancomycin, gentamicin, streptomycin, ciprofloxacin, levofloxacin, norfloxacin, nitrofurantoin, and tetracycline). Enterobacterial repetitive intergenic consensus-PCR classified 58 isolates and three reference strains into nine clusters with a similarity of 75%. This study is the first to investigate the prevalence of E. faecalis in mineral water and spring water in China. The results of this study suggested that spring water could be potential vehicles for transmission of E. faecalis. PMID- 28670304 TI - Monensin and Nisin Affect Rumen Fermentation and Microbiota Differently In Vitro. AB - Nisin, a bacteriocin, is a potential alternative to antibiotics to modulate rumen fermentation. However, little is known about its impacts on rumen microbes. This study evaluated the effects of nisin (1 and 5 MUM) on in vitro rumen fermentation characteristics, microbiota, and select groups of rumen microbes in comparison with monensin (5 MUM), one of the most commonly used ionophores in ruminants. Nisin had greater effects than monensin in inhibiting methane production and decreasing acetate/propionate ratio. Unlike monensin, nisin had no adverse effect on dry matter digestibility. Real-time PCR analysis showed that both monensin and nisin reduced the populations of total bacteria, fungi, and methanogens, while the population of protozoa was reduced only by monensin. Principal component analysis of bacterial 16S rRNA gene amplicons showed a clear separation between the microbiota shaped by monensin and by nisin. Comparative analysis also revealed a significant difference in relative abundance of some bacteria in different taxa between monensin and nisin. The different effects of monensin and nisin on microbial populations and bacterial communities are probably responsible for the discrepancy in their effects on rumen fermentation. Nisin may have advantages over monensin in modulating ruminal microbial ecology and reducing ruminant methane production without adversely affecting feed digestion, and thus it may be used as a potential alternative to monensin fed to ruminants. PMID- 28670303 TI - 3-Hydroxybenzoate 6-Hydroxylase from Rhodococcus jostii RHA1 Contains a Phosphatidylinositol Cofactor. AB - 3-Hydroxybenzoate 6-hydroxylase (3HB6H, EC 1.13.14.26) is a FAD-dependent monooxygenase involved in the catabolism of aromatic compounds in soil microorganisms. 3HB6H is unique among flavoprotein hydroxylases in that it harbors a phospholipid ligand. The purified protein obtained from expressing the gene encoding 3HB6H from Rhodococcus jostii RHA1 in the host Escherichia coli contains a mixture of phosphatidylglycerol and phosphatidylethanolamine, which are the major constituents of E. coli's cytoplasmic membrane. Here, we purified 3HB6H (RjHB6H) produced in the host R. jostii RHA#2 by employing a newly developed actinomycete expression system. Biochemical and biophysical analysis revealed that Rj3HB6H possesses similar catalytic and structural features as 3HB6H, but now contains phosphatidylinositol, which is a specific constituent of actinomycete membranes. Native mass spectrometry suggests that the lipid cofactor stabilizes monomer-monomer contact. Lipid analysis of 3HB6H from Pseudomonas alcaligenes NCIMB 9867 (Pa3HB6H) produced in E. coli supports the conclusion that 3HB6H enzymes have an intrinsic ability to bind phospholipids with different specificity, reflecting the membrane composition of their bacterial host. PMID- 28670305 TI - Optimum O2:CH4 Ratio Promotes the Synergy between Aerobic Methanotrophs and Denitrifiers to Enhance Nitrogen Removal. AB - The O2:CH4 ratio significantly effects nitrogen removal in mixed cultures where aerobic methane oxidation is coupled with denitrification (AME-D). The goal of this study was to investigate nitrogen removal of the AME-D process at four different O2:CH4 ratios [0, 0.05, 0.25, and 1 (v/v)]. In batch tests, the highest denitrifying activity was observed when the O2:CH4 ratio was 0.25. At this ratio, the methanotrophs produced sufficient carbon sources for denitrifiers and the oxygen level did not inhibit nitrite removal. The results indicated that the synergy between methanotrophs and denitrifiers was significantly improved, thereby achieving a greater capacity of nitrogen removal. Based on thermodynamic and chemical analyses, methanol, butyrate, and formaldehyde could be the main trophic links of AME-D process in our study. Our research provides valuable information for improving the practical application of the AME-D systems. PMID- 28670308 TI - Growth Characteristics of an Estuarine Heterocystous Cyanobacterium. AB - A new estuarine filamentous heterocystous cyanobacterium was isolated from intertidal sediment of the Lagoa dos Patos estuary (Brazil). The isolate may represent a new genus related to Cylindrospermopsis. While the latter is planktonic, contains gas vesicles, and is toxic, the newly isolated strain is benthic and does not contain gas vesicles. It is not known whether the new strain is toxic. It grows equally well in freshwater, brackish and full salinity growth media, in the absence of inorganic or organic combined nitrogen, with a growth rate 0.6 d-1. Nitrogenase, the enzyme complex responsible for fixing dinitrogen, was most active during the initial growth phase and its activity was not different between the different salinities tested (freshwater, brackish, and full salinity seawater). Salinity shock also did not affect nitrogenase activity. The frequency of heterocysts was high, coinciding with high nitrogenase activity during the initial growth phase, but decreased subsequently. However, the frequency of heterocysts decreased considerably more at higher salinity, while no change in nitrogenase activity occurred, indicating a higher efficiency of dinitrogen fixation. Akinete frequency was low in the initial growth phase and higher in the late growth phase. Akinete frequency was much lower at high salinity, which might indicate better growth conditions or that akinete differentiation was under the same control as heterocyst differentiation. These trends have hitherto not been reported for heterocystous cyanobacteria but they seem to be well fitted for an estuarine life style. PMID- 28670307 TI - Synthetic Microbial Ecology: Engineering Habitats for Modular Consortia. AB - The metabolic diversity present in microbial communities enables cooperation toward accomplishing more complex tasks than possible by a single organism. Members of a consortium communicate by exchanging metabolites or signals that allow them to coordinate their activity through division of labor. In contrast with monocultures, evidence suggests that microbial consortia self-organize to form spatial patterns, such as observed in biofilms or in soil aggregates, that enable them to respond to gradient, to improve resource interception and to exchange metabolites more effectively. Current biotechnological applications of microorganisms remain rudimentary, often relying on genetically engineered monocultures (e.g., pharmaceuticals) or mixed-cultures of partially known composition (e.g., wastewater treatment), yet the vast potential of "microbial ecological power" observed in most natural environments, remains largely underused. In line with the Unified Microbiome Initiative (UMI) which aims to "discover and advance tools to understand and harness the capabilities of Earth's microbial ecosystems," we propose in this concept paper to capitalize on ecological insights into the spatial and modular design of interlinked microbial consortia that would overcome limitations of natural systems and attempt to optimize the functionality of the members and the performance of the engineered consortium. The topology of the spatial connections linking the various members and the regulated fluxes of media between those modules, while representing a major engineering challenge, would allow the microbial species to interact. The modularity of such spatially linked microbial consortia (SLMC) could facilitate the design of scalable bioprocesses that can be incorporated as parts of a larger biochemical network. By reducing the need for a compatible growth environment for all species simultaneously, SLMC will dramatically expand the range of possible combinations of microorganisms and their potential applications. We briefly review existing tools to engineer such assemblies and optimize potential benefits resulting from the collective activity of their members. Prospective microbial consortia and proposed spatial configurations will be illustrated and preliminary calculations highlighting the advantages of SLMC over co-cultures will be presented, followed by a discussion of challenges and opportunities for moving forward with some designs. PMID- 28670306 TI - Complement Evasion Strategies of Viruses: An Overview. AB - Being a major first line of immune defense, the complement system keeps a constant vigil against viruses. Its ability to recognize large panoply of viruses and virus-infected cells, and trigger the effector pathways, results in neutralization of viruses and killing of the infected cells. This selection pressure exerted by complement on viruses has made them evolve a multitude of countermeasures. These include targeting the recognition molecules for the avoidance of detection, targeting key enzymes and complexes of the complement pathways like C3 convertases and C5b-9 formation - either by encoding complement regulators or by recruiting membrane-bound and soluble host complement regulators, cleaving complement proteins by encoding protease, and inhibiting the synthesis of complement proteins. Additionally, viruses also exploit the complement system for their own benefit. For example, they use complement receptors as well as membrane regulators for cellular entry as well as their spread. Here, we provide an overview on the complement subversion mechanisms adopted by the members of various viral families including Poxviridae, Herpesviridae, Adenoviridae, Flaviviridae, Retroviridae, Picornaviridae, Astroviridae, Togaviridae, Orthomyxoviridae and Paramyxoviridae. PMID- 28670309 TI - Prevalence of Antibiotic-Resistant Escherichia coli in Drinking Water Sources in Hangzhou City. AB - This study investigated the distribution of antibiotic resistant Escherichia coli (E. coli) and examined the possible relationship between water quality parameters and antibiotic resistance from two different drinking water sources (the Qiantang River and the Dongtiao Stream) in Hangzhou city of China. E. coli isolates were tested for their susceptibility to 18 antibiotics. Most of the isolates were resistant to tetracycline (TE), followed by ampicillin (AM), piperacillin (PIP), trimethoprim/sulfamethoxazole (SXT), and chloramphenicol (C). The antibiotic resistance rate of E. coli isolates from two water sources was similar; For E. coli isolates from the Qiantang River, their antibiotic resistance rates decreased from up- to downstream. Seasonally, the dry and wet season had little impact on antibiotic resistance. Spearman's rank correlation revealed significant correlation between resistance to TE and phenicols or ciprofloxacin (CIP), as well as quinolones (ciprofloxacin and levofloxacin) and cephalosporins or gentamicin (GM). Pearson's chi-square tests found certain water parameters such as nutrient concentration were strongly associated with resistance to some of the antibiotics. In addition, tet genes were detected from all 82 TE-resistant E. coli isolates, and most of the isolates (81.87%) contained multiple tet genes, which displayed 14 different combinations. Collectively, this study provided baseline data on antibiotic resistance of drinking water sources in Hangzhou city, which indicates drinking water sources could be the reservoir of antibiotic resistance, potentially presenting a public health risk. PMID- 28670310 TI - Sepsis-Associated Encephalopathy: The Blood-Brain Barrier and the Sphingolipid Rheostat. AB - Sepsis is not only a significant cause of mortality worldwide but has particularly devastating effects on the central nervous system of survivors. It is therefore crucial to understand the molecular structure, physiology, and events involved in the pathogenesis of sepsis-associated encephalopathy, so that potential therapeutic advances can be achieved. A key determinant to the development of this type of encephalopathy is morphological and functional modification of the blood-brain barrier (BBB), whose function is to protect the CNS from pathogens and toxic threats. Key mediators of pathologic sequelae of sepsis in the brain include cytokines, including TNF-alpha, and sphingolipids, which are biologically active components of cellular membranes that possess diverse functions. Emerging data demonstrated an essential role for sphingolipids in the pulmonary vascular endothelium. This raises the question of whether endothelial stability in other organs systems such as the CNS may also be mediated by sphingolipids and their receptors. In this review, we will model the structure and vulnerability of the BBB and hypothesize mechanisms for therapeutic stabilization and repair following a confrontation with sepsis-induced inflammation. PMID- 28670311 TI - What Is the Molecular Signature of Mind-Body Interventions? A Systematic Review of Gene Expression Changes Induced by Meditation and Related Practices. AB - There is considerable evidence for the effectiveness of mind-body interventions (MBIs) in improving mental and physical health, but the molecular mechanisms of these benefits remain poorly understood. One hypothesis is that MBIs reverse expression of genes involved in inflammatory reactions that are induced by stress. This systematic review was conducted to examine changes in gene expression that occur after MBIs and to explore how these molecular changes are related to health. We searched PubMed throughout September 2016 to look for studies that have used gene expression analysis in MBIs (i.e., mindfulness, yoga, Tai Chi, Qigong, relaxation response, and breath regulation). Due to the limited quantity of studies, we included both clinical and non-clinical samples with any type of research design. Eighteen relevant studies were retrieved and analyzed. Overall, the studies indicate that these practices are associated with a downregulation of nuclear factor kappa B pathway; this is the opposite of the effects of chronic stress on gene expression and suggests that MBI practices may lead to a reduced risk of inflammation-related diseases. However, it is unclear how the effects of MBIs compare to other healthy interventions such as exercise or nutrition due to the small number of available studies. More research is required to be able to understand the effects of MBIs at the molecular level. PMID- 28670312 TI - Cervical Cancer Neoantigen Landscape and Immune Activity is Associated with Human Papillomavirus Master Regulators. AB - Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. In addition to HPV antigens, neoantigens derived from somatic mutations may also generate an effective immune response and represent an additional and distinct immunotherapy strategy against this and other HPV-associated cancers. To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides in two large sequencing data sets and analyzed whether mutation and neoantigen load correlate with antigen presentation, infiltrating immune cell types, and a HPV-induced master regulator gene expression signature. We found that targetable neoantigens are detected in most tumors, and there are recurrent mutated peptides from known oncogenic driver genes (KRAS, MAPK1, PIK3CA, ERBB2, and ERBB3) that are predicted to be potentially immunogenic. Our studies show that HPV-induced master regulators are not only associated with HPV load but may also play crucial roles in relation to mutation and neoantigen load, and also the immune microenvironment of the tumor. A subset of these HPV-induced master regulators positively correlated with expression of immune-suppressor molecules such as PD-L1, TGFB1, and IL-10 suggesting that they may be involved in abrogating antitumor response induced by the presence of mutations and neoantigens. Based on these results, we predict that HPV master regulators identified in our study might be potentially effective targets in cervical cancer. PMID- 28670314 TI - Modulatory Effects of Antibody Replacement Therapy to Innate and Adaptive Immune Cells. AB - Intravenous immunoglobulin administered at replacement dosages modulates innate and adaptive immune cells in primary antibody deficiencies (PAD) in a different manner to what observed when high dosages are used or when their effect is analyzed by in vitro experimental conditions. The effects seem to be beneficial on innate cells in that dendritic cells maturate, pro-inflammatory monocytes decrease, and neutrophil function is preserved. The effects are less clear on adaptive immune cells. IVIg induced a transient increase of Treg and a long-term increase of CD4 cells. More complex and less understood is the interplay of IVIg with defective B cells of PAD patients. The paucity of data underlies the need of more studies on patients with PAD before drawing conclusions on the in vivo mechanisms of action of IVIg based on in vitro investigations. PMID- 28670313 TI - Macrophage Polarization Contributes to the Anti-Tumoral Efficacy of Mesoporous Nanovectors Loaded with Albumin-Bound Paclitaxel. AB - Therapies targeted to the immune system, such as immunotherapy, are currently shaping a new, rapidly developing branch of promising cancer treatments, offering the potential to change the prognosis of previously non-responding patients. Macrophages comprise the most abundant population of immune cells in the tumor microenvironment (TME) and can undergo differentiation into functional phenotypes depending on the local tissue environment. Based on these functional phenotypes, tumor-associated macrophages (TAMs) can either aid tumor progression (M2 phenotype) or inhibit it (M1 phenotype). Presence of M2 macrophages and a high ratio of M2/M1 macrophages in the TME are clinically associated with poor prognosis in many types of cancers. Herein, we evaluate the effect of macrophage phenotype on the transport and anti-cancer efficacy of albumin-bound paclitaxel (nAb-PTX) loaded into porous silicon multistage nanovectors (MSV). Studies in a coculture of breast cancer cells (3D-spheroid) with macrophages and in vivo models were conducted to evaluate the therapeutic efficacy of MSV-nAb-PTX as a function of macrophage phenotype. Association with MSV increased drug accumulation within the macrophages and the tumor spheroids, shifting the inflammation state of the TME toward the pro-inflammatory, anti-tumorigenic milieu. Additionally, the treatment increased macrophage motility toward cancer cells, promoting the active transport of therapeutic nanovectors into the tumor lesion. Consequently, apoptosis of cancer cells was increased and proliferation decreased in the MSV-nAb-PTX-treated group as compared to controls. The results also confirmed that the tested system shifts the macrophage differentiation toward an M1 phenotype, possessing an anti-proliferative effect toward the breast cancer cells. These factors were further incorporated into a mathematical model to help analyze the synergistic effect of the macrophage polarization state on the efficacy of MSV-nAb-PTX in alleviating hypovascularized tumor lesions. In conclusion, the ability of MSV-nAb-PTX to polarize TAM to the M1 phenotype, causing (1) enhanced penetration of the drug-carrying macrophages to the center of the tumor lesion and (2) increased toxicity to tumor cells may explain the increased anti-cancer efficacy of the system in comparison to nAb-PTX and other controls. PMID- 28670315 TI - Sequence-Based Genotyping of Expressed Swine Leukocyte Antigen Class I Alleles by Next-Generation Sequencing Reveal Novel Swine Leukocyte Antigen Class I Haplotypes and Alleles in Belgian, Danish, and Kenyan Fattening Pigs and Gottingen Minipigs. AB - The need for typing of the swine leukocyte antigen (SLA) is increasing with the expanded use of pigs as models for human diseases and organ-transplantation experiments, their use in infection studies, and for design of veterinary vaccines. Knowledge of SLA sequences is furthermore a prerequisite for the prediction of epitope binding in pigs. The low number of known SLA class I alleles and the limited knowledge of their prevalence in different pig breeds emphasizes the need for efficient SLA typing methods. This study utilizes an SLA class I-typing method based on next-generation sequencing of barcoded PCR amplicons. The amplicons were generated with universal primers and predicted to resolve 68-88% of all known SLA class I alleles dependent on amplicon size. We analyzed the SLA profiles of 72 pigs from four different pig populations; Gottingen minipigs and Belgian, Kenyan, and Danish fattening pigs. We identified 67 alleles, nine previously described haplotypes and 15 novel haplotypes. The highest variation in SLA class I profiles was observed in the Danish pigs and the lowest among the Gottingen minipig population, which also have the highest percentage of homozygote individuals. Highlighting the fact that there are still numerous unknown SLA class I alleles to be discovered, a total of 12 novel SLA class I alleles were identified. Overall, we present new information about known and novel alleles and haplotypes and their prevalence in the tested pig populations. PMID- 28670317 TI - Safeguarding of Fetal Growth by Mast Cells and Natural Killer Cells: Deficiency of One Is Counterbalanced by the Other. AB - Uterine natural killer cells (uNKs) and mast cells (uMCs) are of crucial importance for spiral artery (SA) remodeling and placentation. Mice deficient for both NKs and MCs including uNKs and uMCs show markedly impaired SA remodeling and their fetuses are growth-retarded. In contrast, the absence of either NKs or MCs results in only minor impairment. This suggests that uNKs can compensate for the effects of uMCs on SA remodeling and vice versa. To test this hypothesis, we assessed uNK numbers in uMC-deficient mice as well as uMC numbers in uNK-depleted mice. Notably, uMC-deficient C57BL/6J-Kit W-sh/W-sh (W-sh) mice showed markedly increased numbers of uNKs in contrast to wild type, and the transfer of bone marrow-derived MCs reverted this phenotype. Vice versa, uNK-deficient C57BL/6NTac IL15 tm1Imx N5 (IL-15-/-) mice had significantly increased numbers of uMCs and MC specific proteases. Our results suggest that uNKs and uMCs can counterbalance their effects at the feto-maternal interface and jointly promote SA remodeling and placentation. PMID- 28670318 TI - Cigarette Smoke Increases CD8alpha+ Dendritic Cells in an Ovalbumin-Induced Airway Inflammation. AB - Asthma is an allergic lung disease and, when associated to cigarette smoke exposition, some patients show controversial signs about lung function and other inflammatory mediators. Epidemiologic and experimental studies have shown both increasing and decreasing inflammation in lungs of subjects with asthma and exposed to cigarette smoke. Therefore, in this study, we analyzed how cigarette smoke affects pro-inflammatory and anti-inflammatory mediators in a murine model of allergic pulmonary inflammation. We sensitized Balb/c mice to ovalbumin (OVA) with two intraperitoneal injections. After sensitization, the animals were exposed to cigarette smoke twice a day, 30 min per exposition, for 12 consecutive days. In order to drive the cell to the lungs, four aerosol challenges were performed every 48 h with the same allergen of sensitization. OVA sensitization and challenge developed pulmonary Th2 characteristic response with increased airway responsiveness, remodeling, increased levels of IgE, interleukin (IL)-4, and IL-13. Cigarette smoke, unexpectedly, reduced the levels of IL-4 and IL-13 and simultaneously decreased anti-inflammatory cytokines as IL-10 and transforming growth factor (TGF)-beta in sensitized and challenged animals. OVA combined with cigarette smoke exposition decreased the number of eosinophils in bronchoalveolar lavage and increased the number of neutrophils in lung. The combination of cigarette smoke and lung allergy increased recruitment of lymphoid dendritic cells (DCs) into lymph nodes, which may be the leading cause to an increase in number and activation of CD8+ T cells in lungs. In addition, lung allergy and cigarette smoke exposure decreased an important regulatory subtype of DC such as plasmacytoid DC as well as its activation by expression of CD86, PDL2, and ICOSL, and it was sufficient to decrease T regs influx and anti-inflammatory cytokines release such as IL-10 and TGF-beta but not enough to diminish the structural changes. In conclusion, we observed, in this model, that OVA sensitization and challenge combined with cigarette smoke exposure leads to mischaracterization of the Th2 response of asthma by decreasing the number of eosinophils, IL-4, and IL-13 and increasing number of neutrophils, which is related to the increased number of CD8alpha+ DCs and CD8+ T cells as well as reduction of the regulatory cells and its released cytokines. PMID- 28670316 TI - The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature. AB - Canonical or classical transient receptor potential channel 6 (TRPC6) is a Ca2+ permeable non-selective cation channel that is widely expressed in the heart, lung, and vascular tissues. The use of TRPC6-deficient ("knockout") mice has provided important insights into the role of TRPC6 in normal physiology and disease states of the pulmonary vasculature. Evidence indicates that TRPC6 is a key regulator of acute hypoxic pulmonary vasoconstriction. Moreover, several studies implicated TRPC6 in the pathogenesis of pulmonary hypertension. Furthermore, a unique genetic variation in the TRPC6 gene promoter has been identified, which might link the inflammatory response to the upregulation of TRPC6 expression and ultimate development of pulmonary vascular abnormalities in idiopathic pulmonary arterial hypertension. Additionally, TRPC6 is critically involved in the regulation of pulmonary vascular permeability and lung edema formation during endotoxin or ischemia/reperfusion-induced acute lung injury. In this review, we will summarize latest findings on the role of TRPC6 in the pulmonary vasculature. PMID- 28670319 TI - Divergence in Life History Traits between Two Populations of a Seed-Dimorphic Halophyte in Response to Soil Salinity. AB - Production of heteromorphic seeds is common in halophytes growing in arid environments with strong spatial and temporal heterogeneity. However, evidence for geographic variation (reflecting local adaptation) is almost nonexistent. Our primary aims were to compare the life history traits of two desert populations of this halophytic summer annual Suaeda corniculata subsp. mongolica and to investigate the phenotypic response of its plant and heteromorphic seeds to different levels of salt stress. Dimorphic seeds (F1) of the halophyte S. corniculata collected from two distant populations (F0) that differ in soil salinity were grown in a common environment under different levels of salinity to minimize the carryover effects from the field environment and tested for variation in plant (F1) and seed (F2) traits. Compared to F1 plants grown in low soil salinity, those grown in high salinity (>0.2 mol?L-1) were smaller and produced fewer seeds but had a higher reproductive allocation and a higher non dormant brown seed: dormant black seed ratio. High salinity during plant growth decreased germination percentage of F2 black seeds but had no effect on F2 brown seeds. Between population differences in life history traits in the common environment corresponded with those in the natural populations. Phenotypic differences between the two populations were retained in F1 plants and in F2 seeds in the common environment, which suggests that the traits are genetically based. Our results indicate that soil salinity plays an ecologically important role in population regeneration of S. corniculata by influencing heteromorphic seed production in the natural habitat. PMID- 28670320 TI - Evidence and Consequence of a Highly Adapted Clonal Haplotype within the Australian Ascochyta rabiei Population. AB - The Australian Ascochyta rabiei (Pass.) Labr. (syn. Phoma rabiei) population has low genotypic diversity with only one mating type detected to date, potentially precluding substantial evolution through recombination. However, a large diversity in aggressiveness exists. In an effort to better understand the risk from selective adaptation to currently used resistance sources and chemical control strategies, the population was examined in detail. For this, a total of 598 isolates were quasi-hierarchically sampled between 2013 and 2015 across all major Australian chickpea growing regions and commonly grown host genotypes. Although a large number of haplotypes were identified (66) through short sequence repeat (SSR) genotyping, overall low gene diversity (Hexp = 0.066) and genotypic diversity (D = 0.57) was detected. Almost 70% of the isolates assessed were of a single dominant haplotype (ARH01). Disease screening on a differential host set, including three commonly deployed resistance sources, revealed distinct aggressiveness among the isolates, with 17% of all isolates identified as highly aggressive. Almost 75% of these were of the ARH01 haplotype. A similar pattern was observed at the host level, with 46% of all isolates collected from the commonly grown host genotype Genesis090 (classified as "resistant" during the term of collection) identified as highly aggressive. Of these, 63% belonged to the ARH01 haplotype. In conclusion, the ARH01 haplotype represents a significant risk to the Australian chickpea industry, being not only widely adapted to the diverse agro-geographical environments of the Australian chickpea growing regions, but also containing a disproportionately large number of aggressive isolates, indicating fitness to survive and replicate on the best resistance sources in the Australian germplasm. PMID- 28670321 TI - An In Vitro Method for Studying the Three-Way Interaction between Soybean, Rhizophagus irregularis and the Soil-Borne Pathogen Fusarium virguliforme. AB - In this work, we described an in vitro system adequate for investigating the pathosystem soybean/arbuscular mycorrhizal fungi (AMF)/Fusarium virguliforme. Pre mycorrhized plantlets with Rhizophagus irregularis were infected by F. virguliforme either locally via a plug of gel supporting mycelium (Method 1) or via a macroconidia suspension applied to the medium surface (Method 2). Root colonization by the AMF and infection by the pathogen were similar to the usual observations in pot experiments. Within a period of 18 days, more than 20% of the roots were colonized by the AMF and infection by the pathogen was observed in all the plants. In presence of AMF, a decrease in symptoms and in the level of root tissue infection was noticed. With Method 1, smaller necrotic lesions were observed in the pre-mycorrhized plantlets. In Method 2, pathogen infection was slower but more homogenous. These results demonstrated the suitability of the in vitro cultivation system to study the pathosystem soybean/AMF/F. virguliforme. We propose this in vitro cultivation system for studying the mechanisms involved in the biocontrol conferred by AMF against F. virguliforme in soybean. PMID- 28670322 TI - A Genetic Transformation Method for Cadmium Hyperaccumulator Sedum plumbizincicola and Non-hyperaccumulating Ecotype of Sedum alfredii. AB - The present study demonstrates the development of an Agrobacterium-mediated genetic transformation method for species of the Sedum genus, which includes the Cd/Zn hyperaccumulator Sedum plumbizincicola and the non-hyperaccumulating ecotype of S. alfredii. Multiple shoots were induced from stem nodes of two Sedum plants using Murashige and Skoog (MS) medium containing 0.1 mg/L cytokinin 6 benzyladenine (6-BA) and 1.0 mg/L auxin 1-naphthaleneacetic acid (NAA). The shoot primordia were used as direct targets for Agrobacterium infection. Selection on hygromycin was highly effective in generating Agrobacterium-transformed explants. This callus-free procedure allowed us to obtain transgenic plantlets after rooting hygromycin-resistant shoots on phytohormone-free MS medium containing the antibiotic. The presence and expression of the reporter genes gusA and GFP in transgenic plants were confirmed by a real-time polymerase chain reaction, histochemical GUS assays, and confocal microscopy. This reliable method for genetic transformation of Sedum plants will help us to understand gene functions and the molecular mechanisms underlying Cd hypertolerance and hyperaccumulation in these species. PMID- 28670323 TI - Recruitment and Patch Establishment by Seed in the Seagrass Posidonia oceanica: Importance and Conservation Implications. AB - Seagrasses are declining globally, and deeper understanding is needed on the recruitment potential and distribution of new populations for many threatened species to support conservation planning in the face of climate change. Recruitment of Posidonia oceanica, a threatened seagrass endemic to the Mediterranean, has long been considered rare due to infrequent flowering, but mounting evidence demonstrates that the species is responding to a changing climate through greater reproductive effort. Due to the fragmentary information on recruit occurrence and distribution, little is known about reproductive success in the species and its contribution to persistence. We assembled P. oceanica recruitment data from published and unpublished sources, including our own, to examine the frequency and extent of recruitment events (establishment of seedlings in a site), seedling growth potential and habitat characteristics at recruitment sites. Results show that at least one recruitment event has occurred about every 3 years, and 18 localities were colonized at least one time since the first seedling record in 1986. Notably, consistently high seedling inputs were observed in four localities of the Western Mediterranean. Seedlings established mainly on unoccupied substrate areas along the coasts of islands, in sheltered sites and at shallower depths (<3 m) than the upper limit of adjacent P. oceanica meadows. Seedling establishment occurred more frequently on rocky than on sandy substrate, and rarely on dead "matte" or meadows of the seagrass Cymodocea nodosa. The chance of colonization success on rock was two times higher than on sand. Our 11 years of observations have allowed for the first time the documentation of the formation and development of patches by P. oceanica seed. These findings contradict the historical assumption that sexual recruitment is rare and usually unsuccessful for P. oceanica, and highlight the potential importance of recruitment for the long-term persistence and adaptation of the species to sea level rise predicted in the next century in the Mediterranean. Unfortunately, management actions have mainly focused on established meadows, ignoring the presence of recruits in outside areas. Therefore, it will be useful to identify and consider regeneration sites in designing future management strategies to improve seagrass conservation effectiveness. PMID- 28670324 TI - Complex Interactions between Fungal Avirulence Genes and Their Corresponding Plant Resistance Genes and Consequences for Disease Resistance Management. AB - During infection, pathogens secrete an arsenal of molecules, collectively called effectors, key elements of pathogenesis which modulate innate immunity of the plant and facilitate infection. Some of these effectors can be recognized directly or indirectly by resistance (R) proteins from the plant and are then called avirulence (AVR) proteins. This recognition usually triggers defense responses including the hypersensitive response and results in resistance of the plant. R-AVR gene interactions are frequently exploited in the field to control diseases. Recently, the availability of fungal genomes has accelerated the identification of AVR genes in plant pathogenic fungi, including in fungi infecting agronomically important crops. While single AVR genes recognized by their corresponding R gene were identified, more and more complex interactions between AVR and R genes are reported (e.g., AVR genes recognized by several R genes, R genes recognizing several AVR genes in distinct organisms, one AVR gene suppressing recognition of another AVR gene by its corresponding R gene, two cooperating R genes both necessary to recognize an AVR gene). These complex interactions were particularly reported in pathosystems showing a long co evolution with their host plant but could also result from the way agronomic crops were obtained and improved (e.g., through interspecific hybridization or introgression of resistance genes from wild related species into cultivated crops). In this review, we describe some complex R-AVR interactions between plants and fungi that were recently reported and discuss their implications for AVR gene evolution and R gene management. PMID- 28670325 TI - More Is Better: Recent Progress in Multi-Omics Data Integration Methods. AB - Multi-omics data integration is one of the major challenges in the era of precision medicine. Considerable work has been done with the advent of high throughput studies, which have enabled the data access for downstream analyses. To improve the clinical outcome prediction, a gamut of software tools has been developed. This review outlines the progress done in the field of multi-omics integration and comprehensive tools developed so far in this field. Further, we discuss the integration methods to predict patient survival at the end of the review. PMID- 28670326 TI - Isolation and biochemical characterization of bradykinin-potentiating peptides from Bitis gabonica rhinoceros. AB - BACKGROUND: Venoms represent a still underexplored reservoir of bioactive components that might mitigate or cure diseases in conditions in which conventional therapy is ineffective. The bradykinin-potentiating peptides (BPPs) comprise a class of angiotensin-I converting enzyme (ACE) inhibitors. The BPPs usually consist of oligopeptides with 5 to 13 residues with a high number of proline residues and the tripeptide Ile-Pro-Pro (IPP-tripeptide) in the C terminus region and have a conserved N-terminal pyroglutamate residue. As a whole, the action of the BPPs on prey and snakebite victims results in the decrease of the blood pressure. The aim of this work was to isolate and characterize novel BPPs from the venom of Bitis gabonica rhinoceros. METHODS: The crude venom of B. g. rhinoceros was fractionated by size exclusion chromatography and the peptide fraction (<7 kDa) was separated by reverse phase chromatography (RP-HPLC) and analyzed by ESI-IT-TOF-MS/MS. One new BPP was identified, synthetized and assayed for ACE inhibition and, in vivo, for edema potentiation. RESULTS: Typical BPP signatures were identified in three RP-HPLC fractions. CID fragmentation presented the usual y-ion of the terminal P-P fragment as a predominant signal at m/z 213.1. De novo peptide sequencing identified one Bothrops-like BPP and one new BPP sequence. The new BPP was synthesized and showed poor inhibition over ACE, but displayed significant bradykinin-induced edema potentiation. CONCLUSIONS: So far, few BPPs are described in Viperinae, and based on the sequenced peptides, two non-canonical sequences were detected. The possible clinical role of this new peptides remains unclear. PMID- 28670327 TI - Asthma pressurised metered dose inhaler performance: propellant effect studies in delivery systems. AB - BACKGROUND: Current pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant' partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured. METHODS: In-vitro studies measured gas volumes produced by pMDIs on air oxygen (O2) levels in valved holding chambers (VHC) and the falls in O2% following actuation into lung ventilator delivery devices. RESULTS: Volumes of propellant gas hydrofluoroalkane (HFA) 134a and 227ea and redundant chlorofluorocarbons (CFC) varied from 7 ml per actuation from a small salbutamol HFA inhaler to 16 ml from the larger. Similar sized CFC pMDI volumes were 15.6 and 20.4 ml. Each HFA salbutamol inhaler has 220 full volume discharges; total volume of gas from a small 134a pMDI was 1640 ml, and large 3885 ml. Sensing the presence of liquid propellant by shaking was felt at the 220th discharge in both large and small inhalers. Because of a partial pressure effect, VHC O2% in air was reduced to 11% in the smallest 127 ml volume VHC following 10 actuations of a large 134a salbutamol inhaler. The four ventilator delivery devices studied lowered 100% oxygen levels to a range of 93 to 81% after five actuations, depending on the device and type of pMDI used. CONCLUSION: Pressurised inhaler propellants require further study to assess smooth muscle relaxing properties. PMID- 28670328 TI - Long-term maintenance of diphtheria-specific antibodies after booster vaccination is hampered by latent infection with Cytomegalovirus. AB - Many currently used vaccines are less immunogenic in the elderly compared to young adults. The impact of latent infection with Cytomegalovirus (CMV) on vaccine-induced antibody responses has been discussed controversially. We have demonstrated that recall responses to diphtheria vaccination are frequently insufficient in elderly persons and that antibody concentrations decline substantially within 5 years. In the current study we show that within a cohort of healthy elderly (n = 87; median age 71 years, range 66-92) antibody responses to a booster vaccination against diphtheria do not differ between CMV-negative and CMV-positive individuals 4 weeks after vaccination.. However, the goal of diphtheria-vaccination is long-term protection and this is achieved by circulating anti-toxin antibodies. Diphtheria-specific antibody concentrations decline faster in CMV-positive compared to CMV-negative older adults leading to an increased proportion of persons without protective antibody concentrations 5 years after booster vaccination and endangering long-term protection. This finding could be relevant for vaccination schedules. PMID- 28670329 TI - The effect of effort-reward imbalance on the health of childcare workers in Hamburg: a longitudinal study. AB - BACKGROUND: The prevalence of effort-reward imbalance (ERI) among qualified childcare workers in Germany is currently estimated at around 65%. High rates of burnout and musculoskeletal symptoms (MS) have also been reported for this group. Previous longitudinal studies show inconsistent results with regard to the association between ERI and MS. As yet, no longitudinal studies have been conducted to investigate the association between ERI and burnout or MS in childcare workers. This study aims to investigate the extent to which a relationship between ERI and MS or burnout can be observed in childcare workers in Germany on a longitudinal basis. METHODS: In 2014 childcare workers (N = 199, response rate: 57%) of a provider of facilities for children and youth in Hamburg were asked about stress and health effects in the workplace. Follow-up was completed one year later (N = 106, follow-up rate: 53%) For the baseline assessment, ERI was determined as the primary influencing factor. Data on MS was recorded using the Nordic questionnaire, and burnout using the personal burnout scale of the Copenhagen Burnout Inventory (CBI). The statistical analysis was carried out using multivariate linear and logistic regression. RESULTS: At baseline ERI was present in 65% of the sample population. The mean burnout score at the time of follow-up was 53.7 (SD: 20.7); the prevalence of MS was between 19% and 62%. ERI was identified as a statistically significant factor for MS, after adjusting especially for physical stress (lower back: OR 4.2; 95% CI: 1.14 to 15.50, neck: OR 4.3; 95% CI: 1.25 to 15.0, total MS: OR 4.0; 95% CI: 1.20 to 13.49). With regard to burnout, a relative increase of 10% in the ERI ratio score increased the burnout score by 1.1 points (p = 0.034). CONCLUSIONS: ERI was revealed to be a major factor in relation to MS and burnout in childcare workers. Based on this observation worksite interventions on the individual and organizational level should be introduced in order to prevent ERI. PMID- 28670330 TI - Retraction Note: Assessment of the influence of whole body vibration on Cochlear function. AB - [This retracts the article DOI: 10.1186/1745-6673-7-12.]. PMID- 28670331 TI - A mobile NMR lab for leaf phenotyping in the field. AB - BACKGROUND: Low field NMR has been used to investigate water status in various plant tissues. In plants grown in controlled conditions, the method was shown to be able to monitor leaf development as it could detect slight variations in senescence associated with structural modifications in leaf tissues. The aim of the present study was to demonstrate the potential of NMR to provide robust indicators of the leaf development stage in plants grown in the field, where leaves may develop less evenly due to environmental fluctuations. The study was largely motivated by the need to extend phenotyping investigations from laboratory experiments to plants in their natural environment. METHODS: The mobile NMR laboratory was developed, enabling characterization of oilseed rape leaves throughout the canopy without uprooting the plant. The measurements made on the leaves of plants grown and analyzed in the field were compared to the measurements on plants grown in controlled conditions and analyzed in the laboratory. RESULTS: The approach demonstrated the potential of the method to assess the physiological status of leaves of plants in their natural environment. Comparing changes in the patterns of NMR signal evolution in plants grown under well-controlled laboratory conditions and in plants grown in the field shows that NMR is an appropriate method to detect structural modifications in leaf tissues during senescence progress despite plant heterogeneity in natural conditions. Moreover, the specific effects of the environmental factors on the structural modifications were revealed. CONCLUSION: The present study is an important step toward the selection of genotypes with high tolerance to water or nitrogen depletion that will be enabled by further field applications of the method. PMID- 28670332 TI - Relationship between Chinese medicine dietary patterns and the incidence of breast cancer in Chinese women in Hong Kong: a retrospective cross-sectional survey. AB - BACKGROUND: This retrospective cross-sectional study aimed to investigate the relationship between Chinese medicine (CM) dietary patterns (hot, neutral, and cold) and the incidence of breast cancer among Chinese women in Hong Kong. METHODS: Breast cancer cases (n = 202) and healthy controls (n = 202) were matched according to demographics. Chinese women residing in Hong Kong for the past 7 years were recruited by media advertisements (e.g., via newspapers, radio, and posters). The control participants were recruited by convenience sampling from health workshops held in clinics and communities of 15 districts of Hong Kong. After completing test-retest reliability, all participants were asked to complete diet pattern questionnaires about their food preferences and dietary patterns. The Student's unpaired t test, Chi square test, and logistic regression were conducted using SPSS software. RESULTS: Three major CM dietary patterns were identified: hot, neutral, and cold. The participants with breast cancer exhibited a stronger preference for hot food than the control group (Chi square test, P < 0.001). A higher frequency of breast cancer was associated with a higher frequency of dining out for breakfast (4-5 times per week, Chi square test, P = 0.015; 6-7 times per week, Chi square test, P < 0.001) and lunch (4-5 times per week, Chi square test, P < 0.001; 6-7 times per week, Chi square test, P = 0.006). The participants with no history of breast cancer consumed CM supplements and Guangdong soups (1-2 times per week, Chi square test, P = 0.05; >3 times per week, Chi square test, P < 0.001) more frequently than those with breast cancer. CONCLUSIONS: Non-breast cancer participants adopted a neutral (healthy and balanced) dietary pattern, and consumed CM supplements and Guangdong soups more frequently. PMID- 28670333 TI - Synchronous bilateral tonsil carcinoma: case presentation and review of the literature. AB - BACKGROUND: The incidence of synchronous bilateral tonsil carcinoma seems to be underreported. For adequate oncologic treatment, it is mandatory to remove all primaries to prevent recurrence or metachronic disease. The purpose of this manuscript is to provide a comprehensive review on this topic and to emphasize the need of bilateral tonsillectomy in cases of cancer of unknown primary (CUP) as well as in the case of a unilateral tonsillar carcinoma. MATERIAL AND METHODS: A systematic review of the literature was performed for "bilateral tonsillar neoplasm", "synchronous cancer of the oropharynx" and "cancer of unknown primary in head and neck". RESULTS: We present a clinical case with bilateral tonsillar carcinoma in initially suggested cancer of unknown primary. Clinically, both tonsillar sites were unsuspicious, but in PET/CT an ipsilateral enhancement of the tonsil area was detected. The pathological work up of bilateral tonsillectomy specimens revealed bilateral squamous cell carcinoma with HPV-type 16 positivity. The review of the literature revealed 29 cases of bilateral tonsil cancer. CONCLUSION: The handling of tonsillar tissue in the frame of panendoscopy in the case of CUP is still controversial. We recommend a bilateral tonsillectomy as a routine procedure for cancer of unknown primary as well as unilateral tonsillar carcinoma. Herewith the detrimental consequences of occult metachronous contralateral tonsillar carcinoma can be prevented. PMID- 28670334 TI - Evaluation of human cytomegalovirus antigen expression in invasive breast carcinoma in a population of Iranian patients. AB - BACKGROUND: The role of human cytomegalovirus (HCMV) in the development of breast carcinoma is questionable. The aim of this study was to evaluate the expression of the immediate early antigen (IE) of HCMV in breast carcinoma and its association with some clinicopathologic factors in a population of Iranian patients. METHODS: Formalin-fixed and paraffin-embedded tissue blocks from the pathology laboratories of the Azahra and Shahid Beheshti hospitals, Isfahan, Iran, from 2013 to 2016, were used in the study. We used immunohistochemistry and real-time PCR to detect the IE-antigen of HCMV in breast carcinoma, normal tissue adjacent to carcinoma, and normal tissue from mammoplasty specimens. RESULTS: A total of 96 samples were evaluated: 70 invasive breast carcinoma of different histologic subtypes and 26 mammoplasty normal breast tissues. All the samples were negative for IE-antigen expression. No relationship was seen between breast cancer and HCMV in this study. CONCLUSIONS: The results of this study failed to show any relationship between HCMV and the development of breast carcinoma. PMID- 28670335 TI - Clinical features of outpatients with somatization symptoms treated at a Japanese psychosomatic medicine clinic. AB - BACKGROUND: Somatization is produced due to the summation of psychological factors, irrespective of the presence or absence of physical factors. A group of diseases with severe pain and other disorders exhibit so-called Medically Unexplained Symptoms (MUS), and the characteristics of patients with MUS are largely unexplained. In this paper, the characteristics of a series of new patients with somatization treated in a Japanese university hospital are discussed. METHOD: The subjects were 871 patients who newly visited the Department of Psychosomatic Medicine, Toho University Omori Medical Center between January and December of 2015. Under the assumption that the definition of somatization is same as that of MUS, the correlation between somatization and the age, sex, academic background, chief complaints, reasons for visiting the medical center, diagnosis, symptoms, presence or absence of a referral form, continued treatment after the first visit, and marital status of these patients at the time of their respective examinations were evaluated. RESULTS: Of the patients studied, 68% suffered from somatization. Among them, 11% met the definition of Functional Somatic Symptoms (FSS) and 74% had somatization associated with mood disorder or anxiety disorder. Digestive symptoms were reported by 33%, headaches by 24%, and unusual sensations by 21%. Whereas no correlation was found between somatization symptoms and the patients' academic background, marital history, or medical history after the first visit, a positive correlation (p < 0.05) was found between somatization and patients who had been referred by their doctor. CONCLUSION: Many of the studied patients who suffered from somatization, regardless of age and sex, were referred to us by doctors from other hospitals. It was concluded that many patients difficult to diagnose or deal with are referred the Department of Psychosomatic Medicine of Japanese university hospitals, thus these hospitals must assume great responsibility for preventing mistaken diagnoses by conducting effective psychological treatment and thorough medical examinations. PMID- 28670336 TI - The relationship between salivary amylase and the physical and psychological changes elicited by continuation of autogenic training in patients with functional somatic syndrome. AB - BACKGROUND: The aim of this study was to clarify the changes in biological measures during autogenic training (AT) sessions and the relationship between these biological measures and the changes in physical and psychological measures induced by continuation of AT in patients with functional somatic syndrome (FSS). We used the salivary amylase (SAMY) level, skin temperature of the finger (TEMP), subjective symptom scores, and psychological characteristics to assess these changes. METHODS: We assessed 24 patients with FSS and 23 healthy controls before and after AT. We then conducted the same tests after the participants had practiced AT at home 1 and 2 months later. RESULTS: The baseline SAMY levels in the first session were significantly higher in the FSS group than in the control group. However, this difference was not significant in the second and third sessions. The pattern of changes in TEMP induced by AT was not different between the FSS and control groups. Tension-anxiety and somatic symptoms in patients with FSS were improved by AT. In the FSS group, the baseline SAMY levels in the first session showed a significant negative correlation with the changes in the subjective symptom score and tension-anxiety score at baseline. CONCLUSIONS: The practice of AT, both during the first session and after 1 month of continuation, eased the dysregulation of the autonomic nervous system that is reflected in SAMY in patients with FSS. AT also contributed to decreases in the tension-anxiety and somatic symptoms in patients with FSS. We suggest that SAMY is related to both physical and psychological effects of AT in patients with FSS. PMID- 28670337 TI - Clinician perceptions of sleep problems, and their treatment, in patients with non-affective psychosis. AB - Aims and method: To assess clinicians' views about their understanding and treatment of sleep problems in people with non-affective psychosis. An online survey was emailed to adult mental health teams in two NHS trusts. Results: One hundred and eleven clinicians completed the survey. All clinicians reported disrupted sleep in their patients, and endorsed the view that sleep and psychotic experiences each exacerbate the other. However, most clinicians (n = 92, 82%) assessed sleep problems informally, rather than using standard assessment measures. There was infrequent use of the recommended cognitive-behavioural treatments for sleep problems such as persistent insomnia, with the approaches typically used being sleep hygiene and medications instead. Clinical implications: Clinicians recognise the importance of sleep in psychosis, but the use of formal assessments and recommended treatments is limited. Barriers to treatment implementation identified by the clinicians related to services (e.g. lack of time), patients (e.g. their lifestyle) and environmental features of inpatient settings. PMID- 28670338 TI - Exploring the potential implementation of a tool to enhance shared decision making (SDM) in mental health services in the United Kingdom: a qualitative exploration of the views of service users, carers and professionals. AB - BACKGROUND: As a response to evidence that mental health service users and carers expect greater involvement in decisions about antipsychotic medication choice and prescribing, shared decision-making (SDM) has increasingly come to be viewed as an essential element of person-centred care and practice. However, this aspiration has yet to be realised in practice, as service users and carers continue to feel alienated from healthcare services. Existing understanding of the factors affecting the use of tools to support SDM is limited to inter individual influences and wider factors affecting potential implementation are underexplored. AIM: To explore the potential use of a tool designed to enhance collaborative antipsychotic prescribing from the perspectives of secondary care mental health service users, carers and professionals. METHODS: We conducted a qualitative study (semi-structured interviews and focus groups) using a convenience sample of 33 participants (10 mental health service users, 10 carers and 13 professionals) involved in antipsychotic prescribing in one Trust in the North of England. Participants were asked about the potential implementation of a tool to support SDM within secondary mental health services. Framework analysis incorporating the use of constant comparative method was used to analyse the data. RESULTS: The study identified a divergence in the views of service users and professionals, including a previously undocumented tendency for stakeholder groups to blame each other for potential implementation failure. This dissonance was shaped by meso and macro level influences relating to paternalism, legislative frameworks, accountability and lack of resources. Participants did not identify any macro level (policy or structural) facilitators to the use of the tool highlighting the negative impact of mental health contexts. Our study indicated that inter-individual factors are likely to be most important to implementation, given their potential to transcend meso and macro level barriers. CONCLUSIONS: Consideration of the meso and macro level influences identified areas for potential intervention, including challenging professionals' and service users' perceptions of each other, rebalancing the notion of accountability within services and introducing new means for service user feedback on the quality of SDM. Multi-level strategies for facilitating the implementation of tools to support SDM are also presented. PMID- 28670339 TI - Mental health services conceptualised as complex adaptive systems: what can be learned? AB - Despite many attempts at promoting systems integration, seamless care, and partnerships among service providers and users, mental health services internationally continue to be fragmented and piecemeal. We exploit recent ideas from complexity science to conceptualise mental health services as complex adaptive systems (CASs). The core features of CASs are described and Australia's headspace initiative is used as an example of the kinds of problems currently being faced. We argue that adopting a CAS lens can transform services, creating more connected care for service users with mental health conditions. PMID- 28670341 TI - Integrated analysis of transcriptome and metabolites reveals an essential role of metabolic flux in starch accumulation under nitrogen starvation in duckweed. AB - BACKGROUND: Duckweed is considered a promising source of energy due to its high starch content and rapid growth rate. Starch accumulation in duckweed involves complex processes that depend on the balanced expression of genes controlled by various environmental and endogenous factors. Previous studies showed that nitrogen starvation induces a global stress response and results in the accumulation of starch in duckweed. However, relatively little is known about the mechanisms underlying the regulation of starch accumulation under conditions of nitrogen starvation. RESULTS: In this study, we used next-generation sequencing technology to examine the transcriptome responses of Lemna aequinoctialis 6000 at three stages (0, 3, and 7 days) during nitrogen starvation in the presence of exogenously applied sucrose. Overall, 2522, 628, and 1832 differentially expressed unigenes (DEGs) were discovered for the treated and control samples. Clustering and enrichment analysis of DEGs revealed several biological processes occurring under nitrogen starvation. Genes involved in nitrogen metabolism showed the earliest responses to nitrogen starvation, whereas genes involved in carbohydrate biosynthesis were responded subsequently. The expression of genes encoding nitrate reductase, glutamine synthetase, and glutamate synthase was down regulated under nitrogen starvation. The expression of unigenes encoding enzymes involved in gluconeogenesis was up-regulated, while the majority of unigenes involved in glycolysis were down-regulated. The metabolite results showed that more ADP-Glc was accumulated and lower levels of UDP-Glc were accumulated under nitrogen starvation, the activity of AGPase was significantly increased while the activity of UGPase was dramatically decreased. These changes in metabolite levels under nitrogen starvation are roughly consistent with the gene expression changes in the transcriptome. CONCLUSIONS: Based on these results, it can be concluded that the increase of ADP-glucose and starch contents under nitrogen starvation is a consequence of increased output from the gluconeogenesis and TCA pathways, accompanied with the reduction of lipids and pectin biosynthesis. The results provide novel insights into the underlying mechanisms of starch accumulation during nitrogen starvation, which provide a foundation for the improvement of advanced bioethanol production in duckweed. PMID- 28670340 TI - Delivery of stromal cell-derived factor 1alpha for in situ tissue regeneration. AB - In situ tissue regeneration approach aims to exploit the body's own biological resources and reparative capability and recruit host cells by utilizing cell instructive biomaterials. In order to immobilize and release bioactive factors in biomaterials, it is important to engineer the load effectiveness, release kinetics and cell recruiting capabilities of bioactive molecules by using suitable bonding strategies. Stromal cell-derived factor 1alpha (SDF-1alpha) is one of the most potent chemokines for stem cell recruitment, and SDF-1alpha loaded scaffolds have been used for the regeneration of many types of tissues. This review summarizes the strategies to incorporate SDF-1alpha into scaffolds, including direct loading or adsorption, polyion complexes, specific heparin mediated interaction and particulate system, which may be applied to the immobilization of other chemokines or growth factors. In addition, we discuss the application of these strategies in the regeneration of tissues such as blood vessel, myocardium, cartilage and bone. PMID- 28670342 TI - 5-Aminolevulinic acid promotes arachidonic acid biosynthesis in the red microalga Porphyridium purpureum. AB - BACKGROUND: The microalga Porphyridium purpureum within Rhodophyta abundantly produces several valuable proteins, polysaccharides, pigments and long-chain polyunsaturated fatty acid; it is especially effective in accumulating arachidonic acid (ARA). However, this high ARA yield is always achieved in conditions unfavourable for cell growth. In this study, we present a method for obtaining desirable ARA levels from P. purpureum while simultaneously promoting cell growth using appropriate concentrations of the growth hormone 5 Aminolevulinic acid (5-ALA). RESULTS: Both the biomass and the ARA content of P. purpureum were enhanced by stimulation with 20 mg/L 5-ALA, leading to an optimal ARA yield of 170.32 mg/L-a 70.82% increase compared with control conditions. This ARA yield is the highest ever reported for microalgae. Based on variations in the fatty acid composition, total lipids, total proteins, total carbohydrates and pigment content during the cultivation period, we propose that the accumulation of ARA stimulated by 5-ALA occurs at the expense of other UFAs and total proteins, which may be related to decreased zeaxanthin. Lipidomic analysis revealed that triacylglycerols (TAGs) accounted for 47.5 +/- 3.6% of all detected lipids, followed by phosphatidylglycerol (PG) and digalactosyldiacylglycerol (DGDG). As the levels of the most abundant TAGs increased under 5-ALA promotion and because 78.1 +/- 3.4% (by weight) of detected TAG-branched chains contained ARA, the increase of ARA was mainly caused by TAG accumulation. CONCLUSIONS: This work demonstrated a simple and effective strategy to promote both biomass and ARA yield in P. purpureum by introducing a small amount of 5-ALA. These results are helpful for understanding the microalgae metabolic pathways affected by phytohormones and for guiding the development of bioproducts from microalgae. PMID- 28670344 TI - The influence of gender and body mass index on the FPI-6 evaluated foot posture of 10- to 14-year-old school children in Sao Paulo, Brazil: a cross-sectional study. AB - BACKGROUND: Adolescence is marked by changes to the body, including the feet. The Foot Posture Index (FPI-6) stands out from other foot type classification methods as valid, reliable, and multidimensional. However, the current literature differs according to age group, with little consolidation of normative data in school children, largely due to the influence of such factors as sex, age and body mass index (BMI). Thus, this study assesses foot posture in adolescents according to age, sex and BMI. METHODS: The study evaluated 1.394 adolescents from Amparo and Pedreira regions in Sao Paulo, Brazil. Subjects were positioned barefoot on a wooden base and each foot was assessed by FPI-6 criteria. Each criterion was scored on a scale of -2 to +2, negative for supinated and positive for pronated posture. Initially the data were assessed for normality using the Shapiro-Wilk test and descriptive statistics were calculated. To investigate and compare the scores of FPI-6 with regards to age and body mass index, analysis of variance (ANOVA) was used, followed by post hoc Tukey. To compare the FPI-6 with regard to gender, an independent student t test was used. All data were analyzed using SPSS version 21.0 and the 5% significance level. RESULTS: Boys had higher scores than girls (p = 0.037) for the right foot, and the group with normal BMI values scored higher than the obese group (p = 0.001). For the left foot, 11- and 13-year-olds differed (p = 0.024) with respect to age in general. The overweight and obese group scored lower than the normal BMI group (p = 0.039; p = 0.001, respectively). CONCLUSIONS: Overall, the feet in this study were classified as normal, with a tendency to pronation, particularly in boys. There were differences between the 11 and 13 year groups and, with regard to BMI, there were higher scores for the group with normal BMI. Therefore, a higher BMI in adolescence is not indicative of a pronated foot type. PMID- 28670343 TI - Differential diagnosis of neuromyelitis optica spectrum disorders. AB - Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disorder of the central nervous system (CNS) mostly manifesting as optic neuritis and/or myelitis, which are frequently recurrent/bilateral or longitudinally extensive, respectively. As the autoantibody to aquaporin-4 (AQP4-Ab) can mediate the pathogenesis of NMOSD, testing for the AQP4-Ab in serum of patients can play a crucial role in diagnosing NMOSD. Nevertheless, the differential diagnosis of NMOSD in clinical practice is often challenging despite the phenotypical and serological characteristics of the disease because: (1) diverse diseases with autoimmune, vascular, infectious, or neoplastic etiologies can mimic these phenotypes of NMOSD; (2) patients with NMOSD may only have limited clinical manifestations, especially in their early disease stages; (3) test results for AQP4-Ab can be affected by several factors such as assay methods, serologic status, disease stages, or types of treatment; (4) some patients with NMOSD do not have AQP4-Ab; and (5) test results for the AQP4-Ab may not be readily available for the acute management of patients. Despite some similarity in their phenotypes, these NMOSD and NMOSD-mimics are distinct from each other in their pathogenesis, prognosis, and most importantly treatment. Understanding the detailed clinical, serological, radiological, and prognostic differences of these diseases will improve the proper management as well as diagnosis of patients. PMID- 28670345 TI - The comparative efficacy of angiosome-directed and indirect revascularisation strategies to aid healing of chronic foot wounds in patients with co-morbid diabetes mellitus and critical limb ischaemia: a literature review. AB - BACKGROUND: Ischaemic ulcerations have been reported to persist and/or deteriorate despite technically successful revascularisations; a higher incidence of which affects patients with diabetes and critical limb ischaemia. In the context of wound healing, it is unclear if applications of the angiosome concept in 'direct revascularisation' (DR) would be able to aid the healing of chronic foot ulcerations better than the current 'best vessel' or 'indirect revascularisation' (IR) strategy in patients with co-morbid diabetes and critical limb ischaemia. METHODS: A literature search was conducted in eight electronic databases, namely AMED, CINAHL, The Cochrane Library, ProQuest Health & Medicine Complete, ProQuest Nursing & Allied Health Source, PubMed, ScienceDirect and TRIP database. Articles were initially screened against a pre-established inclusion and exclusion criteria to determine eligibility and subsequently appraised using the Newcastle-Ottawa Scale. RESULTS: Five retrospective studies of varying methodological quality were eligible for inclusion in this review. Critical analysis of an aggregated population (n = 280) from methodologically stronger studies indicates better wound healing outcomes in subjects who had undergone DR as compared to IR (p < 0.001; p = 0.04). DR also appears to result in a nearly twofold increase in probability of wound healing within 12 months (hazard ratio, 1.97; 95% CI, 1.34-2.90). This suggests that achieving direct arterial perfusion to the site of ulceration may be important for the healing of chronic diabetic foot ulcerations. CONCLUSION: Incorporating an angiosome-directed approach in the lower limb revascularisation strategy could be a very useful adjunct to a solely indirect approach, which could increase the likelihood of wound healing. With the limited data currently available, findings appear promising and merit from further investigation. Additional research to form a solid evidence base for this revised strategy in patients with co-morbid diabetes and critical limb ischaemia is warranted. PMID- 28670346 TI - Molecular characterization of Klebsiella pneumoniae isolates from stool specimens of outpatients in sentinel hospitals Beijing, China, 2010-2015. AB - BACKGROUND: Klebsiella pneumoniae (K. pneumoniae) is an opportunistic pathogen associated with community-acquired infections and nosocomial infections. From 2010 to 2015, K. pneumoniae testing was included into the exiting diarrhea syndrome surveillance with objective to estimate the prevalence of K. pneumoniae in diarrhea-syndrome patients, test antibiotics susceptibility and investigate molecular characteristics. METHODS: Stool specimens from diarrhea-syndrome outpatients were cultured and identified the pathogens by the Vitek2 Compact instrument. The isolated K. pneumoniae strains were tested for antibiotics susceptibility by minimal inhibitory concentration (MIC) method, and subtyped by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: 22 K. pneumoniae strains were identified from 4340 stool specimens of outpatients who visited sentinel hospitals in Beijing during 2010-2015. All strains were sensitive to gentamicin, nalidixic acid, ciprofloxacin, ceftriaxone, cefotaxime, cefepime, imipenem. The highest resistance rate of K. pneumoniae strains was 100% to amoxicillin-clavulanate, followed by 72.7% to ampicillin. These 22 K. pneumoniae strains were characterized into 21 different PFGE types and 20 MLST types with less similarity. CONCLUSIONS: The detection rate of K. pneumoniae in stool specimens from outpatients with diarrhea syndromes was about 0.5% in Beijing. Less similarity of the isolated strains indicated the unlikely long-term circulating of K. pneumoniae in the community. ST23 was the most common genotype. Drug resistance of the community-acquired K. pneumoniae was not a serious problem in comparing with hospital-acquired infections. High vigilance in the community-acquired K. pneumoniae strains and investigation of pathogens' microbiological characteristics are valuable for signals detection for drug resistance in population and strains variation. PMID- 28670347 TI - Low serum adiponectin level is associated with metabolic syndrome and is an independent marker of peripheral arterial stiffness in hypertensive patients. AB - BACKGROUND: Adiponectin has been implicated in metabolic syndrome (MetS) and arterial stiffness (AS). We aim to determine the relationship between serum adiponectin concentration as well as peripheral AS in hypertensive patients. METHODS: Fasting blood samples were obtained from 101 hypertensive patients. Brachial-ankle pulse wave velocity (baPWV) was measured with an automatic pulse wave analyzer. Serum adiponectin concentrations were determined by using an enzyme immunoassay kit. A baPWV >14.0 m/s was defined as high AS. RESULTS: MetS and high AS were present in 62.4 and 71.3% of the study population. Adiponectin was inversely associated with MetS and high AS (both P < 0.001). Serum higher high-density lipoprotein cholesterol (HDL-C) (P = 0.012), triglycerides (P = 0.001), C-reactive protein (P < 0.001), insulin (P = 0.027), body weight (P = 0.002), waist circumference (WC, P < 0.001), body mass index (P = 0.001) bilateral-baPWV (P < 0.001), systolic blood pressure (SBP, P < 0.001), diastolic blood pressure (DBP, P = 0.012), pulse pressure (P = 0.019), homeostasis model assessment of insulin resistance (HOMA1-IR (P = 0.026) and HOMA2-IR (P = 0.020)) and lower glomerular filtration rate (GFR, P = 0.029) were significantly associated with high AS. Multivariate logistic regression analysis of the factors significantly associated with AS revealed that adiponectin [odds ratio: 0.932, 95% confidence interval (CI) 0.881-0.985, P = 0.012], and SBP (odds ratio: 1.059, 95% CI 1.008-1.113, P = 0.022) were the independent predictors of arterial stiffness in hypertensive patients. Subgroup analysis revealed that SBP (odds ratio: 1.126, 95% CI 1.024-1.237, P = 0.014) and GFR (odds ratio: 0.858, 95% CI 0.739-0.996, P = 0.043) were the independent predictors of arterial stiffness in hypertensive patients without MetS; adiponectin (odds ratio: 0.909, 95% CI 0.931 0.996, P = 0.040) was the independent predictor of arterial stiffness in hypertensive patients with MetS. CONCLUSIONS: Hypoadiponectinemia has positive association with MetS and peripheral AS in hypertensive patients. PMID- 28670348 TI - Proton reduction reaction catalyzed by homoleptic nickel bis-1,2-dithiolate complexes: Experimental and theoretical mechanistic investigations. AB - A series of homoleptic monoanionic nickel dithiolene complexes [Ni(bdt)2](NBu4), [Ni(tdt)2](NBu4), and [Ni(mnt)2](NBu4) containing the ligands benzene-1,2 dithiolate (bdt2-), toluene-3,4-dithiolate (tdt2-) and maleonitriledithiolate (mnt2-), respectively, have been employed as electrocatalysts in the hydrogen evolution reaction with trifluoroacetic acid as proton source in acetonitrile. All complexes were active catalysts with TONs reaching 113, 158 and 6 for [Ni(bdt)2](NBu4), [Ni(tdt)2](NBu4), and [Ni(mnt)2](NBu4), respectively. Faradaic yield for hydrogen evolution reaction reaches 88 % for 2- , which also displays the minimal overpotential requirement value (467 mV) within the series. Two pathways for H2 evolution can be hypothesized that differ on on the sequence of protonation and reduction steps. DFT calculations are in agreement with experimental data and indicate that protonation at sulfur follows reduction to the dianion. Hydrogen evolves from the direduced-diprotonated form via a highly distorted nickel hydride intermediate. The effects of acid strength and concentration in the hydrogen-evolving mechanism are also discussed. PMID- 28670350 TI - Computer-aided surgery meets predictive, preventive, and personalized medicine. AB - Computer-aided surgery (CAS) is now nearly 30 years old. It has brought to surgery a variety of tools, techniques, and paradigm changes that have had an impact on how surgeries are planned, executed, and evaluated. In this review, we examine the predictive, preventive, and personalized medicine (PPPM) aspects of CAS. We present a brief history of CAS, summarize its the state of the art, and discuss current trends and future developments related to PPPM. Of the three Ps, we note that the most important impact of CAS is on Personalization, in all the steps of the surgical treatment: preoperative planning, intraoperative execution, and postoperative evaluation. Prediction in CAS is reflected in the preoperative evaluation of the various surgical options and in the evaluation of the possible surgical outcomes. Prevention in CAS is related to intraoperative execution, to help prevent possible surgical complications. We foresee that CAS will play an increasingly important role in PPPM in the coming years. PMID- 28670352 TI - Flow and transport effect caused by the stalk contraction cycle of Vorticella convallaria. AB - Vorticella convallaria is a protozoan attached to a substrate by a stalk which can contract in less than 10 ms, translating the zooid toward the substrate with a maximum Reynolds number of ~1. Following contraction, the stalk slowly relaxes, moving the zooid away from the substrate, which results in creeping flow. Although Vorticella has long been believed to contract to evade danger, it has been suggested that its stalk may contract to enhance food transport near the substrate. To elucidate how Vorticella utilizes its contraction-relaxation cycle, we investigated water flow caused by the cycle, using a computational fluid dynamics model validated with an experimental scale model and particle tracking velocimetry. The simulated flow was visualized and analyzed by tracing virtual particles around the Vorticella. It is observed that one cycle can displace particles up to ~190 MUm with the maximum net vertical displacement of 3-4 MUm and that the net transport effect becomes more evident over repeated cycles. This transport effect appears to be due to asymmetry of the contraction and relaxation phases of the flow field, and it can be more effective on motile food particles than non-motile ones. Therefore, our Vorticella model enabled investigating the fluid dynamics principle and ecological role of the transport effects of Vorticella's stalk contraction. PMID- 28670351 TI - Hereditary pancreatic cancer: related syndromes and clinical perspective. AB - Pancreatic cancer is a very aggressive disease with a poor prognosis. The majority of them are attributed to sporadic causes, especially to many modifiable risk factors such as tobacco or alcohol abuse. The principal histologic subtype of pancreatic cancer is ductal adenocarcinoma. Pancreatic neuroendocrine tumors, which constitute a more indolent entity, represent second type of pancreatic cancer in terms of incidence. Individuals with a family history of pancreatic cancer carry an increased risk of developing the disease, which may be related to an underlying hereditary component. Unfortunately, in the majority of these families the suspected germline genetic cause responsible of the disease will not be identified, but approximately in a 20% of the cases a hereditary cancer predisposition syndrome with increased risk of pancreatic cancer development can be recognized. This review will be focused on the leading hereditary cancer syndromes related to pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Additionally, we will try to explain clinical aspects related to the identification of germline mutations in pancreatic cancer patients and their potential implications in oncologic treatment decisions. PMID- 28670349 TI - Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. AB - Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed. PMID- 28670354 TI - Psychosocial Impact of Postinflammatory Hyperpigmentation in Patients with Acne Vulgaris. AB - Background: Acne vulgaris is a common, often socially distressing skin condition primarily seen in young adults. Quality of life studies have shown that people with acne are more introverted with increased social setting anxiety compared to a control group. Unfortunately, patients with acne may have residual postinflammatory hyperpigmentation, amplifying impaired psychosocial effects. Objective: To quantify the impact of postinflammatory hyperpigmentation in patients with acne using a psychometric scale. Design: A clinic-based survey was conducted among US adults with facial acne and postinflammatory hyperpigmentation. Outcomes included age, race, gender, and acne-related quality of life. A board-certified dermatologist rated each patient's acne severity and postinflammatory hyperpigmentation. Setting: Dermatology clinic, Anheuser Busch Institute and Des Peres Hospital, Saint Louis, Missouri. Participants: 48 subjects (25 patients with acne and postinflammatory hyperpigmentation; 23 with acne only). Measurements: Acne Quality of Life survey, dermatologist rating of acne and postinflammatory hyperpigmentation severity. Results: Subjects with postinflammatory hyperpigmentation reported statistically significant poorer mean scores on the Acne Quality of Life survey than subjects with acne only. Sixty percent of patients with postinflammatory hyperpigmentation had a "very markedly" impact to at least one aspect of the Acne Quality of Life survey scale compared to none of the acne only patients. There was no association between provider reported hyperpigmentation severity and psychosocial impact. No differences in psychosocial impact were noted between males and females. Conclusion: Patients with acne and postinflammatory hyperpigmentation had poorer quality-of-life scores compared to patients with only acne. Having postinflammatory hyperpigmentation with acne negatively impacted self-perceptions and social/emotional functioning, especially in groups. PMID- 28670353 TI - Effects of living cells on the bioink printability during laser printing. AB - Laser-induced forward transfer has been a promising orifice-free bioprinting technique for the direct writing of three-dimensional cellular constructs from cell-laden bioinks. In order to optimize the printing performance, the effects of living cells on the bioink printability must be carefully investigated in terms of the ability to generate well-defined jets during the jet/droplet formation process as well as well-defined printed droplets on a receiving substrate during the jet/droplet deposition process. In this study, a time-resolved imaging approach has been implemented to study the jet/droplet formation and deposition processes when printing cell-free and cell-laden bioinks under different laser fluences. It is found that the jetting behavior changes from no material transferring to well-defined jetting with or without an initial bulgy shape to jetting with a bulgy shape/pluming/splashing as the laser fluence increases. Under desirable well-defined jetting, two impingement-based deposition and printing types are identified: droplet-impingement printing and jet-impingement printing with multiple breakups. Compared with cell-free bioink printing, the transfer threshold of the cell-laden bioink is higher while the jet velocity, jet breakup length, and printed droplet size are lower, shorter, and smaller, respectively. The addition of living cells transforms the printing type from jet impingement printing with multiple breakups to droplet-impingement printing. During the printing of cell-laden bioinks, two non-ideal jetting behaviors, a non straight jet with a non-straight trajectory and a straight jet with a non straight trajectory, are identified mainly due to the local nonuniformity and nonhomogeneity of cell-laden bioinks. PMID- 28670355 TI - A Retrospective Study of Non-thermal Laser Therapy for the Treatment of Toenail Onychomycosis. AB - Objective: The objective of this study was to assess the efficacy of non-thermal laser therapy for treating toenail onychomycosis. Design: This retrospective study analyzed the results of three nonrandomized, open-label studies. The device used was a 635nm/405nm dual-diode laser. Affected toenails were treated for 12 minutes weekly for 2 or 4 weeks. Setting: Treatments occurred in clinic and private office settings. Participants: Subjects with onychomycosis-infected toenails were enrolled. Measurements: Fifty great toenails were included in the analysis based on visually identifiable onychomycosis; thickened, discolored nail plate; and confirmed etiology of onychomycosis. Changes in the extent of clear nail bed was measured using multi-platform image manipulation software. The primary outcome measure was the percent of toenails attaining >=3mm of clear nail growth during the six-month post-treatment period. Overall study success was defined as >=60 percent of treated toenails meeting the individual success criteria. The secondary outcome measure was change in the length of clear nail bed. Results: Most treated toenails (67%) achieved individual treatment success. The extent of clear nail at baseline increased by a mean of 5.18 (4.76) mm after 6 months (p<0.0001). In addition, 89 percent of treated toenails demonstrated an increase in clear nail across the six-month study period. No adverse events were reported. Conclusion: Non-thermal laser therapy is safe and effective for increasing the extent of clear nail in onychomycosis-infected toenails following one weekly treatment for four weeks. ClinicalTrials.gov Identifier: NCT02588599. PMID- 28670356 TI - A Prospective, Randomized, Double-blind, Split-face Clinical Trial Comparing the Efficacy of Two Topical Human Growth Factors for the Rejuvenation of the Aging Face. AB - Background: Cosmeceutical products represent an increasingly important therapeutic option for anti-aging and rejuvenation, either used alone or in combination with dermatologic surgical procedures. Among this group of products, topical growth factors have demonstrated efficacy in randomized, controlled clinical trials. However, comparisons between different products remain uncommon. Objective: The objective of this randomized, double-blind, split-face clinical trial was to compare two different topical growth factor formulations derived from either human fibroblasts or human adipose tissue derived mesenchymal stem cells. Methods: This was an institutional review board-approved, randomized, double-blind, split-face clinical trial involving 20 healthy subjects with moderate-to-severe facial wrinkling secondary to photodamage. One half of the face was randomized to receive topical human fibroblast growth factors and the other topical human mesenchymal stem cell growth factors. Treatment was continued for three months, and evaluations were performed in a double-blind fashion. Results: Both growth factor formulations achieved significant improvement in facial wrinkling. Blinded investigator and subject evaluations did not detect any significant differences between the two formulations in terms of efficacy, safety, or tolerability. Conclusion: Both human fibroblast growth factors and human mesenchymal stem cell growth factors are effective at facial rejuvenation. Topical growth factors represent a useful therapeutic modality. PMID- 28670358 TI - Aesthetic Treatment of Bruxism. AB - Bruxism is a diurnal or nocturnal parafunctional activity that includes unconscious clenching, grinding, or bracing of the teeth. An extensive medical history should be taken in these patients so proper diagnosis can be made. Habits such as biting the tongue, cheeks or lips, chewing gum or eating seeds for many hours per day, biting nails, and/or biting hard objects, will cause and/or exacerbate pre-existing bruxism. The etiology of bruxism is uncertain, but it is hypothesized to be associated with genetic, structural, and psychosocial factors. Over time, chronic clenching of the jaw leads to hypertrophy of masseters and temporalis musculature causing the face to take on a masculine and square appearance. Patients commonly present to dermatology cosmetic practices wishing to have a more slim, softer appearing face. This review is the first paper to discuss aesthetic treatment options for complications of bruxism including masseter and temporalis hypertrophy and the associated accelerated aging of the lower face. PMID- 28670357 TI - Raising Awareness Among Healthcare Providers about Epidermolysis Bullosa and Advancing Toward a Cure. AB - Objective: Epidermolysis bullosa (EB) is an orphan disease that affects about half a million people worldwide, but may not be familiar to all clinicians. The authors' goal was to present a short description of this condition and current research in the form of a narrative review. Methods: The authors reviewed the literature on epidermolysis bullosa in order to describe the condition and current genetic research. Results: There are at least 31 subtypes of EB, including junctional EB, dystrophic EB, and Kindler syndrome. Genetic research is crucial in finding strategies to manage and possibly cure EB, which is often undiagnosed or misdiagnosed. EB may present in newborns and may persist over the course of a lifetime. Serious complications can occur with EB, including chronic blisters, wounds, ulcers, pruritus, clubbing of hands and feet, and amputations. Pain is frequently reported. About 80 percent of patients with recessive dystrophic EB will succumb to squamous cell carcinoma by age 55. Promising directions for future research include genome editing, gene therapy, and cell based therapies. Conclusion: Our growing understanding of genetics and cell therapies may lead to promising therapeutic advances to treat this challenging condition. PMID- 28670359 TI - Red Dot Basal Cell Carcinoma. AB - Red dot basal cell carcinoma, a distinctive morphologic variant of basal cell carcinoma that presents as a small red macule (dot) or papule, is described on a woman's thigh. A high index of suspicion is necessary to consider the diagnosis since the tumor mimics a telangiectasia or an angioma. PMID- 28670360 TI - Pain and the pathogenesis of biceps tendinopathy. AB - Biceps tendinopathy is a relatively common ailment that typically presents as pain, tenderness, and weakness in the tendon of the long head of the biceps brachii. Though it is often associated with degenerative processes of the rotator cuff and the joint, this is not always the case, thus, the etiology remains considerably unknown. There has been recent interest in elucidating the pathogenesis of tendinopathy, since it can be an agent of chronic pain, and is difficult to manage. The purpose of this article is to critically evaluate relevant published research that reflects the current understanding of pain and how it relates to biceps tendinopathy. A review of the literature was conducted to create an organized picture of how pain arises and manifests itself, and how the mechanism behind biceps tendinopathy possibly results in pain. Chronic pain is thought to arise from neurogenic inflammation, central pain sensitization, excitatory nerve augmentation, inhibitory nerve loss, and/or dysregulation of supraspinal structures; thus, the connections of these theories to the ones regarding the generation of biceps tendinopathy, particularly the neural theory, are discussed. Pain mediators such as tachykinins, CGRP, and alarmins, in addition to nervous system ion channels, are highlighted as possible avenues for research in tendinopathy pain. Recognition of the nociceptive mechanisms and molecular of biceps tendinopathy might aid in the development of novel treatment strategies for managing anterior shoulder pain due to a symptomatic biceps tendon. PMID- 28670361 TI - The effect of high Sox3 expression on lymphangiogenesis and lymph node metastasis in esophageal squamous cell carcinoma. AB - OBJECTIVE: This study aimed to investigate the effect of Sox3 expression on biological behaviors of esophageal squamous cell carcinoma (ESCC) and explore its possible mechanism. METHODS: ESCC cell lines that highly expressed Sox3 were selected and transfected with lentivirus carrying sox3 siRNA to establish ESCC cell lines which expressed Sox3 of different levels. Using in vitro experiments including cell invasion, cell scratch, cell proliferation and tube formation of lymphatic endothelial cells, as well as an in vivo experiment of axillary lymph node metastasis in a nude mouse model of a xenotransplanted tumor, the effect of Sox3 expression variation on lymphangiogenesis and lymph node metastasis in ESCC cells was investigated. In addition, ELISA, Western blot and immunohistochemical methods were used to study the regulatory effects of Sox3 on relevant molecules such as VEGF-C/D and to explore the potential mechanisms that affected lymphatic metastasis. RESULTS: The high expression of Sox3 in ESCC cells in vitro could significantly promote the proliferation, invasion, migration and tube formation of lymphatic endothelial cells. High expression of Sox3 in vivo could significantly promote lymph node metastasis of ESCC cells, and we have demonstrated that the upregulation of Sox-3 expression could promote the expression and secretion of VEGF-C and VEGF-D both in vivo and in vitro. After blocking the VEGFR-3 receptors on lymphatic endothelial cells, the effect of Sox3 on promoting lymphangiogenesis has decreased significantly, confirming that Sox3 acts through VEGF-C/D to promote lymphangiogenesis. CONCLUSIONS: It is suggested that Sox3 possibly induces lymphangiogenesis by increasing the expression of VEGF C/D in ESCC cells, thereby promoting the lymph node metastasis of the tumor. Thus, Sox-3 may become a new prognostic marker and therapeutic target in ESCC. PMID- 28670362 TI - The Chinese medicine, Jianpi Huayu Decoction, inhibits the epithelial mesenchymal transition via the regulation of the Smad3/Smad7 cascade. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors in the world. In China, traditional medicine is commonly used in the treatment of cancer. Among these medicines, Jianpi Huayu Decoction (JHD) is a typical clinical prescription against multiple tumors. However, the exact function and targets of JHD are currently unknown. The aim of this study is to assess the efficacy of JHD against HCC. METHODS AND RESULTS: Hepatic carcinoma SMMC7221 cells were treated with JHD drug-serum in a dose- and time-dependent manner. Real-time PCR (RT-PCR), western-blot (WB), and immunofluorescence microscopy revealed that JHD increased both the mRNA and protein levels of Smad7 and decreased the protein level of p-Smad3. It subsequently increased the E-cadherin expression level and decreased those of N cadherin and Vimentin. Metastasis and invasion were eventually inhibited, as determined by the wound healing and transwell invasion assays. Treatment of Tanshinone IIA (Tan IIA) showed similar results as JHD, indicating that it is most likely the main functional drug monomer of JHD. The in vivo assay in nude mice also revealed the efficacy of JHD to inhibit epithelial mesenchymal transition (EMT). CONCLUSION: JHD was shown to be an effective therapeutic strategy against HCC. PMID- 28670363 TI - Verapamil suppresses cardiac alternans and ventricular arrhythmias in acute myocardial ischemia via ryanodine receptor inhibition. AB - T-wave alternans (TWA) is a potent arrhythmia substrate under the conditions of acute myocardial ischemia. Abnormal intracellular calcium cycling contributes to the genesis of cardiac alternans. Ryanodine receptor (RyR) is a pivotal Ca2+ cycling protein central to Ca2+ signaling in the heart. Here, we investigated the potential role of RyR in cardiac alternans and ventricular arrhythmias in acute myocardial ischemia. Transmembrane action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contraction force in the arterially perfused left ventricular wedge preparations. Calcium alternans were induced by incremental frequency of field stimulation in rat ventricular myocytes. TWA, mechanical alternans and ventricular arrhythmias were reproducibly induced by rapid pacing in the acute ischemic wedge preparations. Compared with control group, calcium alternans ratio and spontaneous calcium release were increased in acute ischemic myocytes. Verapamil, a phenylalkylamine calcium channel blocker, can successfully abolish spontaneous calcium release, TWA, and ventricular arrhythmias. The inhibition effect of verapamil could be diminished by low concentration of ryanodine (10 nmol/L). However, nifedipine, a dihydropyridine calcium channel blocker, could not block TWA or arrhythmias. Moreover, verapamil, but not nifedipine, significantly decreased ROS production in ischemic myocytes. Collectively, our results indicate that verapamil can significantly inhibit the development of cardiac alternans and ventricular arrhythmias in acute myocardial ischemia, and the mechanism was related to the inhibition of RyR and the protective function to oxidative stress. PMID- 28670364 TI - Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge. AB - Lipocalin-2 (also known as NGAL) levels are elevated in obesity and diabetes yet relatively little is known regarding effects on the heart. We induced pressure overload (PO) in mice and found that lipocalin-2 knockout (LKO) mice exhibited less PO-induced autophagy and NLRP3 inflammasome activation than Wt. PO-induced mitochondrial damage was reduced and autophagic flux greater in LKO mice, which correlated with less cardiac dysfunction. All of these observations were negated upon adenoviral-mediated restoration of normal lipocalin-2 levels in LKO. Studies in primary cardiac fibroblasts indicated that lipocalin-2 enhanced priming and activation of NLRP3-inflammasome, detected by increased IL-1beta, IL-18 and Caspase-1 activation. This was attenuated in cells isolated from NLRP3-deficient mice or upon pharmacological inhibition of NLRP3. Furthermore, lipocalin-2 induced release of HMGB1 from cells and NLRP3-inflammasome activation was attenuated by TLR4 inhibition. We also found evidence of increased inflammasome activation and reduced autophagy in cardiac biopsy samples from heart failure patients. Overall, this study provides new mechanistic insight on the detrimental role of lipocalin-2 in the development of cardiac dysfunction. PMID- 28670365 TI - LC-0882 targets PAK4 and inhibits PAK4-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells. AB - Gastric cancer is the most common malignant tumor and globally the third leading cause of cancer-related deaths. Therefore, there exists an urgent need to identify new effective gastric cancer treatments. Given the important roles in tumorigenesis and progression, p21-activated kinase 4 (PAK4) has been regarded as an attractive high-value druggable target. In this study, we examined the effects and molecular mechanisms of action of the small molecular compound LC-0882 on gastric cancer cells in vitro. LC-0882 was found to significantly inhibit the proliferation of human gastric cancer cells by repressing phospho-PAK4/cyclin D1 and CDK4/6 expression. In addition, LC-0882 was found to attenuate cell invasion by blocking the PAK4/LIMK1/cofilin signaling pathway. Finally, analysis of immunofluorescence revealed that LC-0882 exposure decreased filopodia formation and induced cell elongation in BGC823 and SGC7901 gastric cancer cells. These findings suggest that targeting PAK4 with the novel compound LC-0882 may provide a new chemotherapeutic approach in gastric cancer treatment. PMID- 28670367 TI - Silencing of advanced glycosylation and glycosylation and product-specific receptor (RAGE) inhibits the metastasis and growth of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) constitutes the main cases of lung cancer and is the world's most common and lethal cancer owing to regional invasion or distant metastasis. Growing morbidity and lethality demonstrates that valid molecular target in management of NSCLC metastasis is still absence. The receptor of advanced glycation end-products (RAGE) has been identified as an oncogenic gene and appears to promote the growth and metastasis of various cancers. Here, we investigated if RAGE targeted by RNA interference (RNAi) might have certain effect on the restraint of the growth of NSCLC and tumor metastasis. Wound healing and Transwell invasion assays indicated that RAGE favored the metastatic capabilities of NSCLC H1975 cells. Besides, soft-agar colony assay revealed that silencing RAGE significantly blocked colony-forming capability of H1975 cells in vitro. Furthermore, we observed that RAGE participated in H1975 cells growth, metastasis and epithelial-mesenchymal transition (EMT) by regulating interdict crux intracellular signaling pathways, including phosphatidylinositol-3 kinase/serine-threonine kinase (PI3K/AKT) and V-Ki-ras2 kirsten rat sarcoma viral oncogene homolog/RAF proto-oncogene serine/threonine-protein kinase (KRAS/RAF-1). In xenograft model, significantly reduction intumor growth and Ki67 expression was demonstrated in nude mice inoculation with RAGE down-regulation H1975 cells. To conclude, our study demonstrated that RAGE played a crucial role in the metastasis and growth of NSCLC by regulating PI3K/AKT and KRAS/RAF-1 signaling pathways, thereby might be a promising therapeutic target for NSCLC. PMID- 28670366 TI - Inhibitory effect of dihydroartemisinin on chondrogenic and hypertrophic differentiation of mesenchymal stem cells. AB - Chondrocytes located in hyaline cartilage may maintain phenotype while the chondrocytes situated in calcified cartilage differentiate into hypertrophy. Chondrogenic and hypertrophic differentiation of mesenchymal stem cells (MSCs) are two subsequent processes during endochondral ossification. However, it is necessary for chondrocytes to hold homeostasis and to inhibit hypertrophic differentiation in stem cell-based regenerated cartilage. Dihydroartemisinin (DHA) is derived from artemisia apiacea which has many biological functions such as anti-malarial and anti-tumor. Whereas the effects of DHA on chondrogenic and hypertrophic differentiation are poorly understand. In this study, the cytotoxicity of DHA was determined by CCK8 assay and the cell apoptosis was analyzed by flow cytometry. Additionally, the effects of DHA on chondrogenic and hypertrophic differentiation of MSCs are explored by RT-PCR, western blotting and immunohistochemistry. The results showed that DHA inhibited expression of chondrogenic markers including Sox9 and Col2a1 by activating Nrf2 and Notch signaling. After induced to chondrogenesis, cells were treated with hypertrophic induced medium with DHA. The results revealed that hypertrophic markers including Runx2 and Col10a1 were down-regulated following DHA treatment through Pax6/HOXA2 and Gli transcription factors. These findings indicate that DHA is negative to chondrogenesis and is protective against chondrocyte hypertrophy to improve chondrocytes stability. Therefore, DHA might be not suited for chondogenesis but be potential as a new therapeutic candidate to maintain the biological function of regenerated cartilage. PMID- 28670368 TI - Effect of ERbeta-regulated ERK1/2 signaling on biological behaviors of prostate cancer cells. AB - Estrogen receptor beta (ERbeta) plays a role in prostate carcinogenesis. In this study, we investigated the effects of ERbeta gene silencing in PC3 androgen independent prostate cancer cells. PC3 cells were transfected with vector alone, scrambled shRNA vector, vector encoding ERbeta-targeting shRNA (shERbeta), or shERbeta followed by addition of PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor (shERbeta+PD98059). Cyclin D1, Bcl-2, matrix metalloproteinase (MMP)2, and phosphorylated (p-) extracellular signal-regulated kinase (ERK1/2) expression was detected by western blotting. While ERK1/2 expression was comparable in all cells, p-ERK1/2 expression was highest in shERbeta cells, and lowest in shERbeta+PD98059 cells. Bcl-2, cyclin D1, and MMP2 expression was highest and lowest in shERbeta and shERbeta+PD98059 cells, respectively. Flow cytometry analysis showed that ERbeta silencing promoted cell proliferation by decreasing the percentage of cells in G0/G1. Analysis of colony formation, migration, and invasion capacities, measured using soft agar colony formation, wound-healing, and transwell invasion assays, respectively, showed that ERbeta silencing augments cell proliferation, migration, and invasion, and that this increase is reversed by PD98059 treatment. A tumor xenograft model in nude mice was used to assess the effect of ERbeta silencing on the biological behavior of PC3 cells. Colony formation assays and tumor transplantation data indicated that ERbeta silencing promotes tumor formation. Immunohistochemical analysis of tumors showed that vascular endothelial growth factor (VEGF) and p ERK1/2 expression, but not that of total ERK1/2, was increased upon ERbeta silencing. In conclusion, out data demonstrate that ERbeta gene silencing enhances malignant biological behaviors of PC3 cells by activating the ERK1/2 signaling pathway. PMID- 28670369 TI - The crosstalk between beta-catenin signaling and type I, type II and type III interferons in lung cancer cells. AB - BACKGROUND/OBJECTIVE: IFNs induce potent antiviral and antitumor activities. beta catenin pathway is a surviving pathway adapted by carcinogenetic mechanisms of various cancers. Crosstalk between these pathways has not been well described in lung cancer cells. METHODS: Lung cancer cell lines, A549 and Calu-3, were used in this study. beta-catenin protein levels and signaling activities were tested by flow cytometry and luciferase assay. Cell proliferation was measured by counting viable cells under microscope, and apoptosis by TUNEL assay and caspase 3 activation. DKK1 and GSK3beta levels were tested by flow cytometry. Secreted DKK1 was measured by ELISA. alphaDKK1 , FLUD and S3I were to inhibit DKK1, STAT1 and STAT3 activities, respectively. RESULTS: All of IFNalpha, IFNgamma and IFNlambda1 suppressed beta-catenin signaling in A549 and Calu-3 cells, where IFNgamma was the strongest (P<0.05). They inhibited cellular proliferation and promoted apoptosis. IFNgamma gave greater induction ability compared to IFNalpha and IFNlambda1 (P<0.05). All tested IFNs promoted DKK1 activation but not GSK3beta in A549 and Calu-3 cells. IFNs activated STAT1 and STAT3. But only STAT3 was vital for IFN-mediated DKK1 activation and apoptosis. Plus, DKK1 antagonist abrogated IFN-mediated apoptosis. The degree of STAT3 activation was corresponding to the level of apoptosis induced by different IFNs (P<0.05). CONCLUSIONS: In lung cancer cells, all three types of IFNs can induce apoptosis via suppressing beta catenin signaling by a STAT3- and DKK1-dependent manner. This findings demonstrate a link between IFNs and beta-catenin signaling, which may possess potentials on the development of novel therapeutic measures against lung cancer. PMID- 28670370 TI - The effects of miRNA-1180 on suppression of pancreatic cancer. AB - The aim of this study was to evaluate the effects of miR-1180 on pancreatic cancer. We sampled adjacent cancer and carcinoma tissues from 30 pancreatic cancer patients and measured miR-1180 expression by qRT-PCR and NF-kappaB protein expression by immunohistochemistry. To explore the effects of this miRNA in cell culture, we used pancreatic cancer (PANC-1) cells that received only vehicle (negative control, NC), miR-1180 mimic, or miR-1180-inhibitor. Cells were treated with cisplatin to induce apoptosis. Proliferation, apoptosis, cell cycle progression, cell invasion, and cell migration were assessed in the three cell groups. The expression levels of relevant proteins (TNIP2, NF-kappaB, MMP-2, MMP 9, Bax, Bcl-2, p21, and cyclin D1) in each cell group were determined by western blotting. Compared with healthy tissue adjacent to carcinoma tissues, miR-1180 expression in cancer tissues was significantly enhanced (P<0.05). NF-kappaB protein had a similar expression pattern to miR-1180; miR-1180 expression was positively correlated with NF-kappaB expression. The invasion and wound healing abilities of miR-1180-inhibited cells were significantly reduced compared with the NC or miR-1180-expressing cells (P<0.05). The cell proliferation rate of miR 1180-inihibited cells was also significantly lower than that of NC or miR-1180 expressing cells (P<0.05), while the cell apoptosis and G1 phase rates of miR 1180-inihibited cells were significantly higher than the NC or miR-1180 expressing cells (P<0.05). In conclusion, suppressing miR-1180 expression may exert anti-cancer effects on pancreatic cancer cells via regulation of TNIP 2/NF kappaB signaling and the downstream MMP-2/-9, Bax, Bcl-2, p21, and cyclin D1 factors. PMID- 28670371 TI - Circulating tumor cells: what we know, what do we want to know about them and are they ready to be used in clinics? AB - Circulating tumor cells (CTC) present in peripheral blood are assigned precursors of advanced tumor disease. Simplicity of blood withdrawal procedure adds practically an unlimited possibility of the CTC-monitoring and the advantages of the repeated biopsies over time. CTC got prognostic, predictive and diagnostic status with the technologic advance. Although the clinical utility of CTC has reached the high evidence, the significance of CTC testing was presented in the treatment strategy mostly with palliative intention. We report on the experiences with the CTC-testing in the CLIA-like laboratory working with the size-based CTC separation and in vitro culture. The data is presented in the form of case reports in patients with breast (BC), colorectal (CRC), prostate (PC) and lung cancer (NSCLC) to support the clinical utility of CTC during the neoadjuvant, adjuvant and palliative treatment. The presented findings support the evidence for liquid biopsy clinical implementation and enhance the ability of malignant disease monitoring and the treatment efficacy prediction. PMID- 28670372 TI - CXCL10 accelerates EMT and metastasis by MMP-2 in hepatocellular carcinoma. AB - Human malignant hepatocellular carcinoma (HCC) is a common tumor, which severely threatens human health and shortens longevity. The poor prognosis of HCC is primarily attributed to distant metastases. C-X-C motif chemokine 10 (CXCL10) regulates the control of several cellular and developmental processes including tumor cell proliferation, apoptosis, and cell metastasis. Previous studies have confirmed that CXCL10 functions as an oncogene in several cancers. However, the expression and biological functions of CXCL10 in HCC, especially with regard to metastasis, need further investigation. In this study, CXCL10 was found to be over expressed in invasive HCC cells and HCC clinical samples. While the over expression of CXCL10 enhanced migration, invasion, and metastasis of HCC cells in vitro as well as in vivo, silencing of CXCL10 resulted in inhibition of HCC cell metastasis. Further, CXCL10 was found to accelerate epithelial-mesenchymal transition of HCC cells. The microarray analysis indicated that matrix metallopeptidase-2 (MMP-2) functions as a downstream factor of CXCL10. This study demonstrates that CXCL10 partakes in the metastasis of HCC by activating MMP-2 expression. PMID- 28670373 TI - ZEB2 promotes tumor metastasis and correlates with poor prognosis of human colorectal cancer. AB - Colorectal cancer remains the most common cause of cancer-related deaths worldwide and it continues to lack an effective treatment. Here, we found that zinc finger E-box binding homeobox 2 (ZEB2) was overexpressed in several colorectal cancer cell lines and colorectal cancer specimens relative to adjacent non-cancerous tissues. Although ZEB2 has been reported to be associated with several tumors, its involvement in colorectal cancer progression remains unclear. In this study, we investigated the biological functions and molecular mechanisms of ZEB2 underlying colorectal carcinoma metastasis and angiogenesis. HCT116 colorectal cancer cells were treated with ZEB2 shRNA or recombinant ZEB2, and the expression of ZEB2 was assessed using reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting, respectively. Ectopic expression of ZEB2 induced proliferation and epithelial-mesenchymal transition (EMT), and increased the metastatic capacity of HCT116 cells in vitro and in vivo. Furthermore, endothelial cell tube formation and angiogenesis in chick embryo chorioallantoic membrane (CAM) were accelerated by conditioned medium from ZEB2-overexpressing HCT116 cells. Further, overexpression of ZEB2 accelerated tumor growth and angiogenesis in xenotransplantation models. However, silencing endogenous ZEB2 caused an opposite outcome. Our results provide new evidence that ZEB2 promotes the progression of colon cancer, and thereby might represent a novel therapeutic target for colorectal carcinoma. PMID- 28670375 TI - Lyn kinase enhanced hepatic fibrosis by modulating the activation of hepatic stellate cells. AB - The non-selectivity of tyrosine kinase inhibitors is the leading cause of drug withdrawals, and limits their application in anti-fibrosis. The role of Src tyrosine kinase Lyn in hepatic fibrosis remains elusive. In this study, we aimed to elucidate the role of Lyn kinase in the pathogenesis of hepatic fibrosis. Through examining Lyn-transgenic (Lyn TG) mice treated with CCl4 (carbon tetrachloride), we determined whether Lyn kinase is involved in the pathogenesis of hepatic fibrosis. On top of that, we also investigated the role of Lyn in the activation of hepatic stellate cells (HSCs) in vitro. Here, we showed that Lyn kinase was highly expressed in liver fibrosis upon CCl4 treatment. Meanwhile, Lyn TG mice showed that perivascular infiltration of mononuclear cells, and the markers of liver injury and hepatocytes apoptosis were significantly increased in liver tissue after CCl4 treatment. In comparison with wild-type (WT) mice after CCl4 treatment, we found that the fibrotic score in liver tissues of Lyn TG mice with the same treatment went up dramatically, so did the gene expression of fibrotic markers. In addition, over-expression of Lyn kinase drastically promoted the expression of HSCs activation markers in vivo or in vitro. Additionally, the Src-specific inhibitor PP2 significantly suppressed the increased expression of integrin alphavbeta3 in TGF-beta1-induced HSCs, and PP2 further induced HSC apoptosis in TGF-beta1-treated cells. These results collectively indicated that Lyn kinase is implicated in the pathogenesis of hepatic fibrosis through the modulating of HSC activation. PMID- 28670374 TI - Combination of circulating miR-19b-3p, miR-122-5p and miR-486-5p expressions correlates with risk and disease severity of knee osteoarthritis. AB - The aim of this study was to investigate the association of circulating miRNAs profile with the risk of knee osteoarthritis (OA), and evaluate their correlation with clinical characteristics. This study was divided into two parts: exploration stage and validation stage. In exploration stage, 8 knee OA patients and 8 age and gender highly matched health controls (HCs) were recruited, and plasma sample were collected for microarray examination. Differentially expressed miRNAs and enrichment analysis were subsequently performed. In validation stage, 100 knee OA patients and 100 age and gender matched HCs were enrolled, and Top 8 differentially expressed miRNAs in microarray were selected for further validation by qPCR. In exploration stage, 41 up-regulated miRNAs and 29 down regulated miRNAs were identified by microarray, and enrichment analysis disclosed these miRNAs were involved in inflammation- and immunity- related process. Top 8 differentially expressed miRNAs in microarray were determined in the validation stage, and miR-19b-3p, miR-92a-3p, miR-122-5p, miR-486-5p and miR-320b expression were increased in knee OA. Univariate and multivariate logistic analysis showed only miR-19b-3p, miR-122-5p and miR-486-5p were independent factors for knee OA risk, and ROC curve showed combination of miR-19b-3p, miR-122-5p and miR-486-5p has a great diagnostic value for knee OA. Besides, miR-19b-3p and miR-486-5p positively correlates with disease severity. This study revealed that circulating miRNA profiles played a key role in knee OA diagnosis, and combined measurement of miR-19b-3p, miR-122-5p and miR-486-5p could be served as a novel and promising biomarker for diagnosis and disease severity of knee OA. PMID- 28670376 TI - CCR2 dependent neutrophil activation and mobilization rely on TLR4-p38 axis during liver ischemia-reperfusion injury. AB - Liver ischemia-reperfusion injury (IRI) is a common clinical problem in which neutrophil recruitment is an essential event. Our previous study revealed the important role of C-C motif chemokine receptor 2 (CCR2) in neutrophils during liver IRI. The aim of the present study was to further investigate the underlying mechanisms mediating the changes in CCR2 expression in neutrophils during this pathophysiological process. Herein, we found that TLR4 ablation reduced neutrophil mobilization from the bone marrow and the subsequent infiltration into the liver during liver IRI; neutrophil-derived CCR2 expression was also repressed. In addition, neutrophil mobilization was dependent on CCR2 expression in neutrophils, which in turn relied on activation of the TLR4-p38 axis during liver IRI. In conclusion, neutrophil-derived CCR2 expression regulates neutrophil mobilization from the bone marrow and infiltration into the liver, which requires activation of the TLR4-p38 axis during liver IRI. PMID- 28670377 TI - Mesenchymal stem cells inhibited development of lung cancer induced by chemical carcinogens in a rat model. AB - Mesenchymal stem cells (MSCs) may play a significant role in carcinogenesis; however, data have shown that MSCs can both promote and inhibit tumor growth. We investigated the effect of MSCs on the development of lung cancer in a rat model. Bone marrow-derived MSCs were isolated from male Wistar rats and fluorescently labeled. Genotoxic carcinogens 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) were instilled into the left lung lobes of female rats to induce tumors. Labeled male MSCs were infused into the female rats via tail vein, and the rats were sacrificed on days 3 and 7. MSC survival and distribution were detected by PCR and fluorescence, respectively. Labeled MSCs aggregated at the injection site in the left lobe (MCA/DEN-treated) on day 3 but not the untreated right lobe. Survival of the MSCs in vivo was confirmed by detection of the male SRY gene in lung tissues by PCR at day 3; however, by day 7, lung tissues were SRY-negative. Next, carcinogen-treated rats were divided into two groups and infused with normal MSCs (experimental group) or PBS (control group) every week for 10 weeks, then sacrificed. Cell proliferation in lung tissues was calculated by Ki67 and PCNA expression. Eighty-percent (8/10) of rats in the control group had tumors, while none of the rats in the experimental group had tumors. There was no difference in cell proliferation in lung tissues between the groups. Therefore, bone marrow-derived MSCs prevented development of carcinogen-induced lung cancer in a rat model. Additional studies are needed to determine mechanism. PMID- 28670378 TI - Overexpression of CD47 predicts poor prognosis and promotes cancer cell invasion in high-grade serous ovarian carcinoma. AB - CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage mediated destruction. CD47 is overexpressed in various human malignancies. However, the expression and functional significance of CD47 in high-grade serous ovarian carcinoma (HGSOC) has not been completely understood. In this study, we reported that CD47 was commonly overexpressed in HGSOC. Higher CD47 expression was significantly correlated with poor prognosis of HGSOC patients. Functional investigations revealed that CD47 overexpression in ovarian cancer cells significantly promoted migration and invasion. Moreover, CD47 induced epithelial mesenchymal transition (EMT) through modulating E-cadherin and N-cadherin. Our findings suggest that up-regulation of CD47 is correlated with ovarian cancer progression and it might be a potential biomarker for predicting clinical outcomes. PMID- 28670379 TI - Vasohibin 2 as a potential predictor of aggressive behavior of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a subtype breast cancer with aggressive behavior, advanced disease status and poor prognosis. Because of the lack of targeting agents and limited therapeutic options, treatment of TNBC remains a great clinical challenge. Vasohibin 2 (VASH2) was previously identified as an angiogenic factor, but its role in TNBC tumorigenesis is unknown. Using quantitative PCR and western blot analyses, we found that VASH2 is overexpressed in TNBC cells and tissues. Knockdown of VASH2 via siRNA inhibited the proliferation of the TNBC cell lines by delaying cell cycle progression and increasing apoptosis. Further analyses showed that the VASH2-mediated increase in the transcription of fibroblast growth factor-2, vascular endothelial growth factor and vasohibin 1 may be the mechanism underlying these effects. Taken together, these data indicate that VASH2 is abnormally expressed in TNBC, indicating a novel and important role for VASH2 in TNBC malignant transformation. PMID- 28670380 TI - Serum levels of WNT1-inducible signaling pathway protein-1 (WISP-1): a noninvasive biomarker of renal fibrosis in subjects with chronic kidney disease. AB - WNT1-inducible signaling pathway protein-1 (WISP-1) is an extracellular matrix related protein that plays multiple roles in cellular physiology and pathology. Accumulating evidence shows that WISP-1 is involved in the process underlying fibrotic diseases. However, the correlation between WISP-1 and renal fibrosis is unknown. In this study, we hypothesized that WISP-1 levels might be correlated with renal fibrosis and could be used as a noninvasive biomarker to screen for renal fibrosis in patients with chronic kidney disease (CKD). We first measured the WISP-1 expression levels using a transforming growth factor-beta (TGF-beta) induced renal fibrosis tubular epithelial cell (TEC) model and a mouse model of obstructive nephropathy. We then evaluated the correlation between serum WISP-1 levels and fibrosis scores in biopsy-proven renal fibrosis of patients with CKD. Based on the findings from both in vivo and in vitro studies, the levels of WISP 1 and fibrotic parameters (collagen I, fibronectin and alpha-smooth muscle actin) were significantly increased in the fibrotic models. Consistently, patients with focal proliferative IgA nephropathy, focal segmental glomerular sclerosis and diabetic nephropathy displayed markedly elevated serum WISP-1 levels and fibrosis scores of renal biopsies compared with normal subjects and patients with minimal change disease (P<0.05). Importantly, the serum WISP-1 levels were positively correlated with fibrosis scores in the renal biopsies of these patients (r=0.475, P=0.0001). Thus, serum WISP-1 levels may be used as a potential noninvasive biomarker of renal fibrosis in patients with CKD. PMID- 28670381 TI - Intermittent activation of notch signaling promotes bone formation. AB - Stimulatory and inhibitory effects of Notch signaling pathway on osteogenesis were both widely reported, questioning the effectiveness of small molecules targeting the Notch pathway for prevention or treatment of bone loss diseases. Here we showed that Notch signaling is activated in osteocytes embedded within the mineralized matrix and in late stages of bone marrow mesenchymal cell osteogenic cultures. Inhibition of Notch signaling markedly reduced mineralization activities of bone marrow mesenchymal cells and inhibited expressions of mineralization-associated genes when Notch ligand Jagged1 was conditionally deleted, confirming the essential roles of Notch signaling in mineralization stages of osteoblast differentiation. Moreover, intermittent activation of Notch signaling showed significant increases of bone formation in mice, rats and ovariectomized rats. A two-phase action model of Notch signaling in osteogenesis is proposed, where activation of Notch signaling in early stages of osteoblast differentiation results in proliferation of immature preosteoblast lineage cells and activation in late stages promotes differentiation of osteoblasts into osteocytes. Moreover, valproic acid is a strong activator of Notch signaling, and yearly administration of valproic acid daily showed little side effects, indicating that long term and intermittent activation of Notch signaling will be a safe and ideal way to promote anabolic bone formation for treatment of osteoporosis. Therefore, Notch signaling pathway is a good therapeutic target for bone loss diseases, and valproic acid, resveratrol and other Notch activators are promising therapeutic molecules for promoting anabolic bone formation when administered intermittently. PMID- 28670382 TI - Stretch-activated channel Piezo1 is up-regulated in failure heart and cardiomyocyte stimulated by AngII. AB - Mechanotransduction is the conversion of extracellular mechanical stimuli into intracellular biochemical signals, and plays an important role in heart responses to its own mechanical environment. Piezo1 as a distinct stretch-activated channel (SAC) in mammal involves in not only vascular remodeling during embryonic development but also arterial remodeling upon to hypertension at adult stage. In the present study, the expression of Piezo1 was up-regulated in failure heart induced by myocardial infarction (MI) by real-time PCR, Western blot and immunohistochemistry analysis. Expression of Piezo1 mRNA and protein was enhanced by AngiotensinII (AngII) in neonatal rat ventricular myocytes via AT1 receptor depended methods. Furthermore, the Piezo1 expression was attenuated by Erk1/2 chemical inhibitor (U0126) only, but not by p38 MAPK inhibitor (SB203580), or JNK inhibitor (SP600125). Finally, systolic function improvement followed by chronic treatment with angiotensin receptor blocker (ARB) losartan prevented Piezo1 up regulation in failure heart in vivo. In conclusion, our studies linked mechanotransduction which involved renin-angiotensin system that mediated up regulation of Piezo1 to a clinically relevant heart failure. PMID- 28670383 TI - MiR-155 up-regulated by TGF-beta promotes epithelial-mesenchymal transition, invasion and metastasis of human hepatocellular carcinoma cells in vitro. AB - It has previously been reported that microRNA (miR)-155 is linked to the recurrence and prognosis of hepatocellular carcinoma (HCC) following liver transplantation. However, the role of miR-155 in the invasion and metastasis of HCC cells remains largely unclear. The aim of this study was to investigate the expression of miR-155 in HCC cells and its role in the invasion and migration of HCC cells in vitro. We found that the level of expression of miR-155 in HCC tissues and cells was significantly increased compared with non-tumorous adjacent tissues. Further study revealed that recombinant human transforming growth factor beta (TGF-beta1) up-regulated the expression of miR-155 in HCC cells in vitro. Further, the overexpression of miR-155 in HCC cell line Huh-7 led to increased levels of cell invasion and migration compared with untreated control Huh-7 cells. MiR-155-overexpressed Huh-7 cells also exhibited altered levels of expression of certain cellular adhesion molecules related to epithelial mesenchymal transition (EMT), including low levels of CDH1 and higher levels of FN1, SNAI1 and ZEB1, compared with control Huh-7 cells. Moreover, it was found that the overexpression of miR-155 and of TGF-beta1 protein decreased the expression of E-Cadherin and increased the expression of Vimentin in Huh-7 cells. These results indicate that an increased level of miR-155 in HCC cells, possibly due to stimulation by TGF-beta1, accelerates the process of EMT, promotes cellular invasion and migration in vitro, and thereby further promotes the progression of HCC. PMID- 28670384 TI - A dual-regulated oncolytic adenovirus carrying TAp63 gene exerts potent antitumor effect on colorectal cancer cells. AB - The purpose of this study is to evaluate possible antitumor activity of a dual regulated oncolytic adenovirus carrying the TAp63 gene on colorectal cancer. The recombinant virus Ad-survivin-ZD55-TAp63 was constructed by inserting the TAp63 gene into the dual-regulated pshuttle-survivin-ZD55 vector. RT-PCR and western blot assays were used to verify the recombinant virus Ad-survivin-ZD55-TAp63. Crystal violet staining was carried out to detect the cytopathic effect of Ad survivin-ZD55-TAp63 in human colorectal cancer cell line HCT-116 and normal liver cell line L-O2. MTT and cell apoptosis assays were applied to explore the biological functions of Ad-survivin-ZD55-TAp63 within HCT116 cells. To further identify the antitumor effects of Ad-survivin-ZD55-TAp63 on HCT116 xenograft in BALB/C nude mice, tumor volumes were calculated and tumor tissues from the xenograft models were examined by TUNEL assays. The results showed that Ad survivin-ZD55-TAp63 was successfully constructed, and could selectively replicate in HCT116 cells without significant toxicity to L-02 cells. Furthermore, Ad survivin-ZD55-TAp63 dose- and time-dependently inhibited cell proliferation and induced cell apoptosis in vitro. In HCT116 xenograft models, intratumoral injection of Ad-survivin-ZD55-TAp63 significantly suppressed tumor growth and caused tumor cell apoptosis. Therefore, these results suggest that the recombinant virus Ad-survivin-ZD55-TAp63 exhibits specific antitumor effects, and may be used in the future for the treatment of colorectal cancer. PMID- 28670385 TI - Zebrafish methanol exposure causes patterning defects and suppressive cell proliferation in retina. AB - PURPOSE: Methanol exposure have been shown to produce retinal abnormalities and visual dysfunctions in rodents and other mammals developing in utero. In this study, we characterized how methanol affects the retinal development in an ex utero embryonic system, the zebrafish. METHODS: Zebrafish embryos were raised for 24 hours in fish water supplemented with various concentrations of methanol at 6 hours after fertilisation. The effects of methanol on retinal morphology were assessed by histologic and immunohistochemical analyses. RESULTS: Zebrafish embryos exposed to moderate (3%) and high (4%) levels of methanol during early embryonic development had a small eye phenotype. Embryos exposed to high (4%) level of methanol had morphological abnormalities of the retinal pigment epithelia and the photoreceptors. Methanol exposure also caused inhibition of cell differentiation and proliferation in the retina at the early developmental stage. CONCLUSIONS: Low concentrations of methanol affect photoreceptor function but do not disturb retinal morphology. Higher levels of methanol exposure cause retinal patterning defects and a small eye phenotype. PMID- 28670386 TI - Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a very common endocrine disorder affecting women of reproductive age. Insulin resistance (IR), a central component of this disease, occurs in 30%-40% of women with PCOS. To date, the molecular mechanism underlying PCOS-IR remains largely unknown. Most recently, increasing evidence has shown that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations plays important roles in the pathogenesis of PCOS-IR. To identify the contribution of mitochondrial tRNA (mt-tRNA) mutations in this disease, we screened 80 women with PCOS-IR and 50 healthy control participants for mt-tRNA mutations. After genetic amplification and direct sequencing, we identified nine mt-tRNA mutations that were potentially associated with PCOS-IR: mt-tRNALeu(UUR) A3302G and C3275A mutations, mt-tRNAGln T4363C and T4395C mutations, mt tRNASer(UCN) C7492T mutation, mt-tRNAAsp A7543G mutation, mt-tRNALys A8343G mutation, mt-tRNAArg T10454C mutation and mt-tRNAGlu A14693G mutation. These mutations were localized at evolutionarily conserved nucleotides and altered the secondary structure of mt-tRNAs, thus resulting in failure of mt-tRNA metabolism. Moreover, molecular and biochemical analysis revealed that levels of 8-OHdG, malondialdehyde and reactive oxygen species were increased in patients with PCOS IR carrying these mt-tRNA mutations compared with in healthy control participants, whereas superoxide dismutase levels, mitochondrial copy number, membrane potential and ATP levels were significantly reduced. Taken together, our data indicate that mt-tRNAs are key locations for pathogenic mutations associated with PCOS-IR. Mitochondrial dysfunction caused by mt-tRNA mutations may be involved in the pathogenesis of PCOS-IR. Thus, our findings provide novel insight into the pathophysiology of this disorder. PMID- 28670387 TI - Down-regulation of long non-coding RNA AFAP1-AS1 inhibits tumor cell growth and invasion in lung adenocarcinoma. AB - An increasing number of deregulated long non-coding RNAs (lncRNA) have been implicated in cancer in humans, suggesting that lncRNAs may be involved in tumorigenesis or tumor progression. In previous investigations, lncRNA, AFAP1-AS1 has been found to be associated with several cancers, including nasopharyngeal carcinoma, lung cancer and esophageal adenocarcinoma. However, the function of AFAP1-AS1 in lung cancer has not been reported. In our present study, we found that AFAP1-AS1 was overexpressed in lung adenocarcinoma and associated with survival time. The low expression of AFAP1-AS1 was an independent predictor for disease-free survival in patients with lung adenocarcinoma. Additionally, we transfected AFAP1-AS1 siRNA into H1975 and HCC827, both lung adenocarcinoma cancer cells, and found that cell growth was suppressed, apoptosis induced and invasion inhibited. Taken together, AFAP1-AS1 down-regulation exerts growth suppression and apoptosis induction in lung adenocarcinoma cells, suggested it may participate in turmorigenesis and be a therapeutic target for treating lung adenocarcinoma in future. PMID- 28670388 TI - Left ventricular myocardial strain in ventricular arrhythmia without structural heart disease using cardiac magnetic resonance. AB - Ventricular arrhythmia (VA) in structurally normal heart is considered as benign. However, these arrhythmias have been recently reported to induce left ventricular (LV) dysfunction. Up to now, there is no efficacious method to detect abnormal myocardial systolic function in VA patients. Therefore, in the current study, we used cardiac magnetic resonance feature tracking (CMR-FT) on balanced steady state free precision (SSFP) cine images to investigate LV myocardial strain in 42 VA patients without known heart disease as well as in 29 normal volunteers. As compared with controls, VA patients had lower peak values of radial and circumferential strain (RS, CS) in both basal and middle parts of LV and the peak value of longitudinal strain (LS) in VA patients was also decreased in middle LV. Moreover, as revealed by LV myocardial segmental peak strain, reduced RS, CS and LS peaks in VA were more significant in anterior, inferoseptal and anterolateral segments, especially for the patients with frequent premature ventricular complexes. Our results suggested that VA in normal heart is associated with abnormal segmental wall motion, which can be efficaciously detected by CMR-FT derived strain analysis. And early clinical management should be considered to prevent further significant symptoms in these patients. PMID- 28670389 TI - Sapylin promotes wound healing in mouse skin flaps. AB - Seroma formation is one of the most common complications after modified radical mastectomy. Sapylin is an agent used to reduce seroma formation following breast cancer surgery. In this article, we aimed to identify the potential mechanism by which Sapylin reduced seroma formation. Thirty-six female C57 mice were randomly divided into three groups. All mice were anaesthetized and a skin flap was generated on their abdomens. Each group was treated with normal saline, 0.5 KE/ml of Sapylin, or 50% hypertonic glucose, respectively. On day 3 and day 7 after the surgery, six mice in each group were sacrificed. Skin flap samples were collected and markers of angiogenesis, collagen synthesis, fibroplasia and matrix remodeling were detected. The skin flaps from the Sapylin- or hypertonic glucose treated mice closed faster than the skin flaps from the mice treated with normal saline. The neovessel density was higher in the skin flaps from the mice in the Sapylin group than those in the other two groups. Increased mRNA and protein expression of angiogenesis markers (VEGF-A and HIF-1alpha) and collagen synthesis markers (FGF2 and TGF-beta1) were observed in the mice in the Sapylin group compared with the saline- or hypertonic glucose-treated mice. The extracellular matrix remodeling marker MMP2 was induced by Sapylin only in the early phase (day 3). In conclusion, Sapylin accelerated wound closure, and promoted angiogenesis, collagen synthesis and the remodeling process, which improved wound healing. Considering the close relationship between wound healing and seroma formation, Sapylin may reduce seroma formation after modified radical mastectomy. PMID- 28670390 TI - KLF16 promotes proliferation in gastric cancer cells via regulating p21 and CDK4. AB - Kruppel-like factors (KLFs), such as KLF4, KLF2, KLF5 and KLF15, have been extensively investigated in multi-cancers. However, KLF16, a member of KLFs, hasn't been well identified in cancer, especially in gastric cancer (GC). Here, we investigated the roles of KLF16 in GC. In present study, we found that KLF16 expression levels were significantly up-regulated in GC tissues compared to adjacent normal tissues both in protein and mRNA levels by using immunohistochemistry assays (IHC) and real-time quantitative PCR (qPCR). And KLF16 expression levels were positively correlated to tumor size, invasion depth, lymphatic metastasis and TNM stage. Furthermore, KLF16 expression also could predict prognosis in patients with GC. Moreover, the knock-down of KLF16 could significantly suppress proliferation via increasing p21 expression and decreasing CDK4 expression in GC cell lines. In summary, these findings demonstrate that KLF16 plays a significant role in GC progression and could be a new therapeutic target for GC patients. PMID- 28670391 TI - URI promotes the migration and invasion of human cervical cancer cells potentially via upregulation of vimentin expression. AB - URI is known to act as an oncoprotein in several tumors. Our previous studies have shown that URI is associated with the migration process in cervical and gastric cancer cells, but the mechanisms remain to be determined. Given the fact that URI positively regulates vimentin expression, we therefore investigated how URI regulated vimentin expression affects the migration and invasion of cells from two human cervical cancer cell lines HeLa and C33A, which differentially express URI. We have shown that knock-down of URI in HeLa cells using URI siRNA caused decreased vimentin mRNA and protein levels along with attenuated cell motility. Meanwhile, overexpression of URI by transfection of PCMV6-URI in C33A cells resulted in increased vimentin expression and enhanced cell migration and invasion. We have also used TGF-beta to induce vimentin expression, which enhanced the cell migration and invasion abilities affected by URI, while inhibition of vimentin by siRNA attenuated URI's effect on cell migration and invasion. In addition, we have performed luciferase reporter and ChIP assays, and the results support that URI indirectly enhances the activity of vimentin promoter. Taken together, our results suggest that URI plays essential roles in the migration and invasion of human cervical cancer cells, possibly via targeting vimentin expression. PMID- 28670392 TI - Interactome analysis of gene expression profiles of cervical cancer reveals dysregulated mitotic gene clusters. AB - Cervical cancer is the second most common malignancy in women worldwide. HPV infections are the leading cause of cervical cancer. Although progress has been made in understanding cervical cancer, knowledge of oncogenic gene clusters that participate in squamous-cell mitosis is still lacking. We performed a computational analysis with qRT-PCR validation of gene expression profiles of cervical cancer tissues. Genes involved in muscle contraction and development were downregulated in cervical cancer tissues, suggesting decreased muscle function in cervical cancer. Among the genes that were upregulated in cervical cancer tissues, several groups of genes were found to interact with each other and synergistically participate in multiple stages of mitosis including DNA replication, cell cycle progression, and cell division. An analysis of gene regulatory networks showed that replicative helicase proteins (MCM2, MCM4, MCM5, MCM6, and MCM10) and DNA polymerases (PLOA1/E2/E3/Q) have enhanced DNA replication in cervical cancer. A group of kinases, cyclins, and transcriptional factors were found to promote cell cycle transitions from G1 phase to S phase and from G2 phase to M phase. Those proteins included CDK1, CCNA2, CCNB2, and TFDP2. Moreover, a set of motor proteins (KIF11, KIF14 and KIF4A) and their partner PRC1 were found to mediate cytokinesis during cervical cancer progression. Those findings present a better understanding of the mechanism of mitosis in cervical cancer from an interactomic perspective and provide potential targets for anticancer therapies. PMID- 28670393 TI - Chronic intermittent hypoxia decreases pulmonary clearance of 99mTc-labelled particulate matter in mice. AB - BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) could cause systematic inflammation including pulmonary inflammatory response, whereas the influence of OSAHS in pulmonary clearance ability remains unknown. The main pathophysiological feature of OSAHS is chronic intermittent hypoxia (CIH). The goal of this study is to clarify the airway clearance of particulate matter (PM) in CIH mice, and to explore the potential mechanism. METHODS: Balb/c mice were divided into a CIH group and a control group, exposed to intermittent hypoxia and air chamber, respectively. A radioactive probe, 99mTc labeled PM, was endotracheally inserted into the mice at 10 mg/kg, with a starting dose of 800 MUCi. The change of radioactive dose reserved in the lung was observed using single-photon emission computed tomography/computed tomography (SPECT/CT) and reconstructed data were analyzed. Special airway resistance (sRaw) of mice was measured by non-invasive airway mechanics sites. Lung resistive load (RL), elastic resistance, and compliance were measured by a multichannel physiological signal system. Lung injury was judged by hematoxylin-eosin staining and histologic score. Change in mucus secretion was determined using periodic acid Schiff staining and enzyme-linked immunosorbent assay. Fresh lung tissue was used for real-time polymerase chain reaction and western blot analysis to explore related change of inflammation and signaling molecules and potential mechanical pathway. RESULTS: Mice in the CIH group had higher PM radioactive deposit than the control group (93.37+/-3.44 MUCi vs. 65.98+/-2.61 MUCi). The average radiation dose in the lung was elevated (0.0005 MUCi/mm3 vs. 0.0001383 MUCi/mm3). Mice in the CIH group have higher value of sRaw, RL, and elastic resistance, whereas pulmonary compliance decreased compared to the control group (2.13+/-0.29 mL/cmH2O vs. 5.37+/-1.02 mL/cmH2O). The CIH group showed a higher histopathological score. Several genes associated with mucin secretion such as chemokine (C-X-C motif) ligand 1 (CXCL1), Clara Cell Secretory Protein 16 (CC16), macrophage inflammatory protein 2 (MIP-2), chloride channel regulator 1 (Gob5), and mucin 5AC (MUC5AC) showed elevated expression. Phosphatidylinostol-3 kinase/serine/threonine-specific protein kinase (PI3K/AKT) pathway was activated in the CIH group. CONCLUSIONS: CIH decreased pulmonary clearance of PM and increased lung airway resistance, which may be related to inflammatory response and mucus hypersecretion in the lung. PMID- 28670394 TI - PFP alleviates nonalcoholic steatohepatitis fatty liver in both Apo E-/- mice and Changliver cell[S]. AB - High-calorie food leads to nonalcoholic fatty liver disease (NAFLD) through the dysregulation of genes involved in lipid metabolism, but the precise mechanism is still unknown. Pomegranate flowers are used to treat diabetes mellitus in traditional Uighur medicine. Here we sought to investigate the effect and mechanism of pomegranate flower polyphenols (PFP) on NAFLD Apo E-/- mice induced by a high-fat diet (HFD) and whether PFP improves NAFLD through decreasing oxidative stress. PFP supplementation in mice significantly reduced the HFD induced gains in body weight compared with the mice fed only with HFD. It also significantly reduced HFD-induced increases in serum lipids, including cholesterol and triglyceride. Consistent with the reduced liver weight, hepatic lipid accumulation, and the size of lipid droplets in the epididymal fat pads were also reduced by PFP supplementation. To further investigate how PFP may reduce obesity, we analyzed lipid metabolism-related genes in the liver. PFP supplementation altered expression profiles of several lipid metabolism-related genes, including ACC, AMPK, CPT-1alpha, FAS, LDLR, Leptin, LXR, PON1, PPAR, SirT3, and SREBP, relative to those in HFD control mice. The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction and AMPK, SirT3, ACC2, and CPT-1A expression were confirmed by immunohistochemical assays. Collectively, our results indicate that PFP prevents HFD-induced obesity in Apo E-/- mice, and its anti-obesity effects may be related to the regulation of lipogenesis at the level of transcription. PMID- 28670395 TI - Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model. AB - BACKGROUND: Investigations in factor VII activating protease (FSAP)-/- mice suggest a role for FSAP in stroke, thrombosis and neointima formation. Here, we analyzed the role of FSAP in vascular remodeling processes related to arteriogenesis and angiogenesis in the mouse hind limb ischemia model. METHODS AND RESULTS: Femoral artery ligation was performed in mice and exogenous FSAP was injected locally to examine its effect on arteriogenesis in the adductor and angiogenesis in the gastrocnemius muscle over 21 days. Perfusion was decreased by FSAP, which was reflected in a lower arterial diameter and was associated with reduced monocyte infiltration in the adductor muscle. There was increased angiogenesis in the gastrocnemius muscle triggered indirectly by less blood supply to the lower limb. Comparison of wild-type (WT) and FSAP-/- mice showed that perfusion was not different between the genotypes but there were 2.5-fold more collateral arteries in the adductor muscle of FSAP-/- mice at day 21. This was associated with a higher infiltration of monocytes at day 3. Capillary density in the gastrocnemius muscle was not altered. Activity of the two major proteolytic pathways associated with vascular remodeling; matrix metalloprotease (MMP)-9 and urokinase-type plasminogen activator (uPA) was elevated in the gastrocnemius but not in the adductor muscle in FSAP-/- mice. CONCLUSIONS: Arteriogenesis is enhanced, and this is associated with a higher infiltration of monocytes, in the absence of endogenous FSAP but angiogenesis is unchanged. Exogenous FSAP had the opposite effect on arteriogenesis indicating a possible therapeutic potential of modulating endogenous FSAP. PMID- 28670396 TI - Effects of chemerin/CMKLR1 in obesity-induced hypertension and potential mechanism. AB - BACKGROUND: Obesity-induced hypertension (OIH) has a high morbidity and mortality, and its prevention and treatment has been a major challenge in clinical practice. Chemerin is a newly discovered adipokine closely related to OIH. METHODS: Male Wistar rats (8W) were divided into either a high-fat diet or a regular diet group. Body weight and blood pressure were measured every two weeks. After 20 weeks, serum, adipose tissue and aortic arteries were collected. Arterial tensions were detected; Immunohistochemistry, ELISA and Western blotting were used to detect the expression of chemerin, CMKLR1, Rock2 and P-MYPT1 in the aorta and perivascular adipose tissues. RESULTS: After 4 weeks, the body weight, systolic blood pressure, diastolic blood pressure and mean arterial pressure were all significantly higher in the high-fat diet group (P<0.05). There was no significant difference in serum chemerin concentration between the OIH group and the control group. However, chemerin and CMKLR1 protein expression was higher in aortic arteries and perivascular adipose tissues of the OIH group (P<0.05). The arterial tension induced by chemerin 9 (1 MUM) and the expression of Rock2 and P MYPT1 were higher in the OIH group (P<0.05). CONCLUSION: OIH positively correlated with chemerin in tissues but not serum. Arterial tension was increased by chemerin 9. Rock2/P-MYPT1 might be involved in the pathogenesis of increased vascular tone in OIH rats. PMID- 28670397 TI - Combined administration of a sedative dose sevoflurane and 60% oxygen reduces inflammatory responses to sepsis in animals and in human PMBCs. AB - Our study aims to investigate the effects of the inhalation of subanesthestic doses of sevoflurane combined with oxygen on sepsis. Male Sprague-Dawley rats or Male ICR/Km mice underwent caecal ligation and puncture (CLP) or intraperitoneal injection of lipopolysccharide (LPS) to induce sepsis, while sham rats were used as control. Then, rats were treated with the inhalation of sevoflurane in oxygen; and air or 100% oxygen was used as control. Seven-day survival, lung injury and inflammatory factors were assessed. In this in vitro experiment, we obtained RAW264.7 macrophages and human peripheral blood mononuclear cells (PBMCs) incubated by LPS or plasma from septic patients to explore the NF-kappaB pathway in the effect of the inhalation of sevoflurane combined with oxygen in sepsis. In this study, we found that the inhalation of 0.5 MAC of sevoflurane in 60% oxygen was the best protocol for protecting against lethality resulting from sepsis and ALI, and there was a time window for these protective effects. We also founded that 0.5 MAC of sevoflurane in 60% oxygen inhibited the nuclear translocation of NF-kappaB in human PBMCs induced by LPS or plasma from septic patients. The subanesthesia dose sevoflurane in 60% oxygen may reduce sepsis-induced inflammatory responses in animals and in PBMCs, and the inhibition to the activation of the NF-kappaB pathway may contribute to this protection. PMID- 28670398 TI - MicroRNA-1825 induces proliferation of adult cardiomyocytes and promotes cardiac regeneration post ischemic injury. AB - In mammals, proliferative capacity of cardiomyocytes is lost soon after birth, while zebrafish and other lower organisms like newts are known to regenerate injured hearts even at an adult age. Here, we show that miR-1825 can induce robust proliferation of adult rat cardiomyocytes and can improve cardiac function in-vivo post myocardial infarction. Rat adult cardiomyocytes transfected with miR 1825 showed a significant increase in DNA synthesis, mitosis, cytokinesis, and an increase in cell number when compared to cel-miR-67 transfected control. We also observed a reduction in mitochondrial number and a decrease in ROS and DNA damage. RNA-sequencing data identified NDUFA10, a key gene involved in the mitochondrial electron transport chain to be a direct target of miR-1825. SiRNA mediated silencing of NDUFA10 showed a significant increase in cardiomyocyte proliferation indicating its role downstream of miRNA-1825. In addition, microRNA microarray results identified miR-1825 to regulate expression of a known proliferation inducing miRNA, miR-199a. We also identified the direct targets of miR-199a, namely p16, Rb1, and Meis2 to be downregulated following miR-1825 transfection. However, miR-199a alone did not have similar proliferation inducing effects as miR-1825, indicating that miR-1825 works through multiple pathways and is a master regulator of cardiomyocyte proliferation. In addition, our in-vivo analysis in animal models of LAD ligation and intra-cardiac miRNA delivery showed proliferation of endogenous cardiomyocytes in the peri-infarcted region and an improvement in heart function. These findings establish miR-1825 as a potential therapeutic agent for induction of cardiomyocyte proliferation and cardiac regeneration, with a significant translational potential. PMID- 28670399 TI - Valproic acid, targets papillary thyroid cancer through inhibition of c-Met signalling pathway. AB - Tyrosine kinase receptors such as c-Met and its ligands are interesting therapeutic targets that have been reported to be involved in the progression of several types of cancers. Histone deacetylase inhibitor, valproic acid (VPA) is one such compound with promising anti-cancer properties. The current study was designed to evaluate the c-Met activity of VPA in thyroid carcinoma. A total 36 nu/nu mice with SW1736 cells-induced tumours were randomised into three treatment groups (5, 15, 30 mg/kg/day p.o. VPA; n = 9/group). Various cellular and enzymatic assays were performed to evaluate the dose-response relationship of VPA in c-Met inhibition. In vitro assays revealed that VPA (IC50, 5-26 nmol/l) shows c-Met phosphorylation and c-Met-dependent inhibition of cellproliferation. This causes inhibition of downstream signalling pathways in human thyroid cancer cell lines (SW1736, WRO). Additionally, VPA also showed anti-angiogenetic activity in HGF-stimulated endothelial cell. VPA showed significant reduction in tumour size in xenograft model (P = 0.023) with high levels of c-Met expression. The anticancer activity was found to be dose dependent and strongly correlated with c Met expression. Thus, this novel finding paves way for investigation of new mechanism of action and its validation in clinical settings. PMID- 28670400 TI - Freeze-Dried Human Platelet-Rich Plasma Retains Activation and Growth Factor Expression after an Eight-Week Preservation Period. AB - STUDY DESIGN: Controlled laboratory study. PURPOSE: This study aimed to evaluate the efficacy of platelet-rich plasma (PRP) stored at room temperature (RT), frozen, or after freeze-drying. OVERVIEW OF LITERATURE: PRP enriches tissue repair and regeneration, and is a novel treatment option for musculoskeletal pathologies. However, whether biological activity is preserved during PRP storage remains uncertain. METHODS: PRP was prepared from blood of 12 healthy human volunteers (200 mL/person) and stored using three methods: PRP was stored at RT with shaking, PRP was frozen and stored at -80C, or PRP was freeze-dried and stored at RT. Platelet counts and growth factor content were examined immediately after preparation, as well as 2, 4, and 8 weeks after storage. Platelet activation rate was quantified by flow cytometry. RESULTS: Platelet counts were impossible to determine in many RT samples after 2 weeks, but they remained at constant levels in frozen and freeze-dried samples, even after 8 weeks of storage. Flow cytometry showed approximately 80% activation of the platelets regardless of storage conditions. Almost no growth factors were detected in the RT samples after 8 weeks, while low but significant expression was detected in the frozen and freeze-dried PRP. Over time, the mean relative concentrations of various growth factors decreased significantly or disappeared in the RT group. In the frozen group, levels were maintained for 4 weeks, but decreased significantly by 8 weeks (p <0.05). The freeze-dried group maintained baseline levels of growth factors for the entire 8-week duration. CONCLUSIONS: Freeze-drying enables PRP storage while maintaining bioactivity and efficacy for extended periods. PMID- 28670401 TI - The Clinical Correlations between Diabetes, Cigarette Smoking and Obesity on Intervertebral Degenerative Disc Disease of the Lumbar Spine. AB - STUDY DESIGN: Retrospective analysis of a nationwide private insurance database. Chi-square analysis and linear regression models were utilized for outcome measures. PURPOSE: The purpose of this study was to investigate any relationship between lumbar degenerative disc disease, diabetes, obesity and smoking tobacco. OVERVIEW OF LITERATURE: Diabetes, obesity, and smoking tobacco are comorbid conditions known to individually have effect on degenerative disc disease. Most studies have only been on a small populous scale. No study has yet to investigate the combination of these conditions within a large patient cohort nor have they reviewed the combination of these conditions on degenerative disc disease. METHODS: A retrospective analysis of insurance billing codes within the nationwide Humana insurance database was performed, using PearlDiver software (PearlDiver, Inc., Fort Wayne, IN, USA), to identify trends among patients diagnosed with lumbar disc degenerative disease with and without the associated comorbidities of obesity, diabetes, and/or smoking tobacco. Patients billed for a comorbidity diagnosis on the same patient record as the lumbar disc degenerative disease diagnosis were compared over time to patients billed for lumbar disc degenerative disease without a comorbidity. There were no sources of funding for this manuscript and no conflicts of interest. RESULTS: The total number and prevalence of patients (per 10,000) within the database diagnosed with lumbar disc degenerative disease increased by 241.4% and 130.3%, respectively. The subsets of patients within this population who were concurrently diagnosed with either obesity, diabetes, tobacco use, or a combination thereof, was significantly higher than patients diagnosed with lumbar disc degenerative disease alone (p <0.05 for all). The number of patients diagnosed with lumbar disc degenerative disease and smoking rose significantly more than patients diagnosed with lumbar disc degenerative disease and either diabetes or obesity (p <0.05). The number of patients diagnosed with lumbar disc degenerative disease, smoking and obesity rose significantly more than the number of patients diagnosed with lumbar disc degenerative disease and any other comorbidity alone or combination of comorbidities (p <0.05). CONCLUSIONS: Diabetes, obesity and cigarette smoking each are significantly associated with an increased diagnosis of lumbar degenerative disc disease. The combination of smoking and obesity had a synergistic effect on increased rates of lumbar degenerative disc disease. Patient education and preventative care is a vital goal in prevention of degenerative disc disease within the general population. PMID- 28670402 TI - Disc Rehydration after Dynamic Stabilization: A Report of 59 Cases. AB - STUDY DESIGN: A retrospective study investigating decrease in the nucleus pulposus signal intensity or disc height on magnetic resonance imaging (MRI) and disc degeneration. PURPOSE: Although a degenerated disc cannot self-regenerate, distraction or stabilization may provide suitable conditions for rehydration and possible regeneration. This study aimed to evaluate clinical outcomes and disc regeneration via MRI in a series of patients with degenerative disc disease (DDD) who underwent lumbar stabilization with a dynamic stabilization system (DSS). OVERVIEW OF LITERATURE: A dynamic system provides rehydration during early DDD. METHODS: Fifty-nine patients (mean age, 46.5 years) who undedwent stabilization with DSS for segmental instability (painful black disc) between 2004 and 2014 were retrospectively evaluated. All patients underwent MRI preoperatively and 12 months postoperatively. Intervertebral disc (IVD) degeneration grades at the implanted segment were categorized using the Pfirrmann classification system. Patients were followed for a mean of 6.4 years, and clinical outcomes were based on visual analog scale (VAS) and Oswestry disability index (ODI) scores. RESULTS: Significant improvements in back pain VAS and ODI scores from before surgery (7 and 68%, respectively) were reported at 6 (2.85 and 27.4%, respectively) and 12 months postoperatively (1.8 and 16.3%, respectively). Postoperative IVD changes were observed in 28 patients. Improvement was observed in 20 patients (34%), whereas progressive degeneration was observed in eight patients (13.5%). Thirty one patients (52.5%) exhibited neither improvement nor progression. Single Pfirrmann grade improvements were observed in 29% of the patients and two-grade improvements were observed in 5%. CONCLUSIONS: Our observations support the theory that physiological movement and a balanced load distribution are necessary for disc regeneration. We conclude that DSS may decelerate the degeneration process and appears to facilitate regeneration. PMID- 28670403 TI - Risk Factors for Failure of Nonoperative Treatment for Unilateral Cervical Facet Fractures. AB - STUDY DESIGN: Retrospective clinical study. PURPOSE: The purpose of this study was to determine what percentage of patients who underwent nonoperative management of unilateral non-displaced or minimally displaced facet fractures progressed radiographically and to determine what percentage of patients required surgical intervention and to identify risk factors for failure of conservative management. OVERVIEW OF LITERATURE: According to most commonly used classification systems, unilateral, non-and minimally displaced facet fractures are be amendable to nonoperative management. METHODS: A retrospective review of the Trauma Registry of a Level I trauma center was performed to identify all patients diagnosed with a non- or minimally displaced unilateral facet fracture which was managed nonoperatively. Several demographic variables and clinical outcomes were recorded. Using computed tomography scanning and plain radiographs, fracture pattern, listhesis, displacement, angle and percentage of the facet that included the fracture were determined. Radiographic progression was defined as the occurrence of listhesis of more than 10% of the anterior-posterior dimensions of the inferior vertebral body during radiographic follow-up. Failure of conservative management was defined as a patient requiring surgical intervention after initially being managed nonoperatively. RESULTS: Seventy-four patients were included. Fifteen patients (20%) progressed radiographically. However, only 2 developed radicular symptoms and none developed myelopathy or other catastrophic cord related symptoms. Seven patients (9%) underwent surgery. Indications for surgery included significant radiographic progression and/or radicular symptoms. Risk factors for failure of conservative management included presence of radiculopathy at the time of presentation, a higher body mass index, increased Injury Severity Score, greater initial fracture displacement and more than 2 mm of listhesis. CONCLUSIONS: Patients with non-displaced or minimally displaced facet fractures who do not have neurological symptoms at the time of presentation can safely be managed conservatively with careful observation and follow-up. PMID- 28670404 TI - Role of Anatomical Landmarks in Identifying Normal and Transitional Vertebra in Lumbar Spine Magnetic Resonance Imaging. AB - STUDY DESIGN: Retrospective study. PURPOSE: Identification of transitional vertebra is important in spine imaging, especially in presurgical planning. Pasted images of the whole spine obtained using high-field magnetic resonance imaging (MRI) are helpful in counting vertebrae and identifying transitional vertebrae. Counting vertebrae and identifying transitional vertebrae is challenging in isolated studies of lumbar spine and in studies conducted in low field MRI. An incorrect evaluation may lead to wrong-level treatment. Here, we identify the location of different anatomical structures that can help in counting and identifying vertebrae. OVERVIEW OF LITERATURE: Many studies have assessed the vertebral segments using various anatomical structures such as costal facets (CF), aortic bifurcation (AB), inferior vena cava confluence (IC), right renal artery (RRA), celiac trunk (CT), superior mesenteric artery root (SR), iliolumbar ligament (ILL) psoas muscle (PM) origin, and conus medullaris. However, none have yielded any consistent results. METHODS: We studied the locations of the anatomical structures CF, AB, IC, RRA, CT, SR, ILL, and PM in patients who underwent whole spine MRI at our department. RESULTS: In our study, 81.4% patients had normal spinal segmentation, 14.7% had sacralization, and 3.8% had lumbarization. Vascular landmarks had variable origin. There were caudal and cranial shifts with respect to lumbarization and sacralization. In 93.8% of cases in the normal group, ILL emerged from either L5 alone or the adjacent disc. In the sacralization group, ILL was commonly seen in L5. In the lumbarization group, ILL emerged from L5 and the adjacent disc (66.6%). CFs were identified at D12 in 96.9% and 91.7% of patients in the normal and lumbarization groups, respectively. The PM origin was observed from D12 or D12-L1 in most patients in the normal and sacralization groups. CONCLUSIONS: CF, PM, and ILL were good identification markers for D12 and L5, but none were 100% accurate. PMID- 28670405 TI - Intradiscal Injection of Autologous Platelet-Rich Plasma Releasate to Treat Discogenic Low Back Pain: A Preliminary Clinical Trial. AB - STUDY DESIGN: Preliminary clinical trial. PURPOSE: To determine the safety and initial efficacy of intradiscal injection of autologous platelet-rich plasma (PRP) releasate in patients with discogenic low back pain. OVERVIEW OF LITERATURE: PRP, which is comprised of autologous growth factors and cytokines, has been widely used in the clinical setting for tissue regeneration and repair. PRP has been shown in vitro and in vivo to potentially stimulate intervertebral disc matrix metabolism. METHODS: Inclusion criteria for this study included chronic low back pain without leg pain for more than 3 months; one or more lumbar discs (L3/L4 to L5/S1) with evidence of degeneration, as indicated via magnetic resonance imaging (MRI); and at least one symptomatic disc, confirmed using standardized provocative discography. PRP releasate, isolated from clotted PRP, was injected into the center of the nucleus pulposus. Outcome measures included the use of a visual analog scale (VAS) and the Roland-Morris Disability Questionnaire (RDQ), as well as X-ray and MRI (T2-quantification). RESULTS: Data were analyzed from 14 patients (8 men and 6 women; mean age, 33.8 years). The average follow-up period was 10 months. Following treatment, no patient experienced adverse events or significant narrowing of disc height. The mean pain scores before treatment (VAS, 7.5+/-1.3; RDQ, 12.6+/-4.1) were significantly decreased at one month, and this was generally sustained throughout the observation period (6 months after treatment: VAS, 3.2+/-2.4, RDQ; 3.6+/-4.5 and 12 months: VAS, 2.9+/-2.8; RDQ, 2.8+/-3.9; p<0.01, respectively). The mean T2 values did not significantly change after treatment. CONCLUSIONS: We demonstrated that intradiscal injection of autologous PRP releasate in patients with low back pain was safe, with no adverse events observed during follow-up. Future randomized controlled clinical studies should be performed to systematically evaluate the effects of this therapy. PMID- 28670406 TI - The Effect of Soft and Rigid Cervical Collars on Head and Neck Immobilization in Healthy Subjects. AB - STUDY DESIGN: Whiplash injury is a prevalent and often destructive injury of the cervical column, which can lead to serious neck pain. Many approaches have been suggested for the treatment of whiplash injury, including anti-inflammatory drugs, manipulation, supervised exercise, and cervical collars. Cervical collars are generally divided into two groups: soft and rigid collars. PURPOSE: The present study aimed to compare the effect of soft and rigid cervical collars on immobilizing head and neck motion. OVERVIEW OF LITERATURE: Many studies have investigated the effect of collars on neck motion. Rigid collars have been shown to provide more immobilization in the sagittal and transverse planes compared with soft collars. However, according to some studies, soft and rigid collars provide the same range of motion in the frontal plane. METHODS: Twenty-nine healthy subjects aged 18-26 participated in this study. Data were collected using a three-dimensional motion analysis system and six infrared cameras. Eight markers, weighing 4.4 g and thickened 2 cm2 were used to record kinematic data. According to the normality of the data, a paired t-test was used for statistical analyses. The level of significance was set at alpha=0.01. RESULTS: All motion significantly decreased when subjects used soft collars (p<0.01). According to the obtained data, flexion and lateral rotation experienced the maximum (39%) and minimum (11%) immobilization in all six motions using soft collars. Rigid collars caused maximum immobilization in flexion (59%) and minimum immobilization in the lateral rotation (18%) and limited all motion much more than the soft collar. CONCLUSIONS: This study showed that different cervical collars have different effects on neck motion. Rigid and soft cervical collars used in the present study limited the neck motion in both directions. Rigid collars contributed to significantly more immobilization in all directions. PMID- 28670407 TI - Effectiveness of Multidisciplinary Group-Based Intervention versus Individual Physiotherapy for Improving Chronic Low Back Pain in Nursing Staff: A Clinical Trial with 3- and 6-Month Follow-Up Visits from Tehran, Iran. AB - STUDY DESIGN: Clinical trial. PURPOSE: To evaluate the effectiveness of a multidisciplinary group-based intervention on improving pain and disability among Iranian nurses with chronic low back pain in Tehran, Iran. OVERVIEW OF LITERATURE: Although low back pain (LBP) is one of the most important health problems, the challenge remains on how to find an effective intervention to reduce pain and related disabilities. METHODS: Overall, 136 eligible nurses with chronic mechanical LBP were classified into two groups. The intervention group (n=66 participants) participated in a physiotherapy educational program (for 120 minutes) plus a health educational program based on predictive constructs of the social cognitive theory (for 120 minutes). These interventions were delivered by a physiotherapist and a health education specialist. The control group (n=70 participants) participated in a physiotherapy educational program (for 120 minutes). Disability rate, pain severity, and back pain prevention behavior were measured initially and at 3- and 6-month follow-up visits using the visual analogue scale, Roland-Morris Disability, and Nursing Low Back Pain Preventive Behaviors Questionnaire. Data were analyzed by SPSS ver. 16. RESULTS: There were statistically significant differences between the two groups in the main outcome measures immediately after the educational program and at 3- and 6-month follow up visits. Preventive behaviors of participants in the intervention group were improved at 3- and 6- month follow-up visits (p<0.001). The mean scores of predictive constructs regarding LBP preventive behaviors in the intervention group were improved after 3 and 6 months (p<0.001). Finally, in the intervention group, pain severity and disability were decreased significantly. CONCLUSIONS: This study showed that a multidisciplinary educational program intervention can be an effective approach for reducing LBP and related disabilities among nurses. PMID- 28670408 TI - Epidemiology of Musculoskeletal Tuberculosis in an Area with High Disease Prevalence. AB - STUDY DESIGN: Retrospective observational study. PURPOSE: The aim of this study was to assess the distribution of age and site of infection in patients with musculoskeletal tuberculosis (TB) and determine the number of TB/human immunodeficiency virus (HIV) coinfections as well as the incidence of multidrugresistant (MDR) TB. OVERVIEW OF LITERATURE: Of all TB cases, 1%-3% show skeletal system involvement and 30% are HIV coinfected. Although the reported distribution of skeletal TB is majorly in the spine, followed by the hip, knee, and foot/ankle, the epidemiology of extrapulmonary TB and especially musculoskeletal TB remains largely unknown, particularly in areas with a high prevalence of the disease. METHODS: This is a retrospective study of a consecutive series of patients admitted to a tertiary care facility in an area with the highest prevalence of TB worldwide. TB was confirmed on tissue biopsy with polymerase chain reaction testing (Xpert for Mycobacterium tuberculosis and rifampicin resistance), culturing, or histological analysis. Data were analyzed regarding demographic information, location of the disease, HIV coinfections, and drug resistance. RESULTS: In all, 125 patients (44 children; 35%) with a mean age of 27 years (range, 1-78 years) were included. Age peaks were observed at 5, 25, and 65 years. Spinal disease was evident in 98 patients (78%). There were 66 HIV negative (53%) and 29 (23%) HIVpositive patients, and in 30 (24%), the HIV status was unknown. Five patients (4%) showed MDR TB. CONCLUSIONS: The age distribution was trimodal, spinal disease was predominant, MDR TB rate in our cohort was high, and a large portion of TB patients in our hospital were HIV coinfected. Hence, spinal services with sufficient access to operating facilities are required for tertiary care facilities in areas with a high TB prevalence. PMID- 28670409 TI - Traumatic Spinal Cord Injury: Long-Term Motor, Sensory, and Urinary Outcomes. AB - STUDY DESIGN: Retrospective study. PURPOSE: To evaluate how motor, sensory, and urinary outcomes of spinal cord injury (SCI) patients were influenced in the long term. OVERVIEW OF LITERATURE: SCI is a potentially disabling and devastating neurological outcome that can occur because of spinal column fractures. Most studies have not evaluated or have failed to show the influence of different surgical approaches and other parameters on neurological recovery. METHODS: A thorough history regarding sensory, motor, and urinary complaints was taken from 103 patients with SCI due to vertebral fracture; patients were followed by a thorough neurological examination. Subsequently, all medical records of patients, including neurological state after trauma, trauma mechanism, treatment protocol, surgical protocol, and imaging findings, were evaluated. RESULTS: Of the 103 patients, 73.8% were survivors of a major earthquake and 26.2% were victims of vehicle accidents; 92.2% patients were surgically treated, while 7.8% underwent conservative management. The mean follow-up duration was 10.3 years. In follow-up visits, 67.0%, 12.6%, 13.6%, and 6.8% patients showed no, partial, substantial, and complete motor improvement, respectively; 68.0%, 26.2%, and 5.8% showed no, mild, and substantial sensory improvement, respectively; and 73.8%, 17.5%, and 8.7% showed no, substantial, and complete urinary improvement, respectively. Logistic regression analysis showed that sex, age at injury time, follow-up duration, trauma mechanism, and stem cell therapy had no effect on motor, sensory, and urinary improvement. Higher initial scores on the American Spinal Injury Association (ASIA) classification, lumbar fracture level, and performance of laminectomy improved motor outcome; higher initial ASIA scores improved urinary and sensory outcomes. CONCLUSIONS: The initial ASIA score is the most important factor for prognosticating motor, sensory, and urinary improvement in SCI patients. Lumbar (L3-L5) and thoracic (T1-T10) fractures have the best and worst prognosis, respectively, in terms of motor recovery. Laminectomy during surgery improves motor function. PMID- 28670410 TI - A Multidisciplinary Workplace Intervention for Chronic Low Back Pain among Nursing Assistants in Iran. AB - STUDY DESIGN: Interventional research with a 6-month follow-up period. PURPOSE: We aimed to establish the effectiveness of a multidisciplinary workplace intervention on reduction of work-related low back pain (WRLBP), using ergonomic posture training coupled with an educational program based on social cognitive theory. OVERVIEW OF LITERATURE: WRLBP is a major occupational problem among healthcare workers, who are often required to lift heavy loads. Patient handling is a particular requirement of nurse aides, and has been reported as the main cause of chronic WRLBP. METHODS: We included 125 nursing assistants from two hospitals affiliated to Qom University of Medical Sciences from May to December 2015. There was an intervention hospital with a number of 63 nursing assistants who received four multidisciplinary educational sessions for 2 hours each plus ergonomic posture training over two days and a control hospital with a number of 62 nursing assistants who didn't receive educational intervention about low back pain. The outcomes of interest were reductions in WRLBP intensity and disability from baseline to the follow up at 6 months, which were measured using a visual analog scale and the Quebec Disability Scale. Descriptive and analytical statistics were used to analyze the data. RESULTS: The comparison tests showed significant change from baseline in reduction of WRLBP intensity following the multidisciplinary program, with scores of 5.01+/-1.97 to 3.42+/-2.53 after 6 months on the visual analog scale in the intervention group (p<0.001) and no significant change in control groups. There was no significant difference in the disability scores between the two groups (p=0.07). CONCLUSIONS: We showed that our multidisciplinary intervention could reduce the intensity of WRLBP among nurse aides, making them suitable for implementation in programs to improve WRLBP among nursing assistants working in hospitals. PMID- 28670411 TI - Polymicrobial and Monomicrobial Infections after Spinal Surgery: A Retrospective Study to Determine which Infection is more Severe. AB - STUDY DESIGN: A retrospective clinical review. PURPOSE: To investigate the difference in clinical manifestations and severity between polymicrobial and monomicrobial infections after spinal surgery. OVERVIEW OF LITERATURE: Surgical site infections (SSIs) after spinal surgery are a major diagnostic and therapeutic challenge for spinal surgeons. Polymicrobial infections after spinal surgery seem to result in poorer outcomes than monomicrobial infections because of complementary resistance to antibiotics. However, comparison of the clinical manifestations and severity between polymicrobial and monomicrobial infections are limited. METHODS: Sixty-seven patients with SSIs after spinal surgery were studied: 20 patients with polymicrobial infections and 47 with monomicrobial infections. Pathogenic bacteria identified were counted and classified. Age, sex, and body mass index were compared between the two groups to identify homogeneity. The groups were compared for clinical manifestations by surgical site, postoperative time to infection, infection site, incisional drainage, incisional swelling, incisional pain, neurological signs, temperature, white blood cell count, and the percentage of neutrophils. Finally, the groups were compared for severity by hospital stay, number of rehospitalizations, number of debridements, duration of antibiotics administration, number of antibiotics administered, and implant removal. RESULTS: Polymicrobial infections comprised 29.9% of SSIs after spinal surgery, and most polymicrobial infections (70.0%) were caused by two species of bacteria only. There was no difference between the groups in terms of clinical manifestations and severity. In total, 96 bacterial strains were isolated from the spinal wounds: 60 strains were gram-positive and 36 were gram negative pathogenic bacteria. Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Enterobacter cloacae were cultured in order of the frequency of appearance. CONCLUSIONS: Most polymicrobial infections were caused by two bacterial species after spinal surgery. There was no difference in clinical manifestations or severity between polymicrobial and monomicrobial infections. PMID- 28670412 TI - Facture of the Pars Interarticularis with or without Spondylolisthesis in an Adult Population in a Developing Country: Evaluation by Multidetector Computed Tomography. AB - STUDY DESIGN: Descriptive cross-sectional study. PURPOSE: To determine the prevalence of lumbar spondylolysis and spondylolisthesis in a general adult population unrelated to lower back pain as evaluated by multidetector computed tomography. OVERVIEW OF LITERATURE: There is a significant paucity of information related to the prevalence of spondylolysis and spondylolisthesis and its degenerative changes in a general adult population unrelated to lower back pain in developing countries. METHODS: A retrospective study was conducted on abdominopelvic computed tomography (CT) scans performed between January 1st 2015 and December 31st 2015 for various clinical indications. Patients with lower back pain, with a history of trauma or road traffic accident, or referred from orthopedic or neurosurgery departments were excluded to avoid any bias. CT scans were reviewed in axial, sagittal, and coronal planes using bone window settings for evaluating spondylolysis and spondylolisthesis. RESULTS: Of 4,348 patients recruited, spondylolysis and spondylolisthesis were identified in 266 (6.1%) and 142 (3.3%) patients, respectively. Age was significantly higher in both spondylolysis and spondylolisthesis patients than in those without spondylolysis and spondylolisthesis (47.19+/-15.45 vs. 42.5+/-15.96, p<0.001 and 53.01+/-15.31 vs. 42.44+/-15.88, p<0.001, respectively). Gender was significantly associated with spondylolisthesis (p=0.029) but not spondylolysis. Of patients who were >60 years old, both spondylolysis (p=0.018) and spondylolisthesis (p=0.025) were significantly more prevalent in females. CONCLUSIONS: The prevalence of pars interarticularis fracture observed higher with gradual increase in the prevalence with advancing age. In particular, preponderance was significantly higher among older females. PMID- 28670413 TI - Circumferential Fusion through All-Posterior Approach in Andersson Lesion. AB - STUDY DESIGN: Retrospective case series. PURPOSE: To assess safety and efficacy of single stage, posterior stabilisation and anterior cage reconstruction through the transforaminal or lateral extra-cavitary route for Andersson lesions. OVERVIEW OF LITERATURE: Pseudoarthrosis in ankylosing spondylitis (Andersson lesion, AL) can cause progressive kyphosis and neurological deficit. Management involves early recognition and surgical stabilisation in patients with instability. However, the need and safety of anterior reconstruction of the vertebral body defect remains unclear. METHODS: Twenty consecutive patients with AL whom presented with instability back pain and or neurological deficit were managed by single stage posterior approach with long segment pedicle screw fixation and anterior vertebral reconstruction. Radiological evaluation included- the regional kyphotic angle, measurement of anterior defect in computed tomography (CT) scan and the spinal cord status in magnetic resonance imaging. Radiological outcomes were assessed for fusion and kyphosis correction. Functional outcomes were assessed with visual analogue scale (VAS), ankylosing spondylitis quality of life (ASQoL) and Oswestry disability index (ODI). RESULTS: The mean age of the patients was 50.1 years (male, 18; female, 2). The levels affected include thoracolumbar (n=12), lower thoracic (n=5) and lumbar (n=3) regions. The mean level of fixation was 6.2+/-2.4 vertebrae. The mean anterior column defect was 1.6+/-0.6 cm. The mean surgical duration, blood loss and hospital stay were 112 minutes, 452 mL and 6.2 days, respectively. The mean followup was 2.1 years. At final follow up, VAS for back pain improved from 8.2 to 2.4 while ODI improved from 62.7 to 18.5 (p <0.05) and ASQoL improved from 14.3+/-2.08 to 7.90+/-1.48 (p <0.05). All patients had achieved radiological union at a mean 7.2+/-4.6 months. The mean regional kyphotic angle was 27 degrees preoperatively, 16.7 degrees postoperatively and 18.1 degrees at the final follow-up. CONCLUSIONS: Posterior stabilisation and anterior reconstruction with cage through an all-posterior approach is safe and can achieve good results in Andersson lesions. PMID- 28670414 TI - Use of Allogenic Mesenchymal Cellular Bone Matrix in Anterior and Posterior Cervical Spinal Fusion: A Case Series of 21 Patients. AB - STUDY DESIGN: Retrospective case series. PURPOSE: To report our early experience using allogenic mesenchymal cellular bone matrix (CBM) products in cervical spine fusion. OVERVIEW OF LITERATURE: Multi-level cervical fusions have historically yielded lower fusion rates than single level fusions, especially in patients with high risk medical comorbidities. At this time, significant literature in cervical fusion outcomes with this cellular allograft technology is lacking. METHODS: Twenty-one patients underwent either multilevel (3 or 4 level) anterior cervical discectomy and fusion, anterior cervical corpectomy and fusion, or posterior cervical fusion. ViviGen (DePuy Synthes Spine, Raynham, MA, USA), an allogenic bone matrix product, was used in addition to standard instrumentation. Radiographic evaluation was performed at 2 weeks, 12 weeks, 24 weeks and 1 year postoperative. Visual analog scale (VAS) and neck disability index (NDI) scores along with return to work and leisure activity were recorded. RESULTS: At 6 months postoperative, all patients had radiographic evidence of bone fusion regardless of age or medical comorbidities. All patients reported subjective improvement with a mean decrease in VAS from 8.3 to 1.5 and a mean decrease in NDI from 40.3% to 6.0% at 1 year. All patients also returned to work and/or regular leisure activity within 3 months. CONCLUSIONS: Twenty-one patients undergoing high-risk anterior and posterior cervical spine fusion, with the use of a commercially available mesenchymal CBM product, went on to radiographic fusion and all had improvement in subjective outcomes. While further effort and research is needed to validate its widespread use, this study shows favorable use of CBM in cervical fusion for high-risk cases. PMID- 28670415 TI - Outcomes of Revision Surgery Following Instrumented Posterolateral Fusion in Degenerative Lumbar Spinal Stenosis: A Comparative Analysis between Pseudarthrosis and Adjacent Segment Disease. AB - STUDY DESIGN: Retrospective study. PURPOSE: We examined the clinical and radiological outcomes of patients who received revision surgery for pseudarthrosis or adjacent segment disease (ASD) following decompression and instrumented posterolateral fusion (PLF). OVERVIEW OF LITERATURE: At present, information regarding the outcomes of revision surgery for complications such as pseudarthrosis and ASD following instrumented PLF is limited. METHODS: This study examined 60 patients who received PLF for degenerative lumbar spinal stenosis and subsequently developed pseudarthrosis or ASD leading to revision surgery. Subjects were divided into a group of 21 patients who received revision surgery for pseudarthrosis (Group P) and a group of 39 patients who received revision surgery for ASD (Group A). Clinical outcomes were evaluated using the visual analogue scales for back pain (VAS-BP) and leg pain (VAS-LP), the Korean Oswestry disability index (K-ODI), and each patient's subjective satisfaction. Radiological outcomes were evaluated from the extent of bone union, and complications in the two groups were compared. RESULTS: VAS-LP at final follow-up was not statistically different between the two groups (p =0.353), although VAS BP and K-ODI at final follow-up were significantly worse in Group P than in Group A (all p <0.05), and only 52% of the patients in Group P felt that their overall well-being had improved following revision surgery. Fusion rates after the first revision surgery were 71% (15/21) in Group P and 95% (37/39) in Group A (p =0.018). The rate of reoperation was significantly higher in Group P (29%) than in Group A (5%) (p =0.021) due to complications. CONCLUSIONS: Clinical and radiological outcomes were worse in patients who had received revision surgery for pseudarthrosis than in those who had revision surgery for ASD. Elderly patients should be carefully advised of the risks and benefits before planning revision surgery for pseudarthrosis. PMID- 28670416 TI - Correlation among Inflammatory Cytokine Expression Levels, Degree of Disk Degeneration, and Predominant Clinical Symptoms in Patients with Degenerated Intervertebral Discs. AB - STUDY DESIGN: Observational study. PURPOSE: To assess the correlation among inflammatory cytokine expression levels, degree of intervertebral disk (IVD) degeneration, and predominant clinical symptoms observed in degenerative disk disease (DDD). OVERVIEW OF LITERATURE: Low back pain (LBP) is associated with inflammatory cytokine expression levels, including those of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and nerve growth factor (NGF). However, the association between cytokine expression levels and the physiological mechanisms of disk degeneration and clinical pain remain controversial. METHODS: Using the enzyme-linked immunosorbent assay, TNF-alpha, IL-6, and NGF expression levels were analyzed in 58 IVD samples that were harvested from patients with lumbar DDD. Patient samples were grouped according to the degree of IVD degeneration using the Pfirrmann grading system and magnetic resonance imaging, and the correlations between the disease groups and each cytokine expression level were assessed. In addition, on the basis of their predominant preoperative symptoms, the patients were assigned to either an LBP or leg pain group to determine the correlation among these disease manifestations and individual cytokine expression levels. RESULTS: A gradual increase in TNF-alpha (R=0.391) and IL-6 (R=0.388) expression levels correlated with the degree of IVD degeneration, whereas NGF (R=0.164) expression levels exhibited a minimal decrease with disease progression. Regarding the predominant clinical manifestation, only the LBP group exhibited a significant increase in TNF-alpha expression levels (p=0.002). CONCLUSIONS: These results suggested that TNF-alpha and IL-6 play an important role in the pathophysiology of IVD degeneration at any stage, whereas NGF plays an important role during the early disease stages. Moreover, because TNF-alpha expression levels were significantly high in the LBP group, we propose that they are involved in LBP onset or progression. PMID- 28670417 TI - Discrimination between Malignant and Benign Vertebral Fractures Using Magnetic Resonance Imaging. AB - STUDY DESIGN: Retrospective analysis using magnetic resonance imaging (MRI). PURPOSE: To identify MRI features that could discriminate benign from malignant vertebral fractures. OVERVIEW OF LITERATURE: Discrimination between benign and malignant vertebral fractures remains challenging, particularly in patients with osteoporosis and cancer. Presently, the most sensitive means of detecting and assessing fracture etiology is MRI. However, published reports have focused on only one or a few discriminators. METHODS: Totally, 106 patients were assessed by MRI within six weeks of sustaining 114 thoracic and/or lumbar vertebral fractures (benign, n=65; malignant, n=49). The fractures were pathologically confirmed if malignant or clinically diagnosed if benign and were followed up for a minimum of six months. Seventeen features were analyzed in all fractures' magnetic resonance images. Single parameters were analyzed using the chi-square test; a logit model was established using multivariate logistic regression analysis. RESULTS: The chi square test revealed 11 malignant and 4 benign parameters. Multivariate logistic regression analysis selected (i) posterior wall diffuse protrusion (odds ratio [OR], 48; 95% confidence interval [CI], 4.2-548; p=0.002), (ii) pedicle involvement (OR, 21; 95% CI, 2.0-229; p=0.01), (iii) posterior involvement (OR, 21; 95% CI, 1.5-21; p=0.02), and (iv) band pattern (OR, 0.047; 95% CI, 0.0005 4.7; p=0.19). The logit model was expressed as P=1/[1+exp (x)], x=-3.88*(i) 3.05*(ii)-3.02*(iii)+3.05*(iv)+5.00, where P is the probability of malignancy. The total predictive value was 97.3%. The only exception was multiple myeloma with features of a benign fracture. CONCLUSIONS: Although each MRI feature had a different meaning with a variable differentiation power, combining them led to an accurate diagnosis. This study identified the most relevant MRI features that would be helpful in discriminating benign from malignant vertebral fractures. PMID- 28670418 TI - Bisphosphonate's and Intermittent Parathyroid Hormone's Effect on Human Spinal Fusion: A Systematic Review of the Literature. AB - There has been a conscious effort to address osteoporosis in the aging population. As bisphosphonate and intermittent parathyroid hormone (PTH) therapy become more widely prescribed to treat osteoporosis, it is important to understand their effects on other physiologic processes, particularly the impact on spinal fusion. Despite early animal model studies and more recent clinical studies, the impact of these medications on spinal fusion is not fully understood. Previous animal studies suggest that bisphosphonate therapy resulted in inhibition of fusion mass with impeded maturity and an unknown effect on biomechanical strength. Prior animal studies demonstrate an improved fusion rate and fusion mass microstructure with the use of intermittent PTH. The purpose of this study was to determine if bisphosphonates and intermittent PTH treatment have impact on human spinal fusion. A systematic review of the literature published between 1980 and 2015 was conducted using major electronic databases. Studies reporting outcomes of human subjects undergoing 1, 2, or 3-level spinal fusion while receiving bisphosphonates and/or intermittent PTH treatment were included. The results of relevant human studies were analyzed for consensus on the effects of these medications in regards to spinal fusion. There were nine human studies evaluating the impact of these medications on spinal fusion. Improved fusion rates were noted in patients receiving bisphosphonates compared to control groups, and greater fusion rates in patients receiving PTH compared to control groups. Prior studies involving animal models found an improved fusion rate and fusion mass microstructure with the use of intermittent PTH. No significant complications were demonstrated in any study included in the analysis. Bisphosphonate use in humans may not be a deterrent to spinal fusion. Intermittent parathyroid use has shown early promise to increase fusion mass in both animal and human studies but further studies are needed to support routine use. PMID- 28670419 TI - Severe Rigid Scoliosis: Review of Management Strategies and Role of Spinal Osteotomies. AB - Severe rigid curves pose a considerable challenge to the treating spine surgeon. In our practice, approximately 30%-40% of patients with scoliosis present late with severe rigid scoliosis (>90 degrees and <30% correction on bending films). Controversy still exists with regard to the ideal surgical strategy for correcting these rigid curves. Rigid scoliosis often presents in the form of either sharp angular or rounded deformities. Rounded deformities can be effectively managed with an anterior release to loosen the apex and posterior instrumentation (with osteotomies, if required). In contrast, severe rigid scoliosis, which is a sharp angular deformity, is not very amenable to anterior release and is best managed by posterior-only vertebral column resection and posterior instrumentation. PMID- 28670420 TI - Letter to the editor: Does Segmental Kyphosis Affect Surgical Outcome after a Posterior Decompressive Laminectomy in Multisegmental Cervical Spondylotic Myelopathy? PMID- 28670421 TI - Response to: Does Segmental Kyphosis Affect Surgical Outcome after a Posterior Decompressive Laminectomy in Multisegmental Cervical Spondylotic Myelopathy? PMID- 28670422 TI - Reactive Oxygen Species Generation and Use of Antioxidants during In Vitro Maturation of Oocytes. AB - In vitro maturation (IVM) is emerging as a popular technology at the forefront of fertility treatment and preservation. However, standard in vitro culture (IVC) conditions usually increase reactive oxygen species (ROS), which have been implicated as one of the major causes for reduced embryonic development. It is well-known that higher than physiological levels of ROS trigger granulosa cell apoptosis and thereby reduce the transfer of nutrients and survival factors to oocytes, which leads to apoptosis. ROS are neutralized by an elaborate defense system that consists of enzymatic and non-enzymatic antioxidants. The balance between ROS levels and antioxidants within IVM media are important for maintenance of oocytes that develop to the blastocyst stage. The effects of antioxidant supplementation of IVM media have been studied in various mammalian species. Therefore, this article reviews and summarizes the effects of ROS on oocyte quality and the use of antioxidant supplementations for IVM, in addition to its effects on maturation rates and further embryo development. PMID- 28670423 TI - Hysterosalpingography in The Assessment of Congenital Cervical Anomalies. AB - Cervical abnormalities may be congenital or acquired. Congenital anomalies of the cervix are rarely isolated, and more commonly accompany other uterine anomalies. Various imaging tools have been used in the assessment of Mullerian duct anomalies (MDAs). Currently, magnetic resonance imaging (MRI) is the modality of choice for definitive diagnosis and classification of these MDAs. Hysterosalpingography is a basic tool for evaluation of infertility and allows us to detect a spectrum of anatomical malformations of the utero-cervix in the setting of MDAs. It provides good outlines of the uterine cavity and fallopian tubes, as well as the cervical canal and isthmus. However, hysterosalpingograms (HSG) cannot be performed in patients with isolated congenital maldevelopment (agenesis/disgenesis) of the cervix. This part of pictorial review illustrates the various radiographic appearances of congenital malformations of the utero cervix with a brief overview of the embryologic features. Accurate diagnosis of such cases is considered essential for optimal treatment and categorization of each anomaly. PMID- 28670424 TI - A Comparison of Outcomes from In Vitro Fertilization Cycles Stimulated with Follicle Stimulating Hormone Plus either Recombinant Luteinizing Hormone or Human Menopausal Gonadotropins in Subjects Treated with Long Gonadotropin Releasing Hormone Agonist Protocols. AB - BACKGROUND: This study compared rates of pregnancy and in vitro fertilization (IVF) parameters in subjects stimulated with follicle stimulating hormone (FSH) plus either recombinant human luteinizing hormone (r-LH) or human menopausal gonadotropin (hMG) in a long gonadotropin releasing hormone (GnRH) agonist IVF protocol. MATERIALS AND METHODS: This cohort study enrolled patients who underwent IVF stimu- lation with a long GnRH agonist protocol and received FSH plus r-LH or hMG. Outcomes measured included: FSH and LH doses, number of oocytes and embryos obtained, pregnancy rate per cycle, and clinical pregnancy rate per cycle. Stepwise logistic regression was performed on continuous and categorical variables to control for confounding effects between all variables analyzed. RESULTS: There were 122 patients who underwent 122 IVF cycles with long GnRH agonist protocols. Similar baseline parameters existed between groups. Patients that received r-LH required a lower FSH dose (3207 +/- 1300 IU) for stimulation compared to the group that received hMG (4213 +/- 1576 IU, P=0.0001). The LH dose was also lower in these patients (1332 +/- 587 IU) compared to the patients who received hMG (1938 +/- 1110 IU, P=0.0001). The number of days of stimulation did not differ between groups (P=1.0). The group that received r-LH also had statistically higher numbers of oocytes (14.4 +/- 6.3) and embryos (7.9 +/- 4.8) compared to the hMG group with 11.0 +/- 5.3 oocytes and 6.0 +/- 3.7 embryos. Pregnancy rates per cycle start were higher for patients in the r-LH group (49%) compared to the hMG group (27%, P=0.025). Patients that received r-LH had higher implantation rates (62%) compared to the hMG group (33%, P=0.001). The r-LH group had a higher trend toward clinical pregnancy rates per cycle start (39%) compared to the hMG group (25%, P=0.065). CONCLUSION: r-LH may offer benefits compared to hMG when combined with FSH for ovarian stimulation in long GnRH agonist protocols in good responders. Prospective studies should be undertaken to confirm these results. PMID- 28670425 TI - Vitrification of Human Germinal Vesicle Oocytes: before or after In Vitro Maturation? AB - BACKGROUND: The use of immature oocytes derived from stimulated cycles could be of great importance, particularly for urgent fertility preservation cases. The current study aimed to determine whether in vitro maturation (IVM) was more successful before or after vitrification of these oocytes. MATERIALS AND METHODS: This prospective study was performed in a private in vitro fertilization (IVF) center. We collected 318 germinal vesicle (GV) oocytes from 104 stimulated oocyte donation cycles. Oocytes were divided into two groups according to whether vitrification was applied at the GV stage (group 1) or in vitro matured to the metaphase II (MII) stage and then vitrified (group 2). In the control group (group 3), oocytes were in vitro matured without vitrification. In all three groups, we assessed survival rate after warming, maturation rate, and MII spindle/chromosome configurations. The chi-square test was used to compare rates between the three groups. Statistical significance was defined at P<0.05 and we used Bonferroni criterion to assess statistical significance regarding the various pairs of groups. The Statistical Package for the Social Sciences version 17.0 was used to perform statistical analysis. RESULTS: There was no significant difference in the survival rate after vitrification and warming of GV (93.5%) and MII oocytes (90.8%). A significantly higher maturation rate occurred when IVM was performed before vitrification (82.9%) compared to after vitrification (51%). There was no significant difference in the incidence of normal spindle/ chromosome configurations among warmed oocytes matured in vitro before (50.0%) or after (41.2%) vitrification. However, a higher incidence of normal spindle/chromosome configurations existed in the in vitro matured oocytes which were not subjected to vitrification (fresh oocytes, 77.9%). CONCLUSION: In stimulated cycles, vitrification of in vitro matured MII oocytes rather than GV oocytes seems to be more efficient. This approach needs to be verified in nonstimulated fertility preservation cases. PMID- 28670426 TI - Comparative Stepwise Pattern of Reactive Oxygen Species Production during In Vitro Development of Fertilized and Nuclear Transferred Goat Embryos. AB - BACKGROUND: A unique feature of embryo metabolism is production of reactive oxygen species (ROS). It is well established that during in vitro culture, ROS levels increase over normal ranges observed for embryos developed in vivo. This study evaluates and compares the stepwise pattern of ROS production during in vitro development of reconstructed goat embryos produced by zona-free method of somatic cell nuclear transfer (SCNT). Furthermore, the pattern of ROS production of SCNT embryos were compared with zona free embryos derived from in vitro fertilization (IVF). MATERIALS AND METHODS: In this experimental study, zona-free oocytes, SCNT and IVF embryos at different stages of in vitro development (2, 4, 8, 16-cells, morula, and blastocyst) were used for assessment of ROS production using 2, 7-dichloro dihydroflourescein diacetate (DCHFDA) probe and the result were presented as fold increase or decrease relative zona free oocytes. RESULTS: The relative level of ROS compared to metaphase-II (MII) oocytes insignificantly decrease during early stages post embryo reconstitution and regained its value by 8-cell and morula stage and, significantly increase compared to MII oocytes by blastocyst stage. CONCLUSION: The pattern of ROS change in SCNT embryos is similar to zona free IVF derived embryos, except it decrease from two cell stage and regain its value at morula stage. The sudden rise in ROS at blastocyst stage, further emphasizes the special need of IVF and SCNT derived embryos during this stage of development. PMID- 28670427 TI - Kisspeptin: A Potential Factor for Unexplained Infertility and Impaired Embryo Implantation. AB - BACKGROUND: Kisspeptin (KP) is a neuropeptide that causes the release of the gonadotropin releasing hormone, which controls hypothalamo pituitary ovarian axis and exerts a number of peripheral effects on reproductive organs. The primary objective of this study was to compare baseline KP levels in females with different types of infertility and identify possible correlations with risk of failure to conceive, preclinical abortion and pregnancy after intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: A longitudinal cohort study was carried out from August 2014 until May 2015 by recruiting 124 female patients undergoing ICSI, after obtaining ethical approval from the Australian Concept Infertility Medical Center. Cause of infertility due to male, female and unexplained factors was at a frequency of 32 (24%), 33 (31%) and 59 (45%) among the individuals respectively. KP levels were measured by ELISA assay before the initiation of the ICSI treatment protocol. Outcome of ICSI was categorized into three groups of non-pregnant with beta-human chorionic gonadotropin (beta-hCG)<5 25 mIU/ml, preclinical abortion with beta-hCG>25 mIU/ml and no cardiac activity, and clinical pregnancy declared upon confirmation of cardiac activity. Results based on cause of infertility and outcome groups were analyzed by one-way ANOVA. RESULTS: Females with unexplained infertility had significantly lower levels of KP when compared with those with male factor infertility (176.69 +/- 5.03 vs. 397.6 +/- 58.2, P=0.001). Clinical pregnancy was observed in 28 (23%) females of which 17 (71%) had a female cause of infertility. In the non-pregnant group of 66 (53%) females, common cause of infertility was unexplained 56(85%). A weak positive correlation of KP levels with fertilized oocytes and endometrial thickness was observed (P=0.04 and 0.01 respectively). CONCLUSION: Deficiency of KP in females with unexplained infertility was associated with reduced chances of implantation after ICSI. PMID- 28670428 TI - Evaluation of Relationship between Body Mass Index with Vitamin D Receptor Gene Expression and Vitamin D Levels of Follicular Fluid in Overweight Patients with Polycystic Ovary Syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder associated with reproductive disorders and metabolic dysfunctions including insulin resistance. The roles of vitamin D in the regulation of metabolic modulations specifically involving insulin and reproduction processing are introduced. In addition, obesity appears to be closely associated with severity of PCOS. The present study is to evaluate the effect of body mass index (BMI) on vitamin D levels in follicular fluid and vitamin D receptor (VDR) expression levels in granulos cells. MATERIALS AND METHODS: A comparative study was conducted on 80 women with average age of 20-35 years referred for in vitro fertilization (IVF). Patients were divided into four groups, and serum levels of testosterone and insulin resistance (IR) were evaluated at the puncture time. Also, vitamin D levels of follicular fluid were evaluated. VDR gene expression was assayed by quantified-polymerase chain reaction (PCR) technique. Correlations were evaluated with calculation of the Spearman coefficient, and also independent relationships were assessed by means of multiple regression analysis. RESULTS: Vitamin D levels of follicular fluid decreased in PCOS patients compared with non PCOS. Also, over-weight individuals had lower vitamin D levels compared with normal-weight patients. Vitamin D levels of follicular fluid were highly correlated with BMI (r=-0.51, P<0.01). Homeostatic model assessment-IR (HOMA-IR) values were significantly higher in women of PCOS/overweight and PCOS/normal weight in comparison with women of non-PCOS/normal weight (P<0.01). The gene expression data of VDR in granulosa cells were significantly lower in the PCOS/overweight group compared with the non-PCOS/normal weight (P<0.01). CONCLUSION: The findings indicated significant differences in VDR gene expression in granulosa cells and vitamin D of follicular fluid in PCOS/overweight patients. PMID- 28670429 TI - Tumor Necrosis Factor Alpha -308 G/A Single Nucleotide Polymorphism and Risk of Sperm Abnormalities in Iranian Males. AB - BACKGROUND: Signaling molecules such as cytokines regulate spermatogenesis during the maturation of germ cells and sperm apoptosis. Tumor necrosis factor alpha (TNFalpha) is one of the most-documented cytokines that is involved in spermatogenesis. We investigated the association of the TNFalpha -308 G/A single nucleotide polymorphism with sperm abnormalities in Iranian males. MATERIALS AND METHODS: This case-control study included 180 infertile men who re- ferred to Yazd Research and Clinical Center for Infertility and 100 healthy normospermic controls. Infertile men were classified into four groups of azoospermia (n=91), oligospermia (n=26), teratospermia (n=30) and asthenoteratospermia (n=33). After sperm analysis, DNA was extracted from blood and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was carried out for the genotyping of TNFalpha- 308 G/A. RESULTS: The A allele was significantly associated with sperm abnormality in our population [(P<0.001, odds ratios (OR) 95% confidence interval (CI)=2.31]. In addition, the A allele was also associated with azoospermia (P<0.001, OR (95% CI)=2.484), oligospermia (P=0.005, OR (95% CI)=2.51) and teratospemia (P<0.001, OR (95% CI)=3.385) but not with asthenoteratospermia (P=0.623). CONCLUSION: Our data suggest that this single nucleotide polymorphism (SNP) maybe associated with the risk of sperm abnormality in infertile men of Iranian origin. PMID- 28670430 TI - Sperm Retrieval in Patients with Klinefelter Syndrome: A Skewed Regression Model Analysis. AB - BACKGROUND: The most common chromosomal abnormality due to non-obstructive azoospermia (NOA) is Klinefelter syndrome (KS) which occurs in 1-1.72 out of 500 1000 male infants. The probability of retrieving sperm as the outcome could be asymmetrically different between patients with and without KS, therefore logistic regression analysis is not a well-qualified test for this type of data. This study has been designed to evaluate skewed regression model analysis for data collected from microsurgical testicular sperm extraction (micro-TESE) among azoospermic patients with and without non-mosaic KS syndrome. MATERIALS AND METHODS: This cohort study compared the micro-TESE outcome between 134 men with classic KS and 537 men with NOA and normal karyotype who were referred to Royan Institute between 2009 and 2011. In addition to our main outcome, which was sperm retrieval, we also used logistic and skewed regression analyses to compare the following demographic and hormonal factors: age, level of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone between the two groups. RESULTS: A comparison of the micro-TESE between the KS and control groups showed a success rate of 28.4% (38/134) for the KS group and 22.2% (119/537) for the control group. In the KS group, a significantly difference (P<0.001) existed between testosterone levels for the successful sperm retrieval group (3.4 +/- 0.48 mg/mL) compared to the unsuccessful sperm retrieval group (2.33 +/- 0.23 mg/mL). The index for quasi Akaike information criterion (QAIC) had a goodness of fit of 74 for the skewed model which was lower than logistic regression (QAIC=85). CONCLUSION: According to the results, skewed regression is more efficient in estimating sperm retrieval success when the data from patients with KS are analyzed. This finding should be investigated by conducting additional studies with different data structures. PMID- 28670431 TI - Evaluation on Hope and Psychological Symptoms in Infertile Couples Undergoing Assisted Reproduction Treatment. AB - BACKGROUND: This study evaluated hope, depression, anxiety, and stress among three groups of infertile couples. MATERIALS AND METHODS: This cross-sectional study consisted of three groups of infertile couples-candidates for oocyte donation (n=60), embryo donation (n=60), and normal infertile (n=60). Participants included couples seen at Royan Institute, Tehran, Iran between 2013 2014 who were at least 18 years of age and could read and write in Persian. Participants provided demographic and general characteristics and completed the Persian version of the Adult Trait Hope Scale (hope, agency and pathway) and Depression, Anxiety, and Stress Scale (DASS). Data was analyzed by the paired t test, ANOVA, ANCOVA and Pearson correlation tests using SPSS statistical software. RESULTS: Overall, 180 infertile couples participated in the three groups. There was a significant higher mean score for hope in husbands compared to wives in the normal infertile group (P=0.046). Husbands in the normal infertile group also had a significantly higher mean score for pathway (P=0.032). The frequency of anxiety significantly differed in female subjects (P=0.028). In the normal infertile group, the anxiety distribution significantly differed between wives and husbands (P=0.006). There was a significantly different stress frequency in male subjects (P=0.048). In the embryo donation group, stress significantly differed between wives and husbands (P=0.002). In the normal infertile group, stress also significantly differed between wives and husbands (P=0.05). CONCLUSION: The results have suggested that hope might be important in reducing psychological symptoms and psychological adjustment in those exposed to infertility problems who follow medical recommendations, which accelerates recovery. It is recommended to hold psychological counseling sessions (hope therapy) during reproduction cycles. PMID- 28670432 TI - Relationship between Chlamydia-Ureaplasma-Mycoplasma Genital Detection with Semen Concentration and Motility among Greek Men. AB - One hundred and seventy two men at the State of Thessaly, Greece, inquiring semen analysis were enrolled in the study in order to investigate the incidence of Chlamydia, Ureaplasma and Mycoplasma (C-U-M) genera in respect to total sperm number (TSN), progressive motility (grades a and b) and total motility (grades a, b and c). Putative relation of C-U-M acquirement with sexual behavior was also investigated. Incidence of C-U-M among non-oligozoospermic and oligozoospermic men was similar. Nuomicron correlation of C-U-M carriage to either oligozoospermia or asthenozoospermia was found. The tested semen parameters were negatively correlated to the age of sexual intercourse initiation and positively correlated to the number of sex partners. Early age of sexual intercourse initiation or high number of sexual partners was not statistical significantly correlated to C-U-M acquirement. Overall, TSN and motility (either progressive or total) were not influenced by the presence of C-U-M genera in a sample of Greek population undergoing semen evaluation. To distinguish the role of C-U-M in male infertility and clarify the so far controversial scarce literature, large control case studies are needed using nucleic acid amplification techniques to detect these pathogens. PMID- 28670433 TI - Thalidomide for the Treatment of Gastrointestinal Bleeding Due to Angiodysplasia in a Patient with Glanzmann's Thrombasthenia. AB - Angiodysplasia is a frequent cause of persistent gastrointestinal (GI) hemorrhage in elderly patients. Although GI bleeding isn't the most common manifestation in patients with bleeding disorders, when present, it represents a challenging complication. We describe a 62-year-old patient with Glanzmann's thrombasthenia, who used thalidomide for severe and recurrent GI bleeding. For 6 months, the patient experienced temporary control of GI bleeding with thalidomide in a daily oral dose of 100 mg. The anti-angiogenic effects of thalidomide have recently been explored by several groups, particularly in the management of bleeding from angiodysplasia, including cases with von Willebrand disease. Here, we review the relevant descriptions of the use of thalidomide in this situation, and also discuss potential reasons why we observed only a temporary control of the GI bleeding in our patient, such as the use of low-dose regimen due to limitations posed by thalidomide side effects. PMID- 28670434 TI - Idiopathic Pulmonary Hemosiderosis Mimicking Iron Deficiency Anemia: A Delayed Diagnosis? AB - Idiopathic pulmonary hemosiderosis (IPH) is an uncommon chronic disorder in children. It is characterized by recurrent pulmonary hemorrhage and may result in hemoptysis and pulmonary insufficiency. The most common hematologic manifestation of IPH is iron deficiency anemia. The etiology of IPH is not known and its diagnosis may be difficult due to the variable clinical courses. The most helpful signs for identifying IPH are iron deficiency anemia and recurrent or chronic cough, hemoptysis, dyspnea, wheezing. We report here 5 pediatric cases of IPH presenting with iron deficiency anemia and without pulmonary symptoms. Mean corpuscular volume was low in all patients; iron was low in 4 out of 5 cases; total iron binding capacity was high in all of them; ferritin was low in 3 patients. At follow up, none of them had responded successfully to the iron therapy. Although they didn't present with pulmonary symptoms, chest radiographs incidentally revealed diffuse reticulonoduler shadows in all of them. Computed tomography revealed diffuse ground-glass opacities, consolidation, increased density. The diagnosis was confirmed by the detection of hemosiderin-laden macrophages in bronchoalveolar lavage fluid and gastric aspirate. If patients with iron deficiency anemia don't respond to iron therapy, they should be examined for IPH. Chest radiographs should be taken even in absence of pulmonary symptoms. Early diagnosis is important for a timely management of IPH. PMID- 28670435 TI - Acute Myeloid Leukemia with RAM Immunophenotype: A Pediatric Case with Unusual Morphologic Features. AB - The RAM immunophenotype has been recently described as a subtype of acute myelogenous leukemia (AML) that is characterized clinically by extremely poor prognosis. We present a case of AML with RAM immunophenotype in a 5-year-old patient that resulted in poor outcome despite early hematopoietic cell transplant. We describe the unusual morphologic features that, along with the distinct immunophenotype, may provide initial diagnostic clues and further justify the classification of this AML variant as a rather distinct subtype. PMID- 28670436 TI - Bridging-to-transplant with Azacitidine for Myelodysplastic Syndrome and Acute Myeloid Leukemia, Reduces the Incidence of Acute Graft-versus-host Disease. AB - Allogeneic stem cell transplantation (allo-SCT) is the only curative option for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Azacitidine (AZA) has a good toxicity profile compared with intensive chemotherapy and can be considered a pre-transplant regimen in elderly patients and in patients with comorbidities. To investigate the impact of pre-transplant AZA on patient outcome after allo-SCT, we conducted a retrospective analysis of AZA pre-treatment followed by allo-SCT in patients with high-risk MDS and AML. Twenty patients who were divided into two groups according to AZA treatment given prior to allo-SCT (AZA vs non-AZA group, 10 each). Overall survival, event-free survival and incidence of chronic graft-versus-host disease (GVHD) were not significantly different between the two groups. The overall incidence of grade II to IV acute GVHD in the AZA group was significantly lower than that in the non-AZA group (P=0.004). Bridging to transplant with AZA should be considered as an immunomodulator and effective treatment strategy for patients with MDS and AML. PMID- 28670437 TI - Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10. AB - BACKGROUND: Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. METHODS: DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. RESULTS: Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3' exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. CONCLUSIONS: The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry matched controls in interpretation of aCGH findings. PMID- 28670438 TI - Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes. AB - BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain. METHODS: In this study, we examined the neuroanatomy of male and female mice from the Mecp2tm1Hzo, Mecp2tm1.1Bird/J, and Mecp2tm2Bird/J mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions. RESULTS: We found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2tm1Hzo brain relative to controls and a decrease in the Mecp2tm1.1Bird/J and Mecp2tm2Bird/J lines. CONCLUSIONS: Our findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments. PMID- 28670440 TI - Phenotype-based variation as a biomarker of sensitivity to molecularly targeted therapy in melanoma. AB - Transcriptomic phenotypes defined for melanoma have been reported to correlate with sensitivity to various drugs. In this study, we aimed to define a minimal signature that could be used to distinguish melanoma sub-types in vitro, and to determine suitable drugs by which these sub-types can be targeted. By using primary melanoma cell lines, as well as commercially available melanoma cell lines, we find that the evaluation of MLANA and INHBA expression is as capable as one based on a combined analysis performed with genes for stemness, EMT and invasion/proliferation, in identifying melanoma subtypes that differ in their sensitivity to molecularly targeted drugs. Using this approach, we find that 75% of melanoma cell lines can be treated with either the MEK inhibitor AZD6244 or the HSP90 inhibitor 17AAG. PMID- 28670439 TI - Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain. AB - BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. PMID- 28670441 TI - ZNF300 tight self-regulation and functioning through DNA methylation and histone acetylation. AB - BACKGROUND: Accumulating evidence demonstrates that the KRAB-ZNFs involve in various biological processes. As a typical member of KRAB-ZNFs, dysregulation of ZNF300 contributes to multiple pathologies such as leukemia and cancer. However, mechanisms underlying ZNF300 tight regulation and its pathophysiological function remain largely unknown. METHODS: The effect of ZNF300ZFR on gene transcriptional activity was measured by Dual luciferase reporter system. ChIP-PCR assay were performed to detect the enrichment of ZNF300 protein and H3K9Ac in the ZNF300 gene. Co-immunoprecipitation assays followed by western blot were performed to detect the interaction between ZNF300 and KAP1. The DNA methylation in the ZNF300 gene promoter was analyzed by BSP. ZNF300 function on K562 cell differentiation was analyzed by flow cytometry. RESULTS: In this study, we found that the zinc finger domain-encoding region (ZFR) of ZNF300 functioned as a repressor possibly by mediating DNA methylation and ZNF300 bound to its ZNF300ZFR, suggesting a potential auto-inhibition mechanism. To support this, DNA methylation inhibition upregulated ZNF300 expression and ZNF300 overexpression inhibited endogenous ZNF300 expression. More importantly, DNA methylation inhibition restored megakaryocyte differentiation in K562 cells suppressed by ZNF300 downregulation, suggesting an important role of DNA methylation in ZNF300 function. Interestingly, ZNF300 knockdown restored global H3K9Ac that was reduced in K562 cells undergoing megakaryocyte differentiation. CONCLUSIONS: Our study revealed novel features of ZNF300 that possibly mediate its regulation and function by modulating epigenetic modifications. PMID- 28670442 TI - Managing patients with acute and chronic non-specific neck pain: are Danish chiropractors compliant with guidelines? AB - BACKGROUND: Non-specific neck pain represents a quarter of all chiropractic patient visits in Denmark. Evidence informed practice can help ensure providers use best available treatment, speed up patient recovery rate and reduce healthcare utilization. It is generally believed that Danish chiropractors treat according to best practice, but we do not know if this is true for management of neck-pain. The objective of this study was to investigate how Danish chiropractors treat patients with acute and chronic non-specific neck pain and determine if management is compliant with recent Canadian guideline recommendations. METHODS: An online survey was sent to 554 members of the Danish chiropractic association. A three-part questionnaire was administered asking participants to: 1) rank the frequency of use of a list of treatment modalities; 2) rank treatment modalities they normally use for acute and chronic non-specific neck pain cases; and 3) provide demographic data. Treatment modalities ranked as "used often" were considered in further analysis and compared to the Canadian Guideline recommendations for neck pain. Chi-squared test was used to investigate differences between treatment and guideline compliance for chronic and acute patients. RESULTS: A 65% (362/544) response rate was achieved. The sample demographics were representative of a recent Danish study of the entire chiropractic profession. Danish chiropractors use a wide range of treatment modalities, including spinal manipulation, manual therapy, exercises and information/patient education on most of their acute neck pain patients. The use of other treatment modalities and especially exercises was more commonly used with chronic cases. Guideline compliance was 10% for recommendations for acute patients and 43% for chronic patients. CONCLUSIONS: Danish chiropractors use a wide range of treatment options for managing adult patients with acute and chronic non-specific neck-pain. However, there were important differences in treatments chiropractors offered for acute and chronic patients, particularly for the use of exercise therapy, which was mainly reserved for chronic patients. Danish chiropractors' compliance with guidelines for neck-pain patients was low, but is neither worse nor better than what is seen for other complaints or health disciplines. Our findings suggest a need for active knowledge translation strategies and robust implementation research. PMID- 28663782 TI - Dose Titration Algorithm Tuning (DTAT) should supersede 'the' Maximum Tolerated Dose (MTD) in oncology dose-finding trials. AB - Background. Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent 'confirmatory' Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational therapy. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of 'the' maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived, not as 'dose-finding', but as dose titration algorithm (DTA)-finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug's population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple DTA targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace 'the' MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible DTA capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. Although here illustrated specifically in relation to cytotoxic chemotherapy, the DTAT principle appears similarly applicable to Phase I studies of cancer immunotherapy and molecularly targeted agents. PMID- 28670444 TI - Model System Study of Environmentally Persistent Free Radicals Formation in a Semiconducting Polymer Modified Copper Clay System at Ambient Temperature. AB - This paper systematically investigates how environmentally persistent free radicals (EPFRs) are formed in a phenol contaminated model soil. Poly-p-phenylene (PPP) modified and copper-loaded montmorillonite (MMT) clays were developed and used as models of soil organic matter and the clay mineral component, respectively, with phenol being employed as a precursor pollutant. The polymer modification of the clays was carried out via surface-confined Kumada catalyst transfer chain-growth polymerization. The presence and location of the polymer were confirmed by a combination of thermogravimetric analysis (TGA), Raman spectroscopy, and X-ray diffraction data. EPFRs were formed by the Cu(II)-clay (Cu(II)CaMMT) and poly-p-phenylene-Cu(II)clay (PPP-Cu(II)CaMMT) composite systems under environmentally relevant conditions. The g-factor and concentration of EPFRs formed by the Cu(II)CaMMT and PPP-Cu(II)CaMMT systems were found to be 2.0034 and 1.22 * 1017 spins/g and 2.0033 and 1.58 * 1017spins/g, respectively. These g-factors are consistent with the formation of phenoxyl radicals. Extended X-Ray absorption fine structure (EXAFS) analysis shows that there are distinct differences in the local stuctures of the phenoxyl radicals associated with only the Cu(II) redox centers and those formed in the presences of the PPP polymer. X ray absorption near edge spectroscopy (XANES) results provided evidence for the reduction of Cu(II) to Cu(I) in the EPFR forming process. The 1/e lifetimes of the formed EPFRs revealed a decay time of ~20 h for the Cu(II)CaMMT system and a two-step decay pattern for the PPP-Cu(II)CaMMT system with decay times of ~13.5 h and ~55.6 h. Finally, the generation of reactive oxygen species (hydroxyl radical; *OH) by these clay systems was also investigated, with higher concentrations of *OH detected for the phenol-dosed Cu(II)CaMMT and PPP Cu(II)CaMMT systems, compared to the non-EPFR containing undosed PPP-Cu(II)CaMMT system. PMID- 28670445 TI - Nano-antacids enhance pH neutralization beyond their bulk counterparts: synthesis and characterization. AB - Antacids are crucial in the treatment of gastro-esophageal reflux disease and peptic ulcers. Antacids based on the calcite phase of bulk calcium carbonate have been the standard for over fifty years. More recent research has shown that nanomaterial forms of such bulk materials often have improved properties. However, the metastable vaterite form of calcium carbonate is particularly difficult to synthesize as a nanomaterial, and thus has not been extensively studied. Here, we describe the synthesis of these particles and investigate them for antacid applications. Experimental and computational approaches show that nanoscale vaterite particles maintain neutral gastric pH values three times longer than commercial antacids. PMID- 28670446 TI - Blue Thermally Activated Delayed Fluorescence from a Biphenyl Difluoroboron beta Diketonate. AB - Optical properties of biphenyl difluoroboron beta-diketonates were studied in poly(lactic acid) (PLA) blends. Increased conjugation lowered the emission energy, decreased the singlet-triplet energy gap and yielded blue thermally activated delayed fluorescence (TADF). The properties of these biphenyl dyes may inform organic light emitting diode (OLED) and bioimaging agent design. PMID- 28670447 TI - Short-term hypoxic preconditioning promotes prevascularization in 3D bioprinted bone constructs with stromal vascular fraction derived cells. AB - Reconstruction of complex, craniofacial bone defects often requires autogenous vascularized bone grafts, and still remains a challenge today. In order to address this issue, we isolated the stromal vascular fraction (SVF) from adipose tissues and maintained the phenotypes and the growth of endothelial lineage cells within SVF derived cells (SVFC) by incorporating an endothelial cell medium. We 3D bioprinted SVFC within our hydrogel bioinks and conditioned the constructs in either normoxia or hypoxia. We found that short-term hypoxic conditioning promoted vascularization-related gene expression, whereas long-term hypoxia impaired cell viability and vascularization. 3D bioprinted bone constructs composed of polycaprolactone/hydroxyapatite (PCL/HAp) and SVFC-laden hydrogel bioinks were then implanted into athymic mice, after conditioning in normoxic or short-term hypoxic environments, in order to determine the in vitro and in vivo vascularization and osteogenic differentiation of the constructs. Short-term hypoxic conditioning promoted microvessel formation in vitro and in vivo and promoted integration with existing host vasculature, but did not affect osteogenic differentiation of SVFC. These findings demonstrate the benefit of short-term hypoxia and the potential for utilization of SVFC and 3D bioprinting for generating prevascularized 3D bioprinted bone constructs. Furthermore, the ability to custom design complex anatomical shapes has promising applications for the regeneration of both large and small craniofacial bone defects. PMID- 28670448 TI - A novel application of the Staudinger ligation to access neutral cyclic di nucleotide analog precursors via a divergent method. AB - Our efforts to develop a scalable and divergent synthesis of cyclic di-nucleotide analog precursors have resulted in (1) an orthogonally protected di-amino carbohydrate as well as (2) the novel application of the Staudinger ligation to provide medium-sized macrocycles featuring carbamate or urea linkages. PMID- 28670449 TI - No nosocomial transmission under standard hygiene precautions in short term contact patients in case of an unexpected ESBL or Q&A E. coli positive patient: a one-year prospective cohort study within three regional hospitals. AB - BACKGROUND: Many Highly Resistant Gram Negative Rod (HR-GNR) positive patients are found unexpectedly in clinical cultures, besides patients who are screened and isolated based on risk factors. As unexpected HR-GNR positive patients are isolated after detection, transmission to contact patients possibly occurred. The added value of routine contact tracing in such situations within hospitals with standard hygiene precautions is unknown. METHODS: In 2014, this study was performed as a prospective cohort study. Index patients were defined as those tested unexpectedly HR-GNR positive in clinical cultures to diagnose a possible infection and were nursed under standard hygiene precautions before tested positive. After detection they were nursed in contact isolation. Contact patients were still hospitalized and shared the same room with the index patient for at least 12 h. HR-GNR screening was performed by culturing a rectal and throat swab. Clonal relatedness of HR-GNR isolates was determined using whole genome sequencing (WGS). RESULTS: Out of 152 unexpected HR-GNR positive patients, 35 patients (23.0%) met our inclusion criteria for index patient. ESBL E. coli was found most frequently (n = 20, 57.1%), followed by Q&A E. coli (n = 10, 28.6%), ESBL K. pneumoniae (n = 3, 8.5%), ESBL R. ornithinolytica (n = 1, 2.9%) and multi resistant P. aeruginosa (n = 1, 2.9%). After contact tracing, 69 patients were identified as contact patient of an index patient, with a median time between start of contact and sampling of 3 days. None were found HR-GNR positive by nosocomial transmission. CONCLUSIONS: In a local setting within hospitals with standard hygiene precautions, routine contact tracing among unexpected HR-GNR positive patients may be replaced by appropriate surveillance as we found no nosocomial transmission in short term contacts. PMID- 28670450 TI - Non-prescribed antimicrobial use and associated factors among customers in drug retail outlet in Central Zone of Tigray, northern Ethiopia: a cross-sectional study. AB - BACKGROUND: Non-prescribed antimicrobial use and their resistance are among the main public health problems, worldwide. In Ethiopia, particularly in the northern part, the magnitude of non-prescribed antimicrobial use and its major determinants is not yet well known. Thus, this study was done to assess the magnitude of non-prescribed anti-microbial use and associated factors among customers in drug retail outlet in Central Zone, Tigray, Ethiopia. METHODS: A drug retail outlet based cross-sectional study was conducted among adults aged 18 years and above. A multistage sampling procedure was used to select study participants. Data were collected using a structured questionnaire by druggists under the supervision of pharmacists. Data were entered into EpiInfo software version 3.5.4. Binary logistic regression was used to identify independently associated variables in bivariate and multivariable analyses using SPSS version 21. Odds Ratios with 95% confidence intervals were estimated. RESULTS: From 829 study samples, a total of 780 respondents participated in this study with a response rate of 94.1%. Of 367 respondents who received non-prescribed antimicrobial, 249 (67.8%), 121 (33%), and 94 (25.6%) of them were males, secondary school and paid employed respectively. The magnitude of non-prescribed antimicrobial use was 47.1% (95% CI: 43.8, 50.5). The factors which were independently associated with non-prescribed antimicrobial use were male sex [AOR = 1.72, 95% CI = 1.21, 2.44], seeking modern health care in private/Non Governmental Organization (NGO) [AOR =0.47, 95% CI; 0.23, 0.98], moderate waiting time in health care facilities [AOR = 1.92, 95% CI; 1.20, 3.09], delayed waiting time in health care facilities [AOR = 1.56, 95% CI; 1.03, 2.38], ever received antimicrobial [AOR = 3.51, 95% CI; 2.45, 5.02], and frequency of purchasing non prescribed antimicrobial (1-3 times and 4 times, [AOR = 2.04, 95% CI; 1.36, 3.06] and [AOR = 2.66, 95% CI; 1.24, 5.68] respectively). CONCLUSION: The magnitude of non-prescribed antimicrobial use was high. Familiarizing with health care utilization and delayed waiting time in health care facilities were the very important factors independently associated with non-prescribed antimicrobial use. Emphasis should be given to community education through involvement of the private health sector and health care providers. Regulation and policy enforcement are also necessary to promote the rational use of antimicrobial. PMID- 28670451 TI - Relationship between hospital ward design and healthcare associated infection rates: what does the evidence really tell us? Comment on Stiller et al. 2016. AB - The systematic review published by Stiller et al. in Antimicrobial Resistance & Infection Control in November 2016 concludes that single-patient bedrooms confer a significant benefit for protecting patients from healthcare associated infection and colonization. This conclusion is not substantiated by the evidence included in their review which has been largely drawn from uncontrolled before and after studies in the absence of a transparent assessment of the risk of bias. There are also errors in the analysis of supporting data. Evaluating the specific impact of single rooms on preventing transmission from a sound epidemiological perspective is essential to assure safe and effective care and a clear evidence base for infection prevention and control advice. PMID- 28670452 TI - Influence of glycerol and an alternative humectant on the immediate and 3-hours bactericidal efficacies of two isopropanol-based antiseptics in laboratory experiments in vivo according to EN 12791. AB - BACKGROUND: Guidelines for hand hygiene recommend the use of alcohol-based hand rubs containing humectants in order to improve dermal tolerance. However, the bactericidal efficacy of pre-surgical hand rubs is negatively affected by the WHO recommended humectant glycerol, especially the 3-h efficacy. The aim of this study was to investigate whether replacing glycerol as humectant increases the bactericidal efficacy of surgical hand rubs based on isopropanol (75%, wt/wt). MATERIAL AND METHODS: The efficacy of 3 and 5 min applications of a modified WHO II-formulation (containing lower glycerol concentrations) and the TPH 5766 hand rub which contains a new humectant (containing ethylhexylglycerin, dexpanthenol and a fatty alcohol) were compared to the European Norm 12,791 reference (n propanol, 60%, vol/vol) immediately following and 3 h after application. RESULTS: Immediately after application both isopropanol-based surgical rubs approximated the performance of the reference. The 3-h effect of the modified WHO II formulation was found to be less efficacious than the EN 12791, showing a 30% decrease in log10 reduction values. The 3-h post application effect for the TPH 5766 hand rub was found to not be different from EN 12791. CONCLUSION: Based on our data, the bactericidal efficacy of isopropanol-based surgical hand rubs can best be obtained if glycerol is not used in the formulation. Unlike glycerol, a humectant comprised of ethylhexylglycerin, dexpanthenol and a fatty alcohol was found not to decrease hand rub effectiveness. Further investigation of the bactericidal efficacy of other humectants is necessary and may prove useful. PMID- 28670453 TI - Novel aspects in diagnostic approach to respiratory patients: is it the time for a new semiotics? AB - Medical approach to patients is a fundamental step to get the correct diagnosis. The aim of this paper is to analyze some aspects of the reasoning process inherent in medical diagnosis in our era. Pathologic signs (anamnestic data, symptoms, semiotics, laboratory and strumental findings) represent informative phenomena to be integrated for inferring a diagnosis. Thus, diagnosis begins with "signs" and finishes in a probability of disease. The abductive reasoning process is the generation of a hypothesis to explain one or more observations (signs) in order to decide between alternative explanations searching the best one. This process is iterative during the diagnostic activity while collecting further observations and it could be creative generating new knowledge about what has not been experienced before. In the clinical setting the abductive process is not only theoretical, conversely the physical exploitation of the patient (palpation, percussion, auscultation) is always crucial. Through this manipulative abduction, new and still unexpressed information is discovered and evaluated and physicians are able "to think through doing" to get the correct diagnosis. Abductive inferential path originates with an emotional reaction (discovery of the signs), step by step explanations are formed and it ends with another emotional reaction (diagnosis). Few bedside instruments are allowed to physicians to amplify their ability to search for signs. Stethoscope is an example. Similarities between ultrasound exploration and percussion can be found. Bedside ultrasonography can be considered an external amplifier of signs, a particular kind of percussion and represents a valid example of abductive manipulation. In this searching for signs doctors act like detectives and sometimes the discovering of a strategic, unsuspected sign during abductive manipulation could represent the key point for the correct diagnosis. This condition is called serendipity. Ultrasound is a powerful tool for detecting soft, hidden, unexpected and strategic signs. PMID- 28670455 TI - Data exclusivity exceptions and compulsory licensing to promote generic medicines in the European Union: A proposal for greater coherence in European pharmaceutical legislation. AB - The challenge of providing access to high-priced patented medicines is a global problem affecting all countries. A decade and a half ago the use of flexibilities contained in the World Trade Organization Agreement on Trade Related Aspects of Intellectual Property Rights, in particular compulsory licensing, was seen as a mechanism to respond to high-price medicines for the treatment of HIV/AIDS in low and middle-income countries. Today a number of upper-income European Union (EU) Member States are contemplating the use of compulsory licensing in their efforts to reduce expenditure on pharmaceutical products. EU regulation of clinical test data protection and the granting of market exclusivity interfere with the effective use of compulsory licensing by EU Member States and can even prevent access to off-patent medicines because they prohibit registration of generic equivalents. EU pharmaceutical legislation should be amended to allow waivers to data and market exclusivity in cases of public health need and when a compulsory or government use license has been issued. Such an amendment can be modelled after existing waivers in the EU Regulation on compulsory licensing of patents for the manufacture of pharmaceutical products for export to countries with public health problems outside the EU. Allowing a public health/compulsory license exception to data and market exclusivity would bring greater coherence between EC regulation of medicinal products and national provisions on compulsory licensing and ensure that Member States can take measures to protect public health and promote access to medicines for all. PMID- 28670454 TI - Post-nano strategies for drug delivery: Multistage porous silicon microvectors. AB - Nanodelivery systems usually improve the biodistribution of drugs, leading to reduced side effects and enhanced therapeutic efficacy. However, only a small portion of the injected nanoparticle dose accumulates in pathological tissue. Challenges in drug delivery arise due to a multitude of transport obstacles in the body, including the endothelium, the extracellular matrix, and the cell membrane. In general, nanoparticles are designed to overcome only a few biological barriers, making them inadequate for localized drug delivery. Accordingly, a multifunctional and multicomponent systems are required to effectively address a wide variety of transport obstacles. A suitable approach to obtain high levels of multifunctionality is to bring together the nanoscale with the microscale, resulting in post-nano strategies for drug delivery. This review discusses several such post-nano approaches, with an emphasis on the multistage vector (MSV) platform. The MSV consists of three components on different spatial scales, each intended to address biological barriers that exist in a specific compartment in the body. The first stage vector is a microparticle that is designed to navigate in the vascular compartment. The second stage vector consists of nanoparticles that are released from the microparticle into the tissue interstitium, where they address biological barriers in extracellular and intracellular compartments. The final component of the system is a small molecule therapeutic agent. A new generation of microparticle-based strategies with expanded applications has recently been developed, including injectable nanoparticle generators and silicon particles for immunotherapy. Notably, the advantage of incorporating microstructures in drug delivery vehicles is apparent from the observation that superior functionality only appears on the microscale, highlighting the inherent functional limitations of nanostructures. PMID- 28670456 TI - Levels of blood lead and urinary cadmium in industrial complex residents in Ulsan. AB - BACKGROUND: Populations neighboring industrial complexes are at an increased health risk, due to constant exposure to various potentially hazardous compounds released during industrial production activity. Although there are many previous studies that focus on occupational exposure to heavy metals, studies that focused on environmental exposure to lead and cadmium are relatively rare. The purpose of this study is to evaluate the extent of the environmental exposure of heavy metals in residents of industrial area. METHODS: Four areas in close proximity to the Ulsan petrochemical industrial complex and the Onsan national industrial complex were selected to be included in the exposure group, and an area remotely located from these industrial complexes was selected as the non-exposure group. Among the residents of our study areas, a total of 1573 subjects aged 20 years and older were selected and all study subjects completed a written questionnaire. Blood and urine samples were obtained from about one third of the subjects (465 subjects) who provided informed consent for biological sample collection. Total 429 subjects (320 subjects from exposure area, 109 subjects from non-exposure area) were included in final analysis. RESULTS: The geometric mean blood lead level among the subjects in the exposed group was 2.449 MUg/dL, which was significantly higher than the non-exposure group's level of 2.172 MUg/dL. Similarly, the geometric mean urine cadmium levels between the two groups differed significantly, at 1.077 MUg/g Cr. for the exposed group, and 0.709 MUg/g Cr. for the non-exposure group. In a multiple linear regression analysis to determine the relationship between blood lead level and related factors, the results showed that blood lead level had a significant positive correlation with age, the male, exposure area, and non-drinkers. In the same way, urine cadmium level was positively correlated with age, the female, exposure area, and smokers. CONCLUSIONS: This study found that blood lead levels and urine cadmium levels were significantly higher among the residents of industrial areas than among the non-exposure area residents, which is thought to be due to the difference in environmental exposure of lead and cadmium. Furthermore, it was clear that at a low level of exposure, differences in blood lead or urine cadmium levels based on age, gender, and smoking status were greater than the differences based on area of residence. Therefore, when evaluating heavy metal levels in the body at a low level of exposure, age, gender, and smoking status must be adjusted, as they are significant confounding factors. PMID- 28670457 TI - Hazards and health problems in occupations dominated by aged workers in South Korea. AB - BACKGROUND: South Korea's population is aging more rapidly than any other country. Aging of the productive population will lead to shortage of labor and the decreasing quality of the labor force in South Korea. South Korea needs health care strategies to support the establishment of work environments that are appropriate for elderly workers who have reduced physical capacity. This paper aims to identify occupations that are dominated by aged workers and assess the exposure to hazards and work-related health problems of aged workers in these occupations. METHODS: We identified the 20 occupations in South Korea that employ the most aged workers (at least 55 years-old), among all 149 occupations that are defined as minor categories (identified by three digits) by the Korean Standard Classification of Occupations (KSCO). Exposure to hazards and work-related health problems of individuals in these occupations were evaluated by analyzing the results of the fourth Working Conditions Survey of 2014. RESULTS: Among the 20 occupations that employ the most aged workers, 'Elementary Occupations', which the KSCO classifies as major category (9), had the largest proportion of aged workers. After this, there were five occupations of skilled manual workers and six occupations of skilled non-manual workers. Aged workers in elementary and skilled manual occupations reported frequent exposure to job-specific hazards, such as noise, vibrations, high and low temperatures, solvents, and chemicals. Relative to other workers, aged workers in the occupations reported more frequent exposure to ergonomic hazards, such as tiring or painful positions, carrying or moving heavy loads, and repetitive movements, and also reported more work-related musculoskeletal disorders and general fatigue. Injury due to accident was common in machinery-handling occupations. CONCLUSION: Job-specific hazards should be reduced to prevent occupation-related disorders in elementary and skilled manual occupations that are dominated by aged workers. PMID- 28670458 TI - The work-relatedness at a case of acute lymphoblastic leukemia in a radiation oncologist. AB - BACKGROUND: Clinicians who perform radiation therapy (RT) are exposed to radiation, which may negatively affect their health. The present study reports a case of acute lymphoblastic leukemia in a healthcare provider who was exposed to radiation at work; we also present a literature review of this topic. CASE PRESENTATION: A 45-year-old patient, who had been a radiation oncologist and had been exposed to radiation while performing brachytherapy 10 years ago, complained of chest pain and was suspected of having leukemia based on the results of a blood test in an outpatient clinic. He was diagnosed with acute lymphoblastic leukemia, and subsequently underwent chemotherapy. However, the case died during treatment. Through epidemiological investigation, it was found that the case's cumulative exposure dose based on personal exposure and spatial dose measured during the work period was in the range of 6.08-12.15 mSv. CONCLUSIONS: Based on the following considerations, acute lymphoblastic leukemia was highly correlated with the level of radiation to which the case was exposed while performing brachytherapy on patients with cancer. Firstly, the latent period of acute lymphoblastic leukemia in the case closely matched the latency time reported in previous published studies (5-10 years). In addition, numerous studies have reported significantly higher relative risks of cancer among clinicians who perform RT compared with the general population. The case was also atypically exposed to radiation through his hands, despite wearing protective equipment. Lastly, the case's coworkers were also found to have been exposed to high levels of radiation. Investigation into the influence of radiation exposure through atypical routes during RT on the health of clinicians is recommended. PMID- 28670459 TI - The associations between blood mercury levels and shark meat intake among workers in Gyeongsangbuk-do. AB - BACKGROUND: Shark meat is used as sacrificial food in Gyeongsangbuk-do, and is a major source of dietary mercury. This study aimed to evaluate the effects of shark meat intake or the ritual of Jesa on blood mercury levels within workers living in Gyeongsangbuk-do. METHODS: This study was conducted from September 2016 to October 2016 in two cities of Gyeongsangbuk-do. To compare the differences between urban and rural areas, two workplaces each in Daegu as the urban area and Yeongcheon as the rural area were selected. General characteristics and characteristics related to shark meat consumption of the workers were acquired by personal interviews during their health examination. Blood mercury concentrations were analyzed by the gold amalgamation method using a direct mercury analyzer (DMA-80; Milestone Inc., Shelton, CT, USA). RESULTS: The shark consumption group had a higher blood mercury concentration than the non-consumption group. The levels of blood mercury increased with the frequency, annual intake, as well as most recent date of shark meat consumption. Moreover, the levels of mercury in blood increased according to the annual frequency of participation in Jesa (times per year) and the annual frequency of shark meat consumption during Jesa (times per year). CONCLUSIONS: Shark meat intake and the ritual of Jesa contributed to an increase in the blood mercury levels of workers in Gyeongsangbuk-do. Therefore, it is necessary to evaluate dietary exposure, occupational as well as other factors that may influence blood mercury concentrations in workers during their health examination, particularly in regions with high mercury exposures. PMID- 28670460 TI - Factors affecting heat-related diseases in outdoor workers exposed to extreme heat. AB - BACKGROUND: The objectives of the present study are to: (i) evaluate the effect of environmental and metabolic heat on heat-related illnesses in outdoor workers; and (ii) evaluate the effect of personal factors, including heat acclimation, on the risk of heat-related illnesses in outdoor workers. METHODS: We identified 47 cases of illnesses from exposure to environmental heat in outdoor workers in Korea from 2010 to 2014, based on review of workers' compensation data. We also obtained the information on location, time, and work environment of each heat related illness. RESULTS: Our major results are that 29 cases (61.7%) occurred during a heat wave. Forty five cases (95.7%) occurred when the maximum estimated WBGT (WBGTmax) was equal to or greater than the case specific threshold value which was determined by acclimatization and metabolic rate. Twenty two cases (46.8%) were not acclimated to the heat. Thirty-seven cases (78.7%) occurred after tropical night (temperature above 25 degrees C), during which many people may find it hard to sleep. CONCLUSION: Personal risk factors such as heat acclimation as well as environmental factors and high metabolic rate during work are the major determinants of heat-related illnesses. PMID- 28670461 TI - Organ-on-chip models: new opportunities for biomedical research. PMID- 28670462 TI - Looking to the future of organs-on-chips: interview with Professor John Wikswo. AB - John Wikswo talks to Francesca Lake, Managing Editor: John is the founding Director of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE). He is also the Gordon A Cain University Professor; a B learned Professor of Living State Physics; and a Professor of Biomedical Engineering, Molecular Physiology and Biophysics, and Physics. John earned his PhD in physics at Stanford University (CA, USA). After serving as a Research Fellow in Cardiology at Stanford, he joined the Department of Physics and Astronomy at Vanderbilt University (TN, USA), where he went on to make the first measurement of the magnetic field of an isolated nerve. He founded VIIBRE at Vanderbilt in 2001 in order to foster and enhance interdisciplinary research in the biophysical sciences, bioengineering and medicine. VIIBRE efforts have led to the development of devices integral to organ-on-chip research. He is focusing on the neurovascular unit-on-a-chip, heart-on-a-chip, a missing organ microformulator, and microfluidic pumps and valves to control and analyze organs on-chips. PMID- 28670463 TI - Institutional profile: Community for Open Antimicrobial Drug Discovery - crowdsourcing new antibiotics and antifungals. AB - The Community for Open Antimicrobial Drug Discovery (CO-ADD) is a not-for-profit, collaborative approach to discovering new antibiotics. We access novel chemical diversity from academic synthetic chemists, who collectively possess millions of untested compounds with chemical diversity that lie outside commercial collections. We perform high-throughput antimicrobial screening of pure compounds derived from both synthetic and natural sources free of charge. The resulting data can be used by participants for publication, patenting and development purposes, and is fed back into the research community through an open-access database after a 2-year period during which information is kept confidential to the provider. CO-ADD is fundamentally asking two questions: can the community work together to address the global threat of antimicrobial resistance; and are there as yet undiscovered, novel antimicrobial compounds already present within our diverse global chemistry community? PMID- 28670464 TI - Diagnostic value of blood thiamine metabolites in Alzheimer's disease examined by 11C-PiB PET scanning. AB - AIM: We evaluated the diagnostic value of blood thiamine metabolites for Alzheimer's disease (AD) by using positron emission tomography with 11C Pittsburgh compound B (11C-PiB PET) scanning. METHODS: Thirty-eight clinically diagnosed AD patients were voluntarily recruited. Blood thiamine metabolites were measured by high-performance liquid chromatography. All the patients received 11C PiB PET scanning for the measurement of cerebral amyloid deposition. RESULTS: Thiamine diphosphate (TDP) had 66.7% sensitivity and 80.0% specificity for AD diagnosis, while the gamma-value representing the best combination of thiamine metabolites and age had 24.2% sensitivity and 100.0% specificity according to the cut-off value of our previous study. CONCLUSION: Blood TDP but not gamma-value exhibited results significant for AD diagnosis. PMID- 28670466 TI - Maintenance of head and neck tumor on-chip: gateway to personalized treatment? AB - AIM: Head and neck squamous cell carcinomas (HNSCC) are solid tumors with low overall survival (40-60%). In a move toward personalized medicine, maintenance of tumor biopsies in microfluidic tissue culture devices is being developed. METHODOLOGY/RESULTS: HNSCC (n = 15) was dissected (5-10 mg) and either analyzed immediately or cultured in a microfluidic device (37 degrees C) for 48 h. No difference was observed in morphology between pre- and postculture specimens. Dissociated samples were analyzed using trypan blue exclusion (viability), propidium iodide flow cytometry (death) and MTS assay (proliferation) with no significant difference observed highlighting tissue maintenance. Computational fluid dynamics showed laminar flow within the system. CONCLUSION: The microfluidic culture system successfully maintained HNSCC for 48 h, the culture system will allow testing of different treatment modalities with response monitoring. PMID- 28670467 TI - Expression and therapeutic significance of estrogen receptor beta in malignant pleural mesothelioma. PMID- 28670465 TI - Microfluidic on-chip biomimicry for 3D cell culture: a fit-for-purpose investigation from the end user standpoint. AB - A plethora of 3D and microfluidics-based culture models have been demonstrated in the recent years with the ultimate aim to facilitate predictive in vitro models for pharmaceutical development. This article summarizes to date the progress in the microfluidics-based tissue culture models, including organ-on-a-chip and vasculature-on-a-chip. Specific focus is placed on addressing the question of what kinds of 3D culture and system complexities are deemed desirable by the biological and biomedical community. This question is addressed through analysis of a research survey to evaluate the potential use of microfluidic cell culture models among the end users. Our results showed a willingness to adopt 3D culture technology among biomedical researchers, although a significant gap still exists between the desired systems and existing 3D culture options. With these results, key challenges and future directions are highlighted. PMID- 28670468 TI - Institutional profile: the national Swedish academic drug discovery & development platform at SciLifeLab. AB - The Science for Life Laboratory Drug Discovery and Development Platform (SciLifeLab DDD) was established in Stockholm and Uppsala, Sweden, in 2014. It is one of ten platforms of the Swedish national SciLifeLab which support projects run by Swedish academic researchers with large-scale technologies for molecular biosciences with a focus on health and environment. SciLifeLab was created by the coordinated effort of four universities in Stockholm and Uppsala: Stockholm University, Karolinska Institutet, KTH Royal Institute of Technology and Uppsala University, and has recently expanded to other Swedish university locations. The primary goal of the SciLifeLab DDD is to support selected academic discovery and development research projects with tools and resources to discover novel lead therapeutics, either molecules or human antibodies. Intellectual property developed with the help of SciLifeLab DDD is wholly owned by the academic research group. The bulk of SciLifeLab DDD's research and service activities are funded from the Swedish state, with only consumables paid by the academic research group through individual grants. PMID- 28670469 TI - An integrated versatile lab-on-a-chip platform for the isolation and nucleic acid based detection of pathogens. AB - AIM: Processing of the samples in molecular diagnostics is complex and labor intensive. An integrated and automated platform for sample preparation and nucleic acid-based detection can significantly relieve this burden for the users. RESULTS: We present a prototype of a versatile and integrated platform for the detection of pathogens in various liquid media. We describe a proof-of-concept for the integrated isolation of bacteria, cell lysis with optional DNA extraction, DNA amplification and detection in two different reactions, loop mediated isothermal amplification and PCR, on a single microfluidic platform. CONCLUSION: The platform enables the transition from large sample volume to microfluidic format. The design and open interface enable its versatile application for various nucleic acid-based assays, from simple to complex setups. PMID- 28670470 TI - Anti-NMDAR antibodies as a new piece in schizophrenia's puzzle. PMID- 28670471 TI - Entering the 'big data' era in medicinal chemistry: molecular promiscuity analysis revisited. AB - The 'big data' concept plays an increasingly important role in many scientific fields. Big data involves more than unprecedentedly large volumes of data that become available. Different criteria characterizing big data must be carefully considered in computational data mining, as we discuss herein focusing on medicinal chemistry. This is a scientific discipline where big data is beginning to emerge and provide new opportunities. For example, the ability of many drugs to specifically interact with multiple targets, termed promiscuity, forms the molecular basis of polypharmacology, a hot topic in drug discovery. Compound promiscuity analysis is an area that is much influenced by big data phenomena. Different results are obtained depending on chosen data selection and confidence criteria, as we also demonstrate. PMID- 28670472 TI - Integration concepts for multi-organ chips: how to maintain flexibility?! AB - Multi-organ platforms have an enormous potential to lead to a paradigm shift in a multitude of research domains including drug development, toxicological screening, personalized medicine as well as disease modeling. Integrating multiple organ-tissues into one microfluidic circulation merges the advantages of cell lines (human genetic background) and animal models (complex physiology) and enables the creation of more in vivo-like in vitro models. In recent years, a variety of design concepts for multi-organ platforms have been introduced, categorizable into static, semistatic and flexible systems. The most promising approach seems to be flexible interconnection of single-organ platforms to application-specific multi-organ systems. This perspective elucidates the concept of 'mix-and-match' toolboxes and discusses the numerous advantages compared with static/semistatic platforms as well as remaining challenges. PMID- 28670473 TI - High level of hemoglobin, white blood cells and obesity among Sudanese women in early pregnancy: a cross-sectional study. AB - AIM: To investigate the association between obesity and anemia/hemoglobin levels. MATERIAL & METHODS: A cross-sectional study was conducted at Khartoum, Sudan. Obstetric data were collected from 388 pregnant women at mean (standard deviation) of 10.5 (3.1) weeks of gestation using questionnaires. Weight and height were determined, and BMI was calculated. RESULTS: There were 15 (4.4%), 95 (28.1%), 127 (37.6) and 101 (29.9%) women who were underweight, normal weight, (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (>=30 kg/m2), respectively. Hemoglobin levels and white blood cell counts were significantly higher in obese than nonobese groups. Compared with normal BMI, overweight and obesity were associated with higher hemoglobin level. CONCLUSION: Obese women had higher white blood cell count and hemoglobin level. PMID- 28670474 TI - On the bridge over the translational valley of death: interview with Per I Arvidsson. AB - Per I Arvidsson speaks to Francesca Lake, Managing Editor: Per received his PhD in organic chemistry from Gothenburg University (Sweden) in 1999, where he continued as a lecturer for a short time. Following 2 years at the ETH Zurich (Switzerland) as a postdoctoral fellow, he went on to establish an independent research group at the Department of Biochemistry and Organic Chemistry at Uppsala University (Sweden). In 2006, he joined AstraZeneca R&D Sodertalje (Sweden). After 1-year in-house training for future leaders in drug discovery and development, he became team leader in Medicinal Chemistry in 2007. In 2008, he was appointed Candidate Drug Delivery team leader with responsibility for preclinical drug discoveries in several CNS and pain projects. In 2010, he became Project Director at the innovative medicine unit for CNS & Pain research in Sodertalje with responsibility from lead optimization to end of Phase II for projects in the neurodegeneration area. After joining AstraZeneca, he continued to pursue academic research as Adjunct Professor in bioorganic chemistry at the Department of Biochemistry and Organic Chemistry, Uppsala University (2007-2010), and the Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University (2010-2013). In 2010, he was appointed honorary professor in Pharmacy and Pharmacology at the University of KwaZulu Natal (South Africa). In 2013, he was recruited to the Karolinska Institute in Stockholm as Director of Drug Discovery & Development, to build up the National Swedish infrastructure for Drug Discovery & Development at the Science for Life Laboratory (SciLifeLab). Since 2013, he has been a part-time research professor at the College of Health Science at the University of KwaZulu Natal. He is named inventor on over 15 patent applications, and coauthor to over 100 publications, two of which have won 'most cited papers' awards. PMID- 28670475 TI - The ascendance of microphysiological systems to solve the drug testing dilemma. AB - The development of drugs is a process obstructed with manifold security and efficacy concerns. Although animal models are still widely used to meet the diligence required, they are regarded as outdated tools with limited predictability. Novel microphysiological systems intend to create systemic models of human biology. Their ability to host 3D organoid constructs in a controlled microenvironment with mechanical and electrophysiological stimuli enables them to create and maintain homeostasis. These platforms are, thus, envisioned to be superior tools for testing and developing substances such as drugs, cosmetics and chemicals. We will present reasons why microphysiological systems are required for the emerging demands, highlight current technological and regulatory obstacles, and depict possible solutions from state-of-the-art platforms from major contributors. PMID- 28670476 TI - Stem cell culture and differentiation in microfluidic devices toward organ-on-a chip. AB - Microfluidic lab-on-a-chip provides a new platform with unique advantages to mimic complex physiological microenvironments in vivo and has been increasingly exploited to stem cell research. In this review, we highlight recent advances of microfluidic devices for stem cell culture and differentiation toward the development of organ-on-a-chip, especially with an emphasis on vital innovations within the last 2 years. Various aspects for improving on-chip stem-cell culture and differentiation, particularly toward organ-on-a-chip, are discussed, along with microenvironment control, surface modification, extracellular scaffolds, high throughput and stimuli. The combination of microfluidic technologies and stem cells hold great potential toward versatile systems of 'organ-on-a-chip' as desired. Adapted with permission from [1-8]. PMID- 28670478 TI - Tailoring cardiac environment in microphysiological systems: an outlook on current and perspective heart-on-chip platforms. PMID- 28670479 TI - Looking to the future of organs-on-chip. PMID- 28670477 TI - Ex vivo tumor culture systems for functional drug testing and therapy response prediction. AB - Optimal patient stratification is of utmost importance in the era of personalized medicine. Prediction of individual treatment responses by functional ex vivo assays requires model systems derived from viable tumor samples, which should closely resemble in vivo tumor characteristics and microenvironment. This review discusses a broad spectrum of model systems, ranging from classic 2D monolayer culture techniques to more experimental 'cancer-on-chip' procedures. We mainly focus on organotypic tumor slices that take tumor heterogeneity and tumor-stromal interactions into account. These 3D model systems can be exploited for patient selection as well as for fundamental research. Selection of the right model system for each specific research endeavor is crucial and requires careful balancing of the pros and cons of each technology. PMID- 28670480 TI - Long-term consumption of caffeine-free high sucrose cola beverages aggravates the pathogenesis of EAE in mice. AB - Epidemiological data provide strong evidence of dramatically increasing incidences of many autoimmune diseases in the past few decades, mainly in western and westernized countries. Recent studies clearly revealed that 'Western diet' increases the risk of autoimmune diseases at least partially via disrupting intestinal tight junctions and altering the construction and metabolites of microbiota. However, the role of high sucrose cola beverages (HSCBs), which are one of the main sources of added sugar in the western diet, is barely known. Recently, a population study showed that regular consumption of sugar-sweetened beverages is associated with increased risk of seropositive rheumatoid arthritis in women, which provokes interest in the genuine effects of these beverages on the pathogenesis of autoimmune diseases and the underlying mechanisms. Here we showed that long-term consumption of caffeine-free HSCBs aggravated the pathogenesis of experimental autoimmune encephalomyelitis in mice in a microbiota dependent manner. Further investigation revealed that HSCBs altered community structure of microbiota and increased Th17 cells. High sucrose consumption had similar detrimental effects while caffeine contamination limited the infiltrated pathogenic immune cells and counteracted these effects. These results uncovered a deleterious role of decaffeinated HSCBs in aggravating the pathogenesis of experimental autoimmune encephalomyelitis in mice. PMID- 28670481 TI - Computer navigation of the acetabular component in total hip arthroplasty: a narrative review. AB - Total hip arthroplasty (THA) is a common procedure for primary osteoarthritis, but increasing numbers are also being performed for other pathologies such as secondary arthritis, inflammatory arthropathies and trauma. Estimates suggest that around 8.5 million people in the UK are affected by joint pain secondary to arthritis and a rising ageing population has resulted in an increase in THA operations of around 4% per year over the last six years.Multiple studies have shown that THA provides improved quality of life scores, but there remains the burden of complications which account for 15% of L1bn NHS liability payouts. DaPalma et al analysed the financial impact of complications following THA and found the additional cost of a dislocation within six weeks of surgery is 342% of the primary cost.Following primary THA, complications may occur as a result of incorrect component positioning of the femoral stem, the acetabular cup or both. It is known that acetabular malposition may lead to increased rates of dislocation, impingement, edge-loading, polyethylene wear, pelvic osteolysis and prosthesis failure.Acetabular component positioning has been described as the single most important factor in dictating risk of dislocation following THA. Furthermore, instability and dislocation after primary THA is the most common single reason for revision surgery accounting for 22.5% of all revisions and 33% of acetabular revisions.We outline the currently available methods of acetabular navigation comparing freehand techniques with computer and robotic-assisted navigation of the acetabular component. Cite this article: Davenport D, Kavarthapu V. Computer navigation of the acetabular component in total hip arthroplasty: a narrative review. EFORT Open Rev 2016;1:279-285. DOI: 10.1302/2058-5241.1.000050. PMID- 28670483 TI - Best practices in social and behavioral research: report from the Enhancing Clinical Research Professional's Training and Qualifications project. AB - INTRODUCTION: This article discusses the process of defining competencies and development of a best practices training course for investigators and clinical research coordinators who conduct social and behavioral research. METHODS: The first project phase established recommendations for training in Good Clinical Practice (GCP) and was done in conjunction with representatives from 62 Clinical and Translational Science Award (CTSA) hubs. Diversity in behavioral clinical trials and differences in regulation of behavioral trials compared with clinical trials involving drugs, devices, or biologics necessitated a separate Social and Behavioral Work Group. This group worked with CTSA representatives to tailor competencies and fundamental GCP principles into best practices for social and behavioral research. RESULTS: Although concepts underlying GCP were deemed similar across all clinical trials, not all areas were equally applicable and the ways in which GCP would be enacted differ for behavioral trials. It was determined that suitable training in best practices for social and behavioral research was lacking. DISCUSSION: Based on the training need, an e-learning course for best practices is available to all CTSA sites. Each institution is able to track outcomes for its employees to help achieve standardized competency based best practices for social and behavioral investigators and staff. PMID- 28670482 TI - Informational and Support Needs of Patients with Head and Neck Cancer: Current Status and Emerging Issues. AB - The objective of this article is to review and summarize the extant literature on head and neck cancer (HNC) patients' informational needs and to characterize emerging issues in this patient population in order to define priorities for future research. HNC patients may undergo challenging treatment regimens and experience treatment-related alterations in primary daily functions such as speech and eating. These changes often persist following treatment and may lead to significant deficits in quality of life and interpersonal relations. Despite empirical evidence demonstrating that receipt of adequate information and support is predictive of improved outcomes post-treatment, relatively limited attention has been paid to the informational and support needs of HNC patients. This review focuses primarily on three topic domains: (1) managing treatment-related side effects; (2) addressing alcohol and tobacco dependence; and (3) informational needs in the areas of human papillomavirus (HPV) and clinical trials. While there is increasing awareness of the rehabilitation and survivorship needs in this patient population, patients note that the impact of treatment on social activities and interactions is under-discussed and of key concern. In addition, there is a significant gap in addressing communication and informational needs of caregivers and family members who are integral for promoting healthy behaviors and self-care post-treatment. Greater integration of programs that address tobacco or alcohol dependency within a comprehensive treatment and support plan may increase patient motivation to seek help and enhance patient success in maintaining long-term abstinence. Finally, emerging patient-provider communication needs, particularly in the context of decision making about clinical trials or surrounding an HPV-related diagnosis, have been noted among both patients and healthcare providers. Future research on the development of novel programs that offer feasible and acceptable methods for addressing unmet informational and support needs is warranted and may yield benefit for improving patient-reported outcomes. PMID- 28670484 TI - Uncertainty quantification in breast cancer risk prediction models using self reported family health history. AB - Introduction. Family health history (FHx) is an important factor in breast and ovarian cancer risk assessment. As such, multiple risk prediction models rely strongly on FHx data when identifying a patient's risk. These models were developed using verified information and when translated into a clinical setting assume that a patient's FHx is accurate and complete. However, FHx information collected in a typical clinical setting is known to be imprecise and it is not well understood how this uncertainty may affect predictions in clinical settings. Methods. Using Monte Carlo simulations and existing measurements of uncertainty of self-reported FHx, we show how uncertainty in FHx information can alter risk classification when used in typical clinical settings. Results. We found that various models ranged from 52% to 64% for correct tier-level classification of pedigrees under a set of contrived uncertain conditions, but that significant misclassification are not negligible. Conclusions. Our work implies that (i) uncertainty quantification needs to be considered when transferring tools from a controlled research environment to a more uncertain environment (i.e, a health clinic) and (ii) better FHx collection methods are needed to reduce uncertainty in breast cancer risk prediction in clinical settings. PMID- 28670485 TI - The Hydrogen Bonded Structures of Two 5-Bromobarbituric Acids and Analysis of Unequal C5-X and C5-X' Bond Lengths (X = X' = F, Cl, Br or Me) in 5,5 Disubstituted Barbituric Acids. AB - The crystal structure of the methanol hemisolvate of 5,5-dibromobarbituric acid (1MH) displays an H-bonded layer structure which is based on N-H?O=C, N-H?O(MeOH) and (MeOH)O-H?O interactions. The barbiturate molecules form an H-bonded substructure which has the fes topology. 5,5'-Methanediylbis(5-bromobarbituric acid) 2, obtained from a solution of 5,5-dibromobarbituric acid in nitromethane, displays a N-H?O=C bonded framework of the sxd type. The conformation of the pyridmidine ring and the lengths of the ring substituent bonds C5-X and C5-X' in crystal forms of 5,5-dibromobarbituric acid and three closely related analogues (X = X' = Br, Cl, F, Me) have been investigated. In each case, a conformation close to a C5-endo envelope is correlated with a significant lengthening of the axial C5-X' in comparison to the equatorial C5-X bond. Isolated molecule geometry optimizations at different levels of theory confirm that the C5-endo envelope is the global conformational energy minimum of 5,5-dihalogenbarbituric acids. The relative lengthening of the axial bond is therefore interpreted as an inherent feature of the preferred envelope conformation of the pyrimidine ring, which minimizes repulsive interactions between the axial substituent and pyrimidine ring atoms. PMID- 28670487 TI - Biology and Management of the Mexican Rice Borer (Lepidoptera: Crambidae) in Rice in the United States. AB - The Mexican rice borer, Eoreuma loftini (Dyar), is an invasive pest of rice, Oryza sativa L., in the Gulf Coast region of the United States. This pest also damages sugarcane, Saccharum spp. hybrids; corn, Zea mays L.; and sorghum, Sorghum bicolor (L.) Moench, and feeds on weedy noncrop grasses. Multiple aspects of integrated pest management including use of pheromone traps, manipulation of planting dates, harvest cutting height, stubble management, noncrop host management, soil fertility management, host plant resistance, use of insecticides, and biological control have been studied for Mexican rice borer management. However, the current management strategy in rice primarily relies on the use of chlorantraniliprole insecticide seed treatments. This profile addresses Mexican rice borer biology and management in rice in the United States. PMID- 28670488 TI - Identification of RING-box 2 as a potential target for combating colorectal cancer growth and metastasis. AB - Development of cancer metastasis is a key contributor to mortality in patients with colorectal cancer. High expression of RING-box 2 (RBX2) in cancer cells is known to play a key role in tumor progression. However, the role of RBX2 in colorectal cancer progression is not well elucidated. In this study, we silenced RBX2 via CRISPR/Cas9 in two colorectal cancer cell lines, HCT116 and SW480. RBX2 knockout attenuated proliferation, colony formation and enhanced sensitivity of colorectal cancer cells to paclitaxel treatment. Invasive property of HCT116 and SW480 cells was also attenuated by RBX2 silencing. We confirmed that increased RBX2 correlated with higher tumor cells growth and metastasis abilities by ectopic expression of RBX2 in HCT116 and SW480 cells. In vivo studies suggested that knockout of RBX2 inhibited xenografts growth and metastasis to lung tissue, whereas ectopic expression of RBX2 promoted these cellular functions. Mechanically, RBX2 induced gastric cancer cell growth and metastasis by activating mammalian target of rapamycin/S6 kinase 1 (mTOR/S6K1). Treatment of everolimus, the specific mTOR inhibitor, significantly attenuated RBX2-mediated cell proliferation and mobility in vitro. Taken together, these results revealed a novel role of RBX2 in colorectal cancer cell growth and metastasis via the mTOR pathway and suggested RBX2 may serve as a therapeutic target in colorectal cancer. PMID- 28670486 TI - Human T-Cell Development and Thymic Egress: An Infectious Disease Perspective. AB - Emigration of mature naive CD4 SP T cells from the human thymus to the periphery is not fully understood, although elucidation of the mechanisms that govern egress of T cells is crucial to understanding both basic immunology and the immune response in diseases such as HIV infection. Recent work has brought to light the requirement for sphingosine-1-phosphate (S1P) and its receptors in a variety of fields including mature naive T-cell egress from the thymus of mice. We are examining the expression and function of this novel requisite T-cell egress receptor within the human thymus, characterizing changes observed in the expression and function of this receptor in infectious diseases. To perform this work, we use a variety of humanized murine models reviewed in this article. Future work in the field of T-cell egress, especially as it pertains to S1P receptors, should advance the fields of basic T-cell immunology and immunopathology and open new avenues for exploration into novel therapeutics. PMID- 28670489 TI - Heat shock protein 70-2 (HSP70-2) a novel cancer testis antigen that promotes growth of ovarian cancer. AB - Heat shock protein 70-2 (HSP70-2) is known to be involved in tumor progression. However, its molecular role and mechanism in epithelial ovarian cancer (EOC) remains unknown. In the present investigation, we examined the role of HSP70-2 in cell cycle, apoptosis and epithelial mesenchymal transition pathways in EOC cells in in vitro and in-vivo xenograft mouse model. To investigate the role of HSP70-2 in ovarian cancer, plasmid driven short hairpin RNA approach was used to examine HSP70-2 gene and protein expression in ovarian cancer cell line A-10 (origin: serous papillary cystadenocarcinoma), Caov-3 (origin: adenocarcinoma) and SKOV3 (origin: adenocarcinoma; derived from metastatic site: ascites) by RT-PCR, quantitative-PCR, immunohistochemistry and Western blotting. Light microscopy, scanning electron microscopy, viability tests, and flow cytometry were used to study the cellular proliferation, onset of senescence, colony forming ability and morphological features of cancer cells. Cell migration and invasion ability was evaluated by wound healing and Boyden chamber assays. Further, we studied the effect of HSP70-2 protein ablation on human ovarian xenograft mice model. At molecular level, various molecules involved in apoptosis, cell cycle and epithelial-mesenchymal-transition were also examined both in in-vitro and in-vivo xenograft mouse model. The knockdown of HSP70-2 expression by gene silencing resulted in the onset of apoptosis, senescence, reduced cellular growth and colony forming ability of EOC cells. Interestingly, the migration, invasion and wound healing abilities of cells were also significantly inhibited. In addition, the ablation of HSP70-2 resulted in the upregulation of cytochrome-C, caspase 3, caspase 7, caspase 9, APAF1, BAX, BIM, BAK, BAD, BID, PUMA, NOXA, p16, p21, Rb, E cadherin, cytokeratin 18, EMA in these cells as well as in the xenograft tumor specimens. However, there was downregulation of PARP1, BCL-2, Bcl-xL, MCL-1, Survivin, XIAP, cIAP2, CDK1, CDK2, CDK4, CDK6, cyclin D1, cyclin E, cyclin A2, cyclin B1, p-Rb, N-cadherin, SNAIL, SLUG, VIMENTIN, SMA, MMP2, MMP3, MMP9 and TWIST in these samples. Furthermore, the xenograft studies showed significant reduction in the tumor growth. Our results suggest that HSP70-2 can promote cellular growth and invasion of EOC cells and therefore may be a potential therapeutic target in EOC. PMID- 28670490 TI - Dehydrocostus lactone, a natural sesquiterpene lactone, suppresses the biological characteristics of glioma, through inhibition of the NF-kappaB/COX-2 signaling pathway by targeting IKKbeta. AB - Dehydrocostus lactone (DHE), a natural sesquiterpene lactone, has been used for treatment of various diseases with its anti-inflammatory activity. Recently, it has caused extensive interest in researchers due to it has anti-cancer abilities in some types of carcinomas. However, the anti-cancer effect and mechanism of DHE in glioma remains unclear. The present study conducted to determine the biological effects of DHE on the glioblastoma cells, as well as the mechanisms underlying these effects. After treatment with DHE, the glioblastoma (U118, U251 or U87) cells were significantly inhibited in their viability, proliferation and migration. At the meantime, DHE also induced mitochondria-mediated apoptosis by promoting the release of cytochrome c into cytosol, which activating caspase signaling pathway. Furthermore, our results fully demonstrate that DHE significantly suppressed COX-2 expression by inhibiting the phosphorylation of IKKbeta via targeting the ATP-binding site, thereby abrogating NF-kappaB binding and p300 recruitment to COX-2 promoter. Moreover, the current study firstly demonstrated that DHE can cross blood-brain barrier (BBB). In addition, treatment with DHE markedly inhibited neoplastic weight and volume without the notable adverse effects in the xenograft nude mice model, and these effects may be mediated through inhibition of the IKKbeta/NF-kappaB/COX-2 signaling pathway. These findings provide the pharmacological evidence for development of DHE as a potential agent against glioma. PMID- 28670491 TI - The transcription factor Ikaros inhibits cell proliferation by downregulating ANXA4 expression in hepatocellular carcinoma. AB - The occurrence and progression of hepatocellular carcinoma (HCC) are affected by complicated signal transduction factors. Our previous study identified Ikaros as a novel reactivated therapeutic target that acts as a transcriptional repressor and reactivates anticancer mechanisms in HCC therapy. Annexin A4 (ANXA4) is a member of the Annexin family that plays an essential role in several cancers, but it has not been investigated in HCC proliferation. Using cDNA microarrays, ANXA4 was shown to be associated with Ikaros in Ikaros-overexpressing cells. The aim of this work was to characterize the relationship between Ikaros and ANXA4 and the role of ANXA4 in HCC. The effect of Ikaros on ANXA4 was analyzed in HCC cell lines and HCC patient samples, and functional recovery experiments were performed between Ikaros and ANXA4. Furthermore, the effect of ANXA4 on cell proliferation in vitro was analyzed by MTT and colony formation assays in HCC cells. We used a subcutaneous xenograft model to elucidate the role of ANXA4 in vivo. We found that ANXA4 overexpression promotes HCC cell proliferation, but Ikaros can inhibit ANXA4 expression by repressing its promoter activity. Moreover, we demonstrated that downregulated expression of ANXA4 inhibited HCC cell proliferation and tumorigenesis in vitro and in vivo. Our findings indicate that ANXA4 may be a critical factor in HCC tumorigenesis. Ikaros is an attractive inhibitor of ANXA4 and may function as an anticancer agent in HCC. PMID- 28670492 TI - The long non-coding RNA HOTAIR promotes thyroid cancer cell growth, invasion and migration through the miR-1-CCND2 axis. AB - The purpose of this study was to explore the potential role of HOTAIR in thyroid cancer carcinogenesis. We found that HOTAIR was unregulated in human thyroid cancer and inversely correlated with miR-1. Functional assays indicated HOTAIR regulates miR-1 directly in thyroid cancer cells. We also revealed that HOTAIR promotes the processes of thyroid cancer cell malignancy through regulation of microRNA-1 (miR-1). Furthermore, we showed that HOTAIR could regulate a downstream target of miR-1, CCND2, in a miR-1-mediated manner. In addition, we also proved, using a tumor formation assay in nude mice, that silencing HOTAIR inhibited tumor formation in vivo. Therefore, our study demonstrated that HOTAIR promotes the development and progression of thyroid cancer through inhibition of microRNA-1 and activation of CCND2. PMID- 28670493 TI - MiR-874 inhibits metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting SOX12. AB - MicroRNA-874 (miR-874), a novel cancer-associated microRNA (miRNA), has been reported to play a suppressive role in multiple malignancies. However, its function in cell migration and invasion in hepatocellular carcinoma (HCC) and the mechanisms responsible remain unclear. Here, we found miR-874 to be significantly downregulated in HCC tissues and cell lines. Moreover, this decreased expression strongly correlated with clinical stage and lymph node metastasis. Accordingly, ectopic expression of miR-874 in HCC cells markedly inhibited their migration, invasion, and epithelial-mesenchymal transition (EMT). Concerning the underlying mechanism, SRY (sex-determining region Y) -box 12 (SOX12) was identified as a direct target of miR-874, and its expression was found to be inversely correlated with that of this miRNA in HCC cells. Importantly, SOX12 knockdown had an inhibitory effect on HCC cells similar to that caused by miR-874 overexpression, whereas SOX12 overexpression in these cells negated the suppressive effects of miR-874 on migration, invasion, and EMT. Overall, these findings demonstrate that miR-874 inhibits metastasis and EMT in HCC by targeting SOX12, suggesting that this miRNA may constitute a promising therapeutic target for this disease. PMID- 28670494 TI - Lycopene reduces ovarian tumor growth and intraperitoneal metastatic load. AB - Mutagens like oxidants cause lesions in the DNA of ovarian and fallopian tube epithelial cells, resulting in neoplastic transformation. Reduced exposure of surface epithelia to oxidative stress may prevent the onset or reduce the growth of ovarian cancer. Lycopene is well-known for its excellent antioxidant properties. In this study, the potential of lycopene in the prevention and treatment of ovarian cancer was investigated using an intraperitoneal animal model. Lycopene prevention significantly reduced the metastatic load of ovarian cancer-bearing mice, whereas treatment of already established ovarian tumors with lycopene significantly diminished the tumor burden. Lycopene treatment synergistically enhanced anti-tumorigenic effects of paclitaxel and carboplatin. Immunostaining of tumor and metastatic tissues for Ki67 revealed that lycopene reduced the number of proliferating cancer cells. Lycopene decreased the expression of the ovarian cancer biomarker, CA125. The anti-metastatic and anti proliferative effects were accompanied by down-regulated expression of ITGA5, ITGB1, MMP9, FAK, ILK and EMT markers, decreased protein expression of integrin alpha5 and reduced activation of MAPK. These findings indicate that lycopene interferes with mechanisms involved in the development and progression of ovarian cancer and that its preventive and therapeutic use, combined with chemotherapeutics, reduces the tumor and metastatic burden of ovarian cancer in vivo. PMID- 28670495 TI - Bitterness in sugar: O-GlcNAcylation aggravates pre-B acute lymphocytic leukemia through glycolysis via the PI3K/Akt/c-Myc pathway. AB - Abnormal cellular energetics has emerged as a hallmark of cancer cells. Deregulating aerobic glycolysis can alter multiple metabolic and signaling pathways in cancer cells, and trigger unlimited growth and proliferation. Accumulating evidence suggests that elevated levels of protein modification with beta-N-acetylglucosamine (O-GlcNAcylation) along with dysregulation of O-GlcNAc transferase (OGT) and/or O-GlcNAcase (OGA) levels may act as a nutrient sensor in cancer cells. However, the underlying mechanism of O-GlcNAcylation and the relationship between O-GlcNAcylation and glycolysis are largely unknown in pre-B acute lymphocytic leukemia (pre-B-ALL). In this study, CD19+ bone marrow mononuclear cells (BM-MNCs) from untreated pre-B-ALL patients displayed increased O-GlcNAcylation levels, upregulated OGT, and downregulated OGA. Patients with higher lactate dehydrogenase (LDH) levels exhibited higher O-GlcNAcylation levels with OGT upregulation and overactivation of the PI3K/Akt/c-Myc pathway. The extracellular acidification rate (ECAR) and the mRNA expression of key enzymes in glycolysis were determined to assess glycolysis activation. Our results revealed the existence of abnormal glycolysis in the CD19+ BM-MNCs of pre-B-ALL patients. The knockdown of OGT decreased the ECAR and downregulated glycolysis-related enzymes in Nalm-6 cells via the PI3K/Akt/c-Myc pathway. The suppression of OGT slowed the rate of proliferation and induced apoptosis in Nalm-6 cells. The glycolysis inhibitor 2-deoxy-D-glucose induced cytotoxicity of Nalm-6 cells, which was potentiated by OGT-siRNA. These findings suggested that O-GlcNAcylation could be a hallmark of pre-B-ALL, which has considerable therapeutic potential in clinical practice. PMID- 28670497 TI - Mucins in pancreatic cancer: biological role, implications in carcinogenesis and applications in diagnosis and therapy. AB - Pancreatic cancer is the fourth highest cause of cancer mortality in the world. It has very low survival rates owing to late diagnosis resulting from the absence of accurate diagnostic tools and effective therapies. Hence, there is a pressing need to develop new diagnostic and therapeutic tools. In the recent years, there has been new evidence implicating the importance of mucins in pancreatic carcinogenesis. Mucins belong to a group of heavily glycosylated proteins, and are often aberrantly expressed in a number of cancers such as pancreatic cancer. Therefore, this literature review will summarise the role of mucins and mucin expression in pancreatic neoplasms. Subsequently the paper will also discuss the most recent advances in the biological properties of mucins and their role in carcinogenesis and resistance to chemotherapy. Then it will conclude on the newest developments in diagnosis and therapy based on mucins for pancreatic cancer. PMID- 28670498 TI - Application of AFP whole blood one-step rapid detection kit in screening for HCC in Qidong. AB - Hepatocellular carcinoma (HCC) is a big problem in China where the Hepatitis B (HBV) infection patients are near to 120 million. Early screening and diagnosis is the key to reduce the incidence and mortality of HCC. Serum AFP detection is the main methods for diagnosis, recurrent monitoring and therapeutic evaluation of primary HCC. Hepatitis patients should detect the AFP at least once every six months to help early diagnosis of HCC. Unfortunately, most hepatitis and other liver disease patients do not test their AFP regularly. Therefore, a rapid, convenient detect kit for AFP is necessary for the hepatitis patients to test AFP at home by themselves. It will be very helpful to the HCC early screening and early diagnosis. We screened 859 individuals who were HBsAg positive and had high risk of HCC in Qidong by using two different kits, AFP one-step rapid detection kit (Shanghai Outdo Biotech) and AFP Diagnostics ELISA kit (Zhengzhou Autobio Diagnostics), and compared the results. As a result, the positive accordance rate and the negative accordance rate of AFP one-step rapid detection kit and the Autobio ELISA kit were 95.65% (22/23) and 99.40% (831/836), respectively. The total diagnose accordance rate reached up to 99.30% (853/859). The screening results showed a high accordance rate of two methods. It is so meaningful to achieve home-test and improve HCC early screening and diagnosis by using AFP one step rapid detection kit. PMID- 28670496 TI - Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators. AB - Chemo-resistance, which is the main obstacle in cancer therapy, is caused by the onset of drug-resistant cells in the heterogeneous cell population in cancer tissues. MicroRNAs regulate gene expression at the post-transcriptional level, and they are involved in many different biological processes, including cell proliferation, differentiation, metabolism, stress response, and apoptosis. The aberrant expression of microRNAs plays a major pathogenic role from the early stages of the carcinogenesis process. Recently, microRNAs have been reported to play an important role in inducing resistance to anti-cancer drugs. Specific microRNA alterations occur selectively in cancer cells, rendering these cells resistant to various chemotherapeutic agents. For example, resistance to 5 fluorouracil is mediated by alterations in miR-21, miR-27a/b, and miR-155; the sensitivity to Docetaxel is influenced by miR-98, miR-192, miR-194, miR-200b, miR 212, and miR-424; and the resistance to Cisplatin is mediated by miR-let-7, miR 15, miR-16 miR-21 and miR-214. Chemo-resistant cancer cells are characterized by altered functions in enzymes that are involved in microRNA maturation, primarily including Dicer, as demonstrated in ovarian cancer, oral squamous cell carcinoma, breast cancer and cervical cancer. Based on the evidence reviewed in this paper, various strategies have been developed to artificially re-establish microRNA expression in resistant cells, thus restoring chemo-sensitivity. These strategies employ synthetic analogs, anti-microRNA oligonucleotides, locked nucleic acid, microRNA sponges, drugs that inhibit DNA methylation or histone deacetylation, and the introduction of microRNA mimics. The ability to modulate microRNA expression is a promising strategy for overcoming the problem of drug resistance in cancer treatment. PMID- 28670500 TI - Peculiar Clinical Presentation of Coxsackievirus B4 Infection: Neonatal Restrictive Cardiomyopathy. AB - Introduction Restrictive cardiomyopathy in fetuses and neonates is extremely rare and has a poor outcome. Its etiology in neonates is elusive: metabolic diseases (e.g., Gaucher, Hurler syndrome), neuromuscular disorders (e.g., muscular dystrophies, myofibrillar myopathies), or rare presentation of genetic syndromes (e.g., Coffin-Lowry syndrome) account for a minority of the cases, the majority remaining idiopathic. Case Study We report the case of a 17-day-old male infant presenting cardiogenic shock following a restrictive dysfunction of the left ventricle. Postmortem investigations revealed coxsackievirus B4 myocarditis with histological lesions limited to the left heart. However, polymerase chain reaction (PCR) for coxsackievirus B4 was positive in the left as well as in the right ventricular samples. Conclusion In conclusion, coxsackievirus myocarditis is a cause of restrictive cardiomyopathy, and its diagnosis should involve PCR screening as a more sensitive technique. PMID- 28670501 TI - PTEN is a negative regulator of mitotic checkpoint complex during the cell cycle. AB - Nuclear PTEN plays an important role during mitosis. To understand the molecular basis by which PTEN mediates mitotic progression, we examined whether PTEN regulated the formation of mitotic checkpoint complex (MCC). We observed that arsenic trioxide, a mitotic inducer, stimulated nuclear translocation of PTEN in a time-dependent manner. PTEN physically interacted with Cdc20 and Mad2, two important components of MCC. Arsenic treatment diminished the physical association of PTEN with BubR1 and Bub3 but not with Cdc20 and Mad2. Our further studies revealed that downregulation of PTEN via RNAi enhanced formation of MCC during the cell cycle. Moreover, PTEN silencing induced chromosomal instability. Given the crucial role of PTEN in suppressing tumor development, our study strongly suggests that PTEN also functions to maintain chromosomal stability, partly through suppressing unscheduled formation of MCC. PMID- 28670499 TI - Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment. AB - Transcription factors are regulatory proteins that either activate or repress the transcription of genes via binding to DNA regulatory sequences and regulating recruitment of transcriptional complexes. Lymphoid enhancer-binding factor 1 (LEF1), a member of the T-cell Factor (TCF)/LEF1 family of high-mobility group transcription factors, is a downstream mediator of the Wnt/beta-catenin signaling pathway, but can also modulate gene transcription independently. LEF1 is essential in stem cell maintenance and organ development, especially in its role in epithelial-mesenchymal transition (EMT) by activating the transcription of hallmark EMT effectors including N-Cadherin, Vimentin, and Snail. Aberrant expression of LEF1 is implicated in tumorigenesis and cancer cell proliferation, migration, and invasion. LEF1's activity in particular cancer cell types, such as chronic lymphocytic leukemia (CLL), Burkitt lymphoma (BL), acute lymphoblastic leukemia (ALL), oral squamous cell carcinoma (OSCC), and colorectal cancer (CRC), makes it a valuable biomarker in predicting patient prognosis. Additionally, due to aberrant LEF1 activity resulting in cancer progression, knockdown and inhibition treatments designed to target LEF1 have proven effective in alleviating cancer growth, migration, and invasion in CLL, CRC, glioblastoma multiforme (GBM), and renal cell carcinoma (RCC). In prostate cancer cells, LEF1 promotes androgen receptor expression and activity in an androgen-independent manner, ultimately increasing prostate cancer growth regardless of androgen ablation therapy. In this review, we review LEF1 regulation, its role in tumorigenesis in several cancer types, and its clinical value as a biomarker for predicting prognoses and as a target for treatment. PMID- 28670502 TI - Impact of Glaucoma and Dry Eye on Text-Based Searching. AB - PURPOSE: We determine if visual field loss from glaucoma and/or measures of dry eye severity are associated with difficulty searching, as judged by slower search times on a text-based search task. METHODS: Glaucoma patients with bilateral visual field (VF) loss, patients with clinically significant dry eye, and normally-sighted controls were enrolled from the Wilmer Eye Institute clinics. Subjects searched three Yellow Pages excerpts for a specific phone number, and search time was recorded. RESULTS: A total of 50 glaucoma subjects, 40 dry eye subjects, and 45 controls completed study procedures. On average, glaucoma patients exhibited 57% longer search times compared to controls (95% confidence interval [CI], 26%-96%, P < 0.001), and longer search times were noted among subjects with greater VF loss (P < 0.001), worse contrast sensitivity (P < 0.001), and worse visual acuity (P = 0.026). Dry eye subjects demonstrated similar search times compared to controls, though worse Ocular Surface Disease Index (OSDI) vision-related subscores were associated with longer search times (P < 0.01). Search times showed no association with OSDI symptom subscores (P = 0.20) or objective measures of dry eye (P > 0.08 for Schirmer's testing without anesthesia, corneal fluorescein staining, and tear film breakup time). CONCLUSIONS: Text-based visual search is slower for glaucoma patients with greater levels of VF loss and dry eye patients with greater self-reported visual difficulty, and these difficulties may contribute to decreased quality of life in these groups. TRANSLATIONAL RELEVANCE: Visual search is impaired in glaucoma and dry eye groups compared to controls, highlighting the need for compensatory strategies and tools to assist individuals in overcoming their deficiencies. PMID- 28670503 TI - Aware, motivated and striving for a 'safe tan': an exploratory mixed-method study of sun-protection during holidays. AB - Background: This article presents an exploratory study, aiming to explore the correspondence between knowledge, motivation and sun-protection practices during holidays. Methods: Seventeen participants aged 21-62 years old, recruited from community settings took part in individual face-to-face semi-structured interviews, completed sun sensitivity questions and an objective assessment of sunscreen use. Holidaymakers' knowledge about sun-safe messages, intentions and perceptions of barriers and facilitators for sun-protection were assessed. Qualitative data were analysed using thematic analysis and integrated with quantitative data, using a pragmatic theory-informed approach to synthesise the findings. Results: Participants were well informed about sun-safe messages, highly motivated to protect themselves from solar UV radiation (UVR) and they perceived themselves as well protected. However, they did not seem to use effective protective practices. Sunscreen was the preferred method of sun protection, but most participants used considerably less than the recommended amount and significantly overestimated the amount of time they could be safely exposed. Seeking shade was the least used method of sun-protection and covering up strategies were mostly implemented as a partial protection (i.e. hats or sunglasses). The desire to reach an optimal balance between getting a tan and using sun-protection to avoid sunburns was preeminent. Several additional barriers and facilitators for sun-protection were identified. Conclusions: Holidaymakers might have a false sense of security when it comes to sun-exposure. They are aware of the need to protect from solar UVR, but the motive for a safe tan, the overreliance on sunscreen, the overestimation of the safe sun-exposure time for their skin type and the insufficient application of sunscreen leaves holidaymakers motivated to protect their skin at significant risk of overexposure, sunburn and skin cancer. Public health messages need to address how to implement effective sun-safe strategies. PMID- 28670504 TI - Does Context Matter? A Multi-Method Assessment of Affect in Adolescent Depression Across Multiple Affective Interaction Contexts. AB - This study utilized a multi-method approach (self-reported affect, observed behavior, and psychophysiology) to investigate differences between clinically depressed and non-depressed adolescents across three different affective interaction contexts with their parents. 152 adolescents (52 males, 14-18 y.o.), and their parents, participated in a laboratory session in which they discussed positive and negative aspects of their relationship, and reminisced on positive and negative memories. We found that across contexts depressed adolescents exhibited higher negative affect and behaviors, lower positive behaviors, and greater autonomic and sympathetic activity. Context specific findings indicated that depressed adolescents 1) exhibited greater persistence of negative affect and dysphoric behavior across the sequence of tasks, whereas these phenomena declined amongst their non-depressed peers, 2) depressed adolescents had greater increases in aggressive behaviors during negative interactions, and 3) depressed adolescents had greater parasympathetic withdrawal during negative interactions, while this response characterized the non-depressed group during positive interactions. PMID- 28670505 TI - Understanding Suicide Risk within the Research Domain Criteria (RDoC) Framework: Insights, Challenges, and Future Research Considerations. AB - Suicide is a leading cause of death worldwide. Prior research has focused primarily on sociodemographic and psychiatric risk factors with little improvement in the prediction or prevention of suicidal behavior over time. The Research Domain Criteria (RDoC) may be an especially useful framework for advancing research in this area. This paper provides a brief and broad overview of research on suicidal behavior relating to each of the RDoC domains highlighting the RDoC construct(s) where research has focused, construct(s) where research is lacking, and suggestions for future research directions. We also discuss major challenges for suicide research within the RDoC framework, including the intersection of RDoC domains, interaction of domains with the environment, incorporation of developmental stage, integration of distal and proximal processes, and inclusion of suicide-specific constructs. We conclude by underscoring important considerations for future research aimed at using the RDoC framework to study suicidal behavior and other forms of psychopathology. PMID- 28670507 TI - Adaptive Clinical Trials: Overview of Early-Phase Designs and Challenges. AB - In this paper, we describe developments in adaptive design methodology and discuss implementation strategies and operational challenges in early phase adaptive clinical trials. The BATTLE trial - the first completed, biomarker based, Bayesian adaptive randomized study in lung cancer - is presented as a case study to illustrate main ideas and share learnings. PMID- 28670508 TI - A unified framework for developing effective hygiene procedures for hands, environmental surfaces and laundry in healthcare, domestic, food handling and other settings. AB - Hygiene procedures for hands, surfaces and fabrics are central to preventing spread of infection in settings including healthcare, food production, catering, agriculture, public settings, and home and everyday life. They are used in situations including hand hygiene, clinical procedures, decontamination of environmental surfaces, respiratory hygiene, food handling, laundry hygiene, toilet hygiene and so on. Although the principles are common to all, approaches currently used in different settings are inconsistent. A concern is the use of inconsistent terminology which is misleading, especially to people we need to communicate with such as the public or cleaning professionals. This paper reviews the data on current approaches, alongside new insights to developing hygiene procedures. Using this data, we propose a more scientifically-grounded framework for developing procedures that maximize protection against infection, based on consistent principles and terminology, and applicable across all settings. A key feature is use of test models which assess the state of surfaces after treatment rather than product performance alone. This allows procedures that rely on removal of microbes to be compared with those employing chemical or thermal inactivation. This makes it possible to ensure that a consistent "safety target level" is achieved regardless of the type of procedure used, and allows us deliver maximum health benefit whilst ensuring prudent usage of antimicrobial agents, detergents, water and energy. PMID- 28670506 TI - Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy. AB - INTRODUCTION: Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. AREAS COVERED: In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. EXPERT OPINION: For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation. PMID- 28670509 TI - Detection of Lysyl Oxidase-Like 2 (LOXL2), a Biomarker of Metastasis from Breast Cancers Using Human Blood Samples. AB - Metastasis accounts for 90% of the mortality associated with breast cancer. Upregulated expression of members of the lysyl oxidase (LOX) family of secreted copper amine oxidases catalyzes the crosslinking of collagens and elastin in the extracellular matrix. LOXs are linked to the development and metastatic progression of breast cancers. Accordingly, aberrant expression of LOX-like 2 (LOXL2) is observed in poorly differentiated, high-grade tumors and is predictive of diseases recurrence, and for decreased overall patient survival. Therefore, LOXL2 expression may serve as a biomarker for breast cancer. Mechanistically, hydrogen peroxide is produced as a byproduct of LOXL2 when using an appropriate substrate, lysine. We exploited this chemistry to generate a revolutionary gold based electrochemical biosensor capable of accurately detecting nanomolar quantities of LOXL2 in mouse blood, and in human blood samples. Two different sources of the blood samples obtained from breast cancer patients were used in this study indicating the applicability of detecting LOXL2 in breast cancers patients. Limited numbers of urine specimens from breast cancer patients were also tested. Collectively, all of these tests show the promise and potential of this biosensor for detecting LOXL2 as a surrogate biomarker of breast cancer. This work is described in WO 052962 A1 (2014). PMID- 28670510 TI - Fertility Preservation in Cancer Patients: In Vivo and In Vitro Options. AB - Oocyte, embryo and ovarian tissue cryopreservation are being increasingly proposed for fertility preservation among cancer patients undergoing therapy to enable them to have babies after the cancer is cured. Embryo cryopreservation is not appropriate for single girls without any sperm partner and also because oocyte retrieval is an extended procedure, it is impossible in cases requiring immediate cancer cure. Thus ovarian tissue cryopreservation has been suggested for fertility preservation especial in cancer patients. The main goal of ovarian cryopreservation is re-implanting the tissue into the body to restore fertility and the hormonal cycle. Different cryopreservation protocols have been examined and established for vitrification of biological samples. We have used Cryopin to plunge ovarian tissue into the liquid nitrogen and promising results have been observed. Ovarian tissue re-implantation after cancer cure has one problem- the possibility of recurrence of malignancy in the reimplanted tissue is high. Xenografting-implantation of the preserved tissue in another species- also has its drawbacks such as molecular signaling from the recipient. In vitro follicle culturing is a safer method to obtain mature oocytes for fertilization and the various studies that have been carried out in this area are reviewed in this paper. PMID- 28670511 TI - Radioactive Iodine Therapy and Glucose Tolerance. AB - Radioactive iodine therapy is commonly used as an adjuvant therapy in follicular and papillary thyroid carcinoma (PTC) and in the treatment of Graves' disease (GD). The basis of this therapy is the accumulation of radioactive iodine by the sodium-iodide symporter (NIS) in the thyroid gland. Expression of NIS by extrathyroidal tissues such as islets of pancreas has been reported. Radioactive iodine uptake by pancreatic beta-cells can potentially damage these cells. In this study, we discuss the possible associations between radioactive iodine and glucose intolerance. Overall, radioactive iodine uptake by the pancreas may damage beta-cells and predispose patients to glucose intolerance or type 2 diabetes, particularly in patients exposed to radioactive iodine therapy following total thyroidectomy. Further studies are needed to clarify and confirm this association. PMID- 28670512 TI - Signaling Molecules Governing Pluripotency and Early Lineage Commitments in Human Pluripotent Stem Cells. AB - Signaling in pluripotent stem cells is a complex and dynamic process involving multiple mediators, finely tuned to balancing pluripotency and differentiation states. Characterizing and modifying the necessary signaling pathways to attain desired cell types is required for stem-cell applications in various fields of regenerative medicine. These signals may help enhance the differentiation potential of pluripotent cells towards each of the embryonic lineages and enable us to achieve pure in vitro cultures of various cell types. This review provides a timely synthesis of recent advances into how maintenance of pluripotency in hPSCs is regulated by extrinsic cues, such as the fibroblast growth factor (FGF) and ACTIVIN signaling pathways, their interplay with other signaling pathways, namely, wingless- type MMTV integration site family (WNT) and mammalian target of rapamycin (mTOR), and the pathways governing the determination of multiple lineages. PMID- 28670514 TI - Delayed Liver Regeneration after Partial Hepatectomy in Aged Nos2 Knockout Mice. AB - OBJECTIVE: Patients over 60 years of age have higher mortality and morbidity after major liver resections. Nitric oxide (NO) derived from the catalytic activity of Nos2 plays a beneficial role in liver regeneration (LR) after partial hepatectomy (PH). In this experiment, we evaluated the effect of Nos2 knockout (KO) on LR in aged mice after PH. MATERIALS AND METHODS: In this experimental study, 52 two-year-old Nos2 KO and 46 the same age wild-type (WT) C57BL/6J mice were subjected to 2/3 PH. Liver tissues were collected at 11 time points after PH. Mice survival ratio and liver coefficient (liver-weight/ body-weight) was calculated. Transcript and protein levels were estimated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. RESULTS: The aged Nos2 KO mice had lower survival ratio (P=0.039) and liver coefficient (P=0.002) at the termination phase. Nos2 transcript level was obviously increased after PH in WT mice and undetected in the Nos2 KO mice. During LR, the expression at the transcript level of Cyclin D1, Cyclin A2 and Cyclin B1 and protein expression level of proliferation marker Ki67 and proliferation-associated transcription factors JNK1, NF-kB and STAT3 were decreased or delayed. The expression of pro-apoptotic proteins, CASPASE3, CASPASE9 and BAX, was increased in the Nos2 KO mice. CONCLUSION: Decreased survival ratio and impaired LR in aged Nos2 KO mice is probably due to decreased liver cell proliferation and increased liver cell apoptosis. PMID- 28670515 TI - Crab Shell Extract Induces Prostate Cancer Cell Line (LNcap) Apoptosis and Decreases Nitric Oxide Secretion. AB - OBJECTIVE: Prostate cancer is the second most common cancer worldwide. Chemotherapeutic agents have been shown to have adverse side-effects, and natural compounds have been recommended for cancer treatment, nowadays. Crab shell has been shown to have cancer preventative and suppressive effects in vivo and in vitro. The aim of present study was to investigate the effect of crab shell extract on prostate cancer cell line (LNcap) in vitro. MATERIALS AND METHODS: In this in vitro experimental study, LNcap cells were treated with different concentrations (0, 100, 200, 400, 800 and 1000 ug/ml) of crab shell hydroalcoholic extract in three different culture periods (24, 48 and 72 hours). LNcap viability was evaluated by trypan blue staining and MTT assay. Cell apoptosis and nitric oxide (NO) secretion were determined by TUNEL and Griess assays, respectively. Data were analyzed by one-way ANOVA test and P<0.05 was considered significant. RESULTS: LNcap viability was decreased dose- and time dependently. Thus 400, 800, and 1000 ug/ml doses showed significant differences compared to control group (P<0.001). Dose-dependent increase in the apoptotic index was also observed in 800 and 1000 ug/ ml concentrations (P<0.001). Nitric oxide secretion of LNcap cell was decreased time- and dose-dependently, while it was significant for 1000 ug/ml (P<0.05). CONCLUSION: Crab shell extract showed anti-prostate cancer effect, by inducing cell apop- tosis and decreasing NO production. PMID- 28670513 TI - In Vitro Generated Hepatocyte-Like Cells: A Novel Tool in Regenerative Medicine and Drug Discovery. AB - Hepatocyte-like cells (HLCs) are generated from either various human pluripotent stem cells (hPSCs) including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), or direct cell conversion, mesenchymal stem cells as well as other stem cells like gestational tissues. They provide potential cell sources for biomedical applications. Liver transplantation is the gold standard treatment for the patients with end stage liver disease, but there are many obstacles limiting this process, like insufficient number of donated healthy livers. Meanwhile, the number of patients receiving a liver organ transplant for a better life is increasing. In this regard, HLCs may provide an adequate cell source to overcome these shortages. New molecular engineering approaches such as CRISPR/ Cas system applying in iPSCs technology provide the basic principles of gene correction for monogenic inherited metabolic liver diseases, as another application of HLCs. It has been shown that HLCs could replace primary human hepatocytes in drug discovery and hepatotoxicity tests. However, generation of fully functional HLCs is still a big challenge; several research groups have been trying to improve current differentiation protocols to achieve better HLCs according to morphology and function of cells. Large-scale generation of functional HLCs in bioreactors could make a new opportunity in producing enough hepatocytes for treating end-stage liver patients as well as other biomedical applications such as drug studies. In this review, regarding the biomedical value of HLCs, we focus on the current and efficient approaches for generating hepatocyte-like cells in vitro and discuss about their applications in regenerative medicine and drug discovery. PMID- 28670516 TI - Generation of Mouse Spermatogonial Stem-Cell-Colonies in A Non-Adherent Culture. AB - OBJECTIVE: The properties of self-renewal and division in spermatogonial stem cells (SSCs) support spermatogenesis. There is a number of reported methods for in vitro SSC culture systems. The development of a culture system that effectively supports isolation and selfrenewal of germline stem cells (GSCs) is of tremendous benefit for clinical trials, experimental research, and as potential treatment for male infertility. The current study aims to consider the cultivation and behavior of GSCs in a non-adherent culture system. MATERIALS AND METHODS: In this experimental study, we cultured testicular cells from neonatal mice in agarose coated plates in the presence of Dulbecco's modified Eagle's medium (DMEM) medium (CTRL group), 10% fetal bovine serum (FBS)+DMEM (10% group), and growth factor (G group) that contained 2% FBS, glial cell-derived neurotrophic factor (GDNF), epidermal growth factor (EGF), and fibroblast growth factor (FGF). Mouse spermatogonial stem-like colonies were isolated approximately 3 weeks after digestion of the testis tissue. After passages 2-3, the identity of the mouse spermatogonial stem-like cells was confirmed by immunocytochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and flow cytometry against the germ cell markers alpha6, beta1, c-Kit, Thy-1, c-Ret, Plzf, and Oct4. The statistical significance between mean values in different groups was determined by one-way analysis of variance (ANOVA). RESULTS: We observed spermatogonial stem-like colonies in the G and 10% groups, but not the CTRL group. Immunocytochemistry, flow cytometry, and RT-PCR confirmed expressions of germ cell markers in these cells. In the spermatogonial stem-like cells, we observed a significant expression (P<0.05) of germ cell markers in the G and 10% groups versus the testis cells (T). Their proliferative and apoptotic activities were examined by Ki67 and PI/annexin V-FITC. Alkaline phosphatase assay showed that mouse spermato- gonial stem-like colonies were partially positive. CONCLUSION: A non-adherent culture system could provide a favorable method for in vitro short-term culture of spermatogonial stem-like cell colonies. PMID- 28670517 TI - Comparative Proteomic Analysis of Tumor Mesenchymal-Like Stem Cells Derived from High Grade versus Low Grade Gliomas. AB - OBJECTIVE: Gliomas are the most common primary brain tumors, and have been ranked as the fourth leading cause of cancer death. Tumor mesenchymal-like stem cells (tMSCs) contribute to the aggressive behavior of glial tumors by providing a favorable microenvironment for the malignant cells. The aim of our study was to identify differential proteome of tMSCs derived from low vs. high grade glioma tumors. MATERIALS AND METHODS: Patients with newly diagnosed low and high grade gliomas were included in this case control study. tMSCs were isolated from tumors using enzymatic digestion validated by flow cytometer analysis after sub culturing. Differential proteomic analysis of tMSCs derived from low and high grade tumors was performed by two-dimensional gel electrophoresis and mass spectrometry. Protein spots with more than two fold differences and P values below 0.05 were considered as differentially expressed ones. RESULTS: In tMSCs isolated from low and high grade gliomas, different isoforms of mesenchymal related proteins vimentin and transgelin were differentially expressed. Overexpressed proteins in tMSCs isolated from low grade gliomas were mitochondrial manganese-containing superoxide dismutase (Mn-SOD), 40S ribosomal protein SA, and GTP-binding nuclear protein, while in tMSCs isolated from high grade gliomas, cathepsin B, endoplasmin, ezrin, peroxiredoxin1, and pyruvate kinase (PK) were found to be significantly overexpressed. CONCLUSION: For the first time, we analyzed the differential proteomic profiles of tMSCs isolated from glioma tumors with different grades. It was found that molecules related to mesenchymal cells (vimentin and transglin), in addition to those related to tumor aggressiveness with potential secretory behavior (e.g. cathepsin B) were among differentially expressed proteins. PMID- 28670518 TI - Hair Follicle Generation by Injections of Adult Human Follicular Epithelial and Dermal Papilla Cells into Nude Mice. AB - OBJECTIVE: Dermal papilla and hair epithelial stem cells regulate hair formation and the growth cycle. Damage to or loss of these cells can cause hair loss. Although several studies claim to reconstitute hairs using rodent cells in an animal model, additional research is needed to develop a stable human hair follicle reconstitution protocol. In this study, we have evaluated hair induction by injecting adult cultured human dermal papilla cells and a mixture of hair epithelial and dermal papilla cells in a mouse model. MATERIALS AND METHODS: In this experimental study, discarded human scalp skins were used to obtain dermal papilla and hair epithelial cells. After separation, cells were cultured and assessed for their characteristics. We randomly allocated 15 C57BL/6 nude mice into three groups that received injections in their dorsal skin. The first group received cultured dermal papilla cells, the second group received a mixture of cultured epithelial and dermal papilla cells, and the third group (control) received a placebo [phosphate-buffered saline (PBS-)]. RESULTS: Histopathologic examination of the injection sites showed evidence of hair growth in samples that received cells compared with the control group. However, the group that received epithelial and dermal papilla cells had visible evidence of hair growth. PKH tracing confirmed the presence of transplanted cells in the new hair. CONCLUSION: Our data showed that injection of a combination of adult human cultured dermal papilla and epithelial cells could induce hair growth in nude mice. This study emphasized that the combination of human adult cultured dermal papilla and epithelial cells could induce new hair in nude mice. PMID- 28670519 TI - Synthesis and Characterization of PMBN as A Biocompatible Nanopolymer for Bio Applications. AB - OBJECTIVE: Poly [2-methacryloyloxyethyl phosphoryl choline (MPC)-co-n-buthyl methacrylate (BMA)-co-p-nitrophenyl-oxycrabonyl poly ethylene glycol-methacrylate (ME- ONP)] (PMBN), a biocompatible terpolymer, is a unique polymer with applications that range from drug delivery systems (DDS) to scaffolds and biomedical devices. In this research, we have prepared a monomer of p-nitrophenyl oxycarbonyl poly (ethylene glycol) methacrylate (MEONP) to synthesize this polymer. Next, we designed and prepared a smart, water soluble, amphiphilic PMBN polymer composed of MPC, BMA, and MEONP. MATERIALS AND METHODS: In this experimental study, we dissolved MPC (4 mmol, 40% mole fraction), BMA (5 mmol, 50% mole fraction), and MEONP (1 mmol, 10% mole fraction) in 20 ml of dry ethanol in two necked flasks equipped with inlet-outlet gas. The structural characteristics of the synthesized monomer and polymer were determined by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (H NMR), dynamic light scattering (DLS), gel permeation chromatography (GPC), scanning electron microscope (SEM), and transmission electron microscope (TEM) analyses for the first time. We treated the polymer with two different cell lines to determine its biocompatibility. RESULTS: FT-IR and H-NMR analyses confirmed the synthesis of the polymer. The size of polymer was approximately 40 nm with a molecular weight (MW) of 52 kDa, which would be excellent for a nano carrier. Microscopic analyses showed that the polymer was rodshaped. This polymer had no toxicity for individual cells. CONCLUSION: We report here, for the first time, the full properties of the PMBN polymer. The approximately 40 nm size with an acceptable zeta potential range of -8.47, PDI of 0.1, and rod-shaped structure indicated adequate parameters of a nanopolymer for nano bioapplications. We used this polymer to design a new smart nano carrier to treat leukemia stem cells based on a target DDS as a type of bio-application. PMID- 28670520 TI - Analysis of Transforming Growth Factor- beta1 Expression in Resorptive Lacunae following Orthodontic Tooth Movement in An Animal Model. AB - OBJECTIVE: Root resorption is a complication of orthodontic treatment and till date, there is a dearth of information regarding this issue. The aim of this study was to determine whether the expression of transforming growth factor-beta1 (TGF-beta1, an inflammatory cytokine) is related to orthodontic force. Moreover, if associated, the expression level may be helpful in differential diagnosis, control and ultimate treatment of the disease. MATERIALS AND METHODS: In this experimental study, a total of 24 eight-week-old male Wistar rats were selected randomly. On day 0, an orthodontic appliance, which consisted of a closed coil spring, was ligated to the upper right first molar and incisor. The upper left first molar in these animals was not placed under orthodontic force, thus serving as the control group. On day 21, after anesthesia, the animals were sacrificed. The rats were then divided into two equal groups where the first group was subjected to histological evaluation and the second group to reverse transcriptase-polymerase chain reaction (RT-PCR). Orthodontic tooth movement was measured in both groups to determine the influence of the applied force. RESULTS: Statistical analysis of data showed a significant root resorption between the experimental group and control group (P<0.05), however, there was no significant difference in the expression level of the inflammatory cytokine, TGF-beta1. CONCLUSION: Based on the findings of this study, we suggest that there is a direct relationship between orthodontic force and orthodontic induced inflammatory root resorption. In addition, no relationship is likely to exist between root resorption and TGF-beta1 expression in the resorptive lacunae. PMID- 28670521 TI - Methoxyamine Enhances 5-Fluorouracil-Induced Radiosensitization in Colon Cancer Cell Line HT29. AB - OBJECTIVE: This study intended to observe the effects of methoxyamine (Mx) on cytotoxic effects and DNA damage caused by 5-Fluorouracil (5-FU) in combination with gamma radiation in a human colon cancer cell line, HT29. MATERIALS AND METHODS: In this experimental study, HT29 cells were cultured as a monolayer and treated with different concentrations of 5-FU along with 1 mM Mx for 24 hours. Next, the cells were irradiated with 2 Gy gamma radiation. After the treatments, we assessed for DNA damage, cytotoxicity, and viability by alkaline comet, clonogenic survival, and trypan blue dye exclusion assays. RESULTS: Cytotoxicity and DNA damage increased with increasing 5-FU concentration. The 1 mM Mx concentration had no significant effect on cytotoxicity and DNA damage from 5-FU; however, it increased the cytotoxic and genotoxic effects of different concentrations of 5-FU when used in combination with 2 Gy gamma radiation. CONCLUSION: Mx combined with 5-FU enhanced the radiosensitivity of colon cancer cells. PMID- 28670522 TI - Co-Administration of Vitamin E and Testosterone Attenuates The Atrazine-Induced Toxic Effects on Sperm Quality and Testes in Rats. AB - OBJECTIVE: Atrazine (ATZ) as a widely used herbicide is considered as a potent endocrine disrupter which adversely affects reproductive systems in both genders. This study aimed to assess the effects of testosterone (T)- and vitamin E (VitE)- alone and their coadministration on testicular function and sperm parameters after exposure to ATZ in rats. MATERIALS AND METHODS: In this experimental study, the rats (n=30) are assigned into the following 5 groups: control-sham group (n=6) receiving corn oil, ATZ group (n=6) receiving 200 mg/kg ATZ alone, ATZ+VitE group (n=6) receiving 150 mg/kg ATZ+VitE, ATZ+T group (n=6) receiving 400 ug/kg ATZ+T, and ATZ+VitE+T group (n=6) receiving ATZ+VitE+T for 48 consecutive days. Total antioxidant capacity (TAC), total thiol molecules (TTM), and malondialdehyde (MDA) were analyzed. Serum levels of T, luteinizing hormone (LH), and inhibin-B (IN-B) were also determined. Histological examination and sperm analysis were performed. The data were analyzed using Graph-Pad Prism software version 2.01. RESULTS: Co-administration of VitE and T significantly (P<0.05) increased ATZ-decreased TAC and TTM levels and reduced ATZ-increased MDA content. T and VitE significantly (P<0.05) increased serum levels of ATZ-reduced T (1.94 +/- 0.96), IN-B (122.10 +/- 24.33) and LH (0.40 +/- 0.10). The T+VitE animals showed a reduction in apoptotic cells and an increase in Leydig cells steroidogenesis. Co-administration of T and VitE significantly (P<0.05) reduced the ATZ-induced DNA disintegrity and chromatin de-condensation. VitE and T protected germinal cells RNA and protein contents against ATZ-induced damages. CONCLUSION: T and VitE in simultaneous form of administration were able to normalize the ATZ-induced derangements through promoting antioxidant capacity and endocrine function. PMID- 28670523 TI - Evaluation of The Protective Effect of Hydro-Alcoholic Extract of Raspberry Fruit on Aquaporin1 Expression in Rats Kidney Treated by Methotrexate. AB - OBJECTIVE: Methotrexate (MTX) is an antimetabolite drug commonly prescribed for the various cancers and autoimmune diseases. Despite its considerable therapeutic effects, nephrotoxicity is the most important side-effect of treatment with MTX. Aquaporin1 (AQP1) is a water channel proteins which is present in mammalian kidney. Raspberry fruit with antioxidant properties is able to protect biological systems from the harmful effects of free radicals. The purpose of this study was to investigate the effect of raspberry extract on expression of AQP1 and the MTX induced nephrotoxicity in rats. MATERIALS AND METHODS: In this experimental study, 60 adult male Wistar rats were divided into nine groups including control, sham, MTX treated group [single dose of 20 mg/kg of body weight (BW) MTX at the third day], raspberry treated groups [intraperitoneal (I.P) injection of 100, 200, 400 mg/kg of BW raspberry extract for ten consecutive days], MTX and raspberry treated groups. At day 11, rats were sacrificed via chloroform inhalation and kidney tissues were fixed in formalin solution for histological and immunohistochemistry analysis. The serological assays for urea, creatinine, uric acid and interleukin-6 (IL-6) levels were also performed. RESULTS: MTX elevated serum level of the urea, creatinine, uric acid, IL-6, renal tissue damage and decreased the AQP1 expression level. Raspberry fruit extract improved the kidney function and reduced side effects of MTX in treated rats. Expression of AQP1, in a dose dependent manner was also ameliorated, as compared to control group. CONCLUSION: According to the findings of this study, it can be concluded that biological activity of compounds presented in raspberry fruit extract especially anthocyanins may have chemo-protective effect on kidney function and AQP1 expression in rats treated by MTX. PMID- 28670524 TI - Attitudes of Infertile Couples, Fertility Clinic Staff and Researchers toward Personhood of The Human Embryo in Iran. AB - OBJECTIVE: After the introduction of assisted reproductive techniques, human embryos were officially introduced into laboratories and now thousands of them are cryopreserved in such settings. Embryonic stem cells and the future application of such cells in the treatment of disease opened the door to further research on human embryos. These developments raise many ethical issues, some of which have religious aspects. The main question is: what is the embryo? Should we consider it a human being? Thus, the purpose of this study was to investigate attitudes towards the personhood of the embryo. MATERIALS AND METHODS: In this cross sectional study, 203 infertile patients (n=406), 54 clinic staff and 49 embryo researchers, selected using convenience sampling at the Royan Institute, completed a questionnaire on personhood of human embryo. The questionnaire had been developed following qualitative research and had satisfied face and content validity tests. RESULTS: At the pre-implantation stage the majority of participants in all three groups considered the human embryo as "not a human being". Also, at the post-implantation stage of development, the majority of infertile couples and clinic staff considered the embryo as "not a human being" but, half the researchers (51%) considered the embryo in this stage as a "potential human". Half of the infertile couples considered the human fetus before ensoulment time (19th week of pregnancy according to the Shiite Islamic scholars) as "not-human being", while more than half of researchers (55.1%) considered it as a "potential human". CONCLUSION: Ensoulment time is a major and important border for personhood. Most infertile couples and clinic staff consider the human embryo as "not a human being" but majority of all study participants considered the human fetus to be a complete human after ensoulment time. PMID- 28670526 TI - Technosocial Competence in Diabetology. PMID- 28670525 TI - Melatonin Ameliorates The Production of COX-2, iNOS, and The Formation of 8-OHdG in Non-Targeted Lung Tissue after Pelvic Irradiation. AB - In this study, we evaluated the bystander effect of radiation on the regulation of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and 8 hydroxydeoxyguanosine (8-OHdG) in lung tissues of Sprague-Dawley rats with and without pre-administration of melatonin. A 2*2 cm2 area of the pelvis of male Sprague-Dawley rats with and without pre-administration of melatonin (100 mg/kg) by oral and intraperitoneal injection was irradiated with a 3 Gy dose of 1.25 MeV gamma-rays. Alterations in the levels of COX-2, iNOS, and 8-OHdG in the out-of field lung areas of the animals were detected by enzyme immunoassay. The bystander effect significantly increased COX-2, iNOS, and 8-OHdG levels in non targeted lung tissues (P<0.05). Melatonin ameliorated the bystander effect of radiation and significantly reduced the level of all examined biomarkers (P<0.05). The results indicated that the ameliorating effect of a pre intraperitoneal (IP) injection of melatonin was noticeably greater compared to oral pre-administration. Our findings revealed that the bystander effect of radiation could induce oxidative DNA damage and increase the levels of imperative COX-2 and iNOS in non-targeted lung tissues. Interestingly, melatonin could modulate the indirect destructive effect of radiation and reduce DNA damage in non-targeted cells. PMID- 28670527 TI - Thyroid Vigilance. PMID- 28670528 TI - Diabetes Care: Evolution of Philosophy. PMID- 28670529 TI - A Prospective Study on Role of Supplemental Oral Calcium and Vitamin D in Prevention of Postthyroidectomy Hypocalcemia. AB - BACKGROUND: Postoperative transient hypocalcemia is sequelae of total thyroidectomy (TT), which is observed in up to 50% of patients. Routine oral calcium and Vitamin D supplementation have been proposed to prevent symptomatic hypocalcemia preventing morbidity and facilitating early discharge. PATIENTS AND METHODS: A total of 208 patients with nontoxic benign thyroid disorders, undergoing TT, were serially randomized into four groups: Group A (no supplements were given), Group B (oral calcium - 2 g/day given), Group C (calcium and calcitriol - 1 mcg/day are given), and Group D (calcium, calcitriol, and cholecalciferol - 60,000 IU/day are given). Patients were monitored for clinical and biochemical hypocalcemia (serum calcium, [Sr. Ca] <8 mg/dl), along with serum intact parathormone (Sr. PTH) and magnesium 6 h after surgery and Sr. Ca every 24 h. Intravenous (IV) calcium infusion was started, if any of the above four groups exhibit frank hypocalcemia. Patients are followed up with Sr. Ca and Sr. PTH at 3 and 6 months. RESULTS: All groups were age and sex matched. Hypocalcemia was observed in 72/208 (34.61%) cases. Incidence of hypocalcemia was higher in Group A (57.69%) and Group B (50%) compared to Group C (15.38%) and Group D (15.38%). Hypocalcemia necessitating IV calcium occurred in 31/208 (14.90%) patients. IV calcium requirement exceeded in Group A (26.92%) and Group B (23.07%) compared to Group C (5.76%) and Group D (3.84%). There was no statistical difference in basal levels of serum Vitamin D, calcium, magnesium, intact PTH, and 6 h after surgery. Permanent hypoparathyroidism developed in five patients on follow-up. CONCLUSION: Routine postoperative supplementation of oral calcium and Vitamin D will help in the prevention of postthyroidectomy transient hypocalcemia significantly. Preoperative Vitamin D levels do not predict postoperative hypocalcemia. PMID- 28670530 TI - Myopathy in Patients Taking Atorvastatin: A Pilot Study. AB - AIM: This study aims to investigate the prevalence and risk factors of statin induced myopathy. SUBJECTS AND METHODS: A total of 200 patients aged >= 40 years and taking atorvastatin 10 mg/day or more for at least 2 weeks were recruited in the study. A detailed history of participants and anthropometry of study participants was recorded, and features of myopathy were explained. Biochemical investigations along with thyroid stimulating hormone (TSH) and Vitamin D were done in all patients. RESULTS: Mean age of study population was 54.81 +/- 9.10 years. Sixty-five percent (65.5%) of atorvastatin users had coronary heart disease, 62.5% were hypertensive, 38% had diabetes. Thirty-five percent (35.5%) patients were taking 10 mg/day atorvastatin, 45% were taking 20 mg/day, and 19.5% were taking 40 mg/day. The overall frequency of myopathy among statin users was 7.5% which was significantly higher with increasing dose of atorvastatin (1.4% in 10 mg/day group, 10% in 20 mg/day group, and 12.8% in 40 mg/day, P < 0.05). The frequency of atorvastatin-related myopathy was higher in females 8.65% compared to 6.25% in males. Serum TSH levels in patients with myopathy were 4.05 +/- 7.76 MUIU/ml while in those without myopathy were 3.13 +/- 2.88 MUIU/ml (P = 0.649). Serum 25-hydroxy Vitamin D levels were measured in 66 patients randomly. Mean levels in patients with myopathy were 15.98 +/- 12.94 ng/ml and without myopathy were 10.20 +/- 5.64 ng/ml (P = 0.285). CONCLUSION: The present study demonstrates that a significantly higher number of patients taking atorvastatin develop myopathy in real life clinical condition. The frequency of myopathy increases with increase in atorvastatin dose. PMID- 28670531 TI - High Prevalence of Serine Protease Inhibitor Kazal Type 1 Gene Variations Detected by Whole Gene Sequencing in Patients with Fibrocalculous Pancreatic Diabetes. AB - AIM OF STUDY: The aim is to study the prevalence and pattern of serine protease inhibitor Kazal type 1 (SPINK1) gene variations in patients with fibrocalculous pancreatic diabetes (FCPD) using whole gene sequencing. MATERIALS AND METHODS: A total of 56 consecutive patients of FCPD were recruited for the study. Diagnosis of FCPD was based on the presence of diabetes mellitus in patients having chronic pancreatitis with radiological evidence of ductal calcifications, in the absence of other known causes for pancreatitis. Ethylenediaminetetraacetic acid samples were collected from all patients, and complete gene sequencing was performed for SPINK1 gene using Sanger technique. RESULTS: Overall 35 patients (62.5%) were detected to have genetic alterations in SPINK1 gene. N34S polymorphism was seen in 23 participants (41.07%) out of which 3 were homozygous. N34S was seen to be in linkage disequilibrium with IVS1 - 37T>C (18/23) and IVS3-69insAAAA (19/23) polymorphisms. Seven patients (12.5%) had a 272 C>T 3'UTR polymorphism while one patient (1.8%) had a P55S polymorphism. Two patients (3.5%) had an IVS3 + 2T>C mutation which has been shown to be associated with loss of function of SPINK protein. Overall 48.2% of FCPD patients had genetic variations that were significant compared to the control population. There was no difference in anthropometric and biochemical parameters between those with or without SPINK1 gene variations. CONCLUSIONS: Variations in SPINK1 gene are frequently observed in FCPD. N34S polymorphism was the most common variation followed by intronic variations. Two patients had the pathogenic intronic IVS3 + 2T>C mutation. Whole gene sequencing of the SPINK1 gene enabled detection of an additional 7.1% of patients with significant SPINK1 gene variations as compared to targeted screening for the N34S variation. PMID- 28670532 TI - Are Predictive Equations for Estimating Resting Energy Expenditure Accurate in Asian Indian Male Weightlifters? AB - BACKGROUND: The accuracy of existing predictive equations to determine the resting energy expenditure (REE) of professional weightlifters remains scarcely studied. Our study aimed at assessing the REE of male Asian Indian weightlifters with indirect calorimetry and to compare the measured REE (mREE) with published equations. A new equation using potential anthropometric variables to predict REE was also evaluated. MATERIALS AND METHODS: REE was measured on 30 male professional weightlifters aged between 17 and 28 years using indirect calorimetry and compared with the eight formulas predicted by Harris-Benedicts, Mifflin-St. Jeor, FAO/WHO/UNU, ICMR, Cunninghams, Owen, Katch-McArdle, and Nelson. Pearson correlation coefficient, intraclass correlation coefficient, and multiple linear regression analysis were carried out to study the agreement between the different methods, association with anthropometric variables, and to formulate a new prediction equation for this population. RESULTS: Pearson correlation coefficients between mREE and the anthropometric variables showed positive significance with suprailiac skinfold thickness, lean body mass (LBM), waist circumference, hip circumference, bone mineral mass, and body mass. All eight predictive equations underestimated the REE of the weightlifters when compared with the mREE. The highest mean difference was 636 kcal/day (Owen, 1986) and the lowest difference was 375 kcal/day (Cunninghams, 1980). Multiple linear regression done stepwise showed that LBM was the only significant determinant of REE in this group of sportspersons. A new equation using LBM as the independent variable for calculating REE was computed. REE for weightlifters = -164.065 + 0.039 (LBM) (confidence interval -1122.984, 794.854]. This new equation reduced the mean difference with mREE by 2.36 + 369.15 kcal/day (standard error = 67.40). CONCLUSION: The significant finding of this study was that all the prediction equations underestimated the REE. The LBM was the sole determinant of REE in this population. In the absence of indirect calorimetry, the REE equation developed by us using LBM is a better predictor for calculating REE of professional male weightlifters of this region. PMID- 28670533 TI - Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity. AB - BACKGROUND: Androgen insensitivity syndrome (AIS) is a rare X-linked disorder due to mutations in the androgen receptor (AR) gene causing end-organ resistance to the androgenic hormone. SUBJECTS AND METHODS: Genetic studies were carried out in two families by karyotype and targeted exome sequencing of the AR gene. RESULTS: Two novel missense mutations were identified, p.L822P and p.P392S, in two families with complete androgen insensitivity (CAIS) and partial androgen insensitivity (PAIS), respectively. Both had 46, XY karyotype. The mother was a heterozygous carrier in PAIS and negative in CAIS. These two were novel mutations, reported for the first time, in the AR gene. In silico analysis predicted that both mutations were damaging. We reviewed the various reported Indian mutations in the AR gene. CONCLUSION: AR gene mutations cause a wide spectrum of disorders from CAIS to male infertility or primary amenorrhea. Early diagnosis is essential for gender assignment and further management, family counseling, and prenatal diagnosis. PMID- 28670534 TI - The Effect of Yoga and Peer Support Interventions on the Quality of Life of Women with Diabetes: Results of a Randomized Controlled Trial. AB - OBJECTIVE: This was an interventional study to understand the effect of two low cost interventions; yoga and peer support on the quality of life (QOL) of women with type 2 diabetes. METHODOLOGY: An open label parallel three-armed randomized control trial was conducted among 124 recruited women with diabetes for 3 months. Block randomization with a block length of six was carried out. In the yoga arm, sessions by an instructor, consisting of a group of postures coordinated with breathing were conducted for an hour, 2 days a week. In the peer support arm, each peer mentor after training visited 13-14 women with diabetes every week followed by a phone call. The meeting was about applying disease management plans in daily life. At the beginning and end of the study, QOL was assessed by the translated, validated World Health Organization QOL-BREF in four domains physical, psychological, social, and environmental domains. RESULTS: The majority (96%) of the study participants perceived the peer support and yoga intervention to be beneficial. Paired t-test revealed significant increases in the social and environmental domain in the peer group and in the environmental domain in the yoga group, though this disappeared in the between-group comparison perhaps due to poor glycemic control (hemoglobin A1c varied from 9.4 to 9.6) and the short duration of 3 months of the study. CONCLUSION: Peer support and yoga improved perceptions of QOL though its impact on scores was not significant due to a short period of study among women with poor glycemic control. PMID- 28670535 TI - Effect of Antithyroid Therapies on Bone and Body Composition: A Prospective, Randomized, Clinical Study Comparing Antithyroid Drugs with Radioiodine Therapy. AB - BACKGROUND: Thyrotoxicosis is associated with loss of body weight and bone mineral content (BMC). Antithyroid drugs (ATD) and radioiodine therapy (RIT) are the common options for the management of thyrotoxicosis. We evaluated the effect of ATD and RIT on BMC and body composition. MATERIALS AND METHODS: In this prospective study, we randomized 60 patients of thyrotoxicosis (20-50 years, treatment naive, males) to receive either ATD (Group 1) using carbimazole or RIT (Group 2). We excluded patients with significant ophthalmopathy and thyroid malignancy. The patients were followed serially for 1 year. Body composition was analyzed using the bioimpedance method and BMC by dual-energy X-ray absorptiometry technique. The data were analyzed using appropriate statistical measures. RESULTS: The patients had a mean age of 33 +/- 4.2 years and mean symptoms duration of 8.2 +/- 2.7 months before the diagnosis. A total of 51 patients had Graves' disease, and the remaining 9 had toxic multinodular goiter. BMC at lumbar spine and femoral neck improved with both the therapies similarly at the end of 1 year. The body weight, protein, and fat content also increased after 1 year of observation similar between the two groups. None of the observed parameters showed a difference with regard to the mode of ATD. CONCLUSION: ATD and RIT have comparable effects on the bone and body composition in the management of thyrotoxicosis. Further long-term studies are needed to confirm the observed findings. PMID- 28670536 TI - Osteoporosis in Otherwise Healthy Patients with Type 2 Diabetes: A Prospective Gender Based Comparative Study. AB - BACKGROUND AND OBJECTIVE: Type 2 diabetes mellitus (T2DM) may affect bone loss differentially in adult males and postmenopausal females. We evaluated the prevalence of osteoporosis in otherwise healthy adults with T2DM. MATERIALS AND METHODS: In a cross-sectional study, adults with T2DM, aged 50 years and above, were evaluated for bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) scan at spine and hip. T-score of <=-2.5 was defined as osteoporosis and score -2.49 to -1.0 as osteopenia at either site. Correlation of low BMD with demographic, clinical, and laboratory parameters including serum Vitamin D and serum testosterone (in males) was evaluated. RESULTS: In 200 patients, mean age was 64.5 +/- 7.0 years and age differed significantly in males and females (P < 0.0001). Osteoporosis was present in 35.5% adults with T2DM. Significantly greater proportion of females had osteoporosis (49.5% vs. 22.3%, P < 0.0001). Frequency of osteoporosis at spine (33.5%) was higher than the same at hip (13.5%). Compared to males, significantly greater proportion of females had osteoporosis and osteopenia at both spine (P < 0.0001) and hip (P < 0.0001). Among all parameters assessed, a significant positive correlation of T-score at spine and hip was seen with body mass index in both males (r = 0.287, P = 0.003 at spine and r = 0.421, P < 0.0001 at hip) and females (r = 0.291, P = 0.004 at spine and r = 0.280, P = 0.010 at hip). There was no association of Vitamin D deficiency (45.5% patients) with either T-score and presence of osteoporosis either at spine (P = 0.388 and P = 0.177) or hip (P = 0.431 and P = 0.593). CONCLUSION: Prevalence of osteoporosis in otherwise healthy T2DM was 35.5% with greater prevalence in females than males. Body mass but not Vitamin D or testosterone has an important role in the determination of bone loss in T2DM. PMID- 28670537 TI - The Serological and Biochemical Markers of Adrenal Cortex and Endocrine Pancreas Dysfunction in Patients with Hashimoto's Thyroiditis: A Hospital-based Pilot Study. AB - BACKGROUND: The prevalence of both islet cell and adrenal autoimmunity among Asian Indian hypothyroidism patients with Hashimoto's thyroiditis (HT) is lacking in literature. OBJECTIVES: The objective of this study was to assess the proportion of Addison's disease (AD) and type 1 diabetes mellitus (T1DM) in patients with HT. MATERIALS AND METHODS: The patients with hypothyroidism due to HT were included in this study over 2 years. Primary hypothyroidism was defined as high serum thyroid-stimulating hormone (>5.5 mIU/L) with or without low thyroxine level. HT was defined by the presence of high thyroid peroxidase antibody (Ab) titer (>35 IU/ml). Autoimmune markers of AD and T1DM, i.e., adrenal (21-hydroxylase) Ab, glutamic acid decarboxylase (GAD) Ab, and insulinoma associated antigen-2 (IA-2) Ab were measured among them. In addition, 250 MUg adrenocorticotropic hormone (ACTH) stimulation test was done in patients with adrenal Ab. Similarly, beta cell function was assessed in patients with GAD and/or IA-2 Ab. RESULTS: Out of 150 patients screened, 136 patients were included in this study. Seven patients had adrenal Ab while 15 had IA-2 Ab. The GAD Ab was not present in any of the patients in the study. ACTH stimulation test was done in four of seven patients with adrenal Ab and beta cell function was assessed in 8 of 15 patients with islet cell Ab. All patients with adrenal Ab had normal adrenal function and 1 out of 15 with IA-2 Ab developed diabetes mellitus during follow-up. CONCLUSIONS: Either adrenal or islet cell Ab was found in 16% Asian Indian hypothyroidism patients with HT. PMID- 28670538 TI - Menstrual Cycle Abnormalities in Patients with Prolactinoma and Drug-induced Hyperprolactinemia. AB - BACKGROUND AND OBJECTIVE: Hyperprolactinemia affects the reproductive endocrine axis; however, the degree of dysfunction may vary depending on etiology. The aim of the present study was to analyze menstrual cyclicity in patients with prolactinoma and drug-induced hyperprolactinemia (DIH). METHODOLOGY: Patients with prolactinoma and DIH were retrospectively analyzed for menstrual cyclicity at presentation and response to therapy. RESULTS: Of 128 females with hyperprolactinemia, 58 had prolactinoma (41 microadenoma and 17 macroadenoma) and 39 had DIH. Patients with prolactinoma had higher prolactin levels and increased frequency of oligomenorrhea (77.5% vs. 46%) as compared to DIH. Patients with macroprolactinoma had more severe menstrual disturbances compared to microprolactinoma. A higher percentage of patients with microprolactinoma and DIH achieved regular menstrual cycles compared to macroprolactinoma postcabergoline treatment (85% and 90% vs. 65%). There was no correlation between time to regularization of menstrual cycles with age, menstrual cycle length, duration of menstrual irregularity, or initial prolactin level in patients with prolactinoma. Linear regression analysis showed a significant association between time to regularization of menstrual cycles with time to normalization of prolactin levels (P = 0.001). CONCLUSION: There is a prompt restoration of menstrual cycles in patients with microprolactinoma and DIH. Patients with macroprolactinoma have more severe menstrual disturbances and lesser frequency of cycle restoration postcabergoline treatment compared to microprolactinoma and DIH. PMID- 28670539 TI - Increased Levels of Serum Interleukin-17 in Patients with Hashimoto's Thyroiditis. AB - BACKGROUND: CD4+ T-cells play important roles in the pathogenesis of Hashimoto's thyroiditis (HT). However, there is limited data about characteristics and function of the newly interleukin (IL)-17-producing T-helper cells in this common autoimmune thyroid disorder. AIM: The purpose of this study was to assess the levels of T-helper 17-related cytokines in sera of patients with HT. MATERIALS AND METHODS: Cytokine concentrations were measured in 48 patients with overt (n = 23) and subclinical hypothyroidism (25) and 35 healthy controls using enzyme linked immunosorbent assay. RESULTS: The serum levels of IL-17 were significantly higher in patients than controls (P = 0.001) while no differences were observed with regard to levels of IL-22 and IL-23 between patients and normal controls. CONCLUSION: These results suggest that IL-17 could play some role in the pathogenesis of HT. PMID- 28670540 TI - Effect of Vitamin D Supplementation on Vascular Functions and Oxidative Stress in Type 2 Diabetic Patients with Vitamin D Deficiency. AB - BACKGROUND: Vitamin D levels are reported to have an inverse liaison with the risk of cardiovascular diseases. Hence, we aimed to evaluate the effect of Vitamin D supplementation on changes in vascular functions and oxidative stress in type 2 diabetic patients with Vitamin D deficiency. SUBJECTS AND METHODS: One hundred and three patients with type 2 diabetes attending endocrinology outpatients department in a tertiary care hospital were screened for Vitamin D deficiency. Patients with serum 25-hydroxy Vitamin D levels <20 ng/ml were considered as deficient and were administered 60,000 IU of oral Vitamin D3 weekly for 8 weeks. In these patients, parameters of vascular functions (carotid-femoral pulse wave velocity, brachial-ankle pulse wave velocity, and arterial stiffness index) and oxidative stress (serum malondialdehyde levels and total antioxidant status) were measured at baseline and after 8 weeks of oral Vitamin D supplementation. RESULTS: Among 103 patients with type 2 diabetes, 75 (72.82%) were found to have Vitamin D deficiency. Amidst these patients, carotid-femoral pulse wave velocity (991.6 +/- 161.82 vs. 899.29 +/- 151.86, P < 0.001), right brachial-ankle pulse wave velocity (1446.16 +/- 204.33 vs. 1350.8 +/- 178.39, P < 0.001), and left brachial-ankle pulse wave velocity (1493.81 +/- 219.65 vs. 1367.61 +/- 220.64, P < 0.001) showed a significant reduction following Vitamin D supplementation. Further, these patients were found to have significant fall in serum malondialdehyde levels with rise in total antioxidant status ensuing Vitamin D supplementation. CONCLUSION: The present study shows that oral Vitamin D supplementation of 60,000 IU/week for 8 weeks significantly improves vascular functions and reduces oxidative stress in type 2 diabetic patients with Vitamin D deficiency. PMID- 28670541 TI - Occurrence and Predictors of Depression and Poor Quality of Life among Patients with Type-2 Diabetes: A Northern India Perspective. AB - BACKGROUND AND AIMS: Globally, depression has been linked to Type-2 diabetes mellitus (T2DM). However, similar data from India are scant. This study evaluated the occurrence and predictors of depression and health-related quality of life (QOL) in patients with T2DM as compared to healthy controls. MATERIALS AND METHODS: One hundred adults with T2DM without prior diagnosis of depression and 100 matched controls were evaluated. Depression was assessed using Patient Health Questionnaire-9. World Health Organization QOL Brief (WHO-QOL-BREF) was used to assess QOL. Demography, anthropometry, biochemical parameters of diabetes control, and microvascular and macrovascular complications in patients were recorded. RESULTS: Depression was significantly more common in T2DM (63%) as compared to controls (48%) (odds ratio [OR] - 1.84 [1.04, 3.24]; P = 0.03). In T2DM, depression was higher in patients with disease duration >5 years (OR = 2.66; P = 0.02), glycated hemoglobin >7% (OR = 3.45; P = 0.004), retinopathy (OR 3.56; P = 0.03), and nephropathy (OR - 4.11; P = 0.07). Occurrence of depression was significantly higher among the patients with macrovascular complications, namely, coronary artery disease (17.4%; P = 0.000006), cerebrovascular disease (14.2%; P = 0.0006), and peripheral vascular disease (7.9%; P = 0.05). Insulin users had higher depression as compared to patients using only oral antihyperglycemic medications (P = 0.034). Patient with depression had significantly low QOL. The WHO-QOL for all the domains was significantly lower in T2DM with microvascular and macrovascular complications, as compared to those without. CONCLUSION: Indian T2DM had higher prevalence of depression and lower QOL as compared to controls, which was associated with poor glycemic control and higher end-organ damage. Public health measures are required to create more awareness for managing depression in diabetes. PMID- 28670542 TI - A Study of the Patients Suffering from Tuberculosis and Tuberculosis-diabetes Comorbidity in Revised National Tuberculosis Control Program Centers of Northern Madhya Pradesh, India. AB - BACKGROUND: Diabetes mellitus (DM) is recognized as an important risk factor to tuberculosis (TB). India has high TB burden, along with rising DM prevalence. AIM: This study was conducted to document the coexistence of DM and TB in persons with established TB under the Revised National Tuberculosis Control Program. TYPE OF STUDY: This was a cross-sectional, descriptive observational study conducted at selected Directly Observed Therapy center in Gwalior North Central India. MATERIALS AND METHODS: A total of 550 patients with confirmed diagnosis of TB and on treatment were recruited. The study participants were screened for DM and diagnoses were made on the basis of the World Health Organization criteria. Clinical parameters were compared between persons with DM and those without DM. RESULTS: DM/TB co-morbidity was noted in 85 individuals and these made up 15.4% of the study population. The mean age was higher in DM patients with TB (43.4 +/- 15.4 vs. 33.1 +/- 16.2 years, P = 0.000); the mean duration of symptoms of TB with DM was more (124 +/- 16.4 vs. 107.49 +/- 10.3 days). Multinomial logistic regression analysis showed that increasing age, positive family history of diabetes, sedentary occupation, and presence of pulmonary TB were significantly associated with diabetes among TB patients. CONCLUSIONS: Diabetes is an important co-morbid feature to be sought in patients with TB. This study re-echo the need to raise awareness on screening for DM in persons with TB. PMID- 28670543 TI - Prevalence of Thyroid Peroxidase Antibody and Pregnancy Outcome in Euthyroid Autoimmune Positive Pregnant Women from a Tertiary Care Center in Haryana. AB - OBJECTIVE: To study the prevalence of thyroid peroxidase autoantibody in euthyroid pregnant women and to evaluate the association between thyroid peroxidase autoantibody and pregnancy outcomes. MATERIALS AND METHODS: One thousand thirty consecutive pregnant women attending the antenatal clinic over a period of 1 year and were carrying a healthy singleton uncomplicated intrauterine pregnancy and consuming iodized salt were recruited for the study. Outcomes of the pregnancy was compared between TPO antibody positive euthyroid women (group 1) and TPO antibody negative euthyroid women (group 2). RESULTS: Out of 1030 women, 164 (18.9%) were detected TPO antibody positive with euthyroid status. The mean FT4 and TSH level were significantly different in those who were TPO Ab positive as compared TPO Ab negative euthyroid pregnant women. No correlation was observed between the maternal age, gestational age and gravidity with anti TPO antibody levels. Eighteen (12%) women in Group 1and 5 (3.3%) women in Group 2 had miscarriages and the difference was found to be statistically significant (P value of 0.004). Twenty-one (14%) women in Group 1 and 5 (3.3%) women in Group 2 had preterm deliveries, which was also found to be statistically significantly (p value of 0.001). Other pregnancy related complications like Intrauterine death, IUGR, preeclampsia and PIH though are present in comparatively higher number in TPO Ab positive euthyroid pregnant women as compared to TPO Ab negative euthyroid pregnant women but this difference was not found to be statistically significant. CONCLUSIONS: To conclude with the present study shows that a good number of pregnant women with euthyroid status have TPO Ab positivity and this is associated with some adverse pregnancy outcomes like miscarriage and preterm birth of the baby. PMID- 28670544 TI - Randomized Placebo Control Study of Metformin in Psoriasis Patients with Metabolic Syndrome (Systemic Treatment Cohort). AB - BACKGROUND: Psoriasis has been found to be associated with obesity, metabolic syndrome (MS), diabetes, and cardiovascular risk factors. Metformin treatment showed improvement in cardiovascular risk factors and hyperinsulinemia. OBJECTIVE: To evaluate the efficacy and safety of metformin in psoriasis patients with MS. MATERIALS AND METHODS: This was a single-center, parallel-group, randomized, open-label study with blinded end point assessment of metformin (1000 mg once daily for 12 weeks; n = 20) and placebo (n = 18) in psoriasis patients with MS. Total sample size was 38 participants. RESULTS: Statistically significant improvement was observed in mean percentage change in erythema, scaling, and induration (ESI) (P = 0.048) in metformin as compared to placebo while mean percentage change in psoriasis area and severity index (PASI) and physician global assessment (PGA) scores was not significant (PASI - P = 0.215, PGA - P = 0.070). There was a statistically significant difference in percentage of parameters of MS improved following 12 weeks of treatment in metformin (19%) as compared to placebo (8.9%) group (P = 0.046). Statistically significant difference in percentage of patients achieving 75% reduction in ESI scores (P = 0.024). Significant improvement was observed in mean weight, body mass index (BMI), total cholesterol, and low-density lipoprotein (LDL) cholesterol in metformin group as compared to placebo. Improvement in BMI, fasting plasma glucose, serum triglycerides, high-density lipoprotein, LDL, systolic blood pressure, diastolic blood pressure, and total cholesterol was statistically significant in metformin group over the period of 12 weeks. There was no significant difference in adverse events in two groups except weight gain. CONCLUSION: Metformin has shown improvement in psoriasis and parameters of MS, hence can be used for the benefit of psoriasis patients having MS. Large, controlled studies are needed to confirm. PMID- 28670545 TI - Gestational Weight Gain and Pregnancy Outcomes in Relation to Body Mass Index in Asian Indian Women. AB - AIM: The aim of the study was to compare the weight gain during pregnancy (using Institute of Medicine guidelines) among Asian Indians across different body mass index (BMI) categories (using World Health Organization Asia Pacific BMI cut points) and to compare the pregnancy outcomes in each of the different BMI categories. METHODOLOGY: Retrospective records of 2728 pregnant women attending antenatal clinics and private maternity centers in Chennai, South India, from January 2011 to January 2014 were studied. Pregnancy outcomes were analyzed in relation to BMI and weight gain across different BMI categories. RESULTS: Overweight and obese women who gained more weight during pregnancy were at high risk of delivering macrosomic infants (overweight - odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-5.2, P = 0.02 and obese - OR: 1.6, 95% CI: 1.1-2.4, P = 0.01). In addition, obese women who gained more weight were also at high risk of preterm labor (OR: 2.1, 95% CI: 1.1-3.8; P = 0.01), cesarean section (OR: 1.9, 95% CI: 1.4-2.5; P < 0.001), and preeclampsia (OR: 2.8, 95% CI: 1.1-7.2, P = 0.03). Normal weight and overweight women who gained less weight had a protective effect from cesarean section and macrosomia. CONCLUSIONS: Overweight/obese women who gained more weight than recommended are at a high risk of developing adverse pregnancy outcomes. Normal and overweight women who gained weight less than recommended have low risk for cesarean section and macrosomia. However, they have a higher (statistically insignificant) risk for low birth weight and preterm birth. This highlights the need for gaining adequate weight during pregnancy. PMID- 28670546 TI - Indirect Calorimetry: From Bench to Bedside. AB - Accurate determination of energy expenditure (EE) is vitally important yet often neglected in clinical practice. Indirect calorimetry (IC) provides one of the most sensitive, accurate, and noninvasive measurements of EE in an individual. Over the last couple of decades, this technique has been applied to clinical circumstances such as acute illness and parenteral nutrition. Beyond assessing the nutritional needs, it has also shed light on various aspects of nutrient assimilation, thermogenesis, the energetics of physical exercise, and the pathogenesis of obesity and diabetes. However, because of little or no experience with IC provided during medical education, the benefits of IC are poorly appreciated. Newer technology, cost-effectiveness, and a better understanding of how to interpret measurements should lead to more frequent use of IC. This review focuses on the physicochemical background of IC, the various indications for use, techniques and instruments, potential pitfalls in measurement, and the recent advances in technology that has adapted the technique to long-term studies in humans. PMID- 28670549 TI - Medication Counseling for Thyroxine. AB - This communication from the National Indian Patient-centered Thyroid Management group provides a useful tool to help in medication counseling during hypothyroidism management. The authors classify and list aspects of thyroxine use which must be discussed with patients on thyroxine supplementation or replacement. Issues related to concomitant food and medications intake, preconception and pregnancy management, as well as sick day care, are also discussed. PMID- 28670548 TI - Dose Modification of Antidiabetic Agents in Patients with Type 2 Diabetes Mellitus and Heart Failure. AB - Heart failure is the most common comorbidity of diabetes. The incidence of heart failure in patients with diabetes is about 9%-22%, which is four times higher Than that in patients without diabetes. Heart failure and diabetes are collectively associated with increased morbidity and mortality compared to either condition alone. Several epidemiological studies have demonstrated an increased risk of heart failure in patients with diabetes; moreover, poor glycemic control accounts for the increased risk of heart failure. At present, several oral (metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, etc.) as well as injectable (insulins, glucagon-like peptide 1 receptor agonists) antidiabetic agents are available. However, optimal treatment strategy to achieve adequate glycemic control in patients with type 2 diabetes mellitus (T2DM) and heart failure has not been well studied. In the view of rising prevalence of heart failure in patients with diabetes mellitus, clinicians need to understand the potential implications of antidiabetic agents in patients with heart failure. A group of experts from across India were involved in a consensus meeting in Pondicherry during the National Insulin Summit in November 2015. They evaluated agents currently available for the treatment of diabetes looking at existing scientific evidence relevant to each class of therapy. In addition, the existing guidelines and prescribing literature available with all these agents were also reviewed. Findings from the expert evaluations were then factored into the national context incorporating personal experience and common clinical practices in India. The purpose of this consensus document is to assist the clinicians while treating patients with T2DM and heart failure. PMID- 28670550 TI - Thyro-stress. AB - Our understanding of the biopsychosocial model of health, and its influence on chronic endocrine conditions, has improved over the past few decades. We can distinguish, for example, between diabetes distress and major depressive disorders in diabetes. Similar to diabetes distress, we suggest the existence of "thyrostress" in chronic thyroid disorders. Thyro-stress is defined as an emotional state, characterized by extreme apprehension, discomfort or dejection, caused by the challenges and demand of living with thyroid disorders such as hypothyroidism. This communication describes the etiology, clinical features, differential diagnosis, and management of thyro-stress. PMID- 28670547 TI - Forum for Injection Technique and Therapy Expert Recommendations, India: The Indian Recommendations for Best Practice in Insulin Injection Technique, 2017. AB - Health-care professionals in India frequently manage injection or infusion therapies in persons with diabetes (PWD). Patients taking insulin should know the importance of proper needle size, correct injection process, complication avoidance, and all other aspects of injection technique from the first visit onward. To assist health-care practitioners in their clinical practice, Forum for Injection Technique and Therapy Expert Recommendations, India, has updated the practical advice and made it more comprehensive evidence-based best practice information. Adherence to these updated recommendations, learning, and translating them into clinical practice should lead to effective therapies, improved outcomes, and lower costs for PWD. PMID- 28670551 TI - Cardiovascular Safety of Oral Antidiabetic Medications: Need of the Hour. PMID- 28670552 TI - Vitamin D Deficiency among Healthy Children: An Undisputed and Booming Problem. PMID- 28670553 TI - Does Testosterone Replacement Therapy Promote an Augmented Risk of Thrombotic Events in Thalassemia Major Male Patients with Hypogonadism? PMID- 28670555 TI - On the Therapy for Polycystic Ovary Syndrome. PMID- 28670554 TI - Pandora's Box: Neurological Manifestations of Hypoparathyroidism. PMID- 28670556 TI - Iodine Deficiency: An under Recognized Problem. PMID- 28670557 TI - Parathyromatosis Following Endoscopic Parathyroid Surgery: A Rare Occurrence. PMID- 28670558 TI - Challenges Facing Optimum Care of Diabetic Children in Iraq. PMID- 28670559 TI - Metabolic Karma in Diabetes Care: Medico-philosophical Reflections. PMID- 28670560 TI - "Syndrome of Inappropriate Antidiuretic Hormone Secretion" as a Diagnostic and a Prognostic Indicator in Olfactory Neuroblastoma. PMID- 28670561 TI - Reader's Forum. PMID- 28670562 TI - Study on the perception of orthodontic treatment according to age: A questionnaire survey. AB - OBJECTIVE: This questionnaire study aimed to estimate the overall frequencies of positive perception towards orthodontic treatment among adults categorized according to age, sex, and area of living, and to identify barriers or negative perceptions preventing them from receiving orthodontic treatment. METHODS: The participants included 598 adults aged over 20 years (230 men and 368 women) who visited the Dental Hospital of Seoul St. Mary's Hospital. The participants' opinions regarding their consideration of receiving orthodontic treatment were recorded using a specially designed questionnaire. RESULTS: The overall rate of positive perception towards orthodontic treatment was 48.5%. Compared to adults in their 20s (63.2%), those in their 40s and 50s had a lower percentage of interest in orthodontic treatment (46.2% and 45.1%, respectively; p < 0.05). Overall, women (52.2%) had a higher rate of interest than did men (42.6%; p < 0.05). The area of living had no effect on the percentage of interest. The order of priority of chief complaints differed according to age: protrusion for those in the 20s and 30s, and spacing for those in the 40s to 60s. Overall, the main reason for not seeking treatment was the treatment fee. Respondents aged over 40 considered themselves "too old" for orthodontic treatment. CONCLUSIONS: The middle-aged had a relatively high percentage of interest (above 45%) in orthodontic treatment. However, demographic characteristics were not significantly associated with the positive interest. These results highlight the need for educating the middle-aged about the limitations and possibilities of orthodontic treatment to increase its acceptance. PMID- 28670563 TI - Repeated injections of botulinum toxin into the masseter muscle induce bony changes in human adults: A longitudinal study. AB - OBJECTIVE: To evaluate soft- and hard-tissue changes in the mandibular angle area after the administration of botulinum toxin type A (BoNT-A) injection to patients with masseteric hypertrophy by using three-dimensional cone-beam computed tomography (3D-CBCT). METHODS: Twenty volunteers were randomly divided into two groups of 10 patients. Patients in group I received a single BoNT-A injection in both masseter muscles, while those in group II received two BoNT-A injections in each masseter muscle, with the second injection being administered 4 months after the first one. In both groups, 3D-CBCT was performed before the first injection and 6 months after the first injection. RESULTS: Masseter muscle thicknesses and cross-sectional areas were significantly reduced in both groups, but the reductions were significantly more substantial in group II than in group I. The intergonial width of the mandibular angle area did not change significantly in either group. However, the bone volume of the mandibular gonial angle area was more significantly reduced in group II than in group I. CONCLUSIONS: The repeated administration of BoNT-A injections may induce bone volume changes in the mandibular angle area. PMID- 28670564 TI - Comparison of mechanical and biological properties of zirconia and titanium alloy orthodontic micro-implants. AB - OBJECTIVE: The aim of this study was to compare the initial stability as insertion and removal torque and the clinical applicability of novel orthodontic zirconia micro-implants made using a powder injection molding (PIM) technique with those parameters in conventional titanium micro-implants. METHODS: Sixty zirconia and 60 titanium micro-implants of similar design (diameter, 1.6 mm; length, 8.0 mm) were inserted perpendicularly in solid polyurethane foam with varying densities of 20 pounds per cubic foot (pcf), 30 pcf, and 40 pcf. Primary stability was measured as maximum insertion torque (MIT) and maximum removal torque (MRT). To investigate clinical applicability, compressive and tensile forces were recorded at 0.01, 0.02, and 0.03 mm displacement of the implants at angles of 0 degrees , 10 degrees , 20 degrees , 30 degrees , and 40 degrees . The biocompatibility of zirconia micro-implants was assessed via an experimental animal study. RESULTS: There were no statistically significant differences between zirconia micro-implants and titanium alloy implants with regard to MIT, MRT, or the amount of movement in the angulated lateral displacement test. As angulation increased, the mean compressive and tensile forces required to displace both types of micro-implants increased substantially at all distances. The average bone-to-implant contact ratio of prototype zirconia micro-implants was 56.88 +/- 6.72%. CONCLUSIONS: Zirconia micro-implants showed initial stability and clinical applicability for diverse orthodontic treatments comparable to that of titanium micro-implants under compressive and tensile forces. PMID- 28670565 TI - Effects of recycling on the biomechanical characteristics of retrieved orthodontic miniscrews. AB - OBJECTIVE: The aim of this study was to compare recycled and unused orthodontic miniscrews to determine the feasibility of reuse. The comparisons included both miniscrews with machined surfaces (MS), and those with etched surfaces (ES). METHODS: Retrieved MS and ES were further divided into three subgroups according to the assigned recycling procedure: group A, air-water spray; group B, mechanical cleaning; and group C, mechanical and chemical cleaning. Unused screws were used as controls. Scanning electron microscopy, energy-dispersive X-ray spectrometry, insertion time and maximum insertion torque measurements in artificial bone, and biological responses in the form of periotest values (PTV), bone-implant contact ratio (BIC), and bone volume ratio (BV) were assessed. RESULTS: Morphological changes after recycling mainly occurred at the screw tip, and the cortical bone penetration success rate of recycled screws was lower than that of unused screws. Retrieved ES needed more thorough cleaning than retrieved MS to produce a surface composition similar to that of unused screws. There were no significant differences in PTV or BIC between recycled and unused screws, while the BV of the former was significantly lower than that of the latter (p < 0.05). CONCLUSIONS: These results indicate that reuse of recycled orthodontic miniscrews may not be feasible from the biomechanical aspect. PMID- 28670566 TI - Clustering of craniofacial patterns in Korean children with snoring. AB - OBJECTIVE: The purpose of this study was to investigate whether the craniofacial patterns of Korean children with snoring and adenotonsillar hypertrophy (ATH) could be categorized into characteristic clusters according to age. METHODS: We enrolled 236 children with snoring and ATH (age range, 5-12 years) in this study. They were subdivided into four age groups: 5-6, 7-8, 9-10, and 11-12 years. Based on cephalometric analysis, the sagittal and vertical skeletal patterns of each individual were divided into Class I, II, and III, as well as the normodivergent, hypodivergent, and hyperdivergent patterns, respectively. Cluster analysis was performed using cephalometric principal components in addition to the age factor. RESULTS: Three heterogeneous clusters of craniofacial patterns were obtained in relation to age: cluster 1 (41.9%) included patients aged 5-8 years with a skeletal Class I or mild Class II and hyperdivergent pattern; cluster 2 (45.3%) included patients aged 9-12 years with a Class II and hyperdivergent pattern; and cluster 3 (12.8%) included patients aged 7-8 years with a Class III and hyperdivergent pattern. CONCLUSIONS: This study found that the craniofacial patterns of Korean children with snoring and ATH could be categorized into three characteristic clusters according to age groups. Although no significantly dominant sagittal skeletal discrepancy was observed, hyperdivergent vertical discrepancy was consistently evident in all clusters. PMID- 28670567 TI - Comparison of changes in the transverse dental axis between patients with skeletal Class III malocclusion and facial asymmetry treated by orthognathic surgery with and without presurgical orthodontic treatment. AB - OBJECTIVE: To evaluate transverse skeletal and dental changes, including those in the buccolingual dental axis, between patients with skeletal Class III malocclusion and facial asymmetry after bilateral intraoral vertical ramus osteotomy with and without presurgical orthodontic treatment. METHODS: This retrospective study included 29 patients with skeletal Class III malocclusion and facial asymmetry including menton deviation > 4 mm from the midsagittal plane. To evaluate changes in transverse skeletal and dental variables (i.e., buccolingual inclination of the upper and lower canines and first molars), the data for 16 patients who underwent conventional orthognathic surgery (CS) were compared with those for 13 patients who underwent preorthodontic orthognathic surgery (POGS), using three-dimensional computed tomography at initial examination, 1 month before surgery, and at 7 days and 1 year after surgery. RESULTS: The 1-year postsurgical examination revealed no significant changes in the postoperative transverse dental axis in the CS group. In the POGS group, the upper first molar inclined lingually on both sides (deviated side, -1.8 degrees +/- 2.8 degrees , p = 0.044; nondeviated side, -3.7 degrees +/- 3.3 degrees , p = 0.001) and the lower canine inclined lingually on the nondeviated side (4.0 degrees +/- 5.4 degrees , p = 0.022) during postsurgical orthodontic treatment. There were no significant differences in the skeletal and dental variables between the two groups at 1 year after surgery. CONCLUSIONS: POGS may be a clinically acceptable alternative to CS as a treatment to achieve stable transverse axes of the dentition in both arches in patients with skeletal Class III malocclusion and facial asymmetry. PMID- 28670568 TI - Maxillary molar derotation and distalization by using a nickel-titanium wire fabricated on a setup model. AB - The purpose of this article is to introduce a simple appliance that uses a setup model and a nickel-titanium (Ni-Ti) wire for correcting the mesial rotation and drift of the permanent maxillary first molar. The technique involves bonding a Ni Ti wire to the proper position of the target tooth on a setup model, followed by the fabrication of the transfer cap for indirect bonding and its transfer to the patient's teeth. This appliance causes less discomfort and provides better oral hygiene for the patients than do conventional appliances such as the bracket, pendulum, and distal jet. The treatment time is also shorter with the new appliance than with full-fixed appliances. Moreover, the applicability of the new appliance can be expanded to many cases by using screws or splinting with adjacent teeth to improve anchorage. PMID- 28670569 TI - Molecular and Microenvironmental Determinants of Glioma Stem-Like Cell Survival and Invasion. AB - Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults with a 5-year survival rate of 5% despite intensive research efforts. The poor prognosis is due, in part, to aggressive invasion into the surrounding brain parenchyma. Invasion is a complex process mediated by cell-intrinsic pathways, extrinsic microenvironmental cues, and biophysical cues from the peritumoral stromal matrix. Recent data have attributed GBM invasion to the glioma stem-like cell (GSC) subpopulation. GSCs are slowly dividing, highly invasive, therapy resistant, and are considered to give rise to tumor recurrence. GSCs are localized in a heterogeneous cellular niche, and cross talk between stromal cells and GSCs cultivates a fertile environment that promotes GSC invasion. Pro migratory soluble factors from endothelial cells, astrocytes, macrophages, microglia, and non-stem-like tumor cells can stimulate peritumoral invasion of GSCs. Therefore, therapeutic efforts designed to target the invasive GSCs may enhance patient survival. In this review, we summarize the current understanding of extrinsic pathways and major stromal and immune players facilitating GSC maintenance and survival. PMID- 28670570 TI - In vitro Pharmacokinetics/Pharmacodynamics Evaluation of Fosfomycin Combined with Amikacin or Colistin against KPC2-Producing Klebsiella pneumoniae. AB - Objectives: The emergence of carbapenem-resistant Enterobacteriaceae, especially Klebsiella pneumoniae, has become a major concern in clinic settings. Combination therapy is gaining momentum to counter the secondary resistance and potential suboptimal efficacy of monotherapy. The aim of this study was to evaluate the bactericidal effect of fosfomycin (FM), amikacin (AMK), or colistin (COL) alone and combinations against KPC2-producing K. pneumoniae using dynamic model by simulating human pharmacokinetics in vitro. Methods: The Pharmacokinetics Auto Simulation System 400 system was employed to simulate different dosing regimens of FM, AMK, and COL alone and combination. Bacterial growth recovery time (RT) and the area between the control growth and antibacterial killing curves (IE) were used as unbiased and comprehensive means for determining the antimicrobial effect. Results: We observed that COL alone was much pronounced than FM or AMK against KPC-Kp. IE of FM (8 g every 8 h) plus AMK (15 mg/kg once-daily) and FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) were higher (>170 and >200 LogCFU/mL.h-1, respectively) than that of monotherapies against sensitive strains. Of note, the rate of resistance was lower when using the combination of FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) than using COL (75,000 IU/kg every 12 h) alone. Conclusions: The combination of FM (8 g every 8 h) plus AMK (15 mg/kg once-daily) and FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) were effective at maximizing bacterial killing and suppressing emergence of resistance. PMID- 28670571 TI - DNA-triplex Forming Purine Repeat Containing Genes in Acinetobacter baumannii and Their Association with Infection and Adaptation. PMID- 28670574 TI - Corrigendum: Interaction of Bacteroides fragilis Toxin with Outer Membrane Vesicles Reveals New Mechanism of Its Secretion and Delivery. AB - [This corrects the article on p. 2 in vol. 7, PMID: 28144586.]. PMID- 28670572 TI - Biological Functions of the Secretome of Neisseria meningitidis. AB - Neisseria meningitidis is a Gram-negative bacterial pathogen that normally resides as a commensal in the human nasopharynx but occasionally causes disease with high mortality and morbidity. To interact with its environment, it transports many proteins across the outer membrane to the bacterial cell surface and into the extracellular medium for which it deploys the common and well characterized autotransporter, two-partner and type I secretion mechanisms, as well as a recently discovered pathway for the surface exposure of lipoproteins. The surface-exposed and secreted proteins serve roles in host-pathogen interactions, including adhesion to host cells and extracellular matrix proteins, evasion of nutritional immunity imposed by iron-binding proteins of the host, prevention of complement activation, neutralization of antimicrobial peptides, degradation of immunoglobulins, and permeabilization of epithelial layers. Furthermore, they have roles in interbacterial interactions, including the formation and dispersal of biofilms and the suppression of the growth of bacteria competing for the same niche. Here, we will review the protein secretion systems of N. meningitidis and focus on the functions of the secreted proteins. PMID- 28670575 TI - CD8+ memory T-cell inflation renders compromised CD4+ T-cell-dependent CD8+ T cell immunity via naive T-cell anergy. AB - Whether inflation of CD8+ memory T (mT) cells, which is often derived from repeated prime-boost vaccinations or chronic viral infections in the elderly, would affect late CD8+ T-cell immunity is a long-standing paradox. We have previously established an animal model with mT-cell inflation by transferring ConA-stimulated monoclonal CD8+ T cells derived from Ova-specific T-cell-receptor transgenic OTI mice into irradiation-induced lymphopenic B6 mice. In this study, we also established another two animal models with mT-cell inflation by transferring, 1) ConA-stimulated monoclonal CD8+ T cells derived from lymphocytic choriomeningitis virus glycoprotein-specific T-cell-receptor transgenic P14 mice, and 2) ConA-stimulated polyclonal CD8+ T cells derived from B6.1 mice into B6 mice with irradiation-induced lymphopenia. We vaccinated these mice with recombinant Ova-expressing Listeria monocytogenes and Ova-pulsed dendritic cells, which stimulated CD4+ T cell-independent and CD4+ T-cell-dependent CD8+ T-cell responses, respectively, and assessed Ova-specific CD8+ T-cell responses by flow cytometry. We found that Ova-specific CD8+ T-cell responses derived from the latter but not the former vaccination were significantly reduced in mice with CD8+ mT-cell inflation compared to wild-type B6 mice. We determined that naive CD8+ T cells purified from splenocytes of mice with mT-cell inflation had defects in cell proliferation upon stimulation in vitro and in vivo and upregulated T cell anergy-associated Itch and GRAIL molecules. Taken together, our data reveal that CD8+ mT-cell inflation renders compromised CD4+ T-cell-dependent CD8+ T-cell immunity via naive T-cell anergy, and thus show promise for the design of efficient vaccines for elderly patients with CD8+ mT-cell inflation. PMID- 28670573 TI - The Intestinal Eukaryotic and Bacterial Biome of Spotted Hyenas: The Impact of Social Status and Age on Diversity and Composition. AB - In mammals, two factors likely to affect the diversity and composition of intestinal bacteria (bacterial microbiome) and eukaryotes (eukaryome) are social status and age. In species in which social status determines access to resources, socially dominant animals maintain better immune processes and health status than subordinates. As high species diversity is an index of ecosystem health, the intestinal biome of healthier, socially dominant animals should be more diverse than those of subordinates. Gradual colonization of the juvenile intestine after birth predicts lower intestinal biome diversity in juveniles than adults. We tested these predictions on the effect of: (1) age (juvenile/adult) and (2) social status (low/high) on bacterial microbiome and eukaryome diversity and composition in the spotted hyena (Crocuta crocuta), a highly social, female dominated carnivore in which social status determines access to resources. We comprehensively screened feces from 35 individually known adult females and 7 juveniles in the Serengeti ecosystem for bacteria and eukaryotes, using a set of 48 different amplicons (4 for bacterial 16S, 44 for eukaryote 18S) in a multi amplicon sequencing approach. We compared sequence abundances to classical coprological egg or oocyst counts. For all parasite taxa detected in more than six samples, the number of sequence reads significantly predicted the number of eggs or oocysts counted, underscoring the value of an amplicon sequencing approach for quantitative measurements of parasite load. In line with our predictions, our results revealed a significantly less diverse microbiome in juveniles than adults and a significantly higher diversity of eukaryotes in high ranking than low-ranking animals. We propose that free-ranging wildlife can provide an intriguing model system to assess the adaptive value of intestinal biome diversity for both bacteria and eukaryotes. PMID- 28670576 TI - Neonatal Meningitis: Overcoming Challenges in Diagnosis, Prognosis, and Treatment with Omics. AB - Neonatal meningitis is a devastating condition. Prognosis has not improved in decades, despite the advent of improved antimicrobial therapy and heightened index of suspicion among clinicians caring for affected infants. One in ten infants die from meningitis, and up to half of survivors develop significant lifelong complications, including seizures, impaired hearing and vision, and delayed or arrested development of such basic skills as talking and walking. At present, it is not possible to predict which infants will suffer poor outcomes. Early treatment is critical to promote more favorable outcomes, though diagnosis of meningitis in infants is technically challenging, time-intensive, and invasive. Profound neuronal injury has long been described in the setting of neonatal meningitis, as has elevated levels of many pro- and anti-inflammatory cytokines. Mechanisms of the host immune response that drive clearance of the offending organism and underlie brain injury due to meningitis are not well understood, however. In this review, we will discuss challenges in diagnosis, prognosis, and treatment of neonatal meningitis. We will highlight transcriptomic, proteomic, and metabolomic data that contribute to suggested mechanisms of inflammation and brain injury in this setting with a view toward fruitful areas for future investigation. PMID- 28670578 TI - Postgraduate Courses in Pharmaceutical Medicine in Italy. AB - Italy has a significant tradition of excellence in the area of clinical trials (CTRs): important achievements in the clinical development of rifampicin and adriamycin, the two most famous drugs discovered in the research laboratories of two Italian pharmaceutical companies, paved the way to the establishment of a culture of clinical development, mainly in the areas of antimicrobials and oncology. Despite the fact that now the Italian market of pharmaceuticals is largely dominated by multinational companies with headquarters outside Italy, the contribution of Italian studies to the clinical development of new drugs is still significant. Indeed, it largely exceeds the percentage of Italian inhabitants versus the ones living in the remaining EU countries, as Italy has about 12% of EU population, but has a 17% share of the EU CTRs. Education in Pharmaceutical Medicine is now a must for all professionals interested to work either in pharma companies or in contract research organizations: several Italian universities are offering high quality courses, and in the last 10 years, more than 1,200 professionals received a postgraduate education in pharmaceutical medicine. This result places Italy on top of countries concerned about the professional education of people involved in drug development and will represent an asset for a larger involvement of Italian clinical sites in the global process of clinical research. PMID- 28670577 TI - Crohn's Strictures-Moving Away from the Knife. AB - Crohn's disease (CD) is a lifelong inflammatory bowel disease with a rapidly rising incidence in the pediatric population. A common complication of CD is the development of fibrotic strictures, which may be present at initial diagnosis or develop many years later. Clinical presentation depends on stricture location and degree of obstruction, and strictures frequently contain a mixture of inflammatory and fibrotic tissue. Histological examination of Crohn's strictures shows thickening of the muscular layers and the submucosa, where increased collagen deposition by activated myofibroblasts is concentrated around islands of smooth muscle cells and at the superficial margin of the muscularis propria. No antifibrotic therapies for Crohn's strictures exist. Profibrotic transforming growth factor-beta (TGFbeta)/bone morphogenetic protein signaling stimulates myofibroblast differentiation and extracellular matrix deposition. Understanding and targeting TGFbeta1 downstream signaling is the main focus of current research, raising the possibility of specific antifibrotic therapy in CD becoming available in the future. PMID- 28670579 TI - Assessment of Circulating Protein Signatures for Kidney Transplantation in Pediatric Recipients. AB - Identification and use of non-invasive biomarkers for kidney transplantation monitoring is an unmet need. A total of 121 biobanked sera collected from 111 unique kidney transplant (KT) patients (children and adolescent) and 10 age matched healthy normal controls were used to profile serum proteins using semi quantitative proteomics. The proteomics data were analyzed to identify panels of serum proteins that were specific to various transplant injuries, which included acute rejection (AR), BK virus nephropathy (BKVN), and chronic allograft nephropathy (CAN). Gene expression data from matching peripheral blood mononuclear cells were interrogated to investigate the association between soluble serum proteins and altered gene expression of corresponding genes in different injury phenotypes. Analysis of the proteomics data identified from different patient phenotypes, with criteria of false discovery rate <0.05 and at least twofold changes in either direction, resulted in a list of 10 proteins that distinguished KT injury from no injury. Similar analyses to identify proteins specific to chronic injury, acute injury, and AR after kidney transplantation identified 22, 6, and 10 proteins, respectively. Elastic-Net logistic regression method was applied on the 137 serum proteins to classify different transplant injuries. This algorithm has identified panels of 10 serum proteins specific for AR, BKVN, and CAN with classification rates 93, 93, and 95%, respectively. The identified proteins could prove to be potential surrogate biomarkers for routine monitoring of the injury status of pediatric KT patients. PMID- 28670580 TI - Whole Genome Sequencing of a Canadian Bovine Gammaherpesvirus 4 Strain and the Possible Link between the Viral Infection and Respiratory and Reproductive Clinical Manifestations in Dairy Cattle. AB - Bovine gammaherpesvirus 4 (BoHV-4) is a herpesvirus widespread in cattle populations, and with no clear disease association. Its genome contains a long unique coding region (LUR) flanked by polyrepetitive DNA and 79 open reading frames (ORFs), with unique 17 ORFs, named Bo1 to Bo17. In 2009, a BoHV-4 strain was isolated (FMV09-1180503: BoHV-4-FMV) from cattle with respiratory disease from Quebec, Canada, and its LUR was sequenced. Despite the overall high similarity, BoHV-4-FMV had the most divergent LUR sequence compared to the two known BoHV-4 reference strain genomes; most of the divergences were in the Bo genes and in the repeat regions. Our phylogenetic analysis based on DNA polymerase and thymidine kinase genes revealed that virus isolate was BoHV-4 gammaherpesvirus and clustered it together with European BoHV-4 strains. Because BoHV-4-FMV was isolated from animals presenting respiratory signs, we have updated the BoHV-4 Canadian cattle seroprevalence data and tried to find out whether there is a link between clinical manifestation and BoHV-4 seropositivity. An indirect immunofluorescence assay (IFA) was performed with nearly 200 randomized sera of dairy cattle from two Canadian provinces, Quebec (n = 100) and Ontario (n = 91). An additional set of sera obtained from Quebec, from the healthy (n = 48) cows or from the animals experiencing respiratory or reproductive problems (n = 75), was also analyzed by IFA. BoHV-4 seroprevalence in Canadian dairy cattle was 7.9% (Quebec: 6% and Ontario: 9.9%). Among animals from the Quebec-based farms, diseased animals showed higher BoHV-4 seropositivity than healthy animals (P < 0.05), with a significant 2.494 odds ratio of being seropositive in sick compared to healthy animals. Although there is no established direct link between BoHV-4 and specific diseases, these seroprevalence data suggest the possible involvement of BoHV-4 in dairy cattle diseases. PMID- 28670581 TI - Mutant Cas9-transcriptional activator activates HIV-1 in U1 cells in the presence and absence of LTR-specific guide RNAs. AB - CRISPR/Cas9 systems have been advanced as promising tools in the HIV eradication armamentarium for sequence-specific disruption or latency reversal. Enthusiasm is balanced by concerns about off-target host genome modification and effects on HIV evolution. In the chronically HIV-1-infected U1 promonocytic latency model, we have confirmed stimulation of HIV-1 production by a mutant Cas9-transcriptional activator and guide RNAs with two guide RNAs apparently more potent than one. However, significant increases were also observed in the absence of guide RNAs. We encourage continued careful evaluation of non-sequence-specific and off-target effects of Cas9-mediated approaches. PMID- 28670582 TI - Other cancers in lung cancer families are overwhelmingly smoking-related cancers. AB - Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology. We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking. The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found. Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor. PMID- 28670583 TI - Quality of Life among Family Caregivers of Patients on Hemodialysis and its Relevant Factors: A Systematic Review. AB - BACKGROUND: Family caregivers are considered as hidden patients experiencing physical and mental disorders. This affects the quality of not only their lives but also the health care provided to patients.This study aimed to investigate the quality of life (QOL) and its related factors among the caregivers of patients undergoing hemodialysis. METHODS: This systematic review was conducted based on the eight-step guidelines presented by the York University. The databases relevant to the medical field including Nursing and Allied Health, Web of Science, Scopus, Pubmed, Embase, PsycINFO and Psychology Library were used. Finally, 12 articles observing the inclusion criteria and with regard to the research questions were found. The data obtained from these articles were summarized, classified, and analyzed. RESULTS: QOL among Family Caregivers of Patients on Hemodialysis is low, compared to the general population; however, their QOL is higher than the patients under their care. Factors relevant to the QOL for caregivers including age, gender, perceived social support, perceived burden of care, affliction with other diseases (lupus, hypertension, hypothyroidism and depression), intellectual understanding of the limitations of the patient's disease in their daily life, employment of adaptation strategies, better marital relationships, accepting self and family relationship with the patient (mother and wife). Furthermore, the factors associated with care takers affecting the quality of caregivers' lives were age, QOL and the type of treatment. CONCLUSIONS: Caregivers of patients undergoing hemodialysis enjoyed low QOL. Since there is a direct relationship between family caregivers' quality and patients' QOL, health care system and health policy makers should pay more attention to family caregivers. PMID- 28670584 TI - Living with Hypertension: A Qualitative Research. AB - BACKGROUND: Hypertension affects many aspects of the patients' life. Factors such as attitudes, beliefs and experiences, and social and cultural conditions of patients have effective roles in hypertension treatment process. The aim of this research was to explore perspectives and experiences of patients with hypertension while living with this disease. METHODS: This is a qualitative research using content analysis approach. 27 hypertensive patients who referred to hospitals affiliated to Tehran University of Medical Sciences were selected based on purposive sampling, and semi-structured interviews were carried out. Graneheim and Lundman's approach was used for analysis of data and Lincoln and Guba's criteria were used to confirm the trustworthiness of the study's findings. RESULTS: Experiences of the participants were divided into three main categories as follows: (1) disease shadow; (2) dual understanding of the effect of drug therapy consisting of two sub-categories known as ''perceived benefits,'' ''negative consequences''; and (3) facing the disease that includes the two subcategories of ''Compatibility'' and ''Negligence and denial''. CONCLUSION: Based on the findings, patients with hypertension had experienced many physical, psychological, social, familial and spiritual problems due to the disease and their cultural context. These patients obtained positive experiences following the compatibility with hypertension. Comprehensive planning tailored to the cultural, social context and their beliefs is necessary to solve problems in these patients. PMID- 28670585 TI - The Impact of Spiritual Care Education on the Self-Efficacy of the Family Caregivers of Elderly People with Alzheimer's Disease. AB - BACKGROUND: Caring for people who suffer from Alzheimer's disease is stressful. Family caregivers of these people usually experience physical and mental burnout and lose their efficacy in doing care-related activities. The present study aimed to examine the impacts of spiritual care education on self-efficacy of the family caregivers of people with Alzheimer's disease. METHODS: This study was conducted from October to December 2015 by using a two-group pretest-posttest quasi experimental design. In total, 60 family caregivers of people with Alzheimer's disease were recruited and randomly allocated to the intervention and control groups. A spiritual care educational intervention was implemented for the caregivers in the intervention group. The data were collected before and three weeks after the study intervention by using the ten-item General Self Efficacy scale. The study data were analyzed in SPSS using Chi-square and independent t test. RESULTS: Before the study intervention, the means of pretest self-efficacy scores in the intervention and control groups were 29.80+/-4.80 and 28.39+/-6.41, respectively. There was no significant difference between the groups regarding the mean score of self-efficacy (P=0.36). After the study, these two scores changed to 32.73+/-4.75 and 27.85+/-5.98, respectively. However, after the intervention, the mean score of self-efficacy in the intervention group was significantly higher than the control group (P=0.002). CONCLUSION: Spiritual care can enhance the self-efficacy of the family caregivers of people who suffer from Alzheimer's disease. Therefore, care providers are recommended to use such spirituality-based interventions for empowering family caregivers. PMID- 28670586 TI - Factor Structure of the Conflict Tactics Scale 1. AB - BACKGROUND: The Conflict Tactics Scale 1 (CTS1) is a widely used self-report measure of abusive attitudes of parents towards children. The factor structure of the CTS1 still remains to be clarified. The aim of this study was to examine the factor structure of the Japanese version of the CTS1 for postpartum women in community settings. METHOD: The data in this study came from the Okayama and Kumamoto's study. These were part of a larger survey using longitudinal questionnaire studies conducted in Japan from 2001 to 2002 and in 2011, respectively. In both study sites, the participant mothers were asked to fill in the CTS1 one month after delivery when they attended for check-up at the out patient clinic. RESULTS: A total of 1,150 questionnaires were collected, excluding the participants with missing values in the CTS1. Finally, 1,078 were included in the statistical analyses. Data of 1,078 women were divided into two parts. In the first halved sample (n=578), an exploratory factor analysis was conducted for the CTS1 items after exluding nine items with extremely low prevalence. It revealed 2-factor or 3-factor models. Then, we conducted a model comparison with the second halved sample (n=500), using confirmatory factor analysis. In terms of goodness-of-fit indeces, the 2-factor model was superior. Its subscales were Reasoning and Psycholosical Aggression. CONCLUSION: The 2 factor model of the CTS1 consisting of Reasoning and Psychological Aggression was superior to the 3-factor model. This is not inconsistent with the original authors' theoretical model. PMID- 28670587 TI - Comparison of Social, Economic and Familial Empowerment in Married Women in Three Cities of Iran. AB - BACKGROUND: Women's empowerment was defined as their ability to achieve awareness and control their personal, social, economic and political forces aiming at taking measures in order to improve their lives. This study aimed to compare the empowerment of the married women in medical sciences university in social, economic and familial domains in three cities, IRAN. METHODS: This was a descriptive-analytical study conducted in 2016 on 399 married and employed women. Data collection instrument was a four-part questionnaire consisting of demographic, social, economic and familial domains and made by researchers. Collected data were analyzed using SPSS, version 16. Using paired t-test for intra-group and Chi-square and t-test for between groups comparisons. The significance level was set at<0.05. RESULTS: The total score of empowerment in Rasht (126.34+/-17.51) was more than the two cities of Shiraz (123.46+/-15.62) and Bandar Abbas (123.42+/-12.34). There was a significant relationship between the mean score of the total empowerment and monthly income of the participants in Bandar Abbas (P=0.04), and job of their husbands in Rasht (P=0.004). The mean score of family empowerment of the women was significantly interrelated with the number of their children in Rasht (P=0.001), and with the education of the participants' husbands in Shiraz (P=0.002). CONCLUSION: The score of social empowerment in Rasht was more than two other cities. In economic domain, the scores of Rasht and Bandar Abbas were more than those of Shiraz. Scores of Rasht and Shiraz were more than Bandar Abbas in the familial domain. It is useful to carry out qualitative studies aiming at determining the effects of various factors on women's empowerment and strategies for improving it. PMID- 28670588 TI - Knowledge, Attitude and Practice of Community Health Workers Regarding Child Abuse in Tabriz Health Centers in 2015-2016. AB - BACKGROUND: Child abuse is a widespread social phenomenon with serious life-time consequences. Since parents bring their children to healthcare centers for growth screening and vaccinations, Community Health Workers play an important role in identifying and reporting child abuse cases. Thus, the current study aimed to investigate knowledge, attitude and performance of Community Health Workers regarding child abuse in Tabriz. METHODS: This is a descriptive (cross-sectional) study; census method was used for sampling. Study population consists of 265 people, employed at units of family health and vaccination in Tabriz healthcare centers in 2015-2016. A questionnaire was used to collect the data. Data analysis was carried out using SPSS, version 23 through descriptive (mean and standard deviation) and analytical (Two Independent Samples T-test and analysis of variance) statistics. RESULTS: Findings indicate that 58.5 percent of Community Health Workers had good knowledge about causes of child abuse and 45 percent had good knowledge of the signs, symptoms and complications of child abuse. Their total knowledge was good (57%). The mean score of awareness (knowledge) was significant according to the variable of training participation (P=0.04). The participants had a favorable attitude toward dealing with child abuse (91.3 %); the mean score of attitude was significant according to the educational field (P<0.001) and their performance in dealing with child abuse was moderate and lower (94.3 %). CONCLUSION: Community Health Workers had good knowledge regarding child abuse, favorable attitude toward dealing with child abuse, and poor performance in dealing with child abuse. This may be due to fear of side issues to deal with child abuse, or lack of clear legal guidelines regarding this. PMID- 28670589 TI - Mothers' Experiences about Febrile Convulsions in Their Children: A Qualitative Study. AB - BACKGROUND: Febrile convulsion in children is a frightening experience for the mothers. This experience may have unknown aspects, which must be investigated in order to plan better support for the mothers and children. This study is conducted with the aim of exploring the experiences of mothers whose children suffer from febrile convulsion. METHODS: This study was based on a qualitative content analysis. 12 mothers in Amir Kabir hospital of Arak city participated in the study and shared their experiences through semi-structured interviews. The gathered data were analysed using Graneheim and Lundman's (2004) method. RESULTS: Exploring the experiences of mothers whose children suffered from febrile convulsion reflected three themes: perceived threat, seeking solution, and difference in adaptation. CONCLUSION: Regarding the findings of this study, comprehensive supportive care plans can be designed for enabling the mothers to better cope with their children's febrile convulsion. PMID- 28670591 TI - Necessity of Rethinking about the Preventive Strategies of Addiction. PMID- 28670590 TI - Development and Psychometric Properties of the Decision Making on the Type of Delivery Questionnaire in Iranian Women. AB - BACKGROUND: A tool which can help to decide on the determinants in selecting the delivery type is an effective step towards the goals of the World Health. This study aimed to develop and evaluate the psychometric properties of a scale based on Iranian culture to make decision on the type of delivery. METHODS: This is a methodological study using a questionnaire proposed by Schneider. The following steps were used to design the project. In the first step, perceptions and experiences of 45 pregnant women, postpartum women, midwives, gynecologists and non-pregnant women were determined based on interviews and observations using focused ethnography. In the second stage, the terms in the questionnaire based on qualitative study was assessed. Then, in the third stage, psychometric testing of the decision making on the type of delivery scale (DMTDS) based on the cultural concepts of decision making towards the type of delivery and its influencing factors based on focused ethnography using face validity, content validity, construct validity, internal consistency and reliability was done on400 pregnant and postpartum women. RESULTS: The initially developed scale consisted of 60 items on a 5-point Likert scale, which reduced to 43 items following measurement of the face and content validity. The results of the exploratory factor analysis elicited 36 items and a seven-factor structure including motivational beliefs on vaginal delivery, social beliefs towards childbirth, motivational beliefs on cesarean delivery, personal beliefs, sources of information, catastrophic thinking and child birth experiences. Cronbach's alpha coefficient (0.80) confirmed the high internal consistency of the scale. CONCLUSION: The developed questionnaire appears to be a valid and reliable tool for health care providers to measure the women's decision making towards type of delivery. Therefore, this tool can be used in the Iranian community. The scale may help the midwives and obstetricians to be aware of the women's decision regarding their choice of delivery and as a result to plan appropriately in order to reduce unnecessary cesarean sections. PMID- 28670592 TI - Choice Rules and Accumulator Networks. AB - This article presents a preference accumulation model that can be used to implement a number of different multi-attribute heuristic choice rules, including the lexicographic rule, the majority of confirming dimensions (tallying) rule and the equal weights rule. The proposed model differs from existing accumulators in terms of attribute representation: Leakage and competition, typically applied only to preference accumulation, are also assumed to be involved in processing attribute values. This allows the model to perform a range of sophisticated attribute-wise comparisons, including comparisons that compute relative rank. The ability of a preference accumulation model composed of leaky competitive networks to mimic symbolic models of heuristic choice suggests that these 2 approaches are not incompatible, and that a unitary cognitive model of preferential choice, based on insights from both these approaches, may be feasible. PMID- 28670593 TI - Laparotomy-Assisted Endoscopic Injection of Jejunal Varices for Overt Small Bowel Bleeding. AB - A 54-year old male liver transplant recipient with Roux-en-Y choledochojejunostomy was admitted for symptomatic anemia. Despite endoscopies and a bleeding scan, active bleeding was not visualized. Angiography and abdominal computed tomography demonstrated possible jejunal varices at the choledochojejunal anastomosis. Double-balloon enteroscopy demonstrated varices with overlying clots in the Roux limb at the anastomosis. Due to the extensive loop formation and unstable position of the endoscope, therapeutic intervention could not be performed. Operative enterotomy and intraoperative endoscopy were subsequently required. A varix in the jejunum with venous flow on Doppler was injected twice with cyanoacrylate and successfully obturated. PMID- 28670594 TI - Intravascular Papillary Endothelial Hyperplasia of the Jejunum as a Cause of Obscure-Overt Gastrointestinal Bleeding. AB - Intravascular papillary endothelial hyperplasia (IPEH), or Masson's tumor, is a rare, benign vascular lesion characterized by reactive endothelial proliferation with venous stasis and thrombus. Lesions typically arise in vascular regions of the head and neck or extremities, but involvement of other organ systems has been reported. Clinically, IPEH mimics other benign lesions (hemangiomas) and malignant neoplasms (angiosarcoma) depending on the affected site. Diagnosis is essential because local excision of certain IPEH subtypes is curative. IPEH in the gastrointestinal tract is rare with few reported cases. We present a case of obscure-overt gastrointestinal bleeding from IPEH of the jejunum. PMID- 28670595 TI - Massive Hepatic Infarction Caused by HELLP Syndrome. PMID- 28670596 TI - Actinomycosis Causing Recurrent Perianal Fistulae. AB - Actinomycosis is a rare but easily curable infection that should be considered in the differential diagnosis of perianal fistulizing disease. We present the case of a 26-year-old woman with complex perianal fistulae, including trans sphincteric and suprasphincteric fistulous tracts and a rectovaginal fistula, requiring multiple abscess drainages, seton placement, and antibiotic courses, with little improvement. After extensive investigation, Actinomyces spp. was identified in anal cytology. The patient underwent a 6-week course of intravenous penicillin followed by oral amoxicillin, with remarkable improvement. This case illustrates the importance of pursuing less common diagnoses in refractory complex perianal disease, such as actinomycosis. PMID- 28670597 TI - Solitary Polypoid Angiodysplastic Lesion Mimicking a Tumor in the Jejunum. AB - Small bowel bleeding should be considered in patients with overt or occult gastrointestinal hemorrhage after normal upper and lower endoscopic examination. Angiodysplasia appearing as multiple flat vascular tufts is the most common cause of small bowel bleeding in patients over 40 years old. Polypoid angiodysplasia, however, is extremely rare. This report illustrates a unique case of solitary polypoid angiodysplasia in the jejunum of an adult with chronic kidney disease, who presented with an occult gastrointestinal bleed. The angiodysplasia mimicked tumorous growth, potentially indicative of malignant neoplasm. The patient underwent surgical resection and was histologically diagnosed as having angiodysplasia. PMID- 28670599 TI - Preface to Special Topic: Transactions from the 66th Annual Meeting of the American Crystallographic Association. PMID- 28670598 TI - Transcranial electric stimulation for the investigation of speech perception and comprehension. AB - Transcranial electric stimulation (tES), comprising transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), involves applying weak electrical current to the scalp, which can be used to modulate membrane potentials and thereby modify neural activity. Critically, behavioural or perceptual consequences of this modulation provide evidence for a causal role of neural activity in the stimulated brain region for the observed outcome. We present tES as a tool for the investigation of which neural responses are necessary for successful speech perception and comprehension. We summarise existing studies, along with challenges that need to be overcome, potential solutions, and future directions. We conclude that, although standardised stimulation parameters still need to be established, tES is a promising tool for revealing the neural basis of speech processing. Future research can use this method to explore the causal role of brain regions and neural processes for the perception and comprehension of speech. PMID- 28670600 TI - Single Quantum Dot with Microlens and 3D-Printed Micro-objective as Integrated Bright Single-Photon Source. AB - Integrated single-photon sources with high photon-extraction efficiency are key building blocks for applications in the field of quantum communications. We report on a bright single-photon source realized by on-chip integration of a deterministic quantum dot microlens with a 3D-printed multilens micro-objective. The device concept benefits from a sophisticated combination of in situ 3D electron-beam lithography to realize the quantum dot microlens and 3D femtosecond direct laser writing for creation of the micro-objective. In this way, we obtain a high-quality quantum device with broadband photon-extraction efficiency of (40 +/- 4)% and high suppression of multiphoton emission events with g(2)(tau = 0) < 0.02. Our results highlight the opportunities that arise from tailoring the optical properties of quantum emitters using integrated optics with high potential for the further development of plug-and-play fiber-coupled single photon sources. PMID- 28670601 TI - Light-Directed Tuning of Plasmon Resonances via Plasmon-Induced Polymerization Using Hot Electrons. AB - The precise morphology of nanoscale gaps between noble-metal nanostructures controls their resonant wavelengths. Here we show photocatalytic plasmon-induced polymerization can locally enlarge the gap size and tune the plasmon resonances. We demonstrate light-directed programmable tuning of plasmons can be self limiting. Selective control of polymer growth around individual plasmonic nanoparticles is achieved, with simultaneous real-time monitoring of the polymerization process in situ using dark-field spectroscopy. Even without initiators present, we show light-triggered chain growth of various monomers, implying plasmon initiation of free radicals via hot-electron transfer to monomers at the Au surface. This concept not only provides a programmable way to fine-tune plasmons for many applications but also provides a window on polymer chemistry at the sub-nanoscale. PMID- 28670602 TI - "Facing Our Fears": Using facilitated film viewings to engage communities in HIV research involving MSM in Kenya. AB - Kenya is a generally homophobic country where homosexuality is criminalised and people who engage in same sex sexuality face stigma and discrimination. In 2013, we developed a 16 min documentary entitled "Facing Our Fears" that aimed at sharing information on how and why men who have sex with men (MSM) are involved in on-going KEMRI HIV prevention research, and associated community engagement. To consider the film's usefulness as a communication tool, and its perceived security risks in case the film was publicly released, we conducted nine facilitated viewings with 122 individuals representing seven different stakeholder groups. The documentary was seen as a strong visual communication tool with potential to reduce stigma related to homosexuality, and facilitated film viewings were identified as platforms with potential to support open dialogue about HIV research involving MSM. Despite the potential, there were concerns over possible risks to LGBT communities and those working with them following public release. We opted-giving emphasis to the "do no harm" principle to use the film only in facilitated settings where audience knowledge and attitudes can be carefully considered and discussed. The results highlight the importance of carefully assessing the range of possible impacts when using visuals in community engagement. PMID- 28670603 TI - In vitro Detection of Neutrophil Traps and Post-attack Cell Wall Changes in Candida Hyphae. AB - In this protocol we describe how to visualize neutrophil extracellular traps (NETs) and fungal cell wall changes in the context of the coculture of mouse neutrophils with fungal hyphae of Candida albicans. These protocols are easily adjusted to test a wide array of hypotheses related to the impact of immune cells on fungi and the cell wall, making them promising tools for exploring host pathogen interactions during fungal infection. PMID- 28670604 TI - RNA Degradation Assay Using RNA Exosome Complexes, Affinity-purified from HEK-293 Cells. AB - The RNA exosome complex plays a central role in RNA processing and regulated turnover. Present both in cytoplasm and nucleus, the exosome functions through associations with ribonucleases and various adapter proteins (reviewed in [Kilchert et al., 2016]). The RNA exosome-associated EXOSC10 protein is a distributive, 3'-5' exoribonuclease. The following protocol describes an approach to monitor the ribonucleolytic activity of affinity-purified EXOSC10-containing RNA exosomes, originating from HEK-293 cells, as reported in (Domanski et al., 2016) and further detailed in the companion bio-protocol to this one (Domanski and LaCava, 2017). PMID- 28670605 TI - Expression and Analysis of Flow-regulated Ion Channels in Xenopus Oocytes. AB - Mechanically-gated ion channels play key roles in mechanotransduction, a process that translates physical forces into biological signals. Epithelial and endothelial cells are exposed to laminar shear stress (LSS), a tangential force exerted by flowing fluids against the wall of vessels and epithelia. The protocol outlined herein has been used to examine the response of ion channels expressed in Xenopus oocytes to LSS (Hoger et al., 2002; Carattino et al., 2004; Shi et al., 2006). The Xenopus oocyte is a reliable system that allows for the expression and chemical modification of ion channels and regulatory proteins (George et al., 1989; Palmer et al., 1990; Sheng et al., 2001; Carattino et al., 2003). Therefore, this technique is suitable for studying the molecular mechanisms that allow flow-activated channels to respond to LSS. PMID- 28670606 TI - Variability in Puff Topography and Exhaled CO in Waterpipe Tobacco Smoking. AB - OBJECTIVES: We examined intra-individual variability in puff topography and CO measures collected during laboratory waterpipe (WP) tobacco smoking using a research-grade waterpipe (RWP). METHODS: WP smoking topography and exhaled CO measures were obtained from 10 established WP smokers in a single-blind, crossover design. Using a previously validated RWP, each participant smoked "Two Apples" WP tobacco ad libitum with a single quick-light charcoal to satiation in 3 laboratory sessions spaced at least one week apart. To examine the intra individual variability, the intraclass correlation coefficient (rho) for topography and CO measures were estimated. Results: The majority of the topography and CO measures were stable. Most stable were puff frequency (rho = 0.88), number of puffs (rho = 0.86), and puff duration (rho = 0.80). Less stable were peak flow (rho = 0.57) and total puff volume (rho = 0.52). CONCLUSIONS: The results provide the first set of empirical evidence that most topography and CO measurements collected using the RWP from a single laboratory smoking session are stable such that they can be representative of a smoker's puffing behaviors and reproducible among 3 sessions spread equally across 3 weeks. PMID- 28670607 TI - Sub-Nyquist sampling boosts targeted light transport through opaque scattering media. AB - Optical time-reversal techniques are being actively developed to focus light through or inside opaque scattering media. When applied to biological tissue, these techniques promise to revolutionize biophotonics by enabling deep-tissue non-invasive optical imaging, optogenetics, optical tweezing, and phototherapy. In all previous optical time-reversal experiments, the scattered light field was well-sampled during wavefront measurement and wavefront reconstruction, following the Nyquist sampling criterion. Here, we overturn this conventional practice by demonstrating that even when the scattered field is under-sampled, light can still be focused through or inside scattering media. Even more surprisingly, we show both theoretically and experimentally that the focus achieved by under sampling can be one order of magnitude brighter than that achieved under the well sampling conditions used in previous works, where 3*3 to 5*5 pixels were used to sample one speckle grain on average. Moreover, sub-Nyquist sampling improves the signal-to-noise ratio and the collection efficiency of the scattered light. We anticipate that this newly explored under-sampling scheme will transform the understanding of optical time reversal and boost the performance of optical imaging, manipulation, and communication through opaque scattering media. PMID- 28670608 TI - Neurobiological Basis of Individual Variation in Stimulus-Reward Learning. AB - Cues in the environment can guide behavior in adaptive ways, leading one towards valuable resources such as food, water, or a potential mate. However, cues in the environment may also serve as powerful motivators that lead to maladaptive patterns of behavior, such as addiction. Importantly, and central to this article, there is considerable individual variation in the extent to which reward cues gain motivational control over behavior. Here we describe an animal model that captures this individual variation, allowing us to better understand the psychological and neurobiological processes that contribute to cue-evoked behaviors. When a discrete cue is paired with a food reward in a Pavlovian manner it acquires greater control over motivated behavior in some rats ("sign-trackers, STs) than in others ("goal-trackers", GTs). We review studies that have exploited this animal model to parse the neurobiological mechanisms involved in learning associations between stimuli vs. those involved in attributing incentive salience to those same stimuli. The latter seems to be dependent on dopamine and subcortical circuits, whereas the former may engage more cortical "top-down" mechanisms. PMID- 28670609 TI - Symptomatic isolated terminal ileal ulcers: etiology and clinical significance. AB - BACKGROUND: With an increasing number of ileal intubations, isolated terminal ileal ulcers (ITIU) are frequently found during colonoscopies. The present study aimed at studying the etiology and clinical significance of these ulcers in patients having gastrointestinal symptoms. METHODS: This was a prospective observational study performed on consecutive patients who underwent ileocolonoscopy for various gastrointestinal symptoms between 1 January 2014 and 31 December 2014. Clinical, endoscopic, and histological findings of patients with ITIUs were assessed to determine the etiology and they were treated accordingly. Symptom resolution was assessed within 3 - 6 months of initial diagnosis, and colonoscopy was repeated for consenting patients. RESULTS: Among 74 (4.9 %) of 1497 patients who had ITIUs on ileocolonoscopy, 41 (55.4 %) had specific etiologies on initial testing. After 3 - 6 months follow-up, definitive diagnosis was ascertained in 44 (59.5 %) patients [Crohn's disease (CD): 19 (25.7 %), NSAID-induced ulcers: 11 (14.9 %), intestinal tuberculosis (ITB): 9 (12.2 %), and eosinophilic enteritis: 5 (6.8 %)], and 30 patients (40.5 %) had nonspecific ulcers. After treatment, symptomatic and endoscopic resolution were noted in 55/60 patients (91.7 %) and 28/36 patients (77.8 %), respectively. Of 5/60 patients who remained symptomatic, three were initially diagnosed with nonspecific ulcers and two with CD, and they were finally diagnosed with CD and ITB respectively, and treated accordingly. CONCLUSIONS: In patients with gastrointestinal symptoms, more than half of the ITIUs have specific etiologies, and timely diagnosis and appropriate treatment can prevent serious complications. Nonspecific ulcers can be managed with symptomatic treatment, but need close monitoring and re-evaluation in the case of persistence of symptoms. PMID- 28670610 TI - In vivo characterization of abnormalities in small-bowel diseases using probe based confocal laser endomicroscopy. AB - BACKGROUND AND STUDY AIMS: Probe-based confocal laser endomicroscopy (pCLE) enables real-time optical biopsy. Little is known about pCLE imaging deep inside the small bowel, therefore the aim of this study was to determine its usefulness. PATIENTS AND METHODS: Between April 2014 and January 2016, we performed 38 pCLE examinations during double-balloon enteroscopy with intravenous fluorescein in 37 patients with: tumors (n = 10), vascular disorders (n = 6), inflammatory diseases and drug injuries (n = 13), other disorders (n = 4), and normal findings (n = 4). We measured the calibers of capillary and lymphatic vessels at 15 different sites and compared the calibers between pCLE images and histopathology. We also compared pCLE findings with pathologic diagnosis. RESULTS: The inner diameters of capillary vessels beneath the epithelium and in the middle of villi were 16.2 +/- 3.0 um and 14.5 +/- 3.1 um, respectively, in the pCLE images, but these were not consistent with formalin-fixed paraffin-embedded histology. In tumors, larger capillary vessels were observed in aggressive malignant lymphoma and metastasis, and a "soccer ball-like pattern" constituting homogenous dark cells packed with polygonal, narrower capillary vessels was characteristic in pCLE images of a malignant lymphoma follicle. Hereditary hemorrhagic telangiectasia and angiodysplasia contained anastomosis of capillary vessels of different calibers. In IgA vasculitis, segmental capillary strictures were observed. Intestinal lymphangiectasia with protein-losing enteropathy contained a reticular network of lymphatic vessels and dilated lymphatic ducts accompanied by numerous cell gaps. pCLE findings corresponded to pathologic diagnosis in 32 examinations (91 %). CONCLUSIONS: pCLE is useful for in vivo analysis of abnormalities of the capillary and lymphatic vessels and epithelium, and for diagnosis in various small-bowel diseases. PMID- 28670611 TI - Does the presence of a trainee compromise success of biliary cannulation at ERCP? AB - BACKGROUND AND STUDY AIMS: Findings in the literature are conflicting on whether trainee involvement in endoscopic retrograde cholangiopancreatography (ERCP) procedures is detrimental to cannulation success rates. We addressed this in a prospective study, where cannulation success with or without trainee presence was the primary outcome measure. PATIENTS AND METHODS: We prospectively recorded data on 2 senior endoscopists and their trainees over an 18-month period for ERCPs in patients with a virgin ampulla. Presence or absence of a trainee at ERCP procedures was pragmatic, reflecting their other service or training commitments or annual leave. For trainee presence, the training protocol allowed them 6 minutes of supervised time in which to achieve biliary cannulation after reaching the ampulla. Study outcome measures included cannulation success, time to cannulation, technique, whether this was achieved independently by the trainee, and complications. RESULTS: There were 219 procedures recorded and analyzed (134 with a trainee, 85 without). Three trainees were involved. Selective biliary cannulation was achieved in 201 (92 %) of cases. When a trainee was present, cannulation was successful in 122/134 procedures (91 %), compared to 79/85 (93 %) with a senior endoscopist alone ( P = 0.8, Fisher's exact test). Mean time to biliary cannulation with a trainee present was 7 minutes, compared with 5 minutes with no trainee. Mean time for successful independent cannulation by the trainee was 4 minutes, and 9 minutes for a consultant following a trainee's attempt. There were no serious adverse events. CONCLUSION: Our study shows that with this training protocol, involvement of a trainee on a routine secondary care ERCP list does not impair biliary cannulation success, and does not prolong a subsequent attempt by the senior endoscopist if initially unsuccessful. These findings support the involvement of trainees in routine ERCP lists with this training protocol. PMID- 28670612 TI - Predicting outcomes of gastric endoscopic submucosal dissection using a Bayesian approach: a step for individualized risk assessment. AB - BACKGROUND AND STUDY AIMS : Efficacy and adverse events probabilities influence decisions regarding the best options to manage patients with gastric superficial lesions. We aimed at developing a Bayesian model to individualize the prediction of outcomes after gastric endoscopic submucosal dissection (ESD). PATIENTS AND METHODS : Data from 245 gastric ESD were collected, including patient and lesion factors. The two endpoints were curative resection and post-procedural bleeding (PPB). Logistic regression and Bayesian networks were built for each outcome; their predictive value was evaluated in-sample and validated through leave-one out and cross-validation. Clinical decision support was enhanced by the definition of risk matrices, direct use of Bayesian inference software and by a developed online platform. RESULTS : ESD was curative in 85.3 % and PPB occurred in 7.7 % of patients. In univariate analysis, male sex, ASA status, carcinoma histology, polypoid or depressed morphology, and lesion size >= 20 mm were associated with non-curative resection, while ASA status, antithrombotics and lesion size >= 20 mm were associated with PPB. Naive Bayesian models presented AUROCs of ~80 % in the derivation cohort and >= 74 % in cross-validation for both outcomes. Risk matrices were computed, showing that lesions with cancer at biopsies, >= 20 mm, proximal or in the middle third, and polypoid are more prone to non-curative resection. PPB risk was < 5 % in lesions < 20 mm in the absence of antithrombotics. CONCLUSIONS : The derived Bayesian model presented good discriminative power in the prediction of ESD outcomes and can be used to predict individualized probabilities, improving patient information and supporting clinical and management decisions. PMID- 28670613 TI - Risk of perforation in balloon dilation associated with steroid injection for preventing esophageal stricture after endoscopic submucosal dissection. AB - BACKGROUND AND STUDY AIMS: Endoscopic local steroid injection (LSI) has been used to prevent esophageal strictures after endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms (SENs). This study aimed to evaluate the safety and efficacy of LSI therapy. PATIENTS AND METHODS: From May 2007 to September 2014, at four institutions, 40 consecutive patients with SENs were treated with ESD that left a mucosal defect of more than three-quarters of the esophageal circumference. Two patients who underwent esophagectomy after ESD were excluded, and 38 patients were analyzed. The incidence of post-ESD strictures and adverse events associated with LSI were retrospectively investigated. RESULTS: Prophylactic LSI was administered in 28 patients (LSI group), and not administered in 10 patients (Non-prevention group). Post-ESD stricture rates were significantly lower in the LSI group (43 %) than in the Non-prevention group (90 %) ( P = 0.012). Endoscopic balloon dilation (EBD) was conducted in 11 patients (39 %) in the LSI group and in 7 (70 %) in the Non-prevention group. In the LSI group, perforation caused by EBD occurred in five patients, while in the Non prevention group, it occurred in only one patient who had received subsequent LSI before the perforation. Four patients with perforation successfully recovered after conservative therapy, but the other two patients required surgical treatment. A review of follow-up examinations with endoscopic ultrasonography and narrow-band imaging showed impaired ulcer-healing process after LSI. CONCLUSION: LSI is useful for preventing post-ESD strictures, but it appears to increase the risk of perforation in cases of EBD. PMID- 28670614 TI - Efficacy and safety of cold snare resection in preventive screening colonoscopy. AB - BACKGROUND AND AIM: Removal of polyps during colonoscopy effectively prevents the development of colorectal cancer. So far, snare resection with high frequency current with or without prior submucosal saline injection is the method of choice. The aim of this study was to evaluate the feasibility, safety, and outcome of cold snare resection during routine endoscopy. METHODS: In this prospective study, 522 patients undergoing outpatient colonoscopy were included. Cold snare resection for diminutive (< 6 mm), small (6 - 9 mm), and larger polyps (> 9 - 15 mm) was performed using a dedicated cold snare device (Exacto (r) ) without prior submucosal injection. Outcome parameters included bleeding rate, perforation rate, procedure time, histologic evaluation of polyp margins, and success rates. The data were compared to a group of patients undergoing hot snare resection. RESULTS: Overall, 1233 polyps were removed using cold snare resection with an overall success rate of 99.4 %. All failures of cold snare resection occurred in the cecum (8/82, failure rate 9.8 %). In the remaining colon, the success rate was 100 %. Immediate post-polypectomy bleeding occurred in 0.49 % of all patients and was most frequently seen in polyps larger than 9 mm. The procedure time was significantly shorter using cold snare resection compared with hot snare resection (27.6 min vs. 35.7 min, P < 0.01). CONCLUSION: Cold snare resection can be performed safely in outpatients for removal of small polyps in screening colonoscopy. It does not require prior saline injection and reduces procedure time without an increased risk of bleeding. PMID- 28670615 TI - Cold snare polypectomy reduced delayed postpolypectomy bleeding compared with conventional hot polypectomy: a propensity score-matching analysis. AB - BACKGROUND AND STUDY AIMS: Cold snare polypectomy (CSP) for small colorectal polyps has lower incidence of adverse events, especially delayed postpolypectomy bleeding (DPPB). However, few data are available on comparisons of the incidence of DPPB of CSP and hot polypectomy (HP). The aim of this study was to evaluate the incidence of DPPB after CSP and compare it with that of HP. A propensity score model was used as a secondary analysis. PATIENTS AND METHODS: This was a retrospective cohort study conducted in a single municipal hospital. We identified 539 patients with colorectal polyps from 2 mm to 11 mm in size who underwent CSP (804 polyps in 330 patients) or HP (530 polyps in 209 patients) between July 2013 and June 2015. RESULTS: There were no cases of DPPB in the CSP group. Conversely, DPPB occurred in 4 patients (1.9 %) after HP, resulting in a significant difference between the CSP and HP groups (0.008 % vs 0 %, P = 0.02). Propensity score-matching analysis created 402 matched pairs, yielding a significantly higher DPPB rate in the HP group than CSP group (0.02 % vs 0 %, P = 0.04). However, significantly more patients in the CSP group had unclear horizontal margins that precluded assessment (83 vs 38 cases, P < 0.001). The retrieval failure rate was significantly higher in the CSP group than in the HP group (3 % vs 0.7 %, P = 0.01). CONCLUSIONS : DPPB was less frequent with CSP than HP, as selected by the propensity score-matching model. Our findings indicate that CSP is recommended polypectomy in daily clinical setting. However, special care should be taken during polyp retrieval and horizontal margin assessment, and these issues could be taken into account in follow-up after CSP. PMID- 28670616 TI - Safety and efficacy of simultaneous colorectal ESD for large synchronous colorectal lesions. AB - BACKGROUND AND STUDY AIMS : Multiple large colorectal lesions are sometimes diagnosed during colonoscopy. However, there have been no investigations of the feasibility of simultaneous endoscopic submucosal dissection (ESD) for multiple lesions. This study aims to reveal the strategy of simultaneous ESD for multiple large colorectal lesions. PATIENTS AND METHODS : 246 patients who underwent ESD for 274 colorectal lesions were retrospectively evaluated in this study. Fifty one large colorectal lesions among 23 patients were treated by ESD simultaneously (simultaneous group), and 223 patients were treated with ESD for a single lesion (single group). RESULTS: En-bloc resection and curative resection rates did not differ. Compared with the single group, each procedure time was faster (31.8 +/- 23.6 min vs. 45.8 +/- 44.8, P = 0.002), but total procedure time was significantly longer in the simultaneous group (70.6 +/- 33.4 vs. 45.8 +/- 44.8 min, P = 0.01). Rates of adverse events including bleeding and perforation were not higher in the simultaneous group but the mean blood pressure, incidence of bradycardia and the amount of sedative drug used during ESD were significantly higher in the simultaneous group. Multiple logistic regression analysis identified non-experienced physician, lesion size >= 40 mm and submucosal fibrosis as an independent risk factor for procedure duration (>= 90 min) (Odds ratio 11.852, 18.280, and 3.672; P < 0.05, respectively). CONCLUSIONS: Simultaneous ESD for multiple synchronous colorectal lesions is safe and feasible compared with single ESD and can reduce the burden to patients, length of hospital stay and medical expense. These results need to be elucidated by further studies. PMID- 28670617 TI - Comparison of removal techniques in the management of buried bumper syndrome: a retrospective cohort study of 82 patients. AB - BACKGROUND AND STUDY AIMS : Buried bumper syndrome is an infrequent complication of percutaneous endoscopic gastrostomy (PEG) that can result in tube dysfunction, gastric perforation, bleeding, peritonitis or death. The aim of this study was to compare the efficacy of different PEG tube removal methods in the management of buried bumper syndrome in a large retrospective cohort. PATIENTS AND METHODS : From 2002 to 2013, 82 cases of buried bumper syndrome were identified from the databases of two endoscopy referral centers. We evaluated the interval between gastrostomy tube placement and diagnosis of buried bumper syndrome, type of treatment, success rate and complications. Four methods were analyzed: bougie, grasp, needle-knife and minimally invasive push method using a papillotome, which were selected based on the depth of the buried bumper. RESULTS: The buried bumper was cut free with a wire-guided papillotome in 35 patients (42.7 %) and with a needle-knife in 22 patients (26.8 %). It could be pushed into the stomach with a dilator without cutting in 10 patients (12.2 %), and was pulled into the stomach with a grasper in 12 patients (14.6 %). No adverse events (AEs) were registered in 70 cases (85.4 %). Bleeding occurred in 7 patients (31.8 %) after cutting with a needle-knife papillotome and in 1 patient (8.3 %) after grasping. No bleeding was recorded after using a standard papillotome or a bougie ( P < 0.05). Ten of 22 patients (45.5 %) treated with the needle-knife had a serious AE and 1 patient died (4.5 %). CONCLUSIONS : We recommend that incomplete buried bumpers be removed with a bougie. In cases of complete buried bumper syndrome, the bumper should be cut with a wire-guided papillotome and pushed into the stomach. PMID- 28670618 TI - Minute Impurities Contribute Significantly to Olfactory Receptor Ligand Studies: Tales from Testing the Vibration Theory. AB - Several studies have attempted to test the vibrational hypothesis of odorant receptor activation in behavioral and physiological studies using deuterated compounds as odorants. The results have been mixed. Here, we attempted to test how deuterated compounds activate odorant receptors using calcium imaging of the fruit fly antennal lobe. We found specific activation of one area of the antennal lobe corresponding to inputs from a specific receptor. However, upon more detailed analysis, we discovered that an impurity of 0.0006% ethyl acetate in a chemical sample of benzaldehyde-d5 was entirely responsible for a sizable odorant evoked response in Drosophila melanogaster olfactory receptor cells expressing dOr42b. Without gas chromatographic purification within the experimental setup, this impurity would have created a difference in the responses of deuterated and nondeuterated benzaldehyde, suggesting that dOr42b be a vibration sensitive receptor, which we show here not to be the case. Our results point to a broad problem in the literature on use of non-GC-pure compounds to test receptor selectivity, and we suggest how the limitations can be overcome in future studies. PMID- 28670619 TI - Examining Hippocampal Mossy Fiber Synapses by 3D Electron Microscopy in Wildtype and Kirrel3 Knockout Mice. AB - Neural circuits balance excitatory and inhibitory activity and disruptions in this balance are commonly found in neurodevelopmental disorders. Mice lacking the intellectual disability and autism-associated gene Kirrel3 have an excitation inhibition imbalance in the hippocampus but the precise synaptic changes underlying this functional defect are unknown. Kirrel3 is a homophilic adhesion molecule expressed in dentate gyrus (DG) and GABA neurons. It was suggested that the excitation-inhibition imbalance of hippocampal neurons in Kirrel3 knockout mice is due to loss of mossy fiber (MF) filopodia, which are DG axon protrusions thought to excite GABA neurons and thereby provide feed-forward inhibition to CA3 pyramidal neurons. Fewer filopodial structures were observed in Kirrel3 knockout mice but neither filopodial synapses nor DG en passant synapses, which also excite GABA neurons, were examined. Here, we used serial block-face scanning electron microscopy (SBEM) with 3D reconstruction to define the precise connectivity of MF filopodia and elucidate synaptic changes induced by Kirrel3 loss. Surprisingly, we discovered wildtype MF filopodia do not synapse exclusively onto GABA neurons as previously thought, but instead synapse with similar frequency onto GABA neurons and CA3 neurons. Moreover, Kirrel3 loss selectively reduces MF filopodial synapses onto GABA neurons but not those made onto CA3 neurons or en passant synapses. In sum, the selective loss of MF filopodial synapses with GABA neurons likely underlies the hippocampal activity imbalance observed in Kirrel3 knockout mice and may impact neural function in patients with Kirrel3-dependent neurodevelopmental disorders. PMID- 28670622 TI - Electrochemical Amplification in Side-by-Side Attoliter Nanogap Transducers. AB - We report a strategy for the fabrication of a new type of electrochemical nanogap transducer. These nanogap devices are based on signal amplification by redox cycling. Using two steps of electron-beam lithography, vertical gold electrodes are fabricated side by side at a 70 nm distance encompassing a 20 attoliter open nanogap volume. We demonstrate a current amplification factor of 2.5 as well as the possibility to detect the signal of only 60 analyte molecules occupying the detection volume. Experimental voltammetry results are compared to calculations from finite element analysis. PMID- 28670620 TI - Linking Chronic Inflammation with Cardiovascular Disease: From Normal Aging to the Metabolic Syndrome. AB - The metabolic syndrome (MetS) is a cluster of clinical disorders including an unhealthy body habitus with a large waistline, dyslipidemia, glucose intolerance and hypertension. It is known that these disorders not only increase the chances of developing type 2 diabetes mellitus (T2DM), but also cardiovascular disease (CVD). Furthermore, the co-occurrence of all these risk factors known as the MetS is linked to pathways sharing common underlying mediators and mechanisms. Though insulin resistance has been considered as the root of the problem to explain the conglomerate of metabolic abnormalities within this syndrome; new evidence points to several pro-inflammatory cytokines, reactive oxygen species and free fatty acid intermediates might play an even greater role in regulating a series of intracellular signaling pathways sustain as well as perpetuate the development of the MetS and its CVD complications. Since having a diagnosis of MetS confers not only a 5-fold increase in the risk of T2DM, but also a 2-fold risk of developing CVD over a period of 5 to 10 years; it is vital to better recognize the mechanisms by which the MetS is associated with such adverse outcomes. Therefore, it is the purpose of this review to address (1) how inflammation modifies insulin sensitivity, (2) known factors believed to contribute to this process, and (3) new concepts of inflammatory markers in regulating the development of MetS and its individual components. PMID- 28670621 TI - Changes in DTI Diffusivity and fMRI Connectivity Cluster Coefficients for Students with and without Specific Learning Disabilities In Written Language: Brain's Response to Writing Instruction. AB - Before and after computerized writing instruction, participants completed assessment with normed measures and DTI and fMRI connectivity scanning. Evidence based differential diagnosis was used at time 1 to assign them to diagnostic groups: typical oral and written language (n=6), dysgraphia (impaired handwriting, n=10), dyslexia (impaired word spelling and reading, n=20), and OWL LD (impaired syntax construction, n=6). The instruction was aimed at subword letter writing, word spelling, and syntax composing. With p <.001 to control for multiple comparisons, the following significant findings were observed in academic achievement, DTI (radial diffusivity RD, axial diffusivity AD, and mean diffusivity MD), and graph cluster coefficients for fMRI connectivity. A time effect (pre-post intervention increase) in handwriting and oral construction of sentence syntax was significant; but diagnostic group effects were significant for dictated spelling and creation of word-specific spellings, with the dyslexia and OWL LD groups scoring lower than the typical control or dysgraphia groups. For RD a time effect occurred in anterior corona radiata and superior frontal. For AD a time effect occurred in superior corona radiata, superior frontal region, middle frontal gyrus, and superior longitudinal fasciculus. For MD a time effect occurred in the same regions as AD and also anterior coronal radiata. A diagnostic group effect occurred for graph cluster coefficients in fMRI connectivity while writing the next letter in alphabet from memory; but the diagnostic group * time interaction was not significant. The only significant time * treatment interaction occurred in right inferior frontal gyrus associated with orthographic coding. Compared to time 1, cluster coefficients increased at time 2 in all groups except in the dysgraphia group in which they decreased. Implications of results are discussed for response to instruction (RTI) versus evidence-based differential diagnosis for identifying students with SLDs in writing which may be best understood at both the behavioral and brain levels of analysis. PMID- 28670623 TI - Bright Bioluminescent BRET Sensor Proteins for Measuring Intracellular Caspase Activity. AB - FRET-based caspase activity probes have become important tools to monitor apoptotic cell signaling. However, their dependence on external illumination is incompatible with light sensitive cells and hampers applications that suffer from autofluorescence and light scattering. Here we report the development of three caspase sensor proteins based on Bioluminescence Resonance Energy Transfer (BRET) that retain the advantages of genetically encoded, ratiometric optical probes but do not require external illumination. These sensors consist of the bright and stable luciferase NanoLuc and the fluorescent protein mNeonGreen, fused together via a linker containing a recognition site for caspase-3, -8, or -9. In vitro characterization showed that each caspase sensor displayed a robust 10-fold decrease in BRET ratio upon linker cleavage, with modest caspase specificity. Importantly, whereas scattering and background fluorescence precluded FRET-based detection of intracellular caspase activity in plate-reader assays, such measurements could be easily performed using our caspase BRET sensors in a high throughput format. The brightness of the BRET sensors also enabled long-term single-cell imaging, allowing BRET-based recording of cell heterogeneity in caspase activity in a heterogenic cell population. PMID- 28670624 TI - Complete mitochondrial genome of the Eurasian collared lemming Dicrostonyx torquatus Pallas, 1779 (Rodentia: Arvicolinae). AB - The complete mitochondrial genome the Eurasian collared lemming was obtained by using PCR amplification and capillary sequencing (GenBank accession no. KX066190). The collared lemming mitochondrial genome is 16,340 base pairs long and shows the gene order, contents and gene strand asymmetry typical for mammals. The mitogenome sequence provides an important new genomic resource for the collared lemming, which is a model study species in Arctic phylogeography and biotic history. PMID- 28670625 TI - Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology. AB - Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and mechanisms of liver injury induced by APAP overdose have been the focus of extensive investigation. Studies in the mouse model, which closely reproduces the human condition, have shown that hepatotoxicity is initiated by formation of a reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes cellular glutathione and forms protein adducts on mitochondrial proteins. This leads to mitochondrial oxidative and nitrosative stress, accompanied by activation of c-jun N-terminal kinase (JNK) and its translocation to the mitochondria. This then amplifies the mitochondrial oxidant stress, resulting in translocation of Bax and dynamin related protein 1 (Drp1) to the mitochondria, which induces mitochondrial fission, and ultimately induction of the mitochondrial membrane permeability transition (MPT). The induction of MPT triggers release of intermembrane proteins such as apoptosis inducing factor (AIF) and endonuclease G into the cytosol and their translocation to the nucleus, causing nuclear DNA fragmentation and activation of regulated necrosis. Though these cascades of events were primarily identified in the mouse model, studies on human hepatocytes and analysis of circulating biomarkers from patients after APAP overdose, indicate that a number of mechanistic events are identical in mice and humans. Circulating biomarkers also seem to be useful in predicting the course of liver injury after APAP overdose in humans and hold promise for significant clinical use in the near future. PMID- 28670627 TI - LR8 Expression in fibroblasts of healthy and fibrotic human tissues. AB - LR8 gene was first reported in a subpopulation of cultured human lung fibroblasts expressing the receptor for C1q-globular domain, and it was not detectable in cultured endothelial cells and smooth muscle cells. LR8 mRNA levels were higher in fibrotic lungs. In this study we assessed LR8 production in human tissues and determined if the distribution of fibroblasts producing LR8 is affected in fibrosis. Normal and fibrotic tissue sections from human liver, lung and kidneys were immunostained with antibodies to LR8 and examined for the presence of fibroblasts staining positively and negatively. The cells were also examined for co-expression of alpha-smooth muscle actin (SMA), a marker for myofibroblasts. The results showed that LR8 was expressed by fibroblasts, smooth muscle cells, endothelial cells, bile duct cells, pulmonary alveolar cells and distal and proximal kidney tubule cells. Connective tissues of normal and fibrotic tissues contained fibroblasts staining positively and negatively with anti- LR8 antibody. The number of LR8-positive cells was higher in fibrotic tissues, but differences were not statistically significant. Fibroblasts producing both LR8 and SMA were present in higher numbers in fibrotic tissues as compared to normal tissues and the differences were statistically significant (p<0.05). Our results show that fibroblast subtypes differing in LR8 expression are present in human tissues, and that in fibrotic tissues cells co-expressing LR8 and SMA are present. Our results indicate that LR8 expressing cells may participate in the early stages of fibrotic diseases and that fibroblasts expressing LR8, not LR8 negative cells, have potential to become myofibroblasts in fibrotic tissues. PMID- 28670626 TI - The Impact of Sterile Inflammation in Acute Liver Injury. AB - BACKGROUND: The liver has a number of functions in innate immunity. These functions predispose the liver to innate immune-mediated liver injury when inflammation goes unchecked. Significant progress has been made in the last 25 years on sterile inflammatory liver injury in a number of models; however, a great deal of controversy and many questions about the nature of sterile inflammation still exist. AIM: The goal of this article is to review sterile inflammatory liver injury using both a basic approach to what constitutes the inflammatory injury, and through examination of current models of liver injury and inflammation. This information will be tied to human patient conditions when appropriate. RELEVANCE FOR PATIENTS: Inflammation is one of the most critical factors for managing in-patient liver disease in a number of scenarios. More information is needed for both scientists and clinicians to develop rational treatments. PMID- 28670629 TI - Statistical Analysis Plan for Stage 1 EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) Study. AB - Antidepressant medications are commonly used to treat depression, but only about 30% of patients reach remission with any single first-step antidepressant. If the first-step treatment fails, response and remission rates at subsequent steps are even more limited. The literature on biomarkers for treatment response is largely based on secondary analyses of studies designed to answer primary questions of efficacy, rather than on a planned systematic evaluation of biomarkers for treatment decision. The lack of evidence-based knowledge to guide treatment decisions for patients with depression has lead to the recognition that specially designed studies with the primary objective being to discover biosignatures for optimizing treatment decisions are necessary. Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) is one such discovery study. Stage 1 of EMBARC is a randomized placebo controlled clinical trial of 8 week duration. A wide array of patient characteristics is collected at baseline, including assessments of brain structure, function and connectivity along with electrophysiological, biological, behavioral and clinical features. This paper reports on the data analytic strategy for discovering biosignatures for treatment response based on Stage 1 of EMBARC. PMID- 28670628 TI - Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges. AB - In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term 'migrastatics' for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers. PMID- 28670630 TI - Impaired suppression of delay-period alpha and beta is associated with impaired working memory in schizophrenia. AB - BACKGROUND: Although people with schizophrenia (PSZ) frequently exhibit reduced working memory capacity relative to healthy comparison subjects (HCS), the mechanisms that underlie this impairment are not yet known. The present study aimed to assess one putative mechanism: impaired suppression of alpha and beta frequency bands during the delay period of a visual working memory task. METHODS: The electroencephalogram (EEG) was recorded from 30 PSZ and 31 HCS while they completed a change detection task in which they were required to remember a briefly presented array of colored squares over an 1800-ms delay interval. RESULTS: Overall, we found that PSZ had significantly reduced alpha and beta-band suppression during the delay interval compared to HCS, and that these significant differences emerged early (100-200 ms after the onset of the memory array). Furthermore, the magnitude of suppression was significantly associated with task performance across both groups. Finally, the magnitude of suppression in alpha and beta frequency bands was significantly associated with a range of cognitive measures among HCS, but not PSZ. CONCLUSIONS: These results implicate impaired alpha/beta suppression during the consolidation period of working memory tasks as a promising neural mechanism that constrains capacity in PSZ. PMID- 28670631 TI - Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation. AB - OBJECTIVE: To test the hypothesis that cardiac-directed expression of the cytoplasmic domains of adenylyl cyclase-6 (AC6) would have beneficial effects on the heart. BACKGROUND: Eliminating the two transmembrane domains of AC6 yields a protein with an intact catalytic domain that is disengaged from membrane associated beta-adrenergic receptor stimulation, but with enhanced propensity for intracellular interactions. METHODS: We constructed a peptide of the C1 and C2 segments of AC6 (C1C2), expressed C1C2 in an adenovirus vector and generated transgenic lines with cardiac-directed C1C2 expression, which underwent sustained isoproterenol (Iso) infusion. RESULTS: Gene transfer of C1C2 in cardiac myocytes showed reduced cAMP generation in response to Iso-stimulation. C1C2 transgenic mice had normal left ventricular (LV) structure and function. LV samples from C1C2 mice showed diminished Iso-stimulated cAMP generation but normal LV contractile responses, suggesting a compensatory mechanism. Cardiac myocytes from C1C2 mice showed increased Iso-stimulated Ca2+ release and reduced time to peak Ca2+ release. After 7 days Iso infusion, control mice tended to show reduced LV function, but C1C2 mice showed increases in both LV peak +dP/dt and peak -dP/dt indicating enhanced LV systolic and diastolic function. LV from C1C2 mice showed a 2.6-fold increase in SERCA2a protein, and cardiac myocytes showed increased Ca2+ release, reduced time to peak Ca2+ release and reduced Tau. CONCLUSIONS: In C1C2 mice, sustained isoproterenol infusion increases rather than decreases LV function. Reduced cAMP generation and resistance to catecholamine cardiomyopathy are attractive features of this novel AC-related protein. PMID- 28670632 TI - Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease. AB - PURPOSE: To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. DESIGN: Observational case review. PARTICIPANTS: Three patients with advanced VHL related juxtapapillary RCH treated with systemic sunitinib malate. METHODS: Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. MAIN OUTCOME MEASURES: Visual acuity, size of RCH, and degree of exudation. RESULTS: Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. CONCLUSIONS: Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other medications in the same class or drugs directed at multiple targets in the tumor, may be safer and more effective for the treatment of advanced VHL-associated RCH. PMID- 28670633 TI - The orphan nuclear receptor ROR alpha and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease. AB - Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that Rora deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition and reduced fibroblast accumulation. Although Rora is best known for its role in ILC2 development, we find that Salmonella-induced fibrosis is independent of eosinophils, STAT6 signaling and Th2 cytokine production arguing that this process is largely ILC2 independent. Instead, we observe reduced levels of ILC3- and T cell-derived IL 17A and IL-22 in infected gut tissues. Furthermore, using Rorasg/sg /Rag1-/- bone marrow chimeric mice, we show that restoring ILC function is sufficient to re establish IL-17A and IL-22 production and a profibrotic phenotype. Our results show that RORalpha-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn's-like diseases. PMID- 28670634 TI - PREVALENCE OF TOXOPLASMA GONDII IGG AND IGM AND ASSOCIATED RISK FACTORS AMONG HIV POSITIVE AND HIV-NEGATIVE PATIENTS IN VHEMBE DISTRICT OF SOUTH AFRICA. AB - BACKGROUND: Toxoplasma gondii is a zoonotic parasite that has arisen as an important opportunistic infection that causes morbidity and mortality especially in HIV positive patients. This study was carried out to determine the sero prevalence of T. gondii (IgG and IgM) and the associated risk factors among HIV positive and negative patients in Northern South Africa. MATERIALS AND METHODS: The study was conducted in the Vhembe District in Limpopo province from April 2012 to January 2013. A well-structured questionnaire was used to collect socio demographic information and possible risk factor information on toxoplasmosis from participants. A total of 161 blood samples of both HIV positive and negative patients visiting the local clinics in the Vhembe district were collected. Serum samples were tested for IgG and IgM against T. gondii using commercially available ELISA protocol. RESULTS: The prevalence of T. gondii IgG was 31.7% while that of T. gondii IgM was 4.9%. The prevalence of T. gondii IgG was higher in HIV positive patients (38%) compared to 16.7% among HIV negative patients (p=0.001). Toxoplasma gondii IgG antibodies were more common in patients who were not taking ARV's (46.2%) compared to those who were taking ARV's (35.2%) (P<0.001). CONCLUSIONS: The present study has shown a high prevalence of T. gondii (IgG) among patients attending different HIV clinics in the Vhembe district with no current infections among pregnant women. In addition to the sero positive status of the patient to HIV, other significant risk factors for toxoplasmosis included high viral load, non-adherence to ARV therapy and age (>25 years). PMID- 28670635 TI - VARIABILITY OF URINE PARAMETERS IN CHILDREN INFECTED WITH SCHISTOSOMA HAEMATOBIUM IN UKAWU COMMUNITY, ONICHA LOCAL GOVERNMENT AREA, EBONYI STATE, NIGERIA. AB - BACKGROUND: Schistosomiasis, a chronic, debilitating and neglected tropical and sub-tropical water-borne ailment, is highly endemic in Nigeria, especially among primary school children in rural communities. The study on the variability of urine parameters in children infected with Schistosomahaematobium in Ukawu community, Onicha Local Government Area of Ebonyi State, was undertaken. MATERIALS AND METHODS: Urine samples were aseptically collected from 400 primary school children in the community and analysed using chemical reagent strips and sedimentation techniques. RESULTS: The study revealed an overall prevalence of 27% as 108 pupils out of 400 were infected with S. haematobium in the area. Proteinuria, haematuria and leucocyturia were observed to occur in 67.0%, 79.0% and 74.9% respectively. Males had higher infections and higher occurrences of proteinuria, haematuria and leucocyturia (72.5%, 88.2% and 82.4% respectively). There was no significant difference with respect to sex (P<0.05). Children within ages 12-15 years had the highest prevalence of S. haematobium (35.5%) while those within the ages of 4-7 had the least prevalence (11.4%). The difference in the rate of infection between the different age groups was significant, statistically (P>0.05). Children within ages 12-15 had the highest occurrence of proteinuria, haematuria and leucocyturia while children within ages 4-7 had the least occurrence of the three urine parameters. All the pupils excreting above 40 egg/10ml of urine had proteinuria, haematuria and leucocyturia. CONCLUSION: The study revealed that the community studied is endemic with Schistosoma haematobium infections and the level of the urine parameters increased with the intensity of infection. Prompt case detection and treatment, good personal hygiene, eradication of snail hosts, public enlightenment and proper waste disposal are hereby recommended. PMID- 28670636 TI - ATTITUDES OF FEMALE STREET VENDORS TOWARDS HIV/AIDS IN VHEMBE DISTRICT OF SOUTH AFRICA. AB - BACKGROUND: The Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) are still global health problems. This study was conducted to describe the attitudes of female street vendors (FSV) in Thohoyandou, Vhembe district, towards HIV/AIDS and those infected with the virus. MATERIALS AND METHODS: A quantitative, cross-sectional survey design was adopted. Data were collected by means of a structured, self-administered questionnaire and analyzed using the Statistical Package for Social Sciences (SPSS) version 20.0. RESULTS: Majority (85.0%) of the participants had completed secondary education, 46.7% were single and 41.5% were aged 40 and above. Most of them (90.5%) indicated that they would accept to do a voluntary HIV test. Fear of stigmatization ranked highest among the reasons given by those not in favour of testing. Whilst 91.0% of the participants reported that they can stay in the same house with a person who is HIV positive and 88.5% said they would not have sex in exchange for money, only 57.5% indicated that they would agree to take antiretroviral drugs if they tested positive in pregnancy. The level of education was found to be significantly associated (p-value = 0.000) with the type of attitude shown towards HIV and those infected. CONCLUSION: It is recommended that HIV information providers and health workers in South Africa pay more attention to enlightening women about the importance of taking antiretroviral drugs in pregnancy to reduce the incidence of mother-to-child transmission of HIV. PMID- 28670637 TI - SEROTYPING AND ANTIMICROBIAL DRUG RESISTANCE OF SALMONELLA ISOLATED FROM LETTUCE AND HUMAN DIARRHEA SAMPLES IN BURKINA FASO. AB - BACKGROUND: In Burkina Faso dirty water in particular those of the stoppings and the gutter ones are used for vegetables irrigation in the gardens. The aim of this study was to determine the prevalence and antibiotic susceptibility of Salmonella serotypes from humans and lettuce samples inBurkina Faso. Materials and Methods:Salmonella strains isolated from patients in 2009 to 2015 and lettuce samples in 2014 in Burkina Faso were serotyped using specific antisera. All strains were subjected to a set of 14 antibiotics to study their antibiogram by using Baeur-Kirby disk diffusion method. RESULTS: Out of 154 Salmonella isolated, 60 were from human and 94 from lettuce samples. Serotyping revealed four different serotypes and 39% (60) untypeable strains from human and lettuce (14 and 46 strains). Salmonella serotypes from human and lettuce samples were: Paratyphi A (10% and 22%), Paratyphi B (34% and 8%), Paratyphi C (14% and 18%) and Typhi (21% and 1%). A high resistance of Salmonella Paratyphi B and Salmonella spp to tetracycline were 70% from human and 35 % from lettuce samples. Multiresistance was observed to tetracycline, chloramphenicol and amoxicillin/clavulanic-acid or ampicillin with Salmonella ParatyphiB 35% and Salmonella Typhi 33% from human samples and Salmonella spp 4% from lettuce samples. CONCLUSION: This study showed the diversity of Salmonella serotypes from both clinical and environmental samples and emergence of multiresistant Salmonella to antibiotics in Burkina Faso. A lettuce is a potential source of transmission of Salmonella causing diarrhea among human in Burkina Faso. List of non-standard Abbreviations : HDB: Hopital du District de Bogodogo, LNSP: Laboratoire National de Sante Publique, DSG : District Sanitaire de Gourcy, DSB : District Sanitaire de Boromo. PMID- 28670638 TI - A COMPARISON OF RAPID DIAGNOSTIC TESTING (BY PLASMODIUM LACTATE DEHYDROGENASE), AND QUANTITATIVE BUFFY COAT TECHNIQUE IN MALARIA DIAGNOSIS IN CHILDREN. AB - BACKGROUND: The World Health Organization (WHO) considers early and rapid diagnosis as one of the strategies to control malaria. This study compared the performance of Quantitative Buffy Coat (QBC) test and the Plasmodium lactate dehydrogenase (pLDH) rapid diagnostic test (RDT) with microscopy as the gold standard. MATERIALS AND METHODS: The study involved children ages 0-5 years who presented with a history of fever at the University College Hospital, Ibadan, Nigeria. Blood was collected from each patient and used for RDT, QBC and Giemsa stained blood films for malaria parasites (MP). Results of QBC and RDT were compared with microscopy results for the diagnosis of malaria. RESULTS: A total of 370 cases (194 boys and 176 girls) were studied giving a male: female ratio of 1.1:1. Of the 370 cases tested using Giemsa-stained thick blood films for MP, 78 (21 %) were positive. For the QBC test, 78 (21%) of the cases were positive with sensitivity, specificity, positive and negative predictive values of 70.5 %, 92.1%, 70.5 % and 92.1 % respectively. Seventy-six (20%) of the cases were positive by RDT with sensitivity, specificity, positive and negative predictive values of 84.2 %, 95.2 %, 82.1 %, and 95.9 % respectively. There was no significant difference in the sensitivity of QBC compared with the RDT. CONCLUSION: Both the QBC and the pfLDH (RDT) performed reasonably well in this study Malaria rapid diagnostic tests are recommended in malaria endemic clinical settings to avoid unnecessary antimalarial treatment. List of Abbreviations: AO: Acridine orange, AIDS: Acquired immunodeficiency syndrome, ACT: Artemisinin-based combination therapy, CM:Cerebral malaria, BCP:Benzothiocarboxypurine, DDT:Dichloro-diphenyl-trichloroethane, DNA:DeoxyriboNucleic Acid, ELAM-1: Endothelial leukocyte adhesion molecule, G6PD: Glucose-6-Phosphate Dehydrogenase, HIV: Human immuno deficiency virus, HRP 2: Histidine Rich Protein 2, ICAM -1: Inter cellular adhesion molecule1, ICER: Incremental cost effectiveness ratio, IL 1: Interleukin -1, IFN-g: Interferon-gamma, IgG: Immunoglobulin G, MP: Malaria parasite, NADP: Oxidised Nicotinamide Adenine Dinucleotide Phosphate, NADPH: Reduced Nicotinamide Adenine Dinucleotide Phosphate, PCV: Packed Cell Volume (haematocrit), P. falciparum: Plasmodium falciparum, PLDH: Plasmodium lactate dehydrogenase, PCR: Polymerase Chain Reaction, PPV: Positive predictive value, QBC: Quantitative Buffy Coat examination, TNF: Tumour necrosis factor, NPV: Negative predictive value, RDT: Rapid diagnostic test, SP: Sulphadoxine Pyrimethamine, SMA: Severe malarial anaemia, UM: Uncomplicated malaria, USA:United States of America, VCAM-1: Vascular cell adhesion molecule, WBC: White Blood Cell, WHO: World Health Organization. PMID- 28670639 TI - EXTENDED-SPECTRUM BETA-LACTAMASE PRODUCING GRAM NEGATIVE BACTERIA IN IRAN: A REVIEW. AB - BACKGROUND: The emergence and spread of extended spectrum beta-lactamase (ESBL) producing Gram- negative bacteria (GNB), particularly in Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, have increased all over the world. ESBLs are characterized by their ability to hydrolyze beta-lactams, early cephalosporins, oxyimino-thiazolyl cephalosporins, and monobactams, but not cephamycins or carbapenems. The rate of nosocomial infections caused by ESBL producing GNB in Asia Pacific has increased and several studies have identified their prevalence in the region. The aim of this study is to review the prevalence of ESBL-producing GNB in the West Asia and the Middle East with a particular focus on Iran. MATERIALS AND METHODS: The available evidence from various studies (Microbia and clinical studies, retrieved from the PubMed, and Scopus databases) regarding the ESBL producing Gram negative bacteria in Iran were evaluated. RESULTS: In almost all parts of the country, high resistance has been observed, especially in the central part of Iran. Up to 89.8% Escherichia coli, 72.1% Klebsiella pneumonia, 84.2% Acinetobacter baumannii, and 83.8% Pseudomonas aeruginosa isolates are ESBL positive. CONCLUSION: The present study showed the increasing prevalence of ESBLs in different regions of Iran, which could be useful to strategic policy towards reducing reduce their prevalence. PMID- 28670641 TI - TICK INFESTATION: A 200-PATIENTS' SERIES. AB - BACKGROUND: A great number of zoonotic diseases with high mortality rate are transmitted by ticks. We performed this study in order to investigate patients admitted to emergency department following a tick bite. We examined the patients and get knowledge about the infestation and we followed up them for possible tick conducted disease symptoms and laboratory findings both clinically and serologically. MATERIALS AND METHODS: The study presented was hold for one year, between 01.01.2012 and 31.12.2012. 200 tick infested cases, admitted to Emergency Department of Haydarpasa Numune Training and Research Hospital, were subjected in the study. Demographic patterns of the patients and the region they come from, infested area on body, admission time and blood analyzing results were detected. RESULTS: Rate of adult patients to pediatric was 2:1; gender distribution was similar to each other. The most common body areas that ticks were removed from were lower extremity. The highest tick bite incidence was in summer and on weekends. No tick bite incident of Istanbul surrounding from the year 2012 progressed to a zoonotic disease. CONCLUSIONS: Although non-of the patients of our study has been diagnosed with Crimean-Congo hemorrhagic fever we informed all of them for the incubation period and call for observation during the time. Tick borne infections may present with vary of symptoms, the most sever of which is hemorrhagic diathesis and patients should be informed for the risks. Knowledge of local area fauna risks may guide physicians so studies on this topic are essential. PMID- 28670640 TI - PERIPHERAL PARASITAEMIA AND ITS ASSOCIATION WITH PLASMA CYTOKINES LEVELS IN MALARIA-INFECTED PREGNANT WOMEN IN ABA, ABIA STATE, NIGERIA. AB - BACKGROUND: Cytokines in pregnant female may not be a normal phenomenon as malarial infection is often associated with strong CD4+ cell activation and up regulation of pro-inflammatory cytokines. We investigated the relationship between peripheral parasitaemia and plasma levels of cytokines among malaria infected pregnant women in Aba, Abia State, Nigeria. MATERIALS AND METHODS: A total of 206 non-HIV positive asymptomatic malaria parasitaemic (n=144) and non parasitaemic (n=62) pregnant women were recruited for this study alongside 80 non pregnant women who served as positive (n=40) and negative (n=40) controls. Blood samples were aseptically collected from each subject and tested for HIV and malaria parasites using standard methods. Also, plasma levels of cytokines were measured using Th1/Th2 human cytokine ELISA kits (Abcam, UK). Analysis of Variance and Student's t-test were used for Comparison of groups while Pearson's Correlation Coefficient was used for tests of association. RESULTS: The results revealed a mean parasite density of 685.56+/-484.55 parasites/ul of blood. Malaria infected pregnant subjects showed significantly higher levels of IFN gamma, TNF-alpha, IL-4, IL-6 and IL-10 when compared with their non-infected counterparts (P< 0.05). The cytokines evaluated were higher in moderate parasitaemia than mild parasitaemia. Positive correlation existed between peripheral parasite density (PPD) and IL-4 (r= 0.24, P=0.004), PPD and IL-6 (r = 0.35, P = 0.001) as well as PPD and IL-10 (r = 0.29, P = 0.001). CONCLUSION: This study showed that increase in peripheral parasitaemia increased levels of some plasma cytokines (IL-4, IL-6 and IL-10) but not IFN-gamma and TNF-alpha in the malaria infected pregnant women studied. PMID- 28670642 TI - MULTILOCUS SEQUENCE TYPING OF CARBAPENEM RESISTANT PSEUDOMONAS AERUGINOSA ISOLATES FROM PATIENTS PRESENTING AT PORT ELIZABETH HOSPITALS, SOUTH AFRICA. AB - BACKGROUND: Pseudomonas aeruginosa is an important nosocomial pathogen that exhibits multiple drug resistance with increasing frequency, especially to carbapenems making patient treatment difficult. Carbapenem-resistance may be caused by porin gene mutations, active drug efflux, and carbapenemase production. This study evaluated the incidence of genes responsible for carbapenemase production in carbapenem-resistant Pseudomonas aeruginosa and assessed the genetic relatedness of the isolates by multi locus sequence typing (MLST). MATERIALS AND METHODS: Identification and antimicrobial susceptibility testing of P. aeruginosa isolates (n=234) by the VITEK 2 system detected 81 carbapenem resistant P. aeruginosa isolates. PCR and DNA sequencing were used to screen isolates for three metallo-beta-lactamase encoding genes. MLST included amplification of seven housekeeping genes and sequence type alignment using the online P. aeruginosa MLST database. RESULTS: Only the blaVIM-2 gene was detected in 15 of the 81 carbapenem resistant isolates. MLST indicated six different novel sequence types among the blaVIM-2 positive P. aeruginosa isolates with the majority of the isolates (9/15) containing identical allelic profiles of the sequence type allocated ST1 (provisionally assigned sequence type, awaiting addition of new sequence types to PubMLST database). Five of these ST1 isolates were from patients and an environmental sample in the same hospital ward suggesting an environmental reservoir. Carbapenem resistance in the blaVIM-2 negative isolates may be due to other mechanisms. CONCLUSION: The incidence of genes responsible for carbapenemase production in carbapenem-resistant Pseudomonas aeruginosa and genetic relatedness of these isolates in public healthcare facilities within the Port Elizabeth area is of concern and requires further investigation. PMID- 28670643 TI - FACTORS ASSOCIATED WITH TB/HIV CO-INFECTION AMONG DRUG SENSITIVE TUBERCULOSIS PATIENTS MANAGED IN A SECONDARY HEALTH FACILITY IN LAGOS, NIGERIA. AB - BACKGROUND: This study assessed factors associated with TB/HIV co-infection among TB patients managed in a secondary health facility in Lagos Nigeria. MATERIALS AND METHODS: A retrospective review of treatment cards of patients seen at a secondary referral hospital between January 1 2014 and December 31 2014 was conducted. Treatment outcomes and factors associated with TB/HIV co-infection were assessed. RESULTS: Of the 334 records of patients reviewed, the proportion of patients with TB/HIV co-infection was 21.6%. The odds of having TB/HIV co infection was 2.7 times higher among patients above 40 years than patients less than 25 years (AOR 2.7 95% CI 1.1 - 6.5, p =0.030). In addition, the odds of having TB/HIV co-infection was 3.3 higher among extra-pulmonary TB cases (AOR 3.3; 95% CI 1.2 - 9.5; p = 0.026) and 2.1 times higher among retreated patients (AOR 2.1; 95% CI 1.1 - 3.9; p = 0.017) than pulmonary TB and new patients respectively. The chance of having TB/HIV co-infection was 2.7-fold more in patients with poor treatment outcomes than patients with treatment success (AOR 2.7; 95%CI 1.3 - 5.4; p =0.006). CONCLUSION: TB/HIV co-infection rate was high in the study area. There is need to put measures in place to improve treatment outcomes of TB/HIV co-infected patients. PMID- 28670644 TI - CARRIAGE OF MULTIDRUG RESISTANT ENTEROCOCCUS FAECIUM AND ENTEROCOCCUS FAECALIS AMONG APPARENTLY HEALTHY HUMANS. AB - BACKGROUND: Enterococci are indigenous flora of the gastro-intestinal tracts of animals and humans. Recently, interest in two major species, E. faecium and E. faecalis, has heightened because of their ability to cause serious infections and their intrinsic resistance to antimicrobials. This study was aimed at determining the prevalence of E. faecium and E. faecalis in human faecal samples and evaluating the susceptibility of the isolates to antibiotics. MATERIALS AND METHODS: One hundred faecal samples were collected from apparently healthy individuals and analysed using conventionalbacteriological methods. The susceptibility profile of the isolates to nine antibiotics were determined using disk diffusion method. RESULTS: Seventy-three (73) Enterococcus were phenotypically identified and 65 of the isolates were differentiated into 36 (55.4%) E. faecium and 29 (44.6%) E. faecalis. Eight (8) isolates could not be identified by the conventional biochemical methods employed. No dual colonization by the E. faecalis and E. faecium was observed and isolation rate was not dependent on sex of the participants. All the isolates were resistant to ceftriaxone, cefuroxime and ceftizoxime. Enterococcus faecium exhibited resistance toerythromycin (88.9%), gentamicin (77.8%), amoxicillin-clavulanate (63.9%), ofloxacin (44.4%), teicoplanin (19.4%) and vancomycin (16.7%). Enterococcus faecalis showed the least resistance to vancomycin (13.8%) and teicoplanin (27.7%). Remarkable multiple antibiotic resistances to the classes of antibiotic tested were observed among the two species. CONCLUSION: The high carriage rate of antibiotic resistant E. faecium and E. faecalis in this study provides information on the local antibiotic patterns of our enterococci isolates thereby suggesting that they could present as important reservoir and vehicle for dissemination of resistant genes in our community. PMID- 28670645 TI - DIAGNOSIS OF ORF IN WEST AFRICAN DWARF GOATS IN UYO, AKWA IBOM STATE, NIGERIA. AB - BACKGROUND: Sixty (60) male West African Dwarf goats were reported with clinical signs of enlarged lymph nodes, scabs on the mouth, nose and ears. Two of the goats died and post mortem examination reveals enlarged submandibular lymph nodes and vesicular lesions on the tongue. Clinical diagnosis of Orf has been reported in Nigeria but this report is the confirmatory diagnosis of Orf in a suspected outbreak in an experimental farm in Uyo, Akwa Ibom State, Nigeria using molecular techniques. MATERIALS AND METHODS: Scabs, spleen and lymph node samples from goats suspected to have died from Orf were collected, transported on ice to the laboratory and homogenized. The DNA was extracted using QIAmp DNA minikit (Qiagen) according to the manufacturer's instructions. Orf virus (ORFV) was amplified using published ORFVspecific primers by PCR. RESULTS: Morbidity and mortality were 100% and 3.3% respectively, while ORFV was detected by PCR. Diagnosis of Orf was confirmed based on clinical signs of enlarged lymph nodes, scabs on the mouth, nose and ears, necropsy findings of enlarged submandibular lymph nodes and vesicular lesions on the tongue and PCR results. CONCLUSION: This may be the first report of molecular diagnosis of Orf in Nigeria. The 100% morbidity and 3.3% mortality rate is higher than previously reported thus Orf is becoming of greater economic importance than previously thought. It is therefore recommended that routine laboratory diagnosis of Orf be carried nationwide to determine the prevalence of Orf in Nigeria. PMID- 28670646 TI - SEROLOGICAL SURVEY OF TOXOPLASMOSIS, NEOSPOROSIS AND BRUCELLOSIS AMONG CATTLE HERDS IN OYO STATE, SOUTH-WESTERN NIGERIA. AB - BACKGROUND: Several zoonotic diseases are known to constitute great impediment to livestock management and production worldwide, especially in developing countries where control measures are largely non-existent. This study sets out to investigate the occurrence of toxoplasmosis, neosporosis and brucellosis among cattle herds in Oyo State, southwest Nigeria. MATERIALS AND METHODS: A cross sectional survey to screen for antibodies to Toxoplasma gondii, Neospora caninum and Brucella abortus was conducted among 174 cattle in 17 herds. Sera obtained from the cattle were screened for antibodies to Toxoplasma gondii and Neospora caninum using enzyme-linked immunosorbent assay (ELISA) and for Brucella abortus antibodies using Rose Bengal test and Competitive Enzyme Linked Immunosorbent Assay (cELISA). RESULTS: Overall, herd level prevalence of 52.9%, 23.5% and 23.5% as well as individual prevalence of 7.5%, 3.4% and 3.4% was obtained for toxoplasmosis, neosporosis and brucellosis, respectively. Antibodies to T. gondii, N. caninum and B. abortus were detected in 2 of the 17 herds, T. gondii and N. caninum in 4 herds, and T. gondii and B. abortus in 4 herds. Statistically significant association was only found between seropositivity to T. gondii antibodies and sex (p<0.05). CONCLUSION: Our results showed that toxoplasmosis, neosporosis and brucellosis are prevalent among cattle herds screened in the study area. Considering the potential impact of these diseases on livestock management and production, extensive surveillance is necessary for development and implementation of effective control and prevention strategies. PMID- 28670647 TI - Farming and the geography of nutrient production for human use: a transdisciplinary analysis. AB - BACKGROUND: Information about the global structure of agriculture and nutrient production and its diversity is essential to improve present understanding of national food production patterns, agricultural livelihoods, and food chains, and their linkages to land use and their associated ecosystems services. Here we provide a plausible breakdown of global agricultural and nutrient production by farm size, and also study the associations between farm size, agricultural diversity, and nutrient production. This analysis is crucial to design interventions that might be appropriately targeted to promote healthy diets and ecosystems in the face of population growth, urbanisation, and climate change. METHODS: We used existing spatially-explicit global datasets to estimate the production levels of 41 major crops, seven livestock, and 14 aquaculture and fish products. From overall production estimates, we estimated the production of vitamin A, vitamin B12, folate, iron, zinc, calcium, calories, and protein. We also estimated the relative contribution of farms of different sizes to the production of different agricultural commodities and associated nutrients, as well as how the diversity of food production based on the number of different products grown per geographic pixel and distribution of products within this pixel (Shannon diversity index [H]) changes with different farm sizes. FINDINGS: Globally, small and medium farms (<=50 ha) produce 51-77% of nearly all commodities and nutrients examined here. However, important regional differences exist. Large farms (>50 ha) dominate production in North America, South America, and Australia and New Zealand. In these regions, large farms contribute between 75% and 100% of all cereal, livestock, and fruit production, and the pattern is similar for other commodity groups. By contrast, small farms (<=20 ha) produce more than 75% of most food commodities in sub-Saharan Africa, southeast Asia, south Asia, and China. In Europe, west Asia and north Africa, and central America, medium-size farms (20-50 ha) also contribute substantially to the production of most food commodities. Very small farms (<=2 ha) are important and have local significance in sub-Saharan Africa, southeast Asia, and south Asia, where they contribute to about 30% of most food commodities. The majority of vegetables (81%), roots and tubers (72%), pulses (67%), fruits (66%), fish and livestock products (60%), and cereals (56%) are produced in diverse landscapes (H>1.5). Similarly, the majority of global micronutrients (53-81%) and protein (57%) are also produced in more diverse agricultural landscapes (H>1.5). By contrast, the majority of sugar (73%) and oil crops (57%) are produced in less diverse ones (H<=1.5), which also account for the majority of global calorie production (56%). The diversity of agricultural and nutrient production diminishes as farm size increases. However, areas of the world with higher agricultural diversity produce more nutrients, irrespective of farm size. INTERPRETATION: Our results show that farm size and diversity of agricultural production vary substantially across regions and are key structural determinants of food and nutrient production that need to be considered in plans to meet social, economic, and environmental targets. At the global level, both small and large farms have key roles in food and nutrition security. Efforts to maintain production diversity as farm sizes increase seem to be necessary to maintain the production of diverse nutrients and viable, multifunctional, sustainable landscapes. FUNDING: Commonwealth Scientific and Industrial Research Organisation, Bill & Melinda Gates Foundation, CGIAR Research Programs on Climate Change, Agriculture and Food Security and on Agriculture for Nutrition and Health funded by the CGIAR Fund Council, Daniel and Nina Carasso Foundation, European Union, International Fund for Agricultural Development, Australian Research Council, National Science Foundation, Gordon and Betty Moore Foundation, and Joint Programming Initiative on Agriculture, Food Security and Climate Change Belmont Forum. PMID- 28670648 TI - Assessing Variability in Brain Tumor Segmentation to Improve Volumetric Accuracy and Characterization of Change. AB - Brain tumor analysis is moving towards volumetric assessment of magnetic resonance imaging (MRI), providing a more precise description of disease progression to better inform clinical decision-making and treatment planning. While a multitude of segmentation approaches exist, inherent variability in the results of these algorithms may incorrectly indicate changes in tumor volume. In this work, we present a systematic approach to characterize variability in tumor boundaries that utilizes equivalence tests as a means to determine whether a tumor volume has significantly changed over time. To demonstrate these concepts, 32 MRI studies from 8 patients were segmented using four different approaches (statistical classifier, region-based, edge-based, knowledge-based) to generate different regions of interest representing tumor extent. We showed that across all studies, the average Dice coefficient for the superset of the different methods was 0.754 (95% confidence interval 0.701-0.808) when compared to a reference standard. We illustrate how variability obtained by different segmentations can be used to identify significant changes in tumor volume between sequential time points. Our study demonstrates that variability is an inherent part of interpreting tumor segmentation results and should be considered as part of the interpretation process. PMID- 28670649 TI - Mesenchymal Stem Cell Therapy on Tendon/Ligament Healing. AB - A normal healing response after ligament and tendon rupture results in scar formation and an inferior tissue that fails to emulate its original structure, composition, and function. More regenerative healing (closer to the original) can be obtained through early suppression of inflammatory cells and associated cytokines. Examination of the immune mediated response of mesenchymal stem/stromal cells (MSCs) during healing indicates that MSCs reprogram macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Based on these studies our objective was to treat ligament and tendon injuries with MSCs in order to modulate their inflammatory response. Our initial studies using allogeneic cells demonstrated an in vivo dose dependency of MSCs on ligament healing. Medial collateral ligaments (MCLs) treated with 1 * 106 (low dose) MSCs exhibited less inflammation and a reduced number of M1 macrophages compared to ligaments treated with 4 * 106 (high dose) MSCs. Strength of ligament was also improved with the low dose treatment. We then examined the in vivo effects of MSCs that had been preconditioned to be more anti-inflammatory. Treatment with these preconditioned MSCs was compared with normally processed (unconditioned) MSCs using the rat Achilles tendon and MCL healing models. Pre conditioned MSCs significantly reduced inflammation by increasing the M2 macrophages and decreasing the M1 macrophages. Most importantly, treatment with pre-conditioned MSCs improved tissue strength to levels comparable to intact tissue. Overall, pre-conditioned MSC-treatment out-performed unconditioned MSCs to improve ligament and tendon healing by stimulating a more robust, paracrine mediated immunosuppressive response. PMID- 28670650 TI - Structured Outlier Detection in Neuroimaging Studies with Minimal Convex Polytopes. AB - Computer assisted imaging aims to characterize disease processes by contrasting healthy and pathological populations. The sensitivity of these analyses is hindered by the variability in the neuroanatomy of the normal population. To alleviate this shortcoming, it is necessary to define a normative range of controls. Moreover, elucidating the structure in outliers may be important in understanding diverging individuals and characterizing prodromal disease states. To address these issues, we propose a novel geometric concept called minimal convex polytope (MCP). The proposed approach is used to simultaneously capture high probability regions in datasets consisting of normal subjects, and delineate outliers, thus characterizing the main directions of deviation from the normative range. We validated our method using simulated datasets before applying it to an imaging study of elderly subjects consisting of 177 controls, 123 Alzheimer's disease (AD) and 285 mild cognitive impairment (MCI) patients. We show that cerebellar degeneration is a major type of deviation among the controls. Furthermore, our findings suggest that a subset of AD patients may be following an accelerated type of deviation that is observed among the normal population. PMID- 28670651 TI - Synthesis and biological evaluation of N-arylated-lactam-type iminosugars as potential immunosuppressive agents. AB - Since the immunosuppressive agents currently used in clinics have significant side effects, it is very important to search for new effective and safe immunosuppressants. Iminosugars as a new class of immunosuppressants are less explored. In this report, 24 new N-arylated iminosugar derivatives, including d talo and d-galacto epimers, were designed and synthesized, and their immunosuppressive effects were evaluated by MTT assay. The experimental data demonstrated that compound 20 showed the strongest inhibition effect (IC50 = 6.94 MUM). Further studies revealed that the inhibitory effects on splenocyte proliferation may come from the suppression of both IFN-gamma and IL-4 cytokines. The preliminary structure-activity relationship (SAR) analysis suggested that N arylated d-galacto-type iminosugars showed better inhibitory activities than d talo-type analogues. The SAR analysis also showed that the inhibition effect of iminosugars can be improved by decreasing the polarity or increasing the hydrophobicity. These results may be beneficial to the discovery of new iminosugar derivatives as immunosuppressive agents. PMID- 28670652 TI - Decision making in advanced heart failure: bench, bedside, practice, and policy. AB - This is an exciting time for patient-centered care. The window of opportunity appears to be open for the medical culture to accept the importance of the patients' values, goals and preferences in guiding medical decisions. Heart failure guidelines are changing to include language around shared decision making for major procedures and end-of-life care. However, while the cultural norms appear to be moving in this direction, the science regarding how to best deliver patient centered care (basic, clinical, delivery, and policy) is still developing. This article will provide a broad overview of the science of decision making in advanced heart failure using a translational science framework. PMID- 28670653 TI - Modified Descemet's stripping automated endothelial keratoplasty for eyes with glaucoma drainage devices and shallow anterior chambers. AB - PURPOSE: To present a modified Descemet's stripping automated endothelial keratoplasty (DSAEK) technique to avoid risks of endothelial cell loss related to the presence of a glaucoma tube in cases with shallow anterior chamber. METHOD: A 72-year-old patient with an only eye and corneal decompensation secondary to a Baerveldt tube was referred for keratoplasty. He was pseudophakic and had shallow anterior chamber. His best-corrected visual acuity was counting fingers close to face. He underwent a combined procedure with withdrawal and shortening of tube followed by a modified DSAEK employing a 7.5-mm donor graft in which a peripheral notch was performed to overlay the silicon tube. RESULTS: No intraoperative or postoperative complications were noted. The endothelial cell count was 2000/mm2 after 15 months of the surgery. His best-corrected visual acuity remains 6/18 with a stable glaucoma. CONCLUSION: This modified technique of DSAEK offers the benefits of endothelial transplant, and it could represent an option to reduce risks of corneal decompensation due to the presence of tubes in cases with shallow anterior chambers. PMID- 28670654 TI - Comparative study of 27-gauge and 25-gauge vitrectomy performed as day surgery. AB - PURPOSE: To compare postoperative outcomes of 27-gauge (G) and 25-G vitrectomy conducted as day surgery. METHODS: In total, 200 consecutive eyes that underwent primary vitrectomy (27-G in 100 eyes, 25-G in 100 eyes) were analyzed. 27-G vitrectomy was performed using a cut rate of 7500 cpm and 25-G vitrectomy using a cut rate of 5000 cpm. RESULTS: The 27-G and 25-G groups did not differ significantly in underlying diseases and preoperative Early Treatment Diabetic Retinopathy Study (ETDRS) score. The time required for vitrectomy was significantly longer in the 27-G group (35.3 vs. 29.8 min, P = 0.0013). Postoperative hypotony was observed in 0 and 3 patients, and ocular hypertension in 10 and 14 patients in the 27-G and 25-G groups, respectively, showing more stabilized postoperative ocular pressure in the 27-G group. Gain in ETDRS score was significantly better in the 27-G group (12.1 +/- 20.2 letters) compared to the 25-G group (10.0 +/- 21.3 letters) (P = 0.0323) at 1 month post-vitrectomy, but not significantly different at 3 and 6 months (P = 0.0686 and 0.0543). Rates of postoperative retinal detachment (1 vs. 1%) and vitreous hemorrhage (2 vs. 3%) were not different between two groups. CONCLUSIONS: 27-G vitrectomy requires longer operative time than 25-G, but using the 27-G system results in earlier visual improvement and stabilized ocular pressure. PMID- 28670655 TI - Erratum to: Tumour genesis syndrome: severe hypophosphatemia and hypokalemia may be ominous presenting findings in childhood acute myeloid leukaemia. PMID- 28670656 TI - Nail dystrophy due to toe malposition in children. AB - : Correct diagnosis of nail disorders could be difficult for a non-trained eye, especially in children. For this reason, sometimes, probative diagnosis and treatment are the outcome of a consultation. This paper wants to underline how podiatric abnormalities should be considered possible causes of nail disorders in children and how they need an appropriate, most of the time non-medical, treatment in order to avoid future complications. CONCLUSION: Physicians should be aware of this possibility and refer these patients to a dermatologist or a podiatrist for a correct management. What is known: * Diagnosis and treatment of nail disorders in children could be difficult. * Differential diagnosis should be as much accurate as possible in order to avoid unnecessary and possible harmful treatments. What is new: * Podiatric abnormalities should not be underestimated. * Podiatric abnormalities should be considered as potential causes of nail abnormalities in children. PMID- 28670658 TI - Snapshots of Baccalaureate Health Humanities Programs. PMID- 28670657 TI - Risk factors for new-onset shunt-dependency after craniotomies for intracranial tumors in adult patients. AB - The risk of developing a de novo shunt-dependent hydrocephalus (HC) after undergoing a craniotomy for brain tumor in adult patients is largely unknown. All craniotomies for intracranial tumors at Oslo University Hospital in adult patients >=18 years of age during a 10-year period (2004-2013) were included. None were lost to follow-up. Patients who developed a shunt-dependent HC were identified by cross-linking our prospectively collected tumor database to patients with a NCSP surgical procedure code of hydrocephalus (AAF). Patients with pre-existing HC or ventriculoperitoneal (VP) shunts were excluded from the study. A total of 4401 craniotomies were performed. Of these, 46 patients (1.0%) developed de novo postoperative HC requiring a VP shunt after a median of 93 days (mean 115 days, range 6-442). Median age was 62.0 years (mean 58.9 years, range 27.3-80.9) at time of VP shunt surgery. Patients without pre-existing HC had a 0.2% (n = 8/4401) risk of becoming VP shunt dependent within 30 days and 0.5% (n = 22/4401) within 90 days. Age, sex, tumor location, primary/secondary surgery, and radiotherapy were not associated with VP shunt dependency. Choroid plexus tumors and craniopharyngiomas had increased risk of VP shunt dependency. In this large, contemporary, single-institution consecutive series, the risk of postoperative shunt-dependency after craniotomies for brain tumors without pre existing HC was very low. This is the largest study with regards to de novo postoperative shunt-dependency after craniotomies for patients with intracranial tumors and can serve as a benchmark for future studies. PMID- 28670659 TI - Ultrasonic motor-induced geometric distortions in magnetic resonance images. AB - Ultrasonic motors (USMs) are common actuators that can be safely used in the magnetic resonance imaging (MRI) environment. However, lack of MRI compatibility results in issues such as image distortion. This fact led researchers to shift focus from USMs to pneumatic and hydraulic actuators in development of surgical robots. The aim is to quantify and compensate the geometric distortion of MR images as generated by the presence of USMs. An ultrasonic motor was positioned in three orientations with respect to the bore axis. The induced distortions were compared across four image sequences. To reduce the distortions, three artifact reduction methods were employed. Geometric distortion is the only artifact in image slices farther from the motor. The various motor orientations lead to different distortions, with the lowest distortion for the z orientation. The maximum measured distortion of ten pixels occurred. This maximal distortion is equal to a 1-cm displacement of the displayed points relative to their actual locations and it is beyond the acceptable level for medical display standards. Bandwidth reduction reduced the distortion, with a 50% reduction for a doubled bandwidth. In conclusion, USMs can be preferred alternative because accurate targeting of pathologies can occur in free distorted images. PMID- 28670660 TI - Memory T Cells in Type 1 Diabetes: the Devil is in the Detail. AB - PURPOSE OF REVIEW: Therapies that target beta-cell antigen-specific T cells subsets have not been as successful in patients with type 1 diabetes as in mice. This might be explained by complexities in the repertoire of beta-cell antigen specific T cells and the variety of T cell subsets involved in type 1 diabetes development in human. RECENT FINDINGS: T cells that infiltrate islets of people with type 1 diabetes (i) react towards known islet cell antigens but also unknown antigens, (ii) differ from one patient to another, and (iii) are also present in the circulation, but not in the islets, of healthy people. Moreover, several circulating memory T cell subsets not recognized as relevant in mouse are significantly associated with clinical outcome. A more detailed understanding of the specificity, phenotype, and function of T cells that are associated with defined clinical outcomes might identify new pathways for therapeutic intervention. PMID- 28670661 TI - Comparison of 4 and 6 weeks of rest period for repair of root resorption. AB - BACKGROUND: The study was designed to evaluate and compare the rest periods of 4 and 6 weeks for healing of orthodontically induced root resorption craters. METHODS: The study was conducted with a split-mouth design, with the right and left mandibular first premolars of 14 subjects serving as the two groups of the study. The right premolars constituted group A and the left ones, group B. Intrusive force was applied on these teeth for a period of 6 weeks, followed by retaining the teeth for 4 weeks (group A) and 6 weeks (group B) as rest periods before extraction. The extracted teeth were prepared for histologic examination with haematoxylin and eosin staining and studied under a light microscope. The histological sections were scored based on the level of repair (none, partial, functional, or anatomic) seen in the deepest craters in the apical third region of the roots. The mean values of the scores in the two groups were compared using Mann-Whitney U test. RESULTS: All the teeth showed healing in their deepest craters. The teeth in group A showed partial repair more frequently (84.6%), with the remaining (15.4%) showing functional repair. The teeth in group B showed anatomic repair more frequently (60%), with the remaining (40%) showing functional repair. The mean level of repair was higher in group B (2.6 +/- 0.5) as opposed to that in group A (1.15 +/- 0.37). The difference between these values was of very high significance (P < 0.05). CONCLUSIONS: Longer rest period of 6 weeks showed more advanced healing than a shorter rest period of 4 weeks. Six weeks of rest period is adequate only for the functional repair of resorption craters. PMID- 28670662 TI - Attitudes of orthodontists and laypersons towards tooth extractions and additional anchorage devices. AB - BACKGROUND: This study investigated the attitudes of orthodontists and laypersons towards the choice of extracting second premolars, rather than first premolars, based on tooth condition and the use of additional anchorage devices. METHODS: Questionnaires were sent to two groups: 324 orthodontists who were members of the Thai Association of Orthodontists, and 100 randomly selected Thai laypersons aged above 20 years and who were unrelated to the field of dentistry. Descriptive and chi-square statistics were used to analyze the data. RESULTS: Questionnaires were returned by 142 orthodontists (43.8%) and completed by 100 laypersons. The larger the size of the caries lesion in the maxillary second premolar was found, the more orthodontists and laypersons both chose to extract a carious maxillary second premolar instead of a healthy maxillary first premolar. For orthodontists, the use of mini-implant anchorage was significantly related to their extraction decision. Orthodontists who were familiar with mini-implants usage would choose to extract the second premolar at a lower size of extent of caries. Besides, when larger sizes of caries lesions in maxillary second premolars were considered, laypersons tended to have greater acceptance of the use of additional anchorage devices in order to keep the healthy maxillary first premolar. CONCLUSIONS: In this study, tooth condition and the use of anchorage devices are currently the main considerations by both orthodontists and laypersons when selecting the teeth to be extracted for orthodontic treatment. PMID- 28670663 TI - Non-resolving inflammation and cancer. PMID- 28670665 TI - Measurement of Pharyngo-laryngeal Volume During Swallowing Using 320-Row Area Detector Computed Tomography. AB - This study aimed to (1) evaluate changes in bolus and air volumes in the pharyngo laryngeal cavity during swallowing and (2) determine how differences in these volumes during swallowing are influenced by bolus amount using 320-row area detector computed tomography (320-ADCT). Three-, 10-, and 20-ml honey-thick liquids (5% w/v) were presented to ten healthy subjects placed in a 45 degrees reclining position. 3D images were created in 29 phases at an interval of 0.1 s for 3.15 s. Changes in bolus and air volumes in the pharyngo-laryngeal cavity were calculated. The two one-sided tests were used to determine equivalency of the pharyngo-laryngeal volume of each event (i.e., onset of hyoid elevation, soft palate closure, true vocal cord closure, closure of laryngeal vestibule, epiglottis inversion, pharyngo-esophageal sphincter opening) for each bolus volume. The pharyngo-laryngeal volume during swallowing was about 20 ml before swallowing. The volume temporarily increased with tongue loading, but decreased to about 0 ml with pharyngeal contraction. Subsequently, the volume returned to the original volume after airway opening. Most of the air was released from the pharyngo-laryngeal space before the bolus flowed into the esophagus during swallowing. As the bolus volume to be swallowed increased, the maximal pharyngo laryngeal volume increased, but changes in air volume remained constant. 320-ADCT allowed for analysis of dynamic volume changes in the pharyngo-laryngeal cavity, which will increase our knowledge of kinematic and volumetric mechanisms during swallowing. PMID- 28670666 TI - Epidemiologic comparisons of soccer-related injuries presenting to emergency departments and reported within high school and collegiate settings. AB - BACKGROUND: Few studies compare sports injury patterns in different settings. This study described the epidemiology of soccer injuries presenting to emergency departments (EDs) and compared injuries presenting to EDs to injuries presenting to collegiate and high school athletic trainers (ATs). METHODS: Soccer-related injuries (product code 1267) in the National Electronic Injury Surveillance System (NEISS) that were sustained by individuals at least two years of age in 2004-2013 were included. High School Reporting Information Online (HS RIO) data for high school soccer injuries during the 2005/06-2013/14 academic years were compared to NEISS data for those aged 14-17 years in 2005-2013. National Collegiate Athletic Association Injury Surveillance Program (NCAA-ISP) data for collegiate soccer injuries during the 2009/10-2013/14 academic years were compared to NEISS data for those aged 18-22 years in 2009-2013. All datasets included weights to calculate national estimates. Injury proportion ratios (IPRs) with 95% confidence intervals (CIs) compared nationally estimated injury distributions between the HS RIO/NCAA-ISP and NEISS data subsets. RESULTS: During the study period, 63,258 soccer-related injuries were captured by NEISS, which translates to an estimated 2,039,250 injuries seen at US EDs nationwide. Commonly injured body parts included the head/face (19.1%), ankle (17.6%), hand/wrist (15.3%), and knee (12.2%). Common diagnoses included sprains/strains (34.0%), fractures (22.2%), and contusions (17.7%). Compared to their respective age ranges in NEISS, sprains/strains comprised a larger proportion of injuries in HS RIO (48.3% vs. 33.7%; IPR = 1.38; 95% CI: 1.33, 1.42) and NCAA-ISP (51.3% vs. 37.0%; IPR = 1.39; 95% CI: 1.31, 1.46). In contrast, fractures comprised a smaller proportion of injuries in HS RIO than in NEISS (7.5% vs. 18.6%; IPR = 0.43; 95% CI: 0.39, 0.47) and NCAA-ISP (2.8% vs. 15.7%; IPR = 0.18; 95% CI: 0.14, 0.22). CONCLUSIONS: ATs more commonly reported injuries that are easily diagnosed and treated (e.g., sprains/strains); EDs more commonly reported injuries with longer recovery times and rehabilitation (e.g., fractures). Although ED surveillance data can identify the most severe sports-related injuries, high school and college sports surveillance may better describe the breadth of sports related injuries. Our findings may provide further support for school-based sports medicine professionals, but further research is needed to comprehensively examine the potential economic and health-related benefits. PMID- 28670664 TI - Clinical Impact of the 2016 Update to the WHO Lymphoma Classification. AB - OPINION STATEMENT: The 2016 revision of the WHO classification of lymphoid neoplasms includes new entities along with a clearer definition of provisional and definitive subtypes based on better understanding of the molecular drivers of lymphomas. These changes impact current treatment paradigms and provide a framework for future clinical trials. Additionally, this update recognizes several premalignant or predominantly indolent entities and underscores the importance of avoiding unnecessarily aggressive treatment in the latter subsets. PMID- 28670667 TI - The Association of a Number of Anatomical Factors with the Success of Retrograde Intrarenal Surgery in Lower Calyceal Stones. AB - PURPOSE: To determine anatomical factors affecting Retrograde Intrarenal Surgery (RIRS) success in the treatment of renal lower calyx stones. MATERIALS AND METHODS: The results of patients were evaluated retrospectively. The patients who have preoperative intravenous urography (IVU) and computed tomography (CT) were divided into two groups as successful (S)(N=103) and unsuccessful(U) (N=29). The anatomic characteristics such as infundibulopelvic angle (IPA), infundibular length (IL), infundibular width (IW) and pelvicaliceal height (PCH) values were compared among two groups. RESULTS: Mean patient age was 47+/-13.6 years in group S and 49.5 +/-11.9 years in group U. The mean stone size was 10mm (6-54mm) in group S and 19mm (8-45mm) in group U (P < .001) Mean IPA was 85.8 +/-16.9 degree in group S versus 54.7 +/- 11.5 degree in group U. The mean PCH was 1.9cm (0.5 4cm) in group S versus 2.3cm (0.7-3.9cm) in group U. The mean IL were 2.7 +/- 0.8 cm and 3.2+/-0.7cm in group S and group U, respectively. The mean IWs were 0.7 cm (0.2-2.3cm) and 0.7cm (0.3-2) in group S and group U, respectively. The differences were statistically significant for IPA, PCH, IL (P < .05) while was not statistically significant for IW (P > .05). After multivariate analyses, PCH, IPA and stone size were statistically significant factors. CONCLUSION: In our study we found that IPA, PCH and stone size were significant anatomical factors affecting RIRS success in the treatment of renal lower calyx stones. The patients whose IPA, PCH and stone size valuables are unsuitable, may need multiple RIRS sessions or additionaltreatment modalities. PMID- 28670668 TI - Serum antioxidant enzyme levels are decreased in patients with urinary calcium oxalate stones. AB - PURPOSE: To compare the serum antioxidant enzyme levels between patients with urinary stone disease and healthy volunteers to determine the effect of cellular oxidative stress on urinary calcium oxalate stones formation.Materials & Methods: A total of 51 patients with proven urinary calcium oxalate stones (female 35.3%, mean age: 49.3 years) and 37 healthy subjects (female 45.9%, mean age: 44.1 years) were included. The serum levels of antioxidant catalase, glutathione peroxidase, superoxide dismutase and lipid peroxidation were measured in serum samples taken from the peripheral venous circulation. RESULTS: Mean serum catalase level of patient group was insignificantly higher than healthy subjects (7.54 mmol- H2O2/mg/sec versus 6.16 mmolH2O2/mg/sec, respectively; P = .06) whereas mean superoxide dismutase level (1.56 U/ml versus 3.86 U/ml, P = .047), glutathione peroxidase level (6.70 U/ml versus 8.19 U/ml, P = .022) and lipid peroxidation level (2.35 nmol/ml versus 3.31 nmol/ml, P = .034) of patient group were significantly lower than healthy subjects. Patients with family history of urinary stone disease had significantly lower mean serumlevels of catalase (P = .037), superoxide dismutase (P = .047) and glutathione peroxidase (P = .01), compared with patients without family history. CONCLUSION: The findings of this study provide evidence regarding the role of oxidative stress in the development of urinary calcium oxalate stones. Future clinical trials are necessary to elucidate the actual mechanisms of the calcium oxalate stone formation in the environment with increased oxidative stress. PMID- 28670669 TI - Primary Report of Totally Tubeless Percutaneous Nephrolithotomy Despite Pelvi calyceal Perforations. AB - PURPOSE: Nephrostomy tube insertion and/or a ureteral stent placement is advised when pelvi-calyceal perforations are encountered during percutaneous nephrolithotomy (PNL) nevertheless totally tubeless PNL is a possible exit strategy in percutaneous renal surgery therefore case series on the short term clinical outcomes of noninvasive management of iatrogenic pelvicalyceal perforations encountered during PNL is presented. PATIENTS AND METHODS: During retrospective analysis of 1271 PNL procedures, 25 incidents of accidental ureteral catheter/ jj stent dislodgement during first 24 post-operative hours were identified in patient who had pelvi calyceal perforations and had no nephrostomy tube (tubeless). Thirteen patients could not be re-stented nor a nephrostomytube could have been placed for them mainly due to patient refusal or comorbid conditions. The main outcome was rate of successful noninvasive management. RESULTS: Eighteen Patients bearing mucosal tears (grade I trauma) or visible peri-pelvic fat (grade II) successfully recovered without need for ureteral stenting or nephrostomy (72.0%). In seven (28.0%) cases of extension of the perforation into the peri-pelvic fat (grade III), either nephrostomy insertion or JJ stenting was needed for resolution of fever and urinoma. The major limitation was the necessity to exclude patients and manage them in the standard fashion according to clinical guidelines. CONCLUSION: Iatrogenic perforations of the collecting system are quite diverse in terms of severity that result in different natural histories and not all might need urinary diversion via nephrostomy or ureteral stenting.Low grade perforations may be successfully managed in totally tubeless fashion nevertheless further prospective investigations seem warranted. PMID- 28670670 TI - Therapeutic Effects of Aqueous Extracts of Cerasus Avium Stem on Ethylene Glycol- Induced Kidney Calculi in Rats. AB - PURPOSE: To investigate the therapeutic effects of the aqueous extract of Cerasus Avium stem on kidney calculi. MATERIALS AND METHODS: In this experimental study, forty-eight (48) male Wistar rats were randomly allocated into six (6) groups and were studied during a 30 day period. Group A served as normal control and Group B received 1% ethylene glycol in drinking water (EG group). C, D, E, and F Groups, received 1% ethylene glycol from day 1 and were used as prevention and treatment subjects. Rats in prevention groups of low dose (C) and high dose (D) extract, were gavaged with 200 and 400 mg/kg extract respectively from first day of the experiment and treatmentgroups of low dose (E) and high dose (F) extract, were gavaged with 200 and 400 mg/kg extract respectively from the 15th day of the experiment. RESULTS: On the 30th days of the experiment, serum level of magnesium and potassium decreased significantly in EG group compared with A,C,D,E and F groups (P < .05), while serum level of calcium, creatinine, uric acid, sodium and urine level of calcium, creatinine, uric acid, increased significantly in EG group compared with A,C,D,E and F groups (P < .05). In the prevention and treatment groups, the number of deposits decreased significantly compared with EG group on the 30th day (P < .05). CONCLUSION: Cerasus Avium stem has a therapeutic effect on calcium oxalate stones in rats with nephrolithiasis and reduces the number of calcium oxalate deposits. PMID- 28670671 TI - Testicular Ischemia Caused by Incarcerated Inguinal Hernia in Infants: Incidence, Conservative treatment procedure, and Follow-up. AB - PURPOSE: Testicular ischemia and necrosis, especially in the infant age, may result from incarcerated inguinal hernia. Duration of ischemia is a significant factor for the affected testicle. We aimed to present a case series on the conservative management in the testicular ischemia caused by incarcerated inguinal hernia. MATERIALS AND METHODS: Inguinal hernia repairs performed in between March 2009 and December 2014 were investigated retrospectively. Patients' characteristics, hernia side, incarceration, testicular ischemia and complications were recorded. Color Doppler ultrasonography was performed in the incarcerated inguinal hernia patients preoperatively and was repeated on 3 and 7 days and then at 1, 3 and 6 months postoperatively. The testicle sizes, volumes, and arterial flow patterns of them were recorded at the same time. RESULTS: Total 785 inguinal hernias were treated in 738 male patients, ranging from 18 days to 16 years. From all male patients, 44 (5.9%) had the IIH. There were 16 (36.3%) irreducible hernias in 44 incarcerated hernia patients. Of these 16, testicular ischemia was determined in 9 (56.2%) infants with the irreducible incarcerated hernia. Orchidopexyprocedure was performed in these patients. Testicular atrophy was occurred in two patients (22.2%). In the others, testicular volumes and perfusions were normal during follow-up (mean 8.3 ± 2.2 months). CONCLUSION: Testicular ischemia resulting from incarcerated inguinal hernia may be treated conservatively without orchiectomy for the ischemic testicle and testicular ischemia may be followed with color Doppler ultrasound for atleast 6 months. The inguinal hernia repair in infants should be subject to urgent surgery rather than elective surgery. So, the testicular ischemia in infants with the inguinal hernia will be an avoidable complication. PMID- 28670672 TI - Anterior Urethral Advancement as a Single-Stage Technique for Repair of Anterior Hypospadias: Our Experience. AB - PURPOSE: Many techniques have been described to correct anterior hypospadias with variable results. Anterior urethral advancement as one stage technique was first described by Ti Chang Shing in 1984. It was also used for the repair of strictures and urethrocutaneous fistulae involving distal urethra. We report our experience of using this technique with some modification for the repair of anterior hypospadias. MATERIALS AND METHODS: In the period between 2013-2015, 20 cases with anterior hypospadias including 2 cases of glanular, 3 cases of coronal, 12 cases of subcoronal and 3 cases of distal penile hypospadias were treated with anterior urethral advancement technique. Patients' age groups ranged from 18 months to 10 years. Postoperatively, patients were passing urine from tip of neomeatus with satisfactory stream during follow up period of 6 months to 2 years. RESULTS: There were no major complications in any of our patients except in one patient who developed meatal stenosis which was treated by periodic dilatation. Three fold urethral mobilization was sufficient in all cases. CONCLUSION: Anterior urethral advancement technique is a single-stage procedure with good cosmetic results and least complications for anterior hypospadias repair in properly selected cases. PMID- 28670673 TI - In-Vitro Application of Pentoxifylline Preserved Ultrastructure of Spermatozoa After Vitrification in Asthenozoospermic Patients. AB - PURPOSE: To evaluate the effect of in vitro application of pentoxifylline (PX) on sperm parameters and ultrastructure after vitrification in asthenozoospermic patients. MATERIALS AND METHODS: A total of 30 asthenozoospermic semen samples (aged 25-45 years) were divided into four groups before vitrification, after vitrification, control (without PX) and experimental (with PX). In experimental group, each sample was exposed for 30 min to 3.6mmol/l PX and the control group without any treatment apposing in 370C for 30 min. After incubation, the samples were washed and analyzed again. Vitrification was done according to straw method. Eosin-nigrosin and Papanicolaou staining were applied for assessment of sperm viability and morphology, respectively. The samples without PX and post treatment with PX were assessed by transmission electron microscopy (TEM). RESULTS: A significant decrease in sperm motility (P ≤ .001), morphology (11.47 ± 2.9 versus 6.73 ± 2.01) and viability (73.37 ± 6.26 versus 54.67 ± 6.73) was observed post vitrification, but sperm motility (19.85 ± 4.75 versus 32.07 ± 5.58, P ≤ .001) was increased significantly following application of PX. This drug had no significant (P >.05) detrimental neither negative effect on ultrastructure acrosome, plasma membrane and coiled tail statues of spermatozoa. CONCLUSION: Vitrification had detrimental effects on sperm parameters, but PX reversed detrimental effects on sperm motility. However, PX had no alteration on ultrastructure morphology of human spermatozoa after vitrification. PMID- 28670674 TI - Mucinous Adenocarcinoma of the Suprapubic Cystostomy Tract without Bladder Involvement. AB - We present a case of adenocarcinoma developing at the vesicocutaneous edge of a vesicostomy, 8 years after it was created, in a patient who had neurogenic bladder secondary to medullitis. The patient died 6 months after the start of surgery therapy. Although transitional and squamous cell carcinoma of a vesicostomy have been reported, to our knowledge, the presence of adenocarcinoma at the vesicostomy edge without bladder involvement has not been reported previously. PMID- 28670675 TI - Transurethral Resection of a Large Urinary Bladder Leiomyoma: A Rare Case Report. AB - Bladder leiomyoma constitutes less than 0.5% of all bladder tumors. Until now, there have been about 250 case reports of bladder leiomyoma. We present a case of large bladder leiomyoma, that was treated successfully with transurethral resection. The patient presented to our clinic with both obstructive and irritative urinary complaints. Cystoscopy showed a mass lesion completely obstructing the bladder neck at the junction of right lateral wall and floor, which did not extend to ureteral orifices. A transurethral resection was performed at the same sessionof cystoscopy. At the postoperative 3rd month control visit, the patient's obstructive symptoms were completely healed but her irritative symptoms continued. A repeat cystoscopy revealed residual tumoral tissue remaining at the floor of the previous surgical area. Transurethral resection was performed, and these tissues were completely resected. At the control visit that was 3 months after the second transurethral resection procedure, the patient was free from any urinary complaints. In conclusion, large bladder leiomyomas can be treated successfully with endoscopic approaches. PMID- 28670676 TI - Yang-Monti Principle in Bridging Long Ureteral Defects: Cases Report and A Systemic Review. AB - Ureteric substitution using the Yang-Monti principle was reported as a modification of simple ileal ureter replacement. During April 2013 to June in 2015, 2 patients underwent ileal ureteral substitution using a reconfigured ileal segment of Yang Monti principle in our clinical center. Some slight modifications were made and then follow-up were carried out up to 12 months. For these 2 cases, no significant intra/post-operative complications occurred. In 1 year follow up, serum creatinine (Scr) and blood urea nitrogen (BUN) of both patients decreased to normal.Glomerular filtration rate (GFR), renogram and pyelogram showed a stable split renal function. To better understand the Yang-Monti principle and potential risks and complications, we conduct an systemic review by searching PubMed, Google Scholar and the Cochrane Library database from January 1996 through June 2016. 10 out of 644 publications were identified, which included 269 patients from cohort studies. The most usual indications for Yang-monti therapy were iatrogenic stricture and retroperitoneal fibrosis. Infection and ileus were indicated as themain short time postoperative complications while the fistula and re- strictures happened in long-term. In general,we believe Yang-Monti Principle is a safer and efficient technique for clinical partial and complete ureteral defects if patients and potential risks could be well prepared. PMID- 28670677 TI - A Randomized Control Trial Comparing Combined Glandular Lidocaine Injection and Intraurethral Lidocaine Gel with Intraurethral Lidocaine Gel Alone in Cystoscopy and Urethral Dilatation. AB - PURPOSE: Cystoscopy is one of the most common urologic procedures. The aim of this study is to investigate the combined effect of intraurethral lidocaine gel and intraglandular injection of lidocaine 2% on pain during and after cystoscopy. Materials & Methods: In this double-blind, parallel group randomized clinical trial, 156 patients referred for double J removal, urethral dilatation, or cystoscopy were enrolled. The patients were divided into two groups, A and B. All patients received 20 cc of intraurethral lidocaine gel 2%. In group A (N = 75), lidocaine 2% was also injected into the glans penis. The patients in group B (N = 81) only received the intraurethral lidocaine gel. Cystoscopy was performed 10 minutes later. The primary outcome of interest was measured in terms of pain score (visual analogue scale) during and 5 minutes after cystoscopy. RESULTS: Immediate pain score after the procedure was 3.4 ± 3 and 4.6 ± 3 in groups A and B, respectively (P = .011). CONCLUSION: Based on the findings of the present study, lidocaine injection into the glans penis significantly reducedpain perception. PMID- 28670678 TI - The economic burden of opioid prescription by dentists: A 12-month survey of consumer expenditure in Brazil. AB - OBJECTIVES: To describe consumer expenditure on opioids prescribed by dentists in Brazil during a 12-month period. METHODS: We surveyed individual dispensed prescriptions of opioids in private pharmacies from October 2012 to September 2013. A descriptive analysis of costs included a calculation of the overall and mean maximum price to consumers. Monetary costs were converted from local currency units (Brazilian Real - BRL) to international dollars using purchasing power parity (PPP) exchanging rates. RESULTS: 129,708 prescriptions were retrieved from the database. The overall expenditure on opioids was R$4,316,383.46 BRL or $2,721,315.82 (PPP). The mean cost of an individual prescription was R$33.27 BRL ($20.98 PPP), ranging from 14.19 to 3,255.60 BRL. Codeine was frequently prescribed (87.2 percent). CONCLUSIONS: The expenditure on opioids is a significant cost to Brazilian patients, especially given that the Brazilian Public Health System should dispense these drugs free of charge. Codeine was the most prescribed opioid. PMID- 28670679 TI - Dynamics of the protein structure of T169S pyranose 2-oxidase in solution: Molecular dynamics simulation. AB - Pyranose 2-oxidase (P2O) from Trametes multicolor contains FAD as cofactor, and forms a tetramer. The protein structure of a mutated P2O, T169S (Thr169 is replaced by Ser), in solution was studied by means of molecular dynamics simulation and analyses of photoinduced electron transfer (ET) from Trp168 to excited isoalloxazine (Iso*), and was compared with wild type (WT) P2O. Hydrogen bonding between Iso and nearby amino acids was very similar as between T169S and WT protein. Distances between Iso and Tyr456 were extremely heterogeneous among the subunits, 1.7 (1.5 in WT) in subunit A (Sub A), 0.97 (2.2 in WT) in Sub B, 1.3 (2.1 in WT) in Sub C, 1.3 nm (2.0 in WT) in Sub D. Mean values of root of mean square fluctuation over all residues were greater by four times than those in WT. This suggests that the protein structure of T169S is much more flexible than that of WT. Electrostatic (ES) energies between Iso anion in one subunit and ionic groups in the entire protein were evaluated. It was found that more than 50% of the total ES energy in each subunit is contributed from other subunits. Reported fluorescence decays were analyzed by a method as WT, previously reported. Electron affinities of Iso* in T169S were appreciably higher than those in WT. Static dielectric constants near Iso and Trp168 were also quite higher in T169S than those in WT. PMID- 28670680 TI - Subcutaneous mycoses in Peru: a systematic review and meta-analysis for the burden of disease. AB - BACKGROUND: There is a worrying lack of epidemiological data on the geographical distribution and burden of subcutaneous mycoses in Peru, hindering the implementation of surveillance and control programs. OBJECTIVES: This study aimed to estimate the disease burden of subcutaneous mycoses in Peru and identify which fungal species were commonly associated with these mycoses. METHODS: We performed a meta-analysis after a systematic review of the published literature in PubMed, LILACS, and SciELO to estimate the burden of subcutaneous mycoses in 25 regions in Peru. The disease burden was determined in terms of prevalence (number of cases per 100,000 inhabitants) and the number of reported cases per year per region. RESULTS: A total of 26 studies were eligible for inclusion. Results showed that sporotrichosis was the most common subcutaneous mycosis (99.7%), whereas lobomycosis, chromoblastomycosis, and subcutaneous phaeohyphomycosis were rare. Cases of eumycetoma and subcutaneous zygomycosis were not found. Of the 25 regions, the burden of sporotrichosis was estimated for four regions classified as endemic; in nine regions, only isolated cases were reported. The highest burden of sporotrichosis was in Apurimac (15 cases/100,000 inhabitants; 57 cases/year), followed by Cajamarca (3/100,000 inhabitants; 30/year), Cusco (0.5/100,000 inhabitants; 4/year), and La Libertad (0.2/100,000 inhabitants; 2/year). In two regions, the mycoses predominantly affected children. CONCLUSIONS: Sporotrichosis is the most common subcutaneous mycosis in Peru, with a high disease burden in Apurimac. Chromoblastomycosis, lobomycosis, and subcutaneous phaeohyphomycosis are rare mycoses in Peru. PMID- 28670681 TI - Gender differences in Parkinson's disease: A clinical perspective. AB - Available data indicate that there are gender differences in many features of Parkinson's disease (PD). Precise identification of the gender differences is important to tailor treatment, predict outcomes, and meet other individual and social needs in women and men with PD. The aim of this study was to review the available clinical data on gender differences in PD. Original articles and meta analyses published between 1990 and 2016 systematically exploring gender differences in PD were reviewed. There is slight male preponderance in incidence and prevalence of PD. PD starts earlier in men. Women tend to be more prone to develop tremor-dominant PD but are less rigid than men. Motor improvement after deep brain stimulation is equal in both sexes, but women tend to show better improvement in activities of daily living. Furthermore, women with PD show better results on tests for general cognitive abilities, outperform men in verbal cognitive tasks, show more pain symptoms, and score higher on depression scales. It seems, however, that the differences in cognition, mood, and pain perception are not disease specific as similar gender differences can be found in healthy subjects and in other neurological conditions. Despite PD being the most frequently studied movement disorder, studies investigating gender differences in PD are still scarce with most of the studies being cross-sectional. Good-quality, prospective, longitudinal studies analyzing gender differences in PD and comparing them to matched healthy controls are needed in order to properly address the issues of gender differences in PD. PMID- 28670682 TI - Identifying Homeless Medicaid Enrollees Using Enrollment Addresses. AB - OBJECTIVE: To design and test the validity of a method to identify homelessness among Medicaid enrollees using mailing address data. DATA SOURCES/STUDY SETTING: Enrollment and claims data on Medicaid expansion enrollees in Hennepin and Ramsey counties who also provided self-reported information on their current housing situation in a psychosocial needs assessment. STUDY DESIGN: Construction of address-based indicators and comparison with self-report data. PRINCIPAL FINDINGS: Among 1,677 enrollees, 427 (25 percent) self-reported homelessness, of whom 328 (77 percent) had at least one positive address indicator. Depending on the type of addresses included in the indicator, sensitivity to detect self reported homelessness ranged from 30 to 76 percent and specificity from 79 to 97 percent. CONCLUSIONS: An address-based indicator can identify a large proportion of Medicaid enrollees who are experiencing homelessness. This approach may be of interest to researchers, states, and health systems attempting to identify homeless populations. PMID- 28670683 TI - TSPAN31 is a critical regulator on transduction of survival and apoptotic signals in hepatocellular carcinoma cells. AB - Tetraspanins are commonly believed to act as 'molecular facilitators', not directly involved in signal transduction. Tetraspanin 31 (TSPAN31), recently discovered to be linked to cancer, has not yet been studied in hepatocellular carcinoma (HCC). Here, we show that TSPAN31 is the natural antisense transcript of cyclin dependent kinase 4 (CDK4), and regulates the expression of CDK4 mRNA and protein. Target analysis indicates that miR-135b can directly regulate TSPAN31 expression. miR-135b-induced TSPAN31 silencing increases CDK4 protein levels. Interestingly, p53 negatively regulates TSPAN31 expression. siRNA-induced TSPAN31 knockdown reduces the expression of Akt signaling pathway components phosphorylated Akt, p-GSK3beta and beta-catenin, and restrains beta-catenin migration to cell nucleus. TSPAN31 knockdown also significantly inhibits HCC cell invasion and migration. These findings thus point to TSPAN31 as a novel regulator in transduction of intracellular survival and apoptotic signals. PMID- 28670684 TI - Apolipoprotein E Polymorphism and Left Ventricular Failure in Beta-Thalassemia: A Multivariate Meta-Analysis. AB - Apolipoprotein E (ApoE) is potentially a genetic risk factor for the development of left ventricular failure (LVF), the main cause of death in beta-thalassemia homozygotes. In the present study, we synthesize the results of independent studies examining the effect of ApoE on LVF development in thalassemic patients through a meta-analytic approach. However, all studies report more than one outcome, as patients are classified into three groups according to the severity of the symptoms and the genetic polymorphism. Thus, a multivariate meta-analytic method that addresses simultaneously multiple exposures and multiple comparison groups was developed. Four individual studies were included in the meta-analysis involving 613 beta-thalassemic patients and 664 controls. The proposed method that takes into account the correlation of log odds ratios (log(ORs)), revealed a statistically significant overall association (P-value = 0.009), mainly attributed to the contrast of E4 versus E3 allele for patients with evidence (OR: 2.32, 95% CI: 1.19, 4.53) or patients with clinical and echocardiographic findings (OR: 3.34, 95% CI: 1.78, 6.26) of LVF. This study suggests that E4 is a genetic risk factor for LVF in beta-thalassemia major. The presented multivariate approach can be applied in several fields of research. PMID- 28670685 TI - Diversity of functional connectivity patterns is reduced in propofol-induced unconsciousness. AB - INTRODUCTION: Recent evidence suggests that the conscious brain is characterized by a diverse repertoire of functional connectivity patterns while the anesthetized brain shows stereotyped activity. However, classical time-averaged methods of connectivity dismiss dynamic and temporal characteristics of functional configurations. Here we demonstrate a new approach which characterizes time-varying patterns of functional connectivity at the subsecond time scale. METHODS: We introduce phase-lag entropy (PLE), a measure of the diversity of temporal patterns in the phase relationships between two signals. The proposed measure was applied to multichannel electroencephalogram (EEG), which were recorded from two distinct experimental settings: (1) propofol was administrated at a constant infusion rate for 60 min (n = 96); (2) administration of propofol by a target effect-site concentration-controlled infusion with simultaneous assessment of the level of consciousness (n = 10). RESULTS: From the first dataset, two substantial changes of the phase relationship during anesthesia was found: (1) the dynamics of the phase relationship between frontal channels became progressively less diverse and more stereotyped during unconsciousness, quantified as a reduction in PLE; and (2) the reduction in PLE was consistent across subjects. Furthermore, PLE provided better performance in the classification of states of consciousness than did phase-lag index, a classical time-averaged connectivity method. From the second dataset, PLE showed the highest agreement with the level of consciousness, compared to existing anesthetic depth indicators. CONCLUSIONS: This study suggests that a scarcity of functional configurations is closely associated with anesthetically induced unconsciousness, and shows promise as a basis for a new consciousness monitoring system during general anesthesia. Hum Brain Mapp 38:4980-4995, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28670686 TI - Anaesthesia practices for endovascular therapy of acute ischaemic stroke: a Nordic survey. AB - BACKGROUND: The optimal method of anaesthesia for endovascular therapy (EVT) in acute ischaemic stroke (AIS) has not been identified. Nordic departments of anaesthesiology may handle EVT cases for AIS differently. The aim of this survey was to describe the current practice patterns of Nordic anaesthesia departments in anaesthetic management of EVT in AIS. METHODS: A survey consisting of 13 questions was sent to one qualified individual at all Nordic departments of anaesthesiology who manage anaesthesia for EVT interventions. The individual completed the questionnaire on behalf of their department. RESULTS: Response rate was 100%. The majority of departments (84%) managed all EVT cases at their respective centres. Most departments have institutional guidelines on anaesthetic management (84%) including blood pressure management (63%) and were able to provide a 24-h immediate response to an EVT request (63%). Conscious sedation was favoured by 68% of the departments using a variety of sedation protocols. Propofol and remifentanil was preferred for GA (58%). Emergent conversion to GA due to uncontrolled patient movements or loss of airway was experienced by 82% and 35% of the departments, respectively. Majority of the departments (89%) responded that non-specialist anaesthetists occasionally handle EVT cases. CONCLUSIONS: This survey indicates that the majority of Nordic anaesthesia departments who manage anaesthesia for EVT are able to provide immediate 24-h response to an EVT request. Most of these departments have institutional guidelines for EVT anaesthesia and haemodynamic management. Conscious sedation appears to be the preferred method of anaesthetic care. PMID- 28670687 TI - Improved estimation of the cumulative incidence of rare outcomes. AB - Studying the incidence of rare events is both scientifically important and statistically challenging. When few events are observed, standard survival analysis estimators behave erratically, particularly if covariate adjustment is necessary. In these settings, it is possible to improve upon existing estimators by considering estimation in a bounded statistical model. This bounded model incorporates existing scientific knowledge about the incidence of an event in the population. Estimators that are guaranteed to agree with existing scientific knowledge on event incidence may exhibit superior behavior relative to estimators that ignore this knowledge. Focusing on the setting of competing risks, we propose estimators of cumulative incidence that are guaranteed to respect a bounded model and show that when few events are observed, the proposed estimators offer improvements over existing estimators in bias and variance. We illustrate the proposed estimators using data from a recent preventive HIV vaccine efficacy trial. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28670689 TI - Highly Bent 1,3-Digerma-2-silaallene. AB - A 1,3-digerma-2-silacyclopenta-1,2-diene, that is, a 1,3-digerma-2-silaallene incorporated into a five-membered ring system, was synthesized and obtained as a stable orange solid. Owing to incorporation into a cyclic framework, the 1,3 digerma-2-silaallene moiety is highly bent, exhibiting a Si0 character for the central silicon moiety. PMID- 28670688 TI - Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells. AB - Ikaros is a transcription factor that regulates lymphocyte development from the level of the haematopoietic stem cell. Lack of Ikaros reduces the ability of progenitor cells to commit to the T-cell lineage, resulting in reduced numbers of early thymic T-cell progenitors and mature T cells. Mature CD4 T cells that lack Ikaros have defects in proliferation, T helper cell differentiation, cytokine expression and the ability to become anergic. A role for Ikaros in the naive T cell has not yet been identified. The receptors interleukin-7 receptor alpha (IL 7Ralpha) and l-selectin are important for ensuring survival and proper homing of naive T cells, respectively. Here we show that lack of Ikaros leads to reduced expression of these receptors in naive T cells, which impacts their ability to home and survive in response to IL-7. We define the mechanism underlying this phenotype as a requirement for Ikaros in maintenance of expression of Foxo1, a transcriptional regulator that is required for their expression. We also demonstrate that CD4 T cells lacking Ikaros are significantly crippled in their ability to become induced regulatory T cells, a phenotype also linked to reduced Foxo1 expression. Finally, we show that restoring Ikaros function to Ikaros deficient CD4 T cells increases levels of Foxo1 message. Together, these studies define, for the first time, a role for Ikaros in naive T cells and establish it as the first transcriptional regulator required for maintaining levels of Foxo1 gene expression in these cells. PMID- 28670690 TI - Possible Involvement of Hypotension in Postprandial Headache: A Case Series. AB - BACKGROUND: It is commonly known that headaches are induced by intake of specific food, drink, and/or additive. In addition, some patients experience postprandial headache independent of ingestion of specific items. Currently, information on the pathophysiology underlying this particular type of headache is scarce. CASE REPORTS: We report two cases in which headaches were observed after each meal. Postprandial hypotension was demonstrated in both cases. Tonometry-based continuous blood pressure measurement during head-up tilt revealed sympathetic dysfunction. In one patient, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy detected cardiac sympathetic denervation, and diagnosis of pure autonomic failure was made. In both cases, treatment of postprandial hypotension was effective in relieving postprandial headache. DISCUSSION: The possibility of postprandial hypotension should be explored in patients with headache that occurs after meal. To this end, tonometry-based blood pressure measurement and MIBG myocardial scintigraphy may be useful diagnostic investigations. Treating postprandial hypotension may be effective in alleviating the symptoms. PMID- 28670691 TI - The performance of T-cell Xtend reagent in increasing blood storage times for interferon gamma release assays. AB - BACKGROUND: T-cell Xtend (TCX) was introduced to extend the blood storage time for T-SPOT.TB test, a widely used commercial interferon gamma release assay (IGRA) for rapid in vitro tuberculosis. METHODS: A total of 99 Uyghur suspected tuberculosis patients were recruited in this study. T-SPOT.TB test was performed with fresh blood (controls), 36 hours delayed blood and delayed and TCX-treated (at 36 hours) blood from each patient, respectively. RESULTS: White blood cells and lymphocytes proportion in peripheral blood mononuclear cells s and spot forming cells in positive control wells decreased significantly in delayed blood samples when compared with controls, while this decrease was not detected in TCX treated group. In the 58 patients with paired T-SPOT.TB results of three groups of samples, a higher positive rate was observed in TCX-treated group than both in controls and untreated group (41.4% vs 37.9% and 25.9%). The concordance of T SPOT.TB results between the treated group and controls was 0.856, whereas the agreement between controls and untreated group was unsatisfactory (0.649). In the 23 elderly patients (>70 years old) with paired T-SPOT.TB results of controls and TCX group, treated group showed a non-significant trend toward higher positive rate than controls (43.5% vs 26.1%, P=.22). Meanwhile, TCX treatment reduced the risk of false negative T-SPOT.TB results in the elderly population. CONCLUSION: Deterioration of blood sample caused by long storage time can be neutralized by TCX treatment. The results provide data for the utility of TCX in a novel population and in Asian region, and reveal the potential of TCX to improve the accuracy of T-SPOT.TB test in elderly population. PMID- 28670692 TI - Reply to 'Low-grade intraductal carcinoma of the prostate: an idea whose time has not yet come': evidence-based medicine suggests that the time is now. PMID- 28670693 TI - CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma. AB - Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR. PMID- 28670694 TI - Medical and non-medical expenditure for breast cancer diagnosis and treatment in China: a multicenter cross-sectional study. AB - AIM: We aimed to assess economic burden of breast cancer (BC) diagnosis and treatment in China through a multicenter cross-sectional study, and to obtain theoretical evidence for policy-making. METHODS: This survey was conducted in 37 hospital centers across 13 provinces in China from September 2012 to December 2014. We collected information on the subject characteristics. We then assessed the medical and non-medical expenditure for BC diagnosis and treatment, factors influencing the average case expense, variations between medical and non-medical expenditure at different clinical stages, economic impact of overall expenditure in newly diagnosed course after reimbursement to the patient's family, composition of non-medical expenditure and time loss for the patient and family. RESULTS: Among 2746 women with BC (72.6% were admitted to specialized hospitals), the overall average expenditure was US $8450 (medical expenditure: $7527; non medical expenditure: $922). Significant differences were found among the overall expenditure in the four clinical stages (P < 0.0001); the expenditure was higher in stages III and IV than that in stages I and II, whereas the stage IV was the highest (P < 0.0001). Moreover, a higher self-reported predicted reimbursement ratio was associated with a less economic impact on the patient's family, and the average time lost was estimated as $1529. CONCLUSIONS: Early detection and treatment of breast cancer might be effective for decreasing the economic burden, because costs escalate as the degree of malignancy increases. PMID- 28670696 TI - Abstracts for the British Association of Dermatologists 97th Annual Meeting, Birmingham, U.K., 4-6 July 2017. PMID- 28670695 TI - Meat allergy associated with galactosyl-alpha-(1,3)-galactose (alpha-Gal)-Closing diagnostic gaps by anti-alpha-Gal IgE immune profiling. AB - BACKGROUND: Glycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl-alpha-(1,3)-galactose (alpha-Gal). It is known that alpha Gal is immunogenic in humans and causes glycan-specific IgG and also IgE responses with clinical relevance. alpha-Gal is part of the IgE-reactive monoclonal therapeutic antibody cetuximab (CTX) and is associated with delayed anaphylaxis to red meat. In this study, different alpha-Gal-containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against alpha-Gal. METHODS: Three serum groups, alpha-Gal-associated meat allergy (MA) patients, idiopathic anaphylaxis (IA) patients with suspected MA, and non-meat-allergic healthy control individuals (HC), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for alpha-Gal-containing analytes CTX, bovine thyroglobulin (Bos d TG), and human serum albumin (HSA)-conjugated alpha Gal. RESULTS: Singleplex allergy diagnostics using the alpha-Gal analytes CTX and Bos d TG confirms the history of MA patients in 91% and 88% of the cases, respectively. A novel dot blot-based assay system for the detection of IgE against alpha-Gal reveals individual IgE sensitization profiles for alpha-Gal containing analytes. An alpha-Gal-associated IgE cross-reactivity profile (IgE against CTX, Bos d TG, and HSA-alpha-Gal) was identified, which is associated with MA. CONCLUSIONS: Detection of individual sensitization patterns with different alpha-Gal-containing analytes provides the basis for an individual allergy diagnosis for alpha-Gal-sensitized patients. Higher amounts of alpha-Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity. PMID- 28670697 TI - Estimation of glomerular filtration rate using serum cystatin C and creatinine in adults with sickle cell anemia. PMID- 28670698 TI - Capabilities of the remainders of nominal Kendrick masses and the referenced Kendrick mass defects for copolymer ions. PMID- 28670699 TI - The desert plant Phoenix dactylifera closes stomata via nitrate-regulated SLAC1 anion channel. AB - Date palm Phoenix dactylifera is a desert crop well adapted to survive and produce fruits under extreme drought and heat. How are palms under such harsh environmental conditions able to limit transpirational water loss? Here, we analysed the cuticular waxes, stomata structure and function, and molecular biology of guard cells from P. dactylifera. To understand the stomatal response to the water stress phytohormone of the desert plant, we cloned the major elements necessary for guard cell fast abscisic acid (ABA) signalling and reconstituted this ABA signalosome in Xenopus oocytes. The PhoenixSLAC1-type anion channel is regulated by ABA kinase PdOST1. Energy-dispersive X-ray analysis (EDXA) demonstrated that date palm guard cells release chloride during stomatal closure. However, in Cl- medium, PdOST1 did not activate the desert plant anion channel PdSLAC1 per se. Only when nitrate was present at the extracellular face of the anion channel did the OST1-gated PdSLAC1 open, thus enabling chloride release. In the presence of nitrate, ABA enhanced and accelerated stomatal closure. Our findings indicate that, in date palm, the guard cell osmotic motor driving stomatal closure uses nitrate as the signal to open the major anion channel SLAC1. This initiates guard cell depolarization and the release of anions together with potassium. PMID- 28670700 TI - Mood and neural correlates of excessive daytime sleepiness in Parkinson's disease. AB - For patients with Parkinson's disease (PD), excessive daytime sleepiness (PD-EDS) is a debilitating non-motor symptom and may be affected by mood symptoms, especially depression and anxiety. Few neuroimaging works have attempted to identify the neural features of PD-EDS, but various findings were reported. The purpose of this study was to systematically review the literature on mood and neuroimaging correlates of PD-EDS. A MEDLINE, PubMed, EMBASE, and PsycInfo search for peer-reviewed original research articles on depression, anxiety, and neuroimaging in PD-EDS identified 26 studies on depression, nine on anxiety, and eight on neuroimaging. Half of the studies reported greater depression in PD-EDS positive patients compared with PD-EDS-negative patients. There was a significantly positive correlation between depression and PD-EDS. Limited studies on anxiety in PD-EDS suggested a weak correlation between anxiety and EDS. For depression and anxiety, the effect sizes were medium when EDS was subjectively measured, but became small when EDS was objective measured. Current neuroimaging studies generally suggested diminished neural structural and functional features (eg, brain volume, white matter integrity as indicated by fractional anisotropy, and cerebral metabolism) in patients with PD-EDS. Future studies should apply objective and subjective measures of mood symptoms and EDS and improve the neuroimaging methodology via using multimodal techniques and whole-brain analysis to provide new clues on the mood and neural correlates of PD-EDS. PMID- 28670702 TI - Occupational Therapy Australia, 27th National Conference and Exhibition, 19-21 July 2017, Perth Convention and Exhibition Centre, Western Australia. PMID- 28670701 TI - Diarrhea-An uncommon presentation of tertiary adrenal insufficiency following heart transplantation. AB - Diarrhea following organ transplantation is usually associated with infection and immunosuppression therapy. We describe two patients with diarrhea following orthotopic heart transplantation due to tertiary adrenal insufficiency. PMID- 28670703 TI - TGF-beta induced PAR-1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone. AB - Although protease activated receptor-1 (PAR-1) has been confirmed as an oncogene in many cancers, the role of PAR-1 in giant cell tumor (GCT) of bone has been rarely reported. The mechanism of PAR-1 in tumor-induced osteoclastogenesis still remains unclear. In the present study, we detected that PAR-1 was significantly upregulated in GCT of bone compared to normal tissues, while TGF-beta was also overexpressed in GCT tissues and could promote the expression of PAR-1 in a dose and time dependent manner. Using the luciferase reporter assay, we found that two downstreams of TGF-beta, Smad3 and Smad4, could activate the promoter of PAR-1, which might explain the mechanism of TGF-beta induced PAR-1 expression. Meanwhile, PAR-1 was also overexpressed in microvesicles from stromal cells of GCT (GCTSCs), and might be transported from GCTSCs to monocytes through microvesicles. In addition, knockout of PAR-1 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. Using the chick CAM models, we further showed that inhibition of PAR-1 suppressed tumor growth and giant cell formation in vivo. Using microarray assay, we detected a number of genes involved in osteoclastogenesis as the possible downstreams of PAR-1, which may partly explain the mechanism of PAR-1 in GCT. In brief, for the first time, these results reveal an upstream regulatory role of TGF-beta in PAR-1 expression, and PAR-1 expression promotes tumor growth, angiogenesis and osteoclast differentiation in GCT of bone. Hence, PAR-1 represents a novel potential therapeutic target for GCT of bone. PMID- 28670706 TI - Abstracts of the AAGBI GAT Annual Scientific Meeting, Cardiff, UK, 5-7 July 2017. PMID- 28670704 TI - Cyclin K dependent regulation of Aurora B affects apoptosis and proliferation by induction of mitotic catastrophe in prostate cancer. AB - Cyclin K plays a critical role in transcriptional regulation as well as cell development. However, the role of Cyclin K in prostate cancer is unknown. Here, we describe the impact of Cyclin K on prostate cancer cells and examine the clinical relevance of Cyclin K as a biomarker for patients with prostate cancer. We show that Cyclin K depletion in prostate cancer cells induces apoptosis and inhibits proliferation accompanied by an accumulation of cells in the G2/M phase. Moreover, knockdown of Cyclin K causes mitotic catastrophe displayed by multinucleation and spindle multipolarity. Furthermore, we demonstrate a Cyclin K dependent regulation of the mitotic kinase Aurora B and provide evidence for an Aurora B dependent induction of mitotic catastrophe. In addition, we show that Cyclin K expression is associated with poor biochemical recurrence-free survival in patients with prostate cancer treated with an adjuvant therapy. In conclusion, targeting Cyclin K represents a novel, promising anti-cancer strategy to induce cell cycle arrest and apoptotic cell death through induction of mitotic catastrophe in prostate cancer cells. Moreover, our results indicate that Cyclin K is a putative predictive biomarker for clinical outcome and therapy response for patients with prostate cancer. PMID- 28670707 TI - Radiosynthesis and evaluation of 1-substituted 3-(2,3-dihydro-1H-inden-2-yl)-6-(1 ethylpropyl)-(3R,6R)-2,5-piperazinedione derivatives as PET tracers for imaging the central oxytocinergic system. AB - Oxytocin is known to be implicated in a variety of functions, such as learning, stress, anxiety, feeding, and pain perception. Oxytocin is also important for social memory and attachment, human bonding, sexual and maternal behaviour, and aggression. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve abnormal oxytocin levels. GSK712043, GSK711320, and GSK664004, three antagonists exhibiting subnanomolar affinity for the human oxytocin receptor (hOTR) and high selectivity over vasopressin receptors were successfully labelled with carbon-11 with suitable yields (0.5-1GBq @EOS), high molar activity (275-700 GBq/MUmol), and radiochemical purities. The in vivo regional uptake of these radiotracers was determined in porcine brain. [11 C]GSK711320 baseline scan showed no significant brain uptake, and limited initial uptake was observed following administration of [11 C]GSK712043 or [11 C]GSK664004. The [11 C]GSK712043 and [11 C]GSK664004 kinetics were slow and peaked at around 2%ID/L at 90 minutes post-injection. For both tracers, the distribution of activity was homogeneous throughout the brain. All the tracers showed high uptake in the pituitary gland, especially [11 C]GSK711320; however, its uptake could not be blocked by pretreatment with the known OTR antagonist, L368,899. In vivo evaluation of these candidates demonstrated that they are not suitable as central OTR PET imaging agents. PMID- 28670708 TI - Do Patient-Centered Medical Homes Improve Health Behaviors, Outcomes, and Experiences of Low-Income Patients? A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To examine: (1) what elements of patient-centered medical homes (PCMHs) are typically provided to low-income populations, (2) whether PCMHs improve health behaviors, experiences, and outcomes for low-income groups. DATA SOURCES/STUDY SETTING: Existing literature on PCMH utilization among health care organizations serving low-income populations. STUDY DESIGN: Systematic review and meta-analysis. DATA COLLECTION/EXTRACTION METHODS: We obtained papers through existing systematic and literature reviews and via PubMed, Web of Science, and the TRIP databases, which examined PCMHs serving low-income populations. A total of 434 studies were reviewed. Thirty-three articles met eligibility criteria. PRINCIPAL FINDINGS: Patient-centered medical home interventions usually were composed of five of the six recommended components. Overall positive effect of PCMH interventions was d = 0.247 (range -0.965 to 1.42). PCMH patients had better clinical outcomes (d = 0.395), higher adherence (0.392), and lower utilization of emergency rooms (d = -0.248), but there were apparent limitations in study quality. CONCLUSIONS: Evidence shows that the PCMH model can increase health outcomes among low-income populations. However, limitations to quality include no assessment for confounding variables. Implications are discussed. PMID- 28670709 TI - Spatial small area smoothing models for handling survey data with nonresponse. AB - Spatial smoothing models play an important role in the field of small area estimation. In the context of complex survey designs, the use of design weights is indispensable in the estimation process. Recently, efforts have been made in these spatial smoothing models, in order to obtain reliable estimates of the spatial trend. However, the concept of missing data remains a prevalent problem in the context of spatial trend estimation as estimates are potentially subject to bias. In this paper, we focus on spatial health surveys where the available information consists of a binary response and its associated design weight. Furthermore, we investigate the impact of nonresponse as missing data on a range of spatial models for different missingness mechanisms and different degrees of missingness by means of an extensive simulation study. The computations were performed in R, using INLA and other existing packages. The results show that weight adjustment to correct for missingness has a beneficial effect on the bias in the missing at random setting for all models. Furthermore, we estimate the geographical distribution of perceived health at the district level based on the Belgian Health Interview Survey (2001). Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28670711 TI - Later school start times for supporting the education, health, and well-being of high school students. AB - BACKGROUND: A number of school systems worldwide have proposed and implemented later school start times as a means of avoiding the potentially negative impacts that early morning schedules can have on adolescent students. Even mild sleep deprivation has been associated with significant health and educational concerns: increased risk for accidents and injuries, impaired learning, aggression, memory loss, poor self-esteem, and changes in metabolism. Although researchers have begun to explore the effects of delayed school start time, no one has conducted a rigorous review of evidence to determine whether later school start times support adolescent health, education, and well-being. OBJECTIVES: We aimed to assess the effects of a later school start time for supporting health, education, and well being in high school students.Secondary objectives were to explore possible differential effects of later school start times in student subgroups and in different types of schools; to identify implementation practices, contextual factors, and delivery modes associated with positive and negative effects of later start times; and to assess the effects of later school start times on the broader community (high school faculty and staff, neighborhood, and families). SEARCH METHODS: We conducted the main search for this review on 28 October 2014 and updated it on 8 February 2016. We searched CENTRAL as well as 17 key electronic databases (including MEDLINE, Embase, ERIC, PsycINFO, and Sociological Abstracts), current editions of relevant journals and organizational websites, trial registries, and Google Scholar. SELECTION CRITERIA: We included any randomized controlled trials, controlled before-and-after studies, and interrupted time series studies with sufficient data points that pertained to students aged 13 to 19 years and that compared different school start times. Studies that reported either primary outcomes of interest (academic outcomes, amount or quality of sleep, mental health indicators, attendance, or alertness) or secondary outcomes (health behaviors, health and safety indicators, social outcomes, family outcomes, school outcomes, or community outcomes) were eligible. DATA COLLECTION AND ANALYSIS: At least two review authors independently determined inclusion and exclusion decisions through screening titles, abstracts, and full-text reports. Two review authors independently extracted data for all eligible studies. We presented findings through a narrative synthesis across all studies. When two or more study samples provided sufficient information to permit effect size calculations, we conducted random-effects meta-analyses to synthesize effects across studies. MAIN RESULTS: Our search located 17 eligible records reporting on 11 unique studies with 297,994 participants; the studies examined academic outcomes, amount and quality of sleep, mental health indicators, attendance, and student alertness. Overall, the quality of the body of evidence was very low, as we rated most studies as being at high or unclear risk of bias with respect to allocation, attrition, absence of randomization, and the collection of baseline data. Therefore, we cannot be confident about the effects of later school start times.Preliminary evidence from the included studies indicated a potential association between later school start times and academic and psychosocial outcomes, but quality and comparability of these data were low and often precluded quantitative synthesis. Four studies examined the association between later school start times and academic outcomes, reporting mixed results. Six studies examined effects on total amount of sleep and reported significant, positive relationships between later school start times and amount of sleep. One study provided information concerning mental health outcomes, reporting an association between decreased depressive symptoms and later school start times. There were mixed results for the association between later school start times and absenteeism. Three studies reported mixed results concerning the association between later school start times and student alertness. There was limited indication of potential adverse effects on logistics, as the qualitative portions of one study reported less interaction between parents and children, and another reported staffing and scheduling difficulties. Because of the insufficient evidence, we cannot draw firm conclusions concerning adverse effects at this time.It is important to note the limitations of this evidence, especially as randomized controlled trials and high-quality primary studies are difficult to conduct; school systems are often unwilling or unable to allow researchers the necessary control over scheduling and data collection. Moreover, this evidence does not speak to the process of implementing later school starts, as the included studies focused on reporting the effects rather than exploring the process. AUTHORS' CONCLUSIONS: This systematic review on later school start times suggests several potential benefits for this intervention and points to the need for higher quality primary studies. However, as a result of the limited evidence base, we could not determine the effects of later school start times with any confidence. PMID- 28670710 TI - Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery. AB - BACKGROUND: Cataract is a leading cause of blindness worldwide. Cataract surgery is commonly performed but can result in postoperative inflammation of the eye. Inadequately controlled inflammation increases the risk of complications. Non steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are used to prevent and reduce inflammation following cataract surgery, but these two drug classes work by different mechanisms. Corticosteroids are effective, but NSAIDs may provide an additional benefit to reduce inflammation when given in combination with corticosteroids. A comparison of NSAIDs to corticosteroids alone or combination therapy with these two anti-inflammatory agents will help to determine the role of NSAIDs in controlling inflammation after routine cataract surgery. OBJECTIVES: To evaluate the comparative effectiveness of topical NSAIDs (alone or in combination with topical corticosteroids) versus topical corticosteroids alone in controlling intraocular inflammation after uncomplicated phacoemulsification. To assess postoperative best-corrected visual acuity (BCVA), patient-reported discomfort, symptoms, or complications (such as elevation of IOP), and cost-effectiveness with the use of postoperative NSAIDs or corticosteroids. SEARCH METHODS: To identify studies relevant to this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (2016, Issue 12), MEDLINE Ovid (1946 to December 2016), Embase Ovid (1947 to 16 December 2016), PubMed (1948 to December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 16 December 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com; last searched 17 June 2013), ClinicalTrials.gov (www.clinicaltrials.gov; searched December 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en; searched December 2016). SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which participants were undergoing phacoemulsification for uncomplicated cataract extraction. We included both trials in which topical NSAIDs were compared with topical corticosteroids and trials in which combination therapy (topical NSAIDs and corticosteroids) was compared with topical corticosteroids alone. The primary outcomes for this review were inflammation and best-corrected visual acuity (BCVA). DATA COLLECTION AND ANALYSIS: Two review authors independently screened the full-text articles, extracted data from included trials, and assessed included trials for risk of bias according to Cochrane standards. The two review authors resolved any disagreements by discussion. We graded the certainty of the evidence using GRADE. MAIN RESULTS: This review included 48 RCTs conducted in 17 different countries and two ongoing studies. Ten included studies had a trial registry record. Fifteen studies compared an NSAID with a corticosteroid alone, and 19 studies compared a combination of an NSAID plus a corticosteroid with a corticosteroid alone. Fourteen other studies had more than two study arms. Overall, we judged the studies to be at unclear risk of bias. NSAIDs alone versus corticosteroids aloneNone of the included studies reported postoperative intraocular inflammation in terms of cells and flare as a dichotomous variable. Inflammation was reported as a continuous variable in seven studies. There was moderate-certainty evidence of no difference in mean cell value in the participants receiving an NSAID compared with the participants receiving a corticosteroid (mean difference (MD) 0.60, 95% confidence interval (CI) -2.19 to 0.99), and there was low-certainty evidence that the mean flare value was lower in the group receiving NSAIDs (MD 13.74, 95% CI -21.45 to -6.04). Only one study reported on corneal edema at one week postoperatively and there was uncertainty as to whether the risk of edema was higher or lower in the group that received NSAIDs (risk ratio (RR) 0.77, 95% CI 0.26 to 2.29). No included studies reported BCVA as a dichotomous outcome and no study reported time to cessation of treatment. None of the included studies reported the proportion of eyes with cystoid macular edema (CME) at one week postoperatively. Based on four RCTs that reported CME at one month, we found low certainty evidence that participants treated with an NSAID alone had a lower risk of developing CME compared with those treated with a corticosteroid alone (RR 0.26, 95% CI 0.17 to 0.41). No studies reported on other adverse events or economic outcomes. NSAIDs plus corticosteroids versus corticosteroids aloneNo study described intraocular inflammation in terms of cells and flare as a dichotomous variable and there was not enough continuous data for anterior chamber cell and flare to perform a meta-analysis. One study reported presence of corneal edema at various times. Postoperative treatment with neither a combination treatment with a NSAID plus corticosteroid or with corticosteroid alone was favored (RR 1.07, 95% CI 0.98 to 1.16). We judged this study to have high risk of reporting bias, and the certainty of the evidence was downgraded to moderate. No included study reported the proportion of participants with BCVA better than 20/40 at one week postoperatively or reported time to cessation of treatment. Only one included study reported on the presence of CME at one week after surgery and one study reported on CME at two weeks after surgery. After combining findings from these two studies, we estimated with low-certainty evidence that there was a lower risk of CME in the group that received NSAIDs plus corticosteroids (RR 0.17, 95% CI 0.03 to 0.97). Seven RCTs reported the proportion of participants with CME at one month postoperatively; however there was low-certainty evidence of a lower risk of CME in participants receiving an NSAID plus a corticosteroid compared with those receiving a corticosteroid alone (RR 0.50, 95% CI 0.23 to 1.06). The few adverse events reported were due to phacoemulsification rather than the eye drops. AUTHORS' CONCLUSIONS: We found insufficient evidence from this review to inform practice for treatment of postoperative inflammation after uncomplicated phacoemulsification. Based on the RCTs included in this review, we could not conclude the equivalence or superiority of NSAIDs with or without corticosteroids versus corticosteroids alone. There may be some risk reduction of CME in the NSAID-alone group and the combination of NSAID plus corticosteroid group. Future RCTs on these interventions should standardize the type of medication used, dosing, and treatment regimen; data should be collected and presented using the Standardization of Uveitis Nomenclature (SUN) outcome measures so that dichotomous outcomes can be analyzed. PMID- 28670712 TI - Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017 Part 1: Definition, risk factors and assessment. PMID- 28670713 TI - Sonography of the Pronator Teres: Normal and Pathologic Appearances. AB - The pronator teres muscle is rarely examined during a routine sonographic examination of the elbow joint. Nevertheless, it can be affected by a variety of conditions, including trauma and tumors, and can be implicated in compression of the median nerve. This pictorial essay first illustrates the anatomy and biomechanics of the pronator teres. Then we present the sonographic technique for examination, normal sonographic appearance, and anatomic variations of the pronator teres and adjacent structures as well as sonography of their main disorders. Normal and pathologic sonographic appearances are correlated with magnetic resonance imaging and radiographic results. PMID- 28670715 TI - Lipid membrane modulation and pigmentation: A cryoprotection mechanism in Arctic pigmented bacteria. AB - The present study aims to address the effect of gradual change in temperature (15 4 degrees C) followed by freeze-thaw on pigmented bacterial strains - Leeuwenhoekiella aequorea, Pseudomonas pelagia, Halomonas boliviensis, Rhodococcus yunnanensis, and Algoriphagus ratkwoskyi, isolated from Kongsfjorden (an Arctic fjord) to understand their survival in present climate change scenario. The total cell count and retrievability of the isolates were not affected despite the variation in temperature. In all the isolates, the saturated fatty acids, particularly stearic and palmitic acid were predominant at higher temperature, while at 4 degrees C, the unsaturated fatty acids, primarily cis-10 pentadecenoic, palmitoleic, and oleic acid, were major constituents, confirming homeoviscous adaptation. Even after freeze-thaw, the unsaturated fatty acid composition was retained in all the isolates except A. ratkwoskyi. The increase in unsaturated fatty acids was at the expense of their saturated analogs, probably by desaturase activity. The major pigment in the isolates resembled Zeaxanthin, whose concentration was found to be 26-65% higher after freeze-thaw, suggesting its vital role as a cryoprotective agent in regulating membrane fluidity. Such experimental simulations related to freeze-thaw in polar bacterial isolates are helpful in understanding the physiological plasticity adaptations, which could be critical for survival in harsh and rapidly changing polar environments. PMID- 28670714 TI - Cervical cancer incidence after up to 20 years of observation among women with HIV. AB - To estimate the incidence of invasive cervical cancer (ICC) across up to 21 years of follow-up among women with human immunodeficiency virus (HIV) and to compare it to that among HIV-uninfected women, we reviewed ICC diagnoses from a 20-year multi-site U.S. cohort study of HIV infected and uninfected women who had Pap testing every 6 months. Incidence rates were calculated and compared to those in HIV-negative women. Incidence ratios standardized to age-, sex-, race-, and calendar-year specific population rates were calculated. After a median follow-up of 12.3 years, four ICCs were confirmed in HIV seropositive women, only one in the last 10 years of observation, and none in seronegative women. The ICC incidence rate did not differ significantly by HIV status (HIV seronegative: 0/100,000 person-years vs. HIV seropositive: 19.5/100,000 person-years; p = 0.53). The standardized incidence ratio for the HIV-infected WIHS participants was 3.31 (95% CI: 0.90, 8.47; p = 0.07). Although marginally more common in women without HIV, for those with HIV in a prevention program, ICC does not emerge as a major threat as women age. PMID- 28670717 TI - Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH 2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH 2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch. PMID- 28670716 TI - Adoptive transfer of murine T cells expressing a chimeric-PD1-Dap10 receptor as an immunotherapy for lymphoma. AB - Adoptive transfer of T cells is a promising cancer therapy and expression of chimeric antigen receptors can enhance tumour recognition and T-cell effector functions. The programmed death protein 1 (PD1) receptor is a prospective target for a chimeric antigen receptor because PD1 ligands are expressed on many cancer types, including lymphoma. Therefore, we developed a murine chimeric PD1 receptor (chPD1) consisting of the PD1 extracellular domain fused to the cytoplasmic domain of CD3zeta. Additionally, chimeric antigen receptor therapies use various co-stimulatory domains to enhance efficacy. Hence, the inclusion of a Dap10 or CD28 co-stimulatory domain in the chPD1 receptor was compared to determine which domain induced optimal anti-tumour immunity in a mouse model of lymphoma. The chPD1 T cells secreted pro-inflammatory cytokines and lysed RMA lymphoma cells. Adoptive transfer of chPD1 T cells significantly reduced established tumours and led to tumour-free survival in lymphoma-bearing mice. When comparing chPD1 receptors containing a Dap10 or CD28 domain, both receptors induced secretion of pro-inflammatory cytokines; however, chPD1-CD28 T cells also secreted anti inflammatory cytokines whereas chPD1-Dap10 T cells did not. Additionally, chPD1 Dap10 induced a central memory T-cell phenotype compared with chPD1-CD28, which induced an effector memory phenotype. The chPD1-Dap10 T cells also had enhanced in vivo persistence and anti-tumour efficacy compared with chPD1-CD28 T cells. Therefore, adoptive transfer of chPD1 T cells could be a novel therapy for lymphoma and inclusion of the Dap10 co-stimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile and T-cell differentiation phenotype for anti-tumour therapies. PMID- 28670718 TI - Ketamine Infusion Combined With Magnesium as a Therapy for Intractable Chronic Cluster Headache: Report of Two Cases. AB - BACKGROUND: Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH. CASE REPORTS: Two Caucasian males, 28 and 45 years-old, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 h) combined with magnesium sulfate (3000 mg over 30 min) in an outpatient setting. This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for one patient and partial relief (50%) for the other patient, for 6 weeks in both cases. CONCLUSION: The NMDA receptor is a potential target for the treatment of chronic CH. Randomized, placebo-controlled studies are warranted to establish both safety and efficacy of such treatment. PMID- 28670719 TI - Association between clinical characteristics and the diagnostic accuracy of circulating single-molecule amplification and resequencing technology on detection epidermal growth factor receptor mutation status in plasma of lung adenocarcinoma. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in the world. Circulating single-molecule amplification and resequencing technology (cSMART) can successfully detect epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC). However, few studies have investigated the association between clinical characteristics and the diagnostic accuracy of cSMART technique in lung adenocarcinoma. METHODS: We enrolled 95 patients, which included paraffin embedded tumor tissues and matched plasma samples. Retrospectively analyzed the correlation between clinical characteristics and sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of cSMART. RESULTS: Of the 95 lung adenocarcinoma cancer patients, 49 (51.5%) and 40 (42.1%) harbored EGFR mutations respectively in tissue and plasma. In younger than 60 years group, sensitivity, specificity and consistency for cSMART were 81.0%, 100%, and 90.9% (P<.001). In metastasis group, sensitivity, specificity, and consistency for cSMART were 92.9%, 77.8%, and 87.0% (P=.001). By univariate analysis, younger than 60 years (OR=5.938; 95% confidence interval: 1.835-19.210; P=.001); metastasis group (OR=4.482; 95% confidence interval: 1.432-14.024; P=.007) were significantly correlated with a higher accuracy. By multivariate analysis, younger than 60 years (P=.003) and metastasis (P=.004) were confirmed as independent factors for diagnostic accuracy of EGFR mutation in plasma through cSMART. CONCLUSION: cSMART is feasible for detection EGFR mutation in plasma when tissue is unavailable. Age and metastasis might be considered as independent factors in diagnostic accuracy of cSMART in lung adenocarcinoma. PMID- 28670720 TI - Mammalian Cu-containing amine oxidases (CAOs): New methods of analysis, structural relationships, and possible functions. PMID- 28670728 TI - Reply. PMID- 28670721 TI - Age is not a bar to PCI: Insights from the long-term outcomes from off-site PCI in a real-world setting. AB - OBJECTIVES: We sought to analyze the percutaneous coronary intervention (PCI) outcomes of very elderly patients (V. Eld. group, age >80 years) and compare their outcomes to a less elderly cohort (Eld. group, age 75-80 years) traditionally reported in the literature. BACKGROUND: Limited data exist on peri procedural and long-term outcomes following PCI in the V. Eld. (age >80 years), with under-representation of this cohort in randomized controlled trials. These patients present with advanced complex coronary disease and multiple comorbidities. METHODS: All 580 consecutive patients aged >=75 years (age 80 +/- 4.9 years, 57.4% males) undergoing PCI between April 2006 and November 2011 were included. A total of 624 consecutive lesions were identified and analyzed. All V. Eld. patients (n = 253) were subsequently selected, and their outcomes compared to Eld. patients (n = 327). Mean follow-up was 30.8 +/- 2.7 months with 98% clinical follow-up achieved. RESULTS: All comparative data are expressed as (V. Eld. vs Eld.) unless otherwise specified. All-cause mortality was significantly higher in the V. Eld. group (11.9% vs 6.1%), although this did not translate into a significant difference in cardiac mortality (6.3% vs 3.7%) or major adverse cardiac and cerebrovascular events (16.2% vs 12.5%). The composite incidence of myocardial infarction (MI), stroke, definite/probable stent thrombosis, and TIMI major bleed was 4.7%, 1.4% 1.9%, and 6.4%, respectively with no significant difference between both cohorts. CONCLUSIONS: This study demonstrates an acceptable occurrence of MI, death, repeat intervention, and stent thrombosis in a high-risk group of V. Eld. patients with de novo lesions. Age alone in the absence of other non-cardiac factors should not prohibit a patient from access to PCI. PMID- 28670729 TI - Reply. PMID- 28670731 TI - Re: Serious maternal complications in relation to severe pre-eclampsia: a retrospective cohort study of the impact of hospital volume; Severe maternal morbidity requires regionalisation of obstetric critical care; Guilt, blame and litigation: can an overenthusiastic 'safety culture' cause harm?: Maternal mortality: the heavy psychological burden on centre obstetricians. PMID- 28670732 TI - Prenatal sonographic diagnosis of nondysraphic intramedullary lipomas: A case report. AB - Nondysraphic intramedullary lipomas of the spinal cord are rare, and there are currently no reports of their observation in utero. Here, we present the sonographic (US) findings in such a case. Four intraspinal hyperechoic masses were observed on US on the dorsal aspect of the fetal spine in a 30-year-old woman at 30 weeks' gestation. Findings were consistent with those of prenatal MRI and were confirmed on autopsy after induced abortion. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:278-281, 2018. PMID- 28670733 TI - Determination of silodosin and its active glucuronide metabolite KMD-3213G in human plasma by LC-MS/MS for a bioequivalence study. AB - A sensitive and selective liquid chromatography-tandem mass spectrometry (LC MS/MS) method is described for the simultaneous determination of silodosin (SLD) and its active metabolite silodosin beta-d-glucuronide (KMD-3213G) in human plasma. Liquid-liquid extraction of plasma samples was carried out with ethyl acetate and methyl tert-butyl ether solvent mixture using deuterated analogs as internal standards. The extraction recoveries of SLD and KMD-3213G were in the ranges 90.8-93.4 and 87.6-89.9%, respectively. The extracts were analyzed on a Symmetry C18 (50 * 4.6 mm, 5 MUm) column under gradient conditions using 10 mm ammonium formate in water and methanol-acetonitrile (40:60, v/v), within 6.0 min. For MS/MS measurements, ionization of the analytes was carried out in the positive ionization mode and the transitions monitored were m/z 496.1 -> 261.2 for SLD and m/z 670.2 -> 494.1 for KMD-3213G. The method showed good linearity, accuracy, precision and stability in the range 0.10-80.0 ng/mL for SLD and KMD 3213G. The IS-normalized matrix factors obtained were highly consistent, ranging from 0.962 to 1.023 for both analytes. The method was used to support a bioequivalence study of SLD and its metabolite in healthy volunteers after oral administration of 8 mg silodosin capsules. PMID- 28670734 TI - Reply to "Non-ST-segment elevation myocardial infarction vs aborted myocardial infarction-triggered takotsubo syndrome?" PMID- 28670735 TI - SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly. AB - Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene deletions, which are known to cause HPE. Both chromosomal microarray and whole exome sequencing (WES) were used to evaluate families with inherited HPE. Two families showed inherited deletions that contain SIX3 and were incompletely penetrant for HPE. Using WES, we ruled out parental mosaicism, a SIX3 hypomorph, and clinically significant variants in genes that are known to interact with SIX3 as causes of incomplete penetrance. We demonstrate the importance of molecular cascade testing in families with HPE and we answer important questions about incomplete penetrance. PMID- 28670736 TI - Amino acids suppress the expression of PAT1 on lysosomes via inducing the cleavage of a targeting signal. AB - The lysosome-associated transporter proton-coupled amino acid transporter 1 (PAT1) promotes nutrient recycling through releasing luminal amino acids into the cytosol. Using HEK293 cells expressing an EGFP-tagged PAT1 (EGFP-PAT1) as a model, we identified a consensus tyrosine-based targeting signal in the cytosolic N-terminal region of PAT1, which facilitates its expression on the lysosome. Interestingly, this signal can be removed via protein cleavage in an amino acid sensitive manner. The cleavage is suppressed upon amino acid starvation and is induced by amino acid replenishment. However, amino acid deficiency does not suppress the cleavage of amino acid-binding mutants of EGFP-PAT1. Our data support a mechanism, whereby amino acid binding induces PAT1 cleavage to remove a targeting signal, thus suppressing the expression of PAT1 on the lysosome. PMID- 28670738 TI - Clinical assessment of the lag-time and tmax of pellets with controlled release of glucose: in vitro/in vivo comparison using 13 C-breath test. AB - Maintaining a stable glycaemia in diabetes mellitus type 1 requires flexible insulin administration and carbohydrate intake to affected individuals. In real life, there might be some situations limiting the insulin-sugar balance control, e.g. night sleep or prolonged sporting activities. Glucose pellets with a pre determined time lag between the pellet administration and glucose release were developed to mimic a 'snack eaten in advance'. In this article, a 13 C-glucose breath test was introduced to translate laboratory dissolution testing to clinical confirmation of the glucose release pattern using 5% delta abundance to differentiate the appearance of in 13 C exhaled breath. An independent two-sample t-test (p = 0.20) confirmed an average clinical lag time of 300 min and an in vitro time of 338 min to be identical at a level of significance of alpha = 0.05. Moreover, using the same statistical method, the clinical tmax (564 min) and the in vitro t50 (594 min) were also considered identical (p = 0.34). It was concluded that dissolution testing is a relevant method to determine the time lags of dosage forms with controlled release of glucose and that the 13 C-glucose breath test is a suitable clinical tool for lag time verification in clinical studies. PMID- 28670737 TI - A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-beta oligomers. AB - Brain accumulation of soluble oligomers of the amyloid-beta peptide (AbetaOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AbetaO species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher order oligomers. However, there is no consensus in the literature regarding which AbetaO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AbetaOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AbetaO species. Here, we report the characterization of a human single chain antibody fragment (scFv) denoted NUsc1, one of a number of scFvs we have identified that stringently distinguish AbetaOs from both monomeric and fibrillar Abeta. NUsc1 readily detected AbetaOs previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked AbetaO binding and reduced AbetaO-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous AbetaOs in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of AbetaOs with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular AbetaO species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics. PMID- 28670740 TI - Correction. PMID- 28670739 TI - CLL progression after one cycle of FCR: Richter's transformation versus EBV associated lympho-proliferation. PMID- 28670742 TI - Consecutive occurrence of isotopic and isomorphic response in a patient: Patchy granuloma annulare arising in the site of herpes zoster scar and seborrhoeic dermatitis. PMID- 28670743 TI - How functional is a trait? Phosphorus mobilization through root exudates differs little between Carex species with and without specialized dauciform roots. AB - Root structures secreting carboxylates and phosphatases are thought to enhance a plant's phosphorus (P) acquisition. But do closely related species with and without such structures really differ in root exudation, P mobilization, or ecological niche? We investigated this by comparing 23 European Carex species with and without 'dauciform roots' (DRs). Plants grown in pots with sand were screened for DR formation, phosphatase activities, carboxylate exudation, and utilization of various organic and inorganic P compounds. Ecological niches were compared using ecological indicator values and nutrient concentrations of plant shoots in natural habitats. Species of subgenus Carex formed DRs, while species of subgenus Vignea did not. Species with DRs had higher root diesterase activity than species without DRs, exuded more citrate but less oxalate and less total carboxylates, and allocated less biomass to roots. Species with and without DRs showed similar growth responses to different forms of P and different amounts of P supplied; their natural habitats do not differ in soil fertility or degree of P limitation. Despite some differences in physiological function, DRs did not influence the P acquisition and nutritional niche of European Carex species, suggesting that species with and without DRs do not exhibit distinct P acquisition strategies. PMID- 28670744 TI - Terminal Iron Carbyne Complexes Derived from Arrested CO2 Reductive Disproportionation. AB - The encumbered tetraisocyanide dianion Na2 [Fe(CNArMes2 )4 ] reacts with two molecules of CO2 to effect reductive disproportionation to CO and carbonate ([CO3 ]2- ). When the reaction is performed in the presence of silyl triflates, reductive disproportionation is arrested by silylative esterification of a mono CO2 adduct. This results in the formation of four-coordinate terminal iron carbynes possessing an aryl carbamate substituent owing to the direct attachment of an C(O)OSiR3 group to an isocyanide nitrogen atom. Crystallographic, spectroscopic, and computational analyses of these iron-carbon multiply bonded species reveal electronic structure properties indicative of a conformationally locked iron carbyne unit. PMID- 28670741 TI - Structural, mutagenic and in silico studies of xyloglucan fucosylation in Arabidopsis thaliana suggest a water-mediated mechanism. AB - The mechanistic underpinnings of the complex process of plant polysaccharide biosynthesis are poorly understood, largely because of the resistance of glycosyltransferase (GT) enzymes to structural characterization. In Arabidopsis thaliana, a glycosyl transferase family 37 (GT37) fucosyltransferase 1 (AtFUT1) catalyzes the regiospecific transfer of terminal 1,2-fucosyl residues to xyloglucan side chains - a key step in the biosynthesis of fucosylated sidechains of galactoxyloglucan. We unravel the mechanistic basis for fucosylation by AtFUT1 with a multipronged approach involving protein expression, X-ray crystallography, mutagenesis experiments and molecular simulations. Mammalian cell culture expressions enable the sufficient production of the enzyme for X-ray crystallography, which reveals the structural architecture of AtFUT1 in complex with bound donor and acceptor substrate analogs. The lack of an appropriately positioned active site residue as a catalytic base leads us to propose an atypical water-mediated fucosylation mechanism facilitated by an H-bonded network, which is corroborated by mutagenesis experiments as well as detailed atomistic simulations. PMID- 28670745 TI - Multiple Magnetic Relaxation Pathways and Dual-Emission Modulated by a Heterometallic Tb-Pt Bonding Environment. AB - A heterometallic Tb-Pt complex, [Tb2 Pt3 (SAc)12 (H2 O)2 ] (SAc=thioacetate), was synthesized. Dual emission was modulated by the presence of a heterometallic Tb Pt bonding environment. The heterometallic Tb-Pt bond lowers the symmetry of the Tb ion and enhanced the emission efficiency. In addition, the Tb-Pt complex shows field-induced multiple magnetic relaxation pathways. Furthermore, it served as an antenna for the observed dual emission. In other words, the heterometallic Tb-Pt bond has a significant effect on the luminescence and magnetic properties of the complex. PMID- 28670747 TI - Rodlike Tetracene Derivatives. AB - Efficient and versatile synthetic access to rodlike tetracene derivatives was developed by means of Diels-Alder cycloaddition, halogenation, halogen-metal exchange, and transition metal mediated coupling reactions. Herein, the synthesis and structural, electrical, and charge-transport properties of three of the resulting materials, namely, 2-(tetracen-2-yl)tetracene, 1,4-bis(2 tetracenyl)benzene, and 2,5-bis(2-tetracenyl)thiophene, are presented. Good crystallization behavior on SiO2 substrates, narrowing of the bandgap by 0.2 eV, and a decrease of the ionization potential of more than 0.5 eV compared to tetracene were observed. Charge-carrier field-effect mobilities on the order of 10-1 cm2 V-1 s-1 , on/off ratios of 105 , and threshold voltages Vth <15 V were found in thin-film organic field-effect transistors prepared by standard high-vacuum deposition techniques. PMID- 28670746 TI - HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in metastatic squamous cell carcinoma of the anal canal: A case report. AB - Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as single-agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single-agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents. PMID- 28670748 TI - SOMANZ guidelines for the investigation and management sepsis in pregnancy. AB - SOMANZ (Society of Obstetric Medicine Australia and New Zealand) has written a guideline to provide evidence-based guidance for the investigation and care of women with sepsis in pregnancy or the postpartum period. The guideline is evidence-based and incorporates recent changes in the definition of sepsis. The etiology, investigation and treatment of bacterial, viral and non-infective causes of sepsis are discussed. Obstetric considerations relevant to anaesthetic and intensive care treatment in sepsis are also addressed. A multi-disciplinary group of clinicians with experience in all aspects of the care of pregnant women have contributed to the development of the guidelines. This is an executive summary of the guidelines. PMID- 28670749 TI - The severely under-recognized public health risk of strongyloidiasis in North American cities-A One Health approach. AB - Strongyloides and other soil-transmitted helminths represent a severely under recognized zoonotic public health risk, especially in North American cities. They are present throughout North America, including in urban areas, causing morbidity and mortality in human and non-human animals. Epidemiological "masking" of strongyloidiasis due to overlapping symptoms with other systemic diseases, including allergies, and diagnostic limitations complicate our understanding of the epidemiological extent of this disease, and auto-infection allows long-term persistence of individual infections. Zoonotic transmission and environmental transmission are critical components in the epidemiology of strongyloidiasis, and other diseases caused by soil-transmitted helminths. In this review, we bring together medical, veterinary and environmental expertise in a "One Health" context, to document and analyse this under-recognized risk. We also present implementable opportunities for action with respect to diagnostics, treatment, community engagement and land management to mitigate the impact and transmission of strongyloidiasis and other diseases caused by soil-transmitted helminths. PMID- 28670750 TI - A hair shaft causing infective endocarditis. PMID- 28670751 TI - Superficial plantar angiomyxoma in a young man. PMID- 28670752 TI - Sudden cardiac death in nonischemic cardiomyopathy: Refining risk assessment. AB - Sudden cardiac death (SCD) risk assessment among patients with nonischemic cardiomyopathy (NICM) has been has been less straightforward than for patients with ischemic cardiomyopathy. The common surrogate that has been associated with highest SCD risk for all cardiomyopathies, and which has been universally used to guide implantation of primary-prevention implantable cardioverter-defibrillators (ICDs), is left ventricular ejection fraction (LVEF) <=35%. However, this practice has been called into question, especially in light of recent trials suggesting that ICD treatment may not be of additional survival benefit among those with NICM treated with optimal medical therapy. This Clinical Review attempts to offer refinements to the current practice of SCD risk assessment among patients with NICM, with specific focus on importance of NICM etiology and efforts to identify myocardial scarring and arrhythmogenic substrate, both of which may provide greater information about SCD risk than the LVEF alone. These concepts are illustrated further as they apply to hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and cardiac sarcoidosis, all of which are increasingly recognized NICM substrates associated with SCD and for which refinements for assessing risk are lacking in conventional guidelines. PMID- 28670753 TI - Human varicella zoster virus is not present in the semen of a man affected by chickenpox during the in vitro fertilisation of his wife. AB - Human varicella zoster virus (VZV) is a member of the herpes virus family and affects humans only. Information about the presence of the virus in the semen samples of men affected by chickenpox is rather limited in the literature. Here, we reported a husband was affected by VZV during in vitro fertilisation treatment of his wife treated in our centre. The semen sample was checked for the presence of VZV by the PCR technique. The PCR result found no detectable viral DNA in the semen sample. The semen sample was then used for conventional IVF insemination and subsequently a healthy baby boy was born. This single case report suggests that the semen sample of men affected by chickenpox may be safe to use for assisted reproduction methods during the VZV infective period. PMID- 28670754 TI - The development and impact of primary health care in China from 1949 to 2015: A focused review. AB - High-quality primary health care (PHC) services are associated with better health outcomes and positive health equity. Providing PHC services to all inhabitants is one of the Chinese government's health care objectives. However, an imbalance between people's increasing health needs and effective health service utilization exists in China. The objective of this review is to identify evidence for PHC development in China and to summarize the challenges as a reference for the future improvement of China's PHC system. Literature searches related to China's PHC were performed in PubMed, Web of Science, China National Knowledge Infrastructure, and Wan-fang databases. Related data were collected from the China Statistical Yearbook on Health and Family Planning 2003-2016, the China National Health Accounts Report 2015, and An Analysis Report of National Health Services Survey in China, 2013. The PHC network and the population's health have improved in China in recent years, with general practitioners as "gatekeepers" who have gradually taken the initiative to offer health services to residents. The limitation of input and shortages of resources and skilled health care providers may restrict the sustainable development of China's PHC system. Therefore, policy support from the government is necessary. PMID- 28670755 TI - Production of low-Cs+ rice plants by inactivation of the K+ transporter OsHAK1 with the CRISPR-Cas system. AB - The occurrence of radiocesium in food has raised sharp health concerns after nuclear accidents. Despite being present at low concentrations in contaminated soils (below MUm), cesium (Cs+ ) can be taken up by crops and transported to their edible parts. This plant capacity to take up Cs+ from low concentrations has notably affected the production of rice (Oryza sativa L.) in Japan after the nuclear accident at Fukushima in 2011. Several strategies have been put into practice to reduce Cs+ content in this crop species such as contaminated soil removal or adaptation of agricultural practices, including dedicated fertilizer management, with limited impact or pernicious side-effects. Conversely, the development of biotechnological approaches aimed at reducing Cs+ accumulation in rice remain challenging. Here, we show that inactivation of the Cs+ -permeable K+ transporter OsHAK1 with the CRISPR-Cas system dramatically reduced Cs+ uptake by rice plants. Cs+ uptake in rice roots and in transformed yeast cells that expressed OsHAK1 displayed very similar kinetics parameters. In rice, Cs+ uptake is dependent on two functional properties of OsHAK1: (i) a poor capacity of this system to discriminate between Cs+ and K+ ; and (ii) a high capacity to transport Cs+ from very low external concentrations that is likely to involve an active transport mechanism. In an experiment with a Fukushima soil highly contaminated with 137 Cs+ , plants lacking OsHAK1 function displayed strikingly reduced levels of 137 Cs+ in roots and shoots. These results open stimulating perspectives to smartly produce safe food in regions contaminated by nuclear accidents. PMID- 28670756 TI - Epicardial fat thickness is associated with aortic intima-media thickness in patients without clinical manifestation of atherosclerotic cardiovascular disease. AB - BACKGROUND: Although the relationship between epicardial fat thickness (EFTh) and coronary atherosclerosis is well established, this relation in the early periods of atherosclerosis has not been fully demonstrated. On the other hand, thoracic aortic intima-media thickness (IMT) rather than carotid IMT was reported as an earlier marker of preclinical atherosclerosis. OBJECTIVE: We aimed to assess the relationship between thoracic aortic IMT and EFTh in patients undergoing transesophageal echocardiography (TEE) examination for different indications. METHODS: We included 104 patients (mean age 38+/-11.4 years), who underwent TEE for various indications. The patients were divided into two groups according to the median thoracic aortic IMT values (IMT normal group<10 mm and IMT abnormal group>=10 mm). EFTh was obtained using two-dimensional transthoracic echocardiography on the right ventricular free wall during systole and diastole. RESULTS: The highest EFTh values (3.3+/-0.96 mm vs. 4.51+/-0.66 mm, P<.001) were observed in the abnormal aortic IMT group. Multivariate linear regression analysis showed that aortic IMT was independently correlate with EFTh (beta=0.423, P<.001). Moreover, EFTh was found to be associated with history of transient ischemic attack (r=.403, P<.001) and abnormal IMT (r=.643, P<.001) in bivariate analysis. CONCLUSION: Epicardial fat thickness is independently related to the extent of subclinical thoracic aortic atherosclerosis. Increase in EFTh may be crucial marker for initial atherosclerosis. PMID- 28670757 TI - An exploration of clinical psychology's response to parental bereavement in adults with intellectual disability. AB - BACKGROUND: The dearth of literature regarding how or when to intervene when an adult with intellectual disability is bereaved may impede clinical practice; this study therefore aimed to explore the current clinical psychology response, so as to enhance understanding of the role of the profession in supporting grief within this population. METHOD: A collective case study design was used. Data for six persons with intellectual disability, including interviews with parentally bereaved persons and involved staff members, were integrated into individual case stories for cross-case synthesis. RESULTS: Data were analysed using thematic analysis. Five overarching themes illustrated that the clinical psychology role is broadly distributed and identified potentially complicating factors such as "gatekeeping" and "staff uncertainty." CONCLUSIONS: A model of bereavement supports reflecting that by Read (Learning Disability Practice, 8, 2005, 31) is being approximated in clinical practice; further research is required to determine how best to implement this, and whether this meets the true needs of the population. PMID- 28670758 TI - Congenital Long QT syndrome and torsade de pointes. AB - Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD. This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT. This review will discuss the genetic, molecular, and phenotype characteristics of congenital LQTS as well as current management strategies and future directions in the field. PMID- 28670759 TI - Limitations of poor bone marrow aspirations (for an accurate diagnosis) despite the multimodal analytical era: A longitudinal retrospective study. PMID- 28670760 TI - Endoscopic Ultrasonography-Guided Fine Needle Aspiration Can Be Used to Rule Out Malignancy in Autoimmune Pancreatitis Patients. AB - OBJECTIVES: The aim of this study was to review the suitability of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) for ruling out malignancy in autoimmune pancreatitis patients. METHODS: We retrospectively reviewed 40 autoimmune pancreatitis patients (type 1:37 patients; type 2: two patients; possible autoimmune pancreatitis: one patient) who received EUS-FNA. Among the 40 autoimmune pancreatitis patients, 34 were not histopathologically diagnosed with autoimmune pancreatitis by EUS-FNA, and they were followed up for more than 6 months in our hospital. Moreover, 14 pancreatic cancer patients who were not diagnosed by EUS-FNA were selected as a control group. These 14 patients constituted 3.9% of the 360 pancreatic cancer patients who received EUS-FNA. We evaluated the prognoses of the 34 autoimmune pancreatitis patients and the clinical differences between these 34 autoimmune pancreatitis patients and the 14 pancreatic cancer patients. RESULTS: All 34 autoimmune pancreatitis patients showed reduced pancreatic swelling. The main pancreatic duct dilation ( > 3 mm), the diameter of the main pancreatic duct, the capsule-like rim sign, and serum CA19-9 levels were significantly different between the autoimmune pancreatitis and pancreatic cancer patients (2.9% versus 69.2%, P < .01; 1.7 +/- 1.6 mm versus 6.8 +/- 5.0 mm, P < .01; 79.4% versus 0%, P < .01; 41.4 +/- 79.0 U/mL versus 2079.1 +/- 275.3 U/mL, P = .02). CONCLUSIONS: Almost all pancreatic cancers can be diagnosed by EUS-FNA. Furthermore, other clinical characteristics of pancreatic cancer undiagnosed by EUS-FNA were different from autoimmune pancreatitis undiagnosed by EUS-FNA. Endoscopic ultrasonography-guided FNA can be used to rule out malignancy in autoimmune pancreatitis patients. PMID- 28670761 TI - Models of childhood cancer survivorship care in Australia and New Zealand: Strengths and challenges. AB - AIM: Childhood cancer survivors remain at risk of developing life-altering and/or life-threatening health conditions following the completion of curative treatment. However, no uniform model of care for childhood cancer survivors exists in Australia and New Zealand (ANZ). This study reports on current childhood cancer survivorship care in ANZ, highlighting the challenges childhood cancer survivor long-term follow-up (LTFU) clinics face. METHODS: We conducted semistructured, telephone interviews with the pediatric medical director and clinical nurse consultant from all 11 LTFU clinics at tertiary referral pediatric oncology units across ANZ (n = 19; 100% response rate). Data were analyzed using NVivo10. RESULTS: Participants unanimously identified limited options for transitioning older survivors out of pediatrics and inadequate funding as central challenges to the provision of best-practice LTFU care. There is duplication of resource development between clinics (e.g. survivorship care plan templates and clinic systems). Although participants recognized an overly prescriptive model of LTFU care as potentially unfeasible, the majority endorsed a national, or even bi national, model of care that could be tailored to meet the needs of their local environment. CONCLUSION: The lack of an accepted model of optimal childhood cancer survivorship care across ANZ prevents the synergistic development of survivorship guidelines, survivorship care plans, transition pathways, information technology solutions, funding streams and late effects data consortiums. Sufficient resources to facilitate growth may be difficult to secure if approached by individual centers rather than via a national, cooperative effort. Improved solutions are urgently needed for transitioning survivors to appropriate care beyond the pediatric age. PMID- 28670762 TI - Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer. AB - Aim was to identify methylated genes with functional involvement in cisplatin resistance development of epithelial ovarian cancer (EOC). Genome-wide analyses of hypermethylated CpG-islands in resistant cell lines in combination with qRT PCR analyses were used to identify epigenetically silenced genes. EOC-Type-II tumors were analyzed for gene methylation and expression and TCGA data were interrogated in-silico. Experiments revealed 37 commonly hypermethylated genes in resistant cells of which Tribbles 2 (TRIB2) showed the most pronounced downregulation on mRNA level and was characterized further. TRIB2 showed a reactivation after 5'-Aza-Cytidine treatment in resistant cells but a cisplatin dependent, prominent upregulation on mRNA level in sensitive cells, only. Re expression in resistant A2780 cells increased the sensitivity to cisplatin and other DNA-damaging agents, but not taxanes. Contrary, knockdown of TRIB2 increased resistance to cisplatin in sensitive cells. TRIB2 was involved in the induction of a cisplatin-dependent cell cycle arrest and apoptosis by influencing p21 and survivin expression. An increased Pt-DNA-adduct formation in TRIB2 re expressing cells did not translate in higher levels of dsDNA damage (yH2AX-foci). Thus, TRIB2 is potentially involved in the signal transduction from nucleotide excision repair of intrastrand cross links. Importantly, patient stratification of two homogenous cohorts of EOC-Type-II patients from Jena (n = 38) and the TCGA (n = 149) by TRIB2 mRNA expression consistently revealed a significantly decreased PFS for patients with low TRIB2 levels (log-rank p < 0.05). Tumors from resistant patients expressed the lowest levels of TRIB2. Downregulation of TRIB2 contributes to platin-resistance and TRIB2 expression should be validated as prognostic and predictive marker for EOC. PMID- 28670763 TI - Silver nanoparticles from Pilimelia columellifera subsp. pallida SL19 strain demonstrated antifungal activity against fungi causing superficial mycoses. AB - In this study, we present the in vitro antifungal activity of silver nanoparticles (AgNPs) synthesized from acidophilic actinobacterium Pilimelia columellifera subsp. pallida SL19 strain, alone and in combination with antibiotics viz., amphotericin B, fluconazole, and ketoconazole against pathogenic fungi, namely Candida albicans, Malassezia furfur, and Trichophyton erinacei. The minimum inhibitory concentration (MIC) and minimum biocidal concentration (MBC) of AgNPs against test fungi were evaluated. The fractional inhibitory concentration (FIC) index was determined to estimate antifungal activity of AgNPs combined with antibiotics. Antifungal activity of AgNPs varied among the tested fungal strains. M. furfur was found to be most sensitive to biogenic silver nanoparticles, followed by C. albicans and T. erinacei. The lowest MIC of AgNPs was noticed against M. furfur (16 MUg ml-1 ). Synergistic effect was observed on C. albicans when AgNP were combined with amphotericin B and ketoconazole and on M. furfur with fluconazole and ketoconazole (FIC index of 0.5). Cytotoxic effect of AgNPs on HeLa and 3T3 cell lines was evaluated. The IC50 values were found to be 55 and 25 MUg ml-1 , respectively. The present study indicates that silver nanoparticles from P. columellifera subsp. pallida SL19 strain have antifungal activity, both alone and in combination with antibiotics, and offer a valuable contribution to nanomedicine. PMID- 28670764 TI - MicroRNA 375 regulates proliferation and migration of colon cancer cells by suppressing the CTGF-EGFR signaling pathway. AB - MicroRNA 375 (MIR375) is significantly down regulated in human colorectal cancer (CRC) tissues; we have previously identified MIR375 as a colon cancer associated microRNA (miRNA). We identified putative MIR375 target genes by comparing the mRNA microarray analysis data of MIR375-overexpressing cells with the candidate MIR375 target genes predicted by public bioinformatic tools. We investigated that the connective tissue growth factor (CTGF) is a direct target gene of MIR375. Expression of CTGF, a ligand of epidermal growth factor receptor (EGFR), was markedly enhanced in human CRC tissues in comparison with the corresponding normal colon tissues. We demonstrated that the expression levels of molecules in EGFR signaling pathways were regulated by MIR375 in colorectal cells. Using immunohistochemistry and the xenograft of MIR375-overexpressing colorectal cells in mice, we showed that MIR375 regulates cell growth and proliferation, angiogenesis, cell migration, cell cycle arrest, apoptosis, and necrosis in colon cells. Furthermore, results of MIR375 overexpression and cetuximab treatment indicated that the apoptosis and necrosis in colon cells were synergistically enhanced. Our results suggest that the down-regulation of MIR375 modulates EGFR signaling pathways in human colorectal cells and tissues by increasing CTGF expression; therefore, MIR375 may have a therapeutic value in relation to human CRC. PMID- 28670765 TI - Publication Ethos in the Immunogenetics community. PMID- 28670766 TI - Peptide-Directed Binding for the Discovery of Modulators of alpha-Helix-Mediated Protein-Protein Interactions: Proof-of-Concept Studies with the Apoptosis Regulator Mcl-1. AB - Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective alpha-helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl 1, commonly exploited by cancers to avoid cell death. Peptide-directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC50 value of less than 100 MUm, and approximately 25 % had IC50 values below 1 MUm to Mcl-1. Compounds show selectivity for Mcl-1 over other anti-apoptotic proteins, possess cytotoxicity to cancer cell lines, and induce hallmarks of apoptosis. This approach represents a novel and economic process for the rapid discovery of new alpha-helical PPI modulators. PMID- 28670768 TI - MOLECULAR DISSECTION OF MYCOPLASMA HOMINIS. PMID- 28670767 TI - Age slowing down in detection and visual discrimination under varying presentation times. AB - The reaction time has been described as a measure of perception, decision making, and other cognitive processes. The aim of this work is to examine age-related changes in executive functions in terms of demand load under varying presentation times. Two tasks were employed where a signal detection and a discrimination task were performed by young and older university students. Furthermore, a characterization of the response time distribution by an ex-Gaussian fit was carried out. The results indicated that the older participants were slower than the younger ones in signal detection and discrimination. Moreover, the differences between both processes for the older participants were higher, and they also showed a higher distribution average except for the lower and higher presentation time. The results suggest a general slowdown in both tasks for age under different presentation times, except for the cases where presentation times were lower and higher. Moreover, if these parameters are understood to be a reflection of executive functions, these findings are consistent with the common view that age-related cognitive deficits show a decline in this function. PMID- 28670769 TI - Co-production of community mental health services: Organising the interplay between public services and civil society in Denmark. AB - Co-production involves knowledge and skills based on both lived experiences of citizens and professionally training of staff. In Europe, co-production is viewed as an essential tool for meeting the demographic, political and economic challenges of welfare states. However, co-production is facing challenges because public services and civil society are rooted in two very different logics. These challenges are typically encountered by provider organisations and their staff who must convert policies and strategies into practice. Denmark is a welfare state with a strong public services sector and a relatively low involvement of volunteers. The aim of this study was to investigate how provider organisations and their staff navigate between the two logics. The present analysis is a critical case study of two municipalities selected from seven participating municipalities, for their maximum diversity. The study setting was the Community Families programme, which aim to support the social network of mental health users by offering regular contact with selected private families/individuals. The task of the municipalities was to initiate and support Community Families. The analysis built on qualitative data generated at the organisational level in the seven participating municipalities. Within the two "case study" municipalities, qualitative interviews were conducted with front-line co-ordinators (six) and line managers (two). The interviews were recorded, transcribed verbatim and coded using the software program NVivo. The results confirm the central role played by staff and identify a close interplay between public services and civil society logics as essential for the organisation of co-production. Corresponding objectives, activities and collaborative relations of provider organisations are keys for facilitating the co-productive practice of individual staff. Organised in this way, co-production can succeed even in a mental health setting associated with social stigma and in a welfare state dominated by public services. PMID- 28670771 TI - Osteoporosis: an Independent Determinant of Bone Erosions in Rheumatoid Arthritis? PMID- 28670770 TI - Are drowned donors marginal donors? A single pediatric center experience. AB - Drowning, a common cause of death in the pediatric population, is a potentially large donor pool for OLT. Anecdotally, transplant centers have deemed these organs high risk over concerns for infection and graft dysfunction. We theorized drowned donor liver allografts do not portend worse outcomes and therefore should not be excluded from the donation pool. We reviewed our single-center experience of pediatric OLTs between 1988 and 2015 and identified 33 drowned donor recipients. These OLTs were matched 1:2 to head trauma donor OLTs from our center. A chart review assessed postoperative peak AST and ALT, incidence of HAT, graft and recipient survival. Recipient survival at one year between patients with drowned donor vs head trauma donor allografts was not statistically significant (94% vs 97%, P=.63). HAT incidence was 6.1% in the drowned donor group vs 7.6% in the control group (P=.78). Mean postoperative peak AST and ALT was 683 U/L and 450 U/L for drowned donors vs 1119 U/L and 828 U/L in the matched cohort. These results suggest drowned donor liver allografts do not portend worse outcomes in comparison with those procured from head trauma donors. PMID- 28670772 TI - The Ca2+ /calmodulin2-binding transcription factor TGA3 elevates LCD expression and H2 S production to bolster Cr6+ tolerance in Arabidopsis. AB - Heavy metal (HM) contamination on agricultural land not only reduces crop yield but also causes human health concerns. As a plant gasotransmitter, hydrogen sulfide (H2 S) can trigger various defense responses and help reduce accumulation of HMs in plants; however, little is known about the regulatory mechanisms of H2 S signaling. Here, we provide evidence to answer the long-standing question about how H2 S production is elevated in the defense of plants against HM stress. During the response of Arabidopsis to chromium (Cr6+ ) stress, the transcription of L-cysteine desulfhydrase (LCD), the key enzyme for H2 S production, was enhanced through a calcium (Ca2+ )/calmodulin2 (CaM2)-mediated pathway. Biochemistry and molecular biology studies demonstrated that Ca2+ /CaM2 physically interacts with the bZIP transcription factor TGA3, a member of the 'TGACG'-binding factor family, to enhance binding of TGA3 to the LCD promoter and increase LCD transcription, which then promotes the generation of H2 S. Consistent with the roles of TGA3 and CaM2 in activating LCD expression, both cam2 and tga3 loss-of-function mutants have reduced LCD abundance and exhibit increased sensitivity to Cr6+ stress. Accordingly, this study proposes a regulatory pathway for endogenous H2 S generation, indicating that plants respond to Cr6+ stress by adjusting the binding affinity of TGA3 to the LCD promoter, which increases LCD expression and promotes H2 S production. This suggests that manipulation of the endogenous H2 S level through genetic engineering could improve the tolerance of grains to HM stress and increase agricultural production on soil contaminated with HMs. PMID- 28670773 TI - Early switch to second-line tyrosine kinase inhibitor in chronic myeloid leukemia patients failing to achieve early molecular response. PMID- 28670775 TI - Tropical Medicine & International Health. PMID- 28670774 TI - Experienced stigma and its impacts in psychosis: The role of social rank and external shame. AB - OBJECTIVES: Experienced stigma is detrimental to those who experience psychosis and can cause emotional distress and hinder recovery. This study aimed to explore the relationship between experienced stigma with emotional distress and recovery in people with psychosis. It explored the role of external shame and social rank as mediators in these relationships. DESIGN: A cross-sectional design was implemented. METHODS: Fifty-two service users were administered a battery of questionnaires examining experienced stigma, external shame, social rank, personal recovery, positive symptoms, depression, and anxiety. Correlation and multiple regression analysis were conducted on the data. Where appropriate, mediation analysis was employed to explore social rank and external shame as mediatory variables. RESULTS: Experienced stigma was significantly related to shame (social rank and external shame), positive symptoms, emotional distress (depression and anxiety), and personal recovery. The impact of experienced stigma on depression was mediated by external shame. Social rank was a mediator between experienced stigma and personal recovery only. CONCLUSION: People with psychosis who have experienced stigma are likely to experience emotional distress and be inhibited in their recovery. This was found to be partly mediated by external shame and low social rank. Clinical approaches to stigma need to target these as potential maintenance factors. PRACTITIONER POINTS: Experienced stigma is significantly related to shame (social rank and external shame) emotional distress, and reduced personal recovery. External shame mediated the relationship between experienced stigma and depression in psychosis. Social rank mediated the relationship between experienced stigma and personal recovery. Clinical approaches to stigma should include the assessment of external shame and low social rank. PMID- 28670776 TI - Myocardial Protective Effect of Antegrade Cardioplegic Cardiac Arrest Versus Ventricular Fibrillation During Cardiopulmonary Bypass on Immediate Postoperative and Mid-Term Left Ventricular Function in Right Ventricular Outflow Tract Surgery. AB - The objective of this study is to examine the myocardial protective effect of antegrade cardioplegic cardiac arrest (ACC) versus ventricular fibrillation (VF) on short-term and mid-term left ventricular (LV) function in right ventricular outflow tract (RVOT) surgery. RVOT operations conducted from January 2006 to December 2015 were reviewed. The numbers of cases using ACC and VF were 71 and 49, respectively. Postoperative mortality and morbidity were compared between the two groups. Before and after propensity score matching, left ventricular ejection fraction (LVEF) and left ventricular end-systolic/end-diastolic diameter (LVESD/LVEDD) in echocardiography were measured immediately after operation and at mid-term follow-up between postoperative 6 and 24 months. There was no perioperative mortality or cerebrovascular accident. There was no statistically significant difference in the incidence of ventricular and atrial arrhythmia. In the overall patient group, LVESD was significantly decreased in the ACC group compared to the VF group immediately after operation (-0.65 +/- 3.55 mm vs. 2.99 +/- 4.98 mm, P = 0.001). Mid-term follow-up data demonstrated that LVEF at midterm was higher in the ACC group than in the VF group (64.80% +/- 7.40% vs. 60.24% +/- 7.93%, P = 0.022). However, the increased amount compared to preoperative value was not statistically significant (1.94% +/- 12.65% vs. -2.94% +/- 9.41%, P = 0.059). After propensity score matching, the LVEF was significantly improved in the ACC group compared to the VF group at the mid-term follow-up (6.16% +/- 6.77% vs. -5.41% +/- 9.05%, P = 0.001). Multiple linear regression model demonstrated that lower preoperative LVEF, ACC rather than VF, and exclusion of RVOT reconstruction procedure were positive prognostic factors for the improvement of LVEF at mid-term follow up. The results of this study suggest that myocardial protection using ACC is safe and may be more beneficial in LV function recovery up to the mid-term follow-up after pulmonary valve replacement and other RVOT procedures. PMID- 28670777 TI - A screening echocardiogram to identify diastolic dysfunction leads to better outcomes. AB - BACKGROUND: Diastolic dysfunction (DD) can lead to heart failure and higher mortality. Echocardiograms can detect DD but are not indicated for screening in older adults. Our aim was to evaluate the prevalence of DD and the impact of identifying it in seniors. METHODS: We performed screening echocardiograms in 5227 consecutive patients between January 2014 and March 2015 in 36 senior focused value-based clinics across six states. We determined the presence of the grade of DD and defined stage B grade II/III (asymptomatic) and of stage C grade II/III (symptomatic) DD by the presence or absence of typical HF symptoms. We obtained prescribed medications from the electronic health record to determine absolute changes in HF therapy before and after the echocardiogram. RESULTS: We included a group with no DD (n=649), a group with grade 1 DD (n=2875), and those with grades 2 and 3 (n=1357) who had normal ejection fraction. The prevalence of grade 2 or 3 DD with preserved ejection fraction was 25%; 95% CI: 24-26. The absolute change of ace-inhibitor use before and after the echocardiogram increased by 14, 19, 23, 27 in patients without DD, those with grade 1, grade 2 or 3 asymptomatic and grade 2 or 3 symptomatic, respectively. The use of beta blocker, statin, and diuretic had similar trends. CONCLUSIONS: Seniors without previously known stage B or stage C heart failure have moderate-to-severe DD, 27% of whom were stage C. Identifying seniors with DD leads to improvement in care. PMID- 28670779 TI - Quantitative Ultrasound Assessment of Myofascial Pain Syndrome Affecting the Trapezius: A Reliability Study. AB - OBJECTIVES: Myofascial pain syndrome is one of the most common causes of chronic pain and is highlighted by the presence of myofascial trigger points. The current practice of diagnosing myofascial pain syndrome among clinicians involves manual detection of myofascial trigger points, which can be inconsistent. However, the detection process can be strengthened with the assistance of ultrasound (US). Therefore, this study aimed to characterize the upper trapezius by using quantitative techniques in healthy asymptomatic individuals with neck pain. METHODS: Study participants were recruited on the basis of the inclusion and exclusion criteria established, and US images of the trapezius, along the axial and longitudinal orientations, were obtained. Each set was obtained by 2 investigators: experienced and inexperienced personnel. RESULTS: Fifteen participants were recruited. The mean gray scale US echo intensity distribution obtained was 41.9. A paired t test of the global mean echo intensity value obtained for each image from the US operators did not show any significant difference (P = .77). A t test was performed, comparing the echo intensity of the group of patients with neck pain and healthy control participants, and the difference was found to be significant (P = .052). The median blob area was 2.71. The quartile range for the blob area was 1.72 for the 25th percentile to 4.90 for the 75th percentile. CONCLUSIONS: This study demonstrated that quantitative analysis of the echo intensity of US images can provide important information. However, further research is necessary to explore the relationships among sex, age, blob area, count, body mass index, regional anatomy, and extent of training or exercise of the particular muscle. PMID- 28670780 TI - Lithium enhances alveolar bone formation during orthodontic retention in rats. AB - OBJECTIVE: To investigate the effect of lithium on alveolar bone formation during orthodontic retention in rats. MATERIALS AND METHODS: After 2 weeks of orthodontic tooth movement (OTM), 42 8-week-old male Wistar rats were randomly divided into two orthodontic retention groups: one without (control) and the other with LiCl treatment (LiCl group). Samples were collected on days 0, 3, 7 and 14 during the retention period. We evaluated the bone volume/total volume (BV/TV) ratio and new bone formation in the region of interests (ie, the root, the periodontal ligament and the adjacent alveolar bone around the distal buccal surface of the distal root of the maxillary first molar). We performed quantitative analyses, including histology, histomorphometry and immunohistochemistry to identify Runx2 and Osterix expression. RESULTS: The density of trabecular bone, the quantity of osteoblasts and the expression of osteogenic markers, Runx2 and Osterix, were significantly higher in the LiCl group than in the control group during the orthodontic retention period. CONCLUSION: LiCl enhances alveolar bone formation during orthodontic retention in rats. PMID- 28670781 TI - Structural characterization and pharmacological evaluation of the new synthetic cannabinoid CUMYL-PEGACLONE. AB - The number of new psychoactive substances (NPS) that have emerged on the European market has been rapidly growing in recent years, with a particularly high number of new compounds from the group of synthetic cannabinoid receptor agonists. There have been various political efforts to control the trade and the use of NPS worldwide. In Germany, the Act to control the distribution of new psychoactive substances (NpSG) came into force in November 2016. In this new act, two groups of substances were defined, the group "cannabimimetics/synthetic cannabinoids" covering indole, indazole, and benzimidazole core structures, and a second group named "compounds derived from 2-phenethylamine." Shortly after, the first retailers of "herbal blends" promoted new products allegedly not violating the German NpSG. We describe the identification and structural elucidation of one of the first synthetic cannabinoids not being covered by the NpSG, 5-pentyl-2-(2 phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one. For isolation of the substance a flash chromatography separation was applied. The structure elucidation was performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatography electrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF MS) and nuclear magnetic resonance (NMR) analysis. Additionally, binding affinity towards the cannabinoid receptors CB1 and CB2 and efficacy in a cAMP accumulation assay were measured, showing full agonistic activity and high potency at both receptors. The new compound bears a gamma-carboline core structure circumventing the German NpSG and the generic definitions in other national laws. As a semi systematic name for 2-cumyl-5-pentyl-gamma-carbolin-1-one CUMYL-PEGACLONE is suggested. PMID- 28670782 TI - A rare cause of severe mitral stenosis and reversible pulmonary hypertension. AB - Myxoma is a rare cause of severe mitral stenosis. We describe a challenging case of severe mitral stenosis and reversible pulmonary hypertension produced by a giant left atrial myxoma. The greatest risk is a diagnostic delay due to focus on discarding a pulmonary etiology of dyspnea. Physical examination and early echocardiographic assessment are the keys to avoid overlooking this uncommon pathology. PMID- 28670783 TI - A de novo germline mutation of DLX3 in a Brown Swiss calf with tricho-dento osseus-like syndrome. AB - OBJECTIVE: A novel congenital disorder affecting a calf was observed, and its phenotype and genetic mutation identified. ANIMAL: A six-month-old female Brown Swiss calf. METHODS: Diagnostic investigation and whole genome sequencing of a case parent trio was performed. RESULTS: The calf had a dull kinky coat with mild hypotrichosis, and teeth with brown staining and enamel defects. Histological examination of skin biopsies was compatible with a follicular dysplasia. Radiography and computed tomography revealed thickening of the skull bones and large pulp cavities with a marked thinning of enamel affecting all teeth. A de novo germline mutation affecting the distal-less homeobox gene (DLX3) was identified. The 10 bp frameshift mutation in exon 3 of the bovine DLX3 gene is predicted to replace the second C-terminal transactivation domain of the wild type protein by a recoded peptide of 99 amino acids without any sequence similarity. CONCLUSION AND CLINICAL IMPORTANCE: A causative mutation for a sporadic phenotype resembling human tricho-dento-osseous syndrome was identified after detection of a de novo germline mutation in the DLX3 gene. PMID- 28670786 TI - Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis. AB - OBJECTIVES: To compare the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (OAB) using network meta-analysis (NMA). PATIENTS AND METHODS: Information sources were searched for blinded randomised controlled trials (RCTs), of >=2 weeks duration, comparing any dose of onabotulinumtoxinA, eligible oral/transdermal anticholinergics, or mirabegron, with each other or placebo, in adults with OAB. Bayesian random effects models were used to synthesise the results at week 12: NMA for responder analyses and network meta-regression (NMR) for change from baseline analyses. The NMR was used to adjust for differences in baseline severity between studies. Sensitivity analysis, excluding studies considered to be at a high risk of methodological bias, was conducted. RESULTS: In all, 56 RCTs were included in the networks. For each outcome, results are reported for all licensed treatment doses. For each NMR, results are based on patients with an average number of episodes of the outcome at baseline. After 12 weeks, all treatments were more efficacious than placebo. Patients who received onabotulinumtoxinA (100 U) had, on average, the greatest reductions in urinary incontinence episodes (UIE), urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and >=50% from baseline in UIE/day. When comparing onabotulinumtoxinA with other pharmacotherapies, mean differences favoured onabotulinumtoxinA 100 U over all comparators for UIE and urgency episodes (credible intervals excluded zero) and all but two of the comparators for micturition frequency. OnabotulinumtoxinA 100 U was also associated with higher odds of achieving a 100% and >=50% decrease in UIE/day than most other licensed treatments in the network. The exclusion of studies with a high risk of bias had little impact on the conclusions. CONCLUSION: The results indicate that, after 12 weeks, onabotulinumtoxinA 100 U provides greater relief of OAB symptoms compared with most other licensed doses of other pharmacotherapies in the network. PMID- 28670785 TI - Constraining the timing of the Great Oxidation Event within the Rubisco phylogenetic tree. AB - Ribulose 1,5-bisphosphate (RuBP) carboxylase/oxygenase (RuBisCO, or Rubisco) catalyzes a key reaction by which inorganic carbon is converted into organic carbon in the metabolism of many aerobic and anaerobic organisms. Across the broader Rubisco protein family, homologs exhibit diverse biochemical characteristics and metabolic functions, but the evolutionary origins of this diversity are unclear. Evidence of the timing of Rubisco family emergence and diversification of its different forms has been obscured by a meager paleontological record of early Earth biota, their subcellular physiology and metabolic components. Here, we use computational models to reconstruct a Rubisco family phylogenetic tree, ancestral amino acid sequences at branching points on the tree, and protein structures for several key ancestors. Analysis of historic substitutions with respect to their structural locations shows that there were distinct periods of amino acid substitution enrichment above background levels near and within its oxygen-sensitive active site and subunit interfaces over the divergence between Form III (associated with anoxia) and Form I (associated with oxia) groups in its evolutionary history. One possible interpretation is that these periods of substitutional enrichment are coincident with oxidative stress exerted by the rise of oxygenic photosynthesis in the Precambrian era. Our interpretation implies that the periods of Rubisco substitutional enrichment inferred near the transition from anaerobic Form III to aerobic Form I ancestral sequences predate the acquisition of Rubisco by fully derived cyanobacterial (i.e., dual photosystem-bearing, oxygen-evolving) clades. The partitioning of extant lineages at high clade levels within our Rubisco phylogeny indicates that horizontal transfer of Rubisco is a relatively infrequent event. Therefore, it is possible that the mutational enrichment periods between the Form III and Form I common ancestral sequences correspond to the adaptation of key oxygen-sensitive components of Rubisco prior to, or coincident with, the Great Oxidation Event. PMID- 28670784 TI - Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium. AB - Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 * 10-4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 * 10-5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21 rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 * 10-4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 * 10-4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed. PMID- 28670787 TI - A Fairly Stable Crystalline Silanone. AB - Silanones 2 substituted by bulky amino- and phosphonium ylide substituents have been synthesized and isolated in crystalline form. Thanks to the steric protection and the strong electron-donating ability of the substituents, silanones 2 are persistent and only slowly dimerizes at room temperature (t1/2 =0.5 or 5 h). Structural and theoretical analysis of 2 indicate a short Si=O bond (1.533 A) and an enhanced polarization toward the O atom compared to Me2 Si=O owing to the strong pi-electron donation from the phosphonium ylide substituent. PMID- 28670788 TI - International variation in the prevalence of preclinical colorectal cancer: Implications for predictive values of noninvasive screening tests and potential target populations for screening. AB - Screening for colorectal cancer (CRC) is implemented in an increasing number of countries. We aimed to assess international variation in the prevalence of preclinical CRC and the resulting variation in positive and negative predictive values (PPVs, NPVs) of existing and potential CRC screening tests in various countries. Using age- and sex-specific CRC incidence data and transition rates from preclinical to clinical CRC we estimated overall and age- and sex-specific prevalence of preclinical CRC in the target population aged 50-74 years in different parts of the world. These prevalence estimates were used to derive PPVs and NPVs for existing and potential noninvasive screening tests with varying levels of sensitivity and specificity. Within all regions and countries, prevalence strongly increases with age and is higher in men than in women. In addition, major variation was seen between regions and countries, with overall prevalence varying between 1 and 0.1%. As a result, PPVs are expected to strongly vary between ~10% for men in high incidence countries, such as Australia and Germany, and 1% for women in low incidence countries, whereas NPVs are expected to be consistently well above 99%. Variation in CRC prevalence profoundly affects expected PPVs of screening tests, and PPVs should be carefully considered when decisions on screening tests and strategies are made for specific populations and health care systems. Here, we provide estimates of preclinical CRC and expected PPVs and NPVs of noninvasive screening tests, which may enhance the empirical basis for planning of population-based CRC screening strategies. PMID- 28670789 TI - Comparison between imported versus domestic drug-eluting stents in China: A large single-center data. AB - BACKGROUND: In recent years, most drug-eluting stents (DESs) were domestically produced in China, but how domestic DESs perform compared to imported DESs was still unknown. METHODS: A total of 9011 consecutive cases with DESs implantation in a single center throughout 2013 were prospectively collected. Two-year clinical outcomes were evaluated between patients implanted with imported and domestic DESs. RESULTS: During 2-year follow-up, the rates of all-cause death, cardiac death, myocardial infarction, stroke, and stent thrombosis were not significantly different between two groups. However, the rate of revascularization was significantly higher in domestic DES group, shown as higher rates of overall revascularization, target vessel revascularization (TVR), and target lesion revascularization (TLR) (9.7% vs 6.4%, P < 0.001; 5.6% vs 3.2%, P < 0.001; 4.5% vs 2.2%, P < 0.001, respectively). Accordingly, major adverse cardiac events (MACE) rate was significantly higher in domestic DES group (12.1% vs 8.5%, P < 0.001). Multivariable Cox regression analysis indicated that domestic DES was an independent risk factor of MACE (HR [95%CI]: 1.22 [1.05-1.41]), overall revascularization (HR [95%CI]: 1.29 [1.09-1.53]), TVR (HR [95%CI]: 1.54 [1.22 1.94]), and TLR (HR [95%CI]: 1.85 [1.41-2.42]). After propensity score matching, the rates of overall revascularization, TVR, and TLR were still significantly higher in domestic DES group, and domestic DES was still predictive of overall revascularization, TVR, and TLR in multivariate Cox regression analysis. CONCLUSIONS: Domestic DESs showed the same safety as imported DESs in this real world cohort. But, patients implanted with domestic DESs had a higher risk of revascularization than imported DESs. PMID- 28670790 TI - Informing infant and young child feeding programming in humanitarian emergencies: An evidence map of reviews including low and middle income countries. AB - Around 200 million people were affected by conflict and natural disasters in 2015. Whereas those populations are at a particular high risk of death, optimal breastfeeding and complementary feeding practices could prevent almost 20% of deaths amongst children less than 5 years old. Yet, coverage of interventions for improving infant and young child feeding (IYCF) practices in emergencies is low, partly due to lack of evidence. Considering the paucity of data generated in emergencies to inform programming, we conducted an evidence map from reviews that included low- and middle-income countries and looked at several interventions: (a) social and behavioural change interpersonal and mass communication for promoting breastfeeding and adequate complementary feeding; (b) provision of donated complementary food; (c) home-based fortification with multiple micronutrient powder; (d) capacity building; (e) cash transfers; (f) agricultural or fresh food supply interventions; and (g) psychological support to caretakers. We looked for availability of evidence of these interventions to improve IYCF practices and nutritional status of infants and young children. We identified 1,376 records and included 28 reviews meeting the inclusion criteria. The highest number of reviews identified was for behavioural change interpersonal communication for promoting breastfeeding, whereas no review was identified for psychological support to caretakers. We conclude that any further research should focus on the mechanisms and delivery models through which effectiveness of interventions can be achieved and on the influence of contextual factors. Efforts should be renewed to generate evidence of effectiveness of IYCF interventions during humanitarian emergencies despite the challenges. PMID- 28670792 TI - What do the stats mean? Improving reporting of quantitative nursing research. PMID- 28670796 TI - Reply. PMID- 28670794 TI - Brassica rapa hairy root extracts promote skin depigmentation by modulating melanin production and distribution. AB - BACKGROUND: Skin whitening products, used for ages by Asian people for cultural and esthetic purposes, are very popular nowadays in Western countries as well, where the need to inhibit skin spots after sun exposure has become not only a cosmetic but also a health-related issue. Thus, the development of effective and safe depigmenting agents derived from natural products gets continuous attention by cosmetic brands and consumers. OBJECTIVES: The aim of this study was to determine the effects of two preparations, obtained from the hairy root cultures of the species Brassica rapa, on melanogenesis and the expression of the extracellular matrix proteins involved in a correct pigment distribution. METHODS: The two preparations, obtained by water-ethanol extraction and by digestion of cell-wall glycoproteins of the root cells, were chemically characterized and tested on skin cell cultures and on human skin explants to investigate on their dermatological activities. RESULTS: Both the extracts were able to decrease melanin synthesis pathway in melanocytes and modulate the expression of genes involved in melanin distribution. One of the extracts was also effective in inducing the expression of laminin-5 and collagen IV, involved into the maintenance of tissue integrity. The two extracts, when tested together on human skin explants, demonstrated a good synergic hypopigmenting activity. CONCLUSIONS: Taken together, the results indicate that the extracts from B. rapa root cultures can be employed as cosmetic active ingredients in skin whitening products and as potential therapeutic agents for treating pigmentation disorders. PMID- 28670797 TI - Cerebral Pulsatility Index Is Elevated in Patients with Elevated Right Atrial Pressure. AB - BACKGROUND AND PURPOSE: Extracerebral venous congestion can precipitate intracranial hypertension due to obstruction of cerebral blood outflow. Conditions that increase right atrial pressure, such as hypervolemia, are thought to increase resistance to jugular venous outflow and contribute to cerebro-venous congestion. Cerebral pulsatility index (CPI) is considered a surrogate marker of distal cerebrovascular resistance and is elevated with intracranial hypertension. Thus, we sought to test the hypothesis that elevated right atrial pressure is associated with increased CPI compared to normal right atrial pressure. METHODS: We retrospectively reviewed 61 consecutive patients with subarachnoid hemorrhage. We calculated CPI from transcranial Doppler studies and correlated these with echocardiographic measures of right atrial pressure. CPIs were compared from patients with elevated and normal right atrial pressure. RESULTS: There was a significant difference between CPI obtained from all patients with elevated right atrial pressure compared to those with normal right atrial pressure (P < .0001). This finding was consistent in sensitivity analysis that compared right and left hemispheric CPI from patients with both elevated and normal right atrial pressure. CONCLUSION: Patients with elevated right atrial pressure had significantly higher CPI compared to patients with normal right atrial pressure. These findings suggest that cerebro-venous congestion due to impaired jugular venous outflow may increase distal cerebrovascular resistance as measured by CPI. Since elevated CPI is associated with poor outcome in numerous neurological conditions, future studies are needed to elucidate the significance of these results in other populations. PMID- 28670798 TI - When it is safe to switch from intravenous to oral antibiotics. PMID- 28670799 TI - Viruses, wheeze and rice krispies. PMID- 28670800 TI - Situs inversus: When an incidental finding is not so incidental. PMID- 28670801 TI - Australian and New Zealand Committee on Resuscitation Neonatal Resuscitation guidelines 2016. AB - New Australian and New Zealand Neonatal Resuscitation guidelines reflect recent advances in neonatal resuscitation science, as critically appraised by the International Liaison Committee on Resuscitation. Substantial changes since the 2010 guidelines include: (i) updates to the Newborn Resuscitation Flowchart to include a greater emphasis on maintaining normal body temperature, and to emphasise the importance of beginning assisted ventilation by 1 min in infants who have absent or ineffective spontaneous breathing; (ii) updates to the physiology of the normal perinatal transition that resuscitation is trying to restore; (iii) recommendations for more frequent reinforcement of training, and for structured feedback for resuscitation training instructors; (iv) new guidance in relation to the timing of cord clamping for preterm newborn infants; (v) recommendation to monitor body temperature on admission to newborn units as a resuscitation quality indicator; (vi) suggestion to consider electrocardiographic (ECG) monitoring (as an adjunct to oximetry) to obtain more rapid and accurate estimation of heart rate during resuscitation; (vii) removal of previous suggestions to intubate meconium-exposed, non-vigorous term infants to suction the trachea; and (viii) suggestion to establish vascular access to enable administration of intravenous adrenaline (epinephrine) as soon as chest compressions are deemed to be needed. PMID- 28670803 TI - Emergency paediatric psychiatry: An emerging sub-specialty. PMID- 28670804 TI - Vitamin D supplementation to prevent acute respiratory tract infections. PMID- 28670805 TI - Bilateral neck of femur fractures in a paediatric patient with graves' disease. PMID- 28670806 TI - Probiotics for recurrent abdominal pain in childhood. PMID- 28670807 TI - Neonatal vitamin D supplementation. PMID- 28670808 TI - Accidental self-injection with adrenaline auto-injectors occurs frequently but is under-reported. PMID- 28670809 TI - Inaccurate diagnosis of paediatric anaphylaxis in three Australian Emergency Departments. AB - AIM: To determine the accuracy of emergency department (ED) paediatric anaphylaxis diagnosis, and to identify factors associated with misdiagnosis. METHODS: Retrospective chart review of children aged 0-18 years with allergic presentations to three Victorian EDs in 2014. Cases were included if an ED diagnosis of anaphylaxis was recorded, or the presentation met international consensus criteria for anaphylaxis. RESULTS: Of the 60 143 paediatric ED presentations during the study period, 1551 allergy-related presentations were identified and reviewed. One hundred and eighty-seven met consensus criteria for anaphylaxis, and another 24 were diagnosed with anaphylaxis without meeting criteria. Of the 211 presentations, 105 cases were given an ED diagnosis of anaphylaxis and 106 cases were given an alternative diagnosis in ED. ED assessment had a sensitivity of 43.2% (95% confidence interval (CI) 36.1-50.7%) and specificity of 97.9% (95% CI 96.9-98.7%) for anaphylaxis. Multiple logistic regression demonstrated that an ED anaphylaxis diagnosis was associated with previous anaphylaxis (odds ratio (OR) 3.20; 95% CI 1.52-6.75), arrival by ambulance (OR 2.80; 95% CI 1.36-5.74), a high-acuity triage category (OR 4.51; 95% CI 2.20-9.25) and presentation to a tertiary hospital (OR 2.86; 95% CI 1.44 5.67). ED diagnosis of anaphylaxis was less likely in those with resolution of symptoms and signs in at least one organ system prior to arrival (OR 0.27; 95% CI 0.12-0.62). CONCLUSION: In children with allergic presentations, ED assessment has a low sensitivity but high specificity for anaphylaxis. Attention to resolved pre-hospital symptoms and awareness of diagnostic criteria are important considerations for accurate ED diagnosis of anaphylaxis. PMID- 28670810 TI - Soft plaque in a girl's thigh. PMID- 28670812 TI - Adolescent use of electronic cigarettes. PMID- 28670811 TI - Prevalence of cytomegalovirus carriage among childcare staff. PMID- 28670815 TI - Reality and trust. PMID- 28670813 TI - An uncommon form of a common disease. PMID- 28670816 TI - Liquid Chromatographic Method for the Determination of Caffeoylquinic Acid Derivates in Hieracium pilosella L. AB - INTRODUCTION: Hieracium pilosella L. is a medicinal plant encountered in Europe in traditional herbal medicinal products. Caffeoylquinic (ortho dihydroxycinnamic) acid derivatives are characteristic constituents used as analytical markers in the quality control of the herbal material. Until now, the caffeoylquinic acid derivatives have been assayed using a colorimetric method according to the French Pharmacopoeia. OBJECTIVE: To develop an HPLC-method for quantification of caffeoylquinic acid derivatives in H. pilosella. METHODOLOGY: Samples were prepared by methanol extraction of H. pilosella, dried herb. An HPLC method suitable for analysis was developed and validated. The content of caffeoylquinic acid derivatives was determined and expressed as chlorogenic acid. Individual substances in the samples were identified by analyses of UV-MS/MS spectra and by comparisons with spectra and chromatographic retention times of authentic reference substances. RESULTS: Validation showed that the chromatographic method has good selectivity with no interfering peaks. Sensitivity, linearity, repeatability and accuracy were shown to be adequate. In analyses of several batches of H. pilosella, contents of caffeoylquinic acids ranging from 0.7 to 1.9% were found. Compared to the colorimetric method, this newly developed HPLC method is more specific and results in detection of nominally lower amounts of caffeoylquinic acid derivatives. A new acceptance limit of 1.0% instead of 2.5% caffeoylquinic acid, expressed as chlorogenic acid, for H. pilosella, is proposed when using this HPLC-method. CONCLUSION: A newly developed HPLC method is shown to be appropriate for quantitative determination of caffeoylquinic acid derivatives in H. pilosella. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28670817 TI - Oral health of pediatric liver transplant recipients. AB - To evaluate oral health conditions in pediatric liver transplant recipients, with special focus on caries, green staining of the teeth, gingival bleeding, and gingival overgrowth. 40 patients (mean age 11.6 years) were examined at a routine follow-up visit, 6 months to 16 years after liver transplantation at the Swiss Center for Liver Disease in Children. After the medical examination, participants were further examined for the presence of dental caries, periodontal disease, GE, and GTC. The mean decay, missing, and filled teeth (dmft/DMFT) score was 3.8. 45% of the participants presented at least one carious lesion. Two-third of the participants had more than 20% of sites with the presence of plaque and gingival inflammation. Signs of GE were found in 18% and GTC in 30% of the participants. A positive correlation was identified between GTC and peak serum bilirubin (P<.001) and primary diagnosis of cholestatic disease (P=.04). Gingival inflammation was associated with plaque (P<.001), use of immunosuppressive medication (P=.04), and was more pronounced in children with cholestatic disease (P=.007). Children and young adults with liver transplants presented a rather poor oral health status. Liver transplant physicians should counsel patients for regular dental follow-up in order to avoid serious dental infections. PMID- 28670818 TI - The effects of psychological interventions on wound healing: A systematic review of randomized trials. AB - PURPOSE: Psychological stress has been shown to delay wound healing. Several trials have investigated whether psychological interventions can improve wound healing, but to date, this evidence base has not been systematically synthesized. The objective was to conduct a systematic review of randomized controlled trials in humans investigating whether psychological interventions can enhance wound healing. METHODS: A systematic review was performed using PsychINFO, CINAHL, Web of Science, and MEDLINE. The searches included all papers published in English up until September 2016. The reference lists of relevant papers were screened manually to identify further review articles or relevant studies. Nineteen studies met inclusion criteria and were included in the review. RESULTS: Fifteen of nineteen studies were of high methodological quality. Six studies were conducted with acute experimentally created wounds, five studies with surgical patients, two studies with burn wounds, two studies with fracture wounds, and four studies were conducted with ulcer wounds. Post-intervention standardized mean differences (SMD) between groups across all intervention types ranged from 0.13 to 3.21, favouring improved healing, particularly for surgical patients and for relaxation interventions. However, there was some evidence for publication bias suggesting negative studies may not have been reported. Due to the heterogeneity of wound types, population types, and intervention types, it is difficult to pool effect sizes across studies. CONCLUSIONS: Current evidence suggests that psychological interventions may aid wound healing. Although promising, more research is needed to assess the efficacy of each intervention on different wound types. Statement of contribution What is already known on this subject? Psychological stress negatively affects wound healing. A number of studies have investigated whether psychological interventions can improve healing. However, no systematic reviews have been conducted. What does this study add? Synthesis and review of 19 trials conducted on psychological interventions and wound healing. Most evidence supports improved healing, particularly for surgical wounds and relaxation interventions. More research is needed on different intervention types with clinical wounds and into mechanisms of action. PMID- 28670820 TI - Inadequate treatment practices for pain relief and adverse event management in cancer patients across 10 countries/regions in Asia: a call for greater efforts to improve standards for patient care. AB - AIM: To examine the treatment practices for cancer pain relief and adverse event management, and the factors related to patient outcomes in the participating countries/regions. METHODS: The study was a cross-sectional survey conducted between September and December 2013 in 10 countries/regions across Asia. Adult patients with a history of cancer pain at least 1 month before study entry completed the survey questionnaire. RESULTS: A total of 1190 patients were included. The mean Box Scale-11 (BS-11) pain score was 6.0 (SD 2.1), with 86.2% experiencing moderate-to-severe pain and 53.2% receiving opioids at time of the survey. The mean BS-11 scores were 5.3 (SD 2.1) in the "others" (single non opioid medication or untreated) group, 6.3 (SD 2.0) in the >=2 non-opioids group and 6.7 (SD 1.9) in the opioid group. The proportions of patients experiencing moderate-to-severe pain were 79.1%, 87.3% and 93.7%, respectively. About 70% of patients reported adverse events due to their pain medications, about half had received medications to manage these symptoms. Adverse events were negatively associated with activities of daily living (P < 0.0001). Pain and hindrance to activities of daily living were negatively associated with employment status (P = 0.003 and 0.021). Unemployment was significantly associated with poorer quality of life (P < 0.0001). CONCLUSION: This analysis demonstrates inadequate management of cancer pain and treatment-related adverse events in the participating cohort. Pain and inadequate management of adverse events were negatively associated with patients' overall well-being. More collaborative efforts should be taken to optimize pain treatment and increase awareness of adverse event management in physicians. PMID- 28670819 TI - Emerging roles of transit-amplifying cells in tissue regeneration and cancer. AB - Most regenerative tissues employ transit-amplifying cells (TACs) that are positioned in between stem cells and differentiated progeny. In a classical hierarchical model, stem cells undergo limited divisions to produce TACs, which then proliferate rapidly to expand the system and produce diverse differentiated cell types. Although TACs are indispensable for generating tissues, they have been largely viewed as a transit point between stem cells and downstream lineages. Studies in the past few years, however, have revealed some fascinating biology and unanticipated functions of TACs. In the hair follicle, recent findings have placed TACs as key players in tissue regeneration by coordinating tissue production, governing stem cell behaviors, and instructing niche remodeling. In the hematopoietic system, rather than being transient, some TACs may participate in long-term hematopoiesis under steady state. Here, we compare and summarize recent discoveries about TACs in the hair follicle and the hematopoietic system. We also discuss how TACs of these two tissues contribute to the formation of cancer. WIREs Dev Biol 2017, 6:e282. doi: 10.1002/wdev.282 For further resources related to this article, please visit the WIREs website. PMID- 28670821 TI - Pain intensity and pain self-management strategies following discharge after surgery: An Australian prospective observational study. AB - WHAT IS KNOWN AND OBJECTIVE: Up to 80% of patients experience acute pain following surgery. This study aimed to improve the current understanding about the strategies individuals use to self-manage pain following discharge after surgery, stratified by pain intensity. METHODS: A prospective observational study conducted at the Royal Hobart Hospital, Australia, between November 2014 and March 2015. Eligible participants were 18 years or older and had undergone surgery requiring an incision. Patients who had undergone surgery related to cancer, childbirth or multitrauma or those with dementia were excluded. Participants were identified through hospital records and mailed a survey within 1 week of discharge. This survey asked about post-discharge pain, management strategies utilized and advice on self-management of pain provided during their inpatient stay. RESULTS: Five hundred surveys were mailed, with 169 (33.8%) being returned. The median age of the respondents was 57 years (range: 18-92 years); 53% were female. The majority (89.3%) of participants recalled receiving information about pain self-management. Analgesic use was reported by 95.4% of participants in the week following discharge. Moderate-severe pain was reported by 80 participants (47.3%); 63.7% and 11.3% of patients reported underuse and overuse of analgesics compared to what was recommended, respectively. WHAT IS NEW AND CONCLUSION: A high proportion of patients underused analgesics despite experiencing moderate-severe pain. Although the vast majority of participants reported receiving advice regarding pain self-management, this did not appear to translate into optimal pain management after discharge. Different approaches to the provision of advice appear to be required. PMID- 28670822 TI - Phenol-yne Click Polymerization: An Efficient Technique to Facilely Access Regio- and Stereoregular Poly(vinylene ether ketone)s. AB - Alkyne-based click polymerizations have been well-established. However, in order to expand the family to synthesize polymers with new structures and novel properties, new types of click polymerizations are highly demanded. In this study, for the first time, we established a new efficient and powerful phenol-yne click polymerization. The activated diynes and diphenols could be facilely polymerized in the presence of the Lewis base catalyst of 4-dimethylaminopyridine (DMAP) under mild reaction conditions. Regio- and stereoregular poly(vinylene ether ketone)s (PVEKs) with high molecular weights (up to 35 200) were obtained in excellent yields (up to 99.0 %). The reaction mechanism was well explained under the assistance of density functional theory (DFT) calculation. Furthermore, since the vinyl ether sequence acts as a stable but acid-liable linkage, the polymers could be decomposed under acid conditions, rendering them applicable in biomedical and environmental fields. PMID- 28670823 TI - Stratifying HPV-positive women for CIN3+ risk after one and two rounds of HPV based screening. AB - A main challenge of human papilloma (HPV)-based screening for cervical cancer is to adequately identify HPV-positive women at highest risk of cervical intraepithelial neoplasia grade 3 or worse, CIN3+. The prognostic value of currently used adjunct markers (HPV16/18 genotyping and reflex cytology) may change after multiple rounds of HPV-based screening because of a change in the proportion of HPV-positive women with incident infections. To this end, we re analyzed results from the POBASCAM trial (Population Based Screening Study Amsterdam). Women were randomized to HPV/cytology cotesting (intervention group) or to cytology-only (HPV blinded; control group) at enrolment. Our analytical population consisted of women with an HPV-positive result at the second round, 5 years after enrolment (n = 381 intervention, n = 392 control). Nine-year CIN3+ risks were estimated by Kaplan-Meier. HPV-positive women were stratified by risk markers: HPV16/18 genotyping, reflex cytology and preceding HPV results. When comparing one to two rounds of HPV-based screening, the prognostic value of an abnormal cytology result did not change (40.0% vs. 42.3%, p = 0.5617), but diminished for an HPV16/18 positive result (25.4% vs. 38.0%, p = 0.0132). HPV16/18 genotyping was nondiscriminative in women with incident HPV infections (HPV16/18 positive 10.0% vs. negative 12.1%, p = 0.3193). Women from the intervention group were more likely to have incident infections compared to women from the control group (incident screen-positive results 75.6% vs. 64.6%, p = 0.001) Our results indicate that at a second round of HPV-based screening, risk differentiation by cytology remained strong, but was diminished for HPV 16/18 genotyping because of a larger proportion of incident infections. PMID- 28670824 TI - A 3D digital atlas of the Nicotiana tabacum root tip and its use to investigate changes in the root apical meristem induced by the Agrobacterium 6b oncogene. AB - Using the intrinsic Root Coordinate System (iRoCS) Toolbox, a digital atlas at cellular resolution has been constructed for Nicotiana tabacum roots. Mitotic cells and cells labeled for DNA replication with 5-ethynyl-2'-deoxyuridine (EdU) were mapped. The results demonstrate that iRoCS analysis can be applied to roots that are thicker than those of Arabidopsis thaliana without histological sectioning. A three-dimensional (3-D) analysis of the root tip showed that tobacco roots undergo several irregular periclinal and tangential divisions. Irrespective of cell type, rapid cell elongation starts at the same distance from the quiescent center, however, boundaries between cell proliferation and transition domains are cell-type specific. The data support the existence of a transition domain in tobacco roots. Cell endoreduplication starts in the transition domain and continues into the elongation zone. The tobacco root map was subsequently used to analyse root organization changes caused by the inducible expression of the Agrobacterium 6b oncogene. In tobacco roots that express the 6b gene, the root apical meristem was shorter and radial cell growth was reduced, but the mitotic and DNA replication indexes were not affected. The epidermis of 6b-expressing roots produced less files and underwent abnormal periclinal divisions. The periclinal division leading to mature endodermis and cortex3 cell files was delayed. These findings define additional targets for future studies on the mode of action of the Agrobacterium 6b oncogene. PMID- 28670825 TI - Sevoflurane metabolite cross-react in the ethyl glucuronide DRI(r) immunoassay. PMID- 28670826 TI - Current practices are variable in the evaluation and management of patients with anomalous aortic origin of a coronary artery: Results of a survey. AB - BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) is the second leading cause of sudden cardiac death in young athletes in the USA. Long-term outcome data for these patients are lacking to date. There is insufficient knowledge on the best approach to these patients and they are managed in a nonuniform manner. METHODS: An online survey of 15 questions regarding management of AAOCA was sent out to 198 cardiac healthcare providers. The goal was to define gaps in knowledge to justify a dedicated scientific forum for discussion of AAOCA. Descriptive statistics were performed. RESULTS: A total of 91 providers (46%) completed the survey including pediatric cardiology subspecialists (40%), general pediatric cardiologists (24%), cardiovascular (CV) surgeons (22%), adult cardiologists (10%), nurse practitioners (8%), cardiology fellows (3%) and CV anesthesiologist (1%). Forty-eight percent had been practicing for over 15 years and 28% were in their first 5 years of practice. Fifty-two percent of the providers cared for adults and 93% cared for children/adolescents. Eighty-eight percent were affiliated with an academic institution. All but one provider practiced in the USA, 62% practiced in Texas. Half of participants (50%) were very comfortable managing AAOCA patients and 36% were somewhat comfortable. Providers utilized various imaging tests to confirm the anatomy including computed tomography angiography 88%, cardiac magnetic resonance imaging 70%, cardiac catheterization 60%, echocardiogram 12%, IVUS 2% and myocardial perfusion scan 1%. The majority felt comfortable in counseling the families and felt that depending on the type of lesion these patients should get surgical referral (85%) vs clinical follow up (67%) with exercise restriction (65%). CONCLUSION: There is heterogeneity in the way AAOCA patients are currently evaluated and managed. A knowledge gap exists even with participants from academic institutions. Long-term data with a defined approach to management of these patients may help to improve outcomes and prevent unnecessary exercise restriction or surgery. PMID- 28670828 TI - Retraction statement: 'Long-term efficacy and safety of blonanserin in patients with first-episode schizophrenia: A 1-year open-label trial' by Y. Ninomiya, S. Miyamoto, T. Tenjin, S. Ogino, N. Miyake, Y. Kaneda, T. Sumiyoshi and N. Yamaguchi. PMID- 28670827 TI - Toward the inclusion of gaming disorder in ICD-11. PMID- 28670829 TI - Redox-Driven Migration of Copper Ions in the Cu-CHA Zeolite as Shown by the In Situ PXRD/XANES Technique. AB - Using quasi-simultaneous in situ PXRD and XANES, the direct correlation between the oxidation state of Cu ions in the commercially relevant deNOx NH3 -SCR zeolite catalyst Cu-CHA and the Cu ion migration in the zeolitic pores was revealed during catalytic activation experiments. A comparison with recent reports further reveals the high sensitivity of the redox-active centers concerning heating rates, temperature, and gas environment during catalytic activation. Previously, Cu+ was confirmed present only in the 6R. Results verify a novel 8R monovalent Cu site, an eventually large Cu+ presence upon heating to high temperatures in oxidative conditions, and demonstrate the unique potential in combining in situ PXRD and XANES techniques, with which both oxidation state and structural location of the redox-active centers in the zeolite framework could be tracked. PMID- 28670830 TI - Resonant Formation of Strand Breaks in Sensitized Oligonucleotides Induced by Low Energy Electrons (0.5-9 eV). AB - Halogenated nucleobases are used as radiosensitizers in cancer radiation therapy, enhancing the reactivity of DNA to secondary low-energy electrons (LEEs). LEEs induce DNA strand breaks at specific energies (resonances) by dissociative electron attachment (DEA). Although halogenated nucleobases show intense DEA resonances at various electron energies in the gas phase, it is inherently difficult to investigate the influence of halogenated nucleobases on the actual DNA strand breakage over the broad range of electron energies at which DEA can take place (<12 eV). By using DNA origami nanostructures, we determined the energy dependence of the strand break cross-section for oligonucleotides modified with 8-bromoadenine (8Br A). These results were evaluated against DEA measurements with isolated 8Br A in the gas phase. Contrary to expectations, the major contribution to strand breaks is from resonances at around 7 eV while resonances at very low energy (<2 eV) have little influence on strand breaks. PMID- 28670831 TI - Varying iron release from transferrin and lactoferrin proteins. A laboratory experiment. AB - Iron metabolism is an important subject of study for undergraduate students of chemistry and biochemistry. Relevant laboratory exercises are scarce in the literature but would be very helpful in assisting students grasp key concepts. The experiment described here deals with different iron release mechanisms of two protagonists in iron metabolism: serum transferrin (Tf) and lactoferrin (Lf). Despite having very similar structures and iron-binding sites, Tf releases practically all its iron at pH 5.5 while Lf requires a significantly lower pH of 3. This difference in behavior is directly related to their respective biological functions as Tf blood-borne iron into the cell, while Lf competes with pathogens to sequester iron in biological fluids at more acidic pHs. During this experiment, the students will carry out iron loading and unloading on both human Lf and Tf and monitor the iron release at different pHs using UV-Vis spectroscopy. With this simple approach, the students will discover the different patterns of iron release of Tf and Lf and how this variance in behavior relates to their biological functions. Furthermore, this laboratory practice can be expanded to allow students to investigate a variety of iron proteins. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 45(6):521-527, 2017. PMID- 28670832 TI - Association between left ventricular perfusion defects and myocardial deformation indexes in heart transplantation recipients. AB - The aim of the study was to analyze possible correlations between strain echocardiography (STE) and PET myocardial perfusion in a population of heart transplantation (HTx) recipients showing preserved left ventricular (LV) ejection fraction. By STE, LV global longitudinal strain (LV GLS) was lower in HTx. PET showed no transient or chronic ischemia in 83 of 115 HTx (73%). Fixed perfusion defects were observed in 17% of HTx and reversible ischemia in 10%. Significant coronary stenosis was observed only in 10 cases. GLS was independently associated with age at HTx and fixed perfusion defects (HR 0.41; P<.001). Such relationships underline STE ability to early identify HTx pts with subclinical myocardial dysfunction during long-term follow-up. PMID- 28670833 TI - Modeling time-to-event (survival) data using classification tree analysis. AB - RATIONALE, AIMS, AND OBJECTIVES: Time to the occurrence of an event is often studied in health research. Survival analysis differs from other designs in that follow-up times for individuals who do not experience the event by the end of the study (called censored) are accounted for in the analysis. Cox regression is the standard method for analysing censored data, but the assumptions required of these models are easily violated. In this paper, we introduce classification tree analysis (CTA) as a flexible alternative for modelling censored data. Classification tree analysis is a "decision-tree"-like classification model that provides parsimonious, transparent (ie, easy to visually display and interpret) decision rules that maximize predictive accuracy, derives exact P values via permutation tests, and evaluates model cross-generalizability. METHOD: Using empirical data, we identify all statistically valid, reproducible, longitudinally consistent, and cross-generalizable CTA survival models and then compare their predictive accuracy to estimates derived via Cox regression and an unadjusted naive model. Model performance is assessed using integrated Brier scores and a comparison between estimated survival curves. RESULTS: The Cox regression model best predicts average incidence of the outcome over time, whereas CTA survival models best predict either relatively high, or low, incidence of the outcome over time. CONCLUSIONS: Classification tree analysis survival models offer many advantages over Cox regression, such as explicit maximization of predictive accuracy, parsimony, statistical robustness, and transparency. Therefore, researchers interested in accurate prognoses and clear decision rules should consider developing models using the CTA-survival framework. PMID- 28670834 TI - Temporal and spatial transcriptomic and microRNA dynamics of CAM photosynthesis in pineapple. AB - The altered carbon assimilation pathway of crassulacean acid metabolism (CAM) photosynthesis results in an up to 80% higher water-use efficiency than C3 photosynthesis in plants making it a potentially useful pathway for engineering crop plants with improved drought tolerance. Here we surveyed detailed temporal (diel time course) and spatial (across a leaf gradient) gene and microRNA (miRNA) expression patterns in the obligate CAM plant pineapple [Ananas comosus (L.) Merr.]. The high-resolution transcriptome atlas allowed us to distinguish between CAM-related and non-CAM gene copies. A differential gene co-expression network across green and white leaf diel datasets identified genes with circadian oscillation, CAM-related functions, and source-sink relations. Gene co-expression clusters containing CAM pathway genes are enriched with clock-associated cis elements, suggesting circadian regulation of CAM. About 20% of pineapple microRNAs have diel expression patterns, with several that target key CAM-related genes. Expression and physiology data provide a model for CAM-specific carbohydrate flux and long-distance hexose transport. Together these resources provide a list of candidate genes for targeted engineering of CAM into C3 photosynthesis crop species. PMID- 28670835 TI - Role of the spinal TrkB-NMDA receptor link in the BDNF-induced long-lasting mechanical hyperalgesia in the rat: A behavioural study. AB - BACKGROUND: Intrathecal/intracisternal BDNF in rodents produces long-lasting hyperalgesia/allodynia, which implies BDNF plays a role in the establishment and maintenance of central sensitization. Both self-regeneration of endogenous BDNF and neuroplastic modifications of spinal NMDA receptors downstream TrkB signalling could be involved in such enduring hyperalgesia. We investigated to what extent BDNF by itself could participate in the generation and maintenance of mechanical hyperalgesia using pharmacological tools. METHODS: We studied sensitivity of mechanical hyperalgesia induced by a single intrathecal (i.t.) injection of BDNF (3 ng/10 MUL i.t.) administered at time zero, for: (1) chronic NMDA receptor inhibition with subcutaneously implanted 7-day delivery osmotic pumps loaded with ketamine; (2) TrkB receptor inhibition with intraperitoneal (i.p.) cyclotraxine-B; and (3) chronic glial inhibition with repeated propentofylline i.t. injections. Nociceptive threshold to paw pressure, tested on days -3, 0, 3, 7, 10 and 14, was used as the index of central sensitization. Locomotor patterns and food and water consumption were assessed with LABORAS. RESULTS: Chronic ketamine prevented the mechanical hyperalgesia induced by BDNF, without affecting locomotion and food and water consumption. After pump depletion, a late hyperalgesic response to paw pressure stimulation emerged, which can be lastingly antagonized by cyclotraxine-B. Chronic propentofylline treatment irreversibly suppressed BDNF-induced hyperalgesia. CONCLUSION: Activation of NMDA receptors downstream to TrkB signalling is essential for behavioural expression of the mechanical hyperalgesia induced by intrathecal BDNF. However, maintenance of the hyperalgesia depends mainly from self regenerating glial BDNF rather than from a NMDA receptor-dependent form of neuroplasticity. SIGNIFICANCE: Intrathecal BDNF induces long-lasting central sensitization via a glial-likely BDNF self-regenerating mechanism, whose behavioural expression depends on downstream activation of NMDA receptors. This knowledge suggests that TrkB antagonists could represent an interesting lead for the development of novel therapeutic strategies for some chronic pain conditions. PMID- 28670836 TI - Epithelial cadherin disassociates from the lateral plasma membrane of uterine epithelial cells throughout pregnancy in a marsupial. AB - The uterine luminal epithelium is the first site of contact between fetal and maternal tissues during therian pregnancy and must undergo specialised changes for implantation of the blastocyst to be successful. These changes, collectively termed the plasma membrane transformation (PMT), allow the blastocyst to attach to the uterine epithelium preceding the formation of a placenta. There are similarities in the morphological and molecular changes occurring in live-bearing eutherian species during the PMT studied so far. Similar cellular remodelling occurs in a marsupial species, the fat-tailed dunnart (Sminthopsis crassicaudata), despite the divergence of marsupials from eutherian mammals over 130 mya, which resulted in the evolution of distinct reproductive strategies. Adhesion molecules along the lateral plasma membrane of uterine epithelium provide a barrier to invasion by the embryo. We thus characterised the presence and change in distribution of epithelial cadherin (E-cadherin) in uterine epithelium from non-pregnant fat-tailed dunnarts and compared it to dunnarts in early-, mid- and late-stage pregnancy. E-cadherin staining is localised to the lateral plasma membrane in uterine epithelium from non-pregnant and early-stage pregnant dunnarts. The E-cadherin staining is cytoplasmic in epithelium from uteri of mid- and late-stage pregnant dunnarts. This loss of localised staining suggests that the adherens junction dissociates from the lateral plasma membrane, allowing for invasion between the epithelial cells by the blastocyst. As the changes during pregnancy to cadherin were similar in the laboratory rat with highly invasive (haemochorial) placentation, a live-bearing lizard species with non-invasive (epitheliochorial) placentation and a marsupial, the fat-tailed dunnart, which has invasive (endotheliochorial) placentation, we suggest that the molecular mechanisms allowing for successful pregnancy are conserved among mammals during the early stages of pregnancy regardless of placental invasiveness. PMID- 28670837 TI - Analytical methodologies for the stereoselective determination of fluoxetine: An overview. AB - Fluoxetine is a widely used antidepressant belonging to the selective serotonin reuptake inhibitor class; it is used in the treatment of major depression, obsessive compulsive, premenstrual dysphoric, panic and post-traumatic stress disorders. Fluoxetine is an optical active pharmaceutical substance, which is used as a racemate in therapy, but stereospecific interactions associated with the serotonin-reuptake carrier, for both the parent drug and its active metabolite, norfluoxetine, have been described in the literature. Therefore, the stereoselective analysis of fluoxetine and norfluoxetine is important in order to characterize the pharmacokinetic and pharmacodynamic profile of the analytes. Several chromatographic and electrophoretic methods have been published in the literature for the chiral discrimination of fluoxetine enantiomers from different matrices. The purpose of the current review is to provide a systematic survey of the analytical techniques used for the chiral determination of fluoxetine and norfluoxetine covering a period of ~25 years. PMID- 28670840 TI - Erratum. AB - In the article by Xia et al., "Alterations of Rat Corticostriatal Synaptic Plasticity After Chronic Ethanol Exposure and Withdrawal," 2006, 30:819-824, there was an error in some of the author names. Jian Xun Xia should be Jianxun Xia, Xiao Hu Zhang should be Xiaohu Zhang, Yin Bing Ge should be Yinbing Ge, and Xiao Ru Yuan should be Xiaoru Yuan. We apologize for this error. Reference Xia J, Li J, Zhou R, Zhang X, Ge Y, Yuan X (2006) Alterations of rat corticostriatal synaptic plasticity after chronic ethanol exposure and withdrawal. Alcohol Clin Exp Res 30:819-824. https://doi.org/10.1111/j.1530-0277.2006.00095.x. PMID- 28670838 TI - Incidence and risk factors of early surgical complications in young renal transplant recipients: A persistent challenge. AB - There is a paucity of data on the rate of urological and vascular complications in very young children after kidney transplant. We conducted a study on the incidence and risk factors for early post-transplant surgical complications in young recipients (<5 years) over three decades. The primary outcome was any urological or vascular complication within 30 days of transplant, and the secondary outcome was incidence rate of graft failure reported as per 1000 person years. Risk factors associated with surgical complications were analyzed by logistic regression. There were 22 (26.5%) complications in 21 children with vascular thrombosis being the most common complication. There was no significant difference in the number of complications in period 1 (1985-1994) and period 2 (1995-2014) (P=.1). The incidence rate of graft failure was higher in period 1 (IR 70.8, 95% CI 41.1, 121.9) compared to period 2 (IR 20.7, 95% CI 9.3, 46.0). Cumulative incidence of graft survival at 1, 3, and 5 years' post-transplant was 96.5%, 92.6%, and 90%, respectively, in those without compared to 71%, 65.1%, and 58.6%, respectively, in children with complications. In conclusion, early surgical, especially vascular, complications are quite common in young renal transplant recipients and lead to significantly reduced graft survival. PMID- 28670841 TI - The sensitivity of 38 heart rate variability measures to the addition of artifact in human and artificial 24-hr cardiac recordings. AB - BACKGROUND: Artifact is common in cardiac RR interval data derived from 24-hr recordings and has a significant impact on heart rate variability (HRV) measures. However, the relative impact of progressively added artifact on a large group of commonly used HRV measures has not been assessed. This study compared the relative sensitivity of 38 commonly used HRV measures to artifact to determine which measures show the most change with increasing increments of artifact. A secondary aim was to ascertain whether short-term and long-term HRV measures, as groups, share similarities in their sensitivity to artifact. METHODS: Up to 10% of artifact was added to 20 artificial RR (ARR) files and 20 human cardiac recordings, which had been assessed for artifact by a cardiac technician. The added artifact simulated deletion of RR intervals and insertion of individual short RR intervals. Thirty-eight HRV measures were calculated for each file. Regression analysis was used to rank the HRV measures according to their sensitivity to artifact as determined by the magnitude of slope. RESULTS: RMSSD, SDANN, SDNN, RR triangular index and TINN, normalized power and relative power linear measures, and most nonlinear methods examined are most robust to artifact. CONCLUSION: Short-term time domain HRV measures are more sensitive to added artifact than long-term measures. Absolute power frequency domain measures across all frequency bands are more sensitive than normalized and relative frequency domain measures. Most nonlinear HRV measures assessed were relatively robust to added artifact, with Poincare plot SD1 being most sensitive. PMID- 28670842 TI - Long-term oncological outcomes and toxicity in 597 men aged <=60 years at time of low-dose-rate brachytherapy for localised prostate cancer. AB - OBJECTIVES: To report oncological and functional outcomes of men treated with low dose-rate (LDR) prostate brachytherapy aged <=60 years at time of treatment. PATIENTS AND METHODS: Of 3262 patients treated with LDR brachytherapy at our centre up to June 2016, we retrospectively identified 597 patients aged <=60 years at treatment with >=3-years post-implantation follow-up and four prostate specific antigen (PSA) measurements, of which one was at baseline. Overall survival (OS), prostate cancer-specific survival (PCSS) and relapse free survival (RFS) were analysed together with prospectively collected physician-reported adverse events and patient-reported symptom scores. RESULTS: The median (range) age was 57 (44-60) years, follow-up was 8.9 (1.5-17.2) years, and PSA follow-up 5.9 (0.8-15) years. Low-, intermediate- and high-risk disease represented 53%, 37% and 10% of the patients, respectively. At 10 years after implantation OS and PCSS were 98% and 99% for low-risk, 99% and 100% for intermediate-risk, and 93% and 95% for high-risk disease, respectively. At 10 years after implantation RFS, using the PSA level nadir plus 2 ng/mL definition, was 95%, 90% and 87% for low-, intermediate-, and high-risk disease, respectively. Urinary stricture was the most common genitourinary adverse event occurring in 19 patients (3.2%). At 5 years after implantation erectile function was preserved in 75% of the patients who were potent before treatment. CONCLUSION: LDR brachytherapy is an effective treatment with long-term control of prostate cancer in men aged <=60 years at time of treatment. It was associated with low rates of treatment-related toxicity and can be considered a first-line treatment for prostate cancer in this patient group. PMID- 28670843 TI - Poorly differentiated vaginal adenocarcinoma with aggressive behavior-Pap smear findings. AB - Vaginal carcinoma is a rare condition. In this report, we describe a case of a poorly differentiated aggressive adenocarcinoma in a woman with a three month history of vaginal bleeding and a negative Pap smear done six months prior to her consultation. Specular examination showed a normal cervix, but there was a bleeding ulcer (2 cm in diameter) in the upper third of the vagina. Cytology revealed poorly differentiated atypical cells, and the biopsy established a diagnosis of vaginal adenocarcinoma with little differentiation. Within two months, the patient died without diagnosis of a primary tumor site other than the vagina. PMID- 28670844 TI - Low serum albumin levels prior to pediatric allogeneic HCT are associated with increased need for critical care interventions and increased 6-month mortality. AB - Poor nutritional status in HCT patients is a negative prognostic factor. There are no pediatric studies evaluating albumin levels prior to HCT and need for critical care interventions. We hypothesized that pediatric patients with low albumin levels, routinely measured 30 days (+/-10 days) prior to allogeneic HCT, have a higher risk of critical care interventions in the post-transplant period. We performed a 5-year retrospective study of pediatric patients who underwent allogeneic HCT for any indication. Patients were categorized based on albumin level. Hypoalbuminemia was defined as <3.1 g/dL. A total of 73 patients were included, with a median age of 7.4 years (IQR 3.3, 13.2). Patients with hypoalbuminemia had higher needs for critical care interventions including non invasive ventilation (44% vs 8%, P=.01), mechanical ventilation (67% vs 17%, P<.01), and vasoactive therapy (56% vs 16%, P=.01). Patients with hypoalbuminemia also had a higher 6-month mortality (56% vs 17%, P=.02). Our data demonstrate that children undergoing allogeneic HCT with hypoalbuminemia in the pretransplant period are more likely to require critical care interventions and have higher 6 month mortality. These findings identify an at-risk population in which nutritional improvements may be instituted prior to HCT in hopes of improving outcomes. PMID- 28670845 TI - A novel homozygous DOCK8 mutation associated with unusual coexistence of gross molluscum contagiosum and epidermodysplasia verruciformis in a DOCK8 deficiency patient. PMID- 28670846 TI - Unpacking the complexity of planning with persons with cognitive disability and complex support needs. AB - BACKGROUND: Planners will engage with people with cognitive disability and complex support needs in the Australian National Disability Insurance Scheme, but the specific skills needed to build sustainable plans with this group are not yet known. METHOD: A qualitative study was conducted to explore the barriers and facilitators to planning with people with cognitive disability and complex support needs. Focus groups were held with 99 planning practitioners across metropolitan and regional locations in New South Wales, Australia. RESULTS: Thematic analysis showed planners need to build a partnership based on mutual trust and respect with a person with complex support needs and harness a range of skills to respond to individual support needs, learning capacity, systemic hurdles and life challenges. CONCLUSIONS: Planner skills can be used to address barriers to planning for people with cognitive disability and complex support needs. Gaining skills took professional support and personal commitment. PMID- 28670847 TI - Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial. AB - BACKGROUND: Although the clinical validity of risk-associated single nucleotide polymorphisms (SNPs) for assessment of disease susceptibility has been consistently established, risk reclassification from increasing numbers of implicated risk-associated SNPs raises concern that it is premature for clinical use. Our objective is to assess the degree and impact of risk reclassification with the increasing number of SNPs. METHODS: A total of 3239 patients from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial were included. Four genetic risk scores (GRSs) were calculated based on sets of sequentially discovered prostate cancer (PCa) risk-associated SNPs (17, 34, 51, and 68 SNPs). RESULTS: Pair-wise correlation coefficients between sets of GRSs increased as more SNPs were included in the GRS: 0.80, 0.86, and 0.95 for 17 versus 34 SNPs, 34 versus 51 SNPs, and 51 versus 68 SNPs, respectively. Using a GRS of 1.5 as a cutoff for higher versus lower risk, reclassification rates of PCa risk decreased: 14.11%, 12.04%, and 8.15% for 17 versus 34 SNPs, 34 versus 51 SNPs, and 51 versus 68 SNPs, respectively. Evolving GRSs, nevertheless, provide a tool for further refining risk assessment. When all four sequential GRSs were considered, the detection rates of PCa for men whose GRSs were consistently <1.5, reclassified, and consistently >=1.5 were 20.8%, 29.67%, and 39.26%, respectively (Ptrend = 1.12 * 10-8 ). In comparison, the detection rates of PCa in men with negative or positive family history were 23.75% and 31.78%, respectively. CONCLUSIONS: Risk assessment using currently available SNPs is justified. Multiple GRS values from evolving sets of SNPs provide a valuable tool for better refining risk. PMID- 28670848 TI - Community Protection versus Individual Healing: Two Traditions in Community Mental Health. AB - This article identifies two major traditions that drive the mandate for a community mental health care system-community protection and individual healing. It discusses the historical antecedents of these two traditions and how these traditions relate to different visions of what the "common good" means. It then discusses how they both operate in the current US-based system, creating inherent conflicts and tensions, and gives specific examples from the personal and professional experiences of the authors. The article proposes ways to reduce the tension and discusses what sacrifices and compromises this resolution would entail for the US community mental health system. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28670849 TI - Redefining the elderly as aged 75 years and older: Proposal from the Joint Committee of Japan Gerontological Society and the Japan Geriatrics Society. PMID- 28670850 TI - Cystic major salivary gland lesions: Utilizing fine needle aspiration to optimize the clinical management of a broad and diverse differential diagnosis. AB - INTRODUCTION: The use of fine-needle aspiration (FNA) cytology for the preoperative evaluation of salivary gland lesions is an accepted but, currently, nonstandardized practice. More specifically, cystic major salivary gland lesions are relatively rare and can be very challenging to diagnose on FNA due to low cellularity and an incredibly broad differential diagnosis. The purpose of this study was to investigate the diagnostic utility of preoperative FNA cytology for cystic major salivary gland lesions. METHODS AND MATERIALS: The electronic pathology archives of The Johns Hopkins Hospital were searched to identify FNA specimens of cystic major salivary gland lesions over a 15 year period (January 1, 2000 to December 21, 2015). The age, race, sex, biopsy site, use of ultrasound guidance, cytopathologic diagnosis, and presence or absence of clinical follow-up were recorded for each patient. Cases were divided into those with and without follow-up. Diagnostic performance between FNA and follow-up data were recorded. RESULTS: A total of 145 cases met the inclusion criteria, while 123 (84.8%) patients had follow-up data available. Of these patients, 67.5% underwent FNA as the only pathologic diagnostic modality. Sensitivity, specificity, positive predictive value, and negative predictive value for the detection of cystic neoplasms were 41.6%, 99.0%, 90.9%, and 87.6%, respectively. For cases containing mucin, 100.0% sensitivity and specificity were achieved. CONCLUSION: FNA of cystic salivary gland lesions is a useful clinical decision-making tool that can reduce the number of patients ultimately requiring surgical excision. Although specificity is high, a relatively low overall sensitivity makes clinical and radiologic correlation imperative. PMID- 28670851 TI - Serological evidence of hepatitis E virus infection in pigs and jaundice among pig handlers in Bangladesh. AB - Hepatitis E virus (HEV) is the most common cause of viral hepatitis in humans. Pigs may act as a reservoir of HEV, and pig handlers were frequently identified with a higher prevalence of antibodies to HEV. The objectives of this study were to identify evidence of HEV infection in pigs and compare the history of jaundice between pig handlers and people not exposed to pigs and pork. Blood and faecal samples were collected from 100 pigs derived from three slaughterhouses in the Gazipur district of Bangladesh from January to June, 2011. We also interviewed 200 pig handlers and 250 non-exposed people who did not eat pork or handled pigs in the past 2 years. We tested the pig sera for HEV-specific antibodies using a competitive ELISA and pig faecal samples for HEV RNA using real-time RT-PCR. Of 100 pig sera, 82% (n = 82) had detectable antibody against HEV. Of the 200 pig handlers, 28% (56/200) demonstrated jaundice within the past 2 years, whereas only 17% (43/250) of controls had a history of jaundice (p < .05). Compared to non-exposed people, those who slaughtered pigs (31% versus 15%, p < .001), reared pigs (37% versus 20%, p < .001), butchered pigs (35% versus 19%, p < .001) or involved in pork transportation (28% versus 13%, p < .001) were more likely to be affected with jaundice in the preceding 2 years. In multivariate logistic regression analysis, exposure to pigs (odds ratio [OR]: 2.2, 95% CI: 1.2-3.9) and age (OR: 0.97, 95% CI: 0.95-0.99) was significantly associated with jaundice in the past 2 years. Pigs in Bangladesh demonstrated evidence of HEV infection, and a history of jaundice was significantly more frequent in pig handlers. Identifying and genotyping HEV in pigs and pig handlers may provide further evidence of the pig's role in zoonotic HEV transmission in Bangladesh. PMID- 28670852 TI - Chemical Composition, Antioxidant Properties, alpha-Glucosidase Inhibitory, and Antimicrobial Activity of Essential Oils from Acacia mollissima and Acacia cyclops Cultivated in Tunisia. AB - The genus Acacia is quite large and can be found in the warm subarid and arid parts, but little is known about its chemistry, especially the volatile parts. The volatile oils from fresh flowers of A. mollissima and A. cyclops (growing in Tunisia) obtained by hydrodistillation were analyzed by GC then GC/MS. Eighteen (94.7% of the total oil composition) and 23 (97.4%) compounds were identified in these oils, respectively. (E,E)-alpha-Farnesene (51.5%) and (E)-cinnamyl alcohol (10.7%) constituted the major compounds of the flower oil of A. mollissima, while nonadecane (29.6%) and caryophyllene oxide (15.9%) were the main constituents of the essential oil of A. cyclops. Antioxidant activity of the isolated oils was studied by varied assays, i.e., 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2 azinobis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS); the isolated oils showed lowest IC50 (4 - 39 MUg/ml) indicating their high antioxidant activity. The alpha glucosidase inhibitor activity was also evaluated and Acacia oils were found to be able to strongly inhibit this enzyme with IC50 values (81 - 89 MUg/ml) very close to that of acarbose which was used as positive control. Furthermore, they were tested against five Gram-positive and Gram-negative bacteria and one Candida species. Essential oil of A. mollissima was found to be more active than that of A. cyclops, especially against Pseudomonas aeruginosa (MIC = 0.31 mg/ml and MBC = 0.62 mg/ml). PMID- 28670853 TI - The pathological roles of NDRG2 in Alzheimer's disease, a study using animal models and APPwt-overexpressed cells. AB - AIMS: To investigate the roles of N-myc downstream-regulated gene 2 (NDRG2) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease (AD). RESULTS: In this study, we confirmed the upregulation of NDRG2 in the brains of aging and AD animal models. To explore the role of NDRG2 in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N-SH cells (SK-N-SH APPwt). By silencing and overexpressing gene of NDRG2, we demonstrated that NDRG2-mediated increase in Abeta1-42 was through the pathways of BACE1 and GGA3. NGRG2 improved tau phosphorylation via enhanced activity of CDK5 and decreased Pin1, but it was not affected by GSK3beta pathway. NDRG2 might also induce cell apoptosis through the extrinsic (caspase 8) apoptotic pathway by interaction with STAT3. CONCLUSION: Our study confirmed the upregulation of NDRG2 in AD animal models and demonstrated its important roles in AD pathology. NDRG2 might be a potential target for studying and treatment of AD. PMID- 28670854 TI - Honokiol attenuates diet-induced non-alcoholic steatohepatitis by regulating macrophage polarization through activating peroxisome proliferator-activated receptor gamma. AB - BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) may develop into hepatic cirrhosis. This study aimed to investigate whether honokiol could prevent NASH induced by high-cholesterol and high-fat (CL) diet in mice and the possible mechanism involved. METHODS: Mice were fed with CL diet for 12 weeks to establish a NASH model; honokiol (0.02% w/w in diet) was added to evaluate its effect on NASH. Murine peritoneal macrophages, RAW264.7 and ANA-1 cells, were used to explore the possible mechanisms of honokiol on macrophage polarization. RESULTS: Mice developed NASH after fed with CL diet for 12 weeks. Honokiol supplementation alleviated insulin resistance, hepatic steatosis, inflammation, and fibrosis induced by CL diet. Immunohistochemistry showed that honokiol induced more M2 macrophages in livers compared with CL diet alone. Honokiol decreased M1 marker genes (TNFalpha and MCP-1) and increased M2 marker gene (YM-1, IL-10, IL-4R and IL-13) expression in mice liver compared with CL diet. Moreover, treatment with honokiol lowered alanine aminotransferase and aspartate aminotransferase in serum and preserved liver from lipid peroxidation, evidenced by lowered hepatic malondialdehyde level. Honokiol has antioxidant function, as honokiol upregulated hepatic glutathione and superoxide dismutase level and downregulated hepatic CYP2E1 protein level. Hepatic peroxisome proliferator-activated receptor gamma (PPARgamma) and its target genes were upregulated by honokiol. Furthermore, honokiol (10 MUM) treatment in mouse peritoneal cells, RAW264.7 cells and ANA-1 cells, led to M2 macrophage polarization, whereas a PPARgamma antagonist, GW9662, abolished this effect of honokiol. CONCLUSIONS: Honokiol can attenuate CL diet induced NASH and the mechanism in which possibly is polarizing macrophages to M2 phenotype via PPARgamma activation. PMID- 28670855 TI - Medication adherence among adolescent solid-organ transplant recipients: A survey of healthcare providers. AB - The aim of this study was to assess healthcare provider perspectives on barriers to medication adherence and to discover recommendations for interventions among providers of pediatric solid-organ transplant patients. An anonymous online survey was administered to a multidisciplinary pool of pediatric transplant providers from February 2015 to March 2016. It consisted of 15 questions regarding transplant providers' attitudes, clinical practice, and beliefs pertaining to medication adherence among teenage solid-organ transplant recipients. Data were analyzed using descriptive statistics. Responses to open ended questions were coded and categorized into themes. One hundred ten surveys were completed by providers specializing in pediatric heart, kidney, liver, lung, and/or intestinal transplantation. Commonly cited reasons for poor adherence were forgetting/poor planning (94%), the desire to be normal (86%), lack of support (86%), and poor parental monitoring (79%). Suggestions to improve adherence included increasing peer and family support, providing education, and incorporating technology into adherence regimens. Barriers to adherence in transplant patients are recognized by providers and are both similar to and disparate from patient and family identified barriers published in the literature. Providers recognize the importance of education, social support, and technologically driven interventions on improving outcomes in the transplant population. PMID- 28670856 TI - Phosphorene Co-catalyst Advancing Highly Efficient Visible-Light Photocatalytic Hydrogen Production. AB - Transitional metals are widely used as co-catalysts boosting photocatalytic H2 production. However, metal-based co-catalysts suffer from high cost, limited abundance and detrimental environment impact. To date, metal-free co-catalyst is rarely reported. Here we for the first time utilized density functional calculations to guide the application of phosphorene as a high-efficiency metal free co-catalyst for CdS, Zn0.8 Cd0.2 S or ZnS. Particularly, phosphorene modified CdS shows a high apparent quantum yield of 34.7 % at 420 nm. This outstanding activity arises from the strong electronic coupling between phosphorene and CdS, as well as the favorable band structure, high charge mobility and massive active sites of phosphorene, supported by computations and advanced characterizations, for example, synchrotron-based X-ray absorption near edge spectroscopy. This work brings new opportunities to prepare highly-active, cheap and green photocatalysts. PMID- 28670857 TI - Effects of family affluence on the health behaviors of Korean adolescents. AB - AIM: To examine the effect of the level of family affluence on the health-related behaviors of South Korean adolescents. METHODS: A stratified, random cluster sampling of 400 middle schools and 400 high schools in Korea lead to the selection of 72,435 middle school and high school students. A logistic regression analysis was carried out to examine the impact of family affluence on the health related behaviors of Korean adolescents. RESULTS: The risk of alcohol intake was 0.824 and 0.809 times lower in those adolescents with low and moderate family affluence, respectively, compared to those with a high level of family affluence. The risk of current smoking was 0.896 times lower in the adolescents with moderate family affluence, compared to those with a high level of family affluence. The risk of not exercising was 1.286 and 1.425 times higher in those adolescents who were associated with moderate and low family affluence, respectively, compared to those with a high level of family affluence. The risk of skipping breakfast was 1.433 times higher in the adolescents with low family affluence, compared to those with high family affluence. The risk for consuming no fruit was 1.890 times higher in the adolescents with low family affluence, compared to those with a high level of family affluence. CONCLUSION: A high level of family affluence had a greater negative impact on alcohol intake and smoking and a greater positive impact on exercise and dietary behaviors, as compared to low and moderate family affluence among Korean adolescents. PMID- 28670858 TI - Rotors exhibit greater surface ECG variation during ventricular fibrillation than focal sources due to wavebreak, secondary rotors, and meander. AB - INTRODUCTION: Ventricular fibrillation is a common life-threatening arrhythmia. The ECG of VF appears chaotic but may allow identification of sustaining mechanisms to guide therapy. HYPOTHESIS: We hypothesized that rotors and focal sources manifest distinct features on the ECG, and computational modeling may identify mechanisms of such features. METHODS: VF induction was attempted in 31 patients referred for ventricular arrhythmia ablation. Simultaneous surface ECG and intracardiac electrograms were recorded using biventricular basket catheters. Endocardial phase maps were used to mechanistically classify each VF cycle as rotor or focally driven. ECGs were analyzed from patients demonstrating both mechanisms in the primary analysis and from all patients with induced VF in the secondary analysis. The ECG voltage variation during each mechanism was compared. Biventricular computer simulations of VF driven by focal sources or rotors were created and resulting ECGs of each VF mechanism were compared. RESULTS: Rotor based VF exhibited greater voltage variation than focal source-based VF in both the primary analysis (n = 8, 110 +/- 24% vs. 55 +/- 32%, P = 0.02) and the secondary analysis (n = 18, 103 +/- 30% vs. 67 +/- 34%, P = 0.009). Computational VF simulations also revealed greater voltage variation in rotors compared to focal sources (110 +/- 19% vs. 33 +/- 16%, P = 0.001), and demonstrated that this variation was due to wavebreak, secondary rotor initiation, and rotor meander. CONCLUSION: Clinical and computational studies reveal that quantitative criteria of ECG voltage variation differ significantly between VF-sustaining rotors and focal sources, and provide insight into the mechanisms of such variation. Future studies should prospectively evaluate if these criteria can separate clinical VF mechanisms and guide therapy. PMID- 28670859 TI - High expression of CPNE3 predicts adverse prognosis in acute myeloid leukemia. AB - CPNE3, a member of a Ca2+ -dependent phospholipid-binding protein family, was identified as a ligand of ERBB2 and has a more general role in carcinogenesis. Here, we identified the prognostic significance of CPNE3 expression in acute myeloid leukemia (AML) patients based on two datasets. In the first microarray dataset (n = 272), compared to low CPNE3 expression (CPNE3low ), high CPNE3 expression (CPNE3high ) was associated with adverse overall survival (OS, P < 0.001) and event-free survival (EFS, P < 0.001). In the second independent group of AML patients (TCGA dataset, n = 179), CPNE3high was also associated with adverse OS and EFS (OS, P = 0.01; EFS, P = 0.036). Notably, among CPNE3high patients, those received allogenic hematopoietic cell transplantation (HCT) had longer OS and EFS than those with chemotherapy alone (allogeneic HCT, n = 40 vs chemotherapy, n = 46), but treatment modules played an insignificant role in the survival of CPNE3low patients (allogeneic HCT, n = 32 vs chemotherapy, n = 54). These results indicated that CPNE3high is an independent, adverse prognostic factor in AML and might guide treatment decisions towards allogeneic HCT. To understand its inherent mechanisms, we investigated genome-wide gene/microRNA expression signatures and cell signaling pathways associated with CPNE3 expression. In conclusion, CPNE3high is an adverse prognostic biomarker for AML. Its effect may be attributed to the distinctive genome-wide gene/microRNA expression and related cell signaling pathways. PMID- 28670860 TI - Transcriptomic biomarkers of altered erythropoiesis to detect autologous blood transfusion. AB - Autologous blood transfusion is a powerful means of improving performance and remains one of the most challenging methods to detect. Recent investigations have identified 3 candidate reticulocytes genes whose expression was significantly influenced by blood transfusion. Using quantitative reverse transcription polymerase chain reaction as an alternative quantitative method, the present study supports that delta-aminolevulinate synthase 2 (ALAS2), carbonic anhydrase (CA1), and solute carrier family 4 member 1 (SLC4A1) genes are down-regulated post-transfusion. The expression of these genes exhibited stronger correlation with immature reticulocyte fraction than with reticulocytes percentage. Moreover, the repression of reticulocytes' gene expression was more pronounced than the diminution of immature reticulocyte fraction and reticulocyte percentage following blood transfusion. It suggests that the 3 candidate genes are reliable predictors of bone marrow's response to blood transfusion and that they represent potential biomarkers for the detection of this method prohibited in sports. PMID- 28670861 TI - Corrigendum. PMID- 28670862 TI - Temporal Analysis and Costs of Ruminant Brucellosis Control Programme in Egypt Between 1999 and 2011. AB - Data for the prevalence of brucellosis in ruminants in Egypt are scarce; recent studies suggest the disease is endemic, with a high prevalence. The aim of this study was to assess the financial costs and the impact of the current control programme on the pattern of brucellosis among ruminants between 1999 and 2011. A univariate binary logistic regression model was used to compare between seropositive proportions for different years for each species. The proportion of seropositive cattle was significantly increased from 2000 to 2004 then significantly decreased from 2005 to 2011. The proportion of seropositive buffalo fluctuated year to year; however, there was a significant increase in 2008 (OR 3.13, 95% CI 2.69-3.66, P < 0.001). There was a decrease in the proportion of seropositive sheep during the study period except in 2001 and 2009 in which there was a significant increase. The proportion of seropositive goats increased in 2000 and 2001, and then decreased from 2002 to 2007. In 2008, there was a significant increase in the seropositive proportion of goats (OR 2.53, 95% CI 2.21-2.90, P < 0.001). The average annual cost for the control programme including testing and compensation was more than US$3 million. The total cost for the control programme including testing and compensation for the period (13 years) between 1999 and 2011 was more than US$40 million, from which more than 56% for cattle. Further studies are required for the effectiveness of the current control strategies and alternative strategies should be considered. The socio economic impact of brucellosis and its control measures should be investigated. PMID- 28670863 TI - Microbiological Zoonotic Emerging Risks, Transmitted Between Livestock Animals and Humans (2007-2015). AB - As part of the Emerging Risk Identification (ERI) activities of the European Food Safety Authority (EFSA), a literature search was conducted to identify the microbiological agents transmitted between livestock animals and humans that have been suggested as having emerged between 2007 and 2015 in peer-reviewed scientific literature published during the same period (2007-2015). According to the criteria set, the search identified seven such zoonotic agents, namely West Nile Fever virus, Rift Valley Fever virus, Crimean-Congo Haemorrhagic Fever virus, Influenza A H1N1 virus, Coxiella burnetii, Streptococcus suis and livestock-associated methicillin-resistant Staphylococcus aureus clonal complex 398. An explanation of the agents' consideration as emerging risks is provided. The experience gained from these emergences has shown that the detection of and response to such risks can be achieved faster and more successfully within a multidisciplinary, collaborative context at the field, local, national and international levels. PMID- 28670864 TI - Reentrant Structural Transitions and Collapse of Charge and Orbital Orders in Quadruple Perovskites. AB - Charge and orbital degrees of freedom determine properties of many materials, and are central to many important phenomena. At high temperatures, thermal fluctuations overcome them, and high-symmetry structures are realized. On decreasing temperature, different charge- and orbital-order transitions take place accompanied by symmetry lowering. Remarkable exceptions to this general tendency, realized in Cu-doped BiMn7 O12 quadruple perovskites, are presented. Introduction of Cu2+ produces mixtures of Mn3+ and Mn4+ and charge degree of freedom. BiCuMn6 O12 (and compositions in the vicinity) exhibits well-defined 1:3 charge order of Mn4+ and Mn3+ and orbital order of Mn3+ near room temperature, but both charge and orbital orders collapse below about 115 K with the reentrance of the high-temperature cubic Im3? phase. What is interesting the collapse can be controlled by a magnetic field even without long-range magnetic order, and the collapsed phase shows nearly zero thermal expansion. PMID- 28670865 TI - Robotic radical perineal cystectomy and extended pelvic lymphadenectomy: initial investigation using a purpose-built single-port robotic system. AB - OBJECTIVES: To assess the feasibility of radical perineal cystoprostatectomy using the latest generation purpose-built single-port robotic surgical system. MATERIALS AND METHODS: In two male cadavers the da Vinci(r) SP1098 Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) was used to perform radical perineal cystoprostatectomy and bilateral extended pelvic lymph node dissection (ePLND). New features in this model include enhanced high-definition three dimensional optics, improved instrument manoeuvrability, and a real-time instrument tracking and guidance system. The surgery was accomplished through a 3 cm perineal incision via a novel robotic single-port system, which accommodates three double-jointed articulating robotic instruments, an articulating camera, and an accessory laparoscopic instrument. The primary outcomes were technical feasibility, intraoperative complications, and total robotic operative time. RESULTS: The cases were completed successfully without conversion. There were no accidental punctures or lacerations. The robotic operative times were 197 and 202 min. CONCLUSIONS: In this preclinical model, robotic radical perineal cystoprostatectomy and ePLND was feasible using the SP1098 robotic platform. Further investigation is needed to assess the feasibility of urinary diversion using this novel approach and new technology. PMID- 28670868 TI - Non-Doped Sky-Blue OLEDs Based on Simple Structured AIE Emitters with High Efficiencies at Low Driven Voltages. AB - Blue organic light-emitting diodes (OLEDs) are necessary for flat-panel display technologies and lighting applications. To make more energy-saving, low-cost and long-lasting OLEDs, efficient materials as well as simple structured devices are in high demand. However, a very limited number of blue OLEDs achieving high stability and color purity have been reported. Herein, three new sky-blue emitters, 1,4,5-triphenyl-2-(4-(1,2,2-triphenylvinyl)phenyl)-1H-imidazole (TPEI), 1-(4-methoxyphenyl)-4,5-diphenyl-2-(4-(1,2,2-triphenylvinyl)phenyl)-1H-imidazole (TPEMeOPhI) and 1-phenyl-2,4,5-tris(4-(1,2,2-triphenylvinyl)phenyl)-1H-imidazole (3TPEI), with a combination of imidazole and tetraphenylethene groups, have been developed. High photoluminescence quantum yields are obtained for these materials. All derivatives have demonstrated aggregation-induced emission (AIE) behavior, excellent thermal stability with high decomposition and glass transition temperatures. Non-doped sky-blue OLEDs with simple structure have been fabricated employing these materials as emitters and realized high efficiencies of 2.41 % (4.92 cd A-1 , 2.70 lm W-1 ), 2.16 (4.33 cd A-1 , 2.59 lm W-1 ) and 3.13 % (6.97 cd A-1 , 4.74 lm W-1 ) for TPEI, TPEMeOPhI and 3TPEI, with small efficiency roll-off. These are among excellent results for molecules constructed from the combination of imidazole and TPE reported so far. The high performance of a 3TPEI-based device shows the promising potential of the combination of imidazole and AIEgen for synthesizing efficient electroluminescent materials for OLED devices. PMID- 28670869 TI - Heroin in Malaysia and Singapore. AB - Clandestine heroin laboratories have been a feature of the Malaysian illicit drug scene since soon after the abuse of heroin emerged in 1972. The first few clandestine heroin laboratories which synthesised heroin via the acetylation of imported morphine were uncovered in 1973 and 1977. By the mid-1980s, this type of laboratory was replaced by heroin-cutting laboratories whereby imported high grade heroin was cut to street heroin. This was to meet the rising demand for the drug owing to the rapid escalation of the number of drug users. Over the years, the most significant change in the composition of the street heroin is the decrease in its purity from 30%-50% to 3%-5%. Caffeine has remained the major adulterant and chloroquine is detected in virtually all recent seizures. PMID- 28670870 TI - The Chemistry behind Health Effects of Whole Grains. PMID- 28670872 TI - The Quest for Excellent Leadership. PMID- 28670871 TI - Clinical practice patterns are relatively uniform between pediatric heart transplant centers: A survey-based assessment. AB - Clinical practice variations are a barrier to the study of pediatric heart transplants and coordination of multicenter RCTs in this patient population. We surveyed centers to describe practice patterns, understand areas of variation, and willingness to modify protocol. Pediatric heart transplant centers were identified, and one survey was completed per center. Simple descriptive statistics were used. The response rate was 77% (40 responses from 52 contacted centers, 37 with complete responses). Median center volume of respondents was eight transplants/year (IQR 3-19). Most centers reported tacrolimus (36/38, 95%) and mycophenolate mofetil (36/38, 95%) as maintenance immunosuppression. Other immunosuppression agents reported were cyclosporine (7/38, 18%), everolimus or sirolimus (3/38, 8%), and azathioprine (2/38, 5%). Overall, respondents answered similarly for questions regarding clinical practices including induction therapy, maintenance immunosuppression, and rejection treatment threshold (>85% agreement for all). Additionally, willingness to change clinical practices was over 70% for all practices surveyed (35 total respondents), and 97% of centers (36/37) were willing to participate in a RCT of maintenance immunosuppression. In conclusion, we found many similar clinical practice protocols. Most centers are willing to collaborate on a common protocol in order to participate in a RCT and support a trial investigating maintenance immunosuppression. PMID- 28670873 TI - A Stimuli-Responsive Zirconium Metal-Organic Framework Based on Supermolecular Design. AB - A flexible, yet very stable metal-organic framework (DUT-98, Zr6 O4 (OH)4 (CPCDC)4 (H2 O)4 , CPCDC=9-(4-carboxyphenyl)-9H-carbazole-3,6-dicarboxylate) was synthesized using a rational supermolecular building block approach based on molecular modelling of metal-organic chains and subsequent virtual interlinking into a 3D MOF. Structural characterization via synchrotron single-crystal X-ray diffraction (SCXRD) revealed the one-dimensional pore architecture of DUT-98, envisioned in silico. After supercritical solvent extraction, distinctive responses towards various gases stimulated reversible structural transformations, as detected using coupled synchrotron diffraction and physisorption techniques. DUT-98 shows a surprisingly low water uptake but a high selectivity for pore opening towards specific gases and vapors (N2 , CO2 , n-butane, alcohols) at characteristic pressure resulting in multiple steps in the adsorption isotherm and hysteretic behavior upon desorption. PMID- 28670874 TI - Corrigendum: Corrigendum for: Disorders of sex development: The evolving role of genomics in diagnosis and gene discovery, 108:337-350 (10.1002/bdrc.21148). PMID- 28670875 TI - Validity of the American Board of Orthodontics Discrepancy Index and the Peer Assessment Rating Index for comprehensive evaluation of malocclusion severity. AB - OBJECTIVES: To assess the validity of the American Board of Orthodontics Discrepancy Index (ABO-DI) and Peer Assessment Rating (PAR) Index in evaluating malocclusion severity in Chinese orthodontic patients. SETTING AND SAMPLE POPULATION: A stratified random sample of 120 orthodontic patients based on Angle classification was collected from six university orthodontic centres. MATERIAL AND METHODS: Sixty-nine orthodontists rated malocclusion severity on a five-point scale by assessing a full set of pre-treatment records for each case and listed reasons for their decision. Their judgement was then compared with ABO-DI and PAR scores determined by three calibrated examiners. RESULTS: Excellent interexaminer reliability of clinician judgement, ABO-DI and PAR index was demonstrated by the Intraclass Correlation Coefficient (rho= 0.995, 0.990 and 0.964, respectively). Both the ABO-DI and US-PAR index showed good correlation with clinician judgement (r=.700 and r=.707, respectively). There was variability among the different Angle classifications: the ABO-DI showed the highest correlation with clinician judgement in Class II patients (r=.780), whereas the US-PAR index showed the highest correlation with clinician judgement in Class III patients (r=.710). Both indices demonstrated the lowest correlations with clinician judgement in Class I patients. CONCLUSION: With strong interexaminer agreement, the panel consensus was used for validating the ABO-DI and US-PAR index for malocclusion severity. Overall, the ABO-DI and US-PAR index were reliable for measuring malocclusion severity with significantly variable weightings for different Angle classifications. Further modification of the indices for different Angle classification may be indicated. PMID- 28670876 TI - Autophagy regulates apoptosis on the level of the death-inducing signalling complex. AB - The interactions between apoptotic and autophagic proteins via the proteolytic systems are known mechanisms through which autophagy and apoptosis regulate each other. In this issue of The FEBS Journal, Gentle and colleagues propose a mechanism through which autophagy regulates the induction of apoptosis at the level of the TIR-domain-containing adaptor-inducing interferon-beta (TRIF) in TLR signaling. PMID- 28670878 TI - Identification of the new HLA-DRB1*14:186 allele in an Italian bone marrow donor. AB - HLA-DRB1*14:186 differs from DRB1*14:58 by a non-synonymous mutation at nucleotide 227 in exon 2. PMID- 28670879 TI - Molecular Subtypes of Breast Cancers from Myanmar Women: A Study of 91 Cases at Two Pathology Centers AB - Background: Breast cancer is the most common cancer in Myanmar women. Revealing the hormonal receptorstatus, human epidermal growth factor receptor 2 (HER2) and Ki-67 expression is useful for estimating patientprognosis as well as determination of treatment strategy. However, immunohistochemical features and classification ofmolecular subtypes in breast cancers from Myanmar remain unknown. Methods: The clinicopathological features of91 breast cancers from Myanmar women were examined. Immunohistochemistry was performed on tissue specimenswith antibodies to estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, cytokeratin (CK)5/6 and CK14.Immunohistochemistry-based molecular subtyping was conducted. Results: Breast cancers in Myanmar women wererelatively large, high grade with frequent metastatic lymph nodes. Of the 91 patients, tumors with ER positive, PgRpositive, and HER2 positive were 57.1%, 37.4%, and 28.6%, respectively. The most prevalent subtype was luminal B(HER2-) (39.6%), followed by HER2 (22.0%), triple negative (TN)-basal-like (12.1%), luminal A (11.0%), TN-null(8.8%) and luminal B (HER2+) (6.6%). The mean Ki-67 expression of 91 cases was 33.9% (33.9% +/- 19.2%) and themedian was 28% (range; 4%-90%). The mean Ki-67 expression of luminal A, luminal B, HER2 and TN-basal-like/null was 7%, 30%, 40%, and 57%/43%, respectively. A higher Ki-67 expression significantly correlated with a highergrade, larger size and higher stage of malignancy. Conclusions: We, for the first time, investigated the histopathologicalfeatures of breast cancers from Myanmar women. Myanmar breast cancers appeared to be aggressive in nature, asevidenced by high frequency of poor-prognosis subtypes with high level of Ki-67 expression. PMID- 28670880 TI - Awareness about Breast Cancer and Its Screening among Rural Egyptian Women, Minia District: a Population-Based Study AB - Background: Recent global cancer statistics indicate rising global incidence of breast cancer and the increase isoccurring at a faster rate in developing countries. Training women how to carry out breast self-examination (BSE) canhelp them to be alert to any abnormalities in their breasts to speedily seek medical consultation. Health behavior maybe influenced by level of awareness about breast cancer. Methods: A cross-sectional community- based study aimedto assess the level of knowledge about breast cancer risk factors, early warning signs, screening approaches and relatedpredictors. Also, to determine the extent of practice of breast self- examination (BSE) among rural women, Minia inthe period from February to May 2016. A total of 600 women were randomly included in the study. A questionnaireincluded socio-demographic characteristics and information related to their knowledge about breast cancer. Dataanalysis was carried out using SPSS version 19. Results: Moderate and high knowledge scores were presented by 46.9%. Nearly 40% of participants had the knowledge that smoking increased the likelihood of cancer breast and almost30% of them affirmed that being obese or having a positive family history of cancer breast made them vulnerable tocancer breast. It was found that 28.7% and 18.2% of them knew that aging and nulliparity increased the likelihood ofbreast cancer. Participants with better knowledge score were 4.8 times more likely to practice BSE. Conclusion: Thisstudy revealed poor knowledge among rural women regarding cancer breast. BSE and clinical breast examination werenot well practiced. It is recommended to create awareness programs about breast cancer and regular patterns of BSE. PMID- 28670881 TI - Ameliorative Effect of Coenzyme Q10 and/or Candesartan on Carboplatin-Induced Nephrotoxicity: Roles of Apoptosis, Transforming Growth Factor-Beta1, Nuclear Factor Kappa-B And The Nrf2/HO-1 Pathway AB - Background: Carboplatin is a drug that is used for treatment of many types of cancer. However, it may produceserious nephrotoxicity. Candesartan is angiotensin II receptor antagonist employed mainly for control of hypertension.Coenzyme Q10 (CoQ10) is a fat-soluble substance which was proven to have potent antioxidant and anti-inflammatoryproperties. Aim: Our aim was to study the effects of candesartan and/or CoQ10 on carboplatin-induced nephrotoxicity inmice. Methods: Sixty mice were divided into 6 equal groups: Control untreated; carboplatin; carboplatin + candesartan;carboplatin + CoQ10; carboplatin + carboxymethyl cellulose; and carboplatin + candesartan + CoQ10 group. Kidneyweight/body weight ratio, blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta D-glucosaminidase(NAG), gamma glutamyl transpeptidase (GGT) and the urinary albumin excretion rate (UAER) were determined.Renal tissue catalase (CAT), glutathione reductase (GR), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO-1), transforming growth factor beta-1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha) and interleukin6 (IL-6) were also determined, along with mitochondrial complex I activity. In addition, portions of the kidney weresubjected to histopathological and immunohistochemical examination. Results: Candesartan and/or CoQ10 inducedsignificant improvement of renal and mitochondrial functions with significant increase in tissue CAT, GR, Nrf2 andHO-1 content associated with significant decrease in the kidney weight/body weight ratio, tissue TGF-beta1, TNF-alpha andIL-6 and alleviation of the histopathological and immunohistochemical changes as compared to carboplatin alonegroup. These effects were more significant in candesartan/CoQ10 combination group compared to either candesartanor CoQ10 alone. Conclusion: Candesartan/CoQ10 combination might represent a beneficial therapeutic modality foramelioration of carboplatin-induced nephrotoxicity. PMID- 28670882 TI - Circulating Hypermethylated RASSF1A as a Molecular Biomarker for Diagnosis of Hepatocellular Carcinoma AB - Background: Detection of circulating DNA can be applied for the diagnosis of many malignant neoplasms,including the hepatocellular carcinoma (HCC). The molecular pathogenesis of HCC is complex, involving differentgenetic and epigenetic alterations, chromosomal aberrations, gene mutations and altered molecular pathways. RASSF1Ais a well-established tumor suppressor gene which suffers frequent inactivation due to promoter hypermethylation ofCPG islands in multiple tumors including HCC, resulting in the reduction or loss of gene expression. Objective: Toexamine the role of circulating RASSF1A as a non-invasive diagnostic marker for HCC. Participant and Methods:A total of 45 HCC patients with a background of HCV infection, 40 cases of HCV infection without tumours and 40apparently healthy controls were subjected to full history taking, clinical examination, routine laboratory investigations,assessment of serum AFP and detection of circulating hypermethylated RASSF1A gene by methylation sensitiverestriction enzyme digestion and real-time PCR. Results: The level of hypermethylated RASSF1A was significantlyelevated in the HCC group as compared to the HCV and control groups (p=0.001 for both). Copy number in serumwas associated with increased tumor size (p value <0.001). On the other hand, no significant correlation was observedbetween RASSF1A and AFP (p=0.5). Using ROC curve analysis, the best cut-off for circulating serum RASSF1A todifferentiate the HCC group was 8 copies/MUl. Conclusion: The presence of hypermethylated RASSF1A in serum may bea useful and informative biomarker for HCC diagnosis and might be introduced as a screening method for populationsat risk of HCC development. PMID- 28670883 TI - Oral Cancer Awareness in Sudan: Assessment of Knowledge, Attitude and Treatment Seeking Behavior AB - Objective: This study was aimed to assess oral cancer awareness among a selected Sudanese population and toevaluate their knowledge and treatment seeking behavior. Methods: A questionnaire- based survey was performed onthe general population who attended the oral cancer awareness campaigns carried between 2015 and 2016 in differentgeographic areas of the Sudan. It was focusing on general awareness of oral cancer, oral cancer risk factors, oral cancerclinical signs/symptoms and treatment seeking behavior. Data were entered by Microsoft excel 2007 and analyzed bySPSS (version 20) using chi square test with P value <0.05. Result: There were 1,370 participants, 634(46.3%) weremales and 736(53.7%) were females. The responses of participants revealed that 66.6% have heard about oral cancerand the media was the common source of information (75.7%). Of all participants only 45.3% mentioned that theydon't have enough knowledge on oral cancer. Some participants believe that oral cancer is treatable (66.5%) whilst30.4% respond by I don't know. More than 80% of the respondents were aware that smokeless tobacco (toombak) isa risk factor for oral cancer. While 60.1% were aware of alcohol as a risk factor and 66.2% were aware of smokingas a risk factor. When qui square test was done, smokers were found to be the least to seek help in comparison tonon-smokers. The same result was obtained from alcohol consumers but it was different in snuff dippers, as the latterresponse was similar to that of the non-snuff dippers. Conclusion: This study revealed a level of around 66.6% of oralcancer awareness in different states of Sudan. Counseling sessions should be conducted when necessary with furtherinvestigations to find out the reasons behind the continued practice of high risk habits, despite knowledge. PMID- 28670884 TI - Low Incidence of the DPD IVS14+1G>A Polymorphism in Jordanian Breast and Colorectal Cancer patients AB - Background: Dihydropyrimidine dehydrogenase (DPD) is a crucial enzyme in the catabolism of 5-fluorouracil(5-FU), a drug that is frequently used in cancer therapy. Patients with deficient DPD activity are at risk of developingsevere 5 FU-associated toxicity. One possible cause of deficiency is genetic polymorphisms in the DPD gene, such asIVS14+1G>A. Aim: The present study was conducted to screen for the IVS14+1G>A polymorphism in cancer patientsreceiving 5-FU and a control group. Methods: A total of 40 cancer patients (30 colorectal cancer (CRC) and 10 breastcancer patients) were enrolled in this study. One hundred healthy controls were also tested using polymerase chainreaction-restriction fragment length polymorphism (PCR-RFLP). DNA sequence analysis was carried out to confirmthe presence of the IVSI14+1G>A polymorphism. Results: Only one CRC patient showed heterozygous IVS14+1G>Apolymorphism in the DPD gene. Conclusion: The results of this study demonstrated a very low frequency of theIVS14+1G>A polymorphism among Jordanian patients with colorectal and breast cancer. PMID- 28670885 TI - Anti-Vascular Endothelial Growth Factor Effects of Sorafenib and Arsenic Trioxide in Acute Myeloid Leukemia Cell Lines AB - Acute myeloid leukemia (AML), is a clonal disorder caused by acquired somatic mutations and chromosomalrearrangements. According to some evidence, progression of hematolymphoid malignancies depends on the inductionof new blood vessel formation under the influence of acute leukemia. Various factors are produced by cancer cellsunder hypoxic conditions to increase vascular formation. Among these, vascular endothelial growth factor (VEGF)plays a crucial role. Cytotoxicity and anticancer effects of arsenic trioxide (ATO) have been reported in many cancers.Sorafenib, known as an angiogenic inhibitor, decreases leukemic cell survival. The aim of this study was to indicatecombination effects of ATO and sorafenib in two AML cell lines, KG-1 and U937. Effective doses was determined byMTT assay for both single and combination treatments. Percentages of apoptotic cells were evaluated by Annexin VFITC staining and mRNA levels of VEGF isoforms and receptor expression were investigated by Real-Time PCR. Ourdata show that sorafenib (5MUM and 7MUM in KG-1 and U937 cell lines respectively), ATO (1.618MUM and 1MUM in KG-1and U937 cell lines respectively), and also their combination significantly increased the percentage of apoptotic cells.In addition the mRNA level of VEGF isoforms was downregulated in the U937 cell line while upregulated in KG-1cells. Taken together, our results suggest that the VEGF autocrine loop may have an influence on AML developmentand progression and could be consider as a therapeutic target. The combination of sorafenib as a VEGF inhibitor withATO synergistically inhibits cell proliferation and promotes apoptosis. PMID- 28670886 TI - Qualitative Improvement Methods Through Analysis of Inquiry Contents for Cancer Registration AB - Background: In Korea, the national cancer database was constructed after the initiation of the national cancerregistration project in 1980, and the annual national cancer registration report has been published every year since 2005.Consequently, data management must begin even at the stage of data collection in order to ensure quality. Objectives:To determine the suitability of cancer registries' inquiry tools through the inquiry analysis of the Korea Central CancerRegistry (KCCR), and identify the needs to improve the quality of cancer registration. Methods: Results of 721 inquiriesto the KCCR from 2000 to 2014 were analyzed by inquiry year, question type, and medical institution characteristics.Using Stata version 14.1, descriptive analysis was performed to identify general participant characteristics, and chi-squareanalysis was applied to investigate significant differences in distribution characteristics by factors affecting the qualityof cancer registration data. Results: The number of inquiries increased in 2005-2009. During this period, there werevarious changes, including the addition of cancer registration items such as brain tumors and guideline updates. Ofthe inquirers, 65.3% worked at hospitals in metropolitan cities and 60.89% of hospitals had 601-1000 beds. Tertiaryhospitals had the highest number of inquiries (64.91%), and the highest number of questions by type were 353 (48.96%)for histological codes, 92 (12.76%) for primary sites, and 76 (10.54%) for reportable. Conclusions: A cancer registrationinquiry system is an effective method when not confident about codes during cancer registration, or when confrontingcancer cases in which previous clinical knowledge or information on the cancer registration guidelines are insufficient. PMID- 28670887 TI - Programmed Death-Ligand 1 (PD-L1) Expression Associated with a High Neutrophil/Lymphocyte Ratio in Cholangiocarcinoma AB - Background: Effective treatments for cholangiocarcinoma (CCA) are still lacking. There are promising resultsof checkpoint inhibitor programmed cell death ligand-1 (PD-L1) activities in early phase trials. This study aimedto investigate the expression of PD-L1 and its relation to possible treatments for CCA. Methods: Formalin-fixedparaffin-embedded tumor samples from 46 patients with cholangiocarcinoma were retrieved. PD-L1 expression wasevaluated by immunohistochemistry using anti-PD-L1 antibody, clone 5H1. A PD-L1 positive response on tumor cellswas defined as >1% of tumor cell membranes stained. The association between PD-L1, clinico-pathological characteristicswas analyzed using Fisher's exact test, and survival analysis was done with the Cox regression model. Results: Out of46 samples, 32 (70%) had positive PD-L1 expression in tumor cell membranes. The median level of PD-L1 expressionwas 1.75% (0-34.7). PD-L1 expression was significantly associated with stage IV disease (OR 3.98, p=0.046) and ahigh neutrophil/lymphocyte ratio (OR 5.36, p=0.018). PD-L1 positivity was associated with worse overall survivalcompared with those with a PD-L1 negative tumor but did not reach a level of significance (7.2 vs. 7.9 months, p=0.32).Conclusion: PD-L1 is widely expressed in CCA but was not predictive for overall survival. PD-L1 positivity was(7.2 and 7.9 months, p=0.32). Significantly associated with stage IV disease and a high neutrophil/lymphocyte ratio. PMID- 28670888 TI - Molecular Screening for Epstein-Barr virus (EBV): Detection of Genomic EBNA-1, EBNA-2, LMP-1, LMP-2 Among Vietnamese Patients with Nasopharyngeal Brush Samples AB - Epstein-Bar virus (EBV) is considered to be intimately associated with development of nasopharyngeal carcinoma(NPC), the most common and high incidence cancer of the head and neck in Asian countries, especially in Vietnam.In this study, we validated associations between highly conserved segments of the EBV genome, including EBNA-1,EBNA-2, LMP-1, LMP-2 and nasopharyngeal cancer, with the aim of applications with non-invasive brush samplesfor early diagnosis and as a prognostic biomarker. The polymerase chain reaction (PCR) was performed to assess thepresence of EBNA-1, EBNA-2, LMP-1, LMP-2 in nasopharyngeal brush samples from Vietnamese NPC patients andnon-cancer controls. Positive rates for EBNA-1, EBNA 2, LMP-1, LMP-2 were 46.3%, 49.5% and 45.3%, and 47.4%,respectively, in cancer cases, much higher than the low frequencies found in non-cancer samples. Notably, at least oneof the four (PI >= 0.25) was found in 57. 9%. Significance was reached when computing the odds ratio (OR) and relativerisk (RR). Our detection of candidate genes. in nasopharyngeal brush samples collected from Vietnamese patients reducesthe need for invasive biopsies and fulfills the characteristics of a non-invasive, specific screening method suitable forroutine, NPC risk assessment for EBV-infected populations. Notably, this procedure may be useful for confirmatoryscreening with large oral brush swabs. PMID- 28670889 TI - Heuristic Classifier for Observe Accuracy of Cancer Polyp Using Video Capsule Endoscopy AB - Methods: Colonoscopy is a technique for examine colon cancer, polyps. In endoscopy, video capsule is universallyused mechanism for finding gastrointestinal stages. But both the mechanisms are used to find the colon cancer orcolorectal polyp. The Automatic Polyp Detection sub-challenge conducted as part of the Endoscopic Vision Challenge(http://endovis.grand-challenge.org). Method: Colonoscopy may be primary way of improve the ability of coloncancer detection especially flat lesions. Which otherwise may be difficult to detect. Recently, automatic polyp detectionalgorithms have been proposed with various degrees of success. Though polyp detection in colonoscopy and othertraditional endoscopy procedure based images is becoming a mature field, due to its unique imaging characteristics,detecting polyps automatically in colonoscopy is a hard problem. So the proposed video capsule cam supports to diagnosethe polyps accurate and easy to identify its pattern. Existing methodology mainly concentrated on high accuracy andless time consumption and it uses many different types of data mining techniques. To analyse these high resolutionvideo scale image we have to take segmentation of image in pixel level binary pattern with the help of a mid-pass filterand relative gray level of neighbours. This work consists of three major steps to improve the accuracy of video capsuleendoscopy such as missing data imputation, high dimensionality reduction or feature selection and classification.The above steps are performed using a dataset called endoscopy polyp disease dataset with 500 patients. Our binaryclassification algorithm relieves human analyses using the video frames. SVM has given major contribution to processthe dataset. Results: In this paper the key aspect of proposed results provide segmentation, binary pattern approachwith Genetic Fuzzy based Improved Kernel Support Vector machine (GF-IKSVM) classifier. The segmented imagesall are mostly round shape. The result is refined via smooth filtering, computer vision methods and thresholding steps.Conclusion: Our experimental result produces 94.4% accuracy in that the proposed fuzzy system and genetic Fuzzy,which is higher than the methods, used in the literature. The GF-IKSVM classifier is well-organized and provides goodaccuracy results for patched VCE polyp disease diagnosis. PMID- 28670890 TI - A Cross Sectional Study on Knowledge, Attitude and Practice related to Human Papillomavirus Vaccination for Cervical Cancer Prevention between Medical and Non Medical Students in Hong Kong AB - Background: One of the most important aetiologies of cervical cancer is Human Papillomavirus (HPV) infection.While vaccination is an effective way in preventing high risk HPV infection, HPV vaccine uptake rate in Hong Konghas been low. Considering the proven effectiveness of HPV vaccination and the low vaccination uptake rate in HongKong, this study was conducted to compare the knowledge, attitude and practice towards HPV vaccination for cervicalcancer prevention between medical and non-medical students in the University of Hong Kong. Methods: A total of420 full time undergraduates from the University of Hong Kong were recruited and evaluated. Questionnaires coveringdemographics, sexual risk profile, knowledge, attitude and practice towards HPV vaccination were applied, withthe Chi-square test analysis. Results: Medical students had more comprehensive knowledge than their non-medicalcounterparts on HPV vaccination, including the carcinogenicity of HPV (P<0.001), available vaccines on the market(P<0.001) and the outcome of vaccination (P<0.001). In particular, senior medical students (Year 3 or above) were shownto be more knowledgeable than their juniors (below Year 3) with statistical significance (P<0.001). Positive attitudestoward HPV vaccination were observed more frequently among medical students when compared to non-medicalstudents, especially regarding the usefulness of HPV vaccination in males (P<0.001). However, there was no significantdifference in the vaccination rate between medical and non-medical students (P=0.671), suggesting an importance forfactors other than knowledge, such as cost of vaccination and anxiety of side effects. Conclusions: Medical studentsin Hong Kong, especially those in senior years, had more comprehensive knowledge and positive attitudes towardsHPV vaccination than non-medical students. Yet, there was no significant difference in the practice of HPV vaccinationbetween medical and non-medical students. In addition to medical education, other factors such as health beliefs, riskperception and financial considerations, may have a role in determining HPV vaccination for cervical cancer prevention. PMID- 28670891 TI - Validation of The Hong Kong Liver Cancer Staging System in Patients with Hepatocellular Carcinoma after Curative Intent Treatment AB - Backgrounds: Recently Hong Kong Liver Cancer (HKLC) staging system has been proposed for staging ofhepatocellular carcinoma (HCC), and has been shown to provide better prognostic ability than the Barcelona Clinic LiverCancer (BCLC) system. However, the HKLC system lacks external validation, and its applicability remains uncertain.The present study was aimed to evaluate the prognostic performance of HKLC in HCC patients treated with curativeintent. Methods: Medical records of HCC patients treated with either resection or radiofrequency ablation (RFA) from2011 to 2016 were retrospectively reviewed. The overall survival and the prognostic ability of the HKLC and BCLCsystem were evaluated. Results: 79 HCC patients were included, of which 64.56% had Child A cirrhosis. Chronicviral hepatitis B infection was the leading cause of HCC, followed by chronic viral hepatitis C infection, alcohol andalcohol with HBV or HCV infection. According to the BCLC system, 82.28% were in stage 0-A, and according to theHKLC system, 93.67% were in stage I-IIb. RFA and liver resection were the primary treatment in 56.96% and 43.04%,respectively. The 5-year survival rate of patients in HKLC stage I, IIa and IIb were 81.64%, 61.66%, and 54.42%,respectively (P<0.001). Whereas, the 5-year survival rate of patients in BCLC stage 0, A and B were 60.00%, 75.90%,and 26.65%, respectively (P=0.053). The AUROC curve of the HKLC and BCLC for the entire cohort was 0.77 and0.64, respectively (P=0.15). Subgroup analysis showed the AUROC curve of the HKLC and BCLC for the patientswith viral associated HCC was 0.79 and 0.68, respectively (P=0.02). Conclusions: Applying the HKLC staging systemprovides a good discriminative ability for survival prediction in HCC patients treated with curative intent. Comparingwith the BCLC system, the HKLC system tends to yield better prognostic accuracy, particularly in viral-associated HCC. PMID- 28670892 TI - Age and Gender Related Renal Side Effects of Cisplatin in Animal Model AB - Backgrounds: Cisplatin (CDDP) is a choice of anti-cancer drug for cancer chemotherapy with serious side effectssuch as nephrotoxicity. It seems that age is an important factor influencing the side effects of CDDP. This study wasdesigned to determine the role of age and gender simultaneously in CDDP induced renal toxicity. Methods: 40 Wistarmale and female rats were assigned as 6 groups in 3 different age categories (10, 16, and 20 weeks old). The single doseof CDDP (7.5 mg/kg, ip) was administrated, and a week later measurements were performed. Results: Body weightchanges in male (not in female) animals aged 16 and 20 weeks were more than 10 weeks old animals (P<0.05). In malerats, the serum levels of creatinine (Cr) and blood urea nitrogen (BUN), and Cr-clearance in aged 10 weeks, normalizedkidney weight (KW) in aged 20 weeks, and serum nitrite, aspartate aminotransferase (AST) and malondialdehyde(MDA) levels and kidney tissue damage score (KTDS) in rats aged 16 weeks were significantly altered (P<0.05). Genderdifference in serum level of Cr, BUN and nitrite, and Cr clearance were observed in animals aged10 weeks (P<0.05).Conclusion: The side effects of CDDP are gender depended, and may be different at various ages. PMID- 28670893 TI - Osteopontin b and c isoforms: Molecular Candidates Associated with Leukemic Stem Cell Chemoresistance in Acute MyeloidLeukemia AB - Despite impressive advances in therapeutic approaches, long-term survival with acute myeloid leukemia (AML) islow as a result of treatment resistance and frequent relapse. Among multitude oncogenic proteins involved in acquisitionof a chemo-resistanr phenotype, osteopontin (OPN) recently has attracted marked attention. In spite of the well-definedassociation between OPN expression and cure rate with solid tumors, there is a scarcity of information on any role of thisprotein in AML cases. Based on the critical role of OPN in cell survival, it seems reasonable to hypothesize that isoformexpression levels may impact on regulation of apoptosis in AML cells in response to conventional chemotherapeuticdrugs and its relation to relapse. To investigate associations between induction of apoptosis and OPN isoform expression,two distinct AML cell lines (KG-1 as a leukemic stem cell model and U937) were treated with chemotherapy drugs,and cell viability and apoptosis were evaluated by MTT and Annexin/PI assay. After determination of appropriate drugdoses, mRNA expression levels of OPN isoforms and OPN-related genes were investigated. Our results demonstratedfor the first time that acquired up-regulation of OPN-b and c isoforms might prevent conventional chemotherapyregimen-induced apoptosis in AML cells. Moreover, upregulation of OPN-b and c in AML cells appears concurrentwith upregulation of AKT/VEGF/CXCR4/STAT3/ IL-6 gene expression. To sum up, this study suggests that OPN-band c isoforms could be considered as unique beneficial molecular biomarkers associated with leukemic stem cellchemoresistance. Hence, they have potential as molecular candidates for detection of minimal residual disease (MRD)and determination of remission in AML patients. Further evaluation with quantative real time PCR on patient samplesfor confirmation appears warranted. PMID- 28670894 TI - Prognostic Value of Tumor Budding in Early-Stage Cervical Adenocarcinomas AB - Background: Tumor budding has recently been reported as an independent adverse prognostic factor forcolorectal adenocarcinomas and other types of carcinoma in the digestive tract. This study aimed to evaluate theprognostic value of tumor budding in patients with early-stage cervical adenocarcinomas and any associationswith other clinical and pathological features. Methods: Histological slides of patients with early-stage (IB-IIA)usual-type endocervical adenocarcinoma who underwent radical hysterectomy and pelvic lymph node dissection,without preoperative chemotherapy, between January 2006 and December 2012 were reviewed. Tumor buddingwas evaluated in routinely-stained sections and defined as detached single cells or clusters of fewer than 5 cells in atumor invasive front and was stratified based on the number of bud counts in 10-high power fields as low (<15 buds)and high (>=15 buds). Correlations between tumor bud count and other clinical and pathological variables includingfollow-up outcomes were assessed. Results: Of 129 patients, a high tumor bud count was observed in 15 (11.6%),positively associated with histologic grade 3 (p<0.001), invasive pattern C (Silva System) (p=0.004), lymph nodemetastasis (p=0.008), stage IB2-IIA (p=0.016), and tumor size >2 cm (p=0.036). Kaplan-Meyer analysis showed asignificant decrease in both disease-free survival and cancer-specific survival for patients with a high tumor bud count(p=0.027 and 0.031, respectively). On multivariate analysis, histologic grade 3 was the only independent predictor fordecreased disease-free survival (p=0.004) and cancer specific survival (p=0.003). Conclusions: A high tumor buddingcount based on assessment of routinely-stained sections was found to be associated with decreased disease-free andcancer-specific survival in patients with early-stage cervical adenocarcinomas. However, it was not found to be anindependent prognostic predictor in this study. PMID- 28670895 TI - Association of GSTO1 A140D and GSTO2 N142D Gene Variations with Breast Cancer Risk AB - Background: Polymorphisms in glutathione S-transferase (GST) genes may contribute to breast cancer risk.The aim of this study was to investigate any association of two common GSTO1 A140D and GSTO2 N142D genepolymorphisms with breast cancer risk in an Iranian population followed by a protein structure analysis. Materialsand Methods: In the case-control study, 303 subjects comprising 153 women with breast cancer and 150 healthycontrols were included. Genotypes of GSTO1 A140D and GSTO2 N142D polymorphisms were assessed by PCRRFLP.Bioinformatics tools were employed to evaluate the damaging effects of A140D and N142D on the structures ofGSTO1 and GSTO2 proteins. Results: Our genetic association study revealed that the GSTO1 A140D polymorphismwas associated with breast cancer in a dominant model (OR= 1.75, 95%CI= 1.07-2.86, p= 0.026). Also, the A allele wassignificantly associated with breast cancer risk (OR= 1.69, 95%CI= 1.09-2.60, p= 0.018). With regard to the N142Dpolymorphism, there were significant associations between the GG genotype (OR= 2.20, 95%CI= 1.14-4.27, p= 0.019)and the G allele (OR= 1.47, 95%CI= 1.06-2.05, p= 0.021) and risk of breast cancer. Structural analysis revealed thatA140D and N142D polymorphisms cause changes in both primary and secondary structures of GSTO1 and GSTO2,respectively. Conclusion: Based on our results, GSTO1 A140D and GSTO2 N142D polymorphisms could be geneticrisk factors for breast cancer, but further studies with larger sample sizes focusing on different ethnicities are neededto obtain more comprehensive results. PMID- 28670896 TI - Lewis Acid-Base Chemistry of 7-Azaisoindigo-Based Organic Semiconductors. AB - Low-band-gap organic semiconductors are important in a variety of organic electronics applications, such as organic photovoltaic devices, photodetectors, and field effect transistors. Building on our previous work, which introduced 7 azaisoindigo as an electron-deficient building block for the synthesis of donor acceptor organic semiconductors, we demonstrate how Lewis acids can be used to further tune the energies of the frontier molecular orbitals. Coordination of a Lewis acid to the pyridinic nitrogen of 7-azaisoindigo greatly diminishes the electron density in the azaisoindigo pi-system, resulting in a substantial reduction in the lowest unoccupied molecular orbital (LUMO) energy. This results in a smaller highest occupied molecular orbital-LUMO gap and shifts the lowest energy electronic transition well into the near-infrared region. Both H+ and BF3 are shown to coordinate to azaisoindigo and affect the energy of the S0 -> S1 transition. A combination of time-dependent density functional theory and UV/vis and 1H NMR spectroscopic titrations reveal that when two azaisoindigo groups are present and high concentrations of acid are used, both pyridinic nitrogens bind Lewis acids. Importantly, we demonstrate that this acid-base chemistry can be carried out at the solid-vapor interface by exposing thin films of aza substituted organic semiconductors to vapor-phase BF3.Et2O. This suggests the possibility of using the BF3-bound 7-azaisoindigo-based semiconductors as n-type materials in various organic electronic applications. PMID- 28670897 TI - Polyphenols: Physicochemical and Biological Properties and Perspectives of Their Use in a Zero-Waste Society. AB - The 28th International Conference on Polyphenols, held in Vienna (Austria) in July 2016, offered a venue for global exchanges on the active research on polyphenols and for the presentation and discussion of the latest advances. The multidisciplinary event attracted 280 scientists from four continents working in different fields, from analytical and biosynthetic chemistry through genetic and metabolic engineering, plant physiology, and ecology to food nutrition and health sciences as well as industrial applications. This special issue presents a selection of papers from oral presentations and poster contributions shown within the framework of sessions focusing on research in the fields of (1) chemistry and physicochemistry, (2) food, nutrition, and health, and (3) applied polyphenolics. This introductory paper also briefly summarizes general properties of this versatile and largest group of secondary metabolites and their use in bioeconomical approaches. PMID- 28670898 TI - Redox Active Binary Logic Gate Circuit for Homeland Security. AB - Bipolar junction transistors are at the frontiers of modern electronics owing to their discrete voltage regulated operational levels. Here we report a redox active binary logic gate (RLG) which can store a "0" and "1" with distinct operational levels, albeit without an external voltage stimuli. In the RLG, a shorted configuration of half-cell electrodes provided the logic low level and decoupled configuration relaxed the system to the logic high level due to self charge injection into the redox active polymeric system. Galvanostatic intermittent titration and electrochemical quartz crystal microbalance studies indicate the kinetics of self-charge injection are quite faster and sustainable in polypyrrole based RLG, recovering more than 70% signal in just 14 s with minor signal reduction at the end of 10000 cycles. These remarkable properties of RLGs are extended to design a security sensor which can detect and count intruders in a locality with decent precision and switching speed. PMID- 28670899 TI - Poly(alkyl methacrylate) Brush-Grafted Silica Nanoparticles as Oil Lubricant Additives: Effects of Alkyl Pendant Groups on Oil Dispersibility, Stability, and Lubrication Property. AB - This article reports on the synthesis of a series of poly(alkyl methacrylate) brush-grafted, 23 nm silica nanoparticles (hairy NPs) and the study of the effect of alkyl pendant length on their use as oil lubricant additives for friction and wear reduction. The hairy NPs were prepared by surface-initiated reversible addition-fragmentation chain transfer polymerization from trithiocarbonate chain transfer agent (CTA)-functionalized silica NPs in the presence of a free CTA. We found that hairy NPs with sufficiently long alkyl pendant groups (containing >8 carbon atoms, such as 12, 13, 16, and 18 in this study) could be readily dispersed in poly(alphaolefin) (PAO), forming clear, homogeneous dispersions, and exhibited excellent stability at low and high temperatures as revealed by visual inspection and dynamic light scattering studies. Whereas poly(n-hexyl methacrylate) hairy NPs cannot be dispersed in PAO under ambient conditions or at 80 degrees C, interestingly, poly(2-ethylhexyl methacrylate) hairy NPs can be dispersed in PAO at 80 degrees C but not at room temperature, with a reversible clear-to-cloudy transition observed upon cooling. High-contact-stress ball-on flat reciprocating sliding tribological tests at 100 degrees C showed significant reductions in both the coefficient of friction (up to 38%) and wear volume (up to 90% for iron flat) for transparent, homogeneous dispersions of hairy NPs in PAO at a concentration of 1.0 wt % compared with neat PAO. The formation of a load-bearing tribofilm at the rubbing interface was confirmed using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy. PMID- 28670900 TI - Manganese Oxide Nanoparticle as a New p-Type Dopant for High-Performance Polymer Field-Effect Transistors. AB - We report a new p-type dopant, manganese oxide (Mn3O4) nanoparticle, to enhance the performance of organic field-effect transistors (OFETs) with conjugated polymers, including poly(3-hexylthiophene-2,5-diyl), poly[[N,N 9-bis(2 octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,59-(2,29 bithiophene)], and poly[[2,5-bis(2-octyldodecyl)-2,3,5,6-tetrahydro-3,6 dioxopyrrolo[3,4-c]pyrrole-1,4-diyl]-alt-[[2,2'-(2,5-thiophene)bis-thieno(3,2b) thiophene]-5,5'-diyl]] (DPPT-TT). Incorporating a small amount of Mn3O4 nanoparticles in the semiconductor film significantly improved the hole mobility and decreased the threshold voltage for all OFETs, indicating efficient Mn3O4 nanoparticle p-type doping. The Mn3O4 nanoparticle showed a better doping efficiency than the widely used FeCl3 dopant due to better mixability with the host conjugated polymers. In particular, doped DPPT-TT OFETs showed significantly improved mobility up to 2.35 (+/-0.4) cm2/(V.s) with enhanced air and operational stability at 0.1 wt % doping concentration from 1.2 cm2/(V.s) for pristine devices. PMID- 28670901 TI - Naphthazarin-Polycyclic Conjugated Hydrocarbons and Iptycenes. AB - The synthesis of a set of naphthazarin-containing polycyclic conjugated hydrocarbons is described herein. Sequential Diels-Alder reactions on a tautomerized naphthazarin core were employed to access the final conjugated systems. Complete conjugation across the backbone can be achieved through complexation with BF2, as observed by 1H NMR analysis and UV/vis spectroscopy. Precise synthetic control over the degree of oxidation of naphthazarin quinone Diels-Alder adduct 10 is additionally demonstrated and enables us to direct its subsequent reactivity. Finally, this work serves to demonstrate the potential for naphthazarin as a building block in the synthesis of novel organic electronic materials. PMID- 28670902 TI - Vertical Orientation of Nanocylinders in Liquid-Crystalline Block Copolymers Directed by Light. AB - The microphase-separated nanostructures of block copolymers are ideal nanotemplates for advanced fabrication, but they are greatly limited by the rapid and precise manipulation especially at room temperature. Here we report one method of light-directed regulation of nanostructures in thin films of liquid crystalline diblock copolymers containing azobenzene units as photoresponsive mesogens. The in-plane orientated nanocylinders in thin film can be light directed into out-of-plane on a time scale of seconds at room temperature. This fast regulation is beneficial from the fast process of photoinduced phase transition of the mesogenic block from liquid crystal to disordered isotropic phase. Several influence factors like the molecular weight of polymer, film thickness, light intensity, and relative humidity were studied in the light directed processes. In addition, the photoregulated nanostructures demonstrate their capability of being photopatterned and further used as nanotemplates for fabrication of nanoparticles. The light-directed method shows noncontact, precise, and reversible features, enabling it to find further applications in fast control of nanostructures for nanofabrication and nanoengineering. PMID- 28670903 TI - Highly Fluorescent Red-Light Emitting Bis(boranils) Based on Naphthalene Backbone. AB - Ten bis(boranils) differently substituted at the boron atom and iminophenyl groups were synthesized from 1,5-dihydroxynaphthalene-2,6-dicarboxaldehyde using a simple one-pot protocol. Their photophysical properties can be easily tuned in a wide range by the variation of substituents. Their absorption and emission spectral bands are significantly red-shifted (lambdamax = 495-590 nm, lambdaem = 533-683 nm) when compared with simple boranils, whereas fluorescence quantum yields are strongly improved to reach 83%. The attachment of pendant NO2 and NEt2 groups at the opposite positions of the pi-conjugated bis(boranil) scaffold resulted in the formation of an unprecedented system featuring push-pull architecture. PMID- 28670904 TI - Stereoselective Synthesis of Functionalized 1,3-Disubstituted Isoindolines via Rh(III)-Catalyzed Tandem Oxidative Olefination-Cyclization of 4-Aryl-cyclic Sulfamidate-5-Carboxylates. AB - A new method for the direct, stereoselective synthesis of highly functionalized 1,3-disubstituted isoindolines 6 from enantiomerically enriched cyclic 4-aryl sulfamidate-5-carboxylates (5) is described. The process involves sulfamidate directed, Rh(III)-catalyzed tandem ortho C-H olefination of the 4-aryl sulfamidate-5-carboxylates and subsequent cyclization by aza-Michael addition. In the reaction, which generates trans-1,3-disubstituted isoindolines exclusively, the configurational integrity of the stereogenic center in the starting cyclic sulfamidate is completely retained in the product. Examples are provided which show that the cyclic sulfamidate moiety not only serves as a chiral directing group but also as a versatile handle for further functionalization of the generated isoindoline ring system. PMID- 28670905 TI - Benzothiazole Sulfinate: A Sulfinic Acid Transfer Reagent under Oxidation-Free Conditions. AB - Sulfinic acids are commonly encountered intermediates found in natural product synthesis and medicinal chemistry. However, because of high reactivity, instability, and harsh reaction conditions, they are difficult to synthesize. Herein we have developed an oxidation-free method to produce sulfinic acids and sulfinate salts using 2-sulfinyl benzothiazole (BTS). We have also demonstrated the synthetic usefulness by developing one-pot syntheses of sulfones and sulfonamides. PMID- 28670907 TI - Recovery of Percent Vital Capacity by Breathing Training in Patients With Panic Disorder and Impaired Diaphragmatic Breathing. AB - Slow diaphragmatic breathing is one of the therapeutic methods used in behavioral therapy for panic disorder. In practice, we have noticed that some of these patients could not perform diaphragmatic breathing and their percent vital capacity was initially reduced but could be recovered through breathing training. We conducted a comparative study with healthy controls to investigate the relationship between diaphragmatic breathing ability and percent vital capacity in patients with panic disorder. Our findings suggest that percent vital capacity in patients with impaired diaphragmatic breathing was significantly reduced compared with those with normal diaphragmatic breathing and that diaphragmatic breathing could be restored by breathing training. Percent vital capacity of the healthy controls was equivalent to that of the patients who had completed breathing training. This article provides preliminary findings regarding reduced vital capacity in relation to abnormal respiratory movements found in patients with panic disorder, potentially offering alternative perspectives for verifying the significance of breathing training for panic disorder. PMID- 28670906 TI - Feasibility and acceptability of a Mediterranean-style diet intervention to reduce cardiovascular risk for low income Hispanic American women. AB - OBJECTIVE: Evidence for the cardioprotective effects of a Mediterranean-style (Med-style) diet is strong, however few Med-style dietary interventions have been developed for and tested among Hispanic Americans (HAs), especially younger HAs of reproductive age whose dietary habits may strongly influence dietary intake for all family members. DESIGN: We adapted a previously tested and evidence informed lifestyle intervention to reduce CVD risk and evaluated its feasibility, acceptability, and effects on self-reported lifestyle behaviors in this study enrolling low-income HA women attending a Title X family planning clinic in eastern North Carolina. The 3-month long intervention, given to all participants, promoted a Med-style dietary pattern with a focus on increasing consumption of foods commonly consumed by HA that have high quality dietary fats (polyunsaturated and monounsaturated fats primarily from plant sources and fish) and carbohydrates (fruits, vegetables, and whole grains). The intervention also recommended increasing physical activity and was given during 2 face-to-face counseling sessions and 2 telephone counseling sessions. Major outcomes were engagement with study activities and intervention acceptability; lifestyle behavior change at 3-month follow-up is also reported. RESULTS: Baseline characteristics (n = 36) were: mean age 33 years, 35 (97%) without health insurance, 32 (89%) born in Mexico, and mean BMI 30 kg/m2. Engagement was high among the 36 participants with 33 (92%) completing the intervention and follow-up measures. At follow-up, most participants thought the intervention was helpful (range: 85-100%) and acceptable (100% agreed 'I would recommend the program to others'). The mean dietary fat quality score improved by 0.5 units (95% CI: 0.0 1.1) and the mean fruit-vegetable servings/day improved by 0.7/day (95% CI: 0.1 1.3). CONCLUSION: Intervention engagement and acceptability were high and there was improvement in self-reported dietary behaviors. This type of Med-style dietary pattern intervention should be evaluated in randomized trials enrolling HAs at risk for CVD. PMID- 28670908 TI - Effects of Lactobacillus rhamnosus GG on the maturation and differentiation of dendritic cells in rotavirus-infected mice. AB - Rotavirus-related diarrhoea is considered one of the most important diseases in field animal production. In addition to the classic vaccine strategy, a number of studies have utilised probiotics, such as Lactobacillus rhamnosus GG (LGG), to prevent rotavirus-induced diarrhoea. Although it has been partially revealed that Toll-like receptors (TLRs) are involved in the LGG-mediated protection against rotavirus infection, the details of the underlying immunologic mechanisms remain largely unknown. In this study, three-to-four-week-old female BALB/c mice were divided into three groups and orally administered phosphate buffered saline (PBS), PBS plus rotavirus or LGG plus rotavirus, respectively. The differentiation and maturation of dendritic cells (DCs) were then determined by FACS, the expression levels of TLR-3 and nuclear factor kappa beta (NF-kappaB) were evaluated using real time PCR, and the production of inflammatory cytokines in mesenteric lymph nodes (MLNs) were determined by ELISA. The results demonstrated that rotavirus infection significantly increased the percentage of CD11c+CD11b+CD8a- DCs and decreased the percentage of CD11c+CD11b-CD8a+ DCs in MLNs. By contrast, the presence of LGG significantly decreased the percentage of CD11c+CD11b+CD8a- DCs and increased the percentage of CD11c+CD11b-CD8a+ DCs, which indicates that the differentiation of DCs is involved in the protective effects of LGG. Rotavirus infection also resulted in the increased expression of surface markers such as CD40, CD80 and MHC-II in DCs, and the administration of LGG significantly increased the expression level further. The mRNA levels of TLR 3 and NF-kappaB in the intestine and MLNs were also significantly increased in the presence of rotavirus, which was further increased in the presence of LGG. The production of inflammatory cytokines was also determined, and the results showed that rotavirus caused the increased production of interleukin (IL)-12 and tumour necrosis factor alpha; this effect was further enhanced by LGG. Meanwhile, although rotavirus infection led to the increased production of IL-6 and IL-10, the presence of LGG significantly decreased the mRNA levels of these cytokines. By contrast, rotavirus infection resulted in the decreased production of interferon gamma (IFN-gamma), and the administration of LGG significantly increased the levels of IFN-gamma. Taken together, the protective effects of LGG were partially due to the modulation of the differentiation and maturation of DCs, the increased production of TLR-3 and NF-kappaB, and the modulation of inflammatory cytokines. PMID- 28670909 TI - Evidence of bias in randomized clinical trials of hepatitis C interferon therapies. AB - INTRODUCTION: Bias may occur in randomized clinical trials in favor of the new experimental treatment because of unblinded assessment of subjective endpoints or wish bias. Using results from published trials, we analyzed and compared the treatment effect of hepatitis C antiviral interferon therapies experimental or control. METHODS: Meta-regression of trials enrolling naive hepatitis C virus patients that underwent four therapies including interferon alone or plus ribavirin during past years. The outcome measure was the sustained response evaluated by transaminases and/or hepatitis C virus-RNA serum load. Data on the outcome across therapies were collected according to the assigned arm (experimental or control) and to other trial and patient-level characteristics. RESULTS: The overall difference in efficacy between the same treatment labeled experimental or control had a mean of +11.9% (p < 0.0001). The unadjusted difference favored the experimental therapies of group IFN-1 (+6%) and group IFN 3 (+10%), while there was no difference for group IFN-2 because of success rates from large multinational trials. In a meta-regression model with trial-specific random effects including several trial and patient-level variables, treatment and arm type remained significant (p < 0.0001 and p = 0.0009 respectively) in addition to drug-schedule-related variables. CONCLUSION: Our study indicates the same treatment is more effective when labeled "experimental" compared to when labeled "control" in a setting of trials using an objective endpoint and even after adjusting for patient and study-level characteristics. We discuss several factors related to design and conduct of hepatitis C trials as potential explanations of the bias toward the experimental treatment. PMID- 28670910 TI - Commentary on Tine et al. PMID- 28670911 TI - Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers. AB - OBJECTIVE: To assess the bioequivalence of generic formulation of rivastigmine (test) and Exelon (reference). METHODS: This randomized, open-label, 2-period, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 40 healthy men under fed condition. Participants were randomized to receive a single dose of Exelon or rivastigmine capsule. RESULTS: A total of 31 participants completed the study. Area under the concentration-time curve from time zero to time t (AUC0- t) and area under the concentration-time curve from time zero to infinity (AUC0 infinity) for Exelon (mean [standard deviation], h.ng/mL) were 126.40 (56.95) and 129.46 (59.94), respectively, while they were 122.73 (43.46) and 125.08 (45.39) for rivastigmine. Geometric mean ratios of rivastigmine/Exelon were 99.17% for AUC0- t, 98.81% for AUC0-infinity, and 105% for maximum observed plasma concentration ( Cmax). The 90% confidence intervals (CIs) were 94.14% to 104.46%, 93.77% to 104.12%, and 93.08% to 118.44%, respectively. Both formulations were well tolerated. CONCLUSION: The generic and reference formulations were bioequivalent, as the 90% CIs for Cmax, AUC0- t, and AUC0-infinity were within the range of 80% to 125%. PMID- 28670912 TI - Mandibular Lytic Lesion in Familial Paraganglioma Syndrome Type I: A Clinical Conundrum. AB - OBJECTIVE: The entity of primary mandibular paraganglioma (PGL) is not well accepted within the head and neck. Mandibular PGLs hitherto reported in literature are malignant metastatic lesions, mostly from a pheochromocytoma. METHODS: We report a case of mandibular lytic lesion in a young female with multifocal PGLs but no family history of PGLs. We also performed a literature search to identify published cases of mandibular PGL. RESULTS: Lack of established criteria for malignancy in a PGL made diagnosis and treatment challenging. Testing was negative for a pheochromocytoma and positive for mutation of succinate dehydrogenase gene encoding subunit D (SDHD), thus rendering a diagnosis of familial PGL syndrome type I. Due to the absence of prior published reports of nonmalignant, primary mandibular PGL, patient was treated with surgery and postoperative radiotherapy. Our literature search revealed 4 published cases of mandibular PGL, all of which had an osteoblastic appearance and were malignant. CONCLUSIONS: Isolated mandibular PGL does not always indicate a malignant metastatic lesion. Genetic testing is recommended in patients with early onset of PGL and/or multifocality even without a positive family history. Surgical resection alone with surveillance can be offered for such isolated lesions in the presence of familial PGL syndrome type I. PMID- 28670913 TI - Potential for False-Positive Results with Serological Assays for HIV in Central Africa: Implications for the HIV Serodiagnosis Algorithm According to the 2015 Consolidated WHO Recommendations for Resource-Constrained Countries. PMID- 28670914 TI - High Prevalence of Chronic Pain With Neuropathic Characteristics After Open Reduction and Internal Fixation of Ankle Fractures. AB - BACKGROUND: Unstable ankle fractures require treatment with open reduction and internal fixation (ORIF). Long-term functional outcome is satisfying in most patients; however, a number of patients have persistent complaints. Superficial nerve complications following ankle surgery may be the cause of chronic pain and disability. METHODS: In this observational retrospective survey, a cohort of 527 women and men, who underwent ORIF in the period from January 2007 to January 2014, were invited to an online questionnaire. Pain symptoms were assessed using the McGill Pain Questionnaire (MPQ) and the Douleur Neuropathic en 4 Questions (DN4) Questionnaire. Descriptive statistics were used to present patient characteristics; a logistic regression model was used to analyze prognostic factors of neuropathic pain. A total of 271 patients completed the questionnaire. Mean follow-up period was 5.8 years (+/-1.9). RESULTS: Persistent neuropathic pain symptoms were present in 61 of all patients, and 51 of these patients reported an impaired quality of life caused by their symptoms. In univariate analysis, the following parameters were associated with neuropathic pain: age, hypertension, a thyroid disorder, lower back pain, fracture dislocations, and late complications such as nonunion, posttraumatic arthritis, or osteochondral injury. In multivariate analysis, an age between 40 and 60 years was found to be a significant predictor of neuropathic pain. Hypertension, dislocation, and late complications were significant predictors of persistent pain without neuropathic characteristics. CONCLUSION: The present study demonstrated a prevalence of persistent neuropathic pain symptoms after ORIF for ankle fractures in 23% of the respondents, which caused an impaired health-related quality of life. We identified 4 significant predictors of chronic and neuropathic pain after ORIF. This knowledge may aid the treating surgeon to identify patients who are at increased risk of persistent postoperative neuropathic pain and may affect the treatment of pain in these patients. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28670915 TI - Phytochemical and pharmacological properties of essential oils from Cedrus species. AB - Natural products frequently exert pharmacological activities. The present review gives an overview of the ethnobotany, phytochemistry and pharmacology of the Cedrus genus, e.g. cytotoxic, spasmolytic immunomodulatory, antiallergic, anti inflammatory and analgesic activities. Cancer patients frequently seek remedies from traditional medicinal plants that are believed to exert less side effects than conventional therapy with synthetic drugs. A long-lasting goal of anti cancer and anti-microbial therapy research is to find compounds with reduced side effects compared to currently approved drugs. In this respect, Cedrus species might be of interest. The essential oil isolated from Cedrus libani leaves may bear potential for drug development due to its high concentrations of germacrene D and beta-caryophyllene. The essential oils from Cedrus species also show bioactivity against bacteria and viruses. More preclinical analyses (e.g. in vivo experiments) as well as clinical trials are required to evaluate the potential of essential oils from Cedrus species for drug development. PMID- 28670916 TI - Gamma irradiation affects the total phenol, anthocyanin and antioxidant properties in three different persian pistachio nuts. AB - The effects of gamma irradiation (GR) on total phenol, anthocyanin and antioxidant activity were investigated in three different Persian pistachio nuts at doses of 0, 1, 2 and 4 kGy. The antioxidant activity, as determined by FRAP and DPPH methods, revealed a significant increase in the 1-2 kGy dose range. Total phenol content (TPC) revealed a similar pattern or increase in this range. However, when radiation was increased to 4 kGy, TPC in all genotypes decreased. A radiation dose of 1 kGy had no significant effect on anthocyanin content of Kale Ghouchi (K) and Akbari (A) genotypes, while it significantly increased the anthocyanin content in the Ghazvini (G) genotype. In addition, increasing the radiation to 4 kGy significantly increased the anthocyanin content of K and G genotypes. To conclude, irradiation could increase the phenolic content, anthocyanin and antioxidant activity of pistachio nuts. PMID- 28670917 TI - Topical Review: MACI as an Emerging Technology for the Treatment of Talar Osteochondral Lesions. AB - : Matrix-induced autologous chondrocyte implantation (MACI) is a viable procedure that can be used as both a primary or revision cartilage regenerative procedure in high-functioning individuals without tibiotalar arthritis. Both short-term and midterm follow-up results demonstrate clinical, radiographic, and functional improvements with high rates of return to full activities. Cost remains a chief concern with the use of this technique, but theoretical improvements in the durability of repair with type II cartilage replacement may offer long-term benefits. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 28670918 TI - Novel Double Osteotomy Technique of Distal Tibia for Correction of Asymmetric Varus Osteoarthritic Ankle. AB - BACKGROUND: A most challenging condition for balancing a varus arthritic ankle is the presence of a defect in the medial tibial plafond. After our initial results with a medial tibial plafondplasty did not fulfill our expectations of success, we hypothesized that adding a correcting supramalleolar osteotomy of the distal tibia would move the loading force to the tibiotalar joint more medially and move the center of rotation of the talus more laterally. In this study, we analyzed midterm clinical and radiographic outcomes in patients with double tibial osteotomy. METHODS: Between January 2005 and February 2010, 20 patients were treated with a medial tibial plafondplasty and a medial supramalleolar osteotomy of the distal tibia. The mean age of the patients was 44 +/- 12 years (range, 17 60 years). Follow-up averaged 5.9 +/- 2.1 years (range, 4-11.2 years). Weight bearing radiographs were used to assess osteotomy union and hindfoot alignment. RESULTS: There were no intraoperative or perioperative complications. The average VAS pain score decreased significantly from 7.9 +/- 1.3 (range, 6-10) to 1.3 +/- 1.6 (range, 0-7). The average AOFAS hindfoot score increased significantly from 49 +/- 15 points (range, 36-68) preoperatively to 86 +/- 12 points (range, 66-96) postoperatively. The varus tilt improved significantly from 19.4 degrees +/- 8.2 degrees (range, 6 degrees -32 degrees ) to 6.9 degrees +/- 3.9 degrees (range, 1 degrees -12 degrees ). CONCLUSION: The novel double osteotomy was found to be an efficient and successful method to restore tibiotalar joint congruency and to normalize hindfoot alignment. LEVEL OF EVIDENCE: Level IV, prospective cohort study. PMID- 28670919 TI - Isolation and structure determination of a new diketopiperazine dimer from marine derived fungus Aspergillus sp. SF-5280. AB - A new diketopiperazine dimer designated as SF5280-415 (1) was isolated from an EtOAc extract of the marine-derived fungus Aspergillus sp. SF-5280 by various chromatographic methods. The structure of 1 was mainly determined by analysis of the NMR spectroscopic data and MS data, along with Marfey's method. This compound is a new diastereoisomer of known bispyrrolidinoindoline diketopiperazine alkaloid WIN 64745, which possesses unique architecture biosynthetically derived from an indole oxidation reaction of tryptophan. PMID- 28670920 TI - Essential oils Constituents of the leaves of Amomum gagnepainii and Amomum repoense. AB - The chemical constituents identified in the essential oils hydrodistilled from the leaves of Amomum gagnepainii T.L.Wu, K.Larsen and Turland and Amomum repoense Pierre ex Gagnep (Zingiberaceae) of Vietnam origin are reported. The chemical analyses were performed by means of gas chromatography-flame ionisation detector (GC-FID) and gas chromatography coupled with mass spectrometry (GC-MS). The main compounds of A. gagnepainii were farnesyl acetate (18.5%), zerumbone (16.4%) and beta-caryophyllene (10.5%). On the other hand, Amomum repoense comprised of monoterpenes dominated by beta-pinene (33.5%), (E)-beta-ocimene (9.6%), gamma terpinene (9.1%) and alpha-pinene (8.4%). This is the first report on the essential oils of A. gagnepainii and A. repoense grown in Vietnam or elsewhere. PMID- 28670921 TI - Progesterone, progesterone/estradiol and ART outcomes in day-5 transfer cycles. AB - The objective of this study was to assess the effects of elevated luteal-phase progesterone levels (PE) and high progesterone/estradiol ratio ('P/E2' ratio) on IVF outcomes, exclusively in GnRH-antagonist cycles with day-5 embryo transfer. PE was not found to have a significant effect on implantation or clinical pregnancy rate (CPR) (OR 0.56, 95% CI 0.25-1.25, p = .16). Elevated 'P/E2' ratio (>=0.55) on trigger day was associated with a poorer response to stimulation and lower clinical pregnancy rates (OR 0.58, 95% CI 0.34-1.00, p = .05). Patients with PE and low 'P/E2' ratio yielded significantly more oocytes than patients with PE and high 'P/E2' ratio. The mean implantation rate per patient decreased by 60% in the group with PE and high 'P/E2' ratio in comparison to the group with PE and low 'P/E2' ratio (17.9%+/-36.6 vs. 45.5%+/-47.2, p = .06), although no statistical significance was observed. The detrimental effect of PE may be mitigated by culturing embryos to day-5 before embryo transfer. Combined assessment of serum progesterone and 'P/E2' ratio may predict pregnancy outcome better than progesterone levels alone. PMID- 28670929 TI - Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer. AB - INTRODUCTION: Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress. Areas covered: We summarize the distinct pathways that induce NOXA RNA and protein, and how this may be exploited in solid and hematopoietic cancers, with a focus on multiple myeloma and chronic lymphocytic leukemia. Expert opinion: The therapeutic potential to induce NOXA is not yet fully explored nor exploited, and we suggest 1) areas that require further fundamental investigation, including replicative stress and epigenetics, 2) areas where translation to therapeutic application seems more imminent (ER stress, ROS, inhibition of NOXA degradation) 3) a complementary approach to inducing NOXA by direct targeting of MCL1 via the novel BH3 mimetic S63845 and similar compounds. PMID- 28670930 TI - Topical delivery of TRPsiRNA-loaded solid lipid nanoparticles confer reduced pain sensation via TRPV1 silencing, in rats. AB - Present work describes a novel composition for encapsulating TRPsiRNA (TRPV1 targeting siRNA) within lipid-matrix (4:1::glyceryl behnate:stearic acid) of SLNs, using suitably modified cold high-pressure homogenisation technique. Optimisation of the method and composition conducted using calf-thymus DNA (ctDNA), to avoid cost of TRPsiRNA molecules, resulted in small size (d50 = 50 100 nm) and high entrapment (77.22-98.5%). Complete masking of extreme negative charge of both ctDNA (-34.50 mV) and TRPsiRNA (-23.98 mV) upon encapsulation in SLNs without employing cationic components is reported herein for the first time. Diffusion-controlled release (90.17% at 72 h) from a rigid matrix shifted to porous matrix (at 24 h) due to solubilisation of stearic acid at 37 degrees C. Efficient in vitro (HEK293 T cells) and in vivo transfection and expression established the proof-of-concept. PEG600 as supporting-surfactant and vitrifying agent promoted small size, effective transfection and rupture of endosomal membrane to affect endosomal escape. Physiological efficacy in terms of significant increase (p < .0001) in paw-withdrawal-latency, following topical and intradermal application of TRPsiRNA-loaded SLNs, in rats, exposed to thermal hyperalgesia (145 and 182%, respectively) and capsaicin-induced pain (155 and 182%, respectively) indicate effective silencing of skin TRPV1. Significant decrease in intensity and duration (one-fifth) of capsaicin-induced nocifensive behaviour was also observed. Naked TRPsiRNA, however, did not show any effect. PMID- 28670932 TI - Alicaforsen for the treatment of inflammatory bowel disease. AB - INTRODUCTION: Intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein of the immunoglobulin family, constitutively expressed on vascular endothelial cells and upregulated in inflamed colonic tissue. Alicaforsen, a 20 base ICAM-1 anti-sense oligonucleotide and highly selective ICAM-1 inhibitor, down-regulates ICAM-1 mRNA. Areas covered: We review mechanism of action, pharmacokinetics, pre-clinical, clinical and safety data of alicaforsen for the treatment of ulcerative colitis (UC), pouchitis and Crohn's disease (CD). Expert opinion: After 6 weeks of treatment, topical alicaforsen was significantly more effective than placebo in inducing remission in patients with moderate-severe distal UC, with treatment effects lasting up to 30 weeks. No difference was observed in head-head comparison with mesalamine topical enema, although alicaforsen appeared to have more durable treatment effect. Clinical trials of an intravenous formulation in Crohn's disease showed no significant treatment effect compared to placebo. An open-label trial in alicaforsen for pouchitis demonstrated encouraging results, now being assessed in a multi-national phase 3 trial. No major safety signals have been observed in UC patients treated with alicaforsen enemas. The potential as a novel therapy for pouchitis has led to orphan designation for this indication by the FDA and European Medicines Agency. PMID- 28670931 TI - Composition and antimicrobial activity of the essential oil from the branches of Jacaranda cuspidifolia Mart. growing in Sichuan, China. AB - This study represents the first report on the chemical composition and antimicrobial activity of the essential oil from the branches of Jacaranda cuspidifolia Mart. Thirty-three compounds were identified by Gas Chromatography Mass Spectrometry (GC-MS) and the major constituents of the essential oil were Palmitic acid (31.36%), (Z) - 9,17-Octadecadienal (12.06%), Ethyl palmitate (3.81%), Perhydrofarnesyl acetone (2.07%), gamma-Maaliene (1.88%), and Cedro (1.42%) and 9,12-Octadecadienoic acid ethyl ester (1.42%). The in vitro antimicrobial activities of the essential oil were evaluated by the disc diffusion method, and the inhibition zones against Escherichia coli, Staphylococcus aureus and Candida albicans were 7.10, 8.20 and 7.25 mm, respectively. The oil showed moderate activities against E. coli, S. aureus and C. albicans with minimum inhibition concentration (MIC) values of 17.3 mg/mL, 12.9 mg/mL and 16.0 mg/mL, respectively. PMID- 28670933 TI - Predictors in use of mental health resources: The role of behaviour problems in patients with severe mental illness. AB - BACKGROUND: In recent years, more variables are being included in the use of mental health resource prediction models. Some studies have shown that how well the patient can function is important for this prediction. However, the relevance of a variable as important as behaviour problems has scarcely been explored. AIM: This study attempted to evaluate the effect of behaviour problems in patients with severe mental illness on the use of mental health resources. METHOD: A total of 185 patients at a Community Mental Health Unit were evaluated using the Behaviour Problem Inventory. Later, a bivariate logistic regression was done to identify what behaviour problems could be specific predictors of use of mental health resources. RESULTS: The results showed that the general index of behaviour problems predicts both use of hospitalization resources and outpatient attention. Underactivity/social withdrawal is the best predictor of all the different areas. CONCLUSION: These results confirm the role of behaviour problems as predictors of the use of mental health resources in individuals with a severe mental illness. PMID- 28670934 TI - Correction to: Thistle J.J. & Wilkinson K., Effects of background color and symbol arrangement cues on construction of multi-symbol messages by young children without disabilities: Implications for aided AAC design. PMID- 28670935 TI - Genetic damage induced by electronic waste leachates and contaminated underground water in two prokaryotic systems. AB - The inappropriate and unsafe management practices related to disposal and recycling of electronic wastes in Nigeria has led to environmental and underground water contamination. Reports on the level and type of contamination as well as the possible DNA damage effects of this contamination are insufficient. This study evaluated the DNA damaging potential of e-waste simulated and raw leachates, and its contaminated underground water using the SOS chromotest on Escherichia coli PQ37 and the Ames Salmonella fluctuation test on Salmonella typhimurium strains TA98 and TA100, without and with metabolic activation. Physico-chemical parameters of the samples were also analyzed. The result of the Ames test showed induction of base pair substitution and frameshift mutation by the test samples. However, the TA100 was the more responsive strain for the three samples in terms of mutagenic index in the absence and presence of metabolic activation. The SOS chromotest results were in agreement with those of the Ames Salmonella fluctuation test. Nevertheless, the E. coli PQ37 system was slightly more sensitive than the Salmonella assay for detecting genotoxins in the tested samples. Lead, cadmium, manganese, copper, nickel, chromium, arsenic, and zinc contents analyzed in the samples were believed to play a significant role in the observed DNA damage in the microbial assays. The results of this study showed that e-waste simulated and raw leachates, and its contaminated underground water are of potential mutagenic and genotoxic risks to the exposed human populace. PMID- 28670936 TI - Identification and characterization of ErbB4 kinase inhibitors for effective breast cancer therapy. AB - The overexpression of ErbB4 is associated with aggressive disease biology and reduced the survival of breast cancer patients. We have used ErbB4 receptor as a novel drug target to spearhead the rational drug design. The present study is divided into two parts. In the first part, we have exploited the hidden information inside ErbB4 kinase receptor both at sequence and structural level. PSI-BLAST algorithm is used to search similar sequences against ErbB4 kinase sequence. Top 15 sequences with high identity were selected for finding conserved and variable regions among sequences using multiple sequence alignment. In the second part, available 3 D structure of ErbB4 kinase is curated using loop modeling, and anomalies in the modeled structure is improved by energy minimization. The resultant structure is validated by analyzing dihedral angles by Ramachandran plot analysis. Furthermore, the potential binding sites were detected by using DoGSite and CASTp server. The similarity-search criterion is used for the preparation of our in-house database of drugs from DrugBank database. In total, 409 drugs yet to be tested against ErbB4 kinase is used for screening purpose. Virtual screening results in identification of 11 compounds with better binding affinity than lapatinib and canertinib. Study of protein ligand interactions reveals information about amino acid residues; Lys726, Thr771, Met774, Cys778, Arg822, Thr835, Asp836 and Phe837 at the binding pocket. The physicochemical properties and bioactivity score calculation of selected compounds suggest them as biological active. This study presents a rich array that assist in expediting new drug discovery for breast cancer. PMID- 28670937 TI - MarR family transcription factors: dynamic variations on a common scaffold. AB - Members of the multiple antibiotic resistance regulator (MarR) family of transcription factors are critical for bacterial cells to respond to chemical signals and to convert such signals into changes in gene activity. Obligate dimers belonging to the winged helix-turn-helix protein family, they are critical for regulation of a variety of functions, including degradation of organic compounds and control of virulence gene expression. The conventional regulatory paradigm is based on a genomic locus in which the gene encoding the MarR protein is divergently oriented from a gene under its control; MarR binding to the intergenic region controls expression of both genes by changing the interaction of RNA polymerase with gene promoters. MarR protein oxidation or binding of a small molecule ligand adversely affects DNA binding, resulting in altered expression of the divergent genes. The generality of this simple paradigm, including the regulation of Escherichia coli MarR by direct binding of antibiotics, has been challenged by reports published in recent years. In addition, structural and biochemical analyses of ligand binding to numerous MarR homologs are converging to identify a shared ligand-binding "hot-spot". This review highlights recent research advances that point to shared features, yet at the same time highlights the remarkable flexibility with which members of this protein family implement responses to inducing signals. A more comprehensive understanding of protein function will pave the way towards the development of both antibacterial agents and biosensors that are based on MarR family proteins. PMID- 28670938 TI - The effect of low-dose aspirin on fetal weight of idiopathic asymmetrically intrauterine growth restricted fetuses with abnormal umbilical artery Doppler indices: a randomized clinical trial. AB - OBJECTIVE: To investigate the effect of aspirin on fetal weight in fetuses with idiopathic asymmetrical intrauterine growth restriction (IUGR) complicated by abnormal umbilical artery Doppler indices. MATERIALS AND METHODS: The study was a randomized controlled trial conducted at Woman's Health Hospital, Assiut, Egypt, between June 2016 and the January 2017 included 60 pregnant women (28-30 weeks) with idiopathic asymmetrical IUGR associated with abnormal umbilical artery Doppler indices. Women were randomly assigned to group I (aspirin 75 mg) daily for four weeks or group II (no intervention). The primary outcome was the fetal weight after four weeks. Secondary outcomes included Doppler blood flow changes in the umbilical artery plus delivery and neonatal outcomes. RESULTS: The estimated fetal weight and umbilical artery blood flow increased significantly in aspirin group (p = .00) when compared with no intervention group. As regard neonatal outcomes; aspirin group showed better results and encouraging outcomes (p < .05). CONCLUSIONS: Aspirin improves fetal weight and umbilical artery blood flow in idiopathic asymmetrical IUGR fetuses complicated by abnormal umbilical artery Doppler blood flow. PMID- 28670939 TI - Zaccaria Lilio and the shape of the earth: A brief response to Allegro's "Flat earth science". AB - This is a response to James J. Allegro's article "The Bottom of the Universe: Flat Earth Science in the Age of Encounter," published in Volume 55, Number 1, of this journal. Against the solid consensus of modern scholars, Allegro contends that the decades around 1500 saw a resurgence of popular and learned doubts about the existence of a southern hemisphere and the concept of a spherical earth more generally. It can be shown that a substantial part of Allegro's argument rests on an erroneous reading of his main textual witness, Zaccaria Lilio's Contra Antipodes (1496), and on a failure adequately to place this source in the context of the cosmographical debate of the late fifteenth and early sixteenth centuries. Once this context is taken into account, the notion that Lilio was a flat-earther falls flat. PMID- 28670940 TI - Rare beta-Globin Gene Mutations in Pakistan. AB - The aim of this study was to analyze the rare beta-thalassemia (beta-thal) mutations in the Pakistani population. A total of 8716 unrelated Pakistani individuals having children with transfusion-dependent thalassemia were investigated by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) for the previously reported common and rare beta-thal mutations. Genomic sequencing of the beta-globin gene and its immediate 5' and 3' flanking regions was done where no known mutation was found. Out of the 8716 individuals studied, 88 (1.0%) were not characterized by ARMS-PCR. Genomic sequencing revealed that 67 (0.82%) individuals had 19 different beta-thal mutations including one novel mutation (HBB: c.136delT). The remaining 21 (0.26%) individuals did not show any mutation on the beta-globin gene and its immediate flanking regions. The characterized alleles included seven (0.09%) in the 5' untranslated region (5'UTR), 29 (0.35%) in the coding regions, and 31 (0.38%) in the splice junction regions. HBB: c.92+1G>A and HBB: c.113G>A were the most frequently seen rare mutations. The spectrum of beta-thal mutations in the Pakistani population is very diverse. In addition to the already reported mutations, another 19 different types of mutations were found. Interestingly, 21 individuals who had children with transfusion-dependent thalassemia and one known beta-thal mutation, did not show any mutation on the beta-globin gene. HBB: c.92+1G>A and HBB: c.113G>A are the most frequently seen rare mutations in Pakistan. PMID- 28670941 TI - Association between serum 25 (OH) vitamin D level at birth and respiratory morbidities among preterm neonates. AB - OBJECTIVES: To determine the association between 25-hydroxyvitamin D [25(OH)D] levels on first day of life with respiratory distress syndrome (RDS), need and duration of mechanical ventilation, and subsequent development of bronchopulmonary dysplasia (BPD) among preterm neonates. STUDY DESIGN: In this case-control study, serum 25(OH)D was measured on first day of life in 65 preterm neonates <34 weeks: 40 with RDS and 25 without RDS and compared between them. Serum 25(OH)D levels were categorized into normal (above 30 ng/ml), insufficiency (20-30 ng/ml), moderate deficiency (10-20 ng/ml), and severe deficiency (<10 ng/ml). Neonates with different 25(OH)D levels were compared as regard grade of RDS, initial pH, initial CO2, need and duration of mechanical ventilation, development of BPD, and mortality. RESULTS: Only one of 65 studied preterm neonates had normal vitamin D level. Neonates with RDS had significantly lower mean serum 25(OH)D level than controls (10.6 versus 13.9 ng/dl) (p = .028). Neonates with severe 25(OH)D deficiency developed more BPD than those with moderate deficiency (29.4 versus 8.7%) but did not reach significant level (p value = .08). There is no correlation between serum 25(OH)D level and duration of mechanical ventilation. Logistic regression analysis shows that low serum 25(OH)D level is an independent risk factor for RDS. CONCLUSION: Low 25(OH)D level is far frequent among Egyptian preterm neonates. Vitamin D deficiency is an independent risk factor for development of RDS in preterm neonates. PMID- 28670942 TI - New Insights on beta-Thalassemia in the Palestinian Population of Gaza: High Frequency and Milder Phenotype Among Homozygous IVS-I-1 (HBB: c.92+1G>A) Patients with High Levels of Hb F. AB - beta-Thalassemia (beta-thal) is a very common disease in the Palestinian population of the Gaza Strip. We studied their mutation frequency and clinical features. Thirteen different mutations were identified. The most common mutation was IVS-I-1 (G>A) (HBB: c.92+1G>A), which was prevalent in 31.5% of the thalassemia alleles studied. The IVS-I-110 (G>A) (HBB: c.93-21G>A) mutation was found in 25.0% of the alleles. Homozygotes for the IVS-I-1 mutation had higher mean hemoglobin (Hb) levels, required less blood transfusions, and lower transferrin saturation than the homozygotes for the IVS-I-110 mutation. This milder phenotype was, most likely, the result of the persistent production of Hb F; it was 9-fold higher in absolute terms (g/dL) and 7.7-fold higher in relative terms (percentage of total Hb). About half of our IVS-I-1 patients carried the XmnI polymorphism, which is known to be associated with elevated Hb F levels. PMID- 28670943 TI - High rates of secondary non-adherence causes decreased efficacy of 0.1% topical tacrolimus in adult eczema patients: results from a multicenter clinical trial. AB - BACKGROUND: Patients tend to apply topical medications less frequently, in improper amounts. Not only frequency but also application amount may influence treatment outcome. However, studies on relationship between application amount and objective treatment outcome have rarely been conducted. OBJECTIVE: To assess efficacy of topical agent according to application amount in adult patients, using the finger-tip unit method. METHODS: The efficacy of 0.1% topical tacrolimus in adult patients with localised atopic dermatitis was assessed using EASI, TIS, IGA, and PGA scores at baseline, follow-up. Adherence in amount was evaluated after 2 weeks of treatment using the ratio of the actual amount applied to the expected amount applied (A/E). RESULTS: Twenty-seven patients (20.93%) used topical tacrolimus in proper amounts (A/E: 0.8-1.2). However, 86 patients (66.67%) underused topical tacrolimus; 16 (12.40%) patients overused topical tacrolimus. Decreases in EASI scores between baseline and 2 weeks of follow-up in each group (under-amount, proper amount, over-amount) were 1.64, 4.65 and 4.21, respectively. Treatment efficacy increased in accordance with application amount. Further, TIS, IGA, PGA, VAS for Itch and DLQI scores improved concomitantly, exhibiting similar tendencies. CONCLUSION: Application amount of topical agent is important in increasing treatment efficacy in adult patients with atopic dermatitis. PMID- 28670944 TI - Acid-labile poly(amino alcohol ortho ester) based on low molecular weight polyethyleneimine for gene delivery. AB - A series of acid-labile poly(amino alcohol ortho ester) (POEeis) were synthesized through ring-opening polymerization between diglycidyl ethers with ortho ester bonded and low molecular weight polyethyleneimine by various feed molar ratios. The obtain POEei 1 and POEei 2 exhibited clear kinetic of degradation and condensed plasmid DNA into nanoparticles of suitable sizes (250-300 nm) and positive zeta potentials (+20-30 mV) while protecting DNA from enzymatic digestion. Further, these polymers have uniform distribution of abundant hydroxyl groups, which could improve their water solubility, biocompatibility, and lower protein adsorption. Significantly, ortho ester groups in POEeis main-chains could hydrolyze rapidly at acidic endosomal pH, resulting in intracellular DNA release and diminished material toxicity. MTT assay revealed that all the polymers exhibited much lower cytotoxicity than 25 kDa PEI in the human neuroblastoma SH SY5Y cells. Moreover, the transfection efficiency of POEei 1 was higher than 25 kDa PEI in serum-free medium or 10% serum medium. PMID- 28670945 TI - Coinheritance of Hb Bristol-Alesha [beta67(E11)Val->Met; HBB: c.202G>A] and the alpha212 Patchwork Allele in a Brazilian Child with Severe Congenital Hemolytic Anemia. AB - Hb Bristol-Alesha [HBB: c.202G>A; beta 67 Val>Met] is a rare structural variant of hemoglobin (Hb) resulting from a GTG>ATG substitution at codon 67 of the beta globin gene that leads to the replacement of valine by methionine in the corresponding position of the beta-globin chain. The methionine residue is subsequently modified to aspartic acid [beta67(E11)Val-Met->Asp], possibly by autoxidation mechanisms. This substitution prevents normal non-polar binding of Val67 to the heme group, resulting in molecular instability and severe hemolysis. We identified Hb Bristol-Alesha (in the heterozygous state), as the cause of severe congenital hemolytic anemia in an 11-month-old girl of mixed (native Indian and European) ethnic origin from the Midwestern region of Brazil, whose parents were clinically and hematologically normal. The mutation on the beta globin gene was found to have been coinherited with the alpha212 patchwork allele. PMID- 28670946 TI - Fear of Immigration Enforcement Among Older Latino Immigrants in the United States. AB - OBJECTIVE: The passage of the 1996 Illegal Immigration Reform and Immigrant Responsibility Act (IIRIRA) and other subsequent restrictive immigration policies have created fear among Latino immigrants. This study examines whether fear of immigration enforcement is socially significant among older (50+ years) foreign born Latino individuals in the United States without citizenship or permanent residence, and whether disapproval of immigrant enforcement policies is directly associated with fear of immigration enforcement among this older population. METHOD: Data used in the analysis come from 2007, 2008, 2010, and 2013 national Latino surveys conducted by the Pew Research Center. Cross-sectional regression models are used to estimate the probabilities of fearing immigration enforcement in the Latino samples, as well as to examine the association between disapproval and fear of immigration enforcement. RESULTS: The study finds that the predicted probabilities of fearing immigration enforcement among foreign-born individuals aged 50 and over without citizenship or permanent residence are not negligible. Moreover, the study finds evidence of a direct association between the disapproval of enforcement measures and fear of immigration enforcement. DISCUSSION: Restrictive immigration measures have implications for conditions of fear and other stressors affecting the well-being of older immigrants. PMID- 28670948 TI - Double versus single thrombophilias during pregnancy. AB - OBJECTIVE: The primary objective of this study was to evaluate whether women with double thrombophilias have a greater risk for obstetric complications as compared with women who have single thrombophilias. STUDY DESIGN: This is a retrospective cohort study of all patients in a single practice with a clinically significant inherited thrombophilia and treated with anticoagulation between 2005 and 2013. Thrombophilias evaluated include: factor V Leiden, prothrombin G20210A gene mutation, protein S deficiency, protein C deficiency, and antithrombin III deficiency. Double thrombophilia was defined as the presence of two thrombophilias or homozygosity for factor V Leiden or prothrombin Gene Mutation. Demographic and obstetrical outcome data were collected. Data on all patients with double thrombophilias who met inclusion criteria was reported. Data was then compared between the patients with double thrombophilias and single thrombophilias with singleton gestations. The data was analyzed with Pearson's chi-squared or Student's t-test as appropriate with p value <.05 used for significance. RESULTS: Eighteen patients with clinically significant double thrombophilias who met inclusion criteria were identified. Most patients delivered full term (88.9%) and appropriate for gestational age (77.8%) infants. One hundred thirty-two patients with single thrombophilias and 14 patients with double thrombophilias with singleton gestations were then compared. Demographic characteristics were not significantly different between the two groups. There were no significant differences in obstetrical outcomes between patients. CONCLUSIONS: There were no significant differences in obstetrical outcomes for patients with clinically significant double thrombophilias versus single thrombophilias when treated with anticoagulation. PMID- 28670949 TI - Preparation and optimization of rivastigmine-loaded tocopherol succinate-based solid lipid nanoparticles. AB - Rivastigmine hydrogen tartrate (RHT) is a pseudo-irreversible inhibitor of cholinesterase and is used for the treatment of Alzheimer's. However, RHT delivery to the brain is limited by the blood-brain barrier (BBB). The purpose of this study was to improve the brain-targeting delivery of RHT by producing and optimizing rivastigmine hydrogen tartrate-loaded tocopherol succinate-based solid lipid nanoparticles (RHT-SLNs). RHT-SLNs were prepared using the microemulsion technique. The impact of significant variables, such as surfactant concentration and drug/lipid ratio, on the size of RHT-SLNs and their drug loading and encapsulation efficiency was analysed using a five-level central composite design (CCD). The minimum size of particles and the maximum efficiency of loading and encapsulation were defined according to models derived from a statistical analysis performed under optimal predicted conditions. The experimental results of optimized RHT-SLNs showed an appropriate particle size of 15.6 nm, 72.4% drug encapsulation efficiency and 6.8% loading efficiency, which revealed a good correlation between the experimental and predicted values. Furthermore, in vitro release studies showed a sustained release of RHT from RHT-SLNs. PMID- 28670947 TI - Genetic Background of the Sickle Cell Disease Pediatric Population of Dakar, Senegal, and Characterization of a Novel Frameshift beta-Thalassemia Mutation [HBB: c.265_266del; p.Leu89Glufs*2]. AB - Sickle cell disease is a genetic disorder with a large variability in the pattern and severity of clinical manifestations. Different genetic modulators have been identified but very few epidemiologic data are available on these modifier genes in Senegal. This study aimed to determine their prevalence in a Senegalese sickle cell disease pediatric population. The following genetic parameters were genotyped in 295 sickle cell disease children of the Dakar pediatric hospital: sickle cell disease genotype [betaS/betaS (HBB: c.20A>T), betaS/betaC (HBB: c.19G>A), betaS/beta0-thalassemia (beta0-thal)], XmnI polymorphism, the five most common alpha-thalassemia (alpha-thal) deletions and the A(-) and Betica glucose-6 phosphate-dehydrogenase (G6PD) deficient variants. Despite very few betaS/betaC and betaS/beta0-thal children (1.0% each), a novel frameshift beta0-thal mutation was characterized: HBB: c.265_266del; p.Leu89Glufs*2. The -alpha3.7 (rightward) deletion was the only alpha-thal deletion identified in this cohort (12.0% allelic frequency). Most of betaS/betaS patients (61.9%) were homozygous for the XmnI polymorphism and assumed to carry a Senegal/Senegal betaS haplotype. The remaining haplotypes were predominantly of the Benin type. While the Betica G6PD variant was quite frequent (13.0%), a low frequency of the A(-) variant was detected (1.0-2.0%). The systematic genotyping of the -alpha3.7 deletion and of the G6PD Betica variant in sickle cell disease patients from Senegal could be useful to identify patients at risk for several complications, such as cerebral vasculopathy, where it has been demonstrated that a normal alpha-globin genotype and G6PD deficiency are predisposing factors. These patients should be eligible for a transcranial Doppler examination that is not routinely offered in Senegal. PMID- 28670950 TI - Understanding the Cognitive Development of Medical Students and Residents. PMID- 28670951 TI - Is Facial or Head Pain Related to the Location of Lesions on Computed Tomography in Chronic Rhinosinusitis? AB - BACKGROUND: Facial or head pain is not an infrequent symptom among patients diagnosed with chronic rhinosinusitis (CRS), but few reports have investigated the pain in CRS, including the relationship between pain and sites of CRS. The aim of this study was to investigate whether pain is related to the location of lesions on computed tomography (CT) in CRS. METHODS: We analyzed 203 patients who underwent endoscopic sinus surgery (ESS) for 2 years. Patients were assessed using the questionnaires on pain, provided 1 day prior to the operation and 6 months post operation. Sites of CRS were evaluated using CT. We analyzed whether the degree of inflammation in each sinus had an effect on the location of pain. RESULTS: Seventy-eight patients (38.4%) had preoperative facial or head pain. There was no difference in the sinus inflammation scores in CT findings, based on the presence of pain. Pain was most commonly located in the periorbital area, followed by the frontal, vertex, occipital, and facial areas. No significant correlation was found between the sinuses and the location of pain. CONCLUSIONS: This study indicates that in CRS patients, several sites of pain are involved, particularly in the periorbital area; these sites were not found to be related to the location of CRS. PMID- 28670952 TI - Assessment of aflatoxin exposure among young children in Ethiopia using urinary biomarkers. AB - The direct measurement of biomarkers of exposure in biological fluids such as urine has become important for assessing aflatoxin exposure in humans as it is the only tool that integrates exposures from various routes. For this reason, a study was conducted to assess aflatoxin exposure among young children in Ethiopia using urinary biomarkers. A cross-sectional study was conducted in ten Woredas (Districts) from Amhara and Tigray regional states of Ethiopia including 200 children (aged 1-4 years). A total of 200 urine samples were collected from 200 children and assessed for the levels of aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1), aflatoxin G2 (AFG2) and aflatoxin M1 (AFM1) using a validated LC-MS/MS method. Aflatoxins were detected in 34/200 (17%) of the urine samples whereby four out of five analysed aflatoxins were detected. AFM1 was detected in 14/200 (7%) of the urine samples in a range of 0.06-0.07 ng/mL. AFB2, AFG2 and AFG1 were detected in respectively 9/200 (4.5%), 6/200 (3%) and 5/200 (2.5%) of the urine samples whereas AFB1 was not detected in any of the samples. In this study, there was no association between the different malnutrition categories (stunted, wasting and underweight) and aflatoxin exposure. However, the biomarker analysis showed a clear exposure of young children to aflatoxins. Therefore, awareness to the public is important to prevent potential health consequences of aflatoxins. PMID- 28670953 TI - The probable role of adrenomedullin and nitric oxide in childhood attention deficit hyperactivity disorder. AB - BACKGROUND: The role of adrenomedullin hormone, which has been shown to be associated with many psychiatric disorders, in the etiology of ADHD and its relation to disease is not yet known. AIM: In this study, it was aimed to compare plasma adrenomedullin and nitric oxide (NO) levels of newly diagnosed, treatment naive patients with ADHD with healthy children. METHODS: A total of 45 children with ADHD and 45 healthy children were included. The Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS), a semi structured interview, was applied to all cases by child and adolescent psychiatrist. Age and gender matched participants who admitted to the hospital for any other reasons without any psychiatric diagnosis according to K-SADS were selected as a control group. Sociodemographic data form and The Turgay DSM-IV Based Child and Adolescent Disruptive Behavioral Disorders Screening and Rating Scale-parental form were applied to the all groups. NO and adrenomedullin levels were analysed by ELISA method with specific commercial kits. RESULTS: There was no statistically significant difference in NO and adrenomedullin levels, neither between the groups nor ADHD subtypes. A positive correlation between adrenomedullin and NO levels was found in both the case (r = 0.659) and the control groups (r = 0.494). CONCLUSIONS: Besides being the first study to evaluate adrenomedullin levels to elucidate the etiology of childhood ADHD as well as NO, significant differences was not found between the case and the control groups in terms of NO and adrenomedullin levels. PMID- 28670955 TI - Equity in nursing care: A grounded theory study. AB - BACKGROUND: Equity in providing care is also a major value in the nursing profession. Equitable care aims to provide the entire population with safe, efficient, reliable, and quality nursing services at all levels of health. OBJECTIVES: This study was conducted to explain the process of the realization of equity in nursing care. RESEARCH DESIGN: This qualitative study uses Glaser's approach to grounded theory. Participants and research context: Sample selection began with convenience sampling and continued with purposive sampling. A total of 27 people were ultimately selected as the study subjects. Data were mainly collected through unstructured in-depth individual interviews plus observation and field notes. The data were then analyzed using the "Six C's" coding family of Glaser. Ethical considerations: The study protocol was approved by the Tehran University of Medical Sciences (91D1302870). Written informed consent was also obtained from all subjects. FINDINGS: According to the findings, participants' main concern in providing equitable care is the rationing of nursing care. The identification of participants' main concern led to the emergence of the core category of the study, that is, "nurses' domination." The other categories revolving around the core category were conceptualized according to the six C's coding family: "nurses being dominated," "nurses' ineffective power in the health system," "low attention to equitable care in health system," "lack of clarity in measuring equitable care," "the health structure's inconsistency with equity," and "the inefficiency of the care system." CONCLUSION: There is a mutual relationship between providing fair care and nurses' perceptions of equity. Nurses who have themselves experienced equity can provide their patients the experience of equity. This mutual relationship is actualized in a context in which fair care is clearly defined and demanded. PMID- 28670956 TI - British Menopause Society vision for menopause care in the UK: Endorsed by Royal College of General Practitioners, Faculty of Sexual and Reproductive Health, Royal College of Nursing, and Royal College of Obstetricians and Gynaecologists. PMID- 28670954 TI - Predictors of Patient Satisfaction in Pediatric Oncology. AB - OBJECTIVE: To understand key drivers of patient satisfaction in pediatric hematology/oncology. METHODS: The "top-box" scores of patient satisfaction surveys from 4 pediatric hematology/oncology practices were collected from 2012 to 2014 at an integrated Children's Health Network. One item, "Likelihood of recommending practice," was used as the surrogate for overall patient satisfaction, and all other items were correlated to this item. RESULTS: A total of 1244 satisfaction surveys were included in this analysis. The most important predictors of overall patient satisfaction were cheerfulness of practice ( r = .69), wait time ( r = .60), and staff working together ( r = .60). The lowest scoring items were getting clinic on phone, information about delays, and wait time at clinic. CONCLUSION: Families bringing their children for outpatient care in a hematology/oncology practice want to experience a cheerful and collaborative medical team. Wait time at clinic may be a key driver in the overall experience for families with children with cancer. Future work should be directed at using this evidence to drive patient experience improvement processes in pediatric hematology/oncology. PMID- 28670957 TI - XPNPEP2 is overexpressed in cervical cancer and promotes cervical cancer metastasis. AB - XPNPEP2 is a proline hydrolytic enzyme that hydrolyzes several biologically active peptides and causes a loss of substrate activity. However, its function in cancer is still unknown. Our study showed that XPNPEP2 expression was significantly upregulated in cervical cancer tissues compared with normal cervical tissues and cervical intraepithelial neoplasm tissues. Statistical analysis showed that XPNPEP2 expression was associated with the International Federation of Gynecology and Obstetrics stage and lymph node metastasis. Overexpression of XPNPEP2 in SiHa and HeLa cells promoted cell invasion and migration without affecting cell proliferation and apoptosis. Mechanistically, we found that XPNPEP2 facilitated cervical cancer cell invasion and migration by inducing epithelial-mesenchymal transition. Furthermore, we demonstrated that XPNPEP2 had significant effects on the metastasis of xenografted tumors in vivo. Collectively, our findings identify the novel function of XPNPEP2 in the metastasis of cervical cancer and suggest that XPNPEP2 could be a novel potential therapeutic target for the treatment of cervical cancer. PMID- 28670958 TI - USP17 is upregulated in osteosarcoma and promotes cell proliferation, metastasis, and epithelial-mesenchymal transition through stabilizing SMAD4. AB - USP17 is upregulated in several cancers, indicating that USP17 might play essential functions in tumor development. However, the function of USP17 in osteosarcoma is still unknown. Our work aimed to investigate the function of USP17 in osteosarcoma. We found that the expression of USP17 was upregulated in osteosarcoma tissues and cell lines, including MG-63 and U2OS. Several functional experiments, such as colony formation analysis, Cell Counting Kit-8 assay, wound healing analysis, and transwell assay, showed that USP17 promoted cell proliferation, migration, and invasion. Moreover, we found that USP17 facilitated migration and invasion through promoting epithelial-mesenchymal transition. SMAD4 has been found to regulate epithelial-mesenchymal transition, co immunopurification, and glutathione S-transferase pull-down analysis demonstrated that USP17 interacted with SMAD4. Furthermore, USP17 stabilized SMAD4 through its deubiquitinase activity. In conclusion, this study shows that USP17 enhances osteosarcoma cell proliferation and invasion through stabilizing SMAD4. PMID- 28670959 TI - Association of NFKB1 and NFKBIA gene polymorphisms with susceptibility of gastric cancer. AB - Xianyou county of Fujian province, located on the southeast coastal of China, has higher gastric cancer mortality. Chronic inflammation plays an important role in the occurrence of gastric cancer, in which the nuclear factor-kappaB signaling pathway of the inflammatory reaction begins and plays an important role in the amplification process. Studies have found that a single-nucleotide polymorphism of nuclear factor-kappaB signaling pathway molecules encoding genes is associated with gastric cancer, but the combined effect of the nuclear factor-kappaB signaling pathway gene has not been explained nor has been cardia and non-cardia gastric cancer risk factors and genetic susceptibility loci. New gastric cancer cases of the Fujian Xianyou Hospital were the research object. They were divided into cardia and non-cardia cancer in order to study a single-nucleotide polymorphism of the nuclear factor-kappaB signaling pathway important node molecules P50 and I kappa B encoding genes NFKB1 and NFKBIA by desorption ionization time of flight mass spectrometry analysis and by matrix-assisted laser mass spectrometry. The results showed that NFKB1 and NFKBIA single-nucleotide polymorphisms and gastric cancer are related and that the combined effects of polymorphisms in two genes and the NFKBIA gene monomer increased the risk of gastric cancer, and it was found that in different types of gastric cancer (the cardia and non-cardia cancer), susceptible polymorphism sites and combined effects are different. PMID- 28670960 TI - Narrative identity in female patients with remitted bipolar disorder: a negative past and a foreshortened future. AB - The present study examined narrative identity and subjective well-being in outpatients with remitted bipolar disorder (BD) and a healthy control group. Fifteen female outpatients with remitted BD and 15 healthy control participants identified past and future chapters in their life stories, gave their age for the beginning and end of each chapter, rated emotional tone as well as positive and negative self-event connections associated with the chapters, and for future chapters rated the probability of the chapter. The BD patients reported less positive emotional tone and self-event connections for past chapters, but not for future chapters. However, the patients did describe fewer future chapters with shorter temporal projection into the future, and reported lower probability of future chapters. These characteristics of chapters were related to lower subjective well-being. The study suggests that a more negative narrative identity with a foreshortened future perspective may contribute to lower subjective well being in patients with BD. PMID- 28670961 TI - Rationales and choices for the treatment of patients with NYHA class II heart failure. AB - Heart failure (HF) in the United States represents a significant burden for patients and a tremendous strain on the healthcare system. Patients receiving a diagnosis of HF can be placed into 1 of 4 New York Heart Association (NYHA) functional classifications; the greatest proportion of patients are in the NYHA class II category, which is defined as patients having a slight limitation of physical activity but who are comfortable at rest, and for whom ordinary physical activity results in symptoms of HF. Because the severity of NYHA class II HF may be perceived as mild or unalarming by this definition, the urgency to treat this type of HF may be overlooked. However, these patients are optimal candidates for active intervention because their HF is at a critical point on the disease progression continuum when untoward changes can be halted or reversed. This review discusses the physiological consequences of NYHA class II HF with reduced ejection fraction and describes recent clinical trials that have demonstrated a therapeutic benefit for patients in this population. In doing so, we hope to establish that patients with NYHA class II disease merit careful attention and to provide reassurance to the treating community that options are available for these patients. PMID- 28670963 TI - An evaluation of positive behavioural support for children with challenging behaviour in community settings. AB - This study employs a multiple baseline across individual design to describe the implementation of positive behavioural supports for seven children and adolescents in residential community settings over a period of 24 months. These individuals with intellectual disability are residing in one county with long standing challenging behaviour resulting in home breakdown and serious physical injury. Four types of outcome are presented: rates of behaviour, rates of medication, psychiatric symptomatology and quality of life (QoL). Behaviours reduced to lower levels for the majority of participants following the implementation of positive behavioural supports, and improvements were largely sustained. The use of psychotropic medications reduced or stabilized for the majority of individuals over the same period. QoL Questionnaire scores improved substantially for four participants. The results are discussed in the context of a framework for supporting children with severe challenging behaviours in the community. PMID- 28670962 TI - Peer Positive Social Control and Men's Health-Promoting Behaviors. AB - Men are generally thought to be less inclined to take care of their health. To date, most studies about men's health have focused on deficits in self-care and difficulties in dealing with this sphere of their life. The present study reframes this perspective, using a salutogenic strengths-based approach and seeking to identify variables that influence men to take care of their health, rather than neglect it. This study focuses on the association between peer positive social control and men's health behaviors, while controlling for other important individual and social determinants (sociodemographic characteristics, health self-efficacy, home neighborhood, spousal positive social control, and the restrictive emotionality norm). In a mixed-method study, 669 men answered a self reported questionnaire, and interviews were conducted with a maximum variation sample of 31 men. Quantitative results indicated that, even after controlling for sociodemographic variables and other important factors, peer positive social control was significantly associated with the six health behaviors measured in the study (health responsibility, nutrition, physical activity, interpersonal relations, stress management, and spirituality). Interview results revealed that peer positive social control influenced men's health behaviors through three different mechanisms: shared activity, being inspired, and serving as a positive role model for others. In summary, friends and coworkers could play a significant role in promoting various health behaviors among adult men in their daily life. Encouraging men to socialize and discuss health, and capitalizing on healthy men as role models appear to be effective ways to influence health behavior adoption among this specific population. PMID- 28670964 TI - Do young adults show conceptual knowledge of previous distractors? AB - Using implicit tests, older adults have been found to retain conceptual knowledge of previously seen task-irrelevant information. While younger adults typically do not show the same effect, evidence from one study [Gopie, N., Craik, F. I. M., & Hasher, L. (2011). A double dissociation of implicit and explicit memory in younger and older adults. Psychological Science, 22, 634-640. doi: 10.1177/0956797611403321 ] suggests otherwise. In that study, young adults showed greater explicit than implicit memory for previous distractors on a word fragment completion task. This was interpreted as evidence for maintaining access to previous conceptual knowledge of the distractors. Here, we report two failures to replicate that original finding, followed by a third study designed to test directly whether young adults use conceptual-level information that was previously irrelevant. Our findings agree with others that young adults show weak to no evidence of conceptual knowledge of previously irrelevant information. PMID- 28670965 TI - Short Communication: False Recent Ratio of the Limiting-Antigen Avidity Assay and Viral Load Testing Algorithm Among Cameroonians with Long-Term HIV Infection. AB - Current serological assays that are used for cross-sectional HIV incidence estimation have been shown to misclassify individuals with chronic infection. Limited information exists on the performance of cross-sectional incidence assays in Central Africa. HIV-positive individuals from Cameroon who were infected for at least 1 or 2 years were evaluated to determine the false recent ratio (FRR) of a two-assay algorithm, which includes the Limiting Antigen Avidity (LAg-Avidity) assay (normalized optical density units, ODn <1.5) and HIV viral load (>1000 copies/ml). The subject-level FRR was 5.3% (95% confidence interval [CI], 2.1 10.5) for individuals infected for >=1 year and 3.9% (95% CI, 0.8-11.0) for individuals infected for >=2 years. These data suggest that the LAg-Avidity plus viral load incidence algorithm may overestimate HIV incidence rates in Central Africa. PMID- 28670967 TI - Prevalence and factors associated with alcohol drinking among HIV and tuberculosis co-infected patients in Dar es Salaam, Tanzania. AB - There is scarcity of information on the burden of alcohol use among people living with HIV in Tanzania despite the high burden of HIV. We examined the prevalence and factors associated with alcohol use among HIV and tuberculosis (TB) co infected patients in fourteen clinics with highest notification of TB in Dar es Salaam, Tanzania, between October 2010 and December 2011. Proportions were used to describe the prevalence and pattern of alcohol use. Logistic regression was used to assess the association of various participant characteristics with alcohol use. Out of the 515 participants, 38 (7.4%) were current alcohol drinkers, 183 (35.5%) were ex-drinkers and the rest, 294 (57.1%) denied ever drinking alcohol. Approximately, 15% of past and current drinkers were classified as heavy drinkers. Patients with normal BMI, cigarette smokers, and those with higher income were more likely to be drinkers. Similarly, compared to civil servants, those in petty trade and other occupations were more likely to be drinkers. We concluded that, the level of current alcohol use among HIV positive people receiving pulmonary TB treatment in this population was low. Nevertheless, alcohol use screening and assessment should be added as an integral part of service provision in HIV clinics given the effect of alcohol on health outcomes among HIV positive patients. PMID- 28670966 TI - Malnutrition in HIV-Infected Children Is an Indicator of Severe Disease with an Impaired Response to Antiretroviral Therapy. AB - This observational study aimed to describe immunopathogenesis and treatment outcomes in children with and without severe acute malnutrition (SAM) and HIV infection. We studied markers of microbial translocation (16sDNA), intestinal damage (iFABP), monocyte activation (sCD14), T-cell activation (CD38, HLA-DR) and immune exhaustion (PD1) in 32 HIV-infected children with and 41 HIV-infected children without SAM prior to initiation of antiretroviral therapy (ART) and cross-sectionally compared these children to 15 HIV-uninfected children with and 19 HIV-uninfected children without SAM. We then prospectively measured these markers and correlated them to treatment outcomes in the HIV-infected children at 48 weeks following initiation of ART. Plasma levels of 16sDNA, iFABP and sCD14 were measured by quantitative real time PCR, ELISA and Luminex, respectively. T cell phenotype markers were measured by flow cytometry. Multiple regression analysis was performed using generalized linear models (GLMs) and the least absolute shrinkage and selection operator (LASSO) approach for variable selection. Microbial translocation, T cell activation and exhaustion were increased in HIV-uninfected children with SAM compared to HIV-uninfected children without SAM. In HIV-infected children microbial translocation, immune activation, and exhaustion was strongly increased but did not differ by SAM-status. SAM was associated with increased mortality rates early after ART initiation. Malnutrition, age, microbial translocation, monocyte, and CD8 T cell activation were independently associated with decreased rates of CD4% immune recovery after 48 weeks of ART. SAM is associated with increased microbial translocation, immune activation, and immune exhaustion in HIV-uninfected children and with worse prognosis and impaired immune recovery in HIV-infected children on ART. PMID- 28670970 TI - The effect of monocular deprivation on unihemispheric sleep in light and dark incubated/reared domestic chicks. AB - Unihemispheric sleep is an aspect of the cerebral lateralization of certain species of birds. During sleep, domestic chicks (Gallus gallus) show brief periods of monocular-unihemispheric sleep (Mo-Un sleep): one eye is open and the connected hemisphere is awaken while the other eye remains shut and the connected hemisphere sleeps. The time spent in Mo-Un sleep was investigated following a brief monocular deprivation (MD) in chicks hatched from eggs incubated in darkness and reared in light (D-L), incubated in light and reared in light (L-L) and incubated in darkness and reared in darkness (D-D). The right eye occluded for 12 h in half of chicks and the left eye in the other half. At the end of MD, the Mo-Un sleep was recorded. The effect of MD (total time and time bias) prevailed in determining the pattern of Mo-Un sleep. Chicks showed more time sleeping with the eye/hemisphere that was in control of visual behaviour during MD and opened more time the eye and awake the hemisphere visually deprived. The Mo-Un pattern was not influenced by incubation, rearing, symmetry/asymmetry of visual pathways and imprinting thereby indicating that Mo-Un sleep pattern depends only on the kind of visual experience during wakefulness. PMID- 28670971 TI - International clinical volunteering in Tanzania: A postcolonial analysis of a Global Health business. AB - This article traces how scarcities characteristic of health systems in low-income countries (LICs), and increasing popular interest in Global Health, have inadvertently contributed to the popularisation of a specific Global Health business: international clinical volunteering through private volunteer placement organisations (VPOs). VPOs market neglected health facilities as sites where foreigners can 'make a difference', regardless of their skill set. Drawing on online investigation and ethnographic research in Tanzania over four field seasons from 2011 to 2015, including qualitative interviews with 41 foreign volunteers and 90 Tanzanian health workers, this article offers a postcolonial analysis of VPO marketing and volunteer action in health facilities of LICs. Two prevalent postcolonial racialised tropes inform both VPO marketing and foreign volunteers' discourses and practices in Tanzania. The first trope discounts Tanzanian expertise in order to envision volunteers in expert roles despite lacking training, expertise, or contextual knowledge. The second trope envisions Tanzanian patients as so impoverished that insufficiently trained volunteer help is 'better than nothing at all'. These two postcolonial racialised tropes inform the conceptual work undertaken by VPO marketing schemes and foreign volunteers in order to remake Tanzanian health professionals and patients into appropriate and justifiable sites for foreign volunteer intervention. PMID- 28670972 TI - Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis. AB - Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease. PMID- 28670973 TI - Cellular mechanisms underlying cardiac engraftment of stem cells. AB - INTRODUCTION: Over the past decade, it has become clear that long-term engraftment of any ex vivo expanded cell product transplanted into injured myocardium is modest and all therapeutic regeneration is mediated by stimulation of endogenous repair rather than differentiation of transplanted cells into working myocardium. Given that increasing the retention of transplanted cells boosts myocardial function, focus on the fundamental mechanisms limiting retention and survival of transplanted cells may enable strategies to help to restore normal cardiac function. Areas covered: This review outlines the challenges confronting cardiac engraftment of ex vivo expanded cells and explores means of enhancing cell-mediated repair of injured myocardium. Expert opinion: Stem cell therapy has already come a long way in terms of regenerating damaged hearts though the poor retention of transplanted cells limits the full potential of truly cardiotrophic cell products. Multifaceted strategies directed towards fundamental mechanisms limiting the long-term survival of transplanted cells will be needed to enhance transplanted cell retention and cell-mediated repair of damaged myocardium for cardiac cell therapy to reach its full potential. PMID- 28670974 TI - Cutaneous leucocytoclastic vasculitis in visceral leishmaniasis. PMID- 28670975 TI - Carbapenem resistant Klebsiella pneumoniae isolated from bloodstream infection: Indian experience. AB - Increased incidence of multidrug resistant (MDR) Gram negative infection has resulted in high rates of morbidity and mortality. Klebsiella pneumoniae is one of the commonest MDR pathogens causing bacteraemia with limited therapeutic options such as colistin and tigecycline. Present study focused on molecular characterisation of MDR K. pneumoniae from bloodstream infection and their clinical outcome. A total of 115 K. pneumoniae from January 2015 to September 2016 were included in the study which comprised of phenotypically identified ESBL and carbapenem resistant (CR) isolates. Multiplex PCR was performed for detection of resistance genes encoding beta-lactam resistance. This includes blaSHV, blaTEM, blaVEB, blaPER, blaCTX-M, blaDHA, blaCIT, blaFOX, blaACC, blaACT, blaNDM, blaOXA48-like, blaVIM and blaKPC. Co-expression of blaSHV, blaTEM and blaCTX-M was predominant with 64% (74/115) prevalence. CTX-M-1 was the variant produced by all the isolates producing CTX-M. AmpC was uncommon, seen in 5% of the isolates (6/115). Among the carbapenemases co-expression of blaNDM and blaOXA48-like was observed in 28% (32/115) and blaNDM in 19% (22/115) and blaOXA48-like in 13% (15/115). blaKPC was absent. Overall mortality was observed to be 57% (64/113) and mortality among CR K. pneumoniae (Kp) was 68% (50/73). The antibiotics that were administered for treatment of CRKp were colistin in 90% (66/73) and tigecycline in 7% (5/73) and in 99% combined with meropenem (72/73). Prevalence of community acquired and nosocomial infections were 5% (4/73) and 95% (69/73) respectively among CRKp. Minocycline and meropenem susceptibilities were comparable and hence minocycline can be a carbapenem sparing agent. The resistance to beta-lactam antibiotics is steadily increasing and are plasmid mediated, their containment in healthcare setting is a challenge. PMID- 28670976 TI - A novel approach to assess clinical competence of postgraduate year 1 surgery residents. AB - BACKGROUND: An increased demand for accountability and transparency in medicine have initiated a shift toward a more objective and standardized approach for postgraduate medical training. OBJECTIVE: To develop and evaluate an objective method to assess clinical competence of postgraduate year 1 surgery residents. DESIGN: Thirty-one postgraduate year 1 surgery residents, who had been trained in the Surgical School of Peking University First Hospital for one year, participated in an objective structured clinical examination as a final assessment of their clinical competence. A test station of irregular wound repair (debridement and suture) was specially designed to test the residents' surgical integrative competence in a complex-trauma treatment procedure. A modified global rating scale, in combination with wound area measurement, was applied to evaluate residents' surgical performance. The validity of the subjective global rating scale was evaluated by the objective measurement results from the software. RESULTS: The global rating scale score had no obvious correlation with the area of the removed tissue and the residual wound area after the suture. There was significant difference in the debridement time and the residual wound area between 0-3 and >3 total stitches. There were significant differences in the area of the removed tissue between 0 and 1-2 grey stitches and 0 and 3-4 grey stitches, and in the residual wound area after suture between 0 and 3-4 grey stitches and 1-2 and 3-4 grey stitches. CONCLUSIONS: An irregular wound repair procedure could be an effective method to assess the integrative competence of surgery residents. The training for surgical thinking in the early stage of junior residents needs to be strengthened. The entire measurement process was more complex and time-consuming than expected. The possibility of measurement by simply counting the numbers of the key spots might be explored in the future. ABBREVIATIONS: ACS/APDS American College of Surgeons/Association of Program Directors in Surgery; GRS Global rating scale; LSD-T Least significant difference test; OSATS Objective structured assessment of technical skills; OSCE Objective structured clinical examination; PBT Proficiency based training; PGY1 Postgraduate Year 1. PMID- 28670977 TI - Ventricular volumes across stages of schizophrenia and other psychoses. AB - OBJECTIVE: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis. METHODS: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years). RESULTS: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia ( p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend ( p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis schizophrenia converters = -18.5%). CONCLUSION: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes. PMID- 28670978 TI - A novel BLK-induced tumor model. AB - B-lymphoid tyrosine kinase (BLK) is a non-receptor tyrosine kinase belonging to the SRC family kinases. BLK is known to be functionally involved in B-cell receptor signaling and B-cell development. New evidence suggests that B-lymphoid tyrosine kinase is ectopically expressed and is a putative oncogene in cutaneous T-cell lymphoma and other T-cell malignancies. However, little is known about the role of BLK in lymphomagenesis, and the oncogenic function seems to depend on the cellular context. Importantly, BLK is also ectopically expressed in other hematological and multiple non-hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells expressing wild type BLK nor non transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK-driven lymphomagenesis and screening of novel BLK inhibitors in vivo. PMID- 28670979 TI - DEK proto-oncogene is highly expressed in astrocytic tumors and regulates glioblastoma cell proliferation and apoptosis. AB - Astrocytic tumors are the most common neuroepithelial neoplasms with high relapse rate after surgery. Understanding the molecular mechanisms for astrocytic tumorigenesis and progression will lead to early diagnosis and effective treatment of astrocytic tumors. The DEK mRNA and protein expression in normal brain tissues and astrocytic tumors was quantified. To investigate DEK functions in tumor cells, DEK gene was silenced with siRNA in U251 glioblastoma cells. Cell proliferation, cell cycle and apoptosis were then measured. The expression and activity of key genes that regulate cell proliferation and apoptosis were also measured. We identified DEK as a high expressed gene in astrocytic tumor tissues. DEK expression level was positively correlated with the pathological grade of astrocytic tumors. Gene silencing of DEK in U251 glioblastomas inhibited cell proliferation and blocked cells at G0/G1 phase of cell cycle. DEK depletion also induced cell apoptosis, with up-regulated expression of P53 and P21 and down regulated expression of Bcl-2 and C-myc. The Caspase-3 activity in U251 cells was also significantly increased after knockdown. Our results provided evidences that DEK regulates proliferation and apoptosis of glioblastomas. DEK gene silencing may induce apoptosis through P53-dependent pathway. Our data indicated DEK plays multiple roles to facilitate tumor growth and maintenance. It can be used as a potential target for astrocytic tumor diagnosis and gene therapy. PMID- 28670980 TI - Black Pastors' Views on preaching about sex: barriers, facilitators, and opportunities for HIV prevention messaging. AB - OBJECTIVES: Despite the disproportionately high rates of heterosexually transmitted HIV infection among US Blacks and ongoing need for effective inexpensive behavioral interventions, the use of sermons as an HIV prevention tool in Black churches has received little research attention. The Black church plays an important role in Black communities and is a potential ally in development and delivery of sexual risk prevention messages. The objective of this study was to examine Black pastors' thoughts about whether sermons should address issues related to heterosexual relationships - and the barriers and facilitators to discussing these topics in a sermon setting. DESIGN: We conducted in-depth semi-structured, individual interviews among 39 pastors of Black churches in North Carolina and analyzed the interview data using thematic analysis strategies based on grounded theory. RESULTS: Pastors expressed widely ranging opinions, especially about discussion of condom use, but generally agreed that sermons should discuss marriage, abstinence, monogamy, dating, and infidelity - behaviors that impact sexual networks and HIV transmission. The major barriers to incorporation of these subjects into sermons include the extent to which a concept undermines their religious beliefs and uncertainty about how to incorporate it. However, scriptural support for a prevention message and the pastor's perception that the message is relevant to the congregation facilitate incorporation of related topics into sermons. CONCLUSIONS: These findings have implications for the potential utility of sermons as an HIV prevention tool and suggest that it is possible for public health professionals and pastors of Black churches to form partnerships to develop messages that are consonant with pastors' religious convictions as well as public health recommendations. PMID- 28670981 TI - Keep an eye out: A rare case of acute-onset Charles Bonnet Syndrome after Stanford type A aortic dissection repair surgery. AB - Charles Bonnet Syndrome describes the triad of complex visual hallucinations secondary to ophthalmic pathology in psychologically normal people. We present a rare case of acute-onset Charles Bonnet Syndrome following cardiac surgery that resulted in profound loss of visual acuity in both eyes with characteristic visual hallucinations that were initially mistaken for delirium. Computed tomography of the brain revealed bilateral occipital infarcts, providing the substrate for Charles Bonnet Syndrome. A high index of suspicion should be maintained in cognitively intact patients with visual loss who are also experiencing visual hallucinations to ensure prompt diagnosis and management of this often overlooked condition. PMID- 28670982 TI - Meeting the demand of the future: a curriculum to stimulate interest in careers in primary care internal medicine. AB - BACKGROUND: There is a growing need for primary care physicians, but only a small percentage of graduating medical students enter careers in primary care. PURPOSE: To assess whether a Primary Care Intraclerkship within the Medicine clerkship can significantly improve students' attitudes by analyzing scores on pre- and post tests. METHODS: Students on the Medicine clerkship at the University of Massachusetts Medical School participated in full-day 'intraclerkships',to demonstrate the importance of primary care and the management of chronic illness in various primary care settings. Pre-and post-tests containing students' self reported, five-point Likert agreement scale evaluations to 26 items (measuring perceptions about the roles of primary care physicians in patient care and treatment) were collected before and after each session. Eleven intraclerkships with 383 students were held between June 2010 and June 2013. Responses were analyzed using the GLM Model Estimate. RESULTS: Results from the survey analysis showed significantly more positive attitudes toward primary care in the post tests compared to the pre-tests. Students who were satisfied with their primary care physicians were significantly more likely to show an improvement in post test attitudes toward primary care in the areas of physicians improving the quality of patient care, making a difference in overall patient health, finding primary care as an intellectually challenging field, and in needing to collaborate with specialists. Older students were more likely than younger students to show more favorable answers on questions concerning the relative value of primary care vs. specialty care. CONCLUSIONS: A curriculum in Primary Care Internal Medicine can provide a framework to positively influence students' attitudes toward the importance of primary care, and potentially to influence career decisions to enter careers in Primary Care Internal Medicine. Ensuring that medical students receive excellent primary care for themselves can also positively influence attitudes toward primary care. PMID- 28670983 TI - Giant isolated transcranial Rosai-Dorfman disease with diffuse involvement of nasal and paranasal tissues: case report and literature review. AB - Rosai-Dorfman disease (RDD) is an uncommon systemic histioproliferative disease process characterized by sinus histiocytosis with massive lymphadenopathy, and isolated transcranial RDD (ITRDD) is extremely rare. We report a patient with giant ITRDD with diffuse involvement of nasal and paranasal tissues, showing favorable response to postoperative steroid therapy. PMID- 28670984 TI - [Adherence to medication after myocardial infarction and its impact on outcome: a registry-based analysis from the Hungarian Myocardial Infarction Registry]. AB - INTRODUCTION AND AIM: The aim was to study the patients' adherence to some evidence-based medication (statins, beta blockers, platelet and RAS inhibitors) after suffering a myocardial infarction, and its impact on the outcome. METHOD: Retrospective observational cohort study was carried out from the data of the Hungarian Myocardial Infarction Registry between January 1, 2013, and December 31, 2014. 14,843 patients were alive at the end of hospital treatment, from them, those who had no myocardial infarction or death until 180 days were followed for one year. The adherence was defined as the proportion of time from the index event to the endpoint (or censoring) covered with prescription fillings. The endpoint was defined as death or reinfarction. Information on filling prescriptions for statins, platelet aggregation inhibitors, beta blockers and ARB/ACEI-inhibitors were obtained. Multivariate regression was used to model adherence and survival time. RESULTS: Good adherence (?>80%) to clopidogrel, statins, beta blockers, aspirin and ARB/ACEI was found in 64.9%, 54.4%, 36.5%, 31.7% and 64.0%, respectively. Patients treated with PCI during the index hospitalization had higher adherence to all medication (all p<0.01), except for beta-blocker (p = 0.484). Multivariate analysis confirmed that adherence to statins, to clopidogrel and ARB/ACEI-inhibitors was associated with 10.1% (p<0.0001), 10.4% (p = 0.0002) and 15.8% (p<0.0001) lower hazard of endpoint respectively for 25% points increase in adherence, controlling for age, sex, performing of PCI, 5 anamnestic data and date of index event. Adherence to aspirin and beta blockers was not significantly associated with the hazard. CONCLUSION: Higher adherence to some evidence-based medications was found to be associated with improved long term prognosis of the patients. Orv Hetil. 2017; 158(27): 1051-1057. PMID- 28670985 TI - [Changes in diagnostic criteria of thrombotic microangiopathy after stem cell transplantation]. AB - Hematopoietic stem cell transplantation associated thrombotic microangiopathy is a multifactorial complication, and has variable incidence in study populations due to different diagnostic criteria. The diversity of activity parameters, like elevated laktat-dehidrogenaz, hematological parameters and kidney function are not specific variables after stem cell transplantation. Dysregulation of the classical and alternative pathway can play an important role in the pathomechanism of thrombotic microangiopathy, but the understanding of the role of complement activation under transplantation conditions requires further investigation. Monitoring of complement parameters, including terminal complement pathway activation complex during transplantation may help physicians to improve diagnostic strategy, to evaluate therapeutical options and to predict and follow up efficacy of complement blockade methods and supportive therapy. This review focuses on the development of diagnostic criteria and therapeutical options in thrombotic microangiopathy, and presents some preliminary findings while using different diagnostic criteria in pediatric patients. Orv Hetil. 2017; 158(27): 1043-1050. PMID- 28670986 TI - [Periprosthetic joint infection caused by Rhodococcus equi. Case report]. AB - Rhodococcus equi is a rare pathogen in humans causing infections mostly in immunocompromised hosts. We present the first case of periprosthetic joint infection caused by Rhodococcus equi. An 88-year-old male patient was referred to our clinic with a history of fever and right hip pain. The patient had multiple hip surgeries including total joint arthroplasty and revision for aseptic loosening on the right side. He was immunocompetent, but his additional medical history was remarkable for diabetes mellitus, diabetic nephropathy and stroke with hemiplegia resulting in immobilization. Radiography showed stable components, joint aspirate yielded Rhodococcus equi. Irrigation and debridement was proposed, but the patient refused any surgical intervention. Therefore antibiotic therapy was administered. At the last follow-up the patient is free of complaints but the C-reactive protein level is still elevated. This case illustrates the possible role of Rhodococcus equi in medical device-associated infections. Orv Hetil. 2017; 158(27): 1071-1074. PMID- 28670987 TI - [Miscellaneous]. PMID- 28670988 TI - [The relationship of attachment features and multi-impulsive symptoms in eating disorders]. AB - INTRODUCTION: Attachment dysfunctions determine borderline personality disorder, which is a frequent background factor of multi-impulsivity; however, the relationship between attachment and multi-impulsive eating disorders is almost unexplored. AIM: To compare attachment features of multi-impulsive and classical eating disorder patients with individuals without eating disorders, and to test attachment as a predictor of multi-impulsivity. METHOD: A cross-sectional survey (148 females, mean age: 30.9 years) investigated maternal, paternal and adult attachment, depression, anxiety, eating disorder and multi-impulsive symptoms in these groups. RESULTS: Altogether 41.3% of the individuals without eating disorders, 17.6% of classical and 11.8% of multi-impulsive eating disorder patients had secure attachment. Multi-impulsive patients had the most severe eating disorder symptoms (F(2) = 17.733) and the lowest paternal care (F(2) = 3.443). Preoccupied and fearful attachment explained 14.5% of multi-impulsive symptoms; however, with adjustment for depression only latter one remained the predictor of multi-impulsivity (t = 5.166, p<0.01). CONCLUSION: Multi-impulsives are a distinct subgroup of eating disorder patients from the aspects of both symptoms and attachment. Handling their negative moods may hold therapeutic potentials. Longitudinal studies are required to investigate the therapeutic value of paternal care, attachment preoccupation and fearfulness. Orv Hetil. 2017; 158(27): 1058-1066. PMID- 28670989 TI - [Sudden cardiac death due to sarcoidosis. Case report]. AB - Sarcoidosis is a systemic granulomatous disease of unknown aetiology, which is characterized by bilateral hilar lymphadenopathy and pulmonary disease. Clinically detected cardiac involvement occurs in 5% of sarcoid patients, although cardiac manifestations are discovered in 25% of the cases at autopsy. Sarcoid heart disease frequently causes atrioventricular block. The authors present the case of a 44-year-old man with bradycardia. On admission, second degree Mobitz II, then third degree atrioventricular block was diagnosed. Coronarography showed normal coronary arteries. 2.5 years following artificial Biotronik Entovis DR type pacemaker implantation, sudden cardiac death occurred. Autopsy revealed sarcoidosis with cardiac, pulmonary, splenic, renal and lymph node involvement. In case of young or middle-aged patients with atrioventricular block, it is best to search for other causes if the most common coronary origin can be excluded. Orv Hetil. 2017; 158(27): 1067-1070. PMID- 28670990 TI - Compressed Sensing for Elastography in Portable Ultrasound. AB - Portable ultrasound is recently emerging as a new medical imaging modality featuring high portability, easy connectivity, and real-time on-site diagnostic ability. However, it does not yet provide ultrasound elastography function that enables the diagnosis of malignant lesions using elastic properties. This is mainly due to the limitations of hardware performance and wireless data transfer speed for processing the large amount of data for elastography. Therefore, data transfer reduction is one of the feasible solutions to overcome these limitations. Recently, compressive sensing (CS) theory has been rigorously studied as a means to break the conventional Nyquist sampling rate and thus can significantly decrease the amount of measurement signals without sacrificing signal quality. In this research, we implemented various CS reconstruction frameworks and comparatively evaluated their reconstruction performance for realizing ultrasound elastography function on portable ultrasound. Combinations of three most common model bases (Fourier transform [FT], discrete cosine transform [DCT], and wave atom [WA]) and two reconstruction algorithms (L1 minimization and block sparse Bayesian learning [BSBL]) were considered for CS frameworks. Echoic and elastography phantoms, were developed to evaluate the performance of CS on B-mode images and elastograms. To assess the reconstruction quality, mean absolute error (MAE), signal-to-noise ratio (SNRe), and contrast-to noise ratio (CNRe) were measured on the B-mode images and elastograms from CS reconstructions. Results suggest that CS reconstruction adopting BSBL algorithm with DCT model basis can yield the best results for all the measures tested, and the maximum data reduction rate for producing readily discernable elastograms is around 60%. PMID- 28670999 TI - Biological variation of holotranscobalamin and cobalamin in healthy individuals. AB - Data on biological variation for cobalamin and holotranscobalamin (holoTC) are limited. The aim of this study was to determine within-subject (CVI) and between subject (CVG) biological variations for these analytes in a healthy population. We collected blood samples from 15 healthy volunteers (12 women and three men, 22 66 years) on the same weekday for 10 consecutive weeks. Serum samples were stored at -80 degrees C until analysis in duplicate in a single analytical run. The CVI and CVG were estimated by nested ANOVA. The CVI (95% CI) for cobalamin and holoTC was 6.7% (5.7-7.7) and 13.0% (11.5-15.0), respectively. The corresponding CVG was 24.1% (16.4-36.0) and 24.6% (16.3-37.7). The analytical variation (CVA) (95% CI) was 3.5% (3.2-4.0) for cobalamin and 2.4% (2.1-2.6) for holoTC. The index of individuality (II) was low (<0.6) for both cobalamin and holoTC and the reference change value (RCV) was 20.1% for cobalamin and 36.6% for holoTC. Our study describes the components of biological variation of cobalamin and holoTC in a healthy population, contributing to a better clinical interpretation of these biomarkers. PMID- 28671000 TI - Brain-derived neurotrophic factor serum and plasma levels in the treatment of acute schizophrenia with olanzapine or risperidone: 6-week prospective study. AB - Antipsychotics have been the mainstay of the treatment of schizophrenia, and their potential role in neuroprotection could be related to brain-derived neurotrophic factor (BDNF). So far different effects on both serum and plasma levels of BDNF were reported related to the various antipsychotic treatments. Aim of this study was to investigate the influence of olanzapine or risperidone on both plasma and serum levels of BDNF in patients with acute schizophrenia. For 50 participants with acute episode of schizophrenia both plasma and serum BDNF, along with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression scale, were assessed pretreatment and post treatment - after 6 weeks of either risperidone or olanzapine. Results show that a weak correlation between pretreatment plasma and serum levels of BNDF was found no longer significant after 6 weeks of treatment. Antipsychotics, olanzapine and risperidone showed no significant effect on post treatment plasma and serum levels of BDNF. Pretreatment plasma level of BDNF and PANSS positive subscale were positively correlated. Post treatment serum level of BDNF and Clinical Global Impression were negatively correlated. In conclusion, plasma and serum BDNF levels could be different markers to some extent with regard to clinical symptoms, response to therapy and outcome. The interrelation between serum and plasma BDNF should be established in further studies. PMID- 28671001 TI - Between pharmaceutical patents and European patients: is a compromise still possible? AB - INTRODUCTION: Pharmaceutical regulation has always attempted to balance the public health objective to make safe and effective drugs available for patients while providing commercial incentives through patents. Here we discuss whether it is still possible to find a balance between the incentives on the supply side and the regulatory framework on the demand side. Areas covered: The current regulatory framework on pharmaceutical exclusivity has been harshly criticized by many experts, arguing about whether it is still fit for public purposes and needs. Here we envisage a different scenario without 'revolutionizing' the whole present system. The main radical change should concern the present management of pharmaceutical patents by introducing a specific agency dedicated to them. Secondly, specific pharmaceutical patents could be restricted to compounds for one (or more) declared indication(s). Thirdly, pharmaceutical patents should be kept only for compounds that start a first clinical trial within five years from the granting date. Expert opinion: We think it is time to reconsider the regulation of pharmaceutical patents in the light of their relevance in terms of public health. New models of enhancing research investments are required for long term sustainability of public pharmaceutical expenditure and the EU can still play a leading role. PMID- 28671002 TI - Offending, Adjudication, and Outcome Patterns of Solo Male, Solo Female, and Partnered Mass Murderers. AB - Research on mass murder is limited due to differences in definitions (particularly with respect to victim count), as well as categorizations based on motive. These limitations restrict our understanding of the offending, adjudication, and outcome patterns of these offenders and can obscure potential underlying similarities to comparable types of offenders (e.g., lone actors or terrorists). To address some of these limitations, this research study, which includes an international sample of 434 cases (455 total offenders), uses descriptive and empirical analyses of solo male, solo female, and partnered mass murderers (teams of two or more) to explore offending, adjudication, and outcome patterns among these different types offenders. While the results from this research study support much previous mass murder research, the findings also emphasize the importance of large international sample sizes, objective categorizations, and the use of empirically based analyses to further advance our understanding of these offenders. PMID- 28671003 TI - Effective antigen delivery via dual entrapment in erythrocytes and autologous plasma beads. AB - Fibrin-based polymeric systems have now emerged as efficient carriers of drugs, growth factors, genes, and cells. Earlier, we have reported fibrin-based plasma beads (PB), prepared from clotted whole plasma, as an efficient system for the controlled release of entrapped therapeutics. In the present study, we investigate the dual entrapment in erythrocytes and PB, as potential particulate antigen delivery system in rabbit and mice, with yeast invertase as the model antigen. Preparations used for immunisation include- invertase entrapped in erythrocytes, the same further entrapped in PB, and crosslinked with glutaraldehyde. While route of administration of the antigen only moderately affected the antibody titres, strategies slowing its release from PB increased the antibody titres remarkably, especially after a booster. Entrapment of erythrocytes entrapped antigen in the PB and further crosslinking with glutaraldehyde also resulted in significant alterations of IgG1/IgG2a ratio, indicating a shift towards humoral response. The elicited immune response was more marked in rabbits as compared to that in mice. Considering the well-known toxicity of the adjuvant, comparable antibody titres induced by the erythrocyte plasma bead system was encouraging in the induction of humoral immunity. PMID- 28671018 TI - GPER-1/GPR30 a novel estrogen receptor sited in the cell membrane: therapeutic coupling to breast cancer. AB - INTRODUCTION: Breast cancer is clinically classified as 'estrogen-positive' when at least 1% of cancer cells stain for the estrogen receptor alpha (ERalpha). However, recent research on both basic and clinical aspects of breast cancer suggests that GPER-1 (G protein-coupled estrogen receptor-1) may have an important role in breast cancer. Areas covered: This review provides a comprehensive and systematic literature search on GPER-1. We have focused on the role of GPER-1 in breast cancer and on resistance to endocrine therapy, an unsolved clinical issue still under discussion. Expert opinion: The discovery of GPER-1 as a novel estrogen receptor is unique and the signaling pathways activated by its stimulation, when compared to the classical nuclear ERalpha, indicate a potential role of GPER-1 in the genesis and mechanisms of drug resistance in breast cancer. Tumors expressing ERalpha represent the largest group of breast cancer patients indicating that more women eventually die from ERalpha-positive breast tumors than from other more malignant breast cancer subtypes such as HER2-positive and the triple negative groups. It is important to develop new strategies on endocrine therapy with regard to ERalpha and GPER-1 receptors to achieve innovative successful therapeutic tools. PMID- 28671019 TI - Identification and prognostic value of anterior gradient protein 2 expression in breast cancer based on tissue microarray. AB - Breast cancer has attracted substantial attention as one of the major cancers causing death in women. It is crucial to find potential biomarkers of prognostic value in breast cancer. In this study, the expression pattern of anterior gradient protein 2 in breast cancer was identified based on the main molecular subgroups. Through analysis of 69 samples from the Gene Expression Omnibus database, we found that anterior gradient protein 2 expression was significantly higher in non-triple-negative breast cancer tissues compared with normal tissues and triple-negative breast cancer tissues (p < 0.05). The data from a total of 622 patients from The Cancer Genome Atlas were analysed. The data from The Cancer Genome Atlas and results from quantitative reverse transcription polymerase chain reaction also verified the anterior gradient protein 2 expression pattern. Furthermore, we performed immunohistochemical analysis. The quantification results revealed that anterior gradient protein 2 is highly expressed in non triple-negative breast cancer (grade 3 excluded) and grade 1 + 2 (triple-negative breast cancer excluded) tumours compared with normal tissues. Anterior gradient protein 2 was significantly highly expressed in non-triple-negative breast cancer (grade 3 excluded) and non-triple-negative breast cancer tissues compared with triple-negative breast cancer tissues (p < 0.01). In addition, anterior gradient protein 2 was significantly highly expressed in grade 1 + 2 (triple-negative breast cancer excluded) and grade 1 + 2 tissues compared with grade 3 tissues (p < 0.05). Analysis by Fisher's exact test revealed that anterior gradient protein 2 expression was significantly associated with histologic type, histological grade, oestrogen status and progesterone status. Univariate analysis of clinicopathological variables showed that anterior gradient protein 2 expression, tumour size and lymph node status were significantly correlated with overall survival in patients with grade 1 and 2 tumours. Cox multivariate analysis revealed anterior gradient protein 2 as a putative independent indicator of unfavourable outcomes (p = 0.031). All these data clearly showed that anterior gradient protein 2 is highly expressed in breast cancer and can be regarded as a putative biomarker for breast cancer prognosis. PMID- 28671020 TI - The Wnt/beta-catenin and PI3K/Akt signaling pathways promote EMT in gastric cancer by epigenetic regulation via H3 lysine 27 acetylation. AB - In this study, we investigated the underlying mechanism of the phosphoinositide 3 kinase/Akt- and Wnt/beta-catenin-mediated promotion of epithelial-to-mesenchymal transition by epigenetic regulation of histone acetylation in gastric cancer. First, we used immunohistochemistry to detect the expression of phosphorylated Akt, phosphorylated glycogen synthase kinase 3 beta, and beta-catenin in gastric cancer tissues and adjacent tissues. In addition, we confirmed that the phosphoinositide 3-kinase/Akt and Wnt/beta-catenin signaling pathways were correlated with tumorigenesis, progression, and maintenance of gastric cancer using the phosphoinositide 3-kinase inhibitor LY294002 and an inhibitor of the beta-catenin/TCF4 complex, FH535. Epithelial-to-mesenchymal transition-related gene expression was measured by western blotting and quantitative real-time polymerase chain reaction assays. Furthermore, we detected the acetylation of histone H3 lysine 4 and lysine 27 using the FH535 and LY294002 inhibitors at different concentrations for 24 and 48 h. Finally, chromatin immunoprecipitation quantitative polymerase chain reaction was performed to detect the specific binding of H3K27ac to the promoter of the epithelial-to-mesenchymal transition related factor, Twist. Taken together, abnormal activation of the phosphoinositide 3-kinase/Akt and Wnt/beta-catenin signaling pathway was correlated with the gastric cancer progression and contributed to epithelial-to mesenchymal transition regulation by controlling histone acetylation. PMID- 28671021 TI - Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool. AB - Labile iron pool is a cellular source of ions available for Fenton reactions resulting in oxidative stress. Living organisms avoid an excess of free irons by a tight control of iron homeostasis. We investigated the altered expression of iron regulatory proteins and iron discrimination in the development of liver fluke-associated cholangiocarcinoma. Additionally, the levels of labile iron pool and the functions of transferrin receptor-1 on cholangiocarcinoma development were also identified. Iron deposition was determined using the Prussian blue staining method in human cholangiocarcinoma tissues. We investigated the alteration of iron regulatory proteins including transferrin, transferrin receptor-1, ferritin, ferroportin, hepcidin, and divalent metal transporter-1 in cholangiocarcinoma tissues using immunohistochemistry. The clinicopathological data of cholangiocarcinoma patients and the expressions of proteins were analyzed. Moreover, the level of intracellular labile iron pool in cholangiocarcinoma cell lines was identified by the RhoNox-1 staining method. We further demonstrated transferrin receptor-1 functions on cell proliferation and migration upon small interfering RNA for human transferrin receptor 1 transfection. Results show that Iron was strongly stained in tumor tissues, whereas negative staining was observed in normal bile ducts of healthy donors. Interestingly, high iron accumulation was significantly correlated with poor prognosis of cholangiocarcinoma patients. The expressions of iron regulatory proteins in human cholangiocarcinoma tissues and normal liver from cadaveric donors revealed that transferrin receptor-1 expression was increased in the cancer cells of cholangiocarcinoma tissues when compared with the adjacent normal bile ducts and was significantly correlated with cholangiocarcinoma metastasis. Labile iron pool level and transferrin receptor-1 expression were significantly increased in KKU-214 and KKU-213 when compared with cholangiocyte cells (MMNK1). Additionally, the suppression of transferrin receptor-1 expression significantly decreased intracellular labile iron pool, cholangiocarcinoma migration, and cell proliferation when compared with control media and control small interfering RNA. In Conclusion, high expression of transferrin receptor-1 resulting in iron uptake contributes to increase in the labile iron pool which plays roles in cholangiocarcinoma progression with aggressive clinical outcomes. PMID- 28671022 TI - Tim-3 as a diagnostic and prognostic biomarker of osteosarcoma. AB - Osteosarcoma is the most frequent primary bone tumor that affects adolescents and children. However, diagnostic and prognostic biomarkers for osteosarcoma remain lacking. (Tim-3) T-cell immunoglobulin domain and mucin domain-3, which negatively regulates T cell helper (Th1) cells and affects cytokine expression, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In this study, we evaluated serum soluble Tim-3 level in osteosarcoma patients to explore its diagnostic and prognostic value for this particular malignancy. Serum soluble Tim-3 level was measured with enzyme linked immunosorbent assay in 120 osteosarcoma patients, 120 benign bone tumors patients and 120 healthy controls, followed by analysis of the correlation with clinic pathological characteristics. Receiver operating curves, Kaplan-Meier curves, and log-rank analyses as well as Cox proportional hazard models were used to evaluate the diagnostic and prognostic significance. Serum solubleTim-3 level was remarkably elevated in osteosarcoma patients. Osteosarcoma patients with larger tumor size, late stages and distant metastases were accompanied with higher levels of Tim-3. ROC/AUC analysis indicated thatTim-3 served as a reliable marker to distinguish healthy participants from Tim-3 patients. Osteosarcoma patients with higher Tim-3 had relatively lower survival. Multivariate analyses for overall survival revealed that high serum soluble Tim-3 level was an independent prognostic factor for osteosarcoma. Furthermore, Tim-3 levels of CD8+ and CD4+ T cells were elevated in peripheral circulation of osteosarcoma patients. Therefore, It was indicated in our research that elevated serum soluble Tim-3 level might be a novel potential diagnostic and prognostic biomarker for osteosarcoma patients. PMID- 28671023 TI - Successful Aging as a Predictor of Long-Term Care Among Oldest Old: The Vitality 90+ Study. AB - AIM: The aim of the study was to investigate whether successful aging (SA) predicts entering long-term care (LTC) among nonagenarians. METHODS: Data originated from the linkage of the Vitality 90+ Study surveys with register data from Finnish Population Register and Care Registers. Altogether 1,966 community dwelling individuals were followed for 2 years and 1,354 individuals for 5 years. Four models of SA were constructed by varying combinations of physical, psychological, and social components. Competing risk regression analysis was used. FINDINGS: The incidence rate for entering LTC was lower for successful agers. Three models of SA presented a significantly decreased risk for entering LTC in the whole group and in women. The impact of SA was attenuated when living alone, needing help, and the year of participation were adjusted for, but was still significant for Model 3. CONCLUSION: Nonagenarians who meet the multidimensional criteria of SA are less likely to enter LTC than those aging less successfully. PMID- 28671024 TI - Prospective Pilot Study Comparing the Need for Adaptive Radiotherapy in Unresected Bulky Disease and in Postoperative Patients With Head and Neck Cancer. AB - BACKGROUND: Adaptive radiotherapy is being used in few institutions in patients with head and neck cancer having bulky disease using periodic computed tomography imaging accounting for volumetric changes in tumor volume and/or weight loss. Limited data are available on ART in the postoperative setting. We aim to identify parameters that would predict the need for ART in patients with head and neck cancer and whether ART should be applied in postoperative setting. MATERIALS AND METHODS: Twenty patients with stage III-IV head and neck cancer were prospectively accrued. A computed tomography simulation was done prior to treatment and repeated at weeks 3 and 6 of concurrent intensity-modulated radiotherapy and chemotherapy. The final plan was coregistered with the subsequent computed tomography images, and dosimetric/volumetric changes at weeks 1 (baseline), 3, and 6 were quantified in high-risk clinical target volumes, low risk clinical target volumes , right parotid , left parotid , and spinal cord . An event to trigger ART was defined as spinal cord maximum dose >45 Gy, parotid mean dose >26 Gy, and clinical target volume coverage <95%. RESULTS: Comparing the 2 groups, the proportion of patients with at least 1 event triggering ART was higher in bulky disease than in postoperative group: 72.7% versus 18.2% ( P = .03) overall; 54.6% versus 1.8% ( P = .064) at week 3; and 63.6% versus 18.2% ( P = .081) at week 6. In the bulky disease group, 8 of 11 patients had events at week 3 and/or 6 as follows: overdose in spinal cord (n = 2), right parotid (n = 3), left parotid (n = 5), coverage < 95% seen in low-risk clinical target volumes (n = 3), and high-risk clinical target volumes (n = 5). In the postoperative group, 2 of 11 patients had events: spinal cord (n = 1) and low-risk clinical target volume (n = 1). CONCLUSION: Our study confirmed the need for ART in patients with head and neck cancer having bulky disease due to target under dosing and/or spinal cord/parotids overdosing in weeks 3 and 6. In contrast, the benefit of ART in postoperative patients is less clear. PMID- 28671025 TI - A Typology of Sex Offending Against Minors: An Empirical Study of Rape and Molestation Cases in China. AB - Efforts to classify sexual offending and offenders continued to evolve over the years based on criteria such as offender and victim characteristics, offender victim relationships, the nature of sexual offenses, and other situational factors. This current study draws up a typology of sexual offending against minors based on 436 adjudicated rape and child molestation cases in China. Specifically, sexual offending against minors is classified into six major categories, including opportunistic offenses, serial offenses, dating couple offenses, educator abuses, gang/party offenses, and incest offenses. Based on this empirical typology, a number of crime prevention measures are suggested. These suggestions aim at involving multiple players and institutions to focus on education, target hardening, and crime investigation. This study makes a significant contribution to comparative studies in this field, and the results could be potentially applied in other cultures. PMID- 28671026 TI - Beyond hypercorrection: remembering corrective feedback for low-confidence errors. AB - Correcting errors based on corrective feedback is essential to successful learning. Previous studies have found that corrections to high-confidence errors are better remembered than low-confidence errors (the hypercorrection effect). The aim of this study was to investigate whether corrections to low-confidence errors can also be successfully retained in some cases. Participants completed an initial multiple-choice test consisting of control, trick and easy general knowledge questions, rated their confidence after answering each question, and then received immediate corrective feedback. After a short delay, they were given a cued-recall test consisting of the same questions. In two experiments, we found high-confidence errors to control questions were better corrected on the second test compared to low-confidence errors - the typical hypercorrection effect. However, low-confidence errors to trick questions were just as likely to be corrected as high-confidence errors. Most surprisingly, we found that memory for the feedback and original responses, not confidence or surprise, were significant predictors of error correction. We conclude that for some types of material, there is an effortful process of elaboration and problem solving prior to making low-confidence errors that facilitates memory of corrective feedback. PMID- 28671027 TI - Coping, Cognitive Emotion Regulation, and Burnout in Long-Term Care Nursing Staff: A Preliminary Study. AB - Direct care workers (e.g., certified nursing assistants [CNAs]) employed in long term care (LTC) are particularly vulnerable to the experience of burnout, yet they have received relatively less research attention compared to Licensed Practical Nurses and Registered Nurses. Within the burnout literature, evidence suggests that the deployment of certain coping strategies influences levels of burnout. The current study examined the extent to which coping (e.g., problem focused, emotion-focused, and dysfunctional coping) and cognitive emotion regulation strategies (e.g., positive reappraisal) predicted burnout after controlling for covariates (age, sleep duration). Fifty-six CNAs were surveyed at four skilled nursing facilities in the United States. Dysfunctional coping was significantly associated with emotional exhaustion and depersonalization. Among cognitive emotion regulation strategies, positive reappraisal was significantly associated with depersonalization. Shorter sleep duration was associated with significantly greater depersonalization. Findings suggest the need to develop interventions for CNAs aimed at reducing dysfunctional coping strategies and increasing sleep duration. PMID- 28671028 TI - Acetylcholinesterase measurement in various brain regions and muscles of juvenile, adolescent, and adult rats. AB - Several insecticides, chemicals, and drugs are known to inhibit acetylcholinesterase (AChE) activity, responsible for the cleavage of the neurotransmitter acetylcholine. The administration of AChE inhibitors leads to typical parasympathomimetic (toxic) symptoms in rats. In order to differentiate between compounds acting in various regions of the brain or in peripheral nerves, regulatory authorities demand the measurement of AChE activity in different compartments and the study of potential toxicity at different developmental stages. In the present paper, instructions are given for the necropsy of various regions of the brain depending on rat age. Furthermore, a method validation procedure is described for measuring AChE in these parts of the brain as well as peripheral nerves, serum, and erythrocytes in juvenile, adolescent, and adult rats according to the US EPA method. All investigations were performed within the frame of a regulatory extended one-generation reproductive study (EOGRTS, OECD TG 443). AChE activity increases age dependently in parts of the forebrain (cortex, hippocampus, striatum, but decreases in the mid- and hindbrain (cerebellum, brain stem, medulla oblongata) as well as in peripheral nerves (heart, diaphragm, gastrocnemius muscle). Sex-dependent differences of the AChE activity occur after an age of 11 weeks. The implication of AChE measurement in different brain regions of various age groups is discussed regarding the assessment of AChE inhibitors. PMID- 28671029 TI - Chemopreventive effect of syringic acid on 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. AB - Oral squamous cell carcinoma is most prevalent and refractory cancers worldwide. Recently, chemoprevention could be a promising approach in developing countries. The present study investigates the mechanism of syringic acid (SA), a phenolic constituent of plant Alpiniacalcarata Roscoe, and their leaves are used as traditional Indian Ayurveda medicines, mediated chemoprevention on 7,12 dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis (HBPC). Lipid peroxidation and antioxidants were measured in the plasma and buccal tissues in experimental hamsters. Modulating effect of SA on the expression pattern of PCNA, Cyclin D1, and mutant p53 markers was used for immunoexpression and western blotting analysis. In the present study, 100% tumor formation with marked abnormalities in the biochemical parameters of lipid peroxidation and antioxidants through up-regulation of molecular markers like PCNA, Cyclin D1, and mutant p53 was accompanied with tumor-bearing hamsters. Oral administration of SA at the doses of 50 and 100 mg/kg body weight (bw) to DMBA treated hamsters significantly inhibited adverse changes in the biochemical parameters of the plasma and buccal mucosal tissues and also down-regulation of molecular marker expression (PCNA, Cyclin D1, and mutant p53). The present study thus suggests that SA has potent anti-lipid peroxidative, antioxidant, anti-cell proliferative, and apoptosis-inducing properties during DMBA-induced HBPC. PMID- 28671030 TI - Continuous in vitro exposure of intestinal epithelial cells to E171 food additive causes oxidative stress, inducing oxidation of DNA bases but no endoplasmic reticulum stress. AB - The whitening and opacifying properties of titanium dioxide (TiO2) are commonly exploited when it is used as a food additive (E171). However, the safety of this additive can be questioned as TiO2 nanoparticles (TiO2-NPs) have been classed at potentially toxic. This study aimed to shed some light on the mechanisms behind the potential toxicity of E171 on epithelial intestinal cells, using two in vitro models: (i) a monoculture of differentiated Caco-2 cells and (ii) a coculture of Caco-2 with HT29-MTX mucus-secreting cells. Cells were exposed to E171 and two different types of TiO2-NPs, either acutely (6-48 h) or repeatedly (three times a week for 3 weeks). Our results confirm that E171 damaged these cells, and that the main mechanism of toxicity was oxidation effects. Responses of the two models to E171 were similar, with a moderate, but significant, accumulation of reactive oxygen species, and concomitant downregulation of the expression of the antioxidant enzymes catalase, superoxide dismutase and glutathione reductase. Oxidative damage to DNA was detected in exposed cells, proving that E171 effectively induces oxidative stress; however, no endoplasmic reticulum stress was detected. E171 effects were less intense after acute exposure compared to repeated exposure, which correlated with higher Ti accumulation. The effects were also more intense in cells exposed to E171 than in cells exposed to TiO2-NPs. Taken together, these data show that E171 induces only moderate toxicity in epithelial intestinal cells, via oxidation. PMID- 28671031 TI - Social inequality in diabetes patients' morbidity patterns from diagnosis to death - A Danish register-based investigation. AB - AIM: Measuring socioeconomic inequalities in health and health care, and understanding determinants of such inequalities, are critical for achieving higher equity in health. Equity in health is a prerequisite for public health and welfare. The aim of the paper is (1) to quantify inequality in diabetes morbidity patterns over patients' entire life span, and (2) to compare levels of inequality measured through income and educational level, respectively, as proxies for socioeconomic status (SES). METHOD: Historic individual register data on the entire Danish diabetes population alive in 2011 were gathered. Cox survival analysis and a concentration index decomposition approach were applied to analyse relevant morbidity indicators reflecting patients' health state at diagnosis and throughout their lives with diabetes. RESULTS: Patients with high education have approximately 26% lower mortality hazard when diagnosed with diabetes and 10-15% lower hazard of developing complications as compared with patients with short education. The outcome variables: 'severe complications at diagnosis' and 'years with severe complications' inhibit the highest negative concentration index value, indicating that morbidity is concentrated among the lower SES groups, whereas the outcome variables 'years without complications' and 'duration of diabetes' concentrate among the socioeconomically better-off patients. CONCLUSIONS: Significant differences in diabetes patients' morbidity patterns and survival indicate that diabetes impacts harder on patients of lower SES; these patients experience more severe complications and die earlier. Hence to reduce inequality in health, it is important to invest in efforts targeted towards socially vulnerable groups. PMID- 28671032 TI - Measuring the Operative Treatment Effect in End-Stage Ankle Arthritis: Are We Asking the Right Questions? A COFAS Multicenter Study. AB - BACKGROUND: Foot and ankle surgeons are increasingly relying on patient-reported outcome measures (PROMs) such as the Ankle Osteoarthritis Scale (AOS) to evaluate treatment options. The objectives of this retrospective cohort study were 2-fold: (1) to examine the AOS instrument using psychometric analysis and (2) to revise the questions on the AOS to improve the effect of questions on the score and remove redundancies. METHODS: Pre- and postoperative patient scores were obtained from AOS questionnaires in the COFAS Prospective Ankle Reconstruction Database, a cohort of patients operatively treated for end-stage ankle arthritis. A split sample approach was used to evaluate the AOS and to propose a revised instrument. RESULTS: A total of 380 patients who had been treated with total ankle replacement or ankle arthrodesis were prospectively followed to the 2-year postoperative time point. Correlation analysis demonstrated that a number of questions on the AOS were highly correlated with other similar questions, frequently incomplete, or showed little variation between respondents. Eight of the original AOS questions were retained in the newly proposed Ankle Arthritis Score (AAS) [3 from the AOS Pain subscale and 5 from the AOS Disability subscale]. Principal components analysis (PCA) showed that these questions equally clustered into 2 domains in AAS: Basic Activity and Advanced Activity. CONCLUSIONS: The AAS is shorter and has improved psychometric properties as compared to the AOS. Further investigation is required to better characterize the clinical utility of this proposed new patient-reported outcome score. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 28671033 TI - Regularized approach for data missing not at random. AB - It is common in longitudinal studies that missing data occur due to subjects' no response, missed visits, dropout, death or other reasons during the course of study. To perform valid analysis in this setting, data missing not at random (MNAR) have to be considered. However, models for data MNAR often suffer from the identifiability issue and hence result in difficulty in estimation and computational convergence. To ameliorate this issue, we propose the LASSO and ridge-regularized selection models that regularize the missing data mechanism model to handle data MNAR, with the regularization parameter selected via a cross validation procedure. The proposed models can be also employed for sensitivity analysis to examine the effects on inference of different assumptions about the missing data mechanism. We illustrate the performance of the proposed models via simulation studies and the analysis of data from a randomized clinical trial. PMID- 28671034 TI - Acrylamide in commercial foods and intake by infants in Estonia. AB - Acrylamide is formed when certain foods with low moisture are prepared at above 120 oC, especially those foods containing asparagine and reducing sugars such as glucose and fructose. Acrylamide is a probable carcinogen, and from animal evidence the margins of exposure indicate a concern for neoplastic effects. On a body weight basis infants' acrylamide intakes are often higher than those of adults. The aim of the study was to determine acrylamide levels in different commercially-available foods and to assess dietary acrylamide intakes by infants. The acrylamide content in samples ranged widely, from A) or Hb E (HBB: c.79 G>A) accounting for 29.2% of the total studied chromosomes, followed by codon 17 (A>T) (HBB: c.52 A>T) (25.0%), and codons 41/42 (-TTCT) (HBB: c.126_129delCTTT) (18.8%). Other mutations with appreciable frequencies (6.3-8.3%) were IVS-I-1 (G>T) (HBB: c.92+1 G>T), codon 26 (G>T) (HBB: c.79 G>T) and codons 71/72 (+A) (HBB: c.216_217insA). Relatively rarer (2.0%) were the promoter -28 (A>G) (HBB: c.78 A>G) mutation, the codon 95 (+A) (HBB: c.287_288insA), which is reported only in the Vietnamese, and the codons 14/15 (+G) (HBB: c.45_46insG) mutation, thus far observed only in Thailand. Results are relevant for implementing appropriate measures for beta-thal prevention and control in the region as well as in the whole country. PMID- 28671036 TI - Control of Progesterone Receptor-A Transrepressive Activity in Myometrial Cells: Implications for the Control of Human Parturition. AB - Uterine quiescence during pregnancy is maintained by progesterone primarily via signaling mediated by the type-B progesterone receptor (PR-B) in myometrial cells. Withdrawal of PR-B-mediated progesterone activity is a principal trigger for labor. One mechanism for PR-B withdrawal is by inhibition of its activity by the type-A PR (PR-A) isoform in myometrial cells. We hypothesized that human parturition involves hormonal interactions that induce the capacity for PR-A to inhibit PR-B in myometrial cells and that pro-inflammatory cytokines are major regulators of this process. We tested this hypothesis in an immortalized human myometrial cell line, hTERT-HMA/B, in which levels of PR-A and PR-B can be experimentally controlled. We found that the capacity for PR-A to repress PR-B, assessed by activity of a transiently transfected reporter DNA controlled by the progesterone response element, and expression of FK506 binding protein 5 ( FKBP5) an endogenous PR-B responsive gene, was increased by serum supplementation and interleukin-1beta. In pregnant uterus, FKBP5 was detected exclusively in myometrial cells and its expression decreased with advancing gestation and in association with the onset of labor at term. These findings suggest that in myometrial cells the repressive activity of PR-A on PR-B increases with advancing gestation and is induced by pro-inflammatory cytokines. This may be a key mechanism linking inflammation with the onset of labor. PMID- 28671037 TI - The Experience of Families With Children With Spinal Muscular Atrophy Type I Across Health Care Systems. AB - Spinal muscular atrophy type I is a genetic disease characterized by degeneration of spinal cord motor neurons resulting in weakness, technology dependence and early demise. While the newly approved treatment nusinersen may alter the morbidity/mortality of this disease there continues to be complex treatment challenges to consider. The aim of this qualitative study was to understand from the parent's perspective, experiences of the family and child in the emergency center, hospital, and clinical care settings to identify gaps in care. Nineteen families interviewed had 22 children with spinal muscular atrophy I (11 deceased, 11 living). Three overarching themes emerged from parent interviews describing a range of experiences surrounding diagnosis, informed medical decision making and acute care practice. Identified quality improvements include development of a diagnostic screening tool, a medical decision tool, and emergency center informational template individualized to the child and providing an overview of spinal muscular atrophy I. PMID- 28671038 TI - Electronic health record innovations: Helping physicians - One less click at a time. AB - BACKGROUND: Physician burnout is becoming an epidemic, due to the pressures of being productive, an imperfect electronic health record (EHR) system, and limited face-to-face time with patients. Poor usability in EHR-user interface can force users to go through more steps (i.e. more clicks on the computer) in accomplishing a task. OBJECTIVE: This increased 'click burden' is a source of frustration for physicians. In the light of increased click burden and time due to meaningful use requirements, there is a need to improve the physician's experience by creating innovations in EHR. METHOD: This case study describes an attempt by physicians at NewYork-Presbyterian Brooklyn Methodist Hospital to enhance the EHR experience with more efficient methods of documentation, chart review, ordering and patient safety. RESULTS: The EHR innovations trialled in this study were: a mobile documentation application; abnormal test results auto populated into an EHR patient summary; physician alerts to reduce inappropriate test ordering; and a system of safety alerts on a dashboard. These innovations led to decreased click burden and allowed physicians to spend less time on the computer and more time with patients. CONCLUSION: Physician-driven changes to EHR systems have the potential to streamline virtual workflows and the management of health information and to improve patient safety, reduce physician burnout and increase physician job satisfaction. PMID- 28671039 TI - LncRNA GAS5 suppresses the tumorigenesis of cervical cancer by downregulating miR 196a and miR-205. AB - Growth arrest special 5 (GAS5) is a long non-coding RNA reported to function as an inhibitor in various tumors including cervical cancer. However, the molecular mechanism of GAS5 involved in cervical cancer progression remains far from being elucidated. The expression of GAS5, forkhead box protein O1 and phosphatase and tensin homolog was examined by quantitative reverse transcription polymerase chain reaction qRT-PCR. cell growth, invasion, and apoptosis were assessed by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, transwell invasion assay, and flow cytometry analysis, respectively. The interaction between GAS5 and miR-196a or miR-205 was confirmed by luciferase reporter assay, RNA immunoprecipitation assay, and qRT-PCR. Xenograft tumor experiments were performed to validate the biological role of GAS5 and its molecular mechanism in cervical cancer in vivo. GAS5 expression was decreased in cervical cancer tissues and cells. GAS5 overexpression suppressed cervical cancer cell proliferation, invasion, and apoptosis. GAS5 was able to directly bind to miR-196a and miR-205 to downregulate their expression. Moreover, GAS5 induced forkhead box protein O1 and phosphatase and tensin homolog expression by repressing miR-196a and miR-205, respectively. Exogenous expression of GAS5 hindered tumor growth in vivo by downregulating miR-196a and miR-205. Upregulation of GAS5 suppressed cell proliferation, invasion, and apoptosis of cervical cancer cells by downregulating miR-196a and miR-205, contributing to our understanding the pathogenesis of cervical cancer and development of long non coding RNA-mediated clinical therapy against this disease. PMID- 28671040 TI - High expressions of BCL6 and Lewis y antigen are correlated with high tumor burden and poor prognosis in epithelial ovarian cancer. AB - Aberrant regulation of BCL6 plays crucial oncogenic roles in various malignant tumors; howbeit, the function of BCL6 in tumorigenesis of ovarian cancer remains unclear. The aim of this study is to investigate the role of BCL6 in ovarian cancer. The methods of immunohistochemical staining, quantitative real-time polymerase chain reaction, immunocytochemical staining, and gene expression profile enrichment analysis were performed to identify the possible role of BCL6 in ovarian cancer. We observed that the expression of BCL6 was significantly higher in ovarian cancer tissues and correlated with higher tumor burden including advanced International Federation of Gynecology and Obstetrics stages, poor differentiation, Type II ovarian cancer, the presence of >1 cm residual tumor size, and appearance of recurrence or death (all p < 0.05). The expression patterns of Lewis y were similar to these of BCL6. Multivariate Cox analysis demonstrated that advanced International Federation of Gynecology and Obstetrics stage, lymph node metastasis, residual tumor size >1 cm, as well as high expressions of BCL6 and Lewis y antigen were independent factors of worse progression-free survival and overall survival (all p < 0.05). There was a positive correlation of the expressions of BCL6 and Lewis y antigen. The associated genes with BCL6 in response to Lewis y antigen were identified, including four upregulated genes ( SOCS3, STAT1, PPARG, and GADD45A) and three downregulated genes ( ACAN, E2F3, and ZBTB7B). In conclusion, the high expressions of BCL6 and Lewis y antigen are associated with development, high tumor burden, and worse prognosis of ovarian cancer and targeting BCL6 could be a novel therapeutic strategy for ovarian cancer treatment. PMID- 28671041 TI - High expression of Rac1 is correlated with partial reversed cell polarity and poor prognosis in invasive ductal carcinoma of the breast. AB - The change of cell polarity is usually associated with invasion and metastasis. Partial reverse cell polarity in IDC-NOS may play a role in lymphatic tumor spread. Rac1 is a kind of polarity related protein. It plays an important role in invasion and metastasis in tumors. We here investigated the expression of Rac1 and partial reverse cell polarity status in breast cancer and evaluated their value for prognosis in breast cancer. The association of the expression of Rac1 and MUC-1 with clinicopathological parameters and prognostic significance was evaluated in 162 cases of IDC-NOS paraffin-embedded tissues by immunohistochemical method. The Rac1 messenger RNA expression was measured by real-time polymerase chain reaction in 30 breast cancer patients, which was divided into two groups of partial reverse cell polarity and no partial reverse cell polarity. We found that lymph node metastasis of partial reverse cell polarity patients was higher than no partial reverse cell polarity patients (Z = 4.030, p = 0.000). Rac1 was upregulated in partial reverse cell polarity group than no partial reverse cell polarity group (Z = -3.164, p = 0.002), and there was correlationship between the expression of Rac1 and partial reverse cell polarity status (rs = 0.249, p = 0.001). The level of Rac1 messenger RNA expression in partial reverse cell polarity group was significantly higher compared to no partial reverse cell polarity group (t = -2.527, p = 0.017). Overexpression of Rac1 and partial reverse cell polarity correlates with poor prognosis of IDC-NOS patients (p = 0.011). Partial reverse cell polarity and lymph node metastasis remained as independent predictors for poor disease-free survival of IDC-NOS (p = 0.023, p = 0.046). Our study suggests that partial reverse cell polarity may lead to poor prognosis of breast cancer. Overexpression of Rac1 may lead to polarity change in IDC-NOS of the breast. Therefore, Rac1 could be a therapeutic target for breast cancer. PMID- 28671042 TI - Progress in the treatment of advanced gastric cancer. AB - Gastric cancer is one of the most common malignant tumors in the digestive system. Surgery is currently considered to be the only radical treatment. As surgical techniques improve and progress is made in traditional radiotherapy, chemotherapy, and the implementation of neoadjuvant therapy, the 5-year survival rate of early gastric cancer can reach >95%. However, the low rate of early diagnosis means that most patients have advanced-stage disease at diagnosis and so the best surgical window is missed. Therefore, the main treatment for advanced gastric cancer is the combination of neoadjuvant chemoradiotherapy, molecular targeted therapy, and immunotherapy. In this article, we summarize several common methods used to treat advanced gastric cancer and discuss the progress made in the treatment of gastric cancer in detail. Only clinical practice and clinical research will allow us to prolong the survival time of patients and allow the patients to truly benefit by paying attention to the individual patient characteristics, drug choice, and developing a reasonable and comprehensive treatment plan. PMID- 28671043 TI - Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery. AB - Tumor response to preoperative chemoradiotherapy and postoperative survival differs among patients with locally advanced rectal cancer. The objective was to find correlations of mutated oncogenes and clinical outcomes in locally advanced rectal cancer. A total of 70 patients with preoperative preoperative chemoradiotherapy followed by radical surgery at a single cancer center between 2006 and 2012 were enrolled. Pretreatment tumor biopsy samples were assayed for 238 mutation hotspots harboring 19 oncogenes by time-of-flight mass spectrometry and OncoCarta Array. Oncogene mutations were found in 48.6% of patients (34/70). KRAS was the most frequent driver mutation, found in 35.7% of patients (25/70), followed by PIK3CA (14.3%), NRAS (5.7%), FLT3 (2.9%), and BRAF (1.4%). Multiple gene mutations were observed in eight patients (11.4%). Tumors with KRAS mutations responded poorly to preoperative chemoradiotherapy (p = 0.044). Patients with oncogene mutations had worse 3-year disease-free survival than those without mutations (67.2% vs 94.2%, p = 0.010). Patients with KRAS or RAS mutations had lower 3-year disease-free survival (68% vs 88.3%, p = 0.016; 65.5% vs 92.3%, p = 0.004, respectively) and 3-year overall survival (88% vs 95.4%, p = 0.020; 89.7% vs 94.9%, p = 0.036, respectively) than those without KRAS or RAS mutations. Oncogene mutation status affected tumor response to treatment and long term survival in locally advanced rectal cancer. PMID- 28671044 TI - Risk factors for spontaneous localized intestinal perforation in the preterm infant. AB - PURPOSE: The aim of this study was to investigate prenatal and postnatal risk factors for spontaneous intestinal perforation (SIP) in preterm infants. MATERIAL AND METHODS: Matched case-control study of 62 preterm infants (matching based on gender, gestational age and birth weight) who developed a SIP over a period of 20 years in a single NICU. Univariate and multivariate logistic regression analysis were performed. RESULTS: Prenatal risk factors were not significantly different between cases and controls. Patients exposed to surfactant and inotropic agents have an increased risk for SIP. No initiation of feeding before development of SIP and IVH >= grade 3 were also associated with an increased risk for SIP. In multivariate analysis inotropic agents, lack of initiation of feeding and IVH >= grade 3 remained significant risk factors (OR 5.58 (95% CI 1.14-27.22), 0.29 (95% CI 0.09-0.88), 15.2 (95% CI 1.09-211.55) respectively). CONCLUSIONS: The study found that patients with SIP are more likely to have been exposed to inotropic agents and to have developed IVH >= grade 3. They were also less likely to have been fed. These risk factors most likely reflect the severity of illness of preterm infants and an increased vulnerability for developing SIP. PMID- 28671045 TI - Prognostic and clinicopathological role of long non-coding RNA taurine upregulated 1 in various human malignancies: A systemic review and meta-analysis. AB - The aberrant dysregulation of taurine upregulated 1, a novel discovered long non coding RNA, was ubiquitous in different human solid tumors. Accumulating researches have indicated that taurine upregulated 1 is an independent prognostic indicator in cancer patients. This investigation aimed to further explore the prognostic and clinical significance of taurine upregulated 1 in various types of cancers. Eligible studies were systematically searched in PubMed, Embase, Medline, and Web of Science databases. A total of 12/14 studies with 1303/1228 individuals were included to evaluate the association of taurine upregulated 1 with overall survival and clinicopathological features by pooled hazard ratio and odds ratio in malignancies. The meta-analysis suggested overexpression of taurine upregulated 1 was significantly correlated with unfavorable overall survival in patients with cancer (pooled hazard ratio = 1.63, 95% confidence interval: 1.29 2.06). There was also a significantly positive correlation between high level of taurine upregulated 1 and high pathological grade carcinoma (pooled odds ratio = 4.41, 95% confidence interval: 3.07-6.43) and positive lymphatic metastasis (pooled odds ratio = 2.00, 95% confidence interval: 1.31-3.06). In summary, upregulated taurine upregulated 1 is correlated with more advanced clinicopathological characteristics and poor prognosis, suggesting that taurine upregulated 1 may serve as a novel predictive biomarker of patients with numerous tumors. PMID- 28671046 TI - Let7b modulates the Wnt/beta-catenin pathway in liver cancer cells via downregulated Frizzled4. AB - Let7 microRNA implicated in many cellular processes and participated in the progress of various tumors. Similarly, Wnt signaling pathway plays an important role in morphogenesis, differentiation, cell survival, and proliferation. However, there is little research focusing on the relevance between Let7b and Wnt/beta-catenin signaling pathway, especially in liver cancer cell. To study this, human liver cancer cells HUH7 and MHCC97H were cultured, enhanced, or inhibited the expression of Let7b in two cell lines. Western blotting was used to measure the expression of Wnt signaling-related protein beta-catenin and Frizzled family receptor. CD24+133+ was used as a cancer stem cell marker, and the proportion of CD24+133+ in liver cancer cell lines was observed by flow cytometry. The proliferation, invasiveness, and migration of liver cancer cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, transwell, and wound healing assays. The research revealed that enhanced expression of Let7b decreased the expression of Frizzled4, while inhibited Let7b expression increased Frizzled4 expression. Enhanced Let7b expression reduced the proportion of cancer stem cell in liver cancer cell; meanwhile, Let7b inhibition increased the proportion of cancer stem cell. Upregulated Let7b expression repressed the proliferation, invasion, and migration of liver cancer cell. This study showed that Let7b modulates the proliferation, invasiveness, and migration of liver cancer cell and reduces the proportion of cancer stem cells in liver cancer cell by inhibiting Wnt/beta-catenin signaling pathway via downregulated Frizzled4. PMID- 28671047 TI - The role of Capon in multiple myeloma. AB - Capon is a ligand protein of nitric oxide synthase 1. Recently, studies have shown that Capon is involved in the development of tumors. It is independent of the regulation of nitric oxide synthase 1 in this process. At the same time, studies have found that nitric oxide synthase 1 is expressed in multiple myeloma, but its role in the development and progression of myeloma remains unclear. In this study, we found that there was a different expression of Capon between the normal multiple myeloma cells and the adherent multiple myeloma cells. In the process of myeloma cell proliferation, the reduced expression of Capon reduces the arrest of the cell cycle in the G1 phase and promotes the proliferation of myeloma cells. Cell adhesion-mediated drug resistance is one of the most important factors, which affect the chemotherapy effect of multiple myeloma. If the expression of Capon is decreased, myeloma cells are adhered to fibronectin or bone marrow stromal cells (bone marrow mesenchymal stem cells). In addition, the sensitivity of the cell line to chemotherapeutic agents was reduced after silencing Capon in the myeloma cell line which was adhered to bone marrow mesenchymal stem cells. We also found that reduced expression of Capon resulted in the activation of the AKT signaling pathway. In conclusion, these results may be helpful in studying the role of Capon in multiple myeloma. PMID- 28671048 TI - Neuron-specific enolase, histopathological types, and age as risk factors for bone metastases in lung cancer. AB - Lung cancer is a malignant tumor with high metastatic ability and bone is the most common site of distant metastasis of it. However, the independent risk factors for bone metastases of lung cancer remain largely to be elucidated. Here, we conducted a retrospective study to evaluate the correlation between clinical pathological parameters, serum levels of neuron-specific enolase and CYFRA21-1, and bone metastases in lung cancer patients. The results revealed that patients with bone metastases were younger than those without metastases. Adenocarcinoma was the most frequent type of histopathology in patients with bone metastases. And the incidence of bone metastasis in patients with adenocarcinoma was significantly higher than those with other histopathological subtypes ( p < 0.001). Furthermore, the serum concentration of neuron-specific enolase was significantly higher in patients with bone lesions than those without bone metastases. Multivariate logistic regression analysis showed that patients' age (odds ratio = 1.024, p < 0.001), concentrations of neuron-specific enolase (odds ratio = 1.212, p = 0.004), and histopathological types (odds ratio = 0.995, p = 0.001) were the independent risk factors for bone metastases in patients with lung cancer. Thus, physicians should pay attention to these factors in order to identify bone metastasis earlier while patient was primarily diagnosed as having lung cancer. PMID- 28671049 TI - Clinicopathological significance of c-MYC in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma is one of the most common malignant tumors. The oncogene c-MYC is thought to be important in the initiation, promotion, and therapy resistance of cancer. In this study, we aim to investigate the clinicopathologic roles of c-MYC in esophageal squamous cell carcinoma tissue. This study is aimed at discovering and analyzing c-MYC expression in a series of human esophageal tissues. A total of 95 esophageal squamous cell carcinoma samples were analyzed by the western blotting and immunohistochemistry techniques. Then, correlation of c-MYC expression with clinicopathological features of esophageal squamous cell carcinoma patients was statistically analyzed. In most esophageal squamous cell carcinoma cases, the c-MYC expression was positive in tumor tissues. The positive rate of c-MYC expression in tumor tissues was 61.05%, obviously higher than the adjacent normal tissues (8.42%, 8/92) and atypical hyperplasia tissues (19.75%, 16/95). There was a statistical difference among adjacent normal tissues, atypical hyperplasia tissues, and tumor tissues. Overexpression of the c-MYC was detected in 61.05% (58/95) esophageal squamous cell carcinomas, which was significantly correlated with the degree of differentiation (p = 0.004). The positive rate of c-MYC expression was 40.0% in well-differentiated esophageal tissues, with a significantly statistical difference (p = 0.004). The positive rate of c-MYC was 41.5% in T1 + T2 esophageal tissues and 74.1% in T3 + T4 esophageal tissues, with a significantly statistical difference (p = 0.001). The positive rate of c-MYC was 45.0% in I + II esophageal tissues and 72.2% in III + IV esophageal tissues, with a significantly statistical difference (p = 0.011). The c-MYC expression strongly correlated with clinical staging (p = 0.011), differentiation degree (p = 0.004), lymph node metastasis (p = 0.003), and invasion depth (p = 0.001) of patients with esophageal squamous cell carcinoma. The c-MYC was differentially expressed in a series of human esophageal tissues, and the aberrant c-MYC expression could be a potential factor in carcinogenesis and progression of esophageal squamous cell carcinoma. There was a statistical signification for c-MYC in esophageal squamous cell carcinoma patients to analyze clinicopathological features. It possibly becomes a new diagnostic indicator of esophageal squamous cell carcinoma. PMID- 28671050 TI - Outcome instruments in moderate-to-severe adult traumatic brain injury: recommendations for use in psychosocial research. AB - BACKGROUND: Traumatic brain injury (TBI) can reduce psychosocial functioning, causing relationship, family, and employment difficulties. The present study by Moving Ahead: Centre for Research Excellence (CRE) in Brain Recovery aimed to identify a set of adult outcome instruments for moderate-to-severe TBI psychosocial research. PROCEDURE: A review of 115 instruments (identified through nomination, literature search, and international expert opinion) was conducted over a 15-month period. Eleven psychosocial areas were examined: Global Outcome, Communication, Social Cognition, Behavioural and Executive Function, Other Neuropsychological Functioning, Psychological Status, TBI-related Symptoms, Activities and Participation, Support and Relationships, Sense of Self, and Health-related Quality of Life. Individual instruments were considered against selection guidelines, and specific measures that best met the guidelines were identified as core (common across all studies), supplemental (dependent on study type) or emerging. RESULTS: The final recommendations, organised in accordance with the World Health Organisation's International Classification of Functioning taxonomy, comprised 56 instruments for use in early recovery, outcome, and intervention studies. CONCLUSION: These recommendations provide a coherent framework along with identified outcome instruments to guide psychosocial research in moderate-to-severe TBI. Adherence to the recommendations will enable data-pooling and comparison across studies and research settings facilitating consistent measurement across the lifespan. PMID- 28671051 TI - Autobiographical memory functions of nostalgia in comparison to rumination and counterfactual thinking: similarity and uniqueness. AB - We compared and contrasted nostalgia with rumination and counterfactual thinking in terms of their autobiographical memory functions. Specifically, we assessed individual differences in nostalgia, rumination, and counterfactual thinking, which we then linked to self-reported functions or uses of autobiographical memory (Self-Regard, Boredom Reduction, Death Preparation, Intimacy Maintenance, Conversation, Teach/Inform, and Bitterness Revival). We tested which memory functions are shared and which are uniquely linked to nostalgia. The commonality among nostalgia, rumination, and counterfactual thinking resides in their shared positive associations with all memory functions: individuals who evinced a stronger propensity towards past-oriented thought (as manifested in nostalgia, rumination, and counterfactual thinking) reported greater overall recruitment of memories in the service of present functioning. The uniqueness of nostalgia resides in its comparatively strong positive associations with Intimacy Maintenance, Teach/Inform, and Self-Regard and weak association with Bitterness Revival. In all, nostalgia possesses a more positive functional signature than do rumination and counterfactual thinking. PMID- 28671052 TI - Prognostic value of primary gross tumor volume and standardized uptake value of 18F-FDG in PET/CT for distant metastasis in locoregionally advanced nasopharyngeal carcinoma. AB - Distant metastasis has become the predominant model of treatment failures in patients with locoregionally advanced nasopharyngeal carcinoma. Effort should therefore be made to stratify locoregionally advanced nasopharyngeal carcinoma patients into different groups based on the risk of metastasis to improve prognosis and tailor individualized treatments. This study aims to assess the value of primary gross tumor volume and the maximum standardized uptake value for predicting distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. A total of 294 locoregionally advanced nasopharyngeal carcinoma patients who were identified from prospectively maintained database and underwent fluor-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging before treatment were included. The maximum standardized uptake value was recorded for the primary tumor (SUVmax-P) and neck lymph nodes (SUVmax-N). Computed tomography-derived primary gross tumor volume was measured using the summation-of-area technique. At 5 years, the distant metastasis-free survival rate was 83.7%. The cut-off of the SUVmax-P, SUVmax-N, and primary gross tumor volume for distant metastasis-free survival was 8.95, 5.75, and 31.3 mL, respectively, by receiver operating characteristic curve. In univariate analysis, only SUVmax-N (hazard ratio: 7.01; 95% confidence interval: 1.70-28.87; p < 0.01) and clinical stage (hazard ratio: 3.03; 95% confidence interval: 1.67-5.47; p = 0.007) were confirmed as independent predictors of distant metastasis-free survival. A prognostic model was derived by SUVmax-N and clinical stage: low risk (SUVmax-N < 5.75 regardless of clinical stage), medium risk (stage III and SUVmax-N >= 5.75), and high risk (stage IV and SUVmax-N >= 5.75). Multivariate analysis revealed that SUVmax-N and the prognostic model remained independent prognostic factors for distant metastasis free survival (p = 0.023 and p < 0.001, respectively), but the clinical stage became insignificant (p = 0.133). Furthermore, the adjusted hazard ratios for the prognostic model were higher than SUVmax-N (hazard ratio = 6.27 vs 5.21, respectively). In summary, compared with SUVmax-P, SUVmax-N may be a better predictor of distant metastasis-free survival for patients with locoregionally advanced nasopharyngeal carcinoma. Combining SUVmax-N with clinical stage gives a more precise picture in predicting distant metastasis. PMID- 28671053 TI - Expression of hypoxia inducible factor 1 alpha and its clinical significance in esophageal carcinoma: A meta-analysis. AB - Many studies have analyzed the relationship between hypoxia inducible factor 1 alpha expression and its relation to differentiation, lymph node metastasis, and other clinicopathological variables of esophageal carcinoma, but the results are still inconsistent. This meta-analysis was carried out to explore hypoxia inducible factor 1 alpha in esophageal carcinoma and its correlation with clinicopathological features and prognosis, in order to provide comprehensive reference for clinic. A total of 18 studies including 1566 patients with esophageal squamous cell carcinoma were enrolled. The results showed that compared with para-carcinoma tissue, the expression of hypoxia inducible factor 1 alpha was significantly enhanced (odds ratio = 0.122, 95% confidence interval = 0.074-0.201, p = 0.000); hypoxia inducible factor 1 alpha was associated with differentiation (odds ratio = 1.458, 95% confidence interval = 1.108-1.920, p = 0.007), T classification (odds ratio = 0.457, 95% confidence interval = 0.265 0.786, p = 0.005), lymph node metastasis (odds ratio = 0.337, 95% confidence interval = 0.185-0.614, p = 0.000), and pathological tumor-node-metastasis stage (odds ratio = 0.362, 95% confidence interval = 0.177-0.740, p = 0.005), whereas there was no relation to histological grade, lymphatic vessel invasion, blood vessel invasion, 3- to 5-year overall survival and disease-free survival. Patients with hypoxia inducible factor 1 alpha overexpression had poor differentiation, increased depth of tumor invasion, more lymph node metastasis, and late pathological tumor-node-metastasis stage. Hypoxia inducible factor 1 alpha could be an indicator for differentiation, T classification, lymph node metastasis, and pathological tumor-node-metastasis stage, and it is worth further study. PMID- 28671054 TI - Biomedical optical spectroscopy for the early diagnosis of gastrointestinal neoplasms. AB - Gastrointestinal cancer is a leading contributor to cancer-related morbidity and mortality worldwide. Early diagnosis currently plays a key role in the prognosis of patients with gastrointestinal cancer. Despite the advances in endoscopy over the last decades, missing lesions, undersampling and incorrect sampling in biopsies, as well as invasion still result in a poor diagnostic rate of early gastrointestinal cancers. Accordingly, there is a pressing need to develop non invasive methods for the early detection of gastrointestinal cancers. Biomedical optical spectroscopy, including infrared spectroscopy, Raman spectroscopy, diffuse scattering spectroscopy and autofluorescence, is capable of providing structural and chemical information about biological specimens with the advantages of non-destruction, non-invasion and reagent-free and waste-free analysis and has thus been widely investigated for the diagnosis of oesophageal, gastric and colorectal cancers. This review will introduce the advances of biomedical optical spectroscopy techniques, highlight their applications for the early detection of gastrointestinal cancers and discuss their limitations. PMID- 28671055 TI - Silencing of long non-coding RNA CCAT2 depressed malignancy of oral squamous cell carcinoma via Wnt/beta-catenin pathway. AB - Oral squamous cell carcinoma is a common and lethal malignancy affecting the head and neck region. CCAT2 (colon cancer-associated transcript 2) gene is affiliated with long non-coding RNAs, which are often found to have important regulatory roles in cancers. This study aims to assess the expression and clinical significance of CCAT2 gene, identify its malignant biological behaviors, and explore the possible mechanisms in oral squamous cell carcinoma. CCAT2 expression was detected by quantitative real-time polymerase chain reaction, and its relationship with clinical factors was assayed using the Kaplan-Meier survival curve. The biological behaviors of CCAT2 and its potential mechanisms in oral squamous cell carcinoma were explored by the combined use of CCAT2 knockdown technology and the Wnt/beta-catenin pathway agonist lithium chloride (LiCl). Our results showed that CCAT2 functioning as a potential oncogene was upregulated in oral squamous cell carcinoma. CCAT2 with high expression level was correlated with poor differentiation, higher T stage, and clinical stage, which made CCAT2 to be a prognostic biomarker in oral squamous cell carcinoma. LiCl-activated Wnt/beta-catenin signaling pathway could partly restore the CCAT2-mediated malignant biological behaviors of oral squamous cell carcinoma cells by suppressing beta-catenin, CCND1, and MYC and activating glycogen synthase kinase 3 beta expression. These findings might assist in the discovery of novel potential diagnostic and therapeutic target for oral squamous cell carcinoma, thereby improve the effects of clinical treatment in patients. PMID- 28671056 TI - Protein Kinase Inhibitors as Therapeutic Drugs in AML: Advances and Challenges. AB - Acute myeloid leukemia (AML) is a malignant blood disorder and the cure rate has been remarkably improved over the past decade. However, recurrent or refractory leukemia remains the major problem of the AML and no clearly effective therapy has been established so far. Traditional treatments such as chemotherapy and hematopoietic stem cell transplantation are both far dissatisfying the patients partly for their individual variety. Besides, conventional treatments usually have many side effects to result in poor prognosis. Therefore, an urgent need is necessary to update therapies of AML. To date, protein kinase inhibitors as new drugs offer hope for AML treatment and many of them are on clinical trials. Here, this review will provide a brief summary of protein kinase inhibitors investigated in AML thus far, mainly including tyrosine protein kinase inhibitors and serine/threonine kinase inhibitors. We also presented the sketch of signal pathways involving protein kinase inhibitors, as well as discussed the clinical applications and the challenges of inhibitors in AML treatment. PMID- 28671057 TI - Polyamine Transport and Synthesis in Trichomonas vaginalis: Potential Therapeutic Targets. AB - Polyamines are essential for many biological processes in all organisms. Here we show a current landscape of studies and strategies implemented for the study of polyamine metabolism, as well as molecular aspects that implicate the role of key enzymes, transport proteins, inhibitors, and the study of novel molecules as potential therapeutic targets. This review focused on the synthesis, interconversion and function of these molecules in Trichomonas vaginalis, a common sexually transmitted parasite of humans. PMID- 28671058 TI - Dual Roles of Pin1 in Cancer Development and Progression. AB - Pin1 is a unique peptidyl-prolyl cis/trans isomerase (PPIase) that catalyzes the cis/trans isomerization of peptidyl-prolyl peptide bonds of its substrate proteins by binding to their specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs. This alters the conformation of target proteins and consequently affects their stability, intracellular localization, and/or biological functions. The abnormal overexpression of Pin1 is observed in some malignancies, which is associated with cancer cell proliferation, migration and invasion. However, a role for Pin1 as a putative tumor suppressor has recently been suggested. Systematic dissection of pro-oncogenic vs. tumor suppressive functions of Pin1 will be necessary. PMID- 28671059 TI - Role of Polyamines in Parasite Cell Architecture and Function. AB - In the absence of accessible, effective vaccines, the fight against parasitic disease relies mostly on chemotherapy. Nevertheless, the considerable side effects, high costs and growing number of refractory cases comprise substantial drawbacks. Thus, the search for new antiparasitic compounds remains a high priority. The polyamine biosynthesis, conversion and transport pathways offer different targets for selective chemotherapy. Polyamine analogues and other antagonists may provide tools in the search for new lead compounds. Light and electron microscopy techniques may encompass valuable approaches to elucidate the possible mechanisms of action of different antiparasitic compounds, allowing the identification of subcellular target compartments, presumably establishing the basis for a more rational drug design and/or planning of therapeutic strategies. PMID- 28671060 TI - Retrospective Analysis of Mosh-Pit-Related Injuries. AB - OBJECTIVES: Moshing is a violent form of dancing found world-wide at rock concerts, festivals, and electronic dance music events. It involves crowd surfing, shoving, and moving in a circular rotation. Moshing is a source of increased morbidity and mortality. The goal of this study was to report epidemiologic information on patient presentation rate (PPR), transport to hospital rate (TTHR), and injury patterns from patients who participated in mosh pits. Materials and Methods Subjects were patrons from mosh-pits seeking medical care at a single venue. The events reviewed were two national concert tours which visited this venue during their tour. The eight distinct events studied occurred between 2011 and 2014. Data were collected retrospectively from prehospital patient care reports (PCRs). A single Emergency Medical Service (EMS) provided medical care at this venue. The following information was gathered from each PCR: type of injury, location of injury, treatment received, alcohol or drug use, Advanced Life Support/ALS interventions required, age and gender, disposition, minor or parent issues, as well as type of activity engaged in when injured. RESULTS: Attendance for the eight events ranged from 5,100 to 16,000. Total patient presentations ranged from 50 to 206 per event. Patient presentations per ten thousand (PPTT) ranged from 56 to 130. The TTHR per 10,000 ranged from seven to 20. The mean PPTT was 99 (95% CI, 77-122) and the median was 98. The mean TTHR was 16 (95% CI, 12-29) and the median TTHR was 17. Patients presenting from mosh pits were more frequently male (57.6%; P<.004). The mean age was 20 (95% CI, 19 20). Treatment received was overwhelmingly at the Basic Life Support (BLS) level (96.8%; P<.000001). General moshing was the most common activity leading to injury. Crowd surfing was the next most significant, accounting for 20% of presentations. The most common body part injured was the head (64% of injuries). CONCLUSIONS: This retrospective review of mosh-pit-associated injury patterns demonstrates a high rate of injuries and presentations for medical aid at the evaluated events. General moshing was the most commonly associated activity and the head was the most common body part injured. Milsten AM , Tennyson J , Weisberg S , Retrospective analysis of mosh-pit-related injuries. Prehosp Disaster Med. 2017;32(6):636-641. PMID- 28671061 TI - The 10-D assessment and evidence-based medicine tool for authors and peer reviewers in clinical pharmacology?. AB - BACKGROUND: Peer reviewers and authors of clinical pharmacology manuscripts need to meet the standards for Evidence-Based Medicine (EBM) and Good Publication Practices (GPP), and editors of clinical pharmacology journals have to maintain an overview of the peer review process. METHODS AND RESULTS: The peer review process can be monitored and facilitated using the 10-D assessment, which comprises peer review criteria to determine if: 1. design of the study, 2. diagnoses employed, 3. drug molecules involved, 4. dosages applied, 5. data collected, 6. discussion of the findings, 7. deductions made, 8. documentation, 9. declarations, and 10. dHS (drug hypersensitivity syndrome) risk assessment is in accord with the objectives of the study and meet the requirements of EBM and GPP. CONCLUSIONS: The 10-D assessment tool, although easy to apply, requires a high level of clinical pharmacology expertise, especially in the fields of drug disposition, pharmacokinetics, and drug action. Its application will facilitate the peer review of clinical research and clinical trial reports and thus promote safety in drug development and pharmacotherapy and meet the needs of Good Publication Practices.?. PMID- 28671062 TI - A 12-week dose-escalating study of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese hemodialysis patients?. AB - AIMS: To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients. MATERIALS AND METHODS: In this multicenter study, IV injections of etelcalcetide (3 times a week for 12 weeks) were administered, with dose escalation every 4 weeks depending on changes in serum intact parathyroid hormone (iPTH) and corrected calcium (cCa). A total of 24 patients participated in this study. RESULTS: Serum iPTH was reduced in a time- and dose-dependent manner, with reductions (in pg/mL) at 12 weeks of -226.1 +/- 125.3, -362.5 +/- 161.5, and -412.4 +/- 130.2, respectively, for maximum doses of 5, 10, and 15 mg. At the end of the treatment, 50% of patients had serum iPTH levels within the target range (60 - 240 pg/mL). Serum cCa and phosphorus were reduced in parallel with iPTH. Adverse events (AEs) occurred in 20 patients (83.3%). The most frequently observed AEs (> 10%) were either mild or moderate nasopharyngitis (29.2%), decreased serum calcium (16.7%), and vomiting (12.5%). CONCLUSIONS: Dose-escalated triweekly etelcalcetide was effective for SHPT in Japanese hemodialysis patients and was satisfactorily tolerated.?. PMID- 28671064 TI - Resistance mechanisms against quinolones in Mycoplasma capricolum subsp. capricolum. AB - Quinolones interact with bacterial DNA gyrase and topoisomerase IV, the subunits of which are encoded by gyrA/gyrB and parC/parE, respectively. The aim of this study was to evaluate the relationship between changes in these genes and quinolone susceptibility of Mycoplasma capricolum subsp. capricolum (Mcc). Using in vitro selected resistant mutants and field isolates from goats, predicted amino acid changes in gyrA, gyrB and parC were associated with higher minimum inhibitory concentration values for quinolones. Alterations in parC predicted amino acid sequences were most frequently associated with quinolone resistance in Mcc. PMID- 28671063 TI - A hierarchical, retinotopic proto-organization of the primate visual system at birth. AB - The adult primate visual system comprises a series of hierarchically organized areas. Each cortical area contains a topographic map of visual space, with different areas extracting different kinds of information from the retinal input. Here we asked to what extent the newborn visual system resembles the adult organization. We find that hierarchical, topographic organization is present at birth and therefore constitutes a proto-organization for the entire primate visual system. Even within inferior temporal cortex, this proto-organization was already present, prior to the emergence of category selectivity (e.g., faces or scenes). We propose that this topographic organization provides the scaffolding for the subsequent development of visual cortex that commences at the onset of visual experience. PMID- 28671065 TI - Association between ascites and primary hyperfibrinolysis: A cohort study in 210 dogs. AB - Coagulation profiles were determined in 70 dogs with ascites, 70 healthy control dogs and 70 sick control dogs without ascites. Dogs with ascites were divided into four sub-groups based on the pathophysiology of fluid formation. Coagulation profile, serum C-reactive protein and frequency of discordant plasma fibrin fibrinogen degradation products and D-dimer assay results, suggesting primary hyperfibrinolysis, were compared between groups. Within the ascites group, 10 samples of ascitic fluid were transudates due to decreased osmotic pressure, 18 were transudates due to increased hydrostatic pressure, 13 were exudates and 29 were haemorrhagic. Plasma fibrinogen concentrations were significantly lower in dogs with ascites compared to sick dogs without ascites. Activated partial thromboplastin time, prothrombin time, plasma concentrations of fibrin-fibrinogen degradation products and D-dimers, and frequency of primary hyperfibrinolysis, were significantly higher for dogs with ascites compared to both control groups. There was no significant difference in platelet count between groups. The frequency of primary hyperfibrinolysis was highest in dogs with transudative ascites due to increased hydrostatic pressure. Serum C-reactive protein was significantly higher in dogs with ascites compared to both control groups, and significantly and positively correlated with plasma D-dimers. In conclusion, dogs with ascites have an increased frequency of primary hyperfibrinolysis, especially with ascites secondary to increased hydrostatic pressure. The increased inflammation present in these dogs may have activated haemostasis in some cases, explaining the higher plasma D-dimers. PMID- 28671066 TI - Lesions found at routine meat inspection on finishing pigs are associated with production system. AB - Pigs raised under free-range conditions are expected to experience a higher level of animal welfare than conventionally raised pigs. However, free-range conditions may challenge prevention and treatment of diseases. In order to identify disease problems associated with raising conditions, this study compared slaughter lesions in pigs from conventional indoor, conventional free-range and organic free-range production systems. The study used data from 1,096,756 pigs slaughtered at one Danish abattoir from 1 January 2013 to 31 December 2015. Associations between production system and lesions at slaughter were tested in statistical models taking year, season and herd of origin into account. Both conventional free-range and organic free-range production systems were associated with increased population averaged odd ratios (ORPA) for several lesions compared with conventional indoor systems. Pigs raised in conventional free-range and organic free-range production systems had higher odds for white liver-spots (ORPA, 5-7), tail lesions (ORPA, 3-4), arthritis (ORPA, 3), skin lesions (ORPA, 3), bone fractures (ORPA, 2), septicaemia (ORPA, 1.1-1.5) and abscesses (ORPA, 1.1-1.3) at slaughter. Pairwise comparisons of the two free-range production systems did not reveal statistically significant differences (P>0.05). In all three production systems, airway infection was the most prevalent disease complex. In contrast to previous studies, this study did not find any association between airway infection and type of production (P>0.05). Three lesions (leg swellings (ORPA, 0.4-0.5), hernia (ORPA, 0.7-0.8) and hoof abscess (ORPA, 0.7 0.9)) had lower ORs in conventional free-range and organic free-range production compared with conventional indoor production. There was a marked herd effect (intraclass correlation coefficients 21-35%) on the occurrence of white liver spots, tail lesions, skin lesions and airway infections. These results suggest possibilities for herd-level management interventions of the problems studied. PMID- 28671067 TI - The antimicrobial activity of bupivacaine, lidocaine and mepivacaine against equine pathogens: An investigation of 40 bacterial isolates. AB - Lameness is the most commonly reported health problem in horses, and lameness investigations which include local anaesthetic injections are routinely performed by equine practitioners. Through this process, bacteria can enter the tissues perforated by the needle and may cause local infections at the injection site. The objective of this in vitro study was to investigate if local anaesthetics at concentrations available in commercially available solutions could inhibit growth and/or kill bacteria that could be inoculated into the synovial space or soft tissues during injection. This study evaluated the antimicrobial activity of the local anaesthetics bupivacaine, lidocaine and mepivacaine against 40 equine clinical bacterial isolates of the Actinobacillus, Corynebacterium, Enterobacter, Escherichia, Pseudomonas, Rhodococcus, Staphylococcus and Streptococcus genera. Minimum inhibitory and minimum bactericidal concentrations (MICs and MBCs) were determined by the broth microdilution method. Clinically applied concentrations of bupivacaine, lidocaine, and mepivacaine inhibited visual growth of 93%, 93%, and 80% of isolates tested, respectively. For the majority (80%) of the inhibited isolates, the concentrations were also bactericidal. The tested local anaesthetics possessed antimicrobial activity against equine pathogens at concentrations that are routinely applied in clinical cases. However, this antimicrobial activity should not discourage antiseptic preparation prior to local anaesthetic injections. PMID- 28671068 TI - What are the monetary losses by BVDV infection and is control cost-effective? PMID- 28671069 TI - Prevalence of hyoid injuries in dogs and cats undergoing computed tomography. AB - Fractures of the hyoid bones have been reported occasionally in dogs, but the prevalence and significance of hyoid injury in dogs and cats are unknown. In human beings, hyoid injury is rare and usually is caused by direct trauma to the greater cornu, which are analogous to the paired canine and feline thyrohyoid bones. The aim of this study was to describe the prevalence and morphology of hyoid bone injury detected in dogs and cats undergoing computed tomography (CT) for unrelated disease. CT studies of 293 dogs and 100 cats from 2012 to 2016 were identified and reviewed retrospectively. Hyoid fracture (total of eight bones) or luxation (total of four sites) was present in 9/293 (3.1%) dogs, but none of the cats. One dog had bilateral fractures and one dog had bilateral luxations. The most frequently fractured bone was the epihyoid bone (4/8 fractures). Fracture margins were tapered and sclerotic, consistent with chronic non-union. There was no history of trauma, dysphagia or dyspnea in 7/9 dogs with hyoid fractures. Hyoid bone injury, particularly epihyoid bone fracture, may be an incidental finding in dogs. PMID- 28671070 TI - Effect of canine mesenchymal stromal cells loaded with paclitaxel on growth of canine glioma and human glioblastoma cell lines. AB - This study investigated whether canine mesenchymal stromal cells (cMSCs) are able to take up and release paclitaxel (PTX) in active form, and therefore whether they have potential as a tool for therapeutic delivery of this drug. cMSCs from bone marrow and adipose tissue were isolated, expanded and characterised phenotypically. cMSCs were loaded with PTX (cMSCs-PTX) and their capacity for release of PTX was determined by their effect on proliferation of cancer cells. cMSCs-PTX derived from bone marrow and adipose tissue were able to take up and then release active PTX. cMSCs-PTC inhibited proliferation of the canine glioma cell line J3T, and the human glioblastoma cell lines T98G and U87MG. The potential of canine cMSCs-PTX for treatment of canine gliomas should be investigated further. PMID- 28671071 TI - Papillomavirus infection and squamous cell carcinoma in horses. AB - Squamous cell carcinoma (SCC) is a common disease that seriously impairs the health and welfare of affected horses and other equids. In humans, almost all cervical carcinomas, a high percentage of anogenital SCCs and a subset of SCCs of the head and neck are caused by high-risk human papillomavirus (hrHPV) infection. Since hrHPV-induced human cancers and equine SCC have similar cytological and histopathological features, it has been hypothesised that equine SCCs could also be induced by papillomaviruses. This review provides an overview of the current evidence for an aetiological association between papillomavirus infections and equine SCCs and SCC precursor lesions. SCC of apparently papillomavirus-unrelated aetiology are also discussed, as are recent advances in equine SCC prophylaxis. PMID- 28671072 TI - Anticoagulant activity of oral rivaroxaban in healthy dogs. AB - Rivaroxaban is an oral, direct factor Xa inhibitor used in human thrombotic disorders. In view of the in vitro concentration dependent anticoagulant effects of rivaroxaban in dogs, the time course of its anticoagulant effects was characterized in healthy dogs. Twenty-four healthy Beagles were randomized into three groups (n = 8 per group) and received orally either a placebo or 20 mg rivaroxaban once or twice at an 8 h interval. Fifteen blood samples were collected over a 30 h period, and blindly assayed for prothrombin time (PT), activated partial thromboplastin time (aPTT), tissue factor induced thrombin generation (TG) and anti-factor Xa activity. Thromboelastography (TEG) was evaluated at 0, 1, 4, 8 and 24 h. Peak/baseline anticoagulant effect ratios were analyzed with generalized linear models using beta distributions and times to return to baseline with survival analyses (alpha = 0.05). Peak/baseline anticoagulant effect ratios of PT, aPTT, anti-factor Xa activity, TG and R (TEG) differed significantly between placebo and both rivaroxaban groups (P <0.0001). The peak anticoagulant effect of rivaroxaban occurred 1.5 to 2 h after dosing. The median return to baseline occurred significantly sooner (P <0.01) with 20 mg rivaroxaban administered once (7.9-18.7 h) versus twice (17.5-26.8 h). The inter individual variability differed amongst assays, but overall was moderate to large. No adverse effects were recorded. Twice oral administration of 2 mg/kg rivaroxaban at an 8 h interval maintained 24 h anticoagulant activity, but larger studies are needed to establish guidelines for the use of rivaroxaban in dogs. PMID- 28671073 TI - Ultrasonographic assessment of the atlanto-occipital space in healthy Thoroughbred foals and Thoroughbred foals with neonatal maladjustment syndrome. AB - Ultrasonography of the atlanto-occipital (AO) space may be useful as a non invasive diagnostic tool in neonatal foals. The aims of the study were establish a range of values for ultrasonographic measurements of the AO space in healthy Thoroughbred foals and to compare these variables in healthy foals with foals diagnosed with neonatal maladjustment syndrome (NMS). Ultrasonography of the AO space was performed on 38 healthy Thoroughbred foals and 28 Thoroughbred foals with NMS<=4days of age. Transverse image spinal cord height (P=0.001), width (P<0.001) and spinal cord cross sectional area (P<0.001), and longitudinal image dorsoventral diameter of the ventral spinal artery, were significantly smaller in foals with NMS than in healthy foals. Ratios of spinal canal to cord width and cross sectional area were significantly smaller in healthy foals than in foals with NMS (P<0.001). Spinal canal variables were not significantly different between groups. Several ultrasonographic measurements of the AO space were significantly different between healthy foals and foals with NMS. Further investigation is warranted to investigate the clinical application of this technique. PMID- 28671075 TI - A novel supra-temporal approach to retrobulbar anaesthesia in dogs: Preliminary study in cadavers. AB - A novel supra-temporal technique for retrobulbar anaesthesia in dogs is described and compared to the inferior temporal palpebral approach. Supra-temporal and inferior temporal palpebral retrobulbar injections were performed in 20 orbits of canine cadavers. Distribution of injected contrast medium within the intraconal space and around the optic nerve was analysed using computed tomography. There was adequate distribution of contrast medium within the intraconal space with both techniques. Concurrent intraconal and extraconal distribution was observed using the inferior temporal palpebral approach in 3/10 orbits and using the supra temporal approach in 5/10 orbits. In 3/10 supra-temporal injections, the injected vehicle was distributed preferentially in the caudal aspect of the retrobulbar cone, closer to the orbital fissure. Accidental intraocular injection was never observed. The supra-temporal approach appears to be a valid alternative to the inferior temporal palpebral approach for retrobulbar anaesthesia in dogs, being less technically challenging. Further studies are required to confirm the clinical efficacy of this approach in dogs. PMID- 28671074 TI - Evaluation of the Mycobacterium tuberculosis SO2 vaccine using a natural tuberculosis infection model in goats. AB - The development of new vaccines against animal tuberculosis (TB) is a priority for improving the control and eradication of this disease, particularly in those species not subjected to compulsory eradication programmes. In this study, the protection conferred by the Mycobacterium tuberculosis SO2 experimental vaccine was evaluated using a natural infection model in goats. Twenty-six goats were distributed in three groups: (1) 10 goats served as a control group; (2) six goats were subcutaneously vaccinated with BCG; and (3) 10 goats were subcutaneously vaccinated with SO2. Four months after vaccination, all groups were merged with goats infected with Mycobacterium bovis or Mycobacterium caprae, and tested over a 40 week period using a tuberculin intradermal test and an interferon-gamma assay for mycobacterial reactivity. The severity of lesions was determined at post-mortem examination and the bacterial load in tissues were evaluated by culture. The two vaccinated groups had significantly lower lesion and bacterial culture scores than the control group (P<0.05); at the end of the study, the SO2 vaccinated goats had the lowest lesion and culture scores. These results suggest that the SO2 vaccine provides some protection against TB infection acquired from natural exposure. PMID- 28671078 TI - Drug use to resistance exercise-induced fatigue based on diclofenac diethylamine emulgel efficacy analysis. AB - In this paper, the author study on the effect of drug treatment on sports injury, and makes a comparative analysis of drug effects. In sports, the incidence of various types of injuries is increasing, especially in muscle injury. In the experiment, we compared the effects of three different drugs on the treatment and relief of muscle loss. After 3 weeks, the average optical density of desmin in muscle fiber positive region have decreased, as xiaotong plaster (0.4708+/ 0.0126), votalin (0.5124+/-0.0264) and placebo (0.3856+/-0.0312). It has a certain effect to promote the repair and regeneration of desmin expression by drugs. Through the analysis of the effect of drug intervention on sports injury repair, we can effectively improve the therapeutic effect of sports injury. PMID- 28671076 TI - Feline asthma or feline heartworm disease: Does the diagnosis matter? PMID- 28671077 TI - Novel sequence variants of viral hexon and fibre genes in two dogs with canine adenovirus type 1-associated disease. AB - There is little information on sequence variation of canine adenovirus type 1 (CAdV-1), the aetiological agent of infectious canine hepatitis (ICH). This study reports hexon and fibre gene sequence variants of CAdV-1 in a dog with systemic ICH and a dog with the ocular form of the disease ('blue eye') in Northern Italy in 2013. One of the sequence variants matched a CAdV-1 fox sequence previously detected in Italy. PMID- 28671079 TI - Analysis of antimicrobial use and cost-benefit rationality in medical emergency department. AB - Rational use of antimicrobial agents can reduce the burden of patients, reduce adverse drug reactions and effectively cure bacterial infections. In this paper the analysis is done on the antimicrobial use and cost-benefit rationality in medical emergency department. Based on the analysis of the use of antibiotics in hospital emergency department, Antimicrobial prescription accounting for 44.26% of the total prescription, involving cephalosporins, fluoroquinolones, macrolides, cephalosporins. According to the stakeholder theory, the use of antimicrobial agents involves multiple interests, too much emphasis on any party also affect the rational use of antimicrobial drugs. Pharmacy management departments need to develop a reasonable and scientific list of antimicrobial drugs, standard training people to correctly use the knowledge of antimicrobial drugs. PMID- 28671080 TI - Targeted surveillance and infection-related risk factors of nosocomial infection in patients after neurosurgical operation. AB - The purpose of this study was to investigate the risk factors of nosocomial infection in patients after neurosurgical operations, so as to provide reasonable, effective preventative measures in the future. A total of 1,600 patients with brain tumors, hydrocephalus, craniocerebral trauma and vascular disease treated in the neurosurgery room were chosen for targeted surveillance; and through analysis on the clinical data of patients, the incidence of nosocomial infection, the site of infection and the distribution of pathogens, we investigated the infection-related risk factors. After operation, there were 128 cases with nosocomial infection, with the infection rate of 8.0%; among the several diseases, the postoperative infection rate of brain tumors was 28.13%, the postoperative infection rate of hydrocephalus was 21.88%, and the susceptible sitesin the first three places were lower respiratory tract, intracranial, urinary tract; a total of 69 pathogens were separated from 128 cases with nosocomial infection, and the first three pathogens were Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus, accounting for 21.74%, 17.39%, 11.59% respectively. The incidence of nosocomial infection was higher in patients with invasive operation during the procedure, with significant difference (P<0.05). By targeted surveillance on the nosocomial infection in patients after neurosurgical operations, the nosocomial infection rate was high after neurosurgical operations. By strictly implementing the aseptic operation, it could reduce the invasive operation; effectively reduce the infection rate of patients, to facilitate the healing of patients and early rehabilitation. PMID- 28671081 TI - Research on hospital drug cost control based on the perspective of pharmaceutical economy. AB - In recent years, the continuous growth of drug costs has become one of the hot issues of society. In this paper, by using principles and methods of pharmacoeconomics, we study on the management of drug cost control in hospital. Pharmacoeconomics involves the effective allocation and rational use of drug resources, and study the economic effect, that is to carry out the study of drug resources utilization efficiency. Through the analysis of the cost-benefit analysis of drug treatment, we could find the a more cost-effective treatment. Pharmacoeconomics can be applied to the clinical diagnosis and treatment, make reasonable prescription cost effect, it could provide patients with high economic efficiency of treatment, so that drug treatment to achieve the best results. PMID- 28671082 TI - Effect of Zhuang medicine medicated thread moxibustion on protomics in serum of postherpetic neuralgia patient with Herpes zoster. AB - The aim of this study was to observe the effect of Zhuang medicine medicated thread moxibustion on protomics in serum of postherpetic neuralgia patient with herpes zoster and discuss the action mechanism of Zhuang medicine medicated thread moxibustion in treating postherpetic neuralgia (PHN). Patients were divided into three groups in clinic, namely the pre-treatment group (n=20), post treatment group (n=20) and healthy group (n=20), patients meeting corresponding conditions were recruited in the voluntary principle to accept PHN pain evaluation and protomics tests respectively. Compared with the pre-treatment group, visual analogue scale (VAS) in post-treatment group obviously reduced, protomics indexes like MFG-ES, Lymphotoxin beta/TNFSF3, IL-19, Neuritin, NCAM 1/CD56 and PECAM-1/CD31 obviously changed. The Zhuang medicine medicated thread moxibustion can treat the postherpetic neuralgia patient with herpes zoster, its internal mechanism is to possibly change the protomics indexes like MFG-ES, Lymphotoxin beta/TNFSF3, IL-19, Neuritin, NCAM-1/CD56 and PECAM-1/CD31. PMID- 28671083 TI - Drug cost management in pharmacy management based on pharmacoeconomics: Antimicrobial treatment cases. AB - With the increasing demand for health care, the consumption and cost of drugs have increased dramatically. Pharmacoeconomics is a new interdisciplinary subject in recent years. It mainly focuses on the cost and benefit of drug treatment. In this paper, the authors analyze the drug cost management based on an antimicrobial treatment case. The results show that by using cost-effectiveness method, we could reduce the cost of drugs in the course of treatment, the proportion of antimicrobial drugs are also reduced accordingly. By using the concept of pharmacoeconomics, in order to standardize the process of diagnosis and treatment, and to increase the economic performance of the drug delivery plan. PMID- 28671084 TI - In vivo anti-tumor effect of DC-CIK cells on human lymphoma cell line Raji. AB - To research on the effect of DC-CIK cells on human lymphoma cell line Raji the immunophenotype of DC-CIK cells was analyzed using flow cytometry, and its proliferation inhibition effect was detected using MTT assay. 24 nude mice (4-6 weeks old) were employed and inoculated Raji cells on right axillaries for constructing human Burkitt lymphoma model. MTT results showed that DC-CIK cells had a significant inhibitory effect on Raji cells with obvious dose- and time- dependent effect. Western Blot results confirmed that DC-CIK cells could significantly down regulate the expression of BCL-2 (P<0.05). DC-CIK cells possesses significant anti-tumor effect on human Burkitt lymphoma bearing nude mice, and down regulation of Raji induced BCL-2 cell apoptosis may be one of the inhibitory mechanisms of DC-CIK cells. PMID- 28671085 TI - Research on the pharmaceutical intellectual property protection and supervision of pharmacy administration. AB - The patent system plays an important role in the pharmaceutical industry. In this paper, the authors analyze the pharmaceutical intellectual property protection and supervision of pharmacy administration. The intellectual property rights of drugs shall be granted to the inventor in accordance with the law, however, the pharmaceutical industry is concerned with the public health and social welfare. Therefore, we focus on the analysis of patent compulsory licensing system in the protection of intellectual property rights. Through case studies, we can see that although many countries do not implement compulsory licensing system, but this system still can become the chip for all countries to obtain authorization or reduce drug price. PMID- 28671086 TI - Deficiency of interfibrillar mitochondria in post-acute myocardial infarction heart failure. AB - Mitochondrial dysfunction plays an important role in the progress of heart failure (HF). A pronounced variability of defects in mitochondrial subpopulations is reported to occur in various disease models. The aim of the study was to define the defects in the ultra structure and bioenergetic function of cardiac mitochondria in acute myocardial infarction-induced HF. AMI-induced HF rats were treated with saline (4.0ml/kg) for 8weeks. The ultra structure of myocardial mitochondrial subpopulations was assessed by electron microscope. The bioenergetic function of myocardial mitochondrial subpopulations was evaluated through Clark oxygen electrode. Results indicated that myocardial mitochondrial subpopulations in Model group had abnormal mitochondrial morphology which manifested as swelling and vacuoles, membrane lysis, fuzzy ridge structure, cristae lysis or disappear in IFM particularly, while SSM was almost survived in AMI induced heart failure. Results showed that the oxidative phosphorylation function of respiratory chain of NADH oxidation was impaired notably. Compared with Sham group, both P/O (P<0.01) and OPR (P<0.01) of myocardial IFM in model rats decreased, and V3 (P<0.01), P/O (P<0.05) and OPR (P<0.01) of SSM in Model group decreased either. Meanwhile, the oxidative phosphorylation function of respiratory chain of FADH oxidation was injured in SSM particularly, which presented as the decreased P/O (P<0.01). We propose that the mitochondrial defect of severe HF mostly lies in the interfibrillar mitochondria rather than in the subsarcolemmal mitochondria. PMID- 28671087 TI - The effect analysis of CYP2D6 gene polymorphism in the toremifene and tamoxifen treatment in patient with breast cancer. AB - The purpose of the present research work was to study the CYP2D6 gene polymorphism survival outcome after breast cancer patient received the toremifene and tamoxifen treatment. Seventy-eight patients who received radical mastectomy and toremifene and tamoxifen treatment after operation were divided into three groups: CYP2D6*1/*1 group (13 cases), CYP2D6*1/*10 group (28cases) and CYP2D6*10/*10 group (35 cases), according to the gene polymorphism of blood serum CYP2D6. The results of treatment of three groups were compared. After operation the content of blood serum CA125, CA153, VEGF, IGF-1 were all lower than before. The content of CYP2D6*10/*10 group was higher than those of CYP2D6*1/*1 group and CYP2D6*1/*10 group. The content of CYP2D6*1/*1 group had no difference with that of CYP2D6*1/*10 group. All patients were followed up for a median duration of 30.5 months. Progression-free survival (PFS) of CYP2D6*10/*10 was shortened. The recurrence rate increased and the survival rate reduced. There were no obvious differences between CYP2D6*1/*1group and CYP2D6*1/*10 group. In summary, CYP2D6 gene polymorphism relates with the effect of toremifene and tamoxifen treatment in patient with ER positive breast cancer and null allele homozygote CYP2D6*10/*10 can lead to a poor prognosis. PMID- 28671088 TI - Correlation study of cough variant asthma and mycoplasma pneumonia infection in children. AB - Cough variant asthma (CVA), as one of bronchitis diseases, features with repeated cough. In clinics, CAV does not show significant abnormal signs, therefore antibiotic therapy can hardly achieve satisfactory treatment effect. With the development of scientific technologies, the correlation between mycoplasma pneumoniae infection and CVA has become a hot research topic in clinics. In clinics, mycoplasma pneumoniae is extensively regarded as major cause for CVA, with complex pathogenic mechanism. The symptoms of CVA is characterized by chronic non abnormal inflammation, normally accompanied with bronchospasm and intestinal infection. Clinical practices show that about 6% of CVA children mainly show continuous cough till midnight during onset period, which is easily to misdiagnosed as bronchitis. Mycoplasma pneumoniae infection is a common disease threatening Children's health in China. With the annual increase of incidence of infantile pneumonia in China, mycoplasma pneumoniae infection has become a major reason leading to the death of child in China. More such mycoplasma pneumoniae infection is a sporadic disease spreading in a small range, and can onset in four seasons, making great impact on living quality and health of children. On this basis, this paper analyzes the correlation between Children's CVA and mycoplasma pneumoniae infection, in the hope of providing valuable reference for clinical treatment. PMID- 28671089 TI - Analysis on curative effects and safety of 2% liranaftate ointment in treating tinea pedis and tinea corporis & cruris. AB - The paper is intended to analyze and evaluate the specific curative effect and safety of 2% liranaftate ointment in treating patients with tinea pedis and tinea cruris. 1,100 cases of patients with tinea pedis and tinea corporis & cruris were selected as research objects and were divided into two groups according to the random number table method. They were treated with different methods: 550 cases of patients were treated with 2% liranaftate ointment for external use in the observation group and the rest 550 cases of patients were treated with 1% bifonazole cream in the control group. The treatment time was two weeks for patients with tinea corporis & cruris and four weeks for those with tinea pedis respectively. Meanwhile, the one-month follow-up visit was conducted among the patients to compare the curative effects of two groups. After the medication, the curative effectiveness rate was 87.65% (482/550) in the observation group, while that was 84.91% (467/550) in the control group. After the average follow-up visits of (15.5+/-2.4), the curative effectiveness rate 96.55% (531/550) in the observation group, while that was 91.45% (503/550) in the control group. Two groups of patients recovered well with a low incidence of adverse reactions in the treatment, and the overall curative effect was good with the inter-group difference at P>0.05, so it was without statistical significance. The curative effect of 2% liranaftate ointment is safe and obvious in treating tinea pedis and tinea corporis & cruris, so it is valuable for clinical popularization and application. PMID- 28671090 TI - Anesthesia with propofol and sevoflurane on postoperative cognitive function of elderly patients undergoing general thoracic surgery. AB - This study is to analyze the effects and variations on cognitive function for elderly patients undergoing general thoracic surgery, who accepted the anesthesia with propofol and sevoflurane. A total of 500 elderly general thoracic surgical patients were selected randomly, all receiving the propofol anesthesia (Propofol group). Meanwhile, another totality of 500 patients in the same condition and period were selected and accepted the sevoflurane anesthesia (Sevoflurane group). Mini-mental state examination (MMSE) and recovery quality after anesthesia were compared among the patients in both groups respectively at the time of pre operation and 1 h, 6 h and 12 h after surgery. There was no statistic difference in preoperative MMES of patients in both two groups (P<0.05); while the results of postoperative MMSE showed that both Propofol group and Sevoflurane group had a certain statistical difference, and that in Propofol group was larger compared that in Sevoflurane group. Moreover, P<0.05 was obtained on comparing the MMSE at the time of 1h, 6h and 12h after surgery and that at pre-operation, revealing statistical significance. Either propofol or sevoflurane, to certain extent, can affect patients' cognitive function when they are applied in the general thoracic surgery for elderly patients. However, the influence of propofol on cognitive function is relatively smaller, which presents a better application value. PMID- 28671091 TI - Research on dezocine in peritoneal gynecology operation under the target organ effect. AB - This paper was aimed to further analyze the concrete clinical efficacy of dezocine as an anesthetic for peritoneal gynecology operation and to offer a scientific guidance for future surgical treatments. This paper randomly selected 1000 peritoneal gynecology operation patients in 5 hospitals from January to December 2015 as research objects in the observation group, who were mainly applied with dezocine in operative anesthesia. By analyzing data of cases, it concluded efficacy characteristics of dezocine in various phases, and thus provide scientific guidance for future surgical treatments. Another 500 patients who were given with fentanyl as anesthetic in peritoneal gynecology operation were selected as research objects in the control group. We compared the two groups in aspects of index changes before and after operative anesthesia, VAS scores and haemodynamics changes in 2 hours of anesthesia. The results showed that, index changes occurred in both of groups after anesthesia, but patients in the observation group presented a more obvious efficacy with a significant difference (P<0.05). Besides, adverse reactions in both of groups during the operation were basically comparative, so there was no significant difference (P>0.05) or statistical value. This research demonstrated that dezocine, as an anaesthetic in gynecology operation, has a good therapeutic effect and value of wide application in clinical anesthesia. PMID- 28671092 TI - Clinical features of capillary bronchitis related to bordetella pertussis. AB - Pertussis infection can mimick the clinical manifestations of lower airway infection, while the symptoms and signs in some cases are like Bronchiolitis. The paper carried out retrospective analysis of infant pertussis bordetella infected cases admitted by the Respiratory Dept. of Tianjin Children's Hospital for "capillary bronchitis" from Sept. 2015 to Feb. 2016. It analyzed its clinical features, radiological features, laboratory characteristics and outcome through comparing the capillary bronchitis cases induced by the non-bordetella pertussis. 26 cases of patients infected with bordetella pertussis were included in the group, 15 male patients and 11 female patients, aging from 40 days to 11 months. Comparing with non-pertussis infected cases, the capillary bronchitis induced by pertussis presents spasmodic cough, vomiting after cough, apnea suspension and lymphocythemia and obvious prolong of LOS. However the clinical symptom score is decreased and the duration of breathing is shorter. The follow-up visit detects that the recurrent number of respiratory symptoms of pertussis infected children is higher than that of non-pertussis infected children. The clinical symptoms of patients with capillary bronchitis infected by bordetella pertussis are not typical and are susceptible to be ignored. The duration of respiratory symptoms is longer and susceptible for recurrence. PMID- 28671093 TI - The study of long term curative effect of chronic obstructive pulmonary disease in remission stage treated with TCM. AB - In this study of long term curative effect of chronic obstructive pulmonary disease in remission stage treated with TCM, we have selected 79 patients from January 2013 to January 2015 in our hospital with chronic obstructive pulmonary disease as the research object, we have divided into observation group (40 cases) and control group (39 cases) randomly, the control group received routine treatment, observation group received TCM pulmonary rehabilitation therapy, compare pulmonary function and clinical curative effect of 2 groups of patients, and dyspnea index (Brog index), blood oxygen saturation after 6 and 12 months' treatment. The lung function of the observation group was better than that of control group, the difference was significant (P<0.05). The effective rate of observation group was 97.50%, which was better than that of control group (84.62%), the difference was significant (P<0.05). Brog score, blood oxygen saturation of 2 groups of patients before treatment was not statistically significant (P>0.05); observation group's Brog scores after 6 and12 months' treatment were (2.96 + 0.87), (1.61 + 0.49), oxygen saturation were 94%, 99%, the control group's Brog scores were (4.65 + 0.54), (2.97 + 0.91), oxygen saturation were 86%, 93%, the observation group's indicators were better than that of control group after treatment, the difference was significant (P<0.05). TCM lung rehabilitation treatment of chronic obstructive pulmonary disease has obvious curative effect, it can improve the function of lung, reduce the occurrence of dyspnea, improve patients' tolerance and have obvious long-term curative effect. PMID- 28671094 TI - Expression of MLAA34-HSP70 fusion gene constructed by SOE-PCR. AB - To construct the pIRES2-MLAA34-HSP70 recombinant vector and express the MLAA34 HSP70 recombinant proteins in Escherichia coli (E. coli). The MLAA34 and the HSP70 genes were extracted from U937 cells by RT-PCR, and then we amplified the fusion gene MLAA34-HSP70 by SOE-PCR and inserted it into the pIRES2-EGFP vector to construct the pIRES2-MLAA34-HSP70 recombinant vector. We amplified the fusion gene MLAA34-HSP70 successfully and identified the correctness of pIRES2-MLAA34 HSP70 recombinant vector by PCR and restriction endonuclease. Moreover, the MLAA34-HSP70 recombinant proteins expressed in E. coli were consistent with the expected molecular weight. We constructed the pIRES2-MLAA34-HSP70 recombinant vector successfully and the MLAA34-HSP70 recombinant proteins were successfully expressed by the induction of IPTG. PMID- 28671095 TI - Combination of locking plate and anti-osteoporosis drug for the treatment of senior osteoporotic proximal humeral fractures. AB - To analyze and evaluate the clinical efficacy of the combination of locking plate and anti-osteoporosis drug for the patients with senior osteoporotic proximal humerus fractures. 120 patients with senior osteoporotic proximal humerus fractures were selected as research objects. According to the differences of treatment options, they were divided into two groups, i.e., 60 patients in observation group accepting the treatment of combination of locking plate and anti-osteoporosis drug, the other 60 patients in the control group accepting simple locking plate treatment. The treatment effect and final result between the two groups were compared. The follow-up result showed that the average fracture healing time of observation group was (94.5+/-4.2) days, with excellent treatment rate reaching to 93.33% (56/60); the average fracture healing time of control group was (116.5+/-3.8) days, with excellent treatment rate of 75% (45/60). The intergroup different was of statistical significance, wherein p<0.05. The treatment efficacy of the combination of locking plate and anti-osteoporosis drug for senior osteoporotic proximal humeral fractures is faster and more precise, which is worth being applied in clinical practice. PMID- 28671096 TI - The reference intervals for renal function indexes in chinese pregnant women. AB - The purpose of the present research was to establish reference intervals for renal function indexes (Cystatin C, Blood Urea Nitrogen Creatinine and Uric Acid) in pregnant women in China. Blood samples were collected from 203 healthy non pregnant women and 623 healthy pregnant women in different trimesters. Samples from 23 healthy consecutive pregnant women were collected to validate. Serum Cystatin C was measured by latex particle enhanced immune turbidity assay (Dade Behring, Germany) using Centaur 2400 (Siemens, New York, USA). Creatinine, Blood Urea Nitrogen and Uric Acid were measured by conventional enzymatic assay using a Centaur 2400 (Siemens, New York, USA). The calculated reference intervals for serum cystatin C were (0.76+/-0.12) mg/L, (0.70+/-0.14) mg/L, (0.75+/-0.16) mg/L, (1.19+/-0.23) mg/L in control group, 1st trimester, 2nd trimester and 3rd trimester, respectively. Creatinine were (54.21+/-7.49) umol/L, (45.90+/-8.55) umol/L, (44.56+/-8.65) umol/L, (52.78+/-11.76) umol/L in each group. Blood Urea Nitrogen were (4.74+/-1.24) mmol/L, (3.52+/-1.44) mmol/L, (3.81+/-2.32) mmol/L, (3.95+/-1.54) mmol/L. And Uric Acid were (281.35+/-63.61) umol/L, (226.93+/ 25.20) umol/L, (252.39+/-62.32) umol/L, (350.86+/-93.31) umol/L. In addition, all the data of consecutive pr egnant women were in the central 95% intervals. The results show the necessity to establish the special reference intervals for pregnancy, even each trimester. Different areas show the different intervals, indicating we need own ones in our region, and we provided. And Cystatin C is the most stable between these indexes. But we also should cautiously treat it in the 3st trimester. PMID- 28671097 TI - Clinical observation on the therapeutic effect of desloratadine citrate disodium in the treatment of chronic urticaria and changes in IL4, IL18, IL23 and IL-33 levels before and after treatment. AB - : The effect of citrate to Desloratadine Citrate Disodium set in the treatment of chronic urticaria in patients with IL4, IL18, and IL23, IL33 levels was investigated. 100 cases of chronic urticaria treated in our hospital from January 2013 to January 2015 were divided into study group and control group by random number table method. Patients in the study group with chloric thunder of citric acid treatment, the control group were treated with mizolastine in the treatment, the treatment time for 2 weeks. The difference of curative effect between the two groups and the changes of IL4, IL18, IL23, IL 33 before and after treatment in two groups were compared. After two weeks of treatment, the total effective rate of the study group was 94%, while the total effective rate of the control group was only 78%, which was statistically significant (P<0.05). Before treatment, the two groups of patients with IL4, IL18, IL23, IL33 levels were higher, and the difference between the groups was not statistically significant (P>0.05), after treatment, the two groups of patients with IL4, IL18, IL23, IL33 were decreased, but the study group patients decreased significantly, the data between the two groups was statistically significant (P<0.05). CONCLUSION: Desloratadine citrate disodium treatment effect of chronic urticaria is better, and after treatment, IL4, IL18, IL23, IL33 levels decreased significantly. PMID- 28671098 TI - Pathogen infection and drug resistance in laparoscopy-assisted total gastrectomy for upper gastric cancer. AB - With the abuse of antibiotics, pathogenic bacteria more resistant to infection, prevention and control of postoperative, we conducted a systematic analysis of the pathogenic bacteria and drug resistance in patients with infection after surgery. At the same time, we evaluate long-term outcomes between laparoscopy assisted and open approaches to total gastrectomy for upper gastric cancer. Overall survival (OS) and disease-free survival (DFS) was evaluated using the Kaplan-Meier method. We matched all 246 laparoscopic cases 1:1 with open cases according to age, sex, body mass index and clinical TNM stage. The laparoscopy assisted approach was associated with a significant decrease in surgical blood loss, number of analgesic injections, time to first flatus and length of hospital stay relative to the open approach. The postoperative morbidity did not differ between the two groups. There were no significant differences between the two groups in OS and DFS. The laparoscopy-assisted approach to total gastrectomy for upper gastric cancer results in comparable long-term survival compared with laparotomy. PMID- 28671099 TI - American export control, technology spillover and innovation of Chinese pharmaceutical Industry. AB - This paper was aimed to analyze whether the U.S. strict export control to China affects the technological innovation of Chinese pharmaceutical industry. This paper selected the data of technological innovation and the expenditure of high and new technology adoption in China's pharmaceutical industry from 1995 to 2014, created panel regression model to study the impact of export controls on technology spillovers and the impact of technology spillovers on innovation capacity. The results show that US export control has a significant impact on technology spillovers, but foreign technology spillovers have no significant impact on the innovation of Chinese pharmaceutical industry. Although the US export control prevented foreign technology spillovers to China, but indirectly stimulated the domestic technology spillovers to pharmaceutical manufacturing industry in China. Statistical analysis show that the correlation coefficient between innovation capacity and expenditure for high technology adoption is not significant, but the expenditure of purchasing domestic technical is essential to pharmaceutical innovation. This study shows that US export control indirectly, not directly, affected the technological innovation of China's pharmaceutical industry, affected the allocation of innovative resources, but failed to prevent the technological progress and competitiveness improvement of Chinese pharmaceutical industry. PMID- 28671100 TI - Antithrombotic drug use effect in the treatment of early gastric cancer by endoscopic submucosal dissection. AB - This study was designed to investigate the efficacy and safety of endoscopic submucosal dissection (ESD) for treatment of early gastric cancer. In this study, we evaluated the effects of antithrombotic drugs on bleeding risk in patients with ESD. Meta analysis showed that the use of antithrombotic drugs before ESD can reduce the risk of postoperative bleeding, but the early recovery of the use of antithrombotic drugs, or combined with a variety of antithrombotic drugs will increase the risk of bleeding. Twenty-four lesions in 524 patients were treated using ESD, and treatment status and efficacy were observed. Patients received intravenous antibiotics 30 minutes before ESD to prevent infection. If infection occurred after ESD, according to susceptibility test results, patients were given sensitive antibiotics. The one-time en bloc resection rate of all 524 lesions was 100%, and the histologic curative resection rate was 100%. The average time of surgery was 48 min. The rate of mild acute bleeding was 4.2% (22/524), the incidence of postoperative abdominal pain was 54.2% (284/524), and no heavy acute bleeding, perforation, or delayed postoperative bleeding occurred. Endoscopic re examination at 2 months revealed an ulcer healing rate of 100%. A 12-month follow up revealed no local residue, relapse, or new lesions. ESD can increase the one time en bloc resection rate and histologic curative resection rate, and is a safe and effective method for treatment of early gastric cancer. PMID- 28671101 TI - Analysis of radiation measurement of FDG radiopharmaceuticals and the development of medical image processing techniques. AB - This paper based on the theory of radiopharmaceuticals and the theory of radiation risk prediction, the author mainly studies the dose distribution of F FDG and its radiation risk. Through the assessment of the risk of radiation carcinogenesis, the effective dose range was 4.61mSv to 8.97mSv, and the range of radiation carcinogenic risk was 1.57 *10-3-3.14*10-3. Also, we reviewed the development trend of medical image processing techniques, and the development of medical imaging processing in three-dimensional (3D) medical imaging visualization and PACS-based medical imaging compression is introduced. PMID- 28671102 TI - Pentoxifylline intervention and drug action in scalping forehead flap for large temporal cutaneous defects. AB - Pentoxifylline is widely used in the treatment of cerebrovascular disease, at present, there are a variety of drugs in the clinical expansion of the role of the skin flap, by improving or promoting blood circulation, to ensure the survival of the flap. We designed scalping forehead flap to reconstruct large temporal cutaneous defects. This flap is reliable and can give us excellent postoperative result. This design has several advantages and is worth to be promoted. The scalping forehead flap we designed is reliable. The posterior auricular artery and it branches provided enough blood supply to the scalp and forehead tissue of the flap. The frontal muscle also make the flap have a high survival rate. Large temporal cutaneous defects can be reconstructed by this novel scalping forehead flap we described. This technique is useful especially for patients who suffered malignant tumor and can not choose free flap. PMID- 28671103 TI - Effects of Codonopsis pilosula water extract on MicroRNA expression profile in D galactose-induced senile mice. AB - This paper aims to observe and analyze effects of Codonopsis pilosula water extract on micro RNA (miRNA) expression profile in liver tissue of senile mice. The 110 Konminmice were randomly divided into five groups, including D-galactose induced senile model group, normal control group, and low, middle and high dose intervention groups. Continuous modeling lasted 40 days. General symptoms and changes of body mass of the model mice were monitored and observed. The levels of serum glutamic pyruvic transaminase (ALT) and alkaline phosphatase (ALP) of mice were compared, and miRNA of differential expression during aging of D-galactose induction and high-dose Codonopsis pilosula intervention was analyzed. The serum ALT and ALP levels in the aging model group were significantly higher than those in the normal control group (P<0.05). The serum ALT and ALP levels of Codonopsis pilosula intervention group were lower than those of aging model group, and decrease in ALP value of high dose intervention group was higher (P<0.05). The expression profile of miRNA in the aging model group was significantly different from that in normal control group and high-dose Codonopsis pilosula intervention group, and miRNA expression profile in high-dose Codonopsis pilosula intervention group was clustered with that in the normal control group. The differentially expressed miRNAs of D-galactose-induced senescence and Codonopsis pilosula anti aging usually belong to 7 miRNA clusters. The target gene function of the differentially expressed miRNAs during senescence process was enriched in 29 signal pathways. There were 67 regulatory signal pathways in differentially expressed miRNA target genes during Codonopsis pilosula intervention. The effect of miRNA targeting may play an important role during D-galactose-induced senescence and Codonopsis pilosula anti-aging period. PMID- 28671104 TI - Nitroglycerin hypotensive effect and application in a combined surgery for reconstruction after ipsilateral maxillectomy and orbit evisceration. AB - The oral and maxillofacial region is rich in blood, and it is often difficult to stop bleeding during the operation of maxilla. Nitroglycerin is one of the most commonly used antihypertensive drugs in our hospital. We observed the effect of controlled hypotension in patients with maxillary resection. In group N, the patients had different degrees of tachycardia after using nitroglycerin only. In addition, nitroglycerin has the characteristics of rapid drug resistance. A combined reversed temporal muscle flap and random forehead flap technique was performed successfully to reconstruct the large defect after ipsilateral maxillectomy and orbit evisceration. There were 43 cases used this method during 2014-2016 without large side effects. PMID- 28671105 TI - Report: Small cell neuroendocrine carcinoma (SCNEC) of the tongue: A case report. AB - Small cell neuroendocrine carcinoma (SCNEC) of the tongue is very rare. We here present a SCNEC impatient with distant metastasis. A 74-year-old Chinese male went to hospital to treat a tongue tumor, which was founded at a conventional physical examination in Weifang Stomatology Hospital. The check of positron emission tomography-computer tomography (PET-CT) by Weifang people's hospital revealed a tumor in the right root of tongue, and distant metastasis in the right submandibular area, neck, mediastinum, right hilar, abdominal, retroperitoneal multiple lymph nodes, left thyroid, right lower lung, right scapula and bilateral adrenal. The patient was diagnosed tongue SCNEC by the pathological analysis of the tissue section. Conforming to the diagnosis of tongue SCNEC, the patient received adjuvant chemotherapy for 6 cycles with etoposide and carboplatin, and is alive now 9 months after the diagnosis. PMID- 28671106 TI - Controlled growth of six-point stars MoS2 by chemical vapor deposition and its shape evolution mechanism. AB - Monolayer semiconductors of molybdenum disulfide (MoS2) crystals have drawn tremendous attention due to their extraordinary electronic and optical properties. A uniform and high-quality crystalline MoS2 monolayer is greatly needed in fundamental studies and practical applications. Three-point star to six point star MoS2 nanosheets are readily synthesized in a controlled manner using the chemical vapor deposition method. A possible coalescent model is proposed to study the evolution of the six-point star MoS2 domain. A comparative study of field effect transistors are performed to disclose the negative effect of grain boundaries on the transport properties based on six-point star MoS2. PMID- 28671107 TI - Volatile compounds in blood headspace and nasal breath. AB - Breath analysis is a form of metabolomics that utilises the identification and quantification of volatile chemicals to provide information about physiological or pathological processes occurring within the body. An inherent assumption of such analyses is that the concentration of the exhaled gases correlates with the concentration of the same gas in the tissue of interest. In this study we have investigated this assumption by quantifying some volatile compounds in peripheral venous blood headspace, and in nasal breath collected in Tedlar bags obtained at the same time from 30 healthy volunteers, prior to analysis by selected ion flow tube mass spectrometry. Some endogenous compounds were significantly correlated between blood headspace and nasal breath, such as isoprene (r p = 0.63) and acetone (r p = 0.68), however many, such as propanol (r p = -0.26) and methanol (r p = 0.23), were not. Furthermore, the relative concentrations of volatiles in blood and breath varied markedly between compounds, with some, such as isoprene and acetone, having similar concentrations in each, while others, such as acetic acid, ammonia and methanol, being significantly more abundant in breath, and others, such as methanal, being detectable only in breath. We also observed that breath propanol and acetic acid concentrations were higher in male compared to female participants, and that the blood headspace methanol concentration was negatively correlated to body mass index. No relationship between volatile concentrations and age was observed. Our data suggest that breath concentrations of volatiles do not necessarily give information about the same compound in the blood stream. This is likely due to the upper airway contributing compounds over and above that originating in the circulation. An investigation of the relationship between breath volatile concentrations and that in the tissue(s) of interest should therefore become a routine part of the development process of breath-based biomarkers. PMID- 28671108 TI - Cell-instructive high-resolution micropatterned polylactic acid surfaces. AB - Micro and nanoscale topographical structuring of biomaterial surfaces has been a valuable tool for influencing cell behavior, including cell attachment, proliferation and differentiation. However, most fabrication techniques for surface patterning of implantable biomaterials suffer from a limited resolution, not allowing controlled generation of sub-cellular three-dimensional features. Here, a direct laser lithography technique based on two-photon absorption was used to construct several patterns varying in size between 500 nm and 15 MUm. Through replication via an intermediate mold, the patterns were transferred into polylactic acid (PLA), a widely used biomedical polymer, while retaining the original geometry. An osteoblast-like cell line, MG-63 was used for characterizing the morphological response to the topographical patterns. The results indicated that semi-continuous (dashed) lines, with a height of 1 MUm were able to induce cell elongation in the direction of the lines. However, when dashes with a height of 0.5 MUm were combined with perpendicularly crossing continuous lines (rails) with a height of 8 MUm, the contact guidance effect of the dashes was lost and elongation of the cells was observed in the direction of the larger features. A second pattern, consisting of different arrays of pillars showed that, depending on the pillar height, the cells were either able to spread over the pattern or were confined between the pattern features. These differences in the ability of cells to spread further resulted in the formation of tension forces through stress fibers and displacement of vimentin. The method for high resolution micropatterning of PLA as presented here can also be applied to other biomedical polymers, making it useful both for fundamental studies and for designing new biomaterials with improved functionality. PMID- 28671109 TI - A.L. Copley Best Paper Prize 2016. PMID- 28671110 TI - Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease. AB - A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3*Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas3/4suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem3/4of 6- and 18-month-old Non-Tg and 3*Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3*Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Roralpha, Csnk1E and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis. PMID- 28671111 TI - Alcohol Intake and Cognitively Healthy Longevity in Community-Dwelling Adults: The Rancho Bernardo Study. AB - To better understand the association of alcohol intake with cognitively healthy longevity (CHL), we explored the association between amount and frequency of alcohol intake and CHL among 1,344 older community-dwelling adults. Alcohol intake was assessed by questionnaire in 1984-1987. Cognitive function was assessed in approximate four-year intervals between 1988 and 2009. Multinomial logistic regression, adjusting for multiple lifestyle and health factors, was used to examine the association between alcohol consumption and CHL (living to age 85 without cognitive impairment), survival to age 85 with cognitive impairment (MMSE score >1.5 standard deviations below expectation for age, sex, and education), or death before age 85. Most participants (88%) reported some current alcohol intake; 49% reported a moderate amount of alcohol intake, and 48% reported drinking near-daily. Relative to nondrinkers, moderate and heavy drinkers (up to 3 drinks/day for women and for men 65 years and older, up to 4 drinks/day for men under 65 years) had significantly higher adjusted odds of survival to age 85 without cognitive impairment (p's < 0.05). Near-daily drinkers had 2-3 fold higher adjusted odds of CHL versus living to at least age 85 with cognitive impairment (odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.21, 3.49) or death before 85 (OR = 3.24; 95% CI: 1.92, 5.46). Although excessive drinking has negative health consequences, these results suggest that regular, moderate drinking may play a role in cognitively healthy longevity. PMID- 28671112 TI - Neural Dynamics of Multiple Object Processing in Mild Cognitive Impairment and Alzheimer's Disease: Future Early Diagnostic Biomarkers? AB - The aim of this study was to investigate the behavioral and electrophysiological dynamics of multiple object processing (MOP) in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to test whether its neural signatures may represent reliable diagnostic biomarkers. Behavioral performance and event related potentials [N2pc and contralateral delay activity (CDA)] were measured in AD, MCI, and healthy controls during a MOP task, which consisted in enumerating a variable number of targets presented among distractors. AD patients showed an overall decline in accuracy for both small and large target quantities, whereas in MCI patients, only enumeration of large quantities was impaired. N2pc, a neural marker of attentive individuation, was spared in both AD and MCI patients. In contrast, CDA, which indexes visual short term memory abilities, was altered in both groups of patients, with a non-linear pattern of amplitude modulation along the continuum of the disease: a reduction in AD and an increase in MCI. These results indicate that AD pathology shows a progressive decline in MOP, which is associated to the decay of visual short-term memory mechanisms. Crucially, CDA may be considered as a useful neural signature both to distinguish between healthy and pathological aging and to characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology. PMID- 28671113 TI - Implication of the APP Gene in Intellectual Abilities. AB - BACKGROUND: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role. OBJECTIVES: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation. METHODS: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls). RESULTS: The ARC complex revealed association with verbal and total IQ (empirical p = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p = 0.018), within the APP gene, was confirmed in the AD sample (p = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2. DISCUSSION: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD. PMID- 28671114 TI - Associations of CAIDE Dementia Risk Score with MRI, PIB-PET measures, and cognition. AB - BACKGROUND: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. OBJECTIVES: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. METHODS: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. RESULTS: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05-1.43), lower total gray matter (beta-coefficient -0.29, p = 0.001) and hippocampal volume (beta-coefficient -0.28, p = 0.003), lower cortical thickness (beta-coefficient -0.19, p = 0.042), and poorer cognition (beta coefficients -0.31 for total NTB score, -0.25 for executive functioning, -0.33 for processing speed, and -0.20 for memory, all p < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00-1.30). No associations were found with periventricular WML or amyloid accumulation. CONCLUSIONS: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes. PMID- 28671115 TI - Iron Concentration in Deep Gray Matter Structures is Associated with Worse Visual Memory Performance in Healthy Young Adults. AB - Abnormally high deposition of iron can contribute to neurodegenerative disorders with cognitive impairment. Since previous studies investigating cognition-brain iron accumulation relationships focused on elderly people, our aim was to explore the association between iron concentration in subcortical nuclei and two types of memory performances in a healthy young population. Gender difference was found only in the globus pallidus. Our results showed that iron load characterized by R2* value on the MRI in the caudate and putamen was related to visual memory, while verbal memory was unrelated to iron concentration. PMID- 28671117 TI - A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting. AB - Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57+/-7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings. PMID- 28671118 TI - Cerebral Hemodynamics in Mild Cognitive Impairment: A Systematic Review. AB - BACKGROUND: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target. OBJECTIVE: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS). METHODS: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity. RESULTS: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies. CONCLUSION: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia. PMID- 28671116 TI - Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI). AB - BACKGROUND: The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. OBJECTIVE: To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. METHODS: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. RESULTS: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. CONCLUSIONS: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality. PMID- 28671120 TI - Neurovascular Specifications in the Alzheimer-Like Brain of Mice Affected by Focal Cerebral Ischemia: Implications for Future Therapies. AB - Alzheimer's disease (AD), the most frequent type of dementia, is a prototypical neurodegenerative disease, but shares with stroke certain common risk factors. Consequently, how vascular pathology may modulate AD pathogenesis has gained scientific attention. Therefore, aside from typical features of AD (e.g., amyloid beta, tau hyperphosphorylation, and cholinergic dysfunction), changes within the 'neurovascular unit' (NVU) are of particular interest. This study focused on cholinergic, choline acetyltransferase (ChAT)-immunopositive, and tyrosine hydroxylase (TH)-containing neurons in association with the vasculature to explore the neurovascular complex of the AD brain affected by stroke. Wild-type and triple-transgenic (3xTg) mice of different ages underwent unilateral permanent focal cerebral ischemia. Histochemical analyses comprised diverse neuronal and vascular NVU components, and markers of AD. Immunofluorescence labeling confirmed the existence of Abeta deposits and phospho-tau together with glial reactions and morphologically altered endothelia, visualized by Solanum tuberosum lectin. Twenty-four hours after ischemia induction, immunoreactivities for ChAT and TH declined in the ischemia-affected striatum and, at least in part, in the ischemic border zone and ipsilateral neocortex. Correlation analyses indicated simultaneous degeneration of neuronal and vascular components. A trend for more severe affection of ChAT was observed in younger as compared with older mice. The present findings suggest complex interactions within the NVU of the AD like brain affected by ischemia, comprising alterations of the cholinergic system in conjunction with vascular pathology. Hence, it may be worthwhile to explore the impact of a cellular stabilization approach on vascular and glial elements in AD in terms of a potential disease-alleviating strategy. PMID- 28671119 TI - Four Decades of Research in Alzheimer's Disease (1975-2014): A Bibliometric and Scientometric Analysis. AB - BACKGROUND: Bibliometric and scientometric methods can be applied to the study of a research field. OBJECTIVE: We hypothesized that a bibliometric and scientometric analysis of the Alzheimer's disease (AD) research field could render trends that provide researchers and funding agencies valuable insight into the history of the field, current tendencies, and potential future directions. METHODS: We performed searches in publicly available databases including PubMed, Scopus, Web of Science, and Alzheimer's Funding Analyzer for the period 1975 2014, and conducted a curve fitting analysis with non-linear regression. RESULTS: While the rate and impact of publications continue to increase, the number of patents per year is currently declining after peaking in the late 2000s, and the funding budget has plateaued in the last 5-10 years analyzed. Genetics is the area growing at a fastest pace, whereas pathophysiology and therapy have not grown further in the last decade. Among the targets of pathophysiology research, amyloid-beta continues to be the focus of greatest interest, with tau and apolipoprotein E stagnant after a surge in the 1990s. The role of inflammation, microglia, and the synapse are other research topics with growing interest. Regarding preventative strategies, education attainment, diet, and exercise are recently gaining some momentum, whereas NSAIDs and statins have lost the spotlight they once had. CONCLUSION: Our bibliometric and scientometric analysis provides distinct trends in AD research in the last four decades, including publication and patent output, funding, impact, and topics. Our findings could inform the decision-making of research funding agencies in the near future. PMID- 28671121 TI - Selenomethionine Attenuates the Amyloid-beta Level by Both Inhibiting Amyloid beta Production and Modulating Autophagy in Neuron-2a/AbetaPPswe Cells. AB - Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-beta (Abeta) has been recognized as the major cause of AD. Inhibiting Abeta production and/or enhancing the clearance of Abeta to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-beta (Abeta) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Abeta levels in Neuron-2a/AbetaPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Abeta generation by suppressing the activity of BACE1. Furthermore, both the LC3 II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Abeta clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se Met on AD. PMID- 28671122 TI - Rosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis. AB - Deeper understanding of processes of protein misfolding, aggregation, formation of oligomers, protofibrils, and fibrils is crucial for the development of future medicine in treatment of amyloid-related diseases. While numerous reports illuminate the field, the above processes are extremely complex, as they depend on many varying parameters, such as the peptide concentration, temperature, pH, presence of metal ions, lipids, and organic solvents. Different mechanisms of amyloid fibril formation have been proposed, but the process of the oligomer-to fibril transition is the least agreed upon. Our studies of a number of amyloidogenic proteins and peptides (insulin, Abeta peptides, the Bgl2 protein from the yeast cell wall), as well as their amyloidogenic fragments, have allowed us to propose a model of the fibril structure generation. We have found that the main building block of fibrils of any morphology is a ring-like oligomer. The varying models of interaction of ring oligomers with each other revealed in our studies make it possible to explain their polymorphism. Crucially, the amino acid sequence determines the oligomer structure for the given protein/peptide. PMID- 28671123 TI - Prion Protein Interactome: Identifying Novel Targets in Slowly and Rapidly Progressive Forms of Alzheimer's Disease. AB - Rapidly progressive Alzheimer's disease (rpAD) is a variant of AD distinguished by a rapid decline in cognition and short disease duration from onset to death. While attempts to identify rpAD based on biomarker profile classifications have been initiated, the mechanisms which contribute to the rapid decline and prion mimicking heterogeneity in clinical signs are still largely unknown. In this study, we characterized prion protein (PrP) expression, localization, and interactome in rpAD, slow progressive AD, and in non-dementia controls. PrP along with its interacting proteins were affinity purified with magnetic Dynabeads Protein-G, and were identified using Q-TOF-ESI/MS analysis. Our data demonstrated a significant 1.2-fold decrease in di-glycosylated PrP isoforms specifically in rpAD patients. Fifteen proteins appeared to interact with PrP and only two proteins3/4histone H2B-type1-B and zinc alpha-2 protein3/4were specifically bound with PrP isoform isolated from rpAD cases. Our data suggest distinct PrP involvement in association with the altered PrP interacting protein in rpAD, though the pathophysiological significance of these interactions remains to be established. PMID- 28671124 TI - Impact of Neuroinflammation on Hippocampal Neurogenesis: Relevance to Aging and Alzheimer's Disease. AB - The cognitive reserve is associated with the capacity of the brain to maintain cognitive performance in spite of being challenged by stressful degenerative insults related to aging. Hippocampal neurogenesis is a life-long process of continuous addition of functional new neurons in the memory processing circuits. Accordingly, adult hippocampal neurogenesis is increasingly seen as a key determinant of cognitive reserve robustness. On the other side, neuroinflammation, by releasing a plethora of proinflammatory cytokines and other inflammatory molecules, is increasingly shown to be one of the key determinant pathophysiological factors that negatively impact on neurogenesis and on the cognitive reserve, playing a detrimental role in hippocampal neurogenic niche dynamics and in the progression of neurodegenerative diseases, such as Alzheimer's disease. In the present manuscript, we highlight the functional interplay between neuroinflammation, dynamics of the neurogenic niche, and spatial memory performance in healthy and age-related pathological processes, including progression of Alzheimer's disease. PMID- 28671125 TI - Distribution of Types of Dementia in the First 100 Patients Seen at a Dementia Clinic in India. AB - The aim of our study was to determine if the distribution of types of dementia could explain the reported lower prevalence of dementia in India. The study is an observational study of the first 100 cases of dementia. All patients were evaluated clinically and with blood tests and MRI of the brain. The causes of dementia were: Lewy body dementia (22%), depression (20%), Alzheimer's disease (13%), and mild cognitive impairment (18%). Other dementias were less common. The distribution of dementia types in this series is different from that reported globally. The observation of Lewy body dementia being the most common cause of dementia needs to be verified. PMID- 28671126 TI - Shear-Induced Amyloid Formation in the Brain: II. An Experimental System for Monitoring Amyloid Shear Processes and Investigating Potential Spinal Tap Problems. AB - Liquid sheared amyloid-beta (Abeta) initiates amyloid cascade reactions, producing unstable, potentially toxic oligomers. There is a need for new analytical tools with which to study these oligomers. A very small bore capillary flow system is proposed as a tool for studying the effects of liquid shear in amyloid research. This simple system consists of injecting a short cylindrical liquid sample plug containing dissolved amyloid into a liquid mobile phase flowing through an empty, very small internal diameter capillary tube. For liquid samples containing a single protein sample, under conditions in which there is laminar flow and limited sample protein molecular diffusion, chromatograms monitoring the optical protein absorbance of capillary effluent contain either one or two peaks, depending on the mobile phase flow rate. By controlling the sample diffusion times through changes in flow rate and/or capillary diameter, this tool can be used to generate aliquot samples with precise, reproducible amounts of shear for exploring the effects of variable shear on amyloid systems. The tool can be used for producing in-capillary stopped flow spectra of shear stressed Abeta monomers as well as for kinetic studies of Abeta dimer- and oligomer-forming reactions between shear stressed Abeta monomers. Many other experiments are suggested using this experimental tool for studying the effects of shear on different Abeta and other amyloid systems, including testing for potentially serious amyloid sampling errors in spinal tap quantitative analysis. The technique has potential as both a laboratory research and a clinical tool. PMID- 28671127 TI - Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer's Disease with Positron Emission Tomography. AB - Aging is a risk factor for Alzheimer's disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD. PMID- 28671128 TI - Evaluation of the Reliability, Validity, and Predictive Validity of the Subscales of the Perceived Stress Scale in Older Adults. AB - BACKGROUND: The Perceived Stress Scale (PSS) is made up of two subscales but is typically used as a single summary measure. However, research has shown that the two subscales may have differential properties in older adults. OBJECTIVE: To evaluate the internal consistency, test-retest reliability, and the concurrent and predictive validity for development of amnestic mild cognitive impairment (aMCI) of the positively-worded (PSS-PW) and negatively-worded (PSS-NW) subscale scores of the PSS in older adults. METHODS: We recruited community residing older adults free of dementia from the Einstein Aging Study. Reliability of the PSS-PW and PSS-NW was assessed using Cronbach's alpha for internal consistency and intraclass correlation for one year test-retest reliability. Concurrent validity was evaluated by examining the relationship between the PSS subscales and depression, anxiety, neuroticism, and positive and negative affect. Predictive validity was assessed using multivariate Cox regression analyses to examine the relationship between baseline PSS-PW and PSS-NW score and subsequent onset of aMCI. RESULTS: Both PSS-PW and PSS-NW showed adequate internal consistency and retest reliabilities. Both the PSS-PW and PSS-NW were associated with depression, neuroticism, and negative affect. The PSS-NW was uniquely associated with anxiety while the PSS-PW was uniquely associated with positive affect. Only the PSS-PW was associated with a statistically significant increased risk of incident aMCI (HR = 1.27; 95% CI: 1.06-1.51 for every 5-point increase in PSS-PW). CONCLUSIONS: Evaluating the separate effects of the two PSS subscales may reveal more information than simply using a single summation score. Future research should investigate the PSS-PW and PSS-NW as separate subscales. PMID- 28671129 TI - Dual Mechanism of Toxicity for Extracellular Injection of Tau Oligomers versus Monomers in Human Tau Mice. AB - The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death. PMID- 28671130 TI - Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States. AB - BACKGROUND: Exposure of the brain to ionizing radiation might promote the development of Alzheimer's disease (AD). OBJECTIVE: Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states. METHODS: Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer's Association. RESULTS: Radon background ionizing radiation was significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.467, p = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.452, p = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (beta= 0.169, p < 0.001), age (beta= 0.231, p < 0.001), hypertension (beta= 0.155, p < 0.001), and diabetes (beta= 0.353, p < 0.001). CONCLUSION: Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor. PMID- 28671131 TI - Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study. AB - BACKGROUND: Olfactory deficits are present in early Alzheimer's disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. OBJECTIVE: This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. METHODS: We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). RESULTS: The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments. CONCLUSION: The no odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system. PMID- 28671132 TI - Capsaicin Attenuates Amyloid-beta-Induced Synapse Loss and Cognitive Impairments in Mice. AB - Alzheimer's disease (AD) is the most common cause of progressive cognitive impairment in the aged. The aggregation of the amyloid beta-protein (Abeta) is a hallmark of AD and is linked to synapse loss and cognitive impairment. Capsaicin, a specific agonist of the transient receptor potential vanilloid 1 (TRPV1), has been proven to ameliorate stress-induced AD-like pathological and cognitive impairments, but it is unclear whether TRPV1 activation can affect cognitive and synaptic functions in Abeta-induced mouse model of AD. In this study, we investigated the effects of TRPV1 activation on spatial memory and synaptic plasticity in mice treated with Abeta. To induce AD-like pathological and cognitive impairments, adult C57Bl/6 mice were microinjected with Abeta42 (100 MUM, 2.5 MUl/mouse, i.c.v.). Two weeks after Abeta42 microinjection, spatial learning and memory as well as hippocampal long-term potentiation (LTP) were examined. The results showed that Abeta42 microinjection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with controls. These behavioral changes were accompanied by synapse loss and impaired LTP in the CA1 area of hippocampus. More importantly, daily capsaicin (1 mg/kg, i.p.) treatment throughout the experiment dramatically improved spatial learning and memory and synaptic function, as reflected by enhanced hippocampal LTP and reduced synapse loss, whereas the TRPV1 antagonist capsazepine (1 mg/kg, i.p.) treatment had no effects on cognitive and synaptic function in Abeta42-treated mice. These results indicate that TRPV1 activation by capsaicin rescues cognitive deficit in the Abeta42-induced mouse model of AD both structurely and functionally. PMID- 28671133 TI - Chinese Medicine: A Hope for Neurodegenerative Diseases? AB - With the increase in the proportion of aged population due to the rapid increase of life expectancy, the worldwide prevalence rate of multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease has been increased dramatically. The demographic trend toward an older population has drawn the attention to new drug discovery and treatment on age related diseases. Although a panel of drugs and/or therapies are currently available for treating the neurodegenerative diseases, side effects or insufficient drug efficacy have been reported. With the long history in prescription of Chinese medicine or natural compounds for modulating aged-related diseases, emerging evidence was reported to support the pharmacological role of Chinese medicine in ameliorating the symptoms, or interfering with the pathogenesis of several neurodegenerative diseases. This review brings evidence about today's trends and development of a list of potential neuroprotective herbal compounds from both the traditional and modern pharmacological point of view. With future projections, the potential hope and implication of using Chinese medicine as an alternative source for novel drug discovery for neurodegenerative diseases is proposed. PMID- 28671135 TI - Fifteen Years of Clinical Trials in Huntington's Disease: A Very Low Clinical Drug Development Success Rate. AB - BACKGROUND: Drug development in Huntington's disease (HD) is particularly challenging, and only two compounds are approved by the FDA. It is therefore essential to appraise drug development programs in order to understand the reasons for their failure during the early stages of development. OBJECTIVES: To describe the landscape of HD therapeutic development and critically explore the causes of compound attrition in the different stages of drug development, from phase 1 to phase 4. METHODS: All HD clinical trials registered in the WHO International Clinical Trials Search Portal, from inception to May 2017, were analyzed. Two independent authors selected and extracted data. Success rate in a trial phase was calculated as the number of compounds that progressed to the next trial phase divided by the number of compounds in that phase. The overall success rate was calculated as the ratio between the number of compounds that receive regulatory approval and the total number of compounds. RESULTS: Ninety-nine trials assessing 41 compounds and eleven non-pharmacological interventions (devices and cell therapies) were identified. Twenty-four (24.2%) were phase 1 trials, 46 (46.5%) phase 2, 20 (20.2%) phase 3, and two (2.0%) phase 4. Sixty trials (60.6%) received industry sponsorship. The most frequently studied compounds were creatine, latrepirdine and pridopidine. The mean number of participants enrolled was 92.0 and the length of treatment was 262.9 days, and both increased from phase 1 to phase 3 trials. The success rate was 25.0% from phase 1 to phase 2, 19.4% from phase 2 to phase 3, and 14.3% from phase 3 to approval. The overall success rate was 3.5%. CONCLUSIONS: Although HD is a rare condition, 99 HD trials were identified in a comprehensive clinical trial registry. We found a low success rate at earlier phases of drug-development and a very low trial success rate at later phases. There is a significant gap between drug discovery and development success rates that warrants careful appraisal and improvement. PMID- 28671134 TI - Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease. AB - BACKGROUND: Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD). OBJECTIVE: In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. METHODS: Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared. RESULTS: Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group. CONCLUSION: This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials. PMID- 28671136 TI - Analysis of Participant Withdrawal in Huntington Disease Clinical Trials. AB - BACKGROUND: Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials. OBJECTIVE: We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal. METHODS: Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models. RESULTS: Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies. CONCLUSIONS: The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status. PMID- 28671138 TI - Upcoming Meetings Related to Huntington's Disease. PMID- 28671137 TI - What do we know about Late Onset Huntington's Disease? AB - BACKGROUND: Although the typical age of onset for Huntington's disease (HD) is in the fourth decade, between 4.4-11.5% of individuals with HD have a late onset (over 60 years of age). Diagnosis of Late onset HD (LoHD) can be missed, due to the perceived low likelihood of HD in the over 60-year-olds. OBJECTIVE: To review the epidemiology, genotype and phenotype of LoHD. METHODS: We systematically searched MEDLINE, EMBASE and Web of Science (inception-November 2016). Web of Science was then used to search for papers citing identified studies. Content experts were consulted for any additional studies. We included all studies reporting the clinical phenotype of LoHD for more than one participant. RESULTS: 20 studies were identified from a potential list of 1243. Among Caucasian HD cohorts, 4.4-11.5% of individuals have LoHD, and this proportion may be increasing. Proportion of LoHD without a positive family history ranges from 3 68%. 94.4% of reported cases of LoHD had CAG repeat lengths of <=44. Motor manifestations are the commonest initial presentation, although 29.2% presented with non-motor manifestations as the first clinical feature in one case series. Individuals with LoHD may have slower progression of illness. Cognitive impairment rather than chorea may be the major source of disability in this group. CONCLUSIONS: LoHD represents a substantial proportion of new diagnoses of HD and has some unique features. Further characterization of this population will aid clinicians in diagnosis. PMID- 28671139 TI - Attitudes Towards Data Collection, Ownership and Sharing Among Patients with Parkinson's Disease. AB - BACKGROUND: The ownership and sharing of patient medical data is an increasingly contentious subject in medicine generally but also within the field of Parkinson's disease (PD). Despite being the providers of the medical data, patients are rarely consulted as to its usage. OBJECTIVE: The objective of this paper is to establish patient attitudes to ownership of their own medical data and the sharing thereof. METHODS: We report here the results of an online survey of people with Parkinson's. A total of 310 people took part in the 'sharing data' component of the survey, answering some or all of the questions for which they were eligible. RESULTS: Most respondents (208/306) were aged between 55 and 74 years. 55% of the sample were female and the mean number of years diagnosed was 7.1. Although 93% of respondents were willing to share data, only 41% were currently doing so and a further 8% did not know whether they were sharing any information in this way. There was a significant association between age and data sharing (p = 0.006). However, no clear relationship was found between data sharing and the number of years diagnosed, sex, medication class or health confidence. There was also no consensus among patients on ownership of, access to and usage of their research data. CONCLUSION: The lack of consensus on data ownership and general absence of clear demographic predictors of data sharing implies impaired communication pathways. We suggest that strategies directed towards improved communication may help to clarify data ownership and promote data sharing. PMID- 28671141 TI - Poor Sleep Quality and Progression of Gait Impairment in an Incident Parkinson's Disease Cohort. AB - Abnormal sleep may associate with cognitive decline in Parkinson's disease (PD). Furthermore, sleep dysfunction may associate with worse motor outcome. We hypothesised that PD patients with poor quality sleep would have greater progression in gait dysfunction, due to structural and functional overlap in networks subserving sleep and gait regulation. 12 PD patients and 12 age-matched controls completed longitudinal follow-up over 36 months. Poor sleep efficiency and greater sleep fragmentation correlated significantly with progression of step width variability, a gait characteristic mediated by postural control, providing evidence that poor sleep in PD is associated with a more rapid deterioration in gait. PMID- 28671140 TI - A Consensus Set of Outcomes for Parkinson's Disease from the International Consortium for Health Outcomes Measurement. AB - BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative condition that is expected to double in prevalence due to demographic shifts. Value-based healthcare is a proposed strategy to improve outcomes and decrease costs. To move towards an actual value-based health care system, condition-specific outcomes that are meaningful to patients are essential. OBJECTIVE: Propose a global consensus standard set of outcome measures for PD. METHODS: Established methods for outcome measure development were applied, as outlined and used previously by the International Consortium for Health Outcomes Measurement (ICHOM). An international group, representing both patients and experts from the fields of neurology, psychiatry, nursing, and existing outcome measurement efforts, was convened. The group participated in six teleconferences over a six-month period, reviewed existing data and practices, and ultimately proposed a standard set of measures by which patients should be tracked, and how often data should be collected. RESULTS: The standard set applies to all cases of idiopathic PD, and includes assessments of motor and non-motor symptoms, ability to work, PD-related health status, and hospital admissions. Baseline demographic and clinical variables are included to enable case mix adjustment. CONCLUSIONS: The Standard Set is now ready for use and pilot testing in the clinical setting. Ultimately, we believe that using the set of outcomes proposed here will allow clinicians and scientists across the world to document, report, and compare PD-related outcomes in a standardized fashion. Such international benchmarks will improve our understanding of the disease course and allow for identification of 'best practices', ultimately leading to better informed treatment decisions. PMID- 28671142 TI - The Role of Lipids Interacting with alpha-Synuclein in the Pathogenesis of Parkinson's Disease. AB - alpha-synuclein is a small protein abundantly expressed in the brain and mainly located in synaptic terminals. The conversion of alpha-synuclein into oligomers and fibrils is the hallmark of a range of neurodegenerative disorders including Parkinson's disease and dementia with Lewy bodies. alpha-synuclein is disordered in solution but can adopt an alpha-helical conformation upon binding to lipid membranes. This lipid-protein interaction plays an important role in its proposed biological function, i.e., synaptic plasticity, but can also entail the aggregation of the protein. Both the chemical properties of the lipids and the lipid-to-protein-ratio have been reported to modulate the aggregation propensity of alpha-synuclein. In this review, the influence of changes in the nature and levels of lipids on the aggregation propensity of alpha-synuclein in vivo and in vitro will be discussed within a common general framework. In particular, while biophysical measurements and kinetic analyses of the time courses of alpha synuclein aggregation in the presence of different types of lipid vesicles allow a mechanistic dissection of the influence of the lipids on alpha-synuclein aggregation, biological studies of cellular and animal models of Parkinson's disease allow the determination of changes in lipid levels and properties associated with the disease. PMID- 28671143 TI - Substantia Nigra Neuromelanin as an Imaging Biomarker of Disease Progression in Parkinson's Disease. AB - BACKGROUND: A specific T1-weighted magnetic resonance imaging (MRI) sequence has been shown to detect substantia nigra (SN) neuromelanin (NM) signal changes that accurately discriminate Parkinson's disease (PD) patients from controls, even in early disease stages. However, it is unclear what happens to these SN changes in later disease stages and if they can be a marker of disease progression. OBJECTIVE: to investigate the pattern of SN-NM area loss and contrast ratio (CR) intensity changes in late-stage PD (LSPD) compared to earlier disease stages. METHODS: A comparative cross-sectional study was performed, analyzing SN-NM MRI signal in LSPD (Schwab and England Activities of Daily Living Scale score <50 or Hoehn Yahr Stage [HY] >3), comparing this group with de novo, 2-5 year PD and controls. SN-NM signal area and CR values for the internal and lateral SN regions were obtained with semi-automated methods. RESULTS: 13 LSPD, 12 de novo patients with PD, 10 PD patients with a 2-5 year disease duration, and 10 controls were included. NM signal area was significantly decreased in LSPD compared to de novo PD (P-value = 0.005; sensitivity: 75%; specificity 92% and AUC: 0.86). In the lateral SN region, a decrease in the CR was detected in all PD groups compared to controls; despite not reaching statistical significance, a slight increment was observed comparing LSPD to 2-5 year PD. NM signal area significantly correlated with HY (R = -0.37; P < 0.05) and Movement disorder Society Unified Parkinson's Disease Rating Scale part II (MDS-UPDRS) (R = -0.4; P < 0.05) while a weak correlation was found with MDS-UPDRS part III (R = -0.26; P: 0.1). CONCLUSION: SN area evaluated by NM-sensitive MRI may be a promising biomarker of nigral degeneration and disease progression in PD patients. PMID- 28671144 TI - A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson's Disease. AB - BACKGROUND: Common genetic variability in the ACMSD gene has been associated with increased risk for Parkinson's disease (PD) but ACMSD mutations in clinical cases of PD have so far not been reported. OBJECTIVE: To describe a case of sporadic PD carrying a novel ACMSD mutation. METHODS: As part of a genetic study to identify potential pathogenic gene defects related to PD in the Mediterranean island Menorca, an initial group of 62 PD patients underwent mutational screening using a panel-based sequencing approach. RESULTS: We report a 74-years-old man with sporadic PD who developed tremor in his right hand and slowness. On examination, moderate rigidity, asymmetric bradykinesia, and bilateral action tremor were present. He was started on levodopa with significant improvement. Two years later, he developed wearing off phenomena. The genetic study in the patient identified a novel ACMSD mutation resulting in p.Glu298Lys amino-acid change which was not present in neurologically normal population. CONCLUSIONS: Our data suggest that not only common genetic variability but also rare variants in ACMSD alone or in combination with other risk factors might increase the risk of PD. PMID- 28671146 TI - Repetitive dynamic stereo test improved processing time in young athletes. AB - BACKGROUND: Current studies revealed the importance of perceptual training for the treatment of amblyopia. To improve stereo vision on a higher level, visual tasks have to be completed within a limited time window like in repetitive visual function tests. "Processing time" as the reaction time in which the absence or presence of depth was identified correctly, is of better predictive value for perceiving the depth than the stereo threshold only. OBJECTIVE: To examine the long-term effects of repetitive dynamic testing of stereopsis on processing time. METHODS: 15 male soccer athletes (13.3+/-3.2 years) underwent twelve sessions of a 15 minutes repetitive dynamic stereovision training over a period of six weeks, presented on a polarized 3D-TV in a four-alternative forced choice setup. We measured the response time of correct identified visual tasks of 11, 22, 44, 55, 66, 77 and 88arcsecs disparity before, after six sessions, after twelve sessions and after six month without testing. As response time is the sum of stereo processing time plus the motor reaction time, we defined the difference between the response times at 11 and 88arcsecs as "stereo processing time at 11arcsecs". A Wilcoxon Signed Rank Test was conducted between the testing sessions to evaluate significant changes in response time and stereo processing time. RESULTS: After six sessions the mean stereo processing time at 11arcsecs decreased significantly from 804.4 ms to 403.7 ms (Z = -2.499, p = 0.012). Six months after the last training the stereo processing time at 11arcsecs remained at the level of the last session. CONCLUSION: Our results suggest that repetitive testing of stereovision is effective in improving processing time of stereoscopic tasks in young male athletes significantly long-term. PMID- 28671147 TI - Sonographic assessment of urolithiasis in university of Abuja teaching hospital, Nigeria. PMID- 28671148 TI - Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. AB - The use of control group in clinical trials has been universally acclaimed by researchers to effectively help discriminate between the actual effects of an intervention and those arising from other factors. However, the choice of the control that provided both scientific and ethical acceptability among researchers has been a source of intense debate. We conducted a literature search on the use of placebo and active controls in clinical trials and X-ray the arguments for and against both choices in randomized control trials and concluded by highlighting the scenarios where the use of placebo is justified. PMID- 28671149 TI - Evaluation of neutrophil gelatinase-associated lipocalin and cystatin C as early markers of diabetic nephropathy. AB - INTRODUCTION: Diabetes mellitus (DM) is a major cause of concern because of its increasing prevalence rate and related microvascular as well as macrovascular complications, including kidney disease. Microalbuminuria has been accepted as the earliest marker for diabetic nephropathy; however, a large proportion of renal impairment occurs in nonalbuminuric state. We planned to investigate the serum and urinary levels of the tubular damage markers (neutrophil gelatinase associated lipocalin [NGAL] and cystatin C [Cys C]) in patients of type 2 diabetes to detect early kidney injury. MATERIALS AND METHODS: This cross sectional hospital-based study included 180 patients with type 2 DM according to the American Diabetes Association criteria. Serum NGAL (S.NGAL) and urine NGAL (U.NGAL) and Cys C were measured in all study participants and investigated for correlation with microalbuminuria. RESULTS: Our results showed that U.NGAL and S.NGAL levels were significantly high in patients with microalbuminuria as compared to normoalbuminuric controls. Serum Cys C was also higher in microalbuminuric patients than who had normoalbuminuria. A positive correlation of urinary albumin excretion with S.NGAL and U.NGAL was noted. U.NGAL also showed positive correlation with duration of diabetes, glycated hemoglobin, and dyslipidemia. Receiver operating characteristic curve analysis showed that the area under the curve for U.NGAL and S.NGAL were 1 and 0.8, respectively, which indicates that they are sensitive markers for early renal damage. CONCLUSION: Urinary biomarkers were significantly elevated in normoalbuminuric type 2 diabetic patients compared with nondiabetic controls and could be used as markers of nephropathy at a very early stage even before the development of microalbuminuria, the current gold standard for early diagnosis. Despite the promise of these new biomarkers, further large, multicenter prospective studies are still needed. PMID- 28671150 TI - Emerging trends of nosocomial pneumonia in intensive care unit of a tertiary care public teaching hospital in Western India. AB - BACKGROUND: Nosocomial pneumonia poses great challenge to an intensivist. Detailed information about hospital-acquired pneumonia (HAP) and ventilator acquired pneumonia (VAP) is crucial for prevention and optimal management, thus improving quality Intensive Care Unit (ICU) care. Hence, we aimed to study the current trend of nosocomial pneumonia in ICU. MATERIALS AND METHODS: It was a prospective observational cohort study, conducted in the ICU of a tertiary care teaching public hospital over a period of 18 months. We studied clinical profile and outcome of 120 adult patients who developed VAP/HAP during the study period. We also analyzed the causative organisms, antibiotic sensitivity, and resistance pattern in these patients. RESULTS: Out of 120 patients, 29 patients were HAP and 91 patients were VAP. Mortality was 60% (72), and development of VAP and requirement of mechanical ventilation showed significant association with mortality (P < 0.00001). Most common organism causing HAP was Staphylococcus aureus (43.4%) and VAP was Klebsiella pneumoniae (49%). Maximum antibiotic sensitivity was found to piperacillin + tazobactam (58.8%), followed by imipenem (49.5%) and meropenem (41.8%), whereas maximum antibiotic resistance was found to cefepime (95.1%), followed by ceftazidime and amoxicillin (91.2%). CONCLUSION: Nosocomial pneumonia showed high incidence (17.44%) and mortality (60%). Common organisms identified were S. aureus and K. pneumoniae. Resistance was high for commonly used antibiotics and high antibiotic sensitivity for piperacillin + tazobactam and carbapenem. Contexte: La pneumonie nosocomiale pose un grand defi a un intensiviste. Des informations detaillees sur la pneumonie acquise dans les hopitaux (HAP) et la pneumonie acquise par le ventilateur (VAP) sont essentielles pour la prevention et la gestion optimale, ameliorant ainsi les soins de soins intensifs de qualite (UTI). Par consequent, nous avons cherche a etudier la tendance actuelle de la pneumonie nosocomiale en UTI. Materiaux et methodes: il s'agissait d'une etude de cohorte observationnelle prospective menee dans l'UCI d'un hopital public d'enseignement tertiaire sur une periode de 18 mois. Nous avons etudie le profil clinique et le resultat de 120 patients adultes qui ont developpe le VAP / HAP pendant la periode d'etude. Nous avons egalement analyse les organismes responsables, la sensibilite aux antibiotiques et le modele de resistance chez ces patients. Resultats: Sur 120 patients, 29 patients etaient HAP et 91 patients etaient VAP. La mortalite etait de 60% (72), et le developpement du VAP et l'exigence de ventilation mecanique ont montre une association significative avec la mortalite (P < 0,00001). L'organisme le plus frequent causant HAP etait Staphylococcus aureus (43,4%) et VAP etait Klebsiella pneumoniae (49%). Une sensibilite antibiotique maximale a ete observee chez la piperacilline + tazobactam (58,8%), suivie de l'imipeneme (49,5%) et du meropenem (41,8%), alors que la resistance antibiotique maximale a ete observee a cefepime (95,1%), suivie de ceftazidime et de l'amoxicilline (91,2%) . CONCLUSION: la pneumonie nosocomiale a montre une incidence elevee (17,44%) et la mortalite (60%). Les organismes communs identifies etaient S. aureus et K. pneumoniae. La resistance etait elevee pour les antibiotiques couramment utilises et une forte sensibilite aux antibiotiques pour la piperacilline + le tazobactam et le carbapeneme. PMID- 28671151 TI - A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria. AB - BACKGROUND: There has been a dearth of comprehensive data on the profile of adverse reactions to antihypertensive medicines in the Nigerian setting despite increased use. OBJECTIVE: This study was aimed to characterize the adverse reactions experienced in the homogenously black African population. METHODS: The study was carried out at the University of Benin Teaching Hospital, Benin City, Nigeria, in consenting eligible hypertensive patients >=18 years. Adverse reactions were sought using patient's self-report and a medicine-induced symptom checklist. RESULTS: A total of 514 patients (340 females) aged 22-97 years were studied. Thirteen percent, 27.6%, 26.7%, 22.0%, and 10.7% were on 1, 2, 3, 4, and >=5 medicines, respectively, for control of their blood pressure with the frequency of adverse effects increasing proportionately up to four medicines. Adverse reactions to antihypertensive medicines were reported by a total of 93 (18.1%) patients. Diuretics - 27.9%, calcium channel blockers (CCBs) - 26.8%, and angiotensin-converting enzyme inhibitors (ACEIs) - 26.8% accounted for most of the adverse reactions seen, notably frequent micturition and headaches (CCB); excessive micturition and dizziness (diuretics); dry irritating cough (ACEI). Notable complaints for all patients using the checklist were increased frequency of micturition, reduction in libido, and headaches. The reactions resulted in the discontinuation and substitution of therapy in 49.5% of the patients. CONCLUSIONS: The characterization of these reactions in Nigerians requires further studies as frequent micturition reported is still a neglected complaint in antihypertensive therapy. PMID- 28671152 TI - Effect of analgesia on the changes in respiratory parameters in blunt chest injury with multiple rib fractures. AB - BACKGROUND: Blunt chest injury with multiple rib fractures can result in such complications as pneumonia, atelectasis, bronchiectasis, empyema thoracis, acute respiratory distress syndrome, and prolonged Intensive Care Unit and hospital stay, with its concomitant mortality. These may be prevented or reduced by good analgesic therapy which is the subject of this study. METHODS: This was a prospective study of effects of analgesia on changes in pulmonary functions of patients with traumatic multiple rib fractures resulting from blunt chest injury. RESULTS: There were 64 adult patients who were studied with multiple rib fractures caused by blunt chest trauma. Of these patients, 54 (84.4%) were male and 10 (15.6%) were female. Motorcycle (popularly known as "okada") and tricycle (popularly known as keke napep) accidents significantly accounted for the majority of the multiple rib fractures, that is, in 50 (78.1%) of the patients. Before analgesic administration, no patient had a normal respiratory rate, but at 1 h following the administration of analgesic, 21 (32.8%) of patients recorded normal respiratory rates and there was a significant reduction in the number (10.9% vs. 39.1%) of patients with respiratory rates> 30 breaths/min. Before commencement of analgesic, no patient recorded up to 99% of oxygen saturation (SpO2) as measured by pulse oximeter, while 43.8% recorded SpO2of 96%. This improved after 1 h of administration of analgesics to SpO2of 100% in 18.8% of patients and 99% in 31.3% of patients and none recording SpO2of < 97% (P = 0.006). Before analgesia, no patient was able to achieve peak expiratory flow rate (PEFR) value> 100% of predicted while only 9 (14.1%) patients were able to achieve a PEFR value in the range of 91%-100% of predicted value. One hour after analgesia, a total of 6 (9.4%) patients were able to achieve PEFR values> 100% predicted, while 35 (54.7%) patients achieved PEFR values in the range of 91% 100% predicted. CONCLUSION: Adequate analgesia is capable of reversing the negative effects of chest pain of traumatic multiple rib fractures on pulmonary function parameters through improvement in respiratory mechanics. PMID- 28671153 TI - Evaluation of locked plate in the osteosynthesis of fractures in osteoporotic bones. AB - BACKGROUND: The use of conventional dynamic compression plates (DCPs) in osteoporotic bones is associated with higher chances of implant failure. The advent and use of locking combi-plates have ensured a stable construct during osteosynthesis of fractures in osteoporotic bones. OBJECTIVES: The study aims to assess the outcome of use of locking combi-plates in the management of fractures in osteoporotic bones in our environment. MATERIALS AND METHODS: Cases of patients with nonunion and localized osteoporosis from January 2014 to December 2014 that were managed with locked combi-plates were reviewed. Outcome was assessed by time to healing, stability of implant construct after 6 and 12 months. RESULTS: There were 10 patients with mean age of 47.4 +/- 12.63 years. There were 9 males and 1 female, and road traffic crashes were the mechanism of injury in 90% (n = 9) and gunshot injuries in 10% (n = 1). Atrophic nonunion was the most common indication for osteosynthesis with 80%, followed by fibrous nonunion with 10.0%. The humerus was the most common long bone involved with 50%. Locked broad DCP was used in 62.5%, and the duration between initial injury and surgery was 6 and 48 months, with an average of 17.5 months. The outcome was such that 90% healed after 12 months on follow-up while one case had the implant backing out and delay union at 6 months. CONCLUSION: The use of locked plate in the management of nonunion in the presence of osteoporosis ensures stable fixation construct and healing. Contexte: L'utilisation de plaques de compression dynamiques conventionnelles dans les os osteoporotiques est associee a des chances plus elevees de defaillance de l'implant. L'avenement et l'utilisation de combi-plaques de verrouillage ont assure une construction stable lors de l'osteosyntheis de fractures dans les os osteoporotiques. Objectifs: L'etude vise a evaluer le resultat de l'utilisation de combi-plaques de verrouillage dans la gestion des fractures dans les os osteoporotiques dans notre environnement. Methodologie: Les cas de patients atteints d'osteoporose non syndiquee et localisee de janvier 2014 a decembre 2014 qui ont ete geres avec des combi plaques verrouillees ont ete examines. Le resultat a ete evalue par le temps de guerison, la stabilite de la construction d'implant apres 6 et 12 mois. Resultats: il y avait 10 patients avec un age moyen de 47,4 12,63. Il y avait 9 hommes et 1 accident de la route et de la route etait le mecanisme de la blessure dans 90% (n = 9) et les blessures par balle dans 10% (n = 1). La non-union atrophique etait l'indication la plus courante pour l'osteosynthese avec 80%, suivie d'une non-union fibreuse avec 10,0%. L'humerus etait l'os le plus frequent implique avec 50%. La plaque de compression dynamique bloquee (DCP) a ete utilisee a 62,5% et la duree entre la blessure initiale et la chirurgie etait de 6 et 48 mois avec une moyenne de 17,5 mois. Le resultat etait tel que 90% ont ete gueris apres 12 mois de suivi, tandis que 1 cas avait l'implantation de l'implant et retarde l'union a 6 mois. CONCLUSION: L'utilisation de la plaque verrouillee dans la gestion de la non-union en presence d'osteoporose assure une construction stable de fixation et une guerison. PMID- 28671154 TI - Cross-sectional, observational study of anterior segment parameters using anterior segment optical coherence tomography in North Indian Population. AB - PURPOSE: To study the anterior segment (AS) parameters using AS optical coherence tomography (AS-OCT) in the North Indian population. METHODS: A hospital-based, observational, cross-sectional study was conducted over a period of 1 year. It included 251 normal individuals aged 20-70 years. Participants underwent imaging with AS-OCT.Ocular parameters included anterior chamber angle (ACA), iris cross sectional area (ICSA), iris thickness (IT), and iris curvature (IC). The parameters were measured nasally and temporally for both sexes and different age groups. RESULTS: The mean age of participants was 48.3 +/- 13.9 years and 50.6% were men. The ACA decreased with age whereas ICSA, IT, and IC increased with age. The ACA (P = 0.0001nasally and temporally), ICSA (P = 0.011 nasally, P = 0.027 temporally), IT750 (P = 0.001 nasally, P = 0.011 temporally), IT1500 (P = 0.002 nasally, P = 0.002 temporally), and IC (P = 0.059 nasally, P = 0.128 temporally) underwent statistically significant changes with increasing age. No significant difference was seen in parameters of different sex. CONCLUSION: In this subset of the Indian population, the change in the AC parameters with age influences the AC dimensions predisposing the eye to glaucomatous conditions. These data are applicable clinically for the assessment and surgical management of patients requiring AS surgery. Objectif: Etudier les parametres du segment anterieur (AS) en utilisant la tomodensitometrie optique AS (AS-OCT) dans la population du nord de l'Inde. Methodes: Une etude axee sur l'hopital, observationnelle et transversale a ete menee sur une periode de 1 an. Il comprenait 251 individus normaux ages de 20 a 70 ans. Les participants ont subi une imagerie avec AS-OCT. Les parametres oculaires comprenaient l'angle de la chambre anterieure (ACA), la surface transversale de l'iris (ICSA), l'epaisseur de l'iris (IT) et la courbure de l'iris (IC). Les parametres ont ete mesures par voie nasale et temporelle pour les deux sexes et differents groupes d'age. Resultats: l'age moyen des participants etait de 48,3 +/- 13,9 ans et 50,6% des hommes. L'ACA a diminue avec l'age alors que ICSA, IT et IC ont augmente avec l'age. L'ACA (P = 0,0001 par voie nasale et temporelle), ICSA (P = 0,011 nasale, P = 0,027 temporellement), IT750 (P = 0,001 par voie nasale, P = 0,011 temporellement), IT1500 (P = 0,002 par voie nasale, P = 0,002 temporellement) Et IC (P = 0,059 nasal, P = 0,128 temporellement) ont subi des changements statistiquement significatifs avec l'age. Aucune difference significative n'a ete observee dans les parametres du sexe different. CONCLUSION: Dans ce sous-ensemble de la population indienne, la variation des parametres CA avec l'age influence les dimensions AC predisposant l'oeil aux conditions glaucomateuses. Ces donnees sont applicables cliniquement pour l'evaluation et la gestion chirurgicale des patients necessitant une chirurgie AS. PMID- 28671155 TI - Low back pain in pregnant women attending antenatal clinic: The Aminu Kano teaching hospital experience. AB - BACKGROUND: The profound physiologic effects of pregnancy affect the musculoskeletal system. Pregnant women are at increased risks of low back/pelvic girdle pains. OBJECTIVE: To determine the incidence of low back/pelvic girdle pains among pregnant women. MATERIALS AND METHODS: This was a cross-sectional study conducted from May 1 to June 30, 2016, among consenting pregnant women at Aminu Kano Teaching Hospital. Ethical approval was obtained from the Hospital Ethics Committee. Information was obtained in a questionnaire on consecutive pregnant women. Data obtained were analyzed using SPSS version 18 (SPSS Inc., Chicago, Illinois, USA, 2012). Fisher's exact test was used for categorical data, and P <= 0.05 was considered statistically significant. RESULTS: A total of 309 pregnant women were recruited from May 1 to June 30, 2016. The mean age +/- standard deviation was 28.4 +/- 5.86 years. The incidence of low back pains (LBPs) and pelvic girdle pains among the pregnant women was 106 (34.3%) and 178 (57.6%), respectively. The pain was severe among 26 (9.2%) pregnant women, which warranted analgesic usage. Pain radiation was reported in> 50% of cases. There was an incidental finding of urinary incontinence in 36 (12.6%) cases. Low back/pelvic girdle pain was not associated with body mass index (BMI) (P = 0.390). CONCLUSION: The incidence of LBPs and pelvic girdle pains was high and found to be 34.3% and 57.6%, respectively. Analgesics were used especially among those with severe pains. There was an incidental finding of urinary incontinence among pregnant women with complaints of low back/pelvic girdle pains. There was no statistically significant association between LBPs and maternal BMI. PMID- 28671156 TI - Overview of extremity musculoskeletal neoplasms at the Ahmadu Bello University Teaching Hospital Zaria, Nigeria. AB - BACKGROUND: The burden of managing patients with musculoskeletal neoplasms in the West African sub-region is quite significant. This is largely due to late presentation, delay in making diagnosis, and failure of obtaining consent to certain surgical procedures. Improvements in diagnosis and treatment over the years have however increased life and limb survival for many patients. This study was aimed at evaluating the clinicopathologic pattern of neoplasm as it affects the upper and lower limbs with a view to determining the most common types, the most involved sites of the body and the age at presentation of these tumors. MATERIALS AND METHODS: A total of 65 patients with histologically confirmed neoplasm of the upper and lower limbs arising from bone, cartilage, skeletal muscle, synovium, and tendon sheath were retrospectively selected 7 years from January 2008 to 2015. RESULTS: Forty-one (63.1%) patients were males, whereas 24 (36.9%) were females. Age range is between 5 and 75 years, average of 30.8 years. Lower limb involvement was recorded in 40 (61.5%) patients, with remaining 25 (38.5%) patients in upper limbs. 28 (43.1%) patients had benign lesion, whereas 37 (56.9%) were malignant. Giant cell tumor (GCT) was the most frequent benign tumor (50%) while osteogenic sarcomas top the list on the malignant variety (32.4%). The most commonly affected bones were tibia, carpal-metacarpal, and femur in that order. CONCLUSION: In our center, GCT and osteogenic sarcoma are the most frequently encountered benign and malignant musculoskeletal extremity neoplasms, respectively, with the tibial bone being most commonly affected. PMID- 28671157 TI - Primary hyperparathyroidism in pregnancy. AB - Primary hyperparathyroidism (PHT) is a frequent and asymptomatic pathology in 80% of patients, and a parathyroidal adenoma is found in the most case. However, rare cases might occur during pregnancy; and the literature reported up to 200 cases. We report three cases of PHT that occurred during the second and last third trimesters of pregnancy stage in patients aged 26, 42 and 32-year-old. Despite diagnosis limitations, since scintigraphy is prohibited in pregnancy, the patients were managed conservatively with good prognosis for both mothers and babies. L'hyperparathyroidie primaire (HTP) est une maladie frequente et asymptomatique chez 80% des patients. Un adenome parathyroidien est retrouve chez une grande majorite des cas. Cependant, l'apparition au cours de la grossesse est particulierement rare et la litterature ne rapporte que 200 cas. Nous en rapportons 3 cas d'hyperparathyroidie ages de 26, 42 et 32 ans, survenue au cours du deuxieme et troisieme trimestre de la grossesse. Malgre les limites diagnostiques dues a l'interdiction de la scintigraphie au cours de la grossesse, la gestion avait ete faite de facon tres conservative de sorte a avoir le meilleur pronostic pour les patientes leurs fetus. PMID- 28671158 TI - Atherogenic index of plasma for the assessment of cardiovascular risk factors. PMID- 28671159 TI - Increased oxidative stress and depleted antioxidant capacity in chronic obstructive pulmonary disease: Searching for applications. PMID- 28671160 TI - Placement of tracheobronchial silicone Y-stents: Multicenter experience and systematic review of the literature. AB - BACKGROUND: Airway obstruction or tracheoesophageal fistula (TEF) near the tracheal carina requires placement of Y-shaped stents. Herein, we describe our multicenter experience with the placement of Dumon silicone Y-stents. We also conduct a systematic review for studies describing the deployment of airway silicone Y-stents. METHODS: This was a retrospective analysis of consecutive subjects who underwent placement of silicone Y-stents. The clinical details including the underlying diagnosis, indication for the placement of silicone Y stents, success of stent placement, and follow-up are presented. The PubMed and EMBASE databases were also reviewed for studies describing the placement of silicone Y-stents. RESULTS: During the study, 27 silicone Y-stents were placed. The mean (standard deviation) age of the study population (85.2% males) was 57.7 (13.5) years. The stents were placed for airway obstruction in 77.8% and TEF in 29.6% of the patients. The most common underlying disease was carcinoma of the esophagus. The degree of airway obstruction was grade 3-4 in 18 subjects, and respiratory failure was encountered in 18 subjects. The stent was deployed successfully in all the subjects. No deaths were encountered during stent placement. Most subjects had rapid relief of symptoms following the procedure. Excessive secretions and mucostasis were the most common stent-related complications followed by the development of granulation tissue. The systematic review yielded nine studies (338 subjects with airway obstruction and/or TEF). The most common indication for silicone Y-stent placement was tracheobronchial obstruction and TEF due to malignancy. Benign disorders that necessitated stent placement included postintubation tracheal stenosis, airway malacia, and others. The stent was successfully placed in 98% with only one periprocedural death. Granulation tissue formation and mucostasis were the most common stent-related complications. CONCLUSION: Placement of silicone Y-stent is a safe and effective procedure that provides quick relief of symptoms in subjects presenting with airway obstruction and TEF at or near the tracheal carina. PMID- 28671161 TI - Video-assisted thoracoscopic surgery for pulmonary aspergilloma. AB - INTRODUCTION: Surgical management of pulmonary aspergilloma in symptomatic patients offers a significant chance of cure. Video-assisted thoracic surgery is a valid alternative for properly selected cases. We herein report our experience with thoracoscopic management of pulmonary aspergilloma. PATIENT AND METHODS: This retrospective analysis was performed on 41 patients operated between 2012 to 2015. The patient records were thoroughly analyzed for demography, clinical presentation, computed tomography , the procedure performed , post-operative complications and course during 6 month's follow up. RESULTS: Out of total 41 patients, 23 (56%) were treated by VATS and 18 (44%) by thoracotomy. Average intraoperative blood loss was 214 ml (+/-106) in VATS group and 461 ml (+/-167) in thoracotomy. Mean operative time was 162 (+/-14) minutes in VATS and 239 (+/ 12) minutes in thoracotomy group. In VATS group, postoperative complications were found in 5 patients and in 11 patients in the thoracotomy group. Average duration of chest tube was 5.43 () days in VATS group and 8.94 () days in thoracotomy group. Average length of hospital stay was 5.04 in VATS group and 6.55 days in thoracotomy group. CONCLUSIONS: VATS for pulmonary aspergilloma, if applicable, may be a safe and efficacious option in experienced hands. Simple aspergilloma, in particular , is considered to be a good indication for VATS. Some cases of complex aspergilloma may also be amenable to VATS. However, the long term results need to be further analyzed using a larger study group. PMID- 28671162 TI - Study of oxidative stress biomarkers in chronic obstructive pulmonary disease and their correlation with disease severity in north Indian population cohort. AB - BACKGROUND: Oxidant-antioxidant imbalance forms a prime component in pathogenesis of chronic obstructive pulmonary disease (COPD). Studies of oxidative stress markers in South Asians were sparse. METHODS: One hundred and eighty COPD patients and eighty healthy nonsmokers were enrolled in the study. Serum malondialdehyde (MDA) and iron levels were estimated for oxidative stress. Three antioxidant markers evaluated-catalase, superoxide dismutase (SOD), and serum copper. Patients on antioxidant therapy and with sepsis and chronic illness were excluded from the study. RESULTS: The mean age of COPD patients was 59.29 +/- 10.3 years. Serum levels of MDA and iron were significantly higher in COPD patients compared to controls (5.21 +/- 1.9 vs. 0.71 +/- 0.29 nmol MDA/ml, P = 0.0001 and 69.85 +/- 85.49 vs. 79.32 +/- 24.39 MUg/dl, P = 0.0001, respectively). Mean level of all antioxidant enzymes catalase, SOD, and copper were significantly diminished in cases when compared to control population (P = 0.001). Levels of MDA and iron were found to be significantly elevated in higher Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes (III, IV) when compared to lower GOLD Classes (I, II). The levels of serum antioxidants were significantly depleted in higher GOLD grades too. COPD patients who were male and smoked had significantly higher levels of oxidants and depleted antioxidant levels compared to female and nonsmoking compatriots. Serum MDA levels negatively correlated with forced expiratory volume 1 s and forced vital capacity (r = -0.19 and r = -0.21, P <= 0.01). The presence of a cough significantly correlated with higher levels of MDA and iron (P = 0.001). The levels of MDA negatively correlated with SOD and catalase levels. CONCLUSION: Oxidative markers (MDA and iron) are higher whereas antioxidants (catalase, copper, and SOD) are significantly reduced in patients of COPD. Serum MDA levels correlate with lung functions and disease severity. PMID- 28671163 TI - Predictors of mortality of severe sepsis among adult patients in the medical Intensive Care Unit. AB - BACKGROUND: Sepsis is an important cause of mortality in the Intensive Care Units (ICUs) worldwide. Information regarding early predictive factors for mortality and morbidity is limited. AIMS AND OBJECTIVES: The primary objective of the study was to estimate the mortality of severe sepsis among adult patients admitted into the medical ICU. The secondary objective was to identify the predictors associated with mortality. MATERIALS AND METHODS: Adult patients admitted with severe sepsis in the medical ICU were studied. The primary outcome was the mortality among the study population. Baseline demographic, clinical, and laboratory data were recorded upon inclusion into the study. Risk factors associated with mortality were studied by univariate analysis. The variables having statistical significance were further included in multivariate analysis to identify the independent predictors of mortality. RESULTS: Out of eighty patients, 54 (67.5%) died. Univariate analysis showed that age >60 years, tachycardia, hypotension, elevated C-reactive protein (CRP) and lactate, thrombocytopenia, need of mechanical ventilation, and high Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores were variables associated with high mortality. The independent predictors of mortality identified by multivariate regression analysis were platelet count below 1 lakhs, serum levels of CRP >100, APACHE II score >25 on the day of admission to the ICU with severe sepsis, and the need for invasive mechanical ventilation. CONCLUSIONS: Low platelet count, elevated serum levels of CRP, APACHE score >25, and the need for invasive mechanical ventilation were found to be independent predictors of mortality of severe sepsis among adult patients with severe sepsis in the medical ICU. PMID- 28671164 TI - Impact of chemotherapy on symptom profile, oxidant-antioxidant balance and nutritional status in non-small cell Lung Cancer. AB - BACKGROUND: Lung cancer is associated with an oxidant-antioxidant imbalance that is implicated in tumor progression. However, the association of this imbalance on disease burden and treatment response is unclear. The effect of chemotherapy on oxidative stress, antioxidant status, and nutritional profile in patients with advanced nonsmall cell lung cancer (NSCLC) was prospectively evaluated. SUBJECTS AND METHODS: Patients with confirmed cytological/histological diagnosis of NSCLC were recruited. Performance status was determined using the Eastern Cooperative Oncology Group grading and the Karnofsky Performance Scale. Skin fold anthropometry was done for nutritional assessment. All patients received chemotherapy with intravenous carboplatin and paclitaxel at three-weekly intervals. Response was assessed after four cycles by repeat imaging. Plasma levels of total antioxidant status (TAS), malondialdehyde (MDA), and glutathione peroxidase (GPx) levels were estimated using commercially available kits, and the change was correlated with clinical outcome, response to chemotherapy, performance status, and nutritional profile. RESULTS: Thirty-five cases were studied (92% males), with a mean (SD) age of 56.2 (9.3) years. Following treatment, majority of patients demonstrated stable disease (n = 15 [42%]), followed by partial response (29%), progressive disease (22%), and complete remission (6%). Significant improvement occurred in respiratory symptoms. Body fat declined while subscapular skinfold thickness and 6-min walk distance increased. Spirometric values and performance status remained unchanged. GPx levels declined significantly while no notable change was observed in MDA and TAS levels. CONCLUSIONS: Chemotherapy for NSCLC improves symptoms, nutritional status, and exercise capacity but worsens the antioxidant status. PMID- 28671165 TI - Diagnostic evaluation of mediastinal lesions: Analysis of 144 cases. AB - BACKGROUND: Mediastinum is a "Pandora's box" with many neoplastic and nonneoplastic lesions. The purpose of this study was to analyze our institutional experience of mediastinal lesions on fine-needle aspiration cytology (FNAC) and/or biopsy. MATERIALS AND METHODS: This study was an analysis of 144 patients who had undergone ultrasound-guided FNAC and/or core biopsy for mediastinal lesions. RESULTS: A total of 144 cases of suspected mediastinal masses were seen, and in 139 cases, tissue diagnosis was attempted. Out of 139 cases, 93 cases were neoplastic in nature (67%), 32 were nonneoplastic (23%), and 14 remained inconclusive (10%). Among neoplastic mediastinal lesions, metastatic carcinoma (37.4%) was the most common neoplastic lesion, followed by non-Hodgkin's lymphoma (12.2%), Hodgkin's lymphoma (7.1%), thymic lesions (3.5%), etc. Among nonneoplastic conditions, tuberculosis was the most common lesion (20.1%). An accurate tissue diagnosis was made in 89.9% cases by FNAC or core biopsy of mediastinal lesions in this study. Procedure-related mortality was nil. Complications were mostly minor and included chest pain in 24.5%, small pneumothorax in 13.6% requiring closed tube thoracostomy in 1.4%, and scanty hemoptysis in 9.3% cases. CONCLUSION: Neoplastic mediastinal lesions are more common than nonneoplastic lesions, with metastatic carcinoma being the most common cause followed by tuberculosis. A wide variety of lesions observed in this study stress on the importance of cytohistological diagnosis in all cases of mediastinal lesions for the final diagnosis and management planning. A guided FNAC or core biopsy is still accurate, well tolerated, and devoid of major complications. PMID- 28671166 TI - Effects of oral montelukast on airway function in acute asthma: A randomized trial. AB - BACKGROUND: The role of leukotriene receptor antagonist is well known in the management of chronic asthma, but their efficacy in acute exacerbation of asthma is unknown. The present study was done to evaluate the clinical efficacy of oral montelukast as an add on therapy to the usual standard therapy of acute attack of bronchial asthma. MATERIALS AND METHODS: A randomized single-blinded controlled study was conducted in a tertiary care teaching hospital. A total of 162 patients with age >18 years of acute exacerbations due to bronchial asthma were included in the study. The patients were randomized into two study and control groups. The study group patients received oral montelukast (10 mg) once daily for 2 weeks, while the control group received a placebo. All the patients received standard therapy according to GINA guidelines. Improvements in lung function tests, clinical symptoms, and relapse rates were monitored at baseline, 1 week, 2 weeks, and 4 weeks. Side effects profile was also monitored. RESULTS: A total of 160 patients were finally assessed. Seventy-eight patients belonged to study group and 82 in the control group. Baseline characteristics were similar and well matched in both groups. Mean age was 39.9 +/- 15.8 years in the study group and 42.8 +/- 12.8 in the control group and majority were female patients in both groups. At the end of 4 weeks, it was observed that the study group patients who received montelukast had better forced expiratory volume in 1 s (FEV1) improvement by 21% (0.21 L) as compared to the control group (P < 0.0033). It was also observed that there was a better improvement in peak expiratory flow rate (PEFR) at 2 weeks (0.4 L/s, 12%) and at 4 weeks (0.9 L/s, 23%) as compared to the control group (P < 0.0376 and P < 0.0003 respectively). There was no difference in forced vital capacity (FVC), FEV1/FVC ratio and relapse rates between the two groups. No serious adverse effects were observed during the study. CONCLUSIONS: In acute asthma exacerbations, the present study showed that additional administration of oral montelukast resulted in significantly higher FEV1at 4 weeks and PEFR at 2 weeks and 4 weeks as compared to the standard treatment alone. These findings should be confirmed by conducting a larger population-based clinical study. PMID- 28671167 TI - Vitamin D and asthma in children: A systematic review and meta-analysis of observational studies. AB - There is growing literature suggesting a link between Vitamin D deficiency and asthma in children, but systematic reviews are lacking. The aim of this study is to evaluate the prevalence of Vitamin D deficiency in asthmatic children and to assess the correlations of Vitamin D levels with asthma incidence, asthma control, and lung functions. PubMed, EMBASE, and Cochrane Library were searched for observational studies on asthma and Vitamin D. Two authors independently extracted data. Meta-analysis was performed using the Review Manager Software. A total of 23 (11 case-control, 5 cohort, and 7 cross-sectional) studies enrolling 13,160 participants were included in the review. Overall, Vitamin D deficiency and insufficiency were prevalent in 28.5% and 26.7% children with asthma, respectively. The mean 25-hydroxyvitamin D (25(OH)D) levels (10 studies) were significantly lower in asthmatic children as compared to nonasthmatic children with a mean difference of -9.41 (95% confidence interval [CI] -16.57, -2.25). The odds ratio of Vitamin D deficiency (eight case-control studies) was significantly higher among asthmatic children as compared to nonasthmatic children (odds ratio 3.41; 95% CI 2.04, 5.69). Correlations between Vitamin D levels and incidence of asthma, lung functions, and control of asthma had mixed results. To conclude, asthmatic children had lower 25(OH)D levels as compared to nonasthmatic children, but the correlations between 25(OH)D and asthma incidence, asthma control, and lung functions were varied. Well-designed randomized controlled trials are required to determine if children with asthma can benefit from Vitamin D supplementation. PMID- 28671168 TI - Multidrug-resistant tuberculosis and leprosy: An unsolved mystery. AB - Tuberculosis (TB) and leprosy are two age-old infections, which we are facing even today. With drug-resistant TB on the rise, we report a case of multidrug resistant TB with leprosy, which has never been reported previously. The peculiar course of this case forces us to rethink about the upcoming challenges due to their cooccurrence. PMID- 28671169 TI - Hemoptysis: Beyond routine chest computed tomography and bronchoscopy. AB - Hemoptysis is considered as a medical emergency which requires urgent stabilization with identification and correction of underlying etiology. Diagnosis of the cause of hemoptysis is not always readily identified after bronchoscopy and conventional computed tomography (CT) chest. Arteriovenous malformation (AVM) is a rare but important cause of massive hemoptysis which can be easily picked up by the use of double turn contrast CT chest. We here report a rare congenital AVM anomaly called Klippel-Trenaunay-Parks-Weber syndrome as a cause of massive hemoptysis and utility of double turn CT in diagnosing AVM as a cause of hemoptysis. PMID- 28671170 TI - Platypnea-orthodeoxia syndrome in idiopathic pulmonary fibrosis with Pneumocystis jiroveci pneumonia. AB - Platypnea-orthodeoxia syndrome (POS), the occurrence of dyspnea and arterial desaturation on changing from supine to sitting position, is a very rare phenomenon. Most case reports have been in association with an intra-atrial communication, and observation of this unusual physiological abnormality in pulmonary conditions has been extremely rare. We present a case of idiopathic pulmonary fibrosis where the patient developed characteristic symptoms of POS when it was complicated by Pneumocystis jiroveci pneumonia. This was objectively confirmed. A similar association has not been reported earlier in literature. PMID- 28671171 TI - Early-onset de novo invasive pulmonary aspergillosis in an orthotopic heart transplant recipient. AB - Invasive aspergillosis generally occurs during the first 1-6 months after heart transplantation. It has been rarely seen in the first 2 weeks postcardiac transplant. We herein describe a unique case of invasive pulmonary aspergillosis (IPA) diagnosed on day 9 postorthotopic heart transplantation. The known risk factors for IPA in cardiac transplant recipients were not identified in our case. The organ recipients from the same donor did not report Aspergillus infection. Hospital environmental samplings failed to demonstrate Aspergillus spores in the patient's room and his adjacent rooms. A diagnosis of early-onset de novo IPA was made. The patient initially received combined antifungal therapy (voriconazole plus micafungin), followed by voriconazole maintenance monotherapy with favorable clinical outcome. PMID- 28671172 TI - Gastric and pulmonary sarcoidosis complicated by hypercalcemia and acute renal failure: Case report and literature review. AB - Gastric sarcoidosis is a very rare manifestation of sarcoidosis. Only few case reports have been described in the literature. We present a case of coexisting gastric and pulmonary sarcoidosis in a 56-year-old female, who presented with gastrointestinal symptoms. Gastric mucosal biopsies, transbronchial needle aspiration, and endobronchial mucosal biopsies revealed noncaseating granulomas. This case report emphasizes on early evaluation of other organ system and initiation of treatment. PMID- 28671173 TI - Metastatic renal carcinoid: To skin, lungs, and pancreas. AB - Carcinoid tumors rarely originate in the urogenital system. We represent a unique case of primary renal carcinoid tumor which was initially diagnosed as renal cell cancer and 10 years later correctly diagnosed as metastatic renal carcinoid. PMID- 28671174 TI - Case of postural complex sleep apnea: effect of gravitational forces. AB - We report a case of an elderly male with predominant obstructive sleep apnea and who developed or complex sleep apnea (CxSA) at the start of continuous positive airway pressure (CPAP) titration. This CxSA was more prominent in supine position, and he was not settling with either CPAP/bilevel positive airway pressure (PAP) in supine position. He finally settled with CPAP along with position therapy. This case highlights the importance of treating CxSA with basic PAP modes like CPAP along with positional therapy before switching to costlier therapies such as adaptive servo-ventilation. PMID- 28671175 TI - A rare cause of ventilatory failure in a patient with post-traumatic intracranial hemorrhage. AB - High minute ventilation is required to lower intracranial pressures in patients with intracranial bleed. Respiratory acidemia consequent to ventilatory difficulty is dangerous in such patients as it further raises intracranial tension. We describe such a case. A 24-year-old man had to be intubated and mechanically ventilated after he met with a road traffic accident and sustained extensive maxillofacial injuries and intracranial bleed. A tooth was accidentally aspirated in this injury and progressively resulted in left lower lobe collapse, pneumomediastinum, and consequent difficult ventilation. Under video bronchoscope guidance, the tooth was removed with grasping forceps. Pneumomediastinum temporarily increased after the tooth removal, but by 12 h postextraction, resolution of both the pneumomediastinum and left lower lobe collapse was observed. There was a 17 h delay postadmission before the cause of ventilatory failure was realized. Aspiration of foreign bodies, in general, and teeth, in particular, should be actively looked for in patients with ventilatory difficulties in the post-trauma setting. PMID- 28671176 TI - Progression of a rare multiple cystic lung disease. PMID- 28671177 TI - A 36-year-old man with breathlessness and anasarca. PMID- 28671178 TI - Metastasis to parotid gland from primary bronchogenic carcinoma: A case letter. PMID- 28671179 TI - Adult right-sided thoracic kidney: A very rare form of renal ectopia. PMID- 28671180 TI - [Evaluation of the notification of dysphonia on the voice profesionals as a sentinel event in Navarra. Period 2013-2015.] AB - OBJECTIVE: Among the lesions produced by the professional use of the voice since 2007, the Vocal Nodules (VN) are recognized in Spain as an Occupational Disease. With the aim of promoting its notification in Navarre, the Sentinel Program was incorporated in 2013 and, with this study, we seek to verify its efficacy. METHODS: The study population were voice professionals reported for dysphonia as sentinel events during the years 2013 to 2015 in Navarre. Its effectiveness was validated by the cumulative incidence of 100,000 workers for each of the years and Positive Predictive Value as an indicator of suspicion. The declaration was verified as an occupational disease. RESULTS: In the period April 2013 to December, 110 cases were reported, 71 nominal and 39 non-nominal. The annual incidence increased from 9.0 cases per 100,000 to 13.4. Of the cases investigated, 63 were women and 8 men. The mean age was 40.8 years (38.5-43.1 95% CI). 58 cases (81.7%) corresponded to teachers. In 22 of the 71 nodules (31%) and 9 coincidences were notified as an occupational disease. We found a greater presence of nodules in professionals with extra work use of voice (OR 4.2 IC 1.3 14.3) and better evolution of pathologies other than VN (OR = 2.5 CI 1.1-5.8 ). The suspicion was confirmed as occupational in 54 cases (positive predictive value 76.1%). CONCLUSIONS: The centinel program is effective in reporting dysphonia although it is important to highlight the low declaration as occupational disease of the cases detected. PMID- 28671181 TI - Cobamide-mediated enzymatic reductive dehalogenation via long-range electron transfer. AB - The capacity of metal-containing porphyrinoids to mediate reductive dehalogenation is implemented in cobamide-containing reductive dehalogenases (RDases), which serve as terminal reductases in organohalide-respiring microbes. RDases allow for the exploitation of halogenated compounds as electron acceptors. Their reaction mechanism is under debate. Here we report on substrate-enzyme interactions in a tetrachloroethene RDase (PceA) that also converts aryl halides. The shape of PceA's highly apolar active site directs binding of bromophenols at some distance from the cobalt and with the hydroxyl substituent towards the metal. A close cobalt-substrate interaction is not observed by electron paramagnetic resonance spectroscopy. Nonetheless, a halogen substituent para to the hydroxyl group is reductively eliminated and the path of the leaving halide is traced in the structure. Based on these findings, an enzymatic mechanism relying on a long-range electron transfer is concluded, which is without parallel in vitamin B12-dependent biochemistry and represents an effective mode of RDase catalysis. PMID- 28671182 TI - A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury. AB - Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a 'big data compacting and data fusion'-concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a 'predictive toxicogenomics space' (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ~2.5 * 108 data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy. PMID- 28671183 TI - Microwave-free nuclear magnetic resonance at molecular scales. AB - The implementation of nuclear magnetic resonance (NMR) at the nanoscale is a major challenge, as the resolution of conventional methods is limited to mesoscopic scales. Approaches based on quantum spin probes, such as the nitrogen vacancy (NV) centre in diamond, have achieved nano-NMR under ambient conditions. However, the measurement protocols require application of complex microwave pulse sequences of high precision and relatively high power, placing limitations on the design and scalability of these techniques. Here we demonstrate NMR on a nanoscale organic environment of proton spins using the NV centre while eliminating the need for microwave manipulation of either the NV or the environmental spin states. We also show that the sensitivity of our significantly simplified approach matches that of existing techniques using the NV centre. Removing the requirement for coherent manipulation while maintaining measurement sensitivity represents a significant step towards the development of robust, non invasive nanoscale NMR probes. PMID- 28671184 TI - The A-B transition in superfluid helium-3 under confinement in a thin slab geometry. AB - The influence of confinement on the phases of superfluid helium-3 is studied using the torsional pendulum method. We focus on the transition between the A and B phases, where the A phase is stabilized by confinement and a spatially modulated stripe phase is predicted at the A-B phase boundary. Here we discuss results from superfluid helium-3 contained in a single 1.08-MUm-thick nanofluidic cavity incorporated into a high-precision torsion pendulum, and map the phase diagram between 0.1 and 5.6 bar. We observe only small supercooling of the A phase, in comparison to bulk or when confined in aerogel, with evidence for a non monotonic pressure dependence. This suggests that an intrinsic B-phase nucleation mechanism operates under confinement. Both the phase diagram and the relative superfluid fraction of the A and B phases, show that strong coupling is present at all pressures, with implications for the stability of the stripe phase. PMID- 28671185 TI - A point-of-care microfluidic biochip for quantification of CD64 expression from whole blood for sepsis stratification. AB - Sepsis, a potentially life-threatening complication of an infection, has the highest burden of death and medical expenses in hospitals worldwide. Leukocyte count and CD64 expression on neutrophils (nCD64) are known to correlate strongly with improved sensitivity and specificity of sepsis diagnosis at its onset. A major challenge is the lack of a rapid and accurate point-of-care (PoC) device that can perform these measurements from a minute blood sample. Here, we report a PoC microfluidic biochip to enumerate leukocytes and quantify nCD64 levels from 10 MUl of whole blood without any manual processing. Biochip measurements have shown excellent correlation with the results from flow cytometer. In clinical studies, we have used PoC biochip to monitor leukocyte counts and nCD64 levels from patients' blood at different times of their stay in the hospital. Furthermore, we have shown the biochip's utility for improved sepsis diagnosis by combining these measurements with electronic medical record (EMR). PMID- 28671186 TI - Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon. AB - Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. Cell replacement of lost neurons using enteric neural stem cells (ENSC) is a possible therapy for these life-limiting disorders. Here we show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase (nNOS-/-) deficient mouse model, which displays slow transit in the colon. We further show that transplantation of ENSC into the colon rescues impaired colonic motility with formation of extensive networks of transplanted cells, including the development of nNOS+ neurons and subsequent restoration of nitrergic responses. Moreover, post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the nNOS-/- colon. These results provide the first direct evidence that ENSC transplantation can modulate the enteric neuromuscular syncytium to restore function, at the organ level, in a dysmotile gastrointestinal disease model. PMID- 28671187 TI - Scanning tunnelling spectroscopy of superconductivity on surfaces of LiTi2O4(111) thin films. AB - Unique superconductivity at surfaces/interfaces, as exemplified by LaAlO3/SrTiO3 interfaces, and the high transition temperature in ultrathin FeSe films, have triggered intense debates on how superconductivity is affected in atomic and electronic reconstructions. The surface of superconducting cubic spinel oxide LiTi2O4 is another interesting system because its inherent surface electronic and atomic reconstructions add complexity to superconducting properties. Investigations of such surfaces are hampered by the lack of single crystals or high-quality thin films. Here, using low-temperature scanning tunnelling microscopy and spectroscopy, we report an unexpected small superconducting energy gap and a long coherence length on the surface of LiTi2O4(111) epitaxial thin films. Furthermore, we find that a pseudogap opening at the Fermi energy modifies the surface superconductivity. Our results open an avenue for exploring anomalous superconductivity on the surface of cubic transition-metal oxides, where the electronic states are spontaneously modulated involving rich many-body interactions. PMID- 28671188 TI - Revising the hygroscopicity of inorganic sea salt particles. AB - Sea spray is one of the largest natural aerosol sources and plays an important role in the Earth's radiative budget. These particles are inherently hygroscopic, that is, they take-up moisture from the air, which affects the extent to which they interact with solar radiation. We demonstrate that the hygroscopic growth of inorganic sea salt is 8-15% lower than pure sodium chloride, most likely due to the presence of hydrates. We observe an increase in hygroscopic growth with decreasing particle size (for particle diameters <150 nm) that is independent of the particle generation method. We vary the hygroscopic growth of the inorganic sea salt within a general circulation model and show that a reduced hygroscopicity leads to a reduction in aerosol-radiation interactions, manifested by a latitudinal-dependent reduction of the aerosol optical depth by up to 15%, while cloud-related parameters are unaffected. We propose that a value of kappas=1.1 (at RH=90%) is used to represent the hygroscopicity of inorganic sea salt particles in numerical models. PMID- 28671189 TI - Fate and freedom in developing neocortical circuits. PMID- 28671190 TI - Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. AB - Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo. We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients. PMID- 28671191 TI - Universal features of amorphous plasticity. AB - Plastic yielding of amorphous solids occurs by power-law distributed deformation avalanches whose universality is still debated. Experiments and molecular dynamics simulations are hampered by limited statistical samples, and although existing stochastic models give precise exponents, they require strong assumptions about fixed deformation directions, at odds with the statistical isotropy of amorphous materials. Here, we introduce a fully tensorial, stochastic mesoscale model for amorphous plasticity that links the statistical physics of plastic yielding to engineering mechanics. It captures the complex shear patterning observed for a wide variety of deformation modes, as well as the avalanche dynamics of plastic flow. Avalanches are described by universal size exponents and scaling functions, avalanche shapes, and local stability distributions, independent of system dimensionality, boundary and loading conditions, and stress state. Our predictions consistently differ from those of mean-field depinning models, providing evidence that plastic yielding is a distinct type of critical phenomenon. PMID- 28671192 TI - Corrigendum to "Use of complementary and alternative medicine by self- or non institutional therapists in South Korea: a community-based survey" [Integr. Med. Res. 2(1) (2013), 25-31]. AB - [This corrects the article DOI: 10.1016/j.imr.2013.02.001.]. PMID- 28671193 TI - Editorial: Phase DOWN vs phase UP. PMID- 28671195 TI - Structural stability and stabilization of Li2MoO3. AB - Due to its better physical and electrochemical properties, Li2MoO3 was proposed to replace Li2MnO3 for constructing new Li-rich cathode materials. However, the molybdenum (Mo)-ion shuttling between the Li layer and the Mo layer upon electrochemical Li-extraction raises concerns on the structural stability of the Mo-based Li-rich materials. In this article, the nudged energy band method was applied using first-principles calculations to understand the reason for the Mo ion migration and to sieve substituent elements for Mo from a number of transition metals. Molecular dynamics calculations were performed to simulate the kinetic properties of the pristine and transition metal substituted Li2MoO3. On the basis of these calculations, antimony (Sb) was proposed as a substituent to enhance the structural stability of Li2MoO3 and improve its rate performance. PMID- 28671196 TI - Emergence of tilt in square honeycomb liquid crystals. AB - First liquid crystalline phases with tilted organization of rod-like aromatics in a square honeycomb structure were discovered. The developing tilt is temperature, chain length and chain volume dependent, and has a dramatic effect on the optical properties, occasionally leading to an inversion of birefringence. The observed effects of chain branching on tilt contributes to a general understanding of lateral chain engineering in tailoring the self-assembly of pi-conjugated molecular rods. PMID- 28671197 TI - Protective effects of fraction 4a of polysaccharides isolated from Lycium barbarum against KBrO3-induced renal damage in rats. AB - Potassium bromate (KBrO3) is widely used as a food additive and is a major by product of water disinfection. The aim of this study was to investigate the protective effects of fraction 4a of polysaccharides isolated from Lycium barbarum (LBP-4a) against renal damage induced by KBrO3 in rats and to determine the relevant mechanisms behind these effects. Male Wistar rats were divided into a normal control group, a KBrO3 control group, and LBP-4a(L) and LBP-4a(H) groups. With the exception of the normal control group, the rats in the other three groups were administered KBrO3 by intraperitoneal injection to induce renal damage. Before the induction of renal damage, rats in the LBP-4a(L) and LBP-4a(H) groups were pretreated with 50 mg per kg b.w. or 100 mg per kg b.w. LBP-4a, respectively, by intragastric administration. Clinical biochemical parameters and markers of oxidative damage were also determined. Treatment by administration of LBP-4a prior to challenge with KBrO3 prevented increases in the levels of nitrite, creatinine, urea nitrogen and uric acid in serum and increased the activities of antioxidant enzymes in kidney tissues. A comet assay and FCS results showed that pretreatment with LBP-4a also alleviated DNA damage and decreases in mitochondrial membrane potentials in renal cells. Histological studies further supported the above results and showed extensive renal damage in animals treated with KBrO3 and greatly reduced tissue injury in groups pretreated with LBP-4a. In conclusion, LBP-4a exhibited protective effects against renal damage induced by KBrO3, and the mechanism was closely correlated with a reduction in levels of lipid peroxidation and an increase in the activities of antioxidant enzymes in kidney tissues, which alleviated DNA damage and increased mitochondrial membrane potentials in renal cells. These observations provide the background for the further development of LBP-4a as a protective agent for use in the treatment of renal damage. PMID- 28671198 TI - Light-activated electric bistability for evaporated silver nanoparticles in organic field-effect transistors. AB - Evaporated naked silver nanoparticles (Ag-NPs) were embedded in the isolated layer of PTB7-based organic field-effect transistors (OFETs), where their electric bistability behavior was successfully activated by photo-irradiation. These devices showed no obvious memory behavior in the dark; while under weak photo-irradiation (0.015 mW cm-2), memory windows of 12.5-35 V have been achieved. Different operation modes have been designed to exhibit the memory behavior and to explore the origin of the formation of a stable charge state. The immobilized photo-generated electrons supplied an additional photo-generated electric field, which confined the trapped charge in the charge storage media after the gate voltage and photo-irradiation being removed. The photo-irradiation created more charges at the interface, and the presence of Ag-NPs allowed effective charge storage of the majority carriers, which increased the drain current and lowered the gate-operating voltage. This method is a novel approach to light-activated electric bistability based charge storage. PMID- 28671200 TI - An enantioselective organocatalytic intramolecular Morita-Baylis-Hillman (IMBH) reaction of dienones, and elaboration of the IMBH adducts to fluorenones. AB - An enantioselective organocatalytic intramolecular Morita-Baylis-Hillman (IMBH) reaction of dienones is reported for the first time. This has been achieved by incorporating entropy and synergy considerations during the substrate design. The reaction conditions are thoroughly verified for an efficient synthesis of highly functionalised cyclopenta-fused arenes and heteroarenes in excellent yields and enantioselectivities. The synthetic utility of the IMBH-adducts has been demonstrated by transforming them into 3,4-disubstituted fluorenones in a serendipitous manner. PMID- 28671199 TI - CoN3 embedded graphene, a potential catalyst for the oxygen reduction reaction from a theoretical perspective. AB - Non-precious metal catalysts have attracted particular interest in recent years due to their promising ORR (oxygen reduction reaction) activity in fuel cells. In this work, the structural stability and ORR mechanism of CoN3 embedded graphene have been studied theoretically in acid media. The results indicate that CoN3 embedded graphene is stable thermodynamically. The kinetically most favorable reaction pathway for the ORR is a four-electron process. The process of OOH hydrogenation to generate O + H2O is the most favorable pathway. In the rate determining step, the energy barrier is 0.38 eV, much smaller than the theoretical value of ~0.80 eV for pure Pt. The predicted working potential is 0.4 V for the most favorite pathway. Besides the lower energy barrier, the smaller Tafel slope compared with pure Pt in both low and high overpotential regions also suggests that CoN3 embedded graphene is a promising electrocatalyst for the ORR. PMID- 28671201 TI - The transferrin receptor: the cellular iron gate. AB - The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron homeostasis. Since the number of TfR1 molecules at the cell surface is the rate-limiting step for iron entry into cells and is essential to prevent iron overload, TfR1 expression is precisely controlled at multiple levels. In this review, we have discussed the latest advances in the molecular regulation of TfR1 expression and we have considered current understanding of TfR1 function beyond its canonical role in providing iron for erythroid precursors and rapidly proliferating cells. PMID- 28671202 TI - Transcriptome dynamics of human pluripotent stem cell-derived contracting cardiomyocytes using an embryoid body model with fetal bovine serum. AB - Cardiomyocyte (CM) differentiation techniques for generating adult-like mature CMs remain imperfect, and the plausible underlying mechanisms remain unclear; however, there are a number of current protocols available. Here, to explore the mechanisms controlling cardiac differentiation, we analyzed the genome-wide transcription dynamics occurring during the differentiation of human pluripotent stem cells (hPSCs) into CMs using embryoid body (EB) formation. We optimized and updated the protocol to efficiently generate contracting CMs from hPSCs by adding fetal bovine serum (FBS) as a medium supplement, which could have a significant impact on the efficiency of cardiac differentiation. To identify genes, biological processes, and pathways involved in the cardiac differentiation of hPSCs, integrative and comparative analyses of the transcriptome profiles of differentiated CMs from hPSCs and of control CMs of the adult human heart (CM AHH) were performed using gene ontology, functional annotation clustering, and pathway analyses. Several genes commonly regulated in the differentiated CMs and CM-AHH were enriched in pathways related to cell cycle and nucleotide metabolism. Strikingly, we found that current differentiation protocols did not promote sufficient expression of genes involved in oxidative phosphorylation to differentiate CMs from hPSCs compared to the expression levels in CM-AHH. Therefore, to obtain mature CMs similar to CM-AHH, these deficient pathways in CM differentiation, such as energy-related pathways, must be augmented prior to use for in vitro and in vivo applications. This approach opens up new avenues for facilitating the utilization of hPSC-derived CMs in biomedical research, drug evaluation, and clinical applications for patients with cardiac failure. PMID- 28671205 TI - PbTiO3-based perovskite ferroelectric and multiferroic thin films. AB - Ferroelectric thin films, especially PbTiO3-based perovskite thin films which possess robust spontaneous electrical polarization, are widely investigated and applied in various devices. With the advances in synthesis, characterization and calculation techniques, diverse phenomena and properties are uncovered in ferroelectric thin films. Herein some typical PbTiO3-based perovskite thin films through composition control are introduced, which gives more choices with various ferroelectric or other properties. Strain engineering, as well as some other interfacial effects, is also included to show the possibilities of controlling the lattice structure, the electronic structure as well as the domain structure which are closely connected to ferroelectricity. Multiferroic thin films, which could achieve magnetic-field-controlled polarization reversal, expand the novel applications of ferroelectric thin films. Typical and remarkable progress made in the case of multiferroic PbTiO3-based perovskite thin films is discussed here. Critical problems such as leakage current and fatigue hinder the practical use of ferroelectric and multiferroic thin films, and are also included in this article. PMID- 28671206 TI - A frustrated phase driven by competition among layer structures. AB - Using our designed ternary system consisting of a semiperfluorinated smectic liquid crystal and two nematic liquid crystals, we investigated their phase transition behaviour using polarizing optical microscopy, differential scanning calorimetry and X-ray diffraction. A mixture containing 20 mol% of the semiperfluorinated compound was found to exhibit the following unusual phase sequence: isotropic liquid - isotropic liquid + smectic A phase - nematic phase - unidentified frustrated phase (X) - modulated phase (Y) - modulated phase (Z). The frustrated phase showed a fan-shaped texture characteristic of a smectic phase, but no peak corresponding to the layer spacing was detected. No difference was found in the shearing stress between the high-temperature N phase and the frustrated phase, but electro-optical switching observed in the N phase was not detected in the frustrated phase. We discuss how the molecules organize the unusual phase transition behaviour. PMID- 28671208 TI - Stepwise, multicomponent assembly of a molecular trapezoid possessing three different metals. AB - A novel terpyridine-based, trapezoidal architecture was synthesized by a coordination-driven multicomponent assembly and features three different tpy-M2+ tpy bonds (M2+ = Ru2+, Fe2+, and Zn2+) in the macrocyclic ring. This trimetallic macrocycle introduces the construction of polymetallosupramolecular assemblies possessing multiple, differing metal centers in an ordered, predetermined pattern. Characterization was accomplished by NMR spectroscopy, mass spectrometry, and UV-Vis spectroscopy. PMID- 28671209 TI - New bio-based monomers: tuneable polyester properties using branched diols from biomass. AB - A family of monomers, including 2,5-hexandiol, 2,7-octandiol, 2,5 furandicarboxylic acid (FDCA), terephthalic acid (TA), and branched-chain adipic and pimelic acid derivatives, all find a common derivation in the biomass-derived platform molecule 5-(chloromethyl)furfural (CMF). The diol monomers, previously little known to polymer chemistry, have been combined with FDCA and TA derivatives to produce a range of novel polyesters. It is shown that the use of secondary diols leads to polymers with higher glass transition temperatures (Tg) than those prepared from their primary diol equivalents. Two methods of polymerisation were investigated, the first employing activation of the aromatic diacids via the corresponding diacid chlorides and the second using a transesterification procedure. Longer chain diols were found to be more reactive than the shorter chain alternatives, generally giving rise to higher molecular weight polymers, an effect shown to be most pronounced when using the transesterification route. Finally, novel diesters with high degrees of branching in their hydrocarbon chains are introduced as potential monomers for possible low surface energy materials applications. PMID- 28671210 TI - A mechanistic study of the non-oxidative decarboxylation catalyzed by the radical S-adenosyl-l-methionine enzyme BlsE involved in blasticidin S biosynthesis. AB - Decarboxylation is a fundamentally important reaction in biology and involves highly diverse mechanisms. Here we report a mechanistic study of the non oxidative decarboxylation catalyzed by BlsE, a radical S-adenosyl-l-methionine (SAM) enzyme involved in blasticidin S biosynthesis. Through a series of biochemical analysis with isotopically labeled reagents, we show that the BlsE catalyzed reaction is initiated by the 5'-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction from a sugar carbon of the substrate cytosylglucuronic acid (CGA), and does not involve a carboxyl radical as has been proposed for 4 hydroxyphenylacetate decarboxylase (HPAD). Our study reveals that BlsE represents a mechanistically new type of radical-based decarboxylase. PMID- 28671212 TI - Room-temperature growth of colloidal Bi2Te3 nanosheets. AB - In this work, we report the colloidal synthesis of Bi2Te3 nanosheets with controlled thickness, morphology and crystallinity at temperatures as low as 20 degrees C. Grown at room temperature, Bi2Te3 exhibits two-dimensional morphology with thickness of 4 nm and lateral size of 200 nm. Upon increasing the temperature to 170 degrees C, the nanosheets demonstrate increased thickness of 16 nm and lateral dimensions of 600 nm where polycrystalline nanosheets (20 degrees C) are replaced by single crystal platelets (170 degrees C). Rapid synthesis of the material at moderately low temperatures with controllable morphology, crystallinity and consequently electrical and thermal properties can pave the way toward its large-scale production for practical applications. PMID- 28671211 TI - Glucose directs amyloid-beta into membrane-active oligomers. AB - Oligomeric amyloid-beta 1-42 (Abeta-42) peptides are considered to be the most toxic species connected to the occurrence of Alzheimer's disease. However, not all aggregation conditions promote oligomer formation in vitro, raising the question whether oligomer formation in vivo also requires a specific suitable cellular environment. We recently found that interaction with neuronal membranes initiates aggregation of Abeta-42 and neuronal uptake. Our data suggest that small molecules in the extracellular space can facilitate the formation of membrane-active Abeta-42 oligomers. We analyzed the early stage of Abeta-42 aggregation in the presence of glucose and sucrose and found that these sugars strongly favor Abeta-42 oligomer formation. We characterized oligomers by dynamic light scattering, atomic force microscopy, immuno-transmission electron microscopy and fluorescence cross correlation spectroscopy. We found that Abeta 42 spontaneously and rapidly forms low molecular weight oligomers in the presence of sugars. Slightly acidic pH (6.7-7) greatly favors oligomer formation when compared to the extracellular physiological pH (7.4). Circular dichroism demonstrated that these Abeta-42 oligomers did not adopt a beta-sheet structure. Unstructured oligomeric Abeta-42 interacted with membrane bilayers of giant unilamellar vesicles (GUV) and neuronal model cells, facilitated cellular uptake of Abeta-42, and inhibition of mitochondrial activity. Our data therefore suggest that elevated concentrations of glucose within the range observed in diabetic individuals (10 mM) facilitate the formation of membrane-active Abeta-42 oligomers. PMID- 28671213 TI - Improved magnetic and magnetoelectric properties in BaFe12O19 nanostructures. AB - The structural, magnetic and magnetoelectric properties were investigated for sol gel prepared BaFe12O19 nanorods and plate-like nanoparticles. Based on comparative experiments with bulk ceramics, it is found that larger structural distortion is present in nanostructures, which could cause the enhancement of magnetocrystalline anisotropy and the off-center displacement of Fe3+ ions, and thus result in improved magnetic and magnetoelectric properties in BaFe12O19 plate-like nanoparticles. Meanwhile, the local (Fe2+-Fe3+) dipoles, which usually appear during a high temperature sintering process, can also contribute to the negative magnetoelectric effect of BaFe12O19 nanorods and a large room temperature magnetodielectric coefficient of about -13% is observed at 104 Hz and 9 kOe. PMID- 28671214 TI - A new method for the preparation of a [Sn2(H2PO2)3]Br SHG-active polar crystal via surfactant-induced strategy. AB - Herein, unprecedented NLO-brominated tin hypophosphites, namely [Sn2(H2PO2)3]Br, were discovered via a facile surfactant-induced method, which displayed a moderate powder SHG intensity (3.0 * KDP) in type - I phase matching behavior. This complex has high chemical and thermal stability at room temperature. DFT calculations and SHG coefficient analyses revealed that the alignment of the SHG active-units SnO3 trigonal pyramids and Br- anions in its structure mainly contribute to the macroscopical SHG behaviors. PMID- 28671215 TI - Catalyst-free N-formylation of amines using BH3NH3 and CO2 under mild conditions. AB - The catalyst-free N-formylation of amines using CO2 as the C1 source and BH3NH3 as the reductant has been developed for the first time. The corresponding formylated products of both primary and secondary amines are obtained in good to excellent yields (up to 96% of isolated yield) under mild conditions. PMID- 28671216 TI - Cellulose nanocrystals by acid vapour: towards more effortless isolation of cellulose nanocrystals. AB - Cellulose nanocrystals (CNCs) are topical in materials science but their full potential is yet to be fulfilled because of bottlenecks in the production: the process consumes huge amounts of water, recycling the strong acid catalyst is difficult, and purification steps are cumbersome, particularly with lengthy dialysis. Production of CNCs with HCl vapour overcomes many of these difficulties but the dispersion of CNCs from the already hydrolysed fibre matrix is a formidable challenge. This study is a fundamental effort to explore very basic means to facilitate CNC dispersion from cotton linter fibres (filter paper), hydrolysed to levelling off degree of polymerization by HCl vapour. The introduction of carboxylic groups on the cellulose crystal surface proved the most efficient method to alleviate dispersion with good yields (ca. 50%) and a provisional possibility to tune the CNC length. By contrast, attempts to directly disperse untreated hydrolysed fibres in various organic solvents and aqueous surfactant solutions were unsuccessful. The results showed that hydrolysis of native cellulose fibres by HCl vapour is indeed a viable method for producing CNCs but it has more potential as a pre-treatment step rather than a full-fledged process on its own. PMID- 28671218 TI - Editorial: Are natural products the solution to antimicrobial resistance? PMID- 28671220 TI - Combining two redox active rare earth elements for oxygen storage - electrical properties and defect chemistry of ceria-praseodymia single crystals. AB - Solid solutions of ceria and praseodymia are highly relevant for electrochemical applications as the incorporation of praseodymium into the ceria lattice shifts the range of mixed ionic electronic conductivity to higher oxygen partial pressures. To better understand the influence of praseodymium substitution on the transport processes and oxygen storage capacity in ceria, single crystals of ceria substituted with 14 mol% praseodymium have been investigated, obtaining the bulk properties without the influence of grain boundaries. Beside the characterization of structural changes caused by the substitution using XRD and Raman spectroscopy, the electrochemical transport properties of ceria-praseodymia single crystals are reported. Measurements of the total electrical conductivity, the ionic transference number and the non-stoichiometry of Ce0.85Pr0.14Zr0.01O2 delta were performed in an oxygen partial pressure range of -25 < lg[p(O2)/bar] < 0 at 700 degrees C. With praseodymium being redox active itself, higher values of oxygen deficiency and electrical conductivity than in pure ceria have been observed in the high oxygen partial pressure region, while no significant structural changes occur due to the similar ionic radii of both cations. From measurements of the impedance at different temperatures, the migration enthalpy for the electronic charge carriers has been determined. By analysing the non stoichiometry at 700 degrees C using a defect chemical model it was also possible to determine the equilibrium constants of Pr and Ce reduction in Ce0.85Pr0.14Zr0.01O2-delta single crystals. PMID- 28671221 TI - A new preparation of a bifunctional crystalline heterogeneous copper electrocatalyst by electrodeposition using a Robson-type macrocyclic dinuclear copper complex for efficient hydrogen and oxygen evolution from water. AB - The development of low-cost, stable bifunctional electrocatalysts, which operate in the same electrolyte with a low overpotential for water splitting, including the oxygen evolution reaction and the hydrogen evolution reaction, remains an attractive prospect and a great challenge. In this study, a water soluble Robson type macrocyclic dicopper(ii) complex has been used for the first time as a catalyst precursor for the generation of a copper-based bifunctional heterogeneous catalyst film, which can be used for both HER and OER at a near neutral pH. In sodium borate buffer at pH 9.20, this complex decomposed to give a Cu(OH)2/Cu2O-based thin film on FTO that catalyzes both hydrogen production and water oxidation. The morphology, nature and composition of the thin film were fully characterized by scanning electron microscopy, powder X-ray diffraction, X ray photoelectron, and energy dispersive X-ray spectroscopies. The catalyst film showed high stability during the course of electrolysis in either the cathodic or the anodic direction for more than 4 h. Faradaic efficiencies of ~92% for HER and ~96% for OER were achieved. The switch between the two half-reactions of catalytic water splitting was fully reversible in nature. PMID- 28671222 TI - Automation of route identification and optimisation based on data-mining and chemical intuition. AB - Data-mining of Reaxys and network analysis of the combined literature and in house reactions set were used to generate multiple possible reaction routes to convert a bio-waste feedstock, limonene, into a pharmaceutical API, paracetamol. The network analysis of data provides a rich knowledge-base for generation of the initial reaction screening and development programme. Based on the literature and the in-house data, an overall flowsheet for the conversion of limonene to paracetamol was proposed. Each individual reaction-separation step in the sequence was simulated as a combination of the continuous flow and batch steps. The linear model generation methodology allowed us to identify the reaction steps requiring further chemical optimisation. The generated model can be used for global optimisation and generation of environmental and other performance indicators, such as cost indicators. However, the identified further challenge is to automate model generation to evolve optimal multi-step chemical routes and optimal process configurations. PMID- 28671223 TI - Differential proteomics highlights macrophage-specific responses to amorphous silica nanoparticles. AB - The technological and economic benefits of engineered nanomaterials may be offset by their adverse effects on living organisms. One of the highly produced nanomaterials under such scrutiny is amorphous silica nanoparticles, which are known to have an appreciable, although reversible, inflammatory potential. This is due to their selective toxicity toward macrophages, and it is thus important to study the cellular responses of this cell type to silica nanoparticles to better understand the direct or indirect adverse effects of nanosilica. We have here studied the responses of the RAW264.7 murine macrophage cells and of the control MPC11 plasma cells to subtoxic concentrations of nanosilica, using a combination of proteomic and targeted approaches. This allowed us to document alterations in the cellular cytoskeleton, in the phagocytic capacity of the cells as well as their ability to respond to bacterial stimuli. More surprisingly, silica nanoparticles also induce a greater sensitivity of macrophages to DNA alkylating agents, such as styrene oxide, even at doses which do not induce any appreciable cell death. PMID- 28671224 TI - Garlic-inspired trisulfide linkers for thiol-stimulated H2S release. AB - Garlic-derived polysulfides (e.g., diallyl trisulfide, DATS) act as potent donors of the cell-signalling mediator H2S when exposed to endogenous thiols. Inspired by this chemistry, we incorporated a trisulfide linkage into a conjugate comprising an mPEG tail and a cholesteryl head via thiol-mediated fragmentation chemistry. The synthesized conjugate releases H2S upon exposure to thiol even at intracellular levels. PMID- 28671225 TI - Mechanisms of carbon monoxide hydrogenation yielding formaldehyde catalyzed by the representative strong mineral acid, H2SO4, and Lewis-Bronsted superacid, HF/AlF3. AB - The mechanism of the CO + H2-> H2CO reaction catalyzed by acidic systems was investigated theoretically using the ab initio MP2 and CCSD(T) methods and the aug-cc-pVDZ basis set (the effects of the surrounding solvent molecules were approximated by employing the polarized continuum solvation model). Two representative acids were chosen to verify the usefulness of such catalysts in this process: sulfuric acid (as a strong mineral acid) and HAlF4 (as a superacid). Detailed mechanisms in both gas and liquid phases proceeding either along a concerted path or according to a stepwise route were investigated and discussed. The most important findings include the observation that both acids seem to catalyze the carbon monoxide hydrogenation in a qualitatively similar way but only the HAlF4 superacid is predicted to effectively reduce the activation barriers to render the whole process plausible. PMID- 28671226 TI - Kinetically modulated specificity against single-base mutants in nucleic acid recycling circuitry using the destabilization motif. AB - Signal amplification in nucleic acid sensing improves detection sensitivity, but difficulties remain in sustaining specificity over time, particularly under excess amounts of single-base mutants. Here, we report simple, self-refining target recycling circuitry, which cumulates differentiation between on and off targets by 2-step cyclic interaction with the sensing probe. In the reaction, the analyte recycles only if the protective strand of the sensing probe is removed. The dissociation kinetics of such interaction was modulated by reacting it with different lengths of assistant strands. When shorter assistant strands are used, the destabilization motif of the sensing probe has to spontaneously dissociate before another assistant strand approaches and fully displaces it. This sets up a high kinetic barrier sensitive to the subtle reaction energy differences imposed by the single-base mutants, and substantially improved specificity. As a proof of concept, a microRNA 21 DNA analogue was chosen as our target analyte together with its 14 point mutants (substitution, insertion, or deletion) for specificity measurements. The experimental results corroborate that our system amplifies signals in a comparable manner to the traditional one-layer recycling approach but with negligible system leakage. With the use of shortened assistant strands, up to 100 fold increase in the discrimination factor against the single-base mutants is observed. Specificity is sustainable or even increased over long period measurements (i.e. 4 days). More importantly, target differentiation is successfully demonstrated even in excess amounts of spurious analogs (100*) and low target frequency mixtures (i.e. 0.1%), which mimic the lean conditions practically encountered. Explicit mechanisms of the system specificity are elucidated through analytical calculations and free energy level diagrams. The modularity of the destabilization motif herein promises detection of different nucleic acid based targets and integration into other signal amplification approaches for specificity enhancement. PMID- 28671227 TI - Five-component trigonal nanoprism with six dynamic corners. AB - The metallo-supramolecular trigonal prism P is based on five different components and three unlike dynamic coordination motifs: the heteroleptic phenanthroline terpyridine complex [Zn(1)(4)]2+ (HETTAP), the heteroleptic phenanthroline pyridine complex [Cu(2)(5A)]+ (HETPYP-I), and the pyridine -> zinc(ii)-porphyrin interaction. PMID- 28671228 TI - Imidazole/benzimidazole-modified cyclotriphosphazenes as highly selective fluorescent probes for Cu2+: synthesis, configurational isomers, and crystal structures. AB - Configurational isomers (cis and trans) of imidazole- or benzimidazole-modified cyclotriphosphazenes (3a, 4a or 3b, 4b) were designed, synthesized and investigated as fluorescent probes for metal ions. The newly synthesized compounds were characterized by 1H and 31P NMR, and MALDI MS spectrometry. The configurations of geometric isomers were analyzed by X-ray crystallography and 31P NMR spectroscopy on addition of CSA. The photophysical behaviour and metal ion selectivity of the compounds were investigated by UV/vis and fluorescence spectroscopy. Among the examined 20 metal ions, the fluorescence emissions of the isomer mixtures were quenched by Cu2+ together with Fe2+, Fe3+, Zn2+ and Ni2+ ions, but each individual isomer (3a,b and 4a,b) exhibited an on-off-type fluorescence response with high selectivity towards only Cu2+ with a low limit of detection ranging from 1.27 MUM to 2.04 MUM. The complex stoichiometries of 3a,b and 4a,b with Cu2+ were determined as 1 : 1 (L/M) using the method of continuous variation (Job's plot) and density functional theory (DFT) calculations; moreover the complex formation of 4a with Cu2+ was unambiguously determined by X-ray crystallographic analysis that is consistent with the results obtained by the Job's plots as well as DFT. PMID- 28671229 TI - Tuning Coulombic interactions to stabilize nematic and smectic ionic liquid crystal phases in mixtures of charged soft ellipsoids and spheres. AB - We have investigated the effect of electrostatic interactions in mixtures of soft ellipsoids and spheres based on the well-known Gay-Berne (GB) and Lennard-Jones (LJ) potential, respectively. These model systems, in their original version, that is without any electrostatic charge, have been thoroughly investigated in the literature both as pure components and mixtures. In particular, mixtures of particles of different shapes, such as spheres and ellipsoids, tend to phase separate because of the excluded volume effects. Common ionic liquid crystals, based on imidazolium or other quaternary ammonium salts, are usually composed of roughly elongated (although flexible) cations and roughly spherical anions, that is, particles with a similar shape such as the GB and LJ models. Therefore, in this work, we present the results of molecular dynamics simulations of mixtures of positively charged GB and negatively charged LJ particles as models of ionic liquid crystals. Interestingly, by modulating the charge of the particles it is possible to stabilize isotropic, nematic, smectic and crystalline ionic phases. The relative weight of Coulomb (a radial, therefore isotropic interaction) and van der Waals (an anisotropic interaction) contributions is a key parameter to tune the stability of various mesophases. PMID- 28671230 TI - Synthesis and characterization of two layered aluminophosphates [R C8H12N]8[H2O]2.[Al8P12O48H4] and [S-C8H12N]8[H2O]2.[Al8P12O48H4] with a mirror symmetric feature and their proton conductivity. AB - The template effect of chiral organic molecules to aluminophosphate open frameworks was investigated by the syntheses of two layered structures, [R C8H12N]8[H2O]2.[Al8P12O48H4] and [S-C8H12N]8[H2O]2.[Al8P12O48H4] (denoted as AlPO CJ72-R and -S), with a mirror symmetric feature. The two structures are obtained separately, which is the first instance in inorganic open-framework materials to our knowledge, by alpha-methylbenzylamine with homochirality. Single-crystal X ray diffraction analysis reveals that the structure of either AlPO-CJ72-R or AlPO CJ72-S crystallizes in the chiral triclinic space group P1, and the existence of AAAA-stacked Al2P3O123- layers made up of alternating AlO4 and PO3([double bond, length as m-dash]O) or PO2([double bond, length as m-dash]O)(OH) tetrahedra to form a 4 * 6 network. Their structures show self-assembled chiral H-bond chains, the chiralities of which are transferred to adjacent helical T-O (T = Al and P) chains. The frameworks are mirror symmetric to each other. The performance of AlPO-CJ72 regarding proton conductivity was tested. It shows an excellent result up to 3.01 * 10-3 S cm-1 (363 K, 98% RH), which might be attributed to the H-bond chains in the structure. PMID- 28671231 TI - Structural stability and the electronic properties of a (SiH)2O-formed siloxene sheet: a computational study. AB - Very recently, a (SiH)2O-formed siloxene sheet has been synthesized in an experiment [S. Li, et al. J. Mater. Chem. A 2016, 4, 15841]. Utilizing first principles calculations, we have systematically investigated the structural stability and the physical properties of this (SiH)2O sheet. We have found a dynamically stable structure because it is a puckered one with bent Si-O-Si connections, which leads to an anisotropic elastic behaviour with negative Poisson ratios. The (SiH)2O sheet has a strain-tunable direct band gap whose valence and conduction band edges straddle the redox potentials of water even in the presence of stress (either tensile or compressive). The calculated carrier mobilities are prominently anisotropic: in its zigzag direction the electron mobility reaches a high value of 5.39 * 103 cm2 V-1 s-1, while the hole mobility remains small. These different carrier mobilities permit fast charge separation and transfer, which is crucial for efficient solar-to-electric energy conversion for photovoltaic and water splitting applications. Similar to phosphorene, a typical linear dichroism phenomenon is also present in the (SiH)2O sheet. Due to its outstanding electronic properties, the (SiH)2O sheet is a promising material in the fields of nano-electronics, sustainable energy and fuel generation. PMID- 28671232 TI - Fast crystalline ice formation at extremely low temperature through water/neon matrix sublimation. AB - Crystalline ice formation requires water molecules to be sufficiently mobile to find and settle on the thermodynamically most stable site. Upon cooling, however, diffusion and rearrangement become increasingly kinetically difficult. Water ice grown by the condensation of water vapor in laboratory is thus generally assumed to be in a metastable amorphous form below 100 K. Here, we demonstrate the possibility of crystalline ice formation at extremely low temperature using a water/neon matrix (1/1000, 30 000 monolayers) prepared at 6 K, which is subsequently warmed to 11-12 K. In situ infrared spectroscopy revealed the assembly of the dispersed water molecules, forming crystalline ice I during the sublimation of the neon matrix for 40-250 seconds. This finding indicates that the high mobility of the water molecules during matrix sublimation can overcome the kinetic barrier to form crystals even at extremely low temperature. PMID- 28671233 TI - Governing effects in the mechanism of the gold-catalyzed cycloisomerization of allenic hydroxylamine derivatives. AB - The formation of chiral heterocycles via cycloisomerization reactions of allene derivatives has gained relevance due to their associated efficiency and atom economy. The only drawback that keeps these reactions away from being routine synthetic strategies is the control in the regioselectivity (most often 5-endo vs. 6-endo). In this work, we computationally explore the experimental chemistry reported by Krause using N-hydroxy-alpha-aminoallenes and hydroxylamine ethers as substrates and provide a rationale for the different reactivity observed. The drastic effects observed experimentally when changing the nature of the gold catalyst have also been studied mechanistically. These results are expected to help in the design of improved regioselective protocols for the formation of medium sized chiral heterocycles from allene substrates. PMID- 28671235 TI - Drugs to Treat Depression. PMID- 28671234 TI - Racism, White Privilege, and Diversity in Mental Health. PMID- 28671236 TI - Vitamin B Supplementation: What's the Right Choice for Your Patients? AB - As many patients turn to vitamins and supplements to enhance energy, relieve fatigue, or generally feel better, it is important to understand the connection between the B vitamins and psychiatric symptomatology. Vitamins B6, B8, and B12 have been shown not only to reduce psychiatric symptoms but also shorten the duration of illness. Vitamin B9, also known as folate or folic acid, has also been associated with psychiatric symptoms. However, when patients lack a specific genetic enzyme, which converts folate/folic acid to its most usable form, L methylfolate, the neuroprotective and neuropsychiatric benefits are lost. L methylfolate allows for the synthesis of the three major neurochemicals serotonin, nor-epinephrine, and dopamine-across the blood-brain barrier. Exploring the conversion of folate/folic acid into L-methylfolate and the various polymorphisms of the MTHFR gene and examining the B vitamins associated with the treatment of psychiatric symptoms will further allow nurses to comprehensively treat their patients with the appropriate B vitamins. [Journal of Psychosocial Nursing and Mental Health Services, 55(7), 7-11.]. PMID- 28671237 TI - Seeing Oneself in the Face of the Other: The Value and Challenge of Human Connectedness for Older Adults. AB - Connection with others is an essential part of our being as humans. Daily interactions provide chances to laugh, argue, empathize, and love. A lack of human connectedness can lead to loneliness, isolation, and deterioration of physical health. Older adults may encounter challenges in maintaining the connections they used to have or in forming new connections. Moreover, human connectedness is sometimes taken for granted and can slip away gradually, unnoticed at first; thus, older adults may find themselves disconnected and experiencing feelings of loneliness without being aware of the steps that brought them to that state. Nurses and other health professionals must be aware of this potential for disconnectedness so that they can offer support for making and sustaining connections and intentionally connect with a client as a whole person. [Journal of Psychosocial Nursing and Mental Health Services, 55(7), 13-17.]. PMID- 28671238 TI - Reducing Falls After Electroconvulsive Therapy: A Quality Improvement Project. AB - Falls after electroconvulsive therapy (ECT) in patients 60 and older have been long recognized as a major clinical care issue across many mental health care settings. The evidence base for fall prevention strategies after receiving ECT is sparse. The risk factors for falls after ECT are vast and complex in nature, especially considering existing comorbid medical conditions. The dearth of research in guiding practitioners on fall reduction interventions for this patient population illuminates a gap in mental health care quality and safety. The purpose of the current nurse-led quality improvement project was to reduce falls in patients undergoing ECT by enhancing safety measures through education and a post-ECT treatment protocol. The project did not prove to be as efficacious as anticipated as measured by fall rate outcomes. Several factors that may account for the project's findings are discussed. [Journal of Psychosocial Nursing and Mental Health Services, 55(7), 20-29.]. PMID- 28671239 TI - Perspectives of Individuals With Mental Illness on Community Mental Health Services in China: A Qualitative Exploration. AB - Little is known about the perspectives of individuals with mental illness on community mental health services (CMHS) in China. The current study aimed to explore these perspectives. Semi-structured interviews were completed with a purposive sample of 25 individuals with mental illness recruited from three communities in Guangzhou City, China. The Colaizzi method was used for data analysis. Three main themes were identified: (a) patients' perceptions of CMHS, (b) patients' barriers to accessing CMHS, and (c) patients' expectations of CMHS. The identified issues should be taken into consideration in improving CMHS. CMHS staff, including nurses, should make patients more aware of CMHS. To increase CMHS use and make it more responsive to patients' expectations, staff should try to resolve patients' stigma and desire to return to society. [Journal of Psychosocial Nursing and Mental Health Services, 55(7), 30-37.]. PMID- 28671242 TI - Untitled by Ann Davis. PMID- 28671240 TI - Positive Mental Health and Prevalence of Psychological Ill-Being in University Nursing Professors in Catalonia, Spain. AB - The aim of the current study was to examine the prevalence of psychological ill being among university nursing professors in Spain and determine their grade of positive mental health. A cross-sectional study was conducted from June 2013 to December 2013 with a sample of 263 university nursing professors. Sociodemographic and occupational variables, as well as variables related to daily habits and lifestyle, were collected. Psychological ill-being was measured using the General Health Questionnaire (GHQ-12) and positive mental health was evaluated with the Positive Mental Health Questionnaire (PMHQ). Prevalence of psychological ill-being (GHQ-12 score >2) among the sample was 27% (range = 21.8% to 32.6%), with a higher prevalence in teachers from first and second cycles (Bachelor's degree and Master's degree, respectively) and a lower prevalence in those having very satisfactory social relationships. Significant differences were found in relation to consumption of tranquilizer drugs and Bach flower remedies. PMHQ scores were lower among teachers with a GHQ-12 score >2. Participants presented a good level of positive mental health. Preventive policies should be applied with the aim of reducing psychological ill-being among professors and potentiating positive mental health. [Journal of Psychosocial Nursing and Mental Health Services, 55(7), 38-48.]. PMID- 28671244 TI - CORRECTION Corrigendum: Correlation between adiponectin (ADPN) and hemorrhagic shock in mice - Genet. Mol. Res. 15 (1): gmr.15017037 (DOI: 10.4238/gmr.15017037). PMID- 28671243 TI - Time-dependent and lesion-dependent HMGB1-selective localization in brains of patients with cerebrovascular diseases. AB - High mobility group box 1 protein (HMGB1) has multiple functions, including the maintenance of nucleosomes and the regulation of gene transcription. HMGB1 is released from activated macrophages, resulting in the induction of inflammatory cytokines. Recently, much research about the role of HMGB1 in cerebrovascular disease (CVD) has been reported. In an animal model, HMGB1 neutralization ameliorates brain infarction, there is an early release of HMGB1 from neurons, and HMGB1 antibody attenuates delayed cerebral vasospasm in experimental subarachnoid hemorrhage. It was also reported that elevation of HMGB1 in serum correlates with severity of acute intracerebral hemorrhage. However, the evidence of HMGB1 localization in brains of patients with CVD is very limited. Therefore, we investigated at autopsy the immunolocalization of HMGB1 in brains of patients with CVD (acute and chronic cerebral infarction, acute cerebral hemorrhage, subarachnoid hemorrhage). In 3 out of 10 acute cerebral infarction cases, the cytoplasm of neurons located around the ischemic core (i.e., penumbra) was positive for HMGB1. In the chronic stage of cerebral infarction, macrophages located in some ischemic regions were positive for HMGB1. Around the hematoma in the basal ganglia, HMGB1-like immunoreactivity (IR) was intense in macrophages. However, around the subarachnoid hematoma, HMGB1-like IR was not seen in the cortex. In arteries surrounded by subarachnoid hematoma, HMGB1-like IR was located in the cytoplasm of vascular smooth muscle cells. These findings, which partially differ from animal model results, may provide translational research and a basis for understanding the role of HMGB1 in brains of patients with CVD. PMID- 28671245 TI - Comparison of physical and chemical characteristics of collagen from the skin of cod (Gadus macrocephaius). AB - Acid and pepsin-soluble collagen (ASC and PSC, respectively) were extracted from cod (Gadus macrocephaius) skin, and yields of 37.36 and 55.96% were obtained for ASC and PSC, respectively. The total yield of ASC and PSC was 93.92%, based on the lyophilized dry weight, which is higher than that obtained from other sources. Electrophoresis revealed that both ASC and PSC consisted of two different alpha-chains (alpha1 and alpha2), which were characterized as type I collagen. Analysis of amino acids showed that both the ASC and PSC contained imino acids (216.1 and 190.6 residues/1000 residues, respectively) and the Fourier transform infrared spectroscopy spectra of both collagens were similar with pepsin hydrolysis having no effect on their triple-helical structure. The thermal denaturation temperature of ASC and PSC, as measured by viscometry, was 26.8 degrees and 25.6 degrees C, respectively. PMID- 28671246 TI - Genetic correlation and genome-wide association study (GWAS) of the length of productive life, days open, and 305-days milk yield in crossbred Holstein dairy cattle. AB - In this study, we estimated the genetic parameters and identified the putative quantitative trait loci (QTL) associated with the length of productive life (LPL), days open (DO), and 305-day milk yield for the first lactation (FM305) of crossbred Holstein dairy cattle. Data comprising 4,739 records collected between 1986 and 2004 were used to estimate the variance-covariance components using the multiple-trait animal linear mixed models based on the average information restricted maximum likelihood (AI-REML) algorithm. Thirty-six animals were genotyped using the Illumina BovineSNP50 Bead Chip [>50,000 single nucleotide polymorphisms (SNPs)] to identify the putative QTL in a genome-wide association study. The heritability of the production trait FM305 was 0.25 and that of the functional traits, LPL and DO, was low (0.10 and 0.06, respectively). The genetic correlation estimates demonstrated favorable negative correlations between LPL and DO (-0.02). However, we observed a favorable positive correlation between FM305 and LPL (0.43) and an unfavorable positive correlation between FM305 and DO (0.1). The GWAS results indicated that 23 QTLs on bovine chromosomes 1, 4, 5, 8, 15, 26, and X were associated with the traits of interest, and the putative QTL regions were identified within seven genes (SYT1, DOCK11, KLHL13, IL13RA1, PRKG1, GNA14, and LRRC4C). In conclusion, the heritability estimates of the LPL and DO were low. Therefore, the approach of multiple-trait selection indexes should be applied, and the QTL identified here should be considered for use in marker assisted selection in the future. PMID- 28671247 TI - Genetic variability among elite popcorn lines based on molecular and morphoagronomic characteristics. AB - Knowledge of genetic diversity among genotypes and relationships among elite lines is of great importance for the development of breeding programs. Therefore, the objective of this study was to evaluate genetic variability based on the morphoagronomic and molecular characterization of 18 elite popcorn (Zea mays var. everta) lines to be used by Universidade Estadual de Maringa breeding programs. We used 31 microsatellite primers (widely distributed in the genome), and 16 morphological descriptors (including the resistance to maize white spot, common rust, polysora rust of maize, cercospora and leaf blights). The molecular data revealed variability among the lines, which were divided into four groups that were partially concordant with unweighted pair group method with arithmetic mean (UPMGA) and Bayesian clusters. The lines G3, G4, G11, and G13 exhibited favorable morphological characters and low disease incidence rates. The four groups were confirmed using the Gower distance in the UPGMA cluster; however, there was no association with the dissimilarity patterns obtained using the molecular data. The absence of a correlation suggests that both characterizations (morphoagronomic and molecular) are important for discriminating among elite popcorn lines. PMID- 28671248 TI - Generic relationships among Molluginaceae inferred from a molecular phylogenetic analysis of the matK gene. AB - The family Molluginaceae (order Caryophyllales) is considered polyphyletic based on the photosynthetic pathway, C4 evolution, and phylogeny of the family. This inference was made based on photosynthetic, anatomical, and molecular datasets. The generic circumscription of this family has greatly been changed owing to the placement of several of its genera into the Caryophyllaceae, Microteaceae, Lophiocarpaceae, and Limeaceae families. However, the generic relationships are largely unknown. By virtue of high substitution rates within the species and the ability to resolve the phylogenetic position of morphologically very closely related species and species complexes, the matK gene has emerged as one of the potential chloroplast DNA molecular markers in plant molecular phylogenetics and DNA barcoding studies. We herein used molecular phylogenetic analyses of matK gene sequences using maximum parsimony and maximum likelihood analyses to infer the generic relationships among currently recognized genera circumscribed under the family Molluginaceae. The resulting phylogenetic tree confirmed the polyphyly of the family Molluginaceae. The genus Hypertelis was found at the base of the Molluginaceae clade. The genus Glinus was close to Glischrothamnus and Mollugo, Suessenguthiella was close to Coelanthum and Pharnaceum, whereas Polpoda grouped with Adenogramma and Psammotropha. The present study constitutes a robust investigation of the molecular phylogenetic relationships among members of the family Molluginaceae. Future study should combine by combined analyses of morphological characters and multiple nuclear and chloroplast DNA sequences with a more comprehensive taxon sampling of the family Molluginaceae. PMID- 28671249 TI - Mechanism of reversal of multidrug resistance by curcumin in human colorectal cancer cell line HCT-8/5-FU. AB - Since there are no studies on the reversal of multidrug resistance by curcumin in the human colorectal cancer cell line HCT-8/5-FU, our aim was to search for highly efficient reversal agents and investigate the underlying mechanisms of this reversal. The cytotoxic effects of curcumin and 5-FU on HCT-8 and HCT-8/5-FU cells and the reversal effects of 5-FU in combination with curcumin on HCT-8/5-FU cells were measured using cell counting kit-8. Apoptosis and the cell cycle were analyzed by flow cytometry. Protein and mRNA expression levels of BCL-2, survivin, P-gp, and HSP-27 were detected by western blotting and quantitative real-time reverse transcription polymerase chain reaction, respectively. Curcumin inhibited the growth of HCT-8 and HCT-8/5-FU cells. It significantly reduced the IC50 of 5-FU for HCT-8/5-FU cells (P < 0.01) and the expression of BCL-2, survivin, P-gp, and HSP-27 in the cells. Curcumin can effectively reverse multidrug resistance in human colorectal cancer drug-resistant HCT-8/5-FU cells. The mechanism through which this occurs may be associated with decreased expression of BCL-2, survivin, P-gp, and HSP-27. Curcumin may therefore have clinical implications as a new agent for colorectal cancer. PMID- 28671250 TI - Artificial neural networks as auxiliary tools for the improvement of bean plant architecture. AB - Classification using a scale of visual notes is a strategy used to select erect bean plants in order to improve bean plant architectures. Use of morphological traits associated with the phenotypic expression of bean architecture in classification procedures may enhance selection. The objective of this study was to evaluate the potential of artificial neural networks (ANNs) as auxiliary tools in the improvement of bean plant architecture. Data from 19 lines were evaluated for 22 traits, in 2007 and 2009 winter crops. Hypocotyl diameter and plant height were selected for analysis through ANNs. For classification purposes, these lines were separated into two groups, determined by the plant architecture notes. The predictive ability of ANNs was evaluated according to two scenarios to predict the plant architecture - training with 2007 data and validating in 2009 data (scenario 1), and vice versa (scenario 2). For this, ANNs were trained and validated using data from replicates of the evaluated lines for hypocotyl diameter individually, or together with the mean height of plants in the plot. In each scenario, the use of data from replicates or line means was evaluated for prediction through previously trained and validated ANNs. In both scenarios, ANNs based on hypocotyl diameter and mean height of plants were superior, since the error rates obtained were lower than those obtained using hypocotyl diameter only. Lower apparent error rates were verified in both scenarios for prediction when data on the means of the evaluated traits were submitted to better trained and validated ANNs. PMID- 28671251 TI - Identification and characterization of the bZIP transcription factor involved in zinc homeostasis in cereals. AB - Members of the basic leucine zipper family, as bZIP19, are considered to be essential regulators of the adaptation to zinc deficiency. Knowing that this gene as well as its targets are conserved in the plant kingdom, we followed an in silico approach to identify and characterize the bzip19 gene in cereals. Through BLASTp in Phytozome database, 33 bzip19 genes were identified on the genomes of Oryza sativa, Sorghum bicolor, Zea mays, Glycine max, Triticum aestivum, and Brachypodium distachyon. The analysis of conserved motifs and bZIP domains was performed using MEME and PFAM databases. In 25 of these genes, CysHis-motifs at the basic N-terminal region were found. This motif is conserved in group bZIP and suggested to play a role as a Zn-sensor. Regarding their phylogeny, it was possible to infer orthologous groups and explore the evolutionary relationship between these BZIP19 proteins. Data mining allowed us to select eight putative orthologous whose expression profile was analyzed under stress conditions in the Genevestigator platform. The comparison between the expression profiles of these eight putative orthologous and the original Arabidopsis bzip19 also seems to indicate conserved transcriptional regulation. Thus, considering that modified expression of bZIP19 genes has already been confirmed as an efficient tool to improve Arabidopsis tolerance to Zn deficiency, and that these new bZIP orthologous have a high level of conservation when compared to the original bZIP19 sequence, they can be useful for the development of tolerant crops enabling plants to grow in areas of low zinc bioavailability. PMID- 28671252 TI - Promoter identification and analysis of key glycosphingolipid biosynthesis-globo series pathway genes in piglets. AB - Glycosphingolipid biosynthesis-globo series pathway genes (FUT1, FUT2, ST3GAL1, HEXA, HEXB, B3GALNT1, and NAGA) play an important regulatory role in the defense against Escherichia coli F18 in piglets. In this study, we identified the transcription initiation site and promoter of this gene cluster by mined previous RNA-seq results using bioinformatics tools. The FUT1 transcription initiation region included five alternative splicing sites and two promoter regions, whereas each of the six other genes had one promoter. Dual luciferase reporter results revealed significantly higher transcriptional activity by FUT1 promoter 2, indicating that it played a more important role in transcription. The promoters of glycosphingolipid biosynthesis genes identified contained a CpG island within the first 500 bp, except for the B3GALNT1 promoter which included fewer CpG sites. These results provide a deeper insight into methylation and the regulatory mechanisms of glycosphingolipid biosynthesis-globo series pathway genes in piglets. PMID- 28671253 TI - Identification of Colletotrichum isolates from Capsicum chinense in Amazon. AB - Chili pepper (Capsicum chinense) is a great economic important culture on the State of Amazonas, and it represents, approximately, a production of 1.9 thousand tons per year. It is one of the hosts of Colletotrichum genus in the North region of Brazil. The aim of the study was to differentiate and to identify isolates of Colletotrichum collected from C. chinense in Amazon. Molecular characterization, using RFLP-PCR, ERIC-PCR and ISSR, was carried out initially for screening of morphologically similar isolates. Furthermore, phylogenetic analyses were performed using combined regions: Actin (ACT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for the three isolates, INPA 2066, INPA 2286 and INPA 1858, plus superoxide dismutase (SOD2) for INPA 2066. We showed that the molecular markers were able to distinguish the isolates of Colletotrichum studied and these results were confirmed with the phylogenetic analyses, three different occurrences of Colletotrichum species (C. siamense, C. scovillei and C. brevisporum) causing anthracnose in C. chinense in the State of Amazonas. This study represents the first report of the species C. siamense and C. scovillei in this host in Brazil. PMID- 28671254 TI - Implications of the clone by harvest interaction in the selection of sugarcane genotypes in a regionalized program. AB - The recommendation of sugarcane clones depends on several factors, as the response or performance of the clones over different cuts or harvests. The clone by harvest interaction might be difficult to identify superior clones in the final stages of the sugarcane breeding program. Thus, the objective of this study was to investigate and describe the implications of the genotype by harvest interaction in the adaptability and stability of genotypes and delineation of mega-environments from a set of multi-environment trials. Fifteen clones and four checks were evaluated in eight environments. The trait TPH (tons of pol per hectare) was evaluated in two harvests (plant cane and ratoon cane) in 2010 and 2011. The joint analysis showed significance for harvest (H), environment (E), and genotype (G) effects. The interactions GxE, ExH, GxH, and ExGxH were also significant. The last three-way interaction indicated the differential response of the genotypes over environments, and that it depends on the harvests. The overall mean of the trials was 12.77 TPH. The coefficient of variation was 8.70% and the selective accuracy was 98.63%, indicating high experimental precision. The genotypes G4, G14, and G16 were statistically superior to the check varieties used; however, these genotypes did not show high stability as described by the additive main effects and multiplicative interaction method. There was a specific adaptation between the E7 and E5 environments and the G4 and G5 genotypes, respectively. In general, the grouping of the environments was inconsistent throughout the harvests, except for the E1 and E4 environments, which exhibited similarities for the different genotypes. PMID- 28671255 TI - Maize hybrid stability in environments under water restriction using mixed models and factor analysis. AB - In several crops, the water deficit is perhaps the main limiting factor in the search for high yields. The objective of this study was to evaluate the phenotypic stability of maize hybrids in environments with and without water restriction using the analytical factor (AF) approach. We evaluated 171 maize hybrids in 14 environments, divided into environments with (A1, A2, A3, A4, A5, A6, and A7) and without (A8, A9, A10, A11, A12, A13, and A14) water restriction, over a period of 7 years. Each year, 36 hybrids were evaluated. A square lattice design (6 x 6) was used, with common treatments between years. The characteristics of grain yield (GY), male flowering (MF) and female flowering (FF), plant height (PH), and ear height (EH) were evaluated. Phenotypic adaptability and stability of the hybrids were also verified. Hybrids G66, G99, G86, and G26 were the most stable and showed potential for use in environments with and without water restriction. The AF models showed to be useful for evaluating hybrids over many years, allowing selection of better hybrids with adaptability, specific and general stability, and correlation of hybrids with their production components, in addition to allowing identification of mega environments that permit stability in the response of the adapted hybrids. PMID- 28671256 TI - Genome-wide analysis of salinity-stress induced DNA methylation alterations in cotton (Gossypium hirsutum L.) using the Me-DIP sequencing technology. AB - Cytosine DNA methylation is a significant form of DNA modification closely associated with gene expression in eukaryotes, fungi, animals, and plants. Although the reference genomes of cotton (Gossypium hirsutum L.) have been publically available, the salinity-stress-induced DNA methylome alterations in cotton are not well understood. Here, we constructed a map of genome-wide DNA methylation characteristics of cotton leaves under salt stress using the methylated DNA immunoprecipitation sequencing method. The results showed that the methylation reads on chromosome 9 were most comparable with those on the other chromosomes, but the greatest changes occurred on chromosome 8 under salt stress. The DNA methylation pattern analysis indicated that a relatively higher methylation density was found in the upstream2k and downstream2k elements of the CDS region and CG-islands. Almost 94% of the reads belonged to LTR-gspsy and LTR copia, and the number of methylation reads in LTR-gypsy was four times greater than that in LTR-copia in both control and stressed samples. The analysis of differentially methylated regions (DMRs) showed that the gene elements upstream2k, intron, and downstream2k were hypomethylated, but the CDS regions were hypermethylated. The GO (Gene Ontology) analysis suggested that the methylated genes were most enriched in cellular processes, metabolic processes, cell parts and catalytic activities, which might be closely correlated with response to NaCl stress. In this study, we completed a genomic DNA methylation profile and conducted a DMR analysis under salt stress, which provided valuable information for the better understanding of epigenetics in response to salt stress in cotton. PMID- 28671257 TI - Haplotypes and polymorphism in the CCR5 gene in sickle cell disease. AB - Sickle cell disease shows several clinical manifestations in distinct levels of severity. This heterogeneity is due to the haplotype variability associated with the HbS gene, levels of fetal hemoglobin and environmental conditions, which modify the disease expression. Science community believes that the presence of a polymorphism in the CCR5 gene, which is related to chronic inflammatory state, could confer a higher survival rate and a lower number of inflammatory events to these patients since the deletion in CCR5Delta32 would knock out the CCR5 gene. Therefore, this study aimed to identify the haplotypes in betaS and betaC genes, as well as to investigate the presence of the CCR5Delta32 deletion in patients with sickle cell disease. For this purpose, DNA was isolated with the QIAamp DNA Investigator Kit, and PCR was the method chosen to detect the mutant allele CCR5Delta32. The haplotypes in betaS and betaC genes were detected by RFLP with the restriction enzymes XmnI, HindIII, HincII, and HinfI analyzing six polymorphic sites on the beta cluster, succeeded by electrophoresis. The atypical haplotype was the most common (54.3%), followed by Benin (28.6%), Bantu (11.5%), Senegal (2.8%), and Cameroon (2.8%). No patients presented CCR5Delta32 deletion. The increase in the frequency of atypical haplotypes suggests that these patients passed by variation in the genetic pattern from ancestral haplotypes throughout the years. PMID- 28671258 TI - Selection of candidate reference genes and validation for real-time PCR studies in rice plants exposed to low temperatures. AB - Rice is a cereal that presents a great ability to adapt to different soil and climate conditions. However, as it is a tropical crop with C3 metabolism, it performs better in warm temperatures with high solar radiation. Tolerance to stress caused by low temperatures is a highly complex process that involves various metabolic pathways and cellular compartments, resulting in general or specific effects on plant growth and development. In order to observe the true effect of a particular stress on genetic expression, reference genes need to be chosen for real-time PCRs, the expression levels of which should remain stable independent of the situation imposed. In this paper, the expression stability was evaluated of the actin 11 (ACT11), ubiquitin-conjugating enzyme 2 (UBC-E2), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), beta tubilin (beta-Tubulin), eukaryotic initiation factor 4alpha (eIF-4-alpha), eukaryotic initiation factor 1alpha (eIF-1-alpha), ubiquitin 10 (UBQ10), ubiquitin 5 (UBQ5), aquaporin (TIP41), and cyclophilin genes, in two rice genotypes cultivated in low temperature (13 degrees C) conditions in vegetative stage (V4). The analysis material (leaves) was collected after 0, 6, 24, 48, and 72 h of exposure to the stress. In this study, the geNorm, BestKeeper, DeltaCt, NormFinder, and RefFinder methods were used to evaluate the expression stability of the candidate reference genes. The results revealed that the most indicated genes for all the analysis methods were UBQ10 and UBQ5 for BRS Bojuru and BRS Pampa, respectively. On the other hand, the eIF-1-alpha gene presents the least expression stability and is not indicated for studies of rice plants subjected to low temperatures. The validation with the antioxidant system genes SODCc1-Cu/Zn, CATC, APX2, and GR2 confirmed the importance of using previously tested normalizing genes for adequate real-time PCR results. PMID- 28671259 TI - Transferability of microsatellite markers in Syagrus coronata (Mart.) Becc. (Arecaceae), an iconic palm tree from the Brazilian semiarid region. AB - The licuri palm Syagrus coronata plays a key role in the ecology and economy of Brazilian semiarid region. Nonetheless, genetic data about populations of this species are absent even though the intensive and uncontrolled exploitation since colonial periods has threatened the sustainability and viability of licuri populations. Therefore, we attempted to test the efficacy of transferability of microsatellite loci isolated from three palm tree species to S. coronata to analyze the population of this species throughout their range. A set of 19 heterologous microsatellite loci was tested in three native populations of S. coronata from the State of Bahia, northeastern Brazil, which amplified using distinct annealing temperatures (50 degrees -60 degrees C). Based on the 10 most polymorphic loci, the selected populations exhibited a mean number of alleles per locus of 9.8, and high genetic diversity values since the expected heterozygosity ranged from 0.573 to 0.754, while the observed heterozygosity varied from 0.785 to 1.000. In conclusion, the tested loci are transferrable and highly efficient to population studies in S. coronata, thus minimizing the lack of species specific loci to the genetic monitoring of licuri populations. PMID- 28671260 TI - Phenotypic and genotypic characterization of Staphylococcus aureus isolates in milk from flocks diagnosed with subclinical mastitis. AB - The Staphylococcus aureus is the most common isolated microorganism in ruminant animal species diagnostic with clinical or subclinical mastitis. Dairy herds with these diseases can transfer S. aureus into the milk supply, which can lead to food poisoning in humans. The objective of this study was to evaluate the profile of antimicrobial susceptibility, the presence of femA gene, the genetic relationships among isolates of S. aureus obtained from milk originating from flocks diagnosed with subclinical mastitis in nine rural properties in the northern of Minas Gerais State. To this end, 498 samples of bovine milk tested positive for the California mastitis test (CMT) were subjected to morphological methods and biochemical patterns for microbiological presumptive identification of S. aureus. The PCR test with the genetic marker femA was used to confirm the species S. aureus. All the 26 isolates presumptively identified as S. aureus amplified a fragment of 132 bp corresponding to the femA gene. The profile of antimicrobial susceptibility was performed according to the disk-diffusion methodology and two isolates were susceptible to all the antibiotics tested. The drug multiresistence was found in 80.76% of the isolates. The determination of the genetic profile and the clonal relationship among the isolates was performed by the method of DNA RAPD-PCR polymorphism. The S. aureus isolates were divided into two groups with 26 distinct subgroups. The analysis of RAPD-PCR showed no genetic diversity among them, heterogeneous profile and absence of clonality. PMID- 28671261 TI - Distinguishment, identification and aroma compound quantification of Portuguese olive oils based on physicochemical attributes, HS-GC/MS analysis and voltammetric electronic tongue. AB - BACKGROUND: In this paper, various extra-virgin and virgin olive oils samples from different Portuguese markets were studied. For this purpose, a voltammetric electronic tongue (VE-tongue), consisting of two kinds of working electrode within the array, together with physicochemical analysis and headspace gas chromatography coupled with mass spectrometry (HS-GC-MS), were applied. In addition, preliminary considerations of relationships between physicochemical parameters and multisensory system were reported. RESULTS: The physicochemical parameters exhibit significant differences among the analyzed olive oil samples that define its qualities. Regarding the aroma profile, 14 volatile compounds were characterized using HS-GC-MS; among these, hex-2-enal, hexanal, acetic acid, hex-3-ene-1-ol acetate and hex-3-en-1-ol were semi-quantitatively detected as the main aroma compounds in the analyzed samples. Moreover, pattern recognition methods demonstrate the discrimination power of the proposed VE-tongue system. The results reveal the VE-tongue's ability to classify olive oil samples and to identify unknown samples based of built models. In addition, the correlation between VE-tongue and physicochemical analysis exhibits a remarkable prediction model aimed at anticipating carotenoid content. CONCLUSION: The preliminary results of this investigation indicate that physicochemical and HS-GC-MS analysis, together with multisensory system coupled with chemometric techniques, presented a satisfactory performance regarding olive oil sample discrimination and identification. (c) 2017 Society of Chemical Industry. PMID- 28671262 TI - An efficient model construction strategy to simulate microalgal lutein photo production dynamic process. AB - Lutein is a high-value bioproduct synthesized by microalga Desmodesmus sp. It has great potential for the food, cosmetics, and pharmaceutical industries. However, in order to enhance its productivity and to fulfil its ever-increasing global market demand, it is vital to construct accurate models capable of simulating the entire behavior of the complicated dynamics of the underlying biosystem. To this aim, in this study two highly robust artificial neural networks (ANNs) are designed for the first time. Contrary to conventional ANNs, these networks model the rate of change of the dynamic system, which makes them highly relevant in practice. Different strategies are incorporated into the current research to guarantee the accuracy of the constructed models, which include determining the optimal network structure through a hyper-parameter selection framework, generating significant amounts of artificial data sets by embedding random noise of appropriate size, and rescaling model inputs through standardization. Based on experimental verification, the high accuracy and great predictive power of the current models for long-term dynamic bioprocess simulation in both real-time and offline frameworks are thoroughly demonstrated. This research, therefore, paves the way to significantly facilitate the future investigation of lutein bioproduction process control and optimization. In addition, the model construction strategy developed in this research has great potential to be directly applied to other bioprocesses. Biotechnol. Bioeng. 2017;114: 2518-2527. (c) 2017 Wiley Periodicals, Inc. PMID- 28671263 TI - Small cause, large effect: Structural characterization of cutinases from Thermobifida cellulosilytica. AB - We have investigated the structures of two native cutinases from Thermobifida cellulosilytica, namely Thc_Cut1 and Thc_Cut2 as well as of two variants, Thc_Cut2_DM (Thc_Cut2_ Arg29Asn_Ala30Val) and Thc_Cut2_TM (Thc_Cut2_Arg19Ser_Arg29Asn_Ala30Val). The four enzymes showed different activities towards the aliphatic polyester poly(lactic acid) (PLLA). The crystal structures of the four enzymes were successfully solved and in combination with Small Angle X-Ray Scattering (SAXS) the structural features responsible for the selectivity difference were elucidated. Analysis of the crystal structures did not indicate significant conformational differences among the different cutinases. However, the distinctive SAXS scattering data collected from the enzymes in solution indicated a remarkable surface charge difference. The difference in the electrostatic and hydrophobic surface properties could explain potential alternative binding modes of the four cutinases on PLLA explaining their distinct activities. Biotechnol. Bioeng. 2017;114: 2481-2488. (c) 2017 Wiley Periodicals, Inc. PMID- 28671264 TI - Overflow metabolism and growth cessation in Clostridium thermocellum DSM1313 during high cellulose loading fermentations. AB - As a model thermophilic bacterium for the production of second-generation biofuels, the metabolism of Clostridium thermocellum has been widely studied. However, most studies have characterized C. thermocellum metabolism for growth at relatively low substrate concentrations. This outlook is not industrially relevant, however, as commercial viability requires substrate loadings of at least 100 g/L cellulosic materials. Recently, a wild-type C. thermocellum DSM1313 was cultured on high cellulose loading batch fermentations and reported to produce a wide range of fermentative products not seen at lower substrate concentrations, opening the door for a more in-depth analysis of how this organism will behave in industrially relevant conditions. In this work, we elucidated the interconnectedness of overflow metabolism and growth cessation in C. thermocellum during high cellulose loading batch fermentations (100 g/L). Metabolic flux and thermodynamic analyses suggested that hydrogen and formate accumulation perturbed the complex redox metabolism and limited conversion of pyruvate to acetyl-CoA conversion, likely leading to overflow metabolism and growth cessation in C. thermocellum. Pyruvate formate lyase (PFL) acts as an important redox valve and its flux is inhibited by formate accumulation. Finally, we demonstrated that manipulation of fermentation conditions to alleviate hydrogen accumulation could dramatically alter the fate of pyruvate, providing valuable insight into process design for enhanced C. thermocellum production of chemicals and biofuels. Biotechnol. Bioeng. 2017;114: 2592-2604. (c) 2017 Wiley Periodicals, Inc. PMID- 28671266 TI - Improving language comprehension in preschool children with language difficulties: a cluster randomized trial. AB - BACKGROUND: Children with language comprehension difficulties are at risk of educational and social problems, which in turn impede employment prospects in adulthood. However, few randomized trials have examined how such problems can be ameliorated during the preschool years. METHODS: We conducted a cluster randomized trial in 148 preschool classrooms. Our intervention targeted language comprehension skills and lasted 1 year and 1 month, with five blocks of 6 weeks and intervention three times per week (about 75 min per week). Effects were assessed on a range of measures of language performance. RESULTS: Immediately after the intervention, there were moderate effects on both near, intermediate and distal measures of language performance. At delayed follow-up (7 months after the intervention), these reliable effects remained for the distal measures. CONCLUSIONS: It is possible to intervene in classroom settings to improve the language comprehension skills of children with language difficulties. However, it appears that such interventions need to be intensive and prolonged. PMID- 28671265 TI - Corticosteroids for adult patients with advanced cancer who have nausea and vomiting (not related to chemotherapy, radiotherapy, or surgery). AB - BACKGROUND: Nausea is a common symptom in advanced cancer, with a prevalence of up to 70%. While nausea and vomiting can be related to cancer treatments, such as chemotherapy, radiotherapy, or surgery, a significant number of people with advanced cancer also suffer from nausea unrelated to such therapies. Nausea and vomiting may also cause psychological distress, and have a negative impact on the quality of life of cancer patients; similarly to pain, nausea is often under treated. The exact mechanism of action of corticosteroids on nausea is unclear, however, they are used to manage a number of cancer-specific complications, including spinal cord compression, raised intracranial pressure, and lymphangitis carcinomatosis. They are also commonly used in palliative care for a wide variety of non-specific indications, such as pain, nausea, anorexia, fatigue, and low mood. However, there is little objective evidence of their efficacy in symptom control, and corticosteroids have a wide range of adverse effects that are dose and time dependent. In view of their widespread use, it is important to seek evidence of their effects on nausea and vomiting not related to cancer treatment. OBJECTIVES: To assess the effects of corticosteroids on nausea and vomiting not related to chemotherapy, radiotherapy, or surgery in adult cancer patients. SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid, Embase Ovid, CINAHL EBSCO, Science Citation Index Web of Science, Latin America and Caribbean Health Sciences (LILACS), Conference Proceedings Citation Index - Science Web of Science, and clinical trial registries, from inception to 23rd August 2016. SELECTION CRITERIA: Any double-blind randomised or prospective controlled trial that included adults aged 18 years and over with advanced cancer with nausea and vomiting not related to chemotherapy, radiotherapy, or surgery were eligible for the review, when using corticosteroids as antiemetic treatment. DATA COLLECTION AND ANALYSIS: All review authors independently assessed trial quality and extracted data. We used arithmetic means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three studies met the inclusion criteria, enrolling 451 participants. The trial size varied from 51 to 280 participants. Two studies compared dexamethasone to placebo, and the third study compared a number of additional interventions in various combinations, including metoclopramide, chlorpromazine, tropisetron, and dexamethasone. The duration of the studies ranged from seven to 14 days. We included two studies (127 participants) with data at eight days in the meta-analysis for nausea intensity; no data were available that incorporated the same outcome measures for the third study. Corticosteroid therapy with dexamethasone resulted in less nausea (measured on a scale of 0 to 10, with a lower score indicating less nausea) compared to placebo at eight days (MD 0.48 lower nausea, 95% CI 1.53 lower to 0.57 higher; very low quality evidence), although this result was not statistically significant (P = 0.37). Frequency of adverse events was not significantly different between groups, and the interventions were well tolerated. Factors limiting statistical analysis included the lack of standardised measurements of nausea, and the use of different agents, dosages, and comparisons. Subgroup analysis according to type of cancer was not possible due to insufficient data. The quality of this evidence was downgraded by three levels, from high to very low due to imprecision, likely selection bias, attrition bias, and the small number of participants in the included studies. AUTHORS' CONCLUSIONS: There are few studies assessing the effects of corticosteroids on nausea and vomiting not related to chemotherapy, radiotherapy, or surgery in adult cancer patients. This review found very low quality evidence which neither supported nor refuted corticosteroid use in this setting. Further high quality studies are needed to determine if corticosteroids are efficacious in this setting. PMID- 28671267 TI - Comparison of facility type outcomes for oral cavity cancer: Analysis of the national cancer database. AB - OBJECTIVE: Determine whether facility type effects overall survival in patients with oral cavity cancer. STUDY DESIGN: Retrospective cohort study. METHODS: Patients included in the National Cancer Database who were diagnosed with oral cavity cancer between 1998 and 2011 were included in the study. Data was stratified by facility where care was provided, including community cancer programs (CCP), comprehensive community cancer programs (CCCP), and academic centers (AC). Univariate analysis was performed using analysis of variance, chi squared, and log-rank test, whereas multivariate analysis was performed using Cox regression. RESULTS: A total of 32,510 patients were included in the study, with 7.58% of patients receiving care at CCPs (n = 2,553), 39.53% at CCCPs (n = 12,852), and 52.61% at ACs (n = 17,105). Between 1998 and 2011, there was a greater percentage of patients receiving care at ACs, and a greater percentage of patients receiving surgical therapy versus nonsurgical therapy. Patients treated at ACs had the best 5-year overall survival of 51.26%, with a significant difference across facility types (P < 0.01). After adjusting for confounders, receiving care at ACs was a positive predictor of survival (hazard ratio: 0.95 95% confidence interval [0.91,0.98])). CONCLUSION: Patients treated at ACs are more likely to receive surgical treatment, and have a greater 5-year overall survival compared to those patients treated at CCPs and CCCPs. Therefore, we advocate referring patients with advanced oral cavity cancers to ACs. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2551-2557, 2017. PMID- 28671268 TI - Microsurgical varicocelectomy for clinical varicocele: A review for potential new indications. AB - Microsurgical varicocelectomy is considered the gold-standard technique treating varicocele in both adults and adolescents, due to relatively more favourable outcomes and lower post-operative recurrence and complication rates. Despite of mounting literature on this topic, several aspects are still not well defined. We summarised the most recent literature and presented findings that might extend its indications. Microsurgical varicocelectomy and intracytoplasmic sperm injection are both effective to father a child for infertile men with clinical varicocele even for those with worst condition of spermatozoa, nonobstructive azoospermia, and prior varicocele repair has substantial benefits for couples with a clinical varicocele. Microsurgical subinguinal and inguinal varicocelectomy seem to have comparable effectiveness for adolescents and infertile men with varicoceles. However, the subinguinal approach may have some advantages to deal with painful varicocele. The superior outcomes of bilateral varicocelectomy for patients with clinical left varicocele and concomitant clinical right varicocele are justified, while the benefit is still uncertain for concomitant subclinical right varicocele. Varicocelectomy may have the potential to improve sexual function along with serum testosterone. In conclusion, indications for microsurgical varicocelectomy may be extended by the concomitant right and left clinical varicocele and sexual dysfunction with varicocele. PMID- 28671269 TI - Src nuclear localization and its prognostic relevance in human osteosarcoma. AB - Osteosarcoma is the most common malignant bone tumor in children and young adults. The identification of proteins which exhibit different subcellular localization in low- versus high-risk osteosarcoma can be instrumental to obtain prognostic information and to develop innovative therapeutic strategies. Beside the well-characterized membrane and cytoplasmic localization of Src protein, this study evaluated the prognostic relevance of its so-far unknown nuclear compartmentalization. We analyzed the subcellular distribution of total and activated (pY418) Src in a tissue microarray including 60 osteosarcoma samples. Immunohistochemical analyses revealed a variable pattern of Src expression and localization, ranging from negative to high-stained nuclei combined with a substantial cytoplasmic staining for total and activated forms. The analysis of Kaplan-Meier survival curves in relationship to the diverse permutations of cytoplasmic and nuclear staining suggested a correlation between Src subcellular localization and the overall survival (OS) of osteosarcoma patients. In order to explain this different subcellular localization, normal osteoblasts and three osteosarcoma cell lines were used to investigate the molecular mechanism. Once confirmed a variable Src localization also in these cell lines, we demonstrated a correlation between the N-myristoyltransferase enzymes expression and activity and the Src nuclear content. In conclusion, these results described a so-far unknown Src nuclear localization in osteosarcoma cells, suggesting that the combined detection of nuclear and cytoplasmic Src levels can be used as a prognostic marker for osteosarcoma patient survival. A correlation between the N myristoyltransferase enzymes and the Src subcellular localization was described as well. PMID- 28671270 TI - Laryngectomy and smoking: An analysis of postoperative risk. AB - OBJECTIVES: To investigate the impact of smoking on complication rates following total laryngectomy. STUDY DESIGN AND METHODS: The National Surgical Quality Improvement Program database was queried for all total laryngectomies between 2005 and 2014. Patients were identified as smokers (n = 561) or nonsmokers (n = 513) and compared via univariate and multivariate analyses. A nearest-neighbor propensity score-generating algorithm was used to build a subpopulation (n = 714) of matched cases and evaluated in a similar manner. Additionally, pack-year data was available for select cases and analyzed appropriately. RESULTS: On multivariate analysis of the unmatched cohort accounting for demographics and confounders, no significant difference in overall medical complications was identified between groups (odds ratio = 0.799, P = 0.495). Propensity matching corrected for all significantly distributed comorbidities, except for alcohol, which remained associated with the smoking group (P = < 0.001). In the matched population, there were no significant differences in complication rates between the two groups. Pack-year data was available for 340 patients. These cases were subdivided into cohorts with < 50 (n = 204) and 51+ (n = 136) pack-years. Postoperative pneumonia, ventilation for more than 48 hours, sepsis, and overall medical complications were associated with > 50 pack-years of smoking. After multivariate regression, sepsis and overall medical complications remained significant for the 51+ pack-year smoking cohort. CONCLUSION: After accounting for confounding comorbidities, smoking is found to play an insignificant role in the development of postoperative complications following total laryngectomy. However, those with 51+ pack-years are at an increased risk for postoperative sepsis and overall medical complications following these complex procedures. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2302-2309, 2017. PMID- 28671271 TI - NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect. AB - Mitochondrial respiratory chain complex I consists of 44 different subunits and contains 3 functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and axonal peripheral neuropathy. We performed complex I assembly analysis using primary skin fibroblasts of both patients. Reduced complex I abundance and an accumulation of Q-module subassemblies were present in both patients but more pronounced in the severe clinical phenotype patient. The latter displayed additional accumulation of P-module subassemblies, which was not present in the milder-phenotype patient. Lentiviral complementation of both patient fibroblast cell lines with wild-type NDUFA9 rescued complex I deficiency and the assembly defects. Our report further characterizes the phenotypic spectrum of NDUFA9 deficiency and demonstrates that the severity of the clinical phenotype correlates with the severity of the effects of the different NDUFA9 variants on complex I assembly. PMID- 28671272 TI - The effects of different spices and fat types on the formation of heterocyclic aromatic amines in barbecued sucuk. AB - BACKGROUND: Sucuk is one of the popular traditional Turkish meat products. The aim of this research was to evaluate the effects of different spices (clove, 0.2%; cinnamon, 0.5%) and animal fat types (beef fat, tallow, subcutaneous and tail fat) on the formation of heterocyclic aromatic amine (HCA) in barbecued sucuk. RESULTS: Although 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) could not be detected in the any of the samples, 2-amino-3-methylimidazo[4,5 f]quinoxaline (IQx) (up to 0.54 ng g-1 ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) (up to 5.96 ng g-1 ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (up to 0.21 ng g-1 ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) (up to 0.34 ng g-1 ), 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx) (up to 0.32 ng g-1 ), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) (up to 0.19 ng g-1 ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (up to 1.94 ng g-1 ) and 2-amino-9H-pyrido[2,3-b]indole (AalphaC) (up to 0.98 ng g-1 ) were found in the barbecued sucuk samples. CONCLUSION: The results of the current study have shown that HCAs could be formed in barbecued sucuk. Total HCA can be affected by adding different fat types; however, adding clove and cinnamon decreased the total HCA content in the subcutaneous fat group of sucuk samples. (c) 2017 Society of Chemical Industry. PMID- 28671273 TI - Laryngeal surgical treatment in transgender women: A systematic review and meta analysis. AB - OBJECTIVE: To identify the effects of laryngeal surgical treatment in the voice of transgender women, especially on the fundamental frequency (f0). STUDY DESIGN: We performed a systematic review in PubMed and Scopus in July 2016, covering the period between 2005 and 2016. METHODS: Inclusion criteria were studies in English or Portuguese about the laryngeal surgical treatment in transgender women, featuring experimental design, title, year of publication, country of origin, journal of publication, participants, intervention, results. For the meta analysis, only studies that had control group were selected. Exclusion criteria were articles that mentioned the use of surgical techniques but did not use the procedure in research, animal studies, studies of revision, and postmortem studies. RESULTS: Four hundred and twenty-three articles were identified in the initial search; 94 were selected for analysis by two referees, independently. After applying all the selection criteria, five studies remained in the meta analysis. The surgical procedures that were identified included laryngoplasty with or without thyrohyoid approximation, Wendler glottoplasty, cricothyroid approximation, laser glottoplasty reduction and the vocal fold shortening and retrodisplacement of anterior commissure. There was no significant difference between the experimental group and the control group in relation to f0. CONCLUSION: No randomized clinical trials and prospective cohort studies are available, and a small number of retrospective cohort and case-control studies of surgical techniques reveal an increase in the f0. The evidence produced is not conclusive regarding which surgical technique would be better for vocal treatment of transgender women. LEVEL OF EVIDENCE: NA Laryngoscope, 127:2596-2603, 2017. PMID- 28671274 TI - Hepatocytes of Wistar and Sprague Dawley rats differ significantly in their central metabolism. AB - Wistar and Sprague-Dawley (SD) rats are most commonly used experimental rats. They have similar genetic background and are therefore, not discriminated in practical research. In this study, we compared metabolic profiles of Wistar and SD rat hepatocytes from middle (6 months) and old (23 months) age groups. Principle component analysis (PCA) on the specific uptake and production rates of amino acids, glucose, lactate and urea indicated clear differences between Wistar and SD rat hepatocytes. SD rat hepatocytes showed higher uptake rates of various essential and non-essential amino acids, particularly in early culture phases (0 12 h) compared to later phases (12-24 h). SD hepatocytes seem to be more sensitive to isolation procedure and in vitro culture requiring more amino acids for cellular maintenance and repair. Major differences between Wistar and SD rat hepatocytes were observed for glucose and branched chain amino acid metabolism. We conclude that the observed differences in the central carbon metabolism of isolated hepatocytes from these two rats should be considered when using one or the other rat type in studies on metabolic effects or diseases such as diabetes or obesity. PMID- 28671276 TI - Love and melancholia in the analysis of women by women. AB - This paper suggests that in the analysis of women by women a melancholic core may be encountered at the centre of the transference/countertransference situation that is an expression of the loss of the primary maternal object that has never been mourned. The attachment to the primary, lost object may be preserved in a melancholic, invisible way, and the longing that it is connected to might only reach representation in the apres coup of the analytic process. The links between this primary love, melancholia and the unrepresentable in the analysis of women will be explored. These analyses powerfully evoke the relationship to the somatic. The internalization of the body of the mother, which is a requirement in the development of a woman, can take on frightening, fragmented, part-object qualities. An example of a five times a week analysis is discussed. PMID- 28671275 TI - Curtailed T-cell activation curbs effector differentiation and generates CD8+ T cells with a naturally-occurring memory stem cell phenotype. AB - Human T memory stem (TSCM ) cells with superior persistence capacity and effector functions are emerging as important players in the maintenance of long-lived T cell memory and are thus considered an attractive population to be used in adoptive transfer-based immunotherapy of cancer. However, the molecular signals regulating their generation remain poorly defined. Here we show that curtailed T cell receptor stimulation curbs human effector CD8+ T-cell differentiation and allows the generation of CD45RO- CD45RA+ CCR7+ CD27+ CD95+ -phenotype cells from highly purified naive T-cell precursors, resembling naturally-occurring human TSCM . These cells proliferate extensively in vitro and in vivo, express low amounts of effector-associated genes and transcription factors and undergo considerable self-renewal in response to IL-15 while retaining effector differentiation potential. Such a phenotype is associated with a lower number of mitochondria compared to highly-activated effector T cells committed to terminal differentiation. These results shed light on the molecular signals that are required to generate long-lived memory T cells with potential application in adoptive cell transfer immunotherapy. PMID- 28671277 TI - A motivational interview promotes retention of blood donors with high internal motivation. AB - BACKGROUND: Based on the hypothesis that self-determined motivation is associated with an increased likelihood of future behavior, the present study examined the ability of a motivational interview to promote internal motivation for giving blood and future donation attempts. STUDY DESIGN AND METHODS: A sample of 484 recent whole-blood and double red blood cell donors (62.4% female; age = 30.2 +/- 11.8 years) were randomly assigned to either a telephone-delivered motivational interview or a control call approximately 6 weeks after donating. Several weeks before the call and again 1 week after the call, participants completed the Blood Donor Identity Survey, a multidimensional measure of donor motivation, to derive indices of amotivation, external motivation, and internal motivation to give blood. Repeat donation attempts were tracked using blood center records. RESULTS: Relative to controls, participants in the motivational interview group showed a shift toward more self-determined motivation, as indicated by significant decreases in amotivation (p = 0.01) and significant increases in external (p = 0.009) and internal (p = 0.002) motivation. Furthermore, those with initially high levels of autonomous motivation were more likely to make a donation attempt in the subsequent year if they completed the motivational interview (71.1%) versus the control call (55.1%). CONCLUSION: Motivational interviewing is a potentially useful strategy to enhance retention of existing blood donors, particularly among those who express a greater sense of internal motivation for giving. PMID- 28671278 TI - The application of aptamer 5TR1 in triple negative breast cancer target therapy. AB - Chemotherapy is one of the standard strategies for treatment of breast cancer. Adriamycin (Dox) is a first-line chemotherapy agent for breast cancer. However, the gastrointestinal reactions, myocardial toxicity and other side effects caused by Dox due to its un-specific cytotoxicity limit the clinical treatment effect. To address this need, aptamer has been regarded as an ideal target molecular carrier. In the present study, we selected an aptamer 5TR1 that can specifically bind to the MUC1 protein which has been regarded as an important tumor biomarker, as well as a potential target in anticancer therapies. Dox was loaded on the modified 5TR1-GC, which specifically targets breast cancer cell MDA-MB-231. Cell viability and apoptosis assays demonstrated that the 5TR1-GC-Dox exhibited target specificity of cytotoxicity in MDA-MB-231. Moreover, in vivo xenograft study also confirmed that 5TR1-GC-Dox had a more effective effect on tumor growth inhibition and induced the apoptosis of malignant tumor cells compared to Dox. We provided a novel experimental and theoretical basis for developing an aptamer targeted drug system, thus to promote the killing effect of drugs on breast cells and to reduce the damage to normal cells and tissues for breast cancer. PMID- 28671279 TI - Impairment of primary cilia contributes to visceral adiposity of high fat diet fed mice. AB - Deficiency of primary cilia formation by knockout kinesin family member 3A (Kif3a) in mature osteoblasts led to osteopenia and enhanced adipogenesis. Adipogenesis plays an important role in adipose tissue expansion by High-fat-diet (HFD) induced obesity. Whether primary cilia participate in high-fat-diet induced adiposity remains unclear. In this study, we found that the number and length of primary cilia and expression levels of KIF3A and intraflagellar transport 88 homolog (IFT88) mRNA and proteins reached peak on the day 3 of adipogenesis, followed by a decrease to reach low basal expression levels at day 9 when differentiated to lipid accumulating adipocytes in VAT-SVFs derived from lean mice. The number of primary cilia was reduced by shRNA and chemical methods, leading to elevated transcripts of Ppargamma, Cebp-alpha, Srebp-1, and Fasn and protein levels of PPARgamma and FASN. Similar to the proadipogenic effect by the inhibition of primary cilia formation in control VAT-SVFs, HFD caused severe reduction of primary cilia formation and enhancement of adipogenesis in VAT-SVFs cultures. Flow cytometry analysis revealed percentage of G2/M phase cells and the protein expression of Cyclin A2 and CDK2 increased in control VAT-SVFs by knockdown of primary cilia with shRNA or chemical methods and HFD induced obese VAT-SVFs. In conclusion, the expression of primary cilia was in reverse correlation with adipogenic differentiation. HFD caused severe defects of primary cilia in VAT-SVFs, leading to adipose tissue expansion by enhancement of adipogenesis through promoting cell cycle re-entry at the early stage of adipogenesis. PMID- 28671280 TI - Impact of obstructive sleep apnea in transsphenoidal pituitary surgery: An analysis of inpatient data. AB - OBJECTIVES/HYPOTHESIS: Although previous studies have reported increased perioperative complications among obstructive sleep apnea (OSA) patients undergoing any surgery requiring general anesthesia, there is a paucity of literature addressing the impact of OSA on postoperative transsphenoidal surgery (TSS) complications. The aim of this study was to analyze postoperative outcomes in transsphenoidal pituitary surgery patients with OSA. Secondarily, we examined patient characteristics and comorbidities. STUDY DESIGN: Retrospective analysis. METHODS: The 2002 to 2013 National Inpatient Sample was queried for patients undergoing TSS for pituitary neoplasm. Patients with an additional diagnosis of OSA were identified, and compared to a non-OSA cohort. RESULTS: There were 17,777 patients identified; 5.0% (N = 889) had an additional diagnosis of OSA. The OSA cohort had more comorbidities including diabetes mellitus, congestive heart failure, chronic pulmonary disease, coagulopathy, hypertension, hypothyroidism, liver disease, obesity, peripheral vascular disease, renal failure, acromegaly, and Cushing's syndrome. Postoperatively, OSA was independently associated with increased risks of tracheostomy (P = .015) and hypoxemia (P < .001), and decreased risk of cardiac complications (P = .034). OSA patients did not have increased rates of cerebrospinal fluid rhinorrhea, diabetes insipidus, reintubation, aspiration pneumonia, infectious pneumonia, thromboembolic complications, or urinary/renal complications. In-hospital mortality rates did not vary between the two cohorts. CONCLUSIONS: In patients who underwent transsphenoidal pituitary surgery, OSA was associated with higher rates of certain pulmonary and airway complications. OSA was not associated with increased non-pulmonary/airway complications or inpatient mortality, despite older average age and higher comorbidity rates. LEVEL OF EVIDENCE: 2C. Laryngoscope, 128:1027 1032, 2018. PMID- 28671281 TI - Water status and must composition in grapevine cv. Chardonnay with different soils and topography and a mini meta-analysis of the delta13 C/water potentials correlation. AB - BACKGROUND: The measurement of carbon isotopic discrimination in grape sugars at harvest (delta13 C) is an integrated assessment of water status during ripening. It is an efficient alternative to assess variability in the field and discriminate between management zones in precision viticulture, but further work is needed to completely understand the signal. RESULTS: This work, spanning over 3 years, performed in a hillslope toposequence in Burgundy, delineates the relationships between main soil properties (gravel amount, slope, texture) and the grapevine water status assessed by delta13 C. The highest delta13 C, indicating most severe water deficit, was recorded in gravelly soils on steep slopes. The amount of sugars and malic and tartaric acids was also related to delta13 C. The relationship between delta13 C and predawn leaf water potentials (Psipd ) was also investigated, because the absolute values of measured delta13 C were lower than the values currently found in the literature. CONCLUSIONS: A mini meta-analysis was performed, which showed that the slope of the relationships between minimum Psipd and delta13 C was stable across studies (a change of 10/00 in delta13 C corresponded to a change of -0.2 MPa in the minimum Psipd ), while the intercept of the comparison delta13 C/Psipd changed, probably because of genetic variations between varieties, or environmental differences. (c) 2017 Society of Chemical Industry. PMID- 28671282 TI - Intra-articular injection of a substance P inhibitor affects gene expression in a joint contracture model. AB - Substance P (SP), a neurotransmitter released after injury, has been linked to deregulated tissue repair and fibrosis in musculoskeletal tissues and other organs. Although SP inhibition is an effective treatment for nausea, it has not been previously considered as an anti-fibrotic therapy. Although there are extensive medical records of individuals who have used SP antagonists, our analysis of human registry data revealed that patients receiving these antagonists and arthroplasty are exceedingly rare, thus precluding a clinical evaluation of their potential effects in the context of arthrofibrosis. Therefore, we pursued in vivo studies to assess the effect of SP inhibition early after injury on pro-fibrotic gene expression and contractures in an animal model of post-traumatic joint stiffening. Skeletally mature rabbits (n = 24) underwent surgically induced severe joint contracture, while injected with either fosaprepitant (a selective SP antagonist) or saline (control) early after surgery (3, 6, 12, and 24 h). Biomechanical testing revealed that differences in mean contracture angles between the groups were not statistically significant (P = 0.27), suggesting that the drug neither mitigates nor exacerbates joint contracture. However, microarray gene expression analysis revealed that mRNA levels for proteins related to cell signaling, pro-angiogenic, pro-inflammatory, and collagen matrix production were significantly different between control and fosaprepitant treated rabbits (P < 0.05). Hence, our study demonstrates that inhibition of SP alters expression of pro-fibrotic genes in vivo. This finding will motivate future studies to optimize interventions that target SP to reduce the formation of post-traumatic joint contractures. PMID- 28671283 TI - Low prevalence of hepatitis C virus RNA in blood donors with anti-hepatitis C virus reactivity in Rwanda. AB - BACKGROUND: Hepatitis C virus (HCV) is the leading cause of severe liver disease worldwide and is highly endemic in Africa, where it often has nosocomial spread. Little is known on the HCV prevalence, risk for transfusion-transmitted HCV, and circulating genotypes in Rwanda. This study was performed to investigate the prevalence of anti-HCV among blood donors from all regions of the country and genetically characterize identified HCV strains. STUDY DESIGN AND METHODS: Data on anti-HCV reactivity for all 45,061 Rwandan blood donations during 2014 were compiled. Samples from 720 blood donors were reanalyzed for anti-HCV in Sweden. Line immunoassay INNO-LIA HCV and detection of HCV RNA by polymerase chain reaction were used to confirm anti-HCV reactivity. The NS5B and core regions were sequenced and phylogenetic analysis was performed. RESULTS: The anti-HCV prevalence among all first-time blood donors was 1.6%, with the highest occurrence in donors from the eastern region. On further analysis, only 25 of 120 primarily anti-HCV-reactive samples could be confirmed reactive and 15 samples had indeterminate results by INNO-LIA. Confirmed reactivity was more common among females than males (p = 0.03) with no regional difference. Phylogenetic analysis of the sequences showed a predominance of subtypes 4k, 4q, and 4r, with no geographical difference in their distribution. CONCLUSION: The prevalence of anti HCV among Rwandan blood donors has probably been overestimated previously due to the high rate of nonconfirmable anti-HCV reactivity. Further study of the involved mechanism is needed to avoid loss of blood products and distress for blood donors and other test recipients. PMID- 28671284 TI - Mandibular condylar hypoplasia in children with isolated unilateral congenital aural atresia. AB - OBJECTIVES/HYPOTHESIS: We hypothesized that children with isolated nonsyndromic unilateral congenital aural atresia have subclinical mandibular condylar hypoplasia ipsilateral to the atretic ear, and that the Jahrsdoerfer score is associated with the degree of condylar hypoplasia. STUDY DESIGN: Retrospective self-controlled case series. METHODS: We reviewed high-resolution computed tomography scans of the temporal bones of 68 children with isolated nonsyndromic unilateral congenital aural atresia. Images were viewed in the transverse (axial) plane perpendicular to the axis of the mandibular ramus and scanned from the mandibular notch to the condylar top. The slice where the condyle had the largest cross-sectional area was measured and checked for correlation with atresia status, age, and sex. The Jahrsdoerfer score of the atretic ear was calculated and correlated with condyle cross-sectional area, age, and sex. RESULTS: Cross sectional area of the condyle ipsilateral to the atretic ear was, on average, 8.41 mm2 smaller than the contralateral condyle (P < .0001). The Jahrsdoerfer score was not associated with the condylar cross-sectional area, age, or sex. CONCLUSION: Isolated nonsyndromic unilateral congenital aural atresia is associated with mild hypoplasia of the mandibular condyle ipsilateral to the atretic ear. This is consistent with the hypothesis that congenital aural atresia is a variant of craniofacial (hemifacial) microsomia. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1191-1195, 2018. PMID- 28671285 TI - Twelve months of implementation of health care performance-based financing in Burkina Faso: A qualitative multiple case study. AB - To improve health services' quantity and quality, African countries are increasingly engaging in performance-based financing (PBF) interventions. Studies to understand their implementation in francophone West Africa are rare. This study analysed PBF implementation in Burkina Faso 12 months post-launch in late 2014. The design was a multiple and contrasted case study involving 18 cases (health centres). Empirical data were collected from observations, informal (n = 224) and formal (n = 459) interviews, and documents. Outside the circle of persons trained in PBF, few in the community had knowledge of it. In some health centres, the fact that staff were receiving bonuses was intentionally not announced to populations and community leaders. Most local actors thought PBF was just another project, but the majority appreciated it. There were significant delays in setting up agencies for performance monitoring, auditing, and contracting, as well as in the payment. The first audits led rapidly to coping strategies among health workers and occasionally to some staging beforehand. No community-based audits had yet been done. Distribution of bonuses varied from one centre to another. This study shows the importance of understanding the implementation of public health interventions in Africa and of uncovering coping strategies. PMID- 28671286 TI - Structural characterization of the NAP; the major adhesion complex of the human pathogen Mycoplasma genitalium. AB - Mycoplasma genitalium, the causative agent of non-gonococcal urethritis and pelvic inflammatory disease in humans, is a small eubacterium that lacks a peptidoglycan cell wall. On the surface of its plasma membrane is the major surface adhesion complex, known as NAP that is essential for adhesion and gliding motility of the organism. Here, we have performed cryo-electron tomography of intact cells and detergent permeabilized M. genitalium cell aggregates, providing sub-tomogram averages of free and cell-attached NAPs respectively, revealing a tetrameric complex with two-fold rotational (C2) symmetry. Each NAP has two pairs of globular lobes (named alpha and beta lobes), arranged as a dimer of heterodimers with each lobe connected by a stalk to the cell membrane. The beta lobes are larger than the alpha lobes by 20%. Classification of NAPs showed that the complex can tilt with respect to the cell membrane. A protein complex containing exclusively the proteins P140 and P110, was purified from M. genitalium and was structurally characterized by negative-stain single particle EM reconstruction. The close structural similarity found between intact NAPs and the isolated P140/P110 complexes, shows that dimers of P140/P110 heterodimers are the only components of the extracellular region of intact NAPs in M. genitalium. PMID- 28671287 TI - Protein misfolding diseases: Prospects of pharmacological treatment. AB - Protein misfolding has been linked to numerous inherited diseases. Loss- and gain of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this respect, including for the treatment of congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG). PMID- 28671288 TI - The Tris(pentafluoroethyl)stannate(II) Anion, [Sn(C2 F5 )3 ]- -Synthesis and Reactivity. AB - Syntheses of salts containing the tris(pentafluoroethyl)stannate(II) ion, [Sn(C2 F5 )3 ]- , were achieved through deprotonation of the corresponding stannane, HSn(C2 F5 )3 , as well as by direct pentafluoroethylation of SnCl2 with LiC2 F5 . The electron-withdrawing substituents have substantial influence on the stability and reactivity of the anion as documented by its treatment with main group halides. Alkyl halides (R-X) underwent nucleophilic substitutions to afford RSn(C2 F5 )3 , whereas Si, Ge, Sn, P halides gave rise to oxidation processes yielding hypervalent [SnX2 (C2 F5 )3 ]- salts (X=Cl, Br, I). Moreover the unsymmetrical distannane, nBu3 SnSn(C2 F5 )3 , was disclosed as an alternative precursor for the Sn(C2 F5 )3 moiety. Although neither the solid state structure nor its spectra in alkane solution reveal unexpected peculiarities, unusual dissociation of the compound in coordinating solvents into [nBu3 Sn(D)n ]+ and [Sn(C2 F5 )3 ]- ions was observed. PMID- 28671289 TI - Mechanistic Characterization of Two Chimeric Sesterterpene Synthases from Penicillium. AB - The products of two bifunctional fungal sesterterpene synthases (StTPS), with prenyl transferase (PT) and terpene synthase (TPS) domains from Penicillium, were structurally characterized and their mechanisms studied in detail by labeling experiments. A phylogenetic analysis of the TPS domains of the new and previously characterized enzymes revealed six distinct clades. Enzymes from the same clade catalyze a common initial cyclization step, which suggests the potential for structural predictions from amino acid sequences. PMID- 28671290 TI - Improving substance information in USEtox(r) , part 2: Data for estimating fate and ecosystem exposure factors. AB - The scientific consensus model USEtox(r) has been developed since 2003 under the auspices of the United Nations Environment Programme-Society of Environmental Toxicology and Chemistry Life Cycle Initiative as a harmonized approach for characterizing human and freshwater toxicity in life cycle assessment and other comparative assessment frameworks. Using physicochemical substance properties, USEtox quantifies potential human toxicity and freshwater ecotoxicity impacts by combining environmental fate, exposure, and toxicity effects information, considering multimedia fate and multipathway exposure processes. The main source to obtain substance properties for USEtox 1.01 and 2.0 is the Estimation Program Interface (EPI SuiteTM) from the US Environmental Protection Agency. However, since the development of the original USEtox substance databases, new chemical regulations have been enforced in Europe, such as the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and the Plant Protection Products regulations. These regulations require that a chemical risk assessment for humans and the environment is performed before a chemical is placed on the European market. Consequently, additional physicochemical property data and new toxicological endpoints are now available for thousands of chemical substances. The aim of the present study was to explore the extent to which the new available data can be used as input for USEtox-especially for application in environmental footprint studies-and to discuss how this would influence the quantification of fate and exposure factors. Initial results show that the choice of data source and the parameters selected can greatly influence fate and exposure factors, leading to potentially different rankings and relative contributions of substances to overall human toxicity and ecotoxicity impacts. Moreover, it is crucial to discuss the relevance of the exposure factor for freshwater ecotoxicity impacts, particularly for persistent highly adsorbing and bioaccumulating substances. Environ Toxicol Chem 2017;36:3463-3470. (c) 2017 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28671291 TI - Apocrine carcinoma with neuroendocrine differentiation. PMID- 28671292 TI - Reply re: "Profile of cognitive impairment and underlying pathology in multiple system atrophy". PMID- 28671293 TI - Long-term effects of sulfidized silver nanoparticles in sewage sludge on soil microflora. AB - The use of silver nanoparticles (AgNPs) in consumer products such as textiles leads to their discharge into wastewater and consequently to a transfer of the AgNPs to soil ecosystems via biosolids used as fertilizer. In urban wastewater systems (e.g., sewer, wastewater treatment plant [WWTP], anaerobic digesters) AgNPs are efficiently converted into sparingly soluble silver sulfides (Ag2 S), mitigating the toxicity of the AgNPs. However, long-term studies on the bioavailability and effects of sulfidized AgNPs on soil microorganisms are lacking. Thus we investigated the bioavailability and long-term effects of AgNPs (spiked in a laboratory WWTP) on soil microorganisms. Before mixing the biosolids into soil, the sludges were either anaerobically digested or directly dewatered. The effects on the ammonium oxidation process were investigated over 140 d. Transmission electron microscopy (TEM) suggested an almost complete sulfidation of the AgNPs analyzed in all biosolid samples and in soil, with Ag2 S predominantly detected in long-term incubation experiments. However, despite the sulfidation of the AgNPs, soil ammonium oxidation was significantly inhibited, and the degree of inhibition was independent of the sludge treatment. The results revealed that AgNPs sulfidized under environmentally relevant conditions were still bioavailable to soil microorganisms. Consequently, Ag2 S may exhibit toxic effects over the long term rather than the short term. Environ Toxicol Chem 2017;36:3305-3313. (c) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28671294 TI - Osteonecrosis after intranasal injection with bevacizumab in treating hereditary hemorrhagic telangiectasia: A case report. AB - Intranasal bevacizumab injections have been used in treating hereditary hemorrhagic telangiectasia (HHT)-related epistaxis since 2009. It is believed to be a safe and effective treatment for a selected group of HHT patients in reducing frequency and intensity of epistaxis, with few or none adverse effects. In this case report, however, we will describe a patient who developed bilateral osteonecrosis in the knees while undergoing regular intranasal submucosal bevacizumab injections. Although osteonecrosis previously has been documented in patients receiving bevacizumab intravenously in oncologic doses, thus far it has not been reported in patients treated with intranasal submucosal injections. Laryngoscope, 128:593-596, 2018. PMID- 28671295 TI - Characterization of the nasopharyngeal viral microbiome from children with community-acquired pneumonia but negative for Luminex xTAG respiratory viral panel assay detection. AB - In the present study, 50 nasopharyngeal swabs from children with community acquired pneumonia (CAP) but negative for 18 common respiratory viruses, as measured by the Luminex xTAG Respiratory Viral Panel Assay, were subjected to multiplex metagenomic analyses using a next-generation sequencing platform. Taxonomic analysis showed that all sequence reads could be assigned to a specific species. An average of 95.13% were assigned to the Bacteria kingdom, whereas, only 0.72% were potentially virus derived. This snapshot of the respiratory tract virome revealed most viral reads to be respiratory tract related, classified into four known virus families: Paramyxoviridae, Herpesviridae, Anelloviridae, and Polyomaviridae. Importantly, we detected a novel human parainfluenza virus 3 (HPIV 3) strain with a 32-bp insertion in the haemagglutinin-neuraminidase (HN) gene that produced a negative result in the Luminex assay, highlighting the strength of virome metagenomic analysis to identify not only novel viruses but also viruses likely to be missed by ordinary clinical tests. Thus, virome metagenomic analysis could become a viable clinical diagnostic method. PMID- 28671296 TI - Blood use in patients receiving intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation: the impact of a health system-wide patient blood management program. AB - BACKGROUND: Little is published on patient blood management (PBM) programs in hematology. In 2008 Western Australia announced a health system-wide PBM program with PBM staff appointments commencing in November 2009. Our aim was to assess the impact this program had on blood utilization and patient outcomes in intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation. STUDY DESIGN AND METHODS: A retrospective study of 695 admissions at two tertiary hospitals receiving intensive chemotherapy for acute leukemia or undergoing hematopoietic stem cell transplantation between July 2010 and December 2014 was conducted. Main outcomes included pre-red blood cell (RBC) transfusion hemoglobin (Hb) levels, single-unit RBC transfusions, number of RBC and platelet (PLT) units transfused per admission, subsequent day case transfusions, length of stay, serious bleeding, and in-hospital mortality. RESULTS: Over the study period, the mean RBC units transfused per admission decreased 39% from 6.1 to 3.7 (p < 0.001), and the mean PLT units transfused decreased 35% from 6.3 to 4.1 (p < 0.001), with mean RBC and PLT units transfused for follow-up day cases decreasing from 0.6 to 0.4 units (p < 0.001). Mean pre RBC transfusion Hb level decreased from 8.0 to 6.8 g/dL (p < 0.001), and single unit RBC transfusions increased 39% to 67% (p < 0.001). This reduction represents blood product cost savings of AU$694,886 (US$654,007). There were no significant changes in unadjusted or adjusted length of stay, serious bleeding events, or in hospital mortality over the study. CONCLUSION: The health system-wide PBM program had a significant impact, reducing blood product use and costs without increased morbidity or mortality in patients receiving intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation. PMID- 28671298 TI - Explaining the relationship between temperament and symptoms of psychiatric disorders from preschool to middle childhood: hybrid fixed and random effects models of Norwegian and Spanish children. AB - BACKGROUND: Four explanations for the concurrent and prospective associations between temperament and psychopathology in children have been suggested: predisposition, complication/scar, common cause/continuity, and pathoplasty/exacerbation. Because the confounding effects of common causes have not been ruled out in prior work, the support for the various explanations is uncertain. METHODS: Screen-stratified community samples of 4-year olds in Trondheim, Norway (n = 1,042), and 3-year olds in Barcelona, Spain (n = 622), were assessed biennially for symptoms of attention-deficit/hyperactivity (ADHD), oppositional defiant (ODD), conduct (CD), anxiety, and depressive disorders through interviewer-based psychiatric interviews across four waves of data collection. The parents completed child temperament ratings. The data were analyzed with random and fixed effects regression adjusted for all time-invariant unmeasured confounders (e.g., genetics, common methods bias, item overlap). RESULTS: In both Norway and Spain and across ages, negative affect predisposed children to symptoms of all disorders except CD, low effortful control predisposed children to ADHD and ODD-symptoms, and surgency predisposed children to increased ADHD-symptoms. Complication effects were observed in the Spanish children for ADHD-symptoms, which increased surgency and diminished effortful control, and for ODD-symptoms, which decreased surgency. The common cause and pathoplasty/exacerbation explanations were not supported. CONCLUSIONS: The present results are consistent with the view that temperament plays a causal role in the development of symptoms of psychiatric disorders in children. Because temperament is malleable, interventions targeting the affective, attentional, and behavioral regulatory components of temperament may reduce psychopathology in children. PMID- 28671297 TI - Standardisation of minimal residual disease in multiple myeloma. AB - The assessment of the effectiveness of chemotherapy in oncology cannot disregard the concept of minimal residual disease (MRD). In fact, the efforts of numerous scientific groups all over the world are currently focusing on this issue, with the sole purpose of defining sensitive, effective assessment criteria that are, above all, able to give acceptable, easily repeatable results worldwide. Regarding this issue, especially with the advent of new drugs, multiple myeloma is one of the haematologic malignancies for which a consensus has not yet been reached. In this review, we analyse various techniques that have been used to improve the sensitivity of response, aimed at reducing the cut-off values previously allowed, as well as serological values like serum-free light chain, or immunophenotypic tools on bone marrow or peripheral blood, like multi-parameter flow cytometry, or molecular ones such as allele-specific oligonucleotide (ASO) qPCR and next-generation/high-throughput sequencing technologies (NGS). Moreover, our discussion makes a brief reference to promising techniques, such as mass spectrometry for identifying Ig light chain (LC) in peripheral blood, and the assessment of gene expression profile not only in defining prognostic risk at the diagnosis but also as a tool for evaluation of response. PMID- 28671299 TI - Distribution and source of rare earth elements in PM2.5 in Xiamen, China. AB - Particulate matter with diameter <=2.5 um (PM2.5 ) is a serious atmospheric pollutant. Composition and source analyses are essential for controlling PM2.5 . Rare earth elements (REEs) have received little attention as a component of PM2.5 . In the present study, PM2.5 samples were collected in urban and suburban areas in Xiamen and analyzed for REEs. The concentration range of total REEs (?REE) is 12.07 to 98.45 mg/kg, with a mean of 38.53 mg/kg, in urban PM2.5 and 16.44 to 160.62 mg/kg, with a mean of 42.94 mg/kg, in suburban PM2.5 . Light REE concentrations are higher in suburban PM2.5 , whereas heavy REE concentrations are higher in urban PM2.5 , implying distinct sources of REEs in urban and suburban PM2.5 . The scatter plots of deltaEu-?REE and La-Ce-Sm suggest that REEs in urban PM2.5 originate from gasoline- and diesel-vehicle exhaust, whereas those in suburban PM2.5 are mainly influenced by gasoline-vehicle exhaust. Environ Toxicol Chem 2017;36:3217-3222. (c) 2017 SETAC. PMID- 28671300 TI - Transcription-dependent association of HDAC2 with active chromatin. AB - Histone deacetylase 2 (HDAC2) catalyzes deacetylation of histones at the promoter and coding regions of transcribed genes and regulates chromatin structure and transcription. To explore the role of HDAC2 and phosphorylated HDAC2 in gene regulation, we studied the location along transcribed genes, the mode of recruitment and the associated proteins with HDAC2 and HDAC2S394ph in chicken polychromatic erythrocytes. We show that HDAC2 and HDAC2S394ph are associated with transcriptionally active chromatin and located in the interchromatin channels. HDAC2S394ph was present primarly at the upstream promoter region of the transcribed CA2 and GAS41 genes, while total HDAC2 was also found within the coding region of the CA2 gene. Recruitment of HDAC2 to these genes was partially dependent upon on-going transcription. Unmodified HDAC2 was associated with RNA binding proteins and interacted with RNA bound to the initiating and elongating forms of RNA polymerase II. HDAC2S394ph was not associated with RNA polymerase II. These results highlight the differential properties of unmodified and phosphorylated HDAC2 and the organization of acetylated transcriptionally active chromatin in the chicken polychromatic erythrocyte. PMID- 28671301 TI - Detection of long term cellular immune response to Japanese encephalitis vaccination using IFN-gamma ELIspot assay. AB - Vaccine is the most effective preventive measure against Japanese Encephalitis infection. Role of IFN-gamma expressing T cells for JE virus clearance has been described as a part of cellular immunity. Vaccine induced immunity also involve the cellular immune response, therefore the study was aimed to observe induction and persistence of IFN-gamma expressing T cells by IFN-gamma ELISpot assay. The cell count increased significantly after 28 (P < 0.0001) days post vaccination, and remained higher at all time points (day 28, day 180, day 360) when compared with prevaccination. This study will be helpful for designing future vaccination strategy and improving vaccine efficacy. PMID- 28671302 TI - Superoxide Dismutase-Loaded Porous Polymersomes as Highly Efficient Antioxidants for Treating Neuropathic Pain. AB - A highly efficient antioxidant is developed by encapsulating superoxide dismutase (SOD) within the aqueous interior of porous polymersomes. The porous polymersomes provide a permeable membrane that allows free superoxide radicals to pass into the aqueous interior and interact with the encapsulated antioxidant enzyme SOD. In vivo studies in the rat demonstrate that administration of SOD-encapsulated porous polymersomes can prevent neuropathic pain after nerve root compression more effectively than treatment with free antioxidant enzyme alone. PMID- 28671303 TI - Increased complement activation during platelet storage. AB - BACKGROUND: It has been shown that platelet transfusion carries a higher incidence of transfusion-related adverse events than any other blood components, and prolonged platelet storage is associated with more transfusion reactions, most of which are considered to be inflammatory responses. However, the role of complement, which has very important proinflammatory activities, in the pathogenesis of platelet-related adverse events has not been fully understood. STUDY DESIGN AND METHODS: Three units of platelets collected by apheresis were stored on a platelet rotator with the temperature controlled between 22 and 24 degrees C. Plasma samples were obtained using a sterile technique on Days 2 through 7. Complement components were assayed to evaluate the activation of complement activation and included C4d (classical pathway), Factor Bb (alternative pathway), C3a (common pathway), C5a (terminal pathway), and C5b-9 (terminal pathway). RESULTS: Both C4d and C3a were elevated on the first day of testing (Day 2) compared with the established normal ranges and continued to increase over time in storage. In contrast, Factor Bb levels remained stable and were within the normal range over time. Over a span of 7 days in storage, the terminal complement factors C5a and C5b-9 were also significantly increased, although the magnitude of increases was not as striking as those in C4d and C3a levels. CONCLUSION: Our results demonstrate that substantial complement activation occurs in platelets under standard storage conditions, and this activation increases with the duration of storage. After transfusion, these activated complement components might result in accelerated complement activation in recipients, leading to transfusion-related adverse events. PMID- 28671304 TI - Fast, precise, and accurate myocardial T1 mapping using a radial MOLLI sequence with FLASH readout. AB - PURPOSE: Quantitative cardiac MRI, and more particularly T1 mapping, has become a most important modality to characterize myocardial tissue. In this work, the value of a radial variant of the conventional modified Look-Locker inversion recovery sequence (raMOLLI) is demonstrated. METHODS: The raMOLLI acquisition scheme consisted of five radial echo trains of 80 spokes acquired using either a fast low-angle shot (FLASH) or a true fast imaging with steady-state-precession (TrueFISP) readout at different time points after a single magnetization inversion. View sharing combined with a compressed sensing algorithm allowed the reconstruction of 50 images along the T1 relaxation recovery curve, to which a dictionary-fitting approach was applied to estimate T1 . The sequence was validated on a nine-vial phantom, on 19 healthy subjects, and one patient suffering from dilated cardiomyopathy. RESULTS: The raMOLLI sequence allowed a significant decrease of myocardial T1 map acquisition time down to five heartbeats, while exhibiting a higher degree of accuracy and a comparable precision on T1 value estimation than the conventional modified Look-Locker inversion recovery sequence. The FLASH readout demonstrated a better robustness to B0 inhomogeneities than TrueFISP, and was therefore preferred for in vivo acquisitions. CONCLUSIONS: This sequence represents a good candidate for ultrafast acquisition of myocardial T1 maps. Magn Reson Med 79:1387-1398, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28671305 TI - Younger trend of cirrhosis incidence in genotype 3 HCV infected patients in Eastern China. AB - The diversity of HCV genotypes is ever-evolving and requires continuous surveillance. The aim of this study was to investigate the dynamics of HCV genotypes, and their associated demographic and clinical patterns in China. By searching computerized hospital information system, a total of 1155 HCV-positive patients eligible for analysis were retrospectively identified from 12 380 consecutive in-patients in the Department of Infectious Diseases, Ruijin Hospital in China between 2009 and 2014. The percentages of HCV genotype 1, 2, 3, or 6 were 61.3%, 12.8%, 18.5%, or 7.4%, respectively. The number of patients hospitalized for HCV infection increased gradually over the study period, particularly those infected by genotype 3 HCV. Patients of genotype 1, 2, 3, or 6 were significantly different. Genotype 1 or two patients were much older, with higher proportion of blood transfusion history. In contrast, genotype 3 or six patients were younger, predominantly male, with more exposure to intravenous drug use. The cirrhosis incidence was higher in genotype 1 or two patients, followed by genotype 3 and six patients. Strikingly, genotype 3 cirrhotic patients were younger, and their estimated infection durations were also shorter, suggestive of a faster disease progression in genotype 3 patients. Multivariate analysis demonstrated that presence of HBcAb was an independent predictor of cirrhosis (OR 2.19, 95%CI 1.27-3.42; P = 0.004). The leading increase and the younger trend of cirrhosis incidence in genotype 3 patients argue for a higher priority to manage the infection in this highly at-risk population. PMID- 28671306 TI - Supplementation of Cerelac baby food with yeast-probiotic cocktail strains induces high potential for aflatoxin detoxification both in vitro and in vivo in mother and baby albino rats. AB - BACKGROUND: Aflatoxins (AFs) are a group of toxic, nephrotoxic, hepatotoxic and carcinogenic fungal metabolites. Heat- and acid-treated yeasts, probiotic bacteria and their combination were used to remove AFB1, AFB2, AFG1 and AFG2 from human and animal food. RESULTS: The in vitro study revealed that the highest removal percentage of AFs in phosphate-buffered saline was recorded after 72 h with the yeast-probiotic coctile, reaching 95.59%. Therefore, this coctile was added to Cerelac contaminated with AFB1, AFB2, AFG1 and AFG2, and the removal percentages were 8.17%, 36.12%, 44.75%, 64.72% and 93.21% after 6, 12, 24, 48 and 72 h of treatment, respectively. Cerelac yeast-probiotic coctile was administered to female rats and the results showed that all AFs (AFB1, AFB2, AFG1 and AFG2) were detected in the serum of mother rats for both AF groups III and IV. On the other hand, AFM1 and AFM2 metabolites were not observed in mothers' sera but were detected in all infants of groups III and IV. Meanwhile, AFB1, AFB2, AFG1 and AFG2 were not observed in infants' sera. CONCLUSION: A mixture of yeast-probiotic coctile was successful in reducing the level of AF in rat sera and diminished the deleterious effect of AFs on animal health. (c) 2017 Society of Chemical Industry. PMID- 28671308 TI - Biological parameters used in setting captive-breeding quotas for Indonesia's breeding facilities. AB - The commercial captive breeding of wildlife is often seen as a potential conservation tool to relieve pressure on wild populations, but laundering of wild sourced specimens as captive bred can seriously undermine conservation efforts and provide a false sense of sustainability. Indonesia is at the center of such controversy; therefore, we examined Indonesia's captive-breeding production plan (CBPP) for 2016. We compared the biological parameters used in the CBPP with parameters in the literature and with parameters suggested by experts on each species and identified shortcomings of the CBPP. Production quotas for 99 out of 129 species were based on inaccurate or unrealistic biological parameters and production quotas deviated more than 10% from what parameters in the literature allow for. For 38 species, the quota exceeded the number of animals that can be bred based on the biological parameters (range 100-540%) calculated with equations in the CBPP. We calculated a lower reproductive output for 88 species based on published biological parameters compared with the parameters used in the CBPP. The equations used in the production plan did not appear to account for other factors (e.g., different survival rate for juveniles compared to adult animals) involved in breeding the proposed large numbers of specimens. We recommend the CBPP be adjusted so that realistic published biological parameters are applied and captive-breeding quotas are not allocated to species if their captive breeding is unlikely to be successful or no breeding stock is available. The shortcomings in the current CBPP create loopholes that mean mammals, reptiles, and amphibians from Indonesia declared captive bred may have been sourced from the wild. PMID- 28671307 TI - Cutaneous microvascular perfusion responses to insulin iontophoresis are differentially affected by insulin resistance after spinal cord injury. AB - NEW FINDINGS: What is the central question of this study? What impact does insulin resistance have on cutaneous perfusion responses to insulin iontophoresis in vascular beds with markedly reduced or functionally ablated sympathetic nervous system vasomotor function resulting from spinal cord injury? What is the main finding and its importance? Persons with spinal cord injury have sublesional microvascular endothelial dysfunction, as indicated by a blunted cutaneous perfusion response to acetylcholine iontophoresis, and the presence of insulin resistance has a further confounding effect on endothelium-mediated changes to cutaneous perfusion in the lower extremities. Endothelium-mediated mechanisms that regulate skin blood flow might play an integral role in optimizing skin perfusion in vascular beds with sympathetic nervous system vasomotor impairment, such as in spinal cord injury (SCI). Insulin is a vasoactive hormone and second messenger of nitric oxide that facilitates endothelium-mediated dilatation. The effects of insulin resistance (IR) on sublesional cutaneous perfusion responses to insulin provocation have yet to be described in persons with SCI. Persons with SCI and an able-bodied (AB) cohort were divided into subgroups based upon fasting plasma insulin concentration cut-offs for IR (>=13.13 mIU ml-1 ) or insulin sensitivity (IS; <13.13 mIU ml-1 ), as follows: AB, IS (ABIS, n = 21); SCI, IS (SCIS, n = 21); AB, IR (ABIR, n = 9); and SCI, IR (SCIR, n = 11). Laser Doppler flowmetry characterized peak blood perfusion unit (BPU) responses (percentage change from baseline) to insulin, acetylcholine or placebo iontophoresis in the lower extremities; BPU responses were log10 transformed to facilitate comparisons, and the net insulin response (NetIns) BPU response was calculated (insulin minus placebo BPU response). The NetIns was significantly greater in both IS groups compared with their corresponding IR group. The acetylcholine mediated BPU responses in the SCI subgroups were significantly lower than those in the ABIS group. The proportional BPU responses of NetIns to acetylcholine in the IS cohorts (i.e. ABIS and SCIS) were significantly greater (P < 0.05) than that of each IR subgroup. The presence of IR has a confounding effect on sublesional microvascular endothelium-mediated cutaneous perfusion responses to provocation. Preservation of endothelial sensitivity to its agonists appears to be an important modifiable risk factor to optimize cutaneous perfusion in the lower extremities of persons with SCI. PMID- 28671310 TI - Resolution of enantiopure (S)-1-(1-napthyl) ethanol from racemic mixture by a novel Bacillus cereus isolate. AB - Chiral intermediates have wide application and high demand in pharmaceutical, agricultural, and other biotechnological industries for the preparation of bulk drug substances or fine chemicals. (S)-1-(1-napthyl) ethanol is an important synthetic intermediate of mevinic acid analog and a potential inhibitor of 3 hydroxy methyl glutaryl coenzyme A reductase enzymes which is rate limiting for cholesterol synthesis. The present study focuses on the resolution of (RS)-1-(1 napthyl) ethanol using whole cell biotransformation approach. The screening of microbial strains for the specific conversion were performed by the enrichment techniques using (RS)-1-(1-napthyl) ethanol. Evaluation of resolution, i.e., the enantioselective conversion of (R)-1-(1-napthyl) ethanol into 1-acetonapthone and production of (S)-1-(1-napthyl) ethanol with high purity were carried out. Among the isolates, a novel strain Bacillus cereus WG3 was found to be potent for the resolution and conversion of (S)-1-(1-napthyl) ethanol. This strain showed 86% conversion of (R)-1-(1-napthyl) ethanol and 95% yield of S-1-(1-napthyl) ethanol with 80% ee after 24 h. Further, the optimization of biotransformation reactions was carried out and the optimal parameters were found to be pH 7.0 and temperature 30 degrees C. PMID- 28671311 TI - Cognitive impairment in multiple system atrophy. PMID- 28671309 TI - Fatal SV40-associated pneumonia and nephropathy following renal allotransplantation in rhesus macaque. AB - Recrudescence of latent and dormant viruses may lead to overwhelming viremia in immunosuppressed hosts. In immunocompromised hosts, Simian virus 40 (SV40) reactivation is known to cause nephritis and demyelinating central nervous system disease. Here, we report SV40 viremia leading to fatal interstitial pneumonia in an immunosuppressed host following renal allotransplantation. PMID- 28671312 TI - Anti-prostate cancer potential of gossypetin via inducing apoptotic and autophagic cell death. AB - Gossypetin (GTIN), a naturally occurring hexahydroxy flavone, has been shown to possess antimutagenic, antioxidant, antimicrobial, and antiatherosclerotic effects. Here, we investigated the mechanism(s) underlying the anticancer potential of GTIN. In this study, investigations were showed that GTIN preferentially induces programed cell death of prostate cancer (PCa) cells in vitro and in vivo. MTT data showed that GTIN exhibited the anti-proliferation effect on human PCa cells in a dose- and time-dependent manner. Among two kinds of PCa cells, androgen-dependent LNCaP cells were the most susceptible to GTIN. GTIN was evaluated for apoptotic and autophagic activities in LNCaP cells, but not in androgen-independent DU145 cells with mutant Atg5 and resistant to autophagy. Molecular data showed the apoptotic effect of GTIN at a high dose in PCa cells might be mediated via mitochondrial pathway. The lower dose of GTIN induced autophagy enhances LNCaP cell death, and is dependent on class III PI3K and Atg5 pathway. Finally, GTIN was evidenced by its inhibition on the growth of LNCaP cells in xenograft tumor studies. As a result, our data presented the first evidence of GTIN as an inducer of apoptotic and autophagic cell death in LNCaP cells, and provide a new mechanism for its anticancer activity. PMID- 28671313 TI - Context and social perceptions of blood donation in donors found positive for human immunodeficiency virus in France. AB - BACKGROUND: In France, information collected during postdonation interviews showed that a majority of human immunodeficiency virus (HIV)-infected donors were not eligible to donate as per donor selection criteria. In the interest of blood safety, this study aimed to explore the mechanisms of noncompliance with blood donor selection criteria, notably the permanent deferral of men who have sex with men (MSM). STUDY DESIGN AND METHODS: Semistructured individual interviews were conducted with 32 blood donors found positive for HIV between mid-2011 and 2014. Topics such as the experience and motivations for donating blood, understanding of selection criteria, sexual risk management, and opinions on donor selection were discussed. Transcripts were analyzed inductively. RESULTS: More than 50% of study participants were noncompliant with donor selection criteria. Reasons for nondisclosure of risk factors in the predonation questionnaire or the predonation interview included stigma, test-seeking motivations, symbolic attachment to blood donation, and context of donation. Compliance to donor criteria was seen as secondary by donors who reaped personal benefits from the symbolism of their donation. Donors lacked self-reflexivity in their assessment of risky sexual behavior. The "window period" and the underlying epidemiologic arguments for donor selection criteria were poorly understood. Nearly all participants disapproved of the permanent ban on blood donations from MSM. CONCLUSION: This study demonstrated the need for more communication on the epidemiologic basis for donor selection criteria and on the window period to facilitate donor compliance. These findings have already advanced improvements to predonation documents, in a larger context of 2016 donor selection criteria revision. PMID- 28671314 TI - No Evidence That Sleep Deprivation Effects and the Vigilance Decrement Are Functionally Equivalent: Comment on Veksler and Gunzelmann (2017). AB - Veksler and Gunzelmann (2017) make an extraordinary claim, which is that sleep deprivation effects and the vigilance decrement are functionally equivalent. Extraordinary claims require extraordinary evidence, which is missing from Veksler and Gunzelmann's study. Their behavioral data offer only weak theoretical constraint, and to the extent their modeling exercise supports any position, it is that these two performance impairments involve functionally distinct underlying mechanisms. PMID- 28671315 TI - Relationship between oxygen cost of walking and level of walking disability after stroke: An experimental study. AB - BACKGROUND AND PURPOSE: Since physical inactivity is the major risk factor for recurrent stroke, it is important to understand how level of disability impacts oxygen uptake by people after stroke. This study investigated the nature of the relationship between level of disability and oxygen cost in people with chronic stroke. METHODS: Level of walking disability was measured as comfortable walking speed using the 10-m Walk Test reported in m/s with 55 ambulatory people 2 years after stroke. Oxygen cost was measured during 3 walking tasks: overground walking at comfortable speed, overground walking at fast speed, and stair walking at comfortable speed. Oxygen cost was calculated from oxygen uptake divided by distance covered during walking and reported in ml?kg-1 ?m-1 . RESULTS: The relationship between level of walking disability and oxygen cost was curvilinear for all 3 walking tasks. One quadratic model accounted for 81% (95% CI [74, 88]) of the variance in oxygen cost during the 3 walking tasks: [Formula: see text] DISCUSSION: The oxygen cost of walking was related the level of walking disability in people with chronic stroke, such that the more disabled the individual, the higher the oxygen cost of walking; with oxygen cost rising sharply as disability became severe. An equation that relates oxygen cost during different walking tasks according to the level of walking disability allows clinicians to determine oxygen cost indirectly without the difficulty of measuring oxygen uptake directly. PMID- 28671316 TI - Use of domperidone and risk of ventricular arrhythmia in the postpartum period: getting to the heart of the matter. PMID- 28671317 TI - Response to "use of domperidone and risk of ventricular arrhythmia in the postpartum period: Getting to the heart of the matter". PMID- 28671318 TI - Eu3+ -labeled IgG-based time-resolved fluoroimmunoassay for highly sensitive detection of aflatoxin B1 in feed. AB - BACKGROUND: Aflatoxin B1 (AFB1 ) is a kind of toxic and carcinogenic mycotoxin. A time-resolved fluoroimmunoassay (TRFIA) was established for quantitative detection of AFB1 in feed using Eu3+ -labeled IgG as tracer. RESULTS: Monoclonal antibody (McAb) against AFB1 (9B11-D7) was prepared through immunization and cell fusion and was identified as high affinity, specificity and sensibility by enzyme linked immunosorbent assay (ELISA). The 50% inhibition value (IC50 ) was 0.81 ng mL-1 , the limit of detection (LOD) was 0.10 ng mL-1 and detection range was 0.10 3.94 ng mL-1 . Goat anti-mouse immunoglobulin G (IgG) was modified by Eu3+ -DATT, generating Eu3+ -labeled IgG. Under optimal assay conditions, TRFIA was shown to be highly sensitive and specific in detection of AFB1 . The IC50 and LOD were 94.73 pg mL-1 and 3.55 pg mL-1 , respectively, and detection range was 3.55-1.11 * 103 pg mL-1 . Cross-reactivity with AFM1 , AFB2 , AFG1 and AFG2 was 31.26%, 37.6%, 127.46% and 35.74%, respectively, but zero with other analogues. In determination of AFB1 spiked in feed sample, TRFIA showed high accuracy and precision. The average recoveries ranged from 93.71% to 97.80%, and coefficient of variation was 1.25-3.73%. Good correlation between TRFIA and HPLC was demonstrated for determination of AFB1 in feeds, confirming the reliability of the developed method. CONCLUSION: The developed TRFIA exhibited good potential for employment in the ultrasensitive detection of AFB1 in feed and could be used to determine total aflatoxins. (c) 2017 Society of Chemical Industry. PMID- 28671319 TI - Neovascular age-related macular degeneration is associated with cataract surgery. AB - PURPOSE: This retrospective cohort study examines the association between cataract surgery and neovascular age-related macular degeneration (AMD) during 5 year follow-up using population-based claims data. METHODS: We analysed data sourced from the Taiwan Longitudinal Health Insurance Database 2005. The study included 3465 patients who had undergone cataract operations and did not have a diagnosis of AMD before or on the surgery date (study group), and 10 395 age- and sex-matched comparison patients selected randomly from the remaining patients without an AMD diagnosis before the index date. We tracked the claims of each patient for a 5-year period to identify patients with a subsequent diagnosis of neovascular AMD. RESULTS: The incidence rate of neovascular AMD was 0.88 (95% confidence interval (CI): 0.66-1.14) per 1000 person-years among all sampled patients, 1.60 (95% CI: 1.04-2.36) among the cataract surgery patients and 0.64 (95% CI: 0.43-0.91) among comparison patients (p < 0.001). Stratified Cox proportional analysis showed that relative to the comparison cohort, the adjusted hazard ratio for neovascular AMD during 5-year follow-up was 2.68 (95% CI: 1.55 4.66) for patients who had undergone cataract operation. We censored those who died during follow-up period and adjusted for patients' monthly income, geographical location, urbanization level, diabetes, hypertension, cardiovascular disease and hyperlipidaemia. CONCLUSION: This study demonstrated epidemiological evidence of a link between cataract surgery and neovascular AMD during a 5-year follow-up period. PMID- 28671320 TI - Design of spectral-spatial phase prewinding pulses and their use in small-tip fast recovery steady-state imaging. AB - PURPOSE: Spectrally selective "prewinding" radiofrequency pulses can counteract B0 inhomogeneity in steady-state sequences, but can only prephase a limited range of off-resonance. We propose spectral-spatial small-tip angle prewinding pulses that increase the off-resonance bandwidth that can be successfully prephased by incorporating spatially tailored excitation patterns. THEORY AND METHODS: We present a feasibility study to compare spectral and spectral-spatial prewinding pulses. These pulses add a prephasing term to the target magnetization pattern that aims to recover an assigned off-resonance bandwidth at the echo time. For spectral-spatial pulses, the design bandwidth is centered at the off-resonance frequency for each spatial location in a field map. We use these pulses in the small-tip fast recovery steady-state sequence, which is similar to balanced steady-state free precession. We investigate improvement of spectral-spatial pulses over spectral pulses using simulations and small-tip fast recovery scans of a gel phantom and human brain. RESULTS: In simulation, spectral-spatial pulses yielded lower normalized root mean squared excitation error than spectral pulses. For both experiments, the spectral-spatial pulse images are also qualitatively better (more uniform, less signal loss) than the spectral pulse images. CONCLUSION: Spectral-spatial prewinding pulses can prephase over a larger range of off-resonance than their purely spectral counterparts. Magn Reson Med 79:1377 1386, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28671321 TI - The influence of small doses of ethanol on the urinary testosterone to epitestosterone ratio in men and women. AB - Endogenous steroid use can increase urinary testosterone/epitestosterone (T/E) values. In addition, ethanol in amounts >0.5 g per kg of body weight (g/kg) can also increase T/E values. However, the effect of smaller doses of ethanol on T/E values is unknown. The influence of 0.2 and 0.4 g/kg of ethanol on baseline T/E values in 20 men and 20 women with low and high baseline T/E values was investigated and correlated with ethyl glucuronide (EtG) and ethyl sulfate (EtS) concentrations. T/E values for 7 of the women were excluded from the study because of undetectable T concentrations or for other reasons. One man and 1 woman with a high T/E baseline value had a significant increase in their T/E value after ingestion of 0.2 g/kg of ethanol. One man and 2 women with a high T/E baseline, and 1 woman with a low T/E baseline had significantly increased T/E values after ingestion of 0.4 g/kg of ethanol. There was wide variability in peak EtG concentrations and a lack of correlation between ethanol dose and EtG concentrations. Interestingly, 1 man and 2 women with increased T/E values following ethanol ingestion had EtG concentrations below the World Anti-Doping Agency (WADA) cut-off of 5000 ng/mL. These findings demonstrate that small amounts of ethanol can elevate T/E values, with women being more susceptible. In addition, consideration should be given to the lowering of the WADA EtG cut-off to detect samples with elevated T/E values from ingestion of low doses of ethanol. PMID- 28671322 TI - Factors related to retinal haemorrhage in infants born at high risk. AB - PURPOSE: This study aims to determine risk factors for retinal haemorrhage (RH) in high-risk infants. METHODS: A total of 3123 cases with high-risk pregnancy and/or neonatal asphyxia 72 hr after delivery were enrolled into this study. Fundus examinations were performed on newborns utilizing a wide-angle imaging system (RetCam III). Retinal haemorrhage (RH) was classified into three grades. Maternal, obstetric and neonatal parameters from high-risk infants with RH were compared with parameters from infants without RH. RESULTS: Retinal haemorrhage (RH) was found in 550 (18%) of 3123 high-risk infants. Retinal haemorrhage (RH) was classified as grade I (39%), grade II (24%) and grade III (37%). Monocular RH occurred in 37% of cases, while the remaining cases were binocular. Moreover, six cases had vitreous haemorrhage. The following parameters correlated (p < 0.05) with RH in this study: delivery mode (chi2 = 469), gestational age (chi2 = 35), birth weight (chi2 = 18), asphyxia (chi2 = 73), scalp hematoma (chi2 = 55), maternal age (chi2 = 8.9), precipitate labour (chi2 = 120) and delivery times (chi2 = 6.1). Logistic regression analysis indicated that delivery mode and asphyxia were risk factors for RH in high-risk infants, with odds ratios of 0.827 and 2.5, respectively. Gender, intracranial haemorrhage and foetal distress were not correlated with RH in high-risk infants. CONCLUSION: The incidence of RH in high-risk infants was 18%, and delivery mode, and neonatal asphyxia were major risk factors for RH in high-risk infants. PMID- 28671323 TI - Band-Gap Opening in Metallic Single-Walled Carbon Nanotubes by Encapsulation of an Organic Salt. AB - The encapsulation of viologen derivatives into metallic single-walled carbon nanotubes (SWNTs) results in the opening of a band gap, making the SWNTs semiconducting. Raman spectroscopy, thermogravimetric analysis, and aberration corrected high-resolution transmission electron microscopy confirm the encapsulation process. Through the fabrication of field-effect transistor devices, the change of the electronic structure of the tubes from metallic to semiconducting upon the encapsulation is confirmed. The opening of a gap in the band structure of the tubes was not detected in supramolecular controls. PMID- 28671324 TI - Rituximab for thrombotic thrombocytopenic purpura: lessons from the STAR trial. PMID- 28671325 TI - Serologic and molecular characterization of weak D type 29. PMID- 28671326 TI - Effect of Nitrogen Doping Level on the Performance of N-Doped Carbon Quantum Dot/TiO2 Composites for Photocatalytic Hydrogen Evolution. AB - Carbon quantum dots (CQDs) have attracted widespread interest for photocatalytic applications, owing to their low cost and excellent electron donor/acceptor properties. However, their advancement as visible-light photosensitizers in CQDs/semiconductor nanocomposites is currently impaired by their poor quantum yields (QYs). Herein, we describe the successful fabrication of a series of nitrogen-doped CQDs (NCDs) with N/C atomic ratios ranging from 0.14-0.30. NCDs with the highest N-doping level afforded a remarkable external QY of 66.8 % at 360 nm, and outstanding electron transfer properties and photosensitization efficiencies when physically adsorbed on P25 TiO2 . A NCDs/P25-TiO2 hybrid demonstrated excellent performance for hydrogen evolution in aqueous methanol under both UV and visible-light illumination relative to pristine P25 TiO2 . Controlled nitrogen doping of CQDs therefore represents a very effective strategy for optimizing the performance of CQDs/semiconductor hybrid photocatalysts. PMID- 28671328 TI - Electrostimulated Release of Neutral Drugs from Polythiophene Nanoparticles: Smart Regulation of Drug-Polymer Interactions. AB - Poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles are loaded with curcumin and piperine by in situ emulsion polymerization using dodecyl benzene sulfonic acid both as a stabilizer and a doping agent. The loaded drugs affect the morphology, size, and colloidal stability of the nanoparticles. Furthermore, kinetics studies of nonstimulated drug release have evidenced that polymer...drug interactions are stronger for curcumin than for piperine. This observation suggests that drug delivery systems based on combination of the former drug with PEDOT are much appropriated to show an externally tailored release profile. This is demonstrated by comparing the release profiles obtained in presence and absence of electrical stimulus. Results indicate that controlled and time programmed release of curcumin is achieved in a physiological medium by applying a negative voltage of -1.25 V to loaded PEDOT nanoparticles. PMID- 28671327 TI - Dental caries clusters among adolescents. AB - OBJECTIVES: There have been very few longitudinal studies of dental caries in adolescents, and little study of the caries risk factors in this age group. The purpose of this study was to describe different caries trajectories and associated risk factors among members of the Iowa Fluoride Study (IFS) cohort. METHODS: The IFS recruited a birth cohort from 1992 to 1995, and has gathered dietary, fluoride and behavioural data at least twice yearly since recruitment. Examinations for dental caries were completed when participants were ages 5, 9, 13 and 17 years. For this study, only participants with decayed and filled surface (DFS) caries data at ages 9, 13 and 17 were included (N=396). The individual DFS counts at age 13 and the DFS increment from 13 to 17 were used to identify distinct caries trajectories using Ward's hierarchical clustering algorithm. A number of multinomial logistic regression models were developed to predict trajectory membership, using longitudinal dietary, fluoride and demographic/behavioural data from 9 to 17 years. Model selection was based on the akaike information criterion (AIC). RESULTS: Several different trajectory schemes were considered, and a three-trajectory scheme-no DFS at age 17 (n=142), low DFS (n=145) and high DFS (n=109)-was chosen to balance sample sizes and interpretability. The model selection process resulted in use of an arithmetic average for dietary variables across the period from 9 to 17 years. The multinomial logistic regression model with the best fit included the variables maternal education level, 100% juice consumption, brushing frequency and sex. Other favoured models also included water and milk consumption and home water fluoride concentration. The high caries cluster was most consistently associated with lower maternal education level, lower 100% juice consumption, lower brushing frequency and being female. CONCLUSIONS: The use of a clustering algorithm and use of Akaike's Information Criterion (AIC) to determine the best representation of the data were useful means in presenting longitudinal caries data. Findings suggest that high caries incidence in adolescence is associated with lower maternal educational level, less frequent tooth brushing, lower 100% juice consumption and being female. PMID- 28671329 TI - Suppression of IL-8 Release by Sweet Olive Ethanolic Extract and Compounds in WiDr Colon Adenocarcinoma Cells. AB - Oxidative stress can stimulate the secretion of pro-inflammatory cytokines. Interleukin-8 (IL-8) has been implicated in the pathogenesis of inflammatory bowel disease and the metastatic spread of colorectal cancer. The flowers of Osmanthus fragrans (sweet olive) are used to alleviate dysentery with blood in the bowel, as well as stomach ache and diarrhea. However, the evidence of their therapeutic effects on these symptoms remains unclear. In the present study, the protective effects of sweet olive flower ethanolic extract (OFE) against oxidative stress in WiDr cells was assessed by evaluating its 1,1-diphenyl-2 picrylhydrazyl (DPPH) free radical scavenging activity. In addition, cellular IL 8 secretion was evaluated. Notably, high-performance liquid chromatography showed verbascoside to be the primary constituent in OFE; it exhibited a DPPH scavenging activity with an IC50 of 8.23 MUg/mL. Moreover, OFE (1 to 100 MUg/mL) showed a potent, dose-dependent inhibitory effect on H2 O2 -induced IL-8 secretion in WiDr cells. Nine compounds were isolated from OFE based on a protective effect-guided purification process. Of these compounds, 5 phenolic compounds-verbascoside, phillygenin, tyrosol, methyl 4-hydroxycinnamate, and eutigoside A-reduced IL-8 secretion at 10 MUg/mL treatment concentrations. Further analysis showed that the anti-inflammatory effects of OFE likely occurred via nuclear factor-kappaB pathway inhibition, which attenuates IL-8 secretion in cells. Collectively, these data suggest that OFE could be developed as an agent that suppresses IL-8 secretion to treat chronic inflammatory diseases. PMID- 28671330 TI - Cytomegaloviral hypophysitis in a simian immunodeficiency virus-infected rhesus macaque (Macacca mulatta). AB - Rhesus macaques experimentally infected with Simian Immunodeficiency Virus (SIV) experience immunosuppression and often opportunistic infection. Among the most common opportunistic infections are rhesus cytomegalovirus (RhCMV), a ubiquitous betaherpesvirus that undergoes continuous low-level replication in immunocompetent monkeys. Upon SIV-mediated immunodeficiency, RhCMV reactivates and results in lesions in numerous organ systems including the nervous and reproductive systems. We report the first case of cytomegaloviral hypophysitis in a SIV-immunocompromised rhesus macaque. PMID- 28671331 TI - Performance of a fast and high-resolution multi-echo spin-echo sequence for prostate T2 mapping across multiple systems. AB - PURPOSE: To evaluate the performance of a multi-echo spin-echo sequence with k-t undersampling scheme (k-t T2 ) in prostate cancer. METHODS: Phantom experiments were performed at five systems to estimate the bias, short-term repeatability, and reproducibility across all systems expressed with the within-subject coefficient of variation (wCV). Monthly measurements were performed on two systems for long-term repeatability estimation. To evaluate clinical repeatability, two T2 maps (voxel size 0.8 * 0.8 * 3 mm3 ; 5 min) were acquired at separate visits on one system for 13 prostate cancer patients. Repeatability was assessed per patient in relation to spatial resolution. T2 values were compared for tumor, peripheral zone, and transition zone. RESULTS: Phantom measurements showed a small bias (median = -0.9 ms) and good short-term repeatability (median wCV = 0.5%). Long-term repeatability was 0.9 and 1.1% and reproducibility between systems was 1.7%. The median bias observed in patients was -1.1 ms. At voxel level, the median wCV was 15%, dropping to 4% for structures of 0.5 cm3 . The median tumor T2 values (79 ms) were significantly lower (P < 0.001) than in the peripheral zone (149 ms), but overlapped with the transition zone (91 ms). CONCLUSIONS: Reproducible T2 mapping of the prostate is feasible with good spatial resolution in a clinically reasonable scan time, allowing reliable measurement of T2 in structures as small as 0.5 cm3 . Magn Reson Med 79:1586-1594, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28671332 TI - Association between malnutrition and hyperhomocysteine in Alzheimer's disease patients and diet intervention of betaine. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, which is associated with malnutrition and hyperhomocysteine. The current study aimed to analyze the relationship between malnutrition and hyperhomocysteine in AD patients, and effects of diet intervention with betaine on the disease. METHODS: The nutritional statuses of the AD patients were assessed by short form mini nutritional assessment (MNA-SF). The levels of Hcy, tau hyperphosphorylation, synaptic proteins, blood inflammatory factors were measured by enzymatic cycling assay, Western blot and ELISA. The cognitive function was measured by AD assessment scale (ADAS-cog). RESULTS: There was a significant difference in mental status between normal people and AD patients (P<.05). Overall, malnutrition was reported in a larger proportion of AD patients and high level of Hcy was closely associated with malnutrition. Betaine decreased the levels of phosphorylated tau, elevated PP2Ac activity and inhibited Abeta accumulation (P<.05). The levels of IL-lbeta and TNF-alpha were significantly higher in the untreatment group while much lower in the intervention group (P<.05). After intervention of betaine treatment, the expression level of Hcy can be restored and betaine can effectively suppress inflammation as well as trigger an increase in memory-related proteins. ADAS-Cog suggested that significant improvement was found after the intervention of betaine. CONCLUSIONS: AD was associated with both malnutrition and higher levels of Hcy. Betaine could restore Hcy expression to normal level in AD patient, which might ameliorate memory deficits. PMID- 28671333 TI - Research Review: Diffusion tensor imaging studies of attention deficit/hyperactivity disorder: meta-analyses and reflections on head motion. AB - BACKGROUND: Diffusion tensor imaging studies have shown atypical fractional anisotropy (FA) in individuals with attention-deficit/hyperactivity disorder (ADHD), albeit with conflicting results. We performed meta-analyses of whole brain voxel-based analyses (WBVBA) and tract-based spatial statistics (TBSS) studies in ADHD, along with a qualitative review of TBSS studies addressing the issue of head motion, which may bias results. METHODS: We conducted a systematic literature search (last search on April 1st, 2016) to identify studies comparing FA values between individuals with ADHD and typically developing (TD) participants. Signed differential mapping was used to compute effect sizes and integrate WBVBA and TBSS studies, respectively. TBSS datasets reporting no between-group motion differences were identified. RESULTS: We identified 14 WBVBA (ADHDn = 314, TDn = 278) and 13 TBSS datasets (ADHDn = 557, TDn = 568). WBVBA meta-analysis showed both significantly lower and higher FA values in individuals with ADHD; TBSS meta-analysis showed significantly lower FA in ADHD compared with TD in four clusters: two in the corpus callosum (isthmus and posterior midbody), one in right inferior fronto-occipital fasciculus, and one in left inferior longitudinal fasciculus. However, four of six datasets confirming no group differences in motion showed no significant between-group FA differences. CONCLUSIONS: A growing diffusion tensor imaging (DTI) literature (total N = 1,717) and a plethora of apparent findings suggest atypical interhemispheric connection in ADHD. However, FA results in ADHD should be considered with caution, since many studies did not examine potential group differences in head motion, and most of the studies reporting no difference in motion showed no significant results. Future studies should address head motion as a priority and assure that groups do not differ in head motion. PMID- 28671334 TI - Alcoholic hepatitis: Continued drinking and the mourning after. PMID- 28671335 TI - Immature pea seeds: effect of storage under modified atmosphere packaging and sanitation with acidified sodium chlorite. AB - BACKGROUND: Appropriate sanitation is a priority for extending the shelf life and promoting the consumption of immature pea seeds, as processing accelerates quality deterioration and microbial growth. RESULTS: The combined effect of disinfection with acidified sodium chlorite (ASC) or sodium hypochlorite (SH) and packaging under a passive modified atmosphere (MAP) at 1 or 4 degrees C on quality was analysed. After 14 days, greenness and vitamin C had decreased, especially in the SH-disinfected samples. Total phenols and antioxidant capacity were not affected by disinfection. Proteins levels fell by around 27%, regardless of the sanitizer and storage temperature. Compared with the initial microbial load, samples stored at 1 degrees C showed an increase of 1 log CFU g-1 in psychrophiles when treated with SH, whereas no increase of note occurred with ASC. In general, microbial counts were always below 3 log CFU g-1 for all the treatments. CONCLUSION: Immature pea seeds could be stored for 14 days at 1-4 degrees C under MAP with only minor quality changes. Disinfection with ASC resulted in better sensory quality, higher content of vitamin C and lower psychrophile counts. More research is needed to analyse the effect of these treatments on other quality parameters. (c) 2017 Society of Chemical Industry. PMID- 28671336 TI - Toxicity of zearalenone on the intestines of pregnant sows and their offspring and alleviation with modified halloysite nanotubes. AB - BACKGROUND: The objective of this study was to examine the effects of maternal exposure to zearalenone (ZEN) on the intestines of pregnant sows and offspring on postnatal days (PD) 1, 21 and 188. Eighteen pregnant sows (six per treatment) were fed a control diet (ZEN, 0.03 mg kg-1 ), ZEN diet (ZEN, 2.77 mg kg-1 ) and ZEN + 1% modified halloysite nanotube (MHNT) diet (ZEN, 2.76 mg kg-1 ) respectively from gestation days (GD) 35 to 70. At the end of the experiment, three sows of each group on GD70 and the offspring on PD1, PD21 and PD188 were killed to analyze the changes of intestines. RESULTS: The results showed that ZEN caused oxidative stress, an inflammatory response, changes in the structure of jejunum and alterations of the bacterial numbers in cecal digesta in pregnant sows and PD1 and PD21 piglets. On PD188, bacterial numbers were also altered. MHNTs supplementation reduced the amount of ZEN in the intestine and reversed to a large extent the effects induced by ZEN on the intestines of pregnant sows and offspring. CONCLUSION: The results obtained from this study indicated that MHNTs treatment was beneficial for the adsorption of ZEN in the intestine of sows. (c) 2017 Society of Chemical Industry. PMID- 28671337 TI - Significant improvement in triglyceride levels after switching from ritonavir to cobicistat in suppressed HIV-1-infected subjects with dyslipidaemia. AB - OBJECTIVES: Cobicistat seems to have a low rate of adverse events compared with ritonavir. METHODS: This restrospective observational study to evaluated changes in lipid parameters and the percentage of subjects with dyslipidemia in virologically suppressed HIV-infected patients who were receiving a regimen containing darunavir/ritonavir and were then switched from ritonavir to cobicistat, carried out from December 2015 to May 2016, included 299 HIV-1 infected patients who were on stable antiretroviral treatment including darunavir/ritonavir (monotherapy, bitherapy or triple therapy for at least 6 months) and were then switched from ritonavir to cobicistat. Lipid parameters, as well as plasma HIV-1 RNA and CD4 cell counts, were recorded at baseline just before the switch, and 24 weeks after the switch. Patients were stratified according to the presence of hypercholesterolaemia [baseline total cholesterol > 200 mg/dL and/or low-density lipoprotein (LDL) cholesterol > 130 mg/dL] or hypertriglyceridaemia (baseline triglyceride levels > 200 mg/dL). RESULTS: Two hundred and ninety-nine patients were enrolled in the study. Fifty-two per cent of the total study population showed dyslipidaemia at baseline. All patients maintained HIV-1 RNA <= 50 HIV-1 RNA copies/mL at week 24. No statistically significant changes were seen in CD4 T-cell count from baseline to week 24 [654 (298) to 643 (313) cells/MUL; P = 0.173]. When patients were stratified according to the presence of hypercholesterolaemia at baseline (n = 124), significant changes were observed in total cholesterol (P < 0.001), LDL cholesterol (P = 0.047), high-density lipoprotein (HDL) cholesterol (P = 0.002) and triglyceride levels (P = 0.025), and when they were stratified according to the presence of hypertriglyceridaemia at baseline (n = 64), changes from baseline to week 24 in triglyceride level were statistically significant [median (interquartile range) 352 (223, 389) mg/dL at baseline and 229 (131, 279) mg/dL at week 24; P < 0.001]. CONCLUSIONS: Cobicistat as a booster of darunavir in HIV-infected subjects had a beneficial effect on the lipid profile in patients with hypercholesterolaemia or hypertrigliceridaemia at baseline. PMID- 28671338 TI - Mixture model analysis identifies irritable bowel syndrome subgroups characterised by specific profiles of gastrointestinal, extraintestinal somatic and psychological symptoms. AB - BACKGROUND: Current subgrouping of Irritable Bowel Syndrome (IBS) is exclusively based on stool consistency without considering other relevant gastrointestinal (GI), extraintestinal somatic or psychological features. AIM: To identify subgroups based on a comprehensive set of IBS-related parameters. METHODS: Mixture model analysis was used, with the following input variables: 13 single item scores from the IBS-specific Gastrointestinal Symptom Rating Scale, average stool consistency and frequency from a 7-day Bristol Stool Form diary, 12 single item extraintestinal symptom scores from the Patient Health Questionnaire-12, and anxiety and depression subscale scores from the Hospital Anxiety and Depression scale. The resulting latent subgroups were compared regarding symptom profiles using analysis of variance followed by pair-wise comparisons. RESULTS: One hundred and seventy-two IBS patients (Rome III; 69% female; mean age 33.7 [range 18-60] years) were included. The optimal subgrouping showed six latent groups, characterised by: (I) constipation with low comorbidities, (II) constipation with high comorbidities, (III) diarrhoea with low comorbidities, (IV) diarrhoea and pain with high comorbidities, (V) mixed GI symptoms with high comorbidities, (VI) a mix of symptoms with overall mild severity. The subgroups showed differences in the distribution of Rome III-subtypes, IBS severity, presence of anxiety and depression, and gender, but not regarding age, IBS duration or reported post infectious onset of IBS. CONCLUSIONS: This model-based subgrouping of IBS partly supports the distinction of subgroups based on bowel habits, but additionally distinguishes subgroups with or without co-morbid extraintestinal somatic and psychological symptoms. The resulting groups show specific profiles of symptom combinations. PMID- 28671339 TI - Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology. AB - The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (Hepatology 2017). PMID- 28671340 TI - Physical activity and myopia in Danish children-The CHAMPS Eye Study. AB - PURPOSE: To determine associations between physical activity (PA) and myopia in Danish school children and investigate the prevalence of myopia. METHODS: This is a prospective study with longitudinal data on PA in a Danish child cohort. Physical activity (PA) was measured objectively by repeated ActiGraph accelerometer measurement four times with different intervals (1-2.5 years) at the mean ages 9.7, 11.0, 12.9 and 15.4 years. Mean intensity of PA was estimated as counts/minutes, and time spent in sedentary, light, moderate and vigorous PA was summed using defined cut-off points. The ophthalmologic examination was conducted at the mean age of 15.4 +/- 0.7 years and included cycloplegic autorefraction and biometry. RESULTS: A total of 307 children participated in the Childhood Health, Activity, and Motor Performance School (CHAMPS) Eye Study. The cycloplegic spherical equivalent (SE) was 0.30 +/- 1.46 dioptres. The prevalence of myopia was 17.9% (SE <=-0.5 dioptres). Mean axial length (AL) was 23.5 +/- 0.9 mm. For all participants, the overall mean daily distribution of PA was 67.2% in sedentary, 25.6% in light, 4.4% in moderate and 2.9% in vigorous PA. Age- and sex adjusted linear regression showed no association between PA and SE or AL. In a prospective slope analysis, there was no association between accumulated PA during the 7 years and AL or SE. CONCLUSION: The prevalence of myopia among Danish children was 17.9%. By logistic regression and slope analysis, we found no association between PA and myopia, in this first of its kind study based on objective and repeated PA data. PMID- 28671341 TI - Ultrasound-Triggered Destruction of Folate-Functionalized Mesoporous Silica Nanoparticle-Loaded Microbubble for Targeted Tumor Therapy. AB - A multifunctional drug delivery vehicle, which combines the active targeted mesoporous silica nanoparticle (MSN) and microbubble (MB) drug delivery system, is proposed and fabricated. The resulting delivery vehicle integrates the merits of high drug loading capacity, multitargeting, and ultrasound-guided releasing. Folate (FA), which serves as an active ligand, is modified to the surface of MSN (MSN-FA) to enhance cell membrane translocation. MSN-FA is loaded with tanshinone IIA (TAN), then encapsulated in a microbubble (denoted as MSN-FA-TAN-MB) for more precise tumor targeting. The conjunction between FA and MSN is confirmed by fourier transform infrared spectroscopy (FTIR). The characteristics and morphology of MSN-FA-TAN-MB are investigated by confocal microscopy and transmission electron microscopy. In vitro cytotoxicity and cellular uptake studies of MSN-FA-TAN-MB are conducted on A549 and HeLa tumor cells. FA facilitated MSN-FA-TAN uptake is shown by HeLa cells that overexpress FA receptors via a FA-receptor-mediated endocytosis mechanism. The ultrasound response property of MSN-FA-TAN-MB is also verified. MSN-FA-TAN-MB shows significant antitumor efficacy in vivo with the assistance of FA, MB, and an external ultrasound irradiation. Thus, this multifunctional vehicle may provide a novel strategy for tumor targeting and imaging in tumor therapy. PMID- 28671342 TI - Nuclear Spin Isomers: Engineering a Et4 N[DyPc2 ] Spin Qudit. AB - Two dysprosium isotopic isomers were synthesized: Et4 N[163 DyPc2 ] (1) with I=5/2 and Et4 N[164 DyPc2 ] (2) with I=0 (where Pc=phthalocyaninato). Both isotopologues are single-molecule magnets (SMMs); however, their relaxation times as well as their magnetic hystereses differ considerably. Quantum tunneling of the magnetization (QTM) at the energy level crossings is found for both systems via ac-susceptibility and MU-SQUID measurements. MU-SQUID studies of 1(I=5/2) reveal several nuclear-spin-driven QTM events; hence determination of the hyperfine coupling and the nuclear quadrupole splitting is possible. Compound 2(I=0) shows only strongly reduced QTM at zero magnetic field. 1(I=5/2) could be used as a multilevel nuclear spin qubit, namely qudit (d=6), for quantum information processing (QIP) schemes and provides an example of novel coordination-chemistry-discriminating nuclear spin isotopes. Our results show that the nuclear spin of the lanthanide must be included in the design principles of molecular qubits and SMMs. PMID- 28671343 TI - Inactivation of Zika virus in platelet components using amotosalen and ultraviolet A illumination. AB - BACKGROUND: Concerned over the risk of Zika virus (ZIKV) transfusion transmission, public health agencies recommended the implementation of mitigation strategies for its prevention. Those strategies included the use of pathogen inactivation for the treatment of plasma and platelets. The efficacy of amotosalen/ultraviolet A to inactivate ZIKV in plasma had been previously demonstrated, and the efficacy of inactivation in platelets with the same technology was assumed. These studies quantify ZIKV inactivation in platelet components using amotosalen/ultraviolet A. STUDY DESIGN AND METHODS: Platelet components were spiked with ZIKV, and ZIKV infectious titers and RNA loads were measured by cell culture-based assays and real-time polymerase chain reaction in spiked platelet components before and after photochemical treatment using amotosalen/ultraviolet A. RESULTS: The mean ZIKV infectivity titers and RNA loads in platelet components before inactivation were either 4.9 log10 plaque forming units per milliliter, or 4.4 log10 50% tissue culture infective dose per milliliter and 7.5 log10 genome equivalents per milliliter, respectively. No infectivity was detected immediately after amotosalen/ultraviolet A treatment. No replicative virus remained after treatment, as demonstrated by multiple passages on Vero cell cultures; and ZIKV RNA was not detected from the first passage after inactivation. Additional experiments in this study demonstrated efficient inactivation to the limit of detection in platelets manufactured in 65% platelet additive solution, 35% plasma, or 100% plasma. CONCLUSION: As previously demonstrated for plasma, robust levels of ZIKV inactivation were achieved in platelet components. With inactivation of higher levels of ZIKV than those reported in asymptomatic, RNA-reactive blood donors, the pathogen-inactivation system using amotosalen/ultraviolet A offers the potential to mitigate the risk of ZIKV transmission by plasma and platelet transfusion. PMID- 28671344 TI - Direct Alkylation of Amines with Primary and Secondary Alcohols through Biocatalytic Hydrogen Borrowing. AB - The reductive aminase from Aspergillus oryzae (AspRedAm) was combined with a single alcohol dehydrogenase (either metagenomic ADH-150, an ADH from Sphingobium yanoikuyae (SyADH), or a variant of the ADH from Thermoanaerobacter ethanolicus (TeSADH W110A)) in a redox-neutral cascade for the biocatalytic alkylation of amines using primary and secondary alcohols. Aliphatic and aromatic secondary amines were obtained in up to 99 % conversion, as well as chiral amines directly from the racemic alcohol precursors in up to >97 % ee, releasing water as the only byproduct. PMID- 28671345 TI - Platelet RNA as a circulating biomarker trove for cancer diagnostics. AB - Platelets are multifunctional cell fragments, circulating in blood in high abundance. Platelets assist in thrombus formation, sensing of pathogens entering the blood stream, signaling to immune cells, releasing vascular remodeling factors, and, negatively, enhancing cancer metastasis. Platelets are 'educated' by their environment, including in patients with cancer. Cancer cells appear to initiate intraplatelet signaling, resulting in splicing of platelet pre-mRNAs, and enhance secretion of cytokines. Platelets can induce leukocyte and endothelial cell modeling factors, for example, through adenine nucleotides (ATP), thereby facilitating extravasation of cancer cells. Besides releasing factors, platelets can also sequester RNAs and proteins released by cancer cells. Thus, platelets actively respond to queues from local and systemic conditions, thereby altering their transcriptome and molecular content. Platelets contain a rich repertoire of RNA species, including mRNAs, small non-coding RNAs and circular RNAs; although studies regarding the functionality of the various platelet RNA species require more attention. Recent advances in high-throughput characterization of platelet mRNAs revealed 10 to > 1000 altered mRNAs in platelets in the presence of disease. Hence, platelet RNA appears to be dynamically affected by pathological conditions, thus possibly providing opportunities to use platelet RNA as diagnostic, prognostic, predictive, or monitoring biomarkers. In this review, we cover the literature regarding the platelet RNA families, processing of platelet RNAs, and the potential application of platelet RNA as disease biomarkers. PMID- 28671346 TI - Prothrombotic aspects of sickle cell disease. AB - Sickle cell disease (SCD) is a hematologic disorder caused by a well characterized point mutation in the beta-globin gene. Abnormal polymerization of hemoglobin tetramers results in the formation of sickle red blood cells that leads to vascular occlusions, hemolytic anemia, vascular inflammation and cumulative, multiple organ damage. Ongoing activation of coagulation is another hallmark of SCD. Recent studies strongly suggested that hypercoagulation in SCD is not just a secondary event but contributes directly to the disease pathophysiology. In this article we summarize mechanisms leading to the activation of coagulation, review data indicating direct contribution of coagulation to the pathology of SCD and, we discuss the anticoagulation as a possible treatment strategy to attenuate the disease progression. PMID- 28671347 TI - Diagnosis of acute pulmonary embolism. AB - Advances in the management of patients with suspected pulmonary embolism (PE) have improved diagnostic accuracy and made management algorithms safer, easier to use, and well standardized. These diagnostic algorithms are mainly based on the assessment of clinical pretest probability, D-dimer measurement, and imaging tests-predominantly computed tomography pulmonary angiography. These diagnostic algorithms allow safe and cost-effective diagnosis for most patients with suspected PE. In this review, we summarize signs and symptoms of PE, current existing evidence for PE diagnosis, and focus on the challenge of diagnosing PE in special patient populations, such as pregnant women, or patients with a prior VTE. We also discuss novel imaging tests for PE diagnosis and highlight some of the additional challenges that might require adjustments to current diagnostic strategies, such as the reduced clinical suspicion threshold, resulting in a lower proportion of PE among suspected patients as well as the overdiagnosis of subsegmental PE. PMID- 28671348 TI - Novel insights into the regulation of coagulation by factor V isoforms, tissue factor pathway inhibitoralpha, and protein S. AB - Factor V (FV) is a regulator of both pro- and anticoagulant pathways. It circulates as a single-chain procofactor, which is activated by thrombin or FXa to FVa that serves as cofactor for FXa in prothrombin activation. The cofactor function of FVa is regulated by activated protein C (APC) and protein S. FV can also function as an anticoagulant APC cofactor in the inhibition of FVIIIa in the membrane-bound tenase complex (FIXa/FVIIIa). In recent years, it has become clear that FV also functions in multiple ways in the tissue factor pathway inhibitor (TFPI) anticoagulant pathway. Of particular importance is a FV splice variant (FV Short) that serves as a carrier and cofactor to TFPIalpha in the inhibition of FXa. FV-Short is generated through alternative splicing of exon 13 that encodes the large activation B domain. A highly negatively charged binding site for TFPIalpha is exposed in the C-terminus of the FV-Short B domain, which binds the positively charged C-terminus of TFPIalpha, thus keeping TFPIalpha in circulation. The binding of TFPIalpha to FV-Short is also instrumental in localizing the inhibitor to the surface of negatively charged phospholipids, where TFPIalpha inhibits FXa in process that is stimulated by protein S. Plasma FV activation intermediates and partially proteolyzed platelet FV similarly bind TFPIalpha with high affinity and regulate formation of prothrombinase. The novel insights gained into the interaction between FV isoforms, TFPIalpha, and protein S have opened a new avenue for research about the mechanisms of coagulation regulation and also for future development of therapeutics aimed at modulating coagulation. PMID- 28671349 TI - High-throughput sequencing approaches for diagnosing hereditary bleeding and platelet disorders. AB - Hereditary bleeding and platelet disorders (BPDs) are characterized by marked genetic heterogeneity, far greater than previously appreciated. The list of genes involved in the regulation of megakaryopoiesis, platelet formation, platelet function and bleeding has been growing rapidly since the introduction of high throughput sequencing (HTS) approaches in research. Thanks to the gradual adoption of HTS in diagnostic practice, these discoveries are improving the diagnostic yield for BPD patients, who may or may not present with bleeding problems and often have other clinical symptoms unrelated to the blood system. However, it was previously found that screening for all known etiologies gives a diagnostic yield of over 90% when the phenotype closely matches a known BPD but drops to 10% when the phenotype is indicative of a novel disorder. Thus, further research is needed to identify currently unknown etiologies for BPDs. Novel genes are likely to be found to be implicated in BPDs. New modes of inheritance, including digenic inheritance, are likely to play a role in some cases. Additionally, identifying and interpreting pathogenic variants outside exons is a looming challenge that can only be tackled with an improved understanding of the regulatory landscape of relevant cell types and with the transition from targeted sequencing to whole-genome sequencing in the clinic. PMID- 28671350 TI - von Willebrand factor and inflammation. AB - Von Willebrand factor (VWF) is a plasma glycoprotein best known for its crucial hemostatic role in serving as a molecular bridge linking platelets to subendothelial components following vascular injury. In addition, VWF functions as chaperone for coagulation factor VIII. In pathological settings, VWF is recognized as a risk factor for both arterial and venous thrombosis, as well as a molecular player that directly promotes the thrombotic process. Recent years have seen the emergence of the concept of immuno-thrombosis by which inflammatory cells participate in thrombotic processes. In return, reports about the involvement of hemostatic proteins or cells (such as platelets) in inflammatory responses have become increasingly common, emphasizing the intricate link between hemostasis and inflammation. However, evidence of a link between VWF and inflammation arose much earlier than these recent developments. At first, VWF was considered only as a marker of inflammation in various pathologies, due to its acute release by the activated endothelium. Later on, a more complex role of VWF in inflammation was uncovered, owing to its capacity to direct the biogenesis of specific endothelial organelles, the Weibel-Palade bodies that contain known inflammation players such as P-selectin. Finally, a more direct link between VWF and inflammation has become apparent with the discovery that VWF is able to recruit leukocytes, either via direct leukocyte binding or by recruiting platelets which in turn will attract leukocytes. This review will focus on these different aspects of the connection between VWF and inflammation, with particular emphasis on VWF-leukocyte interactions. PMID- 28671351 TI - Homeostatic effects of coagulation protease-dependent signaling and protease activated receptors. AB - A homeostatic function of the coagulation system in regard to hemostasis is well established. Homeostasis of blood coagulation depends partially on protease activated receptor (PAR)-signaling. Beyond coagulation proteases, numerous other soluble and cell-bound proteases convey cellular effects via PAR signaling. As we learn more about the mechanisms underlying cell-, tissue-, and context-specific PAR signaling, we concurrently gain new insights into physiological and pathophysiological functions of PARs. In this regard, regulation of cell and tissue homeostasis by PAR signaling is an evolving scheme. Akin to the control of blood clotting per se (the fibrin-platelet interaction) coagulation proteases coordinately regulate cell- and tissue-specific functions. This review summarizes recent insights into homeostatic regulation through PAR signaling, focusing on blood coagulation proteases. Considering the common use of drugs altering coagulation protease activity through either broad or targeted inhibitory activities, and the advent of PAR modulating drugs, an in-depth understanding of the mechanisms through which coagulation proteases and PAR signaling regulate not only hemostasis, but also cell and tissue homeostasis is required. PMID- 28671353 TI - Retinal venous pressure is higher than the airway pressure and the intraocular pressure during the Valsalva manoeuvre. AB - PURPOSE: The aims of this prospective experimental study were to explore the influence of the Valsalva manoeuvre (VM) on retinal venous pressure (RVP) in human volunteers in a university setting and to establish correlations for RVP with the increase in airway pressure (?AirP) and in intraocular pressure (?IOP). METHODS: In total, 31 healthy young volunteers (age: 24 +/- 1.7 years) were investigated. The instruments used included a dynamic contour tonometer, a contact lens dynamometer (Imedos) and an electronic pressure transducer for measuring airway pressure. The following measurements were successively performed in left eyes: tonometry, dynamometry, repeated simultaneous dynamometry and airway pressure measurement during the VM and tonometry during the VM. The pressures obtained during the VM were determined at 10, 20 and 30 seconds after onset of the VM by linear interpolation. RESULTS: The pressures (in mmHg) at baseline and during the VM (median and range with outliers) were as follows: ?AirP: 10 seconds: 10.0 (7.5); 20 seconds: 12.5 (11.0); and 30 seconds: 11.0 (10.0); and RVP: Start: 17.1 (2.4); 10 seconds: 26.0 (7.5); 20 seconds: 25.0 (6.5); and 30 seconds: 24.0 (6.0). During the VM, the RVP was significantly increased compared with the ?AirP (p = 0.0017). The IOP during the VM was 13.5 (2.7), and the increase in IOP (?IOP) was 0.8 (5.6). CONCLUSION: During the VM, the RVP was increased compared with the ?AirP. The increase in RVP (?RVP) was significantly greater than the ?IOP. During the VM, the calculated retinal perfusion pressure may be more strongly reduced by the ?RVP than by the ?IOP. These properties may influence retinal and optic nerve head pathophysiology. PMID- 28671352 TI - Transcriptional profiling of articular cartilage in a porcine model of early post traumatic osteoarthritis. AB - To identify the molecular pathophysiology present in early post-traumatic osteoarthritis (PTOA), the transcriptional profile of articular cartilage and its response to surgical PTOA induction were determined. Thirty six Yucatan minipigs underwent anterior cruciate ligament (ACL) transection and were randomly assigned in equal numbers to no further treatment, reconstruction or ligament repair. Cartilage was harvested at 1 and 4 weeks post-operatively and histology and RNA sequencing were performed and compared to controls. Microscopic cartilage scores significantly worsened at 1 (p = 0.028) and 4 weeks (p = 0.001) post-surgery relative to controls, but did not differ between untreated, reconstruction or repair groups. Gene expression after ACL reconstruction and ACL transection were similar, with only 0.03% (including SERPINB7 and CR2) and 0.2% of transcripts (including INHBA) differentially expressed at 1 and 4 weeks respectively. COL2A1, COMP, SPARC, CHAD, and EF1ALPHA were the most highly expressed non ribosomal, non mitochondrial genes in the controls and remained abundant after surgery. A total of 1,275 genes were differentially expressed between 1 and 4 weeks post-surgery. With the treatment groups pooled, 682 genes were differentially expressed at both time-points, with the most significant changes observed in MMP1, COCH, POSTN, CYTL1, and PTGFR. This study confirmed the development of a microscopic PTOA stage after ACL surgery in the porcine model. Upregulation of multiple proteases (including MMP1 and ADAMTS4) were found; however, the level of expression remained orders of magnitude below that of extracellular matrix protein-coding genes (including COL2A1 and ACAN). In summary, genes with established roles in PTOA as well as novel targets for specific intervention were identified. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:318-329, 2018. PMID- 28671354 TI - Preparing for Value-Based Payment: Five Essential Skills for Success. PMID- 28671355 TI - When It Comes to Quality, It's Not All About You. PMID- 28671356 TI - Lessons From the Road to EHR Usability. PMID- 28671357 TI - Keeping Your Practice Going When You Can't. PMID- 28671358 TI - A Simple Approach to Shared Decision Making in Cancer Screening. PMID- 28671359 TI - Making Sense of MACRA: Advancing Care Information and Improvement Activities. PMID- 28671367 TI - Use of Media by School-Aged Children and Adolescents: A Policy Statement from the AAP. PMID- 28671368 TI - Acupuncture for Migraine Prevention. PMID- 28671360 TI - Using Alcohol Screening and Brief Intervention to Address Patients' Risky Drinking. PMID- 28671369 TI - Arthroscopic Meniscal Surgery Is Equivalent to Nonoperative Management. PMID- 28671370 TI - Developmental Delay: When and How to Screen. AB - An estimated 15% of children in the United States have at least one developmental delay, yet less than one-fifth of those children receive early intervention services before three years of age. Many barriers exist to implementing initial screening and referral, but screening tools can be easily incorporated into the workflow of the primary care practice with preparation. The use of a validated screening tool at regular, repeated intervals, in addition to physician surveillance at well-child visits, may improve early detection. Early intervention is effective in high-risk children and associated with improvements in cognitive and academic performance. Parent-completed tools are preferable to directly administered tools in the primary care setting because of time constraints. The most extensively evaluated parentcompleted tools are the Ages and Stages Questionnaire and the Parents' Evaluation of Developmental Status. Family physicians should be familiar with currently available screening tools and the limitations and strengths of these tools. Additional evaluations and referrals are recommended if screening suggests developmental delays are present. PMID- 28671372 TI - Drug Price Gouging: When Will it End? PMID- 28671371 TI - Problematic Jumps in Drug Prices and What You Can Do. PMID- 28671373 TI - Gluten-Free Diet for Irritable Bowel Syndrome. PMID- 28671374 TI - Pigmented Lesion with a Depigmented Rim. PMID- 28671375 TI - Surgery vs. Medical Therapy for Heavy Menstrual Bleeding. PMID- 28671377 TI - AFP News: AFP Edition. PMID- 28671376 TI - Insomnia: Pharmacologic Therapy. AB - Insomnia accounts for more than 5.5 million visits to family physicians each year. Although behavioral interventions are the mainstay of treatment, pharmacologic therapy may be necessary for some patients. Understanding the risks and benefits of insomnia medications is critical. Controlled-release melatonin and doxepin are recommended as first-line agents in older adults; the so-called z drugs (zolpidem, eszopiclone, and zaleplon) should be reserved for use if the first-line agents are ineffective. For the general population with difficulty falling asleep, controlled-release melatonin and the z-drugs can be considered. For those who have difficulty staying asleep, low-dose doxepin and the z-drugs should be considered. Benzodiazepines are not recommended because of their high abuse potential and the availability of better alternatives. Although the orexin receptor antagonist suvorexant appears to be relatively effective, it is no more effective than the z-drugs and much more expensive. Sedating antihistamines, antiepileptics, and atypical antipsychotics are not recommended unless they are used primarily to treat another condition. Persons with sleep apnea or chronic lung disease with nocturnal hypoxia should be evaluated by a sleep specialist before sedating medications are prescribed. PMID- 28671378 TI - Acute and Chronic Paronychia. AB - Paronychia is inflammation of the fingers or toes in one or more of the three nail folds. Acute paronychia is caused by polymicrobial infections after the protective nail barrier has been breached. Treatment consists of warm soaks with or without Burow solution or 1% acetic acid. Topical antibiotics should be used with or without topical steroids when simple soaks do not relieve the inflammation. The presence of an abscess should be determined, which mandates drainage. There are a variety of options for drainage, ranging from instrumentation with a hypodermic needle to a wide incision with a scalpel. Oral antibiotics are usually not needed if adequate drainage is achieved unless the patient is immunocompromised or a severe infection is present. Therapy is based on the most likely pathogens and local resistance patterns. Chronic paronychia is characterized by symptoms of at least six weeks' duration and represents an irritant dermatitis to the breached nail barrier. Common irritants include acids, alkalis, and other chemicals used by housekeepers, dishwashers, bartenders, florists, bakers, and swimmers. Treatment is aimed at stopping the source of irritation while treating the inflammation with topical steroids or calcineurin inhibitors. More aggressive techniques may be required to restore the protective nail barrier. Treatment may take weeks to months. Patient education is paramount to reduce the recurrence of acute and chronic paronychia. PMID- 28671379 TI - Tenofovir for Prevention of HIV Infection. PMID- 28671380 TI - Paronychia: What You Should Know. PMID- 28671381 TI - Pharmacologic Treatment of Hypertension: ACP and AAFP Release Recommendations for Adults 60 Years and Older. PMID- 28671382 TI - Antibiotic Prophylaxis in Patients with Cirrhosis and Upper Gastrointestinal Bleeding. PMID- 28671383 TI - One-Third of Adults with Diagnosed Asthma Can Be Weaned Off All Asthma Medications. PMID- 28671384 TI - Beta2 Agonists for Acute Cough or a Clinical Diagnosis of Acute Bronchitis. PMID- 28671385 TI - Citrate Salts for Preventing and Treating Calcium-Containing Kidney Stones in Adults. PMID- 28671386 TI - Estimating Cardiovascular Risk. PMID- 28671387 TI - Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older: A Guideline You Can Trust. PMID- 28671389 TI - Oral NSAIDs for Perineal Pain in the Early Postpartum Period. PMID- 28671390 TI - Severe Male Breast Enlargement. PMID- 28671391 TI - Health Maintenance in Postmenopausal Women. AB - Cardiovascular disease is the leading cause of death and disability in postmenopausal women older than 50 years. Clinicians should use the pooled cohort risk assessment equations or another risk calculator every three to five years to estimate a woman's 10-year risk of atherosclerotic cardiovascular disease, including myocardial infarction and stroke. Major guidelines concur that women at average risk of breast cancer benefit from screening mammography at least every other year from 50 to 74 years of age. Several effective options for colorectal cancer screening are recommended for women 50 to 75 years of age. Cervical cancer screening should occur at three- or five-year intervals depending on the test used, and can generally be discontinued after 65 years of age or total hysterectomy for benign disease. Screening for ovarian cancer is not recommended. Clinicians should consider screening for sexually transmitted infections in older women at high risk. Postmenopausal women should be routinely screened for depression, alcohol abuse, and intimate partner violence. PMID- 28671392 TI - Recreational Waterborne Illnesses: Recognition, Treatment, and Prevention. AB - Illness after recreational water activities can be caused by a variety of agents, including bacteria, viruses, parasites, algae, and even chlorine gas. These illnesses are more common in summer. Waterborne illnesses are underreported because most recreational activity occurs in unsupervised venues or on private property, and participants tend to disperse before illness occurs. Symptoms of waterborne illness are primarily gastrointestinal, but upper respiratory and skin manifestations also occur. Gastrointestinal symptoms are usually self-limited, and supportive treatment may be all that is necessary. However, some infections can cause significant morbidity and mortality. Cryptosporidium and Giardia intestinalis are the most common cause of gastrointestinal illness and have partial chlorine resistance. Respiratory infections are typically mild and self limited. However, if legionnaires' disease develops and is unrecognized, mortality may be as high as 10%. Cellulitis caused by Vibrio vulnificus can result in serious illness, amputation, and death. Early and appropriate antibiotic treatment is important. Chronically ill and immunocompromised persons are at high risk of infection and should be counseled accordingly. PMID- 28671393 TI - Top 20 Research Studies of 2016 for Primary Care Physicians. AB - This article summarizes the top 20 original research studies and four practice guidelines of 2016, based on regular literature surveillance and as selected by members of the Canadian Medical Association. The studies, known as POEMs (patient oriented evidence that matters), were rated highly because of their relevance, validity, and potential to change practice. Key hypertension treatment findings include reduced mortality (a benefit not demonstrated in lower-risk persons or persons with diabetes mellitus) but also an increase in harms with a more aggressive blood pressure target in high-risk persons with hypertension and without diabetes. Additionally, one study found that cardiovascular events are rare in patients who meet the criteria for hypertensive urgency. Regarding respiratory conditions, the combination of fluticasone and salmeterol is preferred to fluticasone alone in patients with moderate to severe asthma; nasal irrigation but not steam inhalation is beneficial for patients with chronic sinus symptoms; and delayed prescriptions reduce antibiotic use in patients with symptoms of acute respiratory infection. Studies on musculoskeletal topics found that of the nonsteroidal anti-inflammatory drugs currently available, diclofenac is most likely to be effective for hip or knee osteoarthritis; the benefits of opioids in patients with chronic low back pain are limited and not clearly superior to nonsteroidal anti-inflammatory drugs; and hip radiography is not helpful for diagnosing osteoarthritis of the hip. Regarding diabetes and obesity, the Mediterranean diet is more effective than a low-fat diet for weight loss, and aggressive blood pressure targets are not recommended in patients with diabetes, especially older persons. Other recommendations include use of an oral syringe rather than a medicine cup to measure liquid medications for children, and abrupt smoking cessation preceded by two weeks of nicotine replacement via a patch, rather than a slow phasing out of tobacco use. Finally, although azithromycin has a slightly higher failure rate than doxycycline for the treatment of chlamydia, it still cured 97% of patients in a randomized trial. PMID- 28671395 TI - Treatment of Chronic Insomnia in Adults: ACP Guideline. PMID- 28671394 TI - Waterborne Illnesses. PMID- 28671396 TI - Exophytic Digital Lesion. PMID- 28671397 TI - Screening for Colorectal Cancer. PMID- 28671398 TI - Should Screening Techniques for Colorectal Cancer All Have an 'A' Recommendation? No: When It Comes to Colorectal Cancer Screening, Test Choice Matters. PMID- 28671399 TI - Should Screening Techniques for Colorectal Cancer All Have an 'A' Recommendation? Yes: All Conventional Screening Techniques Should Have an 'A' Recommendation. PMID- 28671400 TI - More Accurate Prediction of the Pretest Probability of Cardiovascular Disease with European Risk Score. PMID- 28671401 TI - Folic Acid Supplementation for the Prevention of Neural Tube Defects: Recommendation Statement. PMID- 28671402 TI - Laceration Repair: A Practical Approach. AB - The goals of laceration repair are to achieve hemostasis and optimal cosmetic results without increasing the risk of infection. Many aspects of laceration repair have not changed over the years, but there is evidence to support some updates to standard management. Studies have been unable to define a "golden period" for which a wound can safely be repaired without increasing risk of infection. Depending on the type of wound, it may be reasonable to close even 18 or more hours after injury. The use of nonsterile gloves during laceration repair does not increase the risk of wound infection compared with sterile gloves. Irrigation with potable tap water rather than sterile saline also does not increase the risk of wound infection. Good evidence suggests that local anesthetic with epinephrine in a concentration of up to 1:100,000 is safe for use on digits. Local anesthetic with epinephrine in a concentration of 1:200,000 is safe for use on the nose and ears. Tissue adhesives and wound adhesive strips can be used effectively in low-tension skin areas. Wounds heal faster in a moist environment and therefore occlusive and semiocclusive dressings should be considered when available. Tetanus prophylaxis should be provided if indicated. Timing of suture removal depends on location and is based on expert opinion and experience. PMID- 28671403 TI - Refractive Eye Surgery: Helping Patients Make Informed Decisions About LASIK. AB - A variety of refractive surgery techniques, which reshape the corneal stroma using laser energy, have been marketed as simple and safe alternatives to glasses or contact lenses. Laser-assisted in-situ keratomileusis (LASIK) is the most common of these procedures. Although there are few high-quality prospective studies of long-term outcomes, complications, or stability for refractive surgery procedures, there is at least general agreement that more than 90% of appropriately selected patients achieve excellent uncorrected distance vision. In addition to well-recognized contraindications (e.g., unstable refraction, pregnancy and lactation, chronic eye disease, systemic illness, corneal abnormalities), there are other conditions that warrant caution (e.g., excessively dry eyes, contact lens intolerance, chronic pain syndromes). Postoperative dry eye, which may in part represent a corneal neuropathy, usually resolves after six to 12 months but persists in up to 20% of patients. Up to 20% of patients may have new visual disturbances, particularly with night driving. Vision-threatening complications are rare. Intraocular lenses, implanted following cataract extraction, may be an alternative to LASIK in older patients. Although the overall dependence on corrective lenses is markedly reduced, many patients still require glasses or contact lenses after LASIK, particularly in low light conditions and as they age. Most patients report satisfaction with the results. Family physicians can help patients make informed decisions by exploring their values, preferences, expectations, and tolerance of uncertainty and risk. PMID- 28671404 TI - Topiramate and Amitriptyline Not Effective for Migraine in Children. PMID- 28671406 TI - Pelvic Floor Exercises Modestly Improve Pelvic Floor Prolapse Symptoms. PMID- 28671408 TI - Sofosbuvir/Velpatasvir (Epclusa) for Hepatitis C. PMID- 28671407 TI - Perioperative Cardiovascular Medication Management in Noncardiac Surgery: Common Questions. AB - Several medications have been used perioperatively in patients undergoing noncardiac surgery in an attempt to improve outcomes. Antiplatelet therapy for primary prevention of cardiovascular events should generally be discontinued seven to 10 days before surgery to avoid increasing the risk of bleeding, unless the risk of a major adverse cardiac event exceeds the risk of bleeding. Antiplatelet therapy for secondary prevention should be continued perioperatively, except before procedures with very high bleeding risk, such as intracranial procedures. Antiplatelet drugs should be continued and surgery delayed, if possible, for at least 14 days after percutaneous coronary intervention without stent placement, 30 days after percutaneous coronary intervention with bare-metal stent placement, and six to 12 months after percutaneous coronary intervention with drug-eluting stent placement. Perioperative beta blockers are recommended for patients already receiving these agents, and it is reasonable to consider starting therapy in patients with known or strongly suspected coronary artery disease or who are at high risk of perioperative cardiac events and are undergoing procedures with a high risk of cardiovascular complications. Long-term statin therapy should be continued perioperatively or started in patients with clinical indications who are not already receiving statins. Clonidine should not be started perioperatively, but long-term clonidine regimens may be continued. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers generally can be continued perioperatively if patients are hemodynamically stable and have good renal function and normal electrolyte levels. PMID- 28671410 TI - Venous Leg Ulcers. PMID- 28671409 TI - Providing Trauma-Informed Care. PMID- 28671411 TI - LASIK: What You Should Know. PMID- 28671412 TI - SIDS and Safe Sleeping Environments for Infants: AAP Updates Recommendations. PMID- 28671413 TI - Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms. AB - Alzheimer disease comprises a syndrome of progressive cognitive and functional decline. Treatments should target cognitive and functional symptoms. Cholinesterase inhibitors, memantine, and a combination of a cholinesterase inhibitor and memantine have produced statistically significant but clinically small delays in various domains of cognitive and functional decline in select patients with Alzheimer disease. Vitamin E has been shown to delay functional decline in patients with mild to moderate Alzheimer disease, especially when taken in combination with a cholinesterase inhibitor. Structured programs of physical exercise improve physical function and reduce rates of neuropsychiatric symptoms in patients with mild to severe Alzheimer disease. Cognitive stimulation programs show benefit in maintenance of cognitive function and improved self reported quality of life in patients with mild to moderate Alzheimer disease. PMID- 28671414 TI - Bariatric Surgery Improves Quality of Life and Results in More Weight Loss Than Intensive Medical Therapy. PMID- 28671415 TI - Correction. PMID- 28671416 TI - Dementia Care: More Than Just Prescription Drugs. PMID- 28671417 TI - Serologic Screening for Genital Herpes Infection. PMID- 28671418 TI - Serologic Screening for Genital Herpes Infection: Recommendation Statement. PMID- 28671419 TI - Erythematous Papules on Dorsum of Both Hands. PMID- 28671420 TI - Family Physicians Practicing High-Volume Obstetric Care Have Recently Dropped by One-Half. PMID- 28671421 TI - Idarucizumab (Praxbind) for Dabigatran (Pradaxa) Anticoagulant Reversal. PMID- 28671423 TI - Paradoxical Insomnia: Misperception of Sleep Can Be a Tormenting Experience. PMID- 28671424 TI - Nonalcoholic Fatty Liver Disease: Identifying Patients at Risk of Inflammation or Fibrosis. PMID- 28671425 TI - Slipped Capital Femoral Epiphysis: Diagnosis and Management. AB - Slipped capital femoral epiphysis (SCFE) is the most common hip disorder in adolescents, occurring in 10.8 per 100,000 children. SCFE usually occurs in those eight to 15 years of age and is one of the most commonly missed diagnoses in children. SCFE is classified as stable or unstable based on the stability of the physis. It is associated with obesity, growth spurts, and (occasionally) endocrine abnormalities such as hypothyroidism, growth hormone supplementation, hypogonadism, and panhypopituitarism. Patients with SCFE usually present with limping and poorly localized pain in the hip, groin, thigh, or knee. Diagnosis is confirmed by bilateral hip radiography, which should include anteroposterior and frog-leg views in patients with stable SCFE, and anteroposterior and cross-table lateral views in unstable SCFE. The goals of treatment are to prevent slip progression and avoid complications such as avascular necrosis, chondrolysis, and femoroacetabular impingement. Stable SCFE is usually treated using in situ screw fixation. Treatment of unstable SCFE also usually involves in situ fixation, but there is controversy about timing of surgery and the value of reduction. Postoperative rehabilitation of patients with SCFE may follow a five-phase protocol. PMID- 28671426 TI - Vaccine Adverse Events: Separating Myth from Reality. AB - Vaccines are one of the most successful medical advances in modern times. Most vaccine-preventable illnesses are unfamiliar to modern parents. Because of this, parents are increasingly questioning the necessity of immunizing their children, especially because no vaccine is completely free of adverse effects or the risk of complications. Family physicians should be aware of the risks and benefits of recommended immunizations. Thimerosal is currently used only in multidose vials of influenza vaccine, and exposure through vaccines is not associated with adverse neurologic outcomes. The measles, mumps, and rubella vaccine is not associated with autism. Vaccines are associated with local reactions, such as pain and erythema. The rotavirus vaccine minimally increases the rate of intussusception, whereas other vaccines minimally increase the risk of syncope. Although immunization with the human papillomavirus vaccine is recommended for all boys and girls, vaccination rates remain low. Physicians should guide parents to credible resources if they are considering vaccine refusal. If a recommended vaccine is refused, proper documentation is essential. The Vaccine Adverse Event Reporting System and National Vaccine Injury Compensation Program track adverse events and allow compensation for documented harms from vaccinations. PMID- 28671427 TI - Fluoroquinolones for Sinusitis Should Be Used As a Last Resort. PMID- 28671428 TI - New Terminology from the National Pressure Ulcer Advisory Panel. PMID- 28671429 TI - Clarification on Zika Vectors in the United States. PMID- 28671430 TI - Vaccinations. PMID- 28671431 TI - Acne Vulgaris: Treatment Guidelines from the AAD. PMID- 28671432 TI - Antibiotics May Equal Surgery for Children with Appendicitis. PMID- 28671433 TI - Efficacy of Direct-Acting Antivirals Compared with Older Agents for Hepatitis C. PMID- 28671434 TI - Bare Arm Best for Blood Pressure Measurement. PMID- 28671435 TI - Comparative Accuracy of Diagnostic Tests for Celiac Disease. PMID- 28671436 TI - Physical Fitness Training for Patients with Stroke. PMID- 28671437 TI - Expanded Newborn Screening: Information and Resources for the Family Physician. AB - Each year, 4 to 5 million newborns receive state-mandated screening. Although the Advisory Committee on Heritable Disorders in Newborns and Children has identified 34 core conditions that should be incorporated into screening programs, each state manages, funds, and maintains its own program. State programs encompass screening, as well as the diagnosis and coordination of care for newborns with positive findings. Testing for core disorders is fairly standardized, but more extensive screening varies widely by state, and the rigorous evaluation of new screening panels is ongoing. The core panel includes testing for three main categories of disorders: metabolic disorders (e.g., amino acid and urea cycle, fatty acid oxidation, and organic acid disorders); hemoglobinopathies; and a group of assorted conditions, including congenital hearing loss. Family physicians must be familiar with the expanded newborn screening tests to effectively communicate results to parents and formulate interventions. They must also recognize signs of metabolic disorders that may not be detected by screening tests or that may not be a part of standard newborn screening in their state. For infants with positive screening results leading to diagnosis, long-term follow-up involves ongoing parental education, regular medical examinations, management at a metabolic treatment center, and developmental and neuropsychological testing to detect associated disorders in time for early intervention. PMID- 28671438 TI - Rash Inside the Mouth. PMID- 28671440 TI - Hormonal Contraceptives in Women Who Are Overweight or Obese. PMID- 28671441 TI - Self-Monitoring and Self-Management of Oral Anticoagulation. PMID- 28671442 TI - Acting on Social Determinants of Health: A Primer for Family Physicians. PMID- 28671443 TI - Subclinical Hyperthyroidism: When to Consider Treatment. AB - Subclinical hyperthyroidism is defined by a low or undetectable serum thyroid stimulating hormone level, with normal free thyroxine and total or free triiodothyronine levels. It can be caused by increased endogenous production of thyroid hormone (e.g., in Graves disease, toxic nodular goiter, or transient thyroiditis), by administration of thyroid hormone to treat malignant thyroid disease, or by unintentional excessive replacement therapy. The prevalence of subclinical hyperthyroidism in the general population is about 1% to 2%; however, it may be higher in iodinedeficient areas. The rate of progression to overt hyperthyroidism is higher in persons with thyroid-stimulating hormone levels less than 0.1 mIU per L than in persons with low but detectable thyroid-stimulating hormone levels. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and heart failure in older adults, increased cardiovascular and all-cause mortality, and decreased bone mineral density and increased bone fracture risk in postmenopausal women. However, the effectiveness of treatment in preventing these conditions is unclear. A possible association between subclinical hyperthyroidism and quality-of-life parameters and cognition is controversial. The U.S. Preventive Services Task Force found insufficient evidence to assess the balance of benefits and harms of screening for thyroid dysfunction in asymptomatic persons. The American Thyroid Association and the American Association of Clinical Endocrinologists recommend treating patients with thyroid-stimulating hormone levels less than 0.1 mIU per L if they are older than 65 years or have comorbidities such as heart disease or osteoporosis. PMID- 28671444 TI - Testosterone Does Not Improve Cognition in Memory-Impaired Older Men with Low Testosterone Levels. PMID- 28671445 TI - Acute and Chronic Urticaria: Evaluation and Treatment. AB - Urticaria commonly presents with intensely pruritic wheals, sometimes with edema of the subcutaneous or interstitial tissue. It has a lifetime prevalence of about 20%. Although often self-limited and benign, it can cause significant discomfort, continue for months to years, and uncommonly represent a serious systemic disease or life-threatening allergic reaction. Urticaria is caused by immunoglobulin E- and non-immunoglobulin E-mediated release of histamine and other inflammatory mediators from mast cells and basophils. Diagnosis is made clinically; anaphylaxis must be ruled out. Chronic urticaria is idiopathic in 80% to 90% of cases. Only a limited nonspecific laboratory workup should be considered unless elements of the history or physical examination suggest specific underlying conditions. The mainstay of treatment is avoidance of triggers, if identified. The first-line pharmacotherapy is second-generation H1 antihistamines, which can be titrated to greater than standard doses. First-generation H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, high-potency antihistamines, and brief corticosteroid bursts may be used as adjunctive treatment. In refractory chronic urticaria, patients can be referred to subspecialists for additional treatments, such as omalizumab or cyclosporine. More than one-half of patients with chronic urticaria will have resolution or improvement of symptoms within a year. PMID- 28671446 TI - Newborn Screening. PMID- 28671447 TI - Subclinical Hyperthyroidism. PMID- 28671448 TI - Hives. PMID- 28671449 TI - Rapid Isolation and Detection of Exosomes and Associated Biomarkers from Plasma. AB - Exosomes found in the circulation are a primary source of important cancer related RNA and protein biomarkers that are expected to lead to early detection, liquid biopsy, and point-of-care diagnostic applications. Unfortunately, due to their small size (50-150 nm) and low density, exosomes are extremely difficult to isolate from plasma. Current isolation methods are time-consuming multistep procedures that are unlikely to translate into diagnostic applications. To address this issue, we demonstrate the ability of an alternating current electrokinetic (ACE) microarray chip device to rapidly isolate and recover glioblastoma exosomes from undiluted human plasma samples. The ACE device requires a small plasma sample (30-50 MUL) and is able to concentrate the exosomes into high-field regions around the ACE microelectrodes within 15 min. A simple buffer wash removes bulk plasma materials, leaving the exosomes concentrated on the microelectrodes. The entire isolation process and on-chip fluorescence analysis is completed in less than 30 min which enables subsequent on-chip immunofluorescence detection of exosomal proteins, and provides viable mRNA for RT-PCR analysis. These results demonstrate the ability of the ACE device to streamline the process for isolation and recovery of exosomes, significantly reducing the number of processing steps and time required. PMID- 28671450 TI - Effects of Fluorine Doping on the Electrical Performance of ZnON Thin-Film Transistors. AB - In this work, the effects of fluorine incorporation in high mobility zinc oxynitride (ZnON) semiconductor are studied by both theoretical calculations and experimental evaluation of thin film transistors (TFTs). From density functional theory (DFT) calculations, fluorine acts as a carrier suppressor in the ZnON matrix when it substitutes a nitrogen vacant site (VN). Thin films of ZnON and ZnON:F were grown by reactively cosputtering Zn metal and ZnF2 targets, and their electrical, physical, and chemical characteristics were studied. X-ray photoelectron spectroscopy (XPS) analyses of the nitrogen 1s peaks in ZnON and ZnON:F suggest that as the fluorine incorporation increases, the relative fraction of Zn-N bonds from stoichiometric Zn3N2 increases. On the other hand, the Zn-N bond characteristics arising from nonstoichiometric ZnxNy and N-N bonds decrease, implying that indeed fluorine anions have an effect of passivating the N-related defects. The corresponding TFTs exhibit optimum transfer characteristics and switching ability when approximately 3.5 atomic percent of fluorine is present in the 40 nm thick ZnON:F active layer. PMID- 28671451 TI - An Ideal Electrode Material, 3D Surface-Microporous Graphene for Supercapacitors with Ultrahigh Areal Capacitance. AB - The efficient charge accumulation of an ideal supercapacitor electrode requires abundant micropores and its fast electrolyte-ions transport prefers meso/macropores. However, current electrode materials cannot meet both requirements, resulting in poor performance. Herein, we creatively constructed three-dimensional cabbage-coral-like graphene as an ideal electrode material, in which meso/macro channels are formed by graphene walls and rich micropores are incorporated in the surface layer of the graphene walls. The unique 3D graphene material can achieve a high gravimetric capacitance of 200 F/g with aqueous electrolyte, 3 times larger than that of commercially used activated carbon (70.8 F/g). Furthermore, it can reach an ultrahigh areal capacitance of 1.28 F/cm2 and excellent rate capability (83.5% from 0.5 to 10 A/g) as well as high cycling stability (86.2% retention after 5000 cycles). The excellent electric double layer performance of the 3D graphene electrode can be attributed to the fast electrolyte ion transport in the meso/macro channels and the rapid and reversible charge adsorption with negligible transport distance in the surface micropores. PMID- 28671452 TI - Multifunctional Nanoplatform Based on Black Phosphorus Quantum Dots for Bioimaging and Photodynamic/Photothermal Synergistic Cancer Therapy. AB - A multifunctional nanoplatform based on black phosphorus quantum dots (BPQDs) was developed for cancer bioimaging and combined photothermal therapy (PTT) and photodynamic therapy (PDT). BPQDs were functionalized with PEG chains to achieve improved biocompatibility and physiological stability. The as-prepared nanoparticles exhibite prominent near-infrared (NIR) photothermal and red-light triggered photodynamic properties. The combined therapeutic application of PEGylated BPQDs were then performed in vitro and in vivo. The results demonstrate that the combined phototherapy significantly promote the therapeutic efficacy of cancer treatment in comparison with PTT or PDT alone. BPQDs could also serve as the loading platform for fluorescent molecules, allowing reliable imaging of cancer cells. In addition, the low cytotoxicity and negligible side effects to main organs were observed in toxicity experiments. The theranostic characteristics of PEGylated BPQDs provide an uplifting potential for the future clinical applications. PMID- 28671453 TI - Growth and Characterization of Metastable Hexagonal Nickel Thin Films via Plasma Enhanced Atomic Layer Deposition. AB - There is a great interest in various branches of the advanced materials industry for the development of novel methods (and improvements to existing ones) for the deposition of conformal ultrathin metallic films. In most of these applications, like enhanced solar absorbers and microelectronics, achieving the capacity to deposit a conformal thin film on a three-dimensional structure is an important condition. Plasma-enhanced atomic layer deposition (ALD) is known for its potential for growth of conformal thin films with a precise control over the thickness and its capability for deposition at relatively low temperatures (below 500 degrees C). This study evaluates the potential of plasma-enhanced ALD for growth of conformal nickel thin films, using bis(ethylcyclopentadienyl)nickel and nitrogen/hydrogen plasma as precursors. A comprehensive analysis of the structure, composition, and physical properties of the films was performed. The results indicate that conformal nickel films with low levels of impurity were successfully deposited on sapphire. The films had a roughness of Ra = 1.5 nm and were seen to be under strain. The deposited nickel had a hexagonal crystal structure, with a random in-plane orientation of the grains, while the grains had their c-axes oriented along the normal to the interface. These results pave the way for conformal low-temperature deposition of high-quality nickel thin films on three-dimensional structures. PMID- 28671454 TI - Multiple Coordination Exchanges for Room-Temperature Activation of Open-Metal Sites in Metal-Organic Frameworks. AB - The activation of open coordination sites (OCSs) in metal-organic frameworks (MOFs), i.e., the removal of solvent molecules coordinated at the OCSs, is an essential step that is required prior to the use of MOFs in potential applications such as gas chemisorption, separation, and catalysis because OCSs often serve as key sites in these applications. Recently, we developed a "chemical activation" method involving dichloromethane (DCM) treatment at room temperature, which is considered to be a promising alternative to conventional thermal activation (TA), because it does not require the application of external thermal energy, thereby preserving the structural integrity of the MOFs. However, strongly coordinating solvents such as N,N-dimethylformamide (DMF), N,N diethylformamide (DEF), and dimethyl sulfoxide (DMSO) are difficult to remove solely with the DCM treatment. In this report, we demonstrate a multiple coordination exchange (CE) process executed initially with acetonitrile (MeCN), methanol (MeOH), or ethanol (EtOH) and subsequently with DCM to achieve the complete activation of OCSs that possess strong extracoordination. Thus, this process can serve as an effective "chemical route" to activation at room temperature that does not require applying heat. To the best of our knowledge, no previous study has demonstrated the activation of OCSs using this multiple CE process, although MeOH and/or DCM has been popularly used in pretreatment steps prior to the TA process. Using MOF-74(Ni), we demonstrate that this multiple CE process can safely activate a thermally unstable MOF without inflicting structural damage. Furthermore, on the basis of in situ 1H nuclear magnetic resonance (1H NMR) and Raman studies, we propose a plausible mechanism for the activation behavior of multiple CE. PMID- 28671455 TI - Amphiphilic siRNA Conjugates for Co-Delivery of Nucleic Acids and Hydrophobic Drugs. AB - Combination therapy of nucleic acids and chemical drugs for cancer treatment is a promising strategy to enhance the therapeutic efficacy by simultaneously regulating multiple troublesome pathways. In this study, we report on polyethylene glycol-siRNA-polycaprolactone (PEG-siRNA-PCL) micelles that encapsulate hydrophobic drugs for efficient co-delivery of siRNA and drugs to cancer cells. Amphiphilic PEG-siRNA-PCL copolymers were synthesized by annealing antisense siRNA-PCL conjugates with sense siRNA-PEG conjugates. After paclitaxel encapsulation, PEG-siRNA-PCL micelles containing antiapoptotic Bcl-2-specific siRNA were stabilized with linear polyethylenimine via electrostatic interactions. Stabilized PEG-siRNA-PCL micelles showed superior anticancer effects, assessed by caspase-3 activity analysis, apoptotic cell staining, and a cytotoxicity test, to those of paclitaxel-free PEG-siRNA-PCL micelles and unmodified siRNAs. The strong anticancer activity of paclitaxel-incorporated siRNA micelles can be attributed to the synergistic effect of Bcl-2 siRNA and paclitaxel. This work provides an efficient co-delivery platform for combination anticancer therapy with siRNA and chemotherapy. PMID- 28671456 TI - pICalculax: Improved Prediction of Isoelectric Point for Modified Peptides. AB - The isoelectric point of a peptide is a physicochemical property that can be accurately predicted from the sequence of the peptide when the peptide is built from natural amino acids. Peptides can however have chemical modifications, such as phosphorylations, amidations, and unnatural amino acids, which can result in erroneous predictions if not accounted for. Here we report on an open source program, pICalculax, which in an extensible way can handle pI calculations of modified peptides. Tests on a database of modified peptides and experimentally determined pI values show an improvement in pI predictions when taking the modifications into account. The correlation coefficient improves from 0.45 to 0.91, and the root-mean-square deviation likewise improves from 3.3 to 0.9. The program is available at https://github.com/EBjerrum/pICalculax. PMID- 28671457 TI - Correction to "Electrocatalytic Z -> E Isomerization of Azobenzenes". PMID- 28671459 TI - Quantification of Element Fluxes in Wastewaters: A Nationwide Survey in Switzerland. AB - The number and quantities of trace elements used in industry, (high-tech) consumer products, and medicine are rapidly increasing, but the resulting emissions and waste streams are largely unknown. We assessed the concentrations of 69 elements in digested sewage sludge and effluent samples from 64 municipal wastewater treatment plants as well as in major rivers in Switzerland. This data set, representative of an entire industrialized country, presents a reference point for current element concentrations, average per-capita fluxes, loads discharged to surface waters, and economic waste-stream values. The spatial distribution of many individual elements could be attributed either to predominant geogenic or to anthropogenic inputs. Per-capita element fluxes ranged from <10 MUg day-1 (e.g., Au, In, and Lu) to >1 mg day-1 (e.g., Zn, Sc, Y, Nb, and Gd) and >1 g day-1 (e.g., for P, Fe, and S). Effluent loads of some elements contributed significantly to riverine budgets (e.g., 24% for Zn, 50% for P, and 83% for Gd), indicating large anthropogenic inputs via the wastewater stream. At various locations, precious metal concentrations in sludge were similar to those in profitable mining ores, with total flux values of up to 6.8 USD per capita per year or 15 USD per metric ton of dry sludge. PMID- 28671458 TI - Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors. AB - Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported. PMID- 28671460 TI - Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure. AB - The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 MUM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2 yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3 yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration. PMID- 28671461 TI - Mechanistic Studies of Formal Thioboration Reactions of Alkynes. AB - Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of DeltaG? = 27.1 +/- 0.1 kcal mol-1 at 90 degrees C, DeltaH? = 13.8 +/- 1.0 kcal mol-1, and DeltaS? = -37 +/- 3 cal mol-1 K-1, measured over the range 70-90 degrees C. Carbon kinetic isotope effects supported a rate-determining AdE3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a rho+ of -1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C6F5)3), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl3 as an activating agent showed why BCl3, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate. PMID- 28671462 TI - The Synthesis of Certain Derivatives and Analogues of (-)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase. AB - Syntheses of certain di- and mono-oxygenated derivatives (e.g., 2 and 3, respectively) and analogues (e.g., 4, a D-ring monoseco-analogue of 2) of both the (-)- and (+)-enantiomeric forms of the alkaloid galanthamine [(-)-1] are reported. All have been assessed for their capacities to inhibit acetylcholine esterase but, in contrast to the predictions from docking studies, none bind strongly to this enzyme. PMID- 28671463 TI - Versatile Design Strategy for Highly Luminescent Vacuum-Evaporable and Solution Processable Tridentate Gold(III) Complexes with Monoaryl Auxiliary Ligands and Their Applications for Phosphorescent Organic Light Emitting Devices. AB - A new class of brightly blue-green-emitting arylgold(III) complexes has been synthesized, characterized, and applied as phosphorescent dopants in the fabrication of solution-processable and vacuum-deposited organic light-emitting devices (OLEDs). These arylgold(III) complexes can be readily synthesized by reacting the corresponding arylboronic acids with the gold(III) precursor complexes in a one-pot Suzuki-Miyaura coupling reaction. When compared to the structurally related alkynylgold(III) complex, arylgold(III) complexes 1 and 2 exhibit much higher photoluminescence quantum yields in solution state. High photoluminescence quantum yields are also observed in solid-state thin films. More importantly, the solid-state emission spectra show strong resemblance to those in solution, irrespective of the dopant concentration, leading to significant improvement in the color purity of the OLEDs by suppressing any excimer emission resulting from the pi-stacking of the tridentate ligand. High performance solution-processable and vacuum-deposited blue-green-emitting OLEDs have also been realized, with maximum external quantum efficiencies of 7.3% and 14.7%, respectively, representing the first demonstration of efficient blue-green emitting OLEDs based on cyclometalated arylgold(III) complexes. PMID- 28671464 TI - Correction to "Monodisperse Au Nanoparticles for Selective Electrocatalytic Reduction of CO2 to CO". PMID- 28671465 TI - In Situ Observation and Electrochemical Study of Encapsulated Sulfur Nanoparticles by MoS2 Flakes. AB - Sulfur is an attractive cathode material for next-generation lithium batteries due to its high theoretical capacity and low cost. However, dissolution of its lithiated product (lithium polysulfides) into the electrolyte limits the practical application of lithium sulfur batteries. Here we demonstrate that sulfur particles can be hermetically encapsulated by leveraging on the unique properties of two-dimensional materials such as molybdenum disulfide (MoS2). The high flexibility and strong van der Waals force in MoS2 nanoflakes allows effective encapsulation of the sulfur particles and prevent its sublimation during in situ TEM studies. We observe that the lithium diffusivities in the encapsulated sulfur particles are in the order of 10-17 m2 s-1. Composite electrodes made from the MoS2-encapsulated sulfur spheres show outstanding electrochemical performance, with an initial capacity of 1660 mAh g-1 and long cycle life of more than 1000 cycles. PMID- 28671466 TI - Fuel-Mediated Transient Clustering of Colloidal Building Blocks. AB - Fuel-driven assembly operates under the continuous influx of energy and results in superstructures that exist out of equilibrium. Such dissipative processes provide a route toward structures and transient behavior unreachable by conventional equilibrium self-assembly. Although perfected in biological systems like microtubules, this class of assembly is only sparsely used in synthetic or colloidal analogues. Here, we present a novel colloidal system that shows transient clustering driven by a chemical fuel. Addition of fuel causes an increase in hydrophobicity of the building blocks by actively removing surface charges, thereby driving their aggregation. Depletion of fuel causes reappearance of the charged moieties and leads to disassembly of the formed clusters. This reassures that the system returns to its initial, equilibrium state. By taking advantage of the cyclic nature of our system, we show that clustering can be induced several times by simple injection of new fuel. The fuel-mediated assembly of colloidal building blocks presented here opens new avenues to the complex landscape of nonequilibrium colloidal structures, guided by biological design principles. PMID- 28671467 TI - Cerium(IV) Neopentoxide Complexes. AB - Treatment of ceric ammonium nitrate (CAN) with varying amounts of sodium neopentoxide led to the isolation of crystalline cerium(IV) complexes [Ce(OCH2tBu)2(NO3)2(HOCH2tBu)2], [Ce(OCH2tBu)3(NO3)-(NCCH3)]2, [Ce2(OCH2tBu)7(NO3)]2, and [Ce2(OCH2tBu)9Na-(THF)] featuring CeIV/(OR) ratios of 1:2, 1:3, 1:3.5, and 1:4.5, respectively. The complexes are light-sensitive and prone to ligand redistribution as evidenced by multicomponent NMR spectra as well as the formation of [{Ce(OCH2tBu)4}2(THF)] and the mixed-valent complex [Ce3(OCH2tBu)9(NO3)2]. The CAN protocol also gave access to the isopropoxide derivative [Ce(OiPr)3(NO3)(THF)]2. The reaction of [Et4N]2[CeCl6] (CAC, ceric organoammonium chloride) with different equivalents of Na(OCH2tBu) was also impaired by ligand reorganization and ate complexation as detected for the tetravalent cerium complex [Ce2(OCH2tBu)7Cl2][Et4N]. Protonolysis of [Ce{N(SiHMe2)2}4] with 4 equiv of HOCH2tBu afforded donor-free homoleptic [Ce(OCH2tBu)4]3 in quantitative yield. All complexes were characterized by NMR, DRIFT, and UV-vis spectroscopy, as well as paramagnetic susceptibility measurements, X-ray structure analysis, and elemental analysis. PMID- 28671469 TI - Total Synthesis of Lycopladine A and Carinatine A via a Base-Mediated Carbocyclization. AB - A concise, enantioselective synthesis of lycopladine A and carinatine A is presented. Our synthetic approach hinges on the recently developed mild carbocyclization of ynones to furnish the hydrindane core of the alkaloids. Their pyridine ring was efficiently installed using the Ciufolini method. Both heterocycles of carinatine A, a rare naturally occurring nitrone, were formed in a single operation. PMID- 28671468 TI - Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol-Lactones as Protein Kinase C Ligands. AB - Protein kinase C (PKC) mediates a central cellular signal transduction pathway involved in disorders such as cancer and Alzheimer's disease. PKC is regulated by binding of the second messenger sn-1,2-diacylglycerol (DAG) to its tandem C1 domains, designated C1a and C1b, leading both to PKC activation and to its translocation to the plasma membrane and to internal organelles. Depending on the isoform, there may be differences in the ligand selectivity of the C1a and C1b domains, and there is different spacing between the C1 domains of the conventional and novel PKCs. Bivalent ligands have the potential to exploit these differences between isoforms, yielding isoform selectivity. In the present study, we describe the synthesis of a series of dimeric derivatives of conformationally constrained diacylglycerol (DAG) analogs (DAG-lactones). We characterize the derivatives in vitro for their binding affinities, both to a single C1 domain (the C1b domain of PKCdelta) as well as to the conventional PKCalpha isoform and the novel PKCdelta isoform, and we measure their abilities to cause translocation of PKCdelta and PKCepsilon in intact cells. The dimeric compound with the 10 carbon linker was modestly more effective for the isolated PKCdelta C1b domain than was the monomeric compound. For the intact PKCalpha and PKCdelta, the shortest DAG-lactone dimer had similar affinity to the monomer and affinity decreased progressively up to the 16-carbon linker. The dimeric derivatives did not cause the Golgi accumulation of PKCdelta. The present results provide important insights into the development of new chemical tools for biological studies on PKC. PMID- 28671472 TI - Giant Optical Second Harmonic Generation in Two-Dimensional Multiferroics. AB - Nonlinear optical properties of materials such as second and higher order harmonic generation and electro-optic effect play pivotal roles in lasers, frequency conversion, electro-optic modulators, switches, and so forth. The strength of nonlinear optical responses highly depends on intrinsic crystal symmetry, transition dipole moments, specific optical excitation, and local environment. Using first-principles electronic structure theory, here we predict giant second harmonic generation (SHG) in recently discovered two-dimensional (2D) ferroelectric-ferroelastic multiferroics-group IV monochalcogenides (i.e., GeSe, GeS, SnSe, and SnS). Remarkably, the strength of SHG susceptibility in GeSe and SnSe monolayers is more than 1 order of magnitude higher than that in monolayer MoS2, and 2 orders of magnitude higher than that in monolayer hexagonal BN. Their extraordinary SHG is dominated by the large residual of two opposite intraband contributions in the SHG susceptibility. More importantly, the SHG polarization anisotropy is strongly correlated with the intrinsic ferroelastic and ferroelectric orders in group IV monochalcogenide monolayers. Our present findings provide a microscopic understanding of the large SHG susceptibility in 2D group IV monochalcogenide multiferroics from first-principles theory and open up a variety of new avenues for 2D ferroelectrics, multiferroics, and nonlinear optoelectronics, for example, realizing active electrical/optical/mechanical switching of ferroic orders in 2D multiferroics and in situ ultrafast optical characterization of local atomistic and electronic structures using noncontact noninvasive optical SHG techniques. PMID- 28671471 TI - Solution-Processed Carbon Nanotube True Random Number Generator. AB - With the growing adoption of interconnected electronic devices in consumer and industrial applications, there is an increasing demand for robust security protocols when transmitting and receiving sensitive data. Toward this end, hardware true random number generators (TRNGs), commonly used to create encryption keys, offer significant advantages over software pseudorandom number generators. However, the vast network of devices and sensors envisioned for the "Internet of Things" will require small, low-cost, and mechanically flexible TRNGs with low computational complexity. These rigorous constraints position solution-processed semiconducting single-walled carbon nanotubes (SWCNTs) as leading candidates for next-generation security devices. Here, we demonstrate the first TRNG using static random access memory (SRAM) cells based on solution processed SWCNTs that digitize thermal noise to generate random bits. This bit generation strategy can be readily implemented in hardware with minimal transistor and computational overhead, resulting in an output stream that passes standardized statistical tests for randomness. By using solution-processed semiconducting SWCNTs in a low-power, complementary architecture to achieve TRNG, we demonstrate a promising approach for improving the security of printable and flexible electronics. PMID- 28671470 TI - Separating Proton and Electron Transfer Effects in Three-Component Concerted Proton-Coupled Electron Transfer Reactions. AB - Multiple-site concerted proton-electron transfer (MS-CPET) reactions were studied in a three-component system. 1-Hydroxy-2,2,6,6-tetramethylpiperidine (TEMPOH) was oxidized to the stable radical TEMPO by electron transfer to ferrocenium oxidants coupled to proton transfer to various pyridine bases. These MS-CPET reactions contrast with the usual reactivity of TEMPOH by hydrogen atom transfer (HAT) to a single e-/H+ acceptor. The three-component reactions proceed by pre-equilibrium formation of a hydrogen-bonded adduct between TEMPOH and the pyridine base, and the adduct is then oxidized by the ferrocenium in a bimolecular MS-CPET step. The second-order rate constants, measured using stopped-flow kinetic techniques, spanned 4 orders of magnitude. An advantage of this system is that the MS-CPET driving force could be independently varied by changing either the pKa of the base or the reduction potential (E degrees ) of the oxidant. Changes in DeltaG degrees MS-CPET from either source had the same effect on the MS-CPET rate constants, and a combined Bronsted plot of ln(kMS-CPET) vs ln(Keq) was linear with a slope of 0.46. These results imply a synchronous concerted mechanism, in which the proton and electron transfer components of the CPET process make equal contributions to the rate constants. The only outliers to the Bronsted correlation are the reactions with sterically hindered pyridines, which apparently hinder the close approach of proton donor and acceptor that facilitates MS-CPET. These three-component reactions are compared with a related HAT reaction of TEMPOH, with the 2,4,6-tri-tert-butylphenoxyl radical. The MS CPET and HAT oxidations of TEMPOH at the same driving force occurred with similar rate constants. While this is an imperfect comparison, the data suggest that the separation of the proton and electron to different reagents does not significantly inhibit the proton-coupled electron transfer process. PMID- 28671473 TI - Determination of Relative Frequency of Carbanion Formation at alpha-Positions of Ketones under Aldol Reaction Catalysis Conditions. AB - To provide insight into aldol reaction catalysis, the relative frequencies of carbanion formation at each alpha-position of ketones under catalysis by DBU, proline, beta-proline, and related catalysts were determined through the deuteration of the ketones in the presence of these catalysts. For selected cases, the deuteration rate was compared with the aldol reaction rate and whether the generated enolate/enamine resulted in return to the ketone or product formation was estimated. PMID- 28671474 TI - Access to Chiral Seven-Member Cyclic Amines via Rh-Catalyzed Asymmetric Hydrogenation. AB - A highly efficient asymmetric hydrogenation of azepine/oxazepine-type seven member cyclic imine hydrochlorides was successfully developed using Rh/bisphosphine-thiourea ligand ZhaoPhos, affording various chiral seven-member cyclic amines with full conversions, high yields, and excellent enantioselectivities (up to 96% yield, >99% ee). Additionally, this asymmetric hydrogenation can proceed well on gram scale with excellent ee value. Moreover, control experimental results displayed that the anion-bonding interaction between the chloride ion of the substrate and thiourea motif of the ZhaoPhos played an important role to obtain excellent enantioselectivity. PMID- 28671475 TI - Computational Synthesis of MoS2 Layers by Reactive Molecular Dynamics Simulations: Initial Sulfidation of MoO3 Surfaces. AB - Transition metal dichalcogenides (TMDC) like MoS2 are promising candidates for next-generation electric and optoelectronic devices. These TMDC monolayers are typically synthesized by chemical vapor deposition (CVD). However, despite significant amount of empirical work on this CVD growth of monolayered crystals, neither experiment nor theory has been able to decipher mechanisms of selection rules for different growth scenarios, or make predictions of optimized environmental parameters and growth factors. Here, we present an atomic-scale mechanistic analysis of the initial sulfidation process on MoO3 surfaces using first-principles-informed ReaxFF reactive molecular dynamics (RMD) simulations. We identify a three-step reaction process associated with synthesis of the MoS2 samples from MoO3 and S2 precursors: O2 evolution and self-reduction of the MoO3 surface; SO/SO2 formation and S2-assisted reduction; and sulfidation of the reduced surface and Mo-S bond formation. These atomic processes occurring during early stage MoS2 synthesis, which are consistent with experimental observations and existing theoretical literature, provide valuable input for guided rational synthesis of MoS2 and other TMDC crystals by the CVD process. PMID- 28671476 TI - Molecular Group 13 Metallaborates Derived from M-O-M Cleavage Promoted by BH3. AB - The reaction of metalloxanes [{MeLM(OH)}2(MU-O)] [M = Al (1), Ga (2); MeL = CH{CMe(NAr)}2-, Ar = 2,4,6-Me3C6H2, Me = methyl] with an excess of BH3.D (D = tetrahydrofuran (THF), SMe2) affords annular metallaborate systems achieved through M-O-M cleavage. Compound 1 led exclusively to the formation of eight membered ring systems [{MeLAl(MU-O){B(OnBu)}(MU-O)}2] (3) and [{MeLAl(MU O)(BH)(MU-O)}2] (6), while for 2 the unprecedented six-membered ring systems [{(MeLGa)2(MU-O)}(MU-O)2{B(OnBu)}] (4) and [(MeLGa)(MU-O)2{(BOnBu)2(MU-O)}] (5) were observed. The use of BH3.THF with 1 and 2 led to the concomitant THF ring opening reaction, while with BH3.SMe2 in THF no such reaction was observed. The metallaborates [MeLAl{OB(pinacol)}(OH)] (7) and [{MeLGa(OB(pinacol))}2(MU-O)] (8) were synthesized from pinacolborane and the corresponding metalloxane, providing structural evidence that supports the reaction pathways proposed for the formation of 3-6. Density functional theory studies were performed on 3-5 to assess the effect of the metal exchange between aluminum and gallium atoms on the energy of the general ring structures. PMID- 28671477 TI - True Vapor-Liquid-Solid Process Suppresses Unintentional Carrier Doping of Single Crystalline Metal Oxide Nanowires. AB - Single crystalline nanowires composed of semiconducting metal oxides formed via a vapor-liquid-solid (VLS) process exhibit an electrical conductivity even without an intentional carrier doping, although these stoichiometric metal oxides are ideally insulators. Suppressing this unintentional doping effect has been a challenging issue not only for metal oxide nanowires but also for various nanostructured metal oxides toward their semiconductor applications. Here we demonstrate that a pure VLS crystal growth, which occurs only at liquid-solid (LS) interface, substantially suppresses an unintentional doping of single crystalline SnO2 nanowires. By strictly tailoring the crystal growth interface of VLS process, we found the gigantic difference of electrical conduction (up to 7 orders of magnitude) between nanowires formed only at LS interface and those formed at both LS and vapor-solid (VS) interfaces. On the basis of investigations with spatially resolved single nanowire electrical measurements, plane-view electron energy-loss spectroscopy, and molecular dynamics simulations, we reveal the gigantic suppression of unintentional carrier doping only for the crystal grown at LS interface due to the higher annealing effect at LS interface compared with that grown at VS interface. These implications will be a foundation to design the semiconducting properties of various nanostructured metal oxides. PMID- 28671478 TI - A qualitative study exploring factors influencing clinical decision-making for influenza-like illness in Solapur city, Maharashtra, India. AB - The co-existence of different types of medical systems (medical pluralism) is a typical feature of India's healthcare system. For conditions such as influenza like illness (ILI), where non-specific disease signs/symptoms exist, clinical reasoning in the context of medical pluralism becomes crucial. Recognising this need, we undertook a qualitative study, which explored factors underpinning clinical decisions on diagnosis and management of ILI. The study involved semi structured interviews including clinical vignettes with 20 healthcare practitioners (working within allopathy, homeopathy and Ayurveda) working in the private healthcare sector in Solapur city, India. An inquiry was conducted into criteria influencing the diagnosis, treatment, referral to specialist care and role of treatment guidelines for ILI. Thematic analysis was used to identify aspects relating to ILI diagnosis, treatment and referral. The diagnosis of influenza was based largely on clinical symptoms suggestive of influenza in the absence of other diagnoses. Referral for laboratory tests was only initiated if illness did not resolve, generally after 2-3 consultations. Antibiotics were often prescribed for persistent illness, with antivirals rarely considered. Some differences between practitioners from different medical systems were observed in relation to treatment and referral in case of persistent illness. A combination of analytical and intuitive clinical reasoning was used by the participants and clinical decisions were based on both social and clinical factors. Clinical decision-making was rarely a linear process and respondents felt that broad guidelines on influenza that allowed doctors to account for the sociocultural context within which they practised medicine would be helpful. PMID- 28671479 TI - Optical Absorption Characteristics For [Formula: see text] and [Formula: see text] Transitions of Trivalent Americium Ion in Aqueous Electrolyte Mixtures. AB - Optical absorption features for [Formula: see text] and [Formula: see text] transitions of trivalent americium ion were investigated in a wide range of aqueous combinations of perchloric and nitric acids (0.1-6.0 mol L-1). The developed qualitative matrix of extinction coefficients measures the cumulative impact of increasing electrolyte content, changes in the hydration zones of americium ion, and inner-sphere perturbation by nitrate on the absorbance. The effects of growing complexity of aqueous electrolyte medium were highlighted for the [Formula: see text] transition. Spectroscopy indicates the perturbation of the inner hydration sphere of trivalent f-element by one nitrate ligand. PMID- 28671480 TI - The impact of experiential avoidance on the relations between illness representations, pain catastrophising and pain interference in chronic pain. AB - OBJECTIVE: The aim of this study was to examine the effects of experiential avoidance (EA) on the indirect relationship of chronic pain patients' illness representations to pain interference, through pain catastrophising Design and main outcome measure: The sample consisted of 162 patients diagnosed with an arthritis-related or a musculoskeletal disorder. The effects of EA on the pathway between illness representations, pain catastrophising and pain interference were examined with PROCESS, a computational tool for SPSS Results: After controlling for patient and illness-related variables and pain severity, the 'illness representations-pain catastrophising-pain interference' pathway was interrupted at the higher levels of EA. The reason was that, at the high levels of EA, either the relation of illness representations to pain catastrophising or the relation of pain catastrophising to pain interference was not statistically significant. CONCLUSION: The findings indicate that EA is not a generalised negative response to highly aversive conditions, at least as far as the factors examined in this study are concerned. EA may rather reflect a coping reaction, the impact of which depends on its specific interactions with the other aspects of the self regulation mechanism. At least in chronic pain, EA should become the focus of potential intervention only when its interaction with the illness-related self regulation mechanism results in negative outcomes. PMID- 28671481 TI - Knowledge, attitudes, beliefs and patterns of waterpipe use among Jordanian adults who exclusively smoke waterpipes. AB - BACKGROUND: Widespread waterpipe smoking (WPS) is reported worldwide. Although remarkable numbers of waterpipe smokers do not smoke cigarettes, very few studies have explored the phenomenon of WPS in people who smoke water pipes exclusively. The aim of this study was to assess levels of knowledge, attitudes, beliefs and patterns of WPS among Jordanian waterpipe-only smokers. METHODS: A cross sectional descriptive design was used; with 247 participants who were recruited through convenience sampling from 23 cafes offering waterpipes. An interview and self-reported questionnaire was used to collect data. RESULTS: The average age for starting WPS was 19.4 +/- 5.6 years, of whom 71% started as teenagers. Participants like WPS because they like its flavor and social environment (46.3% and 29.5% respectively). The majority of participants reported that they smoked a waterpipe for the first time with their friends (66.8%), they usually smoke in the company of others (63.2%), and believe that quitting cigarettes smoking is harder than quitting WPS (61.6%). More than half (56.7%) of participants have extremely poor knowledge about the health effects of WPS. Participants who had smoked cigarettes in the past, were more knowledgeable than those who had never smoked cigarettes. The majority of participants, and specifically women, have high positive feelings and emotions (attitude) toward WPS, and 88.3% of them reported that it is a socially acceptable behavior. CONCLUSIONS: Waterpipe smoking participants started WPS at an early age, and are attracted to the social environment that accompanies WPS. Participants have high positive attitude about WPS however they lack knowledge about harmful health effects of WPS. PMID- 28671482 TI - Correction to: V. Esperidiao-Antonio et al., Neurobiology of emotions: an update. PMID- 28671483 TI - Caregiver burden in amyotrophic lateral sclerosis: A systematic review. AB - BACKGROUND: Informal caregivers of patients with amyotrophic lateral sclerosis experience increased levels of caregiver burden as the disease progresses. Insight in the factors related to caregiver burden is needed in order to develop supportive interventions. AIM: To evaluate the evidence on patient and caregiver factors associated with caregiver burden in amyotrophic lateral sclerosis informal caregivers. DESIGN: A systematic review. DATA SOURCES: Four electronic databases were searched up to 2017. Studies that investigated quantitative relations between patient or caregiver factors and caregiver burden were included. The overall quality of evidence for factors was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: A total of 25 articles were included. High quality of evidence was found for the relation between caregiver burden and the factor "behavioral impairments." Moderate quality of evidence was found for the relations between caregiver burden and the factors "feelings of depression" of the caregiver and "physical functioning" of the patient. The remaining rated caregiver factors "feelings of anxiety," "distress," "social support," "family functioning," and "age"-and patient factors-"bulbar function," "motor function," "respiratory function," "disease duration," "disinhibition," "executive functioning," "cognitive functioning," "feelings of depression," and "age"-showed low to very low quality of evidence for their association with caregiver burden. CONCLUSION: Higher caregiver burden is associated with greater behavioral and physical impairment of the patient and with more depressive feelings of the caregiver. This knowledge enables the identification of caregivers at risk for caregiver burden and guides the development of interventions to diminish caregiver burden. PMID- 28671484 TI - Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document. AB - In patients treated with macitentan (Opsumit(r), Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug-drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH. PMID- 28671485 TI - Replacing a phosphodiesterase-5 inhibitor with riociguat in patients with connective tissue disease-associated pulmonary arterial hypertension: a case series. AB - Patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-PAH-CTD) such as systemic sclerosis (SSc) have a poorer response to treatment and increased mortality compared with patients with idiopathic PAH. Current treatment options for PAH-CTD include prostanoids, phosphodiesterase type 5 inhibitors (PDE-5i), endothelin receptor antagonists, and the soluble guanylate cyclase stimulator riociguat. In this case series, we describe three patients with PAH-CTD related to limited scleroderma who were switched from a PDE-5i to riociguat due to insufficient clinical response. The switch to riociguat was associated with an improvement in respiratory and hemodynamic parameters and a favorable tolerability profile. These cases demonstrate that switching to riociguat is a therapeutic option in patients with PAH-CTD who have not achieved a satisfactory clinical response to a PDE-5i. PMID- 28671486 TI - Repetition priming in mild cognitive impairment and mild dementia: Impact of educational attainment. AB - OBJECTIVE: To examine the role of education on repetition priming performances in healthy aging, mild cognitive impairment (MCI), and mild dementia. METHOD: A total of 72 participants (healthy = 27, with MCI = 28, with mild dementia = 17) took part in the present study. Priming was assessed using the Word Stem Completion Test, and delayed and recognition memory was assessed using the Rey Auditory Verbal Learning Test. A multinomial regression analysis was used to examine whether years of education moderated priming and declarative memory performances in predicting group membership. RESULTS: Priming performances discriminated between individuals with MCI and mild dementia but not between MCI and healthy. Additionally, this effect was most salient in individuals with low levels of education. Education did not moderate explicit memory performances in predicting group membership. CONCLUSION: Little is known about the impact of education on priming in verbal memory. Our findings indicate that formal years of education impact priming performances in MCI and individuals with mild dementia, which may have implications for designing interventions targeting "intact" cognitive abilities in these groups. PMID- 28671489 TI - FDA in the 21st Century. PMID- 28671487 TI - Environmental modifiable risk factors for multiple sclerosis: Report from the 2016 ECTRIMS focused workshop. AB - Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The aetiology of the disease is not well understood; it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research. PMID- 28671490 TI - What Is Your Neurologic Diagnosis? Cervical foreign bodies. PMID- 28671491 TI - Seroprevalences of feline leukemia virus and feline immunodeficiency virus infection in cats in the United States and Canada and risk factors for seropositivity. AB - OBJECTIVE To estimate seroprevalences for FeLV antigen and anti-FIV antibody and risk factors for seropositivity among cats in the United States and Canada. DESIGN Cross-sectional study. ANIMALS 62,301 cats tested at 1,396 veterinary clinics (n = 45,406) and 127 animal shelters (16,895). PROCEDURES Blood samples were tested with a point-of-care ELISA for FeLV antigen and anti-FIV antibody. Seroprevalence was estimated, and risk factors for seropositivity were evaluated with bivariate and multivariable mixed-model logistic regression analyses adjusted for within-clinic or within-shelter dependencies. RESULTS Overall, seroprevalence was 3.1% for FeLV antigen and 3.6% for anti-FIV antibody. Adult age, outdoor access, clinical disease, and being a sexually intact male were risk factors for seropositivity for each virus. Odds of seropositivity for each virus were greater for cats tested in clinics than for those tested in shelters. Of 1,611 cats with oral disease, 76 (4.7%) and 157 (9.7%) were seropositive for FeLV and FIV, respectively. Of 4,835 cats with respiratory disease, 385 (8.0%) were seropositive for FeLV and 308 (6.4%) were seropositive for FIV. Of 1,983 cats with abscesses or bite wounds, 110 (5.5%) and 247 (12.5%) were seropositive for FeLV and FIV, respectively. Overall, 2,368 of 17,041 (13.9%) unhealthy cats were seropositive for either or both viruses, compared with 1,621 of 45,260 (3.6%) healthy cats. CONCLUSIONS AND CLINICAL RELEVANCE Seroprevalences for FeLV antigen and anti-FIV antibody were similar to those reported in previous studies over the past decade. Taken together, these results indicated a need to improve compliance with existing guidelines for management of feline retroviruses. PMID- 28671492 TI - Pathology in Practice. Eosinophilic keratitis in a cat. PMID- 28671494 TI - Stakeholder expectations regarding the ability of new veterinary graduates to perform various diagnostic and surgical procedures. AB - OBJECTIVE To assess stakeholders' expectations regarding new veterinary graduates' ability to perform various diagnostic and surgical procedures. DESIGN Cross-sectional survey. SAMPLE Veterinary students, recent graduates, clinical veterinary college faculty, and general practitioners at or from AVMA Council on Education-accredited colleges of veterinary medicine in the United States and Caribbean. PROCEDURES Respondents rated how proficient they expected new graduates, on their first day of practice, to be in 8 diagnostic procedures and the degree of independence they expected of new graduates in 8 surgical procedures. RESULTS Response rate was 9% (235/2,500) for practitioners, 12% (151/1,275) for faculty members, 14% (70/500) for recent graduates, and 15% (1,731/11,474) for students. All 4 respondent subgroups expected that new graduates would be able to adequately perform a fine-needle aspirate of a subcutaneous mass (96% to 98% expected new graduates to be able to adequately perform this procedure) and a cystocentesis (93% to 97% expected new graduates to be able to adequately perform this procedure). The greatest variability in responses was noted for performing hand ties, ultrasound-guided liver biopsy, and arthrocentesis. Most respondents expected new graduates to be able to independently perform a canine castration (82% to 94% expecting independence), feline subcutaneous mass removal (66% to 75% expecting independence), and canine ovariohysterectomy (65% to 89% expecting independence). CONCLUSIONS AND CLINICAL RELEVANCE Results revealed a diversity of opinion regarding expected proficiency for new graduates performing various diagnostic and surgical procedures. Findings may help colleges of veterinary medicine refine their curricula by providing end points for student training. PMID- 28671495 TI - Effect of different types of classical music played at a veterinary hospital on dog behavior and owner satisfaction. AB - OBJECTIVE To determine the effect of different types of classical music played during a veterinary visit on dog behavior and owner satisfaction. DESIGN Prospective randomized controlled study. ANIMALS 74 dogs examined at a veterinary teaching hospital. PROCEDURES Dogs examined for a wellness visit, presurgical health evaluation, or nonurgent illness were exposed to 1 of 3 treatments (modified classical music, the same music in its original format, and no music [control]) while in the examination room. Owners completed a standardized survey regarding the dog's behavior and their satisfaction with the visit. Clinicians completed a separate standardized survey regarding the dog's behavior. Information regarding monetary charges, procedures performed, diagnoses, and physiologic variables was obtained from the electronic medical record after the appointment. RESULTS Owners rated their dog's anxiety level in the waiting room greater than that in the examination room regardless of treatment. Mean anxiety and aggression scores of dogs during the physical examination as rated by owners were significantly greater than those assigned by clinicians. Visit satisfaction for owners exposed to original classical music was significantly greater than that for owners not exposed to music. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested placing a pet and its owner into an examination room instead of a waiting room immediately after clinic arrival may ameliorate pet anxiety during the veterinary visit. Playing classical music at a low volume can be a simple and cost-effective way to improve owner satisfaction with the veterinary visit. Further research is necessary to determine the effects of music on pet anxiety. PMID- 28671496 TI - Effects of oral megestrol acetate administration on the hypothalamic-pituitary adrenal axis of male bottlenose dolphins (Tursiops truncatus). AB - OBJECTIVE To evaluate the impact of oral megestrol acetate (MA) administration on adrenal function in male bottlenose dolphins (Tursiops truncatus). DESIGN Serial cross-sectional study. ANIMALS 8 adult male dolphins, all of which were receiving MA at various daily doses (range, 0 to 60 mg, PO) for the control of reproductive behavior. PROCEDURES Blood samples were collected every 2 weeks for 1 year from dolphins trained to voluntarily provide them. Cortisol, ACTH, and other hormone concentrations were measured in serum or plasma via radioimmunoassay or ELISA. Fecal samples, also provided by dolphins voluntarily, were assayed for glucocorticoid metabolite concentrations. Effects of daily MA dose on hormone concentrations were evaluated. RESULTS Daily MA doses as low as 10 mg strongly suppressed cortisol secretion in nearly all dolphins, and except for a single measurement, no dolphin had measurable serum concentrations at doses >= 20 mg. Variations in serum cortisol concentration were unrelated to season but were directly related to ACTH concentrations, suggesting primary effects upstream of the adrenal gland. Cessation of MA administration resulted in almost immediate restoration of measurable serum cortisol concentrations, although concentrations continued to rise in a few dolphins over the following weeks to months. CONCLUSIONS AND CLINICAL RELEVANCE Caution should be exercised when administering MA to control reproductive behavior in male dolphins. Because the hypothalamic pituitary-adrenal axis appeared to be sensitive to even small doses of MA in dolphins, duration of treatment may be the most critical consideration. PMID- 28671497 TI - Use of whole-genome sequencing and evaluation of the apparent sensitivity and specificity of antemortem tuberculosis tests in the investigation of an unusual outbreak of Mycobacterium bovis infection in a Michigan dairy herd. AB - OBJECTIVE To describe use of whole-genome sequencing (WGS) and evaluate the apparent sensitivity and specificity of antemortem tuberculosis tests during investigation of an unusual outbreak of Mycobacterium bovis infection in a Michigan dairy herd. DESIGN Bovine tuberculosis (bTB) outbreak investigation. ANIMALS Cattle, cats, dog, and wildlife. PROCEDURES All cattle in the index dairy herd were screened for bTB with the caudal fold test (CFT), and cattle >= 6 months old were also screened with a gamma-interferon (gammaIFN) assay. The index herd was depopulated along with all barn cats and a dog that were fed unpasteurized milk from the herd. Select isolates from M bovis-infected animals from the index herd and other bTB-affected herds underwent WGS. Wildlife around all affected premises was examined for bTB. RESULTS No evidence of bTB was found in any wildlife examined. Within the index herd, 53 of 451 (11.8%) cattle and 12 of 21 (57%) cats were confirmed to be infected with M bovis. Prevalence of M bovis-infected cattle was greatest among 4- to 7-month-old calves (16/49 [33%]) followed by adult cows (36/203 [18%]). The apparent sensitivity and specificity were 86.8% and 92.7% for the CFT and 80.4% and 96.5% for the gammaIFN assay when results for those tests were interpreted separately and 96.1% and 91.7% when results were interpreted in parallel. Results of WGS revealed that M bovis infected barn cats and cattle from the index herd and 6 beef operations were infected with the same strain of M bovis. Of the 6 bTB-affected beef operations identified during the investigation, 3 were linked to the index herd only by WGS results; there was no record of movement of livestock or waste milk from the index herd to those operations. CONCLUSIONS AND CLINICAL RELEVANCE Whole-genome sequencing enhanced the epidemiological investigation and should be used in all disease investigations. Performing the CFT and gammaIFN assay in parallel improved the antemortem ability to detect M bovis-infected animals. Contact with M bovis-infected cattle and contaminated milk were major risk factors for transmission of bTB within and between herds of this outbreak. PMID- 28671498 TI - Correction: Rabies surveillance in the United States during 2015. PMID- 28671499 TI - Focal intramural pericardial effusion and cardiac tamponade associated with necrotic adipose tissue in a dog. AB - CASE DESCRIPTION A 1-year-old castrated male German Shepherd Dog was examined because of an acute onset of lethargy, tachypnea, and inappetence. CLINICAL FINDINGS On initial physical examination, the dog was tachypneic with muffled heart sounds on thoracic auscultation and a palpable abdominal fluid wave. Transthoracic echocardiography revealed focal intramural pericardial effusion and cardiac tamponade. TREATMENT AND OUTCOME The patient underwent emergency therapeutic pericardiocentesis, followed by right lateral intercostal thoracotomy and subtotal pericardiectomy. A 3 * 5-cm mass located between the parietal and visceral layers of the pericardium was resected. The histologic diagnosis was necrotic adipose tissue with granulomatous inflammation and fibroplasia. The patient also underwent exploratory laparotomy and umbilical herniorrhaphy during the same anesthetic episode and recovered from surgery without apparent complications. There were no further clinical signs of cardiac disease. CLINICAL RELEVANCE The patient described in the present report underwent successful subtotal pericardiectomy for treatment of a benign focal lesion causing recurrent pericardial effusion and cardiac tamponade. Prompt diagnosis and intervention may have contributed to the positive outcome in this case. PMID- 28671500 TI - Pathology in Practice. Severe intestinal coccidiosis in a chicken. PMID- 28671501 TI - Anesthesia Case of the Month. PMID- 28671503 TI - What Is Your Diagnosis? Cranial nuchal bursitis. PMID- 28671504 TI - Reliability and validity of a self-administered tool for online neuropsychological testing: The Amsterdam Cognition Scan. AB - INTRODUCTION: To facilitate large-scale assessment of a variety of cognitive abilities in clinical studies, we developed a self-administered online neuropsychological test battery: the Amsterdam Cognition Scan (ACS). The current studies evaluate in a group of adult cancer patients: test-retest reliability of the ACS and the influence of test setting (home or hospital), and the relationship between our online and a traditional test battery (concurrent validity). METHOD: Test-retest reliability was studied in 96 cancer patients (57 female; Mage = 51.8 years) who completed the ACS twice. Intraclass correlation coefficients (ICCs) were used to assess consistency over time. The test setting was counterbalanced between home and hospital; influence on test performance was assessed by repeated measures analyses of variance. Concurrent validity was studied in 201 cancer patients (112 female; Mage = 53.5 years) who completed both the online and an equivalent traditional neuropsychological test battery. Spearman or Pearson correlations were used to assess consistency between online and traditional tests. RESULTS: ICCs of the online tests ranged from .29 to .76, with an ICC of .78 for the ACS total score. These correlations are generally comparable with the test-retest correlations of the traditional tests as reported in the literature. Correlating online and traditional test scores, we observed medium to large concurrent validity (r/rho = .42 to .70; total score r = .78), except for a visuospatial memory test (rho = .36). Correlations were affected-as expected-by design differences between online tests and their offline counterparts. CONCLUSIONS: Although development and optimization of the ACS is an ongoing process, and reliability can be optimized for several tests, our results indicate that it is a highly usable tool to obtain (online) measures of various cognitive abilities. The ACS is expected to facilitate efficient gathering of data on cognitive functioning in the near future. PMID- 28671505 TI - Local Injection of Hyaluronic Acid Filler Improves Open Gingival Embrasure: Validation Through a Rat Model. AB - BACKGROUND: The open gingival embrasure, the so-called black triangle, is one of the unsolved dilemmas in adult dentistry. Although various techniques have been introduced to improve black triangles, the lack of reproducible experimental models has prevented development of successful protocols to regenerate or to compensate loss of the interdental papilla. Therefore, the objective of this study is first to develop a reliable animal model of open gingival embrasure and then to validate a minimally invasive injection technique using hyaluronic acid (HA) filler to augment the interdental papilla. METHODS: To reproduce open gingival embrasure in rats, rapid space opening was induced between the mandibular incisors by attachment of a compression spring. Loss of interdental papilla height was morphologically evaluated and calculated using standardized serial photographs, microcomputed tomography, and histologic sections. Afterward, HA fillers or phosphate-buffered saline (PBS) was locally injected, and changes in the interdental papilla were evaluated. RESULTS: After 7 days of space opening, the margin of the interdental papilla between the mandibular incisors gradually became irregular and flat, indicating a condition similar to the open gingival embrasure (P <0.05). Local injection of HA filler induced an augmentation effect of the interdental papilla compared with injection of PBS (P <0.05). Interdental papilla became convex, and inner granules containing HA were detected within the submucosal layer after its injection. CONCLUSIONS: Open gingival embrasure was reproduced reliably in vivo. Local injection of HA filler was validated as a meaningful minimally invasive procedure to improve open gingival embrasure. PMID- 28671506 TI - Chronic Periodontal Disease, Periodontal Pathogen Colonization, and Increased Risk of Precancerous Gastric Lesions. AB - BACKGROUND: This study assesses the association between periodontal pathogen colonization and the potential risk of developing precancerous lesions of gastric cancer (PLGC) in a clinical setting. METHODS: Included were 35 newly diagnosed patients with PLGC and 70 age-matched individuals without PLGC. A full-mouth intraoral examination was performed to assess periodontal conditions. Stimulated whole saliva and pooled plaque samples were collected to evaluate colonization by Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans and to characterize oral microbial diversity in saliva and dental plaque. RESULTS: Compared with the control group, patients with PLGC experienced higher prevalence of bleeding on probing (31.5% versus 22.4%; P <0.05), higher levels of T. denticola (P <0.01) and A. actinomycetemcomitans (P <0.01), and less bacterial diversity in their saliva (P <0.01). The final multivariate logistic regression model consisting of all key sociodemographic characteristics, oral health behavioral factors, and periodontal assessments revealed that elevated colonization with periodontal pathogens, specifically T. forsythia, T. denticola, and A. actinomycetemcomitans, decreased bacterial diversity in dental plaque, and not flossing teeth regularly was a significant predictor of increased risk of PLGC (P = 0.022). CONCLUSION: Findings of the present study provide new evidence suggesting that periodontal pathogen burdens and bacterial diversity in the oral cavity are important factors contributing to a potentially increased risk of developing precancerous gastric lesions. PMID- 28671507 TI - Clarithromycin as an Adjunct to One-Stage Full-Mouth Ultrasonic Periodontal Debridement in Generalized Aggressive Periodontitis: A Randomized Controlled Clinical Trial. AB - BACKGROUND: The aim of the present study is to evaluate the periodontal clinical and microbiologic responses and possible adverse effects of clarithromycin (CLM) combined with periodontal mechanical therapy in the treatment of patients with generalized aggressive periodontitis. METHODS: Forty patients were selected and randomly assigned into one of two groups: 1) CLM (n = 20): one-stage full-mouth ultrasonic debridement (FMUD) associated with CLM (500 mg, every 12 hours for 3 days); and 2) placebo (n = 20): FMUD associated with placebo pills. Clinical and microbiologic parameters were evaluated at baseline and 3 and 6 months postoperatively. RESULTS: Both treatments presented statistically significant clinical and microbiologic improvements. However, the CLM group presented lower means of probing depth for pockets >=7 mm at 6 months (4.0 +/- 1.7 mm) compared with the placebo group (4.7 +/- 1.3 mm) (P = 0.04). In addition, the CLM group also presented greater reduction of Porphyromonas gingivalis (Pg) DNA counts at 6 months (P = 0.0001). CONCLUSION: Results from this study suggest both treatments are effective; however, adjunct use of CLM to FMUD leads to better reduction of deep pockets and Pg at 6 months compared with FMUD alone. PMID- 28671508 TI - Investigation of a Novel Predictive Biomarker Profile for the Outcome of Periodontal Treatment. AB - BACKGROUND: An ability to predict the response to conventional non-surgical treatment of a periodontal site would be advantageous. However, biomarkers or tests devised to achieve this have lacked sensitivity. The aim of this study is to assess the ability of a novel combination of biomarkers to predict treatment outcome of patients with chronic periodontitis. METHODS: Gingival crevicular fluid (GCF) and subgingival plaque were collected from 77 patients at three representative sites, one healthy (probing depth [PD] <=3 mm) and two diseased (PD >=6 mm), at baseline and at 3 and 6 months after treatment. Patients received standard non-surgical periodontal treatment at each time point as appropriate. The outcome measure was improvement in probing depth of >=2 mm. Concentrations of active enzymes (matrix metalloproteinase [MMP]-8, elastase, and sialidase) in GCF and subgingival plaque levels of Porphyromonas gingivalis, Tannerella forsythia, and Fusobacterium nucleatum were analyzed for prediction of the outcome measure. RESULTS: Using threshold values of MMP-8 (94 ng/MUL), elastase (33 ng/MUL), sialidase (23 ng/MUL), and levels of P. gingivalis (0.23%) and T. forsythia (0.35%), receiver operating characteristic curves analysis demonstrated that these biomarkers at baseline could differentiate healthy from diseased sites (sensitivity and specificity >=77%). Furthermore, logistic regression showed that this combination of these biomarkers at baseline provided accurate predictions of treatment outcome (>=92%). CONCLUSION: The "fingerprint" of GCF enzymes and bacteria described here offers a way to predict the outcome of non-surgical periodontal treatment on a site-specific basis. PMID- 28671509 TI - Periodontitis Prevalence and Severity in Adults: A Cross-Sectional Study in Norwegian Circumpolar Communities. AB - BACKGROUND: The aim of this study is to describe the prevalence, severity, and extent of periodontitis in the adult population of circumpolar communities in Norway using data from the Tromstannen-Oral Health in Northern Norway study. METHODS: In this cross-sectional survey, data were collected from a randomized population sample (aged 20 to 79 years) in Northern Norway. Periodontal conditions were assessed for 1,911 dentate adults with a full-mouth periodontal examination. Probing depth (PD) and bleeding on probing were measured at six sites per tooth. Radiographic bone loss (BL) was examined using orthopantomograms. RESULTS: According to the Centers for Disease Control and Prevention/American Academy of Periodontology case definitions, 49.5% of participants had periodontitis, and 9.1% had severe periodontitis. Periodontitis prevalence and severity increased with age. Extent of BL and PD >=4 mm also increased with age, but more rapidly and to a greater extent for BL. Prevalence of periodontitis was higher among men and varied between urban and rural areas. Periodontitis prevalence was positively associated with smoking, lower levels of education, and income. CONCLUSIONS: This study reveals a high burden of periodontitis among adults living in circumpolar communities in Norway. The results showed sociodemographic disparities regarding periodontitis and highlights the importance of further investigation of factors influencing periodontal health. PMID- 28671510 TI - Medication Administration in Schools: Position Statement. PMID- 28671511 TI - NASN 2017 Endowment Fundraising Activities. PMID- 28671512 TI - NASN's Legislative Priorities. PMID- 28671513 TI - Historic Leadership: One Courageous School Nurse's Heroic Journey-Part 4. AB - School nursing practice establishes itself in the midst of both education and nursing philosophies, ethics, standards, laws, and regulations. Treading these two worlds is difficult at times and requires that a school nurse possess a strong foundational knowledge base, seek professional collaboration, and navigate conflicting professional demands in order to promote student and public safety. This article is Part 4 of a four-part series that recounts the inspiring story of a school nurse, Ellen Johnsen, who did just that back in the 1980s in Broken Arrow, Oklahoma. Part 4 offers lessons to be learned by reflecting on Ellen Johnsen's experience when she challenged the illegal and unsafe medication administration policy in the Broken Arrow Public Schools. The purpose of this series is to enhance understanding of the legal parameters governing school nurse practice, provide examples of ethical decision making, and review the challenges associated with serving as a leader. PMID- 28671514 TI - A Day on the Hill. AB - This article describes the author's advocacy experience at a press briefing on Capitol Hill. At stake is the continuation of Medicaid and Children's Health Insurance Program-funded health insurance to our most vulnerable children-those living in poverty and those with chronic health conditions. Current legislation proposes to impose block grants or per capita caps on federal funding for Medicaid and will put the reauthorization of the Children's Health Insurance Program at risk. Schools stand to lose over 4 billion dollars in reimbursement for services that students need to succeed in school. PMID- 28671515 TI - State-level Collaborations Among School Nurse Organizations: A Year in Review. AB - The passage of the Every Student Succeeds Act provides an impetus for school nurse organizations to advocate for student health and climate goals at the state level. Collaboration between state agencies and associations is a starting point for advocacy. Advocacy also includes legislative involvement. This article explores state advocacy and collaboration efforts among school nurse organizations over the past year identifying common themes, with a focus on Every Student Succeeds Act involvement, as well as listing unique activities by state. PMID- 28671516 TI - Skin Infections: Which Student-Athletes Are at Greatest Risk? AB - Skin infections are a common ailment that affect all students, with increased risk to those students participating in sport and specifically contact sports. The types of skin infections that students are likely to encounter are categorized into three types: (a) bacterial, (b) viral, and (c) fungal. All three types of infection can appear benign at onset but can grow into serious disease and illness if not correctly identified and treated in a timely manner. A strong prevention program should be in place at all schools with appropriate resources in place (human and financial) to carry out proper cleaning of facilities, on site examination by the school nurse or athletic trainer, and sufficient education of coaches, athletes, parents and administrators. PMID- 28671517 TI - Erratum. AB - Johnson, K. H., Maughan, E., Bergren, M. D., Wolfe, L. C., Cole, M., & Watts, H. E. S. (2017). What's Up With Step Up!? Year 2! NASN, 32(2), 100-105. (DOI: 10.1177/1942602X17691808) In the March 2017 issue of NASN, the following abstract and keywords were not included in the manuscript. This has been updated in the online issue: Step Up & Be Counted! (Step Up!) is a joint initiative of the National Association of School Nurses (NASN) and the National Association of State School Nurse Consultants (NASSNC). The aim of Step Up! is for all school nurses across the nation to collect and submit specific, uniform data points for all their students. The program was initiated in 2014. In the second year of data collection, 2015-16, school nurses from more states contributed data, and many states reported on a larger number of school nurses reporting data. This article reports the progress we have made in data collection and reporting in year two. PMID- 28671518 TI - Journey to Leadership. PMID- 28671519 TI - Acinetobacter colistiniresistens sp. nov. (formerly genomic species 13 sensu Bouvet and Jeanjean and genomic species 14 sensu Tjernberg and Ursing), isolated from human infections and characterized by intrinsic resistance to polymyxins. AB - Strains of the genusAcinetobacter, classified as genomic species 13BJ/14TU have been previously associated with human infections and resistance to colistin. To clarify the taxonomy of this provisional group, we investigated 24 strains that have been isolated from humans since the 1960s in 10 countries. The genus-wide analysis of the rpoB and gyrB sequences of all strains and whole-genome sequences of strains representing different rpoB/gyrB genotypes showed that the 24 strains formed a distinct monophyletic group within the so-called haemolytic clade of the genus Acinetobacter. The distinctness of the group at the species level was supported by the results of the cluster analysis of the whole-cell protein fingerprints generated by matrix-assisted laser desorption ionization-time-of flight MS. The 24 strains had very similar metabolic features and could be distinguished from other members of the genus by the combination of strong haemolytic and proteolytic activities and the ability to oxidize d-glucose and grow on phenylacetate and/or l-phenylalanine. The minimum inhibitory concentrations of the 24 strains to colistin and polymyxin B ranged from 16 to 64 mgl-1 and from 4 to 32 mgl-1, respectively, so uniformly reaching the current clinical resistance breakpoint (4 mg l-1) for these drugs. Genus-wide comparison revealed that such a consistently high level of resistance to polymyxins is a unique feature among species of the genus Acinetobacter,which occur in humans. We conclude that genomic species 13BJ/14TU represents a biologically meaningful and medically relevant species, for which the name Acinetobacter colistiniresistens sp. nov. is proposed. The type strain is NIPH 2036T (=CCM 8641T=CIP 110478T=CCUG 67966T=CNCTC 7573T). PMID- 28671520 TI - Cysteiniphilum litorale gen. nov., sp. nov., isolated from coastal seawater. AB - A taxonomic study was performed on strain SYSU D3-2T, isolated from coastal seawater near the estuary of Pearl River in southern China. The strain was observed to be Gram-reaction-negative, non-motile and non-spore-forming. Cells were found to be of coccobacilli shape. Chemotaxonomic analysis of the plasma membrane revealed ubiquinone-8 as the respiratory quinone, diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminolipid, an unidentified aminophospholipid and an unidentified phospholipid as the polar lipids, and anteiso-C15 : 0, C18 : 0 and anteiso-C17 : 0 as the major fatty acids (>10 % of total fatty acids). Comparison of 16S rRNA gene sequences showed that strain SYSU D3-2T shared maximum similarities with Caedibacter taeniospiralis 51T (92.3 %) and Fangia hongkongensis UST040201-002T (90.6 %), while sharing 85.8-90.0 % similarity with species of the genera Allofrancisella and Francisella. Phylogenetic dendrograms based on the 16S rRNA gene sequences showed that the strain clustered within the family Francisellaceae, but formed a separate lineage closely linked to Caedibactertaeniospiralis 51T and F. hongkongensis UST040201 002T. Based on the findings of the polyphasic taxonomic study, strain SYSU D3-2T is proposed to be recognized as a representative of a novel species of a new genus within the order Thiotrichales, with the name Cysteiniphilum litorale gen. nov., sp. nov. The type strain of the type species is SYSU D3-2T (=NBRC 112441T=DSM 101832T=KCTC 52386T=CGMCC 1.15758T). PMID- 28671521 TI - Paucibacter oligotrophus sp. nov., isolated from fresh water, and emended description of the genus Paucibacter. AB - A Gram-stain-negative, rod-shaped, non-spore forming, motile and strictly oxidative bacterium, strain CHU3T, was isolated from fresh water in the Daecheong Reservoir, South Korea. A comparison of the 16S rRNA gene sequence showed that the novel bacterium is closely related to Paucibacter toxinivorans 2C20T (=KCTC 42569T) with a sequence similarity value of 97.8 %, Pelomonas saccharophila DSM 654T (=KCTC 52256T) with 97.4 % similarity and Pelomonas aquatica CCUG 52575T (=KCTC 42961T) with 97.3 % similarity, respectively. The major fatty acids (>10 %) of the isolate were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. Ubiquinone-8 was detected as the respiratory quinone. The polar lipids contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine and an unidentified aminolipid. The DNA G+C content was 62.5 mol%. DNA-DNA hybridization experiments with PaucibactertoxinivoransKCTC 42569T (=2C20T), PelomonassaccharophilaKCTC 52256T (=DSM 654T) and PelomonasaquaticaKCTC 42961T (=CCUG 52575T) resulted in relatedness values of 20 % (reciprocal 11 %), 16 % (reciprocal 17 %) and 15 % (reciprocal 19 %), respectively. The phylogenetic analysis, DNA-DNA hybridization value, polar lipids, fatty acid composition and other physiological characteristics confirmed that strain CHU3T represents a novel species in the genus Paucibacter for which the name Paucibacter oligotrophus sp. nov. is proposed. The type strain is CHU3T (=KCTC 42519T=CICC 24092T). An emended description of the genus Paucibacter is also proposed on the basis of new data obtained in this study. PMID- 28671522 TI - Molecular epidemiology of beta-lactamase producing nosocomial Gram-negative pathogens from North and South Indian hospitals. AB - PURPOSE: Resistant Gram-negative bacterial (GNB) infections, apart from tremendously escalating the cost of treatment, are a cause for substantial morbidity and mortality among hospitalized patients. Such bacteria are rapidly acquiring resistance to many antimicrobial agents, especially the beta-lactams which are the most frequently prescribed antimicrobials in hospital and community patient care settings, and now also to colistin; a last-line drug to treat infections with such bacteria. The greatest threat to antimicrobial treatment is the production of metallo beta-lactamases, and plasmid-mediated serine carbapenemases. METHODOLOGY: We conducted a two-year study to observe the pattern of beta-lactamase enzyme production (extended spectrum beta-lactamases (ESBLs), AmpC and carbapenemases) among the nosocomial GNB isolated from intensive care units (ICUs) of North and South Indian hospitals. A total of 761 non-duplicate GNB were included in the study from North (554; 73 %) and South India (207; 27 %). All strains were subjected to Clinical and Laboratory Standards Institute (CLSI) recommended screening tests for detection of beta-lactamase production, followed by polymerase chain reaction (PCR)-based detection of clinically important beta-lactamase genes mediating resistant phenotypes among these isolates. RESULTS: Out of the 761 GNB, Acinetobacter spp., Klebsiella spp., Pseudomonas spp., Enterobacter spp. and others were 27, 23 , 21 , 17 , 5 and 7 % respectively. A high prevalence of ESBL was found across all genera in these strains. The carbapenem resistance was higher in North than in South Indian GNB. The level of AmpC production was comparatively lower in both North and South Indian strains. CONCLUSION: Beta-lactamases showed tremendous variation in geographic distribution. Thus, their detection and characterization is important from a clinical-epidemiological, laboratory and infection control point of view. Knowledge of this epidemiology can predict the empiric antimicrobial treatment. PMID- 28671523 TI - Bradyrhizobium cajani sp. nov. isolated from nodules of Cajanus cajan. AB - Two slow-growing strains, AMBPC1010T and AMBPC1011, were isolated from nodules of Cajanus cajan in the Dominican Republic. 16S rRNA gene analysis placed these strains within the genus Bradyrhizobium, being phylogenetically equidistant to several species of this genus. Analysis of the recA and atpD genes showed that the strains isolated belong to a cluster containing the strains Bradyrhizobium ottawaense OO99T, 'Bradyrhizobium americanum' CMVU44 and Bradyrhizobium daqingense CCBAU 15774T, and presented similarity values lower than 96 % for both genes with respect to the strains nodulating C. cajan. DNA-DNA hybridization analysis showed averages of 36, 40 and 39 % relatedness with respect to the representative strains of Bradyrhizobium ottawaense, 'Bradyrhizobium americanum' and Bradyrhizobium daqingense, respectively. Phenotypic characteristics also differed from those of the most closely related species of the genus Bradyrhizobium. Therefore, based on the data obtained in this study, we propose to classify the strains AMBPC1010T (=LMG 29967T=CECT 9227T) and AMBPC1011 into a novel species named Bradyrhizobium cajani sp. nov. PMID- 28671524 TI - Comparison of the antiviral potential among soluble forms of herpes simplex virus type-2 glycoprotein D receptors, herpes virus entry mediator A, nectin-1 and nectin-2, in transgenic mice. AB - Herpesvirus entry mediator A (HVEM), nectin-1 and nectin-2 are cellular receptors of glycoprotein D (gD) of herpes simplex virus type-2 (HSV-2). It has been shown that soluble forms of HSV gD receptors have the antiviral potential in cultured cells and transgenic mice. Here, to compare antiviral potential of soluble forms of HVEM, nectin-1 and nectin-2 against HSV-2 infections in vivo, transgenic mice expressing fusion proteins consisting of the entire ectodomain of HVEM, nectin-1 or nectin-2 and the Fc portion of human IgG (HVEMIg, nectin-1Ig and nectin-2Ig, respectively) were intraperitoneally infected with HSV-2. In the infection with 3 MLD50 (50 % mouse lethal dose), effective resistance was not observed in transgenic mice expressing nectin-2Ig. In a transgenic mouse line with high expression of nectin-1Ig, significant protection from the infection with 30 and 300 MLD50 was observed (survival rate of 100 and 71 %, respectively). On the other hand, transgenic mice expressing HVEMIg showed a complete resistance to the lethal infection even with 300 MLD50 (survival rate of 100 %). These results demonstrated that HVEMIg could exert effective antiviral activities against HSV-2 infections in vivo as compared with other soluble forms of HSV gD receptors. PMID- 28671525 TI - Roseobacter ponti sp. nov., isolated from seawater. AB - A Gram-stain-negative, coccoid to oval-shaped and non-motile bacterial strain, designated MM-7T, was isolated from seawater of the Yellow Sea, South Korea, and was subjected to a polyphasic taxonomic study. Strain MM-7T grew optimally at pH 7.0-8.0, at 25 degrees C and in the presence of 2-3 % (w/v) NaCl. A neighbour joining phylogenetic tree based on 16S rRNA gene sequences showed that strain MM 7T joins the branch comprising the species of the genus Roseobacter, clustering with the type strains of Roseobacter litoralis and Roseobacter denitrificans, with which it exhibited 97.9 and 96.8 % sequence similarity values, respectively. The DNA G+C content of strain MM-7T was determined to be 60.8 mol%, and its mean DNA-DNA relatedness values with Rsb. litoralis JCM 21268T was 10.3+/-0.4 %. Strain MM-7T contained Q-10 as the predominant ubiquinone and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) as the major fatty acid. The major polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, an unidentified aminolipid and an unidentified lipid. Differential phenotypic properties, together with the phylogenetic distinctiveness, demonstrated that strain MM-7T is distinguishable from other species of the genus Roseobacter. On the basis of the data presented, strain MM-7T is considered to represent a novel species of the genus Roseobacter, for which the name Roseobacter ponti sp. nov. is proposed. The type strain is MM-7T (=KCTC 52469T=NBRC 112431T). PMID- 28671526 TI - Flavobacterium keumense sp. nov., isolated from freshwater. AB - A yellow-pigmented, oxidase-positive, catalase-negative, Gram-stain-negative, rod shaped, aerobic and non-motile bacterial strain designated K3R-10T was isolated from a freshwater source. The strain grew over a temperature range from 4 to 35 degrees C (optimum, 30 degrees C), pH range pH 6-8 (optimum, pH 7) and in the presence of 0-0.5 % NaCl (optimum, 0 %). Phylogenetic analysis based on 16S rRNA gene sequence revealed that strain K3R-10T belonged to the genus Flavobacterium and shared close similarities with Flavobacterium succinicans LMG 10402T (97.0 %), Flavobacterium chungangense LMG 26729T (96.4 %), Flavobacterium branchiophilum IFO 15030T (96.4 %) and Flavobacteriumpiscis412R-09T (96.3 %), but formed a distinct phylogenetic line of its own in the phylogenetic trees. The polar lipids consisted of phosphatidylethanolamine, an unidentified aminolipid and three unidentified phospholipids. The DNA G+C content was 35.4 mol%, MK-6 was the major isoprenoid quinone, and homospermidine was the predominant polyamine. The predominant cellular fatty acids were iso-C15 : 0 3-OH, iso-C15 : 0, a summed feature comprising C16 : 1omega7c and/or C16 : 1omega6c and iso-C15 : 1 G. The absence of aminophospholipid, acid production from carbohydrates, DNA G+C content and colony morphology differentiated strain K3R-10T from related species of the genus Flavobacterium. Thus, on the basis of phenotypic, chemotaxonomic and phylogenetic features, strain K3R-10T evidently represents a novel species in the genus Flavobacterium, for which the name Flavobacterium keumense sp. nov. is proposed. The type strain is K3R-10T (=JCM 31220T=KCTC 52563T). PMID- 28671527 TI - A proposal of Leuconostoc mesenteroides subsp. jonggajibkimchii subsp. nov. and reclassification of Leuconostoc mesenteroides subsp. suionicum (Gu et al., 2012) as Leuconostoc suionicum sp. nov. based on complete genome sequences. AB - The type strains of four subspecies of Leuconostocmesenteroides, L. mesenteroidessubsp. mesenteroides, L. mesenteroidessubsp. cremoris, L. mesenteroidessubsp. dextranicum and L. mesenteroidessubsp. suionicum, and strain DRC1506T, used as a starter culture for commercial kimchi production in Korea, were phylogenetically analyzed on the basis of their complete genome sequences. Although the type strains of the four L. mesenteroides subspecies and strain DRC1506T shared very high 16S rRNA gene sequence similarities (>99.72 %), the results of analysis of average nucleotide identity (ANI), in silico DNA-DNA hybridization (DDH) and core-genome-based relatedness indicated that they could form five different phylogenetic lineages. The type strains of L. mesenteroidessubsp. mesenteroides, L. mesenteroidessubsp. cremoris and L. mesenteroidessubsp. dextranicum and DRC1506T shared higher ANI and in silico DDH values than the thresholds (95-96 % and 70 %, respectively) generally accepted for different species delineation, whereas the type strain of L. mesenteroidessubsp. suionicum (DSM 20241T) shared lower ANI (<94.1 %) and in silico DDH values (<57.0 %) with the other four L. mesenteroides lineage strains, indicating that DSM 20241T couldn be reclassified as representing a different species. Here, we report that DRC1506T represents a novel subspecies within the species Leuconostoc mesenteroides, for which the name Leuconostoc mesenteroidessubsp. jonggajibkimchii subsp. nov. is proposed. The type strain is DRC1506T (=KCCM 43249T=JCM 31787T). In addition, L. mesenteroidessubsp. suionicum is also reclassified as Leuconostoc suionicum. sp. nov. (type strain DSM 20241T=ATCC 9135T=LMG 8159T=NCIMB 6992T). PMID- 28671528 TI - Bombella apis sp. nov., an acetic acid bacterium isolated from the midgut of a honey bee. AB - As part of a study to investigate the microbial diversity in the intestine of Apis mellifera, we isolated strain MRM1T from the midgut. MRM1T was a Gram-stain negative, strictly aerobic, non-motile, non-spore forming and rod-shaped bacteria. Creamy beige-coloured colonies were circular with entire margins in Lactobacilli MRS agar. The strain grew at 25-37 degrees C (optimum, 30-37 degrees C) and at a pH range of 4.0 to 9.0 (optimum pH, 7.0-8.5). The strain tolerated 0-1 % (w/v) NaCl (optimal growth occurred in the absence of NaCl). On the basis of the results of a phylogenetic analysis based on the 16S rRNA gene sequences, we determined that MRM1T represents a member of the genus Bombella with the highest sequence similarity to Bombella intestini LMG 28161T (98.8 %). The major quinone was Q10, and dominant fatty acids (>10 %) were C19 : 0cyclo omega8c (33.6 %), C16 : 0 (22.2 %), C18 : 1omega7c (15.9 %) and C14 : 0 (12.5 %). The polar lipid profile of MRM1T included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one unidentified phospholipid and four unidentified lipids. The DNA G+C content of MRM1T was 59.5 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, MRM1T represents a novel species of the genus Bombella, for which the name Bombella apis sp. nov. is proposed with the type strain MRM1T (=KCTC 52452T=JCM 31623T). PMID- 28671529 TI - Mycobacterium tuberculosis hypoxic response protein 1 (Hrp1) augments the pro inflammatory response and enhances the survival of Mycobacterium smegmatis in murine macrophages. AB - PURPOSE: The DosR/DosS two-component regulatory system of Mycobacterium tuberculosis regulates the expression of numerous genes under stress conditions and is important for the long-term survival of M. tuberculosis in the host. The rv2626c gene of M. tuberculosis is one of the most strongly induced transcripts of the dormancy regulon. This study focused on the immunological effects and possible function of Rv2626c in maintaining mycobacterial survival under various stress conditions. METHODOLOGY: We heterologously expressed the Rv2626c protein in Mycobacterium smegmatis by constructing a recombinant strain Ms_rv2626c. The viability of Ms_rv2626c was evaluated both in vivo and ex vivo. Different stress conditions, including acidified sodium nitrite, malachite green, low pH, SDS and lysozyme, were used to evaluate the effect of Rv2626c on bacterial resistance. An in vitro assay using a macrophage infection model was utilized to investigate the potential effect of Rv2626c to alter the immune response of host cell and its associated pathways. The effect of Rv2626c on cell necrosis was also explored. RESULTS: The expression of Rv2626c-enhanced M. smegmatis survival under hypoxia and nitric oxide stress in vitro, and this enhancement was maintained within macrophages and in mouse tissues. In addition, macrophages infected with M. smegmatis expressing Rv2626c showed significantly higher interleukin-1beta (IL 1beta), IL-6, tumour necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, as well as a higher level of cell necrosis, compared with the control. CONCLUSION: M. tuberculosis protein Rv2626c plays a significant role in stimulating macrophages to provoke a pro-inflammatory response and in mycobacterial survival during infection. PMID- 28671530 TI - Mobilicoccus caccae sp. nov., isolated from the faeces of the primate Rhinopithecus roxellanae. AB - A novel actinobacterium, designated YIM 101593T, was isolated from the faeces of a primate (Rhinopithecus roxellanae) living in Yunnan Wild Animal Park in Yunnan province, south-west China. The isolate was Gram-stain-positive, facultatively anaerobic, coccus-shaped, oxidase-negative and motile. The cell wall contained meso-diaminopimelic acid as its diagnostic diamino acid, and mannose, ribose, glucose, galactose and arabinose were detected as the main whole-cell sugars. The predominant menaquinone was MK-8(H2). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, two glycolipids, three unidentified phospholipids and two unidentified lipids. The major fatty acids were C17 : 1omega8c, C15 : 0 and summed feature 4 (anteiso-C17 : 1 B and/or iso-C17 : 1 I). The DNA G+C content was 69.8 mol%. The 16S rRNA gene sequence similarity between strain YIM 101593T and Mobilicoccus pelagius was 97.9 %, and the two strains formed a distinct lineage stably on the basis of phylogenetic analysis. In addition, DNA-DNA relatedness between the two strains was 49.0+/-5.1 %. On the basis of chemotaxonomical and physiological characteristics and the phylogenetic analysis, strain YIM 101593T should be considered to represent a novel species of the genus Mobilicoccus, for which we propose the name Mobilicoccus caccae sp. nov., with the type strain YIM 101593T (=DSM 27611T=CCTCC AB 2013229T). PMID- 28671531 TI - Genomic and physiological characterization of a laboratory-isolated Acinetobacter schindleri ACE strain that quickly and efficiently catabolizes acetate. AB - An Acinetobacter strain, designated ACE, was isolated in the laboratory. Phylogenetic tests and average nucleotide identity value comparisons suggested that ACE belongs to the species Acinetobacterschindleri. We report for the first time the complete genome sequence of an A. schindleri strain, which consists of a single circular chromosome of 3 001 209 bp with an overall DNA G+C content of 42.9 mol% and six plasmids that account for 266 844 bp of extrachromosomal material. The presence or absence of genes related to carbon catabolism and antibiotic resistance were in agreement with the phenotypic characterization of ACE. This strain grew faster and with a higher biomass yield on acetate than the reference strain Acinetobacter baylyi ADP1. However, ACE did not use aromatic compounds and was unable to grow on common carbon sources, such as glucose, xylose, glycerol or citrate. The gluconeogenic and the catechol pathways are complete in ACE, but compounds that are converted to protocatechuate did not sustain growth since some genes of this pathway are missing. Likewise, this strain could not grow on glucose because it lacks the genes of the Entner Doudoroff pathway. Minimal inhibitory concentration data showed that ACE was susceptible to most of the antimicrobial agents recommended for the clinical treatment of Acinetobacter spp. Some genes related to a possible human-microbe interaction were found in the ACE genome. ACE is likely to have a low pathogenic risk, as is the case with other A. schindleri strains. These results provide a valuable reference for broadening the knowledge of the biology of Acinetobacter. PMID- 28671532 TI - Paraglaciecola hydrolytica sp. nov., a bacterium with hydrolytic activity against multiple seaweed-derived polysaccharides. AB - A novel bacterial strain, S66T, was isolated from eelgrass collected on the coastline of Zealand, Denmark. Polyphasic analyses involving phenotypic, phylogenetic and genomic methods were used to characterize strain S66T. The strain was Gram-reaction-negative, rod-shaped, aerobic, and displayed growth at 10-25 degrees C (optimum 20-25 degrees C) and at pH 7-9 (optimum pH 7.5). Furthermore, strain S66T grew on seaweed polysaccharides agar, agarose, porphyran, kappa-carrageenan, alginate and laminarin as sole carbon sources. Major fatty acids were C16 : 0, C16 : 1omega7c and C18 : 1omega7c. The respiratory quinone was determined to be Q-8, and major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content was determined to be 42.2 mol%. Phylogenetic analyses based on the 16S rRNA gene and GyrB sequence comparisons showed that the bacterium was affiliated with the genus Paraglaciecola within the family Alteromonadaceae of the class Gammaproteobacteria. The percentage similarity between the 16S rRNA gene and GyrB sequences of strain S66T and other members of the genus Paraglaciecola were 94-95 % and 84-85 %, respectively. Based on the genome sequence of S66T, the average nucleotide identity (ANI) between strain S66T and other members of the genus Paraglaciecola was 77-80 %, and DNA-DNA hybridization prediction showed values of less than 24 % relatedness, respectively, between S66T and other species of the genus Paraglaciecola. The phenotypic, phylogenetic and genomic analyses support the hypothesis that strain S66T represents a novel species of the genus Paraglaciecola, for which the name Paraglaciecola hydrolytica sp. nov. is proposed. The type strain is S66T (=LMG 29457T=NCIMB 15060T=DSM 102834T). PMID- 28671533 TI - Identification of immediate early gene products of bovine herpes virus 1 (BHV-1) as dominant antigens recognized by CD8 T cells in immune cattle. AB - In common with other herpes viruses, bovine herpes virus 1 (BHV-1) induces strong virus-specific CD8 T-cell responses. However, there is a paucity of information on the antigenic specificity of the responding T-cells. The development of a system to generate virus-specific CD8 T-cell lines from BHV-1-immune cattle, employing Theileria-transformed cell lines for antigen presentation, has enabled us to address this issue. Use of this system allowed the study to screen for CD8 T-cell antigens that are efficiently presented on the surface of virus-infected cells. Screening of a panel of 16 candidate viral gene products with CD8 T-cell lines from 3 BHV-1-immune cattle of defined MHC genotypes identified 4 antigens, including 3 immediate early (IE) gene products (ICP4, ICP22 and Circ) and a tegument protein (UL49). Identification of the MHC restriction specificities revealed that the antigens were presented by two or three class I MHC alleles in each animal. Six CD8 T-cell epitopes were identified in the three IE proteins by screening of synthetic peptides. Use of an algorithm (NetMHCpan) that predicts the peptide-binding characteristics of restricting MHC alleles confirmed and, in some cases refined, the identity of the epitopes. Analyses of the epitope specificity of the CD8 T-cell lines showed that a large component of the response is directed against these IE epitopes. The results indicate that these IE gene products are dominant targets of the CD8 T-cell response in BHV-I-immune cattle and hence are prime-candidate antigens for the generation of a subunit vaccine. PMID- 28671534 TI - Salinarchaeum chitinilyticum sp. nov., a chitin-degrading haloarchaeon isolated from commercial salt. AB - Two chitin-degrading halophilic archaeal strains, MC-74T and MC-23, were isolated from commercial salt samples. Cells were motile, rod-shaped and stained Gram negative. Colonies were vermillion-pigmented. Strains MC-74T and MC-23 were able to grow with 1.5-5.1 M NaCl (optimum, 2.6-3.1 M) at pH 6.0-10.0 (optimum, pH 7.0) and at 20-50 degrees C (optimum, 40 degrees C). The orthologous 16S rRNA gene sequence similarity between the two strains was 99.8 %, and the closest phylogenetic relative was Salinarchaeum laminariae JCM 17267T with 99.3-99.5 % similarity. The level of DNA-DNA relatedness between the two strains was 93 and 94 % (reciprocally), and those between the two strains and Salinarchaeumlaminariae JCM 17267T were 35-36 % and 38-39 % (reciprocally). The polar lipids of both strains were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and phosphatidylglycerol sulfate. Glycolipids were not detected. Based on the phenotypic and phylogenetic analyses, the strains represent a novel species of the genus Salinarchaeum, for which the name Salinarchaeum chitinilyticum sp. nov. is proposed. The type strain is MC-74T (=JCM 19597T=KCTC 4262T), isolated from solar salt produced in France. Strain MC 23, isolated from a commercial solar salt sample produced in China, is an additional strain of the species. PMID- 28671535 TI - Comparative analysis of the genomes of clinical isolates of Mycobacterium avium subsp. hominissuis regarding virulence-related genes. AB - PURPOSE: Mycobacterium avium subsp. hominissuis is a member of the M. avium complex, a heterogeneous group of bacteria that cause lung infection in immunocompetent patients or disseminated infection in patients with immunosuppression. The bacteria belonging to this complex have variable virulence, depending on the strain considered, and therefore a representative of the most common clinical phenotype was analysed. METHODOLOGY: The genomic sequences of four M. avium subsp. hominissuis isolates obtained from clinical specimens were completed. Mav101, Mav100 and MavA5 were isolated from the blood of patients with AIDS. MavA5 was disseminated from the lung, while Mav3388 was isolated from the lungs of a patient with chronic lung disease. The sequences were annotated using the published Mav104 genome as a blueprint. Functional and virulence analyses of the sequences were carried out. Mice studies comparing the virulence of the strains were performed. RESULTS: Findings showed that while Mav101 was very similar to Mav104, there were numerous differences between Mav104 and the remaining strains at nucleotide and predicted protein levels. The presence of genes associated with biofilm formation and several known virulence related genes were sometimes differentially present among the isolates, suggesting overlapping functions by different genetic determinants. CONCLUSIONS: The sequences provided important information about M. avium heterogenicity and evolution as a pathogen. The limitation is the lack of understanding on possible overlapping functions of genes/proteins. PMID- 28671536 TI - Paenibacillus polysaccharolyticus sp. nov., a xylanolytic and cellulolytic bacteria isolated from leaves of Bamboo Phyllostachys aureosulcata. AB - A novel xylanolytic and cellulolytic strain, BL9T, was isolated from leaves of the Bamboo plants maintained at the Tamil Nadu Agricultural University Campus, Coimbatore, India. On the basis of the results of 16S rRNA gene analysis, it was determined to be phylogenetically close to the type strains of Paenibacillus amylolyticus NRRL NRS-290T (98.3 %), Paenibacillus barcinonensis BP-23T (98.1 %), Paenibacillus tundrae A10bT (98.0 %) and Paenibacillus xylanexedens B22aT (97.6 %). The strain stained Gram variable and was aerobic, motile and catalase- and oxidase-positive, with rod-shaped cells. Based upon the genome sequence, the average nucleotide identity with the related species ranged from 66 % to 72 %, and the digital DNA-DNA hybridization value ranged from 13 % to 27 %. The DNA G+C content was 45.6 mol%, meso-diaminopimelic acid was identified as the predominant component of the cell wall, and MK-7 was the only menaquinone in cell membranes. The whole-cell fatty acid profile included C16 : 0, iso-C14 : 0, anteiso-C15 : 0 and iso-C16 : 0. The polar lipids identified were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine and diphosphtidylglycerol. On the basis of these polyphasic taxonomic traits, BL9T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus polysaccharolyticus sp. nov. is proposed. The type strain is BL9T (=NBRC 105191T=ICMP 17623T). PMID- 28671537 TI - The distribution of carbapenem- and colistin-resistance in Gram-negative bacteria from the Tamil Nadu region in India. AB - PURPOSE: The occurrence of carbapenem- and colistin-resistance among Gram negative bacteria is increasing worldwide. The aim of this study was to understand the distribution of carbapenem- and colistin-resistance in two areas in Tamil Nadu, India. METHODOLOGY: The clinical isolates (n=89) used in this study were collected from two diagnostic centres in Tamil Nadu, India. The bacterial isolates were screened for meropenem- and colistin-resistance. Further, resistance genes blaNDM-1, blaOXA-48-like, blaIMP, blaVIM, blaKPC, mcr-1 and mcr 2 and integrons were studied. The synergistic effect of meropenem in combination with colistin was assessed. RESULTS: A total of 89 bacterial isolates were studied which included Escherichia coli (n=43), Klebsiella pneumoniae (n=18), Pseudomonas aeruginosa (n=10), Enterobacter cloacae (n=6), Acinetobacter baumannii (n=5), Klebsiella oxytoca (n=4), Proteus mirabilis (n=2) and Salmonella paratyphi (n=1). MIC testing showed that 58/89 (65 %) and 29/89 (32 %) isolates were resistant to meropenem and colistin, respectively, whereas 27/89 (30 %) isolates were resistant to both antibiotics. Escherichia coli, K. pneumoniae, K. oxytoca, Pseudomonas aeruginosa, and Enterobacter cloacae isolates were blaNDM-1 positive (n=20). Some strains of Escherichia coli, K. pneumoniae and K. oxytoca were blaOXA-181-positive (n=4). Class 1, 2 and 3 integrons were found in 24, 20 and 3 isolates, respectively. Nine NDM-1-positive Escherichia coli strains could transfer carbapenem resistance via plasmids to susceptible Escherichia coli AB1157. Meropenem and colistin showed synergy in 10/20 (50 %) isolates by 24 h time-kill studies. CONCLUSION: Our results highlight the distribution of carbapenem- and colistin-resistance in Gram-negative bacteria isolated from the Tamil Nadu region in South India. PMID- 28671538 TI - Getting to Now: The Challenge of Stimulating Innovation in Complex Systems. AB - In this issue of Healthcare Papers, Anne Snowdon clearly articulates the elements necessary for a health system innovation agenda. Although these steps are not easy - witness the slow progress of the adoption and diffusion of innovation across Canadian healthcare - they are relatively simple and provide a nice counterpoint to our usual concerns about how to effect change within the complex environment of healthcare. The commentators in this issue re-enforce the importance of particular elements or the feasibility of taking some of the first hard steps. PMID- 28671539 TI - A Blueprint for Innovation to Achieve Health System Transformation. AB - Global health systems are challenged by escalating costs and growing demands for care created by the demands of aging populations and rising rates of chronic illness which place unsustainable pressure on health systems to meet population health needs. To overcome these challenges, transformational change is needed to strengthen health system performance and sustainability. Innovation is widely viewed as the strategy to drive transformational change in health systems; yet to date, innovation has lacked a clearly defined focus or agenda to achieve transformation. An actionable innovation agenda is needed to achieve transformational change for health systems. The key conditions for success as an innovation strategy are examined, including clearly defined innovation objectives, key milestones, and actionable steps every system stakeholder must pursue in order to guide the innovation agenda and ultimately accelerate the transformational changes needed for a sustainable healthcare system that delivers value to populations. PMID- 28671540 TI - Health System Innovation: Lessons from Tobacco Control. AB - Comprehensive tobacco control is considered by many to be a model for effective population health promotion and chronic disease prevention. Its history holds lessons for the "scalable, actionable, innovation agenda" called for by Anne Snowdon (2017). This commentary discusses lessons from tobacco control related to: changing practices in response to evolving paradigms and scientific evidence; international best practices; the importance of a broadly-accepted, shared vision about elements of an effective strategy; scientific and public service leadership; social actors leading change through advocacy, policy and the media; organizational learning mechanisms and capacity building systems; and, the importance of a continuously renewing, forward-looking agenda. The end-game for tobacco forms part of Canada's health innovation agenda and lessons from tobacco control may inform this important forward-looking strategy. PMID- 28671541 TI - Shifting Paradigms in Canadian Healthcare to Support the Scale and Spread of Innovation. AB - Health systems and healthcare organizations across Canada have identified the need for innovation to transform healthcare by creating the conditions for successful, scalable and impactful system transformation. Meeting these goals requires adopting new leadership paradigms to shape and design policy frameworks, business models, technical structures and funding approaches. In order to scale innovation and achieve system-wide impact, system leaders will need to create a culture that supports innovation and transformational change. PMID- 28671542 TI - Transforming Healthcare Through Technology. AB - In this commentary, we outline the necessity of change in the way we run healthcare systems due to a range of factors, common across the globe, and assert that transformational technology is an important tool for change. We propose that there are seven imperatives to pursue and that emerging evidence from digital health solutions could become an important part of achieving each of them. We provide examples of some of the technologies that respond to each issue we identify, and reference some programs designed to support the acceleration of use of these technologies across the UK's National Health Service. Finally we conclude that even the best ideas do not spread themselves and that there is a key role to play here if we are to maximise the impact on patients and health services at pace and scale. PMID- 28671543 TI - Quality and Innovation: Redesigning a Coordinated and Connected Health System. AB - Nova Scotia's consolidated health system was launched on April 1, 2015. This new approach to organizing health administration and services in the province arose out of necessity. When planning began, Nova Scotia was spending 41% of its annual budget on health services. In comparison to other provinces and territories, our per capita health-related spending was among the highest in the country, we had one of Canada's oldest populations and we had some of the worst health outcomes. Clearly, we could not continue to do the same things and expect different results. Both the life sciences and technology are changing at breakneck speed, while design of healthcare delivery has barely moved beyond a mid-twentieth century paternalistic provider-centric model. Nova Scotia's transformation journey was facilitated by a major policy effort 20 years earlier that had integrated emergency health services across the province. Our aim was to build on that foundation by integrating administration in order to build primary care networks with enhanced regional specialty services, with tertiary services located in Halifax. The goal of health system innovation in Nova Scotia was - and is - based firmly on the dimensions of quality: safe care that avoids harming patients; effective care that is based on levels of evidence to achieve scalability; access to care that is focused on individuals; efficient care that reduces waste, time, energy and supplies; and equitable care that ensures a system is in place that mitigates differences in geography and social economic status. The author offers a sketch of the principal initiatives, challenges, considerations, approaches and lessons involved in this multi-factorial, multi stakeholder innovation process. PMID- 28671544 TI - The Drive towards Sustainable Health Systems Needs an Alignment: Where are the Innovations in Health Systems Planning? AB - Clarifying the healthcare innovation agenda is critical in order to advance the impact of system innovations. As part of this agenda-setting it is important to address the four conditions within which innovations can enhance system sustainability: 1) the innovation agenda reflects and is aligned with healthcare objectives and policy; 2) planning methodologies for services, workforce and funding are aligned with healthcare objectives and policy; 3) innovations in services are accommodated in systems through innovations in policy, planning and funding; and 4) innovations are systematically monitored and evaluated. In order to illustrate these conditions, the authors present a case study of an evaluation of one Canadian Health Authority's efforts to transform healthcare delivery. This case study reveals that aligning innovations in policy, planning, funding and health services is critical to transforming health systems and that, in the absence of such alignment, sustainable health systems are difficult to achieve. PMID- 28671545 TI - Creating Value in Healthcare: The Need for Innovative Solutions. AB - The combined impact of an aging population's healthcare needs and the growing prevalence of chronic disease has, and will continue to have, a significant impact on healthcare capacity and economics. In the context of resource constraints there is a tendency to focus on doing more with less. However, the real opportunity may lie in building capacity by doing things differently. The authors propose a new paradigm for innovative hospital care and illustrate its potential by examining recent endeavours at a large, full-service hospital in Southern Ontario. Innovation is about finding new ways of doing things that lead to better outcomes. Many healthcare leaders characterize their organizations as innovative, asserting they are committed to identifying and implementing best practices in clinical care. Despite this pledge, the lag time in the clinical implementation of translational research can be up to 17 years (Morris et al. 2011). Clearly, there is an opportunity to achieve better outcomes by developing a more systematic approach to implementing this type of research. Creating a culture of innovation in which ideas thrive and there is a commitment to adopting proven best practices should be part of the solution. PMID- 28671546 TI - Key Conditions for Successful Serial Entrepreneurship in Healthcare. AB - As a serial entrepreneur in the medical device industry, the author embraces Snowdon's (2017) effort to create and stimulate dialogue among experts in health system innovation in an effort to define and support Canada's innovation agenda. In this paper, he outlines some of the attributes and skills that companies need to launch their products and scale their companies. He also identifies the main conditions of an innovation ecosystem that create the necessary infrastructure to enable and support highly successful companies while allowing them to accelerate their growth. PMID- 28671547 TI - Health System Transformation through a Scalable, Actionable Innovation Strategy. AB - The authors who contributed to this issue of Healthcare Papers have provided rich insights into a promising innovation agenda to support transformational change aimed at achieving high-performing, person-centric health systems that are sustainable and deliver value. First and foremost, the commentaries make clear that a focused innovation agenda with defined goals, objectives and milestones is needed, if innovation is to be a viable and successful strategy to achieve health system transformation. To date, innovation has been a catch-all term for solving the many challenges health systems are experiencing. Yet, innovation on its own cannot fix all the ills of a health system; strategic goals and objectives are needed to define the way forward if innovation is to achieve value for Canadians. To this end, the authors identify goals and objectives that are worthy of serious consideration by all health system stakeholders. PMID- 28671548 TI - Motoneurons regulate the central pattern generator during drug-induced locomotor like activity in the neonatal mouse. AB - Motoneurons are traditionally viewed as the output of the spinal cord that do not influence locomotor rhythmogenesis. We assessed the role of motoneuron firing during ongoing locomotor-like activity in neonatal mice expressing archaerhopsin 3 (Arch), halorhodopsin (eNpHR), or channelrhodopsin-2 (ChR2) in Choline acetyltransferase neurons (ChAT+) or Arch in LIM-homeodomain transcription factor Isl1+ neurons. Illumination of the lumbar cord in mice expressing eNpHR or Arch in ChAT+ or Isl1+ neurons, depressed motoneuron discharge, transiently decreased the frequency, and perturbed the phasing of the locomotor-like rhythm. When the light was turned off motoneuron firing and locomotor frequency both transiently increased. These effects were not due to cholinergic neurotransmission, persisted during partial blockade of gap junctions and were mediated, in part, by AMPAergic transmission. In spinal cords expressing ChR2, illumination increased motoneuron discharge and transiently accelerated the rhythm. We conclude that motoneurons provide feedback to the central pattern generator (CPG) during drug-induced locomotor-like activity. PMID- 28671549 TI - Minimal-assumption inference from population-genomic data. AB - Samples of multiple complete genome sequences contain vast amounts of information about the evolutionary history of populations, much of it in the associations among polymorphisms at different loci. We introduce a method, Minimal-Assumption Genomic Inference of Coalescence (MAGIC), that reconstructs key features of the evolutionary history, including the distribution of coalescence times, by integrating information across genomic length scales without using an explicit model of coalescence or recombination, allowing it to analyze arbitrarily large samples without phasing while making no assumptions about ancestral structure, linked selection, or gene conversion. Using simulated data, we show that the performance of MAGIC is comparable to that of PSMC' even on single diploid samples generated with standard coalescent and recombination models. Applying MAGIC to a sample of human genomes reveals evidence of non-demographic factors driving coalescence. PMID- 28671550 TI - Amount of fear extinction changes its underlying mechanisms. AB - There has been a longstanding debate on whether original fear memory is inhibited or erased after extinction. One possibility that reconciles this uncertainty is that the inhibition and erasure mechanisms are engaged in different phases (early or late) of extinction. In this study, using single-session extinction training and its repetition (multiple-session extinction training), we investigated the inhibition and erasure mechanisms in the prefrontal cortex and amygdala of rats, where neural circuits underlying extinction reside. The inhibition mechanism was prevalent with single-session extinction training but faded when single-session extinction training was repeated. In contrast, the erasure mechanism became prevalent when single-session extinction training was repeated. Moreover, ablating the intercalated neurons of amygdala, which are responsible for maintaining extinction-induced inhibition, was no longer effective in multiple session extinction training. We propose that the inhibition mechanism operates primarily in the early phase of extinction training, and the erasure mechanism takes over after that. PMID- 28671551 TI - 3D printing for sizing left atrial appendage closure device: head-to-head comparison with computed tomography and transoesophageal echocardiography. AB - AIMS: Device sizing for LAA closure using transoesophageal echocardiography (TEE) can be challenging due to complex LAA anatomy. We investigated whether the use of 3D-printed left atrial appendage (LAA) models based on preprocedural computed tomography (CT) permits accurate device sizing. METHODS AND RESULTS: Twenty-two (22) patients (73+/-8 years, 55% male) with atrial fibrillation requiring anticoagulation at high bleeding risk underwent LAA closure (WATCHMAN device). Preprocedurally, LAA was sized by TEE and third-generation dual-source CT. Based on CT, 3D printing models of LAA anatomy were created for simulation of device implantation. Device compression was assessed in a CT scan of the 3D model with the implanted device. Implantation was successful in all patients. Mean LAA ostium diameter based on TEE was 22+/-4 mm and based on CT 25+/-3 mm (p=0.014). Predicted device size based on simulated implantation in the 3D model was equal to the device finally implanted in 21/22 patients (95%). TEE would have undersized the device in 10/22 patients (45%). Device compression determined in the 3D-CT model corresponded closely with compression upon implantation (16+/-3% vs. 18+/-5%, r=0.622, p=0.003). CONCLUSIONS: Patient-specific CT-based 3D printing models may assist device selection and prediction of device compression in the context of interventional LAA closure. PMID- 28671552 TI - Midterm clinical outcomes with everolimus-eluting bioresorbable scaffolds versus everolimus-eluting metallic stents for percutaneous coronary interventions: a meta-analysis of randomised trials. AB - : bioresorbable vascular scaffold (BVS) versus an everolimus-eluting metallic stent (EES) for percutaneous coronary interventions. METHODS AND RESULTS: We performed a meta-analysis of aggregate data by searching Medline, EMBASE, Cochrane databases and proceedings of international meetings for randomised trials reporting the clinical outcomes beyond one year of patients treated with BVS versus EES. The primary efficacy and safety outcomes were target lesion failure (TLF) and definite/probable stent (scaffold) thrombosis (ST), respectively. Secondary outcomes were the individual components of the primary efficacy outcome (cardiac death, target vessel myocardial infarction [MI], and ischaemia-driven target lesion revascularisation [ID-TLR]). A total of 5,583 patients randomly received BVS (n=3,261) or EES (n=2,322) in seven trials. Weighted median follow-up was 26.6 months. Patients treated with BVS versus EES showed a higher risk of TLF (odds ratio [OR] 1.35, 95% confidence interval [CI]: 1.11-1.65; p=0.0028) due to a higher risk of target vessel MI (OR 1.68, 95% CI: 1.21-2.33; p=0.008) and ID-TLR (OR 1.42, 95% CI: 1.10-1.84; p=0.007) though the risk for cardiac death was not statistically different (OR 0.89, 95% CI: 0.55 1.43; p=0.56). Patients treated with BVS versus EES showed a higher risk of definite/probable ST (OR 3.24, 95% CI: 1.92-5.49; p<0.0001), particularly in the period beyond one year after implantation (OR 4.03, 95% CI: 1.49-10.87; p=0.006). CONCLUSIONS: At midterm follow-up, patients treated with BVS as compared to those treated with EES display a higher risk of target lesion failure and scaffold thrombosis. PMID- 28671553 TI - The ultra-short virological dynamics in response to entecavir or lamivudine during chronic hepatitis B with spontaneous severe acute exacerbation. AB - BACKGROUND: Nucleoside/nucleotide analogue (NA) therapy could be life-saving in chronic hepatitis B (CHB) with spontaneous severe acute exacerbation (SAE). We aimed to investigate the ultra-short virological responses to NA. METHODS: We conducted a randomized controlled trial in which CHB patients with spontaneous SAE were randomized to receive lamivudine (LVD) or entecavir (ETV) between July 2012 and April 2016 (ClinicalTrials.gov: NCT01627223). The serum HBV viral loads on day 1 (baseline), 3, 5, 8, 15, 22, 29, 85 and 180 after initiating NA therapy were checked and analysed. RESULTS: In total, 17 patients (7 in LVD and 10 in ETV group) were recruited, and 3 patients (17.7%) died or received liver transplantation due to hepatic failure. The median (IQR) HBV DNA decline on days 3, 5, 8, 15, 22, 29, 85 and 180 were 1.38 (1.09-1.50), 2.36 (1.89-2.58), 3.19 (2.21-3.51), 3.76 (2.54-4.40), 3.43 (2.44-4.75), 4.00 (3.01-5.04), 5.00 (3.61 6.21) and 6.50 (4.12-7.20) log IU/ml, respectively. The baseline characteristics were basically similar between the two groups, and the dynamic changes in HBV DNA were not significantly different between the two groups. Further analysis of the patients with high HBV viral load (>6 log IU/ml) revealed that a similar baseline HBV DNA level in the two groups (LVD versus ETV: median 8.0 [7.5-8.8] versus 7.7 [6.6-8.4] log IU/ml; P=0.45), and the dynamic changes of HBV DNA were very similar. CONCLUSIONS: CHB with spontaneous SAE responded similarly to treatment using either LVD or ETV, with both drugs inducing a rapid decline of HBV viral load. PMID- 28671554 TI - A machine-learning based analysis for the recognition of progressive central hypovolemia. AB - OBJECTIVE: Traditional patient monitoring during surgery includes heart rate (HR), blood pressure (BP) and peripheral oxygen saturation. However, their use as predictors for central hypovolemia is limited, which may lead to cerebral hypoperfusion. The aim of this study was to develop a monitoring model that can indicate a decrease in central blood volume (CBV) at an early stage. APPROACH: Twenty-eight healthy subjects (aged 18-50 years) were included. Lower body negative pressure (-50 mmHg) was applied to induce central hypovolemia until the onset of pre-syncope. Ten beat-to-beat and four discrete parameters were measured, normalized, and filtered with a 30 s moving window. Time to pre-syncope was scaled from 100%-0%. A total of 100 neural networks with 5, 10, 15, 20, or 25 neurons in their respective hidden layer were trained by 10, 20, 40, 80, 160, or 320 iterations to predict time to pre-syncope for each subject. The network with the lowest average slope of a fitted line over all subjects was chosen as optimal. MAIN RESULTS: The optimal generalized model consisted of 10 hidden neurons, trained using 80 iterations. The slope of the fitted line on the average prediction was -0.64 (SD 0.35). The model recognizes in 75% of the subjects the need for intervention at >200 s before pre-syncope. SIGNIFICANCE: We developed a neural network based on a set of physiological variables, which indicates a decrease in CBV even in the absence of HR and BP changes. This should allow timely intervention and prevent the development of symptomatic cerebral hypoperfusion. PMID- 28671555 TI - GC-MS Fingerprinting Combined with Chemometric Methods Reveals Key Bioactive Components in Acori Tatarinowii Rhizoma. AB - This present study aims to identify the key bioactive components in acorus tatarinowii rhizoma (ATR), a traditional Chinese medicine (TCM) with various bioactivities. Partial least squares regression (PLSR) was employed to describe the relationship between the radical scavenging activity and the volatile components. The PLSR model was improved by outlier elimination and variable selection and was evaluated by 10-fold cross-validation and external validation in this study. Based on the PLSR model, eleven chemical components were identified as the key bioactive components by variable importance in projection. The final PLS regression model with these components has good predictive ability. The Q2 was 0.8284, and the root mean square error for prediction was 2.9641. The results indicated that the eleven components could be a pattern to predict the radical scavenging activity of ATR. In addition, we did not find any specific relationship between the radical scavenging ability and the habitat of the ATRs. This study proposed an efficient strategy to predict bioactive components using the combination of quantitative chromatography fingerprints and PLS regression, and has potential perspective for screening bioactive components in complex analytical systems, such as TCM. PMID- 28671556 TI - Mesenchymal Stromal Cells: What Is the Mechanism in Acute Graft-Versus-Host Disease? AB - After more than a decade of preclinical and clinical development, therapeutic infusion of mesenchymal stromal cells is now a leading investigational strategy for the treatment of acute graft-versus-host disease (GVHD). While their clinical use continues to expand, it is still unknown which of their immunomodulatory properties contributes most to their therapeutic activity. Herein we describe the proposed mechanisms, focusing on the inhibitory activity of mesenchymal stromal cells (MSCs) at immunologic checkpoints. A deeper understanding of the mechanism of action will allow us to design more effective treatment strategies. PMID- 28671557 TI - P300 Source Localization Contrasts in Body-Focused Repetitive Behaviors and Tic Disorders. AB - Tic disorders (TD) and body-focused repetitive behaviors (BFRB) have similar phenotypes that can be challenging to distinguish in clinical settings. Both disorders show high rates of comorbid psychiatric conditions, dysfunctional basal ganglia activity, atypical cortical functioning in the prefrontal and motor cortical regions, and cognitive deficits. Clinicians frequently confound the two disorders and it is important to find reliable objective methods to discriminate TD and BFRB. Neuropsychological tests and event-related potential (ERP) studies have yielded inconsistent results regarding a possible context updating deficit in TD and BFRB patients. However, most previous studies did not control for the presence of comorbid psychiatric condition and medication status, which might have confounded the findings reported to date. Hence, we aimed to investigate the psychophysiology of working memory using ERP in carefully screened TD and BFRB patients excluding those with psychiatric comorbidity and those taking psychoactive medication. The current study compared 12 TD patients, 12 BRFB patients, and 15 healthy control participants using a motor oddball task (button press). The P300 component was analyzed as an index of working memory functioning. Results showed that BFRB patients had decreased P300 oddball effect amplitudes over the right hemisphere compared to the TD and control groups. Clinical groups presented different scalp distributions compared to controls, which could represent a potential endophenotype candidate of BFRB and TD. PMID- 28671558 TI - Brain Functional Connectivity Is Modified by a Hypocaloric Mediterranean Diet and Physical Activity in Obese Women. AB - Functional magnetic resonance imaging (fMRI) in the resting state has shown altered brain connectivity networks in obese individuals. However, the impact of a Mediterranean diet on cerebral connectivity in obese patients when losing weight has not been previously explored. The aim of this study was to examine the connectivity between brain structures before and six months after following a hypocaloric Mediterranean diet and physical activity program in a group of sixteen obese women aged 46.31 +/- 4.07 years. Before and after the intervention program, the body mass index (BMI) (kg/m2) was 38.15 +/- 4.7 vs. 34.18 +/- 4.5 (p < 0.02), and body weight (kg) was 98.5 +/- 13.1 vs. 88.28 +/- 12.2 (p < 0.03). All subjects underwent a pre- and post-intervention fMRI under fasting conditions. Functional connectivity was assessed using seed-based correlations. After the intervention, we found decreased connectivity between the left inferior parietal cortex and the right temporal cortex (p < 0.001), left posterior cingulate (p < 0.001), and right posterior cingulate (p < 0.03); decreased connectivity between the left superior frontal gyrus and the right temporal cortex (p < 0.01); decreased connectivity between the prefrontal cortex and the somatosensory cortex (p < 0.025); and decreased connectivity between the left and right posterior cingulate (p < 0.04). Results were considered significant at a voxel-wise threshold of p <= 0.05, and a cluster-level family-wise error correction for multiple comparisons of p <= 0.05. In conclusion, functional connectivity between brain structures involved in the pathophysiology of obesity (the inferior parietal lobe, posterior cingulate, temporo-insular cortex, prefrontal cortex) may be modified by a weight loss program including a Mediterranean diet and physical exercise. PMID- 28671560 TI - A Steel Ball Surface Quality Inspection Method Based on a Circumferential Eddy Current Array Sensor. AB - To efficiently inspect surface defects on steel ball bearings, a new method based on a circumferential eddy current array (CECA) sensor was proposed here. The best probe configuration, in terms of the coil quality factor (Q-factor), magnetic field intensity, and induced eddy current density on the surface of a sample steel ball, was determined using 3-, 4-, 5-, and 6-coil probes, for analysis and comparison. The optimal lift-off from the measured steel ball, the number of probe coils, and the frequency of excitation current suitable for steel ball inspection were obtained. Using the resulting CECA sensor to inspect 46,126 steel balls showed a miss rate of ~0.02%. The sensor was inspected for surface defects as small as 0.05 mm in width and 0.1 mm in depth. PMID- 28671559 TI - Thiolate-Capped CdSe/ZnS Core-Shell Quantum Dots for the Sensitive Detection of Glucose. AB - A semiconducting water-soluble core-shell quantum dots (QDs) system capped with thiolated ligand was used in this study for the sensitive detection of glucose in aqueous samples. The QDs selected are of CdSe-coated ZnS and were prepared in house based on a hot injection technique. The formation of ZnS shell at the outer surface of CdSe core was made via a specific process namely, SILAR (successive ionic layer adsorption and reaction). The distribution, morphology, and optical characteristics of the prepared core-shell QDs were assessed by transmission electron microscopy (TEM) and spectrofluorescence, respectively. From the analysis, the results show that the mean particle size of prepared QDs is in the range of 10-12 nm and that the optimum emission condition was displayed at 620 nm. Further, the prepared CdSe/ZnS core shell QDs were modified by means of a room temperature ligand-exchange method that involves six organic ligands, L cysteine, L-histidine, thio-glycolic acid (TGA or mercapto-acetic acid, MAA), mercapto-propionic acid (MPA), mercapto-succinic acid (MSA), and mercapto undecanoic acid (MUA). This process was chosen in order to maintain a very dense water solubilizing environment around the QDs surface. From the analysis, the results show that the CdSe/ZnS capped with TGA (CdSe/ZnS-TGA) exhibited the strongest fluorescence emission as compared to others; hence, it was tested further for the glucose detection after their treatment with glucose oxidase (GOx) and horseradish peroxidase (HRP) enzymes. Here in this study, the glucose detection is based on the fluorescence quenching effect of the QDs, which is correlated to the oxidative reactions occurred between the conjugated enzymes and glucose. From the analysis of results, it can be inferred that the resultant GOx:HRP/CdSe/ZnS-TGA QDs system can be a suitable platform for the fluorescence based determination of glucose in the real samples. PMID- 28671561 TI - Detection of Quinoline in G. boninense-Infected Plants Using Functionalized Multi Walled Carbon Nanotubes: A Field Study. AB - Carbon nanotubes (CNTs) reinforced with gold nanoparticles (AuNPs) and chitosan nanoparticles (CTSNPs) were anchored on a screen-printed electrode to fabricate a multi-walled structure for the detection of quinoline. The surface morphology of the nanocomposites and the modified electrode was examined by an ultra-high resolution field emission scanning electron microscope (FESEM), and Fourier transform infrared (FT-IR) spectroscopy was used to confirm the presence of specific functional groups on the multi-walled carbon nanotubes MWCNTs. Cyclic voltammetry (CV) and linear sweep voltammetry (LSV) were used to monitor the layer-by-layer assembly of ultra-thin films of nanocomposites on the surface of the electrode and other electrochemical characterizations. Under optimized conditions, the novel sensor displayed outstanding electrochemical reactivity towards the electro-oxidation of quinoline. The linear range was fixed between 0.0004 and 1.0 MUM, with a limit of detection (LOD) of 3.75 nM. The fabricated electrode exhibited high stability with excellent sensitivity and selectivity, specifically attributable to the salient characteristics of AuNPs, CTSNPs, and MWCNTs and the synergistic inter-relationship between them. The newly developed electrode was tested in the field. The Ipa increased with an increase in the amount of quinoline solution added, and the peak potential deviated minimally, depicting the real capability of the newly fabricated electrode. PMID- 28671562 TI - Development of a PrGO-Modified Electrode for Uric Acid Determination in the Presence of Ascorbic Acid by an Electrochemical Technique. AB - An attractive electrochemical sensor of poly(3,4-ethylenedioxythiophene)/reduced graphene oxide electrode (PrGO) was developed for an electrochemical technique for uric acid (UA) detection in the presence of ascorbic acid (AA). PrGO composite film showed an improved electrocatalytic activity towards UA oxidation in pH 6.0 (0.1 M PBS). The PrGO composite exhibited a high current signal and low charge transfer resistance (Rct) compared to a reduced graphene oxide (rGO) electrode or a bare glassy carbon electrode (GCE). The limit of detection and sensitivity of PrGO for the detection of UA are 0.19 MUM (S/N = 3) and 0.01 MUA/MUM, respectively, in the range of 1-300 MUM of UA. PMID- 28671563 TI - Dose-Dependent Responses of I3C and DIM on T-Cell Activation in the Human T Lymphocyte Jurkat Cell Line. AB - Indole-3-carbinol (I3C) and its dimer diindolylmethane (DIM) are bioactive metabolites of a glucosinolate, glucobrassicin, found in cruciferous vegetables. Both I3C and DIM have been reported to possess pro-apoptotic, anti-proliferative and anti-carcinogenic properties via modulation of immune pathways. However, results from these studies remain inconclusive since they lack thorough evaluation of these bioactives' physiological versus pharmacological effects. In the present study, we investigated I3C and DIM's dose-dependent effects on cytokines production in human T lymphocytes Jurkat cell line (Clone E6-1). The results showed that I3C and DIM pretreatment, at higher concentrations of 50 and 10 MUM, respectively, significantly increased PMA/ionomycin-induced interleukin-2 (IL-2), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) production, measured by real time polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). As a plausible mechanism underlying such pronounced cytokine release, we found robust increase in downstream nuclear factor kappaB (NF-kappaB) and nuclear factor of activated T-cells 1 (NFAT1) signaling with I3C pretreatment, whereas DIM pretreatment only significantly induced NF-kappaB activation, but not NFAT1. We hypothesize that I3C/DIM pretreatment primes the T cells to become hyperresponsive upon PMA/ionomycin stimulation which in turn differentially induces two major downstream Ca2+ dependent inflammatory pathways, NF-kappaB and NFAT1. Our data show novel insights into the mechanisms underlying induction of pro-inflammatory cytokine release by pharmacological concentrations of I3C and DIM, an effect negligible under physiological conditions. PMID- 28671564 TI - Bistratamides M and N, Oxazole-Thiazole Containing Cyclic Hexapeptides Isolated from Lissoclinum bistratum Interaction of Zinc (II) with Bistratamide K. AB - Two novel oxazole-thiazole containing cyclic hexapeptides, bistratamides M (1) and N (2) have been isolated from the marine ascidian Lissoclinum bistratum (L. bistratum) collected in Raja Ampat (Papua Bar, Indonesia). The planar structure of 1 and 2 was assigned on the basis of extensive 1D and 2D NMR spectroscopy and mass spectrometry. The absolute configuration of the amino acid residues in 1 and 2 was determined by the application of the Marfey's and advanced Marfey's methods after ozonolysis followed by acid-catalyzed hydrolysis. The interaction between zinc (II) and the naturally known bistratamide K (3), a cyclic hexapeptide isolated from a different specimen of Lissoclinum bistratum, was monitored by 1H and 13C NMR. The results obtained are consistent with the proposal that these peptides are biosynthesized for binding to metal ions. Compounds 1 and 2 display moderate cytotoxicity against four human tumor cell lines with GI50 values in the micromolar range. PMID- 28671565 TI - Efficient Depth Enhancement Using a Combination of Color and Depth Information. AB - Studies on depth images containing three-dimensional information have been performed for many practical applications. However, the depth images acquired from depth sensors have inherent problems, such as missing values and noisy boundaries. These problems significantly affect the performance of applications that use a depth image as their input. This paper describes a depth enhancement algorithm based on a combination of color and depth information. To fill depth holes and recover object shapes, asynchronous cellular automata with neighborhood distance maps are used. Image segmentation and a weighted linear combination of spatial filtering algorithms are applied to extract object regions and fill disocclusion in the object regions. Experimental results on both real-world and public datasets show that the proposed method enhances the quality of the depth image with low computational complexity, outperforming conventional methods on a number of metrics. Furthermore, to verify the performance of the proposed method, we present stereoscopic images generated by the enhanced depth image to illustrate the improvement in quality. PMID- 28671566 TI - In-Situ Real-Time Focus Detection during Laser Processing Using Double-Hole Masks and Advanced Image Sensor Software. AB - In modern high-intensity ultrafast laser processing, detecting the focal position of the working laser beam, at which the intensity is the highest and the beam diameter is the lowest, and immediately locating the target sample at that point are challenging tasks. A system that allows in-situ real-time focus determination and fabrication using a high-power laser has been in high demand among both engineers and scientists. Conventional techniques require the complicated mathematical theory of wave optics, employing interference as well as diffraction phenomena to detect the focal position; however, these methods are ineffective and expensive for industrial application. Moreover, these techniques could not perform detection and fabrication simultaneously. In this paper, we propose an optical design capable of detecting the focal point and fabricating complex patterns on a planar sample surface simultaneously. In-situ real-time focus detection is performed using a bandpass filter, which only allows for the detection of laser transmission. The technique enables rapid, non-destructive, and precise detection of the focal point. Furthermore, it is sufficiently simple for application in both science and industry for mass production, and it is expected to contribute to the next generation of laser equipment, which can be used to fabricate micro-patterns with high complexity. PMID- 28671567 TI - Evaluation of Marine Microalga Diacronema vlkianum Biomass Fatty Acid Assimilation in Wistar Rats. AB - Diacronema vlkianum is a marine microalgae for which supposed health promoting effects have been claimed based on its phytochemical composition. The potential use of its biomass as health ingredient, including detox-shakes, and the lack of bioavailability studies were the main concerns. In order to evaluate the microalgae-biomass assimilation and its health-benefits, single-dose (CD1-mice) studies were followed by 66-days repeated-dose study in Wistar rats with the highest tested single-dose of microalgae equivalent to 101 mg/kg eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA). Microalgae-supplementation modulated EPA and docosapentaenoic acid enrichment at arachidonic acid content expenditure in erythrocytes and liver, while increasing EPA content of heart and adipose tissues of rats. Those fatty acid (FA) changes confirmed the D. vlkianum-biomass FA assimilation. The principal component analyses discriminated brain from other tissues, which formed two other groups (erythrocytes, liver, and heart separated from kidney and adipose tissues), pointing to a distinct signature of FA deposition for the brain and for the other organs. The improved serum lipid profile, omega-3 index and erythrocyte plasticity support the cardiovascular benefits of D. vlkianum. These results bolster the potential of D. vlkianum biomass to become a "heart-healthy" food supplement providing a safe and renewable source of bioavailable omega-3 FA. PMID- 28671568 TI - Antibacterial Activities of Pyrenylated Coumarins from the Roots of Prangos hulusii. AB - The dichloromethane extract of the roots of Prangos hulusii, a recently described endemic species from Turkey, has yielded nine known and one new prenylated coumarins. The structures were elucidated by spectroscopic methods and direct comparison with the reference compounds where available. The root extract and its prenylated coumarins exhibit antimicrobial activity against nine standard and six clinically isolated strains at a concentration between 5 and 125 ug/mL. In particular, the new coumarin, 4'-senecioiloxyosthol (1), displayed 5 ug/mL MIC (Minimum Inhibitory Concentration) value against Bacillus subtilis ATCC 9372, murraol (4) and auraptenol (5) showed 63 ug/mL MIC value against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 9372, and isoimperatorin (9) exhibited 16 ug/mL MIC value. PMID- 28671569 TI - Influence of Environmental Factors on the Production of Penitrems A-F by Penicillium crustosum. AB - Filamentous fungi produce a multitude of secondary metabolites, some of them known as mycotoxins, which are toxic to vertebrates and other animal groups in low concentrations. Among them, penitrems, which belong to the group of indole diterpene mycotoxins, are synthesized by Penicillium and Aspergillus genera and exhibit potent tremorgenic effects. This is the first complex study of the penitrems A-F production under the influence of different abiotic factors, e.g., media, incubation time, temperature, pH, light, water activity, and carbon and nitrogen source as well as oxidative and salt stress. For this purpose, penitrems A-F were isolated from Penicillium crustosum cultures and used as analytical standards. Among the carbon sources, glucose supplemented to the media at the concentration of 50 g/L, showed the strongest inducing effect on the biosynthesis of penitrems. Among nitrogen sources, glutamate was found to be the most favorable supplement, significantly increasing production of these secondary metabolites. CuSO4-promoted oxidative stress was also shown to remarkably stimulate biosynthesis of all penitrems. In contrast, the salt stress, caused by the elevated concentrations of NaCl, showed an inhibitory effect on the penitrem biosynthesis. Finally, cheese model medium elicited exceptionally high production of all members of the penitrems family. Obtained results give insides into the biosynthesis of toxicologically relevant penitrems A-F under different environmental factors and can be utilized to prevent food contamination. PMID- 28671570 TI - 24-Methyl-Cholesta-5,24(28)-Diene-3beta,19-diol-7beta-Monoacetate Inhibits Human Small Cell Lung Cancer Growth In Vitro and In Vivo via Apoptosis Induction. AB - 24-methyl-cholesta-5,24(28)-diene-3beta,19-diol-7beta-monoacetate (MeCDDA) is a natural steroid compound isolated from a wild-type soft coral (Nephthea erecta). The present study aimed to investigate the anti-small cell lung cancer (SCLC) effects of MeCDDA in vitro and in vivo, as well as to elucidate its underlying mechanism. Our results indicated that H1688 and H146 cells show relevant sensitivity to MeCDDA, and the exposure to MeCDDA in SCLC cells caused dose dependent growth inhibitory responses. In addition, MeCDDA treatment promoted cell apoptosis and increased the activities of caspases in H1688 cells, reducing the mitochondrial membrane potential and stimulating the release of cytochrome c into the cytosol. Along with the increase in Bax expression and reduction in Bcl 2, the MeCDDA treatment also significantly decreased Akt and mTOR phosphorylation. Finally, MeCDDA treatment in the mouse xenograft model of H1688 cells exhibited significant inhibition of tumor growth, corroborating MeCDDA as a potential pre-clinical candidate for the treatment of SCLC. Overall, our results demonstrate that the cytotoxic effects of MeCDDA towards H1688 and H146 cells, possibly through the activation of the mitochondrial apoptotic pathway and inhibition of the PI3K/Akt/mTOR pathway, merit further studies for its possible clinical application in chemotherapy. PMID- 28671571 TI - Improving Processing and Performance of Pure Lignin Carbon Fibers through Hardwood and Herbaceous Lignin Blends. AB - Lignin/lignin blends were used to improve fiber spinning, stabilization rates, and properties of lignin-based carbon fibers. Organosolv lignin from Alamo switchgrass (Panicum virgatum) and yellow poplar (Liriodendron tulipifera) were used as blends for making lignin-based carbon fibers. Different ratios of yellow poplar:switchgrass lignin blends were prepared (50:50, 75:25, and 85:15 w/w). Chemical composition and thermal properties of lignin samples were determined. Thermal properties of lignins were analyzed using thermogravimetric analysis and differential scanning calorimetry. Thermal analysis confirmed switchgrass and yellow poplar lignin form miscible blends, as a single glass transition was observed. Lignin fibers were produced via melt-spinning by twin-screw extrusion. Lignin fibers were thermostabilized at different rates and subsequently carbonized. Spinnability of switchgrass lignin markedly improved by blending with yellow poplar lignin. On the other hand, switchgrass lignin significantly improved thermostabilization performance of yellow poplar fibers, preventing fusion of fibers during fast stabilization and improving mechanical properties of fibers. These results suggest a route towards a 100% renewable carbon fiber with significant decrease in production time and improved mechanical performance. PMID- 28671572 TI - Effects of Aged Garlic Extract on Cholinergic, Glutamatergic and GABAergic Systems with Regard to Cognitive Impairment in Abeta-Induced Rats. AB - Alzheimer's disease (AD) has been linked to the degeneration of central cholinergic and glutamatergic transmission, which correlates with progressive memory loss and the accumulation of amyloid-beta (Abeta). It has been claimed that aged garlic extract (AGE) has a beneficial effect in preventing neurodegeneration in AD. Therefore, the objective of this study was to investigate the effects of AGE on Abeta-induced cognitive dysfunction with a biochemical basis in the cholinergic, glutamatergic, and GABAergic systems in rats. Adult male Wistar rats were orally administered three doses of AGE (125, 250, and 500 mg/kg) daily for 65 days. At day 56, they were injected with 1 MUL of aggregated Abeta (1-42) into each lateral ventricle, bilaterally. After six days of Abeta injection, the rats' working and reference memory was tested using a radial arm maze. The rats were then euthanized to investigate any changes to the cholinergic neurons, vesicular glutamate transporter 1 and 2 proteins (VGLUT1 and VGLUT2), and glutamate decarboxylase (GAD) in the hippocampus. The results showed that AGE significantly improved the working memory and tended to improve the reference memory in cognitively-impaired rats. In addition, AGE significantly ameliorated the loss of cholinergic neurons and increased the VGLUT1 and GAD levels in the hippocampus of rat brains with Abeta-induced toxicity. In contrast, the VGLUT2 protein levels did not change in any of the treated groups. We concluded that AGE was able to attenuate the impairment of working memory via the modification of cholinergic neurons, VGLUT1, and GAD in the hippocampus of Abeta induced rats. PMID- 28671575 TI - A Satellite-Based Imaging Instrumentation Concept for Hyperspectral Thermal Remote Sensing. AB - This paper describes the concept of the hyperspectral Earth-observing thermal infrared (TIR) satellite mission HiTeSEM (High-resolution Temperature and Spectral Emissivity Mapping). The scientific goal is to measure specific key variables from the biosphere, hydrosphere, pedosphere, and geosphere related to two global problems of significant societal relevance: food security and human health. The key variables comprise land and sea surface radiation temperature and emissivity, surface moisture, thermal inertia, evapotranspiration, soil minerals and grain size components, soil organic carbon, plant physiological variables, and heat fluxes. The retrieval of this information requires a TIR imaging system with adequate spatial and spectral resolutions and with day-night following observation capability. Another challenge is the monitoring of temporally high dynamic features like energy fluxes, which require adequate revisit time. The suggested solution is a sensor pointing concept to allow high revisit times for selected target regions (1-5 days at off-nadir). At the same time, global observations in the nadir direction are guaranteed with a lower temporal repeat cycle (>1 month). To account for the demand of a high spatial resolution for complex targets, it is suggested to combine in one optic (1) a hyperspectral TIR system with ~75 bands at 7.2-12.5 um (instrument NEDT 0.05 K-0.1 K) and a ground sampling distance (GSD) of 60 m, and (2) a panchromatic high-resolution TIR imager with two channels (8.0-10.25 um and 10.25-12.5 um) and a GSD of 20 m. The identified science case requires a good correlation of the instrument orbit with Sentinel-2 (maximum delay of 1-3 days) to combine data from the visible and near infrared (VNIR), the shortwave infrared (SWIR) and TIR spectral regions and to refine parameter retrieval. PMID- 28671573 TI - Histone Deacetylase Inhibitors as Anticancer Drugs. AB - Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities. PMID- 28671576 TI - Hybrid Optical Unobtrusive Blood Pressure Measurements. AB - Blood pressure (BP) is critical in diagnosing certain cardiovascular diseases such as hypertension. Some previous studies have proved that BP can be estimated by pulse transit time (PTT) calculated by a pair of photoplethysmography (PPG) signals at two body sites. Currently, contact PPG (cPPG) and imaging PPG (iPPG) are two feasible ways to obtain PPG signals. In this study, we proposed a hybrid system (called the ICPPG system) employing both methods that can be implemented on a wearable device, facilitating the measurement of BP in an inconspicuous way. The feasibility of the ICPPG system was validated on a dataset with 29 subjects. It has been proved that the ICPPG system is able to estimate PTT values. Moreover, the PTT measured by the new system shows a correlation on average with BP variations for most subjects, which could facilitate a new generation of BP measurement using wearable and mobile devices. PMID- 28671574 TI - The Nucleolus: In Genome Maintenance and Repair. AB - The nucleolus is the subnuclear membrane-less organelle where rRNA is transcribed and processed and ribosomal assembly occurs. During the last 20 years, however, the nucleolus has emerged as a multifunctional organelle, regulating processes that go well beyond its traditional role. Moreover, the unique organization of rDNA in tandem arrays and its unusually high transcription rates make it prone to unscheduled DNA recombination events and frequent RNA:DNA hybrids leading to DNA double strand breaks (DSBs). If not properly repaired, rDNA damage may contribute to premature disease onset and aging. Deregulation of ribosomal synthesis at any level from transcription and processing to ribosomal subunit assembly elicits a stress response and is also associated with disease onset. Here, we discuss how genome integrity is maintained within nucleoli and how such structures are functionally linked to nuclear DNA damage response and repair giving an emphasis on the newly emerging roles of the nucleolus in mammalian physiology and disease. PMID- 28671577 TI - Silencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells. AB - Pancreatic cancer remains an intractable cancer with a poor five-year survival rate, which requires new therapeutic modalities based on the biology of pancreatic oncogenesis. Nuclear factor E2 related factor-2 (NRF2), a key cytoprotective nuclear transcription factor, regulates antioxidant production, reduction, detoxification and drug efflux proteins. It also plays an essential role in cell homeostasis, cell proliferation and resistance to chemotherapy. We aimed to evaluate the possibility that modulation of NRF2 expression could be effective in the treatment of pancreatic cancer cells. We investigated whether the depletion of NRF2 by using small interfering RNAs (siRNAs) is effective in the expression of biomarkers of pancreatic cancer stemness such as aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and aldehyde dehydrogenase 3 family, member A1 (ALDH3A1). NRF2 knockdown markedly reduced the expression of NRF2 and glutamate-cysteine ligase catalytic subunit (GCLC) in cell lines established from pancreatic cancers. NRF2 silencing also decreased the ALDH1A1 and ALDH3A1 expression. Furthermore, this NRF2 depletion enhanced the antiproliferative effects of the chemotherapeutic agent, 5-fluorouracil (5-FU) in pancreatic cancer cells. PMID- 28671578 TI - Preparation of Self-Assembled Chitin Nanofiber-Natural Rubber Composite Sheets and Porous Materials. AB - We previously reported the preparation of a self-assembled chitin nanofiber (CNF) film via regeneration from an ion gel with an ionic liquid, followed by sonication and filtration. Based on the finding that CNFs were redispersed in a mixture of the film with ammonia aqueous solution (aq.), in this study, CNF natural rubber (NR) composite sheets were fabricated by mixing redispersed CNF with NR latex stabilized by ammonia, followed by drying under reduced pressure. Tensile testing of the sheets indicated the reinforcing effect of CNFs. Further, CNF-NR composite porous materials were fabricated by evaporating ammonia from the CNF-NR dispersion, followed by lyophilization. The mechanism for the formation of porous structures was evaluated. PMID- 28671579 TI - New Paradigm for a Targeted Cancer Therapeutic Approach: A Short Review on Potential Synergy of Gold Nanoparticles and Cold Atmospheric Plasma. AB - Application of Gold nanoparticles and Cold Atmospheric plasma as a targeted therapeutic adjunct has been widely investigated separately in cancer therapy. Gold nanoparticles, with their biocompatibility, lower cytotoxicity and superior efficacy, are becoming substantially more significant in modern cancer therapy. Likewise, cold atmospheric plasma, with rich reactive species including reactive oxygen species (ROS) and reactive nitrogen species (RNS), is being explored to selectively target and kill cancer cells, making them a promising anticancer agent. Recent scientific studies have shown that there is a potential synergy between these two aspects. Induction of apoptosis/necrosis due to oxidative stress may be a probable mechanism of their cytotoxic effect. The synergetic effect of the two therapeutic approaches could be tantamount to maximized targeted efficacy on the treatment of diseases like cancer. PMID- 28671580 TI - Design and Parametric Study of the Magnetic Sensor for Position Detection in Linear Motor Based on Nonlinear Parametric model order reduction. AB - This paper presents a design approach for a magnetic sensor module to detect mover position using the proper orthogonal decomposition-dynamic mode decomposition (POD-DMD)-based nonlinear parametric model order reduction (PMOR). The parameterization of the sensor module is achieved by using the multipolar moment matching method. Several geometric variables of the sensor module are considered while developing the parametric study. The operation of the sensor module is based on the principle of the airgap flux density distribution detection by the Hall Effect IC. Therefore, the design objective is to achieve a peak flux density (PFD) greater than 0.1 T and total harmonic distortion (THD) less than 3%. To fulfill the constraint conditions, the specifications for the sensor module is achieved by using POD-DMD based reduced model. The POD-DMD based reduced model provides a platform to analyze the high number of design models very fast, with less computational burden. Finally, with the final specifications, the experimental prototype is designed and tested. Two different modes, 90 degrees and 120 degrees modes respectively are used to obtain the position information of the linear motor mover. The position information thus obtained are compared with that of the linear scale data, used as a reference signal. The position information obtained using the 120 degrees mode has a standard deviation of 0.10 mm from the reference linear scale signal, whereas the 90 degrees mode position signal shows a deviation of 0.23 mm from the reference. The deviation in the output arises due to the mechanical tolerances introduced into the specification during the manufacturing process. This provides a scope for coupling the reliability based design optimization in the design process as a future extension. PMID- 28671582 TI - Moving Object Detection in Heterogeneous Conditions in Embedded Systems. AB - This paper presents a system for moving object exposure, focusing on pedestrian detection, in external, unfriendly, and heterogeneous environments. The system manipulates and accurately merges information coming from subsequent video frames, making small computational efforts in each single frame. Its main characterizing feature is to combine several well-known movement detection and tracking techniques, and to orchestrate them in a smart way to obtain good results in diversified scenarios. It uses dynamically adjusted thresholds to characterize different regions of interest, and it also adopts techniques to efficiently track movements, and detect and correct false positives. Accuracy and reliability mainly depend on the overall receipt, i.e., on how the software system is designed and implemented, on how the different algorithmic phases communicate information and collaborate with each other, and on how concurrency is organized. The application is specifically designed to work with inexpensive hardware devices, such as off-the-shelf video cameras and small embedded computational units, eventually forming an intelligent urban grid. As a matter of fact, the major contribution of the paper is the presentation of a tool for real time applications in embedded devices with finite computational (time and memory) resources. We run experimental results on several video sequences (both home-made and publicly available), showing the robustness and accuracy of the overall detection strategy. Comparisons with state-of-the-art strategies show that our application has similar tracking accuracy but much higher frame-per-second rates. PMID- 28671581 TI - Pleiotropic Roles of Non-Coding RNAs in TGF-beta-Mediated Epithelial-Mesenchymal Transition and Their Functions in Tumor Progression. AB - Epithelial-mesenchymal transition (EMT) is a spatially- and temporally-regulated process involved in physiological and pathological transformations, such as embryonic development and tumor progression. While the role of TGF-beta as an EMT inducer has been extensively documented, the molecular mechanisms regulating this transition and their implications in tumor metastasis are still subjects of intensive debates and investigations. TGF-beta regulates EMT through both transcriptional and post-transcriptional mechanisms, and recent advances underline the critical roles of non-coding RNAs in these processes. Although microRNAs and lncRNAs have been clearly identified as effectors of TGF-beta mediated EMT, the contributions of other atypical non-coding RNA species, such as piRNAs, snRNAs, snoRNAs, circRNAs, and even housekeeping tRNAs, have only been suggested and remain largely elusive. This review discusses the current literature including the most recent reports emphasizing the regulatory functions of non-coding RNA in TGF-beta-mediated EMT, provides original experimental evidence, and advocates in general for a broader approach in the quest of new regulatory RNAs. PMID- 28671584 TI - An Infrared Actin Probe for Deep-Cell Electroporation-Based Single-Molecule Speckle (eSiMS) Microscopy. AB - Single-molecule speckle (SiMS) microscopy is a powerful method to directly elucidate biochemical reactions in live cells. However, since the signal from an individual fluorophore is extremely faint, the observation area by epi fluorescence microscopy is restricted to the thin cell periphery to reduce autofluorescence, or only molecules near the plasma membrane are visualized by total internal reflection fluorescence (TIRF) microscopy. Here, we introduce a new actin probe labeled with near infrared (NIR) emissive CF680R dye for easy-to use, electroporation-based SiMS microscopy (eSiMS) for deep-cell observation. CF680R-labeled actin (CF680R-actin) incorporated into actin structures and showed excellent brightness and photostability suitable for single-molecule imaging. Importantly, the intensity of autofluorescence with respect to SiMS brightness was reduced to approximately 13% compared to DyLight 550-labeled actin (DL550 actin). CF680R-actin enabled the monitoring of actin SiMS in actomyosin bundles associated with adherens junctions (AJs) located at 3.5-4 um above the basal surfaces of epithelial monolayers. These favorable properties of CF680R-actin extend the application of eSiMS to actin turnover and flow analyses in deep cellular structures. PMID- 28671583 TI - Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy. AB - Accumulated evidence indicates that autophagy is a response of cancer cells to various anti-cancer therapies. Autophagy is designated as programmed cell death type II, and is characterized by the formation of autophagic vacuoles in the cytoplasm. Numerous herbs, including Chinese herbs, have been applied to cancer treatments as complementary and alternative medicines, supplements, or nutraceuticals to dampen the side or adverse effects of chemotherapy drugs. Moreover, the tumor suppressive actions of herbs and natural products induced autophagy that may lead to cell senescence, increase apoptosis-independent cell death or complement apoptotic processes. Hereby, the underlying mechanisms of natural autophagy inducers are cautiously reviewed in this article. Additionally, three natural compounds-curcumin, 16-hydroxycleroda-3,13-dien-15,16-olide, and prodigiosin-are presented as candidates for autophagy inducers that can trigger cell death in a supplement or alternative medicine for cancer therapy. Despite recent advancements in therapeutic drugs or agents of natural products in several cancers, it warrants further investigation in preclinical and clinical studies. PMID- 28671585 TI - Probing the Characterization of the Interaction of Aflatoxins B1 and G1 with Calf Thymus DNA In Vitro. AB - The binding characterization of aflatoxins with calf thymus DNA (ctDNA) under physiological conditions was investigated. Multispectroscopic techniques, ctDNA melting, viscosity measurements, and molecular docking techniques were employed to elucidate the binding mechanism of the aflatoxins with DNA. The fluorescence results indicated that both aflatoxin B1 (AFB1) and aflatoxin G1 (AFG1) bound to the ctDNA, forming complexes through hydrogen bonding. The binding constants of AFB1 and AFG1 with ctDNA reached up to 103 L.mol-1 and 104 L.mol-1, respectively, and AFG1 exhibited a higher binding propensity than that of AFB1. Furthermore, both AFB1 and AFG1 bound to the ctDNA through groove binding, as evidenced by the results of the spectroscopic, iodide quenching effect, viscosity, and ctDNA melting measurements. Changes in the circular dichroism signal manifested that both AFB1 and AFG1 induced an increase in the right-handed helicity, but only minimally influenced the base stacking of the DNA. A molecular docking study of the aflatoxin's binding with the DNA revealed a groove binding mode, which was driven mainly by hydrogen bonding. This study of aflatoxin-ctDNA interaction may provide novel insights into the toxicological effect of the mycotoxins. PMID- 28671586 TI - An In Vitro Potency Assay for Monitoring the Immunomodulatory Potential of Stromal Cell-Derived Extracellular Vesicles. AB - The regenerative and immunomodulatory activity of mesenchymal stromal cells (MSCs) is partially mediated by secreted vesicular factors. Extracellular vesicles (EVs) exocytosed by MSCs are gaining increased attention as prospective non-cellular therapeutics for a variety of diseases. However, the lack of suitable in vitro assays to monitor the therapeutic potential of EVs currently restricts their application in clinical studies. We have evaluated a dual in vitro immunomodulation potency assay that reproducibly reports the inhibitory effect of MSCs on induced T-cell proliferation and the alloantigen-driven mixed leukocyte reaction of pooled peripheral blood mononuclear cells in a dose dependent manner. Phytohemagglutinin-stimulated T-cell proliferation was inhibited by MSC-derived EVs in a dose-dependent manner comparable to MSCs. In contrast, inhibition of alloantigen-driven mixed leukocyte reaction was only observed for MSCs, but not for EVs. Our results support the application of a cell based in vitro potency assay for reproducibly determining the immunomodulatory potential of EVs. Validation of this assay can help establish reliable release criteria for EVs for future clinical studies. PMID- 28671588 TI - Implications of Neuroinvasive Bacterial Peptides on Rodents Behaviour and Neurotransmission. AB - Neuroinvasive microbes are capable of applying their influences on the autonomic nervous system (ANS) of the host followed by the involvement of central nervous system (CNS) by releasing extracellular metabolites that may cause alterations in the biochemical and neurophysiological environment. Consequently synaptic, neuroendocrine, peripheral immune, neuro-immune, and behavioural responses of the host facilitate the progression of infection. The present study was designed to extrapolate the effects of crude and purified extracellular peptides of neuropathogenic bacteria on behavioural responses and neurotransmission of Sprague Dawley (SD) models. Listeria monocytogenes (Lm) and Neisseria meningitides (Nm) were isolated from the 92 cerebrospinal fluid (CSF) samples collected from mentally compromised patients. Bacillus cereus (Bc) and Clostridium tetani (Ct) were also included in the study. All bacterial strains were identified by the standard biochemical procedures. Filter sterilized cell free cultural broths (SCFBs) were prepared of different culture media. Behavioural study and neurotransmitter analysis were performed by giving an intraperitoneal (i.p.) injection of each bacterial SCFB to four groups (Test; n = 7) of SD rats, whereas two groups each (Control; n = 7) received a nutrient broth (NB) control and sterile physiological saline control, respectively. Extracellular bioactive peptides of these bacteria were screened and purified. All experiments were repeated using purified bacterial peptides on SD rat cohorts. Our study indicated promising behavioural changes, including fever, swelling, and hind paw paralysis, in SD rat cohorts. Purified bacterial peptides of all bacteria used in the present study elicited marked changes in behaviour through the involvement of the autonomic nervous system. Furthermore, these peptides of meningitis bacteria were found to potently affect the dopaminergic neurotransmission in CNS. PMID- 28671587 TI - Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches. AB - Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term "metabolic epilepsy" can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Some of these disorders are amenable to specific treatment interventions; hence timely and appropriate diagnosis is critical to improve outcomes. In this review, we discuss those disorders in which epilepsy is a dominant feature and present an approach to the clinical recognition, diagnosis, and management of these disorders, with a greater focus on primarily treatable conditions. Finally, we propose a tiered approach that will permit a clinician to systematically investigate, identify, and treat these rare disorders. PMID- 28671589 TI - Theranostic Liposome-Nanoparticle Hybrids for Drug Delivery and Bioimaging. AB - Advanced theranostic nanomedicine is a multifunctional approach which combines the diagnosis and effective therapy of diseased tissues. Here, we investigated the preparation, characterization and in vitro evaluation of theranostic liposomes. As is known, liposome-quantum dot (L-QD) hybrid vesicles are promising nanoconstructs for cell imaging and liposomal-topotecan (L-TPT) enhances the efficiency of TPT by providing protection against systemic clearance and allowing extended time for it to accumulate in tumors. In the present study, hydrophobic CdSe/ZnS QD and TPT were located in the bilayer membrane and inner core of liposomes, respectively. Dynamic light scattering (DLS), zeta potential (zeta) measurements and fluorescence/absorption spectroscopy were performed to determine the vesicle size, charge and spectroscopic properties of the liposomes. Moreover, drug release was studied under neutral and acidic pH conditions. Fluorescence microscopy and flow cytometry analysis were used to examine the cellular uptake and intracellular distribution of the TPT-loaded L-QD formulation. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to investigate the in vitro cytotoxicity of the formulations on HeLa cells. According to the results, the TPT-loaded L-QD hybrid has adequate physicochemical properties and is a promising multifunctional delivery vehicle which is capable of a simultaneous co-delivery of therapeutic and diagnostic agents. PMID- 28671590 TI - Egg Consumption and Risk of Metabolic Syndrome in Korean Adults: Results from the Health Examinees Study. AB - Metabolic syndrome (MetS) is defined as a cluster of metabolic alterations such as abdominal obesity, dyslipidemias, elevated fasting glucose, and hypertension. Studies on the association between egg consumption and MetS are limited and inconsistent. A cross-sectional analysis was conducted to examine the association of egg consumption with MetS among Korean adults aged 40-69 years. A total of 130,420 subjects (43,682 men and 86,738 women) from the Health Examinees Study were selected for the final analysis. Egg consumption was estimated using a validated 106-item food frequency questionnaire. MetS was defined using the National Cholesterol Education Program, Adult Treatment Panel III. Logistic regression analyses were performed to identify the association of egg consumption with MetS via odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for potential variables. Among 130,420 subjects, 34,039 (26.1%) people had MetS. Consumption of more than 7 eggs/week was associated with a lower odds of MetS risk compared to those who consumed less than one egg/week in women (OR: 0.77, 95%CI: 0.70-0.84, p trend < 0.0001). Higher egg consumption was inversely associated with the MetS components: elevated waist circumference (OR: 0.80, 0.75 0.86), elevated triglyceride (OR: 0.78, 0.72-0.85), reduced high-density lipoprotein cholesterol (HDL-C) (OR: 0.82, 0.77-0.88), elevated blood pressure (OR: 0.86, 0.80-0.92), and elevated fasting glucose (OR: 0.94, 0.83-0.99) in women; reduced HDL-C (OR: 0.89, 0.80-1.00) in men. Our results suggest that higher egg consumption may be associated with a reduction in the odds for MetS and all five metabolic components in women, and the risk of reduced HDL-C in men. PMID- 28671591 TI - Chocolate Consumption and Risk of Coronary Heart Disease, Stroke, and Diabetes: A Meta-Analysis of Prospective Studies. AB - Although epidemiological studies have examined the role of chocolate in preventing cardiometabolic disease, the results remain inconsistent. Herein, we conducted a meta-analysis of prospective studies to determine the association between chocolate intake and risk of coronary heart disease (CHD), stroke, and diabetes. A systematical search in PubMed and Embase through March 2017, together with reference scrutiny of relevant literatures, was performed to identify eligible studies. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled using random effect models. Fourteen prospective studies of primary prevention with 508,705 participants were finally included, with follow-up durations ranging from 5 to 16 years. The summary RRs for the highest versus lowest chocolate consumption were 0.90 (95% CI: 0.82-0.97; n = 6) for CHD, 0.84 (95% CI: 0.78-0.90; n = 7) for stroke, and 0.82 (95% CI: 0.70-0.96; n = 5) for diabetes. Dose-response meta-analysis suggested a nonlinear association of chocolate consumption with all outcomes. For both CHD and stroke, there was little additional risk reduction when consuming chocolate >=3 servings/week (one serving was defined as 30 g of chocolate). For diabetes, the peak protective effect of chocolate emerged at 2 servings/week (RR: 0.75, 95% CI: 0.63-0.89), with no benefit observed when increasing consumption above 6 servings/week. In conclusion, chocolate intake is associated with decreased risks of CHD, stroke, and diabetes. Consuming chocolate in moderation (<=6 servings/week) may be optimal for preventing these disorders. PMID- 28671592 TI - Polyurethane Foams for Thermal Insulation Uses Produced from Castor Oil and Crude Glycerol Biopolyols. AB - Rigid polyurethane foams were synthesized using a renewable polyol from the simple physical mixture of castor oil and crude glycerol. The effect of the catalyst (DBTDL) content and blowing agents in the foams' properties were evaluated. The use of physical blowing agents (cyclopentane and n-pentane) allowed foams with smaller cells to be obtained in comparison with the foams produced with a chemical blowing agent (water). The increase of the water content caused a decrease in density, thermal conductivity, compressive strength, and Young's modulus, which indicates that the increment of CO2 production contributes to the formation of larger cells. Higher amounts of catalyst in the foam formulations caused a slight density decrease and a small increase of thermal conductivity, compressive strength, and Young's modulus values. These green foams presented properties that indicate a great potential to be used as thermal insulation: density (23-41 kg.m-3), thermal conductivity (0.0128-0.0207 W.m-1.K 1), compressive strength (45-188 kPa), and Young's modulus (3-28 kPa). These biofoams are also environmentally friendly polymers and can aggregate revenue to the biodiesel industry, contributing to a reduction in fuel prices. PMID- 28671593 TI - High Consumption of Iron Exacerbates Hyperlipidemia, Atherosclerosis, and Female Sterility in Zebrafish via Acceleration of Glycation and Degradation of Serum Lipoproteins. AB - Elevated serum iron level is linked with an increased risk of diabetes and atherosclerosis. However, the pathological mechanism by which iron affects serum lipoprotein levels is unknown. To elucidate the mechanism, a high dose of ferrous ion was applied (final 60 uM, 120 uM) to human serum lipoproteins, macrophages, and human dermal fibroblast (HDF) cells. Iron-treated lipoproteins showed loss of antioxidant ability along with protein degradation and multimerization, especially co-treatment with fructose (final 10 mM). In the presence of fructose, HDF cells showed 3.5-fold more severe cellular senescence, as compared to the control, dependent on the dosage of fructose. In macrophages, phagocytosis of acetylated low-density lipoprotein (acLDL) was more accelerated by ferrous ion, occurring at a rate that was up to 1.8-fold higher, than acLDL alone. After 24 weeks supplementation with 0.05% and 0.1% ferrous ion in the diet (wt/wt), serum total cholesterol (TC) level was elevated 3.7- and 2.1-fold, respectively, under normal diet (ND). Serum triglyceride (TG) was elevated 1.4- and 1.7-fold, respectively, under ND upon 0.05% and 0.1% ferrous ion supplementation. Serum glucose level was elevated 2.4- and 1.2-fold under ND and high cholesterol diet (HCD), respectively. However, body weight was decreased by the Fe2+ consumption. Iron consumption caused severe reduction of embryo laying and reproduction ability, especially in female zebrafish via impairment of follicular development. In conclusion, ferrous ion treatment caused more pro-atherogenic, and pro senescence processes in human macrophages and dermal cells. High consumption of iron exacerbated hyperlipidemia and hyperglycemia as well as induced fatty liver changes and sterility along with reduction of female fertility. PMID- 28671594 TI - Measuring Torque and Temperature in a Rotating Shaft Using Commercial SAW Sensors. AB - Real-time monitoring of torque in a rotating shaft is not easy to implement with technologies such as optic fiber sensors or strain gages. Surface acoustic wave (SAW) sensors are wireless and passive and can be used to monitor strain in moving parts. Commercial solutions (sensors, antennas and interrogation unit) can easily be purchased from some companies; however, they are not customized and may not meet the specificity of the measurements. In order to evaluate the adequacy of commercial off-the-shelf (COTS) solutions, temperature and strain sensors fabricated by SENSeOR (Besancon, France) were mounted on a load cell. The sensors were calibrated using a thermal chamber and a universal testing machine. The load cell was then assembled together with a steel shaft that rotated at different speeds inside an oven. The commercial antennas were replaced with an RF (radio frequency) coupler and the sensors were interrogated with the commercial interrogation unit. The influence of rotation in the accuracy on the measurements, as well as the adequacy of the sensors structure, was evaluated. It can be concluded that SAW sensors can be used to measure temperature or torque in a rotating environment; however, some customization of the components is required in order to overcome the limitations posed by COTS sensing solutions. PMID- 28671596 TI - Performance Analysis of the Direct Position Determination Method in the Presence of Array Model Errors. AB - The direct position determination approach was recently presented as a promising technique for the localization of a transmitting source with accuracy higher than that of the conventional two-step localization method. In this paper, the theoretical performance of a direct position determination estimator proposed by Weiss is examined for situations in which the array model errors are present. Our study starts from a matrix eigen-perturbation result, which expresses the perturbation of eigenvalues as a function of the disturbance added to the Hermitian matrix. The first-order asymptotic expression of the positioning errors is presented, from which an analytical expression for the mean square error of the direct localization is available. Additionally, explicit formulas for computing the probabilities of a successful localization are deduced. Finally, Cramer-Rao bound expressions for the position estimation are derived for two cases: (1) array model errors are absent and (2) array model errors are present. The obtained Cramer-Rao bounds provide insights into the effects of the array model errors on the localization accuracy. Simulation results support and corroborate the theoretical developments made in this paper. PMID- 28671595 TI - Anti-Obesity Effect of the Above-Ground Part of Valeriana dageletiana Nakai ex F. Maek Extract in High-Fat Diet-Induced Obese C57BL/6N Mice. AB - Valeriana dageletiana Nakai ex F. Maek (VD) has been used as traditional medicine for the treatment of restlessness and sleeping disorders. However, it is still unclear whether obesity in mice can be altered by diet supplementation with VD. In this study, we first investigated the influences of VD on the accumulation of lipid content in 3T3-L1 cells; and the results showed that the above-ground VD extracts (VDAE) suppressed the differentiation of 3T3-L1 preadipocytes in a concentration-dependent manner without cytotoxicity. Thus, the effects of VDAE on preventing obesity were then studied in the C57BL/6N mice for 10 weeks (n = 6): normal-fat diet, high-fat diet (HFD), HFD supplemented with 1% (10 g/kg) Garcinia combogia extract (positive control), and HFD supplemented with 1% (10 g/kg) VDAE. The results showed that VDAE reduced food efficiency ratio, body weight, epididymal adipose and hepatic tissue weight, hepatic lipid metabolites, and triacylglycerol and cholesterol serum levels compared to the high-fat diet group. Moreover, VD significantly inhibited the expression of adipogenic genes, such as PPAR-gamma, C/EBP-alpha, and aP2, and lipogenic genes, such as SREBP-1c, FAS, SCD 1, and CD36, in epididymal adipose tissue and hepatic tissue. These findings indicate anti-adipogenic and anti-lipogenic effects of VDAE and suggest that it could be a potent functional food ingredient for the prevention of high-fat diet induced obesity. PMID- 28671597 TI - Precipitation and Neutralization of Heparin from Different Sources by Protamine Sulfate. AB - Current therapeutic unfractionated heparin available in Europe and US is of porcine mucosal origin. There is now interest, specifically in the US, to use bovine mucosa as an additional source for the production of heparin. The anticoagulant action of heparin can be neutralized by protamine sulfate, and in this study the ability of protamine to bind and neutralize the anticoagulant activities of heparin from porcine mucosa, bovine mucosa and bovine lung were assessed. Protamine sulfate was able to bind and precipitate similar amounts of heparins from different sources on a mass basis. However, differential amounts of anticoagulant activities were neutralized by protamine sulfate, with neutralization of porcine mucosa more effective than for bovine lung and bovine mucosa. For all heparins, potentiation of thrombin inhibition by antithrombin and heparin cofactor II was preferentially neutralized over antithrombin-mediated inhibition of factor Xa or plasma clotting time. Whole blood thromboelastography showed that neutralization by protamine sulfate was more effective than the antithrombin dependent thrombin inhibition assays indicated. While there was no absolute correlation between average or peak molecular weight of heparin samples and neutralization of anticoagulant activity, correlation was observed between proportions of material with high affinity to antithrombin, specific activities and neutralization of activity. PMID- 28671598 TI - Synthesis and Evaluation of N-(3-Trifluoroacetyl-indol-7-yl) Acetamides for Potential In Vitro Antiplasmodial Properties. AB - A series of novel N-((2,5-diaryl-3-trifluoroacetyl)-1H-indol-7-yl)acetamides has been prepared via a successive and one-pot reaction sequence involving initial trifluoroacetic acid-mediated Beckmann rearrangement of the oximes derived from the 1-(2,5-diaryl-1H-indol-7-yl)ethanones, followed by trifluoroacetylation of the incipient N-(2,5-diaryl-1H-indol-7-yl)-acetamides with trifluoroacetic anhydride. The prepared compounds were evaluated for potential in vitro antiplasmodial properties. Preliminary results from antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum revealed that a combination of 2-(4-flurophenyl)- and 5-(4-fluorophenyl) or 2-(4 flurophenyl)- and 4-fluorostyryl groups in compounds 3(a,f) and 4(a,g), for example, is required for biological activity for both series of compounds. Their possible mode of action against the plasmodial parasite is explained theoretically through molecular docking of the most active compounds against the parasite lactate dehydrogenase (pLDH). These compounds were docked at the entrance of NAD+ in pLDH presumably hindering entry of lactate to cause the observed inhibition effect of pLDH. The four compounds were found to exhibit low toxicity against monkey kidney Vero cells at the highest concentrations tested. PMID- 28671599 TI - Rapid Detection of Ascorbic Acid Based on a Dual-Electrode Sensor System Using a Powder Microelectrode Embedded with Carboxyl Multi-Walled Carbon Nanotubes. AB - In this paper, carboxyl groups were introduced by liquid oxidation methods onto multi-walled carbon nanotubes (MWCNTs) to improve the MWCNTs' electrocatalytic properties. A platinum wire microelectrode (ME) was corroded using aqua regia and subsequently embedded with MWCNTs to achieve more active sites, producing a so called powder microelectrode (PME). Compared with conventional MEs, the PME has a larger specific surface area and more active sites. When PME was used to detect ascorbic acid (AA), the AA oxidation potential shifted negatively and current peak was visibly increased. The calibration curve obtained for AA was in a range of 5.00 * 10-6~9.50 * 10-4 mol.L-1: Ipa(MUA) = 3.259 * 10-2+ 1.801 * 102 C (mol.L 1) under the optimum testing conditions. Moreover, the detection and quantitation limits were confirmed at 4.89 * 10-7 mol.L-1 and 1.63 * 10-7 mol.L-1, respectively. When the fabricated PME was practically applied to detect AA, it was shown a recovery rate of 94~107% with relative standard deviation (RSD) <5%. The proposed strategy thus offers a promising, rapid, selective and low-cost approach to effective analysis of AA. PMID- 28671600 TI - Low-Cost and Rapid Fabrication of Metallic Nanostructures for Sensitive Biosensors Using Hot-Embossing and Dielectric-Heating Nanoimprint Methods. AB - We propose two approaches-hot-embossing and dielectric-heating nanoimprinting methods-for low-cost and rapid fabrication of periodic nanostructures. Each nanofabrication process for the imprinted plastic nanostructures is completed within several seconds without the use of release agents and epoxy. Low-cost, large-area, and highly sensitive aluminum nanostructures on A4 size plastic films are fabricated by evaporating aluminum film on hot-embossing nanostructures. The narrowest bandwidth of the Fano resonance is only 2.7 nm in the visible light region. The periodic aluminum nanostructure achieves a figure of merit of 150, and an intensity sensitivity of 29,345%/RIU (refractive index unit). The rapid fabrication is also achieved by using radio-frequency (RF) sensitive plastic films and a commercial RF welding machine. The dielectric-heating, using RF power, takes advantage of the rapid heating/cooling process and lower electric power consumption. The fabricated capped aluminum nanoslit array has a 5 nm Fano linewidth and 490.46 nm/RIU wavelength sensitivity. The biosensing capabilities of the metallic nanostructures are further verified by measuring antigen-antibody interactions using bovine serum albumin (BSA) and anti-BSA. These rapid and high throughput fabrication methods can benefit low-cost, highly sensitive biosensors and other sensing applications. PMID- 28671601 TI - Effects of an Inhibitor of Monocyte Recruitment on Recovery from Traumatic Brain Injury in Mice Treated with Granulocyte Colony-Stimulating Factor. AB - : Administration of the hematopoietic growth factor granulocyte-colony stimulating Factor (G-CSF) has been reported to enhance recovery from controlled cortical impact (CCI) in rodent models. G-CSF exerts actions in both the periphery (stimulation of hematopoiesis) and in the brain, where it serves as a neurotrophic factor, promoting neuronal survival and stimulating neural stem/progenitor cell proliferation in the hippocampus. In order to distinguish the direct CNS actions of G-CSF from its peripheral actions, experiments were designed to block the recruitment of peripheral monocytes to the site of the lesion produced by CCI. The selective C-C motif receptor 2 (CCR2) antagonist (RS504303) was co-administered with G-CSF for three days after CCI in a chimeric mouse previously transplanted with GFP-expressing (GFP+) blood stem-progenitor cells. RESULTS: The drug significantly impaired infiltration of GFP+ bone marrow derived cells to the frontal cortex and striatum without impeding recovery performance and hippocampal neurogenesis in the behavioral test, the Radial Arm Water Maze (RAWM). Administration of the CCR2 antagonist alone, without G-CSF, was effective in promoting recovery in RAWM. These results support the hypothesis that the direct action of G-CSF on neural cells, independent of its hematopoietic effects, is primarily responsible for enhanced recovery from CCI. In addition, this study confirms the importance of CCR2 and its ligand, monocyte chemotactic protein-1 (MCP-1), in mediating the inflammatory response following CCI. PMID- 28671602 TI - Mechanism Investigation of Rifampicin-Induced Liver Injury Using Comparative Toxicoproteomics in Mice. AB - Tuberculosis is one of the top causes of death among curable infectious diseases; it is an airborne infectious disease that killed 1.1 million people worldwide in 2010. Anti-tuberculosis drug-induced liver injury is the primary cause of drug induced liver injury (DILI). Rifampicin is one of the most common anti tuberculosis therapies and has well-known hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, we performed a global proteomic analysis of liver proteins by LC-MS/MS in a mouse model after the oral administration of 177 and 442.5 mg/kg rifampicin (LD10 and LD25) for 14 days. Based on the biochemical parameters in the plasma after rifampicin treatment, the hepatotoxic effect of rifampicin in the mouse liver was defined as a mixed liver injury. In the present study, we identified 1101 proteins and quantified 1038 proteins. A total of 29 and 40 proteins were up-regulated and 27 and 118 proteins were down-regulated in response to 177 and 442.5 mg/kg rifampicin, respectively. Furthermore, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to characterize the mechanism of rifampicin-induced hepatotoxicity. In the molecular function category, glutathione transferase activity was up-regulated and proteins related to arachidonic acid metabolism were down-regulated. In the KEGG pathway enrichment based clustering analysis, the peroxisome proliferator-activated receptor-gamma (PPARgamma) signaling pathway, cytochrome P450, glutathione metabolism, chemical carcinogenesis, and related proteins increased dose-dependently in rifampicin treated livers. Taken together, this study showed in-depth molecular mechanism of rifampicin-induced liver injury by comparative toxicoproteomics approach. PMID- 28671603 TI - Interleukin-10 Conjugation to Carboxylated PVP-Coated Silver Nanoparticles for Improved Stability and Therapeutic Efficacy. AB - Interleukin-10 (IL-10) is a key anti-inflammatory and immunosuppressive cytokine and therefore represents a potential therapeutic agent especially in inflammatory diseases. However, despite its proven therapeutic efficacy, its short half-life and proteolytic degradation in vivo combined with its low storage stability have limited its therapeutic use. Strategies have been developed to overcome most of these shortcomings, including in particular bioconjugation with stabilizing agents such as polyethylene glycol (PEG) and poly (vinylpyrolidone) (PVP), but so far these have had limited success. In this paper, we present an alternative method consisting of bioconjugating IL-10 to PVP-coated silver nanoparticles (Ag PVPs) in order to achieve its storage stability by preventing denaturation and to improve its anti-inflammatory efficacy. Silver nanoparticles capped with a carboxylated PVP were produced and further covalently conjugated with IL-10 protein by carbodiimide crosslinker chemistry. The IL-10 conjugated Ag-PVPs exhibited increased stability and anti-inflammatory effectiveness in vitro. This study therefore provides a novel approach to bioconjugating PVP-coated silver nanoparticles with therapeutic proteins, which could be useful in drug delivery and anti-inflammatory therapies. PMID- 28671604 TI - Nanofiltration and Tight Ultrafiltration Membranes for Natural Organic Matter Removal-Contribution of Fouling and Concentration Polarization to Filtration Resistance. AB - Nanofiltration (NF) and tight ultrafiltration (tight UF) membranes are a viable treatment option for high quality drinking water production from sources with high concentrations of contaminants. To date, there is limited knowledge regarding the contribution of concentration polarization (CP) and fouling to the increase in resistance during filtration of natural organic matter (NOM) with NF and tight UF. Filtration tests were conducted with NF and tight UF membranes with molecular weight cut offs (MWCOs) of 300, 2000 and 8000 Da, and model raw waters containing different constituents of NOM. When filtering model raw waters containing high concentrations of polysaccharides (i.e., higher molecular weight NOM), the increase in resistance was dominated by fouling. When filtering model raw waters containing humic substances (i.e., lower molecular weight NOM), the increase in filtration resistance was dominated by CP. The results indicate that low MWCO membranes are better suited for NOM removal, because most of the NOM in surface waters consist mainly of humic substances, which were only effectively rejected by the lower MWCO membranes. However, when humic substances are effectively rejected, CP can become extensive, leading to a significant increase in filtration resistance by the formation of a cake/gel layer at the membrane surface. For this reason, cross-flow operation, which reduces CP, is recommended. PMID- 28671605 TI - Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway. AB - Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-NG-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management. PMID- 28671606 TI - The Central Conserved Region (CCR) of Respiratory Syncytial Virus (RSV) G Protein Modulates Host miRNA Expression and Alters the Cellular Response to Infection. AB - Respiratory Syncytial Virus (RSV) infects respiratory epithelial cells and deregulates host gene expression by many mechanisms including expression of RSV G protein (RSV G). RSV G protein encodes a central conserved region (CCR) containing a CX3C motif that functions as a fractalkine mimic. Disruption of the CX3C motif (a.a. 182-186) located in the CCR of the G protein has been shown to affect G protein function in vitro and the severity of RSV disease pathogenesis in vivo. We show that infection of polarized Calu3 respiratory cells with recombinant RSV having point mutations in Cys173 and 176 (C173/176S) (rA2-GC12), or Cys186 (C186S) (rA2-GC4) is associated with a decline in the integrity of polarized Calu-3 cultures and decreased virus production. This is accompanied with downregulation of miRNAs let-7f and miR-24 and upregulation of interferon lambda (IFNlambda), a primary antiviral cytokine for RSV in rA2-GC12/rA2-GC4 infected cells. These results suggest that residues in the cysteine noose region of RSV G protein can modulate IFN lambda expression accompanied by downregulation of miRNAs, and are important for RSV G protein function and targeting. PMID- 28671607 TI - Diabetes and Wound Angiogenesis. AB - Diabetes Mellitus Type II (DM2) is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes. PMID- 28671608 TI - Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress. AB - Lipotoxicity-induced mesangial cell apoptosis is implicated in the exacerbation of diabetic nephropathy (DN). Protein arginine methyltransferases (PRMTs) have been known to regulate a variety of biological functions. Recently, it was reported that PRMT1 expression is increased in proximal tubule cells under diabetic conditions. However, their roles in mesangial cells remain unexplored. Thus, we examined the pathophysiological roles of PRMTs in mesangial cell apoptosis. Treatment with palmitate, which mimics cellular lipotoxicity, induced mesangial cell apoptosis via protein kinase RNA-like endoplasmic reticulum kinase (PERK) and ATF6-mediated endoplasmic reticulum (ER) stress signaling. Palmitate treatment increased PRMT1 expression and activity in mesangial cells as well. Moreover, palmitate-induced ER stress activation and mesangial cell apoptosis was diminished by PRMT1 knockdown. In the mice study, high fat diet-induced glomerular apoptosis was attenuated in PRMT1 haploinsufficient mice. Together, these results provide evidence that lipotoxicity-induced PRMT1 expression promotes ER stress-mediated mesangial cell apoptosis. Strategies to regulate PRMT1 expression or activity could be used to prevent the exacerbation of DN. PMID- 28671609 TI - A Survey of Public Opinion on Cat (Felis catus) Predation and the Future Direction of Cat Management in New Zealand. AB - Cat predation is a prominent issue in New Zealand that provokes strong and opposing views. We explored, via 1011 face-to-face questionnaires, public opinion on (a) support for a National Cat Management Strategy (78% support); (b) concern regarding predation of wildlife by owned and un-owned cats (managed stray, unmanaged stray, and feral cats); (c) the acceptability of management techniques for owned cats; and (d) the acceptability of population management techniques for un-owned cats. The highest concern was expressed regarding the predation of non native and native wildlife by feral cats (60 and 86% repectively), followed by unmanaged stray cats (59 and 86% respectively), managed stray cats (54 and 82% respectively), and finally owned cats (38 and 69% repectively). Limits to the number of cats owned and cat restriction zones received high levels of support (>65%), and compulsory microchipping, Council registration, and de-sexing were supported by the majority (>58%). Public support of population control methods for unowned cats was explored, and the influence of participant demographic variables on responses is described. These findings provide insight into public opinion regarding the management of cats in New Zealand, which should be considered during the development of legislation in this area. PMID- 28671610 TI - Methods to Monitor and Quantify Autophagy in the Social Amoeba Dictyostelium discoideum. AB - Autophagy is a eukaryotic catabolic pathway that degrades and recycles cellular components to maintain homeostasis. It can target protein aggregates, superfluous biomolecular complexes, dysfunctional and damaged organelles, as well as pathogenic intracellular microbes. Autophagy is a dynamic process in which the different stages from initiation to final degradation of cargo are finely regulated. Therefore, the study of this process requires the use of a palette of techniques, which are continuously evolving and whose interpretation is not trivial. Here, we present the social amoeba Dictyostelium discoideum as a relevant model to study autophagy. Several methods have been developed based on the tracking and observation of autophagosomes by microscopy, analysis of changes in expression of autophagy genes and proteins, and examination of the autophagic flux with various techniques. In this review, we discuss the pros and cons of the currently available techniques to assess autophagy in this organism. PMID- 28671611 TI - Update on Senecavirus Infection in Pigs. AB - Senecavirus A (SVA) is a positive-sense single-stranded RNA virus that belongs to the Senecavirus genus within the Picornaviridae family. The virus has been silently circulating in pig herds of the USA since 1988. However, cases of senecavirus-associated vesicular disease were reported in Canada in 2007 and in the USA in 2012. Since late 2014 and early 2015, an increasing number of senecavirus outbreaks have been reported in pigs in different producing categories, with this virus being detected in Brazil, China, and Thailand. Considering the novel available data on senecavirus infection and disease, 2015 may be a divisor in the epidemiology of the virus. Among the aspects that reinforce this hypothesis are the geographical distribution of the virus, the affected pig-producing categories, clinical signs associated with the infection, and disease severity. This review presents the current knowledge regarding the senecavirus infection and disease, especially in the last two years. Senecavirus epidemiology, pathogenic potential, host immunological response, diagnosis, and prophylaxis and control measures are addressed. Perspectives are focused on the need for complete evolutionary, epidemiological and pathogenic data and the capability for an immediate diagnosis of senecavirus infection. The health risks inherent in the swine industry cannot be neglected. PMID- 28671612 TI - Mutations in Cancer Cause Gain of Cysteine, Histidine, and Tryptophan at the Expense of a Net Loss of Arginine on the Proteome Level. AB - Accumulation of somatic mutations is critical for the transition of a normal cell to become cancerous. Mutations cause amino acid substitutions that change properties of proteins. However, it has not been studied as to what extent the composition and accordingly chemical properties of the cell proteome is altered as a result of the increased mutation load in cancer. Here, we analyzed data on amino acid substitutions caused by mutations in about 2000 protein coding genes from the Cancer Cell Line Encyclopedia that contains information on nucleotide and amino acid alterations in 782 cancer cell lines, and validated the analysis with information on amino acid substitutions for the same set of proteins in the Catalogue of Somatic Mutations in Cancer (COSMIC; v78) in circa 18,000 tumor samples. We found that nonsynonymous single nucleotide substitutions in the analyzed proteome subset ultimately result in a net gain of cysteine, histidine, and tryptophan at the expense of a net loss of arginine. The extraordinary loss of arginine may be attributed to some extent to composition of its codons as well as to the importance of arginine in the functioning of prominent tumor suppressor proteins like p53. PMID- 28671613 TI - Overcoming the Intrinsic Difference between Hydrophilic CH3NH3PbI3 and Hydrophobic C60 Thin Films to Improve the Photovoltaic Performance. AB - Dimethylformamide/dimethyl sulfoxide solvent mixtures were used as the CH3NH3PbI3 (MAPbI3) precursor solvent in a one-step spin coating method to fabricate smooth and hydrophilic crystalline MAPbI3 thin films on top of hydrophobic carbon-60 (C60) thin film for highly efficient photovoltaics. The structural, optical, and excitonic characteristics of the resultant MAPbI3 thin films were analyzed using X-ray diffraction (XRD), atomic-force microscopy, absorbance spectroscopy, photoluminescence (PL) spectrometry, and nanosecond time-resolved PL. There was a trade-off between the crystallinity and surface roughness of the MAPbI3 thin films, which strongly influenced the device performance of MAPbI3-based photovoltaics. The high power conversion efficiency (PCE) of 17.55% was achieved by improving the wettability of MAPbI3 precursor solutions on top of the C60 thin films. In addition, it was predicted that the fill factor and PCE could be further improved by increasing the crystallinity of the MAPbI3 thin film while keeping it smooth. PMID- 28671614 TI - Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations. AB - Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2 arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. In addition to autism, the EC system is also involved in several other psychiatric disorders (i.e., anxiety, major depression, bipolar disorder and schizophrenia). This system is a key regulator of metabolic and cellular pathways involved in autism, such as food intake, energy metabolism and immune system control. Early studies in autism animal models have demonstrated alterations in the brain's EC system. Autism is also characterized by immune system dysregulation. This alteration includes differential monocyte and macrophage responses, and abnormal cytokine and T cell levels. EC system dysfunction in a monocyte and macrophagic cellular model of autism has been demonstrated by showing that the mRNA and protein for CB2 receptor and EC enzymes were significantly dysregulated, further indicating the involvement of the EC system in autism-associated immunological disruptions. Taken together, these new findings offer a novel perspective in autism research and indicate that the EC system could represent a novel target option for autism pharmacotherapy. PMID- 28671616 TI - Incidence of Ventilator-Associated Pneumonia in Critically Ill Children Undergoing Mechanical Ventilation in Pediatric Intensive Care Unit. AB - BACKGROUND: Among hospital-acquired infections (HAIs) in children, ventilator associated pneumonia (VAP) is the most common after blood stream infection (BSI). VAP can prolong length of ventilation and hospitalization, increase mortality rate, and directly change a patient's outcome in Pediatric Intensive Care Units (PICU). OBJECTIVES: The research on VAP in children is limited, especially in Iran; therefore, the identification of VAP incidence and mortality rate will be important for both clinical and epidemiological implications. MATERIALS AND METHODS: Mechanically ventilated pediatric patients were assessed for development of VAP during hospital course on the basis of clinical, laboratory and imaging criteria. We matched VAP group with control group for assessment of VAP related mortality in the critically ill ventilated children. RESULTS: VAP developed in 22.9% of critically ill children undergoing mechanical ventilation. Early VAP and late VAP were found in 19.3% and 8.4% of VAP cases, respectively. Among the known VAP risk factors that were investigated, immunodeficiency was significantly greater in the VAP group (p = 0.014). No significant differences were found between the two groups regarding use of corticosteroids, antibiotics, PH (potential of hydrogen) modifying agents (such as ranitidine or pantoprazole), presence of nasogastric tube and total or partial parenteral nutrition administration. A substantial number of patients in the VAP group had more than four risk factors for development of VAP, compared to those without VAP (p = 0.087). Mortality rate was not statistically different between the VAP and control groups (p = 0.477). CONCLUSION: VAP is still one of the major causes of mortality in PICUs. It is found that altered immune status is a significant risk factor for acquiring VAP. Also, occurrence of VAP was high in the first week after admission in PICU. PMID- 28671615 TI - TORC1-Dependent Phosphorylation Targets in Fission Yeast. AB - Target of rapamycin (TOR) kinase controls cell metabolism and growth in response to environmental cues such as nutrients, growth factors, and stress. TOR kinase is widely conserved across eukaryotes. As in other organisms, the fission yeast Schizosaccharomyces pombe has two types of TOR complex, namely TOR complex 1 (TORC1) and TORC2. It is interesting that the two TOR complexes in S. pombe have opposite roles in sexual differentiation, which is induced by nutrient starvation. TORC1, which contains Tor2 as a catalytic subunit, promotes vegetative growth and represses sexual differentiation in nutrient-rich conditions, while TORC2 is required for the initiation of sexual differentiation. Multiple targets of TORC1 have been identified. Some of these, such as S6 kinase and an autophagy regulator Atg13, are known targets in other organisms. In addition, there is a novel group of TORC1 targets involved in the regulation of sexual differentiation. Here, we review recent findings on phosphorylation targets of TORC1 in S. pombe. Furthermore, we briefly report a novel S. pombe target of TORC1. PMID- 28671617 TI - Subcritical Water Technology for Extraction of Phenolic Compounds from Chlorella sp. Microalgae and Assessment on Its Antioxidant Activity. AB - Chlorella sp. microalgae is a potential source of antioxidants and natural bioactive compounds used in the food and pharmaceutical industries. In this study, a subcritical water (SW) technology was applied to determine the phenolic content and antioxidant activity of Chlorella sp. This study focused on maximizing the recovery of Chlorella sp. phenolic content and antioxidant activity measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay as a function of extraction temperature (100-250 degrees C), time (5-20 min) and microalgae concentration (5-20 wt. %) using response surface methodology. The optimal operating conditions for the extraction process were found to be 5 min at 163 degrees C with 20 wt. % microalgae concentration, which resulted in products with 58.73 mg gallic acid equivalent (GAE)/g phenolic content and 68.5% inhibition of the DPPH radical. Under optimized conditions, the experimental values were in close agreement with values predicted by the model. The phenolic content was highly correlated (R2 = 0.935) with the antioxidant capacity. Results indicated that extraction by SW technology was effective and that Chlorella sp. could be a useful source of natural antioxidants. PMID- 28671619 TI - Independent Preharvest Applications of Methyl Jasmonate and Chitosan Elicit Differential Upregulation of Defense-Related Genes with Reduced Incidence of Gray Mold Decay during Postharvest Storage of Fragaria chiloensis Fruit. AB - The Chilean strawberry (Fragaria chiloensis) fruit has interesting organoleptic properties, but its postharvest life is affected by gray mold decay caused by Botrytis cinerea. The effect of preharvest applications of methyl jasmonate (MeJA) or chitosan on the molecular defense-related responses and protection against gray mold decay were investigated in Chilean strawberry fruit during postharvest storage. Specifically, we inoculated harvested fruit with B. cinerea spores and studied the expression of genes encoding for the pathogenesis-related (PR) proteins beta-1,3-glucanases (FcBG2-1, FcBG2-2 and FcBG2-3) and chitinases (FcCHI2-2 and FcCHI3-1), and for polygalacturonase inhibiting proteins (FcPGIP1 and FcPGIP2) at 0, 2, 24, 48, and 72 h post inoculation (hpi). Remarkably, MeJA- and chitosan-treated fruit exhibited a lower incidence of B. cinerea infection than the control-treated at 48 and 72 hpi. At the molecular level, both are efficient elicitors for priming in F. chiloensis fruit since we observed an upregulation of the FcBG2-1, FcBG2-3, FcPGIP1, and FcPGIP2 at 0 hpi. Moreover, a chitosan-mediated upregulation of FcPGIPs at early times post inoculation (2-24 hpi) and MeJA upregulated FcBGs (24-72 hpi) and FcPGIP1 at later times could contribute to reduce B. cinerea incidence by differential upregulation of defense genes. We concluded that preharvest applications of MeJA or chitosan had a long lasting effect on the reduction of B. cinerea incidence during postharvest as well as an enhancer effect on the induction of PR and PGIP gene expression. PMID- 28671618 TI - Vascular Mechanobiology: Towards Control of In Situ Regeneration. AB - The paradigm of regenerative medicine has recently shifted from in vitro to in situ tissue engineering: implanting a cell-free, biodegradable, off-the-shelf available scaffold and inducing the development of functional tissue by utilizing the regenerative potential of the body itself. This approach offers a prospect of not only alleviating the clinical demand for autologous vessels but also circumventing the current challenges with synthetic grafts. In order to move towards a hypothesis-driven engineering approach, we review three crucial aspects that need to be taken into account when regenerating vessels: (1) the structure function relation for attaining mechanical homeostasis of vascular tissues, (2) the environmental cues governing cell function, and (3) the available experimental platforms to test instructive scaffolds for in situ tissue engineering. The understanding of cellular responses to environmental cues leads to the development of computational models to predict tissue formation and maturation, which are validated using experimental platforms recapitulating the (patho)physiological micro-environment. With the current advances, a progressive shift is anticipated towards a rational and effective approach of building instructive scaffolds for in situ vascular tissue regeneration. PMID- 28671620 TI - Epithelial-to-Mesenchymal Transition in the Pathogenesis and Therapy of Head and Neck Cancer. AB - Head and neck cancer (HNC) is one of the most prevalent human malignancies worldwide, with a high morbidity and mortality. Implementation of interdisciplinary treatment modalities has improved the quality of life, but only minor changes in overall survival have been achieved over the past decades. Main causes for treatment failure are an aggressive and invasive tumor growth in combination with a high degree of intrinsic or acquired treatment resistance. A subset of tumor cells gain these properties during malignant progression by reactivating a complex program of epithelia-to-mesenchymal transition (EMT), which is integral in embryonic development, wound healing, and stem cell behavior. EMT is mediated by a core set of key transcription factors, which are under the control of a large range of developmental signals and extracellular cues. Unraveling molecular principles that drive EMT provides new concepts to better understand tumor cell plasticity and response to established as well as new treatment modalities, and has the potential to identify new drug targets for a more effective, less toxic, and individualized therapy of HNC patients. Here, we review the most recent findings on the clinical relevance of a mesenchymal like phenotype for HNC patients, including more rare cases of mucosal melanoma and adenoid cystic carcinoma. PMID- 28671621 TI - A Linear Birefringence Measurement Method for an Optical Fiber Current Sensor. AB - In this work, a linear birefringence measurement method is proposed for an optical fiber current sensor (OFCS). First, the optical configuration of the measurement system is presented. Then, the elimination method of the effect of the azimuth angles between the sensing fiber and the two polarizers is demonstrated. Moreover, the relationship of the linear birefringence, the Faraday rotation angle and the final output is determined. On these bases, the multi valued problem on the linear birefringence is simulated and its solution is illustrated when the linear birefringence is unknown. Finally, the experiments are conducted to prove the feasibility of the proposed method. When the numbers of turns of the sensing fiber in the OFCS are about 15, 19, 23, 27, 31, 35, and 39, the measured linear birefringence obtained by the proposed method are about 1.3577, 1.8425, 2.0983, 2.5914, 2.7891, 3.2003 and 3.5198 rad. Two typical methods provide the references for the proposed method. The proposed method is proven to be suitable for the linear birefringence measurement in the full range without the limitation that the linear birefringence must be smaller than pi/2. PMID- 28671622 TI - Landmark-Based Drift Compensation Algorithm for Inertial Pedestrian Navigation. AB - The navigation of pedestrians based on inertial sensors, i.e., accelerometers and gyroscopes, has experienced a great growth over the last years. However, the noise of medium- and low-cost sensors causes a high error in the orientation estimation, particularly in the yaw angle. This error, called drift, is due to the bias of the z-axis gyroscope and other slow changing errors, such as temperature variations. We propose a seamless landmark-based drift compensation algorithm that only uses inertial measurements. The proposed algorithm adds a great value to the state of the art, because the vast majority of the drift elimination algorithms apply corrections to the estimated position, but not to the yaw angle estimation. Instead, the presented algorithm computes the drift value and uses it to prevent yaw errors and therefore position errors. In order to achieve this goal, a detector of landmarks, i.e., corners and stairs, and an association algorithm have been developed. The results of the experiments show that it is possible to reliably detect corners and stairs using only inertial measurements eliminating the need that the user takes any action, e.g., pressing a button. Associations between re-visited landmarks are successfully made taking into account the uncertainty of the position. After that, the drift is computed out of all associations and used during a post-processing stage to obtain a low drifted yaw angle estimation, that leads to successfully drift compensated trajectories. The proposed algorithm has been tested with quasi-error-free turn rate measurements introducing known biases and with medium-cost gyroscopes in 3D indoor and outdoor scenarios. PMID- 28671624 TI - Effect of Polymers on the Physicochemical Properties and Biological Performance of Fenoprofen Calcium Dihydrate-Triacetyl-beta-Cyclodextrin Complex. AB - BACKGROUND: Fenoprofen calcium dehydrate (FCD) is counted as a non-steroidal, anti-inflammatory, anti-arthritic drug. FCD is slightly water soluble. It is indicated for mild pain relief, where the suggested dosage is 200 mg orally every 4 to 6 h. AIM: Reduce dissolution efficiency, reach an extended therapeutic effect and reduce the frequency of the drug side effects. METHOD: Combination of the co-evaporated drug:triacetyl-beta-cyclodextrin complex prepared in a ratio of 1:3 and either of two polymers-hydroxylpropylmethyl cellulose (HPMC) or ethyl cellulose (EC)-in the same formulation. Invitro dissolution studies were carried in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, by using the USP dissolution tester (rotating paddle apparatus). The FCD in vitro release from EC/drug complex was markedly retarded. Interaction between fenoprofen, TA-beta CD, EC, HPMC in the solid state were confirmed by FT-IR, DSC, XRD and SEM. In vivo studies assessed the anti-inflammatory and analgesic activities and the results were compared with the market product Nalfosab(r) Capsules. RESULTS: Remarkable inhibition of inflammation and nociception after 24 h was attained for EC/drug complex. CONCLUSIONS: EC/drug complex has a sustained effect due to high remaining amount after elapsing with remarkable inhibition of inflammation. PMID- 28671625 TI - Vitamin C Deficiency Reduces Muscarinic Receptor Coronary Artery Vasoconstriction and Plasma Tetrahydrobiopterin Concentration in Guinea Pigs. AB - Vitamin C (vitC) deficiency is associated with increased cardiovascular disease risk, but its specific interplay with arteriolar function is unclear. This study investigates the effect of vitC deficiency in guinea pigs on plasma biopterin status and the vasomotor responses in coronary arteries exposed to vasoconstrictor/-dilator agents. Dunkin Hartley female guinea pigs (n = 32) were randomized to high (1500 mg/kg diet) or low (0 to 50 mg/kg diet) vitC for 10-12 weeks. At euthanasia, coronary artery segments were dissected and mounted in a wire-myograph. Vasomotor responses to potassium, carbachol, sodium nitroprusside (SNP), U46619, sarafotoxin 6c (S6c) and endothelin-1 (ET-1) were recorded. Plasma vitC and tetrahydrobiopterin were measured by HPLC. Plasma vitC status reflected the diets with deficient animals displaying reduced tetrahydrobiopterin. Vasoconstrictor responses to carbachol were significantly decreased in vitC deficient coronary arteries independent of their general vasoconstrictor/vasodilator capacity (p < 0.001). Moreover, in vitC deficient animals, carbachol-induced vasodilator responses correlated with coronary artery diameter (p < 0.001). Inhibition of cyclooxygenases with indomethacin increased carbachol-induced vasoconstriction, suggesting an augmented carbachol-induced release of vasodilator prostanoids. Atropine abolished carbachol-induced vasomotion, supporting a specific muscarinic receptor effect. Arterial responses to SNP, potassium, S6c, U46619 and ET-1 were unaffected by vitC status. The study shows that vitC deficiency decreases tetrahydrobiopterin concentrations and muscarinic receptor mediated contraction in coronary arteries. This attenuated vasoconstrictor response may be linked to altered production of vasoactive arachidonic acid metabolites and reduced muscarinic receptor expression/signaling. PMID- 28671623 TI - Plant Lectins as Medical Tools against Digestive System Cancers. AB - Digestive system cancers-those of the esophagus, stomach, small intestine, colon rectum, liver, and pancreas-are highly related to genetics and lifestyle. Most are considered highly mortal due to the frequency of late diagnosis, usually in advanced stages, caused by the absence of symptoms or masked by other pathologies. Different tools are being investigated in the search of a more precise diagnosis and treatment. Plant lectins have been studied because of their ability to recognize and bind to carbohydrates, exerting a variety of biological activities on animal cells, including anticancer activities. The present report integrates existing information on the activity of plant lectins on various types of digestive system cancers, and surveys the current state of research into their properties for diagnosis and selective treatment. PMID- 28671626 TI - Effects of Carbohydrate and Glutamine Supplementation on Oral Mucosa Immunity after Strenuous Exercise at High Altitude: A Double-Blind Randomized Trial. AB - This study analyzed the effects of carbohydrate and glutamine supplementation on salivary immunity after exercise at a simulated altitude of 4500 m. Fifteen volunteers performed exercise of 70% of VO2peak until exhaustion and were divided into three groups: hypoxia placebo, hypoxia 8% maltodextrin (200 mL/20 min), and hypoxia after six days glutamine (20 g/day) and 8% maltodextrin (200 mL/20 min). All procedures were randomized and double-blind. Saliva was collected at rest (basal), before exercise (pre-exercise), immediately after exercise (post exercise), and two hours after exercise. Analysis of Variance (ANOVA) for repeated measures and Tukey post hoc test were performed. Statistical significance was set at p < 0.05. SaO2% reduced when comparing baseline vs. pre exercise, post-exercise, and after recovery for all three groups. There was also a reduction of SaO2% in pre-exercise vs. post-exercise for the hypoxia group and an increase was observed in pre-exercise vs. recovery for both supplementation groups, and between post-exercise and for the three groups studied. There was an increase of salivary flow in post-exercise vs. recovery in Hypoxia + Carbohydrate group. Immunoglobulin A (IgA) decreased from baseline vs. post-exercise for Hypoxia + Glutamine group. Interleukin 10 (IL-10) increased from post-exercise vs. after recovery in Hypoxia + Carbohydrate group. Reduction of tumor necrosis factor alpha (TNF-alpha) was observed from baseline vs. post-exercise and after recovery for the Hypoxia + Carbohydrate group; a lower concentration was observed in pre-exercise vs. post-exercise and recovery. TNF-alpha had a reduction from baseline vs. post-exercise for both supplementation groups, and a lower secretion between baseline vs. recovery, and pre-exercise vs. post-exercise for Hypoxia + Carbohydrate group. Five hours of hypoxia and exercise did not change IgA. Carbohydrates, with greater efficiency than glutamine, induced anti-inflammatory responses. PMID- 28671627 TI - A 10-Year Follow-Up Study of Social Ties and Functional Health among the Old: The AGES Project. AB - In Asian nations, family ties are considered important. However, it is not clear what happens among older people with no such ties. To investigate the association, we used longitudinal data from the Aichi Gerontological Evaluation Study (AGES) project. Functionally independent older people at baseline (N = 14,088) in 10 municipalities were followed from 2003 to 2013. Social ties were assessed by asking about their social support exchange with family, relatives, friends, or neighbors. Cox proportional hazard models were employed to investigate the association between social ties and the onset of functional disability adjusting for age, health status, and living arrangement. We found that social ties with co-residing family members, and those with friends or neighbors, independently protected functional health with hazard ratios of 0.81 and 0.85 among men. Among women, ties with friend or neighbors had a stronger effect on health compared to their male counterparts with a hazard ratio of 0.89. The fact that social ties with friends or neighbors are associated with a lower risk of functional decline, independent of family support, serves to underscore the importance of promoting social ties, especially among those lacking family ties. PMID- 28671628 TI - Direct Quantification of Cd2+ in the Presence of Cu2+ by a Combination of Anodic Stripping Voltammetry Using a Bi-Film-Modified Glassy Carbon Electrode and an Artificial Neural Network. AB - Abstract: In this study, a novel method based on a Bi/glassy carbon electrode (Bi/GCE) for quantitatively and directly detecting Cd2+ in the presence of Cu2+ without further electrode modifications by combining square-wave anodic stripping voltammetry (SWASV) and a back-propagation artificial neural network (BP-ANN) has been proposed. The influence of the Cu2+ concentration on the stripping response to Cd2+ was studied. In addition, the effect of the ferrocyanide concentration on the SWASV detection of Cd2+ in the presence of Cu2+ was investigated. A BP-ANN with two inputs and one output was used to establish the nonlinear relationship between the concentration of Cd2+ and the stripping peak currents of Cu2+ and Cd2+. The factors affecting the SWASV detection of Cd2+ and the key parameters of the BP-ANN were optimized. Moreover, the direct calibration model (i.e., adding 0.1 mM ferrocyanide before detection), the BP-ANN model and other prediction models were compared to verify the prediction performance of these models in terms of their mean absolute errors (MAEs), root mean square errors (RMSEs) and correlation coefficients. The BP-ANN model exhibited higher prediction accuracy than the direct calibration model and the other prediction models. Finally, the proposed method was used to detect Cd2+ in soil samples with satisfactory results. PMID- 28671629 TI - Motor Imagery EEG Classification for Patients with Amyotrophic Lateral Sclerosis Using Fractal Dimension and Fisher's Criterion-Based Channel Selection. AB - Motor imagery is based on the volitional modulation of sensorimotor rhythms (SMRs); however, the sensorimotor processes in patients with amyotrophic lateral sclerosis (ALS) are impaired, leading to degenerated motor imagery ability. Thus, motor imagery classification in ALS patients has been considered challenging in the brain-computer interface (BCI) community. In this study, we address this critical issue by introducing the Grassberger-Procaccia and Higuchi's methods to estimate the fractal dimensions (GPFD and HFD, respectively) of the electroencephalography (EEG) signals from ALS patients. Moreover, a Fisher's criterion-based channel selection strategy is proposed to automatically determine the best patient-dependent channel configuration from 30 EEG recording sites. An EEG data collection paradigm is designed to collect the EEG signal of resting state and the imagination of three movements, including right hand grasping (RH), left hand grasping (LH), and left foot stepping (LF). Five late-stage ALS patients without receiving any SMR training participated in this study. Experimental results show that the proposed GPFD feature is not only superior to the previously-used SMR features (mu and beta band powers of EEG from sensorimotor cortex) but also better than HFD. The accuracies achieved by the SMR features are not satisfactory (all lower than 80%) in all binary classification tasks, including RH imagery vs. resting, LH imagery vs. resting, and LF imagery vs. resting. For the discrimination between RH imagery and resting, the average accuracies of GPFD in 30-channel (without channel selection) and top-five-channel configurations are 95.25% and 93.50%, respectively. When using only one channel (the best channel among the 30), a high accuracy of 91.00% can still be achieved by the GPFD feature and a linear discriminant analysis (LDA) classifier. The results also demonstrate that the proposed Fisher's criterion-based channel selection is capable of removing a large amount of redundant and noisy EEG channels. The proposed GPFD feature extraction combined with the channel selection strategy can be used as the basis for further developing high-accuracy and high-usability motor imagery BCI systems from which the patients with ALS can really benefit. PMID- 28671630 TI - Prevalence of Inherited Hemoglobin Disorders and Relationships with Anemia and Micronutrient Status among Children in Yaounde and Douala, Cameroon. AB - Information on the etiology of anemia is necessary to design effective anemia control programs. Our objective was to measure the prevalence of inherited hemoglobin disorders (IHD) in a representative sample of children in urban Cameroon, and examine the relationships between IHD and anemia. In a cluster survey of children 12-59 months of age (n = 291) in Yaounde and Douala, we assessed hemoglobin (Hb), malaria infection, and plasma indicators of inflammation and micronutrient status. Hb S was detected by HPLC, and alpha+thalassemia (3.7 kb deletions) by PCR. Anemia (Hb < 110 g/L), inflammation, and malaria were present in 45%, 46%, and 8% of children. A total of 13.7% of children had HbAS, 1.6% had HbSS, and 30.6% and 3.1% had heterozygous and homozygous alpha+thalassemia. The prevalence of anemia was greater among HbAS compared to HbAA children (60.3 vs. 42.0%, p = 0.038), although mean Hb concentrations did not differ, p = 0.38). Hb and anemia prevalence did not differ among children with or without single gene deletion alpha+thalassemia. In multi variable models, anemia was independently predicted by HbAS, HbSS, malaria, iron deficiency (ID; inflammation-adjusted ferritin <12 ug/L), higher C-reactive protein, lower plasma folate, and younger age. Elevated soluble transferrin receptor concentration (>8.3 mg/L) was associated with younger age, malaria, greater mean reticulocyte counts, inflammation, HbSS genotype, and ID. IHD are prevalent but contribute modestly to anemia among children in urban Cameroon. PMID- 28671631 TI - A Damping Grid Strapdown Inertial Navigation System Based on a Kalman Filter for Ships in Polar Regions. AB - The grid strapdown inertial navigation system (SINS) used in polar navigation also includes three kinds of periodic oscillation errors as common SINS are based on a geographic coordinate system. Aiming ships which have the external information to conduct a system reset regularly, suppressing the Schuler periodic oscillation is an effective way to enhance navigation accuracy. The Kalman filter based on the grid SINS error model which applies to the ship is established in this paper. The errors of grid-level attitude angles can be accurately estimated when the external velocity contains constant error, and then correcting the errors of the grid-level attitude angles through feedback correction can effectively dampen the Schuler periodic oscillation. The simulation results show that with the aid of external reference velocity, the proposed external level damping algorithm based on the Kalman filter can suppress the Schuler periodic oscillation effectively. Compared with the traditional external level damping algorithm based on the damping network, the algorithm proposed in this paper can reduce the overshoot errors when the state of grid SINS is switched from the non damping state to the damping state, and this effectively improves the navigation accuracy of the system. PMID- 28671634 TI - Regressions of Breast Carcinoma Syngraft Following Treatment with Piperine in Combination with Thymoquinone. AB - Thymoquinone (TQ) and piperine, the active ingredients in cumin (Nigella sativa) and black pepper (Piper longum), respectively, exhibit various bioactivities including anticancer effects. The aim of the present study is to investigate the antineoplastic activity of a combination of TQ and piperine against breast cancer implanted in mice. The antiproliferative effects of TQ, piperine, and a combination of both agents were tested against mouse epithelial breast cancer cell line (EMT6/P) using MTT assay. The isobolographic method was used to calculate the combination index (CI). Degree of angiogenesis inhibition was detected by measuring vascular endothelial growth factor (VEGF) levels in tissue culture for all treatments. EMT6/P cells were inoculated in Balb/C mice and the antitumor effect of TQ, piperine, and their combination was assessed. Changes in tumor size were calculated for all treatments. Tumor histology was examined using the hematoxylin/eosin staining protocol. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) colorimetric assay and caspase-3 activity assays were used to detect apoptosis. Serum levels of interferon (INF)-gamma, interleukin (IL)-4, IL-2, and IL-10 were measured using ELISA and treatment toxicity was evaluated by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and creatinine. A clear synergistic antiproliferative interaction between TQ and piperine was observed with CI value of 0.788. The combination therapy resulted in significant reduction in tumor size with percentage cure of 60% and percentage death of 0%. High degrees of apoptosis and geographical necrosis were induced in tumors treated with the combination therapy. Combination therapy caused significant decrease in VEGF expression and increased serum INF-gamma levels. Normal serum levels of AST, ALT, and creatinine were observed in tumor-bearing mice treated with the combination therapy. The combination of TQ and piperine acts synergistically to target breast cancer in vitro and in vivo. This novel combination exerts its effect by angiogenesis inhibition, apoptosis induction, and shifting the immune response toward T helper1 response. This combination therapy deserves further investigation (including measurement of hypoxia-inducible factor (HIF)1alpha to be used in clinical studies. PMID- 28671632 TI - A Hybrid FPGA-Based System for EEG- and EMG-Based Online Movement Prediction. AB - A current trend in the development of assistive devices for rehabilitation, for example exoskeletons or active orthoses, is to utilize physiological data to enhance their functionality and usability, for example by predicting the patient's upcoming movements using electroencephalography (EEG) or electromyography (EMG). However, these modalities have different temporal properties and classification accuracies, which results in specific advantages and disadvantages. To use physiological data analysis in rehabilitation devices, the processing should be performed in real-time, guarantee close to natural movement onset support, provide high mobility, and should be performed by miniaturized systems that can be embedded into the rehabilitation device. We present a novel Field Programmable Gate Array (FPGA) -based system for real-time movement prediction using physiological data. Its parallel processing capabilities allows the combination of movement predictions based on EEG and EMG and additionally a P300 detection, which is likely evoked by instructions of the therapist. The system is evaluated in an offline and an online study with twelve healthy subjects in total. We show that it provides a high computational performance and significantly lower power consumption in comparison to a standard PC. Furthermore, despite the usage of fixed-point computations, the proposed system achieves a classification accuracy similar to systems with double precision floating-point precision. PMID- 28671633 TI - L1210 Cells Overexpressing ABCB1 Drug Transporters Are Resistant to Inhibitors of the N- and O-glycosylation of Proteins. AB - Overexpression of P-glycoprotein (P-gp, drug transporter) in neoplastic cells is the most frequently observed molecular cause of multidrug resistance. Here, we show that the overexpression of P-gp in L1210 cells leads to resistance to tunicamycin and benzyl 2-acetamido-2-deoxy-alpha-d-galactopyranoside (GalNAc alpha-O-benzyl). Tunicamycin induces both glycosylation depression and ubiquitination improvement of P-gp. However, the latter is not associated with large increases in molecular mass as evidence for polyubiquitination. Therefore, P-gp continues in maturation to an active membrane efflux pump rather than proteasomal degradation. P-gp-positive L1210 cells contain a higher quantity of ubiquitin associated with cell surface proteins than their P-gp-negative counterparts. Thus, P-gp-positive cells use ubiquitin signaling for correct protein folding to a higher extent than P-gp-negative cells. Elevation of protein ubiquitination after tunicamycin treatment in these cells leads to protein folding rather than protein degradation, resulting at least in the partial lack of cell sensitivity to tunicamycin in L1210 cells after P-gp expression. In contrast to tunicamycin, to understand why P-gp-positive cells are resistant to GalNAc-alpha-O-benzyl, further research is needed. PMID- 28671635 TI - Osteoprotective Effect of Radix Scutellariae in Female Hindlimb-Suspended Sprague Dawley Rats and the Osteogenic Differentiation Effect of Its Major Constituent. AB - A number of medicinal herbs have demonstrated therapeutic effects for the prevention and treatment of disuse-induced osteoporosis. As a common ingredient in proprietary traditional Chinese medicines, the anti-osteoporosis effects of Radix Scutellariae extract (RSE, 50 mg/kg/day) were evaluated in a hindlimb suspended rat model. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and the micro-architecture observed by MicroCT assay with bone biomechanical properties evaluated by a three-point bending test. To elucidate potential mechanisms, the osteogenic differentiation effect of baicalin as the most abundant ingredient in RSE was investigated in rat bone marrow derived mesenchymal stem cells (rBMSC). After drug administration for 42 days, tibia-BMD was significantly increased to 0.176 +/- 0.007 and 0.183 +/- 0.011 g/cm2 and f BMD was enhanced to 0.200 +/- 0.017 and 0.207 +/- 0.021 g/cm2 for RSE and ALE treatment, respectively, whereas tibia-BMD and femur-BMD of the HLS group were 0.157 +/- 0.009 and 0.176 +/- 0.008 g/cm2. Deterioration of bone trabecula microstructure was improved by RSE and ALE with increased morphological parameters such as bone volume fraction, trabecular thickness, and trabecular number, as well as connectivity density compared to the HLS group (p < 0.01). A three-point bending test suggested that bone mechanical strength was also enhanced by RSE and ALE treatments with increased maximum stress, young's modulus, maximum load, and stiffness compared to those of the HLS group (p < 0.05). Besides, serum TRACP levels were significantly suppressed by RSE and ALE treatments. Furthermore, in vitro studies demonstrated that baicalin significantly increased ALP activities and the formation of mineralized nodules in rBMSC. Conclusively, supplementation of RSE could significantly prevent weightlessness induced osteoporosis, which might attribute to the osteogenic differentiation enhancement effect of baicalin. PMID- 28671637 TI - Factors Affecting Dietary Practices in a Mississippi African American Community. AB - This study examined the practices, personal motivation, and barriers of African American communities in Mississippi regarding their dietary practices. We selected the Metro Jackson Area comprised of Hinds, Madison and Rankin Counties because it is a combination of urban and rural communities. The sample consisted of 70 participants from seven sites. A total of seven focus groups responded to six questions to assess practices, personal motivation, and barriers to dietary practices: (1) Where in your community can you access fresh fruits and vegetables? (2) How many meals a day should a person eat? (3) What would you consider to be a healthy breakfast, lunch and dinner? (4) What would you consider to be a healthy snack? (5) What do you consider to be your motivations for eating healthy? (6) What do you consider to be your barriers to eating healthy? Each of the seven focus groups consisted of 6 to 12 participants and provided details of their dietary practices. The focus group interviews were digitally-recorded. The recorded interviews were transcribed. The majority of the participants stated that there is a limited availability of fresh fruits/vegetables in rural areas because of a shortage of grocery stores. When they do find fruits, they are priced very high and are unaffordable. Even though health conditions dictate food frequency and portion size, community members feel that individuals should eat three good balanced meals per day with snacks, and they should adhere to small portion sizes. While the desire to attain overall good health and eliminate associative risks for heart disease (e.g., diabetes, obesity) are personal motivations, the cost of food, transportation, age, and time required for food preparation were seen as barriers to healthy eating. Decisions regarding meal choice and meal frequency can have an impact on long-term health outcomes. Health promotion programs should become an integral part of academic- community collaborative agreements. PMID- 28671639 TI - A Novel Synthesis of 4-Acetoxyl 5(4H)-Oxazolones by Direct alpha-Oxidation of N Benzoyl Amino-Acid Using Hypervalent Iodine. AB - We have developed a new method to prepare 4-acetoxy substituted 5(4H)-oxazolones by direct oxidation of N-benzoyl amino-acids using hypervalent iodine. The method is efficient, economical and easy to perform for the synthesis of quaternary substituted amino acid derivatives. We used online FTIR monitoring techniques to analyze the reaction, and gave a plausible reaction mechanism. PMID- 28671636 TI - Neuroprotective and Anti-Inflammatory Activities of Allyl Isothiocyanate through Attenuation of JNK/NF-kappaB/TNF-alpha Signaling. AB - Allyl isothiocyanate (AITC), present in Wasabia japonica (wasabi), is an aliphatic isothiocyanate derived from the precursor sinigrin, which is a glucosinolate present in vegetables of the Brassica family. Traditionally, it has been used to treat rheumatic arthralgia, blood circulation, and pain. This study focuses on its anti-apoptotic activity through the regulation of lipopolysaccharide (LPS)-induced neuroinflammation. Furthermore, we assessed its neuroprotective efficacy, which it achieves through the upregulation of nerve growth factor (NGF) production. Pretreatment with AITC significantly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, decreased tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO) production in activated microglia, and increased the nerve growth factor (NGF) and neurite outgrowth in neuroblastoma cells. AITC inhibited the nuclear factor (NF-kappaB-mediated transcription by modulating mitogen activated protein kinase (MAPK) signaling, particularly downregulating c-Jun N-terminal kinase (JNK) phosphorylation, which was followed by a reduction in the TNF-alpha expression in activated microglia. This promising effect of AITC in controlling JNK/NF-kappaB/TNF-alpha cross linking maintains the Bcl-2 gene family and protects neuroblastoma cells from activated microglia-induced toxicity. These findings provide novel insights into the anti-neuroinflammatory effects of AITC on microglial cells, which may have clinical significance in neurodegeneration. PMID- 28671638 TI - Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin. AB - Antagonists of the Escherichia coli type-1 fimbrial adhesin FimH are recognized as attractive alternatives for antibiotic therapies and prophylaxes against acute and recurrent bacterial infections. In this study alpha-d-mannopyranosides O- or C-linked with an alkyl, alkene, alkyne, thioalkyl, amide, or sulfonamide were investigated to fit a hydrophobic substituent with up to two aryl groups within the tyrosine gate emerging from the mannose-binding pocket of FimH. The results were summarized into a set of structure-activity relationships to be used in FimH targeted inhibitor design: alkene linkers gave an improved affinity and inhibitory potential, because of their relative flexibility combined with a favourable interaction with isoleucine-52 located in the middle of the tyrosine gate. Of particular interest is a C-linked mannoside, alkene-linked to an ortho substituted biphenyl that has an affinity similar to its O-mannosidic analog but superior to its para-substituted analog. Docking of its high-resolution NMR solution structure to the FimH adhesin indicated that its ultimate, ortho-placed phenyl ring is able to interact with isoleucine-13, located in the clamp loop that undergoes conformational changes under shear force exerted on the bacteria. Molecular dynamics simulations confirmed that a subpopulation of the C-mannoside conformers is able to interact in this secondary binding site of FimH. PMID- 28671640 TI - Chrysin Attenuates VCAM-1 Expression and Monocyte Adhesion in Lipopolysaccharide Stimulated Brain Endothelial Cells by Preventing NF-kappaB Signaling. AB - Adhesion of leukocytes to endothelial cells plays an important role in neuroinflammation. Therefore, suppression of the expression of adhesion molecules in brain endothelial cells may inhibit neuroinflammation. Chrysin (5,7 dihydroxyflavone) is a flavonoid component of propolis, blue passion flowers, and fruits. In the present study, we examined the effects of chrysin on lipopolysaccharide (LPS)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in mouse cerebral vascular endothelial (bEnd.3) cells. In bEnd.3 cells, LPS increased mRNA expression of VCAM-1 in a time-dependent manner, and chrysin significantly decreased LPS-induced mRNA expression of VCAM-1. Chrysin also reduced VCAM-1 protein expression in a concentration-dependent manner. Furthermore, chrysin blocked adhesion of monocytes to bEnd.3 cells exposed to LPS. Nuclear factor-kappaB (NF-kappaB), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, which are all activated by LPS, were significantly inhibited by chrysin. These results indicate that chrysin inhibits the expression of VCAM-1 in brain endothelial cells by inhibiting NF-kappaB translocation and MAPK signaling, resulting in the attenuation of leukocyte adhesion to endothelial cells. The anti-inflammatory effects of chrysin suggest a possible therapeutic application of this agent to neurodegenerative diseases, such as multiple sclerosis, septic encephalopathy, and allergic encephalomyelitis. PMID- 28671641 TI - Fuzzy-Logic Based Distributed Energy-Efficient Clustering Algorithm for Wireless Sensor Networks. AB - Due to the high-energy efficiency and scalability, the clustering routing algorithm has been widely used in wireless sensor networks (WSNs). In order to gather information more efficiently, each sensor node transmits data to its Cluster Head (CH) to which it belongs, by multi-hop communication. However, the multi-hop communication in the cluster brings the problem of excessive energy consumption of the relay nodes which are closer to the CH. These nodes' energy will be consumed more quickly than the farther nodes, which brings the negative influence on load balance for the whole networks. Therefore, we propose an energy efficient distributed clustering algorithm based on fuzzy approach with non uniform distribution (EEDCF). During CHs' election, we take nodes' energies, nodes' degree and neighbor nodes' residual energies into consideration as the input parameters. In addition, we take advantage of Takagi, Sugeno and Kang (TSK) fuzzy model instead of traditional method as our inference system to guarantee the quantitative analysis more reasonable. In our scheme, each sensor node calculates the probability of being as CH with the help of fuzzy inference system in a distributed way. The experimental results indicate EEDCF algorithm is better than some current representative methods in aspects of data transmission, energy consumption and lifetime of networks. PMID- 28671642 TI - Acoustic Sensing and Ultrasonic Drug Delivery in Multimodal Theranostic Capsule Endoscopy. AB - Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components. In this approach, an initial multimodal diagnostic device with high-frequency quantitative microultrasound that complements video imaging allows surface and subsurface visualization and computer-assisted diagnosis. Using focused ultrasound (US) to mark sites of pathology with exogenous fluorescent agents permits follow-up with another device to provide therapy. This is based on an US-mediated targeted drug delivery system with fluorescence imaging guidance. An additional device may then be utilized for treatment verification and monitoring, exploiting the minimally invasive nature of CE. While such a theranostic patient pathway for gastrointestinal treatment is presently incomplete, the description in this paper of previous research and work under way to realize further components for the proposed pathway suggests it is feasible and provides a framework around which to structure further work. PMID- 28671643 TI - PM2.5, Population Exposure and Economic Effects in Urban Agglomerations of China Using Ground-Based Monitoring Data. AB - This paper adopts the PM2.5 concentration data obtained from 1497 station-based monitoring sites, population and gross domestic product (GDP) census data, revealing population exposure and economic effects of PM2.5 in four typical urban agglomerations of China, i.e., Beijing-Tianjin-Hebei (BTH), the Yangtze River delta (YRD), the Pearl River delta (PRD), and Chengdu-Chongqing (CC). The Cokriging interpolation method was used to estimate the PM2.5 concentration from station-level to grid-level. Next, an evaluation was conducted mainly at the grid level with a cell size of 1 * 1 km, assisted by the urban agglomeration scale. Criteria including the population-weighted mean, the cumulative percent distribution and the correlation coefficient were applied in our evaluation. The results showed that the spatial pattern of population exposure in BTH was consistent with that of PM2.5 concentration, as well as changes in elevation. The topography was also an important factor in the accumulation of PM2.5 in CC. Moreover, the most polluted urban agglomeration based on the population-weighted mean was BTH, while the least was PRD. In terms of the cumulative percent distribution, only 0.51% of the population who lived in the four urban agglomerations, and 2.33% of the GDP that was produced in the four urban agglomerations, were associated with an annual PM2.5 concentration smaller than the Chinese National Ambient Air Quality Standard of 35 ug/m3. This indicates that the majority of people live in the high air polluted areas, and economic development contributes to air pollution. Our results are supported by the high correlation between population exposure and the corresponding GDP in each urban agglomeration. PMID- 28671644 TI - Biosensing Motor Neuron Membrane Potential in Live Zebrafish Embryos. AB - The protocols described here are designed to allow researchers to study cell communication without altering the integrity of the environment in which the cells are located. Specifically, they have been developed to analyze the electrical activity of excitable cells, such as spinal neurons. In such a scenario, it is crucial to preserve the integrity of the spinal cell, but it is also important to preserve the anatomy and physiological shape of the systems involved. Indeed, the comprehension of the manner in which the nervous system-and other complex systems-works must be based on a systemic approach. For this reason, the live zebrafish embryo was chosen as a model system, and the spinal neuron membrane voltage changes were evaluated without interfering with the physiological conditions of the embryos. Here, an approach combining the employment of zebrafish embryos with a FRET-based biosensor is described. Zebrafish embryos are characterized by a very simplified nervous system and are particularly suited for imaging applications thanks to their transparency, allowing for the employment of fluorescence-based voltage indicators at the plasma membrane during zebrafish development. The synergy between these two components makes it possible to analyze the electrical activity of the cells in intact living organisms, without perturbing the physiological state. Finally, this non-invasive approach can co-exist with other analyses (e.g., spontaneous movement recordings, as shown here). PMID- 28671645 TI - QTL Mapping and CRISPR/Cas9 Editing to Identify a Drug Resistance Gene in Toxoplasma gondii. AB - Scientific knowledge is intrinsically linked to available technologies and methods. This article will present two methods that allowed for the identification and verification of a drug resistance gene in the Apicomplexan parasite Toxoplasma gondii, the method of Quantitative Trait Locus (QTL) mapping using a Whole Genome Sequence (WGS) -based genetic map and the method of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 -based gene editing. The approach of QTL mapping allows one to test if there is a correlation between a genomic region(s) and a phenotype. Two datasets are required to run a QTL scan, a genetic map based on the progeny of a recombinant cross and a quantifiable phenotype assessed in each of the progeny of that cross. These datasets are then formatted to be compatible with R/qtl software that generates a QTL scan to identify significant loci correlated with the phenotype. Although this can greatly narrow the search window of possible candidates, QTLs span regions containing a number of genes from which the causal gene needs to be identified. Having WGS of the progeny was critical to identify the causal drug resistance mutation at the gene level. Once identified, the candidate mutation can be verified by genetic manipulation of drug sensitive parasites. The most facile and efficient method to genetically modify T. gondii is the CRISPR/Cas9 system. This system comprised of just 2 components both encoded on a single plasmid, a single guide RNA (gRNA) containing a 20 bp sequence complementary to the genomic target and the Cas9 endonuclease that generates a double-strand DNA break (DSB) at the target, repair of which allows for insertion or deletion of sequences around the break site. This article provides detailed protocols to use CRISPR/Cas9 based genome editing tools to verify the gene responsible for sinefungin resistance and to construct transgenic parasites. PMID- 28671646 TI - Glucose Uptake Measurement and Response to Insulin Stimulation in In Vitro Cultured Human Primary Myotubes. AB - Skeletal muscle is the largest glucose deposit in mammals and largely contributes to glucose homeostasis. Assessment of insulin sensitivity of muscle cells is of major relevance for all studies dedicated to exploring muscle glucose metabolism and characterizing metabolic alterations. In muscle cells, glucose transporter type 4 (GLUT4) proteins translocate to the plasma membrane in response to insulin, thus allowing massive entry of glucose into the cell. The ability of muscle cells to respond to insulin by increasing the rate of glucose uptake is one of the standard readouts to quantify muscle cell sensitivity to insulin. Human primary myotubes are a suitable in vitro model, as the cells maintain many features of the donor phenotype, including insulin sensitivity. This in vitro model is also suitable for the test of any compounds that could impact insulin responsiveness. Measurements of the glucose uptake rate in differentiated myotubes reflect insulin sensitivity. In this method, human primary muscle cells are cultured in vitro to obtain differentiated myotubes, and glucose uptake rates with and without insulin stimulation are measured. We provide a detailed protocol to quantify passive and active glucose transport rates using radiolabeled [3H] 2 deoxy-D-Glucose ([3H]2dG). Calculation methods are provided to quantify active basal and insulin-stimulated rates, as well as stimulation fold. PMID- 28671647 TI - Assessment of Hippocampal Dendritic Complexity in Aged Mice Using the Golgi-Cox Method. AB - Dendritic spines are the protuberances from the neuronal dendritic shafts that contain excitatory synapses. The morphological and branching variations of the neuronal dendrites within the hippocampus are implicated in cognition and memory formation. There are several approaches to Golgi staining, all of which have been useful for determining the morphological characteristics of dendritic arbors and produce a clear background. The present Golgi-Cox method, (a slight variation of the protocol that is provided with a commercial Golgi staining kit), was designed to assess how a relatively low dose of the chemotherapeutic drug 5-flurouracil (5 Fu) would affect dendritic morphology, the number of spines, and the complexity of arborization within the hippocampus. The 5-Fu significantly modulated the dendritic complexity and decreased the spine density throughout the hippocampus in a region-specific manner. The data presented show that the Golgi staining method effectively stained the mature neurons in the CA1, the CA3, and the dentate gyrus (DG) of the hippocampus. This protocol reports the details for each step so that other researchers can reliably stain tissue throughout the brain with high quality results and minimal troubleshooting. PMID- 28671648 TI - Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi unit Activity from the Hyperdirect Pathway in Anesthetized Rats. AB - Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the pathophysiological basis of these diseases, it is necessary to precisely characterize in which way the processing of information is disturbed between the different neuronal parts of the circuit. Using extracellular in vivo electrophysiological recordings, it is possible to accurately delineate neuronal activity within a neuronal network. The application of this method has several advantages over alternative techniques, e.g., functional magnetic resonance imaging and calcium imaging, as it allows a unique temporal and spatial resolution and does not rely on genetically engineered organisms. However, the use of extracellular in vivo recordings is limited since it is an invasive technique that cannot be universally applied. In this article, a simple and easy to use method is presented with which it is possible to simultaneously record extracellular potentials such as local field potentials and multiunit activity at multiple sites of a network. It is detailed how a precise targeting of subcortical nuclei can be achieved using a combination of stereotactic surgery and online analysis of multi-unit recordings. Thus, it is demonstrated, how a complete network such as the hyperdirect cortico-basal ganglia loop can be studied in anesthetized animals in vivo. PMID- 28671649 TI - Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate. AB - Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high atomic and step economy. However, this functionality-directed cross-coupling reaction has not been developed, as there are still limited directing groups in practical use. In particular, a stoichiometric amount of oxidant is usually required, producing a large amount of waste. Due to our interest in novel 1,3-butadiene synthesis, we describe the ruthenium-catalyzed olefination of electron-deficient alkenes using allyl acetate and without external oxidant. The reaction of 2 phenyl acrylamide and allyl acetate was chosen as a model reaction, and the desired diene product was obtained in 80% isolated yield with good stereoselectivity (Z,E/Z,Z = 88:12) under optimal conditions: [Ru(p-cymene) Cl2]2 (3 mol %) and AgSbF6 (20 mol %) in DCE at 110 oC for 16 h. With the optimized catalytic conditions in hand, representative alpha- and/or beta-substituted acrylamides were investigated, and all reacted smoothly, regardless of aliphatic or aromatic groups. Also, differently N-substituted acrylamides have proven to be good substrates. Moreover, we examined the reactivity of different allyl derivatives, suggesting that the chelation of acetate oxygen to the metal is crucial for the catalytic process. Deuterium-labeled experiments were also conducted to investigate the reaction mechanism. Only Z-selective H/D exchanges on acrylamide were observed, indicating a reversible cyclometalation event. In addition, a kinetic isotope effect (KIE) of 3.2 was observed in the intermolecular isotopic study, suggesting that the olefinic C-H metalation step is probably involved in the rate-determining step. PMID- 28671650 TI - CAPRRESI: Chimera Assembly by Plasmid Recovery and Restriction Enzyme Site Insertion. AB - Here, we present chimera assembly by plasmid recovery and restriction enzyme site insertion (CAPRRESI). CAPRRESI benefits from many strengths of the original plasmid recovery method and introduces restriction enzyme digestion to ease DNA ligation reactions (required for chimera assembly). For this protocol, users clone wildtype genes into the same plasmid (pUC18 or pUC19). After the in silico selection of amino acid sequence regions where chimeras should be assembled, users obtain all the synonym DNA sequences that encode them. Ad hoc Perl scripts enable users to determine all synonym DNA sequences. After this step, another Perl script searches for restriction enzyme sites on all synonym DNA sequences. This in silico analysis is also performed using the ampicillin resistance gene (ampR) found on pUC18/19 plasmids. Users design oligonucleotides inside synonym regions to disrupt wildtype and ampR genes by PCR. After obtaining and purifying complementary DNA fragments, restriction enzyme digestion is accomplished. Chimera assembly is achieved by ligating appropriate complementary DNA fragments. pUC18/19 vectors are selected for CAPRRESI because they offer technical advantages, such as small size (2,686 base pairs), high copy number, advantageous sequencing reaction features, and commercial availability. The usage of restriction enzymes for chimera assembly eliminates the need for DNA polymerases yielding blunt-ended products. CAPRRESI is a fast and low-cost method for fusing protein-coding genes. PMID- 28671651 TI - An All-on-chip Method for Rapid Neutrophil Chemotaxis Analysis Directly from a Drop of Blood. AB - Neutrophil migration and chemotaxis are critical for our body's immune system. Microfluidic devices are increasingly used for investigating neutrophil migration and chemotaxis owing to their advantages in real-time visualization, precise control of chemical concentration gradient generation, and reduced reagent and sample consumption. Recently, a growing effort has been made by the microfluidic researchers toward developing integrated and easily operated microfluidic chemotaxis analysis systems, directly from whole blood. In this direction, the first all-on-chip method was developed for integrating the magnetic negative purification of neutrophils and the chemotaxis assay from small blood volume samples. This new method permits a rapid sample-to-result neutrophil chemotaxis test in 25 min. In this paper, we provide detailed construction, operation and data analysis method for this all-on-chip chemotaxis assay with a discussion on troubleshooting strategies, limitations and future directions. Representative results of the neutrophil chemotaxis assay testing a defined chemoattractant, N Formyl-Met-Leu-Phe (fMLP), and sputum from a chronic obstructive pulmonary disease (COPD) patient, using this all-on-chip method are shown. This method is applicable to many cell migration-related investigations and clinical applications. PMID- 28671652 TI - Induction of Hypoxia in Living Frog and Zebrafish Embryos. AB - Here, we introduce a novel system for hypoxia induction, which we developed to study the effects of hypoxia in aquatic organisms such as frog and zebrafish embryos. Our system comprises a chamber featuring a simple setup that is nevertheless robust to induce and maintain a specific oxygen concentration and temperature in any experimental solution of choice. The presented system is very cost-effective but highly functional, it allows induction and sustainment of hypoxia for direct experiments in vivo and for various time periods up to 48 h. To monitor and study the effects of hypoxia, we have employed two methods - measurement of levels of hypoxia-inducible factor 1alpha (HIF-1alpha) in whole embryos or specific tissues and determination of retinal stem cell proliferation by 5-ethynyl-2'-deoxyuridine (EdU) incorporation into the DNA. HIF-1alpha levels can serve as a general hypoxia marker in the whole embryo or tissue of choice, here embryonic retina. EdU incorporation into the proliferating cells of embryonic retina is a specific output of hypoxia induction. Thus, we have shown that hypoxic embryonic retinal progenitors decrease proliferation within 1 h of incubation under 5% oxygen of both frog and zebrafish embryos. Once mastered, our setup can be employed for use with small aquatic model organisms, for direct in vivo experiments, any given time period and under normal, hypoxic or hyperoxic oxygen concentration or under any other given gas mixture. PMID- 28671653 TI - Protein-tRNA Agarose Gel Retardation Assays for the Analysis of the N 6 threonylcarbamoyladenosine TcdA Function. AB - We demonstrate methods for the expression and purification of tRNA(UUU) in Escherichia coli and the analysis by gel retardation assays of the binding of tRNA(UUU) to TcdA, an N6-threonylcarbamoyladenosine (t6A) dehydratase, which cyclizes the threonylcarbamoyl side chain attached to A37 in the anticodon stem loop (ASL) of tRNAs to cyclic t6A (ct6A). Transcription of the synthetic gene encoding tRNA(UUU) is induced in E. coli with 1 mM isopropyl beta-D-1 thiogalactopyranoside (IPTG) and the cells containing tRNA are harvested 24 h post-induction. The RNA fraction is purified using the acid phenol extraction method. Pure tRNA is obtained by a gel filtration chromatography that efficiently separates the small-sized tRNA molecules from larger intact or fragmented nucleic acids. To analyze TcdA binding to tRNA(UUU), TcdA is mixed with tRNA(UUU) and separated on a native agarose gel at 4 degrees C. The free tRNA(UUU) migrates faster, while the TcdA-tRNA(UUU) complexes undergo a mobility retardation that can be observed upon staining of the gel. We demonstrate that TcdA is a tRNA(UUU) binding enzyme. This gel retardation assay can be used to study TcdA mutants and the effects of additives and other proteins on binding. PMID- 28671654 TI - Simple Methods for the Preparation of Non-noble Metal Bulk-electrodes for Electrocatalytic Applications. AB - The rock material pentlandite with the composition Fe4.5Ni4.5S8 was synthesized via high temperature synthesis from the elements. The structure and composition of the material was characterized via powder X-ray diffraction (PXRD), Mossbauer spectroscopy (MB), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and energy dispersive X-ray spectroscopy (EDX). Two preparation methods of pentlandite bulk electrodes are presented. In the first approach a piece of synthetic pentlandite rock is directly contacted via a wire ferrule. The second approach utilizes pentlandite pellets, pressed from finely ground powder, which is immobilized in a Teflon casing. Both electrodes, whilst being prepared by an additive-free method, reveal high durability during electrocatalytic conversions in comparison to common drop-coating methods. We herein showcase the striking performance of such electrodes to accomplish the hydrogen evolution reaction (HER) and present a standardized method to evaluate the electrocatalytic performance by electrochemical and gas chromatographic methods. Furthermore, we report stability tests via potentiostatic methods at an overpotential of 0.6 V to explore the material limitations of the electrodes during electrolysis under industrial relevant conditions. PMID- 28671655 TI - Switchable Acoustic and Optical Resolution Photoacoustic Microscopy for In Vivo Small-animal Blood Vasculature Imaging. AB - Photoacoustic microscopy (PAM) is a fast-growing invivo imaging modality that combines both optics and ultrasound, providing penetration beyond the optical mean free path (~1 mm in skin) with high resolution. By combining optical absorption contrast with the high spatial resolution of ultrasound in a single modality, this technique can penetrate deep tissues. Photoacoustic microscopy systems can have either a low acoustic resolution and probe deeply or a high optical resolution and probe shallowly. It is challenging to achieve high spatial resolution and large depth penetration with a single system. This work presents an AR-OR-PAM system capable of both high-resolution imaging at shallow depths and low-resolution deep-tissue imaging of the same sample in vivo. A lateral resolution of 4 um with 1.4 mm imaging depth using optical focusing and a lateral resolution of 45 um with 7.8 mm imaging depth using acoustic focusing were successfully demonstrated using the combined system. Here, in vivo small-animal blood vasculature imaging is performed to demonstrate its biological imaging capability. PMID- 28671656 TI - Preparation of Janus Particles and Alternating Current Electrokinetic Measurements with a Rapidly Fabricated Indium Tin Oxide Electrode Array. AB - This article provides a simple method to prepare partially or fully coated metallic particles and to perform the rapid fabrication of electrode arrays, which can facilitate electrical experiments in microfluidic devices. Janus particles are asymmetric particles that contain two different surface properties on their two sides. To prepare Janus particles, a monolayer of silica particles is prepared by a drying process. Gold (Au) is deposited on one side of each particle using a sputtering device. The fully coated metallic particles are completed after the second coating process. To analyze the electrical surface properties of Janus particles, alternating current (AC) electrokinetic measurements, such as dielectrophoresis (DEP) and electrorotation (EROT)- which require specifically designed electrode arrays in the experimental device- are performed. However, traditional methods to fabricate electrode arrays, such as the photolithographic technique, require a series of complicated procedures. Here, we introduce a flexible method to fabricate a designed electrode array. An indium tin oxide (ITO) glass is patterned by a fiber laser marking machine (1,064 nm, 20 W, 90 to 120 ns pulse-width, and 20 to 80 kHz pulse repetition frequency) to create a four-phase electrode array. To generate the four-phase electric field, the electrodes are connected to a 2-channel function generator and to two invertors. The phase shift between the adjacent electrodes is set at either 90 degrees (for EROT) or 180 degrees (for DEP). Representative results of AC electrokinetic measurements with a four-phase ITO electrode array are presented. PMID- 28671657 TI - A High-performance Compact Photoacoustic Tomography System for In Vivo Small animal Brain Imaging. AB - In vivo small-animal imaging has an important role to play in preclinical studies. Photoacoustic tomography (PAT) is an emerging hybrid imaging modality that shows great potential for both preclinical and clinical applications. Conventional optical parametric oscillator-based PAT (OPO-PAT) systems are bulky and expensive and cannot provide high-speed imaging. Recently, pulsed-laser diodes (PLDs) have been successfully demonstrated as an alternative excitation source for PAT. Pulsed-laser diode PAT (PLD-PAT) has been successfully demonstrated for high-speed imaging on photoacoustic phantoms and biological tissues. This work provides a visualized experimental protocol for in vivo brain imaging using PLD-PAT. The protocol includes the compact PLD-PAT system configuration and its description, animal preparation for brain imaging, and a typical experimental procedure for 2D cross-sectional rat brain imaging. The PLD PAT system is compact and cost-effective and can provide high-speed, high-quality imaging. Brain images collected in vivo at various scan speeds are presented. PMID- 28671658 TI - Analysis of Microglia and Monocyte-derived Macrophages from the Central Nervous System by Flow Cytometry. AB - Numerous studies have demonstrated the role of immune cells, in particular macrophages, in central nervous system (CNS) pathologies. There are two main macrophage populations in the CNS: (i) the microglia, which are the resident macrophages of the CNS and are derived from yolk sac progenitors during embryogenesis, and (ii) the monocyte-derived macrophages (MDM), which can infiltrate the CNS during disease and are derived from bone marrow progenitors. The roles of each macrophage subpopulation differ depending on the pathology being studied. Furthermore, there is no consensus on the histological markers or the distinguishing criteria used for these macrophage subpopulations. However, the analysis of the expression profiles of the CD11b and CD45 markers by flow cytometry allows us to distinguish the microglia (CD11b+CD45med) from the MDM (CD11b+CD45high). In this protocol, we show that the density gradient centrifugation and the flow cytometry analysis can be used to characterize these CNS macrophage subpopulations, and to study several markers of interest expressed by these cells as we recently published. Thus, this technique can further our understanding of the role of macrophages in mouse models of neurological diseases and can also be used to evaluate drug effects on these cells. PMID- 28671659 TI - Highly Multiplexed, Super-resolution Imaging of T Cells Using madSTORM. AB - Imaging heterogeneous cellular structures using single molecule localization microscopy has been hindered by inadequate localization precision and multiplexing ability. Using fluorescent nano-diamond fiducial markers, we describe the drift correction and alignment procedures required to obtain high precision in single molecule localization microscopy. In addition, a new multiplexing strategy, madSTORM, is described in which multiple molecules are targeted in the same cell using sequential binding and elution of fluorescent antibodies. madSTORM is demonstrated on an activated T cell to visualize the locations of different components within a membrane-bound, multi-protein structure called the T cell receptor microcluster. In addition, application of madSTORM as a general tool for visualization of multi-protein structures is discussed. PMID- 28671660 TI - Acute and Chronic Models of Hyperglycemia in Zebrafish: A Method to Assess the Impact of Hyperglycemia on Neurogenesis and the Biodistribution of Radiolabeled Molecules. AB - Hyperglycemia is a major health issue that leads to cardiovascular and cerebral dysfunction. For instance, it is associated with increased neurological problems after stroke and is shown to impair neurogenic processes. Interestingly, the adult zebrafish has recently emerged as a relevant and useful model to mimic hyperglycemia/diabetes and to investigate constitutive and regenerative neurogenesis. This work provides methods to develop zebrafish models of hyperglycemia to explore the impact of hyperglycemia on brain cell proliferation under homeostatic and brain repair conditions. Acute hyperglycemia is established using the intraperitoneal injection of D-glucose (2.5 g/kg bodyweight) into adult zebrafish. Chronic hyperglycemia is induced by immersing adult zebrafish in D glucose (111 mM) containing water for 14 days. Blood-glucose-level measurements are described for these different approaches. Methods to investigate the impact of hyperglycemia on constitutive and regenerative neurogenesis, by describing the mechanical injury of the telencephalon, dissecting the brain, paraffin embedding and sectioning with a microtome, and performing immunohistochemistry procedures, are demonstrated. Finally, the method of using zebrafish as a relevant model for studying the biodistribution of radiolabeled molecules (here,[18F]-FDG) using PET/CT is also described. PMID- 28671661 TI - Scalable Solution-processed Fabrication Strategy for High-performance, Flexible, Transparent Electrodes with Embedded Metal Mesh. AB - Here, the authors report the embedded metal-mesh transparent electrode (EMTE), a new transparent electrode (TE) with a metal mesh completely embedded in a polymer film. This paper also presents a low-cost, vacuum-free fabrication method for this novel TE; the approach combines lithography, electroplating, and imprint transfer (LEIT) processing. The embedded nature of the EMTEs offers many advantages, such as high surface smoothness, which is essential for organic electronic device production; superior mechanical stability during bending; favorable resistance to chemicals and moisture; and strong adhesion with plastic film. LEIT fabrication features an electroplating process for vacuum-free metal deposition and is favorable for industrial mass production. Furthermore, LEIT allows for the fabrication of metal mesh with a high aspect ratio (i.e., thickness to linewidth), significantly enhancing its electrical conductance without adversely losing optical transmittance. We demonstrate several prototypes of flexible EMTEs, with sheet resistances lower than 1 Omega/sq and transmittances greater than 90%, resulting in very high figures of merit (FoM) - up to 1.5 x 104 - which are amongst the best values in the published literature. PMID- 28671662 TI - Long time-lapse nanoscopy with spontaneously blinking membrane probes. AB - Imaging cellular structures and organelles in living cells by long time-lapse super-resolution microscopy is challenging, as it requires dense labeling, bright and highly photostable dyes, and non-toxic conditions. We introduce a set of high density, environment-sensitive (HIDE) membrane probes, based on the membrane permeable silicon-rhodamine dye HMSiR, that assemble in situ and enable long time lapse, live-cell nanoscopy of discrete cellular structures and organelles with high spatiotemporal resolution. HIDE-enabled nanoscopy movies span tens of minutes, whereas movies obtained with labeled proteins span tens of seconds. Our data reveal 2D dynamics of the mitochondria, plasma membrane and filopodia, and the 2D and 3D dynamics of the endoplasmic reticulum, in living cells. HIDE probes also facilitate acquisition of live-cell, two-color, super-resolution images, expanding the utility of nanoscopy to visualize dynamic processes and structures in living cells. PMID- 28671663 TI - Dopant compensation in alloyed CH3NH3PbBr3-xClx perovskite single crystals for gamma-ray spectroscopy. AB - Organic-inorganic halide perovskites (OIHPs) bring an unprecedented opportunity for radiation detection with their defect-tolerance nature, large mobility lifetime product, and simple crystal growth from solution. Here we report a dopant compensation in alloyed OIHP single crystals to overcome limitations of device noise and charge collection, enabling gamma-ray spectrum collection at room temperature. CH3NH3PbBr3 and CH3NH3PbCl3 are found to be p-type and n-type doped, respectively, whereas dopant-compensated CH3NH3PbBr2.94Cl0.06 alloy has over tenfold improved bulk resistivity of 3.6 * 109 Omega cm. Alloying also increases the hole mobility to 560 cm2 V-1 s-1, yielding a high mobility-lifetime product of 1.8 * 10-2 cm2 V-1. The use of a guard ring electrode in the detector reduces the crystal surface leakage current and device dark current. A distinguishable 137Cs energy spectrum with comparable or better resolution than standard scintillator detectors is collected under a small electric field of 1.8 V mm-1 at room temperature. PMID- 28671664 TI - Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses. AB - The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals. PMID- 28671665 TI - Asparagine endopeptidase cleaves alpha-synuclein and mediates pathologic activities in Parkinson's disease. AB - Aggregated forms of alpha-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson's disease (PD). However, the molecular mechanisms underlying the pathogenic effects of alpha-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human alpha-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human alpha-synuclein at N103 in an age dependent manner. AEP is highly activated in human brains with PD, and it fragments alpha-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved alpha-synuclein1-103 fragment in the substantia nigra induces both dopaminergic neuronal loss and movement defects in mice. In contrast, inhibition of AEP-mediated cleavage of alpha-synuclein (wild type and A53T mutant) diminishes alpha-synuclein's pathologic effects. Together, these findings support AEP's role as a key mediator of alpha-synuclein-related etiopathological effects in PD. PMID- 28671667 TI - Mechanochemical evolution of the giant muscle protein titin as inferred from resurrected proteins. AB - The sarcomere-based structure of muscles is conserved among vertebrates; however, vertebrate muscle physiology is extremely diverse. A molecular explanation for this diversity and its evolution has not been proposed. We use phylogenetic analyses and single-molecule force spectroscopy (smFS) to investigate the mechanochemical evolution of titin, a giant protein responsible for the elasticity of muscle filaments. We resurrect eight-domain fragments of titin corresponding to the common ancestors to mammals, sauropsids, and tetrapods, which lived 105-356 Myr ago, and compare them with titin fragments from some of their modern descendants. We demonstrate that the resurrected titin molecules are rich in disulfide bonds and display high mechanical stability. These mechanochemical elements have changed over time, creating a paleomechanical trend that seems to correlate with animal body size, allowing us to estimate the sizes of extinct species. We hypothesize that mechanical adjustments in titin contributed to physiological changes that allowed the muscular development and diversity of modern tetrapods. PMID- 28671668 TI - A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage. AB - This corrects the article DOI: 10.1038/onc.2015.68. PMID- 28671666 TI - Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis. AB - The uridyl transferases TUT4 and TUT7 (collectively called TUT4(7)) switch between two modes of activity, either promoting expression of let-7 microRNA (monoU) or marking it for degradation (oligoU). Lin28 modulates the switch via recruitment of TUT4(7) to the precursor pre-let-7 in stem cells and human cancers. We found that TUT4(7) utilize two multidomain functional modules during the switch from monoU to oligoU. The catalytic module (CM) is essential for both activities, while the Lin28-interacting module (LIM) is indispensable for oligoU. A TUT7 CM structure trapped in the monoU activity staterevealed a duplex-RNA binding pocket that orients group II pre-let-7 hairpins to favor monoU addition. Conversely, the switch to oligoU requires the ZK domain of Lin28 to drive the formation of a stable ternary complex between pre-let-7 and the inactive LIM. Finally, ZK2 of TUT4(7) aids oligoU addition by engaging the growing oligoU tail through uracil-specific interactions. PMID- 28671669 TI - Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma. AB - We provide evidence that the IFN-regulated member of the Schlafen (SLFN) family of proteins, SLFN5, promotes the malignant phenotype in glioblastoma multiforme (GBM). Our studies indicate that SLFN5 expression promotes motility and invasiveness of GBM cells, and that high levels of SLFN5 expression correlate with high-grade gliomas and shorter overall survival in patients suffering from GBM. In efforts to uncover the mechanism by which SLFN5 promotes GBM tumorigenesis, we found that this protein is a transcriptional co-repressor of STAT1. Type-I IFN treatment triggers the interaction of STAT1 with SLFN5, and the resulting complex negatively controls STAT1-mediated gene transcription via interferon stimulated response elements. Thus, SLFN5 is both an IFN-stimulated response gene and a repressor of IFN-gene transcription, suggesting the existence of a negative-feedback regulatory loop that may account for suppression of antitumor immune responses in glioblastoma. PMID- 28671670 TI - Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface. AB - The C-type lectin domain containing group 14 family members CLEC14A and CD93 are proteins expressed by endothelium and are implicated in tumour angiogenesis. CD248 (alternatively known as endosialin or tumour endothelial marker-1) is also a member of this family and is expressed by tumour-associated fibroblasts and pericytes. Multimerin-2 (MMRN2) is a unique endothelial specific extracellular matrix protein that has been implicated in angiogenesis and tumour progression. We show that the group 14 C-type lectins CLEC14A, CD93 and CD248 directly bind to MMRN2 and only thrombomodulin of the family does not. Binding to MMRN2 is dependent on a predicted long-loop region in the C-type lectin domain and is abrogated by mutation within the domain. CLEC14A and CD93 bind to the same non glycosylated coiled-coil region of MMRN2, but the binding of CD248 occurs on a distinct non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously and this occurs at the interface between endothelium and pericytes in human pancreatic cancer. A recombinant peptide of MMRN2 spanning the CLEC14A and CD93 binding region blocks CLEC14A extracellular domain binding to the endothelial cell surface as well as increasing adherence of human umbilical vein endothelial cells to the active peptide. This MMRN2 peptide is anti-angiogenic in vitro and reduces tumour growth in mouse models. These findings identify novel protein interactions involving CLEC14A, CD93 and CD248 with MMRN2 as targetable components of vessel formation. PMID- 28671671 TI - Wnt/beta-catenin activation and macrophage induction during liver cancer development following steatosis. AB - Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/beta catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/beta-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/beta-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/beta-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA) defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/beta-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals. PMID- 28671672 TI - Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: molecular basis and pathophysiological consequences. AB - Cancer cells reprogram their metabolism to maintain both viability and uncontrolled proliferation. Although an interplay between the genetic, epigenetic and metabolic rewiring in cancer is beginning to emerge, it remains unclear how this metabolic plasticity occurs. Here, we report that in prostate cancer cells (PCCs) microRNAs (miRNAs) greatly contribute to deregulation of mitochondrial fatty acid (FA) oxidation via carnitine system modulation. We provide evidence that the downregulation of hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378 induced an increase in both expression and activity of CPT1A, CACT and CrAT in malignant prostate cells. Moreover, the analysis of human prostate cancer and prostate control specimens confirmed the aberrant expression of miR-124-3p, miR-129-5p and miR-378 in primary tumors. Forced expression of the miRNAs mentioned above affected tumorigenic properties, such as proliferation, migration and invasion, in PC3 and LNCaP cells regardless of their hormone sensitivity. CPT1A, CACT and CrAT overexpression allow PCCs to be more prone on FA utilization than normal prostate cells, also in the presence of high pyruvate concentration. Finally, the simultaneous increase of CPT1A, CACT and CrAT is fundamental for PCCs to sustain FA oxidation in the presence of heavy lipid load on prostate cancer mitochondria. Indeed, the downregulation of only one of these proteins reduces PCCs metabolic flexibility with the accumulation of FA-intermediate metabolites in the mitochondria. Together, our data implicate carnitine cycle as a primary regulator of adaptive metabolic reprogramming in PCCs and suggest new potential druggable pathways for prevention and treatment of prostate cancer. PMID- 28671673 TI - EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma. AB - Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1 anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells in vitro and in vivo, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells. PMID- 28671674 TI - Addressing preferred specimen orientation in single-particle cryo-EM through tilting. AB - We present a strategy for tackling preferred specimen orientation in single particle cryogenic electron microscopy by employing tilts during data collection. We also describe a tool to quantify the resulting directional resolution using 3D Fourier shell correlation volumes. We applied these methods to determine the structures at near-atomic resolution of the influenza hemagglutinin trimer, which adopts a highly preferred specimen orientation, and of ribosomal biogenesis intermediates, which adopt moderately preferred orientations. PMID- 28671675 TI - Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. AB - Increased matrix rigidity associated with the fibrotic reaction is documented to stimulate intracellular signalling pathways that promote cancer cell survival and tumour growth. Pancreatic cancer is one of the stiffest of all human solid carcinomas and is characterised by a remarkable desmoplastic reaction. Here we use mouse models, genetically engineered to recapitulate human pancreatic cancer, and several pancreatic cancer cell lines as a model to investigate the effect of matrix stiffness in epithelial-mesenchymal transition (EMT) and resistance to chemotherapeutics. We found that recapitulation of the fibrotic rigidities found in pancreatic cancer tissues promote elements of EMT, including increases in vimentin expression, decreases in E-cadherin expression, nuclear localisation of beta-catenin, YAP and TAZ and changes in cell shape towards a mesenchymal phenotype. We also report that stiffness induces chemoresistance to paclitaxel, but not to gemcitabine, both commonly used therapeutics, suggesting that environmental rigidity underlies an aspect of chemoresistance. PMID- 28671676 TI - JWA regulates TRAIL-induced apoptosis via MARCH8-mediated DR4 ubiquitination in cisplatin-resistant gastric cancer cells. AB - Platinum chemotherapeutics are widely used to treat solid malignant tumors, including gastric cancer (GC). Drug resistance to platinum compounds may result in cancer relapse and decreased survival. The identification and development of novel agents to reactivate apoptosis pathways in platinum-resistant cancer cells is therefore necessary. Here we report that cisplatin-resistant human GC cells (BGC823/DDP and SGC7901/DDP) but not their parental cells (BGC823 and SGC7901) exhibit high sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a result of overexpression of death receptor 4 (DR4). Furthermore, we found that JWA, a molecule that promotes cisplatin-induced apoptosis in GC cells, suppressed TRAIL-induced apoptosis via negative regulation of DR4. Mechanistically, JWA promoted the ubiquitination of DR4 at K273 via upregulation of the ubiquitin ligase membrane-associated RING-CH-8 (MARCH8). In human GC tissues, JWA and DR4 protein levels were negatively correlated. Thus TRAIL may serve as an auxiliary treatment for cisplatin-resistant GC, and JWA may be a potential predictive marker of TRAIL sensitivity and may improve personalized therapeutics for treating human GC. PMID- 28671677 TI - Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma. AB - The proximity of organs at risk makes the treatment of head and neck squamous cell carcinoma (HNSCC) challenging by standard radiotherapy. The higher precision in tumor targeting of proton (P) therapy could promote it as the treatment of choice for HNSCC. Besides the physical advantage in dose deposition, few is known about the biological impact of P versus photons (X) in this setting. To investigate the comparative biological effects of P versus X radiation in HNSCC cells, we assessed the relative biological effectiveness (RBE), viability, proliferation and mRNA levels for genes involved in (lymph)angiogenesis, inflammation, proliferation and anti-tumor immunity. These parameters, particularly VEGF-C protein levels and regulations, were documented in freshly irradiated and/or long-term surviving cells receiving low/high-dose, single (SI)/multiple (MI) irradiations with P/X. The RBE was found to be 1.1 Key (lymph)angiogenesis and inflammation genes were downregulated (except for vegf-c) after P and upregulated after X irradiation in MI surviving cells, demonstrating a more favorable profile after P irradiation. Both irradiation types stimulated vegf-c promoter activity in a NF-kappaB-dependent transcriptional regulation manner, but at a lesser extent after P, as compared to X irradiation, which correlated with mRNA and protein levels. The cells surviving to MI by P or X generated tumors with higher volume, anarchic architecture and increased density of blood vessels. Increased lymphangiogenesis and a transcriptomic analysis in favor of a more aggressive phenotype were observed in tumors generated with X irradiated cells. Increased detection of lymphatic vessels in relapsed tumors from patients receiving X radiotherapy was consistent with these findings. This study provides new data about the biological advantage of P, as compared to X irradiation. In addition to its physical advantage in dose deposition, P irradiation may help to improve treatment approaches for HNSCC. PMID- 28671678 TI - Molecular basis of the evolution of alternative tyrosine biosynthetic routes in plants. AB - L-Tyrosine (Tyr) is essential for protein synthesis and is a precursor of numerous specialized metabolites crucial for plant and human health. Tyr can be synthesized via two alternative routes by different key regulatory TyrA family enzymes, prephenate dehydrogenase (PDH, also known as TyrAp) or arogenate dehydrogenase (ADH, also known as TyrAa), representing a unique divergence of primary metabolic pathways. The molecular foundation underlying the evolution of these alternative Tyr pathways is currently unknown. Here we characterized recently diverged plant PDH and ADH enzymes, obtained the X-ray crystal structure of soybean PDH, and identified a single amino acid residue that defines TyrA substrate specificity and regulation. Structures of mutated PDHs co-crystallized with Tyr indicate that substitutions of Asn222 confer ADH activity and Tyr sensitivity. Reciprocal mutagenesis of the corresponding residue in divergent plant ADHs further introduced PDH activity and relaxed Tyr sensitivity, highlighting the critical role of this residue in TyrA substrate specificity that underlies the evolution of alternative Tyr biosynthetic pathways in plants. PMID- 28671679 TI - 2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist. AB - Transient receptor potential melastatin 2 (TRPM2) is a ligand-gated Ca2+ permeable nonselective cation channel. Whereas physiological stimuli, such as chemotactic agents, evoke controlled Ca2+ signals via TRPM2, pathophysiological stimuli such as reactive oxygen species and genotoxic stress result in prolonged TRPM2-mediated Ca2+ entry and, consequently, apoptosis. To date, adenosine 5' diphosphoribose (ADPR) has been assumed to be the main agonist for TRPM2. Here we show that 2'-deoxy-ADPR was a significantly better TRPM2 agonist, inducing 10.4 fold higher whole-cell currents at saturation. Mechanistically, this increased activity was caused by a decreased rate of inactivation and higher average open probability. Using high-performance liquid chromatography (HPLC) and mass spectrometry, we detected endogenous 2'-deoxy-ADPR in Jurkat T lymphocytes. Consistently, cytosolic nicotinamide mononucleotide adenylyltransferase 2 (NMNAT 2) and nicotinamide adenine dinucleotide (NAD)-glycohydrolase CD38 sequentially catalyzed the synthesis of 2'-deoxy-ADPR from nicotinamide mononucleotide (NMN) and 2'-deoxy-ATP in vitro. Thus, 2'-deoxy-ADPR is an endogenous TRPM2 superagonist that may act as a cell signaling molecule. PMID- 28671680 TI - Monitoring thioredoxin redox with a genetically encoded red fluorescent biosensor. AB - Thioredoxin (Trx) is one of the two major thiol antioxidants, playing essential roles in redox homeostasis and signaling. Despite its importance, there is a lack of methods for monitoring Trx redox dynamics in live cells, hindering a better understanding of physiological and pathological roles of the Trx redox system. In this work, we developed the first genetically encoded fluorescent biosensor for Trx redox by engineering a redox relay between the active-site cysteines of human Trx1 and rxRFP1, a redox-sensitive red fluorescent protein. We used the resultant biosensor-TrxRFP1-to selectively monitor perturbations of Trx redox in various mammalian cell lines. We subcellularly localized TrxRFP1 to image compartmentalized Trx redox changes. We further combined TrxRFP1 with a green fluorescent Grx1-roGFP2 biosensor to simultaneously monitor Trx and glutathione redox dynamics in live cells in response to chemical and physiologically relevant stimuli. PMID- 28671681 TI - Extracellular vesicles are independent metabolic units with asparaginase activity. AB - Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC) derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1). Critically, we show that Asrgl1 activity is selective for asparagine and is devoid of glutaminase activity. We found that mouse and human NSC EVs traffic Asrgl1. Our results demonstrate, for the first time, that NSC EVs function as independent metabolic units that are able to modify the concentrations of critical nutrients, with the potential to affect the physiology of their microenvironment. PMID- 28671683 TI - A molecular rheostat maintains ATP levels to drive a synthetic biochemistry system. AB - Synthetic biochemistry seeks to engineer complex metabolic pathways for chemical conversions outside the constraints of the cell. Establishment of effective and flexible cell-free systems requires the development of simple systems to replace the intricate regulatory mechanisms that exist in cells for maintaining high energy cofactor balance. Here we describe a simple rheostat that regulates ATP levels by controlling the flow down either an ATP-generating or non-ATP generating pathway according to the free-phosphate concentration. We implemented this concept for the production of isobutanol from glucose. The rheostat maintains adequate ATP concentrations even in the presence of ATPase contamination. The final system including the rheostat produced 24.1 +/- 1.8 g/L of isobutanol from glucose in 91% theoretical yield with an initial productivity of 1.3 g/L/h. The molecular rheostat concept can be used in the design of continuously operating, self-sustaining synthetic biochemistry systems. PMID- 28671682 TI - A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. AB - New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromolecular synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB alpha-beta-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors. PMID- 28671684 TI - A new strategy for aromatic ring alkylation in cylindrocyclophane biosynthesis. AB - Alkylation of aromatic rings with alkyl halides is an important transformation in organic synthesis, yet an enzymatic equivalent is unknown. Here, we report that cylindrocyclophane biosynthesis in Cylindrospermum licheniforme ATCC 29412 involves chlorination of an unactivated carbon center by a novel halogenase, followed by a previously uncharacterized enzymatic dimerization reaction featuring sequential, stereospecific alkylations of resorcinol aromatic rings. Discovery of the enzymatic machinery underlying this unique biosynthetic carbon carbon bond formation has implications for biocatalysis and metabolic engineering. PMID- 28671685 TI - Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. AB - Variants in GDF5 are associated with human arthritis and decreased height, but the causal mutations are still unknown. We surveyed the Gdf5 locus for regulatory regions in transgenic mice and fine-mapped separate enhancers controlling expression in joints versus growing ends of long bones. A large downstream regulatory region contains a novel growth enhancer (GROW1), which is required for normal Gdf5 expression at ends of developing bones and for normal bone lengths in vivo. Human GROW1 contains a common base-pair change that decreases enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa but common in Eurasia and is found in Neandertals and Denisovans. Our results suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype that also increases arthritis susceptibility in many human populations. PMID- 28671686 TI - The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. AB - We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TADcPcdh) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins were transcribed by increased numbers of cortical neurons, indicating relaxation of single-cell constraint. SETDB1-dependent loop formations bypassed 0.2-1 Mb of linear genome and radiated from the TADcPcdh fringes toward cis-regulatory sequences within the cPcdh locus, counterbalanced shorter-range facilitative promoter-enhancer contacts and carried loop-bound polymorphisms that were associated with genetic risk for schizophrenia. We show that the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of TADcPcdh. PMID- 28671687 TI - Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. AB - The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4-CD8-) or CD8+ single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-beta selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL. PMID- 28671688 TI - The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. AB - Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches. PMID- 28671689 TI - Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. AB - The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro. PMID- 28671690 TI - Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin. AB - The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells. The total effect of OPN on skewing the leukocyte population balance was observed as host sensitivity to early systemic infection with Candida albicans and T cell-mediated colitis. Our study suggests previously unknown detrimental roles for two OPN isoforms in causing the imbalance of leukocyte populations. PMID- 28671691 TI - Germline Chd8 haploinsufficiency alters brain development in mouse. AB - The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development. PMID- 28671692 TI - Activation of cortical somatostatin interneurons prevents the development of neuropathic pain. AB - Neuropathic pain involves long-lasting modifications of pain pathways that result in abnormal cortical activity. How cortical circuits are altered and contribute to the intense sensation associated with allodynia is unclear. Here we report a persistent elevation of layer V pyramidal neuron activity in the somatosensory cortex of a mouse model of neuropathic pain. This enhanced pyramidal neuron activity was caused in part by increases of synaptic activity and NMDA-receptor dependent calcium spikes in apical tuft dendrites. Furthermore, local inhibitory interneuron networks shifted their activity in favor of pyramidal neuron hyperactivity: somatostatin-expressing and parvalbumin-expressing inhibitory neurons reduced their activity, whereas vasoactive intestinal polypeptide expressing interneurons increased their activity. Pharmacogenetic activation of somatostatin-expressing cells reduced pyramidal neuron hyperactivity and reversed mechanical allodynia. These findings reveal cortical circuit changes that arise during the development of neuropathic pain and identify the activation of specific cortical interneurons as therapeutic targets for chronic pain treatment. PMID- 28671693 TI - Transcriptomic analysis of purified human cortical microglia reveals age associated changes. AB - Microglia are essential for CNS homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. Overall, genes expressed by human microglia were similar to those in mouse, including established microglial genes CX3CR1, P2RY12 and ITGAM (CD11B). However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR, Fcgamma and SIGLEC receptors, as well as TAL1 and IFI16, regulators of proliferation and cell cycle. Age-associated changes in human microglia were enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression and actin (dis)assembly. Limited overlap was observed in microglial genes regulated during aging between mice and humans, indicating that human and mouse microglia age differently. PMID- 28671694 TI - Reorganization of corticospinal output during motor learning. AB - Motor learning is accompanied by widespread changes within the motor cortex, but it is unknown whether these changes are ultimately funneled through a stable corticospinal output channel or whether the corticospinal output itself is plastic. We investigated the consistency of the relationship between corticospinal neuron activity and movement through in vivo two-photon calcium imaging in mice learning a lever-press task. Corticospinal neurons exhibited heterogeneous correlations with movement, with the majority of movement-modulated neurons decreasing activity during movement. Individual cells changed their activity across days, which led to changed associations between corticospinal activity and movement. Unlike previous observations in layer 2/3, activity accompanying learned movements did not become more consistent with learning; instead, the activity of dissimilar movements became more decorrelated. These results indicate that the relationship between corticospinal activity and movement is dynamic and that the types of activity and plasticity are different from and possibly complementary to those in layer 2/3. PMID- 28671697 TI - Direct intramolecular amination of tryptophan esters to prepare pyrrolo[2,3 b]indoles. AB - A metal-free iodine-catalyzed intramolecular amination has been developed for the practical synthesis of pyrrolo[2,3-b]indoles from readily available tryptophan esters. The transformation has been applied to a wide array of substrates and can be performed on gram scale under very mild conditions. PMID- 28671698 TI - Sustainable sources need reliable standards. AB - This review discusses the challenges within the research area of modern biomass fractionation and valorization. The current pulping industry focuses on pulp production and the resulting cellulose fiber. Hemicellulose and lignin are handled as low value streams for process heat and the regeneration of process chemicals. The paper and pulp industry have therefore developed analytical techniques to evaluate the cellulose fiber, while the other fractions are given a low priority. In a strive to also use the hemicellulose and lignin fractions of lignocellulosic biomass, moving towards a biorefining concept, there are severe shortcomings with the current pulping techniques and also in the analysis of the biomass. Lately, new fractionation techniques have emerged which valorize a larger extent of the lignocellulosic biomass. This progress has disclosed the shortcomings in the analysis of mainly the hemicellulose and lignin structure and properties. To move the research field forward, analytical tools for both the raw material, targeting all the wood components, and the generated fractions, as well as standardized methods for evaluating and reporting yields are desired. At the end of this review, a discourse on how such standardizations can be implemented is given. PMID- 28671696 TI - Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders. AB - The postsynaptic density (PSD) contains a collection of scaffold proteins used for assembling synaptic signaling complexes. However, it is not known how the core-scaffold machinery associates in protein-interaction networks or how proteins encoded by genes involved in complex brain disorders are distributed through spatiotemporal protein complexes. Here using immunopurification, proteomics and bioinformatics, we isolated 2,876 proteins across 41 in vivo interactomes and determined their protein domain composition, correlation to gene expression levels and developmental integration to the PSD. We defined clusters for enrichment of schizophrenia, autism spectrum disorders, developmental delay and intellectual disability risk factors at embryonic day 14 and adult PSD in mice. Mutations in highly connected nodes alter protein-protein interactions modulating macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform, Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of disease risk factors and their placement within synaptic protein interaction networks. PMID- 28671695 TI - Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. AB - Adeno-associated viruses (AAVs) are commonly used for in vivo gene transfer. Nevertheless, AAVs that provide efficient transduction across specific organs or cell populations are needed. Here, we describe AAV-PHP.eB and AAV-PHP.S, capsids that efficiently transduce the central and peripheral nervous systems, respectively. In the adult mouse, intravenous administration of 1 * 1011 vector genomes (vg) of AAV-PHP.eB transduced 69% of cortical and 55% of striatal neurons, while 1 * 1012 vg of AAV-PHP.S transduced 82% of dorsal root ganglion neurons, as well as cardiac and enteric neurons. The efficiency of these vectors facilitates robust cotransduction and stochastic, multicolor labeling for individual cell morphology studies. To support such efforts, we provide methods for labeling a tunable fraction of cells without compromising color diversity. Furthermore, when used with cell-type-specific promoters and enhancers, these AAVs enable efficient and targetable genetic modification of cells throughout the nervous system of transgenic and non-transgenic animals. PMID- 28671699 TI - Developing new platform chemicals: what is required for a new bio-based molecule to become a platform chemical in the bioeconomy? AB - This paper proposes a framework with six dimensions that can be useful for evaluating the potential and the current stage of a bio-based platform chemical. The framework considers the technological and strategic challenges to be fulfilled by a company that intends to lead a platform based on a bio-based chemical. A platform chemical should be an intermediate molecule, with a structure able to generate a number of derivatives, that is produced at a competitive cost, capable of allowing exploitation of the scale and scope economies, and inserted within a complete innovation ecosystem that is able to create value with governance mechanisms that are capable of allowing coordination of the innovation process and facilitation of the value capture by the focal company leading the platform, in our case the producer of the platform molecule. Based on these six dimensions, three potential platform chemicals - succinic acid, butanol and farnesene - are compared and discussed. It is possible to identify important differences concerning the technological dimensions and the strategic dimensions as well. Two of the molecules - farnesene and succinic acid adhere to most of the conditions required to structure a platform chemical. However, the innovation ecosystem is not complete and the governance mechanisms are still under development, so it is not clear if they will be capable of allowing a favorable position for value capture by the platform leader. Butanol structuring for a platform does not seem promising. The potential of the molecule is apparently not high and the strategic initiatives are in general not focused on innovation ecosystem structuring. PMID- 28671700 TI - Metabolomics combined with pattern recognition and bioinformatics analysis methods for the development of pharmacodynamic biomarkers on liver fibrosis. AB - The major obstacle for the development of targeted therapies is the lack of pharmacodynamic (PD) biomarkers to provide an early readout of biological activities. As the modulation of metabolites may reflect the biological changes occurring in the targets, metabolomics is promising to be an efficient way to explore PD biomarkers. In the present study, a liver fibrosis rat model was established by intraperitoneal injection of CCl4 twice weekly for 6 weeks, the treatment of total aglycone extracts of Scutellaria baicalensis (TAES) was begun 4 weeks after the modeling, and gas chromatography-mass spectrometry (GC-MS) based metabolomics combined with pattern recognition and network analysis were carried out for the research on PD biomarkers of TAES on liver fibrosis. After 2 weeks of treatment, TAES shows positive effects on CCl4-induced liver fibrosis. In the metabolomics study, 63 urinary metabolites contributing to liver fibrosis were identified. Six metabolic pathways significantly enriched in metabolomics data were mapped onto a network to determine global patterns of metabolic alterations in liver fibrosis. By topological analysis, 6 metabolites with high centrality in the metabolic sub-network were selected as potential PD biomarkers. Within 24 h of the final administration, the 6 identified urine metabolic biomarkers with response to time variation of TAES were validated as PD biomarkers. This integrative study presents an attractive strategy to explore PD biomarkers, which may give insight into the actual pharmacological effect of target drugs, and the information from PD biomarkers can be combined with pharmacokinetics to select the optimal dose and a schedule of administration for the drugs. PMID- 28671701 TI - Demonstration of transgressive overyielding of algal mixed cultures in microdroplets. AB - Algae are ubiquitous in natural ecosystems and have been studied extensively for biofuel production due to their unique metabolic capabilities. Most studies to date have approached biofuel optimization through synthetic biology and process engineering with few industrial scale projects considering algal community interactions. Such interactions can potentially lead to increased productivity and reduced community invasability, both important characteristics for scalable algal biofuel production. It is estimated that over a million species of algae exist such that elucidating the interactions that might be beneficial for biofuel production remains extremely resource and time intensive. Here we describe a strategy for rapid, high-throughput screening of algal community combinations using a microfluidic platform to generate millions of parallel, nanoliter-scale algal mixed cultures for estimation of biomass accumulation. Model communities were first studied in a bench scale flask experiment and then examined using microfluidic droplets. These experiments showed consistent results for both positively interacting algal bicultures that increase biomass when together, and negatively interacting bicultures that decrease biomass. Specifically, these included enhanced performance of two bicultures, Ankistrodesmus falcatus and Chlorella sorokiniana, Chlorella sorokiniana and Selenastrum minutum, and reduced performance of a biculture consisting of Selenastrum capricornutum and Scenedesmus ecornis. While the ultimate techno-economic feasibility of algal bioproducts hinges on an amalgamation of scientific fields, rapid screening of algal communities will prove imperative for efficiently discovering community interactions. PMID- 28671702 TI - Sample-to-answer acoustic detection of DNA in complex samples. AB - The present study demonstrates the sensitive and label-free acoustic detection of dsDNA amplicons produced from whole Salmonella Thyphimurium cells without employing any DNA extraction and/or purification step, in the presence of the lysed bacterial cells and in a hybridization-free assay. A sample-to-answer assay is also shown during DNA detection directly in milk. PMID- 28671704 TI - Charge-transfer states in triazole linked donor-acceptor materials: strong effects of chemical modification and solvation. AB - A series of 1,2,3-triazole linked donor-acceptor chromophores are prepared by Click Chemistry from ene-yne starting materials. The effects of three distinct chemical variations are investigated: enhancing the acceptor strength through oxidation of the sulphur atom, alteration of the double bond configuration, and variation of the triazole substitution pattern. A detailed photophysical characterization shows that these alterations have a negligible effect on the absorption while dramatically altering the emission wavelengths. In addition, strong solvatochromism is found leading to significant red shifts in the case of polar solvents. The experimental findings are rationalized and related to the electronic structure properties of the chromophores by time-dependent density functional theory as well as the ab initio algebraic diagrammatic construction method for the polarization propagator in connection with a new formalism allowing to model the influence of solvation onto long-lived excited states and their emission energies. These calculations highlight the varying degree of intramolecular charge transfer character present for the different molecules and show that the amount of charge transfer is strongly modulated by the conducted chemical modifications, by the solvation of the chromophores, and by the structural relaxation in the excited state. It is, furthermore, shown that enhanced charge separation, as induced by chemical modification or solvation, reduces the singlet-triplet gaps and that two of the investigated molecules possess sufficiently low gaps to be considered as candidates for thermally activated delayed fluorescence. PMID- 28671705 TI - Organ-, body- and disease-on-a-chip systems. PMID- 28671703 TI - Tetracycline-controllable artificial microRNA-HOTAIR + EZH2 suppressed the progression of bladder cancer cells. AB - Previous studies have suggested that EZH2 is up-regulated in bladder cancer tissues and identified it as a biomarker for poor prognosis. However, the biological functions of EZH2 in bladder cancer cells remain unknown. In this research, we discovered that EZH2 expression is irrelevant to the TNM stage and poor prognosis of bladder cancer patients. But suppression of EZH2 can slowdown the progression of bladder cancer cells. Moreover, we used the technology of synthetic biology to construct the tetracycline-controllable artificial microRNA HOTAIR + EZH2, which can decrease the expression of HOTAIR and EZH2 in a doxycycline dosage-dependent manner. And we also found that HOTAIR expression was positively correlated with EZH2 expression. Tetracycline-controllable artificial microRNA-HOTAIR + EZH2 can inhibit the proliferation and migration of bladder cancer cells. Meanwhile, the apoptosis rate of bladder cancer cells was increased. Taken together, our research showed the cancer-promoting effects of EZH2 and created a novel method to rescue the development of bladder cancer cells. PMID- 28671706 TI - An integrative machine learning strategy for improved prediction of essential genes in Escherichia coli metabolism using flux-coupled features. AB - Prediction of essential genes helps to identify a minimal set of genes that are absolutely required for the appropriate functioning and survival of a cell. The available machine learning techniques for essential gene prediction have inherent problems, like imbalanced provision of training datasets, biased choice of the best model for a given balanced dataset, choice of a complex machine learning algorithm, and data-based automated selection of biologically relevant features for classification. Here, we propose a simple support vector machine-based learning strategy for the prediction of essential genes in Escherichia coli K-12 MG1655 metabolism that integrates a non-conventional combination of an appropriate sample balanced training set, a unique organism-specific genotype, phenotype attributes that characterize essential genes, and optimal parameters of the learning algorithm to generate the best machine learning model (the model with the highest accuracy among all the models trained for different sample training sets). For the first time, we also introduce flux-coupled metabolic subnetwork-based features for enhancing the classification performance. Our strategy proves to be superior as compared to previous SVM-based strategies in obtaining a biologically relevant classification of genes with high sensitivity and specificity. This methodology was also trained with datasets of other recent supervised classification techniques for essential gene classification and tested using reported test datasets. The testing accuracy was always high as compared to the known techniques, proving that our method outperforms known methods. Observations from our study indicate that essential genes are conserved among homologous bacterial species, demonstrate high codon usage bias, GC content and gene expression, and predominantly possess a tendency to form physiological flux modules in metabolism. PMID- 28671707 TI - Enlargement of the organic solid-state DFB laser wavelength tuning range by the use of two complementary luminescent dyes doped into the host matrix. AB - The spectral tuning range of dye lasers is closely associated with the gain profile provided by the utilized luminescent compound. Here, we present the results of studies aimed at broadening the wavelength tuning range in distributed feedback (DFB) lasers, made up of polymeric layers doped with a mixture of two complementary dyes. We have used the 3-(2,2-dicyanoethenyl)-1-phenyl-4,5-dihydro 1H-pyrazole (DCNP) luminescent dye, showing stimulated emission in its crystalline form, and the Rhodamine 700 (Rh700) laser dye, which is red-shifted in luminescence relative to DCNP, both doped into a poly(methyl methacrylate) (PMMA) host matrix. We have investigated the relationships between the additives' relative weight to weight ratios and their ability to exhibit a nonradiative energy transfer process that is inherent with a luminescence quenching of the shorter wavelength emitter, the so-called donor. This in turn directly reflects the efficiency of simultaneous utilization of both dyes' emission bands for lasing. By the proper engineering of the gain material composition, it was possible to broaden the DFB lasing tuning spectral range up to 125 nm, which is twice as much compared to the DCNP/PMMA material, i.e. without addition of Rh700. Finally, the presented results have shown that additional random feedback, which is detrimental to the DFB lasing, originating from the presence of DCNP crystals within the polymeric bulk, can be effectively suppressed by the superposition of a temporary DFB resonator. PMID- 28671708 TI - Silica-based hierarchical porous Janus microcapsules: construction and support of Au nano-particle catalyst inside. AB - A facile and novel method was developed to fabricate silica-based hierarchical porous Janus microcapsules (HPJMs SiO2) for catalysis. The resulting Au@HPJMs SiO2 nanocomposites showed enhanced catalysis, great stability, convenient recovery and reuse without losing catalytic efficiency. PMID- 28671709 TI - Transient receptor potential a1 (TRPA1) agonists inhibit contractions of the isolated human ureter. AB - AIMS: Mechanoafferent and peristaltic mechanisms of the human ureter involve transient receptor potential V1 (TRPV1)- and purinoceptor-mediated functions. Hydrogen sulphide, an endogenous TRPA1 ligand, is linked to inhibitory neurotransmission of the pig ureter. No information is available on TRPA1 activity in the human ureter. We therefore examined the distribution and function of TRPA1 in the human ureter. METHODS: Expression of TRPA1 in human ureter tissue was studied by Western blot and immunofluorescence. The TRPA1 distribution was compared to TRPV1, calcitonin gene related peptide (CGRP), tyrosine hydroxylase (TH), and vimentin. Effects of the TRPA1 agonists allyl isothiocyanate (AI), cinnamaldehyde (CA), sodium hydrogen sulfide (NaHS), and capsaicin (TRPV1 agonist) on human ureter preparations were studied in organ baths. RESULTS: By Western blot, bands were detected at the expected molecular weight for TRPA1. TRPA1- and TRPV1-immunoreactivities were located on CGRP-positive nerves, but not on TH-positive nerves. TRPA1 was also located in vimentin-positive interstitial cells. In functional experiments, neither of the TRPA1-agonists (1-100 MUM) had any direct effects on ureter tension (baseline/potassium-induced contractions). However, CA, AI, NaHS, and capsaicin (10 MUM) decreased (P < 0.01-0.05) tetrodotoxin-sensitive electrically induced (2,4,8,16,32 Hz) contractions. Inhibitory activities were 50-61% (CA), 30-56% (AI), 30-40% (NaHS), and 37-67% (Capsaicin). CONCLUSIONS: In the human ureter, TRPA1 is located to sensory nerves and interstitial cells. TRPA1 agonists inhibited electrically induced contractions but had no direct effect on smooth muscle tension of the human ureter. A role for TRPA1 in modulating neurotransmission and possibly peristalsis of the human ureter is proposed. PMID- 28671710 TI - Adult xanthogranuloma diagnosed on reflectance confocal microscopy. PMID- 28671711 TI - An Overview of the Development of Flexible Sensors. AB - Flexible sensors that efficiently detect various stimuli relevant to specific environmental or biological species have been extensively studied due to their great potential for the Internet of Things and wearable electronics applications. The application of flexible and stretchable electronics to device-engineering technologies has enabled the fabrication of slender, lightweight, stretchable, and foldable sensors. Here, recent studies on flexible sensors for biological analytes, ions, light, and pH are outlined. In addition, contemporary studies on device structure, materials, and fabrication methods for flexible sensors are discussed, and a market overview is provided. The conclusion presents challenges and perspectives in this field. PMID- 28671712 TI - Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial. AB - BACKGROUND AND AIM: Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. METHODS: Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (+/- 8.4), and model for end-stage liver disease score 12 (+/- 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. RESULTS: Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-alpha, transforming growth factor beta-1, and high sensitivity C reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin. CONCLUSION: Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040). PMID- 28671714 TI - Significant differentiation in the apolipoprotein(a)/lipoprotein(a) trait between chimpanzees from Western and Central Africa. AB - Elevated Lipoprotein(a) (Lp(a)) plasma concentrations are a risk factor for cardiovascular disease in humans, largely controlled by the LPA gene encoding apolipoprotein(a) (apo(a)). Lp(a) is composed of low-density lipoprotein (LDL) and apo(a) and restricted to Catarrhini. A variable number of kringle IV (KIV) domains in LPA lead to a size polymorphism of apo(a) that is inversely correlated with Lp(a) concentrations. Smaller apo(a) isoforms and higher Lp(a) levels in central chimpanzees (Pan troglodytes troglodytes [PTT]) compared to humans from Europe had been reported. We studied apo(a) isoforms and Lp(a) concentrations in 75 western (Pan troglodytes verus [PTV]) and 112 central chimpanzees, and 12 bonobos (Pan paniscus [PPA]), all wild born and living in sanctuaries in Sierra Leone, Republic of the Congo, and DR Congo, respectively, and 116 humans from Gabon. Lp(a) levels were severalfold higher in western than in central chimpanzees (181.0 +/- 6.7 mg/dl vs. 56.5 +/- 4.3 mg/dl), whereas bonobos showed intermediate levels (134.8 +/- 33.4 mg/dl). Apo(a) isoform sizes differed significantly between subspecies (means 20.9 +/- 2.2, 22.9 +/- 4.4, and 23.8 +/- 3.8 KIV repeats in PTV, PTT, and PPA, respectively). However, far higher isoform associated Lp(a) concentrations for all isoform sizes in western chimpanzees offered the main explanation for the higher overall Lp(a) levels in this subspecies. Human Lp(a) concentrations (mean 47.9 +/- 2.8 mg/dl) were similar to those in central chimpanzees despite larger isoforms (mean 27.1 +/- 4.9 KIV). Lp(a) and LDL, apoB-100, and total cholesterol levels only correlated in PTV. This remarkable differentiation between chimpanzees from different African habitats and the trait's similarity in humans and chimpanzees from Central Africa poses the question of a possible impact of an environmental factor that has shaped the genetic architecture of LPA. Overall, studies on the cholesterol containing particles of Lp(a) and LDL in chimpanzees should consider differentiation between subspecies. PMID- 28671713 TI - Complement C5a-Induced Changes in Neutrophil Morphology During Inflammation. AB - The complement and neutrophil defence systems, as major components of innate immunity, are activated during inflammation and infection. For neutrophil migration to the inflamed region, we hypothesized that the complement activation product C5a induces significant changes in cellular morphology before chemotaxis. Exposure of human neutrophils to C5a dose- and time-dependently resulted in a rapid C5a receptor-1 (C5aR1)-dependent shape change, indicated by enhanced flow cytometric forward-scatter area values. Similar changes were observed after incubation with zymosan-activated serum and in blood neutrophils during murine sepsis, but not in mice lacking the C5aR1. In human neutrophils, Amnis high resolution digital imaging revealed a C5a-induced decrease in circularity and increase in the cellular length/width ratio. Biomechanically, microfluidic optical stretching experiments indicated significantly increased neutrophil deformability early after C5a stimulation. The C5a-induced shape changes were inhibited by pharmacological blockade of either the Cl-/HCO3--exchanger or the Cl -channel. Furthermore, actin polymerization assays revealed that C5a exposure resulted in a significant polarization of the neutrophils. The functional polarization process triggered by ATP-P2X/Y-purinoceptor interaction was also involved in the C5a-induced shape changes, because pretreatment with suramin blocked not only the shape changes but also the subsequent C5a-dependent chemotactic activity. In conclusion, the data suggest that the anaphylatoxin C5a regulates basic neutrophil cell processes by increasing the membrane elasticity and cell size as a consequence of actin-cytoskeleton polymerization and reorganization, transforming the neutrophil into a migratory cell able to invade the inflammatory site and subsequently clear pathogens and molecular debris. PMID- 28671715 TI - The Critically Endangered western chimpanzee declines by 80. AB - African large mammals are under extreme pressure from unsustainable hunting and habitat loss. Certain traits make large mammals particularly vulnerable. These include late age at first reproduction, long inter-birth intervals, and low population density. Great apes are a prime example of such vulnerability, exhibiting all of these traits. Here we assess the rate of population change for the western chimpanzee, Pan troglodytes verus, over a 24-year period. As a proxy for change in abundance, we used transect nest count data from 20 different sites archived in the IUCN SSC A.P.E.S. database, representing 25,000 of the estimated remaining 35,000 western chimpanzees. For each of the 20 sites, datasets for 2 different years were available. We estimated site-specific and global population change using Generalized Linear Models. At 12 of these sites, we detected a significant negative trend. The estimated change in the subspecies abundance, as approximated by nest encounter rate, yielded a 6% annual decline and a total decline of 80.2% over the study period from 1990 to 2014. This also resulted in a reduced geographic range of 20% (657,600 vs. 524,100 km2 ). Poverty, civil conflict, disease pandemics, agriculture, extractive industries, infrastructure development, and lack of law enforcement, are some of the many reasons for the magnitude of threat. Our status update triggered the uplisting of the western chimpanzee to "Critically Endangered" on the IUCN Red List. In 2017, IUCN will start updating the 2003 Action Plan for western chimpanzees and will provide a consensus blueprint for what is needed to save this subspecies. We make a plea for greater commitment to conservation in West Africa across sectors. Needed especially is more robust engagement by national governments, integration of conservation priorities into the private sector and development planning across the region and sustained financial support from donors. PMID- 28671716 TI - Ultraselective Carbon Molecular Sieve Membranes with Tailored Synergistic Sorption Selective Properties. AB - Membrane-based separations can reduce the energy consumption and the CO2 footprint of large-scale fluid separations, which are traditionally practiced by energy-intensive thermally driven processes. Here, a new type of membrane structure based on nanoporous carbon is reported, which, according to this study, is best referred to as carbon/carbon mixed-matrix (CCMM) membranes. The CCMM membranes are formed by high-temperature (up to 900 degrees C) pyrolysis of polyimide precursor hollow-fiber membranes. Unprecedentedly high permselectivities are seen in CCMM membranes for CO2 /CH4 , N2 /CH4 , He/CH4 , and H2 /CH4 separations. Analysis of permeation data suggests that the ultrahigh selectivities result from substantially increased sorption selectivities, which is hypothetically owing to the formation of ultraselective micropores that selectively exclude the bulkier CH4 molecules. With tunable sorption selectivities, the CCMM membranes outperform flexible polymer membranes and traditional rigid molecular-sieve membranes. The capability to increase sorption selectivities is a powerful tool to leverage diffusion selectivities, and has opened the door to many challenging and economically important fluid separations that require ultrafine differentiation of closely sized molecules. PMID- 28671718 TI - Antinociceptive effects of low-level laser therapy at 3 and 8 j/cm2 in a rat model of postoperative pain: possible role of endogenous Opioids. AB - Low-level laser therapy (LLLT) is the direct application of light to stimulate cell responses (photobiomodulation) to promote tissue healing, reduce inflammation, and induce analgesia; the molecular basis for these effects of LLLT remains unclear. The objective of this study was to evaluate the analgesic effect of LLLT in the rat plantar incision model of postoperative pain as well as to investigate some of the possible mechanisms involved in this effect. Wistar rats were submitted to plantar incision and treated with LLLT (830 nm, continuous mode, 30 mW/cm2 , 1-12 J/cm2 ). Postoperative thermal and mechanical hypersensitivity were monitored for 24 hours post-incision. In addition, the animals were pretreated with saline, naloxone (a nonselective opioid receptor antagonist; 20 ug/5 ul) or methysergide (5-HT2C , 5-HT2A , 5-HT7 , 5-HT5a , 5 HT6, and 5-HT1F receptors antagonist; 30 ug/5 ul). Moreover, 24 hours after incision and treatment, the TNF-alpha and IL-1beta levels in serum were evaluated. Our results demonstrate, for the first time, that LLLT at 3 or 8 J/cm2 , but not at 1-2, 4-7, or 9-12 J/cm2 , induced an analgesic effect on postoperative pain. Naloxone, but not methysergide, blocked the LLLT-induced anti nociceptive effect. Additionally, IL-1-beta and TNF-alpha production significantly decreased after LLLT at 3 or 8 J/cm2 . Our results suggest that LLLT at 3 or 8 J/cm2 primarily modulates the endogenous opioids system and is not directly mediated by serotonergic receptors. Reduction of IL-1beta and TNF-alpha may play a role in the antinociceptive action of LLLT. Lasers Surg. Med. 49:844 851, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28671717 TI - The effect of interleukin (IL)-21 and CD4+ CD25++ T cells on cytokine production of CD4+ responder T cells in patients with myasthenia gravis. AB - Impairment of the suppressive function of regulatory T (Treg ) cells has been reported in myasthenia gravis (MG). In this study, cytokine-related mechanisms that may lead to the defect of Treg were investigated in patients with anti acetylcholine receptor antibody-positive MG (AChR + MG). Proliferation and cytokine production of responder T (Tresp ) cells in response to polyclonal activation were measured in a suppression assay. The effect of interleukin (IL) 21 on suppression was evaluated in vitro in co-culture. IL-21 increased the proliferation of Tresp cells in Tresp /Treg co-cultures. Tresp cells from patients with MG secreted significantly lower levels of IL-2. In patients with MG, IL-2 levels did not change with the addition of Treg to cultures, whereas it decreased significantly in controls. In Tresp /Treg co-cultures, IL-4, IL-6 and IL-10 production increased in the presence of Treg in patients. Interferon (IFN) gamma was decreased, whereas IL-17A was increased in both patient and control groups. IL-21 inhibited the secretion of IL-4 in MG and healthy controls (HC), and IL-17A in HC only. The results demonstrated that IL-21 enhances the proliferation of Tresp cells in the presence of Treg . An effect of IL-21 mainly on Tresp cells through IL-2 is implicated. PMID- 28671719 TI - Water-Soluble Sericin Protein Enabling Stable Solid-Electrolyte Interphase for Fast Charging High Voltage Battery Electrode. AB - Spinel LiNi0.5 Mn1.5 O4 (LNMO) is the most promising cathode material for achieving high energy density lithium-ion batteries attributed to its high operating voltage (~4.75 V). However, at such high voltage, the commonly used battery electrolyte is suffered from severe oxidation, forming unstable solid electrolyte interphase (SEI) layers. This would induce capacity fading, self discharge, as well as inferior rate capabilities for the electrode during cycling. This work first time discovers that the electrolyte oxidation is effectively negated by introducing an electrochemically stable silk sericin protein, which is capable to stabilize the SEI layer and suppress the self discharge behavior for LNMO. In addition, robust mechanical support of sericin coating maintains the structural integrity during the fast charging/discharging process. Benefited from these merits, the sericin-based LNMO electrode possesses a much lower Li-ion diffusion energy barrier (26.1 kJ mol-1 ) for than that of polyvinylidene fluoride-based LNMO electrode (37.5 kJ mol-1 ), delivering a remarkable high-rate performance. This work heralds a new paradigm for manipulating interfacial chemistry of electrode to solve the key obstacle for LNMO commercialization, opening a powerful avenue for unlocking the current challenges for a wide family of high operating voltage cathode materials (>4.5 V) toward practical applications. PMID- 28671720 TI - Gradients and dynamics of inner bark and needle osmotic potentials in Scots pine (Pinus sylvestris L.) and Norway spruce (Picea abies L. Karst). AB - Preconditions of phloem transport in conifers are relatively unknown. We studied the variation of needle and inner bark axial osmotic gradients and xylem water potential in Scots pine and Norway spruce by measuring needle and inner bark osmolality in saplings and mature trees over several periods within a growing season. The needle and inner bark osmolality was strongly related to xylem water potential in all studied trees. Sugar concentrations were measured in Scots pine, and they had similar dynamics to inner bark osmolality. The sucrose quantity remained fairly constant over time and position, whereas the other sugars exhibited a larger change with time and position. A small osmotic gradient existed from branch to stem base under pre-dawn conditions, and the osmotic gradient between upper stem and stem base was close to zero. The turgor in branches was significantly driven by xylem water potential, and the turgor loss point in branches was relatively close to daily minimum needle water potentials typically reported for Scots pine. Our results imply that xylem water potential considerably impacts the turgor pressure gradient driving phloem transport and that gravitation has a relatively large role in phloem transport in the stems of mature Scots pine trees. PMID- 28671722 TI - Restoring EEAquilibrium: rebalancing excitation and inhibition in Rett mouse model neurons with early endosome antigen-1. PMID- 28671721 TI - Chloride Passivation of ZnO Electrodes Improves Charge Extraction in Colloidal Quantum Dot Photovoltaics. AB - The tunable bandgap of colloidal quantum dots (CQDs) makes them an attractive material for photovoltaics (PV). The best present-day CQD PV devices employ zinc oxide (ZnO) as an electron transport layer; however, it is found herein that ZnO's surface defect sites and unfavorable electrical band alignment prevent devices from realizing their full potential. Here, chloride (Cl)-passivated ZnO generated from a solution of presynthesized ZnO nanoparticles treated using an organic-solvent-soluble Cl salt is reported. These new ZnO electrodes exhibit decreased surface trap densities and a favorable electronic band alignment, improving charge extraction from the CQD layer and achieving the best-cell power conversion efficiency (PCE) of 11.6% and an average PCE of 11.4 +/- 0.2%. PMID- 28671723 TI - Giving Context to Non-self-marker Theories of Immune Responsiveness. AB - In 2001, long ago by modern standards, Matzinger changed the emphasis of her Danger theory from one that downplayed the self-non-self discrimination to one that concerned itself with the regulation of effector class. This gave her theory a measure of validity that the other non-self-marker theorists have yet to confront. However, precision and clarity are still lacking. PMID- 28671724 TI - Tunneling Photocurrent Assisted by Interlayer Excitons in Staggered van der Waals Hetero-Bilayers. AB - Vertically stacked van der Waals (vdW) heterostructures have been suggested as a robust platform for studying interfacial phenomena and related electric/optoelectronic devices. While the interlayer Coulomb interaction mediated by the vdW coupling has been extensively studied for carrier recombination processes in a diode transport, its correlation with the interlayer tunneling transport has not been elucidated. Here, a contrast is reported between tunneling and drift photocurrents tailored by the interlayer coupling strength in MoSe2 /MoS2 hetero-bilayers (HBs). The interfacial coupling modulated by thermal annealing is identified by the interlayer phonon coupling in Raman spectra and the emerging interlayer exciton peak in photoluminescence spectra. In strongly coupled HBs, positive photocurrents are observed owing to the inelastic band-to band tunneling assisted by interlayer excitons that prevail over exciton recombinations. By contrast, weakly coupled HBs exhibit a negative photovoltaic diode behavior, manifested as a drift current without interlayer excitonic emissions. This study sheds light on tailoring the tunneling transport for numerous optoelectronic HB devices. PMID- 28671725 TI - Trisomy 13-confined placental mosaicism: is there an increased risk of gestational hypertensive disorders? PMID- 28671726 TI - Phenotypic spectrum of mutations in IBA57, a candidate gene for cavitating leukoencephalopathy. AB - IBA57 is involved in the biogenesis of mitochondrial [4Fe-4S] proteins. Eighteen cases with IBA57 mutations have been reported to date. We described a novel phenotype in 11 children with cavitating leukoencephalopathy and summarized the phenotypic spectrum of IBA57 mutations. The median age of onset was 9 months, with an initial presentation of motor regression. Deterioration of neurological function reached its peak within 4 months. The median interval between onset and last follow-up was 2.9 years (0.4-10.0). All cases survived and remained stable. Severe motor handicap was observed in 50.0% of the patients, 52.9% to 71.4% had a delay in communication, problem solving or personal-social skills, and 20.0% had mild symptomatic fluctuations. In the peak phase, magnetic resonance imaging (MRI) lesions were mainly observed in the periventricular/central white matter, and cavitating lesions and patchy high diffusion-weighted imaging (DWI) signals were observed. The numbers and extent of restricted diffusional lesions were reduced, and atrophy was prominent in the recovery phase. Eight novel mutations in IBA57 were identified in our study. This study provided more information about the natural history and evolution of neuroimaging. Combined with previously reported patient studies, our findings suggest that defects in IBA57 can produce diverse phenotypes. IBA57 should be considered a candidate gene for cavitating leukoencephalopathy. PMID- 28671727 TI - Effects of global change factors on fatty acids and mycosporine-like amino acid production in Chroothece richteriana (Rhodophyta). AB - Under natural conditions, Chroothece richteriana synthesizes a fairly high proportion of fatty acids. However, nothing is known about how environmental changes affect their production, or about the production of protective compounds, when colonies develop under full sunshine with high levels of UV radiation. In this study, wild colonies of C. richteriana were subjected to increasing temperature, conductivity, ammonium concentrations and photosynthetically active radiation (PAR), and UV radiations to assess the potential changes in lipid composition and mycosporine-like amino acids (MAAs) concentration. The PERMANOVA analysis detected no differences for the whole fatty acid profile among treatments, but the percentages of alpha-linolenic acid and total polyunsaturated fatty acids increased at the lowest assayed temperature. The percentages of linoleic and alpha-linolenic acids increased with lowering temperature. gamma linolenic and arachidonic acids decreased with increasing conductivity, and a high arachidonic acid concentration was related with increased conductivity. The samples exposed to UVB radiation showed higher percentages of eicosapentaenoic acid and total monounsaturated fatty acids, at the expense of saturated fatty acids. MAAs accumulation increased but not significantly at the lowest conductivity, and also with the highest PAR and UVR exposure, while ammonium and temperature had no effect. The observed changes are probably related with adaptations of both membrane fluidity to low temperature, and metabolism to protect cells against UV radiation damage. The results suggest the potential to change lipid composition and MAAs concentration in response to environmental stressful conditions due to climate change, and highlight the interest of the species in future research about the biotechnological production of both compound types. PMID- 28671728 TI - Clonality analysis of synchronous gastro-oesophageal junction carcinoma and distal gastric cancer by whole-exome sequencing. AB - Gastro-oesophageal junction (GEJ) carcinoma and distal gastric cancer (GC) have distinct epidemiology and clinical features and their relationship is uncertain. Synchronous multiple gastric cancers located mostly at proximal and distal sites provide rare specimens for investigating the comprehensive genomic relationships among these cancers in the context of identical genetic circumstances. Formalin fixed, paraffin-embedded (FFPE) samples from 12 patients with synchronous GEJ carcinoma and distal GC were collected in this study. Whole-exome sequencing (WES) was performed using normal tissues as a control. Mutational profiling, clonality analysis, a detailed clinico-pathological review, determination of MSI status, EBER in situ hybridization (ISH), and programmed cell death 1 (PD 1)/programmed death-ligand 1 (PD-L1) immunohistochemical staining were performed. Twenty-three of the 24 samples were microsatellite-stable (MSS). Subclonal analysis revealed that nine pairs of GEJ and distal GC tumours in neoadjuvant chemotherapy naive patients developed independently from different origins. Two patients who received neoadjuvant chemotherapy shared clonal origins with highly similar somatic alterations. The remaining one patient who shared a rare mutation died within 6.2 months at the N3 stage. However, the enriched pathway identified from the overall mutation spectra in distal GC and GEJ carcinoma showed the close relationship of these cancers. Thus, although these cancers may have similar characteristics, histopathological and genetic profiling from single tumour specimens may still underestimate the mutational burden and somatic heterogeneity of multiple GCs. In addition, this series of cases also showed a PD-L1 expression rate of 58.3% and 66.7% in distal GC and GEJ carcinoma, respectively, with all the cases expressing PD-1. This result suggests the potential benefit of immunotherapeutic treatments. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28671729 TI - Self-reported toileting behaviors in employed women: Are they associated with lower urinary tract symptoms? AB - AIMS: To describe toileting behaviors working women habitually use and investigate behaviors associated with lower urinary tract symptoms (LUTS), especially urinary urgency with or without leakage. METHODS: Non-pregnant female employees of a large academic medical center 18 years and over were eligible to complete an online survey about bladder health and toileting behaviors. RESULTS: One hundred eighty-two women participated in the survey. The majority were white (83.52%), married (52.49%), had >=1 pregnancy (54.40%), and in excellent health (93.41%). The average age and body mass index were 47.28 +/- 13.56 years and 27.92 +/- 6.78, respectively. The sample was further sub-divided into two groups: urinary urgency (N = 119) or no urinary urgency symptoms (N = 51). Habitual toileting behaviors for these groups (N = 170) included: sitting to urinate at home (98.24%), emptying the bladder completely (88.82%), emptying the bladder before leaving home (80.00%), and sitting to urinate when away from home (68.82%). Logistic regression analysis showed age increased the odds of urinary urgency (aOR 1.06, 95%CI 1.02-1.09). Women who waited too long to urinate at work (aOR 7.85, 95%CI 1.57-39.24) and wore panty liners for urinary leakage (aOR 2.86, 95%CI 1.25-6.56) had greater odds of urinary urgency than women who did neither. CONCLUSIONS: Most habitual toileting behaviors were not associated with urinary urgency except waiting too long to urinate when at work. Logistic regression revealed significant relationships among health-related factors, personal characteristics, behaviors, and urinary urgency. LUTS in women is both a women's health and occupational health issue. PMID- 28671730 TI - Solving the Mysteries of Emergent Matter for the Benefit of Society: Research at the RIKEN Center for Emergent Matter Science. PMID- 28671731 TI - Multiple phases of mg-calcite in crustose coralline algae suggest caution for temperature proxy and ocean acidification assessment: lessons from the ultrastructure and biomineralization in Phymatolithon (Rhodophyta, Corallinales)1. AB - Magnesium content, strongly correlated with temperature, has been developed as a climate archive for the late Holocene without considering anatomical controls on Mg content. In this paper, we explore the ultrastructure and cellular scale Mg content variations within four species of North Atlantic crust-forming Phymatolithon. The cell wall has radial grains of Mg-calcite, whereas the interfilament (middle lamella) has grains aligned parallel to the filament axis. The proportion of interfilament and cell wall carbonate varies by tissue and species. Three distinct primary phases of Mg-calcite were identified: interfilament Mg-calcite (mean 8.9 mol% MgCO3 ), perithallial cell walls Mg calcite (mean 13.4 mol% MgCO3 ), and hypothallium Mg-calcite (mean 17.1 mol% MgCO3 ). Magnesium content for the bulk crust, an average of all phases present, showed a strongly correlated (R2 = 0.975) increase of 0.31 mol% MgCO3 per degrees C. Of concern for climate reconstructions is the potential for false warming signals from undetected postgrazing wound repair carbonate that is substantially enriched in Mg, unrelated to temperature. Within a single crust, Mg content of component carbonates ranged from 8 to 20 mol% MgCO3 , representing theoretical thermodynamic stabilities from aragonite-equivalent to unstable higher-Mg-calcite. It is unlikely that existing current predictions of ocean acidification impact on coralline algae, based on saturation states calculated using average Mg contents, provide an environmentally relevant estimate. PMID- 28671732 TI - A Highly Efficient and Photostable Photosensitizer with Near-Infrared Aggregation Induced Emission for Image-Guided Photodynamic Anticancer Therapy. AB - Photodynamic therapy (PDT), which relies on photosensitizers (PS) and light to generate reactive oxygen species to kill cancer cells or bacteria, has attracted much attention in recent years. PSs with both bright emission and efficient singlet oxygen generation have also been used for image-guided PDT. However, simultaneously achieving effective 1 O2 generation, long wavelength absorption, and stable near-infrared (NIR) emission with low dark toxicity in a single PS remains challenging. In addition, it is well known that when traditional PSs are made into nanoparticles, they encounter quenched fluorescence and reduced 1 O2 production. In this contribution, these challenging issues have been successfully addressed through designing the first photostable photosensitizer with aggregation-induced NIR emission and very effective 1 O2 generation in aggregate state. The yielded nanoparticles show very effective 1 O2 generation, bright NIR fluorescence centered at 820 nm, excellent photostability, good biocompatibility, and negligible dark in vivo toxicity. Both in vitro and in vivo experiments prove that the nanoparticles are excellent candidates for image-guided photodynamic anticancer therapy. PMID- 28671733 TI - Centennial Anniversary of Mannich's Report on the Formation of beta-Amino-Ketones in the Archiv der Pharmazie. AB - In order to commemorate Carl Mannich's achievement with many implications in the fields of drug design and synthesis, stability of pharmaceutical preparations, and natural product chemistry, we invited researchers to submit their work related to Mannich's pioneering article at the occasion of its centennial anniversary to the Archiv der Pharmazie - where else? PMID- 28671734 TI - Small "Yaw" Angles, Large "Bite" Angles and an Electron-Rich Metal: Revealing a Stereoelectronic Synergy To Enhance Hydride-Transfer Activity. AB - Cyclometalated complexes are an important class of (pre)catalysts in many reactions including hydride transfer. The ring size of such complexes could therefore be a relevant aspect to consider while modulating their catalytic activity. However, any correlation between the cyclometalating ring size and the catalytic activity should be drawn by careful assessment of the pertinent geometrical parameters, and overall electronic effects thereof. In this study, we investigated the vital role of key stereoelectronic functions of two classes of iridacyclic complexes-five-membered and six-membered cycles-in manupulating the catalytic efficiency in a model hydride-transfer reaction. Our investigation revealed that there exists an interesting multidimensional synergy among all the relevant stereoelectronic factors-yaw angle, bite angle, and the electronic properties of both the ligand and the metal center-that governs the hydride donor ability (hydricity) of the complexes during catalysis. Thus the six-membered chelate complexes with small yaw and large bite angles, strong donor ligand, and electron-rich metal were found to be better catalysts than their five-membered analogues. A frontier molecular orbital analysis supported the significant role of the above stereoelectronic synergistic effect associated with the chelate ring to control the hydride donor ability of the complexes. PMID- 28671735 TI - Lifecycle of Rhipicephalus haemaphysaloides under laboratory conditions. AB - Rhipicephalus haemaphysaloides Supino, 1897 (Ixodida: Ixodidae) is a three-host hard tick widely distributed in Sri Lanka. The lifecycle of the R. haemaphysaloides population in Sri Lanka was studied under laboratory conditions using fully engorged females collected from dogs. Larvae, nymphs and adults were reared on New Zealand rabbits. Engorged females weighed a mean +/- standard deviation (SD) of 470.1 +/- 106.5 mg and laid a mean +/- SD of 4067.4 +/- 3136.2 eggs within 16.1 +/- 3.7 days. The mean +/- SD preoviposition period was 6.5 +/- 1.1 days. The mean +/- SD reproductive efficiency index was 8.5 +/- 4.1, and was higher in heavier females (Pearson correlation, r = 0.8; P = 0.001). The incubation period of eggs was shorter at higher temperatures. The majority (86.9%) of larvae successfully moulted after a mean +/- SD premoulting period of 7.9 +/- 0.7 days following a parasitic period of 3.2 +/- 0.5 days. Unfed larvae survived a mean +/- SD of 103.4 +/- 19.8 days. Nymphs completed the bloodmeal after 3.7 +/- 0.9 days, weighed 5.7 +/- 1.7 mg and demonstrated a premoulting period of 15.1 +/- 1.9 days. Unfed nymphs survived a mean +/- SD of 45.8 +/- 3.8 days. Heavier nymphs moulted into females, whereas lighter nymphs moulted into males (two-sample t-test, P < 0.001). The bodyweight of adult females increased more than 100-fold after feeding. The lifecycle of R. haemaphysaloides was successfully completed on rabbits within a mean of 91.3 days (range: 69-117 days) under laboratory conditions. PMID- 28671736 TI - Overexpression of PCDHB9 promotes peritoneal metastasis and correlates with poor prognosis in patients with gastric cancer. AB - Gastric cancer (GC) is one of the most common human cancers. Genes expressed only in cancer tissue, especially on the cell membrane, may be useful biomarkers for cancer diagnosis and therapeutics. In the present study, we focused on the PCDHB9 gene, which encodes the transmembrane protein protocadherin B9. Immunohistochemical analysis revealed that 62 (36%) of 173 GC cases were positive for protocadherin B9. Protocadherin B9 staining was mainly observed on the GC cell membrane. Expression of protocadherin B9 was frequently found in intestinal type GC and correlated with poor prognosis in patients with intestinal-type GC. Although PCDHB9 knockdown or forced expression of PCDHB9 did not change cell growth or invasion activity in a GC cell line, cell adhesion to fibronectin was significantly reduced by PCDHB9 knockdown and significantly enhanced by overexpression of PCDHB9. Expression levels of ITGA3, ITGA4, ITGA5, and ITGB1 were significantly reduced by knockdown of PCDHB9 and significantly enhanced by overexpression of PCDHB9. Furthermore, both the number and the size of spheres in culture were significantly decreased by PCDHB9 knockdown and significantly increased by overexpression of PCDHB9. In a peritoneal dissemination mouse model, the weight of the total disseminated nodules of MKN-74 cells was significantly increased by forced expression of PCDHB9. These results indicate that protocadherin B9 plays an important role in the progression rather than the pathogenesis of intestinal-type GC. Specific inhibitors of protocadherin B9 may constitute promising anti-cancer drugs with fewer side-effects. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28671738 TI - Enantioselective Oxidative (4+3) Cycloadditions between Allenamides and Furans through Bifunctional Hydrogen-Bonding/Ion-Pairing Interactions. AB - BINOL-based N-trifluoromethanesulfonyl phosphoramides catalyze the enantioselective (4+3) cycloaddition between furans and oxyallyl cations, the latter being generated in situ by oxidation of allenamides. The chiral organic phosphoramide counteranion is proposed to engage in the activation of the oxyallyl cation intermediate through cooperative hydrogen-bonding and ion-pairing interactions, enabling an efficient chirality transfer that provide the final adducts with high diastereo- and enantioselectivities. Remarkably, the reaction shows a wide substrate scope that includes a variety of substituted allenamides and furans. PMID- 28671737 TI - The phase response and state space of slow wave contractions in the small intestine. AB - NEW FINDINGS: What is the central question of this study? What are the dynamical rules governing interstitial cell of Cajal (ICC)-generated slow wave contractions in the small intestine, as reflected in their phase response curve and state space? What is the main finding and its importance? The phase response curve has a region of phase advance surrounding a phase delay peak. This pattern is important in generating a stable synchrony within the ICC network and is related to the state space of the ICC; in particular, the phase delay peak corresponds to the unstable equilibrium point that threads the ICC's limit cycle. Interstitial cells of Cajal (ICCs) generate electrical oscillations in the gut. Synchronization of the ICC population is required for generation of coherent electrical waves ('slow waves') that cause muscular contraction and thereby move gut content. The phase response curve (PRC) is an experimental measure of the dynamical rules governing a population of oscillators that determine their synchrony and gives an experimental window onto the state space of the oscillator, its dynamical landscape. We measured the PRC of slow wave contractions in the mouse small intestine by the novel combination of diameter mapping and single pulse electrical field stimulation. Phase change (tau) was measured as a function of old phase (phi) and distance from the stimulation electrode (d). Plots of tau(phi, d) showed an arrowhead-shaped region of phase advance enclosing at its base a phase delay peak. The phase change mirrored the perturbed pattern of contraction waves in response to a pulse. The (phi, d) plane is the surface of a displacement tube extending from the limit cycle through state space. To visualize the state space vector field on this tube, latent phase (philat ) was calculated from tau. At the transition from advance to delay, isochrons made boomerang turns before tightening and winding around the phase delay peak corresponding to the unstable equilibrium point that threads the limit cycle. This isochron foliation had previously been observed in oscillator models such as the Fitzhugh-Nagumo but has not been demonstrated experimentally. The spatial extension of the PRC afforded by diameter mapping allows a better understanding of the dynamical properties of ICCs and how they synchronize as a population. PMID- 28671739 TI - Homogenous Alloys of Formamidinium Lead Triiodide and Cesium Tin Triiodide for Efficient Ideal-Bandgap Perovskite Solar Cells. AB - The alloying behavior between FAPbI3 and CsSnI3 perovskites is studied carefully for the first time, which has led to the realization of single-phase hybrid perovskites of (FAPbI3 )1-x (CsSnI3 )x (090 % ee (and up to 99 % ee) in many cases, and a "privileged substrate structure" with respect to high enantioselectivity was identified. Furthermore, a surprising phenomenon was observed for the enantiospecificity that is usually not observed in enzyme catalysis. Depending on whether the E or Z isomer of the racemic aldoxime substrate was employed, one or the other enantiomer of the corresponding nitrile was formed preferentially with the same enzyme. PMID- 28671740 TI - ATP prevents Woronin bodies from sealing septal pores in unwounded cells of the fungus Zymoseptoria tritici. AB - Septa of filamentous ascomycetes are perforated by septal pores that allow communication between individual hyphal compartments. Upon injury, septal pores are plugged rapidly by Woronin bodies (WBs), thereby preventing extensive cytoplasmic bleeding. The mechanism by which WBs translocate into the pore is not known, but it has been suggested that wound-induced cytoplasmic bleeding "flushes" WBs into the septal opening. Alternatively, contraction of septum associated tethering proteins may pull WBs into the septal pore. Here, we investigate WB dynamics in the wheat pathogen Zymoseptoria tritici. Ultrastructural studies showed that 3.4 +/- 0.2 WBs reside on each side of a septum and that single WBs of 128.5 +/- 3.6 nm in diameter seal the septal pore (41 +/- 1.5 nm). Live cell imaging of green fluorescent ZtHex1, a major protein in WBs, and the integral plasma membrane protein ZtSso1 confirms WB translocation into the septal pore. This was associated with the occasional formation of a plasma membrane "balloon," extruding into the dead cell, suggesting that the plasma membrane rapidly seals the wounded septal pore wound. Minor amounts of fluorescent ZtHex1-enhanced green fluorescent protein (eGFP) appeared associated with the "ballooning" plasma membrane, indicating that cytoplasmic ZtHex1-eGFP is recruited to the extending plasma membrane. Surprisingly, in ~15% of all cases, WBs moved from the ruptured cell into the septal pore. This translocation against the cytoplasmic flow suggests that an active mechanism drives WB plugging. Indeed, treatment of unwounded and intact cells with the respiration inhibitor carbonyl cyanide m-chlorophenyl hydrazone induced WB translocation into the pores. Moreover, carbonyl cyanide m-chlorophenyl hydrazone treatment recruited cytoplasmic ZtHex1-eGFP to the lateral plasma membrane of the cells. Thus, keeping the WBs out of the septal pores, in Z. tritici, is an ATP-dependent process. PMID- 28671742 TI - The First Triple-Decker Complex with a Carbenium Center, [CpCo(MU-C3 B2 Me5 )RuC5 Me4 CH2 ]+ : Synthesis, Reactivity, X-Ray Structure, and Bonding. AB - The first derivative of the methylium cation with the triple-decker substituent, [CpCo(C3 B2 Me5 )RuC5 Me4 CH2 ]PF6 (2PF6 ), was synthesized from the reaction of the triple-decker complex CpCo(C3 B2 Me5 )RuCp* (1) with the salt of the trityl cation [CPh3 ]+ . The X-ray crystal structure of 2PF6 reveals that the methylium carbon is bound to the ruthenium with Ru-C bond length of 2.259 A and corresponds to the description of its structure as eta6 -fulvene-ruthenium. Reactions of 2PF6 with nucleophiles OH- , Ph3 P, Et3 N led to the corresponding derivatives of 1 in high yields. Aromatic amines PhNEt2 and 4-MeC6 H4 NH2 react with 2PF6 to give the electrophilic aromatic substitution products quantitatively. Chemical reduction of 2PF6 with Zn powder in tetrahydrofuran leads to the formation of the bis(triple-decker) derivative (CpCo(C3 B2 Me5 )RuC5 Me4 CH2 )2 (10) with a CH2 CH2 -bridge. The structures of complexes 4, 7-10 were determined by X-ray diffraction. Density functional calculations support the crystallographically determined geometry of 2 and allow rationalization of some characteristics of its structure, spectroscopy, and reactivity. PMID- 28671743 TI - A Case of Spinal Cord Stimulator Recharging Interruption in Wound Healing. AB - OBJECTIVES: To illustrate the obstacles and problems with electrical fields (EFs) in treatment and management of skin wounds. Unlike the literature that gives evidence for EF promoting wound healing, there is relatively little research to illustrate the interference of wound healing with EFs. MATERIALS AND METHODS: This is a case report of a patient who underwent spinal cord stimulator implantation, and presented with delayed wound healing postoperatively. Postoperative workup for infection was negative. Spinal cord stimulator was programmed to use higher frequencies than traditional settings, which required recharging the pulse generator daily. There was spontaneous improvement of the clinical presentation resulting in adequate wound healing after changing the programming to less frequent recharging requirements. RESULTS: In our case, despite the presence of clinical signs similar to a surgical site infection, the wound healing was most likely interrupted and delayed secondary to the electric field generated due to the frequent recharges of the pulse generator. CONCLUSIONS: It is possible that EF can also negatively impact healing of a wound, and thus should be a consideration to clinicians when a delay in proper wound healing is encountered postoperatively. Therefore, in the postoperative period, when the wound healing is most active, we recommend avoiding programs that require frequent pulse generator recharges. PMID- 28671744 TI - The autonomous cell fate specification of basal cell lineage: the initial round of cell fate specification occurs at the two-celled proembryo stage. AB - In angiosperms, the first zygotic division usually gives rise to two daughter cells with distinct morphologies and developmental fates, which is critical for embryo pattern formation; however, it is still unclear when and how these distinct cell fates are specified, and whether the cell specification is related to cytoplasmic localization or polarity. Here, we demonstrated that when isolated from both maternal tissues and the apical cell, a single basal cell could only develop into a typical suspensor, but never into an embryo in vitro. Morphological, cytological and gene expression analyses confirmed that the resulting suspensor in vitro is highly similar to its undisturbed in vivo counterpart. We also demonstrated that the isolated apical cell could develop into a small globular embryo, both in vivo and in vitro, after artificial dysfunction of the basal cell; however, these growing apical cell lineages could never generate a new suspensor. These findings suggest that the initial round of cell fate specification occurs at the two-celled proembryo stage, and that the basal cell lineage is autonomously specified towards the suspensor, implying a polar distribution of cytoplasmic contents in the zygote. The cell fate transition of the basal cell lineage to the embryo in vivo is actually a conditional cell specification process, depending on the developmental signals from both the apical cell lineage and maternal tissues connected to the basal cell lineage. PMID- 28671745 TI - Specially Treated Aramid Fiber Stabilized Gel-Emulsions: Preparation of Porous Polymeric Monoliths and Highly Efficient Removing of Airborne HCHO. AB - Porous polymeric monoliths with densities as low as ~0.060 g cm-3 are prepared in a gel-emulsion template way, of which the stabilizer employed is a newly discovered acidified aramid fiber that is so efficient that 0.05% (w/v, accounts for continuous phase) is enough to gel the system. The porous monoliths as obtained can be dried at ambient conditions, avoiding energy-consuming processes. Importantly, the monoliths show selective adsorption to HCHO, and the corresponding adsorption capacity (M6) is ~2700 mg g-1 , the best result that is reported until now. More importantly, the monoliths can be reused after drying. PMID- 28671746 TI - Growth attenuation therapy for children with severe physical and cognitive disability: Practice and perspectives of New Zealand paediatricians. AB - AIM: There are currently no clinical guidelines concerning the administration of growth attenuation therapy (GAT) for children (regardless of gender) with both severe physical and cognitive disability in New Zealand (NZ). This survey aimed to explore the attitudes of paediatricians towards GAT and the frequency of requests and initiation of GAT in NZ. METHODS: An online survey of paediatricians in NZ was undertaken. Questions covered both clinical experience with GAT and attitudes towards it. RESULTS: Overall, the response rate was 55% (173/317) with 162 complete responses; 25% of respondents (41/166) reported enquiries about GAT. Five had personally prescribed GAT; in total, six NZ children have undergone GAT. A total of 77% of respondents either believed GAT is appropriate or were neutral on the subject. The majority of responders (59%) believed ethical approval should be obtained as part of preparation for GAT. CONCLUSIONS: This is the first study to investigate attitudes and practices of NZ paediatricians regarding GAT for severely disabled children. Results indicate a range of views but suggest that family requests for GAT do occur and that the majority of paediatricians are not opposed to GAT in the appropriate ethical and clinical context. The development of practice guidelines for GAT may lead to a more informed decision-making process about GAT for families and paediatricians. PMID- 28671747 TI - Tailorable Surface Morphology of 3D Scaffolds by Combining Additive Manufacturing with Thermally Induced Phase Separation. AB - The functionalization of biomaterials substrates used for cell culture is gearing towards an increasing control over cell activity. Although a number of biomaterials have been successfully modified by different strategies to display tailored physical and chemical surface properties, it is still challenging to step from 2D substrates to 3D scaffolds with instructive surface properties for cell culture and tissue regeneration. In this study, additive manufacturing and thermally induced phase separation are combined to create 3D scaffolds with tunable surface morphology from polymer gels. Surface features vary depending on the gel concentration, the exchanging temperature, and the nonsolvent used. When preosteoblasts (MC-3T3 cells) are cultured on these scaffolds, a significant increase in alkaline phosphatase activity is measured for submicron surface topography, suggesting a potential role on early cell differentiation. PMID- 28671748 TI - Benzoxazine/Triphenylamine-Based Dendrimers Prepared through Facile One-Pot Mannich Condensations. AB - A series of thermally polymerizable dendrimers of various generations, equipped with triphenylamine (TPA) and benzoxazine (BZ) groups, is synthesized through facile one-pot Mannich condensations of N1 ,N1 -bis(4-aminophenyl)benzene-1,4 diamine (TPA-3NH2 , as the core group), 4-(bis(4-aminophenyl)amino)phenol (TPA 2NH2 -OH, as the AB2 branching group), and CH2 O in 1,4-dioxane. The ratios of the integrated areas in the 1 H nuclear magnetic resonance spectra of these dendrimers are consistent with the theoretical numbers of protons, suggesting their successful syntheses. Bathochromic shifts of signals are evident in the UV vis and photoluminescence spectra upon increasing the generation of the TPA-BZ dendrimers, consistent with an increase in the effective conjugation length. The TPA-BZ dendrimers are able to undergo thermal polymerization and display unique optical physical properties, resulting in thermoset TPA networks after thermal ring-opening polymerization. PMID- 28671749 TI - Thermoplastic Dielectric Elastomer of Triblock Copolymer with High Electromechanical Performance. AB - Dielectric elastomer (DE) actuators have been shown to have promising applications as soft electromechanical transducers in many emerging technologies. The DE actuators, which are capable of large actuation strain over a wide range of excitation frequencies, are highly desirable. Here, the first single-component DE of a triblock copolymer with attractive electromechanical performance is reported. Symmetric poly(styrene-b-butyl acrylate-b-styrene) (SBAS) is designed and synthesized. The SBAS actuator exhibits about 100% static actuation area strain and excellent dynamic performance, as evidenced by a wide half bandwidth of 300 Hz and a very high specific power of 1.2 W g-1 within the excitation frequency range of 300-800 Hz. PMID- 28671750 TI - Stereospecificity in Intramolecular Photoredox Reactions of Naphthoquinones: Enantioselective Total Synthesis of (-)-Spiroxin C. AB - Intramolecular photoredox reactions of naphthoquinone derivatives were found to proceed in a stereospecific manner. This method was used as a basis for the enantioselective total synthesis of (-)-spiroxin C. PMID- 28671751 TI - Body fat distribution is more predictive of all-cause mortality than overall adiposity. AB - AIMS: The relationship between directly measured body fat and all-cause mortality has been rarely studied. The aim of this study was to evaluate the predictive significance of computed tomography (CT)-measured body fat, including both visceral fat area (VFA) and subcutaneous fat area (SFA), for mortality. METHODS: The study included 36 656 participants who underwent abdominal CT as part of a health check-up at a single university-affiliated healthcare center in 2007 to 2015. Of those, 32 593 participants with data regarding vital status as of May 2016 were included in the final analysis. The main factors evaluated were VFA, SFA and visceral-to-subcutaneous fat area ratio (VSR), and the primary outcome was all-cause mortality. RESULTS: There were 253 deaths during a mean follow-up of 5.7 years. Increased SFA was associated with decreased all-cause mortality, whereas an increased VFA and VSR were related to increased all-cause mortality. Compared with the predictive power of body mass index (BMI), SFA and VSR showed a larger area under the curve than did BMI. In Kaplan-Meier survival curve analysis, increased SFA and VSR were associated with decreased and increased hazard of all-cause death, respectively. However, in multivariate Cox proportional hazard regression analysis, only VSR was independently associated with all-cause mortality. Moreover, this relationship was paralleled by the harmful impact of increased VSR on metabolic profiles. CONCLUSION: Increased VSR was an independent predictor of all-cause mortality. This suggests that the location of fat deposits may be more important than the actual amount of body fat. PMID- 28671752 TI - On the Way to Carbon Nanotubes: The First Synthesis of an Aromatic Nanobelt. AB - Tighten your belt: The first aromatic nanobelt has been prepared by Itami and co workers. This synthesis of a truncated Vogtle belt constitutes a milestone in long-standing efforts of numerous chemists. The realization of such a molecule provides not only new opportunities in materials science, but also paves the way to the rational synthesis of carbon nanotubes. PMID- 28671754 TI - In Situ Gold Nanoparticle Gradient Formation in a 3D Meso- and Macroporous Polymer Matrix. AB - Herein, the development and characterization of a 3D gradient structure of gold nanoparticles is described. The gradient of gold nanoparticles is made in situ in a macroporous nonionic block copolymer hydrogel matrix, through gold ion diffusion control. The polymer provides a matrix for diffusion of gold ions, acts as a template for controlling nanoparticle growth, and facilitates the in situ reduction of gold ions to gold nanoparticles. A clear gradient in gold nanoparticles is observed across the 3D space of the polymer matrix using scanning electron microscopy, fluorescence microscopy, atomic force microscopy, and thermogravimetric analysis. The particle gradient is further functionalized with both hydrophobic and hydrophilic groups via thiol-gold linkage to demonstrate the ability to form gradients with different chemical functionalities. Using additive manufacturing, the polymer can also be printed as a porous network with possible applications for 3D cell culturing in, e.g., biomaterials research. PMID- 28671753 TI - Glycaemic outcomes of an Individualized treatMent aPproach for oldER vulnerable patIents: A randomized, controlled stUdy in type 2 diabetes Mellitus (IMPERIUM). AB - AIMS: To compare the glycaemic outcomes of 2 glucose-lowering treatment strategies in vulnerable (moderately ill and/or frail) patients aged >=65 years with type 2 diabetes whose individual HbA1c targets were not met with diet/exercise and/or oral anti-hyperglycaemic medications (OAMs). METHODS: The primary endpoint of this study was a composite of achieving/maintaining individualized HbA1c targets without "clinically significant" hypoglycaemia (severe hypoglycaemia or repeated hypoglycaemia causing interruption of patients' activities or blood glucose <54 mg/dL). Strategy-A comprised glucose-dependent therapies (n = 99) with a non-sulphonylurea OAM and a glucagon-like peptide-1 receptor agonist as the first injectable. Strategy-B comprised non-glucose dependent therapies (n = 93) with sulphonylurea as the preferred OAM and insulin glargine as the first injectable. RESULTS: There was no significant difference between Strategy-A and Strategy-B in percentages of patients achieving the primary endpoint (64.5% vs 54.9%; P = .190). Mean incidences (A vs B) of total (10.2% vs 53.8%), documented symptomatic (5.1% vs 36.6%), and asymptomatic (8.2% vs 32.3%) hypoglycaemia were lower for Strategy-A (P < .001 each). Proportions of patients achieving/maintaining HbA1c target (A, 63.3% vs B, 55.9%) were similar. CONCLUSION: Similar proportions of older, vulnerable aged >=65 years patients with type 2 diabetes achieved/maintained glycaemic treatment goals without clinically significant hypoglycaemia with Strategies A or B. However, Strategy-A resulted in lower risk of total, documented symptomatic, and asymptomatic hypoglycaemia. These results identify an approach of potential clinical benefit in this age group and will inform future clinical research in older patients with type 2 diabetes. PMID- 28671755 TI - Discriminating Agonist from Antagonist Ligands of the Nuclear Receptors Using Different Chemoinformatics Approaches. AB - Nuclear receptors (NRs) constitute an important class of therapeutic targets. During the last 4 years, we tackled the pharmacological profile assessment of NR ligands for which we constructed the NRLiSt BDB. We evaluated and compared the performance of different virtual screening approaches: mean of molecular descriptor distribution values, molecular docking and 3D pharmacophore models. The simple comparison of the distribution profiles of 4885 molecular descriptors between the agonist and antagonist datasets didn't provide satisfying results. We obtained an overall good performance with the docking method we used, Surflex Dock which was able to discriminate agonist from antagonist ligands. But the availability of PDB structures in the "pharmacological-profile-to-predict-bound state" (agonist-bound or antagonist-bound) and the availability of enough ligands of both pharmacological profiles constituted limits to generalize this protocol for all NRs. Finally, the 3D pharmacophore modeling approach, allowed us to generate selective agonist pharmacophores and selective antagonist pharmacophores that covered more than 99 % of the whole NRLiSt BDB. This study allowed a better understanding of the pharmacological modulation of NRs with small molecules and could be extended to other therapeutic classes. PMID- 28671756 TI - Area Selective Polymer Brush Deposition. AB - Polymer brush films with chemical functionality to attach to site specific substrate areas are introduced for area selective deposition (ASD) application. It is demonstrated that polymer brushes with chemically defined end sites can be selectively bound to copper-specific regions of patterned copper/silica (Cu/SiO2 ) substrates. The process described overcomes various limitations of currently used technology including cost, complexity, and throughput, with potential implications for future electronic devices and nanomanufacturing. A comparative study of amine-terminated polystyrene and amine-terminated poly-2-vinyl pyridine polymer brushes (i.e., PS-NH2 and P2VP-NH2 ) with similar molecular weights display contrasting behavior on patterned Cu/SiO2 line features. Further, a thiol terminated poly-2-vinyl pyridine polymer brush (i.e., P2VP-SH) is investigated as a direct spin-on process to fabricate a metal oxide layer atop Cu areas only. The results presented here detail a novel methodology and open a new exciting process for ASD practices that can facilitate the precise deposition of dense metal, semiconductor, or dielectric films. We also discuss the applicability of polymer brushes to ASD uses going forward. PMID- 28671757 TI - Plasma lipids affect dabigatran etexilate anticoagulation in rats with unbalanced diabetes mellitus. AB - BACKGROUND: Dabigatran etexilate (DE) has similar stroke prevention efficacy in patients with and without diabetes mellitus (DM). However, the benefit of reducing major bleeding was not seen in diabetics. Thus, this study investigated anticoagulant responses to DE and the biological predictors of this response in a DM model. METHODS: Experiments were performed in six control (C), eight DE treated control (CD), five diabetic (D), and eight DE-treated diabetic (DD) rats. Dabigatran etexilate (50 mg/kg/day) was administered in chow for 12 weeks. At the end of the study, plasma glucose, triglycerides, total cholesterol (TC), high density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and plasma creatinine were measured. Correlations were ascertained with the diluted thrombin time (dTT). RESULTS: When corrected for similar DE intake, dTT was significantly higher in DD than CD rats (P < 0.001). There was a significant negative correlation between creatinine clearance (CCr) and dTT (r = -0.91, P < 0.01) in DD rats. In addition, dTT was positively correlated with TC (r = 0.96, P < 0.01), LDL-C (r = 0.75, P = 0.04), and glucose (r = 0.83, P = 0.02). In multiple regression analysis, CCr (r = -0.81, P = 0.01), TC (r = 0.93, P < 0.001), and LDL-C (r = 0.74, P < 0.01) remained the only independent predictors of dTT. CONCLUSIONS: The results show a significantly more intense DE-induced anticoagulation in diabetic rats that does not seem to be solely related to altered kidney function, and demonstrate that plasma cholesterol can significantly affect DE anticoagulation in this setting. PMID- 28671759 TI - Electroactive 3D Scaffolds Based on Silk Fibroin and Water-Borne Polyaniline for Skeletal Muscle Tissue Engineering. AB - Silk fibroin (SF) with good biocompatibility and degradability has great potential for tissue engineering. However, the SF based scaffolds lack the electroactivity to regulate the myogenic differentiation for the regeneration of muscle tissue, which is sensitive to electrical signal. Herein, a series of electroactive biodegradable scaffolds based on SF and water-soluble conductive poly(aniline-co-N-(4-sulfophenyl) aniline) (PASA) via a green method for skeletal muscle tissue engineering are designed. SF/PASA scaffolds are prepared by vortex of aqueous solution of SF and PASA under physiological condition. Murine-derived L929 fibroblast and C2C12 myoblast cells are used to evaluate cytotoxicity of SF/PASA scaffolds. Moreover, myogenic differentiation of C2C12 cells is investigated by analyzing the morphology of myotubes and related gene expression. These results suggest that electroactive SF/PASA scaffolds with a suitable microenvironment, which can enhance the myogenic differentiation of C2C12 cells, have a great potential for skeletal muscle regeneration. PMID- 28671758 TI - Comparison of mediastinal lymph node status and relapse pattern in clinical stage IIIA non-small cell lung cancer patients treated with neoadjuvant chemotherapy versus upfront surgery: A single center experience. AB - BACKGROUND: In spite of the progress made in neoadjuvant therapy for operable non small-cell lung cancer (NSCLC), many issues remain unsolved, especially in locally advanced stage IIIA. METHODS: Retrospective data of 163 patients diagnosed with stage IIIA NSCLC after surgery was analyzed. The patients were divided into two groups: a preoperative chemotherapy group including 59 patients who received platinum-etoposide doublet treatment before surgery, and an upfront surgery group including 104 patients for whom surgical resection was the first treatment step. Adjuvant chemotherapy or/and radiotherapy was administered to 139 patients (85.3%), while 24 patients (14.7%) were followed-up only. RESULTS: The rate of N2 disease was significantly higher in the upfront surgery group ( P < 0.001). The one-year relapse rate was 49.5% in the preoperative chemotherapy group compared to 65.4% in the upfront surgery group. There was a significant difference in relapse rate in relation to adjuvant chemotheraphy treatment ( P = 0.007). The probability of relapse was equal whether radiotherapy was applied or not ( P = 0.142). There was no statistically significant difference in two-year mortality ( P = 0.577). The median survival duration after two years of follow up was 19.6 months in the preoperative chemotherapy group versus 18.8 months in the upfront surgery group ( P = 0.608 > 0.05). CONCLUSION: There was significant difference in preoperative chemotherapy group regarding relapse rate and treatment outcomes related to the lymph node status comparing to the upfront surgery group. Neoadjuvant/adjuvant chemo-therapy is a part of treatment for patients with stage IIIA NSCLC, but further investigation is required to determine optimal treatment. PMID- 28671760 TI - Tuning the pH-Switch of Supramolecular Polymer Carriers for siRNA to Physiologically Relevant pH. AB - The preparation of histidine enriched dendritic peptide amphiphiles and their self-assembly into multicomponent pH-switchable supramolecular polymers is reported. Alternating histidine and phenylalanine peptide synthons allow the assembly/disassembly to be adjusted in a physiologically relevant range of pH 5.3 6.0. Coassembly of monomers equipped with dendritic tetraethylene glycol chains with monomers bearing peripheral primary amine groups leads to nanorods with a tunable cationic surface charge density. These surface functional supramolecular polycations are able to reversibly bind short interfering RNA (siRNA). The nanorod-like supramolecular polymers, their complexation with siRNA, and the pH triggered assembly/disassembly of the supramolecular carriers are characterized via circular dichroism spectroscopy, gel electrophoresis, as well as transmission electron microscopy. Multicomponent supramolecular polymers represent a modular and promising strategy for applications as responsive carrier vehicles, codelivery strategies, and gene therapy. PMID- 28671761 TI - Uptake of Retinoic Acid-Modified PMMA Nanoparticles in LX-2 and Liver Tissue by Raman Imaging and Intravital Microscopy. AB - A primary amino-functionalized methyl methacrylate-based statistical copolymer is covalently coupled with retinoic acid (RA) and a fluorescent dye (DY590) in order to investigate the feasibility of the RA containing polymeric nanoparticles for Raman imaging studies and to study the possible selectivity of RA for hepatic stellate cells via intravital microscopy. Cationic nanoparticles are prepared by utilizing the nanoprecipitation method using modified polymers. Raman studies show that RA functional nanoparticles can be detectable in all tested cells without any need of additional label. Moreover, intravital microscopy indicates that DY590 is eliminated through the hepatobiliary route but not if used as covalently attached tracing molecule for nanoparticles. However, it is a suitable probe for sensitive detection of polymeric nanoparticles. PMID- 28671762 TI - Aqueous-Phase Synthesis of Size-Tunable Copper Nanocubes for Efficient Aryl Alkyne Hydroboration. AB - Copper nanocubes with average sizes of 82, 95, and 108 nm have been synthesized in an aqueous mixture of cetyltrimethylammonium chloride (CTAC) surfactant, copper acetate, and sodium ascorbate reductant heated at 100 degrees C for 40 min. Copper nanowires with an average length of 25 MUm can also be prepared this way by simply increasing the volume of sodium ascorbate introduced. Small shifts in the plasmonic absorption band positions with tunable particle sizes have been observed. The copper nanocubes were employed to catalyze hydroboration of phenylacetylene and various substituted aryl alkynes with 100 % (E)-product selectivity and 82-95 % product yields. The copper nanocubes are cheap to make and should catalyze a broad scope of organic coupling reactions. PMID- 28671763 TI - Synthesis and Spatiotemporal Modification of Biocompatible and Stimuli-Responsive Carboxymethyl Cellulose Hydrogels Using Thiol-Norbornene Chemistry. AB - Carboxymethyl cellulose (CMC) is functionalized with norbornene groups to undergo thiol-norbornene cross-linking reactions. Hydrogels synthesized from a single norbornene-modified carboxymethyl cellulose (NorCMC) via a light-initiated thiol ene cross-linking reaction with a variety of dithiol cross-linkers yield hydrogels with a tunable compression modulus ranging from 1.7 to 103 kPa. Additionally, thermoresponsiveness is spatiotemporally imparted to NorCMC hydrogels by photopatterning a dithiol-terminated poly(N-isopropyl acrylamide) cross-linker, enabling swelling and topological control of the hydrogels as a function of incubation temperature. NorCMC hydrogels are cytocompatible as the viability of encapsulated human mesenchymal stem cells (hMSCs) is greater than 85% after 21 d while using a variety of cross-linkers. Moreover, hMSCs can remodel, adhere, and spread in the NorCMC matrix cross-linked with a matrix metalloproteinase-degradable peptide, further demonstrating the utility of these materials as a tunable biomaterial. PMID- 28671764 TI - The evaluation of non-invasive multi-slice spiral computed tomography-based indices for the diagnosis and prognosis prediction of liver cirrhosis. AB - OBJECTIVE: This study aimed to evaluate easily available computed tomography (CT) based parameters for assessing the presence and severity of cirrhosis and predicting complications in Chinese patients with cirrhosis. METHODS: CT-based morphological indices were determined in 167 patients with cirrhosis and 244 healthy volunteers. The correlation of morphological indices with Child-Pugh score and cirrhotic complications was analyzed using Spearman's correlation analysis. The area under the receiver operating characteristic curve (AUROC) was used to analyze the diagnostic performance of the indices. Sensitivity and specificity were determined. RESULTS: Patients with cirrhosis had a lower total liver volume (TLV) and a larger total splenic volume (SV) than healthy individuals. There was a significant difference in the portal venous diameter, splenic venous diameter and portal venous cross-sectional area between the two groups. A low TLV/SV ratio was strongly associated with liver cirrhosis; with a cut-off value of 4.27 for the diagnosis of cirrhosis TLV/SV had a sensitivity of 87.7% and a specificity of 84.9%, and AUROC of 0.921. Further analysis showed that TLV/SV was accurate in discriminating between mild and moderate/severe cirrhosis and could be used for predicting complications of cirrhosis. CONCLUSION: The easily available parameters of CT can accurately evaluate the severity of cirrhosis in Chinese patients. PMID- 28671765 TI - Guiding cellular activity with polarized light. AB - Actin, cytoskeleton protein forming microfilaments, play a crucial role in cellular motility. Here we show that exposure to very low levels of polarized light guide their orientation in-vivo within the live cell. Using a simple model to describe the role of actin-filament orientation in directional cellular motion, we demonstrate that the actin polymerization/depolymerization mechanism develops primarily along this direction and, under certain conditions, can lead to guidance of the cell movement. Our results also show a dose dependent increase in actin activity in direct correspondence to the level of laser irradiance. We found that total expression of Tau protein, which stabilize microtubules, was decreased by the irradiance, indicating that exposure to the light may change the activity of kinase, leading to increased cell activity. PMID- 28671766 TI - Mechanically Robust Electrospun Hydrogel Scaffolds Crosslinked via Supramolecular Interactions. AB - One of the major challenges in the processing of hydrogels based on poly(ethylene glycol) (PEG) is to create mechanically robust electrospun hydrogel scaffolds without chemical crosslinking postprocessing. In this study, this is achieved by the introduction of physical crosslinks in the form of supramolecular hydrogen bonding ureido-pyrimidinone (UPy) moieties, resulting in chain-extended UPy-PEG polymers (CE-UPy-PEG) that can be electrospun from organic solvent. The resultant fibrous meshes are swollen in contact with water and form mechanically stable, elastic hydrogels, while the fibrous morphology remains intact. Mixing up to 30 wt% gelatin with these CE-UPy-PEG polymers introduce bioactivity into these scaffolds, without affecting the mechanical properties. Manipulating the electrospinning parameters results in meshes with either small or large fiber diameters, i.e., 0.63 +/- 0.36 and 2.14 +/- 0.63 um, respectively. In that order, these meshes provide support for renal epithelial monolayer formation or a niche for the culture of cardiac progenitor cells. PMID- 28671767 TI - Emergence of Gold-Mesoporous Silica Hybrid Nanotheranostics: Dox-Encoded, Folate Targeted Chemotherapy with Modulation of SERS Fingerprinting for Apoptosis Toward Tumor Eradication. AB - Strategically fabricated theranostic nanocarrier delivery system is an unmet need in personalized medicine. Herein, this study reports a versatile folate receptor (FR) targeted nanoenvelope delivery system (TNEDS) fabricated with gold core silica shell followed by chitosan-folic acid conjugate surface functionalization by for precise loading of doxorubicin (Dox), resembled as Au@SiO2 -Dox-CS-FA. TNEDS possesses up to 90% Dox loading efficiency and internalized through endocytosis pathway leading to pH and redox-sensitive release kinetics. The superior FR-targeted cytotoxicity is evaluated by the nanocarrier in comparison with US Food and Drug Administration (FDA)-approved liposomal Dox conjugate, Lipodox. Moreover, TNEDS exhibits theranostic features through caspase-mediated apoptosis and envisages high surface plasmon resonance enabling the nanoconstruct as a promising surface enhanced Raman scattering (SERS) nanotag. Minuscule changes in the biochemical components inside cells exerted by the TNEDS along with the Dox release are evaluated explicitly in a time-dependent fashion using bimodal SERS/fluorescence nanoprobe. Finally, TNEDS displays superior antitumor response in FR-positive ascites as well as solid tumor syngraft mouse models. Therefore, this futuristic TNEDS is expected to be a potential alternative as a clinically relevant theranostic nanomedicine to effectively combat neoplasia. PMID- 28671768 TI - Time-Controllable Lipophilic-Drug Release System Designed by Loading Lipid Nanoparticles into Polysaccharide Hydrogels. AB - A hybrid hydrogel composed of solid lipid nanoparticles (LNPs) entrapped within chemically cross-linked carboxymethylcellulose (CMC) is developed to achieve localized and sustained release of lipophilic drugs. The analysis of LNP stability as well as the hydrogel swelling and mechanical properties confirm the successful incorporation of particles up to a concentration of 50% w/wCMC . The initial LNP release rate can be prolonged by increasing the particle diameter from 50 to 120 nm, while the amount of long-term release can be adjusted by tailoring the particle surface charge or the cross-linking density of the polymer. After 30 d, 58% of 50 nm diameter negatively charged LNPs escape from the matrix while only 17% of positively charged nanoparticles are released from materials with intermediate cross-linking density. A mathematical diffusion model based on Fick's second law is efficient to predict the diffusion of the particles from the hydrogels. PMID- 28671769 TI - Chronic coffee consumption and respiratory disease: A systematic review. AB - PURPOSE: The widespread consumption of coffee means that any biological effects from its use can lead to significant public health consequences. Chronic pulmonary diseases are extremely prevalent and responsible for one of every six deaths on a global level. METHODS: Major medical databases for studies reporting on the effects of coffee or caffeine consumption on a wide range of non-malignant respiratory outcomes, including incidence, prevalence, evolution or severity of respiratory disease in adults were searched. Studies on lung function and respiratory mortality were also considered. RESULTS: Fifteen studies, including seven cohort, six cross-sectional, one case control and one randomized control trial were found. Coffee consumption was generally associated with a reduction in prevalence of asthma. The association of coffee with natural honey was an effective treatment for persistent post-infectious cough. One case-control study found higher risk of chronic obstructive pulmonary disease (COPD) with coffee consumption. No association was found with the evolution of COPD or sarcoidosis. Coffee was associated with a reduction in respiratory mortality, and one study found improved lung function in coffee consumers. Smoking was a significant confounder in most studies. CONCLUSIONS: Coffee consumption was associated with some positive effects on the respiratory system. There was however limited available evidence, mostly from cross sectional and retrospective studies. The only prospective cohort studies were those reporting on respiratory mortality. These results suggest that coffee consumption may be a part of a healthy lifestyle leading to reduced respiratory morbidity. PMID- 28671770 TI - Clinical outcomes of patients with resectable pancreatic acinar cell carcinoma. AB - OBJECTIVE: Given the rarity of the disease, the post-resection clinical course of localized pancreatic acinar cell carcinoma (ACC) is largely unknown. Therefore, we aimed to analyze the outcomes of patients with localized pancreatic ACC who underwent curative surgical resection. METHODS: We retrospectively analyzed the outcomes of 20 patients with resectable pancreatic ACC who underwent surgery. RESULTS: Altogether 20 patients were included in the study, with a median age of 57 years and a male predominance. There were eight pure ACC, 10 mixed acinar neuroendocrine carcinomas and two mixed acinar-ductal adenocarcinomas. Among the 15 patients who were staged histologically, 3, 8 and 4 were at stages IB, IIA and IIB, respectively. Eleven patients received adjuvant chemotherapy (5-fluorouracil based [n = 9]; gemcitabine [n = 1]; etoposide plus cisplatin [n = 1]). In a median follow-up period of 27.1 months, disease recurred in 10 patients, most commonly in the liver (90%). Median recurrence-free survival and overall survival were 16.9 months and 75.0 months, respectively. Elevation of cancer antigen 19-9 (CA19-9), lymph node metastasis and neural invasion were significantly associated with poor overall survival (P = 0.007, P = 0.027 and P = 0.016, respectively). CONCLUSIONS: Compared with ductal adenocarcinoma, resectable pancreatic ACC has a favorable prognosis after surgery. Considering that distant metastasis is the most common pattern of recurrence, further studies are necessary to define the role of adjuvant chemotherapy for improving survival outcomes. PMID- 28671771 TI - Synthetic alienation of microbial organisms by using genetic code engineering: Why and how? AB - The main goal of synthetic biology (SB) is the creation of biodiversity applicable for biotechnological needs, while xenobiology (XB) aims to expand the framework of natural chemistries with the non-natural building blocks in living cells to accomplish artificial biodiversity. Protein and proteome engineering, which overcome limitation of the canonical amino acid repertoire of 20 (+2) prescribed by the genetic code by using non-canonic amino acids (ncAAs), is one of the main focuses of XB research. Ideally, estranging the genetic code from its current form via systematic introduction of ncAAs should enable the development of bio-containment mechanisms in synthetic cells potentially endowing them with a "genetic firewall" i.e. orthogonality which prevents genetic information transfer to natural systems. Despite rapid progress over the past two decades, it is not yet possible to completely alienate an organism that would use and maintain different genetic code associations permanently. In order to engineer robust bio contained life forms, the chemical logic behind the amino acid repertoire establishment should be considered. Starting from recent proposal of Hartman and Smith about the genetic code establishment in the RNA world, here the authors mapped possible biotechnological invasion points for engineering of bio-contained synthetic cells equipped with non-canonical functionalities. PMID- 28671772 TI - Multiplexed Nucleic Acid Hybridization Assays Using Single-FRET-Pair Distance Tuning. PMID- 28671773 TI - ? PMID- 28671774 TI - [Management of suspected meningitis in the emergency department]. AB - Febrile meningeal syndrome is a medical emergency. Lumbar puncture keeps its gold standard status as clinical findings are neither sensitive nor specific enough. Antibiotics and steroids are ideally administered within the first 30 minutes after admission when bacterial meningitis is suspected. A cerebral CT-scan before lumbar puncture is mandatory for selected patients only. PCR for viruses in the cerebrospinal fluid can inform diagnosis and treatment. Meningitis caused by enterovirus can usually be managed at home. PMID- 28671775 TI - [Biliary infections : cholecystitis and cholangitis]. AB - Biliary infections are a common cause of emergency department visit, usually of benign evolution but that can sometimes progress rapidly to a life-threatening emergency.The mainstay of treatment of acute cholecystitis is urgent laparoscopic cholecystectomy, performed in 72 hours.Antibiotic treatment is often sufficient for the initial treatment of mild cholangitis. A percutaneous or endoscopic biliary drainage must be done urgently in case of severe presentations or if the patient doesn't respond to conservative treatment. The definitive treatment of the cause of cholangitis, will be performed in a second time. PMID- 28671776 TI - [Initial management of febrile neutropenia]. AB - Despite major advances in prevention and treatment, febrile neutropenia remains one of the most concerning complications of cancer chemotherapy. Its prognosis depends directly on the quality of the initial management in the emergency department (ED). An initial assessment of circulatory and respiratory function, with vigorous resuscitation where necessary, should be followed by careful examination for potential source of infection. A broad-spectrum empirical antibacterial therapy should be given in a timespan < 1 hour. Multinational Association for Supportive Care in Cancer (MASCC) criteria were developed to help physicians make decisions about the site of care and overall management of these patients. PMID- 28671777 TI - [Cutaneous infections in the emergency department : the devil in the detail]. AB - Skin and soft tissue infections, which are a common cause of admission, are characterized by a clinical polymorphism leading to diagnostic errors. To a certain point, confusion exists between used terms and indicated treatment, especially since the emergence of methicillin-resistant Staphylococcus aureus (MRSA) infections.The paucity of cutaneous findings early in the course of deep soft tissue infections makes diagnosis challenging for physicians in charge. Some of these infections are warranted to achieve a lower mortality and morbidity by the administration of effective surgical treatment. PMID- 28671778 TI - [Emergency medicine and prevention : a contradiction in terms ? Observations based on HIV screening]. AB - In Switzerland, a fifth of people with HIV are unaware of their status and 50 % are diagnosed late (< 350 CD4 / ul). Yet, in the years prior to diagnosis, these patients have often presented to the emergency department (ED) with problems related, or not, to HIV infection, presenting missed opportunities for earlier diagnosis. The current FOPH recommendations assume that doctors can recognise HIV indicator diseases, and patients from high-risk groups, and offer an HIV test (targeted screening). Studies conducted at Lausanne University Hospital ED report that most doctors are unfamiliar with the FOPH recommendations and that HIV screening occurs in only 1 % of patients seen. This review discusses the logic of non-targeted screening in the context of the UNAIDS 2016-2021 strategy to end the AIDS epidemic by 2030. PMID- 28671779 TI - [Sexually transmitted infections in emergency setting]. AB - The emergency room is a stressful environment with poor privacy. Even so, sexually transmitted infections (STIs) need to be handled in such a setting. Some STIs can hide behind common clinical pictures. Signs and symptoms of acute retroviral syndrome, other STIs as well as the initiation of postexposure prophylaxis (PEP) need to be known and managed by an emergency physician and are discussed in this article. PMID- 28671780 TI - ? PMID- 28671781 TI - ? PMID- 28671782 TI - ? PMID- 28671783 TI - ? PMID- 28671784 TI - ? PMID- 28671785 TI - ? PMID- 28671786 TI - ? PMID- 28671787 TI - ? PMID- 28671788 TI - [Therapeutic news in infective endocarditis]. AB - The European recommendations for the management of infective endocarditis have been updated in 2015. The therapeutic modalities depend on both a better prevention in high-risk population, a faster diagnosis through new approaches in medical imaging, and interdisciplinary collaboration by an " endocarditis team. " Treatment involves antimicrobial therapy which can be complex, initially empirical and then targeted, depending on local infectious epidemiology, and whether the infringement affects a native or a prosthetic valve. The surgical indications are identified in the individual patient, based on the response to medical therapy, on complications (heart failure, uncontrolled infection and prevention of embolic events) the germ, the type of valve involved, and of course an integration with the patient's comorbidities. PMID- 28671789 TI - [Esophago-gastric complications after ablation in atrial fibrillation]. AB - Atrial-esophageal fistula (AOF) after ablation in atrial fibrillation has a fatal outcome. Fully documented in 2004, AOF has never completely disappeared despite technological evolvements. Survival depends on early recognition and treatment. Gastroscopy allows early detection of esophageal lesions. We summarize here AOF mechanisms, evoking symptoms and treatment ; contribution of gastroscopy in early detection ; and finally symptoms from vagal and phrenic nerve injuries. This information is useful for emergency doctors, gastroenterologists / endoscopists, and general practitioners. PMID- 28671790 TI - [Update in HIV therapy: tenofovir alafenamide]. AB - Since the first treatments against human immunodeficiency virus (HIV) have appeared in 1987, important progress has been accomplished. Twenty-four molecules are currently available but only some of them are in common use on account of their easy administration or their weak adverse effects. Tenofovir disoproxil fumarate (TDF) is a commonly used nucleoside reverse-transcriptase inhibitor (NRTI) of HIV. However, taking TDF is sometimes associated with renal toxicity and increased bone demineralization. Tenofovir alafenamide (TAF) is a new prodrug of tenofovir (TFV) whose security profile is more interesting as far as renal and bone complications are concerned, due to a much lower serum concentration and a high intracellular concentration. PMID- 28671791 TI - [Cardiovascular protection of patients with type 2 diabetes : from EMPA-REG OUTCOME to LEADER]. AB - Two clinical trials demonstrate the superiority versus a placebo of two antidiabetic drugs in patients with type 2 diabetes and high cardiovascular risk. Empagliflozin, an inhibitor of sodium-glucose type 2 (SGLT2) cotransporters, in EMPA-REG OUTCOME, and liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) receptors, in LEADER, showed a significant reduction in major cardiovascular events (- 14 and - 13 %, respectively), cardiovascular mortality (- 38 and - 22 %, respectively) and all-cause mortality (- 32 and - 15 %, respectively). A lower progression of kidney disease and less renal events were also reported. The underlying protective mechanisms remain controverted as the discussion whether the benefits are specific to each medication or could be extended to other molecules of these two pharmacological classes. PMID- 28671792 TI - [Comparative efficacy of three bariatric surgery procedures in obese patients with type 2 diabetes]. AB - This retrospective work compares the efficacy of three procedures of bariatric surgery in obese patients with type 2 diabetes : gastric bypass (n = 22), sleeve gastrectomy (n = 18) and Magenstrasse & Mill gastroplasty (also known as reversible sleeve (n = 19). The three interventions result in a remarkable weight loss after one year, a better glycaemic control, with often a remission of diabetes, a reduction of blood pressure and an improvement of lipid profile, allowing an interruption or a dose reduction of concomitant medications. Overall, classical sleeve provides almost similar results as gastric bypass and appears slightly better than reversible sleeve. These results deserve confirmation in studies with more patients followed for a longer term. PMID- 28671793 TI - [Gliptin-gliflozin combination for treating type 2 diabetes]. AB - Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycaemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach because the two drugs exert different and potentially complementary glucose-lowering effects. Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. Combining the two pharmacological options is safe and does not induce hypoglycaemia. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. PMID- 28671794 TI - [Pulmonary lymphangioleimyomatosis : review and case report]. AB - Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease, occurring in women of childbearing age, that can occur sporadically (S-LAM) or can be associated with tuberous sclerosis complex (TSC-LAM), an inherited neurocutaneous disorder. This article is illustrated by a case report. We then review clinical manifestations, diagnostic tools, and treatment of this disease. LAM should be considered in young women who present with dyspnea on exertion and/or spontaneous pneumothorax, with typical cystic lesions on high-resolution chest CT. PMID- 28671795 TI - ? PMID- 28671796 TI - ? PMID- 28671797 TI - ? PMID- 28671798 TI - ? PMID- 28671799 TI - ? PMID- 28671800 TI - ? PMID- 28671803 TI - Valvular Heart Disease in Adults: Foreword. PMID- 28671804 TI - Valvular Heart Disease in Adults: Etiologies, Classification, and Diagnosis. AB - The prevalence of valvular heart disease (VHD) in the United States was estimated to be approximately 2.5% in the 1990s. The prevalence currently is thought to be increasing because of more accurate diagnostic methods and aging of the population. Mitral regurgitation (MR) is the most common valve defect, followed by aortic stenosis (AS) and aortic regurgitation (AR). Degenerative disease is the most common etiology of MR, AS, and AR, though these forms of VHD also can be caused by congenital valve defects, systemic inflammatory diseases, endocarditis, and many other conditions. Mitral stenosis, most often caused by rheumatic fever, is uncommon in the United States. When VHD is suspected, transthoracic echocardiography should be obtained first. Other tests, including transesophageal echocardiography, computed tomography scan, magnetic resonance imaging study, and cardiac catheterization, are used in special situations to obtain more detailed diagnostic information. Guidelines for VHD management recommend interval monitoring with echocardiography. The exact interval recommended depends on the severity of the valve dysfunction and whether the patient is symptomatic. Monitoring of asymptomatic patients is important because early intervention, when valve function worsens or symptoms develop, is associated with better outcomes. PMID- 28671805 TI - Valvular Heart Disease in Adults: Management of Native Valve Disease. AB - Patients with valvular heart disease (VHD) should be treated for diabetes, hypertension, and hyperlipidemia. They also should receive therapy for left ventricular dysfunction, undergo interval echocardiography, and participate in aerobic exercise. Valve replacement should be considered for patients with aortic stenosis (AS) and syncope, presyncope, heart failure, angina, or severe AS with left ventricular dysfunction. Valve replacement is performed with open or transcatheter procedures; the latter are preferred for patients with high surgical risk. Patients with chronic aortic regurgitation (AR) should undergo open surgical replacement if they are symptomatic or are asymptomatic but have severe regurgitation and left ventricular dysfunction. No transcatheter procedures currently are approved for AR. Patients with mitral stenosis (MS) should receive drugs for heart rate control and anticoagulation if they have atrial fibrillation. Invasive treatment involves valve replacement or percutaneous commissurotomy. Management of severe chronic mitral regurgitation consists of valve replacement or, for patients with high surgical risk, a percutaneous transcatheter procedure that clips the mitral leaflets together. When severe, tricuspid regurgitation can be managed with valve replacement. Pregnant patients with VHD require special management. Women with severe AS or MS should avoid becoming pregnant until VHD is managed definitively. PMID- 28671806 TI - Valvular Heart Disease in Adults: Management of Prosthetic Heart Valves. AB - Patients undergoing cardiac valve replacement may receive mechanical or bioprosthetic valves. Mechanical valves require lifelong anticoagulation but are durable and the need for a second surgery is up to eightfold times less than with bioprosthetic valves. Bioprosthetic valves do not require lifelong anticoagulation and thus are associated with fewer bleeding complications but they are less durable and associated with higher morbidity and mortality rates, particularly in younger patients. Anticoagulation with mechanical valves is achieved using warfarin; use of direct-acting oral anticoagulants is not indicated. Concomitant low-dose aspirin is recommended for patients with mechanical valves and as sole thromboembolism prophylaxis for patients receiving aortic or mitral bioprosthetic valves. If a patient taking warfarin is to undergo a surgical procedure that requires interruption of anticoagulation, bridging therapy with heparin is indicated if the patient has a mechanical aortic valve and any risk of thromboembolism, an older-generation mechanical aortic valve, or a mechanical mitral valve. Warfarin is teratogenic; pregnant women should take heparin. Patients with mechanical or bioprosthetic valves should receive antibiotic prophylaxis before some dental and surgical procedures to prevent endocarditis. Thrombolytic therapy should be considered in patients who develop a thrombus on a valve that does not resolve with heparin. PMID- 28671807 TI - Valvular Heart Disease in Adults: Infective Endocarditis. AB - A variety of microorganisms can cause infective endocarditis (IE) in patients with native valves. Staphylococci and streptococci are most common in community acquired IE; staphylococci are most common in nosocomial IE. Microbiology of prosthetic valve endocarditis (PVE) depends on timing. Early-onset PVE (ie, 60 days or fewer postsurgery) typically is nosocomial, with Staphylococcus aureus infection being most common. Intermediate-onset PVE (ie, 60 to 365 days postsurgery) typically involves a mix of nosocomial and non-nosocomial organisms. PVE that develops more than 1 year after surgery has microbiology similar to that of native valve endocarditis. Fever is the most common symptom; others include dyspnea, pleuritic pain, anorexia, and myalgias. The Modified Duke Criteria is the standard for diagnosis, with blood cultures being the most important test. If patients are in stable condition, three sets of blood cultures should be obtained more than 6 hours apart and from separate sites before starting antibiotics. Echocardiography aids in diagnosis and can identify conditions best managed with surgery. For empiric therapy for native valve IE, most patients should receive vancomycin. For PVE, vancomycin and gentamicin should be prescribed, plus cefepime or an antipseudomonal carbapenem. Treatment typically continues for 6 weeks after blood culture results are negative. PMID- 28671808 TI - Enhanced Nonenzymatic Glucose-Sensing Properties of Electrodeposited NiCo2O4-Pd Nanosheets: Experimental and DFT Investigations. AB - Here, we report the facile synthesis of NiCo2O4 (NCO) and NiCo2O4-Pd (NCO-Pd) nanosheets by the electrodeposition method. We observed enhanced glucose-sensing performance of NCO-Pd nanosheets as compared to bare NCO nanosheets. The sensitivity of the pure NCO nanosheets is 27.5 MUA MUM-1 cm-2, whereas NCO-Pd nanosheets exhibit sensitivity of 40.03 MUA MUM-1 cm-2. Density functional theory simulations have been performed to qualitatively support our experimental observations by investigating the interactions and charge-transfer mechanism of glucose on NiCo2O4 and Pd-doped NiCo2O4 through demonstration of partial density of states and charge density distributions. The presence of occupied and unoccupied density of states near the Fermi level implies that both Ni and Co ions in NiCo2O4 can act as communicating media to transfer the charge from glucose by participating in the redox reactions. The higher binding energy of glucose and more charge transfer from glucose to Pd-doped NiCo2O4 compared with bare NiCo2O4 infer that Pd-doped NiCo2O4 possesses superior charge-transfer kinetics, which supports the higher glucose-sensing performance. PMID- 28671809 TI - AlN/ITO-Based Hybrid Electrodes with Conducting Filaments: Their Application to Ultraviolet Light-Emitting Diodes. AB - A hybrid-type transparent conductive electrode (H-TCE) structure comprising an AlN rod array with conducting filaments (CFs) and indium tin oxide (ITO) films is proposed to improve both current injection and distribution as well as optical transmittance in the UV region. These CFs, generated in UV-transparent AlN rod areas using an electric field, can be used as conducting paths for carrier injection from a metal to a semiconductor such as p-(Al)GaN, which allows perfect Ohmic behavior with high transmittance (>95% at 365 nm) to be obtained. In addition, conduction across AlN rods and Ohmic conduction mechanisms are investigated by analyzing AlN rods and AlN rod/p-AlGaN film interfaces. We apply these H-TCEs to three near-UV light-emitting diodes (LEDs) (385 nm LEDs with p GaN and p-AlGaN terminated surfaces and 365 nm LED with p-AlGaN terminated surface). We confirm that the light power outputs increase by 66%, 79%, and 103%, whereas the forward voltages reduce by 5.6%, 10.2%, and 8.6% for 385 nm p-GaN terminated, 385 nm p-AlGaN terminated, and 365 nm p-AlGaN terminated LEDs with H TCEs, respectively, compared to LEDs with reference ITOs. PMID- 28671810 TI - Three-Dimensional Plasmonic Nanostructure Design for Boosting Photoelectrochemical Activity. AB - Plasmonic nanostructures have been widely incorporated into different semiconductor materials to improve solar energy conversion. An important point is how to manipulate the incident light so that more light can be efficiently scattered and absorbed within the semiconductors. Here, by using a tunable three dimensional Au pillar/truncated-pyramid (PTP) array as a plasmonic coupler, a superior optical absorption of about 95% within a wide wavelength range is demonstrated from an assembled CdS/Au PTP photoanode. Based on incident photon to current efficiency measurements and the corresponding finite difference time domain simulations, it is concluded that the enhancement is mainly attributed to an appropriate spectral complementation between surface plasmon resonance modes and photonic modes in the Au PTP structure over the operational spectrum. Because both of them are wavelength-dependent, the Au PTP profile and CdS thickness are further adjusted to take full advantage of the complementary effect, and subsequently, an angle-independent photocurrent with an enhancement of about 400% was obtained. The designed plasmonic PTP nanostructure of Au is highly robust, and it could be easily extended to other plasmonic metals equipped with semiconductor thin films for photovoltaic and photoelectrochemical cells. PMID- 28671811 TI - Functional Organophosphonate Interfaces for Nanotechnology: A Review. AB - Optimization of interfaces in inorganic-organic device systems depends strongly on understanding both the molecular processes that are involved in surface modification and the effects that such modifications have on the electronic states of the material. In particular, the last several years have seen passivation and functionalization of semiconductor surfaces to be strategies by which to realize devices with superior function by controlling Fermi level energies, band-gap magnitudes, and work functions of semiconducting substrates. Among all of the synthetic routes and deposition methods available for the optimization of functional interfaces in hybrid systems, organophosphonate chemistry has been found to be a powerful tool to control at the molecular level the properties of materials in many different applications. In this Review, we focus on the relevance of organophosphonate chemistry in nanotechnology, giving an overview about some recent advances in surface modification, interface engineering, nanostructure optimization, and biointegration. PMID- 28671812 TI - Large-Scale Nanofabrication of Designed Nanostructures Using Angled Nanospherical Lens Lithography for Surface Enhanced Infrared Absorption Spectroscopy. AB - Nanophotonics has been a focused research discipline for the past decade and has resulted in many novel concepts that promise to change human life. However, the actual penetration of this research into real products is severely limited mostly due to the slow development of economic nanofabrication. In this study, we have demonstrated a versatile and low-cost nanofabrication method referred to as "angled nanospherical-lens lithography (A-NLL)", which is able to produce large scale and periodic nanopatterns. The nanopatterns designed within a two dimensional polar chart can be carefully fabricated on the substrate. The fabricated patterns easily cover an area larger than 1 cm2, which is beneficial as platforms for surface enhanced infrared absorption (SEIRA) where an expensive and bulky IR microscope is not required. We believe that the proposed A-NLL method is ideal for industrialization of future nanophotonic applications. PMID- 28671813 TI - Self-Powered Acceleration Sensor Based on Liquid Metal Triboelectric Nanogenerator for Vibration Monitoring. AB - An acceleration sensor is an essential component of the vibration measurement, while the passivity and sensitivity are the pivotal features for its application. Here, we report a self-powered and highly sensitive acceleration sensor based on a triboelectric nanogenerator composed of a liquid metal mercury droplet (LMMD) and nanofiber-networked polyvinylidene fluoride (nn-PVDF) film. Due to the ultrahigh surface-to-volume ratio of nn-PVDF film and high surface tension, high mass density, high elastic as well as mechanical robustness of LMMD, the open circuit voltage and short-circuit current reach up to 15.5 V and 300 nA at the acceleration of 60 m/s2, respectively. The acceleration sensor has a wide detection range from 0 to 60 m/s2 with a high sensitivity of 0.26 V.s/m2. Also, the output voltage and current show a negligible decrease over 200,000 cycles, evidently presenting excellent stability. Moreover, a high-speed camera was employed to dynamically capture the motion state of the acceleration sensor for insight into the corresponding work mechanism. Finally, the acceleration sensor was demonstrated to measure the vibration of mechanical equipment and human motion in real time, which has potential applications in equipment vibration monitoring and troubleshooting. PMID- 28671814 TI - Preparation and Gas Permeation Properties of Fluorine-Silica Membranes with Controlled Amorphous Silica Structures: Effect of Fluorine Source and Calcination Temperature on Network Size. AB - Triethoxyfluorosilane (TEFS), which is a pendant-type alkoxysilane with a Si-F bond, was utilized for the development of a molecular sieving membrane. The effect that a source of fluorine and calcination temperature exerted on gas permeation properties and network pore size was evaluated via single-gas permeation properties across a wide range of temperatures. A TEFS membrane calcined at 350 degrees C showed high H2 permeance (2.0 * 10-6 mol m-2 s-1 Pa-1) and high selectivity for H2 over larger molecules (H2/CF4: >300; H2/SF6: >18 000), indicating that this network pore size would be suitable for a H2 permselective membrane that could promote the process of methylcyclohexane (MCH) dehydrogenation to produce toluene (TOL). Based on the gas permeation properties and the results of XPS and FTIR, network pore size depended on the fluorine concentration incorporated in SiO2 that existed as Si-F bonds, irrespective of the fluorine source. A TEFS membrane showed approximately the same pore size distribution and level of gas permeance, irrespective of calcination temperature (350 and 550 degrees C), due to the low Si-OH density in the networks as suggested by the result of FTIR, which can prevent the densification caused by the condensation of Si-OH groups. The pair distribution function also suggested that densification of the network structure for TEFS was apparently suppressed compared with that of a tetraethoxysilane (TEOS)-derived structure. PMID- 28671815 TI - Organic and Polymeric Semiconductors Enhanced by Noncovalent Conformational Locks. AB - Constructing highly planar, extended pi-electron systems is an important strategy for achieving high-mobility organic semiconductors. In general, there are two synthetic strategies for achieving pi-conjugated systems with high planarity. The conventional strategy connects neighboring aromatic rings through covalent bonds to restrict the rotation about single bonds. However, this usually requires a complex sequence of synthetic steps to achieve this target, which can be costly and labor-intensive. More recently, noncovalent through-space intramolecular interactions, which are defined here as noncovalent conformational locks, have been employed with great success to increase the planarity and rigidity of extended pi-electron systems; this has become a well-known and important strategy to design and synthesize highly planar pi-conjugated systems for organic electronics. This review offers a comprehensive and general summary of conjugated systems with such noncovalent conformational locks, including O...S, N...S, X...S (where X = Cl, Br, F), and H...S through-space interactions, together with analysis by density functional theory computation, X-ray diffraction, and microstructural characterization, as well as by evaluation of charge transport in organic thin-film transistors and solar cells. PMID- 28671816 TI - Photopolymerizable Zwitterionic Polymer Patterns Control Cell Adhesion and Guide Neural Growth. AB - Developing materials that reduce or eliminate fibrosis encapsulation of neural prosthetic implants could significantly enhance implant fidelity by improving the tissue/electrode array interface. Here, we report on the photografting and patterning of two zwitterionic materials, sulfobetaine methacrylate (SBMA) and carboxybetaine methacrylate (CBMA), for controlling the adhesion and directionality of cells relevant to neural prosthetics. CBMA and SBMA polymers were photopolymerized and grafted on glass surfaces then characterized by X-ray photoelectron spectroscopy, water contact angle, and protein adsorption. Micropatterned surfaces were fabricated with alternating zwitterionic and uncoated bands. Fibroblasts, cells prevalent in fibrotic tissue, almost exclusively migrate and grow on uncoated bands with little to no cells present on zwitterionic bands, especially for CBMA-coated surfaces. Astrocytes and Schwann cells showed similarly low levels of cell adhesion and morphology changes when cultured on zwitterionic surfaces. Additionally, Schwann cells and inner ear spiral ganglion neuron neurites aligned well to zwitterionic patterns. PMID- 28671817 TI - Spectrally Resolved Super-Resolution Microscopy Unveils Multipath Reaction Pathways of Single Spiropyran Molecules. AB - By recording both the images and emission spectra of thousands of single fluorescent molecules stochastically generated from the ring-opening reaction of a spiropyran, we provide mechanistic insights into its multipath reaction pathways. Through statistics of the measured single-molecule spectra, we identify two spectrally distinct isomers, presumably TTC and TTT cis-trans isomers, for the open-ring merocyanine product, and discover a strong solvent polarity dependence for the relative population of the two isomers. From single-molecule spectral time traces, we further examine isomerization between the two product merocyanine isomers, as well as their ring-closure reaction back to the spiropyran form. PMID- 28671818 TI - An "EAR" on Environmental Surveillance and Monitoring: A Case Study on the Use of Exposure-Activity Ratios (EARs) to Prioritize Sites, Chemicals, and Bioactivities of Concern in Great Lakes Waters. AB - Current environmental monitoring approaches focus primarily on chemical occurrence. However, based on concentration alone, it can be difficult to identify which compounds may be of toxicological concern and should be prioritized for further monitoring, in-depth testing, or management. This can be problematic because toxicological characterization is lacking for many emerging contaminants. New sources of high-throughput screening (HTS) data, such as the ToxCast database, which contains information for over 9000 compounds screened through up to 1100 bioassays, are now available. Integrated analysis of chemical occurrence data with HTS data offers new opportunities to prioritize chemicals, sites, or biological effects for further investigation based on concentrations detected in the environment linked to relative potencies in pathway-based bioassays. As a case study, chemical occurrence data from a 2012 study in the Great Lakes Basin along with the ToxCast effects database were used to calculate exposure-activity ratios (EARs) as a prioritization tool. Technical considerations of data processing and use of the ToxCast database are presented and discussed. EAR prioritization identified multiple sites, biological pathways, and chemicals that warrant further investigation. Prioritized bioactivities from the EAR analysis were linked to discrete adverse outcome pathways to identify potential adverse outcomes and biomarkers for use in subsequent monitoring efforts. PMID- 28671820 TI - Slow Magnetic Relaxation in One-Dimensional Azido-Bridged CoII Complexes. AB - Crystal structures and magnetic properties of three one-dimensional (1D) azido bridged cobalt(II) chains with different amide ligands (L), [Co2(N3)4(DMF)3] (1), [Co4(N3)8(DEF)5] (2), and [Co2(N3)4(DIPF)2] (3) (DMF = N,N-dimethylformamide, DEF = N,N-diethylformamide, and DIPF = N,N-diisopropylformamide), are reported to investigate the influence of L on their structures and magnetic properties. Single-crystal X-ray crystallographic analysis revealed that, although 1-3 all consist of cobalt chains bridged by end-on (EO) azides, the coordination geometry of the CoII ions and the repeating units of the 1D structures are quite different. As the size of L increases, the ratio of L to CoII decreases from 6:4 in 1 to 5:4 and 4:4 in 2 and 3, respectively. In 1, two [CoN5O1] and two [CoN4O2] distorted octahedra form the {[CoN5O1][CoN4O2]2[CoN5O1]} tetramers (denoted as Co4A), which are linked to each other by sharing the N-N edge to form the chain. Similarly, the chain structure of 3 is constructed from a similar tetramer unit {[CoN5][CoN4O2]2[CoN5]} (denoted as Co4B), where half of the CoII centers are in the [CoN5] trigonal bipyramid because of the larger steric effect of the DIPF ligand, while, for compound 2 of the medium-sized amide, it has the transition structure between those of 1 and 3. The chain is composed of two different repeating units: Co4A unit similar to that in 1 and Co4B unit similar to that in 3. Because of their similar structures, compounds 1-3 exhibit analogical magnetic properties. Direct-current magnetic measurements demonstrated that all compounds show intrachain ferromagnetic coupling through the EO azides and interchain anti ferromagnetic interactions. Alternating-current data revealed the slow magnetic relaxation in the anti-ferromagnetic ordered phases. While compound 1 exhibits spin glass behavior, compounds 2 and 3 behave as the single-chain magnets. This difference might come from the interference of the anti-ferromagnetic ordering on the magnetic dynamic of the magnetic chain. PMID- 28671819 TI - Efficient Reduction of Vertebrate Cytoglobins by the Cytochrome b5/Cytochrome b5 Reductase/NADH System. AB - Cytoglobin is a heme-containing protein ubiquitous in mammalian tissues. Unlike the evolutionarily related proteins hemoglobin and myoglobin, cytoglobin shows a six-coordinated heme binding, with the heme iron coordinated by two histidine side chains. Cytoglobin is involved in cytoprotection pathways through yet undefined mechanisms, and it has recently been demonstrated that cytoglobin has redox signaling properties via nitric oxide (NO) and nitrite metabolism. The reduced, ferrous cytoglobin can bind oxygen and will react with NO in a dioxygenation reaction to form nitrate, which dampens NO signaling. When deoxygenated, cytoglobin can bind nitrite and reduce it to NO. This oxidoreductase activity could be catalytic if an effective reduction system exists to regenerate the reduced heme species. The nature of the physiological cytoglobin reducing system is unknown, although it has been proposed that ascorbate and cytochrome b5 could fulfill this role. Here we describe that physiological concentrations of cytochrome b5 and cytochrome b5 reductase can reduce human and fish cytoglobins at rates up to 250-fold higher than those reported for their known physiological substrates, hemoglobin and myoglobin, and up to 100-fold faster than 5 mM ascorbate. These data suggest that the cytochrome b5/cytochrome b5 reductase system is a viable reductant for cytoglobin in vivo, allowing for catalytic oxidoreductase activity. PMID- 28671822 TI - Tuning Sizes, Morphologies, and Magnetic Properties of Monocore Versus Multicore Iron Oxide Nanoparticles through the Controlled Addition of Water in the Polyol Synthesis. AB - The polyol route is a versatile and up-scalable method to produce large batches of iron oxide nanoparticles with well-defined structures and magnetic properties. Importance of parameters such as temperature and reaction time, heating profile, nature of the polyol solvent or organometallic precursors on nanostructure and properties has already been described in the literature. Yet, the crucial role of water in the forced hydrolysis pathway has never been reported, despite its mandatory presence for nanoparticle production. This communication investigates the influence of the water amount and temperature at which it is injected in the reflux system for either a pure polyol solvent system or a mixture with poly(hydroxy)amine. Distinct morphologies of nanoparticles were thereby obtained, from ultra-ultra-small smooth spheres down to 4 nm in diameter to larger ones up to 37 nm. Well-defined multicore assemblies with narrow grain size dispersity termed nanoflowers were also synthesized. A diverse and large library of samples was obtained by manipulating the nature of solvents and the amount of added water while keeping all other parameters constant. The different morphologies lead to magnetic nanoparticles suitable for important biomedical applications such as magnetic hyperthermia, magnetic resonance imaging (MRI) contrast agent, or both. PMID- 28671821 TI - The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed beta2-Microglobulin through Distinct Binding Sites. AB - T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR pMHC interface, and their effects on TCR conformation and dynamics are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR. Our results demonstrate that while TCR-pMHC complex formation significantly stabilizes distinct CDR loops of the TCR, it does not trigger structural changes in receptor segments remote from the binding interface. Intriguingly, our HDX measurements reveal that the TCR alpha-constant domain (C- and F-strand) directly interacts with the unbound MHC light chain, beta2-microglobulin (beta2m). Surface plasmon resonance measurements corroborated a binding event between TCR and beta2m with a dissociation constant of 167 +/- 20 MUM. We propose a model structure for the TCR-beta2m complex based on a refined protein-protein docking approach driven by HDX data and information from molecular dynamics simulations. Using a biological assay based on TCR gene engineered primary human T cells, we did not observe a significant effect of beta2m on T-cell cytotoxicity, suggesting an alternate role for beta2m binding. Overall, we show that binding of beta2m to the TCR occurs in vitro and, as such, not only should be considered in structure-function studies of the TCR-pMHC complex but also could play a hitherto unidentified role in T-cell function in vivo. PMID- 28671823 TI - Field-Induced Slow Magnetic Relaxation in an Octacoordinated Fe(II) Complex with Pseudo-D2d Symmetry: Magnetic, HF-EPR, and Theoretical Investigations. AB - An octacoordinated Fe(II) complex, [FeII(dpphen)2](BF4)2.1.3H2O (1; dpphen = 2,9 bis(pyrazol-1-yl)-1,10-phenanthroline), with a pseudo-D2d-symmetric metal center has been synthesized. Magnetic, high-frequency/-field electron paramagnetic resonance (HF-EPR), and theoretical investigations reveal that 1 is characterized by uniaxial magnetic anisotropy with a negative axial zero-field splitting (ZFS) (D ~ -6.0 cm-1) and a very small rhombic ZFS (E ~ 0.04 cm-1). Under applied dc magnetic fields, complex 1 exhibits slow magnetic relaxation at low temperature. Fitting the relaxation time with the Arrhenius mode combining Orbach and tunneling terms affords a good fit to all the data and yields an effective energy barrier (17.0 cm-1) close to the energy gap between the ground state and the first excited state. The origin of the strong uniaxial magnetic anisotropy for 1 has been clearly understood from theoretical calculations. Our study suggests that high-coordinated compounds featuring a D2d-symmetric metal center are promising candidates for mononuclear single-molecule magnets. PMID- 28671824 TI - Exclusive Extracellular Bioreduction of Methyl Orange by Azo Reductase-Free Geobacter sulfurreducens. AB - Azo dyes are a class of recalcitrant organic pollutants causing severe environmental pollution. For their biodecolorization, the azo reductase system was considered as the major molecular basis in bacteria. However, the intracellular localization of azo reductase limits their function for efficient azo dye decolorization. This limitation may be circumvented by electrochemically active bacteria (EAB) which is capable of extracellular respiration. To verify the essential role of extracellular respiration in azo dye decolorization, Geobacter sulfurreducens PCA, a model EAB, was used for the bioreduction of methyl orange (MO), a typical azo dye. G. sulfurreducens PCA efficiently reduced MO into amines. Kinetic results showed that G. sulfurreducens PCA had the highest decolorization efficiency among the currently known MO reducing bacteria. Electrons from acetate oxidization by this strain were transferred by the respiratory chain to MO. The mass and electron balances, fluorescent probing and proteinase K treatment experimental results indicate that the biodecolorization of MO by G. sulfurreducens PCA is an exclusive extracellular process. OmcB, OmcC and OmcE were identified as the key outer-membrane proteins for the extracellular MO reduction. This work deepens our understanding of EAB physiology and is useful for the decontamination of environments polluted with azo dyes. The contribution of extracellular respiration to pollutants reduction will broaden the environmental applications of EAB. PMID- 28671825 TI - Isospecific, Chain Shuttling Polymerization of Propylene Oxide Using a Bimetallic Chromium Catalyst: A New Route to Semicrystalline Polyols. AB - Hydroxy-telechelic poly(propylene oxide) (PPO) is widely used industrially as a midsegment in polyurethane synthesis. These atactic polymers are produced from racemic propylene oxide using chain shuttling agents and double-metal cyanide catalysts. Unlike atactic PPO, isotactic PPO is semicrystalline with a melting temperature of approximately 67 degrees C. Currently there is no practical route to hydroxy-telechelic isotactic PPO using racemic propylene oxide as the monomer. In this paper, hydroxy-telechelic isotactic PPO is synthesized from racemic propylene oxide with control of molecular weight using enantioselective and isoselective bimetallic catalysts in conjunction with chain shuttling agents. The discovery of an easily accessible bimetallic chromium catalyst is reported for this transformation. Diol, triol, and polymeric chain shuttling agents are used to give hydroxy-telechelic isotactic PPO of varying functionality and structure. Detailed quantum chemical studies are used to reveal the polymerization mechanism and origin of stereoselectivity. PMID- 28671826 TI - Studies on the Photochemical Rearrangements of Enantiomerically Pure, Polysubstituted, and Variously Annulated Bicyclo[2.2.2]octenones. AB - A series of enantiomerically pure bicyclo[2.2.2]octenones, including the lactone annulated system 26, has been prepared by engaging derivatives of an enzymatically derived and homochiral cis-1,2-dihydrocatechol in inter- or intra molecular Diels-Alder reactions. Systems such as 26 readily participate in photochemically promoted oxa-di-pi-methane rearrangement or 1,3-acyl migration processes to give products such as diquinane 34 or mixtures of cyclobutanone 36 and cyclopropane 38, respectively. PMID- 28671827 TI - Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease. AB - Ester and carbamate prodrugs of aldehyde bisulfite adduct inhibitors were synthesized in order to improve their pharmacokinetic and pharmacodynamic properties. The inhibitory activity of the compounds against norovirus 3C-like protease in enzyme and cell-based assays was determined. The ester and carbamate prodrugs displayed equivalent potency to those of the precursor aldehyde bisulfite adducts and precursor aldehydes. Furthermore, the rate of ester cleavage was found to be dependent on alkyl chain length. The generated prodrugs exhibited low cytotoxicity and satisfactory liver microsomes stability and plasma protein binding. The methodology described herein has wide applicability and can be extended to the bisulfite adducts of common warheads employed in the design of transition state inhibitors of serine and cysteine proteases of medical relevance. PMID- 28671828 TI - Experimental and Theoretical Thermochemistry of the Isomers 3- and 4 Nitrophthalimide. AB - This work presents a thermochemical study of two derivatives of phthalimide: the isomers 3-nitrophthalimide and 4-nitrophthalimide. The enthalpies of formation for these compounds in the solid phase were obtained by combustion calorimetry. Using ths thermogravimetry technique, the enthalpies of vaporization were obtained. The enthalpies of sublimation were calculated from enthalpies of fusion and vaporization. From experimental data and by ab initio methods, the enthalpies of formation in the gas phase were calculated. With these results, it was possible to determine their relative stability, and it was found that 4 nitrophthalimide is more stable than its isomer 3-nitrophthalimide. This tendency is similar to that of 3-nitrophthalic anhydride and 4-nitrophthalic anhydride, as reported in a previous work by our research group. The enthalpy of isomerization was also obtained, and a good correlation with that of phthalic anhydride derivatives was found. Finally, with the values obtained, the enthalpic difference resulting when the imide group is substituted by an anhydride group was determined. PMID- 28671829 TI - Fibril-Barrel Transitions in Cylindrin Amyloids. AB - We introduce Replica-Exchange-with-Tunneling (RET) simulations as a tool for studies of the conversion between polymorphic amyloids. For the 11-residue amyloid-forming cylindrin peptide we show that this technique allows for a more efficient sampling of the formation and interconversion between fibril-like and barrel-like assemblies. We describe a protocol for optimized analysis of RET simulations that allows us to propose a mechanism for formation and interconversion between various cylindrin assemblies. Especially, we show that an interchain salt bridge between residues K3 and D7 is crucial for formation of the barrel structure. PMID- 28671830 TI - A Flexible Fluorescent Zr Carboxylate Metal-Organic Framework for the Detection of Electron-Rich Molecules in Solution. AB - A novel Zr(IV) dicarboxylate metal organic framework (MOF) built up from an s tetrazine derived ligand was prepared. This solid, which exhibits a diamond type network, combines a good stability in water, a structural flexibility, and fluorescence properties thanks to the organic ligand. It is noteworthy that this fluorescence is quenched when exposed to electron-rich molecules in solution, such as amines or phenol, this phenomenon being associated with the adsorption of the quencher, as unambiguously proven by X-ray diffraction (XRD) analysis. Finally, the quenching efficiency is shown to be governed not only by electronic and steric factors but also by the relative polarity of the solvent, the MOF, and the quencher. This work thus suggests that it is possible to develop new MOF based sensors presenting in a given medium (such as water) highly selective responses. PMID- 28671831 TI - Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer Mechanisms. AB - Betulin and betulinic acid have been widely studied for their anticancer activities. However, their further development is limited due to low bioavailability, poor aqueous solubility, and limited intracellular accumulation. In the present study, a triphenylphosphonium cation moiety was linked to betulin and betulinic acid to specifically target them to cancer cell mitochondria. Biological characterization established that uptake of mitochondria-targeted compound 1a in the mitochondria of cancer cells was increased compared to betulin. The mitochondria-targeted derivatives of betulin and betulinic acid showed stronger cytotoxicity than their parent drugs and exhibited more cytotoxic effects in cancer cells than normal cells. The mechanisms may involve the mitochondrial apoptotic pathway, probably caused by the induction of reactive oxygen species production and reducing mitochondrial membrane potential. More importantly, 1a significantly inhibited cancer cell proliferation and migration in an in vivo zebrafish xenograft model. Collectively, these results encourage further study of 1a analogs as anticancer agents. PMID- 28671832 TI - Isolation of Premyrsinane, Myrsinane, and Tigliane Diterpenoids from Euphorbia pithyusa Using a Chikungunya Virus Cell-Based Assay and Analogue Annotation by Molecular Networking. AB - Six new premyrsinol esters (1-6) and one new myrsinol ester (8) were isolated from an aerial parts extract of Euphorbia pithyusa, together with a known premyrsinol (7) and two known dideoxyphorbol esters (9 and 10), following a bioactivity-guided purification procedure using a chikungunya virus (CHIKV) cell based assay. The structures of the new diterpene esters (1-6 and 8) were elucidated by MS and NMR spectroscopic data interpretation. Compounds 1-10 were evaluated against CHIKV replication, and results showed that the 4beta dideoxyphorbol ester 10 was the most active compound, with an EC50 value of 4.0 +/- 0.3 MUM and a selectivity index of 10.6. To gain more insight into the structural diversity of diterpenoids produced by E. pithyusa, the initial extract and chromatographic fractions were analyzed by LC-MS/MS. The generated data were annotated using a molecular networking procedure and revealed that dozens of unknown premyrsinane, myrsinane, and tigliane analogues were present. PMID- 28671833 TI - Chip-Based All-Optical Control of Single Molecules Coherently Coupled to a Nanoguide. AB - The feasibility of many proposals in nanoquantum-optics depends on the efficient coupling of photons to individual quantum emitters, the possibility to control this interaction on demand, and the scalability of the experimental platform. To address these issues, we report on chip-based systems made of one-dimensional subwavelength dielectric waveguides (nanoguides) and polycyclic aromatic hydrocarbon molecules. We discuss the design and fabrication requirements, present data on extinction spectroscopy of single molecules coupled to a nanoguide mode, and show how an external optical beam can switch the propagation of light via a nonlinear optical process. The presented architecture paves the way for the investigation of many-body phenomena and polaritonic states and can be readily extended to more complex geometries for the realization of quantum integrated photonic circuits. PMID- 28671834 TI - New Method to Synthesize Highly Active and Durable Chemically Ordered fct-PtCo Cathode Catalyst for PEMFCs. AB - In the bottom-up synthesis strategy performed in this study, the Co-catalyzed pyrolysis of chelate-complex and activated carbon black at high temperatures triggers the graphitization reaction which introduces Co particles in the N-doped graphitic carbon matrix and immobilizes N-modified active sites for the oxygen reduction reaction (ORR) on the carbon surface. In this study, the Co particles encapsulated within the N-doped graphitic carbon shell diffuse up to the Pt surface under the polymer protective layer and forms a chemically ordered face centered tetragonal (fct) Pt-Co catalyst PtCo/CCCS catalyst as evidenced by structural and compositional studies. The fct-structured PtCo/CCCS at low-Pt loading (0.1 mgPt cm-2) shows 6% higher power density than that of the state-of the-art commercial Pt/C catalyst. After the MEA durability test of 30 000 potential cycles, the performance loss of the catalyst is negligible. The electrochemical surface area loss is less than 40%, while that of commercial Pt/C is nearly 80%. After the accelerated stress test, the uniform catalyst distribution is retained and the mean particle size increases approximate 1 nm. The results obtained in this study indicated that highly stable compositional and structural properties of chemically ordered PtCo/CCCS catalyst contribute to its exceptional catalyst durability. PMID- 28671835 TI - Rational Design of Molecular Hole-Transporting Materials for Perovskite Solar Cells: Direct versus Inverted Device Configurations. AB - Due to a still limited understanding of the reasons making 2,2',7,7'-tetrakis(N,N di-p-methoxyphenylamine)-9,9'-spirobifluorene (Spiro-OMeTAD) the state-of-the-art hole-transporting material (HTM) for emerging photovoltaic applications, the molecular tailoring of organic components for perovskite solar cells (PSCs) lacks in solid design criteria. Charge delocalization in radical cationic states can undoubtedly be considered as one of the essential prerequisites for an HTM, but this aspect has been investigated to a relatively minor extent. In marked contrast with the 3-D structure of Spiro-OMeTAD, truxene-based HTMs Trux1 and Trux2 have been employed for the first time in PSCs fabricated with a direct (n-i p) or inverted (p-i-n) architecture, exhibiting a peculiar behavior with respect to the referential HTM. Notwithstanding the efficient hole extraction from the perovskite layer exhibited by Trux1 and Trux2 in direct configuration devices, their photovoltaic performances were detrimentally affected by their poor hole transport. Conversely, an outstanding improvement of the photovoltaic performances in dopant-free inverted configuration devices compared to Spiro OMeTAD was recorded, ascribable to the use of thinner HTM layers. The rationalization of the photovoltaic performances exhibited by different configuration devices discussed in this paper can provide new and unexpected prospects for engineering the interface between the active layer of perovskite based solar cells and the hole transporters. PMID- 28671836 TI - Self-Immolative Chemiluminescence Polymers: Innate Assimilation of Chemiexcitation in a Domino-like Depolymerization. AB - Self-immolative polymers are distinctive materials able to disassemble in a domino-like mechanism from head-to-tail upon a triggering event induced by an external stimulus. We have developed an effective molecular method to intrinsically assimilate a chemiluminescence turn-ON mechanism with a domino-like fragmentation mechanism. A unique molecular unit was synthesized, which could combine the abilities of executing the duel function of quinone-methide elimination and chemiexcitation. Incorporation of this unit as a monomer, results with the first class of stimuli-responsive self-immolative polymers with amplified chemiluminescence output. Responsive groups for various analytes were introduced as a head-trigger during the polymer synthesis. The polymers were demonstrated as chemiluminescence probes for detection of different chemical analytes. The obtained polymers were able to amplify the intensity and the duration of the light emission signal by factors correlated to their length. We anticipate that the chemiluminescence self-immolative polymers described here will find use for various research topics such as signal amplification, light emitting new materials, and molecular probes with long-lasting light emission and imaging capabilities. PMID- 28671838 TI - Developing a Fluorescent Toolbox To Shed Light on the Mysteries of RNA. AB - Technologies that detect and image RNA have illuminated the complex roles played by RNA, redefining the traditional and superficial role first outlined by the central dogma of biology. Because there is such a wide diversity of RNA structure arising from an assortment of functions within biology, a toolbox of approaches have emerged for investigation of this important class of biomolecules. These methods are necessary to detect and elucidate the localization and dynamics of specific RNAs and in doing so unlock our understanding of how RNA dysregulation leads to disease. Current methods for detecting and imaging RNA include in situ hybridization techniques, fluorescent aptamers, RNA binding proteins fused to fluorescent reporters, and covalent labeling strategies. Because of the inherent diversity of these methods, each approach comes with a set of strengths and limitations that leave room for future improvement. This perspective seeks to highlight the most recent advances and remaining challenges for the wide-ranging toolbox of technologies that illuminate RNA's contribution to cellular complexity. PMID- 28671837 TI - Activated-Lignite-Based Super Large Granular Slow-Release Fertilizers Improve Apple Tree Growth: Synthesis, Characterizations, and Laboratory and Field Evaluations. AB - In this work, lignite, a low-grade coal, was modified using the solid-phase activation method with the aid of a Pd/CeO2 nanoparticle catalyst to improve its pore structure and nutrient absorption. Results indicate that the adsorption ability of the activated lignite to NO3-, NH4+, H2PO4-, and K+ was significantly higher than that of raw lignite. The activated lignite was successfully combined with the polymeric slow-release fertilizer, which exhibits typical slow-release behavior, to prepare the super large granular activated lignite slow-release fertilizer (SAF). In addition to the slow-release ability, the SAF showed excellent water-retention capabilities. Soil column leaching experiments further confirmed the slow-release characteristics of the SAF with fertilizer nutrient loss greatly reduced in comparison to traditional and slow-release fertilizers. Furthermore, field tests of the SAF in an orchard showed that the novel SAF was better than other tested fertilizers in improve the growth of young apple trees. Findings from this study suggest that the newly developed SAF has great potential to be used in apple cultivation and production systems in the future. PMID- 28671839 TI - Involvement of Irreversible Vacuolar Membrane Fragmentation in the Lethality of Food Emulsifier Diglycerol Monolaurate against Budding Yeast. AB - Diglycerol monolaurate (DGL) has been manufactured as a novel type of food emulsifier and is being considered for further application as a food preservative. DGL lethality was thus examined against Saccharomyces cerevisiae as a model of a yeast that causes food spoilage. In spite of its molecular structure as a nonionic surfactant, DGL could exhibit lethality at a concentration lower than that which caused disruptive damage to the yeast plasma membrane. DGL lethality was rather accompanied by a dynamic intracellular event such as a marked vacuolar membrane fragmentation. In DGL-treated cells, the tiny dots or particles of fragmented vacuolar membranes failed to fuse into the original large rounded architecture after its removal from medium, which were distinguished from those generated as a result of vacuolar fission normally accelerated under hyperosmotic conditions. Such an irreversible structural damage of the organelle membrane was considered a cause of DGL lethality. PMID- 28671840 TI - Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces. AB - The emergence of antibiotic and anti-inflammatory agents in aquatic and terrestrial systems is becoming a serious threat to human and animal health worldwide. Because pharmaceutical compounds rarely exist individually in nature, interactions between various compounds can have unforeseen effects on their binding to mineral surfaces. This work demonstrates this important possibility for the case of two typical antibiotic and anti-inflammatory agents (nalidixic acid (NA) and niflumic acid (NFA)) bound at goethite (alpha-FeOOH) used as a model mineral surface. Our multidisciplinary study, which makes use of batch sorption experiments, vibration spectroscopy and periodic density functional theory calculations, reveals enhanced binding of the otherwise weakly bound NFA caused by unforeseen intermolecular interactions with mineral-bound NA. This enhancement is ascribed to the formation of a NFA-NA dimer whose energetically favored formation (-0.5 eV compared to free molecules) is predominantly driven by van der Waals interactions. A parallel set of efforts also showed that no cobinding occurred with sulfamethoxazole (SMX) because of the lack of molecular interactions with coexisting contaminants. As such, this article raises the importance of recognizing drug cobinding, and lack of cobinding, for predicting and developing policies on the fate of complex mixtures of antibiotics and anti inflammatory agents in nature. PMID- 28671841 TI - Reverse Osmosis Shifts Chloramine Speciation Causing Re-Formation of NDMA during Potable Reuse of Wastewater. AB - UV-based advanced oxidation processes (AOPs) effectively degrade N nitrosodimethylamine (NDMA) passing through reverse osmosis (RO) units within advanced treatment trains for the potable reuse of municipal wastewater. However, certain utilities have observed the re-formation of NDMA after the AOP from reactions between residual chloramines and NDMA precursors in the AOP product water. Using kinetic modeling and bench-scale RO experiments, we demonstrate that the low pH in the RO permeate (~5.5) coupled with the effective rejection of NH4+ promotes conversion of the residual monochloramine (NH2Cl) in the permeate to dichloramine (NHCl2) via the reaction: 2 NH2Cl + H+ <-> NHCl2 + NH4+. Dichloramine is the chloramine species known to react with NDMA precursors to form NDMA. After UV/AOP, utilities generally use lime or other techniques to increase the pH of the finished water to prevent distribution system corrosion. Modeling indicated that, while the increase in pH halts dichloramine formation, it converts amine-based NDMA precursors to their more reactive, neutral forms. With modeling, and experiments at both bench-scale and field-scale, we demonstrate that reducing the time interval between RO treatment and final pH adjustment can significantly reduce NDMA re-formation by minimizing the amount of dichloramine formed prior to reaching the final target pH. PMID- 28671842 TI - Reversible Crystal Transformations and Luminescence Vapochromism by Fast Guest Exchange in Cu(I) Coordination Polymers. AB - Six Cu(I) coordination polymers (CPs)-[Cu2I2L2]n (1), {[Cu2I2L2].2MeCN}n (2), [Cu4I4L2]n (3), {[Cu4I4L2].CH2Cl2}n (4), {[Cu4I4L2].CHCl3}n (5), and {[Cu4I4L2].C6H6}n (6)-were synthesized by self-assembly reactions of CuI and the flexible mixed N/S donor ligand 4-(2-(cyclohexylthio)ethoxy)pyridine (L). Single crystal X-ray diffraction analyses reveal that these 1D CPs form sets of supramolecular isomers; 1 and 2 are based on Cu2I2 rhomboids, while 3-6 are based on cubane Cu4I4 clusters. Crystal-to-crystal transformations of CPs 1-6 were reversible under heat or in an appropriate solvent (acetonitrile, dichloromethane, chloroform, or benzene). In addition, crystal transformations between CPs 1 and 3 occurred through addition of L or CuI. Moreover, CPs 3-6 exhibited reversible guest exchange and crystal transformations on exposure to the vapor of volatile organic compounds and heat. Remarkably, a guest molecule was exchanged by other guest molecules in the vapor phase within very short times and without the use of acetonitrile as a solvent, which normally plays a key role in trapped solvent exchange experiments. PMID- 28671843 TI - Utilizing Microcavities To Suppress Third-Order Cascades in Fifth-Order Raman Spectra. AB - Nonlinear optical signals in the condensed phase are often accompanied by sequences of lower-order processes, known as cascades, which share the same phase matching and power dependence on the incoming fields and are thus hard to distinguish. The suppression of cascading in order to reveal the desired nonlinear signal has been a major challenge in multidimensional Raman spectroscopy, that is, the chi(5) signal being masked by cascading signals given by a product of two chi(3) processes. Because cascading originates from the exchange of a virtual photon between molecules, it can be manipulated by performing the experiment in an optical microcavity which modifies the density of radiation field modes. Using a quantum electrodynamical (QED) treatment, we demonstrate that the chi(3) cascading contributions can be greatly suppressed. By optimizing the cavity size and the incoming pulse directions, we show that up to ~99.5% suppression of the cascading signal is possible. PMID- 28671844 TI - Sensitivity to Ethephon Degreening Treatment Is Altered by Blue LED Light Irradiation in Mandarin Fruit. AB - Although citrus fruits are not climacteric, exogenous ethylene is widely used in the degreening treatment of citrus fruits. Irradiation with blue light-emitting diode (LED) light (450 nm) for 10 h can promote the formation of good coloration of ethephon-degreened fruit. This study evaluated the effect of blue LED light irradiation on the pigments contents of ethephon-degreened fruit and evaluated whether the blue LED light irradiation could influence the sensitivity of mandarin fruit to ethylene. The results indicated that blue light can accelerate the color change of ethephon-degreened fruit, accompanied by changes in plastid ultrastructure and chlorophyll and carotenoid contents. Ethephon-induced expressions of CitACS1, CitACO, CitETR1, CitEIN2, CitEIL1, and CitERF2 were enhanced by blue LED light irradiation, which increased the sensitivity to ethylene in ethephon-degreened fruits. These results indicate that blue LED light induced changes in sensitivity to ethylene in mandarin fruit may be responsible for the improved coloration of ethephon-degreened mandarin fruits. PMID- 28671845 TI - Understanding the Lewis Acidity of Co(II) Sites on a Silica Surface. AB - Heterogeneous catalysts consisting of isolated transition-metal sites dispersed on the surface of metal oxide supports are commonly used in the chemical industry. Often their reactivity relies on the Lewis acidity of the active sites on the surface of the catalyst. A recent report from our group showed that silica supported Co(II) sites, prepared via surface organometallic chemistry, are active in both alkene hydrogenation and alkane dehydrogenation, possibly linked to the Lewis acidity of the Co(II) sites. Here we use molecular probes and analogues to both qualitatively and quantitatively model the Lewis acidity of the surface sites. Some sites do not bind probe molecules like carbon monoxide, tetrahydrofuran, and olefins, while others exhibit a continuum of Lewis acidities. This is consistent with variations in the coordination environment of Co. These results suggest that only the most Lewis acidic sites are involved in dehydrogenation and hydrogenation, consistent with catalyst poisoning studies. PMID- 28671846 TI - Novel Fabrication of Biodegradable Superabsorbent Microspheres with Diffusion Barrier through Thermo-Chemical Modification and Their Potential Agriculture Applications for Water Holding and Sustained Release of Fertilizer. AB - Synergistic utilization of water and fertilizer has vital contribution to the modern production of agriculture. This work reports on a simple and facile strategy to prepare biodegradable yeast/sodium alginate/poly(vinyl alcohol) superabsorbent microspheres with a diffusion barrier merit by thermo-chemical modification route. The integrated performances, including water absorbency, water retention, water evaporation ratio, leaching loss control, sustained release behaviors, and degradation in soil, were systematically investigated. The results revealed that the modified microspheres were a triumphant water and fertilizer manager to effectively hold water and control the unexpected leakage of fertilizer for sustained release. Therefore, this work provides a promising approach to ameliorate the utilization efficiency of water and fertilizer in potential agriculture applications. PMID- 28671848 TI - O2-.[Polar VOC] Complexes: H-Bonding versus Charge-Dipole Interactions, and the Noninnocence of Formaldehyde. AB - Anion photoelectron imaging was used to measure the photodetachment spectra of molecular complexes formed between O2- and a range of atmospherically relevant polar molecules, including species with a carbonyl group (acetone, formaldehyde) and alcohols (ethanol, propenol, butenol). Experimental spectra are analyzed using a combination of Franck-Condon simulations and electronic structure calculations. Strong charge-dipole interactions and H-bonding stabilize the complex anions relative to the neutrals, resulting in a ca. 1 eV increase in electron binding energy relative to bare O2-, an effect more pronounced in complexes with H-bonding. In addition, broken degeneracy of the O2-local pig orbitals in the complexes results in the stabilization of the low-lying excited O2 (a 1Deltag).[polar VOC] state relative to the ground O2 (X 3Sigmag-).[polar VOC] state when compared to bare O2. The spectra of the O2-.[polar VOC] complexes exhibit less pronounced laser photoelectron angular distribution (PADs). The spectrum of O2-.formaldehyde is unique in terms of both spectral profile and PAD. On the basis of these experimental results in addition to computational results, the complex anion cannot be described as a distinct O2- anion partnered with an innocent solvent molecule; the molecules are more strongly coupled through charge delocalization. Overall, the results underscore how the symmetry of the O2 pig orbitals is broken by different polar partners, which may have implications for atmospheric photochemistry and models of solar radiation absorption that include collision-induced absorption. PMID- 28671847 TI - Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B. AB - Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis. PMID- 28671849 TI - Tuning Light Absorption in Platinum(II) Terpyridyl pi-Conjugated Complexes: A First-Principle Study. AB - Platinum(II) terpyridyl complexes with a donor-acceptor (D-A) framework have long been considered as a promising component of dye-sensitized solar cells (DSSCs). To revealing the structure-property relationship of these highly modular systems, we have conducted a first-principle study at the time-dependent density functional theory (TDDFT) level on the [Pt(tBu3tpy)(-C=C-Ph)n]+ (tBu3tpy is 4,4',4"-tri-tert-butyl-2,2':6',2"-terpyridine) complexes. It was found that their visible absorbance could be improved by elongating the donor chain with n (-C=C Ph) units, reaching a maximum at n = 16. It is noteworthy that such a simple concatenating protocol enables a remarkable charge transfer distance as long as 5 nm, implying a promising solution for the bottleneck problem of low charge separation rate in DSSCs. Furthermore, using a A-D-A system (two Pt(tBu3tpy) acceptors bridged by one donor) effectively doubles the visible-harvesting ability, and twisting an benzene ring in the chain of donors to break pi conjugations can tune down light absorption in a quantitatively angular dependent manner. Finally, replacing the C=C bond linker with C?C double bond in donor leads to comparable light absorption ability while bestowing structural flexibility. These structure-property relationships thus provide efficient knobs for molecular rational design toward high performance dye-sensitized solar cells. PMID- 28671851 TI - Spontaneous change from seated to standing cycling position with increasing power is associated with a minimization of cost functions. AB - Spontaneous changes of movement patterns may allow to elucidate which criteria influence movement pattern preferences. However, the factors explaining the sit stand transition in cycling are unclear. This study investigated if biomechanical and/or muscle activation cost functions could predict the power at which the spontaneous sit-stand transition occurs. Twenty-five participants performed an incremental test leading to the sit-to-stand transition, and subsequent randomized pedaling trials at 20 to 120% of the transition power in seated and standing position. A Moment Cost Function based on lower limbs net joint moments and two Electromyographic Cost Functions based on EMG data were defined. All cost functions increased with increasing crank power (p < 0.001) but at different rates in the seated and standing positions. They had lower values in the seated position below the transition power and lower values in the standing position above the transition power (p < 0.05). These results suggest that spontaneous change of position observed in cycling with increasing crank power represents an optimal choice to minimize muscular efforts. These results support the use of simple cost functions to define optimal settings in cycling and to assess the cost of cycling during short-term efforts. PMID- 28671850 TI - In Vivo Tibial Cartilage Strains in Regions of Cartilage-to-Cartilage Contact and Cartilage-to-Meniscus Contact in Response to Walking. AB - BACKGROUND: There are currently limited human in vivo data characterizing the role of the meniscus in load distribution within the tibiofemoral joint. Purpose/Hypothesis: The purpose was to compare the strains experienced in regions of articular cartilage covered by the meniscus to regions of cartilage not covered by the meniscus. It was hypothesized that in response to walking, tibial cartilage covered by the meniscus would experience lower strains than uncovered tibial cartilage. STUDY DESIGN: Descriptive laboratory study. METHODS: Magnetic resonance imaging (MRI) of the knees of 8 healthy volunteers was performed before and after walking on a treadmill. Using MRI-generated 3-dimensional models of the tibia, cartilage, and menisci, cartilage thickness was measured in 4 different regions based on meniscal coverage and compartment: covered medial, uncovered medial, covered lateral, and uncovered lateral. Strain was defined as the normalized change in cartilage thickness before and after activity. RESULTS: Within each compartment, covered cartilage before activity was significantly thinner than uncovered cartilage before activity ( P < .001). After 20 minutes of walking, all 4 regions experienced significant cartilage thickness decreases ( P < .01). The covered medial region experienced significantly less strain than the uncovered medial region ( P = .04). No difference in strain was detected between the covered and uncovered regions in the lateral compartment ( P = .40). CONCLUSION: In response to walking, cartilage that is covered by the meniscus experiences lower strains than uncovered cartilage in the medial compartment. These findings provide important baseline information on the relationship between in vivo tibial compressive strain responses and meniscal coverage, which is critical to understanding normal meniscal function. PMID- 28671852 TI - A pair of new isocoumarin epimers from soil fungus Hypoxylon sp. AB - In our research on novel secondary metabolites from micro-organisms, two new (1 2) and four known dihydroisocoumarins (3-6) were derived from soil fungus Hypoxylon sp. Their structures were determined with extensive NMR data analysis and ECD calculation comparing with those of experimental CD spectra. Interestingly, compounds 1 and 2 possessed the same planar structure and very similar NMR data, suggesting 1 and 2 were a pair of epimers at either C-3 or at C 4, confirmed by the totally opposite cotton effect around 250 nm in the CD spectra of 1 and 2. Moreover, for the first time, we revealed that the CD absorption peak at 250 nm was dominated by C-3 orientation, rather than the orientation of C-3 substituents, by intensive ECD investigations. PMID- 28671853 TI - Physiological and anthropometric characteristics of top-level youth cross-country cyclists. AB - In the literature there is a lack of data about the development of top level athletes in cross-country mountain biking (XCO). The purpose of this study was to analyze anthropometric and physiological characteristics of some of the best XCO bikers aged between 13 and 16. The study involved 45 bikers (26 males and 19 females) belonging to a youth national team. The evaluations, consisting of anthropometric measures, incremental cycling tests (VO2max, PPO, P@RCP), and 30 s Wingate Tests (PMax, PMean), were conducted over a lapse of 4 years. Our findings showed in bikers, already at young age, a specific athletic profile advantageous for XCO performance. At the age of 16, just before entering the junior category and competing at international level, male and female bikers showed physiological values normalized to the body mass comparable to those reported in literature for high level athletes (VO2max>70 and >60 ml/kg/min, PPO >6.5 and >5.5 W/kg, respectively in males and females). The production of high power-to-weight ratios and high peaks of anaerobic power attests the presence of highly developed aerobic and anaerobic systems in young XCO cyclists reflecting the high physiological demand of this sport. PMID- 28671854 TI - The True Self: A Psychological Concept Distinct From the Self. AB - A long tradition of psychological research has explored the distinction between characteristics that are part of the self and those that lie outside of it. Recently, a surge of research has begun examining a further distinction. Even among characteristics that are internal to the self, people pick out a subset as belonging to the true self. These factors are judged as making people who they really are, deep down. In this paper, we introduce the concept of the true self and identify features that distinguish people's understanding of the true self from their understanding of the self more generally. In particular, we consider recent findings that the true self is perceived as positive and moral and that this tendency is actor-observer invariant and cross-culturally stable. We then explore possible explanations for these findings and discuss their implications for a variety of issues in psychology. PMID- 28671855 TI - Free-weight resistance exercise on pulse wave reflection and arterial stiffness between sexes in young, resistance-trained adults. AB - We sought to determine the sex-specific effects of an acute bout of free-weight resistance exercise (RE) on pulse wave reflection (aortic blood pressures, augmentation index (AIx), AIx at 75 bpm (AIx@75), augmentation pressure (AP), time of the reflected wave (Tr), subendocardial viability ratio (SEVR)), and aortic arterial stiffness in resistance-trained individuals. Resistance-trained men (n = 14) and women (n = 12) volunteered to participate in the study. Measurements were taken in the supine position at rest, and 10 minutes after 3 sets of 10 repetitions at 75% 1-repetition maximum on the squat, bench press, and deadlift. A 2 * 2 * 2 ANOVA was used to analyse the effects of sex (men, women) across condition (RE, control) and time (rest, recovery). There were no differences between sexes across conditions and time. There was no effect of the RE on brachial or aortic blood pressures. There were significant condition * time interactions for AIx (rest: 12.1 +/- 7.9%; recovery: 19.9 +/- 10.5%, p = .003), AIx@75 (rest: 5.3 +/- 7.9%; recovery: 24.5 +/- 14.3%, p = .0001), AP (rest: 4.9 +/- 2.8 mmHg; recovery: 8.3 +/- 6.0 mmHg, p = .004), and aortic arterial stiffness (rest: 5.3 +/- 0.6 ms; recovery: 5.9 +/- 0.7 ms, p = .02) with significant increases during recovery from the acute RE. There was also a significant condition * time for time of the reflected wave (rest: 150 +/- 7 ms; recovery: 147 +/- 9 ms, p = .02) and SEVR (rest: 147 +/- 17%; recovery: 83 +/- 24%, p = .0001) such that they were reduced during recovery from the acute RE compared to the control. These data suggest that an acute bout of RE increases AIx, AIx@75, and aortic arterial stiffness similarly between men and women without significantly altering aortic blood pressures. PMID- 28671856 TI - Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. AB - Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks). Patients were treated until they experienced progression or unacceptable toxicity, with follow up of approximately 2 years. Results Two hundred seventy-two patients were randomly assigned to nivolumab (99% treated) and 133 to ICC (77% treated). More nivolumab-treated patients had brain metastases (20% v 14%) and increased lactate dehydrogenase levels (52% v 38%) at baseline; 41% of patients treated with ICC versus 11% of patients treated with nivolumab received anti-programmed death 1 agents after randomly assigned therapy. Median OS was 16 months for nivolumab versus 14 months for ICC (hazard ratio, 0.95; 95.54% CI, 0.73 to 1.24); median progression-free survival was 3.1 months versus 3.7 months, respectively (hazard ratio, 1.0; 95.1% CI, 0.78 to 1.436). Overall response rate (27% v 10%) and median duration of response (32 months v 13 months) were notably higher for nivolumab versus ICC. Fewer grade 3 and 4 treatment-related adverse events were observed in patients on nivolumab (14% v 34%). Conclusion Nivolumab demonstrated higher, more durable responses but no difference in survival compared with ICC. OS should be interpreted with caution as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the ICC group, and by an increased proportion of patients in the nivolumab group with poor prognostic factors. PMID- 28671858 TI - Atypical Red Blood Cells Are Prevalent in California Sea Lion Pups Born during Anomalous Sea Surface Temperature Events. AB - To date, there is limited knowledge of the effects that abnormal sea surface temperature (SST) can have on the physiology of neonate pinnipeds. However, maternal nutritional deficiencies driven by alimentary restrictions would expectedly impact pinniped development and fitness, as an adequate supply of nutrients is essential for growth and proper functioning of all body systems, including red blood cell synthesis and clearance. Here, we investigated red blood cell morphology of California sea lion (CSL) pups from the San Benito Archipelago born during the 2014 and 2015 anomalously high SST events recorded in the northeastern Pacific Ocean. We examined whether atypical erythrocyte morphologies were more common in 2015, when the high SST event was more pronounced, and whether the stable isotope signature of pup fur, as an indicator of maternal feeding strategies, accounted for the number of atypical cells. Various atypical erythrocyte morphologies were more prevalent and more abundant than reference values. Evidence of iron deficiency was found in both years, and only pups born in 2014 showed evidence of active erythropoiesis. Microcytes and reticulocytes were more common in pups with higher isotopic delta13C and lower delta15N values, suggesting a probable relationship between maternal feeding strategies and the effect of climatic anomalies on red blood cell physiology of their pups. As developing pinnipeds require increased oxygen storage capacity for diving and foraging, the presence of atypical erythrocytes could be relevant to CSL pup fitness if the underlying cause is not reverted. This study is a first step to explore the effects that climatic alterations in the marine environment can have on the blood physiology of developing individuals. PMID- 28671859 TI - Being Underweight Is an Independent Risk Factor for Poor Outcomes Among Acutely Critically Ill Children. AB - BACKGROUND: Malnutrition is associated with impaired immune function; thus, nutrition status assessment is crucial in critical care medicine. We aimed to investigate the impact of being underweight or overweight on major sequelae and mortality among healthy children with an intensive care unit admission. METHODS: In this retrospective study, 282 patients aged 1 month to 18 years were enrolled on intensive care unit admission between 2011 and 2012. Children were excluded if they had underlying chronic diseases and were transferred to other hospitals or discharged against medical advice. The patients were further categorized into 3 nutrition status groups according to the weight-for-age (W/A) z score. RESULTS: The prevalence rates of being underweight and overweight, based on W/A z scores of <=-2 and >=2, were 8.2% and 5.7%, respectively. Patients who were underweight were younger and had a higher rate of mortality, poor outcomes, and longer duration of mechanical ventilation than those with a normal weight. The patients with mortality or major sequelae had significantly higher rates of being underweight, noninfectious diseases and hypotension, and higher Pediatric Index of Mortality 2 (PIM2) score and creatinine level (all P < .01). In multivariate logistic regression interpretation, the W/A z score <=-2 (95% CI, 2.992-47.508; P < .001) and PIM2 score (95% CI, 1.094-1.413; P = .001) were independent risk factors for a poor outcome. CONCLUSION: Being underweight and having a PIM2 score on admission were independent risk factors for poor clinical outcomes among critically ill children without underlying diseases. PMID- 28671857 TI - Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children's Oncology Group. AB - Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age >= 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes. PMID- 28671860 TI - A Giant Left Atrial Diverticulum Diagnosed by Transesophageal Echocardiogram and Multidetector Computed Tomography: A Case Report and Brief Review of the Literature. AB - Giant left atrial diverticulum is a rare congenital malformation that is most commonly diagnosed in incidental finding. Here, we reported a case of a 1-year old asymptomatic child with a giant left atrial diverticulum. Diagnosis was established by transthoracic echocardiography (TTE), and confirmed by multidetector computed tomography (MDCT) and transesophageal echocardiography (TEE). We excised the diverticulum and sewed its base under cardiopulmonary bypass and cardiac arrest. The patient had a good postoperative result. PMID- 28671861 TI - The Transcranial Doppler Sonography for Optimal Monitoring and Optimization of Cerebral Perfusion in Aortic Arch Surgery: A Case Series. AB - OBJECTIVE: To analyze the feasibility and advantages of transcranial doppler sonography (TCD) for monitoring and optimization of selective cerebral perfusion (SCP) in aortic arch surgery. METHODS: From April 2013 to April 2014, nine patients with extensive aortic pathology underwent surgery under moderate hypothermic cardiac arrest with unilateral antegrade SCP under TCD monitoring in our institution. Adequate sonographic window and visualization of circle of Willis were to be confirmed. Intraoperatively, a cerebral cross-filling of the contralateral cerebral arteries on the unilateral SCP was to be confirmed with TCD. If no cross-filling was confirmed, an optimization of the SCP was performed via increasing cerebral flow and increasing PCO2. If not successful, the SCP was to be switched to bilateral perfusion. Air bubble hits were recorded at the termination of SCP. RESULTS: A sonographic window was confirmed in all patients. Procedural success was 100%. The mean operative time was 298 +/- 89 minutes. Adequate cross-filling was confirmed in 8 patients. In 1 patient, inadequate cross-filling was detected by TCD and an optimization of cerebral flow was necessary, which was successfully confirmed by TCD. There was no conversion to bilateral perfusion. Extensive air bubble hits were confirmed in 1 patient, who suffered a postoperative stroke. The 30-day mortality rate was 0. Conclusion: The TCD is feasible for cerebral perfusion monitoring in aortic surgery. It enables a confirmation of adequacy of cerebral perfusion strategy or the need for its optimization. Documentation of calcific or air-bubble hits might add insight into patients suffering postoperative neurological deficits. PMID- 28671862 TI - Median Sternotomy for Lung Transplantation: Techniques and Advantages. AB - Lung transplantation is traditionally performed with a clamshell thoracotomy or bilateral anterior thoracotomy incisions. We have performed 121 lung transplants with a median sternotomy incision from 2013-2017. We present our technique for lung transplantation utilizing cardiopulmonary bypass with a median sternotomy, and discuss the potential advantages of this technique. PMID- 28671863 TI - Rethinking the Paradigm: Modern Approach to Proximal Aortic Reconstruction Demonstrates Excellent Outcomes. AB - BACKGROUND: Techniques for aortic surgery continue to evolve. A real-world snapshot of patients undergoing elective surgery for aneurysm in the modern era is helpful to assist in deciding the appropriate timing for intervention. We herein describe our experience with 100 consecutive patients who underwent primary elective surgery for aneurysm of the proximal thoracic aorta over a two year period at a single institution. METHODS: The majority of our patients were male, mean age 61.19 +/- 13.33 years. Two patients had Marfan syndrome. Twenty eight patients had bicuspid aortic valve. Thirty-four patients underwent aortic root replacement utilizing a composite valve/graft conduit; 23 had valve-sparing root replacements. The ascending aorta was replaced in 89 patients; 80 (89.9%) of these included a period of circulatory arrest at moderate hypothermia utilizing unilateral selective antegrade cerebral perfusion. RESULTS: Thirty-day mortality was zero. Perioperative stroke occurred in 2 patients, both of whom completely recovered prior to discharge. No patients required re-exploration for bleeding. One patient developed a sternal wound infection. Fifteen patients required readmission to hospital within thirty days of discharge. CONCLUSION: Elective surgery for aneurysm of the proximal aorta is safe, reproducible, and is associated with outcomes that are superior to those seen in an acute aortic syndrome. It may be appropriate to offer surgery to younger patients with proximal aortic aneurysms at smaller diameters, even if their aortic dimensions do not yet meet traditional guidelines for surgical intervention. PMID- 28671864 TI - A Case Report on Pulmonary Arteriovenous Fistula with Recurrent Cerebral Infarction. AB - Patent foramen ovale (PFO) and pulmonary arteriovenous fistula (PAVF) have been both proposed as a mechanism for cerebral infarction. However, there are only a few reports on how to distinguish the role of the two factors in cerebral infarction. PMID- 28671865 TI - Quality of Life after Surgery for Stanford Type A Aortic Dissection: Influences of Different Operative Strategies. AB - BACKGROUND: Outcome of surgery for acute Stanford type A aortic dissection extends beyond mortality and morbidity. More than one operative strategy is available but little is known regarding their influence on quality of life. This study analyzes the influence of defensive and aggressive operative strategies on the patients' midterm quality of life (QoL). METHODS: From July 2007 to July 2010, 95 patients underwent surgery for acute Stanford type A aortic dissection in our institution. Patients who survived the procedure, gave consent to inclusion in the institution prospective registry, completed at least 2-years of follow-up protocol, and answered two quality of life questionnaires (SF-36 and WHO-QOL-BREF) were included in the study. Patients were divided into two groups according to operative strategy: defensive (DS) with replacement of the ascending aorta only, and aggressive (AS) with replacement of the ascending aorta, aortic arch with/out a frozen elephant trunk procedure. The preoperative, operative, postoperative and the midterm QoL were analyzed and compared. RESULTS: 39 patients were included in the study. The DS group had a shorter operative time (184 +/- 54 versus 276 +/- 110 minutes respectively, P = .001). The AS group had higher incidence of dialysis (31% versus 4% respectively, P = .038). The midterm QoL analysis showed a collective lower value than the normal population. In the SF-36, DS performed better in all categories but with no statistical significance. In the WHO-QOL-BREF, DS performed significantly better in the global life quality and psychological health categories (P = .038 and .049 respectively). CONCLUSION: In Stanford type A aortic dissection, adopting an aggressive surgical strategy does not improve the quality of life in midterm follow-up compared to a defensive strategy. Unless the clinical setting dictates an aggressive management strategy, a defensive strategy can be safely adopted. PMID- 28671866 TI - Application of Autologous Blood Cell Salvage in Off-Pump Coronary Artery Bypass Graft Operation. AB - OBJECTIVE: To analyze whether application of autologous blood cell salvage can reduce the transfusion volume of allogeneic blood and complications of blood transfusion in off-pump coronary artery bypass operations. Methods: We randomly divided 120 patients into autologous blood cell salvage group (experimental group, n = 60) and non-autologous blood cell salvage group (control group, n = 60). Volume of perioperative allogeneic blood transfusion of each patient was recorded. Moreover, complications and ICU retention times (H) of each patient were also recorded. The data were analyzed using t tests. Results: The volume of allogeneic blood transfusion was significantly less in the experimental group than in the control group. Conclusion: Application of autologous blood cell salvage in off-pump coronary artery bypass graft operation can reduce the volume of allogeneic blood transfusion, alleviate blood shortage, and reduce the incidence of postoperative complications, leading to medical, economic, and social benefits. PMID- 28671867 TI - Knockin' on Heaven's Door: End of Life Decisions and Discussions. AB - More than 2.5 million people die in the United States each year. For the majority who live out their final days in various institutions or in hospice care, decisions must be made about which treatments to administer, which treatments to stop, which treatments to continue, and which treatments to back off of. Thus, while death remains inevitable, its timing is often very much a function of human agency. Once it was common to speak of "nature taking its course," but now it has become as common to view death as something about which people have some control [Meisel 2008]. PMID- 28671868 TI - STEMI and NSTEMI ACS in a 30-Year-Old Patient: An Extremely Rare Complication of a Left Atrial Myxoma. AB - Primary cardiac tumors are a rare entity whose incidence in the general population ranges from 0.0017% to 0.28%. Myxomas represent nearly half of all primary benign cardiac tumors and they prevalently affect female patients. Embolic manifestation is rare with a reported incidence of 0.06%.We present the case of a 30-year-old male patient with acute anterolateral infarction caused by total occlusion of the left anterior descending artery as a consequence of a left atrial myxoma embolization. Urgent surgical resection of the mass didn't avoid early recurrence of atrial myxoma, whose second presentation was again myocardial infarction.This case alerts physicians to "unusual" myocardial infarction patients, when atherosclerotic pathogenesis appears unlikely. In these cases early echocardiographic evaluation should be mandatory and atrial myxoma should be considered among the possible causes. Complete surgical resection is the only effective therapeutic option to improve prognosis; the chance of tumor recurrence should dictate careful research for additional myxomas during surgery and stricter follow-up planning. PMID- 28671869 TI - Prognostic Value of Neutrophil to Lymphocyte Ratio and Risk Factors for Mortality in Patients with Stanford Type A Aortic Dissection. AB - BACKGROUND: Neutrophil to lymphocyte ratio (NLR) is a prognostic predictor in a wide range of cardiovascular disease. Acute aortic dissection (AD) is an uncommon but fatal cardiovascular disease. In this study, we investigated both prognostic factors in patients with AD and whether NLR can be a predictor for mortality. Methods: We analyzed retrospectively the data of 57 patients with AD who had undergone emergent surgery in our hospital and included 128 consecutive patients with chest pain admitted to the emergency room as a control group. Also, patients who were operated on due to aortic dissection as another subgroup were compared to NLR values. Baseline clinical features, cardiovascular risk factors, and surgical and laboratory parameters were obtained from the hospital database. Results: Patients with AD had higher NLR than the control group (1.7 +/- 0.5 versus 7.6 +/- 3.3, P < .001). In the AD group, 15 deaths occurred and non survivors had significantly higher NLR, compared to survivors (11.6 +/- 2.4 versus 6.6 +/- 2.3, P < .001). In multivariate analysis, high NLR (odds ratio [OR] 1.913, 95% CI 1.030-1.081, P = .04) and cross-clamp time (OR 1.265, 95% CI 1.003-1.596, P = .04) were determined as independent predictors of in-hospital mortality. In receiver operating characteristics curve analyses, the NLR > 9.3 predicted the mortality in AD with a specificity of 91% and a sensitivity of 86% (P < .001). CONCLUSION: This study shows that high NLR can be used as a marker for prognosis in short-term mortality of patient with AD. Additionally, increased lactate level in perioperative period, prolonged cardiopulmonary bypass time, and additional cardiac procedures are strong independent predictors of short-term mortality in patients with acute AD. PMID- 28671870 TI - The double-edged sword of evolution. AB - Two gene variants provide different levels of protection against sleeping sickness, but this comes with an increased risk of developing chronic kidney disease. PMID- 28671871 TI - Dislocation-free axial InAs-on-GaAs nanowires on silicon. AB - We report on the growth of axial InAs-on-GaAs nanowire heterostructures on silicon by molecular beam epitaxy using 20 nm diameter Au catalysts. First, the growth parameters of the GaAs nanowire segment were optimized to achieve a pure wurtzite crystal structure. Then, we developed a two-step growth procedure to enhance the yield of vertical InAs-on-GaAs nanowires. We achieved 90% of straight InAs-on-GaAs nanowires by further optimizing the growth parameters. We investigated the composition change at the interface by energy dispersive x-ray spectroscopy and the nanowire crystal structure by transmission electron microscopy. The composition of the nominal InAs segment is found to be In x Ga1-x As with x = 0.85 and corresponds to 6% of lattice mismatch with GaAs. Strain mapping performed by the geometrical phase analysis of high-resolution images revealed a dislocation-free GaAs/In0.85Ga0.15As interface. In conclusion, we successfully fabricated highly mismatched heterostructures, confirming the prediction that axial GaAs/In0.85Ga0.15As interfaces are pseudomorphic in nanowires with a diameter smaller than 40 nm. PMID- 28671872 TI - Camera-based assessment of arterial stiffness and wave reflection parameters from neck micro-motion. AB - : The feasibility of a camera-based extraction of carotid distension waveforms offers the prospect of a user-friendly alternative to laser Doppler velocimetry (LDV) or accelerometry-based systems. Upon supplementary calibration of vessel wall displacement to arterial pressure, our system may also be an appealing alternative to applanation tonometry for extracting cardiac-related features from the central pulse pressure waveform. OBJECTIVE: This paper describes the application of camera-based micro-motion imaging to extract health-related features from the contour of the carotid displacement waveform. APPROACH: We build on the assumption that the cardiac-related frequency components of the skin motion (sMOT) waveform, as acquired at the vicinity of the carotid artery under uneven illumination, receive a dominant contribution from the carotid wall displacement. We propose a two-step approach at which sMOT signals are queried based on the local amplitude of remote-photoplethysmography sensors spanning the neck's skin and then ensemble-averaged for cardiovascular health assessment. MAIN RESULTS: The feasibility of the system is demonstrated for assessing stiffness index, augmentation pressure, augmentation index and reflection magnitude on a dataset comprising 28 participants (ages 23 to 62 yrs; 22 males). SIGNIFICANCE: Although presented here as a standalone system, micro-motion imaging can be an auxiliary technique for improving sensor placement and signal quality of tonometric or LDV technologies. PMID- 28671874 TI - Axillary Nerve Palsy and Deltoid Muscle Atony. PMID- 28671873 TI - Clinical Outcomes of Golimumab as First, Second or Third Anti-TNF Agent in Patients with Moderate-to-Severe Ulcerative Colitis. AB - BACKGROUND: Golimumab efficacy data in ulcerative colitis (UC) are limited to anti-tumor necrosis factor alpha (TNF)-naive patients. The aim of this study was to assess the short-term and long-term efficacy of golimumab used as first, second, or third anti-TNF in UC in a real-life clinical setting. METHODS: This retrospective multicenter cohort study included patients with moderate-to-severe UC treated with golimumab. The primary efficacy endpoints were short-term partial Mayo score response, long-term golimumab failure-free survival, and colectomy free survival. RESULTS: In 142 patients with UC, golimumab was administered as first (40%), second (23%), or third anti-TNF (37%). Ninety-two patients (65%, 95% confidence interval 56.6-73) achieved short-term clinical response. Forty-five patients (32%, 95% confidence interval 23.7-39.7) achieved clinical remission. Response rates for golimumab were 75% as first anti-TNF, 70% as second anti-TNF (ns versus first anti-TNF), and 50% as third anti-TNF (P = 0.007 versus first anti-TNF). After 12 months median follow-up (interquartile range 6-18), 60 patients (42%, 95% confidence interval 34-51) had golimumab failure, and 15 patients (11%) needed colectomy. Thirty-one patients (22%) needed golimumab dose escalation, and 71% of these regained response after escalation. Starting maintenance with 100 mg golimumab doses and short-term nonresponse were independent predictors of golimumab failure. CONCLUSIONS: In this real-life cohort of patients with UC, golimumab therapy was effective for inducing and maintaining clinical response. Although anti-TNF-naive patients had better outcomes, golimumab was also effective in anti-TNF-experienced patients. Only the patients given golimumab after previous failure of 2 anti-TNF agents had significantly worse outcomes. Golimumab dose escalation was beneficial and safe. PMID- 28671875 TI - The Acute Management and Associated Complications of Major Injuries of the Talus. PMID- 28671876 TI - Sustaining multistakeholder alliances. AB - BACKGROUND: Multistakeholder alliances that bring together diverse organizations to work on community-level health issues are playing an increasingly prominent role in the U.S. health care system. Yet, these alliances by their nature are fragile. In particular, low barriers to exit make alliances particularly vulnerable to disruption if key stakeholders leave. What factors are linked to the sustainability of alliances? One way to approach this question is to examine the perceptions of alliance participants, whose on-going involvement in alliances likely will matter much to their sustainability. PURPOSE: This study addresses the question: "Under what conditions do participants in alliances consider that their alliances are well positioned for the future, will perform well over time, and will be able to deal effectively with future challenges?" METHODS: We draw on cross-sectional survey data collected in the summer of 2015 from a total number of 638 participants in 15 alliances that participated in the Robert Wood Johnson Foundation's Aligning Forces for Quality program. RESULTS: Results from regression analyses indicate that alliance participants are more likely to view their alliances as sustainable when they (a) share a common vision, goals, and strategies for the alliance and (b) perceive that the alliance has performed effectively in the past. PRACTICE IMPLICATIONS: Leaders of multistakeholder alliances may need to ensure that alliances are collective efforts that build success one step at a time: to the extent that participants believe they share a vision and strategies and have had some prior success working together, the more likely they are to view the alliance as sustainable. PMID- 28671877 TI - Single-screw Fixation of Adolescent Salter-II Proximal Humeral Fractures: Biomechanical Analysis of the "One Pass Door Lock" Technique. AB - BACKGROUND: Pin fixation of Salter-II proximal humeral fractures in adolescents approaching skeletal maturity has potential complications that can be avoided with single-screw fixation. However, the strength of screw fixation relative to parallel and diverging pin fixation is unknown. To compare the biomechanical fixation strength between these fixation modalities, we used synthetic composite humeri, and then compared these results in composite bone with cadaveric humeri specimens. METHODS: Parallel pinning, divergent pinning, and single-screw fixation repairs were performed on synthetic composite humeri with simulated fractures. Six specimens of each type were tested in axial loading and other 6 were tested in torsion. Five pair of cadaveric humeri were tested with diverging pins and single screws for comparison. RESULTS: Single-screw fixation was statistically stronger than pin fixation in axial and torsional loading in both composite and actual bone. There was no statistical difference between composite and cadaveric bone specimens. CONCLUSION: Single-screw fixation can offer greater stability to adolescent Salter-II fractures than traditional pinning. CLINICAL RELEVANCE: Single-screw fixation should be considered as a viable alternative to percutaneous pin fixation in transitional patients with little expected remaining growth. PMID- 28671878 TI - Application of Low-dose Stereoradiography in In Vivo Vertebral Morphologic Measurements: Comparison With Computed Tomography. AB - BACKGROUND: Though computed tomography (CT) and 3 dimensional (3D) reconstruction of the spine and ribcage are powerful techniques for detailed monitoring of spinal growth and surgical planning of patients, drawbacks can arise. We explored the application of low-dose stereoradiography of the spine to calculate distinct morphologic parameters of the vertebral body in a juvenile patient population with early-onset scoliosis or congenital scoliosis. This study compares the 3D vertebral morphology measurements using low-dose stereoradiography with the currently accepted imaging modality for such measurements, CT scans. METHODS: A total of 86 vertebrae of 6 patients with early-onset scoliosis and 3 patients with congenital scoliosis, age ranged between 7.8 and 12.5 years, who had both thoracic spine CT scan and low-dose stereoradiography of the spine were included. 3D reconstructions of CT and low-dose stereoradiography were generated. Using previously validated image processing techniques, vertebral anterior (A), posterior (P), left (L), and right (R) heights, superior and inferior endplates depth and width (S-D, I-D, S-W, I-W) were measured on the CTs' 3D reconstructions and were compared with the same parameters measured on low-dose stereoradiography reconstructions using a postprocessing custom code. The agreement between the 2 techniques in measurement of the vertebral morphology was assessed using the Bland-Altman plots. RESULTS: No significant difference was observed in the A, P, L, R, S-W, and I-W between the stereoradiography and CT measurements (P>0.05). S D and I-D were significantly greater in low-dose stereoradiography measurements P<0.05. Bland-Altman plots showed an agreement between the stereoradiography and CT techniques in vertebral height measurements (A, P, L, R); however, larger measurement bias and greater limits of agreement in S-D, I-D, S-W, and I-W measurements were shown. CONCLUSIONS: In vivo measurements of the vertebral heights using low-dose stereoradiography 3D reconstructions were comparable with CT measurements except for the superior and inferior vertebral depths. The low dose stereoradiography imaging modality and the postprocessing platform can be used for assessment of the vertebral heights and monitoring asymmetric growth in patients undergoing growth-sparing treatment except for the vertebral levels with congenital deformities. LEVEL OF EVIDENCE: Level IV. PMID- 28671879 TI - Feasibility of Protective Ventilation During Elective Supratentorial Neurosurgery: A Randomized, Crossover, Clinical Trial. AB - BACKGROUND: Traditional ventilation approaches, providing high tidal volumes (Vt), produce excessive alveolar distention and lung injury. Protective ventilation, employing lower Vt and positive end-expiratory pressure (PEEP), is an attractive alternative also for neuroanesthesia, when prolonged mechanical ventilation is needed. Nevertheless, protective ventilation during intracranial surgery may exert dangerous effects on intracranial pressure (ICP). We tested the feasibility of a protective ventilation strategy in neurosurgery. MATERIALS AND METHODS: Our monocentric, double-blind, 1:1 randomized, 2*2 crossover study aimed at studying the effect size and variability of ICP in patients undergoing elective supratentorial brain tumor removal and alternatively ventilated with Vt 9 mL/kg-PEEP 0 mm Hg and Vt 7 mL/kg-PEEP 5 mm Hg. Respiratory rate was adjusted to maintain comparable end-tidal carbon dioxide between ventilation modes. ICP was measured through a subdural catheter inserted before dural opening. RESULTS: Forty patients were enrolled; 8 (15%) were excluded after enrollment. ICP did not differ between traditional and protective ventilation (11.28+/-5.37, 11 [7 to 14.5] vs. 11.90+/-5.86, 11 [8 to 15] mm Hg; P=0.541). End-tidal carbon dioxide (28.91+/-2.28, 29 [28 to 30] vs. 28.00+/-2.17, 28 [27 to 29] mm Hg; P<0.001). Peak airway pressure (17.25+/-1.97, 17 [16 to 18.5] vs. 15.81+/-2.87, 15.5 [14 to 17] mm Hg; P<0.001) and plateau airway pressure (16.06+/-2.30, 16 [14.5 to 17] vs. 14.19+/-2.82, 14 [12.5 to 16] mm Hg; P<0.001) were higher during protective ventilation. Blood pressure, heart rate, and body temperature did not differ between ventilation modes. Dural tension was "acceptable for surgery" in all cases. ICP differences between ventilation modes were not affected by ICP values under traditional ventilation (coefficient=0.067; 95% confidence interval, -0.278 to 0.144; P=0.523). CONCLUSIONS: Protective ventilation is a feasible alternative to traditional ventilation during elective neurosurgery. PMID- 28671880 TI - An Unusual Presentation of Tapia Syndrome Mimicking a Partial Wallenberg Syndrome Following Anterior Cervical Spine Surgery. PMID- 28671881 TI - Treatment of Degenerative Lumbar Spondylolisthesis With Fusion or Decompression Alone Results in Similar Rates of Reoperation at 5 Years. AB - STUDY DESIGN: Population-based analysis of administrative discharge records from California, Florida, and New York inpatient, ambulatory, and emergency department settings between 2005 and 2011, utilizing Healthcare Cost and Utilization Project data. OBJECTIVE: We aimed to compare, and characterize rates of reoperation and readmission among patients with degenerative spondylolisthesis treated with surgical decompression alone versus fusion. SUMMARY OF BACKGROUND DATA: Degenerative lumbar spondylolisthesis with stenosis can be treated by decompression with or without fusion. Fusion has traditionally been preferred. We hypothesized that rates of reoperation after decompression alone would be higher than after fusion. MATERIALS AND METHODS: We undertook a population-based analysis of administrative discharge records from California, Florida, and New York inpatient, ambulatory, and emergency department settings between 2005 and 2011, with Healthcare Cost and Utilization Project data. We identified all patients who had degenerative spondylolisthesis who were treated with decompression alone or with fusion and compared their rates of reoperation at 1, 3, and 5 years from the index operation. We used descriptive statistics and a hierarchical logistic regression model to generate risk-adjusted odds of all cause readmissions. RESULTS: Our study consisted of 75,024 patients with spondylolisthesis; 6712 (8.95%) of them underwent decompression alone and 68,312 (91.05%) of them underwent fusion. Rates of reoperation were higher for decompression versus fusion at 1 year; 6.87% versus 5.53% (P<=0.001), but at 3 years; 13.86% versus 12.91% (P=0.18) and 5 years; 16.9% versus 17.7% (P=0.398) years rates of reoperation were not statistically different. Patients treated with decompression alone that had a second operation tended to have the operation sooner 512.6 versus 567.4 days (P=0.008). CONCLUSIONS: Our study suggests that treatment of degenerative spondylolisthesis with fusion or decompression alone results in similar rates of reoperation at 5 years. This medium term data indicate that decompression alone may be a viable treatment for some patients with degenerative spondylolisthesis. PMID- 28671882 TI - Absence of an Additional Metabolic Effect of Body Contour Surgery in Patients With Massive Weight Loss After Laparoscopic Roux-En-Y Gastric Bypass. AB - INTRODUCTION: Body contour surgery (BCS) is a combination of soft tissue resections that have proven to be an effective treatment for the aesthetic and functional problems related to massive weight loss (MWL). There are no studies analyzing the metabolic effect of large volume adipose tissue flap resection in patients with MWL after bariatric surgery. METHODS: This study was a retrospective review of adults who underwent BCS after gastric bypass. Preoperative clinical and laboratory data were compared with 1- and 2-year postoperative follow-up. RESULTS: A total of 62 patients with a mean age of 41 years were analyzed. Seventy-nine percent of them were women. Most procedures included abdominal flap resection alone or in combination with other areas. Mean resected tissue weight was 6.2 kg. We found that weight and body mass index (BMI) were lower 1 year after BCS (P < 0.05), but this was not maintained after 2 years. There were no differences for systolic or diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, or fasting glucose after 1 and 2 years of the BCS. A subgroup analysis showed that the transient weight and BMI improvement was only apparent 1 year after BCS in those patients with flap resections more than 8 kg. CONCLUSIONS: There are no differences in blood pressure, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, or fasting glucose 1 and 2 years after BCS in patients who experienced MWL after gastric bypass. Although weight and BMI were transiently lower in those patients with tissue flap resections more than 8 kg, this effect disappeared after 2 years. PMID- 28671883 TI - Prevention of Peritendinous Adhesion Formation After the Flexor Tendon Surgery in Rabbits: A Comparative Study Between Use of Local Interferon-alpha, Interferon beta, and 5-Fluorouracil. AB - BACKGROUND: Peritendinous adhesion is the most common complication after tendon surgery, particularly in zone II of the hand. Prevention of inflammation around the tendon, which develops after trauma and surgery, can decrease the tendon adhesion formation. This study compares the effect of some anti-inflammatory cytokines with 5-fluorouracil (5-FU) on the tensile strength and in prevention of peritendinous adhesion formation. METHODS: Sixteen rabbits were allocated equally into 4 groups. Tendons of the index and ring fingers in zone II of the right hind paw were cut in all animals and then repaired. Interferon (IFN)-alpha in group 1, 5-FU in group 2, normal saline in group 3, and IFN-beta in group 4 were locally applied to the repaired sites. Three weeks later, tensometric and histopathologic evaluations were performed. RESULTS: The force required for removing the tendon from the sheath was not different between the groups (P = 0.130), but the time required for removal was significantly shorter in 5-FU group (P = 0.049). The strength of repair was not different between the groups in terms of force and time needed for rupture (P = 0.11 and 0.67, respectively). In histopathologic examination, normal architecture of the tendon and peritendon environment was less disturbed in the IFN groups, especially in IFN-beta specimens. CONCLUSIONS: Local application of 5-FU significantly reduced peritendinous adhesion. Local IFN alpha and IFN-beta had no significant effect on the prevention of peritendinous adhesion formation. The strength of the repair was not affected by these cytokines and 5-FU. PMID- 28671884 TI - Different Recipient Vessels for Free Microsurgical Fibula Flaps in the Treatment of Avascular Necrosis of the Femoral Head: A Systematic Review and Meta-analysis. AB - BACKGROUND: Several recipient vessels can be used in free microsurgical fibula flaps (MFFs) for the treatment of avascular necrosis of the femoral head (ANFH). Few articles investigate the influence of different recipient vessels on outcomes of MFF for ANFH. METHODS: A comprehensive literature search of databases including PubMed-Medline, Ovid-Embase, and Cochrane Library was performed to collect the related studies. The Medical Subject Headings used were "femur head necrosis" and "bone transplantation." The relevant words in title or abstract included but not limited to "fibula flap," "fibular flap," "vascularized fibula," "vascularized fibular," "free fibula," "free fibular," "femoral head necrosis," "avascular necrosis of femoral head," and "ischemic necrosis of femoral head." The methodological index for nonrandomized studies was adopted for assessing the studies included in this review. RESULTS: Finally, 15 studies encompassing a total of 1267 patients (1603 hips) with ANFH were pooled in the overall analysis. Recipient vessels for MFF included the ascending branch of the lateral circumflex femoral artery and vein in 8 studies, descending branch of the lateral circumflex femoral artery and vein in 2 studies, second perforating branch of the deep femoral artery and vein in 4 studies, and inferior gluteal artery and vein in 1 study. Preoperative and postoperative average Harris hip score and pooled analyses of the rate of conversion, radiographic progression, and hip surgery related complications showed no significant difference on the outcomes of MFF on ANFH between using different recipient vessels. CONCLUSIONS: Different recipient vessels did not affect outcomes in MFF procedures for ANFH. High-quality randomized controlled trials and prospective studies would be necessary to clarify reliable advantages and disadvantages between different recipient vessels. Until then, surgeons are justified in using ascending branch of the lateral circumflex femoral artery and vein, descending branch of the lateral circumflex femoral artery and vein, second perforating branch of the deep femoral artery and vein, and inferior gluteal artery and vein vessels according to care circumstances and customary practice. PMID- 28671885 TI - Effects of the Metallic Port in Tissue Expanders on Dose Distribution in Postmastectomy Radiotherapy: A Tridimensional Experimental Model of Dosimetry in Breast Reconstruction. AB - The purpose of this research was to develop an experimental model of dosimetry using a breast phantom and evaluate the effects of the metallic port in tissue expanders on dose distribution in postmastectomy radiotherapy. Dose distribution was assessed using an experimental acrylic dosimetry simulator in the absence and presence of a metallic disc (MD), which is similar to that used in tissue expanders containing a magnetic port, by collecting coronal and sagittal radiochromic films. Dosimetry film analysis did not show any changes in dose distribution, except for a MD shadow in the sagittal film where the dose distribution rate was on average 14% lower than in other areas. This model very closely resembled actual breast reconstruction with a tissue expander containing a magnetic port. Scattering or attenuation of the irradiation dose due to interference of the MD was not evident in areas that could jeopardize the effectiveness of radiation therapy. Therefore, the presence of the MD inside the tissue expander does not likely have an impact on radiotherapy effectiveness during immediate breast reconstruction. PMID- 28671886 TI - Effect of Drain Placement on Infection, Seroma, and Return to Operating Room in Expander-Based Breast Reconstruction. AB - INTRODUCTION: There is significant variability in the location and management of drains in breast reconstruction, with most surgeons attempting to shorten the duration of drains while preventing complications possibly related to early removal. The aim of this work was to compare our experiences with placement of 1 versus 2 drains in tissue expander breast reconstruction. METHODS: This is a retrospective cohort study comparing 2 groups of patients after breast tissue expander placement in a complete submuscular pocket and without the use of acellular dermal matrix. In the first group, a single subcutaneous drain was placed; in the second group, both a subcutaneous and a submuscular drain were placed. These groups were evaluated on their relative duration of drain placement, incidence of seroma formation, incidence of infection, and rates of complication necessitating return to operating room (OR). RESULTS: The single drain group was found to have a significantly shorter duration of drain placement (14.58 vs 22.84 days, P = < 0.01) as well as lower incidence of return to OR for complications after expander placement (8.3% vs 17.6%, P = 0.040), with no difference in rate of seroma formation (6.9% vs 14.7%, P = 0.114) or infection (1.4% in the single-drain group vs 8.8% in the 2-drain group, P = 0.054). CONCLUSIONS: Compared with a two-drain approach, a single subcutaneous drain yields shorter total duration of drain placement and lower rate of complications requiring return to OR while not resulting in higher rates of seroma or infection. It has become our standard approach to use a single subcutaneous drain in patients having a breast tissue expander placed in a submuscular pocket. PMID- 28671887 TI - Defining the Anatomy of the Tendinous Intersections of the Rectus Abdominis Muscle and Their Clinical Implications in Functional Muscle Neurotization. AB - PURPOSE: Little is known about the definitive course of the tendinous intersections from anterior to posterior through the rectus abdominis (RA) muscle. The implications of a full thickness intersection may have effects on the ability to neurotize the RA. We hypothesized that these tendinous inscriptions would be fully adherent to the anterior rectus sheath, but there would be an incomplete penetrance into the posterior surface, thereby allowing for muscle fibers and neurovascular structures to run the entire course of the RA muscle. METHODS: Fifty-five cadaveric, hemiabdominal walls were evaluated. Measurements were taken of RA muscle thickness, depth of penetrance of the tendinous intersections, and intersection thickness. RESULTS: Of the 32 cadavers, 2 had 4 paired tendinous intersections and the remaining 30 cadavers had 3 paired tendinous intersections. Rectus abdominis muscle belly tended to be thicker at midbelly, between intersections than at the level of the corresponding intersection. A total of 168 tendinous intersections were assessed. Thirty (18%) of these inscriptions proved to be full thickness extending from anterior rectus sheath to posterior rectus sheath without any intervening muscle or neurovascular structures. Twenty-three (42%) of the 55 hemiabdomens assessed had at least one full-thickness tendinous intersection. CONCLUSIONS: The majority of RA muscles have 3 paired tendinous intersections. Most intersections are incomplete and only encompass the anterior rectus sheath. However, there may be a higher percentage of full-thickness intersections than previously appreciated and the clinical relevance behind these remains unclear. PMID- 28671888 TI - Complications After Total Skin-Sparing Mastectomy and Expander-Implant Reconstruction: Effects of Radiation Therapy on the Stages of Reconstruction. AB - BACKGROUND: Many patients undergoing total-skin sparing mastectomy (TSSM) and 2 staged expander-implant (TE-I) reconstruction require postmastectomy radiation therapy (PMRT). Additionally, many patients undergoing TSSM for recurrent cancer have a history of lumpectomy and radiation therapy (XRT). Few studies have looked at the impact of XRT on the stages of TE-I reconstruction. METHODS: Patients undergoing TSSM and immediate TE-I reconstruction between 2006 and 2013 were identified from a prospectively maintained database. Rates of TE-I loss and severe infection requiring intravenous antibiotics were compared in patients with prior XRT (85 cases) and PMRT (133 cases). Complications were divided by stage of reconstruction: first stage (TSSM and TE placement) and second stage (TE-I exchange). RESULTS: Mean follow-up time was 2.5 years. Patients with prior XRT had more complications after the first stage of reconstruction than the second (TE-I loss: 15% vs 5%, P = 0.03; infection: 20% vs 8%, P = 0.04). Patients receiving PMRT had low complication rates after the first stage, when they had not yet received radiation (TE-I loss: 2%; infection: 5%). However, complication rates after TE-I exchange (TE-I loss, 18%; infection, 31%) were significantly higher, and nearly 4-fold higher than patients with prior XRT. CONCLUSIONS: Patients with prior XRT are at high risk for complications after the first stage of TE-I reconstruction after TSSM; however, the risk of complications at the second stage is comparable to patients without radiation exposure and significantly lower than patients receiving PMRT. Patients receiving radiation therapy should be given appropriate preoperative counseling regarding their risks. PMID- 28671889 TI - Cell-Based Soft Tissue Reconstruction in a Hydrogel Scaffold. AB - BACKGROUND: Renevia is a hyaluronin-gelatin crosslinked matrix scaffold that has been studied as an alternative to adipose transfer in soft tissue reconstruction. It is designed to emulate the native extracellular matrix environment by supporting stromal vascular fraction (SVF) cell attachment, survival, and proliferation, thus promoting cell-based volume restoration. However, the concentration of incorporated cells for a clinically relevant result has yet to be determined. METHODS: Five experimental groups of seven CD-1 nude immunodeficient mice were given 250 MUL grafts of the following composition: 1 million human SVF cells per mL of Renevia scaffold, 6 million human SVF cells per mL scaffold, 12 million human SVF cells per mL scaffold, Renevia scaffold-alone or human adipose tissue-alone. Volumetric analysis was conducted at discrete time points over 16 weeks using 3-dimensional ultrasound, after which time the grafts were explanted for histologic analysis. RESULTS: At the conclusion of the study at week 16, the Renevia scaffold group incorporating the highest concentration of human SVF cells (12 million cells per mL scaffold) had significantly greater volume retention compared with the 2 lower concentrations, scaffold-alone and fat alone groups. Histology of the 12 million scaffold group revealed abundant adipocyte formation within the scaffold, exceeding that observed in the 6 million, 1 million, and scaffold-alone groups. The 12 million group also demonstrated significantly increased vascularity per CD31 staining. CONCLUSIONS: Stromal vascular fraction cells coupled with Renevia hydrogel scaffold can enhance soft tissue volume reconstruction. In this study, we observed the greatest effect with 12 million cells per mL. From the perspective of volume retention, incorporation of higher concentrations of SVF cells with Renevia may be an alternative to conventional adipose tissue grafting. PMID- 28671890 TI - Management of Infected Mesh After Abdominal Hernia Repair: Systematic Review and Single-Institution Experience. AB - BACKGROUND: Mesh infection after abdominal hernia repair is a devastating complication that affects general and plastic surgeons alike. The purpose of this study was 3-fold: (1) to determine current evidence for treatment of infected abdominal wall mesh via systematic review of literature, (2) to analyze our single-institution experience with treatment of infected mesh patients, and (3) to establish a framework for how to approach this complex clinical problem. METHODS: Literature search was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, followed by single-institution retrospective analysis of infected mesh patients. RESULTS: A total of 3565 abstracts and 92 full-text articles were reviewed. For qualitative and quantitative assessment, articles were subdivided on the basis of treatment approach: "conservative management," "excision of mesh with primary closure," "single-stage reconstruction," "immediate staged repair," and "repair in contaminated field." Evidence for each treatment approach is presented. At our institution, most patients (40/43) were treated by excision of infected mesh and single-stage reconstruction with biologic mesh. When the mesh was placed in a retrorectus or underlay fashion, 21.4% rate of hernia recurrence was achieved. Bridged repairs were highly prone to recurrence (88.9%; P = 0.001), but the bridging biologic mesh seemed to maintain domain and potentially contribute to a more effective repair in the future. Of the patients who underwent additional ("secondary") repairs after recurrence, 75% were eventually able to achieve "hernia-free" state. CONCLUSIONS: This study reviews the literature and our single-institution experience regarding treatment of infected abdominal wall mesh. Framework is developed for how to approach this complex clinical problem. PMID- 28671891 TI - Associations Between Maternal Mental Health and Well-being and Physical Activity and Sedentary Behavior in Children. AB - OBJECTIVE: This study assessed whether aspects of maternal mental health and well being were associated with objective monitor-based measures of child's physical activity (PA) and sedentary behavior (SB) and the extent to which household structure (i.e., single- vs multigenerational/dual-parent) and maternal employment (i.e., full-time vs not full-time) moderated those associations. METHODS: Dyads (N = 191) of mothers and their 8- to 12-year-old children participated in the baseline wave of the Mother's and Their Children's Health study. Mothers (Mage = 40.9 yr [SD = 6.1]; 49% Hispanic) completed a battery of questionnaires to assess maternal mental health and well-being (i.e., self esteem, life satisfaction, depressive symptoms, anxiety, perceived stress, parenting stress, financial stress, and life events stress). Children (Mage = 9.6 yr [SD = 0.9]; 54% Hispanic; 51% girls) wore an accelerometer across 1 week during waking hours to objectively measure moderate-to-vigorous PA (MVPA) and SB. RESULTS: In single-parent families (n = 47), but not multigenerational/dual parent families, mothers' parenting stress was negatively associated with child's MVPA (beta = -.34, p = .02). In corrected analyses, all other aspects of maternal mental health and well-being were not related to children's activity patterns. CONCLUSION: Parenting stress was the only maternal mental health variable associated with objective monitor-based measures of child's PA after adjusting for multiple comparisons. Results indicated weaker associations between maternal mental health and well-being and child's MVPA and SB than previously identified using subjective measures of behavior. Study findings support the need to use objective measurements of child's activity patterns to minimize potential confounding because of maternal report in evaluating child's PA and SB. PMID- 28671892 TI - Physical Activity Interventions for Children with Social, Emotional, and Behavioral Disabilities-A Systematic Review. AB - OBJECTIVE: Perform a systematic review of the available literature regarding the effectiveness of exercise interventions on children with any type of social, emotional, or behavioral disability (SEBD), with attention to a range of physiological, behavioral, and mood outcomes. METHODS: Six databases were searched using a systematic methodology. References of included studies, as well as relevant reviews, were also examined. The review was limited to studies published since 2000 reporting a quantitative analysis of the effects of a physical activity (PA) intervention on at least 1 behavioral, psychological, or cognitive outcome in children aged 21 and under, diagnosed with a SEBD. Only studies with a control group were included. RESULTS: We identified 24 eligible studies. Studies varied in design, participant characteristics, and intervention characteristics (single-bout vs repeated exposure, duration, intensity level, mode of exercise). Of the 20 behavioral outcome assessments, there was 1 negative finding, 12 null findings, 5 positive findings, and 2 mixed findings. For the 25 executive functioning outcome assessments, there were 5 null findings, 18 positive findings, and 2 mixed findings. For the remaining outcome domains, 1 of 2 studies looking at academic performance, 3 of 6 studies looking at objective neurological measures, and 1 of 3 studies looking at affect outcomes found positive results. All other results were null or mixed. CONCLUSION: Although additional research is warranted to further understand the mechanisms by which PA affects behavioral and cognitive outcome measures in children with SEBDs, PA offers a safe and alternative form of treatment for this population. PMID- 28671894 TI - Midrange Braden Subscale Scores Are Associated With Increased Risk for Pressure Injury Development Among Critical Care Patients. AB - PURPOSE: The purpose of the current study was to examine the relationship between pressure injury development and the Braden Scale for Pressure Sore Risk subscale scores in a surgical intensive care unit (ICU) population and to ascertain whether the risk represented by the subscale scores is different between older and younger patients. DESIGN: Retrospective review of electronic medical records. SUBJECTS AND SETTING: The sample comprised patients admitted to the ICU at an academic medical center in the Western United States (Utah) and Level 1 trauma center between January 1, 2008 and May 1, 2013. Analysis is based on data from 6377 patients. METHODS: Retrospective chart review was used to determine Braden Scale total and subscale scores, age, and incidence of pressure injury development. We used survival analysis to determine the hazards of developing a pressure injury associated with each subscale of the Braden Scale, with the lowest-risk category as a reference. In addition, we used time-dependent Cox regression with natural cubic splines to model the interaction between age and Braden Scale scores and subscale scores in pressure injury risk. RESULTS: Of the 6377 ICU patients, 214 (4%) developed a pressure injury (stages 2-4, deep tissue injury, or unstageable) and 516 (8%) developed a hospital-acquired pressure injury of any stage. With the exception of the friction and shear subscales, regardless of age, individuals with scores in the intermediate-risk levels had the highest likelihood of developing pressure injury. CONCLUSION: The relationship between age, Braden Scale subscale scores, and pressure injury development varied among subscales. Maximal preventive efforts should be extended to include individuals with intermediate Braden Scale subscale scores, and age should be considered along with the subscale scores as a factor in care planning. PMID- 28671895 TI - OUTCOMES OF PATIENTS WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION TREATED WITH ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR THREE OR MORE YEARS: A Review of Current Outcomes. AB - PURPOSE: To summarize the findings of long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy (>=36 months) in patients with exudative age-related macular degeneration. METHODS: Studies reporting long-term outcomes (>=36 months) of anti-VEGF therapy (n = 11) were identified and analyzed for changes in visual acuity (VA), optical coherence tomography, and safety findings. RESULTS: Six prospective extension studies of Phase 3 clinical trials and five retrospective evaluation studies were identified. The largest improvements in VA with anti-VEGF treatment were found in Years 1 to 2 after treatment initiation. In five studies, VA ultimately declined below patients' pretreatment initial baseline; in three studies, VA ultimately returned to patients' baseline; in three studies, VA decreased but ultimately remained improved over patients' baseline. There was a trend demonstrating that a higher frequency of intravitreous injections showed a better maintenance in VA. Rates of adverse events were similar to previous registration studies of anti-VEGF drugs. CONCLUSION: The body of evidence to date regarding long-term anti-VEGF treatment indicates a variable course at greater than 36 months follow-up and seems to be dependent on the treatment protocol. Consistent dosing with fluid-free interval is suggested to maintain VA gains in patients with exudative age-related macular degeneration. There is no evidence suggesting that there are additional adverse events from long-term anti-VEGF use. PMID- 28671896 TI - EVALUATION OF MACULAR ISCHEMIA IN EYES WITH CENTRAL RETINAL VEIN OCCLUSION: An Optical Coherence Tomography Angiography Study. AB - PURPOSE: To quantitatively assess macular perfusion status using optical coherence tomography angiography in eyes with aflibercept-treated central retinal vein occlusion and resolved macular edema and to investigate the impact of macular morphology and perfusion status on visual function. METHODS: This prospective consecutive case series included 23 patients with central retinal vein occlusion. All patients received intravitreal aflibercept injections before analysis. Visual acuity, macular sensitivity, and the macular nonperfusion area (NPA) were evaluated in eyes without macular edema. The macular NPA was evaluated by optical coherence tomography angiography using 3 mm * 3 mm images of the macula. Foveal ellipsoid zone disruption was also analyzed. RESULTS: The superficial macular NPA measured 4.15 mm +/- 0.71 mm (95% confidence interval 3.85-4.46), and the deep macular NPA measured 4.23 mm +/- 0.97 mm (95% confidence interval 3.82-4.56). The logarithm of the minimum angle of resolution visual acuity was significantly associated with foveal ellipsoid zone disruption (P = 0.001), the superficial macular NPA (P = 0.015), and the deep macular NPA (P = 0.018). Macular sensitivity correlated negatively with logarithm of the minimum angle of resolution visual acuity (P = 0.007), the superficial macular NPA (P = 0.029), and the deep macular NPA (P = 0.040), but not with the foveal ellipsoid zone disruption (P = 0.435). CONCLUSION: Optical coherence tomography angiography is a novel technique that enables segmented evaluation of the macular perfusion status in eyes with central retinal vein occlusion and provides visual prognostic information. Enlargement of the macular NPA in the superficial and deep layers was significantly correlated with impaired visual acuity and with decreased macular sensitivity in patients with aflibercept-treated central retinal vein occlusion and resolved macular edema. PMID- 28671897 TI - Proactive Safety Management in Trauma Care: Applying the Human Factors Analysis and Classification System. AB - INTRODUCTION: This article examines the reliability of the Human Factors Analysis and Classification System (HFACS) for classifying observational human factors data collected prospectively in a trauma resuscitation center. METHODS: Three trained human factors analysts individually categorized 1,137 workflow disruptions identified in a previously collected data set involving 65 observed trauma care cases using the HFACS framework. RESULTS: Results revealed that the framework was substantially reliable overall (kappa = 0.680); agreement increased when only the preconditions for unsafe acts were investigated (kappa = 0.757). Findings of the analysis also revealed that the preconditions for unsafe acts category was most highly populated (91.95%), consisting mainly of failures involving communication, coordination, and planning. CONCLUSION: This study helps validate the use of HFACS as a tool for classifying observational data in a variety of medical domains. By identifying preconditions for unsafe acts, health care professionals may be able to construct a more robust safety management system that may provide a better understanding of the types of threats that can impact patient safety. PMID- 28671898 TI - Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort. AB - OBJECTIVES: The objectives of this study were to 1) assess patterns of early crystalloid resuscitation provided to sepsis and septic shock patients at initial presentation and 2) determine the association between time to initial crystalloid resuscitation with hospital mortality, mechanical ventilation, ICU utilization, and length of stay. DESIGN: Consecutive-sample observational cohort. SETTING: Nine tertiary and community hospitals over 1.5 years. PATIENTS: Adult sepsis and septic shock patients captured in a prospective quality improvement database inclusion criteria: suspected or confirmed infection, greater than or equal to two systemic inflammatory response criteria, greater than or equal to one organ dysfunction criteria. INTERVENTIONS: The primary exposure was crystalloid initiation within 30 minutes or lesser, 31-120 minutes, or more than 120 minutes from sepsis identification. MEASUREMENTS AND MAIN RESULTS: We identified 11,182 patients. Crystalloid initiation was faster for emergency department patients (beta, -141 min; CI, -159 to -125; p < 0.001), baseline hypotension (beta, -39 min; CI, -48 to -32; p < 0.001), fever, urinary or skin/soft-tissue source of infection. Initiation was slower with heart failure (beta, 20 min; CI, 14-25; p < 0.001), and renal failure (beta, 16 min; CI, 10-22; p < 0.001). Five thousand three hundred thirty-six patients (48%) had crystalloid initiated in 30 minutes or lesser versus 2,388 (21%) in 31-120 minutes, and 3,458 (31%) in more than 120 minutes. The patients receiving fluids within 30 minutes had lowest mortality (949 [17.8%]) versus 31-120 minutes (446 [18.7%]) and more than 120 minutes (846 [24.5%]). Compared with more than 120 minutes, the adjusted odds ratio for mortality was 0.76 (CI, 0.64-0.90; p = 0.002) for 30 minutes or lesser and 0.76 (CI, 0.62-0.92; p = 0.004) for 31-120 minutes. When assessed continuously, mortality odds increased by 1.09 with each hour to initiation (CI, 1.03-1.16; p = 0.002). We observed similar patterns for mechanical ventilation, ICU utilization, and length of stay. We did not observe significant interaction for mortality risk between initiation time and baseline heart failure, renal failure, hypotension, acute kidney injury, altered gas exchange, or emergency department (vs inpatient) presentation. CONCLUSIONS: Crystalloid was initiated significantly later with comorbid heart failure and renal failure, with absence of fever or hypotension, and in inpatient-presenting sepsis. Earlier crystalloid initiation was associated with decreased mortality. Comorbidities and severity did not modify this effect. PMID- 28671899 TI - Clinicians' Perception and Experience of Organ Donation From Brain-Dead Patients. AB - OBJECTIVE: ICU clinicians are primarily involved in organ donation after brain death of ICU patients. Their perceptions of organ donation may affect outcomes. Our objective was to describe ICU clinician's perceptions and experience of organ donation. DESIGN AND SETTING: Cross-sectional study among physicians and nurses (90 ICUs in France). We used factorial correspondence analysis to describe categories of clinicians regarding their perceptions and experience of organ donation. Factors associated with a positive (motivating) or negative (stressful) experiences were studied using multivariate logistic regression. PARTICIPANTS: Physicians and nurses. MEASUREMENTS AND MAIN RESULTS: Three thousand three hundred twenty-five clinicians working in 77 ICUs returned questionnaires. Professionals who experienced organ donation as motivating were younger (odds ratio, 0.41; 95% CI, 0.32-0.53; p < 0.001), more often potential organ donors (odds ratio, 1.92; 95% CI, 1.56-2.35; p < 0.001), less likely to describe inconsistency (odds ratio, 0.43; 95% CI, 0.23-0.8) or complexity (odds ratio, 0.55; 95% CI, 0.45-0.67) of their feelings versus their professional activity, less likely to report that organ donation was not a priority in their ICU (odds ratio, 0.68; 95% CI, 0.55-0.84), and more likely to have participated in meetings of transplant coordinators with relatives (odds ratio, 1.71; 95% CI, 1.37-2.14; p < 0.001). Professionals who felt organ donation was stressful were older (odds ratio, 1.84; 95% CI, 1.34-2.54; p < 0.001), less often physicians (odds ratio, 0.58; 95% CI, 0.44-0.77; p < 0.001), more likely to describe shift from curative care to organ donation as emotionally complex (odds ratio, 1.83; 95% CI, 1.52 2.21; p < 0.001), care of relatives of brain-dead patients as complex (odds ratio, 1.59; 95% CI, 1.32-1.93; p < 0.001), and inconsistency and complexity of personal feelings about organ donation versus professional activity (odds ratio, 3.25; 95% CI, 1.92-5.53; p < 0.001), and more likely to have little experience with caring for potential organ donors (odds ratio, 1.49; 95% CI, 1.09-2.04). CONCLUSIONS: Significant differences exist among ICU clinician's perceptions of organ donation. Whether these differences affect family experience and consent rates deserves investigation. PMID- 28671900 TI - Phenotyping the Immune Response to Trauma: A Multiparametric Systems Immunology Approach. AB - OBJECTIVE: Trauma induces a complex immune response that requires a systems biology research approach. Here, we used a novel technology, mass cytometry by time-of-flight, to comprehensively characterize the multicellular response to trauma. DESIGN: Peripheral blood mononuclear cells samples were stained with a 38 marker immunophenotyping cytometry by time-of-flight panel. Separately, matched peripheral blood mononuclear cells were stimulated in vitro with heat-killed Streptococcus pneumoniae or CD3/CD28 antibodies and stained with a 38-marker cytokine panel. Monocytes were studied for phagocytosis and oxidative burst. SETTING: Single-institution level 1 trauma center. PATIENTS OR SUBJECTS: Trauma patients with injury severity scores greater than 20 (n = 10) at days 1, 3, and 5 after injury, and age- and gender-matched controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Trauma-induced expansion of Th17-type CD4 T cells was seen with increased expression of interleukin-17 and interleukin-22 by day 5 after injury. Natural killer cells showed reduced T-bet expression at day 1 with an associated decrease in tumor necrosis factor-beta, interferon-gamma, and monocyte chemoattractant protein-1. Monocytes showed robust expansion following trauma but displayed decreased stimulated proinflammatory cytokine production and significantly reduced human leukocyte antigen - antigen D related expression. Further analysis of trauma-induced monocytes indicated that phagocytosis was no different from controls. However, monocyte oxidative burst after stimulation increased significantly after injury. CONCLUSIONS: Using cytometry by time-of flight, we were able to identify several major time-dependent phenotypic changes in blood immune cell subsets that occur following trauma, including induction of Th17-type CD4 T cells, reduced T-bet expression by natural killer cells, and expansion of blood monocytes with less proinflammatory cytokine response to bacterial stimulation and less human leukocyte antigen - antigen D related. We hypothesized that monocyte function might be suppressed after injury. However, monocyte phagocytosis was normal and oxidative burst was augmented, suggesting that their innate antimicrobial functions were preserved. Future studies will better characterize the cell subsets identified as being significantly altered by trauma using cytometry by time-of-flight, RNAseq technology, and functional studies. PMID- 28671902 TI - Simulation for Assessment of the Practice of Board-certified Anesthesiologists. PMID- 28671901 TI - Effectiveness and Safety of an Extended ICU Visitation Model for Delirium Prevention: A Before and After Study. AB - OBJECTIVES: To evaluate the effect of an extended visitation model compared with a restricted visitation model on the occurrence of delirium among ICU patients. DESIGN: Prospective single-center before and after study. SETTING: Thirty-one-bed medical-surgical ICU. PATIENTS: All patients greater than or equal to 18 years old with expected length of stay greater than or equal to 24 hours consecutively admitted to the ICU from May 2015 to November 2015. INTERVENTIONS: Change of visitation policy from a restricted visitation model (4.5 hr/d) to an extended visitation model (12 hr/d). MEASUREMENTS AND MAIN RESULTS: Two hundred eighty-six patients were enrolled (141 restricted visitation model, 145 extended visitation model). The primary outcome was the cumulative incidence of delirium, assessed bid using the confusion assessment method for the ICU. Predefined secondary outcomes included duration of delirium/coma; any ICU-acquired infection; ICU acquired bloodstream infection, pneumonia, and urinary tract infection; all-cause ICU mortality; and length of ICU stay. The median duration of visits increased from 133 minutes (interquartile range, 97.7-162.0) in restricted visitation model to 245 minutes (interquartile range, 175.0-272.0) in extended visitation model (p < 0.001). Fourteen patients (9.6%) developed delirium in extended visitation model compared with 29 (20.5%) in restricted visitation model (adjusted relative risk, 0.50; 95% CI, 0.26-0.95). In comparison with restricted visitation model patients, extended visitation model patients had shorter length of delirium/coma (1.5 d [interquartile range, 1.0-3.0] vs 3.0 d [interquartile range, 2.5-5.0]; p = 0.03) and ICU stay (3.0 d [interquartile range, 2.0-4.0] vs 4.0 d [interquartile range, 2.0-6.0]; p = 0.04). The rate of ICU-acquired infections and all-cause ICU mortality did not differ significantly between the two study groups. CONCLUSIONS: In this medical-surgical ICU, an extended visitation model was associated with reduced occurrence of delirium and shorter length of delirium/coma and ICU stay. PMID- 28671903 TI - Simulation-based Assessment of the Management of Critical Events by Board certified Anesthesiologists. AB - BACKGROUND: We sought to determine whether mannequin-based simulation can reliably characterize how board-certified anesthesiologists manage simulated medical emergencies. Our primary focus was to identify gaps in performance and to establish psychometric properties of the assessment methods. METHODS: A total of 263 consenting board-certified anesthesiologists participating in existing simulation-based maintenance of certification courses at one of eight simulation centers were video recorded performing simulated emergency scenarios. Each participated in two 20-min, standardized, high-fidelity simulated medical crisis scenarios, once each as primary anesthesiologist and first responder. Via a Delphi technique, an independent panel of expert anesthesiologists identified critical performance elements for each scenario. Trained, blinded anesthesiologists rated video recordings using standardized rating tools. Measures included the percentage of critical performance elements observed and holistic (one to nine ordinal scale) ratings of participant's technical and nontechnical performance. Raters also judged whether the performance was at a level expected of a board-certified anesthesiologist. RESULTS: Rater reliability for most measures was good. In 284 simulated emergencies, participants were rated as successfully completing 81% (interquartile range, 75 to 90%) of the critical performance elements. The median rating of both technical and nontechnical holistic performance was five, distributed across the nine-point scale. Approximately one-quarter of participants received low holistic ratings (i.e., three or less). Higher-rated performances were associated with younger age but not with previous simulation experience or other individual characteristics. Calling for help was associated with better individual and team performance. CONCLUSIONS: Standardized simulation-based assessment identified performance gaps informing opportunities for improvement. If a substantial proportion of experienced anesthesiologists struggle with managing medical emergencies, continuing medical education activities should be reevaluated. PMID- 28671905 TI - The Impact of Incident Disclosure Behaviors on Medical Malpractice Claims. AB - OBJECTIVES: To provide preliminary estimates of incident disclosure behaviors on medical malpractice claims. METHODS: We conducted a descriptive analysis of data on medical malpractice claims obtained from the Controlled Risk Insurance Company and Risk Management Foundation of Harvard Medical Institutions (Cambridge, Massachusetts) between 2012 and 2013 (n = 434). The characteristics of disclosure and apology after medical errors were analyzed. RESULTS: Of 434 medical malpractice claims, 4.6% (n = 20) medical errors had been disclosed to the patient at the time of the error, and 5.9% (n = 26) had been followed by disclosure and apology. The highest number of disclosed injuries occurred in 2011 (23.9%; n = 11) and 2012 (34.8%; n = 16). There was no incremental increase during the financial years studied (2012-2013). The mean age of informed patients was 52.96 years, 58.7 % of the patients were female, and 52.2% were inpatients. Of the disclosed errors, 26.1% led to an adverse reaction, and 17.4% were fatal. The cause of disclosed medical error was improper surgical performance in 17.4% (95% confidence interval, 6.4-28.4). Disclosed medical errors were classified as medium severity in 67.4%. No apology statement was issued in 54.5% of medical errors classified as high severity. CONCLUSIONS: At the health-care centers studied, when a claim followed a medical error, providers infrequently disclosed medical errors or apologized to the patient or relatives. Most of the medical errors followed by disclosure and apology were classified as being of high and medium severity. No changes were detected in the volume of lawsuits over time. PMID- 28671904 TI - A Sandwich Method Using Kapandji Intrafocal Pinning to Facilitate Palmar Plating of Displaced Distal Radius Fractures. AB - The use of palmar plating in the treatment of dorsally displaced distal radius fracture is very common, and can result in a good functional outcome. We present an easy "sandwich method" to reduce the fracture and to facilitate osteosynthesis. Firstly, the dorsal Kapandji intrafocal wire was applied to achieve the reduction of the dorsally displaced fracture and provide a volar directed force. Then the intra-articular fractures were reduced or the metaphyseal defect is stuffed with bone graft if necessary. Finally, the anatomical plate is used to buttress and push back the distal fragment to complete the osteosynthesis. The postoperative radiographic parameters, comparing with the contralateral noninjured side, could achieve similar radial height, radial inclination, volar tilt, and ulnar variance without significant difference. PMID- 28671906 TI - Does One Size Fit All? Assessing the Need for Organizational Second Victim Support Programs. AB - OBJECTIVE: Second victims are health care providers who are emotionally traumatized after experiencing an unanticipated patient's adverse event. To support second victims, organizations can provide a dedicated support program for their workers. The aim of this study was to assess the extent of the second victim problem in acute care hospitals in the state of Maryland, the availability of emotional support services, and the need for organizational support programs. METHODS: In-depth, semistructured interviews were conducted with 43 patient safety representatives from 38 acute hospitals in Maryland. Data were analyzed using QSR NVivo10 software and a mixed-methods approach to generate codes and extract themes from the interviews. Descriptive statistics were generated for hospital and participant characteristics. RESULTS: The response rate was 83% of hospitals. All participants reported that they and their executives were aware of the second victim problem. Although participants varied in their perceptions of whether a dedicated second victim support program would be helpful for their hospital, all thought that hospitals should offer organizational support programs. Several organizations are attempting to promote a "just culture" in responding to events, and there continues to be stigma associated with speaking up during a root cause analysis, and with accessing support if it were offered. CONCLUSIONS: The second victim problem is recognized in all hospitals in Maryland. However, even when support is available, health care providers face stigma and other barriers in accessing it. Future efforts should assess the need for second victim programs from the perspectives of second victims themselves to identify barriers and improve uptake of needed support. PMID- 28671907 TI - Communication Training, Adverse Events, and Quality Measures: 2 Retrospective Database Analyses in Washington State Hospitals. AB - OBJECTIVE: Washington State's HealthPact program was launched in 2011 as part of AHRQ's Patient Safety and Medical Liability Reform initiative. HealthPact delivered interdisciplinary communication training to health-care professionals with the goal of enhancing safety. We conducted 2 exploratory, retrospective database analyses to investigate training impact on the frequency of adverse events (AEs) and select quality measures across 3 time frames: pretraining (2009 2011), transition (2012), and posttraining (2013). METHODS: Using administrative data from Washington State's Comprehensive Hospital Abstract Reporting System (CHARS) and clinical registry data from the Surgical Care and Outcomes Assessment Program (SCOAP), we compared proportions of AEs and quality measures between HealthPact (n = 4) and non-HealthPact (n = 93-CHARS; n = 48-SCOAP) participating hospitals. Risk ratios enabled comparisons between the 2 groups. Multivariable logistic regression enabled investigation of the association between training and the frequency of AEs. RESULTS: Approximately 9.4% (CHARS) and 7.7% (SCOAP) of unique patients experienced 1 AE or greater. In CHARS, the odds of a patient experiencing an AE in a HealthPact hospital were initially (pretraining) higher than in a non-HealthPact hospital (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.10-1.17), lower in transition (OR, 0.80; 95% CI, 0.76-0.83) and posttraining (OR, 0.72; 95% CI, 0.69-0.75) periods. In SCOAP, ORs were consistently lower in HealthPact hospitals: pretraining (OR, 0.87; 95% CI, 0.80 0.95), transition (OR, 0.75; 95% CI, 0.70-0.81), and posttraining (OR, 0.63; 95% CI, 0.58-0.68). The proportion of at-risk patients that experienced each individual AE was low (<1%) throughout. Adherence to quality measures was high. CONCLUSIONS: Interprofessional communication training is an area of intense activity nationwide. A broad-based training initiative may play a role in mitigating AEs. PMID- 28671909 TI - Effectiveness of Pharmacist Intervention to Reduce Medication Errors and Health Care Resources Utilization After Transitions of Care: A Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVES: Medication errors are common during transitions of care. The main objective of the current investigation was to examine the effectiveness of pharmacist-based transition of care interventions on the reduction of medication errors after hospital discharge. METHODS: A systematic search was conducted to detect published reports of randomized trials using the National Library of Medicine's PubMed database, the Cochrane Database of Systematic Reviews, and Google Scholar inclusive to July 1, 2015. Search terms included pharmacist, medication, errors, readmission, transition, and discharge. A priori main outcomes included medication errors and health-care resources utilization (hospital readmission and/or emergency room visits). Quantitative analysis was performed using a random effect method. RESULTS: Thirteen randomized trials examining 3503 patients were included in the final analysis. The aggregate effect of the 10 studies evaluating the effect of pharmacists intervention on the incidence of medication errors during transitions of care favored pharmacist over control with an odds ratio (95% confidence interval [CI]) of 0.44 (0.31-0.63). The overall effect of 4 studies evaluating the effect of a pharmacist intervention on the incidence of emergency room visits compared with control favored the pharmacist intervention, odds ratio (95% CI) of 0.42 (0.22-0.78), number needed to treat (95% CI) of 6.2 (3.4-31.4). CONCLUSIONS: Pharmacist transition of care intervention is an effective strategy to reduce medication errors after hospital discharge. In addition, a pharmacist intervention also reduces subsequent emergency room visits. Hospitals should consider implementing this intervention to improve patient safety and quality during transitions of care. PMID- 28671908 TI - Development of the Barriers to Error Disclosure Assessment Tool. AB - OBJECTIVES: An interprofessional group of health colleges' faculty created and piloted the Barriers to Error Disclosure Assessment tool as an instrument to measure barriers to medical error disclosure among health care providers. METHODS: A review of the literature guided the creation of items describing influences on the decision to disclose a medical error. Local and national experts in error disclosure used a modified Delphi process to gain consensus on the items included in the pilot. After receiving university institutional review board approval, researchers distributed the tool to a convenience sample of physicians (n = 19), pharmacists (n = 20), and nurses (n = 20) from an academic medical center. Means and SDs were used to describe the sample. Intraclass correlation coefficients were used to examine test-retest correspondence between the continuous items on the scale. Factor analysis with varimax rotation was used to determine factor loadings and examine internal consistency reliability. Cronbach alpha coefficients were calculated during initial and subsequent administrations to assess test-retest reliability. RESULTS: After omitting 2 items with intraclass correlation coefficient of less than 0.40, intraclass correlation coefficients ranged from 0.43 to 0.70, indicating fair to good test retest correspondence between the continuous items on the final draft. Factor analysis revealed the following factors during the initial administration: confidence and knowledge barriers, institutional barriers, psychological barriers, and financial concern barriers to medical error disclosure. alpha Coefficients of 0.85 to 0.93 at time 1 and 0.82 to 0.95 at time 2 supported test retest reliability. CONCLUSIONS: The final version of the 31-item tool can be used to measure perceptions about abilities for disclosing, impressions regarding institutional policies and climate, and specific barriers that inhibit disclosure by health care providers. Preliminary evidence supports the tool's validity and reliability for measuring disclosure variables. PMID- 28671910 TI - Changes to Hospital Inpatient Volume After Newspaper Reporting of Medical Errors. AB - OBJECTIVE: The aim of this study was to investigate the influence of medical error case reporting by national newspapers on inpatient volume at acute care hospitals. DESIGN: A case-control study was conducted using the article databases of 3 major Japanese newspapers with nationwide circulation between fiscal years 2012 and 2013. Data on inpatient volume at acute care hospitals were obtained from a Japanese government survey between fiscal years 2011 and 2014. Panel data were constructed and analyzed using a difference-in-differences design. SETTING: Acute care hospitals in Japan. PARTICIPANTS: Hospitals named in articles that included the terms "medical error" and "hospital" were designated case hospitals, which were matched with control hospitals using corresponding locations, nurse-to patient ratios, and bed numbers. EXPOSURE: Medical error case reporting in newspapers. MAIN OUTCOME MEASURES: Changes to hospital inpatient volume after error reports. RESULTS: The sample comprised 40 case hospitals and 40 control hospitals. Difference-in-differences analyses indicated that newspaper reporting of medical errors was not significantly associated (P = 0.122) with overall inpatient volume. CONCLUSIONS: Medical error case reporting by newspapers showed no influence on inpatient volume. Hospitals therefore have little incentive to respond adequately and proactively to medical errors. There may be a need for government intervention to improve the posterror response and encourage better health care safety. PMID- 28671911 TI - Burnout and Work Engagement Among US Dentists. AB - BACKGROUND: Burnout is a threat to patient safety. It relates to emotional exhaustion, depersonalization, and lack of personal accomplishment. Work engagement conversely composed of levels of vigor, dedication, and absorption in one's profession. The aim of this study was to examine burnout and work engagement among US dentists. METHODS: This study used the extensively validated Maslach Burnout Inventory-Human Services Survey and Utrecht Work Engagement Scale to measure burnout in a self-administered survey of 167 US dentists who attended continuing education courses held in Boston, Pittsburg, Iowa City, and Las Vegas. The mean scores on the 3 subscales of Maslach Burnout Inventory-Human Services Survey and Utrecht Work Engagement Scale were computed. The interscale correlations between the components of burnout and work engagement were assessed using Pearson correlations. We used 1-way analysis of variance and independent 2 sample t tests to examine the relationship between burnout and work engagement across sex and various age categories. Prevalence of burnout in our study population was also computed. RESULTS: We observed that 13.2% of our study population experienced burnout and 16.2% of our study population was highly work engaged. There was a statistically significant, unadjusted association between burnout risk and work engagement (chi = 22.51, P < 0.0001). Furthermore, the scores in the subscales of burnout were significantly correlated with scores in the subscales of work engagement. CONCLUSIONS: In this preliminary study, we observed some evidence of burnout among practicing US dentists. It is imperative that the dental profession understands this and works to promote professional practices that increase work engagement and decrease burnout. PMID- 28671912 TI - Errors During Resuscitation: The Impact of Perceived Authority on Delivery of Care. AB - OBJECTIVE: The aim of this study was to determine the influence of perceived authority on pediatric resuscitation teams' response to an incorrect order given by a medical superior. METHODS: As part of a larger multicenter prospective interventional study, interprofessional pediatric resuscitation teams (n = 48) participated in a video-recorded simulated resuscitation scenario with an infant in unstable, refractory supraventricular tachycardia. A confederate actor playing a senior physician entered the scenario partway through and ordered the incorrect dose and delivery method of the antiarrhythmic, procainamide. Video recordings were analyzed with a modified Advocacy Inquiry Scale, assessing the teams' ability to challenge the incorrect order, and a novel confederate hierarchical demeanor rating. The association between Advocacy Inquiry score and hierarchical demeanor rating, and whether or not the confederate's incorrect order was followed were determined. RESULTS: Fifty percent (n = 24) of resuscitation teams followed the confederate's incorrect order. The teams' ability to challenge the incorrect order (P < 0.0001) and confederate hierarchical demeanor rating (P < 0.05) were significantly associated with whether or not the incorrect order was followed. Significant differences between rates of following the incorrect order at different study sites were observed (P < 0.05). CONCLUSIONS: The reluctance of resuscitation teams to appropriately challenge the incorrect order resulted in a high rate of inappropriate medication administration. The rate of teams following the incorrect order was significantly associated with poor challenging of the incorrect order and the hierarchical demeanor of the perceived authority figure. Institution-based factors may impact this rate of incorrect medication administration. PMID- 28671913 TI - The Consequences of Whistle-blowing: An Integrative Review. AB - BACKGROUND: Whistle-blowing provides an avenue for healthcare workers to express their concerns when there is a breach of patients' safety. Most healthcare organizations have policies in place to prevent reprisals on whistle-blowers. Despite these protective measures, whistle-blowing often leads to negative consequences. METHODS: A search of articles on whistle-blowing was conducted on MEDLINE (PubMed). Articles were included if they described the consequences of whistle-blowing in the following 3 areas: medical, nursing, and research/pharmaceutical research (Fig. 1). RESULTS: The initial search criteria retrieved 1168 articles, 670 of which were identified for full-text review. A total of 82 studies were included in the final set of literature. Negative consequences to whistle-blowers include occupational, legal, financial, socioemotional, and other (e.g., physical health, character assassination) effects. Positive consequences to clinical services include improvements to patient safety and in successes of employment tribunal claims, settlements, and court injunctions. Positive consequences in research include retraction of articles (with fraudulent data) and changes to medical journal publication rules. Consequences of no whistle-blowing include investigations of individuals for not reporting and negative emotions such as guilt. CONCLUSIONS: Whistle-blowing is an avenue to improving patient safety in healthcare. The findings from this integrated review will help shape new whistle-blowing policies. Future whistle blowing policies must minimize negative consequences to whistle-blowers while enhancing levels of patient safety and quality of care rendered. PMID- 28671914 TI - Assessment of Automating Safety Surveillance From Electronic Health Records: Analysis for the Quality and Safety Review System. AB - BACKGROUND AND OBJECTIVES: In an effort to improve and standardize the collection of adverse event data, the Agency for Healthcare Research and Quality is developing and testing a patient safety surveillance system called the Quality and Safety Review System (QSRS). Its current abstraction from medical records is through manual human coders, taking an average of 75 minutes to complete the review and abstraction tasks for one patient record. With many healthcare systems across the country adopting electronic health record (EHR) technology, there is tremendous potential for more efficient abstraction by automatically populating QSRS. In the absence of real-world testing data and models, which require a substantial investment, we provide a heuristic assessment of the feasibility of automatically populating QSRS questions from EHR data. METHODS: To provide an assessment of the automation feasibility for QSRS, we first developed a heuristic framework, the Relative Abstraction Complexity Framework, to assess relative complexity of data abstraction questions. This framework assesses the relative complexity of characteristics or features of abstraction questions that should be considered when determining the feasibility of automating QSRS. Questions are assigned a final relative complexity score (RCS) of low, medium, or high by a team of clinicians, human factors, and natural language processing researchers. RESULTS: One hundred thirty-four QSRS questions were coded using this framework by a team of natural language processing and clinical experts. Fifty-five questions (41%) had high RCS and would be more difficult to automate, such as "Was use of a device associated with an adverse outcome(s)?" Forty-two questions (31%) had medium RCS, such as "Were there any injuries as a result of the fall(s)?' and 37 questions (28%) had low RCS, such as "Did the patient deliver during this stay?' These results suggest that Blood and Hospital Acquired Infections-Clostridium Difficile Infection (HAI-CDI) modules would be relatively easier to automate, whereas Surgery and HAI-Surgical Site Infection would be more difficult to automate. CONCLUSIONS: Although EHRs contain a wealth of information, abstracting information from these records is still very challenging, particularly for complex questions, such as those concerning patient adverse events. In this work, we developed a heuristic framework, which can be applied to help guide conversations around the feasibility of automating QSRS data abstraction. This framework does not aim to replace testing with real data but complement the process by providing initial guidance and direction to subject matter experts to help prioritize, which abstraction questions to test for feasibility using real data. PMID- 28671915 TI - Classifying Adverse Events in the Dental Office. AB - BACKGROUND: Dentists strive to provide safe and effective oral healthcare. However, some patients may encounter an adverse event (AE) defined as "unnecessary harm due to dental treatment." In this research, we propose and evaluate two systems for categorizing the type and severity of AEs encountered at the dental office. METHODS: Several existing medical AE type and severity classification systems were reviewed and adapted for dentistry. Using data collected in previous work, two initial dental AE type and severity classification systems were developed. Eight independent reviewers performed focused chart reviews, and AEs identified were used to evaluate and modify these newly developed classifications. RESULTS: A total of 958 charts were independently reviewed. Among the reviewed charts, 118 prospective AEs were found and 101 (85.6%) were verified as AEs through a consensus process. At the end of the study, a final AE type classification comprising 12 categories, and an AE severity classification comprising 7 categories emerged. Pain and infection were the most common AE types representing 73% of the cases reviewed (56% and 17%, respectively) and 88% were found to cause temporary, moderate to severe harm to the patient. CONCLUSIONS: Adverse events found during the chart review process were successfully classified using the novel dental AE type and severity classifications. Understanding the type of AEs and their severity are important steps if we are to learn from and prevent patient harm in the dental office. PMID- 28671916 TI - Investigation of Electrical Stimulation Levels Over 8 to 10 Years Postimplantation for a Large Cohort of Adults Using Cochlear Implants. AB - OBJECTIVES: This study examined electrical stimulation levels over 8 to 10 years postimplantation in adult Nucleus implant users. The first aim was to investigate long-term trends and amount of change in electrical stimulation levels for each of four electrode array segments. The second aim was to determine long-term trends and amount of change for particular participants who previously showed greater change (i.e., >20% of dynamic range [DR]) in each of the threshold (T) and comfort (C) levels within the first 3 to 6 months postimplantation. The third aim was to determine whether demographic characteristics were predictive of the long-term trends and amount of change in each of the T and C levels. DESIGN: For 128 adults implanted with Nucleus implants, T levels, C levels, and DR were extracted for the following postimplant time points: 6, 9, 12, 18, 24, 48, 72, 96, and 120 months. For each time point, the mean T levels, C levels, and DR were calculated for each of four electrode array segments. For each participant, regression analyses were conducted for each of the levels and DR, separately for each of the four electrode array segments. Proportions of participants with and without statistically significant trends were identified, and the amount of change was determined for all participants. RESULTS: No significant differences in trends and amount of change were evident across segments for either of the T or C levels. On average across the four segments, 42% of participants showed nonsignificant trends in each of the T and C levels; 24% and 18% of the participants showed a significant trend only in C levels or only in T levels, respectively. Only 16% of the participants showed a significant trend in both T and C levels. Separately, 73% of the participants showed a nonsignificant trend in DR. In terms of current levels (CLs), the mean amount of change over 10 years for all participants was 10.4 (SD = 8.2) and 10.8 (SD = 9.8) for T and C levels, respectively. For both T and C levels, approximately 95% of the participants showed <25 CLs of change over the 10 years. For both T and C levels, at least 75% of the participants showed less than 6% change each year as a function of their average DR across the 8 to 10 years. For the participants who were previously reported to show >20% change in levels as a function of DR in the first 3 to 6 months postimplantation, nonsignificant long-term trend in levels was shown for 70% of these participants over the first 8 to 10 years postimplantation. Etiology, onset of hearing loss, and age at implantation were not significant factors in predicting change in levels. Duration of hearing loss and hearing aid use before implantation were both predictive of long-term change in T and C levels, respectively. In terms of the amount of change in CLs, both these factors showed a very small amount of change in CLs. CONCLUSIONS: The majority of adults using Nucleus implants showed a nonsignificant trend in T levels, C levels, and DR over 8 to 10 years postimplantation. The present study provides strong evidence that only a small amount of change in levels should be expected for most adults from 6 months out to 10 years postimplantation. A large proportion of the subgroup of participants who previously showed more change in the first 3 to 6 months showed consistent long-term results with the overall group. The trends in levels and the amount of change in levels in the long term were not significantly associated with the demographic characteristics investigated. For implant users with consistent levels over a number of sessions after the first 6 months postimplantation, the frequency of programming in the long term can be reduced. The translation of the findings from the present study into clinical practice will enable more efficient programming services to be provided to implant users in the long term. PMID- 28671917 TI - Experimental Simulation of Clinical Borderline Situations in Temporal Bone Specimens After Ossiculoplasty. AB - OBJECTIVES: One reason for insufficient hearing improvement with a distinct air bone gap after ossiculoplasty with implantation of partial or total ossicular replacement prostheses can be the dislocation or minimal shifting of the prosthesis. The aim of this study was the simulation of common clinical borderline situations with minimal shifting of the prosthesis in temporal bone specimens after ossiculoplasty. It was furthermore the goal to identify these specific situations through imaging by cone beam computed tomography (cbCT) and direct visual inspection using the operation microscope. Additionally, the functional status was evaluated using laser-Doppler vibrometry (LDV). DESIGN: We used a total of four temporal bone specimens for this study. A reconstruction with a partial ossicular replacement prostheses was performed in three specimens and with a total ossicular replacement prostheses in one specimen, with good initial acoustic properties. Subsequently, one specific type of prosthesis failure was simulated in each specimen, respectively, by minimally shifting, tilting, or bending the prostheses from their initial positions. These changes were introduced step-by-step until a borderline situation just short of complete acoustic decoupling was reached. Each step was examined using both LDV and cbCT and observed through the operation microscope. RESULTS: LDV was able to quantify the mechanic function of the ossicular chain after most of the manipulation steps by demonstrating the effect of any shifting of the prosthesis on the middle ear transfer function. However, in some situations, the middle ear transfer function was better with a visually more advanced failure of the prosthesis. In addition, cbCT showed most of the steps with excellent resolution and was able to delineate changes in soft tissue (e.g., cartilage covering). CONCLUSION: cbCT seems to be a promising imaging technique for middle ear problems. As cbCT and LDV exhibited slightly different advantages and disadvantages regarding the demonstration of borderline situations, the combination of both techniques allowed for a more precise evaluation of middle ear reconstructions. Knowledge of the specific characteristics of these methods and their possible combination might help otologists and otosurgeons to refine indications for revision surgery and improve their personal patient counseling. PMID- 28671918 TI - A Comparison of Distortion Product Otoacoustic Emission Properties in Meniere's Disease Patients and Normal-Hearing Participants. AB - OBJECTIVES: Postmortem examination of temporal bones of Meniere's disease patients consistently show dilated endolymphatic spaces of the inner ear, for which the term endolymphatic hydrops has been coined. During the past decade, magnetic resonance imaging techniques for the inner ear appeared, advancing the diagnosis of Meniere's disease. They require, however, a field-strength of at least 3 T, are costly and not universally available. Alternative, noninvasive, cost-effective tests with high sensitivity and specifity for endolymphatic hydrops are desirable. In this study, we test the suitability of distortion product otoacoustic emissions (DPOAEs) for endolymphatic hydrops detection. Previous measurements of the commonly recorded cubic DPOAEs mainly register cochlear hearing loss and are not specific for Meniere's disease. Simultaneous recordings of cubic and quadratic DPOAEs might be more suitable to detect endolymphatic hydrops, because both DPOAE orders react differently to changes of the cochlear operating point as they might occur in Meniere's disease patients. DESIGN: Cubic and quadratic DPOAEs were recorded in normal-hearing participants (N = 45) and in the affected and unaffected ears of patients with a diagnosis of definite Meniere's disease (N = 32). First, to assess the integrity of DPOAE generating mechanisms, cubic DPOAE-grams were obtained with primary tone frequencies f2 between 1 and 8 kHz with primary tone levels l1 = 60 dB SPL and l2 = 50 dB SPL, and a fixed primary tone frequency ratio of 1.22. Then, cubic and quadratic DPOAEs were simultaneously recorded with primary tone levels l1 = l2 = 65 dB SPL and at primary tone frequencies f2 = 4 and 5 kHz, where f1 was successively varied such that the ratio f2/f1 ranged between 1.1 and 1.6 in 0.04 steps while quadratic and cubic DPOAE levels were extracted from the same recording. RESULTS: Cubic DPOAEs were significantly reduced in the affected ears of Meniere's disease patients, and slightly reduced in the unaffected ears of Meniere's disease patients, relative to the ears of normal-hearing participants. In contrast, no significant changes could be seen in quadratic DPOAEs across the ears of normal-hearing participants and Meniere's disease patients. CONCLUSIONS: We could identify a relatively good preservation of quadratic DPOAE levels in relation to a reduction of cubic DPOAE levels as a potential noninvasive diagnostic approach in the early stage of suspected Meniere's disease. Future studies validating the differential diagnostic power of this parameter in control groups with nonhydropic forms of hearing loss are warranted. PMID- 28671919 TI - Evaluation of Layer-by-Layer Segmented Ganglion Cell Complex Thickness for Detecting Early Glaucoma According to Different Macular Grids. AB - PURPOSE: To investigate the diagnostic performance of layer-by-layer segmented macular ganglion cell complex (GCC) thickness for detecting early glaucoma using spectral-domain optical coherence tomography (SD-OCT) with different macular grids. MATERIALS AND METHODS: Sixty-two early-stage open-angle glaucoma patients and 70 healthy subjects were enrolled in this study. The SD-OCT with automated segmentation was used to obtain macular scans with different grids of "1, 2, and 3 mm"; "1, 2.22, and 3.45 mm"; and "1, 3, and 6 mm" diameters. The separate thicknesses of the macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), ganglion cell-inner plexiform layer (GCIPL: GCL+IPL), and GCC (RNFL+GCL+IPL) were measured in each grid. The areas under the receiver operating characteristics were used to compare their specific diagnostic abilities. RESULTS: In all macular grid diameters, the mRNFL, GCL, and IPL thicknesses, except mRNFL in the 1 to 2 mm macular grid, were significantly thinner in patients with early glaucoma than in healthy subjects. The GCC and GCL in the 3 to 6 mm macular grid diameters were best able to discriminate between early glaucoma and normal groups. When including quadrant parameters in the 3 to 6 mm macular grid diameter, the temporal GCL had the largest areas under the curve of receiver operating characteristics (0.906). CONCLUSIONS: Large macular grids have generally high discriminating power for the diagnosis of early glaucoma by SD-OCT. The GCL or GCC thickness in 3 to 6 mm macular grid could be useful for the identification of early glaucomatous structural loss. PMID- 28671920 TI - Adherence to Follow-up Recommendations Among Individuals in the Philadelphia Glaucoma Detection and Treatment Project. AB - PURPOSE: To evaluate rates of adherence to free follow-up eye exam appointments among participants in the Philadelphia Glaucoma Detection and Treatment Project. PATIENTS AND METHODS: Ophthalmologists and testing equipment were brought directly to participants at risk for glaucoma at 43 community sites in Philadelphia. Those diagnosed with glaucoma-related pathology were recommended to return for follow-up to be reexamined on site. Rates of adherence and clinical and demographic risk factors for adherence were evaluated. RESULTS: Five hundred thirty-one participants were diagnosed with glaucoma-related conditions and recommended to attend community-based follow-up exams. Follow-up adherence rate was 61.2% (n=325/531). Significant factors associated with greater eye exam appointment adherence, based on our univariable analysis, included final diagnosis of glaucoma (risk ratio [RR]=1.33; 95% confidence interval [CI], 1.13 1.57), male sex (RR=1.19; 95% CI, 1.04-1.36), white race (RR=1.26; 95% CI, 1.08 1.48), age (RR=1.17; 95% CI, 1.00-1.37) recommendation for glaucoma medication (RR=1.52; 95% CI, 1.35-1.71), recommendation for laser peripheral iridotomy (RR=1.18; 95% CI, 1.02-1.35), diagnosis of age-related macular degeneration (RR=1.42; 95% CI, 1.13-1.77) and an increased intraocular pressure (>22 mm Hg in the worse eye) (RR=1.23; 95% CI, 1.06-1.42). On the basis of our multivariable model, diagnosis, sex, and recommended glaucoma medications were significantly associated with follow-up adherence. CONCLUSIONS: This study demonstrates that individuals living in underserved urban communities would take advantage of free eye exams in community sites and return for follow-up eye exams in these same settings. Future studies could investigate interventions to improve eye exam appointment adherence in community-based settings to detect glaucoma-eye conditions. PMID- 28671921 TI - Papilloschisis: A Case Report. AB - We report a case of papilloschisis, where the schisis is noted within the optic nerve tissue with no associated disc pit. This has not been reported in the literature to the best of our knowledge. PMID- 28671922 TI - A Case of Bilateral Pigment Dispersion Syndrome Following Many Years of Uninterrupted Treatment With Atropine 1% for Bilateral Congenital Cataracts. AB - PURPOSE: Describe an unusual case of bilateral pigment dispersion syndrome (PDS) following years of uninterrupted treatment with atropine 1% for bilateral congenital cataracts, speculate on potential mechanisms leading to this condition. DESIGN: This is a case report. CASE: A 45-year-old white patient on long-term treatment with atropine 1% ointment since his infancy for bilateral congenital cataracts developed PDS with secondary ocular hypertension. RESULTS: The patient showed all the hallmarks of PDS with secondary ocular hypertension. An anterior segment Swept-Source optical coherence tomography was obtained to review the iris profile. The patient showed good pressure response to topical prostaglandin therapy. CONCLUSIONS: This is the second case report of PDS in a patient with chronic use of topical atropine. The proposed mechanisms for pigment dispersion are discussed and the possibility raised of dispersion being a potential side effect of the drug. PMID- 28671923 TI - lncRNAs, DNA Methylation, and the Pathobiology of Exfoliation Glaucoma. AB - Exfoliation glaucoma (XFG) is a clinically aggressive and genetically distinct form of glaucoma that results in neuronal death and irreversible blindness. Gene variants associate with many neurodegenerative diseases including XFG, Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, variants found within the same gene can either confer risk for or provide protection against all 3 of these diseases, complicating the genetic component of pathology. Unfortunately, studies that examine proteins encoded by genes having relevant variants have failed to produce therapeutic interventions that slow or stop the progression of XFG, PD, or AD in patients. This roadblock has researchers focusing on alternative pathways that may be dysregulated and potentially lead to the development of disease. Two emerging areas of research in PD and AD are the pathobiology of long noncoding RNAs and DNA methylation. This review briefly introduces the roles of long noncoding RNAs and DNA methylation in disease pathogenesis, and highlights some of the cutting edge work that has been carried out in PD and AD, along with the limited but important studies in XFG. Finally, we propose a new direction for XFG research that may explain apparently conflicting genetic data and lead to the discovery of novel dysregulated pathways that will allow for targeted therapeutic development. PMID- 28671924 TI - Long-term Outcome of Surgical Treatment for Late Intraocular Lens Dislocation Associated With High Intraocular Pressure: A Case Series. AB - PURPOSE: To demonstrate the long-term safety and efficacy of transscleral intraocular lens (IOL) fixation combined with an Ahmed glaucoma drainage device implantation for patients with late IOL dislocation and high intraocular pressure (IOP). METHODS: This is a retrospective report of a series of patients who underwent this combined surgery. The main outcome variables studied were change in visual acuity (VA), IOP, and number of medications compared with preoperative levels. Surgical failure was defined as a decrease in VA of at least 3 Snellen lines, IOP above 20 mm Hg or IOP reduction <25% from preoperative levels at >=2 consecutive visits, at least 2 months apart. RESULTS: Eleven patients with median age of 83 years (range, 77 to 92 y) were included in the study. All patients had a previous diagnosis of pseudoexfoliation. After a median follow-up time of 1.75 years (range, 0.83 to 2.5 y), the median IOP decreased from 33 mm Hg (range, 24 to 47 mm Hg) to 13 mm Hg (range, 5 to 16 mm Hg; P<0.01). The number of glaucoma medications also decreased from 3 (range, 1 to 4) to 2 (range, 0 to 4; P=0.03). The median log MAR VA improved from 0.77 (range, 0.3 to 2) preoperatively to 0.44 (range, 0 to 3) postoperatively (P=0.27).Four patients had postoperatory surgical complications: choroidal effusion (2), vitreous hemorrhage and hyphema (1), vertical diplopia (1). The survival probability over 2.5 years was 90.9% (confidence interval, 75.4%-100%). CONCLUSION: Transscleral IOL fixation associated with Ahmed glaucoma drainage device implantation is a safe and effective surgical option for patients with late IOL dislocation and elevated IOP. PMID- 28671925 TI - Ophthalmic Timolol Hallucinations: A Case Series and Review of the Literature. AB - PURPOSE: Systemic absorption and central nervous system (CNS) penetration of timolol drops are a well-studied phenomenon, resulting in common side effects such as bradycardia, bronchospasm, fatigue, and confusion. More serious CNS side effects, such as psychosis and depression, however, are rarely attributed to eye drops. We report a case series in which patients developed visual hallucinations secondary to topical ocular timolol use. METHODS: This study is a case series and review of the literature. RESULTS: Four patients with glaucoma developed visual hallucinations while using topical timolol. The patients were all elderly, caucasian females with associated CNS pathology. All patients had resolution of symptoms upon discontinuation and a positive retrial test to confirm the association. CONCLUSIONS: The rarity of this side effect and its anecdotal predilection for elderly, caucasian females with underlying neurological dysfunction, may involve a yet unknown predisposition or hypersensitivity to beta blocker action, such as blood brain barrier disruption leading to increased susceptibility to the medication. This case series highlights an important, although rare, side effect of this medication which clinicians should be aware of especially when using it in elderly patients who may have coexisting CNS pathology. It is important that this side effect be recognized and appropriately managed to prevent otherwise unnecessary investigations and treatment. PMID- 28671926 TI - High Altitude-associated Changes in Intraocular Pressure Abrogated by Trabeculectomy. AB - PURPOSE: To highlight the effect of ascent to high altitude on intraocular pressure (IOP) in a patient with primary open-angle glaucoma, who had previously undergone trabeculectomy in 1 eye. METHODS: Case report. RESULTS: A 66-year-old mountaineer with primary open-angle glaucoma and previous right trabeculectomy performed self-tonometry using a rebound tonometer (Icare HOME) before and during an expedition in the Himalaya. In the nonoperated eye, there was a statistically significant increase in IOP as the patient ascended to 5000 m over 8 days (R=0.790, P=0.001), consistent with recent literature. IOP increased by 1.73 mm Hg with each 1000 m increase in altitude. In the trabeculectomized eye there was no significant increase in IOP (R=0.219, P=0.172). CONCLUSIONS: Filtration surgery may be protective against IOP fluctuations associated with ascent to high altitude. Self-tonometry complements standard glaucoma care by providing opportunities for IOP monitoring outside office hours and in remote locations. PMID- 28671927 TI - Micropulse Cyclophotocoagulation: Initial Results in Refractory Glaucoma. AB - PURPOSE: The purpose of this study is to evaluate the use of micropulse transscleral cyclophotocoagulation (MP-TSCPC), a new and increasingly popular treatment, in patients with uncontrolled glaucoma. METHODS: A retrospective chart review was performed for all patients who underwent a MP-TSCPC at the Glaucoma Associates of Texas. RESULTS: A total of 84 eyes were treated with MP-TSCPC in this study with a mean follow-up time of 4.3 months. The mean age of treated patients was 74 years and 48 (57%) were female. Preoperatively, mean intraocular pressure (IOP) was 27.7 mm Hg and mean number of ocular antihypertensive medications used was 3.3. Mean postoperative IOP at months 1, 3, 6, and 12 were lowered to 16.3 mm Hg (41.2% reduction), 14.6, 13.0, and 11.1 mm Hg, respectively. Postoperative ocular antihypertensive medication use was also lowered to 1.9, 2.0, 2.0, and 2.3 medications at months 1, 3, 6, and 12, respectively. Five patients required further laser or surgical intervention for adequate IOP control. Complications included hypotony, IOP spike, hyphema, serous choroidal detachment, persistent inflammation, and vision loss. At 3 months, inflammation was still present in 46% of eyes and vision loss of at least 1 line was present in 41% of eyes. CONCLUSIONS: MP-TSCPC is effective at lowering IOP and decreasing the need for ocular antihypertensive medications. Eyes with limited visual potential or at high risk for incisional glaucoma surgery can successfully be treated with MP-TSCPC as a reasonable and effective alternative to traditional CPC. These results present short-term data and both longer follow up and further studies are necessary. PMID- 28671928 TI - Examiner Handedness and the Effects on Intraocular Pressure Readings Using the Tono-Pen XL. AB - PURPOSE: To assess the effect of examiner handedness on intraocular pressure (IOP) readings using the Tono-Pen XL in eyes without corneal pathology or previous ocular surgeries. PATIENTS AND METHODS: Patients 18 years of age or older were included in this prospective study. Participants who had a history of corneal conditions or other characteristics that would prevent reliable IOP measurements were excluded. Five experienced examiners, 2 right-hand dominant and 3 left-hand dominant, took bilateral IOP measurements with a Tono-Pen XL. Each participant was tested by 2 examiners, 1 left-handed and 1 right-handed, in a random order. The time between each examiner's measurements was 15 minutes. A paired t test was used to compare IOP differences between "near" (right eye for right-hand or left eye for left-hand dominant examiner) and "far" (right eye by left-hand or left eye by right-hand dominant examiner) measurements for each eye. RESULTS: Forty-six participants with a mean age of 33.8 years (+/-12.8) were enrolled. No significant difference in IOP between near and far eyes was found (IOP difference=IOPfar-IOPnear=-0.11 [+/-2.74] mm Hg; P=0.70). Right-hand dominant examiners consistently measured significantly higher IOP (0.83+/-2.03 mm Hg; P=0.008) compared with left-hand dominant examiners, regardless of the relative position of the eye with respect to the examiner. CONCLUSIONS: The results suggest that IOP readings are not influenced by the positioning of the patient relative to the dominant hand of the examiner. PMID- 28671929 TI - Up-to-Date on Preventive Care Services Under Affordable Care Act: A Trend Analysis From MEPS 2007-2014. AB - BACKGROUND: The utilization of preventive care services has been less than optimal. As part of an effort to address this, the Affordable Care Act (ACA) mandated that private health insurance plans cover evidence-based preventive services. OBJECTIVES: To evaluate whether the provisions of ACA have increased being up-to-date on recommended preventive care services among privately insured individuals aged 18-64. RESEARCH DESIGN: Multivariate linear regression models were used to examine trends in prevalence of being up-to-date on selected preventive services, diagnosis of health conditions, and health expenditures between pre-ACA (2007-2010) and post-ACA (2011-2014). Adjusted difference-in difference analyses were used to estimate changes in those outcomes in the privately insured that differed from changes in the uninsured (control group). RESULTS: After the passage of ACA, up-to-date rates of routine checkup (2.7%; 95% confidence interval, 0.8%-4.7%; P=0.007) and flu vaccination (5.9%; 95% confidence interval, 4.2%-7.6%; P<0.001) increased among those with private insurance, as compared with the control group. Changes in blood pressure check, cholesterol check and cancer screening (pap smear test, mammography, and colorectal cancer screening) were not associated with the ACA. Prevalence in diagnosis of health conditions remained constant. Slower uptrends in adjusted total health care expenditures and downtrends in adjusted out-of-pocket costs were observed during the study period. CONCLUSIONS: The provisions of the ACA have resulted in trivial increases in being up-to-date on selected preventive care services. Additional efforts may be required to take full advantage of the elimination of cost-sharing under the ACA. PMID- 28671930 TI - ICD Social Codes: An Underutilized Resource for Tracking Social Needs. AB - BACKGROUND: Social determinants of health (SDH) data collected in health care settings could have important applications for clinical decision-making, population health strategies, and the design of performance-based incentives and penalties. One source for cataloging SDH data is the International Statistical Classification of Diseases and Related Health Problems (ICD). OBJECTIVE: To explore how SDH are captured with ICD Ninth revision SDH V codes in a national inpatient discharge database. MATERIALS AND METHODS: Data come from the 2013 Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample, a national stratified sample of discharges from 4363 hospitals from 44 US states. We estimate the rate of ICD-9 SDH V code utilization overall and by patient demographics and payer categories. We additionally estimate the rate of SDH V code utilization for: (a) the 5 most common reasons for hospitalization; and (b) the 5 conditions with the highest rates of SDH V code utilization. RESULTS: Fewer than 2% of overall discharges in the National Inpatient Sample were assigned an SDH V code. There were statistically significant differences in the rate of overall SDH V code utilization by age categories, race/ethnicity, sex, and payer (all P<0.001). Nevertheless, SDH V codes were assigned to <7% of discharges in any demographic or payer subgroup. SDH V code utilization was highest for major diagnostic categories related to mental health and alcohol/substance use-related discharges. CONCLUSIONS: SDH V codes are infrequently utilized in inpatient settings for discharges other than those related to mental health and alcohol/substance use. Utilization incentives will likely need to be developed to realize the potential benefits of cataloging SDH information. PMID- 28671931 TI - Designing an Effective, Small-Scope Practice-based Study. AB - OBJECTIVE: Present a methodology to promote good practices in designing small scale, practice-based studies. STUDY DESIGN: We propose the following methods to assist clinicians and other practice-based researchers in designing and conducting good quality, small-scale studies in a clinical setting. METHODS: Research projects applied to a limited, practice-based study may require modification to increase the consistency of patient research. RESULTS: Although common requests to collaborative methodologists mirror methods for experimental design, clinic-based studies may face different limitations. Each participant enrolled consumes resources, including time, and personnel. If practice-based studies have a different goal, to learn about the health outcomes of patients in a medical practice with limited intent for generalization, should the same methods be used? CONCLUSIONS: When limitations are clearly stated and the findings are described within the study context, these limitations may not be so severe to discourage the research. We propose a systematic method to conduct practice-based research intended for small-scale study use. Relying heavily on existing research from similar areas, the incorporation of data from the practice, and the a priori defined timelines and resources, we set forth some guiding principles to assist clinic-based investigators. Individualized focus and small-scale studies are growing in use and acceptance especially given the focus on personalized health. PMID- 28671932 TI - Associations of Exercise Tolerance With Hemodynamic Parameters for Pulmonary Arterial Hypertension and for Chronic Thromboembolic Pulmonary Hypertension. AB - PURPOSE: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the main subgroups of pulmonary hypertension (PH). Despite differences in their etiologies, both diseases are characterized by vascular remodeling, resulting in progressive right heart failure. Noninvasive periodic evaluation of exercise tolerance has become increasingly important. Cardiopulmonary exercise testing (CPET) and a 6-minute walk test (6MWT) are now both recommended for evaluating exercise tolerance, but there is insufficient knowledge about possible differences in the associations of exercise tolerance with right heart catheterization (RHC) data for patients with PAH and CTEPH. METHODS: A retrospective study was performed with 57 patients with PH (24 with PAH and 33 with CTEPH) all of whom underwent echocardiography, CPET, 6MWT, and RHC. RESULTS: For both patients with PAH and CTEPH, peak heart rate during CPET was significantly higher than that from 6MWT, whereas minimum peripheral oxygen saturation during CPET and 6MWT was similar. For patients with PAH, significant correlations were observed between peak (Equation is included in full-text article.)O2 and cardiac index (CI) (r = 0.59; P = .002) and between (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slopes and CI (r =-0.46, P = .02), as well as a nonsignificant correlation tendency for peak (Equation is included in full-text article.)O2 and pulmonary vascular resistance (PVR) and for (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 and PVR (r =-0.39; P = .05; and r = 0.39; P = .06, respectively). For patients with CTEPH, however, a significant correlation was observed only between (Equation is included in full text article.)E/(Equation is included in full-text article.)CO2 slopes and CI (r =-0.38; P = .02). CONCLUSION: PH etiology should be considered when assessing exercise tolerance, whereas CPET can be effective in addition to hemodynamic assessment by means of RHC for periodic evaluation during followup. PMID- 28671933 TI - Outdoor Reproducibility of a 1-km Treadmill Walking Test to Predict Peak Oxygen Uptake in Cardiac Patients. AB - INTRODUCTION: The aim of this study was to determine whether the 1-km treadmill walking test, previously developed to predict peak oxygen uptake ((Equation is included in full-text article.)O2peak) in stable cardiac outpatients, could be reproduced outdoors. METHODS: Fifty male cardiac outpatients performed the 1-km walking test on a treadmill and on a flat track within 1 week. (Equation is included in full-text article.)O2peak was estimated for both testing conditions considering age, height, weight, walking speed, and heart rate. RESULTS: Average walking speed was slightly higher during outdoor conditions (5.73 +/- 0.77 km/h vs 5.55 +/- 0.84 km/h), whereas mean heart rates were similar for both testing conditions (102 +/- 18 beats/min vs 103 +/- 16 beats/min). (Equation is included in full-text article.)O2peak values for treadmill and outdoor tests were not significantly different (26.4 +/- 4.1 mL/kg/min vs 26.8 +/- 4.5 mL/kg/min) and were strongly correlated (r = 0.93, P < .0001). The slope and the intercept of the (Equation is included in full-text article.)O2peak values were not different from the line of identity. CONCLUSIONS: This moderate and perceptually regulated 1-km walking test administered outdoors gives similar results compared with a similar test performed on a treadmill. Therefore, (Equation is included in full text article.)O2peak can be reasonably estimated using both testing modalities. This suggests that the outdoor 1-km test can be applied for indirect estimations of cardiorespiratory fitness in an outpatient setting. PMID- 28671934 TI - Older Adult Attendance in Cardiac Rehabilitation: IMPACT OF FUNCTIONAL STATUS AND POSTACUTE CARE AFTER ACUTE MYOCARDIAL INFARCTION IN 63 092 MEDICARE BENEFICIARIES. AB - PURPOSE: Older adults who use postacute care (PAC) after hospitalization for myocardial infarction (MI) are often overlooked as cardiac rehabilitation (CR) candidates because of physical limitations. This research describes the impact of functional status and PAC, including inpatient rehabilitation facility (IRF), skilled nursing facility (SNF), or home health care (HHC), on CR initiation in Medicare beneficiaries discharged from the hospital following an index MI. METHODS: The Chronic Condition Warehouse database of Medicare beneficiaries discharged to PAC following index MI in 2008 (n = 63 092) was used for this retrospective study. Functional status at PAC discharge was described as dependent, needed assistance, needed supervision, or independent. Logistic regression examined factors associated with CR initiation. RESULTS: CR was initiated by 3% and 21% of beneficiaries discharged from PAC as dependent or independent, respectively. Beneficiaries who were dependent, needed assistance, or needed supervision were 78% (95% CI, 0.18-0.28), 60% (0.32-0.49), and 51% (0.41-0.57) less likely to initiate CR compared with independent beneficiaries. Those who had used IRF were 40% more likely to initiate CR compared with those who had used HHC, with no difference observed between those who had used SNF compared with HHC. CONCLUSIONS: Functional status at PAC discharge was strongly associated with CR initiation. Beneficiary initiation of CR was at proportions corresponding to the level of independence. Beneficiaries discharged from PAC as independent initiated CR at rates slightly higher than non-PAC users, and those discharged from IRF were more likely to initiate CR. These findings are promising and more targeted recruitment from PAC may increase CR initiation and completion, resulting in continued improvement in functional status. PMID- 28671935 TI - Validation of the English Version of the HeartQoL Health-Related Quality of Life Questionnaire in Patients With Coronary Heart Disease. AB - PURPOSE: The aim of this study was to validate the English version of the HeartQoL health-related quality of life questionnaire for use in patients with angina or myocardial infarction. METHODS: Patients living in the United States and referred, either for percutaneous coronary intervention or to cardiac rehabilitation, completed the HeartQoL, the Short Form-36 Health Survey, and the Hospital Anxiety and Depression Scale at baseline and 3-months later. The data were analyzed for validity, reliability, and responsiveness. RESULTS: Patients (n = 313 with angina and n = 97 with myocardial infarction) who were referred either for percutaneous coronary intervention (n = 164) or to cardiac rehabilitation (n = 246) completed baseline questionnaires. Patients with angina had significantly lower HeartQoL scores (poorer health-related quality of life) compared with patients with myocardial infarction. Exploratory factor analysis largely supported the 2-factor structure of the HeartQoL in both diagnoses, but further investigation is warranted. Internal consistency reliability was adequate, convergent validity correlations were significant, and discriminative validity was fully confirmed in patients with angina and largely confirmed in patients with myocardial infarction. Responsiveness was largely confirmed in patients who underwent percutaneous coronary intervention (n = 67) and those referred to cardiac rehabilitation (n = 167) with conventional statistical tests and clinically with the effect size, a standardized measure of change. CONCLUSIONS: The English HeartQoL health-related quality of life questionnaire is valid, reliable, and responsive in patients with angina and myocardial infarction allowing (1) assessment of baseline, (2) between-diagnosis comparisons, and (3) evaluation of change over time. PMID- 28671936 TI - Relevance of Kinesiophobia in Relation to Changes Over Time Among Patients After an Acute Coronary Artery Disease Event. AB - PURPOSE: To identify levels of kinesiophobia during the first 4 months after an acute episode of coronary artery disease (CAD), while controlling for gender, anxiety, depression, and personality traits. METHODS: In all, 106 patients with CAD (25 women), mean age 63.1 +/- 11.5 years, were included in the study at the cardiac intensive care unit, Sahlgrenska University Hospital, Sweden. The patients completed questionnaires at 3 time points: in the cardiac intensive care unit (baseline), 2 weeks, and 4 months after baseline. The primary outcome measure was kinesiophobia. Secondary outcome measures were gender, anxiety, depression, harm avoidance, and positive and negative affect. A linear mixed model procedure was used to compare kinesiophobia across time points and gender. Secondary outcome measures were used as covariates. RESULTS: Kinesiophobia decreased over time (P = .005) and there was a significant effect of gender (P = .045; higher values for women). The presence of a high level of kinesiophobia was 25.4% at baseline, 19% after 2 weeks, and 21.1% after 4 months. Inclusion of the covariates showed that positive and negative affect and harm avoidance increased model fit. The effects of time and gender remained significant. CONCLUSIONS: This study highlights that kinesiophobia decreased over time after an acute CAD episode. Nonetheless, a substantial part of the patients were identified with a high level of kinesiophobia across time, which emphasizes the need for screening and the design of a treatment intervention. PMID- 28671937 TI - Clinical Model of Exercise-Related Dyspnea in Adult Patients With Cystic Fibrosis. AB - PURPOSE: Dyspnea is a highly distressing symptom of pulmonary disease that can make performing physical activities challenging. However, little is known regarding the strongest predictors of exercise-related dyspnea in adult cystic fibrosis (CF). Therefore, the purpose of the present study was to determine the best clinical model of exercise-related dyspnea in this patient group. METHODS: A retrospective analysis of pulmonary function and cardiopulmonary exercise testing data from patients with CF being followed up at the Adult CF Program at St Michael's Hospital, Toronto, Canada, from 2002 to 2008 were used for the analysis. RESULTS: Patients (n = 88) were male 66%; aged 30.4 +/- 9.4 years; body mass index (BMI) 23.1 +/- 3.3 kg/m; forced expiratory volume in 1 second (FEV1) 70% +/- 19% predicted; and peak oxygen uptake 74% +/- 20% predicted. A multivariate linear regression model assessing the effects of age, sex, BMI, airway obstruction (FEV1), perceived muscular leg fatigue, and dynamic hyperinflation explained 54% of the variance in dyspnea severity at peak exercise (P < .01). Relative importance analysis showed that the presence of dynamic hyperinflation and perceived muscular leg fatigue were the largest contributors. CONCLUSIONS: Pulmonary rehabilitation programs may consider strategies to reduce dynamic hyperinflation and promote muscular function to best improve exercise related dyspnea in this patient group. PMID- 28671938 TI - Cardiac Rehabilitation Participation Rates and Outcomes for Patients With Heart Failure. AB - PURPOSE: Exercise training has been shown to reduce combined cardiovascular mortality and hospitalizations in patients with chronic heart failure (CHF) with reduced ejection fraction (HFrEF). Whereas there are extensive data on exercise training for individuals with HFrEF in a research setting, the experience of delivering cardiac rehabilitation (CR) services in the clinical setting has not been well described. With little knowledge regarding the number of qualifying patients with HFrEF in the United States, we described our 18-month experience recruiting hospitalized inpatients and stable outpatients into phase 2 CR. METHODS: Patients hospitalized with CHF HFrEF were tracked for enrollment in CR. Exercise training response was described for patients identified as inpatients and for stable HFrEF outpatients referred from cardiology clinic or heart failure clinic. RESULTS: The cohort included 83 patients hospitalized with CHF and 36 outpatients. Only 17% (14/83) of eligible HFrEF inpatients enrolled in CR following CHF hospitalization compared with 97% (35/36) outpatient referrals. Improvements in aerobic capacity for the total cohort were observed whether expressed as estimated metabolic equivalents (n = 19, 4.6 +/- 1.6 to 6.2 +/- 2.4, P < .0001) or (Equation is included in full-text article.)O2peak (n = 14, 14.4 +/ 3.5 to 16.4 +/- 4.6 mL/kg/min, P = .02) for those who completed CR. CONCLUSION: Significant barriers to recruiting and enrolling patients with HFrEF were observed and only 17% of inpatients attended CR. Systematic in-hospital referral with close followup in the outpatient setting has the potential to capture more eligible patients. The participation of referred stable outpatients with HFrEF was much higher. Regardless of the referral source, patients with HFrEF completing CR can expect improvements in aerobic capacity, muscle strength, and depressive symptoms. PMID- 28671939 TI - Collagen Type I Alpha 2 (COL1A2) Polymorphism Contributes to Intracranial Aneurysm Susceptibility: A Meta-Analysis. AB - BACKGROUND COL1A2, which encodes collagen type I alpha2, has long been suggested to be a potential positional and functional candidate gene for intracranial aneurysm. We performed a meta-analysis to assess the association between COL1A2 rs42524 polymorphism and the risk of intracranial aneurysm. MATERIAL AND METHODS We conducted a systematic search for relevant literature from the following databases up to 22 July 2016: PubMed, Embase, Web of Science, and China National Knowledge Infrastructure. The strength of association between gene and disease was estimated using odds ratios (ORs) with 95% confidence intervals (CIs) under 5 genetic models. RESULTS A total of 6 qualified studies were enrolled in this meta analysis. Pooling results indicated a significant association between COL1A2 rs42524 polymorphism and intracranial aneurysm risk under 4 genetic models (C vs. G: OR=1.74, 95%CI=1.34-2.26; GC vs. GG: OR=1.81, 95%CI=1.37-2.41; CC+GC vs. GG: OR=1.74, 95%CI=1.28-2.36; CC vs. GC+GG: OR=1.76, 95%CI=1.02-3.04). This association was still robust when stratified by ethnicity, intracranial aneurysm type, or Hardy-Weinberg Equilibrium, which was stronger in Asian than in Caucasians. No publication bias was observed. CONCLUSIONS This meta-analysis suggests COL1A2 rs42524 is a significant risk factor for IA susceptibility, with an especially strong effect in Asian people. Further larger-scale epidemiological studies among different ethnicities are warranted to confirm our findings. PMID- 28671940 TI - Expanding signaling-molecule wavefront model of cell polarization in the Drosophila wing primordium. AB - In developing tissues, cell polarization and proliferation are regulated by morphogens and signaling pathways. Cells throughout the Drosophila wing primordium typically show subcellular localization of the unconventional myosin Dachs on the distal side of cells (nearest the center of the disc). Dachs localization depends on the spatial distribution of bonds between the protocadherins Fat (Ft) and Dachsous (Ds), which form heterodimers between adjacent cells; and the Golgi kinase Four-jointed (Fj), which affects the binding affinities of Ft and Ds. The Fj concentration forms a linear gradient while the Ds concentration is roughly uniform throughout most of the wing pouch with a steep transition region that propagates from the center to the edge of the pouch during the third larval instar. Although the Fj gradient is an important cue for polarization, it is unclear how the polarization is affected by cell division and the expanding Ds transition region, both of which can alter the distribution of Ft-Ds heterodimers around the cell periphery. We have developed a computational model to address these questions. In our model, the binding affinity of Ft and Ds depends on phosphorylation by Fj. We assume that the asymmetry of the Ft-Ds bond distribution around the cell periphery defines the polarization, with greater asymmetry promoting cell proliferation. Our model predicts that this asymmetry is greatest in the radially-expanding transition region that leaves polarized cells in its wake. These cells naturally retain their bond distribution asymmetry after division by rapidly replenishing Ft-Ds bonds at new cell-cell interfaces. Thus we predict that the distal localization of Dachs in cells throughout the pouch requires the movement of the Ds transition region and the simple presence, rather than any specific spatial pattern, of Fj. PMID- 28671941 TI - Bayesian dynamic modeling of time series of dengue disease case counts. AB - The aim of this study is to model the association between weekly time series of dengue case counts and meteorological variables, in a high-incidence city of Colombia, applying Bayesian hierarchical dynamic generalized linear models over the period January 2008 to August 2015. Additionally, we evaluate the model's short-term performance for predicting dengue cases. The methodology shows dynamic Poisson log link models including constant or time-varying coefficients for the meteorological variables. Calendar effects were modeled using constant or first- or second-order random walk time-varying coefficients. The meteorological variables were modeled using constant coefficients and first-order random walk time-varying coefficients. We applied Markov Chain Monte Carlo simulations for parameter estimation, and deviance information criterion statistic (DIC) for model selection. We assessed the short-term predictive performance of the selected final model, at several time points within the study period using the mean absolute percentage error. The results showed the best model including first order random walk time-varying coefficients for calendar trend and first-order random walk time-varying coefficients for the meteorological variables. Besides the computational challenges, interpreting the results implies a complete analysis of the time series of dengue with respect to the parameter estimates of the meteorological effects. We found small values of the mean absolute percentage errors at one or two weeks out-of-sample predictions for most prediction points, associated with low volatility periods in the dengue counts. We discuss the advantages and limitations of the dynamic Poisson models for studying the association between time series of dengue disease and meteorological variables. The key conclusion of the study is that dynamic Poisson models account for the dynamic nature of the variables involved in the modeling of time series of dengue disease, producing useful models for decision-making in public health. PMID- 28671943 TI - Optimization of the photoelectrocatalytic oxidation of landfill leachate using copper and nitrate co-doped TiO2 (Ti) by response surface methodology. AB - In this paper, a statistically-based experimental design with response surface methodology (RSM) was employed to examine the effects of functional conditions on the photoelectrocatalytic oxidation of landfill leachate using a Cu/N co-doped TiO2 (Ti) electrode. The experimental design method was applied to response surface modeling and the optimization of the operational parameters of the photoelectro-catalytic degradation of landfill leachate using TiO2 as a photo anode. The variables considered were the initial chemical oxygen demand (COD) concentration, pH and the potential bias. Two dependent parameters were either directly measured or calculated as responses: chemical oxygen demand (COD) removal and total organic carbon (TOC) removal. The results of this investigation reveal that the optimum conditions are an initial pH of 10.0, 4377.98mgL-1 initial COD concentration and 25.0 V of potential bias. The model predictions and the test data were in satisfactory agreement. COD and TOC removals of 67% and 82.5%, respectively, were demonstrated. Under the optimal conditions, GC/MS showed 73 organic micro-pollutants in the raw landfill leachate which included hydrocarbons, aromatic compounds and esters. After the landfill leachate treatment processes, 38 organic micro-pollutants disappeared completely in the photoelectrocatalytic process. PMID- 28671942 TI - Clearance of viable Mycobacterium ulcerans from Buruli ulcer lesions during antibiotic treatment as determined by combined 16S rRNA reverse transcriptase /IS 2404 qPCR assay. AB - INTRODUCTION: Buruli ulcer (BU) caused by Mycobacterium ulcerans is effectively treated with rifampicin and streptomycin for 8 weeks but some lesions take several months to heal. We have shown previously that some slowly healing lesions contain mycolactone suggesting continuing infection after antibiotic therapy. Now we have determined how rapidly combined M. ulcerans 16S rRNA reverse transcriptase / IS2404 qPCR assay (16S rRNA) became negative during antibiotic treatment and investigated its influence on healing. METHODS: Fine needle aspirates and swab samples were obtained for culture, acid fast bacilli (AFB) and detection of M. ulcerans 16S rRNA and IS2404 by qPCR (16S rRNA) from patients with IS2404 PCR confirmed BU at baseline, during antibiotic and after treatment. Patients were followed up at 2 weekly intervals to determine the rate of healing. The Kaplan-Meier survival analysis was used to analyse the time to clearance of M. ulcerans 16S rRNA and the influence of persistent M ulcerans 16S rRNA on time to healing. The Mann Whitney test was used to compare the bacillary load at baseline in patients with or without viable organisms at week 4, and to analyse rate of healing at week 4 in relation to detection of viable organisms. RESULTS: Out of 129 patients, 16S rRNA was detected in 65% of lesions at baseline. The M. ulcerans 16S rRNA remained positive in 78% of patients with unhealed lesions at 4 weeks, 52% at 8 weeks, 23% at 12 weeks and 10% at week 16. The median time to clearance of M. ulcerans 16S rRNA was 12 weeks. BU lesions with positive 16S rRNA after antibiotic treatment had significantly higher bacterial load at baseline, longer healing time and lower healing rate at week 4 compared with those in which 16S rRNA was not detected at baseline or had become undetectable by week 4. CONCLUSIONS: Current antibiotic therapy for BU is highly successful in most patients but it may be possible to abbreviate treatment to 4 weeks in patients with a low initial bacterial load. On the other hand persistent infection contributes to slow healing in patients with a high bacterial load at baseline, some of whom may need antibiotic treatment extended beyond 8 weeks. Bacterial load was estimated from a single sample taken at baseline. A better estimate could be made by taking multiple samples or biopsies but this was not ethically acceptable. PMID- 28671944 TI - Predominance of asymptomatic and sub-microscopic infections characterizes the Plasmodium gametocyte reservoir in the Peruvian Amazon. AB - Malaria transmission requires that Anopheles mosquitoes ingest Plasmodium gametocyte stages circulating in the human bloodstream. In the context of malaria elimination, understanding the epidemiology of gametocytes relative to all Plasmodium infections and the contribution of asymptomatic and sub-microscopic parasite carriers to the gametocyte reservoir is necessary, especially in low endemic settings with predominance of P.vivax. A 13-month longitudinal study was conducted in two communities (n = 1935 individuals) of Loreto Department, Peru, with five active screenings for Plasmodium infections and gametocyte stages by quantitative real-time PCR (qPCR) and reverse transcription (RT)-qPCR, respectively. Parasite prevalence by qPCR was 7.2% for P.vivax (n = 520/7235; range by survey 6.0%-8.1%) and 3.2% for P.falciparum (n = 235/7235; range by survey 0.4%-7.7%). Sub-microscopic infections accounted for 73.5% of P.vivax (range by survey 60%-89%) and almost the totality of P.falciparum cases. Gametocytes were found in 28.4% P.vivax infections (range by survey 18.7%-34.1%), with a peak of 61.5% in one community at the start of the transmission season. About 59.8% of all P.vivax gametocyte carriers were asymptomatic and 31.9% were sub-microscopic. Age patterns for gametocyte prevalence paralleled asexual stage infections and peaked among >15-25 year old individuals. Asexual parasite density was found to be the strongest predictor for P.vivax gametocyte presence in longitudinal multivariate analysis (odds ratio 2.33 [95% confidence interval 1.96, 2.78]; P<0.001). Despite significant differences in seasonality patterns and P.vivax prevalence found at the local scale, sub-microscopic and asymptomatic infections predominate and contribute significantly to the gametocyte reservoir in different communities of the Peruvian Amazon. Control and elimination campaigns need sensitive tools to detect all infections that escape routine malaria surveillance, which may contribute to maintain transmission in the region. PMID- 28671945 TI - Are scabies and impetigo "normalised"? A cross-sectional comparative study of hospitalised children in northern Australia assessing clinical recognition and treatment of skin infections. AB - BACKGROUND: Complications of scabies and impetigo such as glomerulonephritis and invasive bacterial infection in Australian Aboriginal children remain significant problems and the overall global burden of disease attributable to these skin infections remains high despite the availability of effective treatment. We hypothesised that one factor contributing to this high burden is that skin infection is under-recognised and hence under-treated, in settings where prevalence is high. METHODS: We conducted a prospective, cross-sectional study to assess the burden of scabies, impetigo, tinea and pediculosis in children admitted to two regional Australian hospitals from October 2015 to January 2016. A retrospective chart review of patients admitted in November 2014 (mid-point of the prospective data collection in the preceding year) was performed. Prevalence of documented skin infection was compared in the prospective and retrospective population to assess clinician recognition and treatment of skin infections. RESULTS: 158 patients with median age 3.6 years, 74% Aboriginal, were prospectively recruited. 77 patient records were retrospectively reviewed. Scabies (8.2% vs 0.0%, OR N/A, p = 0.006) and impetigo (49.4% vs 19.5%, OR 4.0 (95% confidence interval [CI 2.1-7.7) were more prevalent in the prospective analysis. Skin examination was only documented in 45.5% of cases in the retrospective review. Patients in the prospective analysis were more likely to be prescribed specific treatment for skin infection compared with those in the retrospective review (31.6% vs 5.2%, OR 8.5 (95% CI 2.9-24.4). CONCLUSIONS: Scabies and impetigo infections are under-recognised and hence under-treated by clinicians. Improving the recognition and treatment of skin infections by clinicians is a priority to reduce the high burden of skin infection and subsequent sequelae in paediatric populations where scabies and impetigo are endemic. PMID- 28671946 TI - Depletion of runt-related transcription factor 2 (RUNX2) enhances SAHA sensitivity of p53-mutated pancreatic cancer cells through the regulation of mutant p53 and TAp63. AB - Suberoylanilide hydroxamic acid (SAHA) represents one of the new class of anti cancer drugs. However, multiple lines of clinical evidence indicate that SAHA might be sometimes ineffective on certain solid tumors including pancreatic cancer. In this study, we have found for the first time that RUNX2/mutant p53/TAp63-regulatory axis has a pivotal role in the determination of SAHA sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 cells. According to our present results, MiaPaCa-2 cells responded poorly to SAHA. Forced depletion of mutant p53 stimulated SAHA-mediated cell death of MiaPaCa-2 cells, which was accomapanied by a further accumulation of gammaH2AX and cleaved PARP. Under these experimental conditions, pro-oncogenic RUNX2 was strongly down-regulated in mutant p53-depleted MiaPaCa-2 cells. Surprisingly, RUNX2 silencing augmented SAHA dependent cell death of MiaPaCa-2 cells and caused a significant reduction of mutant p53. Consistent with these observations, overexpression of RUNX2 in MiaPaCa-2 cells restored SAHA-mediated decrease in cell viability and increased the amount of mutant p53. Thus, it is suggestive that there exists a positive auto-regulatory loop between RUNX2 and mutant p53, which might amplify their pro oncogenic signals. Intriguingly, knockdown of mutant p53 or RUNX2 potentiated SAHA-induced up-regulation of TAp63. Indeed, SAHA-stimulated cell death of MiaPaCa-2 cells was partially attenuated by p63 depletion. Collectively, our present observations strongly suggest that RUNX2/mutant p53/TAp63-regulatory axis is one of the key determinants of SAHA sensitivity of p53-mutated pancreatic cancer cells. PMID- 28671947 TI - Universal features of dendrites through centripetal branch ordering. AB - Dendrites form predominantly binary trees that are exquisitely embedded in the networks of the brain. While neuronal computation is known to depend on the morphology of dendrites, their underlying topological blueprint remains unknown. Here, we used a centripetal branch ordering scheme originally developed to describe river networks-the Horton-Strahler order (SO)-to examine hierarchical relationships of branching statistics in reconstructed and model dendritic trees. We report on a number of universal topological relationships with SO that are true for all binary trees and distinguish those from SO-sorted metric measures that appear to be cell type-specific. The latter are therefore potential new candidates for categorising dendritic tree structures. Interestingly, we find a faithful correlation of branch diameters with centripetal branch orders, indicating a possible functional importance of SO for dendritic morphology and growth. Also, simulated local voltage responses to synaptic inputs are strongly correlated with SO. In summary, our study identifies important SO-dependent measures in dendritic morphology that are relevant for neural function while at the same time it describes other relationships that are universal for all dendrites. PMID- 28671948 TI - Stochasticity in the enterococcal sex pheromone response revealed by quantitative analysis of transcription in single cells. AB - In Enterococcus faecalis, sex pheromone-mediated transfer of antibiotic resistance plasmids can occur under unfavorable conditions, for example, when inducing pheromone concentrations are low and inhibiting pheromone concentrations are high. To better understand this paradox, we adapted fluorescence in situ hybridization chain reaction (HCR) methodology for simultaneous quantification of multiple E. faecalis transcripts at the single cell level. We present direct evidence for variability in the minimum period, maximum response level, and duration of response of individual cells to a specific inducing condition. Tracking of induction patterns of single cells temporally using a fluorescent reporter supported HCR findings. It also revealed subpopulations of rapid responders, even under low inducing pheromone concentrations where the overall response of the entire population was slow. The strong, rapid induction of small numbers of cells in cultures exposed to low pheromone concentrations is in agreement with predictions of a stochastic model of the enterococcal pheromone response. The previously documented complex regulatory circuitry controlling the pheromone response likely contributes to stochastic variation in this system. In addition to increasing our basic understanding of the biology of a horizontal gene transfer system regulated by cell-cell signaling, demonstration of the stochastic nature of the pheromone response also impacts any future efforts to develop therapeutic agents targeting the system. Quantitative single cell analysis using HCR also has great potential to elucidate important bacterial regulatory mechanisms not previously amenable to study at the single cell level, and to accelerate the pace of functional genomic studies. PMID- 28671949 TI - High precision detection of conserved segments from synteny blocks. AB - A conserved segment, i.e. a segment of chromosome unbroken during evolution, is an important operational concept in comparative genomics. Until now, algorithms that are designed to identify conserved segments often return synteny blocks that overlap, synteny blocks that include micro-rearrangements or synteny blocks erroneously short. Here we present definitions of conserved segments and synteny blocks independent of any heuristic method and we describe four new post processing strategies to refine synteny blocks into accurate conserved segments. The first strategy identifies micro-rearrangements, the second strategy identifies mono-genic conserved segments, the third returns non-overlapping segments and the fourth repairs incorrect ruptures of synteny. All these refinements are implemented in a new version of PhylDiag that has been benchmarked against i-ADHoRe 3.0 and Cyntenator, based on a realistic simulated evolution and true simulated conserved segments. PMID- 28671950 TI - Formal reasoning about systems biology using theorem proving. AB - System biology provides the basis to understand the behavioral properties of complex biological organisms at different levels of abstraction. Traditionally, analysing systems biology based models of various diseases have been carried out by paper-and-pencil based proofs and simulations. However, these methods cannot provide an accurate analysis, which is a serious drawback for the safety-critical domain of human medicine. In order to overcome these limitations, we propose a framework to formally analyze biological networks and pathways. In particular, we formalize the notion of reaction kinetics in higher-order logic and formally verify some of the commonly used reaction based models of biological networks using the HOL Light theorem prover. Furthermore, we have ported our earlier formalization of Zsyntax, i.e., a deductive language for reasoning about biological networks and pathways, from HOL4 to the HOL Light theorem prover to make it compatible with the above-mentioned formalization of reaction kinetics. To illustrate the usefulness of the proposed framework, we present the formal analysis of three case studies, i.e., the pathway leading to TP53 Phosphorylation, the pathway leading to the death of cancer stem cells and the tumor growth based on cancer stem cells, which is used for the prognosis and future drug designs to treat cancer patients. PMID- 28671951 TI - An adjustable predictive score of graft survival in kidney transplant patients and the levels of risk linked to de novo donor-specific anti-HLA antibodies. AB - Most predictive models and scores of graft survival in renal transplantation include factors known before transplant or at the end of the first year. They cannot be updated thereafter, even in patients developing donor-specific anti-HLA antibodies and acute rejection.We developed a conditional and adjustable score for prediction of graft failure (AdGFS) up to 10 years post-transplantation in 664 kidney transplant patients. AdGFS was externally validated and calibrated in 896 kidney transplant patients.The final model included five baseline factors (pretransplant non donor-specific anti-HLA antibodies, donor age, serum creatinine measured at 1 year, longitudinal serum creatinine clusters during the first year, proteinuria measured at 1 year), and two predictors updated over time (de novo donor-specific anti-HLA antibodies and first acute rejection). AdGFS was able to stratify patients into four risk-groups, at different post transplantation times. It showed good discrimination (time-dependent ROC curve at ten years: 0.83 (CI95% 0.76-0.89). PMID- 28671953 TI - Clinical assessment and three-dimensional movement analysis: An integrated approach for upper limb evaluation in children with unilateral cerebral palsy. AB - INTRODUCTION: The clinical application of upper limb (UL) three-dimensional movement analysis (3DMA) in children with unilateral cerebral palsy (uCP) remains challenging, despite its benefits compared to conventional clinical scales. Moreover, knowledge on UL movement pathology and how this relates to clinical parameters remains scarce. Therefore, we investigated UL kinematics across different manual ability classification system (MACS) levels and explored the relation between clinical and kinematic parameters in children with uCP. PATIENTS AND METHODS: Fifty children (MACS: I = 15, II = 26, III = 9) underwent an UL evaluation of sensorimotor impairments (grip force, muscle strength, muscle tone, two-point discrimination, stereognosis), bimanual performance (Assisting Hand Assessment, AHA), unimanual capacity (Melbourne Assessment 2, MA2) and UL-3DMA during hand-to-head, hand-to-mouth and reach-to-grasp tasks. Global parameters (Arm Profile Score (APS), duration, (timing of) maximum velocity, trajectory straightness) and joint specific parameters (angles at task endpoint, ROM and Arm Variable Scores (AVS)) were extracted. The APS and AVS refer respectively to the total amount of movement pathology and movement deviations of wrist, elbow, shoulder, scapula and trunk. RESULTS: Longer movement durations and increased APS were found with higher MACS-levels (p<0.001). Increased APS was also associated with more severe sensorimotor impairments (r = -0.30-(-0.73)) and with lower AHA and MA2-scores (r = -0.50-(-0.86)). For the joint specific parameters, stronger movement deviations distally were significantly associated with increased muscle weakness (r = -0.32-(-0.74)) and muscle tone (r = 0.33-(-0.61)); proximal movement deviations correlated only with muscle weakness (r = -0.35-0.59). Regression analysis exposed grip force as the most important predictor for the variability in APS (p<0.002). CONCLUSION: We found increased movement pathology with increasing MACS-levels and demonstrated the adverse impact of especially muscle weakness. The lower correlations suggest that 3DMA provides additional information regarding UL motor function, particularly for the proximal joints. Integrating both methods seems clinically meaningful to obtain a comprehensive representation of all aspects of a child's UL functioning. PMID- 28671954 TI - Breastfeeding practices, beliefs, and social norms in low-resource communities in Mexico: Insights for how to improve future promotion strategies. AB - INTRODUCTION: Breastfeeding is recommended exclusively for the first 6 months after birth, with continued breastfeeding for at least 2 years. Yet prevalence of these recommendations is low globally, although it is an effective and cost effective way to prevent serious infections and chronic illness. Previous studies have reported that social support greatly influences breastfeeding, but there is little evidence on perceived social norms in Mexico and how they affect actual behavior. OBJECTIVE: Our objective was to investigate breastfeeding intention, practices, attitudes, and beliefs, particularly normative, among low-resource communities in central and southern Mexico. METHODS: We performed a secondary analysis using the theory of planned behavior with cross-sectional data, which included semi-structured individual interviews with fathers (n 10), 8 focus groups with mothers (n 50), and 8 focus groups with women community leaders (n 44) with a total of 104 participants. Our data also included a quantitative survey among pregnant women and mothers (n 321). RESULTS: Women reported supplementing breast milk with water and teas soon after birth, as well as introducing small bites of solid food a few months after birth. Social norms appeared to support breastfeeding, but not exclusive breastfeeding or breastfeeding for periods longer than about a year. This may be partially explained by: a) behavioral beliefs that for the first 6 months breast milk alone is insufficient for the baby, and that water in addition to breast milk is necessary to hydrate an infant and b) normative beliefs related to the appropriateness of breastfeeding in public and as the child gets older. CONCLUSIONS: Future strategies should focus on positively influencing social norms to support recommended practices, and emphasize the specific reasons behind the recommendations. Future efforts should take a multi-pronged approach using a variety of influences, not only directed at healthcare providers but close family members, including fathers. PMID- 28671952 TI - Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy. AB - Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication. PMID- 28671955 TI - It's positive to be negative: Achilles tendon work loops during human locomotion. AB - Ultrasound imaging is increasingly used with motion and force data to quantify tendon dynamics during human movement. Frequently, tendon dynamics are estimated indirectly from muscle fascicle kinematics (by subtracting muscle from muscle tendon unit length), but there is mounting evidence that this Indirect approach yields implausible tendon work loops. Since tendons are passive viscoelastic structures, when they undergo a loading-unloading cycle they must exhibit a negative work loop (i.e., perform net negative work). However, prior studies using this Indirect approach report large positive work loops, often estimating that tendons return 2-5 J of elastic energy for every 1 J of energy stored. More direct ultrasound estimates of tendon kinematics have emerged that quantify tendon elongations by tracking either the muscle-tendon junction or localized tendon tissue. However, it is unclear if these yield more plausible estimates of tendon dynamics. Our objective was to compute tendon work loops and hysteresis losses using these two Direct tendon kinematics estimates during human walking. We found that Direct estimates generally resulted in negative work loops, with average tendon hysteresis losses of 2-11% at 1.25 m/s and 33-49% at 0.75 m/s (N = 8), alluding to 0.51-0.98 J of tendon energy returned for every 1 J stored. We interpret this finding to suggest that Direct approaches provide more plausible estimates than the Indirect approach, and may be preferable for understanding tendon energy storage and return. However, the Direct approaches did exhibit speed-dependent trends that are not consistent with isolated, in vitro tendon hysteresis losses of about 5-10%. These trends suggest that Direct estimates also contain some level of error, albeit much smaller than Indirect estimates. Overall, this study serves to highlight the complexity and difficulty of estimating tendon dynamics non-invasively, and the care that must be taken to interpret biological function from current ultrasound-based estimates. PMID- 28671956 TI - A multiscale cerebral neurochemical connectome of the rat brain. AB - Understanding the rat neurochemical connectome is fundamental for exploring neuronal information processing. By using advanced data mining, supervised machine learning, and network analysis, this study integrates over 5 decades of neuroanatomical investigations into a multiscale, multilayer neurochemical connectome of the rat brain. This neurochemical connectivity database (ChemNetDB) is supported by comprehensive systematically-determined receptor distribution maps. The rat connectome has an onion-type structural organization and shares a number of structural features with mesoscale connectomes of mouse and macaque. Furthermore, we demonstrate that extremal values of graph theoretical measures (e.g., degree and betweenness) are associated with evolutionary-conserved deep brain structures such as amygdala, bed nucleus of the stria terminalis, dorsal raphe, and lateral hypothalamus, which regulate primitive, yet fundamental functions, such as circadian rhythms, reward, aggression, anxiety, and fear. The ChemNetDB is a freely available resource for systems analysis of motor, sensory, emotional, and cognitive information processing. PMID- 28671957 TI - Clinimetric properties of lower limb neurological impairment tests for children and young people with a neurological condition: A systematic review. AB - BACKGROUND: Clinicians and researchers require sound neurological tests to measure changes in neurological impairments necessary for clinical decision making. Little evidence-based guidance exists for selecting and interpreting an appropriate, paediatric-specific lower limb neurological test aimed at the impairment level. OBJECTIVE: To determine the clinimetric evidence underpinning neurological impairment tests currently used in paediatric rehabilitation to evaluate muscle strength, tactile sensitivity, and deep tendon reflexes of the lower limb in children and young people with a neurological condition. METHODS: Thirteen databases were systematically searched in two phases, from the date of database inception to 16 February 2017. Lower limb neurological impairment tests were first identified which evaluated muscle strength, tactile sensitivity or deep tendon reflexes in children or young people under 18 years of age with a neurological condition. Papers containing clinimetric evidence of these tests were then identified. The methodological quality of each paper was critically appraised using standardised tools and clinimetric evidence synthesised for each test. RESULTS: Thirteen papers were identified, which provided clinimetric evidence on six neurological tests. Muscle strength tests had the greatest volume of clinimetric evidence, however this evidence focused on reliability. Studies were variable in quality with inconsistent results. Clinimetric evidence for tactile sensitivity impairment tests was conflicting and difficult to extrapolate. No clinimetric evidence was found for impairment tests of deep tendon reflexes. CONCLUSIONS: Limited high-quality clinimetric evidence exists for lower limb neurological impairment tests in children and young people with a neurological condition. Results of currently used neurological tests, therefore, should be interpreted with caution. Robust clinimetric evidence on these tests is required for clinicians and researchers to effectively select and evaluate rehabilitation interventions. PMID- 28671958 TI - Clinical genome sequencing and population preferences for information about 'incidental' findings-From medically actionable genes (MAGs) to patient actionable genes (PAGs). AB - Whole genome or exome sequencing is increasingly used in the clinical contexts, and 'incidental' findings are generated. There is need for an adequate policy for the reporting of these findings to individuals. Such a policy has been suggested by the American College of Medical Genetics and Genomics (ACMG). We argue that ACMG's policy is overly paternalistic, and that an adequate policy must take into account population preferences. We conducted a choice based conjoint survey of population preferences for reporting in a representative sample of the Danish population. In a 12 task survey respondents were asked about their preference for reporting in relation to three scenarios with seven different attributes. Of 1200 respondents 66.4% participated. We show that population preferences for reporting differs from ACMG's recommendations, and suggest a new policy based on both medically and patient actionable genes. PMID- 28671959 TI - Prevalence of Lassa Virus Disease (LVD) in Nigerian children with fever or fever and convulsions in an endemic area. AB - BACKGROUND: Convulsions with fever in children are a common neurologic emergency in the tropics, and determining the contribution of endemic viral infections can be challenging. In particular, there is a dearth of data on the prevalence and clinical differentiation of Lassa virus disease (LVD) in febrile children in endemic areas of Nigeria, which has multiple lineages of the virus. The aim of this study was to determine the prevalence and presentation of LVD in febrile children with and without convulsions. METHODOLOGY/PRINCIPAL FINDINGS: This was a prospective study of consecutive febrile children aged >=1 month- 15 years admitted to the Children's Emergency Room of Irrua Specialist Teaching Hospital over a period of 1 year. Febrile children with convulsions (Cases) were compared with those without convulsions (Controls). LVD was defined by the presence of a positive Lassa virus RT-PCR test. Rates were compared between groups using chi2 or Fisher's exact tests and p <0.05 taken as significant. 373 (40.9%) of 913 admissions had fever. Of these, 108/373 (29%) presented with convulsions. The overall prevalence of LVD was 13/373 (3.5%; 95% CI = 1.9%, 5.7%) in febrile admissions, 3/108 (2.8%) in Cases and 10/265 (3.8%) in Controls [(Odds Ratio (95% Confidence Interval) (OR (95% CI)) of LVD in Cases versus Controls = 0.73 (0.2, 2.7)]. Only vomiting (OR (95% CI) = 0.09 (0.01, 0.70)) and bleeding (OR (95% CI) = 39.56 (8.52, 183.7)) were significantly associated with an increased prevalence of LVD. CONCLUSIONS/SIGNIFICANCE: LVD is an important cause of fever, including undifferentiated fever in children in endemic areas, but it is not significantly associated with convulsions associated with fever. Its prevalence, and lack of clinical differentiation on presentation, underscores the importance of a high index of suspicion in diagnosis. Screening of febrile children with undifferentiated fever in endemic areas for LVD could be an important medical and public health control measure. PMID- 28671960 TI - Stress fibers, autophagy and necrosis by persistent exposure to PM2.5 from biomass combustion. AB - Fine particulate matter (PM2.5) can adversely affect human health. Emissions from residential energy sources have the largest impact on premature mortality globally, but their pathological and molecular implications on cellular physiology are still elusive. In the present study potential molecular consequences were investigated during long-term exposure of human bronchial epithelial BEAS-2B cells to PM2.5, collected from a biomass power plant. Initially, we observed that PM2.5 did not affect cellular survival or proliferation. However, it triggered an activation of the stress response p38 MAPK which, along with RhoA GTPase and HSP27, mediated morphological changes in BEAS-2B cells, including actin cytoskeletal rearrangements and paracellular gap formation. The p38 inhibitor SB203580 prevented phosphorylation of HSP27 and ameliorated morphological changes. During an intermediate phase of long-term exposure, PM2.5 triggered proliferative regression and activation of an adaptive stress response necessary to maintain energy homeostasis, including AMPK, repression of translational elongation, and autophagy. Finally, accumulation of intracellular PM2.5 promoted lysosomal destabilization and cell death, which was dependent on lysosomal hydrolases and p38 MAPK, but not on the inflammasome and pyroptosis. TEM images revealed formation of protrusions and cellular internalization of PM2.5, induction of autophagosomes, amphisomes, autophagosome lysosomal fusion, multiple compartmental fusion, lysosomal burst, swollen mitochondria and finally necrosis. In consequence, persistent exposure to PM2.5 may impair epithelial barriers and reduce regenerative capacity. Hence, our results contribute to a better understanding of PM-associated lung and systemic diseases on the basis of molecular events. PMID- 28671961 TI - Visual outcomes of dense pediatric cataract surgery in eastern China. AB - PURPOSE: To evaluate the visual outcomes of dense pediatric cataract surgery in eastern China. METHODS: Medical records of children who underwent surgery for dense unilateral or bilateral pediatric cataract in Shandong Provincial Hospital between January 2007 and December 2012 were collected. Patients who cooperated with optical correction and aggressive patching of the sound eye and who had a minimum postoperative follow-up of more than 2 years were included. Risk factors for poor visual outcomes were analyzed. RESULTS: Of the 105 eligible patients (181 eyes), 76 had bilateral cataract, and 29 unilateral. With a mean follow up of 46.77 mo (range 24.0~96.0 mo), the final best corrected visual acuity (BCVA) of 158 eyes were recorded, and 4.43% (7/158) achieved 0.1 logarithm of the minimum angle of resolution (logMAR) or better; 15.19% (24/158) obtained a BCVA between 0.1 logMAR and 0.3 logMAR; 18.99%, (30/158) between 0.3 logMAR and 0.5 logMAR; 46.84% (74/158), between 0.5 logMAR and 1 logMAR; 14.55%, worse than 1 logMAR. The mean BCVA of the patients who underwent lensectomy before 3 months of age was significantly better than that of patients who underwent lensectomy between 3 and 12 months (p = 0.001). In the same lensectomy age groups, the final BCVA of the children in the bilateral and unilateral groups did not differ significantly (P>0.05). Lensectomy after 3 months of age, postoperative complications, strabismus and nystagmus were shown to be risk factors for poor visual outcomes. CONCLUSIONS: Lensectomy before 3 months of age, IOL implantation, proper managing of postoperative complications, early optical correction and aggressive postoperative patching of the sound eye would increase the final BCVA for patients with dense pediatric cataract. PMID- 28671962 TI - Subcellular electrical stimulation of neurons enhances the myelination of axons by oligodendrocytes. AB - Myelin formation has been identified as a modulator of neural plasticity. New tools are required to investigate the mechanisms by which environmental inputs and neural activity regulate myelination patterns. In this study, we demonstrate a microfluidic compartmentalized culture system with integrated electrical stimulation capabilities that can induce neural activity by whole cell and focal stimulation. A set of electric field simulations was performed to confirm spatial restriction of the electrical input in the compartmentalized culture system. We further demonstrate that electrode localization is a key consideration for generating uniform the stimulation of neuron and oligodendrocytes within the compartments. Using three configurations of the electrodes we tested the effects of subcellular activation of neural activity on distal axon myelination with oligodendrocytes. We further investigated if oligodendrocytes have to be exposed to the electrical field to induce axon myelination. An isolated stimulation of cell bodies and proximal axons had the same effect as an isolated stimulation of distal axons co-cultured with oligodendrocytes, and the two modes had a non different result than whole cell stimulation. Our platform enabled the demonstration that electrical stimulation enhances oligodendrocyte maturation and myelin formation independent of the input localization and oligodendrocyte exposure to the electrical field. PMID- 28671963 TI - Effects of selective and combined activation of estrogen receptor alpha and beta on reproductive organ development and sexual behaviour in Japanese quail (Coturnix japonica). AB - Excess estrogen exposure of avian embryos perturbs reproductive organ development in both sexes and demasculinizes the reproductive behaviors of adult males. We have previously shown that these characteristic effects on the reproductive organs also can be induced by exposure of Japanese quail (Coturnix japonica) embryos to selective agonists of estrogen receptor alpha (ERalpha). In contrast, the male copulatory behavior is only weakly affected by developmental exposure to an ERalpha agonist. To further elucidate the respective roles of ERalpha and ERbeta in estrogen-induced disruption of sexual differentiation, we exposed Japanese quail embryos in ovo to the selective ERalpha agonist 16alpha-lactone estradiol (16alphaLE2), the selective ERbeta agonist WAY-200070, or both substances in combination. The ERalpha agonist feminized the testes in male embryos and reduced cloacal gland size in adult males. Furthermore, anomalous retention and malformations of the Mullerian ducts/oviducts were seen in embryos and juveniles of both sexes. The ERbeta agonist did not induce any of these effects and did not influence the action of the ERalpha agonist. Male copulatory behavior was not affected by embryonic exposure to either the ERalpha- or the ERbeta-selective agonist but was slightly suppressed by treatment with the two compounds combined. Our results suggest that the reproductive organs become sexually differentiated consequent to activation of ERalpha by endogenous estrogens; excessive activation of ERalpha, but not ERbeta, during embryonic development may disrupt this process. Our results also suggest that the demasculinizing effect of estrogens on male copulatory behavior is only partly mediated by ERalpha and ERbeta, and may rather involve other estrogen-responsive pathways. PMID- 28671964 TI - Simultaneous inhibition of aryl hydrocarbon receptor (AhR) and Src abolishes androgen receptor signaling. AB - Altered c-Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers including prostate cancer. Src is known to regulate several biological functions of tumor cells, including proliferation. There are several Src inhibitors under evaluation for clinical effectiveness but have shown little activity in monotherapy trials of solid tumors. Combination studies are being explored by in vitro analysis and in clinical trials. Here we investigate the effect of simultaneous inhibition of the aryl hydrocarbon receptor (AhR) and Src on androgen receptor (AR) signaling in prostate cancer cells. AhR has also been reported to interact with the Src signaling pathway during prostate development. c-Src protein kinase is associated with the AhR complex in the cytosol and upon ligand binding to AhR, c-Src is activated and released from the complex. AhR has also been shown to regulate AR signaling which remains functionally important in the development and progression of prostate cancer. We provide evidence that co-inhibition of AhR and Src abolish AR activity. Evaluation of total protein and cellular fractions revealed decreased pAR expression and AR nuclear localization. Assays utilizing an androgen responsive element (ARE) and qRT-PCR analysis of AR genes revealed decreased AR promoter activity and transcriptional activity in the presence of both AhR and Src inhibitors. Furthermore, co-inhibition of AhR and Src reduced the growth of prostate cancer cells compared to individual treatments. Several studies have revealed that AhR and Src individually inhibit cellular proliferation. However, this study is the first to suggest simultaneous inhibition of AhR and Src to inhibit AR signaling and prostate cancer cell growth. PMID- 28671965 TI - Characterization of the emerging zoonotic pathogen Arcobacter thereius by whole genome sequencing and comparative genomics. AB - Four Arcobacter species have been associated with human disease, and based on current knowledge, these Gram negative bacteria are considered as potential food and waterborne zoonotic pathogens. At present, only the genome of the species Arcobacter butzleri has been analysed, and still little is known about their physiology and genetics. The species Arcobacter thereius has first been isolated from tissue of aborted piglets, duck and pig faeces, and recently from stool of human patients with enteritis. In the present study, the complete genome and analysis of the A. thereius type strain LMG24486T, as well as the comparative genome analysis with 8 other A. thereius strains are presented. Genome analysis revealed metabolic pathways for the utilization of amino acids, which represent the main source of energy, together with the presence of genes encoding for respiration-associated and chemotaxis proteins. Comparative genome analysis with the A. butzleri type strain RM4018 revealed a large correlation, though also unique features. Furthermore, in silico DDH and ANI based analysis of the nine A. thereius strains disclosed clustering into two closely related genotypes. No discriminatory differences in genome content nor phenotypic behaviour were detected, though recently the species Arcobacter porcinus was proposed to encompass part of the formerly identified Arcobacter thereius strains. The report of the presence of virulence associated genes in A. thereius, the presence of antibiotic resistance genes, verified by in vitro susceptibility testing, as well as other pathogenic related relevant features, support the classification of A. thereius as an emerging pathogen. PMID- 28671967 TI - Implementation of real-time energy management strategy based on reinforcement learning for hybrid electric vehicles and simulation validation. AB - To further improve the fuel economy of series hybrid electric tracked vehicles, a reinforcement learning (RL)-based real-time energy management strategy is developed in this paper. In order to utilize the statistical characteristics of online driving schedule effectively, a recursive algorithm for the transition probability matrix (TPM) of power-request is derived. The reinforcement learning (RL) is applied to calculate and update the control policy at regular time, adapting to the varying driving conditions. A facing-forward powertrain model is built in detail, including the engine-generator model, battery model and vehicle dynamical model. The robustness and adaptability of real-time energy management strategy are validated through the comparison with the stationary control strategy based on initial transition probability matrix (TPM) generated from a long naturalistic driving cycle in the simulation. Results indicate that proposed method has better fuel economy than stationary one and is more effective in real time control. PMID- 28671966 TI - A leprosy clinical severity scale for erythema nodosum leprosum: An international, multicentre validation study of the ENLIST ENL Severity Scale. AB - OBJECTIVES: We wished to validate our recently devised 16-item ENLIST ENL Severity Scale, a clinical tool for measuring the severity of the serious leprosy associated complication of erythema nodosum leprosum (ENL). We also wished to assess the responsiveness of the ENLIST ENL Severity Scale in detecting clinical change in patients with ENL. METHODS: Participants, recruited from seven centres in six leprosy endemic countries, were assessed using the ENLIST ENL Severity Scale by two researchers, one of whom categorised the severity of ENL. At a subsequent visit a further assessment using the scale was made and both participant and physician rated the change in ENL using the subjective categories of "Much better", "somewhat better", "somewhat worse" and "much worse" compared with "No change" or "about the same". RESULTS: 447 participants were assessed with the ENLIST ENL Severity Scale. The Cronbach alpha of the scale and each item was calculated to determine the internal consistency of the scale. The ENLIST ENL Severity Scale had good internal consistency and this improved following removal of six items to give a Cronbach's alpha of 0.77. The cut off between mild ENL and more severe disease was 9 determined using ROC curves. The minimal important difference of the scale was determined to be 5 using both participant and physician ratings of change. CONCLUSIONS: The 10-item ENLIST ENL Severity Scale is the first valid, reliable and responsive measure of ENL severity and improves our ability to assess and compare patients and their treatments in this severe and difficult to manage complication of leprosy. The ENLIST ENL Severity Scale will assist physicians in the monitoring and treatment of patients with ENL. The ENLIST ENL Severity Scale is easy to apply and will be useful as an outcome measure in treatment studies and enable the standardisation of other clinical and laboratory ENL research. PMID- 28671968 TI - Systemic complement activation in central serous chorioretinopathy. AB - PURPOSE: A clear link between several variants in genes involved in the complement system and chronic central serous chorioretinopathy (CSC) has been described. In age-related macular degeneration, a disease that shows clinical features that overlap with CSC, both genetic risk factors and systemic activation of the complement system have previously been found. In this case-control study, we assessed whether there is evidence of either systemic activation or inhibition of the complement system in patients with chronic CSC. METHODS: A prospective case-control study of 76 typical chronic CSC patients and 29 controls without ophthalmological history was conducted. Complement activity assays (classical, alternative, and mannose-binding lectin pathway), complement factors 3, 4, 4A, 4B, B, D, H, I, and P, activation products C3d, C5a, and sC5b-C9, and the C3d/C3 ratio were analysed in either serum or plasma. A correction for possible effects of gender, age, body mass index, and smoking status was performed. RESULTS: In this study, none of the tested variables, including regulation and activation products, proved to be significantly different between the groups. Moreover, no associations with either CSC disease activity or possible CSC related steroid use were observed. CONCLUSION: Despite the available literature regarding a possible relationship between chronic CSC and variants in genes involved in the complement system, we did not find evidence of an association of chronic CSC with either systemic complement activation or inhibition. PMID- 28671969 TI - Reference gene selection for the shell gland of laying hens in response to time points of eggshell formation and nicarbazin. AB - Ten reference genes were investigated for normalization of gene expression data in the shell gland of laying hens. Analyses performed with geNorm revealed that hypoxanthine phosphoribosyltransferase 1 (HPRT1) and hydroxymethylbilane synthase (HMBS) were the two most stable reference genes in response to post-oviposition time alone (POT) or with nicarbazin treatment (POT+N) of laying hens. NormFinder analyses showed that the two most stable reference genes in response to POT and POT+N were 18S ribosomal RNA (18S rRNA), ribosomal protein L4 (RPL4) and HMBS, RPL4, respectively. BestKeeper analyses showed that 18S rRNA, RPL4 and HPRT1, HMBS were the two most stable reference genes for POT, and POT+N, respectively. Of the ten reference genes, all except B2M showed geNorm M <0.5, suggesting that they were stably expressed in the shell gland tissue. Consensus from these three programs suggested HPRT1 and HMBS could be used as the two most stable reference genes in the present study. Expression analyses of four candidate target genes with the two most and the two least stable genes showed that a combination of stable reference genes leads to more discriminable quantification of expression levels of target genes, while the least stable genes failed to do so. Therefore, HMBS and HPRT1 are recommended as the two most stable reference genes for the normalization of gene expression data at different stages of eggshell formation in brown-egg laying hens. Available statistical programs for reference gene ranking should include more robust analysis capability to analyse the gene expression data generated from factorial design experiments. PMID- 28671970 TI - Cardioprotective effects of PKG activation by soluble GC activator, BAY 60-2770, in ischemia-reperfusion-injured rat hearts. AB - Soluble guanylate cyclase (sGC) has been suggested as a therapeutic target for cardiac ischemia-reperfusion (IR) injury. Until now, the molecular mechanism of BAY 60-2770, a sGC activator, in cardiac IR injury has not been assessed. To identify the cardioprotective effects of BAY 60-2770 in IR-injured rat hearts, IR injury was established by occlusion of LAD for 40 min and reperfusion for 7 days, and the effects of BAY 60-2770 on myocardial protection were assessed by echocardiography and TTC staining. 5 nM and 5 MUM of BAY 60-2770 were perfused into isolated rat hearts in a Langendorff system. After 10- or 30-min reperfusion with BAY 60-2770, cGMP and cAMP concentrations and PKG activation status were examined. Hearts were also perfused with 1 MUM KT5823 or 100 MUM 5-HD in conjunction with 5 nM Bay 60-2770 to evaluate the protective role of PKG. Mitochondrial oxidative stress was investigated under hypoxia-reoxygenation in H9c2 cells. In IR-injured rat hearts, BAY 60-2770 oral administration reduced infarct size by TTC staining and improved left ventricular function by echocardiography. Tissue samples from BAY 60-2770-perfused hearts had approximately two-fold higher cGMP levels. BAY 60-2770 increased PKG activity in the myocardium, and the reduced infarct area by BAY 60-2770 was abrogated by KT 5823 in isolated myocardium. In H9c2 cardiac myoblasts, hypoxia-reoxygenation mediated mitochondrial ROS generation was diminished with BAY 60-2770 treatment, but was recovered by pretreatment with KT-5823. BAY 60-2770 demonstrated a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. BAY 60-2770 has a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. These results demonstrated that BAY 60-2770 may be used as a therapeutic agent for cardiac IR injury. PMID- 28671971 TI - Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis. AB - OBJECTIVE: The aim of this study was to determine the effect of exposure to different antithyroid drugs during pregnancy on the incidence of neonatal congenital malformations. METHODS: A meta-analysis was performed to compare the incidence of neonatal congenital malformations after exposure to different antithyroid drugs during pregnancy. Twelve studies that met the inclusion criteria were included in this meta-analysis. PubMed, Embase, and CENTRAL databases were searched from inception until January 2017. Study designs included case-control studies, prospective cohort studies, and retrospective cohort studies. RESULTS: Twelve studies involving 8028 participants with exposure to different antithyroid drugs during pregnancy were included in this study; however, only 10 studies involving 5059 participants involved exposure to different antithyroid drugs exactly during pregnancy. Our results indicated that exposure to methimazole (MMI)/carbimazole (CMZ) only during pregnancy significantly increased the risk of neonatal congenital malformations compared to no antithyroid drug exposure (OR 1.88; 95%CI 1.33 to 2.65; P = 0.0004). No differences were observed between propylthiouracil (PTU) exposure and no antithyroid drug exposure only during pregnancy (OR 0.81; 95%CI 0.58 to 1.15; P = 0.24). Exposure to MMI/CMZ only during pregnancy significantly increased the risk of neonatal congenital malformations compared to that associated with exposure to PTU (OR 1.90; 95%CI 1.30 to 2.78; P = 0.001). CONCLUSION: For pregnant women with hyperthyroidism, exposure to MMI/CMZ significantly increased the incidence of neonatal congenital malformations compared to exposure to PTU and no antithyroid drug exposure; however, no differences were observed between PTU exposure and no antithyroid drug exposure. PMID- 28671972 TI - DiapHRaGM: A mnemonic to describe the work of breathing in patients with respiratory failure. AB - BACKGROUND: The assessment of the work of breathing in the definitions of respiratory failure is vague and variable. OBJECTIVE: Identify a parsimonious set of signs to describe the work of breathing in hypoxemic, acutely ill patients. METHODS: We examined consecutive medical ICU patients receiving oxygen with a mask, non-invasive ventilation, or T-piece. A physician inspected each patient for 10 seconds, rated the level of respiratory distress, and then examined the patient for vital signs and 17 other physical signs. We used the rating of distress as a surrogate for measuring the work of breathing, constructed three multivariate models to identify the one with the smallest number of signs and largest explained variance, and validated it with bootstrap analysis. RESULTS: We performed 402 observations on 240 patients. Respiratory distress was absent in 78, mild in 157, moderate in 107, and severe in 60. Respiratory rate, hypoxia, heart rate, and frequency of most signs increased as distress increased. Respiratory rate and hypoxia explained 43% of the variance in respiratory distress. Diaphoresis, gasping, and contraction of the sternomastoid explained an additional 28%. Heart rate, blood pressure, alertness, agitation, body posture, nasal flaring, audible breathing, cyanosis, tracheal tug, retractions, paradox, scalene or abdominal muscles contraction did not increase the explained variance in respiratory distress. CONCLUSION: Most of the variance is respiratory distress can be explained by five signs summarized by the mnemonic DiapHRaGM (diaphoresis, hypoxia, respiratory rate, gasping, accessory muscle). This set of signs may allow for efficient, standardized assessments of the work of breathing of hypoxic patients. PMID- 28671973 TI - PD-L1 expression in pleomorphic, spindle cell and giant cell carcinoma of the lung is related to TTF-1, p40 expression and might indicate a worse prognosis. AB - Lung sarcomatoid carcinoma of the lung is a rare tumor with a poor prognosis. More than 90% of them are pleomorphic, spindle cell and giant cell carcinoma (PSCGCC). This rare subtype of lung cancer is thought to be more resistant to chemotherapy, and a small subset of them seems to exhibit targetable mutations. Immunotherapy against PD1/PDL-1 is a new emerging treatment, and might be of interest in PSGSCC because they frequently express PD-L1. The aim of our work is to evaluate PD1 and PDL-1 expression in a surgical series of lung PSCGCC and their relationship with morphological and immunohistochemical parameters and prognosis. Thirty-six patients who underwent surgical resection of a PSGSCC were included. PD-L1 (E1L3N) expression on tumor cells and PD1 (NAT105) expression by tumor infiltrating lymphocytes (TILs) were performed by immunohistochemistry. Results were compared to immunohistochemistry tests of TTF1, Napsin A, p40 and to molecular study of EGFR, KRAS, BRAF and HER2. Seventy-five % of PSCGCC were considered as positive for PD-L1.PD-L1 expression in PSGSCC is associated with TTF-1 and/or Napsin A expression (47.2%, p = 0.039). Few p40 positive PSCGCC expressed PD-L1 (8.3%, p = 0.013). PD1 expression was not related to TTF-1 and/or Napsin A expression (p = 0.47), p40 expression (p = 0.68) or survival (p = 0.14). PD-L1 or PD1 expression were not related to the age, gender, pT, pN, stage, visceral pleura invasion, histopathological subtype, the presence of giant cell component, the predominance of sarcomatoid component, and the presence of EGFR or BRAF or HER2 or PIK3CA mutation (p>0.05). PD-L1 expression was correlated with a worse overall survival in PSCGCC (p = 0.045). PD-L1 expression is frequent in PSCGCC and might be associated with the expression of adenocarcinoma markers (TTF 1, Napsin A) or the lack of expression of squamous cell carcinoma marker (p40). PMID- 28671974 TI - The role of group IIA secretory phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults-A systematic review. AB - INTRODUCTION: This paper investigates the role of Group II Secretory Phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults. Sepsis and bacterial infection are common problems encountered by patients in the hospital and often carry adverse outcomes if not managed early. METHODS: Two independent reviewers conducted a comprehensive search using Ovid MEDLINE published from years 1993 to 2016 and SCOPUS published from year 1985 to 2017 to screen for relevant studies. The main inclusion criteria included adult subjects, patients with suspected or confirmed signs of infection and relevant outcomes which looked into the role of sPLA2-IIA in detecting the presence of sepsis and bacterial infection in the subjects. RESULTS AND DISCUSSION: Four studies met the inclusion criteria. SPLA2-IIA was found to be effective in detecting the presence of sepsis and bacterial infection in adults. The levels of serum sPLA2-IIA also correlated well with the presence of sepsis and bacterial infection. CONCLUSION: This systematic review highlights the role of sPLA2-IIA as a reliable tool to diagnose sepsis and bacterial infection in adult patients. Nonetheless, further studies should be done in the future to provide more compelling evidence on its application in the clinical setting. PMID- 28671975 TI - In- and ex-vivo molecular imaging of apoptosis to assess sensitivity of non-small cell lung cancer to EGFR inhibitors using probe-based confocal laser endomicroscopy. AB - BACKGROUND: Prediction of treatment outcome of non-small cell lung cancer (NSCLC) with EGFR inhibitors on the basis of the genetic analysis of the tumor can be incorrect in case of rare or complex mutations, bypass molecular activation pathways, or pharmacodynamic variations. The aim of this study was to develop an ex vivo and in vivo real-time quantitative imaging test for EGFR inhibitors sensitivity assessment. METHODS: Erlotinib resistant (A549, H460, H1975), insensitive (H1650) and hypersensitive (HCC827) cell lines were injected subcutaneously in Nude mice. Tumor xenografts from mice treated with Erlotinib were imaged ex vivo and in vivo using probe-based confocal laser endomicroscopy (pCLE) and NucView 488 Caspase 3 substrate, a fluorescent probe specific for the activated caspase 3. RESULTS: Assessment of apoptosis at 24h post treatment, both ex vivo in explanted tumor xenografts and in vivo, showed a significant difference between resistant cell lines (A549, H460 and H1975) and insensitive (H1650) or hypersensitive (HCC827) ones (p<0.05 for ex vivo imaging, p<=0.02 for in vivo imaging). There was also a significant difference between insensitive and hypersensitive cell lines, both ex vivo (p<0.05) and in vivo (p = 0.01). CONCLUSION: Real-time in vivo and ex vivo assessment of apoptosis using pCLE differentiates resistant from sensitive NSCLC xenografts to Erlotinib. PMID- 28671976 TI - Endothelial keratoplasty versus repeat penetrating keratoplasty after failed penetrating keratoplasty: A systematic review and meta-analysis. AB - OBJECTIVE: This study sought to compare graft survival, graft rejection and the visual acuity outcome of endothelial keratoplasty (EK) with repeat penetrating keratoplasty (PK) after failed PK. METHODS: A systematic literature search with subsequent screening of the identified articles was conducted to obtain potentially eligible randomized clinical trials (RCTs) and comparative cohort studies. To assess the methodological quality of the included studies, the Jadad Scale or Newcastle-Ottawa Scale (NOS) was used based on the study design. To calculate the pooled odds ratios (ORs) for graft survival, graft rejection and the visual acuity outcome with 95% confidential intervals (CIs), a fixed- or random-effects model was applied based on the heterogeneity across studies. RESULTS: Four comparative cohort studies (n = 649 eyes) comparing the outcome of EK with repeat PK after failed PK were included in this review. These studies were considered high quality, with NOS scores ranging from 6 to 9. The EK group showed a significantly lower risk of graft rejection than the repeat PK group [0.43 (95% CI: 0.23-0.80, P = 0.007)]. In addition, no significant differences were observed in a comparison of graft survival and visual acuity (P values ranged from 0.81 to 0.97 using the Der-Simonian and Laird random-effects model). CONCLUSIONS: As an alternative to repeat PK, EK after failed PK allows for potential reduction of the risk of graft rejection; however, it does not appear to confer a significant advantage in graft survival or visual acuity. PMID- 28671977 TI - The moderating role of avoidance behavior on anxiety over time: Is there a difference between social anxiety disorder and specific phobia? AB - Theories of anxiety disorders and phobias have ascribed a critical role to avoidance behavior in explaining the persistence of fear and anxiety, but knowledge about the role of avoidance behavior in the maintenance of anxiety in social anxiety disorder relative to specific phobia is lacking. This study examined the extent to which avoidance behavior moderates the relationship between general anxiety at baseline and 18 months later in women with a diagnosed social anxiety disorder (n = 91) and women with a diagnosed specific phobia (n = 130) at baseline. Circumscribed avoidance of social and specific situations were clinician-rated using the Anxiety Disorders Interview Schedule-Lifetime (ADIS-IV L), and general anxiety was measured using the Beck Anxiety Inventory (BAI). Moderated regression analyses revealed that (a) general anxiety at baseline predicted general anxiety at follow-up in both women with a specific phobia and women with a social anxiety disorder and (b) avoidance behavior moderated this relationship in women with a specific phobia but not in women with a social anxiety disorder. Specifically, high avoidance behavior was found to amplify the effect between general anxiety at baseline and follow-up in specific phobia. Reasons for the absence of a similar moderating effect of avoidance behavior within social anxiety disorder are discussed. PMID- 28671978 TI - Estimated severe pneumococcal disease cases and deaths before and after pneumococcal conjugate vaccine introduction in children younger than 5 years of age in South Africa. AB - INTRODUCTION: Streptococcus pneumoniae is a leading cause of severe bacterial infections globally. A full understanding of the impact of pneumococcal conjugate vaccine (PCV) on pneumococcal disease burden, following its introduction in 2009 in South Africa, can support national policy on PCV use and assist with policy decisions elsewhere. METHODS: We developed a model to estimate the national burden of severe pneumococcal disease, i.e. disease requiring hospitalisation, pre- (2005-2008) and post-PCV introduction (2012-2013) in children aged 0-59 months in South Africa. We estimated case numbers for invasive pneumococcal disease using data from the national laboratory-based surveillance, adjusted for specimen-taking practices. We estimated non-bacteraemic pneumococcal pneumonia case numbers using vaccine probe study data. To estimate pneumococcal deaths, we applied observed case fatality ratios to estimated case numbers. Estimates were stratified by HIV status to account for the impact of PCV and HIV-related interventions. We assessed how different assumptions affected estimates using a sensitivity analysis. Bootstrapping created confidence intervals. RESULTS: In the pre-vaccine era, a total of approximately 107,600 (95% confidence interval [CI] 83,000-140,000) cases of severe hospitalised pneumococcal disease were estimated to have occurred annually. Following PCV introduction and the improvement in HIV interventions, 41,800 (95% CI 28,000-50,000) severe pneumococcal disease cases were estimated in 2012-2013, a rate reduction of 1,277 cases per 100,000 child years. Approximately 5000 (95% CI 3000-6000) pneumococcal-related annual deaths were estimated in the pre-vaccine period and 1,900 (95% CI 1000-2500) in 2012 2013, a mortality rate difference of 61 per 100,000 child-years. CONCLUSIONS: While a large number of hospitalisations and deaths due to pneumococcal disease still occur among children 0-59 months in South Africa, we found a large reduction in this estimate that is temporally associated with PCV introduction. In HIV-infected individuals the scale-up of other interventions, such as improvements in HIV care, may have also contributed to the declines in pneumococcal burden. PMID- 28671980 TI - FceRI density and spontaneous secretion from human basophils. AB - Mast cells and basophils depend on aggregation of the high-affinity IgE receptor, FceRI, to initiate secretion. A variety of studies have shown that FceRI densities vary 100 fold among subjects' basophils and it has been speculated that high densities might be responsible for unusual behaviors of the cells, notably sensitivity to certain monomeric IgE antibodies or spontaneous release. These studies experimentally examined the density dependence of spontaneous release and signaling element expression in subjects' basophils with FceRI densities ranging from approximately 6000 to 600,000 per cell. Through the use of numerical simulation, this study examined the expectations for spontaneous receptor aggregation and aggregate persistence at densities of FceRI ranging from 5000 to 500,000. Experimentally, FceRI density was not associated with greater spontaneous histamine release even when secretion was enhanced by the inclusion of deuterium oxide in the buffers. There was also no association of 15 activating or de-activating signaling elements with FceRI density. The numerical simulations demonstrated that at densities of ~500,000 receptors, 13% of receptors were involved in transient aggregates at any given moment but that these aggregates rarely persisted for greater than 10 milliseconds. In contrast, a weak linear antigen aggregator, with ligand affinities known to induce secretion, would generate aggregates persisting for an average of ~60 milliseconds. These results suggest that although a high density of FceRI likely produces a large number of transient aggregates, these aggregates do not persist long enough to induce signaling that results in secretion and do not induce the cells to alter their expression of several signaling elements known to be important in regulating secretion from human basophils. The results set some boundaries on the aggregation requirements for inducing histamine release from human basophils. PMID- 28671979 TI - Evolution and multiple roles of the Pancrustacea specific transcription factor zelda in insects. AB - Gene regulatory networks (GRNs) evolve as a result of the coevolutionary processes acting on transcription factors (TFs) and the cis-regulatory modules they bind. The zinc-finger TF zelda (zld) is essential for the maternal-to zygotic transition (MZT) in Drosophila melanogaster, where it directly binds over thousand cis-regulatory modules to regulate chromatin accessibility. D. melanogaster displays a long germ type of embryonic development, where all segments are simultaneously generated along the whole egg. However, it remains unclear if zld is also involved in the MZT of short-germ insects (including those from basal lineages) or in other biological processes. Here we show that zld is an innovation of the Pancrustacea lineage, being absent in more distant arthropods (e.g. chelicerates) and other organisms. To better understand zld's ancestral function, we thoroughly investigated its roles in a short-germ beetle, Tribolium castaneum, using molecular biology and computational approaches. Our results demonstrate roles for zld not only during the MZT, but also in posterior segmentation and patterning of imaginal disc derived structures. Further, we also demonstrate that zld is critical for posterior segmentation in the hemipteran Rhodnius prolixus, indicating this function predates the origin of holometabolous insects and was subsequently lost in long-germ insects. Our results unveil new roles of zld in different biological contexts and suggest that changes in expression of zld (and probably other major TFs) are critical in the evolution of insect GRNs. PMID- 28671981 TI - Parents with mental health problems and their children in a German population based sample: Results of the BELLA study. AB - BACKGROUND: Mental health problems (MHP) of parents are associated with an increased risk of psychological and developmental difficulties in their children. This study aims at analyzing population-based data of parents with MHP and their children and the effects of associated risk factors in order to further targeted preventive and therapeutic interventions. METHODS: The BELLA study is the mental health module of the German National Health Interview and Examination Survey among Children and Adolescents. MHP in parents and in their children as well as associated risk factors were examined in a sample of N = 1158 parents with children aged 11 to 17 years. RESULTS: Parental MHP were identified in 18.6% of the sample. Risk factors associated with parental MHP were low SES, parental unemployment, stressful life events, parental daily strain, parental chronic disease, and child MHP. A rate of 19.1% of the children of parents with MHP reported MHP themselves, the corresponding rate among children of parents without MHP was 7.7%. In multiple regression analyses the risk for children of parents with MHP to report MHP themselves was almost two times higher than the risk of children of parents without MHP. Other significant associations with child MHP included gender, the parents' age, and stressful life events. CONCLUSIONS: Parental MHP constitute a significant risk for the mental health of their children. Targeted screening methods and preventive interventions are needed. PMID- 28671982 TI - Clinical services for adults with an intellectual disability and epilepsy: A comparison of management alternatives. AB - BACKGROUND: Intellectual disability (ID) is relatively common in people with epilepsy, with prevalence estimated to be around 25%. Surprisingly, given this relatively high frequency, along with higher rates of refractory epilepsy than in those without ID, little is known about outcomes of different management approaches/clinical services treating epilepsy in adults with ID-we investigate this area. MATERIALS & METHODS: We undertook a naturalistic observational cohort study measuring outcomes in n = 91 adults with ID over a 7-month period (recruited within the period March 2008 to April 2010). Participants were receiving treatment for refractory epilepsy (primarily) in one of two clinical service settings: community ID teams (CIDTs) or hospital Neurology services. RESULTS: The pattern of comorbidities appeared important in predicting clinical service, with Neurologists managing the epilepsy of relatively more of those with neurological comorbidities whilst CIDTs managed the epilepsy of relatively more of those with psychiatric comorbidities. Epilepsy-related outcomes, as measured by the Glasgow Epilepsy Outcome Scale 35 (GEOS-35) and the Epilepsy and Learning Disabilities Quality of Life Scale (ELDQoL) did not differ significantly between Neurology services and CIDTs. DISCUSSION: In the context of this study, the absence of evidence for differences in epilepsy-related outcomes amongst adults with ID and refractory epilepsy between mainstream neurology and specialist ID clinical services is considered. Determining the selection of the service managing the epilepsy of adults with an ID on the basis of the skill sets also required to treat associated comorbidities may hence be a reasonable heuristic. PMID- 28671983 TI - Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling. AB - A patient's recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host's ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils. Isoflurane significantly increased the surface expression of the receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of a soluble form of Mer protein in the medium. Isoflurane treatment also caused a decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface and a concomitant increase in its cytoplasmic fraction. These responses induced by isoflurane were completely reversed by a pharmacological inhibitor or genetic deletion of AMP-activated protein kinase (AMPK). In a mouse model of lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of lung inflammation and injury that was coupled with an increase in the number of alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted mice, administration of isoflurane-pretreated BMDMs facilitated resolution of lung inflammation following lipopolysaccharide challenge. Thus, isoflurane promoted resolution of lipopolysaccharide-induced lung inflammatory injury via enhancement of macrophage efferocytosis. Increased macrophage efferocytosis following isoflurane treatment correlates with upregulation of Mer surface expression through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane. PMID- 28671984 TI - Reclaiming streets for outdoor play: A process and impact evaluation of "Juega en tu Barrio" (Play in your Neighborhood), an intervention to increase physical activity and opportunities for play. AB - BACKGROUND: New strategies are required to create supportive physical and social environments for children and promote active free-play. Juega en tu Barrio (JETB; Play in your Neighborhood) was designed and implemented to explore the effectiveness of closing a street in a low-to-middle income neighborhood in order to increase children's outside play and physical activity. METHODS: A pretest posttest design with control group was employed to investigate the intervention effects in a subsample of 100 children, 51 from the intervention neighborhood and 49 from the control neighborhood. The children wore pedometers for one week, and their parents completed questionnaires at two time points: before the intervention began and during the last two weeks of the intervention. JETB was conducted in the intervention neighborhood from 17:30 to 20:30, twice a week, from September to December 2014. Stewards ensured that the children were safe. Children and adults were assessed using systematic observation. RESULTS: The intervention and control neighborhoods included 177 and 116 children respectively. The average attendance per event was 60 children (SD = 22, reach 34%). In the intervention neighborhood, a significant increase between baseline and final assessment was observed in after-school outdoor playtime (p = 0.02), steps during the 3-hour intervention (p = 0.004), and daily steps Monday to Sunday (p = 0.006). Meanwhile, no changes were observed in the control neighborhood for the same variables. The proportion of children who met recommended daily step counts increased from 27.5% to 53.0% in the intervention neighborhood (p = 0.007), while for control neighborhood no difference was observed (49.0% to 53.0% p = 0.804). CONCLUSIONS: JETB showed high community engagement while offering opportunities for increased outdoor play in children. The intervention showed a significant effect on the number of children meeting the daily pedometer-derived physical activity recommendations. PMID- 28671985 TI - Dectin-2 is a primary receptor for NLRP3 inflammasome activation in dendritic cell response to Histoplasma capsulatum. AB - Inflammasome is an intracellular protein complex that serves as cytosolic pattern recognition receptor (PRR) to engage with pathogens and to process cytokines of the interleukin-1 (IL-1) family into bioactive molecules. It has been established that interleukin-1beta (IL-1beta) is important to host defense against Histoplasma capsulatum infection. However, the detailed mechanism of how H. capsulatum induces inflammasome activation leading to IL-1beta production has not been studied. Here, we showed in dendritic cells (DCs) that H. capsulatum triggers caspase-1 activation and IL-1beta production through NLRP3 inflammasome. By reciprocal blocking of Dectin-1 or Dectin-2 in single receptor-deficient DCs and cells from Clec4n-/-, Clec7a-/-, and Clec7a-/-Clec4n-/- mice, we discovered that while Dectin-2 operates as a primary receptor, Dectin-1 serves as a secondary one for NLRP3 inflammasome. In addition, both receptors trigger Syk-JNK signal pathway to activate signal 1 (pro-IL-1beta synthesis) and signal 2 (activation of caspase-1). Results of pulmonary infection with H. capsulatum showed that CD103+ DCs are one of the major producers of IL-1beta and Dectin-2 and Dectin-1 double deficiency abolishes their IL-1beta response to the fungus. While K+ efflux and cathepsin B (but not ROS) function as signal 2, viable but not heat-killed H. capsulatum triggers profound lysosomal rupture leading to cathepsin B release. Interestingly, cathepsin B release is regulated by ERK/JNK downstream of Dectin-2 and Dectin-1. Our study demonstrates for the first time the unique roles of Dectin-2 and Dectin-1 in triggering Syk-JNK to activate signal 1 and 2 for H. capsulatum-induced NLRP3 inflammasome activation. PMID- 28671986 TI - Three individuals, three stories, three burials from medieval Trondheim, Norway. AB - This article presents the life stories of three individuals who lived in Trondheim, Norway, during the 13th century. Based on skeletal examinations, facial reconstructions, genetic analyses, and stable oxygen isotope analyses, the birthplace, mobility, ancestry, pathology, and physical appearance of these people are presented. The stories are discussed within the relevant historical context. These three people would have been ordinary citizens, without any privileges out of the ordinary, which makes them quite rare in the academic literature. Through the study of individuals one gets a unique look into the Norwegian medieval society. PMID- 28671987 TI - Knowledge of prevention, cause, symptom and practices of malaria among women in Burkina Faso. AB - BACKGROUND: Malaria remains a major public health issue in most southern African countries as the disease remains hyper endemic. Burkina Faso continues to face challenges in the treatment of malaria, as the utilization of preventive measures remains low on a national scale. While it has been acknowledged that understanding women's health-seeking behaviours, perception of malaria and its preventive measures will aid in the control of malaria, there is paucity of information on Knowledge, Attitudes and Practices among women in the reproductive age of 15-49 years in Burkina Faso. This study investigated women's knowledge of malaria, attitudes towards malaria, and practices of malaria control in order to create a synergy between community efforts and governmental/non-governmental malaria control interventions in Burkina Faso. METHODS: The analysis used data from the 2014 Burkina Faso Malaria Indicator Survey (MIS). In total 8111 women aged between 15-49 years were included in the present study. We assessed women's knowledge about 1) preventive measures, 2) causes and 3) symptoms of malaria, as well as malaria prevention practices for their children and during pregnancy. The socio-demographic characteristics were considered for Age, Religion, Education, Wealth index, Number of household members, Sex of household head, Household possession of radio, TV and Received antenatal care. Data were analyzed using STATA, version 14. Associations between variables were tested using a Chi-square and logistic regression, with the level of statistical significance set at 95%. RESULTS: A preponderant proportion of respondents were aged 15-29 years (mean age was 28.63+/-9.41). About three-quarters of the respondents had no formal education. An estimated two-third of the participants were of Islamic faith, while access to media and behavioural communication were generally poor. The level of knowledge was 53% for rural women and 68.2% for urban dwellers. In sum, there was 56.1% level of accurate knowledge of malaria among women in Burkina Faso. In the multivariable logistic regression, women in rural location had 40% reduction in the odds of having accurate knowledge of malaria when compared to urban women (aOR = 0.60; 95%CI: 0.52-0.68). The educational level was a key factor in the knowledge of malaria. The odds of having accurate knowledge of malaria increased as the educational level increased, hence, women with secondary and higher education had 29% and 93% increase in the odds of having accurate knowledge of malaria when compared to the women without formal education. Results indicate that antenatal care (ANC) services were major sources of information on malaria. Women who reportedly received ANC were 3.9 times more likely to have accurate knowledge of malaria when compared to those who did not utilize skilled ANC services (aOR = 3.90; 95%CI = 3.34-4.56). CONCLUSION: The overall knowledge of malaria prevention practices among a large proportion of women was found to be low, which implies that the knowledge about the prevention of malaria should be improved upon by both urban and rural dwellers. There is need for concerted behavioural communication intervention to improve the knowledge of malaria especially for rural dwellers regarding malaria prevention measures, causes and symptoms. Consistent efforts at providing relevant information by health organizations are needed to reduce and control incidences of malaria in the general public. PMID- 28671988 TI - Checkpoints of apicomplexan cell division identified in Toxoplasma gondii. AB - The unusual cell cycles of Apicomplexa parasites are remarkably flexible with the ability to complete cytokinesis and karyokinesis coordinately or postpone cytokinesis for several rounds of chromosome replication, and are well recognized. Despite this surprising biology, the molecular machinery required to achieve this flexibility is largely unknown. In this study, we provide comprehensive experimental evidence that apicomplexan parasites utilize multiple Cdk-related kinases (Crks) to coordinate cell division. We determined that Toxoplasma gondii encodes seven atypical P-, H-, Y- and L- type cyclins and ten Crks to regulate cellular processes. We generated and analyzed conditional tet OFF mutants for seven TgCrks and four TgCyclins that are expressed in the tachyzoite stage. These experiments demonstrated that TgCrk1, TgCrk2, TgCrk4 and TgCrk6, were required or essential for tachyzoite growth revealing a remarkable number of Crk factors that are necessary for parasite replication. G1 phase arrest resulted from the loss of cytoplasmic TgCrk2 that interacted with a P-type cyclin demonstrating that an atypical mechanism controls half the T. gondii cell cycle. We showed that T. gondii employs at least three TgCrks to complete mitosis. Novel kinases, TgCrk6 and TgCrk4 were required for spindle function and centrosome duplication, respectively, while TgCrk1 and its partner TgCycL were essential for daughter bud assembly. Intriguingly, mitotic kinases TgCrk4 and TgCrk6 did not interact with any cyclin tested and were instead dynamically expressed during mitosis indicating they may not require a cyclin timing mechanism. Altogether, our findings demonstrate that apicomplexan parasites utilize distinctive and complex mechanisms to coordinate their novel replicative cycles. PMID- 28671989 TI - TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. AB - Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naive mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150+ CD34- CD48- cells) in bone marrow (BM) are quiescent, we found that during Leishmania donovani infection most LT-HSCs had entered cell cycle. Loss of quiescence correlated with a reduced self-renewal capacity and functional exhaustion, as measured by serial transfer. Quiescent LT-HSCs were maintained in infected RAG2 KO mice, but lost following adoptive transfer of IFNgamma sufficient but not IFNgamma-deficient CD4+ T cells. Using mixed BM chimeras, we established that IFNgamma and TNF signalling pathways converge at the level of CD4+ T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFNgamma+CD4+ T cells that promote the irreversible loss of BM function. These findings provide new insights into the pathogenic potential of CD4+ T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously. PMID- 28671990 TI - Evaluation of Escherichia coli isolates from healthy chickens to determine their potential risk to poultry and human health. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) strains are important pathogens that cause diverse diseases in humans and poultry. Some E. coli isolates from chicken feces contain ExPEC-associated virulence genes, so appear potentially pathogenic; they conceivably could be transmitted to humans through handling and/or consumption of contaminated meat. However, the actual extraintestinal virulence potential of chicken-source fecal E. coli is poorly understood. Here, we assessed whether fecal E. coli isolates from healthy production chickens could cause diseases in a chicken model of avian colibacillosis and three rodent models of ExPEC-associated human infections. From 304 E. coli isolates from chicken fecal samples, 175 E. coli isolates were screened by PCR for virulence genes associated with human-source ExPEC or avian pathogenic E. coli (APEC), an ExPEC subset that causes extraintestinal infections in poultry. Selected isolates genetically identified as ExPEC and non-ExPEC isolates were assessed in vitro for virulence-associated phenotypes, and in vivo for disease-causing ability in animal models of colibacillosis, sepsis, meningitis, and urinary tract infection. Among the study isolates, 13% (40/304) were identified as ExPEC; the majority of these were classified as APEC and uropathogenic E. coli, but none as neonatal meningitis E. coli. Multiple chicken source fecal ExPEC isolates resembled avian and human clinical ExPEC isolates in causing one or more ExPEC-associated illnesses in experimental animal infection models. Additionally, some isolates that were classified as non-ExPEC were able to cause ExPEC-associated illnesses in animal models, and thus future studies are needed to elucidate their mechanisms of virulence. These findings show that E. coli isolates from chicken feces contain ExPEC-associated genes, exhibit ExPEC associated in vitro phenotypes, and can cause ExPEC-associated infections in animal models, and thus may pose a health threat to poultry and consumers. PMID- 28671991 TI - Effects of stimulus duration and vowel quality in cross-linguistic categorical perception of pitch directions. AB - We investigated categorical perception of rising and falling pitch contours by tonal and non-tonal listeners. Specifically, we determined minimum durations needed to perceive both contours and compared to those of production, how stimuli duration affects their perception, whether there is an intrinsic F0 effect, and how first language background, duration, directions of pitch and vowel quality interact with each other. Continua of fundamental frequency on different vowels with 9 duration values were created for identification and discrimination tasks. Less time is generally needed to effectively perceive a pitch direction than to produce it. Overall, tonal listeners' perception is more categorical than non tonal listeners. Stimuli duration plays a critical role for both groups, but tonal listeners showed a stronger duration effect, and may benefit more from the extra time in longer stimuli for context-coding, consistent with the multistore model of categorical perception. Within a certain range of semitones, tonal listeners also required shorter stimulus duration to perceive pitch direction changes than non-tonal listeners. Finally, vowel quality plays a limited role and only interacts with duration in perceiving falling pitch directions. These findings further our understanding on models of categorical perception, the relationship between speech perception and production, and the interaction between the perception of tones and vowel quality. PMID- 28671992 TI - Signaling pathways induced by serine proteases to increase intestinal epithelial barrier function. AB - Changes in barrier function of the gastrointestinal tract are thought to contribute to the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Previous work in our lab demonstrated that apical exposure of intestinal epithelial cell lines to serine proteases results in an increase in transepithelial electrical resistance (TER). However, the underlying mechanisms governing this response are unclear. We aimed to determine the requirement for proteolytic activity, epidermal growth factor receptor (EGFR) activation, and downstream intracellular signaling in initiating and maintaining enhanced barrier function following protease treatment using a canine intestinal epithelial cell line (SCBN). We also examined the role of phosphorylation of myosin regulatory light chain on the serine protease-induced increase in TER through. It was found that proteolytic activity of the serine proteases trypsin and matriptase is required to initiate and maintain the protease-mediated increase in TER. We also show that MMP-independent EGFR activation is essential to the sustained phase of the protease response, and that Src kinases may mediate EGFR transactivation. PI3 K and ERK1/2 signaling were important in reaching a maximal increase in TER following protease stimulation; however, their upstream activators are yet to be determined. CK2 inhibition prevented the increase in TER induced by serine proteases. The bradykinin B(2) receptor was not involved in the change in TER in response to serine proteases, and no change in phosphorylation of MLC was observed after trypsin or matriptase treatment. Taken together, our data show a requirement for ongoing proteolytic activity, EGFR transactivation, as well as downstream PI3-K, ERK1/2, and CK2 signaling in protease-mediated barrier enhancement of intestinal epithelial cells. The pathways mediating enhanced barrier function by proteases may be novel therapeutic targets for intestinal disorders characterized by disrupted epithelial barrier function. PMID- 28671994 TI - Morphological analysis of human umbilical vein endothelial cells co-cultured with ovarian cancer cells in 3D: An oncogenic angiogenesis assay. AB - Antiangiogenic therapy for cancer is a strategy targeted at tumour vasculature, often in combination with conventional cytotoxicity treatments. Animal testing is still the most common method used for evaluating the efficacy of new drugs but tissue-engineered in vitro models are becoming more acceptable for replacing and reducing the use of animals in anti-cancer drug screening. In this study, a 3D co culture model of human endothelial cells and ovarian cancer cells was developed. This model has the potential to mimic the interactions between endothelial cells and ovarian cancer cells. The feasibility of applying this model in drug testing was explored here. The complex morphology of the co-culture system, which features development of both endothelial tubule-like structures and tumour structures, was analysed quantitatively by an image analysis method. The co culture morphology integrity was maintained for 10 days and the potential of the model for anti-cancer drug testing was evaluated using Paclitaxel and Cisplatin, two common anti-tumour drugs with different mechanisms of action. Both traditional cell viability assays and quantitative morphological analyses were applied in the drug testing. Cisplatin proved a good example showing the advantages of morphological analysis of the co-culture model when compared with mono-culture of endothelial cells, which did not reveal an inhibitory effect of Cisplatin on the tubule-like endothelial structures. Thus, the tubule areas of the co-culture reflected the anti-angiogenesis potential of Cisplatin. In summary, in vitro cancer models can be developed using a tissue engineering approach to more closely mimic the characteristics of tumours in vivo. Combined with the image analysis technique, this developed 3D co-culture angiogenesis model will provide more reproducible and reliably quantified results and reveal further information of the drug's effects on both tumour cell growth and tumour angiogenesis. PMID- 28671993 TI - Epithelial cells detect functional type III secretion system of enteropathogenic Escherichia coli through a novel NF-kappaB signaling pathway. AB - Enteropathogenic Escherichia coli (EPEC), a common cause of infant diarrhea, is associated with high risk of mortality in developing countries. The primary niche of infecting EPEC is the apical surface of intestinal epithelial cells. EPEC employs a type three secretion system (TTSS) to inject the host cells with dozens of effector proteins, which facilitate attachment to these cells and successful colonization. Here we show that EPEC elicit strong NF-kappaB activation in infected host cells. Furthermore, the data indicate that active, pore-forming TTSS per se is necessary and sufficient for this NF-kappaB activation, regardless of any specific effector or protein translocation. Importantly, upon infection with wild type EPEC this NF-kappaB activation is antagonized by anti-NF-kappaB effectors, including NleB, NleC and NleE. Accordingly, this NF-kappaB activation is evident only in cells infected with EPEC mutants deleted of nleB, nleC, and nleE. The TTSS-dependent NF-kappaB activation involves a unique pathway, which is independent of TLRs and Nod1/2 and converges with other pathways at the level of TAK1 activation. Taken together, our results imply that epithelial cells have the capacity to sense the EPEC TTSS and activate NF-kappaB in response. Notably, EPEC antagonizes this capacity by delivering anti-NF-kappaB effectors into the infected cells. PMID- 28671995 TI - Dr.seq2: A quality control and analysis pipeline for parallel single cell transcriptome and epigenome data. AB - An increasing number of single cell transcriptome and epigenome technologies, including single cell ATAC-seq (scATAC-seq), have been recently developed as powerful tools to analyze the features of many individual cells simultaneously. However, the methods and software were designed for one certain data type and only for single cell transcriptome data. A systematic approach for epigenome data and multiple types of transcriptome data is needed to control data quality and to perform cell-to-cell heterogeneity analysis on these ultra-high-dimensional transcriptome and epigenome datasets. Here we developed Dr.seq2, a Quality Control (QC) and analysis pipeline for multiple types of single cell transcriptome and epigenome data, including scATAC-seq and Drop-ChIP data. Application of this pipeline provides four groups of QC measurements and different analyses, including cell heterogeneity analysis. Dr.seq2 produced reliable results on published single cell transcriptome and epigenome datasets. Overall, Dr.seq2 is a systematic and comprehensive QC and analysis pipeline designed for parallel single cell transcriptome and epigenome data. Dr.seq2 is freely available at: http://www.tongji.edu.cn/~zhanglab/drseq2/ and https://github.com/ChengchenZhao/DrSeq2. PMID- 28671996 TI - Photoreceptor oxidative stress in hyperoxia-induced proliferative retinopathy accelerates rd8 degeneration. AB - To investigate the impact of photoreceptor oxidative stress on photoreceptor degeneration in mice carrying the rd8 mutation (C57BL/6N). We compared the hyperoxia-induced proliferative retinopathy (HIPR) model in two mouse strains (C57BL/6J and C57BL/6N). Pups were exposed to 75% oxygen, starting at birth and continuing for 14 days (P14). Mice were euthanized at P14, or allowed to recover in room air for one day (P15), seven days (P21), or 14 days (P28). We quantified retinal thickness and the length of residual photoreceptors not affected by rosette formation. In addition we explored differences in retinal immunostaining for NADPH oxidase 4 (NOX4), Rac1, vascular endothelium, and activated Mupsilonller cells. We analyzed photoreceptor oxidative stress using DCF staining in cross sections and quantified NOX4 protein levels using western blotting. C57BL/6N mice in HIPR showed increased oxidative stress, NOX4, and Rac1 in the photoreceptors at P14 and P15 compared to C57BL/6J. In addition, we observed significant progression of photoreceptor degeneration, with significantly accelerated rosette formation in C57BL/6N under HIPR, compared to their room air counterparts. Furthermore, C57BL/6N under HIPR had significantly thinner central retinas than C57BL/6J in HIPR. We did not find a difference in vascular disruption or Mupsilonller cell activation comparing the two strains in hyperoxia. In HIPR, the C57BL/6N strain carrying the rd8 mutation showed significantly accelerated photoreceptor degeneration, mediated via exacerbated photoreceptor oxidative stress, which we believe relates to Rac1-NOX dysregulation in the setting of Crb1 loss-of-function. PMID- 28671997 TI - Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats. AB - Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia. PMID- 28671998 TI - Metal contamination in harbours impacts life-history traits and metallothionein levels in snails. AB - Harbours with limited water exchange are hotspots of contaminant accumulation. Antifouling paints (AF) contribute to this accumulation by leaching biocides that may affect non-target species. In several leisure boat harbours and reference areas in the Baltic Sea, chronic exposure effects were evaluated using caging experiments with the snail Theodoxus fluviatilis. We analysed variations in ecologically relevant endpoints (mortality, growth and reproduction) in concert with variation in metallothionein-like proteins (MTLP) levels. The latter is a biomarker of exposure to metals, such as copper (Cu) and zinc (Zn), which are used in AF paints as active ingredient and stabilizer, respectively. In addition, environmental samples (water, sediment) were analysed for metal (Cu and Zn) and nutrient (total phosphorous and nitrogen) concentrations. All life-history endpoints were negatively affected by the exposure, with higher mortality, reduced growth and lower fecundity in the harbours compared to the reference sites. Metal concentrations were the key explanatory variables for all observed adverse effects, suggesting that metal-driven toxicity, which is likely to stem from AF paints, is a source of anthropogenic stress for biota in the harbours. PMID- 28671999 TI - Speciation trajectories in recombining bacterial species. AB - It is generally agreed that bacterial diversity can be classified into genetically and ecologically cohesive units, but what produces such variation is a topic of intensive research. Recombination may maintain coherent species of frequently recombining bacteria, but the emergence of distinct clusters within a recombining species, and the impact of habitat structure in this process are not well described, limiting our understanding of how new species are created. Here we present a model of bacterial evolution in overlapping habitat space. We show that the amount of habitat overlap determines the outcome for a pair of clusters, which may range from fast clonal divergence with little interaction between the clusters to a stationary population structure, where different clusters maintain an equilibrium distance between each other for an indefinite time. We fit our model to two data sets. In Streptococcus pneumoniae, we find a genomically and ecologically distinct subset, held at a relatively constant genetic distance from the majority of the population through frequent recombination with it, while in Campylobacter jejuni, we find a minority population we predict will continue to diverge at a higher rate. This approach may predict and define speciation trajectories in multiple bacterial species. PMID- 28672000 TI - Synthesis and evaluation of L-arabinose-based cationic glycolipids as effective vectors for pDNA and siRNA in vitro. AB - Glycolipids might become a new type of promising non-viral gene delivery systems because of their low cytotoxicity, structural diversity, controllable aqua- and lipo-solubility, appropriate density and distribution of positive charges, high transfer efficiency and potential targeting function. In this study, four kinds of L-arabinose-based cationic glycolipids (Ara-DiC12MA, Ara-DiC14MA, Ara-DiC16MA and Ara-DiC18MA) containing quaternary ammonium as hydrophilic headgroup and two alkane chains as hydrophobic domain were synthesized and characterized. They were observed to have strong affinities for plasmid DNA (pDNA) and siRNA, the pDNA can be completely condensed at N/P ratio less than 2, and the siRNA can be completely retarded at N/P ratio less than 3. The dynamic light scattering (DLS) experiment and atomic force microscopy (AFM) experiment demonstrated that cationic lipids and their lipoplexes possessed suitable particle sizes with near-spherical shape and proper zeta-potentials for cell transfection. The Ara-DiC16MA liposome was found to have good transfection efficacy in HEK293, PC-3 and Mat cells compared with other three kinds of liposomes, and also maintain low cytotoxicity and better uptake capability in vitro. Furthermore, the gene silencing assay showed that Ara-DiC14MA and Ara-DiC16MA liposomes have demonstrated effective delivery and higher gene knockdown activity (>80%) in the above mentioned cells than Lipofectamine 2000. These results indicated Ara-DiC16MA can be developed for efficient and low toxic gene delivery. PMID- 28672001 TI - Host-seeking efficiency can explain population dynamics of the tsetse fly Glossina morsitans morsitans in response to host density decline. AB - Females of all blood-feeding arthropod vectors must find and feed on a host in order to produce offspring. For tsetse-vectors of the trypanosomes that cause human and animal African trypanosomiasis-the problem is more extreme, since both sexes feed solely on blood. Host location is thus essential both for survival and reproduction. Host population density should therefore be an important driver of population dynamics for haematophagous insects, and particularly for tsetse, but the role of host density is poorly understood. We investigate the issue using data on changes in numbers of tsetse (Glossina morsitans morsitans Westwood) caught during a host elimination experiment in Zimbabwe in the 1960s. During the experiment, numbers of flies caught declined by 95%. We aimed to assess whether models including starvation-dependent mortality could explain observed changes in tsetse numbers as host density declined. An ordinary differential equation model, including starvation-dependent mortality, captured the initial dynamics of the observed tsetse population. However, whereas small numbers of tsetse were caught throughout the host elimination exercise, the modelled population went extinct. Results of a spatially explicit agent-based model suggest that this discrepancy could be explained by immigration of tsetse into the experimental plot. Variation in host density, as a result of natural and anthropogenic factors, may influence tsetse population dynamics in space and time. This has implications for Trypanosoma brucei rhodesiense transmission. Increased tsetse mortality as a consequence of low host density may decrease trypanosome transmission, but hungrier flies may be more inclined to bite humans, thereby increasing the risk of transmission to humans. Our model provides a way of exploring the role of host density on tsetse population dynamics and could be incorporated into models of trypanosome transmission dynamics to better understand how spatio-temporal variation in host density impacts trypanosome prevalence in mammalian hosts. PMID- 28672002 TI - How do protected landscapes associated with high biodiversity and population levels change? AB - Most protected areas (PA) try to limit logging of forests by means of restrictions on access and use, especially in areas where local communities coexist with the forests and depend on resources derived from PAs. In such contexts, achieving full or effective protection of the forests is almost impossible. This fact has led to researching beyond PAs boundaries in order to examine large surrounding landscapes with multiple forms of properties and restriction on forests use. The present study assessed the change in forest cover and fragmentation between 1990 and 2014, in addition to the drivers that explain such changes in a landscape with the presence of PAs and high-density population belonging to the Choco-Darien biodiversity hotspot. Results indicated differences in the extent and spatial patterns of change in forest cover of PAs and their surrounding landscapes. Two PAs exhibited a tendency to increase fragmentation and lose their forests in comparison with the stable protection of the forests in other PAs during this period. However, the greatest change in forest cover and fragmentation was observed in the surrounding landscapes, where the best connection to markets and transport networks were the dominating deforestation drivers. Our findings corroborated that the PAs were a shield against the deforestation of the tropical Andean forest, especially in landscapes with high density population. However, the fragmentation of the forest cannot be avoided around the PAs limits. It is expected that, if this tendency continues in the future, the biodiversity in the Choco-Darien hotspot will be seriously affected. PMID- 28672003 TI - Endogenous small interfering RNAs associated with maize embryonic callus formation. AB - The induction efficiency of maize embryonic callus is highly dependent on the genotype, and only a few lines possess a high capacity for callus formation. Although certain genes and pathways have been reported to contribute to the regulation of callus induction, to the best of our knowledge, the functions of the small interfering RNAs (siRNAs) involved in this process remain unknown. In this study, we identified 861 differentially expressed siRNAs and 576 target genes in the callus induction process. These target genes were classified into 3 clusters, and their functions involve controlling metalloexopeptidase activity, catalase activity, transcription regulation, and O-methyltransferase activity. In addition, certain genes related to auxin transport and stem cell or meristem development (e.g., PLT5-like, ARF15, SAUR-like, FAS1-like, Fea3, SCL5, and Zmwox2A) were regulated by the differentially expressed siRNAs. Moreover, zma siR004119-2 directly cleaves the 5' UTR of Homeobox-transcription factor 25, which further leads to the down-regulation of its expression. Twelve 24-nt-siRNAs led to the hyper-methylation of GRMZM2G013465, which further decreases its expression. These results suggest that differentially expressed siRNAs regulate callus formation by controlling the expression of their target genes. PMID- 28672004 TI - Stroller running: Energetic and kinematic changes across pushing methods. AB - OBJECTIVE: Running with a stroller provides an opportunity for parents to exercise near their child and counteract health declines experienced during early parenthood. Understanding biomechanical and physiological changes that occur when stroller running is needed to evaluate its health impact, yet the effects of stroller running have not been clearly presented. Here, three commonly used stroller pushing methods were investigated to detect potential changes in energetic cost and lower-limb kinematics. METHODS: Sixteen individuals (M/F: 10/6) ran at self-selected speeds for 800m under three stroller conditions (2 Hands, 1-Hand, and Push/Chase) and an independent running control. RESULTS: A significant decrease in speed (p = 0.001) and stride length (p<0.001) was observed between the control and stroller conditions, however no significant change in energetic cost (p = 0.080) or heart rate (p = 0.393) was observed. Additionally, pushing method had a significant effect on speed (p = 0.001) and stride length (p<0.001). CONCLUSIONS: These findings suggest that pushing technique influences stroller running speed and kinematics. These findings suggest specific fitness effects may be achieved through the implementation of different pushing methods. PMID- 28672005 TI - Fatty acid transport protein 1 regulates retinoid metabolism and photoreceptor development in mouse retina. AB - In retinal pigment epithelium (RPE), RPE65 catalyzes the isomerization of all trans-retinyl fatty acid esters to 11-cis-retinol in the visual cycle and controls the rhodopsin regeneration rate. However, the mechanisms by which these processes are regulated are still unclear. Fatty Acid Transport Protein 1 (FATP1) is involved in fatty acid uptake and lipid metabolism in a variety of cell types. FATP1 co-localizes with RPE65 in RPE and inhibits its isomerase activity in vitro. Here, we further investigated the role of FATP1 in the visual cycle using transgenic mice that overexpress human FATP1 specifically in the RPE (hFATP1TG mice). The mice displayed no delay in the kinetics of regeneration of the visual chromophore 11-cis-retinal after photobleaching and had no defects in light sensitivity. However, the total retinoid content was higher in the hFATP1TG mice than in wild type mice, and the transgenic mice also displayed an age-related accumulation (up to 40%) of all-trans-retinal and retinyl esters that was not observed in control mice. Consistent with these results, hFATP1TG mice were more susceptible to light-induced photoreceptor degeneration. hFATP1 overexpression also induced an ~3.5-fold increase in retinosome autofluorescence, as measured by two-photon microscopy. Interestingly, hFATP1TG retina contained ~25% more photoreceptor cells and ~35% longer outer segments than wild type mice, revealing a non-cell-autonomous effect of hFATP1 expressed in the RPE. These data are the first to show that FATP1-mediated fatty acid uptake in the RPE controls both retinoid metabolism in the outer retina and photoreceptor development. PMID- 28672006 TI - Mosquitoes on a plane: Disinsection will not stop the spread of vector-borne pathogens, a simulation study. AB - Mosquito-borne diseases are increasingly being recognized as global threats, with increased air travel accelerating their occurrence in travelers and their spread to new locations. Since the early days of aviation, concern over the possible transportation of infected mosquitoes has led to recommendations to disinsect aircraft. Despite rare reports of mosquitoes, most likely transported on aircraft, infecting people far from endemics areas, it is unclear how important the role of incidentally transported mosquitoes is compared to the role of traveling humans. We used data for Plasmodium falciparum and dengue viruses to estimate the probability of introduction of these pathogens by mosquitoes and by humans via aircraft under ideal conditions. The probability of introduction of either pathogen by mosquitoes is low due to few mosquitoes being found on aircraft, low infection prevalence among mosquitoes, and high mortality. Even without disinsection, introduction via infected human travelers was far more likely than introduction by infected mosquitoes; more than 1000 times more likely for P. falciparum and more than 200 times more likely for dengue viruses. Even in the absence of disinsection and under the most favorable conditions, introduction of mosquito-borne pathogens via air travel is far more likely to occur as a result of an infected human travelling rather than the incidental transportation of infected mosquitoes. Thus, while disinsection may serve a role in preventing the spread of vector species and other invasive insects, it is unlikely to impact the spread of mosquito-borne pathogens. PMID- 28672007 TI - Diagnostic utility of whole body Dixon MRI in multiple myeloma: A multi-reader study. AB - OBJECTIVE: To determine which of four Dixon image types [in-phase (IP), out-of phase (OP), fat only (FO) and water-only (WO)] is most sensitive for detecting multiple myeloma (MM) focal lesions on whole body MRI (WB-MRI) images. METHODS: Thirty patients with clinically-suspected MM underwent WB-MRI at 3 Tesla. Unenhanced IP, OP, FO and WO Dixon images were generated and read by four radiologists. On each image type, each radiologist identified and labelled all visible myeloma lesions in the bony pelvis. Each identified lesion was compared with a reference standard consisting of pre- and post-contrast Dixon and diffusion weighted imaging (read by a further consultant radiologist) to determine whether the lesion was truly positive. Lesion count, true positives, sensitivity, and positive predictive value were compared across the four Dixon image types. RESULTS: Lesion count, true positives, sensitivity and confidence scores were all significantly higher on FO images than on IP images (p>0.05). DISCUSSION: FO images are more sensitive than other Dixon image types for MM focal lesions, and should be preferentially read by radiologists to improve diagnostic accuracy and reporting efficiency. PMID- 28672009 TI - Verb bias and verb-specific competition effects on sentence production. AB - How do speakers choose between structural options for expressing a given meaning? Overall preference for some structures over others as well as prior statistical association between specific verbs and sentence structures ("verb bias") are known to broadly influence language use. However, the effects of prior statistical experience on the planning and execution of utterances and the mechanisms that facilitate structural choice for verbs with different biases have not been fully explored. In this study, we manipulated verb bias for English double-object (DO) and prepositional-object (PO) dative structures: some verbs appeared solely in the DO structure (DO-only), others solely in PO (PO-only) and yet others equally in both (Equi). Structural choices during subsequent free choice sentence production revealed the expected dispreference for DO overall but critically also a reliable linear trend in DO production that was consistent with verb bias (DO-only > Equi > PO-only). Going beyond the general verb bias effect, three results suggested that Equi verbs, which were associated equally with the two structures, engendered verb-specific competition and required additional resources for choosing the dispreferred DO structure. First, DO production with Equi verbs but not the other verbs correlated with participants' inhibition ability. Second, utterance duration prior to the choice of a DO structure showed a quadratic trend (DO-only < Equi > PO-only) with the longest durations for Equi verbs. Third, eye movements consistent with reimagining the event also showed a quadratic trend (DO-only < Equi > PO-only) prior to choosing DO, suggesting that participants used such recall particularly for Equi verbs. Together, these analyses of structural choices, utterance durations, eye movements and individual differences in executive functions shed light on the effects of verb bias and verb-specific competition on sentence production and the role of different executive functions in choosing between sentence structures. PMID- 28672008 TI - Nanofibrous scaffolds for the guidance of stem cell-derived neurons for auditory nerve regeneration. AB - Impairment of spiral ganglion neurons (SGNs) of the auditory nerve is a major cause for hearing loss occurring independently or in addition to sensory hair cell damage. Unfortunately, mammalian SGNs lack the potential for autonomous regeneration. Stem cell based therapy is a promising approach for auditory nerve regeneration, but proper integration of exogenous cells into the auditory circuit remains a fundamental challenge. Here, we present novel nanofibrous scaffolds designed to guide the integration of human stem cell-derived neurons in the internal auditory meatus (IAM), the foramen allowing passage of the spiral ganglion to the auditory brainstem. Human embryonic stem cells (hESC) were differentiated into neural precursor cells (NPCs) and seeded onto aligned nanofiber mats. The NPCs terminally differentiated into glutamatergic neurons with high efficiency, and neurite projections aligned with nanofibers in vitro. Scaffolds were assembled by seeding GFP-labeled NPCs on nanofibers integrated in a polymer sheath. Biocompatibility and functionality of the NPC-seeded scaffolds were evaluated in vivo in deafened guinea pigs (Cavia porcellus). To this end, we established an ouabain-based deafening procedure that depleted an average 72% of SGNs from apex to base of the cochleae and caused profound hearing loss. Further, we developed a surgical procedure to implant seeded scaffolds directly into the guinea pig IAM. No evidence of an inflammatory response was observed, but post surgery tissue repair appeared to be facilitated by infiltrating Schwann cells. While NPC survival was found to be poor, both subjects implanted with NPC-seeded and cell-free control scaffolds showed partial recovery of electrically-evoked auditory brainstem thresholds. Thus, while future studies must address cell survival, nanofibrous scaffolds pose a promising strategy for auditory nerve regeneration. PMID- 28672010 TI - Fibroblasts accelerate islet revascularization and improve long-term graft survival in a mouse model of subcutaneous islet transplantation. AB - Pancreatic islet transplantation has been considered for many years a promising therapy for beta-cell replacement in patients with type-1 diabetes despite that long-term clinical results are not as satisfactory. This fact points to the necessity of designing strategies to improve and accelerate islets engraftment, paying special attention to events assuring their revascularization. Fibroblasts constitute a cell population that collaborates on tissue homeostasis, keeping the equilibrium between production and degradation of structural components as well as maintaining the required amount of survival factors. Our group has developed a model for subcutaneous islet transplantation using a plasma-based scaffold containing fibroblasts as accessory cells that allowed achieving glycemic control in diabetic mice. Transplanted tissue engraftment is critical during the first days after transplantation, thus we have gone in depth into the graft-supporting role of fibroblasts during the first ten days after islet transplantation. All mice transplanted with islets embedded in the plasma-based scaffold reversed hyperglycemia, although long-term glycemic control was maintained only in the group transplanted with the fibroblasts-containing scaffold. By gene expression analysis and histology examination during the first days we could conclude that these differences might be explained by overexpression of genes involved in vessel development as well as in beta-cell regeneration that were detected when fibroblasts were present in the graft. Furthermore, fibroblasts presence correlated with a faster graft re-vascularization, a higher insulin-positive area and a lower cell death. Therefore, this work underlines the importance of fibroblasts as accessory cells in islet transplantation, and suggests its possible use in other graft-supporting strategies. PMID- 28672011 TI - Prognostic role of noninvasive liver reserve markers in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. AB - BACKGROUND: Various noninvasive liver reserve markers were proposed to indicate the severity of liver damage. However, the role and feasibility of these markers to predict the prognosis of patients with hepatocellular carcinoma (HCC) are unknown. We aimed to identify the prognostic role of the 8 currently used hepatic reserve markers in patients with HCC undergoing transarterial chemoembolization (TACE). METHODS: Between 2002 and 2013, a total of 881 patients with HCC undergoing TACE were prospectively identified and retrospectively analyzed. The baseline characteristics, tumor status and noninvasive markers were collected. Homogeneity and corrected Akaike information criteria (AICc) were compared between these markers. The Cox proportional hazards model was used to identify independent predictors of survival. RESULTS: Significant differences in survival distribution were found for albumin-bilirubin (ALBI) grade, Child-Turcotte-Pugh (CTP) class, Lok index, fibrosis index based on 4 factors (FIB-4), Goteborg University cirrhosis index (GUCI), cirrhosis discriminant index (CDI) and model for end-stage liver disease (MELD) score (all p values <0.05). Among these markers, the ALBI grade showed the highest homogeneity and lowest AICc value, indicating a better prognostic performance. Cox multivariate analysis confirmed that ALBI grade 2, ascites, serum alkaline phosphatase and alpha-fetoprotein level, tumor diameter, vascular invasion and performance status were significant independent prognostic predictors. The distribution of the ALBI score well correlated with baseline CTP and MLED scores. CONCLUSIONS: Our data suggest that among the currently used liver reserve markers, ALBI grade may serve as an objective and feasible surrogate to predict the prognosis of HCC patients undergoing TACE. PMID- 28672012 TI - Identification and validation of reference genes for qRT-PCR studies of the obligate aphid pathogenic fungus Pandora neoaphidis during different developmental stages. AB - The selection of stable reference genes is a critical step for the accurate quantification of gene expression. To identify and validate the reference genes in Pandora neoaphidis-an obligate aphid pathogenic fungus-the expression of 13classical candidate reference genes were evaluated by quantitative real-time reverse transcriptase polymerase chain reaction(qPCR) at four developmental stages (conidia, conidia with germ tubes, short hyphae and elongated hyphae). Four statistical algorithms, including geNorm, NormFinder, BestKeeper and Delta Ct method were used to rank putative reference genes according to their expression stability and indicate the best reference gene or combination of reference genes for accurate normalization. The analysis of comprehensive ranking revealed that ACT1and 18Swas the most stably expressed genes throughout the developmental stages. To further validate the suitability of the reference genes identified in this study, the expression of cell division control protein 25 (CDC25) and Chitinase 1(CHI1) genes were used to further confirm the validated candidate reference genes. Our study presented the first systematic study of reference gene(s) selection for P. neoaphidis study and provided guidelines to obtain more accurate qPCR results for future developmental efforts. PMID- 28672013 TI - Realist evaluation of an enhanced health visiting programme. AB - BACKGROUND: The health visitors' role in many countries is changing. In Scotland, the role has undergone substantial changes through the introduction of an enhanced health visiting programme, which includes increased, structured home visits. This evaluation was conducted within NHS Ayrshire and Arran, one of the 14 Scottish Health Boards. Our aim was to understand and explain how, and why, the programme could contribute to improving health and wellbeing outcomes for children and families. METHODS: We used a realist evaluation approach, conducted in three phases. In phase one, eight managerial staff involved in developing and implementing the programme provided data, which were used to develop initial programme theories. In phase two, the programme theories were tested using qualitative data from 25 health visitors and 22 parents. The programme theories were refined through analyses and interpretation of data in phase three. RESULTS: The home visiting context provided by the programme interacted with the mechanisms of the programme and produced outcomes such as early identification of health and wellbeing issues amongst families who needed more support, leading to referral and engagement with sources of additional help. The home visits facilitated development of parent-health visitor relationships, and parents considered health visitors as their first point of contact on children's wellbeing and developmental-related issues. Moreover, the programme provided more clarity to health visitors' role, which in turn enhanced partnership working. However, there were aspects of the programme that may require further development. For instance, both parents and health visitors were concerned about the wide gaps between some home visits. CONCLUSIONS: The enhanced health visiting programme increased opportunities for monitoring and early identification of health and wellbeing concerns. It created structures for a more efficient partnership working and ensured that the needs of children and families were supported. These benefits need to be evaluated further in an effectiveness study. PMID- 28672014 TI - Molecular detection of Coxiella burnetii from the formalin-fixed tissues of Q fever patients with acute hepatitis. AB - BACKGROUND: Serologic diagnosis is one of the most widely used diagnostic methods for Q fever, but the window period in antibody response of 2 to 3 weeks after symptom onset results in significant diagnostic delay. We investigated the diagnostic utility of Q fever PCR from formalin-fixed liver tissues in Q fever patients with acute hepatitis. METHODS: We reviewed the clinical and laboratory data in patients with Q fever hepatitis who underwent liver biopsy during a 17 year period, and whose biopsied tissues were available. We also selected patients who revealed granuloma in liver biopsy and with no Q fever diagnosis within the last 3 years as control. Acute Q fever hepatitis was diagnosed if two or more of the following clinical, serologic, or histopathologic criteria were met: (1) an infectious hepatitis-like clinical feature such as fever (>= 38 degrees C) with elevated hepatic transaminase levels; (2) exhibition of a phase II immunoglobulin G (IgG) antibodies titer by IFA of >= 1:128 in single determination, or a four fold or greater rise between two separate samples obtained two or more weeks apart; (3) histologic finding of biopsy tissue showing characteristic fibrin ring granuloma. RESULTS: A total of 11 patients with acute Q fever hepatitis were selected and analyzed. Of the 11 patients, 3 (27%) had exposure to zoonotic risk factors and 7 (63%) met the serologic criteria. Granulomas with either circumferential or radiating fibrin deposition were observed in 10 cases on liver biopsy and in 1 case on bone marrow biopsy. 8 (73%) revealed positive Coxiella burnetii PCR from their formalin-fixed liver tissues. In contrast, none of 10 patients with alternative diagnosis who had hepatic granuloma revealed positive C. burnetii PCR from their formalin-fixed liver tissues. CONCLUSIONS: Q fever PCR from formalin-fixed liver tissues appears to be a useful adjunct for diagnosing Q fever hepatitis. PMID- 28672015 TI - Transcriptome analysis of Streptococcus gallolyticus subsp. gallolyticus in interaction with THP-1 macrophage-like cells. AB - BACKGROUND: Streptococcus gallolyticus subsp. gallolyticus (S. gallolyticus) is a pathogen of infective endocarditis. It was observed previously that this bacterium survives longer in macrophages than other species and the phagocytic uptake by and survival in THP-1 macrophages is strain-dependent. METHODS: The phagocytosis assay was performed with THP-1 macrophages. S. gallolyticus specific whole genome microarrays were used for transcriptome analysis. RESULTS: Better survival in macrophages was observed for UCN34, BAA-2069 and ATCC43143 than for DSM16831 and LMG17956. S. gallolyticus strains show high resistance to tested bactericidal agents (acid, lysozyme and hydrogen peroxide). S. gallolyticus stimulates significant lower cytokine gene expression and causes less lysis of macrophages compared to the control strain Staphylococcus aureus. S. gallolyticus reacts to oxidative burst with a higher gene expression of NADH oxidase initially at the early phase. Expression of genes involved in D-alanylation of teichoic acid, carbohydrate metabolism and transport systems were upregulated thereafter. CONCLUSION: S. gallolyticus is very resistant to bactericidal agents normally causing degradation of bacteria in phagolysosomes. Additionally, the D alanylation of teichoic acid is an important factor for survival. PMID- 28672016 TI - Quantitative assessment of simultaneous F-18 FDG PET/MRI in patients with various types of hepatic tumors: Correlation between glucose metabolism and apparent diffusion coefficient. AB - PURPOSE: Metabolism and water diffusion may have a relationship or an effect on each other in the same tumor. Knowledge of their relationship could expand the understanding of tumor biology and serve the field of oncologic imaging. This study aimed to evaluate the relationship between metabolism and water diffusivity in hepatic tumors using a simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) system with F-18 fluorodeoxyglucose (FDG) and to reveal the metabolic and diffusional characteristics of each type of hepatic tumor. METHODS: Forty-one patients (mean age 63 +/- 13 years, 31 male) with hepatic tumors (18 hepatocellular carcinoma [HCC], six cholangiocarcinoma [CCC], 10 metastatic tumors, one neuroendocrine malignancy, and six benign lesions) underwent FDG PET/MRI before treatment. Maximum standard uptake (SUVmax) values from FDG PET and the apparent diffusion coefficient (ADC) from the diffusion weighted images were obtained for the tumor and their relationships were examined. We also investigated the difference in SUVmax and ADC for each type of tumor. RESULTS: SUVmax showed a negative correlation with ADC (r = -0.404, p = 0.009). The median of SUVmax was 3.22 in HCC, 6.99 in CCC, 6.30 in metastatic tumors, and 1.82 in benign lesions. The median of ADC was 1.039 * 10-3 mm/s2 in HCC, 1.148 * 10-3 mm/s2 in CCC, 0.876 * 10-3 mm/s2 in metastatic tumors, and 1.323 * 10-3 mm/s2 in benign lesions. SUVmax was higher in metastatic tumors than in benign lesions (p = 0.023). Metastatic tumors had a lower ADC than CCC (p = 0.039) and benign lesions (p = 0.004). HCC had a lower ADC than benign lesions, with a suggestive trend (p = 0.06). CONCLUSION: Our results indicate that SUVmax is negatively correlated with ADC in hepatic tumors, and each group of tumors has different metabolic and water diffusivity characteristics. Evaluation of hepatic tumors by PET/MRI could be helpful in understanding tumor characteristics. PMID- 28672018 TI - Correction: Descriptive study of plant resources in the context of the ethnomedicinal relevance of indigenous flora: A case study from Toli Peer National Park, Azad Jammu and Kashmir, Pakistan. AB - [This corrects the article DOI: 10.1371/journal.pone.0171896.]. PMID- 28672017 TI - The association between Mycoplasma pneumoniae infection and speech and language impairment: A nationwide population-based study in Taiwan. AB - Manifestations of Mycoplasma pneumoniae infection can range from self-limiting upper respiratory symptoms to various neurological complications, including speech and language impairment. But an association between Mycoplasma pneumoniae infection and speech and language impairment has not been sufficiently explored. In this study, we aim to investigate the association between Mycoplasma pneumoniae infection and subsequent speech and language impairment in a nationwide population-based sample using Taiwan's National Health Insurance Research Database. We identified 5,406 children with Mycoplasma pneumoniae infection (International Classification of Disease, Revision 9, Clinical Modification code 4830) and compared to 21,624 age-, sex-, urban- and income matched controls on subsequent speech and language impairment. The mean follow-up interval for all subjects was 6.44 years (standard deviation = 2.42 years); the mean latency period between the initial Mycoplasma pneumoniae infection and presence of speech and language impairment was 1.96 years (standard deviation = 1.64 years). The results showed that Mycoplasma pneumoniae infection was significantly associated with greater incidence of speech and language impairment [hazard ratio (HR) = 1.49, 95% CI: 1.23-1.80]. In addition, significantly increased hazard ratio of subsequent speech and language impairment in the groups younger than 6 years old and no significant difference in the groups over the age of 6 years were found (HR = 1.43, 95% CI:1.09-1.88 for age 0-3 years group; HR = 1.67, 95% CI: 1.25-2.23 for age 4-5 years group; HR = 1.14, 95% CI: 0.54-2.39 for age 6-7 years group; and HR = 0.83, 95% CI:0.23-2.92 for age 8-18 years group). In conclusion, Mycoplasma pneumoniae infection is temporally associated with incident speech and language impairment. PMID- 28672019 TI - Phosphatase and tensin homolog (PTEN) expression on oncologic outcome in renal cell carcinoma: A systematic review and meta-analysis. AB - The phosphatase and tensin homolog (PTEN) gene is suggested to be a dormant tumor suppressor. However, the prognostic value of the loss of PTEN expression in renal cell carcinoma (RCC) remains controversial. Therefore, we conducted a meta analysis to evaluate the association of PTEN expression with the clinicopathological presentations and outcomes of patients with RCC through immunohistochemistry staining analysis. We systematically searched for relevant studies in PubMed, Web of Science, and Embase until March 2016. Data regarding clinical stage, pathological type, Fuhrman grade, overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) was analyzed in the present study. In total, there were 12 studies with 2,368 patients included in this meta-analysis. The low PTEN expression in RCC was significantly associated with unfavorable DSS (HR = 1.568, 95% CI 1.015-2.242) in a random effects model but not with OS (HR = 1.046, 95% CI 0.93-1.176) and PFS (HR = 1.244, 95% CI 0.907-1.704). Other results indicated that PTEN expression was not correlated with clinical stage, pathological type, and Fuhrman grade. This meta analysis suggests that PTEN expression is of limited value in predicting the prognosis of patients with RCC for OS and PFS via immunohistochemistry staining analysis; and that for DSS, low PTEN expression is significantly associated with an unfavorable outcome. PMID- 28672020 TI - Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients. AB - Patients with rheumatoid arthritis (RA) have an increased mortality rate that is associated with the presence of RA-specific autoantibodies in many studies. However, the relative role of rheumatoid factor (RF), anti-CCP antibodies and the most recently established RA-autoantibodies, directed against carbamylated proteins (anti-CarP antibodies), is unclear. Here, we have assessed the role of these three antibodies in 331 patients with established RA recruited from 2001 to 2009 and followed until November 2015. During this time, 124 patients died (37.5%). This death rate corresponds to a mortality rate 1.53 (95% CI 1.26 to 1.80) folds the observed in the reference population. We used for analysis of all cause mortality the Cox proportional hazard regression model with adjustment for age, sex and smoking. It showed a trend for association with increased mortality of each of the three RA autoantibodies in antibody-specific analysis (hazards ratio (HR) from 1.37 to 1.79), but only the HR of the anti-CarP antibodies was significant (HR = 1.79, 95% CI 1.23 to 2.61, p = 0.002). In addition, the multivariate analysis that included all autoantibodies showed a marked decrease in the HR of RF and of anti-CCP antibodies, whereas the HR of anti-CarP remained significant. This increase was specific of respiratory system causes of death (HR = 3.19, 95% CI 1.52 to 6.69, p = 0.002). Therefore, our results suggest a specific relation of anti-CarP antibodies with the increased mortality in RA, and drive attention to their possible connection with respiratory diseases. PMID- 28672021 TI - The clinical burden of human cystic echinococcosis in Palestine, 2010-2015. AB - BACKGROUND: Cystic echinococcosis (CE) is classified by the WHO as a neglected disease inflicting economic losses on the health systems of many countries worldwide. The aim of this case-series study was to investigate the burden of human CE in Palestine during the period between 2010 and 2015. METHODOLOGY/PRINCIPAL FINDINGS: Records of surgically confirmed CE patients from 13 public and private hospitals in the West Bank and Gaza Strip were reviewed. Patients' cysts were collected from surgical wards and formalin-fixed paraffin embedded (FFPE) blocks were collected from histopathology departments. Molecular identification of CE species /genotypes was conducted by targeting a repeat DNA sequence (EgG1 Hae III) within Echinococcus nuclear genome and a fragment within the mitochondrial cytochrome c oxidase subunit 1, (CO1). Confirmation of CE species/genotypes was carried out using sequencing followed by BLAST analysis and the construction of maximum likelihood consensus dendrogram. CE cases were map spotted and statistically significant foci identified by spatial analysis. A total of 353 CE patients were identified in 108 localities from the West Bank and Gaza Strip. The average surgical incidence in the West Bank was 2.1 per 100,000. Spot-mapping and purely spatial analysis showed 13 out of 16 Palestinian districts had cases of CE, of which 9 were in the West Bank and 4 in Gaza Strip. Al-Khalil and Bethlehem were statistically significant foci of CE in Palestine with a six-year average incidence of 4.2 and 3.7 per 100,000, respectively. CONCLUSIONS/SIGNIFICANCE: To the best of our knowledge, this is the first confirmation of human CE causative agent in Palestine. This study revealed that E. granulosus sensu stricto (s.s.) was the predominating species responsible for CE in humans with 11 samples identified as G1 genotype and 2 as G3 genotype. This study emphasizes the need for a stringent surveillance system and risk assessment studies in the rural areas of high incidence as a prerequisite for control measures. PMID- 28672022 TI - APOE epsilon4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans. AB - Patterns of linkage between the epsilon4 allele of Apolipoprotein E (APOE) and '523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer's disease (AD) is unclear. We compared the APOE epsilon4-TOMM40 '523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 '523 genotypes were defined by the poly-T repeat length of rs10524523 (short ['523-S]: poly-T <= 19, long ['523-L]: 20 <= poly-T <= 29, and very long ['523-VL]: poly-T >= 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-epsilon4 carriers and almost all (94.2%) of the epsilon4 carriers had '523-L. The classification was highly concordant. Each epsilon4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 '523-L. In African Americans, nearly none (1.1%) of the non epsilon4 carriers had '523-L, but only 47.8% of the epsilon4 carriers had '523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between epsilon4 and '523-L carriers. Further, both genotypic and allelic data support that among African Americans the epsilon4-'523-L haplotype had stronger effect on risk of AD dementia than other epsilon4-'523 haplotypes. PMID- 28672023 TI - Characterization of injury in isolated rat proximal tubules during cold incubation and rewarming. AB - Organ shortage leads to an increased utilization of marginal organs which are particularly sensitive to storage-associated damage. Cold incubation and rewarming-induced injury is iron-dependent in many cell types. In addition, a chloride-dependent component of injury has been described. This work examines the injury induced by cold incubation and rewarming in isolated rat renal proximal tubules. The tissue storage solution TiProtec(r) and a chloride-poor modification, each with and without iron chelators, were used for cold incubation. Incubation was performed 4 degrees C for up to 168 h, followed by rewarming in an extracellular buffer (3 h at 37 degrees C). After 48, 120 and 168 h of cold incubation LDH release was lower in solutions containing iron chelators. After rewarming, injury increased especially after cold incubation in chelator-free solutions. Without addition of iron chelators LDH release showed a tendency to be higher in chloride-poor solutions. Following rewarming after 48 h of cold incubation lipid peroxidation was significantly decreased and metabolic activity was tendentially better in tubules incubated with iron chelators. Morphological alterations included mitochondrial swelling and fragmentation being partially reversible during rewarming. ATP content was better preserved in chloride-rich solutions. During rewarming, there was a further decline of ATP content in the so far best conditions and minor alterations under the other conditions, while oxygen consumption was not significantly different compared to non-stored control tubules. Results show an iron-dependent component of preservation injury during cold incubation and rewarming in rat proximal renal tubules and reveal a benefit of chloride for the maintenance of tubular energy state during cold incubation. PMID- 28672024 TI - Repositioning Bazedoxifene as a novel IL-6/GP130 signaling antagonist for human rhabdomyosarcoma therapy. AB - Interleukins-6 (IL-6)/GP130 signaling pathway represents a promising target for cancer therapy due to its critical role in survival and progression of multiple types of cancer. We have identified Bazedoxifene, a Food and Drug Administration (FDA)-approved drug used for the prevention of postmenopausal osteoporosis, with novel function as inhibitor of IL-6/GP130 interaction. In this study, we investigate the effect of Bazedoxifene in rhabdomyosarcoma and evaluate whether inhibiting IL-6/GP130 signaling is an effective therapeutic strategy for rhabdomyosarcoma. The inhibitory effect of Bazedoxifene was assessed in rhabdomyosarcoma cell lines in vitro and RH30 xenograft model was used to further examine the suppressive efficacy of Bazedoxifene on tumor growth in vivo. Rhabdomyosarcoma cells showed their sensitivity to GP130 inhibition using gene knockdown or neutralized antibody, suggesting IL-6/GP130 as therapeutic target in rhabdomyosarcoma cells. Bazedoxifene decreased the signal transducer and activator of transcription3 (STAT3) phosphorylation, blocked STAT3 DNA binding, and down-regulated the expression of STAT3 downstream genes. Bazedoxifene also induced cell apoptosis, reduced cell viability, and inhibited colony formation in rhabdomyosarcoma cells. The inhibition of colony formation, STAT3 phosphorylation, or cell viability following Bazedoxifene treatment was partially reversed by addition of excess IL-6 or overexpression of constitutive STAT3, respectively, supporting Bazedoxifene acted through IL-6/GP130 signaling. In addition, Bazedoxifene repressed cell invasion and angiogenesis in vitro. Furthermore, oral administration of Bazedoxifene significantly suppressed tumor growth and expression of STAT3 phosphorylation in nude mice bearing established human rhabdomyosarcoma xenograft. Taken together, these findings validate IL 6/GP130 signaling as therapeutic target in rhabdomyosarcoma and provide first evidence that Bazedoxifene may serve as a novel promising drug targeting IL 6/GP130 for treatment of rhabdomyosarcoma. PMID- 28672026 TI - Weibo sentiments and stock return: A time-frequency view. AB - This study provides new insights into the relationships between social media sentiments and the stock market in China. Based on machine learning, we classify microblogs posted on Sina Weibo, a Twitter's variant in China into five detailed sentiments of anger, disgust, fear, joy, and sadness. Using wavelet analysis, we find close positive linkages between sentiments and the stock return, which have both frequency and time-varying features. Five detailed sentiments are positively related to the stock return for certain periods, particularly since October 2014 at medium to high frequencies of less than ten trading days, when the stock return is undergoing significant fluctuations. Sadness appears to have a closer relationship with the stock return than the other four sentiments. As to the lead lag relationships, the stock return causes Weibo sentiments rather than reverse for most of the periods with significant linkages. Compared with polarity sentiments (negative vs. positive), detailed sentiments provide more information regarding relationships between Weibo sentiments and the stock market. The stock market exerts positive effects on bullishness and agreement of microblogs. Meanwhile, agreement leads the stock return in-phase at the frequency of approximately 40 trading days, indicating that less disagreement improves certainty about the stock market. PMID- 28672025 TI - Interleukin-6 regulates iron-related proteins through c-Jun N-terminal kinase activation in BV2 microglial cell lines. AB - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and subsequent DA depletion in the striatum. Microglia activation and nigral iron accumulation play important roles in the pathogenesis of PD. Activated microglia show increased iron deposits. However, the relationship between microglia activation and iron accumulation remains unclear. In the present study, we aimed to determine how iron levels affect interleukin-6 (IL-6) synthesis, and the effect of IL-6 on cellular iron metabolism in BV2 microglial cells.IL-6 mRNA was up regulated after FAC treatment for 12 h in BV2 cells. Iron regulatory protein 1 (IRP1) and divalent metal transporter 1 (DMT1) were up-regulated and iron exporter ferroportin 1 (FPN1) was down-regulated in BV2 cells after 24 h of IL-6 treatment. Phosphorylated JNK increased significantly compared to the control after BV2 cells were treated with IL-6 for 1 h. Pretreatment with SP600125 attenuated the up-regulation of IRP1 and DMT1 and down-regulation of FPN1 (compared to IL-6-treated group). These results suggest that iron load could increase IL-6 mRNA expression in BV2 cells. Further, IL-6 likely up-regulates IRP1 and DMT1 expression and down-regulates FPN1 expression in BV2 microglial cells through JNK signaling pathways. PMID- 28672027 TI - Parents' views on sex education in schools: How much do Democrats and Republicans agree? AB - More than 93 percent of parents place high importance on sex education in both middle and high school. Sex education in middle and high school is widely supported by parents regardless of their political affiliation. Using data from a large diverse sample of 1,633 parents of children aged 9 to 21 years, we examined whether views on sex education differed by parents' political affiliation. More than 89 percent of parents that identified as Republicans or Democrats support including a wide range of topics in sex education including puberty, healthy relationships, abstinence, sexually transmitted diseases (STDs) and birth control in high school. In middle school, 78 percent or more of both parents that identified as Republicans and Democrats support the inclusion of those topics. Controlling for key demographic factors, parents that identified as Democrats are more likely than those that identified as Republicans to support the inclusion of the topics of healthy relationships, birth control, STDs, and sexual orientation in both middle and high school. However, a strong majority of Republican parents want all these topics included in sex education. Sex education which includes a broad set of topics represents an area of strong agreement between parents of both political parties. PMID- 28672029 TI - Exploring spatial patterns of sudden cardiac arrests in the city of Toronto using Poisson kriging and Hot Spot analyses. AB - INTRODUCTION: Our study looked at out-of-hospital sudden cardiac arrest events in the City of Toronto. These are relatively rare events, yet present a serious global clinical and public health problem. We report on the application of spatial methods and tools that, although relatively well known to geographers and natural resource scientists, need to become better known and used more frequently by health care researchers. MATERIALS AND METHODS: Our data came from the population-based Rescu Epistry cardiac arrest database. We limited it to the residents of the City of Toronto who experienced sudden arrest in 2010. The data was aggregated at the Dissemination Area level, and population rates were calculated. Poisson kriging was carried out on one year of data using three different spatial weights. Kriging estimates were then compared in Hot Spot analyses. RESULTS: Spatial analysis revealed that Poisson kriging can yield reliable rates using limited data of high quality. We observed the highest rates of sudden arrests in the north and central parts of Etobicoke, western parts of North York as well as the central and southwestern parts of Scarborough while the lowest rates were found in north and eastern parts of Scarborough, downtown Toronto, and East York as well as east central parts of North York. Influence of spatial neighbours on the results did not extend past two rings of adjacent units. CONCLUSIONS: Poisson kriging has the potential to be applied to a wide range of healthcare research, particularly on rare events. This approach can be successfully combined with other spatial methods. More applied research, is needed to establish a wider acceptance for this method, especially among healthcare researchers and epidemiologists. PMID- 28672028 TI - Lineage-dependent differences in the disease progression of Zika virus infection in type-I interferon receptor knockout (A129) mice. AB - Zika virus (ZIKV) falls into two lineages: African (ZIKVAF) and Asian (ZIKVAS). These lineages have not been tested comprehensively in parallel for disease progression using an animal model system. Here, using the established type-I interferon receptor knockout (A129) mouse model, it is first demonstrated that ZIKVAF causes lethal infection, with different kinetics of disease manifestations according to the challenge dose. Animals challenged with a low dose of 10 plaque forming units (pfu) developed more neurological symptoms than those challenged with 5-log higher doses. By contrast, animals challenged with ZIKVAS displayed no clinical signs or mortality, even at doses of 106 pfu. However, viral RNA was detected in the tissues of animals infected with ZIKV strains from both lineages and similar histological changes were observed. The present study highlights strain specific virulence differences between the African and Asian lineages in a ZIKV mouse model. PMID- 28672030 TI - Better organized care via care pathways: A multicenter study. AB - An increased need for efficiency and effectiveness in today's healthcare system urges professionals to improve the organization of care. Care pathways are an important tool to achieve this. The overall aim of this study was to analyze if care pathways lead to better organization of care processes. For this, the Care Process Self-Evaluation tool (CPSET) was used to evaluate how healthcare professionals perceive the organization of care processes. Based on information from 2692 health care professionals gathered between November 2007 and October 2011 we audited 261 care processes in 108 organizations. Multilevel analysis was used to compare care processes without and with care pathways and analyze if care pathways led to better organization of care processes. A significant difference between care processes with and without care pathways was found. A care pathway in use led to significant better scores on the overall CPSET scale (p<0.001) and its subscales, "coordination of care" (p<0.001) and "follow-up of care" (p<0.001). Physicians had the highest score on the overall CPSET scale and the five subscales. Care processes organized by care pathways had a 2.6 times higher probability that the care process was well-organized. In around 75% of the cases a care pathway led to better organized care processes. Care processes supported by care pathways were better organized, but not all care pathways were well organized. Managers can use care pathways to make healthcare professionals more aware of their role in the organization of the care process. PMID- 28672032 TI - Mountaintops phylogeography: A case study using small mammals from the Andes and the coast of central Chile. AB - We evaluated if two sigmodontine rodent taxa (Abrothrix olivacea and Phyllotis darwini) from the Andes and Coastal mountaintops of central Chile, experienced distributional shifts due to altitudinal movements of habitat and climate change during and after the Last Glacial Maximum (LGM). We tested the hypothesis that during LGM populations of both species experienced altitudinal shifts from the Andes to the lowlands and the coastal Cordillera, and then range retractions during interglacial towards higher elevations in the Andes. These distributional shifts may have left remnants populations on the mountaintops. We evaluated the occurrence of intraspecific lineages for each species, to construct distribution models at LGM and at present, as extreme climatic conditions for each lineage. Differences in distribution between extreme climatic conditions were interpreted as post-glacial distributional shifts. Abrothrix olivacea displayed a lineage with shared sequences between both mountain systems, whereas a second lineage was restricted to the Andes. A similar scenario of panmictic unit in the past was recovered for A. olivacea in the Andes, along with an additional unit that included localities from the rest of its distribution. For P. darwini, both lineages recovered were distributed in coastal and Andean mountain ranges at present as well, and structuring analyses for this species recovered coastal and Andean localities as panmictic units in the past. Niche modeling depicted differential postglacial expansions in the recovered lineages. Results suggest that historical events such as LGM triggered the descending of populations to Andean refuge areas (one of the A. olivacea's lineages), to the lowlands, and to the coastal Cordillera. Backward movements of populations after glacial retreats may have left isolates on mountaintops of the coastal Cordillera, suggesting that current species distribution would be the outcome of climate change and habitat reconfiguration after LGM. PMID- 28672031 TI - Polymers for binding of the gram-positive oral pathogen Streptococcus mutans. AB - Streptococcus mutans is the most significant pathogenic bacterium implicated in the formation of dental caries and, both directly and indirectly, has been associated with severe conditions such as multiple sclerosis, cerebrovascular and peripheral artery disease. Polymers able to selectively bind S. mutans and/or inhibit its adhesion to oral tissue in a non-lethal manner would offer possibilities for addressing pathogenicity without selecting for populations resistant against bactericidal agents. In the present work two libraries of 2 (dimethylamino)ethyl methacrylate (pDMAEMA)-based polymers were synthesized with various proportions of either N,N,N-trimethylethanaminium cationic- or sulfobetaine zwitterionic groups. These copolymers where initially tested as potential macromolecular ligands for S. mutans NCTC 10449, whilst Escherichia coli MG1655 was used as Gram-negative control bacteria. pDMAEMA-derived materials with high proportions of zwitterionic repeating units were found to be selective for S. mutans, in both isolated and S. mutans-E. coli mixed bacterial cultures. Fully sulfobetainized pDMAEMA was subsequently found to bind/cluster preferentially Gram-positive S. mutans and S. aureus compared to Gram negative E. coli and V. harveyi. A key initial stage of S. mutans pathogenesis involves a lectin-mediated adhesion to the tooth surface, thus the range of potential macromolecular ligands was further expanded by investigating two glycopolymers bearing alpha-mannopyranoside and beta-galactopyranoside pendant units. Results with these polymers indicated that preferential binding to either S. mutans or E. coli can be obtained by modulating the glycosylation pattern of the chosen multivalent ligands without incurring unacceptable cytotoxicity in a model gastrointestinal cell line. Overall, our results allowed to identify a structure property relationship for the potential antimicrobial polymers investigated, and suggest that preferential binding to Gram-positive S. mutans could be achieved by fine-tuning of the recognition elements in the polymer ligands. PMID- 28672033 TI - Structural and dynamical insight into thermally induced functional inactivation of firefly luciferase. AB - Luciferase is the key component of light production in bioluminescence process. Extensive and advantageous application of this enzyme in biotechnology is restricted due to its low thermal stability. Here we report the effect of heating up above Tm on the structure and dynamical properties of luciferase enzyme compared to temperature at 298 K. In this way we demonstrate that the number of hydrogen bonds between N- and C-domain is increased for the free enzyme at 325 K. Increased inter domain hydrogen bonds by three at 325 K suggests that inter domain contact is strengthened. The appearance of simultaneous strong salt bridge and hydrogen bond between K529 and D422 and increased existence probability between R533 and E389 could mechanistically explain stronger contact between N- and C-domain. Mutagenesis studies demonstrated the importance of K529 and D422 experimentally. Also the significant reduction in SASA for experimentally important residues K529, D422 and T343 which are involved in active site region was observed. Principle component analysis (PCA) in our study shows that the dynamical behavior of the enzyme is changed upon heating up which mainly originated from the change of motion modes and associated extent of those motions with respect to 298 K. These findings could explain why heating up of the enzyme or thermal fluctuation of protein conformation reduces luciferase activity in course of time as a possible mechanism of thermal functional inactivation. According to these results we proposed two strategies to improve thermal stability of functional luciferase. PMID- 28672034 TI - Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy. AB - BACKGROUND: Fabry Disease (FD) is characterized by globotriaosylceramide-3 (Gb3) accumulation in several tissues and a small fibre neuropathy (SFN), however the underlying mechanisms are poorly known. This study aimed to: 1) ascertain the presence of Gb3 deposits in skin samples, by an immunofluorescence method collected from FD patients with classical GLA mutations or late-onset FD variants or GLA polymorphisms; 2) correlate skin GB3 deposits with skin innervation. METHODS: we studied 52 genetically-defined FD patients (32 with classical GLA mutations and 20 with late-onset variants or GLA polymorphisms), 15 patients with SFN associated with a specific cause and 22 healthy controls. Subjects underwent skin biopsy to evaluate Gb3 deposits and epi-dermal innervation. RESULTS: Skin Gb3 deposits were found in all FD patients with classical GLA mutations but never in FD patients with late-onset variants or GLA polymorphisms or in patients with SFN and healthy controls. Abnormal deposits were found inside different skin structures but never inside axons. FD patients with GB3 deposits showed lower skin innervation than FD patients with late-onset variants or polymorphisms. CONCLUSIONS: 1) Skin Gb3 deposits are specific to FD patients with classical GLA mutations; 2) Gb3 deposits were associated with lower skin innervation but they were not found inside axons, suggesting an indirect damage on peripheral small fibre innervation. PMID- 28672035 TI - Modern-day SIV viral diversity generated by extensive recombination and cross species transmission. AB - Cross-species transmission (CST) has led to many devastating epidemics, but is still a poorly understood phenomenon. HIV-1 and HIV-2 (human immunodeficiency virus 1 and 2), which have collectively caused over 35 million deaths, are the result of multiple CSTs from chimpanzees, gorillas, and sooty mangabeys. While the immediate history of HIV is known, there are over 45 lentiviruses that infect specific species of primates, and patterns of host switching are not well characterized. We thus took a phylogenetic approach to better understand the natural history of SIV recombination and CST. We modeled host species as a discrete character trait on the viral phylogeny and inferred historical host switches and the pairwise transmission rates between each pair of 24 primate hosts. We identify 14 novel, well-supported, ancient cross-species transmission events. We also find that lentiviral lineages vary widely in their ability to infect new host species: SIVcol (from colobus monkeys) is evolutionarily isolated, while SIVagms (from African green monkeys) frequently move between host subspecies. We also examine the origins of SIVcpz (the predecessor of HIV-1) in greater detail than previous studies, and find that there are still large portions of the genome with unknown origins. Observed patterns of CST are likely driven by a combination of ecological circumstance and innate immune factors. PMID- 28672036 TI - Performance of the SD BIOLINE(r) HAT rapid test in various diagnostic algorithms for gambiense human African trypanosomiasis in the Democratic Republic of the Congo. AB - We carried out a study to compare the performance, in terms of sensitivity and specificity, of the new SD BIOLINE(r) HAT rapid diagnostic test (RDT) with the card agglutination test for trypanosomiasis (CATT) for diagnosis of human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC). Participants were enrolled actively by four mobile teams, and passively at four health facilities in three provinces. Consenting participants were tested concurrently with the RDT and CATT on whole blood. Those found positive by either test were tested with CATT on serial dilutions of plasma, and with a parasitological composite reference standard (CRS). Cases were only the individuals found positive by the CRS, while controls were negative by both CATT and RDT, as well as those that were positive by CATT or RDT, but were negative by the CRS, and had no history of HAT. Over five months, 131 cases and 13,527 controls were enrolled. The sensitivity of the RDT was 92.0% (95% confidence interval (CI) = 86.1-95.5), which was significantly higher than CATT (sensitivity 69.1%; 95% CI = 60.7-76.4). The sensitivity of CATT on plasma at a dilution of 1:8 was 59.0% (95% CI = 50.2 67.2). The specificity of the RDT was 97.1% (95% CIs = 96.8-97.4) while that of CATT was 98.0% (95% CIs = 97.8, 98.2) and specificities of algorithms involving CATT at 1:8 dilution were 99.6% (95% CI = 99.5-99.7). Reproducibility of results was excellent. We concluded that an algorithm in which the SD BIOLINE(r) HAT RDT is used for screening is optimal for case detection in both passive and active screening settings. However, the lower specificity of the RDT compared to that of CATT would result in a larger number of false positive individuals undergoing confirmatory testing. PMID- 28672037 TI - High acceptability of rapid HIV self-testing among a diverse sample of MSM from Buenos Aires, Argentina. AB - INTRODUCTION: The objective of this study was to explore the acceptability of rapid HIV self-testing (RHST) among men who have sex with men (MSM). METHODS: During 2006-2009, a sample of 500 MSM was recruited through Respondent Driven Sampling for an HIV prevalence/incidence study. Attitude toward RHST was explored among HIV negative MSM. Data were weighted prior to analyses. RESULTS: Participants reported they were likely to buy RHST (74%), test themselves more frequently than they currently do (77%), and that the procedure would simplify testing (70%). Furthermore, 71% reported they would probably use it alone, 66% would use it with a steady partner, and 56% with a friend/partner. While a majority acknowledged that RHST use would deprive them of receiving counseling (61%), 74% declared they would go for help if they tested positive; 57% would use an RHST in order to avoid condoms. Probability of use surpassed 70% among gay and non-gay identified MSM as well as those with and without a previous HIV test. Those likely to buy RHST were older (p = 0.025) and more likely to identify as gay (p = 0.036). A total of 17% said they would think about killing themselves and 9% would attempt suicide if they tested positive. These MSM were more likely to be younger (p<0.001), with lower mood level (p<0.001) and greater feelings of loneliness (p = 0.026). CONCLUSIONS: The high acceptability of RHST found among MSM should encourage the authorities to consider the possibility of offering it for self-testing, as it can improve early diagnosis and prevention of future transmissions. However, further research is needed to understand how to best disseminate RHST among MSM who wish to use it and to offer support and linkage to care for those who test HIV-positive. PMID- 28672038 TI - T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab. AB - CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15-35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORgammaT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR mediated T cell activation. We show that Itolizumab but not its F(ab')2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases. PMID- 28672039 TI - Validity and reliability of total body volume and relative body fat mass from a 3 dimensional photonic body surface scanner. AB - OBJECTIVE: Three-dimensional photonic body surface scanners (3DPS) feature a tool to estimate total body volume (BV) from 3D images of the human body, from which the relative body fat mass (%BF) can be calculated. However, information on validity and reliability of these measurements for application in epidemiological studies is limited. METHODS: Validity was assessed among 32 participants (men, 50%) aged 20-58 years. BV and %BF were assessed using a 3DPS (VitusSmart XXL) and air displacement plethysmography (ADP) with a BOD POD(r) device using equations by Siri and Brozek. Three scans were obtained per participant (standard, relaxed, exhaled scan). Validity was evaluated based on the agreement of 3DPS with ADP using Bland Altman plots, correlation analysis and Wilcoxon signed ranks test for paired samples. Reliability was investigated in a separate sample of 18 participants (men, 67%) aged 25-66 years using intraclass correlation coefficients (ICC) based on two repeated 3DPS measurements four weeks apart. RESULTS: Mean BV and %BF were higher using 3DPS compared to ADP, (3DPS-ADP BV difference 1.1 +/- 0.9 L, p<0.01; %BF difference 7.0 +/- 5.6, p<0.01), yet the disagreement was not associated with gender, age or body mass index (BMI). Reliability was excellent for 3DPS BV (ICC, 0.998) and good for 3DPS %BF (ICC, 0.982). Results were similar for the standard scan and the relaxed scan but somewhat weaker for the exhaled scan. CONCLUSIONS: Although BV and %BF are higher than ADP measurements, our data indicate good validity and reliability for an application of 3DPS in epidemiological studies. PMID- 28672040 TI - Comparative transcript profiling explores differentially expressed genes associated with sexual phenotype in kiwifruit. AB - BACKGROUND: Kiwifruit is a perennial, deciduous and functionally dioecious plant. However, very little is known about the whole-genome molecular mechanisms contributing to distinct sexual phenotypes. To gain a global view of genes differentially expressed between male and female flowers, we analyzed genome-wide gene expression profiles in the flowers of male and female plants using high throughput RNA sequencing. RESULTS: A total of 53.5 million reads were generated. Based on the alignments of unigenes to kiwifruit genome predicted genes, a total of 39,040 unique genes with a mean length of 970 bp were identified. There were 2,503 UniGenes differentially expressed between female and male flowers, with 1,793 up-regulated and 710 down-regulated in the female flowers. Moreover, the gene expression pattern of 17 out of 19 unigenes differentially expressed between male and female flowers revealed by RNA-Seq was confirmed by real-time quantitative PCR (qRT-PCR). CONCLUSIONS: Here, we obtained a large number of EST sequences from female and male flowers of kiwifruit. This comparative transcriptome analysis provides an invaluable resource for gene expression, genomics, and functional genomic studies in A. chinensis and its related species. This study also represents a first step toward the investigation of genes involved in kiwifruit sex determination. PMID- 28672041 TI - Comprehensive identification of age-related lipidome changes in rat amygdala during normal aging. AB - Brain lipids are integral components of brain structure and function. However, only recent advancements of chromatographic techniques together with mass spectrometry allow comprehensive identification of lipid species in complex brain tissue. Lipid composition varies between the individual areas and the majority of previous reports was focusing on individual lipids rather than a lipidome. Herein, a mass spectrometry-based approach was used to evaluate age-related changes in the lipidome of the rat amygdala obtained from young (3 months) and old (20 months) males of the Sprague-Dawley rat strain. A total number of 70 lipid species with significantly changed levels between the two animal groups were identified spanning four main lipid classes, i.e. glycerolipids, glycerophospholipids, sphingolipids and sterol lipids. These included phospholipids with pleiotropic brain function, such as derivatives of phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine. The analysis also revealed significant level changes of phosphatidic acid, diacylglycerol, sphingomyelin and ceramide that directly represent lipid signaling and affect amygdala neuronal activity. The amygdala is a crucial brain region for cognitive functions and former studies on rats and humans showed that this region changes its activity during normal aging. As the information on amygdala lipidome is very limited the results obtained in the present study represent a significant novelty and may contribute to further studies on the role of lipid molecules in age-associated changes of amygdala function. PMID- 28672042 TI - Syncytiotrophoblast extracellular vesicles impair rat uterine vascular function via the lectin-like oxidized LDL receptor-1. AB - Syncytiotrophoblast extracellular vesicles (STBEVs) are placenta derived particles that are released into the maternal circulation during pregnancy. Abnormal levels of STBEVs have been proposed to affect maternal vascular function. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a multi-ligand scavenger receptor. Increased LOX-1 expression and activation has been proposed to contribute to endothelial dysfunction. As LOX-1 has various ligands, we hypothesized that, being essentially packages of lipoproteins, STBEVs are able to activate the LOX-1 receptor thereby impairing vascular function via the production of superoxide and decreased nitric oxide bioavailability. Uterine arteries were obtained in late gestation from Sprague-Dawley rats and incubated for 24h with or without human STBEVs (derived from a normal pregnant placenta) in the absence or presence of a LOX-1 blocking antibody. Vascular function was assessed using wire myography. Endothelium-dependent maximal vasodilation to methylcholine was impaired by STBEVs (MCh Emax: 57.7+/-5.9% in STBEV-incubated arteries vs. 77.8+/-2.9% in controls, p<0.05). This was prevented by co incubation of STBEV-incubated arteries with LOX-1 blocking antibodies (MCh Emax: 78.8+/-4.3%, p<0.05). Pre-incubation of the vessels with a nitric oxide synthase inhibitor (L-NAME) demonstrated that the STBEV-induced impairment in vasodilation was due to decreased nitric oxide contribution (DeltaAUC 12.2+/-11.7 in STBEV arteries vs. 86.5+/-20 in controls, p<0.05), which was abolished by LOX-1 blocking antibody (DeltaAUC 98.9+/-17, p<0.05). In STBEV-incubated vessels, LOX-1 inhibition resulted in an increased endothelial nitric oxide synthase expression (p<0.05), to a level similar to control vessels. The oxidant scavenger, superoxide dismutase, did not improve this impairment, nor were vascular superoxide levels altered. Our data support an important role for STBEVs in impairment of vascular function via activation of LOX-1 and reduced nitric oxide mediated vasodilation. Moreover, we postulate that the LOX-1 pathway could be a potential therapeutic target in pathologies associated with vascular dysfunction during pregnancy. PMID- 28672043 TI - The relationship between information carrying words, memory and language skills in school age children with specific language impairment. AB - The receptive language measure information-carrying word (ICW) level, is used extensively by speech and language therapists in the UK and Ireland. Despite this it has never been validated via its relationship to any other relevant measures. This study aims to validate the ICW measure by investigating the relationship between the receptive ICW score of children with specific language impairment (SLI) and their performance on standardized memory and language assessments. Twenty-seven children with SLI, aged between 5;07 and 8;11, completed a sentence comprehension task in which the instructions gradually increased in number of ICWs. The children also completed subtests from The Working Memory Test Battery for children and The Clinical Evaluation of Language Fundamentals- 4. Results showed that there was a significant positive relationship between both language and memory measures and children's ICW score. While both receptive and expressive language were significant in their contribution to children's ICW score, the contribution of memory was solely determined by children's working memory ability. ICW score is in fact a valid measure of the language ability of children with SLI. However therapists should also be cognisant of its strong association with working memory when using this construct in assessment or intervention methods. PMID- 28672044 TI - Life cycle energy efficiency and environmental impact assessment of bioethanol production from sweet potato based on different production modes. AB - The bioethanol is playing an increasingly important role in renewable energy in China. Based on the theory of circular economy, integration of different resources by polygeneration is one of the solutions to improve energy efficiency and to reduce environmental impact. In this study, three modes of bioethanol production were selected to evaluate the life cycle energy efficiency and environmental impact of sweet potato-based bioethanol. The results showed that, the net energy ratio was greater than 1 and the value of net energy gain was positive in the three production modes, in which the maximum value appeared in the circular economy mode (CEM). The environment emission mainly occurred to bioethanol conversion unit in the conventional production mode (CPM) and the cogeneration mode (CGM), and eutrophication potential (EP) and global warming potential (GWP) were the most significant environmental impact category. While compared with CPM and CGM, the environmental impact of CEM significantly declined due to increasing recycling, and plant cultivation unit mainly contributed to EP and GWP. And the comprehensive evaluation score of environmental impact decreased by 73.46% and 23.36%. This study showed that CEM was effective in improving energy efficiency, especially in reducing the environmental impact, and it provides a new method for bioethanol production. PMID- 28672046 TI - Erratum to: The Impact of Stimulus Presentation and Size on Preference. AB - [This corrects the article DOI: 10.1007/s40617-016-0148-6.]. PMID- 28672045 TI - Sex-specific genetic analysis indicates low correlation between demographic and genetic connectivity in the Scandinavian brown bear (Ursus arctos). AB - The degree of gene flow within and among populations, i.e. genetic population connectivity, may closely track demographic population connectivity. Alternatively, the rate of gene flow may change relative to the rate of dispersal. In this study, we explored the relationship between genetic and demographic population connectivity using the Scandinavian brown bear as model species, due to its pronounced male dispersal and female philopatry. Thus, we expected that females would shape genetic structure locally, whereas males would act as genetic mediators among regions. To test this, we used eight validated microsatellite markers on 1531 individuals sampled noninvasively during country wide genetic population monitoring in Sweden and Norway from 2006 to 2013. First, we determined sex-specific genetic structure and substructure across the study area. Second, we compared genetic differentiation, migration/gene flow patterns, and spatial autocorrelation results between the sexes both within and among genetic clusters and geographic regions. Our results indicated that demographic connectivity was not a reliable indicator of genetic connectivity. Among regions, we found no consistent difference in long-term gene flow and estimated current migration rates between males and females. Within regions/genetic clusters, only females consistently displayed significant positive spatial autocorrelation, indicating male-biased small-scale dispersal. In one cluster, however, males showed a dispersal pattern similar to females. The Scandinavian brown bear population has experienced substantial recovery over the last decades; however, our results did not show any changes in its large-scale population structure compared to previous studies, suggesting that an increase in population size and dispersal of individuals does not necessary lead to increased genetic connectivity. Thus, we conclude that both genetic and demographic connectivity should be estimated, so as not to make false assumptions about the reality of wildlife populations. PMID- 28672047 TI - SLNB in cutaneous SCC: A review of the current state of literature and the direction for the future. AB - The concept of the sentinel lymph node biopsy (SLNB) has been universally accepted for melanoma, however, remains controversial for squamous cell carcinoma (SCC). We performed a quantitative review on 260 cases of SCC that had a SLNB. The positivity rate was found to be 14.6%. Literature was qualitatively reviewed to determine whether a positive SLNB has any bearing on prognosis in SCC cases, finding a significant relationship between poor prognosis and a positive SLN (P = 0.0082). PMID- 28672048 TI - Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis. AB - Acquisition of a 'quiescence programme' by naive T cells is important to provide a stress-free environment and resistance to apoptosis while preserving their responsiveness to activating stimuli. Therefore, the survival and proper function of naive T cells depends on their ability to maintain quiescence. Recently we demonstrated that by preventing chronic unresolved endoplasmic reticulum (ER) stress, Schlafen2 (Slfn2) maintains a stress-free environment to conserve a pool of naive T cells ready to respond to a microbial invasion. These findings strongly suggest an intimate association between quiescence and stress signalling. However, the connection between ER stress conditions and loss of T cell quiescence is unknown. Here we demonstrate that homeostasis of cholesterol and lipids, is disrupted in T cells and monocytes from Slfn2-mutant, elektra, mice with higher levels of lipid rafts and lipid droplets found in these cells. Moreover, elektra T cells had elevated levels of free cholesterol and cholesteryl ester due to increased de novo synthesis and higher levels of the enzyme HMG-CoA reductase. As cholesterol plays an important role in the transition of T cells from resting to active state, and ER regulates cholesterol and lipid synthesis, we suggest that regulation of cholesterol levels through the prevention of ER stress is an essential component of the mechanism by which Slfn2 regulates quiescence. PMID- 28672049 TI - Diagnostic and prognostic role of SF1, IGF2, Ki67, p53, adiponectin, and leptin receptors in human adrenal cortical tumors. AB - BACKGROUND: The authors have examined the immunohistochemical expression of several proteins and their relationship with adrenal cortical carcinoma (ACC) diagnosis and progression. MATERIALS AND METHODS: A total of 83 patients with benign and malignant adrenal cortex tumors operated on in a single center were included in the study. Expression of the following proteins was examined: steroidogenic factor 1 (SF1), insulin growth factor 2 (IGF2), Ki67, p53, as well as adiponectin (Adipo R1, Adipo R2), and leptin (Ob-R) receptors. RESULTS: Multivariate analysis revealed that the expression of SF1, IGF2, and Adipo R1 and R2 receptors was associated with ACC diagnosis. An acknowledged proliferation marker Ki67 was related with the size of ACC and was an independent ACC diagnosis marker. The authors also assessed the relationship between immunohistochemical parameters and overall survival (OS) and disease progression. Only high IGF2 expression was associated with longer OS (P = 0.025). The most significant one for the prognosis of ACC patients was tumor resectability of the primary tumor. More favorable prognosis was found for young men (P = 0.033). CONCLUSIONS: The presented data indicate that immunohistochemical assessment (of IGF2, SF1, Adipo R1, and R2 receptors' expression) may be useful in making the diagnosis of uncertain ACC cases. PMID- 28672050 TI - Apgar Scores: Two Methodologic Studies Exploring Their Use in Research. PMID- 28672051 TI - Therapy With a Consensually Nonmonogamous Couple. AB - While a significant minority of people practice some form of consensual nonmonogamy (CNM) in their relationships, there is very little published research on how to work competently and effectively with those who identify as polyamorous or who have open relationships. It is easy to let one's cultural assumptions override one's work in practice. However, cultural competence is an ethical cornerstone of psychotherapeutic work, as is using evidence-based treatment in the services we provide to our clients. This case presents the work of a clinician using both evidence-based practice and practice-based evidence in helping a nonmonogamous couple repair a breach in their relationship. We present a composite case representing a common presenting issue in the first author's psychotherapy practice, which is oriented toward those engaging in or identifying with alternative sexual practices. Resources for learning more about working with poly, open, and other consensually nonmonogamous relationship partners are provided. PMID- 28672052 TI - Direct acting oral anticoagulants for the treatment of suspected heparin-induced thrombocytopenia. AB - OBJECTIVE: To evaluate the efficacy and safety of direct oral anticoagulant (DOAC) therapy in hospitalized patients with suspected heparin-induced thrombocytopenia (HIT). METHODS: Retrospective cohort study of adult patients prescribed apixaban, dabigatran, or rivaroxaban for the treatment of acute HIT from January 1, 2013 to January 1, 2017. Eligibility requirements included an intermediate or high pretest probability for HIT (4T score>=4) and a positive IgG specific anti-PF4/heparin complex assay. The primary outcome measure was the composite of newly diagnosed venous or arterial thromboembolism, gangrene, or amputation due to critical limb ischemia during hospitalization. RESULTS: A total of 12 patients were included for analysis, five of which experienced HIT-related thrombosis prior to initiation of DOAC therapy. Seven patients received parenteral therapy with argatroban prior to initiation of DOAC treatment. Nine patients were treated with apixaban while three received rivaroxaban for an average of 9.33 days while hospitalized. Zero patients experienced the primary outcome of HIT-related thrombosis, and no patients experienced major bleeding post DOAC initiation. All patients achieved platelet recovery while receiving DOAC therapy. CONCLUSIONS: In this small retrospective study of adult patients treated for acute HIT, treatment with DOAC therapy was not associated with in hospital thrombotic or hemorrhagic events. PMID- 28672053 TI - A genome-wide association study suggests that MAPK14 is associated with diabetic foot ulcers. AB - BACKGROUND: Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. OBJECTIVES: To identify genetic contributors to the development of DFUs in the presence of peripheral neuropathy in a Scottish cohort with diabetes using a genome-wide association study. METHODS: A genome-wide association approach was applied. A case was defined as a person with diabetes (type 1 or type 2) who had ever had a foot ulcer (current or previous) in at least one foot, as well as a positive monofilament test result (i.e. evidence of peripheral neuropathy) recorded in their longitudinal e-health records. A control was defined as an individual with diabetes (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot but who had a positive monofilament test result recorded in either foot in their longitudinal e-health records. RESULTS: There were 699 DFU cases and 2695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The single-nucleotide polymorphism rs80028505 (Chr6p21.31) in MAPK14 reached genome-wide significance with a lowest P-value of 2.45 * 10-8 . The narrow-sense heritability of this phenotype is 0.06. CONCLUSIONS: We suggest that MAPK14 is associated with DFUs. PMID- 28672054 TI - Prognostic factors of hydrops fetalis with pleural effusion. AB - BACKGROUND: Hydrops fetalis (HF) has a low survival rate, particularly in the case of preterm birth. In addition, the severity index of HF has not been fully investigated yet. The aim of this study was to clarify the prognostic factors of HF with pleural effusion. METHODS: All live-born HF patients with pleural effusion, except for chromosomal abnormality or complex congenital heart disease, born from 2009 to 2013 in Aichi Prefecture in Japan were included. Prenatal, perinatal, and postnatal information was obtained from the medical records and was retrospectively analyzed. RESULTS: Forty-one HF patients with pleural effusion were included, and 28 patients (68%) survived. On multivariate logistic stepwise analysis, gestational birth week (OR, 0.71; 95% CI: 0.52-0.96, P = 0.027) and standard deviation (SD) score of the birthweight (OR, 1.74; 95% CI: 1.01-2.99, P = 0.045) were significant factors for postnatal death. All patients with both >=32 gestational weeks and <3.0 birthweight SD score survived. CONCLUSIONS: Combined with the gestational weeks data, birthweight SD score may be useful to estimate the prognosis of HF with pleural effusion. PMID- 28672055 TI - Coherent Enantiomer-Selective Population Enrichment Using Tailored Microwave Fields. AB - We report the experimental demonstration of coherent enantiomer-selective enrichment of chiral molecules by employing a novel microwave five-pulse scheme. Our results show that enantiomers can be selectively transferred to a rotational level of choice by applying sequences of resonant microwave pulses in a phase- and polarization-controlled manner. This is achieved by simultaneously exciting all three kinds of electric dipole-allowed rotational transitions and monitoring the effect on a fourth rotational transition of choice. Using molecular beams, we apply our method to two chiral terpenes and obtain a 6 % enantiomeric enrichment, which is one order of magnitude larger than that recently reported in a buffer gas cell experiment. This approach establishes a robust scheme for controlled manipulation of enantiomers using tailored microwave fields and opens up new avenues for chiral purification and enrichment that can be used in a broad scope of analytical or spectroscopic applications. PMID- 28672056 TI - Surgical complications of laparoendoscopic single-site donor nephrectomy: a retrospective study. AB - The single-port approach has been associated with an unacceptably high rate of umbilical port hernias in large series of patients undergoing single-port cholecystectomy and colectomy and with additional surgical risks thought secondary to technical and ergonomic limitations. A retrospective review of 378 consecutive laparoendoscopic single-site(LESS) donor nephrectomies performed between 04/15/2009 and 04/09/2014 was conducted. Twelve patients (3%) developed an umbilical hernia. Eleven (92%) were female and eight (73%) of these patients had a prior pregnancy. Hernias were reported 13.5 +/- 6.9 months after donation, and the mean size was 5.1 +/- 3.7 cm. Seven additional cases (1.9%) required a return to the operating room for internal hernia (2), evisceration (1), bleeding (1), enterotomy (1), and wound infection (2). The original incision was utilized for reexploration. One patient required emergent conversion to an open procedure for bleeding during the initial donation. There were no mortalities. Recipient patient and graft survival were 99% and 99% at 1 year, respectively. Although reports associated with earlier experiences with single-site procedures suggested an unacceptably high rate of hernias at the surgical site, this does not seem to be the case at our center. This technique is a reliable surgical technique for left donor nephrectomy at this institution. PMID- 28672057 TI - Intracellular Salmonella metabolism. AB - Growth of Salmonella inside infected host cells is a key aspect of their ability to cause local enteritis or systemic disease. This growth depends on exploitation of host nutrients through a large Salmonella metabolism network with hundreds of metabolites and enzymes. Studies in cell culture infection models are unravelling more and more of the underlying molecular and cellular mechanisms but also show striking Salmonella metabolic plasticity depending on host cell line and experimental conditions. In vivo studies have revealed a qualitatively diverse, but quantitatively poor, host-Salmonella nutritional interface, which on one side makes Salmonella fitness largely resilient against metabolic perturbations, but on the other side severely limits Salmonella biomass generation and growth rates. This review discusses goals and techniques for studying Salmonella intracellular metabolism, summarises main results and implications, and proposes key issues that could be addressed in future studies. PMID- 28672058 TI - Hydroformylation of Alkenes in a Planetary Ball Mill: From Additive-Controlled Reactivity to Supramolecular Control of Regioselectivity. AB - The Rh-catalyzed hydroformylation of aromatic-substituted alkenes is performed in a planetary ball mill under CO/H2 pressure. The dispersion of the substrate molecules and the Rh-catalyst into the grinding jar is ensured by saccharides: methyl-alpha-d-glucopyranoside, acyclic dextrins, or cyclodextrins (CDs, cyclic oligosaccharides). The reaction affords the exclusive formation of aldehydes whatever the saccharide. Acyclic saccharides disperse the components within the solid mixture leading to high conversions of alkenes. However, they showed typical selectivity for alpha-aldehyde products. If CDs are the dispersing additive, the steric hindrance exerted by the CDs on the primary coordination sphere of the metal modifies the selectivity so that the beta-aldehydes were also formed in non-negligible proportions. Such through-space control via hydrophobic effects over reactivity and regioselectivity reveals the potential of such solventless process for catalysis in solid state. PMID- 28672059 TI - Quantitative and Qualitative Analysis of Three Classes of Sulfur Compounds in Crude Oil. AB - Owing to the environmental hazards arising from sulfur-containing combustion products, strong legal regulations exist to reduce the sulfur content of transportation fuels down to a few ppm. With the ongoing depletion of low-sulfur crude oil reservoirs, increased technological efforts are needed for crude oil refining to meet these requirements. The desulfurization step is a critical part of the refining process but partly suffers from the recalcitrance of certain species to sulfur removal and the inability to quantitatively understand the behavior of individual compound classes during the process. We herein present a new and simple approach for the parallel quantification of three different classes of sulfur species present in crude oils by LC separation and on-line detection and quantification by ICP-MS/MS. This approach will help to estimate the amount of recalcitrant species and thus facilitate the optimization of desulfurization conditions during fuel production. PMID- 28672060 TI - Phytochemical and Biological Activities of Pseudocalymma elegans: A False Garlic. AB - Evaluation of phytochemical constituents and antioxidant and antimicrobial activities of hexane (PELH), dichloromethane (PELDCM), ethyl acetate (PELEA), and MeOH (PELM) extracts of young leaves of Pseudocalymma elegans have been carried out. Moreover, extracts have also been explored for the presence of sulphur containing compounds, 1,2-dithiolane (33), diallyl disulfide (35), 3-vinyl-1,2 dithiacyclohex-5-ene (37), and diallyl trisulfide (38) responsible for the garlic like smell of P. elegans. All the extracts were found to be antioxidant and showed potent inhibition with IC50 values of 0.168 +/- 0.001, 0.128 +/- 0.002, 0.221 +/- 0.011, and 0.054 +/- 0.001, respectively, as compared to standard drugs ascorbic acid (AA) and butylated hydroxytoluene (BHT). The ethyl acetate extract (PELE) showed excellent activities against few Gram-positive and Gram-negative bacteria and some fungi as compared with standard drug ceftriaxone (3rd generation cephalosporin) and nystatin, respectively. Chemical constituents of hexane, dichloromethane, and ethyl acetate extracts were identified by gas chromatography-mass spectrometry and mass spectral library search. Over all 55 chemical constituents were first time identified from the leaves which included branched and n-hydrocarbons, fatty acids, fatty acid methyl esters, fatty alcohols, terpenes, alkaloid, vitamins, glycosides, aromatic compounds, and sulfur containing compounds. Two known chemical constituents, ursolic acid (1) and beta-amyrin (2), were also purified for the first time from the MeOH extract. To elucidate the structures of these compounds, UV, IR, EI-MS, 1 H- and 13 C-NMR spectroscopy were used. PMID- 28672062 TI - Liquid-based cytology for the diagnosis of solid pancreatic tumors with endoscopic ultrasound-guided fine-needle aspiration: Can we dismiss conventional smear? PMID- 28672061 TI - Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats - an experimental study. AB - Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post-transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of thalidomide on the development of CAV. The effect of thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received thalidomide for 30 days post transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post transplant heart rejection. PMID- 28672063 TI - Low weight gain at the start of a family-based intervention for adolescent girls with restrictive eating disorders predicted emergency hospital admission. AB - AIM: This study examined predictors of emergency hospitalisation of adolescent girls with restrictive eating disorders and weight loss treated by a family-based intervention programme. METHODS: We studied 339 girls aged 10-17 years treated in a specialist unit at Uppsala University Children's Hospital, Sweden, from August 2010 to December 2015. Historical weight data were obtained from school health services, and other weight data were determined at presentation. Weight controlling behaviour was recorded, and patients were evaluated using the Eating Disorder Examination Questionnaire. A family-based intervention started after assessment and the early weight gain after one week, one month and three months was assessed. RESULTS: There were 17 emergency admissions of 15 patients for refusing food, progressive weight loss and medical instability. Logistic regression analysis showed that emergency admissions were predicted by a low body mass index standard deviation score at presentation (odds ratio 2.57), a high rate of weight loss before presentation (odds ratio 4.38) and a low rate of weight gain at the start of treatment (odds ratio 4.59). CONCLUSION: Poor weight gain at the start of a family-based intervention for adolescent girls with restrictive eating disorders predicted emergency hospital admission. PMID- 28672064 TI - In Reply. PMID- 28672065 TI - Lean mass explains the association between muscular fitness and bone outcomes in 13-year-old boys. AB - AIM: This study investigated the associations between fitness indices and bone outcomes in young males. METHODS: Data were collected between autumn and winter 2014-2015 on 121 males with a mean age of 13.1 +/- 0.1 years: 41 swimmers, 37 footballers, 29 cyclists and 14 nonathletes. Participants were recruited from athletic clubs and schools across South West England. Lean mass, areal bone mineral density and hip structural estimates were measured using dual-energy X ray absorptiometry. The relationships between bone outcomes and the vertical jump, standing long jump and the 20-m shuttle run test were analysed using three regression models: model 1 was adjusted by age and stature, model 2 added vigorous physical activity and model 3 then added lean mass. RESULTS: The boys' performance in the vertical jump and standing long jump was positively associated with the majority of bone outcomes in models 1 and 2, but most of these disappeared in model 3. The 20-m shuttle run test was positively associated with most bone outcomes in all three models. Lean mass played a key role in the association between muscular fitness and bone outcomes. CONCLUSION: Vigorous physical activity did not explain the associations between fitness and bone outcomes, but lean mass did. PMID- 28672066 TI - Low-molecular-weight color pI markers to monitor on-line the peptide focusing process in OFFGEL fractionation. AB - High-throughput mass spectrometry-based proteomic analysis requires peptide fractionation to simplify complex biological samples and increase proteome coverage. OFFGEL fractionation technology became a common method to separate peptides or proteins using isoelectric focusing in an immobilized pH gradient. However, the OFFGEL focusing process may be further optimized and controlled in terms of separation time and pI resolution. Here we evaluated OFFGEL technology to separate peptides from different samples in the presence of low-molecular weight (LMW) color pI markers to visualize the focusing process. LMW color pI markers covering a large pH range were added to the peptide mixture before OFFGEL fractionation using a 24-wells device encompassing the pH range 3-10. We also explored the impact of LMW color pI markers on peptide fractionation labeled previously for iTRAQ. Then, fractionated peptides were separated by RP_HPLC prior to MS analysis using MALDI-TOF/TOF mass spectrometry in MS and MS/MS modes. Here we report the performance of the peptide focusing process in the presence of LMW color pI markers as on-line trackers during the OFFGEL process and the possibility to use them as pI controls for peptide focusing. This method improves the workflow for peptide fractionation in a bottom-up proteomic approach with or without iTRAQ labeling. PMID- 28672067 TI - Comparison of FEV1 reference equations for evaluating a cystic fibrosis therapeutic intervention. AB - OBJECTIVES: The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV1 ). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008).1,2,4,6 We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV1 (ppFEV1 ) decline. METHODOLOGY: Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV1 from a 2-year pre-index period and 2-year post index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients). RESULTS: Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from -0.58 to +0.30 ppFEV1 /year, but the difference in change in slope between the DA and comparator groups was in a narrower range from +0.53 to +0.89 ppFEV1 /year. CONCLUSIONS: Although individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable. PMID- 28672068 TI - Effect of extending the time after bronchodilator administration on identifying bronchodilator responsiveness in a pediatric pulmonary clinic. AB - OBJECTIVES: American Thoracic Society/European Respiratory Society (ATS/ERS) spirometry interpretation guidelines recommend >=15 min between pre- and post bronchodilator testing to evaluate for a bronchodilator response. We aimed to lengthen the time between albuterol administration and post-bronchodilator testing to adhere to ATS/ERS guidelines and evaluated if lengthening this wait time would increase the percentage of patients classified as bronchodilator responsive. METHODS: We compared the proportion of patients with a positive bronchodilator response between two groups of children with asthma, one group in which post-bronchodilator administration wait times were not standardized (pre intervention) to another in which the wait time was extended to 15 min to adhere to ATS/ERS standards (post-intervention). We also determined the effect of this intervention on clinic appointment duration. RESULTS: The analysis included 271 patients (145 pre-intervention and 126 post-intervention). The average wait time in the pre-intervention group was 6.5 +/- 2.1 (mean +/- SD) minutes compared to 16.2 +/- 3.2 min (P < 0.001) post intervention, and clinic times increased from 83.0 +/- 29.6 min to 91.7 +/-22.5 min (P < 0.007) from the pre- to post intervention group, respectively. In adjusted regression analysis, there was no significant change in FEV1 % predicted between the two groups. CONCLUSIONS: In a busy pediatric pulmonary clinic, while we successfully lengthened time between albuterol administration and post-bronchodilator testing in the vast majority of patients, no difference was seen in the percentage of patients classified as bronchodilator responsive. Results from this study appear to question the ATS/ERS recommended 15 min post-bronchodilator administration wait time for children. PMID- 28672069 TI - The heterogeneity of viral bronchiolitis: A lack of universal consensus definitions. AB - Viral bronchiolitis is one of the most common hospital presentations in infancy and as such represents a major healthcare burden worldwide. However despite this, there are currently no effective targeted therapies nor can those infants at highest risk for developing severe disease or subsequent respiratory morbidity be predicted on initial hospital presentation. Current definitions of bronchiolitis in the published literature vary significantly in terms of the age range at presentation, specific clinical symptoms, causative virus, and the inclusion or exclusion of infants with previous presentations and/or various comorbidities. In this review, we highlight how this heterogeneity among definitions contributes to a lack of clarity on this condition and its likely multiple endotypes. We argue that without a new universal consensus definition or sets of definitions, progress into bronchiolitis will continue to be stalled. PMID- 28672071 TI - Enzymatic Process Enhances the Flavour Profile and Increases the Proportion of Esters in Citrus Essential Oils. AB - Citrus essential oils (CEOs) are important flavors in the food and confectionary industries. A lipase process was proposed for enhancing the flavor profiles and increasing the proportions of esters in CEOs. The effects of the enzymatic process were explored by detecting the constituents of the CEOs of American sweet orange oil (ASO) and Brazil mandarin oil (BMO) through GC/MS and sensory evaluation by a trained panel, and positive effects were confirmed by both methods. A further eleven kinds of CEOs were treated via the lipase process and increments of 10 - 1170% were achieved in the proportions of esters, which were mostly ethyl esters. Enhancement in fruity odor, especially the top note, was demonstrated by all CEOs after enzymatic processing. All CEOs were tested for antimicrobial activities, and only ASO displayed fairly ideal antimicrobial activities. Meanwhile, modified ASO showed a certain increase in antimicrobial activities. This methodology might be considered a sustainable route for acquiring 'natural' essential oils with enhanced flavor profiles and simultaneously enhancing the comprehensive utilization of citrus fruits. PMID- 28672072 TI - 'Blue bubble' technique: an ab interno approach for Descemet separation in deep anterior lamellar keratoplasty using trypan blue stained viscoelastic device. AB - BACKGROUND: In this study, we examined a novel variant of 'big-bubble' deep anterior lamellar keratoplasty using trypan-blue-stained viscoelastic device for the creation of a pre-descemetic bubble. METHODS: Ten corneoscleral rims were mounted on an artificial anterior chamber (AC). The AC was filled with air through a limbal paracentesis. A Melles' triangulated spatula was inserted through the paracentesis, with its tip penetrating the AC, was then slightly retracted and pushed into the deep stroma above the roof of the paracentesis. A mixture of trypan blue and viscoelastic device (Healon, Abbott Medical Optics, Abbott Park, Illinois) was injected into this intra-stromal pocket using a 27-G cannula to create a pre-descemetic separation bubble. Bubble type and visualization of dyed viscoelastic device were noted. The method was later employed in three cases. RESULTS: In all 10 corneoscleral rims, the technique successfully created a visible pre-descemetic (type 1) bubble that could be expanded up to the predicted diameter of trephination. Subsequent trephination and the removal of corneal stroma were uneventful. In two out of four clinical cases, a type 1 bubble was created, while in two others, visco-dissection failed and dyed viscoelastic was seen in the AC. CONCLUSIONS: The presented technique holds promise of being a relatively easy to perform, predictable and well controlled alternative for achieving a type 1 bubble during deep anterior lamellar keratoplasty surgery. The trypan-blue-stained viscoelastic device facilitates proper visualization and control of the separation bubble and assists in identifying the penetrance to the separation bubble prior to removal of the stromal cap. PMID- 28672070 TI - Crystallographic and solution structure of the N-terminal domain of the Rel protein from Mycobacterium tuberculosis. AB - Modulation of intracellular guanosine 3',5'-bispyrophosphate ((p)ppGpp) level, the effector of the stringent response, is crucial for survival as well as optimal growth of prokaryotes and, thus, for bacterial pathogenesis and dormancy. In Mycobacterium tuberculosis (Mtb), (p)ppGpp synthesis and degradation are carried out by the bifunctional enzyme MtRel, which consists of 738 residues, including an N-terminal hydrolase- and synthetase-domain (N-terminal domain or NTD) and a C-terminus with a ribosome-binding site. Here, we present the first crystallographic structure of the enzymatically active MtRel NTD determined at 3.7 A resolution. The structure provides insights into the residues of MtRel NTD responsible for nucleotide binding. Small-angle X-ray scattering experiments were performed to investigate the dimeric state of the MtRel NTD and possible substrate-dependent structural alterations. PMID- 28672074 TI - Collaborative Counseling Considerations for Pharmacogenomic Tests. AB - Increased use of pharmacogenomic (PGx) testing in the clinical setting has revealed a number of challenges to providing this service. PGx is an important component of precision medicine that brings together the fields of genetics and clinical pharmacology. A model that incorporates a multidisciplinary approach to implementation and information delivery may be the most beneficial to patients and providers. In this review, translational considerations in the provision of PGx testing and counseling services are described. Specifically, we report on the selection of PGx tests, the provision of patient education and counseling, and examples of PGx service delivery models that incorporate counseling by pharmacists and genetic counselors. Examples of ancillary risks associated with PGx testing, testing of children, and familial implications of testing are reviewed. Through multispecialty partnerships, including genetic counselors and pharmacists, implementation obstacles to PGx testing can be overcome to provide quality precision medicine to patients. PMID- 28672073 TI - Prediction of treatment outcomes to exercise in patients with nonremitted major depressive disorder. AB - BACKGROUND: Only one-third of patients with major depressive disorder (MDD) achieve remission with initial treatment. Consequently, current clinical practice relies on a "trial-and-error" approach to identify an effective treatment for each patient. The purpose of this report was to determine whether we could identify a set of clinical and biological parameters with potential clinical utility for prescription of exercise for treatment of MDD in a secondary analysis of the Treatment with Exercise Augmentation in Depression (TREAD) trial. METHODS: Participants with nonremitted MDD were randomized to one of two exercise doses for 12 weeks. Participants were categorized as "remitters" (<=12 on the IDS-C), nonresponders (<30% drop in IDS-C), or neither. The least absolute shrinkage and selection operator (LASSO) and random forests were used to evaluate 30 variables as predictors of both remission and nonresponse. Predictors were used to model treatment outcomes using logistic regression. RESULTS: Of the 122 participants, 36 were categorized as remitters (29.5%), 56 as nonresponders (45.9%), and 30 as neither (24.6%). Predictors of remission were higher levels of brain-derived neurotrophic factor (BDNF) and IL-1B, greater depressive symptom severity, and higher postexercise positive affect. Predictors of treatment nonresponse were low cardiorespiratory fitness, lower levels of IL-6 and BDNF, and lower postexercise positive affect. Models including these predictors resulted in predictive values greater than 70% (true predicted remitters/all predicted remitters) with specificities greater than 25% (true predicted remitters/all remitters). CONCLUSIONS: Results indicate feasibility in identifying patients who will either remit or not respond to exercise as a treatment for MDD utilizing a clinical decision model that incorporates multiple patient characteristics. PMID- 28672075 TI - Severity of Suicidal Ideation Matters: Reexamining Correlates of Suicidal Ideation Using Quantile Regression. AB - OBJECTIVE: Numerous risk factors have been identified for suicidal ideation, including perceived burdensomeness, thwarted belongingness, agitation, insomnia, nightmares, cognitive anxiety sensitivity, and rumination. However, the complexity of these associations has not been well studied; the magnitude of these effects may vary at differing levels of suicidal ideation. The present study reexamined established risk factors for suicidal ideation using quantile regression, a statistical technique that calculates the effect at numerous quantiles of suicidal ideation, as opposed to the average effect across all quantiles. METHOD: A sample of 354 psychiatric outpatients (61.3% female, meanage = 27.01 years, standard deviation = 10.40) completed self-report measures of their suicidal ideation and related risk factors prior to their initial intake appointments. RESULTS: The relationship between each suicide risk factor and suicidal ideation was strongest at higher (.9 quantile), as opposed to nonexistent (.5 quantile) and low-moderate (.7 quantile), levels of suicidal ideation. The interaction proposed by the interpersonal theory of suicide was significant at nonexistent and low-moderate, but not high, levels of suicidal ideation. CONCLUSION: Our findings indicated that predictors of suicidal ideation differed in magnitude at varying levels of suicidal ideation. Implications, limitations, and future research directions are discussed. PMID- 28672076 TI - Introduction: Special issue on genetic research of alcohol use disorder in diverse racial/ethnic populations. AB - This special issue of The American Journal on Addictions is an extension of a workshop held at the Research Society on Alcoholism (2015) highlighting several important issues related to studies of the genetic bases of alcohol use disorder among racially/ethnically diverse populations. While not exhaustive in their coverage, the papers in this special issue focus on three important topics: (1) the importance of considering the social and environmental context in genetic analyses; (2) social and cultural considerations for engaging diverse communities in genetic research; and (3) methodologies related to phenotype development for use with racially/ethnically diverse populations. A brief overview of each paper included in these three sections is presented. The issue concludes with additional considerations for genetic research with racially/ethnically diverse population groups along with a commentary. (Am J Addict 2017;26:422-423). PMID- 28672077 TI - Urological complications: learning from the past and preparing for the future. PMID- 28672078 TI - Surgery for recurrence in retroperitoneal leiomyosarcoma: Is it all about selection? PMID- 28672079 TI - Acute kidney injury in congenital cardiac surgery: Pediatric risk-injury-failure loss-end-stage renal disease and Acute Kidney Injury Network. AB - BACKGROUND: Acute kidney injury (AKI) is associated with an increased risk of mortality, especially in pediatric intensive care units. The aim of this study was to determine the risk factors of AKI in children undergoing cardiac surgery for congenital heart disease and to compare two different classification systems: pediatric risk-injury-failure-loss-end-stage renal disease (pRIFLE) and Acute Kidney Injury Network (AKIN). METHODS: We retrospectively analyzed 145 patients undergoing pediatric congenital heart surgery who were between 1 month and 18 years of years, and treated at a cardiovascular surgery department from January 2009 to October 2011. RESULTS: One hundred and thirty-seven patients (mean age, 36.6 +/- 43.3 months) were enrolled: 84 (61.3%) developed AKI according to the pRIFLE criteria (25.5%, risk; 20.4%, injury; 15.3%, failure); and 65 patients (47.4%) developed AKI according to the AKIN criteria (15.3%, stage I; 18.2%, stage II; and 13.9%, stage III). Children younger than 11 months were more likely to develop AKI (P < 0.005). Longer cardiopulmonary bypass time was associated with an increased risk of AKI (P < 0.05). pRIFLE identified AKI more frequently than AKIN (P < 0.0005). pRIFLE may help in the early identification of patient at risk for AKI and seems to be more sensitive in pediatric patients (P < 0.05). Any degree of AKI in both classifications was associated with increased mortality (pRIFLE: OR, 15.1; AKIN: OR, 11.2; P = 0.007). CONCLUSION: pRIFLE identified AKI more frequently than the AKIN criteria. pRIFLE identified patients at risk for AKI earlier, and was more sensitive in pediatric patients. Any degree of AKI in both classifications was associated with increased mortality. Both sets of criteria had the same association with mortality. PMID- 28672082 TI - Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases. AB - Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes. PMID- 28672080 TI - Ki67, CD105, and alpha-SMA expressions better relate the binary oral epithelial dysplasia grading system of World Health Organization. AB - BACKGROUND: The binary system of oral epithelial dysplasia (OED) has never been investigated with reference to the carcinogenesis-related biomarkers. Hence, Ki67, CD105, and alpha-SMA immune-expressions were studied in oral potentially malignant disorders (OPMDs) to assess their relationship with the binary OED grading system of World Health Organization. METHODS: The study was carried out on paraffin-embedded tissues of 30 normal oral mucosa (NOM) and 140 OPMD cases. OPMD cases were classified into two groups "no/questionable/hyperkeratosis/mild"=low-risk epithelial dysplasia (LRED) and "moderate or severe"=high-risk epithelial dysplasia (HRED). The immunohistochemistry was carried out to evaluate the expression of Ki67, CD 105, and alpha-SMA antigen. RESULTS: According to the binary grading system of WHO, 69 (49.28%) cases were LRED, while 71 (50.71%) case showed HRED. There was significant increase in Ki67 labeling index (LI) from NOM to LRED to HRED (P=.000). Similarly, mean vascular density (MVD) also increased significantly from NOM to LRED to HRED (P=.000). The alpha-SMA expression was significantly higher in HERD compared to LRED and NOM (P=.000). A positive correlation was noted among Ki67 LI, MVD, and alpha-SMA expressions in NOM, LRED, and HRED (P=.000). CONCLUSION: The expressions of ki67, CD105, and alpha-SMA markers compliment binary grading system of OED in OPMDS, thus justifying its use in clinical practice. PMID- 28672081 TI - Concurrent biopsies of both grafts in recipients of simultaneous pancreas and kidney demonstrate high rates of discordance for rejection as well as discordance in type of rejection - a retrospective study. AB - It is commonly assumed that in simultaneous pancreas and kidney (SPK) recipients, rejection of the two organs is concordant. As a result, concurrent biopsies of both organs are rarely performed and there are limited histological data on how often rejection is in fact discordant. We reviewed all SPK recipients transplanted at the University of Wisconsin between January 01, 2001, and December 31, 2016, that underwent biopsy of both organs. We included all patients whose biopsies were within 30 days. If patients were treated for rejection between biopsies, they were excluded if the biopsies were more than 4 days apart. Ninety-one simultaneous biopsies were performed within 30 days of each other, and 40 met our inclusion criteria. A total of 25 (62.5%) patients had concordance of biopsy findings: 11 had rejection of both organs, and 14 had no rejection of either organ. The other 15 (37.5%) were discordant for rejection, with 10 having pancreas-only rejection and five kidney-only rejection. It was striking to find that four of the 11 patients with concordance for rejection (36%) had different types (AMR, ACR, or mixed) of rejection in the two organs. This large series of simultaneous pancreas and kidney biopsies demonstrates the continued utility of performing biopsies of both organs. PMID- 28672083 TI - Bleaching Earths as Powerful Additives for Ru-Catalyzed Self-Metathesis of Non Refined Methyl Oleate at Pilot Scale. AB - A practical and cost-effective ruthenium-catalyzed self-metathesis of non-refined methyl oleate (85 %) derived from very high oleic sunflower oils was demonstrated at pilot scale using a robust and kg-scale commercially available SIPr-M71 pre catalyst. The simple addition of 1 wt % bleaching earths (Tonsil 110FF) to a thermally pretreated oil could efficiently prevent catalyst deactivation. Remarkably, without the need for filtration, the catalytic system was able to achieve a turnover number (TON) of more than 744 000 at a catalyst loading of only 1 ppm. At large scale (up to 200 kg), the equilibrium of the self-metathesis reaction was reached within 1 hour at 50 degrees C under neat conditions at a very low 5 ppm catalyst loading to produce the expected primary metathesis products (PMP), that is, 9-octadecene and dimethyl-9-octadecenoate, with a productive TON of 94900. PMID- 28672084 TI - Monitoring Complex Formation by Relaxation-Induced Pulse Electron Paramagnetic Resonance Distance Measurements. AB - Biomolecular complexes are often multimers fueling the demand for methods that allow unraveling their composition and geometric arrangement. Pulse electron paramagnetic resonance (EPR) spectroscopy is increasingly applied for retrieving geometric information on the nanometer scale. The emerging RIDME (relaxation induced dipolar modulation enhancement) technique offers improved sensitivity in distance experiments involving metal centers (e.g. on metalloproteins or proteins labelled with metal ions). Here, a mixture of a spin labelled ligand with increasing amounts of paramagnetic CuII ions allowed accurate quantification of ligand-metal binding in the model complex formed. The distance measurement was highly accurate and critical aspects for identifying multimerization could be identified. The potential to quantify binding in addition to the high-precision distance measurement will further increase the scope of EPR applications. PMID- 28672085 TI - Structural and functional ventilatory impairment in infants with severe bronchopulmonary dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most frequent serious complication in preterm infants. We aimed to describe lung structure and ventilatory function of preterm infants with severe BPD and explored the association between early postnatal growth and these outcomes. METHODS: We included preterm infants born <=32 weeks gestational age (GA) with severe BPD. Lung structure was assessed on chest CT with the PRAGMA-BPD scoring system and ventilatory function by polysomnography (PSG) at 6 months corrected age. Postnatal growth was assessed by weight measured at birth, and at 2 and 6 months corrected age. RESULTS: We included 49 infants (median [IQR] GA of 25.7 [24.6 26.3] weeks and mean [SD] birth weight of 760 [210] g). A 95.5% of the chest CT scans showed architectural distortion of the lung, and an oxygen desaturation index (ODI) >5 was found in 74% of the infants. An increase in GA of 1 week was associated with higher total and normal lung volume (beta coefficient [95% CI]: 1.86 [0.15, 3.57] and 2.03 [0.41, 3.65]), less hypoattenuation (-4.3 [-7.70, 0.90]%) and lower ODI (-36.7 [-64.2, -9.10]%). Higher weight at 6 months was independently associated with higher total and normal lung volume, and with less severe desaturations. Increased weight gain between 2 and 6 months of corrected age was associated with less severe desaturations during sleep (beta coefficient [95% CI]: 2.09 [0.49, 3.70]). CONCLUSION: Most preterm infants with severe BPD have structural lung abnormalities and impaired ventilatory function early in life, partly explained by birth characteristics and infant growth. PMID- 28672086 TI - Circulating branched-chain amino acids in children with obstructive sleep apnea. AB - INTRODUCTION: The effects of obstructive sleep apnea (OSA) on the metabolic system are not well understood, especially in children. Recent studies have provided evidence of the modulation of insulin action by branched-chain amino acids (BCAAs) and suggested novel mechanistic relationships between glucose and amino acid metabolic pathways. We hypothesized that plasma BCAA levels may serve as biomarkers of insulin resistance and metabolic dysfunction in children with OSA. METHODS: A polysomnography was conducted for the diagnosis of OSA in 90 snoring children, in a tertiary hospital. Anthropometric and clinical data were measured and venous blood samples were collected for the measurement of plasma glucose, insulin, HbA1c, and amino acids. RESULTS: Children with OSA had significantly higher levels of BCAAs (leucine, isoleucine, and total BCAAs) compared with those without OSA (P = 0.024). A positive significant correlation was observed between insulin levels and both leucine and isoleucine (r = 0.232; P < 0.05). On multivariate regression analyses, the presence of OSA was significantly associated with leucine, isoleucine, and total BCAA concentrations (P = 0.028), whereas the arousal index was associated with leucine, valine, and total BCAA levels (P = 0.037). CONCLUSIONS: The presence of OSA and sleep fragmentation may induce changes in branched-chain amino acid metabolism in snoring children, independently of obesity. These data may suggest a new mechanism linking OSA and glucose homeostasis. PMID- 28672088 TI - Photocaged Competitor Guests: A General Approach Toward Light-Activated Cargo Release From Cucurbiturils. AB - A general approach toward the light-induced guest release from cucurbit[7]uril by means of a photoactivatable competitor was devised. An o-nitrobenzyl-caged competitor is photolyzed to generate a competitive guest that can displace cargo from the host macrocycle solely based on considerations of chemical equilibrium. With this method the release of terpene guests from inclusion complexes with cucurbit[7]uril was demonstrated. The binding of the herein investigated terpenes, all being lead fragrant components in essential oils, has been characterized for the first time. They feature binding constants of up to 108 L mol-1 and a high differential binding selectivity (spanning four orders of magnitude for the binding constants for the particular set of terpenes). By fine tuning the photoactivatable competitor guest, selective and also sequential release of the terpenes was achieved. PMID- 28672089 TI - Genome packaging of reovirus is mediated by the scaffolding property of the microtubule network. AB - Reovirus replication occurs in the cytoplasm of the host cell, in virally induced mini-organelles called virus factories. On the basis of the serotype of the virus, the virus factories can manifest as filamentous (type 1 Lang strain) or globular structures (type 3 Dearing strain). The filamentous factories morphology is dependent on the microtubule cytoskeleton; however, the exact function of the microtubule network in virus replication remains unknown. Using a combination of fluorescent microscopy, electron microscopy, and tomography of high-pressure frozen and freeze-substituted cells, we determined the ultrastructural organisation of reovirus factories. Cells infected with the reovirus microtubule dependent strain display paracrystalline arrays of progeny virions resulting from their tiered organisation around microtubule filaments. On the contrary, in cells infected with the microtubule-independent strain, progeny virions lacked organisation. Conversely to the microtubule-dependent strain, around half of the viral particles present in these viral factories did not contain genomes (genome less particles). Complementarily, interference with the microtubule filaments in cells infected with the microtubule-dependent strain resulted in a significant increase of genome-less particle number. This decrease of genome packaging efficiency could be rescued by rerouting viral factories on the actin cytoskeleton. These findings demonstrate that the scaffolding properties of the microtubule, and not biochemical nature of tubulin, are critical determinants for reovirus efficient genome packaging. This work establishes, for the first time, a functional correlation between ultrastructural organisation of reovirus factories with genome packaging efficiency and provides novel information on how viruses coordinate assembly of progeny particles. PMID- 28672087 TI - Interventions for chronic kidney disease in people with sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD.Chronic kidney disease is defined as abnormalities of kidney structure or function, present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD.Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, and increases in prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. OBJECTIVES: To assess the effectiveness of any intervention in preventing or reducing kidney complications or chronic kidney disease in people with SCD (including red blood cell transfusions, hydroxyurea and angiotensin-converting enzyme inhibitor (ACEI)), either alone or in combination with each other. SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 05 April 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 13 April 2017. SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent or reduce kidney complications or chronic kidney disease in people with SCD. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias. MAIN RESULTS: We included two trials with 215 participants. One trial was published in 2011 and included 193 children aged 9 months to 18 months, and compared treatment with hydroxyurea to placebo. The second trial was published in 1998 and included 22 adults with normal blood pressure and microalbuminuria and compared ACEI to placebo.We rated the quality of evidence as low to very low across different outcomes according to GRADE methodology. This was due to trials having: a high or unclear risk of bias including attrition and detection bias; indirectness (the available evidence was for children aged 9 months to 18 months in one trial and a small and select adult sample size in a second trial); and imprecise outcome effect estimates of significant benefit or harm. Hydroxyurea versus placebo We are very uncertain if hydroxyurea reduces or prevents progression of kidney disease (assessed by change in glomerular filtration rate), or reduces hyperfiltration in children aged 9 to 18 months, mean difference (MD) 0.58 (95% confidence interval (CI) -14.60 to 15.76 (mL/min per 1.73 m2)) (one study; 142 participants; very low-quality evidence).In children aged 9 to 18 months, hydroxyurea may improve the ability to concentrate urine, MD 42.23 (95% CI 12.14 to 72.32 (mOsm/kg)) (one study; 178 participants; low-quality evidence).Hydroxyurea may make little or no difference to SCD-related serious adverse events including: incidence of acute chest syndrome, risk ratio (RR) 0.39 (99% CI 0.13 to 1.16); painful crisis, RR 0.68 (99% CI 0.45 to 1.02); and hospitalisations, RR 0.83 (99% CI 0.68 to 1.01) (one study, 193 participants; low-quality evidence).No deaths occurred in the trial. Quality of life was not reported. ACEI versus placeboWe are very uncertain if ACEI reduces proteinuria in adults with SCD who have normal blood pressure and microalbuminuria, MD -49.00 (95% CI -124.10 to 26.10 (mg per day)) (one study; 22 participants; very low-quality evidence). We are very uncertain if ACEI reduce or prevent kidney disease as measured by creatinine clearance. The authors state that creatinine clearance remained constant over six months in both groups, but no comparative data were provided (very low-quality evidence).All-cause mortality, serious adverse events and quality of life were not reported. AUTHORS' CONCLUSIONS: In young children aged 9 months to 18 months, we are very uncertain if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration, but it may improve young children's ability to concentrate urine and may make little or no difference on the incidence of acute chest syndrome, painful crises and hospitalisations.We are very uncertain if giving ACEI to adults with normal blood pressure and microalbuminuria has any effect on preventing or reducing kidney complications.This review identified no trials that looked at red cell transfusions nor any combinations of interventions to prevent or reduce kidney complications.Due to lack of evidence this review cannot comment on the management of either children aged over 18 months or adults with any known genotype of SCD.We have identified a lack of adequately-designed and powered studies, and no ongoing trials which address this critical question. Trials of hydroxyurea, ACEI or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction kidney complications in people with SCD. PMID- 28672090 TI - Efficacy of mycophenolate on lung disease and autoimmunity in children with immunodeficiency. AB - The autoimmune manifestations of primary immunodeficiencies, such as autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID), often constitute a great therapeutic challenge and have a significant impact on patients' morbidity and mortality. The most common autoimmune presentations are autoimmune cytopenias, but organ-related autoimmunity is also frequently observed. From a pulmonology perspective, granulomatous/lymphocytic interstitial lung disease (GLILD) is a severe immunological complication which significantly worsens the clinical outcome of these patients and for which there are currently few guidelines or protocols for treatment. We present three cases where the use of Mycophenolate in the context of autoimmune cytopenias proved beneficial also on the lung disease. PMID- 28672092 TI - Oral submucous fibrosis-an increasing global healthcare problem. PMID- 28672091 TI - Young children with severe congenital malformations (VACTERL) expressed mixed feelings about their condition and worries about needles and anaesthesia. AB - AIM: Our knowledge of the perceptions that children with severe congenital malformations have of their health, treatment and how to improve hospital care is limited. This study focused on patients with vertebral defects, anal atresia, cardiac defects, tracheo-oesophageal fistula, renal anomalies and limb abnormalities (VACTERL). METHODS: We interviewed 10 children aged five to eight years with VACTERL association who were treated in a Swedish tertiary paediatric surgical centre, using a computer-assisted technique called In My Shoes. The interviews were analysed by qualitative content analysis. RESULTS: The children described their awareness of their health history and said they felt proud but different due to their physical dysfunction. They were happy to visit the hospital to meet familiar staff, but expressed negative feelings about missing normal life. They were afraid of needle-related procedures and not wakening up after anaesthesia. Various ways of coping with difficult situations were expressed, and suggestions to improve hospital care were voiced. CONCLUSION: Careful follow-up of these children by multidisciplinary teams is crucial to optimise their health and functional status. Fear of medical procedures may be reduced by carefully delivered information, listening to the children, providing continuity of care and creating individual care strategies. PMID- 28672093 TI - Does age matter? Comparing post-treatment psychosocial outcomes in young adult and older adult cancer survivors with their cancer-free peers. AB - OBJECTIVE: Adolescents and young adult cancer survivors (AYA) are a unique subpopulation with high levels of distress and unmet need. To date, studies have not disentangled distress due to developmental life stage from distress due to cancer survivorship. This population-based study allowed a direct comparison between AYA cancer survivors, older adult (OA) cancer survivors, and their cancer free peers. METHODS: We combined 4 annual cycles of the Canadian Community Health Survey (CCHS, 2007-2010) to obtain a final sample of 239 316 respondents. We dichotomized the total sample into AYA (15-39 years, n = 83 770) and OA (40+, n = 155 546). Two standardized questions identified cancer survivors (n = 14 592). The self-reported outcomes of interest included self-perceived health and mental health, and health care professional diagnosed mood and anxiety disorders. We used weighted logistic regression models to examine for associations, including an interaction term to assess for effect modification by age. RESULTS: After adjusting for confounders, cancer survivorship in AYAs was strongly associated with higher prevalence of both mood (OR 2.00, 95% CI 1.44-2.77) and anxiety (OR 2.20, 95% CI 1.70-2.86) disorders as compared to their cancer-free peers. OA survivors had a weaker association in the same direction (OR 1.10, 95% CI 1.01 1.21 and OR 1.15, 95% CI 1.02-1.30, respectively). AYA cancer survivors reported higher levels of poor self-perceived mental health than their cancer-free peers (OR 1.49, 95% CI 1.03-2.14), while there was no significant difference from cancer-free peers for OAs (OR 1.03, 95% CI 0.92-1.15). CONCLUSIONS: AYA cancer survivors experience a significantly higher risk of psychosocial distress than both their cancer-free peers and OA survivors. PMID- 28672094 TI - Noninvasive high-frequency oscillatory ventilation versus nasal continuous positive airway pressure in preterm infants with moderate-severe respiratory distress syndrome: A preliminary report. AB - OBJECTIVE: The aim of this study was to compare the effect of noninvasive high frequency oscillatory ventilation (nHFOV) with nasal continuous positive airway pressure (nCPAP) in preterm infants with moderate-severe respiratory distress syndrome (RDS) after surfactant administration via INSURE (intubation, surfactant, extubation) method on the need for invasive mechanical ventilation (IMV). METHODS: A total of 81 infants with a gestational age (GA) of 28-34 weeks were eligible and were randomized to nCPAP (n = 42) or to nHFOV (n = 39). The need for IMV was the primary outcome. The incidence of bronchopulmonary dysplasia (BPD), occurrence of intraventricular hemorrhage (IVH), and air leaks, and mortality were considered as secondary outcomes. RESULT: A total 76 infants finally completed the study. The need for IMV was significantlylower in the nHFOV group compared with the nCPAP group(24.3% vs 56.4%, P < 0.01). The incidence of IVH, air leaks or BPD was similar between the two groups. In addition, the mortality rate was not statistically different. CONCLUSION: In this prospective, randomized controlled study, nHFOV significantly reduced the need for IMV as compared with nCPAP in preterm infants with moderate-severe RDS without increase in adverse effects. PMID- 28672095 TI - Exploiting Pincer Ligands to Perturb the Geometry at Boron. AB - Boranes are ubiquitous in synthesis and materials but advancements in their development have been primarily restricted to the geometric energetic minima, trigonal planar complexes. This report discloses a class of boranes with expanded bond angles achieved by taking advantage of the structural rigidity of tridentate pincer ligands. The bonding of these novel boranes is investigated by X-ray crystallography and computationally. PMID- 28672096 TI - Metabolomic Tools to Assess the Chemistry and Bioactivity of Endophytic Aspergillus Strain. AB - Endophytic fungi associated with medicinal plants are a potential source of novel chemistry and biology that may find applications as pharmaceutical and agrochemical drugs. In this study, a combination of metabolomics and bioactivity guided approaches were employed to isolate secondary metabolites with cytotoxicity against cancer cells from an endophytic Aspergillus aculeatus. The endophyte was isolated from the Egyptian medicinal plant Terminalia laxiflora and identified using molecular biological methods. Metabolomics and dereplication studies were accomplished by utilizing the MZmine software coupled with the universal Dictionary of Natural Products database. Metabolic profiling, with aid of multivariate data analysis, was performed at different stages of the growth curve to choose the optimized method suitable for up-scaling. The optimized culture method yielded a crude extract abundant with biologically-active secondary metabolites. Crude extracts were fractionated using different high throughput chromatographic techniques. Purified compounds were identified by HR ESI-MS, 1D- and 2D-NMR. This study introduced a new method of dereplication utilizing both high-resolution mass spectrometry and NMR spectroscopy. The metabolites were putatively identified by applying a chemotaxonomic filter. We also present a short review on the diverse chemistry of terrestrial endophytic strains of Aspergillus, which has become a part of our dereplication work and this will be of wide interest to those working in this field. PMID- 28672097 TI - Three-dimensional neural cultures produce networks that mimic native brain activity. AB - Development of brain function is critically dependent on neuronal networks organized through three dimensions. Culture of central nervous system neurons has traditionally been limited to two dimensions, restricting growth patterns and network formation to a single plane. Here, with the use of multichannel extracellular microelectrode arrays, we demonstrate that neurons cultured in a true three-dimensional environment recapitulate native neuronal network formation and produce functional outcomes more akin to in vivo neuronal network activity. PMID- 28672098 TI - Inhaled corticosteroids in transient tachypnea of the newborn: A randomized, placebo-controlled study. AB - OBJECTIVE: Prenatal corticosteroids were shown to reduce the respiratory complication in late preterm infants. Our objective was to determine if early inhaled corticosteroids could alleviate the respiratory distress and morbidity in late preterm and term neonates with transient tachypnea of the newborn (TTN). STUDY DESIGN: Double-blind, randomized placebo-controlled, multicenter pilot study. Infants born at >34 weeks gestational age with TTN at 4 h of age were randomized to two doses, 12 h apart, of inhaled Budesonide 1000 MUg/dose or placebo within 6 h from delivery. Analysis was done by intention to treat. RESULTS: The study (n = 24) and control (n = 25) groups were comparable in birth characteristics (gestational age: 36.8 +/- 1.9 vs 36.4 +/- 1.8 weeks) and clinical condition at the time of recruitment (vital signs, clinical score, ventilation support, and blood gases). There was no difference between the study and control groups in clinical score (based on grunting, retractions, ala nasi, and respiratory rate) at recruitment and at 12, 24, and 48 h after the first inhalation (4.3 +/- 1.6 vs 4.1 +/- 2.1; 1.9 +/- 1.8 vs 1.5 +/- 1.7; 1.1 +/- 1.4 vs 1.3 +/- 1.6; 0.5 +/- 0.8 vs 0.6 +/- 1.0; respectively). Respiratory support at each time point, time to spontaneous unsupported breathing (67.4 +/- 74.1 vs 75.2 +/- 95.2 h), time to full feeds (86.7 +/- 68.7 vs 84.3 +/- 66.6 h) and length of stay (9.9 +/- 5.5 vs 12.4 +/- 8.0 days) did not differ between the groups. We did not detect any side effects. CONCLUSIONS: Our pilot study was unable to detect a beneficial effect of early administration of inhaled steroids on the clinical course of TTN in late preterm and term infants. PMID- 28672099 TI - Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia. AB - Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. PMID- 28672100 TI - Warfarin Pharmacogenomics in Diverse Populations. AB - Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. PMID- 28672101 TI - Impact of neoadjuvant chemotherapy on surgical outcomes among patients with hormone receptor positive breast cancer. AB - BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is a surrogate for outcome, but not necessarily conversion to BCT eligibility. We sought to examine the impact of NACT on surgical decision making among HR+ patients. METHODS: Our IRB-approved breast cancer database was queried for patients who underwent NACT, including the clinicopathologic data and surgeon's pre- and post-NACT assessment. Surgical conversion rate (SCR) was defined as patients ineligible for BCT prior to NACT, who were given the choice following NACT. RESULTS: Among 289 patients, pCR rates were highest among patients with HER2-enriched subtype (60%) and lowest in patients with luminal A disease (4%). Overall, the BCT rate was 41%, while 28% opted for bilateral mastectomy across subtypes. Despite a low pCR, the SCR was still high (54%) among patients with the luminal A subtype. CONCLUSION: Despite poor pCR rates, NACT still has potential to improve surgical outcomes among hormone receptor positive patients. The surgical conversion rate is a superior measure of the impact of NACT on surgical decision making than examining BCT rates. PMID- 28672102 TI - Prognostic and functional role of subtype-specific tumor-stroma interaction in breast cancer. AB - None of the clinically relevant gene expression signatures available for breast cancer were specifically developed to capture the influence of the microenvironment on tumor cells. Here, we attempted to build subtype-specific signatures derived from an in vitro model reproducing tumor cell modifications after interaction with activated or normal stromal cells. Gene expression signatures derived from HER2+, luminal, and basal breast cancer cell lines (treated by normal fibroblasts or cancer-associated fibroblasts conditioned media) were evaluated in clinical tumors by in silico analysis on published gene expression profiles (GEPs). Patients were classified as microenvironment-positive (MUENV+ve), that is, with tumors showing molecular profiles suggesting activation by the stroma, or microenvironment-negative (MUENV-ve) based on correlation of their tumors' GEP with the respective subtype-specific signature. Patients with estrogen receptor alpha (ER)+/HER2-/MUENV+ve tumors were characterized by 2.5 fold higher risk of developing distant metastases (HR = 2.546; 95% CI: 1.751 3.701, P = 9.84E-07), while MUENV status did not affect, or only suggested the risk of distant metastases, in women with HER2+ (HR = 1.541; 95% CI: 0.788-3.012, P = 0.206) or ER-/HER2- tumors (HR = 1.894; 95% CI: 0.938-3.824; P = 0.0747), respectively. In ER+/HER2- tumors, the MUENV status remained significantly associated with metastatic progression (HR = 2.098; CI: 1.214-3.624; P = 0.00791) in multivariable analysis including size, age, and Genomic Grade Index. Validity of our in vitro model was also supported by in vitro biological endpoints such as cell growth (MTT assay) and migration/invasion (Transwell assay). In vitro derived gene signatures tracing the bidirectional interaction with cancer activated fibroblasts are subtype-specific and add independent prognostic information to classical prognostic variables in women with ER+/HER2- tumors. PMID- 28672104 TI - The Structure of Ethylbenzene, Styrene and Phenylacetylene Determined by Total Neutron Scattering. AB - Organic solvents such as phenylacetylene, styrene and ethylbenzene are widely used in industrial processes, especially in the production of rubber or thermoplastics. Despite their important applications detailed knowledge about their structure is limited. In this paper the structures of these three aromatic solvents were investigated using neutron diffraction. The results show that many of their structural characteristics are similar, although the structure of phenylacetylene is more ordered and has a smaller solvation sphere than either ethylbenzene or styrene. Two regions within the first coordination sphere, in which the surrounding molecules show different preferable orientations with respect to the central molecule, were found for each liquid. Additionally, the localisation of the aliphatic chains reveals that they tend to favour closer interactions with each other than to the aromatic rings of the adjacent molecules. PMID- 28672103 TI - Sphingosine-1-phosphate suppresses chondrosarcoma metastasis by upregulation of tissue inhibitor of metalloproteinase 3 through suppressing miR-101 expression. AB - Chondrosarcoma is the second most common primary malignancy form of bone cancer, exhibiting resistance to chemotherapy and radiation therapy as well as developing high metastasis ability in late-stage tumors. Thus, understanding the metastatic processes of chondrosarcoma is considered a strategy for the treatment of this disease. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is produced intracellularly by sphingosine kinase (SphK) and is regarded as a second signaling molecule that regulates inflammation, proliferation, angiogenesis, and metastasis. However, the effect of S1P on chondrosarcoma remains uncertain. As demonstrated by the transwell, immunoblotting, and real-time PCR analyses, we found that S1P inhibited cell migration and MMP-2 expression through the upregulation of the tissue inhibitor of metalloproteinase-3 (TIMP-3) expression in human chondrosarcoma cells. Additionally, we also showed that microRNA (miRNA) 101, which targets the 3' untranslated region (3'UTR) of TIMP-3, decreased significantly following S1P treatment. After transfection with miR-101 mimics, the S1P-regulated cell migration and TIMP-3 expression were both reversed. Furthermore, we also showed that the S1P-inhibited cell migration is mediated through the c-Src/MEK/ERK signaling axis. Meanwhile, the in vivo study indicated that overexpression of SphK1 decreases chondrosarcoma metastasis to the lungs. Our results illustrate the clinical significance between SphK1, TIMP-3, and miR 101 in human chondrosarcoma patients. Taken together, our results suggest that S1P and miR-101 may prove to be potential therapeutic targets for future chondrosarcoma treatment. PMID- 28672105 TI - Comparative landscape genetics of two frugivorous bats in a biological corridor undergoing agricultural intensification. AB - Agricultural intensification in tropical landscapes poses a new threat to the ability of biological corridors to maintain functional connectivity for native species. We use a landscape genetics approach to evaluate impacts of expanding pineapple plantations on two widespread and abundant frugivorous bats in a biological corridor in Costa Rica. We hypothesize that the larger, more mobile Artibeus jamaicensis will be less impacted by pineapple than the smaller Carollia castanea. In 2012 and 2013, we sampled 735 bats in 26 remnant forest patches surrounded by different proportions of forest, pasture, crops and pineapple. We used 10 microsatellite loci for A. jamaicensis and 16 microsatellite loci for C. castanea to estimate genetic diversity and gene flow. Canonical correspondence analyses indicate that land cover type surrounding patches has no impact on genetic diversity of A. jamaicensis. However, for C. castanea, both percentage forest and pineapple surrounding patches explained a significant proportion of the variation in genetic diversity. Least-cost transect analyses (LCTA) and pairwise G"st suggest that for A. jamaicensis, pineapple is more permeable to gene flow than expected, while as expected, forest is the most permeable land cover for gene flow of C. castanea. For both species, LCTA indicate that development may play a role in inhibiting gene flow. The current study answers the call for landscape genetic research focused on tropical and agricultural landscapes, highlights the value of comparative landscape genetics in biological corridor design and management and is one of the few studies of biological corridors in any ecosystem to implement a genetic approach to test corridor efficacy. PMID- 28672106 TI - Graphene Dots Embedded Phosphide Nanosheet-Assembled Tubular Arrays for Efficient and Stable Overall Water Splitting. AB - Bifunctional electrocatalysts are highly desired for overall water splitting. Herein, the design and fabrication of three-dimensional (3D) hierarchical earth abundant transition bimetallic phosphide arrays constructed by one-dimensional tubular array that was derived from assembling two-dimensional nanosheet framework has been reported by tailoring the Co/Ni ratio and tunable morphologies, and zero-dimensional (0D) graphene dots were embedded on Co-Ni phosphide matrix to construct 0D/2D tubular array as a highly efficient electrode in the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). On the basis of advanced merits, such as the high surface-active sites, well dispersed graphene dots, and enhanced electron transfer capacity as well as the confinement effect of the graphene dots on the nanosheets, the integrated GDs/Co0.8Ni0.2P tubular arrays as anode and cathode exhibit excellent OER and HER performance. By use of GDs/Co0.8Ni0.2P arrays in the two-electrode setup of the device, a remarkable electrocatalytic performance for full water splitting has been achieved with a high current density of 10 mA cm-2 at 1.54 V and outstanding long-term operation stability in an alkaline environment, indicating a promising system based on nonprecious-metal electrocatalysts toward potential practical devices of overall water splitting. PMID- 28672107 TI - Toolbox of Fluorescent Probes for Parallel Imaging Reveals Uneven Location of Serine Proteases in Neutrophils. AB - Neutrophils, the front line defenders against infection, express four serine proteases (NSPs) that play roles in the control of cell-signaling pathways and defense against pathogens and whose imbalance leads to pathological conditions. Dissecting the roles of individual NSPs in humans is problematic because neutrophils are end-stage cells with a short half-life and minimal ongoing protein synthesis. To gain insight into the regulation of NSP activity we have generated a small-molecule chemical toolbox consisting of activity-based probes with different fluorophore-detecting groups with minimal wavelength overlap and highly selective natural and unnatural amino acid recognition sequences. The key feature of these activity-based probes is the ability to use them for simultaneous observation and detection of all four individual NSPs by fluorescence microscopy, a feature never achieved in previous studies. Using these probes we demonstrate uneven distribution of NSPs in neutrophil azurophil granules, such that they seem to be mutually excluded from each other, suggesting the existence of unknown granule-targeting mechanisms. PMID- 28672108 TI - Robust Strategy for Crafting Li5Cr7Ti6O25@CeO2 Composites as High-Performance Anode Material for Lithium-Ion Battery. AB - A facile strategy was developed to prepare Li5Cr7Ti6O25@CeO2 composites as a high performance anode material. X-ray diffraction (XRD) and Rietveld refinement results show that the CeO2 coating does not alter the structure of Li5Cr7Ti6O25 but increases the lattice parameter. Scanning electron microscopy (SEM) indicates that all samples have similar morphologies with a homogeneous particle distribution in the range of 100-500 nm. Energy-dispersive spectroscopy (EDS) mapping and high-resolution transmission electron microscopy (HRTEM) prove that CeO2 layer successfully formed a coating layer on a surface of Li5Cr7Ti6O25 particles and supplied a good conductive connection between the Li5Cr7Ti6O25 particles. The electrochemical characterization reveals that Li5Cr7Ti6O25@CeO2 (3 wt %) electrode shows the highest reversibility of the insertion and deinsertion behavior of Li ion, the smallest electrochemical polarization, the best lithium ion mobility among all electrodes, and a better electrochemical activity than the pristine one. Therefore, Li5Cr7Ti6O25@CeO2 (3 wt %) electrode indicates the highest delithiation and lithiation capacities at each rate. At 5 C charge discharge rate, the pristine Li5Cr7Ti6O25 only delivers an initial delithiation capacity of ~94.7 mAh g-1, and the delithiation capacity merely achieves 87.4 mAh g-1 even after 100 cycles. However, Li5Cr7Ti6O25@CeO2 (3 wt %) delivers an initial delithiation capacity of 107.5 mAh.g-1, and the delithiation capacity also reaches 100.5 mAh g-1 even after 100 cycles. The cerium dioxide modification is a direct and efficient approach to improve the delithiation and lithiation capacities and cycle property of Li5Cr7Ti6O25 at large current densities. PMID- 28672109 TI - Effect of Barley beta-Glucan on the Gluten Polymerization Process in Dough during Heat Treatment. AB - Barley (Hordeum vulgare L.) beta-glucan (BBG) is of interest as a result of its health benefits, but BBG presents significant disruptions on the gluten network, with a negative impact on food texture. To clarify the interaction between BBG and gluten in dough, the dynamic rheological, thermochemical process of gluten and microstructure of dough with BBG during heating were detected. The results showed that BBG delayed the gluten thermopolymerization reaction during heating and affected polymerization of specific molecular weight protein subunits. These impacts depended upon the heating temperature and time. When heating under 25-65 degrees C, tan delta of the dough reached the highest level at the BBG concentration of 1%. However, under the temperature of 65-95 degrees C, tan delta was positively correlated with the BBG content (0-3%). The differential scanning calorimetry curves revealed that the peak temperature (TP) of the two endothermic peaks increased by 3.86 and 3.10 degrees C. Size-exclusion high performance liquid chromatography analysis showed that BBG mainly affected the peak area of gliadin and glutenin. Furthermore, after 3% BBG was added, the bands of 59.8 and 64.9 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis patterns delayed, vanishing for 120 s when heating at 95 degrees C. Therefore, BBG delayed the polymerization reaction of specific molecular weight protein subunits rather than all of the proteins. PMID- 28672110 TI - Excited State Biexcitons in Atomically Thin MoSe2. AB - The tightly bound biexcitons found in atomically thin semiconductors have very promising applications for optoelectronic and quantum devices. However, there is a discrepancy between theory and experiment regarding the fundamental structure of these biexcitons. Therefore, the exploration of a biexciton formation mechanism by further experiments is of great importance. Here, we successfully triggered the emission of biexcitons in atomically thin MoSe2, via the engineering of three critical parameters: dielectric screening, density of trions, and excitation power. The observed binding energy and formation dynamics of these biexcitons strongly support the model that the biexciton consists of a charge attached to a trion (excited state biexciton) instead of four spatially symmetric particles (ground state biexciton). More importantly, we found that the excited state biexcitons not only can exist at cryogenic temperatures but also can be triggered at room temperature in a freestanding bilayer MoSe2. The demonstrated capability of biexciton engineering in atomically thin MoSe2 provides a route for exploring fundamental many-body interactions and enabling device applications, such as bright entangled photon sources operating at room temperature. PMID- 28672111 TI - Analyzing Spin Selectivity in DNA-Mediated Charge Transfer via Fluorescence Microscopy. AB - Understanding spin-selective interactions between electrons and chiral molecules is critical to elucidating the significance of electron spin in biological processes and to assessing the potential of chiral assemblies for organic spintronics applications. Here, we use fluorescence microscopy to visualize the effects of spin-dependent charge transport in self-assembled monolayers of double stranded DNA on ferromagnetic substrates. Patterned DNA arrays provide background regions for every measurement to enable quantification of substrate magnetization dependent fluorescence due to the chiral-induced spin selectivity effect. Fluorescence quenching of photoexcited dye molecules bound within DNA duplexes is dependent upon the rate of charge separation/recombination upon photoexcitation and the efficiency of DNA-mediated charge transfer to the surface. The latter process is modulated using an external magnetic field to switch the magnetization orientation of the underlying ferromagnetic substrates. We discuss our results in the context of the current literature on the chiral-induced spin selectivity effect across various systems. PMID- 28672112 TI - Directed Assembly of Janus Cylinders by Controlling the Solvent Polarity. AB - This study demonstrates the possibility of controlling the directed self-assembly of microsized Janus cylinders by changing the solvent polarity of the assembly media. Experimental results are analyzed and theoretical calculations of the free energy of adhesion (DeltaGad) are performed to elucidate the underlying basic principles and investigate the effects of the solvent on the self-assembled structures. This approach will pave a predictive route for controlling the structures of assembly depending on the solvent polarity. In particular, we find that a binary solvent system with precisely controlled polarity induces directional assembly of the microsized Janus cylinders. Thus, the formation of two-dimensional (2D) and three-dimensional (3D) assembled clusters can be reliably tuned by controlling the numbers of constituent Janus cylinders in a binary solvent system. Finally, this approach is expanded to stepwise assembly, which forms unique microstructures via secondary growth of primary seed clusters formed by the Janus cylinders. We envision that this investigation is highly promising for the construction of desired superstructures using a wide variety of polymeric Janus microparticles with chemical and physical multicompartments. PMID- 28672113 TI - Chlorfenapyr, a Potent Alternative Insecticide of Phoxim To Control Bradysia odoriphaga (Diptera: Sciaridae). AB - Bradysia odoriphaga is the major pest affecting Chinese chive production, and in China, it has developed widespread resistance to organophosphorus insecticides. Chlorfenapyr is a promising pyrrole insecticide with a unique mechanism of action that does not confer cross-resistance to neurotoxic insecticides. However, the effect of chlorfenapyr on organophosphate-resistant B. odoriphaga is not well understood. The present study evaluated the potential of chlorfenapyr for the control of phoxim-resistant B. odoriphaga. The results showed that chlorfenapyr had significant insecticidal activity to B. odoriphaga in multiple developmental stages, and there were no significant differences in susceptibility between the field (phoxim-resistant) and laboratory (phoxim-susceptible) populations. The pot experiment and field trials confirmed the results of our laboratory bioassays. In the field trial, chlorfenapyr applied at 3.0, 6.0, or 12.0 kg of active ingredient (a.i.)/ha significantly decreased the number of B. odoriphaga and improved the yield compared to phoxim at 6.0 kg of a.i./ha and the control conditions. Moreover, the final residues of chlorfenapyr on plants were below the maximum residue limits (MRLs) as a result of its non-systemic activity. These results demonstrate that chlorfenapyr has potential as a potent alternative to phoxim for controlling B. odoriphaga. PMID- 28672114 TI - Amaranthus caudatus lectin with polyproline II fold: conformational and functional transitions and molecular dynamics. AB - Polyproline II (PPII) fold, a peculiar structural element was detected in the Amaranthus caudatus seed lectin (ACL) based on far UV circular dichroism spectrum, conformational transitions of the lectin, and a distinct isodichroic point in thermal denaturation. It was confirmed using PolyprOnline database to estimate the percentage of amino acids contributing to PPII fold and showed the values as 13.5 and 13.9% for PROSS and XTLSSTR, respectively. Investigations of the functional and conformational transitions of ACL during thermal-, pH-, and guanidine hydrochloride (GdnHCl)-induced denaturation were carried out using biochemical and biophysical techniques and molecular dynamics (MD) simulations approach. The lectin got aggregated at 60 degrees C with instantaneous structural alterations. The aggregation-prone regions in ACL were predicted using online servers viz. AGGRESCAN, AmylPred, FoldAmyloid, and Waltz that were represented by Visual Molecular Dynamics tools. Nine conserved regions were identified by these softwares as being 'hot-spots' for aggregation. MD simulation studies of the lectin at 60 degrees C revealed increase in radius of gyration. The loss of PPII fold in 2.0 M GdnHCl was reversible. The partially unfolded intermediate of ACL with diminished PPII fold formed at pH 1.0 was stable up to 90 degrees C. The polyproline II fold has been rarely detected in lectins, ACL being the second after the potato lectin. PMID- 28672115 TI - End-of-life care for homeless people: A qualitative analysis exploring the challenges to access and provision of palliative care. AB - BACKGROUND: Being homeless or vulnerably housed is associated with death at a young age, frequently related to medical problems complicated by drug or alcohol dependence. Homeless people experience high symptom burden at the end of life, yet palliative care service use is limited. AIM: To explore the views and experiences of current and formerly homeless people, frontline homelessness staff (from hostels, day centres and outreach teams) and health- and social-care providers, regarding challenges to supporting homeless people with advanced ill health, and to make suggestions for improving care. DESIGN: Thematic analysis of data collected using focus groups and interviews. PARTICIPANTS: Single homeless people ( n = 28), formerly homeless people ( n = 10), health- and social-care providers ( n = 48), hostel staff ( n = 30) and outreach staff ( n = 10). RESULTS: This research documents growing concern that many homeless people are dying in unsupported, unacceptable situations. It highlights the complexities of identifying who is palliative and lack of appropriate places of care for people who are homeless with high support needs, particularly in combination with substance misuse issues. CONCLUSION: Due to the lack of alternatives, homeless people with advanced ill health often remain in hostels. Conflict between the recovery-focused nature of many services and the realities of health and illness for often young homeless people result in a lack of person-centred care. Greater multidisciplinary working, extended in-reach into hostels from health and social services and training for all professional groups along with more access to appropriate supported accommodation are required to improve care for homeless people with advanced ill health. PMID- 28672117 TI - Re: Surgical Options for the Enlarged, Obstructing, Benign Prostate: J. K. Parsons J Urol 2017;197:977-978. PMID- 28672116 TI - Visfatin and resistin in gonadotroph cells: expression, regulation of LH secretion and signalling pathways. AB - Visfatin and resistin appear to interfere with reproduction in the gonads, but their potential action at the hypothalamic-pituitary level is not yet known. The aim of the present study was to investigate the mRNA and protein expression of these adipokines in murine gonadotroph cells and to analyse the effects of different concentrations of recombinant mouse visfatin and resistin (0.01, 0.1, 1 and 10ngmL-1) on LH secretion and signalling pathways in LbetaT2 cells and/or in primary female mouse pituitary cells. Both visfatin and resistin mRNA and protein were found in vivo in gonadotroph cells. In contrast with resistin, the primary tissue source of visfatin in the mouse was the skeletal muscle, and not adipose tissue. Visfatin and resistin both decreased LH secretion from LbetaT2 cells after 24h exposure of cells (P<0.03). These results were confirmed for resistin in primary cell culture (P<0.05). Both visfatin (1ngmL-1) and resistin (1ngmL-1) increased AMP-activated protein kinase alpha phosphorylation in LbetaT2 cells after 5 or 10min treatment, up to 60min (P<0.04). Extracellular signal-regulated kinase 1/2 phosphorylation was transiently increased only after 5min resistin (1ngmL-1) treatment (P<0.01). In conclusion, visfatin and resistin are expressed in gonadotroph cells and they may affect mouse female fertility by regulating LH secretion at the level of the pituitary. PMID- 28672118 TI - An Unusual Cause of Obscure Gastrointestinal Bleeding. PMID- 28672119 TI - An Unusual Cause of Recurrent Gastrointestinal Bleeding After Whipple's Surgery. PMID- 28672120 TI - An Unusual Cause of Right Upper Quadrant Pain. PMID- 28672121 TI - Reply. PMID- 28672122 TI - Safety Signal for the Simple Double Ablation Regimen When Using the Barrx 360 Express Radiofrequency Ablation Balloon Catheter. PMID- 28672123 TI - Submucosal Tumor of the Stomach With Drastic, Short-term Changes in Morphology. PMID- 28672124 TI - A Man With Intermittent Abdominal Pain, Liver Injury, and Renal Impairment. PMID- 28672125 TI - A synthetic peptide derived from staphylokinase enhances FGF-2-induced skin wound healing in mice. PMID- 28672126 TI - Low back cutaneous vibration and its effect on trunk postural control. AB - The current study investigated the effects of a low back pain (LBP) vibration modality on trunk motor control. Trunk repositioning error and responses to a sudden loading trunk perturbation were evaluated pre- and post-vibration (15min vibration exposure while sitting on a standard chair) as well as when concurrent cutaneous low back vibration was applied. Only minor effects were observed post vibration when compared to pre-vibration. However, when vibration was applied at the same time as the sudden trunk perturbations, lumbar erector spinae and external oblique muscles were significantly more delayed in activating following the perturbation. In addition, the resting muscle activation prior to the trunk perturbation was higher in both the back extensor and abdominal muscles when concurrent vibration was applied. These findings suggest that cutaneous low back vibration significantly alters motor control responses and this should be considered before implementing cutaneous vibration as a low back pain management strategy. PMID- 28672127 TI - Local dynamic stability of the spine and its coordinated lower joints during repetitive Lifting: Effects of fatigue and chronic low back pain. AB - The nonlinear Lyapunov exponent (LyE) has been proven effective for evaluating the local stability of human movement and exploring the effects of load, speed and direction of individuals with and without nonspecific chronic low back pain (CLBP). The purpose of this study was to examine spinal and lower joint stability and response to fatigue of individuals with and without CLBP while performing lifting-lowering movements. Fourteen healthy individuals and 14 patients with nonspecific CLBP were recruited to perform lifting movement repeatedly while holding two equally-sized dumbbells in their hands. The participants continued lifting until they reported their highest level of fatigue. Kinematic data for the spine and its coordinated lower joints were recorded during the task (more than 40 lifting cycles on average). The first and last 20 cycles of each cyclic time series were defined as early- and late-fatigue conditions, respectively. The maximum LyE was estimated to quantify the local dynamic stability of the angular displacement time series of the spine, hip, knee and ankle on different anatomical planes in both the early- and late-fatigue conditions. The results revealed that local stability of the spine and hip was affected by fatigue. Spinal stability decreased as fatigue increased on the sagittal plane (p<0.05). The hip exhibited a similar affectation (destabilization under fatigue) on all anatomical planes. Patients with CLBP showed more stable hip movement on the frontal and transverse planes (p<0.05). These results suggested that lifting/progressive fatigue could increase the risk of injury to the spine and hip. These findings indicate that patients with CLBP applied different control strategies for the hip; thus, spinal control stability should be evaluated together with the stability of the lower joints. PMID- 28672128 TI - Exploring pathways linking greenspace to health: Theoretical and methodological guidance. AB - BACKGROUND: In a rapidly urbanizing world, many people have little contact with natural environments, which may affect health and well-being. Existing reviews generally conclude that residential greenspace is beneficial to health. However, the processes generating these benefits and how they can be best promoted remain unclear. OBJECTIVES: During an Expert Workshop held in September 2016, the evidence linking greenspace and health was reviewed from a transdisciplinary standpoint, with a particular focus on potential underlying biopsychosocial pathways and how these can be explored and organized to support policy-relevant population health research. DISCUSSIONS: Potential pathways linking greenspace to health are here presented in three domains, which emphasize three general functions of greenspace: reducing harm (e.g. reducing exposure to air pollution, noise and heat), restoring capacities (e.g. attention restoration and physiological stress recovery) and building capacities (e.g. encouraging physical activity and facilitating social cohesion). Interrelations between among the three domains are also noted. Among several recommendations, future studies should: use greenspace and behavioural measures that are relevant to hypothesized pathways; include assessment of presence, access and use of greenspace; use longitudinal, interventional and (quasi)experimental study designs to assess causation; and include low and middle income countries given their absence in the existing literature. Cultural, climatic, geographic and other contextual factors also need further consideration. CONCLUSIONS: While the existing evidence affirms beneficial impacts of greenspace on health, much remains to be learned about the specific pathways and functional form of such relationships, and how these may vary by context, population groups and health outcomes. This Report provides guidance for further epidemiological research with the goal of creating new evidence upon which to develop policy recommendations. PMID- 28672129 TI - Gestational diabetes mellitus was related to ambient air pollutant nitric oxide during early gestation. AB - BACKGROUND: Ambient air pollution has been linked to the risk of gestational diabetes mellitus (GDM). However, evidence of this association is limited, and no study has examined the effects of nitric oxide (NO). OBJECTIVE: This study investigated the association between air pollution exposure during gestation and GDM. METHODS: The Taiwan Birth Cohort Study database was used to examine the association between the risk of GDM and all routinely monitored air pollutants among 21,248 women who were pregnant during 2004-2005. We further employed a two pollutant model for confirming the effect of each pollutant on GDM. RESULTS: After the exclusion criteria were applied, 19,606 women were included in the final analysis. Among them, 378 (1.9%) had been diagnosed as having GDM. These women were older and had higher BMIs than the women without GDM. The risks of GDM onset were significantly associated with NO exposure during the first [adjusted OR (aOR): 1.05, 95% confidence interval (CI): 1.02-1.08] and second (aOR: 1.05, 95%CI: 1.02-1.08) trimesters. Under the two-pollutant model, the effect of NO exposure was also significant during the first (aOR: 1.05, 95%CI: 1.02-1.08) and second (aOR: 1.05, 95%CI: 1.02-1.09) trimesters. CONCLUSION: The results indicated that exposure to higher NO levels during pregnancy increases the risk of GDM. PMID- 28672130 TI - Exposures to fine particulate matter (PM2.5) and ozone above USA standards are associated with auditory brainstem dysmorphology and abnormal auditory brainstem evoked potentials in healthy young dogs. AB - BACKGROUND: Delayed central conduction times in the auditory brainstem have been observed in Mexico City (MC) healthy children exposed to fine particulate matter (PM2.5) and ozone (O3) above the current United States Environmental Protection Agency (US-EPA) standards. MC children have alpha synuclein brainstem accumulation and medial superior olivary complex (MSO) dysmorphology. The present study used a dog model to investigate the potential effects of air pollution on the function and morphology of the auditory brainstem. METHODOLOGY: Twenty-four dogs living in clean air v MC, average age 37.1 +/- 26.3 months, underwent brainstem auditory evoked potential (BAEP) measurements. Eight dogs (4 MC, 4 Controls) were analysed for auditory brainstem morphology and histopathology. RESULTS: MC dogs showed ventral cochlear nuclei hypotrophy and MSO dysmorphology with a significant decrease in cell body size, decreased neuronal packing density with regions in the nucleus devoid of neurons and marked gliosis. MC dogs showed significant delayed BAEP absolute wave I, III and V latencies compared to controls. CONCLUSIONS: MC dogs show auditory nuclei dysmorphology and BAEPs consistent with an alteration of the generator sites of the auditory brainstem response waveform. This study puts forward the usefulness of BAEPs to study auditory brainstem neurodegenerative changes associated with air pollution in dogs. Recognition of the role of non-invasive BAEPs in urban dogs is warranted to elucidate novel neurodegenerative pathways link to air pollution and a promising early diagnostic strategy for Alzheimer's Disease. PMID- 28672131 TI - Association between serum persistent organic pollutants and DNA methylation in Korean adults. AB - BACKGROUND: Exposure to persistent organic pollutants (POPs) has been associated with epigenetic changes such as DNA methylation, which can influence human health. However, the association between POPs and DNA methylation by sex was not shown in previous studies. OBJECTIVES: We investigated the association between POPs and DNA methylation in men and women using a larger population. METHODS: A cross-sectional study was conducted using the data of 444 Koreans (253 men and 191 women). Measurements for sixteen different POPs, including six organochlorine pesticides (OCPs) and ten polychlorinated biphenyls (PCBs) were taken in serum. DNA methylation via Alu and LINE-1 in peripheral leukocytes was measured by pyrosequencing. To evaluate the association between POPs and DNA methylation, the Pearson's correlation and multiple linear regression analyses were performed. RESULTS: Except for PCB52 and PCB101, we found significant inverse associations between p,p'-DDE, cis-Heptachlor epoxide, and PCBs and Alu assay in men after adjusting for age, BMI, smoking status, and alcohol consumption (beta = -0.67 for p,p'-DDE; -0.28 for cis-Heptachlor epoxide; in the range from -0.43 to -1.60 for PCBs). In women, PCB153 and PCB180 showed statistically significant inverse association with Alu assay (beta = -0.22 for PCB153; -0.22 for PCB180). Except for PCB101, p,p'-DDE and PCBs were positively associated with LINE-1 assay in women (beta = 0.48 for p,p'-DDE; in the range from 0.40-0.89 for PCBs) while p,p' DDE, PCB153, and PCB180 showed positive associations with LINE-1 assay in men (beta = 0.55 for p,p'-DDE; 0.65 for PCB153; 1.02 for PCB180). CONCLUSIONS: We found that several POPs were associated with global DNA hypomethylation in the Alu assay for men and global DNA hypermethylation in the LINE-1 assay for women. PMID- 28672133 TI - Unstable fragility fractures of the ankle in the elderly: Transarticular Steinmann pin or external fixation. AB - INTRODUCTION: Because of poor skin conditions and comorbidity, open reduction and internal fixation in ankle fractures is frequently contra-indicated in the elderly. This study reports the results of two temporary fixation types in fragility fractures in the older patient: transarticular Steinmann pin fixation and external fixation. METHODS: Patients aged over 60 treated with a Steinmann pin or external fixation were retrospectively included. Patient, fracture and treatment characteristics were collected. RESULTS: Fifteen patients were included. Nine were managed using a Steinmann pin and six by external fixation. All reached fracture consolidation. Patients treated with a Steinmann pin underwent a median of 2 operations and the pin was left in situ for 80 days. Three patients suffered from superficial wound infection. X-ray showed malreduction in 67% and only two patients returned to pre-injury mobility. A median of 2 operations with 32 fixation days was reported in the external fixation group. This group showed one deep infection. In 50% there was malreduction, one patient experienced disability in ambulation at the end of treatment. CONCLUSION: Both techniques show few complications, but have, as expected, poor results in fracture reduction and functional outcome. External fixation and subsequent internal fixation could result in better functional outcome. PMID- 28672132 TI - Deficient dorsalis pedis flow in severe idiopathic clubfeet: Does Ponseti casting affect the outcome? AB - BACKGROUND: Arterial deficiency in congenital clubfoot or congenital talipes equinovarus (CTEV) was postulated as either the primary cause of deformity or secondary manifestation of other bony and soft tissue abnormalities. The objectives of the study were to find any association between arterial deficiency with severity of CTEV and its treatment. METHOD: This prospective study conducted on 24 feet with CTEV (18 babies) with Pirani score ranging between 2 to 6. Eighteen normal babies (36 feet) were selected as control. We used Color Doppler Ultrasound to assess dorsalis pedis and posterior tibial arteries before initiating the treatment. Second ultrasound was performed in study group upon completion of Ponseti treatment. RESULTS: The patients were from one week to 15 weeks of life. Dorsalis pedis arterial flows were absent in 7 clubfeet (29.1%) while the remaining 17 clubfeet (70.8%) had normal flow. There was a significant association between Pirani severity score and vascular status in congenital clubfoot. There was a higher proportion of clubfeet having abnormal vascularity when the Pirani severity score was 5 and more. In study group, posterior tibial arteries were detectable and patent in all feet. All normal feet in control group had normal arterial flow. There was a significant difference in vascular flow before and after the Ponseti treatment (p 0.031). CONCLUSION: The study concludes that there is an association between Pirani severity score and arterial deficiency in CTEV. Ponseti treatment is safe in CTEV with arterial deficiency and able to reconstitute the arterial flow in majority of cases. PMID- 28672134 TI - Facial Fractures in Patients With Firearm Injuries: Profile and Outcomes. AB - PURPOSE: Firearm injuries (FAIs) are a major public health issue in the United States. The objective of this study was to examine characteristics and outcomes of patients presenting to emergency departments (EDs) with facial fractures attributed to FAIs. MATERIALS AND METHODS: The Nationwide Emergency Department Sample for the years 2008 to 2013 was used. All patients who visited EDs with FAIs and facial fractures were selected. The study focused on the following variables: 1) demographic characteristics, 2) types of facial fractures, 3) disposition status after ED visit or subsequent hospitalization, 4) charges (ED and hospitalization), and 5) patient outcomes. The inclusion criteria were a visit to a hospital-based ED with facial fractures and an external cause of FAI. Descriptive statistics were used to summarize findings. Multivariate logistic regression analysis was used to examine the simultaneous effects of patient related factors on ED death. RESULTS: During the study period, a total of 15,469 patients (mean age, 34 years) visited hospital-based EDs with facial fractures attributed to FAIs. Most were uninsured male patients. The most common etiology of FAIs was assault. The most common facial fractures were open mandibular fractures and open maxillary and/or malar bone fractures. Approximately 27% of patients had a concomitant intracranial injury. After the ED visit, 74% were admitted. The mean ED charge per patient was $6,403, and the total ED charge across the United States was $76.48 million. The mean hospitalization charge per patient was $167,203. The total hospitalization charge across the United States was $1.9 billion. Patients with intracranial injuries (odds ratio [OR], 21.21; 95% confidence interval [CI], 7.16 to 62.85; P < .01), uninsured patients (OR, 4.24; 95% CI, 1.44 to 12.51; P < .01), and patients residing in areas with high household incomes (OR, 5.60; 95% CI, 2.51 to 12.46; P < .01) were high-risk groups for ED death. CONCLUSIONS: FAIs require substantial resources for stabilization and treatment by EDs. This study highlights the burden and impact of facial fractures in patients with FAIs in the United States. PMID- 28672135 TI - Local Application of Platelet-Rich Fibrin During Lower Third Molar Extraction Improves Treatment Outcomes. AB - PURPOSE: Application of platelet-rich fibrin (PRF) during tooth extraction is able to accelerate wound healing, stimulate osseous and soft tissue regeneration, and reduce unwanted side effects. The aim of this meta-analysis was to investigate the effect of local application of PRF on controlling postoperative signs and symptoms after the extraction of an impacted lower third molar. MATERIALS AND METHODS: A systematic search of PubMed, Web of Science, Embase, and the Cochrane Library was performed to identify all studies published up to October 2016 that investigated the effect of PRF on lower third molar extraction. Pain, swelling, trismus, alveolar osteitis (AO), and osteoblastic activity were extracted to evaluate the effect of PRF. After quality assessment, meta-analysis was performed with RevMan software (version 5.3; Cochrane Library Software, Oxford, UK). RESULTS: After the search and selection process, 10 studies were selected in this meta-analysis, including 468 cases of PRF application and 467 cases of non-PRF application. Of the studies, 9 were randomized controlled trials, including 7 split-mouth studies, and there was 1 retrospective case control study. The results indicated that PRF significantly relieves pain (P = .01) and 3-day postoperative swelling (P = .03) and reduces the incidence of AO (P < .0001). However, there were no significant differences between the PRF and non-PRF groups with respect to 1-day postoperative swelling and osteoblastic activity. CONCLUSIONS: Local application of PRF after lower third molar extraction is a valid method for relieving pain and 3-day postoperative swelling and reducing the incidence of AO. For patients undergoing complicated surgical extraction, PRF might be a recommendation for local application into the sockets. PMID- 28672136 TI - Comparison of Changes in Respiratory Dynamics Immediately After the Start of Propofol Sedation With or Without Midazolam. AB - PURPOSE: The aim of this study was to compare changes in respiratory dynamics starting immediately after administration of propofol alone or a combination of propofol and midazolam. MATERIALS AND METHODS: Twenty-seven healthy adult volunteers participated in a randomized crossover study of undergoing sedation with propofol alone (P group) or with a combination of propofol and midazolam (PM group). In the P group, continuous infusion of propofol through a target controlled infusion (TCI) pump was started with the target effect site (ES) concentration set at 1.2 MUg/mL. In the PM group, participants received a bolus administration of midazolam 0.02 mg/kg simultaneously with the start of continuous infusion of propofol through a TCI pump with the target ES concentration set at 0.8 MUg/mL. The variables measured included the bispectral index (BIS) value, tidal volume (VT), percutaneous arterial oxygen saturation (SpO2), respiratory rate (RR), end-tidal carbon dioxide tension (ETCO2), estimated ES propofol concentration, and minute volume. RESULTS: BIS value, VT, SpO2, and ETCO2 decreased after sedative administration in the 2 groups. RR increased in the 2 groups. These changes occurred sooner in the PM group than in the P group. The ratio of change in VT to change in BIS value decreased in the 2 groups and was markedly smaller in the PM group than in the P group. Ratios of changes in SpO2, RR, and ETCO2 to change in BIS value increased in the 2 groups and were larger in the PM group than in the P group. CONCLUSION: Changes in respiratory dynamics occurred sooner in the PM group than in the P group. In the PM group, although VT began to decrease before the change in BIS value, the increase in RR caused the rate of decrease in SpO2 to be smaller than the rate of decrease in BIS value. PMID- 28672137 TI - Mandibular Rami Implant: A New Approach in Mandibular Reconstruction. AB - PURPOSE: The mandible is an essential esthetic and functional component of the lower third of the face and its reconstruction has always been a challenge, especially after severe post-traumatic injuries. The purpose of the present report was to introduce a new approach of mandibular reconstruction in a patient who had lost the entire mandible except for the rami after being severely injured in a blast. MATERIALS AND METHODS: A new approach using a titanium mandibular rami implant technique was applied using computer-aided 3-dimensional virtual planning and rapid prototyping technology. A prosthetic component was supported by the mandibular implant, which achieved occlusion and dedicated function for the patient. RESULTS: This method offered precise adaptation of the implant and prosthesis and an easier surgical procedure, providing a shortened operation time, no donor site morbidity, and more predictable outcomes. CONCLUSION: This new technique allows reconstruction of large-scale mandibular defects that is not possible by conventional surgical methods. PMID- 28672138 TI - Does the Surgery-First Approach Produce Better Outcomes in Orthognathic Surgery? A Systematic Review and Meta-Analysis. AB - PURPOSE: The surgery-first approach (SFA) in orthognathic surgery, performed without presurgical orthodontic treatment, has gained attention, but the results remain controversial. The purpose of this study was to assess the current evidence on stability, efficacy, and surgical results of SFA versus conventional 3-stage method (CTM) orthognathic surgery. MATERIALS AND METHODS: A comprehensive search in PubMed and Web of Science was conducted. A systematic review and cumulative meta-analysis of all comparative studies were performed to assess the 2 strategies (SFA and CTM) using a random- or a fixed-effects model. Outcomes included treatment duration, postoperative stability, surgical movement, and postoperative occlusion. RESULTS: Ten nonrandomized controlled studies including 513 patients were identified. Compared with CTM, patients in the SFA group benefited from shorter total treatment duration (weighted mean difference [WMD], 5.25; 95% confidence interval [CI], -8.21 to -2.29; P = .0005), similar postoperative stability of the mandible (WMD, 0.35 mm; 95% CI, -0.24 to 0.94; P = .55) and maxilla (WMD, 0.13 mm; 95% CI, -0.35 to 0.60; P = .60), similar surgical movements, and other surgical results. CONCLUSIONS: SFA offers an efficient alternative to CTM with shorter total treatment duration, similar postoperative stability, and other surgical results but longer postoperative orthodontic time. PMID- 28672139 TI - Management of Surgical Third Lower Molar Extraction and Postoperative Progress in Patients With Factor VII Deficiency: A Clinical Protocol and Focus on This Rare Pathologic Entity. AB - PURPOSE: The purpose of the present study was to analyze the management of surgical third molar extraction and postoperative progress in patients with a diagnosis of factor VII deficiency. Close collaboration between the oral maxillofacial surgeon and hematologist will allow the team to categorize the risk and operate safely, thereby minimizing the incidence and severity of intraoperative and postoperative complications. MATERIALS AND METHODS: The present retrospective study included 7 patients with factor VII deficiency who had undergone third lower molar surgery. Their factor VII deficiency ranged from 10.5 to 21.0%. Recombinant activated factor VII (rFVIIa) (coagulation factor VIIa [recombinant]; NovoSeven RT; Novo Nordisk, Bagsvaerd, Denmark) was transfused intravenously in a single dose of 25 MUg/kg body weight, 30 minutes before surgical extractions. After the surgery, betamethasone, an analgesic, and an ice pack were administered. RESULTS: Pretreatment with recombinant activated factor VII resulted in excellent hemostasis. No hemorrhagic complications and no postoperative major bleeding were observed. CONCLUSIONS: The extraction of the third lower molar appears to be a safe procedure for patients with factor VII deficiency when appropriate prophylaxis with rFVIIa is used. PMID- 28672140 TI - Evaluation of Oral and Maxillofacial Surgery Residents' Operative Skills: Feasibility and Engagement Study Using SIMPL Software for a Mobile Phone. AB - PURPOSE: There are no universally accepted tools to evaluate operative skills of surgical residents in a timely fashion. The purpose of this study was to determine the feasibility of using a smartphone application, SIMPL (System for Improving and Measuring Procedural Learning), developed by a multi-institutional research collaborative, to achieve a high rate of timely operative evaluations and resident communication and to collect performance data. The authors hypothesized that these goals would be achieved because the process is convenient and efficient. MATERIALS AND METHODS: This was a prospective feasibility and engagement study using SIMPL to evaluate residents' operative skills. SIMPL requires the attending surgeon to answer 3 multiple-choice questions: 1) What level of help (Zwisch Scale) was required by the trainee? 2) What was the level of performance? 3) How complex was the case? The evaluator also can dictate a narrative. The sample was composed of 3 faculty members and 3 volunteer senior residents. Predictor variables were the surgeons, trainees, and procedures performed. Outcome variables included number and percentage of procedures performed by faculty-and-resident pairs assessed, time required to complete assessments, time lapsed to submission, percentage of assessments with narratives, and residents' response rates. RESULTS: From March through June 2016, 151 procedures were performed in the operating room by the faculty-and-resident teams. There were 107 assessments submitted (71%). Resident response (self assessment) to faculty evaluations was 81%. Recorded time to complete assessments (n = 75 of 107) was shorter than 2 minutes. The time lapsed to submission was shorter than 72 hours (100%). Dictations were submitted for 35 evaluations (33%). Data for the type of help, performance, and complexity of cases were collected for each resident. CONCLUSIONS: SIMPL facilitates timely intraoperative evaluations of surgical skills, engagement by faculty and residents, and collection of detailed procedural data. Additional prospective trials to assess this tool further are planned. PMID- 28672141 TI - Patient Recall of Information on a Third Molar Informed Consent Video. AB - PURPOSE: Experience has shown that in malpractice cases patients often claim certain information was not provided during the informed consent process. The purposes of this study were to determine how much of an informed consent video patients initially remember and how much is recalled when there is a hiatus from viewing the video to the surgery. PATIENTS AND METHODS: In this prospective cohort study, patients presenting for impacted third molar removal in an academic setting (n = 50) or a private office (n = 50) viewed an informed consent video and then met with the treating doctor for further discussion and signing of an informed consent form. Then, they were given a 10-item test containing questions relating to the information provided on the video. At the subsequent time of surgery, they were again given the same test. The number of correct answers at the 2 points was compared. RESULTS: There was a significant difference in the number of correct responses between the 2 time points (P = .0212) and between patients from the 2 practice settings (P = .0076). However, these differences were less than 0.5 of a possible 10. The number of correct responses was not associated with age (P = .1203), gender (P = .6647), or number of days between testing (P = .7272). CONCLUSION: Patients have good recall of the information provided by the informed consent video. However, because some information was forgotten, a presurgical review of the information is advisable. PMID- 28672142 TI - How Effective Is the Tent Screw Pole Technique Compared to Other Forms of Horizontal Ridge Augmentation? AB - PURPOSE: The tent screw pole technique is one of the methods available for practitioners to perform horizontal ridge augmentation to facilitate dental implant placement. The purpose of this study was to evaluate the efficacy of the tent screw pole technique for horizontal ridge augmentation and to compare the results with those of the tunnel technique and open ridge augmentation. PATIENTS AND METHODS: In this retrospective cohort study, 35 patients underwent horizontal ridge augmentation with the tent screw pole technique, a 1:1 ratio of mineralized freeze-dried bone allograft and particulate bovine hydroxyapatite, and a resorbable collagen membrane. The incidence of early wound dehiscence and membrane exposure, the number of courses of antibiotics and postoperative visits required for their management, and the number of sites that subsequently had successful implant placement were recorded. These parameters were compared with those in 21 patients who had undergone horizontal ridge augmentation by the tunnel technique and 31 patients who had been treated using an open procedure and a resorbable polytetrafluoroethylene (PTFE) membrane in the authors' previous study (J Oral Maxillofac Surg 74:1752, 2016). RESULTS: Implant placement rate was similar for all 3 methods (71 to 97%). However, there were significant differences among the 3 surgical techniques for membrane exposure and wound dehiscence (P = .0033), graft loss (P = .0256), courses of antibiotics (P = .0017), and postoperative visits (P = .0043). The PTFE method consistently had the highest rate of complications, whereas the tent screw and tunnel techniques were comparable. CONCLUSIONS: All 3 techniques allowed a high rate of implant placement; however, the PTFE technique was consistently associated with increased postoperative complications compared with the other 2 methods. The tent screw technique might be more favorable than the tunnel technique in cases in which the bony deficiency is flat. PMID- 28672143 TI - Synthesis, characterization and crystal structures of two pentagonal-bipyramidal Fe(III) complexes with dihydrazone of 2,6-diacetylpyridine and Girard's T reagent. Anticancer properties of various metal complexes of the same ligand. AB - : In this work synthesis, characterization and crystal structures of two isothiocyanato Fe(III) complexes with 2,2'-[2,6-pyridinediylbis(ethylidyne-1 hydrazinyl-2-ylidene)]bis[N,N,N-trimethyl-2-oxoethanaminium] dichloride (H2LCl2) ligand, with composition [FeL(NCS)2]SCN.2H2O and [FeL(NCS)2]2[Fe(H2O)(NCS)5].4H2O, has been reported. Both iron(III) complexes possess the same pentagonal-bipyramidal complex cation, while the nature of their anions depends on mole ratio of NH4SCN and FeCl3.6H2O used in reaction. Cytotoxic activity of new Fe(III) complexes, as well as of previously synthesized isothiocyanato Co(II), Ni(II), Mn(II), Zn(II) and Cd(II) complexes with the same ligand, was tested against five human cancer cell lines (HeLa, MDA-MB-453, K562, LS174 and A549) and normal cell line MRC-5. The best activity was observed in the case of Fe(III), Co(II) and Cd(II) complexes. The investigation of potential of these complexes to induce HeLa and K562 cell cycle perturbations was also evaluated. Mechanism of cell death mode was elucidated on the basis of morphological changes of HeLa cells as well as identification of target caspases. It was established that DNA damage could be responsible for the activity of Fe(III) and Co(II) complexes. SYNOPSIS: Pentagonal-bipyramidal Fe(III) complexes with dihydrazone of 2,6-diacetylpyridine and Girard's T reagent have been synthesized and characterized. Cytotoxic activity of Fe(III) complexes and Co(II), Ni(II), Mn(II), Zn(II) and Cd(II) complexes with the same ligand was tested. The best activity was observed in the case of Fe(III), Co(II) and Cd(II) complexes. PMID- 28672144 TI - Zn(II) - pramlintide: Stability, binding sites and unexpected aggregation. AB - Pramlintide is an antidiabetic drug which mimics amylin - a small peptide co secreted from pancreatic beta-cells together with insulin, one of the hallmarks of type 2 diabetes. In the course of the disease, amylin misfolds into small oligomers or to an aggregated beta-sheet amyloid fiber. The misfolding mechanism is not yet quite understood, but it is clear that zinc ions play an important role in the process. This work sheds new light on the role of zinc and pramlintide in the course of the disease, giving a detailed description of the Zn(II)-pramlintide complex, in which the metal ion binds to the imidazole of His18 and the amine group of Lys1, imposing a bend in the peptide between these residues. The most surprising finding is the fact that the initially well soluble, non-aggregating Zn(II)-pramlintide complex forms fibrillar, oligomeric aggregates after a lag-time of 20h. This raises more questions about the relationship between Zn(II) and amylin/pramlintide: could this zinc-induced change in the complex structure be a partial explanation of the formation of oligomeric aggregates of the complex, which might be much more toxic to beta cells than large fibrillar deposits and if so, is pramlintide the optimal choice of an antidiabetic drug? PMID- 28672145 TI - Lactate and lactate clearance as valuable tool to evaluate ECMO therapy in cardiogenic shock. AB - PURPOSE: ECMO support is an ultimate ratio therapy for patients in refractory cardiogenic shock and is linked to high mortality. We assessed the dynamic characteristics of lactate during ECMO therapy and its predictive role on 30-day mortality. MATERIALS AND METHODS: Data were retrospectively collected in all patients receiving ECMO support longer than 48h for cardiogenic shock from 01/2008 to 12/2016. Blood lactate was recorded before ECMO implantation, at prespecified timepoints during ECMO support, 1h and 6h post-ECMO as well as peak lactate during ECMO and peak within 24h after ECMO support. Statistical analysis included t-test and ROC-curves to identify cut-off levels for lactate levels to predict 30-day mortality. RESULTS: 139 patients underwent ECMO therapy longer than 48h for refractory cardiogenic shock resulting in a 30-day mortality of 68%. Lactate before ECMO and peak lactate level during ECMO support showed no significant connection to mortality, while lactate and lactate clearance at 24h were predictive for 30-day mortality with cut-off values of 2.15mmol/l and 0.687 respectively. CONCLUSIONS: Dynamic course of lactate during ECMO therapy is a valuable tool to assess effective circulatory support and is superior to single lactate measurements as a predictive marker for 30-day mortality. PMID- 28672146 TI - Stroke volume guided resuscitation in severe sepsis and septic shock improves outcomes. AB - To determine whether stroke volume (SV) guided fluid resuscitation in patients with severe sepsis and septic shock alters Intensive Care Unit (ICU) fluid balance and secondary outcomes, this retrospective cohort study evaluated consecutive patients admitted to an ICU with the primary diagnosis of severe sepsis or septic shock. Cohorts were based on fluid resuscitation guided by changes in SV or by usual care (UC). The SV group comprised 100 patients, with 91 patients in the UC group. Net fluid balance for the ICU stay was lower in the SV group (1.77L) than in the UC group (5.36L) (p=0.022). ICU length of stay was 2.89days shorter (p=0.03) and duration of vasopressors was 32.8h less (p=0.001) in the SV group. SV group required less mechanical ventilation (RR, 0.51; p=0.0001). The SV group was less likely to require acute hemodialysis (6.25%) compared with the UC group (19.5%) (RR, 0.32; p=0.01). In multivariable analysis, SV was an independent predictor of lower fluid balance, LOS, time on vasopressors, and not needing mechanical ventilation. This study demonstrated that SV guided fluid resuscitation in patients with severe sepsis and septic shock was associated with reduced fluid balance and improved secondary outcomes. PMID- 28672147 TI - Children's exposure to alcohol marketing within supermarkets: An objective analysis using GPS technology and wearable cameras. AB - BACKGROUND AND AIM: Exposure to alcohol marketing within alcohol retailers has been associated with higher rates of childhood drinking, brand recognition, and marketing recall. This study aimed to objectively measure children's everyday exposure to alcohol marketing within supermarkets. METHOD: Children aged 11-13 (n = 167) each wore a wearable camera and GPS device for four consecutive days. Micro-spatial analyses were used to examine exposures within supermarkets. RESULTS: In alcohol retailing supermarkets (n = 30), children encountered alcohol marketing on 85% of their visits (n = 78). Alcohol marketing was frequently near everyday goods (bread and milk) or entrance/exit. CONCLUSION: Alcohol sales in supermarkets should be banned in order to protect children from alcohol marketing. PMID- 28672148 TI - Perfluorinated substances and telomeres in an Arctic seabird: Cross-sectional and longitudinal approaches. AB - Telomeres are non-coding DNA repeats located at the termini of eukaryotic chromosomes, regulated by dynamic processes balancing shortening and maintenance. Despite a mechanism to slow-down telomere shortening, cell division leads to progressive attrition of chromosomes, leading to the onset of cellular senescence or apoptosis. However, telomere restoration based on telomerase activity is the primary mechanism for telomere maintenance. Telomere length is associated to health and survival and can be impacted by a broad panel of environmental factors. However, the effect of contaminants on telomeres is poorly known for living organisms. The aim of this study was to investigate relationships between some poly- and perfluoroalkyl substances (PFASs), body condition and telomere length by using both a cross-sectional and longitudinal approach in adult breeding Black-legged kittiwakes (Rissa tridactyla) from Svalbard. First, we examined the associations between absolute telomere length and PFASs contamination in a given year (cross-sectional approach). Second, we investigated the relationships between telomere dynamics and PFASs contamination within a two years' time frame (longitudinal approach). Our results did not show any significant relationships of PFASs and body condition with absolute telomere length in a given year. Surprisingly, we found a positive and significant relationship between PFASs and telomere dynamics in both sexes with elongated telomere in birds bearing the highest concentrations of PFASs. Our study underlines (i) the need to investigate PFAS effects on telomere dynamics with a longitudinal approach and (ii) a potential positive effect of these contaminants on telomere length, with the most contaminated birds showing the slowest rate of telomere shortening or even displaying elongated ones. Our study is the first to report a relationship between PFASs and telomere length in free-living vertebrates. A possible underlying mechanism and other potential confounding factors are discussed. PMID- 28672149 TI - Enantiomeric profiling of a chemically diverse mixture of chiral pharmaceuticals in urban water. AB - Due to concerns regarding the release of pharmaceuticals into the environment and the understudied impact of stereochemistry of pharmaceuticals on their fate and biological potency, we focussed in this paper on stereoselective transformation pathways of selected chiral pharmaceuticals (16 pairs) at both microcosm (receiving waters and activated sludge wastewater treatment simulating microcosms) and macrocosm (wastewater treatment plant (WWTP) utilising activated sludge technology and receiving waters) scales in order to test the hypothesis that biodegradation of chiral drugs is stereoselective. Our monitoring programme of a full scale activated sludge WWTP and receiving environment revealed that several chiral drugs, those being marketed mostly as racemates, are present in wastewater and receiving waters enriched with one enantiomeric form (e.g. fluoxetine, mirtazapine, salbutamol, MDMA). This is most likely due to biological metabolic processes occurring in humans and other organisms. Both activated sludge and receiving waters simulating microcosms confirmed our hypothesis that chiral drugs are subject to stereoselective microbial degradation. It led, in this research, to preferential degradation of S-(+)-enantiomers of amphetamines, R-(+)-enantiomers of beta-blockers and S-(+)-enantiomers of antidepressants. In the case of three parent compound - metabolite pairs (venlafaxine - desmethylvenlafaxine, citalopram - desmethylcitalopram and MDMA - MDA), while parent compounds showed higher resistance to both microbial metabolism and photodegradation, their desmethyl metabolites showed much higher degradation rate both in terms of stereoselective metabolic and non-stereoselective photochemical processes. It is also worth noting that metabolites tend to be, as expected, enriched with enantiomers of opposite configuration to their parent compounds, which might have significant toxicological consequences when evaluating the metabolic residues of chiral pollutants. PMID- 28672150 TI - Comparative toxicity and endocrine disruption potential of urban and rural atmospheric organic PM1 in JEG-3 human placental cells. AB - Outdoor ambient air particulate matter and air pollution are related to adverse effects on human health. The present study assesses the cytotoxicity and ability to disrupt aromatase activity of organic PM1 extracts from rural and urban areas at equivalent air volumes from 2 to 30 m3, in human placental JEG-3 cells. Samples were chemically analyzed for particle bounded organic compounds with endocrine disrupting potential, i.e. PAH, O-PAH, phthalate esters, but also for organic molecular tracer compounds for the emission source identification. Rural samples collected in winter were cytotoxic at the highest concentration tested and strongly inhibited aromatase activity in JEG-3 cells. No cytotoxicity was detected in summer samples from the rural site and the urban samples, while aromatase activity was moderately inhibited in these samples. In the urban area, the street site samples, collected close to intensive traffic, showed stronger inhibition of aromatase activity than the samples simultaneously collected at a roof site, 50 m above ground level. The cytotoxicity and endocrine disruption potential of the samples were linked to combustion products, i.e. PAH and O-PAH, especially from biomass burning in the rural site in winter. PMID- 28672151 TI - Maternal exposure to air pollutants during the first trimester and foetal growth in Japanese term infants. AB - Evidence supporting an inverse association between maternal exposure to air pollutants and foetal growth has been accumulating. However, the findings from Asian populations are limited, and the question of critical windows of exposure remains unanswered. We examined whether maternal exposure to air pollutants, in particular exposure during the first trimester (an important period of placental development), was associated with foetal growth in Japanese term infants. From the Japan Perinatal Registry Network database, we received birth data for 29,177 term singleton births in western Japan (Kyushu-Okinawa Districts) between 2005 and 2010. Exposure was expressed in terms of average concentrations of air pollutants (ozone, suspended particulate matter, nitrogen dioxide, and sulphur dioxide), as measured at the nearest monitoring stations to the respective delivery hospitals of the pregnant women, during the entire pregnancy and each trimester. As proxy markers of foetal growth restriction, we used small for gestational age (SGA), and adverse birth weight (low birth weight in addition to SGA). For pollutant exposure during the entire pregnancy, we did not observe the association with SGA and adverse birth weight. In the single-trimester model for the first trimester, however, we found a positive association between ozone exposure, and SGA (odds ratio [OR] per 10 ppb increase = 1.07, 95% confidence interval [CI] = 1.01-1.12) and adverse birth weight (OR = 1.07; 95% CI = 1.01 1.14). This association persisted in the multi-trimester model, and no association for exposure during the second or third trimester was observed. Exposure to other pollutants during each trimester was not associated with these outcomes. In conclusion, maternal exposure to ozone during the first trimester was independently associated with an elevated risk of poor foetal growth. PMID- 28672152 TI - Anthracene and benzo(a)pyrene degradation in soil is favoured by compost amendment: Perspectives for a bioremediation approach. AB - In order to validate the use of compost in soil PAH bioremediation, the degradation of anthracene and benzo(a)pyrene was monitored in soils artificially contaminated and incubated in mesocosms under controlled conditions. The dynamics observed in compost amended soil were compared to those observed in soil added with a fungal consortium and untreated soil. At the same time, three microbial enzyme activities usually involved in PAH degradation (laccase, o-diphenol oxidase and peroxidase activities) were monitored. Both PAHs decreased along the time in the three mesocosms, with anthracene, with lower molecular weight, degrading with a higher rate and reaching lower residual values than benzo(a)pyrene. Although at the end of incubation, the residual values of investigated PAHs are similar in the three mesocosm types, PAH dynamics showed a higher degradation rate in the early stage in mesocosms added with the fungal mycelium and amended with compost. Among the three enzyme activities, only peroxidase showed higher values in treated than untreated mesocosms. Considering the ameliorating effects of compost on degraded soils, its use can be suggested in PAH bioremediation. PMID- 28672153 TI - Theoretical study on stabilization mechanisms of nitrate esters using aromatic amines as stabilizers. AB - The propellants of nitrate esters can be stabilized by some aromatic amines practically. To probe the mechanism of this phenomenon, we performed DFT calculations on: (1) The decompositions of nitrate esters (with and without the catalysis of NO2) and (2) the reaction between the stabilizers and the nitro dioxide (NO2 is released during the storage of nitrate esters). The structures on the reaction paths (reactants, intermediates and products) were optimized at the (U)B3LYP/6-31G** level. It was shown that NO2 lowers the activation energy barrier in the decomposition of nitrate ester by 11.82-17.86kJ/mol and efficiently catalyzes the rupture of ONO2 bond. However, the aromatic amines, typical stabilizers for nitrate esters, can easily eliminate NO2 with activation barriers as low as 27-113kJ/mol (with one exception of 128kJ/mol). These values are, for most cases, lower or much lower than the activation energy barriers for reactions between nitrate esters and NO2 (127-137kJ/mol). Consequently, the stabilizers can block the NO2 catalysis for the decompositions of nitrate esters. PMID- 28672154 TI - Gait adaptations with aging in healthy participants and people with knee-joint osteoarthritis. AB - The relationship between age and gait characteristics in people with and without medial compartment osteoarthritis (OA) remains unclear. We aimed to characterize this relationship and to relate biomechanical and structural parameters in a subset of OA patients. Twenty five participants with diagnosed unilateral medial knee OA and 84 healthy participants, with no known knee pathology were recruited. 3D motion capture was used to analyse sagittal and coronal plane gait parameters while participants walked at a comfortable speed. Participants were categorized according to age (18-30, 31-59 and 60+ years), and those with and without OA were compared between and within age groups. In a subset of OA patients, clinically available Computed Tomography images were used to assess joint structure. Differences in coronal plane kinematics at the hip and knee were noted in participants with OA particularly those who were older compared with our healthy controls, as well as increased knee moments. Knee adduction moment correlated with structural parameters in the subset of OA patients. Increased knee moments and altered kinematics were observed in older participants presenting with OA only, which seem to be related to morphological changes in the joint due to OA, as opposed to being related to the initial cause of medial knee OA. PMID- 28672155 TI - The interplay of parental monitoring and socioeconomic status in predicting minor delinquency between and within adolescents. AB - This six-wave multi-informant longitudinal study on Dutch adolescents (N = 824; age 12-18) examined the interplay of socioeconomic status with parental monitoring in predicting minor delinquency. Fixed-effects negative binomial regression analyses revealed that this interplay is different within adolescents across time than between adolescents. Between individuals, parental solicitation and control were not significantly associated with delinquency after controlling for SES: Adolescents whose parents exercised more monitoring did not offend less than others. Within individuals, higher levels of parental control were unexpectedly associated with more delinquency, but this relation was dependent on SES: Low-SES adolescents, but not high-SES adolescents, offended more during periods in which their parents exercised more control than during other periods with less control. In contrast to earlier work, this finding suggests that monitoring could be least effective when needed most. Low-SES parents might not use monitoring effectively and become overcontrolling when their child goes astray. PMID- 28672156 TI - Evidence for a retinal progenitor cell in the postnatal and adult mouse. AB - Progress in cell therapy for retinal disorders has been challenging. Recognized retinal progenitors are a heterogeneous population of cells that lack surface markers for the isolation of live cells for clinical implementation. In the present application, our objective was to use the stem cell factor receptor c-Kit (CD117), a surface marker, to isolate and evaluate a distinct progenitor cell population from retinas of postnatal and adult mice. Here we report that, by combining traditional methods with fate mapping, we have identified a c-Kit positive (c-Kit+) retinal progenitor cell (RPC) that is self-renewing and clonogenic in vitro, and capable of generating many cell types in vitro and in vivo. Based on cell lineage tracing, significant subpopulations of photoreceptors in the outer nuclear layer and bipolar, horizontal, amacrine and Muller cells in the inner nuclear layer are the progeny of c-Kit+ cells in vivo. The RPC progeny contributes to retinal neurons and glial cells, which are responsible for the conversion of light into visual signals. The ability to isolate and expand in vitro live c-Kit+ RPCs makes them a future therapeutic option for retinal diseases. PMID- 28672157 TI - The P2X7 receptor is an upstream regulator of dynamic blebbing and a pluripotency marker in human embryonic stem cells. AB - New methods are needed to reduce dynamic blebbing which inhibits cell attachment and survival during passaging of pluripotent stem cells. We tested the hypothesis that activation of the P2X7 receptor by extracellular ATP during passaging initiates dynamic blebbing. The P2X7 receptor was present in human embryonic stem cells (hESC), but not in differentiating cells. Extracellular ATP concentrations were 14* higher in medium during passaging. Addition of ATP to culture medium prolonged dynamic blebbing and inhibited attachment. Inhibition of P2X7 by specific drugs or by siRNA significantly reduced dynamic blebbing and improved cell attachment. When cells were incubated in calcium chelators (EGTA or BAPTA), blebbing decreased and attachment improved. Calcium influx was observed using Fura-4 when ATP was added to culture medium and inhibited in the presence of the P2X7 inhibitor. Over-expressing activated Rac in hESC reduced blebbing and promoted cell attachment, while a Rac inhibitor prolonged blebbing and reduced attachment. These data identify a pathway involving P2X7 that initiates and prolongs dynamic blebbing during hESC passaging. This pathway provides new insight into factors that increase dynamic blebbing and identifies new targets, such as P2X7, that can be used to improve the culture of cells with therapeutic potential. PMID- 28672158 TI - Biphasic attentional orienting triggered by invisible social signals. AB - Biological motion (BM) is one of the most important social cues for detecting conspecifics, prey, and predators. We show that unconscious BM processing can reflexively direct spatial attention, and that this effect has a biphasic temporal profile. Participants responded to probes that were preceded by intact or scrambled BM cues rendered invisible through continuous flash suppression. With a short inter-stimulus interval (ISI, 100ms) between the invisible BM cues and the probe, responses to probes at the same location as the invisible, nonpredictive BM cue were faster than to probes at the location of the scrambled BM cue. With a longer ISI (800ms) this effect reversed, with slower responses to probes at the location of the invisible, nonpredictive BM. These effects were absent when BM and its scrambled control were made visible with both short and long cue durations across variable length of ISIs, indicating that the saliency of BM itself cannot account for the dynamic orienting effects from invisible social cues. Moreover, this dynamic attentional shifts were specific to upright BM cues and not obtained for inverted stimuli. Thus, this reflexive and dynamic attentional modulation triggered by invisible BM, with initial facilitation followed by inhibition, demonstrates that in the complete absence of conscious awareness, cue predictiveness, and saliency differences, attentional systems promote exploration of our visual environment for social signals. PMID- 28672159 TI - Viruses as vectors of horizontal transfer of genetic material in eukaryotes. AB - Horizontal transfer (HT) of genetic material, mainly transposable elements, is increasingly recognized as an important factor shaping eukaryote genomes. Yet our understanding of the mechanisms and vectors underpinning these transfers is still limited. It has been proposed that such transfers may be facilitated by viruses, because they typically inject their genomes into host cells to replicate and they can be horizontally transmitted between their hosts. Recent evidence from high throughput sequencing of viral populations and paleovirology shows that both virus-to-host and host-to-virus gene flow can be common in a variety of eukaryote lineages. We argue that such studies reinforce the hypothesis of viruses as major vectors of HT in eukaryotes. PMID- 28672160 TI - Origin of the retroviruses: when, where, and how? AB - Retroviruses are a virus family of considerable medical and veterinary importance. Additionally, it is now clear that endogenous retroviruses (ERVs) comprise significant portions of vertebrate genomes. Until recently, very little was known about the deep evolutionary origins of retroviruses. However, advances in genomics and bioinformatics have opened the way for great strides in understanding. Recent research employing a wide variety of bioinformatic approaches has demonstrated that retroviruses evolved during the early Palaeozoic Era, between 460 and 550 million years ago, providing the oldest inferred date estimate for any virus group. This finding presents an important framework to investigate the evolutionary transitions that led to the emergence of the retroviruses, offering potential insights into the infectious origins of a major group of pathogenic viruses. PMID- 28672162 TI - Interaction studies of polybrominated diphenyl ethers (PBDEs) with human serum albumin (HSA): Molecular docking investigations. AB - This work has evaluated the interactions of HSA and typical PBDEs (BDE47, BDE99, BDE100, BDE153 and BDE209) at molecular level by modelling. Apart from the BDE209, PBDEs with higher molecular weight show higher binding energy with the residues of HSA. The BDE209 without H atoms has the lowest binding energy ( DeltaGbinding: 4.30calmol-1) than other PBDEs (-DeltaGbinding: 7.93-8.42calmol 1). The BDE99 shows a higher binding energy than its isomer (BDE100). On the other hand, the lgKow-depth plotting figure shows that a higher Kow value (hydrophobicity) of PBDEs is accompanied by a deeper binding site within the central channel of HSA. This work may provide a theoretical method to assess the transport and distribution of PBDEs in human body. PMID- 28672161 TI - Polintons, virophages and transpovirons: a tangled web linking viruses, transposons and immunity. AB - Virophages are satellite DNA viruses that depend for their replication on giant viruses of the family Mimiviridae. An evolutionary relationship exists between the virophages and Polintons, large self-synthesizing transposons that are wide spread in the genomes of diverse eukaryotes. Most of the Polintons encode homologs of major and minor icosahedral virus capsid proteins and accordingly are predicted to form virions. Additionally, metagenome analysis has led to the discovery of an expansive family of Polinton-like viruses (PLV) that are more distantly related to bona fide Polintons and virophages. Another group of giant virus parasites includes small, linear, double-stranded DNA elements called transpovirons. Recent in-depth comparative genomic analysis has yielded evidence of the origin of the PLV and the transpovirons from Polintons. Integration of virophage genomes into genomes of both giant viruses and protists has been demonstrated. Furthermore, in an experimental coinfection system that consisted of a protist host, a giant virus and an associated virophage, the virophage integrated into the host genome and, after activation of its expression by a superinfecting giant virus, served as an agent of adaptive immunity. There is a striking analogy between this mechanism and the CRISPR-Cas system of prokaryotic adaptive immunity. Taken together, these findings show that Polintons, PLV, virophages and transpovirons form a dynamic network of integrating mobile genetic elements that contribute to the cellular antivirus defense and host-virus coevolution. PMID- 28672163 TI - Evaluation of whole cigarette smoke induced oxidative stress in A549 and BEAS-2B cells. AB - Cigarette smoke is a complex and oxidative aerosol. Previous researches on the hazards of cigarette smoke mainly focused on the adverse bioeffects induced by its condensates or gas vapor phase, which ignored the dynamic processes of smoking and the cigarette smoke aging. To overcome these disadvantages, we performed air-liquid interface exposure of whole smoke, which used native and unmodified smoke and ensured the exposure similar to physiological inhalation. Our results indicated that whole cigarette smoke induced lung epithelial cells (A549) and bronchial epithelial cells (BEAS-2B) damages in cytotoxicity assays (methyl thiazoly tetrazolium and neutral red uptake assays). In addition, A549 and BEAS-2B cells showed oxidative damages in whole smoke exposure, with concentration change of several biomarkers (reduced and oxidized glutathione, malondialdehyde, 4-hydroxyhydroxy-2-nonenal, extracellular superoxide dismutase, and 8-hydroxyl deoxyguanosine). These results indicate that whole smoke-induced oxidative stress occurs in two different kinds of cells at air-liquid interface. PMID- 28672164 TI - N-glycan structures of beta-HlH subunit of Helix lucorum hemocyanin. AB - The carbohydrate structures of molluscan hemocyanins have recently received particular interest due to their specific monosaccharide composition, as well as their immunostimulatory properties and application in clinical studies. For the first time, we investigated N-glycans of the structural subunit beta-HlH of hemocyanin isolated from Helix lucorum. In total, 32 different glycans were enzymatically liberated and characterized by tandem mass spectrometry using a Q Trap mass spectrometer. Our study revealed a highly heterogeneous mixture of glycans with composition Hex3-7HexNAc2-5MeHex0-4Pent0-1Fuc0-1. The oligosaccharide chains are mostly modified at the inner core by beta1-2-linked xylose to beta-mannose, by alpha1-6-fucosylation of the innermost GlcNAc residue (the Asn-bound GlcNAc), and by methylation. The glycans of beta-HlH mainly contain a terminal MeHex residue; in some cases even two, three or four of these residues occur. Several carbohydrate chains in beta-HlH are core-fucosylated without Xyl and also possess a high degree of methylation. This study shows the presence of mono- and bi-antennary N-glycans as well as hybrid type structures with or without core-fucosylation. PMID- 28672165 TI - Hydrogenolytic cleavage of naphthylmethyl ethers in the presence of sulfides. AB - With the aid of a series of model thioether or thioglycoside containing polyols protected with combinations of benzyl ethers and 2-naphthylmethyl ethers it is demonstrated that the latter are readily cleaved selectively under hydrogenolytic conditions in the presence of the frequently catalyst-poisoning sulfides. These results suggest the possibility of employing 2-naphthylmethyl ethers in place of benzyl ethers in synthetic schemes when hydrogenolytic deprotection is anticipated in the presence of thioether type functionality. PMID- 28672166 TI - Structures and gene clusters of the O-antigens of Escherichia albertii O3, O4, O6, and O7. AB - The O-specific polysaccharides (OPSs) called O-antigens were obtained by mild acid degradation of the lipopolysaccharides of Escherichia albertii serotypes O3, O4, O6, and O7 and studied by sugar analysis along with 1D and 2D 1H and 13C NMR spectroscopy. The following structure was established for the OPS of E. albertii O4, which, to our knowledge, is unique among known bacterial polysaccharide structures: ->2)-alpha-l-Rhap-(1 -> 2)-alpha-l-Fucp-(1 -> 2)-beta-d-Galp-(1 -> 3) alpha-d-GalpNAc-(1 -> 3)-beta-d-GlcpNAc-(1-> The OPS structure of the strain of E. albertii O7 studied was identical to that of strain LMG 20973 (= Albert 10457), whose structure has been reported earlier (R. Eserstam et al. Eur. J. Biochem. 269 (2002) 3289-3295). E. albertii O3 and O6 shared the OPS structures with Escherichia coli O181 and O3, respectively, except for the lack of O acetylation in E. albertii O3, which is present in E. coli O181. The gene clusters driving the O-antigen biosynthesis of the E. albertii strains were sequenced, the genes were annotated by comparison with sequences in the available databases, and the predicted functions of the encoded proteins were found to be consistent with the OPS structures established. In accordance with the relatedness of the OPS structures, the O-antigen gene clusters of E. albertii O3 and O6 contain the same genes and have the same organization as those of E. coli O181 and O3, the entire gene clusters being 83% and 98% identical, respectively. PMID- 28672167 TI - Food for thought: how nutrients regulate root system architecture. AB - The spatial arrangement of the plant root system (root system architecture, RSA) is very sensitive to edaphic and endogenous signals that report on the nutrient status of soil and plant. Signalling pathways underpinning RSA responses to individual nutrients, particularly nitrate and phosphate, have been unravelled. Researchers have now started to investigate interactive effects between two or more nutrients on RSA. Several proteins enabling crosstalk between signalling pathways have recently been identified. RSA is potentially an important trait for sustainable and/or marginal agriculture. It is generally assumed that RSA responses are adaptive and optimise nutrient uptake in a given environment, but hard evidence for this paradigm is still sparse. Here we summarize recent advances made in these areas of research. PMID- 28672169 TI - Simulation in mental health nurse education: The development, implementation and evaluation of an educational innovation. AB - Simulation is an important learning approach for the development of skills for healthcare practice. However, it remains under used in the education of mental health practitioners. This article examines the development, implementation and evaluation of a simulated learning experience for final year undergraduate BSc mental health nursing students in the UK. Scenarios involving managing care in an acute in patient ward and community older persons' team were designed to enable students to develop their complex decision making skills. An evaluation of the simulation experience was undertaken. This was informed by the principles of improvement science methodology and data was collected from the student participants using questionnaires. The findings indicated that simulation provided a realistic environment in which students were able to develop skills and manage clinical situations autonomously without fear of being assessed or making mistakes. Reflecting Dieckmann et al.'s (2007) position that simulation is a social situation in itself, the learning approach enabled mental health students to both experience the safety of the Higher Education setting and also the reality of clinical practice. Simulation may therefore provide an important tool to prepare students for the responsibilities of a qualified nurse. PMID- 28672168 TI - Regulating cellular trace metal economy in algae. AB - As indispensable protein cofactors, Fe, Mn, Cu and Zn are at the center of multifaceted acclimation mechanisms that have evolved to ensure extracellular supply meets intracellular demand. Starting with selective transport at the plasma membrane and ending in protein metalation, metal homeostasis in algae involves regulated trafficking of metal ions across membranes, intracellular compartmentalization by proteins and organelles, and metal-sparing/recycling mechanisms to optimize metal-use efficiency. Overlaid on these processes are additional circuits that respond to the metabolic state as well as to the prior metal status of the cell. In this review, we focus on recent progress made toward understanding the pathways by which the single-celled, green alga Chlamydomonas reinhardtii controls its cellular trace metal economy. We also compare these mechanisms to characterized and putative processes in other algal lineages. Photosynthetic microbes continue to provide insight into cellular regulation and handling of Cu, Fe, Zn and Mn as a function of the nutritional supply and cellular demand for metal cofactors. New experimental tools such as RNA-Seq and subcellular metal imaging are bringing us closer to a molecular understanding of acclimation to supply dynamics in algae and beyond. PMID- 28672170 TI - Bio-inspired engineering of thiopeptide antibiotics advances the expansion of molecular diversity and utility. AB - Thiopeptide antibiotics, which are a class of sulfur-rich and highly modified peptide natural products, exhibit a wide variety of important biological properties. These antibiotics are ribosomally synthesized and arise from post translational modifications, exemplifying a process through which nature develops the structural complexity from Ser/Thr and Cys-rich precursor peptides. Following a brief review of the knowledge gained from nature in terms of the formation of a common thiopeptide scaffold and its specialization to individual members, we highlight the significance of bio-inspired engineering, which has greatly expanded the molecular diversity and utility of thiopeptide antibiotics regarding the search for clinically useful agents, investigation into new mechanisms of action and access to typically 'inaccessible' biosynthetic processes over the past two years. PMID- 28672172 TI - Baseline red blood cell distribution width predicts long-term glycemic remission in patients with type 2 diabetes. AB - AIMS: We explored whether red blood cell distribution width (RDW), a routinely checked item of complete blood cell counts, was an indicator of long-term euglycemia remission in patients with type 2 diabetes after short-term continuous subcutaneous insulin infusion (CSII). METHODS: We analyzed the original data of patients enrolled in three randomized control trials from 2002 to 2014. CSII was administered to drug-naive patients with newly diagnosed type 2 diabetes to achieve and maintain euglycemia for 2weeks. RESULTS: A total of 185 patients were involved and 98 patients (52.97%) who achieved and maintained euglycemia for at least 12months were classified as the remission group, and the others as the non remission group. Patients in remission group had a relatively lower value for baseline RDW (38.82+/-2.76vs 39.89+/-2.78fL, p=0.017) compared with those in non remission group. A graded decrease of remission rate (67.50%, 55.00%, 53.66% and 30.77% for Quartile 1 to Quartile 4 respectively, P<0.05) was observed with the increasing of RDWs. The risk of hyperglycemic relapse was significantly increased for those in the highest quartile compared with the lowest (hazard ratio=2.68; 95% CI, 1.38-5.22). Those who achieved euglycemia within 7days or obtained a better fasting glucose after therapy had preferable remission rates. CONCLUSIONS: Patients with lower baseline RDWs are more likely to maintain a one-year euglycemia remission after short-term CSII. A faster normalization of glucose during treatment and a lower fasting glucose after therapy are correlated with a long-term glucose control. PMID- 28672171 TI - Host determinants of adeno-associated viral vector entry. AB - Viral vectors based on adeno-associated virus (AAV) are leading candidates for therapeutic gene delivery. Understanding rate-limiting steps in the entry of AAV vectors may be used in a rational approach to improve efficiency and specificity of transduction. This review describes our current understanding of AAV entry, a key step during infection. We discuss the identity and functions of AAV receptors and attachment factors, including the recently discovered multi-serotype receptor AAVR. We further provide an overview of other host factors that act during the trafficking stage of AAV vector transduction. In particular, we focus on cellular protein complexes associated with retrograde transport from endosomes to the trans-Golgi network. The novel insights in AAV-host interactions facilitated by technological advances in genetic screening approaches provide a greater depth in our understanding how AAV vectors exploit host factors to deliver its genetic cargo to the nucleus. PMID- 28672173 TI - Prevalence of Verocytotoxigenic Escherichia coli strains isolated from raw beef in southern Italy. AB - Verocytotoxin (VT)-producing Escherichia coli (VTEC) are a significant foodborne public health hazard, where most human infections are associated with six serogroups (O157, O26, O103, O145, O111 and O104). VTEC was the fourth most commonly reported zoonosis in the EU in 2015, with 5901 confirmed human cases. Ruminant animals, including cattle, are a major reservoir of VTEC. The consumption of VTEC-contaminated animal-derived foodstuffs, especially undercooked ground beef, is an important transmission route. To the best of our knowledge, there are few data available on the contamination of VTEC in meat products in Italy. During 2015 and 2016, 250 raw meat samples were collected from retail markets in southern Italy (Apulia) and analysed for the occurrence of vtx genes (vtx1/vtx2) at the Istituto Zooprofilattico Sperimentale della Puglia e della Basilicata (IZS PB, Italy). In addition, the isolates were characterized by determining the presence of VTEC main virulence factors, the antimicrobial resistance profiles and the genetic relatedness by pulsed-field gel electrophoresis (PFGE). The results have shown that 8.4% (21/250) of the samples were positive for vtx genes in the preliminary screening step but VTEC strains were isolated from only 2% (5/250) of overall meat analysed samples, including raw ground beef, beef hamburger and beef carpaccio. 5 isolates displayed a multi drug resistance phenotype. All VTEC strains were analysed by XbaI-PFGE and dendrogram revealed 5 distinct restriction profiles, indicating their relatively high genetic diversity. Although this study demonstrates a low prevalence of VTEC in raw beef marketed in southern Italy, the presence of potentially pathogenic E. coli strains points to the need for proper hygiene during meat production to reduce the risk of foodborne illness and transmission of multi-drug resistant organisms via foods to humans. PMID- 28672174 TI - Characterization of small-spored Alternaria from Argentinean crops through a polyphasic approach. AB - Small-spored Alternaria have been isolated from a wide variety of food crops, causing both economic losses and human health risk due to the metabolites produced. Their taxonomy has been discussed widely, but no scientific consensus has been established in this field to date. Argentina is a major exporter of agricultural products, so it is essential to thoroughly understand the physiological behaviour of this pathogen in a food safety context. Thus, the objective of this work was to characterize small-spored Alternaria spp. obtained from tomato fruits, pepper fruits, wheat grains and blueberries from Argentina by a polyphasic approach involving metabolomic and phylogenetic analyses based on molecular and morphological characters. Morphological analysis divided the population studied into three groups; A. arborescens sp.-grp., A. tenuissima sp. grp., and A. alternata sp.-grp. However, when these characters were simultaneously analysed with molecular data, no clearly separated groups were obtained. Haplotype network and phylogenetic analysis (both Bayesian and maximum parsimony) of a conserved region yielded the same result, suggesting that all isolates belong to the same species. Furthermore, no correlation could be established between morphological species-groups and a metabolite or group of metabolites synthesized. Thus, the whole set of analyses carried out in the present work supports the hypothesis that these small-spored Alternaria isolates from food belong to the same species. Identification at species level through classical morphology or modern molecular techniques does not seem to be a useful tool to predict toxicological risk in food matrices. The detection of any small spored Alternaria from Section Alternaria (D.P. Lawr., Gannibal, Peever & B.M. Pryor 2013) in food implies a potential toxicological risk. PMID- 28672175 TI - A longitudinal investigation of perfectionism and repetitive negative thinking in perinatal depression. AB - Repetitive negative thinking and perfectionism have both been proposed as processes that are related to depressive symptoms. The purpose of this study was to investigate concurrent and prospective relationships between antenatal and postnatal depression, perfectionism, and repetitive negative thinking. A longitudinal design was used and 71 women were followed from their third trimester of pregnancy to six weeks post birth. A structural equation model was tested with antenatal perfectionism predicting antenatal repetitive negative thinking, perfectionism predicting postnatal depression, and antenatal repetitive negative thinking predicting antenatal and postnatal depression. The final model provided an adequate fit to the data but the pathway from antenatal repetitive negative thinking to postnatal depression was not significant. The findings provide support for the role of perfectionism and repetitive negative thinking in the onset and maintenance of perinatal symptoms of depression. It is suggested that future research investigates the efficacy of targeting repetitive negative thinking and perfectionism in pregnancy to examine if this can reduce perinatal depression. PMID- 28672176 TI - A Type-2 fuzzy data fusion approach for building reliable weighted protein interaction networks with application in protein complex detection. AB - Detecting the protein complexes is an important task in analyzing the protein interaction networks. Although many algorithms predict protein complexes in different ways, surveys on the interaction networks indicate that about 50% of detected interactions are false positives. Consequently, the accuracy of existing methods needs to be improved. In this paper we propose a novel algorithm to detect the protein complexes in 'noisy' protein interaction data. First, we integrate several biological data sources to determine the reliability of each interaction and determine more accurate weights for the interactions. A data fusion component is used for this step, based on the interval type-2 fuzzy voter that provides an efficient combination of the information sources. This fusion component detects the errors and diminishes their effect on the detection protein complexes. So in the first step, the reliability scores have been assigned for every interaction in the network. In the second step, we have proposed a general protein complex detection algorithm by exploiting and adopting the strong points of other algorithms and existing hypotheses regarding real complexes. Finally, the proposed method has been applied for the yeast interaction datasets for predicting the interactions. The results show that our framework has a better performance regarding precision and F-measure than the existing approaches. PMID- 28672177 TI - A novel method to precisely detect apnea and hypopnea events by airflow and oximetry signals. AB - Sleep apnea hypopnea syndrome (SAHS) affects people's quality of life. The apnea hypopnea index (AHI) is the key indicator for diagnosing SAHS. The determination of the AHI is based on accurate detection of apnea and hypopnea events. This paper provides a novel method to detect apnea and hypopnea events based on the respiratory nasal airflow signal and the oximetry signal. The method uses sliding window and short time slice methods to eliminate systematic and sporadic noise of the airflow signal for improving the detection precision. Using this algorithm, the sleep data of 30 subjects from the Huaxi Sleep Center of Sichuan University (HSCSU) and the Teaching Hospital of Chengdu University of Traditional Chinese Medicine (THCUTCM) were auto-analyzed for detecting the apnea and hypopnea events. The total predicted apnea and hypopnea events were 8470. By manual investigation, the sensitivity and positive predictive value (PPV) of detecting apnea and hypopnea events were 97.6% and 95.7%, respectively. The sleep data of 28 subjects form HSCSU were auto-diagnosed SAHS according to the AHI. The sensitivity and PPV were 92.3% and 92.3%, respectively. This is an effective and precise method to diagnose SAHS. It can fit the home care SAHS screener. PMID- 28672178 TI - The relation between social anxiety and biased interpretations in adolescents with mild intellectual disabilities. AB - BACKGROUND: Cognitive theories of anxiety emphasize the importance of cognitive processes in the onset and maintenance of anxiety disorders. However, little is known about these processes in children and adolescents with Mild Intellectual Disabilities (MID). AIMS: The aim of this study was to investigate interpretation bias and its content-specificity in adolescents with MID who varied in their levels of social anxiety. METHOD AND PROCEDURES: In total, 631 adolescents from seven special secondary schools for MID filled in questionnaires to measure their levels of social anxiety. They also completed the Interpretation Recognition Task to measure how they interpret ambiguous situations. OUTCOMES AND RESULTS: Adolescents with higher self-reported levels of social anxiety interpreted ambiguous scenarios as more negative than adolescents with lower self-reported social anxiety. Furthermore, this negative interpretation was specific for social situations; social anxiety was only associated with ambiguous social anxiety related scenarios, but not with other anxiety-related scenarios. CONCLUSIONS AND IMPLICATIONS: These findings support the hypothesis that socially anxious adolescents with MID display an interpretation bias that is specific for stimuli that are relevant for their own anxiety. This insight is useful for improving treatments for anxious adolescents with MID by targeting content-specific interpretation biases. PMID- 28672179 TI - The relevance of feature selection methods to the classification of obsessive compulsive disorder based on volumetric measures. AB - BACKGROUND: Magnetic resonance images (MRI) show detectable anatomical and functional differences between individuals with obsessive-compulsive disorder (OCD) and healthy subjects. Moreover, machine learning techniques have been proposed as tools to identify potential biomarkers and, ultimately, to support clinical diagnosis. However, few studies to date have investigated feature selection (FS) influences in OCD MRI-based classification. METHODS: Volumes of cortical and subcortical structures, from MRI data of 38 OCD patients (split into two groups according symptoms severity) and 36 controls, were submitted to seven feature selection algorithms. FS aims to select the most relevant and less redundant features which discriminate between two classes. Then, a classification step was applied, from which the classification performances before and after different FS were compared. For the performance evaluation, leave-one-subject-out accuracies of Support Vector Machine classifiers were considered. RESULTS: Using different FS algorithms, performance improvement was achieved for Controls vs. All OCD discrimination (19.08% of improvement reducing by 80% the amount of features), Controls vs. Low OCD (20.10%, 75%), Controls vs. High OCD (17.32%, 85%) and Low OCD vs. High OCD (10.53%, 75%). Furthermore, all algorithms pointed out classical cortico-striato-thalamo-cortical circuitry structures as relevant features for OCD classification. LIMITATIONS: Limitations include the sample size and using only filter approaches for FS. CONCLUSIONS: Our results suggest that FS positively impacts OCD classification using machine-learning techniques. Complementarily, FS algorithms were able to select biologically plausible features automatically. PMID- 28672180 TI - Posttraumatic stress disorder and suicidal ideation, plans, and impulses: The mediating role of anxiety sensitivity cognitive concerns among veterans. AB - BACKGROUND: Although the relationship between posttraumatic stress disorder (PTSD) and suicide has been firmly established, research on underlying mechanisms has been disproportionately low. The cognitive concerns subscale of anxiety sensitivity (AS), which reflects fears of cognitive dyscontrol, has been linked to both PTSD and suicide and thus may serve as an explanatory mechanism between these constructs. METHODS: The sample consisted of 60 male veterans presenting to an outpatient Veteran Affairs (VA) clinic for psychological services. Upon intake, veterans completed a diagnostic interview and brief battery of self report questionnaires to assist with differential diagnosis and treatment planning. RESULTS: Results revealed a significant association between PTSD symptom severity and higher suicidality (i.e., ideation, plans, and impulses), even after accounting for relevant demographic and psychological constructs. Moreover, AS cognitive concerns mediated this association. LIMITATIONS: Limitations include the small sample size and cross-sectional nature of the current study. CONCLUSIONS: These findings add considerably to a growing body of literature examining underlying mechanisms that may help to explain the robust associations between PTSD and suicide. Considering the malleable nature of AS cognitive concerns, research is needed to determine the extent to which reductions in this cognitive risk factor are associated with reductions in suicide among at risk samples, such as those included in the present investigation. PMID- 28672182 TI - Risk factors for suicide in offspring bereaved by sudden parental death from external causes. AB - BACKGROUND: Parentally bereaved offspring have an increased suicide risk as a group, but the ability to identify specific individuals at risk on the basis of risk and protective factors is limited. The present study aimed to investigate to what degree different risk factors influence suicide risk in offspring bereaved by parental death from external causes. METHODS: Based on Norwegian registers, individual-level data were retrieved for 375 parentally bereaved suicide cases and 7500 parentally bereaved gender- and age-matched living controls. Data were analysed with conditional logistic regression. RESULTS: Bereaved offspring with low social support, indicated by offspring's single status and repeated changes in marital status and residence, had a significantly increased suicide risk compared to bereaved offspring with high social support. Moreover, low socioeconomic status, having an immigration background, having lost both parents and loss due to suicide significantly increased suicide risk. LIMITATIONS: Several variables relevant to bereavement outcome, such as coping mechanisms and the quality of the parent-offspring relationship are impossible to examine by utilizing population registers. Moreover, the availability of data did not enable the measurement of marital stability and residence stability across the entire lifespan for older individuals. CONCLUSIONS: Healthcare professionals should be aware of the additional risk posed by the identified risk factors and incorporate this knowledge into existing practice and risk assessment in order to identify individuals at risk and effectively target bereaved family and friends for prevention and intervention programs. Ideal follow-up for bereaved families should include a specific focus on mobilizing social support. PMID- 28672181 TI - Corpus callosum macro and microstructure in late-life depression. AB - BACKGROUND: Differences in corpus callosum (CC) morphology and microstructure have been implicated in late-life depression and may distinguish between late and early-onset forms of the illness. However, a multimodal approach using complementary imaging techniques is required to disentangle microstructural alterations from macrostructural partial volume effects. METHODS: 107 older adults were assessed: 55 currently-depressed patients without dementia and 52 controls without cognitive impairment. We investigated group differences and clinical associations in 7 sub-regions of the mid-sagittal corpus callosum using T1 anatomical data, white matter hyperintensity (WMH) quantification and two different diffusion MRI (dMRI) models (multi-tissue constrained spherical deconvolution, yielding apparent fibre density, AFD; and diffusion tensor imaging, yielding fractional anisotropy, FA and radial diffusivity, RD). RESULTS: Callosal AFD was lower in patients compared to controls. There were no group differences in CC thickness, surface area, FA, RD, nor whole brain or WMH volume. Late-onset of depression was associated with lower FA, higher RD and lower AFD. There were no associations between any imaging measures and psychotic features or depression severity as assessed by the geriatric depression scale. WMH volume was associated with lower FA and AFD, and higher RD in patients. LIMITATIONS: Patients were predominantly treatment-resistant. Measurements were limited to the mid-sagittal CC. dMRI analysis was performed on a smaller cohort, n=77. AFD was derived from low b-value data. CONCLUSIONS: Callosal structure is largely preserved in LLD. WMH burden may impact on CC microstructure in late-onset depression suggesting vascular pathology has additional deleterious effects in these patients. PMID- 28672183 TI - An instrumental approach to combining confocal microspectroscopy and 3D scanning probe nanotomography. AB - In the past decade correlative microscopy, which combines the potentials of different types of high-resolution microscopies with a variety of optical microspectroscopy techniques, has been attracting increasing attention in material science and biological research. One of outstanding solutions in this area is the combination of scanning probe microscopy (SPM), which provides data on not only the topography, but also the spatial distribution of a wide range of physical properties (elasticity, conductivity, etc.), with ultramicrotomy, allowing 3D multiparametric examination of materials. The combination of SPM and ultramicrotomy (scanning probe nanotomography) is very appropriate for characterization of soft multicompound nanostructurized materials, such as polymer matrices and microstructures doped with different types of nanoparticles (magnetic nanoparticles, quantum dots, nanotubes, etc.), and biological materials. A serious problem of this technique is a lack of chemical and optical characterization tools, which may be solved by using optical microspectroscopy. Here, we report the development of an instrumental approach to combining confocal microspectroscopy and 3D scanning probe nanotomography in a single apparatus. This approach retains all the advantages of SPM and upright optical microspectroscopy and allows 3D multiparametric characterization using both techniques. As the first test of the system developed, we have performed correlative characterization of the morphology and the magnetic and fluorescent properties of fluorescent magnetic microspheres doped with a fluorescent dye and magnetic nanoparticles. The results of this study can be used to obtain 3D volume images of a specimen for most high-resolution near-field scanning probe microscopies: SNOM, TERS, AFM-IR, etc. This approach will result in development of unique techniques combining the advantages of SPM (nanoscale morphology and a wide range of physical parameters) and high-resolution optical microspectroscopy (nanoscale chemical mapping and optical properties) and allowing simultaneous 3D measurements. PMID- 28672184 TI - What are Chinese nurses' experiences whilst working overseas? A narrative scoping review. AB - BACKGROUND: Transnational nurse migration has become an apparent attribute of the global nurse shortage and it is foreseeable that China will play an increasingly significant role in nurse exports. These nurses have unique cultural and professional needs throughout their journey of migration and in-depth analysis of Chinese migrant nurses' experiences is urgently required to manage and empower an ethnically diverse workforce. OBJECTIVE: To synthesise Chinese migrant nurses' experiences by examining the findings of existing studies. DESIGN: Scoping review methods incorporating narrative synthesis were conducted. METHOD: Arksey and O'Malley's five-stage scoping review framework was utilised to identify Chinese migrant nurses' experiences. 13 databases were searched, and 5009 articles were retrieved. After screening the titles and abstracts, 169 articles were assessed in full text for eligibility, and finally 22 articles plus 2 manually included ones, representing 19 discrete studies, were further analysed and synthesised with a three-step narrative synthesis. RESULTS: 13 qualitative studies, 5 quantitative studies and 1 mixed- methods study met inclusion criteria. Two main themes were identified. "Contexts and migration" comprised three subthemes: perceptions of nursing, original culture and nursing differences. "The self and migration" included four subthemes: initiating, transition, reality and future. CONCLUSION: This scoping review revealed the literature on Chinese migrant nurses and provided insight into their stories and circumstances. There were external factors which affected Chinese nurses' interpretations and choices. Throughout their migration journeys, they encountered various challenges and also successes. They responded with positive or negative behavioural and psychosocial changes. PMID- 28672185 TI - Utilization of biodiesel by-product as substrate for high-production of beta farnesene via relatively balanced mevalonate pathway in Escherichia coli. AB - Farnesene has been identified as suitable jet fuel substitutes and metabolic engineering for microbial production of farnesene is an alternative and attractive route. In this study, due to accumulation of toxic intermediate isopentenyl pyrophosphate (IPP), an engineered Escherichia coli strain harboring heterologous mevalonate pathway produced only 4.11mg/L beta-farnesene. Through higher-level expression of isopentenyl diphosphate isomerase and farnesyl diphosphate synthase to minimize the accumulated IPP, another engineered strain with relatively balanced mevalonate pathway was constructed and had the highest production of beta-farnesene to date (8.74g/L) by Escherichia coli in a lab bioreactor. Furthermore, this is the first report on utilization of biodiesel by product (simple purification) as substrate for high-production of beta-farnesene by the engineered strain optimized and beta-farnesene concentration reached 2.83g/L in a lab bioreactor. Therefore, the engineered strain optimized could be used as a platform host for high-production of other terpenoids using biodiesel by-product as substrate. PMID- 28672186 TI - Effect of pretreatment and membrane orientation on fluxes for concentration of whey with high foulants by using NH3/CO2 in forward osmosis. AB - Usage of forward osmosis membrane in FO mode, in which active and support layers of the membrane were in contact with the feed and the draw solutions respectively, provided higher initial water flux (12L/m2h) than the usage of membrane in PRO mode (6L/m2h) having opposite orientation but fluxes approached to each other after 4h during concentration of whey with NH3/CO2 as draw salt. High organic and inorganic foulants of whey was considered as reason for observed result in addition to lower solute resistivity. Initial water flux (8,5L/m2h) was lower when pre-treatment was applied before forward osmosis process but final flux (4L/m2h) was equal flux of non pre-treatment. Reduction of solute resistivity or absence of hydraulic pressure can be reasons for lower initial flux. Detection of organic carbon but absence of lactose in draw solution showed passage of molecules being different than lactose into draw solution. PMID- 28672187 TI - Isolation of an indigenous Chlorella vulgaris from swine wastewater and characterization of its nutrient removal ability in undiluted sewage. AB - Bio-treatment of wastewater mediated by microalgae is considered as a promising solution. This work aimed to isolate an indigenous microalgal strain (named MBFJNU-1) from swine wastewater effluent and identify as Chlorella vulgaris. After 12days, the removal efficiencies of total nitrogen (TN) and total phosphorus (TP) in undiluted swine slurry were 90.51% and 91.54%, respectively. Stress tolerance in response to wastewater was verified by cultivating in artificial wastewater containing different levels of chemical oxygen demand (COD), TN and TP. MBFJNU-1 could grow well in undiluted swine slurry and artificial wastewater containing 30,000mg/L COD or 2000mg/L TN. Furthermore, global nuclear DNA methylation (5-mC) of MBFJNU-1 was employed to explore the possible mechanism in response to wastewater stress. The results showed that the level of 5-mC was inversely proportional to the growth of MBFJNU-1 in different diluted swine slurry, helping to understand 5-mC variation in response to stress environment. PMID- 28672188 TI - Effective feather degradation and keratinase production by Bacillus pumilus GRK for its application as bio-detergent additive. AB - An effecient feather-degrading bacterium was isolated from poultry dumping yard and identified as Bacillus pumilus GRK based on 16S rRNA sequencing. Complete feather degradation (98.3+/-1.52%) with high keratinase production (373+/-4 U/ml) was observed in 24h under optimized conditions (substrate 1% (w/w); inoculum size 4% (v/v); pH 10; 200rpm at 37 degrees C) with feathers as sole carbon and nitrogen source in tap water. The fermented broth was enriched with amino acids like tryptophan (221.44ug/ml), isoleucine (15.0ug/ml), lysine (10.81ug/ml) and methionine (7.24ug/ml) suggesting its potential use as feed supplement. The keratinase produced was a detergent stable serine protease and its activity was further enhanced by Ca+2 and Mg+2. Bacillus pumilus GRK keratinase was successfully utilised as bioadditive in detergent formulations for removing the blood stains from cloth without affecting its fiber and texture. PMID- 28672189 TI - Multi-scale modeling of altered synaptic plasticity related to Amyloid beta effects. AB - As suggested by Palop and Mucke (2010) pathologically elevated beta-amyloid (Abeta) impairs long term potentiation (LTP) and enhances long term depression (LTD) possible underlying mechanisms in Alzheimer's Disease (AD). In the present paper we adopt and further elaborate a phenomenological computational model of bidirectional plasticity based on the calcium control hypothesis of Shouval et al. (2002). First, to account for Abeta effects the activation function Omega was modified assuming competition between LTP and LTD, and parameter sets were identified that well describe both normal and pathological synaptic plasticity processes. Second, a biophysically plausible kinetic model of bidirectional synaptic plasticity by D'Alcantara et al. (2003) was used to support findings of the phenomenological model and to further explain underlying kinetic processes. Model fitting pointed out molecular contributors, particularly calcineurin and type 1 protein phosphatase that might contribute to observed physiological disturbances in AD. PMID- 28672190 TI - A novel signal-on photoelectrochemical immunosensor for detection of alpha fetoprotein by in situ releasing electron donor. AB - A signal-on photoelectrochemical (PEC) immunosensor was constructed for detecting tumor marker in this work. alpha-fetoprotein (AFP) was chosen as a model analyte to investigate the prepared procedure and the analytical performance of the exploited sensor. In order to construct the sensor, CdSe QDs were used as photoactive material, biotin conjugated AFP antibody (Bio-anti-AFP) as detecting probe, streptavidin (SA) as signal capturing unit, biotin functionalized apoferritin encapsulated ascorbic acid (Bio-APOAA) as amplification unit, which were assembled onto the electrodes. The sensing strategy was based on in situ enzymatic hydrolysis of Bio-APOAA to release ascorbic acid (AA) as sacrificial electron donor to produce photocurrent. The photocurrent from the immunosensor was monitored as a result of AFP concentrations. The constructed sensing platform displayed high selectivity and good sensitivity for detecting AFP. Under optimal conditions, a wide linear range from 0.001 to 1000ng/mL and a low detection limit of 0.31pg/mL were obtained. The developed immunosensor is expected to be used to determine AFP and other tumor markers in human plasma in clinical laboratories either for pre-cancer screening or cancer monitoring. Moreover, this sensing platform further has the potential to use for the detection of trypsin activity and the corresponding inhibitor-screening. PMID- 28672191 TI - Tear glucose detection combining microfluidic thread based device, amperometric biosensor and microflow injection analysis. AB - The tear glucose analysis is an important alternative for the indirect, simple and less invasive monitoring of blood glucose levels. However, the high cost and complex manufacturing process of tear glucose analyzers combined with the need to exchange the sensor after each analysis in the disposable tests prevent widespread application of the tear in glucose monitoring. Here, we present the integration of a biosensor made by the electropolymerization of poly(toluidine blue O) (PTB) and glucose oxidase (GOx) with an electroanalytical microfluidic device of easy assembly based on cotton threads, low cost materials and measurements by microflow injection analysis (uFIA) through passive pumping for performing tear glucose analyses in a simple, rapid and inexpensive way. A high stability between the analyses (RSD = 2.54%) and among the different systems (RSD = 3.13%) was obtained for the determination of glucose, in addition to a wide linear range between 0.075 and 7.5mmolL-1 and a limit of detection of 22.2umolL 1. The proposed method was efficiently employed in the determination of tear glucose in non-diabetic volunteers, obtaining a close correlation with their blood glucose levels, simplifying and reducing the costs of the analyses, making the tear glucose monitoring more accessible for the population. PMID- 28672192 TI - Ultrasensitive detection of ochratoxin A using aptasensors. AB - Regarding teratogenic, carcinogenic, and immunotoxic nature of ochratoxin A (OTA), selective and sensitive monitoring of this molecule in food samples is of great importance. In recent years, various methods have been introduced for detection of OTA. However, they are usually time-consuming, labor-intensive and expensive. Therefore, these parameters limited their usage. The emerging method of detection, aptasensor, has attracted more attention for OTA detection, due to distinctive advantages including high sensitivity, selectivity and simplicity. In this review, the new developed aptasensors for detection of OTA have been investigated. We also highlighted advantages and disadvantages of different types of OTA aptasensors. This review also takes into consideration the goal to find out which designs are the most rational ones for highly sensitive detection of OTA. PMID- 28672193 TI - Quantitative differentiation of multiple virus in blood using nanoporous silicon oxide immunosensor and artificial neural network. AB - In spite of the rapid developments in various nanosensor technologies, it still remains challenging to realize a reliable ultrasensitive electrical biosensing platform which will be able to detect multiple viruses in blood simultaneously with a fairly high reproducibility without using secondary labels. In this paper, we have reported quantitative differentiation of Hep-B and Hep-C viruses in blood using nanoporous silicon oxide immunosensor array and artificial neural network (ANN). The peak frequency output (fp) from the steady state sensitivity characteristics and the first cut off frequency (fc) from the transient characteristics have been considered as inputs to the multilayer ANN. Implementation of several classifier blocks in the ANN architecture and coupling them with both the sensor chips, functionalized with Hep-B and Hep-C antibodies have enabled the quantification of the viruses with an accuracy of around 95% in the range of 0.04fM-1pM and with an accuracy of around 90% beyond 1pM and within 25nM in blood serum. This is the most sensitive report on multiple virus quantification using label free method. PMID- 28672194 TI - Systematic Analysis of the Expression of the Mitochondrial ATP Synthase (Complex V) Subunits in Clear Cell Renal Cell Carcinoma. AB - Mitochondrial dysfunction is common in cancer and the mitochondrial electron transport chain is often affected in carcinogenesis. To date, little is known about the expression of the ATP synthase subunits in clear cell renal cell carcinoma (ccRCC). The NextBio database was used to determine an expression profile of the ATP synthase subunits based on published microarray studies. We observed down-regulation of 23 out of 29 subunits of the ATP synthase. Differential expression was validated exemplarily for 12 genes (ATP5A1, ATP5B, ATPAF1, ATP5C1, ATP5D, ATP5O, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5I, ATP5S; screening cohort ccRCC n=18 and normal renal tissue n=10) using real-time PCR. Additional eight genes (ATP5A1, ATP5B, ATPAF1, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5S) were internally validated within an enlarged cohort (ccRCC n=74; normal renal tissue n=36). Furthermore, down-regulation of ATP5A1, ATPAF1, ATP5G1/G2/G3 was confirmed on the protein level using Western Blot and immunohistochemistry. We observed that altered expression of ATPAF1 and ATP5G1/G2/G3 was correlated with overall survival in patients with ccRCC. In conclusion, down-regulation of many ATP Synthase subunits occurs in ccRCC and is the basis for the reduced activity of the mitochondrial electron chain. Alteration of the expression of ATP5A1, ATPAF1, and ATP5G1/G2/G3 is characteristic for ccRCC and may be prognostic for ccRCC patients' outcome. PMID- 28672195 TI - Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models. AB - Resistance to chemotherapy remains a major challenge in the treatment of human glioblastoma (GBM). Glycogen synthase kinase-3beta (GSK-3beta), a positive regulator of NF-kappaB-mediated survival and chemoresistance of cancer cells, has been identified as a potential therapeutic target in human GBM. Our objective was to determine the antitumor effect of GSK-3 inhibitor 9-ING-41 in combination with chemotherapy in patient-derived xenograft (PDX) models of human GBM. We utilized chemoresistant PDX models of GBM, GBM6 and GBM12, to study the effect of 9-ING-41 used alone and in combination with chemotherapy on tumor progression and survival. GBM6 and GBM12 were transfected by reporter constructs to enable bioluminescence imaging, which was used to stage animals prior to treatment and to follow intracranial GBM tumor growth. Immunohistochemical staining, apoptosis assay, and immunoblotting were used to assess the expression of GSK-3beta and the effects of treatment in these models. We found that 9-ING-41 significantly enhanced 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) antitumor activity in staged orthotopic GBM12 (no response to CCNU) and GBM6 (partial response to CCNU) PDX models, as indicated by a decrease in tumor bioluminescence in mouse brain and a significant increase in overall survival. Treatment with the combination of CCNU and 9-ING-41 resulted in histologically confirmed cures in these studies. Our results demonstrate that the GSK-3 inhibitor 9-ING-41, a clinical candidate currently in Investigational New Drug (IND)-enabling development, significantly enhances the efficacy of CCNU therapy for human GBM and warrants consideration for clinical evaluation in this difficult-to-treat patient population. PMID- 28672196 TI - Contrast-Enhanced CT Density Predicts Response to Sunitinib Therapy in Metastatic Renal Cell Carcinoma Patients. AB - The first-line therapy in metastatic renal cell carcinoma (mRCC), sunitinib, exhibits an objective response rate of approximately 30%. Therapeutic alternatives such as other tyrosine kinase inhibitors, VEGF inhibitors, or mTOR inhibitors emphasize the clinical need to predict the patient's response to sunitinib therapy before treatment initiation. In this study, we evaluated the prognostic value of pretreatment portal venous phase contrast-enhanced computed tomography (CECT) mean tumor density on overall survival (OS), progression-free survival (PFS), and tumor growth in 63 sunitinib-treated mRCC patients. Higher pretreatment CECT tumor density was associated with longer PFS and OS [hazard ratio (HR)=0.968, P=.002, and HR=0.956, P=.001, respectively], and CECT density was inversely correlated with tumor growth (P=.010). Receiver operating characteristic analysis identified two CECT density cut-off values (63.67 HU, sensitivity 0.704, specificity 0.694; and 68.67 HU, sensitivity 0.593, specificity 0.806) which yielded subpopulations with significantly different PFS and OS (P<.001). Pretreatment CECT is therefore a promising noninvasive strategy for response prediction in sunitinib-treated mRCC patients, identifying patients who will derive maximum therapeutic benefit. PMID- 28672197 TI - Industrial wind turbine post-construction bird and bat monitoring: A policy framework for Canada. AB - Electricity generation from wind energy has proliferated throughout North America and will continue to grow. Given Canada's expected increase in wind energy capacity, consideration of the potential adverse impacts to bird and bat populations is prudent given their sensitivity to these projects. The province of Ontario, Canada is currently the leading jurisdiction for wind energy development, and for provincial guidance on pre- and post-construction monitoring. With uniform monitoring guidance in Ontario, wind energy proponents, and third-party consultants, have developed post-construction monitoring protocols that meet provincial guidance, while also providing standardized reporting. In Atlantic Canada, post-construction guidelines vary between provinces, depending mostly on guidance from the Environment Canada Canadian Wildlife Service and relevant provincial agencies. To ensure quality post construction monitoring results in Atlantic Canada and other provinces, it is imperative that all Canadian provinces adopt similar approaches to those employed in Ontario. This paper reviews major causes of bird and bat mortalities; reviews Canadian federal and Ontario provincial bird and bat monitoring guidelines to elucidate gaps between environmental assessment (EA) theory and application; summarizes post-construction monitoring protocols from eight bird and bat post construction monitoring programs used in Ontario; and, proposes recommendations to support future wind development opportunities across Canada and specifically in Atlantic Canada. PMID- 28672198 TI - Phosphate recovery from liquid fraction of anaerobic digestate using four slow pyrolyzed biochars: Dynamics of adsorption, desorption and regeneration. AB - Four slow pyrolyzed biochars produced from wood (WDB), corncobs (CCB), rice husks (RHB) and sawdust (SDB) were evaluated for adsorption, desorption and regeneration of phosphate (PO43--P) from anaerobically digested liquid swine manure. The PO43--P adsorption capacity increased followed by initial concentrations increasing. Maximum PO43--P adsorptions at initial 150 mg/L of PO43--P (highest load) were average of 7.67, 6.43, 5.73 and 5.41 mg/g for WDB, CCB, RHB and SDB, respectively. Pseudo second order kinetics model could best fit PO43--P adsorption, which indicated the chemisorption via precipitation was the main mechanism for PO43--P removal. The sorption process was reversible and the adsorbed PO43--P could be desorbed in both neutral (57-78%) and acidic solution environments (75-88%) for all biochars. Meanwhile, regenerated biochar could re adsorb up to 5.62 mg/g at the highest initial PO43--P of 150 mg/L. The present finding implied biochar could be effectively used to recover PO43--P from anaerobic digestate. PMID- 28672199 TI - Changes in malnutrition and quality of nutritional care among aged residents in all nursing homes and assisted living facilities in Helsinki 2003-2011. AB - BACKGROUND: While nutritional problems have been recognized as common in institutional settings for several decades, less is known about how nutritional care and nutrition has changed in these settings over time. OBJECTIVES: To describe and compare the nutritional problems and nutritional care of residents in all nursing homes (NH) in 2003 and 2011 and residents in all assisted living facilities (ALF) in 2007 and 2011, in Helsinki, Finland. METHODS: We combined four cross-sectional datasets of (1) residents from all NHs in 2003 (N=1987), (2) residents from all ALFs in 2007 (N=1377), (3) residents from all NHs in 2011 (N=1576) and (4) residents from all ALFs in 2011 (N=1585). All participants at each time point were assessed using identical methods, including the Mini Nutritional Assessment (MNA). RESULTS: The mean age of both samples from 2011 was higher and a larger proportion suffered from dementia, compared to earlier collected samples. A larger proportion of the residents in 2011 were assessed either malnourished or at-risk for malnutrition, according to the MNA, than in 2003 (NH: 93.5% vs. 88.9%, p<0.001) and in 2007 (ALF: 82.1% vs. 78.1%, p=0.007). The use of nutritional, vitamin D and calcium supplements, and snacks between meals was significantly more common in the 2011 residents, compared to the respective earlier samples. CONCLUSIONS: In 2011, institutionalized residents were more disabled and more prone to malnourishment than in 2003 or 2007. Institutions do seem to be more aware of good nutritional care for vulnerable older people, although there is still room for improvement. PMID- 28672200 TI - Impact of smoking on the observed levels of apolipoprotein B: Data from NHANES 2007-2012. AB - Impact of smoking on the levels of apolipoprotein B (APOB) was evaluated by analyzing data from National Health and Nutrition Examination Survey for the years 2007-2012 for US adolescents aged 12-19 years and adults aged >=20 years. When adjustments were made for the effects of age, gender, race/ethnicity, body mass index, and poverty income ratio, smoking did not influence the observed levels of APOB for either adolescents or adults. Moreover, even the variables that represented intensity of smoking indicated, for example, by the number of days participants smoked during the last five days and/or the number of cigarettes smoked on the days they were smoked did not affect the levels of APOB. Also, type of smoking, cigarettes only, cigars only, or smokeless products only did not affect the levels of APOB. Every two years, adjusted levels of APOB decreased by 2.5% for adolescents and by 1.8% for adults. PMID- 28672201 TI - Design of a two-photon fluorescent probe for selective recognition of Au(III) over Au(I) and its application of imaging in vitro and in vivo. AB - A highly selective two-photon fluorescent probe (PyCM-1) for Au3+ was developed with distinct "turn on" fluorescence response, low detection limit (22nM) and large two-photon absorption cross-sections (696 GM at 860nm). Its high selectivity for Au3+ over Au+ was achieved via the modification on the type of coordination atoms in the Schiff base receptor. Co-staining experiments showed that the probe PyCM-1 could co-localize specifically with mitochondria. Moreover, the two-photon confocal fluorescence imaging results demonstrated the probe's capability for visualizing Au3+in vitro and in vivo. PMID- 28672202 TI - Sample preparation of anodised aluminium oxide coatings for scanning electron microscopy. AB - Characterisation of anodic aluminium oxide coatings and measurement of their thickness using microscopic techniques is valuable for analysing the effectiveness of the prior anodising process. Three different methods for preparing samples to view the coating cross-section (mechanical fracturing, cryogenic fracturing and metallography) were trialled and assessed for speed of implementation, simplicity and achievable measurement accuracy. Cryogenic fracturing was found to be destructive to samples. Mechanical fracturing yielded relatively accurate coating thickness measurements and coating structural information. Metallography provided the most accurate coating thickness measurement at the expense of coating structural information. PMID- 28672203 TI - "How complex and even perverse the real world can be": W.D. Hamilton's early work on social wasps (1964-1968). AB - William D. Hamilton's name is often connected to important theoretical accomplishments, from the theory of inclusive fitness and kin selection to the so called Hamilton's rule and the haplodiploidy hypothesis. This article asks: How did Hamilton attempt to test his theory and hypothesis against the complexity of the biological world? The article reconstructs Hamilton's empirical work with social wasps between 1963 and 1968, the years before and after the publication of the groundbreaking "The Genetical Evolution of Social Behavior" in 1964. It points out the centrality of Hamilton's work on wasps and shows how the British scientist attempted to test theories and hypotheses with naturalistic, developmental, and physiological observations as well as, at times, with experimental manipulations. The article offers a new perspective on the history of the scientific understanding of the evolution of social behavior. In contrast to existing narratives, this perspective emphasizes the importance of empirical work-e.g. natural history, physiology, comparative anatomy-which is often obscured by a nearly exclusive focus on theoretical developments in this field. PMID- 28672204 TI - Nanoengineered porous chitosan/CaTiO3 hybrid scaffolds for accelerating Schwann cells growth in peripheral nerve regeneration. AB - To further improve the property of promoting peripheral nerve regeneration of chitosan materials, CaTiO3 nanoparticles with various concentrations were synthesized in chitosan (CS) solution and formed to porous CS/CaTiO3 hybrid scaffolds. The properties including morphology, wettability, porosity, crystallization intensity and surface charges were characterized, respectively. The influence of the porous CS/CaTiO3 hybrid scaffolds on Schwann cells growth was evaluated. The results showed that the CaTiO3 hybridized CS scaffolds possessed homogeneous nanoparticles distribution with concentration-dependent effect. The hybridization of CaTiO3 nanoparticles could increase the hydrophobicity while reduce the porosity and surface charge density of the porous CS/CaTiO3 hybrid scaffolds The crystal structure of the hybridized scaffolds was mainly the orthorhombic structure of the calcium titanate accompanied by the amorphous phase of chitosan. Culture of Schwann cells indicated that the CS/CaTiO3 hybrid scaffolds with a suitable concentration of CaTiO3 nanoparticles could obviously promote the attachment, proliferation and biological function maintenance of Schwann cells, thus showing potentially great significance towards application in peripheral nerve regeneration. PMID- 28672205 TI - Pep-1 peptide-functionalized liposome to enhance the anticancer efficacy of cilengitide in glioma treatment. AB - In this study, we have established an effective and novel nanocarrier system for the effective treatment of glioma. We have established the glioma tissue penetrating nanocarrier system by conjugating Pep-1 as a targeting ligand on the liposome surface to enhance the anticancer efficacy of cilengitide (CGL). The particles were nanosized and exhibited a controlled release of drug in both the pH conditions. The cellular uptake assay showed that conjugation of Pep-1 on the liposome surface remarkably increased the cellular uptake. The uptake of CGT loaded Pep-1 peptide-conjugated liposome (PeCNL) increased to 89.8% compared to 47.5% for CNL indicating the efficient internalization of the nanocarriers. Consistently, PeCNL exhibited a significantly higher cytotoxic effect in cancer cells compared to that of non-targeted CGT-loaded liposome (CNL). PeCNL exhibited a higher apoptosis of cancer cells (~35%) compared to that of CNL. Most importantly, PeCNL exhibited a significantly superior anticancer effect with tumor volume as low as ~350mm3 indicating the superior anticancer potential of targeted formulations. Similarly, PeCNL showed the lowest staining for Ki67 indicating that the targeted NP has the maximum effect in controlling the proliferation of cancer cells. Taken together, Pep-1 conjugated liposome could exhibit better antitumor efficacy when applied to IL-13R2 receptor overexpressed specific brain glioma. PMID- 28672206 TI - Membrane fouling characteristics and mitigation in a coagulation-assisted microfiltration process for municipal wastewater pretreatment. AB - Maximizing the energy-profitable treatment of municipal wastewater (MW) is of significance to achieve energy-neutral operation for wastewater treatment plant. Direct membrane filtration technology has been considered as an effective way to separate organic carbon from MW for subsequent anaerobic energy-recovering process, but its application is restrained by severe membrane fouling issues. Thus, it is essential to identify the substances in MW that are responsible for membrane fouling and find out efficient anti-fouling methods. In this work, an integrated approach through combining multivariate curve resolution-alternating least squares analysis with infrared attenuated total reflection mapping was adopted to explore the membrane fouling process, and three coagulants, i.e., polyacrylamide, Al2(SO4)3 and FeCl3, were individually used to mitigate membrane fouling. Results show that the 1-8 MUm biopolymer clusters, i.e., humic-like and protein-like substances, were the predominant foulants in MW. In addition, membrane fouling caused by proteins was found to be more severe than that by humic substances. Coagulation pretreatment was demonstrated to be effective in mitigating membrane fouling. Al2(SO4)3 or FeCl3 had superior anti-fouling performance comparing to that of polyacrylamide. The dosage of polyacrylamide needs to be optimized according to the actual MW characteristics as its overdose would cause a substantial decline of membrane flux. These results provide a deep understanding of the membrane fouling mechanisms for organic carbon separation from MW and are beneficial for developing efficient and cost-effective membrane fouling mitigation strategies. PMID- 28672207 TI - Removal of disinfection byproduct (DBP) precursors in water by two-stage biofiltration treatment. AB - The removal of precursors of 36 disinfection byproducts (DBPs) in effluents from flocculation/sedimentation process was evaluated across a pilot-scale two-stage biofiltration process, i.e., a sand/anthracite (SA) biofilter (empty bed contact time (EBCT) of 7.5 min) coupled with a biologically-active granular activated carbon (GAC) contactor (EBCT of 15 min). The biofiltration process exhibited a good capacity for removal of the total DBP formation potential (DBPFP) (by 25.90 +/- 2.63%), and GAC contactors contributed most to the DBPFP removal (accounting for 60.63 +/- 16.64% of the total removal). The removal percentage of DBPFPs of different structure types was in the following order: halonitroalkanes (58.50%) > haloaldehydes (33.62%) > haloacetic acids (HAAs, 28.13%) > haloalkanes (20.46%) > haloketones (13.46%) > nitrosamines (10.23%) > halonitriles (-8.82%) > haloalkenes (-9.84%). The precursors of bromo-DBPs (containing only bromine atoms) and maximal halogenated DBPs (containing 3 & 4 halo atoms) were removed largely compared to other DBPs. Among the total DBPFP, trihalomethanes (THMs), HAAs, and chloral hydrate were the dominant DBPs, and they accounted for >92% of the total targeted DBPs by weight. Pearson correlation analysis (CA) and principal components analysis (PCA) indicated a significant association among these dominant DBPs. Canonical correspondence analysis (CCA) revealed specific ultraviolet absorbance (SUVA254) could serve as a good surrogate parameter for DBPFP. Pre-chlorination upstream of the biofilters may not greatly impact the overall removal of DBPFP by SA/GAC biofiltration. In addition, results showed that SA/GAC biofiltration was a useful procedure to remove the inorganic DBP chlorite. PMID- 28672208 TI - Design of waste stabilization pond systems: A review. AB - A better design instruction for waste stabilization ponds is needed due to their growing application for wastewater purification, increasingly strict environmental regulations, and the fact that most of previous design manuals are outdated. To critically review model-based designs of typical pond treatment systems, this paper analyzed more than 150 articles, books, and reports from 1956 to 2016. The models developed in these publications ranged from simple rules and equations to more complex first-order and mechanistic models. From a case study on all four approaches, it appeared that rules of thumb is no longer a proper tool for pond designs due to its low design specification and very high output variability and uncertainty. On the other hand, at the beginning phase of design process or in case of low pressure over land and moderate water quality required, regression equations can be useful to form an idea for pond dimensions. More importantly, mechanistic models proved their capacity of generating more precise and comprehensive designs but still need to overcome their lack of calibration and validation, and overparameterization. In another case study, an essential but often overlooked role of uncertainty analysis in pond designs was investigated via a comparison between deterministic and uncertainty-based approaches. Unlike applying a safety factor representing all uncertainty sources, probabilistic designs quantify the uncertainty of model outputs by including prior uncertainty of inputs and parameters, which generates more scientifically reliable outcomes for decision makers. Based on these findings, we advise engineers and designers to shift from the conventional approaches to more innovative and economic tools which are suitable for dealing with large variations of natural biological systems. PMID- 28672209 TI - The role of nitrite in sulfate radical-based degradation of phenolic compounds: An unexpected nitration process relevant to groundwater remediation by in-situ chemical oxidation (ISCO). AB - As promising in-situ chemical oxidation (ISCO) technologies, sulfate radical based advanced oxidation processes (SR-AOPs) are applied in wastewater treatment and groundwater remediation in recent years. In this contribution, we report for the first time that, thermally activated persulfate oxidation of phenol in the presence of nitrite (NO2-), an anion widely present in natural waters, could lead to the formation of nitrated by-products including 2-nitrophenol (2-NP), 4 nitrophenol (4-NP), 2,4-dinitrophenol (2,4-DNP), and 2,6-dinitrophenol (2,6-DNP). Nitrogen dioxide radical (NO2*), arising from SO4*- scavenging by NO2-, was proposed to be involved in the formation of nitrophenols as a nitrating agent. It was observed that nitrophenols accounted for approximately 70% of the phenol transformed under reaction conditions of [NO2-] = 200 MUM, [PS] = 2 mM and temperature of 50 degrees C. Increasing the concentration of NO2- remarkably enhanced the formation of nitrophenols but did not affect the transformation rate of phenol significantly. The degradation of phenol and the formation of nitrophenols were significantly influenced by persulfate dosage, solution pH and natural organic matter (NOM). Further studies on the degradation of other phenolic compounds, including 4-chlorophenol (4-CP), 4-hydroxybenzoic acid (4 HBA), and acetaminophen (ATP), verified the formation of their corresponding nitrated by-products as well. Therefore, formation of nitrated by-products is probably a common but overlooked phenomenon during SO4*--based oxidation of phenolic compounds in the presence of NO2-. Nitroaromatic compounds are well known for their carcinogenicity, mutagenicity and genotoxicity, and are potentially persistent in the environment. The formation of nitrated organic by products in SR-AOPs should be carefully scrutinized, and risk assessment should be carried out to assess possible health and ecological impacts. PMID- 28672210 TI - Micropollutants in groundwater from septic systems: Transformations, transport mechanisms, and human health risk assessment. AB - Septic systems may contribute micropollutants to shallow groundwater and surface water. We constructed two in situ conventional drainfields (drip dispersal and gravel trench) and an advanced drainfield of septic systems to investigate the fate and transport of micropollutants to shallow groundwater. Unsaturated soil water and groundwater samples were collected, over 32 sampling events (January 2013 to June 2014), from the drainfields (0.31-1.07 m deep) and piezometers (3.1 3.4 m deep). In addition to soil-water and groundwater, effluent samples collected from the septic tank were also analyzed for 20 selected micropollutants, including wastewater markers, hormones, pharmaceuticals and personal care products (PPCPs), a plasticizer, and their transformation products. The removal efficiencies of micropollutants from septic tank effluent to groundwater were similar among three septic systems and were 51-89% for sucralose and 53->99% for other micropollutants. Even with high removal rates within the drainfields, six PPCPs and sucralose with concentrations ranging from <0.3 to 154 ng/L and 121 to 32,000 ng/L reached shallow groundwater, respectively. The human health risk assessment showed that the risk to human health due to consumption of groundwater is negligible for the micropollutants monitored in the study. A better understanding of ecotoxicological effects of micropollutant mixtures from septic systems to ecosystem and human health is warranted for the long-term sustainability of septic systems. PMID- 28672211 TI - Analysis of the functional gene structure and metabolic potential of microbial community in high arsenic groundwater. AB - Microbial functional potential in high arsenic (As) groundwater ecosystems remains largely unknown. In this study, the microbial community functional composition of nineteen groundwater samples was investigated using a functional gene array (GeoChip 5.0). Samples were divided into low and high As groups based on the clustering analysis of geochemical parameters and microbial functional structures. The results showed that As related genes (arsC, arrA), sulfate related genes (dsrA and dsrB), nitrogen cycling related genes (ureC, amoA, and hzo) and methanogen genes (mcrA, hdrB) in groundwater samples were correlated with As, SO42-, NH4+ or CH4 concentrations, respectively. Canonical correspondence analysis (CCA) results indicated that some geochemical parameters including As, total organic content, SO42-, NH4+, oxidation-reduction potential (ORP) and pH were important factors shaping the functional microbial community structures. Alkaline and reducing conditions with relatively low SO42-, ORP, and high NH4+, as well as SO42- and Fe reduction and ammonification involved in microbially-mediated geochemical processes could be associated with As enrichment in groundwater. This study provides an overall picture of functional microbial communities in high As groundwater aquifers, and also provides insights into the critical role of microorganisms in As biogeochemical cycling. PMID- 28672212 TI - Elucidating microbial community adaptation to anaerobic co-digestion of fats, oils, and grease and food waste. AB - Despite growing interest in co-digestion and demonstrated process improvements (e.g., enhanced stability and biogas production), few studies have evaluated how co-digestion impacts the anaerobic digestion (AD) microbiome. Three sequential bench-scale respirometry experiments were conducted at thermophilic temperature (50 degrees C) with various combinations of primary sludge (PS); thickened waste activated sludge (TWAS); fats, oils, and grease (FOG); and food waste (FW). Two additional runs were then performed to evaluate microbial inhibition at higher organic fractions of FOG (30-60% volatile solids loading (VSL; v/v)). Co digestion of PS, TWAS, FOG, and FW resulted in a 26% increase in methane production relative to digestion of PS and TWAS. A substantial lag time was observed in biogas production for vessels with FOG addition that decreased by more than half in later runs, likely due to adaptation of the microbial community. 30% FOG with 10% FW showed the highest increase in methane production, increasing 53% compared to digestion of PS and TWAS. FOG addition above 50% VSL was found to be inhibitory with and without FW addition and resulted in volatile fatty acid (VFA) accumulation. Methane production was linked with high relative activity and abundance of syntrophic fatty-acid oxidizers alongside hydrogenotrophic methanogens, signaling the importance of interspecies interactions in AD. Specifically, relative activity of Syntrophomonas was significantly correlated with methane production. Further, methane production increased over subsequent runs along with methyl coenzyme M reductase (mcrA) gene expression, a functional gene in methanogens, suggesting temporal adaptation of the microbial community to co-digestion substrate mixtures. The study demonstrated the benefits of co-digestion in terms of performance enhancement and enrichment of key active microbial populations. PMID- 28672213 TI - Life cycle water demand coefficients for crude oil production from five North American locations. AB - The production of liquid fuels from crude oil requires water. There has been limited focus on the assessment of life cycle water demand footprints for crude oil production and refining. The overall aim of this paper is address this gap. The objective of this research is to develop water demand coefficients over the life cycle of fuels produced from crude oil pathways. Five crude oil fields were selected in the three North American countries to reflect the impact of different spatial locations and technologies on water demand. These include the Alaska North Slope, California's Kern County heavy oil, and Mars in the U.S.; Maya in Mexico; and Bow River heavy oil in Alberta, Canada. A boundary for an assessment of the life cycle water footprint was set to cover the unit operations related to exploration, drilling, extraction, and refining. The recovery technology used to extract crude oil is one of the key determining factors for water demand. The amount of produced water that is re-injected to recover the oil is essential in determining the amount of fresh water that will be required. During the complete life cycle of one barrel of conventional crude oil, 1.71-8.25 barrels of fresh water are consumed and 2.4-9.51 barrels of fresh water are withdrawn. The lowest coefficients are for Bow River heavy oil and the highest coefficients are for Maya crude oil. Of all the unit operations, exploration and drilling require the least fresh water (less than 0.015 barrel of water per barrel of oil produced). A sensitivity analysis was conducted and uncertainty in the estimates was determined. PMID- 28672214 TI - Polysaccharide matrices used in 3D in vitro cell culture systems. AB - Polysaccharides comprise a diverse class of polymeric materials with a history of proven biocompatibility and continual use as biomaterials. Recent focus on new matrices appropriate for three-dimensional (3D) cell culture offers new opportunities to apply polysaccharides as extracellular matrix mimics. However, chemical and structural bases for specific cell-polysaccharide interactions essential for their utility as 3-D cell matrices are not well defined. This review describes how these naturally sourced biomaterials satisfy several key properties for current 3D cell culture needs and can also be synthetically modified or blended with additional components to tailor their cell engagement properties. Beyond their benign interactions with many cell types in cultures, their economical and high quality sourcing, optical clarity for ex situ analytical interrogation and in situ gelation represent important properties of these polymers for 3D cell culture applications. Continued diversification of their versatile glycan chemistry, new bio-synthetic sourcing strategies and elucidation of new cell-specific properties are attractive to expand the polysaccharide polymer utility for cell culture needs. Many 3D cell culture priorities are addressed with the portfolio of polysaccharide materials available and under development. This review provides a critical analysis of their properties, capabilities and challenges in 3D cell culture applications. PMID- 28672215 TI - Silymarin impacts on immune system as an immunomodulator: One key for many locks. AB - Silymarin is a flavonoid complex extracted from the Silybum marianum plant. It acts as a strong antioxidant and free radical scavenger by different mechanisms. But in addition to antioxidant effects, silymarin/silybin reveals immunomodulatory affects with both immunostimulatory and immunosuppression activities. Different studies have shown that silymarin has the anti-inflammatory effect through the suppression of NF-kappaB signaling pathway and TNF-alpha activation. It also has different immunomodulatory activities in a dose and time dependent manner. As an immunomodulator agent, silymarin inhibits T-lymphocyte function at low doses while stimulates inflammatory processes at high doses. Studies have shown that silymarin has attenuated autoimmune, allergic, preeclampsia, cancer, and immune-mediated liver diseases and also has suppressed oxidative and nitrosative immunotoxicity. Silymarin also has indicated dual effects on proliferation and apoptosis of different cells. In conclusion, based on the current review, silymarin has a broad spectrum of immunomodulatory functions under different conditions. Recognizing the exact mechanisms of silymarin on cellular and molecular pathways would be very valuable for treatment of immune-mediated diseases. Also further studies are needed to assess the utility of silymarin in protection against autoimmune, cancer, allergic and other diseases in human subjects. PMID- 28672216 TI - Cumulative contextual risk at birth and adolescent substance initiation: Peer mediation tests. AB - BACKGROUND: Children who experience multiple adversities, such as prenatal exposure to drugs and poverty, early in development are at increased risk for the early initiation of alcohol and cigarette use. However, studies that examine potentially malleable processes associated with substance use initiation in the context of exposure to cumulative stressors are scant. This study examined associations between cumulative contextual risk at birth and initiation of alcohol and cigarette use in adolescence, testing childhood peer marginalization and peer aggression and behavior problems as mediating mechanisms. Analyses further adjusted for fearfulness/inhibition and hyperactivity/distractibility to determine if the hypothesized mediating mechanisms were significant after accounting for temperamental characteristics associated with substance initiation. METHODS: Participants were 6190 adolescents from the Northern Finland Birth Cohort 1986 Study. Data were collected on cumulative contextual risk (parent reports), substance initiation (adolescent reports), childhood peer processes and behavior problems (teacher reports), and temperamental characteristics (teacher reports). Novel discrete-time survival mediation analysis was conducted to test the hypothesized mediating mechanisms. RESULTS: Initial analyses showed that the associations between cumulative contextual risk and both alcohol and cigarette initiation were mediated by childhood peer processes and behavior problems; however, the indirect effects became statistically non-significant after adding the temperament variables, which themselves predicted substance initiation. CONCLUSIONS: Targeting peer processes may not be an effective way to interrupt pathways leading from early contextual risk to substance initiation. Instead, early screening and intervention efforts to delay substance initiation may need to be tailored to the individual temperamental characteristics of targeted participants. PMID- 28672217 TI - Do people with epilepsy have a different lifestyle? AB - BACKGROUND: Epilepsy is one of the most common neurological diseases. Its high prevalence, economic relevance and impact on daily life make it crucial that we study this condition in further detail. Our study seeks to investigate whether the lifestyle of people diagnosed with epilepsy is different to that of people without epilepsy, in order to better understand our patients. METHODS: We designed and delivered a questionnaire about quality of life and daily habits to patients from our hospital's Epilepsy Unit. We also delivered the questionnaire to a control group with similar demographic characteristics. Lifestyle differences between patients and control group members were analyzed. Patients were further divided according to the type of epilepsy, time since diagnosis, seizure frequency and pharmacotherapy. RESULTS: A total of 278 people were interviewed (85 patients, 193 controls). There was no difference in educational level, marital status and healthy habits (sports, reading and diet) between the groups. However, patients with epilepsy were more often unemployed (p<0.05) and had a healthier lifestyle (lower body mass index, lower alcohol consumption and a tendency towards smoking less). Anxiolytic-antidepressant intake was higher in patients with epilepsy. In terms of the type of epilepsy, patients with focal epilepsy exercised more than those with generalized epilepsy; no other statistically significant differences were found between the individuals studied. DISCUSSION: Epilepsy diagnosis does not seem to negatively alter the daily life of patients; in fact, many adopt a healthier lifestyle after diagnosis. The risk of antidepressant/anxiolytic intake is, however, higher, which could reflect the impact this chronic condition still has at a social level. PMID- 28672218 TI - Nanoscale characterization of forensically relevant epithelial cells and surface associated extracellular DNA. AB - Atomic force microscopy provides a novel morphological and physico-chemical perspective to analyze epithelial cell samples in forensic investigations. As a nanoscale, single cell tool, it allows the investigation of scarce samples in a non-destructive fashion. Using chemical force spectroscopy, it permits the identification of specific functional groups or surface molecules. Of specific interest is the presence of extracellular DNA (eDNA) on the surface of epithelial cells that line the exterior skin and interior cavities of human bodies, and can transfer onto surfaces through contact with skin and saliva. To date, this eDNA has only been measured a bulk level. Here, using nanoscale imaging, we first describe the unique differences between keratinized epithelial cells and non keratinized buccal cells. Then via a force mapping technique, we show how eDNA can be spatially located and quantified on the cell surface. Our results suggest that presence and relative quantity of surface-associated, extracellular DNA signatures can be analyzed on individual epithelial cells from different tissue sources, providing a new tool in the forensic analysis of touch samples. PMID- 28672219 TI - Theophylline increases saliva sonic hedgehog and improves taste dysfunction. AB - OBJECTIVE: To determine changes in saliva sonic hedgehog (Shh) and in taste dysfunction before and after oral theophylline treatment. DESIGN: Shh was measured in parotid saliva of both normal subjects and patients with taste dysfunction of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Taste dysfunction was defined clinically by both subjective inhibition of taste function (including acuity loss) and impaired gustometry. RESULTS: Theophylline treatment increased patient saliva Shh and improved taste dysfunction both subjectively and by gustometry. CONCLUSIONS: By use of these systematic clinical measurements theophylline can be demonstrated to increase saliva Shh and improve taste dysfunction. These results are consistent with saliva Shh acting as a taste bud growth factor which stimulates stem cells of taste buds to initiate development and perpetuation of taste bud receptors. Measurements of saliva Shh provide an important marker for the presence of taste dysfunction and in the improvement by theophylline treatment. PMID- 28672220 TI - Maternal breastfeeding and children's cognitive development. AB - Do children with lower test scores benefit more from breastfeeding than those with higher scores? In this paper, I examine the distributional effects of maternal breastfeeding on the cognitive test scores of 11,544 children who were born in 2000 and 2001 in the United Kingdom using a semiparametric quantile regression model. I find evidence that maternal breastfeeding has larger positive impacts on children with lower test scores. Effects for children below the 20th percentile are about 2-2.5 times greater than those for children above the 80th percentile. I also find that these distributional effects are larger when the duration of breastfeeding is extended. One policy implication is that a public policy aims at promoting breastfeeding might narrow a disparity in children's cognition. PMID- 28672221 TI - Designing structural-motifs for the preparation of acylated proinsulin and their regiospecific conversion into insulin modified at Lys29 (K29). AB - Eight proinsulin encoding genes were prepared and their translation products, when treated with a cocktail of trypsin and carboxypeptidase B, analyzed for the following features. One, their ability to undergo facile removal of the N terminal linker, generating the phenylalanine residue destined to be the N terminal of the B-chain of insulin, at a rate similar to that involved in the removal of the C-peptide. Two, processing of diarginyl insulin, produced in the latter process, by carboxypeptidase B then needed to be rapid to remove the two arginine residues, Three, both these operations were to be efficient whether the N-terminal methionine was acylated or not. Four, the proinsulin constructs needed to contain a minimum number of sites for acylation. The aforementioned features were monitored by mass spectrometry and the proinsulin derivative containing MRR at the N-terminal and K64 mutated to Q64, designated as MRR-(Q64) human proinsulin [MRR-(Q64) hpi] optimally fulfilled these requirements. The derivative was smoothly acylated with reagents of two chain lengths (acetyl and dodecanoyl) to give acetyl/dodecanoyl MRR-(Q64) hpi. Acetyl MRR-(Q64) hpi, using the cocktail of the two enzymes, was smoothly converted into, acetyl insulin. However, when dodecanoyl MRR-(Q64) hpi was processed with the above cocktail, carboxypeptidase B (whether from animal pancreas or recombinant) showed an unexpected specificity of acting on the K29-T30 bond of the insulin derivatives when K29 contained a large hydrophobic acyl group, generating dodecanoyl des-30 insulin. PMID- 28672222 TI - Relationship between behavioural problems and use of mental health services in patients with severe mental illness and the mediating role of the perceived burden of care. AB - Mental health models proposed for predicting more use of mental health resources by patients with severe mental illness are including a wider variety of predictor variables, but there are still many more remaining to be explored for a complete model. The purpose of this study was to enquire into the relationship between two variables, behaviour problems and burden of care, and the use of mental health resources in patients with severe mental illness. Our hypothesis was that perceived burden of care mediates between behaviour problems of patients with serious mental illness and the use of mental health resources. The Behaviour Problem Inventory, which was filled out by the main caregiver, was used to evaluate 179 patients cared for in a community mental health unit. They also answered a questionnaire on perceived family burden. A structural equation analysis was done to test our hypothesis. The results showed that both the behaviour problems and perceived burden of care are good predictors of the use of mental health resources, where perceived burden of care mediates between behaviour problems and use of resources. These variables seem to be relevant for inclusion in complete models for predicting use of mental health resources. PMID- 28672223 TI - Complete genome sequence of Ostreid herpesvirus type 1 uVar isolated during mortality events in the Pacific oyster Crassostrea gigas in France and Ireland. AB - Infections with Ostreid herpesvirus 1 (OsHV-1) microvariants in young Pacific oysters are associated with massive mortality events and significant economic losses. Previous studies, focusing on few regions of the genome, have revealed the genomic diversity of these genotypes with respect to the reference type. We used a NGS process to sequence the whole genome of the OsHV-1 uVar in infected individuals, collected during mortality events in France and Ireland. The final genome length of OsHV-1 uVar was approximately 205kbp, shorter than the reference genotype and the overall genome organisation resembled herpes simplex viruses. 94.4% similarity was observed with the OsHV-1 reference genotype. Large indels, including five deletions and three insertions were found to induce the loss and the addition of several ORFs, summed with codon substitutions in 64% of genes shared with the reference type. This diversity raises the question of the exact origin and evolution of OsHV-1 uVar. PMID- 28672224 TI - Assessment of myocardial viability based on dual-energy computed tomography in patients with chronic myocardial infarction: comparison with magnetic resonance imaging. AB - PURPOSE: To evaluate the diagnostic performance of dual-energy computed tomography (DECT) for the assessment of myocardial viability compared with magnetic resonance imaging (MRI) in patients with chronic myocardial infarction (CMI). METHODS AND MATERIAL: Twenty-six patients were prospectively enrolled, who underwent DECT and MRI at delayed phase. The infarct volumes for DECT and MRI were measured. RESULTS: In per-segment and per-vessel analysis, DECT showed excellent diagnostic performance compared with MRI (diagnostic accuracy: 86.2%, 81.2% respectively). In volume analysis, DECT correlated well with MRI (r=0.966, p<0.0001). CONCLUSIONS: DECT has excellent diagnostic performance for detecting CMI. PMID- 28672225 TI - Acculturation styles and their associations with psychiatric symptoms and quality of life in ethnic minorities with schizophrenia. AB - This study examined whether Berry's model of acculturative stress would predict psychiatric symptom severity and quality of life (QoL) in ethnic minorities with schizophrenia. Tested extensively in non-psychiatric populations, Berry's framework generally suggests that integration, or engagement with both the host and minority culture, is most adaptive. Using the Abbreviated Multidimensional Acculturation Scale (AMAS), we tested the hypothesis that individuals with schizophrenia who employed an integrative acculturation strategy would have the highest QoL and lowest symptom severity, followed by the assimilation and enculturation groups, then the marginalized group. Psychiatric symptoms and QoL were regressed on AMAS assimilation scores, enculturation scores, and the interaction term in a sample of 128 Hispanic and Blacks with schizophrenia (M age = 41.28; 70% male). Acculturation strategy was not found to relate to psychiatric symptoms (measured from the Brief Psychiatric Rating Scale). However, acculturation strategy did predict QoL (measured from the Quality of Life Inventory), and results were in line with Berry's model. Marginalization may exacerbate issues surrounding social identity in schizophrenia, including low self-concept clarity and internalized stigma. Encouraging bicultural individuals with schizophrenia to interact with the host culture while also practicing traditions from their minority culture may help improve their quality of life. PMID- 28672227 TI - Pyrimethanil degradation by photo-Fenton process: Influence of iron and irradiance level on treatment cost. AB - This study evaluates the combined effect of photo-catalyst concentration and irradiance level on photo-Fenton efficiency when this treatment is applied to industrial wastewater decontamination. Three levels of irradiance (18, 32 and 46W/m2) and three iron concentrations (8, 20 and 32mg/L) were selected and their influence over the process studied using a raceway pond reactor placed inside a solar box. For 8mg/L, it was found that there was a lack of catalyst to make use of all the available photons. For 20mg/L, the treatment always improved with irradiance indicating that the process was photo-limited. For 32mg/L, the excess of iron caused an excess of radicals production which proved to be counter productive for the overall process efficiency. The economic assessment showed that acquisition and maintenance costs represent the lowest relative values. The highest cost was found to be the cost of the reagents consumed. Both sulfuric acid and sodium hydroxide are negligible in terms of costs. Iron cost percentages were also very low and never higher than 10.5% while the highest cost was always that of hydrogen peroxide, representing at least 85% of the reagent costs. Thus, the total costs were between 0.76 and 1.39?/m3. PMID- 28672226 TI - Proactive and reactive inhibitory control in eating disorders. AB - Altered inhibitory control has been implicated in the development and maintenance of eating disorders (ED), however it is unclear how different types of inhibitory control are affected across the EDs. We explored whether individuals with bulimia nervosa (BN), binge eating disorder (BED) and anorexia nervosa (AN) differed from healthy individuals (HC) on two types of motor inhibitory control: proactive inhibition (related to the preparation/initiation of a response) and reactive inhibition (withholding a response in reaction to a signal). Ninety-four women (28 AN, 27 BN, 11 BED, 28 HC) completed two neuropsychological tasks (a cued reaction time task and a stop signal task), and questionnaires assessing clinical variables, mood, anxiety, and inhibitory control. Self-reported inhibitory control was poorer in women with BN compared to the HC and AN groups, but greater in women with AN compared to all other groups. However, no group differences in reactive inhibition were observed. Proactive inhibition was augmented in women with AN compared to HC, and this was related to self-reported intolerance of uncertainty. The findings suggest that proactive inhibition may be a relevant target for behavioural interventions for AN, and call for further research into the relationship between intolerance of uncertainty and proactive inhibition. PMID- 28672228 TI - Uranium mining wastes: The use of the Fish Embryo Acute Toxicity Test (FET) test to evaluate toxicity and risk of environmental discharge. AB - Active and abandoned uranium mining sites often create environmentally problematic situations, since they cause the contamination of all environmental matrices (air, soil and water) with stable metals and radionuclides. Due to their cytotoxic, genotoxic and teratogenic properties, the exposure to these contaminants may cause several harmful effects in living organisms. The Fish Embryo Acute Toxicity Test (FET) test was employed to evaluate the genotoxic and teratogenic potential of mine liquid effluents and sludge elutriates from a deactivated uranium mine. The aims were: a) to determine the risk of discharge of such wastes in the environment; b) the effectiveness of the chemical treatment applied to the uranium mine water, which is a standard procedure generally applied to liquid effluents from uranium mines and mills, to reduce its toxicological potential; c) the suitability of the FET test for the evaluation the toxicity of such wastes and the added value of including the evaluation of genotoxicity. Results showed that through the FET test it was possible to determine that both elutriates and effluents are genotoxic and also that the mine effluent is teratogenic at low concentrations. Additionally, liquid effluents and sludge elutriates affect other parameters namely, growth and hatching and that water pH alone played an important role in the hatching process. The inclusion of genotoxicity evaluation in the FET test was crucial to prevent the underestimation of the risks posed by some of the tested effluents/elutriates. Finally, it was possible to conclude that care should be taken when using benchmark values calculated for specific stressors to evaluate the risk posed by uranium mining wastes to freshwater ecosystems, due to their chemical complexity. PMID- 28672229 TI - Chloromethane emissions in human breath. AB - Chloromethane (CH3Cl), currently the most abundant chlorinated organic compound in the atmosphere at around ~550 parts per trillion by volume (pptv), is considered responsible for approximately 16% of halogen-catalyzed stratospheric ozone destruction. Although emissions of CH3Cl are known to occur from animals such as cattle, formation and release of CH3Cl from humans has not yet been reported. In this study a pre-concentration unit coupled with a gas chromatograph directly linked to a mass spectrometer was used to precisely measure concentrations of CH3Cl at the pptv level in exhaled breath from 31 human subjects with ages ranging from 3 to 87years. We provide analytical evidence that all subjects exhaled CH3Cl in the range of 2.5 to 33 parts per billion by volume, levels which significantly exceed those of inhaled air by a factor of up to 60. If the mean of these emissions was typical for the world's population, then the global source of atmospheric CH3Cl from humans would be around 0.66Ggyr-1 (0.33 to 1.48Ggyr-1), which is less than 0.03% of the total annual global atmospheric source strength. The observed endogenous formation of a chlorinated methyl group in humans might be of interest to biochemists and medical scientists as CH3Cl is also known to be a potent methylating agent and thus, could be an important target compound in future medical research diagnostic programs. PMID- 28672230 TI - Understanding fire drivers and relative impacts in different Chinese forest ecosystems. AB - In this study, spatial patterns and driving factors of fires were identified from 2000 to 2010 using Ripley's K (d) function and logistic regression (LR) model in two different forest ecosystems of China: the boreal forest (Daxing'an Mountains) and sub-tropical forest (Fujian province). Relative effects of each driving factor on fire occurrence were identified based on standardized coefficients in the LR model. Results revealed that fires were spatially clustered and that fire drivers vary amongst differing forest ecosystems in China. Fires in the Daxing'an Mountains respond primarily to human factors, of which infrastructure is recognized as the most influential. In contrast, climate factors played a critical role in fire occurrence in Fujian, of which the temperature of fire season was found to be of greater importance than other climate factors. Selected factors can predict nearly 80% of the total fire occurrence in the Daxing'an Mountains and 66% in Fujian, wherein human and climate factors contributed the greatest impact in the two study areas, respectively. This study suggests that different fire prevention and management strategies are required in the areas of study, as significant variations of the main fire-driving exist. Rapid socio economic development has produced similar effects in different forest ecosystems within China, implying a strong correlation between socio-economic development and fire regimes. It can be concluded that the influence of human factors will increase in the future as China's economy continues to grow - an issue of concern that should be further addressed in future national fire management. PMID- 28672231 TI - The surface urban heat island response to urban expansion: A panel analysis for the conterminous United States. AB - Urban heat island (UHI), the phenomenon that urban areas experience higher temperatures compared to their surrounding rural areas, has significant socioeconomic and environmental impacts. With current and anticipated rapid urbanization, improved understanding of the response of UHI to urbanization is important for developing effective adaptation measures and mitigation strategies. Current studies mainly focus on a single or a few big cities and knowledge on the response of UHI to urbanization for large areas is limited. As a major indicator of urbanization, urban area size lends itself well for representation in prognostic models. However, we have little knowledge on how UHI responds to urban area size increase and its spatial and temporal variation over large areas. In this study, we investigated the relationship between surface UHI (SUHI) and urban area size in the climate and ecological context, and its spatial and temporal variations, based on a panel analysis of about 5000 urban areas of 10km2 or larger, in the conterminous U.S. We found statistically significant positive relationship between SUHI and urban area size, and doubling the urban area size led to a SUHI increase as high as 0.7 degrees C. The response of SUHI to the increase of urban area size shows spatial and temporal variations, with stronger SUHI increase in Northern U.S., and during daytime and summer. Urban area size alone can explain as much as 87% of the variance of SUHI among cities studied, but with large spatial and temporal variations. Urban area size shows higher association with SUHI in regions where the thermal characteristics of land cover surrounding the urban area are more homogeneous, such as in Eastern U.S., and in the summer months. This study provides a practical approach for large-scale assessment and modeling of the impact of urbanization on SUHI, both spatially and temporally. PMID- 28672232 TI - Response of bacterial communities to Pb smelter pollution in contrasting soils. AB - Anthropogenic inputs of trace elements (TE) into soils constitute a major public and environmental health problem. Bioavailability of TE is strongly related to the soil physicochemical parameters and thus to the ecosystem type. In order to test whether soil parameters influence the response of the bacterial community to TE pollution, we collected soil samples across contrasting ecosystems (hardwood, coniferous and hydromorphic soils), which have been contaminated in TE and especially lead (Pb) over several decades due to nearby industrial smelting activities. Bacterial community composition was analysed using high throughput amplicon sequencing and compared to the soil physicochemical parameters. Multivariate analyses of the pedological and biological data revealed that the bacterial community composition was affected by ecosystem type in the first place. An influence of the contamination level was also evidenced within each ecosystem. Despite the important variability in bacterial community structure, we found that specific bacterial groups such as gamma-Proteobacteria, Verrucomicrobia and Chlamydiae showed a consistent response to Pb content across contrasting ecosystems. Verrucomicrobia were less abundant at high contamination level whereas Chlamydiae and gamma-Proteobacteria were more abundant. We conclude that such groups and ratio's thereof can be considered as relevant bioindicators of Pb contamination. PMID- 28672233 TI - Implications of changing spatial dynamics of irrigated pasture, California's third largest agricultural water use. AB - Irrigated agriculture is practiced on 680 million acres worldwide. Irrigated grazing land is likely a significant portion of that area but estimating an accurate figure has remained problematic. Due to its significant contribution to agricultural water use worldwide, we develop a methodology to remotely sense irrigated pasture using a California case study. Irrigated pasture is the third largest agricultural water use in California, yet its economic returns are low. As pressures mount for the agricultural sector to be more water efficient and for water to be directed towards its most economically valuable uses, there will likely be a reduction in irrigated pasture acreage. A first step in understanding the importance of irrigated pasture in California is establishing a methodology to quantify baseline information about its area, location, and current rate of loss. This study used a novel object-based image analysis and supervised classification on publicly-available, high resolution, remote sensing National Agriculture Imaging Program (NAIP) imagery to develop a highly accurate map of irrigated pasture in a rural county in California's Sierra foothills. Irrigated pasture was found to have decreased by 19% during the ten-year period, 2005-2014, from 4,273 to 3,470 acres. The implications of this loss include potential impacts to wetland-dependent species, groundwater recharge, game species, traditional ranching culture, livestock production, and land conservation. Overall accuracy in classification across years was consistently over 89%. Comparing these results against available measurements of irrigated pasture provided by state and federal agencies reveals that this method significantly improves upon existing metrics and methods of data collection and points to critical needs for new targeted research and monitoring efforts. Broadly, the analysis presented here provides an improved methodology for mapping irrigated pasture that can be extended to provide accurate and spatially-explicit data for other counties in California and other arid and semi-arid regions worldwide. PMID- 28672234 TI - Zinc fertilisation increases grain zinc and reduces grain lead and cadmium concentrations more in zinc-biofortified than standard wheat cultivar. AB - Given that plant uptake and transport systems for metals have some similarities, zinc (Zn)-biofortified cultivars may concurrently accumulate non-essential toxic heavy metals in grains. However, Zn-biofortified cultivars have never been tested for heavy metal accumulation in grains. In a pot experiment, we compared Zn biofortified wheat (Zincol-2016) with a standard wheat (Faisalabad-2008) cultivar on heavy-metal-contaminated soils for yield response and grain accumulation of Zn, lead (Pb) and cadmium (Cd), without or with Zn fertilisation (8mgZnkg-1). The soils, collected from agricultural fields in (i) industrial zone and (ii) peri urban area, had been receiving industrial and city effluents for >20years. In the two soils, Zn fertilisation significantly (P<=0.05) increased grain yield of both cultivars. Zinc fertilisation increased grain Zn concentration of Zincol-2016 and Faisalabad-2008 by respectively 32 and 18% in industrial-zone soil, and by 15 and 2% in peri-urban soil. Averaged across Zn rates, Zincol-2016 accumulated in grains more than double the Zn amount than Faisalabad-2008 in industrial-zone soil. At 0mgZnkg-1, grain Pb and Cd concentrations were respectively 26 and 33% greater in Zincol-2016 than Faisalabad-2008 in industrial-zone soil, and 86 and 50% greater in Zincol-2016 than Faisalabad-2008 in peri-urban soil. Zinc fertilisation significantly (P<=0.05) decreased concentration of Pb and Cd in grains of both cultivars. In industrial-zone soil, a toxic level of Pb in grains (0.24mgkg-1) was attained at control rate of Zn by Zincol-2016, and was decreased to a safe level (0.07mgkg-1) by application of 8mgZnkg-1. Therefore, biofortified cultivars should not be grown in contaminated soils, and/or sufficient Zn must be applied, to decrease accumulation of non-essential toxic heavy metals in grains. Moreover, future breeding efforts should be directed toward selection of biofortified cultivars that would selectively accumulate Zn in grains, but not the contaminants. PMID- 28672235 TI - Geochemistry and toxicity of a large slag pile and its drainage complex in Sudbury, Ontario. AB - Slag piles from mining activities are common worldwide, but in contrast to mine tailings the environmental impact of runoff from slag piles is less documented. This study was designed to assess the geochemistry and potential toxicity of water draining a large, 62.2ha slag pile in Sudbury, Ontario. The Coniston slag pile contains 12-20Mt of slag from smelting local Ni-Cu ore between 1913 and 1972. Slag leaching experiments confirmed slag is a source of sulphate (SO4), heavy metals (including Fe, Al, Ni, Co, Cu, Zn, Pb, Cr, Mn) and base cations (Ca, K, Mg, Na). Concentrations of some metals draining through slag in column experiments were similar to concentrations measured at the base of the slag pile, although base cations, SO4 and pH were much higher, possibly because of water inputs interacting with the surrounding basic glaciolacustrine landscape. The high pH rapidly precipitates metals, leading to high accumulations in surface sediments in the pond-wetland complex draining from the pile. Away from the pile's base, vegetation cover increases, which increases dissolved organic carbon (DOC) and nutrient concentrations in runoff along with metals with strong binding affinities (e.g. Cu). Total metal concentration in water and sediment exceed provincial guidelines, particularly near the slag pile, however WHAM7 modeling indicated the free metal ion concentration in water is very low. Nevertheless, 48 h toxicity experiments showed that water with greater concentrations of solutes collected close to the slag negatively impacts D. magna, suggesting water draining the slag pile can adversely impact biota in nearby drainage areas. PMID- 28672236 TI - Developing and applying metamodels of high resolution process-based simulations for high throughput exposure assessment of organic chemicals in riverine ecosystems. AB - As defined by Wikipedia (https://en.wikipedia.org/wiki/Metamodeling), "(a) metamodel or surrogate model is a model of a model, and metamodeling is the process of generating such metamodels." The goals of metamodeling include, but are not limited to (1) developing functional or statistical relationships between a model's input and output variables for model analysis, interpretation, or information consumption by users' clients; (2) quantifying a model's sensitivity to alternative or uncertain forcing functions, initial conditions, or parameters; and (3) characterizing the model's response or state space. Using five models developed by the US Environmental Protection Agency, we generate a metamodeling database of the expected environmental and biological concentrations of 644 organic chemicals released into nine US rivers from wastewater treatment works (WTWs) assuming multiple loading rates and sizes of populations serviced. The chemicals of interest have log n-octanol/water partition coefficients (logKOW) ranging from 3 to 14, and the rivers of concern have mean annual discharges ranging from 1.09 to 3240m3/s. Log-linear regression models are derived to predict mean annual dissolved and total water concentrations and total sediment concentrations of chemicals of concern based on their logKOW, Henry's Law Constant, and WTW loading rate and on the mean annual discharges of the receiving rivers. Metamodels are also derived to predict mean annual chemical concentrations in fish, invertebrates, and periphyton. We corroborate a subset of these metamodels using field studies focused on brominated flame retardants and discuss their application for high throughput screening of exposures to human and ecological populations and for analysis and interpretation of field data. PMID- 28672237 TI - Long-term variation in concentrations and mass loads in a semi-arid watershed influenced by historic mercury mining and urban pollutant sources. AB - Urban watersheds are significantly anthropogenically-altered landscapes. Most previous studies cover relatively short periods, without addressing concentrations, loads, and yields in relation to annual climate fluctuations, and datasets on Ag, Se, PBDEs, and PCDD/Fs are rare. Intensive storm-focused sampling and continuous turbidity monitoring were employed to quantify pollution at two locations in the Guadalupe River (California, USA). At a downstream location, we determined loads of suspended sediment (SS) for 14yrs., mercury (HgT), PCBs, and total organic carbon (TOC) (8yrs), total methylmercury (MeHgT) (6yrs), nutrients, and trace elements including Ag and Se (3yrs), DDTs, chlordanes, dieldrin, and PBDEs (2yrs), and PCDD/Fs (1yr). At an upstream location, we determined loads of SS for 4yrs. and HgT, MeHgT, PCBs and PCDD/Fs for 1yr. These data were compared to previous studies, climatically adjusted, and used to critically assess the use of small datasets for estimating annual average conditions. Concentrations and yields in the Guadalupe River appear to be atypical for total phosphorus, DDTs, dieldrin, HgT, MeHgT, Cr, Ni, and possibly Se due to local conditions. Other pollutants appear to be similar to other urban systems. On average, wet season flow varied by 6.5-fold and flow-weighted mean (FWM) concentrations varied 4.4 fold, with an average 7.1-fold difference between minimum and maximum annual loads. Loads for an average runoff year for each pollutant were usually less than the best estimate of long-term average. The arithmetic average of multiple years of load data or a FWM concentration combined with mean annual flow was also usually below the best estimate of long-term average load. Mean annual loads using sampled years were also less than the best estimate of long-term average by a mean of 2.2-fold. Climatic adjustment techniques are needed for computing estimates of long-term average annual loads. PMID- 28672238 TI - Reassessment and update of emission factors for unintentional dioxin-like polychlorinated biphenyls. AB - One of the major goals of the Stockholm Convention on Persistent Organic Pollutants is to continuously reduce the releases of unintentional persistent organic pollutants (POPs) such as polychlorinated dibenzo-para-dioxins and dibenzofurans (PCDD/PCDF) or polychlorinated biphenyls (PCB) from anthropogenic sources. Until now, most efforts have focused on the releases of PCDD/PCDF and to a lesser extent on unintentionally generated PCB, and therefore, release inventories reported as toxic equivalents (TEQ) do not include the twelve dioxin like PCB (dl-PCB). In order to facilitate the development of national release inventories for the total TEQ - consisting of PCDD, PCDF and PCB - this study collected and summarized published emission factors (EFs) of unintentional dl-PCB or calculated them from measured data for the sources listed in the UNEP Toolkit. In total, 286 EFs for dl-PCB were found (or could be calculated) whereby 233 described release to air, 23 EFs addressed to residue, 25 EFs to product; and only 5 EFs addressed releases to land. Taking into account performance criteria such as the facility type and scale or abatement technologies, the EFs were grouped and assigned to the source categories and/or classes used in the UNEP Toolkit. With these newly added data and EFs of dl-PCB, the already existing EFs in the Toolkit can be improved and amended. In addition, a statistically significant correlation between the EFAir of dl-PCB proposed in this study and EFAir of PCDD/PCDF recommended in the Toolkit was observed. PMID- 28672239 TI - Separation and identification of hormone-active compounds using a combination of chromatographic separation and yeast-based reporter assay. AB - Arxula adeninivorans-based yeast cell assays for the detection of steroid hormones demonstrated their efficiency for the determination of total hormone activity in a variety of samples using a microtiter plate format. In this study, a preliminary chromatographic separation using thin-layer chromatography plates is introduced in order to allow a rapid identification of the compounds responsible for this hormonal activity. The yeast whole cell assay can then be performed on the plate, producing a detectable signal where a steroid hormone is present. Simultaneous detection of estrogens, progestogens and androgens on the same plate in the picogram range was achieved, while keeping the assay as simple and affordable as possible. The assay requires a single incubation of the thin layer chromatography plate and the detection of reporter protein production can be performed by fluorescence scanning of the plate at different wavelengths. The chromatographic separation allows the separation of several estrogens, androgens and progestogens, thus making its application for 'real world' samples very useful. In this work, different water-based samples from environmental origins were used to demonstrate the capacity of this new bioassay. Trials showed that most samples, with the exception of complex samples such as wastewater influent, can be assayed. PMID- 28672240 TI - Land-use and fire drive temporal patterns of soil solution chemistry and nutrient fluxes. AB - Land-use type and ecosystem disturbances are important drivers for element cycling and bear the potential to modulate soil processes and hence ecosystem functions. To better understand the effect of such drivers on the magnitude and temporal patterns of organic matter (OM) and associated nutrient fluxes in soils, continuous flux monitoring is indispensable but insufficiently studied yet. We conducted a field study to elucidate the impact of land-use and surface fires on OM and nutrient fluxes with soil solution regarding seasonal and temporal patterns analyzing short (<3months) and medium-term (3-12months) effects. Control and prescribed fire-treated topsoil horizons in beech forests and pastures were monitored biweekly for dissolved and particulate OM (DOM, POM) and solution chemistry (pH value, elements: Ca, Mg, Na, K, Al, Fe, Mn, P, S, Si) over one post fire year. Linear mixed model analyses exhibited that mean annual DOM and POM fluxes did not differ between the two land-use types, but were subjected to strong seasonal patterns. Fire disturbance significantly lowered the annual soil solution pH in both land-uses and increased water fluxes, while DOC fluxes remained unaffected. A positive response of POC and S to fire was limited to short-term effects, while amplified particulate and dissolved nitrogen fluxes were observed in the longer run and co-ocurred with accelerated Ca and Mg fluxes. In summary, surface fires generated stronger effects on element fluxes than the land-use. Fire-induced increases in POM fluxes suggest that the particulate fraction represent a major pathway of OM translocation into the subsoil and beyond. With regard to ecosystem functions, pasture ecosystems were less prone to the risk of nutrient losses following fire events than the forest. In pastures, fire-induced base cation export may accelerate soil acidification, consequently exhausting soil buffer systems and thus may reduce the resilience to acidic depositions and disturbances. PMID- 28672241 TI - Long-term dynamics of a floodplain shallow lake in the Pantanal wetland: Is it all about climate? AB - Hydrological variability over seasonal and multi-annual timescales strongly shapes the ecological structure and functioning of floodplain ecosystems. The current IPCC climate scenario foresees an increase in the frequency of extreme events. This, in conjunction with other anthropogenic disturbances (e.g., river regulation or land-use changes) poses a serious threat to the natural functioning of these ecosystems. In this study we aimed to i) evaluate the long-term variability of the flooded area of the third largest floodplain lake in the Brazilian Pantanal using remote sensing techniques, and ii) analyze the possible factors influencing this variability. Changes in open-water and riparian floodplain-wetland vegetation areas were mapped by applying an ad hoc-developed remote-sensing method (including a newly developed normalized water index, NWI) to 221 Landsat-Thematic Mapper (TM)/Enhanced Thematic Mapper Plus (ETM+) images, acquired between 1984 and 2011. Added to the lake's natural swing between riparian floodplain-wetland vegetation expansion and retraction, our analyses revealed large interannual changes, grouped into three main periods within the studied time interval. Moreover, our results indicate that this floodplain-lake system is losing open-water area, paired with an increase in riparian floodplain wetland vegetation. The system's long-term dynamics are not all climate related, but are the result of a combination of drivers. The start of the Manso dam's operation upstream of the studied system, and the subsequent river regulation because of the dam operation, coupled with climatic oscillation appear to be responsible for the observed changes. However, other factors which were not considered in this study might also be important in this process and contributing to the reduction of the system's resilience to droughts (e.g., land-use changes). This study illustrates the serious conservation risks that the Pantanal faces in the near future, given the current climate-change scenario and the accumulation of dam building projects in this region. PMID- 28672242 TI - Comparison of two methodologies used to estimate erosion rates in Mediterranean ecosystems: 137Cs and exposed tree roots. AB - The 137Cs deposited in soil and exposed tree roots have been widely applied to estimate medium-term soil erosion rates. However, comparative studies between these methods are scarce. For this purpose, three hillsides in two Mediterranean dehesas (rangeland with disperse tree cover) were selected. Regarding the 137Cs technique, a reference site close to the study areas and with similar altitude and rainfall was selected. In order to reduce uncertainties related to the use of point soil profiles, all those collected in an area were combined to form a representative composite profile. The total inventory was 2790+/-50Bq/m2, and the relaxation coefficient indicated it was an undisturbed soil. The radiocaesium inventory in the study areas was 14-23% lower than in the reference area. The erosion rates for 137Cs were in the range 20.9-38.1tha-1y-1. The exposed root technique was applied to holm oak trees (age about 90years), and the erosion rates were in the range 22-34tha-1y-1. The ratio between exposed root and 137Cs techniques was 1.02+/-0.11 (S.D.) within the range 0.89-1.2. Both methods produced very similar results equally with respect to the mean erosion rate as well as the relative difference between the hillslope sections, i.e. displaying the same spatial variation in the study areas. As the accounting time for these two techniques is different, 50 and 90y for 137Cs and exposed roots respectively, results suggest that no change in mid-term erosion rates was implied for these areas for almost a century. The use of 137Cs and exposed roots methodology for the determination of mean erosion rates can be reproduced in other ecosystems, but a careful selection of the reference site for 137Cs is essential. PMID- 28672243 TI - Evidence for a weakening strength of temperature-corn yield relation in the United States during 1980-2010. AB - Temperature is known to be correlated with crop yields, causing reduction of crop yield with climate warming without adaptations or CO2 fertilization effects. The historical temperature-crop yield relation has often been used for informing future changes. This relationship, however, may change over time following alternations in other environmental factors. Results show that the strength of the relationship between the interannual variability of growing season temperature and corn yield (RGST_CY) has declined in the United States between 1980 and 2010 with a loss in the statistical significance. The regression slope which represents the anomalies in corn yield that occur in association with 1 degree temperature anomaly has decreased significantly from -6.9%/K of the first half period to -2.4%/K--3.5%/K of the second half period. This implies that projected corn yield reduction will be overestimated by a fact of 2 in a given warming scenario, if the corn-temperature relation is derived from the earlier historical period. Changes in RGST_CY are mainly observed in Midwest Corn Belt and central High Plains, but are partly reproduced by 11 process-based crop models. In Midwest rain-fed systems, the decrease of negative temperature effects coincides with an increase in water availability by precipitation. In irrigated areas where water stress is minimized, the decline of beneficial temperature effects is significantly related to the increase in extreme hot days. The results indicate that an extrapolation of historical yield response to temperature may bias the assessment of agriculture vulnerability to climate change. Efforts to reduce climate impacts on agriculture should pay attention not only to climate change, but also to changes in climate-crop yield relations. There are some caveats that should be acknowledged as the analysis is restricted to the changes in the linear relation between growing season mean temperature and corn yield for the specific study period. PMID- 28672244 TI - Macrophyte assemblage composition as a simple tool to assess global change in coastal areas. Freshwater impacts and climatic changes. AB - Macrophyte assemblages are one of the most sensitive biological communities to assess anthropogenic impacts and climate changes. Community composition responds very quickly to environmental changes driving towards a predictable composition. The increase or decrease of the trophic status (i.e. nutrient concentrations, suspended particulate matter, Chlorophyll-a) and temperature are the most important factors responsible for the replacement of taxa of high ecological value (sensitive taxa) with opportunistic species. A qualitative and quantitative study of macrophytes in 4 areas along the coasts of the Northern Adriatic Sea, from Venice (Italy) to Savudrija (Croatia) and the analysis of river outflows in this region during one year (May 2012-April 2013) provided information about their spatial variability. The coasts of the Veneto Region and Friuli-Venezia Giulia, which are affected by significant freshwater inputs, showed a strong biodiversity reduction or a dominance of thionitrophilic taxa. No seagrasses colonized these areas. On the other hand, the coasts of Croatia had negligible fresh water inputs and macrophyte communities were dominated by sensitive taxa such as the seagrass Cymodocea nodosa and some species belonging to genus Cystoseira. PMID- 28672245 TI - A method for assessing exposure of terrestrial wildlife to environmental radon (222Rn) and thoron (220Rn). AB - A method is presented to calculate radiation dose rates arising from radon, thoron and their progeny to non-human biota in the terrestrial environment. The method improves on existing methodologies for the assessment of radon to biota by using a generalised allometric approach to model respiration, calculating dose coefficients for the ICRP reference animals and plants, and extending the approach to cover thoron in addition to radon-derived isotopes. The method is applicable to a range of environmental situations involving these radionuclides in wildlife, with an envisaged application being to study the impact of human activities, which bring NORM radionuclides to the biosphere. Consequently, there is a need to determine whether there is an impact on non-human biota from exposure to anthropogenically enhanced radionuclides. PMID- 28672246 TI - Exposure to wastewater effluent affects fish behaviour and tissue-specific uptake of pharmaceuticals. AB - Pharmaceutical active compounds (PhACs) are increasingly being reported in wastewater effluents and surface waters around the world. The presence of these products, designed to modulate human physiology and behaviour, has created concern over whether PhACs similarly affect aquatic organisms. Though laboratory studies are beginning to address the effects of individual PhACs on fish behaviour, few studies have assessed the effects of exposure to complex, realistic wastewater effluents on fish behaviour. In this study, we exposed a wild, invasive fish species-the round goby (Neogobius melanostomus)-to treated wastewater effluent (0%, 50% or 100% effluent dilutions) for 28days. We then determined the impact of exposure on fish aggression, an important behaviour for territory acquisition and defense. We found that exposure to 100% wastewater effluent reduced the number of aggressive acts that round goby performed. We complimented our behavioural assay with measures of pharmaceutical uptake in fish tissues. We detected 11 of 93 pharmaceutical compounds that we tested for in round goby tissues, and we found that concentration was greatest in the brain followed by plasma, then gonads, then liver, and muscle. Fish exposed to 50% and 100% effluent had higher tissue concentrations of pharmaceuticals and concentrated a greater number of pharmaceutical compounds compare to control fish exposed to no (0%) effluent. Exposed fish also showed increased ethoxyresorufin-O deethylase (EROD) activity in liver tissue, suggesting that fish were exposed to planar halogenated/polycyclic aromatic hydrocarbons (PHHs/PAHs) in the wastewater effluent. Our findings suggest that fish in effluent-dominated systems may have altered behaviours and greater tissue concentration of PhACs. Moreover, our results underscore the importance of characterizing exposure to multiple pollutants, and support using behaviour as a sensitive tool for assessing animal responses to complex contaminant mixtures, like wastewater effluent. PMID- 28672247 TI - Biomagnification of persistent organic pollutants in a deep-sea, temperate food web. AB - Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and polychlorinated dibenzo-p-dioxins and -furans (PCDD/Fs) were measured in a temperate, deep-sea ecosystem, the Aviles submarine Canyon (AC; Cantabrian Sea, Southern Bay of Biscay). There was an increase of contaminant concentration with the trophic level of the organisms, as calculated from stable nitrogen isotope data (delta15N). Such biomagnification was only significant for the pelagic food web and its magnitude was highly dependent on the type of top predators included in the analysis. The trophic magnification factor (TMF) for PCB-153 in the pelagic food web (spanning four trophic levels) was 6.2 or 2.2, depending on whether homeotherm top predators (cetaceans and seabirds) were included or not in the analysis, respectively. Since body size is significantly correlated with delta15N, it can be used as a proxy to estimate trophic magnification, what can potentially lead to a simple and convenient method to calculate the TMF. In spite of their lower biomagnification, deep-sea fishes showed higher concentrations than their shallower counterparts, although those differences were not significant. In summary, the AC fauna exhibits contaminant levels comparable or lower than those reported in other systems. PMID- 28672248 TI - Development and application of a novel method for regional assessment of groundwater contamination risk in the Songhua River Basin. AB - The main objective of this study is to quantify the groundwater contamination risk of Songhua River Basin by applying a novel approach of integrating public datasets, web services and numerical modelling techniques. To our knowledge, this study is the first to establish groundwater risk maps for the entire Songhua River Basin, one of the largest and most contamination-endangered river basins in China. Index-based groundwater risk maps were created with GIS tools at a spatial resolution of 30arc sec by combining the results of groundwater vulnerability and hazard assessment. Groundwater vulnerability was evaluated using the DRASTIC index method based on public datasets at the highest available resolution in combination with numerical groundwater modelling. As a novel approach to overcome data scarcity at large scales, a web mapping service based data query was applied to obtain an inventory for potential hazardous sites within the basin. The groundwater risk assessment demonstrated that <1% of Songhua River Basin is at high or very high contamination risk. These areas were mainly located in the vast plain areas with hotspots particularly in the Changchun metropolitan area. Moreover, groundwater levels and pollution point sources were found to play a significantly larger impact in assessing these areas than originally assumed by the index scheme. Moderate contamination risk was assigned to 27% of the aquifers, predominantly associated with less densely populated agricultural areas. However, the majority of aquifer area in the sparsely populated mountain ranges displayed low groundwater contamination risk. Sensitivity analysis demonstrated that this novel method is valid for regional assessments of groundwater contamination risk. Despite limitations in resolution and input data consistency, the obtained groundwater contamination risk maps will be beneficial for regional and local decision-making processes with regard to groundwater protection measures, particularly if other data availability is limited. PMID- 28672250 TI - Comprehensive assessment of regional selenium resources in soils based on the analytic hierarchy process: Assessment system construction and case demonstration. AB - The redundancy or deficiency of selenium in soils can cause adverse effects on crops and even threaten human health. It was necessary to assess selenium resources with a rigorous scientific appraisal. Previous studies of selenium resource assessment were usually carried out using a single index evaluation. A multi-index evaluation method (analytic hierarchy process) was used in this study to establish a comprehensive assessment system based on consideration of selenium content, soil nutrients and soil environmental quality. The criteria for the comprehensive assessment system were classified by summing critical values in the standards with weights and a Geographical Information System was used to reflect the regional distribution of the assessment results. Boshan, a representative region for developing selenium-rich agriculture, was taken as a case area and classified into Zone I-V, which suggested priority areas for developing selenium rich agriculture. Most parts of the North and Midlands of Boshan were relatively suitable for development of selenium-rich agriculture. Soils in south fractions were contaminated by Cd, PAHs, HCHs and DDTs, in which it was forbidden to farm. This study was expected to provide the basis for developing selenium-rich agriculture and an example for comprehensive evaluation of relevant resources in a region. PMID- 28672249 TI - Application of a microalgal slurry to soil stimulates heterotrophic activity and promotes bacterial growth. AB - Active microalgae biomass from wastewater treatment may be given added value as a biofertilizer, but little is known about how this may affect soil nutrient dynamics and biology. If the goal is to recycle waste nutrients and matter, live algae applied in a liquid slurry to soil may add both organic carbon and nutrients while providing other benefits such as biological carbon fixation. However, the potential persistence of unicellular green algae after such an application is not known, nor the influence of their photosynthetic activity on soil organic carbon - the aim of the present study was to probe these basic questions. In a controlled laboratory microcosm experiment, suspensions of Chlorella sp. microalga culture and sterile filtrates were applied to an agricultural soil and incubated for 42days, whereas the effect of darkness was also tested to understand the importance of photosynthetic activity of the algae. Autotrophic microorganism development was 3.5 times higher in treatments with algae application as measured by chlorophyll pigment concentration. Against expectations that increased photosynthetic activity would decrease the CO2-C flux, the algal suspension with a photoperiod significantly increased soil respiration compared to culture filtrates without algal cells, with accumulated quantities of 1.8 and 0.7gCO2-Cm-2, respectively. Also, phospholipid fatty acid (PLFA) analyses showed that the suspension accelerated the development of a stable community of eukaryotic and prokaryotic microorganisms in the soil surface, whereas bacterial PLFA biomarkers were significantly associated with eukaryote biomarkers on the study level. PMID- 28672251 TI - Seagrass blue carbon dynamics in the Gulf of Mexico: Stocks, losses from anthropogenic disturbance, and gains through seagrass restoration. AB - Seagrasses comprise a substantive North American and Caribbean Sea blue carbon sink. Yet fine-scale estimates of seagrass carbon stocks, fluxes from anthropogenic disturbances, and potential gains in sedimentary carbon from seagrass restoration are lacking for most of the Western Hemisphere. To begin to fill this knowledge gap in the subtropics and tropics, we quantified organic carbon (Corg) stocks, losses, and gains from restorations at 8 previously disturbed seagrass sites around the Gulf of Mexico (GoM) (n=128 cores). Mean natural seagrass Corg stocks were 25.7+/-6.7MgCorgha-1 around the GoM, while mean Corg stocks at adjacent barren sites that had previously hosted seagrass were 17.8MgCorgha-1. Restored seagrass beds contained a mean of 38.7+/-13.1MgCorgha-1. Mean Corg losses differed by anthropogenic impact type, but averaged 20.98+/ 7.14MgCorgha-1. Corg gains from seagrass restoration averaged 20.96+/-8.59Mgha-1. These results, when combined with the similarity between natural and restored Corg content, highlight the potential of seagrass restoration for mitigating seagrass Corg losses from prior impact events. Our GoM basin-wide estimates of natural Corg totaled ~36.4Tg for the 947,327ha for the USA-GoM. Including Mexico, the total basin contained an estimated 37.2-37.5Tg Corg. Regional US-GoM losses totaled 21.69Tg Corg. Corg losses differed significantly among anthropogenic impacts. Yet, seagrass restoration appears to be an important climate change mitigation strategy that could be implemented elsewhere throughout the tropics and subtropics. PMID- 28672254 TI - Orally administered recombinant Lactobacillus casei vector vaccine expressing beta-toxoid of Clostridium perfringens that induced protective immunity responses. AB - Clostridium perfringens types B and C cause enteritis and enterotoxemia in animals. The conventional vaccine production systems need time-consuming detoxification and difficult quality control steps. In this study, a modified beta-toxoid gene was synthesized, cloned into the pT1NX vector, and electroporated into Lactobacillus casei competent cells to yield L. casei-beta recombinant strain. Surface expression of the recombinant beta-toxoid was evaluated by ELISA and confirmed by immunofluorescence microscopy. Vaccinated BALB/c mice with L. casei-beta induced potent humoral and cell-mediated immune responses that were protective against lethal challenges with 100 MLD/mL of the beta-toxin. Safety and efficacy of the recombinant clone was evaluated and the presumptive toxicity of L. casei-beta was studied by toxicity test and histopathological findings, which were the same as negative controls. Our results support the use of L. casei as a live oral vector vaccine, and that the recombinant L. casei-beta is a potential candidate for being used in the control of enterotoxemia diseases caused by C. perfringens types B and C. PMID- 28672257 TI - Graphene decorated with Pd4Ir nanocrystals: Ultrasound-assisted synthesis, and application as a catalyst for oxidation of formic acid. AB - An effective strategy of ultrasmall and surface-clean Pd4Ir nanocrystals uniformly decorated on graphene was developed using ultrasnoic-assisted approach. The prepared Us-Pd4Ir@Graphene reduces Pd loading while holds much higher catalytic activity and better stability toward formic acid oxidation than that of commercial Pd-C, offering great promise as a superior anode catalyst for direct formic acid fuel cells. PMID- 28672252 TI - Benthic pelagic coupling in a mesocosm experiment: Delayed sediment responses and regime shifts. AB - A mesocosm experiment was performed to study benthic-pelagic coupling under a eutrophication gradient. Nine mesocosms were deployed in the facilities of the Hellenic Center for Marine Research in Crete, in the Eastern Mediterranean. The mesocosms were 4m deep, containing 1.5m3 of coastal water and, at the bottom, they included 85l of undisturbed sediment, collected from a semi-impacted area in the port of Heraklion, Crete. A eutrophication gradient was created by adding nutrients in the water column (Low and High) and the experiment lasted 58days. Water column and sediment environmental variables were measured at regular intervals. The results indicate that sedimentation caused by eutrophication in the water column affected sediment geochemical variables but in most cases a time lag was observed between the trophic status of the water column and the response of the sediment. Additionally, in the High eutrophication treatment, several fluctuations were observed and the system did not recover within the experimental duration, as opposed to the Low treatment which showed fewer fluctuations and signs of recovery. PMID- 28672255 TI - Lipidomics to investigate the pharmacologic mechanisms of ginkgo folium in the hyperuricemic rat model. AB - Hyperuricemia caused by purine metabolic abnormalities is reported to have close correlation with lipid metabolic disorders. Ginkgo folium, a frequently-used lipid-lowering medicine, has significant anti-hyperuricemia effects. However, it is poorly known about the interaction between lowering uric acid and regulation of lipid metabolic disorders. In this study, hyperuricemic rat model was induced by orally administration with fructose. Ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) combined with pattern recognition approaches were used to determine different lipid metabolites in serum of control group, model group, and different doses of ginkgo folium groups. Principal component analysis (PCA) was applied to analyze the MS data to assess the establishment of model, partial least squares-discriminate analysis (PLS-DA) and independent samples T-test were performed to indicate the differences between different groups of rats and to find biomarkers. Metabolomics pathway analysis (MetPA) was introduced to reveal the pharmacologic mechanisms of ginkgo folium. 19 potential biomarkers associated with hyperuricemia were found. After intervened by ginkgo folium, these biomarkers were returning to normal level. Among these biomarkers, 13 lipid biomarkers were significantly reversed. Ginkgo filum can lower uric acid via adjusting back the level of PCs and LPCs, which suggested that its treatment mechanisms may be related to reducing the activity of PLA2. In sum, the lipidomics analysis in the system level have enhanced our understanding to pathogenesis of hyperuricemia and the results suggested that ginkgo folium could alleviate the abnormal metabolic status of hyperuricemia. These results demonstrated a new mechanism for lowering uric acid, which was helpful to the early treatment for hyperuricemia. PMID- 28672253 TI - Accuracy of a cow-side test for the diagnosis of hyperketonemia and hypoglycemia in lactating dairy cows. AB - The objective of this study was to evaluate the use of a cow-side device (FreeStyle Precision NeoTM) to diagnose ketosis and hypoglycemia based on measures of blood beta-hydroxybutyrate (BHBA) and glucose. Eleven commercial dairy farms were visited and blood samples were taken from Holstein cows between 2 and 14days in milk, yielding 441 samples for BHBA analysis and 308 samples for glucose analysis. Concentrations of BHBA and glucose were measured in two ways, 1) using the cow-side device with whole blood immediately after sampling and 2) serum samples analyzed with a standard laboratory assay (Animal Health Laboratory, University of Guelph, Canada). The accuracy of the device was determined by comparing the results to the laboratory method as well as the ability to diagnose ketosis (BHBA >=1.2mmol/L) and hypoglycemia (glucose <2.5mmol/L). The concordance correlation coefficient (CCC), Bland-Altman plot and Kappa coefficient were calculated to evaluate agreement between the 2 methods using SAS (version 9.3). The CCC was 0.92 for BHBA and 0.56 for glucose measurements. The 95% confidence intervals of the Bland-Altman plot encompassed 97% and 95% of the mean difference between methods for BHBA and glucose measurements, respectively. The Kappa coefficients were 0.78 for BHBA and 0.23 for glucose measurements. These results indicate that the cow-side device is accurate for rapid measurement of blood BHBA and diagnosis of ketosis on farms but is not accurate for measurement of blood glucose concentrations and diagnosis of hypoglycemia. PMID- 28672258 TI - Metallic cobalt nanoparticles imbedded into ordered mesoporous carbon: A non precious metal catalyst with excellent hydrogenation performance. AB - Ordered mesoporous carbon (OMC)-metal composites have attracted great attention owing to their combination of high surface area, controlled pore size distribution and physicochemical properties of metals. Herein, we report the cobalt nanoparticles/ordered mesoporous carbon (CoNPs@OMC) composite prepared by a one-step carbonization/reduction process assisted by a hydrothermal pre reaction. The CoNPs@OMC composite presents a high specific surface area of 544m2g 1, and the CoNPs are uniformly imbedded or confined in the ordered mesoporous carbon matrix. When used as a non-precious metal-containing catalyst for hydrogenation reduction of p-nitrophenol and nitrobenzene, it demonstrates high efficiency and good cycling stability. Furthermore, the CoNPs@OMC composite can be directly used to catalyze the Fischer-Tropsch synthesis for the high-pressure CO hydrogenation, and presents a good catalytic selectivity for C5+ hydrocarbons. The excellent catalytic performance of the CoNPs@OMC composite can be ascribed to synergistic effect between the high specific surface area, mesoporous structure and well-imbedded CoNPs in the carbon matrix. PMID- 28672256 TI - Reduced lateral prefrontal cortical volume is associated with performance on the modified Iowa Gambling Task: A surface based morphometric analysis of previously deployed veterans. AB - Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are two of the most common consequences of combat deployment. Estimates of comorbidity of PTSD and mTBI are as high as 42% in combat exposed Operation Enduring Freedom, Operation Iraqi Freedom and Operation New Dawn (OEF/OIF/OND) Veterans. Combat deployed Veterans with PTSD and/or mTBI exhibit deficits in classic executive function (EF) tasks. Similarly, the extant neuroimaging literature consistently indicates abnormalities of the ventromedial prefrontal cortex (vmPFC) and amygdala/hippocampal complex in these individuals. While studies examining deficits in classical EF constructs and aberrant neural circuitry have been widely replicated, it is surprising that little research examining reward processing and decision-making has been conducted in these individuals, specifically, because the vmPFC has long been implicated in underlying such processes. Therefore, the current study employed the modified Iowa Gambling Task (mIGT) and structural neuroimaging to assess whether behavioral measures related to reward processing and decision-making were compromised and related to cortical morphometric features of OEF/OIF/OND Veterans with PTSD, mTBI, or co-occurring PTSD/mTBI. Results indicated that gray matter morphometry in the lateral prefrontal cortex (lPFC) predicted performance on the mIGT among all three groups and was significantly reduced, as compared to the control group. PMID- 28672259 TI - Facile synthesis of ultrafine cobalt oxide nanoparticles for high-performance supercapacitors. AB - The ultrafine Co3O4 nanoparticles are successfully prepared by a novel solvothermal-precipitation approach which exploits the supernatant liquid of Co3O4 nanoflake micropheres synthesized by solvothermal method before. Interestingly, the water is only employed to obtain the ultrafine nanoparticles in supernatant liquid which was usually thrown away before. The microstructure measurement results of the as-grown samples present the homogeneous disperse ultrafine Co3O4 nanoparticles with the size of around 5-10nm. The corresponding synthesis mechanism of the ultrafine Co3O4 nanoparticles is proposed. More importantly, these ultrafine Co3O4 nanoparticles obtained at 250 degrees C show the highest specific capacitance of 523.0Fg-1 at 0.5Ag-1, 2.6 times that of Co3O4 nanoflake micropheres due to the quantum size effect. Meanwhile, the sample annealed under 350 degrees C possesses the best cycling stability with capacitance retention of 104.9% after 1500 cycles. These results unambiguously demonstrate that this work not only provides a novel, facile, and eco-friendly approach to prepare high-performance Co3O4 nanoparticles electrode materials for supercapacitors but also develops a widely used method for the preparation of other materials on a large scale. PMID- 28672260 TI - Facile fabrication of novel BiVO4/Bi2S3/MoS2 n-p heterojunction with enhanced photocatalytic activities towards pollutant degradation under natural sunlight. AB - The novel three-component BiVO4/Bi2S3/MoS2 heterojunction was successfully fabricated through a facile in-situ hydrothermal method based on the formation of the intermediate Bi2S3 by coupling BiVO4 and MoS2 precursor. The Bi2S3 was easily formed attributing to the strong interaction between Bi3+and S2- ions with the aid of the hydrothermal reaction. The photocatalytic performances of samples were systematically investigated via the photocatalytic degradation of Rhodamine B (RhB), methylene blue (MB) and malachite green (MG) under solar light irradiation. As a result, the photocatalytic degradation rate of BM-10 for RhB, MB and MG are 97%, 93% and 94%, respectively. The enhanced photocatalytic activities could be due to the suppression of charge recombination and the enhanced the visible light absorption of BiVO4/Bi2S3/MoS2 heterojunction. PMID- 28672261 TI - Synthesis of hierarchical flower-like Mg2Al-Cl layered double hydroxide in a surfactant-free reverse microemulsion. AB - Hierarchical flower-like Mg2Al-Cl LDH microspheres were synthesized using a reverse surfactant-free microemulsion (SFME) route at a low temperature (~25 degrees C), and characterized by XRD, TEM, SEM, FT-IR, TG, N2 adsorption/desorption, and elemental analyses. The SFME used consists of n hexane, isopropanol, and water. The so-obtained flower-like microspheres are constructed with LDH nanosheets with ~10nm thickness. After destroyed by calcination, their crystal structure and flower-like morphology can be reconstructed by rehydration. The flower-like LDH and its calcined product (CLDH) have large specific surface areas being ~84.3 and 163.9m2g-1, respectively. The sorption of methyl orange (MO) on the LDH and CLDH were determined, showing high MO sorption capacities of ~559 and 1112gg-1, respectively, which are obviously higher than those reported for conventional LDHs and CLDHs. Possible mechanisms for the flower-like microsphere formation and the MO sorption are discussed. Our results demonstrate that, like traditional surfactant-based microemulsions, SFMEs as microreactors or templates can be used to synthesize nanomaterials. The hierarchical flower-like LDH microspheres and their calcined product have potential applications such as in the treatment of organic waste water. PMID- 28672262 TI - Synthesis and application of magnetic chlorapatite nanoparticles for zinc (II), cadmium (II) and lead (II) removal from water solutions. AB - Magnetic chlorapatite nanoparticles (MNCLAP) was synthesized and used as adsorbent to remove Zn2+, Cd2+ and Pb2+ from aqueous solutions. The synthesized MNCLAP was characterized by scanning electron microscopy (SEM), energy dispersive analysis system of X-ray (EDAX), transmission electron microscopy (TEM) X-ray powder diffraction (XRD) and magnetization curves. Influence of different sorption parameters, such as equilibration time, initial heavy metal concentration, the amount of MNCLAP, pH values and competition adsorption were investigated in this study. Moreover, the desorption experiment was also carried out to explore the adsorption property of MNCLAP. The adsorption kinetic data has a very high correlation coefficient (R2=0.9999) with the pseudo-second-order kinetic model, and the Langmuir model was used in describing adsorption isotherms. The maximum adsorption capacities of MNCLAP adsorbent towards Zn2+, Cd2+ and Pb2+ were 1.1769, 1.1022 and 1.1546mmolg-1, respectively. EDTA solution was the best efficient eluant for heavy metal desorption with 25.94%, 22.95% and 32.84% released rate of Zn2+, Cd2+ and Pb2+, respectively. Experimental results revealed that the prepared MNCLAP combined both the properties of chlorapatite and magnetic material and it showed remarkable advantages in heavy metal removal from aqueous solutions. PMID- 28672263 TI - Functionalizing soy protein nano-aggregates with pH-shifting and mano-thermo sonication. AB - Plant protein-mediated nano-delivery systems have gained increasing attention in the food and pharmaceutical industries in recent years. Several physical and chemical methods for improving the functional properties of plant proteins with respect to the native forms have been proposed. This study presents a new approach, which combines pH-shifting and mano-thermo-sonication (MTS) to produce soy protein nano-aggregates with significantly improved functional properties. Soy-protein isolate (SPI) was treated with pH-shifting at pH 12 or in combination with MTS and high-pressure homogenization (HPH). Response Surface Methodology was used to find the optimal conditions (50 degrees C, 200kPa, and 60s) for the MTS. The combination of pH-shifting and MTS resulted in spherical SPI aggregates of the smallest size, 27.1+/-1nm, as shown by transmission electron microscopy. The SPI nanoaggregates were used to prepare oil-in-water nanoemulsions with canola oil, which exhibited good stability over 21days at 4 degrees C. In addition, the pH 12-MTS samples had resulted in the highest protein solubility, lowest turbidity, free sulfhydryl and disulfide bonds, surface hydrophobicity, antioxidant activity, and rheological and emulsifying properties than the other samples. PMID- 28672264 TI - Synthesis of dodecylamine-functionalized graphene quantum dots and their application as stabilizers in an emulsion polymerization of styrene. AB - Pickering emulsions have attracted considerable interest due to their potential applications in many fields, such as the food, pharmaceutical, petroleum and cosmetics industries. The study reports the synthesis of dodecylamine functionalized graphene quantum dots (d-GQDs) and their implementation as stabilizers in an emulsion polymerization of styrene. First, d-GQDs are prepared by thermal pyrolysis of citric acid and dodecylamine in 0.1M ammonium hydroxide. The resulting d-GQDs consist of small graphene sheets with abundant amino, carboxyl, acylamino, hydroxyl and alkyl chains on the edge. The amphiphilic structure gives the d-GQDs high surface activity. The addition of d-GQDs can reduce the surface tension of water to 30.8mNm-1 and the interfacial tension of paraffin oil/water to 0.0182mNm-1. The surface activity is much better than that of previously reported solid particle surfactants for Pickering emulsions and is close to that of sodium dodecylbenzenesulfonate, which is, a classical organic surfactants. Then, d-GQDs are employed as solid particle surfactants for stabilizing styrene-in-water emulsions. The emulsions exhibit excellent stability at pH 7. However, stability is lost when the pH is more than 9 or less than 4. The pH-switchable behaviour can be attributed to the protonation of amino groups in a weak acid medium and dissociation of carboxyl groups in a weak base medium. Finally, 2,2'-azobis(2-methylpropionitrile) is introduced into the Pickering emulsions to trigger emulsion polymerization of styrene. The as-prepared polystyrene spheres display a uniform morphology with a narrow diameter distribution. The fluorescent d-GQDs coated their surfaces. This study presents an approach for the fabrication of amphiphilic GQDs and GQDs-based functional materials, which have a wide range of potential applications in emulsion polymerization, as well as in sensors, catalysts, and energy storage. PMID- 28672265 TI - Facile preparation of intercrossed-stacked porous carbon originated from potassium citrate and their highly effective adsorption performance for chloramphenicol. AB - Recently, antibiotics pollution has attracted more interests from many researches which causes potential risks on the ecosystem and human health. Herein, the porous carbons (PCs) was prepared by directly simultaneous carbonization/self activation of potassium citrate at 750-900 degrees C for chloramphenicol (CAP) removal from aqueous solution. The batch experiments were studied, which indicated that PCs prepared at 850 degrees C, namely PCPCs-850, possessed excellent adsorption ability for CAP with a maximum adsorption amount of 506.1mgg 1. Additionally, PCPCs-850 showed a large BET surface area of 2337.06m2g-1 and microporosity of 89.11% by N2 adsorption-desorption experiment. The Langmuir and pseudo-second-order model could more precisely describe the experimental data. And thermodynamic analysis illustrated that CAP adsorption onto PCPCs-850 was an endothermic and spontaneous process. Importantly, the adsorbent exhibited good stability and regeneration after four times cycles. Based on these excellent performance, it is potential that PCPCs-850 can be used as a promising adsorbent for treating contaminants in wastewater. PMID- 28672266 TI - Catalytic oxidation of dibromomethane over Ti-modified Co3O4 catalysts: Structure, activity and mechanism. AB - Ti-modified Co3O4 catalysts with various Co/Ti ratios were synthesized using the co-precipitation method and were used in catalytic oxidation of dibromomethane (CH2Br2), which was selected as the model molecule for brominated volatile organic compounds (BVOCs). Addition of Ti distorted the crystal structure and led to the formation of a Co-O-Ti solid solution. Co4Ti1 (Co/Ti molar ratio was 4) achieved higher catalytic activity with a T90 (the temperature needed for 90% conversion) of approximately 245 degrees C for CH2Br2 oxidation and higher selectivity to CO2 at a low temperature than the other investigated catalysts. In addition, Co4Ti1 was stable for at least 30h at 500ppm CH2Br2, 0 or 2vol% H2O, 0 or 500ppm p-xylene (PX), and 10% O2 at a gas hourly space velocity of 60,000h-1. The final products were COx, Br2, and HBr, without the formation of other Br containing organic byproducts. The high catalytic activity was attributed to the high Co3+/Co2+ ratio and high surface acidity. Additionally, the synergistic effect of Co and Ti made it superior for CH2Br2 oxidation. Furthermore, based on the analysis of products and in situ DRIFTs studies, a receivable reaction mechanism for CH2Br2 oxidation over Ti-modified Co3O4 catalysts was proposed. PMID- 28672267 TI - One-pot synthesis of Au@TiO2 yolk-shell nanoparticles with enhanced photocatalytic activity under visible light. AB - Natural biological systems often use hollow structures to decrease reflection and achieve high solar light utilization. Herein, bio-inspired Au@TiO2 yolk-shell nanoparticles (NPs) have been designed to combine the advantages of noble metal coupling and hollow structures, and subsequently synthesized via a facile one-pot hydrothermal approach. The Au@TiO2 yolk-shell NPs not only exhibit reduced reflectance by multiple reflections and scattering within the hollow NPs, but also show enhanced photocatalytic activity in Rhodamine B (RhB) degradation by simultaneously improving light harvesting, charge separation and reaction site accessibility. Specifically, compared to the commercial TiO2 (P25), Au/TiO2 hybrid and Au@TiO2 core-shell NPs, the Au@TiO2 yolk-shell NPs demonstrate lower reflectance over a broader range and superior photocatalytic activity with more than 98.1% of RhB decomposed within 4h under visible light. The bio-inspired nanostructure, as well as the facile and scalable fabrication approach, will open a new avenue to the rational design and preparation of efficient photocatalysts for pollutant removal. PMID- 28672268 TI - Physicochemical correlations between membrane surface hydrophilicity and adhesive fouling in membrane bioreactors. AB - 36 membrane material cases used in membrane bioreactors (MBRs) covering wide range of hydrophilicity/hydrophobicity were used to calculate thermodynamic interactions between membranes and foulants. It was found that adhesive fouling can be represented by the total interaction energy at minimum separation distance (h0). No functional relationship between membrane hydrophilicity and adhesive fouling can be deduced. However, membrane hydrophilicity, in terms of water contact angle or interaction energy between two identical surfaces at h0 in water (DeltaGsws), had high statistical correlations with adhesive fouling. This statistical correlations should be attributed to the major role of acid-base interaction in total interaction associated with adhesion in most of membrane cases. Moreover, the statistical correlations were independent of the changes in membrane surface roughness or hydrophilicity/hydrophobicity of foulants. These findings satisfactorily explained the inconsistent conclusions in the literature regarding effects of membrane hydrophilicity on adhesive fouling, giving implications for membrane fouling mitigation. PMID- 28672269 TI - Underlying mechanisms preserving coronary basal tone and NO-mediated relaxation in obesity: Involvement of beta1 subunit-mediated upregulation of BKCa channels. AB - BACKGROUND AND AIMS: The impact of obesity on vasomotor regulation of coronary arteries and its underlying mechanisms are not completely understood and, in particular, the role of BKCa channels in the NO-mediated coronary vasodilation in obesity remains to be elucidated. METHODS: The effects of selective blockade of BKCa channel was tested on nitric oxide (NO)-mediated vasodilator responses of coronary arteries from lean and obese Zucker rats (LZR and OZR, respectively) by means of simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and tension in endothelium-denuded coronary arteries mounted in microvascular myographs. BKCa channel subunits expression was measured by Western blot. RESULTS: The selective BKCa channel blocker iberitoxin largely reduced the relaxations and decreases in [Ca2+]i induced by a NO donor in coronary arteries from OZR. Iberitoxin increased to a great extent both basal [Ca2+]i and tone in OZR. The agonist of the voltage-gated L-type calcium channels Bay K8644 induced an increase in [Ca2+]i and tone that was significantly smaller in arteries from OZR, which was restored to control levels in LZR after BKCa channel inhibition. Caffeine- and ryanodine-induced intracellular Ca2+ mobilization and BKCa channel beta1 subunit expression were increased in arteries from OZR. CONCLUSIONS: The present study suggests that an enhanced activity of VSM BKCa channels, associated with up-regulation of channel beta1 subunit and with a higher intracellular Ca2+ mobilization, contributes to the preserved NO mediated vasodilatation and basal tone of coronary arteries in obesity. PMID- 28672270 TI - The utility of biochemical, physiological and morphological biomarkers of leaf sulfate levels in establishing Brachylaena discolor leaves as a bioindicator of SO2 pollution. AB - The negative impacts of air pollution have made monitoring of air quality increasingly important, especially in heavily industrialized areas such as the South Durban Basin (SDB), in South Africa. Bioindicators such as trees can complement conventional air quality monitoring and be used to prioritise vulnerable areas. This study assessed the utility of Brachylaena discolor DC. tree leaves as a bioindicator of sulfur dioxide pollution. This involved correlating ground level sulfur dioxide concentrations ([SO2]) with B. discolor leaf sulfate concentrations ([sulfate]) at three industrial (treatment) sites within the SBD and control site at which [SO2] was significantly lower for all four seasons. Based on this significant positive correlation between the aforementioned (p = 0.005; rho = 0.667) leaf sulfate levels were related to various biochemical (intracellular hydrogen peroxide production, total aqueous [TAA] and enzymic antioxidants [superoxide dismutase and catalase], lipid peroxidation [LPO] and electrolyte leakage), physiological (leaf chlorophyll fluorescence [LCF] and relative chlorophyll content) and morphological (leaf area [LA]) biomarkers of stress measured on leaves from trees at the treatment and control sites. Annual [SO2] and leaf [sulfate] at the treatments were significantly (p < 0.05) higher than the control and high by global standards. TAA, LPO, electrolyte leakage, LCF, and LA were significantly (p < 0.05) correlated with seasonal [sulfate]. Except for superoxide dismutase, catalase and relative chlorophyll content all other biomarkers could differentiate between the treatment sites and the control. However, TAA, electrolyte leakage and LA were the only biomarkers sensitive enough to reflect differences in annual [sulfate] across the treatment sites; these should be used to establish B. discolor leaves as a bioindicator of SO2 pollution. PMID- 28672271 TI - The fabrication and characterization of barium titanate/akermanite nano-bio ceramic with a suitable piezoelectric coefficient for bone defect recovery. AB - In recent years, due to the controllable mechanical properties and degradation rate, calcium silicates such as akermanite (Ca2MgSi2O7) with Ca-Mg and Si- containing bio-ceramics have received much more attention. In addition, the piezoelectric effect plays an important role in bone growth, remodeling and defect healing. To achieve our objective, the porous bioactive nano-composite with a suitable piezoelectric coefficient was fabricated by the freeze-casting technique from the barium titanate and nano-akermanite (BT/nAK) suspension. The highest d33of 4pC/N was obtained for BT90/nAK10. The compressive strength and porosity were for BT75/nAK25 and BT60/nAK40 at the highest level, respectively. The average pore channel diameter was 41 for BT75/nAK25. Interestingly enough, the inter-connected pore channel was observed in the SEM images. There was no detectable transformation phase in the XRD pattern for the BT/nAK composites. The manipulation flexibility of this method indicated the potential for the customized needs in the application of bone substitutes. An ((3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)) MTT assay indicated that the obtained scaffolds have no cytotoxic effects on the human bone marrow mesenchymal stem cells. PMID- 28672273 TI - Does a parent-administrated early motor intervention influence general movements and movement character at 3months of age in infants born preterm? AB - BACKGROUND: Studies of preterm and term-born infants have shown absent fidgety movements and an abnormal movement character to be related to brain lesions and unfavourable neurological outcomes. AIMS: The present study examines what effect a parent-administered early intervention program applied to preterm infants in a randomised control trial (RCT) between 34 and 36weeks gestational age has on their fidgety movements and overall movement character at three months of age. STUDY DESIGN: The study was part of the RCT in an early intervention programme including preterm infants born between 2010 and 2014 at three Norwegian university hospitals. SUBJECTS: 130 preterm infants participated in the study, with 59 of them in the control group and 71 in the intervention group. OUTCOME MEASURES: Fidgety movements and overall movement character at three months corrected age. RESULTS: No difference was found between the intervention group and the control group in terms of fidgety movements or movement character. Approximately half of the infants in both groups showed an abnormal movement character. CONCLUSION: No evidence was found in this RCT to suggest that an intervention at 34 to 37weeks gestational age has a significant effect on the fidgety movements or overall movement character of preterm infants. This is in line with the assumption that absent fidgety movements and an abnormal movement character are due to permanent brain injury and are therefore good predictors for later neurological impairments. PMID- 28672274 TI - Aspects on mediated glucose oxidation at a supported cubic phase. AB - A supported liquid crystalline cubic phase housing glucose oxidase on an electrode surface has been suggested as bio-anode in a biofuel. The purpose of this investigation is to clarify some aspect on the mediated enzymatic oxidation of glucose in such a bio-anode where the mediator ferrocene-carboxylic acid and glucose were dissolved in the solution. The enzyme glucose oxidase was housed in the water channels of the mono-olein cubic phase. The system was investigated with cyclic voltammetry at different scan rates and the temperature was varied between 15 degrees C and 30 degrees C. The diffusion coefficient of the mediator and also the film resistance was estimated showing a large decrease in the mass transport properties as the temperature was decreased. The current from mediated oxidation of glucose at the electrode surface increased with decreasing film thickness. The transport of the mediator in the cubic phase was the rate-limiting step in the overall reaction, where the oxidation of glucose took place at the outer surface of the cubic phase. PMID- 28672272 TI - omega-3 Polyunsaturated fatty acids and their cytochrome P450-derived metabolites suppress colorectal tumor development in mice. AB - Many studies have shown that dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) reduces the risks of colorectal cancer; however, the underlying mechanisms are not well understood. Here we used a LC-MS/MS-based lipidomics to explore the role of eicosanoid signaling in the anti-colorectal cancer effects of omega-3 PUFAs. Our results showed that dietary feeding of omega-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor, and modulated profiles of fatty acids and eicosanoid metabolites in C57BL/6 mice. Notably, we found that dietary feeding of omega-3 PUFAs significantly increased levels of epoxydocosapentaenoic acids (EDPs, metabolites of omega-3 PUFA produced by cytochrome P450 enzymes) in plasma and tumor tissue of the treated mice. We further showed that systematic treatment with EDPs (dose=0.5 mg/kg per day) suppressed MC38 tumor growth in mice, with reduced expressions of pro-oncogenic genes such as C-myc, Axin2, and C jun in tumor tissues. Together, these results support that formation of EDPs might contribute to the anti-colorectal cancer effects of omega-3 PUFAs. PMID- 28672275 TI - Genetic divergence of Influenza A(H3N2) amino acid substitutions mark the beginning of the 2016-2017 winter season in Israel. AB - BACKGROUND: Influenza vaccine composition is reevaluated each year due to the frequency and accumulation of genetic changes that influenza viruses undergo. The beginning of the 2016-2017 influenza surveillance period in Israel has been marked by the dominance of influenza A(H3N2). OBJECTIVES: To evaluate the type, subtype, genetic evolution and amino acid substitutions of influenza A(H3N2) viruses detected among community patients with influenza-like illness (ILI) and hospitalized patients with respiratory illness in the first weeks of the 2016 2017 influenza season. STUDY DESIGN: Respiratory samples from community patients with influenza-like illness and from hospitalized patients underwent identification, subtyping and molecular characterization. Hemagglutinin sequences were compared to the vaccine strain, phylogenetic tree was created, and amino acid substitutions were determined. RESULTS: Influenza A(H3N2) predominated during the early stages of the 2016-2017 influenza season. Noticeably, approximately 20% of community patients and 36% of hospitalized patients, positive for influenza3), received the 2016-2017 influenza vaccine. The influenza A(H3N2) viruses demonstrated genetic divergence from the vaccine strain into three separate subgroups within the 3C.2a clade. One resembled the new 3C.2a1 subclade, one resembled the recently proposed 3C.2a2 subclade and the other was not previously described. Diversity was observed within each subgroup, in terms of additional amino acid substitutions. CONCLUSIONS: Characterization of the 2016 2017 A(H3N2) influenza viruses is imperative for determining the future influenza vaccine composition. PMID- 28672276 TI - Biological stress reactivity as an index of the two polarities of the experience model. AB - The two-polarities model of personality argues that experience is organized around two axes: interpersonal relatedness and self-definition. Differential emphasis on one of these poles defines adaptive and pathological experiences, generating anaclitic or introjective tendencies. The anaclitic pattern, on one hand, has been conceptually related with an exaggerated emphasis on interpersonal relatedness. On the other hand, the introjective pattern has been connected to high levels of self-criticism. The aim of this study was to investigate the psychophysiological basis for this relationship. Specifically, we hypothesized that the anaclitic individual should have a higher biological reactivity to stress (BRS), measured by the cortisol concentration in saliva, in an interpersonal stress induction protocol (Trier Social Stress Test). Contrary to what was expected, the results indicated that introjective participants presented a higher BSR than the anaclitic group. Interestingly, in contrast to their higher BSR, the introjective group reported a diminished subjective stress in relation to the average. In the anaclitic group, a tendency that goes in the opposite direction was found. Theoretical implications of these findings were discussed. PMID- 28672277 TI - Four-time 7Li stimulated-echo spectroscopy for the study of dynamic heterogeneities: Application to lithium borate glass. AB - To study the nature of the nonexponential ionic hopping in solids a pulse sequence was developed that yields four-time stimulated-echo functions of previously inaccessible spin-3/2-nuclei such as 7Li. It exploits combined Zeeman and octupolar order as longitudinal carrier state. Higher-order correlation functions were successfully generated for natural-abundance and isotopically enriched lithium diborate glasses. Four-time 7Li measurements are presented and compared with two-time correlation functions. The results are discussed with reference to approaches devised to quantify the degree of nonexponentiality in glass forming systems and evidence for the occurrence of dynamic heterogeneities and dynamic exchange were found. Additional experiments using the 6Li species illustrate the challenge posed by subensemble selection when the dipolar interactions are not very much smaller than the quadrupolar ones. PMID- 28672278 TI - Hydrazinyl arylthiazole based pyridine scaffolds: Synthesis, structural characterization, in vitro alpha-glucosidase inhibitory activity, and in silico studies. AB - Acarbose, miglitol, and voglibose are the inhibitors of alpha-glucosidase enzyme and being clinically used for the management of type-II diabetes mellitus. However, many adverse effects are also associated with them. So, the development of new therapeutic agents is an utmost interest in medicinal chemistry research. Current study is based on the identification of new alpha-glucosidase inhibitors. For that purpose, hydrazinyl arylthiazole based pyridine derivatives 1-39 were synthesized via two step reaction and fully characterized by spectroscopic techniques EI-MS, HREI-MS, 1H-, and 13C NMR. However, stereochemistry of the iminic bond was confirmed by NOESY. All compounds were subjected to in vitro alpha-glucosidase inhibitory activity and found many folds active (IC50 = 1.40 +/ 0.01-236.10 +/- 2.20 MUM) as compared to the standard acarbose having IC50 value of 856.45 +/- 5.60 MUM. A limited structure-activity relationship was carried out in order to make a presumption about the substituent's effect on inhibitory activity which predicted that substituents of more negative inductive effect played important role in the activity as compared to the substituents of less negative inductive effect. However, in order to have a good understanding of ligand enzyme interactions, molecular docking study was also conducted. In silico study was confirmed that substituents like halogens (Cl) and nitro (NO2) which have negative inductive effect were found to make important interactions with active site residues. PMID- 28672279 TI - beta-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1alpha/ATF6 pathway. AB - Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). beta-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin, and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of beta-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo. 3-(4,5-dimethylthiazol 2-yl)-2,5- diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that beta-elemene inhibited lung cancer tumor growth and cell vitality in a dose- and time-dependent manner. Not only that, beta-elemene could up-regulate ERs-related proteins like PERK, IRE1alpha, ATF6, ATF4, CHOP and down regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1alpha inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of beta-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of beta-elemene is closely related to the activation of ERs through PERK/IRE1alpha/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC. PMID- 28672280 TI - Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty. AB - BACKGROUND: Mutations in the imprinted gene MKRN3 have been described as a common genetic cause of idiopathic central precocious puberty (CPP), in particular in familial cases. However, the exact prevalence of mutations is unknown. Single nucleotide polymorphisms in 2 other imprinted genes, DLK1 and KCNK9, have been associated with age at menarche. We investigated the prevalence of mutations in MKRN3, DLK1, and KCNK9 genes in a cohort of girls with idiopathic CPP. METHODS: MKRN3, DLK1, and KCNK9 coding regions were sequenced in 60 girls with idiopathic CPP (familial in 23 cases). RESULTS: Three mutations, including a new one, in MKRN3 were found in 2 familial cases (c.1229G>A; p.Cys410Ter and c.477_485del; p.Pro160Cysfs*14) (8.7%) and in 1 sporadic case (c.982C>T; p.Arg328Cys) (2.8%). We did not find rare variants in DLK1 and KCNK9 genes. CONCLUSIONS: (1) The prevalence of MKRN3 mutations in our cohort was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. This could be due to different inheritance patterns of families studied; (2) we expanded the phenotype of MKRN3 defects describing 3 more patients with MKRN3 mutations; and (3) point mutations in DLK1 and KCNK9 at least do not seem to be a common cause of CPP in girls. PMID- 28672281 TI - Preface. PMID- 28672282 TI - Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: A Cohort Study. AB - Background: Clostridium difficile infection (CDI), the most common health care associated infection, often recurs. Fecal microbiota transplantation is increasingly used to treat multiply recurrent CDI (mrCDI). Objective: To determine whether the incidence of mrCDI is increasing in proportion to CDI and to identify risk factors for mrCDI. Design: Retrospective cohort study. Setting: United States. Participants: 38 911 718 commercially insured patients in the OptumInsight Clinformatics Database, of whom 45 341 developed CDI. Measurements: Age- and sex-standardized incidence rates for CDI and mrCDI. Results: From 2001 to 2012, the annual incidence of CDI and mrCDI per 1000 person-years increased by 42.7% (from 0.4408 to 0.6289 case) and 188.8% (from 0.0107 to 0.0309 case), respectively. The increase in mrCDI incidence was independent of known risk factors for CDI. Those who developed mrCDI were older (median age, 56.0 vs. 49.0 years; adjusted odds ratio [aOR] per 10-year increase in age, 1.25 [95% CI, 1.21 to 1.29]) and were more likely to be female (63.8% vs. 58.7%; aOR, 1.24 [CI, 1.11 to 1.38]) and to have used antibiotics (72.3% vs. 58.8%; aOR, 1.79 [CI, 1.59 to 2.01]), proton-pump inhibitors (24.6% vs. 18.2%; aOR, 1.14 [CI, 1.01 to 1.29]), or corticosteroids (18.3% vs. 13.7%; aOR, 1.15 [CI, 1.00 to 1.32]) within 90 days of CDI diagnosis. Chronic kidney disease (10.4% vs. 5.6%; aOR, 1.49 [CI, 1.24 to 1.80]) and diagnosis in a nursing home (2.1% vs. 0.6%; aOR, 1.99 [CI, 1.34 to 2.93]) were also associated with increased risk for mrCDI. Limitation: The primary analyses included only commercially insured patients in the United States. Conclusion: Relative to CDI, mrCDI incidence has disproportionately increased, indicating a rising demand for mrCDI therapies. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Allergy and Infectious Diseases. PMID- 28672283 TI - Effects of a Conversation-Based Intervention on the Linguistic Skills of Children With Motor Speech Disorders Who Use Augmentative and Alternative Communication. AB - Purpose: This study was conducted to evaluate the effects of a conversation-based intervention on the expressive vocabulary and grammatical skills of children with severe motor speech disorders and expressive language delay who use augmentative and alternative communication. Method: Eight children aged from 8 to 13 years participated in the study. After a baseline period, a conversation-based intervention was provided for each participant, in which they were supported to learn and use linguistic structures essential for the formation of clauses and the grammaticalization of their utterances, such as pronouns, verbs, and bound morphemes, in the context of personally meaningful and scaffolded conversations with trained clinicians. The conversations were videotaped, transcribed, and analyzed using the Systematic Analysis of Language Transcripts (SALT; Miller & Chapman, 1991). Results: Results indicate that participants showed improvements in their use of spontaneous clauses, and a greater use of pronouns, verbs, and bound morphemes. These improvements were sustained and generalized to conversations with familiar partners. Conclusion: The results demonstrate the positive effects of the conversation-based intervention for improving the expressive vocabulary and grammatical skills of children with severe motor speech disorders and expressive language delay who use augmentative and alternative communication. Clinical and theoretical implications of conversation-based interventions are discussed and future research needs are identified. Supplemental Materials: https://doi.org/10.23641/asha.5150113. PMID- 28672285 TI - The Effect of Attention-Deficit/Hyperactivity Disorder and Methylphenidate Treatment on the Adult Auditory Temporal Order Judgment Threshold. AB - Purpose: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition notes that attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood will persist into adulthood among at least some individuals. There is a paucity of evidence, however, regarding whether other difficulties that often accompany childhood ADHD will also continue into adulthood, specifically auditory processing deficits. The aim of this study was to examine the effect of ADHD and the stimulant medication methylphenidate on auditory perception performance among adults. Method: A total of 33 adults diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria (ADHD group) and 48 adults without ADHD (non-ADHD group) performed an auditory temporal order judgment task. Participants with ADHD performed the task twice: with and without taking methylphenidate (Ritalin), in random order. Results: Temporal order judgment thresholds of the ADHD group were significantly higher than those of the non-ADHD group. Methylphenidate significantly decreased temporal order judgment thresholds within the ADHD group, making their performance similar to the non ADHD participants. Conclusions: Auditory processing difficulties of those diagnosed with ADHD seem to persist into adulthood. Similar to findings with children, methylphenidate treatment improves performance on tasks requiring this ability among adults. Therefore, given the association between auditory temporal processing and linguistic skills, the beneficial effect of methylphenidate on adults' academic achievement may be accomplished by positively affecting auditory temporal processing. Further studies in this line of research are needed. PMID- 28672284 TI - Association of Concussion With Abnormal Menstrual Patterns in Adolescent and Young Women. AB - Importance: Brain injury may interrupt menstrual patterns by altering hypothalamic-pituitary-ovarian axis function. Investigators have yet to evaluate the association of concussion with menstrual patterns in young women. Objective: To compare abnormal menstrual patterns in adolescent and young women after a sport-related concussion with those after sport-related orthopedic injuries to areas other than the head (nonhead). Design, Setting, and Participants: This prospective cohort study of adolescent and young women with a sport-related concussion (n = 68) or a nonhead sport-related orthopedic injury (n = 61) followed up participants for 120 days after injury. Patients aged 12 to 21 years who presented within 30 days after a sport-related injury to a concussion or sports medicine clinic at a single academic center were eligible. Menstrual patterns were assessed using a weekly text message link to an online survey inquiring about bleeding episodes each week. The first patient was enrolled on October 14, 2014, and follow-up was completed on January 24, 2016. Inclusion criteria required participants to be at least 2 years postmenarche, to report regular menses in the previous year, and to report no use of hormonal contraception. Exposures: Sport-related concussion or nonhead sport-related orthopedic injury. Main Outcomes and Measures: Abnormal menstrual patterns were defined by an intermenstrual interval of less than 21 days (short) or more than 35 days (long) or a bleeding duration of less than 3 days or more than 7 days. Results: A total of 1784 survey responses were completed of the 1888 text messages received by patients, yielding 487 menstrual patterns in 128 patients (mean [SD] age, 16.2 [2.0] years). Of the 68 patients who had a concussion, 16 (23.5%) experienced 2 or more abnormal menstrual patterns during the study period compared with 3 of 60 patients (5%) who had an orthopedic injury. Despite similar gynecologic age, body mass index, and type of sports participation between groups, the risk of 2 or more abnormal menstrual bleeding patterns after injury was significantly higher among patients with concussion than among those with an orthopedic injury (odds ratio, 5.85; 95% CI, 1.61-21.22). Conclusions and Relevance: Adolescent and young women may have increased risk of multiple abnormal menstrual patterns after concussion. Because abnormal menstrual patterns can have important health implications, monitoring menstrual patterns after concussion may be warranted in this population. Additional research is needed to elucidate the relationship between long-term consequences of concussion and the function of the hypothalamic-pituitary-ovarian axis. PMID- 28672286 TI - Fool Me Thrice: The Evolving Story of Multiply Recurrent Clostridium difficile Infection. PMID- 28672288 TI - Trends in Differences in US Mortality Rates Between Black and White Infants. PMID- 28672287 TI - Association Between Linear Growth and Bone Accrual in a Diverse Cohort of Children and Adolescents. AB - Importance: Prevention of osteoporosis in adulthood begins with optimizing bone health in early life. The longitudinal association between growth and bone accretion during childhood is not fully understood. Objectives: To assess the acquisition of whole-body (WB) and skeletal site-specific bone mineral content (BMC) relative to linear growth in a healthy, diverse, longitudinal cohort of children, adolescents, and young adults and to test for differences related to sex and African American race. Design, Setting, and Participants: This investigation was a mixed longitudinal study with annual assessments for up to 7 years at 5 US clinical centers. Participants were healthy children, adolescents, and young adults. The study dates were July 2002 through March 2010. The dates of the analysis were June through December 2016. Main Outcomes and Measures: Anthropometrics, BMC, and body composition via dual-energy x-ray absorptiometry. The superimposition by translation and rotation (SITAR) analysis method was used to define the mean trajectories for height, WB lean soft tissue, appendicular lean soft tissue, and WB and skeletal site-specific BMC acquisition and to measure the age and magnitude of peak velocity for each parameter. The SITAR modeling was performed separately by sex and self-reported race. Results: Among 2014 healthy children, adolescents, and young adults (1022 [50.7%] female and 479 [23.8%] African American) aged 5 to 19 years at study entry, the mean age of peak height velocity was 13.1 years (95% CI, 13.0-13.2 years) in African American boys vs 13.4 years (95% CI, 13.3-13.4 years) in non-African American boys (difference, -0.3 years; 95% CI, -0.4 to -0.1 years) and 11.0 years (95% CI, 10.8-11.1 years) in African American girls vs 11.6 years (95% CI, 11.5-11.6 years) in non-African American girls (difference, -0.6 years; 95% CI, -0.7 to -0.5 years). Age of peak acquisition of WB BMC was 14.0 years (95% CI, 13.8-14.1 years) in African American boys vs 14.0 years (95% CI, 13.9-14.1 years) in non-African American boys (difference, -0.0 years; 95% CI, -0.2 to 0.2 years) and 12.1 years (95% CI, 12.0-12.3 years) in African American girls vs 12.4 years (95% CI, 12.3-12.5 years) in non-African American girls (difference, -0.3 years; 95% CI, -0.4 to 0.1 years). At age 7 years, children had acquired 69.5% to 74.5% of maximal observed height but only 29.6% to 38.1% of maximal observed WB BMC. Adolescents gained 32.7% to 35.8% of maximal observed WB BMC during the 2 years before and 2 years after peak height velocity. Another 6.9% to 10.7% of maximal observed WB BMC occurred after linear growth had ceased. In the group at highest risk for fracture, non-African American boys, peak fracture incidence occurred approximately 1 year before peak height velocity. Conclusions and Relevance: In this longitudinal study, height gains substantially outpaced gains in BMC during childhood, which could contribute to fracture risk. A significant proportion of bone is accrued after adult height is achieved. Therefore, late adolescence represents a potentially underrecognized window of opportunity to optimize bone mass. PMID- 28672289 TI - Tribalism in Medicine-Us vs Them. PMID- 28672290 TI - Winning the Fight to End Alzheimer Disease. PMID- 28672291 TI - Effects of an Intervention to Reduce Hospitalizations From Nursing Homes: A Randomized Implementation Trial of the INTERACT Program. AB - Importance: Medicare payment initiatives are spurring efforts to reduce potentially avoidable hospitalizations. Objective: To determine whether training and support for implementation of a nursing home (NH) quality improvement program (Interventions to Reduce Acute Care Transfers [INTERACT]) reduced hospital admissions and emergency department (ED) visits. Design, Setting, and Participants: This analysis compared changes in hospitalization and ED visit rates between the preintervention and postintervention periods for NHs randomly assigned to receive training and implementation support on INTERACT to changes in control NHs. The analysis focused on 85 NHs (36 717 NH residents) that reported no use of INTERACT during the preintervention period. Interventions: The study team provided training and support for implementing INTERACT, which included tools that help NH staff identify and evaluate acute changes in NH resident condition and document communication between physicians; care paths to avoid hospitalization when safe and feasible; and advance care planning and quality improvement tools. Main Outcomes and Measures: All-cause hospitalizations, hospitalizations considered potentially avoidable, 30-day hospital readmissions, and ED visits without admission. All-cause hospitalization rates were calculated for all resident-days, high-risk days (0-30 days after NH admission), and lower risk days (>=31 days after NH admission). Results: We found that of 85 NHs, those that received implementation training and support exhibited statistically nonsignificant reductions in hospitalization rates compared with control NHs (net difference, -0.13 per 1000 resident-days; P = .25), hospitalizations during the first 30 days after NH admission (net difference, -0.37 per 1000 resident-days; P = .48), hospitalizations during periods more than 30 days after NH admission (net difference, -0.09 per 1000 resident-days; P = .39), 30-day readmission rates (net change in rate among hospital discharges, -0.01; P = .36), and ED visits without admission (net difference, 0.02 per 1000 resident-days; P = .83). Intervention NHs exhibited a reduction in potentially avoidable hospitalizations overall (net difference, -0.18 per 1000 resident-days, P = .01); however, this effect was not robust to a Bonferroni correction for multiple comparisons. Conclusions and Relevance: Training and support for INTERACT implementation as carried out in this study had no effect on hospitalization or ED visit rates in the overall population of residents in participating NHs. The results have several important implications for implementing quality improvement initiatives in NHs. Trial Registration: clinicaltrials.gov Identifier: NCT02177058. PMID- 28672293 TI - Sharing as the Future of Medicine. PMID- 28672292 TI - Association Between Pregnancy and Perinatal Outcomes Among Women With Epilepsy. AB - Importance: To date, few attempts have been made to examine associations between exposure to maternal epilepsy with or without antiepileptic drug (AED) therapy and pregnancy and perinatal outcomes. Objectives: To investigate associations between epilepsy in pregnancy and risks of pregnancy and perinatal outcomes as well as whether use of AEDs influenced risks. Design, Setting, and Participants: A population-based cohort study was conducted on all singleton births at 22 or more completed gestational weeks in Sweden from 1997 through 2011; of these, 1 424 279 were included in the sample. Information on AED exposure was available in the subset of offspring from July 1, 2005, to December 31, 2011. Data analysis was performed from October 1, 2016, to February 15, 2017. Main Outcomes and Measures: Pregnancy, delivery, and perinatal outcomes. Multivariable Poisson log linear regression was used to estimate adjusted risk ratios (aRRs) and 95% CIs, after adjusting for maternal age, country of origin, educational level, cohabitation with a partner, height, early pregnancy body mass index, smoking, year of delivery, maternal pregestational diabetes, hypertension, and psychiatric disorders. Results: Of the 1 429 652 births included in the sample, 5373 births were in 3586 women with epilepsy; mean (SD) age at first delivery of the epilepsy cohort was 30.54 (5.18) years. Compared with pregnancies of women without epilepsy, women with epilepsy were at increased risks of adverse pregnancy and delivery outcomes, including preeclampsia (aRR 1.24; 95% CI, 1.07-1.43), infection (aRR, 1.85; 95% CI, 1.43-2.29), placental abruption (aRR, 1.68; 95% CI, 1.18-2.38), induction (aRR, 1.31; 95% CI, 1.21-1.40), elective cesarean section (aRR, 1.58; 95% CI, 1.45-1.71), and emergency cesarean section (aRR, 1.09; 95% CI, 1.00-1.20). Infants of mothers with epilepsy were at increased risks of stillbirth (aRR, 1.55; 95% CI, 1.05-2.30), having both medically indicated (aRR, 1.24; 95% CI, 1.08-1.43) and spontaneous (aRR, 1.34; 95% CI, 1.20-1.53) preterm birth, being small for gestational age at birth (aRR, 1.25; 95% CI, 1.13-1.30), and having neonatal infections (aRR, 1.42; 95% CI, 1.17-1.73), any congenital malformation (aRR, 1.48; 95% CI, 1.35-1.62), major malformations (aRR, 1.61; 95% CI, 1.43-1.81), asphyxia-related complications (aRR, 1.75; 95% CI, 1.26-2.42), Apgar score of 4 to 6 at 5 minutes (aRR, 1.34; 95% CI, 1.03-1.76), Apgar score of 0 to 3 at 5 minutes (aRR, 2.42; 95% CI, 1.62-3.61), neonatal hypoglycemia (aRR, 1.53; 95% CI, 1.34-1.75), and respiratory distress syndrome (aRR, 1.48; 95% CI, 1.30-1.68) compared with infants of unaffected women. In women with epilepsy, using AEDs during pregnancy did not increase the risks of pregnancy and perinatal complications, except for a higher rate of induction of labor (aRR, 1.30; 95% CI, 1.10-1.55). Conclusions and Relevance: Epilepsy during pregnancy is associated with increased risks of adverse pregnancy and perinatal outcomes. However, AED use during pregnancy is generally not associated with adverse outcomes. PMID- 28672294 TI - Sharing Medicine-A JAMA Internal Medicine Series. PMID- 28672295 TI - The Effect of Antibody Size and Mechanical Loading on Solute Diffusion Through the Articular Surface of Cartilage. AB - Because of the heterogeneous nature of articular cartilage tissue, penetration of potential therapeutic molecules for osteoarthritis (OA) through the articular surface (AS) is complex, with many factors that affect transport of these solutes within the tissue. Therefore, the goal of this study is to investigate how the size of antibody (Ab) variants, as well as application of cyclic mechanical loading, affects solute transport within healthy cartilage tissue. Penetration of fluorescently tagged solutes was quantified using confocal microscopy. For all the solutes tested, fluorescence curves were obtained through the articular surface. On average, diffusivities for the solutes of sizes 200 kDa, 150 kDa, 50 kDa, and 25 kDa were 3.3, 3.4, 5.1, and 6.0 MUm2/s from 0 to 100 MUm from the articular surface. Diffusivities went up to a maximum of 16.5, 18.5, 20.5, and 23.4 MUm2/s for the 200 kDa, 150 kDa, 50 kDa, and 25 kDa molecules, respectively, from 225 to 325 MUm from the surface. Overall, the effect of loading was very significant, with maximal transport enhancement for each solute ranging from 2.2 to 3.4-fold near 275 MUm. Ultimately, solutes of this size do not diffuse uniformly nor are convected uniformly, through the depth of the cartilage tissue. This research potentially holds great clinical significance to discover ways of further optimizing transport into cartilage and leads to effective antibody-based treatments for OA. PMID- 28672296 TI - Bench to Bedside and Back Again May Be Key to Clinical Breakthroughs. PMID- 28672297 TI - A Large Adrenal Tumor With Marked 18F-Fluorodeoxyglucose Uptake. PMID- 28672298 TI - Hypoglycemia in Diabetes: Does Insulin Type Matter? PMID- 28672299 TI - A First for Giant Cell Arteritis. PMID- 28672301 TI - Expanded Cystic Fibrosis Therapy. PMID- 28672304 TI - Payment Power to the Patients. PMID- 28672300 TI - Precision Approach in Cancer Care. PMID- 28672303 TI - Penicillin Allergy Is Not Necessarily Forever. PMID- 28672312 TI - Physicians Interrupting Patients-Reply. PMID- 28672310 TI - The Joint Commission and the Opioid Epidemic. PMID- 28672307 TI - Physicians Interrupting Patients. PMID- 28672309 TI - Physicians Interrupting Patients. PMID- 28672308 TI - Physicians Interrupting Patients. PMID- 28672313 TI - The Joint Commission and the Opioid Epidemic-Reply. PMID- 28672305 TI - Celebration of the Fourth of July: A Successful Campaign for Improvement. PMID- 28672306 TI - Personal Sound Amplification Products vs a Conventional Hearing Aid for Speech Understanding in Noise. PMID- 28672314 TI - Osteoporotic Fractures Associated With Dabigatran vs Warfarin-Reply. PMID- 28672315 TI - Anaphylaxis and Insect Stings and Bites. PMID- 28672311 TI - Osteoporotic Fractures Associated With Dabigatran vs Warfarin. PMID- 28672316 TI - Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial. AB - Importance: Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death. Objective: To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes. Design, Setting, and Participants: Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014 January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period. Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence. Main Outcomes and Measures: The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted. Results: Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4% 20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to 2.7%). Conclusions and Relevance: Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes. Trial Registration: clinicaltrials.gov Identifier: NCT02034513. PMID- 28672317 TI - Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. AB - Importance: Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control. Objective: To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes. Design, Setting, and Participants: Randomized, double-blind, treat-to target crossover trial including two 32-week treatment periods, each with a 16 week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs. Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) and randomized 1:1 to morning or evening dosing within each treatment sequence. Main Outcomes and Measures: The primary end point was the rate of overall symptomatic hypoglycemic episodes (severe or blood glucose confirmed [<56 mg/dL]) during the maintenance period. Secondary end points were the rate of nocturnal symptomatic hypoglycemic episodes (severe or blood glucose confirmed, occurring between 12:01 am and 5:59 am) and the proportion of patients with severe hypoglycemia during the maintenance period. Results: Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P < .001; difference, -23.66 episodes/100 PYE [95% CI, -33.98 to 13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, -9.1% [95% CI, -13.1% to -5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio = 0.58 [95% CI, 0.46-0.74]; P < .001; difference, -7.41 episodes/100 PYE [95% CI, -11.98 to -2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, -5.1% [95% CI, -8.1% to -2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P = .35; risk difference, -0.8% [95% CI, -2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period. Conclusions and Relevance: Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia. Trial Registration: clinicaltrials.gov Identifier: NCT02030600. PMID- 28672320 TI - Fecal Microbiota Transplantation. PMID- 28672318 TI - Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. AB - Importance: Hypothermia for 72 hours at 33.5 degrees C for neonatal hypoxic ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective: To determine if cooling for 120 hours or to a temperature of 32.0 degrees C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: Randomized 2 * 2 factorial clinical trial in neonates (>=36 weeks' gestation) with hypoxic ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5 degrees C for 72 hours (n = 95), 32.0 degrees C for 72 hours (n = 90), 33.5 degrees C for 120 hours (n = 96), or 32.0 degrees C for 120 hours (n = 83). Main Outcomes and Measures: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5 degrees C and 51 of 162 (31.5%) cooled to 32.0 degrees C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5 degrees C for 72 hours, 34.5% at 32.0 degrees C for 72 hours, 34.4% at 33.5 degrees C for 120 hours, and 28.2% at 32.0 degrees C for 120 hours. Conclusions and Relevance: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5 degrees C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5 degrees C. Trial Registration: clinicaltrials.gov Identifier: NCT01192776. PMID- 28672319 TI - Effect of Radiofrequency Denervation on Pain Intensity Among Patients With Chronic Low Back Pain: The Mint Randomized Clinical Trials. AB - Importance: Radiofrequency denervation is a commonly used treatment for chronic low back pain, but high-quality evidence for its effectiveness is lacking. Objective: To evaluate the effectiveness of radiofrequency denervation added to a standardized exercise program for patients with chronic low back pain. Design, Setting, and Participants: Three pragmatic multicenter, nonblinded randomized clinical trials on the effectiveness of minimal interventional treatments for participants with chronic low back pain (Mint study) were conducted in 16 multidisciplinary pain clinics in the Netherlands. Eligible participants were included between January 1, 2013, and October 24, 2014, and had chronic low back pain, a positive diagnostic block at the facet joints (facet joint trial, 251 participants), sacroiliac joints (sacroiliac joint trial, 228 participants), or a combination of facet joints, sacroiliac joints, or intervertebral disks (combination trial, 202 participants) and were unresponsive to conservative care. Interventions: All participants received a 3-month standardized exercise program and psychological support if needed. Participants in the intervention group received radiofrequency denervation as well. This is usually a 1-time procedure, but the maximum number of treatments in the trial was 3. Main Outcomes and Measures: The primary outcome was pain intensity (numeric rating scale, 0-10; whereby 0 indicated no pain and 10 indicated worst pain imaginable) measured 3 months after the intervention. The prespecified minimal clinically important difference was defined as 2 points or more. Final follow-up was at 12 months, ending October 2015. Results: Among 681 participants who were randomized (mean age, 52.2 years; 421 women [61.8%], mean baseline pain intensity, 7.1), 599 (88%) completed the 3-month follow-up, and 521 (77%) completed the 12-month follow-up. The mean difference in pain intensity between the radiofrequency denervation and control groups at 3 months was -0.18 (95% CI, -0.76 to 0.40) in the facet joint trial; -0.71 (95% CI, -1.35 to -0.06) in the sacroiliac joint trial; and -0.99 (95% CI, -1.73 to -0.25) in the combination trial. Conclusions and Relevance: In 3 randomized clinical trials of participants with chronic low back pain originating in the facet joints, sacroiliac joints, or a combination of facet joints, sacroiliac joints, or intervertebral disks, radiofrequency denervation combined with a standardized exercise program resulted in either no improvement or no clinically important improvement in chronic low back pain compared with a standardized exercise program alone. The findings do not support the use of radiofrequency denervation to treat chronic low back pain from these sources. Trial Registration: trialregister.nl Identifier: NTR3531. PMID- 28672322 TI - No Perfect Choice. PMID- 28672324 TI - High Generic Drug Prices and Market Competition: A Retrospective Cohort Study. AB - Background: Prices for some generic drugs have increased in recent years, adversely affecting patients who rely on them. Objective: To determine the association between market competition levels and the change in generic drug prices in the United States. Design: Retrospective cohort study. Setting: Prescription claims from commercial health plans between 2008 and 2013. Measurements: The 5.5 years of data were divided into 11 study periods of 6 months each. The Herfindahl-Hirschman Index (HHI)-calculated by summing the squares of individual manufacturers' market shares, with higher values indicating a less competitive market-and average drug prices were estimated for the generic drugs in each period. The HHI value estimated in the baseline period (first half of 2008) was modeled as a fixed covariate. Models estimated price changes over time by level of competition, adjusting for drug shortages, market size, and dosage forms. Results: From 1.08 billion prescription claims, a cohort of 1120 generic drugs was identified. After adjustment, drugs with quadropoly (HHI value of 2500, indicating relatively high levels of competition), duopoly (HHI value of 5000), near-monopoly (HHI value of 8000), and monopoly (HHI value of 10 000) levels of baseline competition were associated with price changes of -31.7% (95% CI, -34.4% to -28.9%), -11.8% (CI, -18.6% to -4.4%), 20.1% (CI, 5.5% to 36.6%), and 47.4% (CI, 25.4% to 73.2%), respectively, over the study period. Limitation: Study findings may not be generalizable to drugs that became generic after 2008. Conclusion: Market competition levels were associated with a change in generic drug prices. Such measurements may be helpful in identifying older prescription drugs at higher risk for price change in the future. Primary Funding Source: None. PMID- 28672326 TI - Neonate With Cutaneous Vesicles and Respiratory Distress. PMID- 28672344 TI - Early Animal Exposure and Childhood Illnesses. PMID- 28672343 TI - The Association of Firearm Suicide With Mental Illness, Substance Use Conditions, and Previous Suicide Attempts. PMID- 28672325 TI - Association of Playing High School Football With Cognition and Mental Health Later in Life. AB - Importance: American football is the largest participation sport in US high schools and is a leading cause of concussion among adolescents. Little is known about the long-term cognitive and mental health consequences of exposure to football-related head trauma at the high school level. Objective: To estimate the association of playing high school football with cognitive impairment and depression at 65 years of age. Design, Setting, and Participants: A representative sample of male high school students who graduated from high school in Wisconsin in 1957 was studied. In this cohort study using data from the Wisconsin Longitudinal Study, football players were matched between March 1 and July 1, 2017, with controls along several baseline covariates such as adolescent IQ, family background, and educational level. For robustness, 3 versions of the control condition were considered: all controls, those who played a noncollision sport, and those who did not play any sport. Exposures: Athletic participation in high school football. Main Outcomes and Measures: A composite cognition measure of verbal fluency and memory and attention constructed from results of cognitive assessments administered at 65 years of age. A modified Center for Epidemiological Studies' Depression Scale score was used to measure depression. Secondary outcomes include results of individual cognitive tests, anger, anxiety, hostility, and heavy use of alcohol. Results: Among the 3904 men (mean [SD] age, 64.4 [0.8] years at time of primary outcome measurement) in the study, after matching and model-based covariate adjustment, compared with each control condition, there was no statistically significant harmful association of playing football with a reduced composite cognition score (-0.04 reduction in cognition vs all controls; 97.5% CI, -0.14 to 0.05) or an increased modified Center for Epidemiological Studies' Depression Scale depression score (-1.75 reduction vs all controls; 97.5% CI, -3.24 to -0.26). After adjustment for multiple testing, playing football did not have a significant adverse association with any of the secondary outcomes, such as the likelihood of heavy alcohol use at 65 years of age (odds ratio, 0.68; 95% CI, 0.32-1.43). Conclusions and Relevance: Cognitive and depression outcomes later in life were found to be similar for high school football players and their nonplaying counterparts from mid-1950s in Wisconsin. The risks of playing football today might be different than in the 1950s, but for current athletes, this study provides information on the risk of playing sports today that have a similar risk of head trauma as high school football played in the 1950s. PMID- 28672345 TI - Error in Abstract. PMID- 28672348 TI - Integration of Advanced Practice Clinicians in Neurology Practices. PMID- 28672349 TI - Errors in Figure and Funding/Support Paragraph. PMID- 28672351 TI - Neuroleptics for Delirium: More Research Is Needed. PMID- 28672352 TI - Neuroleptics for Delirium: More Research Is Needed. PMID- 28672353 TI - Neuroleptics for Delirium: More Research Is Needed. PMID- 28672354 TI - Neuroleptics for Delirium: More Research Is Needed. PMID- 28672355 TI - Rates and Consequences of False Penicillin Allergies in Australia. PMID- 28672356 TI - Residency Training in Long-Acting Reversible Contraceptive Methods. PMID- 28672357 TI - Limitations Concerning the Association of Physician Sex and Patient Outcomes. PMID- 28672358 TI - Limitations Concerning the Association of Physician Sex and Patient Outcomes. PMID- 28672359 TI - Limitations Concerning the Association of Physician Sex and Patient Outcomes. PMID- 28672360 TI - Limitations Concerning the Association of Physician Sex and Patient Outcomes. PMID- 28672361 TI - Limitations Concerning the Association of Physician Sex and Patient Outcomes. PMID- 28672362 TI - Conflicts of Interest Reported in an Abbreviated Time Frame. PMID- 28672363 TI - Neuroleptics for Delirium: More Research is Needed-Reply. PMID- 28672364 TI - Limitations Concerning the Association of Physician Sex and Patient Outcomes Reply. PMID- 28672365 TI - Conflicts of Interest Reported in an Abbreviated Time Frame-Reply. PMID- 28672367 TI - Pupil dilation to illusory motion in peripheral drift images: Perception versus reality. AB - Peripheral drift is a specific type of illusory motion that causes observers to perceive motion in a static image. We aimed to determine whether pupil dilation occurs during the perception of illusory motion. In three experiments investigating pupil-size changes to peripheral drift, pupil response differences were observed between symmetric patterns (SPs) that elicited no impression of motion and repeated asymmetric patterns (RAPs) that did. All participants reported the perception of motion in the RAP condition and showed significantly greater pupil dilation to these stimuli as compared with viewing stimuli in the SP condition. As a follow-up, we manipulated the RAP stimuli to reduce and then remove the illusion to determine (a) whether it was the asymmetry per se that induced the pupil dilation and (b) whether the amount of pupil dilation was contingent on the amount of observed illusory motion. Although a reduction in perceived illusory motion did not produce a reduction in pupil dilation, removal of the illusory motion did. Despite previous evidence reporting pupil constriction to the perception of motion, and the positive valence associated with symmetry, these experiments show that pupil dilation occurs during the perception of illusory motion. This is in keeping with previous evidence that pupil dilation is influenced by perceptual factors and not simply light level, and, in particular, shows that illusory motion is physiologically arousing. PMID- 28672368 TI - Perception of object illumination depends on highlights and shadows, not shading. AB - Human observers are able to successfully infer direction and intensity of light from photographed scenes despite complex interactions between light, shape, and material. We investigate how well they are able to distinguish other low-level aspects of illumination, such as the diffuseness and the number of light sources. We use photographs of a teapot, an orange, and a tennis ball from the ALOI database (Geusebroek, Burghouts, & Smeulders, 2005) to create different illumination conditions, varying either in diffuseness of a single light source or in separation angle between two distinct light sources. Our observers were presented with all three objects; they indicated which object was illuminated differently from the other two. We record discrimination performance, reaction times, and eye fixations. We compare the data to a model that uses differences in image structure in same-object comparisons, and outcomes suggest that participants mostly rely on the information contained in cast shadows and highlights. The pattern of eye fixations confirms this, showing that after the first fixation, observers mostly fixate cast shadow areas. However, information in the highlights is rather salient, so it might be available from first fixation, making separate fixations are unnecessary. PMID- 28672369 TI - Using optic flow in the far peripheral field. AB - Self-motion information can be used to update spatial memory of location through an estimate of a change in position. Viewing optic flow alone can create Illusory self-motion or "vection." Early studies suggested that peripheral vision is more effective than central vision in evoking vection, but controlling for retinal area and perceived distance suggests that all retinal areas may be equally effective. However, the contributions of the far periphery, beyond 90 degrees , have been largely neglected. Using a large-field Edgeless Graphics Geometry display (EGG, Christie, Canada, field of view +/-112 degrees ) and systematically blocking central (+/-20 degrees to +/-90 degrees ) or peripheral (viewing through tunnels +/-20 degrees to +/-40 degrees ) parts of the field, we compared the effectiveness of different retinal regions at evoking forwards linear vection. Fifteen participants indicated when they had reached the position of a previously presented target after visually simulating motion down a simulated corridor. The amount of simulated travel needed to match a given target distance was modelled with a leaky spatial integrator model to estimate gains (perceived/actual distance) and a spatial decay factor. When optic flow was presented only in the far periphery (beyond 90 degrees ) gains were significantly higher than for the same motion presented full field or in only the central field, resulting in accurate performance in the range of speeds associated with normal walking. The increased effectiveness of optic flow in the peripheral field alone compared to full-field motion is discussed in terms of emerging neurophysiological studies that suggest brain areas dedicated to processing information from the far peripheral field. PMID- 28672370 TI - Luminance noise as a novel approach for measuring contrast sensitivity within the magnocellular and parvocellular pathways. AB - This study evaluated the extent to which different types of luminance noise can be used to target selectively the inferred magnocellular (MC) and parvocellular (PC) visual pathways. Letter contrast sensitivity (CS) was measured for three visually normal subjects for letters of different size (0.8 degrees -5.3 degrees ) under established paradigms intended to target the MC pathway (steady-pedestal paradigm) and PC pathway (pulsed-pedestal paradigm). Results obtained under these paradigms were compared to those obtained in asynchronous static noise (a field of unchanging luminance noise) and asynchronous dynamic noise (a field of randomly changing luminance noise). CS was measured for letters that were high- and low-pass filtered using a range of filter cutoffs to quantify the object frequency information (cycles per letter) mediating letter identification, which was used as an index of the pathway mediating CS. A follow-up experiment was performed to determine the range of letter duration over which MC and PC pathway CS can be targeted. Analysis of variance indicated that the object frequencies measured under the static noise and steady-pedestal paradigms did not differ significantly (p >= 0.065), but differed considerably from those measured under the dynamic noise (both p < 0.001) and pulsed-pedestal (both p < 0.001) paradigms. The object frequencies mediating letter identification increased as duration increased under the steady-pedestal paradigm, but were independent of target duration (50-800 ms) under the pulsed-pedestal paradigm, in static noise, and in dynamic noise. These data suggest that the spatiotemporal characteristics of noise can be manipulated to target the inferred MC (static noise) and PC (dynamic noise) pathways. The results also suggest that CS within these pathways can be measured at long stimulus durations, which has potential importance in the design of future clinical CS tests. PMID- 28672371 TI - Saccadic eye movements do not disrupt the deployment of feature-based attention. AB - The tight link of saccades to covert spatial attention has been firmly established, yet their relation to other forms of visual selection remains poorly understood. Here we studied the temporal dynamics of feature-based attention (FBA) during fixation and across saccades. Participants reported the orientation (on a continuous scale) of one of two sets of spatially interspersed Gabors (black or white). We tested performance at different intervals between the onset of a colored cue (black or white, indicating which stimulus was the most probable target; red: neutral condition) and the stimulus. FBA built up after cue onset: Benefits (errors for valid vs. neutral cues), costs (invalid vs. neutral), and the overall cueing effect (valid vs. invalid) increased with the cue-stimulus interval. Critically, we also tested visual performance at different intervals after a saccade, when FBA had been fully deployed before saccade initiation. Cueing effects were evident immediately after the saccade and were predicted most accurately and most precisely by fully deployed FBA, indicating that FBA was continuous throughout saccades. Finally, a decomposition of orientation reports into target reports and random guesses confirmed continuity of report precision and guess rates across the saccade. We discuss the role of FBA in perceptual continuity across saccades. PMID- 28672372 TI - On the origin of sensory errors: Contrast discrimination under temporal constraint. AB - Estimation of perceptual variables is imprecise and prone to errors. Although the properties of these perceptual errors are well characterized, the physiological basis for these errors is unknown. One previously proposed explanation for these errors is the trial-by-trial variability of the responses of sensory neurons that encode the percept. In order to test this hypothesis, we developed a mathematical formalism that allows us to find the statistical characteristics of the physiological system responsible for perceptual errors, as well as the time scale over which the visual information is integrated. Crucially, these characteristics can be estimated solely from a behavioral experiment performed here. We demonstrate that the physiological basis of perceptual error has a constant level of noise (i.e., independent of stimulus intensity and duration). By comparing these results to previous physiological measurements, we show that perceptual errors cannot be due to the variability during the encoding stage. We also find that the time window over which perceptual evidence is integrated lasts no more than ~230 ms. Finally, we discuss sources of error that may be consistent with our behavioral measurements. PMID- 28672373 TI - A Research Agenda for Communication Between Health Care Professionals and Patients Living With Serious Illness. AB - Importance: Poor communication by health care professionals contributes to physical and psychological suffering in patients living with serious illness. Patients may not fully understand their illness, prognosis, and treatment options or may not receive medical care consistent with their goals. Despite considerable research exploring the role of communication in this setting, many questions remain, and a clear agenda for communication research is lacking. Observations: Through a consensus conference and subsequent activities, we reviewed the state of the science, identified key evidence gaps in understanding the impact of communication on patient outcomes, and created an agenda for future research. We considered 7 broad topics: shared decision making, advance care planning, communication training, measuring communication, communication about prognosis, emotion and serious illness communication, and cultural issues. We identified 5 areas in which further research could substantially move the field forward and help enhance patient care: measurement and methodology, including how to determine communication quality; mechanisms of communication, such as identifying the specific clinician behaviors that patients experience as both honest and compassionate, or the role of bias in the clinical encounter; alternative approaches to advance care planning that focus on the quality of serious illness communication and not simply completion of forms; teaching and disseminating communication skills; and approaches, such as economic incentives and other clinician motivators, to change communication behavior. Conclusions: Our findings highlight the urgent need to improve quality of communication between health care professionals and patients living with serious illness through a broad range of research that covers communication skills, tools, patient education, and models of care. PMID- 28672374 TI - Reassuring News About Football and Cognitive Decline?: Not So Fast. PMID- 28672375 TI - Ecologically Valid Assessment of Prospective Memory for Task Planning and Execution by Adults With Acquired Brain Injury. AB - Purpose: Individuals with acquired brain injury (ABI) often struggle due to inadequate planning and execution skills for completing nonroutine tasks. This study's purpose was to pilot ecologically valid procedures to assess planning for and execution of prospective daily activities. Method: Participants included 9 adults with histories of severe ABI and 9 controls. Data collection included both prospective task planning and execution. First, participants created a plan for later execution of daily tasks in accordance with preestablished rules. Over the subsequent 10 days, participants independently attempted task completion. Differences within and between participant groups regarding planning and task performance were evaluated statistically and through examiner observation. Results: Participants with ABI implemented minimal planning strategies. They demonstrated highly variable performance and displayed substantially greater difficulty initiating and successfully executing tasks in adherence to rules than participants without ABI. Conclusions: Evaluating planning strategies and execution of novel prospective tasks is a crucial but often neglected aspect of assessment following ABI. Implementing ecologically valid procedures to evaluate this aspect of functioning can reveal individual strengths and challenges and provide guidance for developing effective intervention programs. Examining potential roles played by planning and strategy execution provides critical assessment information relating to independent living. PMID- 28672376 TI - Cluster-Randomized Controlled Trial Evaluating the Effectiveness of Computer Assisted Intervention Delivered by Educators for Children With Speech Sound Disorders. AB - Purpose: The aim was to evaluate the effectiveness of computer-assisted input based intervention for children with speech sound disorders (SSD). Method: The Sound Start Study was a cluster-randomized controlled trial. Seventy-nine early childhood centers were invited to participate, 45 were recruited, and 1,205 parents and educators of 4- and 5-year-old children returned questionnaires. Children whose parents and educators had concerns about speech were assessed (n = 275); 132 children who were identified with phonological pattern-based errors underwent additional assessment. Children with SSD and no difficulties with receptive language or hearing, typical nonverbal intelligence, and English as their primary language were eligible; 123 were randomized into two groups (intervention n = 65; control n = 58), and 3 withdrew. The intervention group involved Phoneme Factory Sound Sorter software (Wren & Roulstone, 2013) administered by educators over 9 weeks; the control group involved typical classroom practices. Participants were reassessed twice by a speech-language pathologist who was unaware of the initial assessment and intervention conditions. Results: For the primary outcome variable (percentage of consonants correct), the significant mean change from pre- to postintervention for the intervention group (mean change = +6.15, p < .001) was comparable in magnitude to the significant change for the control group (mean change = +5.43, p < .001) with a small between-groups effect size for change (Cohen's d = 0.08). Similar results occurred for measures of emergent literacy, phonological processing, participation, and well-being. Conclusion: Computer-assisted input-based intervention administered by educators did not result in greater improvement than typical classroom practices. PMID- 28672377 TI - Case History Risk Factors for Specific Language Impairment: A Systematic Review and Meta-Analysis. AB - Purpose: Research suggests that the best approach to early identification of children with specific language impairment (SLI) should include assessment of risk factors. However, previous attempts to develop a list for this purpose have been unsuccessful. In this study, systematic review and meta-analytic procedures were used to determine whether any case history factors can be used to identify toddlers at risk of developing SLI. Method: Epidemiological studies that examined the association between risk factors and SLI were identified. Results across studies were aggregated to determine more precisely the strength of association between each risk factor and the development of SLI. The clinical significance of these factors was established via comparison to late talker status. Results: Eleven risk factors were found to be statistically significant predictors of SLI. Among these, maternal education level, 5-min Apgar score, birth order, and biological sex met criteria for clinical significance. Conclusions: At least 4 case history factors are as predictive as late talker status in the context of early identification of toddlers at risk for SLI. The findings of this review highlight the importance of taking a child's genetic and environmental context into consideration when deciding whether further evaluation and early intervention services are warranted. Supplemental Materials: https://doi.org/10.23641/asha.5150122. PMID- 28672378 TI - Assessing the Importance of Lexical Tone Contour to Sentence Perception in Mandarin-Speaking Children With Normal Hearing. AB - Purpose: The aim of the present study was to evaluate the influence of lexical tone contour and age on sentence perception in quiet and in noise conditions in Mandarin-speaking children ages 7 to 11 years with normal hearing. Method: Test materials were synthesized Mandarin sentences, each word with a manipulated lexical contour, that is, normal contour, flat contour, or a tone contour randomly selected from the four Mandarin lexical tone contours. A convenience sample of 75 Mandarin-speaking participants with normal hearing, ages 7, 9, and 11 years (25 participants in each age group), was selected. Participants were asked to repeat the synthesized speech in quiet and in speech spectrum-shaped noise at 0 dB signal-to-noise ratio. Results: In quiet, sentence recognition by the 11-year-old children was similar to that of adults, and misrepresented lexical tone contours did not have a detrimental effect. However, the performance of children ages 9 and 7 years was significantly poorer. The performance of all three age groups, especially the younger children, declined significantly in noise. Conclusions: The present research suggests that lexical tone contour plays an important role in Mandarin sentence recognition, and misrepresented tone contours result in greater difficulty in sentence recognition in younger children. These results imply that maturation and/or language use experience play a role in the processing of tone contours for Mandarin speech understanding, particularly in noise. PMID- 28672379 TI - Multitasking and Silent Electronic Health Record Use in Ambulatory Visits. PMID- 28672380 TI - Web Exclusives. Annals Graphic Medicine - Internship. PMID- 28672381 TI - Web Exclusives. Annals Graphic Medicine - July Plunge. PMID- 28672382 TI - Do Sugar-Sweetened Beverages Cause Obesity and Diabetes? PMID- 28672383 TI - Do Sugar-Sweetened Beverages Cause Obesity and Diabetes? PMID- 28672384 TI - Do Sugar-Sweetened Beverages Cause Obesity and Diabetes? PMID- 28672385 TI - Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus. PMID- 28672386 TI - Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus. PMID- 28672387 TI - Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus. PMID- 28672388 TI - Incidental Findings in Research Studies: One Student's Experience. PMID- 28672389 TI - Intensive Care. PMID- 28672390 TI - Counterclockwise. PMID- 28672391 TI - Abandon All. PMID- 28672392 TI - A Letter to New Interns. PMID- 28672393 TI - Management of Newly Diagnosed HIV Infection. AB - No field in medicine has moved as swiftly as HIV/AIDS over the past 35 years. Because of the rapid turnover of key information, this In the Clinic focuses on essential principles of care for newly diagnosed adults with HIV-1 infection and how to prevent infection in persons at risk. To ensure continued usefulness, future directions in therapy and how to access updated information on a continuous basis are emphasized. PMID- 28672394 TI - Annals for Educators - 4 July 2017. PMID- 28672396 TI - Achieving an Optimal Childhood Vaccine Policy. AB - Policies to remove parents' ability to opt-out from school immunization requirements on the basis of religious or personal beliefs (ie, nonmedical exemptions) may be a useful strategy to increase immunization rates and prevent outbreaks of vaccine-preventable disease. However, there is uncertainty about the effectiveness of this strategy and the range of possible outcomes. We advocate for a more deliberative process through which a broad range of outcomes is scrutinized and the balance of values underlying the policy decision to eliminate nonmedical exemptions is clearly articulated. We identify 3 outcomes that require particular consideration before policies to eliminate nonmedical exemptions are implemented widely and outline a process for making the values underlying such policies more explicit. PMID- 28672395 TI - Association Between Motor Symptoms and Brain Metabolism in Early Huntington Disease. AB - Importance: Brain hypometabolism is associated with the clinical consequences of the degenerative process, but little is known about regional hypermetabolism, sometimes observed in the brain of patients with clinically manifest Huntington disease (HD). Studying the role of regional hypermetabolism is needed to better understand its interaction with the motor symptoms of the disease. Objective: To investigate the association between brain hypometabolism and hypermetabolism with motor scores of patients with early HD. Design, Setting, and Participants: This study started in 2001, and analysis was completed in 2016. Sixty symptomatic patients with HD and 15 healthy age-matched control individuals underwent positron emission tomography to measure cerebral metabolism in this cross sectional study. They also underwent the Unified Huntington's Disease Rating Scale motor test, and 2 subscores were extracted: (1) a hyperkinetic score, combining dystonia and chorea, and (2) a hypokinetic score, combining bradykinesia and rigidity. Main Outcomes and Measures: Statistical parametric mapping software (SPM5) was used to identify all hypo- and hypermetabolic regions in patients with HD relative to control individuals. Correlation analyses (P < .001, uncorrected) between motor subscores and brain metabolic values were performed for regions with significant hypometabolism and hypermetabolism. Results: Among 60 patients with HD, 22 were women (36.7%), and the mean (SD) age was 44.6 (7.6) years. Of the 15 control individuals, 7 were women (46.7%), and the mean (SD) age was 42.2 (7.3) years. In statistical parametric mapping, striatal hypometabolism was significantly correlated with the severity of all motor scores. Hypermetabolism was negatively correlated only with hypokinetic scores in the cuneus (z score = 3.95, P < .001), the lingual gyrus (z score = 4.31, P < .001), and the crus I/II of the cerebellum (z score = 3.77, P < .001), a region connected to associative cortical areas. More severe motor scores were associated with higher metabolic values in the inferior parietal lobule, anterior cingulate, inferior temporal lobule, the dentate nucleus, and the cerebellar lobules IV/V, VI, and VIII bilaterally corresponding to the motor regions of the cerebellum (z score = 3.96 and 3.42 in right and left sides, respectively; P < .001). Conclusions and Relevance: Striatal hypometabolism is associated with clinical disease severity. Conversely, hypermetabolism is likely compensatory in regions where it is associated with decreasing motor scores. Hypermetabolism might be detrimental in other structures in which it is associated with more severe motor symptoms. In the cerebellum, both compensatory and detrimental contributions seem to occur. This study helps to better understand the motor clinical relevance of hypermetabolic brain regions in HD. PMID- 28672398 TI - Peripheral Design of Progressive Addition Lenses and the Lag of Accommodation in Myopes. AB - Purpose: Insufficient accommodative response is assumed to result in myopia progression. We have investigated if the accommodative lag in myopes is different between a single vision lens (SVL) and the progressive addition lens PAL 2, clinically trialled for its ability to reduce progression of myopia, and if there exist differences in accommodative lag between PAL 2 and other PALs with the same addition power (+1.50 D). Methods: The influence of spherical SVL and four different designs of PALs that differ in the near zone width (PAL 1) or that have different signs and magnitude of horizontal gradients of mean power adjacent to their near vision zones (PAL 3 and PAL 4) on the accommodative response was investigated for different near viewing distances (40, 33, and 25 cm) in 31 subjects, aged 18 to 25 years. Results: The SVL correction resulted in insufficient accommodative response for the near object viewing distances tested. PAL 2 did significantly reduce accommodative lag for all near object distances tested. The PAL design with a more negative horizontal mean power gradient (PAL 4) provided a lower lag of accommodation when compared with PAL 2 at the shortest object distance of 25 cm (P = 0.03) and was able to reduce the lag of accommodation to a level below the depth of focus for the higher near working distances tested. Conclusions: Designs of PAL with more negative horizontal mean power gradients are the most effective in lowering the lag of accommodation in myopes. This could make them good test candidates for myopia control applications. PMID- 28672397 TI - Structural and Functional Characterization of Human Stem-Cell-Derived Retinal Organoids by Live Imaging. AB - Purpose: Human pluripotent stem cell (hPSC)-derived retinal organoids are a platform for investigating retinal development, pathophysiology, and cellular therapies. In contrast to histologic analysis in which multiple specimens fixed at different times are used to reconstruct developmental processes, repeated analysis of the same living organoids provides a more direct means to characterize changes. New live imaging modalities can provide insights into retinal organoid structure and metabolic function during in vitro growth. This study employed live tissue imaging to characterize retinal organoid development, including metabolic changes accompanying photoreceptor differentiation. Methods: Live hPSC-derived retinal organoids at different developmental stages were examined for microanatomic organization and metabolic function by phase contrast microscopy, optical coherence tomography (OCT), fluorescence lifetime imaging microscopy (FLIM), and hyperspectral imaging (HSpec). Features were compared to those revealed by histologic staining, immunostaining, and microcomputed tomography (micro-CT) of fixed organoid tissue. Results: We used FLIM and HSpec to detect changes in metabolic activity as organoids differentiated into organized lamellae. FLIM detected increased glycolytic activity and HSpec detected retinol and retinoic acid accumulation in the organoid outer layer, coinciding with photoreceptor genesis. OCT enabled imaging of lamellae formed during organoid maturation. Micro-CT revealed three-dimensional structure, but failed to detect lamellae. Conclusions: Live imaging modalities facilitate real time and nondestructive imaging of retinal organoids as they organize into lamellar structures. FLIM and HSpec enable rapid detection of lamellar structure and photoreceptor metabolism. Live imaging techniques may aid in the continuous evaluation of retinal organoid development in diverse experimental and cell therapy settings. PMID- 28672399 TI - The Effect of a p38 Mitogen-Activated Protein Kinase Inhibitor on Cellular Senescence of Cultivated Human Corneal Endothelial Cells. AB - Purpose: We have begun a clinical trial of a cell-based therapy for corneal endothelial dysfunction in Japan. The purpose of this study was to investigate the usefulness of a p38 MAPK inhibitor for prevention cellular senescence in cultivated human corneal endothelial cells (HCECs). Methods: HCECs of 10 donor corneas were divided and cultured with or without SB203580 (a p38 MAPK inhibitor). Cell density and morphology were evaluated by phase-contrast microscopy. Expression of function-related proteins was examined by immunofluorescent staining. Cellular senescence was evaluated by SA-beta-gal staining and Western blotting for p16 and p21. Senescence-associated factors were evaluated by membrane blotting array, quantitative PCR, and ELISA. Results: Phase contrast microscopy showed a significantly higher cell density for HCECs cultured with SB203580 than without SB203580 (2623 +/- 657 cells/mm2 and 1752 +/- 628 cells/mm2, respectively). The HCECs cultured with SB203580 maintained a hexagonal morphology and expressed ZO-1, N-cadherin, and Na+/K+-ATPase in the plasma membrane, whereas the control HCECs showed an altered staining pattern for these marker proteins. HCECs cultured without SB203580 showed high positive SA-beta-gal staining, a low nuclear/cytoplasm ratio, and expression of p16 and p21. IL-6, IL 8, CCL2, and CXCL1 were observed at high levels in low cell density HCECs cultured without SB203580. Conclusions: Activation of p38 MAPK signaling due to culture stress might be a causative factor that induces cellular senescence; therefore, the use of p38 MAPK inhibitor to counteract senescence may achieve sufficient numbers of HCECs for tissue engineering therapy for corneal endothelial dysfunction. PMID- 28672401 TI - Rembrandt, Moses Breaking the Tablets of the Law. PMID- 28672402 TI - Testing for Respiratory Viruses in Children: To Swab or Not to Swab. AB - Importance: While most viral respiratory tract infections can be diagnosed clinically, clinicians frequently order tests to identify the specific offending virus. While there has been tremendous growth in the variety, availability, and sophistication of the types of respiratory viral tests, there may have been less critical thought and discussion among frontline clinicians about the clinical utility and specific indications for testing. We summarize the rationale historically used to support respiratory virus testing in children, with a review of the supporting evidence. We outline potential considerations and limitations of the various types of respiratory viral tests and suggest some clinical indications where viral testing may play an important role in clinical management. Observations: The main value of testing for viruses in children who present with a respiratory tract infection is to differentiate between viral and bacterial infections, hopefully facilitating clinical decision making regarding further investigations and the need for antibiotics. We have highlighted commonly cited rationale used to support testing and the generally poor evidence on which to base this rationale. In addition, difficulties with interpretation of respiratory viral testing results include somewhat poor diagnostic test characteristics for some tests, uncertainty regarding true positives and causation of illness, delay in receiving the test result, and the incidence of concurrent bacterial infections or the presence of multiple viruses. We have given some examples of clinical scenarios where respiratory viral testing results could be expected to contribute to more appropriate clinical management decisions. Conclusions and Relevance: It is not good enough to "do" just because we "can." We suggest that for many healthy immune-competent children presenting with typical viral respiratory tract symptoms, the diagnosis can be made clinically, and frontline clinicians should think critically before automatically requesting a somewhat uncomfortable, expensive respiratory viral test, the result of which may not contribute to the child's treatment. PMID- 28672400 TI - Comparison of Alternative Tumor Size Classifications for Posterior Uveal Melanomas. AB - Purpose: Determine which posterior uveal melanoma (PUM) size classification with three categories has the best prognostic discrimination. Methods: Single institution study of 424 consecutive patients with PUM. The tumor's largest basal diameter (LBD), smallest basal diameter (SBD), and thickness (TH) were estimated by fundus mapping and ultrasonography. Tumors were assigned to "small," "medium," or "large" size categories defined by 11 different classifications (Linear LBD, Rectangular LBD * TH, Cubic LBD * SBD * TH, Warren Original, Warren Modified, Augsburger, COMS Original, COMS Revised, TNM 2002, and modified TNM 2010 classification [a,b]). Prognostic significance of classifications was evaluated by Kaplan-Meier event curves with computation of log rank test for trend statistic. Results: In six classification systems (Warren Original, Warren Modified, COMS Revised, TNM 2002, TNM 2010a, TNM 2010b) >50% of tumors fell within one subgroup. In the Warren Original classification <5% of tumors fell within one subgroup. Separation of Kaplan-Meier curves among three size categories was judged "excellent" in four classifications (Linear LBD, Cubic Volume, TNM 2010a, and TNM 2010b) and "very poor" in the Warren Original. Linear LBD classification was associated with highest log rank statistic value. TNM 2010a, TNM 2010b, TNM 2002, Augsburger, and Cubic Volume classifications were also determined to be quite good. Conclusions: Linear LBD classification was the best three-size category discriminator among low-, intermediate-, and high-risk subgroups. Considering our findings, it seems possible that the arduous work required to apply complex classifications, especially for three-category systems, for PUM may not be justified in routine clinical practice. PMID- 28672403 TI - Annals for the Ages: Annals of Internal Medicine Turns 90. PMID- 28672404 TI - New Updates on Concussions in Girls and Menstrual Patterns. PMID- 28672405 TI - Driving Performance of Depressed Patients who are Untreated or Receive Long-Term Antidepressant (SSRI/SNRI) Treatment. AB - Introduction Depression is a mental disorder likely to affect everyday functions. The present study aimed to assess actual driving performance of depressed patients who were without specific antidepressant treatment or received long-term antidepressant treatment. Methods A standardized on-the-road driving test was used to assess standard deviation of lateral position (SDLP) in 3 patient groups receiving either no antidepressant treatment (with or without benzodiazepine medication) or treatment with selective serotonin/noradrenalin reuptake inhibitors for a period of 6-52 weeks. Severity of depression was assessed using Beck's Depression Inventory and the Hamilton Depression Rating Scale. The performance of patient groups was compared to healthy controls. Results The mean SDLP of untreated and treated patients was significantly higher than that of healthy controls. Driving impairment in the long-term treated group was significantly less than in the untreated groups. SDLP was positively correlated to severity of depression across all groups. Discussion It is concluded that symptoms of depression are a major cause of driving impairment. Reductions in severity of depression through antidepressant treatment reduce severity of driving impairment. PMID- 28672406 TI - ? PMID- 28672407 TI - ? PMID- 28672408 TI - Ginger Extract Modulates the Expression of Chemokines CCL20 and CCL22 and Their Receptors (CCR6 and CCR4) in the Central Nervous System of Mice with Experimental Autoimmune Encephalomyelitis. AB - Background Chemokines facilitate the leukocytes infiltration into the central nervous system (CNS) which is an essential step in the pathogenesis of multiple sclerosis. Ginger has also a broad anti-inflammatory properties. The aim was to evaluate the effects of ginger extract on the expression of CCL20 and CCL22 and their receptors (CCR6 and CCR4, respectively) in experimental autoimmune encephalomyelitis (EAE). Material and Methods Female C57BL/6 mice used for EAE induction by immunization with myelin oligodendroglial glycoprotein. Then, the EAE mice were treated with PBS or ginger extract, from day +3 to +30. At day 31, mice were scarified and the expression of CCL20 and CCL22 and their receptors in the spinal cord measured using real time-PCR. Results The expression of CCL20, CCL22 and CCR4 in the spinal cord of PBS-administrated EAE mice was significantly higher than healthy group (P<0.04, P<0.05 and P<0.02, respectively). In 200- and 300 mg/kg ginger extract-treated EAE mice, the expression of CCL20, CCL22 and CCR4 were significantly reduced as compared with PBS-administrated EAE group (P<0.04, P<0.01 and P<0.002 for 200 mg/kg ginger extract and P<0.01, P<0.005 and P<0.004 for 300 mg/kg ginger extract, respectively). The CCR6 expression in EAE mice treated with 200- or 300 mg/kg ginger extracts was lower than PBS administrated EAE mice (P<0.01 and P=0.07, respectively). Conclusion Treatment of EAE mice with ginger extract down-regulate the expression of CCL20 and CCL22 and their receptors in EAE mice. The possible therapeutic potential of ginger for treatment of MS can be considered in future investigations. PMID- 28672409 TI - Jack Bean Urease Inhibitors, and Antioxidant Activity Based on Palmitic acid Derived 1-acyl-3- Arylthioureas: Synthesis, Kinetic Mechanism and Molecular Docking Studies. AB - A series of acylthioureas was synthesized and their inhibitory effects on the DPPH and jack bean urease were evaluated. The results showed that all of the synthesized compounds exhibited significant jack bean urease inhibitory activities. Especially, 1-(4-chlorophenyl)-3 palmitoylthiourea 5a bearing 4 chloro substituted phenyl ring exhibited the most potent tyrosinase inhibitory activity with an IC50 value 0.0170 MUM compared to the IC50 value of 4.720 MUM of thiourea used as standard. The inhibition mechanism analyzed by Lineweaver-Burk plots revealed that the type of inhibition of compound 5a on tyrosinase was noncompetitive. The docking study against jack bean urease enzyme was also performed to determine the binding affinity of the compounds. The compounds 4c and 4e showed the highest binding affinity with the active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that all compounds and particularly 5a may serve as a structural template for the design and development of novel urease inhibitors Graphical Abstract. PMID- 28672410 TI - [Prescription of Benzodiazepines and Z-Drugs by German General Practitioners: A Cross-Sectional Study]. AB - BACKGROUND: Due to their addictive potential, benzodiazepine (BZ) and non benzodiazepine-agonists (NBZ, so-called Z-drugs) should be taken no longer than 6 weeks. BZ and NBZ are primarily prescribed by general practitioners (GPs). Therefore, we aimed to analyze GPs' data on the patients collective, the amount of BZ/NBZ prescribed and the rate of private prescriptions. METHODS: We analyzed person years of 2-year intervals from 2009 to 2014 of the primary care CONTENT register that contains routine data from 31 general practitioners' practices. We classified BZ/NBZ prescriptions according to risk groups. The association of BZ/NBZ prescription and potential influencing factors was analyzed by calculating the odds ratio with 95% confidence interval (and corresponding p-value) on the basis of a multiple logistic regression model (adjusted by age, sex and type of health insurance). All patients with drug prescription with and without BZ/NBZ prescription were compared. RESULTS: Almost 5% of patients with drug prescriptions received at least one prescription of BZ/NBZ during 1 year of observation. On average these patients were older (67.5 vs. 48 years respectively) and the proportion of women was higher than in the comparison group (69 vs. 58%). About one-third of these patients received more than 600 mg diazepam equivalent dose per person year (according to a 2-month daily intake of more than 10 mg diazepam). About one-third of the prescriptions were private prescriptions. A number of variables were significantly associated with the prescription of BZ/NBZ (e. g. age, gender, diagnosis codes, practices). CONCLUSION: The results provide valuable information about BZ/NBZ prescription routines in general practice. For continuous medical education as well as the development of interventions to reduce the use of BZ/NBZ, patient characteristics (e. g. sex, age, comorbidities, type of insurance) as well as different prescription routines (e. g. private prescriptions, reason and frequency of prescriptions, guideline orientation) should be considered. PMID- 28672411 TI - Rates of Upper Facet Joint Violation in Minimally Invasive Percutaneous and Open Instrumentation: A Comparative Cohort Study of Different Insertion Techniques. AB - BACKGROUND: Minimally invasive pedicle screw placement may have a higher incidence of violation of the superior cephalad unfused facet joint. STUDY AIMS: We investigated the incidence and risk factors of upper facet joint violation in percutaneous robot-assisted instrumentation versus percutaneous fluoroscopy guided and open transpedicular instrumentation. METHODS: A retrospective study including all consecutive patients who underwent lumbar instrumentation, fusion, and decompression for spondylolisthetic stenosis and degenerative disk disease was conducted between January 2012 and January 2016. All operations were performed by the same surgeon; the patients were divided into three groups according to the method of instrumentation. Group 1 involved the robot-assisted instrumentation in 58 patients, group 2 consisted of 64 patients treated with a percutaneous transpedicular instrumentation using fluoroscopic guidance, and 72 patients in group 3 received an open midline approach for pedicle screw insertion. RESULTS: Superior segment facet joint violation occurred in 2 patients in the robot-assisted group 1 (7%), in 22 of the percutaneous fluoroscopy-guided group 2 (34%), and in 6 cases of the open group (8%). The incidence of facet joint violation was present in 5% (3) of the screws in group 1, 22% (28) of the screws in group 2, and 3% (4) of the screws in group 3. CONCLUSION: Meticulous surgical planning of the appropriate entry site (Weinstein's method), trajectory planning, and proper robot-assisted instrumentation of pedicle screws reduced the risk of superior segment facet joint violation. PMID- 28672412 TI - Abdominal Circumference Alone versus Estimated Fetal Weight after 24 Weeks to Predict Small or Large for Gestational Age at Birth: A Meta-Analysis. PMID- 28672413 TI - Long-Acting Reversible Contraception. AB - Unwanted pregnancy is a major public health problem both in developed and developing countries. Although the reduction in the rates of these pregnancies requires multifactorial approaches, increasing access to long-acting contraceptive methods can contribute significantly to change this scenario. In Brazil, gynecologists and obstetricians play a key role in contraceptive counseling, being decisive in the choice of long-acting reversible methods, characterized by intrauterine devices (IUDs) and the contraceptive implant. The vast scope due to the reduced number of situations to indicate long-acting methods should be emphasized in routine contraceptive counseling. On the other hand, gynecologists and obstetricians should adapt the techniques of insertion of long-acting methods, and engage in facilitating conditions to access these contraceptives through public and private health systems in Brazil. This study is part of a project called Diretrizes e Recomendacoes FEBRASGO (Guidelines and Recommendations of the FEBRASGO - Brazilian Federation of Gynecology and Obstetrics Associations from the Portuguese acronym). It aims to review the main characteristics of long-acting contraceptives and critically consider the current situation and future prospects to improve access to these methods, proposing practical recommendations of interest in the routine of gynecologists and obstetricians. PMID- 28672414 TI - [Therapy of Intradialytic Chronic Metabolic Acidosis in Germany - Is it According to Latest Evidence?] AB - Background Chronic metabolic acidosis is a frequent comorbidity in chronic kidney disease, especially in patients undergoing dialysis. Recent study data suggest that treatment of acidosis during dialysis with bicarbonate may result in increased levels of serum bicarbonate, which is associated with increased mortality. Methods We aimed to evaluate the current management of chronic metabolic acidosis in Germany: have recent study results been transferred into daily routine and are nephrologists aware of these new study data? Therefore, we did a survey with 17 questions among 2096 German nephrologists. 280 valid responses were returned and analysed with descriptive statistics. Results Blood gas analysis was done weekly (27 % of respondents), monthly (20 %), every 3 months (19 %), less frequently (5 %) or not routinely (3 %). It was done by most respondents prior to the dialysis session (83 %) and by some (20 %) also afterwards or during the session (3 %). 20 % did blood gas analysis "as required".Oral bicarbonate was discontinued at start of dialysis by 66 % of nephrologists; 22 % of these do generally not use it and 44 % usually discontinue it but might continue if required. 34 % of responding nephrologists continue oral bicarbonate when starting dialysis but might adjust dose. Discussion Recent study data might have to be better promoted among nephrologists. Although KDIGO guidelines recommend at least monthly blood gas analysis, about one quarter of nephrologists stated to do it less frequently. Furthermore, blood gas analysis was rarely done after dialysis treatment and thus, important information about success or failure of bicarbonate correction was not obtained. If alkalotic episodes after dialysis treatment would be detected this way, regular oral bicarbonate might be an option for correction of metabolic acidosis. PMID- 28672415 TI - [Fever of Unknown Origin]. PMID- 28672416 TI - [25-Year-Old Man after a Gunshot Injury at the Neck]. PMID- 28672417 TI - [Infections as a Cause of Unexplained Fever]. AB - Fever of unexplained (or unknown) origin (FUO) remains a relevant clinical problem even with modern diagnostic methods. In addition to the classical definition, new categories of FUO describe different clinical situations: nosocomial FUO, FUO in neutropenic/immundeficient patients and FUO in patients with HIV-infection. The new categories are defined by much shorter duration of fever, i. e. mostly three days. Each category of FUO shows a different spectrum of infectious diseases. Often, subacute bacterial endocarditis is very difficult to verify. In many cases, patients in intensive care suffer from FUO caused by reactivation of CMV. In patients with HIV the most important diagnostic indicator concerning the origin of infection is the degree of immundeficiency. Biological and nuclear medical (PET-CT) verification procedures have been established in diagnostics. A national or international register should be created with the purpose of data transfer and validation of strategies concerning the treatment of FUO. PMID- 28672418 TI - [Fever in Cancer Patients]. AB - Fever in cancer patients is a medical emergency until a severe infection has been ruled out. In case of neutropenia prompt diagnostic work-up should be paralleled by empiric antibiotic treatment. Underlying malignancy as well as treatments may impair immune response and thus pave the way for less virulent pathogens. So the spectrum of infections comprises both pathogens that cause disease in immunocompetent patients and a variety of rarer organisms. After collecting two pairs of blood cultures, broad-spectrum antibiotic treatment should commence within one to two hours. Depending on the individual patient's risk antimicrobial prophylaxis should be considered. PMID- 28672419 TI - [Autoinflammatory Diseases as a Differential Diagnosis of Fever of Unknown Origin]. AB - Fever is the most leading symptom of autoinflammatory diseases (AID). Therefore, AID have to be considered in differential diagnosis concerning fever of unknown origin. Unspecific Inflammatory manifestations may lead to misinterpretations that possibly cause irreversible organ damage. Effective treatment options are available and imply profound diagnostics. PMID- 28672420 TI - [30-year-old Patient with suspected Marfan Syndrome and Progressive Gait disturbance]. AB - History A 30-year-old man presented with a history of progressive muscle weakness, difficulty in concentrating, and a slender habitus since early childhood. Marfan syndrome was suspected since the age of 14. Examinations 13 years later he was examined by Marfan experts and by genetic testing and Marfan syndrome could not be confirmed. Further neurological examination revealed the suspected diagnosis of myotonic dystrophy type 1, which was confirmed by genetic testing. Treatment and course Similar to Marfan syndrome, myotonic dystrophy is a multisystemic disorder with the risk of cardiac arrythmias. It is necessary to provide an interdisciplinary care by neurologists, internists, ophthalmologists, speech therapists, and physiotherapists. Conclusion It is not enough to take the habitus as the principle sign to diagnose Marfan syndrome. Furthermore, it is essential to consider symptoms that are not typical for Marfan syndrome, such as cognitive deficiencies or progressive paresis. PMID- 28672421 TI - [Acute Coronary Syndrome - What should the general practitioner do?] AB - Acute myocardial infarction is the second most common cause of mortality in Germany after chronic ischemic cardiac disease. It is essential to think of acute coronary syndrome also in patients who do not present with typical signs (pressure, tightness, pain, or a squeezing or aching sensation in the chest or arms that may spread to the neck, jaw or back) in the general practitioner's practice. Vital signs (blood pressure, heart rate and oxygen saturation) must be measured; an ECG should be recorded and analyzed within ten minutes of first medical contact. The patient should be sedated, head and shoulders should be supported and an intravenous access should be established. Emergency medication that should be administered in practice is acetylsalicylic acid, an ADP receptor antagonist, morphine, nitrates, low molecular weight heparin and where necessary tranquilizers and oxygen (if peripheral saturation is below 90%). Monitored transport to the nearest clinic with percutaneous coronary intervention standby must be organized and this clinic must be informed about the arriving patient. PMID- 28672422 TI - ? PMID- 28672424 TI - On the reliability of N-mixture models for count data. AB - N-mixture models describe count data replicated in time and across sites in terms of abundance N and detectability p. They are popular because they allow inference about N while controlling for factors that influence p without the need for marking animals. Using a capture-recapture perspective, we show that the loss of information that results from not marking animals is critical, making reliable statistical modeling of N and p problematic using just count data. One cannot reliably fit a model in which the detection probabilities are distinct among repeat visits as this model is overspecified. This makes uncontrolled variation in p problematic. By counter example, we show that even if p is constant after adjusting for covariate effects (the "constant p" assumption) scientifically plausible alternative models in which N (or its expectation) is non-identifiable or does not even exist as a parameter, lead to data that are practically indistinguishable from data generated under an N-mixture model. This is particularly the case for sparse data as is commonly seen in applications. We conclude that under the constant p assumption reliable inference is only possible for relative abundance in the absence of questionable and/or untestable assumptions or with better quality data than seen in typical applications. Relative abundance models for counts can be readily fitted using Poisson regression in standard software such as R and are sufficiently flexible to allow controlling for p through the use covariates while simultaneously modeling variation in relative abundance. If users require estimates of absolute abundance, they should collect auxiliary data that help with estimation of p. PMID- 28672423 TI - ECMO as a bridge to non-transplant cardiac surgery. AB - Cardiac surgery performed on patients in cardiogenic shock is associated with a high mortality and morbidity. This review outlines the current role of preoperative veno-arterial extra corporeal membrane oxygenation to allow hemodynamic stability and organ recovery before definitive cardiac surgery. PMID- 28672426 TI - Issue Information - IFA. PMID- 28672427 TI - Porcine models for the study of small-for-size syndrome. PMID- 28672425 TI - Effects of resveratrol on eNOS in the endothelium and the perivascular adipose tissue. AB - Under physiological conditions, nitric oxide (NO) is produced in the vasculature mainly by the endothelial NO synthase (eNOS). Experiments using gene-disrupted mice have demonstrated that eNOS has antihypertensive, antithrombotic, and antiatherosclerotic effects. Recent studies show that eNOS is expressed not only in the endothelium but also in the perivascular adipose tissue (PVAT). Resveratrol prevents eNOS uncoupling and upregulates eNOS expression and activity. These effects of resveratrol are well established for the eNOS enzyme in the endothelium. Interestingly, resveratrol also improves PVAT function. However, a causal role for eNOS in the effects of resveratrol on PVAT function has not yet been verified and needs to be studied in the future. PMID- 28672428 TI - Re: Porcine models for the study of small-for-size syndrome. PMID- 28672429 TI - Regional Food Causing Symptoms of Gastroesophageal Reflux Disease. PMID- 28672430 TI - The Implication of Gastric Dysmotility in the Pathophysiology of Functional Dyspepsia. PMID- 28672431 TI - The Application of the Rome IV Criteria to Functional Esophagogastroduodenal Disorders in Asia. AB - The Rome criteria were amended as Rome IV. For functional esophageal disorders, the exclusion criteria have been more specifically revised based on further understanding of other esophageal disorders, including eosinophilic esophagitis and spastic and hypercontractile motor disorders. Another revised point is the more restrictive definition of gastroesophageal reflux disease, indicating that sensitivity to a physiological reflux burden may be placed more firmly within the functional group. For functional dyspepsia (FD), only minor changes were introduced, mainly to improve specificity. Among the major symptoms of FD, not only postprandial fullness, but also epigastric pain, epigastric burning, and early satiation should be "bothersome." Investigation on the effect of meal ingestion on symptom generation has indicated that not only postprandial fullness and early satiety, but also epigastric pain, epigastric burning sensation and nausea (not vomiting) may increase after meals. Helicobacter pylori infection is considered a possible cause of dyspepsia if successful eradication leads to sustained resolution of symptoms for more than 6 months, and such status can be termed as "H. pylori-associated dyspepsia." Prompt esophagogastroduodenoscopy and H. pylori testing and treatment would be more beneficial, especially in Asia, which has a high prevalence of gastric cancer. Acotiamide, tandospirone, and rikkunshito are the newly listed as treatment options for FD. For further therapeutic development, clinical studies based on the strict Rome IV criteria should be performed. PMID- 28672432 TI - Pros and Cons While Looking Through an Asian Window on the Rome IV Criteria for Irritable Bowel Syndrome: Pros. AB - A decade after Rome III, in 2016, Rome IV criteria were published. There are major differences between Rome IV and the earlier iteration, some of which are in line with Asian viewpoints. The clinical applicability of the Rome IV criteria of irritable bowel syndrome (IBS) in Asian perspective is reviewed here. Instead of considering functional gastrointestinal disorders (FGIDs) to be largely psychogenic, Rome IV suggested the importance of the gut over brain ("disorders of gut-brain interaction" not "brain-gut interaction"). The word "functional" is underplayed. Multi-dimensional clinical profile attempts to recognize micro organic nature, like slow colon transit and fecal evacuation disorders in constipation and dietary intolerance including that of lactose and fructose, bile acid malabsorption, non-celiac wheat sensitivity, small intestinal bacterial overgrowth, and gastrointestinal infection in diarrhea. Overlap between different FGIDs has been recognized as Rome IV suggests these to be a spectrum rather than discrete disorders. Bloating, common in Asia, received attention, though less. Sub-typing of IBS may be more clinician-friendly now as the patient-reported stool form may be used than a diary. However, a few issues, peculiar to Asia, need consideration; Rome IV, like Rome III, suggests that Bristol type I-II stool to denote constipation though Asian experts include type III as well. Work-up for physiological factors should be given greater importance. Language issue is important. Bloating, common in IBS, should be listed in the criteria. Threshold values for symptoms in Rome IV criteria are based on Western data. Post infectious malabsorption (tropical sprue) should be excluded to diagnose post infectious IBS, particularly in Asia. PMID- 28672434 TI - Effects of Age on Esophageal Motility: Use of High-resolution Esophageal Impedance Manometry. AB - The data "268" in the Abstract should have been written as "279" and the data "277" in the Materials and Methods should have been written as "279." PMID- 28672433 TI - The Increased Level of Depression and Anxiety in Irritable Bowel Syndrome Patients Compared with Healthy Controls: Systematic Review and Meta-analysis. AB - Background/Aims: Irritable bowel syndrome (IBS) patients commonly experience psychiatric disorders, such as depression and anxiety. This meta-analysis sought to compare depression and anxiety levels between IBS patients and healthy controls. Methods: We searched major electronic databases (PubMed, EMBASE, MEDLINE, and Cochrane library) to find comparative studies on IBS patients and healthy controls. The primary outcome was a standardized mean difference (SMD) of anxiety and depression levels; sub-group analyses were conducted according to IBS subtypes. Results: In total, 2293 IBS patients and 4951 healthy controls from 27 studies were included. In random effect analysis, depression and anxiety levels were significantly higher in IBS patients (pooled SMD = 0.76; 95% CI, 0.62-0.90; P < 0.001; I2 = 77.2% and pooled SMD = 0.84; 95% CI, 0.67-1.01; P < 0.001; I2 = 85.6%, respectively). Both analyses' funnel plots showed symmetry. In meta regression analysis, heterogeneity was due to the studied region and questionnaire type for both depression and anxiety. In sub-group analyses of IBS subtype, the pooled SMDs of depression and anxiety levels (IBS with predominant constipation: 0.83 and 0.81, IBS with predominant diarrhea: 0.73 and 0.65, and IBS with mixed bowel habits: 0.62 and 0.75; P < 0.001, respectively) were significantly higher in all IBS-subtypes. Conclusions: The present meta-analysis showed depression and anxiety levels to be higher in IBS patients than in healthy controls, regardless of IBS-subtype. However, the gender effect on psychological factors among IBS patients could not be determined and should be evaluated in prospective studies. PMID- 28672479 TI - Corrigendum. PMID- 28672548 TI - Corrigendum. PMID- 28672561 TI - Corrigendum. PMID- 28672688 TI - Fluoride exposure changed the structure and the expressions of HSP related genes in testes of pubertal rats. AB - Previous studies have indicated that fluoride exposure damaged the male reproductive function; however, the cellular mechanism of fluoride-induced testicular toxicity is still unclear. In this study, twenty-two female pregnant Wistar rats were allotted randomly to two groups: control (deionized water) and sodium fluoride (NaF, contain F-: 67.86 mg/L) groups. After delivery, the dosage was continued for 15 weeks for puppies. Twelve rats in each group were tested at 6 and 9 (pubertal); 12 and 15 (mature) weeks of age. Our results suggested that organ coefficient of epididymis was significantly decreased in the mature (12 and 15 week-old) rats. Epididymal sperm abnormality and femur fluoride concentration were increased with the concomitant decrease in sperm motility and concentration in these experimental periods. Compared to the control, in the NaF group, the seminiferous tubules of each age were reduced in terms of diameter and thickness. The sperm cells were lost and shedding and finally disappeared after 9 weeks. mRNA and protein levels of HSP27 and 90 were decreased with a concomitant increase in HSP70 and HSF mRNA and protein levels in NaF exposed rats. The mRNA and protein levels of HSP27 and HSF (only mRNA) were significantly increased in NaF treated rats at 9 and 15 weeks of age, respectively. In summary, these results emphasize that NaF induces testicular and sperm abnormalities through the involvement of HSPs especially during the pubertal period. PMID- 28672689 TI - Diagnostic ratios for the rapid evaluation of natural attenuation of heavy fuel oil pollution along shores. AB - Marine oil spills are typically followed by complex clean-up and monitoring operations of the shorelines affected. In this regard, determination of the changes in the chemical composition of the spilled product is crucial for evaluation purposes. The "GC-MS fingerprint" approach requires the identification of several key parameters in order to differentiate between weathering processes. In this context, we performed a 900-day study (eight sampling campaigns) of natural attenuation on a rocky shore affected by a heavy fuel oil spill. The residues coating the rocks were studied by extraction, separation and evaluation of SARA fractions, followed by GC-MS analysis for saturates and aromatics. The results identified a group of diagnostic ratios with irregular capabilities to differentiate between volatilization, photodegradation, and biodegradation (using n-alkanes, isoprenoids and PAHs), while a second group of primarily stable ratios (using dibenzothiphenes, tricyclics and hopanes) was also obtained. Notably, this is the first time that some of these ratios have been used for marine spill monitoring purposes. The ratios were applied not only to evaluate weathering at the study site, but also to obtain a comparison with the degradation of floating oil slicks-a demonstration that weathering of the latter was quicker than that of oil on the shore rocks. Additionally, Pyrolysis-GC-MS analysis of the asphaltene fraction of residues coating the rocks revealed moderate changes in the composition of this initially recalcitrant fraction. These changes were consistent with those found in the proportion of resins and asphaltene fractions over time. PMID- 28672690 TI - Valorization of starchy, cellulosic, and sugary food waste into hydroxymethylfurfural by one-pot catalysis. AB - This study aimed to produce a high-value platform chemical, hydroxymethylfurfural (HMF), from food waste and evaluate the catalytic performance of trivalent and tetravalent metals such as AlCl3, CrCl3, FeCl3, Zr(O)Cl2, and SnCl4 for one-pot conversion. Starchy food waste, e.g., cooked rice and penne produced 4.0-8.1 wt% HMF and 46.0-64.8 wt% glucose over SnCl4 after microwave heating at 140 degrees C for 20 min. This indicated that starch hydrolysis was effectively catalyzed but subsequent glucose isomerization was rate-limited during food waste valorization, which could be enhanced by 40-min reaction to achieve 22.7 wt% HMF from cooked rice. Sugary food waste, e.g., kiwifruit and watermelon, yielded up to 13 wt% HMF over Sn catalyst, which mainly resulted from naturally present fructose. Yet, organic acids in fruits may hinder Fe-catalyzed dehydration by competing for the Lewis sites. In contrast, conversion of raw mixed vegetables as cellulosic food waste was limited by marginal hydrolysis at the studied conditions (120-160 degrees C and 20-40 min). It is interesting to note that tetravalent metals enabled HMF production at a lower temperature and shorter time, while trivalent metals could achieve a higher HMF selectivity at an elevated temperature. Further studies on kinetics, thermodynamics, and reaction pathways of food waste valorization are recommended. PMID- 28672691 TI - The relationship between the length of surface ligand and effects of CdTe quantum dots on the physiological functions of isolated mitochondria. AB - The potential toxicity of Quantum dots (QDs) should be assessed comprehensively for their fast spreading applications. Many studies have shown the toxicity of QDs is associated with their surface ligands. In this work, two analog ligands with one carbon difference, 2-mercaptoacetic acid (TGA) and 3-mercaptopropionic acid (MPA) were used as coating materials in the syntheses of two types of CdTe QDs with similar physicochemical properties. Then the biological effects of QDs on isolated mitochondria were studied. It was found that the two types of QDs could impair mitochondrial respiration and induce mitochondrial permeability transition (MPT). However, as compared with TGA-CdTe QDs, MPA-CdTe QDs had a stronger effect on MPT. The weaker effect of TGA-CdTe QDs on MPT might be owing to their better stability and thus less amount of released Cd2+, which could be further explained by the stronger affinity between the ligand (TGA) and the cadmium complexes in the crystal growth of QDs. These results highlighted the importance of ligands responsible for the toxicity of QDs at the sub-cellular level. PMID- 28672692 TI - Cyclic and linear siloxanes in indoor air from several northern cities in Vietnam: Levels, spatial distribution and human exposure. AB - Earlier studies have reported the occurrence of cyclic and linear siloxanes in personal care and household products. Nevertheless, there is a lack of information on the occurrence of siloxanes in indoor air. In this study, four cyclic and six linear siloxanes were measured in 97 indoor air samples collected from various micro-environments in four cities in northern, Vietnam, during September 2016 to January 2017. The total concentrations of siloxanes (TSi) in particulate and gas phases ranged from 141 to 7220 MUg g-1 (mean: 1880) and 23.8 1580 ng m-3 (mean: 321), respectively. The total concentrations of cyclic siloxanes (TCSi), linear siloxanes (TLSi), and TSi in indoor air were 1.91-1500 ng m-3, 21.8-817 ng m-3, and 41.8-1950 ng m-3, respectively. The highest mean concentration of siloxanes was found in indoor air from hair salons in Hanoi. The concentrations of siloxanes in air collected from homes in Hanoi were higher than those from other smaller cities such as Bacninh, Thaibinh, and Tuyenquang. The human exposures to siloxanes through inhalation were estimated for various age groups based on the measured concentrations. The mean inhalation exposure doses to total siloxanes for infants, toddlers, children, teenagers, and adults were 352, 219, 188, 132, and 95.9 ng kg-bw-1 d-1, respectively. PMID- 28672693 TI - Stability of co-existing ZnO and TiO2 nanomaterials in natural water: Aggregation and sedimentation mechanisms. AB - The use of diverse engineered nanomaterials (ENMs) potentially leads to the coexistence of multiple ENMs in the natural environment. The fate such as colloidal stability, transport, and transformation of individual ENMs are dedicated to the coexistence of other types of ENMs in the environment. Here, we for the first time investigated the sedimentation behaviors of two most widely used ENMs (i.e. ZnO and TiO2 nanomaterials, nZnO and nTiO2) copresented in the natural water of China. Sedimentation rates (Vs), homo-aggregation (khom, crit) and hetero-aggregation (khet, crit) rate of nZnO and nTiO2 were calculated based on Von Smoluchowski-Stokes equation and the sedimentation mechanisms were systematically analyzed. The results showed that the coexistence of like negative charge nZnO and nTiO2 effectively enhanced the stability of either ENM by competing hetero-aggregation with natural colloids (NCs) and reducing to form homo-aggregates by the hindrance effect on particle collision. In the natural water, homo-aggregation, hetero-aggregation between ENMs and NCs, as well as the hetero-aggregation between nZnO and nTiO2 were the main aggregation and sedimentation mechanisms. The coexistence of nZnO and nTiO2 made Vs of nZnO decreased by 30.7-49.1% and Vs of nTiO2 decreased by a factor of 42.4%. Value of khet.crit between nZnO and NCs was 0.084-0.132 L mg-1 day-1, was 0.038 L mg-1 day 1 between nTiO2 and NCs, and was 0.011-0.014 L mg-1 day-1 between nZnO and nTiO2. PMID- 28672694 TI - Can coastline plant species be used as biosamplers of emerging contaminants? - UV filters and synthetic musks as case studies. AB - Personal care products, an important class of emerging contaminants, have been frequently detected in different environmental matrices. Included in this category are synthetic musks compounds (SMCs) and UV-filters. Their occurrence in the coastal environment has been poorly studied. Therefore, this work aimed to verify whether five coastline plant species (Carpobrotus edulis, Cakile maritima, Medicago marina, Elymus farctus borealis-atlanticus and Euphorbia paralias) have the ability to accumulate 11 SMCs (cashmeran, celestolide, phantolide, galaxolide, tonalide, exaltolide, musk moskene, tibetene, ambrette, xylene and ketone) and 2 organic UVB filters (3-(4'-methylbenzylidene) camphor and octocrylene), functioning as biosamplers. To accomplish this task, a QuEChERS technique ("Quick, Easy, Cheap, Effective, Rugged, and Safe") was employed to extract the target compounds from the plant material collected in 15 beaches of Matosinhos and Vila Nova de Gaia (Portugal). The resulting extracts were analysed by gas chromatography-mass spectrometry. Limits of detection ranged from 0.02 ng g-1 for celestolide and tonalide to 1.32 ng g-1 for musk ambrette. The obtained recoveries were around 93% and relative standard deviation was generally less than 15%. SMCs were detected at levels ranging from 1.56 to 350 ng g-1 dw and UV filters from 2.9 to 264 ng g-1 dw. Galaxolide and 3-(4'-methylbenzylidene) camphor were the synthetic musk and UV-filter detected in higher concentrations, respectively. Plants with higher water content accumulate better SMCs (hottentot fig), while those with higher lipid content retain better the UV-filters (sea spurge). PMID- 28672695 TI - Tea waste biomass activated carbon electrode for simultaneous removal of Cr(VI) and fluoride by capacitive deionization. AB - Capacitive deionization is promising less energy based desalination technique to achieve pure water. In the present study microporous activated carbon was prepared from tea waste biomass by chemical and thermal modification. Further TWBAC was used for preparation of the electrode. The TWBAC electrode was applied in the self-made CDI set up for simultaneous removal of hexavalent chromium [Cr(VI)] and fluoride (F) form mixed feed solution of Cr(VI) and F. The performance of TWBAC electrode was found effective for simultaneous removal of Cr(VI) and F from mixed feed solution. The maximum electrosorption capacity of Cr(VI) and F were found 0.77 and 0.74 mg g-1 for 10 mg L-1 and 2.83 and 2.49 mg g 1 for 100 mg L-1 mixed feed solution respectively. The higher removal of Cr(VI) was found due to the electrosorption selectivity of the divalent CrO42- is higher than that of the monovalent F-. Multicomponent isotherm modeling and kinetic study were carried out in this study. TWBAC CDI electrode could be useful for treatment of a low concentrated Cr(VI) and F containing wastewater. PMID- 28672696 TI - The physiological characteristics of zebra fish (Danio rerio) based on metabolism and behavior: A new method for the online assessment of cadmium stress. AB - In order to illustrate heavy metal ecotoxicology associated with interactions between chemicals and biological systems, we investigated physiological changes (metabolism and behavior response) of zebra fish (Danio rerio) under 48 h Cadmium chloride (CdCl2) exposure using online monitoring technique. The concentrations of CdCl2 were designed as 4.26, 42.6 and 85.2 mg/L, which were 0.1, 1.0, and 2.0 based on toxic unit (TU), respectively. The metabolism was assessed using the oxygen consumption (OC), and the behavior response was analyzed in behavior strength (BS). Significant inhibition of both OC and BS could be observed: OC was 617.39 +/- 30.48 mg/kg/h in the control, and it decreased rapidly to 229.07 +/- 28.66 mg/kg/h in 2.0 TU treatment. BS changed from 0.76 +/- 0.07 (control) to 0.39 +/- 0.04 (2.0 TU) with the increase of exposure concentrations. Further results suggested that both factors were related to diurnal variation during 48 h exposure, which could be regarded as circadian rhythms: the average values of OC and BS during photo-phase were significantly higher than both during scoto-phase in CdCl2 treatments (p < 0.05). After integrated analysis, the original values of both OC and BS with wide fluctuation showed a negative linear relationship with CdCl2 concentration. The levels of both OC and BS were positively correlated with CdCl2 (r = 0.93 and p < 0.01). It is suggested that both OC and BS provide an objective ground for CdCl2 stress assessment, and that also could be applied to test the changes of organisms quantitatively in toxic physiology. PMID- 28672697 TI - Stratification of chlorinated ethenes natural attenuation in an alluvial aquifer assessed by hydrochemical and biomolecular tools. AB - Biomolecular and hydrochemical tools were used to evaluate natural attenuation of chlorinated ethenes in a Quaternary alluvial aquifer located close to a historical source of large-scale tetrachloroethylene (PCE) contamination. Distinct stratification of redox zones was observed, despite the aquifer's small thickness (2.8 m). The uppermost zone of the target aquifer was characterised by oxygen- and nitrate-reducing conditions, with mixed iron- to sulphate-reducing conditions dominant in the lower zone, along with indications of methanogenesis. Natural attenuation of PCE was strongly influenced by redox heterogeneity, while higher levels of PCE degradation coincided with iron- to sulphate reducing conditions. Next generation sequencing of the middle and/or lower zones identified anaerobic bacteria (Firmicutes, Chloroflexi, Actinobacteria and Bacteroidetes) associated with reductive dechlorination. The relative abundance of dechlorinators (Dehalococcoides mccartyi, Dehalobacter sp.) identified by real time PCR in soil from the lower levels supports the hypothesis that there is a significant potential for reductive dechlorination of PCE. Local conditions were insufficiently reducing for rapid complete dechlorination of PCE to harmless ethene. For reliable assessment of natural attenuation, or when designing monitoring or remedial systems, vertical stratification of key biological and hydrochemical markers should be analysed as standard, even in shallow aquifers. PMID- 28672698 TI - Hexavalent chromium adsorption from aqueous solution using carbon nano-onions (CNOs). AB - The capacity of carbon nano-onions (CNOs) to remove hexavalent chromium (Cr(VI)) from aqueous solution was investigated. Batch experiments were performed to quantify the effects of the dosage rate, pH, counter ions, and temperature. The adsorption of Cr(VI) onto CNOs was best described by a pseudo-second order rate expression. The adsorption efficiency increased with increasing adsorbent dosage and contact time and reached equilibrium in 24 h. The equilibrium data showed better compliance with a Langmuir isotherm than a Freundlich isotherm. Effective removal of Cr(VI) was demonstrated at pH values ranging from 2 to 10. The adsorption capacity of Cr(VI) was found to be highest (82%) at pH 3.4 and greatly depended on the solution pH. We found that Cr(VI) adsorption decreased with increasing pH over the pH range of 3.4-10. The adsorption capacity increased dramatically when the temperature increased from 10 degrees C to 50 degrees C regardless of the amount of CNOs used. Cr(VI) removal decreased by ~13% when Zn(II), Cu(II), and Pb(II) were present, while there were no significant changes observed when NO3- or SO42- was present. The overall results support that CNOs can be used as an alternative adsorbent material to remove Cr(VI) in the water treatment industry. PMID- 28672699 TI - Qualitative screening for new psychoactive substances in wastewater collected during a city festival using liquid chromatography coupled to high-resolution mass spectrometry. AB - The inclusion of new psychoactive substances (NPS) in the wastewater-based epidemiology approach presents challenges, such as the reduced number of users that translates into low concentrations of residues and the limited pharmacokinetics information available, which renders the choice of target biomarker difficult. The sampling during special social settings, the analysis with improved analytical techniques, and data processing with specific workflow to narrow the search, are required approaches for a successful monitoring. This work presents the application of a qualitative screening technique to wastewater samples collected during a city festival, where likely users of recreational substances gather and consequently higher residual concentrations of used NPS are expected. The analysis was performed using liquid chromatography coupled to high resolution mass spectrometry. Data were processed using an algorithm that involves the extraction of accurate masses (calculated based on molecular formula) of expected m/z from an in-house database containing about 2,000 entries, including NPS and transformation products. We positively identified eight NPS belonging to the classes of synthetic cathinones, phenethylamines and opioids. In addition, the presence of benzodiazepine analogues, classical drugs and other licit substances with potential for abuse was confirmed. The screening workflow based on a database search was useful in the identification of NPS biomarkers in wastewater. The findings highlight the specific classical drugs and low NPS use in the Netherlands. Additionally, meta-chlorophenylpiperazine (mCPP), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 4-fluoroamphetamine (FA) were identified in wastewater for the first time. PMID- 28672701 TI - Translocation of isotopically distinct macroalgae: A route to low-cost biomonitoring? AB - Nitrogen stable isotope ratios (delta15N) in macroalgae are often used to identify sources of nitrogenous pollution in fluvial and estuarine settings. This approach assumes that the macroalgal delta15N is representative of the sources of the pollution averaged over a timespan in the order of days to weeks. The preferential uptake of a particular nitrogen compound or potential for fractionation in the water column or during uptake and assimilation by the macroalgae could make this assumption invalid. Laboratory studies were therefore performed to investigate the uptake and assimilation of both nitrate and ammonium at a variety of concentrations using the vegetative (non-fertile) tips of the brown macroalgae, Fucus vesiculosus. Nitrate appeared to fractionate at high concentrations, and was found to be taken up more rapidly than ammonia; within 13 days, the macroalgae tips were in isotopic equilibrium with the nitrate solution at 500 MUM. These experiments were complemented by an investigation involving the translocation of macroalgae collected from a site enriched in 15N relative to natural levels (Staithes, UK), to the River Tees, Middlesbrough (UK), a site depleted in 15N relative to natural levels. The nitrogen isotope signature shifted by ~50% within 7 days, with samples deployed nearer the surface subject to greater change. These findings suggest that the translocation of macroalgae with isotopically distinct signatures can be used as a rapid, cost-efficient method for nitrogen biomonitoring in estuarine environments. PMID- 28672700 TI - Using exposure prediction tools to link exposure and dosimetry for risk-based decisions: A case study with phthalates. AB - A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011-2012). The PBPK-reverse dosimetry estimated daily intakes at the 50th and 95th percentiles were 0.68 and 9.58 MUg/kg/d and 0.089 and 0.68 MUg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 MUg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 MUg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 MUg/kg/d. The PBPK-reverse dosimetry-estimated median intake of DEHP and DnBP was comparable to values previously reported for US populations. These comparisons provide insights into establishing criteria for selecting appropriate exposure prediction tools for use in an integrated modeling platform to link exposure to health effects. PMID- 28672702 TI - Spatial distribution and implications to sources of halogenated flame retardants in riverine sediments of Taizhou, an intense e-waste recycling area in eastern China. AB - Concentrations and spatial distribution pattern of organohalogen flame retardants were investigated in the riverine surface sediments from Taizhou, an intensive e waste recycling region in China. The analytes were syn- and anti- Dechlorane Plus (DP), Dechloranes 602, 603, and 604, a DP monoadduct, two dechlorinated DPs and 8 congeners of polybrominated diphenyl ethers (PBDEs). The concentrations of Sigma8PBDEs, SigmaDP, SigmaDec600s, and SigmaDP-degradates ranged from <100 to 172,000, 100 to 55,000, not detectable (nd) to 1600, and nd to 2800 pg/g dry weight, respectively. BDE-209 and DP, both have been manufactured in China, had similar spatial distribution patterns in the study area, featured by distinctly recognizable hotspots some of which are in proximity to known e-waste dumping or metal recycling facilities. Such patterns were largely shared by Dec602 and dechlorinated DP, although their concentration levels were much lower. These major flame retardants significantly correlate with each other, and cluster together in the loading plot of principle component analysis. In contrast, most non-deca PBDE congeners do not correlate with DPs. Dec604 stood out having distinctly different spatial distribution pattern, which could be linked to historical use of mirex. Organic matter content of the sediment was not the dominant factor in determining the spatial pattern of pollution by halogenated flame retardants in the rivers of this study. PMID- 28672703 TI - Tridentate arsenate complexation with ferric hydroxide and its effect on the kinetics of arsenate adsorption and desorption. AB - The adsorption reactions of arsenate with ferric hydroxide minerals and amorphous ferric hydroxide play an important role in affecting the transport and fate of arsenate in the environment. Previous studies have investigated formation of mono and bidentate complexes between arsenate and ferric hydroxide. Based on AsFe coordination numbers, there is spectroscopic evidence that arsenate may also form tridentate complexes with ferric hydroxide. However, the nature of these complexes and the reaction energies and activation barriers for their formation have not been investigated. This research used density functional theory (DFT) calculations to determine the structure of possible tridentate complexes and to determine reaction energies and activation barriers for forming different structures. Tridentate binding between arsenate and ferric hydroxide was found to be thermodynamically favorable for arsenate binding to two or three adjacent dioctahedral ferric hydroxide clusters. In addition, arsenate was also observed to form AsOAs bonds simultaneously to forming bidentate binuclear bonds with ferric hydroxide. The AsFe distances in the tridentate complexes differed from those calculated for bidentate complexes by an average distance of only 0.045 A. This suggests that spectroscopic methods (EXAFS) may not be able to distinguish bidentate from tridentate complexes based on interatomic distances. Formation of tridentate complexes required overcoming activation barriers ranging from 13 to 51 kcal/mol. Breaking of tridentate complexes had even greater activation barriers ranging from 18 to 62 kcal/mol. This suggests that tridentate complexation may contribute to previously observed extremely slow adsorption and desorption reactions of arsenate with ferric hydroxide. PMID- 28672704 TI - Control of disinfection byproducts (DBPs) by ozonation and peroxone process: Role of chloride on removal of DBP precursors. AB - The objective of this study was to remove regulated DBP precursors by using ozonation and peroxone process (H2O2/O3). Regarding formation potentials of trihalomethanes (THMs) and haloacetic acids (HAAs), the role of chloride in chlorination and ozonation/peroxone processes was revealed. The organic compounds in water samples from rapid sand filtration preferably yielded the THM formation potentials, rather than HAAs. Ozonation with the typical applied doses (1-5 mg L 1) was ineffective for removals of THM and HAA precursors. The peroxone process only decreased the formation potentials of THMs. The reduction of THMs by the peroxone process resulted from decreases in either chloroform or dibromochloromethane. However, the limitation was found in the H2O2/O3 ratios of 2.0-3.0. The removals of HAA precursors were much more difficult than that of THM precursors by ozonation and peroxone processes. The oxidation of organic compounds was able to promote the HAA formations. Ozonation with the typical ozone doses increased the chloroform formations, while decreases in bromide containing THMs occurred. Effect of ozonation on changes in HAAs speciation was unclear. The peroxone process likely promoted the dichloroacetic acids and trichloroacetic acids. The presence of chloride (1-5 g L-1) highly enhanced the THM and HAA formation potentials. NaCl addition greatly increased the bromide containing THMs, while the chloroform decreased. For HAAs, the presence of chloride promoted the bromide-containing HAAs and monochloroacetic acids. The presence of chloride played a role as a promotor for strong chlorinating agents in chlorination, rather than as a scavenger in ozonation and peroxone processes. PMID- 28672705 TI - Human health risk assessment and riskiest heavy metal origin identification in urban soils of Yerevan, Armenia. AB - The pollution of urban soils by heavy metals remains a topical issue because of the risks it represents to human health. Heavy metal pollution levels of Yerevan's soils were evaluated using Pollution index and Enrichment factor, while associated health risk was assessed by US EPA model. The heavy metals with significant amount of PI > 1 values were observed for V (100%), Cr (95.4%), Ni (92.5%), Cu (95.6%), Zn (92.9%), Hg (89.0%), Pb (99.9%), As (72.0%), and Ba (61.6% of samples). EF showed that Yerevan topsoils were significantly contaminated with Hg, and moderately contaminated with V, Ni, Cu, Zn, Cr, and As. Topsoils near the smelting plants of molybdenum concentrate have moderately to extremely high contamination levels for Mo. Topsoils were moderate to extremely highly contaminated with Pb, too. The high amounts of samples with heavy metal contents greater than Maximum Acceptable Concentrations were observed for Pb, Cr, Zn, Ni, and Cu. Pb and Cr exceeded corresponding Soil Screening Levels in 3.39% and 2.43% of samples, correspondingly. The risk assessment showed children's multi-elemental non-carcinogenic risk and low level of arsenic carcinogenic risk in the whole Yerevan. The riskiest element was Pb which high contents in 72 risky sites correlate only with the metals having a natural origin. Moreover, its main source is historically polluted soils and Pb supposed to be redistributed in the city environment linked to the sorption complexes of Fe and Mn oxides. PMID- 28672706 TI - Letter to the Editor Regarding "Analysis of Risk Factors for Secondary New Vertebral Compression Fracture Following Percutaneous Vertebroplasty in Patients with Osteoporosis". PMID- 28672707 TI - In Reply to the Letter to the Editor regarding "Analysis of Risk Factors for Secondary New Vertebral Compression Fracture Following Percutaneous Vertebroplasty in Patients with Osteoporosis". PMID- 28672708 TI - Letter to the Editor Regarding "Expression of Cathepsin K in Skull Base Chordoma". PMID- 28672709 TI - In Reply to the Letter to the Editor Regarding "Expression of Cathepsin K in Skull Base Chordoma". PMID- 28672710 TI - In Reply to the Letter to the Editor Regarding "Expression of Cathepsin K in Skull Base Chordoma". PMID- 28672711 TI - Letter to the Editor Regarding "Risk Factors and Independent Predictors of 30-Day Readmission for Altered Mental Status After Elective Spine Surgery for Spine Deformity: A Single Institutional Study of 1090 Patients". PMID- 28672712 TI - In Reply to the Letter to the Editor Regarding "Risk Factors and Independent Predictors of 30-Day Readmission for Altered Mental Status After Elective Spine Surgery for Spine Deformity: A Single Institutional Study of 1090 Patients". PMID- 28672713 TI - Ulnar Nerve Dislocation at the Elbow: The Role of Ultrasound. PMID- 28672714 TI - In Reply to "Ulnar Nerve Dislocation at the Elbow: The Role of Ultrasound". PMID- 28672715 TI - Bone Flap Resorption: Mysterious Complication of Autologus Bone Flap Cranioplasty with Highly Variable Incidence in Pediatric, Adult, and Older Populations. PMID- 28672716 TI - Biomarker-Based Targeted Therapy of Traumatic Brain Injury: From Prehospital Care to In-Hospital Care to Rehabilitation. PMID- 28672717 TI - Minor Head Injuries in Infants: Recommendations for Computed Tomography Imaging. PMID- 28672718 TI - Outcome of Head Injury in the Elderly. PMID- 28672719 TI - Spinal Epidural Abscess-Conservative or Operative Approach: A Management Dilemma. PMID- 28672720 TI - Peripheral Nerve Sheath Tumors: The "Orphan Disease" of National Databases. PMID- 28672722 TI - Electro-Fenton oxidation of reverse osmosis concentrate from sanitary landfill leachate: Evaluation of operational parameters. AB - The electro-Fenton oxidation of a concentrate from reverse osmosis of a sanitary landfill leachate, with an initial chemical oxygen demand (COD) of 42 g L-1, was carried out using a carbon-felt cathode and a boron doped diamond anode. The influence of the applied current intensity, initial pH and dissolved iron initial concentration on the electro-Fenton process was assessed. For the experimental conditions used, results showed that the initial pH is the parameter that more strongly influences the current efficiency of the electro-Fenton process, being this influence more pronounced on the oxidation rate than on the mineralization rate of the organic matter. The increase in iron initial concentration was found to be detrimental, since the natural amount of iron present in the effluent, 73 mg L-1 of total iron and 61 mg L-1 of dissolved iron, was sufficient to ensure the electro-Fenton process at the applied intensities - 0.2-1.4 A. For the more favourable conditions studied, initial pH of 3 and natural iron concentration, it was found an increase in the organic load and nitrogen removals with the applied current intensity. For the highest current intensity applied, a COD removal of 16.7 g L-1 was achieved after 8-h experiments. PMID- 28672724 TI - Anticancer drugs in Portuguese surface waters - Estimation of concentrations and identification of potentially priority drugs. AB - Anticancer drugs, used in chemotherapy, have emerged as new water contaminants due to their increasing consumption trends and poor elimination efficiency in conventional water treatment processes. As a result, anticancer drugs have been reported in surface and even drinking waters, posing the environment and human health at risk. However, the occurrence and distribution of anticancer drugs depend on the area studied and the hydrological dynamics, which determine the risk towards the environment. The main objective of the present study was to evaluate the risk of anticancer drugs in Portugal. This work includes an extensive analysis of the consumption trends of 171 anticancer drugs, sold or dispensed in Portugal between 2007 and 2015. The consumption data was processed aiming at the estimation of predicted environmental loads of anticancer drugs and 11 compounds were identified as potentially priority drugs based on an exposure based approach (PECb> 10 ng L-1 and/or PECc> 1 ng L-1). In a national perspective, mycophenolic acid and mycophenolate mofetil are suspected to pose high risk to aquatic biota. Moderate and low risk was also associated to cyclophosphamide and bicalutamide exposition, respectively. Although no evidences of risk exist yet for the other anticancer drugs, concerns may be associated with long term effects. PMID- 28672723 TI - Effects of salinity on the performance, microbial community, and functional proteins in an aerobic granular sludge system. AB - The response mechanism of aerobic granular sludge (AGS) systems to salt stress in high-salinity wastewater treatment processes has not been fully elucidated in current studies. The aim of this study was to reveal the comprehensive effects of salinity on AGS characteristics using microbial community and metaproteomics analyses. The results showed that the removal efficiency of COD, TN and TP decreased significantly with increasing salinity. Under salt stress, the Na+ content in AGS decreased, while the K+ and Ca2+ contents increased. This was because the salt-tolerant mechanism of the microorganisms was dependent on the uptake of K+ and ejection of Na+via K+/Na+ pumps, Na+/H+ reversed transport proteins, and K+ channels. Compared with the salt-free condition, 14 of 25 different protein spots were identified successfully by metaproteomic analysis, including porin, periplasmic-binding protein, and ATP-binding cassette-type for phosphonate transporter, which were expressed mainly by members of gamma Proteobacteria and alpha-Proteobacteria. The variations in functional proteins and microbial community revealed that alpha- and gamma-Proteobacteria had disproportionally active and the metabolic activity of beta-Proteobacteria was inhibited by increasing salinity. Additionally, Psychrobacter sp. was confirmed to be a predominant bacterium at 15 g/L NaCl, as the porin was strongly expressed. PMID- 28672725 TI - Pyrethroids in chicken eggs from commercial farms and home production in Rio de Janeiro: Estimated daily intake and diastereomeric selectivity. AB - In this study, pyrethroids were determined in chicken eggs from commercial farm (n = 60) and home egg production (n = 30). These pyrethroids were investigated: bifenthrin, phenothrin, permethrin, cyfluthrin, cypermethrin and fenvalerate, including most diastereomers. Quantification was done using GC-MS in a negative chemical ionization mode. Pyrethroids residues were found in 79% of the analyzed samples. Cypermethrin presented the highest occurrence, being quantified in 62 samples (69%) in concentrations (lipid weight - l w.) varying between 0.29 and 6408 ng g-1, followed by phenothrin (24%), 21-3910 ng g-1, permethrin (14%), 2.96 328 ng g-1, and bifenthrin (11%), 3.77-16.7 ng g-1. Cyfluthrin and fenvalerate were not detected. Home-produced eggs had a higher occurrence of pyrethroids (97%), with a greater predominance of phenothrin. In commercial production, 70% of the samples presented pyrethroid residues (predominantly cypermethrin). This is the first report about the presence of pyrethroids in home-produced eggs and the first description of a selectivity pattern with the predominance of cis diastereomers in chicken eggs. In general, estimated daily intake does not present a risk to human consumption, according to Brazilian and international standards (FAO/WHO). However, one third of the samples (30 eggs) had concentrations above the maximum residue limits (MRLs). The maximum cypermethrin concentration was 66 times the MRL, while the maximum phenothrin concentration was 11 times the limit. Further studies about transfer dynamics, bioaccumulation and metabolic degradation of stereoisomers are required, as well as determining if this selectivity pattern in food can increase consumer's health risk. PMID- 28672726 TI - Resource efficiency analysis for photocatalytic degradation and mineralization of estriol using TiO2 nanoparticles. AB - A resource efficiency analysis was developed that evaluated photocatalyst loading and temperature inputs, and assessed hydroxyl radical (OH) production. Catalyst loading (Aeroxide(r) TiO2 P25) between 1 and 1500 mg L-1 and temperatures between 5 and 50 degrees C were analyzed as input resources for OH production. After, the best experimental conditions were used to degrade and mineralize estriol (E3). The analysis showed that a low catalyst concentration lead to poor absorption of radiation and a slow reaction. When high catalyst concentrations were tested, most of the radiation was absorbed, which produced results near the top of the slowing rate of OH generation. Temperature was found a relevant resource for increasing interfacial transfer to facilitate OH production following the Arrhenius model. Two indices to measure resource efficiency were proposed: 1) the OH generation index (OHI) and 2) the initial degradation efficiency (IDE). OHI was used to measure the efficiency of a catalyst using photonic flux to generate OH production. IDE evaluated the relationship between the photocatalytic reactor set-up, catalyst, and E3 degradation. It was observed that 1.18 OH was produced when a photon interacts with a photocatalyst particle when a load of 5 mg L-1 of photocatalyst is used at 20 degrees C. It was found that at initial time, 2.4 OH was generated in the systems to produce a degradation of one E3 molecule when using a photocatalyst load of 20 mg L-1 at 20 degrees C. Additionally, it was demonstrated that E3 mineralization was feasible under different catalyst loading scenarios. PMID- 28672728 TI - Assessing multiple muscle activation during squat movements with different loading conditions - an EMG study. AB - Surface electromyography (EMG) is a valuable tool in clinical diagnostics and research related to human neuromotor control. Non-linear analysis of EMG data can help with detection of subtle changes of control due to changes of external or internal constraints during motor tasks. However, non-linear analysis is complex and results may be difficult to interpret, particularly in clinical environments. We developed a non-linear analysis tool (SYNERGOS) that evaluates multiple muscle activation (MMA) features and provides a single value for description of activation characteristics. To investigate the responsiveness of SYNERGOS to kinetic changes during cyclic movements, 13 healthy young adults performed squat movements under different loading conditions (100%-120% of body weight). We processed EMG data to generate SYNERGOS indices and used two-way repeated measures ANOVA to determine changes of MMA in response to loading conditions during movement. SYNERGOS values were significantly different for each loading condition. We concluded that the algorithm is sensitive to kinetic changes during cyclic movements, which may have implications for applications in a variety of experimental and diagnostic settings. PMID- 28672727 TI - Soluble microbial products (SMPs) in a sequencing batch reactor with novel cake filtration system. AB - The formation, composition and characteristics of soluble microbial products (SMPs) were investigated in a novel system which coupled a sequencing batch reactor with a cake filtration system. Both suspended solids (SS) and turbidity were significantly removed, resulting in effluent SS of 0.12 mg L-1 and turbidity of 0.72 NTU after cake filtration. The average concentrations of proteins and carbohydrates decreased respectively from 4.0 +/- 0.4 and 7.1 +/- 0.6 mg/L in the sequencing batch reactor (SBR) mixed liquor, to 0.85 +/- 0.21 and 1.39 +/- 0.29 mg/L in the cake filtration effluent. Analysis of the molecular weight (MW) distribution of SMPs revealed a substantial reduction in the intensity of high-MW peaks (503 and 22.71 kDa) after cake filtration, which implied the sludge cake layer and the underlying gel layer may play a role in the effectiveness of cake filtration beyond the physical phenomenon. Three-dimensional excitation emission matrix fluorescence spectroscopy indicated that polycarboxylate- and polyaromatic humic acids were the dominant compounds and a noticeable decrease in the fraction of these compounds was observed in the cake filtration effluent. Analysis with GC MS set for detecting low-MW SMPs identified aromatics, alcohols, alkanes and esters as the dominant compounds. SMPs exhibited both biodegradable and recalcitrant characteristics. More SMPs (total number of 91) were accumulated during the SBR start-up stage. A noticeable increase in the aromatic fractions was seen in the SBR effluent accoutring for 39% of total compounds, compared to the SBR mixed liquor (28%). Fewer compounds (total number of 66) were identified in cake filtration effluent compared to the SBR effluent (total number of 75). PMID- 28672729 TI - Extraordinarily elevated serum CA19-9 in a patient with posterior mediastinum cyst: a case report. PMID- 28672730 TI - Analytical and clinical performance of thyroglobulin autoantibody assays in thyroid cancer follow-up. AB - BACKGROUND: While thyroglobulin autoantibodies (TgAb) can result in false low serum thyroglobulin (Tg) immunoassay (IA) measurements, they might also be indicators of disease persistence/recurrence. Hence, accurate TgAb measurement, in addition to Tg quantification, is crucial for thyroid cancer monitoring. We compared the analytical and clinical performance of four commonly used TgAb IAs. METHODS: We measured Tg by mass spectrometry (Tg-MS) and by four pairs of Tg and TgAb IAs (Beckman, Roche, Siemens, Thermo) in 576 samples. Limit of quantitation (LOQ) and manufacturers' upper reference interval cut-off (URI) were used for comparisons. Clinical performance was assessed by receiving operator characteristics (ROC) curve analysis. RESULTS: Quantitative and qualitative agreement between TgAb-IAs was moderate with R2 of 0.20-0.70 and kappa from 0.41 0.66 using LOQ and 0.47-0.71 using URI. In samples with TgAb interference, detection rates of TgAb were similar using LOQ and URI for Beckman, Siemens, and Thermo, but much lower for the Roche TgAb-IA when the URI was used. In TgAb positive cases, the ROC areas under the curve (AUC) for the TgAb-IAs were 0.59 (Beckman), 0.62 (Siemens), 0.59 (Roche), and 0.59 (Thermo), similar to ROC AUCs achieved with Tg. Combining Tg and TgAb measurements improved the ROC AUCs compared to Tg or TgAb alone. CONCLUSIONS: TgAb-IAs show significant qualitative and quantitative differences. For 2 of the 4 TgAb-IAs, using the LOQ improves the detection of interfering TgAbs. All assays showed suboptimal clinical performance when used as surrogate markers of disease, with modest improvements when Tg and TgAb were combined. PMID- 28672731 TI - Neutrophil gelatinase-associated lipocalin as a risk marker in cardiovascular disease. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is a promising diagnostic biomarker of early acute kidney injury. Increasing evidence suggests that NGAL may also be involved in inflammatory processes in cardiovascular disease. NGAL modulates the enzymatic activity of matrix metalloproteinase-9 (MMP-9), which is an important mediator of plaque instability in atherosclerosis. The complex formation between NGAL and MMP-9 therefore suggests that NGAL might play a role in progression of atherothrombotic disease. This review summarises current data on NGAL in atherosclerosis, acute myocardial infarction, and heart failure. PMID- 28672732 TI - Performance analysis of automated evaluation of Crithidia luciliae-based indirect immunofluorescence tests in a routine setting - strengths and weaknesses. AB - BACKGROUND: Antibodies directed against dsDNA are a highly specific diagnostic marker for the presence of systemic lupus erythematosus and of particular importance in its diagnosis. To assess anti-dsDNA antibodies, the Crithidia luciliae-based indirect immunofluorescence test (CLIFT) is one of the assays considered to be the best choice. To overcome the drawback of subjective result interpretation that inheres indirect immunofluorescence assays in general, automated systems have been introduced into the market during the last years. Among these systems is the EUROPattern Suite, an advanced automated fluorescence microscope equipped with different software packages, capable of automated pattern interpretation and result suggestion for ANA, ANCA and CLIFT analysis. METHODS: We analyzed the performance of the EUROPattern Suite with its automated fluorescence interpretation for CLIFT in a routine setting, reflecting the everyday life of a diagnostic laboratory. Three hundred and twelve consecutive samples were collected, sent to the Central Diagnostic Laboratory of the Maastricht University Medical Centre with a request for anti-dsDNA analysis over a period of 7 months. RESULTS: Agreement between EUROPattern assay analysis and the visual read was 93.3%. Sensitivity and specificity were 94.1% and 93.2%, respectively. The EUROPattern Suite performed reliably and greatly supported result interpretation. CONCLUSIONS: Automated image acquisition is readily performed and automated image classification gives a reliable recommendation for assay evaluation to the operator. The EUROPattern Suite optimizes workflow and contributes to standardization between different operators or laboratories. PMID- 28672733 TI - Excessive hypercortisolemia due to ectopic Cushing's syndrome requiring extending the reportable range for plasma cortisol for management. PMID- 28672734 TI - Subclinical hypothyroidism does not influence the metabolic and hormonal profile of women with PCOS. AB - Background Subclinical hypothyroidism (SCH) is present in 5%-10% of polycystic ovary syndrome (PCOS) patients. To date, its impact on the metabolic and hormonal profile of those women remains controversial. The purpose of our study is to evaluate the impact of SCH on the glycemic, lipid and hormonal profile of PCOS patients. Materials and methods We conducted a prospective case control study of patients that attended the Department of Gynecological Endocrinology of our hospital. Results Overall, 280 women with PCOS were enrolled during a time period of 7 years (2009-2015). Twenty-one patients (7.5%) suffered from SCH. The anthropometric characteristics were comparable among women with PCOS and those with SCH + PCOS. The prevalence of acne, hirsutism and anovulation did not differ. Significant differences were observed in the 2-h oral glucose tolerance test (OGTT) (p = 0.003 for glucose and p = 0.046 for insulin). The QUICKI, Matsuda and homeostatic model assessment-insulin resistance (HOMA-IR) indices where, however, similar. No difference in serum lipids was observed. Slightly elevated levels of follicle stimulating hormone (FSH) and testosterone were noted. The remaining hormonal parameters remained similar among groups. Similarly, the ovarian volume and the endometrial thickness did not differ. Conclusions The impact of SCH on the metabolic and hormonal profile of PCOS patients seems to be negligible. Future studies are needed in the field and their conduct in a multi-institutional basis seems to be required, given the small prevalence of SCH among women with PCOS. PMID- 28672735 TI - Safety concerns associated with second-generation antipsychotic long-acting injection treatment. A systematic update. AB - Background It has been recently suggested that second-generation antipsychotic long-acting injection (SGA-LAIs) are underutilized in clinical practice, despite that their costs significantly impact on national health system budgets. Hence, an updated analysis of safety data shown by SGA-LAIs may contribute to clarify their role in clinical practice. Materials and methods English-language, peer reviewed articles reporting updated, primary findings on the SGA-LAI safety were identified (updated through an electronic search of five databases - PubMed, EMBASE, PsycInfo, DARE and the Cochrane Library). Results The articles reviewed suggest that the most frequent treatment emergent adverse events (TEAEs) associated with aripiprazole long-acting injection (ARI-LAI) are psychotic symptoms, extrapyramidal symptoms (EPS) and weight gain. Data on olanzapine long acting injection (OLA-LAI)-associated TEAEs highlight the risk of psychosis, metabolic disturbances and hyperprolactinemia. Four-hundred and forty cases of post-injection delirium/sedation syndrome (PDSS) have also been recorded. Although not reported in reviewed studies, the risk of impulse-control problem and drug reaction with eosinophilia and systemic symptoms (DRESS) ARI- and OLA associated, respectively, must not be underestimated. With regards paliperidone palmitate 1-month formulation (PP1), the high incidence of clinically relevant weight gain and hyperprolactinemia are both findings of concern. Reviewed data also confirm that the leading cause of death in risperidone long-acting injection (RIS-LAI) clinical trials is suicide. The new 3-month paliperidone palmitate formulation, risperidone sustained release 1-month formulation (RIS-SR1), aripiprazole lauroxil (ARI-LXL) are still lacking exhaustive safety data. Conclusion The risk of specific TEAEs associated with all SGA-LAIs confirms SGA LAIs do not offer advantages in safety compared with FGA-LAIs or oral antipsychotics and, especially, in early-phase schizophrenia patients. Implementing non pharmacological intervention and strategies can be effective for people with schizophrenia and bipolar disorder who adhere poorly to medication regimens. PMID- 28672736 TI - Innate immunity orchestrates adipose tissue homeostasis. AB - Obesity is strongly associated with multiple diseases including insulin resistance, type 2 diabetes, cardiovascular diseases, fatty liver disease, neurodegenerative diseases and cancers, etc. Adipose tissue (AT), mainly brown AT (BAT) and white AT (WAT), is an important metabolic and endocrine organ that maintains whole-body homeostasis. BAT contributes to non-shivering thermogenesis in a cold environment; WAT stores energy and produces adipokines that fine-tune metabolic and inflammatory responses. Obesity is often characterized by over expansion and inflammation of WAT where inflammatory cells/mediators are abundant, especially pro-inflammatory (M1) macrophages, resulting in chronic low grade inflammation and leading to insulin resistance and metabolic complications. Macrophages constitute the major component of innate immunity and can be activated as a M1 or M2 (anti-inflammatory) phenotype in response to environmental stimuli. Polarized M1 macrophage causes AT inflammation, whereas polarized M2 macrophage promotes WAT remodeling into the BAT phenotype, also known as WAT browning/beiging, which enhances insulin sensitivity and metabolic health. This review will discuss the regulation of AT homeostasis in relation to innate immunity. PMID- 28672737 TI - Beiging of white adipose tissue as a therapeutic strategy for weight loss in humans. AB - An imbalance between energy intake and expenditure leads to obesity. Adiposity associated with obesity progressively causes inflammation, type 2 diabetes, hypertension, hyperlipidemia and cardiovascular disease. Excessive dietary intake of fat results in its accumulation and storage in the white adipose tissue (WAT), whereas energy expenditure by fat utilization and oxidation predominately occurs in the brown adipose tissue (BAT). Recently, the presence of a third type of fat, referred to as beige or brite (brown in white), has been recognized in certain kinds of WAT depots. It has been suggested that WAT can undergo the process of browning in response to stimuli that induce and enhance the expression of thermogenes characteristic of those typically associated with brown fat. The resultant beige or brite cells enhance energy expenditure by reducing lipids stored within adipose tissue. This has created significant excitement towards the development of a promising strategy to induce browning/beiging in WAT to combat the growing epidemic of obesity. This review systematically describes differential locations and functions of WAT and BAT, mechanisms of beiging of WAT and a concise analysis of drug molecules and natural products that activate the browning phenomenon in vitro and in vivo. This review also discusses potential approaches for targeting WAT with compounds for site-specific beiging induction. Overall, there are numerous mechanisms that govern browning of WAT. There are a variety of newly identified targets whereby potential molecules can promote beiging of WAT and thereby combat obesity. PMID- 28672738 TI - Comparison of Tanner staging of HIV-infected and uninfected girls at the University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu, Nigeria. AB - BACKGROUND: A number of factors influence sexual maturation in adolescents, including chronic illnesses like HIV. Marshall and Tanner devised a method of classifying the adolescent based on the level of sexual maturation into five stages. This study compared the Tanner staging of HIV-infected and uninfected girls. METHODS: This was a cross-sectional study of 100 HIV-infected girls aged 8 18 years and 100 uninfected counterparts matched for age and social class. Using standard photographs as a guide, stages of sexual maturation were determined according to the method proposed by Marshall and Tanner. Data analysis was done with SPSS version 20. p-values <0.05 were regarded as significant. RESULTS: The study participants were aged 8-17 years. Fifty-five subjects compared to 39 controls were still in pre-pubertal breast developmental stages while 45 subjects (45%) compared to 61 controls (61%) have commenced breast development (p=0.024). Similarly, 52 subjects compared to 31 controls were in the pre-pubertal pubic hair developmental stages, while 48 subjects (48%) compared to 69 controls (69%) had commenced pubic hair development (p=0.003). CONCLUSIONS: Perinatal HIV infection affected the onset of pubic hair and breast development but did not significantly affect the attainment of sexual maturation. PMID- 28672739 TI - Assessment of insulin like growth factor-1 and IGF binding protein-3 in healthy Indian girls from Delhi and their correlation with age, pubertal status, obesity and thyroid hormonal status. AB - BACKGROUND: Population specific data and influence of sub-clinical hypothyroidism on insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3) in Indian children is lacking. This study was undertaken to evaluate serum IGF-1 and IGFBP-3 and their correlation with age, gender, pubertal status and thyroid functions. METHODS: A total of 840 apparently healthy school girls aged 6-18 years, were recruited for the study and underwent assessment of height, weight, body mass index, pubertal status and serum T3, T4, TSH, IGF-1, IGFBP-3 and IGF 1/IGFBP-3 molar ratio. RESULTS: The mean serum levels of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio were 381.8+/-240.5 ng/mL, 4.19+/-2.08 MUg/mL and 40.5+/-37.2%, respectively. The serum IGF-1 and IGF-1/IGFBP-3 molar ratio increased significantly (p<0.0001) at 11 years followed by a steady yet non significant rise till 16 years of age. A similar pattern was observed for IGFBP-3 showing a steep rise at 12 years and peaking at 16 years. Likewise, serum levels of IGF-1 and molar ratio of IGF-1/IGFBP-3 increased significantly with pubertal maturation from stage 1 to 3 and were higher in overweight girls compared to normal weight and obese girls. The growth factors were no different in girls with or without subclinical hypothyroidism. CONCLUSIONS: There was no significant impact of age on IGF-1 and IGFBP-3 in pre-pubertal girls. A sudden marked increase at 11 years followed by a gradual rise in growth factors till 16 years is indicative of pubertal initiation and maturation. Subclinical hypothyroidism did not influence growth factors in girls. PMID- 28672740 TI - Long-term follow-up of a child with Klinefelter syndrome and achondroplasia from infancy to 16 years. AB - BACKGROUND: Achondroplasia (ACH), an autosomal dominant skeletal dysplasia, occurs in approximately 1:20,000 births. On the other hand, 47,XXY aneuploidy (Klinefelter syndrome [KS]) is the most common sex chromosome disorder, with a prevalence of approximately 1:600 males. To the best of our knowledge, only five cases of patients presenting both ACH and KS have been reported to date in the international literature. However, none of these cases has been longitudinally followed during the entire childhood. CASE PRESENTATION: We report a male patient with ACH and KS, diagnosed in early infancy because of his typical phenotype of ACH. The diagnosis was confirmed by molecular analysis revealing a de novo heterozygous 1138 G-to-A mutation of the FGFR3 gene. During his first assessment, a karyotype was performed, which also revealed coexistence of KS. He was followed by our pediatric endocrinology team until the age of 16 years, then he was gradually transferred to adult endocrine care. CONCLUSIONS: This is the first reported case with both conditions that was diagnosed in infancy and was longitudinally followed by a pediatric endocrinology team regularly, from infancy to late adolescence. With a typical phenotype of ACH, it is striking and noteworthy that he did not develop the classical endocrine complications of a child with KS, neither did he necessitate testosterone supplementation during his pubertal development, due to his normal virilization and testosterone levels. PMID- 28672741 TI - Joint association of screen time and physical activity with anthropometric measures in Iranian children and adolescents: the weight disorders survey of the CASPIAN-IV study. AB - BACKGROUND: This study aims to assess the joint association of screen time (ST) and physical activity (PA) with anthropometric indices among Iranian children and adolescents. METHODS: In this national study, 23,183 school students, aged 6-18 years, were studied. By using a multi-stage cluster sampling method, they were selected from rural and urban areas of 30 provinces of Iran. ST and PA were assessed by self-administered validated questionnaires. Height, weight, hip and waist circumferences (WC) were measured according to standard protocols, and body mass index (BMI) was calculated. ST of <2 h per day was categorized as "low" and >=2 h per day as "high". PA levels were obtained by a 7-day recall of sports or activities that made participants sweat or make their legs feel tired, or games that made them breathe heavily. Using this questionnaire, the score of 1-1.9 was categorized as "low" and scores between 2 and 5 as "high" PA. Logistic regression analyses were used to evaluate the joint association of PA and ST categories with odds of anthropometric measures. RESULTS: In both genders, those students categorized as "Low PA & High ST" had the highest levels of BMI z-scores (boys: 0.15+/-1.12, girls: 0.17+/-1.08), WC (boys: 69.93+/-13.89 cm, girls: 67.30+/ 11.26 cm), and hip circumference (boys: 82.41+/-13.90 cm, girls: 84.05+/-13.7 cm), as well as the highest prevalence of overweight (boys: 15.32%, girls: 14.04%) (p<0.001 in all comparisons). In linear multivariate model, students with "High PA & High ST" had significant increased levels of z-scores for BMI, WC and hip circumference (p<0.05). CONCLUSIONS: The current findings underscore the importance of reducing ST along with increasing PA for prevention and control of excess weight in children and adolescents. PMID- 28672742 TI - High prevalence of organ specific autoantibodies in Indian type 1 diabetic patients. AB - BACKGROUND: Type 1 diabetes (T1D) is frequently associated with other autoimmune conditions such as autoimmune thyroiditis, coeliac disease (CD) and Addison's disease. There are sparse data on the prevalence of antibodies against these conditions in Indian patients with T1D. This study aims to evaluate prevalence of these T1D associated autoantibodies in Indian patients. METHODS: Two hundred and fifty-eight patients with T1D were recruited from the Bangalore Diabetes Hospital and the Vydehi Institute of Medical Sciences and Research Centre (VIMS) for the study. Participants diagnosed with diabetes before the age of 18 years, as per the American Diabetes Association (ADA) criteria, and who were classified as T1D based on clinical grounds were recruited for the study. Anti-thyroid peroxidase antibody (TPO) and IgA tissue transglutaminase antibody (tTG) were estimated in all the patients. 21-Hydroxylase antibody (21-OHAb) were estimated in 170 patients. All assays were done by commercial immunoassay. Eighty-eight unrelated age-matched healthy controls were chosen for comparison. RESULTS: The mean age of T1D patients was 14.33 years. The mean duration of diabetes was 4.88 years. Anti TPO was positive in 43 (16.7%) patients with T1D as compared to 3 (3.4%) in controls. IgA tTG was positive in 12 (4.65%) patients with T1D and was absent in controls. 21-OHAb was positive in two (1.1%) patients with T1D and was absent in controls. Both patients who had positive 21-OHab had the other two antibodies. Five patients had positive anti-TPO and IgA-tTG antibodies. CONCLUSIONS: Anti-TPO antibody was the most prevalent antibody in patients with T1D. Anti-TPO and IgA tTG antibodies were significantly higher than in the control population. Further studies will be required to assess the clinical significance of these positive antibodies. PMID- 28672743 TI - Clinical, biochemical and genetic features with nonclassical 21-hydroxylase deficiency and final height. AB - BACKGROUND: The clinical, laboratory, genetic properties and final height of a large cohort of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) in Turkey were analyzed. METHODS: This multicenter, nationwide web-based study collected data. RESULTS: The mean age was 9.79+/-4.35 years (229 girls, 29 boys). The most common symptoms were premature pubarche (54.6%) and hirsutism (28.6%). The peak cortisol was found below 18 MUg/dL in three (15.45%) patients. A mutation was detected in the CYP21A2 gene of 182 (87.5%) patients. The most common mutation was V281L. Final height in female patients who were diagnosed and treated before attaining final height or near final height was found to be shorter than the final height in female patients who were diagnosed after attaining final height or near final height. CONCLUSIONS: The final height of the patients who were treated during childhood was found to be shorter than the final height of patients during the adolescent period. PMID- 28672744 TI - Validation of a new algorithm for the short-term variation of the fetal heart rate: an antepartum prospective study. AB - AIMS: Currently one of the most widespread systems for the computerized analysis of the fetal heart rate (FHR) is the Dawes-Redman system, where the short-term variation (STV) of the FHR is measured by dividing each minute into 16 segments (STV16). Technical progress has allowed for the development of a new algorithm, which measures the STV by dividing each minute into 240 segments (STV240), thus approximating the beat-to-beat variation. The STV240 still lacks reference values. Our aim was to develop clinically relevant reference values for the STV240 and compare them to the ones for the STV16. METHODS: In a single centre, observational study, a total of 228 cardiotocograms were registered and subsequently analyzed with both algorithms (STV240 and STV16). RESULTS: The 95% confidence interval (CI) was calculated for both algorithms. The values of the STV240 were significantly lower in comparison to the ones of the STV16. Not only the mean values but also the 95th percentile of the STV240 lay beneath the existent cut-off value for the STV16. CONCLUSIONS: Every clinician using the new algorithm must be aware that the normal values for the STV240 lie beneath the, up until now, established cut-off values for the STV16. PMID- 28672745 TI - HIV avidity index performance using a modified fourth-generation immunoassay to detect recent HIV infections. AB - BACKGROUND: Detecting recent HIV infections is important to evaluate incidence and monitor epidemic trends. We aimed to evaluate the diagnostic performance and accuracy of the avidity index (AI) for discriminating for recent HIV infections. METHODS: We collected serum samples from HIV-1 positive individuals: A) with known date of infection (midpoint in time between last HIV-negative and first HIV positive test); B) infected for >1 year. Samples were divided into two aliquots: one diluted with phosphate buffered saline (PBS) and the other with 1 M guanidine. Both aliquots were assayed by the Architect HIV Ag/Ab Combo 4th generation assay (Abbott). We compared AI found in recent (RI=<6 months from seroconversion) and established (EI) infections. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. The proportion of samples misclassified as recent (FRR) was calculated. RESULTS: In total, 647 samples were collected: 455 in group A (51.6% RI and 48.4% EI) and 192 in group B. Among these, sixteen samples were from elite controllers, 294 from treated patients, 328 from patients infected with non-B subtypes. Samples before antiretroviral initiation showed a mean AI significantly lower among RI compared to EI (0.66+0.28 vs. 1.00+/-0.12; p<0.000). The FRR was 0% using a cut-off of <=0.70. An extremely low FRR was observed among elite controllers, samples with low VL or CD4. HIV subtype had no impact on AI misclassifications. All individuals in group A reached the AI threshold of 0.80 within 24 months after seroconversion. CONCLUSIONS: The AI is an accurate serological marker for discriminating recent from established HIV infections and meets WHO requirements for HIV incidence assays. PMID- 28672746 TI - Study of kallikrein-related peptidase 6 (KLK6) and its complex with alpha1 antitrypsin in biological fluids. AB - BACKGROUND: Human kallikrein-related peptidase 6 (KLK6) is a member of the kallikrein family of serine proteases. KLK6 is synthesized as a preproenzyme, mainly in tissues of the central nervous system (CNS), and secreted as an inactive precursor. Serum KLK6 is a biomarker of unfavorable prognosis for ovarian cancer, but its sensitivity for early detection is relatively low. Differential glycosylation of KLK6 has been identified in ascites fluid obtained from ovarian cancer patients, suggesting the presence of unique KLK6 isoforms in biological samples. METHODS: In the present study, we applied a two-step enrichment approach for KLK6 in ovarian cancer ascites, followed by mice immunization and production of monoclonal antibodies. Immunoaffinity techniques coupled to mass spectrometric methods were employed for hybridoma screening and target antigen identification. RESULTS: We found that the main target of the newly-generated monoclonal antibodies target was the serine protease inhibitor alpha1-antitrypsin (A1AT). Additional experiments confirmed that A1AT is the main inhibitor of KLK6 in biological fluids. One new antibody (24ED138) was chosen to build a hybrid assay for the accurate quantification of the A1AT-KLK6 complex in biological samples. The aforementioned assay was evaluated with serum samples collected from patients with ovarian cancer (n=24) and normal donors (n=16) and showed slight improvement in sensitivity (~12%) compared to the standard in-house KLK6 assay. CONCLUSIONS: We conclude that KLK6 is present in biological fluids either as free form, or bound to A1AT, and the bound form performs better than total KLK6 as a biomarker of ovarian carcinoma. PMID- 28672747 TI - NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis. AB - BACKGROUND: Neutrophil gelatinase associated lipocalin (NGAL) is expressed in atherosclerotic lesions and was recently implicated in the pathogenesis of cardiovascular pathologies. Statins are known to exert stabilizing effects on atherosclerotic plaque. The aims of our study were (1) to investigate the association of serum NGAL and metalloproteinase (MMP)-9/NGAL complex with the vulnerability of the atherosclerotic plaque, and (2) to reveal the effects of statin treatment on circulating NGAL and MMP-9/NGAL levels in patients with carotid artery stenosis. METHODS: We examined the levels of NGAL and MMP-9/NGAL in blood samples from 136 patients with carotid artery stenosis by specific enzyme-linked immunosorbent assays. RESULTS: Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of American Heart Association [AHA]), displayed the highest levels of NGAL (both p<0.0001) and MMP-9/NGAL complex (p=0.0004 and p=0.004, respectively). Moreover, patients with symptomatic carotid atherosclerosis had significantly higher NGAL levels compared to asymptomatic patients (p=0.0007). The statin-treated group (n=108) demonstrated lower NGAL (73.9 vs. 128.0 MUg/L, p<0.0001) and MMP-9/NGAL (28.9 vs. 40.6 MUg/L, p=0.046) as compared to the non-statin group (n=28). Furthermore, in multivariate regression analysis NGAL, but not MMP-9/NGAL levels, were independently associated with symptomatic carotid artery stenosis. In addition, statin treatment was independently associated with lower NGAL levels. CONCLUSIONS: Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels. PMID- 28672748 TI - Clinical evaluation and mutational analysis of GALK and GALE genes in patients with galactosemia in Greece: one novel mutation and two rare cases. AB - BACKGROUND: Deficiencies of galactokinase (GALK) and UDP-epimerase (GALE) are implicated with galactose metabolic disorders. The aim of the study was the identification of mutations in GALK and GALE genes and clinical evaluation of patients. METHODS: Five patients with GALK and five with GALE deficiency were picked up via the Neonatal Screening Program. Additionally, two females, 4 years old, were referred with late diagnosed galactosemia, as rare cases. Mutational analysis was conducted via Sanger sequencing, while in silico analysis tools were utilized for the novel mutation. Psychomotor and speech development tests were performed, as well. RESULTS: The mutation p.Pro28Thr was identified in both alleles in GALK-deficient patients of Roma (gypsy) origin, whereas the novel p.Asn39Ser was detected in two non-Roma patients. In GALE-deficient patients benign and/or likely benign mutations were found. Psychomotor and speech delay were determined in the Roma GALK patients. In each of the late diagnosed females, four mutations were identified in all galactosemia-related genes. CONCLUSIONS: The mutational spectrums of GALE- and GALK-deficient patients in Greece are presented for the first time along with a clinical evaluation. Mutational analysis in all galactosemia-related genes of symptomatic patients is highly recommended for future cases. PMID- 28672749 TI - Impact of discontinuation of growth hormone treatment on lipids and weight status in adolescents. AB - BACKGROUND: While the main role of growth hormone (GH) replacement therapy in children is to promote linear growth, GH has also an effect on lipids and body composition. There is an ongoing discussion whether discontinuation of GH treatment is associated with deterioration of lipids. METHODS: We analyzed weight status [as body mass index-standard deviation score (BMI-SDS)], insulin like growth factor (IGF)-1, triglycerides, total, low-density liporptoein (LDL)- and high-density lipoprotein (HDL)-cholesterol at the end of GH treatment and in mean 6 months later in 90 adolescents (53 with GH deficiency, 16 with Turner syndrome [TS] and 21 born small-for-gestational age [SGA]). RESULTS: After stopping GH treatment, total cholesterol (+10+/-24 mg/dL vs. -4+/-13 mg/dL) and LDL cholesterol (+15+/-20 mg/dL vs. -6+/-12 mg/dL) increased significantly higher in severe (defined by GH peak in stimulation test <3 ng/mL) compared to moderate GHD. In patients with TS, total cholesterol (+19+/-9 mg/dL), LDL-cholesterol (+9+/-12 mg/dL) and HDL-cholesterol (+4.3+/-3.5 mg/dL) increased significantly. In adolescents born SGA, triglycerides increased (+34+/-51 mg/dL) and HDL cholesterol decreased significantly (-3.8+/-7.1 mg/dL). In multiple linear regression analyses, changes of total and LDL-cholesterol were significantly negatively related to peak GH in stimulation tests, but not to gender, age at GH start, duration of GH treatment, observation time, changes of BMI-SDS or IGF-1 after the end of GH treatment. The BMI-SDS did not change after the end of GH treatment. CONCLUSIONS: Discontinuation of GH treatment leads to a deterioration of lipids in TS, SGA and severe but not moderate GHD. PMID- 28672750 TI - Postprandial hyperinsulinemic hypoglycemia in a child as a late complication of esophageal reconstruction. AB - BACKGROUND: Postprandial hyperinsulinemic hypoglycemia (PHH) is an increasingly recognized complication of gastric bypass surgery in obese adults, distinct from the "dumping syndrome". CASE PRESENTATION: Upon birth, primary repair of esophageal atresia was performed, and at the age of 14 months definite esophageal reconstruction was performed. At the age of 3 years, recurrent brief episodes of symptomatic hypoglycemia started. At the age of 5.7 years the girl was admitted to our clinic and investigations indicated hyperinsulinemic hypoglycemia. Oral glucose tolerance test (OGTT) and continuous glucose monitoring results revealed frequent postprandial hypoglycemic events, which were always preceded by early postprandial hyperglycemia. It was concluded that the patient had PHH caused by a delayed and hyperinsulinemic response to carbohydrate intake as a result of esophagogastric surgery. Treatment with acarbose was titrated using flash glucose monitoring, which resulted in satisfactory glucose regulation. CONCLUSIONS: This is the first described case of a child with PHH following esophageal reconstruction. PMID- 28672751 TI - Sonographic prediction of small and large for gestational age in breech presenting fetuses. PMID- 28672754 TI - Postpartum infection in relation to maternal characteristics, obstetric interventions and complications. AB - The purpose was to evaluate the association between maternal characteristics, obstetrical interventions/complications and postpartum wound infections (WI), urinary tract infection (UTI) and endometritis. Furthermore, this study aimed to determine the time from delivery to onset of infections after discharge from the hospital. Three large Swedish Medical Health Registers were scrutinized for the period 2005-2012. A total of 582,576 women had 795,072 deliveries. Women with diagnosis codes for WIs, UTIs or endometritis, from delivery to 8 weeks postpartum, were compared to non-infected women. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. Increasing age and body mass index (BMI) were both associated with increasing prevalence of postpartum infections. WIs were most strongly associated with cesarean section (CS) (OR 17.2; 95%CI 16.1 18.3), 3rd and 4th degree tears (OR 10.7%; 95%CI 9.80-11.9) and episiotomy (OR 10.2; 95%CI 8.94-11.5). Endometritis was associated with anemia (OR 3.16; 95%CI 3.01-3.31) and manual placental removal (OR 2.72; 95%CI 2.51-2.95). UTI was associated with emergency CS (OR 3.46; 95%CI 3.07-3.89) and instrumental delivery (OR 3.70; 95%CI 3.29-4.16). For women discharged from the delivery hospital the peak occurrence of UTI was 6 days postpartum, while for WIs and endometritis it was 7 days postpartum. PMID- 28672755 TI - Pregnancy outcomes among patients with recurrent pregnancy loss and chromosomal aberration (CA) without PGD. PMID- 28672756 TI - Induction of labor in patients with an unfavorable cervix after a cesarean using an osmotic dilator versus vaginal prostaglandin. AB - BACKGROUND: Trial of labor after cesarean (TOLAC) is a viable option for safe delivery. In some cases cervical ripening and subsequent labor induction is necessary. However, the commonly used prostaglandins are not licensed in this subgroup of patients and are associated with an increased risk of uterine rupture. METHODS: This cohort study compares maternal and neonatal outcomes of TOLAC in women (n=82) requiring cervical ripening agents (osmotic dilator vs. prostaglandins). The initial Bishop scores (BSs) were 2 (0-5) and 3 (0-5) (osmotic dilator and prostaglandin group, respectively). In this retrospective analysis, Fisher's exact test, the Kruskal-Wallis rank sum test and Pearson's chi squared test were utilized. RESULTS: Vaginal birth rate (including operative delivery) was 55% (18/33) in the osmotic dilator group vs. 51% (25/49) in the dinoprostone group (P 0.886). Between 97% and 92% (32/33 and 45/49) (100%, 100%) of neonates had an Apgar score of >8 after 1 min (5, 10 min, respectively). The time between administration of the agent and onset of labor was 36 and 17.1 h (mean, Dilapan-S(r) group, dinoprostone group, respectively). Time from onset of labor to delivery was similar in both groups with 4.4 and 4.9 h (mean, Dilapan S(r) group, dinoprostone group, respectively). Patients receiving cervical ripening with Dilapan-S(r) required oxytocin in 97% (32/33) of cases. Some patients presented with spontaneous onset of labor, mostly in the dinoprostone group (24/49, 49%). Amniotomy was performed in 64% and 49% (21/33 and 24/49) of cases (Dilapan-S(r) group and dinoprostone group, respectively). CONCLUSIONS: This pilot study examines the application of an osmotic dilator for cervical ripening to promote vaginal delivery in women who previously delivered via cesarean section. In our experience, the osmotic dilator gives obstetricians a chance to perform induction of labor in these women. PMID- 28672757 TI - Hypercoiling of the umbilical cord in uncomplicated singleton pregnancies. AB - BACKGROUND: The umbilical coiling index (UCI) is a measure of the number of coils in the umbilical cord in relation to its length. Hypercoiled cords with a UCI of >0.3 coils/cm have been associated with adverse fetal and neonatal outcomes. AIMS: The primary aim is to determine the accuracy of UCI measured on second trimester ultrasound in predicting UCI at birth. The secondary outcome is to investigate the association between hypercoiling of the umbilical cord on prenatal ultrasound and adverse maternal, fetal and neonatal outcomes. METHODS: This was a prospective cohort study of uncomplicated singleton pregnancies. Seventy two patients were included in the study. UCI was measured in the second trimester ultrasound, and compared to UCI measured postnatally. Outcomes of patients with hypercoiled cords on ultrasound were compared to outcomes of patients with normocoiled cords. RESULTS: Our results failed to show a strong correlation between the UCI determined with ultrasound, and the UCI determined with examination of the umbilical cord after delivery. We also did not demonstrate that measurement of the UCI on second trimester ultrasound is able to predict adverse maternal, fetal or neonatal outcomes. CONCLUSION: This study suggests that measurement of the umbilical coiling index should not be part of routine second trimester sonography in patients with uncomplicated singleton pregnancies, with no other medical or surgical comorbidities. PMID- 28672758 TI - The misoprostol vaginal insert compared with oral misoprostol for labor induction in term pregnancies: a pair-matched case-control study. AB - AIM: To compare the efficacy and safety of the misoprostol vaginal insert (MVI) with an off-label use of oral misoprostol (OM). METHODS: Pair-matched case control study comparing the induction of labor with a retrievable MVI to OM. The primary outcomes were the time from induction to delivery and the cesarean section rate. Secondary outcomes included uterine tachysystole, tocolysis, fetal scalp blood testing, meconium-stained amniotic fluid, umbilical arterial pH, and Apgar score. RESULTS: One hundred and thirty eight women >=37/0 weeks pregnant undergoing labor induction with misoprostol were included. The mean time from application to delivery was significantly shorter and the caesarean section rate significantly higher in the MVI group (P<0.01) with an odds ratio of 2.75 (95% CI: 1.21-6.25) in favor of vaginal delivery in the OM group. The mean 5-min Apgar scores and arterial cord pH values were significantly lower in the MVI group. An arterial pH value of 7.10-7.19 was found in 26.1% and 15.9%, and a value <7.10 was found in 4.3% and 0% of MVI and OM cases, respectively. CONCLUSION: The MVI compared with OM significantly shortened the time from application to delivery at the expense of a higher cesarean section rate and negative effects on neonatal outcomes. PMID- 28672752 TI - Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation. AB - OBJECTIVE: Clinical chorioamnionitis is the most common infection/inflammatory process diagnosed in labor and delivery units worldwide. The condition is a syndrome that can be caused by (1) intra-amniotic infection, (2) intra-amniotic inflammation without demonstrable microorganisms (i.e. sterile intra-amniotic inflammation), and (3) maternal systemic inflammation that is not associated with intra-amniotic inflammation. The presence of intra-amniotic inflammation is a risk factor for adverse maternal and neonatal outcomes in a broad range of obstetrical syndromes that includes clinical chorioamnionitis at term. Although the diagnosis of intra-amniotic infection has relied on culture results, such information is not immediately available for patient management. Therefore, the diagnosis of intra-amniotic inflammation could be helpful as a proxy for intra amniotic infection, while results of microbiologic studies are pending. A rapid test is now available for the diagnosis of intra-amniotic inflammation, based on the determination of neutrophil collagenase or matrix metalloproteinase-8 (MMP 8). The objectives of this study were (1) to evaluate the diagnostic indices of a rapid MMP-8 test for the identification of intra-amniotic inflammation/infection in patients with the diagnosis of clinical chorioamnionitis at term, and (2) to compare the diagnostic performance of a rapid MMP-8 test to that of a conventional enzyme-linked immunosorbent assay (ELISA) interleukin (IL)-6 test for patients with clinical chorioamnionitis at term. MATERIALS AND METHODS: A retrospective cohort study was conducted. A transabdominal amniocentesis was performed in patients with clinical chorioamnionitis at term (n=44). Amniotic fluid was analyzed using cultivation techniques (for aerobic and anaerobic bacteria as well as genital Mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI MS). Amniotic fluid IL-6 concentrations were determined by ELISA, and rapid MMP-8 results were determined by Yoon's MMP-8 Check(r). Intra-amniotic inflammation was defined as an elevated amniotic fluid IL-6 concentration >=2.6 ng/mL, and intra amniotic infection was diagnosed by the presence of microorganisms in the amniotic fluid accompanied by intra-amniotic inflammation. The diagnostic indices of Yoon's MMP-8 Check(r) for the identification of intra-amniotic inflammation were calculated. In order to objectively compare Yoon's MMP-8 Check(r) with the ELISA IL-6 test for the identification of intra-amniotic inflammation, we used an amniotic fluid white blood cell (WBC) count >=50 cells/mm3 to define intra amniotic inflammation. RESULTS: (1) A positive rapid MMP-8 test had a sensitivity of 82.4% (28/34), specificity of 90% (9/10), positive predictive value of 96.6% (28/29), negative predictive value of 60% (9/15), positive likelihood ratio 8.2 (95% CI 1.3-53.2), and negative likelihood ratio 0.2 (95% CI 0.1-0.4) for the identification of intra-amniotic inflammation (prevalence 77.3%); (2) a positive rapid MMP-8 test had a sensitivity of 91.7% (22/24), specificity of 65% (13/20), positive predictive value of 75.9% (22/29), negative predictive value of 86.7% (13/15), positive likelihood ratio of 2.6 (95% CI 1.4-4.8), and negative likelihood ratio of 0.1 (95% CI 0.03-0.5) for the identification of intra amniotic infection; (3) the rapid MMP-8 test had a significantly higher specificity than the ELISA IL-6 test in the identification of intra-amniotic inflammation as determined by an amniotic fluid WBC count >=50 cells/mm3. The sensitivity and accuracy of the rapid MMP-8 test were comparable to those of the ELISA IL-6 test; and (4) importantly, the rapid MMP-8 test had 100% sensitivity and 100% negative predictive value in the identification of neonates affected with fetal inflammatory response syndrome (FIRS). CONCLUSION: The rapid diagnosis of intra-amniotic inflammation is possible by analysis of amniotic fluid using a point-of-care test for MMP-8. Patients with a positive test are at risk of delivering a neonate affected with systemic inflammation, a risk factor for adverse neonatal outcome. PMID- 28672753 TI - The combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome increases the risk of intraventricular hemorrhage in preterm neonates. AB - OBJECTIVE: To evaluate the impact of combined exposure to intra-amniotic inflammation and neonatal respiratory distress syndrome (RDS) on the development of intraventricular hemorrhage (IVH) in preterm neonates. METHODS: This retrospective cohort study includes 207 consecutive preterm births (24.0-33.0 weeks of gestation). Intra-amniotic inflammation was defined as an amniotic fluid matrix metalloproteinase-8 concentration >23 ng/mL. According to McMenamin's classification, IVH was defined as grade II or higher when detected by neurosonography within the first weeks of life. RESULTS: (1) IVH was diagnosed in 6.8% (14/207) of neonates in the study population; (2) IVH was frequent among newborns exposed to intra-amniotic inflammation when followed by postnatal RDS [33% (6/18)]. The frequency of IVH was 7% (8/115) among neonates exposed to either of these conditions - intra-amniotic inflammation or RDS - and 0% (0/64) among those who were not exposed to these conditions; and (3) Neonates exposed to intra-amniotic inflammation and postnatal RDS had a significantly higher risk of IVH than those with only intra-amniotic inflammation [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.1-19.3] and those with RDS alone (OR 5.6, 95% CI 1.0 30.9), after adjusting for gestational age. CONCLUSION: The combined exposure to intra-amniotic inflammation and postnatal RDS markedly increased the risk of IVH in preterm neonates. PMID- 28672759 TI - The relationship between maternal and umbilical cord adropin levels with the presence and severity of preeclampsia. AB - AIM: To investigate both maternal and umbilical cord adropin levels in patients with preeclampsia and the possible relations with its severity and perinatal outcomes. MATERIALS AND METHODS: In this study, a total of 38 preeclamptic and 40 age-matched healthy pregnant women between January and June 2016 were included. Serum and cord adropin levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The maternal and umbilical cord adropin levels were significantly lower in the preeclamptic group compared to controls [71.19+/-22.21 vs. 100.76+/-27.02 ng/L and 92.39 (59.77:129.89) vs. 106.20 (74.42:208.02) ng/L, P<0.001, respectively]. While maternal adropin levels were significantly lower in the severe preeclampsia group as compared to the mild preeclamptic group [66.45 (21.49:98.02) vs. 76.17 (58.06:109.58), P=0.007], umbilical cord adropin levels did not differ between each group [91.32 (59.77:113.34) vs. 92.87 (63.12:129.89), P=0.750]. Maternal adropin level was negatively correlated with systolic and diastolic blood pressures (r=-0.60, P<0.001 and r=-0.58, P<0.001, respectively) and positively correlated with platelet count (r=0.27, P=0.016). Moreover, umbilical cord adropin levels were weakly correlated with gestational age at delivery (r=0.28, P=0.012) and birth weight (r=0.28, P=0.014). CONCLUSION: The present study is the first to demonstrate a significant association between maternal and umbilical adropin levels and the presence and severity of preeclampsia. Adropin might be a useful parameter for predicting the presence and severity of preeclampsia. PMID- 28672760 TI - Genetic association test based on principal component analysis. AB - Many gene- and pathway-based association tests have been proposed in the literature. Among them, the SKAT is widely used, especially for rare variants association studies. In this paper, we investigate the connection between SKAT and a principal component analysis. This investigation leads to a procedure that encompasses SKAT as a special case. Through simulation studies and real data applications, we compare the proposed method with some existing tests. PMID- 28672761 TI - Functional control of polypeptide GalNAc-transferase 3 through an acetylation site in the C-terminal lectin domain. AB - O-GalNAc glycans are important structures in cellular homeostasis. Their biosynthesis is initiated by members of the polypeptide GalNAc-transferase (ppGalNAc-T) enzyme family. Mutations in ppGalNAc-T3 isoform cause diseases (congenital disorders of glycosylation) in humans. The K626 residue located in the C-terminal beta-trefoil fold of ppGalNAc-T3 was predicted to be a site with high likelihood of acetylation by CBP/p300 acetyltransferase. We used a site directed mutagenesis approach to evaluate the role of this acetylation site in biological properties of the enzyme. Two K626 mutants of ppGalNAc-T3 (T3K626Q and T3K626A) had GalNAc-T activities lower than that of wild-type enzyme. Direct and competitive interaction assays revealed that GalNAc recognition by the lectin domain was altered in the mutants. The presence of GlcNAc glycosides affected the interaction of the three enzymes with mucin-derived peptides. In GalNAc-T activity assays, the presence of GlcNAc glycosides significantly inhibited activity of the mutant (T3K626Q) that mimicked acetylation. Our findings, taken together, reveal the crucial role of the K626 residue in the C-terminal beta trefoil fold in biological properties of human ppGalNAc-T3. We propose that acetylated residues on ppGalNAc-T3 function as control points for enzyme activity, and high level of GlcNAc glycosides promote a synergistic regulatory mechanism, leading to a metabolically disordered state. PMID- 28672762 TI - Critical congenital heart disease screening with a pulse oximetry in neonates. AB - OBJECTIVE: To compare the results of pulse oximetry screening for critical congenital heart disease (CCHD) in newborn infants performed at <24 h and >24 h following. METHOD: Measurements were taken for each group at <24 h and >24 h following birth. Echocardiography was performed if the SpO2 readings remained abnormal results. RESULTS: A total of 4518 newborns were included in this prospective descriptive study. Of these, 2484 (60.3%) were delivered vaginally and 1685 (39.7%) by cesarean section. Median time points of the screening were 25.4 (25.3-25.5) vs. 17.3 (12.2-22.4) hours after birth. In 4109 infants screened 24 h after birth, the mean pre- and postductal oxygen saturations (SpO2) were 96.5+/-1.99 and 97.7+/-1.98, while 127 infants screened within 24 h of mean preductal and postductal SpO2 were 91.33+/-2.64 and 94.0+/-4.44. No CCHD was detected during the study period. Pulse oximetry screening was false positive for CCHD in 9 of 4109 infants (0.02%); of these, six infants were referred to pediatric cardiology and three cases were diagnosed as other significant, non cardiac pathology. There were two cases with AVSD (atrioventricular septal defect, three cases with ventricular septal defect (VSD), and one case with patent ductus arteriosus (PDA). CONCLUSIONS: Saturation values are different between <24-h and >24-h neonates in pulse oximetry screening. The screening in this study identified infants with other important pathologies, this forms an added value as an assessment tool for newborn infants. PMID- 28672763 TI - A step by step approach in differential diagnosing of adrenal incidentaloma (epinephroma), (with comments on the new Clinical Practice Guidelines of the European Society of Endocrinology). AB - OBJECTIVES: To present a step by step approach for the diagnosis of adrenal incidentaloma (AI). METHOD: An extensive review of the literature was conducted, searching the Pub-Med and Google Scholar using the Mesh terms; Adrenal; Incidentaloma; Adrenal tumours; Radiology; Diagnosis. We also did a cross referencing search of the literature. Comments on the new European guidelines are presented. RESULTS: The majority of the tumours are non-functioning benign adenomas. The most important radiological characteristic of an adrenal incidentaloma is the radiation attenuation coefficient. Wash out percentage and the imaging characteristics of the tumour may help in diagnosis. CONCLUSION: Density less than 10 HU is in most cases characteristic of a lipid rich benign adenoma. More than 10 HU or/and history of malignancy raise the possibility for cancer. 1 mg dexamethasone test and plasma metanephrines should be done in all patients. If there is history of hypokalemia and/or resistant hypertension we test the plasma aldosterone to plasma renin ratio (ARR). Newer studies have shown that tumours even nonfunctioning and less than 4 cm may increase the metabolic risks so we may consider surgery at an earlier stage. PMID- 28672764 TI - Interaction of tubulin and protein kinase CK2 in Trypanosoma equiperdum. AB - A polypeptide band with an apparent molecular weight of 55,000 was phosphorylated in vitro in whole-cell lysates of Trypanosoma equiperdum. This band corresponds to tubulin as demonstrated by immunoprecipitation of the phosphorylated polypeptide from T. equiperdum extracts when anti-alpha and anti-beta tubulin monoclonal antibodies were employed. A parasite protein kinase CK2 was in charge of modifying tubulin given that common mammalian CK2 inhibitors such as emodin and GTP, hindered the phosphorylation of tubulin and exogenously added casein. Interestingly, a divalent cation-dependent translocation of the T. equiperdum tubulin and the CK2 responsible for its phosphorylation was noticed, suggesting a direct interaction between these two proteins. Additionally, this fraction of tubulin and its kinase coeluted using separations based on parameters as different as charge (DEAE-Sepharose anion-exchange chromatography) and size (Sephacryl S-300 gel filtration chromatography). Analyses by non-denaturing polyacrylamide gel electrophoresis and immunoblot of the purified and radioactively labeled fraction containing both tubulin and the CK2 enzyme, established the phosphorylation of a single band that was recognized by anti-CK2 alpha-subunit and anti-tubulin antibodies. All these findings revealed a physical association between a pool of tubulin and a CK2 in T. equiperdum. PMID- 28672765 TI - Discovery and Annotation of Plant Endogenous Target Mimicry Sequences from Public Transcriptome Libraries: A Case Study of Prunus persica. AB - Novel transcript discovery through RNA sequencing has substantially improved our understanding of the transcriptome dynamics of biological systems. Endogenous target mimicry (eTM) transcripts, a novel class of regulatory molecules, bind to their target microRNAs (miRNAs) by base pairing and block their biological activity. The objective of this study was to provide a computational analysis framework for the prediction of putative eTM sequences in plants, and as an example, to discover previously un-annotated eTMs in Prunus persica (peach) transcriptome. Therefore, two public peach transcriptome libraries downloaded from Sequence Read Archive (SRA) and a previously published set of long non coding RNAs (lncRNAs) were investigated with multi-step analysis pipeline, and 44 putative eTMs were found. Additionally, an eTM-miRNA-mRNA regulatory network module associated with peach fruit organ development was built via integration of the miRNA target information and predicted eTM-miRNA interactions. My findings suggest that one of the most widely expressed miRNA families among diverse plant species, miR156, might be potentially sponged by seven putative eTMs. Besides, the study indicates eTMs potentially play roles in the regulation of development processes in peach fruit via targeting specific miRNAs. In conclusion, by following the step-by step instructions provided in this study, novel eTMs can be identified and annotated effectively in public plant transcriptome libraries. PMID- 28672766 TI - The value of peripheral blood eosinophil count in predicting in-stent restenosis in patients with stable angina pectoris undergoing drug eluting stenting. AB - INTRODUCTION: In-stent restenosis (ISR) remains a major limitation of percutaneous coronary intervention (PCI). A role for peripheral blood cells as major regulators of immune and inflammatory systems has been proposed. We aim to evaluate the relationship between eosinophil count and development of restenosis after drug-eluting stent (DES) implantation. METHODS: In this prospective study, all consecutive patients undergoing elective DES implantation for chronic stable angina (CSA) in a university-affiliated heart center within a 6-month period were enrolled and followed for another 6 months. Complete blood count with differentiation was performed 6 weeks after the index procedure. During the follow-up period, the cohort of patients who developed ISR was compared to the cohort of patients without ISR, descriptively and the total number of eosinophilic white cells was used to predict the occurrence of ISR. RESULTS: 153 men and 48 women with CSA underwent PCI with DES implantation, from which, 26 patients needed repeat coronary angiography for recurrent symptoms. There was an established ISR in 17 (8.5%) patients. The total number of eosinophils in their peripheral blood was 267 +/- 132 cells/MUL in patients with ISR, significantly higher than the number of eosinophils in those without ISR 174 +/- 133 cells/MUL (P-value < 0.010). Eosinophil count remained an independent predictor of ISR in multivariate analysis as the eosinophil count value over 242 cells/MUL had sensitivity of 66.7% and specificity of 84.5% for the presence of ISR. CONCLUSION: The total number of eosinophils, counted 6 weeks after DES implantation, prevails as the sole predictor of ISR occurrence in our study. This suggests an association between immune sensitivity reaction to DES material and development of ISR in patients after PCI. PMID- 28672767 TI - A priori knowledge integration for the detection of cerebral aneurysm. AB - The detection of intracranial aneurysms is of a paramount effect in the prevention of cerebral subarachnoid hemorrhage. We propose in this paper, a new approach to detect cerebral aneurysm in digital subtraction angiography (DSA) images by fusing several sources of knowledge. After a brief description of a priori knowledge that the expert has provided about cerebral aneurysm, we propose a system architecture including fuzzy modeling and data fusion. The results on the studied cases are very promising. PMID- 28672768 TI - Circulating CD89-IgA complex does not predict deterioration of kidney function in Korean patients with IgA nephropathy. AB - BACKGROUND: Soluble CD89 (sCD89)-IgA complex plays a key role in the pathogenesis of IgA nephropathy (IgAN). However, there is a lack of evidence supporting this complex as a good biomarker for disease progression. This study aimed to evaluate the usefulness of sCD89-IgA complex for risk stratification of IgAN. METHODS: A total of 326 patients with biopsy-proven IgAN were included. sCD89-IgA complex was measured by sandwich-enzyme-linked immunosorbent assay. The study endpoints were a 30% decline in estimated glomerular filtration rate (eGFR). RESULTS: sCD89 IgA complex levels were inversely and weakly associated with eGFR at the time of biopsy (r=-0.12, p=0.03). However, the significance between the two factors was lost in the multivariate linear regression after adjustment of clinical factors (beta=0.35, p=0.75). In a multivariate Cox model, the highest (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.35-1.61; p=0.45) and middle (HR, 0.93; 95% CI, 0.46-1.89; p=0.84) tertiles of sCD89-IgA complex levels were not associated with an increased risk of developing a 30% decrease in eGFR. Furthermore, the decline rates in eGFR did not differ between groups and C-statistics revealed that the sCD89-IgA complex were not superior to clinical factors in predicting disease progression. CONCLUSIONS: This study found no association between sCD89 IgA complex levels and disease progression in IgAN. Although sCD89 can contribute to the formation of immune complexes, our findings suggest that the sCD89-IgA level is not a good predictor of adverse outcomes and has limited clinical utility as a biomarker for risk stratification in IgAN. PMID- 28672769 TI - Reference intervals and longitudinal changes in copeptin and MR-proADM concentrations during pregnancy. AB - BACKGROUND: Vasopressin and adrenomedullin and their stable by-products copeptin and midregional part of proadrenomedullin (MR-proADM) are promising biomarkers for the development of preeclampsia. However, clinical use is hampered by the lack of trimester-specific reference intervals. We therefore estimated reference intervals for copeptin and MR-proADM in disease-free Dutch women throughout pregnancy. METHODS: Apparently healthy low risk pregnant women were recruited. Exclusion criteria included current or past history of endocrine disease, multiple pregnancy, use of medication known to influence thyroid function and current pregnancy as a result of hormonal stimulation. Women who miscarried, developed hyperemesis gravidarum, hypertension, pre-eclampsia, hemolysis elevated liver enzymes and low platelets, diabetes or other disease, delivered prematurely or had a small for gestational age neonate were excluded from analyses. Blood samples were collected at 9-13 weeks (n=98), 27-29 weeks (n=94) and 36-39 weeks (n=91) of gestation and at 4-13 weeks post-partum (PP) (n=89). Sixty-two women had complete data during pregnancy and PP. All analyses were performed on a Kryptor compact plus. RESULTS: Copeptin increases during pregnancy, but 97.5th percentiles remain below the non-pregnant upper reference limit (URL) provided by the manufacturer. MR-proADM concentrations increase as well during pregnancy. In trimesters 2 and 3 the 97.5th percentiles are over three times the non-pregnant URL provided by the manufacturer. CONCLUSIONS: Trimester- and assay-specific reference intervals for copeptin and MR-proADM should be used. In addition, consecutive measurements and the time frame between measurements should be considered as the differences seen with or in advance of preeclampsia can be expected to be relatively small compared to the reference intervals. PMID- 28672770 TI - Performance of automated digital cell imaging analyzer Sysmex DI-60. AB - BACKGROUND: The Sysmex DI-60 system (DI-60, Sysmex, Kobe, Japan) is a new automated digital cell imaging analyzer. We explored the performance of DI-60 in comparison with Sysmex XN analyzer (XN, Sysmex) and manual count. METHODS: In a total of 276 samples (176 abnormal and 100 normal samples), white blood cell (WBC) differentials, red blood cell (RBC) classification and platelet (PLT) estimation by DI-60 were compared with the results by XN and/or manual count. RBC morphology between pre-classification and verification was compared according to the ICSH grading criteria. The manual count was performed according to the Clinical and Laboratory Standards Institute guidelines (H20-A2). RESULTS: The overall concordance between DI-60 and manual count for WBCs was 86.0%. The agreement between DI-60 pre-classification and verification was excellent (weighted kappa=0.963) for WBC five-part differentials. The correlation with manual count was very strong for neutrophils (r=0.955), lymphocytes (r=0.871), immature granulocytes (r=0.820), and blasts (r=0.879). RBC grading showed notable differences between DI-60 and manual counting on the basis of the ICSH grading criteria. Platelet count by DI-60 highly correlated with that by XN (r=0.945). However, DI-60 underestimated platelet counts in samples with marked thrombocytosis. CONCLUSIONS: The performance of DI-60 for WBC differential, RBC classification, and platelet estimation seems to be acceptable even in abnormal samples with improvement after verification. DI-60 would help optimize the workflow in hematology laboratory with reduced manual workload. PMID- 28672771 TI - Handling the altered test results of hemolyzed samples. Recommendations of the Quality, Management, Safety and Evidence Committee (CCGSE) of the Spanish Association of Medical Biopathology and Laboratory Medicine (AEBM-ML). PMID- 28672772 TI - Mass spectrometry vs. immunoassay in clinical and forensic toxicology: qui modus in rebus est? PMID- 28672773 TI - Generalized Confidence Intervals for Intra- and Inter-subject Coefficients of Variation in Linear Mixed-effects Models. AB - Linear mixed-effects models are linear models with several variance components. Models with a single random-effects factor have two variance components: the random-effects variance, i. e., the inter-subject variance, and the residual error variance, i. e., the intra-subject variance. In many applications, it is practice to report variance components as coefficients of variation. The intra- and inter-subject coefficients of variation are the square roots of the corresponding variances divided by the mean. This article proposes methods for computing confidence intervals for intra- and inter-subject coefficients of variation using generalized pivotal quantities. The methods are illustrated through two examples. In the first example, precision is assessed within and between runs in a bioanalytical method validation. In the second example, variation is estimated within and between main plots in an agricultural split plot experiment. Coverage of generalized confidence intervals is investigated through simulation and shown to be close to the nominal value. PMID- 28672774 TI - Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia. AB - BACKGROUND: Chronic hypobaric hypoxia (cHH) mediated cardiac insufficiencies are associated with pathological damage. Sustained redox stress and work load are major causative agents of cardiac insufficiencies under cHH. Despite the advancements made in pharmacological (anti-oxidants, vasodilators) and non pharmacological therapeutics (acclimatization strategies and schedules), only partial success has been achieved in improving cardiac acclimatization to cHH. This necessitates the need for potent combinatorial therapies to improve cardiac acclimatization at high altitudes. We hypothesize that a combinatorial therapy comprising preconditioning to mild aerobic treadmill exercise and supplementation with nanocurcumin formulation (NCF) consisting of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) might improve cardiac adaptation at high altitudes. METHODS: Adult Sprague-Dawley rats pre-conditioned to treadmill exercise and supplemented with NCF were exposed to cHH (7620 m altitude corresponding to pO2~8% at 28+/-2 degrees C, relative humidity 55%+/-1%) for 3 weeks. The rat hearts were analyzed for changes in markers of oxidative stress (free radical leakage, lipid peroxidation, manganese-superoxide dismutase [MnSOD] activity), cardiac injury (circulating cardiac troponin I [TnI] and T [cTnT], myocardial creatine kinase [CK-MB]), metabolic damage (lactate dehydrogenase [LDH] and acetyl-coenzyme A levels, lactate and pyruvate levels) and bio energetic insufficiency (ATP, p-AMPKalpha). RESULTS: Significant modulations (p<=0.05) in cardiac redox status, metabolic damage, cardiac injury and bio energetics were observed in rats receiving both NCF supplementation and treadmill exercise-preconditioning compared with rats receiving only one of the treatments. CONCLUSIONS: The combinatorial therapeutic strategy showed a tremendous improvement in cardiac acclimatization to cHH compared to either exercise preconditioning or NCF supplementation alone which was evident from the effective modulation in redox, metabolic, contractile and bio-energetic homeostasis. PMID- 28672775 TI - Pediatric toxic polycystic thyroid. AB - BACKGROUND: Polycystic thyroid disease (PCTD) is a rare condition and has been described in adults in the setting of subclinical and clinical hypothyroidism. We present the first known case of a pediatric patient with diffuse macrocystic degeneration of the thyroid. CLINICAL PRESENTATION: A 6-year-old previously healthy patient was evaluated after presenting with a 16-month history of an enlarging polycystic thyroid and hyperthyroidism. Markers of autoimmune thyroid disease including thyroid stimulating immunoglobulin (TSI), thyroid stimulating hormone (TSH) receptor antibody, thyroid peroxidase antibody and thyroglobulin antibody were negative. No family history of benign or malignant thyroid or cystic disease was present. The patient underwent a total thyroidectomy without perioperative complication. She remains euthyroid with thyroid hormone replacement therapy. SUMMARY: To our knowledge, this is the first report of PCTD in the pediatric population associated with hyperthyroidism without evidence of autoimmune disease. Somatic activating thyrotropin-receptor gene mutations are known to cause non-autoimmune hyperthyroidism in children, however it is unknown if similar mechanisms are responsible for pediatric PCTD. CONCLUSIONS: Polycystic thyroid degeneration can occur in children and may result in a hyperthyroid state. PMID- 28672776 TI - Human U3 protein 14a plays an anti-apoptotic role in cancer cells. AB - Human U three protein 14a (hUTP14a) binds p53 and promotes p53 degradation. Here, we report that hUTP14a plays an anti-apoptotic role in tumor cells through a p53 independent pathway. Knockdown of hUTP14a activated the intrinsic pathway of apoptosis and sensitized tumor cells to chemotherapeutic drug-induced apoptosis. In addition, the protein level of hUTP14a decreased upon chemotherapeutic drug- or irradiation-induced apoptosis. Importantly, the decrease of hUTP14a during induced apoptosis was not blocked by pan-caspase inhibitor z-VAD-FMK, indicating that the down-regulation of hUTP14a is an upstream event in apoptosis. Furthermore, ectopically expressed hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis. In summary, our data showed that hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis and thus might possess a potential as a target for anti-tumor therapy. PMID- 28672777 TI - Correction: The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin. PMID- 28672778 TI - Correction: H2O2 treatment or serum deprivation induces autophagy and apoptosis in naked mole-rat skin fibroblasts by inhibiting the PI3K/Akt signaling pathway. PMID- 28672779 TI - Retraction: The role of CEUS in characterization of superficial lymph nodes: a single center prospective study. PMID- 28672780 TI - Recent Progress in Nanomaterial-Based Electrochemical Biosensors for Cancer Biomarkers: A Review. AB - This article reviews recent progress in the development of nanomaterial-based electrochemical biosensors for cancer biomarkers. Because of their high electrical conductivity, high affinity to biomolecules, and high surface area-to weight ratios, nanomaterials, including metal nanoparticles, carbon nanotubes, and graphene, have been used for fabricating electrochemical biosensors. Electrodes are often coated with nanomaterials to increase the effective surface area of the electrodes and immobilize a large number of biomolecules such as enzymes and antibodies. Alternatively, nanomaterials are used as signaling labels for increasing the output signals of cancer biomarker sensors, in which nanomaterials are conjugated with secondary antibodies and redox compounds. According to this strategy, a variety of biosensors have been developed for detecting cancer biomarkers. Recent studies show that using nanomaterials is highly advantageous in preparing high-performance biosensors for detecting lower levels of cancer biomarkers. This review focuses mainly on the protocols for using nanomaterials to construct cancer biomarker sensors and the performance characteristics of the sensors. Recent trends in the development of cancer biomarker sensors are discussed according to the nanomaterials used. PMID- 28672781 TI - Characterization of the Key Aroma Compounds in Chinese Syrah Wine by Gas Chromatography-Olfactometry-Mass Spectrometry and Aroma Reconstitution Studies. AB - The key aroma compounds and the organoleptic quality of two Chinese Syrah wines from the Yunnan Shangri-La region and Ningxia Helan mountain region were characterized. The most important eighty aroma-active compounds were identified by Gas Chromatography-Olfactometry. In both Syrah samples, ethyl 2 methylpropanoate, ethyl 3-methylbutanoate, 3-methylbutyl acetate, 2- and 3-methyl 1-butanol, ethyl hexanoate, ethyl octanoate, 2-phenethyl acetate, methional, 3 methylbutanoic acid, hexanoic acid, octanoic acid, beta-damascenone, guaiacol, 2 phenylethanol, trans-whiskylactone, 4-ethylguaiacol, eugenol, 4-ethylphenol, and sotolon were detected to have the highest odor intensities. In the chemical analysis, 72 compounds were quantitated by Stir Bar Sorptive Extraction combined with Gas Chromatography Mass Spectrometry. Based on the Odor Activity Value (OAV), the aromas were reconstituted by combining aroma compounds in the synthetic wine, and sensory descriptive analysis was used to verify the chemical data. Fatty acid ethyl esters, acetate esters, and beta-damascenone were found with higher OAVs in the more fruity-smelling sample of Helan Mountain rather than Shangri-La. PMID- 28672782 TI - Vitamin E and Alzheimer's Disease-Is It Time for Personalized Medicine? AB - For the last two decades, it has been hotly debated whether vitamin E-the major lipid-soluble antioxidant, which functions to maintain neurological integrity-is efficacious as a therapy for Alzheimer's disease. Several factors key to the debate, include (1) which of the eight naturally-occurring vitamin E forms should be used; (2) how combination treatments affect vitamin E efficacy; and (3) safety concerns that most-recently resurfaced after the results of the Selenium and vitamin E Cancer prevention trial SELECT prostate cancer trial. However, with the advent of new genetic technologies and identifications of vitamin E-modulating single nucleotide polymorphisms (SNPs), we propose that clinical trials addressing the question "Is vitamin E an effective treatment for Alzheimer's disease" should consider a more focused and personalized medicine approach to designing experiments. An individual's naturally-occurring SNP variants may indeed influence vitamin E's therapeutic effect on Alzheimer's disease. PMID- 28672784 TI - Bonnevillamides, Linear Heptapeptides Isolated from a Great Salt Lake-Derived Streptomyces sp. AB - Streptomyces sp. GSL-6B was isolated from sediment collected from the Great Salt Lake and investigation of its organic extract led to the isolation of three new linear heptapeptides, bonnevillamides A (1), B (2), and C (3). The bonnevillamides represent a new class of linear peptides featuring unprecedented non-proteinogenic amino acids. All three peptides contain the newly characterized bonnevillic acid moiety (3-(3,5-dichloro-4-methoxyphenyl)-2-hydroxyacrylic acid), as well as a heavily modified proline residue. Moreover, in bonnevillamide A, the terminal proline residue found in bonnevillamides B and C is replaced with 4 methyl-azetidine-2-carboxylic acid methyl ester. The structures of the three heptapeptides were elucidated by NMR, high-resolution electrospray ionization mass spectroscopy (HRESIMS), and LC-MS/MS, and the absolute configuration of all proteinogenic amino acid residues were determined by advanced Marfey's method. Bonnevillamides A, B and C were evaluated for their effects on zebrafish embryo development. All three heptapeptides were shown to modulate heart growth and cardiac function, with bonnevillamide B having the most pronounced effect. PMID- 28672783 TI - Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor? AB - Vitamin D (VD) is a fat-soluble steroid essential for life in higher animals. It is technically a pro-hormone present in few food types and produced endogenously in the skin by a photochemical reaction. In recent decades, several studies have suggested that VD contributes to diverse processes extending far beyond mineral homeostasis. The machinery for VD production and its receptor have been reported in multiple tissues, where they have a pivotal role in modulating the immune system. Similarly, vitamin D deficiency (VDD) has been in the spotlight as a major global public healthcare burden. VDD is highly prevalent throughout different regions of the world, including tropical and subtropical countries. Moreover, VDD may affect host immunity leading to an increased incidence and severity of several infectious diseases. In this review, we discuss new insights on VD physiology as well as the relationship between VD status and various infectious diseases such as tuberculosis, respiratory tract infections, human immunodeficiency virus, fungal infections and sepsis. Finally, we critically review the latest evidence on VD monitoring and supplementation in the setting of infectious diseases. PMID- 28672785 TI - Comprehensive Expression Profiling and Functional Network Analysis of Porphyra 334, One Mycosporine-Like Amino Acid (MAA), in Human Keratinocyte Exposed with UV radiation. AB - Mycosporine-like amino acids (MAAs) have been highlighted as pharmacologically active secondary compounds to protect cells from harmful UV-radiation by absorbing its energy. Previous studies have mostly focused on characterizing their physiological properties such as antioxidant activity and osmotic regulation. However, molecular mechanisms underlying their UV-protective capability have not yet been revealed. In the present study, we investigated the expression profiling of porphyra-334-modulated genes or microRNA (miRNAs) in response to UV-exposure and their functional networks, using cDNA and miRNAs microarray. Based on our data, we showed that porphyra-334-regulated genes play essential roles in UV-affected biological processes such as Wnt (Wingless/integrase-1) and Notch pathways which exhibit antagonistic relationship in various biological processes; the UV-repressed genes were in the Wnt signaling pathway, while the activated genes were in the Notch signaling. In addition, porphyra-334-regulated miRNAs can target many genes related with UV-mediated biological processes such as apoptosis, cell proliferation and translational elongation. Notably, we observed that functional roles of the target genes for up regulated miRNAs are inversely correlated with those for down-regulated miRNAs; the former genes promote apoptosis and translational elongation, whereas the latter function as inhibitors in these processes. Taken together, these data suggest that porphyra-334 protects cells from harmful UV radiation through the comprehensive modulation of expression patterns of genes involved in UV-mediated biological processes, and that provide a new insight to understand its functional molecular networks. PMID- 28672786 TI - Residential Proximity to Roadways and Ischemic Placental Disease in a Cape Cod Family Health Study. AB - Exposure to air pollution may adversely impact placental function through a variety of mechanisms; however, epidemiologic studies have found mixed results. We examined the association between traffic exposure and placental-related obstetric conditions in a retrospective cohort study on Cape Cod, MA, USA. We assessed exposure to traffic using proximity metrics (distance of residence to major roadways and length of major roadways within a buffer around the residence). The outcomes included self-reported ischemic placental disease (the presence of at least one of the following conditions: preeclampsia, placental abruption, small-for-gestational-age), stillbirth, and vaginal bleeding. We used log-binomial regression models to estimate risk ratios (RR) and 95% confidence intervals (CI), adjusting for potential confounders. We found no substantial association between traffic exposure and ischemic placental disease, small-for gestational-age, preeclampsia, or vaginal bleeding. We found some evidence of an increased risk of stillbirth and placental abruption among women living the closest to major roadways (RRs comparing living <100 m vs. >=200 m = 1.75 (95% CI: 0.82-3.76) and 1.71 (95% CI: 0.56-5.23), respectively). This study provides some support for the hypothesis that air pollution exposure adversely affects the risk of placental abruption and stillbirth; however, the results were imprecise due to the small number of cases, and may be impacted by non-differential exposure misclassification and selection bias. PMID- 28672787 TI - The Efficacy of Dog Assisted Therapy in Detained Drug Users: A Pilot Study in an Italian Attenuated Custody Institute. AB - Drug addiction is a major care and safety challenge in prison context. Nowadays, rehabilitation and specific therapeutic programs are suggested to improve health and well-being of inmates during their detention time and to reduce substance abuse relapse after release from prison. Among these programs, several studies reported the benefits for inmates coming from animal assisted interventions. In this pilot controlled study, we investigated the efficacy of a dog assisted therapy program addressed to 22 drug addicted male inmates housed in an attenuated custody institute in Italy. The study lasted six months, the treated group (12 inmates) was involved once a week for one hour in 20 dog assisted therapy sessions, whereas the control group (10 inmates) followed the standard rehabilitation program. One week before the beginning and one week after the end of the sessions, all inmates involved were submitted to symptom checklist-90 revised and Kennedy axis V. Inmates involved in the dog assisted therapy sessions significantly improved their social skills, reducing craving, anxiety and depression symptoms compared to the control group. Despite the limitation due to the small number of inmates enrolled and to the absence of follow up, we found these results encouraging to the use of dog assisted therapy as co-therapy in drug addicted inmates rehabilitation programs, and we claim the need of more extensive study on this subject. PMID- 28672788 TI - N-3 Polyunsaturated Fatty Acids Decrease the Protein Expression of Soluble Epoxide Hydrolase via Oxidative Stress-Induced P38 Kinase in Rat Endothelial Cells. AB - N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect. PMID- 28672789 TI - Evaluating Modern Techniques for the Extraction and Characterisation of Sunflower (Hellianthus annus L.) Seeds Phenolics. AB - Recently there is a great interest in using high energy techniques (HET) which involve microwave or ultrasound-assisted extraction (MAE and UAE) for isolation of natural bioactive compounds from plant foods. Such bioactive compounds are phenolics which were determined from sunflower (Helianthus annuus L.) kernels and hulls (defatted) utilising two different high energy extraction techniques, ultrasound and microwave assisted solvent extraction. All samples were characterised by ultra-high-performance liquid chromatography-electrospray ionization-mass spectrometry (UHPLC-ESI-MS). The effect of parameters such as the nature of the solvent, volume of solvent, temperature and time is discussed. It is proved that the techniques applied had reduced solvent consumption and shorter extraction times, and extraction yields of the analytes were equal to or to some extent higher than those obtained with conventional techniques. Total Phenolic Composition (TPC) of samples examined was studied by the Folin-Ciocalteu method and results were presented in MUg gallic acid equivalents (GAE)/g dry extract. Kernels proved to have the higher amount of TPC while the press residues had shown comparable TPC results. The antioxidant activity of samples was spectrophotometrically determined by 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay using Butylated hydroxyl toluene (BHT) as reference compound to compare with samples. Sunflower seeds (kernels) showed again the highest antiradical efficiency (AE) compared to hulls and press-residue extract. Afterwards, ferric reducing ability of plasma (FRAP) and trolox equivalent antioxidant capacity (TEAC) assays were used for measuring the antioxidant capacity of samples. Press residue, a by-product of sunflower oil extraction, contained phenolics as shown by UHPLC-ESI-MS analysis. Hence, later on these compounds can be possibly utilised by food or neutraceutical industries. Phenolic substances characterised in hulls, kernels, and press residue were phenolic acids, mainly chlorogenic, caffeic, cinnamic, 4-hydroxybenzoic and p-coumaric. PMID- 28672790 TI - Sugars, Sweet Taste Receptors, and Brain Responses. AB - Sweet taste receptors are composed of a heterodimer of taste 1 receptor member 2 (T1R2) and taste 1 receptor member 3 (T1R3). Accumulating evidence shows that sweet taste receptors are ubiquitous throughout the body, including in the gastrointestinal tract as well as the hypothalamus. These sweet taste receptors are heavily involved in nutrient sensing, monitoring changes in energy stores, and triggering metabolic and behavioral responses to maintain energy balance. Not surprisingly, these pathways are heavily regulated by external and internal factors. Dysfunction in one or more of these pathways may be important in the pathogenesis of common diseases, such as obesity and type 2 diabetes mellitus. PMID- 28672791 TI - Risk of Deficiency in Multiple Concurrent Micronutrients in Children and Adults in the United States. AB - Certain population sub-groups in the United States are vulnerable to micronutrient malnutrition. Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) describing the biochemical status of vitamins A, B6, B12, C, D, E, folate, and anemia, were aggregated to determine the overall risk of multiple concurrent deficiencies in U.S. children and adults (n = 15,030) aged >9 years. The prevalence of deficiency risk according to socio-demographic, life-stage, dietary supplement use, and dietary adequacy categories was investigated. Thirty-one percent of the U.S. population was at risk of at least one vitamin deficiency or anemia, with 23%, 6.3%, and 1.7% of the U.S. population at risk of deficiency in 1, 2, or 3-5 vitamins or anemia, respectively. A significantly higher deficiency risk was seen in women (37%), non-Hispanic blacks (55%), individuals from low income households (40%), or without a high school diploma (42%), and underweight (42%) or obese individuals (39%). A deficiency risk was most common in women 19-50 years (41%), and pregnant or breastfeeding women (47%). Dietary supplement non-users had the highest risk of any deficiency (40%), compared to users of full-spectrum multivitamin-multimineral supplements (14%) and other dietary supplement users (28%). Individuals consuming an adequate diet based on the Estimated Average Requirement had a lower risk of any deficiency (16%) than those with an inadequate diet (57%). Nearly one-third of the U.S. population is at risk of deficiency in at least one vitamin, or has anemia. PMID- 28672792 TI - Biodegradable FeMnSi Sputter-Coated Macroporous Polypropylene Membranes for the Sustained Release of Drugs. AB - Pure Fe and FeMnSi thin films were sputtered on macroporous polypropylene (PP) membranes with the aim to obtain biocompatible, biodegradable and, eventually, magnetically-steerable platforms. Room-temperature ferromagnetic response was observed in both Fe- and FeMnSi-coated membranes. Good cell viability was observed in both cases by means of cytotoxicity studies, though the FeMnSi-coated membranes showed higher biodegradability than the Fe-coated ones. Various strategies to functionalize the porous platforms with transferrin-Alexa Fluor 488 (Tf-AF488) molecules were tested to determine an optimal balance between the functionalization yield and the cargo release. The distribution of Tf-AF488 within the FeMnSi-coated PP membranes, as well as its release and uptake by cells, was studied by confocal laser scanning microscopy. A homogeneous distribution of the drug within the membrane skeleton and its sustained release was achieved after three consecutive impregnations followed by the addition of a layer made of gelatin and maltodextrin, which prevented exceedingly fast release. The here-prepared organic-inorganic macroporous membranes could find applications as fixed or magnetically-steerable drug delivery platforms. PMID- 28672793 TI - Vitamin D: Daily vs. Monthly Use in Children and Elderly-What Is Going On? AB - Vitamin D deficiency is highly prevalent among children and adults worldwide. Agreement exists that vitamin D deficiency should be corrected. However, the definitions of vitamin deficiency and effective vitamin D replacement therapy are inconsistent in the literature. Not only is the dosing regimen still under debate, but also the time and period of administration (i.e., daily vs. monthly dose). In pediatric as well as elderly subjects, dosing regimens with high vitamin D doses at less frequent intervals were proposed to help increase compliance to treatment: these became widespread in clinical practice, despite mounting evidence that such therapies are not only ineffective but potentially harmful, particularly in elderly subjects. Moreover, in the elderly, high doses of vitamin D seem to increase the risk of functional decline and are associated with a higher risk of falls and fractures. Achieving good adherence to recommended prophylactic regimens is definitely one of the obstacles currently being faced in view of the wide segment of the population liable to the treatment and the very long duration of prophylaxis. The daily intake for extended periods is in fact one of the frequent causes of therapeutic drop-outs, while monthly doses of vitamin D may effectively and safely improve patient compliance to the therapy. The aim of our paper is a quasi-literature review on dosing regimens among children and elderly. These two populations showed a particularly significant beneficial effect on bone metabolism, and there could be different outcomes with different dosing regimens. PMID- 28672795 TI - A Direct Georeferencing Method for Terrestrial Laser Scanning Using GNSS Data and the Vertical Deflection from Global Earth Gravity Models. AB - Terrestrial laser scanning is an efficient technique in providing highly accurate point clouds for various geoscience applications. The point clouds have to be transformed to a well-defined reference frame, such as the global Geodetic Reference System 1980. The transformation to the geocentric coordinate frame is based on estimating seven Helmert parameters using several GNSS (Global Navigation Satellite System) referencing points. This paper proposes a method for direct point cloud georeferencing that provides coordinates in the geocentric frame. The proposed method employs the vertical deflection from an external global Earth gravity model and thus demands a minimum number of GNSS measurements. The proposed method can be helpful when the number of georeferencing GNSS points is limited, for instance in city corridors. It needs only two georeferencing points. The validation of the method in a field test reveals that the differences between the classical georefencing and the proposed method amount at maximum to 7 mm with the standard deviation of 8 mm for all of three coordinate components. The proposed method may serve as an alternative for the laser scanning data georeferencing, especially when the number of GNSS points is insufficient for classical methods. PMID- 28672794 TI - Tear Film Steroid Profiling in Dry Eye Disease by Liquid Chromatography Tandem Mass Spectrometry. AB - Dry eye disease (DED) is a multifactorial disorder of the ocular surface unit resulting in eye discomfort, visual disturbance, and ocular surface damage; the risk of DED increases with age in both sexes, while its incidence is higher among females caused by an overall hormonal imbalance. The role of androgens has recently investigated and these hormones were considered to have a protective function on the ocular surface. In order to correlate DED to tear steroid levels, a robust, specific, and selective method for the simultaneous quantification of cortisol (CORT), corticosterone (CCONE), 11-deoxycortisol (11-DECOL), 4 androstene-3,17-dione (ADIONE), testosterone (TESTO), 17alpha-hydroxyprogesterone (17-OHP), and progesterone (PROG) was developed and applied for the analysis of tear samples. The method involves a simple extraction procedure of steroids from tears collected on Schirmer strips, followed by a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. In total, tear samples from 14 DED female patients and 13 healthy female controls were analysed and, CORT, ADIONE, and 17-OHP response levels resulted significantly decreased in dry eye patients respect to controls. The receiver operating characteristic (ROC) curve obtained by the combination of these three steroids (AUC = 0.964) demonstrated the good diagnostic power of the differential tear steroids in identifying DED. In conclusion, the present method made it possible, for the first time, to study steroid profiling directly in tear fluid. PMID- 28672796 TI - Slab Waveguide and Optical Fibers for Novel Plasmonic Sensor Configurations. AB - The use of plasmonic sensor devices often requires replaceable parts and disposable chips for easy, fast and on-site detection analysis. In light of these requests, we propose a novel low-cost surface plasmon resonance sensor platform for possible selective detection of analytes in aqueous solutions. It is based on a Polymethyl methacrylate (PMMA) slab waveguide with a thin gold film on the top surface inserted in a special holder, designed to produce the plasmonic resonance at the gold-dielectric interface. A wide-band light is launched in the PMMA slab waveguide through a trench realized in the holder directly, and illuminated with a PMMA plastic optical fiber (POF) to excite surface Plasmon waves. The output light is then collected by another PMMA POF kept at the end of the slab at an angle of 90 degrees to the trench, and carried to a spectrometer. In this configuration, the trench has been used because a large incident angle is required for surface plasmon resonance excitation. The preliminary results showed that the sensor's performances make it suitable for bio-chemical applications. The easy replacement of the chip allows for the production of an engineered platform by simplifying the measurement procedures. PMID- 28672797 TI - Integrity and Quantity of Total Cell-Free DNA in the Diagnosis of Thyroid Cancer: Correlation with Cytological Classification. AB - Cell-free DNA (cfDNA) quantity and quality in plasma has been investigated as a non-invasive biomarker in cancer. Previous studies have demonstrated increased cfDNA amount and length in different types of cancer with respect to healthy controls. The present study aims to test the hypothesis that the presence of longer DNA strands circulating in plasma can be considered a biomarker for tumor presence in thyroid cancer. We adopted a quantitative real-time PCR (qPCR) approach based on the quantification of two amplicons of different length (67 and 180 bp respectively) to evaluate the integrity index 180/67. Cell-free DNA quantity and integrity were higher in patients affected by nodular thyroid diseases than in healthy controls. Importantly, cfDNA integrity index was higher in patients with cytological diagnosis of thyroid carcinoma (Thy4/Thy5) than in subjects with benign nodules (Thy2). Therefore, cfDNA integrity index 180/67 is a suitable parameter for monitoring cfDNA fragmentation in thyroid cancer patients and a promising circulating biomarker in the diagnosis of thyroid nodules. PMID- 28672798 TI - A Real-Time Contactless Pulse Rate and Motion Status Monitoring System Based on Complexion Tracking. AB - Subject movement and a dark environment will increase the difficulty of image based contactless pulse rate detection. In this paper, we detected the subject's motion status based on complexion tracking and proposed a motion index (MI) to filter motion artifacts in order to increase pulse rate measurement accuracy. Additionally, we integrated the near infrared (NIR) LEDs with the adopted sensor and proposed an effective method to measure the pulse rate in a dark environment. To achieve real-time data processing, the proposed framework is constructed on a Field Programmable Gate Array (FPGA) platform. Next, the instant pulse rate and motion status are transmitted to a smartphone for remote monitoring. The experiment results showed the error of the pulse rate detection to be within 3.44 to +4.53 bpm under sufficient ambient light and -2.96 to + 4.24 bpm for night mode detection, when the moving speed is higher than 14.45 cm/s. These results demonstrate that the proposed method can improve the robustness of image based contactless pulse rate detection despite subject movement and a dark environment. PMID- 28672799 TI - Exosomal MicroRNAs in Breast Cancer towards Diagnostic and Therapeutic Applications. AB - Soon after the discovery of microRNAs over 15 years ago, a myriad of research groups around the world sought to develop clinical applications in breast cancer for these short, noncoding, regulatory RNAs. While little of this knowledge has translated into the clinic, the recent research explosion on cell-to-cell communication via exosomes and other extracellular vesicles has rekindled interest in microRNA-based clinical applications. microRNAs appear to be a preferential and important cargo of exosomes in mediating biological effects in recipient cells. This review highlights recent studies on the biology of exosomal microRNAs (exo-miRNAs) and discusses potential clinical applications. From a diagnostic perspective, circulating exo-miRNAs may represent breast cancer cell content and/or tumor microenvironmental reactions to cancer cell growth. Thus, serum or plasma analysis of exo-miRNAs could be useful for early disease detection or for monitoring treatment response and disease progression. From a therapeutic perspective, exo-miRNAs derived from different cell types have been implicated in supporting or restraining tumor growth, conferring drug resistance, and preparing the metastatic niche. Strategies to interfere with the loading or delivery of tumor-promoting exo-miRNAs or to replenish tumor-suppressive miRNAs via exosomal delivery are under investigation. These recent studies provide new hope and opportunities, but study design limitations and technical challenges will need to be overcome before seriously considering clinical application of exo miRNAs. PMID- 28672800 TI - Use of Vegetable Fibers for PRB to Remove Heavy Metals from Contaminated Aquifers Comparisons among Cabuya Fibers, Broom Fibers and ZVI. AB - The Zero Valent Iron (ZVI) is the material most commonly used for permeable reactive barriers (PRB). For technical and economic reasons, hoter reactive substances usable in alternative to ZVI are investigated. The present study takes into account a vegetable fibers, the cabuya, investigating its capacity to retain heavy metals. The capacity of the cabuya fibers to adsorb heavy metals was verified in laboratory, by batch and column tests. The batch tests were carried out with cabuya and ZVI, using copper (Cu), zinc (Zn), cadmium (Cd) and lead (Pb). The results obtained by the cabuya fibers showed a very high adsorption capacity of heavy metals and resulted very similar to those obtained for the broom fibers in a previous study. The high value of the absorption capacity of the cabuya fibers was also confirmed by the analogous comparison made with the results of the batch tests carried out with ZVI. Column tests, using copper, zinc and cadmium, allowed to determine for the cabuya fibers the maximum removal percentage of the heavy metals considered, the corresponding times and the time ranges of the release phase. For each metal considered, for a given length and three different times, the constant of degradation of cabuya fibers was determined, obtaining values very close to those reported for broom fibers. The scalar behavior of heavy metal removal percentage was verified. An electron microscope analysis allowed to compare, by SEM images, the characteristics of the cabuya and broom fibers. Finally, to investigate the chemical structure of cabuya and broom fibers, the FTIR technique was used, obtaining their respective infrared spectra. PMID- 28672802 TI - Bioethical Considerations of Advancing the Application of Marine Biotechnology and Aquaculture. AB - Normative ethical considerations of growth of the marine biotechnology and aquaculture disciplines in biopharming, food production, and marine products commercialization from a bioethical perspective have been limited. This paucity of information begs the question of what constitutes a bioethical approach (i.e., respect for individuals or autonomy; beneficence, nonmaleficence, and justice) to marine biotechnology and aquaculture, and whether it is one that is appropriate for consideration. Currently, thoughtful discussion on the bioethical implications of use, development, and commercialization of marine organisms or their products, as well as potential environmental effects, defaults to human biomedicine as a model. One must question the validity of using human bioethical principlism moral norms for appropriating a responsible marine biotechnology and aquaculture ethic. When considering potential impacts within these disciplines, deference must be given to differing value systems in order to find common ground to advance knowledge and avoid emotive impasses that can hinder the science and its application. The import of bioethical considerations when conducting research and/or production is discussed. This discussion is directed toward applying bioethical principles toward technology used for food, biomedical development (e.g., biopharming), or as model species for advancement of knowledge for human diseases. PMID- 28672801 TI - MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury. AB - Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of miR-210 provided neuroprotection in neonatal HI brain injury. The present study aims to determine the role of miR-210 in the regulation of BBB integrity in the developing brain. miR-210 mimic was administered via intracerebroventricular injection (i.c.v.) into the brain of rat pups. Forty-eight hours after the injection, a modified Rice-Vannucci model was conducted to produce HI brain injury. Post-assays included cerebral edema analysis, western blotting, and immunofluorescence staining for serum immunoglobulin G (IgG) leakage. The results showed that miR-210 mimic exacerbated cerebral edema and IgG leakage into the brain parenchyma. In contrast, inhibition of miR-210 with its complementary locked nucleic acid oligonucleotides (miR-210 LNA) significantly reduced cerebral edema and IgG leakage. These findings suggest that miR-210 negatively regulates BBB integrity i n the neonatal brain. Mechanistically, the seed sequences of miR-210 were identified complementary to the 3' untranslated region (3' UTR) of the mRNA transcripts of tight junction protein occludin and adherens junction protein beta-catenin, indicating downstream targets of miR-210. This was further validated by in vivo data showing that miR-210 mimic significantly reduced the expression of these junction proteins in rat pup brains. Of importance, miR-210-LNA preserved the expression of junction proteins occludin and beta-catenin from neonatal HI insult. Altogether, the present study reveals a novel mechanism of miR-210 in impairing BBB integrity that contributes to cerebral edema formation after neonatal HI insult, and provides new insights in miR-210-LNA mediated neuroprotection in neonatal HI brain injury. PMID- 28672803 TI - Static and Dynamic Accuracy of an Innovative Miniaturized Wearable Platform for Short Range Distance Measurements for Human Movement Applications. AB - Magneto-inertial measurement units (MIMU) are a suitable solution to assess human motor performance both indoors and outdoors. However, relevant quantities such as step width and base of support, which play an important role in gait stability, cannot be directly measured using MIMU alone. To overcome this limitation, we developed a wearable platform specifically designed for human movement analysis applications, which integrates a MIMU and an Infrared Time-of-Flight proximity sensor (IR-ToF), allowing for the estimate of inter-object distance. We proposed a thorough testing protocol for evaluating the IR-ToF sensor performances under experimental conditions resembling those encountered during gait. In particular, we tested the sensor performance for different (i) target colors; (ii) sensor target distances (up to 200 mm) and (iii) sensor-target angles of incidence (AoI) (up to 60 ? ). Both static and dynamic conditions were analyzed. A pendulum, simulating the oscillation of a human leg, was used to generate highly repeatable oscillations with a maximum angular velocity of 6 rad/s. Results showed that the IR-ToF proximity sensor was not sensitive to variations of both distance and target color (except for black). Conversely, a relationship between error magnitude and AoI values was found. For AoI equal to 0 ? , the IR-ToF sensor performed equally well both in static and dynamic acquisitions with a distance mean absolute error <1.5 mm. Errors increased up to 3.6 mm (static) and 11.9 mm (dynamic) for AoI equal to +/- 30 ? , and up to 7.8 mm (static) and 25.6 mm (dynamic) for AoI equal to +/- 60 ? . In addition, the wearable platform was used during a preliminary experiment for the estimation of the inter-foot distance on a single healthy subject while walking. In conclusion, the combination of magneto inertial unit and IR-ToF technology represents a valuable alternative solution in terms of accuracy, sampling frequency, dimension and power consumption, compared to existing technologies. PMID- 28672804 TI - Wage Differentials between Heat-Exposure Risk and No Heat-Exposure Risk Groups. AB - The goal of this study is to investigate the wage differential between groups of workers who are exposed to heat and those who are not. Workers in the heat exposure risk group are defined as workers who work in conditions that cause them to spend more than 25% of their work hours at high temperatures. To analyze the wage differential, the Blinder-Oaxaca and Juhn-Murphy-Pierce methods were applied to Korea Working Condition Survey data. The results show that the no heat exposure risk group received higher wages. In most cases, this can be interpreted as the endowment effect of human capital. As a price effect that lowers the endowment effect, the compensating differential for the heat-exposure risk group was found to be 1%. Moreover, education level, work experience, and employment status counteracted the compensating differentials for heat-exposure risks. A comparison of data sets from 2011 and 2014 shows that the increasing wage gap between the two groups was not caused by systematic social discrimination factors. This study suggests that wage differential factors can be modified for thermal environmental risks that will change working conditions as the impact of climate change increases. PMID- 28672805 TI - Epigenetic Regulation of the Epithelial to Mesenchymal Transition in Lung Cancer. AB - Lung cancer is the leading cause of cancer deaths worldwide. It is an aggressive and devastating cancer because of metastasis triggered by enhanced migration and invasion, and resistance to cytotoxic chemotherapy. The epithelial to mesenchymal transition (EMT) is a fundamental developmental process that is reactivated in wound healing and a variety of diseases including cancer where it promotes migration/invasion and metastasis, resistance to treatment, and generation and maintenance of cancer stem cells. The induction of EMT is associated with reprogramming of the epigenome. This review focuses on major mechanisms of epigenetic regulation mainly in lung cancer with recent data on EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit ), the catalytic subunit of the PRC2 (Polycomb Group PcG), that behaves as an oncogene in lung cancer associated with gene repression, non-coding RNAs and the epitranscriptome. PMID- 28672806 TI - Phenotypic Discordance in Siblings with Identical Compound Heterozygous PARK2 Mutations. AB - PARK2 mutations are the most common cause of early-onset Parkinson's disease. No genotype-phenotype correlation exists, and phenotypic variability is quite common. We report two siblings with confirmed identical compound heterozygous mutations in the PARK2 gene manifesting strikingly different phenotypes. The older brother demonstrated marked parkinsonism by his mid-20's, whereas the younger brother developed exercise-induced dystonia in his mid-30's with no subsequent clinical progression, highlighting the clinical heterogeneity of the disease and implying the role of other genetic and/or environmental factors in disease progression. The younger sibling, despite his mild symptoms, had a clearly abnormal dopamine transporter (DaT)-SPECT scan. To our knowledge, this is the first such reported case of an abnormal DaT-SPECT scan in a patient with biallelic PARK2 mutations who does not meet the clinical criteria for Parkinson's disease. PMID- 28672807 TI - Solvent-Free Microwave-Assisted Extraction of Polyphenols from Olive Tree Leaves: Antioxidant and Antimicrobial Properties. AB - Response surface methodology (RSM) and artificial neural networks (ANN) were evaluated and compared in order to decide which method was the most appropriate to predict and optimize total phenolic content (TPC) and oleuropein yields in olive tree leaf (Oleaeuropaea) extracts, obtained after solvent-free microwave assisted extraction (SFMAE). The SFMAE processing conditions were: microwave irradiation power 250-350 W, extraction time 2-3 min, and the amount of sample 5 10 g. Furthermore, the antioxidant and antimicrobial activities of the olive leaf extracts, obtained under optimal extraction conditions, were assessed by several in vitro assays. ANN had better prediction performance for TPC and oleuropein yields compared to RSM. The optimum extraction conditions to recover both TPC and oleuropein were: irradiation power 250 W, extraction time 2 min, and amount of sample 5 g, independent of the method used for prediction. Under these conditions, the maximal yield of oleuropein (0.060 +/- 0.012 ppm) was obtained and the amount of TPC was 2.480 +/- 0.060 ppm. Moreover, olive leaf extracts obtained under optimum SFMAE conditions showed antibacterial activity against S.aureus and S.epidermidis, with a minimum inhibitory concentration (MIC) value of 1.25 mg/mL. PMID- 28672808 TI - Ecosystem-Based Incorporation of Nectar-Producing Plants for Stink Bug Parasitoids. AB - Adult parasitoids of pest insects rely on floral resources for survival and reproduction, but can be food-deprived in intensively managed agricultural systems lacking these resources. Stink bugs are serious pests for crops in southwest Georgia. Provisioning nectar-producing plants for parasitoids of stink bugs potentially can enhance biocontrol of these pests. Knowledge of spatial and temporal availability and distribution of stink bugs in host plants is necessary for appropriate timing and placement of flowering plants in agroecosystems. Stink bugs move between closely associated host plants throughout the growing season in response to deteriorating suitability of their host plants. In peanut-cotton farmscapes, stink bugs develop in peanut, and subsequently the adults disperse into adjacent cotton. Parasitism of Nezara viridula (L.) adults by Trichopoda pennipes (F.) at the peanut-cotton interface was significantly higher in cotton with a strip of milkweed or buckwheat between the two crops than in cotton alone. Milkweed and buckwheat also provided nectar to a wide range of insect pollinators. Monarch butterflies fed on milkweed. When placed between peanut and cotton, a strip of soybean was an effective trap crop for cotton, reducing economic damage. Incorporation of buckwheat near soybean enhanced parasitism of Euschistus servus (Say) eggs by Telenomus podisi Ashmead in cotton. In conclusion, nectar provision enhances biocontrol of stink bugs, acts together with other management tactics for stink bug control, and aids in conservation of natural enemies, insect pollinators, and the monarch butterfly. PMID- 28672810 TI - Development and Characterization of an Amorphous Solid Dispersion of Furosemide in the Form of a Sublingual Bioadhesive Film to Enhance Bioavailability. AB - Administered by an oral route, Furosemide (FUR), a diuretic used in several edematous states and hypertension, presents bioavailability problems, reported as a consequence of an erratic gastrointestinal absorption due to various existing polymorphic forms and low and pH-dependent solubility. A mucoadhesive sublingual fast-dissolving FUR based film has been developed and evaluated in order to optimize the bioavailability of FUR by increasing solubility and guaranteeing a good dissolution reproducibility. The Differential Scanning Calorimetry (DSC) analyses confirmed that the film prepared using the solvent casting method entrapped FUR in the amorphous state. As a solid dispersion, FUR increases its solubility up to 28.36 mg/mL. Drug content, thickness, and weight uniformity of film were also evaluated. The measured Young's Modulus, yield strength, and relative elongation of break percentage (EB%) allowed for the classification of the drug-loaded film as an elastomer. Mucoadhesive strength tests showed that the force to detach film from mucosa grew exponentially with increasing contact time up to 7667 N/m2. FUR was quickly discharged from the film following a trend well fitted with the Weibull kinetic model. When applied on sublingual mucosa, the new formulation produced a massive drug flux in the systemic compartment. Overall, the proposed sublingual film enhances drug solubility and absorption, allowing for the prediction of a rapid onset of action and reproducible bioavailability in its clinical application. PMID- 28672809 TI - Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells. AB - Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001). Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies. PMID- 28672812 TI - In-Depth Proteomic Analysis of the Hippocampus in a Rat Model after Cerebral Ischaemic Injury and Repair by Danhong Injection (DHI). AB - Stroke is the second most common cause of death worldwide. A systematic description and characterization of the strokes and the effects induced in the hippocampus have not been performed so far. Here, we analysed the protein expression in the hippocampus 24 h after cerebral ischaemic injury and repair. Drug intervention using Danhong injection (DHI), which has been reported to have good therapeutic effects in a clinical setting, was selected for our study of cerebral ischaemia repair in rat models. A larger proteome dataset and total 4091 unique proteins were confidently identified in three biological replicates by combining tissue extraction for rat hippocampus and LC-MS/MS analysis. A label free approach was then used to quantify the differences among the four experimental groups (Naive, Sham, middle cerebral artery occlusion (MCAO) and MCAO + DHI groups) and showed that about 2500 proteins on average were quantified in each of the experiment group. Bioinformatics analysis revealed that in total 280 unique proteins identified above were differentially expressed (P < 0.05). By combining the subcellular localization, hierarchical clustering and pathway information with the results from injury and repair phase, 12 significant expressed proteins were chosen and verified with respect to their potential as candidates for cerebral ischaemic injury by Western blot. The primary three signalling pathways of the candidates related may be involved in molecular mechanisms related to cerebral ischaemic injury. In addition, a glycogen synthase kinase-3beta (Gsk-3beta) inhibitor of the candidates with the best corresponding expression trends between western blotting (WB) and label-free quantitative results were chosen for further validation. The results of Western blot analysis of protein expression and 2,3,5- chloride three phenyl tetrazole (TTC) staining of rat brains showed that DHI treatment and Gsk-3beta inhibitor are both able to confer protection against ischaemic injury in rat MCAO model. The observations of the present study provide a novel understanding regarding the regulatory mechanism of cerebral ischaemic injury. PMID- 28672811 TI - Hypotheses on the Potential of Rice Bran Intake to Prevent Gastrointestinal Cancer through the Modulation of Oxidative Stress. AB - Previous studies have suggested the potential involvement of oxidative stress in gastrointestinal cancers. In light of this, research efforts have been focused on the potential of dietary antioxidant intake to prevent gastrointestinal cancer through the modulation of oxidative stress. Rice bran, a by-product of rice milling, has been shown to contain an abundance of phytochemicals, which are dietary antioxidants. To date, a number of studies have shown the antioxidative effect of rice bran intake, and some demonstrated that such an effect may contribute to gastrointestinal cancer prevention, largely through the antioxidative properties of rice bran phytochemicals. In addition, these phytochemicals were shown to provide protection against cancer through mechanisms linked to oxidative stress, including beta-catenin-mediated cell proliferation and inflammation. The present article provides an overview of current evidence for the antioxidative properties of rice bran and its phytochemicals, and for the potential of such properties in cancer prevention through the oxidative-stress linked mechanisms mentioned above. The article also highlights the need for an evaluation of the effectiveness of rice bran dietary interventions among cancer survivors in ameliorating oxidative stress and reducing the level of gastrointestinal cancer biomarkers, thereby establishing the potential of such interventions among these individuals in the prevention of cancer recurrence. PMID- 28672813 TI - A Spaceborne Synthetic Aperture Radar Partial Fixed-Point Imaging System Using a Field- Programmable Gate Array-Application-Specific Integrated Circuit Hybrid Heterogeneous Parallel Acceleration Technique. AB - With the development of satellite load technology and very large scale integrated (VLSI) circuit technology, onboard real-time synthetic aperture radar (SAR) imaging systems have become a solution for allowing rapid response to disasters. A key goal of the onboard SAR imaging system design is to achieve high real-time processing performance with severe size, weight, and power consumption constraints. In this paper, we analyse the computational burden of the commonly used chirp scaling (CS) SAR imaging algorithm. To reduce the system hardware cost, we propose a partial fixed-point processing scheme. The fast Fourier transform (FFT), which is the most computation-sensitive operation in the CS algorithm, is processed with fixed-point, while other operations are processed with single precision floating-point. With the proposed fixed-point processing error propagation model, the fixed-point processing word length is determined. The fidelity and accuracy relative to conventional ground-based software processors is verified by evaluating both the point target imaging quality and the actual scene imaging quality. As a proof of concept, a field- programmable gate array-application-specific integrated circuit (FPGA-ASIC) hybrid heterogeneous parallel accelerating architecture is designed and realized. The customized fixed-point FFT is implemented using the 130 nm complementary metal oxide semiconductor (CMOS) technology as a co-processor of the Xilinx xc6vlx760t FPGA. A single processing board requires 12 s and consumes 21 W to focus a 50-km swath width, 5-m resolution stripmap SAR raw data with a granularity of 16,384 * 16,384. PMID- 28672814 TI - Gallic Acid Inhibited Matrix Invasion and AP-1/ETS-1-Mediated MMP-1 Transcription in Human Nasopharyngeal Carcinoma Cells. AB - Gallic acid is a trihydroxybenzoic acid found in natural herbal plants. Gallic acid has been reported to inhibit the migration and invasive capability of various cancers. Little is known about the underlying mechanisms of invasion responsible for cancer metastasis via gallic acid. The present study was intended to investigate the anti-invasive effect of gallic acid on human nasopharyngeal carcinoma cells (NPC-BM1) and its related mechanism. Gallic acid inhibited the invasion of NPC-BM1 cells dose- and time-dependently without significant cytotoxic effect. Affymetrix oligonucleotide microarray analysis revealed matrix metalloproteinase-1 (MMP-1) as the most down-regulated gene in NPC-BM1 cells by gallic acid. The cytosolic and secreted MMP-1 levels were both found to be inhibited by gallic acid as demonstrated by western blot analysis and ELISA respectively. The mRNA expression and transcription of MMP-1 gene was also down regulated as determined by RT/real-time PCR and promoter activity assay. The expression of two major transcription binding factors in the MMP-1 promoter, AP-1 and ETS-1, were demonstrated to be reduced by gallic acid in NPC-BM1 cells. The effect of gallic acid was associated with the inhibition of p38 MAPK signaling pathway. In addition, gallic acid enhanced the gene expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) which further suppressed the MMP 1 activity. These findings may be useful to develop a novel chemotherapeutic agent to inhibit the metastasis of nasopharyngeal cancer. PMID- 28672815 TI - Differential Metabolic Profiles during the Developmental Stages of Plant Parasitic Nematode Meloidogyne incognita. AB - Meloidogyne incognita is a common root-knot nematode with a wide range of plant hosts. We aimed to study the metabolites produced at each stage of the nematode life cycle to understand its development. Metabolites of Meloidogyne incognita were extracted at egg, J2, J3, J4, and female stages and 110 metabolites with available standards were quantified using CE-TOF/MS. Analyses indicated abundance of stage-specific metabolites with the exception of J3 and J4 stages which shared similar metabolic profiles. The egg stage showed increased abundance in glycolysis and energy metabolism related metabolites while the J2 metabolites are associated with tissue formation, motility, and neurotransmission. The J3 and J4 stages indicated amino acid metabolism and urea cycle- related metabolites. The female stage was characterized with polyamine synthesis, antioxidant activity, and synthesis of reproduction related metabolites. Such metabolic profiling helps us understand the dynamic physiological changes related to each developmental stage of the root-knot nematode life cycle. PMID- 28672816 TI - Augmented Anticancer Effects of Cantharidin with Liposomal Encapsulation: In Vitro and In Vivo Evaluation. AB - PEGylated liposomes have received much attention as pharmaceutical carriers to deliver chemotherapeutic agents for therapeutic purpose. The aim of this study was to prepare and characterize PEGylated liposome of cantharidin and investigate its therapeutic effect on human hepatocellular carcinoma treatment in vitro and in vivo. Liposomal cantharidin was evaluated for their anticancer effects in vitro using human hepatocellular carcinoma HepG2 cells and in vivo using HepG2 bearing nude mice compared to free drug. PEGylated liposome of cantharidin had a particle size of 129.9 nm and a high encapsulation efficacy of approximately 88.9%. The liposomal cantharidin had a higher anti-proliferative effect vis-a-vis free cantharidin in inducing G2/M cell cycle arrest and apoptosis. Liposomal cantharidin killed more HepG2 cancer cells at the same concentration equivalent to free cantharidin. Further study in vivo also showed that liposomal cantharidin achieved a higher tumor growth inhibition efficacy than free drug on hepatocellular carcinoma. As our study exhibited enhanced cytotoxicity against HepG2 cells and augmented tumor inhibitory effects in vivo, the results validate the potential value of cantharidin-liposome in improving the therapeutic efficacy of cantharidin for liver cancer. PMID- 28672817 TI - Rational Design of Cyclic Antimicrobial Peptides Based on BPC194 and BPC198. AB - A strategy for the design of antimicrobial cyclic peptides derived from the lead compounds c(KKLKKFKKLQ) (BPC194) and c(KLKKKFKKLQ) (BPC198) is reported. First, the secondary beta-structure of BPC194 and BPC198 was analyzed by carrying out molecular dynamics (MD) simulations. Then, based on the sequence pattern and the beta-structure of BPC194 or BPC198, fifteen analogues were designed and synthesized on solid-phase. The best peptides (BPC490, BPC918, and BPC924) showed minimum inhibitory concentration (MIC) values <6.2 MUM against Pseudomonas syringae pv. syringae and Xanthomonas axonopodis pv. vesicatoria, and an MIC value of 12.5 to 25 MUM against Erwinia amylovora, being as active as BPC194 and BPC198. Interestingly, these three analogues followed the structural pattern defined from the MD simulations of the parent peptides. Thus, BPC490 maintained the parallel alignment of the hydrophilic pairs K1-K8, K2-K7, and K4-K5, whereas BPC918 and BPC924 included the two hydrophilic interactions K3-Q10 and K5-K8. In short, MD simulations have proved to be very useful for ascertaining the structural features of cyclic peptides that are crucial for their biological activity. Such approaches could be further employed for the development of new antibacterial cyclic peptides. PMID- 28672818 TI - Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies. AB - A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin(r) by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products. PMID- 28672819 TI - Eu@C72: Computed Comparable Populations of Two Non-IPR Isomers. AB - Relative concentrations of six isomeric Eu@C 72 -one based on the IPR C 72 cage (i.e., obeying the isolated-pentagon rule, IPR), two cages with a pentagon pentagon junction (symmetries C 2 and C 2 v ), a cage with one heptagon, a cage with two heptagons, and a cage with two pentagon-pentagon fusions-are DFT computed using the Gibbs energy in a broad temperature interval. It is shown that the two non-IPR isomers with one pentagon-pentagon junction prevail at any relevant temperature and exhibit comparable populations. The IPR-satisfying structure is disfavored by both energy and entropy. PMID- 28672820 TI - Improved Method for Reliable HMW-GS Identification by RP-HPLC and SDS-PAGE in Common Wheat Cultivars. AB - The accurate identification of alleles for high-molecular weight glutenins (HMW GS) is critical for wheat breeding programs targeting end-use quality. RP-HPLC methods were optimized for separation of HMW-GS, resulting in enhanced resolution of 1By and 1Dx subunits. Statistically significant differences in retention times (RTs) for subunits corresponding to HMW-GS alleles were determined using 16 standard wheat cultivars with known HMW-GS compositions. Subunits that were not identified unambiguously by RP-HPLC were distinguished by SDS-PAGE or inferred from association with linked subunits. The method was used to verify the allelic compositions of 32 Korean wheat cultivars previously determined using SDS-PAGE and to assess the compositions of six new Korean cultivars. Three cultivars contained subunits that were identified incorrectly in the earlier analysis. The improved RP-HPLC method combined with conventional SDS-PAGE provides for accurate, efficient and reliable identification of HMW-GS and will contribute to efforts to improve wheat end-use quality. PMID- 28672821 TI - General Methodologies Toward cis-Fused Quinone Sesquiterpenoids. Enantiospecific Synthesis of the epi-Ilimaquinone Core Featuring Sc-Catalyzed Ring Expansion. AB - A stereocontrolled approach to the cis-decalin framework of clerodane diterpenes and biologically active quinone sesquiterpenes is reported. Starting from an inexpensive optically pure tetrahydroindanone, Birch reductive alkylation builds two new contiguous chiral centers-one of which is quaternary and all-carbon substituted. Also featured is a highly regioselective diazoalkane-carbonyl homologation reaction to prepare the 6,6-bicyclic skeleton. Therein, the utility of Sc(OTf)3 as a mild catalyst for formal 1C insertion in complex settings is demonstrated. PMID- 28672822 TI - Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors. AB - The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a beta-alanyl or nipecotyl spacer. All compounds 6a-l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles. PMID- 28672823 TI - Simultaneous Calibration: A Joint Optimization Approach for Multiple Kinect and External Cameras. AB - Camera calibration is a crucial problem in many applications, such as 3D reconstruction, structure from motion, object tracking and face alignment. Numerous methods have been proposed to solve the above problem with good performance in the last few decades. However, few methods are targeted at joint calibration of multi-sensors (more than four devices), which normally is a practical issue in the real-time systems. In this paper, we propose a novel method and a corresponding workflow framework to simultaneously calibrate relative poses of a Kinect and three external cameras. By optimizing the final cost function and adding corresponding weights to the external cameras in different locations, an effective joint calibration of multiple devices is constructed. Furthermore, the method is tested in a practical platform, and experiment results show that the proposed joint calibration method can achieve a satisfactory performance in a project real-time system and its accuracy is higher than the manufacturer's calibration. PMID- 28672824 TI - Myrtaceae Plant Essential Oils and their beta-Triketone Components as Insecticides against Drosophila suzukii. AB - Spotted wing drosophila (SWD, Drosophila suzukii (Matsumura), Diptera: Drosophilidae) is recognized as an economically important pest in North America and Europe as well as in Asia. Assessments were made for fumigant and contact toxicities of six Myrtaceae plant essential oils (EOs) and their components to find new alternative types of insecticides active against SWD. Among the EOs tested, Leptospermum citratum EO, consisting mainly of geranial and neral, exhibited effective fumigant activity. Median lethal dose (LD50; mg/L) values of L. citratum were 2.39 and 3.24 for males and females, respectively. All tested EOs except Kunzea ambigua EO exhibited effective contact toxicity. LD50 (ug/fly) values for contact toxicity of manuka and kanuka were 0.60 and 0.71, respectively, for males and 1.10 and 1.23, respectively, for females. The LD50 values of the other 3 EOs-L. citratum, allspice and clove bud were 2.11-3.31 and 3.53-5.22 for males and females, respectively. The non-polar fraction of manuka and kanuka did not show significant contact toxicity, whereas the polar and triketone fractions, composed of flavesone, isoleptospermone and leptospermone, exhibited efficient activity with the LD50 values of 0.13-0.37 and 0.22-0.57 ug/fly for males and females, respectively. Our results indicate that Myrtaceae plant EOs and their triketone components can be used as alternatives to conventional insecticides. PMID- 28672825 TI - Maitotoxin Is a Potential Selective Activator of the Endogenous Transient Receptor Potential Canonical Type 1 Channel in Xenopus laevis Oocytes. AB - Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels. PMID- 28672826 TI - Pathophysiology of Hemophilic Arthropathy. AB - Spontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy-a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the synovial tissue, articular cartilage, and subchondral bone, with early damages and molecular changes determining the perpetuation of a chronic inflammatory condition. Synovitis is one of the earliest complications of hemarthrosis, and is characterized by synovial hypertrophy, migration of inflammatory cells, and a high degree of neo-angiogenesis with subsequent bleeding. The pathogenic mechanisms and molecular pathways by which blood in the joint cavity causes articular cartilage and subchondral bone destruction have yet to be fully elucidated. Both cytokines and matrix metalloproteinases and hydroxyl radicals may induce chondrocyte apoptosis. Members of the tumor necrosis factor receptor superfamily (such as the molecular triad: osteoprotegerin-OPG; receptor activator of nuclear factor kappaB-RANK; RANK ligand-RANKL) seem instead to play a major role in the inflammatory process. These pathogenic processes interact with each other and ultimately lead to a fibrotic joint and the disabling condition characteristic of hemophilic arthropathy. PMID- 28672827 TI - Digital Microfluidics for Nucleic Acid Amplification. AB - Digital Microfluidics (DMF) has emerged as a disruptive methodology for the control and manipulation of low volume droplets. In DMF, each droplet acts as a single reactor, which allows for extensive multiparallelization of biological and chemical reactions at a much smaller scale. DMF devices open entirely new and promising pathways for multiplex analysis and reaction occurring in a miniaturized format, thus allowing for healthcare decentralization from major laboratories to point-of-care with accurate, robust and inexpensive molecular diagnostics. Here, we shall focus on DMF platforms specifically designed for nucleic acid amplification, which is key for molecular diagnostics of several diseases and conditions, from pathogen identification to cancer mutations detection. Particular attention will be given to the device architecture, materials and nucleic acid amplification applications in validated settings. PMID- 28672828 TI - Tunable Fano Resonance in Asymmetric MIM Waveguide Structure. AB - A plasmonic waveguide coupled system that uses a metal-insulator-metal (MIM) waveguide with two silver baffles and a coupled ring cavity is proposed in this study. The transmission properties of the plasmonic system were investigated using the finite element method. The simulation results show a Fano profile in the transmission spectrum, which was caused by the interaction of the broadband resonance of the Fabry-Perot (F-P) cavity and the narrow band resonance of the ring cavity. The Fabry-Perot (F-P) cavity in this case was formed by two silver baffles dividing the MIM waveguide. The maximum sensitivity of 718 nm/RIU and the maximum figure of merit of 4354 were achieved. Furthermore, the effects of the structural parameters of the F-P cavity and the ring cavity on the transmission properties of the plasmonic system were analyzed. The results can provide a guide for designing highly sensitive on-chip sensors based on surface plasmon polaritons. PMID- 28672830 TI - A Novel Range Compression Algorithm for Resolution Enhancement in GNSS-SARs. AB - In this paper, a novel range compression algorithm for enhancing range resolutions of a passive Global Navigation Satellite System-based Synthetic Aperture Radar (GNSS-SAR) is proposed. In the proposed algorithm, within each azimuth bin, firstly range compression is carried out by correlating a reflected GNSS intermediate frequency (IF) signal with a synchronized direct GNSS base-band signal in the range domain. Thereafter, spectrum equalization is applied to the compressed results for suppressing side lobes to obtain a final range-compressed signal. Both theoretical analysis and simulation results have demonstrated that significant range resolution improvement in GNSS-SAR images can be achieved by the proposed range compression algorithm, compared to the conventional range compression algorithm. PMID- 28672829 TI - Fexofenadine Suppresses Delayed-Type Hypersensitivity in the Murine Model of Palladium Allergy. AB - Palladium is frequently used in dental materials, and sometimes causes metal allergy. It has been suggested that the immune response by palladium-specific T cells may be responsible for the pathogenesis of delayed-type hypersensitivity in study of palladium allergic model mice. In the clinical setting, glucocorticoids and antihistamine drugs are commonly used for treatment of contact dermatitis. However, the precise mechanism of immune suppression in palladium allergy remains unknown. We investigated inhibition of the immune response in palladium allergic mice by administration of prednisolone as a glucocorticoid and fexofenadine hydrochloride as an antihistamine. Compared with glucocorticoids, fexofenadine hydrochloride significantly suppressed the number of T cells by interfering with the development of antigen-presenting cells from the sensitization phase. Our results suggest that antihistamine has a beneficial effect on the treatment of palladium allergy compared to glucocorticoids. PMID- 28672831 TI - Air Pollution Monitoring Design for Epidemiological Application in a Densely Populated City. AB - Introduction: Many studies have reported the association between air pollution and human health based on regulatory air pollution monitoring data. However, because regulatory monitoring networks were not designed for epidemiological studies, the collected data may not provide sufficient spatial contrasts for assessing such associations. Our goal was to develop a monitoring design supplementary to the regulatory monitoring network in Seoul, Korea. This design focused on the selection of 20 new monitoring sites to represent the variability in PM2.5 across people's residences for cohort studies. Methods: We obtained hourly measurements of PM2.5 at 37 regulatory monitoring sites in 2010 in Seoul, and computed the annual average at each site. We also computed 313 geographic variables representing various pollution sources at the regulatory monitoring sites, 31,097 children's homes from the Atopy Free School survey, and 412 community service centers in Seoul. These three types of locations represented current, subject, and candidate locations. Using the regulatory monitoring data, we performed forward variable selection and chose five variables most related to PM2.5. Then, k-means clustering was applied to categorize all locations into several groups representing a diversity in the spatial variability of the five selected variables. Finally, we computed the proportion of current to subject location in each cluster, and randomly selected new monitoring sites from candidate sites in the cluster with the minimum proportion until 20 sites were selected. Results: The five selected geographic variables were related to traffic or urbanicity with a cross-validated R2 value of 0.69. Clustering analysis categorized all locations into nine clusters. Finally, one to eight new monitoring sites were selected from five clusters. Discussion: The proposed monitoring design will help future studies determine the locations of new monitoring sites representing spatial variability across residences for epidemiological analyses. PMID- 28672832 TI - A Multi-Resolution Mode CMOS Image Sensor with a Novel Two-Step Single-Slope ADC for Intelligent Surveillance Systems. AB - In this paper, we present a multi-resolution mode CMOS image sensor (CIS) for intelligent surveillance system (ISS) applications. A low column fixed-pattern noise (CFPN) comparator is proposed in 8-bit two-step single-slope analog-to digital converter (TSSS ADC) for the CIS that supports normal, 1/2, 1/4, 1/8, 1/16, 1/32, and 1/64 mode of pixel resolution. We show that the scaled-resolution images enable CIS to reduce total power consumption while images hold steady without events. A prototype sensor of 176 * 144 pixels has been fabricated with a 0.18 MUm 1-poly 4-metal CMOS process. The area of 4-shared 4T-active pixel sensor (APS) is 4.4 MUm * 4.4 MUm and the total chip size is 2.35 mm * 2.35 mm. The maximum power consumption is 10 mW (with full resolution) with supply voltages of 3.3 V (analog) and 1.8 V (digital) and 14 frame/s of frame rates. PMID- 28672833 TI - Children with Physical Disabilities at School and Home: Physical Activity and Contextual Characteristics. AB - The purpose of this study was to assess the physical activity (PA) of children with physical disabilities (PD) in school and home settings and to simultaneously examine selected contextual characteristics in relation to PA in those settings. Children with PD (N = 35; Mean age = 15.67 +/- 4.30 years; 26 boys) were systematically observed using BEACHES (Behaviors of Eating and Activity for Children's Health: Evaluation System) at school (before school, recess, lunch break, after class) and at home (before dinner) during four normal school days. The children spent most of their time in all five settings being physically inactive, but had slightly more PA during recess and lunch break periods. Hierarchical multiple regression revealed that selected contextual characteristics explained 18.9-56.0% (p < 0.01) of the variance predicting moderate-to-vigorous physical activity (MVPA) after controlling for demographic variables. Prompts to be active were positively associated with MVPA at school and the presence of fathers and fathers being motivators at home. This study highlights how little PA that children with PD receive and identifies the importance of the provision of prompts for PA at both school and home with this special population. PMID- 28672834 TI - Individual and Combined Effects of Engineered Peptides and Antibiotics on Pseudomonas aeruginosa Biofilms. AB - Pseudomonas aeruginosa is involved in a variety of difficult-to-treat infections frequently due to biofilm formation. To identify useful antibiofilm strategies, this article evaluated efficacy of two newly engineered cationic antimicrobial peptides (17BIPHE2 and DASamP2), traditional antibiotics, and their combinations against biofilms at different stages. 17BIPHE2 is designed based on the 3D structure of human cathelicidin LL-37 and DASamP2 is derived from database screening. While both peptides show effects on bacterial adhesion, biofilm formation, and preformed biofilms, select antibiotics only inhibit biofilm formation, probably due to direct bacterial killing. In addition, the time dependence of biofilm formation and treatment in a static in vitro biofilm model was also studied. The initial bacterial inoculum determines the peptide concentration needed to inhibit biofilm growth. When the bacterial growth time is less than 8 h, the biomass in the wells can be dispersed by either antibiotics alone or peptides alone. However, nearly complete biofilm disruption can be achieved when both the peptide and antibiotics are applied. Our results emphasize the importance of antibiofilm peptides, early treatment using monotherapy, and the combination therapy for already formed biofilms of P. aeruginosa. PMID- 28672835 TI - Magnetic Solid-phase Extraction with Fe3O4/Molecularly Imprinted Polymers Modified by Deep Eutectic Solvents and Ionic Liquids for the Rapid Purification of Alkaloid Isomers (Theobromine and Theophylline) from Green Tea. AB - Different kinds of deep eutectic solvents (DES) based on choline chloride (ChCl) and ionic liquids (ILs) based on 1-methylimidazole were used to modify Fe3O4/molecularly imprinted polymers (Fe3O4/MIPs), and the resulting materials were applied for the rapid purification of alkaloid isomers (theobromine and theophylline) from green tea with magnetic solid-phase extraction (M-SPE). The M SPE procedure was optimized using the response surface methodology (RSM) to analyze the maximum conditions. The materials were characterized by Fourier transform infrared spectroscopy (FI-IR) and field emission scanning electron microscopy (FE-SEM). Compared to the ILs-Fe3O4/MIPs, the DESs-Fe3O4/MIPs were developed for the stronger recognition and higher recoveries of the isomers (theophylline and theobromine) from green tea, particularly DES-7-Fe3O4/MIPs. With RSM, the optimal recovery condition for theobromine and theophylline in the M-SPE were observed with ratio of methanol (80%) as the washing solution, methanol/acetic acid (HAc) (8:2) as the eluent at pH 3, and an eluent volume of 4 mL. The practical recoveries of theobromine and theophylline in green tea were 92.27% and 87.51%, respectively, with a corresponding actual extraction amount of 4.87 mg*g-1 and 5.07 mg*g-1. Overall, the proposed approach with the high affinity of Fe3O4/MIPs might offer a novel method for the purification of complex isomer samples. PMID- 28672836 TI - Sowing Seeds for Healthier Diets: Children's Perspectives on School Gardening. AB - School gardening programmes are among the most promising interventions to improve children's vegetable intake. Yet, low vegetable intake among children remains a persistent public health challenge. This study aimed to explore children's perspectives, experiences, and motivations concerning school gardening in order to better understand and increase its potential for health promotion. Using participant observation and semi-structured interviews, we provided 45 primary schoolchildren (9-10 years) from Amsterdam, who participated in a comprehensive year-round school gardening programme, the opportunity to share their experiences and ideas on school gardening. Children particularly expressed enjoyment of the outdoor gardening portion of the programme as it enabled them to be physically active and independently nurture their gardens. Harvesting was the children's favourite activity, followed by planting and sowing. In contrast, insufficient gardening time and long explanations or instructions were especially disliked. Experiencing fun and enjoyment appeared to play a vital role in children's motivation to actively participate. Children's suggestions for programme improvements included more autonomy and opportunities for experimentation, and competition elements to increase fun and variety. Our results indicate that gaining insight into children's perspectives allows matching school gardening programmes more to children's wishes and expectations, thereby potentially enhancing their intrinsic motivation for gardening and vegetable consumption. PMID- 28672837 TI - In silico Study of the Pharmacologic Properties and Cytotoxicity Pathways in Cancer Cells of Various Indolylquinone Analogues of Perezone. AB - Several indolylquinone analogues of perezone, a natural sesquiterpene quinone, were characterized in this work by theoretical methods. In addition, some physicochemical, toxicological and metabolic properties were predicted using bioinformatics software. The predicted physicochemical properties are in agreement with the solubility and cLogP values, the penetration across the cell membrane, and absorption values, as well as with a possible apoptosis-activated mechanism of cytotoxic action. The toxicological predictions suggest no mutagenic, tumorigenic or reproductive effects of the four target molecules. Complementarily, the results of a performed docking study show high scoring values and hydrogen bonding values in agreement with the cytotoxicity IC50 value ranking, i.e: indolylmenadione > indolylperezone > indolylplumbagine > indolylisoperezone. Consequently, it is possible to suggest an appropriate apoptotic pathway for each compound. Finally, potential metabolic pathways of the molecules were proposed. PMID- 28672839 TI - Calculation of Five Thermodynamic Molecular Descriptors by Means of a General Computer Algorithm Based on the Group-Additivity Method: Standard Enthalpies of Vaporization, Sublimation and Solvation, and Entropy of Fusion of Ordinary Organic Molecules and Total Phase-Change Entropy of Liquid Crystals. AB - The calculation of the standard enthalpies of vaporization, sublimation and solvation of organic molecules is presented using a common computer algorithm on the basis of a group-additivity method. The same algorithm is also shown to enable the calculation of their entropy of fusion as well as the total phase change entropy of liquid crystals. The present method is based on the complete breakdown of the molecules into their constituting atoms and their immediate neighbourhood; the respective calculations of the contribution of the atomic groups by means of the Gauss-Seidel fitting method is based on experimental data collected from literature. The feasibility of the calculations for each of the mentioned descriptors was verified by means of a 10-fold cross-validation procedure proving the good to high quality of the predicted values for the three mentioned enthalpies and for the entropy of fusion, whereas the predictive quality for the total phase-change entropy of liquid crystals was poor. The goodness of fit (Q2) and the standard deviation (sigma) of the cross-validation calculations for the five descriptors was as follows: 0.9641 and 4.56 kJ/mol (N = 3386 test molecules) for the enthalpy of vaporization, 0.8657 and 11.39 kJ/mol (N = 1791) for the enthalpy of sublimation, 0.9546 and 4.34 kJ/mol (N = 373) for the enthalpy of solvation, 0.8727 and 17.93 J/mol/K (N = 2637) for the entropy of fusion and 0.5804 and 32.79 J/mol/K (N = 2643) for the total phase-change entropy of liquid crystals. The large discrepancy between the results of the two closely related entropies is discussed in detail. Molecules for which both the standard enthalpies of vaporization and sublimation were calculable, enabled the estimation of their standard enthalpy of fusion by simple subtraction of the former from the latter enthalpy. For 990 of them the experimental enthalpy-of fusion values are also known, allowing their comparison with predictions, yielding a correlation coefficient R2 of 0.6066. PMID- 28672840 TI - Influence of Pyranose and Spacer Arm Structures on Phloem Mobility and Insecticidal Activity of New Tralopyril Derivatives. AB - Six new conjugates were designed and synthesized by introducing glucose, methyl glucuronate or glucuronic acid moieties on tralopyril. Phytotoxicity and phloem mobility results demonstrated that the introduction of glucose, methyl glucuronate or glucuronic acid moieties can simultaneously solve the tough phytotoxicity problem and phloem mobility transformation of tralopyril. Conjugates 12 and 18 containing the glucuronic acid moiety exhibited higher phloem mobility than conjugates 9, 11, 15 and 17. Conjugates 15, 17 and 18 with methoxymethyl groups on the tralopyril pyrrole nitrogen atom showed activity against Plutella xylostella, while conjugates 9, 11 and 12 with a methene group on the pyrrole N showed no activity. Cabbage roots were incubated in a buffered solution containing conjugates 15, 17 and 18 at 4 mM for 72 h. Only 18 showed systemic insecticidal activity with 100% mortalityagainst P. xylostella, while 15 and 17 showed lower activity andchlorfenapyr showed no activity. The glucuronic acid promoiety imparted more phloem mobility to tralopyril than glucose and methyl glucuronate. The methoxymethyl group bond on the tralopyril skeleton was the key factor in determining the insecticidal activity of the conjugates. A promising systemic proinsecticide containing glucuronic acid and tralopyril moieties was proposed. PMID- 28672838 TI - Recent Advances in Conotoxin Classification by Using Machine Learning Methods. AB - Conotoxins are disulfide-rich small peptides, which are invaluable peptides that target ion channel and neuronal receptors. Conotoxins have been demonstrated as potent pharmaceuticals in the treatment of a series of diseases, such as Alzheimer's disease, Parkinson's disease, and epilepsy. In addition, conotoxins are also ideal molecular templates for the development of new drug lead compounds and play important roles in neurobiological research as well. Thus, the accurate identification of conotoxin types will provide key clues for the biological research and clinical medicine. Generally, conotoxin types are confirmed when their sequence, structure, and function are experimentally validated. However, it is time-consuming and costly to acquire the structure and function information by using biochemical experiments. Therefore, it is important to develop computational tools for efficiently and effectively recognizing conotoxin types based on sequence information. In this work, we reviewed the current progress in computational identification of conotoxins in the following aspects: (i) construction of benchmark dataset; (ii) strategies for extracting sequence features; (iii) feature selection techniques; (iv) machine learning methods for classifying conotoxins; (v) the results obtained by these methods and the published tools; and (vi) future perspectives on conotoxin classification. The paper provides the basis for in-depth study of conotoxins and drug therapy research. PMID- 28672841 TI - Clinicopathological Phenotype and Genetics of X-Linked Dystonia-Parkinsonism (XDP; DYT3; Lubag). AB - X-linked dystonia-parkinsonism (XDP; OMIM314250), also referred to as DYT3 dystonia or "Lubag" disease, was first described as an endemic disease in the Philippine island of Panay. XDP is an adult-onset movement disorder characterized by progressive and severe dystonia followed by overt parkinsonism in the later years of life. Among the primary monogenic dystonias, XDP has been identified as a transcriptional dysregulation syndrome with impaired expression of the TAF1 (TATA box-binding protein associated factor 1) gene, which is a critical component of the cellular transcription machinery. The major neuropathology of XDP is progressive neuronal loss in the neostriatum (i.e., the caudate nucleus and putamen). XDP may be used as a human disease model to elucidate the pathomechanisms by which striatal neurodegeneration leads to dystonia symptoms. In this article, we introduce recent advances in the understanding of the interplay between pathophysiology and genetics in XDP. PMID- 28672842 TI - Tuning the Sensitivity of the PDR5 Promoter-Based Detection of Diclofenac in Yeast Biosensors. AB - The commonly used drug diclofenac is an important environmental anthropogenic pollutant. Currently, detection of diclofenac is mainly based on chemical and physical methods. Here we describe a yeast biosensor that drives the diclofenac dependent expression of a recombinant fluorescent protein from the authentic promoter of the PDR5 gene. This key component of the pleiotropic drug response encodes a multidrug transporter that is involved in cellular detoxification. We analyse the effects on diclofenac sensitivity of artificial PDR5 promoter derivatives in wild-type and various yeast mutant strains. This approach enabled us to generate sensor strains with elevated drug sensitivity. PMID- 28672843 TI - Applications of Functional Amyloids from Fungi: Surface Modification by Class I Hydrophobins. AB - Class I hydrophobins produced from fungi are amongst the first proteins recognized as functional amyloids. They are amphiphilic proteins involved in the formation of aerial structures such as spores or fruiting bodies. They form chemically robust layers which can only be dissolved in strong acids. These layers adhere to different surfaces, changing their wettability, and allow the binding of other proteins. Herein, the modification of diverse types of surfaces with Class I hydrophobins is reported, highlighting the applications of the coated surfaces. Indeed, these coatings can be exploited in several fields, spanning from biomedical to industrial applications, which include biosensing and textile manufacturing. PMID- 28672844 TI - 5-(3',4'-Dihydroxyphenyl-gamma-valerolactone), a Major Microbial Metabolite of Proanthocyanidin, Attenuates THP-1 Monocyte-Endothelial Adhesion. AB - Several metabolomics of polymeric flavan-3-ols have reported that proanthocyanidins are extensively metabolized by gut microbiota. 5-(3',4' dihydroxyphenyl)-gamma-valerolactone (DHPV) has been reported to be the major microbial metabolite of proanthocyanidins. We demonstrated that DHPV has stronger prevention effect on tumor necrosis factor (TNF)-alpha-stimulated adhesion of THP 1 human monocytic cells to human umbilical vein endothelial cells compared to its potential precursors such as procyanidin A1, A2, B1 and B2, (+)catechin, ( )epicatechin and its microbial metabolites such as 3-(3,4 dihydroxyphenyl)propionic acid and 2-(3,4-dihydroxyphenyl)acetic acid. Mechanism study showed that DHPV prevents THP-1 monocyte-endothelial cell adhesion by downregulating TNF-alpha-stimulated expressions of the two biomarkers of atherosclerosis such as vascular cell adhesion molecule-1 and monocyte chemotactic protein-1, activation of nuclear factor kappa B transcription and phosphorylation of I kappa-B kinase and IkappaBalpha. We suggested that DHPV has higher potentiality in prevention of atherosclerosis among the proanthocyanidin metabolites. PMID- 28672845 TI - Regional Variations in the Risk and Severity of Ciguatera Caused by Eating Moray Eels. AB - Moray eels (Gymnothorax species) from tropical waters have long been known to be high-risk species, and the consumption of particularly the viscera or ungutted eels can result in severe ciguatera (known as Gymnothorax or moray eel poisoning), characterized by prominent neurological features. In this review, the main objective was to describe the risk and severity of ciguatera caused by eating moray eels in different parts of the world. Moray eels can accumulate very high ciguatoxin (CTX) levels in the flesh and particularly the liver. Therefore, even the smaller ones can be toxic and the consumption of an average portion (particularly liver) can result in severe or fatal ciguatera. Moray eels (particularly when ungutted) must never be served in gatherings since they can cause mass poisoning because of their large sizes and high CTX levels. Apart from regulatory measures restricting or excluding access, the public should be repeatedly warned to avoid eating moray eels. PMID- 28672846 TI - Molecular Modeling of the Catalytic Domain of CyaA Deepened the Knowledge of Its Functional Dynamics. AB - Although CyaA has been studied for over three decades and revealed itself to be a very good prototype for developing various biotechnological applications, only a little is known about its functional dynamics and about the conformational landscape of this protein. Molecular dynamics simulations helped to clarify the view on these points in the following way. First, the model of interaction between AC and calmodulin (CaM) has evolved from an interaction centered on the surface between C-CaM hydrophobic patch and the alpha helix H of AC, to a more balanced view, in which the C-terminal tail of AC along with the C-CaM Calcium loops play an important role. This role has been confirmed by the reduction of the affinity of AC for calmodulin in the presence of R338, D360 and N347 mutations. In addition, enhanced sampling studies have permitted to propose a representation of the conformational space for the isolated AC. It remains to refine this representation using structural low resolution information measured on the inactive state of AC. Finally, due to a virtual screening study on another adenyl cyclase from Bacillus anthracis, weak inhibitors of AC have been discovered. PMID- 28672847 TI - Survey of Alternaria Toxins and Other Mycotoxins in Dried Fruits in China. AB - Occurrence of toxigenic molds and mycotoxins on dried fruits is a worldwide problem, but limited information is available in China. A total of 220 dried fruits (raisins, dried apricots, dates and wolfberries) purchased from China were analyzed for 17 mycotoxins (i.e., Alternaria toxins, ochratoxin A (OTA), patulin (PAT) and trichothecenes) by UPLC-MS/MS, combined with a single-step cleanup. The result showed that at least one mycotoxin was detected in 142 samples (64.6%). The lowest incidence of contaminated samples was observed in dried apricots (48.2%), and the highest incidence in dried wolfberries (83.3%). The Alternaria toxins seemed to be the major problem in dried fruits, rather than OTA or PAT. Tenuazonic acid (TeA) was the predominant mycotoxin, in both frequency and concentration, ranging from 6.9 to 5665.3 MUg kg-1, followed by tentoxin (TEN; 20.5%), and mycophenolic acid (MPA; 19.5%). Moreover, raisins are more likely to be contaminated with OTA than the other dried fruits. Penicillic acid (PA) was detected only in dried dates, and PAT was detected only in one apricot sample. In addition, our results also showed that the simultaneous presence of 2-4 mycotoxins was observed in 31.4% of dried fruits. TeA and TEN were the most frequent combination, detected in 29 (13.2%) samples, followed by TeA and MPA with a prevalence of 11.4%. Therefore, the results of this survey suggest the need for wider monitoring on the contamination of these mycotoxins, especially Alternaria toxins in agro-products, and indicate the importance of setting a maximum limit for Alternaria toxins in China. PMID- 28672848 TI - Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods. AB - As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand based three-dimensional quantitative structure-activity relationship (3D-QSAR) study by using both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches was carried out. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q2 = 0.587, non-cross-validated correlation coefficient R2ncv = 0.900 and predicted correlation coefficient for the test set of compounds R2pre = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT2A receptor. Meanwhile, as a docking supplementary tool to study the antagonists' conformation in the binding cavity, molecular dynamics (MD) simulation was also performed, providing further elucidation about the changes in the ligand-receptor complex. Lastly, some new molecules were also newly-designed based on the above results that are potential arylpiperazine antagonists of 5-HT2A receptor. We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antagonists as antidepressant drugs as well as exploring the interaction mechanism of 5-HT2A antagonists. PMID- 28672849 TI - Synergy of Iron Chelators and Therapeutic Peptide Sequences Delivered via a Magnetic Nanocarrier. AB - Here, we report the synthesis, characterization, and efficacy study of Fe/Fe3O4 nanoparticles that were co-labeled with a tumor-homing and membrane-disrupting oligopeptide and the iron-chelator Dp44mT, which belongs to the group of the thiosemicarbazones. Dp44mT and the peptide sequence PLFAERL(D[KLAKLAKKLAKLAK])CGKRK were tethered to the surface of Fe/Fe3O4 core/shell nanoparticles by utilizing dopamine-anchors. The 26-mer contains two important sequences, which are the tumor targeting peptide CGKRK, and D[KLAKLAK]2, known to disrupt the mitochondrial cell walls and to initiate programmed cell death (apoptosis). It is noteworthy that Fe/Fe3O4 nanoparticles can also be used for MRI imaging purposes in live mammals. In a first step of this endeavor, the efficacy of this nanoplatform has been tested on the highly metastatic 4T1 breast cancer cell line. At the optimal ratio of PLFAERD[KLAKLAK]2CGKRK to Dp44mT of 1 to 3.2 at the surface of the dopamine coated Fe/Fe3O4-nanocarrier, the IC50 value after 24 h of incubation was found to be 2.2 times lower for murine breast cancer cells (4T1) than for a murine fibroblast cell line used as control. Based on these encouraging results, the reported approach has the potential of leading to a new generation of nanoplatforms for cancer treatment with considerably enhanced selectivity towards tumor cells. PMID- 28672850 TI - Quality-of-Life (QOL) during Screening for Phase 1 Trial Studies in Patients with Advanced Solid Tumors and Its Impact on Risk for Serious Adverse Events. AB - Background: Serious adverse events (SAEs) and subject replacements occur frequently in phase 1 oncology clinical trials. Whether baseline quality-of-life (QOL) or social support can predict risk for SAEs or subject replacement among these patients is not known. Methods: Between 2011-2013, 92 patients undergoing screening for enrollment into one of 22 phase 1 solid tumor clinical trials at Roswell Park Cancer Institute were included in this study. QOL Questionnaires (EORTC QLQ-C30 and FACT-G), Medical Outcomes Study Social Support Survey (MOSSSS), Charlson comorbidity scores (CCS) and Royal Marsden scores (RMS) were obtained at baseline. Frequency of dose limiting toxicities (DLTs), subject replacement and SAEs that occurred within the first 4 cycles of treatment were recorded. Fisher's exact test and Mann-Whitney-Wilcoxon test were used to study the association between categorical and continuous variables, respectively. A linear transformation was used to standardize QOL scores. p-value <= 0.05 was considered statistically significant. Results: Baseline QOL, MOSSSS, CCS and RMS were not associated with subject replacement nor DLTs. Baseline EORTC QLQ-C30 scores were significantly lower among patients who encountered SAEs within the first 4 cycles (p = 0.04). Conclusions: Lower (worse) EORTC QLQ-C30 score at baseline is associated with SAE occurrence during phase 1 oncology trials. PMID- 28672852 TI - Novel Gas Sensor Arrays Based on High-Q SAM-Modified Piezotransduced Single Crystal Silicon Bulk Acoustic Resonators. AB - This paper demonstrates a novel micro-size (120 MUm * 200 MUm) piezoelectric gas sensor based on a piezotransduced single-crystal silicon bulk acoustic resonator (PSBAR). The PSBARs operate at 102 MHz and possess high Q values (about 2000), ensuring the stability of the measurement. A corresponding gas sensor array is fabricated by integrating three different self-assembled monolayers (SAMs) modified PSBARs. The limit of detection (LOD) for ethanol vapor is demonstrated to be as low as 25 ppm with a sensitivity of about 1.5 Hz/ppm. Two sets of identification code bars based on the sensitivities and the adsorption energy constants are utilized to successfully discriminate isopropanol (IPA), ethanol, hexane and heptane vapors at low and high gas partial pressures, respectively. The proposed sensor array shows the potential to form a portable electronic nose system for volatile organic compound (VOC) differentiation. PMID- 28672851 TI - The Role of Regular Eating and Self-Monitoring in the Treatment of Bulimia Nervosa: A Pilot Study of an Online Guided Self-Help CBT Program. AB - Background: Despite cognitive behavioural therapy (CBT) being regarded as the first-line treatment option for bulimia nervosa (BN), barriers such as its time consuming and expensive nature limit patient access. In order to broaden treatment availability and affordability, the efficacy and convenience of CBT could be improved through the use of online treatments and selective emphasis on its most 'potent' components of which behavioural techniques form the focus. Method: Twenty-six individuals with BN were enrolled in an online CBT-based self help programme and 17 completed four weeks of regular eating and food-monitoring using the online Food Diary tool. Participants were contacted for a weekly check in phone call and had their bulimic symptom severity assessed at five time points (baseline and weeks 1-4). Results: There was a significant decrease in the frequency of self-reported objective binge episodes, associated loss of control and objective binge days reported between pre- and post-treatment measures. Significant improvements were also observed in most subscales of the Eating Disorder Examination-Questionnaire. Conclusion: This study provides encouraging preliminary evidence of the potential of behavioural techniques of online CBT in the treatment of BN. Online therapy with this focus is potentially a viable and practical form of treatment delivery in this illness group. These preliminary findings support the need for larger studies using control groups. PMID- 28672853 TI - Assessment of Industrial Antimony Exposure and Immunologic Function for Workers in Taiwan. AB - This study investigated antimony exposure among employees in industries in Taiwan and evaluated whether their immunologic markers were associated with antimony exposure. We recruited 91 male workers and 42 male office administrators from 2 glass manufacturing plants, 1 antimony trioxide manufacturing plants, and 2 engineering plastic manufacturing plants. Air samples were collected at worksites and administrative offices, and each participant provided specimens of urine, blood, and hair to assay antimony levels. We also determined white blood cells, lymphocyte, and monocyte, IgA, IgE, and IgG in blood specimens. The mean antimony concentration in the air measured at worksites was much higher in the antimony trioxide plant (2.51 +/- 0.57 mg/m3) than in plastic plants (0.21 +/- 0.06 mg/m3) and glass plants (0.14 +/- 0.01 mg/m3). Antimony levels in blood, urine, and hair measured for participants were correlated with worksites and were higher in workers than in administrators. The mean serum IgG, IgA, and IgE levels were lower in workers than in administrators (p < 0.001). Serum IgA and IgE levels in participants were negatively associated with antimony levels in air samples of workplaces, and in blood, urine, and hairs of participants. Serum IgG and IgE of all participants were also negatively associated with antimony levels in their hairs. In conclusion, the antimony exposure is greater for workers employed in the five industrial plants than for administrators. This study suggests serum IgG, IgA, and IgE levels are negatively associated with antimony exposure. PMID- 28672854 TI - An Intervention to Reduce Bicycle Injuries among Middle School Students in Rural China. AB - This study aimed to evaluate the effectiveness of an intervention to reduce bicycle injuries among rural middle school students in China. A one-year cluster randomized controlled trial was conducted with seventh grade students from six middle schools in two towns in rural Chaoshan, China. The two towns were randomly assigned to either the intervention or control group. Road safety education materials, two lectures on road safety, and a series of health education activities were delivered to 1312 students in the intervention group over one year, and the content of the intervention included traffic safety knowledge, methods of preventing bicycle injury and management of bicycle injuries. Questionnaires weere administered to the two groups before and after the intervention to measure the incidence, cognitions, and behaviors related to bicycle injuries. The pre-intervention incidence of bicycle injuries exhibited no significant difference between the two groups, while the difference reached significance after the intervention (chi2 = 13.409, p < 0.001). In the intervention group, the incidence decreased significantly after the intervention (chi2 = 8.137, p = 0.004), while no significant change was observed in the control group. Publicity and education intervention measures have certain short term effects on the prevention of bicycle injuries among rural middle school students; we should approach intervention measures according to the characteristics of traffic injuries in different areas. PMID- 28672856 TI - Novel Hybrid Scheduling Technique for Sensor Nodes with Mixed Criticality Tasks. AB - Sensor networks become increasingly a key technology for complex control applications. Their potential use in safety- and time-critical domains has raised the need for task scheduling mechanisms specially adapted to sensor node specific requirements, often materialized in predictable jitter-less execution of tasks characterized by different criticality levels. This paper offers an efficient scheduling solution, named Hybrid Hard Real-Time Scheduling (H2RTS), which combines a static, clock driven method with a dynamic, event driven scheduling technique, in order to provide high execution predictability, while keeping a high node Central Processing Unit (CPU) utilization factor. From the detailed, integrated schedulability analysis of the H2RTS, a set of sufficiency tests are introduced and demonstrated based on the processor demand and linear upper bound metrics. The performance and correct behavior of the proposed hybrid scheduling technique have been extensively evaluated and validated both on a simulator and on a sensor mote equipped with ARM7 microcontroller. PMID- 28672857 TI - Erratum: Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study; Nutrients 2017, 9, 448. PMID- 28672855 TI - Ginsenoside Rh2 Improves Cardiac Fibrosis via PPARdelta-STAT3 Signaling in Type 1 Like Diabetic Rats. AB - Ginsenoside Rh2 (Rh2) is an active principal ingredient contained in ginseng (Panax ginseng Meyer), a medicinal herb used to enhance health worldwide. The present study is designed to investigate the effect of Rh2 on myocardial fibrosis in diabetic rats. In a streptozotocin-induced model of type-1 diabetic rats (STZ diabetic rats), the increased fasting blood glucose levels and heart weight/body weight (HW/BW) ratio were substantially alleviated by Rh2. Moreover, Rh2 improved cardiac performance in STZ-diabetic rats. Histological results from Masson staining showed that Rh2 attenuated cardiac fibrosis in STZ-diabetic rats. The effects of Rh2 were reversed by GSK0660 at a dose sufficient to inhibit peroxisome proliferator-activated receptor delta (PPARdelta) in STZ-diabetic rats. The role of PPARdelta was subsequently investigated in vitro. Rh2 restored the decreased PPARdelta expression level in high glucose-cultured cardiomyocytes. Moreover, increased protein levels of fibrotic signals, including signal transducer and activator of transcription 3 (STAT3), connective tissue growth factor (CCN2) and fibronectin, were reduced by Rh2 in high glucose-cultured cardiomyocytes. These effects of Rh2 were reversed by GSK0660 or siRNA specific for PPARdelta Taken together, PPARdelta activation may inhibit STAT3 activation to reduce CCN2 and fibronectin expression in diabetic rats with cardiac fibrosis. Moreover, Rh2 improves cardiac function and fibrosis by increasing PPARdelta signaling. Therefore, Rh2 is suitable to develop as an alternative remedy for cardiac fibrosis. PMID- 28672858 TI - Poecillastrosides, Steroidal Saponins from the Mediterranean Deep-Sea Sponge Poecillastra compressa (Bowerbank, 1866). AB - The first chemical investigation of the Mediterranean deep-sea sponge Poecillastra compressa (Bowerbank, 1866) led to the identification of seven new steroidal saponins named poecillastrosides A-G (1-7). All saponins feature an oxidized methyl at C-18 into a primary alcohol or a carboxylic acid. While poecillastrosides A-D (1-4) all contain an exo double bond at C-24 of the side chain and two osidic residues connected at O-2', poecillastrosides E-G (5-7) are characterized by a cyclopropane on the side-chain and a connection at O-3' between both sugar units. The chemical structures were elucidated through extensive spectroscopic analysis (High-Resolution Mass Spectrometry (HRESIMS), 1D and 2D NMR) and the absolute configurations of the sugar residues were assigned after acidic hydrolysis and cysteine derivatization followed by LC-HRMS analyses. Poecillastrosides D and E, bearing a carboxylic acid at C-18, were shown to exhibit antifungal activity against Aspergillus fumigatus. PMID- 28672859 TI - Astrocytic Expression of GSTA4 Is Associated to Dopaminergic Neuroprotection in a Rat 6-OHDA Model of Parkinson's Disease. AB - Idiopathic Parkinson's disease (PD) is a complex disease caused by multiple, mainly unknown, genetic and environmental factors. The Ventral root avulsion 1 (Vra1) locus on rat chromosome 8 includes the Glutathione S-transferase alpha 4 (Gsta4) gene and has been identified in crosses between Dark Agouti (DA) and Piebald Virol Glaxo (PVG) rat strains as being associated to neurodegeneration after nerve and brain injury. The Gsta4 protein clears lipid peroxidation by products, a process suggested to being implicated in PD. We therefore investigated whether PVG alleles in Vra1 are neuroprotective in a toxin-induced model of PD and if this effect is coupled to Gsta4. We performed unilateral 6 hydroxydopamine (6-OHDA) partial lesions in the striatum and compared the extent of neurodegeration in parental (DA) and congenic (DA.VRA1) rats. At 8 weeks after 6-OHDA lesion, DA.VRA1 rats displayed a higher density of remaining dopaminergic fibers in the dorsolateral striatum compared to DA rats (44% vs. 23%, p < 0.01), indicating that Vra1 alleles derived from the PVG strain protect dopaminergic neurons from 6-OHDA toxicity. Gsta4 gene expression levels in the striatum and midbrain were higher in DA.VRA1 congenic rats compared to DA at 2 days post lesion (p < 0.05). The GSTA4 protein co-localized with astrocytic marker GFAP, but not with neuronal marker NeuN or microglial marker IBA1, suggesting astrocyte specific expression. This is the first report on Vra1 protective effects on dopaminergic neurodegeneration and encourages further studies on Gsta4 in relation to PD susceptibility. PMID- 28672860 TI - UVA, UVB Light Doses and Harvesting Time Differentially Tailor Glucosinolate and Phenolic Profiles in Broccoli Sprouts. AB - Broccoli sprouts contain health-promoting glucosinolate and phenolic compounds that can be enhanced by applying ultraviolet light (UV). Here, the effect of UVA or UVB radiation on glucosinolate and phenolic profiles was assessed in broccoli sprouts. Sprouts were exposed for 120 min to low intensity and high intensity UVA (UVAL, UVAH) or UVB (UVBL, UVBH) with UV intensity values of 3.16, 4.05, 2.28 and 3.34 W/m2, respectively. Harvest occurred 2 or 24 h post-treatment; and methanol/water or ethanol/water (70%, v/v) extracts were prepared. Seven glucosinolates and 22 phenolics were identified. Ethanol extracts showed higher levels of certain glucosinolates such as glucoraphanin, whereas methanol extracts showed slight higher levels of phenolics. The highest glucosinolate accumulation occurred 24 h after UVBH treatment, increasing 4-methoxy-glucobrassicin, glucobrassicin and glucoraphanin by ~170, 78 and 73%, respectively. Furthermore, UVAL radiation and harvest 2 h afterwards accumulated gallic acid hexoside I (~14%), 4-O-caffeoylquinic acid (~42%), gallic acid derivative (~48%) and 1 sinapoyl-2,2-diferulolyl-gentiobiose (~61%). Increases in sinapoyl malate (~12%), gallotannic acid (~48%) and 5-sinapoyl-quinic acid (~121%) were observed with UVBH Results indicate that UV-irradiated broccoli sprouts could be exploited as a functional food for fresh consumption or as a source of bioactive phytochemicals with potential industrial applications. PMID- 28672861 TI - Free and Nanoencapsulated Tobramycin: Effects on Planktonic and Biofilm Forms of Pseudomonas. AB - Cystic fibrosis (CF) is a genetic disorder in which frequent pulmonary infections develop secondarily. One of the major pulmonary pathogens colonizing the respiratory tract of CF patients and causing chronic airway infections is Pseudomonasaeruginosa. Although tobramycin was initially effective against P. aeruginosa, tobramycin-resistant strains have emerged. Among the strategies for overcoming resistance to tobramycin and other antibiotics is encapsulation of the drugs in nanoparticles. In this study, we explored the antimicrobial activity of nanoencapsulated tobramycin, both in solid lipid nanoparticles (SLN) and in nanostructured lipid carriers (NLC), against clinical isolates of P. aeruginosa obtained from CF patients. We also investigated the efficacy of these formulations in biofilm eradication. In both experiments, the activities of SLN and NLC were compared with that of free tobramycin. The susceptibility of planktonic bacteria was determined using the broth microdilution method and by plotting bacterial growth. The minimal biofilm eradication concentration (MBEC) was determined to assess the efficacy of the different tobramycin formulations against biofilms. The activity of tobramycin-loaded SLN was less than that of either tobramycin-loaded NLC or free tobramycin. The minimum inhibitory concentration (MIC) and MBEC of nanoencapsulated tobramycin were slightly lower (1-2 logs) than the corresponding values of the free drug when determined in tobramycin-susceptible isolates. However, in tobramycin-resistant strains, the MIC and MBEC did not differ between either encapsulated form and free tobramycin. Our results demonstrate the efficacy of nanoencapsulated formulations in killing susceptible P. aeruginosa from CF and from other patients. PMID- 28672862 TI - Does RAIM with Correct Exclusion Produce Unbiased Positions? AB - As the navigation solution of exclusion-based RAIM follows from a combination of least-squares estimation and a statistically based exclusion-process, the computation of the integrity of the navigation solution has to take the propagated uncertainty of the combined estimation-testing procedure into account. In this contribution, we analyse, theoretically as well as empirically, the effect that this combination has on the first statistical moment, i.e., the mean, of the computed navigation solution. It will be shown, although statistical testing is intended to remove biases from the data, that biases will always remain under the alternative hypothesis, even when the correct alternative hypothesis is properly identified. The a posteriori exclusion of a biased satellite range from the position solution will therefore never remove the bias in the position solution completely. PMID- 28672863 TI - Development of a Computer Writing System Based on EOG. AB - The development of a novel computer writing system based on eye movements is introduced herein. A system of these characteristics requires the consideration of three subsystems: (1) A hardware device for the acquisition and transmission of the signals generated by eye movement to the computer; (2) A software application that allows, among other functions, data processing in order to minimize noise and classify signals; and (3) A graphical interface that allows the user to write text easily on the computer screen using eye movements only. This work analyzes these three subsystems and proposes innovative and low cost solutions for each one of them. This computer writing system was tested with 20 users and its efficiency was compared to a traditional virtual keyboard. The results have shown an important reduction in the time spent on writing, which can be very useful, especially for people with severe motor disorders. PMID- 28672864 TI - Vicarious Calibration of sUAS Microbolometer Temperature Imagery for Estimation of Radiometric Land Surface Temperature. AB - In recent years, the availability of lightweight microbolometer thermal cameras compatible with small unmanned aerial systems (sUAS) has allowed their use in diverse scientific and management activities that require sub-meter pixel resolution. Nevertheless, as with sensors already used in temperature remote sensing (e.g., Landsat satellites), a radiance atmospheric correction is necessary to estimate land surface temperature. This is because atmospheric conditions at any sUAS flight elevation will have an adverse impact on the image accuracy, derived calculations, and study replicability using the microbolometer technology. This study presents a vicarious calibration methodology (sUAS specific, time-specific, flight-specific, and sensor-specific) for sUAS temperature imagery traceable back to NIST-standards and current atmospheric correction methods. For this methodology, a three-year data collection campaign with a sUAS called "AggieAir", developed at Utah State University, was performed for vineyards near Lodi, California, for flights conducted at different times (early morning, Landsat overpass, and mid-afternoon") and seasonal conditions. From the results of this study, it was found that, despite the spectral response of microbolometer cameras (7.0 to 14.0 MUm), it was possible to account for the effects of atmospheric and sUAS operational conditions, regardless of time and weather, to acquire accurate surface temperature data. In addition, it was found that the main atmospheric correction parameters (transmissivity and atmospheric radiance) significantly varied over the course of a day. These parameters fluctuated the most in early morning and partially stabilized in Landsat overpass and in mid-afternoon times. In terms of accuracy, estimated atmospheric correction parameters presented adequate statistics (confidence bounds under +/ 0.1 for transmissivity and +/-1.2 W/m2/sr/um for atmospheric radiance, with a range of RMSE below 1.0 W/m2/sr/um) for all sUAS flights. Differences in estimated temperatures between original thermal image and the vicarious calibration procedure reported here were estimated from -5 degrees C to 10 degrees C for early morning, and from 0 to 20 degrees C for Landsat overpass and mid-afternoon times. PMID- 28672865 TI - Statistical Analysis of the Main Configuration Parameters of the Network Dynamic and Adaptive Radio Protocol (DARP). AB - The present work analyses the wireless sensor network protocol (DARP) and the impact of different configuration parameter sets on its performance. Different scenarios have been considered, in order to gain a better understanding of the influence of the configuration on network protocols. The developed statistical analysis is based on the method known as Analysis of Variance (ANOVA), which focuses on the effect of the configuration on the performance of DARP. Three main dependent variables were considered: number of control messages sent during the set-up time, energy consumption and convergence time. A total of 20,413 simulations were carried out to ensure greater robustness in the statistical conclusions. The main goal of this work is to discover the most critical configuration parameters for the protocol, with a view to potential applications in Smart City type scenarios. PMID- 28672866 TI - Temperature Dependence of the Rayleigh Brillouin Spectrum Linewidth in Air and Nitrogen. AB - The relation between spontaneous Rayleigh Brillouin (SRB) spectrum linewidth, gas temperature, and pressure are analyzed at the temperature range from 220 to 340 K and the pressure range from 0.1 to 1 bar, covering the stratosphere and troposphere relevant for the Earth's atmosphere and for atmospheric Lidar missions. Based on the analysis, a model retrieving gas temperature from directly measured linewidth is established and the accuracy limitations are estimated. Furthermore, some experimental data of air and nitrogen are used to verify the accuracy of the model. As the results show, the retrieved temperature shows good agreement with the reference temperature, and the absolute difference is less than 3 K, which indicates that this method provides a fruitful tool in satellite retrieval to extract the gaseous properties of atmospheres on-line by directly measuring the SRB spectrum linewidth. PMID- 28672867 TI - Spatiotemporal Recurrent Convolutional Networks for Traffic Prediction in Transportation Networks. AB - Predicting large-scale transportation network traffic has become an important and challenging topic in recent decades. Inspired by the domain knowledge of motion prediction, in which the future motion of an object can be predicted based on previous scenes, we propose a network grid representation method that can retain the fine-scale structure of a transportation network. Network-wide traffic speeds are converted into a series of static images and input into a novel deep architecture, namely, spatiotemporal recurrent convolutional networks (SRCNs), for traffic forecasting. The proposed SRCNs inherit the advantages of deep convolutional neural networks (DCNNs) and long short-term memory (LSTM) neural networks. The spatial dependencies of network-wide traffic can be captured by DCNNs, and the temporal dynamics can be learned by LSTMs. An experiment on a Beijing transportation network with 278 links demonstrates that SRCNs outperform other deep learning-based algorithms in both short-term and long-term traffic prediction. PMID- 28672868 TI - Oxygen Partial Pressure Impact on Characteristics of Indium Titanium Zinc Oxide Thin Film Transistor Fabricated via RF Sputtering. AB - Indium titanium zinc oxide (InTiZnO) as the channel layer in thin film transistor (TFT) grown by RF sputtering system is proposed in this work. Optical and electrical properties were investigated. By changing the oxygen flow ratio, we can suppress excess and undesirable oxygen-related defects to some extent, making it possible to fabricate the optimized device. XPS patterns for O 1s of InTiZnO thin films indicated that the amount of oxygen vacancy was apparently declined with the increasing oxygen flow ratio. The fabricated TFTs showed a threshold voltage of -0.9 V, mobility of 0.884 cm2/Vs, on-off ratio of 5.5 * 105, and subthreshold swing of 0.41 V/dec. PMID- 28672869 TI - Calcineurin Antagonizes AMPK to Regulate Lipolysis in Caenorhabditis elegans. AB - Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase, and the target of immunosuppressive agent tacrolimus (TAC). The dysfunction of calcineurin, or clinical applications of tacrolimus, have been reported to be associated with dyslipidemia. The underlying mechanisms of calcineurin and tacrolimus in lipid metabolism are largely unknown. Here, we showed that mutations of tax-6 and cnb-1, which respectively encode the catalytic subunit and the regulatory subunit of calcineurin, together with tacrolimus treatment, consistently led to decreased fat accumulation and delayed growth in the nematode Caenorhabditis elegans. In contrast, disruption of the AMP-activated protein kinase (AMPK) encoded by aak-1 and aak-2 reversed the above effects in worms. Moreover, calcineurin deficiency and tacrolimus treatment consistently activated the transcriptional expression of the lipolytic gene atgl-1, encoding triglyceride lipase. Furthermore, RNAi knockdown of atgl-1 recovered the decreased fat accumulation in both calcineurin deficient and tacrolimus treated worms. Collectively, our results reveal that immunosuppressive agent tacrolimus and their target calcineurin may antagonize AMPK to regulate ATGL and lipolysis, thereby providing potential therapy for the application of immunosuppressive agents. PMID- 28672870 TI - HHV-6A/B Integration and the Pathogenesis Associated with the Reactivation of Chromosomally Integrated HHV-6A/B. AB - Unlike other human herpesviruses, human herpesvirus 6A and 6B (HHV-6A/B) infection can lead to integration of the viral genome in human chromosomes. When integration occurs in germinal cells, the integrated HHV-6A/B genome can be transmitted to 50% of descendants. Such individuals, carrying one copy of the HHV 6A/B genome in every cell, are referred to as having inherited chromosomally integrated HHV-6A/B (iciHHV-6) and represent approximately 1% of the world's population. Interestingly, HHV-6A/B integrate their genomes in a specific region of the chromosomes known as telomeres. Telomeres are located at chromosomes' ends and play essential roles in chromosomal stability and the long-term proliferative potential of cells. Considering that the integrated HHV-6A/B genome is mostly intact without any gross rearrangements or deletions, integration is likely used for viral maintenance into host cells. Knowing the roles played by telomeres in cellular homeostasis, viral integration in such structure is not likely to be without consequences. At present, the mechanisms and factors involved in HHV-6A/B integration remain poorly defined. In this review, we detail the potential biological and medical impacts of HHV-6A/B integration as well as the possible chromosomal integration and viral excision processes. PMID- 28672871 TI - Pamidronate-Conjugated Biodegradable Branched Copolyester Carriers: Synthesis and Characterization. AB - The need for development of comprehensive therapeutic systems, (e.g., polymer apatite composites) as a bone substitute material has previously been highlighted in many scientific reports. The aim of this study was to develop a new multifunctional composite based on hydroxyapatite porous granules doped with selenite ions (SeO32-) and a biodegradable branched copolymer-bisphosphonate conjugate as a promising bone substitute material for patients with bone tumours or bone metastasis. A series of biodegradable and branched copolymer matrices, adequate for delivery of bisphosphonate in the bone-deficient area were synthesized and physico-chemically and biologically (cyto- and genotoxicity assays) characterized. Branched copolymers were obtained using a hyperbranched bis-MPA polyester-16-hydroxyl initiator and Sn(Oct)2, a (co)catalyst of the ring opening polymerization (ROP) of l,l-lactide (LLA) and epsilon-caprolactone (CL). A new amide bond was formed between the hydroxyl end groups of the synthesized copolymer carriers and an amine group of pamidronate (PAM)-the drug inhibiting bone resorption and osteoclast activity in bone. The dependence of the physico chemical properties of the copolymer matrices on the kinetic release of PAM from the synthesized branched copolymer conjugate-coated hydroxyapatite granules doped with selenite ions was observed. Moreover, the correlation of these results with the hydrolytic degradation data of the synthesized matrices was evidenced. Therefore, the developed composite porous hydroxyapatite doped with SeO32- ions/biodegradable copolymer-PAM conjugate appears most attractive as a bone substitute material for cancer patients. PMID- 28672872 TI - Ultra-Weak Fiber Bragg Grating Sensing Network Coated with Sensitive Material for Multi-Parameter Measurements. AB - A multi-parameter measurement system based on ultra-weak fiber Bragg grating (UFBG) array with sensitive material was proposed and experimentally demonstrated. The UFBG array interrogation principle is time division multiplex technology with two semiconductor optical amplifiers as timing units. Experimental results showed that the performance of the proposed UFBG system is almost equal to that of traditional FBG, while the UFBG array system has obvious superiority with potential multiplexing ability for multi-point and multi parameter measurement. The system experimented on a 144 UFBG array with the reflectivity of UFBG ~0.04% for the four target parameters: hydrogen, humidity, temperature and salinity. Moreover, a uniform solution was customized to divide the cross-sensitivity between temperature and other target parameters. It is expected that this scheme will be capable of handling thousands of multi parameter sensors in a single fiber. PMID- 28672873 TI - High-Density Energetic Metal-Organic Frameworks Based on the 5,5'-Dinitro-2H,2'H 3,3'-bi-1,2,4-triazole. AB - High-energy metal-organic frameworks (MOFs) based on nitrogen-rich ligands are an emerging class of explosives, and density is one of the positive factors that can influence the performance of energetic materials. Thus, it is important to design and synthesize high-density energetic MOFs. In the present work, hydrothermal reactions of Cu(II) with the rigid polynitro heterocyclic ligands 5,5'-dinitro 2H,2'H-3,3'-bi-1,2,4-triazole (DNBT) and 5,5'-dinitro-3,3'-bis-1,2,4-triazole-1 diol (DNBTO) gave two high-density MOFs: [Cu(DNBT)(ATRZ)3]n (1) and [Cu(DNBTO)(ATRZ)2(H2O)2]n (2), where ATRZ represents 4,4'-azo-1,2,4-triazole. The structures were characterized by infrared spectroscopy, elemental analysis, ultraviolet-visible (UV) absorption spectroscopy and single-crystal X-ray diffraction. Their thermal stabilities were also determined by thermogravimetric/differential scanning calorimetry analysis (TG/DSC). The results revealed that complex 1 has a two-dimensional porous framework that possesses the most stable chair conformations (like cyclohexane), whereas complex 2 has a one-dimensional polymeric structure. Compared with previously reported MOFs based on copper ions, the complexes have higher density (rho = 1.93 g cm-3 for complex 1 and rho = 1.96 g cm-3 for complex 2) and high thermal stability (decomposition temperatures of 323 degrees C for complex 1 and 333.3 degrees C for complex 2), especially because of the introduction of an N-O bond in complex 2. We anticipate that these two complexes would be potential high-energy density materials. PMID- 28672874 TI - Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents. AB - In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced beta-amyloid (Abeta) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer's disease. PMID- 28672875 TI - Light-Assisted Advanced Oxidation Processes for the Elimination of Chemical and Microbiological Pollution of Wastewaters in Developed and Developing Countries. AB - In this work, the issue of hospital and urban wastewater treatment is studied in two different contexts, in Switzerland and in developing countries (Ivory Coast and Colombia). For this purpose, the treatment of municipal wastewater effluents is studied, simulating the developed countries' context, while cheap and sustainable solutions are proposed for the developing countries, to form a barrier between effluents and receiving water bodies. In order to propose proper methods for each case, the characteristics of the matrices and the targets are described here in detail. In both contexts, the use of Advanced Oxidation Processes (AOPs) is implemented, focusing on UV-based and solar-supported ones, in the respective target areas. A list of emerging contaminants and bacteria are firstly studied to provide operational and engineering details on their removal by AOPs. Fundamental mechanistic insights are also provided on the degradation of the effluent wastewater organic matter. The use of viruses and yeasts as potential model pathogens is also accounted for, treated by the photo-Fenton process. In addition, two pharmaceutically active compound (PhAC) models of hospital and/or industrial origin are studied in wastewater and urine, treated by all accounted AOPs, as a proposed method to effectively control concentrated point-source pollution from hospital wastewaters. Their elimination was modeled and the degradation pathway was elucidated by the use of state-of-the-art analytical techniques. In conclusion, the use of light-supported AOPs was proven to be effective in degrading the respective target and further insights were provided by each application, which could facilitate their divulgation and potential application in the field. PMID- 28672876 TI - Novel Thiazolo[5,4-b]phenothiazine Derivatives: Synthesis, Structural Characterization, and In Vitro Evaluation of Antiproliferative Activity against Human Leukaemia. AB - The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The synthetic strategy applied was based on oxidative cyclization of N (phenothiazin-3-yl)-thioamides and it was validated by the preparation of new 2 alkyl- and 2-aryl-thiazolo[5,4-b]phenothiazine derivatives. Optical properties of the series were experimentally emphasized by UV-Vis absorption/emission spectroscopy and structural features were theoretically modelled using density functional theory (DFT). In vitro activity as antileukemic agents of thiazolo[5,4 b]phenothiazine and N-(phenothiazine-3-yl)-thioamides were comparatively evaluated using cultivated HL-60 human promyelocytic and THP-1 human monocytic leukaemia cell lines. Some representatives proved selectivity against tumour cell lines, cytotoxicity, apoptosis induction, and cellular metabolism impairment capacity. 2-Naphthyl-thiazolo[5,4-b]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent. PMID- 28672877 TI - Immune Modulating Topical S100A8/A9 Inhibits Growth of Pseudomonas aeruginosa and Mitigates Biofilm Infection in Chronic Wounds. AB - Pseudomonas aeruginosa biofilm maintains and perturbs local host defense, hindering timely wound healing. Previously, we showed that P. aeruginosa suppressed S100A8/A9 of the murine innate host defense. We assessed the potential antimicrobial effect of S100A8/A9 on biofilm-infected wounds in a murine model and P. aeruginosa growth in vitro. Seventy-six mice, inflicted with a full thickness burn wound were challenged subcutaneously (s.c.) by 106 colony-forming units (CFUs) of P. aeruginosa biofilm. Mice were subsequently randomized into two treatment groups, one group receiving recombinant murine S100A8/A9 and a group of vehicle controls (phosphate-buffered saline, PBS) all treated with s.c. injections daily for up to five days. Wounds were analyzed for quantitative bacteriology and contents of key inflammatory markers. Count of blood polymorphonuclear leukocytes was included. S100A8/A9-treatment ameliorated wound infection, as evaluated by quantitative bacteriology (p <= 0.05). In vitro, growth of P. aeruginosa was inhibited dose-dependently by S100A8/A9 in concentrations from 5 to 40 MUg/mL, as determined by optical density-measurement (OD-measurement) and quantitative bacteriology. Treatment slightly augmented key inflammatory cytokine Tumor Necrosis Factor-alpha (TNF-alpha), but dampened interferon-gamma (IFN-gamma) levels and blood polymorphonuclear count. In conclusion, topical S100A8/A9 displays remarkable novel immune stimulatory and anti-infective properties in vivo and in vitro. Importantly, treatment by S100A8/A9 provides local infection control. Implications for a role as adjunctive treatment in healing of chronic biofilm-infected wounds are discussed. PMID- 28672879 TI - The Co-Expression Pattern of p63 and HDAC1: A Potential Way to Disclose Stem Cells in Interfollicular Epidermis. AB - Stem cell markers of interfollicular epidermis (IEF) have not been established thus far. The aim of this study is to suggest a new way to disclose IFE-stem cells by combining the expression of histone deacetylases (HDAC) 1 and p63. Immunohistochemical staining of HDAC1 and p63 was performed in six normal human samples. Moreover, a skin equivalent (SE) model was treated with suberoylanilohydroxamic acid (SAHA, an HDAC inhibitor) to elucidate the role of HDAC1. Finally, rapidly adhering (RA) keratinocytes to a type IV collagen, which have been identified to represent epidermal stem cells, were subjected to Western blot analysis with antibodies against HDAC1. In normal samples, there was a minor subpopulation comprised of p63-positive and HDAC1-negative cells in the basal layers. The proportion of this subpopulation was decreased with age. In the SE model, SAHA treatment increased the epidermal thickness and number of p63 positive cells in a dose dependent manner. After SAHA treatment, the expression of differentiation markers was decreased, while that of basement membrane markers was increased. In a Western blot analysis, HDAC1 was not expressed in RA cells. In conclusion, the combination of p63-positive and HDAC1-negative expressions can be a potential new way for distinguishing epidermal stem cells. PMID- 28672880 TI - Ankyrin Repeat Domain 1 Protein: A Functionally Pleiotropic Protein with Cardiac Biomarker Potential. AB - The ankyrin repeat domain 1 (ANKRD1) protein is a cardiac-specific stress response protein that is part of the muscle ankyrin repeat protein family. ANKRD1 is functionally pleiotropic, playing pivotal roles in transcriptional regulation, sarcomere assembly and mechano-sensing in the heart. Importantly, cardiac ANKRD1 has been shown to be highly induced in various cardiomyopathies and in heart failure, although it is still unclear what impact this may have on the pathophysiology of heart failure. This review aims at highlighting the known properties, functions and regulation of ANKRD1, with focus on the underlying mechanisms that may be involved. The current views on the actions of ANKRD1 in cardiovascular disease and its utility as a candidate cardiac biomarker with diagnostic and/or prognostic potential are also discussed. More studies of ANKRD1 are warranted to obtain deeper functional insights into this molecule to allow assessment of its potential clinical applications as a diagnostic or prognostic marker and/or as a possible therapeutic target. PMID- 28672882 TI - A Novel Benzoquinone Compound Isolated from Deep-Sea Hydrothermal Vent Triggers Apoptosis of Tumor Cells. AB - Microorganisms are important sources for screening bioactive natural products. However, natural products from deep-sea microbes have not been extensively explored. In this study, the metabolites of bacteriophage GVE2 -infected (Geobacillus sp. E263 virus) thermophilic bacterium Geobacillus sp. E263, which was isolated from a deep-sea hydrothermal vent, were characterized. A novel quinoid compound, which had anti-tumor activity, was isolated from the phage challenged thermophile. The chemical structure analysis showed that this novel quinoid compound was 2-amino-6-hydroxy-[1,4]-benzoquinone. The results indicated that 2-amino-6-hydroxy-[1,4]-benzoquinone and its two derivatives could trigger apoptosis of gastric cancer cells and breast cancer cells by inducing the accumulation of intracellular reactive oxygen species. Therefore, our study highlighted that the metabolites from the phage-challenged deep-sea microbes might be a kind of promising sources for anti-tumor drug discovery, because of the similarity of metabolic disorder between bacteriophage-infected microbes and tumor cells. PMID- 28672881 TI - Recent Advances in Substrate-Controlled Asymmetric Cyclization for Natural Product Synthesis. AB - Asymmetric synthesis of naturally occurring diverse ring systems is an ongoing and challenging research topic. A large variety of remarkable reactions utilizing chiral substrates, auxiliaries, reagents, and catalysts have been intensively investigated. This review specifically describes recent advances in successful asymmetric cyclization reactions to generate cyclic architectures of various natural products in a substrate-controlled manner. PMID- 28672878 TI - Epigenetic Regulation of the Biosynthesis & Enzymatic Modification of Heparan Sulfate Proteoglycans: Implications for Tumorigenesis and Cancer Biomarkers. AB - Emerging evidence suggests that the enzymes in the biosynthetic pathway for the synthesis of heparan sulfate moieties of heparan sulfate proteoglycans (HSPGs) are epigenetically regulated at many levels. As the exact composition of the heparan sulfate portion of the resulting HSPG molecules is critical to the broad spectrum of biological processes involved in oncogenesis, the epigenetic regulation of heparan sulfate biosynthesis has far-reaching effects on many cellular activities related to cancer progression. Given the current focus on developing new anti-cancer therapeutics focused on epigenetic targets, it is important to understand the effects that these emerging therapeutics may have on the synthesis of HSPGs as alterations in HSPG composition may have profound and unanticipated effects. As an introduction, this review will briefly summarize the variety of important roles which HSPGs play in a wide-spectrum of cancer-related cellular and physiological functions and then describe the biosynthesis of the heparan sulfate chains of HSPGs, including how alterations observed in cancer cells serve as potential biomarkers. This review will then focus on detailing the multiple levels of epigenetic regulation of the enzymes in the heparan sulfate synthesis pathway with a particular focus on regulation by miRNA and effects of epigenetic therapies on HSPGs. We will also explore the use of lectins to detect differences in heparan sulfate composition and preview their potential diagnostic and prognostic use in the clinic. PMID- 28672884 TI - Energy Efficiency Optimization for Downlink Cloud RAN with Limited Fronthaul Capacity. AB - In the downlink cloud radio access network (C-RAN), fronthaul compression has been developed to combat the performance bottleneck caused by the capacity limited fronthaul links. Nevertheless, the state-of-arts focusing on fronthaul compression for spectral efficiency improvement become questionable for energy efficiency (EE) maximization, especially for meeting its requirements of large scale implementation. Therefore, this paper aims to develop a low-complexity algorithm with closed-form solution for the EE maximization problem in a downlink C-RAN with limited fronthaul capacity. To solve such a non-trivial problem, we first derive an optimal solution using branch-and-bound approach to provide a performance benchmark. Then, by transforming the original problem into a parametric subtractive form, we propose a low-complexity two-layer decentralized (TLD) algorithm. Specifically, a bisection search is involved in the outer layer, while in the inner layer we propose an alternating direction method of multipliers algorithm to find a closed-form solution in a parallel manner with convergence guaranteed. Simulations results demonstrate that the TLD algorithm can achieve near optimal solution, and its EE is much higher than the spectral efficiency maximization one. Furthermore, the optimal and TLD algorithms are also extended to counter the channel error. The results show that the robust algorithms can provide robust performance in the case of lacking perfect channel state information. PMID- 28672883 TI - Role of alphabeta T Cell Depletion in Prevention of Graft versus Host Disease. AB - Graft versus host disease (GVHD) represents a major complication of allogeneic hematopoietic stem cell transplantation (allo HCT). Graft cellular manipulation has been used to mitigate the risk of GVHD. The alphabeta T cells are considered the primary culprit for causing GVHD therefore depletion of this T cell subset emerged as a promising cellular manipulation strategy to overcome the human leukocyte antigen (HLA) barrier of haploidentical (haplo) HCT. This approach is also being investigated in HLA-matched HCT. In several studies, alphabeta T cell depletion HCT has been performed without pharmacologic GVHD prophylaxis, thus unleashing favorable effect of donor's natural killer cells (NK) and gammadelta T cells. This article will discuss the evolution of this method in clinical practice and the clinical outcome as described in different clinical trials. PMID- 28672885 TI - Characterization of Sinorhizobium sp. LM21 Prophages and Virus-Encoded DNA Methyltransferases in the Light of Comparative Genomic Analyses of the Sinorhizobial Virome. AB - The genus Sinorhizobium/Ensifer mostly groups nitrogen-fixing bacteria that create root or stem nodules on leguminous plants and transform atmospheric nitrogen into ammonia, which improves the productivity of the plants. Although these biotechnologically-important bacteria are commonly found in various soil environments, little is known about their phages. In this study, the genome of Sinorhizobium sp. LM21 isolated from a heavy-metal-contaminated copper mine in Poland was investigated for the presence of prophages and DNA methyltransferase encoding genes. In addition to the previously identified temperate phage, PhiLM21, and the phage-plasmid, pLM21S1, the analysis revealed the presence of three prophage regions. Moreover, four novel phage-encoded DNA methyltransferase (MTase) genes were identified and the enzymes were characterized. It was shown that two of the identified viral MTases methylated the same target sequence (GANTC) as cell cycle-regulated methyltransferase (CcrM) of the bacterial host strain, LM21. This discovery was recognized as an example of the evolutionary convergence between enzymes of sinorhizobial viruses and their host, which may play an important role in virus cycle. In the last part of the study, thorough comparative analyses of 31 sinorhizobial (pro)phages (including active sinorhizobial phages and novel putative prophages retrieved and manually re annotated from Sinorhizobium spp. genomes) were performed. The networking analysis revealed the presence of highly conserved proteins (e.g., holins and endolysins) and a high diversity of viral integrases. The analysis also revealed a large number of viral DNA MTases, whose genes were frequently located within the predicted replication modules of analyzed prophages, which may suggest their important regulatory role. Summarizing, complex analysis of the phage protein similarity network enabled a new insight into overall sinorhizobial virome diversity. PMID- 28672887 TI - Members of the microRNA-200 family are promising therapeutic targets in cancer. AB - MicroRNAs (miRs) are non-coding, single-stranded RNA molecules that regulate gene expression at the posttranscriptional level. Abnormal expression of miR may result in pathophysiological processes occurring that stimulate the development of various diseases. miRs are commonly dysregulated in cancer and may act as either oncogenes or tumor suppressors. Studies have indicated that members of the miR-200 family are involved in different aspects of cancer biology, including the epithelial-to-mesenchymal transition, tumor angiogenesis and chemoresistance by targeting and repressing the expression of several key messenger RNAs. The present review aims to summarize the role of the miR-200 family and its potential mechanism of action in tumor progression, which may advance the development of novel therapeutic drugs against tumor metastasis in clinical cancer treatment. PMID- 28672888 TI - Green synthesis of copper nanoparticles using Eclipta prostrata leaves extract and their antioxidant and cytotoxic activities. AB - The present study outlines the development of a method to synthesize copper nanoparticles (CuNPs) by mixing copper acetate solution with leaf extract of Eclipta prostrata without using any surfactant or external energy. E. prostrata leaf extract function as an excellent reducing agent of copper ions, and the biosynthesized CuNPs are safer for the environment. The powder X-ray diffraction (XRD) pattern provided evidence for the formation of face-centered cubic structure ranging from 23 to 57 nm, with an average size of 31+/-1.2 nm. Fourier transform infrared spectroscopy (FTIR) was used to identify the biomolecules and capping reagents in the E. prostrata leaf extract that may be responsible for the reduction of copper ions and the stability of the bioreduced nanoparticles. The biosynthesized CuNPs displayed considerable antioxidant capacity. Similarly, in vitro anticancer studies demonstrated the cytotoxicity value of synthesized CuNPs against tested HepG2 cells. The findings of the present study suggested that biosynthesized CuNPs that utilize extracts of E. prostrata may be used for therapeutic application, and thus are a promising nanomaterial. PMID- 28672886 TI - Resveratrol (3,5,4'-trihydroxystilbene) and its properties in oral diseases. AB - Health promotion strategies and lifestyle changes are important in disease prevention. Oral health has received a large amount of attention previously as it is a fundamental component of general health and it contributes to the quality of life. Therefore, the study of associations between diet, health and the presence of bioactive compounds in food is receiving a substantial amount of attention. In the present review the effects and targets of a natural polyohenolic stilbenoid compound; resveratrol (3,5,4'-trihydroxystilbene; RSV) is assessed, and the future prospects for RSV in promoting oral health are considered. RSV is a phytoalexin, synthesized by a wide range of plants and abundantly extracted in grape skin, it has been purported to exert a multiplicity of anti-inflammatory, anti-viral, anti-microbial, estrogenic, anticancer, cardioprotective, neuroprotective and immunomodulatory functions. In this review, following an introduction documenting the biochemistry of RSV and RSV glucosides, the bioavailability and pharmacokinetics of RSV are described. Considering its multiple properties, the present review has focused on the potential benefits of RSV as an antioxidant and chemopreventive agent. PMID- 28672889 TI - Pharmacological postconditioning with atorvastatin calcium attenuates myocardial ischemia/reperfusion injury in diabetic rats by phosphorylating GSK3beta. AB - Diabetes is an independent risk factor for myocardial ischemia, and many epidemiological data and laboratory studies have revealed that diabetes significantly exacerbated myocardial ischemia/reperfusion injury and ameliorated protective effects. The present study aimed to determine whether pharmacological postconditioning with atorvastatin calcium lessened diabetic myocardial ischemia/reperfusion injury, and investigated the role of glycogen synthase kinase (GSK3beta) in this. A total of 72 streptozotocin-induced diabetic rats were randomly divided into six groups, and 24 age-matched male non-diabetic Sprague-Dawley rats were randomly divided into two groups. Rats all received 40 min myocardial ischemia followed by 180 min reperfusion, except sham-operated groups. Compared with the non-diabetic ischemia/reperfusion model group, the diabetic ischemia/reperfusion group had a comparable myocardial infarct size, but a higher level of serum cardiac troponin I (cTnI) and morphological alterations to their myocardial cells. Compared with the diabetic ischemia/reperfusion group, the group that received pharmacological postconditioning with atorvastatin calcium had smaller myocardial infarct sizes, lower levels of cTnI, reduced morphological alterations to myocardial cells, higher levels of p-GSK3beta, heat shock factor (HSF)-1 and heat shock protein (HSP)70. The cardioprotective effect conferred by atorvastatin calcium did not attenuate myocardial ischemia/reperfusion injury following application of TDZD-8, which phosphorylates and inactivates GSK3beta. Pharmacological postconditioning with atorvastatin calcium may attenuate diabetic heart ischemia/reperfusion injury in the current context. The phosphorylation of GSK3beta serves a critical role during the cardioprotection in diabetic rats, and p-GSK3beta may accelerate HSP70 production partially by activating HSF-1 during myocardial ischemic/reperfusion injury. PMID- 28672890 TI - Small interfering RNA targeting of the survivin gene inhibits human tumor cell growth in vitro. AB - The present study aimed to evaluate the impact of small interfering RNA (siRNA) targeting of the survivin gene in human tumor cells and the effect of decreased survivin expression on the proliferation and apoptosis of tumor cells. Human tumor cell lines (MSA-MB-231, SGC-7901, HeLa, A549, SK-OV-3 and Raji, PC-3) were cultured in vitro and divided into three groups: survivin siRNA-treated, scrambled negative control siRNA-treated and an untreated control group. The level of survivin mRNA and protein expression was subsequently determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation was also examined by an MTT assay following transfection and the apoptotic rate of cells was detected by Hoechst and Annexin V/propidium iodide staining. It was observed that relative to the control group, expression of survivin mRNA and protein in the survivin siRNA treated group was significantly downregulated. Furthermore, siRNA targeting of survivin lead to the inhibition of tumor cell proliferation, as well as an increase in their apoptotic rate in vitro. These data suggest that survivin may be a potential tumor biomarker and a novel target for the treatment of cancer. PMID- 28672891 TI - Osteogenic potency of dedifferentiated fat cells isolated from elderly people with osteoporosis. AB - Mature adipocytes are the major cell type in adipose tissue. This study aimed to explore the osteogenic potency of dedifferentiated fat cells obtained from osteoporotic patients (opDFATs) in vitro and in vivo. Mature adipocytes and adipose-derived stem cells (opASCs) were harvested from subcutaneous adipose tissue. Mature adipocytes were dedifferentiated to produce opDFATs by the ceiling culture method. OpDFATs were osteogenically induced in vitro with opASCs as a control. Cell growth, alkaline phosphatase (ALPase) activity and cell mineralization were determined, and expression levels of osteogenesis-specific genes (collagen I, osteocalcin and bone sialoprotein) were analyzed using quantitative reverse transcription polymerase chain reaction. After 14 days, the opDFATs were combined with a poly(lactide-co-glycolide)-beta-tricalcium phosphate porous scaffold after being suspended in collagen I gel and implanted into nude mice for 4 weeks prior to histological analysis. Unilocular lipid droplets in mature adipocytes gradually split into smaller droplets and disappeared from the cytoplasm. Mature adipocytes dedifferentiated to opDFATs and cell morphology changed from spherical to elongated. High levels of ALPase and cell mineralization were observed in opDFATs by staining. No significant differences were found between the growth curves, ALPase activity, cell mineralization and expression levels of osteogenesis-specific genes between opDFATS and opASCs. After implantation for 4 weeks, new bone tissue was observed histologically in the opDFATs-based biocomposite. OpDFATs are implicated as a novel type of seed cell for bone tissue engineering based on their osteogenic potency and higher abundance in adipose tissue compared with opASCs. PMID- 28672892 TI - The mediation of interleukin-17 and chemokine ligand 2 in pelvic pain of experimental autoimmune prostatitis. AB - The present study aimed to determine the expression and mediation of interleukin 17 (IL-17) and chemokine ligand 2 (CCL2) in a rat model with experimental autoimmune prostatitis (EAP). A total of 44 Sprague Dawley (SD) rats were used in the present study. Of these, a total of 20 two-month-old SD rats were randomly divided into a normal control (n=10) and a model group (EAP group, n=10). The remaining 24 two-month old SD rats were treated in the same way as EAP rats and subsequently randomly divided into a tacrolimus group (n=8), a celecoxib group (n=8) and a normal saline (NS) control group (n=8). Rats in the EAP and normal control groups underwent the Von Frey filaments behavioral test; rats in the tacrolimus, celecoxib and normal saline groups received a pain test following intervention treatment. Prostate tissues of SD rats in each group were harvested for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis to observe the expression of IL-17 and CCL2. In the pain reaction test, the occurrence of abnormal pain in the EAP group was significantly higher compared with the control group (P<0.001). The celecoxib group experienced a significant decrease in pain at day 10 compared with the NS group (P<0.01), while the decrease in pain experienced by the tacrolimus group was only significant at day 30 (P<0.001) and the pain experienced by the NS group decreased slightly over this same period. Results of RT-qPCR and western blot analysis indicated that, compared with the control group, the expression of IL-17 and CCL2 in the prostate tissue of EAP rats was significantly upregulated 50 days following modeling (P<0.05). On day 30 following intervention, the expression of IL-17 and CCL2 in the prostate of rats in the tacrolimus and celecoxib groups was significantly downregulated compared with the NS group (P<0.05). Therefore, the results of the current study demonstrate that IL-17 and CCL2 serve a vital role in the morbidity of the experimental autoimmune prostatitis and may also have a mediation effect on pelvic pain associated with chronic prostatitis. PMID- 28672893 TI - Anthocyanins from black rice (Oryza sativa) promote immune responses in leukemia through enhancing phagocytosis of macrophages in vivo. AB - Rice is a staple food in numerous countries around the world. Anthocyanins found in black rice have been reported to reduce the risk of certain diseases, but the effects of crude extract of anthocyanins from Asia University-selected purple glutinous indica rice (AUPGA) on immune responses have not yet been demonstrated. The current study aimed to investigate whether AUPGA treatment could affect immune responses in murine leukemia cells in vivo. Murine acute myelomonocytic leukemia WEHI-3 cells were intraperitoneally injected into normal BALB/c mice to generate leukemia mice. A total of 50 mice were randomly divided into five groups (n=10 in each group) and were fed a diet supplemented with AUPGA at 0, 20, 50 or 100 mg/kg for three weeks. All mice were weighed and the blood, liver and spleen were collected for further experiments. The results indicated that AUPGA did not significantly affect animal body weight, but significantly increased spleen weight (P<0.05) and decreased liver weight (P<0.05) when compared with the control group. AUPGA significantly increased the T cell (CD3) population at treatments of 20 and 100 mg/kg (P<0.05). However, it only significantly increased the B cell (CD19) population at a treatment of 20 mg/kg (P<0.05). Furthermore, AUPGA at 50 and 100 mg/kg significantly increased the monocyte (CD11b) population and the level of macrophages (Mac-3; P<0.05 for both). AUPGA at 50 and 100 mg/kg significantly promoted macrophage phagocytosis in peripheral blood mononuclear cells (P<0.05), and all doses of AUPGA treatment significantly promoted macrophage phagocytotic activity in the peritoneum (P<0.05). AUPGA treatment significantly decreased natural killer cell activity from splenocytes (P<0.05). Finally, AUPGA treatment at 20 mg/kg treatment significantly promoted T cell proliferation (P<0.05), and treatment at 50 and 100 mg/kg significantly decreased B cell proliferation compared with the control group (P<0.05). PMID- 28672894 TI - Emulsified isoflurane postconditioning improves survival and neurological outcomes in a rat model of cardiac arrest. AB - Emulsified isoflurane (EIso) has a protective effect against ischemia/reperfusion (I/R) injury in animal models. However, the protective effects of EIso on global cerebral I/R injury remain unclear. The present study aimed to investigate whether EIso postconditioning was able to improve survival and neurological outcomes in a rat model of cardiac arrest (CA). Rats were randomly divided into five groups, namely the control, EIso-2ml, EIso-4ml, isoflurane (Iso) and emulsion (E) groups. All rats were resuscitated by a standardized method following 6 min of asphyxia. Furthermore, all interventions were administered immediately following the return of spontaneous circulation (ROSC). The animal survival was recorded daily, and evaluations of behavioral and brain morphology were assessed at 1 and 7 days after ROSC. The results showed that EIso treatment increased the survival rate 7 days after ROSC, with a 41.7% 7-day survival in the EIso-2ml group, 66.7% in the EIso-4ml group and 50% in the Iso group compared with 33.3% survival in the control and E groups. Moreover, the neural deficit score and memory function were improved in the EIso-4ml group, and this treatment also ameliorated brain hippocampal cell injury and apoptosis. In addition, a better brain protective effect was observed in the EIso-4ml group compared with the EIso-2ml, Iso and E groups. In summary, the data of the present study suggest that EIso postconditioning improved the survival and neurological outcomes following CA in a dose-dependent manner. PMID- 28672895 TI - Role of transient receptor potential channel 6 in the odontogenic differentiation of human dental pulp cells. AB - Pulp capping is a restorative technique employed in an attempt to maintain pulpal vitality and generate reparative dentin. Ca2+ released from capping materials is suggested to promote reparative dentin formation. Transient receptor potential channel 6 (TRPC6) is a receptor-operated Ca2+ channel that serves an important role in Ca2+ influx in the majority of non-excitable cells, and influences the calcium signaling and cell respond. Therefore, the purpose of the present study was to gain an insight into the role of TRPC6 in the odontoblastic differentiation of human dental pulp cells (HDPCs). Human dental pulp tissues and HDPCs were obtained from healthy third molars. By immunohistochemical staining, TRPC6 was observed to be highly expressed in the dental pulp tissue, particularly in the odontoblast layer. In addition, the protein level of TRPC6 was increased in a time-dependent manner during odontogenic differentiation of HDPCs. Downregulation of TRPC6 by a lentivirus vector containing TRPC6 shRNA inhibited the process of odontogenic differentiation in HDPCs. In conclusion, the current data demonstrated that TRPC6 served a significant role in the odontogenic differentiation of HDPCs, suggesting it may be a promising therapeutic target in regenerative endodontics. PMID- 28672896 TI - Predictive values of urine paraquat concentration, dose of poison, arterial blood lactate and APACHE II score in the prognosis of patients with acute paraquat poisoning. AB - The present study investigated the predictive values of urine paraquat (PQ) concentration, dose of poison, arterial blood lactate and Acute Physiology and Chronic Health Evaluation (APACHE) II score in the prognosis of patients with acute PQ poisoning. A total of 194 patients with acute PQ poisoning, hospitalized between April 2012 and January 2014 at the First Affiliated Hospital of P.R. China Medical University (Shenyang, China), were selected and divided into survival and mortality groups. Logistic regression analysis, receiver operator characteristic (ROC) curve analysis and Kaplan-Meier curve were applied to evaluate the values of urine paraquat (PQ) concentration, dose of poison, arterial blood lactate and (APACHE) II score for predicting the prognosis of patients with acute PQ poisoning. Initial urine PQ concentration (C0), dose of poison, arterial blood lactate and APACHE II score of patients in the mortality group were significantly higher compared with the survival group (all P<0.05). Logistic regression analysis revealed that C0, dose of poison and arterial blood lactate correlated with mortality risk of acute PQ poisoning (all P<0.05). ROC curve analysis suggested that the areas under the curve (AUC) values of C0, dose of poison, arterial blood lactate and APACHE II score in predicting the mortality of patients within 28 days were 0.921, 0.887, 0.808 and 0.648, respectively. The AUC of C0 for predicting early and delayed mortality were 0.890 and 0.764, respectively. The AUC values of urine paraquat concentration the day after poisoning (Csec) and the rebound rate of urine paraquat concentration in predicting the mortality of patients within 28 days were 0.919 and 0.805, respectively. The 28-day survival rate of patients with C0 <=32.2 ug/ml (42/71; 59.2%) was significantly higher when compared with patients with C0 >32.2 ug/ml (38/123; 30.9%). These results suggest that the initial urine PQ concentration may be the optimal index for predicting the prognosis of patients with acute PQ poisoning. Additionally, dose of poison, arterial blood lactate, Csec and rebound rate also have referential significance. PMID- 28672897 TI - Adult community-acquired pneumonia with unusually enlarged mediastinal lymph nodes: A case report. AB - Adult community-acquired pneumonia (ACAP) is the most prevalent pulmonary infectious disease that may be asymptomatic or have varying clinical presentations. Patients with ACAP often present with enlarged mediastinal lymph nodes on their chest computed tomography images. However, large irregular swollen lymph nodes are rarely reported in ACAP, and may therefore be confused with enlarged lymph node masses. In the present case report, the patient presented with lymph node masses, which were ameliorated to their normal size following antimicrobial treatment. The patient was 24 years old and otherwise healthy, which led to a pronounced and excessive immune response to pneumonia in the lymph nodes. Atypical pneumonia is difficult to diagnose based on imaging features. The present case report demonstrates that patients with pneumonia may present with unusually enlarged mediastinal lymph nodes, which are most likely, a result of a strong immune response to pneumonia. PMID- 28672898 TI - Astragalus polysaccharide, a component of traditional Chinese medicine, inhibits muscle cell atrophy (cachexia) in an in vivo and in vitro rat model of chronic renal failure by activating the ubiquitin-proteasome pathway. AB - The present study aimed to determine the effect of Astragalus polysaccharide (APS) in an in vivo and in vitro rat model of muscle atrophy (cachexia) caused by chronic renal failure (CRF), along with the potential corresponding roles of atroglin-1 and the ubiquitin-proteasome pathway. A rat model of CRF was established using subtotal bilateral nephrectomy. It was observed by reverse transcription-quantitative polymerase chain reaction and western blot analysis that APS and the specific inhibitor of nuclear factor (NF)-kappaB, pyrrolidine dithiocarbamate (PDTC), significantly reduced the expression of atrogin-1, ubiquitin and the NF-kappaB subunit p65 mRNA in rat skeletal muscle in vivo and in vitro, respectively (P<0.05). NF-kappaB and PDTC also markedly reduced the expression of atrogin-1, ubiquitin and p65 protein. In addition, cultured rat myoblasts pretreated with tumor necrosis factor (TNF)-alpha exhibited significantly reduced expression of atrogin-1, ubiquitin and p65 mRNA in vitro (P<0.05). Fluorescence microscopy was subsequently used to evaluate TNF-alpha treated myoblasts administered with APS or PDTC, whereby no evidence of muscle cell atrophy was observed in cells treated with APS. These data suggest that APS may delay muscle cell atrophy associated with cachexia in CRF by targeting atrogin-1 and the ubiquitin-proteasome pathway. PMID- 28672899 TI - Pathway-related modules involved in the application of sevoflurane or propofol in off-pump coronary artery bypass graft surgery. AB - Off-pump coronary artery bypass graft (CABG) surgery has recently emerged as a means to avoid the sequelae of extracorporeal circulation, including the whole body inflammatory response, coagulation disorders and multiple organ dysfunction. At present, gas anesthesia, sevoflurane and intravenous anesthesia and propofol have been widely used during the CABG. To further understand the underlying mechanisms of these anesthetics on the gene level, the present study conducted pathway-related module analysis based on a co-expression network. This was performed in order to identify significant pathways in coronary artery disease patients who had undergone off-pump CABG surgery before and after applying sevoflurane or propofol. A total of 269 and 129 differentially expressed genes were obtained in the sevoflurane and propofol groups, respectively. In total, eight and seven pathways (P<0.05) in the sevoflurane and propofol groups were separately obtained via Kyoto Encyclopedia of Genes and Genome pathway analysis. Finally, eight and seven pathway-related modules in the sevoflurane and propofol groups were obtained, respectively. Furthermore, the mean degree of complement and coagulation cascades pathway-related module in both of the groups was the highest. It was predicted that during the CABG, the anesthetics might activate the complement and coagulation systems in order to possess some cardioprotective properties. PMID- 28672900 TI - 5-HT in the dorsal raphe nucleus is involved in the effects of 100-Hz electro acupuncture on the pain-depression dyad in rats. AB - The pain-depression dyad is becoming widespread in the clinic and is attracting increasing attention. A previous study by our group found that 100-Hz electro acupuncture (EA), but not 2-, 50- and 2/100-Hz EA, was effective against the reserpine-induced pain-depression dyad. This finding is in contrast to the fact that low-frequency EA is commonly used to treat supraspinal-originating diseases. The present study aimed to investigate the mechanism underlying the effects of 100-Hz EA on the pain-depression dyad. Repeated reserpine injection was found to induce allodynia and depressive behaviors in rats. It decreased 5 hydroxytryptamine (5-HT) levels and immunoreactive expressions in the dorsal raphe nucleus (DRN). 100-Hz EA alleviated the pain-depression dyad and upregulated 5-HT in the DRN of reserpine-injected rats. Intracerebroventricular injection of para-chlorophenylalanine, an inhibitor of 5-HT resynthesis, suppressed the upregulation of 5-HT in the DRN by 100-Hz EA and partially counteracted the analgesic and anti-depressive effects of 100-Hz EA. The present study was the first to demonstrate that 5-HT in the DRN is involved in mediating the analgesic and anti-depressive effects of 100-Hz EA on the pain-depression dyad. This finding provided a scientific basis for high-frequency EA as a potential treatment for the pain-depression dyad. PMID- 28672902 TI - Analysis of the effect of rutin on GSK-3beta and TNF-alpha expression in lung cancer. AB - The aim of the present study was to investigate the effect of rutin treatment on the expression of glycogen synthase kinase (GSK)-3beta and tumor necrosis factor (TNF)-alpha in A549 human lung carcinoma cells. The A549 cells were divided into control, cisplatin and rutin (low, middle and high) groups. ELISA and western blot analysis of TNF-alpha expression, 4',6-diamino-2-phenylindole (DAPI) staining and GSK-3beta immunofluorescence staining were used to investigate the effect of rutin in the human lung carcinoma cells, using cisplatin as a positive control. TNF-alpha expression was significantly higher in the rutin and cisplatin groups compared with the control group. Additionally, DAPI staining revealed that the number of apoptotic cells was higher in the rutin and cisplatin groups compared with the control group, and immunofluorescence showed that the expression of GSK-3beta in the cisplatin and rutin groups was significantly higher compared with that in the control group. The results of the present study suggest that rutin promotes the TNF-alpha-induced apoptosis of A549 human lung carcinoma cells. Furthermore, rutin may be able to regulate the expression of GSK 3beta protein in these cells. PMID- 28672901 TI - Evaluation of the effect of salmon nasal proteoglycan on biomarkers for cartilage metabolism in individuals with knee joint discomfort: A randomized double-blind placebo-controlled clinical study. AB - A randomized double-blind placebo-controlled clinical trial was conducted to evaluate the chondroprotective action of salmon nasal cartilage proteoglycan on joint health. The effect of oral administration of proteoglycan (10 mg/day) on cartilage metabolism was evaluated in individuals with knee joint discomfort but without diagnosis of knee osteoarthritis. The average age of patients was 52.6+/ 1.1 years old. The effect of proteoglycan was evaluated by analyzing markers for type II collagen degradation (C1,2C) and synthesis (PIICP), and the ratio of type II collagen degradation to synthesis. The results indicated that the change in C1,2C levels significantly differed in the proteoglycan group compared with the placebo group following 16 weeks intervention among subjects with high levels of knee pain and physical dysfunction (total score of Japan Knee Osteoarthritis Measure >=41) and subjects with constant knee pain (both P<0.05). There was a greater increase in PIICP levels in the proteoglycan group than the placebo group following intervention, although this difference was not significant in both sets of patients. Thus, the C1,2C/PIICP ratios decreased in the proteoglycan group, whereas they slightly increased in the placebo group following the intervention. Furthermore, no test supplement-related adverse events were observed during the intervention. Therefore, oral administration of salmon nasal cartilage proteoglycan at a dose of 10 mg/day may exert a chondroprotective action in subjects with knee joint discomfort. This effect was achieved by improving cartilage metabolism (reducing type II collagen degradation and enhancing type II collagen synthesis), without causing apparent adverse effects. PMID- 28672903 TI - Efficacy of fulguration combined with imiquimod cream on condyloma acuminatum, and the effect on immune functions and serums levels of IL-2 and IL-10. AB - The objective of the present study was to investigate the clinical efficacy of high-frequency fulguration combined with 5% imiquimod cream for condyloma acuminatum (CA), and the effect on T cell immune function and serum levels of interleukin (IL)-2 and IL-10. We enrolled 112 patients with CA between January 2014 and January 2016. Patients were randomly divided into the control group (n=56) and observation group (n=56). The control group received high-frequency fulguration combined with intramuscular injection of Bacillus Calmette-Guerin polysaccharide nucleic acid, and the observation group received high-frequency fulguration combined with external application of 5% imiquimod cream. In both groups, the course of treatment lasted for 12 weeks, and the follow-up period was 6 months. Clinical efficacy was compared between the groups. The total effective rate in the observation group was higher than that in the control group (p<0.05), but no significant differences were identified in comparisons of effectiveness and recurrence rate between the two groups (p>0.05). After treatment, the levels of CD3+ and CD4+ cells, and CD4+/CD8+ ratio in both groups were increased compared with those before treatment (p<0.05), while no significant difference was identified in comparison of the levels of CD8+ cells in both groups before and after treatment (p>0.05); in both groups before and after treatment, there was no significant difference in the comparison of T cells (p>0.05). After treatment in both groups, the serum levels of IL-2 were increased, and the levels of IL-10 were decreased compared with those before treatment; the improvement in the observation group was superior to that in the control group (p<0.05). In conclusion, good efficacy can be achieved with the combined treatment of high frequency fulguration and 5% imiquimod cream for CA, which is correlated with enhanced immune functions of T cells, and improvements in the serum levels of IL 2 and IL-10. PMID- 28672904 TI - KATP channels in high glucose-induced rat mesangial cell proliferation and release of MMP-2 and fibronectin. AB - ATP-sensitive potassium (KATP) channels are well characterized in cardiac, pancreatic and many other muscle cells. The purpose of this study was to determine if KATP channels play a role in diabetic nephropathy (DN). In the present study, functional expression of the KATP channel was examined in rat mesangial cells with or without high glucose (HG) stimulation. The mesangial cell proliferation and the release of matrix metalloproteinase (MMP)-2 and fibronectin in response to high glucose with a selective opener of KATP (diazoxide, DZX), or with a selective inhibitor of KATP (5-hydroxydecanoate, 5-HD) were also measured. The cell proliferation was observed using Cell Counting Kit-8 assay, and the mRNA expressions of KATP subunit, including Kir6.1, Kir6.2, sulfonylurea receptor 1 (SUR1), SUR2A and SUR2B, were assessed using quantitative real-time PCR. MMP-2 and fibronectin release was measured by ELISA. The present study clarified expression of SUR subunit of KATP in plasma. HG treatment could cause increased cell proliferation and release of MMP-2 and fibronectin in a dose-dependent manner. HG also significantly decreased the expression of Kir6.1, SUR2A and SUR2B. Pretreatment of DZX markedly decreased the expression of SUR1, SUR2A and SUR2B, but had no effect on Kir6.1 expression compared with HG alone, while these changes were inhibited by 5-HD pretreatment. Moreover, DZX also inhibited cell proliferation and release of MMP-2 and fibronectin in HG-induced rat mesangial cells, and that was corrected by 5-HD. These data suggest that HG stimulates mesangial cell proliferation and cellular matrix release via inhibiting KATP channel activity, leading us to propose that KATP channel dysfunction may be involved in the development of DN. PMID- 28672905 TI - Severe septic arthritis of the temporomandibular joint with pyogenic orofacial infections: A case report and review of the literature. AB - Septic arthritis of the temporomandibular joint (SATMJ) is a rare entity that has only been reported a few dozen times worldwide. However, SATMJ is an acute infectious disease and associated with a high risk for misdiagnosis, which results in severe complications for patients. The present study reported a case of an 83-year-old female patient with severe pyogenic orofacial infections caused by right-side SATMJ, which was not cured by abscess incision drainage and anti microbial treatment. Finally, the clinical signs were resolved by condylectomy and debridement of the erosive septic TMJ, after which the function of the TMJ was completely restored. In conclusion, a timely and correct diagnosis with early treatment is critical to preventing acute complications and late sequelae of SATMJ. In addition, literature associated with this topic was reviewed and discussed. PMID- 28672907 TI - Good recovery of subarachnoid hemorrhage concomitant with ischemia due to anterior cerebral artery dissection by conservative treatment: A case report. AB - The present report describes the case of a 57-year-old woman presenting with subarachnoid hemorrhage (SAH) and acute ischemic stroke (AIS) due to anterior cerebral artery (ACA) dissection, which exhibited severe stenosis at the origin with distal dilatation of the A2 segment and occlusion of the A3 segment. In this case, computed tomography (CT) revealed SAH in right superior frontal sulcus and the interhemispheric fissure. Magnetic resonance imaging demonstrated acute infarct in the territory of the right ACA. Brain digital subtraction angiography showed severe stenosis at the origin of the A2 segment with distal dilatation and occlusion at the origin of the A3 segment of the right ACA, suggesting a diagnosis of dissection. Only treatment with atorvastatin, her clinical condition subsequently improved. The stenosis and dilatation of A2 segment were ameliorated as demonstrated by a follow-up CT angiography 5 months after onset. SAH concomitant with ischemia caused by ACA dissection is rare. Conservative treatment may be a safe and effective choice for patients with SAH concomitant with AIS due to ACA dissection. PMID- 28672906 TI - T-lymphocyte Kv1.3 channel activation triggers the NLRP3 inflammasome signaling pathway in hypertensive patients. AB - The aim of the current study was to investigate the correlation between voltage gated potassium 1.3 (Kv1.3) channel of peripheral blood T-lymphocytes and the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in hypertensive patients. Peripheral blood samples from the hypertensive Kazakh patients (n=30) and healthy Kazakh subjects (n=30) were collected. The T lymphocytes and serum were separated, and the state of Kv1.3 channels was detected using the patch clamp technique. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were used to detect the mRNA and protein expression levels of key molecules [NLRP3, caspase-1 and interleuking (IL)-beta] in the lymphocyte NLRP3 inflammasome pathway, while serum IL-1beta content was measured by ELISA assay. The results demonstrated no statistical difference in the subject baseline data between the two groups. While more significantly activated Kv1.3 channels were identified in the peripheral blood T-lymphocytes of the hypertension group compared to the normotension group, the mRNA and protein expression levels of NLRP3, caspase-1 and IL-1beta were elevated and their peripheral serum interleukin-1beta levels were significantly increased. After inhibiting the Kv1.3 channels using the classic potassium channel blocker, these indicators were all decreased significantly. The results indicate that the NLRP3 inflammasome pathway of peripheral blood T-lymphocytes in hypertensive Kazakh patients is activated, which may be correlated with the opening of the Kv1.3 channel. PMID- 28672908 TI - Correlation analysis of human embryo LeY glycan antigen expression and embryo quality. AB - This study assessed the feasibility of using LeY glycan secretion level in human embryos as a method of judging embryo quality. Embryo culture media from patients receiving in vitro fertilization-embryo transfer was collected, and quality scores of embryos were recorded. Secretions of LeY in the culture media in different development stages (from 4-cell to 10-cell), embryos in the same development stage of the same patients (8-cell/I) and embryos in the same development stage of different patients (8-cell/I) were examined by dot-blot. Embryos were divided into a hypersecretion group and hyposecretion group, based on their LeY secretion level. The embryo quality was evaluated by clinical observations, the number which developed to D3 cell stage and the number of successful embryo transplantations. LeY secretion increased as embryos developed from 4-cell to 10-cell (P<0.05); secretion of LeY of 8/I is not identical; development speed of embryos with different secretion level of LeY was also different. The number of embryos which developed to 6-cell or higher was 82.2% in the LeY hypersecretion group but only 60% in the hyposecretion group. The rate of successful transplantation was significantly higher in the hypersecretion group (71.1 vs. 40%). In conclusion, LeY glycan secretion level in human embryos is closely related to embryo quality. LeY may become a useful measure to evaluate embryo quality in the future. PMID- 28672909 TI - Feasibility of dual-low scheme combined with iterative reconstruction technique in acute cerebral infarction volume CT whole brain perfusion imaging. AB - The feasibility of application of low-concentration contrast agent and low tube voltage combined with iterative reconstruction in whole brain computed tomography perfusion (CTP) imaging of patients with acute cerebral infarction was investigated. Fifty-nine patients who underwent whole brain CTP examination and diagnosed with acute cerebral infarction from September 2014 to March 2016 were selected. Patients were randomly divided into groups A and B. There were 28 cases in group A [tube voltage, 100 kV; contrast agent, iohexol (350 mg I/ml), reconstructed by filtered back projection] and 31 cases in group B [tube voltage, 80 kV; contrast agent, iodixanol (270 mg I/ml), reconstructed by algebraic reconstruction technique]. The artery CT value, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), dose length product, effective dose (ED) of radiation and brain iodine intake of both groups were measured and statistically analyzed. Two physicians carried out kappa (kappa) analysis on the consistency of image quality evaluation. The difference in subjective image quality evaluation between the groups was tested by chi2. The differences in CT value, SNR, CNR, CTP and CT angiography subjective image quality evaluation between both groups were not statistically significant (P>0.05); the diagnosis rate of the acute infarcts between the two groups was not significantly different; while the ED and iodine intake in group B (dual low-dose group) were lower than group A. In conclusion, combination of low tube voltage and iterative reconstruction technique, and application of low-concentration contrast agent (270 mg I/ml) in whole brain CTP examination reduced ED and iodine intake without compromising image quality, thereby reducing the risk of contrast-induced nephropathy. PMID- 28672910 TI - Pre-treatment with spermine for acute cerebral ischemia/reperfusion injuries. AB - Acute cerebral ischemia/reperfusion injury (ACIR) rat model was used to investigate the effect of spermine on oxidative stress and apoptosis. Sixty healthy and clean male Sprague-Dawley rats were randomly divided into 3 groups: The sham-operated group (n=12), the model group (n=12) and the experiment group (n=36). The experiment group was further divided into 3 subgroups: The SPE-10 group (n=12), the SPE-25 group (n=12) and the SPE-50 group (n=12). Rats in the experimental sub-groups SPE-10, SPE-25 and SPE-50 were injected with 10, 25 and 50 mg/kg of spermine, respectively, one week before the establishment of rat models. Rats in the sham-operated and model groups were injected with 0.9% NaCl solution. We evaluated the effect of spermine on malondialdehyde (MDA) level and superoxide dismutase (SOD) activity using ELISA kits. Bax and Bcl-2 levels were measured using western blot analysis. Our results showed that after spermine injection, MDA levels markedly decreased, while SOD activity increased significantly. The variations in MDA levels and SOD activity were dose (spermine) dependent. Bax protein levels increased significantly, while Bcl-2 levels decreased significantly after the onset of ACIR injuries. After spermine injection, there was a significant decrease in Bax levels. Bcl-2 levels in these rats markedly increased. The observed decline in Bax levels and the increase in Bcl-2 levels in the experimental groups were dose-dependent. We concluded that spermine protected nerve tissues in rats with ACIR by decreasing the MDA level, increasing SOD activity and modifying the balance between Bax and Bcl-2 proteins. PMID- 28672911 TI - MicroRNA-30a-5p inhibits the proliferation and invasion of gastric cancer cells by targeting insulin-like growth factor 1 receptor. AB - MicroRNAs (miRs) are a class of small non-coding RNAs of 18-25 nucleotides in length that serve as key regulators in the development and progression of human cancers. Recently, miR-30b-5p, as a member of the miR-30 family, has been reported to act as a tumor suppressor in gastric cancer. However, the expression and function of miR-30a-5p in gastric cancer, as well as the corresponding underlying mechanism, remain unknown. In the present study, it was demonstrated that the expression of miR-30a-5p was significantly reduced in gastric cancer tissues (n=43) compared with normal gastric tissues (n=10; P<0.01). Similarly, miR-30a-5p was significantly downregulated in the gastric cancer cell lines AGS, HGC27, BGC823 and SGC7901, when compared with the normal gastric mucosa epithelial cell line GES-1 (P<0.01). In addition, overexpression of miR-30a-5p significantly inhibited the proliferation and invasion of AGS cells (P<0.01). Insulin-like growth factor 1 receptor (IGF-1R) was identified as a novel target of miR-30a-5p, and the protein expression of IGF-1R was negatively regulated by miR-30a-5p in AGS cells (P<0.01). Furthermore, overexpression of IGF-1R significantly reversed the inhibitory effect of miR-30a-5p on the proliferation and invasion of AGS cells (P<0.01), indicating that IGF-1R was involved in miR 30a-5p-mediated proliferation and invasion of AGS cells. It was also observed that the expression of IGF-1R mRNA was upregulated in gastric cancer tissues compared with normal gastric tissues (P<0.01), and its levels of expression were reversely correlated with that of miR-30a-5p in gastric cancer tissues (R2=0.3892; P<0.01). Collectively, these data suggest that miR-30a-5p inhibits the growth and metastasis of gastric cancer by directly targeting IGF-1R. Therefore, the miR-30a-5p/IGF-1R axis may be a potential therapeutic target in the treatment of gastric cancer. PMID- 28672912 TI - Rutin suppresses high glucose-induced ACTA2 and p38 protein expression in diabetic nephropathy. AB - The present study investigated the effect of rutin on high glucose-induced actin, alpha2, smooth muscle, aorta (ACTA2) and p38 protein expression in diabetic nephropathy (DN). Human mesangial cells were divided into a control group, high glucose-induced mesangial cell group, high glucose + captopril group, and high glucose + rutin group (low, middle and high doses of rutin). Cell viability, adenosine 5'-triphosphate (ATP) content, cell cycle, and ACTA2 and p38 protein expression were examined using MTT assay, ATP assay kit, flow cytometry and immunofluorescence staining in cultured human mesangial cells, respectively. Cell viability, ATP content, and ACTA2 and p38 expression increased significantly in high glucose-induced mesangial cells (P<0.05). However, at concentrations of 0.2, 0.4 and 0.8 umol/l rutin was able to inhibit high glucose-induced human mesangial cell viability, ATP content, and ACTA2 and p38 expression and improve the cell cycle progression of mesangial cells. In conclusion, ACTA2 and p38 proteins may have important roles in DN. Rutin may inhibit the expression of ACTA2 and p38 and may be utilized in the prevention and treatment of DN. PMID- 28672913 TI - Amniotic membrane-derived stem cells help repair osteochondral defect in a weight bearing area in rabbits. AB - Our study evaluated the use of amniotic membrane-derived stem cells for repairing osteochondral defects in a weight-bearing area in rabbits. Twenty-four 3-month old male or female New Zealand white rabbits were selected. The rabbits were randomly divided into 3 groups of eight, according to the treatment received for an experimentally inflicted femoral medial malleolus lesion, group I received a human acellular amniotic membrane seeded with bone marrow-derived mesenchymal stem cells (HAAM-BMSCs) implant; group II received a simple HAAM implant and the control group received no experimental lesion or treatment. The rabbits were sacrificed at 12 and 24 weeks after the procedures (4 rabbits in each time-point) and the cartilage repair status in each animal was evaluated under the microscope. The tissue of the HAAM-BMSCs group grew well covering an area in the visual field that was significantly larger than that of the HAAM group (p<0.05). The percentage of collagen II-positive area in the HAAM-BMSC group was significantly higher than that in HAAM group (p<0.05). The number of chondrocytes determined by toluidine blue staining was higher in the HAAM-BMSC group than that in the HAAM group (p<0.05). The Wakitani scores of the HAAM and HAAM-BMSC groups were significantly higher (worse) than those of the normal control group (p<0.05), but the score in the HAAM-BMSC group was significantly lower than that in the HAAM group (p<0.05). The Wakitani scores in the HAAM-BMSC group were not different between the two time-points taken. Based on our findings, the amniotic membrane-derived stem cells had a good therapeutic effect in repairing the osteochondral defects in the weight-bearing area, and the number of chondrocytes in the injured area was increased significantly, which accelerated the repair of the damaged tissue in rabbits. PMID- 28672914 TI - The levels of serum pro-calcitonin and high-sensitivity C-reactive protein in the early diagnosis of chronic obstructive pulmonary disease during acute exacerbation. AB - The level of of procalcitonin (PCT) and high-sensitivity C-reactive protein (hs CRP) in the acute exacerbation of COPD (AECOPD) was investigated. Total of 20 patients with acute exacerbation of COPD who were admitted to the Department of Respiratory Medicine, Binzhou Center Hospital in the period of October 2012 to April 2015 were enrolled in the AECOPD group. According to the color of the sputum, the patients with AECOPD were divided into purulent sputum group (n=8) and non-purulent sputum group (n=12). In addition, 15 healthy people from the outpatient medical center were also selected as healthy control group. The levels of serum PCT and hs-CRP in both groups were determined by chemiluminescence and immunoturbidimetry, respectively for the comparison analysis. The serum PCT concentration in AECOPD group was 2.07+/-5.57 ng/ml, while that in healthy control group was 0.21+/-0.17 ng/ml. Significant difference was found between serum PCT levels in the two groups (p<0.05). The serum concentration of hs-CRP in AECOPD group was 3.66+/-3.95 mg/l, which is significantly higher than that of the healthy control group (0.49+/-0.17) (p<0.001). In AECOPD group, the sensitivity of PCT, hs-CRP and white blood cell count was 75, 40 and 40%, respectively, while the specificity was 80, 100 and 100%, respectively, indicating that PCT has higher sensitivity than hs-CRP and white blood cell count (p<0.05). However, no significant difference was found in specificity among these three methods (p>0.05). PCT level of the patients in purulent sputum group was 3.72+/-8.80 ng/ml, while that of the patients in non-purulent sputum group was 0.97+/-1.06 ng/ml. The serum hs-CRP level of patients in purulent sputum group was 4.94+/ 4.60 mg/l, while that of the patients in non-purulent sputum group was (2.80+/ 3.38 mg/l). Both the above parameters showed no significant difference between the purulent sputum group and the non-purulent sputum group (p>0.05). In conclusion, serum PCT and hs-CRP levels can be used as auxiliary diagnosis index for acute exacerbation of COPD. Measurement of serum PCT and hs-CRP levels in patients with AECOPD may be helpful in guiding antibacterial drug therapy. PMID- 28672915 TI - Induction of reprogramming of human amniotic epithelial cells into iPS cells by overexpression of Yap, Oct4, and Sox2 through the activation of the Hippo-Yap pathway. AB - The present study has reported a novel method for producing induced pluripotent stem (iPS) cells. Primary human amniotic epithelial cells (HuAECs) were isolated from the amniotic membranes of pregnant women who received Cesarean sections. These cells were infected with retroviruses carrying octamer-binding transcription factor 4 (Oct4), (sex determining region Y)-box 2 (Sox2) and Yes associated protein (Yap) (OSY). Following in vitro culture for ~14 days, epithelial-like HuAECs exhibited several iPS clone-like cell colonies (OSY-iPS). These cell clones presented positive alkaline phosphatase features and expressed high levels of embryonic stem cell-like markers (Nanog homeobox, Sox2, Oct4, reduced expression protein 1, and SSES3/4). Additionally, epigenetic analysis results indicated that the methylation of CpG islands on endogenous Oct4 and Sox2 promoters was reduced in OSY-iPS cells. Furthermore, the majority of the histone H3 at lysine 9 sites that interacted with the Oct4 and Sox2 promoters were acetylated, suggesting that the transcription activities of the above two transcription factors significantly increased. In vivo and in vitro induced differentiation experiments demonstrated that OSY-iPS could develop into embryoid bodies in vitro, and express numerous cellular markers in the three germ layers. Furthermore, OSY-iPS could form teratomas in immunodeficient mice. The pathological detection results suggest that these teratomas contain numerous types of cells from the three germ layers. However, the results from the quantitative polymerase chain reaction and western blot analyses suggest that the Hippo-Yap signaling pathway was significantly activated in OSY-iPS cells. In conclusion, a novel method for iPS induction was established in the present study. HuAECs were successfully induced to reprogram iPS cells through the introduction of OSY to activate the Hippo-Yap signaling pathway. PMID- 28672916 TI - Diagnostic accuracy of coronary CT angiography combined with dual-energy myocardial perfusion imaging for detection of myocardial infarction. AB - The aim of the present study was to evaluate the diagnostic accuracy of second generation dual-energy computed tomography (DECT) myocardial perfusion imaging for the detection of myocardial infarction (MI) in patients with suspected MI. In total, 56 patients underwent DECT. Among those, 40 patients had MI that was detected by catheter coronary angiography and cardiac troponin I elevation and evolution of acute MI detected by electrocardiogram changes. The diagnostic accuracy, including the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the detection of MI were evaluated, as well as the coronary image quality of coronary artery and radiation dose. The sensitivity, specificity, PPV and NPV for the detection of MI were 95.0, 97.0, 86.4 and 98.9%, respectively. Moreover, the image quality was rated excellent (score 1) in 90.2% (515/571), good (score 2) in 6.5% (37/571), adequate (score 3) in 1.9% (11/571) and non-diagnostic (score 4) in 1.4% (8/571) of the coronary segments. The effective radiation dose was on average 6.1+/-1.5 mSv (3.1-10.9 mSv). Therefore, combined DE iodine maps and coronary CT angiography using the DECT may provide a high diagnostic accuracy for detecting MI with lower radiation exposure in patients with suspected MI. PMID- 28672917 TI - Downregulation of P16 promotes cigarette smoke extract-induced vascular smooth muscle cell proliferation via preventing G1/S phase transition. AB - The proliferation of vascular smooth muscle cells (VSMCs) serves an important role in cigarette smoking-associated vascular diseases; however, the underlying mechanisms responsible for this remain unclear. The aim of the present study was to elucidate the role of P16 in cigarette smoke extract (CSE)-induced VSMC proliferation and the underlying mechanism responsible. Human aortic smooth muscle cells (HAOSMCs) were exposed to CSE, and an MTT assay and flow cytometry were performed to evaluate cell proliferation and cell cycle distribution. Western blotting was conducted to examine protein expression and bisulfite genomic sequencing polymerase chain reaction was used to determine the methylation status of the P16 promoter CpG island. It was demonstrated that treatment with CSE significantly promoted the proliferation of HAOSMCs in a concentration- and time-dependent manner and induced a downregulation in P16 expression (all P<0.05). A luciferase reporter gene assay data demonstrated that CSE treatment induced hypermethylation of the P16 promoter, which led to a significant decrease in its transcriptional activity and significantly reduced P16 protein expression in HAOSMCs (both P<0.01). Furthermore, P16 downregulation induced a significant increase in the expression of cyclin-dependent kinase (CDK) 4, CDK6 and phosphorylated retinoblastoma (p-Rb) protein (all P<0.001) and significantly increased the ratio of cells in S phase in CSE-treated HAOSMCs (P<0.001). Overexpression of P16 inhibited CSE-induced cell proliferation through inducing cell cycle arrest in G1 phase (P<0.001), and led to decreased levels of CDK4 (P<0.01), CDK6 (P<0.01) and p-Rb (P<0.001) in HASMCs. The results of the present study therefore demonstrate that P16 may be associated with the CSE induced proliferation of VSMCs, suggesting that P16 serves a role in the development of cigarette smoke-associated vascular diseases. PMID- 28672918 TI - Liver metastasis is established by metastasis of micro cell aggregates but not single cells. AB - Cancer cell engraftment in the target organ is necessary to establish metastasis. Clinically, lymph node metastasis of single cells has been confirmed using cytokeratin staining. In the current study, a LacZ-labeled cancer cell line was used to visualize intrahepatic metastasis of single cells or liver micrometastasis. KM12SM-lacZ stably expressing LacZ was prepared with a highly metastatic colon cancer cell line, KM12SM. KM12SM-lacZ was injected into the spleen of nude mice and following 1 week the spleen was excised. The liver was then examined for metastasis following 1, 2 or 3 weeks. Confirmation of liver metastasis was completed by observing the grade of metastasis. Grade-1 metastasis (DNA level), human DNA in liver tissue was detected; Grade-2 metastasis (metastasis of single cells), confirmed by X-gal staining; Grade-3 metastasis (histopathological micrometastasis), diagnosed by light microscopy and Grade-4 metastasis (typical metastasis), easily detected macroscopically or by hematoxylin and eosin staining. The Grade-1 metastasis detection rates 1, 2 and 3 weeks following splenectomy were 50, 100 and 100%, respectively. Grade-2 metastasis was not detected by microscopy. The Grade-3 metastasis detection rates for 1, 2 and 3 weeks were 75, 100 and 100%, respectively. Micrometastasis was observed in the portal vein lumen and wall. The Grade-4 metastasis detection rates were 50, 100 and 100% for 1, 2 and 3 weeks respectively. Cancer cells were present in vessels surrounding the main tumor. In conclusion, a specific number of cancer cell aggregates may be necessary to establish hematogenous metastasis. PMID- 28672919 TI - Brain injury with systemic inflammation in newborns with congenital heart disease undergoing heart surgery. AB - The potential role of systemic inflammation on brain injury in newborns with congenital heart disease (CHD) was assessed by measuring levels of central nervous system (CNS)-derived proteins in serum prior to and following cardiac surgery. A total of 23 newborns (gestational age, 39+/-1 weeks) with a diagnosis of CHD that required cardiac surgery with cardiopulmonary bypass (CPB) were enrolled in the current study. Serum samples were collected immediately prior to surgery and 2, 24 and 48 h following CPB, and serum levels of phosphorylated neurofilament-heavy subunit (pNF-H), neuron-specific enolase (NSE) and S100B were analyzed. Systemic inflammation was assessed by measuring serum concentrations of complement C5a and complement sC5b9, and the following cytokines: Interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL12p70, interferon gamma and tumor necrosis factor (TNF)-alpha. Analysis of cord blood from normal term deliveries (n=26) provided surrogate normative values for newborns. pNF-H and S100B were 2.4- to 2.8-fold higher (P<0.0001) in patient sera than in cord blood prior to surgery and remained elevated following CPB. Pre-surgical serum pNF-H and S100B levels directly correlated with interleukin (IL)-12p70 (rho=0.442, P<0.05). pNF-H was inversely correlated with arterial pO2 prior to surgery (rho=-0.493, P=0.01) and directly correlated with arterial pCO2 post-CPB (rho=0.426, P<0.05), suggesting that tissue hypoxia and inflammation contribute to blood brain barrier (BBB) dysfunction and neuronal injury. Serum IL12p70, IL-6, IL-8, IL-10 and TNF-alpha levels were significantly higher in patients than in normal cord blood and levels of these cytokines increased following CPB (P<0.001). Activation of complement was observed in all patients prior to surgery, and serum C5a and sC5b9 remained elevated up to 48 h post-surgery. Furthermore, they were correlated (P<0.05) with low arterial pO2, high pCO2 and elevated arterial pressure in the postoperative period. Length of mechanical ventilation was associated directly with post surgery serum IL-12p70 and IL-8 concentrations (P<0.05). Elevated serum concentrations of pNF-H and S100B in neonates with CHD suggest BBB dysfunction and CNS injury, with concurrent hypoxemia and an activated inflammatory response potentiating this effect. PMID- 28672920 TI - In vivo repair of full-thickness cartilage defect with human iPSC-derived mesenchymal progenitor cells in a rabbit model. AB - Cell-based tissue engineering has the potential to restore cartilage defects. Induced pluripotent stem cells (iPSCs) are regarded as an alternative cell source in regenerative medicine. The purpose of the present study was to evaluate the use of mesenchymal stem cells (MSCs) derived from human iPSCs (hiPSCs) for the regeneration of cartilage defects in a rabbit model. Cartilage defects were made in the patellar grooves of New Zealand white rabbits. The rabbits were then divided into three groups according to implantation: Control group, scaffold implantation group and scaffold/hiPSCs-MSCs (experimental) group. MSCs were generated from hiPSCs via a step of embryoid body formation. Following flow cytological analysis, the hiPSCs-MSCs were plated onto poly(lactic-co-glycolide) and then transplanted into the cartilage defects in the experimental group. Six rabbits from each group were sacrificed at each time point. The outcome was assessed macroscopically and histologically at 3 and 6 weeks post-surgery. At 3 and 6 weeks, the experimental group showed more cartilage defect filling compared with the control and scaffold implantation groups. At 3 weeks, the experimental group showed much more repair tissue in the cartilage defect, although no cartilage-like tissue was observed. At 6 weeks, cartilage-like tissue was observed in the experimental group but not in the control or scaffold implantation groups. No teratoma formation was observed in any of the groups. The results indicate that iPSCs have the potential to repair cartilage defects in vivo. Therefore, iPSCs could be a new cell source for cartilage defect repair. PMID- 28672921 TI - The mechanism of blood concentrations of the Shenqi pill repairing injured epithelial cells of renal tubular in vitro. AB - In the present study, we investigated the best blood concentration of the mechanism of Shenqi pill repairing the injured epithelial cells of renal tubular in vitro. First, the injured hypoxia/reoxygenation model of rat proximal renal tubular epithelial cell strain (NRK-52E) was established. The animals were divided randomly into control, model, low concentration (5 ug/ml), moderate concentration (10 ug/ml) and high concentration (20 ug/ml) groups. The apoptotic rate was measured with flow cytometry and Jag2/Notch2/hes1 mRNA, and the protein expression was measured for 1, 3 and 7 days. It was found that in comparison to the control group, the growth of each group was prolonged with time, the levels of apoptosis, and the Jag2/Notch2/hes1 mRNA and protein expression decreased. Furthermore, the levels of the apoptotic rate, Jag2/Notch2/hes1 mRNA and protein expression of the moderate concentration and high concentration groups were significantly lower than those of the model and low-dose groups at each time point (P<0.05). In conclusion, the Shenqi Pill alleviates the damage of renal tubular epithelial cells by inhibiting the Jag2/Notch2/hes1 signaling pathway; suitable concentration such as 10-20 ug/ml can exert protective effect. PMID- 28672922 TI - Combining affinity propagation clustering and mutual information network to investigate key genes in fibroid. AB - The aim of the present study was to investigate key genes in fibroids based on the multiple affinity propogation-Krzanowski and Lai (mAP-KL) method, which included the maxT multiple hypothesis, Krzanowski and Lai (KL) cluster quality index, affinity propagation (AP) clustering algorithm and mutual information network (MIN) constructed by the context likelihood of relatedness (CLR) algorithm. In order to achieve this goal, mAP-KL was initially implemented to investigate exemplars in fibroid, and the maxT function was employed to rank the genes of training and test sets, and the top 200 genes were obtained for further study. In addition, the KL cluster index was applied to determine the quantity of clusters and the AP clustering algorithm was conducted to identify the clusters and their exemplars. Subsequently, the support vector machine (SVM) model was selected to evaluate the classification performance of mAP-KL. Finally, topological properties (degree, closeness, betweenness and transitivity) of exemplars in MIN constructed according to the CLR algorithm were assessed to investigate key genes in fibroid. The SVM model validated that the classification between normal controls and fibroid patients by mAP-KL had a good performance. A total of 9 clusters and exemplars were identified based on mAP-KL, which were comprised of CALCOCO2, COL4A2, COPS8, SNCG, PA2G4, C17orf70, MARK3, BTNL3 and TBC1D13. By accessing the topological analysis for exemplars in MIN, SNCG and COL4A2 were identified as the two most significant genes of four types of methods, and they were denoted as key genes in the progress of fibroid. In conclusion, two key genes (SNCG and COL4A2) and 9 exemplars were successfully investigated, and these may be potential biomarkers for the detection and treatment of fibroid. PMID- 28672923 TI - Terlipressin protects intestinal epithelial cells against oxygen-glucose deprivation/re-oxygenation injury via the phosphatidylinositol 3-kinase pathway. AB - Intestinal ischemia/reperfusion (I/R) injury is associated with a high morbidity and mortality. Vasopressin is administered to critically ill patients with potential intestinal I/R. However, the impacts of vasopressin on intestinal epithelia under ischemic/anoxic conditions remain unclear. The aim of the present study was to evaluate the effects of terlipressin, a highly selective vasopressin V1 receptor agonist, on oxygen and glucose deprivation/re-oxygenation (OGD/R) induced damage in intestinal epithelial cells (IEC-6). IEC-6 cells were subjected to OGD for 4 h, followed by 4 h re-oxygenation. Terlipressin was incubated with cells for 4 h following OGD. Following OGD/R, IEC-6 cell viability, proliferation and apoptosis, as well as cell cycle dynamics, were assessed and the levels of tumor necrosis factor (TNF)-alpha and 15-F2t-isoprostane in the culture medium were measured. In addition, wortmannin, a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, was administrated to investigate the mechanism of terlipressin action. The results demonstrated that IEC-6 cell viability and proliferation decreased, and cell apoptosis increased, following OGD/R. However, IEC-6 cell cycle dynamics did not significantly change 4 h after OGD. Incubation with 25 nM terlipressin significantly improved cell viability, proliferation and apoptosis. Furthermore, terlipressin inhibited the secretion of TNF-alpha and 15-F2t isoprostane from IEC-6 cells following OGD/R. The aforementioned effects of terlipressin were completely abolished following the application of 2 uM wortmannin. Therefore, the current study demonstrated that terlipressin administration following OGD attenuates OGD/R-induced cell damage via the PI3K signaling pathway. These results may help physicians to better understand and more effectively use terlipressin in a clinical setting. PMID- 28672924 TI - Plasma proteins as potential targets of abnormal Savda syndrome in asthma patients treated with unique Uighur prescription. AB - The therapeutic effect of Uighur prescription on abnormal Savda in asthma patients was evaluated using plasma proteomics in order to elucidate the biological mechanism and identify potential therapeutic targets of abnormal Savda. In the present study, 40 asthma patients with abnormal Savda including abnormal Savda Munziq and Savda Mushil were enrolled and treated with Uighur prescription. The effect of Uighur prescription on protein expression and potential targets was investigated by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and bioinformatics analysis. Expression of candidate proteins was verified by an enzyme-linked immunosorbent assay. Following treatment with the Uighur prescription, 22 proteins were differentially expressed in the plasma of patients with asthma and abnormal Savda. The majority of these proteins were localized in intermediate filaments and the cytoskeleton and acted as antioxidant enzymes and binding proteins. Furthermore, they participated in the defense and inflammatory response, and the response to oxidative stress and wound healing. Peroxiredoxin 2 and carboxypeptidase B2 expression was significantly upregulated, whereas S100A7 was considerably downregulated in the whole plasma of patients (all P<0.05) in accordance with the iTRAQ proteomics data. Uighur prescription of abnormal Savda may affect the whole regulatory network of protein expression that is altered following the development of abnormal Savda in patients with asthma. PMID- 28672925 TI - Dietary soy isoflavones alleviate dextran sulfate sodium-induced inflammation and oxidative stress in mice. AB - It has been hypothesized that soy isoflavones exhibit anti-oxidative and anti inflammatory functions, however, the effects of soy isoflavones on inflammatory bowel diseases remain unknown. Therefore, the present study aimed to investigate the effect and underlying mechanism of dietary soy isoflavones on dextran sulfate sodium (DSS)-induced colitis. Mice were administered DSS and soy isoflavones, and histomorphometry, oxidative stress, inflammation and intestinal tight junctions were determined. The current study demonstrated that dietary soy isoflavones alleviated DSS-induced growth suppression, colonic inflammatory response, oxidative stress and colonic barrier dysfunction. DSS treatment was indicated to activate Toll-like receptor 4 (TRL4) and myeloid differentiation protein 88 (MyD88) in mice, whereas dietary soy isoflavones inhibited Myd88 expression in DSS-challenged mice. In conclusion, dietary soy isoflavones alleviate DSS-induced inflammation in mice, which may be associated with enhancing antioxidant function and inhibiting the TLR4/MyD88 signal. PMID- 28672926 TI - Bilateral diffuse lamellar keratitis triggered by permanent eyeliner tattoo treatment: A case report. AB - Diffuse lamellar keratitis (DLK) is a sterile inflammation of the cornea, which may occur after laser-assisted in situ keratomileusis (LASIK) surgery. Little is known about the association of DLK with permanent eyeliner tattoo. The present case report describes the case of a 37-year-old Chinese woman who developed severe foreign body sensation in both eyes 1 week after receiving bilateral permanent eyeliner tattoo treatment. The patient had received bilateral LASIK surgery 10 years previously. Slit-lamp biomicroscopy revealed diffused granular infiltrates precipitated around the edge of the corneal flaps in both eyes. After topical treatment, DLK persisted. Therefore, the patient underwent surgery to remove the corneal epithelium around the DLK lesion. There was no recurrence of the disease during the 3-month observation period. To our knowledge, this is the first case report describing a case of late-onset of DLK that was triggered by permanent eyeliner tattoo. Doctors should be aware of the diagnosis and treatment of this complication associated with the application of permanent eyeliner tattoo as the popularity of this cosmetic procedure increases. PMID- 28672927 TI - Fungal chorioretinitis with systemic candidiasis in an infant following treatment with broad spectrum antibiotics: A case report. AB - Fungal chorioretinitis is a rare complication of neonatal fungemia that may lead to vision loss. Early diagnosis and aggressive treatment are essential to avoid vision loss. This study describes a case of a full term infant with candidiasis infection, which disseminated from the eye to the hip joint, and the diagnosis and treatment of fungal chorioretinitis and hip osteoarthritis with systemic candidiasis. The current case report indicates that the duration of therapy for fungal chorioretinitis should be at least 4-6 weeks long and should ideally continue until all clinical evidence of intraocular infection has been resolved. Close follow-up of infants who survive fungemia is essential. Therefore, early diagnosis and appropriate duration of antifungal treatment are necessary. PMID- 28672928 TI - Mechanism of Mongolian medical warm acupuncture in treating insomnia by regulating miR-101a in rats with insomnia. AB - MicroRNAs (miRNAs or miRs) and the target genes before and after warm acupuncture at the genetic level were assessed, and the cytokines and neurotransmitters related to insomnia were studied. Male Sprague-Dawley rats were used to create PCPA insomnia rat models and randomly divided into the normal, model, warm acupuncture, and drug groups. The Dinghui Acupoint, Heyi Acupoint, and Xin Acupoint were inserted in the Mongolian medicine warm acupuncture group. The differential expression profile of microRNA in the brain tissue of the insomnia rats was determined before and after Mongolian medicine warm acupuncture for establishment of miR-101a mimics and inhibitor. qPCR was used to detect the expression level of miR-101a. Western blotting was used to detect the expression level of PAX8. The rats receiving Mongolian medicine warm acupuncture had 141 miRNAs with differential expression compared with the normal rats. The expression level of miR-101a in the cells of the hippocampus of the insomnia rats transfected with miR-101a mimics increased significantly at 72 h (P<0.05). The activity of the neuronal cells transfected with miR-101a inhibitor increased significantly at 72 h (P<0.05). The western blotting result indicated that the expression of the PAX8 protein in the neuronal cells of the insomnia model rats was inhibited and downregulated significantly at 72 h after addition of miR-101a mimics compared with that in the scramble added group (P<0.01). The levels of the interleukins IL-1, IL-2, and IL-6 and the tumor necrosis factor-alpha in the hypothalamus, hippocampus, and prefrontal cortex decreased significantly compared with those in the blank control group (P<0.05). The levels of noradrenaline, dopamine, and glutamic decreased significantly following warm acupuncture or western medicine treatment (P<0.05). In conclusion, this study demonstrates that the upregulation of miR-101a in the rats treated with warm acupuncture is directly associated with PAX8 regulation. PMID- 28672929 TI - Evaluation of clinical curative effects of disposable stitching instrument in redundant prepuce patients. AB - The present study aimed to investigate the clinical curative effect of disposable stitching instrument operation in patients with redundant prepuce or phimosis. A total of 102 cases of patients with circumcision were randomly selected (from June 2013 to December 2014) from the department of plastic and aesthetic surgery of our hospital and were randomly divided into control and observation groups (n=51). Patients in the control group were treated by traditional circumcision operation, while patients in the observation group were treated by novel disposable circumcision stitching instrument. Operation time, bleeding volume, incision healing time, postoperative complications and incision aesthetic satisfaction in the groups were observed. As a result, intraoperative bleeding volume of patients in the observation group was significantly less in comparison to the control group. Operation time and incision healing time of patients in the observation group was shorter than that of the control group. Additionally, the incidence of postoperative complications of patients in the observation group was noted to be lower than that of the control group. On the other hand, the incision aesthetic satisfaction of patients in the observation group was higher than that of the control group. Blood vessel counting and nerve fiber counting of tissue specimen in the observation group were more than those of the control group. Postoperative VAS scores of patients in the observation group were significantly lower than that of the control group. Each rating scale scores of EPQ of patients in the observation group improved significantly compared with that of the control group. In conclusion, the present findings show that disposable circumcision stitching instrument operation is more advantageous in comparison to the traditional procedure along with minimal compilations and better post surgery health condition of patients. PMID- 28672930 TI - Isolation and characterization of in vitro culture of hair follicle cells differentiated from umbilical cord blood mesenchymal stem cells. AB - The present investigation explored the in vitro culture, isolation and characterization of hair follicle cell differentiation from umbilical cord blood mesenchymal stem cells (MSCs). Flow cytometry was used to obtain MSCs from the isolation and purification of human umbilical cord blood MSCs. Culture suspension of hair follicle organ was centrifuged and the supernatant used in the culture medium of MSCs, and the entire process of induced differentiation was recorded by photomicroscopy. The expression level of surface marker CK15 of hair follicle cells obtained from induced differentiation was detected with immunofluorescence. RT-PCR method was used to further detect the difference in expression of CK15 between hair follicle cells and umbilical cord blood MSCs, and statistical analysis was carried out. CD44+CD29+ double-labeled cells accounted for 50.8% of all the samples of umbilical cord blood MSCs in this study. The diameter of hair follicle cells differentiated from umbilical cord blood stem cells reached 800*10 3 mm after 3 weeks of cell culture. Based on the detection and colocalization of CK15 expression in induced hair follicle cells, the overlap ratio between CK15 and nuclei reached 83% in hair follicle cells, which was obviously higher than that in umbilical cord blood stem cells. The difference had statistical significance (P<0.05). In conclusion, hair follicle cells can be successfully differentiated from umbilical cord blood stem cells by using the supernatant from hair follicle cells. This method can be used for high-speed induced differentiation with high purity, which is promising for clinical application. PMID- 28672932 TI - Intravascular application of electrocautery in a rabbit model of abdominal aortic endarterectomy. AB - Effective therapies for preventing perioperative complications such as thrombosis and inflammation after coronary endarterectomy (CE) are lacking. Electrocoagulation electrotomes have been routinely used in surgery for their cutting, clotting, and hemostatic properties. As strong flattening tools, their electrocautery function may prevent mechanical intimal-adventitial injury to arterial circulation and attenuate stenosis. The present study investigated the effects of intravascular application of electrocautery on ameliorating inflammation and thrombosis in a rabbit model of abdominal aortic endarterectomy. New Zealand rabbits were randomly divided into the sham, control (endarterectomy), and study (endarterectomy + electrocautery) groups with 10 in each group. Abdominal aortas were partially blocked and intima was removed. Electrocautery was performed with an electrocoagulation electrotome through the entire blocked vessel lumen. Vascular ultrasound parameters, molecular biological and histological characteristics of the abdominal aorta including vascular diameter, blood flow velocity, serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels, and apoptosis rate of vascular endothelial cells (ECs) were evaluated postoperatively by vascular Doppler ultrasound, ELISA, real time RT-PCR, flow cytometry, and immunofluorescence at various time points. Compared with the endarterectomy + electrocautery group, the isolated endarterectomy group had significantly increased levels and gene expression of TNF-alpha and IL-6 (P<0.05), and rates of apoptosis of vascular ECs (P<0.05), with gradual vascular stenosis and decreased blood flow velocity. In conclusion, intravascular application of electrocautery has favorable short-term effects on the abdominal aorta and can reduce inflammation in a rabbit model of abdominal aorta endarterectomy. Long-term anti-inflammatory and anti-thrombotic effects on arterial remodeling and the clinical value of electrocautery in CE remain to be determined. PMID- 28672931 TI - Resveratrol enhances vascular reactivity in mice following lipopolysaccharide challenge via the RhoA-ROCK-MLCP pathway. AB - The aim of the present study was to identify whether sepsis-induced vascular hyporeactivity is associated with microcirculation disturbance and multiple organ injuries. The current study assessed the impact of resveratrol (Res) treatment on lipopolysaccharide (LPS) challenge mediated vascular hyporeactivity. Effects of Res treatment (30 mg/kg; i.m.) at 1 h following LPS stimulation (5 mg/kg; i.v.) on the survival time, mean arterial pressure (MAP), and maximal difference of MAP (DeltaMAP) to norepinephrine (NE; 4.2 ug/kg) in mice were observed. The reactivity to gradient NE of isolated mesenteric arterioles and the association with the RhoA-RhoA kinase (ROCK)-myosin light chain phosphatase (MLCP) pathway were investigated by myography, and the signaling molecule protein levels were assessed using ELISA. Res treatment prolonged the survival time of mice subjected to LPS challenge, but did not prevent the LPS-induced hypotension and increase in DeltaMAP. Res treatment and RhoA agonist U-46619 incubation prevented LPS-induced vascular hyporeactivity ex vivo, which were suppressed by incubation with ROCK inhibitor Y-27632. LPS-induced vascular hyporeactivity was not affected by the MLCP inhibitor okadaic acid incubation, but was further downregulated by the co incubation of OA plus Y-27632. The inhibiting effect of Y-27632 on Res treatment was eradicated by incubation with U-46619. Furthermore, RhoA inhibitor C3 transferase did not significantly inhibit the enhancing role of Res treatment, which was further increased by U-46619 plus C3 transferase co-incubation. In addition, Res treatment eradicated the LPS-induced decreases in p-RhoA and p Mypt1 levels and increases in MLCP levels. The results of the present study indicate that post-treatment of Res significantly ameliorates LPS-induced vascular hyporeactivity, which is associated with the activation of the RhoA-ROCK MLCP pathway. PMID- 28672934 TI - First branchial cleft anomalies in children: Experience with 30 cases. AB - First branchial cleft anomalies (FBCA) are rare in the clinical setting, as they account for 1 to 8% of all branchial abnormalities. The purpose of this study is to explore the relationship between the fistula tract and facial nerve and the surgical method of FBCA. This retrospective study included 30 cases of FBCA in children managed from 2009 to 2016. All patients underwent surgery to remove the tract of the FBCA. We reviewed the clinical data of the patients to obtain their demographics and management. Thirty patients (11 male and 19 female) with anomalies of FBCA were diagnosed. The ages ranged from 1 to 13 years (median, 3 years). Twenty cases had a close relationship with the parotid gland. The facial nerve was identified in 20 of the 30 patients. The tract ran deep to the facial nerve in 3 cases, superficial to it in 21 cases, and passed between the branches of the nerve in 6 cases. The facial nerve was not identified in ten patients, as the tract was superficial to it. There were 2 cases of postoperative temporary facial paralysis (2/30, 6.7%). The symptoms gradually improved after one month, 1 case had permanent facial paralysis (1/30, 3.3%), and 1 case had postoperative recurrence. Complete excision of the tract is the only way to manage FBCA, and the course of the tracts vary and have different relationships with the facial nerve. There are 3 types: Superficial, deep to the facial nerve, and between the branches of the nerve. Therefore, surgical approaches differ among the various types, and careful preoperative planning and protecting the facial nerve during resection of the tract are essential. PMID- 28672933 TI - A systematic review and meta-analysis of published randomized controlled trials of combination of clopidogrel and aspirin in transient ischemic attack or minor stroke. AB - The use of antiplatelet agents in patients with ischemic stroke is recommended. In this study, we compared the efficacy and safety of the treatment of clopidogrel plus aspirin (ASA) and that of ASA alone in patients with mild stroke/transient ischemic attack (TIA). Randomized controlled trial (RCT) studies of Clop + ASA vs. ASA therapy in the patients with minor stroke/TIA were identified by electronic bibliographic searches. The primary result was recurrent stroke, while myocardial infarction (MI) as well as vascular mortalities were the secondary result, and major hemorrhagic events were the safety result. A comparative analysis of binary outcomes was performed on the treatment groups, with the employment of fixed effect models and the measurement of risk ratios (95% CI). Five RCT studies involving 9,527 patients were included. Compared with the group with ASA treatment, there was significant reduction in the incidence of recurrent stroke in the group with Clop + ASA (RR=0.76, 95% CI=0.67-0.87, P<0.0001), and there was no significant increase in the incidence of vascular mortalities and MI (RR=1.08, 95% CI=0.83-1.41, P=0.56) and no significant change in major hemorrhagic events (RR=1.55, 95% CI=0.72-3.36, P=0.26). Therefore, the treatment with Clop + ASA seems safe as well as effective for decreasing stroke recurrence. In addition, this is related to a statistically insignificant trend in increasing vascular mortalities, MI, and primary hemorrhagic events. These findings need to be confirmed in prospective studies. PMID- 28672935 TI - Next-generation sequencing reveals lymph node metastasis associated genetic markers in colorectal cancer. AB - Colorectal cancer is the third most prevalent type of cancer in the United States. Early diagnosis of lymph node metastases is essential to improve the prognosis for patients with colorectal cancer. Therefore, the present study aimed to screen genetic markers, including single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and mRNA expression, associated with lymph node metastases in patients with colorectal cancer to enable an early diagnosis. Targeted next-generation sequencing was applied to capture SNPs and CNVs in tumor related candidate genes within tumor tissues from 39 colorectal cancer patients; reverse transcription-quantitative polymerase chain reaction was used to detect the specific mRNA level of tumor-related candidate genes, including vascular endothelial growth factor C, cyclin-A2, Interleukin-2, ATP-binding cassette sub family G member 2, epidermal growth factor (EGF) and nuclear factor kappa B subunit 1 (NFKB1) on chromosome 4. The SNPs in solute carrier family 28 member 3 (SLC28A3), breast cancer 1 (BRCA1), ribonucleotide reductase regulators subunit M2 (RRM2), PMS1 homolog 2 (PMS2), cytidine deaminase (CDA), epoxide hydrolase 1 (EPHX1), heterogenous ribonucleoprotein particle-associated with lethal yellow (RALY), Siglec-3 (CD33), B cell lymphoma 10 (BCL10), ETS variant 1 (ETV1), macrophage stimulating 1 receptor 1 (MST1R), lysine methyltransferase 2B (KMT2B), B cell lymphoma 2 (BCL2), U6 small nuclear RNA-associated Sm-like protein 3 (LSM3), thyroid transcription factor 1 (TTF1) and mitogen-activated protein 3 kinase 1 (MAP3K1) were significantly associated with lymphatic metastasis (P<0.05). EGF and NFKB1 were both observed to be significantly downregulated in the lymph node metastases group (P<0.05). Although no association between CNVs and lymph node metastases in patients with colorectal cancer was observed in the present study, SNPs in SLC28A3, BRCA1, RRM2, PMS2, CDA, EPHX1, RALY, CD33, BCL10, ETV1, MST1R, KMT2B, BCL2, LSM3, TTF1 and MAP3K1 were significantly associated with colorectal cancer. Downregulation of EGF and NFKB1 was also identified to be associated with lymph node metastases in colorectal cancer. The findings of the current study provide a scientific basis for the clinical inspection of lymphatic metastasis and prognosis prediction, intervention and guidance therapy for patients with colorectal cancer. PMID- 28672936 TI - Apoptosis-inducing effect of myxoma virus on human neuroglioma cell lines. AB - The purpose of this study was to further evaluate the role of myxoma virus (MYXV) as an oncolytic agent against experimental human gliomas in vitro, and analyze the effect of MYXV on malignant glioma cells at different incubation periods and infected at different multiplicities of infection. Neuroglioma cell lines U251 and A172 were cultured with various infective doses of myxoma virus at different time points (0-3 days) and cellular survival rates were evaluated using an MTT assay. Cell viability and cell death rates were assessed using Annexin V/propidium iodide and applying flow cytometry. Furthermore, the expression levels of phosphorylated AKT (p-AKT) in malignant gliomas were detected by western blot analysis to investigate the possible cell signaling targets in the pathway. MYXV exhibited a dose and time-dependent cytotoxic effect on neuroglioma cells, and there was increased expression of p-AKT in malignant gliomas. The present study confirms that MYXV induces oncolysis of malignant gliomas through regulating the activation of AKT. As such, MYXV is a potential therapeutic agent against human malignant gliomas. PMID- 28672937 TI - Is it cardiac involvement mimicking acute myocardial infarction in idiopathic inflammatory myopathy? AB - Idiopathic inflammatory myopathy (IIM) comprises a group of rare systemic diseases characterized by progressive weakness of the symmetrical proximal limb muscles, elevated muscle enzymes, inflammation or necrosis on muscle biopsy. IIM may impair the function of multiple organs, particularly the heart. However, it rarely manifests as acute myocardial infarction (AMI) at initial presentation. The present study described the case of a 39-year-old woman with AMI, whose muscle biopsy on the left arm conformed to polymyositis. Coronary arteriography showed irregularities in the left descending and right coronary artery (25% diameter reduction in middle segment). It was concluded that AMI was the chief manifestation of IIM at initial presentation. Furthermore, to the best of our knowledge, the present study was the first to provide a systematic literature review to assess AMI in IIM patients and discuss the possible causes of AMI. PMID- 28672938 TI - Edaravone improves spatial memory and modulates endoplasmic reticulum stress mediated apoptosis after abdominal surgery in mice. AB - Patients who receive major surgery often develop postoperative cognitive dysfunction (POCD); however, there is a lack of effective management as the pathogenesis of this disorder has not been fully elucidated. The neuroprotective effects of edaravone have been characterized in both in vitro cultured cells and in experimental animal models. The present study aimed to determine the potential role of edaravone in surgery-induced cognitive decline in mice. Animals were assigned to three groups: Control group (n=32), where mice received local anesthesia; surgery group (n=32), where mice underwent abdominal surgery under anesthesia; and edaravone group (n=32), where mice received abdominal surgery and were administered with edaravone (3 mg/kg). Morris water maze and T-maze tests demonstrated that edaravone attenuated surgery-induced cognitive impairment. Nissl staining indicated that edaravone prevented neuronal loss in the hippocampus of mice that underwent surgery. Furthermore, treatment with edaravone mitigated the surgery-induced upregulation of glucose-regulated protein 78 and CCAAT-enhancer-binding homologous protein and reduced the number of terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling-positive nuclei in mice hippocampi. In conclusion, edaravone may prevent POCD-induced neuronal apoptosis through attenuating endoplasmic reticulum stress. PMID- 28672939 TI - Triptolide suppresses ultraviolet B-enhanced sebum production by inhibiting the biosynthesis of triacylglycerol in hamster sebaceous glands in vivo and in vitro. AB - Ultraviolet B (UVB) irradiation causes alterations in cutaneous barrier function, including excessive production of sebum in sebaceous glands, which is associated with the aggravation of acne. This study aimed to evaluate the inhibitory effects of triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, on sebocytic lipogenesis in UVB-irradiated hamster skin in vivo and in vitro. Topical application of triptolide decreased the UVB-enhanced sebum accumulation in the sebaceous glands of hamster skin. The level of triacylglycerol (TG), a major sebum component, on the skin surface was reduced by triptolide treatment in UVB-irradiated hamsters, whereas there was no change in that of free-fatty acids and cholesterol, which are minor sebum components. UVB irradiation significantly enhanced TG production (P<0.01 in extracellular lipids, P<0.05 in intracellular lipids), and the activity of acyl coenzyme A/diacylglycerol acyltransferase (DGAT), a rate-limiting enzyme of TG synthesis, in differentiated hamster sebocytes (P<0.05 at 6 h and UVB of 0.62 kJ/m2, P<0.001 at 24 h and UVB 0.37 or 0.62 kJ/m2). Furthermore, triptolide significantly inhibited UVB-enhanced TG production (P<0.05 at 28 nM and P<0.01 at 56 and 112 nM triptolide) and DGAT activity (P<0.01 at 28 nM and P<0.001 at 56 and 112 nM triptolide) in differentiated hamster sebocytes. These results provide novel evidence that triptolide decreases UVB-enhanced sebum production by inhibiting DGAT-dependent TG biosynthesis in differentiated hamster sebocytes. These findings may be applicable to the prevention of acne aggravation. PMID- 28672940 TI - Overactivated autophagy contributes to steroid-induced avascular necrosis of the femoral head. AB - Steroid-induced avascular necrosis of the femoral head (SANFH) is a mainly bilateral complication of steroid therapy that involves extensive necrosis, and frequently occurs in young and middle-aged individuals, with a high disability rate. Autophagy is an intracellular lysosomal degradation process occurring in numerous diseases. However, the effect of dexamethasone (DXM)-induced autophagy on osteoblasts is unclear. The aim of the present study was to investigate the effects of autophagy on SANFH. In the present study, femoral head of SANFH patients was collected, and the autophagy in the samples was evaluated. In addition, cell proliferation, membrane integrity and differentiation of osteoblasts were also detected to confirm the effect of DXM on a mouse osteoblasts cell MC3T3-E1 in vitro. Beclin 1 and microtubule-associated protein 1 light chain 3 were used as the markers of autophagy, while the autophagy inhibitor 3-methyladenine (3-MA) was used to investigate the role of autophagy in DXM-challenged osteoblasts. Immunohistochemistry results demonstrated that Beclin1 was markedly increased in the femoral head of SANFH patients. Furthermore, the treatment of osteoblasts with DXM decreased cell viability, increased lactate dehydrogenase activity in the cell culture supernatant, and reduced the alkaline phosphatase activity and bone morphogenetic protein-2 expression in osteoblasts in vitro. By contrast, 3-MA treatment attenuated the cell injury induced by DXM. The present study indicates that overactivated autophagy may be an important factor contributing to SANFH, and autophagy may be a potential target for the prevention of SANFH. PMID- 28672941 TI - Ectopic pregnancy in the liver incidentally diagnosed by imaging: A case report. AB - The present report describes the case of a 31-year-old woman diagnosed with an ectopic pregnancy in the liver. The patient presented with amenorrhea for 40 days and abdominal distention for 27 days. A liver mass had been detected 6 days prior to presentation. Using ultrasound (US), a hyperechoic mass with a fluid sonolucent area was detected in the right hepatic lobe. Examination by computed tomography (CT) revealed the presence of a mass in the right hepatic lobe with a slightly low-density peripheral region and an oval central portion of lower density in the plain scan; the enhanced scan revealed a significantly enhanced peripheral region and a non-enhanced central portion. 18F-fluodeoxyglucose (FDG) positron emission tomography (PET)-CT showed a mass in the right hepatic lobe with an increased intake of FDG in the peripheral region (maximum standard uptake value, 5.7) and a non-increased intake of FDG in the central portion. The patient was then subjected to hysteroscopy and laparoscopy. Histopathologically, the mass was an ectopic pregnancy. The patient recovered following the surgery. In conclusion, a timely diagnosis of ectopic pregnancy was made for a 31-year-old women with an ectopic pregnancy in the liver on the basis of US, CT and PET-CT imaging results, which enabled surgery to be undertaken prior to any serious consequences. These observations may be helpful for the diagnosis of similar cases in the future. PMID- 28672942 TI - Adenovirus-mediated bone morphogenetic protein-2 promotes osteogenic differentiation in human mesenchymal stem cells in vitro. AB - Delayed and failed bone union following fracture is a common clinical complication that requires treatment in orthopedics. Cell-based therapies and tissue-engineering approaches are potential therapeutic strategies for bone repair and fracture healing. However, the effect of adenovirus expressing bone morphogenetic protein-2 (Ad-BMP-2) on the osteogenic ability of human mesenchymal stem cells (hMSCs) has remained to be fully elucidated. Therefore, in the present study, hMSCs were transduced using Ad-BMP-2 to assess the effects of its application and to determine whether Ad-BMP-2 promotes the osteogenic differentiation of hMSCs. The purity of the hMSC cultures was assessed using flow cytometric analysis. In order to assess the osteogenic activity, alkaline phosphatase activity (ALP) was measured and to estimate the osteoblastic mineralization and calcification, von Kossa staining for phosphates was performed. Cells positive for Src homology 2 domain were determined to be hMSCs and the presence of CD34 was used to distinguish hematopoietic lineages. Following treatment, the Ad-BMP-2 and control group had significantly increased ALP levels (P<0.05). Compared to the blank group and the group transfected with adenoviral vector containing LacZ, the phosphate deposition in the Ad-BMP-2 group and the positive control group treated with dexamethasone was markedly increased. The results of the present study suggested that Ad-BMP-2 promotes osteogenic differentiation in hMSCs and may have a potential application in treating delayed union and nonunion following bone fracture. PMID- 28672943 TI - Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes. AB - The present study aimed to explore the renoprotective effect of metformin on diabetic nephropathy in type 2 diabetic rats. A rat model of type 2 diabetic nephropathy (T2DN) was successfully induced via a high-fat diet combined with a single low-dose of streptozotocin. Metformin was administered intragastrically for 13 weeks, and fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), HDL-c, LDL-c, urinary and serum creatinine levels were subsequently examined at the end of administration. Renal function was determined after the treatment protocol. Expression levels of transforming growth factor (TGF)-beta1 and connective tissue growth factor (CTGF) were assessed via immunohistochemical analysis. Superoxide dismutase activity, malondialdehyde content and glutathione peroxidase levels were assessed in kidney tissues using commercially available kits. The results of the present study demonstrated that metformin administration significantly decreased the levels of serum blood urea nitrogen, serum creatinine, creatinine clearance, urinary albumin excretion and fasting blood glucose in rats with T2DN. Furthermore, TG, TC and LDL-c levels were significantly decreased following metformin treatment, whereas HDL-c was increased. Metformin treatment significantly increased SOD activity and significantly decreased malondialdehyde levels, as compared with the model group. It was also demonstrated that metformin administration significantly decreased the expression levels of TGF-beta1 and attenuated the morphological changes associated with T2DN in rats. These data clearly demonstrated the renoprotective effects of metformin against the development and progression of T2DN in rats. The underlying mechanism of this protective effect may be associated with glycemic control, lipid metabolism, and anti-oxidative and anti-inflammatory functions. PMID- 28672944 TI - Effective prediction of preeclampsia by measuring serum angiotensin II, urinary angiotensinogen and urinary transforming growth factor beta1. AB - The aim of the current study was to analyze serum angiotensin II (Ang II), urinary angiotensinogen (AGT) and urinary transforming growth factor beta1 (TGFbeta1) levels in relation to the clinical manifestation of preeclampsia, and to explore the effects of circulating and renal renin angiotensin system (RAS) in preeclampsia patients. An enzyme-linked immunosorbent assay was used to evaluate serum Ang II, urinary AGT and urinary TGFbeta1 in preeclampsia, pregnancy-induced hypertension and normotensive pregnancy patients. The correlation between urinary AGT and serum Ang II, urinary TGFbeta1, blood pressure and urinary albumin/creatinine ratio (ACR) were then analyzed. Receiver operating characteristic (ROC) curves were also constructed. Negative correlations were observed between urinary AGT and blood pressure, and urinary AGT and ACR, whereas positive correlations were found between urinary AGT and serum Ang II, and urinary AFT and TGFbeta1. Moreover, the area under the curve (AUC) of AGT was 0.841 [95% confidence interval (CI): 0.742-0.940, P<0.001], which was significantly higher than that of serum Ang II or urinary TGFbeta1 (P<0.001). The optimal cut-off value of urinary AGT at 193 ng/l showed a high diagnostic value in preeclampsia. The AUC of combined serum Ang II, urinary AGT and urinary TGFbeta1 was 0.918 (95% CI: 0.845-0.990, P<0.001), with a sensitivity of 83.9% and a specificity of 89.7%. Decreased levels of urinary AGT in preeclampsia patients suggested that local renal RAS was suppressed, and this was associated with hypertension and proteinuria. A high value preeclampsia diagnosis could be achieved by measuring urinary AGT or a combination of urinary AGT, serum Ang II and urinary TGFbeta1. PMID- 28672945 TI - O6-methyl-guanine-DNA methyltransferase methylation and IDH1/2 mutation in small cell lung cancer. AB - Small cell lung cancer (SCLC) is sensitive to first-line chemotherapy and radiotherapy, but frequently recurs. Temozolomide is a chemotherapeutic drug suitable for the treatment of relapsed SCLC, particularly when brain metastases are present. The response of SCLC to temozolomide may be associated with the methylation status of O6-methyl-guanine-DNA methyltransferase (MGMT). Isocitrate dehydrogenase (IDH) mutation is an independent prognostic factor of good outcome in gliomas and appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. In order to identify the status of MGMT promoter methylation and IDH1/2 mutation of SCLC in China, 33 SCLC specimens from patients that underwent surgery were retrospectively collected in Zhejiang Cancer Hospital (Hangzhou, China) between 2008 and 2014. High-resolution melting analysis and methylation-specific polymerase chain reaction were used to detect MGMT promoter methylation, and polymerase chain reaction amplification and Sanger sequencing were utilized to detect IDH1/2 mutation. Of the 33 examined SCLC specimens, MGMT promoter methylation was detected in 17 patients (51.5%), and no IDH1/2 mutations were detected in the analyzed samples. These findings indicate that the IDH1/2 mutation may not be an ideal marker in SCLC patients treated with temozolomide. Future studies on the predictive and prognostic value of MGMT promoter methylation are urgently required for patients with relapsed SCLC treated with temozolomide in China. PMID- 28672946 TI - Enterovirus 71 infection impairs the reproductive capacity of female mice. AB - Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD); however, no clinically approved vaccine or antiviral treatment is currently available for EV71 infection. In the present study, a murine model of EV71 infection was constructed. The clinical isolates of EV71 were amplified in Vero cells and used to challenge adult mice via hydrodynamic injection (HI) and intraperitoneal injection (IP). Following two challenges, >50% of the mice succumbed to EV71 infection. Surviving female mice were identified to have impaired fertility and their litter sizes were significantly decreased compared with the control group. The antibody against EV71-VP1 persisted in the sera of female mice at a high titer for >2 years after challenge. The maternal antibody in the offspring sera also persisted for ~1 year and disappeared after ~2 years. Results from the present study suggest that a high titer of active EV71 was able to impair the reproductivity of adult female mice, and that high levels of maternal antibody persisted in the offspring and protected postnatal mice from EV71-induced mortality. The promising antigenicity, immunogenicity and reactogenicity of EV71 suggests that it a potential vaccine target that may be beneficial to the control of HFMD, through immunizing infants and women of reproductive age. PMID- 28672947 TI - Peucedanum japonicum Thunb. ethanol extract suppresses RANKL-mediated osteoclastogenesis. AB - The constituents of Peucedanum japonicum Thunb. (PJ) exhibit biological and pharmacological activities, including anti-obesity, anti-oxidant and anti allergic activities. The aim of the present study was to examine in vitro effects of PJ in RANKL-induced signaling pathways, which determine osteoclast differentiation. PJ ethanol extract (PEE) exhibited anti-osteoporotic activity by disrupting the phospholipase C (PLC)-Ca2+-c-Fos/cAMP response element-binding protein (CREB)-nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) signaling pathway during osteoclastogenesis. Murine bone marrow-derived macrophages (BMMs) were cultured and used to determine the effects of PJ in the receptor activator of nuclear factor kappaB ligand (RANKL)-mediated osteoclastogenesis. The effects of PEE in the RANKL-mediated signaling cascade were evaluated using a standard in vitro osteoclastogenesis system. PEE treatment of BMMs significantly reduced the number of RANKL-mediated tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells (P<0.05 for 5 and 10 ug/ml PEE, P<0.01 for 25 and 50 ug/ml PEE), without cytotoxic effects. Furthermore, the expression of differentiation-related marker genes, including TRAP, Oscar, Cathepsin K, dendrocyte expressed seven transmembrane protein, ATPase H+ Transporting V0 Subunit D2 and NFATc1, were markedly suppressed. PEE induced a transient increase in free cytoplasmic Ca2+ ([Ca2+]i) mobilization via voltage gated Ca2+ channels and PLC-sensitive pathways. Transient [Ca2+]i increase consequently resulted in the suppression of c-Fos, CREB and NFATc1 activities. These findings highlight the potential use of PJ in treating bone disorders caused by osteoclast overgrowth. PMID- 28672948 TI - (-)-Epigallocatechin gallate but not chlorogenic acid upregulates osteoprotegerin synthesis through regulation of bone morphogenetic protein-4 in osteoblasts. AB - Chlorogenic acid (CGA) is a primary phenolic component of coffee and (-) epigallocatechin gallate (EGCG) is a primary flavonoid component of green tea, both of which have been documented to possess beneficial health properties. A previous study by the present authors demonstrated that p38 mitogen-activated protein kinase (MAPK) may be associated with osteoprotegerin synthesis stimulated by bone morphogenetic protein-4 (BMP-4) in osteoblast-like MC3T3-E1 cells. In the present study, the effects of CGA and EGCG on BMP-4-stimulated osteoprotegerin synthesis in MC3T3-E1 cells were investigated. It was observed that CGA had no effect on osteoprotegerin release stimulated by BMP-4, whereas EGCG significantly enhanced BMP-4-stimulated osteoprotegerin release (P=0.003). Levels of osteoprotegerin mRNA expression induced by BMP-4 were also significantly increased by EGCG (P=0.03). By contrast, EGCG had no significant effect on phosphorylation of Smad1 or p38 MAPK induced by BMP-4. In addition, EGCG had little effect on BMP-induced phosphorylation of p70 S6 kinase; however rapamycin, as an inhibitor of p70 S6 kinase, significantly suppressed osteoprotegerin release (P=0.007). These data suggest that EGCG but not CGA may upregulate the synthesis of osteoprotegerin induced by BMP-4 in osteoblasts. PMID- 28672949 TI - Long-term adefovir therapy may induce Fanconi syndrome: A report of four cases. AB - Fanconi syndrome is a rare disease characterized by dysfunction of the proximal renal tubules as a result of various pathogenic events. Drug-induced Fanconi syndrome may be neglected or misdiagnosed, which increases the level of suffering. The aim of the present study was to conduct an investigation into the effects of adefovir (ADV)-induced Fanconi syndrome. Four typical cases of Fanconi syndrome caused by long-term ADV therapy (2-9 years) were diagnosed at our hospital. A complete medical and therapy history was collected from all four patients prior to a physical examination. Laboratory and diagnostic examinations were also conducted. Following this, the patients were diagnosed and a treatment regimen was decided upon. Outcomes of the treatment regimen were observed. Common manifestations of all the four patients were: Renal tubular reabsorption dysfunction; imbalanced electrolyte acid-base ratio; elevated cystatin C levels; severe hypophosphatemia and diffused systemic pain; osteoporosis; and difficultly walking. When ADV was replaced with supportive treatment, all the four patients exhibited symptom relief. These findings indicate that long-term ADV therapy may induce Fanconi syndrome. For patients with a history of such therapy, the possibility of Fanconi syndrome should be assessed and monitored closely for indicators, including altered glomerular and renal tubular function. Once diagnosed, the agent should be immediately discontinued and prompt symptomatic treatment should be administered. PMID- 28672950 TI - Tocotrienol alleviates inflammation and oxidative stress in a rat model of spinal cord injury via suppression of transforming growth factor-beta. AB - In recent years accumulating evidence has indicated that tocotrienol exhibits an oxidation resistance function, decreased cholesterol function, inhibits cancer function and has unique physiological functions, including anti-inflammatory, anti-apoptotic and anti-oxidative properties. The present study investigated the effect of tocotrienols on spinal cord injury (SCI) by evaluating oxidative stress, inflammation and inducible nitric oxide synthase (iNOS) in rats. A rat model of SCI was induced by operation. SCI rats were treated with 120 mg/kg/day tocotrienol once a day for eight consecutive weeks. Functional recovery following SCI was measured by using the Basso Beattie Bresnahan (BBB) locomotor rating scale. Then the volume of spinal cord contusions was measured following induction of SCI in the rats. In SCI rats, serum malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, nuclear factor-kappaB p65 unit, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6 levels were analyzed using respective commercial immunoassay kits. Firstly, iNOS, transforming growth factor (TGF)-beta, collagen type IV and fibronectin protein expression levels, in addition to iNOS activity and plasma nitric oxide (NO) production in SCI rats was analyzed using western blot analysis, commercial kits and Griess reagent, respectively. Tocotrienol treatment elevated BBB scores and contused volume in the SCI rats. Tocotrienol protected against SCI with reduced oxidative stress and inflammation, and inhibited iNOS protein expression iNOS activity and plasma NO production in rats. In addition, treatment with tocotrienols suppressed TGF-beta, collagen type IV and fibronectin protein expression levels in SCI rats. These results suggest that tocotrienols protect SCI, and suppress oxidative stress, inflammation and iNOS in this model of SCI through TGF-beta, collagen type IV and fibronectin signaling pathways. PMID- 28672951 TI - Hypothalamic-pituitary-adrenal axis hypersensitivity in female rats on a post weaning high-fat diet after chronic mild stress. AB - A high-fat diet (HFD) is highly correlated to obesity, metabolic diseases and certain behavioral changes. However, the effects of post-weaning HFD in rats during puberty and the role of the hypothalamic-pituitary-adrenal (HPA) axis in this process have remained elusive. The present study hypothesized that the HPA axis mediates the behavioral alterations induced by a post-weaning HFD. To investigate this, female rats were divided into two groups, one of which was fed a HFD from postnatal weeks (PWs) 4-12, while the other group received standard chow. Rats in each group were then subdivided into two subgroups each, and from PW 9-12, animals from one of the two subgroups were subjected to chronic mild stress (CMS), while the other subgroup received no stress. At PW 12, the body weight of rats receiving a HFD but no DMS was significantly higher than that in the control group. The frequency of crossing and rearing in the open field test and the time in the center of the Y-maze were decreased following CMS. Total time to escape was decreased in rats receiving HFD and after CMS. The serum levels of adrenocorticotropic hormone and corticosterone were increased in rats receiving an HFD and after CMS, and the mRNA levels of corticotropin-releasing hormone and arginine vasopressin in the hypothalamus were increased in the HFD + CMS group compared to that in the control group. The mRNA expression of glucocorticoid receptor (GR) in the hippocampi of rats in the HFD + CMS group was significantly decreased and the mineralocorticoid receptor/GR ratio was increased compared to that in the groups receiving either CMS or a HFD. In conclusion, these results indicated that female rats fed a post-weaning HFD showed HPA axis hypersensitivity under CMS, which may mediate behavioral alterations. PMID- 28672952 TI - Emodin protects against oxidative stress and apoptosis in HK-2 renal tubular epithelial cells after hypoxia/reoxygenation. AB - The aim of the present study was to determine the effects of emodin, a natural compound with antioxidant properties, on oxidative stress and apoptosis induced by hypoxia/reoxygenation (H/R) in HK-2 human renal tubular cells. In HK-2 cells subjected to H/R, it was observed that pre-treatment with emodin lead to an increase in cellular viability and a reduction in the rate of apoptosis and the B cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 ratio. H/R alone caused a significant increase in the levels of reactive oxygen species and malondialdehyde (P<0.05) and a significant decrease in the activities of superoxide dismutase, catalase and glutathione peroxidase (P<0.05), relative to normoxic cells. In turn, parameters of oxidative stress were improved by emodin pre-treatment. In addition, emodin pre-treatment significantly inhibited the phosphorylation of extracellular signal-regulated protein kinase and c-Jun N-terminal kinase mitogen activated protein kinases (MAPKs) induced by H/R (P<0.05). These data suggest that emodin may prevent H/R-induced apoptosis in human renal tubular cells through the regulation of cellular oxidative stress, MAPK activation and restoration of the Bax/Bcl-2 ratio. PMID- 28672953 TI - Anti-rheumatic effects of Aconitum leucostomum Worosch. on human fibroblast-like synoviocyte rheumatoid arthritis cells. AB - The aim of the present study was to investigate the effects of Aconitum leucostomum Worosch. crude drug, processed products and monomer components on human fibroblast-like synoviocyte rheumatoid arthritis (HFLS-RA) cells, and its associated mechanisms. Following drug treatment, cell proliferation was assessed using a Cell Counting Kit-8 assay. Cellular apoptosis and cell cycle were evaluated using flow cytometry. Levels of hypoxia-inducible factor 1alpha (HIF 1alpha), vascular endothelial growth factor (VEGF) and toll-like receptor 4 (TLR4) mRNA and protein were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. Levels of pro-inflammatory cytokines were evaluated using ELISA. Analysis of cell proliferation indicated that crude drug and processed products markedly inhibited the cell proliferation. Compared with the control group, the apoptosis rates were significantly elevated in all treatment groups (all P<0.05). Furthermore, the proportion of cells in G0/G1 phase was significantly decreased in all treatment groups compared with the control group (all P<0.05). RT-qPCR and western blotting indicated that, compared with the control group, mRNA and protein expression levels of HIF-1alpha, and TLR4 were significantly downregulated in all treatment groups (P<0.05). The mRNA and protein expression levels of VEGF in all treatment groups were decreased compared with those in the control group, but the difference was not significant. Results from ELISA demonstrated that the levels of interleukin (IL)-6, IL-1beta and tumor necrosis factor-alpha in the cell culture supernatant were all significantly decreased following drug treatment in HFLS-RA cells (all P<0.05). Therefore, A. leucostomum Worosch. crude drug, processed products and monomer components may exert anti-rheumatic effects on HFLS-RA cells, inhibiting cell proliferation and enhancing cellular apoptosis. These effects may be attributable to the downregulated expression of HIF-1alpha and TLR4, as well as decreased levels of pro-inflammatory cytokines. PMID- 28672954 TI - Importance of metabolomics analyses of maternal parameters and their influence on fetal growth. AB - Metabolomics is the scientific study of chemical processes involving metabolites. Specifically, metabolomics is the systematic study of the unique chemical fingerprints that specifically conveys cell processes. Fetal growth aberrations, including fetal growth restriction and macrosomia, convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. We searched the electronic database PubMed for preclinical as well as clinical controlled studies pertaining to metabolomics analyses of maternal parameters and their influence on fetal growth. It was observed clearly that metabolic profiling/metabolomics approaches in maternal urine samples provide information on early-life exposure and are potentially linked to child health outcomes, in addition to identifying new biomarkers of exposure. This review article is aimed to discuss intra- and inter-individual variations in maternal urine profiles during pregnancy, fetal growth outcomes and environmental sources of metabolic variations. The review concludes that metabolic profiling of mother is a useful tool for the evaluation of influences on the growth of the fetus. PMID- 28672955 TI - miRNAs in vascular integrity. AB - Endothelial cells (ECs) are confirmed as important regulators of vascular integrity, particularly in relation to angiogenesis, wound repair post-injury, and during embryogenesis. Futher, miRNAs have been implicated in EC function and proliferation. Moreover, knockdown of these miRNAs resulted in altered expressions of several important regulators of endothelial biology and angiogenesis including vascular endothelial growth factor receptor 2, endothelial nitric oxide synthase and tubule formation capacity. Several miRNAs have been identified to play a role in the regulation of function, proliferation and growth of vascular ECs. These miRNAs may be important therapeutic targets in the treatment of a range of ischemic diseases, as well as in the regulation of angiogenesis during cancer and tumour progression. The present review discuss some of the important miRNAs having confirmed regulatory role in EC in connection espically with cardiovascular disease. PMID- 28672956 TI - Chronic conditions in adolescents. AB - The health problems related to the nervous system are on rise in young infants leading to high mortality amongst this age group. A chronic medical condition (CC) is present in this age group to the tune of 10-20%. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting variable chronic conditions especially in pediatric patients. Most of these reports revealed that type 1 diabetes mellitus is the most common CC in young infants. In female patients, metabolic control is often disturbed during CC in this age group. Poor metabolism regulation often results in long-term complications, including cognitive disorders. In cognitive disorders, memory loss and learning problems are the most among adolescents. Executive problems are observed to be associated with low physical activities. The review article concludes that knowledge about factors influencing treatment adherence is crucial in chronically ill infants. Further, we should focus on protective factors in order to prevent health risk behavior. PMID- 28672957 TI - Involvement of receptor-interacting protein 140 in palmitate-stimulated macrophage infiltration of pancreatic beta cells. AB - Receptor-interacting protein 140 (RIP140) in macrophages stimulates the nuclear factor-kappaB subunit RelA to activate tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 transcription. However, under lipotoxic conditions, the involvement of RIP140 in the infiltration of beta cells by macrophages remains unknown. In the present study, murine RAW264.7 macrophages were transfected with a RIP140 overexpression plasmid or siRNA prior to macrophage activation with 500 uM palmitate. Palmitate-free conditioned media was then collected and added to murine insulinoma MIN6 cells. Significant decreases were observed in cell viability (P<0.01), glucose-stimulated insulin secretion (P<0.01) and levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (P<0.05), phosphoenolpyruvate carboxykinase and proliferating cell nuclear antigen mRNA (P<0.01) in MIN6 cells. In addition, conditioned media from palmitate-treated and RIP140-upregulated macrophages significantly increased the levels of uncoupling protein-2 (P<0.01), inducible nitric oxide synthase 1 (P<0.01) and pancreatic and duodenal homeobox 1 (P<0.05) mRNA and levels of activated Jun N-terminal kinase (JNK) (P<0.01) and extracellular signal-regulated kinase (ERK) 1/2 (P<0.01). In turn, the conditioned media was found to be significantly enriched in TNF-alpha and IL-6 (both P<0.05). These results were the opposite of those obtained from MIN6 cells treated with conditioned media from palmitate-treated and RIP140 knockdown macrophages. MIN6 cells were transfected with RIP140 overexpression plasmid or siRNA prior to treatment with 500 uM palmitate and supernatant was collected for use in macrophage chemotaxis assays. In the palmitate-activated and RIP140-overexpressing MIN6 cells, TNF-alpha and IL-6 secretion increased significantly (both P<0.05) and macrophage chemotaxis towards MIN6 cells was enhanced. By contrast, downregulating RIP140 in MIN6 cells had the opposite effect. These data suggest that RIP140 in macrophages mediates the transcription of inflammatory cytokines when concentration of palmitate is high. Macrophage RIP140 may also impair beta cell function by activating the JNK and ERK1/2 signaling pathways and promoting specific gene transcription. Furthermore, expression of RIP140 in pancreatic beta cells may stimulate macrophage chemotaxis, thus triggering local low-grade inflammation. PMID- 28672958 TI - miR-16-1 expression, heat shock protein 70 and inflammatory reactions in astrocytes of mice with epilepsy induced by encephalitis B virus infection. AB - The upregulation of miR-16-1 expression and heat shock protein 70 (HSP70) and inflammatory reaction mechanism in astrocytes of mice with epilepsy induced by encephalitis B virus infection were studied. Six-to-eight-week-old healthy male C57BL/6 mice received intraperitoneal injection of pilocarpine (320-340 mg/kg, 40 mg/ml) to induce status epilepsy. After 7 days, mice were inoculated with 100 ul Dulbecco's modified Eagle's medium (DMEM) in the neck, including 6.25*23 PFU Japanese encephalitis virus P3 wild strain. The experiment was divided into 4 groups, including, the healthy control group, the epilepsy model group, the model group + negative inoculation group and the virus infection group with 10 mice in each group. The healthy control group received intraperitoneal injection of the same amount of normal saline; the model group + negative inoculation group was injected with the same amount of DMEM without P3. One and three days after infection, 5 mice from each group were sacrificed, hippocampus tissues were obtained and astrocytes were isolated. After purification, glial fibrillary acidic protein was identified by immunohistochemical staining. Infected glial cells were detected by P3 antigen of immunofluorescence staining. RT-PCR method was used to detect the expression of miR-16-1 mRNA in astrocytes. Western blot analysis was used to detect the expression of HSP70. ELISA method was used to detect the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and nuclear factor-kappaB (NF-kappaB) inflammatory factors in tail vein blood. Level of expression of miR-16-1 mRNA, HSP70 as well as IL-6, TNF-alpha and NF-kappaB inflammatory factor levels of virus infected mice of 1 and 3 days were significantly higher (P<0.05) than those of model group and negative inoculation group and lowest in control group. In conclusion, the level of expression of miR 16-1 and HSP70 can be increased by the infection of Japanese encephalitis virus on the astrocytes of mice with epilepsy, to promote the expression of IL-6, TNF alpha and NF-kappaB of inflammatory factors. PMID- 28672959 TI - Antimicrobial peptide LL-37 promotes the viability and invasion of skin squamous cell carcinoma by upregulating YB-1. AB - Antimicrobial peptide LL-37 serves a function in the host defense against microbial invasion, and also regulates cell proliferation, immune activity and angiogenesis. Previous studies have reported that LL-37 participates in the development of numerous tumour types, such as ovarian cancer, lung cancer, melanoma and breast cancer. However, the function of LL-37 in the development of skin squamous cell carcinoma (SCC) has not yet been fully elucidated. The aim of the current study was to investigate how LL-37 promotes the expression of Y-box binding protein 1 (YB-1) in SCC. Short interfering RNA (siRNA) was used to inhibit the expression of YB-1, and in vitro MTT and Transwell migration assays were used to evaluate the effect of reduced YB-1 on the viability and invasion of A431 cells. A431 cells were stimulated with LL-37, and quantitative polymerase chain reaction, immunofluorescence and western blot analyses were used to detect changes in YB-1 expression. Mitogen-activated protein kinase kinase, mitogen activated protein kinase and nuclear factor (NF)-kappaB signaling pathway inhibitors were also used to evaluate the mechanism of LL-37-induced YB-1 protein expression. It was found that YB-1 expression was increased in SCC tissue compared with normal tissue. Inhibiting YB-1 expression using siRNA significantly reduced the viability and suppressed the invasion of tumour cells (P<0.05 for both). LL-37 treatment at 0.05 ug/ml for 24 or 48 h significantly promoted YB-1 protein expression (P<0.05), and this was dependent on the NF-kappaB signaling pathway. In conclusion, the current study demonstrated that by upregulating the expression of YB-1, LL-37 can promote the occurrence and development of SCC, and this process involves the NF-kappaB signaling pathway. PMID- 28672960 TI - Baicalin promotes the viability of Schwann cells in vitro by regulating neurotrophic factors. AB - The proliferation and migration of Schwann cells (SCs) are key events in the process of peripheral nerve repair. This is required to promote the growth of SCs and is a challenge during the treatment of peripheral nerve injury. Baicalin is a natural herb-derived flavonoid compound, which has been reported to possess neuroprotective effects on rats with permanent brain ischemia and neuronal differentiation of neural stem cells. The association of baicalin with neuroprotection leads to the suggestion that baicalin may exert effects on the growth of SCs. In the present study, the effects of baicalin on SCs of RSC96 were investigated. RSC96 SCs were treated with various concentrations of baicalin (0, 5, 10 or 20 uM) for 2, 4 and 6 days. Cell attachment, viability and gene expression were monitored via the MTT assay and reverse transcription quantitative polymerase chain reaction. The gene expression levels of several neurotrophic factors, such as glial cell-derived neurotrophic factor, brain derived neurotrophic factor and ciliary neurotrophic factor, which are considered important factors in the process of never cell regeneration, were detected. The results indicated that baicalin was able to promote the viability of RSC96 SCs in a dose-dependent manner and the concentration of 20 uM of baicalin exhibited the greatest cell viability and gene expression of the studied neurotrophic factors. The present findings suggested that baicalin likely affects SCs metabolism, through modulating the expression of neurotrophic factors. To conclude, the present study indicates that baicalin may be potential therapeutic agent for treating peripheral nerve regeneration. PMID- 28672961 TI - Salidroside inhibits high-glucose induced proliferation of vascular smooth muscle cells via inhibiting mitochondrial fission and oxidative stress. AB - The mitochondria are highly dynamic organelles, carefully maintaining network homeostasis by regulating mitochondrial fusion and fission. Mitochondrial dynamics are involved in the regulation of a variety of pathophysiological processes, including cell proliferation. Oxidative stress serves an important role in the remodeling of arterial vascular tissue in diabetic patients by affecting the proliferation of vascular smooth muscle cells (VSMCs). Salidroside is the primary active component of Rhodiola rosea and has been demonstrated to be an antioxidant with cardio- and vascular-protective effects, in addition to improving glucose metabolism. Therefore, the present study aimed to examine the impact of Salidroside on VSMC proliferation, reactive oxygen species (ROS) generation and mitochondrial dynamics under high glucose conditions and the potential mechanisms involved. The current study used Salidroside and a mitochondrial division inhibitor, specifically of Drp1 (Mdivi-1) to treat VSMCs under high glucose conditions for 24 h and assessed VSMCs proliferation, the state of mitochondrial fission and fusion and the expression level of proteins related to mitochondrial dynamics including dynamin-related protein (Drp1) and mitofusin 2 (Mfn2), ROS level and nicotinamide adenine dinucleotide phosphate oxidase activity. The results of the present study indicate that Salidroside and Mdivi-1 inhibit VSMC proliferation, Drp1 expression and oxidative stress and upregulate Mfn2 expression (all P<0.05). The inhibitive effect on VSMC proliferation may be partly reversed by exogenous ROS. In addition, the inhibitive effect on VSMCs proliferation and oxidative stress may also be in part reversed by Mfn2-siRNA. Collectively, these data suggest that Salidroside inhibits VSMCs proliferation induced by high-glucose and may perform its therapeutic effect via maintaining mitochondrial dynamic homeostasis and regulating oxidative stress level, with Mfn2 as a therapeutic target. PMID- 28672962 TI - Enhanced regeneration of large cortical bone defects with electrospun nanofibrous membranes and low-intensity pulsed ultrasound. AB - Poly-L-lactic acid (PLLA) nanofibrous membranes are widely utilized for tissue regeneration. Low intensity pulsed ultrasound (LIPUS) has been considered as a feasible modality for bone union. The aim of the present study was to investigate the potential synergistic effect of LIPUS and PLLA electrospun nanofibrous membranes on large cortical bone defects in rabbits in vivo. The bilateral rabbit tibia defect model was constructed using 18 adult NZ rabbits and the defect sites were treated with the nanofibrous membranes combined with LIPUS or nanofibrous membranes alone. A total of 3 to 6 weeks after surgery, bone defect healing was evaluated radiologically and histologically. Radiographs demonstrated that nascent bone formation in the central part of the defect regions was only observed in the nanofibrous membrane plus LIPUS group, whereas the bone defects were not fully healed in the group treated with nanofibrous membrane alone. Histology analysis of the LIPUS-treated group indicated that bone formation was thicker and more mature in the center of the defect site of the nanofibrous membrane plus LIPUS group. However, no differences were detected in the spatial and temporal pattern of the newly formed bone. Furthermore, the bone scores in the nanofibrous membrane plus LIPUS group were significantly greater than the scores exhibited in the nanofibrous membrane group at 3 and 6 weeks after surgery, respectively (P<0.01). In conclusion, the PLLA electrospun nanofibrous membrane combined with LIPUS indicated the capacity to improve the formation of nascent bone in rabbits with tibia defects. Further studies are required to fully elucidate the cell ingrowth depths inside nanofibrous membranes with scanning electron microscopy and the molecular effects of LIPUS on integrin and fibronectin. PMID- 28672963 TI - EASApprox(r) skin-stretching system: A secure and effective method to achieve wound closure. AB - Large skin defects are commonly observed in the clinic and have attracted much attention recently. Therefore, finding an effective solution for large skin defects is a global problem. The objective of the present study was to assess the effectiveness of the EASApprox(r) skin-stretching system for closing large skin defects. Skin defects (5*5 cm) were created on the forearms of 9 Bama miniature pigs, which were randomly divided into the following three groups: Direct suture, the new EASApprox(r) skin-stretching device and Kirschner wires. Microcirculation was assessed before surgery and after wound closure. Following the different treatments, the defects were sutured, and wound healing was assessed based on a clinical score. Furthermore, microscopic and ultramicroscopic structures were evaluated, including collagen, elastic fibers and the microvessel density. Significant differences in the clinical score and microvessel density were observed among the groups. Additionally, the mean length obtained for elastic fibers was larger than that obtained for the other two groups. Finally, the new EASApprox(r) skin-stretching device resulted in successful wound management and with only minor side effects on skin histology and microcirculation. Therefore, this method has the potential to be used for healing large skin defects. PMID- 28672964 TI - The effects and possible mechanism of beta2AR gene expression in cardiocytes of canines with heart failure. AB - The objective of the present study was to observe the changes of beta2-adrenergic receptor (beta2AR) protein expression in a canine model of heart failure (HF), and the function of cardiocytes after transfection with Adv-beta2AR. The canine model of chronic HF was induced by rapid right ventricular pacing and cardiocytes were isolated with collagenase II. Cardiocytes were transfected with Adv-beta2AR to observe contractile function with a motion edge-detection system of single cells. Expression of beta2AR protein in cardiocytes was measured by immunoblotting and the levels of intracellular cAMP were measured by ELISA. Compared with the control group (the sham group), the expression of beta2AR protein in HF cardiocytes did not change, but the basal (1 mM Ca2+) contraction amplitude percentage (1.809+/-0.922 vs. 1.120+/-0.432%, P<0.05), the maximum contraction amplitude percentage (14.855+/-2.377 vs. 10.784+/-2.675%, P<0.01) and the basal levels of intracellular cAMP (9.39+/-2.54 vs. 5.26+/-0.95 pmol/ml, n=6, P<0.05) of HF cardiocytes were significantly decreased. However, when HF cardiocytes were transfected with Adv-beta2AR and cultured for 48 h, compared with the non-transfected group, the basal contraction amplitude percentage (0.851+/-0.324 vs. 1.629+/-0.522%, P<0.05), the maximum contraction amplitude percentage (9.260+/-2.208% vs. 12.205+/-1.437%, P<0.01) and the basal levels of intracellular cAMP (5.26+/-0.95 vs. 9.03+/-1.03 pmol/ml, n=6, P<0.05) of cardiocytes in the transfected group were significantly increased. In conclusion, the expression of beta2AR protein in HF cardiocytes did not change, but contraction function was impaired. The moderate overexpression of beta2AR gene in the HF cardiocytes increased the levels of intracellular cAMP and improved contraction function. PMID- 28672965 TI - Endobronchial aspergilloma: A case report and literature review. AB - The present study aimed to investigate the clinical and radiological characteristics in addition to the bronchoscopic appearance in patients with endobronchial aspergilloma (EBA). Clinical and radiological characteristics were analyzed alongside the bronchoscopic appearance in 17 patients with EBA diagnosed by bronchoscopy with histological examination. The present study assessed the relevant literature and 13 males and 4 females were included in the comparison, with a median age of 59. Associated diseases included 8 previous diagnoses of pulmonary tuberculosis (47.6%), 4 previous diagnoses lung cancer (23.5%), 1 pulmonary resection (5.9%) and 1 bronchial foreign body (5.9%). The primary symptom was hemoptysis (9/17, 53%). Chest computed tomography (CT) indicated a markedly higher incidence of aspergillosis lesion in the left lung (13/17; 76.5%) compared with the right lung (4/17; 23.5%). CT manifestation included space occupying disease in 10 patients (58.8%), aspergilloma in 3 patients (17.6%), pneumonic consolidation in 2 patients (11.8%) and ground glass opacity in 1 patient (5.9%). Bronchoscopy examination identified masses in all 17 patients' bronchial lumen and 15 patients had endobronchial obstruction by necrotic material. The case presented in the current study demonstrated the merits of combining bronchosopic intervention with voriconazole. The dominant symptom of EBA was hemoptysis. Chest CT demonstrated that aspergillosis lesions were more frequently identified in the left lung compared with the right. EBA often occurs in individuals with underlying lung diseases, which cause lumen structural change or bronchial obstruction. EBA may be clearly diagnosed by bronchoscopy biopsy, although the potential for a co-exististing tumor requires consideration. Bronchoscopic intervention and anti-fungal therapy may have an advantage in the effective treatment of patients with EBA. PMID- 28672966 TI - Role of magnetic resonance imaging in the diagnosis of primary central nervous system angiitis. AB - The present study reported on the use of magnetic resonance imaging (MRI) in the diagnosis of primary angiitis of the central nervous system (PACNS). A total of 19 consecutive patients with a clinical diagnosis of PACNS confirmed by clinical follow-up were enrolled in the present study. All patients underwent unenhanced and enhanced MRI prior to and after steroids or steroids plus immunosuppressive therapy. At baseline, all patients showed lesions on MRI in the grey and white matter. Lesions presented as slightly hypointense on T1-weighted images (T1WI), slightly hyperintense on T2WI, hyperintense on fluid-attenuated inversion recovery, iso- or slightly hyperintense on diffusion-weighted images (DWI) and hyperintense on apparent diffusion coefficient (ADC) mapping. After contrast injection, the lesions showed patchy, cord-like or goral enhancement. Seven cases had unilateral lesions and the other 12 cases had bilateral lesions. On all sequences, indistinct margins characterised most of the lesions, and certain lesions were oedematous. Treatment with steroids or steroids plus immunosuppressive agents resulted in improvement or disappearance of symptoms, and seventeen patients had evidently improved according to MRI. In conclusion, PACNS has unique characteristics on MRI; DWI, ADC mapping and enhanced images are of great importance for the diagnosis and clinical management of early-stage PACNS. PMID- 28672967 TI - Artesunate ameliorates lung fibrosis via inhibiting the Notch signaling pathway. AB - The present study aimed to determine the underlying molecular mechanism of the antifibrotic effect of artesunate in pulmonary fibrosis (PF). Primary lung fibroblasts were isolated from the lung tissues of rats, and treated with artesunate (8 ug/ml) and transforming growth factor (TGF)-beta1 (5 ng/ml). For in vivo experiments, the rats were administered bleomycin intratracheally, followed by daily intraperitoneal artesunate injections for 27 days. Western blotting, and immunohistochemical and immunofluorescent staining were used to assess the expression of key components of the Notch signaling pathway, including alpha smooth muscle actin (alpha-SMA) and type IV collagen. Artesunate (8 ug/ml) was identified to inhibit TGF-beta1-induced alpha-SMA and collagen protein expression, and repress the Notch signaling pathway, in primary lung fibroblasts. Downregulation of alpha-SMA and collagen by artesunate was associated with inhibition of the Notch signaling pathway. The daily intraperitoneal injection of artesunate (1 mg/kg) in rats was determined to inhibit bleomycin-induced overexpression of alpha-SMA and type IV collagen proteins, and inhibit the Notch signaling pathway, in lung tissues. In conclusion, the results of the current study indicate that artesunate inhibits the TGF-beta1-induced differentiation of rat primary lung fibroblasts into myofibroblasts and ameliorates bleomycin induced PF. In addition, the results of the present study suggest that the underlying molecular mechanism for these effects of artesunate is repression of the Notch signaling pathway. PMID- 28672969 TI - Comparative study on the biomechanics between improved PVP and traditional PKP in the treatment of vertebral peripheral wall damage-type OVCF. AB - We compared the biomechanics between improved percutaneous vertebroplasty (improved PVP) and traditional percutaneous kyphoplasty (PKP) in the treatment of vertebral peripheral wall damage-type osteoporotic vertebral compression fracture (OVCF). A total of 15 vertebral peripheral wall damage-type OVCF models of new calves (12-14 weeks) were treated with a decalcifying agent (Shandon TBD-1) with the vertebral compression fracture. The vertebral volume and anterior height before modeling, and the vertebral BMD before and after modeling were measured. The models were randomly divided into three groups: the improved PVP group (Group A), the traditional PKP group (Group B) and the control group (Group C). BMD of Groups A, B and C after decalcification was significantly lower than that before decalcification (P<0.05). There were no significant differences in BMD before and after decalcification among Groups A, B and C (P>0.05). There was no significant difference in the initial strength and stiffness among the three groups (P>0.05). The postoperative strength of Groups A and B was 1.036+/-300 and 1.045+/-200 N, respectively, which was significantly higher than the initial strength (P<0.05). The postoperative stiffness of Groups A and B was 395+/-250 and 470+/-270 N/mm, respectively, which was slightly lower than the initial stiffness, however, the differences were not statistically significant (P>0.05). In the comparison of postoperative strength and stiffness between Groups A and B, the postoperative strength in Group A was lower than that in Group B; differences were not statistically significant (P>0.05); there was no significant difference in the postoperative stiffness between Groups A and B (P>0.05). There were no significant differences of injection of bone cement between the two groups (P>0.05). Therefore, an improved PVP can basically realize the curative effects of traditional PKP in the treatment of vertebral peripheral wall damage-type OVCF, which can be used as clinical reference. PMID- 28672968 TI - Clinical analysis of 42 cases of EBV-positive mature T/NK-cell neoplasms. AB - The pathogenesis of Epstein-Barr virus-positive (EBV+) mature T-cell and natural killer (NK)-cell neoplasms is challenging to understand. The clinical features are diverse, with no typical manifestation. Therefore, it is important to analyze the association of the clinical characteristics and prognoses of patients with various factors associated with EBV+ T/NK-cell neoplasms, particularly extranodal NK/T cell lymphoma, systemic EBV+ T/NK cell lymphoproliferative disorders, aggressive NK cell leukemia and EBV+ peripheral T-cell lymphoma. Therefore, 42 cases of EBV+ T/NK-cell neoplasms with information on age, gender, fever, LDH level, complete blood count (CBC) and immunophenotype (CD5/CD20) were retrospectively analyzed to examine the clinical features, prognoses and related factors. It was found that patients <=60 years old accounted for 86% of cases. The frequency of stage III/IV disease was higher in groups with pancytopenia (P=0.005), high LDH level (P=0.020), CD5-expression status (P=0.031) and fever (P=0.024). There were significant differences in the mean International Prognostic Index (IPI) scores according to the presence or absence of fever (P=0.022), elevated or normal lactose dehydrogenase (LDH) levels (P=0.001), and pancytopenia or normal complete blood count (CBC; P=0.046). Analysis of overall survival showed that CD5 expression, CBC, IPI scores and LDH levels were factors associated with OS. CD5 expression (P=0.003), CBC (P=0.003) and IPI scores (P=0.017) were identified to be important risk factors on the basis of Cox regression analysis. The mean survival time was longer in the CD5+, CD20+ and normal CBC groups, and there was no clear difference in survival time according to LDH level or fever. In summary, CD5 and CD20 may be prognostic factors in EBV+ T/NK lymphoid neoplasms, and CBC and fever are most likely to influence the IPI score and Ann Arbor stage. PMID- 28672970 TI - Effect of vitamin D on the learning and memory ability of FGR rat and NMDA receptor expression in hippocampus. AB - The aim of this study is to investigate the effect of vitamin D (VD) on the learning and memory ability of fetal growth restriction (FGR) rat and the expression of NMDA receptor in hippocampus. The FGR models of rat were established through passive smoking, and divided into two groups randomly, i.e. the control group and the observation group. Rats were fed regular diet with the addition of VD in the observation group. The serum level of 25(OH)-D3 was assayed in both groups of the rats at different time points using ELISA, and the learning and memory ability of rat aged 30 days were evaluated using Morris water maze and passive avoidance test. In addition, we also compared the brain weight of rats at different age and detected the mRNA expression of NRI subunit of NMDA receptor of hippocampus of rats aged 30 days using quantitative RT-PCR. After 7 days, the serum level of 25(OH)D3 in rats of the observation group was significantly higher than that of the control group (P<0.05); during the Morris water maze, we found no significant difference in comparison of the latency between the two groups in the first 2 days (P>0.05), but from the 3rd day, the latency of the observation group was shorter than that in the control group (P<0.05); in the passive avoidance test, no significant difference was identified when comparing the electric shock times between the two groups in the first 2 days, but from the 3rd day, the electric shock times in the observation group were significantly lower than those in the control group (P<0.05); the brain weight of rats in the observation group on the 1st, 7th and 14th day were all lower than those in the control group (P<0.05), but the comparison of brain weight at 21st and 30th day showed no significant difference (P>0.05) between the two groups. We also found that the mRNA and protein expression of NRI subunit of NMDA receptor in hippocampus was significantly higher in the observation group than in the control group (P<0.05). VD can increase the learning and memory ability of FGR rats, significantly ameliorating the cognitive dysfunction of FGR rat and improving the learning and memory ability of rats, which may be related to the upregulation of NRI subunit of NMDA receptor. PMID- 28672971 TI - Effect of alpha-receptor blockers on lower urinary tract symptoms, sexual function and quality of life in young and middle-aged men with benign prostatic hyperplasia. AB - The purpose of the present study was to compare the effectiveness of two common alpha1-receptor blockers, alfuzosin and tamsulosin, on lower urinary tract symptoms, sexual function, and quality of life in young and middle-aged people with benign prostatic hyperplasia. We recruited 80 young and middle-aged patients with benign prostatic hyperplasia and divided them into two groups that received either the non-selective alpha1-receptor blocker alfuzosin or the selective alpha1A-receptor blocker tamsulosin for 18 consecutive days. After intervention, maximum urinary flow, bladder compliance, maximum detrusor pressure, maximum urethral pressure, 72 h urination frequency and urination frequency at night, average urinary volume, residual urinary volume, urinary symptom distress score were significantly better in the tamsulosin group than in the alfuzosin group. Also, sperm density, sperm motility, sperm activity, and sperm DNA fragmentation index were significantly better in the tamsulosin group compared to the alfuzosin group. Finally, international index of erectile function-5 scores, increased libido and erection, retrograde ejaculation, and the quality of life were significantly better in the tamsulosin group compared to the alfuzosin group. Overall, tamsulosin effectively relieved the lower urinary tract symptoms, improved semen quality, and increased sexual life and quality of life in young and middle-aged patients with benign prostatic hyperplasia. PMID- 28672972 TI - JNK pathway mediates curcumin-induced apoptosis and autophagy in osteosarcoma MG63 cells. AB - Human osteosarcoma is a common primary malignancy of the bone in children and adolescents. It has been reported that curcumin is able to induce apoptosis in osteosarcoma MG63 cells through the mitochondrial pathway. However, whether curcumin is able to induce autophagy and the interaction between apoptosis and autophagy in osteosarcoma cells has yet to be fully elucidated. In the current study, it was determined that curcumin was able to significantly induce apoptosis, and lead to autophagy in MG63 cells. Notably, inhibition of apoptosis enhanced curcumin-induced autophagy due to upregulation of the c-Jun N-terminal kinase (JNK) signaling pathway. This finding was confirmed by the use of JNK specific inhibitor, SP600125. Furthermore, our data showed that curcumin-induced apoptosis was increased when autophagy was completely inhibited by 3 methyladenine in MG63 cells. These results suggest that autophagy may have an important role in resistance to apoptosis when MG63 cells are incubated with curcumin. Thus, these results provide important insights into the interaction between apoptosis and autophagy in osteosarcoma cells and clinical treatment strategies using curcumin. PMID- 28672973 TI - Compound anisodine affects the proliferation and calcium overload of hypoxia induced rat retinal progenitor cells and brain neural stem cells via the p ERK1/2/HIF-1alpha/VEGF pathway. AB - As a Traditional Chinese Medicine, compound anisodine (CA) has previously been shown to regulate the vegetative nervous system, improve microcirculation and scavenge reactive oxygen species, and has been commonly utilized as a neuroprotective agent to treat ischemic optic neuropathy and choroidoretinopathy. The present study aimed to investigate the neuroprotective effects of CA on the proliferation and calcium overload of hypoxia-induced rat retinal progenitor cells (RPCs) and brain neural stem cells (BNSCs) harvested from neonatal Sprague Dawley rats. Cells were treated with CA at 0.126, 0.252, 0.505 or 1.010 g/l for four hours prior to or after hypoxia (<1% oxygen) for four h, followed by re oxygenation for four hours; a normal control group and a CA-untreated hypoxia model group were also included. An MTT assay demonstrated that the cell viability was markedly improved following treatment with 0.126-1.010 g/l CA, compared with that in the hypoxia model group (P<0.05). Bromodeoxyuridine (BrdU) immunocytochemical staining and flow cytometry indicated that after culture in hypoxia for 4 h, the number of BrdU+ RPCs and BNSCs was significant decreased, as well as the cell population in S+G2 phase of the cell cycle, which was significantly attenuated by treatment with 1.010 g/l CA for 4 h prior to hypoxia (P<0.05). Furthermore, laser scanning confocal microscopy showed that the intracellular calcium concentration in hypoxia-cultured RPCs and BNSCs was markedly increased, which was attenuated by 0.126-1.010 g/l CA in a concentration dependent manner (P<0.05). Furthermore, western blot analysis demonstrated that after hypoxia, the protein levels of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) were upregulated in RPCs and BNSCs, whereas phosphorylated extracellular signal-regulated kinase (phospho-ERK 1/2Thr202/Tyr204) and Cyclin D1 were downregulated; of note, treatment with 1.010 g/l CA significantly attenuated these changes (P<0.05). The results of the present study suggested that CA may improve the proliferation and inhibit calcium overload in hypoxia-induced RPCs and BNSCs by altering the protein levels of Cyclin D1 as well as signaling through the p-ERK1/2/HIF-1alpha/VEGF pathway. PMID- 28672974 TI - Efficacies of rosiglitazone and retinoin on bleomycin-induced pulmonary fibrosis in rats. AB - The present study investigated the intervention efficacies of rosiglitazone (ROS) and retinoin (RET) on bleomycin-induced pulmonary fibrosis in rats. A total of 48 rats were randomly divided into the control group (group C), the model group (group M), the dexamethasone group (group D), the ROS group (group R), the RET group (group W) and the ROS + RET group (group L). Group M and the treatment groups were intratracheally injected with 5 mg/kg bleomycin, while group C was injected with saline. The lungs of rats in each group were inspected using high resolution computed tomography (HRCT), lung tissue hematoxylin and eosin staining and Masson staining; furthermore, lung L-hydroxyproline (Hyp) content and the concentration of transforming growth factor beta1 (TGF-beta1) serum of each group were also determined. The fibrosis score, Hyp content and TGF-beta1 concentration of each treatment group were significantly lower when compared with group M (P<0.01), while the imaging results were improved when compared with group M, with lower alveolitis and fibrosis scores. Group L, R and W exhibited significantly lower fibrosis scores, Hyp content and TGF-beta1 concentrations when compared with group D (P<0.05). Imaging results for group L, R and W indicated that while the imaging results were superior to group D, group L was lower than groups R and W (P<0.05). No significant difference in the fibrosis score, Hyp content and TGF-beta1 concentration was exhibited between groups R and W (P>0.05). Findings from the present study conclude that ROS and RET are able to suppress bleomycin-induced pulmonary fibrosis with improved efficacies when compared with dexamethasone; furthermore, the combination of these two pharmacological agents may exert synergistic effects. PMID- 28672975 TI - The protective effect of Ginsenoside Rg1 on aging mouse pancreas damage induced by D-galactose. AB - The protective effect and mechanism of Ginsenoside Rg1 on aging mouse pancreas damaged by D-galactose (D-gal)-induced was studied. Two-month-old male C57BL/6J mice were randomly divided into three groups of 10 mice per group. The D-gal group of mice received hypodermic injection of D-gal (120 mg/kg/day) for 42 days; the Rg1+D-gal group of mice receiving D-gal + intraperitoneal injection Rg1 (40 mg/kg/day) for 27 days from the 16th day of D-gal replication; and the naive group that constituted the normal control mice receiving the same dose of saline instead of the drug. The related indicators were tested on the second day after modeling and administration. Fasting blood glucose (FBG), oral glucose tolerance test (OGTT) and fasting insulin level were measured by taking peripheral blood. Samples of pancreas were weighed and visceral index was calculated. Paraffin sections were prepared. H&E staining sections were produced to observe pancreatic tissue morphology. Immunohistochemical staining was used to observe advanced glycation end products (AGEs) and integral optical density (IOD) of stained positive tissue in pancreas. Ultrathin slices were used to observe ultrastructural change of pancreatic tissue. Frozen sections were prepared to test the relative optical density of positive cells that were stained by senescence-associated beta-galactosidase (SA-beta-gal) in pancreatic tissue. Superoxide dismutase (SOD), malonaldehyde (MDA) and total antioxidant capacity (T AOC) were detected by preparing pancreas tissue homogenates. Compared with the control group, Rg1+D-gal mice had significantly decreased pancreatic wet weight and visceral index and significantly lower FBG; OGTT for 30 and 120 min. There was no significant difference of the blood sugar level between the groups. The area under the curve and the number and size of the nucleated cells within islet were markedly reduced. In addition, SA-beta-gal-positive particles in pancreas tissue intracytoplasmic cells significantly decreased and relative optical density also reduced. The IOD of AGEs in pancreas tissue and MDA content decreased. SOD and T-AOC activity significantly increased. Ginsenoside Rg1 can be effective antagonistic structure and function of the pancreas injury induced by D gal. The mechanism may be associated with reducing oxidative damage. PMID- 28672976 TI - Suncon medical adhesive is a suitable alternative to fibrin glue in the 23G minimally invasive vitrectomy. AB - Fibrin glue is frequently used to close the incision of the sclera and conjunctiva. However, its use is limited due to its blood-borne origins. The study evaluated the suitability of Suncon medical adhesive as a replacement for fibrin glue in 23G minimally invasive vitrectomy as an animal study. One eye of Japanese white rabbits (total, 18 rabbits) received an intravitreal injection of 0.05 ml of Suncon medical adhesive, while the other eye was injected with 0.05 ml of saline and served as the control eye. Slit lamp, indirect ophthalmoscope and electroretinogram (ERG) examinations were carried out before and 28 days after the interventions. At the end of the observation period (28 days), ophthalmectomy was performed for the light microscopy examination. ERG measurements included the b-wave amplitude of rod cell response (Rod-R), maximum mixing response (Max-R) and cone cell response (Cone-R), P2-wave amplitude of oscillatory potentials (Ops) and mean amplitude of 30 Hz scintillation response. The slit lamp examination showed no abnormal inflammatory reactions in the control or treatment eyes. The difference in ERG measurements was not statistically significant between the control or treatment eyes. Furthermore, the cells in each layer of retinas exposed to Suncon medical adhesive or saline were morphologically normal under light microscopy. In conclusion, Suncon medical adhesive injected at doses of 0.05 ml is well-tolerated by the retina. Therefore, the Suncon medical adhesive is a suitable alternative to fibrin glue. PMID- 28672977 TI - In vitro evaluation of novel antiviral activities of 60 medicinal plants extracts against hepatitis B virus. AB - Currently, >35 Saudi Arabian medicinal plants are traditionally used for various liver disorders without a scientific rationale. This is the first experimental evaluation of the anti-hepatitis B virus (HBV) potential of the total ethanolic and sequential organic extracts of 60 candidate medicinal plants. The extracts were tested for toxicity on HepG2.2.15 cells and cytotoxicity concentration (CC50) values were determined. The extracts were further investigated on HepG2.2.15 cells for anti-HBV activities by analyzing the inhibition of HBsAg and HBeAg production in the culture supernatants, and their half maximal inhibitory concentration (IC50) and therapeutic index (TI) values were determined. Of the screened plants, Guiera senegalensis (dichloromethane extract, IC50=10.65), Pulicaria crispa (ethyl acetate extract, IC50=14.45), Coccinea grandis (total ethanol extract, IC50=31.57), Fumaria parviflora (hexane extract, IC50=35.44), Capparis decidua (aqueous extract, IC50=66.82), Corallocarpus epigeus (total ethanol extract, IC50=71.9), Indigofera caerulea (methanol extract, IC50=73.21), Abutilon figarianum (dichloromethane extract, IC50=99.76) and Acacia oerfota (total ethanol extract, IC50=101.46) demonstrated novel anti-HBV activities in a time- and dose-dependent manner. Further qualitative phytochemical analysis of the active extracts revealed the presence of alkaloids, tannins, flavonoids and saponins, which are attributed to antiviral efficacies. In conclusion, P. crispa, G. senegalensis and F. parviflora had the most promising anti-HBV potentials, including those of C. decidua, C. epigeus, A. figarianum, A. oerfota and I. caerulea with marked activities. However, a detailed phytochemical study of these extracts is essential to isolate the active principle(s) responsible for their novel anti-HBV potential. PMID- 28672978 TI - Oral administration of lactobacilli isolated from Jeotgal, a salted fermented seafood, inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice. AB - Certain strains of lactobacilli have been reported to exert favorable effects on atopic dermatitis (AD). Jeotgal, a traditional Korean food, is a salted fermented seafood known to harbor many lactic acid bacteria. In the present study, two novel lactobacillus strains were isolated from Jeotgal, and their anti-AD effects were investigated. Lactobacilli isolated from Jeotgal were identified, according to conjugated linoleic acid-producing activity, as Lactobacillus plantarum (JBCC105645 and JBCC105683). AD-like skin lesions were induced in BALB/c mice using dinitrofluorobenzene (DNFB). Ear swelling, histological analysis and serum immunoglobulin E (IgE) levels in mice were evaluated to investigate the anti-AD effects of lactobacilli. Cytokine production of ex vivo cluster of differentiation (CD)4+ T cells, and interleukin (IL)-12 production of in vitro macrophages were also evaluated to establish a putative mechanism of the action of lactobacilli. Administration of JBCC105645 or JBCC105683 suppressed ear swelling and serum IgE levels in DNFB-treated mice (P<0.05). Notably, JBCC105645 was more effective than JBCC105683 (P<0.05). Treatment with the lactobacilli also induced a significant decrease in IL-4 production with concomitant increase in interferon (IFN)-gamma production in DNFB-exposed CD4+ T cells, and an increase in IL-12 production in macrophages (P<0.05). Taken together, the lactobacilli isolated from Jeotgal may suppress the development of AD-like skin inflammation in mice by modulating IL-4 and IFN-gamma production in CD4+ T cells, presumably via enhancing IL-12 production by macrophages. PMID- 28672979 TI - Applying negative pressure wound therapy in associating liver partition and portal vein ligation for staged hepatectomy: A case report. AB - Staged hepatectomy, particularly associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a recently developed advanced surgery for resecting liver tumors. However, large wound surfaces, incomplete drainage and high rates of mortality are vital limitations of ALPPS. The present case study describes a patient with liver cancer who underwent ALPPS surgery combined with negative pressure wound therapy. A 46-year-old male patient was hospitalized due to right upper abdominal pain. Computed tomography and magnetic resonance cholangiopancreatography scan results indicated gallbladder cancer, accompanied by multiple liver metastases. Resection of the right trisegment and partial resection of metastatic nodules in the left outer lobe were performed. Vacuum sealing drainage was pre-implanted at liver cross-sections with drainage tubes to drain the bile. The patient exhibited improved wound healing compared with conventional ALPPS. PMID- 28672980 TI - Overexpression of long non-coding RNA zinc finger antisense 1 in acute myeloid leukemia cell lines influences cell growth and apoptosis. AB - The association between long non-coding RNA zinc finger antisense 1 (ZFAS1) and acute myeloid leukemia (AML) has not yet been investigated. The present study aimed to assess the potential role of ZFAS1 in AML cell proliferation and apoptosis. The expression of ZFAS1 mRNA in various AML cell lines (HL-60, KG-1, ML-1 and SKNO-1) was measured by reverse transcription-quantitative polymerase chain reaction. The results showed that ZFAS1 expression was increased in all four human AML cell lines compared with the control cell lines (T lymphocytic leukemia or Burkitt's lymphoma). Transfection with small interfering RNA into human AML cells established ZFAS1 knockdown. A cell-counting kit-8 (CCK-8) assay was used to investigate the effect of ZFAS1 on AML cell proliferation and the effect of ZFAS1 on the cell cycle and cell apoptosis was assessed using flow cytometry. Notably, the CCK-8 assay demonstrated that ZFAS1 knockdown inhibited cell proliferation in HL-60 and SKNO-1 cell lines and flow cytometry analysis indicated that ZFAS1 knockdown induced AML cell cycle G1 phase arrest and triggered cell apoptosis. Therefore, the present study indicated that ZFAS1 promoted the proliferation and inhibited the apoptosis of AML cells. PMID- 28672981 TI - Neurotrophic factor and Trk signaling mechanisms underlying the promotion of motor recovery after acute spinal cord injury in rats. AB - Neurotrophic factor (NF) and Trk signaling mechanisms underlying the promotion of motor recovery following acute spinal cord injury (SCI) in rats were investigated. Thirty-six adult Sprague-Dawley rats of both genders were randomly divided into three groups: Sham-operated, model, and NF/Trk. Each group consisted of 12 rats, with four subgroups in each group: 1, 3, 5 and 7 days. Sham-operated rats received a laminectomy without SCI, while in model group rats, SCI was induced using an improved version of the Allen's method. After analepsia, sham operated and model group rats were given normal saline via gavage, while the NF/Trk group received NFs and Trk. Lower limb function was measured using the Basso, Beattie and Bresnahan scale 1, 3, 5 and 7 days before and after surgery. Results were analyzed statistically. Six rats from each group were randomly selected for sacrifice at 1, 3, 5 and 7 days after the operation. Morphological changes in motor neurons in the anterior gray column were observed by hematoxylin and eosin, and Nissl staining. Brain-derived expression of NF (BNDF) and neurotrophin-3 (NT-3) was detected by immunofluorescence, and the number of positive cells was counted. Expression of Trk B and Trk protein C receptor was measured by western blotting. In the NF/Trk group, the expression of NF/Trk pathway components remarkably increased. In addition, the morphology of motor neurons in the anterior gray column was improved. Expression of BNDF and NT-3 was significantly increased in motor neurons of the anterior gray column in NF/Trk rats compared with those of sham-operated and model rats (P<0.05). NFs promote motor recovery following acute SCI in rats and may have valuable clinical applications. PMID- 28672982 TI - Upregulation of miR-125b is associated with poor prognosis and trastuzumab resistance in HER2-positive gastric cancer. AB - Gastric cancer is one of the most common types of human cancer associated with a poor prognosis. MicroRNAs (miRs), a class of non-coding RNAs that are 18-25 nucleotides in length, act as key regulators in gene expression, and have been implicated in various human cancer types. miR-125b has been implicated in the malignant progression of gastric cancer. However, the association between miR 125b expression, clinicopathological characteristics and trastuzumab resistance in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains unclear. In the current study, in situ hybridization data demonstrated that 81.8% (108/132) of gastric cancer tissues exhibited positive expression of miR-125b, while only 26.3% (10/38) of non-tumor gastric tissues were miR-125b positive. Reverse transcription-quantitative polymerase chain reaction data indicated that the expression level of miR-125b was markedly increased in gastric cancer tissues compared with non-cancerous gastric tissues. Furthermore, the miR 125b level was significantly associated with tumor (T) stage, lymph node metastasis, distant metastasis and TNM stage of gastric cancer (P<0.05). Increased miR-125b expression predicated poor prognosis in patients with gastric cancer. For HER2-positive gastric cancer, the upregulation of miR-125b expression was significantly associated with advanced malignant progression, as well as a poor prognosis (P<0.05). Furthermore, data from the present study indicated that the increased miR-125b level was significantly associated with trastuzumab resistance in HER2-positive gastric cancer (P<0.05). Therefore, the current study suggests that miR-125b may become a potential biomarker for predicting prognoses and clinical outcomes in patients with HER2-positive gastric cancer that receive trastuzumab treatment. PMID- 28672983 TI - Neuroprotective effect of carnosine against salsolinol-induced Parkinson's disease. AB - Carnosine is a dipeptide of beta-alanine and histidine amino acids. It is widely present in muscle and brain tissues. Carnosine has been demonstrated to be an antioxidant agent that is beneficial in animals. Reactive oxygen species (ROS) and aldehydes are are generated from membrane fatty acid oxidation. The antioxidant potential and toxicity of salsolinol had been extensively studied in vivo and in vitro. The present study analyzed the protective effect of carnosine against Parkinson's disease in the salsolinol-induced rat brain and rat brain endothelial cells. Antioxidant and biochemical markers were determined in vitro and in vivo. Histopathological examination was completed in order to evaluate the protective effect of carnosine on the cellular architecture of salsolinol-induced brain tissue. In order to confirm the protective effect of carnosine further, it was also investigated at an in vitro level using rat brain endothelial cells. Fluorescence and confocal studies indicated reduced apoptosis in the endothelial cells of the rat brain tissue. Antioxidant enzymes and lipid peroxidation levels were renormalized following treatment with carnosine. In addition, carnosine treatment reduced mitochondria-derived ROS in the rat brain endothelial cells. These findings suggest that carnosine may be a therapeutic agent against salsolinol-induced Parkinson's. PMID- 28672984 TI - Biliverdin administration ameliorates cerebral ischemia reperfusion injury in rats and is associated with proinflammatory factor downregulation. AB - Biliverdin (BV), one of the heme oxygenase-1 (HO-1) catalytic products, has been demonstrated to have protective effects in liver ischemia reperfusion injury (IRI). The present study aimed to explore the effects of BV on cerebral IRI, and to investigate the potential mechanisms thereof. Adult male SD rats, weighing 200 240 g, were randomly divided into sham (group S), cerebral ischemia reperfusion control (group C) and BV (group BV) groups. Rats in group C underwent transient middle cerebral artery occlusion (tMCAO) and received 2 ml normal saline; rats in group BV received BV (35 mg/kg) intraperitoneally 15 min prior to reperfusion and 4 h after reperfusion, then twice a day thereafter for 5 days. Group S served as the control. Neurological Severity Scores (NSS) were evaluated at days 1-5 following reperfusion. Staining with 2, 3, 5-triphenyltetrazolium chloride was performed to determine the cerebral infarction at 48 h post reperfusion. mRNA expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL 1beta, inducible nitric oxide synthase (iNOS) and HO-1 in the ischemic cerebral cortex were detected via reverse transcription-quantitative polymerase chain reaction at 3, 6, 12 and 24 h after reperfusion. Western blotting was used to detect the protein expression levels at 3 h after reperfusion. Compared with group S, the NSS, cerebral infarct volume, and the mRNA and protein expression levels of TNF-alpha, IL-6, IL-1beta, iNOS and HO-1 of Group C were significantly increased (P<0.05). However, BV administration significantly improved and reduced these expression levels (P<0.01). The present study indicates that BV is able to ameliorate cerebral IRI in rats and that the mechanism may be associated with the downregulation of proinflammatory factors. PMID- 28672985 TI - Comparison of diagnostic values of ultrasound micro-flow imaging and contrast enhanced ultrasound for neovascularization in carotid plaques. AB - The aim of the present study was to compare the diagnostic values of ultrasound micro-flow imaging (SMI) and contrast-enhanced ultrasound (CEUS) for neovascularization in carotid plaques, and to investigate their capacities for predicting the risks of cerebral stroke. A total of 39 patients (64 carotid plaques) with severe carotid artery stenosis undergoing carotid endarterectomy were selected between February 2015 and February 2016, and SMI and CEUS were used to detect neovascularization in plaques. According to the CEUS dynamic graph of plaques, the enhanced intensity visual scales and contrast parameters were obtained. Carotid atherosclerotic plaques were divided into 4 groups. The differences in the enhanced intensity visual scales, contrast parameters, and gray-scale median (GSM) values among the 4 groups were analyzed. Carotid plaque tissue samples from patients were stained for CD34, and the consistency of the methods for the diagnosis of neovascularization in plaques was analyzed. The differences in GSM values, enhanced intensities, and enhanced densities among the 4 groups of plaques were statistically significant (F=29.365, chi2=29.025, chi2=30.871, P<0.001); the differences in enhanced intensities of carotid atherosclerotic plaques with different echo types were statistically significant (chi2=17.951, P<0.001). The enhanced intensity of plaques was negatively correlated with the GSM value (r=-0.376, P<0.01), and the enhanced density of plaques was negatively correlated with the GSM value (r=-0.252, P<0.01). SMI and CEUS grading had good consistency (kappa=0.860>0), there were statistically significant differences in new vessel densities with different SMI gradings (P<0.001), and the clinical symptoms and severity were positively correlated with SMI grading (rs=0.592>0). In conclusion, SMI and CEUS have good consistency for evaluating neovascularization in carotid plaques, and have good clinical value for evaluating neovascularization in carotid plaques. PMID- 28672986 TI - Dexmedetomidine attenuates hypoxia/reoxygenation injury in primary neonatal rat cardiomyocytes. AB - Systemic administration of dexmedetomidine provides cardioprotection against ischemia/reperfusion (I/R) injury; however, the direct effects of dexmedetomidine on cardiomyocytes have not been clarified. The present study investigated the effects of dexmedetomidine on primary neonatal rat cardiomyocytes under hypoxic/reoxygenation (H/R) conditions. In order to simulate in vivo I/R injury, primary neonatal rat cardiomyocytes were cultured under hypoxic conditions for 1 h and subsequently reoxygenated for 24 h. The effects of preconditioning with dexmedetomidine 2 h before hypoxia and postconditioning during reoxygenation were also examined. Cellular viability and activity were analyzed by monitoring the dynamic response profile of living cells using a real-time cell analyzer system. A special scaled index, defined as the normalized cell index (NCI), was used to minimize the influence of inter-experimental variations. The dose-effect curve was generated from the area under the time-course curve values of NCI. H/R exposure markedly decreased cell viability and activity. Furthermore, no cytotoxicity was associated with a clinically relevant concentration of dexmedetomidine. Preconditioning with dexmedetomidine concentration-dependently ameliorated the reductions in NCI in cardiomyocytes following H/R injury. Additionally, postconditioning with dexmedetomidine improved the reductions in NCI at concentrations between 3 and 200 nM. Finally, the effect of 3-40 nM dexmedetomidine postconditioning was greater than preconditioning. These results indicated that preconditioning and postconditioning with dexmedetomidine attenuated H/R injury in primary neonatal rat cardiomyocytes at the cellular level. PMID- 28672987 TI - Evaluation of the safety of irreversible electroporation on the stomach wall using a pig model. AB - The aim of the present study was to evaluate the effects of irreversible electroporation (IRE) on the stomach wall following the direct application of IRE onto the organ surface. IRE ablation was performed in 8 Tibetan mini-pigs, which were randomly assigned into two groups based on their ablated areas: Group A, gastric cardia, fundus of stomach, gastric body and group B, lesser gastric curvature, greater gastric curvature, stomach pylorus. Two IRE needles were placed in the space between the stomach wall and the liver (not inserted into the stomach tissue), and three lesions were created in each pig. Serum aminotransferase and white blood cell (WBC) levels were measured. Gastroscopy and endoscopic ultrasonography were performed. From each group, 2 pigs were sacrificed on day 7 post-IRE; the remaining pigs were sacrificed on day 28 post IRE. There were no signs of perforation on the stomach wall. Serum aminotransferase and WBC levels increased in both groups on day 1 post-IRE and decreased gradually thereafter. The gastroscopy procedure revealed oval ulcers on day 7 post-IRE and smaller ulcers on day 28 post-IRE. Transmural necrosis, inflammation and fibrosis were observed at 7 days post-IRE. Healing ulcers were observed at 28 days post-IRE. In conclusion, IRE ablation caused damage to the stomach wall; however, IRE did not induce any perforation. PMID- 28672988 TI - Ascorbate ameliorates Echis coloratus venom-induced oxidative stress in human fibroblasts. AB - Reports related to the effects of Echis coloratus venom (EcV) on the antioxidant capacity of human tissues is very scarce. The present study was undertaken to investigate the activities and gene expression levels of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT), as well as the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and the generation rates of superoxide anions (SOA), hydrogen peroxide (H2O2) and lipid peroxides (LPO) in cultured human fibroblasts incubated with EcV, ascorbate (Asc) and EcV plus Asc at concentrations and incubation periods that maintained cell viability. Results indicated that the activities of all antioxidant enzymes and their corresponding transcripts underwent highly significant decreases and downregulation in EcV treated cultures (0.5 ug/ml medium for 4 h) compared to venom-free controls (P<0.001). Additionally, there were concurrent equally significant increases in SOA, H2O2 and LPO generation rates in the venom-incubated cultures compared to controls (P<0.001). Results also indicated very significant decreases and parallel equally significant increases in GSH and GSSG levels respectively in the envenomed cultures compared to controls (P<0.001) leading to a drastically lower GSH/GSSG ratio. However, further incubation of the EcV-treated cultures with Asc (400 uM for 12 h) restored the activities and levels of all investigated parameters including the expression levels of the antioxidant genes to control venom-free values. It is concluded that Asc acted to neutralize the increased reactive oxygen species generation, thus ameliorating the EcV-induced oxidative stress and alleviating the downregulation of antioxidant genes. PMID- 28672989 TI - Altered expression of regulatory T and Th17 cells in murine bronchial asthma. AB - Alteration of the careful balance of the ratio of Th1/Th2 cell subsets impacts immune function and plays an important role in the pathogenesis of asthma. There is little research on the impact of changes on the balance of the regulatory T (Treg)/Th17 subset ratio and its possible repercussions for asthma. This investigation used a murine model of asthma to measure the expression levels of Treg and Th17 cells and the levels of their transcription factors Foxp3 and retinoic acid receptor-related orphan nuclear receptor (ROR)gammat in bronchial asthma while assessing indexes of airway inflammation. Thirty female SPF BALB/c mice were divided into three equally numbered groups: a normal control, an asthma and a dexamethasone treatment group. All the airway inflammation indexes measured were more prominent in the asthma group and less so in the control group. The percentage of the lymphocyte subset CD4+CD25+Foxp3+ cells in the CD4+ cells in the asthma group was significantly lower than that in the normal control group (P<0.01). The percentage of the lymphocyte subset CD4+IL-17+ cells in the CD4+ cells in the asthma group was significantly higher than that in the normal control group (P<0.01). The ratio of CD4+CD25+Foxp3+ cells/CD4+IL-17+ cells in the asthma group decreased compared with that in the normal control group (P<0.01). The expression level of Foxp3 of the mice in the asthma group was significantly lower than that in the control group (P<0.01). The expression intensity of RORgammat in the asthma group was higher than that in the normal control group (P<0.01). Finally, the Foxp3/RORgammat protein expression ratio in the asthma group was significantly lower than that in the normal control group (P<0.01). The Foxp3/RORgammat protein expression ratio and the airway responsiveness were negatively correlated. The average levels of inflammation markers in the dexamethasone group were intermediate between the other groups. During the course of bronchial asthma the unbalanced expression of Treg and Th17 affects mostly the expression of Foxp3/RORgammat, leading to inflammation of the airways. Dexamethasone may inhibit airway inflammation by regulating the balance between Treg and Th17. PMID- 28672990 TI - Effects of conditioned medium from LL-37 treated adipose stem cells on human fibroblast migration. AB - Adipose stem cell-conditioned medium may promote human dermal fibroblast (HDF) proliferation and migration by activating paracrine peptides during the re epithelization phase of wound healing. Human antimicrobial peptide LL-37 is upregulated in the skin epithelium as part of the normal response to injury. The effects of conditioned medium (CM) from LL-37 treated adipose stem cells (ASCs) on cutaneous wound healing, including the mediation of fibroblast migration, remain to be elucidated, therefore the aim of the present study was to determine how ASCs would react to an LL-37-rich microenvironment and if CM from LL-37 treated ASCs may influence the migration of HDFs. The present study conducted migration assays with HDFs treated with CM from LL-37 treated ASCs. Expression of CXC chemokine receptor 4 (CXCR4), which controls the recruitment of HDFs, was analyzed at the mRNA and protein levels. To further characterize the stimulatory effects of LL-37 on ASCs, the expression of stromal cell-derived factor-1alpha (SDF-1alpha), a CXC chemokine, was investigated. CM from LL-37-treated ASCs induced migration of HDFs in a time- and dose-dependent manner, with a maximum difference in migration observed 24 h following stimulation with LL-37 at a concentration of 10 ug/ml. The HDF migration and the expression of CXCR4 in fibroblasts was markedly increased upon treatment with CM from LL-37-treated ASCs compared with CM from untreated ASCs. SDF-1alpha expression was markedly increased in CM from LL-37 treated ASCs. It was additionally observed that SDF 1alpha blockade significantly reduced HDF migration. These findings suggest the feasibility of CM from LL-37-treated ASCs as a potential therapeutic for human dermal fibroblast migration. PMID- 28672991 TI - Diffusion-weighted whole-body magnetic resonance imaging with background body signal suppression/T2 image fusion for the diagnosis of acute cholecystitis. AB - Prompt and accurate diagnosis is critical in the treatment of acute cholecystitis. Diffusion-weighted whole-body magnetic resonance imaging with background body signal suppression/T2 image fusion (DWIBS/T2) identifies areas with high signal intensity, corresponding to inflammation. In the present study, the records and images of patients with acute cholecystitis who underwent DWIBS/T2 between January 2013 and March 2014 were retrospectively analyzed. A total of 11 patients with acute cholecystitis were enrolled. In one patient, DWIBS/T2 identified a thickened wall and high signal intensity, with high signal intensity in the pericholecystic space that suggested localized peritonitis. Positive DWIBS/T2 results indicating acute cholecystitis were obtained in 10/11 patients, with a sensitivity of 90.9%. In addition, wall thickening and high signal intensity were absent in DWIBS/T2 images when wall thickening was not detected by computed tomography. Wall thickening and high signal intensity was attenuated when patients with acute cholecystitis were clinically treated. These data suggest that a thickened gallbladder wall and high signal intensity are indicative of acute cholecystitis and that DWIBS/T2 may be a useful technique in evaluating the severity of acute cholecystitis. PMID- 28672992 TI - Inhibition of viral replication by small interfering RNA targeting of the foot and-mouth disease virus receptor integrin beta6. AB - In animals, foot-and-mouth disease (FMD) causes symptoms such as fever, limping and the development of blister spots on the skin and mucous membranes. RNA interference (RNAi) may be a novel way of controlling the FMD virus (FMDV), specifically by targeting its cognate receptor protein integrin beta6. The present study used RNAi technology to construct and screen plasmids that expressed small interfering RNA molecules (siRNAs) specific for the integrin beta6 subunit. Expression of green fluorescence protein from the RNAi plasmids was observed following transfection into porcine embryonic fibroblast (PEF) cells, and RNAi plasmids were screened using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. A fragment (5'AAAGGCCAAGTGGCAAACGGG 3') with marked interference activity was ligated into a PXL-EGFP-NEO integration plasmid and transfected into PEF cells. Transfected cells were selected using G418, and interference of the integrated plasmid was subsequently evaluated by FMDV challenge experiments, in which the levels of viral replication were determined using optical microscopy and RT-qPCR. A total of seven interference plasmids were successfully constructed, including the pGsi-Z4 plasmid, which had a significant interference efficiency of 91.7% in PEF cells (**P<0.01). Upon transfection into PEF cells for 36 h, a Z4 integration plasmid exhibited significant inhibitory effects (**P<0.01) on the integrin beta6 subunit. Subsequent challenge experiments in transfected PEF cells also demonstrated that viral replication was reduced by 24.2 and 12.8% after 24 and 36 h, respectively. These data indicate that RNAi technology may inhibit intracellular viral replication in PEF cells by reducing expression of the FMDV receptor integrin beta6. PMID- 28672993 TI - Diagnosis of complications associated with acute cholecystitis using computed tomography and diffusion-weighted imaging with background body signal suppression/T2 image fusion. AB - In a clinical setting, it is important to diagnose complications of acute cholecystitis accurately. Diffusion-weighted whole body imaging with background body signal suppression/T2-weighted image fusion (DWIBS/T2) provides high signal intensity with a strong contrast against surrounding tissues in anatomical settings. In the present study, patients who were being treated for acute cholecystitis and underwent DWIBS/T2 in the National Hospital Organization Shimoshizu Hospital between December 2012 and August 2015 were enrolled. A total of 10 men and 4 women underwent DWIBS/T2. Records, including DWIBS/T2 and computed tomography (CT) imaging, were retrospectively analyzed for patients with acute cholecystitis. CT images revealed thickened gallbladder walls in patients with acute cholecystitis, and high signal intensity was observed in DWIBS/T2 images for the thickened gallbladder wall. Inflammation of the pericholecystic space and the liver resulted in high intensity signals with DWIBS/T2 imaging, whereas CT imaging revealed a low-density area in the cholecystic space. Plain CT scanning identified a low-density area in the liver, which became more obvious with contrast-enhanced CT. DWIBS/T2 imaging showed the inflammation of the liver and pericholesyctic space as an area of high signal intensity. Detectability of inflammation of the pericholecystic space and the liver was the same for DWIBS/T2 and CT, which suggests that DWIBS/T2 has the same sensitivity as CT scanning for the diagnosis of complicated acute cholecystitis. However, the strong contrast shown by DWIBS/T2 allows for easier evaluation of acute cholecystitis than CT scanning. PMID- 28672994 TI - Rapamycin enhances the antiproliferative effect of transforming growth factor beta on MCF-7 human breast cancer cells. AB - Transforming growth factor-beta (TGF-beta), a well-known cytokine with pleiotropic biological functions, has an important role in the regulation of cellular proliferation. Rapamycin has specific antagonistic activity on the function of the mammalian target of the rapamycin signaling pathway. The cooperation of TGF-beta and rapamycin on the proliferation of Michigan Cancer Foundation (MCF)-7 human breast cancer cells is unclear. The present study demonstrated that TGF-beta had a growth-arresting effect on MCF-7 cancer cells. TGF-beta stimulation resulted in the upregulation of several cyclin-dependent kinase inhibitors, including p14ARF, p15INK4b, p16INK4a and p21WAF1/CIP1. The present study also demonstrated that rapamycin enhances the antiproliferative effect of TGF-beta. The combination of rapamycin and TGF-beta induced apoptosis of MCF-7 tumor cells. These findings advance the current understanding of the biological effects of TGF-beta and rapamycin. PMID- 28672995 TI - Human bocavirus induces apoptosis and autophagy in human bronchial epithelial cells. AB - Human bocavirus (HBoV) is classified in the Bocavirus genus within the Parvoviridae family, first identified from children with respiratory diseases. Previous studies have investigated the stimulating effect of HBoV on cell apoptosis and autophagy. In the present study, human bronchial epithelial cells (HBECs) were utilized to examine the mechanism of HBoV recombination expressing vector (pWHL-1) on the promotion of cell apoptosis and autophagy. The results from the present study indicated that pWHL-1 inhibited the proliferation of HBECs in a time-dependent manner. Additionally, pWHL-1induced apoptosis, as substantiated by an increased apoptotic rate and presence of autophagosomes. Following pWHL-1 transfection, proliferating cell nuclear antigen, caspase-3 and B cell lymphoma 2 (Bcl-2) protein expression levels were decreased, with the exception of Bcl-2 associated * (Bax) protein, which increased. mRNA and protein expression levels of microtubule-associated protein 1A/1B-light chain 3 (LC3) II and autophagy protein 5 were increased in pWHL-1-transfected HBECs, whereas, the mRNA and protein levels of LC3I and sequestosome 1 were decreased. Notably, pWHL 1 also enhanced the activation of p53 and inhibited AKT activation in HBECs. Results from the present study suggest that pWHL-1 induces apoptosis and autophagy, thus providing a novel insight into the effect of HBoV and its uses in respiratory diseases. PMID- 28672996 TI - Salvianolic acid B attenuates lipopolysaccharide-induced acute lung injury in rats through inhibition of apoptosis, oxidative stress and inflammation. AB - The present study was performed to assess the protective effect of salvianolic acid B on lipopolysaccharide (LPS)-induced acute lung injury (ALI). Sprague Dawley rats were injected with 100 ug/kg LPS through a 24-gauge catheter. One group of rats was pre-treated with salvianolic acid B (1 mg/ml; 20 ml/kg body weight) 1 h prior to LPS challenge, then 20 ml/kg salvianolic acid B every 2 days for 4 weeks thereafter. Salvianolic acid B attenuated LPS-induced increases in the lung wet/dry weight rate and lung tissue injury in ALI model rats. LPS induced changes in the content of caspase-3, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, tumor necrosis factor-alpha and interleukin-6 in ALI model rats were attenuated by treatment with salvianolic acid B. Furthermore, treatment with salvianolic acid B inhibited the protein expression of type I collagen I, endogenous transforming growth factor-beta1 production and alpha-smooth muscle actin in ALI model rats. These findings indicated that salvianolic acid B attenuates LPS-induced ALI through inhibition of apoptosis, oxidative stress and inflammation in rats and therefore exertsa protective effect against ALI. PMID- 28672997 TI - Anticonvulsant effect of exogenous beta-hydroxybutyrate on kainic acid-induced epilepsy. AB - The present study aimed to investigate the anticonvulsant effects of beta hydroxybutyrate (BHB) in a kainic acid (KA)-induced rat seizure model. The concentrations of BHB and glucose were detected in the blood prior to exogenous BHB administration. Three different doses of BHB (2, 4 and 8 mmol/kg) were then injected into male Wistar rats intraperitoneally, and the concentrations of BHB and glucose in the blood were detected. Rats received 0.9% normal saline intraperitoneally at a dose of 4 ml/kg as a control. Subsequently, a KA-induced rat seizure model was established and the anticonvulsant effects of BHB were investigated. The onset time of seizure and the degree of seizure behavior were recorded. Nissl and Timm staining were used to evaluate neuronal loss and mossy fiber sprouting, respectively. The present study demonstrated that exogenous BHB administration could significantly increase BHB concentration in the blood and this concentration was maintained for 90 min without affecting blood glucose levels. Furthermore, it was determined that a dose of 4 mmol/kg BHB is optimal for exogenous administration. The onset time of seizure was significantly prolonged in BHB-pretreated rats (63.31+/-4.050 min) compared with the control group (37.08+/-1.958 min; P=0.039). In addition, neuronal loss and mossy fiber sprouting were both alleviated in the BHB-pretreated model group. Exogenous BHB administration at a dose of 4 mmol/kg may be an alternative to a ketogenic diet to exert a protective effect in the epileptic model induced by KA. The results of the present study may allow novel therapeutic strategies to be developed to treat epilepsy. PMID- 28672998 TI - Role of angiopoietin-2 in the cardioprotective effect of fibroblast growth factor 21 on ischemia/reperfusion-induced injury in H9c2 cardiomyocytes. AB - Fibroblast growth factor 21 (FGF21) exerts a protective effect in ischemia/reperfusion (I/R)-induced cardiac injury. However, the exact molecular mechanism underlying the FGF21 action remains unclear. The present study aimed to evaluate the role of angiopoietin-2 (Angpt2) in the cardioprotective effect of FGF21. For this purpose, the H9C2 cell line was subjected to simulated I/R or aerobic conditions with or without FGF21 administration. Certain groups were also transfected with Angpt2 small interfering RNA (siRNA). Cell viability, apoptosis rate and cell migration were examined, and the expression levels of Angpt2, glucose transporter 1 (GLUT1) and caspase-3 were measured by quantitative polymerase chain reaction (qPCR) and western blot analyses. The results demonstrated that FGF21 administration suppressed apoptosis and increased the cell migration ability following I/R-induced injury. qPCR and western blot data showed a decreased level of GLUT1 after I/R-induced injury, which was reversed by FGF21 administration. Furthermore, inhibition of Angpt2 expression using siRNA enhanced the cardioprotective effect of FGF21 by upregulation of GLUT1. In conclusion, FGF21 administration protected against I/R-induced injury in cardiomyocytes, and further inhibition of Angpt2 with FGF21 administration induced the expression of GLUT1, which may promote the energy metabolism in cardiomyocytes, consequently resulting in a more efficient cardioprotective effect. These results suggested that FGF21 administration and inhibition of Angpt2 could be a novel therapeutic approach for I/R-induced cardiac injury. PMID- 28672999 TI - Continuous intrathecal administration of liposomal amphotericin B for treatment of refractory Cryptococcus neoformans encephalitis: A case report. AB - The aim of the present study was to investigate the treatment of refractory Cryptococcus neoformans encephalitis with continuous administration of liposomal amphotericin B (AmB). Liposomal AmB was administered to a 28-year-old male by intravenous injection, with daily increasing dosages up to 150 mg per day and combined use of fluconazole (0.4 g per day) and oral flucytosine tablets (1.5 g per day). Following 5 months of treatment, C. neoformans could still be detected in the ink stain of cerebrospinal fluid, but the patient could not tolerate a further increase in the dosage of liposomal AmB. Instead, continuous intrathecal administration of AmB through tube drainage on the lumbar cistern was used. A total dosage of 28 mg liposomal AmB was administered to the patient over the course of 1 month. The effect of AmB administered by intravenous injection was not as great as expected and the patient's tolerance was not good. However, the patient recovered following treatment by continuous intrathecal administration of AmB through tube drainage on the lumbar cistern for 1 month. This case suggests that continuous intrathecal administration of liposomal AmB should be considered for clinical treatment of refractory cryptococcal encephalitis. PMID- 28673000 TI - Effect of AXL on the epithelial-to-mesenchymal transition in non-small cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality in the United States. AXL, which is a member of the receptor tyrosine kinases, has been established as a strong candidate for the targeted therapy of cancer. Therefore, the present study aimed to investigate the role of AXL in NSCLC; in particular the molecular mechanisms underlying the involvement of AXL in the epithelial-to-mesenchymal transition (EMT). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis demonstrated that AXL, EMT-inducing Twist and the mesenchymal marker N-cadherin were upregulated, and the epithelial markers E-cadherin and beta-cadherin were downregulated, in the PC9 NSCLC cell line. Furthermore, downregulation of AXL expression by RNA interference was shown to inhibit cell growth by inducing the apoptosis of PC9 cells, as demonstrated by MTT and flow cytometry analyses. Notably, inhibition of AXL attenuated the regulation of EMT-associated genes, specifically downregulating Twist and N-cadherin, and upregulating E-cadherin and beta-cadherin. Conversely, downregulation of Twist did not affect the expression levels of AXL. These results suggested that AXL may inhibit the EMT by the regulation of EMT-associated genes in the PC9 cell line. The results of the present study indicated that AXL may have a role in the regulation of EMT and the cell cycle of the PC9 cells; thus suggesting that AXL may have clinical significance in the design of therapeutic strategies targeting NSCLC and EMT signaling pathways. PMID- 28673001 TI - Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork. AB - Glaucoma is a major cause of irreversible blindness. Nuclear factor (erythroid derived 2)-like 2 (Nrf2) regulates the expression of numerous antioxidants within cells and is therefore a focus of current ophthalmic research. To determine the roles of Nrf2 in mediating the glaucoma trabecular meshwork (GTM), the present study evaluated the levels of Nrf2 expression in GTM and human trabecular meshwork (HTM) cells by reverse-transcription-quantitative polymerase chain reaction and western blot analysis. It was principally observed that Nrf2 expression was downregulated in GTM cells. In addition, to determine the influence of Nrf2 on the apoptosis and proliferation of GTM and HTM cells, transfection assays and western blotting were performed to evaluate the expression of apoptosis-related proteins. The results of the current study indicated that Nrf2 may promote viability and reduce apoptosis in GTM and HTM cells. Collectively, these data suggest that Nrf2 may be a novel therapeutic target to treat glaucoma. PMID- 28673002 TI - IGF-1 may predict the severity and outcome of patients with sepsis and be associated with microRNA-1 level changes. AB - IGF-1 functions as an anti-oxidative stress molecule and some critical patients with sepsis have a lower level of serum IGF-1. However, the association between IGF-1 and the severity or prognosis of sepsis remains unclear. This study aimed to elucidate the relationship between serum IGF-1 levels and the severity and prognosis of sepsis, and the possible mechanism was analyzed. Clinical characteristics of patients with sepsis were recorded and analyzed. Serum IGF-1 levels and micro (mi)RNA-1 levels were tested using radioimmunoassay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, respectively. The A549 cell line and HKC cell line were cultured in vitro and exposed to H2O2 with or without IGF-1 treatment. Cell death was detected by analyzing cell death markers via ELISA kits, and miRNA-1 levels were detected after H2O2 exposure using RT-qPCR analysis. miRNA-1 in cells was upregulated by transfection and IGF-1 mRNA was detected to determine its relationship with miRNA 1. Once again, cell ELISA kits were used to analyze cell death markers after transfection. Serum IGF-1 levels were reduced in patients with sepsis, whereas miRNA-1 levels were higher (P<0.05 vs. healthy control). Patients in the septic shock subgroup or dead patients had the lowest IGF-1 levels and the highest miRNA 1 levels (P<0.05 vs. sepsis and severe sepsis). IGF-1 levels were inversely proportional to the miRNA-1 level. In vitro, IGF-1 reduced the cell death caused by H2O2. miRNA-1 transfection effectively increased the sensitivity of cells to H2O2 damage by reducing the expression of IGF-1, which was able to prevent cells from injury caused by H2O2. The transfection of negative control miRNA did not influence the level of IGF-1 miRNA and the sensitivity to H2O2 damage. In conclusion, low IGF-1 levels in patients with sepsis may predict increased severity of the condition and poor prognosis. The possible mechanism is that the excessive miRNA-1 levels reduce IGF-1 levels, resulting in insufficient anti oxidative action by IGF-1 which increases the injury caused by oxidative stress in patients with sepsis. PMID- 28673003 TI - Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways. AB - Osteosarcoma (OS) is the most commonly diagnosed tumor of the bones in children and young adults. Even with conventional therapies the 5-year survival rate is ~65% in patients with OS. Considering the side effects and aggressiveness of malignant bone tumors, research is focussing on multi-targeted strategies in treatment. Cucurbitacin B, a triterpenoid compound has been demonstrated to induce apoptosis in various cancer cell types. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling cascades and mitogen activated protein kinases (MAPK) signalling cascades are critical regulators of tumorigenesis. The present study assessed the influence of cucurbitacin B on the viability and expression of MAPKs and proteins of the JAK2/STAT3 cascades in human OS cells (U-2 OS). Cucurbitacin B (20-100 uM) significantly reduced cell viability (P<0.05) and induced apoptosis, as assessed by MTT and Annexin V/propidium iodide staining, along with inhibiting cell migration. Gelatin zymography revealed supressed activities of matrix metalloproteinase (MMP-)2 and 9. Furthermore, cucurbitacin B effectively upregulated the apoptotic pathway and caused the effective inhibition of MAPK signalling and JAK2/STAT3 cascades. Multifold suppression of vascular endothelial growth factor by cucurbitacin B was also observed, indicating inhibition of angiogenesis. Thus, by downregulating major pathways-MAPK and JAK2/STAT3 and MMPs, cucurbitacin B has potent anti-proliferative and anti-metastatic effects that require further investigation with regards to cancer treatment. PMID- 28673004 TI - Puerarin prevents tumor necrosis factor-alpha-induced apoptosis of PC12 cells via activation of the PI3K/Akt signaling pathway. AB - Tumor necrosis factor-alpha (TNF-alpha), a potential proinflammatory cytokine, is an important component involved in neuronal apoptosis associated with neuroinflammation in the central nervous system. It has been reported that puerarin possesses pharmacological effects, such as anti-apoptotic, antioxidant, anti-osteoporosis, anti-inflammatory, cardioprotective and neuroprotective actions. The aim of the present study was to explore the effect of puerarin on apoptosis induced by TNF-alpha (3*105 U/l) and its detailed mechanisms in PC12 cells. MTT and flow cytometric assays were performed to evaluate cell cytotoxicity and apoptosis, respectively. An enzymatic assay was used to detect the activity of caspase-3 and caspase-9. Western blot analysis was performed to assess changes in the levels of proteins, including B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, Akt and phosphorylated Akt. The results showed that puerarin (25 and 50 uM) significantly suppressed TNF-alpha induced apoptosis in PC12 cells. The TNF-alpha-induced in crease in the Bax/Bcl-2 ratio was markedly inhibited by pre-treatment with puerarin for 2 h. In addition, puerarin decreased the level of TNF-alpha-induced cleaved caspase-3. Furthermore, puerarin inhibited the TNF-alpha-induced decrease in the phosphorylation of Akt, which was abolished by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, suggesting that the PI3K/Akt pathway participated in the suppressive effect of puerarin. Taken together, these findings indicated that puerarin prevented TNF-alpha-induced apoptosis in PC12 cells via activating of the PI3K/Akt signaling pathway, suggesting that puerarin may be a potential neuroprotective drug in the clinical treatment of neuroinflammation via anti apoptotic mechanisms. PMID- 28673005 TI - Celastrol inhibits migration and invasion through blocking the NF-kappaB pathway in ovarian cancer cells. AB - Metastatic ovarian cancer is a major clinical challenge with poor prognosis and high mortality. Celastrol is a natural compound that has exhibits antiproliferative activity; however, its effects on metastasis-related phenotypes in ovarian cancer models are unclear. In the current study, the anti-invasive activities and associated signaling pathways of celastrol were determined in ovarian cancer cells. Cell proliferation was tested by MTT assay. Cell migration was detected by wound healing and Transwell assays, while cell invasion was detected by a Matrigel-coated Transwell method. In addition, nuclear factor (NF) kappaB and matrix metalloproteinase (MMP) expression was examined by western blotting, and MMP-2/-9 activities were determined by gelatin zymography. At sub toxic concentrations (<0.5 uM), celastrol inhibited migration and invasion in a concentration-dependent manner in SKOV-3 and OVCAR-3 cells. At the molecular level, celastrol blocked the canonical NF-kappaB pathway by inhibiting IkappaBalpha phosphorylation, and preventing IkappaBalpha degradation and p65 accumulation. Furthermore, the expression and activity of the NF-kappaB target protein MMP-9, but not MMP-2, were inhibited by celastrol. Furthermore, celastrol showed no synergistic effect with MG132, an NF-kappaB inhibitor. In conclusion, celastrol exhibited significant anti-invasive activities in ovarian cancer cells. Such functions may be mediated via NF-kappaB pathway blockade. The results of this in vitro study strengthen the value of applying celastrol as a potential clinical intervention modality for delaying ovarian cancer metastasis. This, celastrol warrants further preclinical investigation. PMID- 28673006 TI - Comparison of the gas-liquid dual support fixation and Heitzman fixation techniques for preparing lung specimens. AB - The aim of the present study was to compare the gas-liquid dual support fixation and Heitzman fixation techniques for the preparation of lung specimens. A total of 40 fresh lung samples were surgically collected from 40 male patients with lung cancer by biopsy. Patients were recruited from the Affiliated Hospital of Qingdao University Medical College (Qingdao, China) between July 2007 and June 2014. Samples were prepared using either the gas-liquid dual support fixation method (group A; n=26) or the Heitzman fixation method (group B; n=14). High resolution computed tomography (HRCT) scanning was performed prior to surgery and corresponding postoperative HRCT scanning was conducted for the lung specimens; the gross transverse specimen section, cord photography images and histological sections were evaluated. Morphological observations of lung specimens indicated that there were 22 cases in group A with grade I (84.6%) and 4 cases with grade II (15.4%), whereas, in group B, there were 5 cases with grade II (35.7%) and 9 cases with grade III (64.3%). Statistical analysis demonstrated that the grades of specimens between the two groups were significantly different (P<0.01). Results from imaging and histological studies found that the quality of lung specimens was superior in group A, compared with group B. In conclusion, the present study demonstrated that, compared with the Heitzman fixation method, gas liquid dual support fixation may be a superior technique for the preparation of lung specimens. This finding may facilitate the improvement of lung HRCT and pathological studies. PMID- 28673007 TI - Cytokine-induced killer cell therapy for modulating regulatory T cells in patients with non-small cell lung cancer. AB - Previous studies have reported that regulatory T cells (Tregs), which are physiologically engaged in the maintenance of immunological self-tolerance, have a critical role in the regulation of the antitumor immune response. Targeting Tregs has the potential to augment cancer vaccine approaches. The current study therefore aimed to evaluate the role of cytokine-induced killer (CIK) cell infusion in modulating Tregs in patients with non-small cell lung cancer (NSCLC). A total of 15 patients with advanced NSCLC were treated by an infusion of CIK cells derived from autologous peripheral blood mononuclear cells (PBMCs). By using flow cytometry and liquid chip analysis, subsets of T cells and natural killer (NK) cells in peripheral blood, and plasma cytokine profiles in the treated patients, were analyzed at 2 and 4 weeks after CIK cell infusion. Cytotoxicity of PBMCs (n=15) and NK cells (n=6) isolated from NSCLC patients was evaluated before and after CIK cell therapy. Progression-free survival (PFS) and overall survival (OS) were also assessed. Analysis of the immune cell populations before and after treatment showed a significant increase in NK cells (P<0.05) concomitant with a significant decrease in Tregs (P<0.01) at 2 weeks post infusion of CIK cells compared with the baseline. NK group 2D receptor (NKG2D) expression on NK cells was also significantly increased at 2 weeks post-infusion compared with the baseline (P<0.05). There was a positive correlation between NKG2D expression and the infusion number of CIK cells (P<0.05). When evaluated at 2 weeks after CIK cell therapy, the cytotoxicity of PBMCs and isolated NK cells was significantly increased compared with the baseline (P<0.01 and P<0.05). Correspondingly, plasma cytokine profiles showed significant enhancement of the following antitumor cytokines: Interferon (IFN)-gamma (P<0.05), IFN-gamma inducible protein 10 (P<0.01), tumor necrosis factor-alpha (P<0.001), granulocyte macrophage colony-stimulating factor (P<0.01), monocyte chemotactic protein-3 (P<0.01) and interleukin-21 (P<0.05) at 2 weeks post-infusion, compared with the baseline. At the same time, the expression of transforming growth factor-beta1, which is primarily produced by Tregs, was significantly decreased compared with the baseline (P<0.05). Median PFS and OS in the CIK cell treatment group were significantly increased compared with the control group (PFS, 9.98 vs. 5.44 months, P=0.038; OS, 24.17 vs. 20.19 months, P=0.048). No severe side-effects were observed during the treatment period. In conclusion, CIK cell therapy was able to suppress Tregs and enhance the antitumor immunity of NK cells in advanced NSCLC patients. Therefore, CIK cell treatment may improve PFS and OS in patients with advanced NSCLC. CIK cell infusion may have therapeutic value for patients with advanced NSCLC, as a treatment that can be combined with chemotherapy and radiotherapy. PMID- 28673008 TI - Sesamol attenuates oxidative stress, apoptosis and inflammation in focal cerebral ischemia/reperfusion injury. AB - The aim of the present study was to evaluate the therapeutic potential of sesamol treatment on focal ischemia/reperfusion (I/R) injury in the rat brain. The results demonstrated that pretreatment with sesamol seven days prior to focal cerebral I/R injury had significant positive effects, including improvements in neurological deficits (P<0.05), and a reduction in malondialdehyde content and elevation of antioxidant levels (superoxide dismutase, glutathione and glutatione peroxidase; both P<0.05). Furthermore, levels of B cell lymphoma-2 (Bcl-2) associated X protein and caspase-3 were significantly downregulated, whereas the level of Bcl-2 was effectively increased. Conversely, the mRNA expression of proinflammatory cytokines were significantly reduced in focal cerebral I/R injury rats upon sesamol intervention. Therefore, the beneficial effects of sesamol on cerebral I/R injury may be due to the reduction of oxidative stress, inhibition of apoptosis and inflammation. The findings of the present study suggest that sesamol supplementation may serve as potent adjuvant in the treatment of focal cerebral ischemia/reperfusion injury due to its neuroprotective effects. PMID- 28673009 TI - Oleanolic acid protects against diabetic cardiomyopathy via modulation of the nuclear factor erythroid 2 and insulin signaling pathways. AB - Oleanolic acid (OL) is a pentacyclic triterpene compound used for the treatment of hepatitis, liver fibrosis and liver cirrhosis. In China, there is no published research on the effect or biological utilization of OL on liver diseases. The aim of the present study was to investigate the protective effects of OL against diabetic cardiomyopathy and its possible mechanism. A rat model of diabetes was established using streptozotocin and the effect of OL on diabetic cardiomyopathy (DCM) was evaluated. The results demonstrated that OL significantly reversed the DCM-induced changes to body weight, heart rate, echocardiography and hemodynamics, phosphorylated-glycogen synthase (GS) and glycogen phosphorylase (GP) activity in diabetic rats (all P<0.01). Treatment of diabetic rats with OL significantly inhibited oxidative stress and activated heme oxygenase (HO) 1/nuclear factor erythroid 2 (Nrf2) signaling in a rat model of diabetes (both P<0.01). The results of the present study indicate that OL protects against DCM through the HO-1/Nrf2 and insulin modulating GS/GP signaling pathways. PMID- 28673010 TI - Rhubarb vs. glycerin enema for treatment of critically ill patients with intra abdominal hypertension. AB - Rhubarb has been used as an evacuant for thousands of years. However, recent research has indicated that rhubarb inhibits inflammation and protects organ function. In the current study, the use of rhubarb was investigated in patients with intra-abdominal hypertension (IAH). Specifically, its dual role in attenuating lung and bowel injury by catharsis and inhibiting inflammation was evaluated. Patients in the glycerin group (n=56) received 110 ml of glycerin enema by coloclysis once daily for 7 to 9 days. Patients in the rhubarb group (n=56) were treated with a mixture of 0.3 g/kg body weight rhubarb powder in 100 ml warm water. The Acute Physiology and Chronic Health Evaluation II (APACHE II), Sepsis-Related Organ Failure Assessment (SOFA), intra-abdominal pressure, procalcitonin (PCT), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF alpha) and interleukin (IL)-6 levels were recorded. The duration of mechanical ventilation (MV), respiratory parameters, first day of enteral nutrition (EN), intensive care unit (ICU) hospital stay and 30-day mortality were also recorded. The APACHE II scores were significantly lower in the rhubarb group compared with the glycerin group from day 3 to 9 (P<0.05 at day 3 and 4; P<0.01 at day 5, 7 and 9). The SOFA scores were significantly lower in the rhubarb group compared with the glycerin group from day 5 to 9 (P<0.05). PCT levels were significantly lower from day 4 to 9 (P<0.05) and the CRP level was significantly lower from day 3 to 9 (P<0.05) in the rhubarb group compared with the glycerin group. The TNF-alpha and IL-6 were significantly lower in the rhubarb group compared with the glycerin group from day 3 to 9 (P<0.05 at day 3 and 4, P<0.01 at day 5, 7 and 9). The positive end-expiratory pressure and peak inspiratory pressure were significantly lower in the rhubarb group compared with the glycerin group at day 3, 5 and 7 (P<0.05 at day 3 and 5, P<0.01 at day 7), while the oxygenation index (P<0.05) and alveolar-arterial partial pressure of oxygen (P<0.05 at day 3 and 5, P<0.01 at day 7) were significantly improved. Significantly shorter durations of MV and ICU hospital stay, and earlier EN, were observed in the rhubarb group compared with the glycerin group (all P<0.05). Rhubarb treatment was indicated to be beneficial in IAH, by inhibiting inflammation and restoring intestinal function. PMID- 28673011 TI - Tribbles homolog 1 enhances cholesterol efflux from oxidized low-density lipoprotein-loaded THP-1 macrophages. AB - Macrophage foam cell formation plays a pivotal role in the pathogenesis of atherosclerosis. The protein Tribbles homolog 1 (Trib1), a member of the Tribbles protein family, functions as an adaptor or scaffold protein. Recent studies have indicated its implication in lipoprotein metabolism. In the present study, the role of Trib1 in macrophage foam cell formation was investigated. Oil red O staining was used to analyze intracellular lipid deposition, while the effects of Trib1 overexpression on cholesterol efflux were also examined. Furthermore, quantitative polymerase chain reaction and western blot analysis were performed to measure the expression levels of genes involved in cholesterol efflux. The results revealed that overexpression of Trib1 inhibited lipid accumulation in oxidized low density lipoprotein-treated THP-1 macrophages and facilitated macrophage cholesterol efflux to apolipoprotein A-I. Overexpression of Trib1 also upregulated the expression levels of ATP-binding cassette A1 (ABCA1), ABCG1, liver X receptor alpha (LXRalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma). In addition, silencing of LXRalpha or PPARgamma via small interfering RNA transfection significantly reversed the Trib1-induced cholesterol efflux. In conclusion, Trib1 inhibits macrophage foam cell formation and enhances cholesterol efflux, which is associated with regulation of the PPARgamma, LXRalpha, ABCA1 and ABCG1 expression levels. PMID- 28673012 TI - microRNA-605 promotes cell proliferation, migration and invasion in non-small cell lung cancer by directly targeting LATS2. AB - Lung cancer is the most common cause of cancer- associated mortality for men and women worldwide. An increasing number of studies have reported that the abnormal expression of microRNAs contributes to the pathogenesis of the majority of human cancer types, including non-small cell lung cancer (NSCLC). The present study aimed to measure microRNA-650 (miR-650) expression in NSCLC and evaluate its function in NSCLC cells. Reverse transcription-quantitative polymerase chain reaction was used to determine miR-650 expression in NSCLC tissue samples and cell lines. Assays for cell proliferation, migration and invasion were performed to investigate the roles of miR-650 on NSCLC progression. Furthermore, the mechanisms underlying the effects of miR-650 on NSCLC cell growth and metastasis were determined. In the current study, miR-650 was demonstrated to be highly expressed in NSCLC tissue samples and cell lines. Inhibition of expression of miR 650 suppressed NSCLC cell proliferation, migration and invasion in vitro. Additionally, large tumor suppressor kinase 2 (LATS2) was identified as a direct target gene of miR-650 in NSCLC. LATS2 was revealed to be significantly downregulated in NSCLC tissues and was negatively correlated with miR-650 expression. Notably, LATS2 re-expression decreased NSCLC cell proliferation, migration and invasion; similar to the effects induced by miR-650 underexpression. In conclusion, the results of the current study suggest that miR 650 may serve as an oncogene by direct targeting LATS2 in NSCLC formation and progression. PMID- 28673013 TI - Coumarins from the roots of Angelica dahurica cause anti-allergic inflammation. AB - Allergic inflammation is induced by allergens and leads to various allergic diseases, including rhinitis, asthma and conjunctivitis. Histamine is important in the pathogenesis of an immunoglobulin E-dependent allergic reaction and results in the secretion of cytokines associated with inflammation. Angelica dahurica (A. dahurica) is a medicinal plant widely used in China for the treatment of symptoms related to allergic inflammation. The present study investigated the chemical constituents from A. dahurica and evaluated their reductive effect on allergic inflammation. As a result, 15 compounds including 13 coumarins have been identified as isoimperatorin (1), imperatorin (2), oxypeucedanin (3), oxypeucedanin hydrate (4), bergapten (5), byakangelicin (6), phellopterin (7), byakangelicol (8), isopimpinellin (9), xanthotoxol (10), xanthotoxin (11), pimpinellin (12), scopoletin (13), beta-sitosterol (14) and daucosterol (15). Compounds 1-13 were able to reduce the release of histamine, with compounds 4-6 exhibiting the most potent activity. Furthermore, compounds 1 12 were able to inhibit the secretion of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-4, with compounds 5 and 7 exhibiting the strongest inhibitory effects. These compounds implemented the inhibitory effects on the expression of inflammatory cytokine genes through the inhibition of nuclear factor-kappaB activation. Virtual screening by a docking program indicated that compound 3 is a potent histamine H1 receptor antagonist. Additionally, the calculated physicochemical properties of these compounds support most furanocoumarins to be delivered to binding sites and permeate the cell membrane. The present findings contribute to understanding how A. dahurica attenuates allergic inflammation. PMID- 28673014 TI - The clinical characteristics of posterior reversible encephalopathy syndrome in patients with chronic renal failure. AB - Few studies have investigated posterior reversible encephalopathy syndrome (PRES) in patients with chronic renal failure (CRF). The present study analyzed the clinical manifestations, laboratory examinations and imaging features of PRES in patients with CRF. A total of 42 patients with CRF with or without PRES were recruited in the current retrospective case-control study. Patient data taken prior to the onset of PRES in patients with CRF and PRES (n=21) were collected and analyzed. At the same time, data from patients with CRF but without PRES (n=21) were also analyzed. Brain magnetic resonance imaging (MRI) scans were collected from patients in the PRES group. The mean blood pressure of patients in the PRES group was significantly higher than that of the control group (systolic blood pressure: 172+/-15 mmHg vs. 135+/-14 mmHg, P<0.01; diastolic blood pressure: 95+/-16 mmHg vs. 64+/-13 mmHg, P<0.01). Furthermore, compared with the control group, mean serum albumin (Alb) and hemoglobin (Hb) concentrations in the PRES group were significantly lower (Alb: 29.1+/-5.3 g/l vs. 34.6+/-6.1 g/l, P=0.001; Hb: 74+/-16 g/l vs. 89+/-28 g/l, P=0.037). By contrast, mean LDH concentration was significantly higher in the PRES group (LDH: 336+/-141 U/l vs. 235+/-89 U/l, P=0.004). In the PRES group, 24 h urine volume was significantly lower in the PRES group than in the control group (24 h urine volume: 651+/-520 ml vs. 982+/-518 ml, P=0.046). No significant differences in levels of serum potassium (4.5+/-0.6 mmol/l vs. 4.4+/-0.5 mmol/l, P=0.377), sodium (138.3+/-4.9 mmol/l vs. 139.0+/-6.8 mmol/l, P=0.325), calcium (2.0+/-0.24 mmol/l vs. 1.9+/ 0.24 mmol/l, P=0.673), alanine aminotransferase; (24+/-14 U/l vs. 18+/-8 U/l, P=0.975); aspartate aminotransferase (29+/-11 U/l vs. 24+/-9 U/l, P=0.619) and uric acid (448+/-148 umol/l vs. 378+/-116 umol/l, P=0.599) were found between the two groups. PRES is a relatively common nervous system complication arising in patients with CRF. Certain biochemical markers, including Hb and Alb, may be associated with PRES. Diagnosing PRES is difficult as computed tomography (CT) brain scans may be normal and MRI scans, which are more sensitive than CT scans at diagnosing PRES, are not always performed in patients with CRF. Thus, brain MRI scans should be taken first in such patients when PRES is suspected. PMID- 28673015 TI - Preliminary asthma -related outcomes following glucagon - like peptide 1 agonist therapy. PMID- 28673016 TI - FALCON: a toolbox for the fast contextualization of logical networks. AB - Motivation: Mathematical modelling of regulatory networks allows for the discovery of knowledge at the system level. However, existing modelling tools are often computation-heavy and do not offer intuitive ways to explore the model, to test hypotheses or to interpret the results biologically. Results: We have developed a computational approach to contextualize logical models of regulatory networks with biological measurements based on a probabilistic description of rule-based interactions between the different molecules. Here, we propose a Matlab toolbox, FALCON, to automatically and efficiently build and contextualize networks, which includes a pipeline for conducting parameter analysis, knockouts and easy and fast model investigation. The contextualized models could then provide qualitative and quantitative information about the network and suggest hypotheses about biological processes. Availability and implementation: FALCON is freely available for non-commercial users on GitHub under the GPLv3 licence. The toolbox, installation instructions, full documentation and test datasets are available at https://github.com/sysbiolux/FALCON. FALCON runs under Matlab (MathWorks) and requires the Optimization Toolbox. Contact: thomas.sauter@uni.lu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28673017 TI - Prognostic factors for death from visceral leishmaniasis in patients treated with liposomal amphotericin B in an endemic state in Brazil. AB - Objective: To characterize the clinical and epidemiological profiles of patients with visceral leishmaniasis (VL) treated with liposomal amphotericin B (LAmB) and to identify prognostic factors for death from VL in 2008-2012 in the state of Minas Gerais, Brazil. Methods: A historical cohort study was conducted using data obtained from treatment requests forms, Brazilian Notifiable Disease Information System and the Mortality Information System. Case-fatality rates of patients with VL treated with LAmB were compared with patients treated with other therapies. Logistic regression analysis was used to identify prognostic factors for death. Results: The overall case-fatality rate of the 577 patients treated with LAmB was 19.4%. Prognostic factors for death from VL were age between 35 and 49 years (OR 2.7; 95% CI 1.3-5.4) and above 50 years (OR 2.6; 95% CI 1.3-4.9), jaundice (OR 2.2; 95% CI 1.2-3.7), kidney disease (OR 2.8; 95% CI 1.6-4.9), presence of other infections (OR 2.4; 95% CI 1.5-4.1), edema (OR 2.0; 95% CI 1.1-3.4), platelet count below 50.000/mm3 (OR 3.6; 95% CI 2.1-6.0), AST higher than 100 U/L (OR 2.2; 95% CI 1.3-3.8), and assistance in non-specialized institutions (OR 1.9; 95% CI 1.0-3.5). Conclusions: Case-fatality rates were higher than that observed among patients with VL treated with other therapies. Identification of prognostic factors of death from VL may allow early diagnosis of patients prone to such outcome and prompt an expeditious and appropriate management of VL to reduce fatality rates. PMID- 28673018 TI - Hypertension in treated and untreated patients with HIV: a study from 2011 to 2013 at the Jos University Teaching Hospital, Nigeria. AB - Background: Individuals with HIV, especially those on antiretroviral therapy (ART), may have increased risk of hypertension. We investigated the prevalence of hypertension at enrolment and 12 months after commencing ART in a Nigerian HIV clinic. Methods: Data from patients enrolled for ART from 2011 to 2013 were analysed, including 2310 patients at enrolment and 1524 re-evaluated after 12 months of ART. The presence of hypertension, demographic, clinical and biochemical data were retrieved from standardized databases. Bivariate and logistic regressions were used to identify baseline risk factors for hypertension. Results: Prevalence of hypertension at enrolment was 19.3% (95% CI 17.6-20.9%), and age (p<0.001), male sex (p=0.004) and body mass index (BMI) (p<0.001) were independent risk factors for hypertension. Twelve months after initiating ART, a further 31% (95% CI 17.6-20.9%) had developed hypertension. Total prevalence at that point was 50.2%. Hypertension among those on ART was associated with age (p=0.009) and BMI (p=0.008), but not with sex. There were no independently significant associations between hypertension and CD4+ counts, viral load or type of ART. Conclusions: Hypertension is common in HIV infected individuals attending the HIV clinic. Patients initiating ART have a high risk of developing hypertension in the first year of ART. Since BMI is modifiable, life style advice aimed at weight reduction is strongly advisable. PMID- 28673019 TI - Gastrointestinal tract involvement in melioidosis. AB - Background: Little is known about the involvement of the human gut in carriage and disease associated with Burkholderia pseudomallei, the cause of melioidosis. Methods: A hospital-based study was conducted in Northeast Thailand to culture stools or rectal swabs from patients with melioidosis, stools from controls with non-infectious diseases, and gastric biopsies from patients undergoing routine endoscopic investigation. Results and Conclusion: B. pseudomallei was isolated from 9/83 (11%) stools and 9/58 (16%) rectal swabs from 141 patients with melioidosis. All stools from 244 control patients and 799 gastric biopsies from 395 patients with no evidence of melioidosis were culture negative for B. pseudomallei. It is not uncommon for melioidosis patients to shed B. pseudomallei in stool. Colonization of the gut of individuals without signs and symptoms of melioidosis may be rare. PMID- 28673020 TI - The case for integrated human papillomavirus vaccine and HIV prevention with broader sexual and reproductive health and rights services for adolescent girls and young women. PMID- 28673021 TI - Emergence of West Nile virus in West Bengal, India: a new report. AB - Background: The ICMR virus unit in Kolkata functions as an Appex Referral Laboratory for the detection of dengue (DENV) and chikungunya (CHIKV) infections in the eastern part of India. In spite of efforts for confirmatory diagnosis, some samples remain undiagnosed every year. West Nile virus (WNV) infection may mimic either dengue (flavivirus) or chikungunya (alphavirus) like illness. WNV is endemic in the tropical region where its principal/potential vectors are Aedes and Culex. Methods: We explored the existence of WNV within undiagnosed samples to identify the emergence of a new public health problem. Results: Of 1278 sera samples, 574 were negative for DENV and CHIKV either by ELISA or by reverse transcriptase (RT)-PCR. Of these 574 negative samples, 83 (14.5%) and 141 (24.56%) were positive for WNV by ELISA and RT-PCR, respectively; no samples were positive for WNV by both methods. After assembling raw sequencing data, partial envelope genome sequence of West Bengal isolates, WNV was compared through BLAST with other WNV Indian strains and 98% homology detected. Phylogenetic analysis of one West Bengal isolates (Accession No. KY421790) and 28 Indian isolates available in GenBank, indicated close clustering. Conclusions: The serological and molecular approaches have clearly established the emergence of WNV in West Bengal. Hence, for proper case management, detection of WNV in common febrile illness is strongly recommended. PMID- 28673022 TI - Secondary prevention for screening detected rheumatic heart disease: opportunities to improve adherence. AB - Background: Secondary prevention is an effective treatment for rheumatic heart disease (RHD), but ensuring high adherence to prophylaxis over many years is challenging and requires understanding of local factors. Methods: Participants were young people diagnosed with RHD through echocardiographic screening in Fiji. We used a structured interview to evaluate the following: health seeking behaviours; attitudes, practice, barriers and potential improvement strategies for adherence to antibiotic prophylaxis; and adolescent-friendly qualities of the health service. Results: One hundred and one participants were interviewed (median age, 17.2 years). Adherence was very low overall (adequate in 6%). Sore throat and fever with sore joints were experienced in the preceding year by 42% and 28%, respectively. Barriers to receiving treatment included taking alternate treatments and the perception that symptoms were benign and self-limiting. Reasons for missing prophylaxis injections included lack of awareness, feeling well, transport cost and access, and medication unavailability (>40% of participants each). The injection health service had many perceived strengths, but inclusion of adolescents in decision making, and quality of educational materials were deficiencies. Reminder strategies, particularly phone-based reminders, were considered helpful by 94%. Conclusions: We identified several factors influencing secondary prevention that may be used to develop interventions to improve adherence. PMID- 28673023 TI - Anemia and growth retardation associated with Schistosoma haematobium infection in Mali: a possible subtle impact of a neglected tropical disease. AB - Background: The aim of this cross-sectional study was to investigate a possible association of Schistosoma haematobium with child growth development and describe a plausible schistosomiasis-related anemia in children and adults in a highly schistosomiasis endemic area of Mali. Methods: Urine, feces and blood samples from 399 participants of both sexes (2-40 years of age) were analyzed and supplemented by anthropometric measurements. Results: S. haematobium prevalence was 79.8%, S. mansoni 13.2% and Plasmodium falciparum 80.2%. S. haematobium infection intensity as five categories was significantly associated with anemia; i.e., odds of having anemia in the highest and the next highest category was 3.25 (95% CL 1.61-6.55; p<0.01) and 2.45 (95% CL 1.28-4.70; p<0.01), respectively, of that in the three lower categories combined after adjusting for age group and gender and the interaction between the two factors. Anemia was most pronounced in the 2-5 year olds males (55.5%, n=98). P. falciparum infection was not significantly associated with anemia. Stunting (body mass index [BMI] for age z score<-2.00) was observed in 2.6% (2/78) of the 2-5 years olds and in 7.7% (14/182) in the 6-19 years age group. Lower BMI-z-scores (as continuous variable) were associated with anemia (p<0.05) while high intensity of S. haematobium infection was not significant when adjusting for age group and anemia. Participants with malaria infection had lower z-scores (as continuous variables) of weight and height for age. Lower height for age z-scores were also associated with anemia. Conclusions: S. haematobium infection is likely to impact on child growth and possibly also anemia in all age groups and advocates for inclusion of whole populations into future control programes. PMID- 28673025 TI - Alignment-free inference of hierarchical and reticulate phylogenomic relationships. AB - We are amidst an ongoing flood of sequence data arising from the application of high-throughput technologies, and a concomitant fundamental revision in our understanding of how genomes evolve individually and within the biosphere. Workflows for phylogenomic inference must accommodate data that are not only much larger than before, but often more error prone and perhaps misassembled, or not assembled in the first place. Moreover, genomes of microbes, viruses and plasmids evolve not only by tree-like descent with modification but also by incorporating stretches of exogenous DNA. Thus, next-generation phylogenomics must address computational scalability while rethinking the nature of orthogroups, the alignment of multiple sequences and the inference and comparison of trees. New phylogenomic workflows have begun to take shape based on so-called alignment-free (AF) approaches. Here, we review the conceptual foundations of AF phylogenetics for the hierarchical (vertical) and reticulate (lateral) components of genome evolution, focusing on methods based on k-mers. We reflect on what seems to be successful, and on where further development is needed. PMID- 28673024 TI - Ancestry-Adjusted Vitamin D Metabolite Concentrations in Association With Cytochrome P450 3A Polymorphisms. AB - We investigated the association between genetic polymorphisms in cytochrome P450 (CYP2R1, CYP24A1, and the CYP3A family) with nonsummer plasma concentrations of vitamin D metabolites (25-hydroxyvitamin D3 (25(OH)D3) and proportion 24,25 dihydroxyvitamin D3 (24,25(OH)2D3)) among healthy individuals of sub-Saharan African and European ancestry, matched on age (within 5 years; n = 188 in each ancestral group), in central suburban Pennsylvania (2006-2009). Vitamin D metabolites were measured using high-performance liquid chromatography with tandem mass spectrometry. Paired multiple regression and adjusted least-squares mean analyses were used to test for associations between genotype and log transformed metabolite concentrations, adjusted for age, sex, proportion of West African genetic ancestry, body mass index, oral contraceptive (OC) use, tanning bed use, vitamin D intake, days from summer solstice, time of day of blood draw, and isoforms of the vitamin D receptor (VDR) and vitamin D binding protein. Polymorphisms in CYP2R1, CYP3A43, vitamin D binding protein, and genetic ancestry proportion remained associated with plasma 25(OH)D3 after adjustment. Only CYP3A43 and VDR polymorphisms were associated with proportion 24,25(OH)2D3. Magnitudes of association with 25(OH)D3 were similar for CYP3A43, tanning bed use, and OC use. Significant least-squares mean interactions (CYP2R1/OC use (P = 0.030) and CYP3A43/VDR (P = 0.013)) were identified. A CYP3A43 genotype, previously implicated in cancer, is strongly associated with biomarkers of vitamin D metabolism. Interactive associations should be further investigated. PMID- 28673027 TI - Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children. AB - Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged <=12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL >1000 copies/mL was done. The 2015 IAS-USA mutation list and Stanford algorithm were used to score drug resistance mutations (DRMs) and susceptibility. Virological failure (VF) was defined as two consecutive VLs >1000 copies/mL or death after 6 months of ART. Factors associated with failure and acquired drug resistance (ADR) were assessed in a logistic regression analysis. Results: Among 317 children enrolled, median age was 4.9 years and 91.5% received NNRTI-based regimens. PDR was detected in 47/278 (16.9%) children, of whom 22 (7.9%) had resistance against their first-line regimen and were therefore on a partially active regimen. After 24 months of follow-up, 92/287 (32.1%) had experienced VF. Children with PDR had a higher risk of VF (OR 15.25, P < 0.001) and ADR (OR 3.58, P = 0.01). Conclusions: Almost one-third of children experienced VF within 24 months of NNRTI-based first-line treatment. PDR was the strongest predictor of VF and ADR, and therefore presents a major threat in children. There is a need for ART regimens that maximize effectiveness of first-line therapy for long-term treatment success in the presence of PDR or incorporation of routine VL testing to detect VF and change treatment in time, in order to prevent clinical deterioration and accumulation of additional drug resistance. Children <=3 years should be initiated on a PI-based regimen as per WHO guidelines. PMID- 28673026 TI - 3beta-Hydroxy-urs-12-en-28-oic Acid Modulates Dietary Restriction Mediated Longevity and Ameliorates Toxic Protein Aggregation in C. elegans. AB - Species from lower invertebrates to a spectrum of mammals show antiaging health benefits of phytochemical(s). Here, we explored the pro-longevity effects of a natural triterpenoid, ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid; UA) in Caenorhabditis elegans with maximal life span being evident at 25 uM UA. Similar to eat-2 mutants, UA uptake by worm results in reduced fat storage and attenuation of reactive oxygen species (ROS), independent of superoxide dismutase(s) activation. The genetic requirements for UA-mediated longevity are quite similar to dietary restriction (DR) achieved through SKN-1/NRF-2 exhibiting upregulation of downstream target genes gcs-1 and daf-9. Longevity mechanism was independent of PHA-4/FOXA and attributed to partial dependence on sir-2.1. Altogether, our study suggests differential use of UA-elicited signaling cascades in nutrient sensing for longevity. Both the redox state and the proteostasis of an organism play critical role in aging and disease resistance. Interestingly, we observed a reduction of toxic protein aggregation in transgenic polyglutamine (polyQ) C. elegans model and UA-mediated JNK-1 (c-Jun-NH2-terminal kinase) activation in wild-type animals. Thus, our study demonstrates a small extent of prevention against proteotoxic stress by UA coupled with positive aspects of DR mediated longevity. PMID- 28673029 TI - Predictive Factors of Surgical Outcome in Frontal Lobe Epilepsy Explored with Stereoelectroencephalography. AB - BACKGROUND: Resective surgery established treatment for pharmacoresistant frontal lobe epilepsy (FLE), but seizure outcome and prognostic indicators are poorly characterized and vary between studies. OBJECTIVE: To study long-term seizure outcome and identify prognostic factors. METHODS: We retrospectively analyzed 42 FLE patients having undergone surgical resection, mostly preceded by invasive recordings with stereoelectroencephalography (SEEG). Postsurgical outcome up to 10-yr follow-up and prognostic indicators were analyzed using Kaplan-Meier analysis and multivariate and conditional inference procedures. RESULTS: At the time of last follow-up, 57.1% of patients were seizure-free. The estimated chance of seizure freedom was 67% (95% confidence interval [CI]: 54-83) at 6 mo, 59% (95% CI: 46-76) at 1 yr, 53% (95% CI: 40-71) at 2 yr, and 46% (95% CI: 32-66) at 5 yr. Most relapses (83%) occurred within the first 12 mo. Multivariate analysis showed that completeness of resection of the epileptogenic zone (EZ) as defined by SEEG was the main predictor of seizure outcome. According to conditional inference trees, in patients with complete resection of the EZ, focal cortical dysplasia as etiology and focal EZ were positive prognostic indicators. No difference in outcome was found in patients with positive vs negative magnetic resonance imaging. CONCLUSION: Surgical resection in drug-resistant FLE can be a successful therapeutic approach, even in the absence of neuroradiologically visible lesions. SEEG may be highly useful in both nonlesional and lesional FLE cases, because complete resection of the EZ as defined by SEEG is associated with better prognosis. PMID- 28673028 TI - Sugary secretions of wasp galls: a want-to-be extrafloral nectar? AB - Background and Aims: The most widespread form of protective mutualisms is represented by plants bearing extrafloral nectaries (EFNs) that attract ants and other arthropods for indirect defence. Another, but less common, form of sugary secretion for indirect defence occurs in galls induced by cynipid wasps. Until now, such galls have been reported only for cynipid wasps that infest oak trees in the northern hemisphere. This study provides the first evidence of galls that exude sugary secretions in the southern hemisphere and asks whether they can be considered as analogues of plants' EFNs. Methods: The ecology and anatomy of galls and the chemical composition of the secretion were investigated in north western Argentina, in natural populations of the host trees Prosopis chilensis and P. flexuosa . To examine whether ants protect the galls from natural enemies, ant exclusion experiments were conducted in the field. Key Results: The galls produce large amounts of sucrose-rich, nectar-like secretions. No typical nectary and sub-nectary parenchymatic tissues or secretory trichomes can be observed; instead there is a dense vascularization with phloem elements reaching the gall periphery. At least six species of ants, but also vespid wasps, Diptera and Coleoptera, consumed the gall secretions. The ant exclusion experiment showed that when ants tended galls, no differences were found in the rate of successful emergence of gall wasps or in the rate of parasitism and inquiline infestation compared with ant-excluded galls. Conclusions: The gall sugary secretion is not analogous to extrafloral nectar because no nectar-producing structure is associated with it, but is functionally equivalent to arthropod honeydew because it provides indirect defence to the plant parasite. As in other facultative mutualisms mediated by sugary secretions, the gall secretion triggers a complex multispecies interaction, in which the outcome of individual pair-wise interactions depends on the ecological context in which they take place. PMID- 28673030 TI - Analysis of Turnaround Time for Intraoperative Red Blood Cell Issues: A Single Center Study. AB - Background: When unpredicted surgical blood loss occurs, it is essential that blood arrive from the blood bank in a timely manner. Objective: To evaluate the turnaround time (TAT) for red blood cells (RBCs) from the blood bank to the operating suite. Cases with delayed TATs were further analyzed to determine potential causes for the delays. Methods: During a 6-month period, intraoperative RBC requests were included among the blood component request lists at a single tertiary care hospital. Results: A total of 387 RBC-product requests were received from the operating room, of which 220 (56.8%) cases were intraoperative requests. The overall mean (SD) TAT was 19.4 (9.8) minutes. Mean (SD) preparation to-issuance time (14.9 [7.8] minutes) contributed more to the overall TAT than did mean (SD) request-to-preparation time (4.5 [7.4] minutes). The 31 cases (14.1%) exceeded the internally mandated TAT threshold (> 30 minutes). Prolonged compatibility testing and delayed courier arrival contributed to TAT delay. Conclusions: TAT standards for issuing RBCs from the blood bank to the operating suite should be established and carefully monitored for quality improvement of transfusion services. PMID- 28673031 TI - Samoan Smokers Talk About Smoking and Quitting: A Focus Group Study. AB - Introduction: Samoa, like other Pacific Island countries, faces a persistent challenge to reduce smoking use with relatively limited resources. As a signatory to the WHO FCTC, Samoa is obligated to introduce measures to reduce tobacco use and is currently trialing a text message smoking cessation programme (mCessation) to achieve this outcome. Cigarettes remain relatively cheap and are widely available, but little is known about how smoking is initiated or why and how people quit smoking in the Samoa. Methods: Six focus groups with smokers and ex smokers were conducted in Apia, Samoa. Groups were homogenous according to age, gender and smoking status. Focus groups were conducted in Samoan and transcribed and translated to English for analysis. Results: Smoking is initiated most commonly in late teens and early twenties and most frequently in (non-family) social contexts. Smoking reflects a widely held (mis)perceptions of tangible benefits, including aiding feelings of strength and energy, relief from indigestion and as a means to accelerate the effects of alcohol. Smoking was deeply connected to social life in Samoa among friends and for some, with family members. Drivers to quit originate out of concern regarding health effects, concern for family and the costs of purchasing tobacco. Conclusions: Smoking is well entrenched in Samoan society; efforts to reduce smoking need to be based on implicit understanding of Samoan cultural norms and priorities around family, social networks and culture. Efforts to support quitting are important, alongside other well validated measures to reverse the trajectory of smoking related disease. Implications: This study offers an insight into smoking as a behavior and as cultural practice perceived by smokers and non-smokers in Samoa. A thorough understanding of smoking behaviors and cessation patterns is critical in efforts to reduce smoking especially in resource-limited settings. The results from this study was used to inform the development of a Samoan mHealth smoking cessation programme. PMID- 28673032 TI - Non-invasive management of post-partum spontaneous left main coronary artery dissection using cardiac computed tomography angiography. PMID- 28673034 TI - Giant triple coronary artery aneurysms. PMID- 28673033 TI - Comparison of four DNA extraction methods for comprehensive assessment of 16S rRNA bacterial diversity in marine biofilms using high-throughput sequencing. AB - High-throughput DNA sequencing technologies are increasingly used for the metagenomic characterisation of microbial biodiversity. However, basic issues, such as the choice of an appropriate DNA extraction method, are still not resolved for non-model microbial communities. This study evaluates four commonly used DNA extraction methods for marine periphyton biofilms in terms of DNA yield, efficiency, purity, integrity and resulting 16S rRNA bacterial diversity. Among the tested methods, the Plant DNAzol(r) Reagent (PlantDNAzol) and the FastDNA(r) SPIN Kit for Soil (FastDNA Soil) methods were best suited to extract high quantities of DNA (77-130 MUg g wet wt-1). Lower amounts of DNA were obtained (<37 MUg g wet wt-1) with the Power Plant(r) Pro DNA Isolation Kit (PowerPlant) and the Power Biofilm(r) DNA Isolation Kit (PowerBiofilm) methods, but integrity and purity of the extracted DNA were higher. Results from 16S rRNA amplicon sequencing demonstrate that the choice of a DNA extraction method significantly influences the bacterial community profiles generated. A higher number of bacterial OTUs were detected when DNA was extracted with the PowerBiofilm and the PlantDNAzol methods. Overall, this study demonstrates the potential bias in metagenomic diversity estimates associated with different DNA extraction methods. PMID- 28673035 TI - Getting back to nature: a reality check for experiments in controlled environments. AB - Irradiance from sunlight changes in a sinusoidal manner during the day, with irregular fluctuations due to clouds, and light-dark shifts at dawn and dusk are gradual. Experiments in controlled environments typically expose plants to constant irradiance during the day and abrupt light-dark transitions. To compare the effects on metabolism of sunlight versus artificial light regimes, Arabidopsis thaliana plants were grown in a naturally illuminated greenhouse around the vernal equinox, and in controlled environment chambers with a 12-h photoperiod and either constant or sinusoidal light profiles, using either white fluorescent tubes or light-emitting diodes (LEDs) tuned to a sunlight-like spectrum as the light source. Rosettes were sampled throughout a 24-h diurnal cycle for metabolite analysis. The diurnal metabolite profiles revealed that carbon and nitrogen metabolism differed significantly between sunlight and artificial light conditions. The variability of sunlight within and between days could be a factor underlying these differences. Pairwise comparisons of the artificial light sources (fluorescent versus LED) or the light profiles (constant versus sinusoidal) showed much smaller differences. The data indicate that energy efficient LED lighting is an acceptable alternative to fluorescent lights, but results obtained from plants grown with either type of artificial lighting might not be representative of natural conditions. PMID- 28673036 TI - Invited Commentary: Agent-Based Models-Bias in the Face of Discovery. AB - Agent-based models (ABMs) have grown in popularity in epidemiologic applications, but the assumptions necessary for valid inference have only partially been articulated. In this issue, Murray et al. (Am J Epidemiol. 2017;186(2):131-142) provided a much-needed analysis of the consequence of some of these assumptions, comparing analysis using an ABM to a similar analysis using the parametric g formula. In particular, their work focused on the biases that can arise in ABMs that use parameters drawn from distinct populations whose causal structures and baseline outcome risks differ. This demonstration of the quantitative issues that arise in transporting effects between populations has implications not only for ABMs but for all epidemiologic applications, because making use of epidemiologic results requires application beyond a study sample. Broadly, because health arises within complex, dynamic, and hierarchical systems, many research questions cannot be answered statistically without strong assumptions. It will require every tool in our store of methods to properly understand population dynamics if we wish to build an evidence base that is adequate for action. Murray et al.'s results provide insight into these assumptions that epidemiologists can use when selecting a modeling approach. PMID- 28673037 TI - Phylogeny of the 'orchid-like' bladderworts (gen. Utricularia sect. Orchidioides and Iperua: Lentibulariaceae) with remarks on the stolon-tuber system. AB - Background and Aims: The 'orchid-like' bladderworts ( Utricularia ) comprise 15 species separated into two sections: Orchidioides and Iperua . These robust and mostly epiphytic species were originally grouped within the section Orchidioides by the first taxonomical systems. These species were later split into two sections when sect. Iperua was proposed. Due to the lack of strong evidence based on a robust phylogenetic perspective, this study presents a phylogenetic proposal based on four different DNA sequences (plastid and nuclear) and morphology to test the monophyly of the two sections. Methods: In comparison with all previous phylogenetic studies, the largest number of species across the sections was covered: 11 species from sections Orchidioides and Iperua with 14 species as an external group. Maximum likelihood and Bayesian inferences were applied to DNA sequences of rps16 , trnL-F , matK , the internal transcribed spacer (ITS) and three morphological characters: (1) the crest of the corolla; (2) the primary organs in the embryo; and (3) tubers. Additionally, a histochemical analysis of the stolons and tubers is presented from an evolutionary perspective. Key Results: The analyses showed the paraphyly of sect. Iperua , since Utricularia humboldtii is more related to the clade of sect. Orchidioides . Utricularia cornigera is grouped in the sect. Iperua clade based on chloroplast DNA sequences, but it is nested to sect. Orchidioides according to ITS dataset. Morphological characters do not support the breaking up of the 'orchid-like' species into two sections, either. Moreover, the stolon-tuber systems of both sections serve exclusively for water storage, according to histological analyses. Conclusions: This study provides strong evidence, based on DNA sequences from two genomic compartments (plastid and nucleus) and morphology to group the Utricularia sect. Orchidioides into the sect. Iperua . The tubers are important adaptations for water storage and have been derived from stolons at least twice in the phylogenetic history of 'orchid-like' bladderworts. PMID- 28673039 TI - A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications. AB - In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant. PMID- 28673038 TI - Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study. AB - Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase 1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P < .001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P = .012). RHI correlated negatively with arginase-1 and positively with l-arginine (P = .001). Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels. PMID- 28673040 TI - Evaluation of Prognostic Factors for Early Mortality After Stereotactic Radiosurgery for Brain Metastases: a Single Institutional Retrospective Review. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is used commonly for patients with brain metastases (BM) to improve intracranial disease control. However, survival of these patients is often dictated by their systemic disease course. The value of SRS becomes less clear in patients with anticipated short survival. OBJECTIVE: To evaluate prognostic factors, which may predict early death (within 90 d) after SRS. METHODS: A total of 1427 patients with BM were treated with SRS at our institution (2000-2012). There were 1385 cases included in this study; 1057 patients underwent upfront SRS and 328 underwent salvage SRS. The primary endpoint of the study was all-cause mortality within 90 d after first SRS. Multivariate analyses were performed to develop prognostic indices. RESULTS: Two hundred sixty-six patients (19%, 95% confidence interval 17%-21%) died within 90 d after SRS. Multivariate analysis of upfront SRS patients showed that Karnofsky Performance Status, primary tumor type, extracranial metastases, age at SRS, boost treatment, total tumor volume, prior surgery, and interval from primary to BM were independent prognostic factors for 90-d mortality. The first 4 factors were also independent predictors in patients treated with salvage SRS. Based on these factors, an index was defined for each group that categorized patients into 3 and 2 prognostic groups, respectively. Ninety-day mortality was 5% to 7% in the most favorable cohort and 36% to 39% in the least favorable. CONCLUSION: Indices based on readily available patient, clinical, and treatment factors that are highly predictive of early death in patients treated with upfront or salvage SRS can be calculated and used to define well-separated prognostic groups. PMID- 28673041 TI - Using metagenomics to investigate human and environmental resistomes. AB - Antibiotic resistance is a global health concern declared by the WHO as one of the largest threats to modern healthcare. In recent years, metagenomic DNA sequencing has started to be applied as a tool to study antibiotic resistance in different environments, including the human microbiota. However, a multitude of methods exist for metagenomic data analysis, and not all methods are suitable for the investigation of resistance genes, particularly if the desired outcome is an assessment of risks to human health. In this review, we outline the current state of methods for sequence handling, mapping to databases of resistance genes, statistical analysis and metagenomic assembly. In addition, we provide an overview of important considerations related to the analysis of resistance genes, and recommend some of the currently used tools and methods that are best equipped to inform research and clinical practice related to antibiotic resistance. PMID- 28673042 TI - Independent prognostic value of left ventricular contractile reserve and chronotropic response in patients with reduced left ventricular ejection fraction undergoing vasodilator stress myocardial perfusion imaging with Rb-82 positron emission tomography. AB - Objectives: We evaluated the prognostic value of heart rate reserve (DeltaHR) and left ventricular ejection fraction reserve (DeltaLVEF) among patients with systolic dysfunction. Background: Inadequate DeltaHR (maximal stress HR - resting HR) and DeltaLVEF (LVEF at stress - LVEF at rest) in response to stress are associated with adverse cardiac events. However, the significance of an abnormal DeltaHR and DeltaLVEF in patients with systolic dysfunction has not been described. Methods and results: We performed a retrospective analysis of patients with rest LVEF < 45% who underwent dipyridamole stress-rest gated Rb-82 PET myocardial perfusion imaging (PET-MPI) at the Cleveland Clinic between 2006 and 2009. Stress LVEF and volumes were calculated using commercially available software (4DM). A Cox proportional hazards model (CPH) was used to examine the association between DeltaLVEF, DeltaHR, and all-cause death (ACD). Among 461 patients (mean age 65.7 +/- 11.3 years, 82% men) 167 experienced ACD (median follow-up 1045 days). Survival was reduced among patients with DeltaHR < 0 (1090 vs. 1300 days, P = 0.04) and DeltaLVEF < 0 (1002 vs. 1057 days, P = 0.03). In a CPH after adjusting for confounding variables, DeltaHR <= 0 and DeltaLVEF <= 0 were associated with reduced survival (hazard ratio 0.93, P < 0.01 and 0.84, P = 0.01, respectively) with an interaction between age and DeltaHR (chi2 = 8.1, P < 0.01). Our model predicts that the magnitude of DeltaHR is associated with improved survival among younger patients. For any given DeltaLVEF the magnitude of DeltaHR has a greater positive effect on survival among younger patients. Conclusion: Both DeltaHR and DeltaLVEF during pharmacologic stress PET-MPI provide incremental value in predicting ACD among patients with systolic dysfunction. PMID- 28673043 TI - Lifestyles in transition: evolution and natural history of the genus Lactobacillus. AB - Lactobacillus species are found in nutrient-rich habitats associated with food, feed, plants, animals and humans. Due to their economic importance, the metabolism, genetics and phylogeny of lactobacilli have been extensively studied. However, past research primarily examined lactobacilli in experimental settings abstracted from any natural history, and the ecological context in which these bacteria exist and evolve has received less attention. In this review, we synthesize phylogenetic, genomic and metabolic metadata of the Lactobacillus genus with findings from fine-scale phylogenetic and functional analyses of representative species to elucidate the evolution and natural history of its members. The available evidence indicates a high level of niche conservatism within the well-supported phylogenetic groups within the genus, with lifestyles ranging from free-living to strictly symbiotic. The findings are consistent with a model in which host-adapted Lactobacillus lineages evolved from free-living ancestors, with present-day species displaying substantial variations in terms of the reliance on environmental niches and the degree of host specificity. This model can provide a framework for the elucidation of the natural and evolutionary history of Lactobacillus species and valuable information to improve the use of this important genus in industrial and therapeutic applications. PMID- 28673044 TI - Ctenopharyngodon idella IKKbeta interacts with PKR and IkappaBalpha. AB - Inhibitor of nuclear factor kappa-B kinase beta (IKKbeta) is a subunit of the IKK complex. It can activate the NF-kappaB pathway through phosphorylating IkappaB in response to a wide range of stimuli. In the present study, an IKKbeta gene from grass carp (Ctenopharyngodon idella; KT282114) was cloned and identified by homologous cloning and rapid-amplification of cDNA ends (RACE) technique. The complete CiIKKbeta cDNA is 3428 bp in length, with the longest open reading frame (ORF) of 2337 bp encoding a polypeptide of 778 amino acids. The deduced amino acid sequence of CiIKKbeta has similar domain distribution to those of mammalian. For example, CiIKKbeta consists of a serine/threonine kinase domain at the N terminal, a basic region leucin zipper (BRLZ) domain in the middle, a homeobox associated leucin zipper (HALZ) domain and an IKKbeta NEMO (NF-kappaB essential modulator) binding domain at the C-terminal. Phylogenetic tree analysis also showed that CiIKKbeta is highly homologous to zebrafish IKKbeta (DrIKKbeta) and clearly distinct from the mammalian and amphibian counterparts. The expression of CiIKKbeta was ubiquitously found in the liver, intestine, kidney, gill, spleen, heart, and brain tissues of grass carp and significantly up-regulated in CIK cells under the stimulation with Poly I:C and UV-inactivated grass carp hemorrhagic virus. To investigate the activation mechanism of NF-kappaB pathway in fish and the role of CiIKKbeta in the pathway, we explored the protein interactions of protein kinase R (PKR) with IKKbeta and IKKbeta with IkappaBalpha by co-immunoprecipitation and GST-pull down assays. The interaction between each pair was confirmed. The results suggest that CiIKKbeta may be a primary member in the activation of NF-kappaB pathway in fish. PMID- 28673046 TI - Generation and characterization of a monoclonal antibody to the cytoplasmic tail of MUC16. AB - MUC16 is a large transmembrane mucin expressed on the apical surfaces of the epithelium covering the ocular surface, respiratory system and female reproductive tract. The transmembrane mucin is overexpressed by ovarian carcinomas, it is one of the most frequently used diagnostic markers for the disease and it is considered a promising target for immunotherapeutic intervention. Immunodetection of the mucin has to date been through antibodies that recognize its exceptionally large ectodomain. Similar to other membrane anchored mucins, MUC16 has a short cytoplasmic tail (CT), but studies of the biological relevance of the C-terminal domain of MUC16 has been limited by lack of availability of monoclonal antibodies that recognize the native CT. Here, we report the development of a novel monoclonal antibody to the CT region of the molecule that recognizes native MUC16 and its enzymatically released CT region. The antibody is useful for immunoprecipitation of the released CT domain as demonstrated with the OVCAR3 ovarian cancer cell line and can be used for detailed cytolocalization in cells as well as in frozen sections of ocular surface and uterine epithelium. PMID- 28673045 TI - The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB Lipoprotein Response. AB - Context: Proprotein convertase subtilisin kexin 9 (PCSK9) mediates degradation of the low-density lipoprotein receptor (LDLR), thereby increasing plasma low density lipoprotein cholesterol (LDL-C). Variations in the PCSK9 gene associated with loss of function (LOF) of PCSK9 result in greater expression of hepatic LDLR, lower concentrations of LDL-C, and protection from cardiovascular disease (CVD). Apolipoprotein-B (apoB) remnants also contribute to CVD risk and are similarly cleared by the LDLR. We hypothesized that PCSK9-LOF carriers would have lower fasting and postprandial remnant lipoproteins on top of lower LDL-C. Objective: To compare fasting and postprandial concentrations of triglycerides (TGs), total apoB, and apoB48 as indicators of remnant lipoprotein metabolism in PCSK9-LOF carriers with those with no PCSK9 variants. Design: Case-control, metabolic study. Setting: Clinical Research Center of The Ottawa Hospital. Participants: Persons with one or more copies of the L10ins/A53V and/or I474V and/or R46L PCSK9 variant and persons with no PCSK9 variants. Intervention: Oral fat tolerance test. Main Outcomes Measures: Fasting and postprandial plasma TG, apoB48, total apoB, total cholesterol, and PCSK9 were measured at 0, 2, 4, and 6 hours after an oral fat load. Results: Participants with PCSK9-LOF variants (n = 22) had reduced fasting LDL-C (-14%) as well as lower fasting TG (-21%) compared with noncarrier controls (n = 23). LOF variants also had reduced postprandial total apoB (-17%), apoB48 (-23%), and TG (-18%). Postprandial PCSK9 declined in both groups (-24% vs -16%, respectively). Conclusions: Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk. PMID- 28673047 TI - Assessing Community Health: An Innovative Tool for Measuring Height and Length. AB - Anthropometric measurements, including height and length, are routinely needed for health research worldwide. Measurement boards are the current gold standard for obtaining the height and length of children. In community-based research, however, the size and weight of the measurement boards make them difficult and cumbersome to carry in the field. In addition, children and infants may express an unwillingness to be placed onto the measurement board. Electronic measuring tools commonly used in industry and contracting work are precise and portable. This study piloted a protocol to use an adapted laser measurement tool, the anthropometric measurement assist (AMA), to obtain height and recumbent length in children in Western Kenya. Intra- and inter-observer variability were determined and compared with measurement board measurements. Results of this initial pilot indicated that the AMA may be a viable alternative to measurement boards. The AMA can measure height/length accurately and reliably, is portable and is equivalent in price to measuring boards, making it a viable option for fieldwork in low resourced countries. PMID- 28673048 TI - Taming the BEAST-A Community Teaching Material Resource for BEAST 2. AB - Phylogenetics and phylodynamics are central topics in modern evolutionary biology. Phylogenetic methods reconstruct the evolutionary relationships among organisms, whereas phylodynamic approaches reveal the underlying diversification processes that lead to the observed relationships. These two fields have many practical applications in disciplines as diverse as epidemiology, developmental biology, palaeontology, ecology, and linguistics. The combination of increasingly large genetic data sets and increases in computing power is facilitating the development of more sophisticated phylogenetic and phylodynamic methods. Big data sets allow us to answer complex questions. However, since the required analyses are highly specific to the particular data set and question, a black-box method is not sufficient anymore. Instead, biologists are required to be actively involved with modeling decisions during data analysis. The modular design of the Bayesian phylogenetic software package BEAST 2 enables, and in fact enforces, this involvement. At the same time, the modular design enables computational biology groups to develop new methods at a rapid rate. A thorough understanding of the models and algorithms used by inference software is a critical prerequisite for successful hypothesis formulation and assessment. In particular, there is a need for more readily available resources aimed at helping interested scientists equip themselves with the skills to confidently use cutting-edge phylogenetic analysis software. These resources will also benefit researchers who do not have access to similar courses or training at their home institutions. Here, we introduce the "Taming the Beast" (https://taming-the-beast.github.io/) resource, which was developed as part of a workshop series bearing the same name, to facilitate the usage of the Bayesian phylogenetic software package BEAST 2. PMID- 28673049 TI - Localized Surface Plasmon Resonance Dependence on Misaligned Truncated Ag Nanoprism Dimer. AB - Misaligned edge-to-edge dimers are the common products during the preparation of Ag nanoprism dimers using self-assembly method. However, in the self-assembly method, Ag nanoprisms are easily truncated because they are easy to oxidize in an acidic environment. In this work, modeling a truncated Ag nanoprism on a misaligned edge-to-edge dimer provides a better understanding of the effects of the truncation and misalignment on localized surface plasmon resonance (LSPR) of the dimer. The resonant wavelength and intensity of the dimer are flexibly modulated by changing the misalignment length of the dimer. As the misalignment length increases, a stronger peak at the shorter wavelength and a weaker one at the longer wavelength are observed. The resonant wavelengths and intensities of the two peaks are also flexibly tuned by adjusting the truncated length of the Ag nanoprism in the dimer. The results are numerically demonstrated based on the finite element method (FEM) and show promising potential for nanoswitch, multi channel tunable biosensor and other nanodevice applications. PMID- 28673050 TI - The Study of a Novel Nanoparticle-Enhanced Wormlike Micellar System. AB - In this work, a novel nanoparticle-enhanced wormlike micellar system (NEWMS) was proposed based on the typical wormlike micelles composed of cetyltrimethylammonium bromide (CTAB) and sodium salicylate (NaSal). In order to strengthen the structure of wormlike micelles, silica nanoparticles are used to design the novel nanoparticle-enhanced wormlike micelle. The stability and morphologies of silica nanoparticles were studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM) at first. After the formation of NEWMS, the rheological properties were discussed in detail. The zero-shear viscosity of NEWMS increases with the addition of silica nanoparticles. Dynamic oscillatory measurements show the viscoelastic properties of NEWMS. Through comparison with the original wormlike micelles, the entanglement length and mesh size of NEWMS are nearly unchanged, while the contour length increases with the increase of silica concentration. These phenomena confirm the enhanced influence of silica nanoparticles on wormlike micelles. The formation mechanism of NEWMS, especially the interactions between wormlike micelles and nanoparticles, is proposed. This work can deepen the understanding of the novel NEWMS and widen their applications. PMID- 28673051 TI - Investigations of Heavy Metal Ion Sorption Using Nanocomposites of Iron-Modified Biochar. AB - Magnetic biochar nanocomposites were obtained by modification of biochar by zero valent iron. The article provides information on the impact of contact time, initial Cd(II), Co(II), Zn(II), and Pb(II) ion concentrations, dose of the sorbents, solution pH and temperature on the adsorption capacity. On the basis of experiments, it was found that the optimum parameters for the sorption process are phase contact time 360 min (after this time, the equilibrium of all concentrations is reached), the dose of sorbent equal to 5 g/dm3, pH 5 and the temperature 295 K. The values of parameters calculated from the kinetic models and isotherms present the best match to the pseudo second order and Langmuir isotherm models. The calculated thermodynamic parameters ?H 0, ?S 0 and ?G 0 indicate that the sorption of heavy metal ions is an exothermic and spontaneous process as well as favoured at lower temperatures, suggesting the physical character of sorption. The solution of nitric acid(V) at the concentration 0.1 mol/dm3 was the best acidic desorbing agent used for regeneration of metal-loaded magnetic sorbents. The physicochemical properties of synthesized composites were characterized by FTIR, SEM, XRD, XPS and TG analyses. The point characteristics of the double layer for biochar pHPZC and pHIEP were designated. PMID- 28673052 TI - Synthesis of Electrical Conductive Silica Nanofiber/Gold Nanoparticle Composite by Laser Pulses and Sputtering Technique. AB - Biocompatible-sensing materials hold an important role in biomedical applications where there is a need to translate biological responses into electrical signals. Increasing the biocompatibility of these sensing devices generally causes a reduction in the overall conductivity due to the processing techniques. Silicon is becoming a more feasible and available option for use in these applications due to its semiconductor properties and availability. When processed to be porous, it has shown promising biocompatibility; however, a reduction in its conductivity is caused by its oxidization. To overcome this, gold embedding through sputtering techniques are proposed in this research as a means of controlling and further imparting electrical properties to laser induced silicon oxide nanofibers. Single crystalline silicon wafers were laser processed using an Nd:YAG pulsed nanosecond laser system at different laser parameters before undergoing gold sputtering. Controlling the scanning parameters (e.g., smaller line spacings) was found to induce the formation of nanofibrous structures, whose diameters grew with increasing overlaps (number of laser beam scanning through the same path). At larger line spacings, nano and microparticle formation was observed. Overlap (OL) increases led to higher light absorbance's by the wafers. The gold sputtered samples resulted in greater conductivities at higher gold concentrations, especially in samples with smaller fiber sizes. Overall, these findings show promising results for the future of silicon as a semiconductor and a biocompatible material for its use and development in the improvement of sensing applications. PMID- 28673053 TI - One-Pot Green Synthesis of Ag-Decorated SnO2 Microsphere: an Efficient and Reusable Catalyst for Reduction of 4-Nitrophenol. AB - In this paper, hierarchical Ag-decorated SnO2 microspheres were synthesized by a facile one-pot hydrothermal method. The resulting composites were characterized by XRD, SEM, TEM, XPS, BET, and FTIR analysis. The catalytic performances of the samples were evaluated with the reduction of 4-nitrophenol to 4-aminophenol by potassium borohydride (KBH4) as a model reaction. Time-dependent experiments indicated that the hierarchical microspheres assembled from SnO2 and Ag nanoparticles can be formed when the react time is less than 10 h. With the increase of hydrothermal time, SnO2 nanoparticles will self-assemble into SnO2 nanosheets and Ag nanoparticles decorated SnO2 nanosheets were obtained. When evaluated as catalyst, the obtained Ag-decorated SnO2 microsphere prepared for 36 h exhibited excellent catalytic performance with normalized rate constant (kappa nor) of 6.20 min-1g-1L, which is much better than that of some previous reported catalysts. Moreover, this Ag-decorated SnO2 microsphere demonstrates good reusability after the first five cycles. In addition, we speculate the formation mechanism of the hierarchical Ag-decorated SnO2 microsphere and discussed the possible origin of the excellent catalytic activity. PMID- 28673054 TI - Bismuth Quantum Dots in Annealed GaAsBi/AlAs Quantum Wells. AB - Formation of bismuth nanocrystals in GaAsBi layers grown by molecular beam epitaxy at 330 degrees C substrate temperature and post-growth annealed at 750 degrees C is reported. Superlattices containing alternating 10 nm-thick GaAsBi and AlAs layers were grown on semi-insulating GaAs substrate. AlAs layers have served as diffusion barriers for Bi atoms, and the size of the nanoclusters which nucleated after sample annealing was correlating with the thickness of the bismide layers. Energy-dispersive spectroscopy and Raman scattering measurements have evidenced that the nanoparticles predominantly constituted from Bi atoms. Strong photoluminescence signal with photon wavelengths ranging from 1.3 to 1.7 MUm was observed after annealing; its amplitude was scaling-up with the increased number of the GaAsBi layers. The observed photoluminescence band can be due to emission from Bi nanocrystals. The carried out theoretical estimates support the assumption. They show that due to the quantum size effect, the Bi nanoparticles experience a transition to the direct-bandgap semiconducting state. PMID- 28673055 TI - Composite Membranes Containing Nanoparticles of Inorganic Ion Exchangers for Electrodialytic Desalination of Glycerol. AB - Composite membranes were obtained by modification of heterogeneous polymer cation and anion-exchange membranes with nanoparticles of zirconium hydrophosphate and hydrated zirconium dioxide, respectively. The ion-exchange materials were investigated with the methods of electron microscopy, potentiometry, voltammetry, and impedance spectroscopy. Single nanoparticles, which were precipitated in aqueous media, form aggregates, when the composites are in a contact with polar organic solvent. Both single nanoparticles (up to 10 nm) and their aggregates (up to 200 nm) were precipitated in ion-exchange polymers in glycerol media. Non aggregated nanoparticles improve electrical conductivity of the ion-exchange materials, the aggregates are barriers against fouling. The membranes were applied to NaCl removal from highly concentrated glycerine-water mixture containing organic additives (byproduct of biodiesel production). As opposite to pristine materials, the composites demonstrate stability against fouling. PMID- 28673057 TI - Expected Next-Generation Drugs. PMID- 28673056 TI - Resveratrol-Loaded Albumin Nanoparticles with Prolonged Blood Circulation and Improved Biocompatibility for Highly Effective Targeted Pancreatic Tumor Therapy. AB - Human serum albumin (HSA) is an intrinsic protein and important carrier that transports endogenous as well as exogenous substances across cell membranes. Herein, we have designed and prepared resveratrol (RV)-loaded HSA nanoparticles conjugating RGD (arginine-glycine-aspartate) via a polyethylene glycol (PEG) "bridge" (HRP-RGD NPs) for highly effective targeted pancreatic tumor therapy. HRP-RGD NPs possess an average size of 120 +/- 2.6 nm with a narrow distribution, a homodisperse spherical shape, a RV encapsulation efficiency of 62.5 +/- 4.21%, and a maximum RV release ratio of 58.4.2 +/- 2.8% at pH 5.0 and 37 degrees C. In vitro biocompatibility of RV is improved after coating with HSA and PEG. Confocal fluorescence images show that HRP-RGD NPs have the highest cellular uptake ratio of 47.3 +/- 4.6% compared to HRP NPs and HRP-RGD NPs with free RGD blocking, attributing to an RGD-mediated effect. A cell counting kit-8 (CCK-8) assay indicates that HRP-RGD NPs without RV (HP-RGD NPs) have nearly no cytotoxicity, but HRP-RGD NPs are significantly more cytotoxic to PANC-1 cells compared to free RV and HRP NPs in a concentration dependent manner, showing apoptotic morphology. Furthermore, with a formulated PEG and HSA coating, HRP-RGD NPs prolong the blood circulation of RV, increasing approximately 5.43-fold (t1/2). After intravenous injection into tumor-bearing mice, the content of HRP-RGD NPs in tumor tissue was proven to be approximately 3.01- and 8.1-fold higher than that of HRP NPs and free RV, respectively. Based on these results, HRP-RGD NPs were used in an in vivo anti-cancer study and demonstrated the best tumor growth suppression effect of all tested drugs with no relapse, high in vivo biocompatibility, and no significant systemic toxicity over 35 days treatment. These results demonstrate that HRP-RGD NPs with prolonged blood circulation and improved biocompatibility have high anti-cancer effects with promising future applications in cancer therapy. PMID- 28673058 TI - Targeting Moderate and Severe Male Stress Urinary Incontinence With Adjustable Male Slings and the Perineal Artificial Urinary Sphincter: Focus on Perioperative Complications and Device Explantations. AB - PURPOSE: To analyze perioperative complications and postoperative explantation rates for selected readjustable male sling systems and the perineal single-cuff artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. METHODS: Two hundred eighty-two male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in the study (n=127 adjustable male sling [n=95 Argus classic, n=32 Argus T], n=155 AUS). Perioperative characteristics and postoperative complications were analyzed. The explantation rates of the respective devices were assessed using the Fisher exact test and the Mann-Whitney U-test. A Kaplan-Meier curve was generated. Potential features associated with device explantation were analyzed using a multiple logistic regression model (P<0.05). RESULTS: We found significantly increased intraoperative complication rates after adjustable male sling implantation (15.9% [adjustable male sling] vs. 4.2% [AUS], P=0.003). The most frequent intraoperative complication was bladder perforation (n=17). Postoperative infection rates did not vary significantly between the respective devices (P=0.378). Device explantation rates were significantly higher after AUS implantation (9.7% [adjustable male sling] vs. 21.5% [AUS], P=0.030). In multivariate analysis, postoperative infection was a strong independent predictor of decreased device survival (odds ratio, 6.556; P=0.001). CONCLUSIONS: Complication profiles vary between adjustable male slings and AUS. Explantation rates are lower after adjustable male sling implantation. Any kind of postoperative infections are independent predictors of decreased device survival. There is no significant effect of the experience of the implanting institution on device survival. PMID- 28673059 TI - Assessing the Readjustable Sling Procedure (Remeex System) for Female Stress Urinary Incontinence With Detrusor Underactivity. AB - PURPOSE: Many surgeons worry about postoperative voiding problems in patients with stress urinary incontinence (SUI) and detrusor underactivity (DU). This study hypothesized that adjusting the tension after surgery would benefit patients with DU, and therefore researchers evaluated the outcomes and quality of life of women with SUI and DU who underwent the readjustable sling procedure (Remeex). METHODS: The medical records of 27 patients who were treated with the Remeex system for SUI and DU between 2007 and 2013 were retrospectively analyzed. The incontinence visual analogue scale (I-VAS), incontinence quality of life questionnaire (I-QOL) and the Sandvik incontinence severity index (ISI) were used to evaluate the efficacy of the Remeex system both prior to surgery and at the last visit after surgery. The treatment was considered successful if there was no urine leakage based on the Sandvik questionnaire. RESULTS: The mean follow-up period was 38.0 months (range, 1-75 months), and the treatment success rate was 81.5%. Despite no urine leakage, 7 patients wanted the Remeex system to be removed due to persistent postoperative urinary retention within a year of surgery. One patient underwent a long-term adjustment under local anesthesia 6 years after the initial surgery. The I-VAS, ISI and all domains of the I-QOL scores improved significantly postoperatively and the maximum flow rate decreased significantly after the procedure. However, the postvoid residual did not change significantly. CONCLUSIONS: The Remeex system provided a good cure rate and improved the quality of life of women with SUI and DU. Therefore, the Remeex system should be considered as a treatment option for female patients with concomitant SUI and DU. PMID- 28673060 TI - Urethral Closure Pressure at Stress: A Predictive Measure for the Diagnosis and Severity of Urinary Incontinence in Women. AB - PURPOSE: Maintaining urinary continence at stress requires a competent urethral sphincter and good suburethral support. Sphincter competence is estimated by measuring the maximal urethral closure pressure at rest. We aimed to study the value of a new urodynamic measure, the urethral closure pressure at stress (s UCP), in the diagnosis and severity of female stress urinary incontinence (SUI). METHODS: A total of 400 women without neurological disorders were included in this observational study. SUI was diagnosed using the International Continence Society definition, and severity was assessed using a validated French questionnaire, the Mesure du Handicap Urinaire. The perineal examination consisted of rating the strength of the levator ani muscle (0-5) and an assessment of bladder neck mobility using point Aa (cm). The urodynamic parameters were maximal urethral closure pressure at rest, s-UCP, Valsalva leak point pressure (cm H2O), and pressure transmission ratio (%). RESULTS: Of the women, 358 (89.5%) were diagnosed with SUI. The risk of SUI significantly increased as s-UCP decreased (odds ratio [OR], 0.92; 95% confidence interval, 0.88-0.98). The discriminative value of the measure was good for the diagnosis of SUI (area under curve>0.80). s-UCP values less than or equal to 20 cm H2O had a sensitivity of 73.1% and a specificity of 93.0% for predicting SUI. The association between s-UCP and SUI severity was also significant. CONCLUSIONS: s UCP is the most discriminative measure that has been identified for the diagnosis of SUI. It is strongly inversely correlated with the severity of SUI. It appears to be a specific SUI biomarker reflecting both urethral sphincter competence and urethral support. PMID- 28673061 TI - The Risk of Upper Urinary Tract Involvement in Patients With Ketamine-Associated Uropathy. AB - PURPOSE: The aims of this study were to investigate the prevalence of upper tract involvement in ketamine-associated uropathy, and to determine the predictors of hydronephrosis in patients with a history of ketamine abuse. METHODS: This was a cross-sectional study of a prospective cohort of patients with ketamine associated uropathy. Data including demographics, pattern of ketamine abuse, pelvic pain and urgency or frequency (PUF) symptom score, uroflowmetry (UFM) parameters, serum renal function, and liver function tests were collected. Upon consultation, ultrasonography was performed to assess the function of the urinary system. RESULTS: From December 2011 to October 2015, we treated 572 patients with ketamine-associated uropathy. Of these patients, 207 (36.2%) had managed to achieve abstinence at the time of their first consultation. Ninety-six patients (16.8%) in the cohort were found to have hydronephrosis on ultrasonography. Univariate analysis identified age, duration of ketamine abuse, PUF symptom score, voided volume on UFM, serum creatinine levels >100 MUmol/L, and an abnormal serum liver enzyme profile as factors associated with hydronephrosis. Logistic regression revealed the following parameters to be statistically related to hydronephrosis: age (adjusted odds ratio [OR], 1.090; 95% confidence interval [CI], 1.020-1.166; P=0.012), functional bladder capacity (adjusted OR, 0.997; 95% CI, 0.995-0.999; P=0.029), serum creatinine >100 MUmol/L (adjusted OR, 3.107; 95% CI, 1.238-7.794; P=0.016, and an abnormal serum liver enzyme profile (adjusted OR, 1.967; 95% CI, 1.213-3.187; P=0.006). CONCLUSIONS: Ketamine-associated uropathy can involve the upper urinary tract. Patient demographics as well as investigations of UFM, renal function tests, and liver function tests may allow us to identify at-risk patients. PMID- 28673062 TI - Long-term Outcomes of Augmentation Enterocystoplasty in Patients With End-Stage Bladder Diseases: A Single-Institute Experience Involving 102 Patients. AB - PURPOSE: Augmentation enterocystoplasty (AE) has been shown to improve clinical symptoms in patients with end-stage bladder disease (ESBD). Herein, we report the long-term outcomes of a series of patients with different etiologies of ESBD who received AE. METHODS: We retrospectively reviewed 102 patients with ESBD who received AE at the Hualien Tzu Chi General Hospital from 1992 to 2014. ESBD in this study was defined as including neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) or myelomeningocele, inflammatory bladder disease (IBD), ESBD occurring after pelvic cancer surgery, and other etiologies. Complications including active lower urinary tract problems and urinary tract infection (UTI), as well as patients' self-reported satisfaction with the procedure, were evaluated. RESULTS: A total of 102 patients were included in the study. A majority of patients received AE for NLUTD (n=43), followed by IBD (n=38), ESBD after pelvic cancer surgery (n=15), and the other etiologies (n=6). Patients had a mean age of 39.4+/-18.7 years and were followed for a mean of 78 months. All patients had significantly increased cystometric bladder capacity and compliance at the time of follow-up. Fifty-four patients (52.9%) reported moderate to excellent satisfaction with the outcome, and there were no significant differences among the groups (P=0.430). The most common reason for dissatisfaction was the need for clean intermittent catheterization (CIC; 41.7%), followed by urinary incontinence (25.0%) and recurrent UTI (16.7%). CONCLUSIONS: AE is a safe and effective procedure for patients with ESBD. Postoperative urinary incontinence and UTI as well as the need for CIC may affect quality of life and decrease patient satisfaction. PMID- 28673063 TI - A Study of Clinical Predictors Associated With Intrinsic Sphincter Deficiency in Women With Stress Urinary Incontinence. AB - PURPOSE: Recently, intrinsic sphincter deficiency (ISD) has been identified as one important factor in the outcome of stress urinary incontinence (SUI) related surgery. Clinical factors that can predict ISD are uncommon. The aim of this study was to determine predictive clinical factors for ISD in female patients with SUI. METHODS: The patients were classified into 3 groups according to the value of Valsalva leak point pressure (VLPP)>90 cm H2O (anatomical incontinence, AI), between 61 and 90 cm H2O (equivocal, EV), and <60 cm H2O (ISD). All groups underwent a full examination, history evaluation, physical examination, uroflowmetry, and complete urodynamic study. Univariate analysis was performed by chi-square or t-test for categorical variables, respectively. A multivariate study was performed by Pearson correlation analysis in order to get clinical predictors of VLPP<60 cm H2O. Statistical significance was set at P<0.05. RESULTS: There were 3 groups with a total of 189 patients: 56 patients (AI, 29.7%), 64 patients (EV, 33.8%), and 69 patients (ISD, 36.5%). The univariate analysis revealed a significant difference associated with maximal urethral closing pressure (P=0.03) and Stamey classification (P=0.006) between ISD and AI. The more severe the urinary symptom grade, the higher the frequency of ISD. However, the multivariate analysis showed the independent predictor of ISD is only present in grades II and III symptoms in the Stamey classification (P=0.001). CONCLUSIONS: It was found that the more severe the symptoms of urinary incontinence, the higher the possibility of ISD. In other words, the degree of urinary incontinence was found to be one relevant clinical factor in predicting ISD. This finding may help in evaluating and identifying the appropriate surgical technique for EV. Currently, absolute cutoff value to diagnose ISD has not yet been determined. More research is needed to identify clinical factors that can predict ISD. PMID- 28673064 TI - Effects of Acute Sacral Neuromodulation at Different Frequencies on Bladder Overactivity in Pigs. AB - PURPOSE: We investigated the effects of different stimulation frequencies on the inhibition of bladder overactivity by sacral neuromodulation (SNM) in pigs. METHODS: Implant-driven stimulators were used to stimulate the S3 spinal nerve in 13 pigs. Cystometry was performed by infusing normal saline (NS) or acetic acid (AA). SNM (pulse width, 210 usec) at frequencies ranging from 5 to 50 Hz was conducted at the intensity threshold at which observable perianal and/or tail movement was induced. Multiple cystometrograms were performed to determine the effects of different frequencies on the micturition reflex. RESULTS: AA-induced bladder overactivity significantly reduced the bladder capacity (BC) to 34.4%+/ 4.7% of the NS control level (354.4+/-35.9 mL) (P<0.05). During AA infusion, SNM at 5 Hz did not significantly change the BC (48.1%+/-6.9% of the NS control level) (P>0.05), but SNM at 15, 30, and 50 Hz significantly increased the BC to 54.5%+/-7.1%, 55.2%+/-6.5%, and 57.2%+/-6.1% of the NS control level (P<0.05), respectively. No significant differences were found among the results obtained using frequencies of 15, 30, and 50 Hz (P>0.05). CONCLUSIONS: This study demonstrated that 15 Hz was an appropriate frequency for SNM and that frequencies higher than 15 Hz did not lead to better surgical outcomes. PMID- 28673065 TI - Sociodemographic Factors Related to Lower Urinary Tract Symptoms in Men: A Korean Community Health Survey. AB - PURPOSE: This study estimated the prevalence of lower urinary tract symptoms (LUTS) in Korean men and the conditions for being diagnosed with or treated for LUTS/benign prostatic hyperplasia (BPH). METHODS: We analyzed cross-sectional data collected from 69,851 Korean men who were 40 years of age or older and had participated in the Korean Community Health Survey performed in 2011. Interviewers performed face-to-face surveys that included sociodemographic questions, the International Prostate Symptom Score (IPSS), and questions regarding whether the subjects had been diagnosed with or treated for LUTS/BPH. We estimated the prevalence of LUTS and assessed whether the subjects had been diagnosed with or treated for LUTS/BPH. RESULTS: Moderate to severe LUTS, storage symptoms, and voiding symptoms increased with age. The IPSS quality of life score was 1.5+/-0.004 in the mild LUTS group (n=57,701), 3.3+/-0.01 in the moderate LUTS group (n=9,203), and 4.3+/-0.02 in the severe LUTS group (n=2,947) (P<0.0001). The prevalence of moderate to severe LUTS in those who had not been diagnosed with LUTS/BPH was 64.5% (7,847 of 12,150), and the prevalence of moderate to severe LUTS in those who had been diagnosed with LUTS/BPH but had not been treated was 23.5% (2,853 of 12,150). CONCLUSIONS: The severity of LUTS in Korean men increased with age, and the IPSS quality of life score increased with the severity of LUTS. Many Korean men with moderate to severe LUTS had not been diagnosed or treated for LUTS/BPH. Socioeconomic conditions played an important role in health-seeking behavior among patients with LUTS/BPH. PMID- 28673067 TI - Expected Next-Generation Drugs Under Development in Relation to Voiding Symptoms. AB - New drug development is a high-risk venture, but if successful, will bring great revenues to those willing to accept the risk. In the field of urology, in particular for lower urinary tract symptoms (LUTS), the recent successful landing of drugs (e.g., mirabegron, botulinum toxin A, and tadalafil) has resulted in increased interest in new drug development. Benign prostatic hyperplasia and overactive bladder syndrome, representative LUTS diseases, are attractive targets because of their prevalence and market size in the field of urology. Additionally, the awareness about new stream of research is very important not only because of the market size and economic factors, but also because to keep steady attention to these research for the researcher's. We have reviewed a selection of new drugs currently under development for the treatment of the two aforementioned diseases and hope to offer urologists an overview of the current situation and future directions in the field of urology. PMID- 28673069 TI - Hepatitis B core-related antigen: a novel biomarker for chronic hepatitis B treatment. PMID- 28673070 TI - Update in gastroesophageal reflux disease. PMID- 28673068 TI - Long-Term Outcomes of Using Endoscopic Submucosal Dissection to Treat Early Gastric Cancer. AB - Endoscopic submucosal dissection (ESD) is becoming the main procedure for the resection of early gastric cancer (EGC). The absolute indications for treating EGC with endoscopic resection were established by the Japanese Gastric Cancer Association and have been generally accepted. However, the absolute indications for treating EGC are rather strict, and expanded indications have been developed. Many studies have reported favorable long-term outcomes for patients who received curative resection for the expanded indication. ESD preserves the stomach, thereby improving patients' quality of life compared to surgery; however, a generally higher incidence of metachronous gastric cancer has been reported after ESD for EGC. Therefore, clinicians must pay careful attention during surveillance endoscopy, even after a curative ESD. PMID- 28673066 TI - Extracellular Vesicles as a Source of Urological Biomarkers: Lessons Learned From Advances and Challenges in Clinical Applications to Major Diseases. AB - Extracellular vesicles (EVs) not only eliminate unwanted molecular components, but also carry molecular cargo essential for specific intercellular communication mechanisms. As the molecular characteristics and biogenetical mechanisms of heterogeneous EVs are different, many studies have attempted to purify and characterize EVs. In particular, exosomal molecules, including proteins, lipids, and nucleic acids, have been suggested as disease biomarkers or therapeutic targets in various diseases. However, several unresolved issues and challenges remain despite these promising results, including source variability before the isolation of exosomes from body fluids, the contamination of proteins during isolation, and methodological issues related to the purification of exosomes. This paper reviews the general characteristics of EVs, particularly microvesicles and exosomes, along with their physiological roles and contribution to the pathogenesis of major diseases, several widely used methods to isolate exosomes, and challenges in the development of disease biomarkers using the molecular contents of EVs isolated from body fluids. PMID- 28673071 TI - Lactase non-persistent genotype distribution in Italy. AB - BACKGROUND: Adult-type hypolactasia is a frequent condition of lactose malabsorption; in Europe the distribution of adult-type hypolactasia have been shown to display a North-South gradient. Genotyping for LCT-13910 C>T polymorphism has been proposed as a useful diagnostic marker of adult-type hypolactasia. Data concerning lactase non-persistent genotype distribution in Italy are confused and not well characterized. The aim of this study was to determine the prevalence of CC-genotype corresponding to lactase non-persistence in Italian population. METHODS: We genotyped 1312 adult Italian subjects for LCT 13910 C>T polymorphism by KASPar chemistry (KBioscience Ltd., Hoddesdon, England, UK). RESULTS: The frequency of the lactase non-persistence genotype of our sample was 62.3% that was higher than the values published for adult hypolactasia in Italy. In our study a frequency of 58.6%, 74.1% and 67.1% was detected in the three main macro-regions of Italy (North, Center, and South), respectively. CONCLUSIONS: For the first time we analyzed the distribution of the LCT-13910 CC genotype in a big population of Italian subjects. Our data did not validate the presence of a North-South gradient for adult hypolactasia along the Italian peninsula. PMID- 28673072 TI - Tubularized proximally-incised plate in distal/midshaft hypospadias repair. AB - The aim of this study was to verify the validity, feasibility, and the functional results, by uroflowmetry, of Tubularized proximallyincised plate technique in selected case of distal/midshaft hypospadias. Out of 120 patients scheduled to undergo TIP (or Snodgrass) procedure, 23 were selected between January 2013 and January 2016 (19.1%). This case series comprised 16 patients with distal and 7 with midshaft hypospadias. Mean age at surgery was 2.9 years. The inclusion criteria were a deep and wide glandular groove and a proximal narrow urethral plate. The procedure was carried out as described by Snodgrass but the incision of the urethral plate, including the mucosal and submucosal tissue, was made only proximally, between the original meatus and the glandular groove in no case extending to the entire length of the plate. Postoperatively a foley catheter was left in place from 4 to 7 days. Uroflowmetry was performed when the patients age ranged from 2.5 to 5.7 years (mean age 3.11 years and mean follow-up 1.8 years, body surface 2). No patient presented fistulas nor perioperative complications. At uroflowmetry, eighteen patients presented values above the 25th percentile and 5 showed a borderline flow. All patients in this group remained stable without urinary symptoms. In selected cases, the tubularized proximally-incised plate yields satisfactory cosmetic and functional results for the treatment of midshaft proximal hypospadias. A long-term follow-up study is needed for further evaluation. Patient selection is crucial for the success of this technique. PMID- 28673073 TI - Primary monosymptomatic nocturnal enuresis and associated factors in a referral continence clinic of Abu Dhabi. AB - The aim of the present study was to investigate the prevalence of primary monosymptomatic nocturnal enuresis (PMNE) and its associated factors in a major referral centre for nocturnal enuresis in the City of Abu Dhabi. Children referred to the Pediatric Continence Clinic of Department of Pediatric and Urology Surgery at Al Noor Hospital, Abu Dhabi (UAE), between January 2014 and January 2016 for the suspected diagnosis of NE were considered. The inclusion criteria of our study were: age 5-14 years; full medical history and physical examination; urine dipstick to exclude glycosuria and proteinuria; completion of diagnostic urological work-up; final diagnosis of PMNE. Parents were encouraged to follow a program on urotherapy. All children underwent renal and bladder ultrasound, abdominal X-ray and uroflowmetry with electromyography. Constipation was treated, if present. 39 patients had a diagnosis of PMNE. A constipation was present in 17 children (43.6%). Statistical analysis documented a higher incidence of PMNE in the male groups. 38 out of 39 children (97.4%) resolved PMNE, 14 following urotherapy and 24 required medical therapy with desmopressin. Our experience clearly confirms a higher prevalence rate of PMNE in boys than in girls. In the study population, the large intake of dry and reducedin- fibers foods, the excessive intake of carbonated drinks and the hot climatic condition might negatively influence the incidence of fecal retention and the subsequent PMNE. A multi-modal assessment seems to be effective in the management of PMNE, showing a very high rate of resolution. PMID- 28673074 TI - Pediatric pleural empyema: one of the management challenges in children of Democratic Republic of Congo. AB - Empyema is a serious complication characterized by purulent exudate and bacteria in the pleural space, which may progress to necrosis, cavitations or fistulas in the thoracic cavity. It remains a major challenge throughout low-income countries. Objectives were to emphasize the role of basic medical and radiologic approach and to resolve a severe lung complication when facilities are inadequate. A five-year-old female was referred with distress respiratory to the Emergency Unit of Monkole, a large public-private missionary hospital in Kinshasa, Congo. Chest X-ray showed a massive empyema that was resolved by immediate drainage and antibiotiocs. Results were rapid improvement and discharge after 3 weeks. A classic medical and imaging approach is a winning return in low income countries. According to the British Thoracic Society guidelines, pleural effusion with compromising respiratory function can be managed by drainage and antibiotics. PMID- 28673075 TI - [Triorchidism: which therapy?] AB - Polyorchidism is an anomaly characterized by more than two gonads; triorchidism is the most common variant. Its management is controversial, mostly when surgical treatment is occasional. CB, 14 year-old, came to the hospital due to right-sided testicular torsion. During surgery, testis was rotated and the contralateral testis, which presented as an anatomically continuum with a gonadic structure similar to the other testes but with a smaller diameter, was fixed. We performed biopsy on both left testes and decided to preserve the supernumerary one. Following the anatomic and functional classification of polyorchidism by Singer, preservation is justified on the grounds of the presence of a supernumerary testis that drains into the epididymis of the normal testis, merging into one single deferent duct (Singer Type 1). At biopsy, both testes had a valid spermatogenic asset. The diagnostic follow-up at 6 and 12 months did not show any pathological alteration. Diagnosis of polyorchidism is occasional. Its treatment varies depending on the site, dimension, and anatomy of the drainage system of the supernumerary testis. If the supernumerary testis is preserved, a standardized diagnostic follow-up is recommended. PMID- 28673076 TI - Human milk: composition and health benefits. AB - Breastfeeding is widely acknowledged as the normal and unequalled method for feeding infants due to its associated health benefits, both for the infant and the mother. The World Health Organization recommends that infants are exclusively breastfed up to the completion of six months of age, with breastfeeding continuing to be an important part of the diet until the infant is at least two years old. The several health benefits associated with breastfeeding are driven by the combined action of the nutritional and bioactive components in human milk and the magnitude of the majority of the ascertained biological effects is directly dependent on breastfeeding duration.This review briefly summarizes the current knowledge on the composition of human milk and provides an overview on its functional effects on health outcomes, focusing on the latest research results. PMID- 28673077 TI - Breastfeeding promotion: evidence and problems. AB - Although breastfeeding is associated with many health benefits in children and mothers, and World Health Organization (WHO) recommends exclusive breastfeeding until 6 months of age and continued breastfeeding until 2 years of age, overall breastfeeding rates remain low. Italian rates of exclusive breastfeeding do not differ from international data. The aim of this review is to evaluate evidence of breastfeeding promotion interventions and the remaining problems to achieve them. We found that breastfeeding support is a complex system of interventions, including individual, structural and environmental factors. Many systematic reviews report evidence that breastfeeding support offered to women increases duration and exclusivity of breastfeeding, both in full term healthy newborns and in preterm infants. Political and economic efforts should be made to ensure breastfeeding support to all women in the different settings, assuming it as a collective target. PMID- 28673078 TI - Nutritional and metabolic programming during the first thousand days of life. AB - The latest scientific acquisitions are demonstrating what has already been hypothesized for more than twenty years about the development of the state of health/illness of individuals. Indeed, certain stimuli, if applied to a sensible phase of development, are able to modify, through epigenetic mechanisms, gene expression of DNA, resulting in adaptive modifications of phenotype to the environment, which may reflect negatively on the health of every individual. This concept, applied to nutrition, has opened up important prospects for research in this area. The nutritional history of an individual, linked to the development of a healthy state, would begin very early. In fact, since the pregnancy and for the next two years (for a total of about 1000 days), the maternal eating habits, the type of breastfeeding and then the main stages of nutrition in the evolutionary phase represent those sensitive moments, essential for the development of important endocrine, metabolic, immunological alterations, better known as metabolic syndrome. This condition would represent the physiopathogenetic basis for explaining a series of disorders, known as non communicable diseases (NCDs) such as obesity, diabetes, hypertension, cardiovascolar disease and all those conditions that today affect the health of most industrialized countries and through the years are emerging especially in developing countries (South America, Asia), where new environmental conditions and increased food availability are changing food habits, with far-reaching public health impacts. This paper analyzes these new nutritional perspectives and the main implications of what has been termed the 1000-day theory. PMID- 28673079 TI - Feeding of preterm infants and fortification of breast milk. AB - The administration of the adequate amount of nutrients helps to improve a correct short-term linear growth and long-term neurocognitive development. To reduce the extra-uterine growth delay in very low birth weight infants (VLBW) the best strategy of nutrition (parenteral or enteral) should be established rapidly, since the first day of life. In preterm infants, nutrition can be administered parenterally and enterally. Prematurity is the most frequent indication for parenteral nutritional support due to intestinal functional immune deficiency, deficiency of digestive enzymatic systems and reduced nutritional reserve of these infants. In terms of enteral nutrition, breast milk is the first choice. In case of preterm and VLBW infants, fortifiers are used to overcome breast milk's protein and mineral deficiencies. When breast milk is not available, specific infant formula is the alternative. PMID- 28673080 TI - Enteral nutrition for preterm infants: by bolus or continuous? An update. AB - Optimization of nutritional management of preterm infants is crucial for achievement of their long-term health. Enteral nutrition is preferred to total parenteral nutrition (TPN) because the former avoids complications related to vascular catheterization, sepsis, adverse effects of TPN, and fasting. Due to the lack of ability of preterm infants to coordinate suckling, swallowing, and breathing, tube feeding is necessary for most infants less than 1500 g to ensure sufficient feeding tolerance, to support optimal growth and to reduce the risk of aspiration. Therefore, feeding by orogastric or nasogastric tube using either continuous or intermittent bolus delivery of formula or human milk is common practice for these infants. Theoretical risks and benefits of both continuous nasogastric milk feeding and intermittent bolus milk feeding have been proposed. According to the literature, continuous nutrition could be preferred in smaller infants (as those with a birthweight below 1250 g) or hemodynamically impaired infants; in stable growing infants nutrition can be administered intermittently as in healthy term infants. PMID- 28673081 TI - Enteral feeding of intrauterine growth restriction preterm infants: theoretical risks and practical implications. AB - Intrauterine growth restriction (IUGR) infants are thought to have impaired gut function after birth secondary to intrauterine redistribution of the blood flow, due to placental insufficiency, with a consequent reduction of gut perfusion. For this reason, infants complicated by IUGR have been considered at higher risk of feeding intolerance. Postnatal evaluation of splanchnic perfusion, through Doppler of the superior mesenteric artery, and of splanchnic oxygenation, through near infrared spectroscopy measurements, may be useful in evaluating the persistence (or not) of the redistribution of blood flow occurred in utero. PMID- 28673083 TI - Transformation and Sorption of Illicit Drug Biomarkers in Sewer Biofilms. AB - In-sewer transformation of drug biomarkers (excreted parent drugs and metabolites) can be influenced by the presence of biomass in suspended form as well as attached to sewer walls (biofilms). Biofilms are likely the most abundant and biologically active biomass fraction in sewers. In this study, 16 drug biomarkers were selected, including the parent forms and the major human metabolites of mephedrone, methadone, cocaine, heroin, codeine, and tetrahydrocannabinol (THC). Transformation and sorption of these substances were assessed in targeted batch experiments using laboratory-scale biofilm reactors operated under aerobic and anaerobic conditions. A one-dimensional model was developed to simulate diffusive transport, abiotic and biotic transformation, and partitioning of drug biomarkers. Model calibration to experimental results allowed estimating biotransformation rate constants in sewer biofilms, which were compared to those obtained for suspended biomass. Our results suggest that sewer biofilms can enhance the biotransformation kinetics of most selected compounds. Through scenario simulations, we demonstrated that the estimation of biotransformation rate constants in biofilm can be significantly biased if the boundary layer thickness is not accurately estimated. This study complements our previous investigation on the transformation and sorption of drug biomarkers in the presence of only suspended biomass in untreated sewage. A better understanding of the role of sewer biofilms-also relative to the in-sewer suspended solids-and improved prediction of associated fate processes can result in more accurate estimation of daily drug consumption in urban areas in wastewater-based epidemiological assessments. PMID- 28673082 TI - Unprecedented (MU-1,1-Peroxo)diferric Structure for the Ambiphilic Orange Peroxo Intermediate of the Nonheme N-Oxygenase CmlI. AB - The final step in the biosynthesis of the antibiotic chloramphenicol is the oxidation of an aryl-amine substrate to an aryl-nitro product catalyzed by the N oxygenase CmlI in three two-electron steps. The CmlI active site contains a diiron cluster ligated by three histidine and four glutamate residues and activates dioxygen to perform its role in the biosynthetic pathway. It was previously shown that the active oxidant used by CmlI to facilitate this chemistry is a peroxo-diferric intermediate (CmlIP). Spectroscopic characterization demonstrated that the peroxo binding geometry of CmlIP is not consistent with the MU-1,2 mode commonly observed in nonheme diiron systems. Its geometry was tentatively assigned as MU-eta2:eta1 based on comparison with resonance Raman (rR) features of mixed-metal model complexes in the absence of appropriate diiron models. Here, X-ray absorption spectroscopy (XAS) and rR studies have been used to establish a refined structure for the diferric cluster of CmlIP. The rR experiments carried out with isotopically labeled water identified the symmetric and asymmetric vibrations of an Fe-O-Fe unit in the active site at 485 and 780 cm-1, respectively, which was confirmed by the 1.83 A Fe-O bond observed by XAS. In addition, a unique Fe...O scatterer at 2.82 A observed from XAS analysis is assigned as arising from the distal O atom of a MU 1,1-peroxo ligand that is bound symmetrically between the irons. The (MU-oxo)(MU 1,1-peroxo)diferric core structure associated with CmlIP is unprecedented among diiron cluster-containing enzymes and corresponding biomimetic complexes. Importantly, it allows the peroxo-diferric intermediate to be ambiphilic, acting as an electrophilic oxidant in the initial N-hydroxylation of an arylamine and then becoming a nucleophilic oxidant in the final oxidation of an aryl-nitroso intermediate to the aryl-nitro product. PMID- 28673084 TI - Transcriptome Landscape of Porcine Intramuscular Adipocytes during Differentiation. AB - The adipocyte differentiation process, controlled by a tightly regulated transcriptional cascade, contributes partly to determine intramuscular adipose tissue (IMAT) mass, which is associated with meat quality in food animals, as well as obesity and related metabolic complications in human. Thus, this study aimed to characterize genes critical for intramuscular preadipocyte differentiation. Primary intramuscular preadipocytes were isolated from pigs, and mRNA profiles were performed at several key points (0 h, 4 h, 8 h, 1 day, 2 days, and 6 days) during adipogenesis using microarrays. By gene functional analysis, we identified numerous differentially expressed genes among distinct stages of intramuscular preadipocyte differentiation, which included numbers of transcription factors in the early stages. We obtained 4 clusters of differential gene expression pattern, including crucial candidate genes associated with adipogenesis of intramuscular adipocytes. Further, we demonstrated that POSTN and FGFR4 suppressed, whereas AKR1CL1 promoted, the expression of adipogenic marker PPARgamma and C/EBPalpha. Taken together, our data delineated the transcriptome landscape during porcine intramuscular preadipocyte differentiation, which provided a valuable resource for finding the genes responsible for IMAT formation. PMID- 28673086 TI - Compound Specific and Enantioselective Stable Isotope Analysis as Tools To Monitor Transformation of Hexachlorocyclohexane (HCH) in a Complex Aquifer System. AB - Technical hexachlorocyclohexane (HCH) mixtures and Lindane (gamma-HCH) have been produced in Bitterfeld-Wolfen, Germany, for about 30 years until 1982. In the vicinity of the former dump sites and production facilities, large plumes of HCHs persist within two aquifer systems. We studied the natural attenuation of HCH in these groundwater systems through a combination of enantiomeric and carbon isotope fractionation to characterize the degradation of alpha-HCH in the areas downstream of a former disposal and production site in Bitterfeld-Wolfen. The concentration and isotope composition of alpha-HCH from the Quaternary and Tertiary aquifers were analyzed. The carbon isotope compositions were compared to the source signal of waste deposits for the dumpsite and highly contaminated areas. The average value of delta13C at dumpsite was -29.7 +/- 0.3 0/00 and -29.0 +/- 0.1 0/00 for (-) and (+)alpha-HCH, respectively, while those for the beta-, gamma-, delta-HCH isomers were -29.0 +/- 0.3 0/00, -29.5 +/- 0.4 0/00, and -28.2 +/- 0.2 0/00, respectively. In the plume, the enantiomer fraction shifted up to 0.35, from 0.50 at source area to 0.15 (well T1), and was found accompanied by a carbon isotope enrichment of 5 0/00 and 2.9 0/00 for (-) and (+)alpha-HCH, respectively. The established model for interpreting isotope and enantiomer fractionation patterns showed potential for analyzing the degradation process at a field site with a complex history with respect to contamination and fluctuating geochemical conditions. PMID- 28673087 TI - Effect of Off-Diagonal Exciton-Phonon Coupling on Intramolecular Singlet Fission. AB - Intramolecular singlet fission (iSF) materials provide remarkable advantages in terms of tunable electronic structures, and quantum chemistry studies have indicated strong electronic coupling modulation by high frequency phonon modes. In this work, we formulate a microscopic model of iSF with simultaneous diagonal and off-diagonal coupling to high-frequency modes. A nonperturbative treatment, the Dirac-Frenkel time-dependent variational approach is adopted using the multiple Davydov trial states. It is shown that both diagonal and off-diagonal coupling can aid efficient singlet fission if excitonic coupling is weak, and fission is only facilitated by diagonal coupling if excitonic coupling is strong. In the presence of off-diagonal coupling, it is found that high frequency modes create additional fission channels for rapid iSF. Results presented here may help provide guiding principles for design of efficient singlet fission materials by directly tuning singlet-triplet interstate coupling. PMID- 28673085 TI - Large-Scale Analysis of Breast Cancer-Related Conformational Changes in Proteins Using SILAC-SPROX. AB - Proteomic methods for disease state characterization and biomarker discovery have traditionally utilized quantitative mass spectrometry methods to identify proteins with altered expression levels in disease states. Here we report on the large-scale use of protein folding stability measurements to characterize different subtypes of breast cancer using the stable isotope labeling with amino acids in cell culture and stability of proteins from rates of oxidation (SILAC SPROX) technique. Protein folding stability differences were studied in a comparison of two luminal breast cancer subtypes, luminal-A and -B (i.e., MCF-7 and BT-474 cells, respectively), and in a comparison of a luminal-A and basal subtype of the disease (i.e., MCF-7 and MDA-MB-468 cells, respectively). The 242 and 445 protein hits identified with altered stabilities in these comparative analyses included a large fraction with no significant expression level changes. This suggests thermodynamic stability measurements create a new avenue for protein biomarker discovery. A number of the identified protein hits are known from other biochemical studies to play a role in tumorigenesis and cancer progression. This not only substantiates the biological significance of the protein hits identified using the SILAC-SPROX approach, but it also helps elucidate the molecular basis for their disregulation and/or disfunction in cancer. PMID- 28673088 TI - Targeted Feature Detection for Data-Dependent Shotgun Proteomics. AB - Label-free quantification of shotgun LC-MS/MS data is the prevailing approach in quantitative proteomics but remains computationally nontrivial. The central data analysis step is the detection of peptide-specific signal patterns, called features. Peptide quantification is facilitated by associating signal intensities in features with peptide sequences derived from MS2 spectra; however, missing values due to imperfect feature detection are a common problem. A feature detection approach that directly targets identified peptides (minimizing missing values) but also offers robustness against false-positive features (by assigning meaningful confidence scores) would thus be highly desirable. We developed a new feature detection algorithm within the OpenMS software framework, leveraging ideas and algorithms from the OpenSWATH toolset for DIA/SRM data analysis. Our software, FeatureFinderIdentification ("FFId"), implements a targeted approach to feature detection based on information from identified peptides. This information is encoded in an MS1 assay library, based on which ion chromatogram extraction and detection of feature candidates are carried out. Significantly, when analyzing data from experiments comprising multiple samples, our approach distinguishes between "internal" and "external" (inferred) peptide identifications (IDs) for each sample. On the basis of internal IDs, two sets of positive (true) and negative (decoy) feature candidates are defined. A support vector machine (SVM) classifier is then trained to discriminate between the sets and is subsequently applied to the "uncertain" feature candidates from external IDs, facilitating selection and confidence scoring of the best feature candidate for each peptide. This approach also enables our algorithm to estimate the false discovery rate (FDR) of the feature selection step. We validated FFId based on a public benchmark data set, comprising a yeast cell lysate spiked with protein standards that provide a known ground-truth. The algorithm reached almost complete (>99%) quantification coverage for the full set of peptides identified at 1% FDR (PSM level). Compared with other software solutions for label-free quantification, this is an outstanding result, which was achieved at competitive quantification accuracy and reproducibility across replicates. The FDR for the feature selection was estimated at a low 1.5% on average per sample (3% for features inferred from external peptide IDs). The FFId software is open-source and freely available as part of OpenMS ( www.openms.org ). PMID- 28673090 TI - Semantics and expanding the treatment goals in bipolar disorder. PMID- 28673089 TI - Rural Collaborative Model for Diabetes Prevention and Management: A Case Study. AB - : Diabetes disproportionately affects racial and ethnic minorities, rural, and impoverished populations. This case study describes the program components and key lessons learned from implementing Vivir Mejor! (Live Better!), a diabetes prevention and management program tailored for the rural, Mexican American population. The program used workforce innovations and multisector partnerships to engage and activate a rural, mostly Hispanic population. Community health worker (CHW) roles were designed to reach and support distinct populations. Promotoras focused exclusively on health education and patient navigators individually coached patients with chronic disease management issues for the high risk patient population. To extend diabetes health education to the broader community in Santa Cruz County, promotoras trained lay leaders to become peer educators. Multisector partnerships allowed the program to offer health and social services around diabetes care. The partners also supported provider engagement through continuing education workshops and digital story screening to encourage referrals to the program. Multisector partnerships, including partnering with critical access hospitals, for diabetes management and prevention, as well as using different types of CHWs to implement programs that target high- and low-risk populations are innovative and valuable components of the Vivir Mejor! MODEL: PMID- 28673091 TI - Review of Primary Cutaneous Mucinoses in Nonlupus Connective Tissue Diseases. AB - Lichen myxedematosus is an idiopathic, cutaneous mucinosis with 2 clinicopathologic subsets. There is the generalised papular and sclerodermoid form, more properly termed scleromyxedema, and the localised papular form. We report the first case, to our knowledge, of lichen myxedematosus in association with rheumatoid arthritis as well as a case in association with dermatomyositis. An up-to-date literature review on cutaneous mucinoses and connective tissue diseases, excluding the common association of primary and secondary mucinoses with systemic lupus erythematosus, was also performed. PMID- 28673092 TI - Observational Study of the Association Between Tongue Exam and the Kampo Diagnostic Procedure of Fuku Shin (Abdominal Exam) in Blood Stasis. AB - Blood stasis is a very important pathophysiological concept not only in Kampo but also in traditional Chinese medicine. Blood stasis indicates severe disease. Fuku shin (the abdominal exam) and Zetsu shin (the tongue exam) are the most important approaches of the 4 diagnostic procedures in Kampo. Tenderness of the lower abdominal region ( Sho fuku koh man) and distended sublingual veins have been mentioned as typical signs of blood stasis in Kampo or traditional Chinese medicine. The aim of the present study was to determine the association between Sho fuku koh man and distended sublingual veins. An appearance of sublingual veins and a level of Sho fuku koh man showed a significant and positive correlation ( rs = .5248; n = 279; P < .0001). In conclusion, the relationship between the appearance of sublingual veins and the level of Sho fuku koh man showed a significant and positive correlation. PMID- 28673093 TI - Di-(2-ethylhexyl) phthalate suppresses IL-12p40 production by GM-CSF-dependent macrophages via the PPARalpha/TNFAIP3/TRAF6 axis after lipopolysaccharide stimulation. AB - Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) by di (2-ethylhexyl) phthalate (DEHP) has an anti-inflammatory effect. This study investigated the potential combined influence of PPARalpha, tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20), and tumor necrosis factor receptor associated factor 6 (TRAF6) on interleukin (IL)-12p40 production by macrophages exposed to DEHP and stimulated with lipopolysaccharide (LPS). LPS upregulated IL 12p40 expression by granulocyte-macrophage colony-stimulating factor-dependent macrophages (on day 9 of culture), whereas adding DEHP to cultures significantly attenuated the response of IL-12p40 to LPS stimulation. PPARalpha protein was also reduced by DEHP. Interestingly, transfection of macrophages with small interfering RNA (siRNA) duplexes for PPARalpha, TNFAIP3/A20, or dual oxidase 2 restored the response of IL-12p40 protein to LPS stimulation in the presence of DEHP. siRNAs for various protein kinase Cs (PKCs) (alpha, beta, gamma, or delta) also restored IL-12p40 production by macrophages exposed to LPS and DEHP. While LPS upregulated both IL-12p40 and TNFAIP3/A20 production, adding DEHP to cultures dramatically reduced IL-12p40 and TNFAIP3/A20 levels. Silencing of PKCalpha reduced TNFAIP3/A20 production, whereas PKCgamma siRNA (but not PKCbeta or delta siRNA) significantly increased TNFAIP3/A20. TRAF6 was also attenuated by macrophages with DEHP. The PPARalpha/TNFAIP3/TRAF6 axis may have an important role in the mechanism through which DEHP reduces IL-12p40 production by LPS stimulated macrophages. PMID- 28673094 TI - Screening of anionic-modified polymers in terms of stability, disintegration, and swelling behavior. AB - This study aimed to screen the stability, disintegration, and swelling behavior of chemically modified anionic polymers. Investigated polymers were well-known and widely used staples of the pharmaceutical and medical field, namely, alginate (AL), carboxymethyl cellulose (CMC), polycarbophil (PC), and hyaluronic acid (HA). On the basis of amide bond formation between the carboxylic acid moieties of anionic polymers and the primary amino group of the modification ligand cysteine (CYS), the modified polymers were obtained. Unmodified polymers served as controls throughout all studies. With the Ellman's assay, modification degrees were determined of synthesized polymeric excipients. Stability assay in terms of erosion study at physiological conditions were performed. Moreover, water uptake of compressed polymeric discs were evaluated and further disintegration studies according to the USP were carried out to define the potential ranking. Results ranking figured out PCCYS > CMCCYS > HACYS > ALCYS in terms of water uptake capacity compared to respective controls. Cell viability assays on Caco-2 cell line as well as on RPMI 2650 (ATTC CCL30) proved modification not being harmful to those. Due to the results of this study, an intense screening of prominent anionic polymer derivate was performed in order to help the pharmaceutical research for the best choice of polymeric excipients for developments of controlled drug release systems. PMID- 28673095 TI - Screening of ionically crosslinked chitosan-tripolyphosphate microspheres using Plackett-Burman factorial design for the treatment of intrapocket infections. AB - OBJECTIVE: Application of Plackett-Burman factorial design to investigate the effect of processing factors in the fabrication of ionically crosslinked chitosan tripolyphosphate (CS-TPP) microspheres. SIGNIFICANCE: Microspheres were screened and optimized to provide maximum process yield (PY), encapsulation efficiency (EE), and time for 80% drug release (T80%) and minimum burst and particles size (PS), for successful application in periodontitis. METHODS: Processing factors viz. method of preparation (MOP), CS, TPP, crosslinking time (CT), agitation (AS), and drying technique (DT) were selected. Solid state characterization was performed by Fourier-Transform infrared (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Mucoadhesion, cytocompatibility, and stability of microspheres were also evaluated. RESULTS: Pareto analysis and analysis of variance, screened most significantly (p < .05) impacting process factors on selected responses. The optimized microspheres demonstrated: o/w emulsification method, CS (2.5%), TPP (5%), CT (120 min), AS (2000 rpm), and DT (freeze-dried), and provided PY- 95.67%, PS- 168.45%, EEOZ- 85.56%, EEDX- 91.34%, BOZ- 15.26%, BDX- 12.91%, TOZ- 47.09 and TDX- 67.95 minutes. FTIR illustrated compatibility between excipients and complexation of CS and TPP. XRD and DSC showed loss of crystallinity of entrapped drugs in microspheres. Biphasic drug release was observed for four days with non-Fickian kinetics. Furthermore, microspheres exhibited good mucoadhesivity (82.51%), antimicrobial activity against Staphylococcus aureus and Escherichia coli, cytocompatibility for L929 cells, and long-term stability. CONCLUSIONS: Therefore, CS-TPP microspheres were found mucoadhesive, safe, stable and provided controlled and prolonged release of drugs. These properties confirmed its high potential and applicability in chronic periodontitis. PMID- 28673096 TI - Review and analysis of FDA approved drugs using lipid-based formulations. AB - Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule. PMID- 28673097 TI - ERRATUM. PMID- 28673100 TI - The need for prospective longitudinal cohort studies on the psychopathology and biology early in bipolar disorder: A commentary to the review by Pfennig et al. PMID- 28673101 TI - Mood instability and regulatory oversight: Checkpoints on the pursuit of 'true' mood stabilisers. PMID- 28673098 TI - Long-Term Metabolic Effects in French-Canadian Children and Adolescents Treated with Second-Generation Antipsychotics in Monotherapy or Polytherapy: A 24-Month Descriptive Retrospective Study. AB - OBJECTIVE: To compare weight and glucose changes of long-term second-generation antipsychotic (SGA) monotherapy versus polytherapy (switching or combining SGAs) in children and adolescents. METHODS: This is a 24-month retrospective study conducted between November 2005 and June 2013. From 147 antipsychotic-naive patients selected (mean age, 12.8 years; 95% confidence interval [CI], 9.8-15.9), 116 (78.9%) received SGA monotherapy and 31 (21.1%) SGA polytherapy for up to 24 months. Height, weight, and fasting glucose (FG) were measured at baseline and 1, 3, 6, 12, and 24 months. Linear mixed-model analysis was used to compare weight, body mass index z score (BMI z score), and glucose changes between the 2 SGA treatment groups, with the repeated factor being the time relative to baseline at 1, 3, 6, 12, and 24 months. RESULTS: Overall, after 24 months of SGA treatment, mean weight increased significantly by 12.8 kg (95% CI, 10.4-15.0), BMI z score by 0.44 (95% CI, 0.21-0.68), and FG levels by 0.29 mmol/L (95% CI, 0.11-0.47). Incidence of overweight/obesity was 22.6%, BMI z score increase over 0.5 was 9.4%, impaired fasting glucose was 9.4%, and type 2 diabetes mellitus was 3.1%. Regarding metabolic effects, no significant difference was found between the subjects taking a single SGA and those exposed to an SGA polytherapy. CONCLUSION: Our study confirms the significant increase of metabolic complications during 24 months of SGA treatment without excluding or confirming a difference between the 2 groups of treatment (mono vs. poly). PMID- 28673099 TI - Suicidal Ideation and Schizophrenia: Contribution of Appraisal, Stigmatization, and Cognition. AB - OBJECTIVE: To predict suicidal ideation in people with schizophrenia, certain studies have measured its relationship with the variables of defeat and entrapment. The relationships are positive, but their interactions remain undefined. To further their understanding, this research sought to measure the relationship between suicidal ideation with the variables of loss, entrapment, and humiliation. METHOD: The convenience sample included 30 patients with schizophrenia spectrum disorders. The study was prospective (3 measurement times) during a 6-month period. Results were analyzed by stepwise multiple regression. RESULTS: The contribution of the 3 variables to the variance of suicidal ideation was not significant at any of the 3 times (T1: 16.2%, P = 0.056; T2: 19.9%, P = 0.117; T3: 11.2%, P = 0.109). Further analyses measured the relationship between the variables of stigmatization, perceived cognitive dysfunction, symptoms, depression, self-esteem, reason to live, spirituality, social provision, and suicidal ideation. Stepwise multiple regression demonstrated that the contribution of the variables of stigmatization and perceived cognitive dysfunction to the variance of suicidal ideation was significant at all 3 times (T1: 41.7.5%, P = 0.000; T2: 35.2%, P = 0.001; T3: 21.5%, P = 0.012). Yet, over time, the individual contribution of the variables changed: T1, stigmatization (beta = 0.518; P = 0.002); T2, stigmatization (beta = 0.394; P = 0.025) and perceived cognitive dysfunction (beta = 0.349; P = 0.046). Then, at T3, only perceived cognitive dysfunction contributed significantly to suicidal ideation (beta = 0.438; P = 0.016). CONCLUSION: The results highlight the importance of the contribution of the variables of perceived cognitive dysfunction and stigmatization in the onset of suicidal ideation in people with schizophrenia spectrum disorders. PMID- 28673102 TI - Open Reduction Assisted With an External Fixator and Internal Fixation With Calcaneal Locking Plate for Intra-articular Calcaneal Fractures. AB - BACKGROUND: The extensile lateral approach (ELA) has been considered to be a standard approach for displaced intra-articular calcaneal fractures (DICF) because it provides excellent exposure and allows direct reduction of the depressed posterior facet fragment. But continuous retraction during surgery needs sufficient manpower and may cause ischemia. Failure of rigid fixation of DICF will not allow for early weight bearing and may lead to a loss of reduction. To avoid these disadvantages, this study presents open reduction assisted with an external fixator and internal fixation with a calcaneal locking plate. METHODS: A series of 58 patients with 62 DICFs were treated over a period of 49 months. All patients were clinically and radiologically followed up with a mean follow-up of 35 (range 29-42) months. Clinical follow-up included visual analog scale (VAS), the American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score, and ability to work. Radiologic follow-up included axial and lateral radiographs and measurements of the Bohler angle and Gissane angle. RESULTS: At the final follow up, all fractures had healed. The mean VAS score was 2.9 (range 0 to 8, SD 1.9) and the average AOFAS score was 71 (range 55-85, SD 8.1). The mean postoperative Bohler angle immediately after the surgery was 28.3 degrees (range 13.0-44.6, SD 7.0), which decreased to 27.5 degrees (range 12.2-43.3, SD 7.0) at the final follow-up, and the mean postoperative Gissane angle after the surgery was 116.3 degrees (range 94.9-131.5, SD 9.0) which finally increased to 118.4 degrees (range 94.5-135.8, SD 9.3). No statistically significant differences regarding Bohler and Gissane angles were found between different Sanders fracture types ( P>.05). CONCLUSION: The presented operative technique was found to provide comparable reduction of Sanders type II-IV injuries. LEVEL OF EVIDENCE: Level III, case control study. PMID- 28673103 TI - A method of treating comminuted phalangeal fractures by ligamentotaxis using a single Kirschner wire. PMID- 28673104 TI - Biopsy in idiopathic pulmonary fibrosis: back to the future. AB - INTRODUCTION: Idiopathic Pulmonary Fibrosis (IPF) is a relentlessly progressive, fibrosing interstitial pneumonia characterized by a radiologic and/or histologic pattern of usual interstitial pneumonia (UIP). The availability of two effective anti-fibrotic drugs in IPF has encouraged the identification and treatment of patients in early stages in order to maximize clinical benefit. The ability of high-resolution computed tomography (HRCT) to identify a 'definite' UIP pattern is suboptimal, particularly in the absence of honeycombing. Therefore, radiologic criteria for UIP are currently being redefined. Histology represents the major source of information to define a UIP pattern. Novel and less invasive approaches (particularly cryobiopsy) to sample interstitial lung diseases have demonstrated high sensitivity and specificity. In parallel, researchers are focusing on molecular mechanisms underlying IPF with the aim to identify more specific druggable targets. Lung tissue is therefore essential for diagnostic, pathogenetic and therapeutic purposes. Areas covered: We identified and critically reviewed the most relevant recent literature related to the limitations of current radiologic criteria, new lung sampling procedures, and molecular pathways in support of the need of lung tissue to better understand IPF. Expert commentary: The development of truly effective treatments for IPF requires the identification of key pathogenetic molecules and pathways. To this end, the availability of lung tissue is vital. PMID- 28673105 TI - Small molecules as activators in medicinal chemistry (2000-2016). AB - INTRODUCTION: From therapeutic point of view, it is often beneficial to enhance the expression of certain enzymes whose low expression is responsible for the observed ailment. Small molecules as activators of several enzymes have great biological potential as anti-microbial and anti-cancer agents, for the treatment of diabetes, obesity, metabolic disorders, and for the treatment of neurological disorders including Alzheimer's disease. This review covers patents describing small molecules as activators, and provides structural leads for the design of even more potent activators. Area covered: This review is focused on small molecules that have been explored as activators of enzymes in the last and current decade (2000-2016). Expert opinion: The ability to modulate activity of enzymes has long been a quest of medicinal chemistry. This has been the impetus behind the development of a plethora of drugs as enzyme inhibitors. However only a few enzyme activators as drugs have made it to the market. Disorders characterized by supressed enzyme activity can be treated by enhancing the activity of a specific enzyme. PMID- 28673106 TI - Sofosbuvir, velpatasvir and voxilaprevir combination for the treatment of hepatitis C. AB - INTRODUCTION: The advent of direct-acting antiviral (DAA) treatments for chronic hepatitis C virus (HCV) infection has dramatically increased rates of cure. However, there remain difficult-to-treat populations, including patients with genotype 3 infection and cirrhosis, and limited salvage treatment options for those that have failed first-line DAA therapy. Areas covered: This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection. All relevant literature from 2015 through June of 2017 is included. Expert commentary: Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy. PMID- 28673107 TI - Annuloplasty for Aortic Regurgitation in Infantile Takayasu Arteritis: A Case Report. AB - Aortic regurgitation (AR) is a life-threatening complication of Takayasu arteritis (TA). Takayasu arteritis is a large-vessel vasculitis with a predominance in young adolescent and adult females. Inflammation involves the aorta and its major branches resulting in arterial dilatation, stenosis, aneurysm, occlusion, and thrombosis formation. Pediatric TA cases have been reported to also cause severe complications such as coronary aneurysms, retinopathy, and hypertension due to renovascular stenosis. In this report, we present a rare occurrence of infantile TA with severe AR requiring surgical intervention after failing medical therapy. Due to the patient's age and clinical status, a valve-sparing aortic annuloplasty with aortoplasty was performed. PMID- 28673108 TI - Melody Transcatheter Pulmonary Valve Placement in a HeartMate II Patient. AB - Transcatheter pulmonary valve placement is emerging as a standard therapy for dysfunctional right ventricular outflow tract conduits. The Melody transcatheter pulmonary valve is indicated for use in the management of pediatric and adult patients with right ventricular outflow tract conduits measuring at least 16 mm in diameter. This is the first reported case of placement in a patient with a left ventricular assist device. We outline the preprocedural evaluation process, the procedural methods, and the outcomes of a successful implantation in a complex patient. With a team-based approach including thoughtful preprocedural evaluation, and close monitoring, successful deployment of a transcatheter pulmonary valve is possible in complex patients in the setting of mechanical circulatory support. PMID- 28673109 TI - Takotsubo Cardiomyopathy Complicating Percutaneous Pulmonary Valve Implantation in a Child. AB - Takotsubo cardiomyopathy describes a sudden onset cardiomyopathy with acute impairment of left ventricular function and spontaneous resolution over time. Only a few cases of Takotsubo cardiomyopathy in childhood have been described. We report the case of a 12-year-old girl with repaired tetralogy of Fallot who experienced acute onset of left ventricular dysfunction without coronary arterial involvement, suggesting Takotsubo cardiomyopathy, during an interventional catheterization procedure. Cardiogenic shock necessitated mechanical circulatory support with extracorporeal membrane oxygenator for ten days and mechanical ventilation for 12 days. The girl recovered without sequelae. Percutaneous pulmonary valve implantation was performed four months later without complications. Unusual aspects of this case include the use of mechanical circulatory support during the recovery phase of Takotsubo cardiomyopathy in a patient with congenital heart disease. PMID- 28673110 TI - Valve-Sparing Root and Total Arch Replacement for Cutis Laxa Aortopathy. AB - Aortic aneurysms requiring surgery in early childhood are rare. Herein we describe the case of a three-year-old with massive aneurysmal aortic dilation secondary to the rare and often lethal genetic disorder, cutis laxa. Initial thoracic aortic aneurysm gene panel was negative. Parents of the child were not known to be consanguineous, but high-density SNP array revealed several regions of homozygosity. This prompted targeted sequence analysis that identified a novel homozygous missense mutation in the gene for cutis laxa, EFEMP2. The patient underwent aortic valve-sparing aortic root and ascending aorta replacement and total aortic arch replacement, with continuous, moderately hypothermic cardiopulmonary bypass, using a dual cannulation technique. He was discharged well on the third postoperative day and remains free of aneurysmal disease at two year follow-up. PMID- 28673111 TI - Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS - YES. PMID- 28673112 TI - Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS - NO. PMID- 28673113 TI - Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS - Commentary. PMID- 28673114 TI - How to cut a nerve: morphological implications of instruments used in preparation of severed nerves for neurorrhaphy. PMID- 28673115 TI - Usability testing of a developed assistive robotic system with virtual assistance for individuals with cerebral palsy: a case study. AB - This paper presents a novel application of an assistive robotic system with virtual assistance to enhance manual performance of individuals with cerebral palsy. Cerebral palsy affects one's voluntary motor movements resulting in limited opportunities to actively engage in physical manipulative activities that require fine motor movements and coordination. Lack of object manipulation and environmental exploration can result in further impairments such as cognitive and social delays. The proposed assistive robotic system has been developed to enhance hand movements of people with disabilities when performing a functional task colouring. This paper presents the usability testing of the effectiveness of the developed system with an individual with cerebral palsy in a set of colouring tasks. Assisted and unassisted approaches were compared and analysed through quantitative and qualitative measures. The robotic-based approach was further compared with the participant's typical alternate access method to perform the same proposed tasks. The robotic system with virtual assistance was clinically validated to be significantly more effective, compared to both unassisted and typical approaches, by increasing the hand controllability, reducing the physical load and increasing the easiness of maintaining movements within the lines. Future studies will inform the use of the system for children with disabilities to provide them with assisted play for functional and playful activities. Implications for rehabilitation Robotic system can enhance manual performance in individuals with disabilities. Participating in a robot-mediated play activity could increase children's motivation and engagement. The developed robotic system can contribute to a basis for clinical and home-based implementation of the technology to promote manual play activities for children with disabilities. PMID- 28673116 TI - Patterns of care and burden of chronic idiopathic thrombocytopenic purpura in Brazil. AB - AIMS: Although several therapeutic options are available for chronic immune thrombocytopenic purpura (cITP), little is known about the treatment of cITP in Brazil. MATERIALS AND METHODS: A multi-center, retrospective chart review, observational study was designed to describe the treatment patterns, clinical burden, resources use, and associated costs for adult patients diagnosed with cITP and treated in public and private institutions in Brazil. Patient charts were screened in reverse chronological order based on their last visit post January 1, 2012. (All costs were calculated using 1.00 USD = 3.9571 BRL, from February 2016.) Results: Of 340 patient charts screened, 50 patients were eligible for inclusion in the study. Single-drug therapy (prednisone, dexamethasone, or dapsone) was the most commonly used treatment, followed by combination therapies (azathioprine + prednisone, azathioprine + prednisone + danazol, and prednisone + dapsone). Splenectomy was performed in 22% of patients after at least first-line treatment. Platelet count and number of bleeding episodes at diagnosis were 31,561.1/mm3 (SD = +/-26,396.1) and 40 episodes, respectively; in first-line, 92,631.1/mm3 (SD = +/-79,955.3) and 19 episodes, respectively; in second-line, 96,950.0/mm3 (SD = +/-76,476.4) and 17 episodes, respectively. Private system patients had a higher median cost compared to public system patients (USD 17.49/month, range = 0-2,020.77 vs USD 9.51/month, range = 0 192.64, respectively). LIMITATIONS: This study does not allow conclusions for causal explanations due to the cohort study design, and treatment patterns represent only the practices of physicians who have agreed to participate in the study. CONCLUSIONS: The data indicate that available therapeutic strategies for second- and third-line therapies appear to be limited. PMID- 28673117 TI - Using a social robot to teach gestural recognition and production in children with autism spectrum disorders. AB - While it has been argued that children with autism spectrum disorders are responsive to robot-like toys, very little research has examined the impact of robot-based intervention on gesture use. These children have delayed gestural development. We used a social robot in two phases to teach them to recognize and produce eight pantomime gestures that expressed feelings and needs. Compared to the children in the wait-list control group (N = 6), those in the intervention group (N = 7) were more likely to recognize gestures and to gesture accurately in trained and untrained scenarios. They also generalized the acquired recognition (but not production) skills to human-to-human interaction. The benefits and limitations of robot-based intervention for gestural learning were highlighted. Implications for Rehabilitation Compared to typically-developing children, children with autism spectrum disorders have delayed development of gesture comprehension and production. Robot-based intervention program was developed to teach children with autism spectrum disorders recognition (Phase I) and production (Phase II) of eight pantomime gestures that expressed feelings and needs. Children in the intervention group (but not in the wait-list control group) were able to recognize more gestures in both trained and untrained scenarios and generalize the acquired gestural recognition skills to human-to human interaction. Similar findings were reported for gestural production except that there was no strong evidence showing children in the intervention group could produce gestures accurately in human-to-human interaction. PMID- 28673118 TI - Muscle recruitment patterns of the subscapularis, serratus anterior and other shoulder girdle muscles during isokinetic internal and external rotations. AB - The aims of this study were to investigate the differences in peak muscle activity and recruitment patterns during high- and low-velocity, concentric and eccentric, internal and external isokinetic shoulder rotations. Electromyographic activity of the rotator cuff and eight superficial muscles of the shoulder girdle was recorded on 25 healthy adults during isokinetic internal and external shoulder rotation at 60 degrees /s and 240 degrees /s. Peak muscle activity, electromyographic envelopes and peak isokinetic moments were analyzed using three factor ANOVA and statistical parametric mapping. The subscapularis and serratus anterior showed moderate to high peak activity levels during each conditions, while the middle and posterior deltoids, upper, middle and lower trapezius, infraspinatus and supraspinatus showed higher peak activity levels during external rotations (+36.5% of maximum voluntary activation (MVA)). The pectoralis major and latissimus dorsi were more active during internal rotations (+40% of MVA). Only middle trapezius and pectoralis major electromyographic activity decreased with increasing velocity. Peak muscle activity was similar or lower during eccentric contractions, although the peak isokinetic moment increased by 35% on average. The subscapularis and serratus anterior appear to be important stabilizers of the glenohumeral joint and scapula. Isokinetic eccentric training at high velocities may allow for faster recruitment of the shoulder girdle muscles, which could improve joint stability during shoulder internal and external rotations. PMID- 28673119 TI - Biomechanical differences of arm swing countermovement jumps on sand and rigid surface performed by elite beach volleyball players. AB - The purpose of this study was to investigate the possible arm swing effect on the biomechanical parameters of vertical counter movement jump due to differences of the compliance of the take-off surface. Fifteen elite male beach-volleyball players (26.2 +/- 5.9 years; 1.87 +/- 0.05 m; 83.4 +/- 6.0 kg; mean +/- standard deviation, respectively) performed counter movement jumps on sand and on a rigid surface with and without an arm swing. Results showed significant (p < .05) surface effects on the jump height, the ankle joint angle at the lowest height of the body center of mass and the ankle angular velocity. Also, significant arm swing effects were found on jump height, maximum power output, temporal parameters, range of motion and angular velocity of the hip. These findings could be attributed to the instability of the sand, which resulted in reduced peak power output due to the differences of body configuration at the lowest body position and lower limb joints' range of motion. The combined effect of the backward arm swing and the recoil of the sand that resulted in decreased resistance at ankle plantar flexion should be controlled at the preparation of selected jumping tasks in beach-volleyball. PMID- 28673120 TI - Infravec2: expanding researcher access to insect vector tools and resources. PMID- 28673121 TI - Gender and validity of self-rated health in nineteen European countries. AB - AIMS: The aims of this study were to: (1) examine the concurrent validity of self rated health for mental and physical health in Europe; and (2) evaluate whether self-rated health predicts health problems differentially by gender. METHODS: Data are from 19 European countries surveyed in the 2014 European Social Survey. We applied ordinary least squares regression to examine the association between self-rated health and summary indicators of physical and mental health problems. RESULTS: We observed an association between self-rated health and both physical and mental health problems in all countries. Gender differences in the concurrent validity of self-rated health were documented in eleven out of 19 countries. CONCLUSIONS: Self-rated health is a valid and efficient measure of physical and mental health across the European continent, with significantly greater concurrent validity among women. PMID- 28673122 TI - Rejuvenating Effect of Long-Term Insulin-Like Growth Factor-I Gene Therapy in the Hypothalamus of Aged Rats with Dopaminergic Dysfunction. AB - The aging female rat constitutes an interesting model of spontaneous and progressive age-related dopaminergic dysfunction as it allows assessing new therapeutic strategies for Parkinson's disease. Insulin-like growth factor I (IGF I) is emerging as a powerful neuroprotective molecule, strongly induced in the central nervous system after different insults. We constructed a helper-dependent recombinant adenoviral vector (HDRAd-IGFI) harboring the gene for rat IGF-I. This was used to implement long-term IGF-I gene therapy in the hypothalamus of aged female rats, which display hypothalamic dopaminergic (DA) dysfunction and, as a consequence, chronic hyperprolactinemia. Rejuvenating long-term IGF-I gene therapy was implemented in young (3 months) and aged (24 months) female rats, which received a single intrahypothalamic injection of 4 * 109 viral particles of either HD-RAd-IGFI or HD-RAd-DsRed (control vector) and were sacrificed 119 days postinjection. In the young animals, neither vector modified serum prolactin (PRL) levels, but in the RAd-IGFI-injected aged rats a nearly full reversion of their hyperprolactinemic status was recorded. Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase (TH)-positive cells in the hypothalamus of experimental compared with control aged animals (5874 +/- 486 and 3390 +/- 498, respectively). Our results indicate that IGF-I gene therapy in aged female rats is highly effective in rejuvenating the hypothalamic DA neuron groups. PMID- 28673123 TI - The gender gap in accrued pension rights - an indicator of women's accumulated disadvantage over the course of working life. The Hordaland Health Study (HUSK). AB - AIMS: Economic gender equality is one of the goals of the Nordic Welfare states. Despite this, there is a considerable gender gap in pensionable income in the European Union, and an unmet need for measures that absorb more of the complexity associated with accumulated (dis)advantages across gender and population groups. The aims of the present study were to examine the gender difference in association between average earned pension points and 1) education and 2) current occupational prestige, and to discuss pension points as a possible indicator of accumulated disadvantages. METHODS: We linked a community-based survey, the Hordaland Health study (HUSK), to the national register of insurance benefits (FD trygd). This made it possible to trace gendered patterns of economic (dis)advantages associated with educational level, career development and gainful work over the life course for 17,275 individuals. RESULTS: We found profound differences in earned accrued pension rights between men and women across socioeconomic strata, and a significant interaction between pension rights and gender in the association with education and occupational prestige. Our findings indicate that men, as a group, may have lower educational attainment and occupational prestige than women, and still earn more pension points throughout their career. These differences place women at risk for future economic strain and deprivation over and above their similarly educated and positioned male counterparts. CONCLUSIONS: We suggest that accrued pension rights may be a relevant measure of accumulated (dis)advantages over the course of working life, and a useful indicator when gender equality is measured and discussed. PMID- 28673124 TI - The choice of methods in determining the optimal cut-off value for quantitative diagnostic test evaluation. AB - Introduction The choice of criteria in determining optimal cut-off value is a matter of concern in quantitative diagnostic tests. Several indexes such as Youden's index, Euclidean index, product of sensitivity and specificity in receiver operator characteristic space and diagnostic odds ratio have been used in clinical practices but their advantages and limitations are not well understood by clinicians. This study aimed to compare these methods in determining optimal cut-off values for quantitative diagnostic test. Methods The different configurations of binormal and bilogistic distributions with equal and unequal variances for nondiseased and diseased subjects were examined. The cut off values with increment of 0.1 in Z-scale were varied. Then, the Youden's index, Euclidean index, product of sensitivity and specificity, and diagnostic odds ratio were calculated over various cut-off values under distributional assumptions with confirmed parameters. Results According to the obtained data from binormal model and equal variances, the optimal cut-off values derived from Youden's index, Euclidean index, and product method were similar but the diagnostic odds ratio yielded either extremely low or extremely high optimal cut off value. For bilogistic pair distributions with equal variances, the Youden's, Euclidean indexes and product method resulted in an identical cut-off value but the diagnostic odds ratio was constant over various cut-points. By both binormal and bilogistic data with more variations in nondiseased population, the Youden's index produced a higher sensitive optimal cut-off value; but with more variation for diseased distribution, the Euclidean index showed a more sensitive optimal cut-off. For bilogistic data with unequal variance, the log(diagnostic odds ratio) had a straight line relationship over cut-off values with either positive or negative slope. Conclusion As a measure of association, diagnostic odds ratio cannot be informative in determining an optimal cut-off value. The advantage of receiver operator characteristic analysis to obtain the optimal cut-off value is to use Youden's index, Euclidean index, or product index which is recommended. The choice between them depends on variability of test results in diseased and nondiseased subjects and the desired sensitivity. PMID- 28673125 TI - Reasons for using workplace wellness services: Cross-sectional study among 6000 employees. AB - AIMS: While workplace wellness services are proactively established to improve well-being and reduce sickness absence, knowledge of reasons for using these services remains sparse. This study investigates which factors determine use of an in-house wellness service at a large organization (the Danish Police) with several departments in different geographical locations. METHODS: All potential users of the Wellness service ( n = 15,284) were invited to respond to a cross sectional questionnaire. Of 6060 eligible respondents, 58% had used the service at least once (any use) and 17% had used the service at least three times (frequent users). Two items assessed the frequency of statements of justifications for using or not using the Wellness service. Associations between 32 demographic and psychosocial variables and use of the Wellness service were evaluated with unadjusted bivariate logistic regression analyses. RESULTS: The two primary justifications for using the Wellness service were: to get a blood pressure assessment (37%) and to rehabilitate injury (26%). The two most common justifications for not using the Wellness service were: no perceived need (44%) and already physically active (34%). Of the 32 demographical and psychosocial variables included, 28 were associated with any use and 24 with frequent use. CONCLUSIONS: Use of the Wellness service appears to be driven by a complex configuration of factors that resist easy translation into practical advice. Non participation was accounted for in terms of both positive and negative barriers. Use of the service for purposes of primary prevention and health promotion was, relatively speaking, lagging behind. PMID- 28673126 TI - Physical activity stages of change surveillance data shows that the majority of Hawai'i's Keiki (Children) meet the guidelines. AB - Targeting Native Hawaiian and other Pacific Islander (NHOPI) children based on their physical activity (PA) stages of change (SOC) may improve intervention effectiveness. No known SOC surveillance system exists for NHOPI jurisdictions. The purpose was to determine the PA SOC prevalence over 5 years in children living in Hawai'i. Self-reported PA SOC from 5 cohorts (3-6 grade students) in Hawai'i were compared between cohorts and sex. The combined PA SOC distribution (n = 1726, 50.7% female) was: Precontemplation, 7.5%; Contemplation, 7.6%; Preparation, 9.9%; Action, 33.4%; Maintenance, 41.5%. There were no significant difference between cohorts 1 and 2 (n = 258), chi2 (16) = 21.75, p = 0.15; 2 and 3 (n = 129), chi2 (16) = 17.51, p = 0.35; 3 and 4 (n = 171), chi2 (16) = 17.28, p = 0.77; 4 and 5 (n = 129), chi2 (16) = 17.51, p = 0.35; and for all cohorts between males and females (p > 0.05). Most participants were in Action and Maintenance. Prevention efforts should emphasize maintaining PA levels. Extending PA behavior surveillance systems to include intention in NHOPI jurisdictions is warranted. PMID- 28673127 TI - Abscisic acid modulates salicylic acid biosynthesis for systemic acquired resistance in tomato. AB - Among the regulatory mechanisms of systemic acquired resistance (SAR) in tomato, antagonistic interaction between salicylic acid (SA) and abscisic acid (ABA) signaling pathways was investigated. Treatment with 1,2-benzisothiazol-3(2H) one1,1-dioxide (BIT) induced SAR in tomato thorough SA biosynthesis. Pretreatment of ABA suppressed BIT-induced SAR including SA accumulation, suggesting that ABA suppressed SAR by inhibiting SA biosynthesis. PMID- 28673128 TI - Escherichia coli yjjPB genes encode a succinate transporter important for succinate production. AB - Under anaerobic conditions, Escherichia coli produces succinate from glucose via the reductive tricarboxylic acid cycle. To date, however, no genes encoding succinate exporters have been established in E. coli. Therefore, we attempted to identify genes encoding succinate exporters by screening an E. coli MG1655 genome library. We identified the yjjPB genes as candidates encoding a succinate transporter, which enhanced succinate production in Pantoea ananatis under aerobic conditions. A complementation assay conducted in Corynebacterium glutamicum strain AJ110655DeltasucE1 demonstrated that both YjjP and YjjB are required for the restoration of succinate production. Furthermore, deletion of yjjPB decreased succinate production in E. coli by 70% under anaerobic conditions. Taken together, these results suggest that YjjPB constitutes a succinate transporter in E. coli and that the products of both genes are required for succinate export. PMID- 28673129 TI - How social policy contributes to the distribution of population health: the case of gender health equity. AB - AIMS: In this study we aimed to analyze gender health equity as a case of how social policy contributes to population health. We analyzed three sets of social investment policies implemented in Europe and previously hypothesized to reduce gender inequity in labor market outcomes: childcare; active labor market programs; and long-term care. METHODS: We use 12 indicators of social-investment policies from the OECD Social Expenditure Database, the OECD Family Database, and the Social Policy Indicators' Parental Leave Benefit Dataset. We draw outcome data from the 2015 Global Burden of Disease for years lived with disability and all-cause mortality among men and women ages 25-54 for 18 European nations over the 1995-2010 period. We estimate 12 linear regression models each for mortality and morbidity (i.e. years lived with disability), one per social-investment indicator. All models use country fixed-effects and cluster-robust standard errors. RESULTS: For years lived with disability, women benefit more from social investment for most indicators. The only exception is the percentage of young children in publicly funded childcare or schooling, which equally benefits men. For all-cause mortality, men benefit more or equally from social investment for most indicators, while women benefit more from government spending on direct job creation through civil employment. CONCLUSIONS: Social policy contributes to the distribution of population health. Social-investment advocates argue such policies in particular enhance economic gender equity. Our results show that these polices have ambiguous effects on gender health equity and even differential improvements among men for some outcomes. PMID- 28673130 TI - Attitudes to and implementation of video interpretation in a Danish hospital: A cross-sectional study. AB - AIMS: Immigrants, refugees, and their descendants comprise 12% of Denmark's population. Some of these people do not speak or understand Danish well enough to communicate with the staff in a healthcare setting and therefore need interpreter services. Interpretation through video conferencing equipment (video interpretation) is frequently used and creates a forum where the interpreter is not physically present in the medical consultation. The aim of this study was to investigate the attitudes to and experiences with video interpretation among charge nurses in a Danish university hospital. METHODS: An electronic questionnaire was sent to 99 charge nurses. The questionnaire comprised both closed and open-ended questions. The answers were analysed using descriptive statistics and thematic text condensation. RESULTS: Of the 99 charge nurses, 78 (79%) completed the questionnaire. Most charge nurses, 21 (91%) of the daily/monthly users, and 21 (72%) of the monthly/yearly users, said that video interpretation increased the quality of their conversations with patients. A total of 19 (24%) departments had not used video interpretation within the last 12 months. CONCLUSIONS: The more the charge nurses used video interpretation, the more satisfied they were. Most of the charge nurses using video interpretation expressed satisfaction with the technology and found it easy to use. Some charge nurses are still content to allow family or friends to interpret. To reach its full potential, video interpretation technology has to be reliable and easily accessible for any consultation, including at the bedside. PMID- 28673131 TI - Health literacy and participation in sports club activities among adolescents. AB - AIMS: The aim of this research was to compare the levels of perceived health literacy among adolescents who do or do not participate in sports club activities. Organized sport club activities reach a high proportion of adolescents, and have the potential to contribute to the development of their health literacy. METHODS: The cross-sectional data on health literacy among school children in Finland (aged 13 and 15, n=3852) were measured, as a part of the Health Behaviour in School-Aged Children (HBSC) study, using the Health Literacy for School-aged Children (HLSAC) instrument. Sports club participation and its association with health literacy were examined in relation to age, gender, family affluence, school achievement, and physical activity. The statistical analyses included cross-tabulation and the multilevel mixed-effects logistic regression analyses. RESULTS: Perceived health literacy was higher among adolescents who participated in sports club activities. This conclusion was valid for boys and girls, for both age groups, among those who were physically active 6 7 days a week, had at least moderate school achievement, and those who belonged to the middle or high affluence families. From the health literacy perspective, participation in sports club activities was especially beneficial for those having low or moderate school achievement level. CONCLUSIONS: The sports club setting may work towards equalizing health literacy differences related to school achievement. However, the clubs should ensure that access is available to as many adolescents as possible; by this means they may spread beneficial influences, supporting the development of health literacy among broader population groups. PMID- 28673132 TI - Snus use during the life-course and risk of the metabolic syndrome and its components. AB - OBJECTIVE: We aimed to investigate the association between life-course exposure to snus and prevalence of the metabolic syndrome and its components in adulthood. DESIGN AND METHOD: Tobacco habits at baseline (age 16) and three follow-ups (ages 21, 30 and 43) were assessed among 880 participants in a population-based cohort in Northern Sweden. Presence of the metabolic syndrome at age 43 was ascertained using the International Diabetes Federation criteria. Odds ratios and CIs for risk of the metabolic syndrome and its components by snus use at 16, 21, 30 and 43 years were calculated using logistic regression. Cumulative snus use was defined as number of life periods (1-4) with current snus use. RESULTS: At age 43, 164 participants (18.6%) were current snus users. We found no association between exclusive snus use at the ages of 16, 21, 30 and 43 years and the metabolic syndrome at age 43 years. Snus use (among non-smokers) was associated with raised triglycerides and high blood pressure in crude analysis, but not in multivariable models. There was no association between cumulative snus use and risk of the metabolic syndrome. Cumulative snus use was associated with central obesity, raised triglycerides and impaired fasting glucose/diabetes mellitus type 2 in crude analyses, but not after adjustments. CONCLUSIONS: The health consequences of snus exposure from adolescence to mid-adulthood do not seem to include increased risk of the metabolic syndrome or its components. The cardio metabolic risk of dual exposure to snus and cigarettes may warrant further attention. PMID- 28673140 TI - Minimally invasive coronary artery bypass grafting: a systematic review. AB - To minimize surgical morbidity in coronary artery bypass grafting, minimally invasive cardiac surgery has gained popularity. Minimally invasive coronary artery bypass grafting offers unique advantages compared to conventional off-pump coronary artery bypass or minimally invasive direct coronary artery bypass in that it enables the surgeon to harvest and graft bilateral internal thoracic arteries via a small thoracotomy while being conducted completely off-pump. This review focuses on current evidence behind off-pump coronary artery bypass, multi arterial revascularization, patient populations that would most benefit from bilateral internal thoracic artery minimally invasive coronary artery bypass grafting, the surgical technique, and early outcomes. By overcoming the perceived inability to utilize bilateral internal thoracic arteries in minimally invasive coronary artery bypass grafting, the new technique further expands the armamentarium of surgeons and cardiologists. Hybrid coronary revascularization with bilateral internal thoracic artery minimally invasive coronary artery bypass grafting further augments the appeal of the next generation of minimally invasive cardiac surgery. PMID- 28673151 TI - Errata. AB - REPORT: Hufanga, S. and Bennett, V.(2007). Mortality data in the Kingdom of Tonga: a review of changing trends over the ten years since 1996. Health Information Management Journal, 36(2): 43-48. The authors sincerely apologise for the omission of the following references and acknowledgement in the previous edition of the journal. and any confusion caused by this oversight. The following should be noted when reading the above report. PMID- 28673141 TI - A case of chondrosarcoma originating from the pulmonary artery. PMID- 28673165 TI - Response to the letter to the editor: delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease. PMID- 28673184 TI - Toxicogenomics of iron oxide nanoparticles in the nematode C. elegans. AB - We present a mechanistic study of the effect of iron oxide nanoparticles (SPIONs) in Caenorhabditis elegans combining a genome-wide analysis with the investigation of specific molecular markers frequently linked to nanotoxicity. The effects of two different coatings were explored: citrate, an anionic stabilizer, and bovine serum albumin, as a pre-formed protein corona. The transcriptomic study identified differentially expressed genes following an exposure to SPIONs. The expression of genes involved in oxidative stress, metal detoxification response, endocytosis, intestinal integrity and iron homeostasis was quantitatively evaluated. The role of oxidative stress was confirmed by gene expression analysis and by synchrotron Fourier Transform infrared microscopy based on the higher tissue oxidation of NP-treated animals. The observed transcriptional modulation of key signaling pathways such as MAPK and Wnt suggests that SPIONs might be endocytosed by clathrin-mediated processes, a putative mechanism of nanotoxicity which deserves further mechanistic investigations. PMID- 28673185 TI - A case control study of syngeneic transplantation versus autologous transplantation for multiple myeloma: two decades of experiences from a single center. PMID- 28673186 TI - Too much to tell: Narrative styles of the first descriptions of the natural world of the Indies. AB - Describing a Mundus Novus was a very singular task in the sixteenth century. It was an effort shaped by a permanent inherent tension between novelty and normality, between the immense variety of new facts (some extraordinary) and the demand of credibility. How did these inner strains affect the narrative style of the first descriptions of the natural world of 'the Indies'? How were the first European observers of the nature of America able to simultaneously transmit the idea of immensity and regularity ( mundus), and that of novelty ( novus)? How did they attempt to describe new worlds knowing that there was a lot - perhaps too much - to tell? This paper focuses not on the much-discussed epistemological issues related to those questions, but on their narrative and stylistic consequences. We argue that the first Europeans meeting the new realities of the Americas or India had to meet new challenges, and these translated into texts with specific characteristics. Thus, their first descriptions are essentially different from the texts about the natural world that were written before or after the 'discovery'. We show that they adopted very specific discursive approaches, and were deeply influenced by the credibility strategies of the medical profession in which they had been trained. PMID- 28673187 TI - Iberian science: Reflections and studies. AB - Over the last two decades early modern historical studies of science, medicine, and technology in the Iberian world have developed into a broad-ranging field with contributions from scholars coming from different historiographical traditions and building upon the solid scholarship of earlier generations. This special issue is an opportunity to explore the field, its recent trends, acknowledge new perspectives that have contributed to the field's growth, and gauge future directions for the field. The six articles offer both reflections on the field's historiography and serve as examples of work currently under way. PMID- 28673188 TI - Being beyond: The Black Legend and how we got over it. AB - We used to think it was the job of a historian of Spanish science to combat the negative evaluations of Hispanic cultures that came to be known as the Black Legend. Paradoxically, attempts to amend dominant narratives of the history of science (such as the Scientific Revolution) so that they might accommodate Spain bolstered the very stories we meant to dismantle. Caring about the Black Legend deformed the history we were trying to write and never convinced the people we hoped to sway. In this article, we provide an overview of the historiographic tendencies that most shaped our careers - responses to the Black Legend, such as contributionist history and bibliometrics - and explain why we have chosen to move on. PMID- 28673189 TI - And yet, we were modern. The paradoxes of Iberian science after the Grand Narratives. AB - In this article, we try to explain the origin of a disagreement; the sort that often arises when the subject is the history of early modern Spanish science. In the decades between 1970 and 1990, while some historians were trying to include Spain in the grand narrative of the rise of modern science, the very historical category of the Scientific Revolution was beginning to be dismantled. It could be said that Spaniards were boarding the flagship of modern science right before it sank. To understand this decalage it would be helpful to recall the role of the history of science during the years after the Franco dictatorship and Spain's transition to democracy. It was a discipline useful for putting behind us the Black Legend and Spanish exceptionalism. PMID- 28673190 TI - Phylogenetic relationships of Podarcis siculus (Rafinesque-Schmaltz, 1810) and Podarcis tauricus (Pallas, 1814) in Turkey, based on mitochondrial DNA. AB - The Italian wall lizard and the Balkan wall lizard have a series of taxonomic revisions. However, their phylogenetic relationships still remain uncertain in Turkey. In the present study, we have assessed taxonomic relationships, both of Podarcis siculus and Podarcis tauricus through estimation of phylogenetic relationships among 43 and 42 specimens, respectively, using mtDNA (16 S rRNA and cytb) from great main populations in Turkey. The genetic distances among the populations of P. siculus in Turkey were very low and they were ranged from 0.2 to 1.6% in 16 S rRNA while they were ranged from 0.0% to 3.3% in cytb. On the other hand, the p-distances among the populations of P. tauricus were ranged from 0.0 to 0.6% in 16 S rRNA while they were 0.2% cytb in Turkey. Finally, most of the topologically identical trees of phylogenetic analyses and p-distances showed that monophyly was found in extant populations of P. siculus and P. tauricus. The nominate subspecies, P. s. siculus and P. t. tauricus are representatives of these lizards in Turkey. PMID- 28673191 TI - Advanced Holistic Nursing Practice Narratives: A View of Caring Praxis. AB - Advanced holistic nurses (AHNs), emerging as leaders in health care transformation, are described as caregivers, but caring and caring-within practice are often difficult for AHNs to explicate. Nursing research that describes caring in advanced practice is limited. Only one study has been reported that focused on describing practice for advanced practice nurses. This article presents a secondary analysis of narratives from a larger qualitative study of holistic pediatric nursing practice. From that study, narratives provided by six holistic advanced practice nurse participants, working in a variety of settings, were extracted and analyzed to illuminate caring-within practice. Participants were asked to write a reflective narrative on a patient exemplar of caring and use John's model for structured reflection to provide a deeper reflection on their narrative of caring. Researchers analyzed the extracted narratives to identify common themes of caring-within-practice. Seven themes emerged depicting AHNs caring-within-practice: normalizing the environment, creating sacred space, being rooted in compassion, the art of being present, establishing trust-caring, coaching the family as caregiver, and inspiration for the future. This article provides excerpts from the narratives that support the themes, discusses the findings, and presents implications of the study. PMID- 28673192 TI - Association Between Clinicopathological Factors and Genomic Abnormalities Detected by FISH Analysis in Epithelioid Diffuse Malignant Pleural Mesothelioma. AB - BACKGROUND: Abnormality of genes including 9p21 is known in malignant mesothelioma and we have examined the frequency of gene deletion and amplification using the fluorescence in situ hybridization (FISH) method. We formerly reported that abnormality of the genes was more common in the sarcomatoid type than epithelioid type. In this study, we compared the clinicopathological factors including nuclear grade (NG) and genomic abnormality in epithelioid malignant pleural mesothelioma (MPM). METHODS: Using paraffin embedded tissues of 31 epithelioid MPMs, we investigated the presence of gene abnormalities in the genes 9p21, 1p36, 14q32, 22q12, 5p15, 6p, 8q24, and 7p12 by the FISH method, and compared the results with NG, clinical stage, and prognosis. RESULTS: In the higher NG group of epithelioid MPM, more gene amplifications [in particular 5p15 and 8q24(MYC)] were observed, and clinical stage was more advanced. Cases with the amplification of 7p12(EGFR) tended to exhibit a worse prognosis. The significant correlation between histological differentiation and clinical features such as prognosis was not confirmed. CONCLUSIONS: NG status in epithelioid MPM may be related to gene alteration and clinical features. PMID- 28673193 TI - Cancer beliefs in cancer survivors, cancer relatives and persons with no cancer experience. AB - AIMS: Negative cancer beliefs have been associated with late stage at cancer diagnosis. High levels of negative cancer beliefs have been found among individuals with low socioeconomic position and ethnic minority women, but the impact of cancer experience on cancer beliefs is unexamined. The aim of this study was to examine whether cancer beliefs are associated with cancer experience. METHODS: This was a cross-sectional population-based study. Telephone interviews of 2992 Danish residents (30+) were carried out using the Awareness and Beliefs about Cancer Measure (ABC). Respondents reported whether they or someone close had been diagnosed with cancer and whether they agreed/disagreed with three positively and three negatively framed cancer beliefs. RESULTS: Respondents with someone close diagnosed was reference group. Compared with these, respondents with no cancer experience (RRadj=0.91, 95% CI=0.84-0.98) or who had had cancer themselves (RRadj=0.87, 0.77-0.98) were less likely to believe that cancer treatment is worse than the cancer itself, and respondents with no cancer experience were less likely to believe that a diagnosis of cancer is a death sentence (RRadj=0.83, 0.70-0.98), but more likely to report that they did not want to know if they had cancer (RRadj=1.31, 1.01-1.71). CONCLUSIONS: The results suggest that cancer beliefs are sensitive to cancer experience. This is an important addition to previous results focusing on the association between cancer beliefs and static factors such as socioeconomic position and ethnicity. Since cancer beliefs may determine health-related behaviour, it is important that negative cancer beliefs are addressed and possibly reframed in population-based interventions. PMID- 28673194 TI - Evaluation of CTAD (citrate-theophylline-adenosine-dipyridamole) as a universal anticoagulant in dogs. AB - CTAD (citrate-theophylline-adenosine-dipyridamole) has been shown to be an almost universal anticoagulant in human and feline medicine, allowing most hematology, coagulation, and biochemical analyses. Forty canine blood specimens were collected in CTAD, EDTA, heparin, and citrate for hematology, biochemistry, and coagulation analyses. CTAD partially limited platelet aggregation observed in EDTA blood smears. CTAD specimens gave similar and well-correlated results for most variables of a complete blood cell count, except for mean corpuscular volume, which was moderately higher, and mean corpuscular hemoglobin concentration, which was moderately lower in CTAD than in EDTA; reticulocyte and platelet indexes were poorly correlated. CTAD plasma gave similar results to citrate for fibrinogen, antithrombin, and D-dimers, and relatively similar results for prothrombin time, but activated partial thromboplastin time was poorly correlated. Triglycerides, cholesterol, glucose, total proteins, phosphate, iron, alanine aminotransferase, gamma-glutamyl transferase, and lipase were similar and well correlated in CTAD and heparin plasmas. Urea, creatinine, albumin, alkaline phosphatase, amylase, and aspartate aminotransferase showed moderate-to-marked bias, but these variables could be measured in CTAD plasma if new reference intervals were determined. Creatine kinase activity, potassium, chloride, and total carbon dioxide measurements are not recommended in CTAD plasma. CTAD is a prospective candidate as an almost universal anticoagulant for routine hematology, some plasma coagulation, and many biochemistry variables in dogs. Definitive recommendations will require study of abnormal canine blood specimens. PMID- 28673195 TI - The provision of nurse-led school based health services. AB - BACKGROUND: Internationally, nurses have been in the forefront of delivering health care services in the school environment and whilst health care delivery in secondary and high schools is evaluated, this is not the case for services delivered in primary/elementary schools. In countries such as New Zealand there is no significant inter-service collaboration between health and education; therefore, the delivery of health services remains fragmented and underdeveloped. OBJECTIVES: This discussion paper reviews the history and development of nurse led school-based health services internationally and provides an insight into the current provision of primary school-based health services in New Zealand. DESIGN: The initial approach to this paper was to gain an understanding of the history of school-based health services internationally and to explore the relationship between health and education in relation to this. This assisted in providing some context and comparison with the current provision of school-based health services in New Zealand. Discussion outcome: Internationally, it is acknowledged that schools provide not only a location to deliver health services to children but also the opportunity to reach entire families and communities yet surprisingly, the development of school-based health services within the primary/elementary school sector has received minimal attention in New Zealand and worldwide. CONCLUSIONS: This paper supports the need for further research concerning the feasibility, provision and effectiveness of school-based health services in primary/elementary schools. In order to be effective, this should incorporate the shared needs and values of all stakeholders. The authors argue the need to develop an inter-service, collaborative, national framework for the delivery of school nursing services within the primary school sector in New Zealand. Impact statement: A collaborative framework for health service delivery into primary schools can enable early establishment of supportive health relationships with families. PMID- 28673197 TI - Flexor pulley reconstruction using a palmar fascia strip: a case report. PMID- 28673196 TI - Magnetic Resonance and Ultrastructural Characterization of PEGylation-associated Vacuolation in Nonclinical Models. AB - Conjugation with polyethylene glycol (PEG) is a strategy for improving the pharmaceutical properties of therapeutic proteins. In nonclinical studies of PEGylated compounds, microscopic tissue vacuolation is often observed, characterized ultrastructurally in this report by lysosomal distension. Although PEGylation-associated vacuolation appears to be of limited toxicologic concern when alternative therapies are limited, the risk-benefit considerations may be impacted by uncertainty about reversibility, lack of methods for monitoring PEG accumulation in vivo without biopsy, and the variability in tissues affected depending on species studied. We demonstrate the use of magnetic resonance spectroscopy (MRS) to measure PEG concentrations at multiple time points in vivo in the kidney with comparison to PEG concentrations ex vivo in body fluids and tissue extracts using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, we demonstrate the use of these techniques to study distribution and elimination of PEG in a dog model of PEGylation-associated vacuolation. This report suggests that MRS could be further investigated as a feasible imaging-based method for monitoring PEG accumulation in a clinical setting in conjunction with NMR quantitation of PEG in plasma and urine. PMID- 28673198 TI - Does preoperative mental health affect length of hospital stay and functional outcomes following arthroplasty surgery? A registry-based cohort study. AB - AIM: It has been reported in the literature that patients with poor preoperative mental health are more likely to have worse functional outcomes following primary total hip and knee arthroplasty. We could find no studies investigating whether preoperative mental health also affects length of hospital stay following surgery. The aim of this study was to determine whether preoperative mental health affects length of hospital stay and long-term functional outcomes following primary total hip and knee arthroplasty. We also aimed to determine whether mental health scores improve after arthroplasty surgery and, finally, we looked specifically at a subgroup of patients with diagnosed mental illness to determine whether this affects length of hospital stay and functional outcomes after surgery. METHOD: Through a review of prospectively collected regional joint registry data, we compared preoperative mental health scores (SF-12 MH) with length of hospital stay and post-operative (1 and 5 years) functional outcome scores (Oxford and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)) in 2279 primary total hip and knee arthroplasty surgeries performed in the Bay of Plenty District Health Board between 2006 and 2010. RESULTS: Based on Pearson product-moment correlation coefficients, there was a significant correlation between preoperative mental health scores and post-operative Oxford scores at 1 year as well as post-operative WOMAC scores at both 1 and 5 years. There was no significant correlation between preoperative mental health and length of hospital stay. Mental health scores improved significantly after arthroplasty surgery. Those patients with a formally diagnosed mental illness had significantly worse preoperative mental health and function scores. Following surgery, they had longer hospital stays although their improvement in function was not significantly different to those without mental illness. CONCLUSION: The results of this study support reports in the literature that there is a correlation between preoperative mental health and long-term functional outcomes following primary total hip and knee arthroplasty. Patients with poor preoperative mental health are more likely to have worse functional outcomes at 1 and 5 years following surgery. No correlation between preoperative mental health and length of hospital stay was identified. Mental health scores improved significantly after surgery. Patients with mental illness had longer hospital stays and despite worse preoperative mental health and function had equal improvements in functional outcomes. PMID- 28673199 TI - Accuracy of pedicle screw placement based on preoperative computed tomography versus intraoperative data set acquisition for spinal navigation system. AB - AIM: To investigate the accuracy of pedicle screw placement based on preoperative computed tomography in comparison with intraoperative data set acquisition for spinal navigation system. METHODS: The PubMed (MEDLINE), EMBASE, and Web of Science were systematically searched for the literature published up to September 2015. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Statistical analysis was performed using the Review Manager 5.3. The dichotomous data for the pedicle violation rate was summarized using relative risk (RR) and 95% confidence intervals (CIs) with the fixed effects model. The level of significance was set at p < 0.05. RESULTS: For this meta-analysis, seven studies used a total of 579 patients and 2981 screws. The results revealed that the accuracy of intraoperative data set acquisition method is significantly higher than preoperative one using 2 mm grading criteria (RR: 1.82, 95% CI: 1.09, 3.04, I2 = 0%, p = 0.02). However, there was no significant difference between two kinds of methods at the 0 mm grading criteria (RR: 1.13, 95% CI: 0.88, 1.46, I2 = 17%, p = 0.34). Using the 2-mm grading criteria, there was a higher accuracy of pedicle screw insertion in O-arm-assisted navigation than CT-based navigation method (RR: 1.96, 95% CI: 1.05, 3.64, I2 = 0%, p = 0.03). The accuracy between CT-based navigation and two-dimensional-based navigation showed no significant difference (RR: 1.02, 95% CI: 0.35-3.03, I2 = 0%, p = 0.97). CONCLUSIONS: The intraoperative data set acquisition method may decrease the incidence of perforated screws over 2 mm but not increase the number of screws fully contained within the pedicle compared to preoperative CT-based navigation system. A significantly higher accuracy of intraoperative (O-arm) than preoperative CT-based navigation was revealed using 2 mm grading criteria. PMID- 28673200 TI - Analysis of functional outcome of Hoffa fractures: A retrospective review of 32 patients. AB - PURPOSE: Hoffa fractures are uncommon intra-articular fractures of femoral condyle in coronal plane. The purpose of our study is to assess radiologic and functional outcome in operatively treated Hoffa fractures. METHODS: We retrospectively reviewed 32 patients of isolated Hoffa fracture from January 2010 to March 2015. All were treated with open reduction and internal fixation using lateral approach for lateral Hoffa and medial approach for medial Hoffa fracture. Cancellous screws in lag mode and/or antiglide plate were employed for fixation in accordance with fracture anatomy. All patients were subjected to aggressive physical therapy postoperatively. Knee Society Score (KSS), International Knee Documentation Committee Score (IKDC), and Knee range of motion (ROM) were documented at final follow-up for functional evaluation. RESULTS: All fractures united by mean time of 11.56 +/- 1.5 weeks. No evidence of subsequent displacement or fixation failure, arthritis, Avascular necrosis (AVN) of femoral condyle was elicited in any of the patients. Documented mean KSS and mean IKDC Score at final follow-up were 83.19 +/- 8.43 and 81.62+/- 6.95, respectively. ROM at final follow-up was ranging from 0 degrees to mean 116.41 degrees +/- 13.98 degrees . Complications included stiffness of the involved knee in four patients, including one patient who developed infection and had to undergo implant removal after fracture union. CONCLUSION: Operative treatment of Hoffa fractures yields fairly good functional outcome. One must endeavor to achieve adequate intraoperative exposure and stable congruous articular reconstruction. Early aggressive physical therapy is a harbinger of optimal outcome. PMID- 28673201 TI - Health and budget impact of combined HIV prevention - first results of the BELHIVPREV model. AB - OBJECTIVES: We developed a pragmatic modelling approach to estimate the impact of treatment as prevention (TasP); outreach testing strategies; and pre-exposure prophylaxis (PrEP) on the epidemiology of HIV and its associated pharmaceutical expenses. METHODS: Our model estimates the incremental health (in terms of new HIV diagnoses) and budget impact of two prevention scenarios (outreach+TasP and outreach+TasP+PrEP) against a 'no additional prevention' scenario. Model parameters were estimated from reported Belgian epidemiology and literature data. The analysis was performed from a healthcare payer perspective with a 15-year time horizon. It considers subpopulation differences, HIV infections diagnosed in Belgium having occurred prior to migration, and the effects of an ageing HIV population. RESULTS: Without additional prevention measures, the annual number of new HIV diagnoses rises to over 1350 new diagnoses in 2030 as compared to baseline, resulting in a budget expenditure of ?260.5 million. Implementation of outreach+TasP and outreach+TasP+PrEP results in a decrease in the number of new HIV diagnoses to 865 and 663 per year, respectively. Respective budget impacts decrease by ?20.6 million and ?33.7 million. CONCLUSION: Foregoing additional investments in prevention is not an option. An approach combining TasP, outreach and PrEP is most effective in reducing the number of new HIV diagnoses and the HIV treatment budget. Our model is the first pragmatic HIV model in Belgium estimating the consequences of a combined preventive approach on the HIV epidemiology and its economic burden assuming other prevention efforts such as condom use and harm reduction strategies remain the same. PMID- 28673202 TI - The Study on Mental Health at Work: Design and sampling. AB - AIMS: The Study on Mental Health at Work (S-MGA) generates the first nationwide representative survey enabling the exploration of the relationship between working conditions, mental health and functioning. This paper describes the study design, sampling procedures and data collection, and presents a summary of the sample characteristics. METHODS: S-MGA is a representative study of German employees aged 31-60 years subject to social security contributions. The sample was drawn from the employment register based on a two-stage cluster sampling procedure. Firstly, 206 municipalities were randomly selected from a pool of 12,227 municipalities in Germany. Secondly, 13,590 addresses were drawn from the selected municipalities for the purpose of conducting 4500 face-to-face interviews. The questionnaire covers psychosocial working and employment conditions, measures of mental health, work ability and functioning. Data from personal interviews were combined with employment histories from register data. Descriptive statistics of socio-demographic characteristics and logistic regressions analyses were used for comparing population, gross sample and respondents. RESULTS: In total, 4511 face-to-face interviews were conducted. A test for sampling bias revealed that individuals in older cohorts participated more often, while individuals with an unknown educational level, residing in major cities or with a non-German ethnic background were slightly underrepresented. CONCLUSIONS: There is no indication of major deviations in characteristics between the basic population and the sample of respondents. Hence, S-MGA provides representative data for research on work and health, designed as a cohort study with plans to rerun the survey 5 years after the first assessment. PMID- 28673203 TI - Bra band size measurements derived from three-dimensional scans are not accurate in women with large, ptotic breasts. AB - This study investigated differences in standard measurements used to determine bra size, under-bust chest circumference (UBCC) and over-bust chest circumference (OBCC), measured from a three-dimensional scan (hand-held scanner) compared to the direct measurement in 111 women (age 21-56 years; right breast volume 57-1672 mL; bra size 10A-18G). Bland-Altman plots of UBCC measurements showed a large positive bias and wide limits of agreement (12 cm; -4.6 to 28 cm), which increased as band size increased but decreased when the breasts were digitally removed from the scan prior to the UBCC measurement. The difference in UBCC measurements determined from scans compared to direct measurement had a strong positive correlation with breast volume and breast ptotis. The OBCC measurements showed a small positive bias (2.4 cm; -3.4 to 8.4), consistent across the range of bra sizes. Bra band size measurements determined from three-dimensional scans can be inaccurate in women with large, ptotic breasts. Practitioner Summary: We investigated potential errors in anthropometric data derived from three dimensional scans used for bra design and fit. Bra band size measurements taken from three-dimensional scans were over-estimated in women with large breasts, whereas bra cup size measurements were accurate to within one-cup size across the entire range of bra sizes. PMID- 28673204 TI - Abnormality of Klotho Signaling Is Involved in Polycystic Ovary Syndrome. AB - This study investigated the involvement of the klotho-associated signaling in the apoptosis of granulosa cells (GCs) from the ovaries of patients with polycystic ovary syndrome (PCOS) and PCOS animals. Primary GCs were obtained from 26 healthy women and 43 women with PCOS. The PCOS animal model was established by the injection of dehydroepiandrosterone (DHEA). Klotho protein and associated microRNA expression in human primary GCs and rats' ovarian tissues were measured by Western blot and real-time polymerase chain reaction, respectively. Results showed that significantly lower miR-126-5p and miR-29a-5p microRNA expressions, higher klotho protein expression, lower insulin growth factor 1 (IGF-1R) and Wnt family member 1 (Wnt1) protein expressions, and lower Akt phosphorylation at Ser473 and Thr308 residues were observed in the GCs from patients with PCOS and the ovarian tissues of PCOS rats compared to that in GCs from healthy women and ovarian tissues of normal control rats, respectively. Knockdown of klotho gene expression normalized IGF-1R and Wnt1 protein expressions and Akt phosphorylation in GCs from patients with PCOS and the ovarian tissues from PCOS rats; it also blocked the effects of insulin on apoptosis and proliferation in GCs from patients with PCOS and inhibited caspase-3 activity in ovarian tissues of PCOS rats. Knockdown of klotho gene expression increased the pregnancy rate in DHEA treated female rats and increased the body weight of their newborns through normalizing the ovarian function and decreasing the formation of cystic follicles. In conclusion, the miR-126-5p, miR-29a-5p/klotho/insulin-IGF-1, Wnt, and Akt signal pathway may be involved in the apoptosis of GCs and subsequent development of PCOS. PMID- 28673205 TI - Nerve Growth Factor Is Associated With Sexual Pain in Women With Endometriosis. AB - Endometriosis is present in 1 in 10 reproductive-age women, and half experience deep dyspareunia (pelvic pain with sexual intercourse). Our objective was to investigate nerve growth factor (NGF) and its receptors (TrkA/p75NTR) in endometriosis-associated deep dyspareunia. A total of 32 women with endometriosis in the posterior pelvic compartment (cul-de-sac/uterosacrals) were included, either with (n = 17) or without (n = 15) deep dyspareunia symptoms confirmed by endovaginal ultrasound-assisted palpation on examination. Expression of NGF, TrkA, and p75NTR in the surgically excised cul-de-sac/uterosacral endometriosis was examined by immunohistochemistry and Histoscore blinded to pain phenotypes. Additionally, endometriotic stromal cells (ESCs; n = 3) from ectopic endometriosis lesions were cultured and incubated with/without NGF and/or Trk inhibitor K252a, followed by expression analysis of prostaglandin-endoperoxide synthase 2 (PTGS-2)/cyclooxygenase 2 (COX-2; reverse transcription quantitative real-time polymerase chain reaction and Western blot) and prostaglandin E2 (PGE2) secretion (enzyme-linked immunosorbent assay). We found that the immunointensity of NGF and TrkA, but not p75NTR, was significantly elevated in endometriotic stroma and epithelium from women with deep dyspareunia compared to women without deep dyspareunia. Nerve growth factor immunoreactivity in the stroma was also significantly associated with deep dyspareunia intensity and local nerve bundle density. In cultured ESCs, NGF significantly increased PTGS-2/COX-2 mRNA and protein levels as well as PGE2 secretion, and these effects could be abolished by pretreatment of Trk inhibitor K252a. In conclusion, elevated NGF levels were associated with deep dyspareunia in women with cul-de-sac/uterosacral endometriosis. This association may be mediated by increased nerve bundle density and by COX-2/PGE2 stimulation via Trk receptor. Nerve growth factor signaling may play an important role in endometriosis-associated sexual pain. PMID- 28673207 TI - A cone beam computed tomographic evaluation of the size of the sella turcica in patients with cleft lip and palate. AB - OBJECTIVE: Changes in the size of the sella turcica are frequently related to pathologies and syndromes. The aim of this was to compare the sella turcica dimensions in patients with unilateral and bilateral cleft lip and palate and non cleft subjects. METHODS: Cone beam computed tomography (CBCT) images of three groups consisted of 20 patients with unilateral cleft lip and palate; 20 patients with bilateral cleft lip and palate and a control group consisting of 20 non cleft subjects were the research population in this pilot study. The sella turcica linear dimensions in terms of length, depth and diameter were measured for all subjects. One-way ANOVA test was used to determine any significant differences among the three groups for the measured parameters. RESULTS: The length, depth and diameter of sella turcica were found to be significantly smaller in the unilateral and bilateral groups compared with the normal age and gender matched group. No significant differences were found in the measured variables between the unilateral and bilateral cleft patients. CONCLUSION: CBCT images showed a greater likelihood of abnormal sella turcica dimensions in patients with unilateral and bilateral cleft lip and palate. Therefore, the sella turcica dimensions may have an intrinsic relationship to the cleft condition. PMID- 28673206 TI - Overexpression of Four Joint Box-1 Protein (FJX1) in Eutopic Endometrium From Women With Endometriosis. AB - The four jointed box 1 (FJX1) is a regulator of angiogenesis, and the levels of FJX1 are increased in several types of cancer. Angiogenesis plays a critical role in endometrial growth as well as in several gynecologic disorders including endometriosis. However, the function of FJX1 has not been studied in endometriosis. Therefore, we examined the levels of FJX1 in eutopic endometrium from women with or without endometriosis. The levels of FJX1 protein did not change in endometrial cells during the menstrual cycle in endometrium from women without endometriosis. However, its levels were significantly higher in the secretory phase of the eutopic endometrium from women with endometriosis when compared to women without endometriosis. Hypoxia-inducible factor-1alpha (HIF1alpha) is known as a key mediator of endometriosis by regulating genes essential to estrogen production, angiogenesis, proliferation, inflammation, and extracellular invasion. It has been reported that FJX1 induces an increase in HIF1alpha through posttranslational stabilization. The results of our Western blot analysis reveal a significant positive correlation between FJX1 and HIF1alpha proteins in endometrium of women with and without endometriosis. This overexpression of FJX1 was confirmed by sequential analysis of the eutopic endometrium during endometriosis progression, using an induced model of endometriosis in the baboon. Therefore, our results suggest that high levels of FJX1 proteins may play an important role in the pathogenesis of endometriosis. PMID- 28673208 TI - The variable and chaotic nature of professional golf performance. AB - In golf, unlike most other sports, individual performance is not the result of direct interactions between players. Instead decision-making and performance is influenced by numerous constraining factors affecting each shot. This study looked at the performance of PGA TOUR golfers in 2011 in terms of stability and variability on a shot-by-shot basis. Stability and variability were assessed using Recurrence Quantification Analysis (RQA) and standard deviation, respectively. About 10% of all shots comprised short stable phases of performance (3.7 +/- 1.1 shots per stable phase). Stable phases tended to consist of shots of typical performance, rather than poor or exceptional shots; this finding was consistent for all shot categories. Overall, stability measures were not correlated with tournament performance. Variability across all shots was not related to tournament performance; however, variability in tee shots and short approach shots was higher than for other shot categories. Furthermore, tee shot variability was related to tournament standing: decreased variability was associated with better tournament ranking. The findings in this study showed that PGA TOUR golf performance is chaotic. Further research on amateur golf performance is required to determine whether the structure of amateur golf performance is universal. PMID- 28673209 TI - The introduction of intravenous crystalloids. PMID- 28673210 TI - Changing of the guard. PMID- 28673211 TI - Pain after surgery-acute becomes chronic: might there be a silver ROCKet? PMID- 28673212 TI - Awareness during general anaesthesia in the first 4,000 incidents reported to webAIRS. AB - The aim of this study was to analyse the incidents related to awareness during general anaesthesia in the first 4,000 cases reported to webAIRS-an anaesthetic incident reporting system established in Australia and New Zealand in 2009. Included incidents were those in which the reporter selected "neurological" as the main category and "awareness/dreaming/nightmares" as a subcategory, those where the narrative report included the word "awareness" and those identified by the authors as possibly relevant to awareness. Sixty-one awareness-related incidents were analysed: 16 were classified as "awareness", 31 were classified as "no awareness but increased risk of awareness" and 14 were classified as "no awareness and no increased risk of awareness". Among 47 incidents in the former two categories, 42 (89%) were associated with low anaesthetic delivery and 24 (51%) were associated with signs of intraoperative wakefulness. Memory of intraoperative events caused significant ongoing distress for five of the 16 awareness patients. Patients continue to be put at risk of awareness by a range of well-described errors (such as syringe swaps) but also by some new errors related to recently introduced anaesthetic equipment, such as electronic anaesthesia workstations. PMID- 28673213 TI - Primary prevention in the intensive care unit: a prospective single-centre study of the risk factors for invasive pneumococcal disease. AB - Invasive pneumococcal disease is a significant health burden in Australia, with immunisation recommended for children and at-risk adults. Health benefits of immunisation are clear, but less effective when immunisation rates are low, as in Western Australia. We hypothesised that patients admitted unplanned to the intensive care unit (ICU) would have high eligibility for pneumococcal immunisation, but low rates of recorded vaccine administration. We performed a prospective observational study of 119 emergency admissions to Royal Perth ICU, a 20-bed mixed ICU at a tertiary teaching hospital in Western Australia. Each admission was screened for vaccine eligibility (age and risk factors as per Australian Technical Advisory Group of Immunisation guidelines), with patients' health records examined and primary care providers contacted after ICU discharge. Risk factors for invasive pneumococcal disease were common, with 52% of the study population having one or more. Fifty-four of 119 admitted patients (45%) were assessed as eligible for immunisation after ICU discharge. ICU survivors represent a high-risk population for which intervention against modifiable targets, such as invasive pneumococcal disease, may reduce both their chronic health burden and future health expenditure. Future efforts should concentrate on assessing the feasibility of a screening program for modifiable factors in ICU survivors, and the logistics of delivering these interventions in a timely manner during their hospital stay. PMID- 28673214 TI - Randomised comparison of three types of continuous anterior abdominal wall block after midline laparotomy for gynaecological oncology surgery. AB - Effective analgesia after midline laparotomy surgery is essential for enhanced recovery programs. We compared three types of continuous abdominal wall block for analgesia after midline laparotomy for gynaecological oncology surgery. We conducted a single-centre, double-blind randomised controlled trial. Ninety-four patients were randomised into three groups to receive two days of programmed intermittent boluses of ropivacaine (18 ml 0.5% ropivacaine every four hours) via either a transversus abdominis plane (TAP) catheter, posterior rectus sheath (PRS) catheter, or a subcutaneous (SC) catheter. All groups received patient controlled analgesia with morphine, and regular paracetamol and non-steroidal anti-inflammatory medication. Measured outcomes included analgesic and antiemetic usage and visual analog scores for pain, nausea, vomiting, and satisfaction. Eighty-eight patients were analysed (29 SC, 29 PRS and 30 TAP). No differences in the primary outcome were found (median milligrams morphine usage on day two SC 28, PRS 25, TAP 21, P=0.371). There were differences in secondary outcomes. Compared with the SC group, the TAP group required less morphine in recovery (0 mg versus 6 mg, P=0.01) and reported less severe pain on day one (visual analog scores 36.3 mm versus SC 55 mm, P=0.04). The TAP group used fewer doses of tropisetron on day one compared with the PRS group (8 versus 21, P=0.016). Programmed intermittent boluses of ropivacaine delivered via PRS, TAP and SC catheters can be provided safely to patients undergoing midline laparotomy surgery. Initially TAP catheters appear superior, reducing early opioid and antiemetic requirements and severe pain, but these advantages are lost by day two. PMID- 28673215 TI - The effect of a perioperative ketamine infusion on the incidence of chronic postsurgical pain-a pilot study. AB - Chronic postsurgical pain (CPSP) is a common and debilitating complication of major surgery. We undertook a pilot study at three hospitals to assess the feasibility of a proposed large multicentre placebo-controlled randomised trial of intravenous perioperative ketamine to reduce the incidence of CPSP. Ketamine, 0.5 mg/kg pre-incision, 0.25 mg/kg/hour intraoperatively and 0.1 mg/kg/hour for 24 hours, or placebo, was administered to 80 patients, recruited over a 15-month period, undergoing abdominal or thoracic surgery under general anaesthesia. The primary endpoint was CPSP in the area of the surgery reported at six-month telephone follow-up using a structured questionnaire. Fourteen patients (17.5%) reported CPSP (relative risk [95% confidence interval] if received ketamine 1.18 [0.70 to 1.98], P=0.56). Four patients in the treatment group and three in the control group reported ongoing analgesic use to treat CPSP and two patients in each group reported their worst pain in the previous 24 hours at >=3/10 at six months. There were no significant differences in adverse event rates, quality of recovery scores, or cumulative morphine equivalents consumption in the first 72 hours. Numeric Rating Scale pain scores (median [interquartile range, IQR]) for average pain in the previous 24 hours among those patients reporting CPSP were 17.5 [0 to 40] /100 with no difference between treatment groups. A large (n=4,000 to 5,000) adequately powered multicentre trial is feasible using this population and methodology. PMID- 28673216 TI - Does anyone ever expect to die? AB - Patients who come to the intensive care unit are amongst the sickest patients in our hospitals. Patients can be admitted to the intensive care unit unexpectedly (following accidents or sudden onset of illness) or as unplanned but not necessarily truly 'unexpected' admissions. These patients often have significant underlying chronic health issues, including metastatic cancer, advanced cardiac, respiratory, renal, or hepatic failure, or frailty, with a high likelihood of death in the ensuing months. Using the Australian and New Zealand Intensive Care Society Clinical Trials Group Point Prevalence Program, a prospective single-day observational study across 46 Australian hospitals in 2014 and 2015, we found that less than 9% of intensive care unit patients (51/577) had an advance directive available. From these results, we provide two suggestions to increase intensive care's understanding of patients' end-of-life wishes. First, systematically target 'high risk of dying' patient groups for goals of care conversations in the outpatient setting. Such groups include those where one would not be 'surprised' if they died within a year. Second, as a society, more conversations about end-of-life wishes are needed. PMID- 28673217 TI - Validity evidence of non-technical skills assessment instruments in simulated anaesthesia crisis management. AB - We sought to evaluate the validity of two non-technical skills evaluation instruments, the Anaesthetists' Non-Technical Skills (ANTS) behavioural marker system and the Ottawa Global Rating Scale (GRS), to apply them to anaesthesia training. The content validity, response process, internal structure, relations with other variables and consequences were described for validity evidence. Simulated crisis management sessions were initiated during which two trained raters evaluated the performance of postgraduate first-, second- and third-year (PGY-1, PGY-2 and PGY-3) anaesthesia residents. The study included 70 participants, composed of 24 PGY-1, 24 PGY-2 and 22 PGY-3 residents. Both instruments differentiated the non-technical skills of PGY-1 from PGY-3 residents (P <0.05). Inter-rater agreement was measured using the intraclass correlation coefficient (ICC). For the ANTS instrument, the intraclass correlation coefficients for task management, team-working, situation awareness and decision making were 0.79, 0.34, 0.81 and 0.70, respectively. For the Ottawa GRS, the intraclass correlation coefficients for overall performance, leadership, problem solving, situation awareness, resource utilisation and communication skills were 0.86, 0.83, 0.84, 0.87, 0.80 and 0.86, respectively. The Cronbach's alpha for internal consistency of the ANTS instrument was 0.93, and was 0.96 for the Ottawa GRS. There was a high correlation between the ANTS and Ottawa GRS. The raters reported the ease of use of the Ottawa GRS compared to the ANTS. We found sufficient evidence of validity in the ANTS instrument and the Ottawa GRS for the evaluation of non-technical skills in a simulated anaesthesia setting, but the Ottawa GRS was more practical and had higher reliability. PMID- 28673218 TI - The rapid and accurate categorisation of critically ill patients (RACE) to identify outcomes of interest for longitudinal studies: a feasibility study. AB - The capacity to measure the impact of an intervention on long-term functional outcomes might be improved if research methodology reflected our clinical approach, which is to individualise goals of care to what is achievable for each patient. The objective of this multicentre inception cohort study was to evaluate the feasibility of rapidly and accurately categorising patients, who were eligible for simulated enrolment into a clinical trial, into unique categories based on premorbid function. Once a patient met eligibility criteria a rapid 'baseline assessment' was conducted to categorise patients into one of eight specified groups. A subsequent 'gold standard' assessment was made by an independent blinded assessor once patients had recovered sufficiently to allow such an assessment to occur. Accuracy was predefined as agreement in >80% of assessments. One hundred and twenty-two patients received a baseline assessment and 104 (85%) were categorised to a unique category. One hundred and six patients survived to have a gold standard assessment performed, with 100 (94%) assigned to a unique category. Ninety-two patients had both a baseline and gold standard assessment, and these agreed in 65 (71%) patients. It was not feasible to rapidly and accurately categorise patients according to premorbid function. PMID- 28673219 TI - The effect of oral intake during the immediate pre-colonoscopy time period on volume depletion in patients who receive sodium picosulfate. AB - Sodium picosulfate, used in combination with magnesium oxide and citric acid for bowel cleansing, can result in dehydration. We investigated whether enhanced carbohydrate fluid intake pre-colonoscopy could mitigate this effect. We enrolled 398 elective colonoscopy patients in a prospective, controlled, single-blinded study. The control group (n=194) fasted routinely (minimum seven hours) whilst the treatment group (n=197) drank 1,200 ml carbohydrate solution leading up to admission (up until two hours pre-colonoscopy). On admission a patient survey was completed, and urine specific gravity obtained. Supine blood pressure and pulse rate were measured, and repeated within three minutes of standing. The carbohydrate group had reduced symptoms and signs of dehydration, including thirst (34% versus 65%, P <0.001), dry mouth (45% versus 59%, P=0.008), dizziness (10% versus 20%, P=0.010), lower mean urine specific gravity (1.007 versus 1.017, P <0.001), lower incidence of orthostatic hypotension (2.6% versus 11%, P <0.001), and lower mean erect pulse rate (78 versus 81 /minute, P=0.047). The postural change in systolic blood pressure was less in the treatment group (mean 0.4 mmHg, median -1 mmHg [interquartile range, IQR -7 to 7]) than in the control group (mean -4.1 mmHg, median -1 mmHg [IQR -12 to 3], P=0.028). These findings indicate that hydration with carbohydrate solution in patients taking sodium picosulfate has clinical benefit. PMID- 28673220 TI - Anaesthetic management of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei: a retrospective audit. AB - Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to improve quality of life and survival rates in patients suffering from pseudomyxoma peritonei. The procedure is long and associated with significant intraoperative blood loss. As such, the anaesthetic management of patients undergoing this procedure can be challenging. The aim of this paper is to describe our perioperative management of pseudomyxoma peritonei patients who received CRS and to report a retrospective audit of our outcomes and complications over a six-year period at a large tertiary centre. A total of 70 patients were included, of whom three (4.3%) had CRS alone, 42 (60.0%) had CRS with HIPEC, and 25 (35.7%) had CRS with HIPEC and early postoperative intraperitoneal chemotherapy. There were no intraoperative deaths. A total of four patients (5.7%) died during their hospital admission. At one-year follow-up, six patients (9.0%) had died, and at the end of the study 15 (22.4%) had died. No statistically significant difference in blood loss was seen between patients who received tranexamic acid (30 patients, 42.9%) and those who did not, but the incidence of deep venous thrombosis was much higher (10/30 versus 1/40). Different intravenous fluid strategies appeared not to influence the incidence of postoperative acute renal failure. Further research is required to evaluate the effects of intraoperative tranexamic acid and different intraoperative fluid strategies on outcomes in patients undergoing CRS with HIPEC. PMID- 28673221 TI - Intravascular catheters-an ultrasound imaging based observational study of position and function. AB - Peripheral intravenous and intra-arterial catheters often block with movement of the limb in which they are inserted. Although the cause of this blockage is commonly attributed to a valve or other structure within the vein, evidence for this is lacking. We used ultrasound to assess the cause of blockage on movement, and degree of tip movement, of 62 venous and 21 radial arterial catheters. In both venous and arterial catheters, blockage was predominantly caused by impingement of the catheter on the vessel wall, with catheter kinking and spasm of the vessel also seen. Mean potential tip movement was 12.3 mm and 5.7 mm in hand and forearm venous catheters respectively and 9.5 mm in radial artery catheters. There was a significantly lower rate of blockage for forearm (20%) compared to dorsal hand venous catheters (83%, P <0.001) and 52% of radial artery catheters showed damping and blockage on wrist flexion. This study emphasises the advantages of placement of venous catheters in the straight veins of the forearm. PMID- 28673222 TI - Rational Clinical Pathology Assessment in the Intensive Care Unit. AB - Blood tests are ordered on a daily basis in intensive care units (ICU). There are no widely accepted guidelines for testing requirements. This study investigated the impact on ICU laboratory test costs of a multi-strategy change in practice involving routine blood testing. A single centre, prospective, interventional study using historical controls was undertaken to investigate the impact of ICU specialist authorisation of high-volume routine tests on ICU laboratory test costs. Prior to commencement of the study, ICU nursing and junior ICU doctors were able to order tests. During the six-month intervention period, the ICU specialists authorised routine blood tests. Adverse events related to not performing blood tests were also recorded. Overall ICU laboratory test costs decreased by 12.3% over the six months (P=0.0022 versus historical control) with a mean compliance of 51% with the test authorisation protocol. The costs of frequently ordered tests (classified as high-volume) decreased by 20% (P=0.0022 versus historical control). These accounted for an average of 54 +/- 3% of the overall ICU blood test costs (blood gas analyses 17%, simple chemistry tests consisting of electrolytes, liver function, calcium, phosphate, magnesium 14%, coagulation 12% and full blood count 11%). Two protocol-related adverse events were recorded and judged as minor and were resolved by ordering tests during the day. No adverse patient outcomes resulted from these two events. Blood testing authorisation by an ICU specialist was associated with significant cost savings in ICU and no adverse patient outcomes. PMID- 28673223 TI - Proceedings of the 12th International Conference on Rapid Response Systems and Medical Emergency Teams. AB - Rapid Response Teams (RRTs) have been introduced into hospitals worldwide in an effort to improve the outcomes of deteriorating hospitalised patients. Recently, there has been increased awareness of the need to develop systems other than RRTs for deteriorating patients. In May 2016, the 12th International Conference on Rapid Response Systems and Medical Emergency Teams was held in Melbourne. This represented a collaboration between the newly constituted International Society for Rapid Response Systems (iSRRS) and the Australian and New Zealand Intensive Care Society. The conference program included broad ranging presentations related to general clinical deterioration in the acute care setting, as well as deterioration in the emergency department, during pregnancy, in the paediatric setting, and deterioration in mental health status. This article briefly summarises the key features of the conference, links to presentations, and the 18 abstracts of the accepted free papers. PMID- 28673224 TI - Fluid resuscitation in critically ill patients-timing and dose matters. AB - Fluid management is a complex subject in healthcare, particularly when pertaining to critically ill patients. Following a literature search on international recommendations regarding fluid administration for shocked patients, an audit was undertaken at Rotorua Public Hospital, New Zealand, to assess how the local fluid resuscitation strategy could be improved. The first part of the audit looked at the fluid resuscitation approach used to treat shocked patients admitted to the ICU of Rotorua Hospital in 2014 and changes required to achieve best practice recommendations. The second part tested the success and impact of the subsequently implemented, more measured approach to fluid resuscitation in 2016. Data was extracted from patient files, fluid charts and electronic records to assess fluid administration and de-escalation measures. The collated information was analysed and compared to recommendations found in the literature. The complete audit cycle revealed not only a significant improvement in adherence to best practice guidelines, but also an association with better patient outcomes. PMID- 28673225 TI - Veno-venous extracorporeal membrane oxygenation in pregnancy: does foetal viability matter? PMID- 28673226 TI - The limitations of using baseline cerebral tissue oxygen saturation to stratify perioperative risk. PMID- 28673227 TI - In reply to Grocott. PMID- 28673228 TI - Mitigating risks of tracheal tube migration during transport. PMID- 28673229 TI - Discussing goals of care. PMID- 28673230 TI - In Reply to Blum. PMID- 28673231 TI - A free paediatric animation application. PMID- 28673232 TI - Expression of Ciona intestinalis AOX causes male reproductive defects in Drosophila melanogaster. AB - BACKGROUND: Mitochondrial alternative respiratory-chain enzymes are phylogenetically widespread, and buffer stresses affecting oxidative phosphorylation in species that possess them. However, they have been lost in the evolutionary lineages leading to vertebrates and arthropods, raising the question as to what survival or reproductive disadvantages they confer. Recent interest in using them in therapy lends a biomedical dimension to this question. METHODS: Here, we examined the impact of the expression of Ciona intestinalis alternative oxidase, AOX, on the reproductive success of Drosophila melanogaster males. Sperm competition assays were performed between flies carrying three copies of a ubiquitously expressed AOX construct, driven by the alpha-tubulin promoter, and wild-type males of the same genetic background. RESULTS: In sperm-competition assays, AOX conferred a substantial disadvantage, associated with decreased production of mature sperm. Sperm differentiation appeared to proceed until the last stages, but was spatially deranged, with spermatozoids retained in the testis instead of being released to the seminal vesicle. High AOX expression was detected in the outermost cell-layer of the testis sheath, which we hypothesize may disrupt a signal required for sperm maturation. CONCLUSIONS: AOX expression in Drosophila thus has effects that are deleterious to male reproductive function. Our results imply that AOX therapy must be developed with caution. PMID- 28673233 TI - Fixed-length haplotypes can improve genomic prediction accuracy in an admixed dairy cattle population. AB - BACKGROUND: Fitting covariates representing the number of haplotype alleles rather than single nucleotide polymorphism (SNP) alleles may increase genomic prediction accuracy if linkage disequilibrium between quantitative trait loci and SNPs is inadequate. The objectives of this study were to evaluate the accuracy, bias and computation time of Bayesian genomic prediction methods that fit fixed length haplotypes or SNPs. Genotypes at 37,740 SNPs that were common to Illumina BovineSNP50 and high-density panels were phased for ~58,000 New Zealand dairy cattle. Females born before 1 June 2008 were used for training, and genomic predictions for milk fat yield (n = 24,823), liveweight (n = 13,283) and somatic cell score (n = 24,864) were validated within breed (predominantly Holstein Friesian, predominantly Jersey, or admixed KiwiCross) in later-born females. Covariates for haplotype alleles of five lengths (125, 250, 500 kb, 1 or 2 Mb) were generated and rare haplotypes were removed at four thresholds (1, 2, 5 or 10%), resulting in 20 scenarios tested. Genomic predictions fitting covariates for either SNPs or haplotypes were calculated by using BayesA, BayesB or BayesN. This is the first study to quantify the accuracy of genomic prediction using haplotypes across the whole genome in an admixed population. RESULTS: A correlation of 0.349 +/- 0.016 between yield deviation and genomic breeding values was obtained for milk fat yield in Holstein-Friesians using BayesA fitting covariates. Genomic predictions were more accurate with short haplotypes than with SNPs but less accurate with longer haplotypes than with SNPs. Fitting only the most frequent haplotype alleles reduced computation time with little decrease in prediction accuracy for short haplotypes. Trends were similar for all traits and breeds and there was little difference between Bayesian methods. CONCLUSIONS: Fitting covariates for haplotype alleles rather than SNPs can increase prediction accuracy, although it decreased drastically for long (>500 kb) haplotypes. In this population, fitting 250 kb haplotypes with a 1% frequency threshold resulted in the highest genomic prediction accuracy and fitting 125 kb haplotypes with a 10% frequency threshold improved genomic prediction accuracy with comparable computation time to fitting SNPs. This increased accuracy is likely to increase genetic gain by changing the ranking of selection candidates. PMID- 28673234 TI - Genomic variability in Mexican chicken population using copy number variants. AB - BACKGROUND: Copy number variations are genome polymorphism that influence phenotypic variation and are an important source of genetic variation in populations. The aim of this study was to investigate genetic variability in the Mexican Creole chicken population using CNVs. RESULTS: The Hidden Markov Model of the PennCNV software detected a total of 1924 CNVs in the genome of the 256 samples processed with Axiom(r) Genome-Wide Chicken Genotyping Array (Affymetrix). The mapped CNVs comprised 1538 gains and 386 losses, resulting at population level in 1216 CNV regions (CNVRs), of which 959 gains, 226 losses and 31 complex (i.e. containing both losses and gains). The CNVRs covered a total of 47 Mb of the whole genome sequence length, corresponding to 5.12% of the chicken galGal4 autosome assembly. CONCLUSIONS: This study allowed a deep insight into the structural variation in the genome of unselected Mexican chicken population, which up to now has not been genetically characterized. The genomic study disclosed that the population, even if presenting extreme morphological variation, cannot be organized in differentiated genetic subpopulations. Finally this study provides a chicken CNV map based on the 600 K SNP chip array jointly with a genome-wide gene copy number estimates in a native unselected for more than 500 years chicken population. PMID- 28673236 TI - Erratum to: comparative genomics and evolution of the amylase-binding proteins of oral streptococci. PMID- 28673235 TI - Comparative analysis of lincRNA in insect species. AB - BACKGROUND: The ever increasing availability of genomes makes it possible to investigate and compare not only the genomic complements of genes and proteins, but also of RNAs. One class of RNAs, the long noncoding RNAs (lncRNAs) and, in particular, their subclass of long intergenic noncoding RNAs (lincRNAs) have recently gained much attention because of their roles in regulation of important biological processes such as immune response or cell differentiation and as possible evolutionary precursors for protein coding genes. lincRNAs seem to be poorly conserved at the sequence level but at least some lincRNAs have conserved structural elements and syntenic genomic positions. Previous studies showed that transposable elements are a main contribution to the evolution of lincRNAs in mammals. In contrast, plant lincRNA emergence and evolution has been linked with local duplication events. However, little is known about their evolutionary dynamics in general and in insect genomes in particular. RESULTS: Here we compared lincRNAs between seven insect genomes and investigated possible evolutionary changes and functional roles. We find very low sequence conservation between different species and that similarities within a species are mostly due to their association with transposable elements (TE) and simple repeats. Furthermore, we find that TEs are less frequent in lincRNA exons than in their introns, indicating that TEs may have been removed by selection. When we analysed the predicted thermodynamic stabilities of lincRNAs we found that they are more stable than their randomized controls which might indicate some selection pressure to maintain certain structural elements. We list several of the most stable lincRNAs which could serve as prime candidates for future functional studies. We also discuss the possibility of de novo protein coding genes emerging from lincRNAs. This is because lincRNAs with high GC content and potentially with longer open reading frames (ORF) are candidate loci where de novo gene emergence might occur. CONCLUSION: The processes responsible for the emergence and diversification of lincRNAs in insects remain unclear. Both duplication and transposable elements may be important for the creation of new lincRNAs in insects. PMID- 28673237 TI - Contribution of pilus type 2b to invasive disease caused by a Streptococcus agalactiae ST-17 strain. AB - BACKGROUND: Group B Streptococcus (GBS) is a major cause of invasive disease especially in neonates. In GBS three structurally distinct pilus polymers have been identified as important virulence factors and promising vaccine candidates. The vast majority of Group B Streptococci belonging to the hypervirulent serotype III ST-17 lineage bear pilus types 1 and 2b. The purpose of this study was to investigate the relative contribution of these two pilus types to the pathogenesis of a ST-17 strain. RESULTS: We performed in vivo and in vitro analysis of isogenic knockout mutants derived from the GBS COH1 ST-17 strain deprived of either pilus type 1 or 2b. We compared the two pilus mutants with the wild type strain in a mouse model of invasive disease, in vitro survival in macrophages, and adherence/invasion assays using human brain endothelial and lung epithelial cell lines. Significantly less of the pilus 2b mutant was recovered from the blood, lungs and brain tissue of infected mice compared to the wild-type and pilus 1 mutant strains. Further, while the pilus 2b mutant survived similarly in murine macrophages, it exhibited a lower capacity to adhere and invade human brain epithelial and lung endothelial cell lines. CONCLUSIONS: The data suggest an important role of pilus 2b in mediating GBS infection and host cell interaction of strains belonging to the hypervirulent GBS ST-17 lineage. PMID- 28673239 TI - Erratum to: Impact of e-publication changes in the International Code of Nomenclature for algae, fungi and plants (Melbourne Code, 2012) - did we need to "run for our lives"? PMID- 28673238 TI - Report of an unsual case of anophthalmia and craniofacial cleft in a newborn with Toxoplasma gondii congenital infection. AB - BACKGROUND: We present one unusual case of anophthalmia and craniofacial cleft, probably due to congenital toxoplasmosis only. CASE PRESENTATION: A two-month-old male had a twin in utero who disappeared between the 7th and the 14th week of gestation. At birth, the baby presented anophthalmia and craniofacial cleft, and no sign compatible with genetic or exposition/deficiency problems, like the Wolf Hirschhorn syndrome or maternal vitamin A deficiency. Congenital toxoplasmosis was confirmed by the presence of IgM abs and IgG neo-antibodies in western blot, as well as by real time PCR in blood. CMV infection was also discarded by PCR and IgM negative results. Structures suggestive of T. gondii pseudocysts were observed in a biopsy taken during the first functional/esthetic surgery. CONCLUSIONS: We conclude that this is a rare case of anophthalmia combined with craniofacial cleft due to congenital toxoplasmosis, that must be considered by physicians. This has not been reported before. PMID- 28673240 TI - Association of Platelet to lymphocyte ratio with non-culprit atherosclerotic plaque vulnerability in patients with acute coronary syndrome: an optical coherence tomography study. AB - BACKGROUND: The platelet to lymphocyte ratio (PLR), an indirect inflammatory biomarker, has been recently demonstrated to be associated with severity of coronary artery disease. In the present study, we sought to investigate whether PLR is associated with vulnerable plaque characteristics of non-culprit lesions in patients with acute coronary syndrome (ACS). METHODS: The patients in our study were divided into two groups (high PLR group and low PLR group). A total of 119 non-culprit plaques from 71 patients with ACS were assessed by optical coherence tomography (OCT). RESULTS: The non-culprit plaques in high PLR group exhibited thinner fibrous cap thickness (FCT) (88.60 +/- 44.70 vs. 119.28 +/- 50.22 MUm, P = 0.001), greater maximum lipid arc (271.73 +/- 71.66 vs. 240.60 +/- 76.69 degrees , P = 0.027) and increased incidence of thin-cap fibroatheroma (TCFA) (34.0% vs. 15.9%, P = 0.022) compared with those in low PLR group. Meanwhile, PLR was negatively associated with FCT (r = -0.329, P < 0.001). Furthermore, multivariate regression analysis showed that PLR [OR: 1.023 (95% CI: 1.005-1.041), P = 0.012] and LDL-C [OR: 1.892 (95% CI: 1.106-3.239), P = 0.020] were significant predictors of TCFA. CONCLUSIONS: High level of PLR may be associated with vulnerable plaque features of non-culprit lesions in patients with ACS. PLR, a cheap and easily available index, may surve as a useful inflammatory marker in reflecting plaque vulnerability. PMID- 28673241 TI - Effects of melanin from Sepiella Maindroni ink (MSMI) on the intestinal Microbiome of mice. AB - BACKGROUND: By the search for new natural compounds with beneficial health effects, cephalopod ink has been considered as an attempt to develop new drugs and functional foods, which is an especially active field in Asia, where cephalopods are a major fishery catch, for which ink sacs are a bi-product and where homeopathic medicine has deep roots. There is a demand to evaluate the safety and influence to the organism. The specific composition and relative abundance of the gut microbiota, which is potentially a major modulator of host metabolism, drives the interaction between functional foods and host health. We explore the effects of melanin from Sepiella Maindroni, most common cuttlefish in China, on the intestinal microbiome of mice. RESULTS: ICR mice were randomly divided four groups, which were normal group (S), low melanin dose group (D; 120 mg/kg), medium melanin dose group (Z; 240 mg/kg), and high melanin dose group (G; 480 mg/kg). Melanin was delivered for 28 consecutive days. Fecal samples were used to generate 7715 operational taxonomic units (OTUs) via high-throughput sequencing. There were significant shifts in relative abundance of the dominant taxa at the phylum, class, order, family, and genus levels following melanin treatment. CONCLUSIONS: MSMI had no significant effect on the structure of intestinal flora in mice. The main effect was in the proportion of dominant bacterial communities. The effect positively correlated with the dose. From a health point of view, the use of melanin does not cause intestinal flora disorder. Our results may have important implications for MSMI as functional food component and potential therapeutic for manipulating gut microbiota. PMID- 28673242 TI - The PIN gene family in cotton (Gossypium hirsutum): genome-wide identification and gene expression analyses during root development and abiotic stress responses. AB - BACKGROUND: Cell elongation and expansion are significant contributors to plant growth and morphogenesis, and are often regulated by environmental cues and endogenous hormones. Auxin is one of the most important phytohormones involved in the regulation of plant growth and development and plays key roles in plant cell expansion and elongation. Cotton fiber cells are a model system for studying cell elongation due to their large size. Cotton is also the world's most utilized crop for the production of natural fibers for textile and garment industries, and targeted expression of the IAA biosynthetic gene iaaM increased cotton fiber initiation. Polar auxin transport, mediated by PIN and AUX/LAX proteins, plays a central role in the control of auxin distribution. However, very limited information about PIN-FORMED (PIN) efflux carriers in cotton is known. RESULTS: In this study, 17 PIN-FORMED (PIN) efflux carrier family members were identified in the Gossypium hirsutum (G. hirsutum) genome. We found that PIN1-3 and PIN2 genes originated from the At subgenome were highly expressed in roots. Additionally, evaluation of gene expression patterns indicated that PIN genes are differentially induced by various abiotic stresses. Furthermore, we found that the majority of cotton PIN genes contained auxin (AuxREs) and salicylic acid (SA) responsive elements in their promoter regions were significantly up-regulated by exogenous hormone treatment. CONCLUSIONS: Our results provide a comprehensive analysis of the PIN gene family in G. hirsutum, including phylogenetic relationships, chromosomal locations, and gene expression and gene duplication analyses. This study sheds light on the precise roles of PIN genes in cotton root development and in adaption to stress responses. PMID- 28673243 TI - Genetic effects of PDGFRB and MARCH1 identified in GWAS revealing strong associations with semen production traits in Chinese Holstein bulls. AB - BACKGROUND: Using a genome-wide association study strategy, our previous study discovered 19 significant single-nucleotide polymorphisms (SNPs) related to semen production traits in Chinese Holstein bulls. Among them, three SNPs were within or close to the phosphodiesterase 3A (PDE3A), membrane associated ring-CH-type finger 1 (MARCH1) and platelet derived growth factor receptor beta (PDGFRB) genes. The present study was designed with the objectives of identifying genetic polymorphism of the PDE3A, PDGFRB and MARCH1 genes and their effects on semen production traits in a Holstein bull population. RESULTS: A total of 20 SNPs were detected and genotyped in 730 bulls. Association analyses using de-regressed estimated breeding values of each semen production trait revealed four statistically significant SNPs for one or more semen production traits (P < 0.05): one SNP was located downstream of PDGFRB and three SNPs were located in the promoter of MARCH1. Interestingly, for MARCH1, haplotype-based analysis revealed significant associations of haplotypes with semen volume per ejaculate. Furthermore, high expression of the MARCH1 gene was observed in sperm cells. One SNP (rs43445726) in the regulatory region of MARCH1 had a significant effect on gene expression. CONCLUSION: Our study demonstrated the significant associations of genetic variants of the PDGFRB and MARCH1 genes with semen production traits. The identified SNPs may serve as genetic markers to optimize breeding programs for semen production traits in Holstein bull populations. PMID- 28673244 TI - A comprehensive genomic pan-cancer classification using The Cancer Genome Atlas gene expression data. AB - BACKGROUND: The Cancer Genome Atlas (TCGA) has generated comprehensive molecular profiles. We aim to identify a set of genes whose expression patterns can distinguish diverse tumor types. Those features may serve as biomarkers for tumor diagnosis and drug development. METHODS: Using RNA-seq expression data, we undertook a pan-cancer classification of 9,096 TCGA tumor samples representing 31 tumor types. We randomly assigned 75% of samples into training and 25% into testing, proportionally allocating samples from each tumor type. RESULTS: We could correctly classify more than 90% of the test set samples. Accuracies were high for all but three of the 31 tumor types, in particular, for READ (rectum adenocarcinoma) which was largely indistinguishable from COAD (colon adenocarcinoma). We also carried out pan-cancer classification, separately for males and females, on 23 sex non-specific tumor types (those unrelated to reproductive organs). Results from these gender-specific analyses largely recapitulated results when gender was ignored. Remarkably, more than 80% of the 100 most discriminative genes selected from each gender separately overlapped. Genes that were differentially expressed between genders included BNC1, FAT2, FOXA1, and HOXA11. FOXA1 has been shown to play a role for sexual dimorphism in liver cancer. The differentially discriminative genes we identified might be important for the gender differences in tumor incidence and survival. CONCLUSIONS: We were able to identify many sets of 20 genes that could correctly classify more than 90% of the samples from 31 different tumor types using TCGA RNA-seq data. This accuracy is remarkable given the number of the tumor types and the total number of samples involved. We achieved similar results when we analyzed 23 non-sex-specific tumor types separately for males and females. We regard the frequency with which a gene appeared in those sets as measuring its importance for tumor classification. One third of the 50 most frequently appearing genes were pseudogenes; the degree of enrichment may be indicative of their importance in tumor classification. Lastly, we identified a few genes that might play a role in sexual dimorphism in certain cancers. PMID- 28673245 TI - Takotsubo cardiomyopathy complicated with apical thrombus formation on first day of the illness: a case report and literature review. AB - BACKGROUND: Takotsubo cardiomyopathy is characterized by transient systolic dysfunction of the apical and mid segments of the left ventricle in the absence of obstructive coronary artery disease. Intraventricular thrombus formation is a rare complication of Takotsubo cardiomyopathy and current data almost exclusively consists of isolated case reports and a few case series. Here we describe a case of Takotsubo cardiomyopathy with formation of an apical thrombus within 24 h of symptom onset, which has been reported in the literature only once previously, to the best of our knowledge. We have reviewed the available literature that may aid clinicians in their approach to the condition, since no published guidelines are available. CASE PRESENTATION: A 68-year-old Sri Lankan female presented to a local hospital with chest pain. Electrocardiogram (ECG) showed ST elevation, and antiplatelets, intravenous streptokinase and a high dose statin were administered. Despite this ST elevation persisted; however the coronary angiogram was negative for obstructive coronary artery disease. Echocardiogram revealed hypokinesia of the mid and apical segments of the left ventricle with typical apical ballooning and a sizable apical thrombus. She had recently had a viral infection and was also emotionally distressed as her sister was recently diagnosed with a terminal cancer. A diagnosis of Takotsubo cardiomyopathy was made and anticoagulation was started with heparin and warfarin. The follow up echocardiogram performed 1 week later revealed a small persistent thrombus, which had completely resolved at 3 weeks. CONCLUSION: Though severe systolic dysfunction is observed in almost all the patients with Takotsubo cardiomyopathy, intraventricular thrombus formation on the first day of the illness is rare. The possibility of underdiagnosis of thrombus can be prevented by early echocardiogram in Takotsubo cardiomyopathy. The majority of reports found in the literature review were of cases that had formed an intraventriclar thrombus within the first 2 weeks, emphasizing the importance of follow up echocardiography at least 2 weeks later. The management of a left ventricular thrombus in Takotsubo cardiomyopathy is controversial and in most cases warfarin and heparin were used for a short duration. PMID- 28673246 TI - Effects of AMPD1 gene C34T polymorphism on cardiac index, blood pressure and prognosis in patients with cardiovascular diseases: a meta-analysis. AB - BACKGROUND: The meta-analysis was aimed to evaluate the effects of AMPD1 gene C34T polymorphism on cardiac function indexes, blood pressure and prognosis in patients with cardiovascular diseases (CVD). METHODS: Eligible studies were retrieved through a comprehensive search of electronic databases and manual search. Then the high-quality studies met the rigorous inclusion and exclusion criteria, as well as related to the subject was selected for the study. Comprehensive data analyses were conducted using STATA software 12.0. RESULTS: The study results revealed that CVD patients with CT + TT genotype of AMPD1 C34T polymorphism presented elevated left ventricular ejection fraction (LVEF) (%) and reduced left ventricular end diastolic dimension (LVEDD) (mm) as compared with CC genotype, moreover, the subgroup analysis found that the LVEF (%) was markedly higher in heart failure (HF) patients carrying CT + TT genotype than CC genotype. Besides, the systolic blood pressure (SBP) (mmHg) in CVD patients with CT + TT genotype was obviously decreased in contrast with the CC genotype. Patients suffered from HF with different genotypes (CT + TT and CC) of AMPD1 C34T polymorphism exhibited no significant differences in total survival rate and cardiac survival rate. CONCLUSIONS: Our current meta-analysis indicated that the T allele of AMPD1 gene C34T polymorphism may be correlated with LVEF, LVEDD and SBP, which plays a protective role in the cardiac functions and blood pressure in CVD patients, but had no effects on total survival rate and cardiac survival rate for HF. PMID- 28673247 TI - De novo transcriptome analysis shows differential expression of genes in salivary glands of edible bird's nest producing swiftlets. AB - BACKGROUND: Edible bird's nest (EBN), produced from solidified saliva secretions of specific swiftlet species during the breeding season, is one of the most valuable animal by-products in the world. The composition and medicinal benefits of EBN have been extensively studied, however, genomic and transcriptomic studies of the salivary glands of these birds have not been conducted. RESULTS: The study described the transcriptomes of salivary glands from three swiftlet species (28 samples) generated by RNASeq. A total of 14,835 annotated genes and 428 unmapped genes were cataloged. The current study investigated the genes and pathways that are associated with the development of salivary gland and EBN composition. Differential expression and pathway enrichment analysis indicated that the expression of CREB3L2 and several signaling pathways involved in salivary gland development, namely, the EGFR, BMP, and MAPK signaling pathways, were up regulated in swiftlets producing white EBN (Aerodramus fuciphagus) and black EBN (Aerodramus maximus) compared with non-EBN-producing swiftlets (Apus affinis). Furthermore, MGAT, an essential gene for the biosynthesis of N-acetylneuraminic acid (sialic acid), was highly expressed in both white- and black-nest swiftlets compared to non-EBN-producing swiftlets. Interspecies comparison between Aerodramus fuciphagus and Aerodramus maximus indicated that the genes involved in N-acetylneuraminic and fatty acid synthesis were up-regulated in Aerodramus fuciphagus, while alanine and aspartate synthesis pathways were up-regulated in Aerodramus maximus. Furthermore, gender-based analysis revealed that N-glycan trimming pathway was significantly up-regulated in male Aerodramus fuciphagus from its natural habitat (cave) compared to their female counterpart. CONCLUSIONS: Transcriptomic analysis of salivary glands of different swiftlet species reveal differential expressions of candidate genes that are involved in salivary gland development and in the biosynthesis of various bioactive compounds found in EBN. PMID- 28673248 TI - Transcriptome analysis of Haloquadratum walsbyi: vanity is but the surface. AB - BACKGROUND: Haloquadratum walsbyi dominates saturated thalassic lakes worldwide where they can constitute up to 80-90% of the total prokaryotic community. Despite the abundance of the enigmatic square-flattened cells, only 7 isolates are currently known with 2 genomes fully sequenced and annotated due to difficulties to grow them under laboratory conditions. We have performed a transcriptomic analysis of one of these isolates, the Spanish strain HBSQ001 in order to investigate gene transcription under light and dark conditions. RESULTS: Despite a potential advantage for light as additional source of energy, no significant differences were found between light and dark expressed genes. Constitutive high gene expression was observed in genes encoding surface glycoproteins, light mediated proton pumping by bacteriorhodopsin, several nutrient uptake systems, buoyancy and storage of excess carbon. Two low expressed regions of the genome were characterized by a lower codon adaptation index, low GC content and high incidence of hypothetical genes. CONCLUSIONS: Under the extant cultivation conditions, the square hyperhalophile devoted most of its transcriptome towards processes maintaining cell integrity and exploiting solar energy. Surface glycoproteins are essential for maintaining the large surface to volume ratio that facilitates light and organic nutrient harvesting whereas constitutive expression of bacteriorhodopsin warrants an immediate source of energy when light becomes available. PMID- 28673249 TI - Comparative transcriptomics uncovers alternative splicing and molecular marker development in radish (Raphanus sativus L.). AB - BACKGROUND: Alternative splicing (AS) plays important roles in gene expression and proteome diversity. Single nucleotide polymorphism (SNP) and insertion/deletion (InDel) are abundant polymorphisms and co-dominant inheritance markers, which have been widely used in germplasm identification, genetic mapping and marker-assisted selection in plants. So far, however, little information is available on utilization of AS events and development of SNP and InDel markers from transcriptome in radish. RESULTS: In this study, three radish transcriptome datasets were collected and aligned to the reference radish genome. A total of 56,530 AS events were identified from three radish genotypes with intron retention (IR) being the most frequent AS type, which accounted for 59.4% of the total expressed genes in radish. In all, 22,412 SNPs and 9436 InDels were identified with an average frequency of 1 SNP/17.9 kb and 1 InDel/42.5 kb, respectively. A total of 43,680 potential SSRs were identified in 31,604 assembled unigenes with a density of 1 SSR/2.5 kb. The ratio of SNPs with nonsynonymous/synonymous mutations was 1.05:1. Moreover, 35 SNPs and 200 InDels were randomly selected and validated by Sanger sequencing, 83.9% of the SNPs and 70% of the InDels exhibited polymorphism among these three genotypes. In addition, the 15 SNPs and 125 InDels were found to be unevenly distributed on 9 linkage groups. Furthermore, 40 informative InDel markers were successfully used for the genetic diversity analysis on 32 radish accessions. CONCLUSIONS: These results would not only provide new insights into transcriptome complexity and AS regulation, but also furnish large amount of molecular marker resources for germplasm identification, genetic mapping and further genetic improvement of radish in breeding programs. PMID- 28673250 TI - Risk factors for measles death: Kyegegwa District, western Uganda, February September, 2015. AB - BACKGROUND: On 18 August 2015, Kyegegwa District reported eight deaths during a measles outbreak to the Uganda Ministry of Health (MoH). We investigated this death cluster to verify the cause, identify risk factors, and inform public health interventions. METHODS: We defined a probable measles case as onset of fever and generalised rash in a Kyegegwa District resident from 1 February - 15 September 2015, plus >=1 of the following: coryza, conjunctivitis, and cough. A confirmed measles case was a probable case with measles-specific IgM positivity. A measles death was a death of a probable or confirmed case-person. We conducted an active case-finding to identify measles patients who survived or died. In a case-control study, we compared risk factors between 16 measles patients who died (cases) and 48 who survived (controls), matched by age (+/-4 years) and village of residence. RESULTS: We identified 94 probable measles cases, 10 (11%) were confirmed by positive measles-specific IgM. Of the 64 probable measles patients aged <5 years, 16 died (case-fatality rate = 25%). In the case-control study, no history of vaccination against measles was found in 94% (15/16) among the case persons (i.e., measles patients who died) and 54% (26/48) among the controls (i.e., measles patients who survived) (ORM-H = 12; 95% CI = 1.6-104), while 56% (9/16) of case-persons and 67% (17/48) of controls (ORM-H = 2.3; 95% CI =0.74 7.4) did not receive vitamin A supplementation during illness. 63% (10/16) among the case-persons and 6.3% (3/48) of the controls (ORM-H = 33; 95% CI = 6.8-159) were not treated for measles illness at a health facility (a proxy for more appropriate treatment), while 38% (6/16) of the case-persons and 25% (12/48) of the controls (ORM-H = 2.5; 95% CI = 0.67-9.1) were malnourished. CONCLUSION: Lack of vaccination and no treatment in a health facility increased the risk for measles deaths. The one-dose measles vaccination currently in the national vaccination schedule had a protective effect against measles death. We recommended enhancing measles vaccination and adherence to measles treatment guidelines. PMID- 28673251 TI - Efficacy of an enhanced linkage to HIV care intervention at improving linkage to HIV care and achieving viral suppression following home-based HIV testing in rural Uganda: study protocol for the Ekkubo/PATH cluster randomized controlled trial. AB - BACKGROUND: Though home-based human immunodeficiency virus (HIV) counseling and testing (HBHCT) is implemented in many sub-Saharan African countries as part of their HIV programs, linkage to HIV care remains a challenge. The purpose of this study is to test an intervention to enhance linkage to HIV care and improve HIV viral suppression among individuals testing HIV positive during HBHCT in rural Uganda. METHODS: The PATH (Providing Access To HIV Care)/Ekkubo Study is a cluster-randomized controlled trial which compares the efficacy of an enhanced linkage to HIV care intervention vs. standard-of-care (paper-based referrals) at achieving individual and population-level HIV viral suppression, and intermediate outcomes of linkage to care, receipt of opportunistic infection prophylaxis, and antiretroviral therapy initiation following HBHCT. Approximately 600 men and women aged 18-59 who test HIV positive during district-wide HBHCT in rural Uganda will be enrolled in this study. Villages (clusters) are pair matched by population size and then randomly assigned to the intervention or standard-of care arm. Study teams visit households and participants complete a baseline questionnaire, receive HIV counseling and testing, and have blood drawn for HIV viral load and CD4 testing. At baseline, standard-of-care arm participants receive referrals to HIV care including a paper-based referral and then receive their CD4 results via home visit 2 weeks later. Intervention arm participants receive an intervention counseling session at baseline, up to three follow-up counseling sessions at home, and a booster session at the HIV clinic if they present for care. These sessions each last approximately 30 min and consist of counseling to help clients: identify and reduce barriers to HIV care engagement, disclose their HIV status, identify a treatment supporter, and overcome HIV related stigma through links to social support resources in the community. Participants in both arms complete interviewer-administered questionnaires at six and 12 months follow-up, HIV viral load and CD4 testing at 12 months follow-up, and allow access to their medical records. DISCUSSION: The findings of this study can inform the integration of a potentially cost-effective approach to improving rates of linkage to care and HIV viral suppression in HBHCT. If effective, this intervention can improve treatment outcomes, reduce mortality, and through its effect on individual and population-level HIV viral load, and decrease HIV incidence. TRIAL REGISTRATION: NCT02545673. PMID- 28673253 TI - An improved filtering algorithm for big read datasets and its application to single-cell assembly. AB - BACKGROUND: For single-cell or metagenomic sequencing projects, it is necessary to sequence with a very high mean coverage in order to make sure that all parts of the sample DNA get covered by the reads produced. This leads to huge datasets with lots of redundant data. A filtering of this data prior to assembly is advisable. Brown et al. (2012) presented the algorithm Diginorm for this purpose, which filters reads based on the abundance of their k-mers. METHODS: We present Bignorm, a faster and quality-conscious read filtering algorithm. An important new algorithmic feature is the use of phred quality scores together with a detailed analysis of the k-mer counts to decide which reads to keep. RESULTS: We qualify and recommend parameters for our new read filtering algorithm. Guided by these parameters, we remove in terms of median 97.15% of the reads while keeping the mean phred score of the filtered dataset high. Using the SDAdes assembler, we produce assemblies of high quality from these filtered datasets in a fraction of the time needed for an assembly from the datasets filtered with Diginorm. CONCLUSIONS: We conclude that read filtering is a practical and efficient method for reducing read data and for speeding up the assembly process. This applies not only for single cell assembly, as shown in this paper, but also to other projects with high mean coverage datasets like metagenomic sequencing projects. Our Bignorm algorithm allows assemblies of competitive quality in comparison to Diginorm, while being much faster. Bignorm is available for download at https://git.informatik.uni-kiel.de/axw/Bignorm . PMID- 28673252 TI - Comparative muscle transcriptome associated with carcass traits of Nellore cattle. AB - BACKGROUND: Commercial cuts yield is an important trait for beef production, which affects the final value of the products, but its direct determination is a challenging procedure to be implemented in practice. The measurement of ribeye area (REA) and backfat thickness (BFT) can be used as indirect measures of meat yield. REA and BFT are important traits studied in beef cattle due to their strong implication in technological (carcass yield) and nutritional characteristics of meat products, like the degree of muscularity and total body fat. Thus, the aim of this work was to study the Longissimus dorsi muscle transcriptome of Nellore cattle, associated with REA and BFT, to find differentially expressed (DE) genes, metabolic pathways, and biological processes that may regulate these traits. RESULTS: By comparing the gene expression level between groups with extreme genomic estimated breeding values (GEBV), 101 DE genes for REA and 18 for BFT (false discovery rate, FDR 10%) were identified. Functional enrichment analysis for REA identified two KEGG pathways, MAPK (Mitogen-Activated Protein Kinase) signaling pathway and endocytosis pathway, and three biological processes, response to endoplasmic reticulum stress, cellular protein modification process, and macromolecule modification. The MAPK pathway is responsible for fundamental cellular processes, such as growth, differentiation, and hypertrophy. For BFT, 18 biological processes were found to be altered and grouped into 8 clusters of semantically similar terms. The DE genes identified in the biological processes for BFT were ACHE, SRD5A1, RSAD2 and RSPO3. RSAD2 has been previously shown to be associated with lipid droplet content and lipid biosynthesis. CONCLUSION: In this study, we identified genes, metabolic pathways, and biological processes, involved in differentiation, proliferation, protein turnover, hypertrophy, as well as adipogenesis and lipid biosynthesis related to REA and BFT. These results enlighten some of the molecular processes involved in muscle and fat deposition, which are economically important carcass traits for beef production. PMID- 28673255 TI - Prevalence of malnutrition and associated factors among hospitalized elderly patients in King Abdulaziz University Hospital, Jeddah, Saudi Arabia. AB - BACKGROUND: Malnutrition is a nutritional disorder that adversely affects the body from a functional or clinical perspective. It is very often observed in the elderly population. This study aimed to estimate the prevalence of malnutrition among hospitalized elderly patients and its associated factors and outcomes in terms of length of stay and mortality in King Abdulaziz University Hospital, Jeddah, Saudi Arabia. METHODS: In a cross-sectional study, we evaluated the nutritional status of hospitalized elderly patients using the most recent version of the short form of Mini Nutritional Assessment (MNA-SF). RESULTS: A total of 248 hospitalized patients were included (70.0 +/- 7.7 years; 60% female). According to the MNA-SF, a total of 76.6% patients were either malnourished or at risk of malnutrition. Malnourished patients had significantly lower levels of serum albumin (28.2 +/- 7.7), hemoglobin (10.5 +/- 1.8), and lymphocyte (1.7 +/- 0.91). They had increased tendency to stay in the hospital for longer durations (IQR, 5-11 days; median = 7 days) and had a mortality rate of 6.9%. CONCLUSION: Malnutrition was highly prevalent among hospitalized elderly and was associated with increased length of stay and mortality. PMID- 28673254 TI - A cross-sectional study to evaluate second line virological failure and elevated bilirubin as a surrogate for adherence to atazanavir/ritonavir in two urban HIV clinics in Lilongwe, Malawi. AB - BACKGROUND: Malawi's national antiretroviral therapy program provides atazanavir/ritonavir-based second line regimens which cause concentration dependent rise in indirect bilirubin. We sought to determine if elevated bilirubin, as a surrogate of atazanavir/ritonavir adherence, can aid in the evaluation of second line virological failure in Malawi. METHODS: We conducted a cross-sectional study of HIV-infected patients >=15 years who were on boosted protease inhibitor-based second line antiretroviral therapy for at least 6 months in two urban HIV clinics in Lilongwe, Malawi. Antiretroviral therapy history and adherence data were extracted from the electronic medical records and blood was drawn for viral load, complete blood count, total bilirubin, and CD4 cell count at a clinic visit. Factors associated with virological failure were assessed using multivariate logistic regression model. RESULTS: Out of 376 patients on second line antiretroviral therapy evaluated, 372 (98.9%) were on atazanavir/ritonavir-based therapy and 142 (37.8%) were male. Mean age was 40.9 years (SD +/- 10.1), mean duration on second line antiretroviral therapy was 41.9 months (SD +/- 27.6) and 256 patients (68.1%) had elevated bilirubin >1.3 mg/dL. Overall, 35 (9.3%) patients had viral load >1000 copies/ml (virological failure). Among the virologically failing vs. non-failing patients, bilirubin was elevated in 34.3% vs. 72.0% respectively (p < 0.001), although adherence by pill count was similar (62.9% vs. 60.7%, p = 0.804). The odds of virological failure were higher for adults aged 25-40 years (adjusted odds ratio (aOR) 2.5, p = 0.048), those with CD4 cell count <100 (aOR 17.5, p < 0.001), and those with normal bilirubin levels (aOR 5.4, p < 0.001); but were lower for the overweight/obese patients (aOR 0.3, p = 0.026). Poor pill count adherence (aOR 0.7, p = 0.4) and male gender (aOR 1.2, p = 0.698) were not associated with second line virological failure. CONCLUSIONS: Among patients receiving atazanavir/ritonavir-based second line antiretroviral therapy, bilirubin levels better predicted virological failure than pill count adherence. Therefore, strategic use of bilirubin and viral load testing to target adherence counseling and support may be cost effective in monitoring second line antiretroviral therapy adherence and virological failure. Drug resistance testing targeted for patients with virological failure despite elevated bilirubin levels would facilitate timely switch to third line antiretroviral regimens whenever available. PMID- 28673256 TI - Cryptococcosis in patients with hematological diseases: a 14-year retrospective clinical analysis in a Chinese tertiary hospital. AB - BACKGROUND: Cryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare. METHODS: HIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed. RESULTS: In total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35-0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events. CONCLUSIONS: CNS cryptococcal infection was more frequent in patients with hematological non malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases. PMID- 28673257 TI - Experiences of end of life amongst family carers of people with advanced dementia: longitudinal cohort study with mixed methods. AB - BACKGROUND: Many studies have examined the mental health of carers of people with dementia. Few have examined their experiences in the advanced stages of disease and into bereavement. We aimed to understand the experiences of carers during advanced dementia exploring the links between mental health and experiences of end of life care. METHODS: Mixed methods longitudinal cohort study. Thirty-five family carers of people with advanced dementia (6 at home, 29 in care homes) were recruited and assessed monthly for up to nine months or until the person with dementia died, then at two and seven months into bereavement. Assessments included: Hospital Anxiety and Depression Scale, Short Form 12 health-related quality of life, 22-item Zarit Burden Interview, Brief Coping Orientation to Problems Experienced, Inventory of Complicated Grief and Satisfaction with Care at End of Life in Dementia. Subsequently, 12 carers (34%) were bereaved and 12 undertook a qualitative interview two months after death; these data were analysed thematically. We analysed quantitative and qualitative data independently and then merged findings at the point of interpretation. RESULTS: At study entry psychological distress was high; 26% reached caseness for depression and 41% for anxiety and median complicated grief scores were 27 [IQR 22-37] indicating that on average 11 of the 16 grief symptoms occurred at least monthly. Physical health reflected population norms (mean = 50) and median burden scores were 17 [IQR 9-30]. Three qualitative themes were identified: the importance of relationships with care services, understanding of the progression of dementia, and emotional responses to advanced dementia. An overarching theme tying these together was the carer's ability to control and influence end of life care. CONCLUSIONS: While carers report high levels of psychological distress during advanced dementia, the experience of end of life care in dementia may be amenable to change with the provision of sensitive and timely information about the natural progression of dementia. Regular health status updates and end of life discussions can help families understand dementia progression and prepare for end of life. The extent to which our findings reflect practice across the UK or internationally warrants further investigation. PMID- 28673258 TI - Differential regulation of miRNA and mRNA expression in the myocardium of Nrf2 knockout mice. PMID- 28673259 TI - Cost-effectiveness analysis of N95 respirators and medical masks to protect healthcare workers in China from respiratory infections. AB - BACKGROUND: There are substantial differences between the costs of medical masks and N95 respirators. Cost-effectiveness analysis is required to assist decision makers evaluating alternative healthcare worker (HCW) mask/respirator strategies. This study aims to compare the cost-effectiveness of N95 respirators and medical masks for protecting HCWs in Beijing, China. METHODS: We developed a cost effectiveness analysis model utilising efficacy and resource use data from two cluster randomised clinical trials assessing various mask/respirator strategies conducted in HCWs in Level 2 and 3 Beijing hospitals for the 2008-09 and 2009-10 influenza seasons. The main outcome measure was the incremental cost effectiveness ratio (ICER) per clinical respiratory illness (CRI) case prevented. We used a societal perspective which included intervention costs, the healthcare costs of CRI in HCWs and absenteeism costs. RESULTS: The incremental cost to prevent a CRI case with continuous use of N95 respirators when compared to medical masks ranged from US $490-$1230 (approx. 3000-7600 RMB). One-way sensitivity analysis indicated that the CRI attack rate and intervention effectiveness had the greatest impact on cost-effectiveness. CONCLUSIONS: The determination of cost-effectiveness for mask/respirator strategies will depend on the willingness to pay to prevent a CRI case in a HCW, which will vary between countries. In the case of a highly pathogenic pandemic, respirator use in HCWs would likely be a cost-effective intervention. PMID- 28673260 TI - Gene expression variations in high-altitude adaptation: a case study of the Asiatic toad (Bufo gargarizans). AB - BACKGROUND: Genome-wide investigation of molecular mechanisms for high-altitude adaptation has attracted great attention in the last few years. In order to understand the contribution of gene expression level variations to high-altitude adaptation in Asiatic toads (Bufo gargarizans), we implemented a reciprocal transplant experiment between low- and high-altitude sites and sequenced 12 transcriptomes from brain, heart, and liver tissues. RESULTS: A large number of genes with expression differences (DEGs) between high- and low-altitude individuals (193 fixed and 844 plastic) were identified, and the majority of them were tissue specific. Heart displayed the largest number of DEGs, both plastic and fixed. Fixed DEGs were particularly concentrated in functions associated with muscle contraction, and the majority of them were down-regulated in high-altitude individuals. Plastic DEGs were highly concentrated in several energy metabolism related functional categories, and the majority of them were also down-regulated at high-altitude environments. In liver samples, genes associated with nutrient metabolism experienced a broad-scale expression down-regulation in high-altitude toads. CONCLUSIONS: These broadly suppressed expression patterns at high altitudes are in strong contrast to those of endothermic homeotherms, suggesting poikilothermic vertebrates may have adopted different strategies at high altitudes. Our results strongly support that both genotypic specialization and phenotypic plasticity play crucial role in adaptation to high altitude for Asiatic toads. Poikilothermic vertebrates are among the most hypoxia-tolerant animals known, and many molecular mechanisms remain elusive. We hope that our results will provide useful directions for future research. PMID- 28673261 TI - Paternal personality and social status influence offspring activity in zebrafish. AB - BACKGROUND: Evidence for the transmission of non-genetic information from father to offspring is rapidly accumulating. While the impact of chemical and physical factors such as toxins or diet on the fitness of the parents and their offspring have been studied extensively, the importance of behavioural and social circumstances has only recently been recognised. Behavioural traits such as personality characteristics can be relatively stable, and partly comprise a genetic component but we know little about the non-genetic transmission of plastic behavioural traits from parents to offspring. We investigated the relative effect of personality and of social dominance as indicators at the opposite ends of the plasticity range on offspring behaviour in the zebrafish (Danio rerio). We assessed male boldness, a behavioural trait that has previously been shown previously to possess genetic underpinnings, and experimentally manipulated male social status to assess the association between the two types of behaviour and their correlation with offspring activity. RESULTS: We found a clear interaction between the relatively stable and putative genetic effects based on inherited differences in personality and the experimentally induced epigenetic effects from changes in the social status of the father on offspring activity. CONCLUSIONS: Our study shows that offspring behaviour is determined by a combination of paternal personality traits and on-genetic effects derived from the social status of the father. PMID- 28673262 TI - Increasing the treatment motivation of patients with somatic symptom disorder: applying the URICA-S scale. AB - BACKGROUND: Therapeutic intervention programs for somatic symptom disorder (SSD) show only small-to-moderate effect sizes. These effects are partly explained by the motivational problems of SSD patients. Hence, fostering treatment motivation could increase treatment success. One central aspect in SSD patients might be damage to motivation because of symptomatic relapses. Consequently, the aim of the present study was to investigate associations between motivational relapse struggle and therapeutic outcome in SSD patients. METHODS: We assessed 84 inpatients diagnosed with SSD in the early, middle and late stages of their inpatient treatment. The maintenance subscale of the University of Rhode Island Change Assessment-Short (URICA-S) was applied as a measure to assess motivational relapse struggle. Additionally, patients completed measures of treatment outcome that focus on clinical symptoms, stress levels and interpersonal functioning. RESULTS: The results from multiple regression analyses indicate that higher URICA S maintenance scores assessed in early stages of inpatient treatment were related to more negative treatment outcomes in SSD patients. CONCLUSIONS: SSD patients with ambivalent treatment motivation may fail in their struggle against relapse over the course of therapy. The URICA-S maintenance score assessed at therapy admission facilitated early identification of SSD patients who are at greater risk of relapse. Future studies should incorporate randomized controlled trials to investigate whether this subgroup could benefit from motivational interventions that address relapse. PMID- 28673263 TI - Dietary diversity is related to socioeconomic status among adult Saharawi refugees living in Algeria. AB - BACKGROUND: There is limited knowledge about dietary quality among the adult population in low- and middle income countries (LMICs). This study aims to describe dietary quality among the adult Saharawi refugee population and to investigate whether dietary quality is associated with socioeconomic status. METHODS: In 2014, a cross-sectional survey was carried out in the Saharawi refugee camps, Algeria. A three-staged cluster sampling was performed and 180 women and 175 men, aged 18-82 years, were randomly selected. The dietary intake was assessed by 24-h dietary recall and dietary diversity score (DDS) was calculated. Socioeconomic status was assessed using the WAMI index (sanitation, assets, education and income). RESULTS: The mean DDS among the total sample was 3.8 +/- 1.4 and 2/3 of participant were at risk of low dietary adequacy. The main food groups consumed were starchy staple foods, flesh foods, and dairy. Vitamin A rich dark green leafy vegetables, nuts and seeds and eggs were the food groups least consumed. The multiple regression model showed a positive association between DDS and the WAMI index (P < 0.001) and a negative association between DDS and age (p = 0.01). CONCLUSIONS: Low DDS was associated with low socioeconomic status. Programmes to improve the dietary quality among the Saharawi refugees should be implemented. PMID- 28673264 TI - Distribution of axial length in Chinese congenital ectopia lentis patients: a retrospective study. AB - BACKGROUND: Congenital ectopia lentis (CEL) usually leads to refractive error and may influence the axial length development. But few investigations have reported patient demographics and the distribution of axial length (AL) before surgery in Chinese pediatric patients with CEL. To describe the distribution of AL before surgery in CEL patients and its relationship with patients' demographics, such as age, Marfan syndrome, sex, and laterality. METHODS: This retrospective study reviewed 306 CEL patients from January 1, 2006 to December 31, 2015. One eye was randomly selected from each patient if both eyes were EL. The influences of Marfan syndrome, sex, and laterality to AL in different age subgroups were evaluated and compared. The differences of the AL between groups were assessed using the student t test or paired t-test. P-values less than 0.05 were considered statistically significant. RESULTS: Two hundred forty-seven eyes were enrolled. 58.3% of all the patients had binoculus EL, 70% of all the patients were male and 36% of all the patients were diagnosed with Marfan syndrome. The mean AL of EL patients was 25.1 +/- 2.5 mm. There was no statistical difference in the AL between patients with and without Marfan syndrome, and in the AL between male and female patients. There was statistical difference in AL between the EL-affected eye and the unaffected eye in monocular EL patients younger than 12 years old. CONCLUSIONS: This study suggests that AL can be influenced by CEL, but the influence of CEL may be reduced after the age of 12 years old, which will likely provide a useful reference when considering the most appropriate time of surgery. PMID- 28673265 TI - A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein intervention). AB - BACKGROUND: Elevated serum levels of luteinizing hormone and slightly decreased serum levels of testosterone (mild Leydig cell insufficiency) is a common hormonal disturbance in testicular cancer (TC) survivors. A number of studies have shown that low serum levels of testosterone is associated with low grade inflammation and increased risk of metabolic syndrome. However, so far, no studies have evaluated whether testosterone substitution improves metabolic dysfunction in TC survivors with mild Leydig cell insufficiency. METHODS/DESIGN: This is a single-center, randomized, double-blind, placebo-controlled study, designed to evaluate the effect of testosterone replacement therapy in TC survivors with mild Leydig cell insufficiency. Seventy subjects will be randomized to receive either testosterone replacement therapy or placebo. The subjects will be invited for an information meeting where informed consent will be obtained. Afterwards, a 52-weeks treatment period begins in which study participants will receive a daily dose of transdermal testosterone or placebo. Dose adjustment will be made three times during the initial 8 weeks of the study to a maximal daily dose of 40 mg of testosterone in the intervention arm. Evaluation of primary and secondary endpoints will be performed at baseline, 26 weeks post-randomization, at the end of treatment (52 weeks) and 3 months after completion of treatment (week 64). DISCUSSION: This study is the first to investigate the effect of testosterone substitution in testicular cancer survivors with mild Leydig cell insufficiency. If positive, it may change the clinical handling of testicular cancer survivors with borderline low levels of testosterone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02991209 (November 25, 2016). PMID- 28673266 TI - Ultra-widefield fundus imaging in gas-filled eyes after vitrectomy. AB - BACKGROUND: To evaluate the quality of the images obtained by an ultra-widefield device in gas-filled eyes after vitrectomy for a retinal detachment. METHODS: Retrospective case series. The ultra-widefield scanning laser ophthalmoscopic images (Optos 200Tx imaging system) of 40 eyes that were gas-filled with 40 to 90% of the vitreous cavity after vitrectomy for a rhegmatogenous retinal detachment were studied. The rates of detecting the rates of reattachments and the causative retinal tears that were treated and were in the superior or inferior areas in eyes with intravitreal gas of >=60% were compared to that to eyes with intravitreal gas of <60% of the vitreous cavity. The widefield images recorded with 532 nm (green) or 633 nm (red) wavelength laser lights were compared to determine which wavelength had clearer images in 20 eyes of retinal detachment with superior retinal tears and were more than 50% gas-filled. RESULTS: The ultra-widefield images showed a retinal reattachment in all eyes on postoperative days 1 to 40 (mean; 8.7 +/- 7.5 days). A superior retinal break was not visible in 5 of 26 eyes due to a reflection from the intravitreal gas bubbles when the gas was <60%. However, the superior retinal breaks were visible when the patients were requested to gaze downward to reduce the reflection of the gas bubble. The retinal breaks treated with laser burns and the retinal vasculature were imaged better with green laser than red laser light, and the choroidal vasculature was seen better with red laser light. CONCLUSIONS: Ultra-widefield fundus images can be used to evaluate and document the retinal breaks and retinal reattachments in gas-filled eyes. The green and red laser lights can image different depths of the retina and choroid in gas-filled eyes. PMID- 28673267 TI - Sleep disturbances among Chinese clinical nurses in general hospitals and its influencing factors. AB - BACKGROUND: This study aimed to determine the prevalence of sleep disturbances among clinical nurses in general hospitals in Mainland China, and identify its associate factors. METHODS: Using a cross-sectional design, a total of 5012 clinical nurses selected by random cluster sampling completed the survey on the Pittsburgh Sleep Quality Index (PSQI), measures of quality of life indexed by the Medical Outcomes Study 12-item Short-Form Health Survey, occupational stress evaluated by the Job Content Questionnaire, lifestyle and sociodemographic details. RESULTS: The average PSQI score of 4951 subjects was 7.32 +/- 3.24, including 3163 subjects with PSQI >=5, accounting for 63.9%. Multivariate Logistic regression analysis showed that the risk factors for sleep disturbances in nurses were female gender, the Emergency department and ICU, many years of service, high night shift frequency, professional status: primary and intermediate, employment status: temporary, poor quality of life: poor mental health, low perceived health, high occupational stress (high psychological demand, low job control and low workplace social support). CONCLUSIONS: Sleep disturbances are highly prevalent among clinical nurses in general hospitals in Mainland China. Many of the factors listed above were associated with the prevalence of sleep disturbances in nurses, and occupational stress plays an important role in the development of sleep disturbances in Chinese clinical nurses. PMID- 28673268 TI - Confirmatory factor analysis and examination of the psychometric properties of the eating beliefs questionnaire. AB - BACKGROUND: The Eating Beliefs Questionnaire (EBQ) is a 27-item self-report measure that assesses positive and negative beliefs about binge eating. It has been validated and its factor structure explored in a non-clinical sample. This study tested the psychometric properties of the EBQ in a clinical and a non clinical sample. METHOD: A sample of 769 participants (573 participants recruited from the university and general community, 76 seeking treatment for an eating disorder and 120 participating in obesity research) completed a battery of questionnaires. A subset of clinical participants with a diagnosis of Bulimia Nervosa or Binge Eating Disorder completed the test-battery before and after receiving a psychological treatment (n = 27) or after allocation to a wait-list period (n = 28), and a subset of 35 community participants completed the test battery again after an interval of two-weeks. Confirmatory Factor Analysis (CFA) was performed. RESULTS: CFA found a two-factor structure that provided a good fit to the data, supporting the solution presented in the development paper. Items with poor psychometric properties were removed, resulting in a 16 item measure. EBQ scores were found to correlate with binge eating episode frequency, increases in body mass index (BMI), and measures of eating disorder behaviours and related psychopathology. The EBQ was found to have excellent internal consistency (alpha = .94), good test-retest reliability (r = .91) and sensitivity to treatment. CONCLUSION: These findings indicate that the EBQ is a psychometrically sound and clinically useful measure. PMID- 28673269 TI - Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury. AB - BACKGROUND: This study aimed to investigate the effects of regulating autonomic nervous system (ANS) homeostasis by inhibiting sympathetic hyperactivity and/or enhancing parasympathetic activity on pulmonary inflammation and functional disturbance. METHODS: An animal model of acute lung injury (ALI) was established in rabbits by an intratracheal injection of hydrochloric acid (HCl) in rabbits. Animals in control groups were received saline or HCl only, and the others received both HCl and followed treatments: vagus nerve stimulation (VNS), intravenous injection of tetrahydroaminoacridine (THA), or stellate ganglion block (SGB). The effects of different treatments on the changes in autonomic nervous system homeostasis, pulmonary and systemic inflammation, and functional disturbance were detected. RESULTS: Sympathetic nervous activity was higher than parasympathetic nervous activity in rabbits after HCl aspiration, as demonstrated by the significant changes in the discharge frequency of cervical sympathetic/vagus trunk, and heart rate variability. VNS, THA and SGB could significantly alleviate the changes of ANS induced by HCl aspiration and improved the pulmonary function, especially for SGB treatment. CONCLUSIONS: The disturbance of ANS homeostasis is attributed to a predominance of SNS activity. Administration of VNS, THA and SGB are capable to regulate disequilibrium of the ANS in rabbits with HCl-induced ALI and SGB is supposed to be the most effective approach. PMID- 28673271 TI - Attaching metabolic expenditures to standard occupational classification systems: perspectives from time-use research. AB - BACKGROUND: Traditionally, time-use data have been used to inform a broad range of economic and sociological research topics. One of the new areas in time-use research is the study of physical activity (PA) and physical activity energy expenditure (PAEE). Time-use data can be used to study PAEE by assigning MET values to daily activities using the Ainsworth Compendium of Physical Activities. Although most diarists record their daily activities accurately and in detail, they are only required to record their paid working hours, not the job-specific tasks they undertake. This makes it difficult to assign MET values to paid work episodes. METHODS: In this methodological paper, we explain how we addressed this problem by using the detailed information about respondents' occupational status included in time-use survey household and individual questionnaires. We used the 2008 ISCO manual, a lexicon of the International Labour Organization of occupational titles and their related job-specific tasks. We first assigned a MET value to job-specific tasks using the Ainsworth compendium (2011) then calculated MET values for each of the 436 occupations in the ISCO-08 manual by averaging all job-specific MET values for each occupation. RESULTS: The ISCO-08 Major Groups of 'elementary occupations' and 'craft and related trades workers' are associated with high PAEE variation in terms of their job-specific MET values and together represented 21.6% of the Belgian working population in 2013. We recommend that these occupational categories should be prioritised for further in-depth research into occupational activity (OA). CONCLUSIONS: We developed a clear and replicable procedure to calculate occupational activity for all ISCO-08 occupations. All of our calculations are attached to this manuscript which other researchers may use, replicate and refine. PMID- 28673270 TI - Built environment and physical activity: domain- and activity-specific associations among Brazilian adolescents. AB - BACKGROUND: Physical activity is likely to be determined as a complex interplay between personal, interpersonal, and environmental factors. Studying the built environment involves expanding the focus from the individual perspective to a public health one. Therefore, the objetive of this study was to examine the association between the built environment and objectively-measured physical activity among youth. METHODS: Cross-sectional analysis of data from of a Brazilian birth cohort during adolescence. Physical activity was measured using accelerometers (GENEActiv) and self-report (International Physical Activity Questionnaire, long version). Participants' home addresses were geocoded and built environment characteristics such as streets' pattern and quality, and public open spaces attributes for physical activity practice were evaluated in a 500-m circular buffer surrounding their homes. RESULTS: A total of 3379 participants were included. Street lighting (beta = 2.2; 95%CI: 0.5; 3.9) was positively associated with objectively-measured moderate-vigorous physical activity (MVPA) and proportion of paved streets and buffer's average family income were associated with lower MVPA. Living near the beach increased the odds of leisure-time MVPA practice by 3.3 (95%CI: 1.37; 8.02) times. There was a built environment-by-socioeconomic status (SES) interaction for the associations with commuting physical activity; street lighting [Odds ratio (OR) = 1.22; 95%CI: 1.01; 1.47] and presence of cycle lanes (OR = 1.77; 95%CI: 1.05; 2.96) were positively associated with commuting physical activity only among the intermediate SES tertile. CONCLUSION: Beachfront, street lighting, paved streets and cycle lanes were associated with physical activity patterns. This suggests that infrastructure interventions may influence physical activity levels of Brazilian adolescents. PMID- 28673272 TI - Identifying maternal needs following childbirth: A qualitative study among mothers, fathers and professionals. AB - BACKGROUND: Pregnancy and childbirth are two critical stages in a woman's life. Various studies have suggested that psychological distress is common during the year after childbirth. The objectives of this exploratory study were (1) to explore the needs of mothers in the year following childbirth; (2) to compare these needs between mothers who did not have the feeling of living a psychological disorder or a depression and mothers who lived a psychological disorder or had the impression of living a depression; and (3) to compare the needs expressed by mothers with the perception of professionals and fathers about the mothers' needs. METHODS: First, we proceeded to 22 individual qualitative interviews followed by one focus group, with mothers, with and without experience of psychological distress. Then, we conducted 2 focus groups: one with professionals and one with fathers. RESULTS: Needs of mothers after childbirth have been indexed in four categories: need of information, need of psychological support, need to share experience, and need of practical and material support. Women do not feel sufficiently informed about this difficult period of life. They do not feel sufficiently supported, not only from a psychological point of view but also from a more practical point of view, for example with household chores. They need to share their experience of life, they need to be reassured and they need to feel understood. It seems that some differences exist between mothers' and professionals' experiences but also between mothers' and fathers' experiences. CONCLUSION: Young mothers apparently feel a lack of support at different levels in the year following childbirth. This study provides ways to meet women's needs and to try to prevent the risk of postpartum psychological distress during this period of time. PMID- 28673273 TI - Dementia ascertainment using existing data in UK longitudinal and cohort studies: a systematic review of methodology. AB - BACKGROUND: Studies investigating the risk factors for or causation of dementia must consider subjects prior to disease onset. To overcome the limitations of prospective studies and self-reported recall of information, the use of existing data is key. This review provides a narrative account of dementia ascertainment methods using sources of existing data. METHODS: The literature search was performed using: MEDLINE, EMBASE, PsychInfo and Web of Science. Included articles reported a UK-based study of dementia in which cases were ascertained using existing data. Existing data included that which was routinely collected and that which was collected for previous research. After removing duplicates, abstracts were screened and the remaining articles were included for full-text review. A quality tool was used to evaluate the description of the ascertainment methodology. RESULTS: Of the 3545 abstracts screened, 360 articles were selected for full-text review. 47 articles were included for final consideration. Data sources for ascertainment included: death records, national datasets, research databases and hospital records among others. 36 articles used existing data alone for ascertainment, of which 27 used only a single data source. The most frequently used source was a research database. Quality scores ranged from 7/16 to 16/16. Quality scores were better for articles with dementia ascertainment as an outcome. Some papers performed validation studies of dementia ascertainment and most indicated that observed rates of dementia were lower than expected. CONCLUSIONS: We identified a lack of consistency in dementia ascertainment methodology using existing data. With no data source identified as a "gold standard", we suggest the use of multiple sources. Where possible, studies should access records with evidence to confirm the diagnosis. Studies should also calculate the dementia ascertainment rate for the population being studied to enable a comparison with an expected rate. PMID- 28673274 TI - Spatial variation and hot-spots of district level diarrhea incidences in Ghana: 2010-2014. AB - BACKGROUND: Diarrhea is a public health menace, especially in developing countries. Knowledge of the biological and anthropogenic characteristics is abundant. However, little is known about its spatial patterns especially in developing countries like Ghana. This study aims to map and explore the spatial variation and hot-spots of district level diarrhea incidences in Ghana. METHODS: Data on district level incidences of diarrhea from 2010 to 2014 were compiled together with population data. We mapped the relative risks using empirical Bayesian smoothing. The spatial scan statistics was used to detect and map spatial and space-time clusters. Logistic regression was used to explore the relationship between space-time clustering and urbanization strata, i.e. rural, peri-urban, and urban districts. RESULTS: We observed substantial variation in the spatial distribution of the relative risk. There was evidence of significant spatial clusters with most of the excess incidences being long-term with only a few being emerging clusters. Space-time clustering was found to be more likely to occur in peri-urban districts than in rural and urban districts. CONCLUSION: This study has revealed that the excess incidences of diarrhea is spatially clustered with peri-urban districts showing the greatest risk of space-time clustering. More attention should therefore be paid to diarrhea in peri-urban districts. These findings also prompt public health officials to integrate disease mapping and cluster analyses in developing location specific interventions for reducing diarrhea. PMID- 28673275 TI - Correlates of domestic waste management and related health outcomes in Sunyani, Ghana: a protocol towards enhancing policy. AB - BACKGROUND: Domestic waste generation has contributed significantly to hampering national waste management efforts. It poses serious threat to national development and requires proper treatment and management within and outside households. The problem of improper waste management has always been a challenge in Ghana, compelling several national surveys to report on the practice of waste management. However, little is known about how much waste is generated and managed within households and there is a serious dearth of information for national policy and planning. This paper seeks to document the handling and practice of waste management, including collection, storage, transportation and disposal along with the types and amount of waste generated by Households and their related health outcome. METHODS: The study was a descriptive cross sectional study and used a multi-stage sampling technique to sample 700 households. The study was planned and implemented from January to May 2015. It involved the use of structured questionnaires in the data collection over the period. Factors such as demographic characteristics, amount of waste generated, types of waste bins used within households, waste recycling, cost of disposing waste, and distance to dumpsite were all assessed. RESULTS: The paper shows that each surveyed household generated 0.002 t of waste per day, of which 29% are both organic and inorganic. Though more than half of the respondents (53.6%) had positive attitude towards waste management, only 29.1% practiced waste management. The study reveals that there is no proper management of domestic waste except in few households that segregate waste. The study identified several elements as determinants of waste management practice. Female respondents were less likely to practice waste management (AOR 0.45; 95% Cl 0.29, 0.79), household size also determined respondents practice (AOR 0.26; Cl 0.09, 0.77). Practice of recycling (AOR 0.03; Cl 0.02, 0.08), distance to dumpsite (AOR 0.45; Cl 0.20, 0.99), were all significant predictors of waste management practice. Cholera which is a hygiene related disease was three times more likely to determine households' waste management practice (AOR 3.22; Cl 1.33, 7.84). CONCLUSION: Considering the low waste management practice among households, there is the need for improved policy and enhanced education on proper waste management practice among households. PMID- 28673276 TI - Worldwide view of nephropathic cystinosis: results from a survey from 30 countries. AB - BACKGROUND: Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN]. METHODS: A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries. RESULTS: A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5-/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis. CONCLUSIONS: Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources. PMID- 28673277 TI - Impact of a protein-based assay that predicts prostate cancer aggressiveness on urologists' recommendations for active treatment or active surveillance: a randomized clinical utility trial. AB - BACKGROUND: Of the more than 1.1 million men diagnosed worldwide annually with prostate cancer, the majority have indolent tumors. Distinguishing between aggressive and indolent cancer is an important clinical challenge. The current approaches for assessing tumor aggressiveness are recognized as insufficient. A validated protein-based assay has been shown to predict tumor aggressiveness from prostate biopsy. The main objective of this study was to measure the clinical utility of this new assay in the management of early-stage prostate cancer. METHODS: One hundred twenty nine board-certified urologists were asked to participate in a randomized, two-arm experiment. We collected data over 2 rounds using simulated clinical cases administered via an online platform. The cases were all newly diagnosed Gleason 3 + 3 or 3 + 4 prostate camcer patients. Urologists in the intervention arm received a 15-min webinar on this protein based assay and given assay test results for their simulated patients in round 2. Each case had a preferred recommendation of either active surveillance or active treatment. The measured outcome was rate of preferred recommendation, defined as urologists who recommended the proper treatment course. Analyses were done using difference-in-difference estimations. RESULTS: Using multinomial logistical regression, urologists who were given the assay results were significantly more likely to choose the preferred recommendation (active surveillance or active treatment) compared to controls (p = 0.004). These urologists were also significantly more likely to involve their patients in the treatment decision compared to controls (p = 0.001). CONCLUSIONS: By providing additional information to inform the physician's treatment plan, a protein-based assay shows demonstrable clinical utility confirmed through a rigorous randomized controlled study design and regression analyses to test for effects. PMID- 28673278 TI - The new trauma score (NTS): a modification of the revised trauma score for better trauma mortality prediction. AB - BACKGROUND: Since its introduction, the Revised Trauma Score (RTS) has been widely used to determine the prognosis of trauma patients. Recent studies have revealed a need to change the parameters of the RTS. We have designed a new trauma score (NTS) based on revised parameters, including the adoption of the actual Glasgow Coma Scale (GCS) score instead of a GCS code, the revision of the systolic blood pressure interval used for the code value and the incorporation of peripheral oxygen saturation (SpO2) instead of respiratory rate. The purpose of this study was to evaluate the predictive performance of the NTS for in-hospital mortality compared with the RTS and other trauma scores. METHODS: This was a prospective observational study using data from the trauma registry of a tertiary hospital. The subjects were selected from patients who arrived at the ED between July 1, 2014, and June 30, 2016, and, for external validation purposes, those who arrived at the ED between July 1, 2011, and June 30, 2013. Demographic data and physiological data were analyzed. NTS models were calculated using logistic regression for GCS score, SBP code values, and SpO2. The mortality predictive performance of NTS was compared with that of other trauma scores. RESULTS: A total of 3263 patients for derivation and 3106 patients for validation were included in the analysis. The NTS showed better discrimination than the RTS (AUC = 0.935 vs. 0.917, respectively, AUC difference = 0.018, p = 0.001; 95% CI, 0.0071-0.0293) and similar discrimination to that of mechanism, Glasgow Coma scale, age, and arterial pressure (MGAP) and the Glasgow Coma Scale, age, and systolic arterial pressure (GAP). In the validation cohort, the global properties of the NTS for mortality prediction were significantly better than those of the RTS (AUC = 0.919 vs. 0.906, respectively; AUC difference = 0.013, p = 0.013; 95% CI, 0.0009-0.0249) and similar to those of the MGAP and GAP. CONCLUSIONS: The NTS predicts in-hospital mortality substantially better than the RTS. PMID- 28673279 TI - Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report. AB - BACKGROUND: Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study. CASE PRESENTATION: A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles. CONCLUSIONS: We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics. PMID- 28673280 TI - Incidence, clinical features, and implications on outcomes of neonatal late-onset sepsis with concurrent infectious focus. AB - BACKGROUND: Neonatal bloodstream infection (BSI) is the most important cause of morbidity and mortality in the neonatal intensive care unit (NICU). Although most neonatal BSIs are primary bacteremia, some are associated with a focus of infection. This distinction is not well characterized. METHODS: All patients with neonatal late-onset sepsis (LOS) between January 2006 and December 2013 were enrolled. LOS was categorized as a BSI with a concurrent focus of infection if LOS occurred before or within 24 h after the diagnosis of a specific infectious entity, and as "primary bacteremia" if no concurrent focus of infection was identified. Data concerning demographics, hospital course, microbiology, and outcomes were compared via univariate and multivariate analyses. RESULTS: Of 948 episodes of neonatal LOS, 781 (82.4%) were primary bacteremia, whereas 167 (17.6%) were associated with a known focus of infection, including meningitis (n = 51, 5.4%), ventilator-associated pneumonia (VAP) (n = 36, 3.8%), catheter related bloodstream infections (n = 57, 6.0%), and necrotizing enterocolitis (NEC) (n = 21, 2.2%). The majority of NEC-associated BSIs were caused by gram negative bacilli (85.7%). Group B streptococcus accounted for nearly one-third of all meningitis cases (29.4%). Although sepsis-attributable mortality was comparable between primary bacteremia and neonatal BSIs with a focus of infection, neonatal BSIs with meningitis, VAP, and NEC had significantly higher rates of infectious complications. The independent risk factors of sepsis attributable mortality were infectious complications (Odds ratio [OR] 6.98; 95% confidence interval [CI] 3.64-13.39, P < 0.001); history of one or more than one previous episode(s) of BSI (OR 2.40 and 7.40; 95% CI 1.21-4.74 and 3.70-14.78, P = 0.012 and <0.001, respectively); and underlying secondary pulmonary hypertension in neonates (OR 4.77; 95% CI 1.91-11.96, P = 0.001). CONCLUSIONS: A considerable proportion of neonatal LOS can be associated with known infectious foci in the NICU. The microbiologic etiology of neonatal LOS with a concurrent focus of infection is significantly different from that of primary bacteremia. Neonatal BSIs with concurrent meningitis, VAP, or NEC are significantly more likely to have infectious complications. This association independently leads to sepsis-attributable mortality. PMID- 28673281 TI - The V sign in lateral talar process fractures: an experimental study using a foot and ankle model. AB - BACKGROUND: Lateral talar process fractures (LTPF) are often missed on conventional radiographs. A positive V sign is an interruption of the contour of the LTP. It has been suggested, but not proven to be pathognomonic for LTPF. The objective was to study whether the V sign is pathognomonic for LTPF and if it can be properly assessed in different ankle positions and varying fracture types. METHODS: An experimental study was conducted. Two investigators assessed lateral radiographs (n = 108) of a foot and ankle model. The exposure variables were different ankle positions and fracture types. The primary outcome was the correct detection of a V sign. The secondary outcomes were the detection of the V sign depending on ankle position and fracture type as well as the uncertainty. RESULTS: The interobserver agreement on the V sign and type of fracture were fair (kappa = 0.35, 95% CI 0.18-0.53, p < 0.001 and kappa = 0.37, 95% CI 0.26-0.48, p < 0.001). The mean sensitivity, specificity, PPV, NPV, and likelihood ratio for the detection of the V sign were 77% (95% CI 67-86%), 59% (95% CI 39-78%), 85% (95% CI 75-92%), 46% (95% CI 29-63%), and 2. The mean uncertainty in the V sign detection was 38%. The V sign identification stratified by ankle position and fracture type showed significant better results with increasing inversion (p = 0.035 and p = 0.011) and type B fractures (p = 0.001 and p = 0.013). CONCLUSIONS: The V sign may not be pathognomonic and is not recommended as the only modality for the detection of LTPF. It is better visualized with inversion, but does not depend on plantar flexion or internal rotation. It is also better seen in type B fractures. It is difficult to detect and investigator-dependent. It may be helpful in a clinical setting to point into a direction, but a CT scan may be used if in doubt about a LTPF. PMID- 28673282 TI - Hyperbaric oxygen treatment of spinal cord injury in rat model. AB - BACKGROUND: The purpose of this study was to investigate the therapeutic effects and mechanisms of hyperbaric oxygen (HBO) treatment on rats following spinal cord injury (SCI). METHODS: A total of 45 Sprague-Dawley (SD) rats were randomly divided into three groups. Sham-SCI group was surgically exposed but not subjected to the SCI procedure. SCI-control group was administered SCI and treated with regular air. SCI-HBO group was administered SCI and HBO treatment. Neuromotor functions were examined using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and the inclined plane assessment at before SCI (baseline) and after SCI. Superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels were measured. RESULTS: Starting from Day 1 after SCI but except Day 2, the SCI-HBO group has significantly higher BBB scores than the SCI-control group. After SCI, the maximum inclination angles at which rats could maintain were significantly lower in both SCI groups. But the maximum angles were significantly bigger for the rats in the SCI-HBO group than those on the SCI-control group at 5, 10 and 20 days after SCI. SOD activities in SCI-HBO rats were significantly higher and MDA levels were significantly lower than in SCI-control rats, at two and five days after SCI. There was also less cystic degeneration of spinal cord in SCI-HBO rats, compared to SCI-control rats. CONCLUSIONS: These results suggest that HBO treatment has a therapeutic value in treating SCI. Increased oxygen free radical scavenging and reduced lipid oxidation may be one of the mechanisms. PMID- 28673283 TI - Evaluating the comparative effectiveness of different demand side interventions to increase maternal health service utilization and practice of birth spacing in South Kivu, Democratic Republic of Congo: an innovative, mixed methods approach. AB - BACKGROUND: In this protocol we describe a mixed methods study in the province of South Kivu, Democratic Republic of Congo evaluating the effectiveness of different demand side strategies to increase maternal health service utilization and the practice of birth spacing. Conditional service subsidization, conditional cash transfers and non-monetary incentives aim to encourage women to use maternal health services and practice birth spacing in two different health districts. Our methodology will comparatively evaluate the effectiveness of different approaches against each other and no intervention. METHODS/DESIGN: This study comprises four main research activities: 1) Formative qualitative research to determine feasibility of planned activities and inform development of the quantitative survey; 2) A community-based, longitudinal survey; 3) A retrospective review of health facility records; 4) Qualitative exploration of intervention acceptability and emergent themes through in-depth interviews with program participants, non participants, their partners and health providers. Female community health workers are engaged as core members of the research team, working in tandem with female survey teams to identify women in the community who meet eligibility criteria. Female community health workers also act as key informants and community entry points during methods design and qualitative exploration. Main study outcomes are completion of antenatal care, institutional delivery, practice of birth spacing, family planning uptake and intervention acceptability in the communities. Qualitative methods also explore decision making around maternal health service use, fertility preference and perceptions of family planning. DISCUSSION: The innovative mixed methods design allows quantitative data to inform the relationships and phenomena to be explored in qualitative collection. In turn, qualitative findings will be triangulated with quantitative findings. Inspired by the principles of grounded theory, qualitative analysis will begin while data collection is ongoing. This "conversation" between quantitative and qualitative data will result in a more holistic, context-specific exploration and understanding of research topics, including the mechanisms through which the interventions are or are not effective. In addition, engagement of female community health workers as core members of the research team roots research methods in the realities of the community and provides teams with key informants who are simultaneously implicated in the health system, community and target population. PMID- 28673284 TI - Defining and describing birth centres in the Netherlands - a component study of the Dutch Birth Centre Study. AB - BACKGROUND: During the last decade, a rapid increase of birth locations for low risk births, other than conventional obstetric units, has been seen in the Netherlands. Internationally some of such locations are called birth centres. The varying international definitions for birth centres are not directly applicable for use within the Dutch obstetric system. A standard definition for a birth centre in the Netherlands is lacking. This study aimed to develop a definition of birth centres for use in the Netherlands, to identify these centres and to describe their characteristics. METHODS: International definitions of birth centres were analysed to find common descriptions. In July 2013 the Dutch Birth Centre Questionnaire was sent to 46 selected Dutch birth locations that might qualify as birth centre. Questions included: location, reason for establishment, women served, philosophies, facilities that support physiological birth, hotel facilities, management, environment and transfer procedures in case of referral. Birth centres were visited to confirm the findings from the Dutch Birth Centre Questionnaire and to measure distance and time in case of referral to obstetric care. RESULTS: From all 46 birth locations the questionnaires were received. Based on this information a Dutch definition of a birth centre was constructed. This definition reads: "Birth centres are midwifery-managed locations that offer care to low risk women during labour and birth. They have a homelike environment and provide facilities to support physiological birth. Community midwives take primary professional responsibility for care. In case of referral the obstetric caregiver takes over the professional responsibility of care." Of the 46 selected birth locations 23 fulfilled this definition. Three types of birth centres were distinguished based on their location in relation to the nearest obstetric unit: freestanding (n = 3), alongside (n = 14) and on-site (n = 6). Transfer in case of referral was necessary for all freestanding and alongside birth centres. Birth centres varied in their reason for establishment and their characteristics. CONCLUSIONS: Twenty-three Dutch birth centres were identified and divided into three different types based on location according to the situation in September 2013. Birth centres differed in their reason for establishment, facilities, philosophies, staffing and service delivery. PMID- 28673285 TI - Multiple entries and exits and other complex human patterns of insecticide treated net use: a possible contributor to residual malaria transmission? AB - BACKGROUND: Increased insecticide-treated net (ITN) use over the last decade has contributed to dramatic declines in malaria transmission and mortality, yet residual transmission persists even where ITN coverage exceeds 80%. This article presents observational data suggesting that complex human net use patterns, including multiple entries to and exits from ITNs by multiple occupants throughout the night, might be a contributing factor. METHODS: The study included dusk-to-dawn observations of bed net use in 60 households in the Peruvian Amazon. Observers recorded number of net occupants and the time and number of times each occupant entered and exited each net. The study team then tabulated time of first entry, total times each net was lifted, and, where possible, minutes spent outside by each occupant. RESULTS: The sample included 446 individuals and 171 observed sleeping spaces with nets. Household size ranged from 2 to 24 occupants; occupants per net ranged from 1 to 5. Nets were lifted a mean 6.1 times per night (SD 4.35, range 1-22). Observers captured substantial detail about time of and reasons for net entry and exit as well as length of time and activities undertaken outside. CONCLUSIONS: These findings suggest that the ITN use patterns observed in this study may contribute to residual transmission. As a result, respondents to net use surveys may truthfully report that they slept under a net the previous night but may not have received the anticipated protection. More research is warranted to explore the impact of this phenomenon. Concurrent entomological data would help assess the magnitude of the effect. PMID- 28673286 TI - Diet quality and carotid atherosclerosis in intermediate cardiovascular risk individuals. PMID- 28673287 TI - New gorilla adenovirus vaccine vectors induce potent immune responses and protection in a mouse malaria model. AB - BACKGROUND: A DNA-human Ad5 (HuAd5) prime-boost malaria vaccine has been shown to protect volunteers against a controlled human malaria infection. The potency of this vaccine, however, appeared to be affected by the presence of pre-existing immunity against the HuAd5 vector. Since HuAd5 seroprevalence is very high in malaria-endemic areas of the world, HuAd5 may not be the most appropriate malaria vaccine vector. This report describes the evaluation of the seroprevalence, immunogenicity and efficacy of three newly identified gorilla adenoviruses, GC44, GC45 and GC46, as potential malaria vaccine vectors. RESULTS: The seroprevalence of GC44, GC45 and GC46 is very low, and the three vectors are not efficiently neutralized by human sera from Kenya and Ghana, two countries where malaria is endemic. In mice, a single administration of GC44, GC45 and GC46 vectors expressing a murine malaria gene, Plasmodium yoelii circumsporozoite protein (PyCSP), induced robust PyCSP-specific T cell and antibody responses that were at least as high as a comparable HuAd5-PyCSP vector. Efficacy studies in a murine malaria model indicated that a prime-boost regimen with DNA-PyCSP and GC-PyCSP vectors can protect mice against a malaria challenge. Moreover, these studies indicated that a DNA-GC46-PyCSP vaccine regimen was significantly more efficacious than a DNA-HuAd5-PyCSP regimen. CONCLUSION: These data suggest that these gorilla-based adenovectors have key performance characteristics for an effective malaria vaccine. The superior performance of GC46 over HuAd5 highlights its potential for clinical development. PMID- 28673289 TI - Semantic relatedness and similarity of biomedical terms: examining the effects of recency, size, and section of biomedical publications on the performance of word2vec. AB - BACKGROUND: Understanding semantic relatedness and similarity between biomedical terms has a great impact on a variety of applications such as biomedical information retrieval, information extraction, and recommender systems. The objective of this study is to examine word2vec's ability in deriving semantic relatedness and similarity between biomedical terms from large publication data. Specifically, we focus on the effects of recency, size, and section of biomedical publication data on the performance of word2vec. METHODS: We download abstracts of 18,777,129 articles from PubMed and 766,326 full-text articles from PubMed Central (PMC). The datasets are preprocessed and grouped into subsets by recency, size, and section. Word2vec models are trained on these subtests. Cosine similarities between biomedical terms obtained from the word2vec models are compared against reference standards. Performance of models trained on different subsets are compared to examine recency, size, and section effects. RESULTS: Models trained on recent datasets did not boost the performance. Models trained on larger datasets identified more pairs of biomedical terms than models trained on smaller datasets in relatedness task (from 368 at the 10% level to 494 at the 100% level) and similarity task (from 374 at the 10% level to 491 at the 100% level). The model trained on abstracts produced results that have higher correlations with the reference standards than the one trained on article bodies (i.e., 0.65 vs. 0.62 in the similarity task and 0.66 vs. 0.59 in the relatedness task). However, the latter identified more pairs of biomedical terms than the former (i.e., 344 vs. 498 in the similarity task and 339 vs. 503 in the relatedness task). CONCLUSIONS: Increasing the size of dataset does not always enhance the performance. Increasing the size of datasets can result in the identification of more relations of biomedical terms even though it does not guarantee better precision. As summaries of research articles, compared with article bodies, abstracts excel in accuracy but lose in coverage of identifiable relations. PMID- 28673288 TI - Nanobodies raised against monomeric alpha-synuclein inhibit fibril formation and destabilize toxic oligomeric species. AB - BACKGROUND: The aggregation of the protein alpha-synuclein (alphaS) underlies a range of increasingly common neurodegenerative disorders including Parkinson's disease. One widely explored therapeutic strategy for these conditions is the use of antibodies to target aggregated alphaS, although a detailed molecular-level mechanism of the action of such species remains elusive. Here, we characterize alphaS aggregation in vitro in the presence of two alphaS-specific single-domain antibodies (nanobodies), NbSyn2 and NbSyn87, which bind to the highly accessible C-terminal region of alphaS. RESULTS: We show that both nanobodies inhibit the formation of alphaS fibrils. Furthermore, using single-molecule fluorescence techniques, we demonstrate that nanobody binding promotes a rapid conformational conversion from more stable oligomers to less stable oligomers of alphaS, leading to a dramatic reduction in oligomer-induced cellular toxicity. CONCLUSIONS: The results indicate a novel mechanism by which diseases associated with protein aggregation can be inhibited, and suggest that NbSyn2 and NbSyn87 could have significant therapeutic potential. PMID- 28673290 TI - Seasonal variation of malaria cases in children aged less than 5 years old following weather change in Zomba district, Malawi. AB - BACKGROUND: Malaria is seasonal and this may influence the number of children being treated as outpatients in hospitals. The objective of this study was to investigate the degree of seasonality in malaria in lakeshore and highland areas of Zomba district Malawi, and influence of climatic factors on incidence of malaria. METHODS: Secondary data on malaria surveillance numbers and dates of treatment of children <5 years of age (n = 374,246) were extracted from the Zomba health information system for the period 2012-2016, while data on climatic variables from 2012 to 2015 were obtained from meteorological department. STATA version 13 was used to analyse data using non-linear time series correlation test to suggest a predictor model of malaria epidemic over explanatory variable (rainfall, temperature and humidity). RESULTS: Malaria cases of children <5 years of age in Zomba district accounts for 45% of general morbidity. There was no difference in seasonality of malaria in highland compared to lakeshore in Zomba district. This study also found that an increase in average temperature and relative humidity was associated of malaria incidence in children <5 year of age in Zomba district. On the other hand, the difference of maximum and minimum temperature (diurnal temperature range), had a strong negative association (correlation coefficients of R2 = 0.563 [All Zomba] beta = -1295.57 95% CI 1683.38 to -907.75 p value <0.001, R2 = 0.395 [Zomba Highlands] beta = -137.74 95% CI -195.00 to -80.47 p value <0.001 and R2 = 0.470 [Zomba Lakeshores] beta = 263.05 95% CI -357.47 to -168.63 p value <0.001) with malaria incidence of children <5 year in Zomba district, Malawi. CONCLUSION: The diminishing of malaria seasonality, regardless of strong rainfall seasonality, and marginal drop of malaria incidence in Zomba can be explained by weather variation. Implementation of seasonal chemoprevention of malaria in Zomba could be questionable due to reduced seasonality of malaria. The lower diurnal temperature range contributed to high malaria incidence and this must be further investigated. PMID- 28673291 TI - Erratum to: A cohort study examining emergency department visits and hospital admissions among people who use drugs in Ottawa, Canada. PMID- 28673293 TI - Left ventricular outflow tract velocity time integral outperforms ejection fraction and Doppler-derived cardiac output for predicting outcomes in a select advanced heart failure cohort. AB - BACKGROUND: Left ventricular outflow tract velocity time integral (LVOT VTI) is a measure of cardiac systolic function and cardiac output. Heart failure patients with low cardiac output are known to have poor cardiovascular outcomes. Thus, extremely low LVOT VTI may predict heart failure patients at highest risk for mortality. METHODS: Patients with heart failure and extremely low LVOT VTI were identified from a single-center database. Baseline characteristics and heart failure related clinical outcomes (death, LVAD) were obtained at 12 months. Correlation between clinical endpoints and the following variables were analyzed: ejection fraction (EF), pulmonary artery systolic pressure (PASP), NYHA class, renal function, Doppler cardiac output (CO), and LVOT VTI. RESULTS: Study cohort consisted of 100 patients. At the 12-month follow up period, 30 events (28 deaths, 2 LVADs) were identified. Occurrence of death and LVAD implantation was statistically associated with a lower LVOT VTI (p = 0.039) but not EF (p = 0.169) or CO (p = 0.217). In multivariate analysis, LVOT VTI (p = 0.003) remained statistically significant, other significant variables were age (p = 0.033) and PASP (p = 0.022). Survival analysis by LVOT VTI tertile demonstrated an unadjusted hazard ratio of 4.755 (CI 1.576-14.348, p = 0.006) for combined LVAD and mortality at one year. CONCLUSIONS: Extremely low LVOT VTI strongly predicts adverse outcomes and identifies patients who may benefit most from advanced heart failure therapies. PMID- 28673292 TI - Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women. AB - BACKGROUND: Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women. METHODS: Pregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol. RESULTS: In total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4-17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in pregnant women followed up for 28 days (P = 0.018). CONCLUSIONS: Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women. PMID- 28673294 TI - Lipid management in India: a nationwide, cross-sectional physician survey. AB - BACKGROUND: Current international guidelines on dyslipidemia are not concordant on various aspects of management. Also, there are no uniformly accepted Indian guidelines. We, therefore, performed a physician survey to understand lipid management practices in India. METHODS: An anonymous survey questionnaire was administered to gauge physicians' self-reported behavior regarding lipid management aspects. Results were expressed in terms of percentages based on the number of responses obtained. RESULTS: A total of 404 physicians participated in the survey. Eighty-eight percent respondents ordered a lipid profile before starting statin therapy, and 80% preferred to set lipid targets, though the tools used for calculating cardiovascular risk varied. Atorvastatin was preferred over rosuvastatin in primary prevention (72.9 vs. 32.4%), secondary prevention (54.6 vs. 46.7%), diabetic patients (56.3 vs. 40.3%) and post-ACS (78.3 vs. 34%). High intensity statins were preferred by 73.7% of respondents in post-ACS cases. Fifty percent doctors chose not to use a statin in diabetic patients, irrespective of their LDL-C levels. The most preferred drug option for managing atherogenic dyslipidemia and moderate hypertriglyceridemia was statin-fibrate combination (55.1%) and fibrates (35.4%), respectively. Sixty-three percent doctors preferred to prescribe statins in patients with moderately high LDL-C and normal triglycerides, without CHD or CHD risk equivalents. Around 28% of doctors preferred not to use pharmacotherapy for managing isolated low HDL. Of the participants, 73% used fibrates in <=20% of their dyslipidemic patients, with fenofibrate being the most preferred (90.5%). Ezetimibe was mainly used in patients with uncontrolled LDL-C despite statin therapy (52.4% respondents). Most preferred approaches to manage statin intolerance included reducing statin dose (39%) and stopping and restarting statins at a lower dose (34.5%). Fifty-two percent of doctors chose not to alter pre-existing therapy in patients who had LDL-C levels at goal but elevated non-HDL-C levels. CONCLUSION: This is the first survey in India that provides useful insights into Indian physicians' self reported perspectives on managing dyslipidemia in routine clinical practice. Despite concordance with the currently available guidelines in certain aspects, there is incongruence in managing specific dyslipidemia problems. Further continuing medical education and the development of evidence-based, India specific lipid guidelines can help reduce some of these differences. PMID- 28673295 TI - The impact of racial discrimination on the health of Australian Indigenous children aged 5-10 years: analysis of national longitudinal data. AB - BACKGROUND: A growing body of literature highlights that racial discrimination has negative impacts on child health, although most studies have been limited to an examination of direct forms of racism using cross-sectional data. We aim to provide further insights on the impact of early exposure to racism on child health using longitudinal data among Indigenous children in Australia and multiple indicators of racial discrimination. METHODS: We used data on 1239 Indigenous children aged 5-10 years from Waves 1-6 (2008-2013) of Footprints in Time, a longitudinal study of Indigenous children across Australia. We examined associations between three dimensions of carer-reported racial discrimination (measuring the direct experiences of children and vicarious exposure by their primary carer and family) and a range of physical and mental health outcomes. Analysis was conducted using multivariate logistic regression within a multilevel framework. RESULTS: Two-fifths (40%) of primary carers, 45% of families and 14% of Indigenous children aged 5-10 years were reported to have experienced racial discrimination at some point in time, with 28-40% of these experiencing it persistently (reported at multiple time points). Primary carer and child experiences of racial discrimination were each associated with poor child mental health status (high risk of clinically significant emotional or behavioural difficulties), sleep difficulties, obesity and asthma, but not with child general health or injury. Children exposed to persistent vicarious racial discrimination were more likely to have sleep difficulties and asthma in multivariate models than those with a time-limited exposure. CONCLUSIONS: The findings indicate that direct and persistent vicarious racial discrimination are detrimental to the physical and mental health of Indigenous children in Australia, and suggest that prolonged and more frequent exposure to racial discrimination that starts in the early lifecourse can impact on multiple domains of health in later life. Tackling and reducing racism should be an integral part of policy and intervention aimed at improving the health of Australian Indigenous children and thereby reducing health disparities between Indigenous and non-Indigenous children. PMID- 28673296 TI - Better survival after breast-conserving therapy compared to mastectomy when axillary node status is positive in early-stage breast cancer: a registry-based follow-up study of 6387 Norwegian women participating in screening, primarily operated between 1998 and 2009. AB - BACKGROUND: Recent registry studies on early-stage breast cancer have shown better survival rates when women underwent breast-conserving therapy (BCT) compared with mastectomy (MTX). The aim of this study is to investigate women participating in screening, in all four stages of early breast cancer (T1N0M0, T2N0M0, T1N1M0, and T2N1M0), as to whether there is a survival benefit when women undergo BCT compared to MTX. METHOD: A cohort of 6387 women aged 50-69, with primary-operated breast cancer from January 1998 to December 2009, participating in screening and followed-up until the end of 2010. Life tables were calculated by stages (pT1N0M0, pT2N0M0, pT1N1M0, and pT2N1M0), surgery groups (BCT and MTX), and screening detection (first screening, later screening, or interval cancer). Cox regression was used to calculate hazard ratios (HR) between BCT and MTX in crude and adjusted analyses. RESULTS: In stage T1N1M0, women who underwent MTX had an HR of 2.91 (95% CI 1.30-6.48) for breast cancer death compared to women who underwent BCT, after adjusting for screening detection, years of diagnosis, age at diagnosis, histology, grade, and hormone receptor status. For all other TNM categories of early breast cancer, there was no difference in survival. 10 year breast cancer-specific survival (BCSS) in T1N0M0 was 98% for women undergoing BCT and 96% for women undergoing MTX. 10-year BCSS in T1N1M0 was 97% for women undergoing BCT and 89% for women undergoing MTX. CONCLUSIONS: For women participating in screening, there is a benefit of BCT over MTX in stage T1N1M0. No such effects were observed in the other early stages of breast cancer. PMID- 28673297 TI - Risk factors of liver metastasis from advanced pancreatic adenocarcinoma: a large multicenter cohort study. AB - BACKGROUND: Clinical prognostic parameters of liver metastasis from pancreatic adenocarcinoma have not been specifically identified.This study is to explore the risk factors of liver metastasis in advanced pancreatic adenocarcinoma (PDAC) patients in China. METHODS: A multicenter cohort study was conducted to explore whether liver metastasis in locally advanced and metastatic PDAC could be reflected by some common laboratory indexes. We collected 1787 advanced PDAC patients from three participating hospitals between 2004 and 2014. The associations between some laboratory indexes and risks of liver metastases were analyzed. RESULTS: Results have shown that 87% of stage IV patients developed synchronous liver metastasis. Primary tumor location (body/tail vs. head/neck, OR 0.55, 95% CI 0.36-0.83), primary tumor diameter (>=20 mm vs. <20 mm, OR 1.77, 95% CI 1.16-2.70), elevated ALT and AST (OR 1.62, 95% CI 0.92-2.83), and elevated CA19-9 (OR 2.72, 95% CI 1.85-3.99) upon diagnosis are significantly associated with risk of synchronous liver metastasis. Among stage III patients, 30.1% developed metachronous liver metastasis. However, no risk factors were identified among these patients. CONCLUSIONS: Primary tumor location, diameter, elevated ALT and AST, and increased CA19-9 are independent risk factors of synchronous liver metastasis in PDAC patients. PMID- 28673299 TI - Efficacy and safety evaluation of a novel trioxaquine in the management of cerebral malaria in a mouse model. AB - BACKGROUND: The emergence of multidrug-resistant strains of Plasmodium falciparum poses a great threat of increased fatalities in cases of cerebral and other forms of severe malaria infections in which parenteral artesunate monotherapy is the current drug of choice. The study aimed to investigate in a mouse model of human cerebral malaria whether a trioxaquine chemically synthesized by covalent linking of a 4,7-dichloroquinoline pharmacophore to artesunate through a recent drug development approach termed 'covalent bitherapy' could improve the curative outcomes in cerebral malaria infections. METHODS: Human cerebral malaria rodent model, the C57BL/6 male mice were infected intraperitoneally (ip) with Plasmodium berghei ANKA and intravenously (iv) treated with the trioxaquine from day 8 post infection (pi) at 12.5 and 25 mg/kg, respectively, twice a day for 3 days. Treatments with the trioxaquine precursors (artesunate and 4,7-dichloroquine), and quinine were also included as controls. In vivo safety evaluation for the trioxaquine was done according to Organization for Economic Co-operation and Development (OECD) guidelines 423, where female Swiss albino mice were orally administered with either 300 or 2000 mg/kg of the trioxaquine and monitored for signs of severity, and or mortality for 14 days post-treatment. RESULTS: The trioxaquine showed a potent and a rapid antiplasmodial activity with 80% parasite clearance in the first 24 h for the two dosages used. Long-term parasitaemia monitoring showed a total parasite clearance as the treated mice survived beyond 60 days post-treatment, with no recrudescence observed. Artesunate treated mice showed recrudescence 8 days post-treatment, with all mice in this group succumbing to the infection. Also, 4,7-dichloroquinoline and quinine did not show any significant parasitaemia suppression in the first 24 h post-treatment, with the animals succumbing to the infection. CONCLUSION: Covalent bitherapy proves to be a viable source of urgently needed new anti-malarials for management of cerebral malaria, and this polypharmacology approach could be a potential strategy to protect artesunate from parasite resistance and in potentially improving clinical outcomes in severe forms of malaria infections. PMID- 28673298 TI - Is outdoor vector control needed for malaria elimination? An individual-based modelling study. AB - BACKGROUND: Residual malaria transmission has been reported in many areas even with adequate indoor vector control coverage, such as long-lasting insecticidal nets (LLINs). The increased insecticide resistance in Anopheles mosquitoes has resulted in reduced efficacy of the widely used indoor tools and has been linked with an increase in outdoor malaria transmission. There are considerations of incorporating outdoor interventions into integrated vector management (IVM) to achieve malaria elimination; however, more information on the combination of tools for effective control is needed to determine their utilization. METHODS: A spatial individual-based model was modified to simulate the environment and malaria transmission activities in a hypothetical, isolated African village setting. LLINs and outdoor attractive toxic sugar bait (ATSB) stations were used as examples of indoor and outdoor interventions, respectively. Different interventions and lengths of efficacy periods were tested. Simulations continued for 420 days, and each simulation scenario was repeated 50 times. Mosquito populations, entomologic inoculation rates (EIRs), probabilities of local mosquito extinction, and proportion of time when the annual EIR was reduced below one were compared between different intervention types and efficacy periods. RESULTS: In the village setting with clustered houses, the combinational intervention of 50% LLINs plus outdoor ATSBs significantly reduced mosquito population and EIR in short term, increased the probability of local mosquito extinction, and increased the time when annual EIR is less than one per person compared to 50% LLINs alone; outdoor ATSBs alone significantly reduced mosquito population in short term, increased the probability of mosquito extinction, and increased the time when annual EIR is less than one compared to 50% LLINs alone, but there was no significant difference in EIR in short term between 50% LLINs and outdoor ATSBs. In the village setting with dispersed houses, the combinational intervention of 50% LLINs plus outdoor ATSBs significantly reduced mosquito population in short term, increased the probability of mosquito extinction, and increased the time when annual EIR is less than one per person compared to 50% LLINs alone; outdoor ATSBs alone significantly reduced mosquito population in short term, but there were no significant difference in the probability of mosquito extinction and the time when annual EIR is less than one between 50% LLIN and outdoor ATSBs; and there was no significant difference in EIR between all three interventions. A minimum of 2 months of efficacy period is needed to bring out the best possible effect of the vector control tools, and to achieve long-term mosquito reduction, a minimum of 3 months of efficacy period is needed. CONCLUSIONS: The results highlight the value of incorporating outdoor vector control into IVM as a supplement to traditional indoor practices for malaria elimination in Africa, especially in village settings of clustered houses where LLINs alone is far from sufficient. PMID- 28673300 TI - Volunteer navigation partnerships: Piloting a compassionate community approach to early palliative care. AB - BACKGROUND: A compassionate community approach to palliative care provides important rationale for building community-based hospice volunteer capacity. In this project, we piloted one such capacity-building model in which volunteers and a nurse partnered to provide navigation support beginning in the early palliative phase for adults living in community. The goal was to improve quality of life by developing independence, engagement, and community connections. METHODS: Volunteers received navigation training through a three-day workshop and then conducted in-home visits with clients living with advanced chronic illness over one year. A nurse navigator provided education and mentorship. Mixed method evaluation data was collected from clients, volunteer navigators, the nurse navigator, and other stakeholders. RESULTS: Seven volunteers were partnered with 18 clients. Over the one-year pilot, the volunteer navigators conducted visits in home or by phone every two to three weeks. Volunteers were skilled and resourceful in building connections and facilitating engagement. Although it took time to learn the navigator role, volunteers felt well-prepared and found the role satisfying and meaningful. Clients and family rated the service as highly important to their care because of how the volunteer helped to make the difficult experiences of aging and advanced chronic illness more livable. Significant benefits cited by clients were making good decisions for both now and in the future; having a surrogate social safety net; supporting engagement with life; and ultimately, transforming the experience of living with illness. Overall the program was perceived to be well-designed by stakeholders and meeting an important need in the community. Sustainability, however, was a concern expressed by both clients and volunteers. CONCLUSIONS: Volunteers providing supportive navigation services during the early phase of palliative care is a feasible way to foster a compassionate community approach to care for an aging population. The program is now being implemented by hospice societies in diverse communities across Canada. PMID- 28673301 TI - Effects of deployment on diet quality and nutritional status markers of elite U.S. Army special operations forces soldiers. AB - BACKGROUND: Special Operations Forces (SOF) Soldiers deploy frequently and require high levels of physical and cognitive performance. Nutritional status is linked to cognitive and physical performance. Studies evaluating dietary intake and nutritional status in deployed environments are lacking. Therefore, this study assessed the effects of combat deployment on diet quality and serum concentrations of nutritional status markers, including iron, vitamin D, parathyroid hormone (PTH), glucose, and lipids, among elite United States (U.S.) Army SOF Soldiers. METHODS: Changes from baseline to post-deployment were determined with a repeated measure within-subjects design for Healthy Eating Index-2010 (HEI-2010) scores, intake of foods, food groups, key nutrients, and serum nutritional status markers. Dietary intake was assessed with a Block Food Frequency Questionnaire. The association between post-deployment serum 25-hydroxy vitamin D (25-OH vitamin D) and PTH was determined. Analyses of serum markers were completed on 50 participants and analyses of dietary intake were completed on 33 participants. RESULTS: In response to deployment, HEI-2010 scores decreased for total HEI-2010 (70.3 +/- 9.1 vs. 62.9 +/- 11.1), total fruit (4.4 +/- 1.1 vs. 3.7 +/- 1.5), whole fruit (4.6 +/- 1.0 vs. 4.2 +/- 1.4), dairy (6.2 +/- 2.7 vs. 4.8 +/- 2.4), and empty calories (14.3 +/- 3.2 vs. 11.1 +/- 4.5) (P <= 0.05). Average daily intakes of foods and food groups that decreased included total dairy (P < 0.01), milk (P < 0.01), and non-juice fruit (P = 0.03). Dietary intake of calcium (P = 0.05) and vitamin D (P = 0.03) decreased. PTH increased from baseline (3.4 +/- 1.6 vs. 3.8 +/- 1.4 pmol/L, P = 0.04), while there was no change in 25-OH vitamin D. Ferritin decreased (385 +/- 173 vs. 354 +/- 161 pmol/L, P = 0.03) and soluble transferrin receptor increased (16.3 +/- 3.7 vs. 17.1 +/- 3.5 nmol/L, P = 0.01). There were no changes in glucose or lipids. Post deployment, serum 25-OH vitamin D was inversely associated with PTH (r = -0.43, P < 0.01). CONCLUSIONS: HEI-2010 scores and dietary intake of milk, calcium, and vitamin D decreased following deployment. Serum PTH increased and iron stores were degraded. No Soldiers were iron deficient. Personnel that deploy frequently should maintain a high diet quality in the U.S. and while deployed by avoiding empty calories and consuming fruits, vegetables, and adequate sources of calcium, vitamin D, and iron. Improving availability and quality of perishable food during deployment may improve diet quality. PMID- 28673302 TI - Area-level socioeconomic deprivation and mortality differentials in Thailand: results from principal component analysis and cluster analysis. AB - BACKGROUND: Despite achievement of universal health coverage in Thailand, socioeconomic inequality in health has been a major policy concern. This study examined mortality patterns across different socioeconomic strata in Thailand. METHODS: We conducted a cross-sectional analysis of the 2010 Population and Housing Census on area-level socioeconomic deprivation against the 2010 mortality from the vital registration database at the super-district level. We used principal components analysis to construct a socioeconomic deprivation index and K-mean cluster analysis to group socioeconomic status and cause-specific mortality. RESULTS: Excess mortality rates from all diseases, except colorectal cancer, were observed among super-districts with low socioeconomic status. Spatial clustering was evident in the distribution of socioeconomic status and mortality rates. Cluster analysis revealed that super-districts which were predominantly urban tended to have low all-cause standardize mortality ratio but a high colorectal cancer-specific mortality rate. Deaths due to liver cancer, diabetes, and renal diseases were common in the low socioeconomic super-districts which hosted one third of the total Thai population. CONCLUSION: Socially deprived areas have an excess of overall and cause specific deaths. Populations living in more affluent areas, despite low general mortality, still have many preventable deaths such as colorectal cancer. These findings warrant future epidemiological studies investigating various causes of excessive deaths in non deprived areas and implementation of policies to reduce the mortality gap between rich and poor areas. PMID- 28673303 TI - An analysis of respondent-driven sampling with injecting drug users in a high HIV prevalent state of India. AB - BACKGROUND: Personal networks are significant social spaces to spread of HIV or other blood-borne infections among hard-to-reach population, viz., injecting drug users, female sex workers, etc. Sharing of infected needles or syringes among drug users is one of the major routes of HIV transmission in Manipur, a high HIV prevalence state in India. This study was carried out to describe the network characteristics and recruitment patterns of injecting drug users and to assess the association of personal network with injecting risky behaviors in Manipur. METHODS: A total of 821 injecting drug users were recruited into the study using respondent-driven sampling (RDS) from Bishnupur and Churachandpur districts of Manipur; data on demographic characteristics, HIV risk behaviors, and network size were collected from them. Transition probability matrices and homophily indices were used to describe the network characteristics, and recruitment patterns of injecting drug users. Univariate and multivariate binary logistic regression models were performed to analyze the association between the personal networks and sharing of needles or syringes. RESULTS: The average network size was similar in both the districts. Recruitment analysis indicates injecting drug users were mostly engaged in mixed age group setting for injecting practice. Ever married and new injectors showed lack of in-group ties. Younger injecting drug users had mainly recruited older injecting drug users from their personal network. In logistic regression analysis, higher personal network was found to be significantly associated with increased likelihood of injecting risky behaviors. CONCLUSION: Because of mixed personal network of new injectors and higher network density associated with HIV exposure, older injecting drug users may act as a link for HIV transmission or other blood-borne infections to new injectors and also to their sexual partners. The information from this study may be useful to understanding the network pattern of injecting drug users for enriching the HIV prevention in this region. PMID- 28673304 TI - Lost in translation? A multilingual Query Builder improves the quality of PubMed queries: a randomised controlled trial. AB - BACKGROUND: MEDLINE is the most widely used medical bibliographic database in the world. Most of its citations are in English and this can be an obstacle for some researchers to access the information the database contains. We created a multilingual query builder to facilitate access to the PubMed subset using a language other than English. The aim of our study was to assess the impact of this multilingual query builder on the quality of PubMed queries for non-native English speaking physicians and medical researchers. METHODS: A randomised controlled study was conducted among French speaking general practice residents. We designed a multi-lingual query builder to facilitate information retrieval, based on available MeSH translations and providing users with both an interface and a controlled vocabulary in their own language. Participating residents were randomly allocated either the French or the English version of the query builder. They were asked to translate 12 short medical questions into MeSH queries. The main outcome was the quality of the query. Two librarians blind to the arm independently evaluated each query, using a modified published classification that differentiated eight types of errors. RESULTS: Twenty residents used the French version of the query builder and 22 used the English version. 492 queries were analysed. There were significantly more perfect queries in the French group vs. the English group (respectively 37.9% vs. 17.9%; p < 0.01). It took significantly more time for the members of the English group than the members of the French group to build each query, respectively 194 sec vs. 128 sec; p < 0.01. CONCLUSIONS: This multi-lingual query builder is an effective tool to improve the quality of PubMed queries in particular for researchers whose first language is not English. PMID- 28673305 TI - Oligomerization triggered by foldon: a simple method to enhance the catalytic efficiency of lichenase and xylanase. AB - BACKGROUND: Effective and simple methods that lead to higher enzymatic efficiencies are highly sough. Here we proposed a foldon-triggered trimerization of the target enzymes with significantly improved catalytic performances by fusing a foldon domain at the C-terminus of the enzymes via elastin-like polypeptides (ELPs). The foldon domain comprises 27 residues and can forms trimers with high stability. RESULTS: Lichenase and xylanase can hydrolyze lichenan and xylan to produce value added products and biofuels, and they have great potentials as biotechnological tools in various industrial applications. We took them as the examples and compared the kinetic parameters of the engineered trimeric enzymes to those of the monomeric and wild type ones. When compared with the monomeric ones, the catalytic efficiency (k cat /K m ) of the trimeric lichenase and xylanase increased 4.2- and 3.9- fold. The catalytic constant (k cat ) of the trimeric lichenase and xylanase increased 1.8- fold and 5.0- fold than their corresponding wild-type counterparts. Also, the specific activities of trimeric lichenase and xylanase increased by 149% and 94% than those of the monomeric ones. Besides, the recovery of the lichenase and xylanase activities increased by 12.4% and 6.1% during the purification process using ELPs as the non chromatographic tag. The possible reason is the foldon domain can reduce the transition temperature of the ELPs. CONCLUSION: The trimeric lichenase and xylanase induced by foldon have advantages in the catalytic performances. Besides, they were easier to purify with increased purification fold and decreased the loss of activities compared to their corresponding monomeric ones. Trimerizing of the target enzymes triggered by the foldon domain could improve their activities and facilitate the purification, which represents a simple and effective enzyme-engineering tool. It should have exciting potentials both in industrial and laboratory scales. PMID- 28673307 TI - Limited evidence to recommend lactate kinetics-guided therapy. PMID- 28673306 TI - Toxicity and antitumor potential of Mesosphaerum sidifolium (Lamiaceae) oil and fenchone, its major component. AB - BACKGROUND: The essential oil from Mesosphaerum sidifolium (L'Herit.) Harley & J.F.B.Pastore (syn. Hyptis umbrosa), Lamiaceae (EOM), and its major component, have been tested for toxicity and antitumor activity. METHODS: EOM was obtained from aerial parts of M. sidifolium subjected to hydro distillation, and gas chromatography-mass spectrometry was used to characterize the EOM chemical composition. The toxicity was evaluated using haemolysis assay, and acute toxicity and micronucleus tests. Ehrlich ascites carcinoma model was used to evaluate the in vivo antitumor activity and toxicity of EOM (50, 100 and 150 mg/kg), and fenchone (30 and 60 mg/kg) after 9 d of treatment. RESULTS: The EOM major components were fenchone (24.8%), cubebol (6.9%), limonene (5.4%), spathulenol (4.5%), beta-caryophyllene (4.6%) and alpha-cadinol (4.7%). The HC50 (concentration producing 50% haemolysis) was 494.9 MUg/mL for EOM and higher than 3000 MUg/mL for fenchone. The LD50 for EOM was approximately 500 mg/kg in mice. The essential oil induced increase of micronucleated erythrocytes only at 300 mg/kg, suggesting moderate genotoxicity. EOM (100 or 150 mg/kg) and fenchone (60 mg/kg) reduced all analyzed parameters (tumor volume and mass, and total viable cancer cells). Survival also increased for the treated animals with EOM and fenchone. For EOM 150 mg/kg and 5-FU treatment, most cells were arrested in the G0/G1 phase, whereas for fenchone, cells arrested in the S phase, which represents a blockage in cell cycle progression. Regarding the toxicological evaluation, EOM induced weight loss, but did not induce hematological, biochemical or histological (liver and kidneys) toxicity. Fenchone induced decrease of AST and ALT, suggesting liver damage. CONCLUSIONS: The data showed EOM caused in vivo cell growth inhibition on Ehrlich ascites carcinoma model by inducing cell cycle arrest, without major changes in the toxicity parameters evaluated. In addition, this activity was associated with the presence of fenchone, its major component. PMID- 28673308 TI - Two cases of low birth weight infant survival by prehospital emergency hysterotomy. AB - BACKGROUND: During maternal cardiac arrest, emergency hysterotomy (EH) is recommended after four minutes of resuscitation, if no signs of spontaneous circulation are detected. This extreme procedure is believed to be potentially beneficial for both the mother and the infant. Both maternal and neonatal survivals seem to be associated to the time delay between the cardiac arrest and the delivery and in-hospital resuscitation location. In addition to this, gestational age is an important determinant to neonatal outcome. CASE PRESENTATION: We report two emergency hysterotomies executed in an out-of hospital location. The infants delivered by EH were low birth weight infants and born 20-23 min after maternal cardiac arrest. Both infants survived and had normal physical and neurological growth at the age of two years. Unfortunately, mothers in these both cases died in the field. CONCLUSION: Contrary to earlier beliefs, it is possible to perform a successful EH also in out-of-hospital setting, even with incomplete surgical skills. However, training and preparation are extremely important for achieving the highest possible readiness to treat maternal cardiac arrest situations also prehospitally. PMID- 28673309 TI - Abnormal circadian oscillation of hippocampal MAPK activity and power spectrums in NF1 mutant mice. AB - Studies have implied that the circadian oscillation of mitogen-activated protein kinase (MAPK) signal pathways is crucial for hippocampus-dependent memory. NF1 mouse models (Nf1 heterozygous null mutants; Nf1 +/-) displayed enhanced MAPK activity in the hippocampus and resulted in memory deficits. We assumed a link between MAPK pathways and hippocampal rhythmic oscillations, which have never been explored in Nf1 +/- mice. We demonstrated that the level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation in Nf1 +/- mice were significantly higher at nighttime than at daytime. Moreover, the in vivo recording revealed that for the Nf1 +/- group, the power spectral density of theta rhythm significantly decreased and the firing rates of pyramidal neurons increased. Our results indicated that the hippocampal MAPK oscillation and theta rhythmic oscillations in Nf1 +/- mice were disturbed and hinted about a possible mechanism for the brain dysfunction in Nf1 +/- mice. PMID- 28673310 TI - The evaluation of enhanced feedback interventions to reduce unnecessary blood transfusions (AFFINITIE): protocol for two linked cluster randomised factorial controlled trials. AB - BACKGROUND: Blood for transfusion is a frequently used clinical intervention, and is also a costly and limited resource with risks. Many transfusions are given to stable and non-bleeding patients despite no clear evidence of benefit from clinical studies. Audit and feedback (A&F) is widely used to improve the quality of healthcare, including appropriate use of blood. However, its effects are often inconsistent, indicating the need for coordinated research including more head-to head trials comparing different ways of delivering feedback. A programmatic series of research projects, termed the 'Audit and Feedback INterventions to Increase evidence-based Transfusion practIcE' (AFFINITIE) programme, aims to test different ways of developing and delivering feedback within an existing national audit structure. METHODS: The evaluation will comprise two linked 2*2 factorial, cross-sectional cluster-randomised controlled trials. Each trial will estimate the effects of two feedback interventions, 'enhanced content' and 'enhanced follow-on support', designed in earlier stages of the AFFINITIE programme, compared to current practice. The interventions will be embedded within two rounds of the UK National Comparative Audit of Blood Transfusion (NCABT) focusing on patient blood management in surgery and use of blood transfusions in patients with haematological malignancies. The unit of randomisation will be National Health Service (NHS) trust or health board. Clusters providing care relevant to the audit topics will be randomised following each baseline audit (separately for each trial), with stratification for size (volume of blood transfusions) and region (Regional Transfusion Committee). The primary outcome for each topic will be the proportion of patients receiving a transfusion coded as unnecessary. For each audit topic a linked, mixed-method fidelity assessment and cost effectiveness analysis will be conducted in parallel to the trial. DISCUSSION: AFFINITIE involves a series of studies to explore how A&F may be refined to change practice including two cluster randomised trials linked to national audits of transfusion practice. The methodology represents a step-wise increment in study design to more fully evaluate the effects of two enhanced feedback interventions on patient- and trust-level clinical, cost, safety and process outcomes. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN15490813. PMID- 28673311 TI - A decision support system for electrode shaping in multi-pad FES foot drop correction. AB - BACKGROUND: Functional electrical stimulation (FES) can be applied as an assistive and therapeutic aid in the rehabilitation of foot drop. Transcutaneous multi-pad electrodes can increase the selectivity of stimulation; however, shaping the stimulation electrode becomes increasingly complex with an increasing number of possible stimulation sites. We described and tested a novel decision support system (DSS) to facilitate the process of multi-pad stimulation electrode shaping. The DSS is part of a system for drop foot treatment that comprises a custom-designed multi-pad electrode, an electrical stimulator, and an inertial measurement unit. METHODS: The system was tested in ten stroke survivors (3-96 months post stroke) with foot drop over 20 daily sessions. The DSS output suggested stimulation pads and parameters based on muscle twitch responses to short stimulus trains. The DSS ranked combinations of pads and current amplitudes based on a novel measurement of the quality of the induced movement and classified them based on the movement direction (dorsiflexion, plantar flexion, eversion and inversion) of the paretic foot. The efficacy of the DSS in providing satisfactory pad-current amplitude choices for shaping the stimulation electrode was evaluated by trained clinicians. The range of paretic foot motion was used as a quality indicator for the chosen patterns. RESULTS: The results suggest that the DSS output was highly effective in creating optimized FES patterns. The position and number of pads included showed pronounced inter-patient and inter session variability; however, zones for inducing dorsiflexion and plantar flexion within the multi-pad electrode were clearly separated. The range of motion achieved with FES was significantly greater than the corresponding active range of motion (p < 0.05) during the first three weeks of therapy. CONCLUSIONS: The proposed DSS in combination with a custom multi-pad electrode design covering the branches of peroneal and tibial nerves proved to be an effective tool for producing both the dorsiflexion and plantar flexion of a paretic foot. The results support the use of multi-pad electrode technology in combination with automatic electrode shaping algorithms for the rehabilitation of foot drop. TRIAL REGISTRATION: This study was registered at the Current Controlled Trials website with ClinicalTrials.gov ID NCT02729636 on March 29, 2016. PMID- 28673312 TI - Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial. AB - BACKGROUND: The Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration jurisdiction over the regulation of all tobacco products, including their nicotine content. Under this act, a major strategy to reduce harm from cigarette tobacco is lowering the nicotine content without causing unintended adverse consequences. Initial research on reduced nicotine content (RNC) cigarettes has shown that smokers of these cigarettes gradually decrease their smoking frequency and biomarkers of exposure. The effectiveness of this strategy needs to be demonstrated in different populations whose response to RNC cigarettes might be substantially mediated by personal or environmental factors, such as low socioeconomic status (SES) populations. This study aims to evaluate the response to a reduced nicotine intervention in low SES smokers, as defined here as those with less than 16 years of education, by switching smokers from high nicotine commercial cigarettes to RNC cigarettes. METHODS/DESIGN: Adults (N = 280) who have smoked five cigarettes or more per day for the past year, have not made a quit attempt in the prior month, are not planning to quit, and have less than 16 years of education are recruited into a two-arm, double-blinded randomized controlled trial. First, participants smoke their usual brand of cigarettes for 1 week and SPECTRUM research cigarettes containing a usual amount of nicotine for 2 weeks. During the experimental phase, participants are randomized to continue smoking SPECTRUM research cigarettes that contain either (1) usual nicotine content (UNC) (11.6 mg/cigarette) or (2) RNC (11.6 to 0.2 mg/cigarette) over 18 weeks. During the final phase of the study, all participants are offered the choice to quit smoking with nicotine replacement therapy, continue smoking the research cigarettes, or return to their usual brand of cigarettes. The primary outcomes of the study include retention rates and compliance with using only research cigarettes and no use of other nicotine containing products. Secondary outcomes are tobacco smoke biomarkers, nicotine dependence measures, smoking topography, stress levels, and adverse health consequences. DISCUSSION: Results from this study will provide information on whether low SES smokers can maintain a course of progressive nicotine reduction without increases in incidence of adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01928719 . Registered on 21 August 2013. PMID- 28673314 TI - Cardiovascular disease risk profiles in inflammatory joint disease entities. AB - BACKGROUND: Patients with inflammatory joint diseases (IJD) have increased risk of cardiovascular disease (CVD). Our aim was to compare CVD risk profiles in patients with IJD, including rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) and evaluate the future risk of CVD. METHODS: The prevalence and numbers of major CVD risk factors (CVD-RFs) (hypertension, elevated cholesterol, obesity, smoking, and diabetes mellitus) were estimated in patients with RA, axSpA and PsA. Relative and absolute risk of CVD according to Systematic Coronary Risk Evaluation (SCORE) was calculated. RESULTS: In total, 3791 patients were included. CVD was present in 274 patients (7.2%). Of those without established CVD; hypertension and elevated cholesterol were the most frequent CVD-RFs, occurring in 49.8% and 32.8% of patients. Patients with PsA were more often hypertensive and obese. Overall, 73.6% of patients had a minimum of one CVD-RF, which increased from 53.2% among patients aged 30 to <45 years, to 86.2% of patients aged 60 to <=80 years. Most patients (93.5%) had low/moderate estimated risk of CVD according to SCORE. According to relative risk estimations, 35.2% and 24.7% of patients had two or three times risk or higher, respectively, compared to individuals with no CVD-RFs. CONCLUSIONS: In this nationwide Norwegian project, we have shown for the first time that prevalence and numbers of CVD-RFs were relatively comparable across the three major IJD entities. Furthermore, estimated absolute CVD risk was low, but the relative risk of CVD was markedly high in patients with IJD. Our findings indicate the need for CVD risk assessment in all patients with IJD. PMID- 28673315 TI - Mortality due to traumatic spinal cord injuries in Europe: a cross-sectional and pooled analysis of population-wide data from 22 countries. AB - BACKGROUND: Traumatic spinal cord injuries (TSCI) pose a significant burden globally, while existing epidemiological data-especially on population mortality are limited. The aim of this study was to calculate the age-standardized population mortality rates attributable to TSCI in 22 European countries, along with the pooled age-standardized mortality rate attributable to TSCI in Europe. METHODS: A descriptive cross-sectional epidemiological study was conducted. Crude and age-standardized mortality rates attributable to TSCI for the year 2012 for 22 European countries were compared using data from death certificates provided by Eurostat. Pooled age-standardized mortality rates were calculated using the random effects model, and overall number of cases were estimated by extrapolating our findings to the populations of EU and Europe (48 countries), in 2012. RESULTS: A total of 1840 TSCI-related deaths were identified, of which 1084 (59%) were males. The pooled age-standardized TSCI-related mortality rate of 6.7 per million (95% CI: 5.2 to 8.2) overall, 9.4 (95% CI: 7.3 to 11.5) for males, and 4.5 (95% CI: 3.4 to 5.6) for females. Extrapolating our results, 3152 (95% CI: 2441 to 3915) deaths would occur in 2012 in the EU-28 and 4570 (95% CI: 3538 to 5675) deaths in the whole Europe. TSCI-related deaths contributed by 2% (95% CI: 1.8% to 2.2%) to the overall injury related mortality. 61% of fatal TSCI were located in the cervical spine area. CONCLUSION: To our knowledge, this is the largest study that reports TSCI-related population-based mortalities to date which brings valuable information that can inform further research or prevention strategies. Our study presents a comprehensive and large-scale overview of TSCI related population mortality in Europe. With an estimated toll of nearly five thousand lives that could be potentially saved by prevention, our findings confirm TSCI as an important cause of injury related deaths in Europe. Further action towards harmonization of case ascertainment and towards prevention strategies targeted mainly on the elderly is warranted. PMID- 28673313 TI - MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. AB - The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53 regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers. PMID- 28673316 TI - Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis. AB - BACKGROUND: Upregulation of estrogen receptor beta (ERbeta) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERbeta and breast carcinogenesis is still missing. METHODS: To study the role of ERbeta in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERbeta and p53 in the mammary gland epithelium. For epithelium specific knockout of ERbeta and p53, ERbeta F/F and p53 F/F mice were crossed to transgenic mice that express the Cre recombinase under the control of the human keratin 14 promoter. RESULTS: Somatic loss of ERbeta significantly accelerated formation of p53-deficient mammary tumors. Loss of the receptor also resulted in the development of less differentiated carcinomas with stronger spindle cell morphology and decreased expression of luminal epithelial markers. CONCLUSIONS: Our results show that synergism between ERbeta and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression. PMID- 28673317 TI - The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis. AB - BACKGROUND: UBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown. METHODS: Mass spectrometry was applied to identify c-Maf ubiquitination-associated proteins. Immunoprecipitation was applied for c-Maf and UBE2O interaction. Immunoblotting was used for Maf protein stability. Luciferase assay was used for c-Maf transcriptional activity. Lentiviral infections were applied for UBE2O function in multiple myeloma (MM) cells. Flow cytometry and nude mice xenografts were applied for MM cell apoptosis and tumor growth assay, respectively. RESULTS: UBE2O was found to interact with c-Maf, a critical transcription factor in MM, by the affinity purification/tandem mass spectrometry assay and co-immunoprecipitation assays. Subsequent studies showed that UBE2O mediated c-Maf polyubiquitination and degradation. Moreover, UBE2O downregulated the transcriptional activity of c-Maf and the expression of cyclin D2, a typical gene modulated by c-Maf. DNA microarray revealed that UBE2O was expressed in normal bone marrow cells but downregulated in MGUS, smoldering MM and MM cells, which was confirmed by RT-PCR in primary MM cells, suggesting its potential role in myeloma pathophysiology. When UBE2O was restored, c-Maf protein in MM cells was significantly decreased and MM cells underwent apoptosis. Furthermore, the human MM xenograft in nude mice showed that re-expression of UBE2O delayed the growth of myeloma xenografts in nude mice in association with c-Maf downregulation and activation of the apoptotic pathway. CONCLUSIONS: UBE2O mediates c-Maf polyubiquitination and degradation, induces MM cell apoptosis, and suppresses myeloma tumor growth, which provides a novel insight in understanding myelomagenesis and UBE2O biology. PMID- 28673318 TI - Choice of relative or cause-specific approach to cancer survival analysis impacts estimates differentially by cancer type, population, and application: evidence from a Canadian population-based cohort study. AB - BACKGROUND: Cause-specific (CS) and net survival in a relative survival framework (RS) are two of the most common methods for estimating cancer survival. In this paper, we assess the differences in results produced by two permutations of cause specific and relative survival applied to estimating cancer survival and disparities in cancer survival, using data from First Nations and non-Aboriginal populations in Canada. METHODS: Subjects were members of the 1991 Canadian Census Mortality Cohort, a population-based cohort of adult respondents to the 1991 Long Form Census who have been followed up for incident cancers and death through linkage to administrative databases. We compared four methods: relative survival analyses with ethnicity-specific life tables (RS-ELT); relative survival with general population life tables (RS-GLT); cause-specific survival with a broad definition of cancer death (CS-Broad); and cause-specific survival with a narrow definition of cause of death (CS-Narrow) and applied these to the nine most common cancers among First Nations. RESULTS: Apart from breast and prostate cancers, RS-ELT, RS-GLT, and CS-Broad tended to produce similar estimates of age standardized five-year survival, whereas CS-Narrow yielded higher estimates of survival. CS-Narrow estimates were particularly unlike those based on the other methods for cancers of the digestive and respiratory tracts. Estimates of disparities in survival were generally comparable across the four methods except for breast and prostate cancers. CONCLUSIONS: Cancer surveillance efforts in sub populations defined by race, ethnicity, geography, socioeconomic status, or similar factors are necessary for identifying disparities and monitoring progress toward reducing them. In the absence of routine monitoring of cancer survival and cancer survival disparities in these populations, estimates generated by different methods will inevitably be compared over time and across populations. In this study, we demonstrate that caution should be exercised in making these comparisons, particularly in interpreting cause-specific survival rates with an unknown or narrow definition of cancer death and in estimates of breast and prostate cancer survival and/or disparities in survival generated by different methods. PMID- 28673319 TI - In vitro and in vivo cytotoxicity of troglitazone in pancreatic cancer. AB - BACKGROUND: Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that has been investigated as a potential chemopreventive and chemotherapeutic agent. However, the antitumor efficacy and mechanisms of TGZ in pancreatic cancer have not been extensively investigated. This study was performed to investigate the in vitro and in vivo effects of TGZ against pancreatic cancer cell lines, as well as its action mechanisms in terms of PPARgamma dependency and the Akt and mitogen-activated protein kinase (MAPK) pathways. We also evaluated the effects of TGZ on cell invasion and migration. METHODS: MIA Paca2 and PANC-1 human pancreatic cancer cell lines were used. Cell viability and caspase-3 activity were detected using fluorescent reagents, and chromatin condensation was observed after staining the cells with Hoechst 33342. Protein expression levels were detected by western blot analysis. Invasion and migration assays were performed using 24-well chambers. The in vivo antitumor effects of TGZ were investigated in nude mice inoculated with MIA Paca2 cells. Mice were orally administered TGZ (200 mg/kg) every day for 5 weeks, and tumor volumes were measured bi-dimensionally. RESULTS: TGZ showed dose-dependent cytotoxicity against both cell lines, which was not attenuated by a PPARgamma inhibitor. Further, TGZ induced chromatin condensation, elevated caspase-3 activity, and increased Bax/Bcl-2 relative expression in MIA Paca2 cells. TGZ also increased phosphorylation of Akt and MAPK (ERK/p38/JNK) in both cell lines, and a JNK inhibitor significantly increased the viability of MIA Paca2 cells. TGZ moderately inhibited cell migration. Tumor growth in the MIA Paca2 xenograft model was inhibited by TGZ administration, while mouse body weights in the treated group were not different from those of the vehicle administration group. CONCLUSION: We demonstrated for the first time the in vivo antitumor effects of TGZ in pancreatic cancer without marked adverse effects. TGZ induced mitochondria mediated apoptosis in MIA Paca2 cells, and its cytotoxic effects were PPARgamma independent and occurred via the JNK pathway. Our results indicate that TGZ is a potential approach for the treatment of pancreatic cancer and warrants further studies regarding its detailed mechanisms and clinical efficacy. PMID- 28673320 TI - The clinical importance of tumour-infiltrating macrophages and dendritic cells in periampullary adenocarcinoma differs by morphological subtype. AB - BACKGROUND: Dendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype. METHODS: The density of tolerogenic immature CD1a+ dendritic cells (DC), and MARCO+, CD68+ and CD163+ tissue-associated macrophages (TAM) was analysed by immunohistochemistry in tissue micro arrays with tumours from 175 consecutive cases of periampullary adenocarcinoma who had undergone pancreaticoduodenectomy, 110 with pancreatobiliary type (PB-type) and 65 with intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analyses were applied to determine the impact of immune cell infiltration on 5-year overall survival (OS). RESULTS: High density of CD1a+ DCs was an independent prognostic factor for a reduced OS in PB-type but not in I-type tumours (adjusted HR = 2.35; 95% CI 1.13-4.87). High density of CD68+ and CD163+ TAM was significantly associated with poor OS in the whole cohort, however only in unadjusted analysis (HR = 1.67; 95% CI 1.06-2.63, and HR = 1.84; 95% CI 1.09-3.09, respectively) and not in strata according to morphological subtype. High density of MARCO+ macrophages was significantly associated with poor prognosis in I-type but not in PB-type tumours (HR = 2.14 95% CI 1.03-4.44), and this association was only evident in patients treated with adjuvant chemotherapy. The prognostic value of the other investigated immune cells did not differ significantly in strata according to adjuvant chemotherapy. CONCLUSIONS: The results from this study demonstrate that high infiltration of tolerogenic immature DCs independently predicts a shorter survival in patients with PB-type periampullary adenocarcinoma, and that high density of the MARCO+ subtype of TAMs predicts a shorter survival in patients with I-type tumours. These results emphasise the importance of taking morphological subtype into account in biomarker studies related to periampullary cancer, and indicate that therapies targeting dendritic cells may be of value in the treatment of PB-type tumours, which are associated with the worst prognosis. PMID- 28673321 TI - Open-chest versus closed-chest cardiopulmonary resuscitation in blunt trauma: analysis of a nationwide trauma registry. AB - BACKGROUND: Although open-chest cardiopulmonary resuscitation (OCCPR) is often considered as the last salvage maneuver in critically injured patients, evidence on the effectiveness of OCCPR has been based only on the descriptive studies of limited numbers of cases or expert opinions. This study aimed to compare the effectiveness of OCCPR with that of closed-chest cardiopulmonary resuscitation (CCCPR) in an emergency department (ED). METHODS: A nationwide registry-based, retrospective cohort study was conducted. Patients with blunt trauma, undergoing cardiopulmonary resuscitation (CPR) in an ED between 2004 and 2015 were identified and divided into OCCPR and CCCPR groups. Their outcomes (survival to hospital discharge and survival over 24 hours following ED arrival) were compared with propensity score matching analysis and instrumental variable analysis. RESULTS: A total of 6510 patients (OCCPR, 2192; CCCPR, 4318) were analyzed. The in-hospital and 24-hour survival rates in OCCPR patients were 1.8% (40/2192) and 5.6% (123/2192), and those in CCCPR patients were 3.6% (156/4318) and 9.6% (416/4318), respectively. In the propensity score-matched subjects, OCCPR patients (n = 1804) had significantly lower odds of survival to hospital discharge (odds ratio (95% CI)) = 0.41 (0.25-0.68)) and of survival over 24 hours following ED arrival (OR (95% CI) = 0.59 (0.45-0.79)) than CCCPR patients (n = 1804). Subgroup analysis revealed that OCCPR was associated with a poorer outcome compared to CCCPR in patients with severe pelvis and lower extremity injury. CONCLUSIONS: In this large cohort, OCCPR was associated with reduced in-hospital and 24-hour survival rates in patients with blunt trauma. Further comparisons between OCCPR and CCCPR using additional information, such as time course details in pre-hospital and ED settings, anatomical details regarding region of injury, and neurological outcomes, are necessary. PMID- 28673322 TI - The effect of electroacupuncture combined with donepezil on cognitive function in Alzheimer's disease patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Alzheimer's disease is a progressive neurodegenerative disease. Although some of the current treatments offer some symptomatic relief, this disease cannot be cured at present. Electroacupuncture may be effective for Alzheimer's disease for cognitive function, but the evidence for its effectiveness is still limited. The aim of this study is to evaluate the add-on effect of electroacupuncture to donepezil for improving the cognitive function of Alzheimer's disease. METHODS/DESIGN: A total of 334 participants with Alzheimer's disease will be randomly assigned to either an electroacupuncture combined with donepezil group or a donepezil group with a ratio of 1:1. Participants in the electroacupuncture combined with donepezil group will receive electroacupuncture in addition to donepezil for 12 weeks and will keep taking donepezil for the following 24 weeks. Participants in the control group will take donepezil only. The primary outcome is the change from baseline in the total score of the Alzheimer's Disease Assessment Scale-cognition at week 12. A follow-up will be conducted 24 weeks after the treatment. DISCUSSION: We expect to verify the hypothesis that acupuncture in addition to donepezil is better than donepezil in improving the cognitive function of patients with Alzheimer's disease. This trial has a limitation that participant blinding is impossible. TRIAL REGISTRATION: Clinical Trials.gov: ID: NCT02305836 . Registered on 13 November 2014. PMID- 28673323 TI - Bracelet- and self-directed observational therapy for control of tuberculosis: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Approximately 80% of global tuberculosis (TB) cases occur in low resource settings, with little opportunity for TB control. We hypothesized that the rapid increase in smartphone users and advances in digital technology would render bracelet-based applications possible; specifically, that bracelet- and self-directed observational therapy (BSDOT) can be used by patients with TB to ensure adherence to TB medication regimens and by basic village physicians to monitor care. This will ultimately allow TB to be controlled in low-resource environments. METHODS AND DESIGN: This study will have three phases: development of a bracelet capable of storing pills and recording adherence to medication regimens; creation of a BSDOT smartphone application capable of supporting reminders to patients and health care interactions between patients and village physicians; and performance of a cluster randomized controlled trial in Hunan Province, China. Patients in the intervention group will receive free bracelets and smartphones, and their daily medication intake will be directed by the smartphones; the control group will receive no intervention. The primary outcome will be the TB treatment result as defined by the World Health Organization (WHO) as follows: Cured, Treatment completed, Treatment failed, Died, Lost to follow up, Not evaluated, or Treatment success. The secondary outcome will be treatment adherence, defined as the percentage of patients receiving TB treatment who missed fewer than 5% of doses. We will also assess self-reported adherence using the Morisky, Green, and Levine Adherence Scale (MGLS) and evaluate respondents' knowledge about TB and quality of life. A regression model will be used to explore whether the interventions improve drug adherence and other outcome measures. DISCUSSION : This will be a powerful means by which to strengthen TB control and prevent TB, especially multidrug-resistant epidemics of the disease. In addition, our novel smartphone-based tool can be readily adopted for use in low-resource remote environments with limited health care facilities and few economic assets. ETHICS AND DISSEMINATION: The protocol has been approved by the Ethics Committee of Xiangya School of Public Health, Central South University (reference number: XYGW-2016-14). TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-16008424 . Registered on 5 June 2016. PMID- 28673324 TI - Is it time to consider visual feedback systems the gold standard for chest compression skill acquisition? PMID- 28673325 TI - Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice. AB - BACKGROUND: Maternal and paternal high-fat (HF) diet intake before and/or during pregnancy increases mammary cancer risk in several preclinical models. We studied if maternal consumption of a HF diet that began at a time when the fetal primordial germ cells travel to the genital ridge and start differentiating into germ cells would result in a transgenerational inheritance of increased mammary cancer risk. METHODS: Pregnant C57BL/6NTac mouse dams were fed either a control AIN93G or isocaloric HF diet composed of corn oil high in n-6 polyunsaturated fatty acids between gestational days 10 and 20. Offspring in subsequent F1-F3 generations were fed only the control diet. RESULTS: Mammary tumor incidence induced by 7,12-dimethylbenz[a]anthracene was significantly higher in F1 (p < 0.016) and F3 generation offspring of HF diet-fed dams (p < 0.040) than in the control offspring. Further, tumor latency was significantly shorter (p < 0.028) and burden higher (p < 0.027) in F1 generation HF offspring, and similar trends were seen in F3 generation HF offspring. RNA sequencing was done on normal mammary glands to identify signaling differences that may predispose to increased breast cancer risk by maternal HF intake. Analysis revealed 1587 and 4423 differentially expressed genes between HF and control offspring in F1 and F3 generations, respectively, of which 48 genes were similarly altered in both generations. Quantitative real-time polymerase chain reaction analysis validated 13 chosen up- and downregulated genes in F3 HF offspring, but only downregulated genes in F1 HF offspring. Ingenuity Pathway Analysis identified upregulation of Notch signaling as a key alteration in HF offspring. Further, knowledge-fused differential dependency network analysis identified ten node genes that in the HF offspring were uniquely connected to genes linked to increased cancer risk (ANKEF1, IGFBP6, SEMA5B), increased resistance to cancer treatments (SLC26A3), poor prognosis (ID4, JAM3, TBX2), and impaired anticancer immunity (EGR3, ZBP1). CONCLUSIONS: We conclude that maternal HF diet intake during pregnancy induces a transgenerational increase in offspring mammary cancer risk in mice. The mechanisms of inheritance in the F3 generation may be different from the F1 generation because significantly more changes were seen in the transcriptome. PMID- 28673326 TI - Therapeutic effect of a novel histone deacetylase 6 inhibitor, CKD-L, on collagen induced arthritis in vivo and regulatory T cells in rheumatoid arthritis in vitro. AB - BACKGROUND: Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA). METHODS: CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry. RESULTS: In the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3+ T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1beta, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation. CONCLUSION: CKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1beta, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA. PMID- 28673327 TI - Special role of JUN in papillary thyroid carcinoma based on bioinformatics analysis. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignancy in thyroid tissue, and the number of patients with PTC has been increasing in recent years. Discovering the mechanism of PTC genesis and progression and finding new potential diagnostic biomarkers/therapeutic target genes of PTC are of great significance. METHODS: In this work, the datasets GSE3467 and GSE3678 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified with the limma package in R. GO function and KEGG pathway enrichment were conducted with DAVID tool. The interaction network of the DEGs and other genes was performed with Cytoscape plugin BisoGenet, while clustering analysis was performed with Cytoscape plugin ClusterOne. RESULTS: A total of 1800 overlapped DEGs were detected in two datasets. Enrichment analysis of the DEGs found that the top three enriched GO terms in three ontologies and four significantly enriched KEGG pathways were mainly concerned with intercellular junction and extracellular matrix components. Interaction network analysis found that transcription factor hepatocyte nuclear factor 4, alpha (HNF4A) and DEG JUN had higher connection degrees. Clustering analysis indicated that two function modules, in which JUN was playing a central role, were highly relevant to PTC genesis and progression. CONCLUSIONS: JUN may be used as a specific diagnostic biomarker/therapeutic molecular target of PTC. However, further experiments are still needed to confirm our results. PMID- 28673328 TI - Effect of a 6-month pedometer-based walking intervention on functional capacity in patients with chronic heart failure with reduced (HFrEF) and with preserved (HFpEF) ejection fraction: study protocol for two multicenter randomized controlled trials. AB - BACKGROUND: Regular physical activity is recommended for patients with chronic heart failure to improve their functional capacity, and walking is a popular, effective, and safe form of physical activity. Pedometers have shown potential to increase the amount of walking across a range of chronic diseases, but it is unknown whether a pedometer-based intervention improves functional capacity and neurohumoral modulation in heart failure patients. METHODS: Two multicenter randomized controlled trials will be conducted in parallel: one in patients with chronic heart failure with reduced ejection fraction (HFrEF), the other in patients with chronic heart failure with preserved ejection fraction (HFpEF). Each trial will consist of a 6-month intervention with an assessment at baseline, at 3 months, at the end of the intervention, and 6 months after completing the intervention. Each trial will aim to include a total of 200 physically inactive participants with chronic heart failure who will be randomly assigned to intervention or control arms. The 6-month intervention will consist of an individualized pedometer-based walking program with weekly step goals, behavioral face-to-face sessions with a physician, and regular telephone calls with a research nurse. The intervention will be based on effective behavioral principles (goal setting, self-monitoring, personalized feedback). The primary outcome is the change in 6-min walk distance at the end of the 6-month intervention. Secondary outcomes include changes in serum biomarkers levels, pulmonary congestion assessed by ultrasound, average daily step count measured by accelerometry, anthropometric measures, symptoms of depression, health-related quality of life, self-efficacy, and MAGGIC risk score. DISCUSSION: To our knowledge, these are the first studies to evaluate a pedometer-based walking intervention in patients with chronic heart failure with either reduced or preserved ejection fraction. The studies will contribute to a better understanding of physical activity promotion in heart failure patients to inform future physical activity recommendations and heart failure guidelines. Trial registration The trials are registered in ClinicalTrials.gov, identifiers: NCT03041610, registered 29 January 2017 (HFrEF), NCT03041376, registered 1 February 2017 (HFpEF). PMID- 28673329 TI - Experience and lessons from health impact assessment guiding prevention and control of HIV/AIDS in a copper mine project, northwestern Zambia. AB - BACKGROUND: To avoid or mitigate potential project-related adverse health effects, the Trident copper project in Kalumbila, northwestern Zambia, commissioned a health impact assessment. HIV was identified a priority health issue based on the local vulnerability to HIV transmission and experience from other mining projects in Africa. Hence, an HIV/AIDS management plan was developed, including community and workplace interventions, with HIV testing and counselling (HTC) being one of the key components. We present trends in HTC data over a 4-year period. METHODS: In 13 communities affected by the Trident project, HTC was implemented from 2012 onwards, using rapid diagnostic tests, accompanied by pre- and post-test counselling through trained personnel. In addition, HTC was initiated in the project workforce in 2013, coinciding with the launch of the mine development. HTC uptake and HIV positivity rates were assessed in the study population and linked to demographic factors using regression analysis. RESULTS: In total, 11,638 community members and 5564 workers have taken up HTC with an increase over time. The HIV positivity rate in the community was 3.0% in 2012 and 3.4% in 2015, while positivity rate in the workforce was 5.2% in 2013 and 4.3% in 2015. Females showed a significantly higher odds of having a positive test result than males (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.55-2.50 among women in the community and OR = 2.90, 95% CI: 1.74-4.84 among women in the workforce). HTC users in the 35-49 years age group were most affected by HIV, with an average positivity rate of 6.6% in the community sample and 7.9% in the workforce sample. These study groups had 4.50 and 4.95 higher odds of being positive, respectively, compared to their younger counterparts (15-24 years). CONCLUSIONS: While HTC uptake increased five-fold in the community and almost three-fold in the workplace, the HIV positivity rates were insignificantly higher in 2015 compared to 2012. Our data can be used alongside other surveillance data to track HIV transmission in this specific context. Guided by the health impact assessment, the HIV prevention and control programme was readily adapted to the current setting through the identification of socioeconomic and environmental determinants of health. PMID- 28673330 TI - UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression. AB - BACKGROUND: Uridine 5'-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naive patients. METHODS: We determined the expression of UGT2B15, UGT2B17, and UGT2B28 enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each protein's percent positive and H-score, a weighted score of staining intensity, and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were divided at the median and we tested the association between UGT2B17 group and risk of BCR. RESULTS: The median follow-up for all patients was 118 months (IQR: 85-144). Of 190, 83 (44%) patients developed BCR. We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend for an association between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found that patients with UGT2B17 higher levels of expression had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041), although this association was attenuated in the multivariable model (HR = 1.50, 95% CI 0.94 2.40, p = 0.088). CONCLUSIONS: Our findings suggest that UGT2B17 overexpression may be associated with a significant increased risk of BCR. These results are consistent with previous reports which showed UGT2B17 significantly expressed in advanced prostate cancer including prostate tumor metastases. PMID- 28673331 TI - TMPYP4 exerted antitumor effects in human cervical cancer cells through activation of p38 mitogen-activated protein kinase. AB - BACKGROUND: The aim of the present study was to investigate the potential effects of the 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4) on the proliferation and apoptosis of human cervical cancer cells and the underlying mechanisms by which TMPyP4 exerted its actions. RESULTS: After human cervical cancer cells were treated with different doses of TMPyP4, cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method, the apoptosis was observed by flow cytometry (FCM), and the expression of p38 mitogen-activated protein kinase (MAPK), phosphated p38 MAPK (p p38 MAPK), capase-3, MAPKAPK2 (MK-2) and poly ADP-ribose polymerase (PARP) was measured by Western blot analysis. The analysis revealed that TMPyP4 potently suppressed cell viability and induced the apoptosis of human cervical cancer cells in a dose-dependent manner. In addition, the up-regulation of p-p38 MAPK expression levels was detected in TMPyP4-treated human cervical cancer cells. However, followed by the block of p38 MAPK signaling pathway using the inhibitor SB203580, the effects of TMPyP4 on proliferation and apoptosis of human cervical cancer cells were significantly changed. CONCLUSIONS: It was indicated that TMPyP4-inhibited proliferation and -induced apoptosis in human cervical cancer cells was accompanied by activating the p38 MAPK signaling pathway. Taken together, our study demonstrates that TMPyP4 may represent a potential therapeutic method for the treatment of cervical carcinoma. PMID- 28673332 TI - A multicenter survey of first-line treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous non-small cell lung cancer in China (CTONG 1506). AB - BACKGROUND: In recent years, systemic chemotherapy and molecular targeted therapy have become standard first-line treatments for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The objective of this survey was to investigate first-line anticancer treatment patterns and gene aberration test status of patients with advanced nonsquamous NSCLC in China. METHODS: Patients included in this study had unresectable Stage IIIB/IV nonsquamous NSCLC and were admitted during August 2015 to March 2016 into one of 12 tertiary hospitals throughout China for first-line anticancer treatment. Patient data (demographics, NSCLC histologic type, Eastern Cooperative Oncology Group [ECOG] Performance Status [PS], gene aberration test and results [if performed], and first-line anticancer treatment regimen) were extracted from medical charts and entered into Medical Record Abstraction Forms (MERAFs), which were collated for analysis. RESULTS: Overall, 1041 MERAFs were collected and data from 932 MERAFs were included for analysis. Patients with unresectable Stage IIIB/IV nonsquamous NSCLC had a median age of 59 years, 56.4% were male, 58.2% were never smokers, 95.0% had adenocarcinoma, and 92.9% had an ECOG PS <=1. A total of 665 (71.4%) patients had gene aberration tests; 46.5% (309/665) had epidermal growth factor receptor (EGFR) gene mutations, 11.5% (48/416) had anaplastic lymphoma kinase (ALK) gene fusions, and 0.8% (1/128) had a c-ros oncogene 1 gene fusion. The most common first-line treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC was chemotherapy (72.5%, 676/932), followed by tyrosine kinase inhibitors (TKIs; 26.1%, 243/932), and TKIs plus chemotherapy (1.4%, 13/932). Most chemotherapy regimens were platinum-doublet regimens (93.5%, 631/676) and pemetrexed was the most common nonplatinum chemotherapy-backbone agent (70.2%, 443/631) in platinum doublet regimens. Most EGFR mutation-positive patients (66.3%, 205/309) were treated with EGFR-TKIs. CONCLUSIONS: Findings from our survey of 12 tertiary hospitals throughout China showed an increased rate of gene aberration testing, compared with those rates reported in previous surveys, for patients with advanced nonsquamous NSCLC. In addition, pemetrexed/platinum-doublet chemotherapy was the predominant first-line chemotherapy regimen for this population. Most patients were treated based on their gene aberration test status and results. PMID- 28673333 TI - Telephone consultations for general practice: a systematic review. AB - BACKGROUND: The use of information technology, including internet- and telephone based resources, is becoming an alternative and supporting method of providing many forms of services in a healthcare and health management setting. Telephone consultations provide a promising alternative and supporting service for face-to face general practice care. The aim of this review is to utilize a systematic review to collate evidence on the use of telephone consultation as an alternative to face-to-face general practice visits. METHODS: A systematic search of MEDLINE, CINAHL, The Cochrane Library, and the International Clinical Trials Registry Platform was performed using the search terms for the intervention (telephone consultation) and the comparator (general practice). Systematic reviews and randomized control trials that examined telephone consultation compared to normal face-to-face consultation in general practice were included in this review. Papers were reviewed, assessed for quality (Cochrane Collaboration's 'Risk of bias' tool) and data extracted and analysed. RESULTS: Two systematic reviews and one RCT were identified and included in the analysis. The RCT (N = 388) was of patients requesting same-day appointments from two general practices and patients were randomized to a same-day face-to-face appointment or a telephone call back consultation. There was a reduction in the time spent on consultations in the telephone group (1.5 min (0.6 to 2.4)) and patients in the telephone arm had 0.2 (0 to 0.3) more follow-up consultations than the face-to-face group. One systematic review focused on telephone consultation and triage on healthcare use, and included one RCT and one other observational study that examined telephone consultations. The other systematic review focused on patient access and included one RCT and four observational studies that examined telephone consultations. Both systematic reviews provided narrative interpretations of the evidence and concluded that telephone consultations provided an appropriate alternative to telephone consultations and reduced practice work load. CONCLUSION: There is a lack of high level evidence for telephone consultations in a GP setting; however, current evidence suggests that telephone consultations as an alternative to face to-face general practice consultations offers an appropriate option in certain settings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015025225. PMID- 28673334 TI - Population levels of wellbeing and the association with social capital. AB - BACKGROUND: This research investigates wellbeing at the population level across demographic, social and health indicators and assesses the association between wellbeing and social capital. METHOD: Data from a South Australian monthly chronic disease/risk factor surveillance system of randomly selected adults (mean age 48.7 years; range 16-99) from 2014/5 (n = 5551) were used. Univariable analyses compared wellbeing/social capital indicators, socio-demographic, risk factors and chronic conditions. Multi-nominal logistic regression modelling, adjusting for multiple covariates was used to simultaneously estimate odds ratios for good wellbeing (reference category) versus neither good nor poor, and good wellbeing versus poor wellbeing. RESULTS: 48.6% were male, mean age 48.7 (sd 18.3), 54.3% scored well on all four of the wellbeing indicators, and positive social capital indicators ranged from 93.1% for safety to 50.8% for control over decisions. The higher level of social capital corresponded with the good wellbeing category. Modeling showed higher odds ratios for all social capital variables for the lowest level of wellbeing. These higher odds ratios remained after adjusting for confounders. CONCLUSIONS: The relationship between wellbeing, resilience and social capital highlights areas for increased policy focus. PMID- 28673335 TI - Developing a framework for a novel multi-disciplinary, multi-agency intervention(s), to improve medication management in community-dwelling older people on complex medication regimens (MEMORABLE)--a realist synthesis. AB - BACKGROUND: Medication-related adverse events have been estimated to be responsible for 5700 deaths and cost the UK L750 million annually. This burden falls disproportionately on older people. Outcomes from interventions to optimise medication management are caused by multiple context-sensitive mechanisms. The MEdication Management in Older people: REalist Approaches BAsed on Literature and Evaluation (MEMORABLE) project uses realist synthesis to understand how, why, for whom and in what context interventions, to improve medication management in older people on complex medication regimes residing in the community, work. METHOD: This realist synthesis uses secondary data and primary data from interviews to develop the programme theory. A realist logic of analysis will synthesise data both within and across the two data sources to inform the design of a complex intervention(s) to help improve medication management in older people. 1. Literature review The review (using realist synthesis) contains five stages to develop an initial programme theory to understand why processes are more or less successful and under which situations: focussing of the research question; developing the initial programme theory; developing the search strategy; selection and appraisal based on relevance and rigour; and data analysis/synthesis to develop and refine the programme theory and context, intervention and mechanism configurations. 2. Realist interviews Realist interviews will explore and refine our understanding of the programme theory developed from the realist synthesis. Up to 30 older people and their informal carers (15 older people with multi-morbidity, 10 informal carers and 5 older people with dementia), and 20 care staff will be interviewed. 3. Developing framework for the intervention(s) Data from the realist synthesis and interviews will be used to refine the programme theory for the intervention(s) to identify: the mechanisms that need to be 'triggered', and the contexts related to these mechanisms. Intervention strategies that change the contexts so the mechanisms are triggered to produce desired outcomes will be developed. Feedback on these strategies will be obtained. DISCUSSION: This realist synthesis aims to develop a framework (underpinned by our programme theory) for a novel multi-disciplinary, multi-agency intervention(s), to improve medication management in community dwelling older people on complex medication regimens. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016043506. PMID- 28673336 TI - Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults. AB - BACKGROUND: This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults. METHODS: CSF amyloid beta1-42 (Abeta42), phospho-tau 181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100. RESULTS: CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Abeta42 concentration varied according to age, gender, and APOE genotype (interaction of age * gender * epsilon4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01). CONCLUSIONS: Female APOE-epsilon4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age. PMID- 28673337 TI - Rare presentation of intractable tuberculous panophthalmitis with intraocular and intraorbital abscesses: a case report. AB - BACKGROUND: We report a rare presentation of extrapulmonary tuberculosis. CASE PRESENTATION: A 29-year-old Burmese woman with human immunodeficiency virus infection and known pulmonary tuberculosis who had been treated for 5 months presented to our hospital with unilateral progressive painful visual loss of 1 month's duration. She was diagnosed with tuberculous panophthalmitis with subretinal and intraorbital abscesses, conjunctival abscess, and extraocular muscle tuberculoma. The diagnosis was confirmed by a conjunctival pus swab with a positive result for acid-fast bacilli and a positive result for a mycobacterial culture. There was high suspicion of multidrug-resistant tuberculosis. Despite receiving ongoing aggressive treatment with conventional antituberculous medications, this patient required subtotal orbital exenteration to control her infection and prevent further progression. Second-line antituberculous medications were added to the first-line therapy, with satisfactory results achieved. CONCLUSIONS: Tuberculous panophthalmitis with intraocular and intraorbital abscesses is a rare presentation of extrapulmonary tuberculosis. Patients who do not respond to first-line antituberculous therapy might be infected with either single-drug or multidrug-resistant Mycobacterium tuberculosis. Patient compliance is one of the key factors that can alter the course of treatment. Careful patient monitoring can improve disease progression, outcome, and prognosis. PMID- 28673338 TI - Sustained hyperosmolarity increses TGF-beta1 and Egr-1 expression in the rat renal medulla. AB - BACKGROUND: Although TGF-beta and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-beta and Egr-1 expression. METHODS: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. RESULTS: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-beta and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-beta and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-beta and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. CONCLUSION: We conclude that both TGF-beta and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components. PMID- 28673340 TI - Anti-citrullinated protein antibodies and bone loss in patients with early arthritis: comment on the article "Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis" by Bugatti et al. PMID- 28673339 TI - Human limbal fibroblast-like stem cells induce immune-tolerance in autoreactive T lymphocytes from female patients with Hashimoto's thyroiditis. AB - BACKGROUND: Due to their "natural immune privilege" and immunoregulatory properties human fibroblast-like limbal stem cells (f-LSCs) have acquired great interest as a potential tool for achieving immunotolerance. Hashimoto's thyroiditis (HT) is the most common thyroid autoimmune disease and cause of hypothyroidism. To date, conventional hormone replacement therapy and unspecific immunosuppressive regimens cannot provide a definitive cure for HT subjects. We explored the immunosuppressant potential of human f-LSCs on circulating lymphomonocytes (PBMCs) collected from healthy donors and female HT patients. METHODS: We assessed the immunophenotyping of f-LSCs, both untreated and after 48 h of proinflammatory cytokine exposure, by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. The immunosuppressant effects of f-LSCs on healthy activated PBMCs were investigated in cell-cell contact and transwell settings through cell cycle assay, acridine orange staining, and caspase-3 detection. We also studied T-cell responses and possible Treg conversion by means of flow cytometry. Functional assays were conducted in activated HT lymphocytes cocultured with f-LSCs after carboxyfluorescein succinimidyl ester labeling and intracellular detection of pro and anti-inflammatory cytokines. RESULTS: The hypo-immunogenicity of the f-LSC population depended on both cell contact and soluble factors produced, as well as the undetectable expression of all those molecules required to fully activate T lymphocytes. Following exposure to Th1 cytokines, f-LSCs augmented expression of programmed death-ligand 1 and 2 (PDL-1 and -2), indoleamine-pyrrole-2,3 dioxygenase (IDO), interleukin (IL)-6, and monocyte chemotactic protein 1 (MCP-1) while maintaining their negative phenotype for major histocompatibility (MHC) class II and costimulatory molecules. During coculture, f-LSCs suppressed up to 40% of proliferation in healthy activated PBMCs, arrested them in the G0/G1 cell cycle phase without inducing apoptosis cascade, inverted the CD4/CD8 ratio, and promoted sustained expression of the immunomodulator marker CD69. Under coculture conditions the Th imbalance of autoreactive T cells from female HT patients was fully restored. CONCLUSIONS: Our study describes an in vitro coculture system able to prevent inappropriate activation of autoreactive T lymphocytes of female HT patients and to generate a tolerogenic environment even in an inflammatory background. Further investigations are necessary to establish whether this stem cell-based therapy approach in HT could avoid lifetime hormone replacement therapy by inducing T-cell education. PMID- 28673341 TI - How can latent trajectories of back pain be translated into defined subgroups? AB - BACKGROUND: Similar types of trajectory patterns have been identified by Latent Class Analyses (LCA) across multiple low back pain (LBP) cohorts, but these patterns are impractical to apply to new cohorts or individual patients. It would be useful to be able to identify trajectory subgroups from descriptive definitions, as a way to apply the same definitions of mutually exclusive subgroups across populations. In this study, we investigated if the course trajectories of two LBP cohorts fitted with previously suggested trajectory subgroup definitions, how distinctly different these subgroups were, and if the subgroup definitions matched with LCA-derived patterns. METHODS: Weekly measures of LBP intensity and frequency during 1 year were available from two clinical cohorts. We applied definitions of 16 possible trajectory subgroups to these observations and calculated the prevalence of the subgroups. The probability of belonging to each of eight LCA-derived patterns was determined within each subgroup. LBP intensity and frequency were described within subgroups and the subgroups of 'fluctuating' and 'episodic' LBP were compared on clinical characteristics. RESULTS: All of 1077 observed trajectories fitted with the defined subgroups. 'Severe episodic LBP' was the most frequent pattern in both cohorts and 'ongoing LBP' was almost non-existing. There was a clear relationship between the defined trajectory subgroups and LCA-derived trajectory patterns, as in most subgroups, all patients had high probabilities of belonging to only one or two of the LCA patterns. The characteristics of the six defined subgroups with minor LBP were very similar. 'Fluctuating LBP' subgroups were significantly more distressed, had more intense leg pain, higher levels of activity limitation, and more negative expectations about future LBP than 'episodic LBP' subgroups. CONCLUSION: Previously suggested definitions of LBP trajectory subgroups could be readily applied to patients' observed data resulting in subgroups that matched well with LCA-derived trajectory patterns. We suggest that the number of trajectory subgroups can be reduced by merging some subgroups with minor LBP. Stable levels of LBP were almost not observed and we suggest that minor fluctuations in pain intensity might be conceptualised as 'ongoing LBP'. Lastly, we found clear support for distinguishing between fluctuating and episodic LBP. PMID- 28673342 TI - Knowledge and provision of misoprostol among pharmacy workers in Senegal: a cross sectional study. AB - BACKGROUND: Making misoprostol widely available for management of postpartum haemorrhage (PPH) and post abortion care (PAC) is essential for reducing maternal mortality. Private pharmacies (thereafter called "pharmacies") are integral in supplying medications to the general public in Senegal. In the case of misoprostol, pharmacies are also the main supplier to public providers and therefore have a key role in increasing its availability. This study seeks to understand knowledge and provision of misoprostol among pharmacy workers in Dakar, Senegal. METHODS: A cross-sectional survey was conducted in Dakar, Senegal. 110 pharmacy workers were interviewed face-to-face to collect information on their knowledge and practice relating to the provision of misoprostol. RESULTS: There are low levels of knowledge about misoprostol uses, registration status, treatment regimens and side effects among pharmacy workers, and corresponding low levels of training on its uses for reproductive health. Provision of misoprostol was low; of the 72% (n = 79) of pharmacy workers who had heard of the product, 35% (n = 27) reported selling it, though rarely for reproductive health indications. Almost half (49%, n = 25) of the respondents who did not sell misoprostol expressed willingness to do so. The main reasons pharmacy workers gave for not selling the product included stock outs (due to product unavailability from the supplier), perceived lack of demand and unwillingness to stock an abortifacient. CONCLUSIONS: Knowledge and availability of misoprostol in pharmacies in Senegal is low, posing potential challenges for delivery of post-abortion care and obstetric care. Training is required to address low levels of knowledge of misoprostol registration and uses among pharmacy workers. Barriers that prevent pharmacy workers from stocking misoprostol, including weaknesses in the supply chain and stigmatisation of the product must be addressed. Low reported sales for reproductive health indications also suggest limited prescribing of the product by health providers. Further research is needed to explore the reasons for this barrier to misoprostol availability. PMID- 28673343 TI - Prevalence and factors associated with urogenital schistosomiasis among primary school children in barrage, Magba sub-division of Cameroon. AB - BACKGROUND: The purpose of this study was to determine the prevalence and intensity as well as the factors associated with urogenital schistosomiasis (US) in Barrage, a rural community around the Mape? dam, in the West region of Cameroon not previously documented for transmission. METHODS: In this cross sectional parasitological survey, 382 children were enrolled from three primary schools in the study area between March and May 2016. A semi-structured questionnaire was used to collect information on demographics, clinical and predisposing factors. The syringe filtration technique was used to analyse urine samples. Samples with visible or gross haematuria were recorded prior to filtration. The Pearson chi-square, the student T-test and logistic regression were all performed as part of the statistical analyses. RESULTS: The overall prevalence of US was 41.1% (95% CI: 36.1-46.2). Infection was more common in children below 10 years (p = 0.009), in males (p = 0.029), and in children who frequently come into contact with water from the dam (p < 0.001). Furthermore, US was more common in children attending Ecole Public (EP) Manbonko Bord (81.1%, p < 0.001) which is very close to the dam and in children from a fishing background (80.9%, p < 0.001). On the contrary, knowledge about schistosomiasis was not observed to be associated with prevalence. In this study, the intensity of infection was observed to be higher in children below 10 years (p < 0.001), in males (p = 0.001), and in children attending EP Manbonko Bord (p < 0.001). The intensity of infection was also highest in children presenting with haematuria (p < 0.001). Frequent contact with water from the dam and having parents whose occupation was fishing were identified as the associated factors for US. CONCLUSION: A high prevalence of US was observed in school-aged children in the study area especially in those attending EP Manbonko Bord. Limiting contact with water from the dam, control of the snail intermediate host, provision of portable water and mass treatment of the entire population are proposed as some of the measures to reduce and eventually eliminate transmission in the area. PMID- 28673344 TI - The Association of Health Insurance with institutional delivery and access to skilled birth attendants: evidence from the Kenya Demographic and health survey 2008-09. AB - BACKGROUND: Healthcare financing through health insurance is gaining traction as developing countries strive to achieve universal health coverage and address the limited access to critical health services for specific populations including pregnant women and their children. However, these reforms are taking place despite limited evaluation of impact of health insurance on maternal health in developing countries including Kenya. In this study we evaluate the association of health insurance with access and utilization of obstetric delivery health services for pregnant women in Kenya. METHODS: Nationally representative data from the Kenya Demographic and Health Survey 2008-09 was used in this study. 4082 pregnant women with outcomes of interest - Institutional delivery (Yes/No - delivery at hospital, dispensary, maternity home, and clinic) and access to skilled birth attendants (help by a nurse, doctor, or trained midwife at delivery) were selected from 8444 women ages 15-49 years. Linear and logistic regression, and propensity score adjustment are used to estimate the causal association of enrollment in insurance on obstetric health outcomes. RESULTS: Mothers with insurance are 23 percentage points (p < 0.01) more likely to deliver at an institution and 20 percentages points (p < 0.01) more likely have access to skilled birth attendants compared to those not insured. In addition mothers of lower socio-economic status benefit more from enrollment in insurance compared to mothers of higher socio-economic status. For both institutional delivery and access to skilled birth attendants, the average difference of the association of insurance enrollment compared to not enrolling for those of low SES is 23 percentage points (p < 0.01), and 6 percentage points (p < 0.01) for those of higher SES. CONCLUSIONS: Enrolling in health insurance is associated with increased access and utilization of obstetric delivery health services for pregnant women. Notably, those of lower socio-economic status seem to benefit the most from enrollment in insurance. PMID- 28673345 TI - Pesticide poisoning in Chitwan, Nepal: a descriptive epidemiological study. AB - BACKGROUND: Globally, there is a growing concern over pesticides use, which has been linked to self-harm and suicide. However, there is paucity of research on the epidemiology of pesticides poisoning in Nepal. This study is aimed at assessing epidemiological features of pesticides poisoning among hospital admitted cases in selected hospitals of Chitwan District of Nepal. METHODS: A hospital-based quantitative study was carried out in four major hospitals of Chitwan District. Information on all pesticides poisoning cases between April 1 and December 31, 2015, was recorded by using a Pesticides Exposure Record (PER) form. RESULTS: A total of 439 acute pesticides poisoning cases from 12 districts including Chitwan and adjoining districts attended the hospitals during the 9 month-long study period. A majority of the poisoned subjects deliberately used pesticides (89.5%) for attempted suicide. The total incidence rate was 62.67/100000 population per year. Higher annual incidence rates were found among young adults (111.66/100000 population), women (77.53/100000 population) and individuals from Dalit ethnic groups (98.22/100000 population). Pesticides responsible for poisoning were mostly insecticides (58.0%) and rodenticides (20.8%). The most used chemicals were organophosphates (37.3%) and pyrethroids (36.7%). Of the total cases, 98.6% were hospitalized, with intensive care required for 41.3%. The case fatality rate among admitted cases was 3.8%. CONCLUSIONS: This study has indicated that young adults, females and socially disadvantaged ethnic groups are at a higher risk of pesticides poisoning. Pesticides are mostly misused intentionally as an easy means for committing suicide. It is recommended that the supply of pesticides be properly regulated to prevent easy accessibility and misuse. A population-based study is warranted to reveal the actual problem of pesticides exposure and intoxication in the community. PMID- 28673346 TI - Risk stratification system to predict recurrence of intrahepatic cholangiocarcinoma after hepatic resection. AB - BACKGROUND: Previous nomograms for intrahepatic cholangiocarcinoma (ICC) were conducted to predict overall survival, which could be influenced by various factors. Herein, we conducted our nomogram to predict recurrence of the tumor only after hepatic resection. METHODS: The nomogram was established with prognostic factors for the relapse-free survival (RFS) analyzed from our single center cohort and was evaluated by comparing with the American Joint Committee on Cancer (AJCC) staging system for the predictive accuracy. RESULTS: Seropositivity of hepatitis B surface antigen (hazard ratio [HR], 0.505; 95% confidence interval [CI], 0.279 to 0.914; P = 0.024), tumor size of larger than 5 cm (HR, 1.947; 95% CI, 1.177 to 3.219; P = 0.009), Child-Pugh score of B (HR, 3.067; 95% CI, 1.293 to 7.275; P = 0.011), and lymph node metastasis (HR, 2.790; 95% CI, 1.628 to 4.781; P < 0.001) were found to be independent prognostic factors that significantly affected RFS. The calibration curve for the prediction revealed excellent agreement between estimation by our stratification system and actual RFS. The concordance C index of the nomogram (0.71; 95% CI, 0.65 to 0.77) revealed to be significantly higher than the AJCC staging system (0.66; 95% CI, 0.60 to 0.72). In the validation cohort, our risk stratification system (C-index 0.65; 95% CI, 0.59 to 0.71) also revealed more precise prediction than the AJCC staging system (C-index, 0.57; 95% CI, 0.50 to 0.64). CONCLUSIONS: Our nomogram could more accurately predict recurrence of ICC after hepatic resection than the AJCC staging system. PMID- 28673347 TI - Searching for ivermectin resistance in a Strongylidae population of horses stabled in Poland. AB - BACKGROUND: There are no available studies describing the possible resistance of strongyles to ivermectin in horses in Poland. One hundred seventy three horses from nine stud farms from South-Western Poland were studied. The effectiveness of ivermectin was studied on the 14th day after ivermectin administration using the fecal egg count reduction test, and a long-term observation of the egg reappearance period was carried out. The fecal study was carried out using a modified McMaster method, which typically detects 20 eggs per gram of stool. The results were subjected to statistical analysis that enabled quantification of the eggs in the stool samples. RESULTS: The study revealed high efficacy of ivermectin on the 14th day after administration without a shortening of the egg reappearance period. CONCLUSION: The results indicate that strongyles resistance to ivermectin in Poland is not a serious problem. PMID- 28673348 TI - Anti-malarial treatment outcomes in Ethiopia: a systematic review and meta analysis. AB - BACKGROUND: Ethiopia is among countries with a high malaria burden. There are several studies that assessed the efficacy of anti-malarial agents in the country and this systematic review and meta-analysis was performed to obtain stronger evidence on treatment outcomes of malaria from the existing literature in Ethiopia. METHODS: A systematic literature search using the preferred reporting items for systematic review and meta-analysis (PRISMA) statement was conducted on studies from Pubmed, Google Scholar, and ScienceDirect databases to identify published and unpublished literature. Comprehensive meta-analysis software was used to perform all meta-analyses. The Cochrane Q and the I 2 were used to evaluate heterogeneity of studies. Random effects model was used to combine studies showing heterogeneity of Cochrane Q p < 0.10 and I 2 > 50. RESULTS: Twenty-one studies were included in the final analysis with a total number of 3123 study participants. Treatment outcomes were assessed clinically and parasitologically using World Health Organization guidelines. Adequate clinical and parasitological response was used to assess treatment success at the 28th day. Overall, a significant high treatment success of 92.9% (95% CI 89.1-96.6), p < 0.001, I 2 = 98.39% was noticed. However, treatment success was higher in falciparum malaria patients treated with artemether-lumefantrine than chloroquine for Plasmodium vivax patients [98.1% (97.0-99.2), p < 0.001, I 2 = 72.55 vs 94.7% (92.6-96.2), p < 0.001, I 2 = 53.62%]. Seven studies reported the adverse drug reactions to anti-malarial treatment; of 822 participants, 344 of them were exposed to adverse drug reactions with a pooled event rate of 39.8% (14.1-65.5), p = 0.002. CONCLUSIONS: On the basis of this review, anti-malarial treatment success was high (92.9%) and standard regimens showed good efficacy against Plasmodium falciparum (98.1%) and P. vivax (94.7%) infections in Ethiopia, but associated with high rates of adverse drug reactions (ADRs). However, these ADRs were not serious enough to discontinue anti-malarial treatment. The results of this study suggest that the current anti-malarial medications are effective and safe; however, greater priority should be placed on the discovery of new anti malarial drugs to achieve successful outcomes as resistance seems inevitable since cases of anti-malarial drug resistance have been reported from other areas of the world. PMID- 28673349 TI - Site-specific chemical conjugation of human Fas ligand extracellular domain using trans-cyclooctene - methyltetrazine reactions. AB - BACKGROUND: Fas ligand plays a key role in the human immune system as a major cell death inducing protein. The extracellular domain of human Fas ligand (hFasLECD) triggers apoptosis of malignant cells, and therefore is expected to have substantial potentials in medical biotechnology. However, the current application of this protein to clinical medicine is hampered by a shortage of the benefits relative to the drawbacks including the side-effects in systemic administration. Effective procedures for the engineering of the protein by attaching useful additional functions are required to overcome the problem. RESULTS: A procedure for the site-specific chemical conjugation of hFasLECD with a fluorochrome and functional proteins was devised using an inverse-electron demand Diels-Alder reaction between trans-cyclooctene group and methyltetrazine group. The conjugations in the present study were attained by using much less molar excess amounts of the compounds to be attached as compared with the conventional chemical modification reactions using maleimide derivatives in the previous study. The isolated conjugates of hFasLECD with sulfo-Cy3, avidin and rabbit IgG Fab' domain presented the functional and the structural integrities of the attached molecules without impairing the specific binding activity toward human Fas receptor extracellular domain. CONCLUSIONS: The present study provided a new fundamental strategy for the production of the engineered hFasLECDs with additional beneficial functions, which will lead to the developments of the improved diagnostic systems and the effective treatment methods of serious diseases by using this protein as a component of novel molecular tools. PMID- 28673350 TI - Psychophysical responses in patients receiving a mock laser within context of an acupuncture clinical trial: an interoceptive perspective. AB - BACKGROUND: The psychophysical responses induced by verum acupuncture are characterized by a constellation of unique subjective sensory responses commonly termed De Qi. Furthermore, a variety of sham interventions have been used as a control for acupuncture clinical trials. Indeed, one such control has been mock laser which has been used as control intervention in several acupuncture clinical controlled trials. The current study aim was to examine the De Qi sensory responses and its related characteristics elicited from acupuncture and compare them to those reported following sham laser in participants enrolled in a clinical trial. METHODS: The study was embedded in a multi-center, two-arm randomised clinical trial, which evaluated the effect of acupuncture on lateral elbow pain. De Qi was assessed using the Massachusetts General Hospital Acupuncture Sensation Scale (MASS). Ninety-six participants were randomly allocated to receive either acupuncture (n = 47) or mock laser (n = 49) at the acupoints LI 10 and LI 11. RESULTS: Participants in both intervention groups reported similar De Qi psychophysical characteristics; however, both intensity and frequency of the individually perceived De Qi characteristics were significantly higher in the acupuncture group. 'Soreness', 'deep pressure', and 'fullness-distension' in the acupuncture group and 'tingling', and 'sharp pain' in mock laser group, were identified as the leading characteristics. Similar level of MASS De Qi Index (MDI) scores were reported for 'Hong Kong-China' and 'Australia-Italy' with a significantly higher level of De Qi reported by 'Hong Kong-China'. Furthermore, two distinct De Qi categories were identified, namely De Qi (in line with classical sensory responses of Suan, Ma, Zhang, and Zhong) and pain. CONCLUSIONS: Subjective 'somatic or interoceptive awareness' should be taken into account when De Qi psychophysical responses are examined. The study accentuates the necessity and the significance of further research into interoception phenomenon which may contribute to a better understanding of the placebo effect and De Qi psychophysical responses. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry reference: ACTRN12613001138774 on 11th of October 2013. PMID- 28673351 TI - Is it possible to claim or refute sputum eosinophils >= 3% in asthmatics with sufficient accuracy using biomarkers? AB - The concept of asthma inflammatory phenotypes has proved to be important in predicting response to inhaled corticosteroids. Induced sputum, which has been pivotal in the development of the concept of inflammatory phenotypes, is however not widely available. Several studies have proposed to use surrogate exhaled or blood biomarkers, like fractional exhaled nitric oxide (FENO), blood eosinophils and total serum immunoglobulin E (IgE). However, taken alone, each of these biomarkers has moderate accuracy to identify sputum eosinophilia. Here, we propose a new approach based on the likelihood ratio to study which thresholds of these biomarkers, taken alone or in combination, were able to rule in or rule out sputum eosinophils >=3%. We showed in a large population of 869 asthmatics that combining FENO, blood eosinophils and total serum IgE could accurately predict sputum eosinophils >= or <3% in 58% of our population. PMID- 28673352 TI - Fish oil supplementation and insulin sensitivity: a systematic review and meta analysis. AB - BACKGROUND: Fish oil supplementation has been shown to be associated with a lower risk of metabolic syndrome and benefit a wide range of chronic diseases, such as cardiovascular disease, type 2 diabetes and several types of cancers. However, the evidence of fish oil supplementation on glucose metabolism and insulin sensitivity is still controversial. This meta-analysis summarized the exist evidence of the relationship between fish oil supplementation and insulin sensitivity and aimed to evaluate whether fish oil supplementation could improve insulin sensitivity. METHODS: We searched the Cochrane Library, PubMed, Embase database for the relevant studies update to Dec 2016. Two researchers screened the literature independently by the selection and exclusion criteria. Studies were pooled using random effect models to estimate a pooled SMD and corresponding 95% CI. This meta-analysis was performed by Stata 13.1 software. RESULTS: A total of 17 studies with 672 participants were included in this meta-analysis study after screening from 498 published articles found after the initial search. In a pooled analysis, fish oil supplementation had no effects on insulin sensitivity compared with the placebo (SMD 0.17, 95%CI -0.15 to 0.48, p = 0.292). In subgroup analysis, fish oil supplementation could benefit insulin sensitivity among people who were experiencing at least one symptom of metabolic disorders (SMD 0.53, 95% CI 0.17 to 0.88, p < 0.001). Similarly, there were no significant differences between subgroups of methods of insulin sensitivity, doses of omega-3 polyunsaturated fatty acids (n-3 PUFA) of fish oil supplementation or duration of the intervention. The sensitivity analysis indicated that the results were robust. CONCLUSIONS: Short-term fish oil supplementation is associated with increasing the insulin sensitivity among those people with metabolic disorders. PMID- 28673353 TI - Anatomical landmarks for safely implementing resuscitative balloon occlusion of the aorta (REBOA) in zone 1 without fluoroscopy. AB - BACKGROUND: Resuscitative balloon occlusion of the aorta (REBOA) can maintain hemodynamic stability during hemorrhagic shock after a following torso injury, although inappropriate balloon placement may induce brain or visceral organ ischemia. External anatomical landmarks [the suprasternal notch (SSN) and xiphoid process (Xi)] are empirically used to implement REBOA in zone 1. We aimed to confirm if these landmarks were useful for determining a balloon catheter length for safe implementation of REBOA in zone 1 without using fluoroscopy. METHOD: We selected 25 successive adult blunt trauma cases requiring contrast-enhanced chest/abdominal computed tomography (CT) treated at our emergency department (in an urban area of Kyoto city, Japan) between October 1, 2016 and January 31, 2017. We retrospectively evaluated anonymized CT images. We used three-dimensional multiplanar reconstructions to measure the length along the aorta's central axis, from the bilateral common femoral arteries (FA) to the celiac trunk (CeT) (FA CeT) and to the origin of the left subclavian artery (LSCA) (FA-LSCA). Volume rendering reconstruction images were used to measure the external distance from common FAs to SSN (FA-SSN) and to Xi (FA-Xi). RESULT: FA-LSCA was significantly longer than FA-SSN. FA-CeT was significantly shorter than FA-Xi. DISCUSSION: Based on these results, the REBOA balloon catheter should be shorter than FA-SSN, and longer than FA-Xi to avoid placement outside zone 1. The advantages of this method are that it can rapidly and easily predict a safe balloon catheter length, and it reflects each patient's individual torso height. CONCLUSION: To safely implement REBOA, the balloon catheter length should be shorter than FA-SSN and longer than FA-Xi. We believe that these anatomical landmarks are good references for safe implementation of REBOA in zone 1 without radiographic guidance. PMID- 28673355 TI - What do young people with rheumatic disease believe to be important to research about their condition? A UK-wide study. AB - BACKGROUND: The involvement of people of all ages including young people in research is now widely advocated but prioritisation of research topics is still driven largely by professional agendas. Evidence from adult literature has reported a mismatch between a researcher and patient generated list of research topics. There have been no studies to date exploring the priorities of young people with long term conditions other than in SLE. The study aimed to explore the research priorities of young people across the UK with respect to rheumatic conditions. METHODS: Focus groups were undertaken with young people aged 11-24 years with rheumatic conditions recruited across the UK via members of the Barbara Ansell National Network for Adolescent Rheumatology BANNAR and relevant national charities. Data was analysed using a Framework approach. Participants discussed their beliefs about what should be researched in: Basic Science; Clinical Medicine; Health Services, Psychosocial, and Public Health. They were then invited to prioritize these areas in terms of how much funding they should receive. RESULTS: Thirteen focus groups were held involving 63 participants (18 males: 45 females, mean age 16 years, range 10 to 24) in all four nations of the UK. Young people's research priorities were influenced by whether they felt research would achieve benefits for all or just some patients and long or short term goals. Another influence was whether participants felt that research areas were already well funded. Across all groups, Basic Science was a key priority and participants felt that psychosocial research should be prioritized more. Health Services Research was a lower priority, as the majority of participants were happy with their care. Clinical medicine was not a high priority as young people were happy with their medication or uncomfortable with trying new ones. Finally, for nearly all groups, Public Health was a low priority. Differences were also observed between the two age groups and across the geographically diverse focus groups. CONCLUSION: Understanding young people's research priorities is important to develop research that is in tune with their needs. The results highlight the importance of considering the whole age range of adolescence and young adulthood as well as geographical diversity. The findings from this work will inform the future research of the Barbara Ansell National Network for Adolescent Rheumatology BANNAR in the UK. PMID- 28673354 TI - The footprint of the ageing stroma in older patients with breast cancer. AB - BACKGROUND: Tumours are not only composed of malignant cells but also consist of a stromal micro-environment, which has been shown to influence cancer cell behaviour. Because the ageing process induces accumulation of senescent cells in the body, this micro-environment is thought to be different in cancers occurring in old patients compared with younger patients. More specifically, senescence related fibroblastic features, such as the senescence-associated secretory profile (SASP) and the induction of autophagy, are suspected to stimulate tumour growth and progression. METHODS: We compared gene expression profiles in stromal fields of breast carcinomas by performing laser capture microdissection of the cancer-associated stroma from eight old (aged >=80 years at diagnosis) and nine young (aged <45 years at diagnosis) patients with triple-negative breast cancer. Gene expression data were obtained by microarray analysis (Affymetrix). Differential gene expression and gene set enrichment analysis (GSEA) were performed. RESULTS: Differential gene expression analysis showed changes reminiscent of increased growth, de-differentiation and migration in stromal samples of older versus younger patients. GSEA confirmed the presence of a SASP, as well as the presence of autophagy in the stroma of older patients. CONCLUSIONS: We provide the first evidence in humans that older age at diagnosis is associated with a different stromal micro-environment in breast cancers. The SASP and the presence of autophagy appear to be important age-induced stromal features. PMID- 28673356 TI - Quality indicators for care of depression in primary care settings: a systematic review. AB - BACKGROUND: Despite the growing interest in assessing the quality of care for depression, there is little evidence to support measurement of the quality of primary care for depression. This study identified evidence-based quality indicators for monitoring, evaluating and improving the quality of care for depression in primary care settings. METHODS: Ovid MEDLINE and Ovid PsycINFO databases, and grey literature, including relevant organizational websites, were searched from 2000 to 2015. Two reviewers independently selected studies if (1) the study methodology combined a systematic literature search with assessment of quality indicators by an expert panel and (2) quality indicators were applicable to assessment of care for adults with depression in primary care settings. Included studies were appraised using the Appraisal of Indicators through Research and Evaluation (AIRE) instrument, which contains four domains and 20 items. A narrative synthesis was used to combine the indicators within themes. Quality indicators applicable to care for adults with depression in primary care settings were extracted using a structured form. The extracted quality indicators were categorized according to Donabedian's 'structure-process-outcome' framework. RESULTS: The search revealed 3838 studies. Four additional publications were identified through grey literature searching. Thirty-nine articles were reviewed in detail and seven met the inclusion criteria. According to the AIRE domains, all studies were clear on purpose and stakeholder involvement, while formal endorsement and usage of indicators in practice were scarcely described. A total of 53 quality indicators were identified from the included studies, many of which overlap conceptually or in content: 15 structure, 33 process and four outcome indicators. This study identified quality indicators for evaluating primary care for depression among adult patients. CONCLUSIONS: The identified set of indicators address multiple dimensions of depression care and provide an excellent starting point for further development and use in primary care settings. PMID- 28673357 TI - Strong epistatic and additive effects of linked candidate SNPs for Drosophila pigmentation have implications for analysis of genome-wide association studies results. AB - BACKGROUND: The mapping resolution of genome-wide association studies (GWAS) is limited by historic recombination events and effects are often assigned to haplotype blocks rather than individual SNPs. It is not clear how many of the SNPs in the block, and which ones, are causative. Drosophila pigmentation is a powerful model to dissect the genetic basis of intra-specific and inter-specific phenotypic variation. Three tightly linked SNPs in the t-MSE enhancer have been identified in three D. melanogaster populations as major contributors to female abdominal pigmentation. This enhancer controls the expression of the pigmentation gene tan (t) in the abdominal epidermis. Two of the three SNPs were confirmed in an independent study using the D. melanogaster Genetic Reference Panel established from a North American population. RESULTS: We determined the functional impact of SNP1, SNP2, and SNP3 using transgenic lines to test all possible haplotypes in vivo. We show that all three candidate SNPs contribute to female Drosophila abdominal pigmentation. Interestingly, only two SNPs agree with the effect predicted by GWAS; the third one goes in the opposite direction because of linkage disequilibrium between multiple functional SNPs. Our experimental design uncovered strong additive effects for the three SNPs, but we also found significant epistatic effects explaining up to 11% of the total variation. CONCLUSIONS: Our results suggest that linked causal variants are important for the interpretation of GWAS and functional validation is needed to understand the genetic architecture of traits. PMID- 28673358 TI - Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread out Bragg peak. AB - BACKGROUND: Cellular responses to proton beam irradiation are not yet clearly understood, especially differences in the relative biological effectiveness (RBE) of high-energy proton beams depending on the position on the Spread-Out Bragg Peak (SOBP). Towards this end, we investigated the differences in the biological effect of a high-energy proton beam on the target cells placed at different positions on the SOBP, using two human esophageal cancer cell lines with differing radiosensitivities. METHODS: Two human esophageal cancer cell lines (OE21, KYSE450) with different radiosensitivities were irradiated with a 235-MeV proton beam at 4 different positions on the SOBP (position #1: At entry; position #2: At the proximal end of the SOBP; position #3: Center of the SOBP; position #4: At the distal end of the SOBP), and the cell survivals were assessed by the clonogenic assay. The RBE10 for each position of the target cell lines on the SOBP was determined based on the results of the cell survival assay conducted after photon beam irradiation. In addition, the number of DNA double-strand breaks was estimated by quantitating the number of phospho-histone H2AX (gammaH2AX) foci formed in the nuclei by immunofluorescence analysis. RESULTS: In regard to differences in the RBE of a proton beam according to the position on the SOBP, the RBE value tended to increase as the position on the SOBP moved distally. Comparison of the residual number of gammaH2AX foci at the end 24 h after the irradiation revealed, for both cell lines, a higher number of foci in the cells irradiated at the distal end of the SOPB than in those irradiated at the proximal end or center of the SOBP. CONCLUSIONS: The results of this study demonstrate that the RBE of a high-energy proton beam and the cellular responses, including the DNA damage repair processes, to high-energy proton beam irradiation, differ according to the position on the SOBP, irrespective of the radiosensitivity levels of the cell lines. PMID- 28673359 TI - Determinants of treatment completion among rural smear positive pulmonary tuberculosis patients: a cross-sectional survey conducted in south-western Uganda. AB - BACKGROUND: Treatment completion among tuberculosis patients remains low across various regions of Uganda, despite implementation of directly observed treatment short course. This study evaluated the determinants of treatment completion in a rural health sub-district of south western Uganda. METHODS: In April 2012, health facility records were reviewed to identify tuberculosis patients who had been initiated on treatment between June 2008 and May 2011, in Rwampara Health Sub District, south-western Uganda. Out of the 162 patients identified, 128 (79%) were traced and subsequently interviewed during a survey conducted in June 2012. Eleven (6.8%) of the 162 patients died, while 23 (14.2%) could not be traced. A review of records showed that 17 of those that could not be traced completed treatment while the other six did not have definitive records. RESULTS: Treatment completion among the 128 patients interviewed was 89.8%. Pre-treatment counselling (aOR = 24.3, 95% CI: 1.4-26.6, P = 0.03), counselling at the time of submission of sputum during follow up (aOR = 6.8, 95% CI: 1.4-33.7, P = 0.02), and refill of drugs on the exact appointment date (aOR = 13.4, 95% CI: 1.9-93.0, P = 0.01), were independently associated with treatment completion. CONCLUSIONS: The level of treatment completion was higher than the national average, with service- related determinants identified as being critical for ensuring treatment completion. These data provide further evidence for the need to provide ongoing counselling support to tuberculosis patients. Enhancing the opportunities for counselling of tuberculosis patients should therefore be rigorously promoted as an approach to increase treatment completion in rural settings. PMID- 28673360 TI - How great is the medical burden of disease on the aged? Research based on "System of Health Account 2011". AB - BACKGROUND: The aging of population and the burden of disease among the aged have become one of the hot topics in the international health, and also brought tremendous pressure in the development of health service. METHODS: A total of 1,377,681 patients aged 65 years and over were collected with multistage stratified cluster random sampling in 252 medical institutions in Liaoning China, and "System of Health Account 2011" was conducted to analyze the expenditure of disease for the elderly. Influencing factors were performed using multiple stepwise regression analysis. RESULTS: The curative care expenditure for the aged was 233.18 billion RMB. Most of the expenditure for the old people was in hospital. Moreover, by the disease, the highest expenditure was incurred by non communicable diseases. The financing scheme of the aged was concentrated on social health insurance and family health expenditure. Hospitalization expenditure was significantly associated with length of stay, operation, etc. CONCLUSIONS: This study intends to capture large data from various medical institutions with a new accounting system. The finding illustrates that the burden of old people is still heavy. PMID- 28673361 TI - Harmonizing community-based health worker programs for HIV: a narrative review and analytic framework. AB - BACKGROUND: Many countries have created community-based health worker (CHW) programs for HIV. In most of these countries, several national and non governmental initiatives have been implemented raising questions of how well these different approaches address the health problems and use health resources in a compatible way. While these questions have led to a general policy initiative to promote harmonization across programs, there is a need for countries to develop a more coherent and organized approach to CHW programs and to generate evidence about the most efficient and effective strategies to ensure their optimal, sustained performance. METHODS: We conducted a narrative review of the existing published and gray literature on the harmonization of CHW programs. We searched for and noted evidence on definitions, models, and/or frameworks of harmonization; theoretical arguments or hypotheses about the effects of CHW program fragmentation; and empirical evidence. Based on this evidence, we defined harmonization, introduced three priority areas for harmonization, and identified a conceptual framework for analyzing harmonization of CHW programs that can be used to support their expanding role in HIV service delivery. We identified and described the major issues and relationships surrounding the harmonization of CHW programs, including key characteristics, facilitators, and barriers for each of the priority areas of harmonization, and used our analytic framework to map overarching findings. We apply this approach of CHW programs supporting HIV services across four countries in Southern Africa in a separate article. RESULTS: There is a large number and immense diversity of CHW programs for HIV. This includes integration of HIV components into countries' existing national programs along with the development of multiple, stand-alone CHW programs. We defined (i) coordination among stakeholders, (ii) integration into the broader health system, and (iii) assurance of a CHW program's sustainability to be priority areas of harmonization. While harmonization is likely a complex political process, with in many cases incremental steps toward improvement, a wide range of facilitators are available to decision-makers. These can be categorized using an analytic framework assessing the (i) health issue, (ii) intervention itself, (iii) stakeholders, (iv) health system, and (v) broad context. CONCLUSIONS: There is a need to address fragmentation of CHW programs to advance and sustain CHW roles and responsibilities for HIV. This study provides a narrative review and analytic framework to understand the process by which harmonization of CHW programs might be achieved and to test the assumption that harmonization is needed to improve CHW performance. PMID- 28673362 TI - Clinical outcomes of retrograde intra-arterial chemotherapy concurrent with radiotherapy for elderly oral squamous cell carcinoma patients aged over 80 years old. AB - BACKGROUND: The aim of this retrospective observational study was to evaluate toxicities, overall survival, and locoregional control in elderly oral squamous cell carcinoma patients who had undergone retrograde intra-arterial chemotherapy combined with radiotherapy. METHODS: Thirty-one elderly patients over 80 years old with oral squamous cell carcinoma were enrolled in present study. The treatment schedule consisted of intra- arterial chemotherapy (docetaxel, total 60 mg/m2; cisplatin, total 150 mg/m2) and daily concurrent radiotherapy (total, 60 Gy) for 6 weeks. RESULTS: The median patient age was 82.5 years old (range, 80-88 years). Of the 31 patients, six (19%) had stage II, 6 (19%) had stage III, 17 (55%) had stage IVA, and 2 (6%) had stage IVB. The median follow-up period for all patients was 37 months (range, 7-86 months). The 3-year overall survival and locoregional control rates were 78% and 81%, respectively. The major acute grade 3 adverse events were oral mucositis in 22 (71%) patients, neutropenia in 16 (52%), and dermatitis in 11 (35%). With respect to late toxicities, 1 patient (3%) developed grade 3 osteoradionecrosis of the jaw. No grade 4 or higher toxicities were observed during the treatment and follow-up periods. CONCLUSIONS: Retrograde intra-arterial chemotherapy combined with radiotherapy was effective in improving overall survival and locoregional control even for elderly patients. PMID- 28673363 TI - A red yeast rice-olive extract supplement reduces biomarkers of oxidative stress, OxLDL and Lp-PLA2, in subjects with metabolic syndrome: a randomised, double blind, placebo-controlled trial. AB - BACKGROUND: Metabolic syndrome (MetS) refers to clustered cardiovascular risk factors (abdominal obesity, pre-diabetes, high blood pressure, dyslipidaemia). Therapies targeting oxidative stress may delay progression to atherosclerosis and diabetes. We investigated the anti-oxidative effect of a supplement combining red yeast rice and olive extract in patients with MetS. METHODS: A double-blind, placebo-controlled, randomised trial was conducted with 50 patients with MetS as defined by National Cholesterol Education Program Adult Treatment Panel III criteria. Forty-nine subjects randomly assigned to red yeast rice-olive extract (RYR-olive extract; 10.82 mg of monacolins and 9.32 mg of hydroxytyrosol per Cholesfytolplus capsule) or placebo completed the 8-week trial. Whereas effects on cardiovascular risk parameters of MetS have been reported recently, the observed significant 20% increase in oxidised low-density lipoprotein (OxLDL) prompted us to investigate other oxidative stress-related parameters: malondialdehyde (MDA), lipoprotein-associated phospholipase A2 (Lp-PLA2) and 8 hydroxy-2'-deoxyguanosine (8-OHdG). Statistical calculations included univariate quantitative analysis, multivariate linear regression and correlation analysis. RESULTS: The updated results indicate that an RYR-olive extract supplement significantly reduced Lp-PLA2 by 7% (p < 0.001), but it failed to show a significant decrease in plasma MDA and 8-OHdG (p > 0.05). Reductions in OxLDL (20%) and Lp-PLA2 (7%) were associated with each other (r = 0.740, p < 0.001). CONCLUSIONS: RYR-olive extract significantly reduced Lp-PLA2 in correlation with the marked reduction in plasma OxLDL, which may lead to a reduced risk for cardiovascular disease in patients with MetS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02065180 . Registered on 13 February 2014. PMID- 28673364 TI - Malnutrition in patients admitted to the medical wards of the Douala General Hospital: a cross-sectional study. AB - BACKGROUND: Malnutrition is common in acutely ill patients occurring in 30-50% of hospitalized patients. Awareness and screening for malnutrition is lacking in most health institutions in sub-Saharan Africa. This study aimed at screening for malnutrition using anthropometric and laboratory indices in patients admitted to the internal medicine wards. METHODS: A cross-sectional study. We screened for malnutrition in 251 consecutive patients admitted from January to March 2013 in the internal medicine wards. Malnutrition defined as body mass index (BMI) less than 18.5 kg/m2 and/or mid upper arm circumference (MUAC) less than 22 cm in women and 23 cm in men. Weight loss greater than 10% in the last 6 months prior to admission, relevant laboratory data, diagnosis at discharge and length of hospital stay (LOS) were also recorded. RESULTS: Mean age was 47 (SD 16) years. 52.6% were male. Mean BMI was 24.44 (SD 5.79) kg/m2 and MUAC was 27.8 (SD 5.0) cm. Median LOS was 7 (IQR 5-12) days. 42.4% of patients reported weight loss greater than 10% in the 6 months before hospitalization. MUAC and BMI correlated significantly (r = 0.78; p < 0.0001) and malnutrition by the two methods showed moderate agreement (kappa = 0.56; p < 0.0001). Using the two methods in combination, the prevalence of malnutrition was 19.34% (35/251). Blood albumin and hemoglobin were significantly lower in malnourished patients. Malnourished patients had a significantly longer LOS (p = 0.019) when compared to those with no malnutrition. Malnutrition was most common amongst patients with malignancy. CONCLUSION: Malnutrition is common in patients admitted to the medical wards of the Douala General Hospital. Nutritional screening and assessment should be integrated in the care package of all admitted patients. PMID- 28673365 TI - Is health coaching effective in changing the health status and behaviour of prisoners?-a systematic review protocol. AB - BACKGROUND: This is a protocol for a systematic review of the impact of health coaching on changing the health behaviour of offenders. Prisoners are more likely to suffer from health-related issues when compared to the general population. Health coaching has been shown to influence health outcomes of patients with chronic conditions. This review, therefore, aims to assess the effectiveness of health coaching interventions on the health of adolescent and adult offenders in custodial institutions. METHODS: We plan to conduct a systematic review of the current literature on health coaching interventions delivered in the prison setting. We will include randomised controlled trials and observational studies that compare health coaching to the usual care or other alternative interventions. The ideal interventions will be delivered either by health professionals or peer coaches, and the outcomes extracted in the data collection will be disease-specific, clients' life and self-management skills, behavioural and psychosocial outcomes. If appropriate, a meta-analysis of the data collected will be carried out on the last stage of the review. DISCUSSION: This systematic review will identify and gather evidence on the impact of health coaching interventions delivered in the prison setting and can function as a supporting material for health professionals, prison staff, the healthcare system, and public health departments when considering delivering health coaching. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016053237 . PMID- 28673366 TI - Significance of lung anomalies in fetuses affected by tetralogy of Fallot with absent pulmonary valve syndrome. AB - OBJECTIVES: Tetralogy of Fallot with absent pulmonary valve syndrome is a rare form of tetralogy of Fallot with dilatation of large pulmonary arteries. Prognosis is related to the severity of the cardiac malformation and to bronchial tree compression by dilated pulmonary arteries. This study analyses the prenatal echographic lung appearance in fetuses with tetralogy of Fallot with absent pulmonary valve and discusses its significance. METHODS: We carried out a retrospective review of fetal and postnatal files of nine fetuses diagnosed with tetralogy of Fallot with absent pulmonary valve syndrome in our institution. Correlations of prenatal ultrasound and cardiac imaging findings were obtained with outcome. RESULTS: Abnormal heterogeneous fetal lung echogenicity was detected in eight cases out of nine, always associated with significant lobar arterial dilatation. This aspect was well correlated with postnatal imaging and outcome in the four neonatal cases. The only fetus with normal lung echogenicity also had lower degree of pulmonary artery dilatation in the series. CONCLUSIONS: This study demonstrates that a heterogeneous ultrasound appearance of the fetal lungs can be detected in utero in the most severe cases. This aspect suggests an already significant compression of the fetal bronchial tree by the dilated arteries that may have prognostic implications. PMID- 28673367 TI - Association between spicy food consumption and lipid profiles in adults: a nationwide population-based study. AB - CVD remains the leading cause of mortality worldwide, with abnormal lipid metabolism as a major risk factor. The aim of this study was to investigate associations between spicy food consumption and serum lipids in Chinese adults. Data were extracted from the 2009 phase of the China Health and Nutrition Survey, consisting of 6774 apparently healthy Chinese adults aged 18-65 years. The frequency of consumption and degree of pungency of spicy food were self-reported, and regular spicy food consumption was assessed using three consecutive 24-h recalls. Total cholesterol, TAG, LDL-cholesterol and HDL-cholesterol in fasting serum were measured. Multilevel mixed-effects models were constructed to estimate associations between spicy food consumption and serum lipid profiles. The results showed that the frequency and the average amount of spicy food intake were both inversely associated with LDL-cholesterol and LDL-cholesterol:HDL-cholesterol ratio (all P for trend<0.05) after adjustment for potential confounders and cluster effects. HDL-cholesterol in participants who usually consumed spicy food (>=5 times/week) and who consumed spicy food perceived as moderate in pungency were significantly higher than those who did not (both P<0.01). The frequency and the average amount of spicy food intake and the degree of pungency in spicy food were positively associated with TAG (all P for trend<0.05). Spicy food consumption was inversely associated with serum cholesterol and positively associated with serum TAG, and additional studies are needed to confirm the findings as well as to elucidate the potential roles of spicy food consumption in lipid metabolism. PMID- 28673368 TI - Compliance of tranexamic acid administration to trauma patients at a level-one trauma centre. AB - : Introduction Current practice for the treatment of traumatic hemorrhage includes fluid resuscitation and the administration of blood products. The administration of tranexamic acid (TXA) within 8 hours of injury has been shown to significantly reduce mortality in a large, prospective, randomized controlled trial. As a result, TXA is widely used in trauma centres to manage trauma patients with major bleeding. The primary aim of this study was to assess the compliance of TXA administration at a level-one trauma centre in Hamilton, Ontario, Canada. METHODS: We conducted a retrospective medical record review of consecutive adult trauma patients received at the Hamilton General Hospital between January 1, 2012 and December 31, 2014. Compliance with TXA administration was based on the inclusion criteria of the CRASH-2 trial. RESULTS: Five hundred and thirty-four of 2,475 trauma patients met the inclusion criteria for TXA administration. Twenty-one patients who received TXA at peripheral hospital prior to their arrival at the level-one trauma centre were excluded from the analysis, and 18 patients were excluded due to missing data. One hundred and thirty-four patients received TXA, representing a compliance rate of 27%. Mean time from arrival to TXA administration was 47 minutes. Compliance increased for those who required massive transfusion and as the number of criteria for TXA administration increased. CONCLUSIONS: Compliance with TXA administration to trauma patients with suspected major bleeding was low. Quality improvement strategies aimed at increasing appropriate use of TXA are warranted. PMID- 28673369 TI - The yolk syncytial layer of loach, Misgurnus fossilis (Teleostei) during early development. AB - The yolk syncytial layer (YSL) of Teleostei is a dynamic multifunctional temporary system. This paper describes the YSL structure of Misgurnus fossilis (Cobitidae) during its early developmental stages, studied using histological methods. YSL formation is prolonged. From the late blastula stage, the basal surface of the YSL is uneven and has protuberances, but becomes smoother during development. There are syncytial 'islands' with 1-2 yolk syncytial nuclei in the yolk mass. During epiboly, gastrulation and early segmentation, loach YSL is of different thickness in different regions along the dorso-ventral and antero posterior axes of an embryo. The YSL is thickened in the dorsal region of gastrulae compared with the ventral region. Although the development of M. fossilis is similar to the development of zebrafish, there are important differences in YSL formation and organization that await further study and analysis. The study of YSL organization contributes to our knowledge of teleost developmental diversity and to the biology of temporary structures. PMID- 28673370 TI - Glasgow encounters with tropical diseases. AB - The period 1875-1925 was remarkable in the history of parasitology mainly for the elucidation of the life cycles of parasites causing important parasitic diseases and the incrimination of vectors in their transmission. These discoveries were made by a small number of scientists working in the tropics a number of whom were Scots. Sir Patrick Manson, the discoverer of the mosquito transmission of filarial worms, was instrumental in directly or indirectly encouraging other Scots including Douglas Argyll-Robertson, David Blacklock, David Bruce, David Cunningham, Robert Leiper, William Leishman, George Low, Muriel Robertson and Ronald Ross, who all made significant discoveries across a wide spectrum of tropical diseases. Among these, William Leishman, Robert Leiper and Muriel Robertson were all graduates of the University of Glasgow and their achievements in the fields of leishmaniasis, schistosomiasis, dracunculiasis and African sleeping sickness, together with subsequent developments in these fields, are the subjects of the ten papers in this Special Issue of Parasitology. PMID- 28673371 TI - Mass-Fatality Incident Preparedness Among Faith-Based Organizations. AB - : Introduction Members of faith-based organizations (FBOs) are in a unique position to provide support and services to their local communities during disasters. Because of their close community ties and well-established trust, they can play an especially critical role in helping communities heal in the aftermath of a mass-fatality incident (MFI). Faith-based organizations are considered an important disaster resource and partner under the National Response Plan (NRP) and National Response Framework; however, their level of preparedness and response capabilities with respect to MFIs has never been evaluated. The purpose of this study was threefold: (1) to develop appropriate measures of preparedness for this sector; (2) to assess MFI preparedness among United States FBOs; and (3) to identify key factors associated with MFI preparedness. Problem New metrics for MFI preparedness, comprised of three domains (organizational capabilities, operational capabilities, and resource sharing partnerships), were developed and tested in a national convenience sample of FBO members. METHODS: Data were collected using an online anonymous survey that was distributed through two major, national faith-based associations and social media during a 6-week period in 2014. Descriptive, bivariate, and correlational analyses were conducted. RESULTS: One hundred twenty-four respondents completed the online survey. More than one-half of the FBOs had responded to MFIs in the previous five years. Only 20% of respondents thought that roughly three-quarters of FBO clergy would be able to respond to MFIs, with or without hazardous contamination. A higher proportion (45%) thought that most FBO clergy would be willing to respond, but only 37% thought they would be willing if hazardous contamination was involved. Almost all respondents reported that their FBO was capable of providing emotional care and grief counseling in response to MFIs. Resource sharing partnerships were typically in place with other voluntary organizations (73%) and less likely with local death care sector organizations (27%) or Departments of Health (DOHs; 32%). CONCLUSIONS: The study suggests improvements are needed in terms of staff training in general, and specifically, drills with planning partners are needed. Greater cooperation and inclusion of FBOs in national planning and training will likely benefit overall MFI preparedness in the US. Zhi Q , Merrill JA , Gershon RR . Mass-fatality incident preparedness among faith-based organizations. Prehosp Disaster Med. 2017;32(6):596-603. PMID- 28673373 TI - Quand le raz-de-maree a un impact mondial : S'attaquer au defi planetaire de la demence. PMID- 28673372 TI - Simplifying Electron Beam Channeling in Scanning Transmission Electron Microscopy (STEM). AB - Sub-angstrom scanning transmission electron microscopy (STEM) allows quantitative column-by-column analysis of crystalline specimens via annular dark-field images. The intensity of electrons scattered from a particular location in an atomic column depends on the intensity of the electron probe at that location. Electron beam channeling causes oscillations in the STEM probe intensity during specimen propagation, which leads to differences in the beam intensity incident at different depths. Understanding the parameters that control this complex behavior is critical for interpreting experimental STEM results. In this work, theoretical analysis of the STEM probe intensity reveals that intensity oscillations during specimen propagation are regulated by changes in the beam's angular distribution. Three distinct regimes of channeling behavior are observed: the high-atomic number (Z) regime, in which atomic scattering leads to significant angular redistribution of the beam; the low-Z regime, in which the probe's initial angular distribution controls intensity oscillations; and the intermediate-Z regime, in which the behavior is mixed. These contrasting regimes are shown to exist for a wide range of probe parameters. These results provide a new understanding of the occurrence and consequences of channeling phenomena and conditions under which their influence is strengthened or weakened by characteristics of the electron probe and sample. PMID- 28673374 TI - Self-awareness of computed tomography ordering in the emergency department. AB - OBJECTIVES: Physician variation in the use of computed tomography (CT) is concerning due to the risks of ionizing radiation, cost, and downstream effects of unnecessary testing. The objectives of this study were to describe variation in CT-ordering rates among emergency physicians (EPs), to measure correlation between perceived and actual CT-ordering rates, to assess attitudes that influence decisions to order imaging tests, and to identify EP attitudes associated with higher CT utilization. METHODS: This study was a retrospective review of imaging and administrative billing records at two emergency department sites of a tertiary care adult teaching hospital. The study also included a cross sectional survey of EPs at this hospital. We asked physicians about their perceived ordering behaviour, and what factors influenced their decision to order a CT. We examined correlations between perceived and actual CT-ordering rates. We adjusted ordering rates for shift distribution using a logistic regression model and identified outlier physicians whose ordering rate was significantly lower or higher than expected. We used multivariable regression analysis to determine which survey responses predicted higher CT utilization. RESULTS: During the study period, 59 EPs saw 45,854 patients, and ordered 6,609 CTs - a mean ordering rate of 14.4% (standard deviation (SD)=4.3%). The ordering rate for individual physicians ranged from 5.9% to 25.9%. Of the 59 EPs, 13 EPs were low-ordering outliers; 12 were high-ordering outliers. Forty-five EPs (76.3%) completed the survey. Mean perceived ordering rate was 12.6%, and was weakly correlated with actual ordering (r=0.19, p=0.21). 42 EPs (93.3%) believed they ordered "about the same" or "fewer" CTs than their peers. Of the 17 EPs in the two highest ordering quintiles, only 3 (18%) knew they were high orderers. In the multivariable analysis, higher ordering was associated with increasing strength of response to the following predictors: medico-legal risk (relative risk [RR]=1.18, 95% CI: 1.03-1.21), risk of contrast (RR=1.14, 95% CI: 1.07-1.22), what colleagues would do (RR=1.09, 95% CI: 0.99-1.19), risk of missing a diagnosis (RR=1.08, 95% CI: 0.98-1.21), and patient wishes (RR=1.07, 95% CI: 0.97-1.17). CONCLUSIONS: There is large variation in CT ordering among EPs. Physicians' self-reported ordering rate correlates poorly with actual ordering. High CT orderers were rarely aware that they ordered more than their colleagues. Higher rates of ordering were observed among physicians who reported increased concern with 1) risk of missing a diagnosis, 2) medico-legal risk, 3) risk of contrast, 4) patient wishes, and 5) what colleagues would do. PMID- 28673375 TI - Dietary inflammatory index in relation to sub-clinical atherosclerosis and atherosclerotic vascular disease mortality in older women. AB - Arterial wall thickening, stimulated by low-grade systemic inflammation, underlies many cardiovascular events. As diet is a significant moderator of systemic inflammation, the dietary inflammatory index (DIITM) has recently been devised to assess the overall inflammatory potential of an individual's diet. The primary objective of this study was to assess the association of the DII with common carotid artery-intima-media thickness (CCA-IMT) and carotid plaques. To substantiate the clinical importance of these findings we assessed the relationship of DII score with atherosclerotic vascular disease (ASVD)-related mortality, ischaemic cerebrovascular disease (CVA)-related mortality and ischaemic heart disease (IHD)-related mortality more. The study was conducted in Western Australian women aged over 70 years (n 1304). Dietary data derived from a validated FFQ (completed at baseline) were used to calculate a DII score for each individual. In multivariable-adjusted models, DII scores were associated with sub clinical atherosclerosis: a 1 sd (2.13 units) higher DII score was associated with a 0.013-mm higher mean CCA-IMT (P=0.016) and a 0.016-mm higher maximum CCA IMT (P=0.008), measured at 36 months. No relationship was seen between DII score and carotid plaque severity. There were 269 deaths during follow-up. High DII scores were positively associated with ASVD-related death (per sd, hazard ratio (HR): 1.36; 95 % CI 1.15, 1.60), CVA-related death (per sd, HR: 1.30; 95 % CI 1.00, 1.69) and IHD-related death (per sd, HR: 1.40; 95 % CI 1.13, 1.75). These results support the hypothesis that a pro-inflammatory diet increases systemic inflammation leading to development and progression of atherosclerosis and eventual ASVD-related death. PMID- 28673376 TI - Adaptive process triage system cannot identify patients with gastrointestinal perforation. AB - INTRODUCTION: Adaptive process triage (ADAPT) is a triage tool developed to assess the severity and address the priority of emergency patients. In 2009-2011, ADAPT was the most frequently used triage system in Denmark. Until now, no Danish triage system has been evaluated based on a selective group of patients in need of acute abdominal surgery. Gastrointestinal perforation (GIP) is acknowledged as one of the surgical conditions with the highest mortality rates. The aim of this study was to evaluate whether ADAPT can identify patients with GIP. METHODS: All abdominal emergency laparoscopies and laparotomies performed over a one-year period at Herlev Hospital, Denmark, were included. Patient data and triage levels were collected from medical records. We defined patients suspected of less severe surgical illness as green-yellow and patients suspected of severe/life threatening illness as orange-red. RESULTS: A total of 803 patients with a known triage level were identified: 47% green, 38% yellow, 13% orange and 2% red. Of these patients, 136 were identified with a GIP. The negative predictive value was 83.2% (95% confidence interval: 80.1-85.7), meaning that one out of six abdominal surgery patients triaged as green or yellow had a GIP that was not identified by the triage system. CONCLUSION: ADAPT is incapable of identifying one of the most critically ill patient groups in need of emergency abdominal surgery. FUNDING: none. TRIAL REGISTRATION: HEH-2013-034 I-Suite: 02336. PMID- 28673377 TI - Low incidence of perineal hernia repair after abdominoperineal resection for rectal cancer. AB - INTRODUCTION: Perineal hernia may be a long-term complication to conventional abdominoperineal resection or proctocolectomy. We analysed the incidence of post operative perineal hernia repair and described patient-reported outcome measures (PROMS) after perineal hernia repair. METHODS: This was a nationwide retrospective analysis of consecutive Danish patients undergoing conventional abdominoperineal resection or proctocolectomy for rectal cancer from 1 January 2004 to 31 December 2014 combined with patients undergoing a subsequent repair for a perineal hernia during the follow-up period from 1 January 2004 to 31 December 2016. Patients were sent a quality of life questionnaire (HerQles A) and related PROMS. RESULTS: The incidence of perineal hernia repair was 0.83%. A total of 2,170 patients underwent proctocolectomy and conventional abdominoperineal resection, and 18 patients had a subsequent perineal hernia repair. Four patients developed a clinical hernia recurrence, another four patients reported moderate/severe perineal pain or heaviness during physical activity and complained of poor perception of health, and one patient reported that the perineal hernia repair had a negative impact on sexual function. CONCLUSIONS: The incidence of perineal hernia repair was below 1% after conventional abdominoperineal resection and proctocolectomy. PROMS and risk of recurrence may benefit from centralising perineal hernia repair. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 28673378 TI - Newly diagnosed obstructive sleep apnoea and type 2 diabetes mellitus. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is frequent in type 2 diabetes mellitus (DM) and is seen in 12-30% of patients with newly diagnosed OSA according to previous studies. Our aim was to determine the referral pattern and prevalence of patients with self-reported type 2 DM in a Danish cohort of patients with newly diagnosed OSA. Furthermore, we compared clinical data related to the sleep disorder in patients with and without type 2 DM and different OSA severities. METHODS: This retrospective observational study was based on data from a cohort including all patients offered continuous positive airway pressure therapy in the course of a 14-month period after being referred to a sleep disorders clinic. RESULTS: A total of 54 of 696 (7.8%) patients had type 2 DM. The majority of the patients in the type 2 DM group were referred from a general practitioner and only 8% from diabetes clinics. BMI, age and cardiovascular morbidity in type 2 DM patients were significantly higher than in the group without diabetes, while the Epworth Sleepiness Scale (ESS) score, the Apnea Hypopnea Index (AHI) and the Oxygen Desaturation Index (ODI) were not statistically different. Daytime sleepiness was similar in patients with mild-to moderate compared with severe OSA. CONCLUSIONS: AHI, ESS and ODI were similar in type 2 DM and the non-diabetic group. The prevalence of type 2 DM was lower than expected. Attention of healthcare providers to the association between type 2 DM and OSA is needed. FUNDING: The study was funded by the Central Region Denmark Region Research Fund. TRIAL REGISTRATION: not relevant. PMID- 28673379 TI - Return to work after lumbar disc surgery is related to the length of preoperative sick leave. AB - INTRODUCTION: Lumbar disc herniation (LDH) is associated with high morbidity and significant socio-economic impact as the majority of the patients are of working age. The purpose of this study was to determine the impact of length of sick leave on the return-to-work rate after lumbar disc herniation surgery. METHODS: This was a single-centre study of LDH patients who underwent surgery from 18 May 2009 through 28 November 2014. Data were collected prospectively from the DaneSpine database. Questions in DaneSpine include preoperative length of sick leave and working status one year post-operatively. RESULTS: A total of 678 patients were included and 72% of the patients had returned to work one year after their surgery. The rate of patients returning to work decreases significantly with the length of preoperative sick leave. Among the patients who were on sick leave prior to their surgery, 83% returned to work if surgically treated within three months. In contrast, only 50% of those whose sick leave exceeded three months returned to work. CONCLUSION: The present analysis suggests that the return-to-work rate after lumbar disc herniation surgery is affected by the length of sick leave. FUNDING: none. TRIAL REGISTRATION: This study was registered with the Danish Data Protection Agency. PMID- 28673380 TI - Possible adverse effects of the quadrivalent human papillomavirus vaccine in the Region of Southern Denmark: a retrospective, descriptive cohort study. AB - INTRODUCTION: Since the introduction of the quadrivalent human papillomavirus vaccine, young girls and women have reported a broad range of symptoms. These have been described as possible adverse effects of the vaccine. In this study, we describe demographic characteristics, symptomatology, clinical and laboratory test results in patients referred with suspected adverse effects in the Region of Southern Denmark. METHODS: We conducted a retrospective, descriptive study. The patients filled out a questionnaire, were interviewed by a doctor and received a standard physical examination and laboratory tests. RESULTS: The study comprised 200 patients. The median age at referral was 22 (interquartile range (IQR): 19.5 26) years, and age at first vaccination was 14 (IQR: 12-21) years. The most common symptoms were headache (93%), fatigue/tiredness (93%) and dizziness when standing up (90%). The median number of symptoms in each patient was 15. Five patients (2.5%) were diagnosed with postural orthostatic tachycardia syndrome (POTS). Of all patients, 183 (91.5%) were terminated without a somatic diagnosis, one patient (0.5%) was terminated with a functional disorder and 11 patients (5.5%) were still in diagnostic workup when the present study concluded. CONCLUSIONS: The patients reported a wide range of symptoms. We found an overall low prevalence of POTS. It should be further investigated whether these patients might suffer from a functional disorder rather than from adverse effects associated with the vaccine. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 28673381 TI - Biomarkers of Necrotising Soft Tissue Infections Aspects of the Innate Immune Response. AB - Necrotising soft tissue infection (NSTI) is a life-threatening and rapidly progressing bacterial infection involving one or more layers of the soft tissue compartments causing necrosis. The amputation and mortality rates remain high despite increased focus on the patients. Timely treatment, including surgical intervention, reduces the risk of severe disability and death. However, the lack of pathognomonic signs impedes early diagnosis and treatment. Moreover, the rarity of the disease makes it difficult to conduct large prospective studies, thus prospective research is almost non-existent in this group of patients. Instead data regarding biomarkers are extrapolated from the wide and heterogenic group of patients with sepsis, even though the immunological responses are likely to differ because of the large amount of necrotic tissue seen in patients with NSTI. We performed the largest prospective, observational studies to date of patients with NSTI in Scandinavia sampled over more than two years with up to a 2.7-year follow-up. Blood samples were taken on admission (baseline) and the following three days and subsequently analysed for relevant plasma biomarkers. We elaborated on three aspects of the innate immune response, which included the investigation of acute-phase proteins, pattern recognition molecules of the lectin complement pathway, and inflammatory cytokines. The objective was to investigate aspects of the innate immune response in patients with NSTI, focusing on biomarkers as prognostic markers of disease severity and mortality. The overall hypothesis was that plasma biomarkers, representing the early innate immune response, can be used as prognostic markers of disease severity and mortality assessed by ICU scoring systems (SAPS II and SOFA score), the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, presence of septic shock, microbial aetiology, renal replacement therapy, and amputation. In Study 1, we assessed the following acute-phase proteins in 135 patients with NSTI: pentraxin-3 (PTX3), procalcitonin, and C-reactive protein. We found that a high baseline PTX3 level above the median was significantly associated with the presence of septic shock, amputation, and 180-day mortality, albeit PTX3 was not an independent predictor of mortality. PTX3 and procalcitonin performed equally well, whereas C-reactive protein correlated poorly with clinically relevant outcomes. In Study 2, we assessed the following plasma pattern recognition molecules in the same cohort as in Study 1: mannose-binding lectin, Ficolin-1, Ficolin-2, and Ficolin-3. We found that baseline Ficolin-2 level below the median was associated with short- and long-term mortality and correlated with the SAPS II, whereas low levels of mannose-binding lectin and Ficolin-3 were associated only with short-term mortality. In Study 3, we assessed the following inflammatory cytokines in 159 patients with NSTI: interleukin-1beta, interleukin 6, interleukin-10, and tumor necrosis factor-alpha. We found no significant association between the LRINEC score and baseline cytokine levels. In addition, interleukin-6 had the strongest correlation with the disease severity scores (SAPS II and SOFA score), whereas interleukin-1beta and interleukin-10 had the strongest association with 30-day mortality. Moreover, patients with beta haemolytic streptococcal infection had higher levels of interleukin-6 and tumor necrosis factor-alpha compared with each subgroup stratified by microbial aetiology. This thesis provides new knowledge on the aspects of the innate immune response in patients with NSTI. The results prove that NSTI is characterised by a pronounced inflammatory response and that the innate immune response differs according to disease severity, microbial aetiology, and mortality. Through the three studies we have identified relevant biomarkers that are useful in the risk stratification of patients with NSTI, thus perhaps enhancing prognostication and decision making in these critically ill patients. PMID- 28673382 TI - Rational use of dopamine in hypotensive newborns: Improving our understanding of the effect on cerebral autoregulation. AB - Hypotension in critically ill newborn infants is associated with higher mortality and higher risk of cerebral injuries. Yet treating hypotension has never been shown to improve outcomes. In fact, some studies have found that hypotensive newborn infants who were treated with dopamine fared worse than a comparable group of newborn infants who were not. Therefore, a concern has been raised that dopamine might cause the observed adverse outcomes. Cerebral autoregulation is a protective mechanism that maintains a fairly constant cerebral blood flow despite fluctuations in blood pressure. We hypothesized that dopamine might impair the cerebral autoregulation by inducing a rightward shift of the cerebral autoregulation curve. An increased cerebrovascular resistance due to a dopaminergic stimulation of alpha-adrenoceptors might cause this effect. The main focus of this thesis is to clarify whether dopamine induces a rightward shift of the cerebral autoregulatory pressure curve. The thesis is based on four papers: (I) A methodological study comparing the two most commonly used methods of estimating cerebral autoregulation: time-domain analysis and frequency-domain analysis. We found that the consistency between the two methods was poor, and that time-domain analysis appeared a more robust - and simpler - method for describing cerebral autoregulation when estimates of cerebral autoregulation are based on spontaneous changes in blood pressure. (II) A retrospective study estimating cerebral autoregulation in very preterm infants by time domain analysis. This study found an association between dopamine therapy and impaired cerebral autoregulation. (III) An experimental animal study examining whether dopamine affected cerebral autoregulation in newborn piglets with low blood pressure. We found that dopamine did not negatively affect cerebral venous saturation, cerebral blood flow, or cerebral autoregulation capacity in hypotensive newborn piglets. (IV) An in vitro experiment where middle cerebral arteries from newborn piglets were examined by wire myography and pressure myography. In the wire myograph, increasing concentrations of dopamine caused a biphasic response: starting with vasodilation at low concentrations followed by vasoconstrictions at higher concentrations. In the pressure myograph, dopamine mainly induced vasodilation and the internal arterial diameter only tended to decrease at the highest concentrations. In summary, dopamine has been associated with impaired cerebral autoregulation and our conclusions in study II accorded with this. However, other work has found that initiation of dopamine infusion does not affect cerebral autoregulation. This may indicate that dopamine itself does not lead to impaired cerebral autoregulation. In support of these counter observations, we did not find any causal relationship between dopamine therapy and impaired cerebral autoregulation in newborn piglets in study III. Also, dopamine in therapeutic concentrations did not induce vasoconstriction in pial arteries in study IV. Based on a review of the current literature, and on the studies included in this thesis, the answer to the central question in this thesis is: "No, dopamine did not induce a rightward shift of the cerebral autoregulation curve". PMID- 28673383 TI - Preoperative embolization in surgical treatment of metastatic spinal cord compression. AB - An increasing number of patients develop symptomatic spinal metastasis and increasing evidence supports the benefit of surgical decompression and spinal stabilization combined with radiation therapy. However, surgery for metastatic spinal disease is known to be associated with a risk of substantial intraoperative blood loss and perioperative allogenic blood transfusion. Anemia is known to increase morbidity and mortality in patients undergoing surgery, but studies also indicate that transfusion with allogenic red blood cells (RBC) may lead to worse outcomes. To reduce intraoperative bleeding preoperative embolization has been used in selected cases suspected for hypervascular spinal metastases, but no randomized trial has examined the effect. The final decision on whether preoperative embolization should be performed is based on the preoperative digital subtraction angiography (DSA) tumor blush, and as such considered the "gold standard" for determining the vascularity of spinal metastases. Reliability studies evaluating vascularity ratings of DSA tumor blush have not been published before. This PhD thesis is based on three studies with the following aims: I. To assess whether perioperative allogenic blood transfusions in patients undergoing surgical treatment for spinal metastases independently influence patient survival (Study 1). II. To assess whether preoperative transcatheter arterial embolization of spinal metastases reduces blood loss, the need for transfusion with allogenic RBC and surgery time in the surgical treatment of patients with symptomatic metastatic spinal cord compression (Study 2). III. To describe the vascularity of metastasis causing spinal cord compression (Study 2). IV. To evaluate inter- and intra-observer agreement in the assessment of the vascularity of spinal metastases using DSA tumor blush (Study 3). In conclusion the findings of this thesis demonstrate that preoperative embolization in patients with symptomatic spinal metastasis independent of primary tumor diagnosis does not reduce intraoperative blood loss and the need for allogenic RBC transfusion significantly, but does reduce the surgery time. However, a small reduction of intraoperative blood loss was observed in the hypervascular metastases. This tendency could be underestimated because of the study design and furthermore the tendency may be enhanced in metastases of only the most pronounced hypervascularity. The findings furthermore support that perioperative blood transfusion of less than 5 units does not decrease survival in patients operated for spinal metastases and transfusion of 1 2 units seems to be weakly associated with increased 12-month survival. It was demonstrated that approximately 75 percent of spinal metastases are hypervascular in a consecutive series of patients with symptoms of metastatic medullary compression and spinal instability operated by decompression and instrumented spinal stabilization. In addition the findings show that there is satisfactory moderate inter- and intrarater agreement in classifying the vascularity of spinal metastases on a three-step ordinal scale for DSA tumor blush. Nevertheless, there is a call for an accurate preoperative way to evaluate the vascularity of spinal metastases in order to select patients most likely to benefit from preoperative embolization. PMID- 28673384 TI - Testosterone therapy of men with type 2 diabetes mellitus - a randomized, double blinded, placebo-controlled study. AB - The prevalence of chronic diseases including obesity and type 2 diabetes mellitus (T2D) are increasing. The usage of testosterone replacement therapy (TRT) has escalated in the Western countries during the past decades especially in aging men without clear organic indication for TRT although the safety of long-term TRT has not been clarified regarding the risk of cardiovascular disease (CVD). Aging men with T2D have an increased risk of CVD and these patients are often characterized by lowered T-levels, ectopic fat depots, a deranged adipokine profile with e.g. low adiponectin levels and hyperleptinaemia. However, the causal relations are unclear, and lowered T-levels could simply be a marker of illness, i.e. T2D and obesity. The aim of this randomized, double-blind, placebo controlled study was to contribute to the clarification of the beneficial and potential harmful effects of testosterone therapy in aging men with T2D. Our results did not support evidence to beneficial effects of testosterone therapy on insulin resistance, glycemic control, or on substrate-oxidation in aging men with T2D and we cannot recommend TRT as a novel treatment for T2D. Regarding risk of CVD, the substantially reduction in subcutaneous fat (thigh and abdomen) and HDL cholesterol levels along with unchanged ectopic fat (visceral and hepatic) during TRT might suggest an increased CVD risk. However, TRT has an ambiguous impact on the adipokine profile with a potential harmful decrease in levels of adiponectin, whereas the decrease in leptin levels and leptin: adiponectin ratio could reflect an amelioration of the CVD risk linked to hyperleptinaemia in aging men with T2D. We found that TRT for 24 weeks in aging men with T2D and lowered bio-available T levels improved body composition with an increase in LBM and a reduction in regional and TFM. In addition to increased lean leg mass, TRT preserved knee extensor muscle mechanical function. Although physical function was unchanged, TRT may potentially diminish the risk of developing sarcopenia resulting in a longer independent life and shorten the length of rehabilitation periods. It is still unclear whether the positive effects of TRT on muscle mass and muscle mechanical function outweigh potential negative effects especially regarding the risk for CVD. In conclusion, testosterone replacement therapy is indicated in men with clinically symptomatic hypogonadism regardless of status for T2D. PMID- 28673385 TI - Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa. AB - Exophilin-8 has been reported to play a role in anchoring secretory granules within the actin cortex, due to its direct binding activities to Rab27 on the granule membrane and to F-actin and its motor protein, myosin-Va. Here, we show that exophilin-8 accumulates granules in the cortical F-actin network not by direct interaction with myosin-Va, but by indirect interaction with a specific form of myosin-VIIa through its previously unknown binding partner, RIM-BP2. RIM BP2 also associates with exocytic machinery, Cav1.3, RIM, and Munc13-1. Disruption of the exophilin-8-RIM-BP2-myosin-VIIa complex by ablation or knockdown of each component markedly decreases both the peripheral accumulation and exocytosis of granules. Furthermore, exophilin-8-null mouse pancreatic islets lose polarized granule localization at the beta-cell periphery and exhibit impaired insulin secretion. This newly identified complex acts as a physical and functional scaffold and provides a mechanism supporting a releasable pool of granules within the F-actin network beneath the plasma membrane. PMID- 28673387 TI - Memory representations, tree structures, and parameter polysemy: Comment on Cooper, Greve, and Henson (2017). PMID- 28673386 TI - Polyglycerol-opioid conjugate produces analgesia devoid of side effects. AB - Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects. PMID- 28673388 TI - Targeting Aberrant Signaling in Myeloid Malignancies: Promise Versus Reality. AB - Clonal myeloid disorders are characterized by genetic alterations that activate cytokine signaling pathways and stimulate cell proliferation. These activated signaling pathways have been extensively studied as potential therapeutic targets, and tyrosine kinase inhibitors have indeed had extraordinary success in treating BCR/ABL-positive chronic myeloiud leukemia. However, although inhibitors of other activated kinases have been developed that perform well in preclinical studies, the therapeutic efficacy of these drugs in patients has been unimpressive. This article discusses potential reasons for these discordant results and outlines recent scientific advances that are informing future efforts to target activated kinases in clonal myeloid disorders. PMID- 28673389 TI - Tyrosine Kinase Inhibitor Treatment for Newly Diagnosed Chronic Myeloid Leukemia. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disorder that accounts for approximately 10% of new cases of leukemia. The introduction of tyrosine kinase inhibitors has led to a reduction in mortalities. Thus, the estimated prevalence of CML is increasing. The National Comprehensive Cancer Network and the European Leukemia Net guidelines incorporate frequent molecular monitoring of the fusion BCR-ABL transcript to ensure that patients reach and keep treatment milestones. Most patients with CML are diagnosed in the chronic phase, and approximately 10% to 30% of these patients will at some time in their course meet definition criteria of resistance to imatinib. PMID- 28673391 TI - The Development and Use of Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms. AB - Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera. Additional JAK2 inhibitors are currently in advanced phased clinical trials. PMID- 28673392 TI - Mechanisms of Resistance to JAK2 Inhibitors in Myeloproliferative Neoplasms. AB - Myeloproliferative neoplasms are driven by activated JAK2 signaling due to somatic mutations in JAK2, the thrombopoietin receptor MPL or the chaperone calreticulin in hematopoietic stem/progenitor cells. JAK2 inhibitors have been developed, but despite clinical benefits, they do not signficantly reduce the mutant clone. Loss of response to JAK2 inhibitors occurs and several mechanisms of resistance, genetic and functional, have been identified. Resistance mutations have not been reported in MPN patients suggesting incomplete target inhibition. Alternative targeting of JAK2 by HSP90 inhibitors or type II JAK2 inhibition overcomes resistance to current JAK2 inhibitors. Additional combined therapy approaches are currently being evaluated. PMID- 28673390 TI - Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors. AB - Chronic myeloid leukemia is increasingly viewed as a chronic illness; most patients have a life expectancy close to that of the general population. Despite progress made using BCR-ABL1 tyrosine kinase inhibitors (TKIs), drug resistance via BCR-ABL1-dependent and BCR-ABL1-independent mechanisms continues to be an issue. BCR-ABL1-dependent resistance is primarily mediated through oncoprotein kinase domain mutations and usually results in overt resistance to TKIs. However, BCR-ABL1-independent resistance in the setting of effective BCR-ABL1 inhibition is recognized as a major contributor to minimal residual disease. Efforts to eradicate persistent leukemic stem cells have focused on combination therapy. PMID- 28673393 TI - Tyrosine Kinase Inhibitors in the Treatment of Eosinophilic Neoplasms and Systemic Mastocytosis. AB - The World Health Organization's semimolecular classification of eosinophilias emphasizes neoplasms driven by fusion tyrosine kinases. More than 80% of patients with systemic mastocytosis carry the KIT D816V mutation, the primary driver of disease pathogenesis. Genetic annotation of these diseases is critical and affords opportunities for targeted therapy. This article discusses our understanding of the mutated tyrosine kinome of eosinophilic neoplasms and systemic mast cell disease, and the successes and limitations of available therapies. Use of tyrosine kinase inhibitors as a bridge to hematopoietic stem cell transplantation, and development of more selective and potent tyrosine kinase inhibitors is also highlighted. PMID- 28673394 TI - The Development of FLT3 Inhibitors in Acute Myeloid Leukemia. AB - FLT3 mutations, generally associated with a poor prognosis, are found in approximately one-third of patients with acute myeloid leukemia (AML) and represent an attractive therapeutic target. FLT3 inhibitors undergoing clinical evaluation include first-generation relatively non-specific small molecules and second-generation compounds with higher potency and selectivity against mutant FLT3. Recently presented results from a prospective randomized clinical trial will likely lead to a change in the standard of care for younger patients with FLT3-mutated AML: addition of the multi-targeted FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy. Thus, personalized therapies for this subset of AML will soon be possible. PMID- 28673396 TI - Kinase Inhibitor Screening in Myeloid Malignancies. AB - Kinase pathways are primary effectors of many targeted therapy approaches for cancer. Kinase pathways can be dysregulated by mechanisms far more diverse than chromosomal rearrangements or point mutations, which drove the initial application of kinase inhibitors to cancer. Functional screening with kinase inhibitors is one tool by which we can understand the diversity of target kinases and candidate drugs for patients before fully understanding the mechanistic rationale for kinase pathway dysregulation. By combining functional screening with genomic data, it is also possible to accelerate understanding of these mechanistic underpinnings. PMID- 28673395 TI - Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment. AB - The presence of FLT3 mutations in acute myeloid leukemia (AML) carries a particularly poor prognosis, making the development of FLT3 inhibitors an imperative goal. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the recent approval by the US Food and Drug Administration of Midostaurin for the treatment of FLT3-mutated AML. Initial success has been followed by the emergence of clinical resistance. Although novel FLT3 inhibitors are being developed, studies into mechanisms of resistance raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease. PMID- 28673397 TI - Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms. AB - Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective. These findings suggest that a personalized approach in which patient-specific alterations are identified and targeted may be a critically important therapeutic approach. PMID- 28673398 TI - Kinase Inhibitors in the Treatment of Myeloid Malignancies. PMID- 28673402 TI - Correction. PMID- 28673401 TI - An exposome perspective: Early-life events and immune development in a changing world. AB - Advances in metagenomics, proteomics, metabolomics, and systems biology are providing a new emphasis in research; interdisciplinary work suggests that personalized medicine is on the horizon. These advances are illuminating sophisticated interactions between human-associated microbes and the immune system. The result is a transformed view of future prevention and treatment of chronic noncommunicable diseases, including allergy. Paradigm-shifting gains in scientific knowledge are occurring at a time of rapid global environmental change, urbanization, and biodiversity losses. Multifactorial and multigenerational implications of total environmental exposures, the exposome, require coordinated interdisciplinary efforts. It is clear that the genome alone cannot provide answers to urgent questions. Here we review the historical origins of exposome research and define a new concept, the metaexposome, which considers the bidirectional effect of the environment on human subjects and the human influence on all living systems and their genomes. The latter is essential for human health. We place the metaexposome in the context of early-life immune functioning and describe how various aspects of a changing environment, especially through microbiota exposures, can influence health and disease over the life course. PMID- 28673399 TI - Environmental determinants of allergy and asthma in early life. AB - Allergic disease prevalence has increased significantly in recent decades. Primary prevention efforts are being guided by study of the exposome (or collective environmental exposures beginning during the prenatal period) to identify modifiable factors that affect allergic disease risk. In this review we explore the evidence supporting a relationship between key components of the external exposome in the prenatal and early-life periods and their effect on atopy development focused on microbial, allergen, and air pollution exposures. The abundance and diversity of microbial exposures during the first months and years of life have been linked with risk of allergic sensitization and disease. Indoor environmental allergen exposure during early life can also affect disease development, depending on the allergen type, dose, and timing of exposure. Recent evidence supports the role of ambient air pollution in allergic disease inception. The lack of clarity in the literature surrounding the relationship between environment and atopy reflects the complex interplay between cumulative environmental factors and genetic susceptibility, such that no one factor dictates disease development in all subjects. Understanding the effect of the summation of environmental exposures throughout a child's development is needed to identify cost-effective interventions that reduce atopy risk in children. PMID- 28673404 TI - The Journal of Allergy and Clinical Immunology: An update on style and substance. PMID- 28673405 TI - The Current State of Sports Concussion. AB - Concussion is a complex injury that requires a multimodal assessment to identify and manage the resulting dysfunction. To appropriately manage concussion, clinicians must be aware of the accompanying pathophysiology and dysfunction that occurs following the injury. The current best practice model of care includes symptom, motor, and neurocognitive assessment and management. Furthermore, clinicians should be aware that lifetime accumulation of head impacts may also play a role in neurologic presentation and response to concussion. This article reviews recent evidence concerning terminology, pathophysiology, epidemiology, and best practices in concussion management and potential long-term and cumulative implications of concussion. PMID- 28673400 TI - The environment, epigenome, and asthma. AB - Asthma prevalence has been on the increase, especially in North America compared with other continents. However, the prevalence of asthma differs worldwide, and in many countries the prevalence is stable or decreasing. This highlights the influence of environmental exposures, such as allergens, air pollution, and the environmental microbiome, on disease etiology and pathogenesis. The epigenome might provide the unifying mechanism that translates the influence of environmental exposures to changes in gene expression, respiratory epithelial function, and immune cell skewing that are hallmarks of asthma. In this review we will introduce the concept of the environmental epigenome in asthmatic patients, summarize previous publications of relevance to this field, and discuss future directions. PMID- 28673406 TI - Pathophysiology of Sports-Related Concussion. AB - Concussion pathophysiology is complicated and involves numerous mechanisms, including excessive neurotransmitter release, metabolic derangements, neuroinflammation, cerebral blood flow changes, and axonal disruption. The initial biomechanical impact in a concussion results in abnormal function at the cellular level, which initiates a cascade of events that leads to microstructural changes and, in the minority of cases, more persistent, permanent damage. PMID- 28673407 TI - Estimating Concussion Incidence Using Sports Injury Surveillance Systems: Complexities and Potential Pitfalls. AB - Numerous sports injury surveillance systems exist with the capability of tracking concussion incidence data. It is important for the consumers of sport-related concussion data, be they researchers or the public, to have a comprehensive understanding of the strengths and limitations of sports injury surveillance systems. This article discusses issues of system design and analysis that affect the interpretation and understanding of sport-related concussion incidence data from sports injury surveillance systems. Such understanding will help inform the design of sports injury surveillance systems and research studies that aim to identify risk factors, develop prevention strategies, and evaluate prevention mechanisms. PMID- 28673408 TI - Sideline Sports Concussion Assessment. AB - The sideline assessment of concussions is a complex multisystem assessment to detect whether an athlete shows signs or symptoms of concussion and should be removed from practice or competition to prevent greater neurologic compromise. Sideline concussion assessments are challenging given some of the environmental conditions, substitution rules of some sports, the possibility of athletes underreporting symptoms, and the difficulties of defining a concussion. The SCAT is the standard of care and is augmented with other procedures to enhance sensitivity and specificity. Serial assessments acutely are important to detect any evolving neurologic emergencies. This article provides a detailed review of the procedures in performing a sideline concussion assessment. PMID- 28673409 TI - Neurosurgical Emergencies in Sport. AB - Sports related severe brain and spinal cord injuries are medical and potentially surgical emergencies that require timely intervention in order to reduce worsening secondary injury. For this reason, it is important for all medical professionals managing athletic injuries to be knowledgeable in the clinical approach to this type of acute event. This article reviews the initial evaluation of the athlete that occurs on the field and also within the emergency department with a focus on presenting clinical signs of a neurosurgical emergency. We present a basic overview of the types of intracranial injuries requiring emergent neurosurgical intervention. PMID- 28673410 TI - Blood-Based Biomarkers for the Identification of Sports-Related Concussion. AB - Sports-related concussions (SRCs) are common among athletes in the United States. Most athletes who sustain an SRC recover within 7 to 10 days; however, many athletes who sustain the injury do not recover as expected and experience prolonged, persistent symptoms. In this document, the authors provide an overview of the empirical evidence related to the use of blood-based brain biomarkers in the athlete population for diagnosis of SRCs, prognosis of recovery and return to play guidelines, and indications of neurodegeneration. The authors also provide a summary of research challenges, gaps in the literature, and future directions for research. PMID- 28673411 TI - Neuropsychological Screening of Sport-Related Concussion. AB - Neuropsychological assessment is a key component of the multidimensional approach recommended by international consensus guidelines for evaluation of athletes affected by sport-related concussion (SRC). Over the past 2 decades, a number of conventional and computerized neuropsychological test batteries have been developed for the assessment of SRC. Standardized neurocognitive assessment tools are now commonly used across the continuum of concussion care, ranging from the sports sideline to critical care setting and the outpatient concussion clinic. We provide a brief, high-level overview of current approaches to best practice in neuropsychological assessment of SRC. PMID- 28673412 TI - Sport-Related Headache. AB - Headache occurring in a sports setting may be primary or secondary headache. Headache is the primary symptom reported after concussion. Cumulative incidence and prevalence of posttraumatic headache (PTH) are higher following mild traumatic brain injury (TBI) compared with moderate to severe TBI. Frequency is higher in those with more severe PTH. Migraine or probable migraine is the most common headache type after any severity TBI using primary headache disorder criteria. Management is empiric. Expert opinion recommends treating PTH according to clinical characteristics of primary headache. The most important factor in this approach is the recognition of the severity of headache. PMID- 28673413 TI - Neurologic Health in Combat Sports. AB - Neurologic injuries of both an acute and chronic nature have been reported in the literature for various combat sport styles; however, reports of the incidence and prevalence of these injury types vary greatly. Combat sports clinicians must continue to strive for the development, implementation, and enforcement of uniform minimum requirements for brain safety. These health care providers must also seize on the honor to provide this oft-underserved population with the health care advocacy they very much deserve, but often do not receive. PMID- 28673414 TI - Psychiatric Comorbidities in Sports. AB - Athletes are not immune to mental illness, despite outward appearances of strength and wellness. Depression and anxiety disorders may occur in athletes at least as commonly as in the general population. Eating disorders, attention deficit/hyperactivity disorder, and substance use disorders may occur even more frequently in athletes than in the general population. Thus, it is imperative that medical professionals across all specialties are aware of these psychiatric comorbidities, and how to initiate evaluation for and treatment of them. PMID- 28673415 TI - Sleep, Recovery, and Performance in Sports. AB - Poor sleep can lead to decreases in performance and recovery for athletes. Sleep disorders and symptoms are commonly seen in athletes, and may be unrecognized. It is important to educate athletes on adequate duration, quality, and timing of sleep. Interventions may include changes to practice times or careful planning for travel to games in different time zones. It is important to screen and treat sleep disorders such as sleep apnea and insomnia that are seen in some athletes. In patients who suffer concussion, it is important to address sleep issues, as poor sleep can prolong or exacerbate other concussion symptoms. PMID- 28673416 TI - Peripheral Nerve Injuries in Sport. AB - Sport-related peripheral nerve injuries (SRNIs) can occur in virtually any sport whether or not enjoyed by an amateur or in the career of a professional athlete. The diagnosis of SRNIs can be difficult, especially when trying to differentiate nerve injury from musculoskeletal pain. Clinicians should be able to recognize when a significant SRNI occurs and how to initiate a diagnostic and treatment pathway and referral to a specialist. This article reviews SRNIs and their specific sports, how to diagnose SRNIs, and how to select conservative or surgical management of these injuries. PMID- 28673417 TI - Neurologic Injuries in Noncontact Sports. AB - Noncontact sports are associated with a variety of neurologic injuries. Concussion, vascular injury (arterial dissection), and spinal cord trauma may be less common in noncontact sports, but require special attention from the sports neurologist. Complex regional pain disorders, muscle injury from repetitive use, dystonia, heat exposure, and vascular disorders (patent foramen ovale), occur with similar frequency in noncontact and contact sports. Management of athletes with these conditions requires an understanding of the neurologic consequences of these disorders, the risk of injury with return to play, and consideration for the benefits of exercise in health restoration and disease prevention. PMID- 28673418 TI - Sports Neurology. PMID- 28673419 TI - Preservatives in Personal Hygiene and Cosmetic Products, Topical Medications, and Household Cleaners in Spain. AB - INTRODUCTION: Preservatives are added to cosmetic, household cleaning, and other industrial products to prevent the growth of microorganisms. Unfortunately, exposure to these substances can cause sensitization. MATERIAL AND METHODS: Between January and June 2015, we analyzed the ingredients of 2300 products commercially available in Spain to identify the frequency of a wide variety of preservatives in different product categories. We analyzed 1093 skin care and cosmetic products sold exclusively in pharmacies (dermocosmetics), 458 household cleaning and personal hygiene and cosmetic products sold in supermarkets, 636 topical medications, and 113 cosmetic products sold in a herbal shop. RESULTS: Phenoxyethanol, citric acid, sodium benzoate, and potassium sorbate were very common in all the cosmetic product categories. Parabens were present in 16.1% of dermocosmetic products, 14.45% of cosmetic products available in supermarkets, 0.88% of cosmetic products available in the herbal shop, 5.18% of topical medications, and in none of the cleaning products. Isothiazolinones were identified in 2.56% of dermocosmetic products, 18% of cosmetic products in supermarkets, 7.9% of cosmetic products in the herbal shop, 63.63% of household cleaners, and in none of the topical medications. Formaldehyde releasers were detected in 5.76% of dermocosmetic products, 6.42% of cosmetic products sold in supermarkets, 7.96% of cosmetic products sold in the herbal shop, 3.93% of topical medications, and 16.74% of household cleaners. CONCLUSIONS: Evaluation of the presence of preservatives in everyday products allows us to indirectly estimate exposure levels to each one. Measures restricting the use of the most problematic preservatives need to be strengthened. PMID- 28673420 TI - Linear Palmoplantar Keratoderma. PMID- 28673421 TI - Department of Error. PMID- 28673422 TI - Human African trypanosomiasis. AB - Human African trypanosomiasis (sleeping sickness) is a parasitic infection that almost invariably progresses to death unless treated. Human African trypanosomiasis caused devastating epidemics during the 20th century. Thanks to sustained and coordinated efforts over the past 15 years, the number of reported cases has fallen to an historically low level. Fewer than 3000 cases were reported in 2015, and the disease is targeted for elimination by WHO. Despite these recent successes, the disease is still endemic in parts of sub-Saharan Africa, where it is a considerable burden on rural communities, most notably in central Africa. Since patients are also reported from non-endemic countries, human African trypanosomiasis should be considered in differential diagnosis for travellers, tourists, migrants, and expatriates who have visited or lived in endemic areas. In the absence of a vaccine, disease control relies on case detection and treatment, and vector control. Available drugs are suboptimal, but ongoing clinical trials provide hope for safer and simpler treatments. PMID- 28673423 TI - Chagas disease. AB - Chagas disease is an anthropozoonosis from the American continent that has spread from its original boundaries through migration. It is caused by the protozoan Trypanosoma cruzi, which was identified in the first decade of the 20th century. Once acute infection resolves, patients can develop chronic disease, which in up to 30-40% of cases is characterised by cardiomyopathy, arrhythmias, megaviscera, and, more rarely, polyneuropathy and stroke. Even after more than a century, many challenges remain unresolved, since epidemiological control and diagnostic, therapeutic, and prognostic methods must be improved. In particular, the efficacy and tolerability profile of therapeutic agents is far from ideal. Furthermore, the population affected is older and more complex (eg, immunosuppressed patients and patients with cancer). Nevertheless, in recent years, our knowledge of Chagas disease has expanded, and the international networking needed to change the course of this deadly disease during the 21st century has begun. PMID- 28673424 TI - Measles. AB - Measles is a highly contagious disease that results from infection with measles virus and is still responsible for more than 100 000 deaths every year, down from more than 2 million deaths annually before the introduction and widespread use of measles vaccine. Measles virus is transmitted by the respiratory route and illness begins with fever, cough, coryza, and conjunctivitis followed by a characteristic rash. Complications of measles affect most organ systems, with pneumonia accounting for most measles-associated morbidity and mortality. The management of patients with measles includes provision of vitamin A. Measles is best prevented through vaccination, and the major reductions in measles incidence and mortality have renewed interest in regional elimination and global eradication. However, urgent efforts are needed to increase stagnating global coverage with two doses of measles vaccine through advocacy, education, and the strengthening of routine immunisation systems. Use of combined measles-rubella vaccines provides an opportunity to eliminate rubella and congenital rubella syndrome. Ongoing research efforts, including the development of point-of-care diagnostics and microneedle patches, will facilitate progress towards measles elimination and eradication. PMID- 28673425 TI - Differences in rocky reef habitats related to human disturbances across a latitudinal gradient. AB - This study tested for differences in the composition of intertidal and shallow subtidal rocky reef habitats subjected to a range of human pressures across ~1000 km of coastline in New South Wales, Australia over 5 years. Percentage covers of habitats were sampled using aerial photography and a large grain size (20 m2 intertidal; 800 m2 subtidal) in a nested hierarchical design. Results were consistent with anthropogenic impacts on habitat structure only around estuaries with the most heavily urbanised or agriculturally-intense catchments. The most convincing relationships documented here related to environmental variables such as SST, latitude, reef width and proximity to large estuaries irrespective of human disturbance levels. Moreover, there were suggestions that any influences of estuarine waters (be they anthropogenic or natural) on reef assemblages could potentially extend 10s of kilometres from major estuaries. In general, our results supported those of studies that utilised smaller grain sizes (greatest variability often at smallest spatial scales), but we found that variability over scales of 100s of km can be similar to or greater than variability over scales of 10s of metres. PMID- 28673426 TI - Transcriptional and biochemical analysis of antioxidant enzymes in the mussel Mytilus galloprovincialis during experimental exposures to the toxic dinoflagellate Prorocentrum lima. AB - The genotoxic and cytotoxic effects of Diarrhetic Shellfish Poisoning (DSP) toxins have been widely investigated in bivalve molluscs, representing the main vectors of these compounds in the Atlantic coast of Europe. DSP toxins are produced by Harmful Algal Blooms (HABs) of Dinophysis and Prorocentrum dinoflagellates, being subsequently accumulated by marine organisms and biomagnified throughout trophic webs. Yet, bivalves display increased resistance to the harmful effects of these toxins during HAB episodes. While previous reports have suggested that such resilience might be the result of an increased activity in the bivalve antioxidant system, very little is still known about the specific mechanism underlying the protective effect observed in these organisms. The present work aims to fill this gap by studying transcriptional expression levels and biochemical activities of antioxidant enzymes in different tissues the mussel Mytilus galloprovincialis during experimental exposures to DSP toxins produced by the dinoflagellate Prorocentrum lima. Results are consistent with the presence of a compensatory mechanism involving a down-regulation in the expression of specific genes encoding antioxidant enzymes [i.e., SuperOxide Dismutase (SOD) and CATalase (CAT)] which is counterbalanced by the up-regulation of other antioxidant genes such as Glutathione S-Transferase pi-1 (GST-pi) and Selenium-dependent Glutathione PeroXidase (Se-GPx), respectively. Enzymatic activity analyses mirror gene expression results, revealing high antioxidant activity levels (consistent with a protective role for the antioxidant system) along with reduced lipid peroxidation (increasing the defense against oxidative stress). PMID- 28673427 TI - Linear variant of large plaque-type blue naevus with subcutaneous cellular nodules. PMID- 28673428 TI - Indolent T-cell lymphoproliferative disease of the gastrointestinal tract in a renal transplant patient: diagnostic pitfalls and clinical challenges. PMID- 28673429 TI - A novel fibrinogen gamma chain mutation (c.1096C>G; p.His340Asp), fibrinogen Ankara, causing hypofibrinogenaemia and hepatic storage. PMID- 28673430 TI - Does Gender Matter? The Prostate: Male, Female or Both? PMID- 28673431 TI - Urethral Perforation During Penile Implant Surgery: What to Do? PMID- 28673432 TI - Pharmacokinetics, Clinical Efficacy, Safety Profile, and Patient-Reported Outcomes in Patients Receiving Subcutaneous Testosterone Pellets 900 mg for Treatment of Symptoms Associated With Androgen Deficiency. AB - BACKGROUND: Implantation of testosterone doses of at least 150 to 450 mg (ie, two to six pellets) is common clinical practice despite a lack of prospective data. AIM: To evaluate pharmacokinetics, clinical efficacy, safety, and patient reported outcomes in men with androgen deficiency who received implantation of testosterone pellets (900 mg) in an open-label study. METHODS: Men with androgen deficiency (serum testosterone < 300 ng/dL [10.4 nmol/L]) were screened and received 12 testosterone pellets (900 mg). Serum hormone measurements (total and free testosterone, dihydrotestosterone, and estradiol) were obtained on days 1, 5, 8, 15, 29, 57, 85, and 113. All hormones were assayed using validated liquid chromatography and tandem mass spectrometry. OUTCOMES: Pharmacokinetics of selected hormones was determined. The patient-reported International Index of Erectile Function (IIEF), Center for Epidemiologic Studies Depression (CES-D), and Androgen Deficiency in the Aging Male (qADAM) questionnaires also were performed. Patients rated their satisfaction on a scale from 1 (very satisfied) to 5 (very dissatisfied). Adverse events were monitored throughout. RESULTS: Fifteen patients were included (mean age = 54.5 years, SD = 8.6 years). Mean baseline total testosterone concentration was 241.6 ng/dL (SD = 88.8 ng/dL; mean = 8.4 nmol/L, SD = 3.1 nmol/L). Mean testosterone serum concentrations fluctuated during the first 2 weeks (range = 300-1,000 ng/dL, 10.4-34.7 nmol/L) but remained higher than or equal to 300 ng/dL (10.4 nmol/L) through day 113. Concentrations of free testosterone, dihydrotestosterone, and estradiol mirrored that of total testosterone. Male functioning (IIEF score), depression (CES-D total score), and androgen-deficiency symptoms (qADAM total score) improved from baseline. Most patients were "very satisfied" (40.0%) or "quite satisfied" (26.7%) with treatment. Testosterone pellets were well tolerated. Pellet extrusion and polycythemia occurred in one patient each. CLINICAL IMPLICATIONS: Implantation of high doses (900 mg) of testosterone pellets are generally well tolerated and could provide clinical benefit for some patients. STRENGTHS AND LIMITATIONS: This study provides standardized data for the implantation of 12 testosterone pellets. However, the open-label uncontrolled design of this study and its small and ethnically non-diverse patient population limit the interpretation of these data, particularly the patient-reported outcomes. CONCLUSION: Implantation of 12 testosterone pellets (900 mg) was well tolerated and provided adequate and sustained serum testosterone concentrations. Additional randomized controlled trials are needed to confirm efficacy and safety findings. McMahon CG, Shusterman N, Cohen B. Pharmacokinetics, Clinical Efficacy, Safety Profile, and Patient Reported Outcomes in Patients Receiving Subcutaneous Testosterone Pellets 900 mg for Treatment of Symptoms Associated With Androgen Deficiency. J Sex Med 2017;14:883-890. PMID- 28673433 TI - Low-Intensity Shockwave Therapy Improves Hemodynamic Parameters in Patients With Vasculogenic Erectile Dysfunction: A Triplex Ultrasonography-Based Sham Controlled Trial. AB - BACKGROUND: Although several reports have documented the subjective improvement of erectile function after low-intensity extracorporeal shockwave therapy (LI ESWT) in patients with vasculogenic erectile dysfunction (ED), objective assessment data of penile hemodynamics are lacking. AIM: To assess penile hemodynamics before and 3 months after LI-ESWT in a group of patients with documented vasculogenic ED. METHODS: This was a double-blinded, randomized, sham controlled trial. Forty-six patients with ED were randomized; 30 underwent LI ESWT and 16 had a sham procedure in double-blinded fashion. All patients underwent penile triplex ultrasonography by the same investigator immediately before and 3 months after treatment. Patient demographics, International Index of Erectile Function erectile function domain (IIEF-ED) score, and minimal clinically important difference were assessed at baseline and 1, 3, 6, 9, and 12 months after treatment. OUTCOMES: Changes in peak systolic velocity and resistance index as measured by triplex ultrasonography at baseline and 3 months after treatment were the main outcomes of the study. Secondary outcomes were changes in the IIEF-EF score from baseline to 1, 3, 6, 9, and 12 months after treatment and the percentage of patients reaching a minimal clinically important difference during the same period for the two groups. RESULTS: IIEF-EF minimal clinically important differences for the active vs sham group were observed for 56.7% vs 12.5% (P = .005) at 1 month, 56.7% vs 12.5% (P = .003) at 3 months, 63.3% vs 18.8% (P = .006) at 6 months, 66.7% vs 31.3% (P = .022) at 9 months, and 75% vs 25% (P = .008) at 12 months. Mean peak systolic velocity increased by 4.5 and 0.6 cm/s in the LI-ESWT and sham groups, respectively (P < .001). CLINICAL IMPLICATIONS: Such results offer objective and subjective documentation of the value of this novel treatment modality for men with vasculogenic ED. STRENGTHS AND LIMITATIONS: Strengths include the prospective, randomized, sham-controlled type of study and the assessment of penile hemodynamics. Limitations include the small sample and strict inclusion criteria that do not reflect everyday clinical practice. CONCLUSION: The present study confirms the beneficial effect of LI-ESWT on penile hemodynamics and the beneficial effect of this treatment up to 12 months. Kalyvianakis D, Hatzichristou D. Low-Intensity Shockwave Therapy Improves Hemodynamic Parameters in Patients With Vasculogenic Erectile Dysfunction: A Triplex Ultrasonography-Based Sham-Controlled Trial. J Sex Med 2017;14:891-897. PMID- 28673434 TI - Sexual Activity and Physical Tenderness in Older Adults: Cross-Sectional Prevalence and Associated Characteristics. AB - BACKGROUND: Despite a common misconception, older adults engage in sexual behavior. However, there is limited sexual behavior research in older adults, which is often restricted to small samples, to cohorts recruiting adults from 45 years old, and to questions regarding only sexual intercourse. AIM: To assess the cross-sectional prevalence of and characteristics associated with sexual activity and physical tenderness in community-dwelling older adults. METHODS: From the Rotterdam Study, sexual activity and physical tenderness were assessed in 2,374 dementia-free, community-dwelling men and women at least 65 years old from 2009 through 2012 in the Netherlands. Analyses were stratified by sex and partner status. OUTCOMES: Sexual activity and physical tenderness (eg, fondling or kissing) in the last 6 months. Potential associated characteristics included measurements of demographics, socioeconomic position, health behavior, and health status. RESULTS: The vast majority of partnered participants (men, n = 858; women, n = 724) had experienced physical tenderness in the previous 6 months (83.7% of men and 82.9% of women) and nearly half had engaged in sexual activity (49.5% and 40.4% respectively). Very few unpartnered women (n = 675) had engaged in sexual activity (1.3%) or physical tenderness (5.2%), whereas prevalence rates were slightly higher for unpartnered men (n = 117; 13.7% or 17.1%). Engaging in sexual behavior was generally associated with younger age, greater social support, healthier behaviors, and better physical and psychological health. CLINICAL IMPLICATIONS: Findings show that older adults engage in sexual activity. It is important not to assume that an older person is not interested in sexual pleasure or that an older person is unhappy with not having a sexual partner. Offering an opportunity for open discussion of sexuality and medical assistance without imposing is a difficult balance. We encourage health care professionals to proactively address sexuality and extend knowledge about safe sex and sexual function to older adults. STRENGTHS AND LIMITATIONS: Thus far, this is one of the largest samples of sexual behavior assessment in adults older than 60 years. Limitations of this study are common in sexual behavior research, including low sexual behavior engagement among unpartnered older adults and a small sample of unpartnered men, which restricted sex- and age-specific implications. CONCLUSION: Almost half of partnered older adults engaged in sexual activity and more than two thirds engaged in physical tenderness, but very few unpartnered older adults engaged in these behaviors. The greatest barrier to being sexually active at an older age is lack of a partner, which particularly affects women. Sexuality is an important aspect of active aging. Freak-Poli R, Kirkman M, De Castro Lima G, et al. Sexual Activity and Physical Tenderness in Older Adults: Cross-Sectional Prevalence and Associated Characteristics. J Sex Med 2017;14:918-927. PMID- 28673435 TI - Male Sexual Function in New Zealand: A Population-Based Cross-Sectional Survey of the Prevalence of Erectile Dysfunction in Men Aged 40-70 Years. AB - BACKGROUND: Sexual function declines with age and erectile dysfunction (ED) is a common condition worldwide; however, prevalence rates vary markedly between populations and reliable data specific to New Zealand (NZ) are lacking. AIM: To assess the prevalence of ED in NZ men using a population-based cross-sectional survey. METHODS: Postal questionnaires were sent, according to a modified Dillman method, to a randomly selected age-stratified population-based sample of 2,000 men 40 to 70 years old obtained from the electoral roll. Self-reported erectile function was assessed using the five-item International Index of Erectile Function (IIEF-5) and the single-question self-assessment tool. OUTCOMES: The prevalence of ED is presented as crude, age-adjusted to the distribution of the NZ population, and standardized to the World Health Organization World Standard Population (WSP). Associations between sexual function and age were analyzed using chi2 test. RESULTS: The response rate was 30% (599) and 28% (562) were complete for analysis. The crude prevalence of ED was 42% (22% mild, 10% mild to moderate, 6% moderate, and 4% severe), the age-adjusted prevalence was 38%, and the WSP-adjusted prevalence was 37%. Among men reporting ED, 16% were medically diagnosed and 22% were treated. ED affected 24% of men in their 40s, 38% in their 50s, and 60% in their 60s (P < .001). Age was associated with a significant increase in diagnosed ED (P = .001), treated ED (P = .006), dissatisfaction with current sexual function (P < .001), associated anxiety or depression (P = .023), and a decrease in sexual activity (P < .001). CLINICAL TRANSLATION: Approximately one in three NZ men 40 to 70 years old might have ED. Although comparable to overseas populations, this prevalence is high. STRENGTHS AND LIMITATIONS: This study provides the most reliable, comprehensive, and current information on ED and its risk factors in NZ men. Strengths include the large sample, the use of random selection from a population-based sampling frame, established effective survey methods, and the validated IIEF-5. Limitations include the inability of cross-sectional data to determine causation, non-sampling errors associated with the population-based sampling frame, the low response rate, the inability to assess non-respondents, the possibility of men with ED who were sexually inactive not responding or not completing the IIEF-5, and the inherent inability to rule out recall bias. CONCLUSION: ED is a marker of subclinical cardiovascular disease. The high prevalence and low levels of diagnosis and treatment indicate a lost opportunity for timely intervention to delay or prevent the progression toward clinical disease. Quilter M, Hodges L, von Hurst P, et al. Male Sexual Function in New Zealand: A Population-Based Cross-Sectional Survey of the Prevalence of Erectile Dysfunction in Men Aged 40-70 Years. J Sex Med 2017;14:928 936. PMID- 28673436 TI - A Survey of Female Sexual Functioning in the General Dutch Population. AB - BACKGROUND: After the diagnosis and treatment of disease, a major barrier to research on psychosexual functioning is the lack of a consistent estimate for the prevalence of female sexual dysfunction in the general population. AIM: To clarify the prevalence of age-related female sexual functioning in the general population. METHODS: A sample was compiled by random selection of women from the general population in the northern part of the Netherlands and was categorized by age. Women completed the Female Sexual Function Index (FSFI), personal medical items and daily activities, the Body Image Scale, the SF-36 Health Survey, the Hospital Anxiety and Depression Scale, and the Multidimensional Fatigue Inventory. Participants' representativeness was assessed by comparing their characteristics with data from the Dutch Central Agency for Statistics and the Dutch Health Monitor. General health, fatigue, and well-being were compared with national or international data. OUTCOMES: Age-related total and domain scores of the FSFI. RESULTS: We evaluated female sexual functioning of 521 sexually active women. For women 20 to 80 years old, sexual functioning showed wide variance and was poor in 28% of all sexually active women, with FSFI scores being below the defined clinical cutoff (FSFI score < 26.55). Although sexual activity and functioning significantly decreased with increasing age, sexual satisfaction decreased only non-significantly. CLINICAL IMPLICATIONS: This study provides valuable age-specific ranges for female sexual functioning in the general population and can inform upcoming clinical studies. STRENGTHS AND LIMITATIONS: This is the largest study on female sexual function in a representative Dutch population using internationally validated tools and described by age categories, providing valuable information that can help in the understanding of how female sexual function changes with age. The FSFI has been criticized for not assessing personal distress related to sexual problems, so the lack of the Female Sexual Distress Scale in our study is an unfortunate shortcoming. The high rate of sexual inactivity (31%) resulted in fewer women being available to evaluate sexual functioning, but this could reflect the actual level of sexual (in)activity among women in a general population. CONCLUSION: FSFI total and domain scores showed wide variation across all age categories, but overall, one in four sexually active women scored below the diagnostic cutoff score. Sexual activity and functioning also decreased with age, whereas sexual satisfaction decreased only slightly. Lammerink EAG, de Bock GH, Pascal A, et al. A Survey of Female Sexual Functioning in the General Dutch Population. J Sex Med 2017;42:937 949. PMID- 28673437 TI - 'I didn't want to let it go too far.' The decisions and experiences of people who inject drugs who received a liver disease assessment as part of a liver health promotion campaign: The LiveRLife study. AB - BACKGROUND: An open cohort study (LiveRLife) evaluating an intervention integrating non-invasive liver disease assessment via transient elastography (TE) among people who inject drugs (PWID) was conducted in New South Wales, Australia. Participant follow-up occurred 2-16 weeks post-enrolment. It is imperative that PWID understand liver assessment results in order to make informed decisions about their health. The aim of this study was to evaluate the decisions and experiences of participants who received a liver disease assessment, including interpretation of TE score and subsequent health behaviours, using a health literacy framework. METHODS: Participants who had participated in LiveRLife were recruited from two opioid substitution treatment clinics and one medically supervised injecting centre between November 2015 and February 2016. The four recruitment categories were: (a) high TE score (>=9.5kPa)/attended follow-up, n=12; (b) high score/did not attend follow-up, n=2; (c) low score (<9.5kPa)/attended follow-up, n=11; and (d) low score/did not attend follow-up, n=8. Participants were not reminded of their category during recruitment. Inclusion criteria were: participants who received a TE score and informed consent. RESULTS: Of 33 semi-structured interviews, reasons for receiving a TE assessment were varied. Most participants interpreted level of liver disease correctly based on their TE score. Participants with higher TE scores frequently described feeling surprised by their result and also, often incorrectly identified drug use as a cause of advanced liver disease. In contrast, persons with lower TE scores felt encouraged by their result and spoke more to maintenance of healthy behaviours. When applicable, participants spoke of HCV therapy. CONCLUSION: Findings highlight some positive health changes made by PWID following liver disease assessment as well as ongoing misunderstandings of chronic liver disease in relation to illicit drug use. Results will inform strategies for targeted liver health education and 'linkage to care' for PWID with, and at-risk of, advanced liver disease. PMID- 28673438 TI - Comments on Brown et al. (2016). PMID- 28673439 TI - [Neuroendocrine prostate cancer: Natural history, molecular features, therapeutic management and future directions]. AB - Neuroendocrine prostate cancer is a rare malignancy with a an adverse prognostic. Histologically, It can be pure (small cells or large cells neuroendocrine carcinoma) or mixed with a adenocarcinoma component. Rarely diagnosed de novo, neuroendocrine prostate cancer is generally associated with advanced stage disease resistant to castration. As such, this histological subtype could represent an aggressive evolution of prostatic adenocarcinoma, through the epithelio-neuroendocrine transdifferentiation mechanism (phenomenon of lineage plasticity). Nonetheless, neuroendocrine prostate cancer is a heterogeneous malignancy with multiple histopathological variants showing distinct clinical features. The broad variety of molecular analyses could help to understand the ontogeny of this histological subtype and its signaling pathways. This may also allow identifying diagnostic and prognostic biomarkers as well as potential molecular targets. However, treatment options are currently limited and consist only in platinium-based chemotherapy for advanced stage disease. PMID- 28673440 TI - A lung sound analysis in a child thought to have cough variant asthma: A case report. PMID- 28673441 TI - Reply to: Does High-Frequency Deep Brain Stimulation in Dorsal Regions of the Ventral Striatum Impair Extinction of Morphine-Induced Place Preference? PMID- 28673443 TI - Does High-Frequency Deep Brain Stimulation in Dorsal Regions of the Ventral Striatum Impair Extinction of Morphine-Induced Place Preference? PMID- 28673442 TI - When Habits Are Dangerous: Alcohol Expectancies and Habitual Decision Making Predict Relapse in Alcohol Dependence. AB - BACKGROUND: Addiction is supposedly characterized by a shift from goal-directed to habitual decision making, thus facilitating automatic drug intake. The two step task allows distinguishing between these mechanisms by computationally modeling goal-directed and habitual behavior as model-based and model-free control. In addicted patients, decision making may also strongly depend upon drug associated expectations. Therefore, we investigated model-based versus model-free decision making and its neural correlates as well as alcohol expectancies in alcohol-dependent patients and healthy controls and assessed treatment outcome in patients. METHODS: Ninety detoxified, medication-free, alcohol-dependent patients and 96 age- and gender-matched control subjects underwent functional magnetic resonance imaging during the two-step task. Alcohol expectancies were measured with the Alcohol Expectancy Questionnaire. Over a follow-up period of 48 weeks, 37 patients remained abstinent and 53 patients relapsed as indicated by the Alcohol Timeline Followback method. RESULTS: Patients who relapsed displayed reduced medial prefrontal cortex activation during model-based decision making. Furthermore, high alcohol expectancies were associated with low model-based control in relapsers, while the opposite was observed in abstainers and healthy control subjects. However, reduced model-based control per se was not associated with subsequent relapse. CONCLUSIONS: These findings suggest that poor treatment outcome in alcohol dependence does not simply result from a shift from model based to model-free control but is instead dependent on the interaction between high drug expectancies and low model-based decision making. Reduced model-based medial prefrontal cortex signatures in those who relapse point to a neural correlate of relapse risk. These observations suggest that therapeutic interventions should target subjective alcohol expectancies. PMID- 28673444 TI - Infant crawling orthosis and home program to strengthen a neurologically impaired upper extremity. PMID- 28673445 TI - Does injection flow rate have an impact on arterial phase image degradation in liver MRI? A comparison of gadoxetic acid versus gadobutrol. AB - AIM: To evaluate retrospectively the impact of injection flow rate on arterial phase image degradation in liver magnetic resonance imaging (MRI) with gadoxetic acid (Gd-EOB-DTPA) compared to gadobutrol. MATERIALS AND METHODS: Two hundred consecutive patients who had undergone liver MRI were enrolled in this Health Insurance Portability and Accountability Act (HIPAA)-compliant institutional review board (IRB)-approved study and were divided into three groups. Group 1 (50 patients) and 2 (50 patients) had undergone MRI performed with gadoxetic acid (fixed 10 ml) at flow rate of 1 and 2 ml/s, respectively. Group 3 (100 patients) had undergone MRI performed with gadobutrol (0.1 mmol/kg) at 1 ml/s. Precontrast and post-contrast (arterial, portal venous, and hepatic venous phases) image degradation was assessed by two blinded independent readers using a four-point rating scale. The numbers of patients with arterial phase image degradation were compared using the Fisher exact test among the three groups. RESULTS: The incidence of arterial phase image degradation was 12% (6/50) in group 1 and 16% (8/50) in group 2 for both readers, 6% (6/100) for reader 1 and 5% (5/100) for reader 2 in group 3. Group 2 had a higher incidence of arterial phase image degradation when compared with group 3 for reader 2 (p=0.032). Severe arterial phase image degradation, resulting in non-diagnostic image quality, occurred in 4% (2/50) of patients when performed with gadoxetic acid administration at 2 ml/s and 2% (1/50) at 1 ml/s. CONCLUSION: A slower injection flow rate has a trend to reduce the incidence and severity of arterial phase image degradation during liver MRI with gadoxetic acid when compared to gadobutrol. PMID- 28673446 TI - Diagnostic efficacy of the Liver Imaging-Reporting and Data System (LI-RADS) with CT imaging in categorising small nodules (10-20 mm) detected in the cirrhotic liver at screening ultrasound. AB - AIM: To estimate the diagnostic accuracy of the Liver Imaging-Reporting and Data System (LI-RADS) with computed tomography (CT) for diagnosing hepatic nodules (10 20 mm) detected in cirrhotic livers. MATERIALS AND METHODS: Fifty-five patients with liver cirrhosis and a solitary nodule (10-20 mm in diameter) detected via ultrasound surveillance, underwent hepatic CT and fine-needle biopsy. All the CT images were analysed and the lesions were categorised into five categories according to the LI-RADS. RESULTS: Final diagnoses of the 55 nodules were as follows: 34 hepatocellular carcinomas (HCCs), one intrahepatic cholangiocarcinomas, one adrenocortical carcinoma metastasis, and 19 benign lesions. None (0%) of four LI-RADS category 1 lesions, two (22%) of nine category 2 lesions, seven (50%) of 14 category 3 lesions, two (67%) of three category 4 lesions, 22 (96%) of 23 category 5 lesions and one (50%) of two lesions classified as other malignancies was HCC. One category 5 lesion was adrenocortical carcinoma metastasis and one of two lesions categorised as other malignancies was intrahepatic cholangiocarcinoma. In patients with nodules detected at surveillance ultrasound, the best threshold for confident HCC diagnosis was more than LI-RADS category 3. The use of this threshold produced a sensitivity and specificity of 72.7% and 90%, respectively. So combining LI-RADS 4 and 5 categories for confident HCC diagnosis would improve accuracy and sensitivity with no significant impairment of specificity or positive predictive value. CONCLUSION: LIRADS with CT provides a strong validity for the diagnosis of small hepatic nodules, and is very useful to improve the accuracy of CT reports. PMID- 28673447 TI - Bleeding from gestational trophoblastic neoplasia: embolotherapy efficacy and tumour response to chemotherapy. AB - AIM: To evaluate retrospectively the impact of selective arterial embolisation (SAE) on the prognosis of patients with gestational trophoblastic neoplasia (GTN). MATERIALS AND METHODS: A retrospective analysis of the records of all patients with GTN between January 2005 and January 2015 was performed. Forty-one patients (mean age, 28.9 +/- 7.6 years) with massive vaginal haemorrhage from GTN (including 27 cases of choriocarcinoma and 14 cases of invasive mole) were treated with SAE. The complications, control of haemorrhage, and outcome of chemotherapy were reviewed retrospectively. RESULTS: SAE successfully controlled the haemorrhage for 38 patients (92.7%). All patients with successful SAE received systemic chemotherapy without recurrent massive bleeding during the period of chemotherapy. The average number of chemotherapy cycles was 9.8 for every patient. Complete remission (CR) was achieved in 34 patients (89.5%), two patients had partial remission, and two patients died. Two patients with CR required repeated embolisation for recurrence of massive bleeding 30 and 47 months after the first embolisation procedure due to uterine arteriovenous malformation (AVM). CONCLUSIONS: SAE can effectively control haemorrhage from GTN and these patients had good response to systemic chemotherapy following successful SAE. Uterine bleeding may recur due to uterine AVMs, even following complete embolisation and CR of GTN. PMID- 28673448 TI - Renovascular CT: comparison between adaptive statistical iterative reconstruction and model-based iterative reconstruction. AB - AIM: To compare contrast enhancement and image quality between renovascular computed tomography (CT) images with adaptive statistical iterative reconstruction (ASiR) and that with model-based iterative reconstruction (MBIR). MATERIAL AND METHODS: This retrospective study was approved by the institutional review board and written informed consent was waived. Twenty-five consecutive patients who underwent renovascular CT were enrolled in this study. The same raw projection data were reconstructed using ASiR 40%, 100%, and MBIR. Background noise, CT attenuation, and signal-to-noise ratio (SNR) of the renal vessels and kidneys, and image quality were compared among the three reconstruction techniques. RESULTS: Mean background noise was significantly lower with MBIR at the first and second phases than those with ASiR 40% and 100% (p<0.0001). Mean CT attenuation of the abdominal aorta, renal artery, and renal cortex obtained at the first phase and those of the renal vein and renal medulla at the second phase were comparable among the three techniques (p=0.051-1.00). Mean SNRs of the abdominal aorta, renal artery, renal cortex, renal vein, and renal medulla were significantly higher with MBIR than with ASiR 40% or 100% (both p<0.0001). The depiction of the renal artery and vein as well as image quality significantly improved with MBIR compared with those with ASiR 40% and 100% (p<0.0001-0.0016). CONCLUSION: Reconstruction of renovascular CT images with MBIR significantly reduces background noise, leading to an improvement in SNR and image quality compared with that using ASiR. PMID- 28673449 TI - Arterial spin labelling MRI for detecting pseudocapsule defects and predicting renal capsule invasion in renal cell carcinoma. AB - AIM: To evaluate prospectively the performance of combining morphological and arterial spin labelling (ASL) magnetic resonance imaging (MRI) for detecting pseudocapsule defects in renal cell carcinoma (RCC), and to predict renal capsule invasion confirmed histopathologically. MATERIALS AND METHODS: Twenty consecutive patients with suspicious renal tumours underwent MRI. Renal ASL imaging was performed and renal blood flow was measured quantitatively. The diagnostic performance of T2-weighted images alone, and a combination of T2-weighted and ASL images for predicting renal capsule invasion were assessed. RESULTS: Twenty renal lesions were evaluated in 20 patients. All lesions were clear cell RCCs (ccRCCs) confirmed at post-surgical histopathology. Fifteen ccRCCs showed pseudocapsule defects on T2-weighted images, of which 12 cases showed existing blood flow in defect areas on perfusion images. To predict renal capsule invasion, the sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 71.4%, 86.7%, 100%, respectively, for T2-weighted images alone, and 92.3%, 100%, 100%, 87.5%, respectively, for the combination of T2-weighted and ASL images. CONCLUSION: ASL images can reflect the perfusion of pseudocapsule defects and as such, the combination of T2-weighted and ASL images produces promising diagnostic accuracy for predicting renal capsule invasion. PMID- 28673450 TI - Race and ethnicity as predictors of hospital-acquired conditions after total hip arthroplasty and total knee arthroplasty. PMID- 28673451 TI - A prospective, proteomics study identified potential biomarkers of encapsulating peritoneal sclerosis in peritoneal effluent. AB - Encapsulating peritoneal sclerosis (EPS) is a potentially devastating complication of peritoneal dialysis (PD). Diagnosis is often delayed due to the lack of effective and accurate diagnostic tools. We therefore examined peritoneal effluent for potential biomarkers that could predict or confirm the diagnosis of EPS and would be valuable in stratifying at-risk patients and driving appropriate interventions. Using prospectively collected samples from the Global Fluid Study and a cohort of Greek PD patients, we utilized 2D SDSPAGE/ MS and iTRAQ to identify changes in the peritoneal effluent proteome from patients diagnosed with EPS and controls matched for treatment exposure. We employed a combinatorial peptide ligand library to compress the dynamic range of protein concentrations to aid identification of low-abundance proteins. In patients with stable membrane function, fibrinogen gamma-chain and heparan sulphate proteoglycan core protein progressively increased over time on PD. In patients who developed EPS, collagen alpha1(I), gamma-actin and Complement factors B and I were elevated up to five years prior to diagnosis. Orosomucoid-1 and a2-HS-glycoprotein chain-B were elevated about one year before diagnosis, while apolipoprotein A-IV and alpha1 antitrypsin were decreased compared to controls. Dynamic range compression resulted in an increased number of proteins detected with improved resolution of protein spots, compared to the full fluid proteome. Intelectin-1, dermatopontin, gelsolin, and retinol binding protein-4 were elevated in proteome-mined samples from patients with EPS compared to patients that had just commenced peritoneal dialysis. Thus, prospective analysis of peritoneal effluent uncovered proteins indicative of inflammatory and pro-fibrotic injury worthy of further evaluation as diagnostic/prognostic markers. PMID- 28673453 TI - High-ability Learners. PMID- 28673452 TI - Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy. AB - IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR 5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression. PMID- 28673454 TI - "Duration of bronchoprotection of the long-acting muscarinic antagonists tiotropium & glycopyrronium against methacholine-induced bronchoconstriction in mild asthmatics" [Respiratory Medicine 118 (September 2016) 96-101]. PMID- 28673455 TI - Neorickettsia risticii, Rickettsia sp. and Bartonella sp. in Tadarida brasiliensis bats from Buenos Aires, Argentina. AB - Bats are potential reservoirs of many vector-borne bacterial pathogens. The aim of the present study was to detect species of Anaplasma, Ehrlichia, Neorickettsia, Rickettsia, Borrelia and Bartonella in Brazilian free-tailed bats (Tadarida brasiliensis, Molossidae) from Buenos Aires city, Argentina. Between 2012 and 2013, 61 T. brasiliensis from urban areas of Buenos Aires city were studied. The samples were molecularly screened by PCR and sequencing. Five bats (8.2%) were positive to Neorickettsia risticii, one (1.6%) was positive to Rickettsia sp. and three bats (4.9%) to Bartonella sp. For molecular characterization, the positive samples were subjected to amplification and sequencing of a fragment of p51 gene for N. risticii, a fragment of citrate synthase gene (gltA) for Rickettsia genus and a fragment of gltA for Bartonella genus. Phylogenetic tree was constructed using the maximum-likelihood method. Phylogenetic analysis of N. risticii detect in our study revealed that it relates to findings in the USA West Coast; Rickettsia sp. detected is phylogenetically within R. bellii group, which also includes many other Rickettsia endosymbionts of insects; and Bartonella sp. found is related to various Bartonella spp. described in Vespertilionidae bats, which are phylogenetically related to Molossidae. Our results are in accordance to previous findings, which demonstrate that insectivorous bats could be infected with vector-borne bacteria representing a potential risk to public health. Future research is necessary to clarify the circulation of these pathogens in bats from Buenos Aires. PMID- 28673456 TI - Pathogenic Leptospira spp. in bats: Molecular investigation in Southern Brazil. AB - The present study aimed to investigate the frequency of pathogenic Leptospira spp. in Brazilian bats and to determine possible risk factors associated to it. Ninety two bats of 12 species were evaluated. Whole genomic DNA from kidneys was extracted and real-time PCR specific to pathogenic Leptospira spp. was applied. Association between the frequency of specimens positive for Leptospira spp. and sex, age, bat species or family, season of collection, geographic localization and feeding habits was evaluated. The results showed that 39.13% of analyzed bats were found positive for Leptospira spp. Nine bat species had at least one positive result. There was no association among the evaluated variables and frequency of pathogenic Leptospira spp. Although the limitations due to lack of Leptospira spp. isolation, leptospiral carriage was demonstrated in bats of different species from southern Brazil, which reinforces the need for surveillance of infectious agents in wild animals. PMID- 28673457 TI - Incidence and vertical transmission rate of Neospora caninum in sheep. AB - The infection by Neospora caninum in sheep can lead to abortion and the birth of weak and debilitated lambs. The aim of this study was to assess the incidence of natural infection by Neospora caninum and the vertical transmission rate among sheep. A flock of 50 sheep was monitored for serum antibody titres against N. caninum and seroconversion over a period of six months using an indirect ELISA technique. The offspring of the herd was also investigated regarding anti-N. caninum antibodies to determine the vertical transmission rate through the indirect immunofluorescence technique. The initial and final prevalences of infection by N. caninum were 26.0% (13/50) and 72.0% (36/50), respectively, and the incidence of infection by N. caninum in the present study was 62.2% (23/37). The vertical transmission rate found was 15.4% (2/13). A high incidence of infection by N. caninum in sheep was observed, and this is the first report assessing the incidence of N. caninum among naturally infected sheep. PMID- 28673458 TI - Performance, endoparasitary control and blood values of ewes locally adapted in semiarid region. AB - This study evaluated the variation in the prevalence of endoparasitoses and their impact on body condition and blood values of sheep of the Morada Nova breed. A total of 138 ewes were examined for their morphology (body weight, BW; body condition score, BCS), parasitology (faecal egg count, FEC; Famacha(c) score; coproculture), hematology (red blood cell count,RBC); hemoglobin concentration, HE; packet cell volume, PCV; mean corpuscular volume, MCV,; mean corpuscular hemoglobin, MCH; mean corpuscular hemoglobin concentration, MCHC; leukocytes, WBC) and serum biochemistry (glucose, cholesterol, triglycerides, urea, creatinine, total protein, albumin, globulin, AST and ALT). Overall the animals presented higher BW and BCS in the months of September and December, however, with high FEC, in addition to a large number of animals with Famacha score 4 and 5. The results showed that the main hematophagous worm affecting the sheep, the genus Haemonchus ssp, appeared in a greater proportion (30-71.66%) than the other worms in all months of the study, except in March. About 30% of the hematological values found in the study are outside the reference ranges for suable sheep e 45.50% for serum biochemistry. These findings demonstrate the most healthy period of the year was from March to June for endoparasites control, however, in the months of September and December the animals showed better performance measures. PMID- 28673459 TI - Serological survey of Neospora caninum and Toxoplasma gondii in cattle (Bos indicus) and water buffaloes (Bubalus bubalis) in ten provinces of Brazil. AB - The objective of this study was to determine the prevalence of antibodies to Neospora caninum and Toxoplasma gondii among 500 cattle (Bos indicus) and 500 buffaloes (Bubalus bubalis) using the indirect fluorescent antibody test (IFAT) technique. Blood samples from were collected from water buffalo and cattle in 10 municipalities in the northern region of Brazil. The frequency of cattle and water buffaloes seropositive for Neospora caninum in Para state, Brazil, was 55% and 44%, respectively, and the frequency of cattle and water buffaloes seropositive for Toxoplasma gondii was 52% and 39%, respectively. Seropositivity for both N. caninum and T. gondii was detected in 10.6% of the cattle samples and 14.8% of the buffalo samples. The frequency of cattle positive for N. caninum and T. gondii was significantly (p<0.05) higher than that of buffalo in two and three provinces, respectively. Buffaloes had a lower seroprevalence for N. caninum or T. gondii in all of the provinces studied. These results suggest that both species, when exposed to the same risks for N. caninum and T. gondii infection, have a high serological prevalence. Cattle showed a higher probability of being seropositive when exposed to the same risks for N. caninum and T. gondii. Our study, which included an extensive number of blood samples, provides important epidemiological information pertinent to buffalo production in tropical countries that can be used as a basis for disease-management practices in Latin America. PMID- 28673460 TI - A survey of canine haemoprotozoan parasites from Turkey, including molecular evidence of an unnamed Babesia. AB - Canine tick-borne apicomplexan parasites have emerged in recent years, showing a wider geographic distribution and increased global prevalence. A reverse line blot assay was performed on 219 blood samples collected from domestic dogs for simultaneous detection of all named canine piroplasm species as well as Hepatozoon canis. Ten samples hybridized to the Theileria/Babesia and Babesia catch all probes but did not hybridize to any species-specific probe tested, suggesting the presence of an unrecognized Babesia species or genotype. Sequencing results showed 91.5%, 91.9%, 92.4%, 92.4%, and 89.2% similarity to B. canis, B. vogeli, B. rossi, B. gibsoni, and B. conradae, respectively. The highest homology (98.1-98.5%) observed was with unnamed Babesia sp. isolates (Ludhiana and Malbazar) described in dogs, Babesia sp. of buffalo origin, Babesia sp. Kashi 2, and Babesia orientalis, along with Babesia occultans of cattle origin. The partial cox1 sequence indicated that this isolate was most similar to Babesia sp. 1 HG-2012, with an identity of 86.5%. The survey revealed high prevalence of haemoprotozoans in domestic dogs (57.5%, CI 50.7-64.2), with Hepatozoon canis the most prevalent (54.3%, CI 47.5-61.117%), followed by Babesia sp. (4.6%, CI 2.2-8.2), B. vogeli (1.4%; CI 0.3-3.9), and B. canis (0.4%, CI 0 2.5). Combined infection of Hepatozoon canis and Babesia sp. was detected in five (2.3%, CI 0.7-5.2) samples and of H. canis and B. vogeli in two (0.9%, CI 0.1 3.2) dogs. The study contributes insight into the distribution and phylogenetic diversity of canine piroplasms in Turkey. PMID- 28673461 TI - Experimental infection of Artibeus intermedius with a vampire bat rabies virus. AB - Experimental infection of Artibeus intermedius, the great fruit-eating bat, was performed with vampire bat rabies isolates. Bats (n=35) were captured in the wild and quarantined prior to experimental infection. No rabies antibodies were detected by rapid fluorescent focus inhibition test (RFFIT) prior to infection. Three doses of rabies virus (RV) and three different routes of infection were used. One out of 35 bats died without showing any clinical signs at day 14 and was positive for rabies. None of the 34 other bats showed clinical signs for rabies, but high antibody titers were detected post-inoculation, suggesting either innate immune response to the vampire bat rabies virus or possible pre exposure to RV and inoculation leading to a booster effect. Rabies virus was detected by hemi-nested RT-PCR (hnRT-PCR) in the brain (n=3), stomach (n=1) of bats that were negative by immunofluorescence and that survived rabies infection. The bat that died on day 14 was positive by hnRT-PCR on the brain, heart and liver. These results suggest that either previous non-lethal exposure to RV or natural low susceptibility to vampire bat viruses somehow protected Artibeus intermedius from clinical rabies infection leading to a marginal lethality effect on this bats species population in the wild. PMID- 28673462 TI - Cell-free DNA-induced alteration of autophagy response and TLR9-signaling: Their relation to amelioration of DSS-colitis. AB - BACKGROUND: The influence of cell-free DNA (fDNA) administration on the TLR9 autophagy regulatory crosstalk within inflammatory circumstances remains unclear. AIMS: To examine the immunobiologic effects of iv. fDNA injection on the TLR9 mediated autophagy response in murine DSS-colitis. METHODS: Different types of modified fDNAs were administered to DSS-colitic mice. Disease and histological activities, spleen index were measured. Changes of the TLR9-associated and autophagy-related gene expression profiles of lamina proprial cells and splenocytes were assayed by quantitative real-time PCR, and validated by immunohistochemistries. Ultrastructural changes of the colon were examined by transmission electron microscopy (TEM). RESULTS: A single intravenous injection of colitic fDNA (C-DNA) exhibited beneficial clinical and histological effects on DSS-colitis, compared to normal (N-DNA). C-DNA administration displayed a more prominent impact on the outcome of the TLR9-autophagy response than N-DNA. C-DNA resulted in a decreased spleen index in DSS-colitic mice. C-DNA treatment of normal mice resulted in a downregulation of Beclin1 and ATG16L1 mRNA and protein expression in the colon. These as well as LC3B were downregulated in the spleen. In contrast, the Beclin1, ATG16L1 and LC3B gene and protein expressions were upregulated in both the colon and the spleen by C-DNA injection. Moreover, C-DNA administration to DSS-colitic mice resulted in a remarkable increase of epithelial autophagic vacuoles representing an intensified macroautophagy. CONCLUSIONS: The effect of intravenously administered fDNA on the TLR9-mediated autophagy response is expressly dependent on the origin of fDNA (i.e. inflammatory or not) and on the characteristics of the local immunobiologic milieu (i.e. inflammatory or not, as well). PMID- 28673463 TI - Occurrence of hemotropic mycoplasmas in non-human primates (Alouatta caraya, Sapajus nigritus and Callithrix jacchus) of southern Brazil. AB - Hemoplasmas, the erythrocyte-associated mycoplasmas, have been detected in several primates, causing mostly subclinical infection. This study aimed to determine the prevalence of hemoplasma infection in captive and free-ranging monkeys from southern Brazil, as well as factors and hematological abnormalities associated with infection. Blood samples from 40 non-human primates (NHP) were tested for hemoplasmas and coinfections. An overall of 10/40 (25.0%) NHP tested positive for hemoplasmas using PCR-based assays, including 9/14 (64.3%) black howler monkeys (Alouatta caraya) and 1/24 (4.2%) black-horned capuchin (Sapajus nigritus). Infection was not statistically associated with anemia, but wild-born monkeys and male black howler monkeys were more likely to be positive when compared with captive-born animals and female black howler monkeys, respectively. The sequences from the black howler monkey hemoplasma were similar (94% identity) to the squirrel monkey hemoplasma ("Candidatus Mycoplasma kahanei") and were phylogenetically located in a different cluster when compared to the human hemoplasma ("Candidatus Mycoplasma haemohominis"). PMID- 28673464 TI - Force related hemodynamic responses during execution and imagery of a hand grip task: A functional near infrared spectroscopy study. AB - We examined force related hemodynamic changes during the performance of a motor execution (ME) and motor imagery (MI) task by means of multichannel functional near infrared spectroscopy (fNIRS). The hemodynamic responses of fourteen healthy participants were measured while they performed a hand grip execution or imagery task with low and high grip forces. We found an overall higher increase of [oxy Hb] concentration changes during ME for both grip forces but with a delayed peak maximum for the lower grip force. During the MI task with lower grip force, the [oxy-Hb] level increases are stronger compared to the MI with higher grip force. The facilitation in performing MI with higher grip strength might thus indicate less inhibition of the actual motor act which could also explain the later increase onset of [oxy-Hb] in the ME task with the lower grip force. Our results suggest that execution and imagery of a hand grip task with high and low grip forces, leads to different cortical activation patterns. Since impaired control of grip forces during object manipulation in particular is one aspect of fine motor control deficits after stroke, our study will contribute to future rehabilitation programs enhancing patient's grip force control. PMID- 28673465 TI - [Protagonism of HPV genotypes in a population subject to organized screening]. PMID- 28673466 TI - Emergency Nurse Competence in Electrocardiographic Interpretation in Spain: A Cross-Sectional Study. AB - INTRODUCTION: Electrocardiographic interpretation skills are key to provide a fast attention to patients with thoracic pain. The aim of the study was to determine the current level of competence in electrocardiographic interpretation of nurses in emergency departments. METHODS: Cross-sectional, multicenter study via an ad hoc questionnaire. Subjects were nurses from three Spanish emergency departments with at least a year experience in this area. A two-part questionnaire was created consisting of a professional profile, and 12 questions (2 theoretical questions and 10 questions on practical cases with electrocardiographic register [readout]). A pilot test was carried out to evaluate the validity of the questionnaire, the content validity index. The reliability of the questionnaire was also tested on a subsample through intraclass correlation coefficient with a value of 0.869 (CI 95% 0.712-0.941). Descriptive and bivariate analyses were conducted using an independent t-test or one-way ANOVA as appropriate. A statistical significance of P < .05 was assumed. RESULTS: Fifty-seven usable questionnaires were obtained (47.2% response rate). Women comprised 84.2% of the sample and the mean age of the sample was 40.5 (SD = 9.3) years. Slightly more than 91% had taken electrocardiographic interpretation training courses, the main modality for which was face-to-face (84.2%). The average score on our questionnaire was 8.6 (SD=1.1) points. No significant differences between nursing experience and hospitals were observed. Nurses who had received training within the previous five years scored significantly higher than those who had not (P = .031). DISCUSSION: The electrocardiographic knowledge of emergency nurses is high. Level of knowledge was not influenced by experience or hospital but was influenced by training when provided in the previous 5 years. Therefore, refreshing courses should be taken at least every 5 years. Contribution to Emergency Nursing Practice. PMID- 28673467 TI - Fatal Dialysis Vascular Access Hemorrhage. AB - Bleeding from dialysis vascular access (arteriovenous fistulas, arteriovenous grafts, and vascular catheters) is uncommon. Death from these bleeds is rare and likely to be under-reported, with incident rates of fewer than 1 episode for every 1,000 patient-years on dialysis, meaning that dialysis units may experience this catastrophic event only once a decade. There is an opportunity to learn from (and therefore prevent) these bleeding deaths. We reviewed all reported episodes of death due to vascular access bleeding in Australia and New Zealand over a 14 year period together with individual dialysis units' root cause analyses on each event. In this perspective, we provide a clinically useful summary of the evidence and knowledge gained from these rare events. Our conclusion is that death due to dialysis vascular access hemorrhage is an uncommon, catastrophic, but potentially preventable event if the right policies and procedures are put in place. PMID- 28673468 TI - Consumption of a liquid high-fat meal increases triglycerides but decreases high density lipoprotein cholesterol in abdominally obese subjects with high postprandial insulin resistance. AB - Abdominal obesity is associated with an increased risk of insulin resistance, which may be a potential contributor to dyslipidemia. However, the relationship between postprandial insulin resistance and lipid metabolism in abdominally obese subjects remains unknown. We hypothesized that postprandial dyslipidemia would be exaggerated in abdominally obese subjects with high postprandial insulin resistance. To test this hypothesis, serum glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B were measured at baseline and postprandial state at 0.5, 1, 2, 4, 6, and 8 hours after a liquid high-fat meal in non-abdominally obese controls (n=44) and abdominally obese subjects with low (AO-LPIR, n=40), middle (n=40), and high postprandial insulin resistance (AO-HPIR, n=40) based on the tertiles ratio of the insulin to glucose areas under the curve (AUC). Their serum adipokines were tested at baseline only. Fasting serum leptin was higher (P<.05) in AO-HPIR than that in AO LPIR and controls. Postprandial triglycerides AUC was higher (P<.05), whereas high-density lipoprotein cholesterol AUC was lower (P<.05), in AO-HPIR than those in AO-LPIR and controls. Postprandial AUCs for total cholesterol and apolipoprotein B were similar in abdominally obese subjects with different degrees of postprandial insulin resistance and controls. The present study indicated that the higher degree of postprandial insulin resistance, the more adverse lipid profiles in abdominally obese subjects, which provides insight into opportunity for screening in health. PMID- 28673469 TI - Effect of Roux-en-Y gastric bypass on carotid intima-media thickness in Chinese obese patients with type 2 diabetes mellitus. PMID- 28673470 TI - Differential acute and chronic responses in insulin action in cultured myotubes following from nondiabetic severely obese humans following gastric bypass surgery. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery has been shown to induce positive metabolic adaptations for individuals with severe obesity (body mass index >=40 kg/m2), including improved peripheral insulin action. Although a major site of insulin action, the time course changes in skeletal muscle glucose metabolism following RYGB is unclear. OBJECTIVES: To investigate the acute and chronic effects of RYGB surgery on insulin-stimulated glucose metabolism in cultured human primary myotubes derived from nondiabetic severely obese humans. SETTING: East Carolina University Bariatric Surgery Center and East Carolina Diabetes and Obesity Institute. METHODS: Primary human skeletal muscle cells were isolated from biopsies obtained from 8 women with severe obesity before, 1 month, and 7 months following RYGB surgery. Glucose metabolism, glycogen content, and insulin signal transduction were determined in differentiated myotubes. RESULTS: Insulin-stimulated glycogen synthesis and glucose oxidation increased in human myotubes derived from patients with severe obesity at both 1 and 7 months post RYGB. However, there were no alterations indicative of enhanced insulin signal transduction. At 1 month post-RYGB, muscle glycogen levels were lower (-23%) and phosphorylation of acetyl CoA carboxylase 2 (ACC2) was elevated (+16%); both returned to presurgery levels at 7 months after RYGB in myotubes derived from patients. At 7 months post-RYGB, there was an increase in peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1alpha) protein content (+54%). CONCLUSION: These data indicate that insulin action intrinsically improves in cultured human primary myotubes derived from nondiabetic severely obese patients following RYGB surgery; however, the cellular alterations involved appear to consist of distinct acute and chronic components. PMID- 28673472 TI - The diverse morphogenetic patterns in spirotrichs and philasterids: Researches based on five-year-projects supported by IRCN-BC and NSFC. AB - In the five years 2012-2016, the ciliate research group at Ocean University of China and their collaborators have performed several investigations on the morphogenesis of ciliated protists during binary division. Multiple samples were collected from 17 cities and cortical development studied in 42 species belonging to 32 genera and 13 families (Amphisiellidae, Euplotidae, Kahliellidae, Oxytrichidae, Philasteridae, Pseudokeronopsidae, Pseudourostylidae, Schmidingerotrichidae, Spirofilidae, Strobilidiidae, Uroleptidae, Uronychiidae and Urostylidae). Among these, 12 genera were investigated morphogenetically for the first time, revealing some unusual pattern formations and allowing four new genera to be established: Heterokeronopsis, Apobakuella, Parabistichella and Apoholosticha. The objective of this review is to: 1) summarize the morphogenetic studies supported by the IRCN-BC and NSFC projects during these five years; 2) summarize the patterns of development and document deviations from normal morphogenetic events within a group; 3) discuss how studies on morphogenesis have helped to advance understanding in the three dimensions of biodiversity, i.e. taxonomy, genetics and function; and 4) suggest potential future directions for the morphogenetic study of ciliated protists. PMID- 28673471 TI - Unusual features of non-dividing somatic macronuclei in the ciliate class Karyorelictea. AB - Genome structure and nuclear organization have been intensely studied in model ciliates such as Tetrahymena and Paramecium, yet few studies have focused on nuclear features of other ciliate clades including the class Karyorelictea. In most ciliates, both the somatic macronuclei and germline micronuclei divide during cell division and macronuclear development only occurs after conjugation. However, the macronuclei of Karyorelictea are non-dividing (i.e. division minus (Div-)) and develop anew from micronuclei during each asexual division. As macronuclei age within Karyorelictea, they undergo changes in morphology and DNA content until they are eventually degraded and replaced by newly developed macronuclei. No less than two macronuclei and one micronucleus are present in karyorelictid species, which suggests that a mature macronucleus 1) might be needed to sustain the cell while a new macronucleus is developing and 2) likely plays a role in guiding the development of the new macronucleus. Here we use a phylogenetic framework to compile information on the morphology and development of nuclei in Karyorelictea, largely relying on the work of Dr. Igor Raikov (1932 1998). We synthesize data to speculate on the functional implications of key features of Karyorelictea including the presence of at least two macronuclei in each cell and the inability for macronuclei to divide. PMID- 28673473 TI - Clinical manifestations and imaging tools in the diagnosis of splanchnic and cerebral vein thromboses. AB - Splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT) are uncommon manifestation of venous thromboembolism (VTE), occurring less frequently than deep vein thrombosis of the lower extremities and pulmonary embolism. SVT encompasses portal vein thrombosis, mesenteric vein thrombosis, splenic vein thrombosis and the Budd-Chiari syndrome. It is therefore a heterogeneous disease, with differences in clinical manifestations according to the site of thrombosis. CVT includes thrombosis of the cortical or deep cerebral veins and thrombosis of the major dural venous sinuses. Clinical presentation is variable, with a wide spectrum of signs and symptoms that can mimic other cerebral diseases. There are no clinical algorithms or specific laboratory tests that can guide in the identification of SVT and CVT; therefore, the diagnosis relies exclusively on imaging tests. Conventional angiography once was the gold standard for the diagnosis of SVT and CVT, but it is rarely used nowadays. Abdominal ultrasound (US), computed tomography (CT) and magnetic resonance (MR) with angiography are currently used for the diagnosis of SVT; while cerebral CT and MR with angiography are currently used for the diagnosis of CVT. These imaging tests have different sensitivities/specificities and different advantages/disadvantages that should be kept into consideration when choosing the appropriate imaging test based on the suspected site of thrombosis. This narrative review summarizes the clinical and diagnostic approach to SVT and CVT. PMID- 28673474 TI - New developments and future challenges of nuclear medicine and molecular imaging for pulmonary embolism. AB - Although widely validated, current tests for pulmonary embolism (PE) diagnosis, i.e. computed tomography pulmonary angiography (CTPA) and V/Q planar scintigraphy, have some limitations. Drawbacks of CTPA include the radiation dose, some contra indications and a rising concern about a possible overdiagnosis/overtreatment of PE. On the other hand, V/Q planar scintigraphy has a high rate of non-diagnostic tests responsible for complex diagnostic algorithms. Since the PIOPED study, imaging equipment and radiopharmaceuticals have greatly evolved allowing the introduction of techniques that improve imaging of lung ventilation and perfusion. Single photon emission computed tomography (SPECT) and SPECT/CT techniques are already largely used in daily practice and have been described to have greater diagnostic performance and much fewer non diagnostic tests as compared with planar scintigraphy. However, they have not yet been firmly validated in large scale prospective outcome studies. More recently, it has also been proposed to image pulmonary perfusion and ventilation using positron emission tomography (PET), which has an inherent technical superiority as compared to conventional scintigraphy and may provide new insight for pulmonary embolism. Regardless of modality, these new thoracic imaging modalities have to be integrated into diagnostic strategies. The other major challenge for venous thromboembolism diagnosis may be the potential additional value of molecular imaging allowing specific targeting of thrombi in order, for example, to differentiate venous thromboembolism from tumor or septic thrombus, or acute from residual disease. In this article, the new imaging procedures of lung ventilation perfusion imaging with SPECT, SPECT/CT and PET/CT are discussed. We also review the current status and future challenge of molecular imaging for the in vivo characterization of venous thromboembolism. PMID- 28673475 TI - Associations of multiple trauma types and MAOA with severe aggressive behavior and MAOA effects on training outcome. AB - Previous research showed that the disposition to react with disproportionate aggression in adults is influenced by an interaction between a variant in the X chromosomal monoamine oxidase A gene (MAOA) and early traumatic events. Such studies have often focused on a single type of trauma, whereas we know that experiencing multiple trauma types is associated with more detrimental consequences. The differential susceptibility hypothesis suggests that individuals who are most susceptible to adversity, are also most likely to benefit from supportive experiences in childhood. Differences in susceptibility are thought to be partly genetically driven. In the present study we explored whether a genotype of MAOA linked to lower expression of the gene (MAOA-L) modified the effect of multiple types of trauma on aggression and/or altered responsiveness to treatment among adults with severe aggression. Forensic psychiatric outpatients (FPOs) (N=150) receiving treatment for aggression regulation problems were recruited. Traumatic events and aggression were measured using self-report. FPOs with multiple trauma types and those with the MAOA-L allele reported more severe levels of aggression. No interaction effects between MAOA genotype and trauma emerged. There were no differences in response to the intervention between FPOs with and without the MAOA-L variant, whereas FPOs with a single type of trauma showed the slowest reduction of aggression. FPOs with multiple types of trauma reported the highest levels of aggression over the course of treatment. Future research is needed to elucidate this association in further detail. The current study emphasized the importance of early recognition of early traumatic events. PMID- 28673476 TI - Prediction for Improvement and Remodeling in First-Onset Myocardial Infarction by Speckle Tracking Echocardiography: Is Global or Regional Selection Better? AB - Cardiac function improvement and chamber remodeling after the onset of acute myocardial infarction (AMI) is crucial as it is closely related to the outcomes of patients. We sought to investigate the predictive value of left ventricular (LV) global and region of interest (ROI) assessment for prognosis of AMI patients by speckle tracking echocardiography (STE). We prospectively enrolled 81 first onset AMI patients for baseline and 6-mo follow-up analysis. The echocardiography derived parameters were compared in receiver operator characteristics (ROC) analysis for prediction of LV remodeling (LVR) (a minimum 20% increase of LV end diastolic volume) and cardiac function improvement (a minimum 5% increase of LV ejection fraction). The ROI strain was selected by wall motion score index (WMSI) scores >=2. The time of whole analysis process was recorded. Cut-off values of 9.92% for global circumferential strain (CS) and -5.53% for ROI CS predicted LVR. Cut-off values of -10.40% for global longitudinal strain (LS) and -5.33% for ROI LS predicted cardiac function improvement. Areas under curves of global and ROI parameters were comparable in ROC analysis (p > 0.05, all). The time of global analysis was less than the time of ROI analysis (p < 0.05) and the reproducibility of global analysis was slightly better than the ROI analysis. Our results demonstrated that STE was valuable for the prediction of LVR and cardiac function improvement after AMI. Compared with ROI parameters, global parameters were more integral and efficient as predictive factors with high predictive power, less analysis time and better reproducibility. PMID- 28673477 TI - Image Monitoring of the Impaired Phagocytic Activity of Kupffer Cells and Liver Oxygen Saturation in a Mouse Cholangitis Model Using Contrast-Enhanced Ultrasound Imaging and Photoacoustic Imaging. AB - Bile duct ligation (BDL) can cause cholangitis, which is known to induce impaired Kupffer cell (KC) function and increased oxygen consumption in a mouse model. It is important to monitor changes in KC function and tissue oxygen saturation, both of which are critical factors in the progression of cholangitis. The purpose of this study is to investigate the impaired phagocytic activity of KC and liver oxygen saturation (sO2) in a mouse cholangitis model using contrast-enhanced ultrasound imaging (CEUS) and photoacoustic imaging (PAI). A mouse cholangitis model was created by ligation of the common bile duct (CBDL, n = 20), and the left intrahepatic bile duct (BDL-L, n = 19), both of which were compared with the non-ligation groups-right lobe measurement group after left intrahepatic bile duct ligation (BDL-R, n = 19) and the control group (n = 14). The echogenicity and sO2 were measured by CEUS and PAI and the KC fraction was assessed at 1, 2 and 4 wk after ligation. We found a significantly lower echogenicity of the Kupffer phase in the CBDL and BDL-L groups compared with that in the control and BDL-R groups at 2 wk (p < .01). The CBDL and BDL-L groups showed a lower echogenicity than that of the BDL-R group at 4 wk (p < .01). We found a significantly lower sO2 of the CBDL and BDL-L groups compared with that of the control and BDL-R groups at 4 wk (p < .01). The CBDL and BDL-L groups showed a higher KC fraction than that of the BDL-R and control groups at each time point (p < .01). In conclusion, our study suggests that the Sonazoid CEUS and PAI could be a useful tool for monitoring impaired KC phagocytic activity and the liver hypoxic state. PMID- 28673478 TI - Comparing Performance of Combinations of Shear Wave Elastography and B-Mode Ultrasound in Diagnosing Breast Masses: Is It Influenced by Mass Size? AB - We determined the diagnostic performance of combinations of shear wave elastography (SWE) and B-mode ultrasound (US) in differentiating malignant from benign breast masses, and we investigated whether performance is affected by mass size. In this prospective study of 315 consecutive patients with 326 breast masses, US and SWE were performed before biopsy. Masses were categorized into two subgroups on the basis of mass size (<=15 mm and >15 mm), and the optimal thresholds for the SWE parameters were determined for each subgroup using receiver operating characteristic curves. The combination proposed here achieved an area under the receiver operating characteristic curve of 0.943, 95.00% sensitivity and 81.18% specificity, which approximated the diagnostic performance of US alone. The performance of the combinations using the subgroups' thresholds did not differ significantly from those based on the entire study group's thresholds, but the optimal thresholds were higher in the subgroup of larger masses. Further research is needed to determine whether mass size affects the performance of combinations of SWE and US. PMID- 28673479 TI - Plaque microvascularization and permeability: Key players in atherogenesis and plaque rupture. PMID- 28673481 TI - CS-specific modifications of auditory evoked potentials in the behaviorally conditioned rat. AB - The current report provides a detailed analysis of the changes in the first two components of the auditory evoked potential (AEP) that accompany associative learning. AEPs were recorded from the primary auditory cortex before and after training sessions. Experimental subjects underwent one (n=5) or two (n=7) days of conditioning in which a tone, serving as a conditioned stimulus (CS), was paired with mild foot shock. Control subjects received one (n=5) or two (n=7) days of exposure to the same stimuli delivered randomly. Only animals receiving paired CS US training developed a conditioned tachycardia response to the tone. Our analyses demonstrated that both early components of the AEP recorded from the granular layer of the cortex undergo CS-specific associative changes: (1) the first, negative component (occurring ~21ms following tone onset) was significantly augmented after one and two days of training while maintaining its latency, and (2) the second, positive component (occurring ~50ms following tone onset) was augmented after two days of training, and showed a significant reduction in latency after one and two days of training. We view these changes as evidence of increased cortical synchronization, thereby lending new insight into the temporal dynamics of neural network activity related to auditory learning. PMID- 28673480 TI - Association of descending thoracic aortic plaque with brain atrophy and white matter hyperintensities: The Framingham Heart Study. AB - BACKGROUND AND AIMS: Aortic atherosclerosis is an aggregate marker of vascular risk factor exposure and has been associated with intracranial atherosclerosis and stroke. We hypothesized that atherosclerosis of the descending aorta (DAo) could be a risk marker for brain aging and injury. METHODS: We evaluated 1527 participants (mean age 59.9 years, 53.5% women) in the Framingham Offspring cohort who underwent both aortic and brain MRI. Participants were free of clinical stroke, dementia, or other neurological illness at the time of axial MRI of the thoracic and abdominal DAo and subsequent brain MRI. We related the prevalence and burden of aortic plaque to total cerebral brain volume (TCBV) and white matter hyperintensity volume (WMHV). An additional analysis compared incidence of stroke or TIA in participants with and without DAo plaques. RESULTS: Presence of thoracic DAo plaque (8%) was associated with decreased TCBV in sex pooled analysis (-0.77, SE 0.25, p = 0.002, equivalent to 4.5 years of aging) and with increased WMHV only in men (0.26, SE 0.12, p = 0.032, equivalent to 6.5 years aging). We observed similar associations of DAo plaque burden with TCBV and WMHV. There were 43 strokes and 11 TIAs in prospective follow-up (median 7 years). Presence of DAo plaque was not associated with subsequent stroke or TIA. CONCLUSIONS: In this cross-sectional community-based study, we found DAo plaque is associated with accelerated brain aging. These data underscore the potential implications of incidentally identified subclinical aortic atherosclerosis and question whether targeted intervention in these high risk individuals can modulate cognitive decline. PMID- 28673482 TI - High performance modelling of the transport of energetic particles for photon radiotherapy. AB - This work consists of the validation of a new Grid Based Boltzmann Solver (GBBS) conceived for the description of the transport and energy deposition by energetic particles for radiotherapy purposes. The entropic closure and a compact mathematical formulation allow our code (M1) to calculate the delivered dose with an accuracy comparable to the Monte-Carlo (MC) codes with a computational time that is reduced to the order of few minutes without any special processing power requirement. A validation protocol with heterogeneity inserts has been defined for different photon sources. The comparison with the MC calculated depth-dose curves and transverse profiles of the beam at different depths shows an excellent accuracy of the M1 model. PMID- 28673483 TI - Persuasive texts for prompting action: Agency assignment in HPV vaccination reminders. AB - Vaccination reminders must both inform and persuade, and text messages designed for this purpose must do so in 160 characters or less. We tested a strategy for improving the impact of HPV vaccination text message reminders through strategic wording. In an experiment conducted in community settings, 167 Spanish-speaking Latina mothers reviewed text message reminders that assigned the cause or "agency" for HPV transmission to their daughters or the virus, and assigned protection agency to the mothers or the vaccine. Reminder messages framing transmission as an action of the virus prompted mothers to perceive the threat as more severe than messages describing their daughters as the cause. Assigning transmission agency to the virus also held a persuasive advantage in boosting mothers' intentions to seek vaccination, particularly when the message cast mothers as agents of protection rather than the vaccine. PMID- 28673484 TI - Safety of inadvertent anthrax vaccination during pregnancy: An analysis of birth defects in the U.S. military population, 2003-2010. AB - BACKGROUND: Anthrax vaccine adsorbed (AVA) vaccination is compulsory for United States military servicemembers with operational indicators. As the number of female military servicemembers has increased, so has the chance of inadvertent AVA vaccination during pregnancy. Building upon past analyses assessing AVA vaccination during pregnancy and birth defects risk, this study sought to determine if inadvertent AVA vaccination during pregnancy is significantly associated with risk of birth defects after adjusting for other potential risk factors. METHODS: The study population included 126,839 liveborn infants in the Department of Defense Birth and Infant Health Registry (2003-2010). Mothers were categorized by AVA vaccination exposure timing in relation to pregnancy. Infant medical records were assessed for birth defect diagnoses within the first year of life. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Infants of first trimester AVA vaccinated mothers versus receipt at any other time point (OR, 1.10; 95% CI, 0.93 1.29) were not at higher odds of birth defects in adjusted models. Infants of mothers vaccinated prepregnancy versus postpregnancy had a 1.11 (95% CI, 1.01 1.22) higher odds of having a birth defect. Vaccination postpregnancy versus never vaccinated revealed a 10% lower odds of birth defects (OR, 0.90; 95% CI, 0.83-0.99). CONCLUSIONS: No strong associations between inadvertent AVA vaccination during pregnancy and birth defects risk were observed. Marginal associations between prepregnancy vaccination or never vaccinated women and birth defects risk was observed when compared to postpregnancy vaccination. These findings may be due to self-selection and/or reverse causation bias when assessing comparisons with postpregnancy vaccination, and a "healthy worker" effect when assessing comparisons with women never vaccinated. PMID- 28673485 TI - High resolution crystal structure of a fluoride-inhibited organophosphate degrading metallohydrolase. AB - Metal ion-dependent, organophosphate-degrading enzymes (OP hydrolases) have received increasing attention due to their ability to degrade and thus detoxify commonly used pesticides and nerve agents such as sarin and VX. These enzymes thus garner strong potential as bioremediators. The OP hydrolase from Agrobacterium radiobacter (OpdA) is one of the most efficient members of this group of enzymes. Previous studies have indicated that the choice of the hydrolysis-initiating nucleophile may depend on the pH of the reaction, with a metal ion-bridging hydroxide being preferred at lower pH (i.e. pH<=8.5), and a terminally coordinated hydroxide at higher pH (i.e. pH>9.0). Furthermore, fluoride was shown to be a potent inhibitor of the reaction, but only at low pH. Here, the crystal structure (1.3A, pH6) of OpdA in presence of fluoride is described. While the first coordination sphere in the active site displays minimal changes in the presence of fluoride, the hydrogen bonding network that connects the dimetallic metal center to the substrate binding pocket is disrupted. Thus, the structure of fluoride-inhibited OpdA demonstrates the significance of this hydrogen bond network in controlling the mechanism and function of this enzyme. PMID- 28673486 TI - Quantifying dimensional severity of obsessive-compulsive disorder for neurobiological research. AB - Current research to explore genetic susceptibility factors in obsessive compulsive disorder (OCD) has resulted in the tentative identification of a small number of genes. However, findings have not been readily replicated. It is now broadly accepted that a major limitation to this work is the heterogeneous nature of this disorder, and that an approach incorporating OCD symptom dimensions in a quantitative manner may be more successful in identifying both common as well as dimension-specific vulnerability genetic factors. As most existing genetic datasets did not collect specific dimensional severity ratings, a specific method to reliably extract dimensional ratings from the most widely used severity rating scale, the Yale-Brown Obsessive Compulsive Scale (YBOCS), for OCD is needed. This project aims to develop and validate a novel algorithm to extrapolate specific dimensional symptom severity ratings in OCD from the existing YBOCS for use in genetics and other neurobiological research. To accomplish this goal, we used a large data set comprising adult subjects from three independent sites: the Brazilian OCD Consortium, the Sunnybrook Health Sciences Centre in Toronto, Canada and the Hospital of Bellvitge, in Barcelona, Spain. A multinomial logistic regression was proposed to model and predict the quantitative phenotype [i.e., the severity of each of the five homogeneous symptom dimensions of the Dimensional YBOCS (DYBOCS)] in subjects who have only YBOCS (categorical) data. YBOCS and DYBOCS data obtained from 1183 subjects were used to build the model, which was tested with the leave-one-out cross-validation method. The model's goodness of fit, accepting a deviation of up to three points in the predicted DYBOCS score, varied from 78% (symmetry/order) to 84% (cleaning/contamination and hoarding dimensions). These results suggest that this algorithm may be a valuable tool for extracting dimensional phenotypic data for neurobiological studies in OCD. PMID- 28673487 TI - Experimental Infection of Goats with a Newly Isolated Strain of Akabane Virus that Causes Encephalomyelitis. AB - In 2010, there was a large-scale outbreak of bovine encephalomyelitis in Korea, and 15 new strains of Akabane virus (AKAV) were isolated. To identify the pathogenicity of one of these strains, we infected adult goats with AKAV-7 via different routes. Twenty-five female goats were used in this study and were divided into five groups: intracerebral (IC) and intrasubarachnoid (IS) viral inoculation (n = 8 each), intravenous (IV) inoculation (n = 4), and vaccinated before IV inoculation (n = 4), in addition to a negative control animal. All animals inoculated with AKAV-7 had AKAV-neutralizing antibodies at 6-8 days post infection (dpi). During the experimental period, infected animals showed no clinical signs. In the IC group, 5/8 goats had non-suppurative encephalomyelitis affecting the cerebrum. Virus S RNA segments were detected in nearly all areas of the brain. In the IS group, 3/8 goats had encephalomyelitis affecting the cerebrum, cerebellum and spinal cord. At 7 and 21 dpi, virus S RNA segments were found mostly in the spinal cord, especially around the area of injection (L5-L6). Antibody titres in the serum of the vaccinated group had an early onset and slightly increased titre compared with the IV group. Histopathologically, there were no obvious lesions in the central nervous tissues in the vaccinated group, while one of four goats in the IV group showed encephalomyelitis in the parietal lobe of the cerebrum. The newly isolated AKAV-7 can cause encephalomyelitis in goats after experimental injection. The attenuated AKAV vaccine currently used in Korea may provide partial protective immunity against AKAV-7 infection, but the real effect of the vaccine requires further investigation in goats. PMID- 28673488 TI - Anthralin modulates the expression pattern of cytokeratins and antimicrobial peptides by psoriatic keratinocytes. AB - BACKGROUND: Psoriasis is an inflammatory skin disease with aberrant keratinocyte proliferation, presumably as a result of immune cell activation. Th17 cytokines like IL-17A and IL-22 are critically implicated in epidermal thickening, altered keratinocyte differentiation and production of innate factors such as antimicrobial peptides. Psoriasis treatment options include modern targeted therapies using anti-cytokine antibodies and traditional non-targeted treatments like anthralin (dithranol). While the mode of action of anti-cytokine antibodies is defined, the effects of topical anthralin on psoriatic skin are not fully understood. OBJECTIVE: This study aims to unravel the direct effects of anthralin on keratinocyte proliferation, differentiation and production of psoriasis associated factors. METHODS: We tested the effects of anthralin on cell proliferation, cytokeratin expression and changes in the expression of antimicrobial peptides using primary keratinocytes and 3D psoriasis tissue models with and without stimulation of the psoriasis-promoting cytokines IL-17A and IL 22. Moreover, we compared the findings derived from monolayer and multilayer cultures to data derived from lesional skin of patients with psoriasis before and under treatment with anthralin. RESULTS: Our study shows that anthralin directly induces cell apoptosis in vitro in monolayer cultures but not in 3D psoriasis tissue models treated with IL-17A and IL-22. Yet, keratinocyte proliferation as determined by Ki-67 staining is impaired by anthralin in vivo. In lesional skin but not in 3D psoriasis tissue models anthralin rapidly normalizes cytokeratin (CK)16 expression. Furthermore, anthralin directly inhibits DEFB4 expression in vitro and in vivo, while other antimicrobial peptides and cytokines studied like IL-6 and IL-8 are regulated differently in vitro and in vivo. CONCLUSIONS: Our results show that anthralin directly regulates DEFB4A expression. However, its beneficial effects on psoriasis cannot be explained by direct effects on keratinocyte differentiation or cytokine expression. PMID- 28673489 TI - Verona Coding Definitions of Emotional Sequences (VR-CoDES): Conceptual framework and future directions. AB - OBJECTIVE: To discuss the theoretical and empirical framework of VR-CoDES and potential future direction in research based on the coding system. METHODS: The paper is based on selective review of papers relevant to the construction and application of VR-CoDES. RESULTS: VR-CoDES system is rooted in patient-centered and biopsychosocial model of healthcare consultations and on a functional approach to emotion theory. According to the VR-CoDES, emotional interaction is studied in terms of sequences consisting of an eliciting event, an emotional expression by the patient and the immediate response by the clinician. The rationale for the emphasis on sequences, on detailed classification of cues and concerns, and on the choices of explicit vs. non-explicit responses and providing vs. reducing room for further disclosure, as basic categories of the clinician responses, is described. CONCLUSIONS: Results from research on VR-CoDES may help raise awareness of emotional sequences. Future directions in applying VR-CoDES in research may include studies on predicting patient and clinician behavior within the consultation, qualitative analyses of longer sequences including several VR CoDES triads, and studies of effects of emotional communication on health outcomes. PRACTICE IMPLICATIONS: VR-CoDES may be applied to develop interventions to promote good handling of patients' emotions in healthcare encounters. PMID- 28673490 TI - Accuracy of Cone-beam Computed Tomography in Measuring Dentin Thickness and Its Potential of Predicting the Remaining Dentin Thickness after Removing Fractured Instruments. AB - INTRODUCTION: The purpose of this study was to evaluate the accuracy of cone-beam computed tomographic (CBCT) to measure dentin thickness and its potential of predicting the remaining dentin thickness after the removal of fractured instrument fragments. METHODS: Twenty-three human mandibular molars were selected, and 4-mm portions of #25/.06 taper K3 files (SybronEndo, Orange, CA) were fractured in mesial canals. The teeth were then scanned using a micro computed tomographic (micro-CT) system and a CBCT unit. Dentin thickness was measured and compared between both micro-CT and CBCT images to study the accuracy of CBCT readings. Then, the process of removing the fragments was simulated in CBCT images using the MeVisLab package (MeVis Research, Bremen, Germany); the predicted minimal remaining dentin thickness after removal was measured in different layers using VGStudio MAX software (Volume Graphics, Heidelberg, Germany). Data were compared with the actual minimal remaining dentin thickness acquired from micro-CT images, which were scanned after removing fractured instruments using the microtrepan technique. The results were analyzed statistically using intraclass correlation coefficients (ICCs) and a forecasting regression model analysis. RESULTS: The ICC for the dentin thickness was 0.988. The forecasting regression model of CBCT imaging estimating dentin thickness was micro-CT imaging = 15.835 + 1.080*CBCT, R2 = 0.963. The ICC for the remaining dentin thickness was 0.975 (P < .001). The forecasting regression model of CBCT imaging forecasting remaining dentin thickness was micro-CT imaging = 147.999 + 0.879*adjusted CBCT, R2 = 0.906. CONCLUSIONS: The study showed that CBCT imaging could measure dentin thickness accurately. Furthermore, using CBCT images, it is reliable and feasible to forecast the remaining dentin thickness after simulated instrument removal. PMID- 28673491 TI - Assessment of Volumetric Distortion Artifact in Filled Root Canals Using Different Cone-beam Computed Tomographic Devices. AB - INTRODUCTION: Artifacts in cone-beam computed tomographic (CBCT) imaging may compromise radiodiagnosis. Obturation materials for endodontic treatment may present with variable material density and thus also cause distinct artifact expression. The aim of this study was to assess the volume distortion artifact of root canal sealers using CBCT devices and micro-CT imaging as a reference. METHODS: Thirty single-root mandibular central incisors were used for this study. Teeth were prepared with EndoSequence rotary nickel-titanium files (Brasseler USA, Savannah, GA) and divided into 3 groups. Canals were obturated with gutta percha and AH Plus root canal sealer (Dentsply Maillefer, Ballaigues, Switzerland) using single-cone filling techniques. Each tooth was scanned with different CBCT devices (ie, Promax 3D Max [Planmeca Inc, Roselle, IL], NewTom VGi evo [NewTom, Verona, Italy], and 3D Accuitomo 170 [J Morita, Kyoto, Japan]) with the same voxel size (0.2 mm3) and compared with micro-CT imaging as a reference standard. RESULTS: The results showed a significant difference in terms of volume distortion between micro-CT and CBCT images (P < .05). There were also significant differences among CBCT devices. Promax 3D Max measurements showed significantly larger root canal volumes than the other CBCT machines (P < .05). However, NewTom VGi evo and 3D Accuitomo 170 showed similar results without any significant difference (P > .05). CONCLUSIONS: CBCT devices showed more volumetric distortion artifact than micro-CT imaging. The volume was variable for different CBCT devices while scanning at the same voxel size. However, to assess the effect of sealer materials on CBCT imaging, further studies should be conducted for different sealers. PMID- 28673492 TI - Further Treatments of Root-filled Teeth in the Swedish Adult Population: A Comparison of Teeth Restored with Direct and Indirect Coronal Restorations. AB - INTRODUCTION: The aim of this study was to evaluate the frequencies of nonsurgical retreatment, root-end surgery, extraction, and further restoration of root-filled teeth in Sweden in 2009 during a follow-up period of 5 years and to compare the outcomes in teeth restored with direct or indirect restorations. METHODS: Data from the Swedish Social Insurance Agency were analyzed, and the frequencies of nonsurgical retreatment, root-end surgery, extractions, and further restoration were calculated for all teeth registered as root filled during 2009. Chi-square tests were applied to detect any significant differences in the frequency of further treatment in teeth registered as restored with either a direct or an indirect restoration within 6 months of root filling. RESULTS: Of the 248,299 teeth reported root filled in Sweden in 2009, nonsurgical retreatment was registered in 2.2%, root-end surgery in 1.0%, and extractions in 9.2% during the follow-up period. Of the teeth restored with a direct restoration within 6 months after the root filling, 30.3% were registered as having undergone at least 1 further direct restoration; the corresponding percentage of teeth with indirect restorations was 6.4%. A statistically significant difference in the frequency of nonsurgical retreatment, extraction, and further restoration was found; teeth restored with an indirect restoration within 6 months of root filling had fewer of these treatments than those restored by direct restoration. CONCLUSIONS: Low frequencies of nonsurgical retreatment and root-end surgery were reported 5 years after root filling, whereas extraction was more common. Fewer additional treatment procedures were registered for teeth with indirect restorations than for those with direct restorations. PMID- 28673494 TI - Partial Pulpotomy in Mature Permanent Teeth with Clinical Signs Indicative of Irreversible Pulpitis: A Randomized Clinical Trial. AB - INTRODUCTION: This study aimed to assess the outcome of partial pulpotomy using mineral trioxide aggregate (MTA) compared with calcium hydroxide (CH) in mature cariously exposed permanent molars. METHODS: Fifty permanent molar teeth with carious exposures in 50 patients >20 years old were included. Preoperative pulpal and periapical diagnosis was established based on a history of presenting pain, results of cold testing, and radiographic findings. After informed consent, the tooth was anesthetized, isolated via a dental dam, and disinfected with 5% sodium hypochlorite before caries excavation. Partial pulpotomy was performed by amputating 2 mm of the exposed pulp, hemostasis was achieved, and the tooth was randomly assigned for the placement of either white MTA (White ProRoot; Dentsply, Tulsa, OK) or CH (Dycal; Dentsply Caulk, Milford, DE) as the pulpotomy agent. Postoperative periapical radiographs were taken after placement of the permanent restoration. Clinical and radiographic evaluation was completed after 6 months and 1 and 2 years postoperatively. Statistical analysis was performed using the Fisher exact test. RESULTS: Clinical signs and symptoms suggestive of irreversible pulpitis were established in all teeth. Immediate failure occurred in 4 teeth. At 1 year, MTA showed a higher tendency toward success compared with the CH group, and the difference was statistically significant after 2 years (83% vs 55%, P = .052 at 1 year; 85% vs 43%, P = .006 at 2 years). Sex did not have a statistically significant effect on the outcome. CONCLUSIONS: MTA partial pulpotomy sustained a good success rate over the 2-year follow-up in mature permanent teeth clinically diagnosed with irreversible pulpitis. More than half of the CH cases failed within 2 years. PMID- 28673493 TI - Variations of Palatal Canal Morphology in Maxillary Molars: A Case Series and Literature Review. AB - A series of challenging cases with unusual canal anatomy in the palatal roots of maxillary first and second molars is presented. A review of the literature was done to elucidate the prevalence of anatomic variations in the palatal canal of maxillary first and second molars. An uncertain or indefinite radiographic appearance of the palatal canal, or eccentric deviation of the master cone or previous root canal filling was considered an indication of a bifurcated palatal canal. Five maxillary molars with a bifurcated palatal canal were identified. A MEDLINE database search was performed to identify studies on the palatal canal morphology of maxillary first and second molars. Data were categorized based on the methodology used in each study. The overall prevalence of anatomic variations in the palatal canal of maxillary first and second molars was less than 2%; however, anatomic variations occurred more frequently in certain ethnic groups, reaching up to 33% in maxillary first molars and up to 14% in maxillary second molars. This case series showed that even experienced endodontic clinicians can miss a bifurcated palatal canal if they are not aware of or overlook the hidden clues for these anatomic variations. The traditional assumption of an exclusively single-canal anatomy in palatal canals of maxillary molars needs to be changed, even though it is the most prevalent anatomy. The overall low percentage of more than 1 palatal canal in maxillary molars is disturbingly misleading, because in certain ethnic groups this prevalence can be considerably higher. PMID- 28673495 TI - Proteomic Profiling and Differential Messenger RNA Expression Correlate HSP27 and Serpin Family B Member 1 to Apical Periodontitis Outcomes. AB - INTRODUCTION: Understanding protein expression profiles of apical periodontitis may contribute to the discovery of novel diagnostic or therapeutic molecular targets. METHODS: Periapical tissue samples (n = 5) of patients with lesions characterized as nonhealing were submitted for proteomic analysis. Two differentially expressed proteins (heat shock protein 27 [HSP27] and serpin family B member 1 [SERPINB1]) were selected for characterization, localization by immunofluorescence, and association with known biomarkers of acute inflammatory response in human apical periodontitis (n = 110) and healthy periodontal ligaments (n = 26). Apical periodontitis samples were categorized as stable/inactive (n = 70) or progressive/active (n = 40) based on the ratio of expression of receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG). Next, the expression of HSP27, SERPINB1, C-X-C motif Chemokine Receptor 1 (CXCR1), matrix metalloproteinase 8 (MMP8), myeloperoxidase (MPO), and cathepsin G (CTSG) messenger RNA was evaluated using real-time polymerase chain reaction. Data analysis was performed using the Shapiro-Wilk test, analysis of variance, and the Pearson test. P values <.05 were considered statistically significant. RESULTS: Proteomic analysis revealed 48 proteins as differentially expressed in apical periodontitis compared with a healthy periodontium, with 30 of these proteins found to be expressed in all 4 lesions. The expression of HSP27 and SERPINB1 was ~2-fold higher in apical periodontitis. Next, an increased expression of HSP27 was detected in epithelial cells, whereas SERPINB1 expression was noted in neutrophils and epithelial cells. HSP27 and SERPINB1 transcripts were highly expressed in stable/inactive lesions (P < .05). Significant negative correlations were found between the expression of HSP27 and SERPINB1 with biomarkers of acute inflammation including CXCR1, MPO, and CTSG. CONCLUSIONS: Our data suggest HSP27 and SERPINB1 as potential regulators of the inflammatory response in apical periodontitis. Additional functional studies should be performed to further characterize the role of these molecules during the development/progression of apical periodontitis. PMID- 28673496 TI - Optimization of Tube Current in Cone-beam Computed Tomography for the Detection of Vertical Root Fractures with Different Intracanal Materials. AB - INTRODUCTION: There is no consensus about the accuracy of cone-beam computed tomography (CBCT) for detecting vertical root fractures (VRFs), nor is there certainty about the isolated effect of different tube current parameters on the diagnosis of VRF through CBCT scans. This study aimed to evaluate how tube current affects the detection of VRF on CBCT examinations in the absence of intracanal materials and in the presence of gutta-percha (GP) and metal (MP) or fiberglass (FP) intracanal posts. METHODS: The sample consisted of 320 CBCT scans of tooth roots with and without VRF divided into 8 groups: no fracture/no intracanal material; no fracture + GP; no fracture + MP; no fracture + FP; fracture/no intracanal material; fracture + GP; fracture + MP; fracture + FP. The scans were acquired with an OP300 unit using 4 different milliamperes (4 mA, 8 mA, 10 mA, 13 mA). Five oral radiologists analyzed the images. The area under the receiver operating characteristic curve (Az), sensitivity, specificity, positive and negative predictive values, and interobserver agreement were calculated. RESULTS: Diagnostic performance for the different milliamperes tested was similar for teeth without root filling materials or with FP. Teeth with GP and MP showed the highest Az values for 8 mA and 10 mA, respectively. For teeth with MP, specificity was significantly higher when 10 mA was used. CONCLUSIONS: For teeth without root filling materials or with FP, the use of a reduced milliampere does not seem to influence the detection of VRF in a significant manner. For teeth with GP and MP, an increased milliampere may lead to increased diagnostic performance. PMID- 28673497 TI - ? PMID- 28673498 TI - Revised guidelines for the publication of genetic population data. PMID- 28673499 TI - Occult hepatitis B infection and transfusion-transmission risk. AB - Advances in serology and viral nucleic acid testing (NAT) over the last decades significantly reduced the risk of transfusion-transmitted hepatitis B virus (HBV). The combination of HBsAg testing and NAT efficiently prevents the majority of HBV transmission. However, a specific residual risk remains associated with extremely low viral DNA levels in blood donors with occult HBV infection (OBI) that are intermittently or not detectable even by highly sensitive individual donation (ID) NAT. Studies have reported HBV transfusion-transmission with blood components from donors with OBI that contained low amount of viruses (<200 virions). HBV transfusion-transmission seems to depend on a combination of several factors including the volume of plasma associated with the infected blood components transfused, the anti-HBV immune status of both recipient and donor, and possibly the viral fitness of the infecting HBV strain. Models based on clinical and experimental evidences estimate a residual transmission risk of 3 14% associated with OBI donations testing HBsAg and ID-NAT non-reactive. Anti-HBc testing has the potential to improve further blood safety but it may also compromise blood availability in settings with medium/high HBV prevalence. Pathogen reduction procedures might be considered. PMID- 28673500 TI - [State of the art: Direct oral anticoagulants and transfusion]. AB - Direct oral anticoagulants (DOAC) are indicated for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism. As any anticoagulant, they are associated with a bleeding risk. Management of DOAC induced bleeding is challenging. Idarucizumab, antidote for dabigatran, is currently available and is part of the therapeutic strategy, whereas antidotes for anti-Xa agents are under development. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. We propose an update on DOAC-associated bleeding management, integrating the availability of idarucizumab and the critical place of DOAC concentration measurements. PMID- 28673501 TI - Management of iron overload in hemoglobinopathies. AB - Hemoglobinopathies, thalassemia and sickle cell disease are among the most frequent monogenic diseases in the world. Transfusion has improved dramatically their prognosis, but provokes iron overload, which induces multiple organ damages. Iron overload is related to accumulation of iron released from hemolysis and transfused red cell, but also, in thalassemic patients, secondary to ineffective erythropoiesis, which increases intestinal iron absorption via decreased hepcidin production. Transfusion-related cardiac iron overload remains a main cause of death in thalassemia in well-resourced countries, and is responsible for severe hepatic damages in sickle cell disease. Regular monitoring by Magnetic Resonance Imaging (MRI) using myocardial T2* (ms) and Liver Iron Content (LIC) (mg of iron/g dry weight) are now standards of care in chronically transfused patients. Serum ferritin level measurements and record of the total number of transfused erythrocyte concentrates are also helpful tools. Three iron chelators are currently available, deferoxamine, which must be injected subcutaneously or intravenously, and two oral chelators, deferiprone and deferasirox. We will review the main characteristics of these drugs and their indications. PMID- 28673502 TI - The storage lesions: From past to future. AB - Red blood cell (RBC) concentrates are stored in additive solutions at 4oC for up to 42 days, whereas platelets concentrates (PCs) are stored at 22oC with continuous agitation for up to 5 to 7 days, according national regulations, and the use or not of pathogen inactivation procedures. Storage induces cellular lesion and alters either RBC or platelet metabolism, and is associated with protein alterations. Some age-related alterations prove reversible, while other changes are irreversible, notably following protein oxidation. It is likely that any irreversible damage affects the blood component quality and thus the transfusion efficiency. Nevertheless, there still exists a debate surrounding the impact of storage lesions, for both RBCs and PCs. Uncertainty is not completely resolved. Several studies show a tendency for poorer outcomes to occur in patients receiving older blood products; however, no clear significant association has yet been demonstrated. The present short review aims to promote a better understanding of the occurrence of storage lesions, with particular emphasis on biochemical modifications opening discussions of the future advancement of blood transfusion processes. The paper is also an advocacy for the implementation of an independent international organization in charge of planning and controlling clinical studies in transfusion medicine, in order to base transfusion medicine practices both on security principles, but also on clinical evidences. PMID- 28673503 TI - [Thirty years of platelet immunology in fetal and neonatal alloimmune thrombocytopenia management, current situation]. AB - Fetal and neonatal allo-immune thrombocytopenia (FNAIT) is considered as a rare disease due to the incidence (1/1000-1/2000 births). The major complication of severe thrombocytopenia is bleeding and particularly intra-cranial hemorrhage and neurologic sequelae following. Serology and molecular biology developments have reconfigured the platelet immunology diagnosis. Anti-HPA-1a allo-immunisation is responsible for more than 80% FNAIT cases with a high recurrence rate of severe bleeding complications. Therapeutic management has changed over the coming years from an invasive concept associating fetal blood sampling and in utero platelet transfusion to a non invasive treatment by intravenous immunoglobulins injection (IVIg). The purpose of this article is to provide an update on FNAIT management in the light of current developments over the past 30years. PMID- 28673504 TI - Additional Improvements in Clinical Response From Adjuvant Biologic Response Modifiers in Adults With Moderate to Severe Systemic Lupus Erythematosus Despite Immunosuppressive Agents: A Systematic Review and Meta-analysis. AB - PURPOSE: The role of biologic disease-modifying drugs in patients with systemic lupus erythematosus (SLE) remains controversial. METHODS: Following systematic review and meta-analysis protocol, we searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov in January 2017 to identify all studies of people with SLE treated with biologic response modifiers. We performed direct frequentist random effects meta-analyses, calculated pooled relative risk and number needed to treat to achieve an outcome in 1 patient (NNT) as reciprocal to statistically significant absolute risk difference, and graded the quality of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation criteria. FINDINGS: Seven meta-analyses, 33 publications of randomized controlled trials (RCTs), and 5 observational studies met inclusion criteria. All studies enrolled previously treated adults with moderate to severe SLE despite conventional immunosuppression. In patients with extrarenal SLE, adjunctive belimumab (10 mg/kg) increases the rates of clinical response (moderate quality evidence from 2 RCTs, 1125 patients, NNT = 8 [95% CI, 6-16]), whereas adjunctive rituximab or abatacept are ineffective. In adults with lupus nephritis, adjunctive rituximab (4000 mg, very-low-quality evidence from 1 RCT, 144 patients, NNT = 5 [95% CI, 3 18]), but not abatacept, improves renal function. Belimumab and rituximab do not increase the risk of serious intolerable adverse effects leading to treatment discontinuation. Rigerimod, blisibimod, sifalimumab, and anifrolumab show promising results in early RCTs, whereas epratuzumab and tabalumab have an unfavorable benefit-to-harm balance. IMPLICATIONS: In adults with moderate to severe SLE despite conventional immunosuppressive agents, adjunctive belimumab in extrarenal SLE and off-label rituximab in lupus nephritis may offer additional modest benefits. PMID- 28673505 TI - The first sign of loss of consciousness. AB - The first clinically observable sign of an unconsciousness episode (UNCE) serves as the temporal sequence (kinetics) onset point for neurological events occurring during the loss of consciousness, unconsciousness and recovery of consciousness phases of the UNCE. The initial neurologic signs of 212 individuals exposed to gradual (N=114) and rapid (N=98) onset +Gz acceleration stress, inducing the ischemic LOC phase in 83.3+/-18.6s and 8.89+/-1.52s; p<0.001 respectively, were determined. The duration of the unconscious phase (considered absolute incapacitation) was 10.42+/-5.3s and 9.36+/-3.99s; p>0.1 for gradual and rapid onset +Gz-stress, respectively. Cerebral autoregulation may play a role in determination of ischemic UNCE induction and recovery. Five signs: loss of muscle control, eyelid closure, eye fixation, upward eye deviation, and muscular twitching occurred at LOC phase onset. The most frequent initial sign of LOC phase onset was loss of muscle control (84% of the episodes), followed by eye fixation (8.5%), and upward eye deviation (6.1%). Signs play a key role in differential diagnosis of syncopal, epileptic, psychogenic and other causes of UNCEs. Sign kinetics may provide insight into localization of the essential components and networks within the cephalic nervous system associated with UNCEs. PMID- 28673506 TI - Ventilation responses to predator odors and conspecific chemical alarm cues in the frillfin goby. AB - The chemical detection of predation risk is direct when based on predator odors, or indirect when an injured conspecific or heterospecific signal it. Physiological adjustments may be necessary in parallel to defensive reactions to cope with an imminent risk. Here, we tested the effects of predator odors and conspecific chemical alarm cues in ventilation response (VR) of frillfin goby, Bathygobius soporator, because this response increases oxygen uptake for supporting behavioral tasks. No VR change was detected in response to odors of predators (catfish) that fed on conspecific, heterospecific fish (tilapia), or were deprived of food and to non-predator (tilapia) that fed chow (non-specific odor control) and odor eluent. The goby's VR, however, increased in response to conspecific alarm cues, but not to heterospecific cues or eluent. Clearly, the VR response in fish depends on the nature of the chemical cue. It is in line with 'threat-sensitive hypothesis' as a chemical cue from an injured prey might mean a foraging predator, whilst the mere presence of a predator odor might not. In addition, because VR can increase, decrease or remains unchanged in response to predation risk in other fish species (including other gobies), we reinforces the species-specific chracteristic of VR responses in fish, regarding the results obtained here for frillfin gobies. PMID- 28673507 TI - An improved algorithm calculated from intrathoracic impedance can precisely diagnose preclinical heart failure events: Sub-analysis of a multicenter MOMOTARO (Monitoring and Management of OptiVol Alert to Reduce Heart Failure Hospitalization) trial study. AB - BACKGROUND: Ambulatory measurement of intrathoracic impedance (ITI) with an implanted device has potential to assess fluid accumulation in patients with heart failure (HF), but it has failed to reduce HF-related hospitalization because of a high false-positive rate. OBJECTIVE: We aimed to examine whether a modified algorithm (OptiVol 2.0) could reduce false-positive HF events documented in our multicenter trial (MOMOTARO). METHODS: The MOMOTARO trial assessed the potential that fluid index could predict fluid accumulation and therefore HF. The MOMOTARO trial assessed whether HF events could be detected based on fluid accumulation as assessed by fluid index. We re-analyzed raw data of ITI trends of the threshold-crossing events with the modified algorithm. RESULTS: The study consisted of 195 patients who had been implanted with a high-energy device. During a mean follow-up period of 658+/-165 days, there were 154 primary HF events detected by the previous algorithm (OptiVol 1.0). With the previous algorithm, there was no significant difference in log concentration of brain natriuretic peptide (BNP) between baseline and alert (p=0.21). Among 150 alerts of the previous algorithm, only 37 reached the threshold by the modified algorithm, and log BNP was significantly higher in these 37 events compared with the baseline value (2.40+/-0.46 vs. 2.27+/-0.52, p<0.01). CONCLUSION: Our simulation study demonstrates that fluid index calculated with the modified algorithm reduces the number of false-positive threshold-crossing HF events and is promising for accurate diagnosis of fluid accumulation in patients. PMID- 28673508 TI - Comparison of prasugrel versus clopidogrel in Korean patients with acute myocardial infarction undergoing successful revascularization. AB - BACKGROUND: Although there have been several reports that prasugrel can improve clinical outcomes, the efficacy and safety of prasugrel is unknown in Korean patients with acute myocardial infarction (AMI) undergoing successful revascularization. METHODS: A total of 4421 patients [637 patients were prescribed prasugrel (60/10 or 5mg, loading/maintenance dose) and 3784 patients clopidogrel (600 or 300/75mg)] with AMI undergoing successful revascularization were enrolled from the core clinical cohort of Korea Acute Myocardial Infarction Registry-National Institute of Health. RESULTS: After propensity score matching (637 pairs), there were no significant differences in baseline clinical and procedural characteristics and in-hospital medications between the two groups. The primary efficacy endpoint, defined as the composite of cardiac death, MI, stroke, or target vessel revascularization at 6 months showed no significant difference between prasugrel and clopidogrel (2.4% vs. 2.9%, p=0.593). Also, no difference was observed in the composite of cardiac death, MI, or stroke during hospitalization between two groups (0.8% vs. 0.9%, p=0.762). However, the incidence of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding was significantly higher in prasugrel compared with clopidogrel (5.3% vs. 2.7%, p=0.015). In multivariate linear regression analysis, trans femoral intervention, use of glycoprotein IIb/IIIa inhibitors, use of calcium channel blocker, and use of prasugrel were independent predictors of in-hospital TIMI major or minor bleeding [odds ratio (OR)=6.918; 95% confidence interval (CI)=2.453-19.510, OR=2.577; 95% CI=1.406-4.724, OR=4.016; 95% CI=1.382-11.668, OR=2.022; 95% CI=1.101-3.714]. CONCLUSIONS: Our study shows that the recommended dose of prasugrel had significantly higher in-hospital bleeding complications without reducing ischemic events compared with clopidogrel. However, further large-scale, long-term, randomized clinical trials are required to accurately assess the efficacy and safety of prasgurel and to find out the optimal dose for Korean AMI patients. PMID- 28673509 TI - Discovery of a new mexiletine-derived agonist of the hERG K+ channel. AB - The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in the rapid component (IKr) of cardiac action potential repolarization phase. A large number of structurally different compounds block hERG and cause a high risk of arrhythmias. Among the drugs that block hERG channel, a few compounds have been identified as hERG channel activators. Such compounds may be useful, at least in theory, for the treatment of long term QT syndrome. Here we describe a new activator of hERG channel, named MC450. This compound is a symmetric urea, derived from (R)-mexiletine. Using patch-clamp recordings, we found that MC450 increased the activation current of hERG channel, with an EC50 of 41+/-4MUM. Moreover MC450 caused a depolarizing shift in the voltage dependence of inactivation from -64.1+/-1.2mV (control), to -35.9+/-1.4mV, whereas it had no effect on the voltage dependence of activation. Furthermore, MC450 slowed current inactivation and the effect of MC450 was attenuated by the inactivation-impaired double mutant G628C/S631C. PMID- 28673510 TI - Eye movements in essential tremor patients with parkinsonian and cerebellar signs. AB - : Apart from intention tremor essential tremor (ET) patients may display other cerebellar signs, like dysmetria or tandem gait disturbances as well as parkinsonian signs like resting tremor, cogwheel sign, subtle bradykinesia. Previous reports claimed the occurrence of the eye movement abnormalities characteristic for dysfunction of cerebellar dorsal vermis in ET patients with concomitant cerebellar signs. There are no previous reports evaluating the eye movement abnormalities in ET patients with concomitant parkinsonian signs. The objective of this study was to determine the relationship between the occurrence of parkinsonian and cerebellar signs and the oculomotor abnormalities in ET patients. METHOD: Fifty ET patients including 6 (12.0%) patients with concomitant parkinsonian signs (ET-P), 20 (40.0%) patients with cerebellar signs (ET-C), 7 (14.0%) with mixed parkinsonian and cerebellar signs (ET-M), 17 (34.0%) patients with the only tremor (ET-T) together with 42 healthy controls were included to the study. Reflexive, pace-induced and cued saccades were recorded using Saccadometer Advanced. Smooth pursuit and fixation were tested using EOG. RESULTS: Latency of pace-induced saccades was significantly longer in ET-C and ET M patients compared to ET-T and ET-P patients. Latency of cued saccades was significantly longer in ET-M patients compared to ET-T. There were no significant differences of the eye movement parameters between ET-P patients compared to ET-T patients. CONCLUSION: In ET patient with concomitant cerebellar signs prolonged volitional saccades latency was detected. There are no particular differences in the eye movements in ET patients with concomitant parkinsonian signs compared to ET patients without concomitant signs. PMID- 28673511 TI - Reirradiation of the spine with stereotactic radiosurgery: Efficacy and toxicity. AB - PURPOSE: To determine the potential benefits and adverse effects associated with reirradiating the spinal cord when at least 1 course of radiation therapy (RT) is stereotactic radiosurgery (SRS). METHODS AND MATERIALS: This institutional review board-approved retrospective review included 162 patients (237 reirradiated spine lesions). All patients received SRS at our institution between 2001 and 2013. Electronic medical records were reviewed for clinical exams and radiologic tests (computed tomography/magnetic resonance imaging). Primary endpoints were pain, neurological, radiographic responses, and the development of adverse effects. RESULTS: A total of 120 patients (74.1%) were deceased with a median survival of 13 months. Time between courses of RT was a median of 10.2 months. Median SRS dose was 16 Gy in 1 fraction, whereas the median conventional external beam radiation therapy (cEBRT) dose was 30 Gy in 10 fractions. The median tumor equivalent dose in 2-Gy fractions (EQD2) for SRS doses was 34.7 Gy, whereas the median tumor EQD2 for cEBRT was 32.5 Gy, providing a median total tumor EQD2 of 69.3 Gy (22-145.6 Gy). The median critical nervous tissue EQD2 for SRS and cEBRT was 56 Gy and 37.5 Gy, respectively, resulting in a median total critical nervous tissue EQD2 of 93.5 Gy. Overall pain, neurological, and radiographic response rates were 81%, 82%, and 71%, respectively. Adverse effects occurred in 11 (6.8%) patients. Seventy-seven vertebral compression fractures were observed, 22 (9.3%) of which may be attributed to RT. CONCLUSIONS: Our results demonstrate that reirradiation achieves favorable response rates with minimal toxicity if recommended dose constraints to the spinal cord with SRS are carefully observed. To the best of our knowledge, this is the largest reported single-institution experience analyzing the efficacy and toxicity of reirradiation of the spine when at least 1 course of RT is stereotactic radiosurgery. PMID- 28673512 TI - Ready! Set? Let's Train!: Feasibility of an intensive attention training program and its beneficial effect after childhood traumatic brain injury. AB - BACKGROUND: Attention deficits are common after pediatric Traumatic Brain Injury (TBI); they complicate return to activities of daily living and disrupt socioacademic reintegration. Yet, clinicians in rehabilitation settings have limited access to cognitive remediation protocols for which feasibility has been demonstrated. OBJECTIVE: The aim of this study was to evaluate the feasibility of intensive attention process training program Ready! Set? Let's Train! (RST), based on an adaptation of the Attention Process Training-I program. MATERIALS AND METHODS: In a randomized controlled trial, participants with attention deficits were assigned to receive the attention process training intervention (RST) or Homework Assistance (HWA). Pre- and post-intervention assessments consisted of standardized attentional and executive tests and a behavior checklist. RESULTS: Analyses conducted for 17 participants (RST, n=8; HWA, n=9; mean age 14.70+/-2.17 years, 11 males) indicated the study was successful in that it showed improvements in working memory (F(14)=5.44, P=0.04; eta2=0.19), inhibition (F(14)=10.18, P=0.007; eta2=0.75) and cognitive flexibility (F(14)=5.36, P=0.04; eta2=0.57). CONCLUSIONS: These findings indicate positive support for combined process-specific and metacognitive strategy training for attention and executive functions. PMID- 28673513 TI - Genome-wide identification of nuclear receptor (NR) genes and the evolutionary significance of the NR1O subfamily in the monogonont rotifer Brachionus spp. AB - Nuclear receptors (NRs) are a large family of transcription factors that are involved in many fundamental biological processes. NRs are considered to have originated from a common ancestor, and are highly conserved throughout the whole animal taxa. Therefore, the genome-wide identification of NR genes in an animal taxon can provide insight into the evolutionary tendencies of NRs. Here, we identified all the NR genes in the monogonont rotifer Brachionus spp., which are considered an ecologically key species due to their abundance and world-wide distribution. The NR family was composed of 40, 32, 29, and 32 genes in the genomes of the rotifers B. calyciflorus, B. koreanus, B. plicatilis, and B. rotundiformis, respectively, which were classified into seven distinct subfamilies. The composition of each subfamily was highly conserved between species, except for NR1O genes, suggesting that they have undergone sporadic evolutionary processes for adaptation to their different environmental pressures. In addition, despite the dynamics of NR evolution, the significance of the conserved endocrine system, particularly for estrogen receptor (ER)-signaling, in rotifers was discussed on the basis of phylogenetic analyses. The results of this study may help provide a better understanding the evolution of NRs, and expand our knowledge of rotifer endocrine systems. PMID- 28673514 TI - Kisspeptins and their receptors in the brain-pituitary-gonadal axis of Odonthestes bonariensis: Their relationship with gametogenesis along the reproductive cycle. AB - In vertebrates, the reproduction is controlled by the brain-pituitary-gonadal (BPG) axis and kisspeptin has emerged as a key player of this axis. In this study, we analyzed changes in the expression levels of kiss1, kiss2, and their receptors, kissr2 and kissr3 during gametogenesis in the BPG axis of feral Odontesthes bonariensis. In females, levels of brain kiss1 showed an increase at final maturation (Fm), while kiss2 levels were shown to be high at primary growth (Pg) stage, with no differences in the expression of their receptors. In the pituitary, kiss1 and kiss2 peaked at the cortical alveoli (Ca) stage, and kissr3 at initial vitellogenesis. In parallel, there was an increase of kiss1, kissr2 and kissr3 in the ovary during the Ca stage and both receptors again at Fm stage. In males, the four genes were highly expressed in the brain at the arrested (A) stage. In the pituitary, kiss2 peaked at spermatogonial (SG) and spermatocytary (SC) stages; while kissr3 reached a peak at the spermiogenic stage (SP). In testes, kiss1 and kiss2 significantly increased during the SG and SC stages; meanwhile, kissr2 increased at SG and SC, whereas kissr3 levels were significantly high at SC and SP stages. Taken together these results showed that the kisspeptin system in pejerrey is expressed in the three levels of the BPG axis with different expression profiles during the gonadal cycle. These findings pointed that kisspeptins have different roles in gametogenesis in this species. PMID- 28673516 TI - Metabolic engineering of oleaginous fungus Mortierella alpina for high production of oleic and linoleic acids. AB - The aim of this work was to study the molecular breeding of oleaginous filamentous Mortierella alpina for high production of linoleic (LA) or oleic acid (OA). Heterologous expression of the Delta12-desaturase (DS) gene derived from Coprinopsis cinerea in the Delta6DS activity-defective mutant of M. alpina increased the LA production rate as to total fatty acid to 5 times that in the wild strain. By suppressing the endogenous Delta6I gene expression by RNAi in the Delta12DS activity-defective mutant of M. alpina, the OA accumulation rate as to total fatty acid reached 68.0%. The production of LA and OA in these transformants reached 1.44 and 2.76g/L, respectively, on the 5th day. The Delta6I transcriptional levels of the RNAi-treated strains were suppressed to 1/10th that in the parent strain. The amount of Delta6II RNA in the Delta6I RNAi-treated strain increased to 8 times that in the wild strain. PMID- 28673515 TI - High glucose-induced p53 phosphorylation contributes to impairment of endothelial antioxidant system. AB - High levels of glucose (HG) induce reactive oxygen species-mediated oxidative stress in endothelial cells (ECs), which leads to endothelial dysfunction and tissue damage. However, the molecular mechanisms involved in HG-induced endothelial oxidative stress and damage remain elusive. Here we show that cellular ATP level-modulated p53 Thr55 phosphorylation plays a critical role in the process. Upon HG exposure, the elevated ATP levels induced the kinase activity of TAF1 (TBP-associated factor 1), which leads to p53 Thr55 phosphorylation. The phosphorylation dissociates p53 from the glutathione peroxidase 1 (GPX1) promoter and results in reduction of GPX1 expression. Inhibition of TAF1-mediated p53 Thr55 phosphorylation abolished those events, supporting the role of TAF1 in sensing cellular ATP elevation and in regulating GPX1 expression under the HG condition. Importantly, treating cells with HG increased intracellular H2O2 and cell apoptosis, as well as suppressed nitric oxide (NO) bioavailability and tube network formation. These effects were also remarkably reversed by inhibition of TAF1 and p53 Thr55 phosphorylation. We conclude that HG leads to endothelial dysfunction via TAF1-mediated p53 Thr55 phosphorylation and subsequent GPX1 inactivation. Our study thus revealed a novel mechanism by which HG induces endothelial oxidative stress and damage and possibly provided an avenue for targeted therapy for diabetes-associated cardiovascular diseases. PMID- 28673517 TI - Semi-continuous production of high-activity pectinases by immobilized Rhizopus oryzae using tobacco wastewater as substrate and their utilization in the hydrolysis of pectin-containing lignocellulosic biomass at high solid content. AB - In this study, highly reactive endo- and exo-polygalacturonases (PGs) were produced from the tobacco industry wastewater using immobilized Rhizopus oryzae. Compared with free cells, immobilized cells increased enzyme activity 2.8-fold and reduced production time to 24h by shake-flask production. Moreover, the immobilized cells enabled the semi-continuous production of enzymes through repeated-batch mode for seven consecutive cycles in a scale-up bioreactor. During the first five cycles, the average endo-PG and exo-PG activities reached 307.5 and 242.6U/ml, respectively. The addition of crude enzyme for the hydrolysis of pectin-containing lignocellulosic biomass under high-gravity conditions increased glucose release 4.2-fold (115.4 vs. 29.0g/L), compared with hydrolysis using cellulase alone. This process achieves the efficient production of pectin degrading enzymes, provides a cost-effective method for tobacco wastewater treatment, and offers the possibility to obtain fermentable sugars with high titer from pectin-containing lignocellulosic biomass, which has important potential for the commercial production of bio-fuels. PMID- 28673518 TI - Seasonality distribution of the abundance and activity of nitrification and denitrification microorganisms in sediments of surface flow constructed wetlands planted with Myriophyllum elatinoides during swine wastewater treatment. AB - Surface flow constructed wetlands (SFCWs) planted with Myriophyllum elatinoides for treatment of swine wastewater were examined to evaluate the effect of season, segment (site S1, S2, and S3), and treatment (100mgL-1 TN, T1; 300mgL-1 TN, T2; 500mgL-1 TN, T3) on the activity, and abundances of nitrifying and, denitrifying microorganisms, and on the abundance of sediment bacteria. The activity and abundances of nitrifiers, denitrifiers, and the abundance of bacteria were the highest in T3 samples, especially in S1 (P<0.05). The potential nitrification rate (PNR) was highest in the summer and potential denitrification rate (PDR) showed an increasing trend over seasons. The abundance of ammonia-oxidizing bacteria (AOB) was strongly correlated with PNR, while abundance of denitrifying gene (nirK) was strongly correlated with PDR. These results indicate that M. elatinoides SFCWs for swine wastewater treatment stimulate the growth of nitrifiers, denitrifiers and bacteria in sediments. PMID- 28673519 TI - Efficient assimilation of cyanobacterial nitrogen by water hyacinth. AB - A 15N labeling technique was used to study nitrogen transfer from cyanobacterium Microcystis aeruginosa to water hyacinth. 15N atom abundance in M. aeruginosa peaked (15.52%) after cultivation in 15N-labeled medium for 3weeks. Over 87% of algal nitrogen was transferred into water hyacinth after the 4-week co cultivation period. The nitrogen quickly super-accumulated in the water hyacinth roots, and the labeled nitrogen was re-distributed to different organs (i.e., roots, stalks, and leaves). This study provides a new strategy for further research on cyanobacterial bloom control, nitrogen migration, and nitrogen cycle in eutrophic waters. PMID- 28673520 TI - Similarities between induced membrane and amniotic membrane: Novelty for bone repair. AB - Previous clinical studies have shown the efficacy of a two-stage surgical procedure - the induced membrane (IM) technique - for reconstruction of large bone defects or bone non-union. The first stage involves radical debridement and insertion of a cement spacer into the bone defect. The second stage, performed weeks to months later, consists of removing the spacer while leaving the foreign body membrane induced by the cement in place, and then filling the cavity with bone autograft. The IM has been shown to (1) act as a protective physical barrier by preventing bone autograft resorption and (2) act as a bioreactor by promoting healing through revascularisation and growth factor secretion, and by concentrating mesenchymal stem cells (MSC) with osteogenic properties. New solutions to reduce this surgical procedure to a single step are being explored, for example by using an IM-like bioactive and protective barrier inserted into the bone defect at the same time as bone graft. PMID- 28673521 TI - Addiction consultation services - Linking hospitalized patients to outpatient addiction treatment. AB - BACKGROUND: Approximately 15% of hospitalized patients have an active substance use disorder (SUD). Starting treatment for SUD, including medications, during acute hospitalizations can engage patients in addiction care. In July 2015, the Boston Medical Center Addiction Consult Service (ACS), began providing inpatient diagnostic, management, and discharge linkage consultations. We describe this implementation. METHODS: The ACS staff recorded SUDs diagnoses and medication recommendations and tracked follow-up data for affiliated outpatient office-based addiction clinics and methadone maintenance programs. We assessed the number of consults, SUDs diagnoses, medications recommended and initiated, and outpatient addiction clinic follow-up. RESULTS: Over 26weeks, the BMC ACS completed 337 consults: 78% had an opioid use disorder (UD), 37% an alcohol UD, 28% a cocaine UD, 9% a benzodiazepine UD, 3% a cannabinoid (including K2) UD, and <1% a methamphetamine UD. Methadone was initiated in 70 inpatients and buprenorphine in 40 inpatients. Naltrexone was recommended 45 times (for opioid UD, alcohol UD, or both). Of the patients initiated on methadone, 76% linked to methadone clinic, with 54%, 39%, and 29% still retained at 30, 90, and 180days, respectively. For buprenorphine, 49% linked to clinic, with 39%, 27%, and 18% retained at 30, 90, and 180days, respectively. For naltrexone, 26% linked to clinic, all with alcohol UD alone. CONCLUSIONS: A new inpatient addiction consultation service diagnosed and treated hospitalized patients with substance use disorders and linked them to outpatient addiction treatment care. Initiating addiction medications, particularly opioid agonists, was feasible in the inpatient setting. Optimal linkage and retention of hospitalized patients to post-discharge addiction care warrants further innovation and program development. PMID- 28673523 TI - Interagency collaboration and receipt of substance abuse treatment services for child welfare-involved caregivers. AB - Caregivers dealing with problematic substance use pose persistent challenges for families involved with the child welfare (CW) system. Research has indicated that receipt of substance use disorder (SUD) services help improve family outcomes. However, there are many challenging stages of intervention in the SUD treatment process, including detection, assessment, referral, entry, and completion. Considerable work is needed to illuminate factors that strengthen the delivery of SUD-related services at various points in the treatment services continuum. Although a growing body of work has focused on individual-level correlates, few studies have examined organizational factors that potentially affect the delivery of SUD-related services. This study sought to further understanding of the relationship between CW organizational factors (interagency collaboration and organizational resources) and delivery of SUD-related services in a nationally representative sample of CW-involved caregivers. In this study sample, engagement in collaboration through a memorandum of understanding (MOU) and co-location supported caregiver receipt of a referral to SUD services. Caregivers were more likely to receive a formal assessment for SUD problems when their CW agencies reported the availability of a standardized SUD assessment tool. Also, having arrangements with SUD agencies so that CW-involved families had priority status to enter treatment was pertinent to caregiver receipt of SUD treatment services. These results provide evidence that engagement in collaboration activities and greater organizational resources can increase an organization's capacity to deliver services to clients. PMID- 28673522 TI - Very early disengagement and subsequent re-engagement in primary care Office Based Opioid Treatment (OBOT) with buprenorphine. AB - INTRODUCTION: Patients with opioid use disorder often require multiple treatment attempts before achieving stable recovery. Rates of disengagement from buprenorphine are highest in the first month of treatment and termination of buprenorphine therapy results in return to use rates as high as 90%. To better characterize these at-risk patients, this study aims to describe: 1) the frequency and characteristics of patients with very early disengagement (<=1month) from Office Based Opioid Treatment (OBOT) with buprenorphine and 2) the frequency and characteristics of patients who re-engage in care at this same OBOT clinic within 2years, among the subset of very early disengagers. METHODS: This is a retrospective cohort study of adult patients enrolled in a large urban OBOT program. Descriptive statistics were used to characterize the sample and the proportion of patients with very early (<=1month) disengagement and their re engagement. Multivariable logistic regression models were used to identify patient characteristics associated with the outcomes of very early disengagement and re-engagement. Potential predictors included: sex, age, race/ethnicity, education, employment, opioid use history, prior substance use treatments, urine drug testing, and psychiatric diagnoses. RESULTS: Overall, very early disengagement was unusual, with only 8.4% (104/1234) of patients disengaging within the first month. Among the subset of very early disengagers with 2years of follow-up, the proportion who re-engaged with this OBOT program in the subsequent 2years was 11.9% (10/84). Urine drug test positive for opiates within the first month (AOR: 2.01, 95% CI: 1.02-3.93) was associated with increased odds of very early disengagement. Transferring from another buprenorphine prescriber (AOR: 0.09, 95% CI: 0.01-0.70) was associated with decreased odds of very early disengagement. No characteristics were significantly associated with re engagement. CONCLUSIONS: Early disengagement is uncommon; however, continued opioid use appeared to be associated with higher odds of treatment disengagement and these patients may warrant additional support. Re-engagement was uncommon, suggesting the need for a more formal explicit system to encourage and facilitate re-engagement among patients who disengage. PMID- 28673524 TI - Examining the reach of a brief alcohol intervention service in routine practice at a level 1 trauma center. AB - The American College of Surgeons requires Level I and II trauma centers to provide brief intervention services to traumatically injured patients who screen positive for alcohol. Despite evidence supporting substantial cost savings and reduced re-injury associated with these services, brief interventions may not be uniformly delivered owing to a variety of demographic, clinical and operational characteristics. To inform service adjustments that may improve the reach of such services, we compared trauma patients who did and did not receive brief alcohol intervention services during their hospitalizations. Electronic medical records of injured patients admitted to a Level I trauma center between September 27, 2013 and March 11, 2014 with a positive blood alcohol concentration (N=189) were coded for demographic and clinical variables. Records of those who did not receive a brief intervention during their admission were reviewed for possible reasons why interventions were not delivered. Of the total sample, 115 patients (60.8%) received brief interventions. Patients who did and did not receive brief interventions did not differ on age, sex, race, blood alcohol concentration at admission, or mechanism of injury, indicating that patient characteristics were unlikely to bias service delivery. Instead, common features of patients who were referred but did not receive SBIRT interventions included admissions lasting fewer than two working days (12.7%) and persistent cognitive impairment following injury (9.0%). These findings align with previous studies suggesting that service reach could be improved by promoting dedicated and flexible staffing and adapting services to allow for SBIRT delivery in follow-up care settings. PMID- 28673525 TI - Helping concerned family members of individuals with substance use and concurrent disorders: An evaluation of a family member-oriented treatment program. AB - There is a growing body of research demonstrating that families of individuals with substance use and concurrent disorders (SUCD) experience a wide range of biopsychosocial problems that significantly impedes their quality of life and health. However, there has been a relative lack of treatment programs primarily focused on improving the well-being and quality of life of these family members. The current study assessed the efficacy of such a program at reducing stress, increasing perceived social support from family and friends, and increasing general, dyadic, and self-rated family functioning within these concerned family members. A sample of 125 family members of individuals with SUCDs was recruited, of which 97 participated in the treatment program and 28 were used as the comparison group. Results indicated that the treatment program significantly reduced stress, increased perceived social support from family and friends, and increased general, dyadic and self-rated family functioning. A perceived personal benefits questionnaire demonstrated that participants had a better understanding of SUCDs, better coping capabilities in regard to emotional difficulties, adopted stronger coping methods, participated in more leisure activities, and improved their relationship with the individual with a SUCD. The results of the current study further demonstrate the need to implement more of these family-member oriented psycho-educational treatment programs. PMID- 28673526 TI - Health care cost trajectories in the year prior to and following intake into Veterans Health Administration outpatient substance use disorders treatment. AB - Veterans Health Administration (VHA) patients with substance use disorder (SUD) diagnoses incur significantly higher overall health care costs compared to the average annual costs of VHA patients. Because SUDs are relapsing/remitting chronic illnesses, it is important to understand how service costs shift over time in relation to active SUD treatment episodes in order to identify strategies which may enhance treatment outcomes and thereby reduce costs. The primary aim of the current study was to examine VHA health care costs derived from VHA administrative data for 330 Veterans during the years prior to and following patient entry into outpatient SUD treatment in two VHA facilities. Secondary aims were to examine the impact on treatment costs of patient diagnosis (alcohol dependence only vs. stimulant dependence) and participation in an abstinence incentive intervention. There was a significant effect of time on health care costs (p<0.001). Average total costs per patient per quarter were $2204 for quarters 1 through 3, increased significantly to $7507 in quarter 4 and $8030 in quarter 5, then decreased significantly to $3969 in quarters 6 through 8. Increases in quarter 4 and 5 were attributable to inpatient costs whereas increases in the quarters following treatment entry were attributable to outpatient costs (quarters 5-8). Overall costs for patients with alcohol dependence only were approximately 30% higher than overall costs for patients whose diagnoses included stimulant dependence, attributable to higher outpatient costs. There was no significant effect of the 8-week incentive intervention on post-treatment entry costs. Overall, entering SUD treatment corresponded to an increase in health care costs in the quarters both immediately preceding and immediately following treatment entry followed by a tapering down of costs through 12month follow-up; however, longer follow-up is needed to inform the stability of this pattern. Additional research will be needed to determine whether efforts to increase access to SUD treatment, identify patients with SUD earlier on in the course of their disorder and integrate SUD treatment services into primary care settings may assist in engaging patients in treatment prior to experiencing a mental or physical health crisis requiring inpatient treatment and thereby reduce health care costs associated with SUD diagnoses. PMID- 28673529 TI - Psychometric evaluation of a Swedish version of the Shortened Desires for Alcohol Questionnaire (Shortened-DAQ). AB - INTRODUCTION: Craving is a clinically important feature of alcohol use disorders (AUD), representing a diagnostic criterion as well as a target for treatment. The Desire for Alcohol Questionnaire (DAQ) is a widely used scale to measure craving. The aim of the current study was to evaluate the psychometric properties of a Swedish version of the Shortened-DAQ. METHOD: The English DAQ was translated into Swedish and back translated to English. Individuals with a diagnosis of AUD (n=118) participated in a laboratory experiment comprising presentation of alcohol and non-alcohol cues, as well as consumption of an alcoholic drink, with the aim of exploring changes in the craving responses following pharmacological treatment for AUD. Subjective craving across the experimental conditions was recorded using Shortened-DAQ and a Visual Analogue Scale (VAS). The psychometric analysis of the Shortened-DAQ investigated some important aspects of reliability, validity and the factor solution using principal components analysis. RESULTS: Cronbach's alphas were above 0.8 across all sessions, the test-retest correlations were statistically significant. In the alcohol cue session the Shortened-DAQ total score was significantly greater compared to the non-alcohol cue session, and correlated significantly with the VAS craving item across all sessions. The principal component analysis resulted in two significant factors comprised of (1) Alcohol desire and reinforcement and (2) Ability to control drinking. No difference in psychometric properties between treatment and placebo groups were found. CONCLUSION: In future clinical studies on alcohol craving responses in Swedish patients with AUD, we suggest the use of the Swedish Shortened-DAQ, due to its comparably swift administration and overall acceptable psychometric properties. PMID- 28673527 TI - Marijuana use in the context of alcohol interventions for mandated college students. AB - OBJECTIVE: Concurrent use of marijuana and alcohol among college students is highly prevalent and associated with negative consequences. It remains unclear whether marijuana use is influenced by or lessens the efficacy of alcohol interventions delivered within a stepped-care approach. METHOD: Participants were 530 college students who violated campus alcohol policy and were mandated to an alcohol-focused brief advice (BA) session. Participants who reported continued risky alcohol use (4+ heavy drinking episodes and/or 5+ alcohol-related consequences in the past month) six weeks following the BA session were randomized to a brief motivational intervention (BMI; n=211) or assessment only (AO; n=194) condition. Follow-up assessments were conducted 3, 6, and 9months' post-intervention. RESULTS: Multiple regression analyses revealed that marijuana user status did not influence drinking outcomes following the BA session. However, hierarchical linear models suggested that marijuana users who were randomized to BMI or AO reported higher levels of binge drinking, pBAC and consequences compared to non-users, regardless of condition. Despite this, heavy drinking marijuana users and nonusers had equivalent reductions on alcohol use outcomes following the BMI sessions. Marijuana users who received a BMI did not significantly reduce marijuana use frequency compared to participants in the AO group. CONCLUSION: Use of marijuana did not lessen the efficacy of the BA session on alcohol use or consequences. Findings suggest that marijuana users respond similarly to alcohol interventions as do non-users and can benefit from brief or more intensive alcohol interventions. A marijuana-focused intervention may be warranted to facilitate changes in marijuana use. PMID- 28673528 TI - Benefit-cost analysis of SBIRT interventions for substance using patients in emergency departments. AB - Screening, brief intervention, and referral to treatment (SBIRT) has been widely implemented as a method to address substance use disorders in general medical settings, and some evidence suggests that its use is associated with decreased societal costs. In this paper, we investigated the economic impact of SBIRT using data from Screening, Motivational Assessment, Referral, and Treatment in Emergency Departments (SMART-ED), a multisite, randomized controlled trial. Utilizing self-reported information on medical status, health services utilization, employment, and crime, we conduct a benefit-cost analysis. Findings indicate that neither of the SMART-ED interventions resulted in any significant changes to the main economic outcomes, nor had any significant impact on total economic benefit. Thus, while SBIRT interventions for substance abuse in Emergency Departments may be appealing from a clinical perspective, evidence from this economic study suggests resources could be better utilized supporting other health interventions. PMID- 28673531 TI - Corrigendum to "Evidence-based treatment for opioid disorders: A 23-year national study of methadone dose levels" [Journal of Substance Abuse Treatment 47 (2014) 245-250]. PMID- 28673530 TI - Comparison of the Substance Use Brief Screen (SUBS) to the AUDIT-C and ASSIST for detecting unhealthy alcohol and drug use in a population of hospitalized smokers. AB - Hospitalized patients have high rates of unhealthy substance use, which has important impacts on health both during and after hospitalization, but is infrequently identified in the absence of screening. The Substance Use Brief Screen (SUBS) was developed as a brief, self-administered instrument to identify use of tobacco, alcohol, illicit drugs, and non-medical use of prescription drugs, and was previously validated in primary care patients. This study assessed the diagnostic accuracy of the SUBS in comparison to longer screening instruments to identify unhealthy and high-risk alcohol and drug use in hospitalized current smokers. Participants were 439 patients, aged 18 and older, who were admitted to either two urban safety-net hospitals in New York City and enrolled in a smoking cessation trial. We measured the performance of the SUBS for identifying illicit drug and non-medical use of prescription drugs in comparison to a modified Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and its performance for identifying excessive alcohol use in comparison to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). At the standard cutoff (response other than 'never' indicates a positive screen), the SUBS had a sensitivity of 98% (95% CI 95-100%) and specificity of 61% (95% CI 55-67%) for unhealthy alcohol use, a sensitivity of 85% (95% CI 80-90%) and specificity of 75% (95% CI 78-87%) for illicit drug use, and a sensitivity of 73% (95% CI 61 83%) and specificity of 83% (95% CI 78-87%) for prescription drug non-medical use. For identifying high-risk use, a higher cutoff (response of '3 or more days' of use indicates a positive screen), the SUBS retained high sensitivity (77-90%), and specificity was 62-88%. The SUBS can be considered as an alternative to longer screening instruments, which may fit more easily into busy inpatient settings. Further study is needed to evaluate its validity using gold standard measures in hospitalized populations. PMID- 28673532 TI - Drug use among Asian Americans: Differentiating use by acculturation status and gender. AB - This study examined past-year drug use among Asian Americans with respect to ethnic subgroup, acculturation, and gender differences. Survey data were collected during the National Latino and Asian American Survey, a national epidemiological household survey of behavioral health prevalence and service utilization rates. The analytical sample consisted of 505 Filipino, 598 Chinese, 518 Vietnamese, and 466 other Asian respondents. Results indicated that among ethnic subgroups, Filipinos had the highest rates of drug use. Among all Asian Americans, those who were born in the United States, those with higher levels of English proficiency, males, those who were younger, those with lifetime prevalence of a major depressive episode, and those who were frequent drinkers were all more likely to have reported past-year drug use. Findings suggest the need to better understand the heterogeneous character of Asian American drug use when considering the provision of culturally competent and linguistically appropriate prevention and treatment services. PMID- 28673533 TI - Successful corpus callosotomy for Doose syndrome. AB - Doose syndrome (epilepsy with myoclonic-atonic seizures) is an epilepsy syndrome with an incidence of approximately 1-2% of childhood-onset epilepsies. Although this syndrome is associated with multiple types of generalized seizures, the diagnosis is based on the presence of myoclonic-atonic seizures. Eighteen percent of patients have refractory seizures and intellectual disabilities. There have, however, been a few reports on the efficacy of surgical treatment for Doose syndrome. We describe a case of Doose syndrome in a 10-year-old boy. He developed generalized tonic-clonic seizures at 3years 8months of age and subsequently developed myoclonic-atonic, myoclonic, and tonic seizures. The frequent myoclonic seizures were refractory to multiple antiepileptic medications. His cognitive development was moderately delayed. Anterior four fifths corpus callosotomy was performed at 8years 5months of age. His seizures, especially myoclonic seizures, were markedly reduced. He was given vagus nerve stimulation therapy at 9years and 1month of age, which led to complete resolution of the myoclonic seizures. Corpus callosotomy can be a good treatment strategy in patients with Doose syndrome with medically refractory generalized seizures. PMID- 28673534 TI - The intraoperative assessment of sentinel nodes - Standards and controversies. AB - Intraoperative assessment of sentinel lymph nodes (SLNs) has the advantage of allowing breast cancer patients with tumor-positive SLNs to avoid a second surgery by immediately proceeding to axillary lymph node dissection (ALND). However, there are several reasons why the use of intraoperative assessment should be questioned. Whereas ALND was traditionally advised for all breast cancer patients with tumor-positive lymph nodes for axillary staging and locoregional control, more recent studies have demonstrated safety of omitting ALND in a substantial number of patients. In addition, there are concerns about the accuracy of intraoperative assessment methods including frozen section analysis, touch preparation cytology and one-step nucleic acid amplification. Moreover, intraoperative assessment of SLNs denies patients the opportunity to contribute to their treatment planning. In our opinion, intraoperative assessment of axillary lymph nodes should be reserved for patients who still have a strict indication for ALND. Patients with clinical node negative disease (cN0) and one or two positive SLNs can be safely treated with breast conserving surgery and radiotherapy. There has been more controversy for cN0 patients who are treated with mastectomy since radiotherapy is not routinely administered in these patients. However, there is increasing evidence that ALND may be omitted in patients undergoing mastectomy who have a low tumor-burden in their SLNs. Therefore, we defend the position that in cN0 patients undergoing mastectomy, SLNB should be performed and full pathologic evaluation of the SLN should be awaited. In cN0 patients undergoing neoadjuvant systemic therapy (NST) intraoperative assessment of SLNs can be omitted since ALND will not provide therapeutic benefit. It is being hypothesized that patients with limited axillary disease prior to NST who remain node-positive after NST could be treated safely with axillary radiotherapy instead of ALND. In these patients, omitting intraoperative assessment might be a reasonable option. In patients with extensive nodal disease prior to NST intraoperative assessment of axillary lymph nodes should be performed. PMID- 28673535 TI - Nipple-sparing and skin-sparing mastectomy: Review of aims, oncological safety and contraindications. AB - Skin-sparing (SSM) and nipple-sparing (NSM) mastectomies are relatively new conservative surgical approaches to breast cancer. In SSM most of the breast skin is conserved to create a pocket that facilitates immediate breast reconstruction with implant or autologous graft to achieve a quality cosmetic outcome. NSM is closely similar except that the nipple-areola complex (NAC) is also conserved. Meta-analyses indicate that outcomes for SSM and NSM do not differ from those for non-conservative mastectomies. Recurrence rates in the NAC after NSM are acceptably low (0-3.7%). Other studies indicate that NSM is associated with high patient satisfaction and good psychological adjustment. Indications are carcinoma or DCIS that require mastectomy (including after neoadjuvant chemotherapy). NSM is also suitable for women undergoing risk-reducing bilateral mastectomy. Tumor not less than 2 cm from the NAC is recommended, but may be less important than no evidence of nipple involvement on mandatory intraoperative nipple margin assessment. A positive margin is an absolute contraindication for nipple preservation. Other contraindications are microcalcifications close to the subareolar region and a positive nipple discharge. Complication rates are similar to those for other types of post-mastectomy reconstructions. The main complication of NSM is NAC necrosis, however as surgeon experience matures, frequency declines. Factors associated with complications are voluminous breast, ptosis, smoking, obesity, and radiotherapy. Since the access incision is small, breast tissue may be left behind, so only experienced breast surgeons should do these operations in close collaboration with the plastic surgeon. For breast cancer patients requiring mastectomy, NSM should be the option of choice. PMID- 28673536 TI - Post-mastectomy radiation therapy after breast reconstruction: Indications, timing and results. AB - Around 50% of women undergoing mastectomy choose to pursue breast reconstruction to improve their psychological, social and sexual well-being, and many of them will require subsequent radiotherapy. The optimal integration of mastectomy and radiotherapy may create a therapeutic challenge. This review addresses selected aspects of this problem. PMID- 28673537 TI - De-escalating and escalating surgery in the management of early breast cancer. AB - In the setting of increased awareness regarding the need to address potential overtreatment in the management of breast cancer patients with favorable prognosis disease, this article reviews three relevant instances in which the extent of surgery has been safely decreased: margin width in patients with ductal carcinoma in situ; axillary management in clinically node-negative women undergoing primary breast-conserving surgery; and the use of neoadjuvant chemotherapy followed by sentinel node biopsy for patients presenting with node positive breast cancer. The management of the axillary nodes over the past decade highlights the potential to de-escalate surgery in the era of multimodality therapy. Similar opportunities exist for the use of radiotherapy. To fully realize the potential of de-escalating surgery, new communication strategies must be developed to convince patients that bigger is not necessarily better. PMID- 28673538 TI - Tailoring radiotherapy according to cancer subtypes. AB - Radiotherapy is able to improve locoregional control in breast cancer patients both after breast conserving surgery or mastectomy, with positive impact in high risk patients for long-term survival. Recent advances in the precision of radiotherapy were based on the choice of the appropriate fractionation and technique. But the concept of adaptive radiotherapy is not only technical, and includes the biologic characterisation of the breast tumor. The knowledge that different subtypes of breast cancer can have distinct locoregional patterns of recurrence is consisted in the literature data. Luminal A tumor are at the lower risk of locoregional failure, and HER2 positive and triple negative at the higher risk. More evidence in the use of molecular markers for adjuvant radiotherapy can held in choosing the best treatment on individual. The combination of radiotherapy with molecular targeted therapies may enhance radiosensitivity, thus increasing the cytotoxic effects and improving treatment response. The appropriateness of an alternative fractionation, partial breast irradiation, intensification or de-intensification approaches, could be assessed better according the stratification of the risk categories. PMID- 28673539 TI - Trial designs and results supporting treatment de-escalation and escalation. AB - Trials for escalation and de-escalation of treatment aim to improve patient care, but from different sides of the same coin with respect to disease control and burdens of treatment. De-escalation of therapy is inherently a non-inferiority question. A design with random assignment to standard of care versus de-escalated therapy is typically implemented but ordinarily will require a large sample size. Some research questions of treatment de-escalation might be asked in select patient populations using single-arm designs. Trials of therapy escalation may better inform the care of individual patients by posing a clinically-oriented research question in an enriched patient population, or by planning analyses that exploit the heterogeneity of a broadly-defined enrolled population. PMID- 28673540 TI - Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation. AB - Alternative splicing (AS) generates isoform diversity for cellular identity and homeostasis in multicellular life. Although AS variation has been observed among single cells, little is known about the biological or evolutionary significance of such variation. We developed Expedition, a computational framework consisting of outrigger, a de novo splice graph transversal algorithm to detect AS; anchor, a Bayesian approach to assign modalities; and bonvoyage, a visualization tool using non-negative matrix factorization to display modality changes. Applying Expedition to single pluripotent stem cells undergoing neuronal differentiation, we discover that up to 20% of AS exons exhibit bimodality. Bimodal exons are flanked by more conserved intronic sequences harboring distinct cis-regulatory motifs, constitute much of cell-type-specific splicing, are highly dynamic during cellular transitions, preserve reading frame, and reveal intricacy of cell states invisible to conventional gene expression analysis. Systematic AS characterization in single cells redefines our understanding of AS complexity in cell biology. PMID- 28673541 TI - A Novel RNA Phosphorylation State Enables 5' End-Dependent Degradation in Escherichia coli. AB - RNA modifications that once escaped detection are now thought to be pivotal for governing RNA lifetimes in both prokaryotes and eukaryotes. For example, converting the 5'-terminal triphosphate of bacterial transcripts to a monophosphate triggers 5' end-dependent degradation by RNase E. However, the existence of diphosphorylated RNA in bacteria has never been reported, and no biological role for such a modification has ever been proposed. By using a novel assay, we show here for representative Escherichia coli mRNAs that ~35%-50% of each transcript is diphosphorylated. The remainder is primarily monophosphorylated, with surprisingly little triphosphorylated RNA evident. Furthermore, diphosphorylated RNA is the preferred substrate of the RNA pyrophosphohydrolase RppH, whose biological function was previously assumed to be pyrophosphate removal from triphosphorylated transcripts. We conclude that triphosphate-to-monophosphate conversion to induce 5' end-dependent RNA degradation is a two-step process in E. coli involving gamma-phosphate removal by an unidentified enzyme to enable subsequent beta-phosphate removal by RppH. PMID- 28673542 TI - BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. AB - Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy. PMID- 28673545 TI - Eric Reiman: aiming to prevent Alzheimer's disease. PMID- 28673543 TI - Autogenous Control of 5'TOP mRNA Stability by 40S Ribosomes. AB - Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5'TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5'TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q- syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5'TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5'TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q- syndrome. PMID- 28673544 TI - TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III. AB - Loss-of-function mutations in TTC19 (tetra-tricopeptide repeat domain 19) have been associated with severe neurological phenotypes and mitochondrial respiratory chain complex III deficiency. We previously demonstrated the mitochondrial localization of TTC19 and its link with complex III biogenesis. Here we provide detailed insight into the mechanistic role of TTC19, by investigating a Ttc19?/? mouse model that shows progressive neurological and metabolic decline, decreased complex III activity, and increased production of reactive oxygen species. By using both the Ttc19?/? mouse model and a range of human cell lines, we demonstrate that TTC19 binds to the fully assembled complex III dimer, i.e., after the incorporation of the iron-sulfur Rieske protein (UQCRFS1). The in situ maturation of UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. We show that, in normal conditions, these UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment. PMID- 28673546 TI - Whole genome characterisation of a porcine-like human reassortant G26P[19] Rotavirus A strain detected in a child hospitalised for diarrhoea in Nepal, 2007. AB - A rare G26 Rotavirus A strain RVA/Human-wt/NPL/07N1760/2007/G26P[19] was detected in a child hospitalised for acute diarrhoea in Kathmandu, Nepal. The complete genome of 07N1760 was determined in order to explore its evolutionary history as well as examine its relationship to a Vietnamese strain RVA/Human wt/VNM/30378/2009/G26P[19], the only G26 strain whose complete genotype constellation is known. The genotype constellation of 07N1760 was G26-P[19]-I12 R1-C1-M1-A8-N1-T1-E1-H1, a unique constellation identical to that of the Vietnamese 30378 except the VP6 gene. Phylogenetic analysis revealed that both strains were unrelated at the lineage level despite their similar genotype constellation. The I12 VP6 gene of 07N1760 was highly divergent from the six currently deposited I12 sequences in the GenBank. Except for its NSP2 gene, the remaining genes of 07N1760 shared lineages with porcine and porcine-like human RVA genes. The NSP2 gene belonged to a human RVA N1 lineage which was distinct from typical porcine and porcine-like human lineages. In conclusion, the Nepali G26P[19] strain 07N1760 was a porcine RVA strain which derived an NSP2 gene from a human Wa-like RVA strain by intra-genotype reassortment probably after transmission to the human host. PMID- 28673547 TI - Geometric morphometrics in mosquitoes: What has been measured? AB - The field of morphometrics is developing quickly. Recent advances have enabled geometric techniques to be applied to many zoological problems, particularly those involving epidemiologically-relevant mosquitoes. Herein, we briefly introduce geometric morphometric (GM) techniques and then review selected groups of mosquitoes (Culicidae) to which those techniques have been applied. In most of the reviewed cases, GM was capable of satisfactorily discriminating among the tested groups primarily when the studies considered differences within and among species, sexual dimorphism, treatments and the separation of laboratory strains. Although GM approaches have developed quite rapidly, some caution must be taken during data processing for a reliable biometrical approach, such as allometry and asymmetry analyses, scale removal and wing clarification staining for landmark digitization. We also critically forecast directions in this field and discuss how the creation of image databases should enhance species identification in culicids. PMID- 28673549 TI - Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder. AB - Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype. PMID- 28673548 TI - Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice. AB - Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2 arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Delta9 tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1-2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids. PMID- 28673550 TI - A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: Biochemical and molecular characterization. AB - Inborn defects of cholesterol biosynthesis are metabolic disorders presenting with multi-organ and tissue anomalies. An autosomal recessive defect involving the demethylating enzyme C4-methyl sterol (SC4MOL) has been reported in only 4 patients so far. In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability. Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly. Our patient had abundant scalp dandruff, without other skin manifestations. Analysis of the blood sterol profile showed accumulation of C4-monomethyl and C4-dimethyl sterols suggesting a deficiency of the SC4MOL enzyme. Sequencing of the MSMO1 gene (also known as the "SC4MOL" gene) confirmed mutations in each allele (c.731A>G, p.Y244C, which is already known, and c.605G>A, p.G202E, which is a novel variant). His father carried c.731A>G mutation, whereas his mother carried c.605G>A. Thus, the combination of multiple skills and methodologies, in particular, blood sterol profiling and genetic analysis, led to the diagnosis of a new case of a very rare defect of cholesterol biosynthesis. Consequently, we suggest that these two analyses should be performed as soon as possible in all undiagnosed patients affected by bilateral cataracts and developmental delay. PMID- 28673551 TI - Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. AB - OBJECTIVE: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. METHODS: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. RESULTS: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. SIGNIFICANCE: Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease. PMID- 28673552 TI - Pushing the Limits of Detection of Weak Binding Using Fragment-Based Drug Discovery: Identification of New Cyclophilin Binders. AB - Fragment-based drug discovery is an increasingly popular method to identify novel small-molecule drug candidates. One of the limitations of the approach is the difficulty of accurately characterizing weak binding events. This work reports a combination of X-ray diffraction, surface plasmon resonance experiments and molecular dynamics simulations for the characterization of binders to different isoforms of the cyclophilin (Cyp) protein family. Although several Cyp inhibitors have been reported in the literature, it has proven challenging to achieve high binding selectivity for different isoforms of this protein family. The present studies have led to the identification of several structurally novel fragments that bind to diverse Cyp isoforms in distinct pockets with low millimolar dissociation constants. A detailed comparison of the merits and drawbacks of the experimental and computational techniques is presented, and emerging strategies for designing ligands with enhanced isoform specificity are described. PMID- 28673553 TI - HIV-1 Sequence Necessary and Sufficient to Package Non-viral RNAs into HIV-1 Particles. AB - Genome packaging is an essential step to generate infectious HIV-1 virions and is mediated by interactions between the viral protein Gag and cis-acting elements in the full-length RNA. The sequence necessary and sufficient to allow RNA genome packaging into an HIV-1 particle has not been defined. Here, we used two distinct reporter systems to determine the HIV-1 sequence required for heterologous, non viral RNAs to be packaged into viral particles. Although the 5' untranslated region (UTR) of the HIV-1 RNA is known to be important for RNA packaging, we found that its ability to mediate packaging relies heavily on the context of the downstream sequences. Insertion of the 5' UTR and the first 32-nt of gag into two different reporter RNAs is not sufficient to mediate the packaging of these RNA into HIV-1 particles. However, adding the 5' half of the gag gene to the 5' UTR strongly facilitates the packaging of two reporter RNAs; such RNAs can be packaged at >50% of the efficiencies of an HIV-1 near full-length vector. To further examine the role of the gag sequence in RNA packaging, we replaced the 5' gag sequence in the HIV-1 genome with two codon-optimized gag sequences and found that such substitutions only resulted in a moderate decrease of RNA packaging efficiencies. Taken together, these results indicated that both HIV-1 5' UTR and the 5' gag sequence are required for efficient packaging of non-viral RNA into HIV-1 particles, although the gag sequence likely plays an indirect role in genome packaging. PMID- 28673554 TI - Implementation of hypofractionated prostate radiation therapy in the United States: A National Cancer Database analysis. AB - PURPOSE: Preclinical and clinical research over the past several decades suggests that hypofractionated (HFxn) radiation therapy schedules produce similar treatment outcomes compared with conventionally fractionated (CFxn) radiation therapy for definitive treatment of localized prostate cancer (PCa). We sought to evaluate national trends and identify factors associated with HFxn utilization using the US National Cancer Database. METHODS AND MATERIALS: We queried the National Cancer Database for men diagnosed with localized (N0,M0) PCa from 2004 through 2013 treated with external beam radiation therapy. Patients were grouped by dose per fraction (DpF) in Gray: CFxn was defined as DpF <=2.0, moderate HFxn as DpF >2.0 but <5.0, and extreme HFxn as DpF >=5.0. Men receiving DpF <1.5 or >15.0 were excluded, as were those receiving <25 or >90 Gy total dose. Multiple logistic regression was performed to identify demographic, clinical, and treatment factor associations. RESULTS: A total of 132,403 men were identified, with 120,055 receiving CFxn, 7264 moderate HFxn, and 5084 extreme HFxn. Although CFxn was by far the most common approach over the analysis period, HFxn use increased from 6.2% in 2004 to 14.2% in 2013 (P < .01). Extreme HFxn use increased the most (from 0.3% to 8.5%), whereas moderate HFxn utilization was unchanged (from 5.9% to 5.7%). HFxn use was independently associated with younger age, later year of diagnosis, non-black race, non-Medicaid insurance, non-Western residence, higher income, academic treatment facility, greater distance from treatment facility, low-risk disease group (by National Comprehensive Cancer Network criteria), and nonreceipt of hormone therapy. CONCLUSIONS: Although CFxn remains the most common radiation therapy schedule for localized PCa, use of HFxn appears to be increasing in the United States as a result of increased extreme HFxn use. Financial and logistical factors may accelerate adoption of shorter schedules. Considering the multiple demographic and prognostic differences identified between these groups, randomized outcome data comparing extreme HFxn to alternatives are desirable. PMID- 28673555 TI - Brain involvement in Charcot-Marie-Tooth disease due to ganglioside-induced differentiation associated-protein 1 mutation. AB - Charcot-Marie-Tooth (CMT) due to ganglioside-induced differentiation associated protein 1 (GDAP1) gene mutation can be inherited as an autosomal recessive (severe phenotype) or dominant (milder phenotype) disorder. GDAP1 protein, located in the outer mitochondrial membrane, is involved in the mitochondrial fission. Brain imaging abnormalities have not been reported in this condition. We described an 8-year-old boy who had an early onset autosomal recessive neuropathy. Whole exome sequencing revealed compound heterozygous mutations in the GDAP1 gene: c.313_313delA, p.Arg105Glufs*3 - a novel mutation (maternally inherited) and c.358C>T, pR120W - a known pathogenic mutation (paternally inherited). He had abnormal brain MRI findings since infancy localized to the middle cerebellar peduncles and cerebellar white matter with sparing of the supratentorial brain. We speculate that GDAP1 protein due to its widespread distribution and mitochondrial location is responsible for these imaging abnormalities. This report expands the spectrum of brain imaging abnormalities seen in different types of CMT. PMID- 28673556 TI - Exome sequencing identifies targets in the treatment-resistant ophthalmoplegic subphenotype of myasthenia gravis. AB - Treatment-resistant ophthalmoplegia (OP-MG) is not uncommon in individuals with African genetic ancestry and myasthenia gravis (MG). To identify OP-MG susceptibility genes, extended whole exome sequencing was performed using extreme phenotype sampling (11 OP-MG vs 4 control-MG) all with acetylcholine receptor antibody positive MG. This approach identified 356 variants that were twice as frequent in OP-MG compared to control-MG individuals. After performing probability test estimates and filtering variants according to those 'suggestive' of association with OP-MG (p < 0.05), only three variants remained which were expressed in extraocular muscles. Validation in 25 OP-MG and 50 control-MG cases supported the association of DDX17delG (p = 0.014) and SPTLC3insACAC (p = 0.055) with OP-MG, but ST8SIA1delCCC could not be verified by Sanger sequencing. A parallel approach, using a semantic model informed by current knowledge of MG pathways, identified an African-specific interleukin-6 receptor (IL6R) variant, IL6R c.*3043 T>C, that was more frequent in OP-MG compared to control-MG cases (p = 0.069) and population controls (p = 0.043). A weighted genetic risk score, derived from the odds ratios of association of these variants with OP-MG, correlated with the OP-MG phenotype as opposed to control MG. This unbiased approach implicates several potentially functional gene variants in the gangliosphingolipid and myogenesis pathways in the development of the OP-MG subphenotype. PMID- 28673557 TI - Long-term follow-up of motor function and muscle strength in the congenital and childhood forms of myotonic dystrophy type 1. AB - The aims of this study were to explore how motor function and muscle strength change over time in the congenital and childhood forms of myotonic dystrophy type 1, further to investigate whether sex, age, disease severity or size of the mutation could explain these changes. Motor function and isometric muscle strength were evaluated at three occasions during 1999-2013 in 57 patients aged 0.7-28.9 years. Median time between first and last assessment was 11.5 years ranging from 9.6 to 13.3 years. The study shows that motor function improves during the first decade, is most pronounced during the first six years, reaches a plateau during adolescence and starts to deteriorate in the beginning of the second decade. The most predictive variables for change are age (p < 0.0001) and number of CTG-repeat expansions (p = 0.0018). Sex or disease severity grade do not predict changes in motor function. Deterioration of muscle strength is most pronounced in ankle dorsiflexors. Knowledge of development and deterioration of motor function is important for clinical decision making and for planning of interventions. This knowledge can also be of interest for patient recruitment in drug trials, since treatment effect might be easier to evaluate in the stable phases of this progressive disorder. PMID- 28673558 TI - Characterization of first hemin-requiring Pseudomonas aeruginosa small-colony variants from the blood of an octogenarian male-patient with double pneumonitis. AB - A hemin-requiring Pseudomonas aeruginosa small-colony variant (SCV) was isolated from the blood of an octogenarian male-patient with double pneumonitis. The isolate was capable of growing on both sheep blood and chocolate agars but not on MacConkey agars without blood ingredient. Furthermore, the isolate revealed to grow only around the X-factor impregnated discs when examined using the X and V disc strips. However, not only RapID-NH system but also the VITEK2 system failed to identify the isolate. The isolate was finally identified as P. aeruginosa by the sequence of the 16S rRNA genes and the MALDI-TOF MS analysis. Interestingly, the isolate represented positive reaction for delta-aminolaevulinic acid (ALA) test despite the requirement of hemin. Detailed analysis indicated that the isolate produced protoporphyrin IX from ALA. Therefore, the reason for the hemin dependence was deduced the dysfunction of hemH-encoded ferrochelatase behaving at the end of biosynthetic pathway of heme. However, the genetic analysis of hemH gene demonstrated no variations of both the DNA and the amino-acid sequences. To the best of our knowledge, this is the first clinical isolation of a hemin dependent P. aeruginosa SCV from blood. PMID- 28673559 TI - CON4EI: Bovine Corneal Opacity and Permeability (BCOP) test for hazard identification and labelling of eye irritating chemicals. AB - Assessment of ocular irritation potential is an international regulatory requirement in the safety evaluation of industrial and consumer products. None in vitro ocular irritation assays are capable of fully categorizing chemicals as stand-alone. Therefore, the CEFIC-LRI-AIMT6-VITO CON4EI consortium assessed the reliability of eight in vitro test methods and computational models as well as established a tiered-testing strategy. One of the selected assays was Bovine Corneal Opacity and Permeability (BCOP). In this project, the same corneas were used for measurement of opacity using the OP-KIT, the Laser Light-Based Opacitometer (LLBO) and for histopathological analysis. The results show that the accuracy of the BCOP OP-KIT in identifying Cat 1 chemicals was 73.8% while the accuracy was 86.3% for No Cat chemicals. BCOP OP-KIT false negative results were often related to an in vivo classification driven by conjunctival effects only. For the BCOP LLBO, the accuracy in identifying Cat 1 chemicals was 74.4% versus 88.8% for No Cat chemicals. The BCOP LLBO seems very promising for the identification of No Cat liquids but less so for the identification of solids. Histopathology as an additional endpoint to the BCOP test method does not reduce the false negative rate substantially for in vivo Cat 1 chemicals. PMID- 28673560 TI - Down-regulation of the expression of alcohol dehydrogenase 4 and CYP2E1 by the combination of alpha-endosulfan and dioxin in HepaRG human cells. AB - Pesticides and other persistent organic pollutants are considered as risk factors for liver diseases. We treated the human hepatic cell line HepaRG with both 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and the organochlorine pesticide, alpha-endosulfan, to evaluate their combined impact on the expression of hepatic genes involved in alcohol metabolism. We show that the combination of the two pollutants (25nM TCDD and 10MUM alpha-endosulfan) led to marked decreases in the amounts of both the mRNA (up to 90%) and protein (up to 60%) of ADH4 and CYP2E1. Similar results were obtained following 24h or 8days of treatment with lower concentrations of these pollutants. Experiments with siRNA and AHR agonists and antagonist demonstrated that the genomic AHR/ARNT pathway is necessary for the dioxin effect. The PXR, CAR and estrogen receptor alpha transcription factors were not modulators of the effects of alpha-endosulfan, as assessed by siRNA transfection. In another human hepatic cell line, HepG2, TCDD decreased the expression of ADH4 and CYP2E1 mRNAs whereas alpha-endosulfan had no effect on these genes. Our results demonstrate that exposure to a mixture of pollutants may deregulate hepatic metabolism. PMID- 28673562 TI - Erratum. PMID- 28673561 TI - TCDD-induced mitochondrial superoxide production does not lead to mitochondrial degeneration or genomic instability in human SH-SY5Y neuroblastoma cells. AB - Several genotoxic and non-genotoxic agents have been reported to cause delayed genetic damage in the progeny of the exposed cells. Such induced genomic instability (IGI) may be a driving force in carcinogenesis, and it is thus highly important to understand the cellular events accompanying it. The aim of this study was to investigate whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects mitochondrial integrity and can consequently induce genomic instability. Mitochondrial integrity was evaluated by measuring mitochondrial superoxide production, mitochondrial membrane potential, and mitochondrial activity. Micronucleus formation was used to assess immediate genetic damage and IGI. The assays were performed either immediately, 8 or 15d after the exposure. Mitochondrial superoxide production was increased by TCDD immediately after the exposure. No consistent effects on mitochondrial integrity were observed at later time points, although slightly decreased mitochondrial membrane potential at 8d and increased mitochondrial superoxide potential production at 15 after exposure were observed in the TCDD-exposed cells. TCDD did not cause immediate genetic damage, and significant IGI was not observed. In conclusion, the present results suggest that immediate TCDD-induced increase in mitochondrial superoxide level does not lead to persistent loss of mitochondrial integrity or IGI in human SH SY5Y neuroblastoma cells. PMID- 28673563 TI - The role of oligomenorrhea in melasma. AB - Melasma is a facial hyperpigmentation in the upper lips, cheeks, forehead and chin. It is mostly seen in women. Melasma treatments include topical methods that are not only costly, but also temporary. Melasma recurs shortly after cessation of the treatment. Considering the relationship between melasma and elevated estrogen levels in patients with oligomenorrhea, systemic anti-estrogen therapies are not used for melasma. In this study, by searching in the scientific databases such as Scopus, Pubmed and the authentic books of traditional medicine such as the Canon of medicine, melasma treatment was evaluated based on oligomenorrhea systemic therapy. The results of this study showed that if melasma is due to oligomenorrhea, the use of systemic anti-estrogenic therapies can improve melasma by reducing of Melanogenesis due to decreasing alpha msh (alpha-Melanocyte stimulating hormone) in addition to oligomenorrhea improvement. However, because of the extreme attention to the advertising cosmetic creams, attention to systemic therapies has been faded. According to traditional medicine, the use of menstruation-inducing systemic therapies can be more effective in melasma than topical treatments because of removing of the disease agent. Given the important role of oligomenorrhea in creating of melasma, it is suggested conducting more studies on the effect of systemic therapy of oligomenorrhea on melasma treatment. If proven, to be considered as the treatment strategies for this disease. PMID- 28673564 TI - Demyelinating diseases as a result of cerebral edema? AB - Due to the elastic properties of the human organs, tissue edema causes an increased tissue pressure. This phenomenon leads to a reduction of blood circulation or ischemia, and thus leads to the hypothesis that tissue edema can be the cause of demyelinating lesions. Even though brain edema occurs in the whole brain, the authors assume that the characteristically focal appearance of demyelinated lesions, for instance of multiple sclerosis plaques, are attributable to anatomical and structural characteristics of the brain. In an experimental section, a balloon inserted into the brain and other organs removed during autopsies produces an increased tissue pressure. This model shows tissue pressure in the vicinity of the balloon up to 80mmHg. The height of the produced pressure varies in different organs and special regions of the brain. The verified pressures in the pons cerebri show that stretched myelinated fiber bundles in outer regions can induce strong pressures in enclosed edematous tissue, as seen in central pontine myelinolysis. The presented experimental results support the hypothesis that demyelinated lesions, as seen in multiple sclerosis, may be caused by increased tissue pressure, or respectively, brain edema. PMID- 28673565 TI - Monocyte subpopulations study in patients with plaque psoriasis. AB - Psoriasis is a chronic and systemic, immune-mediated, inflammatory disease, mainly manifested by skin and / or joints lesions, presenting with a wide degree of clinical severity, but generally with great impact on patients' quality of life. Despite advances in the understanding of its pathogenesis, especially regarding the participation of T-lymphocytes and the key role of TNF, the triggering factor of the disease at the molecular level remains unknown, as well as the function of other cell populations. By presenting antigens to T lymphocytes, monocytes assume an important role in both innate and adaptive immune response. In the last two decades, by using flow cytometry with antibodies against CD14 (receptor for lipopolysaccharide) and CD16 (low affinity receptor for IgG), human blood monocytes were classified into three subpopulations: classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14+CD16++). Under normal conditions the population of classical monocytes corresponds to about 85%, while intermediate to 5.4%, and nonclassical to 9.2%. However, intermediate and nonclassical subsets are increased in various inflammatory situations, such as moderate to severe asthma, colorectal cancer, and rheumatoid arthritis. Despite psoriasis being considered a disease of inflammatory nature, scarce studies evaluating the frequency of subpopulations of monocytes in psoriatic patients are found on current medical literature, and they are restricted to peripheral blood analysis. This study aims to identify the frequency of monocyte subpopulations in blood levels as well as lesional skin of plaque psoriasis patients, and to evaluate their association to cytokines, and clinical disease severity. PMID- 28673566 TI - Cancer is an adaptation that selects in animals against energy dissipation. AB - As cancer usually follows reproduction, it is generally assumed that cancer does not select. Graham has however argued that juvenile cancer, which precedes reproduction, could during evolution have implemented a "cancer selection" that resulted in novel traits that suppress this juvenile cancer; an example is protection against UV sunlight-induced cancer, required for the emergence of terrestrial animals from the sea. We modify the cancer selection mechanism to the posited "cancer adaptation" mechanism, in which juvenile mortality is enhanced through the diminished care received by juveniles from their (grand) parents when these suffer from cancer in old age. Moreover, it is posited that the cancer adaptation selects against germline "dissipative genes", genes that result in enhanced free energy dissipation. Cancer's progression is interpreted as a cascade at increasing scale of repeated amplification of energy dissipation, a cascade involving heat shock, the Warburg effect, the cytokine IL-6, tumours, and hypermetabolism. Disturbance of any physiological process must enhance energy dissipation if the animal remains functioning normally, what explains multicausality, why "everything gives you cancer". The hypothesis thus comprises two newly invoked partial processes-diminished (grand) parental care and dissipation amplification-and results in a "selection against enhanced energy dissipation" which gives during evolution the benefit of energy conservation. Due to this benefit, cancer would essentially be an adaptation, and not a genetic disease, as assumed in the "somatic mutation theory". Cancer by somatic mutations is only a side process. The cancer adaptation hypothesis is substantiated by (1) cancer's extancy, (2) the failure of the somatic mutation theory, (3) cancer's initiation by a high temperature, (4) the interpretation of cancer's progression as a thermal process, and (5) the interpretation of tumours as organs that implement thermogenesis. The hypothesis could in principle be verified by monitoring in a population over several generations (1) the presence of dissipative genes, (2) the incidence of cancer, and (3) the beneficial effect of dissipative gene removal by cancer on starvation/famine survival. PMID- 28673567 TI - Is there a link between hyperhomocysteinemia and Vogt-Koyanagi-Harada syndrome? PMID- 28673568 TI - Metformin exerts anti-obesity effect via gut microbiome modulation in prediabetics: A hypothesis. AB - Prediabetic individuals are characterized by high levels of insulin, an anabolic hormone having an important role in the maintenance of glucose homeostasis. However, insulin has also been found to increase the growth of certain bacteria which form the non-butyrate producing part of the gut microbiome. The gut microbiome is recently in focus for its strong association with many chronic diseases such as type 2 diabetes mellitus and obesity. Metformin, a widely popular anti-diabetic medication has been shown to prevent weight gain in many trials. There are many studies postulating the mechanisms of the anti-obesity effect of metformin including improvement in insulin sensitivity (and consequently a reduction in insulin levels). Recently, however, it is becoming evident that metformin's action is likely to be primarily mediated by the gut. Further, metformin has also shown to affect the growth characteristics of certain bacteria which form the part of the human gut microbiome. With this frame of reference in mind, we hypothesize that metformin is likely to exert its anti obesity effect by altering the composition of the gut microbiome. If proved, this has the potential to contribute to the management of obesity and pave the way for the development of novel anti-obesity drugs. PMID- 28673569 TI - Calcium-channel blockers as therapeutic agents for acquired sensorineural hearing loss. AB - Acquired sensorineural hearing loss represents a challenging clinical scenario. Currently, there are few approved therapies for treating this type of hearing loss, and diagnosis is often made after permanent damage has occurred. There are numerous etiologies for acquired hearing loss, with complex mechanisms underlying each cause. Despite these complexities, apoptosis of the structures within the inner ear, is a theme common to many forms of acquired hearing loss. Apoptosis is a calcium-dependent process, and within the inner ear, L- and T-type calcium channels are believed to contribute to calcium availability during this process. There are few studies limited to animal models evaluating the role of calcium channel blockers (CCBs) as otoprotective agents in the setting of acquired hearing loss. Here, I hypothesize that CCBs will provide utility as a therapy against acquired forms of sensorineural hearing loss by preventing calcium influx that occurs during inner ear cellular apoptosis. PMID- 28673570 TI - Are non-communicable diseases chronically communicable: A role for the human microbiota? PMID- 28673571 TI - High altitude and pre-eclampsia: Adaptation or protection. AB - Adaptive genes of high altitude can also be protective in diseases like preeclampsia, hypertension, and diabetes mellitus, Alzheimer, Parkinson Disease and Cancer, which may result from deregulation of hypoxia pathway. The example of pre-eclampsia and normal pregnancy were studied to see if the hypoxia-induced disorders can be dragged towards adaptation. Here, we analyse the genetic variants that are known to be associated with adaptation to high altitude hypoxia. Our results demonstrated that the genetic variants of EPAS1, ADAM9, and EGLN1 increased approximately three-fold in the cases of preeclampsia compared to normal pregnancy. This may suggest the ability of the hypoxic cells of preeclampsia to respond to the high selective pressure of hypoxia with a higher degree of genetic variability, which can lead to adaptation. Signs of "acclimatisation" were seen both in cases and controls but with higher frequencies in controls. This can be a new approach that follows patients' genetic selection and susceptibility of individuals for adaptability, which could be enhanced by drug development. PMID- 28673572 TI - Elimination of cancer stem cells and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking inhibition of tumorigenesis and the potential eradication of HIV-1. AB - Although promising treatments are currently in development to slow disease progression and increase patient survival, cancer remains the second leading cause of death in the United States. Cancer treatment modalities commonly include chemoradiation and therapies that target components of aberrantly activated signaling pathways. However, treatment resistance is a common occurrence and recent evidence indicates that the existence of cancer stem cells (CSCs) may underlie the limited efficacy and inability of current treatments to effectuate a cure. CSCs, which are largely resistant to chemoradiation therapy, are a subpopulation of cancer cells that exhibit characteristics similar to embryonic stem cells (ESCs), including self-renewal, multi-lineage differentiation, and the ability to initiate tumorigenesis. Interestingly, intracellular mechanisms that sustain quiescence and promote self-renewal in adult stem cells (ASCs) and CSCs likely also function to maintain latency of HIV-1 in CD4+ memory T cells. Although antiretroviral therapy is highly effective in controlling HIV-1 replication, the persistence of latent but replication-competent proviruses necessitates the development of compounds that are capable of selectively reactivating the latent virus, a method known as the "shock and kill" approach. Homeostatic proliferation in central CD4+ memory T (TCM) cells, a memory T cell subset that exhibits limited self-renewal and differentiation and is a primary reservoir for latent HIV-1, has been shown to reinforce and stabilize the latent reservoir in the absence of T cell activation and differentiation. HIV-1 has also been found to establish durable and long-lasting latency in a recently discovered subset of CD4+ T cells known as T memory stem (TSCM) cells. TSCM cells, compared to TCM cells, exhibit stem cell properties that more closely match those of ESCs and ASCs, including self-renewal and differentiation into all memory T cell subsets. It is our hypothesis that activation of AMPK, a master regulator of cellular metabolism that plays a critical role in T cell activation and differentiation of ESCs and ASCs, will lead to both T cell activation-induced latent HIV-1 reactivation, facilitating virus destruction, as well as "activation", differentiation, and/or apoptosis of CSCs, thus inhibiting tumorigenesis. We also propose the novel observation that compounds that have been shown to both facilitate latent HIV-1 reactivation and promote CSC differentiation/apoptosis (e.g. bryostatin-1, JQ1, metformin, butyrate, etc.) likely do so through a common mechanism of AMPK activation. PMID- 28673573 TI - Exercise for type 1 diabetes mellitus management: General considerations and new directions. AB - Type 1 diabetes mellitus (T1DM) is characterized by the loss of insulin secreting cells due to a directed autoimmune process, which is linked to oxidative stress and inflammation. Exercise training is known to induce several benefits by reducing inflammation and improving antioxidant defenses. In this context, exercise training may be considered as an efficient and relatively inexpensive non-pharmacological tool for diabetes treatment, added to the usual insulin administration. Unfortunately, most people with T1DM do not reach the recommended levels of physical activity due to concerns with hypoglycemic episodes. Recent data have demonstrated that exercise sessions composed by strength exercises or high-intensity interval exercise reduce the risk of hypoglycemia during and after the physical effort, when compared with continuous aerobic exercise in insulin dependent patients. However, no studies have tested the chronic effects of this combination of protocols on health-related markers yet. Herein, we suggest a combination of hypertrophic strength exercises (3 sets at 8-RM) with a high intensity interval protocol (10*60-s bouts at ~90% HRmax interspersed with 60s recovery) in the same exercise session, three times per week, for T1DM patients free of micro and macrovascular complications. Our hypothesis is that this training protocol may minimize the exercise-associated rapid drop of glucose levels in T1DM, due to glucoregulatory hormones and transient reduction of insulin-mediated glucose uptake. This training is also likely to cover long-term glycaemic, bioenergetic, neuromuscular and cardiorespiratory adaptations, implicating in improved health and decreased risk of micro and macro complications. PMID- 28673574 TI - LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge. AB - The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our conjecture this deleterious state has the potential to account for the inverse association between LDL-C level and CVD risk observed in older people. PMID- 28673575 TI - Can the combined administration of labelled fluoro-2 deoxy d glucose and insulin or chrome increase the diagnostic sensitivity of Positron Emission Tomography (PET)? AB - In this letter to editor I hypothesize that administering insulin or chrome along with fluoro-2 deoxy d-glucose (FDG) to enhance its uptake in malignant lesions that are known to have low levels of tumor glycolysis, and therefore, improve the sensitivity of PET imaging in this setting. The logic behind this idea stems from the known fact that there is substantial increase in uptake of d-glucose following administration of insulin/chrome in many tissues, and as such, the same pattern would apply to FDG. PMID- 28673576 TI - Worn is born: The role of the maxillo-mandibular relation in management of worn dentition. AB - Worn dentition, often accompanied by occlusion changes such as reduced vertical dimension, poses a big challenge to both diagnosis and treatment. Current established causes fail to explain the observed tooth wearing patterns, and the treatments based on the documented pathogeneses are often unpredictable and require frequent maintenance. From the perspective of stomatognathic system, we postulate that the role of maxillo-mandibular relation is a crucial part in the tooth wear progression patterns, and should be well addressed in treatment planning. Incompatible occlusion with the inherent tendency of maxillo-mandibular relation has a profound effect on either wearing of natural teeth or failures of restorations. With the aid of cephalometrics and analysis of occlusion it is now possible to reduce this fallacy and achieve a harmony by re-designing the occlusion. According to our treated worn dentition cases, the restoring treatment guided by the tendency of maxillo-mandibular relation showed very promising results. PMID- 28673577 TI - Cognitive impairment in diabetes and poor glucose utilization in the intracellular neural milieu. AB - The main characteristic of diabetes is hyperglycemia. Depending on whether diabetes is type-1 or type-2, it is characterized by deficiencies in insulin secretion, insulin receptor sensitivity, hexokinase activity, and glucose transport. Current drug treatments are able to lower circulating glucose but do not address the problem of glucose utilization in the intracellular milieu, the consequence of which is tissue damage. In the long-term, such changes can produce structural damage in many cortical and subcortical brain areas that are related to cognitive function. Many epidemiological reports consider anxiety and depression as clinical entities that accompany diabetes. However, anxiety and depression in diabetes appear to occur in parallel and do not follow a causal relationship. From a behavioral perspective, anxiety may be considered adaptive, whereas depression can be considered reactive in response to changes in lifestyle and ailments that are caused by the disease. Therefore, the main alteration in diabetes seems to be cognitive function. We hypothesized that in type-2 diabetes, hypoglycemic medications do not restore the function of glucose in the intracellular compartment, which may have deleterious effects on neural tissue with behavioral consequences. In such a case, it is important to develop pharmacological interventions that directly restore plasma insulin levels, insulin receptor function, and hexokinase activity, thereby avoiding damage to neural tissue that is associated with cognitive deficits in diabetic patients, particularly patients with type-2 diabetes. The better management of such alterations in diabetes should be directed toward improving glucose utilization by neural tissue. PMID- 28673578 TI - Granulocytes as an effector mechanism of BCG therapy for bladder cancer. AB - The overall efficacy of BCG therapy is remarkably high but the mechanism of its action is still elusive. The success of BCG therapy depends on several factors that may give clues to its effector mechanism: a competent immune system, a sufficient number of live BCG, a development of fever and the death of cancer cells. Here we propose a theory for the action mechanism of the BCG therapy for the bladder cancer treatment by establishing the logical connection of these required elements. The center concept of the BCG therapy mechanism is to activate granulocytes that in turn kill bladder cancer cells directly by its major effector mechanism: degranulation. PMID- 28673579 TI - The "chloride theory", a unifying hypothesis for renal handling and body fluid distribution in heart failure pathophysiology. AB - Body fluid volume regulation is a complex process involving the interaction of various afferent (sensory) and neurohumoral efferent (effector) mechanisms. Historically, most studies focused on the body fluid dynamics in heart failure (HF) status through control of the balance of sodium, potassium, and water in the body, and maintaining arterial circulatory integrity is central to a unifying hypothesis of body fluid regulation in HF pathophysiology. The pathophysiologic background of the biochemical determinants of vascular volume in HF status, however, has not been known. I recently demonstrated that changes in vascular and red blood cell volumes are independently associated with the serum chloride concentration, but not the serum sodium concentration, during worsening HF and its recovery. Based on these observations and the established central role of chloride in the renin-angiotensin-aldosterone system, I propose a unifying hypothesis of the "chloride theory" for HF pathophysiology, which states that changes in the serum chloride concentration are the primary determinant of changes in plasma volume and the renin-angiotensin-aldosterone system under worsening HF and therapeutic resolution of worsening HF. PMID- 28673580 TI - The enteric toxicity of gluten enhances graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Pro-inflammatory peptides present in wheat and related grains are associated with celiac disease and non-celiac gluten sensitivity. We hypothesize that these peptides induce enteric responses that may exacerbate the gastrointestinal manifestations of graft-versus-host disease after an allogeneic hematopoietic stem cell transplant. Therefore, we propose that a gluten free diet should be tested as a prophylactic and/or therapeutic intervention against gastrointestinal graft-versus-host disease for patients undergoing an allogeneic hematopoietic stem cell transplant. PMID- 28673581 TI - Environmental contributors to modulation of brain estrogen signaling and male gender bias in autism: A reply to the oral contraceptive use hypothesis by Strifert (2015). AB - Strifert has recently put forward an interesting hypothesis regarding the role of oral contraceptive (OC) use in mothers and risk of offspring autism spectrum disorder (ASD). First, the author reports that combined oral contraceptives (COCs), containing both estrogen and progesterone, were developed in the late 1950s and early 60s, which is a time-frame distinct from Leo Kanner's documentation of infantile ASD in 1943 that Strifert just briefly mentions. While this important temporal inconsistency of ASD origin does not invalidate the potential role of OC use in contributing to the rise of ASD, it does support the likely possibility of other environmental exposures at play. Second, the epigenetic basis of the hypothesis is that the endocrine-disrupting components (i.e., ethinylestradiol) of OC perturb estrogenic signaling in the fetal brain by triggering aberrant DNA methylation of the estrogen receptor beta (ERbeta) gene, and such methylation patterns may be imprinted to future generations and could theoretically increase subsequent ASD offspring risk. The premise of the hypothesis is challenged, however, with the recognition that MeCP2, a "reader" of DNA methylation sites, is not only associated with age-dependent alteration in ERbeta in females but is also significantly reduced in ASD brain. Furthermore, Strifert does not clearly address how the OC hypothesis accounts for the male bias in ASD. Therefore, the purpose of this correspondence is to address these inconsistencies by proposing a hypothesis that challenges these points. That is, gestational exposure to the agricultural and combustion air pollutant, nitrous oxide (N2O), may be a leading contributor to the development of an ASD phenotype. The mechanism undergirding this hypothesis suggests that compensatory estrogenic activity may mitigate the effects of fetal N2O exposure and thereby confer a protective effect against ASD development in a sex-dependent manner (i.e., male bias in ASD). PMID- 28673582 TI - Endothelial dysfunction mediated by interleukin-18 in patients with ischemic heart disease undergoing coronary artery bypass grafting surgery. AB - When medication management or percutaneous coronary intervention is not successful in patients with advanced ischemic heart disease, surgical revascularisation-predominantly coronary artery bypass grafting (CABG)-is considered the gold standard. However, CABG surgery can lead to ischemia/reperfusion injury, which is characterized by a strong inflammatory response. Interleukin (IL)-18, is a strong inflammatory mediator, that is released from cardiomyocytes and can be found in the systemic circulation of patients during and immediately after CABG surgery. The existing damage of endothelial glycocalyx in patients with ischemic heart disease is further impaired concurrently during the surgery due to the anaesthesia-surgical technique used and intravascular fluid loading. This results in the increased incidence of adverse events, including myocardial infarction. IL-18 leads to the activation of lymphocyte cytotoxicity via cytotoxic mediators (Fas ligand, Tumour necrosis factor (TNF)-related apoptosis-inducing ligand, perforin, and granulysin). We hypothesize that IL-18 is released locally in the heart and the systemic circulation in patients undergoing CABG surgery and may be correlated with the level of activity of circulating lymphocytes. In turn, this may lead to lymphocyte-mediated cytotoxicity directed toward damaged and activated endothelial cells. Shear stress glycocalyx, as well as damaged and activated endothelial cells then become the main the source of pro-inflammatory cytokines, chemokines, and adhesion molecules. These attract activated lymphocytes to adhere to the endothelium or enter the subintimal layer, increasing existing or initiating the formation of new plaques, which leads to the development of myocardial infarction during or shortly after surgery. To evaluate our hypothesis, we will measure the local concentration of IL-18 in the sinus coronarius and systemic circulation. These values will then be correlated with immunological and biochemical parameters, predominantly with the concentration of degradation products of glycocalyx and cytotoxic mediators in activated lymphocytes. If our hypothesis is correct, measuring the IL-18 concentration that is responsible for glycocalyx deterioration, may become a useful tool for predicting myocardial infarction occurrence in patients undergoing CABG surgery. PMID- 28673583 TI - MicroRNA targeting microtubule cross-linked protein (MACF1) would suppress the invasion and metastasis of malignant tumor. AB - Cancer is one of the most serious diseases that endanger human health in the world today, and the incidence and mortality of cancer increases year by year. Invasion and metastasis is the most prominent feature of malignant tumors, but also becomes the primary factor of threatening patient's health. Tumor cell invasion and metastasis which closely related to the dynamic changes of the cytoskeleton is an important factor influencing the survival of patients. Therefore, inhibition of tumor cell invasion and metastasis is a key strategy for the treatment of cancer. MACF1 is a microtubule microfilament cross-linking factor that plays an important role in cell polarization, cell migration, and maintenance of tissue integrity. A lot of studies have shown that microRNAs play an important role in tumorigenesis, invasion and metastasis. Therefore, we propose the following scientific assumptions: MACF1, an important molecule in adjusting the invasion and metastasis of tumor cells, regulates microfilaments, microtubules participating in cytoskeleton dynamics to promote malignant tumor cell migration and invasion; MicroRNA targeting MACF1 can decrease the expression of MACF1 and thus disrupt the dynamic balance of microtubule or microfilaments as an effective way to inhibit the invasion and metastasis of tumor cells. So we can use it as a new target for clinical early diagnosis and treatment of malignant tumor invasion and metastasis. PMID- 28673584 TI - PARP inhibitors in acute myeloid leukaemia therapy: How a synthetic lethality approach can be a valid therapeutic alternative. AB - Acute myeloid leukaemia (AML) is a malignancy in need of new therapeutic options. The current standard of care chemotherapy, leads to complete remission (CR) in the vast majority of adult patients under the age of 60. In contrast, CR rates in patients over the age of 60 reaches only 40-60%. While achievement of a CR is an important stepping stone in the treatment of AML, the majority of these patients experience relapse and die of their disease without adequate consolidation chemotherapy. Blood and marrow transplantation (BMT) can improve outcome in a select patient with AML but unfortunately, it is not a valid treatment option for the majority of older patients. Thus, the development of novel chemotherapy regimens that capitalizes on AML biology to eliminate the malignant clone with little to no side effects on the normal haematopoiesis is paramount in the treatment of elderly patients. In the current paper, we propose to take advantage of the dysfunctional DNA repair mechanisms present in AML cells and induce synthetic lethality using a combination of PARP inhibitors with low dose anthracycline and DNMT inhibitors. Such a combination, while effectively eliminating leukaemia should be well tolerated and thus, suitable for the treatment of frail patients. PMID- 28673585 TI - Adenomatoid odontogenic tumor revisited. PMID- 28673586 TI - Potential therapeutic effect of alkaline reduced water in polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic disorder characterized by hormonal disturbances including hyperandrogenemia, insulin resistance, and hyperinsulinemia culminating into obesity, multiple ovarian cysts and anovulatory infertility in women. There has been no effective medication against PCOS and its complication. However, weight loss can reduce insulin resistance, which in turn helps to restore hormonal balance and ovulation resulting to improved fertility. Previously, we reported that alkaline reduced water (ARW) could significantly reduce obesity by alleviating adiposity, regulating the levels of adipokines/pro-inflammatory cytokines and by inducing cholesterol homeostasis. Herein, we hypothesize that ARW might ameliorate the pathophysiological (hormonal, metabolic, and immunological) imbalances incurred by PCOS, thereby improving the infertility of PCOS patients. PMID- 28673587 TI - Bariatric surgery may reduce the risk of Alzheimer's diseases through GLP-1 mediated neuroprotective effects. AB - Obesity and diabetes are associated with deficits in multiple neurocognitive domains and increased risk for dementia. Over the last two decades, there has been a significant increase in bariatric and metabolic surgery worldwide, driven by rising intertwined pandemics of obesity and diabetes, along with improvement in surgical techniques. Patients undergoing bariatric surgery achieve a significant decrease in their excess weight and a multitude of sequela associated with obesity, diabetes, and metabolic syndrome. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide that has been implicated as one of the weight loss independent mechanisms in how bariatric surgery affects type 2 diabetes. GLP-1 improves insulin secretion, inhibits apoptosis and induce pancreatic islet neogenesis, promotes satiety, and can regulate heart rate and blood pressure. Moreover, numerous studies have demonstrated potential neuroprotective and neurotrophic effects of GLP-1. Increased GLP-1 activity has been shown to increase cortical activity, promote neuronal growth, and inhibit neuronal degeneration. Specifically, in experimental studies on Alzheimer's disease, GLP-1 decreases amyloid deposition and neurofibrillary tangles. Furthermore, recent studies have also suggested that GLP-1 based therapies, new class of antidiabetic drugs, have favorable effects on neurodegenerative disorders such as Alzheimer's disease. We present a hypothesis that bariatric surgery can help delay or even prevent the onset of Alzheimer's disease in long-term by increasing the levels of GLP-1. This hypothesis has a potential for many studies from basic science projects to large population studies to fully understand the neurological and cognitive consequences of bariatric surgery and associated rise in GLP-1. PMID- 28673588 TI - Biological functions of melatonin in relation to pathogenesis of oral lichen planus. AB - Oral lichen planus (OLP) is considered as a chronic inflammatory immune-mediated disease causing oral mucosal damage and ulcerations. Accumulated data support the involvement of cell-mediated immune dysfunction in the development of OLP. However, the connection between neuroendocrine system and oral immune response in OLP patients has never been clarified. Melatonin is considered as a major chronobiotic hormone produced mainly by the pineal gland. This gland is recognized as a regulator of circadian rhythm and a sensor in the immune response through the NF-kB transduction pathway. It was suggested that pineal-derived melatonin and extra-pineal melatonin synthesized at the site of inflamed lesion might play a role in inflammatory response. According to our immunohistochemical study, expression of melatonin could be detected in human oral mucosa. In addition, increased levels of melatonin were observed in inflamed oral mucosa of OLP patients. We hypothesize that chronic inflammation possibly induces the local biosynthesis of melatonin in inflamed oral mucosa. We also speculate that melatonin in oral mucosa may play a cytoprotective role through its anti oxidative and anti-inflammatory properties. Moreover, melatonin may play an immunomodulatory role in relation to pathogenesis of OLP. Our hypothesis provides a new implication for upcoming research on the connection between circadian neuroendocrine network and immune response in oral mucosal compartments. PMID- 28673589 TI - Hepatitis B vaccine non response: A predictor of latent autoimmunity? AB - Unresponsiveness to Hepatitis B virus (HBV) vaccine has been associated with interleukins involved with Th1 functioning including Interleukin-8 (IL-18) and Interferon-gamma (IFN-gamma). IL-18 and IFN-gamma have also been implicated in the onset of different types of immune-mediate inflammatory conditions such as Type 1 Diabetes (T1D), Celiac disease (CD), rheumatoid arthritis (RA), obesity and systemic lupus erythematosus (SLE). Taking into account that HBV vaccination is provided in the 1st year of life worldwide, I propose that all babies should be tested for anti-HBs response after completion of the vaccine series. And I suggest that children with undetectable anti-HBs titers after recommended immunization schedule as well as the additional booster doses should be followed up over time because they may be at risk of developing a number of autoimmune disorders. In this light, the non-responsiveness to HBV vaccine might be a predictor of latent autoimmunity. For that reason, research studies are needed in order to verify the existence of potential IL-18 and IFN-gamma gene polymorphisms to utilize as biomarkers of latent autoimmunity. As a final point, administration of neutralizing antibodies against IFN-gamma and/or IL-18 might represent a future target for immune-modulatory therapeutic approach to halt or even reverse autoimmune phenomena. PMID- 28673590 TI - Parkinson's disease; the hibernating spore hypothesis. AB - The authors support the hypothesis that a causative agent in Parkinson's disease (PD) might be either fungus or bacteria with fungus-like properties - Actinobacteria, and that their spores may serve as 'infectious agents'. Updated research and the epidemiology of PD suggest that the disease might be induced by environmental factor(s), possibly with genetic susceptibility, and that alpha synuclein probably should be regarded as part of the body's own defense mechanism. To explain the dual-hit theory with stage 1 involvement of the olfactory structures and the 'gut-brain'-axis, the environmental factor is probably airborne and quite 'robust' entering the body via the nose/mouth, then to be swallowed reaching the enteric nervous system with retained pathogenicity. Similar to the essence of smoking food, which is to eradicate microorganisms, a viable agent may be defused by tobacco smoke. Hence, the agent is likely to be a 'living' and not an inert agent. Furthermore, and accordant with the age dependent incidence of LPD, this implies that a dormant viable agent have been escorted by alpha-synuclein via retrograde axonal transport from the nose and/or GI tract to hibernate in the associated cerebral nuclei. In the brain, PD spreads like a low-grade infection, and that patients develop symptoms in later life, indicate a relatively long incubation time. Importantly, Actinomyces species may form endospores, the hardiest known form of life on Earth. The authors hypothesize that certain spores may not be subject to degradation by macroautophagy, and that these spores become reactivated due to the age-dependent or genetic reduced macroautophagic function. Hence, the hibernating spore hypothesis explains both early-onset and late-onset PD. Evaluation of updated available information are all consistent with the hypothesis that PD may be induced by spores from fungi or Actinobacteria and thus supports Broxmeyer's hypothesis put forward 15years ago. PMID- 28673591 TI - Male predominance in Meckel's diverticulum: A hyperacidity hypotheses. AB - The symptomatic presentation of Meckel's diverticulum (MD) depends on a person's age, sex, and presence or absence of ectopic gastric tissue. There are no differences in the prevalence of asymptomatic MD between males and females; however, symptomatic MD has a distinct male predominance with a male-to-female ratio ranging from 2:1 to 5:1 in children. Furthermore, if the ectopic tissue contains gastric mucosa, MD has a greater chance of becoming symptomatic. Studies have shown that acid secretion is more likely to occur in male infants compared to female infants. In adults, men are known to have a higher level of acid production compared to women. Peptic ulcers (PU) are more common in males due to high acid secretion, and gastric tissues are affected by gastrin secretion in both conditions. MD is typically accompanied by ectopic gastric tissue, and could therefore be affected by gastrin and acid secretion in a similar manner to PU. Some of the major complications of MD are diverticulitis, ulcers, and bleeding from adjacent ectopic gastric tissue, and such complications resemble PU. PU also have male to female ratios ranging from 2:1 to 5:1, which is again similar to MD. Since the secretion of both gastrin and acid decrease with age, symptomatic presentation of MD also declines with age. Therefore, we hypothesize that higher gastrin and acid levels in males affect the ectopic gastric mucosa and lead to an increase in MD symptoms, which result an increased incidence of MD in males. PMID- 28673593 TI - Boron - A potential goiterogen? AB - The iodine deficiency disorders (IDD) include a variety of disturbances such as decreased fertility, increased perinatal and infant mortality, impaired physical and intellectual development, mental retardation, cretinism, hypothyroidism, and endemic goiter (EG). The occurrence of the latter is determined by interplay between genetic and environmental factors. The major environmental factor is iodine status that is required for normal thyroid hormone synthesis. However, other factors like intake of micronutrients and goiterogens also have a significant impact. Essential and toxic trace elements both play a significant role in thyroid physiology. We hypothesize that in terms of overexposure boron may serve as a potential goiterogen. In particular, it is proposed that boron overload may impair thyroid physiology ultimately leading to goiter formation. Certain studies provide evidential support of the hypothesis. In particular, it has been demonstrated that serum and urinary B levels are characterized by a negative association with thyroid hormone levels in exposed subjects. Single indications on the potential efficiency of B in hypothyroidism also exist. Moreover, the levels of B were found to be interrelated with thyroid volume in children environmentally exposed to boron. Experimental studies also demonstrated a significant impact of boron on thyroid structure and hormone levels. Finally, the high rate of B cumulation in thyroid may also indicate that thyroid is the target for B activity. Chemical properties of iodine and boron also provide a background for certain competition. However, it is questionable whether these interactions may occur in the biological systems. Further clinical and experimental studies are required to support the hypothesis of the involvement of boron overexposure in goiter formation. If such association will be confirmed and the potential mechanisms elucidated, it will help to regulate the incidence of hypothyroidism and goiter in endemic regions with high boron levels in soil and water. PMID- 28673594 TI - Management of temporomandibular joint degenerative disorders with human amniotic membrane: Hypothesis of action. AB - Approaches providing the positioning of human amniotic membrane (HAM) within the intra-articular space of arthritic TMJs have never been investigated. This contrasts with the increasing amount of evidence suggesting the potential positive effects of HAM on a number of surgical conditions, even included the interpositional arthroplasty for TMJ ankylosis. Thus, the possible usefulness of HAM to restore joint functions in severely damaged TMJs could be hypothesized. Based on these premises, the clinical research question "Is human amniotic membrane positioning effective to reduce symptoms and restore jaw function in patients with severe inflammatory-degenerative disorders of the temporomandibular joint?" has been addressed by performing a systematic review of the literature. Out of potential 11988 and 8883 citations in the PubMed and Scopus databases, respectively, only five were of possible interest for inclusion in the review, but none of them addressed specifically the clinical research question. Thus, the hypothetical background for usefulness was discussed. The benefits of HAM positioning in TMJs with severe inflammatory-degenerative disorders could be related with its anti-inflammatory and anti-microbial and analgesic properties as well as its low immunogenicity. Studies in which HAM is positioned within the joint space of patients with severe TMJ degeneration, either as a disc-replacing film during major surgeries for discectomy and arthroplasty or as an injectable solution that can be needle-inserted after an arthrocentesis procedure, should be designed to test the hypothesis. PMID- 28673592 TI - Bottom-up gamma and stages of waking. AB - Gamma activity has been proposed to promote the feed forward or "bottom-up" flow of information from lower to higher regions of the brain during perception. The pedunculopontine nucleus (PPN) modulates waking and REM sleep, and is part of the reticular activating system (RAS). The properties of PPN cells are unique in that all PPN neurons fire maximally at gamma band frequency regardless of electrophysiological or transmitter type, thus proposed as one origin of "bottom up" gamma. This property is based on the presence of intrinsic membrane oscillations subserved by high threshold, voltage-dependent calcium channels. Moreover, some PPN cells are electrically coupled. Assuming that the population of PPN neurons has the capacity to fire at ~40Hz coherently, then the population as a whole can be expected to generate a stable gamma band signal. But what if not all the neurons are firing at the peaks of the oscillations? That means that some cells may fire only at the peaks of every second oscillation. Therefore, the population as a whole can be expected to be firing at a net ~20Hz. If some cells are firing at the peaks of every fourth oscillation, then the PPN as a whole would be firing at ~10Hz. Firing at rates below 10Hz would imply that the system is seldom firing at the peaks of any oscillation, basically asleep, in slow wave sleep, thus the activation of the RAS is insufficient to promote waking. This hypothesis carries certain implications, one of which is that we awaken in stages as more and more cells are recruited to fire at the peaks of more and more oscillations. For this system, it would imply that, as we awaken, we step from ~10Hz to ~20Hz to ~30Hz to ~40Hz, that is, in stages and presumably at different levels of awareness. A similar process can be expected to take place as we fall asleep. Awakening can then be considered to be stepwise, not linear. That is, the implication is that the process of waking is a stepwise event, not a gradual increase, suggesting that the brain can spend time at each of these different stages of arousal. PMID- 28673595 TI - Translocator Protein (18kDa) Downregulation Contributes to Low Cortisol and Neurosteroid Levels in Patients with Post Traumatic Stress Disorder. PMID- 28673597 TI - Infections caused by resistant organisms: Could organic arsenic compounds be an effective treatment? AB - Without question one of the most important medicinal chemistry discoveries of the 20th century was made by Paul Ehrlich and his colleagues, chemist, Alfred Bertheim and bacteriologist, Sahachiro Hata. They ushered in the age of targeted chemotherapy in 1910 with the discovery of the anti-syphilitic organic arsenic agent, arsphenamine or Salvarsan (also known as 606). It was the clinical compound of choice for treating syphilis until penicillin and other antibiotics were introduced clinically in the 1940s. Yet now, more than 100years after its discovery, the precise biochemical mechanism by which this compound eliminates the syphilis spirochete in vivo from humans and animals remains unknown. Other organic arsenic compounds such as melarsoprol and roxarson have been used to treat parasitic infections. More recently, arsenic trioxide has been shown effective in producing remissions and possibly cures in a high percentage of patients with acute promyelocytic leukemia. However, the exact biochemical mechanism by which this clinical result is manifested remains to be determined. The purpose of this publication is to propose a possible mechanism, by which these apparently diverse arsenic compounds function to produce their clinical results and to suggest their potential for the treatment of infections caused by resistant organisms. PMID- 28673598 TI - The network model of delirium. AB - The coordinated function of brain networks underlies consciousness, attention and reality testing, all of which are impaired in delirium. The default-mode network, salience network, frontoparietal control network and dorsal attention network are brain networks with integral roles in the maintenance and modulation of the aforementioned functions. Multiple lines of evidence point to their dysfunction in delirium. The convergence of neurotransmitter changes, neuroendocrine and inflammatory stressors on brain networks disrupts bottom-up and top-down attentional control. Neuroimaging and neuroanatomy correlates are potentially consistent with this hypothesis. Overall, this model appears to have significant utility in connecting the seemingly disparate precipitants of delirium while accounting for the clinical manifestations of the syndrome. PMID- 28673596 TI - Intra-spinal microstimulation may alleviate chronic pain after spinal cord injury. AB - Chronic pain after spinal cord injury (SCI) is a form of central neuropathic pain that is debilitating and often refractory to current pharmacological treatments. Neurostimulation pain therapies, such as epidural spinal cord stimulation, have only moderate success in reducing SCI pain. The pathogenesis of SCI pain may involve a state of central neuronal hyperexcitability, especially in the spinal cord dorsal horn, that develops after injury. We hypothesize that the neuronal structures near the spinal cord injury site may be an important pain generator, and intraspinal microstimulation (ISMS) may normalize dorsal horn neuronal hyperexcitability and hence alleviate SCI pain. Specifically, ISMS may induce frequency-dependent conduction block on axons of afferent sensory neurons, in the spinothalamic tract and Lissauer's tract. ISMS may also facilitate primary afferent depolarization that elicits presynaptic inhibition of incoming afferent inputs. Together, these actions will reduce abnormal afferent inputs and ascending pain signals before they can reach the brain. Furthermore, ISMS may directly induce inhibitory postsynaptic potentials in dorsal horn neurons, and trigger the release of endogenous inhibitory neurotransmitters, opioids and serotonin to inhibit postsynaptic neurons and restore the compromised segmental pain inhibition after SCI. Finally, ISMS may alter the frequency and pattern of discharge such that the rostrally conducted impulses no longer code pain or activate brain areas concerned with pain signaling. Based on recent progress in understanding spinal learning and plasticity, we also postulate that repetitive or long-term ISMS may help the dorsal horn "reset" neuronal excitability and regain normal pain processing for a prolonged period. By finely tuning the stimulation parameters (e.g., intensity, pulse width, frequency), position, and geometry of ISMS electrode, multiple spinal structures (e.g., dorsal horn, dorsal column, spinothalamic tract) may be modulated to induce synergistic pain inhibition. Our hypothesis can be readily tested in preclinical models of SCI pain by using a combination of in vivo electrophysiological (neuronal activity) and animal behavioral (pain response) approaches. Since ISMS electrodes stimulate the spinal structures directly, we expect that the effective stimulus intensity and energy consumption can be lower than that for epidural spinal cord stimulation. The proposed hypothesis may provide insights and rationales for developing a novel neurostimulation pain therapy by directly inhibiting the pain generators in the spinal cord, and ISMS may be an alternative strategy to treat SCI pain. PMID- 28673599 TI - Iron chelation as novel treatment for lung inflammation in cystic fibrosis. AB - Cystic fibrosis (CF) is an autosomal recessive genetic disorder that results in defective cystic fibrosis transmembrane conductance regulator (CFTR) protein expression and function in various tissues. The leading cause of CF mortality and morbidity is the progressive destruction of the lungs due to recurrent infections and chronic inflammation. CFTR defect also affects immune cells, including neutrophils, resulting in ineffective, severe and persistent inflammatory response. Since unopposed recruitment of neutrophils significantly contributes to lung tissue damage through the generation of reactive oxygen species (ROS), we hypothesize that the administration of iron chelators could serve as a novel treatment to attenuate chronic inflammation in CF lungs since iron is significantly involved in ROS production by neutrophils. Ideally, the iron chelator should sequester host iron effectively, prevent bacterial access to chelator-bound iron and penetrates lung tissues efficiently, e.g. by inhalational route of administration. PMID- 28673600 TI - On the chemotherapeutic agents localization in tissue by means of snake venoms. AB - The efficiency of anti-tumour drug strongly depends on its dose. Higher drug doses and exposure times usually result in better treatment. It is why the implementation of high-dose treatment is always attractive. However, most of the drug delivery techniques meet essential limitations. In isolated regional perfusion a tumour can be exposed to high-dose therapeutic influence but the target organ may be isolated from the rest of circulatory system only for a relatively short period of time. During systemic injection of anti-tumour agents dose limitations are dictated by side toxicity danger. Viperidae venoms are known to cause local stagnation of blood flow and blood-tissue exchange processes in the place of snakebite. In present paper we suggest to use Viperidae snake venoms in addition to anti-tumour drugs for regional anti-cancer therapy. We suppose that Viperidae venoms will assist in drug localization. We state that their usage will help in high-dosage therapy implementation. PMID- 28673601 TI - Femoroacetabular impingement causes osteoarthritis of the hip by migration and micro-instability of the femoral head. AB - Femoroacetabular impingement is the condition whereby parts of the proximal femur mechanically collide with the acetabular rim leading to adjacent and contrecoup acetabular damage. Evidence is growing that at least for cam impingement, and perhaps less so for pincer impingement, there is a relation to the development of osteoarthritis. It has been demonstrated that surgery for impingement can improve function and decrease pain. Intuitively, it would then make sense that surgical intervention would prevent further degeneration. However, available literature to date cannot assure that it does. Therefore, the impingement itself seems not a sufficient cause to consistently cause osteoarthritis. For many years we have observed a phenomenon whereby the femoral head 'migrates' anteriorly and superiorly in the acetabulum in patients with cam impingement. The same, but less constant, can be observed in pincer impingement, where the head may migrate posteriorly and medially. Migration of the femoral head is known in the literature and seen as caused by, or as part of, osteoarthritis of the hip. We suggest that the migration is caused by the impingement, and that the femoral head wanders into the impingement-related area with cartilage damage. In cam impingement this may be anterolateral, in pincer impingement posteromedial. The effect must be a huge increase in compression forces, especially in cam impingement. The migration may even lead to, or be a sign of, micro-instability of the femoral head in the acetabulum, which may produce an increase in shear forces. We therefore hypothesise that impingement may lead to osteoarthritis by means of migration and the possible existence of micro-instability of the femoral head. Detecting and quantifying these phenomena seem of uttermost importance and may add a new dimension to conservative hip surgery. PMID- 28673602 TI - Platelet rich plasma as a minimally invasive approach to uterine prolapse. AB - Pelvic organ prolapse (POP) is a major health problem that affects many women with potentially severe physical and psychological impact as well as impact on their daily activities, and quality of life. Several surgical techniques have been proposed for the treatment of POP. The FDA has published documents that refer to concerns about the use of synthetic meshes for the treatment of prolapse, in view of the severe complications that may occur. These led to hesitancy in use of these meshes and partial increase in use of other biological grafts such as allografts and xenografts. Although there seems to be an increasing tendency to use grafts in pelvic floor reconstructive procedures due to lower risks of erosion than synthetic meshes, there are inconclusive data to support the routine use of biological grafts in pelvic organ prolapse treatment. In light of these observations new strategies are needed for the treatment of prolapse. Platelet rich plasma (PRP) is extremely rich in growth factors and cytokines, which regulate tissue reconstruction and has been previously used in orthopaedics and plastic surgery. To date, however, it has never been used in urogynaecology and there is no evidence to support or oppose its use in women who suffer from POP, due to uterine ligament defects. PRP is a relatively inexpensive biological material and easily produced directly from patients' blood and is, thus, superior to synthetic materials in terms of potential adverse effects such as foreign body reaction. In the present article we summarize the existing evidence, which supports the conduct of animal experimental and clinical studies to elucidate the potential role of PRP in treating POP by restoring the anatomy and function of ligament support. PMID- 28673603 TI - Abdominal Applications of a Novel Detector-Based Spectral CT. AB - Detector-based spectral computed tomography (SDCT) is a recently introduced technology that uses a single x-ray tube and 2 layers of detectors to simultaneously collect low- and high-energy data. In this article, we provide an overview of this novel SDCT technology in abdominal imaging. Several applications of SDCT in abdominal imaging are discussed and illustrated, along with a brief description of current literature on the status of dual-energy computed tomography in these applications. This includes urinary calculus composition, characterization of masses (renal, adrenal, hepatic, and others), tumor perfusion, improving vascular contrast, improving lesion conspicuity, decreasing artifacts, and reducing radiation dose. PMID- 28673604 TI - No change in patellar height following open wedge high tibial osteotomy using a novel femur-referenced measurement method. AB - BACKGROUND: Open wedge high tibial osteotomy (HTO) can influence the tibial slope and thereby the landmarks of currently used patellar height indices. The purpose of this retrospective study was to compare and validate a new femur-referenced patella height measurement method to currently used patellar height indices in a cohort of HTO patients. METHODS: Patellar height (Caton-Deschamps, Blackburne Peel and Insall-Salvati Indices and our newly developed Femoral Patellar Height Index) as well as tibial slope were analysed. Full-weight-bearing long-leg anteroposterior radiographs as well as anteroposterior and lateral radiographs of the knee in 0 degrees of extension were used. Radiographs were performed preoperatively, and at six weeks, three, six, 12 and 18months postoperatively. Measurements were recorded twice by two observers. The second observation was performed after a delay of three months. RESULTS: A total of 99 patients with a mean age of 46.2+/-8years were included. A statistically significant pre- to postoperative increase in tibial slope was found in all methods. Patellar height decreased according to Caton-Deschamps and Blackburne-Peel Indices. The Insall Salvati Index as well as the novel Femoral Patellar Height Index remained unchanged. Intra-rater (interclass correlation coefficient (ICC) 0.914-0.998) and inter-rater (ICC 0.955-0.989) reliability were highest in the new index. CONCLUSION: Detected changes of patellar height following open wedge HTO depend on the method used. Tibial slope increases following surgery. Our new index with a femoral reference for measuring patellar height was validated and good to excellent intra- and inter-rater reliability were demonstrated. Following HTO, the Femoral Patellar Height Index can be recommended as a standardized method to measure patellar height. PMID- 28673605 TI - Some additional remarks to the solution of the protein folding puzzle: Reply to comments on "There and back again: Two views on the protein folding puzzle". PMID- 28673606 TI - Evaluation of the Relative Validity and Test-Retest Reliability of a 15-Item Beverage Intake Questionnaire in Children and Adolescents. AB - BACKGROUND: Added sugar intake, in the form of sugar-sweetened beverages (SSBs), may contribute to weight gain and obesity development in children and adolescents. A valid and reliable brief beverage intake assessment tool for children and adolescents could facilitate research in this area. OBJECTIVE: The purpose of this investigation was to evaluate the relative validity and test retest reliability of a 15-item beverage intake questionnaire (BEVQ) for assessing usual beverage intake in children and adolescents. DESIGN: This cross sectional investigation included four study visits within a 2- to 3-week time period. PARTICIPANTS/SETTING: Participants (333 enrolled; 98% completion rate) were children aged 6 to 11 years and adolescents aged 12 to18 years recruited from the New River Valley, VA, region from January 2014 to September 2015. Study visits included assessment of height/weight, health history, and four 24-hour dietary recalls (24HRs). The BEVQ was completed at two visits (BEVQ 1, BEVQ 2). MAIN OUTCOME MEASURES: To evaluate relative validity, BEVQ 1 was compared with habitual beverage intake determined by the averaged 24HR. To evaluate test-retest reliability, BEVQ 1 was compared with BEVQ 2. STATISTICAL ANALYSES PERFORMED: Analyses included descriptive statistics, independent sample t tests, chi2 tests, one-way analysis of variance, paired sample t tests, and correlational analyses. RESULTS: In the full sample, self-reported water and total SSB intake were not different between BEVQ 1 and 24HR (mean differences 0+/-1 fl oz and 0+/-1 fl oz, respectively; both P values >0.05). Reported intake across all beverage categories was significantly correlated between BEVQ 1 and BEVQ 2 (P<0.001). In children (n=126), reported intake of milk and energy (in kilocalories) for total beverages was not different (all P values >0.05) between BEVQ 1 and 24HR (mean differences: whole milk=3+/-4 kcal, reduced-fat milk=9+/-5 kcal, and fat-free milk=7+/-6 kcal, which is 7+/-15 total beverage kilocalories). In adolescents (n=200), water and SSB kilocalories were not different (both P values >0.05) between BEVQ 1 and 24HR (mean differences: -1+/-1 fl oz and 12+/-9 kcal, respectively). CONCLUSIONS: A 15-item BEVQ provides results that are similar relative to multiple 24HRs for determining habitual milk and total beverage intake in children, and water and SSB intake in adolescents. The 15-item BEVQ is a reliable indicator of habitual beverage intake in both children and adolescents. Future studies could explore whether adjustments to BEVQ beverage categories, portion size, and format could improve the tool's ability to measure beverage intake in young populations. PMID- 28673607 TI - Nanoparticle formulations to enhance tumor targeting of poorly soluble polyphenols with potential anticancer properties. AB - Polyphenols have been extensively studied for their relevant anticancer activity. Quite often however their instability, extensive metabolization, low bioavailability and poor solubility limit their application in cancer prevention and therapy. Formulation in nanoparticles has been widely proposed as a means to overcome these limits, maximize localization and specific activity at tumor site. The present review is intended as an update of literature regarding nanoparticulate carriers aimed to deliver polyphenols to the cancer site. Three molecules were chosen, all of which were hydrophobic and poorly soluble, representative of different polyphenol classes: quercetin (QT) among the flavonoid group, curcumin (CUR) as representative of curcuminoids, and resveratrol (RSV) among the stilbenes. In particular, nanoparticulate systems suitable for poorly soluble drugs will be described and attention will be paid to characteristics designed to improve tumor targeting, specific delivery and interaction with tumor cells. PMID- 28673608 TI - Mitochondrial biology in cancer stem cells. AB - Cancer stem cells (CSCs) have been suggested to be responsible for tumor re growth and relapse. Physiological and morphological knowledge of CSCs may be essential for the development of new therapeutic strategies targeting cancer development, progression, and recurrence. Current research is focused on a deeper understanding of CSCs metabolic profiles, taking into consideration their energy demands. Energy metabolism and mitochondrial function are important factors operating on stemness maintenance and cell fate specification. Due to the role of mitochondria as central hubs in the overall cell metabolism and death and survival pathways, research on their physiology in CSCs is of paramount importance to decipher mechanisms underlying their therapy-resistant phenotype. In this review, we focus on CSCs mitochondrial biology and mitochondria-related signaling pathways that contribute to CSCs survival and maintenance, thereby representing possible therapeutic targets. PMID- 28673609 TI - Strong synergism of dexamethasone in combination with fluconazole against resistant Candida albicans mediated by inhibiting drug efflux and reducing virulence. AB - Candida albicans is the most commonly isolated Candida spp. in the clinic and its resistance to fluconazole (FLC) has been emerging rapidly. Combination therapy may be a potentially effective approach to combat drug resistance. In this study, the combination antifungal effects of dexamethasone (DXM) and FLC against resistant C. albicans in vitro were assayed using minimum inhibitory concentrations (MICs), sessile MICs and time-kill curves. The in vivo efficacy of this drug combination was evaluated using a Galleria mellonella model by determining survival rate, fungal burden and histological damage. In addition, the impact of DXM on efflux pump activity was investigated using a rhodamine 6G assay. Expression of CDR1, CDR2 and MDR1 was determined by real-time quantitative PCR, and extracellular phospholipase activity was detected by the egg yolk agar method to reveal the potential synergistic mechanism. The results showed that DXM potentiates the antifungal effect of FLC against resistant C. albicans strains both in vitro and in vivo, and the synergistic mechanism is related to inhibiting the efflux of drugs and reducing the virulence of C. albicans. PMID- 28673610 TI - Clinical efficacy, cost analysis and patient acceptability of outpatient parenteral antibiotic therapy (OPAT): a decade of Sheffield (UK) OPAT service. AB - Outpatient parenteral antimicrobial therapy (OPAT) has evolved relatively slowly in the UK. This study describes the OPAT service based in a large UK teaching hospital in Sheffield, and examines the clinical efficacy, patient acceptability and costs saved over a 10-year period. Data on 3812 episodes of OPAT administered between January 2006 and January 2016 were retrieved from a prospectively maintained electronic database. This study compared the real costs of the OPAT service with estimated costs of conventional inpatient care for these patient episodes, and analysed patient feedback questionnaires that were administered randomly between January 2014 and January 2015. A wide range of infections were managed during the 10-year period. Skin and soft tissue infections accounted for 57% of OPAT episodes. The total number of bed-days saved was 49,854. A successful outcome (cure or improvement) was found in 3357 (88%) episodes. Re-admission occurred in 265 (7%) episodes. The rates of healthcare-associated infections were low: 15 intravenous-line-related infections were recorded (0.3 per 1000 OPAT patient-days). Patient acceptance and satisfaction with OPAT were high. OPAT cost 15%, 39%, 40% and 44% of inpatient costs for an infectious diseases unit, national average costs, other departments (non-infectious diseases unit), and the minimum national average costs for each diagnostic category, respectively. This study shows that OPAT is safe, clinically efficacious and acceptable for treating a wide range of infections with high levels of patient satisfaction and substantial cost savings. PMID- 28673611 TI - Effects of curved-walking training on curved-walking performance and freezing of gait in individuals with Parkinson's disease: A randomized controlled trial. AB - INTRODUCTION: The purpose of this study was to investigate the effects of curved walking training (CWT) on curved-walking performance and freezing of gait (FOG) in people with Parkinson's disease (PD). METHODS: Twenty-four PD subjects were recruited and randomly assigned to the CWT group or control exercise (CE) group and received 12 sessions of either CWT with a turning-based treadmill or general exercise training for 30 min followed by 10 min of over-ground walking in each session for 4-6 weeks. The primary outcomes included curved-walking performance and FOG. All measurements were assessed at baseline, after training, and at 1 month follow-up. RESULTS: Our results showed significant improvements in curved walking performance (speed, p = 0.007; cadence, p = 0.003; step length, p < 0.001) and FOG, measured by a FOG questionnaire (p = 0.004). The secondary outcomes including straight-walking performance (speed, cadence and step length, p < 0.001), timed up and go test (p = 0.014), functional gait assessment (p < 0.001), Unified Parkinson's disease Rating Scale III (p = 0.001), and quality of life (p < 0.001) were also improved in the experimental group. We further noted that the improvements were maintained for at least one month after training (p < 0.05). CONCLUSION: A 12-session CWT program can improve curved-walking ability, FOG, and other measures of functional walking performance in individuals with PD. Most of the improvements were sustained for at least one month after training. PMID- 28673612 TI - Central and systemic C-type Natriuretic Peptide are both reduced in Parkinson's Disease. AB - INTRODUCTION: C-type Natriuretic Peptide is a neuropeptide widely expressed in the central nervous system including dopaminergic neurons projecting to basal ganglia. Previous work shows that concentrations of the peptide in cerebrospinal fluid are depressed in drug naive PD subjects, decline over time and can be restored by doses of monoamine oxidase inhibitors that delay the need for levodopa. Whether plasma levels are similarly depressed in drug naive subjects, or affected by dopaminergic drugs, is unknown. Our objectives were to determine whether (i) peptide products in plasma differ from normal in PD, and (ii) levels are affected by dopaminergic treatment. METHODS: Plasma C-type Natriuretic Peptide and amino-terminal proCNP were measured in two groups - 27 drug naive subjects with PD, and 30 subjects stabilized on dopaminergic drugs for at least 3 years. Values were compared with standard deviation scores from a population reference group without neurological disorder. Independent associations with predetermined variables known to affect plasma concentrations were assessed by multivariate analysis. RESULTS: In both PD groups, plasma amino-terminal proCNP was significantly depressed compared to the reference range. Concentrations did not differ between the two groups. No correlation with disease duration or phenotype was found. Across all subjects, in a model initially comprising 7 factors, serum creatinine, PD and age were independent significant associations with amino-terminal proCNP. CONCLUSIONS: Plasma concentrations of amino-terminal proCNP are depressed in PD, are likely to result from diminished reabsorption from central sources, and may be useful in monitoring onset and effects of therapeutic interventions in PD. PMID- 28673613 TI - Parkinsonism and other movement disorders in 23 cases of neurocysticercosis. AB - INTRODUCTION: Parkinsonism and other movement disorders have been occasionally described in neurocysticercosis (NCC) but their clinical features and pathogenesis are not well understood. METHODS: This is a descriptive study conducted over 20 years. We studied 590 consecutive patients from the NCC Registry at Eugenio Espejo Hospital, Quito, Ecuador, and found 23 subjects who developed movement disorders. We investigated the clinical features, localization of brain lesions, severity of infection and neurological deficit as well as the outcome of the patients. Patients were treated with albendazole, dexamethasone, acetazolamide and surgery. We established the diagnosis of NCC, by absolute, imaging and clinical/exposure criteria. RESULTS: Fifteen patients had parkinsonism, 5 tremor, 2 dystonia and 1 chorea. Patients with chorea and dystonia were young females and had cystic lesions in the thalamus and putamen, respectively. Parkinsonism was more frequent in middle aged subjects with subarachnoid and ventricular cysts, hydrocephalus, brain cysts and frequently abnormal cerebrospinal fluid. After anthelmintic treatment no patient died and all patients with chorea, dystonia and tremor fully recovered; 7 of the 15 patients with parkinsonism required treatment with steroids, surgery and long term l-DOPA therapy. CONCLUSIONS: Chorea and dystonia in NCC are due to selective lesions of the basal ganglia. Parkinsonism, the most common movement disorder in NCC, is not related to specific localization of the lesions but the patients show widespread and large lesions, associated with inflammation and distortions of brain structures. In patients with NCC, chorea, dystonia, tremor have a better prognosis, Parkinsonism has a worse one. PMID- 28673615 TI - HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles. AB - Viruses are known to exploit the autophagic machinery for their own benefit. In case of the hepatitis C virus autophagy is induced. As autophagy serves as a degradation pathway to maintain cellular homeostasis, it is activated in response to cellular stress such as elevated levels of reactive oxygen species (ROS). Elevated levels of ROS trigger phosphorylation of the autophagic adaptor protein p62 on Ser349 (pS[349] p62) that is involved in the induction of autophagy. Consequently, pS[349] p62 binds with a higher affinity to Keap1 thereby releasing Nrf2 from the complex with Keap1. Although the released Nrf2 should induce as a heterodimer with the sMaf proteins the expression of Nrf2/ARE-dependent genes, in HCV-positive cells no activation of cytoprotective genes occurs even though elevated amounts of pS[349] p62 are present. In HCV-positive cells, free Nrf2 is trapped via delocalized sMaf proteins at the replicon complexes on the cytoplasmic face of the ER and is therefore prevented from its entry into the nucleus. Scavenging of ROS leads to decreased levels of pS[349] p62 and impaired induction of autophagy. Both, inhibition of autophagy and scavenging of ROS result in decreased amounts of released viral particles. Taken together, these data identify an intricate mechanism of HCV-dependent inhibition of Nrf2/ARE mediated gene expression which counteracts pS[349] p62-induced activation of Nrf2. Thereby elevated ROS-levels are preserved that in turn activate autophagy to favor HCV particle release. PMID- 28673614 TI - ROS-dependent activation of RhoA/Rho-kinase in pulmonary artery: Role of Src family kinases and ARHGEF1. AB - The role of reactive oxygen species (ROS) in smooth muscle contraction is poorly understood. We hypothesised that G-protein coupled receptor (GPCR) activation and hypoxia induce Rho-kinase activity and contraction in rat intra-pulmonary artery (IPA) via stimulation of ROS production and subsequent Src-family kinase (SrcFK) activation. The T-type prostanoid receptor agonist U46619 induced ROS production in pulmonary artery smooth muscle cells (PASMC). U46619 also induced c-Src cysteine oxidation, SrcFK auto-phosphorylation, MYPT-1 and MLC20 phosphorylation and contraction in IPA, and all these responses were inhibited by antioxidants (ebselen, Tempol). Contraction and SrcFK/MYPT-1/MLC20 phosphorylations were also inhibited by combined superoxide dismutase and catalase, or by the SrcFK antagonist PP2, while contraction and MYPT-1/MLC20 phosphorylations were inhibited by the Rho guanine nucleotide exchange factor (RhoGEF) inhibitor Y16. H2O2 and the superoxide-generating quinoledione LY83583 both induced c-Src oxidation, SrcFK auto-phosphorylation and contraction in IPA. LY83583 and H2O2 induced contractions were inhibited by PP2, while LY83583-induced contraction was also inhibited by antioxidants and Y16. SrcFK auto-phosphorylation and MYPT 1/MLC20 phosphorylation was also induced by hypoxia in IPA and this was blocked by mitochondrial inhibitors rotenone and myxothiazol. In live PASMC, sub-cellular translocation of RhoA and the RhoGEF ARHGEF1 was triggered by both U46619 and LY83583 and this translocation was blocked by antioxidants and PP2. RhoA translocation was also inhibited by an ARHGEF1 siRNA. U46619 enhanced ROS dependent co-immunoprecipitation of ARHGEF1 with c-Src. Our results demonstrate a link between GPCR-induced cytosolic ROS or hypoxia-induced mitochondrial ROS and SrcFK activity, Rho-kinase activity and contraction. ROS and SrcFK activate RhoA via ARHGEF1. PMID- 28673617 TI - Recent findings on phenoloxidases in bivalves. AB - The production of melanin is a complex process involving biochemical cascades, such as the pro-phenoloxidase (proPO) system, and enzymes, such as phenoloxidases (POs). Different studies have shown a strong correlation between the decrease in PO activities and the occurrence of diseases in bivalve invertebrates, leading to mortalities in the host. Results of these studies suggest that POs could play a fundamental role in defense mechanisms in bivalves. This article reviews the fundamental knowledge on the proPO system in bivalves and the methods used to assess PO activities. Finally, this is the first report on the major findings of laboratory and field studies that indicate that a type of PO in bivalves, the laccase enzyme, is inducible and involved in the 1) immune 2) antioxidant and 3) detoxification roles in bivalves, and might be an ecological potential biomarker of environmental stress. PMID- 28673616 TI - Mapping the Universe of RNA Tetraloop Folds. AB - We report a map of RNA tetraloop conformations constructed by calculating pairwise distances among all experimentally determined four-nucleotide hairpin loops. Tetraloops with similar structures are clustered together and, as expected, the two largest clusters are the canonical GNRA and UNCG folds. We identify clusters corresponding to known tetraloop folds such as GGUG, RNYA, AGNN, and CUUG. These clusters are represented in a simple two-dimensional projection that recapitulates the relationship among the different folds. The cluster analysis also identifies 20 novel tetraloop folds that are peculiar to specific positions in ribosomal RNAs and that are stabilized by tertiary interactions. In our RNA tetraloop database we find a significant number of non GNRA and non-UNCG sequences adopting the canonical GNRA and UNCG folds. Conversely, we find a significant number of GNRA and UNCG sequences adopting non GNRA and non-UNCG folds. Our analysis demonstrates that there is not a simple one to-one, but rather a many-to-many mapping between tetraloop sequence and tetraloop fold. PMID- 28673619 TI - Performing Hand Surgery Under Local Anesthesia Without a Tourniquet in China. AB - In China, wide-awake surgeries are increasingly used by surgeons in a growing number of hospitals for hand and upper extremity surgeries. Experience suggests that wide-awake surgery is safe, economical, and patient-friendly, optimizing hospital resource allocation and increasing efficiency. This article discusses which procedures are most suitable, variations in procedures, departmental impacts, and future direction. PMID- 28673618 TI - Extracorporeal Membrane Oxygenation and Interfacility Transfer: A Regional Referral Experience. AB - BACKGROUND: The number of adults referred to high-volume centers for extracorporeal membrane oxygenation (ECMO) is increasing. Outcomes of patients requiring transport are not well characterized, and referral guidelines are lacking. This study describes the experience and outcomes of a single high-volume center. METHODS: A retrospective study was performed that included adults undergoing ECMO between June 2009 and December 2015. Patient characteristics and outcomes were acquired from the medical record. Logistic regression was used to identify predictors of survival to hospital discharge. The Kaplan-Meier method was used to depict rates of survival. RESULTS: Of 133 patients, 77 (57.9%) underwent venoarterial (VA) ECMO and 56 (42.1%) underwent venovenous (VV) ECMO. Median transport distance was 88.8 miles (range 0.2-1,434 miles). Median duration of support was 6 days (range, 1-32.5 days). Age older than 60 years, pulmonary hypertension, and body mass index (BMI) greater than 30 were associated with worse survival to discharge for VA ECMO; a history of hypertension and presence of left ventricular (LV) vent were associated with better survival. Age older than 60 years and diabetes were associated with worse survival to hospital discharge for VV ECMO. Survival to decannulation was 66.2% and 76.8%, and to hospital discharge it was 48.1% and 69.6% for VA and VV ECMO, respectively. Of hospital survivors, Kaplan-Meier estimates of 1-year survival were 82.4% and 95.5% for VA and VV, respectively. CONCLUSIONS: Outcomes are favorable after transport to high-volume ECMO centers. Guidelines and infrastructure for short- and long-distance ECMO transport is imperative for the efficient and successful management of these patients. PMID- 28673620 TI - Microsurgical Flaps in Repair and Reconstruction of the Hand. AB - The authors' strategy for soft-tissue coverage of the hand is presented. The concept of replacing like with like and reconstruction with similar adjacent tissue enhances functional and aesthetic outcomes. In this viewpoint, the pedicle perforator flap is an ideal flap. A decision-making algorithm to select an ideal flap for a particular hand defect is challenging, requiring experiential consideration of functional outcome, appearance, donor-site morbidity, and patient satisfaction. To assist surgeons in determining the most appropriate flap with more evidence, studies are necessary to compare the outcomes of each flap by evaluating hand function, aesthetics, donor site morbidity, and patient satisfaction. PMID- 28673621 TI - Technical Points of 5 Free Vascularized Flaps for the Hand Repairs. AB - In this article, we present the experiences from Chinese microsurgeons on 5 less commonly used free vascularized flaps in hand reconstruction. In many units in China, these flaps have become the mainstays of treatment; they are routinely used for fingertip and thumb reconstruction. Their combined experience has demonstrated the reliability and versatility of these flaps for hand reconstruction, as well as their cosmetic value. PMID- 28673622 TI - Strong Digital Flexor Tendon Repair, Extension-Flexion Test, and Early Active Flexion: Experience in 300 Tendons. AB - Over the past 2 decades, repair and rehabilitation methods of primary repair of the digital flexor tendon have changed. In this article, we outline interim results from ongoing investigations in several units. Surgeons in these units now perform digital flexor tendon repairs according to a treatment protocol. Before adopting the protocol, they had no history of tendon-related research; they had not used any of the repair and rehabilitation methods described in the protocol. The surgeons involved are junior or midlevel attending surgeons. At the end of this article, we outline current practice of digital flexor tendon repair in Asian countries. PMID- 28673623 TI - Primary Flexor Tendon Repair with Early Active Motion: Experience in Europe. AB - The protocol for primary flexor tendon repair in zones 1 and 2 of the hand is changing. This article discusses recent changes. Immediate repair within 48 hours is performed whenever possible. A 6-strand core suture is performed using the M modification of Tang's technique. The pulleys are divided to allow free excursion of the repaired tendon within the tendon sheath. To avoid repaired structures within the sheath being too bulky, the authors generally repair only half of the flexor digitorum superficialis. In some cases, the flexor digitorum superficialis is excised completely. Rehabilitation remains based on controlled active motion. PMID- 28673624 TI - The Nonoperative Management of Hand Fractures in United Kingdom. AB - Hand fractures (excluding small avulsion fractures and scaphoid fractures) almost always unite with bone. The role of the hand surgeon is not to achieve bone union but to achieve stability in an adequate position, often with some displacement, and maintenance of good soft tissue gliding. This article establishes that many fractures treated operatively do no better and often could not realistically do better than with good nonoperative treatment. Yet many are treated surgically to satisfy surgical egos, the desire to produce excellent radiographs, or just the mistaken belief that current surgical techniques can improve on nonoperative treatment. PMID- 28673625 TI - Current European Practice in the Treatment of Proximal Interphalangeal Joint Arthritis. AB - There are increasing numbers of proximal interphalangeal (PIP) arthroplasties performed in Europe. Meanwhile, most surgeons prefer arthroplasty over arthrodesis. Silastic arthroplasties remain the most widely used implants. The main disadvantage of the Silastic implants is the limited stability they provide. Correction of pre-existing deformation is difficult. Soft tissue handling and postoperative scarring have an influence on the results of PIP arthroplasty. Different surgical approaches are possible. The most popular approach in Europe is dorsal. Different surface replacement implants are on the market in Europe. The main advantage of these implants is the lateral stability provided through their more anatomic form. PMID- 28673626 TI - Treatment of Scaphoid Fractures: European Approaches. AB - Scaphoid fractures account for 2% of all fractures. In Europe, the incidence is 12.4/100,000/y. This article focuses on the European perspective on understanding and management of these injuries. These fractures occur in young, active patients. The aim of treatment is union. Osteoarthritis is almost inevitable if the fracture does not unite. Cast immobilization is the treatment of choice in occult or stable fractures with 90% to 95% healing. Acute/primary surgery may be considered in some patients. The European literature stresses the importance of taking the patient's wishes into consideration after careful counseling about alternative treatment methods. PMID- 28673627 TI - Carpal Ligaments: A Functional Classification. AB - Recent laboratory research has disclosed that carpal ligaments exhibit different kinetic behaviors depending on the direction and point of application of the forces being applied to the wrist. The so-called helical antipronation ligaments are mostly active when the wrist is axially loaded, whereas the helical antisupination ligaments constrain supination torques to the distal row. This novel way of interpreting the function of the carpal ligaments may help in developing better strategies to treat carpal instabilities. PMID- 28673628 TI - Current European Practice in Wrist Arthroplasty. AB - The results of wrist arthroplasty for severely destroyed and painful wrists are generally good in pain reduction, increased grip strength, and upper limb function. The wrist range of motion is usually preserved but not improved. Implant survival seems better than it was with earlier implant designs; however, there are problems of carpal component loosening. Patient selection plays an important role, requiring experience, careful patient information, and discussing the pros and cons of arthroplasty and partial or total wrist arthrodesis. PMID- 28673629 TI - Treatment of Intra-articular Distal Radius Fractures. AB - This review of current literature discusses the morphology of the volar aspect of the distal radius; the surgical procedure, arthroscopic findings, and clinical results of a plate presetting and arthroscopic reduction technique for acute intra-articular fractures; and a novel simulation guidance system for malunited intra-articular fractures. Classification of intra-articular distal radius fractures is also discussed, focusing on central depression fracture fragments, associated soft tissue injuries, and results for measuring scapholunate distances at different sites. Problems of the distal radioulnar joint are reviewed, in particular, functional outcomes of the authors' prospective cohort study on unstable intra-articular fractures involving the distal radioulnar joint. PMID- 28673630 TI - Peripheral Nerve Defects: Overviews of Practice in Europe. AB - Many surgical techniques are available for the repair of peripheral nerve defects. Autologous nerve grafts are the gold standard for most clinical conditions. In selected cases, alternative types of reconstructions are performed to fill the nerve gap. Non-nervous autologous tissue-based conduits or synthetic ones are alternatives to nerve autografts. Allografts represent another new field of interest. Decision making in the treatment of nerve defects is based on timing of referral, level of the injury, type of lesion, and size of any gap. This review focuses on current clinical practice, influenced by the numerous new experimental researches. PMID- 28673631 TI - Mobilization of Joints of the Hand with Symphalangism. AB - This article classifies symphalangism of the hand into three grades and suggests surgical indications. Grade I and early grade II joints can be mobilized with early surgical intervention. Surgical results may vary but even a 20 degrees gain in motion could be helpful for children and their parents. Postoperative passive range-of-motion exercises are very important in maintaining mobility of the joints. It is important that the parents understand exercise may cause some pain and they must be motivated to help their children during the rehabilitation period. PMID- 28673632 TI - Common Hand Problems with Different Treatments in Countries in Asia and Europe. AB - Common hand problems are treated differently in different countries. This article attempts to bring together the views of surgeons from different countries on some of the most common hand problems that hand surgeons encounter in daily practice. In practice, the correct treatment of these problems may be the most important and influential to patients. PMID- 28673633 TI - Evolution and Current Status of Hand Surgery Practice in Asia and Europe. PMID- 28673634 TI - Orthogonality measurements for multidimensional chromatography in three and higher dimensional separations. AB - Orthogonality metrics (OMs) for three and higher dimensional separations are proposed as extensions of previously developed OMs, which were used to evaluate the zone utilization of two-dimensional (2D) separations. These OMs include correlation coefficients, dimensionality, information theory metrics and convex hull metrics. In a number of these cases, lower dimensional subspace metrics exist and can be readily calculated. The metrics are used to interpret previously generated experimental data. The experimental datasets are derived from Gilar's peptide data, now modified to be three dimensional (3D), and a comprehensive 3D chromatogram from Moore and Jorgenson. The Moore and Jorgenson chromatogram, which has 25 identifiable 3D volume elements or peaks, displayed good orthogonality values over all dimensions. However, OMs based on discretization of the 3D space changed substantially with changes in binning parameters. This example highlights the importance in higher dimensions of having an abundant number of retention times as data points, especially for methods that use discretization. The Gilar data, which in a previous study produced 21 2D datasets by the pairing of 7 one-dimensional separations, was reinterpreted to produce 35 3D datasets. These datasets show a number of interesting properties, one of which is that geometric and harmonic means of lower dimensional subspace (i.e., 2D) OMs correlate well with the higher dimensional (i.e., 3D) OMs. The space utilization of the Gilar 3D datasets was ranked using OMs, with the retention times of the datasets having the largest and smallest OMs presented as graphs. A discussion concerning the orthogonality of higher dimensional techniques is given with emphasis on molecular diversity in chromatographic separations. In the information theory work, an inconsistency is found in previous studies of orthogonality using the 2D metric often identified as %O. A new choice of metric is proposed, extended to higher dimensions, characterized by mixes of ordered and random retention times, and applied to the experimental datasets. In 2D, the new metric always equals or exceeds the original one. However, results from both the original and new methods are given. PMID- 28673635 TI - Chymase inhibitor prevents the development and progression of non-alcoholic steatohepatitis in rats fed a high-fat and high-cholesterol diet. AB - The effect of the chymase inhibitor TY-51469 on the development and progression of non-alcoholic steatohepatitis (NASH) was evaluated in rats fed a high-fat and high-cholesterol (HFC) diet. To evaluate the preventive effect of TY-51469 on the development of NASH, stroke-prone spontaneously hypertensive rat 5 (SHRSP5)/Dmcr rats were fed either a normal or HFC diet for 8 weeks, and concurrently administered either placebo or TY-51469 (1 mg/kg per day). To evaluate the effect of TY-51469 on the survival rate, TY-51469 was administered either concurrently with HFC diet (pretreated group) or 8 weeks after HFC diet at which point NASH had developed (posttreated group). Eight weeks after HFC diet, significant increases of steatosis, fibrosis and chymase-positive cells were observed in liver from the placebo-treated rats. Significant increases of myeloperoxidase, transforming growth factor-beta, matrix metalloproteinase-9, and collagen I mRNA levels were also observed. However, all parameters were significantly attenuated in the TY-51469-treated group. A survival rate of the placebo-treated group fed the HFC diet was 0% at 14 weeks. In comparison, the rates of TY-51469-pretreated and TY-51469-posttreated groups were 100% and 50% at 14 weeks, respectively. Chymase inhibitor may be applicable to preventing the development and progression of NASH. PMID- 28673636 TI - Bariatric surgery: Are we responsible but not guilty? PMID- 28673637 TI - Premenopausal women with early breast cancer treated with estradiol suppression have severely deteriorated bone microstructure. AB - BACKGROUND: In premenopausal women with early estrogen-receptor-positive breast cancer, combined ovarian suppression and aromatase inhibition reduce estradiol production precipitously. The resulting unbalanced and rapid bone remodelling replaces older bone with less bone that is less fully mineralized. We hypothesized that these changes result in severe microstructural deterioration and reduced matrix mineralization density. METHODS: Images of the distal radius and distal tibia were acquired using high-resolution peripheral quantitative computed tomography in a cross-sectional study of 27 premenopausal women, mean age 43.3years (range 30.4 to 53.7) with early breast cancer made estradiol deficient for 17months (range 6-120) using ovarian suppression and aromatase inhibition, 42 healthy age-matched premenopausal and 35 postmenopausal controls, mean age 62.6years (range 60.2 to 65.5). Cortical and trabecular microstructure were quantified using Strax software. RESULTS: Compared with premenopausal controls, the women with breast cancer had 0.75 SD (95% CI 0.21 to 1.29) lower distal radial trabecular bone volume due to 1.29 SD (0.71 to 1.87) fewer trabeculae. Cortical porosity was 1.25 SD (0.59 to 1.91) higher but cortical thickness was not reduced. Compared with postmenopausal controls 20years older, cases had comparable or lower trabecular bone volume and comparable cortical porosity and thickness. Matrix mineral density was 1.56 SD (0.90 to 2.22) lower than in premenopausal controls and 2.17 SD (1.50 to 2.84) lower than in postmenopausal controls. Results at the tibia were similar. CONCLUSION: The severe cortical porosity and trabecular deterioration associated with estradiol depletion and the longevity of premenopausal women with early breast cancer treated with endocrine therapy provide a compelling rationale to investigate the efficacy of antiresorptive therapy initiated at the time of breast cancer treatment. PMID- 28673638 TI - Effect of Percutaneous Edge-to-Edge Repair on Mitral Valve Area and Its Association With Pulmonary Hypertension and Outcomes. AB - Percutaneous edge-to-edge repair using the MitraClip system causes reduction in mitral valve area (MVA). However, its clinical impact is not fully elucidated. This study assessed the impact of postprocedural MVA reduction on pulmonary hypertension and outcomes. A total of 92 patients with grades 3 to 4 + mitral regurgitation (MR) who underwent MitraClip therapy were retrospectively reviewed. Using intraprocedural, 3-dimensional transesophageal echocardiography, postprocedural MVA was obtained by 2 optimized planes through the medial and lateral orifices of the repaired valve. MVA was reduced by 60.1% immediately after MitraClip procedure (p <0.001). Postprocedural MVA correlated moderately with mean transmitral pressure gradient (TMPG) in the majority of patients (r = 0.56, p <0.001), but discordance of MVA and TMPG was observed in 40% of patients. In multivariable linear regression analysis, postprocedural MVA <=1.94 cm2 was independently associated with a blunted decrease in systolic pulmonary artery pressure at 1-month follow-up (beta-estimate -4.63, 95% confidence interval -9.71 to -0.15, p = 0.042). Postprocedural MVA <=1.94 cm2 was an independent predictor of all-cause mortality and heart failure hospitalization after MitraClip (hazard ratio 4.28, 95% confidence interval 1.56 to 11.7, p = 0.005) even after adjustment for age, gender, atrial fibrillation, cause of MR, left ventricular systolic function, pre-existing pulmonary hypertension, and residual MR. After further adjustment for TMPG >=5 mm Hg, postprocedural MVA <=1.94 cm2 remained predictive for adverse outcomes (p = 0.048). In conclusion, the intraprocedural assessment of MVA by 3-dimensional transesophageal echocardiography can predict hemodynamic response and postprocedural prognosis after MitraClip therapy. PMID- 28673639 TI - Management and Outcome of Residual Aortic Regurgitation After Transcatheter Aortic Valve Implantation. AB - We aimed to evaluate the success rates of balloon valvuloplasty post-dilation (BVPD) and a second-valve deployment in reducing residual aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) and its impact on outcome. Residual AR immediately post-TAVI in patients with aortic stenosis is a common condition that adversely affects outcome. Patients who underwent TAVI who had more-than-mild residual AR were managed either with medical therapy, re intervention with BVPD, or a second valve. The clinical impact of these strategies was evaluated, and the anatomical features of patients with successful and unsuccessful intervention were compared. Among 572 patients with TAVI, 110 (19%) had significant residual AR after initial device deployment. Sixty patients were treated by BVPD (n = 49) or second-device deployment (n = 11), whereas 50 patients were treated medically. Successful reduction in residual AR to mild and below was achieved in 56% of the intervention group. Eccentric and calcified annuli were present in patients in whom residual AR remained despite re intervention (p = 0.004). Interventions to reduce residual AR were independently associated with improved survival compared with conservative medical therapy (hazard ratio 0.45, 95% confidence interval 0.94 to 0.21, p = 0.03). BVPD or a second valve were safe and were not associated with increased rate of periprocedural complications. In conclusion, both BVPD and a second-valve deployment to reduce residual AR post-TAVI are effective and safe. The success rates are inversely correlated with the annulus eccentricity and calcification. These measures should be encouraged to reduce acute residual AR as they are associated with improved long-term survival. PMID- 28673640 TI - Small tube thoracostomy (20-22 Fr) in emergent management of chest trauma. AB - BACKGROUND: The optimal tube size for an emergent thoracostomy for traumatic pneumothorax or hemothorax is unknown. Both small catheter tube thoracostomy and large-bore chest tube thoracostomy have been shown to work for the nonemergent management of patients with traumatic pneumothorax or hemothorax. This study was conducted to compare the efficacy of a small chest tube with that of a large tube in emergent thoracostomy due to chest trauma. Our hypothesis was that there would be no difference in clinical outcomes including tube-related complications, the need for additional tube placement, and thoracotomy, with the replacement of large tubes with small tubes. METHODS: A retrospective review of all patients with chest trauma requiring tube thoracostomy within the first 2h from arrival at our emergency department over a 7-year period was conducted. Charts were reviewed for demographic data and outcomes including complications and initial drainage output. Small chest tubes (20-22 Fr) were compared with a large tube (28 Fr). Our primary outcome was tube-related complications. Secondary outcomes included additional invasive procedures, such as additional tube insertion and thoracotomy. RESULTS: There were 124 tube thoracostomies (small: 68, large: 56) performed in 116 patients. There were no significant differences between the small- and large-tube groups with regard to age, gender, injury mechanism, systolic blood pressure, heart rate, and injury severity score. Both groups were similar in the posterior direction of tube insertion, initial drainage output, and the duration of tube insertion. There was no significant difference in the primary outcomes of tube-related complications, including empyema (small: 1/68 vs. large: 1/56; p=1.000) or retained hemothorax (small: 2/68 vs. large: 2/56; p=1.000). Secondary outcomes, including the need for additional tube placement (small: 2/68 vs. large: 4/56; p=0.408) or thoracotomy (small: 2/68 vs. large: 1/56; p=1.000), were also similar. CONCLUSION: For patients with chest trauma, emergent insertion of 20-22 Fr chest tubes has no difference in the efficacy of drainage, rate of complications, and need for additional invasive procedures compared with a large tube (28 Fr). PMID- 28673641 TI - Effective professional development strategies for dealing with issues men face in nursing. PMID- 28673642 TI - Utility of contrast-enhanced harmonic EUS for evaluating the effects of steroid therapy in a case of immunoglobulin G4-negative focal autoimmune pancreatitis. PMID- 28673643 TI - Sevelamer resin bezoar presenting as a cecal mass. PMID- 28673644 TI - Rectal metastases from malignant mucinous cystic neoplasm of the pancreas mimicking a rectal carcinoma. PMID- 28673645 TI - Evaluating the feasibility and acceptability of self-injection of subcutaneous depot medroxyprogesterone acetate (DMPA) in Senegal: a prospective cohort study. AB - OBJECTIVES: Expanding contraceptive options through self-injection may improve access and confidentiality. There are few published studies on contraceptive self injection in sub-Saharan Africa and none in West Africa, a region with high unmet need. This study was performed to assess feasibility of subcutaneous DMPA self injection in Senegal; objectives were to (1) measure the proportion of participants who self-injected competently 3 months after training, (2) measure the proportion who self-injected on time (defined conservatively as within 7 days of reinjection date), and (3) assess acceptability of self-injection. STUDY DESIGN: In this prospective cohort study, 378 women aged 18-49 years were trained to self-inject by study nurses. Three months later, women returned unprompted to the clinic to self-inject, and technique and visit timing were evaluated. Women continuing with a third self-injection were followed up at home after their next scheduled injection date. At each interaction, participants were interviewed to learn about their experience; additional questions during the final home visit focused on storage and disposal practices, and acceptability. RESULTS: Among the 337 participants followed up 3 months post-training, 310 self-injected, and 87% did so competently. Factoring in women who declined to self-inject, electing to have the provider administer the injection instead, a total of 80% [95% confidence interval (CI)=75-84%] self-injected competently 3 months post training, and 84% [95% CI=80-88%] reinjected on time, while 72% [95% CI=67-77%] were both on time and competent. The vast majority (93%) expressed a desire to continue. CONCLUSIONS: Self-injection is feasible and acceptable among most study participants in Senegal. IMPLICATIONS: These first research results on contraceptive self-injection in West Africa indicate initial feasibility and acceptability of the practice. Results underscore the importance of designing self-injection programs that empower and support women, including those with limited education. PMID- 28673646 TI - An investor perspective on forming and funding your medical device start-up. AB - Novel and transformative medical technologies of all forms have the potential to make a significant positive impact on the lives of patients and on the health care system, and one common pathway for guiding such innovations from concept through commercialization is via the formation of a company. For entrepreneurs looking to build a medical technology company, several common challenges await, including questions around how and where to raise funding. Here, we review key considerations for the formation of medical technology companies as viewed through the lens of an investor. We survey common sources of capital for early stage companies, including grants, angel investors, and venture capital, and offer insights into how to differentiate among them to select the best partners for your start-up's needs. Finally, we discuss the critical components of pitching your ideas to potential investors, and offer guidance on best practices and common mistakes. We hope this primer on fundamental concepts and the various health care funding alternatives will prepare entrepreneurs to achieve their mission to improve patients' lives through commercialization of their medical innovations. PMID- 28673647 TI - Regulation and Device Development: Tips for Optimizing Your Experience With the Food and Drug Administration. AB - Physician-inventors are in a unique position to identify unserved patient needs, and innovate solutions to clinical problems. These solutions may also have associated commercial opportunities. The logistics of developing these medical products, however, can seem a daunting task. One of the primary barriers in the United States is the regulatory process of the Food and Drug Administration (FDA). In this article, we will explore the risk-based approach used by the FDA which forms a framework to consider the regulatory pathway and the process to gain regulatory clearance or approval for medical devices. Inherent device properties and the procedural risk of the devices will determine the rigor with which they are scrutinized by FDA, and the evidentiary requirements to legally market them. Data and evidentiary development will vary depending on risk and regulatory precedent and may or may not require clinical data This regulatory paradigm will determine into which risk-based device class they fit, and whether they are regulated under the 510(k) or premarket approval application pathways. The FDA, although gatekeeper of the US market and tasked with determining which products are safe and effective, can be a powerful ally for product development. They have significant scientific and medical expertise, and mechanisms to both provide guidance, and also to consider novel approaches to product development and evidence development. Early interaction for routine and novel products alike can result in expedited and efficient development. This collaborative approach can be best practice to most expeditiously develop the next generation of products, getting them into the hands of US doctors and into the treatment of US patients. PMID- 28673648 TI - A Short Introduction to Intellectual Property Rights. AB - Intellectual property (IP) is a term that describes a number of distinct types of intangible assets. IP protection allows a rightsholder to exclude others from interfering with or using the property right in specified ways. The main forms of IP are patents, copyrights, trademarks, and trade secrets. Each type of IP protection is different, varying in the subject matter that can be covered, timeframe of protection, and total expense. Although some inventions may be covered by multiple types of IP protection, it is important to consider a number of business and legal factors before selecting the best protection strategy. Some technologies require strong IP protection to commercialize, but unnecessary costs can derail bringing a product to market. IP departments of organizations weigh these various considerations and perform essential IP protection functions. This primer introduces researchers to the main forms of IP and its legal aspects. PMID- 28673649 TI - If You Build It, They Will Come: How to Establish an Academic Innovation Enterprise. AB - The rapid growth of minimally invasive, image-guided intervention has redefined the procedural management of multiple disease entities. The process of innovation which has characterized the growth of interventional radiology can be best described as "needs-based," whereby practicing interventionalists identify unmet clinical needs and subsequently invent solutions to achieve desired technical and clinical outcomes. Historically, catheters and other percutaneous devices were developed with rudimentary manufacturing techniques and subsequently translated to patients with relatively little regulatory oversight. Since then, the resources required and financial costs of interventional technology development have grown exponentially. Fortunately, advances in software development, new methods of rapid prototyping, and commoditization of hardware components have made in-house engineering feasible once again. This has created an opportunity for academic medical centers to translate their research into testable prototypes in humans sooner and at reduced costs, and academic interventional radiology divisions are now leveraging these developments to create collaborative centers of innovation. This article describes five such organizational formats for collaboration and innovation in the academic setting, describing the structure, opportunities, requirements, and caveats of each model. PMID- 28673650 TI - Innovation in Interventional Radiology. PMID- 28673651 TI - Needs-Based Innovation in Interventional Radiology: The Biodesign Process. AB - There are many possible mechanisms for innovation and bringing new technology into the marketplace. The Stanford Biodesign innovation process is based in a deep understanding of clinical unmet needs as the basis for focused ideation and development. By identifying and vetting a compelling unmet need, the aspiring innovator can "derisk" a project and maximize chances for successful development in an increasingly challenging regulatory and economic environment. As a specialty founded by tinkerers, with a history of disruptive innovation that has yielded countless new ways of delivering care with minimal invasiveness, lower morbidity, and lower cost, interventional radiologists are uniquely well positioned to identify unmet needs and develop novel solutions free of dogmatic convention. PMID- 28673652 TI - Innovation Best Practices in the Medical Device Industry. AB - Advances in patient care often germinate from keen clinical insights and a needs based approach to innovation. Although there is an important role for incremental improvements to existing solutions, transformational innovation is what truly drives real shifts in clinical outcomes and subsequently patient satisfaction, market access, and economic value. A good example of this is the evolution of the coronary stent market. The best innovation programs are focused on unmet needs rather than solutions, call for a careful articulation of the specific problems to be solved, involve a deep dive within a clinical area, and seek to prioritize research and development investments into areas where the greatest impact can be expected. To enhance its ability to pursue breakthrough innovation, Johnson and Johnson (J&J) has organized itself along priority disease areas, created the global J&J Innovation organization to pursue external technology and know-how, and continues to partner closely with clinical practitioners. The process undertaken at J&J to acquire a microwave ablation technology and enter the interventional oncology space is a recent case study of these innovation principles and organizational focus in action. PMID- 28673653 TI - Not Just Guess Work: Tips for Observation, Brainstorming, and Prototyping. AB - Much has been written about brainstorming and prototyping in medical devices. These 2 topics are the crucial ingredients to innovation; which, if well seeded by organized and structured forays into each, will net much higher quality and more valuable results. Structure and process, although slightly counterintuitive as applied to brainstorming and prototyping, can greatly improve the value proposition of the innovation itself. PMID- 28673655 TI - Peak inspiratory flow as predictor for tracheotomy. AB - OBJECTIVES: Quantitative evaluation of upper airway obstruction cannot be commonly performed under acute dyspnea, especially in head and neck cancer (HNC); the decision whether or not to perform airway control surgery may be difficult to reach. Peak inspiratory flow (PIF) has been previously demonstrated to be a useful tool to decide on decannulation after HNC surgery. The aim of the present study was to assess the role of PIF as a standardized non-invasive tool in quantifying severe inspiratory dyspnea requiring emergency tracheostomy. MATERIALS AND METHODS: A single-center prospective observational pilot study analyzed PIF measurements in 22 patients exhibiting acute dyspnea due to upper airway obstruction. MAIN OUTCOME MEASURES: The decision whether or not to perform tracheotomy was taken prior to PIF measurement. PIF was measured with a hand-held PIF meter (In-Check method), and laryngeal fiberoscopy was then performed. Obstruction severity was defined by PIF values. RESULTS: PIF could be measured prior to tracheotomy (imminent in 21 cases, postponed in 1) in all cases. PIF values below 53.1 L/min (i.e., 18.3% of theoretic value) correlated with necessity for emergency tracheotomy. This threshold is concordant with that previously found for the feasibility of decannulation (60L/min). CONCLUSIONS: PIF is a non-invasive quantitative parameter assessing severity of upper airway obstruction, that may be helpful in decision-making for tracheostomy. Testing is simple, quick and reproducible. PMID- 28673654 TI - Competent antigen-presenting cells are generated from the long-term culture of splenocytes with granulocyte-macrophage colony-stimulating factor. AB - Dendritic cells (DCs) are routinely produced from the culture of mouse bone marrow (BM) with granulocyte-macrophage colony-stimulating factor (GM-CSF) within a period of 10days. Although splenic extramedullary myelopoiesis was suggested to occur under the influence of GM-CSF, the hematopoietic outcome of splenic culture with GM-CSF has not been scrutinized. We have cultured mouse splenocytes with GM CSF for an extended period of time, where we discovered that the CD11b+CD11c+ cells began to proliferate prominently after 10days and their number increased until the 4th week of the culture. In parallel experiments, FMS-like tyrosine kinase 3 (FLT3) and its ligand, FLT3L, were not found to influence the culture of splenocytes. Like DCs in the culture of BM with GM-CSF, a distinct population of CD11b+CD11c+MHC IIhi cells was readily identified as DCs in the long-term culture of splenocytes. After being isolated and plated overnight the CD11b+CD11c+MHC IIhi cells exhibited non-adherent dendritic morphology, while the other CD11b+CD11c+ cells became adherent. Besides, these CD11b+CD11c+MHC IIhi cells possessed relatively weak endocytic and phagocytic abilities but displayed strong antigen-presenting capacities, revealing DC-like characteristics; in contrast, the other CD11b+CD11c+ cells showed strong endocytosis and phagocytosis of antigens but were poor at antigen presentation, indicating macrophage-like traits. Therefore, we demonstrated that phenotypically as well as functionally genuine DCs are generated in the long-term culture of splenocytes with GM-CSF. PMID- 28673656 TI - A pigmented lesion of the nasopharynx. PMID- 28673657 TI - Image-Guided Percutaneous Radiofrequency Ablation of Central Renal Cell Carcinoma: Assessment of Clinical Efficacy and Safety in 31 Tumors. AB - PURPOSE: To assess clinical efficacy and safety of image-guided percutaneous radiofrequency (RF) ablation of central renal cell carcinoma with adjunctive pyeloperfusion. MATERIALS AND METHODS: Patients with central renal tumors who underwent percutaneous RF ablation between 2005 and 2010 were retrospectively evaluated. Thirty patients with 31 central renal tumors underwent 39 RF ablation sessions. Mean tumor diameter was 3.7 cm (range, 2-7 cm). Median distance between tumor and renal pelvis was 5 mm (range, 0-15 mm). Pyeloperfusion was performed in 27 patients (27/30; 90%). Contrast-enhanced CT or MR imaging was performed to evaluate treatment response. RESULTS: Technical success of RF ablation was achieved in 38/39 (97.4%) ablation sessions. Primary efficacy was 83.9% (26/31) on first follow-up imaging. One (3.2%) case of local tumor progression was detected 6 months after initial ablation. Secondary efficacy was 96.8% (30/31) after repeat RF ablation for residual tumor or local tumor progression. Median follow-up was 88 months (mean 82.6 mo +/- 30.7; range, 9-121 mo). Major complications occurred in 5/39 (12.8%) RF ablation sessions. Complications were significantly higher for tumors located within 5 mm of the renal pelvis or 0 mm of a major calyx (28.6% vs 4.0%; P < .05). Overall survival was 96.0% (95% CI, 88.4%-100.0%), and progression-free survival at 5 years was 80.9% (95% CI, 65.8% 95.9%). CONCLUSION: Image-guided percutaneous RF ablation combined with pyeloperfusion has satisfactory clinical efficacy in treating central renal tumors. Although clinically effective, RF ablation of central tumors may also be associated with significant major complications. PMID- 28673659 TI - Joseph Jumentie (1879-1928), a forgotten neurologist. AB - Joseph Jumentie (1879-1928), through his clinical skill and expertise in anatomical pathology, enhanced the prestige of the master neurologists he studied under- Jules Dejerine, Augusta Dejerine-Klumpke and Joseph Babinski -and their fame overshadowed the crucial support that Jumentie provided them. Following a remarkable doctoral thesis in 1911, which defined the semiology of tumors in the cerebellopontine angle, Jumentie conducted research into various areas of neurology and authored numerous publications. The present report discusses, as examples of his work, his research on the cerebellum and brain tumors, as well as his contribution to Dejerine-Klumpke's use of serial sectioning to identify the 'fasciculi' of corticospinal tracts. This discussion is introduced by a brief biography illustrated by photographs, most of which have never before been published. PMID- 28673658 TI - Long-Term Hepatotoxicity of Yttrium-90 Radioembolization as Treatment of Metastatic Neuroendocrine Tumor to the Liver. AB - PURPOSE: To determine long-term hepatotoxicity of yttrium-90 (90Y) radioembolization in patients treated for metastatic neuroendocrine tumor (mNET) and evaluate if imaging and laboratory findings of cirrhosis-like morphology are associated with clinical symptoms. MATERIALS AND METHODS: Retrospective review from 2003 to 2016 was performed for patients with mNET treated with 90Y glass microspheres. Fifty-four patients with > 2 year follow-up were stratified into unilobar (n = 15) vs whole-liver (n = 39) treatment. The most common primary mNET sites were small bowel (19 of 54), pancreas (19 of 54), and unknown (8 of 54). Preradioembolization imaging and laboratory findings were compared with most recent follow-up for indications of worsening portal hypertension and decline in hepatic function. RESULTS: Among patients who underwent unilobar radioembolization, imaging follow-up at a mean of 4.1 years (range, 2.0-15.2 y) revealed cirrhosis-like morphology in 26.7% (4 of 15), ascites in 13.3% (2 of 15), varices in 6.7% (1 of 15), and a 21.9% increase in splenic volume. The respective incidences in patients treated with whole-liver 90Y radioembolization were 56.4% (22 of 39), 41.0% (16 of 39), and 15.4% (6 of 39), with a 64.7% increase in splenic volume. Patients treated with whole-liver radioembolization exhibited significantly decreased platelet counts (P = .023) and lower albumin levels (P = .0002). Eight patients (20.5%) treated with whole-liver radioembolization who exhibited cirrhosis-like morphology showed clinical signs of hepatic decompensation; only 2 of 39 patients (5.1%) had no other causes of hepatotoxicity. CONCLUSIONS: Whole-liver 90Y radioembolization for patients with mNET results in long-term imaging findings of cirrhosis-like morphology and portal hypertension in > 50% of treated patients, but the majority remain clinically asymptomatic. Long-term hepatotoxicity solely attributable to 90Y develops in a small percentage of patients. PMID- 28673661 TI - Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma. AB - OBJECTIVE: Ovarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis. METHODS: A retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC. RESULTS: The estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects. CONCLUSIONS: Both substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival. PMID- 28673662 TI - Characterization of nanoparticles doped composites using ultrasound. AB - The aim of this work is the non-destructive automatic mechanical characterization of nanoparticles doped composites using ultrasound in order to understand and control the dispersion of the dopant nanoparticles in the final product. We present a method which is able to measure the elastic constants of composites (Youngs, Bulk, Shear Modulus and Poissons ratio), in addition to other parameters as density, sound velocity and thickness, providing information of the nanoparticles dispersion in the samples. All results are obtained with a single ultrasonic measure at each point of the samples' surface in an immersion setup with both pulse-echo and through-transmission measurements simultaneously, obtaining detailed information for all the samples' surface in a XY scanning. All the analysis is performed automatically, that is, no manual correction or adjustment is needed at any stage of the process. To validate the results, a polyester based resin has been analyzed with different concentrations of graphene nanoparticles as dopant. The method has shown to be very accurate and reliable. The resolution of the values obtained for the elastic constants is limited by the resolution in the velocities measurements, for which we have achieved a resolution in the order of cm/s, thus providing very accurate measurements of the elastic constants. PMID- 28673660 TI - The RAPID-II Neuropsychological Test battery for subjects aged 20 to 49 years: Norms and cognitive profile. AB - INTRODUCTION: Cognitive evaluation of young subjects is now widely carried out for non-traumatic diseases such as multiple sclerosis, HIV, or sleep disorders. This evaluation requires normative data based on healthy adult samples. However, most clinicians use a set of tests that were normed in an isolated manner from different samples using different cutoff criteria. Thus, the score of an individual may be considered either normal or impaired according to the norms used. It is well established that healthy adults obtained low-test scores when a battery of tests is administered. Thus, the knowledge of low base rates is required so as to minimize false diagnosis of cognitive impairment. The aim of this study was twofold (1) to provide normative data for RAPID-II battery in healthy adults, and (2) estimate the proportion of healthy adults having low scores across this battery. METHODS: Norms for the 44 test scores of the RAPID-II test battery were developed using the overall sample of 335 individuals based on three categories of age (20 to 29, 30 to 39, and 40 to 49 years) and two educational levels: Baccalaureate or higher educational degree (high educational level), lower than baccalaureate (low educational level). The 5th, 25th, 50th, and 75th percentiles were calculated from the six age and education subsamples and used to define norms. The frequency of low scores on the RAPID-II battery was calculated by simultaneously examining the performance of 33 primary scores. A low score was defined as less than or equal to the 5th percentile drawn from the six age and education normative subsamples. In addition, the percentages of low scores were also determined when all possible combinations of two-test scores across the RAPID-II were considered in the overall normative sample. RESULTS: Our data showed that 59.4% subjects of the normative sample obtained at least one or more low score. With more than 9 test scores, this percentage was equal to 0% in the normative sample. Among all combinations of two-test scores, 96% had a false positive rate<2%. CONCLUSION: Low scores are very common in young healthy subjects and are more obvious when simultaneously analyzing test scores across a battery of tests and are thus not necessarily indicative of cognitive impairment. The combinations of two-test scores can be a useful tool to improve the interpretation of low scores. PMID- 28673663 TI - Participation in a National Lifestyle Change Program is associated with improved diabetes Control outcomes. AB - AIMS: Clinical trials show lifestyle change programs are beneficial, yet large scale, successful translation of these programs is scarce. We investigated the association between participation in the largest U.S. lifestyle change program, MOVE!, and diabetes control outcomes. METHODS: This longitudinal, retrospective cohort study used Veterans Health Administration databases of patients with diabetes who participated in MOVE! between 2005 and 2012, or met eligibility criteria (BMI >=25kg/m2) but did not participate. Main outcomes were diabetic eye disease, renal disease, and medication intensification. RESULTS: There were 400,170 eligible patients with diabetes, including 87,366 (22%) MOVE! PARTICIPANTS: Included patients were 96% male, 77% white, with mean age 58years and BMI 34kg/m2. Controlling for baseline measurements and age, race, sex, BMI, and antidiabetes medications, MOVE! participants had lower body weight (-0.6kg), random plasma glucose (-2.8mg/dL), and HbA1c (-0.1%) at 12months compared to nonparticipants (each p<0.001). In multivariable Cox models, MOVE! participants had lower incidence of eye disease (hazard ratio 0.80, 95% CI 0.75-0.84) and renal disease (HR 0.89, 95% CI 0.86-0.92) and reduced medication intensification (HR 0.82, 95% CI 0.80-0.84). CONCLUSIONS: If able to overcome participation challenges, lifestyle change programs in U.S. health systems may improve health among the growing patient population with diabetes. PMID- 28673664 TI - On the choice of outlet boundary conditions for patient-specific analysis of aortic flow using computational fluid dynamics. AB - Boundary conditions (BCs) are an essential part in computational fluid dynamics (CFD) simulations of blood flow in large arteries. Although several studies have investigated the influence of BCs on predicted flow patterns and hemodynamic wall parameters in various arterial models, there is a lack of comprehensive assessment of outlet BCs for patient-specific analysis of aortic flow. In this study, five different sets of outlet BCs were tested and compared using a subject specific model of a normal aorta. Phase-contrast magnetic resonance imaging (PC MRI) was performed on the same subject and velocity profiles extracted from the in vivo measurements were used as the inlet boundary condition. Computational results obtained with different outlet BCs were assessed in terms of their agreement with the PC-MRI velocity data and key hemodynamic parameters, such as pressure and flow waveforms and wall shear stress related indices. Our results showed that the best overall performance was achieved by using a well-tuned three element Windkessel model at all model outlets, which not only gave a good agreement with in vivo flow data, but also produced physiological pressure waveforms and values. On the other hand, opening outlet BCs with zero pressure at multiple outlets failed to reproduce any physiologically relevant flow and pressure features. PMID- 28673665 TI - Real-time observation of fluid flows in tissue during stress relaxation using Raman spectroscopy. AB - This paper outlines a technique to measure fluid levels in articular cartilage tissue during an unconfined stress relaxation test. A time series of Raman spectrum were recorded during relaxation and the changes in the specific Raman spectral bands assigned to water and protein were monitored to determine the fluid content of the tissue. After 1000s unconfined compression the fluid content of the tissue is reduced by an average of 3.9%+/-1.7%. The reduction in fluid content during compression varies between samples but does not significantly increase with increasing strain. Further development of this technique will allow mapping of fluid distribution and flows during dynamic testing making it a powerful tool to understand the role of interstitial fluid in the functional performance of cartilage. PMID- 28673666 TI - The peculiar properties of the falx and tentorium in brain injury biomechanics. AB - The influence of the falx and tentorium on brain injury biomechanics during impact was studied with finite element (FE) analysis. Three detailed 3D FE head models were created based on the images of a healthy, normal size head. Two of the models contained the addition of falx and tentorium with material properties from previously published experiments. Impact loadings from a reconstructed concussive case in a sport accident were applied to the two players involved. The results suggested that the falx and tentorium could induce large strains to the surrounding brain tissues, especially to the corpus callosum and brainstem. The tentorium seemed to constrain the motion of the cerebellum while inducing large strain in the brainstem in both players involved in the accident (one player had mainly coronal head rotation and the other had both coronal and transversal rotations). Since changed strain levels were observed in the brainstem and corpus callosum, which are classical sites for diffuse axonal injuries (DAI), we confirmed the importance of using accurate material properties for falx and tentorium in a FE head model when studying traumatic brain injuries. PMID- 28673667 TI - Circulating microRNAs as biomarkers for depression: Many candidates, few finalists. AB - BACKGROUND: Recent research has highlighted the potential of microRNAs to serve as physiological indicators of disease process among clinically depressed patients. METHODS: In a comprehensive literature search through PubMed, we identified 23 articles comparing circulating (blood, plasma, or serum) microRNA expression levels in depressed versus healthy human subjects. Six studies examining circulatory microRNA expression through animal models of depression were also identified through the search and details of each study were outlined. A meta-analytic evaluation of these studies was not considered feasible, given the absence of concordance in the literature to date. RESULTS: A total of 178 specific microRNA candidates were identified in the human studies as significantly expressed among depressed samples. Ninety-seven of these microRNAs were upregulated, 75 were downregulated, and 6 showed mixed expression in depressed samples. Few microRNAs were consistently expressed across studies; the most consistent evidence was for microRNA-132, with replication in 4 different studies. Among animal studies, 2 studies investigated microRNA-16 through distinct stress-induced depression models. LIMITATIONS: Structural variations in microRNA sequences, methodological inconsistencies in technology used among studies to measure microRNA expression levels, differences in the clinical severity and forms of depression among subjects, and the overall paucity of studies make it difficult to ascertain any robust, preliminary targets deserving of biomarker potential. CONCLUSIONS: Ongoing research needs to address this high rate of non-replication as well as the methodological and reporting challenges of microRNA experimentation in order to determine valid effect sizes for the more proliferative candidates associated with depression. PMID- 28673668 TI - Impact of thermooxidation of phytosteryl and phytostanyl fatty acid esters on cholesterol micellarization in vitro. AB - The effects of thermooxidation of a phytosteryl/-stanyl and a phytostanyl fatty acid ester mixture on cholesterol micellarization were investigated using an in vitro digestion model simulating enzymatic hydrolysis by cholesterol esterase and subsequent competition of the liberated phytosterols/-stanols with cholesterol for incorporation into mixed micelles. As a first step, relationships between different doses of the ester mixtures and the resulting micellarized cholesterol were established. Subsequent subjection of the thermooxidized ester mixtures to the in vitro digestion model resulted in three principal observations: (i) thermal treatment of the ester mixtures led to substantial decreases of the intact esters, (ii) in vitro digestion of cholesterol in the presence of the thermooxidized ester mixtures resulted in significant increases of cholesterol micellarization, and (iii) the extents of the observed effects on cholesterol micellarization were strongly associated to the remaining contents of intact esters. The loss of efficacy to inhibit cholesterol micellarization due to thermally induced losses of intact esters corresponded to a loss of efficacy that would have been induced by an actual removal of these amounts of esters prior to the in vitro digestion. The obtained results suggest that in particular oxidative modifications of the fatty acid moieties might be responsible for the observed increases of cholesterol micellarization. PMID- 28673669 TI - Cerebral venous sinus thrombosis complicated with acute development of dural arteriovenous fistula: A case report. AB - Development of dural arteriovenous fistula (dAVF) after cerebral venous sinus thrombosis (CVST) was very uncommon and for all these reported cases, the dAVF was a chronic complication. We present a case of acute development of dAVF after CVST. A 40-year-old female was admitted into our department with 2day's headache and vomiting for 9h. Head computed tomography (CT) scan showed only scattered minor hematomas over the right frontal lobe. Blood test indicated an elevated D dimer. The patient experienced transient paralysis (Todd's paralysis) after intermittent focal epilepsy from day 3, which progressed into sustained epilepsy on day 6. Magnetic resonance imaging (MRI) on day 7 confirmed the thrombosis of the superior sagittal sinus and a large area of infarction and edema in the left frontal and parietal lobe. She was then treated with heparin and warfarin. Cerebral angiography on day 9 demonstrated a dAVF which was classified as Borden Type II and fed by the left occipital artery. Subsequently, endovascular occlusion of the fistula was conducted and the patient recovered well with only slight right limbs weakness at 1year follow up. PMID- 28673670 TI - Complete recovery of restless legs syndrome after unilateral thalamic and tegmental infarction: A case report. PMID- 28673671 TI - Relationship among clinical, pathological and bio-molecular features in low-grade epilepsy-associated neuroepithelial tumors. AB - The aim of this study was to evaluate the relationship between molecular markers and clinicopathological features in patients operated on for low-grade epilepsy associated neuroepithelial tumors. Molecular-genetic signatures are becoming increasingly important in characterizing these lesions, which represent the second most common cause of focal epilepsy in patients undergoing epilepsy surgery. Data from 22 patients operated on for histopathologically confirmed low grade epilepsy-associated neuroepithelial tumors were retrospectively collected. All specimens were examined for BRAF and IDH mutational status, 1p/19q codeletion and CD34 expression. The relationship between bio-molecular markers and several demographic, clinical and pathological features were analyzed. BRAF mutation was found in 11 (50.0%) patients and CD34 expression in 13 (59.1%). No patients presented IDH mutation or 1p/19q codeletion. Multiple seizure types were present in 5 (45.5%) patients with BRAF mutation and in none of those with BRAF wild type (p=0.035). Moreover, BRAF mutation was predominant in right-sided lesions (p=0.004) and CD34 expression was significantly associated with a longer duration of epilepsy (p=0.027). Several other clinicopathological features, such as association with focal cortical dysplasia and postoperative seizure outcome, showed no significant correlation with molecular markers. Further studies are necessary both to confirm these data in larger cohort of patients and to investigate possible relationships between molecular markers and other clinicopathological features. PMID- 28673672 TI - Electrophysiological influence of temporal occlusion of the parent artery during aneurysm surgery. AB - Intraoperative monitoring of the motor evoked potential (MEP) during cerebral aneurysm surgery has been widely used to confirm surgical safety. In this study, we retrospectively analyzed the influence of the MEP amplitude resulting from temporal occlusion of the parent artery, and appropriate judgement in the surgery was discussed. Ten patients underwent temporal occlusion of the parent artery during aneurysm surgery, and five of these patients showed a decrease in the MEP amplitude following temporal arterial occlusion. Clinical factors in patients with and without MEP decrease were compared. The time gap between the surgical procedure and the MEP change and recovery was then investigated. A decrease in the MEP amplitude caused by temporal occlusion had a significantly higher occurrence compared with permanent clip failure. The time from the release procedure to MEP amplitude recovery was relatively longer than the time from the occlusion procedure to the decrease in MEP amplitude. The time from release procedure to MEP amplitude recovery showed a weak correlation with the parent artery occlusion time. There is a time gap between releasing the temporal arterial occlusion and MEP recovery that is similar to temporal parent arterial occlusion and the MEP decrease. The cause of MEP amplitude should be judged carefully, and influence of parent artery temporal occlusion should be taken into consideration during aneurysm clipping. PMID- 28673673 TI - Bilateral traumatic abducens nerve avulsion: A case series and literature review. AB - Although abducens nerve palsy is an established sequela of head trauma - given the prolonged intracranial course of the nerve - bilateral injury is rare. Here, we present two cases of bilateral traumatic abducens nerve avulsion, in the absence of regional fractures, one of which presented two months following the initial trauma. Additionally, we review the current literature on bilateral abducens nerve palsy secondary to trauma, discussing the anatomy of the nerve's course and potential mechanisms of injury. PMID- 28673674 TI - Is CT angiography of the pulmonary arteries indicated in patients with high clinical probability of pulmonary embolism? AB - When a diagnostic test confirms clinical suspicion, the indicated treatment can be administered. A problem arises when the diagnostic test does not confirm the initially suspected diagnosis; when the suspicion is grounded in clinically validated predictive rules and is high, the problem is even worse. This situation arises in up to 40% of patients with high suspicion for acute pulmonary embolism, raising the question of whether CT angiography of the pulmonary arteries should be done systematically. This paper reviews the literature about this issue and lays out the best evidence about the relevant recommendations for patients with high clinical suspicion of acute pulmonary embolism and negative findings on CT angiography. It also explains the probabilistic concepts derived from Bayes' theorem that can be useful for ascertaining the most appropriate approach in these patients. PMID- 28673675 TI - [Zika virus infection: A review]. AB - Zika Virus (ZIKV), originally identified in 1947, is a re-emerging Flavivirus transmitted mainly through bites by Aedes mosquitos. Until the recent outbreaks in the Pacific islands and Central and South America, it was known to cause benign disease, in most cases asymptomatic or with mild and nonspecific symptoms (fever, rash, conjunctivitis, arthralgia, etc.). The unprecedented current epidemic has highlighted new modes of transmission (through blood, perinatally and sexually) as well as serious neurological complications such as congenital defects in the fetuses of infected mothers and Guillain-Barre syndrome in adults. This situation, coupled with the threat of worldwide spread, prompted the WHO to declare the ZIKV a public health emergency of international concern in February 2016. PMID- 28673676 TI - Detection of cholesteatoma: High-resolution DWI using RS-EPI and parallel imaging at 3 tesla. AB - The purpose of this study is to evaluate the impact of RS-EPI-DWI in the detection of cholesteatoma and to compare with single-shot echo-planar DWI (SS EPI-DWI). Diffusion-weighted and apparent diffusion-coefficient (ADC) images were obtained using RS-EPI and SS-EPI techniques in 30 patients. Presence of cholesteatoma (3 point scale), amount of artefacts (4 point scale), visibility (4 point scale), and ADC values of the lesions were assessed. The results of both techniques were compared with each other and gold-standard (GS) test results. Lesion visibility and presence of artefact scores of RS-EPI-DWI group were significantly different from those of the SS-EPI group. RS-EPI-DWI images had fewer artefacts and higher visibility scores. The sensitivity, specificity, negative/positive-predictive, and overall-agreement values of RS-EPI-DWI technique were 100%, 78%, 100%, 74%, and 87%; respectively. These values for SS EPI-DWI technique were 91%, 60%, 88%, 67%, and 75%; respectively. Also, these values were higher on axial plane than coronal plane images for ADC measurements. Based on gold-standard test findings, agreement values were good (kappa=0.74) for RS-EPI-DWI and moderate for SS-EP-DWI (kappa=0.50) techniques (P<0.001 for both). The RS-EPI-DWI technique allows a higher spatial-resolution and this technique is less susceptible to artefacts when compared with SS-EPI technique. PMID- 28673678 TI - Foreword to the special issue on applications of atomic force microscopy in cell biology. PMID- 28673679 TI - Secreted molecules inducing epithelial-to-mesenchymal transition in cancer development. AB - The epithelial-mesenchymal transition (EMT) is a biologic process that allows a polarized epithelial cell to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype. EMT is involved in embryo development, wound healing, tissue regeneration, organ fibrosis and has also been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells. These cells have been shown to acquire a mesenchymal phenotype when localized at the invasive front of primary tumours increasing aggressiveness, invasiveness, metastatic potential and resistance to chemotherapy. There is now increasing evidence demonstrating that a crucial role in the development of this process is played by factors secreted by cells of the tumour microenvironment or by the tumour cells themselves. This review summarises the current knowledge of EMT induction in cancer by paracrine or autocrine mechanisms, by exosomes or free proteins and miRNAs. PMID- 28673677 TI - Studying protein-DNA interactions using atomic force microscopy. AB - Atomic force microscopy (AFM) has made significant contributions to the study of protein-DNA interactions by making it possible to topographically image biological samples. A single protein-DNA binding reaction imaged by AFM can reveal protein binding specificity and affinity, protein-induced DNA bending, and protein binding stoichiometry. Changes in DNA structure, complex conformation, and cooperativity, can also be analyzed. In this review we highlight some important examples in the literature and discuss the advantages and limitations of these measurements. We also discuss important advances in technology that will facilitate the progress of AFM in the future. PMID- 28673680 TI - Animal-assisted interventions: A national survey of health and safety policies in hospitals, eldercare facilities, and therapy animal organizations. AB - BACKGROUND: Animal-assisted intervention (AAI) programs are increasing in popularity, but it is unknown to what extent therapy animal organizations that provide AAI and the hospitals and eldercare facilities they work with implement effective animal health and safety policies to ensure safety of both animals and humans. Our study objective was to survey hospitals, eldercare facilities, and therapy animal organizations on their AAI policies and procedures. METHODS: A survey of United States hospitals, eldercare facilities, and therapy animal organizations was administered to assess existing health and safety policies related to AAI programs. RESULTS: Forty-five eldercare facilities, 45 hospitals, and 27 therapy animal organizations were surveyed. Health and safety policies varied widely and potentially compromised human and animal safety. For example, 70% of therapy animal organizations potentially put patients at risk by allowing therapy animals eating raw meat diets to visit facilities. In general, hospitals had stricter requirements than eldercare facilities. DISCUSSION: This information suggests that there are gaps between the policies of facilities and therapy animal organizations compared with recent guidelines for animal visitation in hospitals. CONCLUSIONS: Facilities with AAI programs need to review their policies to address recent AAI guidelines to ensure the safety of animals and humans involved. PMID- 28673681 TI - The association between self-perceived proficiency of personal protective equipment and objective performance: An observational study during a bioterrorism simulation drill. AB - BACKGROUND: The recent Ebola virus disease outbreak emphasized the potential misuse of personal protective equipment (PPE) by health care workers (HCWs) during such an event. We aimed to compare self-perceived proficiency of PPE use and objective performance, and identify predictors of low compliance and PPE misuse. METHODS: An observational study combined with subjective questionnaires were carried out during a bioterror simulation drill. Forty-two observers evaluated performance under PPE. Mistakes were recorded and graded using a structured observational format and were correlated with the subjective questionnaires and with demographic parameters. RESULTS: One hundred seventy eight HCWs from community clinics and hospitals were included. The mean self perceived proficiency was high (6.1 out of 7), mean level of comfort was moderate (4.0 out of 7), and mean objective performance was intermediate (9.5 out of 13). There was no correlation between comfort and objective performance scores. Self perceived proficiency was in correlation with donning and continuous performance with PPE but not with doffing. Clinic personnel performed better than personnel in hospitals (40.3% vs 67.8% with 3 or more mistakes, respectively; P = .001). Demographic characteristics had no correlation with objective or self-perceived performance. CONCLUSIONS: Self-perceived proficiency is a poor predictor of appropriate PPE use. The results suggest poor awareness of the possibility of PPE misuse. PMID- 28673682 TI - Efficient neural differentiation of mouse pluripotent stem cells in a serum-free medium and development of a novel strategy for enrichment of neural cells. AB - Pluripotent stem cells (PSCs) offer an excellent model to study neural development and function. Although various protocols have been developed to direct the differentiation of PSCs into desired neural cell types, many of them suffer from limitations including low efficiency, long duration of culture, and the use of expensive, labile, and undefined growth supplements. In this study, we achieved efficient differentiation of mouse PSCs to neural lineage, in the absence of exogenous molecules, by employing a serum-free culture medium containing knockout serum replacement (KSR). Embryoid bodies (EBs) cultured in this medium predominantly produced neural cells which included neural progenitors (15-18%), immature neurons (8-24%), mature neurons (10-26%), astrocytes (27-61%), and oligodendrocytes (~1%). Different neuronal subtypes including glutamatergic, GABAergic, cholinergic, serotonergic, and dopaminergic neurons were generated. Importantly, neurons generated in the KSR medium were electrically active. Further, the EB scooping strategy, involving the removal of the EB core region from the peripheral EB outgrowth, resulted in the enrichment of PSC-derived neural cells. Taken together, this study provides the evidence that the KSR medium is ideal for the rapid and efficient generation of neural cells, including functional neurons, from PSCs without the requirement of any other additional molecule. PMID- 28673683 TI - Single-walled carbon nanotubes (SWCNTs) inhibit heat shock protein 90 (HSP90) signaling in human lung fibroblasts and keratinocytes. AB - Single-walled carbon nanotubes (SWCNTs) are carbon-based nanomaterials that possess immense industrial potential. Despite accumulating evidence that exposure to SWCNTs might be toxic to humans, our understanding of the mechanisms for cellular toxicity of SWCNTs remain limited. Here, we demonstrated that acute exposure of short (1-3MUm) and regular-length (5-30MUm) pristine, carboxylated or hydroxylated SWCNTs inhibited cell proliferation in human somatic and human stem cells in a cell type-dependent manner. The toxicity of regular-length pristine SWCNT was most evidenced in NP69>CYT00086>MCF-10A>MRC-5>HaCaT > HEK-293T>HepG2. In contrast, the short pristine SWCNTs were relatively less toxic in most of the cells being tested, except for NP69 which is more sensitive to short pristine SWCNTs as compared to regular-length pristine SWCNTs. Interestingly, carboxylation and hydroxylation of regular-length SWCNTs, but not the short SWCNTs, significantly reduced the cytotoxicity. Exposure of SWCNTs also induced caspase 3 and 9 activities, mitochondrial membrane depolarization, and significant apoptosis and necrosis in MRC-5 embryonic lung fibroblasts. In contrast, SWCNTs inhibited the proliferation of HaCaT human keratinocytes without inducing cell death. Further analyses by gene expression profiling and Connectivity Map analysis showed that SWCNTs induced a gene expression signature characteristic of heat shock protein 90 (HSP90) inhibition in MRC-5 cells, suggesting that SWCNTs may inhibit the HSP90 signaling pathway. Indeed, exposure of MRC-5 cells to SWCNTs results in a dose-dependent decrease in HSP90 client proteins (AKT, CDK4 and BCL2) and a concomitant increase in HSP70 expression. In addition, SWCNTs also significantly inhibited HSP90-dependent protein refolding. Finally, we showed that ectopic expression of HSP90, but not HSP40 or HSP70, completely abrogated the cytotoxic effects of SWCNTs, suggesting that SWCNT induced cellular toxicity is HSP90 dependent. In summary, our findings suggest that the toxic effects of SWCNTs are mediated through inhibition of HSP90 in human lung fibroblasts and keratinocytes. PMID- 28673685 TI - Controversies in the treatment of seizures associated with neurocysticercosis. AB - Seizures are the commonest manifestation of brain parenchymal cysticercosis. In terms of pathophysiological basis and prognostic significance of the seizures, a distinction might be applied between viable cysts, solitary cysticercus granuloma and calcific cysticerci. A number of uncertainties shroud the management of seizures in people with neurocysticercosis (NCC). Although antihelminthic treatment is effective in eliminating viable cysts and possibly cysticercus granulomas, its effect on seizure outcome remains uncertain. Corticosteroids and combinations of antihelminthic and corticosteroid treatments reduce the incidence of seizures in the short term at least. Although antiepileptic drugs (AEDs) are routinely employed in the treatment of seizures associated with NCC, there is no clear consensus regarding the choice and optimal duration of AED treatment. Long term AED treatment is warranted in people with calcific residue following involution of brain parenchymal cysticercosis. This article is part of a Special Issue entitled "Neurocysticercosis and Epilepsy". PMID- 28673686 TI - Correction of 25-OH-vitamin D deficiency improves control of secondary hyperparathyroidism and reduces the inflammation in stable haemodialysis patients. AB - INTRODUCTION: Patients on haemodialysis (HD) have a high prevalence of 25-OH vitamin D (25-OH-D)deficiency. Secondary hyperparathyroidismis a common condition in these patients, which is very important to control. 25-OH-D is involved in regulating calcium homeostasis. As such, appropriate levels of this vitamin could help to control bone mineral metabolism. OBJECTIVE: To evaluate the effect 25-OH D repletion in HD patients with 25-OH-D deficiency (<20ng/ml) on the control of secondary hyperparathyroidism and microinflammation status. PATIENTS AND METHODS: Prospective observational study in which stable patients on HD with 25-OH-D deficiency (<20ng/ml) were treated with oral calcifediol 0.266mcg/every 2 weeks for three months. Dialysis characteristics, biochemical parameters and drug doses administered were analysed before and after the correction of the deficiency. RESULTS: Forty-five stable HD patients with a mean age of 74.08+/-12.49 years completed treatment. Twenty-seven patients (60%) achieved 25-OH-D levels above 20ng/ml (23 with levels>30ng/ml and 4 between 20-30ng/ml). Parathyroid hormone levels decreased in 32 of the 45 patients, 23 of which (51%) achieved a>30% decrease from baseline. In terms of concomitant treatment, we observed a significant reduction in the selective vitamin D receptor activator dose, but no changes in calcimimetic or phosphate binders administration. In terms of malnutrition-inflammation status, a decrease in C-reactive protein was noted, although other microinflammation parameters, such as activated monocytes (CD14+/CD16+ and CD 14++/CD16+) were unchanged. No changes were observed in the levels of FGF-23. CONCLUSIONS: Correcting 25-OH-D deficiency in HD patients is associated with better secondary hyperparathyroidism control with lower doses of vitamin D analogues, as well as an improvement in inflammatory status. Our results support the recommendation to determine 25-OH-D levels and correct its deficiency in these patients. PMID- 28673687 TI - [Weight loss, fever and arthralgia in a 43-year-old man treated for follicular lymphoma]. PMID- 28673684 TI - The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis. AB - Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four week old male Fgf15-/- and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH. PMID- 28673688 TI - Cerebral Palsy and Intellectual Disability in the Children of Women With Chronic Kidney Disease. AB - BACKGROUND: This study examined the risk of adverse maternal and neonatal outcomes, especially cerebral palsy and intellectual disability, in pregnant women with and without chronic kidney disease and their children. METHOD: In total, 156 pregnancies involving 139 women with chronic kidney disease who were treated at our center between 2001 and 2010 were identified. We also selected 3067 women without chronic kidney disease who delivered their infants without suffering any medical complications during the same period as control groups. Long-term neonatal prognosis was assessed based on the frequencies of cerebral palsy and/or intellectual disability. RESULTS: The pregnant women had the following types of chronic kidney disease: immunoglobulin A nephropathy (n = 54), glomerulonephritis (n = 17), chronic renal failure (n = 16), nephrotic syndrome (n = 12), nephritis (n = 11), diabetic nephropathy (n = 10), congenital malformations and deformations (n = 10), purpura nephritis (n = 7), and others (n = 19). Of the children who were born to mothers with chronic kidney disease, one developed cerebral palsy, and another developed cerebral palsy with intellectual disability. Seven of the children who were born to mothers without chronic kidney disease developed cerebral palsy. The posterior probability of these conditions was 0.01900 and 0.002610 in the children born to mothers with and without chronic kidney disease, respectively. A primiparous mother (odds ratio [OR]: 4.07, 95% confidence interval [CI]): 2.78 to 5.95), preeclampsia (OR: 6.44, 95% CI: 3.92 to 10.59), grade 1 to 4 intraventricular hemorrhaging (OR: 7.71, 95% CI: 2.05 to 28.92), and an Apgar score of less than 7 at five minutes (OR: 0.51, 95% CI: 0.27 to 0.96) were found to influence the risk of cerebral palsy and/or intellectual disability in children born to women with chronic kidney disease. CONCLUSION: We found that the incidence of cerebral palsy and/or intellectual disability is 7.2 fold higher in children born to women with chronic kidney disease than in those born to women without chronic kidney disease. PMID- 28673689 TI - Higher adherence to the 'vegetable-rich' dietary pattern is related to longer telomere length in women. AB - BACKGROUND & AIMS: Increasing evidence suggests a role of nutrition in aging process measured by telomere length (TL). However, data from Chinese are scarce. Moreover, the potential mechanism underlying diet and aging is not clear. Although inflammation has been hypothesized as one of the main factors, direct evidence is lacking. We examined whether dietary patterns were associated with TL in Chinese adults, with particular attention paid to body fat (excessive accumulation of body fat is a state of high-systematic oxidative stress and inflammation) and C-reactive protein (CRP, a marker of inflammation). METHODS: Principal components analysis was used to identify dietary patterns from a 66 item food frequency questionnaire. TL was measured by Southern blots-based assay (Telomere restriction fragments, TRF). Data on sociodemographic characteristics, lifestyle behaviors, anthropometry and metabolism were collected. Multivariate linear regressions were performed in 553 Chinese adults (50.8% men) aged 25-65 years. RESULTS: Four main dietary patterns were identified. After adjustment for potential confounders, only the 'vegetable-rich' pattern characterized by higher intake of fruits, whole grains, various vegetable groups, dairy products, nuts, eggs and tea, was positively related to TL in women (beta = 160.81, P for trend <0.05). The strength of this relation was almost identical with further adjustment for body fat (beta = 160.50, P for trend <0.05), but was attenuated slightly with additional adjustment for CRP (beta = 152.02, P for trend <0.05). No significant relations were observed in men between dietary patterns and TL. CONCLUSIONS: Chinese women with higher adherence to 'vegetable-rich' dietary pattern have a longer TL. This relation was partially explained by CRP but not by body fat. PMID- 28673690 TI - Associations of lipid parameters with insulin resistance and diabetes: A population-based study. AB - OBJECTIVE: A dramatic gap exists between the clinical practice and guidelines for the dyslipidemia control in patients with diabetes. It is still uncertain which routinely available lipid measure is more applicable in estimation of insulin sensitivity and blood glucose control. The present study aims to investigate associations of routine lipid profiles with insulin resistance and diabetes, respectively. METHODS: We conducted a population-based study in 9764 Chinese participants. The homeostasis model assessment of insulin resistance was calculated to estimate insulin sensitivity. Diabetes was diagnosed according to the 1999 World Health Organization diagnostic criteria. RESULTS: Participants with insulin resistance or diabetes presented with significantly higher triglycerides (TG), Non-high-density lipoprotein cholesterol (Non-HDL-C), Non-HDL C/HDL-C, TG/HDL-C and lower HDL-C when compared with control subjects (all P < 0.0001). Such lipid measures were significantly correlated with fasting insulin, fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) 2 h glucose and Hemoglobin A1c (HbA1c) in Pearson's correlation analysis and multivariate linear regression analysis (all P < 0.0001). In logistic regression analysis, subjects were more likely to have prevalent insulin resistance and diabetes with the elevated quartiles of TG, Non-HDL-C, Non-HDL-C/HDL-C and TG/HDL-C (all P < 0.05). TG/HDL-C ratio, compare with other lipid parameters, have shown the strongest correlation with increased odds of insulin resistance and diabetes. CONCLUSION: Our study suggests a discordant association of lipid parameters with blood glucose level and TG/HDL-C is a better marker for evaluating insulin resistance and diabetes in Chinese population when compared with other routine lipid measures. PMID- 28673694 TI - Transient ischemic attack: A diagnosis of convenience. PMID- 28673692 TI - Combination of docetaxel, trastuzumab and pertuzumab or treatment with trastuzumab-emtansine for metastatic salivary duct carcinoma. PMID- 28673691 TI - EMX2 activates slow myosin heavy chain 2 gene expression in embryonic muscle fibers. AB - Avian myogenesis is partly characterized by commitment of distinct myoblast cell lineages to the formation of specific muscle fiber types. Previous studies have identified the transcription factor EMX2 as a regulator of slow myosin heavy chain 2 (MyHC2) gene expression in fast/slow primary muscle fibers. We report here the interaction of EMX2 with the slow MyHC2 transcriptional regulatory region in fast/slow embryonic muscle fibers. Promoter activity and electromobility shift assays localized the site of interaction of EMX2 with the slow MyHC2 gene within a defined binding site located between 3336 and 3326bp from the 3' end of the cloned slow MyHC2 DNA containing the transcriptional regulatory region. Using clonally-derived myoblasts stably committed to the formation of fast/slow muscle fibers, we also report the effect of altered EMX2 gene expression on genome-wide gene expression within these myoblasts. Increased EMX2 gene expression in fast/slow myoblasts caused altered gene expression of 1185 genes, indicating that EMX2 plays a central role in the gene expression profile of embryonic myoblasts. PMID- 28673693 TI - Spiritual/religious coping and depressive symptoms in informal caregivers of hospitalized older adults. AB - This aim of this study was assess whether positive and negative spiritual/religious coping (SRC) strategies are associated with depressive symptoms (DS) of informal caregiver (IC) of hospitalized older adults. A cross sectional study was conducted among 98 IC of hospitalized older adults in the medical clinic of a Brazilian School Hospital. The functionality, Positive and Negative SRC strategies and DS were evaluated. The IC had high average use of SRC, with Positive SRC being more used than Negative SRC. In the unadjusted regression model, Positive and Negative SRC were associated with DS. However, when adjusted for confounding factors, only Negative SRC remained associated with DS. The IC had used their religious and spiritual beliefs as a way to cope with the stress that comes from caring for hospitalized older adults. Although the positive strategy use of these beliefs was more common, only the negative strategies were associated with a higher DS. PMID- 28673695 TI - Scoring systems used to predict mortality in patients with acute upper gastrointestinal bleeding in the ED. AB - OBJECTIVE: Acute upper gastrointestinal bleeding (UGIB) is a potentially life threatening condition that requires rapid assessment in the emergency department (ED). We aimed to compare the performance of the AIMS65, Glasgow-Blatchford (Blatchford), preendoscopic Rockall (pre-Rockall), and preendoscopic Baylor bleeding (pre-Baylor) scores in predicting 30-day mortality in patients with acute UGIB in the ED setting. METHODS: Consecutive patients with acute UGIB who were admitted to the ED ward during 2012-2016 were retrospectively recruited. Data were retrieved from the admission list of the ED using international classification of disease codes via computer registration. The predictive accuracy of these four scores was compared using the area under the receiver operating characteristic curve (AUC) method. RESULTS: Among the 395 patients included during the study period, the total 30-day mortality rate was 10.4% (41/395). The AIMS65 and Glasgow-Blatchford scores performed better with an AUC of 0.907 (95% confidence interval (CI), 0.852-0.963; P<0.001) and 0.870 (95% confidence interval, 0.833-0.902; P<0.001) compared with other scoring systems (preendoscopic Rockall score: AUC, 0.709; 95% CI, 0.635-0.784; P<0.001; preendoscopic Baylor score: AUC, 0.523; 95% CI, 0.472-0.573; P>0.05). CONCLUSION: In patients with acute UGIB in the ED, the AIMS65 and Glasgow-Blatchford scores are clinically more useful for predicting 30-day mortality than the preendoscopic Rockall and preendoscopic Baylor scores. The AIMS65 score might be more ideal for risk stratification in the ED setting. PMID- 28673696 TI - Appendicitis following blunt abdominal trauma. AB - Appendicitis is a frequently encountered surgical problem in the Emergency Department (ED). Appendicitis typically results from obstruction of the appendiceal lumen, although trauma has been reported as an infrequent cause of acute appendicitis. Intestinal injury and hollow viscus injury following blunt abdominal trauma are well reported in the literature but traumatic appendicitis is much less common. The pathophysiology is uncertain but likely results from several mechanisms, either in isolation or combination. These include direct compression/crush injury, shearing injury, or from indirect obstruction of the appendiceal lumen by an ileocecal hematoma or traumatic impaction of stool into the appendix. Presentation typically mirrors that of non-traumatic appendicitis with nausea, anorexia, fever, and right lower quadrant abdominal tenderness and/or peritonitis. Evaluation for traumatic appendicitis requires a careful history and physical exam. Imaging with ultrasound or computed tomography is recommended if the history and physical do not reveal an acute surgical indication. Treatment includes intravenous antibiotics and surgical consultation for appendectomy. This case highlights a patient who developed acute appendicitis following blunt trauma to the abdomen sustained during a motor vehicle accident. Appendicitis must be considered as part of the differential diagnosis in any patient who presents to the ED with abdominal pain, including those whose pain begins after sustaining blunt trauma to the abdomen. Because appendicitis following trauma is uncommon, timely diagnosis requires a high index of suspicion. PMID- 28673697 TI - [Antibiotic-induced fever, does it really exist ?] PMID- 28673698 TI - Restaurant menu labeling laws and alcohol use. AB - The goal of this study was to analyze the effect of local and state mandatory restaurant menu labeling laws on alcohol use. Using a difference-in-differences estimation approach and data on adults aged 21 and older (n=2,157,722) from the 2002-2012 Behavioral Risk Factor Surveillance System, we estimated the effect of menu labeling laws on self-reported consumption of alcoholic beverages in the past month. The regression analysis indicates that on average implementation of menu labeling laws is associated with a 1.2 percentage-point drop in the fraction of survey respondents reporting that they drank an alcoholic beverage in the past month (95% confidence interval=-0.020, -0.004), compared with jurisdictions that had not implemented menu labeling laws. Moreover, we find that the estimated policy effects on alcohol use are larger among men than among women and larger among minorities than among non-Hispanic whites. Further provision of calorie information on foods and beverages in food service establishments, such as through federal menu labeling regulations, may have the potential to lead to a meaningful reduction in alcohol use throughout the U.S. and may result in larger reductions in alcohol use among men and minorities. PMID- 28673700 TI - Antimicrobial resistance and the current refugee crisis. AB - In the past few years, Europe has experienced an enormous influx of refugees and migrants owing to the ongoing civil war in Syria as well as conflicts, violence and instability in other Asian and African countries. Available data suggest that refugees carry a significant burden of multidrug-resistant (MDR) organisms, which is attributed to the rising antimicrobial resistance (AMR) rates in their countries of origin, both in healthcare settings and in the community. Transmission of MDR pathogens among refugees is facilitated by the collapsed housing, hygiene and healthcare infrastructures in several communities as well as poor hygiene conditions during their trip to destination countries. These findings highlight the fact that refugees may serve as vehicles of AMR mechanisms from their countries of origin along the immigration route. Following risk assessment, routine microbiological screening for MDR organism carriage of refugees and migrants as well as effective infection control measures should be considered upon admission. This will on the one hand address the possibility of dissemination of novel AMR mechanisms in non- or low-endemic countries and on the other will ensure safety for all patients. PMID- 28673699 TI - Plasma metabolomics study of the hepatoprotective effect of glycyrrhetinic acid on realgar-induced sub-chronic hepatotoxicity in mice via 1H NMR analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Realgar, a type of mineral drug that contains arsenic, is concurrently used with Glycyrrhizae Radx et Rhizoma to reduce its toxicity in many Chinese herbal formulations. Glycyrrhetinic acid (GA) is the bioactive ingredient in Glycyrrhizae Radx et Rhizoma. In this study, the protective effects of GA on realgar-induced hepatotoxicity was investigated using 1H nuclear magnetic resonance (1H NMR)-based metabolomic approaches. MATERIALS AND METHODS: Mice were divided into control, GA, realgar, and GA and realgar co administration groups. Their plasma samples were used for a metabolomics study. RESULTS: GA can protect the mice against realgar-induced hepatotoxicity to some extent by relieving alterations in the clinical biochemical parameters and the damage to hepatocytes. Metabolic profiling via principal components analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) indicated that the metabolic perturbation caused by realgar was reduced by GA. Six metabolites, including 3-hydroxybutyrate (3-HB), very low density/low density lipoprotein (VLDL/LDL), N-acetylglycoprotein (NAc), lactate, choline and D-glucose, were considered as potential biomarkers that are involved in the toxicity reduction effect of GA on realgar-induced hepatotoxicity. The correlation analysis showed that these potential biomarkers were all positively correlated with ALT and AST activities (correlation coefficient > 0.5). Lipid and energy metabolism pathways were found to be primarily associated with the hepatoprotective effect of GA. CONCLUSIONS: GA has an effective protection function by regulating the lipid and energy metabolism to liver injuries that are induced by realgar. PMID- 28673701 TI - Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin resistant Staphylococcus aureus. AB - OBJECTIVES: Currently, only a few antibiotics are available to treat methicillin resistant Staphylococcus aureus (MRSA). One alternative approach includes adjuvants to antibiotic therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) are non-antibiotic drugs reported to exhibit antibacterial activity. The objective of this study was to investigate the interaction between NSAIDs with selected antibiotics (cefuroxime and chloramphenicol) against strains of S. aureus. METHODS: The antibacterial activity of four NSAIDs (aspirin, ibuprofen, diclofenac and mefenamic acid) were tested against ten pathogenic bacterial strains using the microdilution broth method. The interaction between NSAIDs and antibiotics (cefuroxime/chloramphenicol) was estimated by calculating the fractional inhibitory concentration (FICI) of the combination. RESULTS: Aspirin, ibuprofen and diclofenac exhibited antibacterial activity against the selected pathogenic bacteria. The interaction between ibuprofen/aspirin with cefuroxime was demonstrated to be synergistic against methicillin-sensitive S. aureus (MSSA) and the MRSA reference strain, whereas for MRSA clinical strains additive effects were observed for both NSAIDs and cefuroxime combinations. The combination of chloramphenicol with ibuprofen/aspirin was synergistic against all of the tested MRSA strains and displayed an additive effect against MSSA. A 4-8192-fold reduction in the cefuroxime minimum inhibitory concentration (MIC) and a 4-64 fold reduction of the chloramphenicol MIC were documented. CONCLUSIONS: Overall, the NSAIDs ibuprofen and aspirin showed antibacterial activity against strains of S. aureus. Although individually less potent than common antibiotics, these NSAIDs are synergistic in action with cefuroxime and chloramphenicol and could potentially be used as adjuvants in combating multidrug-resistant MRSA. PMID- 28673702 TI - Sinus of Valsalva-right atrial tunnel causing heart failure in a 38-year-old. PMID- 28673703 TI - Discussion. PMID- 28673704 TI - Spinal cord ischemia-reperfusion injury: MicroRNAs and mitophagy at a crossroads. PMID- 28673705 TI - Reoperative aortic root replacement: Outcome in a contemporary series. AB - OBJECTIVES: Reoperative aortic root replacement is a challenging procedure associated with significant mortality and morbidity. The purpose of this study was to investigate the outcomes of reoperative aortic root replacement when performed in a number of complex clinical settings and to identify risk factors for operative mortality and long-term survival. METHODS: From 2006 to 2015, 280 consecutive patients at an academic center underwent reoperative aortic root replacement after a variety of previous aortic or cardiac operations. Logistic regression and extended Cox proportional hazards regression analyses were used to determine risk factors for operative mortality and long-term survival, respectively. RESULTS: The mean age of patients was 52.5 +/- 14.1 years. Prior operations included proximal aortic replacement in 113 patients, valve surgery in 162 patients, and coronary artery bypass grafting in 46 patients. Concomitant procedures included arch replacement in 135 patients, coronary artery bypass grafting in 68 patients, and mitral valve repair/replacement in 18 patients. Operative mortality was 14.3%. Five-year survival was 74.0%. Univariable analysis did not find previous root replacement, prior proximal aortic surgery, and concomitant arch replacement to be risk factors for operative mortality. In the multivariable analysis, chronic lung disease, prior myocardial infarction, and concomitant mitral valve surgery were risk factors for operative mortality. Age, peripheral artery disease, emergency, and concomitant mitral valve surgery were risk factors for mortality in the late phase. CONCLUSIONS: Reoperative aortic root replacement represents complex procedures carrying significant morbidity and mortality. Chronic lung disease, prior myocardial infarction, and concomitant mitral valve surgery were risk factors for operative mortality. Age, peripheral artery disease, emergency, and concomitant mitral valve surgery were risk factors for long-term mortality. PMID- 28673706 TI - The unexpected in grown-up congenital heart disease: Takotsubo syndrome. PMID- 28673707 TI - Predictors of survival, functional survival, and hospital readmission in octogenarians after surgical aortic valve replacement. AB - OBJECTIVE: To analyze outcomes and predictors of functional survival (personal care home admission and mortality) and hospital readmission in patients aged >=80 years who underwent surgical aortic valve replacement (SAVR) in a Manitoba hospital. METHODS: This was a retrospective cohort study of patients aged >=80 years who underwent SAVR with or without coronary artery bypass grafting in Manitoba between 1995 and 2014. Data from the Manitoba Adult Cardiac Surgery database and the Manitoba Centre for Health Policy were used. Kaplan-Meier estimates of outcomes and Cox multivariate regression analysis of risk factors were performed. Survival was compared with that of age- and sex-matched life expectancy. RESULTS: A total of 1872 patients were aged >=50 years and 378 were aged >=80 years, 55% of whom (n = 208) underwent concurrent coronary artery bypass grafting. Compared with younger patients, octogenarians had higher in hospital mortality (8.5%; P <.001), longer median intensive care unit stay (47.2 hours; P <.001), and longer median in-hospital stay (13 days; P <.001). The median follow-up was 5.2 years. Functional survival was 82.4% at 1 year and 56.5% at 5 years, and freedom from hospital readmission was 61.5% at 1 year and 28.4% at 5 years. Survival approximated the age- and sex-matched life expectancy at 1 year (83.8%) and 5 years (60.8%). Preoperative atrial fibrillation, peripheral vascular disease, female sex, postoperative acute kidney injury, and blood transfusion were associated with adverse outcomes. CONCLUSIONS: In eligible octogenarians, SAVR has acceptable 1- and 5-year functional survival and hospital readmission rates, but significant perioperative mortality and morbidity. PMID- 28673708 TI - The courage to learn. PMID- 28673709 TI - Patient-tailored aortic root repair in adult marfanoid patients: Surgical considerations and outcomes. AB - OBJECTIVE: The aim of the study was to evaluate the operative and functional results after individual, patient-tailored aortic root repair in marfanoid patients. METHODS: Among 518 patients who underwent operation between 2002 and January 2016, using patient-tailored aortic root repair with isolated sinus replacement, 42 patients fulfilled the original Ghent criteria. None/trivial, mild, moderate, and severe insufficiency grades were present in 5, 16, 10, and 11 patients, respectively. RESULTS: The repair was adjusted to the existing aortic annulus diameter. Replacement of 1, 2, or 3 sinuses of Valsalva was performed in 1, 14, and 27 patients, respectively. Concomitant cusp repair was performed in 17 patients (40.5%), and 10 patients (23.8%) underwent arch repair (total in 3). All patients survived surgery, and the follow-up (mean, 6.1 +/- 3.1; range, 0.8-14.2 years) was 100% complete. No patient had a change in the form or size of the aortic neo-root, especially the size of aortic annulus and sinotubular junction during the follow-up time. No and trivial/mild insufficiency were present in 22 and 18 patients, respectively, and 2 patients with recurrent aortic insufficiency caused by cusp pathology underwent aortic valve replacement 43 and 66 months after the primary surgery, respectively. Thus, the estimated survival free from aortic valve/root reoperation for any reason at 5 and 8 years was 96.8% +/- 3.2% and 91.4% +/- 6.0%, respectively. CONCLUSIONS: Patient-tailored root repair using isolated sinus replacement is an effective and durable method of valve-sparing repair in select marfanoid patients with a satisfactory quality of aortic cusps, which seems to be decisive for long-term valve function. PMID- 28673710 TI - Improved proprioceptive function by application of subsensory electrical noise: Effects of aging and task-demand. AB - The application of subsensory noise stimulation over the lower limbs has been shown to improve proprioception and postural control under certain conditions. Whereas the effect specificity seems to depend on several factors, studies are still needed to determine the appropriate method for training and rehabilitation purposes. In the current study, we investigated whether the application of subsensory electrical noise over the legs improves proprioceptive function in young and older adults. We aimed to provide evidence that stronger and age related differential effects occur in more demanding tasks. Proprioceptive function was initially assessed by testing the detection of passive ankle movement (kinesthetic perception) in twenty-eight subjects (14 young and 14 older adults). Thereafter, postural control was assessed during tasks with different sensory challenges: i) by removing visual information (eyes closed) and; ii) by moving the visual scene (moving room paradigm). Tests performed with the application of electrical noise stimulation were compared to those performed without noise. The results showed that electrical noise applied over the legs led to a reduction in the response time to kinesthetic perception in both young and older adults. On the other hand, the magnitude of postural sway was reduced by noise stimulation only during a more challenging task, namely, when the optical flow was changing in an unpredictable (nonperiodic) manner. No differential effects of stimulation between groups were observed. These findings suggest that the relevance of proprioceptive inputs in tasks with different challenges, but not the subjects' age, is a determining factor for sensorimotor improvements due to electrical noise stimulation. PMID- 28673711 TI - Activation of P2X3 receptors in the cerebrospinal fluid-contacting nucleus neurons reduces formalin-induced pain behavior via PAG in a rat model. AB - The cerebrospinal fluid (CSF)-contacting nucleus is implicated in the descending inhibitory pathway in pain processing, whereas the cellular and molecular mechanisms underpinning CSF-contacting nucleus regulating pain signals remains largely elusive. ATP is evidenced to inhibit pain transmission at supraspinal level by the mediation of the receptor P2X, wherein its subtype P2X3 is identified as the most potent. Our present experiment investigated the functionality of P2X3 receptors in CSF-contacting nucleus in the formalin-evoked inflammatory pain. Immunofluorescence and western blot revealed the expression of P2X3 receptors in the CSF-contacting nucleus and their upregulated expression subsequent to administration of formalin in rat model. ATP (a P2X3 receptor agonist, 100nmol/5ul) by intracerebroventricular (i.c.v.) administration ameliorated pain behaviors and enhanced c-Fos immunoreactivity in the neurons of the periaqueductal gray (PAG), both of which were discounted by pre administration of A-317491 (a selective P2X3 receptor antagonist, 25nmol/5ul). After the CSF-contacting nucleus was ablated by cholera toxin subunit B-saporin, ATP failed to induce analgesia, with the c-Fos immunoreactivity in the PAG neurons remaining intact. Our results validated that P2X3 receptors in the CSF contacting nucleus are pivotal in inflammatory pain processing via the activation of PAG neurons. PMID- 28673712 TI - Vibrissa sensory neurons: Linking distinct morphology to specific physiology and function. AB - Rodents use an array of long tactile facial hairs, the vibrissae, to locate and discriminate objects. Each vibrissa is densely innervated by multiple different types of trigeminal (TG) sensory neurons. Based on the sensory ending morphology, there are at least six types of vibrissa innervating neurons; whereas based on electrophysiological recordings, vibrissa neurons are generally classified as rapidly adapting (RA) and slowly adapting (SA), and show different responses to whisking movement and/or touch. There is a clear missing link between the morphologically defined neuronal types and their exact physiological properties and functions. We briefly summarize recent advances and consider single-cell transcriptome profiling, together with optogenetics-assisted in vivo electrophysiology, as a way to fill this major gap in our knowledge of the vibrissa sensory system. PMID- 28673713 TI - Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice. AB - Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain. PMID- 28673714 TI - Physiological profiles of cortical responses to mechanical stimulation of the tooth in the rat: An optical imaging study. AB - The periodontal ligament (PDL) includes several types of nerve endings, such as Abeta-, Adelta-, and C-fibers, which play critical roles in detecting the strength and direction of occlusal force. Previous studies have demonstrated that electrical stimulation of the PDL activates the somatosensory and insular cortices. However, the profile of cortical excitation in response to mechanical PDL stimulation mostly remains unknown. To investigate the differences in cortical responses to electrical and mechanical stimulation of the maxillary first molar, we performed optical imaging to determine the responding cortical regions in combination with a pharmacological approach. The molar was mechanically stimulated by pulling in the rostral direction, and electrical stimulation was applied via bipolar electrodes inserted into the mesial PDL. Mechanical stimulation initially excited the primary somatosensory cortex (S1), whereas electrical stimulation evoked an initial response between the secondary somatosensory cortex (S2) and insular oral region (IOR). The characteristic feature responding to mechanical stimulation was the rebound response evoked at the end of mechanical stimulation. A longer mechanical stimulation evoked a larger amplitude of the rebound response. A paired-pulse protocol of mechanical stimulation revealed that the amplitude of the second response was smaller than the first response, in accordance with the shorter interstimulus interval. Systemic application of morphine, a potent blocker of nociception, reduced the amplitude of the maximum excitation, particularly in S2/IOR compared to S1. These results suggest that S1 and S2/IOR are principally excited by mechanical and electrical stimulation, respectively, and that S2/IOR is involved in nociception processing. PMID- 28673716 TI - Contribution of the supplementary motor area and the cerebellum to the anticipatory postural adjustments and execution phases of human gait initiation. AB - Several brain structures including the brainstem, the cerebellum and the frontal cortico-basal ganglia network, with the primary and premotor areas have been shown to participate in the functional organization of gait initiation and postural control in humans, but their respective roles remain poorly understood. The aim of this study was to better understand the role of the supplementary motor area (SMA) and posterior cerebellum in the gait initiation process. Gait initiation parameters were recorded in 22 controls both before and after continuous theta burst transcranial stimulation (cTBS) of the SMA and cerebellum, and were compared to sham stimulation, using a randomized double-blind design study. The two phases of gait initiation process were analyzed: anticipatory postural adjustments (APAs) and execution, with recordings of soleus and tibialis anterior muscles. Functional inhibition of the SMA led to a shortened APA phase duration with advanced and increased muscle activity; during execution, it also advanced muscle co-activation and decreased the duration of stance soleus activity. Cerebellar functional inhibition did not influence the APA phase duration and amplitude but increased muscle co-activation, it decreased execution duration and showed a trend to increase velocity, with increased swing soleus muscle duration and activity. The results suggest that the SMA contributes to both the timing and amplitude of the APAs with no influence on step execution and the posterior cerebellum in the coupling between the APAs and execution phases and leg muscle activity pattern during gait initiation. PMID- 28673715 TI - Muscle pain induced by static contraction in rats is modulated by peripheral inflammatory mechanisms. AB - Muscle pain is an important health issue and frequently related to static force exertion. The aim of this study is to evaluate whether peripheral inflammatory mechanisms are involved with static contraction-induced muscle pain in rats. To this end, we developed a model of muscle pain induced by static contraction performed by applying electrical pulses through electrodes inserted into muscle. We also evaluated the involvement of neutrophil migration, bradykinin, sympathetic amines and prostanoids. A single session of sustained static contraction of gastrocnemius muscle induced acute mechanical muscle hyperalgesia without affecting locomotor activity and with no evidence of structural damage in muscle tissue. Static contraction increased levels of creatine kinase but not lactate dehydrogenase, and induced neutrophil migration. Dexamethasone (glucocorticoid anti-inflammatory agent), DALBK (bradykinin B1 antagonist), Atenolol (beta1 adrenoceptor antagonist), ICI 118,551 (beta2 adrenoceptor antagonist), indomethacin (cyclooxygenase inhibitor), and fucoidan (non-specific selectin inhibitor) all reduced static contraction-induced muscle hyperalgesia; however, the bradykinin B2 antagonist, bradyzide, did not have an effect on static contraction-induced muscle hyperalgesia. Furthermore, an increased hyperalgesic response was observed when the selective bradykinin B1 agonist des Arg9-bradykinin was injected into the previously stimulated muscle. Together, these findings demonstrate that static contraction induced mechanical muscle hyperalgesia in gastrocnemius muscle of rats is modulated through peripheral inflammatory mechanisms that are dependent on neutrophil migration, bradykinin, sympathetic amines and prostanoids. Considering the clinical relevance of muscle pain, we propose the present model of static contraction-induced mechanical muscle hyperalgesia as a useful tool for the study of mechanisms underlying static contraction-induced muscle pain. PMID- 28673717 TI - Distinctive features of Phox2b-expressing neurons in the rat reticular formation dorsal to the trigeminal motor nucleus. AB - Phox2b encodes a paired-like homeodomain-containing transcription factor essential for development of the autonomic nervous system. Phox2b-expressing (Phox2b+) neurons are present in the reticular formation dorsal to the trigeminal motor nucleus (RdV) as well as the nucleus of the solitary tract and parafacial respiratory group. However, the nature of Phox2b+ RdV neurons is still unclear. We investigated the physiological and morphological properties of Phox2b+ RdV neurons using postnatal day 2-7 transgenic rats expressing yellow fluorescent protein under the control of Phox2b. Almost all of Phox2b+ RdV neurons were glutamatergic, whereas Phox2b-negative (Phox2b-) RdV neurons consisted of a few glutamatergic, many GABAergic, and many glycinergic neurons. The majority (48/56) of Phox2b+ neurons showed low-frequency firing (LF), while most of Phox2b- neurons (35/42) exhibited high-frequency firing (HF) in response to intracellularly injected currents. All, but one, Phox2b+ neurons (55/56) did not fire spontaneously, whereas three-fourths of the Phox2b- neurons (31/42) were spontaneously active. K+ channel and persistent Na+ current blockers affected the firing of LF and HF neurons. The majority of Phox2b+ (35/46) and half of the Phox2b- neurons (19/40) did not respond to stimulations of the mesencephalic trigeminal nucleus, the trigeminal tract, and the principal sensory trigeminal nucleus. Biocytin labeling revealed that about half of the Phox2b+ (5/12) and Phox2b- RdV neurons (5/10) send their axons to the trigeminal motor nucleus. These results suggest that Phox2b+ RdV neurons have distinct neurotransmitter phenotypes and firing properties from Phox2b- RdV neurons and might play important roles in feeding-related functions including suckling and possibly mastication. PMID- 28673719 TI - Newly Developed Drugs for Alzheimer's Disease in Relation to Energy Metabolism, Cholinergic and Monoaminergic Neurotransmission. AB - Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions. PMID- 28673718 TI - D-limonene exhibits superior antihyperalgesic effects in a beta-cyclodextrin complexed form in chronic musculoskeletal pain reducing Fos protein expression on spinal cord in mice. AB - Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in beta-cyclodextrin (LIM-betaCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-betaCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-betaCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-betaCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with betaCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options. PMID- 28673720 TI - Schizophrenia affects speech-induced functional connectivity of the superior temporal gyrus under cocktail-party listening conditions. AB - The superior temporal gyrus (STG) is involved in speech recognition against informational masking under cocktail-party-listening conditions. Compared to healthy listeners, people with schizophrenia perform worse in speech recognition under informational speech-on-speech masking conditions. It is not clear whether the schizophrenia-related vulnerability to informational masking is associated with certain changes in FC of the STG with some critical brain regions. Using sparse-sampling fMRI design, this study investigated the differences between people with schizophrenia and healthy controls in FC of the STG for target-speech listening against informational speech-on-speech masking, when a listening condition with either perceived spatial separation (PSS, with a spatial release of informational masking) or perceived spatial co-location (PSC, without the spatial release) between target speech and masking speech was introduced. The results showed that in healthy participants, but not participants with schizophrenia, the contrast of either the PSS or PSC condition against the masker only condition induced an enhancement of functional connectivity (FC) of the STG with the left superior parietal lobule and the right precuneus. Compared to healthy participants, participants with schizophrenia showed declined FC of the STG with the bilateral precuneus, right SPL, and right supplementary motor area. Thus, FC of the STG with the parietal areas is normally involved in speech listening against informational masking under either the PSS or PSC conditions, and declined FC of the STG in people with schizophrenia with the parietal areas may be associated with the increased vulnerability to informational masking. PMID- 28673721 TI - Contribution of presynaptic HCN channels to excitatory inputs of spinal substantia gelatinosa neurons. AB - Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are pathological pain-associated voltage-gated ion channels. They are widely expressed in central nervous system including spinal lamina II (also named the substantia gelatinosa, SG). Here, we examined the distribution of HCN channels in glutamatergic synaptic terminals as well as their role in the modulation of synaptic transmission in SG neurons from SD rats and glutamic acid decarboxylase 67 (GAD67)-GFP mice. We found that the expression of the HCN channel isoforms was varied in SG. The HCN4 isoform showed the highest level of co-localization with VGLUT2 (23+/-3%). In 53% (n=21/40 neurons) of the SG neurons examined in SD rats, application of HCN channel blocker, ZD7288 (10MUM), decreased the frequency of spontaneous (s) and miniature (m) excitatory postsynaptic currents (EPSCs) by 37+/-4% and 33+/-4%, respectively. Consistently, forskolin (FSK) (an activator of adenylate cyclase) significantly increased the frequency of mEPSCs by 225+/-34%, which could be partially inhibited by ZD7288. Interestingly, the effects of ZD7288 and FSK on sEPSC frequency were replicated in non-GFP-expressing neurons, but not in GFP-expressing GABAergic SG neurons, in GAD67-GFP transgenic C57/BL6 mice. In summary, our results represent a previously unknown cellular mechanism by which presynaptic HCN channels, especially HCN4, regulate the glutamate release from presynaptic terminals that target excitatory, but not inhibitory SG interneurons. PMID- 28673723 TI - Corrections. PMID- 28673722 TI - Involvement of substance P in the antinociceptive effect of botulinum toxin type A: Evidence from knockout mice. AB - The antinociceptive action of botulinum toxin type A (BoNT/A) has been demonstrated in behavioral animal studies and clinical settings. It was shown that this effect is associated with toxin activity in CNS, however, the mechanism is not fully understood. Substance P (SP) is one of the dominant neurotransmitters in primary afferent neurons transmitting pain and itch. Thus, here we examined association of SP-mediated transmission and BoNT/A antinociceptive action by employing gene knockouts. Antinociceptive activity of intraplantarly (i.pl.) injected BoNT/A was examined in mice lacking the gene encoding for SP/neurokinin A (tac1-/-) or SP-preferred receptor neurokinin 1 (tac1r-/-), compared to control C57Bl/6J wild type animals. BoNT/A action was assessed in inflammatory pain induced by formalin and CFA, and neuropathic pain induced by partial sciatic nerve ligation. BoNT/A activity in CNS was examined by c-Fos and BoNT/A-cleaved SNAP-25 immunohistochemistry. In wild type mice, acute (formalin-evoked) and chronic pain (neuropathic and inflammatory) was reduced by peripherally injected BoNT/A. In tac1-/- and tac1r-/- knockout mice, BoNT/A exerted no analgesic effect. In control animals BoNT/A reduced the formalin evoked c-Fos expression in lumbar dorsal horn, while in knockout mice the c-Fos expression was not reduced. After peripheral toxin injection, cleaved SNAP-25 occurred in lumbar dorsal horn in all animal genotypes. BoNT/A antinociceptive activity is absent in animals lacking the SP and neurokinin 1 receptor encoding genes, in spite of presence of toxin's enzymatic activity in central sensory regions. Thus, we conclude that the integrity of SP-ergic system is necessary for the antinociceptive activity of BoNT/A. PMID- 28673724 TI - Three-dimensional printed haptic model from a prenatal surface-rendered oropalatal sonographic view: a new tool in the surgical planning of cleft lip/palate. AB - Three-dimensional (3D) ultrasound has significantly improved prenatal screening and perinatal care in the area of cleft lip/palate and other deformities, providing essential preoperative information to the surgical team. However, current 3D reconstruction modalities are limited primarily to display on a two dimensional surface. In contrast, a 3D printed haptic model allows both the surgeon and the parents to develop a better understanding of the anatomy and the surgical procedure through the ability to interact directly with the printed model. The production of a 3D printed haptic model of cleft lip and palate obtained from a surface-rendered oropalatal sonographic view is presented here. The development of this 3D printed haptic model will allow the surgical team to perform preoperative planning with a highly accurate medical model, and it therefore represents a new tool in the management of cleft lip/palate. It also provides better prenatal information for the parents. PMID- 28673725 TI - Traction suture modification to tongue-in-groove caudal septoplasty. AB - Caudal septal deviation leads to unfavorable esthetic as well as functional effects on the nasal airway. A modification to the tongue-in-groove (TIG) technique to correct these caudal septal deformities is described. With placement of a temporary suspension suture to the caudal septum, manual traction is applied, assuring that the caudal septum remains in the midline position while it is being secured with multiple through-and-through, trans-columellar and trans septal sutures. From 2003 to 2016, 148 patients underwent endonasal septoplasty using this modified technique, with excellent functional and cosmetic outcomes and a revision rate of 1.4%. This modified TIG technique replaces the periosteal suture that secures the caudal septum to the midline nasal crest in the original TIG technique. This simplifies the procedure and minimizes the risk of securing the caudal septum off-midline when used in endonasal septoplasty. PMID- 28673726 TI - Compensating the asymmetric probe response in broad MAS NMR spectra of quadrupolar nuclei. AB - The spinning sidebands envelope of satellite transitions often display an asymmetric shape, which is caused by an asymmetric response of the NMR probe circuit. In this work, we revisit the basic concepts of the RLC circuit at the heart of every NMR probe and present two approaches capable of minimizing this artifact. While the first one consists of deliberately mistuning the probe, the second one relies on measuring the probe's response function and deconvoluting its contribution from the spectra. Both approaches are validated with 23Na NMR spectra of a lead-free relaxor ferroelectric (BNT-1BT). This material is particularly suitable as an example of the applicability of both strategies for samples with a disordered local structure. PMID- 28673727 TI - Central serous chorioretinopathy and glucocorticoids: an update on evidence for association. AB - Central serous chorioretinopathy is a common idiopathic retinal disease characterized by central vision loss from serous detachment of the neurosensory retina, serous pigment epithelial detachments, and leakage of fluid through the retinal pigment epithelium into the subretinal space. The concept of an association between exogenous glucocorticoid use and central serous chorioretinopathy is widely accepted among ophthalmologists. Here, we review the evidence for and against such an association. This evidence includes 2 large, case-control studies that found strong associations, and a smaller, population based study that found no association. We conclude that the preponderance of the literature on this topic supports the existence of an association. Both exogenous and endogenous glucocorticoids have been implicated. Although a mechanism and a causal relationship remain to be established, the association deserves broader recognition among physicians who prescribe glucocorticoids. PMID- 28673728 TI - Introduction to "Non-Epithelial Lesions of the Breast" Issue. PMID- 28673729 TI - Histopathology of parasitic infections of the lung. PMID- 28673730 TI - Syphilitic coronary artery ostial stenosis resulting in acute myocardial infarction. AB - Cardiovascular abnormalities are well-known manifestations of a late form of syphilis - tertiary syphilis. Since the era of antibiotics, the incidence of late manifestations of syphilis has declined almost to a rare entity. The injury of aorta (the aortitis with a dilatation of aortic root and its associated complications) is the most common between all the cardiovascular lesions. A less common manifestation of syphilitic aortitis is coronary artery ostial narrowing related to aortic wall thickening. We present the case of a 37-year-old male who was treated for an acute myocardial infarction due to bilateral coronary artery ostial stenosis secondary to syphilitic aortitis. According to the multidisciplinary decision, surgical revascularization (coronary artery bypass grafting, CABG) was performed. According to dermatologist recommendation, patient postoperative cardiovascular treatment was supplemented with intramuscular doses of benzathine penicillin recommended for tertiary syphilis. Further follow-up visits were also planned to detect possible changes of the aortic wall, dynamics of aortic regurgitation or potential anastomotic restenosis due to progression of aortitis. PMID- 28673731 TI - Systematic influences on the areas of peaks in gamma-ray spectra that have a large statistical uncertainty. AB - A method is presented for calculating the expected number of counts in peaks that have a large relative peak-area uncertainty and appear in measured gamma-ray spectra. The method was applied to calculations of the correction factors for peaks occurring in the spectra of radon daughters. It was shown that the factors used for correcting the calculated peak areas to their expected values decrease with an increasing relative peak-area uncertainty. The accuracy of taking the systematic influence inducing the correction factors into account is given by the dispersion of the correction factors corresponding to specific peaks. It was shown that the highest accuracy is obtained in the peak analyses with the GammaVision and Gamma-W software. PMID- 28673732 TI - Design, synthesis and biological evaluation of GPR55 agonists. AB - GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained. PMID- 28673733 TI - Enhanced soluble production of cholera toxin B subunit in Escherichia coli by co expression of SKP chaperones. AB - The cholera toxin B subunit (CTB) is a nontoxic portion of the cholera toxin that retains mucosal adjuvant properties. Expression of CTB in Escherichia coli is difficult as CTB aggregates and accumulates as insoluble inclusion bodies. To remedy this problem, the periplasmic chaperone, SKP, was investigated as possible co-expression partner to increase the solubility of recombinant CTB (rCTB) in E. coli. The result showed co-expression of SKP enhanced the soluble expression of rCTB in E. coli. Moreover, soluble rCTB was successfully expressed and secreted into the periplasmic space through the direction of the LTB leader signal. rCTB in periplasm was purified using an immobilized d-galactose resin; GM1-ELISA experiments showed that rCTB retains strong GM1 ganglioside-binding activity. Intranasal administration of ovalbumin (OVA) with rCTB significantly induced both mucosal and humoral immune responses specific to OVA. These data indicate that co expression of the molecular chaperone SKP with CTB increased the solubility of rCTB while maintaining its function. PMID- 28673734 TI - Evolution and Progression of Spondylodiskitis: A Case Presentation. AB - : Pyogenic infection of the spinal column is a relatively rare condition. Spondylodiskitis is characterized by infection of the intervertebral disk and the adjacent vertebrae. Diagnosis is often delayed because the symptoms are often nonspecific and also because of the high incidence of nonspecific low back pain in the general population. We report the case of a 42-year-old woman who developed low back pain secondary to spondylodiskitis. Her diagnosis was delayed because of a lack of supporting findings on initial magnetic resonance imaging. The case highlights the clinical scenario in which maintaining a high index of suspicion may lead to follow-up imaging and an accurate diagnosis. LEVEL OF EVIDENCE: V. PMID- 28673735 TI - Properties of Paraspinal Muscles in Japanese High School Baseball Players With Terminal-Stage Lumbar Spondylolysis. AB - BACKGROUND: Lumbar spondylolysis is a defect in the pars interarticularis that is common in young athletes; the stress distribution at the pars interarticularis is the highest in extension and rotation movements. The paraspinal muscles play an important role in stabilization of the lumbar spine; however, no study has assessed the properties of paraspinal muscles in athletes with lumbar spondylolysis. OBJECTIVE: To evaluate the properties of paraspinal muscles in athletes with lumbar spondylolysis. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Six high school baseball players with terminal-stage lumbar spondylolysis and 11 high school baseball players without organic lumbar lesions of similar anthropometric characteristics. METHODS: All subjects performed the unsupported trunk holding test combined with surface electromyographic (EMG) power spectral analysis until exhaustion. The results of EMG power spectral analysis were compared between the spondylolysis and control groups. MAIN OUTCOME MEASUREMENTS: The median frequency (MF) was computed from the raw EMG signal of the erector spinae and multifidus during trunk holding test using fast Fourier transform spectrum analysis. The initial MF and MF slope were calculated. RESULTS: No significant differences in endurance time were found between the spondylolysis and control groups. The initial MF and the MF slopes of the erector spinae and multifidus were significantly lower in the spondylolysis group than in the control group. CONCLUSIONS: The results suggest lower fast twitch motor unit recruitment in the erector spinae and multifidus of high school baseball players with terminal-stage lumbar spondylolysis compared with the control. LEVEL OF EVIDENCE: IV. PMID- 28673736 TI - Everolimus eluting stent vs first generation drug-eluting stent in primary angioplasty: A pooled patient-level meta-analysis of randomized trials. AB - BACKGROUND: Several concerns have emerged about the higher risk of very late stent thrombosis (ST) with first generation drug-eluting stent (DES) especially among STEMI patients. Newer generation DES has demonstrated to reduce ST at mid term follow-up. Therefore, the aim of the present study is to perform an individual patient's data meta-analysis of trials comparing 1st generation DES vs. 2nd generation DES (everolimus-eluting stent, EES) in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI. METHODS: We performed a formal search of electronic databases (MEDLINE and CENTRAL) and scientific session presentations from January 2010 to June 2016. We included all completed randomized trials comparing 1st vs. EES for patient presenting with STEMI. RESULTS: Individual patients data were obtained from 3 trials, including a total of 1581 patients (686 or 43.4% randomized to 1st generation DES and 895 or 56.4% randomized to EES). At long-term follow-up (1584+/-588days), EES did not significantly reduce mortality (7.8.% vs 11.7%, HR [95%CI]=0.77 [0.52, 1.13], p=0.18, pheterogeneity=0.93), cardiac mortality (6.2% vs 7.6%, HR [95%CI]=0.90 [0.56, 1.44], p=0.65, pheterogeneity=0.85), and reinfarction (8.1% versus 11.2%, respectively; HR [95%CI]=0.74 [0.51, 1.07], p=0.11, pheterogeneity=0.52). However, EES significantly reduced the occurrence of ST (3.4% versus 6.1% respectively, HR [95%CI]=0.56 [0.32, 0.97], p=0.04, pheterogeneity=0.42) and target vessel revascularization (TVR) (14.2% versus 20.1%; HR [95%CI]=0.63 [0.42, 0.96], p=0.03, pheterogeneity=0.55). Landmark analysis showed more consistent benefits in ST with EES within 1year, whereas benefits in TVR were mostly observed later than 1year. CONCLUSIONS: The present pooled patient-level meta analysis demonstrates that among STEMI patients undergoing primary PCI, EES as compared to 1st generation DES is associated with a significant reduction in ST and TVR at long-term follow-up. PMID- 28673737 TI - Fluoroscopic anatomy of the tricuspid valve: Implications for Transcatheter procedures. PMID- 28673738 TI - Chronic use of low-dose aspirin is not associated with lower bone mineral density in the general population. AB - BACKGROUND: Low-dose aspirin is the cornerstone of secondary prevention of cardiovascular disease. Previous studies suggested that the use of aspirin is associated with an increased fracture risk. However, there is uncertainty whether this is due to an effect of aspirin on bone mineral density (BMD). METHODS: Between 2008 and 2012, information on medication use and dual X-ray absorptiometry measured vertebral and femoral BMD of 916 participants was collected in the Netherland Epidemiology of Obesity study. The cross-sectional association between chronic low-dose aspirin use and BMD was estimated using linear regression, controlling for demography, body composition, comorbidity and other medication use which could affect BMD. A subgroup analysis in postmenopausal women (n=329) was conducted. RESULTS: After full adjustment, there was no difference between aspirin users and non-users for vertebral BMD (adjusted mean difference: 0.036 (95% CI -0.027 to 0.100) g/cm2) and femoral BMD (adjusted mean difference: 0.001 (-0.067 to 0.069) g/cm2). Also in the subgroup of postmenopausal women, aspirin use was not associated with lower vertebral (adjusted mean difference: 0.069 (-0.046 to 0.184) g/cm2) or femoral BMD (adjusted mean difference: -0.055 (-0.139;0.029) g/cm2). CONCLUSION: Chronic use of low-dose aspirin is not associated with lower BMD in the general population. The increased risk of fractures observed in aspirin users in previous studies is therefore more likely to be the result of common causes of aspirin use and fractures, but not of direct effects of aspirin on BMD. PMID- 28673739 TI - Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant alpha-synuclein rat model of parkinsonism. AB - Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1-2% of the population over 60years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD. Genetic and post mortem studies have shown a large number of mitochondrial abnormalities in the substantia nigra pars compacta (SNc) of the parkinsonian brain. Furthermore, physiologically, mitochondria of nigral neurons are constantly under unusually high levels of metabolic stress because of the excitatory properties and architecture of these neurons. The protein deacetylase, Sirtuin 3 (SIRT3) reduces the impact subcellular stresses on mitochondria, by stabilising the electron transport chain (ETC), and reducing oxidative stress. We hypothesised that viral overexpression of myc-tagged SIRT3 (SIRT3-myc) would slow the progression of PD pathology, by enhancing the functional capacity of mitochondria. For this study, SIRT3-myc was administered both before and after viral induction of parkinsonism with the AAV-expressing mutant (A53T) alpha synuclein. SIRT3-myc corrected behavioural abnormalities, as well as changes in striatal dopamine turnover. SIRT3-myc also prevented degeneration of dopaminergic neurons in the SNc. These effects were apparent, even when SIRT3-myc was transduced after the induction of parkinsonism, at a time point when cell stress and behavioural abnormalities are already observed. Furthermore, in an isolated mitochondria nigral homogenate prepared from parkinsonian SIRT3-myc infected animals, SIRT3 targeted the mitochondria, to reduce protein acetylation levels. Our results demonstrate that transduction of SIRT3 has the potential to be an effective disease-modifying strategy for patients with PD. This study also provides potential mechanisms for the protective effects of SIRT3-myc. PMID- 28673741 TI - Long-Term Effects of Telephone-Delivered Psychotherapy for Late-Life GAD. AB - OBJECTIVE: To examine the long-term effects of telephone-delivered cognitive behavioral therapy (CBT-T) compared with nondirective supportive therapy (NST-T) in rural older adults with generalized anxiety disorder (GAD). METHODS: 141 adults aged 60 years and older with a principal/co-principal diagnosis of GAD were randomized to either CBT-T or NST-T. CBT-T consisted of up to 11 sessions (9 were required) focused on recognition of anxiety symptoms, relaxation, cognitive restructuring and use of coping statements, problem-solving, worry control, behavioral activation, exposure therapy, and relapse prevention, with optional chapters on sleep and pain. NST-T consisted of 10 sessions focused on providing a supportive atmosphere in which participants could share and discuss their feelings and did not provide any direct suggestions. Primary outcomes included interviewer-rated anxiety severity and self-report worry severity measured at 9 months and 15 months after randomization. Mood-specific secondary outcomes included self-report GAD symptoms and depressive symptoms. RESULTS: At 15 months, after adjustment for multiple testing, there was a significantly greater decline in general anxiety symptoms (difference in improvement: 3.31; 95% CI: 0.45-6.17; t = 2.29; df = 136; p = 0.024) and worry (difference in improvement: 3.13; 95% CI: 0.59-5.68; t = 2.43; df = 136; p = 0.016) among participants in CBT-T compared with those in the NST-T group. There were no significant differences between the conditions in terms of depressive symptoms (difference in improvement: 2.88; 95% CI: 0.17-5.60; t = 2.10; df = 136; p = 0.0376) and GAD symptoms (difference in improvement: 1.65; 95% CI: -0.20 to 3.50; t = 1.76; df = 136; p = 0.080). CONCLUSIONS: CBT-T is superior to NST-T in reducing worry and anxiety symptoms 1 year after completing treatment. PMID- 28673740 TI - Forebrain knock-out of torsinA reduces striatal free-water and impairs whole brain functional connectivity in a symptomatic mouse model of DYT1 dystonia. AB - Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABAergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to antimuscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease. PMID- 28673742 TI - Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles. AB - : Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of reactive oxygen species (ROS) that are also known to upregulate RA receptor alpha (RARalpha) levels. Data showed that neural stem cells from the subventricular zone (SVZ) exposed to blue light (405nm laser) transiently induced NADPH oxidase dependent ROS, resulting in beta-catenin activation and neuronal differentiation, and increased RARalpha levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR NP). The synergy between blue light and LR-NP led to amplified neurogenesis both in vitro and in vivo, while offering a temporal and spatial control of RA release. In conclusion, this combinatory treatment offers great advantages to potentiate neuronal differentiation, and provides an innovative and efficient application for brain regenerative therapies. STATEMENT OF SIGNIFICANCE: Controlling the differentiation of stem cells would support the development of promising brain regenerative therapies. Blue light transiently increased reactive oxygen species, resulting in neuronal differentiation and increased retinoic acid receptor (RARalpha) levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR NP). The synergy between blue light and LR-NP led to amplified neurogenesis, while offering a temporal and spatial control of RA release. In this sense, our approach relying on the modulation of endogenous stem cells for the generation of new neurons may support the development of novel clinical therapies. PMID- 28673743 TI - "Ice Axe Wrist": A Case Report of Intersection Syndrome in 2 Climbers. AB - Intersection syndrome is an inflammatory condition located at the crossing point between the first and second dorsal compartments in the wrist. It is an uncommon presentation but has been recognized as an injury typical of rowers (when it is named oarsman's wrist) and other sports such as racquet sports, baseball, cycling, hockey, golf, ice hockey, skiing, and softball. It has not been previously described in climbers. This report details 2 cases of intersection associated with the use of an ice axe. The first presentation was in a female climber who was using an ice axe for climbing in the Nepal Himalayas and the second was in a male climber using an ice axe for winter climbing training in the Alps. Both climbers presented with wrist pain, swelling, and crepitus over the dorsum of the wrist, about 5 cm proximal to Lister's tubercle. Although well documented in other sporting populations, there seems to be limited reporting of intersection syndrome in the climbing population. It may be worth considering a diagnosis of "ice axe wrist" as a differential in patients who have been using ice axes in climbing or mountaineering. PMID- 28673744 TI - The Ham and Eggs Plant, Lantana camara. PMID- 28673745 TI - High Altitude Pulmonary Edema in a Mining Worker With an Abnormal Rise in Pulmonary Artery Pressure in Response to Acute Hypoxia Without Prior History of High Altitude Pulmonary Edema. AB - High altitude pulmonary edema (HAPE) is a potentially life-threatening form of noncardiogenic pulmonary edema that may develop in otherwise healthy individuals upon ascent to high altitude. A constitutional susceptibility has been noted in some individuals, whereas others appear not to be susceptible at all. In our report, we present a case of HAPE triggered by concurrent respiratory tract infection and strenuous exercise in a mining worker with an abnormal rise in pulmonary artery pressure in response to acute hypoxia, without a prior history of HAPE during almost a year of commuting between high altitude and lowland areas. PMID- 28673746 TI - Unilateral proptosis as the initial manifestation of malignancy. AB - Proptosis, a common sign with a broad differential diagnosis, is defined as anterior displacement and protrusion of one or both orbital globes. Patients can present with varying degrees of chronicity, visual loss and associated symptoms. The etiology of acquired unilateral proptosis is diverse, ranging from benign to life-threatening. The causes of unilateral proptosis include traumatic, vascular, endocrine, inflammatory, infective and malignant. Breast carcinoma is the most common metastatic cause of proptosis; however, proptosis has never been reported as the initial manifestation of breast carcinoma. Our patient presented with unilateral proptosis secondary to an intraorbital lesion and histopathology of orbital lesion was suggestive of metastatic breast adenocarcinoma. She was later diagnosed to have primary breast carcinoma. We present this unusual case of a 56 year-old woman who presented with proptosis as the initial manifestation of a metastatic breast malignancy. PMID- 28673747 TI - Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Methods and Screening Results. AB - PURPOSE: To describe methodology and screening results from the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study. DESIGN: Screening program results for a prospective randomized clinical trial. METHODS: Individuals were recruited who were African-American, Hispanic/Latino, or Asian over age 40 years; white individuals over age 65 years; and any ethnicity over age 40 years with a family history of glaucoma or diabetes. Primary care offices and Federally Qualified Health Centers were used for telemedicine (Visit 1). Two posterior fundus photographs and 1 anterior segment photograph were captured per eye in each participant, using a nonmydriatic, autofocus, hand-held fundus camera (Volk Optical, Mentor, Ohio, USA). Medical and ocular history, family history of glaucoma, visual acuity, and intraocular pressure measurements using the ICare rebound tonometer (ICare, Helsinki, Finland) were obtained. Images were read remotely by a trained retina reader and a glaucoma specialist. RESULTS: From April 1, 2015, to February 6, 2017, 906 individuals consented and attended Visit 1. Of these, 553 participants were female (61.0%) and 550 were African-American (60.7%), with a mean age of 58.7 years. A total of 532 (58.7%) participants had diabetes, and 616 (68%) had a history of hypertension. During Visit 1, 356 (39.3%) participants were graded with a normal image. Using image data from the worse eye, 333 (36.8%) were abnormal and 155 (17.1%) were unreadable. A total of 258 (28.5%) had a suspicious nerve, 62 (6.8%) had ocular hypertension, 102 (11.3%) had diabetic retinopathy, and 68 (7.5%) had other retinal abnormalities. CONCLUSION: An integrated telemedicine screening intervention in primary care offices and Federally Qualified Health Centers detected high rate of suspicious optic nerves, ocular hypertension, and retinal pathology. PMID- 28673748 TI - Late Solitary Extraocular Recurrence From Previously Resected Iris Melanoma. AB - PURPOSE: To report on cases of late extraocular relapse of previously resected iris melanoma, without concurrent intraocular recurrence. DESIGN: Retrospective case series. METHODS: A retrospective chart review of 4 patients diagnosed with late subconjunctival relapse of previously resected iris melanoma. RESULTS: Three female patients and 1 male patient underwent iris tumor resection and presented to our service with suspicious conjunctival lesions at a median of 22 years later (mean: 21 years). None showed intraocular relapse. Treatment of the conjunctival tumors included excisional biopsy (n = 4), followed by cryotherapy (n = 3) and/or brachytherapy (n = 3). In all cases, histopathology confirmed malignant melanoma, with no intraepithelial component or associated melanosis. Genetic sequencing (n = 3) showed wild-type BRAF and NRAS in all. GNA11 mutation was found in 1 case. On array-based comparative genomic hybridization (n = 3), gain of 6p was found in 2 cases and gain of 8 in 2. Overall, findings were strongly suggestive of a diagnosis of late extraocular relapse from previously resected iris melanoma. In a median of 2.5 years (mean: 7.7 years) from the subconjunctival relapse, no further episodes of intraocular/extraocular recurrence were recorded, and all patients were free from distant metastasis. CONCLUSIONS: Patients undergoing iris melanoma resection are at risk of developing late solitary extraocular relapse even more than 30 years after surgery. In the absence of an intraocular component, diagnosis may be challenging, as tumors mimic a primary conjunctival lesion. Management by excisional biopsy followed by adjuvant therapy was successful, and histopathology and genetic analysis supported a diagnosis of extraocular uveal tumor spread rather than a primary conjunctival tumor. PMID- 28673749 TI - Microcystoid Macular Changes in Association With Idiopathic Epiretinal Membranes in Eyes With and Without Glaucoma: Clinical Insights. AB - PURPOSE: To describe the clinical and surgical significance of microcystoid macular changes in the inner nuclear layer in patients with idiopathic epiretinal membranes, with and without glaucomatous optic neuropathy. DESIGN: Retrospective case series. METHODS: Clinical charts and spectral-domain optical coherence tomography images of 264 eyes of 234 consecutive patients diagnosed with idiopathic epiretinal membranes were reviewed and analyzed. Surgical data were analyzed in a subgroup of eyes with microcystoid macular changes treated with pars plana vitrectomy and epiretinal and internal limiting membrane peel. In surgical cases, postoperative functional and anatomic results at 1 and 6 months were compared between glaucomatous and nonglaucomatous eyes. Associations of microcystoid macular changes with visual acuity and other morphometric parameters were assessed by means of linear or multiple logistic regressions. RESULTS: Microcystoid macular changes in the inner nuclear layer were diagnosed in 52 out of 264 eyes with epiretinal membranes (19.7%), of which 28 (55.0%) had concomitant glaucoma. The likelihood to develop microcystoid macular changes increased at advanced glaucoma and epiretinal membrane stages. The morphology of microcystoid macular changes was similar between glaucomatous and nonglaucomatous eyes. Forty-four out of 52 eyes (84.6%) with microcystoid macular changes, of which 20 were with glaucoma and 24 without glaucoma, underwent surgery with pars plana vitrectomy and epiretinal and internal limiting membrane peel. At 1 and 6 months after surgery the mean number of microcysts decreased significantly from baseline in nonglaucomatous eyes (P = .003 and P = .002, respectively) and remained unchanged in glaucomatous eyes (P = .400 and P = .700, respectively). CONCLUSIONS: This study reports a high frequency of microcystoid macular changes in the inner nuclear layer in eyes with concomitant epiretinal membrane and glaucomatous optic neuropathy. In glaucomatous eyes, pars plana vitrectomy with epiretinal and internal limiting membrane peel was ineffective in the treatment of microcystoid macular changes. PMID- 28673750 TI - Quality of Vision in Eyes With Epiphora Undergoing Lacrimal Passage Intubation. AB - PURPOSE: To investigate visual function and optical quality in eyes with epiphora undergoing lacrimal passage intubation. DESIGN: Prospective case series. METHODS: Thirty-four eyes of 30 patients with lacrimal passage obstruction were enrolled. Before and 1 month after lacrimal passage intubation, functional visual acuity (FVA), higher-order aberrations (HOAs), lower tear meniscus, and tear clearance were assessed. An FVA measurement system was used to examine changes in continuous visual acuity (VA) over time, and visual function parameters such as FVA, visual maintenance ratio, and blink frequency were obtained. Sequential ocular HOAs were measured for 10 seconds after the blink using a wavefront sensor. Aberration data were analyzed in the central 4 mm for coma-like, spherical-like, and total HOAs. Fluctuation and stability indices of the total HOAs over time were calculated. Lower tear meniscus was assessed by anterior segment optical coherence tomography. RESULTS: After lacrimal passage intubation, visual function significantly improved, as indicated by improved FVA (P = .003) and visual maintenance ratio (P < .001). Blink frequency decreased significantly after treatment (P = .01). Optical quality significantly improved, as indicated by a decrease in coma-like aberrations (P = .003), spherical-like aberrations (P = .018), and total HOAs (P = .001). Stability index increased (P < .001) and fluctuation index decreased (P = .019), and tear meniscus dimension decreased (P < .001). CONCLUSIONS: Lacrimal passage intubation for eyes with epiphora significantly improved visual function and optical quality via patency of the lacrimal passage. PMID- 28673751 TI - Intensive repetitive transcranial magnetic stimulation changes EEG microstates in schizophrenia: A pilot study. PMID- 28673752 TI - Polymorphisms in immune-inflammatory response genes and the risk of deficit schizophrenia. AB - Polymorphisms in immune-inflammatory response genes are believed to impact schizophrenia susceptibility. However, it remains unknown whether immunogenetic factors play a role in the etiology of deficit schizophrenia (D-SCZ). Therefore, we genotyped four polymorphisms in genes encoding two immune system regulatory proteins (CTLA-4 rs231775 and CD28 rs3116496), interleukin-6 (IL6 rs1800795) and transforming growth factor-beta (TGFB1 rs1800470) in 513 schizophrenia patients and 374 controls. The CD28 rs3116496-CC genotype and C-allele were significantly more frequent in the whole group of patients and D-SCZ patients compared to controls. Our results indicate that the CD28 rs3116496 polymorphism might impact the risk of schizophrenia, especially D-SCZ. PMID- 28673754 TI - The longevity gene Klotho is differentially associated with cognition in subtypes of schizophrenia. AB - Cognitive impairment is a core feature of schizophrenia and impacts negatively the functioning of affected individuals. Cognitive decline correlates with aging, and is the primary cause of loss of independence and reduced quality of life. The klotho gene is a key modulator of aging, with expression deficiency resulting in premature aging, while overexpression extends lifespan and enhances cognition. A haplotype and functional human variant of the gene, KL-VS, increases expression and promotes longevity. KL-VS heterozygosity is associated with enhanced cognition and a larger volume of the right dorsolateral prefrontal cortex, a region involved in planning and decision-making, which is especially susceptible to shrinkage with age. We examined the effect of KL-VS heterozygosity on cognition in 497 schizophrenia patients and 316 healthy controls from the Western Australian Family Study of Schizophrenia (WAFSS) who had been comprehensively characterised by neurocognitive tests and classified into cognitively deficient (CD) and cognitively "spared" (CS) clusters. An older, cognitively normal population sample from the Health in Men Study (HIMS) was included to allow assessment of heterozygosity and memory in aged individuals. We show that heterozygosity is associated with better learning and memory in the younger WAFSS healthy controls but not in the aging HIMS sample. However, in schizophrenia patients, KL-VS has a selective effect on memory, with heterozygotes in CD and CS clusters performing worse than non-carriers. This effect was significant and more severe in the CD cluster, reinforcing the utility of subtyping patients into CD and CS clusters that may differ in their genetic underpinnings. PMID- 28673753 TI - Relationship between effortful motivation and neurocognition in schizophrenia. AB - Effortful motivation and reward valuation learning deficits are associated with negative symptoms and impaired cognition in schizophrenia (SZ) patients. Whereas clinical assessments of motivation and reward value typically rely upon clinician ratings or self-report scales, behavioral measures often confound these constructs. Simple reverse-translated behavioral tasks that independently quantify motivation and reward valuation-which could then be linked to cognition may facilitate the development of pro-cognitive therapeutics by bridging the "preclinical-to-clinical" gap. This study determined whether novel behavioral measures of effortful motivation and reward valuation are associated with impaired cognition in SZ patients (n=36). Patients completed the Progressive Ratio Breakpoint task (PRBT; physical effort motivation) and the Probabilistic Learning Task (PLT; reward learning/valuation) in conjunction with the MATRICS Consensus Cognitive Battery (MCCB). SZ patients exhibited statistically significant deficits in global cognition and all individual MCCB subdomains. Significant correlations were observed between PRBT and MCCB global cognition (r=0.52), speed of processing (r=0.56) and attention vigilance (r=0.48) subdomains, but not with PLT or clinical symptoms. Results indicate that effort and reward learning deficits are dissociable targets that can improve our understanding of cognitive impairments associated among patients with SZ. More importantly, the results support the long-standing notion that the measurement of cognitive impairments in SZ is highly linked to a willingness to expend effort. The availability of a PRBT designed for use in both rodents and humans could improve our understanding of the nature of cognitive impairments in neuropsychiatric disorders and accelerate the development of novel pro-cognitive therapeutics. PMID- 28673755 TI - Psychomotor assessment as a tool to differentiate schizophrenia from other psychotic disorders. AB - GOAL: The aim of this study is to assess to what extent psychomotor assessment can aid the clinician in differentiating between schizophrenia and other psychotic disorders. METHODS: Enrolled subjects were recent in remission patients (n=304), who all met DSM-IV (APA, 2013) criteria for either schizophrenia (Sz; n=117), schizoaffective disorder (SaD; n=36), psychotic disorder not otherwise specified (P-NOS) (n=86), substance/medication-induced psychotic disorder (SIPD; n=33) or major depressive disorder with psychotic features (MDD-p; n=32). The patients were submitted to a psychomotor test battery. RESULTS: Patients with schizophrenia generally perform worse on most tests. Using cluster analysis a combination of three tests, namely the sensory integration subscale of the Neurological Evaluation Scale (NES), a Figure Copying Task (FCT) and the finger tapping test (FTT), came out to be useful to clinically differentiate between schizophrenia and substance-induced psychotic disorder (SIPD) or psychosis not otherwise specified (P-NOS). When comparing schizophrenia only to a group of patients with SIPD, the differentiation potential becomes even greater with a 76.1% chance to correctly diagnose patients with schizophrenia and 75% chance for patients with SIPD. CONCLUSION: A combination of NES, FCT and FTT shows promising results as a clinical tool in daily practice to differentiate schizophrenia from other psychotic disorders. Future prospective studies to confirm these results are necessary. PMID- 28673756 TI - In vitro simulation of realistic gastric pressure profiles. AB - Novel in vitro dissolution tools can aid the development of orally administered drugs by explaining dosage form related in vivo phenomena that are not explainable with standard test apparatuses. Such novel tools are able to mimic various parameters in accordance with gastrointestinal conditions. Hereby, in vivo occurring pressure events were shown to be of major importance since they largely affect dosage form disintegration, drug dissolution and subsequently resulting drug plasma concentration profiles. The aim of the present study was to investigate the feasibility of producing biorelevant pressure events with standard test apparatuses and with the dynamic open flow through test apparatus. For this purpose, we used the SmartPill(r), a swallowable capsule that houses a pressure sensor and that was already applied to gather human in vivo data. Among the standard apparatuses, highest pressures were measured in the reciprocating cylinder apparatus and the disintegration tester. No relevant pressure peaks could be detected in the paddle apparatus and the mini paddle apparatus. In contrast, the dynamic open flow through test apparatus enabled the simulation of complete gastric pressure profiles as they occur in vivo. The present work underlines the potential of novel in vitro dissolution models as useful tools during the drug development process as well as for explanatory purposes. PMID- 28673757 TI - Anti-Inflammatory, Antiapoptotic and Proproliferative Effects of Vitis vinifera Seed Ethanolic Extract in the Liver of Streptozotocin-Nicotinamide-Induced Type 2 Diabetes in Male Rats. AB - OBJECTIVES: Consumption of Vitis vinifera seed has been reported to ameliorate liver pathology in diabetes mellitus; however, the mechanisms underlying its effects remain unknown. In this study, the anti-inflammatory, anti-apoptotic and pro-proliferative effects of the ethanolic seed extract of V. vinifera (VVSEE) in the liver in cases of diabetes were identified. METHODS: Adult male rats with streptozotocin-nicotinamide-induced diabetes were given 50, 100 or 200 mg/kg body weight VVSEE orally for 28 days. At the end of the treatment, body weights were determined, and the blood was collected for analyses of fasting blood glucose, insulin and liver enzyme levels. Following sacrifice, livers were harvested and their wet weights and glycogen contents were measured. Histologic appearances of the livers were observed under light microscopy, and the expression and distribution of inflammatory, apoptosis and proliferative markers in the livers were identified by molecular biologic techniques. RESULTS: Treatment of rats with diabetes by VVSEE attenuates decreased body weight, liver weight and liver glycogen content. Additionally, increases in fasting blood glucose levels and liver enzyme levels and decreases in serum insulin levels were ameliorated. Lesser histopathologic changes were also observed: decreased inflammation and apoptosis, as indicated by decreased levels of inflammatory markers (TNF-alpha, NF-Kbeta, IKK-beta, IL-6, IL-1beta) and apoptosis markers (caspase-3, caspase-9 and Bax). VVSEE treatment induces increase in hepatocyte regeneration, as indicated by increased PCNA and Ki-67 distribution in the livers of rats with diabetes. Several molecules identified in VVSEE via gas chromatography mass spectrometry might contribute to these effects. CONCLUSIONS: The anti inflammatory, anti-apoptotic and pro-proliferative effects of VVSEE could account for its hepatoprotective actions in diabetes. PMID- 28673758 TI - Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms. AB - Schizophrenia is a complex neuropsychiatric illness with marked sex differences. Women have later onset and lesser symptoms, which has led to the hypothesis that estrogens are protective in schizophrenia. Cognitive dysfunction is a hallmark of the disease and the symptom most correlated with functional outcome. Here we describe a number of mechanisms by which estrogens may be therapeutic in schizophrenia, with a focus on cognitive symptoms. We review the relationship between estrogens and brain derived neurotrophic factor, neuroinflammation, NMDA receptors, GABA receptors, and luteinizing hormone. Exploring these pathways may enable novel treatments for schizophrenia and a greater understanding of this devastating disease. PMID- 28673759 TI - Biomechanical and functional efficacy of knee sleeves: A literature review. AB - BACKGROUND: Knee sleeves are widely used for the symptomatic relief and subjective improvements of knee problems. To date, however, their biomechanical effects have not been well understood. OBJECTIVE: To determine whether knee sleeves can significantly improve the biomechanical variables for knee problems. METHOD: Systematic literature search was conducted on four online databases - PubMed, Web of Science, ScienceDirect and Springer Link - to find peer-reviewed and relevant scientific papers on knee sleeves published from January 2005 to January 2015. Study quality was assessed using the Structured Effectiveness Quality Evaluation Scale (SEQES). RESULTS: Twenty studies on knee sleeves usage identified from the search were included in the review because of their heterogeneous scope of coverage. Twelve studies found significant improvement in gait parameters (3) and functional parameters (9), while eight studies did not find any significant effects of knee sleeves usage. CONCLUSION: Most improvements were observed in: proprioception for healthy knees, gait and balance for osteoarthritic knees, and functional improvement of injured knees. This review suggests that knee sleeves can effect functional improvements to knee problems. However, further work is needed to confirm this hypothesis, due to the lack of homogeneity and rigor of existing studies. PMID- 28673760 TI - The influence of sleep disordered breathing in REM sleep behavior disorder. AB - OBJECTIVES/BACKGROUND: Because both REM sleep behavior disorder (RBD) and Obstructive Sleep Apnea (OSA) can present with similar symptoms, it is important to understand the influence of OSA in the clinical manifestations of RBD and whether RBD modulates OSA severity. Our objectives were to compare: 1. the intensity of non-motor symptoms between RBD patients with (RBD-OSA) and without OSA (RBD-non-OSA), and 2. polysomnographic features between RBD-OSA and OSA without RBD (OSA-non-RBD) patients. METHODS: 32 RBD cases were divided in two groups according to the presence of moderate to severe OSA [Apnea Hypopnea Index (AIH) > 14] (RBD-OSA vs. RBD-non-OSA). Non-motor symptoms were assessed with Montreal Cognitive Assessment Scale, SCOPA-Sleep and the Non-Motor Symptom Scale (NMSS) for Parkinson's disease. RBD-OSA patients were compared to 20 OSA-non-RBD patients matched for age, AHI and gender. RESULTS: Compared to RBD-non-OSA (n = 22) patients, RBD-OSA patients (n = 10) showed significantly higher scores in SCOPA-Sleep Daytime and NMSS Attention/Memory, Gastrointestinal and Urinary domains, as well as higher sleep fragmentation, more oxygen desaturation and higher AIH in NREM sleep. RBD-OSA patients presented with less O2 desaturation, snoring, and BMI when compared to OSA-non-RBD patients. DISCUSSION: Our data suggests that OSA contributes to hypersomnolence, gastro-intestinal, memory, and urinary complaints in RBD patients. RBD patients seem to have a milder OSA phenotype (possible reflecting a protective role conferred by the maintenance of muscle tone during REM sleep) and to be less prone to obesity and snoring than non-RBD patients. PMID- 28673761 TI - Primary Percutaneous Coronary Intervention As Treatment for ST-Elevation Myocardial Infarction in a Centenarian: Choosing Carefully. AB - We report on a 105-year-old woman presenting with inferior ST-elevation myocardial infarction (STEMI). She was managed with primary percutaneous intervention (PCI) to the right coronary artery with a single bare-metal stent. There were no acute complications, although she experienced delirium and functional decline requiring prolonged hospital admission. She was discharged home and celebrated her 106th birthday. This report describes the oldest centenarian with STEMI found in the literature and managed with PCI. No data exist on how best to manage centenarians with STEMI. Patient comorbidities, functional status, and values should be considered in managing such patients. PMID- 28673762 TI - Diffusion-weighted MRI in image-guided adaptive brachytherapy: Tumor delineation feasibility study and comparison with GEC-ESTRO guidelines. AB - PURPOSE: To examine the feasibility of using diffusion-weighted images (DWIs) coregistered with T2-weighted (T2w) sequence in treatment planning system to improve target delineation for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer patients. METHODS AND MATERIALS: We retrospectively examined the records of consecutive patients who were referred to our institution for pulse-dose-rate IGABT between May and December 2015 after concurrent chemoradiation. An MRI with T2w and DWI sequences with a maximum diffusion factor of 1000 s/mm2 on a 1.5 or 3.0-T MR scanner was performed after placement of the vaginal mold applicator. T2w defined gross tumor volume (GTVT2) and diffusion volume on DWI sequences (CTVDWI) were retrospectively delineated, if achievable, by radiologist and radiation oncologist. Concordances between CTVDWI and GTVT2, high-risk and intermediate-risk clinical target volumes (CTVHR and CTVIR) were evaluated. RESULTS: Forty-four patients were identified: 23 patients (52%) had a GTVT2 delineated, CTVDWI was delineated in 42 patients (95%). Intraobserver and interobserver conformity indexes were <0.75 in 11 patients (26%) and 23 patients (54%), respectively. There was a positive correlation between GTVT2 and CTVDWI volumes (p = 0.038, r = 0.58). Median CTVHR and CTVDWID90 were 37.3 Gy (17.1-48.9 Gy) and 33 Gy (22-97 Gy), respectively (p = 0.659). CTVDWI could have pointed CTVHR delineation modifications in a total of 32 of 44 (73%) patients with CTVDWI/CTVHR conformity < 1. CTVDWI volume was totally encompassed by CTVIR in all patients. CONCLUSIONS: These results suggest that DWI images as anatomical sequence without apparent diffusion coefficient mapping might have led to CTVHR modifications. Still, interobserver and intraobserver variations in delineation are substantial, and artifacts make it difficult to implement. PMID- 28673763 TI - Demographic characterization and spatial cluster analysis of human Salmonella 1,4,[5],12:i:- infections in Portugal: A 10year study. AB - Salmonella 1,4,[5],12:i:- is presently considered one of the major serovars responsible for human salmonellosis worldwide. Due to its recent emergence, studies assessing the demographic characterization and spatial epidemiology of salmonellosis 1,4,[5],12:i:- at local- or country-level are lacking. In this study, a analysis was conducted over a 10year period, from 2000 to the first quarter of 2011 at the Portuguese National Laboratory in Portugal mainland, with a total of 215 Salmonella 1,4,[5],12:i:- serotyped isolates obtained from human infections by a passive surveillance system. Data regarding source, year and month of sampling, gender, age, district and municipality of the patients were registered. Descriptive statistical analysis and a spatial scan statistic combined with a geographic information system were employed to characterize the epidemiology and identify spatial clusters. Results showed that most districts have reports of Salmonella 1,4,[5],12:i:-, with a higher number of cases at the Portuguese coastland, including districts like Porto (n=60, 27.9%), Lisboa (n=29, 13.5%) and Aveiro (n=28, 13.0%). An increased incidence was observed in the period from 2004 to 2011 and most infections occurred during May and October. Spatial analysis revealed 4 clusters of higher than expected infection rates. Three were located in the north of Portugal, including two at the coastland (Cluster 1 [RR=3.58, p<=0.001] and 4 [RR=10.42 p<=0.230]), and one at the countryside (Cluster 3 [RR=17.76, p<=0.001]). A larger cluster was detected involving the center and south of Portugal (Cluster 2 [RR=4.85, p<=0.001]). The present study was elaborated with data provided by a passive surveillance system, which may originate an underestimation of disease burden. However, this is the first report describing the incidence and the distribution of areas with higher risk of infection in Portugal, revealing that Salmonella 1,4,[5],12:i:- displayed a significant geographic clustering and these areas should be further evaluated to identify risk factors in order to establish prevention programs. PMID- 28673764 TI - How to Assess Sensory Recovery After Breast Reconstruction Surgery? AB - BACKGROUND: We evaluated clinical against psychophysical (tactile and thermal quantitative sensory test [QST]), neurophysiologic (somatosensory evoked potential [SEP]), and epithelial nerve fiber density (ENFD) examinations in detection and follow-up of sensory alterations after breast reconstruction done with or without nerve anastomoses. PATIENTS AND METHODS: In a prospective 2-year follow-up design, 56 breast cancer patients underwent innervated and 20 patients noninnervated free rectus abdominis muscle-sparing flap (ms-TRAM) breast reconstruction. Healthy contralateral breasts (36 patients) and 20 healthy volunteer women served as control participants. The diagnostic values of clinical examination, QST, SEP, and ENFD tests were assessed at baseline, and 1 and 2 years postoperatively. RESULTS: Sensation of mastectomized thoracic skin was impaired before reconstruction surgery, confirmed with QST (P < .001 for tactile, warm and cool detection; others not significant). All tests were further impaired at 1 year (P < .012-.0001), but mostly showed improvement during subsequent follow-up (P < .001-.0001), except for vibration and 2-point discrimination, ENFD, and SEP. QST improved diagnostic accuracy for large as well as small fiber function performing best in assessing sensory recovery at 2 years. Of clinical tests, sharp-blunt discrimination was modestly useful (sensitivity, 0.85; poor specificity, 0.17). Two-point and vibration discrimination tests had poor diagnostic values. SEP recording was modestly sensitive (0.50), but not specific (0.25). Because of sparse epithelial innervation already at baseline, ENFD performed poorly. CONCLUSION: Most tests could identify sensory nerve damage postoperatively. Tactile and thermal QST were most reliable, and sensitive also in confirming sensory recovery. SEP recording was useful especially in differentiating surgical techniques, whereas ENFD and clinical examination performed poorly, with the exception of sharp-blunt discrimination. PMID- 28673765 TI - Cyanoacrylate Adhesive Reduces Seroma Production After Modified Radical Mastectomy or Quadrantectomy With Lymph Node Dissection-A Prospective Randomized Clinical Trial. AB - INTRODUCTION: The accumulation of fluid, a seroma, is a frequent complication after modified radical mastectomy or quadrantectomy with lymph node dissection. The aim of the present study was to examine whether a new adhesive material made of cyanoacrylate can effectively provide a sealing coat to tissues and thus reduce the incidence of seroma significantly. PATIENTS AND METHODS: The present prospective, randomized case-control study included 128 women with a breast cancer diagnosis and scheduled for modified radical mastectomy or quadrantectomy with lymph node dissection in Thessaloniki, Greece. In 64 patients (cases), a cyanoacrylate adhesive was applied at the operative field after removal of the tumor and lymph nodes; the remaining 64 patients served as the controls. RESULTS: Seroma production (P = .001), drainage duration (P = .001), and drainage amount (P = .001) were all significantly less for cases than for controls. The results from a stepwise multiple regression model incorporating the use of adhesive, body mass index, tumor size, and number of infiltrated lymph nodes were significant and able to explain 51.6% of the variability in seroma amount. CONCLUSION: The results of our study have demonstrated that the cyanoacrylate adhesive can contribute to the reduction of seromas produced after mastectomy and subsequently decrease the duration of postoperative drainage and the frequency of seroma aspirations. However, because the pathogenesis of seroma formation is multifaceted and complex, further research of larger sample sizes is required to confirm the results of our study. PMID- 28673766 TI - Abnormal cortical-basal ganglia network in amyotrophic lateral sclerosis: A voxel wise network efficiency analysis. AB - Evidence suggests that dysfunctional cortical-basal ganglia (CBG) network plays important roles in the motor symptoms in amyotrophic lateral sclerosis (ALS). However, little effort has been made to investigate the functional abnormalities of CBG network in ALS. Here, we constructed voxel-wise CBG networks using the resting-state fMRI data of 20 patients with ALS and 21 normal controls, and characterized the differences of their efficiency parameters between the two groups. Compared to normal controls, patients with ALS exhibited decreased nodal efficiency in the right thalamus (THA), the left caudate (CAU) and the right precentral gyrus (preCG), and increased nodal efficiency in the left preCG. In the patient group, we observed a significant negative correlation between the nodal efficiency of the right preCG and disease progression rate. These results demonstrate that both ineffective information transfer and compensatory mechanisms are involved in the pathophysiological mechanism underlying the motor dysfunctions in patients with ALS. In summary, the present study provides a novel perspective on pathophysiological explanation for the motor symptoms in patients with ALS. PMID- 28673767 TI - Diminished motor imagery capability in adults with motor impairment: An fMRI mental rotation study. AB - Recent research has demonstrated that adults with probable Developmental Coordination Disorder (pDCD) show similar behavioural deficits as those observed in children DCD when performing a motor imagery task. The aim of this study was to investigate whether the pattern of neural activation in adults with pDCD during motor imagery differed from adults without motor skill impairment. Twelve adults with pDCD (5 male; age M=24.5 yrs) and 11 adults without pDCD (6 male; age M=26.7 yrs) participated. The hand rotation task was used to assess motor imagery ability, while functional neural images were acquired using a 3T MR scanner. Performance on the hand task in both groups conformed to the biomechanical constraints of real movement, supporting the use of motor imagery to complete the task. Comparisons of response time and accuracy data showed no significant group differences. Comparison of the BOLD signal activation maps identified a significant parametric difference between groups. The% BOLD signal change for increasing angle of rotation showed greater activation in controls compared to the pDCD group in the occipito-parietal and parieto-frontal networks including the middle frontal gyrus bilaterally, the left superior parietal lobe as well as in the cerebellum (lobule VI). The pattern of reduced activation in adults with pDCD is consistent with recent studies of childhood DCD that suggest atypical activation in frontal, parietal and cerebellar areas, and supports the theory that this type of impairment may be associated with disruption of parieto-frontal and parieto-cerebellar networks. PMID- 28673768 TI - Prefrontal mRNA expression of long and short isoforms of D2 dopamine receptor: Possible role in delayed learning deficit caused by early life interleukin-1beta treatment. AB - Long (D2L) and short (D2S) isoform of the D2 dopamine receptor are believed to play different roles in behavioral regulation. However, little is known about differential regulation of these isoforms mRNA expression during the process of learning in physiological and pathological states. In this study, we have investigated the combined effect of training in active avoidance (AA) paradigm and chronic early life treatment with pro-inflammatory cytokine interleukin (IL) 1beta (1MUg/kg i.p., P15-21) on D2S and D2L dopamine receptor mRNA expression in the medial prefrontal cortex (mPFC) of adult rats. We have shown differential regulation of D2 short and long mRNA isoform expression in the mPFC. There was no effect of AA-training on D2S mRNA expression, while D2L mRNA was downregulated in AA-trained control (intact and saline-treated) animals, and this effect was not observed in rats treated with IL-1beta. D2S mRNA expression level negatively correlated with learning ability within control (saline-treated and intact) groups but not in IL-1beta-treated animals. Thus, prefrontal expression of distinct D2 dopamine receptor splice variants is supposed to be implicated in cognitive decline caused by early life immune challenge. PMID- 28673770 TI - Alterations of the nuclear transport system in hepatocellular carcinoma - New basis for therapeutic strategies. AB - Hepatocellular carcinoma (HCC) is among the most prevalent human malignancies worldwide with rising incidence in industrialised countries, few therapeutic options and poor prognosis. To expand and improve therapeutic strategies, identification of drug targets involved in several liver cancer-related pathways is crucial. Virtually all signal transduction cascades cross the nuclear envelope and therefore require components of the nuclear transport system (NTS), including nuclear transport receptors (e.g. importins and exportins) and the nuclear pore complex. Accordingly, members of the NTS represent promising targets for therapeutic intervention. Selective inhibitors of nuclear export have already entered clinical trials for various malignancies. Herein, we review the current knowledge regarding alterations of the NTS and their potential for targeted therapy in HCC. PMID- 28673769 TI - Age-related deficits in the mnemonic similarity task for objects and scenes. AB - Using the Mnemonic Similarity Task (MST), we have demonstrated an age-related impairment in lure discrimination, or the ability to recognize an item as distinct from one that was similar, but not identical to one viewed earlier. A growing body of evidence links these behavioral changes to age-related alterations in the hippocampus. In this study, we sought to evaluate a novel version of this task, utilizing scenes that might emphasize the role of the hippocampus in contextual and spatial processing. In addition, we investigated whether, by utilizing two stimulus classes (scenes and objects), we could also interrogate the roles of the PRC and PHC in aging. Thus, we evaluated differential contributions to these tasks by relating performance on objects versus scenes to volumes of the hippocampus and surrounding medial temporal lobe structures. We found that while there was an age-related impairment on lure discrimination performance for both objects and scenes, relationships to brain volumes and other measure of memory performance were stronger when using objects. In particular, lure discrimination performance for objects showed a positive relationship with the volume of the hippocampus, specifically the combined dentate gyrus (DG) and CA3 subfields, and the subiculum. We conclude that though using scenes was effective in detecting age-related lure discrimination impairments, it does not provide as strong a brain-behavior relationship as using objects. PMID- 28673771 TI - What Do We Learn From Explant Analysis Programs? PMID- 28673772 TI - Methyl-4-phenylpyridinium (MPP+) differentially affects monoamine release and re uptake in murine embryonic stem cell-derived dopaminergic and serotonergic neurons. AB - 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to selectively damage dopaminergic (DA) cells in the substantia nigra and to produce symptoms which are alike to those observed in Parkinson's disease (PD). Based on the similarity between MPTP-induced neurotoxicity and PD-related neuropathology, application of MPTP or its metabolite methyl-4-phenylpyridinium (MPP+) was successfully established in experimental rodent models to study PD-related neurodegenerative events. MPP+ is taken up by the dopamine transporter (DAT) into DA neurons where it exerts its neurotoxic action on mitochondria by affecting complex I of the respiratory chain. MPP+ is also a high affinity substrate for the serotonin transporter (SERT), however little is known about possible toxic effects of MPP+ on serotonergic (5-HT) neurons. In order to compare cell type specific effects of MPP+ treatment, we have differentiated mouse embryonic stem (ES) cells into DA and 5-HT neurons and studied the impact of MPP+ treatment on both types of monoaminergic neurons in vitro. MPP+ treatment impacts on mitochondrial membrane potential in DA as well as 5-HT ES cell-derived neurons. Although mitochondria metabolisms are similarly affected, synaptic vesicle cycling is only impaired in DA ES cell-derived neurons. Most importantly we show that MPP+ induces DAT externalization in DA neurons, but internalization of SERT in 5-HT neurons. This diverse MPP+-induced transporter trafficking is reflected by elevated substrate uptake in DA neurons, and diminished substrate uptake in 5 HT neurons. In summary, our experimental data point toward differential effects of MPP+ intoxication on neurotransmitter release and re-uptake in different types of monoaminergic neurons. PMID- 28673773 TI - Erratum to "Doppler ultrasonography helps discriminate between cirrhotic and non cirrhotic patients with viral B and C hepatitis" [Diagn. Interv. Imaging 97 (3) (2016) 339-45]. PMID- 28673775 TI - Intramyocardial bone marrow mononuclear cells versus bone marrow-derived and adipose mesenchymal cells in a rat model of dilated cardiomyopathy. AB - BACKGROUND: Effects of cell therapy on dilated cardiomyopathy (DCM) have been investigated in pre-clinical models using distinct cellular types in each study. A single study that compares the effectiveness of different cells is lacking. METHODS: We have compared the effects of intramyocardial injection (IMI) of bone marrow (BM)-derived mononuclear cells (MNCs), BM and adipose tissue (AT) mesenchymal stromal cells (BM-MSCs and AT-MSCs) on heart function, histological changes and myocardial ultrastructure in a rat model of DCM. Isogenic Wistar rats were used to isolate the different cell types and to induce DCM by autoimmune myocarditis. Animals were randomly assigned to receive BM-MNCs, BM-MSCs, AT-MSCs or placebo at day 42 by IMI. Serial echocardiography was used to assess cardiac function and hearts obtained after sacrifice at day 70, were used for histological and ultrastructural analysis. Serum levels of type B-natriuretic peptide (BNP) and vascular endothelial growth-factor (VEGF) were determined at different time points. RESULTS: BM-MSC treatment induced significant improvement in ejection fraction (EF), fractional shortening (FS), left ventricular systolic diameter (LVESD) and systolic volume (LVESV). In contrast, changes in echocardiographic parameters with respect to pre-treatment values in animals receiving placebo, AT-MSCs or BM-MNCs were not statistically significant. EF and FS in animals receiving AT-MSCs were superior to those receiving placebo. BM-MSC transplantation induced also improvement in cardiac fibers organization and capillary density, fibrotic tissue reduction, increase in final VEGF concentration and BNP decrease. DISCUSSION: IMI of BM or AT-MSCs improves LV function and induces more angiogenesis processes than BM-MNCs. In addition, BM MSCs showed more anti-fibrotic effects and more ability to reorganize myocardial tissue compared with the other cell types. PMID- 28673774 TI - Development, functional characterization and validation of methodology for GMP compliant manufacture of phagocytic macrophages: A novel cellular therapeutic for liver cirrhosis. AB - BACKGROUND AIMS: Autologous macrophage therapy represents a potentially significant therapeutic advance for the treatment of severe progressive liver cirrhosis. Administration of macrophages has been shown to reduce inflammation and drive fibrotic scar breakdown and tissue repair in relevant models. This therapeutic approach is being assessed for safety and feasibility in a first-in human trial (MAcrophages Therapy for liver CirrHosis [MATCH] trial). METHODS: We outline the development and validation phases of GMP production. This includes use of the CliniMACS Prodigy cell sorting system to isolate CD14+ cells; optimizing macrophage culture conditions, assessing cellular identity, product purity, functional capability and determining the stability of the final cell product. RESULTS: The GMP-compliant macrophage products have a high level of purity and viability, and have a consistent phenotypic profile, expressing high levels of mature macrophage markers 25F9 and CD206 and low levels of CCR2. The macrophages demonstrate effective phagocytic capacity, are constitutively oriented to an anti-inflammatory profile and remain responsive to cytokine and TLR stimulation. The process validation shows that the cell product in excipient is remarkably robust, consistently passing the viability and phenotypic release criteria up to 48 hours after harvest. CONCLUSIONS: This is the first report of validation of a large-scale, fully Good Manufacturing Practice-compliant, autologous macrophage cell therapy product for the potential treatment of cirrhosis. Phenotypic and functional assays confirm that these cells remain functionally viable for up to 48 h, allowing significant flexibility in administration to patients. PMID- 28673776 TI - Private Practice Radiologist Subspecialty Classification Using Medicare Claims. AB - PURPOSE: The aim of this study was to assess both existing Medicare provider code assignments and a new claims-based system for subspecialty classification of private practice radiologists. METHODS: Websites of the 100 largest US radiology private practices were used to identify 1,476 radiologists self-identified with a single subspecialty ([1] abdominal, [2] breast, [3] cardiothoracic, or [4] musculoskeletal imaging; [5] nuclear medicine; [6] interventional radiology; [7] neuroradiology). Concordance of existing Medicare radiology subspecialty provider codes (present only for nuclear medicine and interventional radiology) was first assessed. Next, using a classification approach based on Neiman Imaging Types of Service (NITOS) piloted among academic practices, the percentage of subspecialty work relative value units (wRVUs) from 2012 to 2014 Medicare claims were used to assign each radiologist a unique subspecialty. RESULTS: Existing Medicare provider codes matched only 8.0% of nuclear medicine physicians and 10.7% of interventional radiologists to their self-reported subspecialties. The NITOS based system mapped a median 51.9% of private practice radiologists' wRVUs to self-identified subspecialties (range, 23.3% [nuclear medicine] to 73.6% [neuroradiology]). The 50% NITOS-based wRVU threshold previously established for academic radiologists correctly assigned subspecialties to 48.8% of private practice radiologists but incorrectly categorized 2.9%. Practice patterns of the remaining 48.3% were sufficiently varied such that no single subspecialty assignment was possible. CONCLUSIONS: Existing Medicare provider codes poorly mirror subspecialty radiologists' own practice website-designated subspecialties. Actual payer claims data permit far more granular and accurate subspecialty identification for many radiologists. As new payment models increasingly focus on subspecialty-specific performance measures, claims-based identification methodologies show promise for reproducibly and transparently matching radiologists to practice-relevant metrics. PMID- 28673777 TI - Predicting No-Shows in Radiology Using Regression Modeling of Data Available in the Electronic Medical Record. AB - PURPOSE: To test whether data elements available in the electronic medical record (EMR) can be effectively leveraged to predict failure to attend a scheduled radiology examination. MATERIALS AND METHODS: Using data from a large academic medical center, we identified all patients with a diagnostic imaging examination scheduled from January 1, 2016, to April 1, 2016, and determined whether the patient successfully attended the examination. Demographic, clinical, and health services utilization variables available in the EMR potentially relevant to examination attendance were recorded for each patient. We used descriptive statistics and logistic regression models to test whether these data elements could predict failure to attend a scheduled radiology examination. The predictive accuracy of the regression models were determined by calculating the area under the receiver operator curve. RESULTS: Among the 54,652 patient appointments with radiology examinations scheduled during the study period, 6.5% were no-shows. No show rates were highest for the modalities of mammography and CT and lowest for PET and MRI. Logistic regression indicated that 16 of the 27 demographic, clinical, and health services utilization factors were significantly associated with failure to attend a scheduled radiology examination (P <= .05). Stepwise logistic regression analysis demonstrated that previous no-shows, days between scheduling and appointments, modality type, and insurance type were most strongly predictive of no-show. A model considering all 16 data elements had good ability to predict radiology no-shows (area under the receiver operator curve = 0.753). The predictive ability was similar or improved when these models were analyzed by modality. CONCLUSION: Patient and examination information readily available in the EMR can be successfully used to predict radiology no-shows. Moving forward, this information can be proactively leveraged to identify patients who might benefit from additional patient engagement through appointment reminders or other targeted interventions to avoid no-shows. PMID- 28673778 TI - Careerism in Radiology. PMID- 28673779 TI - Percutaneous closure of prosthetic paravalvular leaks - should it be considered the first therapeutic option? PMID- 28673780 TI - Fat intake and cardiac autonomic dysfunction in obese children: What is the relationship? PMID- 28673781 TI - Serum sodium levels and blood pressure monitoring in heart failure: Added diagnostic and prognostic value. PMID- 28673782 TI - Percutaneous closure of periprosthetic paravalvular leaks: A viable alternative to surgery? AB - INTRODUCTION AND OBJECTIVES: Paravalvular leak (PVL) is a possible complication after prosthetic valve implantation. PVL can cause significant symptoms of congestive heart failure and/or hemolysis. Medical therapy is palliative and reoperation has a high mortality rate. Percutaneous transcatheter closure is a promising alternative for symptomatic patients at high surgical risk. We aim to review the efficacy and safety of percutaneous PVL closure in a consecutive series of patients referred to our center. METHODS: We performed a retrospective analysis of clinical and technical procedural data of patients referred to our center for percutaneous PVL closure between January 2009 and November 2015. RESULTS: Twenty procedures were performed in 18 patients under general anesthesia and under transesophageal echocardiographic and radiographic guidance. Fourteen mitral PVLs were successfully treated in 13 patients and one aortic PVL in one patient. Most (eight) of the PVLs closed were in mitral bioprostheses. Two patients underwent a second intervention, which was technically successful in one. Technical success was achieved in 15 (75%) of the procedures. At discharge, median NYHA functional class decreased by one and hemolytic anemia decreased from seven cases (38.9%) to two (11.1%). Two patients had minor bleeding at the femoral vascular access site. Survival rates at six, 12 and 24 months were 77.8%, 77.8% and 61.1%, respectively. CONCLUSIONS: In our experience, percutaneous PVL closure was overall effective and safe. The procedure is complex and a second intervention may be necessary. Percutaneous PVL closure may be a feasible alternative for selected symptomatic patients at high surgical risk refractory to medical therapy. PMID- 28673783 TI - Combined MitraClip implantation and left atrial appendage occlusion using the Watchman device: A case series from a referral center. AB - INTRODUCTION: Patients referred for percutaneous transcatheter mitral valve repair using the MitraClip(r) system frequently have atrial fibrillation, which imposes additional challenges due to the need for oral anticoagulation. Left atrial appendage occlusion is currently regarded as a non-inferior alternative to anticoagulation in patients with non-valvular atrial fibrillation and both high thromboembolic and bleeding risk. Considering that both MitraClip implantation and left atrial appendage occlusion are percutaneous techniques that require transseptal puncture, it is technically attractive to consider their concomitant use. OBJECTIVES: We aim to evaluate the feasibility of a combined approach with MitraClip implantation and left atrial appendage occlusion in a single procedure. METHODS: We report the first case series regarding this issue, discussing the specific advantages, pitfalls and technical aspects of combining these two procedures. RESULTS: Five patients underwent left atrial appendage occlusion with the Watchman(r) device followed by MitraClip implantation in the same procedure. All patients experienced significant reduction in mitral valve regurgitation of at least two grades, optimal occluder position, no associated complications and significant clinical improvement assessed by NYHA functional class (reduction of at least one functional class, with four patients in class I at one-month follow up). CONCLUSION: In selected patients rejected for surgical mitral valve repair, with atrial fibrillation and increased risk of bleeding and embolic events, a combined approach with MitraClip implantation and left atrial appendage occlusion in a single procedure is feasible, safe and effective. PMID- 28673784 TI - Ambulatory blood pressure monitoring in heart failure and serum sodium levels. AB - AIMS: To determine whether there are differences in blood pressure profile on dynamic assessment by ambulatory blood pressure monitoring (ABPM) according to serum sodium levels in stable heart failure patients. METHODS: Data were collected from the Spanish National Registry on Ambulatory Blood Pressure Monitoring in Heart Failure (DICUMAP). Patients underwent ABPM by the oscillometric principle using a Spacelabs 90121 monitor. The sample was divided into three groups according to sodium levels and their clinical and laboratory data and echocardiographic findings were analyzed. Robust statistical methods were used to compare the groups in univariate and multivariate models. RESULTS: A total of 175 patients (44.57% male) were analyzed. We found a predominance of anomalous circadian blood pressure profiles in all three groups, with a significantly higher percentage of risers in the lowest serum sodium group (p=0.05). In addition, in this group there were significant differences in mean 24-hour systolic blood pressure (SBP) (24-h SBP, p=0.05) and in mean daytime SBP (dSBP, p=0.008), with significant differences in nocturnal fall in SBP (p=0.05) and in diastolic blood pressure (p=0.005). In multivariate analysis a significant relationship was found between sodium levels and 24-h SBP (OR 0.97, 95% CI 0.95 0.99, p=0.01) and dSBP (OR 0.96, 95% CI 0.94-0.99, p=0.004). CONCLUSION: A relationship was found between lower sodium levels and lower systolic blood pressure, especially during waking hours, with a lower decline between daytime and night-time blood pressure. PMID- 28673785 TI - Barbaloin pretreatment attenuates myocardial ischemia-reperfusion injury via activation of AMPK. AB - Myocardial ischemia/reperfusion (MI/R) injury is a major cause of cardiac dysfunction during cardiovascular surgery and heart transplantation and characterized by hyperactive oxidative stress and inflammatory response. Barbaloin (BAR) is the main medicinal composition of the Chinese traditional medicine aloe vera. BAR has strong anti-oxidant, anti-inflammatory and anti-tumor properties. However, the effect of BAR on MI/R-induced myocardial injury is not explored. This study aims to investigate whether BAR provides cardio-protection against MI/R injury and the underlying mechanisms. BAR (20 mg/kg/d) or vehicle was intragastrically administered to Sprague-Dawley rats for 5 days before MI/R operation. BAR pretreatment conferred cardio-protective effects against MI/R injury by improving hemodynamic function and limiting infarction size. Moreover, BAR pretreatment effectively inhibited I/R-induced myocardial oxidative stress and inflammatory response. Furthermore, BAR pretreatment activated adenosine monophosphate-activated protein kinase (AMPK) signaling in MI/R hearts. AMPK inhibitor compound C inhibited BAR-induced AMPK activation, and blunted BAR mediated anti-oxidative, anti-inflammatory effects and cardio-protection. Taken together our study has identified a novel function of BAR and provided a molecular basis for BAR potential applications in the treatment of MI/R injury and other ischemic disorders. PMID- 28673786 TI - Diurnal variations in iron concentrations and expression of genes involved in iron absorption and metabolism in pigs. AB - Diurnal variations in serum iron levels have been well documented in clinical studies, and serum iron is an important diagnostic index for iron-deficiency anemia. However, the underlying mechanism of dynamic iron regulation in response to the circadian rhythm is still unclear. In this study, we investigated daily variations in iron status in the plasma and liver of pigs. The transcripts encoding key factors involved in iron uptake and homeostasis were evaluated. The results showed that iron levels in the plasma and liver exhibited diurnal rhythms. Diurnal variations were also observed in transcript levels of divalent metal transporter 1 (DMT1), membrane-associated ferric reductase 1 (DCYTB), and transferrin receptor (TfR) in the duodenum and jejunum, as well as hepcidin (HAMP) and TfR in the liver. Moreover, the results showed a network in which diurnal variations in systemic iron levels were tightly regulated by hepcidin and Tf/TfR via DCYTB and DMT1. These findings provide new insights into circadian iron homeostasis regulation. The diurnal variations in serum iron levels may also have pathophysiological implications for clinical diagnostics related to iron deficiency anemia in pigs. PMID- 28673787 TI - Optimized incubation regime for nitric oxide measurements in murine macrophages using the Griess assay. AB - The Griess assay is used to measure nitric oxide concentrations in liquid solutions after reaction into nitrite. The assay is challenging when applied to cell culture supernatants. During optimization, we focused on the anti inflammatory potential of test compounds in murine RAW264.7 macrophages. This led to (i) the required inductivity of cells by lipopolysaccharide (LPS) and allowed (ii) the characterization of putative anti-inflammatory test compounds with high sensitivity. The modifications reported here prominently improved resolution and efficiency of the widely used Griess assay and are of broad interest for studies on the pharmacological modulation of macrophages activation. PMID- 28673788 TI - The transferrin isoforms in chronic hepatitis. AB - BACKGROUND: The aim of this study was to evaluate the effect of chronic hepatitis on the serum profile of transferrin isoforms. METHODS: Tested group consist of 160 patients with chronic hepatitis. The samples were analyzed by capillary electrophoresis on MINICAP electrophoretic system (Sebia, France). RESULTS: In patients with chronic hepatitis tetrasialotransferrin level was increased (P=0.002) and pentasialotransferrin decreased (P=0.009). Moreover, statistical analysis revealed that trisialotransferrin level was different according to the grade of portal/periportal activity (P=0.009), the grade of lobular activity (P=0.004) and the stage of fibrosis (P=0.022). There were no differences in tetrasialotransferrin and pentasialotransferrin according to the advancement of hepatitis activity and the stage of fibrosis (P>0.05 for all comparisons). CONCLUSIONS: We conclude that chronic hepatitis affect the serum profile of transferrin isoforms, but only trisialotransferrin level could be useful in determining progression of chronic hepatitis and the stage of fibrosis. PMID- 28673789 TI - Efficacy and safety of biological DMARDs modulating B cells in primary Sjogren's syndrome: Systematic review and meta-analysis. AB - OBJECTIVE: In this review, we summarise the clinical efficacy and safety of B cell targeted therapies for primary Sjogren's syndrome (pSS). METHODS: A systematic literature review was conducted using databases including MEDLINE, EMBASE and Cochrane. Only articles reporting controlled or prospective studies of b-DMARDs modulating B cells in treatment of pSS were selected. The highest quality studies were selected for meta-analysis. The primary outcome of interest was clinical efficacy at week 24 on fatigue, dryness, Schirmer test, salivary flow rate and the full ESSDAI score including biological domain. For the efficacy criteria used, the difference between rituximab and placebo groups was expressed as mean difference (MD). RESULTS: Eighteen articles (13 of rituximab, 3 of belimumab, 1 of epratuzumab and 1 of baminercept) were identified for detailed evaluation. 4 controlled randomised trials of rituximab treatment vs. placebo involving 300 patients were included for quantitative analysis. No significant differences were observed between groups in the meta-analysis of mean improvements between baseline and week 24 in fatigue VAS [MD -3,24 95% CI (-30,21 to 23,72)], oral dryness VAS [MD -8,41 95% CI (-35,06 to 18,24)], salivary flow rate [MD 0,04 95% CI (-0,03 to 0,11)] and Schirmer test [MD 0,35 95% CI (-2,13 to 2,82)]. Rituximab was relatively safe compared to placebo. CONCLUSION: Our review shows that rituximab is not effective in pSS with the designs and outcomes proposed in the trials. Controlled randomised trials are needed to prove the efficacy of belimumab and epratuzumab in this indication. The randomised controlled trial evaluating baminercept failed to achieve its primary endpoint. PMID- 28673790 TI - Identifying the vaginal fornix in cesarean hysterectomy for an abnormally invasive placenta: an alternative technique. PMID- 28673791 TI - Where do I fit? PMID- 28673792 TI - Cervical cerclage placement decreases local levels of proinflammatory cytokines in patients with cervical insufficiency. AB - BACKGROUND: Cervical insufficiency is characterized by premature, progressive dilation and shortening of the cervix during pregnancy. If left unattended, this can lead to the prolapse and rupture of the amniotic membrane, which usually results in midtrimester pregnancy loss or preterm birth. Previous studies have shown that proinflammatory cytokines such as interleukin-1beta, interleukin-6, interleukin-8, and tumor necrosis factor alpha are up-regulated in normal parturition but are also associated with preterm birth. Studies evaluating such markers in patients with cervical insufficiency have evaluated only their diagnostic potential. Even fewer studies have studied them within the context of cerclage surgery. OBJECTIVES(S): The objective of the study was to evaluate the impact of local and systemic inflammatory markers on the pathogenesis of cervical insufficiency and the effect of cerclage surgery on the local immune microenvironment of women with cervical insufficiency. STUDY DESIGN: We recruited 28 pregnant women (12-20 weeks' gestation) diagnosed with insufficiency and referred for cerclage surgery and 19 gestational age-matched normal pregnant women as controls. Serum and cervicovaginal fluid samples were collected before and after cerclage surgery and during a routine checkup for normal women and analyzed using a targeted 13-plex proinflammatory cytokine assay. RESULTS: Before surgery, patients with cervical insufficiency had higher levels of interleukin 1beta, interleukin-6, interleukin-12, monocyte chemoattractant protein-1 and tumor necrosis factor alpha in cervicovaginal fluid compared to controls, but after surgery, these differences disappeared. No differences were found in serum of insufficiency versus control women. In patients with insufficiency, the levels of interleukin-1beta, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and interferon gamma in cervicovaginal fluid declined significantly after cerclage compared with before intervention, but these changes were not detected in serum. CONCLUSION: Compared with normal women, patients with cervical insufficiency have elevated levels of proinflammatory cytokines in cervicovaginal fluid but not in serum, suggesting a dysregulation of the local immune environment. Cerclage intervention led to a significant decline in these proinflammatory cytokines, suggesting that cerclage may help reduce local inflammation in cervical insufficiency. PMID- 28673793 TI - Perinatal mortality in unplanned births outside institutions: experience of prehospital teams in a French urban environment. PMID- 28673794 TI - Giggle incontinence: Evolution of concept and treatment. AB - BACKGROUND: Giggle incontinence is a sudden and involuntary episode of urinary incontinence that is provoked by an episode of laughter. Decades of case studies and small research studies have formed the basis of what is known about giggle incontinence; however, much remains unknown about this type of incontinence, leaving the recommendations for clinical management somewhat unguided. METHODS: A systematic review of 22 articles on the topic of "giggle incontinence" and related terms was conducted, including all published articles and commentaries since the term was first seen in print in 1959. RESULTS: This review provides a historical context for the diagnosis, a summary of what is known about its etiology, and a summary of current treatments. CONCLUSIONS: There is disagreement about the pathophysiology of laughter incontinence, with two differing explanations. The first emphasizes the neurologic origin of the cascade of events during laughter and urination, and draws a likeness to cataplexy and other CNS disorders, and emphasizes treatment with methylphenidate. The second emphasizes urologic dysfunction, with biofeedback and bladder retraining as the recommended therapy. Comprehensive treatment of children with laughter incontinence requires an appreciation of both concepts. Since inception of the concept there has been question about the appropriateness of the term "giggle incontinence." This review encourages discussion among readers/clinicians about the term and the essential qualities of the diagnosis. PMID- 28673795 TI - Use of 3D reconstruction cloacagrams and 3D printing in cloacal malformations. AB - INTRODUCTION: Cloacal anomalies are complex to manage, and the anatomy affects prognosis and management. Assessment historically includes examination under anesthesia, and genitography is often performed, but these do not consistently capture three-dimensional (3D) detail or spatial relationships of the anatomic structures. Three-dimensional reconstruction cloacagrams can provide a high level of detail including channel measurements and the level of the cloaca (<3 cm vs. >3 cm), which typically determines the approach for surgical reconstruction and can impact long-term prognosis. Yet this imaging modality has not yet been directly compared with intra-operative or endoscopic findings. OBJECTIVES: Our objective was to compare 3D reconstruction cloacagrams with endoscopic and intraoperative findings, as well as to describe the use of 3D printing to create models for surgical planning and education. STUDY DESIGN: An IRB-approved retrospective review of all cloaca patients seen by our multi-disciplinary program from 2014 to 2016 was performed. All patients underwent examination under anesthesia, endoscopy, 3D reconstruction cloacagram, and subsequent reconstructive surgery at a later date. Patient characteristics, intraoperative details, and measurements from endoscopy and cloacagram were reviewed and compared. One of the 3D cloacagrams was reformatted for 3D printing to create a model for surgical planning. RESULTS: Four patients were included for review, with the Figure illustrating 3D cloacagram results. Measurements of common channel length and urethral length were similar between modalities, particularly with confirming the level of cloaca. No patient experienced any complications or adverse effects from cloacagram or endoscopy. A model was successfully created from cloacagram images with the use of 3D printing technology. DISCUSSION: Accurate preoperative assessment for cloacal anomalies is important for counseling and surgical planning. Three-dimensional cloacagrams have been shown to yield a high level of anatomic detail. Here, cloacagram measurements are shown to correlate well with endoscopic and intraoperative findings with regards to level of cloaca and Mullerian development. Measurement discrepancies may be due to technical variation indicating a need for further evaluation. The translation of the cloacagram images into a 3D printed model demonstrates potential applications of these models for pre-operative planning and education of both families and trainees. CONCLUSIONS: In our series, 3D reconstruction cloacagrams yielded accurate measurements of urethral length and level of cloaca common channel and urethral length, similar to those found on endoscopy. Three dimensional models can be printed from using cloacagram images, and may be useful for surgical planning and education. PMID- 28673796 TI - Sleep disordered breathing in enuretic children and controls. AB - INTRODUCTION: Nocturnal enuresis and sleep disordered breathing are common childhood problems that are reported to be associated with each other. Sleep disordered breathing is often found in children with upper airway obstruction and, according to some studies, its presence is associated with an increased risk of nocturnal enuresis. Respiration during sleep in children with therapy resistant enuresis, but no history of snoring or sleep apneas, has previously been investigated, and subclinical signs of disordered respiration were found in this group. However, sleep disordered breathing in enuretic children without a history of snoring or sleep apneas has not been thoroughly studied before. AIM: To evaluate sleep disordered breathing in enuretic children and compare them with healthy control children. SUBJECTS AND METHODS: Children aged 8-13 years with nocturnal enuresis were included. Exclusion criteria were: daytime incontinence, on-going anti-enuretic treatment, and concomitant urological, endocrinological, nephrological or psychiatric disorders. Twenty children (19 boys and 1 girl) suffering from therapy-resistant nocturnal enuresis, and 21 healthy controls (18 boys and 3 girls) underwent one night of polygraphic sleep registration focused on respiratory variables. The registration included electroencephalography as well as assessment of respiratory movements, nasal airflow and oxygen saturation; it was performed with a portable sleep device at the subjects' homes. In addition to this, OSA 18, a health-related quality of life instrument, was used to evaluate subjective issues related to sleep and breathing. RESULTS: The mean apnea hypopnea index values were 0.96 +/- 0.8 for the patient group and 0.46 +/- 0.4 for the control group. The oxygen desaturation index was slightly higher for the children with nocturnal enuresis compared with the healthy controls (P = 0.05). No other differences were found in the respiratory variables. Both groups of children showed low levels of arousals (Summary Table). The enuretic children reported significantly more subjective sleep disturbances and a lower quality of life than their healthy peers. DISCUSSION: This was the first controlled study of sleep disordered breathing in children with nocturnal enuresis. One limitation of the study was that some variables were known to be underestimated when scoring polygraphic data. The apnea hypopnea index was such a variable and was indeed lower than in a previous study. CONCLUSION: No major differences in respiration during sleep were found between enuretic children and controls. PMID- 28673797 TI - Management of Clinical Stage I Nonseminomatous Germ Cell Testicular Tumors: A 25 year Single-center Experience. AB - BACKGROUND: Surveillance after orchiectomy alone has become popular in the management of clinical stage I nonseminomatous germ cell testicular tumors (CSI NSGCTT). Efforts to identify patients at high risk of disease progression led to a search for risk factors in CSI NSGCTT. The aim of this study was to analyze a 25-year single-center experience with risk-adapted therapeutic approaches-active surveillance (AS) versus adjuvant chemotherapy (ACT). PATIENTS AND METHODS: From January 1992 to January 2017, a total of 485 patients with CSI NSGCTT were stratified into the AS group (low-risk patients) and the ACT group (high-risk patients). Differences between relapse rates and overall survival rates in these groups were statistically analyzed. RESULTS: In the AS group, relapse occurred in 52 (17.3%) of 301 patients with a median follow-up of 7.2 months (range, 2-86 months). Six (2.0%) patients of this group died, with a median follow-up of 34.3 months (range, 11-102 months). In the ACT group, relapse occurred in 2 (1.1%) of 184 patients with a median follow-up of 56.2 months (range, 42-70 months). One (0.54%) patient died at 139.4 months following orchiectomy. The relapse rate for the AS group was 16.7 times higher than that for the ACT group. The groups did not differ in overall survival. The 3-year overall survival of all patients with CSI NSGCTT was 99.1% (95% confidence interval, 97.7%-99.7%). Three of a total of 7 deaths occurred thereafter. CONCLUSIONS: The policy of AS is recommended only in patients with low-risk CSI NSGCTT. PMID- 28673798 TI - Rapid Response to Nivolumab in a Patient With Sarcomatoid Transformation of Chromophobe Renal Cell Carcinoma. PMID- 28673799 TI - Education in Sepsis: A Review for the Clinician of What Works, for Whom, and in What Circumstances. AB - Sepsis is a major cause of morbidity and mortality in both the general and obstetric populations. Concerns have been raised regarding some cases of substandard care in the management of the septic and there is a real need for continuing multidisciplinary medical education in the recognition and management of the pregnant patient experiencing sepsis. This review aims to summarize studies on medical education in sepsis to both inform clinicians working in obstetrics and gynaecology and to assist in planning educational programs. PMID- 28673800 TI - Modeling HCV cure after an ultra-short duration of therapy with direct acting agents. AB - BACKGROUND: Cases of sustained-virological response (SVR or cure) after an ultra short duration (<=27 days) of direct-acting antiviral (DAA)-based therapy, despite HCV being detected at end of treatment (EOT), have been reported. Established HCV mathematical models that predict the treatment duration required to achieve cure do not take into account the possibility that the infectivity of virus produced during treatment might be reduced. The aim of this study was to develop a new mathematical model that considers the fundamental and critical concept that HCV RNA in serum represents both infectious virus (Vi) and non infectious virus (Vni) in order to explain the observation of cure with ultrashort DAA therapy. METHODS: Established HCV models were compared to the new mathematical model to retrospectively explain cure in 2 patients who achieved cure after 24 or 27 days of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin or sofosbuvir plus ribavirin, respectively. RESULTS: Fitting established models with measured longitudinal HCV viral loads indicated that in both cases, cure would not have been expected without an additional 3-6 weeks of therapy after the actual EOT. In contrast, the new model fits the observed outcome by considering that in addition to blocking Vi and Vni production (epsilon~0.998), these DAA + ribavirin treatments further enhanced the ratio of Vni to Vi, thus increasing the log (Vni/Vi) from 1 at pretreatment to 6 by EOT, which led to <1 infectious-virus particle in the extracellular body fluid (i.e., cure) prior to EOT. CONCLUSIONS: This new model can explain cure after short duration of DAA + ribavirin therapy by suggesting that a minimum 6-fold increase of log (Vni/Vi) results from drug-induced enhancement of the Vni/Vi. PMID- 28673801 TI - Novel peptidyl alpha-aminoalkylphosphonates as inhibitors of hepatitis C virus NS3/4A protease. AB - Herein, we describe the synthesis and application of novel phosphonic inhibitors designed to target the NS3/4A protease, which is crucial for the life cycle of hepatitis C virus. We examined the inhibitory potency of our synthesized compounds against two genotypes (1a and 1b) of NS3/4A protease and four mutant strains of HCV. The most potent inhibitors displayed k2/KI values of 79 850 M-1s 1 and 60 850 M-1s-1 against genotype 1a and 1b protease, respectively. Further in vitro evaluation of the most potent inhibitors revealed that vastly reduced HCV replication. Cellular toxicity, plasma stability, reactivity with selected human proteases as well the stability of inhibitor-protease complex and its intracellular availability are also discussed. PMID- 28673802 TI - Regular activity breaks combined with physical activity improve postprandial plasma triglyceride, nonesterified fatty acid, and insulin responses in healthy, normal weight adults: A randomized crossover trial. AB - BACKGROUND: Compared with prolonged sitting, regular activity breaks immediately lower postprandial glucose and insulin, but not triglyceride responses. Postprandial triglycerides can be lowered by physical activity but the effect is often delayed by ~12 to 24 hours. OBJECTIVE: The objective of the study was to determine whether regular activity breaks affect postprandial triglyceride response in a delayed manner similar to physical activity. METHODS: In a randomized crossover trial, 36 adults (body mass index 23.9 kg/m2 [standard deviation 3.9]) completed four 2-day interventions: (1) prolonged sitting (SIT); (2) prolonged sitting with 30 minutes of continuous walking (60% VO2max), at the end of Day 1 (SIT + PAD1); (3) Sitting with 2 minutes of walking (60% VO2max) every 30 minutes (RAB); (4) A combination of the continuous walking and regular activity breaks in 2 and 3 above (RAB + PAD1). Postprandial plasma triglyceride, nonesterified fatty acids, glucose, and insulin responses were measured in venous blood over 5 hours on Day 2. RESULTS: Compared with SIT, both RAB (difference: 43.61 mg/dL.5 hours; 95% confidence interval [CI] -83.66 to -2.67; P = .035) and RAB + PAD1 (-65.86 mg/dL.5 hours; 95% CI -112.14 to -19.58; P = .005) attenuated triglyceride total area under the curve (tAUC). RAB + PAD1 produced the greatest reductions in insulin tAUC (-23%; 95% CI -12% to -31%; P < .001), whereas RAB resulted in the largest increase in nonesterified fatty acids (tAUC, 10.08 mg/dL.5 hours; 95% CI 5.60-14.84; P < .001). There was no effect on glucose tAUC (P = .290). CONCLUSIONS: Postprandial triglyceride response is attenuated by regular activity breaks, when measured ~24 hours after breaks begin. Combining regular activity breaks with 30 minutes of continuous walking further improves insulinemic and lipidemic responses. PMID- 28673803 TI - Residents and Program Director Perspectives Often Differ on Optimal Preparation Strategies and the Value of the Orthopedic In-Training Examination. AB - OBJECTIVES: The purpose of this work was to compare resident and program director (PD) perspectives on the value of the Orthopaedic In-Training Examination (OITE), resident study habits, and best resources for optimal performance. DESIGN: A national survey of orthopedic surgery residents and PDs. SETTING: Mayo Clinic, Rochester, MN PARTICIPANTS: The survey was completed by 445 (41.5%) eligible orthopedic surgery residents and 37 (77.1%) PDs. RESULTS: Although residents and PDs agreed on when (p = 0.896) and how much (p = 0.171) residents currently study, residents felt that the OITE was not as valuable of an assessment of their knowledge, and also felt their individual scores were less likely to remain confidential compared to PDs (p < 0.001). The mean OITE score below which residents were concerned about their ability to pass American Board of Orthopaedic Surgeons Part 1 was 9.7 percentile points higher than PDs threshold (42.3% vs. 32.6%, respectively, p = 0.003). Both groups agreed that it is important to dedicate focused study time to the OITE (p = 0.680) and to perform well (p = 0.099). Regarding the best resources and preparation strategies, both residents and PDs tended to agree on the value of most (6 of 10) study methods. Residents ranked practice question websites (mean ranking of 2.6 vs. 3.8 of 10, respectively; p < 0.001) and formal rotations in a subspecialty (6.0 vs. 7.7 respectively, p < 0.001) higher than PDs. In contrast, PDs tended to value their program's formal OITE prep program (4.1. vs. 5.3, respectively, p = 0.012) and reading primary literature (5.6 vs. 6.6, respectively, p = 0.012) more than residents. CONCLUSION: Residents and PDs agreed on many critical components of this process; however, a number of key differences in perspectives exist. PMID- 28673804 TI - Modeling Learning in Surgical Practice. AB - OBJECTIVE: Methods that model surgical learning curves are frequently descriptive and lack the mathematical rigor required to extract robust, meaningful, and quantitative information. We aimed to formulate a method to model learning that is tailored to dealing with the high variability seen in surgical data and can readily extract important quantitative information such as learning rate, length of learning, and learnt level of performance. METHODS: We developed a method where progressively more complex models are fitted to learning data. These include novel models that split the learning data into 2 linear phases and fit adjoining lines using least squares regression. The models were compared and the least complex model was selected unless a more complex one was significantly better. Significance was tested by Fischer tests. We applied this method to total hip and knee replacements using imageless navigation, analyzing the operative time for a surgeon's first 50 and 60 operations, respectively. This method was then tested against 4 sets of simulated learning data. RESULTS: The proposed method of progressive model complexity successfully modeled the learning curve among real operative data. It was also effective in deducing the underlying trends in simulated scenarios, created to represent typical situations that can practically arise in any learning process. CONCLUSIONS: The novel modeling method can be used to extract meaningful and quantitative information from learning data displaying high variability seen in surgical practice. By using simple and intuitive models, the method is accessible to researchers and educators without the need for specialist statistical knowledge. PMID- 28673805 TI - A New Synthetic Model for Microvascular Anastomosis Training? A Randomized Comparative Study Between Silicone and Polyvinyl Alcohol Gelatin Tubes. AB - INTRODUCTION: Assessment of a resident's microsurgical competency with the rodent model remains the current gold standard. However, cost and ethical issues related to animal welfare may limit training opportunities. Therefore, synthetic alternatives such as silicone tubes have been developed to provide easy access to training, shorten the learning curve, and have been incorporated into microsurgical courses as a low-fidelity model for basic skills acquisition. This study compares the use of polyvinyl alcohol (PVA) gelatin tubes with silicone for resident microsurgical training. MATERIAL AND METHODS: Residents were randomized into silicone (S) or PVA (P) groups and underwent the same training. Following basic instruction, microsurgical anastomoses were performed with the rat's aorta or carotid artery or both. Performance was assessed using the Objective Structured Assessment of Technical Skills (OSATS) score and 5 different items to assess the quality of the anastomosis. Posttest questionnaires were also conducted for qualitative assessment of both students' and trainers' experience with silicone and PVA in comparison with rat vessels. RESULTS: OSATS score in Group P was higher than Group S (18.2 +/- 2.6 vs 16.6 +/- 2.5, p = 0.015). Results of anastomoses were similarly better in Group P based on OSATS score (19.3 +/- 1.2 vs 17.7 +/- 0.7, p = 0.027). Subjectively, both students and trainers found that PVA tubes resembled the rat aorta more closely than silicone. The number of rats used was also significantly lower in Group P than Group S (65 vs 75 total, p = 0.023). CONCLUSION: PVA gelatin tubes may be a viable alternative to silicone for microsurgical training because this synthetic model mirrors better rat vessels and can improve training performance based on objective assessment while using less animals overall. PMID- 28673806 TI - Improved SNR for combined TMS-fMRI: A support device for commercially available body array coil. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation tool extensively used in clinical and cognitive neuroscience research. TMS has been applied during functional magnetic resonance imaging (i.e., concurrent/interleaved TMS-fMRI) to understand neural mechanisms underlying cognitive functions. However, no advanced commercial multi-channel whole-brain array MR coils can fit the large TMS coil. We developed a low-cost and easy-to-configure setup that takes advantage of the superior signal-to-noise ratio (SNR) performance of commercially available flexible body array coils that can accommodate the TMS coil. NEW METHOD: Two flexible MRI body array coils (i.e., the Combo coil) were fitted on a simple coil support with a TMS-coil holder. Phantom and in vivo images acquired using the Combo coil with and without a TMS coil were compared with those from a product 12-channel (12CH) form-fit head array coil. RESULTS: Relative to the 12CH head coil, images acquired using the Combo coil were of similar quality, but with increased noise levels, leading to moderately reduced temporal SNR values. COMPARISON WITH EXISTING METHOD: A previous study reported that the temporal SNR of a product 12CH head coil was twice that of a transmit/receive volume birdcage coil commonly used in combined TMS-fMRI. Together with the results of the present work, they indicate that the Combo-coil setup improves SNR performance for combined TMS-fMRI acquisition. CONCLUSION: The inexpensive and easy-to-configure Combo-coil setup offers an effective and likely superior alternative to transmit/receive birdcage coil for combined TMS-fMRI. PMID- 28673807 TI - Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer. AB - Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel 7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo. PMID- 28673808 TI - The effect of television watching and portion size on intake during a meal. AB - Watching television while eating and eating from larger portion sizes of food are factors that have been found to independently increase food intake. When combined, these factors may further enhance consumption. This investigation, using a 4 * 2 * 2 mixed factorial design, with a between-subjects factor of order of conditions and within-subjects factors of television watching (NO TV and TV) and portion size (SMALL and LARGE), tested the independent effects and interaction of these factors in seventeen women and three men (21.6 +/- 2.3 kg/m2, 22.3 +/- 3.7 years, 80% white and 95% non-Hispanic). In each condition, participants had 30 min to eat a meal containing macaroni and cheese and salad with dressing. For NO TV, participants sat for 30 min while eating, while for TV, participants viewed a 30-min show containing no food cues while eating. In SMALL the meal provided 1083 kcal, while in LARGE the meal provided 200% of SMALL. Mixed factorial analysis of variance revealed a significant main effect of portion size on grams and energy consumed of the total meal. Participants consumed more grams (577.9 +/- 150.5 g vs. 453.1 +/- 96.6 g; p < 0.001) and energy (903.9 +/- 270.4 kcal vs. 734.6 +/- 187.1 kcal; p < 0.001) in LARGE as compared to SMALL. No significant effect of television watching or interaction of television watching and portion size was found. Results of this study suggest that to assist with reducing intake, smaller portion sizes should be implemented in all types of eating situations. PMID- 28673809 TI - Intravenous Thrombolysis for Acute Ischemic Stroke in Patients with Cervicocephalic Dolichoarteriopathy. AB - BACKGROUND AND PURPOSE: Cervicocephalic dolichoarteriopathy is not rare in patients with acute stroke. Results of intravenous (IV) tissue plasminogen activator (tPA) treatment have not been documented in this specific population. METHODS: One hundred (58 females, age: 69 +/- 13 years) consecutive patients treated with IV tPA for acute anterior circulation stroke were analyzed. Smoker's criteria were used to score basilar artery dolichoarteriopathy and combined criteria of Weibel-Fields and Metz for cervical carotid artery dolichoarteriopathy. RESULTS: Adjusted rates of effective response to tPA (defined as a decrease of the National Institutes of Health Stroke Scale [NIHSS] score to 1 or 0, or a total decrease >=4 point by the end of the first 24 hours; in 51%); first-day dramatic response (>=8 NIHSS score decrease; seen in 27%); 3 month favorable (modified Rankin score <=2; in 46%) and excellent (modified Rankin score <=1; in 37%) functional prognosis, and hemorrhagic complications (any hemorrhage in 34%, significant Fiorelli's parenchymal hemorrhage type 2 in 8%) of IV tPA were not modified with presence and categories of the basilar and extracranial carotid artery dolichoarteriopathy. Univariate analysis documented that basilar artery dolichoarteriopathy was significantly more prevalent in patients with effective response to IV tPA (22% versus 6%, odds ratio: 4.22, P = .041). However, an exploratory multiple regression analysis disclosed that NIHSS (per 1 point, beta = -.256, P = .009) and time to needle (per 15-minutes, beta = 2.389, P = .019) were significant determiners of early favorable prognosis, whereas dolichoectasia was not (beta = .141, P = .159). CONCLUSION: IV tPA is safe and effective in acute anterior circulation stroke coexistent with intracranial posterior circulation dolichoarteriopathy and cervical carotid artery kinking, tortuosity, or coiling. PMID- 28673810 TI - Repeated Mechanical Thrombectomy in the Same Intracranial Artery Segment. AB - We report a patient with an important scenario that may arise in the management of an acute ischemic stroke: the need for a repeated mechanical thrombectomy in the same intracranial artery segment. The patient had a history of atrial fibrillation and a mechanical mitral valve replacement. In her first stroke, she had an occlusion of the proximal segment of the right middle cerebral artery; 58 days later, she presented with an occlusion in the same segment of that cerebral artery. In both instances, the thrombus was extracted by a stent retriever with good clinical and radiographic results. To the best of our knowledge, this is the first report of a repeated mechanical thrombectomy in the same intracranial artery segment using stent retriever devices. PMID- 28673811 TI - Fluid-Attenuated Inversion Recovery Vascular Hyperintensities in Patients with Transient Ischemic Attack. AB - BACKGROUND: Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVHs) are common in patients with acute ischemic stroke, possibly representing impaired hemodynamics in the ischemic territory due to intracranial steno occlusive disease. There are few reports on FVHs in patients with transient ischemic attack (TIA). AIMS: We investigated the prevalence of FVHs and its clinical correlations in patients with TIA. METHODS: We evaluated consecutive patients admitted with TIA from February 2009 to June 2012 who had undergone magnetic resonance imaging within 30 hours of symptoms onset and intracranial and extracranial vascular imaging. Two independent neuroradiologists determined the presence of FVHs. We assessed the relationship between FVHs, clinical presentation, vascular risk factors, neuroimaging characteristics, and the presence of large artery stenosis or occlusion. RESULTS: Seventy-two patients with TIA were evaluated. FVHs were present in 12 (16.7%) patients. The overall agreement between examiners was good (kappa = .67). There were no differences in the frequency of intracranial or cervical arterial stenosis in patients with and without FVH. In a multivariate logistic regression analysis including atrial fibrillation (AF), congestive heart failure, and diabetes, only AF remained in the final model. CONCLUSIONS: FVH signals on FLAIR images occur in patients with TIA and might correlate with clinical variables like AF and not only with large vessel occlusion. The presence of FVH in patients with TIA and AF might be a surrogate marker for a large vessel occlusion spontaneously recanalized or for impaired autoregulation in a previously ischemic vascular territory. PMID- 28673812 TI - Utility of Brain Magnetic Resonance Imaging in the Surgical Management of Infective Endocarditis. AB - BACKGROUND: Brain magnetic resonance imaging (MRI) is frequently obtained in patients with infective endocarditis, yet its utility in predicting outcomes for valve replacement surgery in patients is unknown. The objective of this study was to determine how brain MRI findings impact clinical management and outcomes. METHODS: Demographic and clinical data from electronic medical records at Mayo Clinic were retrospectively reviewed for patients hospitalized with definite or possible infective endocarditis according to the modified Duke criteria between January 1, 2007 and December 31, 2014. There were 364 patients included in the study. RESULTS: Cardiac valve replacement surgery was performed in 195 of 364 (53.6%) patients, and 95 (48.7%) of the surgical patients underwent preoperative MRI, which was associated with preoperative neurologic symptoms in 56 of 95 (58.9%) patients (odds ratio = 12.92; 95% confidence interval, 5.98-27.93; P <.001). Postoperative neurologic complications occurred in 24 of 195 (12.3%) patients, including new ischemic stroke in 4 of 195 (2.1%) and new intracerebral hemorrhage in 3 of 195 (1.5%). No patients with microhemorrhages developed postoperative hemorrhage. No significant differences existed in rates of postoperative complications between patients with and those without preoperative MRI. There were no substantial associations between preoperative MRI findings and postoperative neurologic complications, functional outcomes as described by the modified Rankin Scale score, or 6-month mortality. CONCLUSIONS: In patients undergoing valve replacement surgery, preoperative MRI findings were not associated with differences in postoperative outcomes, irrespective of finding or timing of valve replacement surgery. PMID- 28673813 TI - Advanced developmental toxicity test method based on embryoid body's area. AB - Embryonic stem cell test (EST) evaluates the embryotoxic potential of substances and measures the half inhibition in viability of mouse embryonic stem cells (ESCs), fibroblasts (3T3 cells) and in cardiac differentiation of ESC. In this study, we suggest the developmental toxicity test method (termed EBT) applying area of embryoid bodies (EBs) instead of cardiac differentiation of EST. In the assessment of 21 substances, EB area was logarithmically decreased in dose dependent manner. Decline in EB area resulted in decrease of beating ratio during differentiation of ESCs. In classification by the EBT-based prediction model reflecting decline in cell viability and EB area, toxicity for 21 chemicals showed 90.5% accuracy. In the results of next generation sequencing, reduction in EB area resulted from cell cycle arrest mediated by HDAC2 and CDKN2A. Conclusively, EBT is advanced and is a useful tool to assess and classify various embryotoxicants in a short time with less effort. PMID- 28673814 TI - Comparison Between Pressure-Regulated Volume-Controlled and Volume-Controlled Ventilation on Oxygenation Parameters, Airway Pressures, and Immune Modulation During Thoracic Surgery. AB - OBJECTIVES: To compare 2 different ventilatory strategies: pressure-regulated volume-controlled (PRVC) versus volume-controlled ventilation during thoracotomy. DESIGN: Prospective randomized study. SETTING: University hospital. PARTICIPANTS: The study comprised 70 adult patients undergoing thoracic surgery. INTERVENTIONS: Evaluation of oxygenation parameters, airway pressures, and immune modulation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was arterial oxygen tension/fraction of inspired oxygen (PaO2/FIO2) ratio, whereas secondary outcomes included arterial and central venous blood gases, deadspace volume/tidal volume ratio, peak inspiratory pressure, mean inspiratory pressure, and plateau inspiratory pressure obtained at the following 4 time points: 20 minutes after total lung ventilation (T0), 20 minutes after 1-lung ventilation (T1), 20 minutes after return to total lung ventilation (T2), and at the end of surgery (T3). Furthermore, alveolar and plasma levels of interleukin-8 and tumor necrosis factor-alpha and changes in alveolar albumin levels and cell numbers were measured at the same time points. Oxygenation parameters (PaO2/FIO2 and PaO2) were significantly better in the PRVC group (PaO2/FIO2 ratio at T1 was 176 v 146 in the PRVC and volume-controlled groups, respectively, with a p value of 0.004). Deadspace volume/tidal volume ratio and inspiratory airway pressures were significantly lower in the PRVC group. Furthermore, all inflammatory parameters (alveolar and plasma interleukins, alveolar albumin levels, and cell numbers) were significantly lower in the PRVC group. CONCLUSIONS: The PRVC mode during 1 lung ventilation in thoracic surgery caused a favorable effect on oxygenation parameters, respiratory mechanics, and immune modulation during thoracic surgery. PMID- 28673815 TI - Autoantibodies to Su/Argonaute 2 in Japanese patients with inflammatory myopathy. AB - BACKGROUND: Anti-Su antibodies are found in 5-20% of cases of various systemic autoimmune rheumatic diseases and in 5-10% of dermatomyositis (DM)/polymyositis (PM) patients. In 2006, the 100kDa Su antigen was identified as argonaute2 (Ago2), and it was found to play a major role in RNA interference. However, immunoprecipitation (IP) remains the main method for detecting anti-Su and the clinical significance of the antibodies is uncertain. METHODS: Sera from patients with DM/PM (n=224) were screened by an ELISA that uses recombinant biotinylated Ago2 protein. Some serum samples were tested by IP and by indirect immunofluorescence (IIF) analysis. RESULTS: Seventeen (7.5%, 17/224) sera from DM/PM were positive in ELISA. Of the 33 IP-tested sera (17 ELISA-positive and 16 ELISA-negative with high background), 13 were found to be anti-Ago2/Su-positive in IP and ELISA. Only one IP-positive serum was judged to be ELISA-negative. Among the 13 patients with anti-Su/Ago2, 7 cases also had myositis-specific autoantibodies. Six sera that were positive by both IP and ELISA showed the GW body pattern in IIF. Interestingly, one ELISA-positive serum with an inconclusive result in IP also showed the GW body pattern. CONCLUSION: Our novel ELISA appears to be useful for screening anti-Su/Ago2 antibodies (sensitivity: 93%, specificity: 79%). PMID- 28673816 TI - A collective national approach to fostering innovation in complex care. AB - The Complex Care Innovation Lab convenes 15 organizations from across the country that are innovators in health care delivery for low-income populations with complex needs. These organizations have identified several elements that are core to successful complex care programs, including: (1) incorporating patient centered approaches to care; (2) utilizing a non-traditional workforce; (3) employing data-driven strategies; and (4) leveraging flexible payment models that assign accountability to providers and facilitate interventions to integrate health and social services. Insights from the Innovation Lab may help other health care stakeholders to cost-effectively serve high-need, high-cost populations in an evolving policy environment. PMID- 28673817 TI - A state-led framework for value-based purchasing to incent integration. AB - Addressing healthcare costs requires incenting providers to address both physical and behavioral health conditions, as well as social determinants of health. The most complex, and expensive, patients are often those with comorbid mental illness and/or addiction, who are at higher risk for exposure to violence, food insecurity, unstable housing and other adversities that negatively affect health. Yet today's value-based payment models and associated quality measures do not incent providers to address patients' behavioral and social needs. We propose a state-led framework for moving towards fully integrated accountability through improved value-based payment and measurement. PMID- 28673818 TI - Distinct cis elements in the 3' UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development. AB - The 3' untranslated regions (3' UTRs) of mRNAs mediate post-transcriptional regulation of genes in many biological processes. Cis elements in 3' UTRs can interact with RNA-binding factors in sequence-specific or structure-dependent manners, enabling regulation of mRNA stability, translation, and localization. Caenorhabditis elegans CEBP-1 is a conserved transcription factor of the C/EBP family, and functions in diverse contexts, from neuronal development and axon regeneration to organismal growth. Previous studies revealed that the levels of cebp-1 mRNA in neurons depend on its 3' UTR and are also negatively regulated by the E3 ubiquitin ligase RPM-1. Here, by systematically dissecting cebp-1's 3' UTR, we test the roles of specific cis elements in cebp-1 expression and function in neurons. We present evidence for a putative stem-loop in the cebp-1 3' UTR that contributes to basal expression levels of mRNA and to negative regulation by rpm-1. Mutant animals lacking the endogenous cebp-1 3' UTR showed a noticeable increased expression of cebp-1 mRNA and enhanced the neuronal developmental phenotypes of rpm-1 mutants. Our data reveal multiple cis elements within cebp 1's 3' UTR that help to optimize CEBP-1 expression levels in neuronal development. PMID- 28673819 TI - Automated tools for comparative sequence analysis of genic regions using the GenePalette application. AB - Comparative sequence analysis methods, such as phylogenetic footprinting, represent one of the most effective ways to decode regulatory sequence functions based upon DNA sequence information alone. The laborious task of assembling orthologous sequences to perform these comparisons is a hurdle to these analyses, which is further aggravated by the relative paucity of tools for visualization of sequence comparisons in large genic regions. Here, we describe a second generation implementation of the GenePalette DNA sequence analysis software to facilitate comparative studies of gene function and regulation. We have developed an automated module called OrthologGrabber (OG) that performs BLAT searches against the UC Santa Cruz genome database to identify and retrieve segments homologous to a region of interest. Upon acquisition, sequences are compared to identify high-confidence anchor-points, which are graphically displayed. The visualization of anchor-points alongside other DNA features, such as transcription factor binding sites, allows users to precisely examine whether a binding site of interest is conserved, even if the surrounding region exhibits poor sequence identity. This approach also aids in identifying orthologous segments of regulatory DNA, facilitating studies of regulatory sequence evolution. As with previous versions of the software, GenePalette 2.1 takes the form of a platform-independent, single-windowed interface that is simple to use. PMID- 28673821 TI - The effects of chemical fixation on the cellular nanostructure. AB - Chemical fixation is nearly indispensable in the biological sciences, especially in circumstances where cryo-fixation is not applicable. While universally employed for the preservation of cell organization, chemical fixatives often introduce artifacts that can confound identification of true structures. Since biological research is increasingly probing ever-finer details of the cellular architecture, it is critical to understand the nanoscale transformation of the cellular organization due to fixation both systematically and quantitatively. In this work, we employed Partial Wave Spectroscopic (PWS) Microscopy, a nanoscale sensitive and label-free live cell spectroscopic-imaging technique, to analyze the effects of the fixation process through three commonly used fixation protocols for cells in vitro. In each method investigated, we detected dramatic difference in both nuclear and cytoplasmic nanoarchitecture between live and fixed states. But significantly, despite the alterations in cellular nanoscale organizations after chemical fixation, the population differences in chromatin structure (e.g. induced by a specific chemotherapeutic agent) remains. In conclusion, we demonstrated that the nanoscale cellular arrangement observed in fixed cells was fundamentally divorced from that in live cells, thus the quantitative analysis is only meaningful on the population level. This finding highlights the importance of live cell imaging techniques with nanoscale sensitivity or cryo-fixation in the interrogation of cellular structure, to complement more traditional chemical fixation methods. PMID- 28673822 TI - Discovery of novel long non-coding RNAs induced by subgroup J avian leukosis virus infection in chicken. AB - Avian leukosis virus subgroup J (ALV-J) is an avian oncogenic retrovirus that has led to severe economic losses in the poultry industry in China in recent decades. Here, using high throughput transcriptome sequencing of HD11 and CEF cells infected with ALV-J, a set of 4804 novel long non-coding transcripts and numerous differentially expressed long non-coding RNAs (lncRNAs) were identified. We also found that they share relatively shorter transcripts and fewer exon numbers compared to mRNA. Correlation analysis suggested that many lncRNAs may activate gene expression in an enhancer-like manner other than through transcriptional regulation. Expression level analyses in vivo showed that three lncRNAs (NONGGAT001975.2, NONGGAT005832.2 and NONGGAT009792.2) may be associated with immune response regulation and could function as novel biomarkers for ALV-J infection. Our findings provides new insight into the pathological process of ALV J infection and should serve as a high-quality resource for further research on epigenetic influences on disease-resistance breeding as well as immune system and genomic studies. PMID- 28673820 TI - PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant. AB - Hedgehog (Hh) signaling is thought to occur in primary cilia, but the molecular basis of Gli2 and Gli3 activation by Hh signaling in cilia is unknown. Similarly, how ciliary gene mutations result in reduced Gli3 processing that generates a repressor is also not clear. Here we show that Hh signaling inhibits Gli2 and Gli3 phosphorylation by protein kinase A (PKA) in cilia. The cilia related gene Talpid3 (Ta3) mutation results in the reduced processing and phosphorylation of Gli2 and Gli3. Interestingly, Ta3 interacts and colocalizes with PKA regulatory subunit PKARIIbeta at centrioles in the cell. The centriolar localization and PKA binding regions are located in the N- and C-terminal regions of Ta3, respectively. PKARIIbeta fails to localize at centrioles in some Ta3 mutant cells. Therefore, our study provides the direct evidence that Gli2 and Gli3 are dephosphorylated and activated in cilia and that impaired Gli2 and Gli3 processing in Ta3 mutant is at least in part due to a decrease in Gli2 and Gli3 phosphorylation. PMID- 28673823 TI - A role of tumor susceptibility gene 101 (TSG101) in innate immune response of crayfish Procambarus clarkii. AB - Tumor susceptibility gene 101 (TSG101) is a multi-functional gene involved in cell growth and proliferation in vertebrates. However, its role in the innate immune response of crustaceans remains unclear. Here, a TSG101 gene was identified in crayfish Procambarus clarkii with an open reading frame of 1320 bp that encoded a predicted 48.3-kDa protein highly homologous to those in other invertebrates. TSG101 mRNA was highly expressed in stomach and hepatopancreas, and its expression was induced significantly in different tissues (hemocytes, gills and intestine) by lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I: C) with various expression patterns. Recombinant TSG101 protein was expressed in Escherichia coli, and a possible protein-protein interaction between TSG101 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) was explored by far-western blotting. RNA interference of TSG101 affected the gene expression of members of the Toll pathway. These results suggest that TSG101 is involved in the innate immune responses of P. clarkii. PMID- 28673824 TI - Incorporating ligament laxity in a finite element model for the upper cervical spine. AB - BACKGROUND CONTEXT: Predicting physiological range of motion (ROM) using a finite element (FE) model of the upper cervical spine requires the incorporation of ligament laxity. The effect of ligament laxity can be observed only on a macro level of joint motion and is lost once ligaments have been dissected and preconditioned for experimental testing. As a result, although ligament laxity values are recognized to exist, specific values are not directly available in the literature for use in FE models. PURPOSE: The purpose of the current study is to propose an optimization process that can be used to determine a set of ligament laxity values for upper cervical spine FE models. Furthermore, an FE model that includes ligament laxity is applied, and the resulting ROM values are compared with experimental data for physiological ROM, as well as experimental data for the increase in ROM when a Type II odontoid fracture is introduced. DESIGN/SETTING: The upper cervical spine FE model was adapted from a 50th percentile male full-body model developed with the Global Human Body Models Consortium (GHBMC). FE modeling was performed in LS-DYNA and LS-OPT (Livermore Software Technology Group) was used for ligament laxity optimization. METHODS: Ordinate-based curve matching was used to minimize the mean squared error (MSE) between computed load-rotation curves and experimental load-rotation curves under flexion, extension, and axial rotation with pure moment loads from 0 to 3.5 Nm. Lateral bending was excluded from the optimization because the upper cervical spine was considered to be primarily responsible for flexion, extension, and axial rotation. Based on recommendations from the literature, four varying inputs representing laxity in select ligaments were optimized to minimize the MSE. Funding was provided by the Natural Sciences and Engineering Research Council of Canada as well as GHMBC. The present study was funded by the Natural Sciences and Engineering Research Council of Canada to support the work of one graduate student. There are no conflicts of interest to be reported. RESULTS: The MSE was reduced to 0.28 in the FE model with optimized ligament laxity compared with an MSE 0f 4.16 in the FE model without laxity. In all load cases, incorporating ligament laxity improved the agreement between the ROM of the FE model and the ROM of the experimental data. The ROM for axial rotation and extension was within one standard deviation of the experimental data. The ROM for flexion and lateral bending was outside one standard deviation of the experimental data, but a compromise was required to use one set of ligament laxity values to achieve a best fit to all load cases. Atlanto-occipital motion was compared as a ratio to overall ROM, and only in extension did the inclusion of ligament laxity not improve the agreement. After a Type II odontoid fracture was incorporated into the model, the increase in ROM was consistent with experimental data from the literature. CONCLUSIONS: The optimization approach used in this study provided values for ligament laxities that, when incorporated into the FE model, generally improved the ROM response when compared with experimental data. Successfully modeling a Type II odontoid fracture showcased the robustness of the FE model, which can now be used in future biomechanics studies. PMID- 28673825 TI - The medicolegal landscape of spine surgery: how do surgeons fare? AB - BACKGROUND CONTEXT: Because of the limited and confidential nature of most legal data, scarce literature is available to physicians about reasons for litigation in spine surgery. To optimally compensate patients while protecting physicians, further understanding of the medicolegal landscape is needed for high-risk procedures such as spine surgery. Based on these, surgeons can explore ways to better protect both their patients and themselves. PURPOSE: To characterize the current medicolegal environment of spine surgery by analyzing a recent dataset of malpractice litigation. STUDY DESIGN: A retrospective study. PATIENT SAMPLE: All malpractice cases involving spine surgery available to public query between the years of 2010 and 2014. OUTCOME MEASURES: Case outcome for spine surgery malpractice cases between the years of 2010 and 2014. METHODS: WestlawNext was used to analyze spine surgery malpractice cases at the state and federal level between the years 2010 and 2014. WestlawNext is a subscription-based, legal search engine that contains publicly available federal and state court records. All monetary values were inflation adjusted for 2016. One hundred three malpractice cases were categorized by case descriptors and outcome measures. Claims were categorized as either intraoperative complaints or preoperative complaints. RESULTS: Rulings in favor of the defendant (surgeon) were noted in 75% (77 of 103) of the cases. Lack of informed consent was cited in 34% of cases. For the 26 cases won by the plaintiff, the average amount in settlement was $2,384,775 versus $3,945,456 in cases brought before a jury. Cases involving consent averaged a compensation of $2,029,884, whereas cases involving only intraoperative complaints averaged a compensation of $3,667,530. A significant correlation was seen between increased compensation for plaintiffs and cases involving orthopedic surgeons (p=.020) or nerve injury (p=.005). Wrong-level surgery may be associated with lower plaintiff compensation (p=.055). The length of cases resulting in defense verdicts averaged 5.51 years, which was significantly longer than the 4.34 years average length of settlements or verdicts in favor of plaintiffs (p=.016). CONCLUSIONS: Spine surgeons successfully defended themselves in 75% of lawsuits, although the cases won by physicians lingered significantly longer than those settled. Better understanding of these cases may help surgeons to minimize litigation. More than one third of cases involved a claim of insufficient informed consent. Surgeons can protect themselves and optimize care of patients through clear and documented patient communication, education, and intraoperative vigilance to avoid preventable complications. PMID- 28673826 TI - The 5-year cost-effectiveness of two-level anterior cervical discectomy and fusion or cervical disc replacement: a Markov analysis. AB - BACKGROUND CONTEXT: Anterior cervical discectomy and fusion (ACDF) and cervical disc replacement (CDR) are both acceptable surgical options for the treatment of cervical myelopathy and radiculopathy. To date, there are limited economic analyses assessing the relative cost-effectiveness of two-level ACDF versus CDR. PURPOSE: The purpose of this study was to determine the 5-year cost-effectiveness of two-level ACDF versus CDR. STUDY DESIGN: The study design is a secondary analysis of prospectively collected data. PATIENT SAMPLE: Patients in the Prestige cervical disc investigational device exemption (IDE) study who underwent either a two-level CDR or a two-level ACDF were included in the study. OUTCOME MEASURES: The outcome measures were cost and quality-adjusted life years (QALYs). MATERIALS AND METHODS: A Markov state-transition model was used to evaluate data from the two-level Prestige cervical disc IDE study. Data from the 36-item Short Form Health Survey were converted into utilities using the short form (SF)-6D algorithm. Costs were calculated from the payer perspective. QALYs were used to represent effectiveness. A probabilistic sensitivity analysis (PSA) was performed using a Monte Carlo simulation. RESULTS: The base-case analysis, assuming a 40 year-old person who failed appropriate conservative care, generated a 5-year cost of $130,417 for CDR and $116,717 for ACDF. Cervical disc replacement and ACDF generated 3.45 and 3.23 QALYs, respectively. The incremental cost-effectiveness ratio (ICER) was calculated to be $62,337/QALY for CDR. The Monte Carlo simulation validated the base-case scenario. Cervical disc replacement had an average cost of $130,445 (confidence interval [CI]: $108,395-$152,761) with an average effectiveness of 3.46 (CI: 3.05-3.83). Anterior cervical discectomy and fusion had an average cost of $116,595 (CI: $95,439-$137,937) and an average effectiveness of 3.23 (CI: 2.84-3.59). The ICER was calculated at $62,133/QALY with respect to CDR. Using a $100,000/QALY willingness to pay (WTP), CDR is the more cost-effective strategy and would be selected 61.5% of the time by the simulation. CONCLUSIONS: Two-level CDR and ACDF are both cost-effective strategies at 5 years. Neither strategy was found to be more cost-effective with an ICER greater than the $50,000/QALY WTP threshold. The assumptions used in the analysis were strongly validated with the results of the PSA. PMID- 28673827 TI - The impact of spine stability on cervical spinal cord injury with respect to demographics, management, and outcome: a prospective cohort from a national spinal cord injury registry. AB - BACKGROUND CONTEXT: Emergent surgery for patients with a traumatic spinal cord injury (SCI) is seen as the gold standard in acute management. However, optimal treatment for those with the clinical diagnosis of central cord syndrome (CCS) is less clear, and classic definitions of CCS do not identify a unique population of patients. PURPOSE: The study aimed to test the authors' hypothesis that spine stability can identify a unique group of patients with regard to demographics, management, and outcomes, which classic CCS definitions do not. STUDY DESIGN/SETTING: This is a prospective observational study. PATIENT SAMPLE: The sample included participants with cervical SCI included in a prospective Canadian registry. OUTCOME MEASURES: The outcome measures were initial hospitalization length of stay, change in total motor score from admission to discharge, and in hospital mortality. METHODS: Patients with cervical SCI from a prospective Canadian SCI registry were grouped into stable and unstable spine cohorts. Bivariate analyses were used to identify differences in demographic, injury, management, and outcomes. Multivariate analysis was used to better understand the impact of spine stability on motor score improvement. No conflicts of interest were identified. RESULTS: Compared with those with an unstable spine, patients with cervical SCI and a stable spine were older (58.8 vs. 44.1 years, p<.0001), more likely male (86.4% vs. 76.1%, p=.0059), and have more medical comorbidities. Patients with stable spine cervical SCI were more likely to have sustained their injury by a fall (67.4% vs. 34.9%, p<.0001), and have high cervical (C1-C4; 58.5% vs. 43.3%, p=.0009) and less severe neurologic injuries (ASIA Impairment Scale C or D; 81.3% vs. 47.5%, p<.0001). Those with stable spine injuries were less likely to have surgery (67.6% vs. 92.6%, p<.0001), had shorter in-hospital lengths of stay (median 84.0 vs. 100.5 days, p=.0062), and higher total motor score change (20.7 vs. 19.4 points, p=.0014). Multivariate modeling revealed that neurologic severity of injury and spine stability were significantly related to motor score improvement; patients with stable spine injuries had more motor score improvement. CONCLUSIONS: We propose that classification of stable cervical SCI is more clinically relevant than classic CCS classification as this group was found to be unique with regard to demographics, neurologic injury, management, and outcome, whereas classic CCS classifications do not . This classification can be used to assess optimal management in patients where it is less clear if and when surgery should be performed. PMID- 28673828 TI - Gender trends in authorship of spine-related academic literature-a 39-year perspective. AB - BACKGROUND CONTEXT: Despite recent advances in gender equity in medicine, the representation of women in orthopedic and neurosurgery remains particularly low. Furthermore, compared with their male colleagues, female faculty members are less likely to publish research, limiting opportunities in the academic promotion process. Understanding disparities in research productivity provides insight into the "gender gap" in the spine surgeon workforce. PURPOSE: This study aims to determine the representation and longevity of female physician-investigators among the authors of five spine-related research journals from 1978 to 2016. STUDY DESIGN: This is a retrospective bibliometric review. METHODS: The authors of original research articles from five prominent spine-related journals (European Spine Journal, The Spine Journal, Spine, Journal of Spinal Disorders and Techniques, and Journal of Neurosurgery: Spine) were extracted from PubMed. For authors with a complete first name listed, gender was determined by matching first name using an online database containing 216,286 distinct names across 79 countries and 89 languages. The proportion of female first and senior authors was determined during the time periods 1978 to 1994, 1995 to 1999, 2000 to 2004, 2005 to 2009, and 2010 to 2016. The authors who had their first paper published between 2000 and 2009 were included in additional analyses for publication count and longevity (whether additional articles were published 5 years after first publication). Student t test, chi-square analysis, and Cochran-Armitage trend test were used to determine significance between groups. RESULTS: From 1978 to 2016, 28,882 original research articles were published in the five spine-related journals. A total of 24,334 abstracts (90.9%) had first names listed, identifying 120,723 authors, in total of which 100,286 were successfully matched to a gender. A total of 33,480 unique authors were identified (female authors: 31.8%). Female representation increased for first and senior authors from 6.5% and 4.7% (1978 1994) to 18.5% and 13.6% (2010-2016, p<.001). Growth in female senior author representation declined after 2000 (12.3% vs. 12.9% vs. 13.5% between 2000-2004, 2005-2009, and 2010-2016). Compared with male authors, on average, female authors published fewer articles (mean: 2.1 vs. 3.3, p<.001). Of 15,304 authors who first published during 2000 to 2009, 3,478 authors (22.7%) continued to publish 5 years after their first publication. Female authors were less likely to continue publishing after their first article (15.3% of female authors vs. 24.8%, p<.001). CONCLUSIONS: Female representation in academic spine research has doubled over the past 4 decades, although the growth of female representation as senior author has plateaued. Female physician-investigators are half as likely to continue participating in spine-related research longer than 5 years and on average publish half as many articles as senior author. In addition to recruiting more women into research, efforts should be made to identify and address barriers in research advancement and promotion for female physician-investigators. PMID- 28673829 TI - Lumbar spine surgery in patients with rheumatoid arthritis (RA): what affects the outcomes? AB - BACKGROUND CONTEXT: Although the cervical spine is only occasionally involved in rheumatoid arthritis (RA), involvement of the lumbar spine is even less common. A few reports on lumbar spinal stenosis in patients with RA have appeared. Although disc space narrowing occurs in aging, postoperative adjacent segment disease (ASD) in patients with RA has not been subject to much analysis. PURPOSE: The objective of this study was to investigate differences in ASD and clinical outcomes between lumbar spinal decompression with and without fusion in patients with RA. STUDY DESIGN/SETTING: This is a retrospective comparative study. PATIENT SAMPLE: A total of 52 patients with RA who underwent surgery for lumbar spinal disorders were included. Twenty-seven patients underwent decompression surgery with fusion and 25 underwent decompression surgery alone. OUTCOME MEASURES: Intervertebral disc space narrowing and spondylolisthesis of the segment immediately cranial to the surgical site were measured using a three-dimensional volume rendering software. Pre- and postoperative evaluation of RA activity and Japanese Orthopaedic Association (JOA) scores were conducted. MATERIALS AND METHODS: All patients had preoperative and annual postoperative lumbar radiographs and were followed up for a mean of 5.1 years (range 3.5-10.9 years). Pre- and postoperative (2 years after surgery) JOA scores were recorded and any postoperative complications were investigated. Degrees of intervertebral disc narrowing and spondylolisthesis at the adjacent levels were evaluated on radiographs and were compared between the two groups. Analysis was performed to look for any correlation between ASD and RA disease activities. RESULTS: Postoperative JOA scores were significantly improved in both groups. The rate of revision surgery was significantly higher in the fusion group than that in the non-fusion group. The rate of ASD was significantly greater in the fusion group than that in the non-fusion group at the final follow-up examination. Both matrix metalloproteinase 3 (MMP-3) and the 28-joint disease activity score incorporating C-reactive protein levels (DAS28-CRP) were significantly associated with the incidence and severity of ASD. CONCLUSIONS: Adjacent segment disease and the need for revision surgery were significantly higher in the fusion group than those in the non-fusion group. A preoperative high MMP-3 and DAS28-CRP are likely to be associated with postoperative ASD. PMID- 28673830 TI - Motion preservation following total lumbar disc replacement at the lumbosacral junction: a prospective long-term clinical and radiographic investigation. AB - BACKGROUND CONTEXT: Total lumbar disc replacement (TDR) intends to avoid fusion related negative side effects by means of motion preservation. Despite their widespread use, the adequate quality and quantity of motion, as well as the correlation between radiographic data with the patient's clinical symptomatology, remains to be established. Long-term data are lacking in particular. PURPOSE: This study aimed to perform a clinical and radiographic long-term investigation following TDR with special emphasis on motion preservation assessment and to establish any potential correlation with patient-reported outcome parameters. STUDY DESIGN/SETTING: A prospective, single-center, clinical, and radiological investigation following TDR with ProDisc II (Synthes, Paoli, PA, USA) was carried out. PATIENT SAMPLE: Patients with a minimum 5-year follow-up (FU) after TDR performed for the treatment of intractable and predominant (>=80%) axial low back pain resulting from single-level degenerative disc disease without instabilities or deformities at the lumbosacral junction (L5-S1) comprised the sample. OUTCOME MEASURES: Visual analogue scale (VAS), Oswestry Disability Index (ODI), and patient satisfaction rates (three-scale outcome rating), range of motion (ROM) at the index- and cranially adjacent level as well as segmental lumbar lordosis (SLL) and global lumbar lordosis (GLL) were the outcome measures. METHODS: All data were acquired within the framework of an ongoing prospective clinical trial. Patients were examined preoperatively, 3, 6, and 12 months postoperatively, and annually thereafter. X-rays were performed in antero-posterior and lateral views as well as functional flexion/extension images. Radiological examinations included ROM at the index and cranially adjacent level as well as SLL and GLL. X ray measurements were correlated with the clinical outcome parameters. A longitudinal analysis was performed between baseline data with those from the early (3-6 months), mid- (12-24 months), and late FU stages (>=5 years). RESULTS: Results from 51 patients with a mean FU of 7.8 years (range 5.0-13.3 years) were available for the final analysis. X-ray measurements revealed a maintained mobility with a trend toward gradually declining ROM values. Although no statistically significant difference in ROM was detected between the preoperative and early FU (6.8 degrees vs. 5.8 degrees , p=.1), a further reduction in ROM became statistically significant at the mid- and final FU, with mean ROM of 5.2 degrees and 4.4 degrees , respectively (p<.001). Global lumbar lordosis increased from 48.8 degrees to 54.4 degrees (p<.0001) which was attributed to a lordotic shift from 18.2 degrees to 28.0 degrees at the index segment (p<.00001) and which was positively correlated with the applied implant lordosis (p<.05). A compensatory reduction of lordosis was observed at the cranially adjacent segment (p<.0001). The mobility of the cranially adjacent level remained unchanged (p>.05). The clinical outcome scores (VAS, ODI) revealed a significant improvement from baseline levels (p<.05). The reduction in ROM was not negatively correlated with the patient's clinical symptomatology (p>.05). CONCLUSION: The present data reveal an increased GLL resulting from a lordotic shift of the index segment, which was strongly correlated with the applied implant lordosis. This lordotic shift was accompanied by a compensatory reduction of lordosis at the cranially adjacent segment. A gradual and statistically significant decline of the device mobility was noted over time which, however, did not negatively impact the patient's clinical symptomatology. Although the present long-term investigation provides additional insight into longitudinal radiographic changes and their influence on the patient's clinical symptomatology following TDR, the adequate quality and quantity of motion with artificial motion-preserving implants remains to be established, which will aid in defining more refined treatment concepts for both fusion and motion preserving techniques alike. PMID- 28673831 TI - Risk factors for laryngeal penetration-aspiration in patients with acute traumatic cervical spinal cord injury. AB - BACKGROUND CONTEXT: Laryngeal penetration-aspiration, the entry of material into the airways, is considered the most severe subtype of dysphagia and is common among patients with acute cervical spinal cord injury (SCI). PURPOSE: The aim of this study was to investigate risk factors for penetration-aspiration in patients with acute traumatic cervical spinal cord injury (TCSCI). STUDY DESIGN: This is a prospective cohort study. PATIENT SAMPLE: Thirty-seven patients with TCSCI were included in the study. OUTCOME MEASURES: The highest Rosenbek penetration aspiration scale (PAS; range 1-8) score of each patient was the primary outcome measure. The risk factors consisted of patient characteristics, demographics, and clinical signs observed during a clinical swallowing trial. MATERIALS AND METHODS: A clinical swallowing trial and videofluoroscopic swallowing study (VFSS) was performed on all patients within 28 days post injury. For group comparisons, the patients were divided into two groups: (1) penetrator-aspirators (PAS score >=3) and (2) non-penetrator-aspirators (PAS score <=2). RESULTS: Of the 37 patients, 83.8% were male. The mean age at the time of the injury was 61.2 years. Most patients had an incomplete TCSCI (78.4%) caused by a fall (75.7%). In the VFSS, 51.4% of the patients were penetrator-aspirators, and 71.4% had silent aspiration. The risk factors for predicting penetration-aspiration were (1) necessity of bronchoscopies, (2) lower level of anterior cervical operation, (3) coughing, throat clearing, choking related to swallowing, and (4) changes in voice quality related to swallowing. Binary logistic regression identified coughing, throat clearing, choking, and changes in voice quality related to swallowing as independent risk factors for penetration-aspiration. CONCLUSIONS: The necessity of bronchoscopies, postinjury lower cervical spine anterior surgery, coughing, throat clearing, choking, and changes in voice quality related to swallowing was a markedrisk factor for aspiration and penetration following a cervical SCI. These factors and signs should be used to suspect injury-related pharyngeal dysfunction and to initiate preventive measures to avoid complications. The clinical swallowing evaluation is a relevant adjunct in the management of these patients and can improve the detection of penetration and aspiration. PMID- 28673832 TI - Neural functional correlates of empathic face processing. AB - OBJECTIVES: Empathy is a human trait related to the ability to share someone else's feelings, and emotional face processing is one of its measures. Functional Magnetic Resonance Imaging (fMRI) studies showed significant neural correlates of empathic face processing. We aimed to identify those brain areas most consistently involved in empathy for emotional faces. METHODS: We carried ALE meta-analysis of whole-brain data from fMRI studies during empathic face processing tasks. We included 23 studies conducted on a total of 568 participants (247 males and 321 females, mean age 32.2 years). RESULTS: Emotional vs. control faces processing significantly correlated with activations of the left anterior cingulate cortex (BA 32), right precentral gyrus (BA 6), left amygdala, right superior frontal gyrus (BA 9), left middle occipital gyrus (BA 37), right insula (BA 13), left putamen, and left posterior cingulate cortex (BA 31). CONCLUSIONS: Empathy is a complex process correlating with bi-hemispheric cortico-limbic activations involved in emotional cue processing, self-other/same-different discrimination, perspective-taking, theory of mind, emotional arousal, and decision-making. PMID- 28673833 TI - The glutamate receptor antagonists CNQX and MPEP decrease fast ripple events in rats treated with kainic acid. AB - Fast ripples (FR) are high frequency oscillations (250-600Hz) that have been associated with epilepsy. FR are assumed to be generated in small areas of the hippocampus (1mm3) that contain pathologically interconnected glutamate pyramidal cell clusters. Additionally, a relation between glutamate neurotransmission and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite (AMPA/KA) and metabotropic mGluR5 receptors is well established. Therefore, we hypothesized that antagonism of these glutamate receptors would decrease FR activity. For this propose, we induced status epilepticus with a kainic acid injection in the posterior right hippocampus and performed intracranial EEG recordings to detect and evaluate the presence of FR 15days after the injection. The glutamate AMPA/KA receptor antagonist CNQX (10mg/kg) and the mGluR5 antagonist MPEP (20mg/kg) were administered intraperitoneally, and the effects of the drugs were evaluated for a period of three hours after their administration. The results show a decrease in the number of FR in the first hour after drug administration in both cases (CNQX, p=0.0125; MPEP, p=0.0132) and a return to basal values in the third hour of the experiment, but not significant differences in the number of oscillations per event of FR, and the frequency and duration of each event of FR. We therefore conclude that blockade of AMPA/KA and mGluR5 receptors transiently decreases the generation of FR; however, the mechanisms by which this effect is achieved are to be further analyzed in future experiments. PMID- 28673835 TI - When should parapneumonic pleural effusions be drained in children? AB - Pneumonia is an important health problem in children, and parapneumonic pleural effusion (PPE) is a frequent complication. There is no standard strategy for treating PPE, reflected in the few international guidelines that have been published on the issue. Compared to adults, there is no consensus on the utility of pleural fluid analysis in paediatric PPE. This is because of the lack of good evidence either in favour or against it and the risks of procedural sedation for acquiring pleural fluid for analysis to guide management. In this paper we provide a succinct review of the different approaches to the management of PPE, including diagnosis, pleural fluid analysis (Light's criteria) and treatment, both medical and surgical. PMID- 28673834 TI - Enzymatic O-GlcNAcylation of alpha-synuclein reduces aggregation and increases SDS-resistant soluble oligomers. AB - Neurodegenerative diseases including dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, and Parkinson's disease are associated with the aberrant aggregation of alpha-synuclein, which is influenced by several post-translational modifications (PTMs). O-GlcNAcylation is one PTM that has an important role in many fundamental processes. The O-GlcNAcylation of endogenous alpha-synuclein at residues 53, 64, 72 and 87 has been reported in an unbiased mass spectrum analysis. The consequences of O-GlcNAcylation at residues 72 or 87 have been studied by using a synthetic alpha-synuclein bearing O-GlcNAcylation at threonine residue 72 or serine 87, respectively. O-GlcNAcylation at Thr72 or Ser87 suppresses the aggregation of alpha-synuclein. However, the effect of enzymatic O GlcNAcylation of alpha-synuclein at multiple residues is not clear. Here, we successfully generated O-GlcNAcylated alpha-synuclein by co-expressing a shorter form of OGT (sOGT) with alpha-synuclein. The O-GlcNAcylation inhibited alpha synuclein aggregation and promoted the formation of soluble SDS-resistant and Thioflavine T negative oligomers. Our data warrant further studies on the role of O-GlcNAcylation in the progression/treatment of Parkinson's disease in animal models. PMID- 28673836 TI - Microneedles enhance topical delivery of 15-deoxy-Delta12,14-prostaglandin J2 and reduce nociception in temporomandibular joint of rats. AB - The pain arising from temporomandibular disorders is often treated with opioids and agents that inhibit the immune response and are associated with substantial adverse effects and long-term risks. Thus, the development of new therapies that are safer and more effective is of great interest to patients and clinicians. 15 deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is naturally produced in the human body and has anti-inflammatory properties. We have previously shown in a rat temporomandibular joint (TMJ) model that injection of 15d-PGJ2 into the rat TMJ can provide antinociceptive relief against a subsequent noxious challenge from formalin injection into the same TMJ. However, intra-TMJ injections are painful. Thus, to make the treatment patient friendly, this study aimed to evaluate whether the antinociceptive property of 15d-PGJ2 cream can be enhanced with microneedles (MNs). We found that topical application of 15d-PGJ2 cream for 15min directly on the rat TMJ skin did not induce any significant antinociceptive effect. However, if MNs were inserted in the skin for 5min, removed, and then 15d PGJ2 cream was applied, a significant reduction in formalin-induced nociceptive behavior was observed. This reduction in nociception was comparable to an intra TMJ injection of 15d-PGJ2. A concentration-dependent effect of 15d-PGJ2 was observed, with higher concentrations of 15d-PGJ2 in the cream showing a more durable effect up to 8h. 15d-PGJ2 cream associated with MNs also significantly reduced the release of tumor necrosis factor-alpha and interleukin-1 beta, which are pro-inflammatory cytokines. Our findings suggest that 15d-PGJ2 cream associated with MNs provides antinociceptive and anti-inflammatory effect, and can offer a potential patient-friendly therapeutic option for pain control related to inflammatory disorders of the TMJ. PMID- 28673837 TI - Respiratory viruses detected in Mexican children younger than 5 years old with community-acquired pneumonia: a national multicenter study. AB - BACKGROUND: Acute respiratory infections are the leading cause of mortality in children worldwide, especially in developing countries. Pneumonia accounts for 16% of all deaths of children under 5 years of age and was the cause of death of 935000 children in 2015. Despite its frequency and severity, information regarding its etiology is limited. The aim of this study was to identify respiratory viruses associated with community-acquired pneumonia (CAP) in children younger than 5 years old. METHODS: One thousand four hundred and four children younger than 5 years of age with a clinical and/or radiological diagnosis of CAP in 11 hospitals in Mexico were included. Nasal washes were collected, placed in viral medium, and frozen at -70 degrees C until processing. The first 832 samples were processed using the multiplex Bio-Plex/Luminex system and the remaining 572 samples using the Anyplex multiplex RT-PCR. Clinical data regarding diagnosis, clinical signs and symptoms, radiographic pattern, and risk factors were obtained and recorded. RESULTS: Of the samples tested, 81.6% were positive for viruses. Respiratory syncytial virus (types A and B) was found in 23.7%, human enterovirus/rhinovirus in 16.6%, metapneumovirus in 5.7%, parainfluenza virus (types 1-4) in 5.5%, influenza virus (types A and B) in 3.6%, adenovirus in 2.2%, coronavirus (NL63, OC43, 229E, and HKU1) in 2.2%, and bocavirus in 0.4%. Co-infection with two or more viruses was present in 22.1%; 18.4% of the samples were negative. Using biomass for cooking, daycare attendance, absence of breastfeeding, and co-infections were found to be statistically significant risk factors for the presence of severe pneumonia. CONCLUSIONS: Respiratory syncytial virus (types A and B), human enterovirus/rhinovirus, and metapneumovirus were the respiratory viruses identified most frequently in children younger than 5 years old with CAP. Co infection was present in an important proportion of the children. PMID- 28673838 TI - Benzo(a)pyrene induced cell cycle arrest and apoptosis in human choriocarcinoma cancer cells through reactive oxygen species-induced endoplasmic reticulum-stress pathway. AB - Cigarette smoke (CS) contains over 60 well established carcinogens. In this study, we examined the effects of benzo(a)pyrene (B(a)P), a main CS component, on the viability and apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cell lines. An MTT assay confirmed that B(a)P decreased the cell viability of JEG-3 and BeWo cells in a dose-dependent manner. Additionally, Western blot (WB) assay revealed that protein expression of cyclin D and cyclin E decreased, while protein expression of p21 and p27 was increased in response to B(a)P treatment for 48 h. The changes in reactive oxygen species (ROS) levels in JEG-3 and BeWo cells exposed to B(a)P were also measured by a dichlorofluorescein diacetate (DCF DA) assay, which revealed that ROS levels increased in response to B(a)P treatment for 48 h. WB assay also confirmed that each B(a)P treatment of JEG-3 and BeWo cells for 4 h promoted the expression of phosphorylated eukaryotic initiation factor 2 alpha protein (p-eIF2alpha) and C/EBP homologous protein (CHOP), which are known to be involved in ROS-mediated endoplasmic reticulum stress (ER-stress) related apoptosis. Overall, the protein expression of Bax (a pro-apoptosis marker) increased, while the expression of Bcl-xl (an anti apoptotic marker) decreased and the number of apoptotic cells increased in response to B(a)P treatment for 48 h. Taken together, these results suggest that B(a)P has the potential to induce apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cells by increasing the ROS level and simultaneously activating ER-stress. PMID- 28673839 TI - Incentive salience attribution is not the sole determinant of suboptimal choice in rats: Conditioned inhibition matters. AB - Previous research has identified clear differences between pigeons and rats in the suboptimal choice procedure. Pigeons behave suboptimally, preferring an alternative with discriminative stimuli and a smaller probability of reinforcement, over another with a higher probability of reinforcement, but without discriminative stimuli. In contrast, rats behave optimally showing the opposite preference. It has been proposed that these dissimilarities are consequence of a higher sensitivity to conditioned inhibition in rats than in pigeons. Alternatively, recent research suggests that differences in optimality can be accounted for by a differential incentive salience of the stimuli employed as discriminative stimuli, and that both species are suboptimal when such stimuli have high incentive salience; specifically, rats were found to be suboptimal when levers were used as discriminative stimuli. However, in the evaluation of this hypothesis, a conditioned inhibitor was not employed. In the present report, eight rats were exposed to a choice procedure that integrated both variables discussed above: a conditioned inhibitor was associated with the discriminative alternative and the stimuli had high incentive salience. A clear preference for the optimal alternative was found, suggesting that the conditioned inhibitor had a considerable impact on rats' preference, and that species-differences remain even in procedures in which the discriminative stimuli have incentive salience. PMID- 28673840 TI - Characterization of an exopolysaccharide with distinct rheological properties from Paenibacillus edaphicus NUST16. AB - Microbial exopolysaccharides (EPSs) have been commercially used for decades owing to their distinct rheological properties. New EPSs with special traits are being explored continuously. The strain Paenibacillus edaphicus NUST16 was isolated in this study. NUST16 produces 12.5g/L EPS after 72h cultivation in shaker flask. Moreover, the purified EPS, POS16, has the molecular weight of 1.2*107Da and consists of five types of glycosides, namely, D-Glc, D-Man, L-Fuc, D-GlcA, and D Gal. Methylation, NMR, and FT-IR results indicate that three glucosides and three mannosides make up the main chain of POS16 via 1->3 linkage. The Gal(1->3)Fuc(1 >3)Fuc(1-> and GlcA(1-> branches link to the C6 positions of two mannosides, respectively. The other mannoside is partially derivatized by the acetyl group at C2 position. Rheological analysis shows that POS16 has typical shear-thinning pattern which fits the Hershel-Bulkley model well. More importantly, POS16 shows ideal saline tolerance as the apparent viscosity keeps high in solutions containing 100g/L salts, such as NaCl, KCl, MgCl2, and CaCl2. Furthermore, POS16 behaves more viscous than xanthan gum and sodium carboxymethylcellulose in divalent ion solutions. The results suggest that POS16 is a potential rheological modulator that can be used in operations where high concentrations of salts exist. PMID- 28673841 TI - Application and comparison in biosynthesis and biodegradation by Fusarium solani and Aspergillus fumigatus cutinases. AB - In this study, two synthesized cutinase genes from Fusarium solani and Aspergillus fumigatus were expressed in Pichia pastoris X33. The characteristics of these two cutinases were investigated and compared. The results indicated that F. solani and A. fumigatus cutinases hydrolyzed p-nitrophenyl substrates with different carbon chain lengths. A. fumigatus cutinase predominately hydrolyzed p nitrophenyl butyrate, but F. solani cutinase preferred p-nitrophenyl decanoate. The abilities of polymer synthesis and bioplastic degradation were tested and compared between F. solani and A. fumigatus cutinases. The results showed that F. solani cutinase had degradation ability on poly(epsilon-caprolactone) (PCL) and synthesized polymer with a molecular weight (MW) of 2300 in organic solvent. However, A. fumigatus cutinase completely degraded PCL and synthesized molecules with a MW of 25,000, suggesting that A. fumigatus cutinase has more promising applications. PMID- 28673842 TI - Sensitive complex micelles based on host-guest recognition from chitosan-graft beta-cyclodextrin for drug release. AB - In this paper, pH-sensitive complex micelles were developed based on the host guest recognition from chitosan-graft-beta-cyclodextrin (CS-g-CD) and benzimidazole-terminated poly(epsilon-caprolactone) (BM-PCL) for controlled drug release. The formation and characterization of complex micelles were confirmed by fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM) and laser particle analyzer. The size of complex micelles was about 200nm with the core formed by BM-PCL/beta-CD and the shell composed of chitosan. Doxorubicin (DOX), a model anticancer drug, was effectively loaded into the complex micelles via hydrophobic interactions. The encapsulation efficiency of DOX was up to 75%. The release of DOX from complex micelles was suppressed at neutral pH solutions due to the stability of micelles but accelerated at acidic solutions and high temperatures. These sensitive complex micelles might possess potential applications as intelligent nanocarriers for anticancer drug delivery. PMID- 28673843 TI - Synthesis, characterization and biological activity of C6-Schiff bases derivatives of chitosan. AB - C6-Schiff bases derivatives of chitosan were synthesized for the first time. C2 amino groups and C3-hydroxy groups were firstly protected by CuSO4.5H2O, and the C6-hydroxy was then transformed into aldehyde, which then reacted with anilines through nucleophilic addition to introduce the CN group at C6-position in chitosan chain. Finally, C6-Schiff bases derivatives of chitosan were got by the deprotection of C2-NH2 with cation exchange resin. The structures and properties of the new synthesized products were characterized by Fourier transform infrared spectroscopy, 13C NMR, SEM image, and elemental analysis. The antibacterial activities of derivatives were tested in the experiment, and the results showed that the prepared chitosan derivatives had significantly improved antibacterial activity toward Staphylococcus aureus and Escherichia coli. The Cytotoxicity test showed that the prepared chitosan derivatives had low Cytotoxicity, compared with chitosan and C2-benzaldehyde Schiff bases of chitosan. This paper allowed a new method for the synthesis of Schiff bases of chitosan, which was enlightening. PMID- 28673844 TI - Optimization of paddy parboiling process for higher starch crystallinity by response surface methodology. AB - Paddy parboiling has received considerable attention as far as nutritional and milling improvement is concerned. Parboiling is also advantageous as it renders enhanced head rice yield and insect resistance. However, lower starch crystallinity of parboiled rice invites easy fungal infestation under favourable moisture and temperature conditions during storage. Additionally, parboiled rice is expected to possess higher resistant starch. Unfortunately, conventional processing conditions lead to either very less or moderate resistant starch content. Thus, improving starch crystallinity in parboiled rice is desirable to make a portion of starch, less accessible to amylolytic enzymes and to impart slow digestible behaviour. The four independent factors selected were pH of soaking solution (3-7), steaming time (10-30min), cooling temperature (5-25 degrees C) and cooling time (0-6h). The experimental data were fitted to quadratic second-order polynomial models to study the relationship between independent and dependent variables. The controlled cooling of parboiled paddy exhibit a higher crystallinity%, along with better starch reorganization, as evaluated by XRD, FTIR and Visible spectrum. Further equilibrium moisture content on soaking (ambient temperature) and sediment value of optimally processed parboiled paddy showed reduced water absorption as compared to conventionally parboiled paddy sample, which is indicative about enhanced crystallinity parboiled rice. PMID- 28673845 TI - Trehalose radial networks protect Renilla luciferase helical layers against thermal inactivation. AB - Renilla luciferase (Rluc) from Renilla reniformis is an appropriate protein reporter for the detection of specific molecular targets due to its bioluminescent feature, although its relatively low stability limits the application. To investigate the effects of trehalose and sucrose as chemical chaperones on the kinetic stability of Rluc, we assayed the activity of the enzyme in the presence of these additives at high temperatures and to comprehend the mechanism of stability, molecular dynamic (MD) simulation was carried out. In the presence of trehalose a thermostabilizing effect which was considerable in comparison with other systems was observed. It is proposed that a wide radial like network of trehalose molecules supports alpha-helix structures that are located in the N-terminus and C-terminus of the protein. However, in the water simulation box, these helices alter to instable structures at high temperatures. Reduction of the fluctuation of these helices in the presence of trehalose molecules, may prevent the protein from unfolding and increase its shelf life. PMID- 28673846 TI - ZnSe-WO3 nano-hetero-assembly stacked on Gum ghatti for photo-degradative removal of Bisphenol A: Symbiose of adsorption and photocatalysis. AB - In this research work we report Gum-ghatti supported ZnSe-WO3 nano-hetero assembly for solar powered degradation of endocrine disruptor Bisphenol S (BPA). The photocatalyst was characterized by Scanning electron microscopy (SEM), High resolution transmission electron microscopy (HRTEM), Small area electron diffraction (SAED), X-Ray diffraction (XRD), Fourier transform infra red spectroscopy (FTIR), Photoluminescence (PL), Energy dispersive X-ray (EDX), UV vis spectrophotometry and Brauner Emmet Teller surface area analyzer (BET). We achieve a Z-scheme photocatalyst (ZnSe-WO3) with a higher charge flow and visible absorption. Gum ghatti acts as a superadsorbent and a sink for charge carriers. The removal of BPA has been studied under three experimental protocols where 99.5% removal was achieved by symbiose of photocatalysis-adsorption-ozonation in just 45min hetero-assembly has a high surface area, stability and reduced carrier recombination. The results have been analyzed by scavenger effect, mass spectrometry, kinetics and total organic carbon (TOC) analysis. 49.4% of TOC was removed and COD was reduced to 16.7% after 2h in symbiotic condition. From the band edges and scavenger effect it was inferred that superoxide radical anions are major attacking species. The work paves way for designing of novel photocatalysts with increasing biogenic quotient and higher efficiency. PMID- 28673847 TI - Effects of selenylation modification on structural and antioxidant properties of pectic polysaccharides extracted from Ulmus pumila L. AB - The present study was carried out to determine the effects of selenylation on structural and antioxidant activities of pectic polysaccharides extracted from Ulmus pumila L. (PPU). Selenylation of PPU (Se-PPU) was synthesized by different concentrations of sodium selenites (0.2, 0.4, 0.6, 0.8, and 1.0g). Structural properties of Se-PPUs were characterized using ICP-OES, HPGPC, FE-SEM, XRD, FT-IR and NMR. After selenylation, the selenium contents and the molecular weights of PPU increased. In FT-IR analysis, a new intensive absorption band at around 667cm 1 was observed in Se-PPU. From 13C NMR spectra, the new peak at 62.41ppm was found in Se-PPU probably due to the substitution of selenyl groups. In vitro antioxidant activities of all samples were evaluated by reducing power, nitrite scavenging, superoxide dismutase like scavenging activities, hydroxyl radical scavenging activities, and DPPH radical scavenging activities. The antioxidant activities of Se-PPUs were significantly higher than those of PPU. In conclusion, Se-PPU exhibited the potential possibility of the use as an antioxidant in foods and pharmaceuticals. Furthermore, the expanded use of Se-PPU produced from Ulmus sources may be taken in account for better health improvement. PMID- 28673848 TI - First described case of prosthetic joint infection with Clostridium disporicum. AB - An orthopedic hardware infection with Clostridium disporicum is described. C. disporicum is a gram positive anaerobic bacillus which can contain two subterminal spores. C. disporicum had not previously been reported in musculoskeletal infections. Gram stains demonstrating gram positive bacilli with two subterminal spores should alert practitioners to the possibility of C. disporicum infection. PMID- 28673850 TI - Clinical Utility of Wilms' Tumor 1 Monitoring in Patients with Myeloid Malignancy and Prior Allogeneic Hematopoietic Stem Cell Transplantation. AB - Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is 1 of the standard treatments for myeloid malignancy, relapse remains a major obstacle to cure. Early detection of relapse by monitoring of minimal residual disease (MRD) may enable us to intervene pre-emptively and potentially prevent overt relapse. Wilms' tumor 1 (WT1) is well known as a pan-leukemic marker. We retrospectively examined serially monitored WT1 levels of peripheral blood in 98 patients (84 with acute myeloid leukemia and 14 with myelodysplastic syndrome). At the time of allo-HSCT, 49 patients (50%) were in complete remission. Patients were divided into 3 groups according to WT1 levels (<50 copies/ug RNA, 50 to 500 copies/ug RNA and >500 copies/ug RNA). The cumulative incidence of relapse (CIR) and overall survival (OS) differed statistically according to the WT1 levels before allo-HSCT and at days 30 and 60 after allo-HSCT. In multivariate analysis, WT1 >500 copies/ug RNA before and at day 60 after allo-HSCT and WT1 >=50 copies/ug RNA at day 30 were correlated with CIR. Moreover, WT1 >500 copies/ug RNA at day 60 after allo-HSCT was only correlated with worse OS. Our data suggest that serial monitoring of WT1 levels in peripheral blood may be useful for MRD monitoring and as a predictor of hematological relapse in allo-HSCT. PMID- 28673849 TI - Hematopoietic Stem Cell Transplantation for Patients with Mucopolysaccharidosis II. AB - There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiologic findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were collected from 27 new cases and 119 published cases and were compared with 51 ERT and 15 untreated cases. Glycosaminoglycan (GAG) levels were analyzed by liquid chromatography tandem mass spectrometry in blood samples from HSCT, ERT, and untreated patients as well as age-matched controls. Long-term magnetic resonance imaging (MRI) findings were investigated in 13 treated patients (6 ERT and 7 HSCT). Mean age at HSCT was 5.5 years (range, 2 to 21.4 years) in new patients and 5.5 years (range, 10 months to 19.8 years) in published cases. None of the 27 new patients died as a direct result of the HSCT procedure. Graft-versus-host disease occurred in 8 (9%) out of 85 published cases, and 9 (8%) patients died from transplantation-associated complications. Most HSCT patients showed greater improvement in somatic features, joint movements, and activity of daily living than the ERT patients. GAG levels in blood were significantly reduced by ERT and levels were even lower after HSCT. HSCT patients showed either improvement or no progression of abnormal findings in brain MRI while abnormal findings became more extensive after ERT. HSCT seems to be more effective than ERT for MPS II in a wide range of disease manifestations and could be considered as a treatment option for this condition. PMID- 28673851 TI - Peptide multifunctionalized gold nanorods decrease toxicity of beta-amyloid peptide in a Caenorhabditis elegans model of Alzheimer's disease. AB - The properties of nanometric materials make nanotechnology a promising platform for tackling problems of contemporary medicine. In this work, gold nanorods were synthetized and stabilized with polyethylene glycols and modified with two kinds of peptides. The D1 peptide that recognizes toxic aggregates of Abeta, a peptide involved in Alzheimer's disease (AD); and the Angiopep 2 that can be used to deliver nanorods to the mammalian central nervous system. The nanoconjugates were characterized using absorption spectrophotometry, dynamic light scattering, and transmission electron microscopy, among other techniques. We determined that the nanoconjugate does not affect neuronal viability; it penetrates the cells, and decreases aggregation of Abeta peptide in vitro. We also showed that when we apply our nanosystem to a Caenorhabditis elegans AD model, the toxicity of aggregated Abeta peptide is decreased. This work may contribute to the development of therapies for AD based on metallic nanoparticles. PMID- 28673853 TI - Enhanced simultaneous overlap extension-PCR by gold nanoparticles. AB - Methods to fuse multiple DNA fragments are extremely useful in synthetic biology and protein engineering. Here, we report a gold nanoparticle-mediated simultaneous overlap extension-PCR (AuNP-mediated SOE-PCR) method that enables the fusion of multiple DNA fragments simultaneously with their amplification in a single reaction using typical PCR conditions. Using greater concentrations of rTaq DNA polymerase and AuNPs significantly improves the performance of SOE-PCR especially for the fusion of more than three DNA fragments. We show that up to six lambda DNA fragments can be simultaneously fused by AuNP-mediated SOE-PCR. PMID- 28673852 TI - Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer. AB - Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells. PMID- 28673854 TI - Nano-therapeutics: A revolution in infection control in post antibiotic era. AB - With the arrival of antibiotics 70 years ago, meant a paradigm shift in overcoming infectious diseases. For decades, drugs have been used to treat different infections. However, with time bacteria have become resistant to multiple antibiotics, making some diseases difficult to fight. Nanoparticles (NPs) as antibacterial agents appear to have potential to overcome such problems and to revolutionize the diagnosis and treatment of bacterial infections. Therefore, there is significant interest in the use of NPs to treat variety of infections, particularly caused by multidrug-resistant (MDR) strains. This review begins with illustration of types of NPs followed by the literature of current research addressing mechanisms of NPs antibacterial activity, steps involved in NP mediated drug delivery as well as areas where NPs use has potential to improve the treatment, like NP enabled vaccination. Besides, recently emerged innovative NP platforms have been highlighted and their progress made in each area has been reviewed. PMID- 28673855 TI - Immiscible phase filter extraction and equivalent amplification of genotypes 1-6 of hepatitis C RNA: The building blocks for point-of-care diagnosis. AB - The lack of hepatitis C virus (HCV) diagnostic tests designed for use in decentralized settings is a major obstacle for providing access to treatment and prevention services particularly in low and middle income countries. Here we describe the development and validation of two building blocks of the HCV Quant Assay, a test in development for point-of-care use: 1) an RT-qPCR assay with noncompetitive internal control that equivalently detects the 6 major HCV genotypes and 2) an automated sample prep method using immiscible phase filter technology. This novel assay has wide dynamic range of HCV quantification and a limit of detection of 30IU/ml with 200MUl specimen volume. In a preliminary study of 61 clinical specimens, the HCV Quant Assay demonstrated 100% sensitivity and specificity and gave comparable viral load results across 4 logs of IU/ml when compared to the Abbott RealTime HCV Assay. PMID- 28673856 TI - A Luciferase Immunoprecipitation System (LIPS) assay for profiling human norovirus antibodies. AB - A luciferase immunoprecipitation systems (LIPS) assay was developed to define the antigenic specificity and titer of antibodies directed against human norovirus (HuNoV). Recombinant proteins, expressed by plasmid constructs encoding Renilla luciferase (Ruc) fused to the full-length HuNoV major capsid protein (VP1) (Ruc antigen), were generated for ten HuNoV strains. In addition, subdomain constructs Ruc-Shell (S) and Ruc-Protruding (P) were engineered for a representative GII.4 norovirus (strain GII.4/2006b). The LIPS assay measured antibody levels in a well defined panel of HuNoV-specific sera, and the results were compared to an ELISA standard. In hyperimmune sera, the LIPS produced titers similar to or higher than those measured by the ELISA of HuNoV-specific antibodies. The specificity of antibodies in various sera was profiled by LIPS with a panel of diverse Ruc antigens containing full-length HuNoV VP1 proteins or VP1 subdomains, and the assay detected both specific and cross-reactive antibodies. Competition assays, in which antibodies were pre-incubated with one or more intact VLPs representing different genotypes, proved useful in further assessment of the antibody specificity detected by LIPS in complex polyclonal sera. The profiling of HuNoV specific antibodies in the high-throughput LIPS format may prove useful in defining the strength or specificity of the adaptive immune response following natural infection or vaccination. PMID- 28673857 TI - Development and application of a reverse transcriptase droplet digital PCR (RT ddPCR) for sensitive and rapid detection of Japanese encephalitis virus. AB - Japanese encephalitis (JE) is one of the most common zoonoses caused by Japanese encephalitis virus (JEV). Droplet digital PCR (ddPCR) is a novel sensitive, accurate method that enables absolute quantitation without the need for calibration curves. The aim of this study was to develop a RT-ddPCR method to detect JEV, and to compare its sensitivity with real-time TaqMan RT-PCR by analysis of clinical samples. The methods of JEV real-time RT-PCR and RT-ddPCR were established and optimal reaction conditions were confirmed. Each method was evaluated for linearity, limit of detection and specificity. A total of 103 porcine samples were analysed by both methods and the detection rate was calculated. Both methods showed a high degree of linearity and positive correlation for standards (R2>=0.999). The assays indicated that the detection limit for RT-ddPCR was approximately 2 copies/20MUL well, a 100-fold greater sensitivity than TaqMan real-time RT-PCR. The detection results for clinical samples showed that the positive detection rate of RT-ddPCR (27.2%) was higher than that of TaqMan real-time RT-PCR (16.5%). The cross-reaction was performed with other porcine pathogens, and negative amplification of the cross-reaction assay demonstrated the high specificity of this method. The novel JEV RT-ddPCR assay could be used as an efficient molecular biology tool to diagnose JEV, which would facilitate the surveillance of reproductive failure disease in swineries and would be beneficial for public health security. PMID- 28673858 TI - Investigate the control release effect of ion-pair in the development of escitalopram transdermal patch using FT-IR spectroscopy, molecular modeling and thermal analysis. AB - The aim of this study was to develop a controlled release drug-in-adhesive patch containing escitalopram (ESP) using ion-pair technique. Special attention was paid on the mechanism of how counter ion controlled the release of ESP. Five organic acids were chosen as the counter ions. Formulation factors including adhesive matrix, drug loading and permeation enhancers were investigated through in vitro experiments using rat skin and the optimized patch was evaluated using in vivo pharmacokinetic study. Drug-counter ion-PSA interactions were characterized by FT-IR, molecular modeling and DSC at molecular level. The optimized patch prepared with ESP-BA showed zero-order skin permeation profile and a satisfied permeation amount of three days (1059+/-104.9MUg/cm2) in vitro, which also showed a steady-state drug plasma concentration lasting 36h in vivo and the Cmax was significantly controlled compared with the control group. The controlled release of ESP was attributed to the interactions among ESP-counter ion-PSA by hydrogen bonding, and counter ion enhanced the interaction between ESP and PSA molecule, which acted as a "bridge" between them. In conclusion, a controlled release ESP transdermal patch was developed and a novel insight of ion pair controlled release was proposed at molecular level. PMID- 28673859 TI - A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides. AB - Inhibition of gene expression by nucleic acids is a promising strategy in the treatment of ocular diseases. However, intraocular delivery of nucleic acids to the posterior ocular tissues remains a great challenge due to the presence of various biological barriers. To circumvent this problem, we established a novel penetratin (P) modified poly(amidoamine) dendrimer (D)/hyaluronic acid (H) complex to deliver antisense oligonucleotides (ASOs, O). Complexes (D/O, HD/O and PHD/O) were easily prepared and modification layers (hyaluronic acid and penetratin) were respectively absorbed on the surface via electrostatic interaction. Complexes with different outer layers were characterized as spherical particles with reversed charges. In vitro cellular uptake of ASOs in PHD/O complex was significantly increased than those in other formulations. In vivo studies were carried out after topical instillation of the complexes in the conjunctival sac of mice. Compared with D/O and HD/O, PHD/O exhibited much more distribution in the posterior segment of the eyes and prolonged retention time of ASOs in retina for more than 8h. Taken together, these results indicated that PHD/O complex possessed substantially improved ocular permeability and distribution in the posterior ocular tissues. This work provided a promising noninvasive intraocular delivery strategy for nucleic acids via topical administration. PMID- 28673860 TI - 3D printing of tablets using inkjet with UV photoinitiation. AB - Additive manufacturing (AM) offers significant potential benefits in the field of drug delivery and pharmaceutical/medical device manufacture. Of AM processes, 3D inkjet printing enables precise deposition of a formulation, whilst offering the potential for significant scale up or scale out as a manufacturing platform. This work hypothesizes that suitable solvent based ink formulations can be developed that allow the production of solid dosage forms that meet the standards required for pharmaceutical tablets, whilst offering a platform for flexible and personalized manufacture. We demonstrate this using piezo-activated inkjetting to 3D print ropinirole hydrochloride. The tablets produced consist of a cross-linked poly(ethylene glycol diacrylate) (PEGDA) hydrogel matrix containing the drug, photoinitiated in a low oxygen environment using an aqueous solution of Irgacure 2959. At a Ropinirole HCl loading of 0.41mg, drug release from the tablet is shown to be Fickian. Raman and IR spectroscopy indicate a high degree of cross linking and formation of an amorphous solid dispersion. This is the first publication of a UV inkjet 3D printed tablet. Consequently, this work opens the possibility for the translation of scalable, high precision and bespoke ink-jet based additive manufacturing to the pharmaceutical sector. PMID- 28673862 TI - Sjogren's syndrome: New paradigms and areas for future research. PMID- 28673861 TI - CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target: Role of CPSF6 in Breast Cancer. AB - Breast cancer represents a major health challenge. The majority of breast cancer deaths are due to cancer progression/recurrence for which no efficient therapies exist. Aggressive breast cancers are characterized by loss of cellular differentiation. Defining molecular mechanisms/targets contributing to cancer aggressiveness is needed to guide the design of new screening and targeted treatments. Here, we describe a novel tumor promoting function for the Cleavage and Polyadenylation Factor-6 (CPSF6). Importantly, aggressive breast cancer cells of luminal B, HER2-overexpressing and triple negative subtypes show dependency on CPSF6 for viability and tumorigenic capacity. Mechanistically, we found CPSF6 to interact with components of the A-to-I RNA editing machinery, paraspeckles and ADAR1 enzyme, and to be required for their physical integrity. Clinically, we found CPSF6 and all core paraspeckles proteins to be overexpressed in human breast cancer cases and their expression to correlate with poor patient outcomes. Finally, we found prolactin, a key mammary differentiation factor, to suppress CPSF6/RNA editing activity. Together, this study revealed CPSF6 as a molecular target with clinical relevance for prognosis and therapy in breast cancer. PMID- 28673863 TI - MPV17 hepatocerebral mitochondrial DNA depletion syndrome presenting as acute flaccid paralysis - A case report. AB - Mutations in human MPV17 have been reported in patients with severe mitochondrial DNA (mtDNA) depletion manifesting as early childhood onset failure to thrive, hypoglycemia, encephalopathy and progressive liver failure. We describe an 11 year old girl, born to consanguineous parents, who presented with rapidly progressive weakness of all 4 limbs with symmetrical proximal and distal weakness, gastrointestinal disease and leukoencephalopathy. Genetic analysis of the patient revealed a homozygous pathogenic mutation c.121C>T (p.R41W) in the MPV17 gene. Further, screening for this mutation in the parents revealed the presence of heterozygous mutation in both the parents, suggesting the recessive nature of the disease. PMID- 28673864 TI - Analysis of endometrial carcinoma in young women at a high-volume cancer center. AB - OBJECTIVE: To investigate the clinicopathological characteristics, treatment, survival, and prognosis of endometrial cancer in women aged <=40 years. METHODS: Women who underwent surgery for endometrial cancer at a single high-volume cancer center between January 1995 and December 2014 were retrospectively reviewed. Women aged >40, patients with missing data, and those who did not undergo surgical staging were excluded. Univariate and multivariate regression models were used to identify the risk factors for overall survival and progression-free survival. RESULTS: A total of 40 patients with endometrial cancer were assessed. The median age at diagnosis was 38 (range, 21-40) years, and most of the uterine tumors found were early-stage (85%), low-grade (67.5%), and endometrioid carcinomas (97.5%). The median serum cancer antigen 125 level was 10.9 IU/mL (range, 3-1284 IU/mL). Optimal cytoreductive surgery was achieved in 35 patients (87.5%). All patients underwent total abdominal hysterectomy, and 97.5% of the patients underwent hysterectomy plus bilateral salpingo-oophorectomy. Among the total group of 40 patients, 21 (52.5%) underwent pelvic and para-aortic lymph node dissection, and 15 (37.5%) underwent only pelvic lymph node dissection. Multivariate analysis confirmed that a cancer antigen 125 level >=35 was the only independent prognostic factor for both progression-free survival (hazard ratio, 22.997; 95% confidence interval, 1.783-296.536; p = 0.016) and overall survival (hazard ratio, 22.541; 95% confidence interval, 1.75-290.364; p = 0,017). CONCLUSIONS: Our study demonstrated that a cancer antigen 125 level >= 35 is the only independent prognostic factor for both progression-free survival and overall survival in patients aged <=40 years with endometrial cancer. PMID- 28673865 TI - Support for reporting guidelines in surgical journals needs improvement: A systematic review. AB - INTRODUCTION: Evidence-based medicine works best if the evidence is reported well. Past studies have shown reporting quality to be lacking in the field of surgery. Reporting guidelines are an important tool for authors to optimize the reporting of their research. The objective of this study was to analyse the frequency and strength of recommendation for such reporting guidelines within surgical journals. METHODS: A systematic review of the 198 journals within the Journal Citation Report 2014 (surgery category) published by Thomson Reuters was undertaken. The online guide for authors for each journal was screened by two independent groups and results compared. Data regarding the presence and strength of recommendation to use reporting guidelines was extracted. RESULTS: 193 journals were included (as five appeared twice having changed their name). These had a median impact factor of 1.526 (range 0.047-8.327), with a median of 145 articles published per journal (range 29-659), with 34,036 articles published in total over the two-year window 2012-2013. The majority (62%) of surgical journals made no mention of reporting guidelines within their guidelines for authors. Of the 73 (38%) that did mention them, only 14% (10/73) required the use of all relevant reporting guidelines. The most frequently mentioned reporting guideline was CONSORT (46 journals). CONCLUSIONS: The mention of reporting guidelines within the guide for authors of surgical journals needs improvement. Authors, reviewers and editors should work to ensure that research is reported in line with the relevant reporting guidelines. Journals should consider hard-wiring adherence to them. PMID- 28673866 TI - Far distance control scores for assessing intermittent exotropia. AB - PURPOSE: To assess the level of control in intermittent exotropia by applying the office-based 6-point control scale to far-distance testing. METHODS: Fifty-two children with intermittent exotropia were enrolled in this prospective, noninterventional case series. Control of exodeviation was assessed at indoor distance (ID) of 3 m and near distance of 33 cm using the office-based 6-point control scale, which was additionally applied to indoor far distance (IFD) fixation of 30 m and outdoor far distance (OFD) fixation of 50 m. RESULTS: In all 52 patients, the level of control at OFD fixation was either worse than (31%) or the same as (70%) the level of control at IFD fixation and the level of control at IFD fixation was worse than (64%) or the same as (35%) the level of control at ID fixation. The level of control at OFD fixation was worse than (69%) or the same as (31%) the level of control at ID fixation for all 52 patients. The differences between mean control scores of OFD and IFD fixation (P = 0.002), IFD and ID fixation (P < 0.001), OFD and ID fixation (P < 0.001) were statistically significant. CONCLUSIONS: The outdoor and indoor far distance control scores can increase the sensitivity of the office-based 6-point control scale. The office control scale for assessing control in patients with intermittent exotropia could have application for the management of intermittent exotropia. PMID- 28673867 TI - A semi-continuous process based on an ePBR for the production of EPS using Trichocoleus sociatus. AB - Biodiversity forms the basis for a large pool of potential products and productive organisms offered by terrestrial cyanobacteria. They are stuck together by EPS (extracellular polymeric substances) that can obtain antiviral, antibacterial or anti-inflammatory substances. Most stress conditions, e.g. drought, induce the production of protective EPS or biotechnological-products for pharmaceutical application. However, the growth of a phototrophic biofilm is limited under submerged conditions. Therefore, a semi-continuous process to produce EPS by cyanobacteria was developed in an aerosol-based ePBR (emerse photobioreactor) that imitates the natural habitat of terrestrial cyanobacteria. The process consists of a growth-phase (biomass production), followed by a dry phase (EPS-production) and a consecutive extraction. The EPS-productivities of Trichocoleus sociatus (ranging from 0.03 to 0.04gL-1d-1) were 32 times higher than described in topic-related literature. In comparison to submerge cultivations in shaking flasks, the EPS-productivities were sevenfold higher. To ensure that the extraction solvent has no influence on cell viability, a cell vitality-test was performed. However, no statistically significant difference between the amount of living and dead cells before and after the extraction was detected. A bioactivity assay was then performed to identify antimicrobial activity within EPS extracts from emerse and submerge cultivations. The EPS revealed an antibacterial effect against gram-negative bacteria (E. coli) which was two times higher than EPS from a submerged cultivation. PMID- 28673868 TI - Complete nucleotide sequences and virion particle association of two satellite RNAs of panicum mosaic virus. AB - Over six decades ago, panicum mosaic virus (PMV) was identified as the first viral pathogen of cultivated switchgrass (Panicum virgatum). Subsequently, PMV was demonstrated to support the replication of both a satellite RNA virus (SPMV) and satellite RNA (satRNA) agents during natural infections of host grasses. In this study, we report the isolation and full-length sequences of two PMV satRNAs identified in 1988 from St. Augustinegrass (Stenotaphrum secundatum) and centipedegrass (Eremochloa ophiuroides) hosts. Each of these satellites have sequence relatedness at their 5'- and 3'-ends. In addition, satC has a region of ~100 nt complementary to the 3'-end of the PMV genome. These agents are associated with purified virions of SPMV infections. Additionally, satS and satC RNAs contain conserved in-frame open reading frames in the complementary-sense sequences that could potentially generate 6.6- and 7.9-kDa proteins, respectively. In protoplasts and plants satS is infectious, when co-inoculated with the PMV RNA alone or PMV+SPMV RNAs, and negatively affects their accumulation. PMID- 28673869 TI - Impact of deletions and mutations in Hepatitis B virus envelope proteins on serological profile and clinical evolution. AB - The Hepatitis B virus (HBV) envelope glycoproteins are essential for viral entry into the hepatocyte and are also targets for host immune response. The study of these proteins could allow us to highlight molecular hot points influencing HBV fitness, which would subsequently modify the clinical evolution of the disease, both under anti-viral therapy or without treatment. The present short communication underlines the importance of the high variability in HBV envelope proteins, in regard with the literature and in our hands, for HBV-infected patients either on anti-HBV treatment or not. We report mutations in antigenic areas of S protein, i.e. CD8+/CD4+ T-cell epitopes and B-cell epitopes in the major hydrophilic region (MHR), such as sI126N and sG145R possibly involved in the rare coexisting Hepatitis B surface Antigen (HBsAg)/anti-HBs serological pattern. We mostly report serial mutations in preS region including preS1 deletion (aa 1-6, 31-71, 38-73, 72-104) and preS2 deletion (aa132-141) in patients with various clinical evolutions. Some of these viral envelope mutations, due to immune selection pressure, may result in a worsening of the hepatic disease. PMID- 28673870 TI - Fluorescence lifetime imaging ophthalmoscopy. AB - Imaging techniques based on retinal autofluorescence have found broad applications in ophthalmology because they are extremely sensitive and noninvasive. Conventional fundus autofluorescence imaging measures fluorescence intensity of endogenous retinal fluorophores. It mainly derives its signal from lipofuscin at the level of the retinal pigment epithelium. Fundus autofluorescence, however, can not only be characterized by the spatial distribution of the fluorescence intensity or emission spectrum, but also by a characteristic fluorescence lifetime function. The fluorescence lifetime is the average amount of time a fluorophore remains in the excited state following excitation. Fluorescence lifetime imaging ophthalmoscopy (FLIO) is an emerging imaging modality for in vivo measurement of lifetimes of endogenous retinal fluorophores. Recent reports in this field have contributed to our understanding of the pathophysiology of various macular and retinal diseases. Within this review, the basic concept of fluorescence lifetime imaging is provided. It includes technical background information and correlation with in vitro measurements of individual retinal metabolites. In a second part, clinical applications of fluorescence lifetime imaging and fluorescence lifetime features of selected retinal diseases such as Stargardt disease, age-related macular degeneration, choroideremia, central serous chorioretinopathy, macular holes, diabetic retinopathy, and retinal artery occlusion are discussed. Potential areas of use for fluorescence lifetime imaging ophthalmoscopy will be outlined at the end of this review. PMID- 28673871 TI - Rectal Shaving Using Plasma Energy in Deep Infiltrating Endometriosis of the Rectum: Four Years of Experience. AB - STUDY OBJECTIVE: To evaluate postoperative complications, digestive function and fertility outcomes in patients managed by rectal shaving using plasma energy in deep infiltrating endometriosis of the rectum. DESIGN: A single-center retrospective cohort study using data recorded prospectively. DESIGN CLASSIFICATION: Canadian Task Force classification II-2. SETTINGS: Department of Gynecology and Obstetrics of Rouen University Hospital (France). PATIENTS: One hundred and ten patients treated between December 2012 and December 2016. INTERVENTIONS: Laparoscopic rectal shaving using plasma energy. MEASUREMENTS AND MAIN RESULTS: Clinical history, baseline symptoms, preoperative assessment, intraoperative findings, and postoperative outcomes were recorded prospectively. Follow-up evaluations were performed at 1 year and 3 years. Mean age of patients was 37 +/- 6.4 years. Most patients had rectal nodules infiltrating either the mid or upper rectum and measuring <3 cm long. No intraoperative complications were recorded. One patient with multiple previous surgical procedures presented with a postoperative rectovaginal fistula (0.9%), and 1 patient presented with a postoperative rectouterine fistula treated exclusively with antibiotics (0.9%). Two patients (1.8%) had bladder atony necessitating >=3 weeks of daily self catheterization. Four patients (3.6%) had Clavien-Dindo grade I complications, 12 (10.9%) had grade II complications, 1 (0.9%) had a grade IIIa complication, 5 (4.5%) had grade IIIb complications, and 1 (0.9%) had a grade 4a complication. The vast majority of patients (n = 103 patients; 93.6%) were free of serious complications. Significant improvements in constipation and gastrointestinal quality of life were recorded at 1 year and 3 years postoperatively. Thirty-two patients attempted pregnancy after surgery (29.1%), and 17 of them conceived (53.1%). CONCLUSIONS: Rectal shaving using plasma energy allows for a low rate of postoperative complications with good digestive function and fertility outcomes and appears to be suitable in selected women with symptomatic rectal endometriosis. PMID- 28673872 TI - Bowel Preparation Improves the Accuracy of Transvaginal Ultrasound in the Diagnosis of Rectosigmoid Deep Infiltrating Endometriosis: A Prospective Study. AB - STUDY OBJECTIVE: To compare the accuracy of transvaginal ultrasound (TVUS) with and without bowel preparation (BP) to detect and describe intestinal nodules of deep infiltrating endometriosis (DIE) with laparoscopic findings. DESIGN: A prospective study of paired data (Canadian Task Force classification II.1). SETTING: A tertiary university hospital from November 2014 to November 2015. PATIENTS: A cohort of women awaiting surgery for endometriosis. INTERVENTIONS: The wall of the rectum and the lower sigmoid colon of the patients were evaluated by 2 TVUSs: the first ultrasound was performed without previous BP, and the second was done after a 3-day low-residue diet and two 250-mL enemas 12 hours and 3 hours before TVUS. MEASUREMENTS AND MAIN RESULTS: The presence or absence of rectosigmoid nodules visualized by TVUS with and without BP was compared with laparoscopic results. Forty patients with a mean age of 36.8 +/- 5.0 years were included in the study. By comparing the surgical findings histologically confirmed (the presence or absence of bowel nodules and localization) with those of the 2 TVUSs with and without BP, the sensitivity, specificity, and Cohen kappa were 100%, 96%, and 0.95 and 73%, 88%, and 0.61, respectively. Laparoscopy showed that up to 37.5% of patients (15/40) presented bowel involvement. Variables were clearly more evaluable with than without BP. CONCLUSION: TVUS with BP has a higher accuracy than TVUS without BP. BP allows and facilitates the detection of more rectal nodules of DIE in patients with suspected endometriosis and surgical criteria. PMID- 28673873 TI - Independent Roll-Down Ring for Contained Tissue Extraction. AB - An independent roll-down ring can be used to improve exposure during contained tissue extraction. We have used this technique in approximately 50 cases to date with good success. In this article we briefly describe our technique. PMID- 28673874 TI - Postoperative Outcomes after Single-port Laparoscopic Removal of Adnexal Masses in Patients Referred to Gynecologic Oncology at a Large Academic Center. AB - STUDY OBJECTIVE: To report surgical and pathologic outcomes after single-port laparoscopy (SPL) for adnexal masses in patients referred to a gynecologic oncology practice at a single academic institution. DESIGN: A retrospective analysis (Canadian Task Force Classification II.2). SETTING: A single academic institution with multiple hospital centers. PATIENTS: Women who underwent at least 1 single-port laparoscopic surgery for the treatment of an adnexal mass from 2009 to 2015 after referral to a gynecologic oncology practice. INTERVENTION: Data were collected on the surgical procedure, patient demographic variables, 30-day surgical outcomes, and hernia development. MEASUREMENTS AND MAIN RESULTS: Three hundred twenty-five surgeries were performed in 322 patients with a median follow-up of 42.7 months. The median age was 54.5 years, and the median body mass index was 28.1 kg/m2. All patients underwent unilateral or bilateral salpingectomy or oophorectomy with or without hysterectomy (26.5%). The median operative time was 90.0 minutes. The median mass dimension was 6.4 cm with 17.9% (n = 60) greater than 10 cm. Masses were categorized as simple (11.4%) and complex (69.5%). Although the majority (87.4%) of masses were benign, 7.4% were malignant, and 5.2% were borderline. Benign masses were physiologic (16.6%), serous cystadenomas (19.1%), mucinous cystadenomas (6.8%), endometriomas (12.3%), myomas (12.3%), and mature teratomas (9.2%). In malignant cases (7.4%), serous carcinoma was the most frequent histology (58.3%). The rate of adverse outcomes within 30 days, including reoperation (0.0%), intraoperative injury (1.5%), venous thromboembolism (0.3%), and transfusion (0.6%), was low. The development of incisional cellulitis was 4.6%. The rate of incisional hernia was 4.0%, with a median occurrence of 18.3 months. Diabetes mellitus (p = .03) and obesity (p = .04) were significant predictors for a hernia, but mass complexity (p = .28), American Society of Anesthesiologists class (p = .83), and smoking (p = .82) were not. CONCLUSION: In patients undergoing SPL for the removal of adnexal masses in a gynecologic oncology practice, the rate of benign disease is high. SPL removal of adnexal masses is feasible and safe with favorable surgical outcomes, rare short-term adverse outcomes, and a low incisional hernia rate. PMID- 28673875 TI - Numerical investigation of transient transport and deposition of microparticles under unsteady inspiratory flow in human upper airways. AB - In the present study, unsteady airflow patterns and particle deposition in healthy human upper airways were simulated. A realistic 3-D computational model of the upper airways including the vestibule to the end of the trachea was developed using a series of CT scan images of a healthy human. Unsteady simulations of the inhaled and exhaled airflow fields in the upper airway passages were performed by solving the Navier-Stokes and continuity equations for low breathing rates corresponding to low and moderate activities. The Lagrangian trajectory analysis approach was utilized to investigate the transient particle transport and deposition under cyclic breathing condition. Particles were released uniformly at the nostrils' entrance during the inhalation phase, and the total and regional depositions for various micro-particle sizes were evaluated. The transient particle deposition fractions for various regions of the human upper airways were compared with those obtained from the equivalent steady flow condition. The presented results revealed that the equivalent constant airflow simulation can approximately predict the total particle deposition during cyclic breathing in human upper airways. While the trends of steady and unsteady model predictions for local deposition were similar, there were noticeable differences in the predicted amount of deposition. In addition, it was shown that a steady simulation cannot properly predict some critical parameters, such as the penetration fraction. Finally, the presented results showed that using a detached nasal cavity (commonly used in earlier studies) for evaluation of total deposition fraction of particles in the nasal cavity was reasonably accurate for the steady flow simulations. However, in transient simulation for predicting the deposition fraction in a specific region, such as the nasal cavity, using the full airway system geometry becomes necessary. PMID- 28673876 TI - Abnormal respiration under hyperoxia in TASK-1/3 potassium channel double knockout mice. AB - Despite intensive research, the exact function of TASK potassium channels in central and peripheral chemoreception is still under debate. In this study, we investigated the respiration of unrestrained TASK-3 (TASK-3-/-) and TASK-1/TASK-3 double knockout (TASK-1/3-/-) adult male mice in vivo using a plethysmographic device. Ventilation parameters of TASK-3-/- mice were normal under control condition (21% O2) and upon hypoxia and hypercapnia they displayed the physiological increase of ventilation. TASK-1/3-/- mice showed increased ventilation under control conditions. This increase of ventilation was caused by increased tidal volumes (VT), a phenomenon similarly observed in TASK-1-/- mice. Under acute hypoxia, TASK-1/3-/- mice displayed the physiological increase of the minute volume. Interestingly, this increase was not related to an increase of the respiratory frequency (fR), as observed in wild-type mice, but was caused by a strong increase of VT. This particular respiratory phenotype is reminiscent of the respiratory phenotype of carotid body-denervated rodents in the compensated state. Acute hypercapnia (5% CO2) stimulated ventilation in TASK-1/3-/- and wild type mice to a similar extent; however, at higher CO2 concentrations (>5% CO2) the stimulation of ventilation was more pronounced in TASK-1/3-/- mice. At hyperoxia (100% O2), TASK-1-/-, TASK-3-/- and wild-type mice showed the physiological small decrease of ventilation. In sharp contrast, TASK-1/3-/- mice exhibited an abnormal increase of ventilation under hyperoxia. In summary, these measurements showed a grossly normal respiration of TASK-3-/- mice and a respiratory phenotype of TASK-1/3-/- mice that was characterized by a markedly enhanced tidal volume, similar to the one observed in TASK-1-/- mice. The abnormal hyperoxia response, exclusively found in TASK-1/3-/- double mutant mice, indicates that both TASK-1 and TASK-3 are essential for the hyperoxia-induced hypoventilation. The peculiar respiratory phenotype of TASK-1/3 knockout mice is reminiscent of the respiration of animals with long-term carotid body dysfunction. Taken together, TASK-1 and TASK-3 appear to serve specific and distinct roles in the complex processes underlying chemoreception and respiratory control. PMID- 28673878 TI - Invariance of surface color representations across illuminant changes in the human cortex. AB - A central problem in color vision is that the light reaching the eye from a given surface can vary dramatically depending on the illumination. Despite this, our color percept, the brain's estimate of surface reflectance, remains remarkably stable. This phenomenon is called color constancy. Here we investigated which human brain regions represent surface color in a way that is invariant with respect to illuminant changes. We used physically realistic rendering methods to display natural yet abstract 3D scenes that were displayed under three distinct illuminants. The scenes embedded, in different conditions, surfaces that differed in their surface color (i.e. in their reflectance property). We used multivariate fMRI pattern analysis to probe neural coding of surface reflectance and illuminant, respectively. While all visual regions encoded surface color when viewed under the same illuminant, we found that only in V1 and V4alpha surface color representations were invariant to illumination changes. Along the visual hierarchy there was a gradient from V1 to V4alpha to increasingly encode surface color rather than illumination. Finally, effects of a stimulus manipulation on individual behavioral color constancy indices correlated with neural encoding of the illuminant in hV4. This provides neural evidence for the Equivalent Illuminant Model. Our results provide a principled characterization of color constancy mechanisms across the visual hierarchy, and demonstrate complementary contributions in early and late processing stages. PMID- 28673877 TI - Remifentanil effects on respiratory drive and timing during pressure support ventilation and neurally adjusted ventilatory assist. AB - We assessed the effects of varying doses of remifentanil on respiratory drive and timing in patients receiving Pressure Support Ventilation (PSV) and Neurally Adjusted Ventilatory Assist (NAVA). Four incrementing remifentanil doses were randomly administered to thirteen intubated patients (0.03, 0.05, 0.08, and 0.1MUg.Kg-1.min-1) during both PSV and NAVA. We measured the patient's (Ti/Ttotneu) and ventilator (Ti/Ttotmec) duty cycle, the Electrical Activity of the Diaphragm (EAdi), the inspiratory (Delaytrinsp) and expiratory (Delaytrexp) trigger delays and the Asynchrony Index (AI). Increasing doses of remifentanil did not modify EAdi, regardless the ventilatory mode. In comparison to baseline, remifentanil infusion >0.05MUg/Kg-1/min-1 produced a significant reduction of Ti/Ttotneu and Ti/Ttotmec, by prolonging the expiratory time. Delaytrinsp and Delaytrexp were significantly shorter in NAVA, respect to PSV. AI was not influenced by the different doses of remifentanil, but it was significantly lower during NAVA, compared to PSV. In conclusion remifentanil did not affect the respiratory drive, but only respiratory timing, without differences between modes. PMID- 28673879 TI - Information-theoretical analysis of resting state EEG microstate sequences - non Markovianity, non-stationarity and periodicities. AB - We present an information-theoretical analysis of temporal dependencies in EEG microstate sequences during wakeful rest. We interpret microstate sequences as discrete stochastic processes where each state corresponds to a representative scalp potential topography. Testing low-order Markovianity of these discrete sequences directly, we find that none of the recordings fulfils the Markov property of order 0, 1 or 2. Further analyses show that the microstate transition matrix is non-stationary over time in 80% (window size 10 s), 60% (window size 20 s) and 44% (window size 40 s) of the subjects, and that transition matrices are asymmetric in 14/20 (70%) subjects. To assess temporal dependencies globally, the time-lagged mutual information function (autoinformation function) of each sequence is compared to the first-order Markov model defined by the classical transition matrix approach. The autoinformation function for the Markovian case is derived analytically and numerically. For experimental data, we find non Markovian behaviour in the range of the main EEG frequency bands where distinct periodicities related to the subject's EEG frequency spectrum appear. In particular, the microstate clustering algorithm induces frequency doubling with respect to the EEG power spectral density while the tail of the autoinformation function asymptotically reaches the first-order Markov confidence interval for time lags above 1000 ms. In summary, our results show that resting state microstate sequences are non-Markovian processes which inherit periodicities from the underlying EEG dynamics. Our results interpolate between two diverging models of microstate dynamics, memoryless Markov models on one side, and long-range correlated models on the other: microstate sequences display more complex temporal dependencies than captured by the transition matrix approach in the range of the main EEG frequency bands, but show finite memory content in the long run. PMID- 28673880 TI - Differential spatial representation of precision and power grasps in the human motor system. AB - Power and precision grasps are two interrelated, kinematically distinct types of finger movements. We examined whether these types of motor actions may be spatially differently represented in the human central nervous system. In healthy participants representations of finger movements were mapped by delivering single pulse TMS to multiple scalp regions covering the left primary motor cortex (M1). Finger joint motions were recorded from the right hand using a data glove. Principal component analysis was used to extract local subspaces representing the TMS-evoked movement data from each scalp region. Voluntary power and precision grasps were reconstructed with these subspaces. The spatial properties of these reconstructions were analyzed for each grasp type using a general linear model. We found overlapping, yet distinct spatial representations for precision and power grasps with precision grasps represented slightly posterior compared to a more uniform distribution for power grasps. Differential spatial encoding of both grasp types may point towards a representation of power grasps within a phylogenetically older M1 area at the crown of the precentral gyrus and of precision grasps in a newer area in the depth of the central sulcus. Results also support the idea of separate synergistic movement representations in the human motor system. PMID- 28673881 TI - A multimodal encoding model applied to imaging decision-related neural cascades in the human brain. AB - Perception and cognition in the brain are naturally characterized as spatiotemporal processes. Decision-making, for example, depends on coordinated patterns of neural activity cascading across the brain, running in time from stimulus to response and in space from primary sensory regions to the frontal lobe. Measuring this cascade is key to developing an understanding of brain function. Here we report on a novel methodology that employs multi-modal imaging for inferring this cascade in humans at unprecedented spatiotemporal resolution. Specifically, we develop an encoding model to link simultaneously measured electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) signals to infer high-resolution spatiotemporal brain dynamics during a perceptual decision. After demonstrating replication of results from the literature, we report previously unobserved sequential reactivation of a substantial fraction of the pre-response network whose magnitude correlates with a proxy for decision confidence. Our encoding model, which temporally tags BOLD activations using time localized EEG variability, identifies a coordinated and spatially distributed neural cascade that is associated with a perceptual decision. In general the methodology illuminates complex brain dynamics that would otherwise be unobservable using fMRI or EEG acquired separately. PMID- 28673882 TI - Evaluating g-ratio weighted changes in the corpus callosum as a function of age and sex. AB - Recent years have seen a growing interest in relating MRI measurements to the structural-biophysical properties of white matter fibers. The fiber g-ratio, defined as the ratio between the inner and outer radii of the axon myelin sheath, is an important structural property of white matter, affecting signal conduction. Recently proposed modeling methods that use a combination of quantitative-MRI signals, enable a measurement of the fiber g-ratio in vivo. Here we use an MRI based g-ratio estimation to observe the variance of the g-ratio within the corpus callosum, and evaluate sex and age related differences. To estimate the g-ratio we used a model (Stikov et al., 2011; Duval et al., 2017) based on two different WM microstructure parameters: the relative amounts of myelin (myelin volume fraction, MVF) and fibers (fiber volume fraction, FVF) in a voxel. We derived the FVF from the fractional anisotropy (FA), and estimated the MVF by using the lipid and macromolecular tissue volume (MTV), calculated from the proton density (Mezer et al., 2013). In comparison to other methods of estimating the MVF, MTV represents a stable parameter with a straightforward route of acquisition. To establish our model, we first compared histological MVF measurements (West et al., 2016) with the MRI derived MTV. We then implemented our model on a large database of 92 subjects (44 males), aged 7 to 81, in order to evaluate age and sex related changes within the corpus callosum. Our results show that the MTV provides a good estimation of MVF for calculating g-ratio, and produced values from the corpus callosum that correspond to those found in animals ex vivo and are close to the theoretical optimum, as well as to published in vivo data. Our results demonstrate that the MTV derived g-ratio provides a simple and reliable in vivo g-ratio-weighted (GR*) measurement in humans. In agreement with theoretical predictions, and unlike other tissue parameters measured with MRI, the g-ratio estimations were found to be relatively stable with age, and we found no support for a significant sexual dimorphism with age. PMID- 28673883 TI - Microsurgical Performance After Sleep Interruption: A NeuroTouch Simulator Study. AB - OBJECTIVE: In times of the ubiquitous debate about doctors' working hour restrictions, it is still questionable if the physician's performance is impaired by high work load and long shifts. In this study, we evaluated the impact of sleep interruption on neurosurgical performance. METHODS: Ten medical students and 10 neurosurgical residents were tested on the virtual-reality simulator NeuroTouch by performing an identical microsurgical task, well rested (baseline test), and after sleep interruption at night (stress test). Deviation of total score, timing, and excessive force on tissue were evaluated. In addition, vital parameters and self-assessment were analyzed. RESULTS: After sleep interruption, total performance score increased significantly (45.1 vs. 48.7, baseline vs. stress test, P = 0.048) while timing remained stable (10.1 vs. 10.4 minutes for baseline vs. stress test, P > 0.05) for both students and residents. Excessive force decreased in both groups during the stress test for the nondominant hand (P = 0.05). For the dominant hand, an increase of excessive force was encountered in the group of residents (P = 0.05). In contrast to their results, participants of both groups assessed their performance worse during the stress test. CONCLUSIONS: In our study, we found an increase of neurosurgical simulator performance in neurosurgical residents and medical students under simulated night shift conditions. Further, microsurgical dexterity remained unchanged. Based on our results and the data in the available literature, we cannot confirm that working hour restrictions will have a positive effect on neurosurgical performance. PMID- 28673884 TI - Serum Concentrations of Fibrinogen in Patients with Spinal Cord Injury and Its Relationship with Neurologic Function. AB - BACKGROUND: Many studies have focused on axon regeneration after spinal cord injury (SCI), and fibrinogen has been reported to be an inhibitory factor for axon regeneration. However, most of these studies were based on animal experiments and in vitro trials. Few studies reported serum concentrations of fibrinogen in patients with SCI. OBJECTIVE: We sought to investigate the circulating serum concentrations of fibrinogen in patients with SCI and determine the relationship between fibrinogen concentrations and patients' neurologic function. METHODS: A total of 306 patients who were diagnosed with acute SCI between January 2008 and March 2016 were included in this study. Patients with traumatic fractures of the extremities at the same period (220 of them with single fracture and 207 with multiple fractures) were enrolled as a control group. Additionally, 151 patients with no injury were involved as the normal group. The fibrinogen concentrations in each group were recorded and compared at different time points, and the correlation between fibrinogen serum concentrations and American Spinal Injury Association impairment scale in patients with SCI were analyzed. RESULTS: The mean serum concentrations of fibrinogen within 2 days after injury were 2.63 +/- 0.76 g/L in the SCI group, 3.03 +/- 0.82 g/L in the single-fracture group, and 2.86 +/- 0.91 g/L in the multiple-fractures group, respectively, which were significant higher than those in the normal group (2.33 +/- 0.43 g/L). Additionally, the concentrations of fibrinogen in SCI group were significantly lower compared with those in single- and multiple-fractures groups (P < 0.001 and P = 0.001). The positive rate of fibrinogen concentrations was 12.42% in the SCI group, which was significantly lower than that of the single-fracture group (25.45%) and multiple-fractures group (25.13%) (P < 0.01). In patients with SCI, Spearman correlation analysis revealed that a significant correlation was found between fibrinogen serum concentrations and patients' American Spinal Injury Association impairment scales (r = 0.17, P < 0.001). CONCLUSIONS: The serum concentrations of fibrinogen in patients with SCI were significantly increased after injury and were correlated with the severity of neurologic deficit in patients with SCI. PMID- 28673885 TI - Clinical Features of Hemorrhagic Moyamoya Disease in China. AB - OBJECTIVE: To elucidate the clinical features of patients with hemorrhagic moyamoya disease (MMD) in China. METHODS: We retrospectively reviewed 471 patients with hemorrhagic MMD at Beijing Tiantan Hospital. Clinical features and radiologic findings were analyzed. RESULTS: The mean age at diagnosis was 35.3 +/ 11.5 years, with 1 peak distribution in patients from 35 to 39 years of age. The ratio of women to men was 1.2:1. Familial occurrence was 3.8%. The primary symptoms at initial presentation were intraventricular hemorrhage (42.0%), intracerebral hemorrhage (23.6%), intracerebral hemorrhage with intraventricular hemorrhage (18.3%), and subarachnoid hemorrhage (16.1%). Before the diagnosis, 68 patients experienced a second episode of bleeding. Rebleeding tends to be common within 6 years after the first bleeding (83.8%). The second bleeding episode was characterized by a change in which hemisphere bleeding occurred in 7 patients (10.3%) and by the type of bleeding in 23 patients (33.8%). Most patients presented with Suzuki stage 3 or 4 MMD (61.7%). Posterior cerebral artery involvement was observed in 28 (18.4%) patients. Forty-three intracranial aneurysms were identified in 39 patients (8.3%). CONCLUSIONS: A 1-peak pattern in age distribution and mild female dominance in sex distribution were observed in patients with hemorrhagic MMD. Rebleeding tends to be common within 6 years after the first bleeding; however, some cases of rebleeding occur after a long period. Furthermore, the second bleeding episode was characterized frequently by a change in hemisphere and the type of bleeding. Early surgical treatment in both hemispheres is recommended. PMID- 28673886 TI - Newly Diagnosed Sellar Tumors in Patients with Cancer: A Diagnostic Challenge and Management Dilemma. AB - BACKGROUND: The use of combined positron emission tomography/computed tomography for staging in patients with cancer and the widespread use of magnetic resonance imaging has led to increased detection of incidental sellar masses. The imaging findings can be suggestive of a benign pituitary tumor, but metastasis can never be completely ruled out with noninvasive work-up. Appropriate diagnosis of sellar masses is critical, as the treatment paradigm might change in the presence of a pituitary metastasis. Definitive tissue diagnosis might prevent unnecessary radiotherapy to the skull base or the need for systemic treatment when benign pituitary disease is confirmed. METHODS: A retrospective chart review from 2010 to 2015 of all patients with recently diagnosed cancer and undergoing surgery for sellar region masses was performed. RESULTS: There were 9 patients (3 female and 6 male) identified. Lung cancer was the primary condition in 4 patients; the remaining 5 patients had breast cancer, follicular thyroid cancer, cutaneous melanoma, colorectal carcinoma, and renal cell carcinoma. On final pathology, the sellar mass was a benign pituitary adenoma in 5 patients, metastatic cancer in 3 patients, and a granular cell tumor in 1 patient. CONCLUSIONS: Surgical resection of a sellar mass in patients with known cancer helps in the definitive diagnosis, relieves compressive symptoms, and avoids unnecessary empiric radiotherapy in cases of confirmed benign pituitary disease. PMID- 28673887 TI - Clinical, Radiologic, and Pathologic Features of 56 Cases of Intracranial Lymphoplasmacyte-Rich Meningioma. AB - OBJECTIVE: Intracranial lymphoplasmacyte-rich meningioma (LPRM) is rarely reported because of its extremely low incidence, and current understanding of this disease is poor. We analyzed the incidence and clinical, radiologic, pathologic, and prognostic features of intracranial LPRMs. METHODS: Approximately 10,908 intracranial meningiomas were surgically resected in Beijing Tiantan Hospital between June 2009 and November 2016. All pathologically proven LPRM cases were identified. Statistical analysis was performed to determine which parameters were associated with prognoses and tumor resection. RESULTS: LPRMs accounted for approximately 0.51% of intracranial meningiomas (56 of 10,908). Patients with LPRM had a mean age of 44.6 years and there was no significant gender preference (28 male and 28 female). Gross total resection was achieved in 45 cases, subtotal resection in 9 cases, and partial resection in 2 cases. At discharge, Karnofsky Performance Scale scores and neurologic function improved in 42 cases (75.0%) and worsened in 14 cases (25.0%). At the 41.5 months median follow-up (range, 5-97 months), 5 patients had tumor recurrence, and the 3-year and 5-year progression-free survival rates were 94.6% and 92.9%, respectively. One patient died of tumor recurrence. At the latest follow-up, Karnofsky Performance Scale scores improved in 48 cases (85.7%), worsened in 7 cases (12.5%), and 1 patient died (1.8%). Univariate analysis showed that the extent of tumor resection and tumors located in the skull base were significantly associated with short-term outcomes. Skull base location was significantly associated with increased risk of worse long-term outcomes. Tumor size >=45 mm, poorly defined tumor border, and skull base location significantly limited the extent of tumor resection. CONCLUSIONS: Intracranial LPRM is a rare subtype of meningioma with no gender difference and low recurrence. Long-term survival is expected, although tumors located in the skull base and bone destruction are independent risk factors of poor long-term outcomes. Microsurgical treatment of skull base LPRM remains a formidable challenge because of poorly defined borders and critical neurovascular structure encasement. Radical tumor resection, which induces severe neurologic deficits, is unnecessary. PMID- 28673888 TI - Two-Year Results of the Prospective Spine Treatment Outcomes Study: An Analysis of Complication Rates, Predictors of Their Development, and Effect on Patient Derived Outcomes at 2 Years for Surgical Management of Cervical Spondylotic Myelopathy. AB - OBJECTIVES: To investigate the baseline patient characteristics, nonoperative modalities, surgical procedures, and complications rates of surgical cervical spondylotic myelopathy (CSM) patients. To evaluate risk factors for developing complications and compare the changes in health-related quality of life (HRQOL) from baseline to 2 years postoperatively. METHODS: A retrospective review was performed on a prospectively collected database of CSM patients. Baseline patient demographic data, comorbidities, clinical information, nonoperative treatment modalities, surgical procedures, and complication rates were collected. HRQOL outcomes were assessed using the Short Form 36 (SF-36) Physical Score Component (PCS) and Mental Score Component (MCS) and the Neck Disability Index (NDI) at baseline and 2 years postoperatively. Statistical analyses included paired-sample t tests and multivariate logistic regression controlling for age, sex, and body mass index (BMI). RESULTS: A total of 203 surgical CSM patients were identified (43% female). Average age was 57.7 years and average BMI was 29.6 kg/m2. Before surgical intervention, patients underwent various nonoperative treatment modalities, most commonly nonsteroidal anti-inflammatory drugs (34%), analgesics (32%), and physical therapy (26%). The overall rate of complications was 7.4%. Complications included cerebrospinal fluid leak (2.5%), postoperative radiculopathy (1.0%), and excessive bleeding (1.0%). A previous history of cervical spine surgery was the sole significant risk factor for developing a complication (odds ratio, 9.22; P = 0.034). Average HRQOL scores improved significantly from baseline to 2 years postsurgery. CONCLUSIONS: The overall complication rate was 7.4% for the cohort. Baseline clinical information, comorbidities, use of nonoperative treatment modalities, and procedure type were not significantly associated with an increased risk of complications. Previous cervical spine surgery increased the risk of complications by 9-fold. The patients showed significantly improved SF-36 PCS, SF-36 MCS, and NDI scores at 2 years after surgery. PMID- 28673889 TI - Presurgical Planning for Supratentorial Lesions with Free Slicer Software and Sina App. AB - BACKGROUND: Neuronavigation systems are used widely in the localization of intracranial lesions with satisfactory accuracy. However, they are expensive and difficult to learn. Therefore, a simple and practical augmented reality (AR) system using mobile devices might be an alternative technique. OBJECTIVE: We introduce a mobile AR system for the localization of supratentorial lesions. Its practicability and accuracy were examined by clinical application in patients and comparison with a standard neuronavigation system. METHODS: A 3-dimensional (3D) model including lesions was created with 3D Slicer. A 2-dimensional image of this 3D model was obtained and overlapped on the patient's head with the Sina app. Registration was conducted with the assistance of anatomical landmarks and fiducial markers. The center of lesion projected on scalp was identified with our mobile AR system and standard neuronavigation system, respectively. The difference in distance between the centers identified by these 2 systems was measured. RESULTS: Our mobile AR system was simple and accurate in the localization of supratentorial lesions with a mean distance difference of 4.4 +/- 1.1 mm. Registration added on an average of 141.7 +/- 39 seconds to operation time. There was no statistically significant difference for the required time among 3 registrations (P = 0.646). CONCLUSIONS: The mobile AR system presents an alternative technology for image-guided neurosurgery and proves to be practical and reliable. The technique contributes to optimal presurgical planning for supratentorial lesions, especially in the absence of a neuronavigation system. PMID- 28673890 TI - Rates of Seizure Freedom After Surgical Resection of Diffuse Low-Grade Gliomas. AB - OBJECTIVE: Patients with diffuse low-grade gliomas (DLGGs) typically present with seizures. We sought to review the neurosurgical literature for seizure outcome after resection of these tumors. METHODS: Using PubMed, we identified surgical series reporting seizure freedom rates for grade II astrocytoma, oligoastrocytoma, and oligodendroglioma. Inclusion criteria included seizure outcomes reported specifically for DLGGs and at least 10 patients with follow-up data. RESULTS: Twelve articles met the inclusion criteria. The median seizure free rate after surgery in these patients was 71%, with an interquartile range of 64%-82%. In 10 studies, more than 60% of patients were seizure free. Studies used varying reporting times for seizure outcome determination. In the 6 studies that reported postoperative antiepileptic medication use, 5%-69% of seizure-free patients were weaned off these agents (median, 32%). The durability of seizure freedom has not been clearly studied to date. The most commonly reported prognostic factor for seizure freedom after resection was increasing extent of resection. CONCLUSIONS: Among articles reporting seizure outcomes after resection of DLGG, the median seizure-free rate was 71% (interquartile range, 64%-82%). Seizure freedom is likely associated with extent of resection. PMID- 28673891 TI - Dural Arteriovenous Fistula and Foix-Alajouanine Syndrome: Assessment of Functional Scores with Review of Pathogenesis. AB - OBJECTIVE: To assess the use of functional scores in the evaluation of patients with dural arteriovenous fistula and Foix-Alajouanine syndrome. METHODS: We systematically surveyed the literature to identify relevant patients. Aminoff Logue Scale (ALS) and modified Rankin Scale (mRS) scores were ascertained and combined to form a novel functional score, the Aminoff-Rankin Composite (ARC) score. We compared functional scores between surgery and embolization groups and ran one-sided point-biserial analyses to test our expectation that positive correlations exist between functional scores and treatment outcomes. Finally, we reviewed the pathogenesis of dural arteriovenous fistula formation. RESULTS: The quantitative synthesis included 18 patients. Surgery alone was performed in 11 patients (61.11%); 7 patients underwent embolization alone (38.89%). There were no significant differences in functional scores or symptom outcomes when we compared surgery to embolization. The pre-intervention ALS gait, mRS, and ARC scores were correlated with improved symptoms (rpb = 0.43, P = 0.04; rpb = 0.47, P = 0.02; rpb = 0.48, P = 0.04, respectively). In patients whose symptoms were improved, post-intervention ALS gait and micturition scores (2.55 vs. 4.43, P = 0.02 and 1.09 vs. 2.71, P = 0.01, respectively) and post-intervention ARC scores (6.66 vs. 11.57, P = 0.01) were on average lower than in patients whose symptoms were unimproved. CONCLUSIONS: We believe that patients with dAVF and Foix Alajouanine syndrome present with worse function (higher functional scores) as a result of an acute myelopathic episode, and that if diagnosed and treated appropriately, will experience some level of symptom improvement that is evidenced by reduced post-intervention functional scores. PMID- 28673892 TI - How introns enhance gene expression. AB - In many eukaryotes, including mammals, plants, yeast, and insects, introns can increase gene expression without functioning as a binding site for transcription factors. This phenomenon was termed 'intron-mediated enhancement'. Introns can increase transcript levels by affecting the rate of transcription, nuclear export, and transcript stability. Moreover, introns can also increase the efficiency of mRNA translation. This review discusses the current knowledge about these processes. The role of splicing in IME and the significance of intron position relative to the sites of transcription and translation initiation are elaborated. Particular emphasis is placed on the question why different introns, present at the same location of the same genes and spliced at a similar high efficiency, can have very different impacts on expression - from almost no effect to considerable stimulation. This situation can be at least partly accounted for by the identification of splicing-unrelated intronic elements with a special ability to enhance mRNA accumulation or translational efficiency. The many factors that could lead to the large variation observed between the impact of introns in different genes and experimental systems are highlighted. It is suggested that there is no sole, definite answer to the question "how do introns enhance gene expression". Rather, each intron-gene combination might undergo its own unique mixture of processes that lead to the perceptible outcome. PMID- 28673893 TI - From intronization to intron loss: How the interplay between mRNA-associated processes can shape the architecture and the expression of eukaryotic genes. AB - Transcription-coupled processes such as capping, splicing, and cleavage/polyadenylation participate in the journey from genes to proteins. Although they are traditionally thought to serve only as steps in the generation of mature mRNAs, a synthesis of available data indicates that these processes could also act as a driving force for the evolution of eukaryotic genes. A theoretical framework for how mRNA-associated processes may shape gene structure and expression has recently been proposed. Factors that promote splicing and cleavage/polyadenylation in this framework compete for access to overlapping or neighboring signals throughout the transcription cycle. These antagonistic interactions allow mechanisms for intron gain and splice site recognition as well as common trends in eukaryotic gene structure and expression to be coherently integrated. Here, I extend this framework further. Observations that largely (but not exclusively) revolve around the formation of DNA-RNA hybrid structures, called R loops, and promoter directionality are integrated. Additionally, the interplay between splicing factors and cleavage/polyadenylation factors is theorized to also affect the formation of intragenic DNA double-stranded breaks thereby contributing to intron loss. The most notable prediction in this proposition is that RNA molecules can mediate intron loss by serving as a template to repair DNA double-stranded breaks. The framework presented here leverages a vast body of empirical observations, logically extending previous suggestions, and generating verifiable predictions to further substantiate the view that the intracellular environment plays an active role in shaping the structure and the expression of eukaryotic genes. PMID- 28673895 TI - Genomic complexity and targeted genes in anaplastic thyroid cancer cell lines. PMID- 28673896 TI - Serum androgen levels and their relation to performance in track and field: mass spectrometry results from 2127 observations in male and female elite athletes. AB - OBJECTIVE: To describe and characterise serum androgen levels and to study their possible influence on athletic performance in male and female elite athletes. METHODS: 2127 observations of competition best performances and mass spectrometry measured serum androgen concentrations, obtained during the 2011 and 2013 International Association of Athletics Federations World Championships, were analysed in male and female elite track and field athletes. To test the influence of serum androgen levels on performance, male and female athletes were classified in tertiles according to their free testosterone (fT) concentration and the best competition results achieved in the highest and lowest fT tertiles were then compared. RESULTS: The type of athletic event did not influence fT concentration among elite women, whereas male sprinters showed higher values for fT than male athletes in other events. Men involved in all throwing events showed significantly (p<0.05) lower testosterone and sex hormone binding globulin than men in other events. When compared with the lowest female fT tertile, women with the highest fT tertile performed significantly (p<0.05) better in 400 m, 400 m hurdles, 800 m, hammer throw, and pole vault with margins of 2.73%, 2.78%, 1.78%, 4.53%, and 2.94%, respectively. Such a pattern was not found in any of the male athletic events. CONCLUSION: Female athletes with high fT levels have a significant competitive advantage over those with low fT in 400 m, 400 m hurdles, 800 m, hammer throw, and pole vault. PMID- 28673897 TI - An Aggregate Biomarker Risk Score Predicts High Risk of Near-Term Myocardial Infarction and Death: Findings From BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes). AB - BACKGROUND: In a previous study, we found that a biomarker risk score (BRS) comprised of C-reactive protein, fibrin-degradation products, and heat shock protein-70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk. METHODS AND RESULTS: Two thousand thirty-two subjects with coronary artery disease were followed for 5.3+/-1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut-off values (C reactive protein >3 mg/L, heat shock protein-70 >0.313 ng/mL, and fibrin degradation products >1 MUg/mL). After adjustment for covariates, those with a BRS of 3 had a 4-fold increased risk of all-cause death and a 6.8-fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9-16.0; P<0.0001). All individual biomarkers decreased by 1 year, with ~80% of patients decreasing their BRS. BRS recalibrated at 1 year also predicted risk. Those with 1-year BRS of 2 to 3 had a 4-year mortality rate of 21.1% versus 7.4% for those with BRS of 0 to 1 (P<0.0001). CONCLUSIONS: Our results validate the ability of the BRS to identify coronary artery disease patients at very high near-term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy. PMID- 28673898 TI - Platelet-Derived Factor V Is a Critical Mediator of Arterial Thrombosis. AB - BACKGROUND: Coagulation factor V (FV) plays a key role in hemostasis, is present in plasma and platelets, and has both pro- and anticoagulant properties; however, the contribution of platelet-derived FV to arterial thrombosis remains undetermined. METHODS AND RESULTS: Using transgenic mice with various levels of FV gene expression that was restricted to the plasma or platelets, the roles of platelet FV were evaluated in the regulation of arterial thrombosis and platelet activation. Mice with higher levels of platelet FV exhibited faster thrombotic occlusion of the carotid artery after injury compared with mice with lower platelet FV levels. Infusion of platelets with higher levels of FV into transgenic mice with undetectable levels of platelet FV reduced the time to carotid artery occlusion. In contrast, infusion of purified recombinant plasma FV into mice with undetectable platelet FV levels failed to reduce the carotid occlusion times following injury. Evaluation of isolated platelets revealed that platelet-derived FV was critical for the regulation of platelet activation. These effects were associated with an increased level of expression of P-selectin and increased cGMP in platelets. CONCLUSIONS: We established that platelet-derived FV is a critical mediator of arterial thrombosis that involves platelet activation. PMID- 28673899 TI - Outcomes and Prognostic Impact of Prophylactic Oral Anticoagulation in Anterior ST-Segment Elevation Myocardial Infarction Patients With Left Ventricular Dysfunction. AB - BACKGROUND: The contemporary role of prophylactic anticoagulation following extensive anterior wall ST-segment myocardial infarction (STEMI) is unclear. METHODS AND RESULTS: We evaluated anterior STEMI patients with left ventricle dysfunction (left ventricular ejection fraction <=40%) ("high risk"), categorized by prophylactic warfarin use, within a regional STEMI. Patients with pre-existing atrial fibrillation were excluded. The primary outcome was an adjusted (for Global Registry of Acute Coronary Events risk score) 1-year composite of recurrent ischemia, stroke/transient ischemic attack/systemic embolism, or all cause death. Of the 2032 STEMI admissions, 436 (21.5%) were high risk. After excluding 19 (4.4%) patients with definite left ventricle thrombus and 21 (4.8%) in-hospital deaths (2 had left ventricle thrombus), prophylactic warfarin was utilized in 236/398 (59.3%) high-risk survivors. Prescriptions were comparable across sex, but recipients were on average younger (58.5 years versus 64.0 years, P<0.001) and lower risk (Global Registry of Acute Coronary Events risk: 163 versus 181, P<0.001). No association on the adjusted ischemic composite (23.3% versus 25.3%, odds ratio 0.96, 95% CI 0.60-1.55) or thromboembolic events (2.1% versus 1.2%, odds ratio 1.99, 95% CI 0.38-10.51) was observed, but reduced 1-year all-cause mortality was noted (2.5% versus 8.6%, odds ratio 0.30, 95% CI 0.11 0.81); numerically higher major bleeding was observed at 1 year (2.5% versus 1.2%, odds ratio 2.17, 95% CI 0.43-10.96). CONCLUSIONS: A high utilization of prophylactic warfarin occurs in anterior STEMI patients with left ventricle dysfunction, yet appears to provide no additional benefit on the ischemic composite. The association with lower all-cause mortality, but higher bleeding, calls for an improved understanding of its role in high-risk STEMI. PMID- 28673902 TI - Positive effects of total and dairy protein intakes on peripheral skeleton bone strength. PMID- 28673903 TI - Reply to D Xie and Z Sheng. PMID- 28673901 TI - Implications of American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Guidelines on Statin Underutilization for Prevention of Cardiovascular Disease in Diabetes Mellitus Among Several US Networks of Community Health Centers. AB - BACKGROUND: Little is known about statin underutilization among diabetes mellitus patients cared for in community health centers, which tend to serve socioeconomically disadvantaged populations. Implications of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on preexisting gaps in statin treatment in this population are unclear. METHODS AND RESULTS: We included 32 440 adults (45% male, 63% nonwhite, 29% uninsured/Medicaid) aged 40 to 75 years with diabetes mellitus who received care within 16 community health center groups in 11 states in the Community Health Applied Research Network during 2013. Statin prescribing was analyzed as a function of concordance with the National Cholesterol Education Program Adult Treatment Panel 2001 and ACC/AHA 2013 guidelines. More patients' treatments were concordant with the ACC/AHA (52.8%) versus the National Cholesterol Education Program Adult Treatment Panel (36.2%) guideline. Female sex was associated with lower concordance for both (odds ratio [OR] 0.90, CI 0.85-0.94; and OR 0.84, CI 0.80-0.88, respectively). Being insured, an Asian/Pacific Islander, or primarily Spanish speaking were associated with greater concordance for both guidelines: 35.5% (11 526/32 440) were concordant with neither guideline, the majority (79.7%) having no statin prescribed; 28.2% (9168/32 440) were concordant with ACC/AHA but not the National Cholesterol Education Program Adult Treatment Panel. 8.7% of these patients had a low-density lipoprotein cholesterol >160 mg/dL despite having a moderate- or high intensity statin prescribed. And 11.6% (3772/32 440) were concordant with the National Cholesterol Education Program Adult Treatment Panel but not with ACC/AHA. Most of these patients had a low-density lipoprotein cholesterol between 70 and 99 mg/dL with no or a low-intensity statin prescribed. CONCLUSIONS: Opportunities exist to improve cholesterol management in diabetes mellitus patients in community health centers. Addressing care gaps could improve cardiovascular disease prevention in this high-risk population. PMID- 28673904 TI - Dairy fat and cardiovascular disease: adjusting for potential confounders. PMID- 28673900 TI - Inhibition of IkappaB Kinase at 24 Hours After Acute Kidney Injury Improves Recovery of Renal Function and Attenuates Fibrosis. AB - BACKGROUND: Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease. Nuclear factor-kappaB is a nuclear transcription factor activated post-ischemia, responsible for the transcription of proinflammatory proteins. The role of nuclear factor-kappaB in the renal fibrosis post-AKI is unknown. METHODS AND RESULTS: We used a rat model of AKI caused by unilateral nephrectomy plus contralateral ischemia (30 minutes) and reperfusion injury (up to 28 days) to show impairment of renal function (peak: 24 hours), activation of nuclear factor-kappaB (peak: 48 hours), and fibrosis (28 days). In humans, AKI is diagnosed by a rise in serum creatinine. We have discovered that the IkappaB kinase inhibitor IKK16 (even when given at peak serum creatinine) still improved functional and structural recovery and reduced myofibroblast formation, macrophage infiltration, transforming growth factor-beta expression, and Smad2/3 phosphorylation. AKI resulted in fibrosis within 28 days (Sirius red staining, expression of fibronectin), which was abolished by IKK16. To confirm the efficacy of IKK16 in a more severe model of fibrosis, animals were subject to 14 days of unilateral ureteral obstruction, resulting in tubulointerstitial fibrosis, myofibroblast formation, and macrophage infiltration, all of which were attenuated by IKK16. CONCLUSIONS: Inhibition of IkappaB kinase at peak creatinine improves functional recovery, reduces further injury, and prevents fibrosis. PMID- 28673906 TI - Erratum for Perfilyev et al. Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial. Am J Clin Nutr 2017;105:991-1000. PMID- 28673905 TI - Reply to DR Thomas. PMID- 28673908 TI - Supplement-Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) TOC link. PMID- 28673909 TI - Physiological mechanisms underlying animal social behaviour. AB - Many species of animal live in groups, and the group represents the organizational level within which ecological and evolutionary processes occur. Understanding these processes, therefore, relies on knowledge of the mechanisms that permit or constrain group formation. We suggest that physiological capacities and differences in physiology between individuals modify fission fusion dynamics. Differences between individuals in locomotor capacity and metabolism may lead to fission of groups and sorting of individuals into groups with similar physiological phenotypes. Environmental impacts such as hypoxia can influence maximum group sizes and structure in fish schools by altering access to oxygenated water. The nutritional environment determines group cohesion, and the increase in information collected by the group means that individuals should rely more on social information and form more cohesive groups in uncertain environments. Changing environmental contexts require rapid responses by individuals to maintain group coordination, which are mediated by neuroendocrine signalling systems such as nonapeptides and steroid hormones. Brain processing capacity may constrain social complexity by limiting information processing. Failure to evaluate socially relevant information correctly limits social interactions, which is seen, for example, in autism. Hence, functioning of a group relies to a large extent on the perception and appropriate processing of signals from conspecifics. Many if not all physiological systems are mechanistically linked, and therefore have synergistic effects on social behaviour. A challenge for the future lies in understanding these interactive effects, which will improve understanding of group dynamics, particularly in changing environments.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673910 TI - Injury-mediated decrease in locomotor performance increases predation risk in schooling fish. AB - The costs and benefits of group living often depend on the spatial position of individuals within groups and the ability of individuals to occupy preferred positions. For example, models of predation events for moving prey groups predict higher mortality risk for individuals at the periphery and front of groups. We investigated these predictions in sardine (Sardinella aurita) schools under attack from group hunting sailfish (Istiophorus platypterus) in the open ocean. Sailfish approached sardine schools about equally often from the front and rear, but prior to attack there was a chasing period in which sardines attempted to swim away from the predator. Consequently, all sailfish attacks were directed at the rear and peripheral positions of the school, resulting in higher predation risk for individuals at these positions. During attacks, sailfish slash at sardines with their bill causing prey injury including scale removal and tissue damage. Sardines injured in previous attacks were more often found in the rear half of the school than in the front half. Moreover, injured fish had lower tail beat frequencies and lagged behind uninjured fish. Injuries inflicted by sailfish bills may, therefore, hinder prey swimming speed and drive spatial sorting in prey schools through passive self-assortment. We found only partial support for the theoretical predictions from current predator-prey models, highlighting the importance of incorporating more realistic predator-prey dynamics into these models.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673911 TI - The role of physiological traits in assortment among and within fish shoals. AB - Individuals of gregarious species often group with conspecifics to which they are phenotypically similar. This among-group assortment has been studied for body size, sex and relatedness. However, the role of physiological traits has been largely overlooked. Here, we discuss mechanisms by which physiological traits particularly those related to metabolism and locomotor performance-may result in phenotypic assortment not only among but also within animal groups. At the among group level, varying combinations of passive assortment, active assortment, phenotypic plasticity and selective mortality may generate phenotypic differences among groups. Even within groups, however, individual variation in energy requirements, aerobic and anaerobic capacity, neurological lateralization and tolerance to environmental stressors are likely to produce differences in the spatial location of individuals or associations between group-mates with specific physiological phenotypes. Owing to the greater availability of empirical research, we focus on groups of fishes (i.e. shoals and schools). Increased knowledge of physiological mechanisms influencing among- and within-group assortment will enhance our understanding of fundamental concepts regarding optimal group size, predator avoidance, group cohesion, information transfer, life-history strategies and the evolutionary effects of group membership. In a broader perspective, predicting animal responses to environmental change will be impossible without a comprehensive understanding of the physiological basis of the formation and functioning of animal social groups.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673913 TI - Relation between travel strategy and social organization of migrating birds with special consideration of formation flight in the northern bald ibis. AB - A considerable proportion of the world's bird species undertake seasonal long distance migrations. These journeys are energetically demanding. Two major behavioural means to reduce energy expenditure have been suggested: the use of thermal uplifts for a soaring-gliding migration style and travelling in echelon or V-shaped formation. Both strategies have immediate consequences for the social organization of the birds as they either cause large aggregations or require travelling in small and stable groups. Here, we first discuss those consequences, and second present an analysis of formation flight in a flock of northern bald ibis on their first southbound migration. We observe clear correlations between leading and trailing on the dyadic level but only a weak correlation on the individual level during independent flight and no convincing correlation during the human guided part of the migration. This pattern is suggestive of direct reciprocation as a means for establishing cooperation during formation flight. In general, we conclude that behavioural adaptations for dealing with physiological constraints on long-distance migrations either necessitate or ultimately foster formation of social groups with different characteristics. Patterns and social organization of birds travelling in groups have been elusive to study; however, new tracking technology-foremost lightweight GPS units-will provide more insights in the near future.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673912 TI - Boldness traits, not dominance, predict exploratory flight range and homing behaviour in homing pigeons. AB - Group living has been proposed to yield benefits that enhance fitness above the level that would be achieved through living as solitary individuals. Dominance hierarchies occur commonly in these social assemblages, and result, by definition, in resources not being evenly distributed between group members. Determinants of rank within a dominance hierarchy can be associated with morphological characteristics, previous experience of the individual, or personality traits such as exploration tendencies. The purpose of this study was to investigate whether greater exploration and positive responses to novel objects in homing pigeons (Columba livia) measured under laboratory conditions were associated with (i) greater initial exploration of the local area around the home loft during spontaneous exploration flights (SEF), (ii) faster and more efficient homing flights when released from further afield, and (iii) whether the traits of greater exploration and more positive responses to novel objects were more likely to be exhibited by the more dominant individuals within the group. There was no relationship between laboratory-based novel object exploration and position within the dominance hierarchy. Pigeons that were neophobic under laboratory conditions did not explore the local area during SEF opportunities. When released from sites further from home, neophobic pigeons took longer routes to home compared to those birds that had not exhibited neophobic traits under laboratory conditions, and had spontaneously explored to a greater extent. The lack of exploration in the neophobic birds is likely to have resulted in the increased costs of homing following release: unfamiliarity with the landscape likely led to the greater distances travelled and less efficient routes taken. Birds that demonstrated a lack of neophobia were not the dominant individuals inside the loft, and thus would have less access to resources such as food and potentially mates. However, a lack of neophobia makes the subordinate position possible, because subordinate birds that incur high travel costs would become calorie restricted and lose condition. Our results address emerging questions linking individual variation in behaviour with energetics and fitness consequences.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673914 TI - The effect of hypoxia on fish schooling. AB - Low-oxygen areas are expanding in the oceans as a result of climate change. Work carried out during the past two decades suggests that, in addition to impairing basic physiological functions, hypoxia can also affect fish behaviour. Given that many fish species are known to school, and that schooling is advantageous for their survival, the effect of hypoxia on schooling behaviour may have important ecological consequences. Here, we review the effects of hypoxia on school structure and dynamics, together with the mechanisms that cause an increase in school volume and that ultimately lead to school disruption. Furthermore, the effect of hypoxia generates a number of trade-offs in terms of schooling positions and school structure. Field observations have found that large schools of fish can exacerbate hypoxic conditions, with potential consequences for school structure and size. Therefore, previous models that predict the maximum size attainable by fish schools in relation to oxygen levels are also reviewed. Finally, we suggest that studies on the effect of hypoxia on schooling need to be integrated with those on temperature and ocean acidifications within a framework aimed at increasing our ability to predict the effect of multiple stressors of climate change on fish behaviour.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673915 TI - Collective foraging in spatially complex nutritional environments. AB - Nutrition impinges on virtually all aspects of an animal's life, including social interactions. Recent advances in nutritional ecology show how social animals often trade-off individual nutrition and group cohesion when foraging in simplified experimental environments. Here, we explore how the spatial structure of the nutritional landscape influences these complex collective foraging dynamics in ecologically realistic environments. We introduce an individual-based model integrating key concepts of nutritional geometry, collective animal behaviour and spatial ecology to study the nutritional behaviour of animal groups in large heterogeneous environments containing foods with different abundance, patchiness and nutritional composition. Simulations show that the spatial distribution of foods constrains the ability of individuals to balance their nutrient intake, the lowest performance being attained in environments with small isolated patches of nutritionally complementary foods. Social interactions improve individual regulatory performances when food is scarce and clumpy, but not when it is abundant and scattered, suggesting that collective foraging is favoured in some environments only. These social effects are further amplified if foragers adopt flexible search strategies based on their individual nutritional state. Our model provides a conceptual and predictive framework for developing new empirically testable hypotheses in the emerging field of social nutrition.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673916 TI - Costs and benefits of group living in primates: an energetic perspective. AB - Group size is a fundamental component of sociality, and has important consequences for an individual's fitness as well as the collective and cooperative behaviours of the group as a whole. This review focuses on how the costs and benefits of group living vary in female primates as a function of group size, with a particular emphasis on how competition within and between groups affects an individual's energetic balance. Because the repercussions of chronic energetic stress can lower an animal's fitness, identifying the predictors of energetic stress has important implications for understanding variation in survivorship and reproductive success within and between populations. Notably, we extend previous literature on this topic by discussing three physiological measures of energetic balance-glucocorticoids, c-peptides and thyroid hormones. Because these hormones can provide clear signals of metabolic states and processes, they present an important complement to field studies of spatial and temporal changes in food availability. We anticipate that their further application will play a crucial role in elucidating the adaptive significance of group size in different social and ecological contexts.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673917 TI - Physiology modulates social flexibility and collective behaviour in equids and other large ungulates. AB - Though morphologically very similar, equids across the extant species occupy ecological niches that are surprisingly non-overlapping. Occupancy of these distinct niches appears related to subtle physiological and behavioural adaptations which, in turn, correspond to significant differences in the social behaviours and emergent social systems characterizing the different species. Although instances of intraspecific behavioural variation in equids demonstrate that the same body plan can support a range of social structures, each of these morphologically similar species generally shows robust fidelity to its evolved social system. The pattern suggests a subtle relationship between physiological phenotypes and behavioural flexibility. While environmental conditions can vary widely within relatively short temporal or spatial scales, physiological changes and changes to the behaviours that regulate physiological processes, are constrained to longer cycles of adaptation. Physiology is then the limiting variable in the interaction between ecological variation and behavioural and socio-structural flexibility. Behavioural and socio-structural flexibility, in turn, will generate important feedbacks that will govern physiological function, thus creating a coupled web of interactions that can lead to changes in individual and collective behaviour. Longitudinal studies of equid and other large-bodied ungulate populations under environmental stress, such as those discussed here, may offer the best opportunities for researchers to examine, in real time, the interplay between individual behavioural plasticity, socio structural flexibility, and the physiological and genetic changes that together produce adaptive change.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673918 TI - Developmental stress and social phenotypes: integrating neuroendocrine, behavioural and evolutionary perspectives. AB - The social world is filled with different types of interactions, and social experience interacts with stress on several different levels. Activation of the neuroendocrine axis that regulates the response to stress can have consequences for innumerable behavioural responses, including social decision-making and aspects of sociality, such as gregariousness and aggression. This is especially true for stress experienced during early life, when physiological systems are developing and highly sensitive to perturbation. Stress at this time can have persistent effects on social behaviours into adulthood. One important question remaining is to what extent these effects are adaptive. This paper initially reviews the current literature investigating the complex relationships between the hypothalamic-pituitary-adrenal (HPA) axis and other neuroendocrine systems and several aspects of social behaviour in vertebrates. In addition, the review explores the evidence surrounding the potential for 'social programming' via differential development and activation of the HPA axis, providing an insight into the potential for positive effects on fitness following early life stress. Finally, the paper provides a framework from which novel investigations could work to fully understand the adaptive significance of early life effects on social behaviours.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673919 TI - Dynamic modulation of sociality and aggression: an examination of plasticity within endocrine and neuroendocrine systems. AB - Endocrine and neuroendocrine systems are key mediators of behavioural plasticity and allow for the ability to shift social behaviour across dynamic contexts. These systems operate across timescales, modulating both rapid responses to environmental changes and developmental plasticity in behavioural phenotypes. Thus, not only do endocrine systems mediate behavioural plasticity, but also the systems themselves exhibit plasticity in functional capabilities. This flexibility at both the mechanistic and behavioural levels can be crucial for reproduction and survival. Here, we discuss how plasticity in nonapeptide and steroid actions may influence the expression of, and allow rapid shifts between, sociality and aggression-behavioural shifts that can be particularly important for social interactions. Recent findings of overlap in the mechanisms that modulate social and aggressive behaviour suggest the potential for a mechanistic continuum between these behaviours. We briefly discuss the potential for a sociality-aggression continuum and novel techniques that will enable probing of the functional connectivity of social behaviours. From an evolutionary perspective, we suggest that plasticity in endocrine and neuroendocrine mechanisms of behaviour may be important targets of selection, and discuss the conditions under which we would predict selection to have resulted in differences in endocrine plasticity across species that differ in social organization.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673922 TI - Correction to 'Modelling auditory attention'. PMID- 28673923 TI - Authors' reply to Evans. PMID- 28673920 TI - Why are there so many explanations for primate brain evolution? AB - The question as to why primates have evolved unusually large brains has received much attention, with many alternative proposals all supported by evidence. We review the main hypotheses, the assumptions they make and the evidence for and against them. Taking as our starting point the fact that every hypothesis has sound empirical evidence to support it, we argue that the hypotheses are best interpreted in terms of a framework of evolutionary causes (selection factors), consequences (evolutionary windows of opportunity) and constraints (usually physiological limitations requiring resolution if large brains are to evolve). Explanations for brain evolution in birds and mammals generally, and primates in particular, have to be seen against the backdrop of the challenges involved with the evolution of coordinated, cohesive, bonded social groups that require novel social behaviours for their resolution, together with the specialized cognition and neural substrates that underpin this. A crucial, but frequently overlooked, issue is that fact that the evolution of large brains required energetic, physiological and time budget constraints to be overcome. In some cases, this was reflected in the evolution of 'smart foraging' and technical intelligence, but in many cases required the evolution of behavioural competences (such as coalition formation) that required novel cognitive skills. These may all have been supported by a domain-general form of cognition that can be used in many different contexts.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673921 TI - Two social brains: neural mechanisms of intersubjectivity. AB - It is the aim of this article to present an empirically justified hypothesis about the functional roles of the two social neural systems, namely the so-called 'mirror neuron system' (MNS) and the 'mentalizing system' (MENT, also 'theory of mind network' or 'social neural network'). Both systems are recruited during cognitive processes that are either related to interaction or communication with other conspecifics, thereby constituting intersubjectivity. The hypothesis is developed in the following steps: first, the fundamental distinction that we make between persons and things is introduced; second, communication is presented as the key process that allows us to interact with others; third, the capacity to 'mentalize' or to understand the inner experience of others is emphasized as the fundamental cognitive capacity required to establish successful communication. On this background, it is proposed that MNS serves comparably early stages of social information processing related to the 'detection' of spatial or bodily signals, whereas MENT is recruited during comparably late stages of social information processing related to the 'evaluation' of emotional and psychological states of others. This hypothesis of MNS as a social detection system and MENT as a social evaluation system is illustrated by findings in the field of psychopathology. Finally, new research questions that can be derived from this hypothesis are discussed.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. PMID- 28673924 TI - Evaluation of the effect of baseline MRI sacroiliitis and C reactive protein status on etanercept treatment response in non-radiographic axial spondyloarthritis: a post hoc analysis of the EMBARK study. PMID- 28673925 TI - Acetylation regulates monopolar attachment at multiple levels during meiosis I in fission yeast. PMID- 28673926 TI - Structural basis for recruitment of BRCA2 by PALB2. PMID- 28673927 TI - Role of glycosylation in nucleating protein folding and stability. AB - Glycosylation constitutes one of the most common, ubiquitous and complex forms of post-translational modification. It commences with the synthesis of the protein and plays a significant role in deciding its folded state, oligomerization and thus its function. Recent studies have demonstrated that N-linked glycans help proteins to fold as the stability and folding kinetics are altered with the removal of the glycans from them. Several studies have shown that it alters not only the thermodynamic stability but also the structural features of the folded proteins modulating their interactions and functions. Their inhibition and perturbations have been implicated in diseases from diabetes to degenerative disorders. The intent of this review is to provide insight into the recent advancements in the general understanding on the aspect of glycosylation driven stability of proteins that is imperative to their function and finally their role in health and disease states. PMID- 28673928 TI - Transcriptional Profiling of Biofilm Regulators Identified by an Overexpression Screen in Saccharomyces cerevisiae. AB - Biofilm formation by microorganisms is a major cause of recurring infections and removal of biofilms has proven to be extremely difficult given their inherent drug resistance . Understanding the biological processes that underlie biofilm formation is thus extremely important and could lead to the development of more effective drug therapies, resulting in better infection outcomes. Using the yeast Saccharomyces cerevisiae as a biofilm model, overexpression screens identified DIG1, SFL1, HEK2, TOS8, SAN1, and ROF1/YHR177W as regulators of biofilm formation. Subsequent RNA-seq analysis of biofilm and nonbiofilm-forming strains revealed that all of the overexpression strains, other than DIG1 and TOS8, were adopting a single differential expression profile, although induced to varying degrees. TOS8 adopted a separate profile, while the expression profile of DIG1 reflected the common pattern seen in most of the strains, plus substantial DIG1 specific expression changes. We interpret the existence of the common transcriptional pattern seen across multiple, unrelated overexpression strains as reflecting a transcriptional state, that the yeast cell can access through regulatory signaling mechanisms, allowing an adaptive morphological change between biofilm-forming and nonbiofilm states. PMID- 28673930 TI - Short-term efficacy of psychological and psychopharmacological interventions for panic disorder appears not to be different. PMID- 28673931 TI - Mechanical cue-induced YAP instructs Skp2-dependent cell cycle exit and oncogenic signaling. AB - Mechanical tensions are usually generated during development at spatially defined regions within tissues. Such physical cues dictate the cellular decisions of proliferation or cell cycle arrest. Yet, the mechanisms by which mechanical stress controls the cell cycle are not yet fully understood. Here, we report that mechanical cues function upstream of Skp2 transcription in human breast cancer cells. We found that YAP, the mechano-responsive oncogenic Hippo signaling effector, directly promotes Skp2 transcription. YAP inactivation induces cell cycle exit (G0) by down-regulating Skp2, causing p21/p27 to accumulate. Both Skp2 reconstitution and p21/p27 depletion can rescue the observed defect in cell cycle progression. In the context of a tissue-mimicking 3D culture system, Skp2 inactivation effectively suppresses YAP-driven oncogenesis and aberrant stiff 3D matrix-evoked epithelial tissue behaviors. Finally, we also found that the expression of Skp2 and YAP is positively correlated in breast cancer patients. Our results not only reveal the molecular mechanism by which mechanical cues induce Skp2 transcription, but also uncover a role for YAP-Skp2 oncogenic signaling in the relationship between tissue rigidity and cancer progression. PMID- 28673933 TI - Survivor: Ribosome Edition. PMID- 28673932 TI - Integrin alphavbeta3 enhances the suppressive effect of interferon-gamma on hematopoietic stem cells. AB - Hematopoietic homeostasis depends on the maintenance of hematopoietic stem cells (HSCs), which are regulated within a specialized bone marrow (BM) niche. When HSC sense external stimuli, their adhesion status may be critical for determining HSC cell fate. The cell surface molecule, integrin alphavbeta3, is activated through HSC adhesion to extracellular matrix and niche cells. Integrin beta3 signaling maintains HSCs within the niche. Here, we showed the synergistic negative regulation of the pro-inflammatory cytokine interferon-gamma (IFNgamma) and beta3 integrin signaling in murine HSC function by a novel definitive phenotyping of HSCs. Integrin alphavbeta3 suppressed HSC function in the presence of IFNgamma and impaired integrin beta3 signaling mitigated IFNgamma-dependent negative action on HSCs. During IFNgamma stimulation, integrin beta3 signaling enhanced STAT1-mediated gene expression via serine phosphorylation. These findings show that integrin beta3 signaling intensifies the suppressive effect of IFNgamma on HSCs, which indicates that cell adhesion via integrin alphavbeta3 within the BM niche acts as a context-dependent signal modulator to regulate the HSC function under both steady-state and inflammatory conditions. PMID- 28673934 TI - Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues. AB - The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues. PMID- 28673935 TI - Functions of long non-coding RNAs in human disease and their conservation in Drosophila development. AB - Genomic analysis has found that the transcriptome in both humans and Drosophila melanogaster features large numbers of long non-coding RNA transcripts (lncRNAs). This recently discovered class of RNAs regulates gene expression in diverse ways and has been involved in a large variety of important biological functions. Importantly, an increasing number of lncRNAs have also been associated with a range of human diseases, including cancer. Comparative analyses of their functions among these organisms suggest that some of their modes of action appear to be conserved. This highlights the importance of model organisms such as Drosophila, which shares many gene regulatory networks with humans, in understanding lncRNA function and its possible impact in human health. This review discusses some known functions and mechanisms of action of lncRNAs and their implication in human diseases, together with their functional conservation and relevance in Drosophila development. PMID- 28673936 TI - Targeting the hepatocyte growth factor/Met pathway in cancer. AB - Hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase, drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Typical paracrine HGF/Met signaling is regulated by HGF activation at target cell surfaces, HGF binding-induced receptor activation, internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis, tumor angiogenesis and invasiveness, and tumor metastasis in many types of cancer, leading to the rapid growth of pathway-targeted anticancer drug development programs. We review here HGF and Met structure and function, basic properties of HGF/Met pathway antagonists now in clinical development, and recent clinical trial results. Presently, the main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of effective therapy combinations. The wealth of basic information, analytical reagents and model systems available regarding normal and oncogenic HGF/Met signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective cancer treatment. PMID- 28673937 TI - Exercise protects from cancer through regulation of immune function and inflammation. AB - Exercise training has been extensively studied in cancer settings as part of prevention or rehabilitation strategies, yet emerging evidence suggests that exercise training can also directly affect tumor-specific outcomes. The underlying mechanisms for this exercise-dependent cancer protection are just starting to be elucidated. To this end, evasion of immune surveillance and tumor associated inflammation are established as hallmarks of cancer, and exercise may target cancer incidence and progression through regulation of these mechanisms. Here, I review the role of exercise in protection from cancer through mobilization and activation of cytotoxic immune cells, restriction of inflammatory signaling pathways in myeloid immune cells, and regulation of acute and chronic systemic inflammatory responses. In conclusion, I propose that exercise has the potential to target tumor growth through regulation of immune and inflammatory functions, and exercise may be pursued as anticancer treatment through incorporation into standard oncological therapy to the benefit of the cancer patients. PMID- 28673938 TI - Design starch: stochastic modeling of starch granule biogenesis. AB - Starch is the most widespread and abundant storage carbohydrate in plants and the main source of carbohydrate in the human diet. Owing to its remarkable properties and commercial applications, starch is still of growing interest. Its unique granular structure made of intercalated layers of amylopectin and amylose has been unraveled thanks to recent progress in microscopic imaging, but the origin of such periodicity is still under debate. Both amylose and amylopectin are made of linear chains of alpha-1,4-bound glucose residues, with branch points formed by alpha-1,6 linkages. The net difference in the distribution of chain lengths and the branching pattern of amylose (mainly linear), compared with amylopectin (racemose structure), leads to different physico-chemical properties. Amylose is an amorphous and soluble polysaccharide, whereas amylopectin is insoluble and exhibits a highly organized structure of densely packed double helices formed between neighboring linear chains. Contrarily to starch degradation that has been investigated since the early 20th century, starch production is still poorly understood. Most enzymes involved in starch growth (elongation, branching, debranching, and partial hydrolysis) are now identified. However, their specific action, their interplay (cooperative or competitive), and their kinetic properties are still largely unknown. After reviewing recent results on starch structure and starch growth and degradation enzymatic activity, we discuss recent results and current challenges for growing polysaccharides on granular surface. Finally, we highlight the importance of novel stochastic models to support the analysis of recent and complex experimental results, and to address how macroscopic properties emerge from enzymatic activity and structural rearrangements. PMID- 28673939 TI - The sweet tooth of the circadian clock. AB - The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic and intrinsic metabolic cues. The bidirectional interaction between circadian clocks and metabolism involves both transcriptional and post translational mechanisms. Nuclear receptors exemplify the transcriptional programs that couple molecular clocks to metabolism. The post-translational modifications of the core clock machinery are known to play a key role in metabolic entrainment of circadian clocks. O-linked N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is a key mediator of metabolic response to nutrient availability. This review highlights our current understanding of the role of protein O-GlcNAcylation in mediating metabolic input and output of the circadian clock. PMID- 28673941 TI - Recalibrating the risks and benefits of lithium therapy. AB - Recent data might subtly recalibrate the risk/benefit ratio of lithium, the prototypical mood stabiliser for bipolar disorder. There are hints that lithium might be associated with a reduction in dementia risk and as noted in this Journal, a surprising reduction in the risk of cancer. PMID- 28673942 TI - Prevention of bipolar episodes with lithium in the perinatal period. AB - Because lithium is now recommended as the initial long-term treatment for bipolar disorder in general and has a lower teratogenic potential than originally reported, it may become more frequently prescribed in childbearing women. The article by Wesseloo et al in this issue provides helpful data and guidance for managing lithium dosing in the perinatal period. PMID- 28673944 TI - From lesion theory of mental illness to Westworld and back - psychiatry in the movies. PMID- 28673943 TI - Befriending: active placebo or effective psychotherapy? AB - Befriending allows for control of the non-specific factors of the therapist patient interaction in psychosocial research. Manualised befriending is at the very least an active placebo and potentially an effective intervention. Befriending now merits increased research attention to determine indications for use and to elucidate mechanisms of action. PMID- 28673945 TI - Corporal Clegg - psychiatry in music. PMID- 28673946 TI - Lithium dosing strategies during pregnancy and the postpartum period. AB - BackgroundLithium is challenging to dose during pregnancy.AimsTo provide guidance for dosing lithium during pregnancy.MethodRetrospective observational cohort study. Data on lithium blood level measurements (n = 1101), the daily lithium dose, dosing alterations/frequency and creatinine blood levels were obtained from 113 pregnancies of women receiving lithium treatment during pregnancy and the postpartum period.ResultsLithium blood levels decreased in the first trimester ( 24%, 95% CI -15 to -35), reached a nadir in the second trimester (-36%, 95% CI 27 to -47), increased in the third trimester (-21%, 95% CI -13 to -30) and were still slightly increased postpartum (+9%, 95% CI +2 to +15). Delivery itself was not associated with an acute change in lithium and creatinine blood levels.ConclusionsWe recommend close monitoring of lithium blood levels until 34 weeks of pregnancy, then weekly until delivery and twice weekly for the first 2 weeks postpartum. We suggest creatinine blood levels are measured to monitor renal clearance. PMID- 28673947 TI - Western depression is not a universal condition. PMID- 28673948 TI - Does prescribing psychiatric medication really make it less likely that alcohol is involved in a self-poisoning? PMID- 28673949 TI - Co-consumption of alcohol and psychotropic medications in episodes of non-fatal self-poisoning attended by ambulance services in Victoria, Australia: evidence of potential modification by medical severity. PMID- 28673951 TI - The Lunatic House, Guy's Hospital, London, of 1797 - psychiatry in pictures. PMID- 28673950 TI - Authors' reply. PMID- 28673958 TI - Identifying primary care quality indicators for people with serious mental illness: a systematic review. AB - BACKGROUND: Serious mental illness (SMI) - which comprises long-term conditions such as schizophrenia, bipolar disorder, and other psychoses - has enormous costs for patients and society. In many countries, people with SMI are treated solely in primary care, and have particular needs for physical care. AIM: The objective of this study was to systematically review the literature to create a list of quality indicators relevant to patients with SMI that could be captured using routine data, and which could be used to monitor or incentivise better-quality primary care. DESIGN AND SETTING: A systematic literature review, combined with a search of quality indicator databases and guidelines. METHOD: The authors assessed whether indicators could be measured from routine data and the quality of the evidence. RESULTS: Out of 1847 papers and quality indicator databases identified, 27 were included, from which 59 quality indicators were identified, covering six domains. Of the 59 indicators, 52 could be assessed using routine data. The evidence base underpinning these indicators was relatively weak, and was primarily based on expert opinion rather than trial evidence. CONCLUSION: With appropriate adaptation for different contexts, and in line with the relative responsibilities of primary and secondary care, use of the quality indicators has the potential to improve care and to improve the physical and mental health of people with SMI. However, before the indicators can be used to monitor or incentivise primary care quality, more robust links need to be established, with improved patient outcomes. PMID- 28673959 TI - Pharmacists' perceptions of their emerging general practice roles in UK primary care: a qualitative interview study. AB - BACKGROUND: UK general practice is experiencing a workload crisis. Pharmacists are the third largest healthcare profession in the UK; however, their skills are a currently underutilised and potentially highly valuable resource for primary health care. This study forms part of the evaluation of an innovative training programme for pharmacists who are interested in extended roles in primary care, advocated by a UK collaborative '10-point GP workforce action plan'. AIM: To explore pharmacists' perceptions of primary care roles including the potential for greater integration of their profession into general practice. DESIGN AND SETTING: A qualitative interview study in UK primary care carried out between October 2015 and July 2016. METHOD: Pharmacists were purposively sampled by level of experience, geographical location, and type of workplace. Two confidential semi-structured telephone interviews were conducted - one before and one after the training programme. A constant comparative, inductive approach to thematic analysis was used. RESULTS: Sixteen participants were interviewed. The themes related to: initial expectations of the general practice role, varying by participants' experience of primary care; the influence of the training course with respect to managing uncertainty, critical appraisal skills, and confidence for the role; and predictions for the future of this role. CONCLUSION: There is enthusiasm and willingness among pharmacists for new, extended roles in primary care, which could effectively relieve GP workload pressures. A definition of the role, with examples of the knowledge, skills, and attributes required, should be made available to pharmacists, primary care teams, and the public. Training should include clinical skills teaching, set in context through exposure to general practice, and delivered motivationally by primary care practitioners. PMID- 28673960 TI - Helpful strategies for GPs seeing patients with medically unexplained physical symptoms: a focus group study. AB - BACKGROUND: Patients with long-lasting and disabling medically unexplained physical symptoms (MUPS) are common in general practice. GPs have previously described the challenges regarding management and treatment of patients with MUPS. AIM: To explore GPs' experiences of the strategies perceived as helpful when seeing patients with MUPS. DESIGN AND SETTING: Three focus group interviews with a purposive sample of 24 experienced GPs were held in southern Norway. METHOD: Discussions were audiotaped and transcribed. Systematic text condensation was used for analysis. RESULTS: Several strategies were considered helpful during consultations with patients with MUPS. A comprehensive outline of the patient's medical past and present could serve as the foundation of the dialogue. Reviewing the patient's records and sharing relevant information with them or conducting a thorough clinical examination could offer 'golden moments' of trust and common understanding. A very concrete exchange of symptoms and diagnosis interpretation sometimes created a space for explanations and action, and confrontations could even strengthen the alliance between the GP and the patient. Bypassing conventional answers and transcending tensions by negotiating innovative explanations could help patients resolve symptoms and establish innovative understanding. CONCLUSION: GPs use tangible, down-to-earth strategies in consultations with patients with MUPS. Important strategies were: thorough investigation of the patient's symptoms and story; sharing of interpretations; and negotiation of different explanations. Sharing helpful strategies with colleagues in a field in which frustration and dissatisfaction are not uncommon can encourage GPs to develop sustainable responsibility and innovative solutions. PMID- 28673961 TI - Understanding the molecular differential recognition of muramyl peptide ligands by LRR domains of human NOD receptors. AB - Human nucleotide-binding oligomerization domain proteins, hNOD1 and hNOD2, are host intracellular receptors with C-terminal leucine-rich repeat (LRR) domains, which recognize specific bacterial peptidoglycan (PG) fragments as their ligands. The specificity of this recognition is dependent on the third amino acid of the stem peptide of the PG ligand, which is usually meso-diaminopimelic acid (mesoDAP) or l-lysine (l-Lys). Since the LRR domains of hNOD receptors had been experimentally shown to confer the PG ligand-sensing specificity, we developed three-dimensional structures of hNOD1-LRR and the hNOD2-LRR to understand the mechanism of differential recognition of muramyl peptide ligands by hNOD receptors. The hNOD1-LRR and hNOD2-LRR receptor models exhibited right-handed curved solenoid shape. The hot-spot residues experimentally proved to be critical for ligand recognition were located in the concavity of the NOD-LRR and formed the recognition site. Our molecular docking analyses and molecular electrostatic potential mapping studies explain the activation of hNOD-LRRs, in response to effective molecular interactions of PG ligands at the recognition site; and conversely, the inability of certain PG ligands to activate hNOD-LRRs, by deviations from the recognition site. Based on molecular docking studies using PG ligands, we propose few residues - G825, D826 and N850 in hNOD1-LRR and L904, G905, W931, L932 and S933 in hNOD2-LRR, evolutionarily conserved across different host species, which may play a major role in ligand recognition. Thus, our integrated experimental and computational approach elucidates the molecular basis underlying the differential recognition of PG ligands by hNOD receptors. PMID- 28673962 TI - Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation. AB - 2-Hydroxyglutarate (2-HG) is a hypoxic metabolite with potentially important epigenetic signaling roles. The mechanisms underlying 2-HG generation are poorly understood, but evidence suggests a potential regulatory role for the sirtuin family of lysine deacetylases. Thus, we hypothesized that the acetylation status of the major 2-HG-generating enzymes [lactate dehydrogenase (LDH), isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH)] may govern their 2-HG generating activity. In vitro acetylation of these enzymes, with confirmation by western blotting, mass spectrometry, reversibility by recombinant sirtuins and an assay for global lysine occupancy, yielded no effect on 2-HG-generating activity. In addition, while elevated 2-HG in hypoxia is associated with the activation of lysine deacetylases, we found that mice lacking mitochondrial SIRT3 exhibited hyperacetylation and elevated 2-HG. These data suggest that there is no direct link between enzyme acetylation and 2-HG production. Furthermore, our observed effects of in vitro acetylation on the canonical activities of IDH, MDH and LDH appeared to contrast with previous findings wherein acetyl-mimetic lysine mutations resulted in the inhibition of these enzymes. Overall, these data suggest that a causal relationship should not be assumed between acetylation of metabolic enzymes and their activities, canonical or otherwise. PMID- 28673964 TI - Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. AB - Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m-chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib. PMID- 28673963 TI - Yeast PAH1-encoded phosphatidate phosphatase controls the expression of CHO1 encoded phosphatidylserine synthase for membrane phospholipid synthesis. AB - The PAH1-encoded phosphatidate phosphatase (PAP), which catalyzes the committed step for the synthesis of triacylglycerol in Saccharomyces cerevisiae, exerts a negative regulatory effect on the level of phosphatidate used for the de novo synthesis of membrane phospholipids. This raises the question whether PAP thereby affects the expression and activity of enzymes involved in phospholipid synthesis. Here, we examined the PAP-mediated regulation of CHO1-encoded phosphatidylserine synthase (PSS), which catalyzes the committed step for the synthesis of major phospholipids via the CDP-diacylglycerol pathway. The lack of PAP in the pah1Delta mutant highly elevated PSS activity, exhibiting a growth dependent up-regulation from the exponential to the stationary phase of growth. Immunoblot analysis showed that the elevation of PSS activity results from an increase in the level of the enzyme encoded by CHO1 Truncation analysis and site directed mutagenesis of the CHO1 promoter indicated that Cho1 expression in the pah1Delta mutant is induced through the inositol-sensitive upstream activation sequence (UASINO), a cis-acting element for the phosphatidate-controlled Henry (Ino2-Ino4/Opi1) regulatory circuit. The abrogation of Cho1 induction and PSS activity by a CHO1 UASINO mutation suppressed pah1Delta effects on lipid synthesis, nuclear/endoplasmic reticulum membrane morphology, and lipid droplet formation, but not on growth at elevated temperature. Loss of the DGK1-encoded diacylglycerol kinase, which converts diacylglycerol to phosphatidate, partially suppressed the pah1Delta-mediated induction of Cho1 and PSS activity. Collectively, these data showed that PAP activity controls the expression of PSS for membrane phospholipid synthesis. PMID- 28673965 TI - Accumulation of autophagosomes confers cytotoxicity. AB - Autophagy comprises the processes of autophagosome synthesis and lysosomal degradation. In certain stress conditions, increased autophagosome synthesis may be associated with decreased lysosomal activity, which may result in reduced processing of the excessive autophagosomes by the rate-limiting lysosomal activity. Thus, the excessive autophagosomes in such situations may be largely unfused to lysosomes, and their formation/accumulation under these conditions is assumed to be futile for autophagy. The role of cytotoxicity in accumulating autophagosomes (representing synthesis of autophagosomes subsequently unfused to lysosomes) has not been investigated previously. Here, we found that accumulation of autophagosomes compromised cell viability, and this effect was alleviated by depletion of autophagosome machinery proteins. We tested whether reduction in autophagosome synthesis could affect cell viability in cell models expressing mutant huntingtin and alpha-synuclein, given that both of these proteins cause increased autophagosome biogenesis and compromised lysosomal activity. Importantly, partial depletion of autophagosome machinery proteins Atg16L1 and Beclin 1 significantly ameliorated cell death in these conditions. Our data suggest that production/accumulation of autophagosomes subsequently unfused to lysosomes (or accumulation of autophagosomes) directly induces cellular toxicity, and this process may be implicated in the pathogenesis of neurodegenerative diseases. Therefore, lowering the accumulation of autophagosomes may represent a therapeutic strategy for tackling such diseases. PMID- 28673966 TI - Mediator 1 contributes to enamel mineralization as a coactivator for Notch1 signaling and stimulates transcription of the alkaline phosphatase gene. AB - Tooth enamel is mineralized through the differentiation of multiple dental epithelia including ameloblasts and the stratum intermedium (SI), and this differentiation is controlled by several signaling pathways. Previously, we demonstrated that the transcriptional coactivator Mediator 1 (MED1) plays a critical role in enamel formation. For instance, conditional ablation of Med1 in dental epithelia causes functional changes in incisor-specific dental epithelial stem cells, resulting in mineralization defects in the adult incisors. However, the molecular mechanism by which Med1 deficiency causes these abnormalities is not clear. Here, we demonstrated that Med1 ablation causes early SI differentiation defects resulting in enamel hypoplasia of the Med1-deficient molars. Med1 deletion prevented Notch1-mediated differentiation of the SI cells resulting in decreased alkaline phosphatase (ALPL), which is essential for mineralization. However, it does not affect the ability of ameloblasts to produce enamel matrix proteins. Using the dental epithelial SF2 cell line, we demonstrated that MED1 directly activates transcription of the Alpl gene through the stimulation of Notch1 signaling by forming a complex with cleaved Notch1-RBP Jk on the Alpl promoter. These results suggest that MED1 may be essential for enamel matrix mineralization by serving as a coactivator for Notch1 signaling regulating transcription of the Alpl gene. PMID- 28673967 TI - Piperlongumine Induces Reactive Oxygen Species (ROS)-Dependent Downregulation of Specificity Protein Transcription Factors. AB - Piperlongumine is a natural product found in the plant species Piper longum, and this compound exhibits potent anticancer activity in multiple tumor types and has been characterized as an inducer of reactive oxygen species (ROS). Treatment of Panc1 and L3.6pL pancreatic, A549 lung, 786-O kidney, and SKBR3 breast cancer cell lines with 5 to 15 MUmol/L piperlongumine inhibited cell proliferation and induced apoptosis and ROS, and these responses were attenuated after cotreatment with the antioxidant glutathione. Piperlongumine also downregulated expression of Sp1, Sp3, Sp4, and several pro-oncogenic Sp-regulated genes, including cyclin D1, survivin, cMyc, EGFR and hepatocyte growth factor receptor (cMet), and these responses were also attenuated after cotreatment with glutathione. Mechanistic studies in Panc1 cells showed that piperlongumine-induced ROS decreased expression of cMyc via an epigenetic pathway, and this resulted in downregulation of cMyc-regulated miRNAs miR-27a, miR-20a, and miR-17 and induction of the transcriptional repressors ZBTB10 and ZBTB4. These repressors target GC-rich Sp binding sites to decrease transactivation. This pathway observed for piperlongumine in Panc1 cells has previously been reported for other ROS-inducing anticancer agents and shows that an important underlying mechanism of action of piperlongumine is due to downregulation of Sp1, Sp3, Sp4, and pro-oncogenic Sp regulated genes. Cancer Prev Res; 10(8); 467-77. (c)2017 AACR. PMID- 28673968 TI - Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress. AB - Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14-/- (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6alpha transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders. PMID- 28673969 TI - BAK alpha6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove. AB - BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3 only proteins with both the canonical hydrophobic binding groove (alpha2-5) and alpha6 at the rear of BAK, with interaction at alpha6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein-protein interfaces in BAK self-association are limited to the alpha2-5 homodimerization domain. PMID- 28673970 TI - Phylogenomics reveals rapid, simultaneous diversification of three major clades of Gondwanan frogs at the Cretaceous-Paleogene boundary. AB - Frogs (Anura) are one of the most diverse groups of vertebrates and comprise nearly 90% of living amphibian species. Their worldwide distribution and diverse biology make them well-suited for assessing fundamental questions in evolution, ecology, and conservation. However, despite their scientific importance, the evolutionary history and tempo of frog diversification remain poorly understood. By using a molecular dataset of unprecedented size, including 88-kb characters from 95 nuclear genes of 156 frog species, in conjunction with 20 fossil-based calibrations, our analyses result in the most strongly supported phylogeny of all major frog lineages and provide a timescale of frog evolution that suggests much younger divergence times than suggested by earlier studies. Unexpectedly, our divergence-time analyses show that three species-rich clades (Hyloidea, Microhylidae, and Natatanura), which together comprise ~88% of extant anuran species, simultaneously underwent rapid diversification at the Cretaceous Paleogene (K-Pg) boundary (KPB). Moreover, anuran families and subfamilies containing arboreal species originated near or after the KPB. These results suggest that the K-Pg mass extinction may have triggered explosive radiations of frogs by creating new ecological opportunities. This phylogeny also reveals relationships such as Microhylidae being sister to all other ranoid frogs and African continental lineages of Natatanura forming a clade that is sister to a clade of Eurasian, Indian, Melanesian, and Malagasy lineages. Biogeographical analyses suggest that the ancestral area of modern frogs was Africa, and their current distribution is largely associated with the breakup of Pangaea and subsequent Gondwanan fragmentation. PMID- 28673971 TI - Polymorphism at a mimicry supergene maintained by opposing frequency-dependent selection pressures. AB - Explaining the maintenance of adaptive diversity within populations is a long standing goal in evolutionary biology, with important implications for conservation, medicine, and agriculture. Adaptation often leads to the fixation of beneficial alleles, and therefore it erodes local diversity so that understanding the coexistence of multiple adaptive phenotypes requires deciphering the ecological mechanisms that determine their respective benefits. Here, we show how antagonistic frequency-dependent selection (FDS), generated by natural and sexual selection acting on the same trait, maintains mimicry polymorphism in the toxic butterfly Heliconius numata Positive FDS imposed by predators on mimetic signals favors the fixation of the most abundant and best protected wing-pattern morph, thereby limiting polymorphism. However, by using mate-choice experiments, we reveal disassortative mate preferences of the different wing-pattern morphs. The resulting negative FDS on wing-pattern alleles is consistent with the excess of heterozygote genotypes at the supergene locus controlling wing-pattern variation in natural populations of H. numata The combined effect of positive and negative FDS on visual signals is sufficient to maintain a diversity of morphs displaying accurate mimicry with other local prey, although some of the forms only provide moderate protection against predators. Our findings help understand how alternative adaptive phenotypes can be maintained within populations and emphasize the need to investigate interactions between selective pressures in other cases of puzzling adaptive polymorphism. PMID- 28673972 TI - FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres. AB - In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers. PMID- 28673973 TI - Glacial/interglacial wetland, biomass burning, and geologic methane emissions constrained by dual stable isotopic CH4 ice core records. AB - Atmospheric methane (CH4) records reconstructed from polar ice cores represent an integrated view on processes predominantly taking place in the terrestrial biogeosphere. Here, we present dual stable isotopic methane records [delta13CH4 and deltaD(CH4)] from four Antarctic ice cores, which provide improved constraints on past changes in natural methane sources. Our isotope data show that tropical wetlands and seasonally inundated floodplains are most likely the controlling sources of atmospheric methane variations for the current and two older interglacials and their preceding glacial maxima. The changes in these sources are steered by variations in temperature, precipitation, and the water table as modulated by insolation, (local) sea level, and monsoon intensity. Based on our deltaD(CH4) constraint, it seems that geologic emissions of methane may play a steady but only minor role in atmospheric CH4 changes and that the glacial budget is not dominated by these sources. Superimposed on the glacial/interglacial variations is a marked difference in both isotope records, with systematically higher values during the last 25,000 y compared with older time periods. This shift cannot be explained by climatic changes. Rather, our isotopic methane budget points to a marked increase in fire activity, possibly caused by biome changes and accumulation of fuel related to the late Pleistocene megafauna extinction, which took place in the course of the last glacial. PMID- 28673974 TI - MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress. AB - The partner and localiser of BRCA2 (PALB2) plays important roles in the maintenance of genome integrity and protection against cancer. Although PALB2 is commonly described as a repair factor recruited to sites of DNA breaks, recent studies provide evidence that PALB2 also associates with unperturbed chromatin. Here, we investigated the previously poorly described role of chromatin associated PALB2 in undamaged cells. We found that PALB2 associates with active genes through its major binding partner, MRG15, which recognizes histone H3 trimethylated at lysine 36 (H3K36me3) by the SETD2 methyltransferase. Missense mutations that ablate PALB2 binding to MRG15 confer elevated sensitivity to the topoisomerase inhibitor camptothecin (CPT) and increased levels of aberrant metaphase chromosomes and DNA stress in gene bodies, which were suppressed by preventing DNA replication. Remarkably, the level of PALB2 at genic regions was frequently decreased, rather than increased, upon CPT treatment. We propose that the steady-state presence of PALB2 at active genes, mediated through the SETD2/H3K36me3/MRG15 axis, ensures an immediate response to DNA stress and therefore effective protection of these regions during DNA replication. This study provides a conceptual advance in demonstrating that the constitutive chromatin association of repair factors plays a key role in the maintenance of genome stability and furthers our understanding of why PALB2 defects lead to human genome instability syndromes. PMID- 28673975 TI - Origin of long lifetime of band-edge charge carriers in organic-inorganic lead iodide perovskites. AB - Long carrier lifetime is what makes hybrid organic-inorganic perovskites high performance photovoltaic materials. Several microscopic mechanisms behind the unusually long carrier lifetime have been proposed, such as formation of large polarons, Rashba effect, ferroelectric domains, and photon recycling. Here, we show that the screening of band-edge charge carriers by rotation of organic cation molecules can be a major contribution to the prolonged carrier lifetime. Our results reveal that the band-edge carrier lifetime increases when the system enters from a phase with lower rotational entropy to another phase with higher entropy. These results imply that the recombination of the photoexcited electrons and holes is suppressed by the screening, leading to the formation of polarons and thereby extending the lifetime. Thus, searching for organic-inorganic perovskites with high rotational entropy over a wide range of temperature may be a key to achieve superior solar cell performance. PMID- 28673976 TI - Changes in ventromedial prefrontal and insular cortex support the development of metamemory from childhood into adolescence. AB - Metamemory monitoring, or the ability to introspect on the accuracy of one's memories, improves considerably during childhood, but the underlying neural changes and implications for intellectual development are largely unknown. The present study examined whether cortical changes in key brain areas hypothesized to support metacognition contribute to the development of metamemory monitoring from late childhood into early adolescence. Metamemory monitoring was assessed among 7- to 12-y-old children (n = 145) and adults (n = 31). Children returned for up to two additional assessments at 8 to 14 y of age (n = 120) and at 9 to 15 y of age (n = 107) (n = 347 longitudinal scans). Results showed that metamemory monitoring continues to improve from childhood into adolescence. More pronounced cortical thinning in the anterior insula and a greater increase in the thickness of the ventromedial prefrontal cortex over the three assessment points predicted these improvements. Thus, performance benefits are linked to the unique patterns of regional cortical change during development. Metamemory monitoring at the first time point predicted intelligence at the third time point and vice versa, suggesting parallel development of these abilities and their reciprocal influence. Together, these results provide insights into the neuroanatomical correlates supporting the development of the capacity to self-reflect, and highlight the role of this capacity for general intellectual development. PMID- 28673977 TI - LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. AB - Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current. LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis. PMID- 28673979 TI - Profile of Raymond J. Deshaies. PMID- 28673978 TI - Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution. AB - Sesterterpenoids are a rare terpene class harboring untapped chemodiversity and bioactivities. Their structural diversity originates primarily from the scaffold generating sesterterpene synthases (STSs). In fungi, all six known STSs are bifunctional, containing C-terminal trans-prenyltransferase (PT) and N-terminal terpene synthase (TPS) domains. In plants, two colocalized PT and TPS gene pairs from Arabidopsis thaliana were recently reported to synthesize sesterterpenes. However, the landscape of PT and TPS genes in plant genomes is unclear. Here, using a customized algorithm for systematically searching plant genomes, we reveal a suite of physically colocalized pairs of PT and TPS genes for the biosynthesis of a large sesterterpene repertoire in the wider Brassicaceae. Transient expression of seven TPSs from A. thaliana, Capsella rubella, and Brassica oleracea in Nicotiana benthamiana yielded fungal-type sesterterpenes with tri-, tetra-, and pentacyclic scaffolds, and notably (-)-ent-quiannulatene, an enantiomer of the fungal metabolite (+)-quiannulatene. Protein and structural modeling analysis identified an amino acid site implicated in structural diversification. Mutation of this site in one STS (AtTPS19) resulted in premature termination of carbocation intermediates and accumulation of bi-, tri-, and tetracyclic sesterterpenes, revealing the cyclization path for the pentacyclic sesterterpene (-)-retigeranin B. These structural and mechanistic insights, together with phylogenetic analysis, suggest convergent evolution of plant and fungal STSs, and also indicate that the colocalized PT-TPS gene pairs in the Brassicaceae may have originated from a common ancestral gene pair present before speciation. Our findings further provide opportunities for rapid discovery and production of sesterterpenes through metabolic and protein engineering. PMID- 28673980 TI - Profile of Xiang-Jin Meng. PMID- 28673982 TI - Starch granule evidence for the earliest potato use in North America. AB - The prehistory of wild potato use, leading to its domestication and diversification, has been well-documented in, and confined to, South America. At least 20 tuber-bearing, wild species of Solanum are known from North and Central America, yet their importance in ancient diets has never been assessed from the archaeological record. Here, we report the earliest evidence of wild potato use in North America at 10,900-10,100 calendar years (cal) B.P. in the form of well preserved starch granules extracted from ground stone tools at North Creek Shelter, southern Utah. These granules have been identified as those of Solanum jamesii Torr. (Four Corners potato), a tuber-bearing species native to the American Southwest. Identification was based on applying five strictly defined diagnostic characteristics (eccentric hilum, longitudinal fissure, lack of fissure branching, fissure ratio, and maximum granule size) to each of 323 archaeological granules. Of those, nine were definitively assigned to S. jamesii based on possession of all characteristics, and another 61 were either likely or possibly S. jamesii depending on the number of characteristics they possessed. The oldest granules were found in substratum 4k (10,900-10,100 cal B.P.). Younger deposits, dating to ~6,900 cal B.P., also contained tools with S. jamesii granules, indicating at least 4,000 y of intermittent use. Ethnographic and historical accounts extend the period of use to more than 10,000 y. The question then arises as to whether some S. jamesii populations could have undergone transport, cultivation, and eventual domestication over such a long period of time. PMID- 28673981 TI - Synergistic effects of treating the spinal cord and brain in CLN1 disease. AB - Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1 deficient (Ppt1-/- ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1-/- mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1-/- mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders. PMID- 28673983 TI - QnAs with Karel Svoboda. PMID- 28673984 TI - Improved color constancy in honey bees enabled by parallel visual projections from dorsal ocelli. AB - How can a pollinator, like the honey bee, perceive the same colors on visited flowers, despite continuous and rapid changes in ambient illumination and background color? A hundred years ago, von Kries proposed an elegant solution to this problem, color constancy, which is currently incorporated in many imaging and technological applications. However, empirical evidence on how this method can operate on animal brains remains tenuous. Our mathematical modeling proposes that the observed spectral tuning of simple ocellar photoreceptors in the honey bee allows for the necessary input for an optimal color constancy solution to most natural light environments. The model is fully supported by our detailed description of a neural pathway allowing for the integration of signals originating from the ocellar photoreceptors to the information processing regions in the bee brain. These findings reveal a neural implementation to the classic color constancy problem that can be easily translated into artificial color imaging systems. PMID- 28673985 TI - Last name analysis of mobility, gender imbalance, and nepotism across academic systems. AB - In biology, last names have been used as proxy for genetic relatedness in pioneering studies of neutral theory and human migrations. More recently, analyzing the last name distribution of Italian academics has raised the suspicion of nepotism, with faculty hiring their relatives for academic posts. Here, we analyze three large datasets containing the last names of all academics in Italy, researchers from France, and those working at top public institutions in the United States. Through simple randomizations, we show that the US academic system is geographically well-mixed, whereas Italian academics tend to work in their native region. By contrasting maiden and married names, we can detect academic couples in France. Finally, we detect the signature of nepotism in the Italian system, with a declining trend. The claim that our tests detect nepotism as opposed to other effects is supported by the fact that we obtain different results for the researchers hired after 2010, when an antinepotism law was in effect. PMID- 28673986 TI - Cytokinin induces genome-wide binding of the type-B response regulator ARR10 to regulate growth and development in Arabidopsis. AB - The plant hormone cytokinin affects a diverse array of growth and development processes and responses to the environment. How a signaling molecule mediates such a diverse array of outputs and how these response pathways are integrated with other inputs remain fundamental questions in plant biology. To this end, we characterized the transcriptional network initiated by the type-B ARABIDOPSIS RESPONSE REGULATORs (ARRs) that mediate the cytokinin primary response, making use of chromatin immunoprecipitation sequencing (ChIP-seq), protein-binding microarrays, and transcriptomic approaches. By ectopic overexpression of ARR10, Arabidopsis lines hypersensitive to cytokinin were generated and used to clarify the role of cytokinin in regulation of various physiological responses. ChIP-seq was used to identify the cytokinin-dependent targets for ARR10, thereby defining a crucial link between the cytokinin primary-response pathway and the transcriptional changes that mediate physiological responses to this phytohormone. Binding of ARR10 was induced by cytokinin with binding sites enriched toward the transcriptional start sites for both induced and repressed genes. Three type-B ARR DNA-binding motifs, determined by use of protein-binding microarrays, were enriched at ARR10 binding sites, confirming their physiological relevance. WUSCHEL was identified as a direct target of ARR10, with its cytokinin enhanced expression resulting in enhanced shooting in tissue culture. Results from our analyses shed light on the physiological role of the type-B ARRs in regulating the cytokinin response, mechanism of type-B ARR activation, and basis by which cytokinin regulates diverse aspects of growth and development as well as responses to biotic and abiotic factors. PMID- 28673987 TI - Diatom centromeres suggest a mechanism for nuclear DNA acquisition. AB - Centromeres are essential for cell division and growth in all eukaryotes, and knowledge of their sequence and structure guides the development of artificial chromosomes for functional cellular biology studies. Centromeric proteins are conserved among eukaryotes; however, centromeric DNA sequences are highly variable. We combined forward and reverse genetic approaches with chromatin immunoprecipitation to identify centromeres of the model diatom Phaeodactylum tricornutum We observed 25 unique centromere sequences typically occurring once per chromosome, a finding that helps to resolve nuclear genome organization and indicates monocentric regional centromeres. Diatom centromere sequences contain low-GC content regions but lack repeats or other conserved sequence features. Native and foreign sequences with similar GC content to P. tricornutum centromeres can maintain episomes and recruit the diatom centromeric histone protein CENH3, suggesting nonnative sequences can also function as diatom centromeres. Thus, simple sequence requirements may enable DNA from foreign sources to persist in the nucleus as extrachromosomal episomes, revealing a potential mechanism for organellar and foreign DNA acquisition. PMID- 28673988 TI - Four-stranded mini microtubules formed by Prosthecobacter BtubAB show dynamic instability. AB - Microtubules, the dynamic, yet stiff hollow tubes built from alphabeta-tubulin protein heterodimers, are thought to be present only in eukaryotic cells. Here, we report a 3.6-A helical reconstruction electron cryomicroscopy structure of four-stranded mini microtubules formed by bacterial tubulin-like Prosthecobacter dejongeii BtubAB proteins. Despite their much smaller diameter, mini microtubules share many key structural features with eukaryotic microtubules, such as an M loop, alternating subunits, and a seam that breaks overall helical symmetry. Using in vitro total internal reflection fluorescence microscopy, we show that bacterial mini microtubules treadmill and display dynamic instability, another hallmark of eukaryotic microtubules. The third protein in the btub gene cluster, BtubC, previously known as "bacterial kinesin light chain," binds along protofilaments every 8 nm, inhibits BtubAB mini microtubule catastrophe, and increases rescue. Our work reveals that some bacteria contain regulated and dynamic cytomotive microtubule systems that were once thought to be only useful in much larger and sophisticated eukaryotic cells. PMID- 28673990 TI - Correction for Rodesney et al., Mechanosensing of shear by Pseudomonas aeruginosa leads to increased levels of the cyclic-di-GMP signal initiating biofilm development. PMID- 28673991 TI - Correction to Supporting Information for Conos et al., Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. PMID- 28673989 TI - Quadrupling efficiency in production of genetically modified pigs through improved oocyte maturation. AB - Assisted reproductive technologies in all mammals are critically dependent on the quality of the oocytes used to produce embryos. For reasons not fully clear, oocytes matured in vitro tend to be much less competent to become fertilized, advance to the blastocyst stage, and give rise to live young than their in vivo produced counterparts, particularly if they are derived from immature females. Here we show that a chemically defined maturation medium supplemented with three cytokines (FGF2, LIF, and IGF1) in combination, so-called "FLI medium," improves nuclear maturation of oocytes in cumulus-oocyte complexes derived from immature pig ovaries and provides a twofold increase in the efficiency of blastocyst production after in vitro fertilization. Transfer of such blastocysts to recipient females doubles mean litter size to about nine piglets per litter. Maturation of oocytes in FLI medium, therefore, effectively provides a fourfold increase in piglets born per oocyte collected. As they progress in culture, the FLI-matured cumulus-oocyte complexes display distinctly different kinetics of MAPK activation in the cumulus cells, much increased cumulus cell expansion, and an accelerated severance of cytoplasmic projections between the cumulus cells outside the zona pellucida and the oocyte within. These events likely underpin the improvement in oocyte quality achieved by using the FLI medium. PMID- 28673992 TI - Quantification of habitat fragmentation reveals extinction risk in terrestrial mammals. AB - Although habitat fragmentation is often assumed to be a primary driver of extinction, global patterns of fragmentation and its relationship to extinction risk have not been consistently quantified for any major animal taxon. We developed high-resolution habitat fragmentation models and used phylogenetic comparative methods to quantify the effects of habitat fragmentation on the world's terrestrial mammals, including 4,018 species across 26 taxonomic Orders. Results demonstrate that species with more fragmentation are at greater risk of extinction, even after accounting for the effects of key macroecological predictors, such as body size and geographic range size. Species with higher fragmentation had smaller ranges and a lower proportion of high-suitability habitat within their range, and most high-suitability habitat occurred outside of protected areas, further elevating extinction risk. Our models provide a quantitative evaluation of extinction risk assessments for species, allow for identification of emerging threats in species not classified as threatened, and provide maps of global hotspots of fragmentation for the world's terrestrial mammals. Quantification of habitat fragmentation will help guide threat assessment and strategic priorities for global mammal conservation. PMID- 28673993 TI - Coherent alpha oscillations link current and future receptive fields during saccades. AB - Oscillations are ubiquitous in the brain, and they can powerfully influence neural coding. In particular, when oscillations at distinct sites are coherent, they provide a means of gating the flow of neural signals between different cortical regions. Coherent oscillations also occur within individual brain regions, although the purpose of this coherence is not well understood. Here, we report that within a single brain region, coherent alpha oscillations link stimulus representations as they change in space and time. Specifically, in primate cortical area V4, alpha coherence links sites that encode the retinal location of a visual stimulus before and after a saccade. These coherence changes exhibit properties similar to those of receptive field remapping, a phenomenon in which individual neurons change their receptive fields according to the metrics of each saccade. In particular, alpha coherence, like remapping, is highly dependent on the saccade vector and the spatial arrangement of current and future receptive fields. Moreover, although visual stimulation plays a modulatory role, it is neither necessary nor sufficient to elicit alpha coherence. Indeed, a similar pattern of coherence is observed even when saccades are made in darkness. Together, these results show that the pattern of alpha coherence across the retinotopic map in V4 matches many of the properties of receptive field remapping. Thus, oscillatory coherence might play a role in constructing the stable representation of visual space that is an essential aspect of conscious perception. PMID- 28673994 TI - Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood. AB - Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20-22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course. PMID- 28673995 TI - Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway. AB - The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-gamma-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-gamma gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-gamma-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-gamma expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT. PMID- 28673996 TI - Host-mediated impairment of parasite maturation during blood-stage Plasmodium infection. AB - Severe malaria and associated high parasite burdens occur more frequently in humans lacking robust adaptive immunity to Plasmodium falciparum Nevertheless, the host may partly control blood-stage parasite numbers while adaptive immunity is gradually established. Parasite control has typically been attributed to enhanced removal of parasites by the host, although in vivo quantification of this phenomenon remains challenging. We used a unique in vivo approach to determine the fate of a single cohort of semisynchronous, Plasmodium berghei ANKA or Plasmodium yoelii 17XNL-parasitized red blood cells (pRBCs) after transfusion into naive or acutely infected mice. As previously shown, acutely infected mice, with ongoing splenic and systemic inflammatory responses, controlled parasite population growth more effectively than naive controls. Surprisingly, however, this was not associated with accelerated removal of pRBCs from circulation. Instead, transfused pRBCs remained in circulation longer in acutely infected mice. Flow cytometric assessment and mathematical modeling of intraerythrocytic parasite development revealed an unexpected and substantial slowing of parasite maturation in acutely infected mice, extending the life cycle from 24 h to 40 h. Importantly, impaired parasite maturation was the major contributor to control of parasite growth in acutely infected mice. Moreover, by performing the same experiments in rag1-/- mice, which lack T and B cells and mount weak inflammatory responses, we revealed that impaired parasite maturation is largely dependent upon the host response to infection. Thus, impairment of parasite maturation represents a host-mediated, immune system-dependent mechanism for limiting parasite population growth during the early stages of an acute blood-stage Plasmodium infection. PMID- 28673997 TI - Endogenous orienting in the archer fish. AB - The literature has long emphasized the neocortex's role in volitional processes. In this work, we examined endogenous orienting in an evolutionarily older species, the archer fish, which lacks neocortex-like cells. We used Posner's classic endogenous cuing task, in which a centrally presented, spatially informative cue is followed by a target. The fish responded to the target by shooting a stream of water at it. Interestingly, the fish demonstrated a human like "volitional" facilitation effect: their reaction times to targets that appeared on the side indicated by the precue were faster than their reaction times to targets on the opposite side. The fish also exhibited inhibition of return, an aftermath of orienting that commonly emerges only in reflexive orienting tasks in human participants. We believe that this pattern demonstrates the acquisition of an arbitrary connection between spatial orienting and a nonspatial feature of a centrally presented stimulus in nonprimate species. In the literature on human attention, orienting in response to such contingencies has been strongly associated with volitional control. We discuss the implications of these results for the evolution of orienting, and for the study of volitional processes in all species, including humans. PMID- 28673998 TI - Insight into the mechanism of nonenzymatic RNA primer extension from the structure of an RNA-GpppG complex. AB - The nonenzymatic copying of RNA templates with imidazole-activated nucleotides is a well-studied model for the emergence of RNA self-replication during the origin of life. We have recently discovered that this reaction can proceed through the formation of an imidazolium-bridged dinucleotide intermediate that reacts rapidly with the primer. To gain insight into the relationship between the structure of this intermediate and its reactivity, we cocrystallized an RNA primer-template complex with a close analog of the intermediate, the triphosphate-bridged guanosine dinucleotide GpppG, and solved a high-resolution X-ray structure of the complex. The structure shows that GpppG binds the RNA template through two Watson Crick base pairs, with the primer 3'-hydroxyl oriented to attack the 5'-phosphate of the adjacent G residue. Thus, the GpppG structure suggests that the bound imidazolium-bridged dinucleotide intermediate would be preorganized to react with the primer by in-line SN2 substitution. The structures of bound GppG and GppppG suggest that the length and flexibility of the 5'-5' linkage are important for optimal preorganization of the complex, whereas the position of the 5'-phosphate of bound pGpG explains the slow rate of oligonucleotide ligation reactions. Our studies provide a structural interpretation for the observed reactivity of the imidazolium-bridged dinucleotide intermediate in nonenzymatic RNA primer extension. PMID- 28673999 TI - RsmA and AmrZ orchestrate the assembly of all three type VI secretion systems in Pseudomonas aeruginosa. AB - The type VI secretion system (T6SS) is a weapon of bacterial warfare and host cell subversion. The Gram-negative pathogen Pseudomonas aeruginosa has three T6SSs involved in colonization, competition, and full virulence. H1-T6SS is a molecular gun firing seven toxins, Tse1-Tse7, challenging survival of other bacteria and helping P. aeruginosa to prevail in specific niches. The H1-T6SS characterization was facilitated through studying a P. aeruginosa strain lacking the RetS sensor, which has a fully active H1-T6SS, in contrast to the parent. However, study of H2-T6SS and H3-T6SS has been neglected because of a poor understanding of the associated regulatory network. Here we performed a screen to identify H2-T6SS and H3-T6SS regulatory elements and found that the posttranscriptional regulator RsmA imposes a concerted repression on all three T6SS clusters. A higher level of complexity could be observed as we identified a transcriptional regulator, AmrZ, which acts as a negative regulator of H2-T6SS. Overall, although the level of T6SS transcripts is fine-tuned by AmrZ, all T6SS mRNAs are silenced by RsmA. We expanded this concept of global control by RsmA to VgrG spike and T6SS toxin transcripts whose genes are scattered on the chromosome. These observations triggered the characterization of a suite of H2 T6SS toxins and their implication in direct bacterial competition. Our study thus unveils a central mechanism that modulates the deployment of all T6SS weapons that may be simultaneously produced within a single cell. PMID- 28674000 TI - Genome-wide screen for genes involved in eDNA release during biofilm formation by Staphylococcus aureus. AB - Staphylococcus aureus is a leading cause of both nosocomial and community acquired infection. Biofilm formation at the site of infection reduces antimicrobial susceptibility and can lead to chronic infection. During biofilm formation, a subset of cells liberate cytoplasmic proteins and DNA, which are repurposed to form the extracellular matrix that binds the remaining cells together in large clusters. Using a strain that forms robust biofilms in vitro during growth under glucose supplementation, we carried out a genome-wide screen for genes involved in the release of extracellular DNA (eDNA). A high-density transposon insertion library was grown under biofilm-inducing conditions, and the relative frequency of insertions was compared between genomic DNA (gDNA) collected from cells in the biofilm and eDNA from the matrix. Transposon insertions into genes encoding functions necessary for eDNA release were identified by reduced representation in the eDNA. On direct testing, mutants of some of these genes exhibited markedly reduced levels of eDNA and a concomitant reduction in cell clustering. Among the genes with robust mutant phenotypes were gdpP, which encodes a phosphodiesterase that degrades the second messenger cyclic di-AMP, and xdrA, the gene for a transcription factor that, as revealed by RNA sequencing analysis, influences the expression of multiple genes, including many involved in cell wall homeostasis. Finally, we report that growth in biofilm inducing medium lowers cyclic-di-AMP levels and does so in a manner that depends on the gdpP phosphodiesterase gene. PMID- 28674001 TI - Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. AB - The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. PMID- 28674002 TI - Chromosome segregation drives division site selection in Streptococcus pneumoniae. AB - Accurate spatial and temporal positioning of the tubulin-like protein FtsZ is key for proper bacterial cell division. Streptococcus pneumoniae (pneumococcus) is an oval-shaped, symmetrically dividing opportunistic human pathogen lacking the canonical systems for division site control (nucleoid occlusion and the Min system). Recently, the early division protein MapZ was identified and implicated in pneumococcal division site selection. We show that MapZ is important for proper division plane selection; thus, the question remains as to what drives pneumococcal division site selection. By mapping the cell cycle in detail, we show that directly after replication both chromosomal origin regions localize to the future cell division sites, before FtsZ. Interestingly, Z-ring formation occurs coincidently with initiation of DNA replication. Perturbing the longitudinal chromosomal organization by mutating the condensin SMC, by CRISPR/Cas9-mediated chromosome cutting, or by poisoning DNA decatenation resulted in mistiming of MapZ and FtsZ positioning and subsequent cell elongation. Together, we demonstrate an intimate relationship between DNA replication, chromosome segregation, and division site selection in the pneumococcus, providing a simple way to ensure equally sized daughter cells. PMID- 28674003 TI - Genome sequence of a diabetes-prone rodent reveals a mutation hotspot around the ParaHox gene cluster. AB - The sand rat Psammomys obesus is a gerbil species native to deserts of North Africa and the Middle East, and is constrained in its ecology because high carbohydrate diets induce obesity and type II diabetes that, in extreme cases, can lead to pancreatic failure and death. We report the sequencing of the sand rat genome and discovery of an unusual, extensive, and mutationally biased GC rich genomic domain. This highly divergent genomic region encompasses several functionally essential genes, and spans the ParaHox cluster which includes the insulin-regulating homeobox gene Pdx1. The sequence of sand rat Pdx1 has been grossly affected by GC-biased mutation, leading to the highest divergence observed for this gene across the Bilateria. In addition to genomic insights into restricted caloric intake in a desert species, the discovery of a localized chromosomal region subject to elevated mutation suggests that mutational heterogeneity within genomes could influence the course of evolution. PMID- 28674005 TI - Spontaneous fine-tuning to environment in many-species chemical reaction networks. AB - A chemical mixture that continually absorbs work from its environment may exhibit steady-state chemical concentrations that deviate from their equilibrium values. Such behavior is particularly interesting in a scenario where the environmental work sources are relatively difficult to access, so that only the proper orchestration of many distinct catalytic actors can power the dissipative flux required to maintain a stable, far-from-equilibrium steady state. In this article, we study the dynamics of an in silico chemical network with random connectivity in an environment that makes strong thermodynamic forcing available only to rare combinations of chemical concentrations. We find that the long-time dynamics of such systems are biased toward states that exhibit a fine-tuned extremization of environmental forcing. PMID- 28674004 TI - Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy. AB - Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile. PMID- 28674006 TI - Clusters of calcium release channels harness the Ising phase transition to confine their elementary intracellular signals. AB - Intracellular Ca signals represent a universal mechanism of cell function. Messages carried by Ca are local, rapid, and powerful enough to be delivered over the thermal noise. A higher signal-to-noise ratio is achieved by a cooperative action of Ca release channels such as IP3 receptors or ryanodine receptors arranged in clusters (release units) containing a few to several hundred release channels. The channels synchronize their openings via Ca-induced Ca release, generating high-amplitude local Ca signals known as puffs in neurons and sparks in muscle cells. Despite the positive feedback nature of the activation, Ca signals are strictly confined in time and space by an unexplained termination mechanism. Here we show that the collective transition of release channels from an open to a closed state is identical to the phase transition associated with the reversal of magnetic field in an Ising ferromagnet. Our simple quantitative criterion closely predicts the Ca store depletion level required for spark termination for each cluster size. We further formulate exact requirements that a cluster of release channels should satisfy in any cell type for our mapping to the Ising model and the associated formula to remain valid. Thus, we describe deterministically the behavior of a system on a coarser scale (release unit) that is random on a finer scale (release channels), bridging the gap between scales. Our results provide exact mapping of a nanoscale biological signaling model to an interacting particle system in statistical physics, making the extensive mathematical apparatus available to quantitative biology. PMID- 28674007 TI - Effective temperature concept evaluated in an active colloid mixture. AB - Thermal energy agitates all matter, and its competition with ordering tendencies is a fundamental organizing principle in the physical world; this observation suggests that an effective temperature might emerge when external energy input enhances agitation. However, despite the repeated proposal of this concept based on kinetics for various nonequilibrium systems, the value of an effective temperature as a thermodynamic control parameter has been unclear. Here, we introduce a two-component system of driven Janus colloids, such that collisions induced by external energy sources agitate the system, and we demonstrate quantitative agreement with hallmarks of statistical thermodynamics for binary phase behavior: the archetypal phase diagram with equilibrium critical exponents, Gaussian displacement distributions, and even capillarity. The significance is to demonstrate a class of dynamical conditions under which thermodynamic analysis extends quantitatively to systems that are decidedly nonequilibrium except that the effective temperature differs from the physical temperature. PMID- 28674008 TI - Network analysis reveals strongly localized impacts of El Nino. AB - Climatic conditions influence the culture and economy of societies and the performance of economies. Specifically, El Nino as an extreme climate event is known to have notable effects on health, agriculture, industry, and conflict. Here, we construct directed and weighted climate networks based on near-surface air temperature to investigate the global impacts of El Nino and La Nina. We find that regions that are characterized by higher positive/negative network "in" weighted links are exhibiting stronger correlations with the El Nino basin and are warmer/cooler during El Nino/La Nina periods. In contrast to non-El Nino periods, these stronger in-weighted activities are found to be concentrated in very localized areas, whereas a large fraction of the globe is not influenced by the events. The regions of localized activity vary from one El Nino (La Nina) event to another; still, some El Nino (La Nina) events are more similar to each other. We quantify this similarity using network community structure. The results and methodology reported here may be used to improve the understanding and prediction of El Nino/La Nina events and also may be applied in the investigation of other climate variables. PMID- 28674009 TI - Observing a quantum Maxwell demon at work. AB - In apparent contradiction to the laws of thermodynamics, Maxwell's demon is able to cyclically extract work from a system in contact with a thermal bath, exploiting the information about its microstate. The resolution of this paradox required the insight that an intimate relationship exists between information and thermodynamics. Here, we realize a Maxwell demon experiment that tracks the state of each constituent in both the classical and quantum regimes. The demon is a microwave cavity that encodes quantum information about a superconducting qubit and converts information into work by powering up a propagating microwave pulse by stimulated emission. Thanks to the high level of control of superconducting circuits, we directly measure the extracted work and quantify the entropy remaining in the demon's memory. This experiment provides an enlightening illustration of the interplay of thermodynamics with quantum information. PMID- 28674010 TI - Fibroblast growth factor signaling instructs ensheathing glia wrapping of Drosophila olfactory glomeruli. AB - The formation of complex but highly organized neural circuits requires interactions between neurons and glia. During the assembly of the Drosophila olfactory circuit, 50 olfactory receptor neuron (ORN) classes and 50 projection neuron (PN) classes form synaptic connections in 50 glomerular compartments in the antennal lobe, each of which represents a discrete olfactory information processing channel. Each compartment is separated from the adjacent compartments by membranous processes from ensheathing glia. Here we show that Thisbe, an FGF released from olfactory neurons, particularly from local interneurons, instructs ensheathing glia to wrap each glomerulus. The Heartless FGF receptor acts cell autonomously in ensheathing glia to regulate process extension so as to insulate each neuropil compartment. Overexpressing Thisbe in ORNs or PNs causes overwrapping of the glomeruli their axons or dendrites target. Failure to establish the FGF-dependent glia structure disrupts precise ORN axon targeting and discrete glomerular formation. PMID- 28674011 TI - Elucidating reaction mechanisms on quantum computers. AB - With rapid recent advances in quantum technology, we are close to the threshold of quantum devices whose computational powers can exceed those of classical supercomputers. Here, we show that a quantum computer can be used to elucidate reaction mechanisms in complex chemical systems, using the open problem of biological nitrogen fixation in nitrogenase as an example. We discuss how quantum computers can augment classical computer simulations used to probe these reaction mechanisms, to significantly increase their accuracy and enable hitherto intractable simulations. Our resource estimates show that, even when taking into account the substantial overhead of quantum error correction, and the need to compile into discrete gate sets, the necessary computations can be performed in reasonable time on small quantum computers. Our results demonstrate that quantum computers will be able to tackle important problems in chemistry without requiring exorbitant resources. PMID- 28674012 TI - Cross-talk between topological defects in different fields revealed by nematic microfluidics. AB - Topological defects are singularities in material fields that play a vital role across a range of systems: from cosmic microwave background polarization to superconductors and biological materials. Although topological defects and their mutual interactions have been extensively studied, little is known about the interplay between defects in different fields-especially when they coevolve within the same physical system. Here, using nematic microfluidics, we study the cross-talk of topological defects in two different material fields-the velocity field and the molecular orientational field. Specifically, we generate hydrodynamic stagnation points of different topological charges at the center of star-shaped microfluidic junctions, which then interact with emergent topological defects in the orientational field of the nematic director. We combine experiments and analytical and numerical calculations to show that a hydrodynamic singularity of a given topological charge can nucleate a nematic defect of equal topological charge and corroborate this by creating [Formula: see text], [Formula: see text], and [Formula: see text] topological defects in four-, six-, and eight-arm junctions. Our work is an attempt toward understanding materials that are governed by distinctly multifield topology, where disparate topology carrying fields are coupled and concertedly determine the material properties and response. PMID- 28674013 TI - Global priorities for conservation across multiple dimensions of mammalian diversity. AB - Conservation priorities that are based on species distribution, endemism, and vulnerability may underrepresent biologically unique species as well as their functional roles and evolutionary histories. To ensure that priorities are biologically comprehensive, multiple dimensions of diversity must be considered. Further, understanding how the different dimensions relate to one another spatially is important for conservation prioritization, but the relationship remains poorly understood. Here, we use spatial conservation planning to (i) identify and compare priority regions for global mammal conservation across three key dimensions of biodiversity-taxonomic, phylogenetic, and traits-and (ii) determine the overlap of these regions with the locations of threatened species and existing protected areas. We show that priority areas for mammal conservation exhibit low overlap across the three dimensions, highlighting the need for an integrative approach for biodiversity conservation. Additionally, currently protected areas poorly represent the three dimensions of mammalian biodiversity. We identify areas of high conservation priority among and across the dimensions that should receive special attention for expanding the global protected area network. These high-priority areas, combined with areas of high priority for other taxonomic groups and with social, economic, and political considerations, provide a biological foundation for future conservation planning efforts. PMID- 28674014 TI - E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape. AB - Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin-Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell-cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of E-cadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of trans engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions. PMID- 28674015 TI - Limits of Brazil's Forest Code as a means to end illegal deforestation. AB - The 2012 Brazilian Forest Code governs the fate of forests and savannas on Brazil's 394 Mha of privately owned lands. The government claims that a new national land registry (SICAR), introduced under the revised law, could end illegal deforestation by greatly reducing the cost of monitoring, enforcement, and compliance. This study evaluates that potential, using data from state-level land registries (CAR) in Para and Mato Grosso that were precursors of SICAR. Using geospatial analyses and stakeholder interviews, we quantify the impact of CAR on deforestation and forest restoration, investigating how landowners adjust their behaviors over time. Our results indicate rapid adoption of CAR, with registered properties covering a total of 57 Mha by 2013. This suggests that the financial incentives to join CAR currently exceed the costs. Registered properties initially showed lower deforestation rates than unregistered ones, but these differences varied by property size and diminished over time. Moreover, only 6% of registered producers reported taking steps to restore illegally cleared areas on their properties. Our results suggest that, from the landowner's perspective, full compliance with the Forest Code offers few economic benefits. Achieving zero illegal deforestation in this context would require the private sector to include full compliance as a market criterion, while state and federal governments develop SICAR as a de facto enforcement mechanism. These results are relevant to other tropical countries and underscore the importance of developing a policy mix that creates lasting incentives for sustainable land-use practices. PMID- 28674016 TI - QnAs with Rodolphe Barrangou. PMID- 28674017 TI - Disruption of a horizontally transferred phytoene desaturase abolishes carotenoid accumulation and diapause in Tetranychus urticae. AB - Carotenoids underlie many of the vibrant yellow, orange, and red colors in animals, and are involved in processes ranging from vision to protection from stresses. Most animals acquire carotenoids from their diets because de novo synthesis of carotenoids is primarily limited to plants and some bacteria and fungi. Recently, sequencing projects in aphids and adelgids, spider mites, and gall midges identified genes with homology to fungal sequences encoding de novo carotenoid biosynthetic proteins like phytoene desaturase. The finding of horizontal gene transfers of carotenoid biosynthetic genes to three arthropod lineages was unprecedented; however, the relevance of the transfers for the arthropods that acquired them has remained largely speculative, which is especially true for spider mites that feed on plant cell contents, a known source of carotenoids. Pigmentation in spider mites results solely from carotenoids. Using a combination of genetic approaches, we show that mutations in a single horizontally transferred phytoene desaturase result in complete albinism in the two-spotted spider mite, Tetranychus urticae, as well as in the citrus red mite, Panonychus citri Further, we show that phytoene desaturase activity is essential for photoperiodic induction of diapause in an overwintering strain of T. urticae, consistent with a role for this enzyme in provisioning provitamin A carotenoids required for light perception. Carotenoid biosynthetic genes of fungal origin have therefore enabled some mites to forgo dietary carotenoids, with endogenous synthesis underlying their intense pigmentation and ability to enter diapause, a key to the global distribution of major spider mite pests of agriculture. PMID- 28674018 TI - High serum serotonin in sudden infant death syndrome. AB - Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, likely comprises heterogeneous disorders with the common phenotype of sudden death without explanation upon postmortem investigation. Previously, we reported that ~40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. Here we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) [SIDS, 177.2 +/- 15.1 (mean +/- SE) ng/mL versus controls, 91.1 +/- 30.6 ng/mL] (P = 0.014), as determined by ELISA. This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SDs above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT. There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum 5-HT level. This study demonstrates that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects. PMID- 28674019 TI - Changes in E-cadherin rigidity sensing regulate cell adhesion. AB - Mechanical cues are sensed and transduced by cell adhesion complexes to regulate diverse cell behaviors. Extracellular matrix (ECM) rigidity sensing by integrin adhesions has been well studied, but rigidity sensing by cadherins during cell adhesion is largely unexplored. Using mechanically tunable polyacrylamide (PA) gels functionalized with the extracellular domain of E-cadherin (Ecad-Fc), we showed that E-cadherin-dependent epithelial cell adhesion was sensitive to changes in PA gel elastic modulus that produced striking differences in cell morphology, actin organization, and membrane dynamics. Traction force microscopy (TFM) revealed that cells produced the greatest tractions at the cell periphery, where distinct types of actin-based membrane protrusions formed. Cells responded to substrate rigidity by reorganizing the distribution and size of high-traction stress regions at the cell periphery. Differences in adhesion and protrusion dynamics were mediated by balancing the activities of specific signaling molecules. Cell adhesion to a 30-kPa Ecad-Fc PA gel required Cdc42- and formin dependent filopodia formation, whereas adhesion to a 60-kPa Ecad-Fc PA gel induced Arp2/3-dependent lamellipodial protrusions. A quantitative 3D cell-cell adhesion assay and live cell imaging of cell-cell contact formation revealed that inhibition of Cdc42, formin, and Arp2/3 activities blocked the initiation, but not the maintenance of established cell-cell adhesions. These results indicate that the same signaling molecules activated by E-cadherin rigidity sensing on PA gels contribute to actin organization and membrane dynamics during cell-cell adhesion. We hypothesize that a transition in the stiffness of E-cadherin homotypic interactions regulates actin and membrane dynamics during initial stages of cell-cell adhesion. PMID- 28674020 TI - Brain regions and functional interactions supporting early word recognition in the face of input variability. AB - Perception and cognition in infants have been traditionally investigated using habituation paradigms, assuming that babies' memories in laboratory contexts are best constructed after numerous repetitions of the very same stimulus in the absence of interference. A crucial, yet open, question regards how babies deal with stimuli experienced in a fashion similar to everyday learning situations namely, in the presence of interfering stimuli. To address this question, we used functional near-infrared spectroscopy to test 40 healthy newborns on their ability to encode words presented in concomitance with other words. The results evidenced a habituation-like hemodynamic response during encoding in the left frontal region, which was associated with a progressive decrement of the functional connections between this region and the left-temporal, right-temporal, and right-parietal regions. In a recognition test phase, a characteristic neural signature of recognition recruited first the right-frontal region and subsequently the right-parietal ones. Connections originating from the right temporal regions to these areas emerged when newborns listened to the familiar word in the test phase. These findings suggest a neural specialization at birth characterized by the lateralization of memory functions: the interplay between temporal and left-frontal regions during encoding and between temporo-parietal and right-frontal regions during recognition of speech sounds. Most critically, the results show that newborns are capable of retaining the sound of specific words despite hearing other stimuli during encoding. Thus, habituation designs that include various items may be as effective for studying early memory as repeated presentation of a single word. PMID- 28674021 TI - Traffic is a major source of atmospheric nanocluster aerosol. AB - In densely populated areas, traffic is a significant source of atmospheric aerosol particles. Owing to their small size and complicated chemical and physical characteristics, atmospheric particles resulting from traffic emissions pose a significant risk to human health and also contribute to anthropogenic forcing of climate. Previous research has established that vehicles directly emit primary aerosol particles and also contribute to secondary aerosol particle formation by emitting aerosol precursors. Here, we extend the urban atmospheric aerosol characterization to cover nanocluster aerosol (NCA) particles and show that a major fraction of particles emitted by road transportation are in a previously unmeasured size range of 1.3-3.0 nm. For instance, in a semiurban roadside environment, the NCA represented 20-54% of the total particle concentration in ambient air. The observed NCA concentrations varied significantly depending on the traffic rate and wind direction. The emission factors of NCA for traffic were 2.4.1015 (kgfuel)-1 in a roadside environment, 2.6.1015 (kgfuel)-1 in a street canyon, and 2.9.1015 (kgfuel)-1 in an on-road study throughout Europe. Interestingly, these emissions were not associated with all vehicles. In engine laboratory experiments, the emission factor of exhaust NCA varied from a relatively low value of 1.6.1012 (kgfuel)-1 to a high value of 4.3.1015 (kgfuel)-1 These NCA emissions directly affect particle concentrations and human exposure to nanosized aerosol in urban areas, and potentially may act as nanosized condensation nuclei for the condensation of atmospheric low-volatile organic compounds. PMID- 28674022 TI - FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness. AB - Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesis-related testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-induced FSIP1 knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial-mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1 into nu/nu mice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1 gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial-mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1 on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy. PMID- 28674023 TI - Fast and accurate HLA typing from short-read next-generation sequence data with xHLA. AB - The HLA gene complex on human chromosome 6 is one of the most polymorphic regions in the human genome and contributes in large part to the diversity of the immune system. Accurate typing of HLA genes with short-read sequencing data has historically been difficult due to the sequence similarity between the polymorphic alleles. Here, we introduce an algorithm, xHLA, that iteratively refines the mapping results at the amino acid level to achieve 99-100% four-digit typing accuracy for both class I and II HLA genes, taking only [Formula: see text]3 min to process a 30* whole-genome BAM file on a desktop computer. PMID- 28674026 TI - Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. AB - Despite significant improvements in the signs and symptoms of myelofibrosis (MF), and possible prolongation of patients' survival, some have disease that is refractory to ruxolitinib and many lose their response over time. Furthermore, patients with >=3 mutations are less likely to respond to ruxolitinib. Here we describe outcomes after ruxolitinib discontinuation in MF patients enrolled in a phase 1/2 study at our center. After a median follow-up of 79 months, 86 patients had discontinued ruxolitinib (30 of whom died while on therapy). The median follow-up after ruxolitinib discontinuation for the remaining 56 patients was 32 months, with median survival after discontinuation of 14 months. Platelets <260 * 109/L at the start of therapy or <100 * 109/L at the time of discontinuation were associated with shorter survival after discontinuation. Of 62 patients with molecular data at baseline and follow-up, 22 (35%) acquired a new mutation while receiving ruxolitinib (14 [61%] in ASXL1). Patients showing clonal evolution had significantly shorter survival after discontinuation (6 vs 16 months). Transfusion dependency was the only clinical variable associated with clonal evolution. These findings underscore the need for novel therapies and suggest that clonal evolution or decreasing platelet counts while on ruxolitinib therapy may be markers of poor prognosis. PMID- 28674029 TI - AtlA Mediates Extracellular DNA Release, Which Contributes to Streptococcus mutans Biofilm Formation in an Experimental Rat Model of Infective Endocarditis. AB - Host factors, such as platelets, have been shown to enhance biofilm formation by oral commensal streptococci, inducing infective endocarditis (IE), but how bacterial components contribute to biofilm formation in vivo is still not clear. We demonstrated previously that an isogenic mutant strain of Streptococcus mutans deficient in autolysin AtlA (DeltaatlA) showed a reduced ability to cause vegetation in a rat model of bacterial endocarditis. However, the role of AtlA in bacterial biofilm formation is unclear. In this study, confocal laser scanning microscopy analysis showed that extracellular DNA (eDNA) was embedded in S. mutans GS5 floes during biofilm formation on damaged heart valves, but an DeltaatlA strain could not form bacterial aggregates. Semiquantification of eDNA by PCR with bacterial 16S rRNA primers demonstrated that the DeltaatlA mutant strain produced dramatically less eDNA than the wild type. Similar results were observed with in vitro biofilm models. The addition of polyanethol sulfonate, a chemical lysis inhibitor, revealed that eDNA release mediated by bacterial cell lysis is required for biofilm initiation and maturation in the wild-type strain. Supplementation of cultures with calcium ions reduced wild-type growth but increased eDNA release and biofilm mass. The effect of calcium ions on biofilm formation was abolished in DeltaatlA cultures and by the addition of polyanethol sulfonate. The VicK sensor, but not CiaH, was found to be required for the induction of eDNA release or the stimulation of biofilm formation by calcium ions. These data suggest that calcium ion-regulated AtlA maturation mediates the release of eDNA by S. mutans, which contributes to biofilm formation in infective endocarditis. PMID- 28674028 TI - Gemtuzumab ozogamicin in infants with AML: results from the Children's Oncology Group trials AAML03P1 and AAML0531. PMID- 28674027 TI - Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States. AB - In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults >=70 years with hematologic malignancies across the United States. Adults >=70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients >=70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008 2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index >=3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients >=70 years. Select adults >=70 years with hematologic malignancies should be considered for transplant. PMID- 28674030 TI - S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria. AB - Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P < 0.0001), despite higher parasite burdens (P < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4+ and CD8+ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism. PMID- 28674031 TI - Role of sapA and yfgA in Susceptibility to Antibody-Mediated Complement-Dependent Killing and Virulence of Salmonella enterica Serovar Typhimurium. AB - The ST313 pathovar of Salmonella enterica serovar Typhimurium contributes to a high burden of invasive disease among African infants and HIV-infected adults. It is characterized by genome degradation (loss of coding capacity) and has increased resistance to antibody-dependent complement-mediated killing compared with enterocolitis-causing strains of S Typhimurium. Vaccination is an attractive disease-prevention strategy, and leading candidates focus on the induction of bactericidal antibodies. Antibody-resistant strains arising through further gene deletion could compromise such a strategy. Exposing a saturating transposon insertion mutant library of S Typhimurium to immune serum identified a repertoire of S Typhimurium genes that, when interrupted, result in increased resistance to serum killing. These genes included several involved in bacterial envelope biogenesis, protein translocation, and metabolism. We generated defined mutant derivatives using S Typhimurium SL1344 as the host. Based on their initial levels of enhanced resistance to killing, yfgA and sapA mutants were selected for further characterization. The S Typhimurium yfgA mutant lost the characteristic Salmonella rod-shaped appearance, exhibited increased sensitivity to osmotic and detergent stress, lacked very long lipopolysaccharide, was unable to invade enterocytes, and demonstrated decreased ability to infect mice. In contrast, the S Typhimurium sapA mutants had similar sensitivity to osmotic and detergent stress and lipopolysaccharide profile and an increased ability to infect enterocytes compared with the wild type, but it had no increased ability to cause in vivo infection. These findings indicate that increased resistance to antibody dependent complement-mediated killing secondary to genetic deletion is not necessarily accompanied by increased virulence and suggest the presence of different mechanisms of antibody resistance. PMID- 28674032 TI - Genetic Adjuvantation of a Cell-Based Therapeutic Vaccine for Amelioration of Chagasic Cardiomyopathy. AB - Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a leading cause of heart disease ("chagasic cardiomyopathy") in Latin America, disproportionately affecting people in resource-poor areas. The efficacy of currently approved pharmaceutical treatments is limited mainly to acute infection, and there are no effective treatments for the chronic phase of the disease. Preclinical models of Chagas disease have demonstrated that antigen specific CD8+ gamma interferon (IFN-gamma)-positive T-cell responses are essential for reducing parasite burdens, increasing survival, and decreasing cardiac pathology in both the acute and chronic phases of Chagas disease. In the present study, we developed a genetically adjuvanted, dendritic cell-based immunotherapeutic for acute Chagas disease in an attempt to delay or prevent the cardiac complications that eventually result from chronic T. cruzi infection. Dendritic cells transduced with the adjuvant, an adenoviral vector encoding a dominant negative isoform of Src homology region 2 domain-containing tyrosine phosphatase 1 (SHP-1) along with the T. cruzi Tc24 antigen and trans-sialidase antigen 1 (TSA1), induced significant numbers of antigen-specific CD8+ IFN-gamma positive cells following injection into BALB/c mice. A vaccine platform transduced with the adenoviral vector and loaded in tandem with the recombinant protein reduced parasite burdens by 76% to >99% in comparison to a variety of different controls and significantly reduced cardiac pathology in a BALB/c mouse model of live Chagas disease. Although no statistical differences in overall survival rates among cohorts were observed, the data suggest that immunotherapeutic strategies for the treatment of acute Chagas disease are feasible and that this approach may warrant further study. PMID- 28674033 TI - Haemophilus parainfluenzae Strain ATCC 33392 Forms Biofilms In Vitro and during Experimental Otitis Media Infections. AB - Haemophilus parainfluenzae is a nutritionally fastidious, Gram-negative bacterium with an oropharyngeal/nasopharyngeal carriage niche that is associated with a range of opportunistic infections, including infectious endocarditis and otitis media (OM). These infections are often chronic/recurrent in nature and typically involve bacterial persistence within biofilm communities that are highly resistant to host clearance. This study addresses the primary hypothesis that H. parainfluenzae forms biofilm communities that are important determinants of persistence in vivo The results from in vitro biofilm studies confirmed that H. parainfluenzae formed biofilm communities within which the polymeric matrix was mainly composed of extracellular DNA and proteins. Using a chinchilla OM infection model, we demonstrated that H. parainfluenzae formed surface-associated biofilm communities containing bacterial and host components that included neutrophil extracellular trap (NET) structures and that the bacteria mainly persisted in these biofilm communities. We also used this model to examine the possible interaction between H. parainfluenzae and its close relative Haemophilus influenzae, which is also commonly carried within the same host environments and can cause OM. The results showed that coinfection with H. influenzae promoted clearance of H. parainfluenzae from biofilm communities during OM infection. The underlying mechanisms for bacterial persistence and biofilm formation by H. parainfluenzae and knowledge about the survival defects of H. parainfluenzae during coinfection with H. influenzae are topics for future work. PMID- 28674035 TI - Early-Life Detection of Hypertension Risks: Implications for Clinical Practice and Research. PMID- 28674034 TI - Antibody-Mediated Catalysis in Infection and Immunity. AB - The existence of catalytic antibodies has been known for decades. Natural antibodies capable of cleaving nucleic acid, protein, and polysaccharide substrates have been described. Although the discovery of catalytic antibodies initially aroused great interest because of their promise for the development of new catalysts, their enzymatic performance has been disappointing due to low reaction rates. However, in the areas of infection and immunity, where processes often occur over much longer times and involve high antibody concentrations, even low catalytic rates have the potential to influence biological outcomes. In this regard, the presence of catalytic antibodies recognizing host antigens has been associated with several autoimmune diseases. Furthermore, naturally occurring catalytic antibodies to microbial determinants have been correlated with resistance to infection. Recently, there has been substantial interest in harnessing the power of antibody-mediated catalysis against microbial antigens for host defense. Additional work is needed, however, to better understand the prevalence, function, and structural basis of catalytic activity in antibodies. Here we review the available information and suggest that antibody-mediated catalysis is a fertile area for study with broad applications in infection and immunity. PMID- 28674036 TI - Influence of Child and Adult Elevated Blood Pressure on Adult Arterial Stiffness: The Cardiovascular Risk in Young Finns Study. AB - Elevated blood pressure (BP) in childhood has been associated with increased adult arterial stiffness, the independent predictor of cardiovascular and all cause mortality. The favorable BP change from childhood to adulthood and the risk of high adult arterial stiffness has not been reported. We examined the effect of child and adult BP on pulse wave velocity (PWV) assessed in adulthood among 1540 white adults followed-up for 27 years since baseline (1980, aged 6-18 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated if systolic BP >=120 mm Hg, diastolic BP >=80 mm Hg, or self-reported use of antihypertensive medications. PWV was measured in 2007 by whole-body impedance cardiography, and high PWV was defined as values at or above the age-, sex-, and heart rate-specific 80th percentile. Individuals with persistently elevated BP and individuals with normal child but elevated adult BP had increased risk of high adult PWV (relative risk [95% confidence interval], 3.18 [2.22-4.55] and 2.64 [1.79-3.88], respectively) in comparison with individuals with normal (both child and adult) BP. In contrast, individuals with elevated BP in childhood but not in adulthood did not have significantly increased risk of high PWV (relative risk [95% confidence interval], 1.26[0.80-1.99]). The results were consistent when different definitions for child and adult elevated BP were applied. These findings highlight the importance of BP control in the primary prevention of cardiovascular diseases. PMID- 28674037 TI - Blood Pressure and Risk of Cardiovascular Events in Patients on Chronic Hemodialysis: The CRIC Study (Chronic Renal Insufficiency Cohort). AB - We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34; P<0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of cardiovascular events, with the nadir risk between 140 and 170 mm Hg. In contrast, there was a linear stepwise association between out-of-dialysis-unit SBP with risk of cardiovascular events. Participants with out-of-dialysis-unit SBP >=128 mm Hg (top 2 quartiles) had >2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP <=112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12-3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42 5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target. PMID- 28674038 TI - Genetic Interference With Endothelial PPAR-gamma (Peroxisome Proliferator Activated Receptor-gamma) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. AB - Pharmacological activation of PPAR-gamma (peroxisome proliferator-activated receptor-gamma) protects the vasculature. Much less is known on the cell-specific impact of PPAR-gamma when driven by endogenous ligands. Recently, we found that endothelial PPAR-gamma protects against angiotensin II-induced endothelial dysfunction. Here, we explored that concept further examining whether effects were sex dependent along with underlying mechanisms. We studied mice expressing a human dominant-negative mutation in PPAR-gamma driven by the endothelial-specific vascular cadherin promoter (E-V290M), using nontransgenic littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from nontransgenic and E-V290M mice. Incubation of isolated arteries with angiotensin II (1 nmol/L) overnight had no effect in nontransgenic, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice (P<0.05). Endothelial function in E-V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS-2870), Rho kinase (Y-27632), ROCK2 (SLX-2119), NF-kappaB (nuclear factor-kappa B essential modulator-binding domain peptide), or interleukin-6 (neutralizing antibody). In addition, we hypothesized that PPAR-gamma may influence the angiotensin 1-7 arm of the renin-angiotensin system. In the basilar artery, dilation to angiotensin 1 7 was selectively reduced in E-V290M mice by >50% (P<0.05), an effect reversed by Y-27632. Thus, effects of angiotensin II are augmented by interference with endothelial PPAR-gamma through sex-independent mechanisms, involving oxidant inflammatory signaling and ROCK2 (Rho kinase). The study also provides the first evidence that endothelial PPAR-gamma interacts with angiotensin 1-7 responses. These critical roles for endothelial PPAR-gamma have implications for pathophysiology and therapeutic approaches for vascular disease. PMID- 28674040 TI - Blood Pressure and Cardiovascular Risk in the Dialysis Patient: How Low Can You Go? PMID- 28674039 TI - Aortic Arch Pulse Wave Velocity Assessed by Magnetic Resonance Imaging as a Predictor of Incident Cardiovascular Events: The MESA (Multi-Ethnic Study of Atherosclerosis). AB - The predictive value of aortic arch pulse wave velocity (PWV) assessed by magnetic resonance imaging for cardiovascular disease (CVD) events has not been fully established. The aim of the present study was to evaluate the association of arch PWV with incident CVD events in MESA (Multi-Ethnic Study of Atherosclerosis). Aortic arch PWV was measured using magnetic resonance imaging at baseline in 3527 MESA participants (mean age, 62+/-10 years at baseline; 47% men) free of overt CVD. Cox regression was used to evaluate the risk of incident CVD (coronary heart disease, stroke, transient ischemic attack, or heart failure) in relation to arch PWV adjusted for age, sex, race, and CVD risk factors. The median value of arch PWV was 7.4 m/s (interquartile range, 5.6-10.2). There was significant interaction between arch PWV and age for outcomes, so analysis was stratified by age categories (45-54 and >54 years). There were 456 CVD events during the 10-year follow-up. Forty-five to 54-year-old participants had significant association of arch PWV with incident CVD independent of CVD risk factors (hazard ratio, 1.44; 95% confidence interval, 1.07-1.95; P=0.018; per 1 SD increase for logarithmically transformed PWV), whereas >54-year group did not (P=0.93). Aortic arch PWV assessed by magnetic resonance imaging is a significant predictor of CVD events among middle-aged (45-54 years old) individuals, whereas arch PWV is not associated with CVD among an elderly in a large multiethnic population. PMID- 28674042 TI - A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations. AB - Mice lacking distal tubular expression of CLDN10, the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin 10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype. PMID- 28674041 TI - Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice. AB - RATIONALE: Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes. OBJECTIVE: To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility. METHODS AND RESULTS: To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (inducible Notch intracellular domain [iNICD]). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including Nkx2-5 (NK2 homeobox 5), Tbx3, and Tbx5 are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including Scn5a (Nav1.5) and Gja5 (connexin 40), are persistently downregulated long after a transient Notch pulse. Consistent with the reduction in Scn5a transcript, Notch induces global changes in the atrial action potential, including a reduced dVm/dtmax. In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology and predisposes to an arrhythmogenic substrate. CONCLUSIONS: Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes, resulting in sinus bradycardia, sinus pauses, and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome. PMID- 28674043 TI - Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy. AB - Multilineage-differentiating stress-enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be collected from various organs. Intravenously administered Muse cells have been shown to spontaneously migrate to damaged tissue and replenish lost cells, but the effect in FSGS is unknown. We systemically administered human bone marrow-derived Muse cells without concurrent administration of immunosuppressants to severe combined immune-deficient (SCID) and BALB/c mouse models with adriamycin-induced FSGS (FSGS-SCID and FSGS-BALB/c, respectively). In FSGS-SCID mice, human Muse cells preferentially integrated into the damaged glomeruli and spontaneously differentiated into cells expressing markers of podocytes (podocin; 31%), mesangial cells (megsin; 13%), and endothelial cells (CD31; 41%) without fusing to the host cells; attenuated glomerular sclerosis and interstitial fibrosis; and induced the recovery of creatinine clearance at 7 weeks. Human Muse cells induced similar effects in FSGS BALB/c mice at 5 weeks, despite xenotransplant without concurrent immunosuppressant administration, and led to improvement in urine protein, creatinine clearance, and plasma creatinine levels more impressive than that in the FSGS-SCID mice at 5 weeks. However, functional recovery in FSGS-BALB/c mice was impaired at 7 weeks due to immunorejection, suggesting the importance of Muse cell survival as glomerular cells in the FSGS kidney for tissue repair and functional recovery. In conclusion, Muse cells are unique reparative stem cells that preferentially home to damaged glomeruli and spontaneously differentiate into glomerular cells after systemic administration. Introduction of genes to induce differentiation is not required before Muse cell administration; thus, Muse cells may be a feasible therapeutic strategy in FSGS. PMID- 28674044 TI - PLA2R and THSD7A: Disparate Paths to the Same Disease? AB - The phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major autoantigens in primary membranous nephropathy (MN), and define two molecular subclasses of this disease. Both proteins are large transmembrane glycoproteins expressed by the podocyte, and both induce IgG4 predominant humoral immune responses that produce circulating autoantibodies that can be used clinically for diagnostic and monitoring purposes. The biologic roles of these proteins remain speculative, although several features of THSD7A suggest a role in adhesion. PLA2R-associated MN was initially found to associate with risk alleles within HLA-DQA1, but subsequent studies have shifted the focus to the HLA-DRB locus. Three distinct humoral epitope-containing regions have been defined within the extracellular portion of PLA2R, and it appears that the number of targeted epitopes may determine disease severity. Although similar information is not yet available for THSD7A-associated MN, this form of MN may have a unique association with malignancy. Finally, it appears likely that other autoantigens in primary MN exist. Although protocols similar to those that identified PLA2R and THSD7A may be successful in the identification of novel antigenic targets in MN, newer techniques such as laser-capture mass spectrometry or protein arrays may be helpful as well. PMID- 28674045 TI - Digital PCR for Detection and Quantification of Fluoroquinolone Resistance in Legionella pneumophila. AB - The emergence of fluoroquinolone (FQ)-resistant mutants of Legionella pneumophila in infected humans was previously reported using a next-generation DNA sequencing (NGS) approach. This finding could explain part of the therapeutic failures observed in legionellosis patients treated with these antibiotics. The aim of this study was to develop digital PCR (dPCR) assays allowing rapid and accurate detection and quantification of these resistant mutants in respiratory samples, especially when the proportion of mutants in a wild-type background is low. We designed three dPCRgyrA assays to detect and differentiate the wild-type and one of the three gyrA mutations previously described as associated with FQ resistance in L. pneumophila: at positions 248C->T (T83I), 259G->A (D87N), and 259G->C (D87H). To assess the performance of these assays, mixtures of FQ-resistant and susceptible strains of L. pneumophila were analyzed, and the results were compared with those obtained with Sanger DNA sequencing and real-time quantitative PCR (qPCR) technologies. The dPCRgyrA assays were able to detect mutated gyrA sequences in the presence of wild-type sequences at up to 1:1,000 resistant/susceptible allele ratios. By comparison, Sanger DNA sequencing and qPCR were less sensitive, allowing the detection of gyrA mutants at up to 1:1 and 1:10 ratios, respectively. When testing 38 respiratory samples from 23 legionellosis patients (69.6% treated with an FQ), dPCRgyrA detected small amounts of gyrA mutants in four (10.5%) samples from three (13.0%) patients. These results demonstrate that dPCR is a highly sensitive alternative to quantify FQ resistance in L. pneumophila, and it could be used in clinical practice to detect patients that could be at higher risk of therapeutic failure. PMID- 28674046 TI - Repurposing Thiram and Disulfiram as Antibacterial Agents for Multidrug-Resistant Staphylococcus aureus Infections. AB - Thiram and disulfiram were evaluated as antibacterial agents against multidrug resistant Staphylococcus aureus Against a 30-member panel comprised of vancomycin susceptible, vancomycin-intermediate, and vancomycin-resistant S. aureus strains, the MIC90 values of the respective test agents were 4 and 16 MUg/ml. Additional analyses revealed that thiram and disulfiram are rapid-acting bacteriostatic agents with narrow, Gram-positive-bacterium spectrum activity. Synergy studies further determined that disulfiram increases the vancomycin susceptibility of three clinical vancomycin-resistant S. aureus strains in vitro, thus establishing a potential use in combination therapy. PMID- 28674047 TI - Subinhibitory Concentrations of Trimethoprim and Sulfamethoxazole Prevent Biofilm Formation by Acinetobacter baumannii through Inhibition of Csu Pilus Expression. AB - Acinetobacter baumannii is emerging as a multidrug-resistant nosocomial pathogen of increasing threat to human health worldwide. Pili are important bacterial virulence factors, playing a role in attachment to host cells and biofilm formation. The Csu pilus, which is assembled via the chaperone-usher secretion system, has been studied in A. baumannii ATCC 19606. Here we show that, in opposition to previous reports, the common laboratory strain ATCC 17978 produces Csu pili. We found that, although ATCC 17978 was resistant to sulfamethoxazole (Smx) and trimethoprim (Tmp), subinhibitory concentrations of these antibiotics abolished the expression of Csu and consequently produced a dramatic reduction in biofilm formation by ATCC 17978. Smx and Tmp acted synergistically to inhibit the enzymatic systems involved in the bacterial synthesis of tetrahydrofolate (THF), which is required for the synthesis of nucleotides. The effects of these antibiotics were partially relieved by exogenous THF addition, indicating that Smx and Tmp turn off Csu assembly by inducing folate stress. We propose that, for Acinetobacter, nanomolar concentrations of Smx and Tmp represent a "danger signal." In response to this signal, Csu expression is repressed, allowing biofilm dispersal and escape from potentially inhibitory concentrations of antibiotics. The roles of antibiotics as signaling molecules are being increasingly acknowledged, with clear implications for both the treatment of bacterial diseases and the understanding of complex microbial interactions in the environment. PMID- 28674048 TI - In Vitro Antibiotic Susceptibilities of Francisella tularensis Determined by Broth Microdilution following CLSI Methods. AB - In vitro susceptibilities for 47 antibiotics were determined in 30 genetic diverse strains of Francisella tularensis by the broth microdilution method following Clinical and Laboratory Standards Institute (CLSI) methods. The F. tularensis strains demonstrated susceptibility to aminoglycosides, fluoroquinolones, and tetracyclines. There was a distinct difference in macrolide susceptibilities between A and B type strains, as has been noted previously. The establishment and comparison of antibiotic susceptibilities of a diverse but specific set of F. tularensis strains by standardized methods and the establishment of population ranges and MIC50/90 values provide reference information for assessing new antibiotic agents and a baseline to monitor any future emergence of resistance, whether natural or intentional. PMID- 28674049 TI - Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus. AB - Mycobacterium abscessus is a highly pathogenic drug-resistant rapidly growing mycobacterium. In this study, we evaluated the in vitro, intracellular, and in vivo activities of LCB01-0371, a novel and safe oxazolidinone derivative, for the treatment of M. abscessus infection and compared its resistance to that of other oxazolidinone drugs. LCB01-0371 was effective against several M. abscessus strains in vitro and in a macrophage model of infection. In the murine model, a similar efficacy to linezolid was achieved, especially in the lungs. We induced laboratory-generated resistance to LCB01-0371; sequencing analysis revealed mutations in rplC of T424C and G419A and a nucleotide insertion at the 503 position. Furthermore, LCB01-0371 inhibited the growth of amikacin-, cefoxitin-, and clarithromycin-resistant strains. Collectively, our data indicate that LCB01 0371 might represent a promising new class of oxazolidinones with improved safety, which may replace linezolid for the treatment of M. abscessus. PMID- 28674050 TI - Plasmids of Diverse Inc Groups Disseminate the Fosfomycin Resistance Gene fosA3 among Escherichia coli Isolates from Pigs, Chickens, and Dairy Cows in Northeast China. AB - Thirty-nine fosfomycin-resistant Escherichia coli isolates carrying fosA3 were obtained from pigs, chickens, dairy cows, and staff in four northeastern provinces of China between June 2015 and April 2016. The fosA3 gene was colocated with blaCTX-M genes on conjugative plasmids of the incompatibility groups IncN (n = 12), IncN-F33:A-:B-(n = 2), IncF33:A-:B-(n = 14), IncF14:A-:B-(n = 2), and IncI1/sequence type 136 (ST136) (n = 9). Four different genetic contexts of fosA3 were detected among the 39 E. coli isolates. Three potential epidemic plasmids circulated among E. coli strains from this region. PMID- 28674051 TI - Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid Organ Transplant Patients. AB - We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring. PMID- 28674053 TI - In Vitro Activity of Ceftolozane-Tazobactam and Other Antimicrobial Agents against Burkholderia cepacia Complex and Burkholderia gladioli. AB - We tested the activities of ceftolozane-tazobactam and 13 other antimicrobial agents against 221 strains of Burkholderia cepacia complex and Burkholderia gladioli Most strains (82%) were cultured from persons with cystic fibrosis, and most (85%) were recovered since 2011. The ceftolozane-tazobactam MIC was <=8 MUg/ml for 77% of the strains. However, the MIC range was broad (<=0.5 to >64 MUg/ml; MIC50/90, 2/32 MUg/ml). Significant differences in susceptibility to some antimicrobial agents were observed between species. PMID- 28674052 TI - Characterization of a Large Antibiotic Resistance Plasmid Found in Enteropathogenic Escherichia coli Strain B171 and Its Relatedness to Plasmids of Diverse E. coli and Shigella Strains. AB - Enteropathogenic Escherichia coli (EPEC) is a leading cause of severe infantile diarrhea in developing countries. Previous research has focused on the diversity of the EPEC virulence plasmid, whereas less is known regarding the genetic content and distribution of antibiotic resistance plasmids carried by EPEC. A previous study demonstrated that in addition to the virulence plasmid, reference EPEC strain B171 harbors a second, larger plasmid that confers antibiotic resistance. To further understand the genetic diversity and dissemination of antibiotic resistance plasmids among EPEC strains, we describe the complete sequence of an antibiotic resistance plasmid from EPEC strain B171. The resistance plasmid, pB171_90, has a completed sequence length of 90,229 bp, a GC content of 54.55%, and carries protein-encoding genes involved in conjugative transfer, resistance to tetracycline (tetA), sulfonamides (sulI), and mercury, as well as several virulence-associated genes, including the transcriptional regulator hha and the putative calcium sequestration inhibitor (csi). In silico detection of the pB171_90 genes among 4,798 publicly available E. coli genome assemblies indicates that the unique genes of pB171_90 (csi and traI) are primarily restricted to genomes identified as EPEC or enterotoxigenic E. coli However, conserved regions of the pB171_90 plasmid containing genes involved in replication, stability, and antibiotic resistance were identified among diverse E. coli pathotypes. Interestingly, pB171_90 also exhibited significant similarity with a sequenced plasmid from Shigella dysenteriae type I. Our findings demonstrate the mosaic nature of EPEC antibiotic resistance plasmids and highlight the need for additional sequence-based characterization of antibiotic resistance plasmids harbored by pathogenic E. coli. PMID- 28674054 TI - Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens. AB - Candida albicans is a major cause of fungal diseases in humans, and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small-scale screening of a library of 199 natural plant compounds (i.e., natural products [NPs]). In vitro susceptibility profiling experiments identified 33 NPs with activity against C. albicans (MIC50s <= 32 MUg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato (Solanum lycopersicum) and exhibited high levels of fungistatic activity against Candida species (MIC50s <= 1 MUg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated C. albicans cells revealed a major alteration (upregulation) in the expression of ergosterol genes, suggesting that the ergosterol pathway is targeted by this NP. Consistent with this transcriptional response, analysis of the sterol content of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) activity but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in Saccharomyces cerevisiae coupled with whole-genome sequencing identified 2 nonsynonymous mutations in ERG6 (amino acids D249G and G132D) responsible for tomatidine resistance. Our results therefore unambiguously identified Erg6, a C 24 sterol methyltransferase absent in mammals, to be the main direct target of tomatidine. We tested the in vivo efficacy of tomatidine in a mouse model of C. albicans systemic infection. Treatment with a nanocrystal pharmacological formulation successfully decreased the fungal burden in infected kidneys compared to the fungal burden achieved by the use of placebo and thus confirmed the potential of tomatidine as a therapeutic agent. PMID- 28674056 TI - Multicenter Study of Clinical Features of Breakthrough Acinetobacter Bacteremia during Carbapenem Therapy. AB - Breakthrough Acinetobacter bacteremia during carbapenem therapy is not uncommon, and it creates therapeutic dilemmas for clinicians. This study was conducted to evaluate the clinical and microbiological characteristics of breakthrough Acinetobacter bacteremia during carbapenem therapy and to assess the efficacy of various antimicrobial therapies. We analyzed 100 adults who developed breakthrough Acinetobacter bacteremia during carbapenem therapy at 4 medical centers over a 6-year period. Their 30-day mortality rate was 57.0%, and the carbapenem resistance rate of their isolates was 87.0%. Among patients with carbapenem-resistant Acinetobacter bacteremia, breakthrough bacteremia during carbapenem therapy was associated with a significantly higher 14-day mortality (51.7% versus 37.4%, respectively; P = 0.025 by bivariate analysis) and a higher 30-day mortality (P = 0.037 by log rank test of survival analysis) than in the nonbreakthrough group. For the treatment of breakthrough Acinetobacter bacteremia during carbapenem therapy, tigecycline-based therapy was associated with a significantly higher 30-day mortality (80.0%) than those with continued carbapenem therapy (52.5%) and colistin-based therapy (57.9%) by survival analysis (P = 0.047 and 0.045 by log rank test, respectively). Cox regression controlling for confounders, including severity of illness indices, demonstrated that treatment with tigecycline-based therapy for breakthrough Acinetobacter bacteremia was an independent predictor of 30-day mortality (hazard ratio, 3.659; 95% confidence interval, 1.794 to 7.465; P < 0.001). Patients with breakthrough Acinetobacter bacteremia during carbapenem therapy posed a high mortality rate. Tigecycline should be used cautiously for the treatment of breakthrough Acinetobacter bacteremia that develops during carbapenem therapy. PMID- 28674055 TI - Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery. AB - Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research. PMID- 28674057 TI - Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation. AB - The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 h using a trough concentration target of >10 MUg/ml for mild to moderate infections and a trough concentration target of >15 MUg/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.). PMID- 28674058 TI - A Novel 6-Benzyl Ether Benzoxaborole Is Active against Mycobacterium tuberculosis In Vitro. AB - We identified a novel 6-benzyl ether benzoxaborole with potent activity against Mycobacterium tuberculosis The compound had an MIC of 2 MUM in liquid medium. The compound was also able to prevent growth on solid medium at 0.8 MUM and was active against intracellular bacteria (50% inhibitory concentration [IC50] = 3.6 MUM) without cytotoxicity against eukaryotic cells (IC50 > 100 MUM). We isolated resistant mutants (MIC >= 100 MUM), which had mutations in Rv1683, Rv3068c, and Rv0047c. PMID- 28674059 TI - In Vivo Emergence of Resistance to Novel Cephalosporin-beta-Lactamase Inhibitor Combinations through the Duplication of Amino Acid D149 from OXA-2 beta-Lactamase (OXA-539) in Sequence Type 235 Pseudomonas aeruginosa. AB - Resistance development to novel cephalosporin-beta-lactamase inhibitor combinations during ceftazidime treatment of a surgical infection by Pseudomonas aeruginosa was investigated. Both initial (97C2) and final (98G1) isolates belonged to the high-risk clone sequence type (ST) 235 and were resistant to carbapenems (oprD), fluoroquinolones (GyrA-T83I, ParC-S87L), and aminoglycosides (aacA7/aacA8/aadA6). 98G1 also showed resistance to ceftazidime, ceftazidime avibactam, and ceftolozane-tazobactam. Sequencing identified blaOXA-2 in 97C2, but 98G1 contained a 3-bp insertion leading to the duplication of the key residue D149 (designated OXA-539). Evaluation of PAO1 transformants producing cloned OXA 2 or OXA-539 confirmed that D149 duplication was the cause of resistance. Active surveillance of the emergence of resistance to these new valuable agents is warranted. PMID- 28674060 TI - In Vitro Susceptibility of the Relapsing-Fever Spirochete Borrelia miyamotoi to Antimicrobial Agents. AB - Hard-tick-borne relapsing fever (HTBRF) is an emerging infectious disease throughout the temperate zone caused by the relapsing-fever spirochete Borrelia miyamotoi Antibiotic treatment of HTBRF is empirically based on the treatment of Lyme borreliosis; however, the antibiotic susceptibility of B. miyamotoi has not been studied to date. Thus, we set out to determine the in vitro antimicrobial susceptibility of B.miyamotoi A microdilution method with 96-well microtiter plates was used to determine the antibiotic susceptibilities of two B.miyamotoi strains isolated on two different continents (Asia and North America), two Borrelia burgdorferisensu lato strains, and one Borrelia hermsii isolate for purposes of comparison. The MIC and minimal bactericidal concentration (MBC) were determined by both microscopy and colorimetric assays. We were able to show that relative to the B. burgdorferi sensu lato isolates, both B.miyamotoi strains and B. hermsii demonstrated greater susceptibility to doxycycline and azithromycin, equal susceptibility to ceftriaxone, and resistance to amoxicillin in vitro The MIC and MBC of amoxicillin for B. miyamotoi evaluated by microscopy were 16 to 32 mg/liter and 32 to 128 mg/liter, respectively. Since B. miyamotoi is susceptible to doxycycline, azithromycin, and ceftriaxone in vitro, our data suggest that these antibiotics can be used for the treatment of HTBRF. Oral amoxicillin is currently used as an alternative for the treatment of HTBRF; however, since we found that the B. miyamotoi strains tested were resistant to amoxicillin in vitro, this issue warrants further study. PMID- 28674061 TI - Assessment of Clinical Pharmacokinetic Drug-Drug Interaction of Antimalarial Drugs alpha/beta-Arteether and Sulfadoxine-Pyrimethamine. AB - Antimalarial drug combination therapy is now being widely used for the treatment of uncomplicated malaria. The objective of the present study was to investigate the effects of coadministration of intramuscular alpha/beta-arteether (alpha/beta AE) and oral sulfadoxine-pyrimethamine (SP) on the pharmacokinetic properties of each drug as a drug-drug interaction study to support the development of a fixed dose combination therapy. A single-dose, open-label, crossover clinical trial was conducted in healthy adult Indian male volunteers (18 to 45 years, n = 13) who received a single dose of AE or SP or a combination dose of AE and SP. Blood samples were collected up to 21 days postadministration, and concentrations of alpha-AE, beta-AE, sulfadoxine, and pyrimethamine were determined by using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and statistically analyzed to calculate the geometric mean ratio and confidence interval. Following single-dose coadministration of intramuscular AE and oral SP, the pharmacokinetic properties of alpha/beta-AE were not significantly affected, and alpha/beta-AE had no significant effect on the pharmacokinetic properties of SP in these selected groups of healthy volunteers. However, more investigations are needed to explore this further. (This study has been registered in the clinical trial registry of India under approval no. CTRI/2011/11/002155.). PMID- 28674062 TI - Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers. AB - The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28 day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A->G, m.3197T->C, and m.3010G->A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts. PMID- 28674063 TI - First Report of Klebsiella oxytoca Strain Simultaneously Producing NDM-1, IMP-4, and KPC-2 Carbapenemases. AB - The nucleotide sequences of five plasmids from one Klebsiella oxytoca isolate were determined using the PacBio RS II system. Plasmid analysis revealed that blaNDM-1 was carried on an IncX3 plasmid. The blaIMP-4 and blaKPC-2 genes were located on IncN and IncP-6 plasmids, respectively. Comparative sequence analysis highlighted the successful spread of carbapenemase-harboring plasmids among different enterobacterial species. We report for the first time, to our knowledge, coproducing NDM-1, KPC-2, and IMP-4 carbapenemases on a K. oxytoca isolate. PMID- 28674064 TI - OXA-244-Producing Escherichia coli Isolates, a Challenge for Clinical Microbiology Laboratories. AB - OXA-244 is a single-point-mutant derivative of OXA-48 displaying reduced carbapenemase activity. Here, we report the microbiological features of seven OXA 244-producing Escherichia coli isolates. Only one isolate grew on ChromID Carba Smart medium (bioMerieux), but six of the seven isolates grew on ChromID extended spectrum-beta-lactamase (ESBL) medium (bioMerieux), as they coproduced an ESBL and/or a plasmid-encoded cephalosporinase. The production of a carbapenemase was detected in 57.1%, 71.4%, 71.4%, and 100% of the E. coli isolates using the Carba NP test, the Rapidec Carba NP test (bioMerieux), a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) hydrolysis assay (Bruker), and the OXA-48 K-SeT assay (Coris BioConcept), respectively. Our results indicate that OXA-244-producing E. coli isolates are difficult to detect, which may lead to their silent spread. PMID- 28674065 TI - Attention Seeker: Production, Modification, and Release of Inflammatory Peptidoglycan Fragments in Neisseria Species. AB - Maintenance of the structural macromolecule peptidoglycan (PG), which involves regulated cycles of PG synthesis and PG degradation, is pivotal for cellular integrity and survival. PG fragments generated from the degradation process are usually efficiently recycled by Gram-negative bacteria. However, Neisseria gonorrhoeae and a limited number of Gram-negative bacteria release PG fragments in amounts sufficient to induce host tissue inflammation and damage during an infection. Due to limited redundancy in PG-modifying machineries and genetic tractability, N. gonorrhoeae serves as a great model organism for the study of biological processes related to PG. This review summarizes the generation, modification, and release of inflammatory PG molecules by N. gonorrhoeae and related species and discusses these findings in the context of understanding bacterial physiology and pathogenesis. PMID- 28674066 TI - Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance. AB - One of the first identified and best-studied toxin-antitoxin (TA) systems in Escherichia coli is the F-plasmid-based CcdAB system. This system is involved in plasmid maintenance through postsegregational killing. More recently, ccdAB homologs have been found on the chromosome, including in pathogenic strains of E. coli and other bacteria. However, the functional role of chromosomal ccdAB genes, if any, has remained unclear. We show that both the native ccd operon of the E. coli O157 strain (ccdO157) and the ccd operon from the F plasmid (ccdF), when inserted on the E. coli chromosome, lead to protection from cell death under multiple antibiotic stress conditions through formation of persisters, with the O157 operon showing higher protection. While the plasmid-encoded CcdB toxin is a potent gyrase inhibitor and leads to bacterial cell death even under fully repressed conditions, the chromosomally encoded toxin leads to growth inhibition, except at high expression levels, where some cell death is seen. This was further confirmed by transiently activating the chromosomal ccd operon through overexpression of an active-site inactive mutant of F-plasmid-encoded CcdB. Both the ccdF and ccdO157 operons may share common mechanisms for activation under stress conditions, eventually leading to multidrug-tolerant persister cells. This study clearly demonstrates an important role for chromosomal ccd systems in bacterial persistence.IMPORTANCE A large number of free-living and pathogenic bacteria are known to harbor multiple toxin-antitoxin systems, on plasmids as well as on chromosomes. The F-plasmid CcdAB system has been extensively studied and is known to be involved in plasmid maintenance. However, little is known about the function of its chromosomal counterpart, found in several pathogenic E. coli strains. We show that the native chromosomal ccd operon of the E. coli O157 strain is involved in drug tolerance and confers protection from cell death under multiple antibiotic stress conditions. This has implications for generation of potential therapeutics that target these TA systems and has clinical significance because the presence of persisters in an antibiotic-treated population can lead to resuscitation of chronic infection and may contribute to failure of antibiotic treatment. PMID- 28674067 TI - Genome Scale Mutational Analysis of Geobacter sulfurreducens Reveals Distinct Molecular Mechanisms for Respiration and Sensing of Poised Electrodes versus Fe(III) Oxides. AB - Geobacter sulfurreducens generates electrical current by coupling intracellular oxidation of organic acids to the reduction of proteins on the cell surface that are able to interface with electrodes. This ability is attributed to the bacterium's capacity to respire other extracellular electron acceptors that require contact, such as insoluble metal oxides. To directly investigate the genetic basis of electrode-based respiration, we constructed Geobacter sulfurreducens transposon-insertion sequencing (Tn-Seq) libraries for growth, with soluble fumarate or an electrode as the electron acceptor. Libraries with >33,000 unique insertions and an average of 9 insertions/kb allowed an assessment of each gene's fitness in a single experiment. Mutations in 1,214 different genomic features impaired growth with fumarate, and the significance of 270 genes unresolved by annotation due to the presence of one or more functional homologs was determined. Tn-Seq analysis of -0.1 V versus standard hydrogen electrode (SHE) electrode-grown cells identified mutations in a subset of genes encoding cytochromes, processing systems for proline-rich proteins, sensory networks, extracellular structures, polysaccharides, and metabolic enzymes that caused at least a 50% reduction in apparent growth rate. Scarless deletion mutants of select genes identified via Tn-Seq revealed a new putative porin-cytochrome conduit complex (extABCD) crucial for growth with electrodes, which was not required for Fe(III) oxide reduction. In addition, four mutants lacking components of a putative methyl-accepting chemotaxis-cyclic dinucleotide sensing network (esnABCD) were defective in electrode colonization but grew normally with Fe(III) oxides. These results suggest that G. sulfurreducens possesses distinct mechanisms for recognition, colonization, and reduction of electrodes compared to Fe(III) oxides.IMPORTANCE Since metal oxide electron acceptors are insoluble, one hypothesis is that cells sense and reduce metals using the same molecular mechanisms used to form biofilms on electrodes and produce electricity. However, by simultaneously comparing thousands of Geobacter sulfurreducens transposon mutants undergoing electrode-dependent respiration, we discovered new cytochromes and chemosensory proteins supporting growth with electrodes that are not required for metal respiration. This supports an emerging model where G. sulfurreducens recognizes surfaces and forms conductive biofilms using mechanisms distinct from those used for growth with metal oxides. These findings provide a possible explanation for studies that correlate electricity generation with syntrophic interspecies electron transfer by Geobacter and reveal many previously unrecognized targets for engineering this useful capability in other organisms. PMID- 28674068 TI - Structural and Functional Analysis of the Escherichia coli Acid-Sensing Histidine Kinase EvgS. AB - The EvgS/EvgA two-component system of Escherichia coli is activated in response to low pH and alkali metals and regulates many genes, including those for the glutamate-dependent acid resistance system and a number of efflux pumps. EvgS, the sensor kinase, is one of five unconventional histidine kinases (HKs) in E. coli and has a large periplasmic domain and a cytoplasmic PAS domain in addition to phospho-acceptor, HK and dimerization, internal receiver, and phosphotransfer domains. Mutations that constitutively activate the protein at pH 7 map to the PAS domain. Here, we built a homology model of the periplasmic region of EvgS, based on the structure of the equivalent region of the BvgS homologue, to guide mutagenesis of potential key residues in this region. We show that histidine 226 is required for induction and that it is structurally colocated with a proline residue (P522) at the top of the predicted transmembrane helix that is expected to play a key role in passing information to the cytoplasmic domains. We also show that the constitutive mutations in the PAS domain can be further activated by low external pH. Expression of the cytoplasmic part of the protein alone also gives constitutive activation, which is lost if the constitutive PAS mutations are present. These findings are consistent with a model in which EvgS senses both external and internal pH and is activated by a shift from a tight inactive to a weak active dimer, and we present an analysis of the purified cytoplasmic portion of EvgS that supports this.IMPORTANCE One of the ways bacteria sense their environment is through two-component systems, which have one membrane-bound protein to do the sensing and another inside the cell to turn genes on or off in response to what the membrane-bound protein has detected. The membrane-bound protein must thus be able to detect the stress and signal this detection event to the protein inside the cell. To understand this process, we studied a protein that helps E. coli to survive exposure to low pH, which it must do before taking up residence in the gastrointestinal tract. We describe a predicted structure for the main sensing part of the protein and identify some key residues within it that are involved in the sensing and signaling processes. We propose a mechanism for how the protein may become activated and present some evidence to support our proposal. PMID- 28674069 TI - Cyclic Di-GMP and VpsR Induce the Expression of Type II Secretion in Vibrio cholerae. AB - Vibrio cholerae is a human pathogen that alternates between growth in environmental reservoirs and infection of human hosts, causing severe diarrhea. The second messenger cyclic di-GMP (c-di-GMP) mediates this transition by controlling a wide range of functions, such as biofilms, virulence, and motility. Here, we report that c-di-GMP induces expression of the extracellular protein secretion (eps) gene cluster, which encodes the type II secretion system (T2SS) in V. cholerae Analysis of the eps genes confirmed the presence of two promoters located upstream of epsC, the first gene in the operon, one of which is induced by c-di-GMP. This induction is directly mediated by the c-di-GMP-binding transcriptional activator VpsR. Increased expression of the eps operon did not impact secretion of extracellular toxin or biofilm formation but did increase expression of the pseudopilin protein EpsG on the cell surface.IMPORTANCE Type II secretion systems (T2SSs) are the primary molecular machines by which Gram negative bacteria secrete proteins and protein complexes that are folded and assembled in the periplasm. The substrates of T2SSs include extracellular factors, such as proteases and toxins. Here, we show that the widely conserved second messenger cyclic di-GMP (c-di-GMP) upregulates expression of the eps genes encoding the T2SS in the pathogen V. cholerae via the c-di-GMP-dependent transcription factor VpsR. PMID- 28674070 TI - Bacillus subtilis Intramembrane Protease RasP Activity in Escherichia coli and In Vitro. AB - RasP is a predicted intramembrane metalloprotease of Bacillus subtilis that has been proposed to cleave the stress response anti-sigma factors RsiW and RsiV, the cell division protein FtsL, and remnant signal peptides within their transmembrane segments. To provide evidence for direct effects of RasP on putative substrates, we developed a heterologous coexpression system. Since expression of catalytically inactive RasP E21A inhibited expression of other membrane proteins in Escherichia coli, we added extra transmembrane segments to RasP E21A, which allowed accumulation of most other membrane proteins. A corresponding active version of RasP appeared to promiscuously cleave coexpressed membrane proteins, except those with a large periplasmic domain. However, stable cleavage products were not observed, even in clpP mutant E. coli Fusions of transmembrane segment-containing parts of FtsL and RsiW to E. coli maltose binding protein (MBP) also resulted in proteins that appeared to be RasP substrates upon coexpression in E. coli, including FtsL with a full-length C terminal domain (suggesting that prior cleavage by a site 1 protease is unnecessary) and RsiW designed to mimic the PrsW site 1 cleavage product (suggesting that further trimming by extracytoplasmic protease is unnecessary). Purified RasP cleaved His6-MBP-RsiW(73-118) in vitro within the RsiW transmembrane segment based on mass spectrometry analysis, demonstrating that RasP is an intramembrane protease. Surprisingly, purified RasP failed to cleave His6-MBP-FtsL(23-117). We propose that the lack of alpha-helix-breaking residues in the FtsL transmembrane segment creates a requirement for the membrane environment and/or an additional protein(s) in order for RasP to cleave FtsL.IMPORTANCE Intramembrane proteases govern important signaling pathways in nearly all organisms. In bacteria, they function in stress responses, cell division, pathogenesis, and other processes. Their membrane-associated substrates are typically inferred from genetic studies in the native bacterium. Evidence for direct effects has come sometimes from coexpression of the enzyme and potential substrate in a heterologous host and rarely from biochemical reconstitution of cleavage in vitro We applied these two approaches to the B. subtilis enzyme RasP and its proposed substrates RsiW and FtsL. We discovered potential pitfalls and solutions in heterologous coexpression experiments in E. coli, providing evidence that both substrates are cleaved by RasP in vivo but, surprisingly, that only RsiW was cleaved in vitro, suggesting that FtsL has an additional requirement. PMID- 28674071 TI - Major Tom to Ground Control: How Lipoproteins Communicate Extracytoplasmic Stress to the Decision Center of the Cell. AB - The envelope of bacteria is a complex multilayered shield that ensures multiple essential functions, including protecting the cell from external assaults. Hence, bacterial cells have evolved intricate mechanisms called envelope stress response systems (ESRS) to monitor all kinds of perturbations affecting the integrity of their envelope and to mount an appropriate response to contain or repair the damage. In the model bacterium Escherichia coli, several ESRS are built around a two-component system, in which envelope stress triggers a phosphotransfer between a sensor protein in the inner membrane of the envelope and a response regulator in the cytoplasm. In this review, we focus on two major ESRS in E. coli, the Rcs and Cpx pathways, in which additional proteins not directly involved in the phosphotransfer modulate signal transduction. Both the Rcs and Cpx systems can be turned on by a lipoprotein anchored in the outer membrane, RcsF and NlpE, respectively, providing a molecular connection between the most exterior layer of the envelope and the ground control center in the cytoplasm. Here, we review how these two lipoproteins, which share a striking set of features while being distinct in several aspects, act as sentinels at the front line of the bacterium by sensing and transducing stress to the downstream components of the Rcs and Cpx systems. PMID- 28674073 TI - Effects of NSAIDs on myocardial infarction may be overestimated. PMID- 28674072 TI - Counterbalancing Regulation in Response Memory of a Positively Autoregulated Two Component System. AB - Fluctuations in nutrient availability often result in recurrent exposures to the same stimulus conditions. The ability to memorize the past event and use the "memory" to make adjustments to current behaviors can lead to a more efficient adaptation to the recurring stimulus. A short-term phenotypic memory can be conferred via carryover of the response proteins to facilitate the recurrent response, but the additional accumulation of response proteins can lead to a deviation from response homeostasis. We used the Escherichia coli PhoB/PhoR two component system (TCS) as a model system to study how cells cope with the recurrence of environmental phosphate (Pi) starvation conditions. We discovered that "memory" of prior Pi starvation can exert distinct effects through two regulatory pathways, the TCS signaling pathway and the stress response pathway. Although carryover of TCS proteins can lead to higher initial levels of transcription factor PhoB and a faster initial response in prestarved cells than in cells not starved, the response enhancement can be overcome by an earlier and greater repression of promoter activity in prestarved cells due to the memory of the stress response. The repression counterbalances the carryover of the response proteins, leading to a homeostatic response whether or not cells are prestimulated. A computational model based on sigma factor competition was developed to understand the memory of stress response and to predict the homeostasis of other PhoB-regulated response proteins. Our insight into the history-dependent PhoBR response may provide a general understanding of how TCSs respond to recurring stimuli and adapt to fluctuating environmental conditions.IMPORTANCE Bacterial cells in their natural environments experience scenarios that are far more complex than are typically replicated in laboratory experiments. The architectures of signaling systems and the integration of multiple adaptive pathways have evolved to deal with such complexity. In this study, we examined the molecular "memory" that is generated by previous exposure to stimulus. Under our experimental conditions, activating effects of autoregulated two-component signaling and inhibitory effects of the stress response counterbalanced the transcriptional output to approach response homeostasis whether or not cells had been preexposed to stimulus. Modeling allows prediction of response behavior in different scenarios and demonstrates both the robustness of the system output and its sensitivity to historical parameters such as timing and levels of exposure to stimuli. PMID- 28674075 TI - Clathrin-mediated post-fusion membrane retrieval influences the exocytic mode of endothelial Weibel-Palade bodies. AB - Weibel-Palade bodies (WPBs), the storage organelles of endothelial cells, are essential to normal haemostatic and inflammatory responses. Their major constituent protein is von Willebrand factor (VWF) which, following stimulation with secretagogues, is released into the blood vessel lumen as large platelet catching strings. This exocytosis changes the protein composition of the cell surface and also results in a net increase in the amount of plasma membrane. Compensatory endocytosis is thought to limit changes in cell size and retrieve fusion machinery and other misplaced integral membrane proteins following exocytosis; however, little is known about the extent, timing, mechanism and precise function of compensatory endocytosis in endothelial cells. Using biochemical assays, live-cell imaging and correlative spinning-disk microscopy and transmission electron microscopy assays we provide the first in-depth high resolution characterisation of this process. We provide a model of compensatory endocytosis based on rapid clathrin- and dynamin-mediated retrieval. Inhibition of this process results in a change of exocytic mode: WPBs then fuse with previously fused WPBs rather than the plasma membrane, leading, in turn, to the formation of structurally impaired tangled VWF strings.This article has an associated First Person interview with the first authors of the paper. PMID- 28674077 TI - Physicians are more likely than non-physicians to use brand-name drugs to treat their chronic conditions. AB - BACKGROUND: Little is known about the treatments physicians choose for themselves compared with how they treat their patients. We determine if physicians prescribe different treatments to patients than to themselves. METHODS: Population-based cohort study from 2004 to 2012 examining prescription claims of all Danish primary care physicians (PCP; n=3088) and all other Danish adults (n=2 334 590) who received a first-time prescription from a PCP for a statin (n=455 586), calcium channel blocker (CCB, n=330 369), serotonin-norepinephrine/selective serotonin reuptake inhibitors (SN/SSRIs, n=423 740), proton pump inhibitor (PPI, n=671 965) or antihistamine (n=456 018). The main outcome is the brand-name or generic status of the first prescribed drug. A logistic regression model compared outcomes, unadjusted and adjusted for sociodemographic characteristics and coverage information. RESULTS: For drugs that require chronic treatment (statins, CCBs, SN/SSRIs), the relative risk (RR) for PCPs (PCP patients) being treated with a brand drug was 3.86 (95% CI 3.33 to 4.47; p<0.001). This difference remained significant when adjusting for covariates (adjusted RR=2.51 (95% CI 2.16 to 2.92; p<0.001)). For non-chronic drugs (PPIs, antihistamines), the RR for PCP patients was (RR=1.13 (95% CI 1.08 to 1.20; p<0.001)), and this difference was explained by higher income. Physicians are not more likely than non-physicians, however, to be treated with brand-name versions of drugs that are available as generics. CONCLUSION: Physicians are more likely than non-physicians to be treated with brand-name drugs without generic equivalents in three chronic treatment drug classes but not in two acute treatment drug classes. Guidelines can lead to lower brand-name drug use than physicians prefer for themselves. PMID- 28674076 TI - Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study. AB - OBJECTIVE: We assessed the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the SEARCH for Diabetes in Youth (SEARCH) study. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was used to assess DPN in 1,734 youth with T1D (mean +/- SD age 18 +/- 4 years, T1D duration 7.2 +/- 1.2 years, and HbA1c 9.1 +/- 1.9%) and 258 youth with T2D (age 22 +/- 3.5 years, T2D duration 7.9 +/- 2 years, and HbA1c 9.4 +/- 2.3%) who were enrolled in the SEARCH study and had >=5 years of diabetes duration. DPN was defined as an MNSI exam score of >2. Glycemic control over time was estimated as area under the curve for HbA1c. RESULTS: The prevalence of DPN was 7% in youth with T1D and 22% in youth with T2D. Risk factors for DPN in youth with T1D were older age, longer diabetes duration, smoking, increased diastolic blood pressure, obesity, increased LDL cholesterol and triglycerides, and lower HDL cholesterol (HDL-c). In youth with T2D, risk factors were older age, male sex, longer diabetes duration, smoking, and lower HDL-c. Glycemic control over time was worse among those with DPN compared with those without for youth with T1D (odds ratio 1.53 [95% CI 1.24; 1.88]) but not for youth with T2D (1.05 [0.7; 1.56]). CONCLUSIONS: The high rates of DPN among youth with diabetes are a cause of concern and suggest a need for early screening and better risk factor management. Interventions in youth that address poor glycemic control and dyslipidemia may prevent or delay debilitating neuropathic complications. PMID- 28674078 TI - TP53INP1 Downregulation Activates a p73-Dependent DUSP10/ERK Signaling Pathway to Promote Metastasis of Hepatocellular Carcinoma. AB - Identifying critical factors involved in the metastatic progression of hepatocellular carcinoma (HCC) may offer important therapeutic opportunities. Here, we report that the proapoptotic stress response factor TP53INP1 is often selectively downregulated in advanced stage IV and metastatic human HCC tumors. Mechanistic investigations revealed that TP53INP1 downregulation in early-stage HCC cells promoted metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway. The DUSP10 promoter included putative binding sites for p73 directly implicated in modulation by TP53INP1. Overall, our findings show how TP53INP1 plays a critical role in limiting the progression of early-stage HCC, with implications for developing new therapeutic strategies to attack metastatic HCC. Cancer Res; 77(17); 4602-12. (c)2017 AACR. PMID- 28674079 TI - Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis. AB - Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24-) still retain aggressive phenotypes in vitro and in vivo Here, we resolve this apparent paradox with the discovery of biologically active, nuclear CD24 (nucCD24) and finding that its levels are unchanged in surCD24- cells. Using the complementary techniques of biochemical cellular fractionation and immunofluorescence, we demonstrate a signal for CD24 in the nucleus in cells from various histologic types of cancer. Nuclear-specific expression of CD24 (NLS-CD24) increased anchorage-independent growth in vitro and tumor formation in vivo Immunohistochemistry of patient tumor samples revealed the presence of nucCD24, whose signal intensity correlated positively with the presence of metastatic disease. Analysis of gene expression between cells expressing CD24 and NLS-CD24 revealed a unique nucCD24 transcriptional signature. The median score derived from this signature was able to stratify overall survival in four patient datasets from bladder cancer and five patient datasets from colorectal cancer. Patients with high scores (more nucCD24-like) had reduced survival. These findings define a novel and functionally important intracellular location of CD24; they explain why surCD24- cells can remain aggressive, and they highlight the need to consider nucCD24 in both fundamental research and therapeutic development. Cancer Res; 77(18); 4858-67. (c)2017 AACR. PMID- 28674080 TI - Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. AB - Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR-21 expression influences foam cell formation, sensitivity to ER-stress-induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post-translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR-21 in atherogenesis. PMID- 28674081 TI - MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF-1 and SRSF-5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of LmnaG609G/G609G mice locally reduces SRSF-1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS. PMID- 28674082 TI - Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity. AB - Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs-can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T cell checkpoint-modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease. Intratumoral administration of the STING agonist cyclic di-GMP (CDG) or Flt3 Ligand (Flt3L) augmented the therapeutic effect of systemic triple checkpoint modulation and promoted the cure of 75% of mice with bilateral TRAMP-C2; however, when all agents were administered locally, only CDG mobilized abscopal immunity. Combination efficacy correlated with globally enhanced ratios of CD8+ T cells to regulatory T cells (Treg), macrophages, and myeloid-derived suppressor cells, and downregulation of the M2 marker CD206 on tumor-associated macrophages. Flt3L improved CD8+ T-cell and dendritic cell infiltration of tumors, but was diminished in efficacy by concomitant Treg expansion. Although intratumoral CDG/checkpoint therapy invokes substantial ulceration at the injection site, reduced CDG dosing can preserve tissue integrity without sacrificing therapeutic benefit. For high-order combinations of T-cell checkpoint antibodies and local myeloid agonists, systemic antibody administration provides the greatest efficacy; however, local administration of CDG and antibody provides substantial systemic benefit while minimizing the potential for immune-related adverse events. Cancer Immunol Res; 5(8); 676-84. (c)2017 AACR. PMID- 28674083 TI - Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anticancer Immunity. AB - Immune checkpoint blockade using antibodies to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) benefits a limited number of cancer patients. SS1P and LMB-100 are immunotoxins that target mesothelin. We observed delayed responses to SS1P in patients with mesothelioma suggesting that antitumor immunity was induced. Our goal was to stimulate antitumor immunity by combining SS1P or LMB-100 with anti CTLA-4. We constructed a BALB/c breast cancer cell line expressing human mesothelin (66C14-M), which was implanted in one or two locations. SS1P or LMB 100 was injected directly into established tumors and anti-CTLA-4 administered i.p. In mice with two tumors, one tumor was injected with immunotoxin and the other was not. The complete regression rate was 86% for the injected tumors and 53% for the uninjetced tumors. No complete regressions occurred when drugs were given separately. In regressing tumors, dying and dead tumor cells were intermingled with PMNs and surrounded by a collar of admixed eosinophils and mononuclear cells. Tumor regression was associated with increased numbers of tumor-infiltrating CD8+ cells and blocked by administration of antibodies to CD8. Surviving mice were protected from tumor rechallenge by 66C14 cells not expressing mesothelin, indicating the development of antitumor immunity. The antitumor effect was abolished when a mutant noncytotoxic variant was used instead of LMB-100, showing that the antitumor response is not mediated by recognition of a foreign bacterial protein. Our findings support developing a therapy composed of immunotoxins and checkpoint inhibitors for patients. Cancer Immunol Res; 5(8); 685-94. (c)2017 AACR. PMID- 28674086 TI - Mapping Myocardial Salvage Index by Extracellular Volume Fraction: Are We There Yet? PMID- 28674084 TI - Utility of 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines in HIV-Infected Adults With Carotid Atherosclerosis. AB - BACKGROUND: Although HIV is associated with increased atherosclerotic cardiovascular disease (CVD) risk, it is unknown whether guidelines can identify HIV-infected adults who may benefit from statins. We compared the 2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III recommendations in HIV-infected adults and evaluated associations with carotid artery intima-media thickness and plaque. METHODS AND RESULTS: Carotid artery intima-media thickness was measured at baseline and 3 years later in 352 HIV-infected adults without clinical atherosclerotic CVD and not on statins. Plaque was defined as IMT >1.5 mm in any segment. At baseline, the median age was 43 (interquartile range, 39-49), 85% were men, 74% were on antiretroviral medication, and 50% had plaque. The American College of Cardiology/American Heart Association guidelines were more likely to recommend statins compared with the Adult Treatment Panel III guidelines, both overall (26% versus 14%; P<0.001), in those with plaque (32% versus 17%; P=0.0002), and in those without plaque (16% versus 7%; P=0.025). In multivariable analysis, older age, higher low-density lipoprotein cholesterol, pack per year of smoking, and history of opportunistic infection were associated with baseline plaque. Baseline IMT (hazard ratio, 1.18 per 10% increment; 95% confidence interval, 1.05-1.33; P=0.005) and plaque (hazard ratio, 2.06; 95% confidence interval, 1.02-4.08; P=0.037) were each associated with all-cause mortality, independent of traditional CVD risk factors. CONCLUSIONS: Although the American College of Cardiology/American Heart Association guidelines recommended statins to a greater number of HIV-infected adults compared with the Adult Treatment Panel III guidelines, both failed to recommend therapy in the majority of HIV-affected adults with carotid plaque. Baseline carotid atherosclerosis but not atherosclerotic CVD risk scores was an independent predictor of mortality. HIV-specific guidelines that include detection of subclinical atherosclerosis may help to identify HIV-infected adults who are at increased atherosclerotic CVD risk and may be considered for statins. PMID- 28674085 TI - Acute Infarct Extracellular Volume Mapping to Quantify Myocardial Area at Risk and Chronic Infarct Size on Cardiovascular Magnetic Resonance Imaging. AB - BACKGROUND: Late gadolinium enhancement (LGE) imaging overestimates acute infarct size. The main aim of this study was to investigate whether acute extracellular volume (ECV) maps can reliably quantify myocardial area at risk (AAR) and final infarct size (IS). METHODS AND RESULTS: Fifty patients underwent cardiovascular magnetic resonance imaging acutely (24-72 hours) and at convalescence (3 months). The cardiovascular magnetic resonance protocol included cines, T2-weighted imaging, native T1 maps, 15-minute post-contrast T1 maps, and LGE. Optimal AAR and IS ECV thresholds were derived in a validation group of 10 cases (160 segments). Eight hundred segments (16 per patient) were analyzed to quantify AAR/IS by ECV maps (ECV thresholds for AAR is 33% and IS is 46%), T2-weighted imaging, T1 maps, and acute LGE. Follow-up LGE imaging was used as the reference standard for final IS and viability assessment. The AAR derived from ECV maps (threshold of >33) demonstrated good agreement with T2-weighted imaging-derived AAR (bias, 0.18; 95% confidence interval [CI], -1.6 to 1.3) and AAR derived from native T1 maps (bias=1; 95% CI, -0.37 to 2.4). ECV demonstrated the best linear correlation to final IS at a threshold of >46% (R=0.96; 95% CI, 0.92-0.98; P<0.0001). ECV maps demonstrated better agreement with final IS than acute IS on LGE (ECV maps: bias, 1.9; 95% CI, 0.4-3.4 versus LGE imaging: bias, 10; 95% CI, 7.7-12.4). On multiple variable regression analysis, the number of nonviable segments was independently associated with IS by ECV maps (beta=0.86; P<0.0001). CONCLUSIONS: ECV maps can reliably quantify AAR and final IS in reperfused acute myocardial infarction. Acute ECV maps were superior to acute LGE in terms of agreement with final IS. IS quantified by ECV maps are independently associated with viability at follow-up. PMID- 28674087 TI - Cardiovascular Disease Imaging in HIV: Novel Phenotypes and New Targets for Risk Reduction. PMID- 28674088 TI - Doctors in India meet to condemn practice of paying referral kickbacks to GPs. PMID- 28674089 TI - Grounding Cardio-Oncology in Basic and Clinical Science. PMID- 28674090 TI - Obese Heart Failure With Preserved Ejection Fraction Phenotype: From Pariah to Central Player. PMID- 28674091 TI - Nitroglycerine and Angina: Evolving Clinical Coronary Physiology Beyond Fractional Flow Reserve and Coronary Flow Reserve. PMID- 28674092 TI - Preeclampsia and Fetal Congenital Heart Defects: Spurious Association or Maternal Confounding? PMID- 28674093 TI - Long Noncoding RNAs and Angiogenesis: Regulatory Information for Chromatin Remodeling. PMID- 28674095 TI - Breaking Meeting News: ACC.17. PMID- 28674097 TI - Letter by Cerit Regarding Article, "Recurrent Hospitalization Among Patients With Atrial Fibrillation Undergoing Intracoronary Stenting Treated With 2 Treatment Strategies of Rivaroxaban or a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy". PMID- 28674096 TI - Idiopathic Ventricular Fibrillation in a 29-Year-Old Man. PMID- 28674098 TI - Response by Gibson and Fox to Letter Regarding Article, "Recurrent Hospitalization Among Patients With Atrial Fibrillation Undergoing Intracoronary Stenting Treated With 2 Treatment Strategies of Rivaroxaban or a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy". PMID- 28674094 TI - Is Cardioprotection Dead? AB - For >4 decades, the holy grail in the treatment of acute myocardial infarction has been the mitigation of lethal injury. Despite promising initial results and decades of investigation by the cardiology research community, the only treatment with proven efficacy is early reperfusion of the occluded coronary artery. The remarkable record of failure has led us and others to wonder if cardioprotection is dead. The path to translation, like the ascent to Everest, is certainly littered with corpses. We do, however, highlight a therapeutic principle that provides a glimmer of hope: cellular postconditioning. Administration of cardiosphere-derived cells after reperfusion limits infarct size measured acutely, while providing long-term structural and functional benefits. The recognition that cell therapy may be cardioprotective, and not just regenerative, merits further exploration before we abandon the pursuit entirely. PMID- 28674099 TI - Letter by Koh Regarding Article, "Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism". PMID- 28674101 TI - Circulation Editors and Editorial Board. PMID- 28674100 TI - Response by Watts et al to Letter Regarding Article, "Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism". PMID- 28674102 TI - Benzodiazepines and pneumonia risk in people with Alzheimer's disease. PMID- 28674103 TI - Single-inhaler triple therapy for prevention of COPD exacerbations. PMID- 28674104 TI - Repeat warning on ? valproate in pregnancy as message fails to raise awareness. PMID- 28674105 TI - Antibiotic use in pregnancy and spontaneous abortion. PMID- 28674106 TI - CRISPR-Cas adaptive immunity and the three Rs. AB - In this summary, we focus on fundamental biology of Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-Cas (CRISPR-associated proteins) adaptive immunity in bacteria. Emphasis is placed on emerging information about functional interplay between Cas proteins and proteins that remodel DNA during homologous recombination (HR), DNA replication or DNA repair. We highlight how replication forks may act as 'trigger points' for CRISPR adaptation events, and the potential for cascade-interference complexes to act as precise roadblocks in DNA replication by an invader MGE (mobile genetic element), without the need for DNA double-strand breaks. PMID- 28674107 TI - Long noncoding RNA DANCR regulates miR-1305-Smad 4 axis to promote chondrogenic differentiation of human synovium-derived mesenchymal stem cells. AB - miRNAs have been reported to regulate cellular differentiation by modulating multiple signaling pathways. Long noncoding RNA (lnc RNA) DANCR was previously identified to be critical for the chondrogenesis of human synovium-derived mesenchymal stem cells (SMSC), however, the underlying molecular mechanism requires better understanding. Here, miRNA expression profiling in DANCR overexpressed in SMSCs identified significant down-regulation of miR-1305, which serves as a downstream target of DANCR. Notably, miR-1305 overexpression reversed DANCR-induced cell proliferation and chondrogenic differentiation of SMSCs, which suggested that miR-1305 antagonized the function of DANCR. Mechanistically, highly expressed miR-1305 resulted in the decreased expression of the TGF-beta pathway member Smad4, and inhibition of miR-1305 enhanced the expression level of Smad4. Depletion of Smad4 suppressed the promotion of DANCR in cell proliferation and chondrogenesis of SMSCs. Collectively, our results characterized miR-1305 Smad4 axis as a major downstream functional mechanism of lncRNA DANCR in promoting the chondrogenesis in SMSCs. PMID- 28674109 TI - Left Ventricular Assist Device Malfunctions: It Is More Than Just the Pump. AB - BACKGROUND: Reports of left ventricular assist device (LVAD) malfunction have focused on pump thrombosis. However, the device consists of the pump, driveline, and peripherals, all of which are potentially subject to failure. METHODS: Prospectively collected data were reviewed for all LVAD device malfunctions (DMs) occurring in rotary LVADs implanted at a single center between April 2004 and May 2016. Durable LVADs included 108 Heartmate II (HM II) and 105 HeartWare VAD (HVAD). DM data were categorized according to device type and into categories related to the component that failed: (1) controller, (2) peripheral components, and (3) implantable blood pump or its integral electric driveline. Pump-related events were analyzed as pump-specific (suspected or confirmed thrombosis) or nonpump-specific (driveline failure). DM rates were reported as events per 1000 patient-days, and Cox proportional hazard models were used for time-to-event analyses. Cumulative rates of malfunction were examined for the main components of each type of LVAD. RESULTS: Types of DM included controller failure (30%), battery failure (19%), or patient cable failure (14%), whereas only 13% were because of pump failure. DMs were more common in the HM II device (3.73 per 1000 patient-days versus 3.06 per 1000 patient-days for the HVAD, P<0.01). A higher rate of pump-specific malfunctions was discovered in those implanted with an HM II versus an HVAD (0.55 versus 0.39, respectively; P<0.01) and peripheral malfunctions (2.32 versus 1.78 for the HM II and HVAD, respectively; P<0.01); no difference occurred in the incidence of controller DM between the 2 LVADs. Patients with HVAD were 90% free of a pump-specific malfunction at 3 years compared with 56% for the HM II (log-rank P<0.003). Only 74% of the patients with HM II were free of pump thrombosis at 3 years compared with 90% of the patients with HVAD. Freedom from failure of the integrated driveline was 79% at 3 years for the HM II but 100% for the HVAD (log-rank P<0.02). CONCLUSIONS: Device malfunction is much broader than pump failure alone and occurs for different components at different rates based on the type of LVAD. PMID- 28674108 TI - Reciprocal regulation of signaling and endocytosis: Implications for the evolving cancer cell. AB - Cell surface receptor uptake via clathrin-mediated endocytosis (CME) and subsequent intracellular sorting for degradation or recycling regulates the strength and specificity of downstream signaling. Signaling, in turn, modulates early endocytic trafficking. This reciprocal regulation of signaling and endocytosis provides opportunities for the establishment of feedback loops to enhance or suppress surface-derived signals. Recent studies suggest that dynamin 1, a presumed neuron-specific isoform of the large, membrane fission GTPase, can be activated in nonneuronal cells downstream of cancer-relevant signaling pathways and thereby function as a nexus between signaling and early endocytic trafficking. I speculate that sustained up-regulation and/or acute activation of dynamin-1 in cancer cells contributes to a program of "adaptive" CME that alters signaling to enhance cancer cell survival, migration, and proliferation. PMID- 28674111 TI - Probiotics in the Child Care Center: Context Matters. PMID- 28674110 TI - A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective. AB - BACKGROUND: Dickkopf-related protein 3 (DKK3) is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. METHODS: We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed with apolipoprotein E-/- mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. RESULTS: In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and 5-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced reendothelialization, and neointima formation in both DKK3-/-/apolipoprotein E-/- and DKK3+/+/apolipoprotein E-/- mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed reendothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration activated ROR2 and DVL1, activated Rac1 GTPases, and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of the ROR2 receptor using specific siRNA or transfection of a dominant-negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. CONCLUSIONS: This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis. PMID- 28674112 TI - Allergy Testing in Children With Low-Risk Penicillin Allergy Symptoms. AB - BACKGROUND: Penicillin allergy is commonly reported in the pediatric emergency department (ED). True penicillin allergy is rare, yet the diagnosis results from the denial of first-line antibiotics. We hypothesize that all children presenting to the pediatric ED with symptoms deemed to be low-risk for immunoglobulin E mediated hypersensitivity will return negative results for true penicillin allergy. METHODS: Parents of children aged 4 to 18 years old presenting to the pediatric ED with a history of parent-reported penicillin allergy completed an allergy questionnaire. A prespecified 100 children categorized as low-risk on the basis of reported symptoms completed penicillin allergy testing by using a standard 3-tier testing process. The percent of children with negative allergy testing results was calculated with a 95% confidence interval. RESULTS: Five hundred ninety-seven parents completed the questionnaire describing their child's reported allergy symptoms. Three hundred two (51%) children had low-risk symptoms and were eligible for testing. Of those, 100 children were tested for penicillin allergy. The median (interquartile range) age at testing was 9 years (5-12). The median (interquartile range) age at allergy diagnosis was 1 year (9 months-3 years). Rash (97 [97%]) and itching (63 [63%]) were the most commonly reported allergy symptoms. Overall, 100 children (100%; 95% confidence interval 96.4% 100%) were found to have negative results for penicillin allergy and had their labeled penicillin allergy removed from their medical record. CONCLUSIONS: All children categorized as low-risk by our penicillin allergy questionnaire were found to have negative results for true penicillin allergy. The utilization of this questionnaire in the pediatric ED may facilitate increased use of first-line penicillin antibiotics. PMID- 28674113 TI - Probiotics and Child Care Absence Due to Infections: A Randomized Controlled Trial. AB - OBJECTIVES: The risk of infections is higher in children attending child care compared with children cared for at home. This study examined the effect of a combination of probiotics on absence from child care because of respiratory and gastrointestinal infections in healthy infants aged 8 to 14 months at the time of enrollment in child care. METHODS: The ProbiComp study was a randomized, double blind, placebo-controlled study. A total of 290 infants were randomly allocated to receive a placebo or a combination of Bifidobacterium animalis subsp lactis and Lactobacillus rhamnosus in a dose of 109 colony-forming units of each daily for a 6-month intervention period. Absence from child care, occurrence of infant symptoms of illness, and doctor visits were registered by the parents using daily and weekly Web-based questionnaires. RESULTS: Median absence from child care was 11 days (interquartile range: 6-16). Intention-to-treat analysis showed no difference between the probiotics and placebo groups (P = .19). Additionally, there was no difference in any of the secondary outcomes between groups; the number of children with doctor-diagnosed upper or lower respiratory tract infections, the number of doctor visits, antibiotic treatments, occurrence and duration of diarrhea, and days with common cold symptoms, fever, vomiting, or caregivers' absence from work. CONCLUSIONS: A daily administration of a combination of B animalis subsp lactis and L rhamnosus for 6 months did not reduce the number of days absent from child care in healthy infants at the time of enrollment in child care. PMID- 28674115 TI - FDG PET and FES PET Predict PFS on Endocrine Therapy-Letter. PMID- 28674116 TI - FDG PET and FES PET Predict PFS on Endocrine Therapy-Response. PMID- 28674117 TI - Genetic Counselor Recommendations for Cancer Predisposition Evaluation and Surveillance in the Pediatric Oncology Patient. AB - As the understanding of the genetic etiology of childhood cancers increases, the need for the involvement of experts familiar with the provision of genetic counseling for this population is paramount. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in pediatric cancer predisposition met to establish surveillance guidelines for children with cancer predisposition. Identifying for whom, when, why, and how these cancer predisposition surveillance guidelines should be implemented is essential. Genetic counselors invited to this workshop provide a genetic counseling framework for oncology professionals in this article. Points of entry and recommendations regarding the provision and timing of the initial and subsequent genetic counseling sessions are addressed. The genetic counseling and testing processes are reviewed, and the psychologic impact related to surveillance is explored. Pediatric cancer genetics will continue to grow and evolve as a field, and genetic counseling services will be vital to ensure appropriate identification and management of at-risk children moving forward. Clin Cancer Res; 23(13); e91-e97. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28674118 TI - Retinoblastoma and Neuroblastoma Predisposition and Surveillance. AB - Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. Clin Cancer Res; 23(13); e98-e106. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28674119 TI - Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. AB - Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107 e14. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28674120 TI - Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. AB - A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations. Clin Cancer Res; 23(13); e115-e22. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28674122 TI - Effectiveness of a targeted lifestyle intervention in primary care on diet and physical activity among South Asians at risk for diabetes: 2-year results of a randomised controlled trial in the Netherlands. AB - OBJECTIVES: In South Asian populations, little is known about the effects of intensive interventions to reduce the risk of type 2 diabetes on health behaviour. We examined the effectiveness at 2 years of a culturally targeted lifestyle intervention on diet, physical activity and determinants of behaviour change among South Asians at risk for diabetes. DESIGN: Randomised controlled trial with de facto masking. SETTING: Primary care. PARTICIPANTS: A total of 536 18- to 60-year-old South Asians at risk for diabetes (ie, with impaired glucose tolerance, impaired fasting glucose or relatively high insulin resistance) were randomised to the intervention (n=283) or a control (n=253) group. Data of 314 participants (n=165 intervention, n=149 control) were analysed. INTERVENTIONS: The culturally targeted intervention consisted of individual counselling using motivational interviewing (six to eight sessions in the first 6 months plus three to four booster sessions), a family session, cooking classes and a supervised physical activity programme. The control group received generic lifestyle advice. OUTCOME MEASURES: We compared changes in physical activity, diet and social cognitive underlying determinants between the two groups at 2-year follow-up with independent-sample t-tests, chi-square tests and Fisher's exact tests. RESULTS: At the 2-year follow-up, participants in the intervention group were more moderately to vigorously active than at baseline, but compared with changes in the control group, the difference was not significant (change min/week 142.9 vs 0.5, p=0.672). Also, no significant difference was found between the two groups in changes on any of the components of the diet or the social-cognitive determinants of diet and physical activity. CONCLUSIONS: The culturally targeted lifestyle intervention led to high drop-out and was not effective in promoting healthy behaviour among South Asians at risk for diabetes. Given the high a priori risk, we recommend to develop new strategies, preferably more acceptable, to promote healthy behaviour. TRIAL REGISTRATION: NTR1499; Results. www.trialregister.nl/trialreg/admin/rctview.asp?TC=1499. PMID- 28674121 TI - Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. AB - Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and MEN2B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome. Clin Cancer Res; 23(13); e123-e32. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28674123 TI - Dietary and physical activity strategies to prevent type 2 diabetes in South Asian adults: protocol for a systematic review. AB - INTRODUCTION: Type 2 diabetes (T2D) is a major health concern among populations of South Asian ethnicity. Although dietary and physical activity interventions may reduce the risk of T2D, the effectiveness has been moderate among South Asians. This might (in part) be because this subgroup follows strategies that were originally developed for interventions among other populations. Therefore, this review aims to assess the evidence for the current dietary and physical activity strategies recommended in T2D prevention intervention studies and guidelines for South Asians. METHODS AND ANALYSIS: Included will be all studies and guidelines on dietary and/or physical activity strategies to prevent T2D in adult South Asians. Two reviewers will search online databases from their start until the present date for published and unpublished experimental/quasiexperimental studies, with at least an abstract in English. References of identified articles and key reviews will be screened for additional studies. Guidelines will be identified by searches in online databases and websites of public organisations. Finally, expert consultations will be held to supplement any missing information. Trial quality will be assessed with the Quality Assessment Tool for Quantitative Studies Data, and guidelines with the Appraisal of Guidelines for Research & Evaluation II. Data on the strategies recommended, targeting and evidence on effectiveness will be extracted by two reviewers and presented in tabular and narrative forms. Recommendations will be compared with the National Institute for Health and Care Excellence guidelines [PH35]. Overall findings on dietary and physical activity recommendations, as well as findings for specific subgroups (eg, by sex), will be discussed. ETHICS AND DISSEMINATION: Ethics assessment is not required. Start date: 1 January 2016, finishing and reporting date 31 July 2016. Results will be published in a peer reviewed scientific journal, the project report of EuroDHYAN (www.eurodhyan.eu) and in a PhD dissertation. TRIAL REGISTRATION NUMBER: The protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO) registration number CRD42015027067. PMID- 28674124 TI - Evaluation of seven recombinant VCA-IgA ELISA kits for the diagnosis of nasopharyngeal carcinoma in China: a case-control trial. AB - OBJECTIVE: Seven recombinant viral capsid antigen-IgA (VCA-IgA) ELISA kits are widely used in China, but their diagnostic effects have not been evaluated. In this study, we evaluated whether the diagnostic effects of these kits are similar to those of the standard kit (EUROIMMUN, Lubeck, Germany). METHODS: A diagnostic case-control trial was conducted with 200 cases of nasopharyngeal carcinoma (NPC) and 200 controls from NPC-endemic areas in southern China. The areas under the curve (AUCs), the sensitivities and the specificities of testing kits were compared with those of the standard kit. The test-retest reliability of each kit was determined by intraclass correlation coefficient (ICC). Their diagnostic accuracy in combination with Epstein-Barr virus nuclear antigen 1-IgA (EBNA1-IgA) was also evaluated in logistic models. RESULTS: Three testing kits-BB, HA and KSB showed diagnostic accuracy equal to that of the standard kit, with good performance in the AUCs (0.926-0.945), and no significant differences in sensitivity were found between early-stage and advanced-stage NPCs. ICCs exceeded 0.8. Three logistic regression models were built, and the AUCs of these models (0.961-0.977) were better than those of the individual VCA-IgA kits. All new models had diagnostic accuracy equal to that of the standard kit. New cut-off values of these three kits and their corresponding combinations for researchers to replicate and use in NPC early detection and screening in the future were provided. CONCLUSIONS: Three recombinant VCA-IgA kits-BB,HA and KSB-had diagnostic effects equal to those of the standard kit, and, in combination with EBNA1-IgA in logistic regression models, can be used in future screening for NPC. PMID- 28674125 TI - The effect of guided self-determination on self-management in persons with type 1 diabetes mellitus and HbA1c >=64 mmol/mol: a group-based randomised controlled trial. AB - OBJECTIVES: To determine whether the impact of guided self-determination (GSD) applied in group training (GSD-GT) in people with chronically elevated HbA1c and type 1 diabetes mellitus (DM) was superior to 'care as usual' in improving HbA1c and psychological functioning. SETTING: An outpatient clinic at a university hospital in Western Norway. PARTICIPANTS: A total of 178 adults (all Caucasian) aged 18-55 (mean age 36.7+/-10.7, 62% women) with type 1 DM for at least 1 year and HbA1c >=64 mmol/mol (8.0%) were randomly assigned to participate in either GSD-GT or a control group (CG). Exclusion criteria were severe comorbidity, major psychiatric disorder, cognitive deficiency/language barriers and pregnancy. INTERVENTION: Intervention group met seven times for 2 hours over 14 weeks to promote patient autonomy and intrinsic motivation using reflection sheets and advanced professional communication in accordance with the GSD methodology. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was HbA1c and secondary outcomes (all outcomes 9 months post intervention) were self-monitored blood glucose frequency, self-reported diabetes competence, autonomy support by healthcare providers (Health Care Climate Questionnaire), autonomous versus controlled diabetes motivation (Treatment Self-Regulation Questionnaire), diabetes distress (Problem Areas In Diabetes Scale (PAID) and Diabetes Distress Scale (DDS)), self-esteem (Rosenberg Self-Esteem Scale) and psychological well being (World Health Organization five-item Well-Being Index scale). RESULTS: Among participants allocated to the GSD-GT (=90) 48 completed the study, whereas 83 completed in the CG (n=88). With 95% CIs GSD-GT did not have effect on HbA1c (B -0.18, CI (-0.48, 0.12), p=0.234). GSD-GT improved autonomy-motivated behaviour (B 0.51, CI (0.25, 0.77), p<0.001), diabetes distress (PAID, B -6.96, CI (-11.40, -2.52), p=0.002), total DDS (B -5.15, CI (-9.34, -0.96), p=0.016), DDS emotional burden (B -7.19, CI (-13.20, -1.19), p=0.019) and self-esteem (B 1.43, CI (0.34, 2.52), p=0.011). CONCLUSIONS: Results from this behavioural intervention must be interpreted cautiously because of recruitment and attrition problems. Medical outcomes did not improve. Psychological outcomes improved, especially reduced diabetes distress. TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT 01317459. PMID- 28674126 TI - Healthcare professional perceptions of family-centred rounds in French NICUs: a cross-sectional study. AB - OBJECTIVE: To assess the perceptions of healthcare professionals (HCPs) regarding parental presence at medical rounds in French neonatal intensive care units (NICUs). We hypothesised that HCPs would perceive barriers against allowing parental participation in round discussions. METHODS: This cross-sectional study approached 304 HCPs from three groups; group 1: French professionals that attended an annual French-speaking meeting of the Neonatal Individualized Developmental Care and Assessment Program (NIDCAP); group 2: NICU professionals from a tertiary care academic hospital in western France; and group 3: paediatric residents from six French universities. We invited all HCPs to complete a questionnaire about medical round practices and their perceptions towards parent participation in family-centred rounds (FCRs). RESULTS: Of the 176 (58%) questionnaires returned, 159 were included in the analysis. The majority of medical rounds took place at the bedside for groups 1 and 3 (68%, 95% CI 54 to 80 and 71%, 95% CI 56 to 84, respectively) and in a conference room for group 2 (65%, 95% CI 51 to 78). Overall, respondents positively perceived FCR for themselves, parents and students. However, most respondents agreed with the following claims: 'Parental attendance at medical rounds prevents some discussions between health professionals' (66%, 95% CI 57 to 73), 'FCR increases round durations' (63%,95% CI 55 to 71) and 'Some decisions made during medical rounds may be stressful for parents' (51%, 95% CI 42 to 59). Nevertheless, responses varied significantly according to NIDCAP training and NICU experience and consequently group 1 displayed a significantly more positive attitude than other groups (p<0.001); they expressed less concern about potentially inhibiting discussions between HCPs (p<0.001), the feasibility (p=0.02) and prolonged round durations (p<0.001). Several difficulties and facilitators of FCR implementation were variously reported, but all groups agreed that routine workload was an important difficulty and that medical leadership would be an important facilitator. CONCLUSION: French HCPs expressed rather positive perceptions towards parental presence in NICU rounds. However, some concerns need to be addressed. PMID- 28674127 TI - Multimorbidity and patterns of chronic conditions in a primary care population in Switzerland: a cross-sectional study. AB - OBJECTIVE: To characterise in details a random sample of multimorbid patients in Switzerland and to evaluate the clustering of chronic conditions in that sample. METHODS: 100 general practitioners (GPs) each enrolled 10 randomly selected multimorbid patients aged >=18 years old and suffering from at least three chronic conditions. The prevalence of 75 separate chronic conditions from the International Classification of Primary Care-2 (ICPC-2) was evaluated in these patients. Clusters of chronic conditions were studied in parallel. RESULTS: The final database included 888 patients. Mean (SD) patient age was 73.0 (12.0) years old. They suffered from 5.5 (2.2) chronic conditions and were prescribed 7.7 (3.5) drugs; 25.7% suffered from depression. Psychological conditions were more prevalent among younger individuals (<=66 years old). Cluster analysis of chronic conditions with a prevalence >=5% in the sample revealed four main groups of conditions: (1) cardiovascular risk factors and conditions, (2) general age related and metabolic conditions, (3) tobacco and alcohol dependencies, and (4) pain, musculoskeletal and psychological conditions. CONCLUSION: Given the emerging epidemic of multimorbidity in industrialised countries, accurately depicting the multiple expressions of multimorbidity in family practices' patients is a high priority. Indeed, even in a setting where patients have direct access to medical specialists, GPs nevertheless retain a key role as coordinators and often as the sole medical reference for multimorbid patients. PMID- 28674128 TI - Predictors for future activity limitation in women with chronic low back pain consulting primary care: a 2-year prospective longitudinal cohort study. AB - OBJECTIVES: To assess if body function, activity, participation, health-related quality of life and lifestyle behavioural factors can predict activity limitation in women with chronic low back pain (CLBP) in primary healthcare (PHC) 2 years later. DESIGN: A 2-year prospective longitudinal cohort study within PHC. SETTINGS: PHC in southwestern Sweden. PARTICIPANTS: The cohort comprised 130 women with CLBP attending PHC at baseline 2004-2005 and were reassessed after 2 years. MEASURES: The dependent outcome variable was self-reported activity limitation (Roland Morris disability questionnaire (RMDQ)) at 2-year follow-up. Independent predictors at baseline were age, body mass index, smoking, alcohol consumption, sleep quantity and quality, leisure time physical activity, a questionnaire of clinical manifestation of stress (Stress and Crises Inventory (SCI-93)), pain localisation, pain intensity, fatigue, anxiety, depression, RMDQ, work status, private social support, health-related quality of life and measures of physical performance specified as 6 min walk test (6MWT) and hand grip strength. Relation between baseline predictors and variation in later self reported activity limitation (RMDQ) was analysed using multivariate linear regression. RESULTS: Ninety-five per cent (n=123/130) were followed up after 2 years. The participants were middle-aged (mean 45 (SD 10) years), mostly educated >9 years (88%; 108/123), mainly living with another adult (76%; 93/122) and born in Sweden (90%; 111/123). Seventy-nine per cent (97/123) were categorised as having work ability at baseline. The final prognostic model including 6MWT, SCI 93 and RMDQ at baseline explained 54% of the variance in self-reported activity limitation (RMDQ) at the 2-year follow-up. CONCLUSIONS: Lower physical performance, more severe clinical stress symptoms and more severe activity limitation predicted activity limitation after 2 years in women with CLBP within PHC. The results can give guidance for interventional trials aiming to improve physical capacity and decrease stress. The impact of the interaction between prognostic factors and interventions on activity limitation needs further investigation. PMID- 28674129 TI - In utero and early childhood exposure to secondhand smoke in Taiwan: a population based birth cohort study. AB - OBJECTIVES: This study provides secondhand smoke (SHS) exposure data in utero and after birth when children were at 18 months, 36 months and 66 months old, and it identifies risk factors for the early childhood SHS among 18-month-old infants living in smoker and non-smoker households. STUDY DESIGN: The data come from the Taiwan Birth Cohort Study, a longitudinal survey of a birth cohort born in 2005. This study used the survey wave when children were 18 months old (n=18 845) for statistical analysis of early childhood SHS exposure. Logistic regression was used to identify the risk factors of the SHS exposure. RESULTS: Approximately 62% of the 18-month-old infants lived in a household with at least one smoker, with the father being the smoker in 84% of those households. Among these infants living in a smoker household, 70% were exposed to SHS and 36% were exposed to heavy SHS in utero, and the prevalence was approximately 66% and 17% after birth for SHS and heavy SHS, respectively. The number and the existence of smokers in the household, parents' smoking status, father's educational attainment and being a first-born baby are strong predictors of early childhood heavy SHS exposure. CONCLUSIONS: Encouraging families to have a smoke-free home environment, empowering women to ensure their perspectives and rights are embedded into tobacco control efforts and educating families about the health risks from childhood SHS exposure, especially among people living in households with smokers, will protect non-smoking adults and children from SHS exposure. PMID- 28674130 TI - A cross-sectional study estimating the burden of illness related to genital warts in South Korea. AB - OBJECTIVES: Estimate the prevalence of genital warts (GW) and GW-related healthcare resource use and costs among male and female patients seeking treatment in South Korea. DESIGN: To estimate GW prevalence, physicians in five major South Korean regions recorded daily logs of patients (n=71 655) seeking care between July 26 and September 27, 2011. Overall prevalence estimates (and 95% CIs) were weighted by the estimated number of physicians in each specialty and the estimated proportion of total patients visiting each specialist type. Healthcare resource use was compared among different specialties. Corresponding p values were calculated using Mann-Whitney U tests. SETTING: The database covers 5098 clinics and hospitals for five major regions in South Korea: Seoul, Busan, Daegu, Gwangju and Daejeon. PARTICIPANTS: Primary care physicians (general practice/family medicine), obstetricians/gynaecologists, urologists and dermatologists with 2-30 years' experience. RESULTS: The estimated overall GW prevalence was 0.7% (95% CI 0.7% to 0.8%). Among women, GW prevalence was 0.6% (95% CI 0.6% to 0.7%); among men prevalence was 1.0% (95% CI 0.9% to 1.0%), peaking among patients aged 18-24 years. Median costs for GW diagnosis and treatment for male patients were US$58.2 (South Korean Won (KRW) ?66 857) and US$66.3 (KRW?76 113) for female patients. CONCLUSIONS: The estimated overall GW prevalence in South Korea was 0.7% and was higher for male patients. The overall median costs associated with a GW episode were higher for female patients than for male patients. PMID- 28674131 TI - Impact of daylight saving time on road traffic collision risk: a systematic review. AB - BACKGROUND: Bills have been put forward in the UK and Republic of Ireland proposing a move to Central European Time (CET). Proponents argue that such a change will have benefits for road safety, with daylight being shifted from the morning, when collision risk is lower, to the evening, when risk is higher. Studies examining the impact of daylight saving time (DST) on road traffic collision risk can help inform the debate on the potential road safety benefits of a move to CET. The objective of this systematic review was to examine the impact of DST on collision risk. METHODS: Major electronic databases were searched, with no restrictions as to date of publication (the last search was performed in January 2017). Access to unpublished reports was requested through an international expert group. Studies that provided a quantitative analysis of the effect of DST on road safety-related outcomes were included. The primary outcomes of interest were road traffic collisions, injuries and fatalities. FINDINGS: Twenty-four studies met the inclusion criteria. Seventeen examined the short-term impact of transitions around DST and 12 examined long-term effects. Findings from the short-term studies were inconsistent. The long-term findings suggested a positive effect of DST. However, this cannot be attributed solely to DST, as a range of road collision risk factors vary over time. INTERPRETATION: The evidence from this review cannot support or refute the assertion that a permanent shift in light from morning to evening will have a road safety benefit. PMID- 28674132 TI - Exploration into lipid management and persistent risk in patients hospitalised for acute coronary syndrome in Japan (EXPLORE-J): protocol for a prospective observational study. AB - INTRODUCTION: The present study is the largest registry study ever conducted in Japan exploring the prevalence of familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). Our study aims to (1) evaluate the status of lipid management and the subsequent risk of major cardiovascular events following hospitalisation of Japanese patients with ACS in real-world clinical practice; (2) determine the proportion of Japanese patients with ACS who achieve the lipid management goal and have a reduction of event risks with strict lipid management (low-density lipoprotein-cholesterol <1.81 mmol/L); (3) determine the prevalence of FH and (4) investigate the clinical significance of proprotein convertase subtilisin kexin 9 (PCSK9) level. METHODS AND ANALYSIS: We will conduct a multicentre, prospective, observational study of approximately 2000 Japanese patients with ACS with/without FH hospitalised between April 2015 and August 2016. The primary end point is the incidence of major adverse cardiovascular events (MACEs) after initial hospitalisation. The secondary end points are (1) MACE developed from visit 1 to visit 2 (day 30); (2) MACE developed from visit 2 (day 30) to visit 5 (day 730); (3) treatment rate by lipid lowering therapies (any statin or intensive, PCSK9 inhibitor, fibrates and ezetimibe); (4) incidence of events by the addition of the following outcomes to the primary end point: coronary revascularisation due to myocardial ischaemia, revascularisation other than coronary artery, inpatient treatment for occurrence or exacerbation of heart failure, transient ischaemic attack, acute arterial occlusion, central retinal artery occlusion and other adverse events prolonging or requiring hospitalisation and (5) proportion of subjects achieving target lipid levels. ETHICS AND DISSEMINATION: The study protocol was submitted to the ethical review committee of each participating centre for approval. Participation in the study is voluntary and anonymous. The study findings will be disseminated in international peer-reviewed journals and presented at relevant conferences. CLINICAL TRIAL REGISTRATION: UMIN000018946. PMID- 28674133 TI - Effect of adherence to antihypertensive medication on stroke incidence in patients with hypertension: a population-based retrospective cohort study. AB - OBJECTIVE: High blood pressure is a modifiable risk factor for stroke, but non adherence to antihypertensive medication is a growing concern for healthcare providers in controlling blood pressure. This study aimed to investigate the effect of adherence to antihypertensive medication on stroke incidence. DESIGN: Retrospective cohort study. SETTING: We analysed National Health Insurance claim data and check-up data from 2009 to 2013. PARTICIPANTS: 38520patients with hypertension were defined as those diagnosed with hypertension and prescribed antihypertensive medication. INTERVENTIONS: No interventions were made. OUTCOME MEASURE: Poisson regression analysis using generalised estimating equations models was performed to examine the association between adherence to antihypertensive medication and stroke incidence. RESULTS: Among 38 520 patients with hypertension, 957 (2.5%) strokes occurred during the study period. Non adherence to medication was significantly associated with a higher risk of stroke (intermediate adherence: adjusted relative risk (aRR)=1.13, 95% CI=1.06 to 1.21; poor adherence: aRR=1.27, 95% CI=1.17 to 1.38). CONCLUSIONS: Non-adherence to antihypertensive medication in patients with hypertension was associated with an increased risk of stroke. Therefore, healthcare providers need to focus on interventional strategies to ensure that these patients adhere to medication therapy and to provide continuing support to achieve long-term adherence, ultimately minimising negative health outcomes. PMID- 28674134 TI - Test accuracy of drug and antibody assays for predicting response to antitumour necrosis factor treatment in Crohn's disease: a systematic review and meta analysis. AB - OBJECTIVE: To present meta-analytic test accuracy estimates of levels of antitumour necrosis factor (anti-TNF) and antibodies to anti-TNF to predict loss of response or lack of regaining response in patients with anti-TNF managed Crohn's disease. METHODS: MEDLINE, Embase, the Cochrane Library and Science Citation Index were searched from inception to October/November 2014 to identify studies which reported 2*2 table data of the association between levels of anti TNF or its antibodies and clinical status. Hierarchical/bivariate meta-analysis was undertaken with the user-written 'metandi' package of Harbord and Whiting using Stata V.11 software, for infliximab, adalimumab,anti-infliximab and anti adalimumab levels as predictors of loss of response. Prevalence of Crohn's disease in included studies was meta-analysed using a random effects model in MetaAnalyst software to calculate positive and negative predictive values. The search was updated in January 2017. RESULTS: 31 studies were included in the review. Studies were heterogeneous with respect to the type of test used, criteria for establishing response and loss of response, population examined and results. Meta-analytic summary point estimates for sensitivity and specificity were 65.7% and 80.6% for infliximab trough levels and 56% and 79% for antibodies to infliximab, respectively. Pooled results for adalimumab trough levels and antibodies to adalimumab were similar. Pooled positive and negative predictive values ranged between 70% and 80% implying that between 20% and 30% of both positive and negative test results may be incorrect in predicting loss of response. CONCLUSION: The available evidence suggests that these tests have modest predictive accuracy for clinical status; direct test accuracy comparisons in the same population are needed. More clinical trial evidence from test-treat studies is required before the clinical utility of the tests can be reliably evaluated. PMID- 28674135 TI - Mechanism evaluation of a lifestyle intervention for patients with musculoskeletal pain who are overweight or obese: protocol for a causal mediation analysis. AB - INTRODUCTION: Low back pain (LBP) and knee osteoarthritis (OA) are highly prevalent and disabling conditions that cause societal and economic impact worldwide. Two randomised controlled trials (RCTs) will evaluate the effectiveness of a multicomponent lifestyle intervention for patients with LBP and knee OA who are overweight or obese. The key targets of this intervention are to improve physical activity, modify diet and correct pain beliefs. These factors may explain how a lifestyle intervention exerts its effects on key patient relevant outcomes: pain, disability and quality of life. The aim of this protocol is to describe a planned analysis of a mechanism evaluation for a lifestyle intervention for overweight or obese patients with LBP and knee OA. METHODS AND ANALYSIS: Causal mediation analyses of 2 two-armed RCTs. Both trials are part of a cohort-multiple RCT, embedded in routine health service delivery. In each respective trial, 160 patients with LBP and 120 patients with knee OA waiting for orthopaedic consultation will be randomised to a lifestyle intervention, or to remain part of the original cohort. The intervention consists of education and advice about the benefits of weight loss and physical activity, and the Australian New South Wales Get Healthy Service. All outcome measures including patient characteristics, primary and alternative mediators, outcomes, and potential confounders will be measured at baseline (T0). The primary mediator, weight, will be measured at 6 months post randomisation; alternative mediators including diet, physical activity and pain beliefs will be measured at 6 weeks post randomisation. All outcomes (pain, disability and quality of life) will be measured at 6 months post randomisation. Data will be analysed using causal mediation analysis with sensitivity analyses for sequential ignorability. All mediation models were specified a priori before completing data collection and without prior knowledge about the effectiveness of the intervention. ETHICS AND DISSEMINATION: The study is approved by the Hunter New England Health Human Research Ethics Committee (13/12/11/5.18) and the University of Newcastle Human Research Ethics Committee (H-2015-0043). The results will be disseminated in peer reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12615000490572 and ACTRN12615000478516; Pre-results. PMID- 28674136 TI - A systematic review of the cost and cost-effectiveness of electronic discharge communications. AB - BACKGROUND: The transition between acute care and community care can be a vulnerable period in a patients' treatment due to the potential for postdischarge adverse events. The vulnerability of this period has been attributed to factors related to the miscommunication between hospital-based and community-based physicians. Electronic discharge communication has been proposed as one solution to bridge this communication gap. Prior to widespread implementation of these tools, the costs and benefits should be considered. OBJECTIVE: To establish the cost and cost-effectiveness of electronic discharge communications compared with traditional discharge systems for individuals who have completed care with one provider and are transitioning care to a new provider. METHODS: We conducted a systematic review of the published literature, using best practices, to identify economic evaluations/cost analyses of electronic discharge communication tools. Inclusion criteria were: (1) economic analysis and (2) electronic discharge communication tool as the intervention. Quality of each article was assessed, and data were summarised using a component-based analysis. RESULTS: One thousand unique abstracts were identified, and 57 full-text articles were assessed for eligibility. Four studies met final inclusion criteria. These studies varied in their primary objectives, methodology, costs reported and outcomes. All of the studies were of low to good quality. Three of the studies reported a cost effectiveness measure ranging from an incremental daily cost of decreasing average discharge note completion by 1 day of $0.331 (2003 Canadian), a cost per page per discharge letter of ?9.51 and a dynamic net present value of ?31.1 million for a 5-year implementation of the intervention. None of the identified studies considered clinically meaningful patient or quality outcomes. DISCUSSION: Economic analyses of electronic discharge communications are scarcely reported, and with inconsistent methodology and outcomes. Further studies are needed to understand the cost-effectiveness and value for patient care. PMID- 28674137 TI - Key priority areas for patient safety improvement strategy in Libya: a protocol for a modified Delphi study. AB - INTRODUCTION: Patient safety is a global public health problem. Estimates and size of the problem of patient safety in low-income and developing countries are scarce. A systems approach is needed for ensuring that patients are protected from harm while receiving care. The primary objective of this study will be to use a consensus-based approach to identify the key priority areas for patient safety improvement in Libya as a developing country. DESIGN: A modified Delphi study. METHODS AND ANALYSIS: A three-phase modified Delphi study will be conducted using an anonymous web-based questionnaires. 15 international experts in the field of patient safety will be recruited to prioritise areas of patient safety that are vital to developing countries such as Libya. The participants will be given the opportunity to rank a list of elements on five criteria. The participants will also be asked to list five barriers that they believe hinder the implementation of patient safety systems. Descriptive statistics will be used to evaluate consensus agreement, including percentage agreement and coefficient of variation. Kendall's coefficient of concordance will be used to evaluate consensus across all participants. ETHICS AND DISSEMINATION: Ethical approval has been granted from Imperial College Research Ethics Committee (ICREC: 16IC3598). The findings of the study will be published in a PhD thesis. A manuscript will also be prepared for publication in a high-impact peer-reviewed journal describing the Delphi process and the findings of the study. PMID- 28674138 TI - The determinants and outcomes of good provider communication: a cross-sectional study in seven African countries. AB - OBJECTIVES: To determine the extent of provider communication, predictors of good communication and the association between provider communication and patient outcomes, such as patient satisfaction, in seven sub-Saharan African countries. DESIGN: Cross-sectional, multicountry study. SETTING: Data from recent Service Provision Assessment (SPA) surveys from seven countries in sub-Saharan Africa. SPA surveys include assessment of facility inputs and processes as well as interviews with caretakers of sick children. These data included 3898 facilities and 4627 providers. PARTICIPANTS: 16 352 caregivers visiting the facility for their sick children. PRIMARY AND SECONDARY OUTCOME MEASURES: We developed an index of four recommended provider communication items for a sick child assessment based on WHO guidelines. We assessed potential predictors of provider communication and considered whether better provider communication was associated with intent to return to the facility for care. RESULTS: The average score of the composite indicator of provider communication was low, at 35% (SD 26.9). Fifty four per cent of caregivers reported that they were told the child's diagnosis, and only 10% reported that they were counselled on feeding for the child. Caregivers' educational attainment and provider preservice education and training in integrated management of childhood illness were associated with better communication. Private facilities and facilities with better infrastructure received higher communication scores. Caretakers reporting better communication were significantly more likely to state intent to return to the facility (relative risk: 1.19, 95% CI 1.16 to 1.22). CONCLUSIONS: There are major deficiencies in communication during sick child visits. These are associated with lower provider education as well as less well-equipped facilities. Poor communication, in turn, is linked to lower satisfaction and intention to return to facility among caregivers of sick children. Countries should test strategies for enhancing quality of communication in their efforts to improve health outcomes and patient experience. PMID- 28674139 TI - Factors associated with return to work among people on work absence due to long term neck or back pain: a narrative systematic review. AB - OBJECTIVE: The purpose of this narrative systematic review was to summarise prognostic factors for return to work (RTW) among people with long-term neck/shoulder or back pain. METHODS: A systematic literature search was performed through three databases (Medline, CINAHL and PsycINFO) for studies published until February 2016. Only observational studies of people on work absence (a0/00Y2 weeks) due to neck/shoulder or back pain were included. The methodological quality of the included studies was assessed using guidelines for assessing quality in prognostic studies on the basis of Framework of Potential Biases. Factors found in the included studies were grouped into categories based on similarities and then labelled according to the aspects covered by the factors in the category. RESULTS: Nine longitudinal prospective cohort studies and one retrospective study fulfilled the inclusion criteria. From these, five categories of factors were extracted. Our findings indicate that recovery beliefs, health related factors and work capacity are important for RTW among people with long term neck or back pain. We did not find support for workplace factors and behaviour being predictive of RTW. CONCLUSIONS: Our findings suggest that recovery beliefs, perceived health and work capacity may be important targets of intervention for people with long-term neck or back pain. However, more high quality prospective studies are needed to confirm the results and improve our understanding of what is needed to facilitate RTW in this population. PMID- 28674140 TI - Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): A single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol. AB - INTRODUCTION: Primary sclerosing cholangitis (PSC) is a progressive inflammatory liver disease characterised by relentless liver fibrosis and a high unmet need for new therapies. Preventing fibrosis represents an important area of interest in the development of vital new drugs. Vascular adhesion protein-1 (VAP-1) drives inflammation in liver disease, and provision of an antibody against VAP-1 blunts fibrosis in murine models of liver injury. METHODS AND ANALYSIS: BUTEO is a single-arm, two-stage, open-label, multi-centre, phase II clinical trial. Up to 59 patients will receive treatment with anti-VAP monoclonal antibody, BTT1023, over a 78-day treatment period. Adults with PSC and a serum alkaline phosphatase (ALP) of at least 1.5 times the upper limit of normal will be included. Our primary outcome measure is a reduction in ALP by >25% from baseline to Day 99. Secondary outcome measures include safety and tolerability, changes pre therapy/post therapy in circulating serum VAP-1 as well as imaging findings. The first patient participant was recruited on 08 September 2015. ETHICS AND DISSEMINATION: This protocol has been approved by the Research Ethics Committee (REC, reference 14/EM/1272). The first REC approval date was 06 January 2015 with three subsequent approved amendments. This article refers to protocol V3.0, dated 16 March 2016. Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION: The trial is registered with the European Medicines agency (EudraCT: 2014-002393-37), the National Institute for Health Research (Portfolio ID: 18051) and ISRCTN: 11233255. The clinicaltrials.gov identifier is NCT02239211. Pre-results. PMID- 28674141 TI - A cohort study on physician documentation and the accuracy of administrative data coding to improve passive surveillance of transient ischaemic attacks. AB - BACKGROUND: Administrative health data are valuable in health research and disease surveillance, but have low to moderate sensitivity in identifying transient ischaemic attacks (TIA) in the emergency department (ED). We aimed to identify the predictors of coding accuracy for TIA. METHODS: The study population was obtained from two ongoing studies on the diagnosis of TIA, minor stroke and stroke mimic. ED charts were manually reviewed by a stroke neurologist to obtain the clinical diagnosis, patient characteristics and content of physician documentation. Administrative data codes were compared with the chart-adjudicated diagnosis to determine cases of misclassification by administrative data. Univariable regression was used to evaluate candidate predictors of disagreement, and the significant variables were tested in a multivariable model to obtain an adjusted estimate of effect. RESULTS: Among 417 patients (39.1% TIA, 37.2% minor stroke and 23.7% stroke mimics), there were 122 cases of disagreement between adjudications and administrative data codes for the diagnosis of TIA. The majority of disagreement (n=103/122, 84.4%) arose from adjudicated TIA cases that were misclassified as non-TIA in administrative data coding. There were 78 (18.7%) charts with documented uncertain diagnosis, and 73 (17.5%) charts had no definite diagnosis. The relative risk of disagreement between chart adjudication and administrative data coding when the final diagnosis was uncertain or absent was 1.82(1.36, 2.44) and the risk difference was 18.5%. Multivariable logistic regression analyses confirmed this association using different case definition algorithms. CONCLUSIONS: In suspected patients with TIA and minor stroke presenting to the ED, physician documentation was the dominant factor in coding accuracy, supporting the concept that physicians are active participants in administrative data coding. Strategies to improve chart documentation are predicted to have a positive effect on coding accuracy. PMID- 28674142 TI - Methods, applications, interpretations and challenges of interrupted time series (ITS) data: protocol for a scoping review. AB - OBJECTIVES: Interrupted time series (ITS) design involves collecting data across multiple time points before and after the implementation of an intervention to assess the effect of the intervention on an outcome. ITS designs have become increasingly common in recent times with frequent use in assessing impact of evidence implementation interventions. Several statistical methods are currently available for analysing data from ITS designs; however, there is a lack of guidance on which methods are optimal for different data types and on their implications in interpreting results. Our objective is to conduct a scoping review of existing methods for analysing ITS data, to summarise their characteristics and properties, as well as to examine how the results are reported. We also aim to identify gaps and methodological deficiencies. METHODS AND ANALYSIS: We will search electronic databases from inception until August 2016 (eg, MEDLINE and JSTOR). Two reviewers will independently screen titles, abstracts and full-text articles and complete the data abstraction. The anticipated outcome will be a summarised description of all the methods that have been used in analysing ITS data in health research, how those methods were applied, their strengths and limitations and the transparency of interpretation/reporting of the results. We will provide summary tables of the characteristics of the included studies. We will also describe the similarities and differences of the various methods. ETHICS AND DISSEMINATION: Ethical approval is not required for this study since we are just considering the methods used in the analysis and there will not be identifiable patient data. Results will be disseminated through open access peer-reviewed publications. PMID- 28674143 TI - Linked symptom monitoring and depression treatment programmes for specialist cancer services: protocol for a mixed-methods implementation study. AB - INTRODUCTION: There is growing awareness that cancer services need to address patients' well-being as well as treating their cancer. We developed systematic approaches to (1) monitoring patients' symptoms including depression using a 'Symptom Monitoring Service' and (2) providing treatment for those with major depression using a programme called 'Depression Care for People with Cancer'. Used together, these two programmes were found to be highly effective and cost effective in clinical trials. The overall aims of this project are to: (1) study the process of introducing these programmes into routine clinical care in a large cancer service, (2) identify the challenges associated with implementation and how these are overcome, (3) determine their effectiveness in a routine non research setting and (4) describe patients' and clinicians' experience of the programmes. METHODS AND ANALYSIS: This is a mixed-methods longitudinal implementation study. We will study the process of implementation in three phases (April 2016-December 2018): 'Pre-implementation' (setting up of the new programmes), 'Early Implementation' (implementation of the programmes in a small number of clinics) and 'Implementation and Maintenance' (implementation in the majority of clinics). We will use the following methods of data collection: (1) contemporaneous logs of the implementation process, (2) interviews with healthcare professionals and managers, (3) interviews with patients and (4) routinely collected clinical data. ETHICS AND DISSEMINATION: The study has been reviewed by a joint committee of Oxford University Hospitals National Health Service Foundation Trust Research and Development Department and the University of Oxford's Clinical Trials and Research Governance Department and judged to be service evaluation, not requiring ethics committee approval. The findings of this study will guide the scaling up implementation of the programmes across the UK and will enable us to construct an implementation toolkit. We will disseminate our findings in publications and at relevant national and international conferences. PMID- 28674144 TI - Effectiveness of recruitment to a smartphone-delivered nutrition intervention in New Zealand: analysis of a randomised controlled trial. AB - OBJECTIVES: Delivery of interventions via smartphone is a relatively new initiative in public health, and limited evidence exists regarding optimal strategies for recruitment. We describe the effectiveness of approaches used to recruit participants to a smartphone-enabled nutrition intervention trial. METHODS: Internet and social media advertising, mainstream media advertising and research team networks were used to recruit New Zealand adults to a fully automated smartphone-delivered nutrition labelling trial (no face-to-face visits were required). Recruitment of Maori and Pacific participants was a key focus and ethically relevant recruitment materials and approaches were used where possible. The effectiveness of recruitment strategies was evaluated using Google Analytics, monitoring of study website registrations and randomisations, and self-reported participant data. The cost of the various strategies and associations with participant demographics were assessed. RESULTS: Over a period of 13 months, there were 2448 registrations on the study website, and 1357 eligible individuals were randomised into the study (55%). Facebook campaigns were the most successful recruitment strategy overall (43% of all randomised participants) and for all ethnic groups (Maori 44%, Pacific 44% and other 43%). Significant associations were observed between recruitment strategy and age (p<0.001), household size (p<0.001), ethnicity (p<0.001), gender (p=0.005) and interest in healthy eating (p=0.022). Facebook campaigns resulted in the highest absolute numbers of study registrations and randomisations (966 and 584, respectively). Network strategies and Facebook campaigns cost least per randomised participant (NZ$4 and NZ$5, respectively), whereas radio advertising costs most (NZ$179 per participant). CONCLUSION: Internet and social media advertising were the most effective and least costly approaches to recruiting participants to a smartphone-delivered trial. These approaches also reached diverse ethnic groups. However, more culturally appropriate recruitment strategies are likely to be necessary in studies where large numbers of participants from specific ethnic groups are sought. TRIAL REGISTRATION: ACTRN12614000644662; Post-results. PMID- 28674145 TI - The STRATAA study protocol: a programme to assess the burden of enteric fever in Bangladesh, Malawi and Nepal using prospective population census, passive surveillance, serological studies and healthcare utilisation surveys. AB - INTRODUCTION: Invasive infections caused by Salmonella enterica serovar Typhi and Paratyphi A are estimated to account for 12-27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidal Salmonellae infections is hindered by lack of population-based studies and adequate laboratory diagnostics.The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidal Salmonellae infections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history of Salmonella transmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies. METHODS/DESIGN: Using census-defined denominator populations of >=100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidal Salmonellae (seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers. ETHICS AND DISSEMINATION: This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN 12131979. ETHICS REFERENCES: Oxford (Oxford Tropical Research Ethics Committee 39 15).Bangladesh (icddr,b Institutional Review Board PR-15119).Malawi (National Health Sciences Research Committee 15/5/1599).Nepal (Nepal Health Research Council 306/2015). PMID- 28674146 TI - Self-reported sleep duration and napping, cardiac risk factors and markers of subclinical vascular disease: cross-sectional study in older men. AB - STUDYOBJECTIVES: Daytime sleep has been associated with increased risk of cardiovascular disease and heart failure (HF), but the mechanisms remain unclear. We have investigated the association between daytime and night-time sleep patterns and cardiovascular risk markers in older adults including cardiac markers and subclinical markers of atherosclerosis (arterial stiffness and carotid intima-media thickness (CIMT)). METHODS: Cross-sectional study of 1722 surviving men aged 71-92 examined in 2010-2012 across 24 British towns from a prospective study initiated in 1978-1980. Participants completed a questionnaire and were invited for a physical examination. Men with a history of heart attack or HF (n=251) were excluded from the analysis. RESULTS: Self-reported daytime sleep duration was associated with higher fasting glucose and insulin levels (p=0.02 and p=0.01, respectively) even after adjustment for age, body mass index, physical activity and social class. Compared with those with no daytime sleep, men with daytime sleep >1 hour, defined as excessive daytime sleepiness (EDS), had a higher risk of raised N-terminal pro-brain natriuretic peptide of >=400 pg/mL, the diagnostic threshold for HF (OR (95% CI)=1.88 (1.15 to 3.1)), higher mean troponin, reduced lung function (forced expiratory volume in 1 s) and elevated von Willebrand factor, a marker of endothelial dysfunction. However, EDS was unrelated to CIMT and arterial stiffness. By contrast, night-time sleep was only associated with HbA1c (short or long sleep) and arterial stiffness (short sleep). CONCLUSIONS: Daytime sleep duration of >1 hour may be an early indicator of HF. PMID- 28674147 TI - Evaluation of the Gold Coast Integrated Care for patients with chronic disease or high risk of hospitalisation through a non-randomised controlled clinical trial: a pilot study protocol. AB - INTRODUCTION: Chronic diseases are the leading cause of illness, disability and death in Australia. The prevalence and associated health expenditure are projected to soar. There is no 'whole system' approach to healthcare in Australia. To overcome this fragmentation, the Gold Coast Hospital and Health Service (GCHHS) is developing a new model known as Gold Coast Integrated Care (GCIC). To evaluate GCIC a 4-year pilot trial commenced in March 2015. This protocol paper describes the evaluation of GCIC. METHODS AND ANALYSIS: A pragmatic non-randomised controlled clinical trial is conducted to test the hypothesis that GCIC will result in improved health and well-being at no additional cost to the healthcare system. Using a mixed methods approach, impact, outcome and process evaluations will be undertaken to assess the effectiveness and acceptability, including the balance of costs between primary and public secondary care sectors, staff and training requirements, clinical service delivery, and trial implementation.Fifteen general practices have agreed to deliver GCIC. One thousand five hundred of their adult patients with treated chronic diseases, high risk of hospitalisation or healthcare utilisation were recruited to the intervention arm. Approximately 3000 patients not associated with the participating general practices were identified as controls using propensity matching which will provide service utilisation and disease data for usual care.Baseline data and follow-up observations are collected annually until the end of 2018. Quantitative analyses will measure patient healthcare costs, utilisation of health services, and health outcomes, and general practice clinical service delivery according to clinical guidelines (number of foot exams, HbA1c tests). Qualitative analyses will focus on patient and staff experiences, satisfaction, engagement and implementation of the programme as planned. ETHICS AND DISSEMINATION: Approval was received from the GCHHS and Griffith University. The study is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12616000821493). Findings will be communicated via yearly reports to funding bodies and scientific publications. TRIAL REGISTRATION NUMBER: ACTRN12616000821493; Pre-results. PMID- 28674148 TI - Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm. AB - INTRODUCTION: Individual cohort studies in various populations and study-level meta-analyses have shown interarm differences (IAD) in blood pressure to be associated with increased cardiovascular and all-cause mortality. However, key questions remain, such as follows: (1) What is the additional contribution of IAD to prognostic risk estimation for cardiovascular and all-cause mortality? (2) What is the minimum cut-off value for IAD that defines elevated risk? (3) Is there a prognostic value of IAD and do different methods of IAD measurement impact on the prognostic value of IAD? We aim to address these questions by conducting an individual patient data (IPD) meta-analysis. METHODS AND ANALYSIS: This study will identify prospective cohort studies that measured blood pressure in both arms during recruitment, and invite authors to contribute IPD datasets to this collaboration. All patient data received will be combined into a single dataset. Using one-stage meta-analysis, we will undertake multivariable time-to event regression modelling, with the aim of developing a new prognostic model for cardiovascular risk estimation that includes IAD. We will explore variations in risk contribution of IAD across predefined population subgroups (eg, hypertensives, diabetics), establish the lower limit of IAD that is associated with additional cardiovascular risk and assess the impact of different methods of IAD measurement on risk prediction. ETHICS AND DISSEMINATION: This study will not include any patient identifiable data. Included datasets will already have ethical approval and consent from their sponsors. Findings will be presented to international conferences and published in peer reviewed journals, and we have a comprehensive dissemination strategy in place with integrated patient and public involvement. PROSPERO REGISTRATION NUMBER: CRD42015031227. PMID- 28674149 TI - Serum 25-hydroxyvitamin D level, chronic diseases and all-cause mortality in a population-based prospective cohort: the HUNT Study, Norway. AB - OBJECTIVE: To investigate the association of vitamin D status with all-cause mortality in a Norwegian population and the potential influences of existing chronic diseases on the association. DESIGN: A population-based prospective cohort study. SETTING: Nord-Trondelag County, Norway. PARTICIPANTS: A random sample (n=6613) of adults aged 20 years or older in a cohort. METHODS: Serum 25 hydroxyvitamin D (25(OH)D) levels were measured in blood samples collected at baseline (n=6377). Mortality was ascertained from the Norwegian National Registry. Cox regression models were applied to estimate the HRs with 95% CIs for all-cause mortality in association with serum 25(OH)D levels after adjustment for a wide spectrum of confounding factors as well as chronic diseases at baseline. RESULTS: The median follow-up time was 18.5 years, during which 1539 subjects died. The HRs for all-cause mortality associated with the first quartile level of 25(OH)D (<34.5 nmol/L) as compared with the fourth quartile (>=58.1 nmol/L) before and after adjustment for chronic diseases at baseline were 1.30 (95% CI 1.11 to 1.51) and 1.27 (95% CI 1.09 to 1.48), respectively. In the subjects without chronic diseases at baseline and with further exclusion of the first 3 years of follow-up, the corresponding adjusted HR was 1.34 (95% CI 1.09 to 1.66). CONCLUSIONS: Low serum 25(OH)D level was associated with increased all-cause mortality in a general Norwegian population. The association was not notably influenced by existing chronic diseases. PMID- 28674150 TI - Temporal Regulation of a Salmonella Typhimurium Virulence Factor by the Transcriptional Regulator YdcR. AB - We previously examined Salmonella proteome within infected host cells and found differential expression of many proteins with defined functional roles such as metabolism or virulence. However, the precise roles of other altered proteins in Salmonella pathogenesis are largely unknown. A putative transcriptional regulator, YdcR, was highly induced intracellularly whereas barely expressed in vitro, implicating potential relevance to bacterial infection. To unveil its physiological functions, we exploited quantitative proteomics of intracellular Salmonella and found that genetic ablation of ydcR resulted in severe repression of SrfN, a known virulence factor. Immunoblotting, qRT-PCR, and beta galactosidase assays further demonstrate YdcR-dependent transcription and expression of srfN Moreover, we found physical interaction of YdcR with the promoter region of srfN, suggesting direct activation of its transcription. Importantly, a Salmonella mutant lacking ydcR was markedly attenuated in a mouse model of infection. Our findings reveal that YdcR temporally regulates the virulence factor SrfN during infection, thus contributing to Salmonella pathogenesis. Our work also highlights the utility of combining quantitative proteomics and bacterial genetics for uncovering the functional roles of transcription factors and likely other uncharacterized proteins as well. PMID- 28674151 TI - Kinase activity ranking using phosphoproteomics data (KARP) quantifies the contribution of protein kinases to the regulation of cell viability. AB - Cell survival is regulated by a signaling network driven by the activity of protein kinases; however, determining the contribution that each kinase in the network makes to such regulation remains challenging. Here, we report a computational approach that uses mass spectrometry-based phosphoproteomics data to rank protein kinases based on their contribution to cell regulation. We found that the scores returned by this algorithm, which we have termed kinase activity ranking using phosphoproteomics data (KARP), were a quantitative measure of the contribution that individual kinases make to the signaling output. Application of KARP to the analysis of eight hematological cell lines revealed that cyclin dependent kinase (CDK) 1/2, casein kinase (CK) 2, extracellular signal-related kinase (ERK), and p21-activated kinase (PAK) were the most frequently highly ranked kinases in these cell models. The patterns of kinase activation were cell line specific yet showed a significant association with cell viability as a function of kinase inhibitor treatment. Thus, our study exemplifies KARP as an untargeted approach to empirically and systematically identify regulatory kinases within signaling networks. PMID- 28674153 TI - Spotlight on the July 4 issue. PMID- 28674154 TI - Message from the Editors to our Reviewers. PMID- 28674152 TI - Human Arylamine N-Acetyltransferase 1 Is Inhibited by the Dithiocarbamate Pesticide Thiram. AB - Thiram (tetramethylthiuram disulfide) is a representative dithiocarbamate (DTC) pesticide used in both the field and as a seed protectant. The widespread use of Thiram and other DTC pesticides has raised concerns for health, because these compounds can exert neuropathic, endocrine disruptive, and carcinogenic effects. These toxic effects are thought to rely, at least in part, on the reaction of Thiram (and certain of its metabolites) with cellular protein thiols with subsequent loss of protein function. So far, a limited number of molecular targets of Thiram have been reported, including few enzymes such as dopamine beta hydroxylase, 11beta-hydroxysteroid dehydrogenase, and brain glycogen phosphorylase. We provide evidence that Thiram is an inhibitor (KI = 23 MUM; kinact = 0.085 second-1; kinact/KI = 3691 M-1?s-1) of human arylamine N acetyltransferase 1 (NAT1), a phase II xenobiotic-metabolizing enzyme that plays a key role in the biotransformation of aromatic amine xenobiotics. Thiram was found to act as an irreversible inhibitor through the modification of NAT1 catalytic cysteine residue as also reported for other enzymes targeted by this pesticide. We also showed using purified NAT1 and human keratinocytes that Thiram impaired the N-acetylation of 3,4-dichloroaniline (3,4-DCA), a major toxic metabolite of aromatic amine pesticides (such as Diuron or Propanil). As coexposure to different classes of pesticides is common, our data suggest that pharmacokinetic drug-drug interactions between DTC pesticides such as Thiram and aromatic amine pesticides may occur through alteration of NAT1 enzymes functions. PMID- 28674155 TI - Correcting honest pervasive errors in the scientific literature: Retractions without stigma. PMID- 28674156 TI - The botulinum toxin legend of Reinhard Heydrich's death: The end of "Himmler's brain". AB - The high-ranking German Nazi Reinhard Heydrich (1904-1942) was one of the main organizers of the mass murder of Jews during the Second World War. He died on June 4, 1942, in Prague after having been wounded in Operation Anthropoid planned by the British intelligence services. Since the 1970s and 1980s, Heydrich's death has been frequently presented in British, American, and French literature as the consequence of a bacteriologic attack. Botulinum toxin would have been used in the grenades or ammunition. We discuss the botulinum toxin hypothesis using the now declassified British archives of Operation Anthropoid and of the chemical and bacteriologic warfare centers to assess this hypothesis. PMID- 28674157 TI - Proatlantal intersegmental artery with internal carotid artery stenosis. PMID- 28674158 TI - Editors' Note. PMID- 28674159 TI - Letter re: Long-term cortisol measures predict Alzheimer disease risk. PMID- 28674160 TI - Author response: Long-term cortisol measures predict Alzheimer disease risk. PMID- 28674161 TI - Letter re: Mediodorsal nucleus and its multiple cognitive functions. PMID- 28674163 TI - Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT). PMID- 28674162 TI - Author response: Mediodorsal nucleus and its multiple cognitive functions. PMID- 28674164 TI - Decrease in Abeta42 predicts dopa-resistant gait progression in early Parkinson disease. PMID- 28674165 TI - Clinical Reasoning: A 58-year-old man with progressive ptosis and walking difficulty. PMID- 28674166 TI - Teaching NeuroImages: Abnormal cervical and cerebral vasculature in 22q11 deletion syndrome. PMID- 28674167 TI - Mesoscale Mapping of Mouse Cortex Reveals Frequency-Dependent Cycling between Distinct Macroscale Functional Modules. AB - Connectivity mapping based on resting-state activity in mice has revealed functional motifs of correlated activity. However, the rules by which motifs organize into larger functional modules that lead to hemisphere wide spatial temporal activity sequences is not clear. We explore cortical activity parcellation in head-fixed, quiet awake GCaMP6 mice from both sexes by using mesoscopic calcium imaging. Spectral decomposition of spontaneous cortical activity revealed the presence of two dominant frequency modes (<1 and ~3 Hz), each of them associated with a unique spatial signature of cortical macro parcellation not predicted by classical cytoarchitectonic definitions of cortical areas. Based on assessment of 0.1-1 Hz activity, we define two macro-organizing principles: the first being a rotating polymodal-association pinwheel structure around which activity flows sequentially from visual to barrel then to hindlimb somatosensory; the second principle is correlated activity symmetry planes that exist on many levels within a single domain such as intrahemispheric reflections of sensory and motor cortices. In contrast, higher frequency activity >1 Hz yielded two larger clusters of coactivated areas with an enlarged default mode network-like posterior region. We suggest that the apparent constrained structure for intra-areal cortical activity flow could be exploited in future efforts to normalize activity in diseases of the nervous system.SIGNIFICANCE STATEMENT Increasingly, functional connectivity mapping of spontaneous activity is being used to reveal the organization of the brain. However, because the brain operates across multiple space and time domains a more detailed understanding of this organization is necessary. We used in vivo wide-field calcium imaging of the indicator GCaMP6 in head-fixed, awake mice to characterize the organization of spontaneous cortical activity at different spatiotemporal scales. Correlation analysis defines the presence of two to three superclusters of activity that span traditionally defined functional territories and were frequency dependent. This work helps define the rules for how different cortical areas interact in time and space. We provide a framework necessary for future studies that explore functional reorganization of brain circuits in disease models. PMID- 28674168 TI - Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia. AB - Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline a novel concept of functional connectome-wide alterations that are linked to dystonia phenotype and genotype. Using a neural community detection strategy and graph theoretical analysis of functional MRI data in human patients with the laryngeal form of dystonia (LD) and healthy controls (both males and females), we identified an abnormally widespread hub formation in LD, which particularly affected the primary sensorimotor and parietal cortices and thalamus. Left thalamic regions formed a delineated functional community that highlighted differences in network topology between LD patients with and without family history of dystonia. Conversely, marked differences in the topological organization of parietal regions were found between phenotypically different forms of LD. The interface between sporadic genotype and adductor phenotype of LD yielded four functional communities that were primarily governed by intramodular hub regions. Conversely, the interface between familial genotype and abductor phenotype was associated with numerous long-range hub nodes and an abnormal integration of left thalamus and basal ganglia. Our findings provide the first comprehensive atlas of functional topology across different phenotypes and genotypes of focal dystonia. As such, this study constitutes an important step toward defining dystonia as a large scale network disorder, understanding its causative pathophysiology, and identifying disorder-specific markers.SIGNIFICANCE STATEMENT The architecture of the functional connectome in focal dystonia was analyzed in a large population of patients with laryngeal dystonia. Breaking with the empirical concept of dystonia as a basal ganglia disorder, we discovered large-scale alterations of neural communities that are significantly influenced by the disorder's clinical phenotype and genotype. PMID- 28674169 TI - Overlapping Representation of Primary Tastes in a Defined Region of the Gustatory Cortex. AB - Both physiological and imaging approaches have led to often-disparate conclusions about the organization of taste information in gustatory cortex (GC). In this study, we used neuroanatomical and imaging approaches to delineate the likely area of insular cortex given to gustatory function and to characterize taste responses within this delineated area in female and male C57BL/6J mice. Anterograde tracers were injected into the taste thalamus (the medial parvicellular portion of the ventral posterior medial division, VPMpc) of mice and the thalamic terminal field was investigated across the cortex. Working within the delineated area, we used two-photon imaging to measure basic taste responses in >780 neurons in layer 2/3 located just posterior to the middle cerebral artery. A nonbiased, hierarchical cluster analysis revealed multiple clusters of cells responding best to either individual or combinations of taste stimuli. Taste quality was represented in the activity of taste-responsive cells; however, there was no apparent spatial organization of primary taste qualities in this region.SIGNIFICANCE STATEMENT Recent studies investigating taste coding within the gustatory cortex have reported highly segregated, taste-specific regions containing only narrowly tuned cells responding to a single taste separated by large non-taste-coding areas. However, focusing on the center of this area, we found a large number of taste responsive cells ranging from narrowly to broadly responsive with no apparent local spatial organization. Further, population analysis reveals that activity in the neuronal population in this area appears to be related to measures of taste quality or hedonics. PMID- 28674170 TI - The MNK-eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain. AB - Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5' cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Phosphorylation of ser209 on eIF4E regulates the translation of a subset of mRNAs. We show that pronociceptive and inflammatory factors, such as nerve growth factor (NGF), interleukin-6 (IL-6), and carrageenan, produce decreased mechanical and thermal hypersensitivity, decreased affective pain behaviors, and strongly reduced hyperalgesic priming in mice lacking eIF4E phosphorylation (eIF4ES209A ). Tests were done in both sexes, and no sex differences were found. Moreover, in patch-clamp electrophysiology and Ca2+ imaging experiments on dorsal root ganglion neurons, NGF- and IL-6-induced increases in excitability were attenuated in neurons from eIF4ES209A mice. These effects were recapitulated in Mnk1/2-/- mice and with the MNK1/2 inhibitor cercosporamide. We also find that cold hypersensitivity induced by peripheral nerve injury is reduced in eIF4ES209A and Mnk1/2-/- mice and following cercosporamide treatment. Our findings demonstrate that the MNK1/2-eIF4E signaling axis is an important contributing factor to mechanisms of nociceptor plasticity and the development of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease affecting approximately one in three Americans. Chronic pain is thought to be driven by changes in the excitability of peripheral nociceptive neurons, but the precise mechanisms controlling these changes are not elucidated. Emerging evidence demonstrates that mRNA translation regulation pathways are key factors in changes in nociceptor excitability. Our work demonstrates that a single phosphorylation site on the 5' cap-binding protein eIF4E is a critical mechanism for changes in nociceptor excitability that drive the development of chronic pain. We reveal a new mechanistic target for the development of a chronic pain state and propose that targeting the upstream kinase, MAPK interacting kinase 1/2, could be used as a therapeutic approach for chronic pain. PMID- 28674171 TI - Vascular Pericyte Impairment and Connexin43 Gap Junction Deficit Contribute to Vasomotor Decline in Diabetic Retinopathy. AB - Adequate blood flow is essential to brain function, and its disruption is an early indicator in diseases, such as stroke and diabetes. However, the mechanisms contributing to this impairment remain unclear. To address this gap, in the diabetic and nondiabetic male mouse retina, we combined an unbiased longitudinal assessment of vasomotor activity along a genetically defined vascular network with pharmacological and immunohistochemical analyses of pericytes, the capillary vasomotor elements. In nondiabetic retina, focal stimulation of a pericyte produced a robust vasomotor response, which propagated along the blood vessel with increasing stimulus. In contrast, the magnitude, dynamic range, a measure of fine vascular diameter control, and propagation of vasomotor response were diminished in diabetic retinas from streptozotocin-treated mice. These functional changes were linked to several mechanisms. We found that density of pericytes and their sensitivity to stimulation were reduced in diabetes. The impaired response propagation from the stimulation site was associated with lower expression of connexin43, a major known gap junction unit in vascular cells. Indeed, selective block of gap junctions significantly reduced propagation but not initiation of vasomotor response in the nondiabetic retina. Our data establish the mechanisms for fine local regulation of capillary diameter by pericytes and a role for gap junctions in vascular network interactions. We show how disruption of this balance contributes to impaired vasomotor control in diabetes.SIGNIFICANCE STATEMENT Identification of mechanisms governing capillary blood flow in the CNS and how they are altered in disease provides novel insight into early states of neurological dysfunction. Here, we present physiological and anatomical evidence that both intact pericyte function as well as gap junction-mediated signaling across the vascular network are essential for proper capillary diameter control and vasomotor function. Changes to capillary blood flow precede other anatomical and functional hallmarks of diabetes establishing a significant window for prevention and treatment. PMID- 28674173 TI - Occipitotemporal Category Representations Are Sensitive to Abstract Category Boundaries Defined by Generalization Demands. AB - Categorization involves organizing perceptual information so as to maximize differences along dimensions that predict class membership while minimizing differences along dimensions that do not. In the current experiment, we investigated how neural representations reflecting learned category structure vary according to generalization demands. We asked male and female human participants to switch between two rules when determining whether stimuli should be considered members of a single known category. When categorizing according to the "strict" rule, participants were required to limit generalization to make fine-grained distinctions between stimuli and the category prototype. When categorizing according to the "lax" rule, participants were required to generalize category knowledge to highly atypical category members. As expected, frontoparietal regions were primarily sensitive to decisional demands (i.e., the distance of each stimulus from the active category boundary), whereas occipitotemporal representations were primarily sensitive to stimulus typicality (i.e., the similarity between each exemplar and the category prototype). Interestingly, occipitotemporal representations of stimulus typicality differed between rules. While decoding models were able to predict unseen data when trained and tested on the same rule, they were unable to do so when trained and tested on different rules. We additionally found that the discriminability of the multivariate signal negatively covaried with distance from the active category boundary. Thus, whereas many accounts of occipitotemporal cortex emphasize its important role in transforming visual information to accentuate learned category structure, our results highlight the flexible nature of these representations with regards to transient decisional demands.SIGNIFICANCE STATEMENT Occipitotemporal representations are known to reflect category structure and are often assumed to be largely invariant with regards to transient decisional demands. We found that representations of equivalent stimuli differed between strict and lax generalization rules, and that the discriminability of these representations increased as distance from abstract category boundaries decreased. Our results therefore indicate that occipitotemporal representations are flexibly modulated by abstract decisional factors. PMID- 28674172 TI - Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice. AB - Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking CDKL5 display multiple behavioral abnormalities reminiscent of the disorder, but the cellular origins of these phenotypes remain unclear. Here, we find that ablating CDKL5 expression specifically from forebrain glutamatergic neurons impairs hippocampal-dependent memory in male conditional knock-out mice. Hippocampal pyramidal neurons lacking CDKL5 show decreased dendritic complexity but a trend toward increased spine density. This morphological change is accompanied by an increase in the frequency of spontaneous miniature EPSCs and interestingly, miniature IPSCs. Using voltage sensitive dye imaging to interrogate the evoked response of the CA1 microcircuit, we find that CA1 pyramidal neurons lacking CDKL5 show hyperexcitability in their dendritic domain that is constrained by elevated inhibition in a spatially and temporally distinct manner. These results suggest a novel role for CDKL5 in the regulation of synaptic function and uncover an intriguing microcircuit mechanism underlying impaired learning and memory.SIGNIFICANCE STATEMENT Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although Cdkl5 constitutive knock-out mice have recapitulated key aspects of human symptomatology, the cellular origins of CDKL5 deficiency-related phenotypes are unknown. Here, using conditional knock-out mice, we show that hippocampal-dependent learning and memory deficits in CDKL5 deficiency have origins in glutamatergic neurons of the forebrain and that loss of CDKL5 results in the enhancement of synaptic transmission and disruptions in neural circuit dynamics in a spatially and temporally specific manner. Our findings demonstrate that CDKL5 is an important regulator of synaptic function in glutamatergic neurons and serves a critical role in learning and memory. PMID- 28674174 TI - Cooperation Not Competition: Bihemispheric tDCS and fMRI Show Role for Ipsilateral Hemisphere in Motor Learning. AB - What is the role of ipsilateral motor and premotor areas in motor learning? One view is that ipsilateral activity suppresses contralateral motor cortex and, accordingly, that inhibiting ipsilateral regions can improve motor learning. Alternatively, the ipsilateral motor cortex may play an active role in the control and/or learning of unilateral hand movements. We approached this question by applying double-blind bihemispheric transcranial direct current stimulation (tDCS) over both contralateral and ipsilateral motor cortex in a between-group design during 4 d of unimanual explicit sequence training in human participants. Independently of whether the anode was placed over contralateral or ipsilateral motor cortex, bihemispheric stimulation yielded substantial performance gains relative to unihemispheric or sham stimulation. This performance advantage appeared to be supported by plastic changes in both hemispheres. First, we found that behavioral advantages generalized strongly to the untrained hand, suggesting that tDCS strengthened effector-independent representations. Second, functional imaging during speed-matched execution of trained sequences conducted 48 h after training revealed sustained, polarity-independent increases in activity in both motor cortices relative to the sham group. These results suggest a cooperative rather than competitive interaction of the two motor cortices during skill learning and suggest that bihemispheric brain stimulation during unimanual skill learning may be beneficial because it harnesses plasticity in the ipsilateral hemisphere.SIGNIFICANCE STATEMENT Many neurorehabilitation approaches are based on the idea that is beneficial to boost excitability in the contralateral hemisphere while attenuating that of the ipsilateral cortex to reduce interhemispheric inhibition. We observed that bihemispheric transcranial direct current stimulation (tDCS) with the excitatory anode either over contralateral or ipsilateral motor cortex facilitated motor learning nearly twice as strongly as unihemispheric tDCS. These increases in motor learning were accompanied by increases in fMRI activation in both motor cortices that outlasted the stimulation period, as well as increased generalization to the untrained hand. Collectively, our findings suggest a cooperative rather than a competitive role of the hemispheres and imply that it is most beneficial to harness plasticity in both hemispheres in neurorehabilitation of motor deficits. PMID- 28674175 TI - Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice. AB - Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS (Fmr1 KO), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS.SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS. PMID- 28674176 TI - Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism. AB - Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene mPer2 within brain areas that regulate motivation and emotion. Administration of the kappa-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in mPer2 Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness.SIGNIFICANCE STATEMENT Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in humans. Whereas some of these alterations recover quickly upon cessation of stress, others persist. Administration of a kappa-opioid receptor (KOR) antagonist reduced stress effects or hastened recovery, consistent with the previously reported antistress effects of this class of agents. Use of endpoints, such as sleep and circadian rhythm, that are homologous across species will facilitate the implementation of translational studies that better predict clinical outcomes in humans, improve the success of clinical trials, and facilitate the development of more effective therapeutics. PMID- 28674178 TI - CCL5 Promotes Resolution-Phase Macrophage Reprogramming in Concert with the Atypical Chemokine Receptor D6 and Apoptotic Polymorphonuclear Cells. AB - The engulfment of apoptotic polymorphonuclear cells (PMN) during the resolution of inflammation leads to macrophage reprogramming culminating in reduced proinflammatory and increased anti-inflammatory mediator secretion. The atypical chemokine receptor D6/ACKR2 is expressed on apoptotic PMN and plays an important role in regulating macrophage properties during and after engulfment. In this study, we found that the inflammatory chemokine CCL5 is mostly retained (75%) during the resolution of zymosan A peritonitis in mice. Moreover, this chemokine is secreted by resolution-phase macrophages (2.5 ng/ml) and promotes their reprogramming in vivo in D6+/+ mice (2-fold increase in IL-10/IL-12 ratio) but not their D6-/- counterparts. In addition, CCL5 enhanced macrophage reprogramming ex vivo exclusively when bound to D6+/+ apoptotic PMN. Signaling through p38MAPK and JNK in reprogrammed macrophages was enhanced by CCL5-bound apoptotic PMN (3.6 4 fold) in a D6-dependent manner, and was essential for reprogramming. Thus, CCL5 exerts a novel proresolving role on macrophages when acting in concert with apoptotic PMN-expressed D6. PMID- 28674177 TI - Retinotopic Organization of Scene Areas in Macaque Inferior Temporal Cortex. AB - Primates have specialized domains in inferior temporal (IT) cortex that are responsive to particular image categories. Though IT traditionally has been regarded as lacking retinotopy, several recent studies in monkeys have shown that retinotopic maps extend to face patches along the lower bank of the superior temporal sulcus (STS) and neighboring regions of IT cortex. Here, we used fMRI to map the retinotopic organization of medial ventral temporal cortex in four monkeys (2 male and 2 female). We confirm the presence of visual field maps within and around the lower bank of the STS and extend these prior findings to scene-selective cortex in the ventral-most regions of IT. Within the occipitotemporal sulcus (OTS), we identified two retinotopic areas, OTS1 and OTS2. The polar angle representation of OTS2 was a mirror reversal of the OTS1 representation. These regions contained representations of the contralateral periphery and were selectively active for scene versus face, body, or object images. The extent of this retinotopy parallels that in humans and shows that the organization of the scene network is preserved across primate species. In addition retinotopic maps were identified in dorsal extrastriate, posterior parietal, and frontal cortex as well as the thalamus, including both the lateral geniculate nucleus and pulvinar. Together, it appears that most, if not all, of the macaque visual system contains organized representations of visual space.SIGNIFICANCE STATEMENT Primates have specialized domains in inferior temporal (IT) cortex that are responsive to particular image categories. Though retinotopic maps are considered a fundamental organizing principle of posterior visual cortex, IT traditionally has been regarded as lacking retinotopy. Recent imaging studies have demonstrated the presence of several visual field maps within the lateral IT. Using neuroimaging, we found multiple representations of visual space within ventral IT cortex of macaques that included scene-selective cortex. Scene domains were biased toward the peripheral visual field. These data demonstrate the prevalence of visual field maps throughout the primate visual system, including late stages in the ventral visual hierarchy, and support the idea that domains representing different categories are biased toward different parts of the visual field. PMID- 28674179 TI - Inflammasome and Fas-Mediated IL-1beta Contributes to Th17/Th1 Cell Induction in Pathogenic Bacterial Infection In Vivo. AB - CD4+ Th cells play crucial roles in orchestrating immune responses against pathogenic microbes, after differentiating into effector subsets. Recent research has revealed the importance of IFN-gamma and IL-17 double-producing CD4+ Th cells, termed Th17/Th1 cells, in the induction of autoimmune and inflammatory diseases. In addition, Th17/Th1 cells are involved in the regulation of infection caused by the intracellular bacterium Mycobacterium tuberculosis in humans. However, the precise mechanism of Th17/Th1 induction during pathogen infection is unclear. In this study, we showed that the inflammasome and Fas-dependent IL 1beta induces Th17/Th1 cells in mice, in response to infection with the pathogenic intracellular bacterium Listeria monocytogenes In the spleens of infected wild-type mice, Th17/Th1 cells were induced, and expressed T-bet and Rorgammat. In Pycard-/- mice, which lack the adaptor molecule of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain), Th17/Th1 induction was abolished. In addition, the Fas-mediated IL-1beta production was required for Th17/Th1 induction during bacterial infection: Th17/Th1 induction was abolished in Fas-/- mice, whereas supplementation with recombinant IL-1beta restored Th17/Th1 induction via IL-1 receptor 1 (IL-1R1), and rescued the mortality of Fas-/- mice infected with Listeria IL-1R1, but not apoptosis-associated speck-like protein containing a caspase recruitment domain or Fas on T cells, was required for Th17/Th1 induction, indicating that IL-1beta stimulates IL-1R1 on T cells for Th17/Th1 induction. These results indicate that IL-1beta, produced by the inflammasome and Fas-dependent mechanisms, contributes cooperatively to the Th17/Th1 induction during bacterial infection. This study provides a deeper understanding of the molecular mechanisms underlying Th17/Th1 induction during pathogenic microbial infections in vivo. PMID- 28674180 TI - Suppression of Lipopolysaccharide-Induced Inflammatory Response by Fragments from Serum Amyloid A. AB - Serum amyloid A (SAA) is known as an acute-phase protein and a biomarker for inflammatory diseases. Published studies have shown that SAA possesses proinflammatory cytokine-like activity and is chemotactic for phagocytes, but the structural basis for these activities remains unidentified. In this article, we report that truncated SAA1 proteins lacking N- and C-terminal sequences exhibit reduced proinflammatory activity and strongly suppress LPS-induced expression of IL-1beta, IL-6, and TNF-alpha in macrophages. A truncated SAA1 containing aa 11 58 was examined further and found to facilitate p38 MAPK phosphorylation while reducing LPS-stimulated phosphorylation of ERK and JNK. In LPS-challenged mice, aa 11-58 reduced the severity of acute lung injury, with significantly less neutrophil infiltration in the lungs and attenuated pulmonary expression of IL 1beta, IL-6, and TNF-alpha. Coadministration of aa 11-58 markedly improved mouse survival in response to a lethal dose of LPS. A potent induction of IL-10 was observed in a TLR2-dependent, but TLR4-independent, manner in macrophages stimulated with aa 11-58. However, the aa 11-58 fragment of SAA1 was unable to induce chemotaxis or calcium flux through formyl peptide receptor 2. These results indicate that the N- and C-terminal sequences contain structural determinants for the proinflammatory and chemotactic activities of SAA1, and their removal switches SAA1 to an anti-inflammatory role. Given that proteolytic processing of SAA is associated with the pathological changes in several diseases, including secondary amyloidosis, our findings may shed light on the structure-function relationship of SAA1 with respect to its role in inflammation. PMID- 28674181 TI - Lung Epithelial Cell-Derived Microvesicles Regulate Macrophage Migration via MicroRNA-17/221-Induced Integrin beta1 Recycling. AB - Robust lung inflammation is one of the prominent features in the pathogenesis of acute lung injury (ALI). Macrophage migration and recruitment are often seen at the early stage of lung inflammatory responses to noxious stimuli. Using an acid inhalation-induced lung injury model, we explored the mechanisms by which acid exposure initiates macrophage recruitment and migration during development of ALI. The lung epithelium comprises a large surface area and functions as a first line defense against noxious insults. We found that acid exposure induced a remarkable microvesicle (MV) release from lung epithelium as detected in bronchoalveolar lavage fluid. Significantly elevated RNA, rather than protein, was found in these epithelium-derived MVs after acid and included several highly elevated microRNAs, including microRNA (miR)-17 and miR-221. Acid-induced epithelial MV release promoted macrophage migration in vitro and recruitment into the lung in vivo and required, in part, MV shuttling of miR-17 and/or miR-221. Mechanistically, acid-induced epithelial MV miR-17/221 promoted beta1 integrin recycling and presentation back onto the surface of macrophages, in part via a Rab11-mediated pathway. Integrin beta1 is known to play an essential role in regulating macrophage migration. Taken together, acid-induced ALI results in epithelial MV shuttling of miR-17/221 that in turn modulates macrophage beta1 integrin recycling, promoting macrophage recruitment and ultimately contributing to lung inflammation. PMID- 28674182 TI - Mesenchymal Cell-Specific MyD88 Signaling Promotes Systemic Dissemination of Salmonella Typhimurium via Inflammatory Monocytes. AB - Enteric pathogens including Salmonella enteric serovar Typhimurium can breach the epithelial barrier of the host and spread to systemic tissues. In response to infection, the host activates innate immune receptors via the signaling molecule MyD88, which induces protective inflammatory and antimicrobial responses. Most of these innate immune responses have been studied in hematopoietic cells, but the role of MyD88 signaling in other cell types remains poorly understood. Surprisingly, we found that Dermo1-Cre;Myd88fl/fl mice with mesenchymal cell specific deficiency of MyD88 were less susceptible to orogastric and i.p. STyphimurium infection than their Myd88fl/fl littermates. The reduced susceptibility of Dermo1-Cre;Myd88fl/fl mice to infection was associated with lower loads of S. Typhimurium in the liver and spleen. Mutant analyses revealed that S. Typhimurium employs its virulence type III secretion system 2 to promote its growth through MyD88 signaling pathways in mesenchymal cells. Inflammatory monocytes function as a major cell population for systemic dissemination of S. Typhimurium Mechanistically, mesenchymal cell-specific MyD88 signaling promoted CCL2 production in the liver and spleen and recruitment of inflammatory monocytes to systemic organs in response to STyphimurium infection. Consistently, MyD88 signaling in mesenchymal cells enhanced the number of phagocytes including Ly6ChiLy6G- inflammatory monocytes harboring STyphimurium in the liver. These results suggest that S. Typhimurium promotes its systemic growth and dissemination through MyD88 signaling pathways in mesenchymal cells. PMID- 28674183 TI - N-terminal part of Dishevelled DEP domain is required for Wnt/beta-catenin signaling in mammalian cells. AB - Dishevelled (DVL) proteins are key mediators of Wnt/beta-catenin signaling pathway. All DVL proteins contain three conserved domains -- DIX, PDZ and DEP. There is a consensus in the field that DIX domain is critical for Wnt/beta catenin signaling but contradictory evidence exists regarding the function of the DEP domain. It has been difficult until recently to test the importance of the DEP domain rigorously because of the interference with endogenous DVL, expressed in all Wnt-responsive cell lines. In this study, we took advantage of DVL KO (DVL1/DVL2/DVL3-triple knockout) cells, fully deficient in Wnt3a-induced signaling events, and performed series of rescue experiments. Using this complementation assays we analyze the role of individual DVL isoforms. Further domain mapping of DVL1 showed that DVL1 DEP domain, and especially its N-terminal region, is both required and sufficient for Wnt3a-induced phosphorylation of LRP6 and TopFlash reporter activation. On the contrary, multiple DEP domain mutants deficient in the planar cell polarity (PCP) pathway could fully rescue the Wnt3a response. This study provides conclusive evidence that DVL DEP domain is essential for Wnt/beta-catenin signaling in mammalian cells and establishes an experimental system suitable for further functional testing of DVL. PMID- 28674184 TI - Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells. AB - Although deregulation of MEK/extracellular signal-regulated kinase (ERK) activity is a key feature in cancer, high-magnitude MEK/ERK activity can paradoxically induce growth inhibition. Therefore, additional mechanisms may exist to modulate MEK/ERK activity in favor of tumor cell proliferation. We previously reported that mortalin/HSPA9 can facilitate proliferation of certain KRAS and BRAF tumor cells by modulating MEK/ERK activity. In this study, we demonstrated that mortalin can regulate MEK/ERK activity via protein phosphatase 1alpha (PP1alpha). We found that PP1alpha inhibition increases steady-state levels of phosphorylated MEK1/2 in various tumor cells expressing B-RafV600E or K-RasG12C/D Intriguingly, coimmunoprecipitation and in vitro binding assays revealed that mortalin facilitates PP1alpha-mediated MEK1/2 dephosphorylation by promoting PP1alpha MEK1/2 interaction in an ATP-sensitive manner. The region spanning Val482 to Glu491 in the substrate-binding cavity and the substrate lid of mortalin were necessary for these physical interactions, which is consistent with conventional heat shock protein 70 (HSP70)-client interaction mechanisms. Nevertheless, mortalin depletion did not affect cellular PP1alpha levels or its regulatory phosphorylation, suggesting a nonconventional role for mortalin in promoting PP1alpha-MEK1/2 interaction. Of note, PP1alpha was upregulated in human melanoma and pancreatic cancer biopsy specimens in correlation with mortalin upregulation. PP1alpha may therefore have a role in tumorigenesis in concert with mortalin, which affects MEK/ERK activity in tumor cells. PMID- 28674185 TI - Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism. AB - Termination of Saccharomyces cerevisiae RNA polymerase II (Pol II) transcripts occurs through two alternative pathways. Termination of mRNAs is coupled to cleavage and polyadenylation while noncoding transcripts are terminated through the Nrd1-Nab3-Sen1 (NNS) pathway in a process that is linked to RNA degradation by the nuclear exosome. Some mRNA transcripts are also attenuated through premature termination directed by the NNS complex. In this paper we present the results of nuclear depletion of the NNS component Nab3. As expected, many noncoding RNAs fail to terminate properly. In addition, we observe that nitrogen catabolite-repressed genes are upregulated by Nab3 depletion. PMID- 28674186 TI - Transforming Growth Factor beta/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38alpha (Mitogen-Activated Protein Kinase 14) Dependent. AB - Transforming growth factor beta (TGF-beta)-induced migration of triple-negative breast cancer (TNBC) cells is dependent on nuclear export of the orphan receptor NR4A1, which plays a role in proteasome-dependent degradation of SMAD7. In this study, we show that TGF-beta induces p38alpha (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-beta/p38alpha and NR4A1 also play essential roles in the induction of epithelial-to-mesenchymal transition (EMT) and induction of beta catenin in TNBC cells, and these TGF-beta-induced responses and nuclear export of NR4A1 are blocked by NR4A1 antagonists, the p38 inhibitor SB202190, and kinase dead [p38(KD)] and dominant-negative [p38(DN)] forms of p38alpha. Inhibition of NR4A1 nuclear export results in nuclear export of TGF-beta-induced beta-catenin, which then undergoes proteasome-dependent degradation. TGF-beta-induced beta catenin also regulates NR4A1 expression through formation of the beta-catenin-TCF 3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF-beta-induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of beta-catenin, and all of these pathways are inhibited by bis-indole-derived NR4A1 antagonists that inhibit nuclear export of the receptor and thereby block TGF-beta-induced migration and EMT. PMID- 28674189 TI - Fowler Receives de Hevesy Nuclear Pioneer Award. PMID- 28674190 TI - Pomper Recognized with 2017 Aebersold Award. PMID- 28674187 TI - PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion. AB - Secreted exosomes carrying lipids, proteins, and nucleic acids conduct cell-cell communications within the microenvironment of both physiological and pathological conditions. Exosome secretion is triggered by extracellular or intracellular stress signals. Little is known, however, about the signal transduction between stress cues and exosome secretion. To identify the linker protein, we took advantage of a unique finding in human keratinocytes. In these cells, although transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) share the same EGF receptor and previously indistinguishable intracellular signaling networks, only TGF-alpha stimulation causes exosome-mediated secretion. However, deduction of EGF-activated pathways from TGFalpha-activated pathways in the same cells allowed us to identify the proline-rich Akt substrate of 40 kDa (PRAS40) as the unique downstream effector of TGF-alpha but not EGF signaling via threonine 308-phosphorylated Akt. PRAS40 knockdown (KD) or PRAS40 dominant negative (DN) mutant overexpression blocks not only TGF-alpha- but also hypoxia- and H2O2-induced exosome secretion in a variety of normal and tumor cells. Site directed mutagenesis and gene rescue studies show that Akt-mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion without affecting the endoplasmic reticulum/Golgi pathway. Identification of PRAS40 as a linker protein paves the way for understanding how stress regulates exosome secretion under pathophysiological conditions. PMID- 28674188 TI - NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells. AB - Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used Keap1-deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to Keap1 deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response. PMID- 28674192 TI - SNMMI-TS Leadership Update: Demonstrating the Crucial Role of NMTs and Strengthening the Profession. PMID- 28674193 TI - SNMMI Leadership Update: SNMMI's New Value Initiative and Strategic Plan. PMID- 28674195 TI - This Month in JNM. PMID- 28674196 TI - Integrated Residency in Radiology and Nuclear Medicine in The Netherlands. PMID- 28674198 TI - Inner Workings: How saving some of the Southeast's oldest trees might help scientists monitor climate change. PMID- 28674202 TI - Enrico Mihich, MD: In Memoriam (1928-2016). PMID- 28674200 TI - The deep, hot biosphere: Twenty-five years of retrospection. AB - Twenty-five years ago this month, Thomas Gold published a seminal manuscript suggesting the presence of a "deep, hot biosphere" in the Earth's crust. Since this publication, a considerable amount of attention has been given to the study of deep biospheres, their role in geochemical cycles, and their potential to inform on the origin of life and its potential outside of Earth. Overwhelming evidence now supports the presence of a deep biosphere ubiquitously distributed on Earth in both terrestrial and marine settings. Furthermore, it has become apparent that much of this life is dependent on lithogenically sourced high energy compounds to sustain productivity. A vast diversity of uncultivated microorganisms has been detected in subsurface environments, and we show that H2, CH4, and CO feature prominently in many of their predicted metabolisms. Despite 25 years of intense study, key questions remain on life in the deep subsurface, including whether it is endemic and the extent of its involvement in the anaerobic formation and degradation of hydrocarbons. Emergent data from cultivation and next-generation sequencing approaches continue to provide promising new hints to answer these questions. As Gold suggested, and as has become increasingly evident, to better understand the subsurface is critical to further understanding the Earth, life, the evolution of life, and the potential for life elsewhere. To this end, we suggest the need to develop a robust network of interdisciplinary scientists and accessible field sites for long-term monitoring of the Earth's subsurface in the form of a deep subsurface microbiome initiative. PMID- 28674203 TI - Retraction: Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor-CTL Interaction. PMID- 28674204 TI - Correction: Rescue of p53 Function by Small-Molecule RITA in Cervical Carcinoma by Blocking E6-Mediated Degradation. PMID- 28674205 TI - Correction: Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity. PMID- 28674206 TI - Correction: Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth. PMID- 28674217 TI - Genomic restructuring in F1 Hordeum chilense * durum wheat hybrids and corresponding hexaploid tritordeum lines revealed by DNA fingerprinting analyses. PMID- 28674219 TI - Low genetic diversity of the endangered Indian wild ass Equus hemionus khur, as revealed by microsatellite analyses. PMID- 28674218 TI - Development and characterization of genomic microsatellite markers in Tinospora cordifolia. PMID- 28674220 TI - Isolation and characterization of microsatellite markers in Garcinia gummi-gutta by next-generation sequencing and cross-species amplification. AB - Garcinia gummi-gutta (L.) Roxb. (Clusiaceae) is an endemic, semidomesticated, fruit-yielding tree species distributed in the Western Ghats of India and Sri Lanka. Various bioactive phytochemicals, such as garcinol, benzophenones and xanthones are isolated from G. gummi-gutta and have shown antibacterial, antiviral and antioxidant activities. We sequenced the total genomic DNA using Illumina Hiseq 2000 platform and examined 241,141,804 bp high quality data, assembled into 773,889 contigs. In these contigs, 27,313 simple-sequence repeats (SSRs) were identified, among which mononucleotide repeats were predominant (44.98%) followed by dinucleotide and trinucleotide repeats. Primers were designed for 9964 microsatellites among which 32 randomly selected SSR primer pairs were standardized for amplification. Polymerase chain reaction (PCR) amplification of genomic DNA in 30 G. gummi-gutta genotypes revealed polymorphic information content (PIC) across all 32 loci ranging from 0.867 to 0.951, with a mean value of 0.917. The observed and expected heterozygosity ranged from 0.00 to 0.63 and 0.896 to 0.974, respectively. Alleles per locus ranged from 12 to 27. This is the first report on the development of genomic SSR markers in G. gummi gutta using next-generation sequencing technology. The genomic SSR markers developed in this study will be useful in identification, mapping, diversity and breeding studies. PMID- 28674221 TI - Genetic analysis of drug metabolizing phase-I enzymes CYP3A4 in Tibetan populations. AB - The enzymatic activity of CYP3A4 results in broad interindividual variability in response to certain pharmacotherapies. The present study aimed to screen Tibetan volunteers for CYP3A4 genetic polymorphisms. Previous research has focussed on Han Chinese patients, while little is known about the genetic variation of CYP3A4 in the Tibetan populations. Here, we adopted DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A4 gene in 96 unrelated healthy Tibetan individuals.We identified 20 different CYP3A4 polymorphisms in the Tibetan population, including two novel variants (21824 A>G and 15580 G>C). In addition, we also determined the allele frequencies of CYP3A4*1A and CYP3A4*1H were 82.29% and 28.13%, respectively. CYP3A4*1P and *1G were relatively rare with frequencies of only 1.04% and 0.52%, respectively. Our results provide information on CYP3A4 polymorphisms in Tibetan individuals which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group. PMID- 28674222 TI - Small suitability of the DLEC1, MLH1 and TUSC4 mRNA expression analysis as potential prognostic or differentiating markers for NSCLC patients in the Polish population. AB - According to the latest data, lung cancer is one of the most common cancer worldwide, men contributing nearly 21.2% and women 8.6% of all diagnosed cancers. Late detection of tumour drastically reduces the chance for a cure. Thus, it is important to search for candidate biomarkers for screening of early stage nonsmall cell lung carcinoma (NSCLC). Tumour suppressor genes, DLEC1, TUSC4 and MLH1, localized on 3p21 are recognized to play a role in NSCLC carcinogenesis. The aim of this study was to assess the relationship between the DLEC1, TUSC4 and MLH1 mRNA expression, and clinical features of NSCLC patients, tobacco addiction, and tumour histopathological characteristics. The DLEC1, TUSC4 and MLH1 expression was analysed in lung tumour tissue samples obtained from 69 patients diagnosed with NSCLC: squamous cell carcinoma (n = 34), adenocarcinoma (n = 24), large cell carcinoma (n = 5), carcinoma adenosquamosum (n = 5). A decreased gene expression (RQ < 0.7) was observed for DLEC1 in 60.9% of tumour samples, for MLH1 in 50.7% and for TUSC4 in 26% of NSCLC samples. DLEC1 was decreased in more aggressive subtypes: large cell carcinoma and adenocarcinoma-squamous cell carcinoma. The simultaneous downregulation of two of the studied genes, DLEC1 andMLH1,was observed in 30.4% of NSCLCsamples, highlighting the importance of these two genes in lung carcinogenesis. We found no correlation between the DLEC1, TUSC4 and MLH1 gene expression and NSCLC patient characteristics (gender, age and smoking) or cancer histopathology. No significant differences in the gene expression among NSCLC subtypes indicate the weakness of DLEC1, TUSC4 and MLH1 expression analysis as potential differentiating markers of NSCLC subtypes in the Polish population. PMID- 28674223 TI - Expression analysis of argonaute, Dicer-like, and RNA-dependent RNA polymerase genes in cucumber (Cucumis sativus L.) in response to abiotic stress. AB - Posttranscriptional control of gene expression can be achieved through RNA interference when the activities of Dicer-like (DCL), argonaute (AGO) and RNA dependent RNA polymerase (RDR) proteins are significant. In this study, we analysed the expression of seven AGO, five DCL and eight RDR genes in cucumber under cold, heat, hormone, salinity and dehydration treatments using quantitative reverse-transcription PCR (qRT-PCR). All CsAGO, CsDCL and CsRDR genes were differentially expressed under abiotic stress treatment. In response to abiotic stress treatment, most genes were expressed at higher levels in flowers or stems than in other organs, whereas some CsAGOs (CsAGO1c, CsAGO6 and CsAGO7) and CsRDRs (CsRDR1d and CsRDR2) were highly expressed in roots during dehydration treatment. The expression patterns indicate that most CsDCLs, CsAGOs and CsRDRs respond to abiotic stress, and stems or flowers are the most sensitive organs, followed by roots. This is the first report of expression analysis of all CsDCL, CsAGO and CsRDR family genes in cucumber under abiotic stress, which provides basic information and insights into the putative roles of these genes in abiotic stress. The results of this study should serve as a basis for further functional characterization of these gene families in cucumber and related Cucurbitaceae species. PMID- 28674224 TI - Association of NFKB1A and microRNAs variations and the susceptibility to atherosclerosis. AB - Atherosclerosis (AT) is a chronic immuno-inflammatory disease characterized by inflammatory mediators and immune activation in arterial wall. Although NF-kappaB and microRNAs are involved in the atherosclerotic lesions, the pathogenesis of atherosclerosis is still unknown. The aim of this study was to investigate the association of atherosclerosis with NFKB1-rs28362491, NFKBIA-rs696, pre-miRNA 146a-rs2910164 and pre-miRNA-499-rs3746444 polymorphisms as well as the analysis of their single and combined effects on its susceptibility in a Turkish population. We analysed the distribution of NFKB1-94 ins/del ATTG (rs28362491), NFKBIA (rs696), pre-miR-146a (rs2910164) and pre-miR-499 (rs3746444) genetic polymorphisms using PCR-RFLP assay in 150 atherosclerotic patients and 145 healthy controls in a Turkish population. The data revealed no significant differences in the distribution of the genotype and alleles of rs28362491 ,whereas AA genotype of rs696 lead to a higher risk for atherosclerotic patients. TT genotype and T allele of pre-miR-499 rs3746444 were found to be associated with atherosclerosis risk. In addition, significant differences were found between atherosclerotic patients and control subjects, concerning pre-miR-146a rs2910164 polymorphism. The subjects carrying the GG genotype and G allele of rs2910164 were found to have an increased risk against AT. The results of combined genotype analysis, showed no notable differences between the multiple comparisons of rs28362491- rs696 whereas rs28362491-rs2910164 ins/ins/GG is associated with increased AT risk. The combined genotypes of rs28362491/rs3746444 ins/ins/TT, revealed a significant protective effect on AT. These findings indicate that genetic polymorphisms of NFKB1A rs696, pre-miR-146a rs2910164 and pre-miR-499 rs3746444 may represent novel markers of AT susceptibility. PMID- 28674225 TI - Ne2 encodes protein(s) and the altered RuBisCO could be the proteomics leader of hybrid necrosis in wheat (Triticum aestivum L.). AB - Wheat hybrid necrosis is caused by the interaction of two dominant complementary genes, Ne1 and Ne2, located on chromosome arms 5BL and 2BS, respectively. The sequences of Ne1 or Ne2 have not yet been identified. It is also not known whether Ne1 and Ne2 are structural or regulatory genes. Understanding the proteomic pathways may provide a knowledge base for protecting or maximizing the photosynthesis capacity of wheat. Using DIGE and MALDITOF- TOF MS, the flag leaf protein patterns of the two unique F14 near-isogenic line siblings (NILs), the necrotic ShunMai 12Ah (Ne1Ne1Ne2Ne2) and the normal ShunMai 12Af (Ne1Ne1ne2ne2) were compared. Due to the presence or absence of Ne2, (i) three protein spots were expressed or disappeared, (ii) seven RuBisCO-related proteins were altered significantly, and (iii) 21 photosynthesis/glucose related proteins were changed significantly. Three hypotheses were deduced, (i) Ne1 may also encode protein(s), (ii) genetic maladjustment of RuBisCO could lead to early leaf death, and (iii) interactions between nuclear genes and chloroplast genes could determine photosynthetic traits. Our hypothetical model presents the RuBisCO pathway of hybrid necrosis in wheat and explains how Ne1 and Ne2 interact at molecular level. PMID- 28674226 TI - Identification and validation of reference genes for gene expression studies in sweet osmanthus (Osmanthus fragrans) based on transcriptomic sequence data. AB - Accurate normalized data is a primary requisite for quantifying gene expression using RT-qPCR technology. Despite this importance, however, suitable reference genes in Osmanthus fragrans are not available. In this study, seven potential candidate reference genes (OfL25-1, OfL25-10, OfRP2, OfTUA, OfTUB3, OfUBQ2 and Of18S) were evaluated to determine which one would be the most reliable reference genes. The expression levels of the candidate reference genes were analysed by RT qPCR in flower, leaf, pedicel, blossom bud tissues, as well as in floral organs at different developmental stages.GeNormand NormFinderwere used to statistically analyse transcript variation.Results indicated that OfRP2 and OfL25-10 were the optimal reference genes for use in RT-qPCR when analysing different stages of floral development; while OfTUB3 and OfL25-1 were optimal across tissues. The selected reference genes were used to examineOfMYB1 expression. The results appeared to be useful for future gene expression analyses aiming to characterize developmental stages and tissues of O. fragrans. PMID- 28674227 TI - A systematic analysis of the association studies between CASP8 D302H polymorphisms and breast cancer risk. AB - Caspase 8 (CASP8) is a regulator of apoptosis, whose genetic variation has been reported to be associated with the risk of various cancers. Especially, the single-nucleotide polymorphism (SNP) rs1045485, which generates the substitution D302H in CASP8, is likely to be associated with breast cancer. Several previous studies have reported the association of CASP8 D302H polymorphism with breast cancer; however, the results are inconsistent. To validate the association between CASP8 D302H polymorphism and breast cancer risk, we performed an updated meta-analysis of 18 studies including 27,807 cases and 32,332 controls. We tested the overall association between this SNP and breast cancer susceptibility and stratified subgroups based on countries where cases are from. We confirmed a significant correlation between CASP8 D302H polymorphism and the reduced breast cancer susceptibility in population from UK, Germany and Poland, but no significant association was observed in other countries, such as Finland or USA. Our findings indicate the relationship of SNP CASP8 D302H and breast cancer would not be universal but only be sensitive in some particular European countries. The genetic difference for diverse countries may be useful in individual and precision medicine or health. PMID- 28674228 TI - Genetics and mapping of a new leaf rust resistance gene in Triticum aestivum L. * Triticum timopheevii Zhuk. derivative 'Selection G12'. AB - A Triticum timopheevii-derived bread wheat line, Selection G12, was screened with 40 pathotypes of leaf rust pathogen, Puccinia triticina at seedling stage and with two most commonly prevalent pathotypes 77-5 and 104-2 at adult plant stage. Selection G12 showed resistance at both seedling and adult plant stages. Genetic analysis in F1, F2and F2.3 families at the seedling stage revealed that leaf rust resistance in Selection G12 is conditioned by a single incompletely dominant gene. The leaf rust resistance gene was mapped to chromosome 3BL with SSR markers Xgwm114 and Xgwm547 flanking the gene at a distance of 28.3 cM and 6 cM, respectively. Based on the nature of resistance and chromosomal location, it is inferred that Selection G12 carries a new gene for leaf rust resistance, tentatively named as LrSelG12. PMID- 28674229 TI - Prion protein gene polymorphisms in Turkish native goat breeds. AB - Susceptibility to 'scrapie' disease in goats is influenced by polymorphisms of the prion protein (PRNP) gene. The aim of this study was to identify PRNP gene polymorphisms in a total of 356 scrapie disease-free goats from 10 Turkish native breeds. Eighteen single-nucleotide polymorphisms were detected in the caprine PRNP open-reading frame. Ten previously described amino acid substitutions (I142M, H143R, N146S, N146D, R151H, R154H, P168Q, R211Q, Q222K and P240S) and two novel dimorphisms (G134E and Q163P) were identified. The strongest association between caprine PRNP and relative resistance to scrapie disease has been reported previously for polymorphisms at codons 146 (S/D) and 222 (K). In the present study, these three PrP variants were relatively rare with 6.3%. This is the first report on PRNP gene variation in Turkish native goat breeds and our knowledge of these polymorphisms will assist goat breeding programmes to reduce the risk of scrapie. PMID- 28674230 TI - cDNA cloning, structural analysis, SNP detection and tissue expression profile of the IGF1 gene in Malabari and Attappady Black goats of India. AB - Insulin-like growth factor 1 (IGF1) plays an important role in growth, reproduction, foetal development and cell proliferation. The present study was conducted to clone and sequence the full-length coding sequence of the caprine IGF1 gene from Attappady Black and Malabari breeds, two indigenous goat breeds of south India, to analyse its structure, and to ascertain the relative abundance of IGF1 mRNA in different tissues. The caprine IGF1 cDNA (GenBank accession nos: KJ549851 and KJ549852) contained a 465-bp open reading frame encoding IGF1 protein with 154 amino acid residues. A novel SNP was detected in the 3'UTR region, g.931A>G. Genotyping was performed in 277 goats from the two genetic groups using the PCR-single strand conformational polymorphism (SSCP) and two genotypes, AA and AG were observed at this locus. IGF1 is a secretary pathway protein with 49 amino acid-long signal peptide with 19 phosphorylation sites. Caprine IGF1 amino acid sequence was 83-99% identical to other species with highest identity with the ruminants. Relative expression of IGF1 was highest in uterus and liver (P < 0.05), followed by oviduct and muscle. This work provided an important experimental basis for further research on the functions of IGF1 in goats. PMID- 28674231 TI - Molecular characterization and expression of the GDF9 gene in New Zealand white rabbits. AB - Growth differentiation factor 9 (GDF9) has been shown to be involved in regulating follicular development and reproduction in many mammalian species. However, related information about the effect of the GDF9 gene on reproductive traits of New Zealand white rabbits was rarely reported. In this study, rabbits were distributed into two groups (poor and prolific offspring productions) and cloning and quantitative real-time PCR (qPCR) were employed to characterize the rabbit GDF9 gene. By cloning, 2515-bp genomic DNA and 1359-bp cDNA sequences were obtained. Comparing the two cDNA sequences, three potential mutation sites (C.539C>T,C.562G>C and C.718C>G) in exon 2 of the GDF9 gene were found, and the corresponding amino acids changed (P.183T>M, P.188E>Q and P.240L>V). The qPCR results revealed that GDF9 was not tissue-specific, but rather expressed in all collected tissues. The expression level of the GDF9 gene was highest in the ovary, and was significantly increased (P< 0.05) compared with the other tissues. The liver had the second highest expression, and the heart and spleen had the least expression in New Zealand white rabbits. In the prolific group, the expression quantity of the GDF9 gene significantly increased (P < 0.05) in the heart, spleen, ovary, liver and uterus (P < 0.01) than the other groups. The amino acid sequence identities of human, sheep, goat, mouse, cattle, pig, cat, donkey, Nancy Ma's night monkey and olive baboon were 72, 68, 69, 66, 69, 71, 67, 73, 75 and 73%, respectively. Bioinformatics analysis was executed, and a random coil was determined to be the primary secondary structure. PMID- 28674232 TI - A cross-sectional study of PRNP gene in two native Sicilian goat populations in Italy: a relation between prion gene polymorphisms and scrapie incidence. AB - Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases affecting humans and animals, and scrapie in small ruminants is considered the archetype of TSEs. Derivata di Siria is a native dairy goat of Sicily (south Italy), which is related to Syrian goat breeds. Scrapie disease is considered endemic in Sicily since 1997, following the administration of an infected vaccine.Derivata di Siria goatswere involved in six of 66 scrapie infected flocks in Sicily. Prion protein gene (PRNP) analysis revealed that none of the scrapie cases carried the p.Gln222Lys variant. Sequencing of PRNP in this goat population showed a high frequency (15%) of p.Gln222Lys variant confirming its association with scrapie resistance. PRNP polymorphisms were also analysed in the population of Pantelleria, a small Sicilian Island, where scrapie has never been reported. The native goat breed 'Pantesca' was maintained up to almost 80 years and the size of the sheep population on this island has historically been very low. Currently, a crossbreed goat population of 253 heads is present on the island. PRNP genotyping of Pantelleria goats showed genetic variation, with low presence of wild-type goats and the lack of protective alleles. These data reinforce the association between PRNP polymorphisms in small ruminants and scrapie incidence. PMID- 28674233 TI - Prevalence and spectrum of thalassaemia in Changsha, Hunan province, China: discussion of an innovative screening strategy. AB - Hunan province located in the south of China has a high incidence of haemoglobinopathies. In the present study, we surveyed the accurate population frequency data of the local population in Changsha city of Hunan province in China. The data includes the carrying rate, gene mutation types and their distribution features for thalassaemia. In total, 7500 consecutive samples from five geographical areas of Changsha were analysed for both haematological and molecular parameters. Therewas a high prevalence of carriers of alpha thalassaemia (2.57%), beta-thalassaemia (1.9%) and both alpha-thalassaemia and beta-thalassaemia (0.08%). Overall, 4.54% of the population in this area represented heterozygous carriers of alpha-thalassaemia and beta-thalassaemia. The mutation spectrum of alpha-thalassaemia and beta-thalassaemia and its haematological characterization were fully described for this area. The present study is the first to report the prevalence of thalassaemia in Hunan province population. Both alpha-thalassaemia and beta-thalassaemia carriers are widely distributed in Changsha. The knowledge gained from the present study will allow for an estimation of the projected number of pregnant women at risk for thalassaemia, and the design of a screening strategy for the control of thalassaemia in Changsha. PMID- 28674234 TI - Expression and imprinting of DIO3 and DIO3OS genes in Holstein cattle. AB - DIO3 and DIO3OS are two imprinted genes identified in mouse and humans. The DIO3 gene, which encodes for the type 3 deiodinase, is preferentially expressed from the paternal allele, while the DIO3OS transcript is transcribed in opposite orientation to DIO3, multiple noncoding and alternatively splicing isoforms from maternal allele. In this study, the five splice variants of DIO3OS were identified in Holstein cattle and had complex, tissue-specific expression patterns observed in eight tissues, including heart, liver, spleen, lung, kidney, muscle, fat and brain. In the G+C rich region, upstream from the cattle DIO3 gene, there were three small conserved regions and some promoter elements similar to those observed in mouse and humans. An allele-specific expression analysis based SNP method revealed that DIO3 and DIO3OS genes exhibited monoallelic expression in the eight tissues, indicating that DIO3 and DIO3OS are imprinted in cattle. PMID- 28674235 TI - Molecular characterization, expression profile of the FSHRgene and its association with egg production traits in muscovy duck. AB - Follicle-stimulating hormone (FSH) and its receptor play a key role in the follicular development and regulation of steroidogenesis in the ovary and spermatogenesis in the testis. The purpose of this study was to characterize themuscovy duck FSHR gene, identify SNPs and their association with egg production traits in muscovy ducks. Here, we cloned the complementary DNA (cDNA) sequence of FSHR, and examined the expression patterns of FSHR gene in adult female muscovy duck tissues. The cloned cDNA of the muscovy duck FSHR gene shared high similarity to those of pekin duck (Anas platyrhynchos) (95.7%) and chicken (93.2%). Three different muscovy duck FSHR transcripts were identified. Quantitative real-time PCR (RT-qPCR) results showed that the FSHR gene was expressed in all the 14 tested tissues, and the highest expression level was seen in the ovary. A total of 16 SNPs were identified, among which, four SNPs were located in the coding region of FSHR. The SNP C320T is significantly associated with egg production at 59 weeks of age (P < 0.05), whereas the SNP A227G is significantly associated with age at first egg stage (P < 0.05). These results suggest that the two SNPs (A227G and C320T) of FSHR gene are associated with egg production traits and could be potential markers that can be used for marker assisted selection programmes to increase egg production in muscovy duck. PMID- 28674236 TI - Molecular systematics of Indian Alysicarpus (Fabaceae) based on analyses of nuclear ribosomal DNA sequences. AB - Alysicarpus Necker ex Desvaux (Fabaceae, Desmodieae) consists of ~30 species that are distributed in tropical and subtropical regions of theworld. In India, the genus is represented by ca. 18 species, ofwhich seven are endemic. Sequences of the nuclear Internal transcribed spacer from38 accessions representing 16 Indian specieswere subjected to phylogenetic analyses. The ITS sequence data strongly support the monophyly of the genus Alysicarpus. Analyses revealed four major well supported clades within Alysicarpus. Ancestral state reconstructions were done for two morphological characters, namely calyx length in relation to pod (macrocalyx and microcalyx) and pod surface ornamentation (transversely rugose and nonrugose). The present study is the first report on molecular systematics of Indian Alysicarpus. PMID- 28674237 TI - Study of bantam miRNA expression in brain tumour resulted due to loss of polarity modules in Drosophila melanogaster. AB - Disturbance of delicate concordance between stem cell proliferation, specification and differentiation during brain development leads to several neural disorders including tumours. Accumulating evidences have demonstrated involvement of short noncoding microRNAs (miRNAs) in governing several biological as well as pathological processes, including tumourigenesis across various species. Drosophila bantam miRNA, known to regulate critical physiological functions is reported to have elevated expression in ovarian tumour. Here, we provide an update on the expression of bantam miRNA in Drosophila brain tumour background resulting due to loss of well characterized polarity proteins, Brat, Lgl and Scrib. Since, both miRNA TaqMan assay and bantam sensor assay showed elevated expression of bantam in brain tumour background, it clearly reflects presence of an antagonistic relationship between polarity proteins and bantam miRNA indicating of its involvement in tumour progression. PMID- 28674238 TI - Characterization of duck (Anas platyrhynchos) MHC class I gene in two duck lines. AB - To enrich gene polymorphism ofDuMHCI and provide data for further studies on disease resistance, 14DuMHCI genes from Weishan Ma duck and Cherry Valley duck were cloned, and their characterization were investigated. The overall conservation of the 14 alleles could be observed within the sequences, and relative conservation were also displayed in the peptide-binding domain and CD8 interaction sites. Based on full-length amino acid homology, MHC class I from different duck lines could be divided into 13 gene groups and three novel gene groups existed.Moreover, 14 key variable residues corresponding to gene groups division were exhibited on the homology modelling constructed based on the resolved protein structure of DuMHC I. This study explicit the characteristics of DuMHC I in the two duck lines and could contribute to design effective diagnostics and vaccines for the species against various infections. PMID- 28674239 TI - Genetic diversity and population structure of blue-crested lizard, Calotes mystaceus Dumeril & Bibron, 1837 (Squamata: Agamidae) in Thailand. AB - The blue-crested lizard, Calotes mystaceus Dumeril & Bibron, 1837, is listed as a protected wild animal in Thailand. Its population is likely to be dramatically reduced due to massive hunting in several areas in this country. Basic information on its population genetics is therefore needed to facilitate its conservation. Thus, in this study we investigated the mitochondrial cytochrome c oxidase subunit 1 (CO1) sequence variation of 238 individualC.mystaceus from 42 different geographical localities of the north, west, central, east and northeast regions of Thailand. High genetic diversity and genetic differentiation at the intrapopulation and interpopulation levels was observed.We detected 63 unique haplotypes and 12 common/shared haplotypes. The phylogenetic analysis reveals two major lineages, I and II. These two lineages are separated by mountain ranges, which play an important role as natural barriers blocking gene flow. Our finding reveal at least two cryptic lineages represented in C. mystaceus populations in Thailand. However, a comprehensive investigation of the morphology, biology, ecology and genetic diversity of C. mystaceus in other regions within its area of distribution is needed. PMID- 28674240 TI - Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene. AB - Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6 MFSD2A ANKLE2 and CIT (Khan et al. 2014; Yamamoto et al. 2014; Alakbarzade et al. 2015;Morris-Rosendahl and Kaindl 2015; Basit et al. 2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C>T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain. PMID- 28674241 TI - Mutation analysis of COL4A3 and COL4A4 genes in a Chinese autosomal-dominant Alport syndrome family. AB - Autosomal dominant Alport syndrome (ADAS) accounts for 5% of all cases of Alport syndrome (AS), a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family.Mutations in COL4A3 and COL4A4 genes were reported to be associated with ADAS. In this study, clinical data in a large consanguineous family with seven affected members were reviewed, and genomic DNA was extracted. For mutation screening, all exons of COL4A3 and COL4A4 genes were polymerase chain reaction-amplified and direct sequenced from genomic DNA, and the mutations were analyzed by comparing with members in this family, 100 ethnicitymatched controls and the sequence of COL4A3 and COL4A4 genes from GenBank. A novel mutation determining a nucleotide change was found, i.e. c.4195 A>T (p.Met1399Leu) at 44th exon of COL4A4 gene, and this mutation showed heterozygous in all patients of this family. Also a novel intron mutation (c.4127+11 C>T) was observed at COL4A4 gene. Thus the novel missense mutation c.4195 A>T (p.Met1399Leu) and the intron mutation (c.4127+11 C>T) at COL4A4 gene might be responsible for ADAS of this family. Our results broadened the spectrum of mutations in COL4A4 and had important implications in the diagnosis, prognosis, and genetic counselling of ADAS. PMID- 28674242 TI - The indefinable term 'prokaryote' and the polyphyletic origin of genes. AB - An analysis has been performed on implications existing between the presence/absence of the evolutionary stage of the prokaryote, that is to say, the presence/absence of common characteristics between archaea and bacteria, and the monophyletic/polyphyletic origin of genes of proteins. Thereafter, a theorem stating that: 'the polyphyletic origin of proteins would imply the absence of common characteristics between bacteria and archaea and therefore the lack of the evolutionary stage of the prokaryote, and vice versa that the indefinable prokaryote stage implies a polyphyletic origin of proteins', has been made and validated. The conclusion is that given the absence of truth in common characteristics between archaea and bacteria, the origin of genes of proteins should have been polyphyletic. PMID- 28674243 TI - Size-Dependency of the Surface Ligand Density of Liposomes Prepared by Post insertion. AB - In the active targeting of a drug delivery system (DDS), the density of the ligand on the functionalized liposome determines its affinity for binding to the target. To evaluate these densities on the surface of different sized liposomes, 4 liposomes with various diameters (188, 137, 70, 40 nm) were prepared and their surfaces were modified with fluorescently labeled ligand-lipid conjugates by the post-insertion method. Each liposomal mixture was fractionated into a series of fractions using size exclusion chromatography (SEC), and the resulting liposome fractions were precisely analyzed and the surface ligand densities calculated. The data collected using this methodology indicate that the density of the ligand on a particle is greatly dependent on the size of the liposome. This, in turn, indicates that smaller liposomes (75-40 nm) tend to possess higher densities. For developing active targeting systems, size and the density of the ligands are two important and independent factors that can affect the efficiency of a system as it relates to medical use. PMID- 28674244 TI - Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline. AB - The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound Ki values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound Ki values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency. PMID- 28674245 TI - A C8-Modified Graphene@mSiO2 Composites Based Method for Quantification of Gallic Acid in Rat Plasma after Oral Administration of Changtai Granule and Its Application to Pharmacokinetics. AB - A rapid, effective extraction technique has been established for measuring the gallic acid in rat plasma by using sandwich-structured graphene/mesoporous silica composites with C8-modified interior pore-walls as adsorbent. The unique characteristics of the graphene-silica composites excluded large molecules, like proteins, from the mesopore channels as a result of size exclusion effect, leading to a direct extraction of drug molecules from protein-rich biological samples such as plasma without any other pretreatment procedure. Followed by elution and centrifugation, the gallic acid-absorbed composites were rapidly isolated before LC-MS/MS. Serving as a reliable tool for analysis of Traditional Chinese Medicine: Changtai Granule, the newly developed method was fully validated and successfully applied in the pharmacokinetic study of gallic acid in rat plasma. Extraction recovery, matrix effect and stability were satisfactory in rat plasma. According to the results of pharmacokinetic studies, Changtai Granule exhibited greater adsorption, distribution and clearance properties of gallic acid in the treatment of ulcerative colitis. Hence, this study may offer a valuable alternative to simplify and speed up sample preparation, and be useful for clinical studies of related preparations. PMID- 28674246 TI - Intracellular Growth and Morphological Characteristics of Legionella pneumophila during Invasion and Proliferation in Different Cells. AB - Various studies have been made to attempt to study the interaction between Legionella pneumophila and the host cells. In this research, we successfully constructed a L. pneumophila mutant strain that stably expressed high levels of green fluorescent protein and used this strain to evaluate the adherence, invasion and proliferation of L. pneumophila in association with several cell lines, including seven cell lines [human macrophage-like cell lines (U937, THP 1), murine macrophage-like cell lines (J774.1A, Raw264.7), human bronchial epithelial cell lines (16HBE, Beas-2B) and human cerrical cancer cell line (HeLa)] which have been used as the host models of L. pneumophila, and two breast carcinoma cell lines (MCF-7 and MDA-MB-231). Our results showed that the two newly tested cell lines are able to support the intracellular proliferation of L. pneumophila, and there were some morphological variations during the invasion and intracellular replication of L. pneumophila in different cell lines. These results can help us find out the common and special patterns of invasion and proliferation of L. pneumophila within different hosts. This is conducive to our knowledge on the relationship and interaction between bacteria and host. PMID- 28674247 TI - Osthole Enhances the Therapeutic Efficiency of Stem Cell Transplantation in Neuroendoscopy Caused Traumatic Brain Injury. AB - Neuroendoscopy processes can cause severe traumatic brain injury. Existing therapeutic methods, such as neural stem cell transplantation and osthole have not been proven effective. Therefore, there is an emerging need on the development of new techniques for the treatment of brain injuries. In this study we propose to combine the above stem cell based methods and then evaluate the efficiency and accuracy of the new method. Mice were randomly divided into four groups: group 1 (brain injury alone); group 2 (osthole); group 3 (stem cell transplantation); and group 4 (osthole combined with stem cell transplantation). We carried out water maze task to exam spatial memory. Immunocytochemistry was used to test the inflammatory condition of each group, and the differentiation of stem cells. To evaluate the condition of the damaged blood brain barrier restore, we detect the Evans blue (EB) extravasation across the blood brain barrier. The result shows that osthole and stem cell transplantation combined therapeutic method has a potent effect on improving the spatial memory. This combined method was more effective on inhibiting inflammation and preventing neuronal degeneration than the single treated ones. In addition, there was a distinct decline of EB extravasation in the combined treatment groups, which was not observed in single treatment groups. Most importantly, the combined usage of osthole and stem cell transplantation provide a better treatment for the traumatic brain injury caused by neuroendoscopy. The collective evidence indicates osthole combined with neural stem cell transplantation is superior than either method alone for the treatment of traumatic brain injury caused by neuroendoscopy. PMID- 28674248 TI - A Nanoparticle-Based Ophthalmic Formulation of Dexamethasone Enhances Corneal Permeability of the Drug and Prolongs Its Corneal Residence Time. AB - We designed ophthalmic formulations containing dexamethasone-loaded solid nanoparticles (DEXnano dispersion), and investigated corneal permeability and toxicity. 0.1% dexamethasone (DEX) powder (DEX microparticles), 0.026% methyl p hydroxybenzoate (MP), 0.014% propyl p-hydroxybenzoate (PP), and 0.5% methylcellulose were used, and the DEXnano dispersion was prepared by the bead mill method. The mean particle size of DEXnano dispersion was 78 nm. Antimicrobial activity of the DEXnano dispersion were measured by using Escherichia coli, and the corneal epithelium-debrided rat model and HCE-T cells (immortalized human corneal epithelial cell line) were used to estimate the corneal toxicity. The transcorneal penetration of the DEXnano dispersion were evaluated in the corneas of rabbit. The DEXnano dispersion was found to be highly stable until 14 d after its preparation. Although DEX itself did not exhibit antimicrobial activity, the DEXnano dispersion containing parabens (MP and PP) showed high antimicrobial activity, approximately equal to that of the solution containing parabens without DEX. The corneal penetration rate (Jc) and mean residence time (MRT) of DEX from the DEXnano dispersion were approximately 5.1- and 1.3-fold higher, respectively, than those of a dispersion containing DEX microparticles (mean particle size, 11.3 um). In addition, no significant difference was found in corneal stimulation between the vehicle and DEXnano dispersion. In conclusion, we successfully prepared high quality dispersion containing DEX solid nanoparticles, and the nanoparticle-based ophthalmic formulation of DEX enhanced the corneal permeability and residence time of the drug. It is possible that DEXnano dispersion will show increased effectiveness in treating ocular inflammation. PMID- 28674249 TI - Effects of Gintonin-Enriched Fraction in an Atopic Dermatitis Animal Model: Involvement of Autotaxin Regulation. AB - Ginseng extract has been used for prevention of atopic dermatitis (AD) in experimental animal models. However, little is known about its active ingredients and the molecular mechanisms underlying its anti-AD effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin, from ginseng. Gintonin, the glycolipoprotein fraction of ginseng, contains LPAs, mainly LPA C18 : 2 with other minor lysophospholipid components. A line of evidence showed that serum autotaxin (ATX) activity and level are significantly elevated in human AD patients compared to those in normal controls, which indicates that ATX may be involved in human AD. In a previous study, we demonstrated that gintonin exerted anti-inflammatory effects via inhibition of microglial activation and proinflammatory cytokine production by immune cells and that it strongly inhibited ATX activity. In this study, we investigated whether oral administration of the gintonin-enriched fraction (GEF) could ameliorate the symptoms of 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/Nga mice. We found that oral administration of GEF to DNFB-induced AD mice for 2 weeks reduced ear swelling and AD skin index. In addition, oral administration of GEF reduced the serum levels of immunoglobulin E, histamine, interleukin-4, and interferon-gamma. Histological examination showed that oral administration of GEF attenuated skin inflammation and significantly reduced eosinophil and mast cell infiltration into the skin. Moreover, oral administration of GEF not only decreased serum ATX level but also reduced serum ATX activity. The present study shows that the anti-AD effects of ginseng might be attributed to GEF-induced anti-inflammatory activity and ATX regulation. PMID- 28674250 TI - Prophylactic Oral Administration of Magnesium Ameliorates Dextran Sulfate Sodium Induced Colitis in Mice through a Decrease of Colonic Accumulation of P2X7 Receptor-Expressing Mast Cells. AB - The number of patients with colitis has been increasing year by year. Recently, intestinal inflammation, as one of the factors for its onset, has been demonstrated to be induced by P2X7 receptor-mediated activation of colonic immune cells such as mast cells. Activation of P2X7 receptor (P2X7R) is known to be inhibited by divalent metal cations such as magnesium, but whether or not magnesium administration prevents/relieves colitis is unknown so far. Here, we report that oral (per os (p.o.)) administration of MgCl2 and ingestion of commercially available magnesium-rich mineral hard water relieves dextran sulfate sodium (DSS)-induced colitis in mice. Colitis was induced through ingestion of a 3% (w/v) DSS solution ad libitum for 10 d. Brilliant blue G (BBG, a P2X7R antagonist), MgCl2 or magnesium-rich mineral hard water was administered p.o. to mice via gastric intubation once a day or ad libitum from a day before DSS administration for 11 times or 11 d, respectively. DSS-treated mice exhibited a low disease activity index, a short colon and a high histological score compared to in control mice. As BBG (250 mg/kg, p.o.), administration of a MgCl2 solution (100 or 500 mg/kg, p.o.) and ad libitum ingestion of the magnesium-rich mineral hard water (212 ppm as magnesium) partially, but significantly, attenuated the severity of colitis by decreasing the accumulation of P2X7R-immunopositive mast cells in the colon. Therefore, prophylactic p.o. administration/ingestion of magnesium is considered to be partially effective to protect mice against DSS induced colitis by inhibiting P2X7R-mediated activation/accumulation of colonic mast cells. PMID- 28674251 TI - Co-administration of Fluvastatin and CYP3A4 and CYP2C8 Inhibitors May Increase the Exposure to Fluvastatin in Carriers of CYP2C9 Genetic Variants. AB - Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2C8. Predictions of drug-drug interactions (DDI) are important for the safety of combination therapies with statins, in particular drugs that are metabolized by CYP3A4. Little information is available regarding drug interactions with fluvastatin. Since CYP2C9 is a polymorphic enzyme, we investigated the effect of DDI via CYP2C9, CYP3A4, and CYP2C8 on fluvastatin pharmacokinetics by using a validated prediction method in relation to CYP2C9 variants. The predicted increases in the area under the concentration-time curve (AUC) ratios of fluvastatin in carriers with CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 versus that found in carriers with CYP2C9*1/*1 were 1.16, 1.35, 1.37, 1.65, and 2.06, respectively. Our in silico model predicted that administration of fluvastatin in conjunction with the potent inhibitors that completely inhibited CYP3A4 and CYP2C8 in carriers with the CYP2C9*3/*3 variant would cause a 3.23- and 2.60-fold increase in the AUC ratios, respectively, when compared to that for the carriers with the CYP2C9*1/*1 taking fluvastatin alone. We also predicted the effect of telmisartan when coadministered with fluvastatin. Our prediction results showed that the interaction between telmisartan and fluvastatin via CYP enzymes were negligible in clinical situations. PMID- 28674252 TI - The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity. AB - Distigmine bromide (distigmine), a reversible, long-lasting cholinesterase (ChE) inhibitor, is used for the treatment of underactive bladder in Japan and has been shown to potentiate urinary bladder (UB) contractility. We studied the duration of distigmine's potentiating effects on acetylcholine (ACh)-induced UB contraction and its inhibitory effects on ChE activity, and compared that with those of other ChE inhibitors (neostigmine, pyridostigmine, and ambenonium). The duration of potentiating/inhibitory effects of ChE inhibitors, including distigmine, on ACh-induced guinea pig UB contraction/ChE activity was evaluated for 12 h following washout. Dissociation rate constants (k) of the inhibitors were also tentatively calculated based on the time courses of their ChE inhibitory effects. The potentiating effect of distigmine (10-6 M) on ACh-induced UB contraction and its inhibitory effect on ChE activity were significantly sustained 12 h after washout. The potentiating effect of other ChE inhibitors on ACh-induced UB contraction, however, was sustained only until 3 h after washout. The ChE inhibitory effects of these inhibitors dissipated in a time-dependent manner after washout, with more than 75% of ChE activity restored by 4 h after washout. The k values of ChE inhibitors approached 0.50 h-1, except for distigmine, where k could not be determined. Compared with that of other ChE inhibitors, the potentiating effect of distigmine on UB contractile function was significantly more sustainable following washout, which was likely associated with its corresponding long-lasting ChE inhibitory effect. Distigmine may associate more strongly with UB ChE than other ChE inhibitors, which would partly explain its sustained effects. PMID- 28674253 TI - Effect of Valerian/Hop Mixture on Sleep-Related Behaviors in Drosophila melanogaster. AB - The aim of this study was to investigate the sleep-promoting effect of a Valerian/Hops mixture in fruit flies. The HPLC analysis showed that Valerenic acid (1260.53 ug/g of extract) and Xanthohumol (Cascade: 827.49 ug/g, Hallertau: 763.60 ug/g, Saaz: 186.93 ug/g) were contained in Valerian and Hop, respectively. The sleep patterns of fruit flies on the Valerian/Hops were examined in both baseline and caffeine-treated conditions. Total activities of flies significantly decreased in 20 mg/mL Valerian (74%), 10 mg/mL Cascade (25%), and 5 mg/mL Hallertau (11%) during nighttime or daytime compared with the control. Valerian/Cascade mixture showed longer sleeping time (ca. 20%) than control group. This mixture-mediated effect was partly observed in caffeine-treated flies. Valerian/Cascade mixture upregulated mRNA expressions of gamma aminobutyric acid (GABA) receptors and serotonin receptor, and GABA receptors were more strongly regulated than serotonin receptor. In competitive GABA receptor binding assay, Valerian/Cascade mixture extract showed a higher binding ability on GABA receptor than Valerenic acid or/and Xanthohumol which are estimated to be active compounds in the extract. This study demonstrates that a Valerian/Cascade mixture extract improves sleep-related behaviors, including sleeping time, by modulating GABAergic/serotonergic signaling. PMID- 28674254 TI - Caffeine Increases Hippocampal Sharp Waves in Vitro. AB - Caffeine promotes memory consolidation. Memory consolidation is thought to depend at least in part on hippocampal sharp waves (SWs). In the present study, we investigated the effect of bath-application of caffeine in spontaneously occurring SWs in mouse acute hippocampal slices. Caffeine induced an about 100% increase in the event frequency of SWs at concentrations of 60 and 200 uM. The effect of caffeine was reversible after washout of caffeine and was mimicked by an adenosine A1 receptor antagonist, but not by an A2A receptor antagonist. Caffeine increased SWs even in dentate-CA3 mini-slices without the CA2 regions, in which adenosine A1 receptors are abundantly expressed in the hippocampus. Thus, caffeine facilitates SWs by inhibiting adenosine A1 receptors in the hippocampal CA3 region or the dentate gyrus. PMID- 28674255 TI - Amelioration of the Development of Osteoarthritis by Daily Intake of beta Cryptoxanthin. AB - beta-Cryptoxanthin, which is primarily obtained from citrus fruits such as Satsuma mandarins, is a major carotenoid routinely found in human serum. Recently, we demonstrated that daily oral intake of beta-cryptoxanthin prevented ovariectomy-induced bone loss and ameliorated neuropathic pain in mice. Although beta-cryptoxanthin exerts preventive effects on various lifestyle-related diseases, there have been no studies on the effect of beta-cryptoxanthin on the development of osteoarthritis, the most common degenerative joint disease, which frequently leads to loss of ability and stiffness in the elderly. Here we showed that daily oral administration of beta-cryptoxanthin significantly prevented the development of osteoarthritis developed by surgically inducing knee joint instability in mice in vivo. Furthermore, in vitro experiments revealed that beta cryptoxanthin markedly inhibited the expression of inflammatory cytokines and enzymes critical for the degradation of the extracellular matrix in primary chondrocytes. Our results suggest that oral supplementation of beta-cryptoxanthin would be beneficial for the maintenance of joint health and as prophylaxis against osteoarthritis. PMID- 28674256 TI - Prenatal Exposure to Tributyltin Decreases GluR2 Expression in the Mouse Brain. AB - Tributyltin (TBT), a common environmental contaminant, is widely used as an antifouling agent in paint. We previously reported that exposure of primary cortical neurons to TBT in vitro decreased the alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor subunit glutamate receptor 2 (GluR2) expression and subsequently increased neuronal vulnerability to glutamate. Therefore, to identify whether GluR2 expression also decreases after TBT exposure in vivo, we evaluated the changes in GluR2 expression in the mouse brain after prenatal or postnatal exposure to 10 and 25 ppm TBT through pellet diets. Although the mean feed intake and body weight did not decrease in TBT-exposed mice compared with that in control mice, GluR2 expression in the cerebral cortex and hippocampus decreased after TBT exposure during the prenatal period. These results indicate that a decrease in neuronal GluR2 may be involved in TBT-induced neurotoxicity, especially during the fetal period. PMID- 28674257 TI - A Novel Role of MerC in Methylmercury Transport and Phytoremediation of Methylmercury Contamination. AB - MerC, encoded by merC in the transposon Tn21 mer operon, is a heavy metal transporter with potential applications for phytoremediation of heavy metals such as mercuric ion and cadmium. In this study, we demonstrate that MerC also acts as a transporter for methylmercury. When MerC was expressed in Escherichia coli XL1 Blue, cells became hypersensitive to CH3Hg(I) and the uptake of CH3Hg(I) by these cells was higher than that by cells of the isogenic strain. Moreover, transgenic Arabidopsis plants expressing bacterial MerC or MerC fused to plant soluble N ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) accumulated CH3Hg(I) effectively and their growth was comparable to the wild-type plants. These results demonstrate that when the bacterium-derived merC gene is ectopically introduced in genetically modified plants, MerC expression in the transgenic plants promotes the transport and sequestration of methylmercury. Thus, our results show that the expression of merC in Arabidopsis results in transgenic plants that could be used for the phytoremediation and elimination of toxic methylmercury from the environment. PMID- 28674258 TI - Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN), characterized by symptoms of paresthesia, dysesthesia, numbness, and pain, is a common adverse effect of several chemotherapeutic agents, including platinum-based agents, taxanes, and vinca alkaloids. However, no effective prevention or treatment strategies exist for CIPN because the mechanisms underpinning this neuropathy are poorly understood. Recent accumulating evidence suggests that some transient receptor potential (TRP) channels functioning as nociceptors in primary sensory neurons are responsible for CIPN. In this review, we focus on the specific roles of redox sensitive TRP ankyrin 1 (TRPA1), which was first reported to be a cold nociceptor, in acute cold hypersensitivity induced by oxaliplatin, a platinum based agent, because it induces a peculiar cold-triggered CIPN during or within hours after its infusion. Oxaliplatin-induced rapid-onset cold hypersensitivity is ameliorated by TRPA1 blockade or deficiency in mice. Consistent with this, oxaliplatin enhances the responsiveness of TRPA1 stimulation, but not of TRP melastatin 8 (TRPM8) and TRP vanilloid 1 (TRPV1), in mice and cultured mouse dorsal root ganglion neurons. These responses are mimicked by an oxaliplatin metabolite, oxalate. In human TRPA1 (hTRPA1)-expressing cells, oxaliplatin or oxalate causes TRPA1 sensitization to reactive oxygen species (ROS) by inhibiting prolyl hydroxylases (PHDs). Inhibition of PHD-mediated hydroxylation of a proline residue within the N-terminal ankyrin repeat of hTRPA1 endows TRPA1 with cold sensitivity by its sensing of cold-evoked ROS. This review discusses these findings and summarizes the evidence demonstrating that oxaliplatin-induced acute cold hypersensitivity is caused by TRPA1 sensitization to ROS via PHD inhibition, which enables TRPA1 to convert ROS signaling into cold sensitivity. PMID- 28674259 TI - Pinanamine Is a Promising Lead Compound against Influenza A Virus: Evidence from in Vitro and in Vivo Efficacy Compared to Amantadine. AB - Influenza A viruses with the presence of mutations in M2 still circulate and threaten to avian species and human in China. A novel M2 inhibitor pinanamine was previously identified as an antiviral agent by an in vitro assay. In this study, we monitored the activity of pinanamine against influenza A/FM1/47 (H1N1) virus infection in cell culture and mice. Pinanamine showed more potent antiviral effect than ribavirin, and was as effective as oseltamivir carboxylate and amantadine in Madin-Darby canine kidney (MDCK) cells. Pinanamine at dose of 50 mg/kg/d administrated once a day for 6 d starting 24 h prior to virus exposure promoted survival rate of infected mice to 100% (p<0.001) and produced significant reduction (p<0.001) in lung virus yields and lung index. Even lower the dose of 3.1 mg/kg/d, pinanamine was 60% protective (p<0.05), which was equivalent to treatment with amantadine at 50 mg/kg/d. Our finding highlights the potential of pinanamine as a promising lead compound for influenza A virus. PMID- 28674260 TI - Relaxin Ameliorates Renal Fibrosis and Expression of Endothelial Cell Transition Markers in Rats of Isoproterenol-Induced Heart Failure. AB - There may be cardio-renal interactions in rats of isoproterenol-induced heart failure, which may be associated with renal fibrosis and endothelial-to mesenchymal transition (EndMT). Since its discovery, relaxin (RLX) which was regarded as a reproductive hormone for a long time, is recently considered an effective antifibrotic hormone in cardiac and renal fibrosis. We studied whether RLX diminished renal fibrosis in rats of isoproterenol (Iso)-induced heart failure and investigated the mechanism. Fifty male Sprague-Dawley rats were separated into five groups for treatment: control; Iso subcutaneously injection to induce heart failure, which led to renal fibrosis; RLX subcutaneously injection at low, medium and high dose (0.2, 2, 20 ug.kg-1.d-1 for 21 d). Indices of cardiac function and organ fibrosis were examined. Expression and changes in levels of collagen, cluster of differentiation 31 (CD31), alpha-smooth muscle actin (SMA), and transforming growth factor beta (TGF-beta) were measured in renal tissues. In rats with heart failure induced by Iso, treatment with RLX significantly ameliorated cardiac function and inhibited cardiac and renal fibrosis. RLX decreased renal collagen types I and III deposition, increased CD31 expression, and decreased the expression of alpha-SMA and TGF-beta, thereby possibly indicating inhibited renal EndMT in kidneys. Iso-induced heart and renal fibrosis was inhibited even greater with high-dose RLX, so the antifibrotic effect of RLX may be dose-related. In conclusion, RLX may ameliorate renal fibrosis in rats of Iso-induced heart failure, and it is infered that prevention of the EndMT may be one of the possible potential signaling pathways. PMID- 28674261 TI - Preliminary Evaluation of Three-Dimensional Primary Human Hepatocyte Culture System for Assay of Drug-Metabolizing Enzyme-Inducing Potential. AB - Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR)). After 2 d exposure of hepatocyte spheroids to omeprazole, phenobarbital and rifampicin (typical inducers of CYP1A2, 2B6 and 3A4, respectively), CYP1A2, 2B6 and 3A4 mRNA expression levels were significantly increased. The mRNA induction of CYP2B6 remained reasonably stable between days 2 and 14 of exposure to inducers, while induction of both CYP1A2 and 3A4 continued to increase up to day 14. These enzyme activities were all significantly increased compared with the control until day 14. Our findings indicate that our 3D hepatocyte spheroids system would be especially suitable for long-term testing of enzyme activity induction by drugs, either to predict or to verify clinical events. PMID- 28674262 TI - Time-Dependent Alterations of Vancomycin-Induced Nephrotoxicity in Mice. AB - Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic that is commonly used against methicillin-resistant, Gram-positive cocci despite the nephrotoxic side effects. VCM-induced nephrotoxicity has been reported in 5-28% of recipient patients. Therefore, renal failure induced by VCM has become an important clinical problem. However, the exceedingly complex mechanism of VCM-induced nephrotoxicity is not fully understood. Therefore, this study was designed to clarify time-dependent alterations of VCM-induced nephrotoxicity in mice as a step toward decreasing the risks of kidney injury associated with VCM therapy. VCM was injected intraperitoneally into mice at a dose of 400 mg/kg body weight at 24-h intervals for 3, 5, 7, and 14 d. At 24 h after the last injection, we examined histopathological alterations of the kidney as well as blood biochemistry. VCM administration resulted in a decrease of body weight and increase of kidney weight. Histological examination revealed renal damage such as dilated proximal tubules with occasional casts and interstitial fibrosis in VCM treated mice. Furthermore, immunohistochemical staining with anti-CD10 and anti single-stranded DNA antibodies highlighted damaged renal proximal tubules with marked dilatation as well as numerous apoptotic cells as early as day 4 of VCM treatment. The severity of symptoms progressed until day 15. These results suggest that VCM-induced renal damage and incipient renal failure begin soon after the start of treatment and progressively worsen. This is the first report describing the time-dependence of VCM-induced nephrotoxicity in mice and depicting a model that clarifies the mechanisms of this tissue damage. PMID- 28674263 TI - Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration. AB - The pharmacological profile of fimasartan, [2-n-butyl-5-dimethylamino thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl} pyrimidin-4(3H)-one, a new non-peptide angiotensin type 1 (AT1)-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, fimasartan showed slow dissociation and irreversible binding to AT1 subtype receptors in membrane fractions of HEK-293 cells with a Kd of 0.03 nM and a T1/2 of 63.7 min. The inhibitory effect of fimasartan on angiotensin II (Ang II)-induced contraction persisted longer after washout than that of losartan or candesartan. In conscious rats, a single dose of fimasartan (0.3, 1, or 3 mg/kg; per os (p.o.)) dose dependently antagonized Ang II-induced pressor responses. Both orally administrated fimasartan and losartan dose-dependently decreased mean arterial pressure in furosemide-treated rats and dogs, and fimasartan administered orally at 1, 3, or 10 mg/kg reduced blood pressure in conscious spontaneously hypertensive rats. Taken together, these findings indicate that fimasartan has potent and sustained binding affinity at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in various conscious rats and dogs models after its oral administration. PMID- 28674264 TI - A Rare Case of Ulcerative Colitis with Neurofibromatosis Type 1. AB - Concomitant association of histologically proven inflammatory bowel disease (IBD) and neurofibromatosis type 1 (NF1) is a rare finding documented in only 5 adult clinical cases. A 34-year-old woman with known neurofibromatosis was admitted to our department with a 6-month history of intractable bloody diarrhea and abdominal pain. After a thorough clinical examination and paraclinical assessments, including colonoscopy and biopsy, ulcerative colitis (UC) was confirmed as the cause of gastrointestinal bleeding. NF1 is considered an autosomal dominant condition caused by mutations in the NF1 gene, which is located on chromosome 17q11.2 [1]. A wide variety of NF1 mutations have been found in patients with NF1, but no frequently recurring mutation has been identified. Since the pathogenesis of IBD is also associated with genetic make up, these two entities may be associated with a genetic factor. PMID- 28674265 TI - Temporal Trends in the Incidence and Clinical Features of Acute Myocardial Infarction in a Japanese Rural Area From 2006 to 2014. AB - BACKGROUND: Recent temporal trends in the incidence and clinical features of acute myocardial infarction (MI) in the Japanese population are not well known.Methods and Results:This study used comprehensive registration for first ever MI during the 9-year period from 2006 to 2014 in a rural area of northeastern Japan. The study period was divided into three 3-year terms (T1, 2006-2008; T2, 2009-2011; T3, 2012-2014). During the study period, a total of 814 patients with MI were registered. Although the age-adjusted incidence rate (100,000 person-years) in the middle-aged group (<70 years) was relatively stable, the rate for the elderly group (>=70 years) in T3 was significantly lower than that in T1 in both men (368 vs. 279; P<0.01) and women (204 vs. 108; P<0.01). In the general population of the study area, the rate of prescribed anticholesterol drugs was significantly increased during the study period, especially in the elderly population (P<0.01). From a clinical perspective, although the performance rate of primary percutaneous coronary intervention significantly increased with a shortened duration of hospital stay, the in hospital mortality rate, especially in the elderly, did not significantly decrease during the study period. CONCLUSIONS: The present study is the first to demonstrate a decreased age-adjusted incidence of MI during the period from 2006 to 2014 in a Japanese rural population, especially in the elderly. PMID- 28674266 TI - Pilot Cohort Study Assessing the Efficacy of Endovascular Revascularization in the Restoration of Peripheral Sensory Disturbance in Patients With Critical Limb Ischemia. AB - BACKGROUND: Sensory disturbance (SD) is a common consequence of peripheral nerve damage associated with diabetes and severe ischemia. Progression of SD places patients at high risk for lower extremity ulcers and amputations. SD has been thought to be progressive and irreversible, and possibly caused by microvascular dysfunction. The aim of this study was to determine whether endovascular revascularization (EVR) induces quantifiable changes in SD in chronic critical limb ischemia (CLI) patients with neuropathy.Methods and Results:In all, 36 legs from 28 chronic CLI patients who underwent elective EVR were prospectively enrolled in this study (64% with diabetes and 54% on maintenance hemodialysis). The current perception threshold (CPT), an established diagnostic parameter for SD, was measured before and 3 months after EVR. Of the target lesions, 11%, 47%, and 81% were in the aortoiliac, femoropopliteal, and below-the-knee arteries, respectively, and 58% were totally occluded. Overall CPT in the target foot had improved significantly 3 months after EVR (from 53 to 30 uA; P=0.010); however, EVR did not change CPT in the non-target foot (from 44 to 33 uA; P=0.33). Patients with improved SD after EVR had a significantly higher 180-day survival rate (94% vs. 63%; P=0.040). CONCLUSIONS: EVR improved CPT in target limbs of patients with CLI, and may be a promising option to improve SD associated with peripheral ischemic sensory neuropathy. PMID- 28674267 TI - Do We Expect Any Pleiotropic Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition for Reducing Cardiovascular Events Beyond Low-Density Lipoprotein Cholesterol Reduction? PMID- 28674268 TI - Oral Steroid Use and Abdominal Aortic Aneurysm Expansion - Positive Association. AB - BACKGROUND: The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041). CONCLUSIONS: Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD. PMID- 28674269 TI - Detection of Ceramide, a Risk Factor for Coronary Artery Disease, in Human Coronary Plaques by Fluorescent Angioscopy. AB - BACKGROUND: The presence of ceramide in human coronary plaques is a risk factor for ischemic heart disease, but its visualization in the human vessel wall is currently beyond the scope of any available imaging techniques.Methods and Results:Deposition of ceramide was examined by fluorescent angioscopy (FA) and microscopy (FM) using golden fluorescence (Go) as a specific marker of ceramide in yellow plaques, which were obtained from 23 autopsy subjects and classified by conventional angioscopy and histology. Ceramide was observed by FM in 34 of the 41 yellow plaques with a necrotic core (NC) but rarely in the 28 without. Ceramide and macrophages/foam cells co-deposited mainly in the border zone of the NC and fibrous cap (FC). The Go of ceramide was seen when the fibrous cap thickness was <=100 um. FA was performed to detect coronary plaques exhibiting Go in patients with coronary artery disease. Ceramide was also detected by FA in 6 of 18 yellow plaques (33.3%) in 8 patients with stable angina and in 18 of 24 yellow plaques (75.0%, P<0.05 vs. stable angina) in 8 patients with old myocardial infarction. CONCLUSIONS: The Go of ceramide in human coronary plaques is detectable by FA and Go could be used as a marker of vulnerable plaque (i.e., thin FC with NC). PMID- 28674270 TI - Fate of methylated/unmethylated H19 imprinting control region after paternal and maternal pronuclear injection. AB - The paternal-allele-specific methylation of the Igf2/H19 imprinting control region (ICR) is established during gametogenesis and maintained throughout development. To elucidate the requirement of the germline passage in the maintenance of the imprinting methylation, we established a system introducing a methylated or unmethylated ICR-containing DNA fragment (ICR-F) into the paternal or maternal genome by microinjecting into the paternal or maternal pronucleus of fertilized eggs, and traced the methylation pattern in the ICR-F. When the ICR-F was injected in a methylated form, it was demethylated approximately to half degree at blastocyst stage but was almost completely remethylated at 3 weeks of age. In the case of the unmethylated form, the ICR-F remained unmethylated at the blastocyst stage, but was almost half-methylated at 3 weeks of age. Interestingly, the paternally injected ICR-F was highly methylated compared with maternally injected ICR-F at 3 weeks of age, partially mimicking the endogenous methylation pattern. Moreover, introduction of mutations in the CTCF (CCCTC binding factor) binding sites of the ICR-F, which are known to be important for the maintenance of hypomethylated maternal ICR, induced hypermethylation of the mutated ICR-F in both paternal and maternal pronuclear injected 3-week-old mice. Our results suggest the presence of a protection-against-methylation activity of the CTCF binding site in establishing the preferential paternal methylation during post-fertilization development and the importance of germline passage in the maintenance of the parental specific methylation at H19 ICR. PMID- 28674272 TI - Frequent generation of mutants with coincidental changes in multiple traits via ion-beam irradiation in soybean. AB - Ion beams are powerful mutagens that can induce novel mutants in plants. We previously established a system for producing a mutant population of soybean via ion-beam irradiation, isolated plants that had chlorophyll deficiency, and maintained their progeny via self-fertilization. Here we report the characterization of the progeny plants in terms of chlorophyll content, flowering time and isoflavone content in seeds. Chlorophyll deficiency in the leaf tissues was linked with reduced levels of isoflavones, the major flavonoid compounds accumulated in soybean seeds, which suggested the involvement of metabolic changes associated with the chlorophyll deficiency. Intriguingly, flowering time was frequently altered in plants that had a reduced level of chlorophyll in the leaf tissues. Plant lines that flowered either earlier or later than the wild type plants were detected. The observed coincidental changes were presumed to be attributable to the following origins: structural changes of DNA segments leading to the loss of multiple gene functions, or indirect effects of mutations that affect one of these traits, which were manifested as phenotypic changes in the background of the duplicated composition of the soybean genome. PMID- 28674271 TI - Pharmacological properties of various anesthetic protocols in 10-day-old neonatal rats. AB - In general, the anesthesia in neonates involves high risk. Although hypothermic anesthesia is recommended in rats up to the age of 7 days, neonatal anesthesia for later periods has not been standardized. The present study investigated the pharmacological properties of conventional anesthetic protocols in 10-day-old SD rats. The rats were anesthetized with four anesthetics: a combination of ketamine and xylazine (K/X); a combination of medetomidine, midazolam, and butorphanol (M/M/B); isoflurane; and sevoflurane. Anesthetic depth was scored by reflex response to noxious stimuli. Induction and recovery times were recorded. Vital signs and mortality rate were evaluated for safety assessment. All rats died after administration of K/X at a dose of 60/6 mg/kg, whereas K/X at 40/4 mg/kg resulted in insufficient anesthetic depth, indicating inappropriate for neonatal anesthesia. Although M/M/B at the adult rat dose (0.15/2/2.5 mg/kg) did not provide surgical anesthetic depth, the mouse dose (0.3/4/5 mg/kg) showed sufficient anesthetic depth with relatively stable vital signs. Isoflurane required a long induction period, and caused remarkable respiratory depression and hypothermia, resulted in a 25% mortality rate. In contrast, sevoflurane provided consistent surgical anesthetic depth with rapid induction. Although respiratory rate decrease was markedly observed, all rats survived. Among the anesthetic protocols investigated in the present study, sevoflurane and M/M/B at the mouse dose were recommended for the neonatal anesthesia. Compared with adult rats, the required dose of both anesthetics in neonates was higher, possibly associated with their lower anesthetic sensitivity. PMID- 28674273 TI - Septal membrane localization by C-terminal amphipathic alpha-helices of MinD in Bacillus subtilis mutant cells lacking MinJ or DivIVA. AB - The Min system, which inhibits assembly of the cytokinetic protein FtsZ, is largely responsible for positioning the division site in rod-shaped bacteria. It has been reported that MinJ, which bridges DivIVA and MinD, is targeted to the cell poles by an interaction with DivIVA, and that MinJ in turn recruits MinCD to the cell poles. MinC, however, is located primarily at active division sites at mid-cell when expressed from its native promoter. Surprisingly, we found that Bacillus subtilis MinD is located at nascent septal membranes and at an asymmetric site on lateral membranes between nascent septal membranes in filamentous cells lacking MinJ or DivIVA. Bacillus subtilis MinD has two amphipathic alpha-helices rich in basic amino acid residues at its C-terminus; one of these, named MTS1 here, is the counterpart of the membrane targeting sequence (MTS) in Escherichia coli MinD while the other, named MTS-like sequence (MTSL), is the nearest helix to MTS1. These amphipathic helices were located independently at nascent septal membranes in cells lacking MinJ or DivIVA, whereas elimination of the helices from the wild type protein reduced its localization considerably. MinD variants with altered MTS1 and MTSL, in which basic amino acid residues were replaced with proline or acidic residues, were not located at nascent septal membranes, indicating that the binding to the nascent septal membranes requires basic residues and a helical structure. The septal localization of MTSL, but not of MTS1, was dependent on host cell MinD. These results suggest that MinD is targeted to nascent septal membranes via its C terminal amphipathic alpha-helices in B. subtilis cells lacking MinJ or DivIVA. Moreover, the diffuse distribution of MinD lacking both MTSs suggests that only a small fraction of MinD depends on MinJ for its localization to nascent septal membranes. PMID- 28674274 TI - All are equal, but some are more equal than others: Epigenetic regulation of germline stem cell fate in Drosophila melanogaster. AB - Adult stem cells are capable of both symmetric and asymmetric cell divisions. Asymmetric cell division allows self-renewal and gives rise to intermediate cells that ultimately differentiate into specific cell types. Consequently, adult stem cells play a key role in development and tissue homeostasis during the life span of an organism. Typically, adult stem cell divisions are regulated through coordination between non-autonomous signaling from the niche and cell-autonomous influences from stem cell-intrinsic factors. Although localized distribution of proteins, RNA and organelles during cell division contributes significantly to the differences between fates of daughter cells, recent studies have also implicated epigenetic factors in this process. A number of epigenetic modifications remain associated with the chromosomes during mitosis and serve as a template to reestablish fates after mitosis. Whether the distribution of epigenetic modifications is random on each chromatid or there is a bias in their distribution is therefore under extensive investigation. The nonrandom distribution of epigenetic modifications on mitotic chromosomes provides an attractive possible explanation of how bias is generated during chromatid segregation. In Drosophila male germline stem cells, the histone modifications present in the stem cells are distinct from those in the differentiating daughter cells. These modifications help to retain pre-existing histones in the mother cell while imparting newly synthesized histones to the daughter cell. Importantly, the retention of pre-existing histones in the stem cells is a prerequisite to maintain their ability to self-renew. Here we summarize recent studies that focus on the role of different epigenetic modifications in the regulation of asymmetric adult germline stem cell divisions in Drosophila. We further describe how epigenetic modifications potentially lead to variations in the otherwise equivalent chromatids, and discuss the role of biased chromatid segregation in asymmetric cell divisions. PMID- 28674275 TI - Spontaneous tyrosinase mutations identified in albinos of three wild frog species. AB - The present study reports spontaneous tyrosinase gene mutations identified in oculocutaneous albinos of three Japanese wild frog species, Pelophylax nigromaculatus, Glandirana rugosa and Fejervarya kawamurai. This represents the first molecular analyses of albinic phenotypes in frogs. Albinos of P. nigromaculatus collected from two different populations were found to suffer from frameshift mutations. These mutations were caused by the insertion of a thymine residue within each of exons 1 and 4, while albinos in a third population lacked three nucleotides encoding lysine in exon 1. Albinos from the former two P. nigromaculatus populations were also associated with splicing variants of mRNA that lacked either exons 2-4 or exon 4. In the other two frog species examined, missense mutations that resulted in amino acid substitutions from glycine to arginine and glycine to aspartic acid were identified in exons 1 and 3, respectively. The two glycines in F. kawamurai and G. rugosa, and the lysine deleted in one P. nigromaculatus albino, were highly conserved in vertebrates, which suggested that they were situated in regions of critical importance to tyrosinase function. In fact, the glycine of G. rugosa is located within a predicted copper-binding domain. The five mutations identified in the present study are candidates for causing the albinic phenotypes, and, if directly confirmed, they are all unique among vertebrates, which suggests that molecular analysis of albino frogs could contribute to research on albinos in humans and vertebrates by providing new information about tyrosinase structure and transcript processing. PMID- 28674277 TI - Telomere-binding factors in the regulation of DNA replication. AB - Recent studies have indicated new roles for telomere-binding factors in the regulation of DNA replication, not only at the telomeres but also at the arm regions of the chromosome. Among these factors, Rif1, a conserved protein originally identified in yeasts as a telomere regulator, plays a major role in the spatiotemporal regulation of DNA replication during S phase. Its ability to interact with phosphatases and to create specific higher-order chromatin structures is central to the mechanism by which Rif1 exerts this function. In this review, we discuss recent progress in elucidating the roles of Rif1 and other telomere-binding factors in the regulation of chromosome events occurring at locations other than telomeres. PMID- 28674276 TI - Brown hagfish from the northwest and east coasts of Honshu, Japan are genetically different. AB - The brown hagfish (Eptatretus atami) is one of several known hagfish species occurring in Japanese coastal waters. To date, there has been no research studying genetic polymorphisms in the species. In the present study, we analyzed differences in nucleotide sequences between two populations: one from Suruga Bay on the Pacific coast of Honshu, Japan, and the other from the Sea of Japan, off Akita on the northwest coast of Honshu. We sequenced part of the cytochrome oxidase subunit 1 gene (COX1) from the mitochondrial genome, and three G protein coupled receptor genes from the nuclear genome. Phylogenetic networks of all four genes showed divergence between the two populations. Further, comparison of the COX1 data using a phylogenetic tree for a range of hagfish species indicated clear differences between the populations, suggesting that they differ at the species level. The numbers of their teeth, in particular of fused cusps (anterior/posterior multicusps), also supported these findings. Individuals of the Suruga Bay population had 3/3 fused cusps, as described for E. atami, whereas individuals of the Akita population had 3/2 fused cusps. These results suggest that the brown hagfish from the Sea of Japan, off the northwest coast of Honshu, is a distinct species from E. atami. PMID- 28674278 TI - Genetic characterization and fine mapping of S25, a hybrid male sterility gene, on rice chromosome 12. AB - Hybrid male sterility genes are important factors in creating postzygotic reproductive isolation barriers in plants. One such gene, S25, is known to cause severe transmission ratio distortion in inter-subspecific progeny of cultivated rice Oryza sativa ssp. indica and japonica. To further characterize the S25 gene, we fine-mapped and genetically characterized the S25 gene using near-isogenic lines with reciprocal genetic backgrounds. We mapped the S25 locus within the 0.67-1.02 Mb region on rice chromosome 12. Further genetic analyses revealed that S25 substantially reduced male fertility in the japonica background, but not in the indica background. In first-generation hybrid progeny, S25 had a milder effect than it had in the japonica background. These results suggest that the expression of S25 is epistatically regulated by at least one partially dominant gene present in the indica genome. This finding supports our previous studies showing that hybrid male sterility due to pollen killer genes results from epistatic interaction with other genes that are hidden in the genetic background. PMID- 28674279 TI - Characterization of a half-pipe-like leaf1 mutant that exhibits a curled leaf phenotype. AB - Leaf forms are diverse in angiosperms, and different types of cells are differentiated depending on the species. Rice leaves are composed of a leaf blade, a leaf sheath and the junction region between them. Cells with characteristic features, such as bulliform cells and sclerenchyma cells, are differentiated in the leaf blade, together with standard epidermal and mesophyll cells. To understand the genetic mechanism underlying leaf morphogenesis in rice, we focused on a mutant, half-pipe-like leaf1 (hal1), whose leaves are adaxially curled. Histological observation revealed that the bulliform cells, which are responsible for leaf rolling under dry conditions, were small in size and abnormal in shape in a semidominant hal1-d mutant. Bulliform cell files were often ambiguous in semi-transparent hal1-d leaves cleared by the TOMEI method, suggesting that the bulliform cells were undeveloped. Therefore, a reduction in the growth of the bulliform cells seemed to be a major cause of leaf curling in the hal1-d mutant. The hal1-d mutation also affected the size of the leaf blade and the spikelet. PMID- 28674281 TI - Errata for J. Oleo Science, Vol.66, No.6, contents (2017). PMID- 28674280 TI - Interplay between chromatin modulators and histone acetylation regulates the formation of accessible chromatin in the upstream regulatory region of fission yeast fbp1. AB - Numerous noncoding RNA transcripts are detected in eukaryotic cells. Noncoding RNAs transcribed across gene promoters are involved in the regulation of mRNA transcription via chromatin modulation. This function of noncoding RNA transcription was first demonstrated for the fission yeast fbp1 gene, where a cascade of noncoding RNA transcription events induces chromatin remodeling to facilitate transcription factor binding. We recently demonstrated that the noncoding RNAs from the fbp1 upstream region facilitate binding of the transcription activator Atf1 and thereby promote histone acetylation. Histone acetylation by histone acetyl transferases (HATs) and ATP-dependent chromatin remodelers (ADCRs) are implicated in chromatin remodeling, but the interplay between HATs and ADCRs in this process has not been fully elucidated. Here, we examine the roles played by two distinct ADCRs, Snf22 and Hrp3, and by the HAT Gcn5 in the transcriptional activation of fbp1. Snf22 and Hrp3 redundantly promote disassembly of chromatin in the fbp1 upstream region. Gcn5 critically contributes to nucleosome eviction in the absence of either Snf22 or Hrp3, presumably by recruiting Hrp3 in snf22? cells and Snf22 in hrp3? cells. Conversely, Gcn5-dependent histone H3 acetylation is impaired in snf22?/hrp3? cells, suggesting that both redundant ADCRs induce recruitment of Gcn5 to the chromatin array in the fbp1 upstream region. These results reveal a previously unappreciated interplay between ADCRs and histone acetylation in which histone acetylation facilitates recruitment of ADCRs, while ADCRs are required for histone acetylation. PMID- 28674282 TI - Spiroketalcarminic Acid, a Novel Minor Anthraquinone Pigment in Cochineal Extract Used in Food Additives. AB - Cochineal extract prepared from the scale insect Dactylopus coccus (American cochineal) has been used as a natural red dye for food, cosmetics, and pharmaceuticals. The major pigment in cochineal extract is carminic acid (CA), an anthraquinone glucoside, and several minor pigments have been previously reported. Our investigation aimed at establishing the safety of cochineal dye products using ultra performance liquid chromatography-photo diode array electrospray ionization-time of flight (UPLC-PDA-ESI-TOF)/MS found an unknown minor pigment, spiroketalcarminic acid (1), in three commercial cochineal extract samples; cochineal extract used in food additives, carmine that is an aluminum salt of cochineal extract used as natural dye, and a research reagent of CA. The purification of 1 from cochineal extract involved sequential chromatographic techniques, including preparative reversed-phase HPLC. Two dimensional (2D)-NMR and mass analyses established the structure of 1 to be a novel anthraquinone with an unusual 6,5-spiroketal system instead of the C-glucosyl moiety of CA. The absolute stereochemistry of the spiroketal moiety in 1 was determined by nuclear Overhauser effect spectroscopy (NOESY) correlations and optical rotation. No data corresponding to 1 had previously been reported for extracts of dried cochineal insects and traditional art products dyed with cochineal extract, indicating that 1 is likely produced during the preparation of commercial cochineal extract. PMID- 28674283 TI - Neutral ceramidase activity inhibition is involved in palmitate-induced apoptosis in INS-1 cells. AB - Neutral ceramidase (NCDase) is a class of ceramidases, a key enzyme in ceramide degradation. Recently, it was observed that NCDase activity was suppressed by saturated fatty acids to increase ceramide content in rat muscle. However, little is known about its changes in activity and roles in palmitate (Palm)-induced lipotoxicity in pancreatic beta cells. Here, we demonstrated that Palm treatment significantly down-regulated NCDase activity, mRNA and protein levels in rat INS 1 cells. In addition, Palm caused a significant accumulation of ceramide, while SPH level remained unchanged, suggesting that inhibition of NCDase activity led to no change of SPH level after treatment with Palm for 24 h. Furthermore, NCDase overexpression significantly reduced Palm-induced apoptosis in INS-1 cells. Conversely, NCDase siRNA knockdown markedly exacerbated Palm-induced apoptosis. In conclusion, Palm treatment suppressed the activity of NCDase and down regulated its mRNA and protein expression. Furthermore, NCDase inhibition was involved in Palm-induced apoptosis by blocking ceramide degradation in INS-1 cells. PMID- 28674284 TI - C1qTNF-related protein 1 improve insulin resistance by reducing phosphorylation of serine 1101 in insulin receptor substrate 1. AB - C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p < 0.05). There was no significant correlation between CTRP1 and other IRS-1 serine sites (Ser302, Ser307, Ser612, Ser636/639, and Ser789). Collectively, our results suggested that CTRP1 might improve insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine. PMID- 28674285 TI - A high sucrose and high fat diet induced the development of insulin resistance in the skeletal muscle of Bama miniature pigs through the Akt/GLUT4 pathway. AB - A high sucrose and high fat (HSHF) diet induces insulin resistance (IR) and increased susceptibility to type 2 diabetes mellitus (T2DM), but the underlying mechanisms are poorly characterized. This study aimed to investigate the molecular mechanisms by which the HSHF diet impairs insulin sensitivity in Bama miniature pigs (sus scrofa domesticus). Twelve Bama miniature pigs were randomly assigned to the control diet (CD) group (n=6) or the HSHF group (n=6) for 6 months. Biochemical parameters were measured. Western blot, RT-qPCR and immunohistochemistry were used to profile the changes of protein expression, mRNA expression and glucose transporter 4 (GLUT4) expression in skeletal muscle tissues, respectively. In comparison to the CD group, the homeostasis model assessment-insulin resistance (HOMA-IR) index of the HSHF group demonstrated a 2.9-fold increase, and the insulin sensitivity showed a 24.8% decrease. Compared with the CD group, p-Akt S473 decreased by approximately 59% and GLUT4 decreased by 43.8% in the skeletal muscle of the HSHF group. However, the expression of p mTOR S2448 between the 2 groups was not significantly different (P=0.309). This study demonstrates that a 6-month HSHF diet caused IR, decreased insulin sensitivity, and reduced the expression of p-Akt S473 and GLUT4 in the skeletal muscle of Bama miniature pigs. PMID- 28674286 TI - Evaluation of a TPTX model induced by ischemia. AB - Parathyroidectomy (PTX), especially total parathyroidectomy (TPTX), is often recommended for severe secondary hyperparathyroidism (SHPT) if other medical treatments fail. Accurate identification and resection of parathyroid gland (PTG) tissue is the cornerstone of PTX. The establishment of a rat TPTX model would be beneficial for several applications but faces the same problems. In this experiment, we studied the mechanisms of ischemia for the accurate identification and excision of PTG tissue to establish TPTX rat models and to analyze the effects of surgical removal of PTG tissue as well as the effects of different types of water intake in rats on clinical indices. We found that the ischemia method had advantages when establishing a rat TPTX model. Removal of the PTG tissue resulted in significantly changed postoperative indices, and varying the types of water intake induced significant differences in these indices after removal of the PTG tissue. The absolute value of the difference between the serum calcium and phosphorus concentrations (|Ca-P|) accurately reflected the effect of removal of the PTG tissue and was superior to the calcium-phosphorus product (Ca * P); Ca * P accurately reflected the effect of varying the types of water intake in rats and was superior to the |Ca-P|. PMID- 28674287 TI - A case of myasthenia gravis and myositis induced by nivolumab. AB - A 74-year-old woman, who developed advanced colon cancer with focal recurrence, received two courses of a low dose of nivolumab. Five days after the second course she noticed bilateral ptosis. Her symptoms rapidly progressed to generalized manifestations including limb and neck weakness, dyspnea, and myalgia within the following two weeks. Neurological and laboratory findings supported the diagnosis of myasthenia gravis and myositis induced by nivolumab. The combination immunotherapy including oral prednisolone, intravenous immunoglobulin and plasma exchange with noninvasive positive-pressure ventilation successfully avoid tracheal intubation. Nivolumab, one of the immune checkpoint inhibitors, is the anti-programmed cell death-1 (PD-1) protein monoclonal antibody, which is effective for various cancers. Since the immune checkpoint inhibitors are going to be used widely, it is important to recognize the specific subtype of myasthenia gravis for neurologists. PMID- 28674288 TI - Pathophysiology Derived from Down Syndrome Related Genes on the 21st Chromosome. PMID- 28674289 TI - Molecular Mechanism Underlying Abnormal Differentiation of Neural Progenitor Cells in the Developing Down Syndrome Brain. AB - Down syndrome (DS) is caused by trisomy for human chromosome 21. Individuals with DS commonly exhibit mental retardation, which is associated with abnormal brain development. In the neocortex of the DS brain, the density of neurons is markedly reduced, whereas that of astrocytes is increased. Similar to abnormalities seen in DS brains, mouse models of DS show deficits in brain development, and neural progenitor cells that give rise to neurons and glia show dysregulation in their differentiation. These suggest that the dysregulation of progenitor fate choices contributes to alterations in the numbers of neurons and astrocytes in the DS brain. Nevertheless, the molecular basis underlying these defects remains largely unknown. We showed that the overexpression of two human chromosome 21 genes, DYRK1A and DSCR1, contributes to suppressed neuronal differentiation of progenitors in the Ts1Cje mouse model of DS. In addition, the effect of DYRK1A and DSCR1 overexpression on neuronal differentiation is mediated by excessive attenuation of the transcription factor NFATc. Additionally, we demonstrated that an increased dosage of DYRK1A contributes to elevated potential of Ts1Cje progenitors to differentiate into astrocytes and enhanced astrogliogenesis in the Ts1Cje neocortex. Further, we linked the increased dosage of DYRK1A to dysregulation of STAT, a transcription factor critical for astrogliogenesis. Together, our studies identify critical pathways responsible for the proper differentiation of neural progenitors into neurons and astrocytes, with direct implications for the anomalies in brain development observed in DS. PMID- 28674290 TI - Elucidating Pathogenic Mechanisms of Early-onset Alzheimer's Disease in Down Syndrome Patients. AB - Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neurofibrillary tangles by age 40-50 years. It has been considered for a number of years that 1.5-fold expression of the gene for the amyloid precursor protein (APP) located on chromosome 21 leading to overproduction of amyloid-beta peptide (Abeta) results in the early onset of AD in adults with DS. However, the mean age of onset of familial AD with the Swedish mutation on APP which has high affinity for beta secretase associated with a dramatic increase in Abeta production is about 55 years. This paradox indicates that there is a poor correlation between average ages of AD onset and the theoretical amount of Abeta production and that there are factors exacerbating AD on chromosome 21. We therefore focused on dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), since overexpressing transgenic mice show AD-like brain pathology. The overexpression of DYRK1A caused suppression of the activity of neprilysin (NEP), which is a major Abeta-degrading enzyme in the brain, and phosphorylation at the NEP cytoplasmic domain. NEP activity was markedly reduced in fibroblasts derived from DS patients compared with that in fibroblasts derived from healthy controls. This impaired activity of NEP was rescued by DYRK1A inhibition. These results show that DYRK1A overexpression causes suppression of NEP activity through its phosphorylation in DS patients. Our results suggest that DYRK1A inhibitors could be effective against AD not only in adults with DS but also in sporadic AD patients. PMID- 28674291 TI - Comprehensive Analyses of Molecules with Altered Expression in the Brain of a Mouse Model of Down Syndrome for Identification of Pharmacotherapeutic Targets. AB - Down syndrome, caused by the triplication of human chromosome 21, is the most frequent genetic cause of mental retardation. Mice with a segmental trisomy for mouse chromosome 16, which is orthologous to human chromosome 21, exhibit abnormalities similar to those in individuals with Down syndrome and therefore offer the opportunity for a genotype-phenotype correlation. In the current review, I present several mouse lines with trisomic regions of various lengths and discuss their usefulness for elucidating the mechanisms underlying Down syndrome-associated developmental cognitive disabilities. In addition, our recent comprehensive study attempting to identify molecules with disturbed expression in the brain of a mouse model of Down syndrome in order to develop a pharmacologic therapy for Down syndrome is described. PMID- 28674292 TI - Diverse Functions of a Disintegrin and Metalloproteinase with Thrombospondin Motif-1. AB - A disintegrin and metalloproteinase with thrombospondin motif-1 (ADAMTS1) was initially cloned from a colon cachexia cell line. In the last 20 years, novel matrix metalloproteinase (MMP) genes were found, and in addition to their original members (MMPs and membrane-type MMPs), the current MMP family contains a disintegrin and metalloproteinases (ADAMs) and ADAMTS. ADAM and ADAMTS play essential roles in organogenesis as well as various diseases including osteoarthritis. ADAMTS has 19 members and can be divided into several groups according to their substrates. ADAMTS1, the first member of ADAMTS identified, is located on chromosome 21 very close to another ADAMTS member, ADAMTS5. Interestingly, ADAMTS1 is not highly expressed in normal tissues. One stimulation such as inflammation quickly induces ADAMTS1 expression. We found that hypoxia induced ADAMTS1 expression in endothelial cells, and serum ADAMTS1 levels were elevated in acute myocardial infarction patients. Once the artery was reperfused, the serum ADAMTS1 level quickly returned to the normal level. We also found that ADAMTS1 has specific roles in angiogenesis and lymphangiogenesis, and these functions were not related to its protease activity. It is also interesting that ADAMTS1 is likely to have a unique role in the tumor microenvironment. We also analyzed ADAMTS1-deficient mice and the results suggested that ADAMTS1 has diverse biological functions. PMID- 28674293 TI - Insight in the Evolution of Therapeutic Monoclonal Antibodies-Fundamental Technologies for Creation and Evaluation of Next Generation mAbs. PMID- 28674294 TI - Antibody Therapeutics: Bench to Bedside. AB - Monoclonal antibodies have been considered promising therapeutic entities due to their highly specific binding to antigens. For oncology in particular, the tumor specific binding of an antibody, without affecting normal tissue, is considered an ideal cancer therapy. Although the proposed mechanism of action of antibody therapeutics varies by targets and indications, antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), ligand neutralization and inhibition of the signaling pathway are commonly used. Recent advances in genomic information, genetic engineering, and transgenic technology have greatly accelerated drug development processes. It is also possible to add new functions to antibody molecules through molecular engineering. For example, antibody-drug conjugates (ADC), which combine a monoclonal antibody and a small-molecule cytotoxic drug, have been successfully used for cancer treatment. It has been more than 20 years since the first therapeutic antibody was approved in Japan, and there are now more than 30 antibodies on the market, with many new molecules under development. Despite some drawbacks and challenges, antibody therapeutics hold great promise as we advance our knowledge and technologies in the coming years. PMID- 28674295 TI - Development of a Rapid Identification Method for a Variety of Antibody Candidates Using High-throughput Sequencing. AB - As an alternative to hybridoma technology, the antibody phage library system can also be used for antibody selection. This method enables the isolation of antigen specific binders through an in vitro selection process known as biopanning. While it has several advantages, such as an avoidance of animal immunization, the phage cloning and screening steps of biopanning are time-consuming and problematic. Here, we introduce a novel biopanning method combined with high-throughput sequencing (HTS) using a next-generation sequencer (NGS) to save time and effort in antibody selection, and to increase the diversity of acquired antibody sequences. Biopannings against a target antigen were performed using a human single chain Fv (scFv) antibody phage library. VH genes in pooled phages at each round of biopanning were analyzed by HTS on a NGS. The obtained data were trimmed, merged, and translated into amino acid sequences. The frequencies (%) of the respective VH sequences at each biopanning step were calculated, and the amplification factor (change of frequency through biopanning) was obtained to estimate the potential for antigen binding. A phylogenetic tree was drawn using the top 50 VH sequences with high amplification factors. Representative VH sequences forming the cluster were then picked up and used to reconstruct scFv genes harboring these VHs. Their derived scFv-Fc fusion proteins showed clear antigen binding activity. These results indicate that a combination of biopanning and HTS enables the rapid and comprehensive identification of specific binders from antibody phage libraries. PMID- 28674296 TI - Next Generation Antibody Therapeutics Using Bispecific Antibody Technology. AB - Nearly fifty monoclonal antibodies have been approved to date, and the market for monoclonal antibodies is expected to continue to grow. Since global competition in the field of antibody therapeutics is intense, we need to establish novel antibody engineering technologies to provide true benefit for patients, with differentiated product values. Bispecific antibodies are among the next generation of antibody therapeutics that can bind to two different target antigens by the two arms of immunoglobulin G (IgG) molecule, and are thus believed to be applicable to various therapeutic needs. Until recently, large scale manufacturing of human IgG bispecific antibody was impossible. We have established a technology, named asymmetric re-engineering technology (ART)-Ig, to enable large scale manufacturing of bispecific antibodies. Three examples of next generation antibody therapeutics using ART-Ig technology are described. Recent updates on bispecific antibodies against factor IXa and factor X for the treatment of hemophilia A, bispecific antibodies against a tumor specific antigen and T cell surface marker CD3 for cancer immunotherapy, and bispecific antibodies against two different epitopes of soluble antigen with pH-dependent binding property for the elimination of soluble antigen from plasma are also described. PMID- 28674298 TI - Thorough Discussion! What Does IPE Bring to Pharmaceutical Education? PMID- 28674297 TI - Characterization of Therapeutic Monoclonal Antibodies by Using FcgammaR expressing Reporter Cell Lines. AB - Fcgamma receptors (FcgammaRs), which bind to the Fc regions of antibodies, play an important role in antibody effector functions. In humans, there are four types of activating FcgammaRs: FcgammaRI, FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb. These are expressed on various effector cells such as natural killer (NK) cells, neutrophils and macrophages. FcgammaRIIIa expressed on NK cells is known to play a pivotal role in antibody-dependent cellular cytotoxicity (ADCC) by therapeutic monoclonal antibodies (mAbs). To assess the ADCC activity of mAbs, the killing of target cells is often measured using human peripheral mononuclear blood cells (hPBMCs) or isolated primary NK cells as effector cells. These assays can directly assess the cytotoxicity induced by mAbs, but require fresh blood from donors, and are insufficiently reproducible due to differences in effector cell activity among donors. We developed a cell-based assay using reporter cell lines expressing human FcgammaR and a nuclear factor of activated T cells (NFAT)-driven luciferase reporter gene (Jurkat/FcgammaR/NFAT-Luc), which can estimate the activation of various FcgammaRs by antigen-bound mAbs in vitro, with high reproducibility. The usefulness of this assay was confirmed by comparing mAbs activity with different abilities to activate FcgammaRs, including Fc-engineered anti-CD20 mAbs and anti-EGFR mAbs with different IgG subclasses. We also confirmed the application of this assay for the characterization of mAbs product related substances. Our FcgammaR reporter assay is a promising new tool for the characterization of therapeutic mAbs in various stages of mAbs development. PMID- 28674299 TI - Introduction: Interprofessional Education (IPE) and Pharmaceutical Education: Saitama Interprofessional Education Project. AB - In 2002, the Centre for the Advancement of Interprofessional Education (CAIPE) defined interprofessional education (IPE) as: Interprofessional Education occurs when two or more professions learn with, from, and about each other to improve collaboration and the quality of care. Since 2005, also in Japan, IPE has been introduced within educational institutions to train professionals in healthcare and welfare. Within pharmaceutical education, to acquire the "10 qualities required for pharmacists" indicated by revised model core curricula for pharmaceutical education in 2015, IPE is thought quite important. Meanwhile, highly advanced medical treatment is rapidly developing, and as a consequence home healthcare and long-term care must also be enlarged. As a countermeasure, an integrated community care system must be established, and pharmacists will be responsible for urgent tasks within the system. Four universities-Prefectural University, Saitama Medical University, Josai University, and the Nippon Institute of Technology-decided to implement a collaborative project with the philosophy of "realizing high-quality lifestyles for local residents". This project was adopted by the Ministry of Education, Culture, Sports, Science and Technology as a Program for Promoting Inter-University Collaborative Education for fiscal year 2012. In this symposium, I report on the relationship between this initiative and pharmacy education, as well as discuss expectations of IPE for pharmacist education in the future. PMID- 28674300 TI - Systematic and Stepwise Interprofessional Education in Showa University. AB - At Showa University, which consists of the schools of medicine, dentistry, pharmacy, nursing and rehabilitation sciences, systematic interprofessional education was introduced with the cooperation of all 4 schools and through all undergraduate grades with the purpose of training medical staff who can contribute positively to the medical team. In the lower grades, students study the basics of medical team care based on a 4-school joint curriculum of experience learning (such as early exposure) and problem-based learning (PBL) tutorial inside and outside of the university. In the upper grades, students study the practice of medical team care by joint curriculum of participatory learning in the hospitals and community so as to acquire practical skills. Since 2014, we introduced systematic interprofessional education for home care and narrative-based medicine. Through these curriculums, I expect that the number of medical staff who actively promote patient-centered team medical care in a variety of medical fields, including hospitals and community, will continue to grow in the future. PMID- 28674301 TI - The Development of a New IPE Program for Family Pharmacists. AB - Due to the rapid aging of the population, it has become important to ensure the provision of primary health care services. To respond to this challenge, it will be insufficient to offer services only at medical institutions; indeed, there are extremely high expectations for pharmacists because they work in close contact with the population at drugstores and pharmacies. Moreover, the Japanese government intends to promote family pharmacies (pharmacists) that not only prepare drugs but also give advice on health issues. In this context, pharmacists are expected to play new roles that surpass those in the existing framework, and this will require a new program to facilitate the acquisition of new abilities (skill mix). As an example, we would like to introduce an education program for pharmacists designed to develop clinical reasoning skills for patients' symptoms. To care properly for patients with symptoms and to decide whether to encourage self-medication or to recommend consultation with a doctor, pharmacists need to develop the ability to take a medical history in a systematic and reasonable way, and then to make an adequate assessment. Therefore on the basis of cooperation between doctors and pharmacists, we have developed an education program, as well as a medical interview support tool to assist pharmacists in obtaining necessary and comprehensive medical histories. PMID- 28674302 TI - Effect of IPE on Medical Profession Education and Expectations of Pharmacists From the Perspective of Nurses. AB - On January 1, 2015, the Interprofessional Education Research Center (IPERC) was opened at the Graduate School of Nursing at Chiba University, while being positioned as one of the Inohana Campus High Functionality Initiatives by the university. As the result of the establishment of an education research center in the nursing graduate school, various changes are coming into view. In particular, the active participation of young instructors of the medical, nursing, and pharmacology departments and university hospital in interprofessional education (IPE) efforts deserve special mention. In addition, IPE training with treatment participation, which had been a pending matter for many years, is being implemented on a trial basis in the university hospital ICU and pediatric departments starting this year. During this training, treatment plan proposals will be conducted in cooperation with university hospital specialists. IPE is also having a great influence on the formation of curriculums in each department. A factor behind this is the awareness of issues by young instructors such as whether practical training fully utilizes the team building, conference management, and joint learning ability being nurtured at IPE. IPE is unable to perform fundamental education without influencing professional education, and professional education also cannot help but change into "training of specialists with the ability to make contributions considered necessary as a specialist under any circumstances", The degree to which instructors in these three departments can together support curbing of resistance to this change and promoting transformation of values is considered key. PMID- 28674303 TI - Global Practices of Interprofessional Education (IPE) and Relevant International Activities. AB - Activities related to interprofessional education (IPE) vary between countries according to local and national health needs and systems. The International Pharmaceutical Federation (FIP) Education Initiative endeavors to provide a global vision in IPE by the sharing of experiences and gathering of evidence collaboratively to facilitate country-level initiatives. The purpose of this paper is to contribute to the further development of IPE activities in pharmacy in Japan through sharing global perspectives and activities related to IPE. FIP Education Initiative published the Interprofessional Education in a Pharmacy Context: Global Report in September 2015, which marked a milestone in the growing recognition of IPE in pharmacy globally. The paper shared global and regional perspectives and experiences in IPE in pharmacy, both from the report and FIP activities. This paper can be seen as a snapshot of IPE-related international activities, which enables gaps and challenges in implementing IPE activities in Japan to be identified. This paper provides an opportunity to explore global trends and initiatives regarding IPE, and to consider how to form and implement IPE specifically based on Japanese health needs and systems. PMID- 28674304 TI - Current Status of Doping in Japan Based on Japan Anti-Doping Disciplinary Panels of the Japan Anti-Doping Agency (JADA): A Suggestion on Anti-Doping Activities by Pharmacists in Japan. AB - In 2009, the Japan Anti-Doping Agency (JADA) established the "Sports Pharmacist Accreditation Program" to prevent doping in sports. Since then, anti-doping activities in Japan have been attracting attention. In this study, we investigated research about the current status of doping from 2007 to 2014 in Japan to make anti-doping activities more concrete, and we also discussed future anti-doping activities by pharmacists. In Japan, bodybuilding was the sporting event with the highest number and rate of doping from 2007 to 2014. Many of the positive doping cases were detected for class S1 (anabolic agents), S5 (diuretics and masking agents), and S6 (stimulants). Within class S1, supplements were the main cause of positive doping. Within class S5, medicines prescribed by medical doctors were the main cause of positive doping. Within class S6, non-prescription medicines (e.g., OTC) were the main cause of positive doping. When we looked at the global statistics on doping, many of the positive doping cases were detected for class S1. On comparing the Japanese statistics with the global statistics, the rate of positive doping caused by class S1 was significantly lower, but that caused by classes S5 and S6 was significantly higher in Japan than in the world. In conclusion, pharmacists in Japan should pay attention to class S1, S5, and S6 prohibited substances and to the sport events of bodybuilding. Based on this study, sports pharmacists as well as common pharmacists should suggest new anti doping activities to prevent doping in the future. PMID- 28674305 TI - The Survey of the Compliance Situation to the Antihypertensive Therapy Guideline by Analyzing Japanese National Claims Data. AB - Kidney disease (KD) is a serious risk factor for cardiovascular event, and it is important to protect the heart and kidneys during treatment of the high blood pressure to prevent cardiovascular event. Japanese guideline (JSH2014) suggests using combination therapy to reduce the risk of comorbidities rather than high dose monotherapy for the patients with cardiovascular disease and KD. Therefore, the present study assessed antihypertensive prescription patterns in Japanese patients with ischemic heart disease related diseases (IHDRD) and KD, and evaluated whether the prescription patterns match with the guideline-suggested therapies by analyzing the national insurance claims database (NDB). We extracted antihypertensive prescription patterns among Japanese IHDRD patients from the data of October 2011 of NDB, and examined the effect of KD on the prescription patterns. The number of prescribed antihypertensive was associated with KD among patients regardless of IHDRD. Patients with IHDRD and KD were more frequently prescribed combination therapy (calcium channel blockers/angiotensin II receptor blockers) than the calcium channel blocker monotherapy, based on the JSH2014. On the other hand, we did not observe the standard use of diuretics for patients with heart failure, which is suggested by the JSH2014. These findings suggested that patients with IHDRD and KD were frequently prescribed combination therapy to achieve its cardioprotective and renoprotective effects, according to the JSH2014, but the prescription profile to the patients with heart failure didn't match that of guideline-suggested therapies. This study provided a clinically important information and demonstrated the utility of NDB for compliance assessment for therapeutics guideline. PMID- 28674306 TI - A Comparison of the Phosphorus Content in Prescription Medications for Hemodialysis Patients in Japan. AB - A high dietary intake of phosphorus is considered to be a significant health threat for hemodialysis (HD) patients. Prescription medications, which might be a major source of phosphorus, is largely unrecognized in Japan. However, the amount of phosphorus indicated on the package label, is not quantified. In this study, the phosphorus content of 22 of the most widely prescribed medications that are used in conjunction with HD therapy were examined and differences between branded and generic prescription medications were compared. All samples were selected from medications that are typically prescribed for HD patients. The samples were ground prior to analysis. Phosphorus was measured using the Wako L-Type Phosphate method. All instruments used in the study were calibrated according to the manufacturers' specifications. Amlodipine (15 mg/tablet) and paroxetine (30.0 mg/tablet) were found to contain higher contents of phosphorus than the medications tested. Differences in phosphorus content between branded and generic drugs was also determined. The phosphorus content of all generic paroxetine preparations was significantly lower than the values for identical branded medications. On the other hand, the phosphorus content of several generic amlodipine preparations were significantly different from those of similar, branded preparations. Specific information regarding the phosphorus content of prescribed medications used by HD patient needs to be made available to the dialysis community. PMID- 28674307 TI - Effects of Teicoplanin on the PT-INR Controlled by Warfarin in Infection Patients. AB - Warfarin (WF) shows a number of interactions with other drugs, which alter its anticoagulant effects. The albumin binding interaction is one such pharmacokinetic mechanism of drug interaction with WF, which induces a rise in the free WF concentration and thus increases the risk of WF toxicity. Teicoplanin (TEIC) is an anti-methicillin-resistant Staphylococcus aureus drug, which also binds strongly to albumin in the plasma. Therefore, co-administration of TEIC may displace WF from the albumin binding site, and possibly result in a toxicity. The present study was performed to investigate the drug-drug interaction between WF and TEIC in comparison with controls treated with vancomycin (VCM), which has the same spectrum of activity as TEIC but a lower albumin binding ratio.The records of 49 patients treated with WF and TEIC or VCM at Fukuoka University Hospital between 2010 and 2015 were retrospectively reviewed. These 49 patients consisted of 18 treated with TEIC in combination with WF, while 31 received VCM in combination with WF. Prothrombin time-international normalized ratio (PT-INR) showed a significant increase of 80.9 (52.0-155.3) % after co-administration of TEIC with WF. In contrast, the rate of PT-INR elevation associated with VCM plus WF was 30.6 (4.5-44.1) %. These observations suggested that TEIC can cause a rise in free WF concentration by albumin binding interaction. Therefore, careful monitoring of PT-INR elevation is necessary in patients receiving WF plus TEIC. PMID- 28674308 TI - Improved Clinical Outcomes in Patients with Positive Blood Culture by Proactive Intervention of Antimicrobial Use-Impact of Antimicrobial Stewardship Program Implementation on Clinical Practice. AB - Bacteremia is one of the most serious infectious illness resulting from nosocomial infection. Therefore, appropriate antimicrobial chemotherapy should be provided as soon as possible to patients exhibiting symptoms of infectious disease and having positive blood culture results. Antimicrobial stewardship (AS) guidelines were recently released by the Infectious Diseases Society of America. The guidelines recommend "proactive intervention and feedback" as one of the core strategies for implementing optimal antimicrobial drug use to improve patient outcomes in clinical settings. We began using the AS program for optimizing antimicrobial chemotherapy in patients with positive blood culture results. The results of blood cultures and antimicrobial prescriptions for the corresponding patients were daily reviewed by a pharmacist and a physician, members of the infection control team (ICT). If the antimicrobial agents selected were inappropriate, ICT made a recommendation to the attending physicians who prescribed the antibiotics. To evaluate the outcomes of this program, we conducted a single-center, retrospective investigation for near a hundred of patients who underwent intervention by infection-control physician and pharmacist. Resolution of bacteremia (determined by blood culture results) was 96.3% in the group that accepted intervention, whereas only 16.7% of the cases resolved in the group that did not accept intervention. These results strongly suggest the importance of the infection disease-specialist team intervention. This program could become an important method for improving clinical outcomes in patients with bacteremia. PMID- 28674309 TI - Pathogenic analysis of the pandemic 2009 H1N1 influenza A viruses in ferrets. AB - The pandemic 2009 H1N1 influenza A virus emerged in humans and caused the first influenza pandemic of the 21st century. Mexican isolates, A/Mexico/4108/2009 (H1N1) (Mex4108) and A/Mexico/InDRE4478/2009 (H1N1) (Mex4487) derived from a mild case and from a cluster of severe cases, showed heterogeneity in virulence in a cynomolgus macaque model. To compare the more pathogenic differences, we generated recombinant viruses and compared their virulence in ferrets. Ferrets infected with recombinant Mex4487 displayed a slightly higher rate of viral replication and severe pneumonia in the early stage of infection. In contrast, prolonged lower virus shedding of recombinant Mex4108 than that of recombinant Mex4487 was detected in throat swabs. Thus, Mex4487 induces severe pneumonia in infected individuals, whereas Mex4108 might have wide-spreading potential with mild disease. PMID- 28674310 TI - Distribution of Rotavirus Genotypes from the 2008/2009 to the 2015/2016 Season in Nara Prefecture, Japan. AB - This study was conducted to investigate the distribution of rotavirus genotypes in Nara Prefecture, Japan before and after the introduction of rotavirus vaccination in 2011. Since the 2011/2012 season, DS-1-like G1P[8] strains have been detected in Nara Prefecture, accounting for about half of all strains in the 2014/2015 season. During the 2015/2016 season, no DS-1-like G1P[8] strains were detected; G2P[4] was the predominant genotype. PMID- 28674311 TI - Molecular Epidemiology of Japanese Isolates of Microsporum canis Based on Multilocus Microsatellite Typing Fragment Analysis. AB - Intraspecies polymorphisms of Microsporum canis strains isolated from human lesions and domesticated cats in Japan were examined by multilocus microsatellite (MS) analysis. Using 9 MS markers, 70 strains were classified into 20 genotypes (genotypes A to T). Of the 9 MS markers used, 5 were considered useful for genotyping, whereas the other 4 were not. The combination of MS2, MS4, and MS7 had the highest resolution power for inter-strain differentiation. Genotype A, present in 15 strains (21.4%), was the most frequent, followed by genotypes H (10 strains, 14.3%), P (8 strains, 11.4%), I (6 strains, 8.6%), and S (6 strains, 8.6%). Eight individual genotypes were present in one strain each. Five episodes of infection of humans and cats living in the same household were analyzed, with strains in all 5 respective households showing the same genotypes. Analysis of geographical distribution established that both genotypes A and H were isolated from 6 prefectures of Honshu and Kyushu islands. To our knowledge, this is the first report showing intraspecies polymorphisms of M. canis isolated in Japan using molecular methods. PMID- 28674313 TI - First Detection of an Escherichia coli Strain Harboring the mcr-1 Gene in Retail Domestic Chicken Meat in Japan. AB - Global spread of the plasmid-mediated colistin resistance gene, mcr-1 poses a challenge to public health because colistin is the last-line-of-defense against severe infections of multidrug-resistant Gram-negative bacteria. In Japan, a few studies have reported the prevalence of mcr-1 among food animal-derived Escherichia coli isolates, but the prevalence of mcr-1 in retail meats is not well known. We report here the first detection of mcr-1 in retail chicken meat. A total of 70 extended-spectrum beta-lactamase-producing E. coli isolates, recovered from retail chicken meats between August 2015 and June 2016, were screened for mcr-1. We found 1 CTX-M-1 beta-lactamase-producing E. coli isolate belonging to ST1684, phylogroup A. The mcr-1 gene was not located on an IncI1 plasmid encoding the blaCTX-M-1 gene. However, whole plasmid sequencing revealed that mcr-1 was located on an IncI2 plasmid. The sequences of the nikB-mcr-1-pap2 ydfA-topB region of the IncI2 plasmid in this study was almost identical to that of the previously described IncI2 plasmid, pECJS-61-63 present in E. coli isolated from pig feces in China, except for containing a synonymous mutation in the mcr-1 gene. Plasmid carrying the mcr-1 gene have not yet been identified in human isolates in Japan. Thus, strict monitoring or surveillance of colistin resistance among Gram-negative bacteria recovered from retail meat of food animals under colistin pressure, and humans, is crucial. PMID- 28674312 TI - Molecular Subtyping of Salmonella enterica Serovar Typhi by Pulsed-Field Gel Electrophoresis and Multiple-Locus Variable-Number Tandem-Repeat Analysis in India: Their Association with Antimicrobial Resistance Profiles. AB - Molecular subtyping and DNA sequencing-based methods, which are commonly used for discriminating Salmonella enterica serovar Typhi (S. Typhi) isolates, lead to improved molecular epidemiological investigations for prevention and control of typhoid fever. We obtained S. Typhi blood isolates (n = 66) from India during 2007-14 for molecular subtyping by pulsed-field gel electrophoresis (PFGE) and multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) in association with antibiotic resistance profiles. Genotypic diversity was observed more by MLVA (Simpson's index of diversity, D value = 0.997) than PFGE (D value = 0.864). Two prevalent pulsotypes containing nalidixic acid-resistant (NALR) and NALR-ciprofloxacin-resistant (CIPR) S. Typhi isolates circulated in India. Multidrug-resistant (MDR), NALR-CIPR, and most NALR isolates were found to be clonal by PFGE. MLVA could differentiate the clonal isolates. Most of the MDR and NALR-CIPR isolates showed variation in single or double VNTR loci, whereas NALR isolates varied in more than 2 loci, reflecting higher genetic diversity among the NALR isolates. Of the 6 VNTR loci, TR4,699 (D value = 0.838) and Sal02 (D value = 0.890) loci played important roles as MLVA cluster-supporting alleles. The rapid turnaround time and high-level discriminatory power of MLVA may be useful for tracking and controlling the transmission of S. Typhi isolates during epidemiological investigations. PMID- 28674314 TI - Time-Lapse Tracking of Candida tropicalis Biofilm Formation and the Antifungal Efficacy of Liposomal Amphotericin B. AB - Candida species bloodstream infection, or candidemia, remains an important health issue with high morbidity and mortality. Bloodstream infections caused by Candida species are often associated with the ability of Candida to form biofilms on medical devices, such as central venous catheters. Non-albicans Candida species have been increasing gradually in clinical settings. Another Candida species, C. tropicalis, has a propensity to form biofilms and is also an independent risk factor for high morbidity and mortality in hospitalized patients. This study was conducted to investigate the process of biofilm formation by C. tropicalis and the antifungal activity of liposomal amphotericin B (LAB) against both forming biofilms and developed biofilms using time-lapse imaging. We found that C. tropicalis has a high capacity for hyphal growth and gas generation due to its high metabolic activity. Thus, we visually observed the formation of aggressive C. tropicalis biofilms, which are fast-growing biofilms. We found that LAB acts immediately and completely inhibits forming biofilms. Furthermore, we demonstrated that LAB was effective against developed C. tropicalis biofilms by reducing the growth of hyphae and morphological changes. These results suggest that LAB may be effective for the treatment of infections caused by catheter related C. tropicalis biofilms. PMID- 28674315 TI - Genomic Characterization of Travel-Associated Dengue Viruses Isolated from the Entry-Exit Ports in Fujian Province, China, 2013-2015. AB - Over the past decade, indigenous dengue outbreaks have occurred occasionally in Fujian province in southeastern China because of sporadic imported dengue viruses (DENV). In this study, 3 DENV-2 and 2 DENV-4 strains were isolated from suspected febrile travelers at 2 ports of entry in Fujian between 2013-2015. Complete viral genome sequences of these new isolates were obtained with Sanger chemistry. Genomic sequence analyses revealed that these strains belonged to genotypes of 2 Cosmopolitan and 4-II. Consistent with the patients' travel information, phylogenetic analyses of the complete coding regions also indicated that most of the new isolates were genetically similar to the circulating strains in Southeast Asia rather than previous Chinese strains that were available. Therefore, phylogenetic analyses of the imported DENV demonstrated that multiple introductions of DENV emerged continuously in Fujian, and highlighted the importance of dengue surveillance at entry-exit ports in the subtropical regions of southern China. PMID- 28674316 TI - Vibrio cholerae O1 Ogawa Strains Carrying the ctxB7 Allele Caused a Large Cholera Outbreak during 2014 in the Tribal Areas of Odisha, India. AB - The large outbreak of cholera reported during July to September 2014 in the Narla block of Kalahandi district, India, was investigated to determine the causative organism. Rectal swabs collected from patients with diarrhea and environmental water samples were cultured following standard techniques. The causative organism was identified as Vibrio cholerae O1 Ogawa biotype El Tor, and analysis by double mismatch mutation assay PCR confirmed that all strains were the ctxB7 variant of Haitian V. cholerae O1. The environmental water samples were negative for V. cholerae. The V. cholerae O1 strains were sensitive to tetracycline, ciprofloxacin, norfloxacin, ofloxacin, doxycycline, and azithromycin, but were resistant to erythromycin, gentamicin, chloramphenicol, furazolidone, neomycin, cotrimoxazole, nalidixic acid, and ampicillin. In the 2014 cholera outbreak, the early reporting of the pathogen enabled the government authorities to implement adequate control measures in time to curtail the spread of the disease. That was the second large cholera outbreak due to Haitian variants of V. cholerae O1 after the 2010 Haiti cholera outbreak reported from Odisha, India, and other locations globally. Active surveillance is required to track the spread of this strain in the Odisha region. PMID- 28674317 TI - Cerebral Syphilitic Gumma: Case Report of a Brainstem Mass Lesion and Brief Review of the Literature. PMID- 28674318 TI - A Case of Type 54 Human Mastadenovirus Keratoconjunctivitis Causing Severe Broad Epithelial Defect Ten Years after LASIK Surgery. PMID- 28674319 TI - A Comparative Study on the Lot Release Systems for Vaccines as of 2016. AB - Many countries have already established their own vaccine lot release system that is designed for each country's situation: while the World Health Organization promotes for the convergence of these regulatory systems so that vaccines of assured quality are provided globally. We conducted a questionnaire-based investigation of the lot release systems for vaccines in 7 countries and 2 regions. We found that a review of the summary protocol by the National Regulatory Authorities was commonly applied for the independent lot release of vaccines, however, we also noted some diversity between countries, especially in regard to the testing policy. Some countries and regions, including Japan, regularly tested every lot of vaccines, whereas the frequency of these tests was reduced in other countries and regions as determined based on the risk assessment of these products. Test items selected for the lot release varied among the countries or regions investigated, although there was a tendency to prioritize the potency tests. An understanding of the lot release policy may contribute to improving and harmonizing the lot release system globally in the future. PMID- 28674320 TI - Effects of 24-Week Aerobic and Resistance Training on Carotid Artery Intima-Media Thickness and Flow Velocity in Elderly Women with Sarcopenic Obesity. AB - AIM: Sarcopenic obesity (SO) is closely associated with cardiovascular disease (CVD) in elderly women. Increases in body fat and decreases in muscle mass are closely associated with increased carotid intima-media thickness (CIMT). The aim of this study was to examine the influence of a 24-week aerobic and resistance training program on carotid parameters in SO. METHODS: Fifty elderly women (74.1+/-6.1 years) with SO were randomly divided into an exercise group and a control group. The exercise group performed combined exercise over 24 weeks, consisting of resistance and aerobic training for 50-80 min, 5 times a week. Carotid variables were measured using B-mode ultrasound. The differences in the carotid variables and the relative changes between baseline and after 24 weeks were evaluated. RESULTS: In the analysis of variance (ANOVA) results, CIMT (p=0.013), systolic flow velocity (p=0.007), diastolic flow velocity (p=0.006), and wall shear rate (p=0.010) showed significant interactions. In paired t-test results of the exercise group, CIMT significantly decreased (p<0.01) and systolic flow velocity (p<0.01), diastolic flow velocity (p<0.001), and wall shear rate (p<0.05) significantly increased after 24 weeks. CONCLUSION: The 24-week combined exercise effectively decreased CIMT and increased carotid flow velocity and wall shear ratio. Therefore, combined exercise is thought to contribute to the improvement of the risk of CVD in elderly women with SO. PMID- 28674321 TI - Incremental Prognostic Value of Coronary Computed Tomography Angiography: High Risk Plaque Characteristics in Asymptomatic Patients. AB - AIM: Coronary computed tomography angiography (CCTA) findings of positive remodeling (index >1.1) and low-attenuation plaque (<30 Hounsfield units) are recognized as CT-verified high-risk plaque (CT-HRP). Therefore, we investigated the incremental prognostic value of evaluation of plaque characteristics using CCTA in asymptomatic patients. METHODS: Overall, 495 consecutive patients without any known coronary artery disease who underwent CCTA were included in this study. Patients who underwent revascularization within 30 days of CCTA or had scans with poor image quality were excluded. Clinical follow-up data (716.5+/-262.6 days) were available for 339 patients, who were analyzed for the current study. Framingham risk score (FRS), coronary artery calcium score (CACS), and CT-HRP were investigated as predictors of cardiac events by multivariable analysis using Cox proportional hazard model. Improvement of predictive accuracy by including CT findings was evaluated from reclassification [net reclassification indices (NRI) and integrated discrimination improvement (IDI)] standpoints. RESULTS: During the follow-up period, 9 cardiac events (cardiac death: 0, nonfatal myocardial infarction: 2, hospitalization for unstable or progressive angina: 7) occurred. Multivariate Cox proportional hazard analysis demonstrated that CACS (HR, 13.23; 95% CI, 1.62-107.78, p<0.0164) and CT-HRP (HR, 11.27; 95% CI, 1.24-102.12, p<0.0321) were the independent predictors of cardiac events. NRI was 0.9556 (p<0.0007) and IDI was 0.2582 (p<0.0203), and the diagnostic performance improved by CT-HRP added to the combination of CACS and FRS. CONCLUSION: Although the cardiac event rate was low, the evaluation of CCTA plaque characteristics may provide incremental prognostic value to CACS in asymptomatic patients. PMID- 28674322 TI - Oxidative Stress is Closely Associated with Increased Arterial Stiffness, Especially in Aged Male Smokers without Previous Cardiovascular Events: A Cross Sectional Study. AB - AIM: Cigarette smoking is one of the major risk factors for cardiovascular diseases and induces deleterious vascular damage. Oxidative stress is involved in vascular inflammation, the process of atherosclerosis. The purpose of the present study was to investigate whether the effects of oxidative stress on the arterial wall differ between smokers and non-smokers. METHODS: Male smokers and non smokers without physical deconditioning who visited Enshu hospital for an annual physical check-up were enrolled in the study. To assess oxidative stress, serum levels of derivative reactive oxygen metabolites (d-ROM) were measured. The radial augmentation index (RAI) was measured using an automated device and was used as an index for arterial stiffness. RESULTS: Univariate and multivariate linear regression analysis showed that RAI was independently associated with d ROM levels only in smokers. Moreover, RAI was significantly higher in smokers than in non-smokers. Logistic regression analysis with the endpoint of a higher RAI than the mean revealed that older age (>65 years), hypertension, and smoking were independently associated with higher RAI. Similarly, logistic regression analysis with the endpoint of higher d-ROM levels than the mean showed that older age and smoking were independently associated with higher d-ROM levels. CONCLUSIONS: Increased RAI is significantly associated with smoking and, in smokers, with increased d-ROM levels. These results suggest that the effects of oxidative stress on arterial properties differ between smokers and non-smokers and that oxidative stress is closely associated with arterial stiffness, especially in smokers. PMID- 28674323 TI - Newly Developed Rat Model of Chronic Kidney Disease-Mineral Bone Disorder. AB - AIM: Chronic kidney disease-mineral bone disorder (CKD-MBD) is associated with all-cause and cardiovascular morbidity and mortality in patients with CKD. Thus, elucidating its pathophysiological mechanisms is essential for improving the prognosis. We evaluated characteristics of CKD-MBD in a newly developed CKD rat model. METHODS: We used male Sprague-Dawley (SD) rats and spontaneously diabetic Torii (SDT) rats, which are used as models for nonobese type 2 diabetes. CKD was induced by 5/6 nephrectomy (Nx). At 10 weeks, the rats were classified into six groups and administered with a vehicle or a low- or high-dose paricalcitol thrice a week. At 20 weeks, the rats were sacrificed; blood and urinary biochemical analyses and histological analysis of the aorta were performed. RESULTS: At 20 weeks, hemoglobin A1c (HbA1c) levels, blood pressure, and renal function were not significantly different among the six groups. Serum calcium and phosphate levels tended to be higher in SDT-Nx rats than in SD-Nx rats. The urinary excretion of calcium and phosphate was significantly greater in SDT-Nx rats than in SD-Nx rats. After administering paricalcitol, serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels were significantly higher in SDT-Nx rats than in SD-Nx rats. The degree of aortic calcification was significantly more severe and the aortic calcium content was significantly greater in SDT-Nx rats than in SD-Nx rats. CONCLUSIONS: We suggest that our new CKD rat model using SDT rats represents a useful CKD-MBD model, and this model was greatly influenced by paricalcitol administration. Further studies are needed to clarify the detailed mechanisms underlying this model. PMID- 28674324 TI - Flow Mediated Dilatation as a Biomarker in Vascular Surgery Research. AB - Endothelial dysfunction is one of the hallmarks of atherogenesis, and correlates with many cardiovascular risk factors. One of the features of endothelial dysfunction is the loss of nitric oxide (NO) bioavailability, resulting in derangements in the vasodilatory response of the vessel wall. Flow mediated dilatation (FMD) of the brachial artery is an accepted method for non-invasive assessment of systemic endothelial function. FMD is examined extensively in the context of cardiovascular research, and has been utilised as a routine assessment in large cohorts such as the Framingham Heart Study, Young Finns Study, and Gutenberg Heart Study. However, FMD is less known in the context of vascular surgery research, despite the similarities between the underpinning disease mechanisms. This review will provide a summary of FMD in terms of its history of development and the conduct of the test in research settings. It will further highlight the key literature of FMD as a biomarker for vascular surgeons, particularly in the context of abdominal aortic aneurysms and lower limb peripheral arterial disease. PMID- 28674325 TI - Is the Association between Dietary Trans Fatty Acids and Insulin Resistance Remarkable in Japan? PMID- 28674326 TI - Defect of rabies virus phosphoprotein in its interferon-antagonist activity negatively affects viral replication in muscle cells. AB - Attenuated derivative rabies virus Ni-CE replicates in muscle cells less efficiently than does the parental pathogenic strain Nishigahara. To examine the mechanism underlying the less efficient replication of Ni-CE, we compared the activities of Ni-CE and Nishigahara phosphoproteins, viral interferon (IFN) antagonists, to suppress IFN-beta promoter activity in muscle cells and we demonstrated a defect of Ni-CE phosphoprotein in this ability. Treatment with an IFN-beta-neutralizing antibody improved the replication efficiency of Ni-CE in muscle cells, indicating that produced IFN inhibits Ni-CE replication. The results indicate the importance of IFN antagonism of rabies virus phosphoprotein for viral replication in muscle cells. PMID- 28674327 TI - Esterification of Mixed Carboxylic-fatty Anhydrides Using Amberlyst-15 as Heterogeneous Catalyst. AB - The article deals with the use of mixed anhydrides for the synthesis of fatty esters. Both aliphatic and aromatic acids are involved, indicating different behaviors according to the chain length of the aliphatic acid. We describe a novel and efficient method for the synthesis of fatty esters by the esterification reaction of primary, secondary and tertiary alcohols with mixed carboxylic-palmitic anhydrides using resin Amberlyst-15 as heterogeneous acid catalyst. Influence of various reaction parameters such as molar ratio (anhydride/alcohol), catalyst amount, type of alcohol and type of mixed anhydride were studied to optimize the conditions for maximum yield. Among tested anhydrides we quote mainly the 4-chlorobenzoic palmitic anhydride because it was both reactive and selective for the preparation of palmitic acid ester. This anhydride gave a good yield of palmitic ester. PMID- 28674328 TI - Screening of a Bacillus subtilis Strain Producing Multiple Types of Cyclic Lipopeptides and Evaluation of Their Surface-tension-lowering Activities. AB - Sixty Bacillus subtilis strains were investigated for their ability to produce cyclic lipopeptides (CLPs). Among them, B. subtilis NBRC 109107 produced at least three types of CLPs by high-performance liquid chromatography (HPLC) analysis, and these CLPs were thought to be surfactin, iturin A, and fengycin by polymerase chain reaction amplification of respective CLP synthetase-encoding genes. However, after HPLC fractionation and purification, structural analysis of the CLPs revealed that these were surfactin homologues, iturin A, and unknown CLPs, whose surface-tension-lowering activities were 29.4, 56.7, and 48.6 mN/m, respectively. By contrast, fengycin was not detected. PMID- 28674329 TI - Decomposition of Fatty Acid and Detergency Using a System Combining Horseradish Peroxidase and p-Iodophenol. AB - The reactivity and detergency of a horseradish peroxidase reaction system with oleic acid, a non-hydrogen donor used as a soil component, were studied. Under a coexistent system of horseradish peroxidase and p-iodophenol, oleic acid decomposed quickly. In addition, because the coexistence of p-iodophenol provided detergency, a new function of horseradish peroxidase was shown. PMID- 28674330 TI - Potential of Enzymomics Methodologies to Characterize Disease-Related Protein Functions. AB - Enzymatic functions are often altered during disease onset and progression, and therefore chemical-biological studies, which utilize chemical knowledge to discover novel protein functions, are often employed to find proteins with functions closely related to disease phenotypes. Such studies are known as forward chemical-biological approaches and form part of the emerging field of enzymomics (omics of enzymes). This review provides an overview of methodologies available for discovering and characterizing disease-related alterations of enzymatic functions and prospects for the future. PMID- 28674331 TI - Foreword. PMID- 28674332 TI - Recent Advances in Endogenous and Exogenous Stimuli-Responsive Nanocarriers for Drug Delivery and Therapeutics. AB - Significant progress has been achieved in the development of stimuli-responsive nanocarriers for drug delivery, diagnosis, and therapy. Various types of triggers are utilized in the development of nanocarrier delivery. Endogenous factors such as changes in pH, redox, gradient, and enzyme concentration which are linked to disease progression have been utilized for controlling biodistribution and releasing drugs from nanocarriers, as well as increasing subsequent pharmacological activity at the disease site. Nanocarriers which respond to artificially-induced exogenous factors (such as temperature, light, magnetic field, and ultrasound) have also been developed. This review aims to discuss recent advances in the design of stimuli-responsive nanocarriers which appear to have a promising future in medicine. PMID- 28674333 TI - Peptide-Based Cancer-Targeted DDS and Molecular Imaging. AB - Targeting cancer cell-surface receptors is an attractive approach for cancer treatment and diagnosis. Peptides having high binding affinities to receptors overexpressed in cancer cells are useful because of their simple structure, low immunogenicity, and easy, cost-effective chemical synthesis. A number of peptide ligands have been developed for cancer cell-surface receptors and applied to nanoparticles with anticancer drugs, genes, small interfering RNAs (siRNAs), and molecular imaging agents. In particular, recent findings have revealed that peptide-modified PEGylated liposome-encapsulated drugs are effective in cancer targeted therapy and cancer cell-specific imaging. This review discusses peptide modified nanoparticles for drug delivery systems (DDS) and molecular imaging, focusing on peptide ligands for somatostatin receptors, integrin, transferrin receptor, human epidermal growth factor 2 (HER2), etc. In addition, methods to improve binding affinity or endosomal escape with spacer peptides and stimuli (internal and external) are discussed. PMID- 28674334 TI - Gold Nanorods as Nanodevices for Bioimaging, Photothermal Therapeutics, and Drug Delivery. AB - Gold nanorods are promising metals in several biomedical applications such as bioimaging, thermal therapy, and drug delivery. Gold nanorods have strong absorption bands in near-infrared (NIR) light region and show photothermal effects. Since NIR light can penetrate deeply into tissues, their unique optical, chemical, and biological properties have attracted considerable clinical interest. Gold nanorods are expected to act not only as on-demand thermal converters for photothermal therapy but also as mediators of a controlled drug release system responding to light irradiation. In this review, we discuss current progress using gold nanorods as bioimaging platform, phototherapeutic agents, and drug delivery vehicles. PMID- 28674335 TI - Photodynamic Action of Single-Walled Carbon Nanotubes. AB - Photodynamic therapy is achieved by the combination of photosensitizers, harmless visible or near-infrared (NIR) light, and molecular oxygen (O2). Photosensitizers transfer their absorbed light energy to O2 to generate a major active species in photodynamic therapy, singlet oxygen. In this review, I will discuss the possibility of single-walled carbon nanotubes as NIR photosensitizers, while explaining the general photophysics and photochemistry underlying photodynamic therapy as well as summarizing recent advances in the purification technologies for single-walled carbon nanotubes to reduce their toxicity concerns. PMID- 28674336 TI - Nanoparticle-Based Photodynamic Therapy: Current Status and Future Application to Improve Outcomes of Cancer Treatment. AB - Photodynamic therapy (PDT) is an emerging cancer treatment that uses photosensitizers (PS), along with light to activate them, resulting in oxidation of various biological components in cancer tissues. However, since most potential PS are solubilized and given as aqueous solution, PS is non-specifically distributed in the body, leading to the induction of various side effects in normal tissues that are exposed to daylight such as skin and eyes. To overcome the problem associated with non-specific in vivo disposition of PS, various approaches have been applied to develop safer dosage forms for PS with more efficient tumor delivery and lower disposition to normal tissues. Passive drug targeting to tumors with nanoparticulate formulations has been recognized as one of the potentially useful approaches to improve the poor tissue specificity of conventional cancer chemotherapy and this approach should also be applicable for more efficient tumor delivery of PS. In this review article, several issues concerning the efficacy of PDT using nanoparticle-based formulations are discussed and our recent attempts to temporally enhance the vascular permeability within tumors with photodynamic treatment for the better therapeutic outcome of nanoparticle-based therapy are introduced. PMID- 28674337 TI - Methods for Evaluating the Stimuli-Responsive Delivery of Nucleic Acid and Gene Medicines. AB - In this review, we have summarized evaluation methods for the analysis of external stimuli-mediated nucleic acid and gene delivery. Prior to reviewing these evaluation methods, we describe various delivery processes of nucleic acid and gene medicines (small interfering RNA (siRNA), micro RNA, mRNA, plasmid DNA, etc.), which include interaction with blood components, bio-distribution, disposition in the target tissue, cell entry, intracellular trafficking, nuclear localization, and dissociation from the carriers. Next, we discuss the advantages of external stimuli-mediated nucleic acid and gene delivery. External stimuli enable us to effectively deliver nucleic acids and genes to targeted regions. Evaluation methods are required to elucidate the behaviors of nucleic acid and gene medicines in the body. Quantitative analyses of the bio-distribution and in situ disposition in perfused organs, as well as visualization of bio distribution, transgene expression in the body, and intracellular trafficking of nucleic acid and gene medicines, are all useful in evaluating not only the efficacy and safety of delivery, but also serve as guidelines for the further development of nucleic acid and gene medicines by elucidating delivery problems. Progress in evaluation methods, including tissue optical clearing and super resolution microscopy, will help to better elucidate the in vivo fate of nucleic acid and gene medicines. PMID- 28674338 TI - A Novel Strategy for Etiologic Factor Removal: Drug-Navigated Clearance System (DNCS). AB - Here, we propose a novel therapeutic concept named drug-navigated clearance system (DNCS), in which a "navigator" decreases the concentration of a target etiologic factor in the blood by steering it to an unusual metabolic pathway. The navigator is composed of protein A (ProA) and dextran sulfate (DexS) and it successfully navigated antibodies (ABs), a model etiologic factor of dilated cardiomyopathy, to hepatocytes in vitro in the presence of low-density lipoprotein (LDL). ProA captured the Fc region of the target antibody while the DexS bound to LDL via the well-known electrostatic interaction. The hepatocytes simultaneously took up LDL via the LDL-receptor and internalized the AB/ProA-DexS complex that was bound to LDL. Therefore, this process demonstrates our attempt to navigate the etiologic factor to an alternate target pathway such as the LDL salvage. PMID- 28674339 TI - Effect of Self-healing Encapsulation on the Initial Burst Release from PLGA Microspheres Containing a Long-Acting Prostacyclin Agonist, ONO-1301. AB - The purpose of this study was to perform self-healing encapsulation of ONO-1301, a long-acting prostacyclin agonist, into poly(lactide-co-glycolide) (PLGA) microspheres using the oil-in-water (o/w) emulsion solvent evaporation method in order to try to limit the initial burst release of drug. Adequate self-healing of PLGA seemed to be achieved by stirring during the evaporation of solvent at 40 degrees C close to the glass transition temperature (Tg) of the polymer (40.1 degrees C). The plasticizers dimethylphthalate (DEP) or tributyl O-acetylcitrate (TBAC), at concentrations of 0.1-1.0%, to the internal oleogeneous phase in the o/w emulsion system was effective in restricting the initial burst release of the prepared microspheres. The combination of a self-healing at Tg of the polymer and the addition of 1% of each plasticizer was ultimately found to be the most effective in restricting the initial burst release. It is suggested that this is due to the synergistic effect of smooth surface morphology promoted by self healing at Tg of the polymer and a decrease of the Tg of PLGA caused by the addition of plasticizers. PMID- 28674340 TI - Aromaticity of Phenylalanine Residues Is Essential for Amyloid Formation by Alzheimer's Amyloid beta-Peptide. AB - The abnormal aggregation of amyloid beta-peptide (Abeta) is central to the pathogenesis of Alzheimer's disease, the major form of dementia. Aromatic pi-pi interactions have been suggested to play a crucial role in the aggregation of not only Abeta, but also other amyloidogenic proteins. In this study, each or all phenylalanine (Phe) residues at the 4th, 19th, and 20th positions of Abeta-(1-40) were substituted by hydrophobic cyclohexylalanine (Cha), which is sterically similar to Phe, but lacks pi-electrons, to reveal effects of interactions involving pi-electrons on the aggregation of Abeta both in aqueous solution and GM1-containing membranes. We found that each Cha substitution significantly inhibited fibril formation by Abeta, indicating a pivotal role of aromatic interactions. Furthermore, the Abeta analog with three Cha residues effectively retarded the fibrillation of the wild-type Abeta. PMID- 28674341 TI - The in Vitro Release of Indomethacin from Suppositories: Effects of Bases and Comparison of Different Dissolution Methods. AB - The suitability of apparatuses for the quality control of indomethacin (IND, 50 mg) compounded suppositories was evaluated and the effects of the type of suppository base on release profiles was investigated. The release characteristics of hydrophilic and lipophilic suppositories containing IND were compared using four types of dissolution methods: basket (RB), paddle (PD), dialysis tubing (DT) and flow-through cell (FTC). The release process was evaluated using the following model independent parameters: the mean dissolution time (MDT), cumulative percent of drug released (Q) at the end of the sampling time, and dissolution efficiency (DE). The fastest and most reproducible release profiles were observed for a hydrophilic base (macrogols), which resulted in more than 90% of the drug being released in 30 min using PD, RB and FTC. After 90 min, 90% of the total amount of the drug was released from a mixture of hydrophilic bases with a lipophilic base (macrogols and hard fat) in compendial dissolution methods and the mixture base was the second fastest only to the hydrophilic base. The slowest release profiles in each method were observed for the lipophilic base (hard fat). Poor drug release from any type of suppository base was noted using DT. Based on the results of the present study, FTC may be regarded as an adequate technique allowing sufficient discriminating power for the quality control of IND compounded suppositories. PMID- 28674342 TI - Hydroxymethylation of Rutin Induced by Radiolysis as Novel alpha-Glucosidase Inhibitors. AB - Rutin, a major flavonoid glycoside found in many higher plants, was exposed at 25 kGy of gamma-ray and produced three new hydroxymethylated products 2-4 in the C ring by gamma-irradiation. Structures of the new compounds, including absolute configurations, were elucidated based on spectroscopic interpretation (NMR, UV, [alpha]D, MS, and circular dichroism (CD)). The new unusual rutin derivatives 2 and 3 exhibited significantly enhanced inhibitory effects against alpha glucosidase with IC50 values of 23.1+/-1.2 and 11.2+/-0.7 uM, respectively, when compared to the parent rutin. PMID- 28674343 TI - New Triterpenoids from the Stems of Cornus walteri. AB - A new 28-norlupane triterpenoid, 3-acetate-28-norlup-20(29)-en-3beta-hydroxy 17beta-hydroperoxide (1) and a new tirucallane triterpenoid, cornusalterin M (2), together with one known triterpenoid, 3-acetate-28-norlup-20(29)-en-3beta,17beta diol (3), were isolated from a MeOH extract of the stems of Cornus walteri. The chemical structures of the new compounds (1 and 2) were elucidated based on comprehensive one- and two-dimensional (1D and 2D) NMR spectroscopic experiments and high resolution-electrospray ionization (HR-ESI)-MS. Among the isolates, compound 1 was a relatively rare triterpenoid identified as a 28-norlupane-type triterpene with a 17beta-hydroperoxide group and compound 3 was previously reported but only as a synthetic product. The cytotoxic activities of the isolated compounds 1-3 were evaluated by determining their inhibitory effects on human tumor cell lines (A549 (non-small cell lung carcinoma), SK-OV-3 (ovary malignant ascites), SK-MEL-2 (skin melanoma), and HCT-15 (colon adenocarcinoma)). PMID- 28674344 TI - Total Synthesis of Sphingofungin E and 4,5-Di-epi-sphingofungin E. AB - Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E was achieved from an intermediate same as that of myriocin and mycestericin D via antipodal stereoselective dihydroxylations. PMID- 28674345 TI - Trend of Malpractice Litigation against Neurosurgeons in Japan: An Analysis of Disclosed Database by Courts in Japan from 2001 through 2015. AB - Following the modern raising of public awareness, the numbers of malpractice litigation are increasing in the health care delivery system in Japan despite the extensive efforts of physicians. Authors reviewed the issues of litigation and the reasons for court decision from the healthcare-related negligence lawsuits in the past 15 years in Japan and investigated the cautionary points for reducing potential litigation. Healthcare-related negligence lawsuits between January 2001 and December 2015 were retrieved and sorted in each clinical field from the database in Courts in Japan and investigated on the proportional factors of the claims and court decisions in the neurosurgical field. During the period, 446 of healthcare-related court decisions including 41 against neurosurgeons (9.2%) were retrieved. Three of 41 decisions retrieved were decisions to retries for lower court decisions. In 38 claims against the neurosurgeons, 26 identified the negligence and 12 dismissed. In 26 decisions in favor of the plaintiffs, identified negligence in diagnosis in 4, clinical judgment in 3, technical skills in 5, clinical management in 7 and process of informed consent in 7. Five out of 18 decisions after 2006 were identified as negligence in an informed consent process, and additional one, who was mainly identified in inadequate technical skills also identified existing an inadequate informed consent process as a fundamental cause of litigation. Neurosurgeons are a higher risk group for malpractice litigation in Japan and adequate informed consent is important to reduce the risk of litigation. PMID- 28674346 TI - Diagnosis and Treatment of Traumatic Cerebrovascular Injury: Pitfalls in the Management of Neurotrauma. AB - Traumatic cerebrovascular injury (TCVI) is an uncommon clinical entity in traumatic brain injury (TBI), yet it may cause devastating brain injury with high morbidity and mortality. Early recognition and prioritized strategic treatment are of paramount importance. A total of 1966 TBI patients admitted between 1999 and 2015 in our tertiary critical care center were reviewed. Screening of TCVI was based on the Guidelines for the Management of Severe Head Injury in Japan. TCVI was confirmed in 33 (1.7%) patients; 29 blunt and 4 penetrating injuries. The primary location of the injury included 16 cervical, 6 craniofacial, and 11 intracranial lesions. On arrival, 15 patients presented with hemorrhage, 5 of these arrived in shock status with massive hemorrhage. Ten presented with ischemic symptoms. Sixteen patients underwent surgical or endovascular intervention, 13 of whom required immediate treatment upon arrival. Surgical procedures included clipping or trapping for traumatic aneurysms, superficial temporal artery - middle cerebral artery bypass, carotid endarterectomy, and direct suture of the injured vessels. Endovascular intervention was undertaken in 7 patients; embolization with Gelfoam (Pharmacia and Upjohn Company, Kalamazoo, MI, USA) or coil for 6 hemorrhagic lesions and stent placement for 1 lesion causing ischemia. Patients' outcome assessed by the Glasgow Outcome Scale at 3 months were good recovery in 8, moderate disability in 3, severe disability in 9, persistent vegetative state in 1, and death in 12, respectively. In order to rescue potentially salvageable TCVI patients, neurosurgeons in charge should be aware of TCVI and master basic skills of cerebrovascular surgical and endovascular procedures to utilize in an emergency setting. PMID- 28674347 TI - Cardiovascular and Metabolic Diseases Comorbid with Psoriasis: Beyond the Skin. AB - A close association of systemic inflammation with cardiovascular diseases and metabolic syndrome is recently a popular topic in medicine. Psoriasis is a chronic inflammatory skin disease with a prevalence of approximately 0.1-0.5% in Asians. It is characterized by widespread scaly erythematous macules that cause significant physical and psychological burdens for the affected individuals. The accelerated inflammation driven by the TNF-alpha/IL-23/IL-17A axis is now known to be the major mechanism in the development of psoriasis. Psoriasis is not a mere skin disease; it is significantly associated with cardiovascular diseases and metabolic syndrome, which suggests that the chronic skin inflammation extends the systemic inflammation beyond the skin. In this article, we review the epidemiological and pathological aspects of psoriasis and its comorbidities. PMID- 28674348 TI - Randomized Trial Comparing Esomeprazole and Rabeprazole in First-line Eradication Therapy for Helicobacter pylori Infection based on the Serum Levels of Pepsinogens. AB - Objective CYP2C19 metabolic activity influences the efficacy of Helicobacter pylori eradication therapies comprising PPIs. Rabeprazole (RPZ) and esomeprazole (EPZ) are PPIs not extensively metabolized by CYP2C19. The aim of this study was to elucidate whether or not first-line triple therapies using RPZ or EPZ are equally effective in Japanese patients with different CYP2C19 genotypes. Methods Two-hundred patients infected with H. pylori were randomized to receive one of the following regimens: amoxicillin (750 mg), clarithromycin (200 mg), and either esomeprazole (20 mg) (EAC group) or rabeprazole (10 mg) (RAC group), twice a day for one week. The CYP2C19 polymorphisms were determined by polymerase chain reaction and the serum level of pepsinogens was measured. Results The eradication rates of the EAC and RAC regimens were 79.8% (95% confidential interval: 71.7 89.0%) and 74.7% (66.0-83.4%), respectively, in a per protocol (PP) analysis (p=0.488). The eradication rates of the EAC and RAC regimens were not significantly different between patients with the homo EM genotype (p=0.999) or hetero IM or PM genotypes (p=0.286). A lower PG I/II ratio was associated with lower eradication rates (p=0.025). Conclusion Although the eradication rate was less than 80%, the EAC and RAC regimens were equally effective in each CYP2C19 genotype group. The PG I/II ratio was associated with the results of EAC and RAC therapy in this series of patients. PMID- 28674349 TI - Postprandial Symptoms Felt at the Lower Part of the Epigastrium and a Possible Association of Pancreatic Exocrine Dysfunction with the Pathogenesis of Functional Dyspepsia. AB - Objective In symptom-dependent diseases such as functional dyspepsia (FD), matching the pattern of epigastric symptoms, including severity, kind, and perception site, between patients and physicians is critical. Additionally, a comprehensive examination of the stomach, duodenum, and pancreas is important for evaluating the origin of such symptoms. Methods FD-specific symptoms (epigastric pain, epigastric burning, early satiety, and postprandial fullness) and other symptoms (regurgitation, nausea, belching, and abdominal bloating) as well as the perception site of the above symptoms were investigated in healthy subjects using a new questionnaire with an illustration of the human body. A total of 114 patients with treatment-resistant dyspeptic symptoms were evaluated for their pancreatic exocrine function using N-benzoyl-L-tyrosyl-p-aminobenzoic acid. Results A total of 323 subjects (men:women, 216:107; mean age, 52.1 years old) were initially enrolled. Most of the subjects felt the FD-specific symptoms at the epigastrium, while about 20% felt them at other abdominal sites. About 30% of expressed as epigastric symptoms were FD-nonspecific symptoms. At the epigastrium, epigastric pain and epigastric burning were mainly felt at the upper part, and postprandial fullness and early satiety were felt at the lower part. The prevalence of patients with pancreatic exocrine dysfunction was 71% in the postprandial fullness group, 68% in the epigastric pain group, and 82% in the diarrhea group. Conclusion We observed mismatch in the perception site and expression between the epigastric symptoms of healthy subjects and FD-specific symptoms. Postprandial symptoms were often felt at the lower part of the epigastrium, and pancreatic exocrine dysfunction may be involved in the FD symptoms, especially for treatment-resistant dyspepsia patients. PMID- 28674350 TI - Depression Is Significantly Associated with the Health Status in Patients with Idiopathic Pulmonary Fibrosis. AB - Objective Depression is reported to be relatively common in idiopathic pulmonary fibrosis (IPF) patients. Thus far, however, whether or not depression independently determines the health-related quality of life (HRQOL) has not been evaluated exclusively in IPF patients. We designed this study to identify independent determinants of the St. George' s Respiratory Questionnaire (SGRQ) score among various factors, including a depression scale, in IPF patients. Methods We retrospectively analyzed consecutive subjects with IPF who completed a systematic evaluation including pulmonary function tests, PaO2 at rest, 6-minute walk test (6MWT), SGRQ, Baseline Dyspnea Index (BDI), and Hospital Anxiety and Depression Scale (HADS). All eligible patients in the present study had newly diagnosed IPF and had not received any prior treatments, such as antidepressants, pirfenidone, corticosteroids, immunosuppressants, or long-term oxygen therapy. Results The 121 patients with IPF included 99 men. On the SGRQ, mild to moderate disturbance was observed in the total and each component score. According to the HADS, 27 patients (22.3%) had borderline or definite depression. In a univariate regression analysis, the forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLco), PaO2 at rest, BDI, HADS for Anxiety (HADS-A) and Depression (HADS-D), 6-minute walk distance (6MWD), and lowest SpO2 during the 6MWT were significantly correlated with the SGRQ total score. In a stepwise multiple regression model, BDI, 6MWD, and HADS-D were selected as independent determinants of the total SGRQ score. The total variance in this model was 59% (p<0.001). Conclusion We concluded that depression was a significant determinant of the HRQOL or health status in patients with IPF. PMID- 28674351 TI - Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis. AB - Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors. Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment. Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts. PMID- 28674352 TI - A Customized Online Nutrition Guidance System Is Effective for Treating Patients with Nonalcoholic Fatty Liver Disease by Supporting Continuity of Diet Therapy at Home: A Pilot Study. AB - Continuity is required for diet therapy, but it depends on patients. We examined the utility of a new tool, the customized online nutrition guidance system, in patients with nonalcoholic fatty liver disease (NAFLD). Seven patients plotted their body weight (BW) and marked a customized task card on completion for 90 days on a website. The instructors encouraged them by e-mail. BW, serum transaminase levels, and system usage were evaluated. The results showed that BW and serum alanine aminotransferase levels were significantly lower than at baseline. BW and task visualization as well as encouragement by e-mails were effective in ensuring continuity. Thus, this system is effective in keeping NAFLD patients motivated to continue their diet therapy. PMID- 28674354 TI - Left Mandibular Pain: A Rare Initial Symptom of Acute Aortic Dissection Without Coronary Obstruction. AB - An 88-year-old woman experienced sharp pain in the left mandible for a few minutes 3 days prior to hospital presentation. On the day of hospital presentation, the patient experienced similar pain and cold sweating for more than an hour early in the morning. On arrival, there was only mild discomfort ranging from the left mandible to the neck, without definite pain. Computed tomography revealed Stanford type A acute aortic dissection. Blood vessel prosthesis implantation was performed. Intraoperatively, the coronary arteries were confirmed to be intact. Mandibular pain is a rare but potential symptom of aortic dissection without coronary artery obstruction. PMID- 28674353 TI - Acute Acalculous Cholecystitis Caused by Giardia lamblia. AB - We report a case of a 70-year-old man with acute acalculous cholecystitis caused by Giardia lamblia. Contrast-enhanced computed tomography (CT) showed distention of the gallbladder due to a pericholecystic abscess without gallstones. Magnetic resonance cholangiopancreatography and drip infusion cholecystocholangiography-CT demonstrated a stricture of the hilar bile duct and cystic duct obstruction. We conducted transpapillary bile duct brush cytology and a biopsy of the hilar bile duct stricture; numerous active trophozoites of Giardia lamblia were observed without malignant findings. We considered this bile duct lesion to be biliary giardiasis. Biliary giardiasis should be taken into consideration when diagnosing acute acalculous cholecystitis. PMID- 28674355 TI - The Successful Removal of Two Retrievable Inferior Vena Cava (IVC) Filters after 67 Days in a Patient with a Double IVC. AB - We herein present a case in which two retrievable inferior vena cava (IVC) filters, which were implanted to treat deep-vein thrombosis caused by the compression of a double IVC, were successfully removed on the 67th day after placement. The filters were individually placed in both the left and right IVCs. With a prevalence of only 0.2%, a double IVC is an extremely rare anatomical variation. The long-term effects of IVC filters are unknown, and the placement of a filter potentially introduces the risk of complications. Thus, if the patient's clinical condition allows, the endovascular retrieval of the filter should be considered within a few months after implantation. PMID- 28674356 TI - Atypical Ketoacidosis and Protracted Hyperglycosuria after Treatment with Ipragliflozin, an SGLT2 Inhibitor. AB - We herein present the case of a 21-year-old diabetic obese woman who developed ketoacidosis following the administration of ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. At the time of admission, although her serum glucose level was only 175 mg/dL, laboratory tests showed ketoacidosis. Interestingly, hyperglycosuria persisted, even after the discontinuation of ipragliflozin. This is the first report of non-hyperglycemic ketoacidosis that might have been caused by protracted hyperglycosuria after the discontinuation of ipragliflozin. The development of non-hyperglycemic ketoacidosis should be monitored following the discontinuation of SGLT2 inhibitors, especially in patients who start to feel unwell and exhibit protracted hyperglycosuria after the discontinuation of treatment. PMID- 28674357 TI - Single-dose Rituximab Therapy for Refractory Idiopathic Membranous Nephropathy: A Single-center Experience. AB - To date, a recognized treatment for refractory membranous nephropathy (MN) has not been established. Recently, several reports have indicated the efficacy of rituximab as a novel treatment option. However, only a few published accounts exist of rituximab therapy for idiopathic MN (IMN) in the Asian population. We present the cases of three IMN patients who were treated with single-dose rituximab after they showed no response to conventional therapies, including corticosteroids, cyclosporine, cyclophosphamide, mizoribine, and mycophenolate mofetil. Although one case showed no response, a complete or incomplete remission was achieved in the other two cases. Rituximab may therefore be a beneficial treatment option for IMN. PMID- 28674358 TI - Acute Kidney Injury from Excessive Potentiation of Calcium-channel Blocker via Synergistic CYP3A4 Inhibition by Clarithromycin Plus Voriconazole. AB - CYP3A4-inhibitors can potentiate the hypotensive effect of calcium-channel blockers. However, insufficient attention to such drug interactions may result in serious adverse reactions. A 71-year-old hypertensive man prescribed nifedipine was hospitalized for infectious endophthalmitis. Antimicrobial therapy with voriconazole lowered the blood pressure, and then clarithromycin further lowered it through the excessively elevated nifedipine concentration, leading to ischemic acute kidney injury. After the discontinuation of clarithromycin and voriconazole, the blood pressure and renal function were recovered. The combination of CYP3A4-inhibitors such as clarithromycin plus voriconazole can synergistically potentiate calcium-channel blockers. Co-prescription of multiple CYP3A4-inhibitors with calcium-channel blockers increases the risk of hypotension and acute kidney injury. PMID- 28674359 TI - A Rare Adult Case with Diffuse Segmental Membranous Glomerulonephritis. AB - A 71-year-old man with hypertension and diabetes mellitus presented with proteinuria. Laboratory data showed proteinuria of 3.1 g/g creatinine, serum albumin of 3.5 g/dL and serum creatinine of 1.03 mg/dL without autoantibodies. A renal biopsy revealed segmental granular IgG depositions on glomerular capillary walls. Electron microscopy showed segmentally subepithelial, intramembranous and mesangial deposits. Diffuse segmental membranous glomerulonephritis (MGN) was diagnosed with only IgG1 deposition and without M-type phospholipase A2 receptor or thrombospondin type-1 domain-containing 7A staining, suggesting secondary MGN with an unknown target antigen in immune deposits. Physicians should keep in mind the existence of segmental MGN to better understand the clinicopathological characteristics. PMID- 28674360 TI - Diffuse Alveolar Hemorrhage Induced by Irinotecan for a Patient with Metastatic Thymic Carcinoma: A Case Report and Literature Review. AB - We herein report a 73-year-old Japanese woman with metastatic thymic carcinoma who developed diffuse alveolar hemorrhage (DAH) during irinotecan chemotherapy. She presented with a mild fever and exertional dyspnea after the second cycle of weekly irinotecan monotherapy. Chest images showed diffuse ground-glass opacities. The diagnosis of DAH was based on the findings of the bronchoalveolar lavage fluid, which was bloody and contained hemosiderin-laden macrophages. The discontinuation of irinotecan and introduction of oral prednisolone improved her symptoms and chest abnormal shadows. This is the first case of DAH caused by irinotecan. PMID- 28674361 TI - Non-smoking Chronic Obstructive Pulmonary Disease Attributed to Occupational Exposure to Silica Dust. AB - An 85-year-old, never-smoking man presented with exertional dyspnea. He had been exposed to silica dust in the work place. Chest computed tomography revealed bronchial wall thickening without emphysema. A pulmonary function test showed airflow obstruction without impaired gas transfer. Airway hyperresponsiveness and reversibility were not evident. A transbronchial lung biopsy showed findings suggestive of mineral dust exposure, such as fibrosis and slight pigmentation of bronchioles. He was diagnosed with non-smoking chronic obstructive pulmonary disease (COPD) due to occupational exposure to silica dust. His symptoms were improved using an inhaled long-acting bronchodilator. The clinical characteristics of non-smoking COPD are discussed in this report. PMID- 28674362 TI - The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a JAK2 Exon 12 Mutation. AB - Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L). This case suggests that ruxolitinib is a treatment option for post-PV MF in patients with thrombocytopenia or JAK2 exon 12 mutations. PMID- 28674363 TI - EBV-positive Diffuse Large B-cell Lymphoma as a Secondary Malignancy Arising in a Myelodysplastic Syndrome Patient who Was Treated with Azacitidine. AB - We report a case of secondary diffuse large B-cell lymphoma (DLBCL) after azacitidine (AZA) treatment in a 63-years-old man with myelodysplastic syndrome. The patient suffered from febrile neutropenia after 10 cycles of AZA treatment. Despite the performance of a whole-body CT scan, which showed a multifocal low density area in the liver and a multifocal nodular shadow in the lung, no malignant neoplasms could be detected. An autopsy was performed 6 months later, and a histopathological examination of the lesions of the liver and lung revealed the infiltration of large round-shaped tumor cells with necrotizing lesions. Immunohistochemically, the tumor cells were positive for CD20 and EBER, indicating EBV-positive DLBCL as a secondary malignancy. PMID- 28674364 TI - Diffuse Cerebral Vasoconstriction in a Intravascular Lymphoma Patient with a High Serum MPO-ANCA Level. AB - An 87-year-old woman presented with a 3-month history of fever, edema of the lower legs, and gait disturbance. A laboratory examination revealed high serum levels of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO ANCA). Although microscopic polyangiitis was initially suspected and treated, the patient subsequently developed transient hemiparesis and disturbed consciousness. Brain magnetic resonance imaging/angiography revealed infarct-like lesions, pachymeningeal involvement, and diffuse cerebral vasoconstriction. A random skin biopsy confirmed the histological diagnosis of intravascular lymphoma. Diffuse cerebral vasoconstriction and a high serum MPO-ANCA level have rarely been reported in patients with intravascular lymphoma. Endothelial damage due to immune-mediated mechanisms, tumor derived factors, or the direct interaction of lymphoma cells with endothelial cells may commonly predispose patients to both cerebral vasoconstriction and the development of ANCAs. PMID- 28674365 TI - Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage. AB - A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA. PMID- 28674366 TI - M-protein-negative Myeloma Mimicking Lumbar Disc Herniation. AB - A 60-year-old man was referred to us with high levels of aspartate aminotransferase and lactate dehydrogenase (LDH). He did not complain of any symptoms; however, he had been diagnosed with lumbar disc herniation, even though his back pain improved only to half of its previous level with pregabalin. Thus, we asked about the red flag of back pain and confirmed that he had involuntary body weight loss, which led us to diagnose truly non-secretory multiple myeloma, a variant of multiple myeloma that is associated with M-protein negativity and a normal serum free light chain level. PMID- 28674367 TI - Neuromyelitis Optica Spectrum Disorder with Recurrent Intracranial Hemorrhage. AB - The patient was a woman without hypertension who had previously experienced intracranial hemorrhage twice at 48 and 56 years of age. At 59 years of age, she was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) based on the presence of a brain stem lesion and the detection of anti-aquaporin 4 (AQP4) antibodies. After 5 months of continuous treatment with prednisolone (15 mg/day), she presented with optic neuritis and intracranial bleeding. A recurrent attack of NMOSD and intracranial hemorrhage were concurrently diagnosed. We herein report a case of NMOSD with recurrent intracranial hemorrhage, which indicates an association between NMOSD and cerebellar vascular dysfunction. PMID- 28674368 TI - Thymoma-associated Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) with Myasthenia Gravis. AB - We report a case of a 72-year-old woman who initially presented with symptoms of bulbar myasthenia and was positive for anti-acetylcholine receptor antibodies. She subsequently developed painful muscle spasms, myoclonus, and stiffness. Thymoma was detected, and both anti-glycine receptor and anti-glutamic acid decarboxylase antibodies were found. She was diagnosed with thymoma-associated progressive encephalomyelitis with rigidity and myoclonus (PERM). She experienced marked improvement after thymectomy followed by plasma exchange and intravenous immunoglobulin and prednisolone. This case suggests that thymectomy followed by sufficient immunosuppression may be useful in the treatment of thymoma-associated PERM. Myasthenia gravis may develop in thymoma-associated PERM patients. PMID- 28674369 TI - Upper-extremity Deep Vein Thrombosis Complicating Apheresis in a Healthy Donor. AB - Venous thrombus was recognized in the upper extremity of a 53-year-old man after blood donation. The patient presented with a 15-day history of swelling in the left upper-extremity that started 6 hours after apheresis. Contrast-enhanced computed tomography revealed clots in the deep veins of the left arm and the peripheral pulmonary artery. Blood donation had proceeded smoothly, and the patient had no thrombotic predisposition, except for a smoking habit. The thrombus resolved following anticoagulant therapy, and the patient' s clinical course was uncomplicated. Despite a thorough investigation, the cause of this thrombus remains unknown. PMID- 28674370 TI - Double-Orifice Mitral Valve with Leaflet Perforation. PMID- 28674371 TI - Pontine Syphilitic Gumma in an HIV-negative Patient. PMID- 28674372 TI - Deep Cutaneous Ulcers in Dermatomyositis. PMID- 28674373 TI - Endocarditis due to Gemella morbillorum. PMID- 28674374 TI - Gastric Syphilis. PMID- 28674375 TI - Chest Necrotizing Fasciitis with Mediastinitis. PMID- 28674376 TI - Characterization of H-box region mutants of WalK inert to the action of waldiomycin in Bacillus subtilis. AB - The WalK/WalR two-component system is essential for cell wall metabolism and thus for cell growth in Bacillus subtilis. Waldiomycin was previously isolated as an antibiotic that targeted WalK, the cognate histidine kinase (HK) of the response regulator, WalR, in B. subtilis. To gain further insights into the action of waldiomycin on WalK and narrow down its site of action, mutations were introduced in the H-box region, a well-conserved motif of the bacterial HKs of WalK. The half-maximal inhibitory concentrations (IC50s) of waldiomycin against purified WalK protein with triple substitutions in the H-box region, R377M/R378M/S385A and R377M/R378M/R389M, were 26.4 and 55.1 times higher than that of the wild-type protein, respectively, indicating that these residues of WalK are crucial for the inhibitory effect of waldiomycin on its kinase activity. Surprisingly, this antibiotic severely affected cell growth in a minimum inhibitory concentration (MIC) assay, but not transcription of WalR-regulated genes or cell morphology in B. subtilis strains that harbored the H-box triple substitutions on the bacterial chromosome. We hypothesized that waldiomycin targets other HKs as well, which may, in turn, sensitize B. subtilis cells with the H-box triple mutant alleles of the walK gene to waldiomycin. Waldiomycin inhibited other HKs such as PhoR and ResE, and, to a lesser extent, CitS, whose H-box region is less conserved. These results suggest that waldiomycin perturbs multiple cellular processes in B. subtilis by targeting the H-box region of WalK and other HKs. PMID- 28674377 TI - Sirtuin A regulates secondary metabolite production by Aspergillus nidulans. AB - Late-stage cultures of filamentous fungi under nutrient starvation produce valuable secondary metabolites such as pharmaceuticals and pigments, as well as deleterious mycotoxins, all of which have remarkable structural diversity and wide-spectrum bioactivity. The fungal mechanisms regulating the synthesis of many of these compounds are not fully understood, but sirtuin A (SirA) is a key factor that initiates production of the secondary metabolites, sterigmatocystin and penicillin G, by Aspergillus nidulans. Sirtuin is a ubiquitous NAD+-dependent histone deacetylase that converts euchromatin to heterochromatin and silences gene expression. In this study, we have investigated the transcriptome of a sirA gene disruptant (SirADelta), and found that SirA concomitantly repressed the expression of gene clusters for synthesizing secondary metabolites and activated that of others. Extracts of SirADelta cultures grown on solid agar and analyzed by HPLC indicated that SirA represses the production of austinol, dehydroaustinol and sterigmatocystin. These results indicated that SirA is a transcriptional regulator of fungal secondary metabolism. PMID- 28674378 TI - Donor Selection and Prophylactic Strategy for Venous Thromboembolic Events in Living Donors of Liver Transplantation Based on Results of Thrombophilia Screening Tests. AB - BACKGROUND We reported a strategy of thrombophilia testing-guided venous thromboembolic events (VTE) prophylaxis for living donors of liver transplantation in 2011. The aim of the present study was to evaluate the safety and efficacy of this protocol for VTE prophylaxis. MATERIAL AND METHODS Thrombophilia testing, including protein S (PS), protein C (PC), antithrombin (AT) III, and anti-phospholipid antibody (APLA), was performed in 306 living donor candidates between July 2005 and June 2016. Donors who met any of the criteria of PS <60%, PC <64%, AT-III <70%, and positive APLA were classified into the borderline group and received continuous venous infusion of heparin immediately after surgery, in addition to use of elastic stockings and intermittent pneumatic compression (IPC) until patients were ambulatory. Other donors who were classified into the normal group used elastic stockings and IPC with no anticoagulants. The efficacy and safety endpoints were VTE occurrence and bleeding events, respectively. RESULTS PS was considerably decreased in 3 candidates and PC was considerably reduced in 1 candidate, and they were excluded for high risk of VTE. Seventeen candidates in the borderline group and 137 in the normal group underwent donor surgery. One donor in the borderline group developed a wound hematoma. Postoperative complications were similar between the 2 groups. None of the donors in either group developed VTE. CONCLUSIONS Thrombophilia testing-guided VTE prophylaxis is safe and may contribute to reduced VTE risk in donors, although further investigations are warranted to assess the necessity of thrombophilia testing prior to surgery among living donors. PMID- 28674379 TI - The Reliability of Panoramic Radiography Versus Cone Beam Computed Tomography when Evaluating the Distance to the Alveolar Nerve in the Site of Lateral Teeth. AB - BACKGROUND The aim of this study was to compare the reliability of panoramic radiography (PR) and cone beam computed tomography (CBCT) in the evaluation of the distance of the roots of lateral teeth to the inferior alveolar nerve canal (IANC). MATERIAL AND METHODS 100 PR and 100 CBCT images that met the selection criteria were selected from the database. In PR images, the distances were measured using an electronic caliper with 0.01 mm accuracy and white light x-ray film reviewer. Actual values of the measurements were calculated taking into consideration the magnification used in PR images (130%). Measurements on CBCT images were performed using i-CAT Vision software. Statistical data analysis was performed using R software and applying Welch's t-test and the Wilcoxon test. RESULTS There was no statistically significant difference in the mean distance from the root of the second premolar and the mesial and distal roots of the first molar to the IANC between PR and CBCT images. The difference in the mean distance from the mesial and distal roots of the second and the third molars to the IANC measured in PR and CBCT images was statistically significant. CONCLUSIONS PR may be uninformative or misleading when measuring the distance from the mesial and distal roots of the second and the third molars to the IANC. PMID- 28674380 TI - Exceptionally High Creatine Kinase (CK) Levels in Multicausal and Complicated Rhabdomyolysis: A Case Report. AB - BACKGROUND Rhabdomyolysis is a syndrome caused by muscle breakdown. It can be caused by traumatic as well as non-traumatic factors such as drugs, toxins, and infections. Although it has been initially associated with only traumatic causes, non-traumatic causes now appear to be at least 5 times more frequent. In rhabdomyolysis, the CK levels can range anywhere from 10 000 to 200 000 or even higher. The higher the CK levels, the greater will be the renal damage and associated complications. We present the case of a patient with exceptionally massive rhabdomyolysis with unusually high CK levels (nearly 1 million) caused by combined etiologic factors and complicated with acute renal failure. CASE REPORT A 36-year-old African American male patient with no significant past medical history and a social history of cocaine and alcohol abuse presented with diarrhea and generalized weakness of 2 days' duration. He was found to be febrile, tachycardic, tachypneic, and hypoxic. The patient was subsequently intubated and admitted to the medical ICU. Laboratory work-up showed acute renal failure with deranged liver functions test results, and elevated creatine kinase of 701,400 U/L. CK levels were subsequently too high for the lab to quantify. Urine legionella testing was positive for L. pneumophilia serogroup 1 antigen and urine toxicology was positive for cocaine. The patient had a protracted course in the ICU. He was initially started on CVVH, and later received intermittent hemodialysis for about 1 month. CONCLUSIONS In the presence of multiple etiologic factors, rhabdomyolysis can be massive with resultant significant morbidity. Clinicians should have a high index of suspicion for rhabdomyolysis in the presence of multiple factors, as early recognition of this diseases is very important in the prevention and active management of life-threatening conditions. PMID- 28674381 TI - Engineered botulinum neurotoxin B with improved efficacy for targeting human receptors. AB - Botulinum neurotoxin B is a Food and Drug Administration-approved therapeutic toxin. However, it has lower binding affinity toward the human version of its major receptor, synaptotagmin II (h-Syt II), compared to mouse Syt II, because of a residue difference. Increasing the binding affinity to h-Syt II may improve botulinum neurotoxin B's therapeutic efficacy and reduce adverse effects. Here we utilized the bacterial adenylate cyclase two-hybrid method and carried out a saturation mutagenesis screen in the Syt II-binding pocket of botulinum neurotoxin B. The screen identifies E1191 as a key residue: replacing it with M/C/V/Q enhances botulinum neurotoxin B binding to human synaptotagmin II. Adding S1199Y/W or W1178Q as a secondary mutation further increases binding affinity. Mutant botulinum neurotoxin B containing E1191M/S1199Y exhibits ~11-fold higher efficacy in blocking neurotransmission than wild-type botulinum neurotoxin B in neurons expressing human synaptotagmin II, demonstrating that enhancing receptor binding increases the overall efficacy at functional levels. The engineered botulinum neurotoxin B provides a platform to develop therapeutic toxins with improved efficacy.Humans are less sensitive to the therapeutic effects of botulinum neurotoxin B (BoNT/B) than the animal models it is tested on due to differences between the human and the mouse receptors. Here, the authors engineer BoNT/B to improve its affinity to human receptors and enhance its therapeutic efficacy. PMID- 28674382 TI - The destiny of the resistance/susceptibility against GCRV is controlled by epigenetic mechanisms in CIK cells. AB - Hemorrhagic disease caused by grass carp reovirus (GCRV) has severely threatened the grass carp (Ctenopharyngodon idella) cultivation industry. It is noteworthy that the resistance against GCRV infection was reported to be inheritable, and identified at both individual and cellular levels. Therefore, this work was inspired and dedicated to unravel the molecular mechanisms of fate decision post GCRV infection in related immune cells. Foremost, the resistant and susceptible CIK (C. idella kidney) monoclonal cells were established by single cell sorting, subculturing and infection screening successively. RNA-Seq, MeDIP-Seq and small RNA-Seq were carried out with C1 (CIK cells), R2 (resistant cells) and S3 (susceptible cells) groups. It was demonstrated that genome-wide DNA methylation, mRNA and microRNA expression levels in S3 were the highest among three groups. Transcriptome analysis elucidated that pathways associated with antioxidant activity, cell proliferation regulation, apoptosis activity and energy consuming might contribute to the decision of cell fates post infection. And a series of immune-related genes were identified differentially expressed across resistant and susceptible groups, which were negatively modulated by DNA methylation or microRNAs. To conclude, this study systematically uncovered the regulatory mechanism on the resistance from epigenetic perspective and provided potential biomarkers for future studies on resistance breeding. PMID- 28674383 TI - MR imaging features of benign retroperitoneal extra-adrenal paragangliomas. AB - The goal of this study was to retrospectively review the magnetic resonance imaging (MRI) features of retroperitoneal extra-adrenal paragangliomas and to evaluate the diagnostic capabilities of MRI. Twenty-four patients with confirmed benign retroperitoneal extra-adrenal paragangliomas who underwent preoperative MRI and surgical resection were enrolled. The patients' clinical characteristics and MRI features were reviewed by two radiologists. There were no significant differences in the qualitative and quantitative MRI features were determined by the reviewers. High signal intensity in T2-weighted imaging (T2WI) and diffusion weighted imaging (DWI) was observed in all tumors. In contrast T1-weighted imaging (T1WI) in the arterial phase, 83.33% of the tumors were clearly enhanced. In 87.5% of cases, a persistent enhancement pattern was observed in the venous and delayed phases, and 12.5% of tumors showed a "washout" pattern. The tumor capsule, intratumoral septum and degenerations were visualized in the tumors and may be helpful in the qualitative diagnosis of extra-adrenal paragangliomas in MRI. MRI was useful in locating the position, determining the tumor ranges and visualizing the relationship between the tumors and adjacent structures. The presence of typical clinical symptoms and positivity of biochemical tests are also important factors in making an accurate preoperative diagnosis. PMID- 28674384 TI - Impact of climate and host availability on future distribution of Colorado potato beetle. AB - Colorado Potato Beetle (CPB) is a devastating invasive pest of potato both in its native North America and now across Eurasia. It also damages eggplant, tomato and feeds on several wild species in the Solanaceae, such as S. eleagnifolium and S. rostratum Dunal (SR). Since first categorized as a pest in 1864, CPB has spread rapidly across North America, Europe and Asia. In light of its invasiveness and economic importance, it is necessary to study how climate change and host availability may alter the distribution of the CPB. Maximum Entropy (MaxEnt) models were used to anticipate global range expansion as influenced by environmental conditions, and by the possibility of cooperative invasion of CPB and its wild host SR. The results indicate that both CPB and SR can occupy warm areas of North America, South Africa, Europe, China, and Australia. Future climate conditions may promote CPB expansion into northern regions and SR into the circumpolar latitudes. The existing range and continued spread of SR may also assist the global expansion of CPB. Future management of this pest should consider the impacts of global climate change and host availability on its potential global distribution. PMID- 28674385 TI - Sea ice phenology and primary productivity pulses shape breeding success in Arctic seabirds. AB - Spring sea ice phenology regulates the timing of the two consecutive pulses of marine autotrophs that form the base of the Arctic marine food webs. This timing has been suggested to be the single most essential driver of secondary production and the efficiency with which biomass and energy are transferred to higher trophic levels. We investigated the chronological sequence of productivity pulses and its potential cascading impacts on the reproductive performance of the High Arctic seabird community from Svalbard, Norway. We provide evidence that interannual changes in the seasonal patterns of marine productivity may impact the breeding performance of little auks and Brunnich's guillemots. These results may be of particular interest given that current global warming trends in the Barents Sea region predict one of the highest rates of sea ice loss within the circumpolar Arctic. However, local- to regional-scale heterogeneity in sea ice melting phenology may add uncertainty to predictions of climate-driven environmental impacts on seabirds. Indeed, our fine-scale analysis reveals that the inshore Brunnich's guillemots are facing a slower advancement in the timing of ice melt compared to the offshore-foraging little auks. We provide a suitable framework for analyzing the effects of climate-driven sea ice disappearance on seabird fitness. PMID- 28674386 TI - Metabolic and microbial signatures in rat hepatocellular carcinoma treated with caffeic acid and chlorogenic acid. AB - Hepatocellular carcinoma (HCC) treatment remains lack of effective chemopreventive agents, therefore it is very attractive and urgent to discover novel anti-HCC drugs. In the present study, the effects of chlorogenic acid (ChA) and caffeic acid (CaA) on HCC induced by diethylnitrosamine (DEN) were evaluated. ChA or CaA could reduce the histopathological changes and liver injury markers, such as alanine transarninase, aspartate aminotransferase, alkaline phosphatase, total bile acid, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol. The underlying mechanisms were investigated by a data integration strategy based on correlation analyses of metabonomics data and 16 S rRNA gene sequencing data. ChA or CaA could inhibit the increase of Rumincoccaceae UCG-004 and reduction of Lachnospiraceae incertae sedis, and Prevotella 9 in HCC rats. The principal component analysis and partial least squares discriminant analysis were applied to reveal the metabolic differences among these groups. 28 different metabolites showed a trend to return to normal in both CaA and ChA treatment. Among them, Bilirubin, L-Tyrosine, L-Methionine and Ethanolamine were correlated increased Rumincoccaceae UCG-004 and decreased of Lachnospiraceae incertae sedis and Prevotella 9. These correlations could be identified as metabolic and microbial signatures of HCC onset and potential therapeutic targets. PMID- 28674387 TI - Activation of the mTOR signaling pathway is required for asthma onset. AB - The mTOR pathway has been implicated in immune functions; however, its role in asthma is not well understood. We found that patients experiencing an asthma attack, when compared with patients in asthma remission, showed significantly elevated serum mTOR pathway activation, increased Th17 cells and IL-4, and decreased Treg cells and IFN-gamma. In patients experiencing asthma, mTOR activation was positively correlated with the loss of Th17/Treg and Th1/Th2 balance. The role of mTOR in asthma was further confirmed using an ovalbumin induced asthmatic mouse model. The mTOR pathway was activated in asthmatic mice, demonstrated by elevated levels of p-PI3K, p-Akt, p-mTOR, and p-p70S6k, and this activation was significantly reduced by treatment with budenoside or mTOR pathway inhibitors. Moreover, mTOR pathway inhibitor treatment reduced asthmatic markers and reversed the Th17/Treg and Th1/Th2 imbalances in asthmatic mice. Finally, different mTOR pathway inhibitor treatments have different inhibitory effects on signaling molecules in asthmatic mice. In summary, mTOR is activated during asthma onset and suppressed during asthma remission, and inhibiting the mTOR pathway in asthmatic mice alleviates asthmatic markers and restores the balances of Th17/Treg and Th1/Th2 cytokines. These data strongly suggest a critical requirement for mTOR pathway activation in asthma onset, suggesting potential targets for asthma treatments. PMID- 28674388 TI - Lateral multilayer/monolayer MoS2 heterojunction for high performance photodetector applications. AB - Inspired by the unique, thickness-dependent energy band structure of 2D materials, we study the electronic and optical properties of the photodetector based on the as-exfoliated lateral multilayer/monolayer MoS2 heterojunction. Good gate-tunable current-rectifying characteristics are observed with a rectification ratio of 103 at V gs = 10 V, which may offer an evidence on the existence of the heterojunction. Upon illumination from ultraviolet to visible light, the multilayer/monolayer MoS2 heterojunction shows outstanding photodetective performance, with a photoresponsivity of 103 A/W, a photosensitivity of 1.7 * 105 and a detectivity of 7 * 1010 Jones at 470 nm light illumination. Abnormal photoresponse under positive gate voltage is observed and analyzed, which indicates the important role of the heterojunction in the photocurrent generation process. We believe that these results contribute to a better understanding on the fundamental physics of band alignment for multilayer/monolayer MoS2 heterojunction and provide us a feasible solution for novel electronic and optoelectronic devices. PMID- 28674389 TI - Insulated transcriptional elements enable precise design of genetic circuits. AB - Rational engineering of biological systems is often complicated by the complex but unwanted interactions between cellular components at multiple levels. Here we address this issue at the level of prokaryotic transcription by insulating minimal promoters and operators to prevent their interaction and enable the biophysical modeling of synthetic transcription without free parameters. This approach allows genetic circuit design with extraordinary precision and diversity, and consequently simplifies the design-build-test-learn cycle of circuit engineering to a mix-and-match workflow. As a demonstration, combinatorial promoters encoding NOT-gate functions were designed from scratch with mean errors of <1.5-fold and a success rate of >96% using our insulated transcription elements. Furthermore, four-node transcriptional networks with incoherent feed-forward loops that execute stripe-forming functions were obtained without any trial-and-error work. This insulation-based engineering strategy improves the resolution of genetic circuit technology and provides a simple approach for designing genetic circuits for systems and synthetic biology.Unwanted interactions between cellular components can complicate rational engineering of biological systems. Here the authors design insulated minimal promoters and operators that enable biophysical modeling of bacterial transcription without free parameters for precise circuit design. PMID- 28674390 TI - Empathy skill-dependent modulation of working memory by painful scene. AB - As an important online information retaining and processing function, working memory plays critical roles in many other cognitive functions. Several long-term factors, such as age, addiction and diseases, have been affirmed to impair working memory, but whether or how the short-term factors, like painful stimuli or emotions, regulate the human working memory ability is not well explored. Here we investigated the influences of empathic pain on upcoming working memory and existing working memory, by presenting human subjects with the pictures depicting painful or neutral scene. After separating the subjects into two groups, the more empathic group and relatively indifferent group, according to a well-accepted questionnaire (the Interpersonal Reactivity Index (IRI)), the modulatory effect emerged. Empathic pain might exerted either a facilitating effect or an impairing effect, which was closely correlated with the personal empathy skills. Meanwhile, different aspects of subjects' empathy traits exerted distinct effects, and female subjects were more vulnerable than male subjects. Present study reveals a new modulatory manner of the working memory, via empathy skill-dependent painful experience. PMID- 28674391 TI - Observation of reflectionless absorption due to spatial Kramers-Kronig profile. AB - As a fundamental phenomenon in electromagnetics and optics, material absorption has been extensively investigated for centuries. However, omnidirectional, reflectionless absorption in inhomogeneous media has yet to be observed. Previous research on transformation optics indicated that such absorption cannot easily be implemented without involving gain media. A recent theory on wave propagation, however, implies the feasibility to implement such absorption requiring no gain, provided that the permittivity profile of this medium can satisfy the spatial Kramers-Kronig relations. In this work, we implement such a profile over a broad frequency band based on a novel idea of space-frequency Lorentz dispersion. A wideband, omnidirectionally reflectionless absorption is then experimentally observed in the gigahertz range, and is in good agreement with theoretical analysis and full-wave simulations. The proposed method based on the space frequency dispersion implies the practicability to construct gain-free omnidirectionally non-reflecting absorbers.Reflectionless absorption independent of the angle of incidence usually requires the introduction of gain media into the system. Here, Ye et al. implement a recent theoretical proposal to achieve this with a spatially varying permittivity, showing that this approach is experimentally feasible. PMID- 28674392 TI - Task relevance modulates the cortical representation of feature conjunctions in the target template. AB - Little is known about the cortical regions involved in representing task-related content in preparation for visual task performance. Here we used representational similarity analysis (RSA) to investigate the BOLD response pattern similarity between task relevant and task irrelevant feature dimensions during conjunction viewing and target template maintenance prior to visual search. Subjects were cued to search for a spatial frequency (SF) or orientation of a Gabor grating and we measured BOLD signal during cue and delay periods before the onset of a search display. RSA of delay period activity revealed that widespread regions in frontal, posterior parietal, and occipitotemporal cortices showed general representational differences between task relevant and task irrelevant dimensions (e.g., orientation vs. SF). In contrast, RSA of cue period activity revealed sensory-related representational differences between cue images (regardless of task) at the occipital pole and additionally in the frontal pole. Our data show that task and sensory information are represented differently during viewing and during target template maintenance, and that task relevance modulates the representation of visual information across the cortex. PMID- 28674393 TI - Identifying affective personality profiles: A latent profile analysis of the Affective Neuroscience Personality Scales. AB - Based on evolutionary theory, a recent model in affective neuroscience delineated six emotional brain systems at the core of human personality: SEEKING, CARING, PLAYFULNESS, FEAR, ANGER, SADNESS. The Affective Neuroscience Personality Scales (ANPS) assess their functioning. Using a person-centred approach of the ANPS, this study: (i) examined the existence of latent personality profiles, (ii) studied their gender invariance, (iii) assessed their longitudinal (4 years) stability, and (iv) explored how they relate to several intrapersonal, interpersonal, and emotion regulation skills. Latent Profile Analysis in 2 samples (Canadian, longitudinal, N = 520; French, cross-sectional, N = 830) found that, qualitatively, 3 profiles characterized both populations and genders, with one distinction for the second profile where the French women endorsed slightly higher and lower scores for, respectively, the negative and positive emotions. Whilst not being quantitatively similar across genders, the personality profiles remained consistent across time in the longitudinal sample. Associations between profiles and intrapersonal (e.g. depression), interpersonal (e.g. empathy), and emotion regulation skills measures (e.g. emotional intelligence) offered concurrent validity evidence. This person centred approach to ANPS offers a holistic and parsimonious way to study affective personality dimensions. It opens promising avenues for future studies on the predictive value of ANPS profiles, and for personality-targeted interventions. PMID- 28674395 TI - Comparative transcriptome analysis on the synthesis pathway of honey bee (Apis mellifera) mandibular gland secretions. AB - Secretions from mandibular glands (MGs) have important caste-specific functions that are associated with the social evolution of honey bees. To gain insights into the molecular architecture underlying these caste differences, we compared the gene expression patterns of MGs from queens, queenright workers (WQRs) and queenless workers (WQLs) using high-throughput RNA-sequencing technology. In total, we identified 46 candidate genes associated with caste-specific biosynthesis of fatty acid pheromones in the MG, including members of cytochrome P450 (CYP450) family and genes involved in fatty acid beta-oxidation and omega oxidation. For further identification of the CYP450s genes involved in the biosynthesis of MG secretions, we analyzed by means of qPCR, the expression levels of six of the CYP450 genes most abundantly expressed in the transcriptome analysis across different castes, ages, tasks and tissues. Our analysis revealed that CYP6AS8 and CYP6AS11, the most abundantly expressed CYP450 genes in worker and queen MGs, respectively, are selectively expressed in the MGs of workers and queens compared to other tissues. These results suggest that these genes might be responsible for the critical bifurcated hydroxylation process in the biosynthesis pathway. Our study contributes to the description of the molecular basis for the biosynthesis of fatty acid-derived pheromones in the MGs. PMID- 28674394 TI - Genetic association analysis of the RTK/ERK pathway with aggressive prostate cancer highlights the potential role of CCND2 in disease progression. AB - The RTK/ERK signaling pathway has been implicated in prostate cancer progression. However, the genetic relevance of this pathway to aggressive prostate cancer at the SNP level remains undefined. Here we performed a SNP and gene-based association analysis of the RTK/ERK pathway with aggressive prostate cancer in a cohort comprising 956 aggressive and 347 non-aggressive cases. We identified several loci including rs3217869/CCND2 within the pathway shown to be significantly associated with aggressive prostate cancer. Our functional analysis revealed a statistically significant relationship between rs3217869 risk genotype and decreased CCND2 expression levels in a collection of 119 prostate cancer patient samples. Reduced expression of CCND2 promoted cell proliferation and its overexpression inhibited cell growth of prostate cancer. Strikingly, CCND2 downregulation was consistently observed in the advanced prostate cancer in 18 available clinical data sets with a total amount of 1,095 prostate samples. Furthermore, the lower expression levels of CCND2 markedly correlated with prostate tumor progression to high Gleason score and elevated PSA levels, and served as an independent predictor of biochemical relapse and overall survival in a large cohort of prostate cancer patients. Together, we have identified an association of genetic variants and genes in the RTK/ERK pathway with prostate cancer aggressiveness, and highlighted the potential importance of CCND2 in prostate cancer susceptibility and tumor progression to metastasis. PMID- 28674396 TI - Enhanced-quantum yield sulfur/nitrogen co-doped fluorescent carbon nanodots produced from biomass Enteromorpha prolifera: synthesis, posttreatment, applications and mechanism study. AB - Enteromorpha prolifera (E. prolifera), one of the main algae genera for green tide, significantly influences both the coastal ecological environment and seawater quality. How to effectively utilize this waste as reproducible raw resource with credible application mechanism are urgent environmental issues to be solved. Herein, E. prolifera was converted to attractive fluorescent carbon nanodots (CNDs) by one-pot green hydrothermal process. The purity and quantum yields for the as-prepared CNDs can be enhanced upon the post-treatment of ethanol sedimentation. The CNDs can be well dispersed in aqueous medium with uniform spherical morphology, narrow size distribution and average size of 2.75 +/- 0.12 nm. The ease synthesis and relatively high quantum yields of the CNDs make E. prolifera inexpensive benefit to the human and nature, such as applications in efficient cell imaging and fiber staining. Furthermore, it was discovered that the fluorescence intensity of the CNDs can be selectively quenched upon Fe3+ addition, which can be used for specific sensitive assay and removal of Fe3+ in aqueous medium. More importantly, it was reasonably proposed that the quenching was resulted from the synergistic effects of CNDs aggregation and Fe3+-CNDs charge-transfer transitions due to the coordination interactions between Fe3+ and the oxygenous groups on the CNDs. PMID- 28674397 TI - Re-distribution of oxygen at the interface between gamma-Al2O3 and TiN. AB - Interface of TiN electrode with gamma-Al2O3 layers was studied using near edge X ray absorption fine structure, conventional X-ray photoelectron spectroscopy and photoelectron spectroscopy with high energies. Despite the atomic-layer deposited Al2O3 being converted into thermodynamically-stable polycrystalline cubic gamma phase by high-temperature (1000 or 1100 degrees C) anneal, our results reveal formation of a thin TiNxOy (~1-nm thick) interlayer at the interface between gamma-Al2O3 film and TiN electrode due to oxygen scavenging from gamma-Al2O3 film. Formation of the TiO2 was not observed at this interface. As environmental effect, a strong oxidation resulting in formation of a TiO2(1.4 nm)/TiNxOy(0.9 nm) overlayers on the top of the TiN electrode is traced. Development of O deficiency of gamma-Al2O3 is observed and related to the polarization anisotropy due to the preferential orientation of spin states involved in the X-ray absorption in the plane parallel to the surface. Investigation of the TiN electrode reveals the predominantly "stretched" octahedra in its structure with the preferential orientation relative the interface with gamma-Al2O3. This anisotropy can be correlated with ~200 meV electron barrier height increase at the O-deficient TiN/gamma-Al2O3 interface as compared to the TiN/gamma-Al2O3 barrier formed under abundant oxidant supply condition as revealed by internal photoemission of electrons from TiN into the oxide. PMID- 28674398 TI - Enhanced thermoelectric properties of AgSbTe2 obtained by controlling heterophases with Ce doping. AB - We report the enhanced thermoelectric properties of Ce-doped AgSbTe2 (AgSb1 xCexTe2) compounds. As the Ce contents increased, the proportion of heterophase Ag2Te in the AgSbTe2 gradually decreased, along with the size of the crystals. The electrical resistivity and Seebeck coefficient were dramatically affected by Ce doping and the lattice thermal conductivity was reduced. The presence of nanostructured Ag2Te heterophases resulted in a greatly enhanced dimensionless figure of merit, ZT of 1.5 at 673 K. These findings highlight the importance of the heterophase and doping control, which determines both electrical and thermal properties. PMID- 28674399 TI - Field-driven dynamics and time-resolved measurement of Dzyaloshinskii-Moriya torque in canted antiferromagnet YFeO3. AB - Electrical spin switching in an antiferromagnet is one of the key issues for both academic interest and industrial demand in new-type spin devices because an antiferromagnetic system has a negligible stray field due to an alternating sign between sub-lattices, in contrast to a ferromagnetic system. Naturally, questions arise regarding how fast and, simultaneously, how robustly the magnetization can be switched by external stimuli, e.g., magnetic field and spin current. First, the exploitation of ultrafast precessional motion of magnetization in antiferromagnetic oxide has been studied intensively. Regarding robustness, the so-called inertia-driven switching scenario has been generally accepted as the switching mechanism in antiferromagnet system. However, in order to understand the switching dynamics in a canted antiferromagnet, excited by magnetic field, accurate equation of motion and corresponding interpretation are necessary. Here, we re-investigate the inertia-driven switching process, triggered by the strict phase matching between effective driving field, dh/dt, and antiferromagnetic order parameters, l. Such theoretical approaches make it possible to observe the static parameters of an antiferromagnet, hosting Dzyaloshinskii-Moriya (DM) interaction. Indeed, we estimate successfully static parameters, such as DM, exchange, and anisotropy energies, from dynamical behaviour in YFeO3, studied using terahertz time-domain spectroscopy. PMID- 28674400 TI - Endotoxin tolerance in mast cells, its consequences for IgE-mediated signalling, and the effects of BCL3 deficiency. AB - Stimulation with lipopolysaccharide (LPS; endotoxin) not only causes rapid production of proinflammatory cytokines, but also induces a state of LPS hypo responsiveness to a second LPS stimulation (endotoxin tolerance (ET)). Murine bone marrow-derived MCs (BMMCs) and peritoneal MCs (PMCs) developed ET as shown by an abrogated production of Il6/Tnf RNAs and IL-6/TNF-alpha proteins. In naive BMMCs, LPS stimulation induced a transient decline in the trimethylation of lysine 9 of the core histone H3 (H3K9me3), a suppressive chromatin mark, at the Il6/Tnf promoters, which correlated with p50(NFkappaB) and p65(NFkappaB) binding. Both demethylation and NFkappaB binding were abrogated in tolerant cells. In addition, cytosolic NFkappaB activation was suppressed in tolerant BMMCs. Intriguingly, antigen stimulation of naive and tolerant MCs induced comparable production of Il6/Tnf and IL-6/TNF-alpha, although ET also affected antigen triggered activation of NFkappaB; pharmacological analysis indicated the importance of Ca2+-dependent transcription in this respect. In macrophages, the IkappaB member BCL3 is induced by LPS and known to be involved in ET, which was not corroborated comparing wild-type and Bcl3-deficient BMMCs. Interestingly, Bcl3-deficient PMCs produce markedly increased amounts of IL-6/TNF-alpha after LPS stimulation. Collectively, ET in MCs is BCL3-independent, however, in PMCs, BCL3 negatively regulates immediate LPS-induced cytokine production and quantitatively affects ET. PMID- 28674401 TI - Quantitative Protein Topography Measurements by High Resolution Hydroxyl Radical Protein Footprinting Enable Accurate Molecular Model Selection. AB - We report an integrated workflow that allows mass spectrometry-based high resolution hydroxyl radical protein footprinting (HR-HRPF) measurements to accurately measure the absolute average solvent accessible surface area () of amino acid side chains. This approach is based on application of multi-point HR-HRPF, electron-transfer dissociation (ETD) tandem MS (MS/MS) acquisition, measurement of effective radical doses by radical dosimetry, and proper normalization of the inherent reactivity of the amino acids. The accuracy of the resulting measurements was tested by using well-characterized protein models. Moreover, we demonstrated the ability to use measurements from HR HRPF to differentiate molecular models of high accuracy (<3 A backbone RMSD) from models of lower accuracy (>4 A backbone RMSD). The ability of data from HR HRPF to differentiate molecular model quality was found to be comparable to that of data obtained from X-ray crystal structures, indicating the accuracy and utility of HR-HRPF for evaluating the accuracy of computational models. PMID- 28674402 TI - Origin of proton affinity to membrane/water interfaces. AB - Proton diffusion along biological membranes is vitally important for cellular energetics. Here we extended previous time-resolved fluorescence measurements to study the time and temperature dependence of surface proton transport. We determined the Gibbs activation energy barrier DeltaG ?r that opposes proton surface-to-bulk release from Arrhenius plots of (i) protons' surface diffusion constant and (ii) the rate coefficient for proton surface-to-bulk release. The large size of DeltaG ?r disproves that quasi-equilibrium exists in our experiments between protons in the near-membrane layers and in the aqueous bulk. Instead, non-equilibrium kinetics describes the proton travel between the site of its photo-release and its arrival at a distant membrane patch at different temperatures. DeltaG ?r contains only a minor enthalpic contribution that roughly corresponds to the breakage of a single hydrogen bond. Thus, our experiments reveal an entropic trap that ensures channeling of highly mobile protons along the membrane interface in the absence of potent acceptors. PMID- 28674403 TI - Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica. AB - Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment. PMID- 28674404 TI - Third-person self-talk facilitates emotion regulation without engaging cognitive control: Converging evidence from ERP and fMRI. AB - Does silently talking to yourself in the third-person constitute a relatively effortless form of self control? We hypothesized that it does under the premise that third-person self-talk leads people to think about the self similar to how they think about others, which provides them with the psychological distance needed to facilitate self control. We tested this prediction by asking participants to reflect on feelings elicited by viewing aversive images (Study 1) and recalling negative autobiographical memories (Study 2) using either "I" or their name while measuring neural activity via ERPs (Study 1) and fMRI (Study 2). Study 1 demonstrated that third-person self-talk reduced an ERP marker of self referential emotional reactivity (i.e., late positive potential) within the first second of viewing aversive images without enhancing an ERP marker of cognitive control (i.e., stimulus preceding negativity). Conceptually replicating these results, Study 2 demonstrated that third-person self-talk was linked with reduced levels of activation in an a priori defined fMRI marker of self-referential processing (i.e., medial prefrontal cortex) when participants reflected on negative memories without eliciting increased levels of activity in a priori defined fMRI markers of cognitive control. Together, these results suggest that third-person self-talk may constitute a relatively effortless form of self control. PMID- 28674405 TI - Lack of evidence for involvement of TonEBP and hyperosmotic stimulus in induction of autophagy in the nucleus pulposus. AB - Nucleus pulposus (NP) cells reside in a physiologically hyperosmotic environment within the intervertebral disc. TonEBP/NFAT5 is an osmo-sensitive transcription factor that controls expression of genes critical for cell survival under hyperosmotic conditions. A recent report on NP and studies of other cell types have shown that hyperosmolarity triggers autophagy. However, little is known whether such autophagy induction occurs through TonEBP. The goal of this study was to investigate the role of TonEBP in hyperosmolarity-dependent autophagy in NP. Loss-of-function studies showed that autophagy in NP cells was not TonEBP dependent; hyperosmolarity did not upregulate autophagy as previously reported. NP tissue of haploinsufficient TonEBP mice showed normal pattern of LC3 staining. NP cells did not increase LC3-II or LC3-positive puncta under hyperosmotic conditions. Bafilomycin-A1 treatment and tandem mCherry-EGFP-LC3B reporter transfection demonstrated that the autophagic flux was unaffected by hyperosmolarity. Even under serum-free conditions, NP cells did not induce autophagy with increasing osmolarity. Hyperosmolarity did not change the phosphorylation of ULK1 by mTOR and AMPK. An ex vivo disc organ culture study supported that extracellular hyperosmolarity plays no role in promoting autophagy in the NP. We conclude that hyperosmolarity does not play a role in autophagy induction in NP cells. PMID- 28674406 TI - Exposure history determines pteropod vulnerability to ocean acidification along the US West Coast. AB - The pteropod Limacina helicina frequently experiences seasonal exposure to corrosive conditions (Omegaar < 1) along the US West Coast and is recognized as one of the species most susceptible to ocean acidification (OA). Yet, little is known about their capacity to acclimatize to such conditions. We collected pteropods in the California Current Ecosystem (CCE) that differed in the severity of exposure to Omegaar conditions in the natural environment. Combining field observations, high-CO2 perturbation experiment results, and retrospective ocean transport simulations, we investigated biological responses based on histories of magnitude and duration of exposure to Omegaar < 1. Our results suggest that both exposure magnitude and duration affect pteropod responses in the natural environment. However, observed declines in calcification performance and survival probability under high CO2 experimental conditions do not show acclimatization capacity or physiological tolerance related to history of exposure to corrosive conditions. Pteropods from the coastal CCE appear to be at or near the limit of their physiological capacity, and consequently, are already at extinction risk under projected acceleration of OA over the next 30 years. Our results demonstrate that Omegaar exposure history largely determines pteropod response to experimental conditions and is essential to the interpretation of biological observations and experimental results. PMID- 28674407 TI - HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a "cancer-like" pro proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. We found that HDAC6 is significantly up-regulated in lungs, distal PAs, and isolated PASMCs from PAH patients and animal models. Inhibition of HDAC6 reduced PAH-PASMC proliferation and resistance to apoptosis in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 maintains Ku70 in a hypoacetylated state, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo, pharmacological inhibition of HDAC6 improved established PAH in two experimental models and can be safely given in combination with currently approved PAH therapies. Moreover, Hdac6 deficient mice were partially protected against chronic hypoxia-induced pulmonary hypertension. Our study shows for the first time that HDAC6 is implicated in PAH development and represents a new promising target to improve PAH. PMID- 28674408 TI - Anisotropically biaxial strain in non-polar (112-0) plane In x Ga1-x N/GaN layers investigated by X-ray reciprocal space mapping. AB - In this study, the indium composition x as well as the anisotropically biaxial strain in non-polar a-plane In x Ga1-x N on GaN is studied by X-ray diffraction (XRD) analysis. In accordance with XRD reciprocal lattice space mapping, with increasing indium composition, the maximum of the In x Ga1-x N reciprocal lattice points progressively shifts from a fully compressive strained to a fully relaxed position, then to reversed tensile strained. To fully understand the strain in the ternary alloy layers, it is helpful to grow high-quality device structures using a-plane nitrides. As the layer thickness increases, the strain of In x Ga1 x N layer releases through surface roughening and the 3D growth-mode. PMID- 28674409 TI - Conformable Holographic Metasurfaces. AB - Metasurface holograms are typically fabricated on rigid substrates. Here we experimentally demonstrate broadband, flexible, conformable, helicity multiplexed metasurface holograms operating in the visible range, offering increased potential for real life out-of-the-lab applications. Two symmetrically distributed holographic images are obtained when circularly polarized light impinges on the reflective-type metasurface positioned on non-planar targets. The two off-axis images with high fidelity are interchangeable by controlling the helicity of incident light. Our metasurface features the arrangement of spatially varying gold nanorods on a flexible, conformable epoxy resist membrane to realize a Pancharatnam-Berry phase profile. These results pave the way to practical applications including polarization manipulation, beam steering, novel lenses, and holographic displays. PMID- 28674410 TI - Mobile nucleic acid amplification testing (mobiNAAT) for Chlamydia trachomatis screening in hospital emergency department settings. AB - Management of curable sexually-transmitted infections (STI) such as Chlamydia can be revolutionized by highly sensitive nucleic acid testing that is deployable at the point-of-care (POC). Here we report the development of a mobile nucleic acid amplification testing (mobiNAAT) platform utilizing a mobile phone and droplet magnetofluidics to deliver NAAT in a portable and accessible format. By using magnetic particles as a mobile substrate for nucleic acid capture and transport, fluid handling is reduced to particle translocation on a simple magnetofluidic cartridge assembled with reagents for nucleic acid purification and amplification. A mobile phone user interface operating in tandem with a portable Bluetooth-enabled cartridge-processing unit facilitates process integration. We tested 30 potentially Chlamydia trachomatis (CT)-infected patients in a hospital emergency department and confirmed that mobiNAAT showed 100% concordance with laboratory-based NAAT. Concurrent evaluation by a nontechnical study coordinator who received brief training via an embedded mobile app module demonstrated ease of use and reproducibility of the platform. This work demonstrates the potential of mobile nucleic acid testing in bridging the diagnostic gap between centralized laboratories and hospital emergency departments. PMID- 28674411 TI - In Vitro Assembly and Stabilization of Dengue and Zika Virus Envelope Protein Homo-Dimers. AB - Zika virus (ZIKV) and the 4 dengue virus (DENV) serotypes are mosquito-borne Flaviviruses that are associated with severe neuronal and hemorrhagic syndromes. The mature flavivirus infectious virion has 90 envelope (E) protein homo-dimers that pack tightly to form a smooth protein coat with icosahedral symmetry. Human antibodies that strongly neutralize ZIKV and DENVs recognize complex quaternary structure epitopes displayed on E-homo-dimers and higher order structures. The ZIKV and DENV E protein expressed as a soluble protein is mainly a monomer that does not display quaternary epitopes, which may explain the modest success with soluble recombinant E (sRecE) as a vaccine and diagnostic antigen. New strategies are needed to design recombinant immunogens that display these critical immune targets. Here we present two novel methods for building or stabilizing in vitro E protein homo-dimers that display quaternary epitopes. In the first approach we immobilize sRecE to enable subsequent dimer generation. As an alternate method, we describe the use of human mAbs to stabilize homo-dimers in solution. The ability to produce recombinant E protein dimers displaying quaternary structure epitopes is an important advance with applications in flavivirus diagnostics and vaccine development. PMID- 28674412 TI - Advanced microscopy and imaging techniques in immunology and cell biology. PMID- 28674413 TI - Heterogeneous Reaction of SO2 on Manganese Oxides: the Effect of Crystal Structure and Relative Humidity. AB - Manganese oxides from anthropogenic sources can promote the formation of sulfate through catalytic oxidation of SO2. In this study, the kinetics of SO2 reactions on MnO2 with different morphologies (alpha, beta, gamma and delta) was investigated using flow tube reactor and in situ Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS). Under dry conditions, the reactivity towards SO2 uptake was highest on delta-MnO2 but lowest on beta-MnO2, with a geometric uptake coefficient (gammaobs) of (2.42 +/- 0.13) *10-2 and a corrected uptake coefficient (gammac) of (1.48 +/- 0.21) *10-6 for the former while gammaobs of (3.35 +/- 0.43) *10-3 and gammac of (7.46 +/- 2.97) *10-7 for the latter. Under wet conditions, the presence of water altered the chemical form of sulfate and was in favor for the heterogeneous oxidation of SO2. The maximum sulfate formation rate was reached at 25% RH and 45% for delta-MnO2 and gamma MnO2, respectively, possibly due to their different crystal structures. The results suggest that morphologies and RH are important factors influencing the heterogeneous reaction of SO2 on mineral aerosols, and that aqueous oxidation process involving transition metals of Mn might be a potential important pathway for SO2 oxidation in the atmosphere. PMID- 28674414 TI - Hidden defensive morphology in rotifers: benefits, costs, and fitness consequences. AB - To cope with predation, many prey species have developed inducible defenses in terms of morphology, behavior, and life history. Rotifers were the first model organisms used to evaluate the ecology and evolution of inducible defenses in aquatic ecosystems. Since the middle of last century, only visible morphological defenses, such as spine development, have been found and only in a few rotifer species. Given the development of ultrastructural defenses is taxonomically widespread in aquatic ecosystems, we hypothesize that rotifer prey, particularly small-sized species, can develop such inducible defenses. We evaluated morphological response of two common Brachionus herbivores (B. calyciflorus and B. angularis) to predatory rotifer Asplanchna brightwellii. Results confirmed existence of predator-induced ultrastructural defenses, which are expressed as increased lorica thickness and enhanced lorica hardness. Such inducible defenses are more evident and effective in the smaller sized B. angularis, leading to higher fitness of B. angularis in predator-prey interactions. As anticipated, development of defenses has inevitable fitness costs manifested as decreased reproduction or reduced sex investment. Our results not only extend understanding of inducible ultrastructural defense to other planktonic taxa that were previously observed only in cladocerans, but also verify effective mechanical protection of such hidden defensive morphology. PMID- 28674415 TI - MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. AB - Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08-2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3'-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33-3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07-3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk. PMID- 28674416 TI - Genotyping-by-sequencing reveals three QTL for clubroot resistance to six pathotypes of Plasmodiophora brassicae in Brassica rapa. AB - Clubroot, caused by Plasmodiophora brassicae, is an important disease of Brassica crops worldwide. F1 progeny from the Brassica rapa lines T19 (resistant) * ACDC (susceptible) were backcrossed with ACDC, then self-pollinated to produce BC1S1 lines, From genotyping-by-sequencing (GBS) of the parental lines and BC1 plants, about 1.32 M sequences from T19 were aligned into the reference genome of B. rapa with 0.4-fold coverage, and 1.77 M sequences with 0.5-fold coverage in ACDC. The number of aligned short reads per plant in the BC1 ranged from 0.07 to 1.41 M sequences with 0.1-fold coverage. A total of 1584 high quality SNP loci were obtained, distributed on 10 chromosomes. A single co-localized QTL, designated as Rcr4 on chromosome A03, conferred resistance to pathotypes 2, 3, 5, 6 and 8. The peak was at SNP locus A03_23710236, where LOD values were 30.3 to 38.8, with phenotypic variation explained (PVE) of 85-95%. Two QTLs for resistance to a novel P. brassicae pathotype 5x, designated Rcr8 on chromosome A02 and Rcr9 on A08, were detected with 15.0 LOD and 15.8 LOD, and PVE of 36% and 39%, respectively. Bulked segregant analysis was performed to examine TIR-NBS-LRR proteins in the regions harboring the QTL. PMID- 28674417 TI - Serial femtosecond crystallography structure of cytochrome c oxidase at room temperature. AB - Cytochrome c oxidase catalyses the reduction of molecular oxygen to water while the energy released in this process is used to pump protons across a biological membrane. Although an extremely well-studied biological system, the molecular mechanism of proton pumping by cytochrome c oxidase is still not understood. Here we report a method to produce large quantities of highly diffracting microcrystals of ba 3-type cytochrome c oxidase from Thermus thermophilus suitable for serial femtosecond crystallography. The room-temperature structure of cytochrome c oxidase is solved to 2.3 A resolution from data collected at an X ray Free Electron Laser. We find overall agreement with earlier X-ray structures solved from diffraction data collected at cryogenic temperature. Previous structures solved from synchrotron radiation data, however, have shown conflicting results regarding the identity of the active-site ligand. Our room temperature structure, which is free from the effects of radiation damage, reveals that a single-oxygen species in the form of a water molecule or hydroxide ion is bound in the active site. Structural differences between the ba 3-type and aa 3-type cytochrome c oxidases around the proton-loading site are also described. PMID- 28674418 TI - Commensal-to-pathogen transition: One-single transposon insertion results in two pathoadaptive traits in Escherichia coli -macrophage interaction. AB - Escherichia coli is both a harmless commensal in the intestines of many mammals, as well as a dangerous pathogen. The evolutionary paths taken by strains of this species in the commensal-to-pathogen transition are complex and can involve changes both in the core genome, as well in the pan-genome. One way to understand the likely paths that a commensal strain of E. coli takes when evolving pathogenicity is through experimentally evolving the strain under the selective pressures that it will have to withstand as a pathogen. Here, we report that a commensal strain, under continuous pressure from macrophages, recurrently acquired a transposable element insertion, which resulted in two key phenotypic changes: increased intracellular survival, through the delay of phagosome maturation and increased ability to escape macrophages. We further show that the acquisition of the pathoadaptive traits was accompanied by small but significant changes in the transcriptome of macrophages upon infection. These results show that under constant pressures from a key component of the host immune system, namely macrophage phagocytosis, commensal E. coli rapidly acquires pathoadaptive mutations that cause transcriptome changes associated to the host-microbe duet. PMID- 28674419 TI - Isoelectric point-based fractionation by HiRIEF coupled to LC-MS allows for in depth quantitative analysis of the phosphoproteome. AB - Protein phosphorylation is involved in the regulation of most eukaryotic cells functions and mass spectrometry-based analysis has made major contributions to our understanding of this regulation. However, low abundance of phosphorylated species presents a major challenge in achieving comprehensive phosphoproteome coverage and robust quantification. In this study, we developed a workflow employing titanium dioxide phospho-enrichment coupled with isobaric labeling by Tandem Mass Tags (TMT) and high-resolution isoelectric focusing (HiRIEF) fractionation to perform in-depth quantitative phosphoproteomics starting with a low sample quantity. To benchmark the workflow, we analyzed HeLa cells upon pervanadate treatment or cell cycle arrest in mitosis. Analyzing 300 ug of peptides per sample, we identified 22,712 phosphorylation sites, of which 19,075 were localized with high confidence and 1,203 are phosphorylated tyrosine residues, representing 6.3% of all detected phospho-sites. HiRIEF fractions with the most acidic isoelectric points are enriched in multiply phosphorylated peptides, which represent 18% of all the phospho-peptides detected in the pH range 2.5-3.7. Cross-referencing with the PhosphoSitePlus database reveals 1,264 phosphorylation sites that have not been previously reported and kinase association analysis suggests that a subset of these may be functional during the mitotic phase. PMID- 28674420 TI - Improved risk stratification in prevention by use of a panel of selected circulating microRNAs. AB - Risk stratification is crucial in prevention. Circulating microRNAs have been proposed as biomarkers in cardiovascular disease. Here a miR panel consisting of miRs related to different cardiovascular pathophysiologies, was evaluated to predict outcome in the context of prevention. MiR-34a, miR-223, miR-378, miR-499 and miR-133 were determined from peripheral blood by qPCR and combined to a risk panel. As derivation cohort, 178 individuals of the DETECT study, and as validation cohort, 129 individuals of the SHIP study were used in a case-control approach. Overall mortality and cardiovascular events were outcome measures. The Framingham Risk Score(FRS) and the SCORE system were applied as risk classification systems. The identified miR panel was significantly associated with mortality given by a hazard ratio(HR) of 3.0 (95% (CI): 1.09-8.43; p = 0.034) and of 2.9 (95% CI: 1.32-6.33; p = 0.008) after adjusting for the FRS in the derivation cohort. In a validation cohort the miR-panel had a HR of 1.31 (95% CI: 1.03-1.66; p = 0.03) and of 1.29 (95% CI: 1.02-1.64; p = 0.03) in a FRS/SCORE adjusted-model. A FRS/SCORE risk model was significantly improved to predict mortality by the miR panel with continuous net reclassification index of 0.42/0.49 (p = 0.014/0.005). The present miR panel of 5 circulating miRs is able to improve risk stratification in prevention with respect to mortality beyond the FRS or SCORE. PMID- 28674421 TI - Chronic stress and intestinal barrier dysfunction: Glucocorticoid receptor and transcription repressor HES1 regulate tight junction protein Claudin-1 promoter. AB - Chronic stress and elevated glucocorticoid hormone are associated with decreases in the intestinal epithelial tight junction protein claudin-1 (CLDN1). Human/rat CLDN1 promoters contain glucocorticoid response elements (GREs) and adjacent transcription repressor HES1 binding N-boxes. Notch signaling target HES1 expression was high and glucocorticoid receptor (NR3C1) low at the crypt base and the pattern reversed at the crypt apex. Chronic stress reduced overall rat colon HES1 and NR3C1 that was associated with CLDN1 downregulation. Chromatin immunoprecipitation experiments showed that HES1 and NR3C1 bind to the CLDN1 promoter in rat colon crypts. The binding of NR3C1 but not HES1 to CLDN1 promoter significantly decreased in chronically stressed animals, which was prevented by the NR3C1 antagonist RU486. We employed the 21-day Caco-2/BBe cell model to replicate cell differentiation along the crypt axis. HES1 siRNA treatment early in differentiation increased CLDN1. In contrast, stress levels of cortisol decreased CLDN1 in late differentiation stage but not in the early stage. HES1 was high, whereas NR3C1 and CLDN1 were low in the early stage which reversed in the late stage, e.g. HES1/NR3C1 binding to CLDN1 promoter demonstrates a dynamic and reciprocal pattern. These results suggest that chronic stress impairs colon epithelium homeostasis and barrier function via different mechanisms along the crypt axis. PMID- 28674422 TI - Increased methylation and decreased expression of homeobox genes TLX1, HOXA10 and DLX5 in human placenta are associated with trophoblast differentiation. AB - Homeobox genes regulate embryonic and placental development, and are widely expressed in the human placenta, but their regulatory control by DNA methylation is unclear. DNA methylation analysis was performed on human placentae from first, second and third trimesters to determine methylation patterns of homeobox gene promoters across gestation. Most homeobox genes were hypo-methylated throughout gestation, suggesting that DNA methylation is not the primary mechanism involved in regulating HOX genes expression in the placenta. Nevertheless, several genes showed variable methylation patterns across gestation, with a general trend towards an increase in methylation over gestation. Three genes (TLX1, HOXA10 and DLX5) showed inverse gains of methylation with decreasing mRNA expression throughout pregnancy, supporting a role for DNA methylation in their regulation. Proteins encoded by these genes were primarily localised to the syncytiotrophoblast layer, and showed decreased expression later in gestation. siRNA mediated downregulation of DLX5, TLX1 and HOXA10 in primary term villous cytotrophoblast resulted in decreased proliferation and increased expression of differentiation markers, including ERVW-1. Our data suggest that loss of DLX5, TLX1 and HOXA10 expression in late gestation is required for proper placental differentiation and function. PMID- 28674424 TI - Cytotaxonomy and molecular phylogeny of the genus Cerapanorpa Gao, Ma & Hua, 2016 (Mecoptera: Panorpidae). AB - The species of the genus Cerapanorpa Gao, Ma & Hua, 2016 (Mecoptera: Panorpidae) are characterized mainly by the presence of a finger-like anal horn on tergum VI of males and are distributed in the Oriental and eastern Palearctic regions. Herein, we investigated the pachytene banding patterns and reconstructed the Bayesian time-calibrated tree of some species of Cerapanorpa. All species examined display achiasmate meiosis and the same meiformula 2n = 42 + X0, reconfirming the monophyly of Cerapanorpa. The great variations in the size and number of heterochromatic bands suggest that they are reliable traits for species delimitation in Cerapanorpa. The existence of natural C-banding polymorphism indicates that chromosomal rearrangements likely have contributed to the diversification of chromosomal bands in Cerapanorpa. The closely related species of Cerapanorpa are reconfirmed to be evolutionarily independent entities by cytogenetic and molecular data. The divergence time estimated from the BEAST analysis shows that Cerapanorpa likely originated in the period from the Rupelian (30.7 Ma) to the Burdigalian (19.9 Ma), and most diversification occurred from the Burdigalian to the Piacenzian (17.4-2.8 Ma) in the Neogene. Our data suggest that chromosome rearrangements likely play a significant role in the speciation of Cerapanorpa. PMID- 28674425 TI - Improving transportation networks: Effects of population structure and decision making policies. AB - Transportation networks are one of the fundamental tools for human society to work, more so in our globalized world. The importance of a correct, efficient design of a transportation network for a given region or country cannot be overstated. We here study how network design is affected by the geography of the towns or nuclei to be connected, and also by the decision process necessary to choose which connections should be improved (in a generic sense) first. We begin by establishing that Delaunay networks provide an efficient starting point for the network design and at the same time allow us to introduce a computationally amenable model. Subsequent improvements lead to decentralized designs in geographies where towns are more or less homogeneously distributed, whereas radial designs arise when there is a core-periphery distribution of nodes. We also show that optimization of Delaunay networks outperforms that of complete networks at a lower cost, by allowing for a proper selection of the links to improve. In closing, we draw conclusions relevant to policy making applied to designing transportation networks and point our how our study can be useful to identify mechanisms relevant to the historical development of a region. PMID- 28674423 TI - A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients. AB - Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML. PMID- 28674426 TI - The impact of the butterfly effect on human parainfluenza virus haemagglutinin neuraminidase inhibitor design. AB - Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first structure-based study on the rearrangement of key active site amino acid residues by an induced opening of the 216-loop, through the accommodation of appropriately functionalised neuraminic acid-based inhibitors. We discovered that the rearrangement is influenced by the degree of loop opening and is controlled by the neuraminic acid's C-4 substituent's size (large or small). In this study, we found that these rearrangements induce a butterfly effect of paramount importance in HN inhibitor design and define criteria for the ideal substituent size in two different categories of HN inhibitors and provide novel structural insight into the druggable viral HN protein. PMID- 28674427 TI - Comparison of laboratory testing methods for the diagnosis of tuberculous pleurisy in China. AB - To evaluate the diagnostic utilities of different methods for Mycobacterium tuberculosis (M. tuberculosis) detection in pleural fluid that represent potentially cost-effective measures for resource-limited settings in China. We compared diagnostic characteristics of the AmpSure simultaneous amplification and testing method, the BACTEC MGIT 960 system, and acid-fast bacilli staining of specimen smears for detection of M. tuberculosis in pleural fluids of 438 patients with suspected tuberculous pleurisy. Chest radiographs, computed tomography scans and the results of sputum and pleural biopsy testing were used for confirmations of tuberculosis diagnoses. The sensitivity of the AmpSure test (21.2%) was significantly higher than that of smear analysis (3.1%; p < 0.001), but was similar to that of the BACTEC culture method (17.8%; p > 0.05). The specificity of the AmpSure, BACTEC, and smear tests were 100%, 96.4%, and 100%, respectively. The positive and negative predictive values of the AmpSure, BACTEC, and smear tests were 100%/23.1%; 78.6%/19.8%; and 100%/22.4%, respectively. The sensitivity of ADA, IFNgamma and histopathological analyses of pleural biopsies were all 100%. The sensitivities of all three methods were suboptimal for the detection of M. tuberculosis in pleural fluid. Future studies of a composite diagnostic index consisting of a combination of these tests are warranted. PMID- 28674428 TI - Failure of phylogeny inferred from multilocus sequence typing to represent bacterial phylogeny. AB - Although multilocus sequence typing (MLST) is highly discriminatory and useful for outbreak investigations and epidemiological surveillance, it has always been controversial whether clustering and phylogeny inferred from the MLST gene loci can represent the real phylogeny of bacterial strains. In this study, we compare the phylogenetic trees constructed using three approaches, (1) concatenated blocks of homologous sequence shared between the bacterial genomes, (2) genome single-nucleotide polymorphisms (SNP) profile and (3) concatenated nucleotide sequences of gene loci in the corresponding MLST schemes, for 10 bacterial species with >30 complete genome sequences available. Major differences in strain clustering at more than one position were observed between the phylogeny inferred using genome/SNP data and MLST for all 10 bacterial species. Shimodaira-Hasegawa test revealed significant difference between the topologies of the genome and MLST trees for nine of the 10 bacterial species, and significant difference between the topologies of the SNP and MLST trees were present for all 10 bacterial species. Matching Clusters and R-F Clusters metrics showed that the distances between the genome/SNP and MLST trees were larger than those between the SNP and genome trees. Phylogeny inferred from MLST failed to represent genome phylogeny with the same bacterial species. PMID- 28674429 TI - Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway. AB - In this study we have tested the efficacy of citrate therapy in various cancer models. We found that citrate administration inhibited A549 lung cancer growth and additional benefit accrued in combination with cisplatin. Interestingly, citrate regressed Ras-driven lung tumors. Further studies indicated that citrate induced tumor cell differentiation. Additionally, citrate treated tumor samples showed significantly higher infiltrating T-cells and increased blood levels of numerous cytokines. Moreover, we found that citrate inhibited IGF-1R phosphorylation. In vitro studies suggested that citrate treatment inhibited AKT phosphorylation, activated PTEN and increased expression of p-eIF2a. We also found that p-eIF2a was decreased when PTEN was depleted. These data suggest that citrate acts on the IGF-1R-AKT-PTEN-eIF2a pathway. Additionally, metabolic profiling suggested that both glycolysis and the tricarboxylic acid cycle were suppressed in a similar manner in vitro in tumor cells and in vivo but only in tumor tissue. We reproduced many of these observations in an inducible Her2/Neu driven breast cancer model and in syngeneic pancreatic tumor (Pan02) xenografts. Our data suggests that citrate can inhibit tumor growth in diverse tumor types and via multiple mechanisms. Dietary supplementation with citrate may be beneficial as a cancer therapy. PMID- 28674430 TI - Remote control of BBB: A tale of exosomes and microRNA. AB - Exosome-mediated intercellular communication has become an emerging field of human health and diseases. A recent study published by Cell Research reports that in zebrafish neurons can remotely regulate blood-brain barrier integrity by delivering miR-132 through secretion of exosomes. PMID- 28674431 TI - 9-cis retinoic acid induces neurorepair in stroke brain. AB - The purpose of this study was to examine the neurorestorative effect of delayed 9 cis retinoic acid (9cRA) treatment for stroke. Adult male rats received a 90-min right distal middle cerebral artery occlusion (dMCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after dMCAo. 9cRA or vehicle was given via an intranasal route daily starting from day 3. Stroke rats receiving 9cRA post-treatment showed an increase in brain 9cRA levels and greater recovery in motor function. 9cRA enhanced the proliferation of bromodeoxyuridine (+) cells in the subventricular zone (SVZ) and lesioned cortex in the stroke brain. Using subventricular neurosphere and matrigel cultures, we demonstrated that proliferation and migration of SVZ neuroprogenitor cells were enhanced by 9cRA. Our data support a delayed and non-invasive drug therapy for stroke. Intranasal 9cRA can facilitate the functional recovery and endogenous repair in the ischemic brain. PMID- 28674432 TI - Candidate regulators of Early Leaf Development in Maize Perturb Hormone Signalling and Secondary Cell Wall Formation When Constitutively Expressed in Rice. AB - All grass leaves are strap-shaped with a series of parallel veins running from base to tip, but the distance between each pair of veins, and the cell-types that develop between them, differs depending on whether the plant performs C3 or C4 photosynthesis. As part of a multinational effort to introduce C4 traits into rice to boost crop yield, candidate regulators of C4 leaf anatomy were previously identified through an analysis of maize leaf transcriptomes. Here we tested the potential of 60 of those candidate genes to alter leaf anatomy in rice. In each case, transgenic rice lines were generated in which the maize gene was constitutively expressed. Lines grouped into three phenotypic classes: (1) indistinguishable from wild-type; (2) aberrant shoot and/or root growth indicating possible perturbations to hormone homeostasis; and (3) altered secondary cell wall formation. One of the genes in class 3 defines a novel monocot-specific family. None of the genes were individually sufficient to induce C4-like vein patterning or cell-type differentiation in rice. A better understanding of gene function in C4 plants is now needed to inform more sophisticated engineering attempts to alter leaf anatomy in C3 plants. PMID- 28674433 TI - Random lasing from structurally-modulated silk fibroin nanofibers. AB - Structural arrangement and dimension play vital roles in wave transport and amplification as they can restrict the volume explored by the waves. However, it is challenging to systematically investigate the interplay among structural, optical, and mechanical properties, in part because of limited experimental platforms that modulate the structural arrangement in a continuous manner. We present light amplification action in Rhodamine B doped silk fibroin (SF) nanofibrous scaffolds and its modulation via the control of the alignment or directionality of SF nanofibers through an electrospinning procedure. Random lasing features of such scaffolds are examined as a function of structural arrangement of the SF nanofibers, and optical-structural-mechanical relationships of the SF-based structures are examined. As SF nanofibers are aligned parallel undergoing a transition from three to quasi-two dimension, light amplification features (e.g., lasing threshold and output power) enhanced, which also strongly correlated with mechanical characteristics (i.e., Young's moduli) of the scaffolds. We confirm such optical characteristics using quasi-mode analyses based on the finite element method. We further demonstrate non-contact, in situ measurement of alternations in lasing features of the scaffolds while the specimens are under tensile loads. These results may highlight potential utility of the scaffolds as a flexible and biocompatible sensor. PMID- 28674434 TI - Distribution and UV protection strategies of zooplankton in clear and glacier-fed alpine lakes. AB - Zooplankton, a group of aquatic animals important as trophic link in the food web, are exposed to high levels of UV radiation (UVR) in clear alpine lakes, while in turbid glacier-fed lakes they are more protected. To study the interplay between behavioral and physiological protection responses in zooplankton from those lakes, we sampled six lakes of different UVR transparency and glacial turbidity. Copepods were absent in the upper water layers of the clearest lake, while in glacier-fed lakes they were more evenly distributed in the water column. Across all lakes, the weighted copepod mean depth was strongly related to food resources (chlorophyll a and rotifers), whereas in the fishless lakes, glacial turbidity largely explained the vertical daytime distribution of these organisms. Up to ~11-times (mean 3.5) higher concentrations of photo-protective compounds (mycosporine-like amino acids, MAAs) were found in the copepods from the clear than from the glacier-fed lakes. In contrast to carotenoid concentrations and antioxidant capacities, MAA levels were strongly related to the lake transparency. Copepods from alpine lakes rely on a combination of behavioral and physiological strategies adapted to the change in environmental conditions taking place when lakes shift from glacially turbid to clear conditions, as glacier retreat proceeds. PMID- 28674435 TI - E3 ubiquitin ligase Nedd4 inhibits AP-1 activity and TNF-alpha production through targeting p38alpha for polyubiquitination and subsequent degradation. AB - p38alpha plays an important role in many inflammatory diseases, such as skin inflammation, endotoxic shock and arthritis. Ubiquitination is a vital posttranslational modification of proteins and plays a crucial regulatory role in inflammatory cells. It has been reported that ubiquitination of Tak1 and TAB1 upstream of p38alpha can regulate p38alpha activation respectively. However, p38alpha ubiquitination is not yet clear. In this paper, we showed that E3 ubiquitin ligase Nedd4 is a regulatory component of the p38alpha pathway and is responsible for polyubiquitination of p38alpha through K48-linked and K63-linked polyubiquitination. The levels of p38alpha and its downstream target TNF-alpha were increased in Nedd4 deficient macrophages response to LPS compared with wild type cells. AP-1 activity and degradation of p38alpha were induced by Nedd4 in a dose-dependent manner. Furthermore, we found that phosphorylation of p38alpha is involved in the interactions between p38alpha and Nedd4 and subsequently promotes polyubiquitination of p38alpha, especially K48-linked polyubiquitination by Nedd4. The different conformation of two p38alpha isoforms (p38alphaV1 and p38alphaV2) might be the cause of their different interactions with Nedd4 and their polyubiquitination sites by Nedd4. Thus, NEDD4 is a previously unknown component of the p38alpha signaling complex necessary for TNF-alpha activation. PMID- 28674436 TI - Photonics and fracture toughness of heterogeneous composite materials. AB - Fracture toughness measures the resistance of a material to fracture. This fundamental property is used in diverse engineering designs including mechanical, civil, materials, electronics and chemical engineering applications. In spite of the advancements made in the past 40 years, the evaluation of this remains challenging for extremely heterogeneous materials such as composite concretes. By taking advantage of the optical properties of a thin birefringent coating on the surface of opaque, notched composite concrete beams, here we sense the evolution of the maximum shear stress distribution on the beams under loading. The location of the maximum deviator stress is tracked ahead of the crack tip on the experimental concrete samples under the ultimate load, and hence the effective crack length is characterised. Using this, the fracture toughness of a number of heterogeneous composite beams is evaluated and the results compare favourably well with other conventional methods using combined experimental and numerical/analytical approaches. Finally a new model, correlating the optically measured shear stress concentration factor and flexural strength with the fracture toughness of concretes is proposed. The current photonics-based study could be vital in evaluating the fracture toughness of even opaque and complex heterogeneous materials more effectively in future. PMID- 28674437 TI - Response of Atlantic salmon Salmo salar to temperature and dissolved oxygen extremes established using animal-borne environmental sensors. AB - Understanding how aquatic species respond to extremes of DO and temperature is crucial for determining how they will be affected by climate change, which is predicted to increasingly expose them to levels beyond their optima. In this study we used novel animal-borne DO, temperature and depth sensors to determine the effect of extremes of DO and temperature on the vertical habitat use of Atlantic salmon Salmo salar in aquaculture cages. Salmon showed a preference for temperatures around 16.5 to 17.5 degrees C, however, selection of preferred temperatures was trumped by active avoidance of low DO (<35% saturation) at the bottom of the cage. In addition to low DO, salmon also avoided warm surface waters (>20.1 degrees C), which led to a considerable contraction in the available vertical habitat. Despite their avoidance behavior, fish spent a large amount of time in waters with suboptimal DO (<60% saturation). These results show that vertical habitat contraction could likely be a significant consequence of climate change if the reduction in DO outpaces the increase in hypoxia tolerance through local adaptation. They furthermore highlight that site-specific environmental conditions and stock-specific tolerance thresholds may need to be considered when determining stocking densities. PMID- 28674439 TI - Improving biodiversity assessment via unsupervised separation of biological sounds from long-duration recordings. AB - Investigating the dynamics of biodiversity via passive acoustic monitoring is a challenging task, owing to the difficulty of identifying different animal vocalizations. Several indices have been proposed to measure acoustic complexity and to predict biodiversity. Although these indices perform well under low-noise conditions, they may be biased when environmental and anthropogenic noises are involved. In this paper, we propose a periodicity coded non-negative matrix factorization (PC-NMF) for separating different sound sources from a spectrogram of long-term recordings. The PC-NMF first decomposes a spectrogram into two matrices: spectral basis matrix and encoding matrix. Next, on the basis of the periodicity of the encoding information, the spectral bases belonging to the same source are grouped together. Finally, distinct sources are reconstructed on the basis of the cluster of the basis matrix and the corresponding encoding information, and the noise components are then removed to facilitate more accurate monitoring of biological sounds. Our results show that the PC-NMF precisely enhances biological choruses, effectively suppressing environmental and anthropogenic noises in marine and terrestrial recordings without a need for training data. The results may improve behaviour assessment of calling animals and facilitate the investigation of the interactions between different sound sources within an ecosystem. PMID- 28674438 TI - Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation (ISET). We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p < 0.001). Patients with >3 CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3-3 CTC/ml (P = 0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRAS G12V mutation in their CTC (n = 14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P = 0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 "tumor-CTC-pairs" (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P = 0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology. PMID- 28674440 TI - Submicron-scale broadband polarization beam splitter using CMOS-compatible materials. AB - We propose a polarization beam splitter (PBS) with a footprint of only 600 * 790 nm2 operating at a wavelength of lambda = 1550 nm, which is the smallest PBS ever demonstrated. This device uses CMOS-compatible materials, namely, silicon and silica. The present PBS comprises two Si waveguides with different geometrical aspect ratios adjoined side-by-side, which separates the transverse-electric (TE) and transverse-magnetic (TM) modes without relying on an additional coupling region. The designed PBS achieves a polarization extinction ratio of approximately 25 dB for both modes and insertion losses of approximately 0.87 and 1.09 dB for the TE and TM polarizations, respectively. Over a wide bandwidth of 150 nm (from lambda = 1475-1625 nm), a high polarization extinction ratio (greater than 20 dB) and a low inversion loss (lower than 1.3 dB) can be obtained. The proposed PBS allows for geometrical errors of +/-15 nm while maintaining a polarization extinction ratio of >20 dB and inversion losses of >1.1 and 1.3 dB for the TE and TM modes, respectively. With the submicron footprint, the reported PBS may be able to be used in high-density photonic integrated circuits and nanophotonic devices. PMID- 28674442 TI - Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue. AB - BACKGROUND: Despite successful preclinical testing, 85% of early clinical trials for novel drugs fail. Most futilities originate from molecular mechanisms of the drug(s) tested. It is critically important to develop validated human cell-based model systems in which animal-based research can be translated in order to complement the preclinical in vivo findings prior to implementation of a clinical trial. Obesity is associated with reduced circulating levels of Orexin-A (OX-A) in humans. OX-A increases thermogenesis in rodent brown adipose tissue (AT), yet this phenomenon has not been explored in humans. METHODS: We established a cell based model system of human brown and white adipocytes and tested the effects of OX-A on thermogenesis. RESULTS: Contrary to published in vivo and in vitro reports in rodents, OX-A treatment alone or in combination with an adrenergic stimulus did neither enhance thermogenesis nor its related transcriptional program in a human in vitro model of brown adipocytes or AT explants. CONCLUSIONS: Translating preclinical findings in human model systems poses a challenge that must be overcome for the development of effective therapeutic compounds and targets. PMID- 28674444 TI - Investigation of multilevel data storage in silicon-based polycrystalline ferroelectric tunnel junction. AB - Multilevel data ferroelectric tunnel junction is a breakthrough for further improving the storage density of ferroelectric random access memories. However, the application of these ferroelectric tunnel junctions is limited by high cost of epitaxial perovskite heterostructures, unsatisfactory retention and difficulty of exactly controlling the middle polarization states. In order to overcome the issues, we develop a ferroelectric tunnel junction with smooth ultrathin polycrystalline BiFeO3 (BFO) film. Through controlling the polarization state and oxygen vacancy migration using voltage pulses, we demonstrate that voltage controlled barrier yields a memristive behavior in the device, in which the resistance variations exceed over two orders of magnitude. And we achieve multi logic states written and read easily using voltage pulses in the device. Especially the device is integrated with the silicon technology in modern microelectronics. Our results suggest new opportunity for ferroelectrics as high storage density nonvolatile memories. PMID- 28674443 TI - Modification of as Synthesized SBA-15 with Pt nanoparticles: Nanoconfinement Effects Give a Boost for Hydrogen Storage at Room Temperature. AB - In this work, Pt nanoparticles were incorporated into SBA-15 to prepare the materials for hydrogen spillover adsorption. We provide a direct modification (DM) strategy to improve the content of Pt nanoparticles inside the channels of SBA-15. In this strategy, the Pt precursor was directly incorporated into as synthesized SBA-15 by a solid-state grinding method. The subsequent calcination in air, then H2/Ar gases was conducted to obtain the resultant materials of PtAS. For the samples of PtAS, Pt nanoparticles up to 5.0 wt% have a high dispersion inside the channels of SBA-15. The size of nanoparticles is in control of 3.7 nm. Although much work so far has focused on modification of SBA-15 with Pt nanoparticles. Here, it is the first time the loading amount of Pt nanoparticles raises up to 5.0 wt%, and the location of the Pt nanoparticles is interior channels of SBA-15. We reveal that the high dispersion behaviors of Pt nanoparticles are ascribed to the nanoconfinement effects provided by as synthesized SBA-15. However, the samples derived from template free SBA-15 (PtCS) show sparsely dispersion of Pt nanoparticles with the size of 7.7 nm. We demonstrate that the PtAS samples show better hydrogen adsorption performance than PtCS. PMID- 28674441 TI - A high salt diet inhibits obesity and delays puberty in the female rat. AB - BACKGROUND/OBJECTIVES: Processed foods are considered major contributors to the worldwide obesity epidemic. In addition to high sugar and fat contents, processed foods contain large amounts of salt. Owing to the correlations with rising adiposity, salt has recently been proposed to be obesogenic. This study investigated three hypotheses: (i) high salt contributes to weight gain and adiposity in juvenile female rats, (ii) puberty onset would be altered because salt is known to affect neuronal systems involved in activating the reproductive system, and (iii) enhanced adiposity will act synergistically with salt to drive early puberty onset. DESIGN: Female weanling rats (post-natal day 21, n=105) were fed a low fat/low salt diet, low fat/high salt diet, high fat/low salt diet or a high salt/high fat diet for 24 days. Metabolic measures, including weight gain, food intake, fecal output, activity and temperature were recorded in subsets of animals. RESULTS: Body weight, retroperitoneal and perirenal fat pad weight, and adipocyte size were all lower in animals fed high fat/high salt compared with animals fed high fat alone. Leptin levels were reduced in high fat/high salt fed animals compared with high fat/low salt-fed animals. Daily calorie intake was higher initially but declined with adjusted food intake and was not different among groups after 5 days. Osmolality and corticosterone were not different among groups. Fecal analysis showed excess fat excretion and a decreased digestive efficiency in animals fed high fat/low salt but not in animals fed high fat/high salt. Although respiratory exchange ratio was reduced by high dietary fat or salt, aerobic-resting metabolic rate was not affected by the diet. High salt delayed puberty onset, regardless of dietary fat content. CONCLUSIONS: Salt delays puberty and prevents the obesogenic effect of a high fat diet. The reduced weight gain evident in high salt-fed animals is not due to differences in food intake or digestive efficiency. PMID- 28674445 TI - Paranoia and the social representation of others: a large-scale game theory approach. AB - Current definitions of paranoia include two key components: unfounded ideas of harm and the idea that the harm is intended by others. However, attributions of harmful intent have been poorly studied and mainly using artificial scenarios rather than participation in genuine social interactions where genuine resources are at stake. Using a large non-clinical population (N = 3229) recruited online, we asked people to complete a measure of paranoid ideation before playing a modified Dictator Game, where the 'dictator' can allocate money to the partner (the 'receiver'). Participants were allocated to the role of receiver or of an uninvolved observer; and evaluated to what extent they believed dictator decisions were motivated by (i) self-interest or (ii) harmful intent. All participants attributed more harmful intent to unfair as opposed to fair dictators. Paranoia had a positive effect on harmful intent attribution, for both fair and unfair dictators. Paranoia did not interact with attributions of self interest. Importantly, highly paranoid participants attributed equally strong harmful intent to the dictator in the observer role as in the receiver role. This challenges the assumption that paranoia is mainly due to an exaggerated sense of personalised threat and suggests instead that paranoia involves a negative social representations of others. PMID- 28674446 TI - Stress state measured at ~7 km depth in the Tarim Basin, NW China. AB - The in-situ stress state in the Tarim Basin, Northwest China, down to 7 km depth is constrained using the anelastic strain recovery (ASR) method and wellbore failure analysis. Results are consistent between the two methods, and indicate that the maximum principal stresses (sigma1) are close to vertical and the intermediate and minimum principal stresses (sigma2 and sigma3) are approximately horizontal. The states of stress at the studied wellbore is in the normal faulting stress regime within the Tarim Basin rather than in the compressional tectonic stress regime as in the periphery of the Tarim Basin, which explains the presence of the normal faults interpreted in 3-D seismic profiles collected from adjacent areas. Our results demonstrate that the ASR method can be used for rocks recovered from depths as deep as 7 km to recover reliable stress state information. The in-situ stress measurement results revealed in this paper will help future development of the petroleum resources and kinematics study in the Tarim Basin. PMID- 28674447 TI - Origin of abnormal structural transformation in a (BiPb)FeO3/SrRuO3/SrTiO3 hetero structure probed by Rutherford backscattering. AB - Scientific efforts are growing to understand artificial BiFeO3/SrRuO3/SrTiO3 heterostructures, wherein an altered environment at each interface, caused by epitaxial strains, broken symmetry, off-stoichiometry and charge transfer, can generate a rich spectrum of exotic properties. Herein, (BiPb)FeO3/SrRuO3/SrTiO3 heterostructures were sputtered with various top (BiPb)FeO3-layers at different growth temperatures (T g). Strain relaxation at each interface changes with T g and generates an additional peak alongside with (BiPb)FeO3 at a high T g of 700 degrees C. Rutherford backscattering (RBS) was employed to understand this unusual behavior as to whether it is a mixture of two phases, layer splitting or inter-diffusion of elements. Surprisingly, complete overlapping of random and aligned RBS spectra from the sample with T g = 700 degrees C indicates the presence of a large amount of defects/distortions at the interfaces. The RBS compositional analysis gives clear evidence of Fe and Ru vacancies to an extent that the structural integrity may not be maintained. This abnormal condition can be explained by the inter-diffusion of Pb and Bi elements into whole films and even into the top layer of the SrTiO3 substrate, which compensates for these vacancies by substitutional replacement and is responsible for the generation of the additional SrTi(BiPb)O3-peak. Below T cSrRuO3, the magnetic properties change significantly with T g . PMID- 28674448 TI - Element-Specific Orbital Character in a Nearly-Free-Electron Superconductor Ag5Pb2O6 Revealed by Core-Level Photoemission. AB - Ag5Pb2O6 has attracted attentions due to its novel nearly-free-electron superconductivity, but its electronic structure and orbital character of the Cooper-pair electrons remain controversial. Here, we present a method utilizing core-level photoemission to show that Pb 6s electrons dominate near the Fermi level. We observe a strongly asymmetric Pb 4 f 7/2 core-level spectrum, while a Ag 3d 5/2 spectrum is well explained by two symmetric peaks. The asymmetry in the Pb 4 f 7/2 spectrum originates from the local attractive interaction between conducting Pb 6s electrons and a Pb 4 f 7/2 core hole, which implies a dominant Pb 6s contribution to the metallic conduction. In addition, the observed Pb 4 f 7/2 spectrum is not explained by the well-known Doniach-Sunjic lineshape for a simple metal. The spectrum is successfully generated by employing a Pb 6s partial density of states from local density approximation calculations, thus confirming the Pb 6s dominant character and free-electron-like density of states of Ag5Pb2O6. PMID- 28674449 TI - Dexamethasone induced inhibition of Dectin-1 activation of antigen presenting cells is mediated via STAT-3 and NF-kappaB signaling pathways. AB - Treatment of patients with glucocorticoids can result in an increased risk of infection with pathogens such as fungi. Dectin-1 is a member of the C-type lectin receptor superfamily and was shown to be one of the major receptors for fungal beta-glucans. Activation of Dectin-1 increases the production of cytokines and chemokines and T-cell stimulatory capacity of DC and mediates resolution of fungal infections. Here we show that antigen-presenting cells generated in the presence of dexamethasone (Dex-DC) have a reduced capacity to stimulate T-cell proliferation and decreased expression of costimulatory molecules, that can not be enhanced upon stimulation with Dectin-1 ligands. Stimulation of Dex-DC with beta-glucans induced a strong upregulation of Syk phosphorylation and increased secretion of IL-10, while the production of IL-12, IL-23 and TNF-alpha was reduced. Downstream of Syk stimulation of Dectin-1 on Dex-DC resulted in phosphorylation of STAT3 and reduced nuclear localization of transcription factors involved in DC activation and function. PMID- 28674450 TI - Triplex DNA-based Bioanalytical Platform for Highly Sensitive Homogeneous Electrochemical Detection of Melamine. AB - Melamine detection has attracted much attention since the discovery of the damage of melamine to human health. Herein, we have developed a sensitive homogeneous electroanalytical platform for melamine detection, which is relied on the formation of triplex molecular beacon integrated with exonuclease III (Exo III) mediated signal amplification. The formation of triplex molecular beacon was triggered by the recognition and incorporation of melamine to the abasic (AP) site contained in the triplex stem. The stem of the triplex molecular beacon was designed to have a protruding double-strand DNA, which can be recognized and hydrolyzed by Exo III for releasing methylene blue (MB)-labeled mononucleotide. These released MB molecules exhibit high diffusivity toward indium tin oxide electrode with negative charge, thus producing a significantly increased electrochemical response. Taking advantages of the high binding affinity of the DNA triplex structure containing AP sites towards melamine and the unique features of Exo III, this sensing platform is capable for sensitive and selective melamine assay with a detection limit as low as 8.7 nM. Furthermore, this strategy shows good applicability for melamine assay in real samples. Therefore, this strategy broadens the application of triplex DNA and presents a new method for sensitive detection of melamine. PMID- 28674451 TI - Novel Interventional Management of Hepatic Hydatid Cyst with Nanosecond Pulses on Experimental Mouse Model. AB - The nanosecond pulsed electric field (nsPEF) is investigated as an alternative plan for benign hepatic hydatid cyst. Altogether 72 C57B6 mice were included. Normal group (n = 12) had no parasite injection and the other 60 mice were used to induce hydatid cyst in liver by injecting protoscolices in portal vein. The liver hydatid cysts were exposed to nsPEF with different doses and then follow up. The standard surgery was performed as positive control. The hydatid cyst growth was monitored by ultrasound; the morphology was checked by gross anatomy and pathology was tested by H&E stain. In nsPEF-treated groups no hepatic failure nor bleeding were observed. As a comparison, in the surgery group, high post treatment complications occurred (50%). Significant parasite growth inhibition was seen in high nsPEF dose group as compared with control group (P < 0.05). Pathological analysis confirmed destruction of hydatid cyst with sharp demarcation defined by the electrodes. Laboratory analysis showed nsPEF stimulated a time-dependent infection and recoverable liver function. The traumatic reactions defined by white blood count was significant lower than surgery groups (P < 0.05).Preliminary studies demonstrate nsPEF ablation can be applied on hepatic hydatid by inhibiting parasite growth, destructing the cyst and stimulating infections. PMID- 28674452 TI - Superior high creep resistance of in situ nano-sized TiCx/Al-Cu-Mg composite. AB - The tensile creep behavior of Al-Cu-Mg alloy and its composite containing in situ nano-sized TiCx were explored at temperatures of 493 K, 533 K and 573 K with the applied stresses in the range of 40 to 100 MPa. The composite reinforced by nano sized TiCx particles exhibited excellent creep resistance ability, which was about 4-15 times higher than those of the unreinforced matrix alloy. The stress exponent of 5 was noticed for both Al-Cu-Mg alloy and its composite, which suggested that their creep behavior was related to dislocation climb mechanism. During deformation at elevated temperatures, the enhanced creep resistance of the composite was mainly attributed to two aspects: (a) Orowan strengthening and grain boundary (GB) strengthening induced by nano-sized TiCx particles, (b) theta' and S' precipitates strengthening. PMID- 28674453 TI - On noise-resolution uncertainty in quantum field theory. AB - An uncertainty inequality is presented that establishes a lower limit for the product of the variance of the time-averaged intensity of a mode of a quantized electromagnetic field and the degree of its spatial localization. The lower limit is determined by the vacuum fluctuations within the volume corresponding to the width of the mode. This result also leads to a generalized form of the Heisenberg uncertainty principle for boson fields in which the lower limit for the product of uncertainties in the spatial and momentum localization of a mode is equal to the product of Planck's constant and a dimensionless functional which reflects the joint signal-to-noise ratio of the position and momentum of vacuum fluctuations in the region of the phase space occupied by the mode. Experimental X-ray synchrotron measurements provide an initial verification of the proposed theory in the case of Poisson statistics. PMID- 28674454 TI - Territoriality ensures paternity in a solitary carnivore mammal. AB - In solitary carnivorous mammals, territoriality is assumed to benefit male fitness by ensuring the exclusivity of matings within territories via mate guarding and female defence. However, this hypothesis remains empirically untested. Here, we examined this hypothesis for solitary territorial carnivores using the Iberian lynx (Lynx pardinus) as a case study. We expected that territorial males sire all litters born within their territories, translating into the absence of multi-paternity cases within the same litter. We analysed parentage in 43 kittens, belonging to 20 different litters. For 42 kittens, a father could be assigned using microsatellites and always coincided with the individual holding the territory. For 16 kittens from 10 litters for which we also had information on SNPs, paternity assignments coincided with microsatellites, except for a litter (two kittens) from the same litter for which a different male was assigned, but the territorial male could not be excluded. Our results indicated that multi-paternity in the Iberian lynx must be a rare event, and that territorial males sire all litters born from the females with which they share territories. We propose that both the low number of mature individuals in the lynx population and the fact that female oestrus is induced by male presence may explain results. PMID- 28674455 TI - Heterologous expression of the yeast Tpo1p or Pdr5p membrane transporters in Arabidopsis confers plant xenobiotic tolerance. AB - Soil contamination is a major hindrance for plant growth and development. The lack of effective strategies to remove chemicals released into the environment has raised the need to increase plant resilience to soil pollutants. Here, we investigated the ability of two Saccharomyces cerevisiae plasma-membrane transporters, the Major Facilitator Superfamily (MFS) member Tpo1p and the ATP Binding Cassette (ABC) protein Pdr5p, to confer Multiple Drug Resistance (MDR) in Arabidopsis thaliana. Transgenic plants expressing either of the yeast transporters were undistinguishable from the wild type under control conditions, but displayed tolerance when challenged with the herbicides 2,4-D and barban. Plants expressing ScTPO1 were also more resistant to the herbicides alachlor and metolachlor as well as to the fungicide mancozeb and the Co2+, Cu2+, Ni2+, Al3+ and Cd2+ cations, while ScPDR5-expressing plants exhibited tolerance to cycloheximide. Yeast mutants lacking Tpo1p or Pdr5p showed increased sensitivity to most of the agents tested in plants. Our results demonstrate that the S. cerevisiae Tpo1p and Pdr5p transporters are able to mediate resistance to a broad range of compounds of agricultural interest in yeast as well as in Arabidopsis, underscoring their potential in future biotechnological applications. PMID- 28674456 TI - PAX2 is dispensable for in vitro nephron formation from human induced pluripotent stem cells. AB - The kidney is formed by reciprocal interactions between the nephron progenitor and the ureteric bud, the former of which gives rise to the epithelia of nephrons consisting of glomeruli and renal tubules. The transcription factor PAX2 is essential for this mesenchymal-to-epithelial transition of nephron progenitors, as well as ureteric bud lineage development, in mice. PAX2 mutations in humans cause renal coloboma syndrome. We previously reported the induction of nephron progenitors and three-dimensional nephron structures from human induced pluripotent stem (iPS) cells. Here we generate iPS cells lacking PAX2, and address the role of PAX2 in our in vitro induction protocol. While PAX2-null human nephron progenitors were properly formed, they unexpectedly became epithelialised to form glomeruli and renal tubules. However, the mutant glomerular parietal epithelial cells failed to transit to the squamous morphology, retaining the shape and markers of columnar epithelia. Therefore, PAX2 is dispensable for mesenchymal-to-epithelial transition of nephron progenitors, but is required for morphological development of glomerular parietal epithelial cells, during nephron formation from human iPS cells in vitro. PMID- 28674457 TI - Molecular diodes with rectification ratios exceeding 105 driven by electrostatic interactions. AB - Molecular diodes operating in the tunnelling regime are intrinsically limited to a maximum rectification ratio R of ~103. To enhance this rectification ratio to values comparable to those of conventional diodes (R >= 105) an alternative mechanism of rectification is therefore required. Here, we report a molecular diode with R = 6.3 * 105 based on self-assembled monolayers with Fc-C=C-Fc (Fc, ferrocenyl) termini. The number of molecules (n(V)) involved in the charge transport changes with the polarity of the applied bias. More specifically, n(V) increases at forward bias because of an attractive electrostatic force between the positively charged Fc units and the negatively charged top electrode, but remains constant at reverse bias when the Fc units are neutral and interact weakly with the positively charged electrode. We successfully model this mechanism using molecular dynamics calculations. PMID- 28674458 TI - Molecular diodes: Breaking the Landauer limit. PMID- 28674459 TI - Photo-excited hot carrier dynamics in hydrogenated amorphous silicon imaged by 4D electron microscopy. AB - Charge carrier dynamics in amorphous semiconductors has been a topic of intense research that has been propelled by modern applications in thin-film solar cells, transistors and optical sensors. Charge transport in these materials differs fundamentally from that in crystalline semiconductors owing to the lack of long range order and high defect density. Despite the existence of well-established experimental techniques such as photoconductivity time-of-flight and ultrafast optical measurements, many aspects of the dynamics of photo-excited charge carriers in amorphous semiconductors remain poorly understood. Here, we demonstrate direct imaging of carrier dynamics in space and time after photo excitation in hydrogenated amorphous silicon (a-Si:H) by scanning ultrafast electron microscopy (SUEM). We observe an unexpected regime of fast diffusion immediately after photoexcitation, together with spontaneous electron-hole separation and charge trapping induced by the atomic disorder. Our findings demonstrate the rich dynamics of hot carrier transport in amorphous semiconductors that can be revealed by direct imaging based on SUEM. PMID- 28674461 TI - Test anxiety and a high-stakes standardized reading comprehension test: A behavioral genetics perspective. AB - Past research suggests that reading comprehension test performance does not rely solely on targeted cognitive processes such as word reading, but also on other non-target aspects such as test anxiety. Using a genetically sensitive design, we sought to understand the genetic and environmental etiology of the association between test anxiety and reading comprehension as measured by a high-stakes test. Mirroring the behavioral literature of test anxiety, three different dimensions of test anxiety were examined in relation to reading comprehension, namely intrusive thoughts, autonomic reactions, and off-task behaviors. Participants included 426 sets of twins from the Florida Twin Project on Reading. The results indicated test anxiety was negatively associated with reading comprehension test performance, specifically through common shared environmental influences. The significant contribution of test anxiety to reading comprehension on a high stakes test supports the notion that non-targeted factors may be interfering with accurately assessing students' reading abilities. PMID- 28674460 TI - High-speed logic integrated circuits with solution-processed self-assembled carbon nanotubes. AB - As conventional monolithic silicon technology struggles to meet the requirements for the 7-nm technology node, there has been tremendous progress in demonstrating the scalability of carbon nanotube field-effect transistors down to the size that satisfies the 3-nm node and beyond. However, to date, circuits built with carbon nanotubes have overlooked key aspects of a practical logic technology and have stalled at simple functionality demonstrations. Here, we report high-performance complementary carbon nanotube ring oscillators using fully manufacturable processes, with a stage switching frequency of 2.82 GHz. The circuit was built on solution-processed, self-assembled carbon nanotube arrays with over 99.9% semiconducting purity, and the complementary feature was achieved by employing two different work function electrodes. PMID- 28674462 TI - A Global Meta-Analysis of the Value of Ecosystem Services Provided by Lakes. AB - This study presents the first meta-analysis on the economic value of ecosystem services delivered by lakes. A worldwide data set of 699 observations drawn from 133 studies combines information reported in primary studies with geospatial data. The meta-analysis explores antagonisms and synergies between ecosystem services. This is the first meta-analysis to incorporate simultaneously external geospatial data and ecosystem service interactions. We first show that it is possible to reliably predict the value of ecosystem services provided by lakes based on their physical and geographic characteristics. Second, we demonstrate that interactions between ecosystem services appear to be significant for explaining lake ecosystem service values. Third, we provide an estimation of the average value of ecosystem services provided by lakes: between 106 and 140 USD$2010 per respondent per year for non-hedonic price studies and between 169 and 403 USD$2010 per property per year for hedonic price studies. PMID- 28674463 TI - Degrowth - Taking Stock and Reviewing an Emerging Academic Paradigm. AB - Degrowth has evolved within a decade from an activist movement into a multi disciplinary academic paradigm. However, an overview taking stock of the peer refereed degrowth literature is yet missing. Here, we review 91 articles that were published between 2006 and 2015. We find that the academic degrowth discourse occupies a small but expanding niche at the intersection of social and applied environmental sciences. The discourse is shaped by authors from high income, mainly Mediterranean, countries. Until 2012, articles largely constitute conceptual essays endorsed by normative claims. More recently, degrowth has branched out into modelling, empirical assessments, and the study of concrete implementations. Authors tend to agree in that economic growth cannot be sustained ad infinitum on a resource constraint planet and that degrowth requires far reaching societal change. Whether degrowth should be considered as a collectively consented choice or an environmentally-imposed inevitability constitutes a major debate among degrowth thinkers. We argue that the academic discourse could benefit from rigid hypotheses testing through input-output modelling, material flow analysis, life-cycle assessments, or social surveys. By analyzing the potentials for non-market value creation and identifying concrete well-being benefits, the degrowth discourse could receive wider public support and contribute to a paradigmatic change in the social sciences. PMID- 28674464 TI - Assessment of critical steps of a GC/MS based indirect analytical method for the determination of fatty acid esters of monochloropropanediols (MCPDEs) and of glycidol (GEs). AB - Fatty acid esters of 2- and 3-chloropropanediol (MCPDEs) and fatty acid esters of glycidol (GEs) are commonly monitored in edible fats and oils. A recommendation issued by the European Commission emphasizes the need of generating data on the occurrence of these substances in a broad range of different foods. So far, analytical methods for the determination of MCPDEs and GEs are fully validated only for oils, fats and margarine. This manuscript presents the assessment of critical steps in the AOCS Cd 29a-13 method for the simultaneous determination of MCPDEs and GEs in the fat phase obtained from bakery and potato products, smoked and fried fish and meat, and other cereal products. The trueness of the method is affected by the additional formation of 3-MBPD esters from monoacylglycerols (MAGs), which are frequently present in food. The overestimation of GE contents for some samples was confirmed by the comparison of results with results obtained by an independent analytical method (direct analysis of GE by HPLC-MS/MS). An additional sample pre-treatment by SPE was introduced to remove MAGs from fat prior to the GEs conversion, while the overall method sensitivity was not significantly affected. Trueness of the determination of GEs by the modified analytical procedure was confirmed by comparison with a direct analysis of GEs. The potential impact on accuracy of results of the final sample preparation step of the analytical procedure, the derivatization of free forms MCPD and MBPD with PBA, was evaluated as well. Different commercial batches of PBA showed differences in solubility in a non-polar organic solvent. The PBA derivatization in organic solvent did not affect precision and trueness of the method due to the isotopic standard dilution. However, method sensitivity might be significantly compromised. PMID- 28674465 TI - Graduated Sovereignty and Global Governance Gaps: Special Economic Zones and the Illicit Trade In Tobacco Products. AB - Illicit trade in tobacco products has been a significant problem globally for many years. It allows cigarettes to be sold far below their legal price and thus contributes to higher consumption, morbidity and mortality, and deprives state treasuries of a substantial amount of revenue. This article identifies special economic zones (SEZs), particularly free trade zones, as a key conduit for this illicit trade. The development of SEZs as weak points in the global governance architecture is explained with reference to the concept of 'graduated sovereignty', whereby the uniform management of territory by modern states has given way to a more spatially selective form of territorial governance, in which some slices of territory are more fully integrated into the world economy than others via various forms of differential regulation. Attempts to comprehensively (re)regulate SEZs, in the face of growing evidence of the dysfunctionalities that they can engender, have so far been unsuccessful. It is concluded that the neo liberal global economy has facilitated a regulatory 'race to the bottom', a problem that can only ultimately be overcome by international negotiation and agreement. PMID- 28674466 TI - Strengthen Your Resolve: No Unlabeled Containers Anywhere, Ever! AB - Strengthen your resolve: no unlabeled containers anywhere, ever! PMID- 28674468 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 28674467 TI - Significant Change Coming in 2018 in Tiering Exceptions Policy for Part D. AB - A significant change in tiering exceptions policy for Part D is coming in 2018. PMID- 28674469 TI - Pharmaceutical Approval Update. AB - Niraparib (Zejula) for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; ocrelizumab (Ocrevus) for relapsing or primary progressive multiple sclerosis; and dupilumab (Dupixent) for moderate-to-severe atopic dermatitis. PMID- 28674470 TI - Eluxadoline (Viberzi): A Mu-Opioid Receptor Agonist for the Treatment Of Irritable Bowel Syndrome With Diarrhea. AB - Eluxadoline (Viberzi) for the treatment of irritable bowel syndrome with diarrhea. PMID- 28674471 TI - Continuing the Debate: Branko Furst's Alternative Model And the Role of the Heart. PMID- 28674472 TI - Drug Industry Groups Oppose FDA "Quality Metrics" Plan: The Agency Wants to Use Manufacturing Data to Attack Drug Shortages. AB - Raising their voices in nearly unanimous opposition, pharmaceutical manufacturers and their suppliers have mounted a campaign to dissuade the FDA from launching a voluntary program in 2018 that is aimed at reducing drug shortages. PMID- 28674473 TI - Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical Considerations. AB - This article, the second in a series of three, provides an overview of the efficacy and safety of cancer immunotherapies ranging from monoclonal antibodies to vaccines, including additional clinical considerations regarding immune checkpoint blockers. PMID- 28674474 TI - Heart Failure: A Class Review of Pharmacotherapy. AB - A recent guideline update for the treatment of heart failure has created the need for a new look at the medication classes and trials related to the disease. The authors focus on pharmacological options available for treating the problem. PMID- 28674475 TI - Drug-Induced QT Prolongation And Torsades de Pointes. AB - Torsades de pointes (TdP)-an uncommon but life-threatening polymorphic ventricular tachycardia-is almost always drug induced. The authors describe the causes, risk factors, symptoms, diagnosis, and treatment of TdP. PMID- 28674476 TI - Seeking Solutions to the Opioid Crisis. AB - At an event focusing on population-health approaches to the opioid epidemic, discussants agreed that better coordination of care, community involvement in finding solutions, and more consistent use of improved pain-control options are required. PMID- 28674477 TI - Research Briefs. PMID- 28674478 TI - Mind the gulfs: An analysis of medication-related cognitive artifacts used by older adults with heart failure. AB - Medication management is a patient health-related activity characterized by poor performance in older adults with chronic disease. Interventions focus on educating and motivating the patient with limited long-term effects. Cognitive artifacts facilitate cognitive tasks by making them easier, faster, and more effective and can potentially improve medication management performance. This study examined how older adult patients with heart failure use cognitive artifacts and how representational structure and physical properties facilitated or impeded medication-related tasks and processes. Interview, observation, medical record, and photographic data of and about older patients with heart failure (N = 30) and their informal caregivers (N=14) were content analyzed for cross-cutting themes about patient goals, representations, and actions. Results illustrated patient artifacts designed from a clinical rather than patient perspective, disparate internal and external representations threatening safety, and incomplete information exchange between patients and clinicians. Implications for design were the need for bridging artifacts, automatic information transfer, and cognitive artifacts designed from the perspective of the patient. PMID- 28674479 TI - Developing publicly acceptable tree health policy: public perceptions of tree breeding solutions to ash dieback among interested publics in the UK. AB - The UK needs to develop effective policy responses to the spread of tree pathogens and pests. This has been given the political urgency following the media and other commentary associated with the arrival of a disease that causes 'dieback' of European Ash (Fraxinus excelsior) - a tree species with deep cultural associations. In 2014 the UK government published a plant biosecurity strategy and linked to this invested in research to inform policy. This paper reports the findings of a survey of informed UK publics on the acceptability of various potential strategies to deal with ash dieback, including "no action". During the summer of 2015, we conducted a face-to-face survey of 1152 respondents attending three major countryside events that attract distinct publics interested in the countryside: landowners & land managers; naturalists and gardeners. We found that UK publics who are likely to engage discursively and politically (through letter writing, petitions etc.) with the issue of ash dieback a) care about the issue, b) want an active response, c) do not really distinguish between ash trees in forestry or ecological settings, and d) prefer traditional breeding solutions. Further that e) younger people and gardeners are open to GM breeding techniques, but f) the more policy-empowered naturalists are more likely to be anti-GM. We suggest that these findings provide three 'steers' for science and policy: 1) policy needs to include an active intervention component involving the breeding of disease-tolerant trees, 2) that the development of disease tolerance using GM-technologies could be part of a tree-breeding policy, and 3) there is a need for an active dialogue with publics to manage expectations on the extent to which science and policy can control tree disease or, put another way, to build acceptability for the prospect that tree diseases may have to run their course. PMID- 28674480 TI - Tetrazine ligation for chemical proteomics. AB - Determining small molecule-target protein interaction is essential for the chemical proteomics. One of the most important keys to explore biological system in chemical proteomics field is finding first-class molecular tools. Chemical probes can provide great spatiotemporal control to elucidate biological functions of proteins as well as for interrogating biological pathways. The invention of bioorthogonal chemistry has revolutionized the field of chemical biology by providing superior chemical tools and has been widely used for investigating the dynamics and function of biomolecules in live condition. Among 20 different bioorthogonal reactions, tetrazine ligation has been spotlighted as the most advanced bioorthogonal chemistry because of their extremely faster kinetics and higher specificity than others. Therefore, tetrazine ligation has a tremendous potential to enhance the proteomic research. This review highlights the current status of tetrazine ligation reaction as a molecular tool for the chemical proteomics. PMID- 28674481 TI - Pre-Microporation Improves Outcome of Pancreatic Islet Labelling for Optical and 19F MR Imaging. AB - BACKGROUND: In vitro labelling of cells and small cell structures is a necessary step before in vivo monitoring of grafts. We modified and optimised a procedure for pancreatic islet labelling using bimodal positively charged poly(lactic-co glycolic acid) nanoparticles with encapsulated perfluoro crown ethers and indocyanine green dye via microporation and compared the method with passive endocytosis. RESULTS: Pancreatic islets were microporated using two pulses at various voltages. We tested a standard procedure (poration in the presence of nanoparticles) and a modified protocol (pre-microporation in a buffer only, and subsequent islet incubation with nanoparticles on ice for 10 min). We compared islet labelling by microporation with labelling by endocytosis, i.e. pancreatic islets were incubated for 24 h in a medium with suspended nanoparticles. In order to verify the efficiency of the labelling procedures, we used 19F magnetic resonance imaging, optical fluorescence imaging and confocal microscopy. The experiment confirmed that microporation, albeit fast and effective, is invasive and may cause substantial harm to islets. To achieve sufficient poration and to minimise the reduction of viability, the electric field should be set at 20 kV/m (two pulses, 20 ms each). Poration in the presence of nanoparticles was found to be unsuitable for the nanoparticles used. The water suspension of nanoparticles (which served as a surfactant) was slightly foamy and microbubbles in the suspension were responsible for sparks causing the destruction of islets during poration. However, pre-microporation (poration of islets in a buffer only) followed by 10-min incubation with nanoparticles was safer. CONCLUSIONS: For labelling of pancreatic islets using poly(lactic-co-glycolic acid) nanoparticles, the modified microporation procedure with low voltage was found to be safer than the standard microporation procedure. The modified procedure was fast, however, efficiency was lower compared to endocytosis. PMID- 28674482 TI - Feasibility of Using Electrocochleography for Objective Estimation of Electro Acoustic Interactions in Cochlear Implant Recipients with Residual Hearing. AB - Although cochlear implants (CI) traditionally have been used to treat individuals with bilateral profound sensorineural hearing loss, a recent trend is to implant individuals with residual low-frequency hearing. Patients who retain some residual acoustic hearing after surgery often can benefit from electro-acoustic stimulation (EAS) technologies, which combine conventional acoustic amplification with electrical stimulation. However, interactions between acoustic and electrical stimulation may affect outcomes adversely and are time-consuming and difficult to assess behaviorally. This study demonstrated the feasibility of using the Advanced Bionics HiRes90K Advantage implant electronics and HiFocus Mid Scala/1j electrode to measure electrocochleography (ECochG) responses in the presence of electrical stimulation to provide an objective estimate of peripheral physiologic EAS interactions. In general, electrical stimulation reduced ECochG response amplitudes to acoustic stimulation. The degree of peripheral EAS interaction varied as a function of acoustic pure tone frequency and the intra cochlear location of the electrically stimulated electrode. Further development of this technique may serve to guide and optimize clinical EAS system fittings in the future. PMID- 28674483 TI - Hypotensive Response to Angiotensin II Type 2 Receptor Stimulation in the Rostral Ventrolateral Medulla Requires Functional GABA-A Receptors. AB - Objectives: Angiotensin II, glutamate and gamma-aminobutyric acid (GABA) interact within the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus (PVN) modulating the central regulation of blood pressure and sympathetic tone. Our aim was to assess the effects of local angiotensin II type 2 receptor stimulation within the RVLM and the PVN on neurotransmitter concentrations and mean arterial pressure (MAP). Methods:In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for local infusion of the angiotensin II type 2 receptor agonist Compound 21 in the RVLM and the PVN of conscious normotensive Wistar rats. The MAP response to local Compound 21 was monitored with a pressure transducer under anaesthesia. Angiotensin II type 2 receptor selectivity was assessed using the angiotensin II type 2 receptor antagonist PD123319; the GABA-A receptor antagonist bicuculline was used to assess the involvement of GABA-A receptors. Results: Infusion of Compound 21 (0.05 MUg/MUl/h) in the RVLM significantly increased GABA levels and lowered blood pressure. These effects were abolished by co-infusion with PD123319. No changes in neurotransmitter levels or effects on blood pressure were seen with PD123319 infusion alone. Co-infusion of bicuculline abolished the Compound 21 evoked decrease in MAP. Infusion of Compound 21 within the PVN did not change extracellular neurotransmitter levels nor MAP. Conclusion: Selective stimulation of angiotensin II type 2 receptor within the RVLM by local Compound 21 infusion reduces blood pressure and increases local GABA levels in normotensive rats. This hypotensive response requires functional GABA-A receptors, suggesting that GABAergic neurons are involved in the sympatho-inhibitory action underlying this hypotensive response. PMID- 28674484 TI - Corrigendum: Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement. AB - [This corrects the article on p. 77 in vol. 11, PMID: 28270744.]. PMID- 28674486 TI - Advanced Oxidative Protein Products Cause Pain Hypersensitivity in Rats by Inducing Dorsal Root Ganglion Neurons Apoptosis via NADPH Oxidase 4/c-Jun N terminal Kinase Pathways. AB - Pain hypersensitivity is the most common category of chronic pain and is difficult to cure. Oxidative stress and certain cells apoptosis, such as dorsal root ganglion (DRG) neurons, play an essential role in the induction and development of pain hypersensitivity. The focus of this study is at a more specific molecular level. We investigated the role of advanced oxidative protein products (AOPPs) in inducing hypersensitivity and the cellular mechanism underlying the proapoptotic effect of AOPPs. Normal rats were injected by AOPPs Rat serum albumin (AOPPs-RSA) to cause pain hypersensitivity. Primary cultured DRG neurons were treated with increasing concentrations of AOPPs-RSA or for increasing time durations. The MTT, flow cytometry and western blot analyses were performed in the DRG neurons. A loss of mitochondrial membrane potential (MMP) and an increase in intracellular reactive oxygen species (ROS) were observed. We found that AOPPs triggered DRG neurons apoptosis and MMP loss. After AOPPs treatment, intracellular ROS generation increased in a time- and dose-dependent manner, whereas, N-acetyl-L-cysteine (NAC), a specific ROS scavenger could inhibit the ROS generation. Proapoptotic proteins, such as Bax, caspase 9/caspase 3, and PARP-1 were activated, whereas anti-apoptotic Bcl-2 protein was down regulated. AOPPs also increased Nox4 and JNK expression. Taken together, these findings suggest that AOPPs cause pain hypersensitivity in rats, and extracellular AOPPs accumulation triggered Nox4-dependent ROS production, which activated JNK, and induced DRG neurons apoptosis by activating caspase 3 and PARP 1. PMID- 28674485 TI - The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS. AB - In vertebrates, during an early wave of hematopoiesis in the yolk sac between embryonic day E7.0 and E9.0, cells of mesodermal leaflet addressed to macrophage lineage enter in developing central nervous system (CNS) and originate the developing native microglial cells. Depending on the species, microglial cells represent 5-20% of glial cells resident in adult brain. Here, we briefly discuss some canonical functions of the microglia, i.e., cytokine secretion and functional transition from M1 to M2 phenotype. In addition, we review studies on the non-canonical functions of microglia such as regulation of phagocytosis, synaptic pruning, and sculpting postnatal neural circuits. In this latter context the contribution of microglia to some neurodevelopmental disorders is now well established. Nasu-Hakola (NHD) disease is considered a primary microgliopathy with alterations of the DNAX activation protein 12 (DAP12)-Triggering receptor expressed on myeloid cells 2 (TREM-2) signaling and removal of macromolecules and apoptotic cells followed by secondary microglia activation. In Rett syndrome Mecp2-/- microglia shows a substantial impairment of phagocytic ability, although the role of microglia is not yet clear. In a mouse model of Tourette syndrome (TS), microglia abnormalities have also been described, and deficient microglia mediated neuroprotection is obvious. Here we review the role of microglial cells in neurodevelopmental disorders without inflammation and on the complex role of microglia in developing CNS. PMID- 28674487 TI - Pyramidal Neurons in Different Cortical Layers Exhibit Distinct Dynamics and Plasticity of Apical Dendritic Spines. AB - The mammalian cerebral cortex is typically organized in six layers containing multiple types of neurons, with pyramidal neurons (PNs) being the most abundant. PNs in different cortical layers have distinct morphology, physiology and functional roles in neural circuits. Therefore, their development and synaptic plasticity may also differ. Using in vivo transcranial two-photon microscopy, we followed the structural dynamics of dendritic spines on apical dendrites of layer (L) 2/3 and L5 PNs at different developmental stages. We show that the density and dynamics of spines are significantly higher in L2/3 PNs than L5 PNs in both adolescent (1 month old) and adult (4 months old) mice. While spine density of L5 PNs decreases during adolescent development due to a higher rate of spine elimination than formation, there is no net change in the spine density along apical dendrites of L2/3 PNs over this period. In addition, experiences exert differential impact on the dynamics of apical dendritic spines of PNs resided in different cortical layers. While motor skill learning promotes spine turnover on L5 PNs in the motor cortex, it does not change the spine dynamics on L2/3 PNs. In addition, neonatal sensory deprivation decreases the spine density of both L2/3 and L5 PNs, but leads to opposite changes in spine dynamics among these two populations of neurons in adolescence. In summary, our data reveal distinct dynamics and plasticity of apical dendritic spines on PNs in different layers in the living mouse cortex, which may arise from their distinct functional roles in cortical circuits. PMID- 28674488 TI - Dancing or Fitness Sport? The Effects of Two Training Programs on Hippocampal Plasticity and Balance Abilities in Healthy Seniors. AB - Age-related degenerations in brain structure are associated with balance disturbances and cognitive impairment. However, neuroplasticity is known to be preserved throughout lifespan and physical training studies with seniors could reveal volume increases in the hippocampus (HC), a region crucial for memory consolidation, learning and navigation in space, which were related to improvements in aerobic fitness. Moreover, a positive correlation between left HC volume and balance performance was observed. Dancing seems a promising intervention for both improving balance and brain structure in the elderly. It combines aerobic fitness, sensorimotor skills and cognitive demands while at the same time the risk of injuries is low. Hence, the present investigation compared the effects of an 18-month dancing intervention and traditional health fitness training on volumes of hippocampal subfields and balance abilities. Before and after intervention, balance was evaluated using the Sensory Organization Test and HC volumes were derived from magnetic resonance images (3T, MP-RAGE). Fourteen members of the dance (67.21 +/- 3.78 years, seven females), and 12 members of the fitness group (68.67 +/- 2.57 years, five females) completed the whole study. Both groups revealed hippocampal volume increases mainly in the left HC (CA1, CA2, subiculum). The dancers showed additional increases in the left dentate gyrus and the right subiculum. Moreover, only the dancers achieved a significant increase in the balance composite score. Hence, dancing constitutes a promising candidate in counteracting the age-related decline in physical and mental abilities. PMID- 28674489 TI - Multi-Finger Interaction and Synergies in Finger Flexion and Extension Force Production. AB - The aim of this study was to discover finger interaction indices during single finger ramp tasks and multi-finger coordination during a steady state force production in two directions, flexion, and extension. Furthermore, the indices of anticipatory adjustment of elemental variables (i.e., finger forces) prior to a quick pulse force production were quantified. It is currently unknown whether the organization and anticipatory modulation of stability properties are affected by force directions and strengths of in multi-finger actions. We expected to observe a smaller finger independency and larger indices of multi-finger coordination during extension than during flexion due to both neural and peripheral differences between the finger flexion and extension actions. We also examined the indices of the anticipatory adjustment between different force direction conditions. The anticipatory adjustment could be a neural process, which may be affected by the properties of the muscles and by the direction of the motions. The maximal voluntary contraction (MVC) force was larger for flexion than for extension, which confirmed the fact that the strength of finger flexor muscles (e.g., flexor digitorum profundus) was larger than that of finger extensor (e.g., extensor digitorum). The analysis within the uncontrolled manifold (UCM) hypothesis was used to quantify the motor synergy of elemental variables by decomposing two sources of variances across repetitive trials, which identifies the variances in the uncontrolled manifold (VUCM) and that are orthogonal to the UCM (VORT). The presence of motor synergy and its strength were quantified by the relative amount of VUCM and VORT. The strength of motor synergies at the steady state was larger in the extension condition, which suggests that the stability property (i.e., multi-finger synergies) may be a direction specific quantity. However, the results for the existence of anticipatory adjustment; however, no difference between the directional conditions suggests that feed-forward synergy adjustment (changes in the stability property) may be at least independent of the magnitude of the task-specific apparent performance variables and its direction (e.g., flexion and extension forces). PMID- 28674491 TI - Microglial Activation in the Pathogenesis of Huntington's Disease. AB - Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expanded CAG trinucleotide repeats (>36) in exon 1 of HTT gene that encodes huntingtin protein. Although HD is characterized by a predominant loss of neurons in the striatum and cortex, previous studies point to a critical role of aberrant accumulation of mutant huntingtin in microglia that contributes to the progressive neurodegeneration in HD, through both cell-autonomous and non cell-autonomous mechanisms. Microglia are resident immune cells in the central nervous system (CNS), which function to surveil the microenvironment at a quiescent state. In response to various pro-inflammatory stimuli, microglia become activated and undergo two separate phases (M1 and M2 phenotype), which release pro-inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), anti inflammatory cytokines, and growth factors (TGF-beta, CD206, and Arg1), respectively. Immunoregulation by microglial activation could be either neurotoxic or neuroprotective. In this review, we summarized current understanding about microglial activation in the pathogenesis and progression of HD, with a primary focus of M1 and M2 phenotype of activated microglia and their corresponding signaling pathways. PMID- 28674490 TI - What the Spectrum of Microglial Functions Can Teach us About Fetal Alcohol Spectrum Disorder. AB - Alcohol exposure during gestation can lead to severe defects in brain development and lifelong physical, behavioral and learning deficits that are classified under the umbrella term fetal alcohol spectrum disorder (FASD). Sadly, FASD is diagnosed at an alarmingly high rate, affecting 2%-5% of live births in the United States, making it the most common non-heritable cause of mental disability. Currently, no standard therapies exist that are effective at battling FASD symptoms, highlighting a pressing need to better understand the underlying mechanisms by which alcohol affects the developing brain. While it is clear that sensory and cognitive deficits are driven by inappropriate development and remodeling of the neural circuits that mediate these processes, alcohol's actions acutely and long-term on the brain milieu are diverse and complex. Microglia, the brain's immune cells, have been thought to be a target for alcohol during development because of their exquisite ability to rapidly detect and respond to perturbations affecting the brain. Additionally, our view of these immune cells is rapidly changing, and recent studies have revealed a myriad of microglial physiological functions critical for normal brain development and long-term function. A clear and complete understanding of how microglial roles on this end of the spectrum may be altered in FASD is currently lacking. Such information could provide important insights toward novel therapeutic targets for FASD treatment. Here we review the literature that links microglia to neural circuit remodeling and provide a discussion of the current understanding of how developmental alcohol exposure affects microglial behavior in the context of developing brain circuits. PMID- 28674492 TI - Aberrant Intrinsic Activity and Connectivity in Cognitively Normal Parkinson's Disease. AB - Disturbances in intrinsic activity during resting-state functional MRI (rsfMRI) are common in Parkinson's disease (PD), but have largely been studied in a priori defined subnetworks. The cognitive significance of abnormal intrinsic activity is also poorly understood, as are abnormalities that precede the onset of mild cognitive impairment. To address these limitations, we leveraged three different analytic approaches to identify disturbances in rsfMRI metrics in 31 cognitively normal PD patients (PD-CN) and 30 healthy adults. Subjects were screened for mild cognitive impairment using the Movement Disorders Society Task Force Level II criteria. Whole-brain data-driven analytic approaches first analyzed the amplitude of low-frequency intrinsic fluctuations (ALFF) and regional homogeneity (ReHo), a measure of local connectivity amongst functionally similar regions. We then examined if regional disturbances in these metrics altered functional connectivity with other brain regions. We also investigated if abnormal rsfMRI metrics in PD-CN were related to brain atrophy and executive, visual organization, and episodic memory functioning. The results revealed abnormally increased and decreased ALFF and ReHo in PD-CN patients within the default mode network (posterior cingulate, inferior parietal cortex, parahippocampus, entorhinal cortex), sensorimotor cortex (primary motor, pre/post-central gyrus), basal ganglia (putamen, caudate), and posterior cerebellar lobule VII, which mediates cognition. For default mode network regions, we also observed a compound profile of altered ALFF and ReHo. Most regional disturbances in ALFF and ReHo were associated with strengthened long-range interactions in PD-CN, notably with regions in different networks. Stronger long-range functional connectivity in PD CN was also partly expanded to connections that were outside the networks of the control group. Abnormally increased activity and functional connectivity appeared to have a pathological, rather than compensatory influence on cognitive abilities tested in this study. Receiver operating curve analyses demonstrated excellent sensitivity (>=90%) of rsfMRI variables in distinguishing patients from controls, but poor accuracy for brain volume and cognitive variables. Altogether these results provide new insights into the topology, cognitive relevance, and sensitivity of aberrant intrinsic activity and connectivity that precedes clinically significant cognitive impairment. Longitudinal studies are needed to determine if these neurocognitive associations presage the development of future mild cognitive impairment or dementia. PMID- 28674493 TI - A Systematic Strategy for Discovering a Therapeutic Drug for Alzheimer's Disease and Its Target Molecule. AB - Natural medicines are attractive sources of leading compounds that can be used as interventions for neurodegenerative disorders. The complexity of their chemical components and undetermined bio-metabolism have greatly hindered both the use of natural medicines and the identification of their active constituents. Here, we report a systematic strategy for evaluating the bioactive candidates in natural medicines used for Alzheimer's disease (AD). We found that Drynaria Rhizome could enhance memory function and ameliorate AD pathologies in 5XFAD mice. Biochemical analysis led to the identification of the bio-effective metabolites that are transferred to the brain, namely, naringenin and its glucuronides. To explore the mechanism of action, we combined the drug affinity responsive target stability with immunoprecipitation-liquid chromatography/mass spectrometry analysis, identifying the collapsin response mediator protein 2 protein as a target of naringenin. Our study indicates that biochemical analysis coupled with pharmacological methods can be used in the search for new targets for AD intervention. PMID- 28674495 TI - Anti-allergic Hydroxy Fatty Acids from Typhonium blumei Explored through ChemGPS NP. AB - Increasing prevalence of allergic diseases with an inadequate variety of treatment drives forward search for new alternative drugs. Fatty acids, abundant in nature, are regarded as important bioactive compounds and powerful nutrients playing an important role in lipid homeostasis and inflammation. Phytochemical study on Typhonium blumei Nicolson and Sivadasan (Araceae), a folk anti-cancer and anti-inflammatory medicine, yielded four oxygenated fatty acids, 12R hydroxyoctadec-9Z,13E-dienoic acid methyl ester (1) and 10R-hydroxyoctadec-8E,12Z dienoic acid methyl ester (2), 9R-hydroxy-10E-octadecenoic acid methyl ester (3), and 12R*-hydroxy-10E-octadecenoic acid methyl ester (4). Isolated compounds were identified by spectroscopic methods along with GC-MS analysis. Isolated fatty acids together with a series of saturated, unsaturated and oxygenated fatty acids were evaluated for their anti-inflammatory and anti-allergic activities in vitro. Unsaturated (including docosahexaenoic and eicosapentaenoic acids) as well as hydroxylated unsaturated fatty acids exerted strong anti-inflammatory activity in superoxide anion generation (IC50 2.14-3.73 MUM) and elastase release (IC50 1.26 4.57 MUM) assays. On the other hand, in the anti-allergic assays, the unsaturated fatty acids were inactive, while hydroxylated fatty acids showed promising inhibitory activity in A23187- and antigen-induced degranulation assays (e.g., 9S hydroxy-10E,12Z-octadecadienoic acid, IC50 92.4 and 49.7 MUM, respectively). According to our results, the presence of a hydroxy group in the long chain did not influence the potent anti-inflammatory activity of free unsaturated acids. Nevertheless, hydroxylation of fatty acids (or their methyl esters) seems to be a key factor for the anti-allergic activity observed in the current study. Moreover, ChemGPS-NP was explored to predict the structure-activity relationship of fatty acids. The anti-allergic fatty acids formed different cluster distant from clinically used drugs. The bioactivity of T. blumei, which is historically utilized in folk medicine, might be related to the content of fatty acids and their metabolites. PMID- 28674494 TI - The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers. AB - Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets. PMID- 28674496 TI - In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma. AB - Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients' survival is poor. The polyphenol 4',5,7,-trihydroxyflavone Apigenin (API) is a "multifunctional drug". Several studies have demonstrated API anti-tumoral effects. However, little is known on the in vitro and in vivo anti-tumoral effects of API in MM. Thus, we analyzed the in vitro effects of API on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, and autophagy of human and mouse MM cells. We evaluated the in vivo anti-tumor activities of API in mice transplanted with MM #40a cells forming ascites. API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage. API activated apoptosis but not autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage of PARP-1, and increase of the percentage of cells in subG1 phase. API treatment affected the phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell type specific manner, inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, and inhibited NF-kappaB nuclear translocation. Intraperitoneal administration of API increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of tumor growth. Our findings may have important implications for the design of MM treatment using API. PMID- 28674497 TI - Veronica officinalis Product Authentication Using DNA Metabarcoding and HPLC-MS Reveals Widespread Adulteration with Veronica chamaedrys. AB - Studying herbal products derived from local and traditional knowledge and their value chains is one of the main challenges in ethnopharmacology. The majority of these products have a long history of use, but non-harmonized trade and differences in regulatory policies between countries impact their value chains and lead to concerns over product efficacy, safety and quality. Veronica officinalis L. (common speedwell), a member of Plantaginaceae family, has a long history of use in European traditional medicine, mainly in central eastern Europe and the Balkans. However, no specified control tests are available either to establish the quality of derived herbal products or for the discrimination of its most common substitute, V. chamaedrys L. (germander speedwell). In this study, we use DNA metabarcoding and high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) to authenticate sixteen V. officinalis herbal products and compare the potential of the two approaches to detect substitution, adulteration and the use of unreported constituents. HPLC-MS showed high resolution in detecting phytochemical target compounds, but did not enable detection of specific plant species in the products. DNA metabarcoding detected V. officinalis in only 15% of the products, whereas it detected V. chamaedrys in 62% of the products. The results confirm that DNA metabarcoding can be used to test for the presence of Veronica species, and detect substitution and/or admixture of other Veronica species, as well as simultaneously detect all other species present. Our results confirm that none of the herbal products contained exactly the species listed on the label, and all included substitutes, contaminants or fillers. This study highlights the need for authentication of raw herbals along the value chain of these products. An integrative methodology can assess both the quality of herbal products in terms of target compound concentrations and species composition, as well as admixture and substitution with other chemical compounds and plants. PMID- 28674499 TI - Phytochemicals Approach for Developing Cancer Immunotherapeutics. AB - Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings suggest that phytochemicals or their derivatives confer a spectrum of different pharmacological activities, which contrasts with the current cytotoxic anticancer drugs commonly used in clinics. In this review, we have collected together pertinent information from recent studies about the biochemical and cellular mechanisms through which specific phytochemicals regulate target immune systems in defined tumor microenvironments. We have further highlighted the potential application of these immunotherapeutic modifiers in cell-based cancer vaccine systems. This knowledge provides useful technological support and know how for future applications of phytochemicals in cancer immunotherapy. PMID- 28674498 TI - Nimotuzumab Induces NK Cell Activation, Cytotoxicity, Dendritic Cell Maturation and Expansion of EGFR-Specific T Cells in Head and Neck Cancer Patients. AB - Survival benefit and long-term duration of clinical response have been seen using the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody (mAb) nimotuzumab. Blocking EGFR signaling may not be the only mechanism of action underlying its efficacy. As an IgG1 isotype mAb, nimotuzumab's capacity of killing tumor cells by antibody dependent cellular cytotoxicity (ADCC) and to induce an immune response in cancer patients have not been studied. ADCC-induced by nimotuzumab was determined using a 51Cr release assay. The in vitro effect of nimotuzumab on natural killer (NK) cell activation and dendritic cell (DC) maturation and the in vivo frequency of circulating regulatory T cells (Tregs) and NK cells were assessed by flow cytometry. Cytokine levels in supernatants were determined by ELISA. ELISpot was carried out to quantify EGFR-specific T cells in nimotuzumab-treated head and neck cancer (HNSCC) patients. Nimotuzumab was able to kill EGFR+ tumor cells by NK cell-mediated ADCC. Nimotuzumab activated NK cells promoted DC maturation and EGFR-specific CD8+ T cell priming. Interestingly, nimotuzumab led to upregulation of some immune checkpoint molecules on NK cells (TIM-3) and DC (PD-L1), to a lower extent than another EGFR mAb, cetuximab. Furthermore, circulating EGFR-specific T cells were identified in nimotuzumab-treated HNSCC patients. Notably, nimotuzumab combined with cisplatin based chemotherapy and radiation increased the frequency of peripheral CD4+CD39+FOXP3+Tregs which otherwise were decreased to baseline values when nimotuzumab was used as monotherapy. The frequency of circulating NK cells remained constant during treatment. Nimotuzumab-induced, NK cell-mediated DC priming led to induction of anti-EGFR specific T cells in HNSCC patients. The association between EGFR-specific T cells and patient clinical benefit with nimotuzumab treatment should be investigated. PMID- 28674500 TI - Dynamic Skin Patterns in Cephalopods. AB - Cephalopods are unrivaled in the natural world in their ability to alter their visual appearance. These mollusks have evolved a complex system of dermal units under neural, hormonal, and muscular control to produce an astonishing variety of body patterns. With parallels to the pixels on a television screen, cephalopod chromatophores can be coordinated to produce dramatic, dynamic, and rhythmic displays, defined collectively here as "dynamic patterns." This study examines the nature, context, and potential functions of dynamic patterns across diverse cephalopod taxa. Examples are presented for 21 species, including 11 previously unreported in the scientific literature. These range from simple flashing or flickering patterns, to highly complex passing wave patterns involving multiple skin fields. PMID- 28674501 TI - The Digestive Tract of Cephalopods: Toward Non-invasive In vivo Monitoring of Its Physiology. AB - Ensuring the health and welfare of animals in research is paramount, and the normal functioning of the digestive tract is essential for both. Here we critically assess non- or minimally-invasive techniques which may be used to assess a cephalopod's digestive tract functionality to inform health monitoring. We focus on: (i) predatory response as an indication of appetitive drive; (ii) body weight assessment and interpretation of deviations (e.g., digestive gland weight loss is disproportionate to body weight loss in starvation); (iii) oro anal transit time requiring novel, standardized techniques to facilitate comparative studies of species and diets; (iv) defecation frequency and analysis of fecal color (diet dependent) and composition (parasites, biomarkers, and cytology); (v) digestive tract endoscopy, but passage of the esophagus through the brain is a technical challenge; (vi) high resolution ultrasound that offers the possibility of imaging the morphology of the digestive tract (e.g., food distribution, indigestible residues, obstruction) and recording contractile activity; (vii) needle biopsy (with ultrasound guidance) as a technique for investigating digestive gland biochemistry and pathology without the death of the animal. These techniques will inform the development of physiologically based assessments of health and the impact of experimental procedures. Although intended for use in the laboratory they are equally applicable to cephalopods in public display and aquaculture. PMID- 28674502 TI - Treatment of Abnormal Vaginal Microbiota before Frozen Embryo Transfer: Case Report and Minireview to Discuss the Longitudinal Treatment Efficacy of Oral Clindamycin. AB - Abnormal vaginal microbiota (AVM) or bacterial vaginosis (BV) might negatively impact reproductive outcomes of in vitro fertilization (IVF). However, before randomized controlled trials are initiated to investigate cause and effect, it is necessary to establish the optimal treatment for AVM. Metronidazole seems ineffective to treat the biofilm in AVM; thus, clindamycin could be suggested as a relevant antibiotic agent for future intervention based studies. In the present case report, we present the first longitudinal follow-up of the vaginal microbiota with molecular methods during and after oral clindamycin treatment. Furthermore, we review the recent literature with the aim to discuss the optimal AVM treatment in a fertility setting. The patient was 40 years old suffering from unexplained secondary infertility. Prior to the present transfer cycle, she had had two failed IVF cycles. The tentative explanation of failed treatment was age related aneuploidy. However, the patient asked for AVM diagnosis and she was subsequently diagnosed and treated successfully. Unfortunately, the patient did not achieve pregnancy after clindamycin treatment and two subsequent frozen embryo transfer cycles. Taken together, we report an excellent AVM treatment efficacy both short-term and long-term following oral clindamycin treatment. We discuss the potential impact on the vaginal microbiota of co-treatment with estrogen patches in the stimulated frozen embryo transfer cycle. Furthermore, we discuss future aspects of AVM treatment such as the potential impact of estrogen and live biotherapeutic products to positively modulate the microbiota of the reproductive tract. PMID- 28674503 TI - Male Seminal Relaxin Contributes to Induction of the Post-mating Cytokine Response in the Female Mouse Uterus. AB - The hormone relaxin is important in female reproduction for embryo implantation, cardiovascular function, and during labor and lactation. Relaxin is also synthesized in males by organs of the male tract. We hypothesized that relaxin might be one component of seminal plasma responsible for eliciting the female cytokine response induced in the uterus at mating. When recombinant relaxin was injected into the uterus of wild-type (Rln+/+) mice at estrus, it evoked the production of Cxcl1 mRNA and its secreted protein product CXCL1 in four of eight animals. Mating experiments were then conducted using mice with a null mutation in the relaxin gene (Rln-/- mice). qRT-PCR analysis of mRNA expression in wild type females showed diminished uterine expression of several cytokine and chemokine genes in the absence of male relaxin. Similar differences were also noted comparing Rln-/- and Rln+/+ females mated to wild-type males. Quantification of uterine luminal fluid cytokine content confirmed that male relaxin provokes the production of CXCL10 and CSF3 in Rln+/+ females. Differences were also seen comparing Rln-/- and Rln+/+ females mated with Rln-/- males for CXCL1, CSF3, and CCL5, implying that endogenous relaxin in females might prime the uterus to respond appropriately to seminal fluid at coitus. Finally, pan leukocyte CD45 mRNA was increased in wild-type matings compared to other combinations, implying that male and female relaxin may trigger leukocyte expansion in the uterus. We conclude that male and/or female relaxin may be important in activating the uterine cytokine/chemokine network required to initiate maternal immune adaptation to pregnancy. PMID- 28674504 TI - Antigliadin Antibodies (AGA IgG) Are Related to Neurochemistry in Schizophrenia. AB - Inflammation may play a role in schizophrenia; however, subgroups with immune regulation dysfunction may serve as distinct illness phenotypes with potential different treatment and prevention strategies. Emerging data show that about 30% of people with schizophrenia have elevated antigliadin antibodies of the IgG type, representing a possible subgroup of schizophrenia patients with immune involvement. Also, recent data have shown a high correlation of IgG-mediated antibodies between the periphery and cerebral spinal fluid in schizophrenia but not healthy controls, particularly AGA IgG suggesting that these antibodies may be crossing the blood-brain barrier with resulting neuroinflammation. Proton magnetic resonance spectroscopy (MRS) is a non-invasive technique that allows the quantification of certain neurochemicals in vivo that may proxy inflammation in the brain such as myoinositol and choline-containing compounds (glycerophosphorylcholine and phosphorylcholine). The objective of this exploratory study was to examine the relationship between serum AGA IgG levels and MRS neurochemical levels. We hypothesized that higher AGA IgG levels would be associated with higher levels of myoinositol and choline-containing compounds (glycerophosphorylcholine plus phosphorylcholine; GPC + PC) in the anterior cingulate cortex. Thirty-three participants with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder had blood drawn and underwent neuroimaging using MRS within 9 months. We found that 10/33 (30%) had positive AGA IgG (>=20 U) similar to previous findings. While there were no significant differences in myoinositol and GPC + PC levels between patients with and without AGA IgG positivity, there were significant relationships between both myoinositol (r = 0.475, p = 0.007) and GPC + PC (r = 0.36, p = 0.045) with AGA IgG levels. This study shows a possible connection of AGA IgG antibodies to putative brain inflammation as measured by MRS in schizophrenia. PMID- 28674505 TI - Vulnerability or Sensitivity to the Environment? Methodological Issues, Trends, and Recommendations in Gene-Environment Interactions Research in Human Behavior. AB - Research on the potential role of gene-environment interactions (GxE) in explaining vulnerability to psychopathology in humans has witnessed a shift from a diathesis-stress perspective to differential susceptibility approaches. This paper critically reviews methodological issues and trends in this body of research. Databases were screened for studies of GxE in the prediction of personality traits, behavior, and mental health disorders in humans published between January 2002 and January 2015. In total, 315 papers were included. Results showed that 34 candidate genes have been included in GxE studies. Independent of the type of environment studied (early or recent life events, positive or negative environments), about 67-83% of studies have reported significant GxE interactions, which is consistent with a social susceptibility model. The percentage of positive results does not seem to differ depending on the gene studied, although publication bias might be involved. However, the number of positive findings differs depending on the population studied (i.e., young adults vs. older adults). Methodological considerations limit the ability to draw strong conclusions, particularly as almost 90% (n = 283/315) of published papers are based on samples from North America and Europe, and about 70% of published studies (219/315) are based on samples that were also used in other reports. At the same time, there are clear indications of methodological improvements over time, as is shown by a significant increase in longitudinal and experimental studies as well as in improved minimum genotyping. Recommendations for future research, such as minimum quality assessment of genes and environmental factors, specifying theoretical models guiding the study, and taking into account of cultural, ethnic, and lifetime perspectives, are formulated. PMID- 28674506 TI - Sun Exposure and Psychotic Experiences. AB - OBJECTIVE: Sun exposure is considered the single most important source of vitamin D. Vitamin D deficiency has been suggested to play a role in the etiology of psychotic disorders. The aim of the present study was to evaluate the association between sun exposure and psychotic experiences (PEs) in a general population sample of Swedish women. METHODS: The study population included participants from The Swedish Women's Lifestyle and Health cohort study. The 20-item community assessment of psychic experiences (CAPEs) was administered between ages 30 and 50 to establish PEs. Sun exposure as measured by (1) sunbathing holidays and (2) history of sunburn was measured between ages 10 and 39. The association between sun exposure and PEs was evaluated by quantile regression models. RESULTS: 34,297 women were included in the analysis. Women who reported no sunbathing holidays and 2 or more weeks of sunbathing holidays scored higher on the CAPE scale than women exposed to 1 week of sunbathing holidays across the entire distribution, when adjusting for age and education. Similarly, compared with women who reported a history of one sunburn, the women with none or two or more sunburns showed higher scores on the CAPE scale. CONCLUSION: The results of the present study suggest that, in a population-based cohort of middle aged women, both low and high sun exposure is associated with increased level of positive PEs. PMID- 28674508 TI - "It's Just More Acceptable To Be White or Mixed Race and Gay Than Black and Gay": The Perceptions and Experiences of Homophobia in St. Lucia. AB - Lesbian, gay, and bisexual (LGB) individuals come from diverse cultural groups with differing ethnic and racial identities. However, most research on LGB people uses white western samples and studies of Afro-Caribbean diaspora often use Jamaican samples. Thus, the complexity of Afro-Caribbean LGB peoples' experiences of homophobia is largely unknown. The authors' analyses explore experiences of homophobia among LGB people in St. Lucia. Findings indicate issues of skin-shade orientated tolerance, regionalized disparities in levels of tolerance toward LGB people and regionalized passing (regionalized sexual identity shifting). Finally, the authors' findings indicate that skin shade identities and regional location influence the psychological health outcomes of homophobia experienced by LGB people in St. Lucia. PMID- 28674509 TI - Acceptance and Commitment Therapy for the Treatment of Music Performance Anxiety: A Pilot Study with Student Vocalists. AB - This study investigated the use of Acceptance and Commitment Therapy (ACT) as a treatment for music performance anxiety (MPA) in an uncontrolled pilot design. ACT is a newer, "third-wave" therapy that differs from previous MPA treatments, because its goal is not to reduce symptoms of MPA. Rather, ACT aims to enhance psychological flexibility in the presence of unwanted symptoms through the promotion of six core processes collectively known as the ACT "Hexaflex." A small group of student vocalists (N = 7) from an elite choral college were recruited using objective criteria for evaluating MPA. Participants received 12 ACT sessions, and their baseline functioning served as a pre-treatment control. Treatment consisted of an orientation to ACT, identifying experientially avoidant behaviors, facilitation of Hexaflex processes, group performances in which valued behaviors were practiced in front of one another, meditations, homework, and completion of self-report measures before, during, and after treatment (at a 1- and 3-month follow-up). Improvements were observed in participants' cognitive defusion, acceptance of MPA symptoms, and psychological flexibility at post treatment and follow-ups. Students also appeared to improve their performance quality and reduce their shame over having MPA. These results add to existing research suggesting ACT is a promising intervention for MPA, while also highlighting how vocal students may be less impaired by physical MPA symptoms. PMID- 28674507 TI - Impaired Coupling between the Dorsomedial Prefrontal Cortex and the Amygdala in Schizophrenia Smokers Viewing Anti-smoking Images. AB - BACKGROUND: Cigarette smoking is highly prevalent in schizophrenia and is one of the main factors contributing to the significantly decreased life expectancy in this population. Schizophrenia smokers, compared to their counterparts with no comorbid psychiatric disorder, are largely unaware and indifferent to the long term negative consequences of cigarette smoking. The objective of this study was to determine, for the first time, if these meta-cognitive deficits are associated with neuro-functional alterations in schizophrenia smokers. METHODS: Twenty-four smokers with no psychiatric disorder and 21 smokers with schizophrenia (DSM-IV criteria) were scanned using functional magnetic resonance imaging and exposed to anti-smoking images. Granger causality analyses were used to examine the effective connectivity between brain regions found to be significantly activated. RESULTS: Across groups, potent activations were observed in the left ventro lateral prefrontal cortex, the left amygdala (AMG), and the dorsomedial prefrontal cortex (dmPFC). Using the dmPFC as a seed region, we found an abnormal negative connectivity from the dmPFC to the AMG in schizophrenia smokers during the viewing of anti-smoking stimuli. This abnormal connectivity was not present during the viewing of aversive stimuli unrelated to tobacco. DISCUSSION: Given the well-established roles of the dmPFC in social cognition and of the AMG in emotional processing, our results suggest that the relative indifference of schizophrenia smokers regarding the negative consequences of tobacco smoking could be explained by a cognitive-affective dissonance. PMID- 28674510 TI - The Future of Musical Emotions. PMID- 28674511 TI - The Role of Semantic Context in Early Morphological Processing. AB - There is extensive evidence pointing to an early, automatic segmentation of written words into their constituent units (farm-er, wit-ness); however, less is known about the potential role of contextual information in modulating this analysis. We adapted the standard masked priming paradigm to include an overt semantic prime in order to examine whether semantic context influences morpho orthographic segmentation of complex words. In particular, we asked how the context will affect processing of semantically opaque forms (witness), where the embedded stem (wit) is incompatible with the meaning of the whole form. Results showed no masked priming facilitation for opaque forms in the presence of a semantic prime, indicating that context can influence early morphological analysis. Priming was found for both semantically transparent and opaque forms (farmer-farm, witness-wit) when there was no semantically-related context, consistent with the literature and an account positing early blind segmentation. These findings provide an important update to the long-standing debate on early morphological processing in written word recognition. PMID- 28674512 TI - Temporal Organization of Sound Information in Auditory Memory. AB - Memory is a constructive and organizational process. Instead of being stored with all the fine details, external information is reorganized and structured at certain spatiotemporal scales. It is well acknowledged that time plays a central role in audition by segmenting sound inputs into temporal chunks of appropriate length. However, it remains largely unknown whether critical temporal structures exist to mediate sound representation in auditory memory. To address the issue, here we designed an auditory memory transferring study, by combining a previously developed unsupervised white noise memory paradigm with a reversed sound manipulation method. Specifically, we systematically measured the memory transferring from a random white noise sound to its locally temporal reversed version on various temporal scales in seven experiments. We demonstrate a U-shape memory-transferring pattern with the minimum value around temporal scale of 200 ms. Furthermore, neither auditory perceptual similarity nor physical similarity as a function of the manipulating temporal scale can account for the memory transferring results. Our results suggest that sounds are not stored with all the fine spectrotemporal details but are organized and structured at discrete temporal chunks in long-term auditory memory representation. PMID- 28674513 TI - Isolated Striatocapsular Infarcts after Endovascular Treatment of Acute Proximal Middle Cerebral Artery Occlusions: Prevalence, Enabling Factors, and Clinical Outcome. AB - BACKGROUND: Striatocapsular infarcts (SCIs) are defined as large subcortical infarcts involving the territory of more than one lenticulostriate artery. SCI without concomitant ischemia in the more distal middle cerebral artery (MCA) territory [isolated SCI (iSCI)] has been described as a rare infarct pattern. The purpose of this study was to assess the prevalence of iSCI in patients treated with endovascular thrombectomy (ET), to evaluate baseline and procedural parameters associated with this condition, and to describe the clinical course of iSCI patients. METHODS: A retrospective analysis of 206 consecutive patients with an isolated MCA occlusion involving the lenticulostriate arteries and treated with ET was performed. Baseline patient and procedural characteristics and ischemic involvement of the striatocapsular and distal MCA territory [iSCI, as opposed to non-isolated SCI (niSCI)] were analyzed using multivariate logistic regression models. Prevalence of iSCI was assessed, and clinical course was determined with the rates of substantial neurological improvement and good functional short- and mid-term outcome (discharge/day 90 Modified Rankin Scale <=2). RESULTS: iSCI was detected in 53 patients (25.7%), and niSCI was detected in 153 patients (74.3%). Successful reperfusion [thrombolysis in cerebral infarction (TICI) 2b/3] [adjusted odds ration (aOR) 8.730, 95% confidence interval (95% CI) 1.069-71.308] and good collaterals (aOR 2.100, 95% CI 1.119 3.944) were associated with iSCI. In successfully reperfused patients, TICI 3 was found to be an additional factor associated with iSCI (aOR 5.282, 1.759-15.859). Patients with iSCI had higher rates of substantial neurological improvement (71.7 vs. 37.9%, p < 0.001) and higher rates of good functional short- and mid-term outcome (58.3 vs. 23.7%, p < 0.001 and 71.4 vs. 41.7%, p < 0.001). However, while iSCI patients, in general, had a more favorable outcome, considerable heterogeneity in outcome was observed. CONCLUSION: High rates of successful reperfusion (TICI 2b/3) and in particular, complete reperfusion (TICI 3) are associated with iSCIs. The high prevalence of iSCI in successfully reperfused patients with good collaterals corroborates previous concepts of iSCI pathogenesis. iSCI, once considered a rare pattern of cerebral ischemia, is likely to become more prevalent with increases in endovascular stroke therapy. This may have implications for patient rehabilitation and pathophysiological analyses of ischemic damage confined to subcortical regions of the MCA territory. PMID- 28674515 TI - Investigating the Blood Oxygenation Level-Dependent Functional MRI Response to a Verbal Fluency Task in Early Stroke before and after Hemodynamic Scaling. AB - BACKGROUND AND OBJECTIVE: Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) has been extensively used as a marker of brain dysfunction and subsequent recovery following stroke. However, growing evidence suggests that straightforward interpretation of BOLD fMRI changes with aging and disease is challenging. In this study, we investigated the effect of calibrating task fMRI data by applying a hemodynamic calibration method using the resting-state fluctuation amplitude (RSFA). Task fMRI responses were obtained during a covert verbal fluency task in a group of early stage stroke patients and matched healthy normal controls. METHODS: Fifteen acute left hemisphere stroke patients (less than 7 days from stroke; aged 44-84 years, average ~64 years) and 21 healthy controls (aged 55-77 years, average ~61 years) were prospectively studied. All subjects completed a 3-min covert verbal fluency task, and a 10-min eyes-closed resting-state fMRI scan, from which the calibration factor (RSFA) was computed. A behavioral measure on the verbal fluency task was also collected outside the scanner. Whole brain activation volumes and region-of-interest (ROI)-wise percent signal change and activation volumes before and after calibration were computed. RESULTS: Between-group differences in whole brain activation volumes, although statistically significant before calibration failed to be significant after calibration. There were significant within-group differences before and after calibration with RSFA. Statistically significant between-group differences on ROI wise measures before calibration also significantly reduced after calibration. Exploratory brain-behavior correlations revealed a similar pattern: significant correlations before calibration failed to survive after calibration. DISCUSSION AND CONCLUSION: BOLD fMRI changes with aging and disease is confounded by changes in neurofunctional coupling leading to challenges in the straightforward interpretation of task fMRI results. Application of the hemodynamic calibration using the RSFA technique in the current study appeared to mitigate any differences between stroke and age-matched healthy controls. Our study indicates that estimating neural activity after applying hemodynamic scaling is important for studies of aging and for studies tracking post-stroke changes. We recommend that further investigation of hemodynamic calibration with RSFA in healthy subjects and in stroke in larger samples is necessary. PMID- 28674516 TI - Pulsatile Proptosis due to Intraorbital Meningocele. AB - We present a case of a 79-year-old man with a non-symptomatic pulsatile proptosis of the left eye. Magnetic resonance imaging revealed a meningocele into the left orbit due to an osseous defect in the orbital roof. PMID- 28674517 TI - Neuroimaging Predictors of Clinical Outcome in Acute Basilar Artery Occlusion. AB - Certain early neuroimaging findings are independent predictors of clinical outcome in acute basilar artery occlusion. These imaging findings may serve as important baseline imaging characteristics as well as subgroups in future randomized controlled trials. The purpose of this review is to review and compare early neuroimaging findings seen on non-invasive cranial imaging that predict clinical outcome in acute basilar artery occlusion. PMID- 28674514 TI - Aspects on the Physiological and Biochemical Foundations of Neurocritical Care. AB - Neurocritical care (NCC) is a branch of intensive care medicine characterized by specific physiological and biochemical monitoring techniques necessary for identifying cerebral adverse events and for evaluating specific therapies. Information is primarily obtained from physiological variables related to intracranial pressure (ICP) and cerebral blood flow (CBF) and from physiological and biochemical variables related to cerebral energy metabolism. Non-surgical therapies developed for treating increased ICP are based on knowledge regarding transport of water across the intact and injured blood-brain barrier (BBB) and the regulation of CBF. Brain volume is strictly controlled as the BBB permeability to crystalloids is very low restricting net transport of water across the capillary wall. Cerebral pressure autoregulation prevents changes in intracranial blood volume and intracapillary hydrostatic pressure at variations in arterial blood pressure. Information regarding cerebral oxidative metabolism is obtained from measurements of brain tissue oxygen tension (PbtO2) and biochemical data obtained from intracerebral microdialysis. As interstitial lactate/pyruvate (LP) ratio instantaneously reflects shifts in intracellular cytoplasmatic redox state, it is an important indicator of compromised cerebral oxidative metabolism. The combined information obtained from PbtO2, LP ratio, and the pattern of biochemical variables reveals whether impaired oxidative metabolism is due to insufficient perfusion (ischemia) or mitochondrial dysfunction. Intracerebral microdialysis and PbtO2 give information from a very small volume of tissue. Accordingly, clinical interpretation of the data must be based on information of the probe location in relation to focal brain damage. Attempts to evaluate global cerebral energy state from microdialysis of intraventricular fluid and from the LP ratio of the draining venous blood have recently been presented. To be of clinical relevance, the information from all monitoring techniques should be presented bedside online. Accordingly, in the future, the chemical variables obtained from microdialysis will probably be analyzed by biochemical sensors. PMID- 28674518 TI - Brain Susceptibility Changes in a Patient with Natalizumab-Related Progressive Multifocal Leukoencephalopathy: A Longitudinal Quantitative Susceptibility Mapping and Relaxometry Study. AB - BACKGROUND: Brain MRI plays an essential role in both diagnosis and follow-up of the JC virus infection of the brain. Recently, MR studies with susceptibility weighted imaging (SWI) sequences have shown hypointensities in U-fibers adjacent to white matter (WM) lesions of progressive multifocal leukoencephalopathy (PML). This finding has been confirmed with the use of quantitative susceptibility mapping (QSM), allowing to hypothesize a paramagnetic effect in these regions. Here, we report the first longitudinal assessment of QSM and R2* maps in natalizumab-associated PML to evaluate serial changes in susceptibility contrast images and their role in PML diagnosis and follow-up. CASE PRESENTATION: We report the case of a 42-year-old woman with multiple sclerosis (MS) who eventually developed, after the 28th natalizumab infusion, subacute cognitive decline and received a laboratory-confirmed diagnosis of PML, leading to immediate drug discontinuation. Three months later, she suffered a new clinical exacerbation, with a brain scan revealing significant inflammatory activity compatible with the radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS). She was then treated with corticosteroids until the clinico-radiological spectrum became stable, with the final outcome of a severe functional impairment. Quantitative maps obtained in the early symptomatic stage clearly showed increased QSM and R2* values in the juxtacortical WM adjacent to PML lesions, which persisted during the subsequent disease course. DISCUSSION AND CONCLUSION: High QSM and R2* values in U-fibers adjacent to WM lesions were early and seemingly time-independent radiological findings in the presented PML case. This, coupled to the known absence of significant paramagnetic effect of new active MS lesions, could support the use of quantitative MRI as an additional tool in the diagnosis and follow-up of natalizumab-related PML in MS. PMID- 28674519 TI - Somatostatin-IRES-Cre Mice: Between Knockout and Wild-Type? AB - The neuropeptide somatostatin (SOM) is widely expressed in rodent brain and somatostatin-IRES-Cre (SOM-cre) mouse strains are increasingly used to unravel the physiology of SOM-containing neurons. However, while knock-in targeting strategy greatly improves Cre-Lox system accuracy, recent reports have shown that genomic insertion of Cre construct per se can markedly affect physiological function. We show that Cre transgene insertion into the 3'UTR of the somatostatin gene leads to the selective and massive depletion of endogenous SOM in all tested brain regions. It also strongly impacts SOM-related neuroendocrine responses in a similar manner to what has been reported for SST KO mice: increased corticosterone levels after 30-min restraint stress, decreased amplitude and regularity of ultradian growth hormone secretory patterns accompanied by changes in sexually dimorphic liver gene expression (serpina1, Cyp2b9, Cyp2a4, Cyp2d9, and Cyp7b1). In addition to demonstrating the need for examination of the consequences of Cre transgenesis, these results also reveal how this SOM-cre strain may be a useful tool in studying the functional consequences of moderate to low SOM levels as reported in neurological and psychiatric disorders. PMID- 28674521 TI - Ghrelin Is a Regulator of Glucagon-Like Peptide 1 Secretion and Transcription in Mice. AB - The gut hormones ghrelin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) have been intensively studied for their role in metabolism. It is, however, not well known whether the hormones interplay and regulate the secretion of each other. In this study, we studied the effect of ghrelin on GLP-1, GIP, and insulin secretion during an oral glucose tolerance test (OGTT) in mice. Intravenous administration of ghrelin caused increased GLP-1 secretion during the OGTT. On the other hand, ghrelin had no effect on circulating levels of glucose, insulin, and GIP. Furthermore, ghrelin treatment reduced proglucagon mRNA expression in GLUTag cells. The effect of ghrelin on GLP 1 secretion and proglucagon transcription was reinforced by the presence of GHS R1a in human and mouse ileal L-cells, as well as in GLUTag cells. In summary, ghrelin is a regulator of GLP-1 secretion and transcription, and interfering with GHS-R1a signaling may be a way forward to enhance endogenous GLP-1 secretion in subjects with type 2 diabetes. PMID- 28674520 TI - Endocrine Disruption of Vasopressin Systems and Related Behaviors. AB - Endocrine disrupting chemicals (EDCs) are chemicals that interfere with the organizational or activational effects of hormones. Although the vast majority of the EDC literature focuses on steroid hormone signaling related impacts, growing evidence from a myriad of species reveals that the nonapeptide hormones vasopressin (AVP) and oxytocin (OT) may also be EDC targets. EDCs shown to alter pathways and behaviors coordinated by AVP and/or OT include the plastics component bisphenol A (BPA), the soy phytoestrogen genistein (GEN), and various flame retardants. Many effects are sex specific and likely involve action at nuclear estrogen receptors. Effects include the elimination or reversal of well characterized sexually dimorphic aspects of the AVP system, including innervation of the lateral septum and other brain regions critical for social and other non reproductive behaviors. Disruption of magnocellular AVP function has also been reported in rats, suggesting possible effects on hemodynamics and cardiovascular function. PMID- 28674522 TI - Desynchronization of Circadian Clocks in Cancer: A Metabolic and Epigenetic Connection. AB - Circadian clocks are innate oscillators that drive daily rhythms in metabolism, physiology, and behavior. 24-h rhythms in gene expression, driven by core clock transcription factors, reflect the epigenetic state of the cell, which in turn is dictated by the metabolic environment. Cancer cells alter their metabolic state and gene expression and therefore are likely to tweak circadian clock function in their favor. Over the past decade, we have witnessed an extraordinary increase in systems-level studies that suggest intricate mechanistic links between the cellular metabolome and the circadian epigenome. In parallel, reprogramming of cellular clock function in cancers is increasingly evident and the role of clock genes in the development of hematological tumors, as well as their pathophysiological effects on tissues distal to the tumor, has been described. Furthermore, the interplay between components of the circadian clock, metabolic enzymes, and oncogenes is starting to be better understood, such as the close association between overexpression of the Myc oncogene and perturbation of circadian and metabolic rhythms, thus opening new avenues to treat cancers. This review article explores current knowledge on the circadian metabolome and the molecular pathways they control, with a focus on their involvement in the development of hematopoietic malignancies. PMID- 28674523 TI - Systemic Lupus Erythematosus and Thyroid Autoimmunity. AB - Most of the studies present in the literature show a high prevalence, and incidence, of new cases of hypothyroidism and autoimmune thyroiditis (AT) in systemic lupus erythematosus (SLE) patients, overall in female gender. A limited number of cases of Graves' disease have been also reported in SLE patients, in agreement with the higher prevalence of thyroid autoimmunity. It has been also demonstrated that a Th1 predominance is associated with AT in SLE patients. Furthermore, a higher prevalence of papillary thyroid cancer has been recently reported in SLE, in particular in the presence of thyroid autoimmunity. However, studies in larger number of SLE patients are needed to confirm findings about thyroid cancer. On the whole, data from literature strongly suggest that female SLE patients, with a high risk (a normal but at the higher limit thyroid stimulating hormone value, positive antithyroid peroxidase antibodies, a hypoechoic pattern, and small thyroid), should undergo periodic thyroid function follow-up, and appropriate treatments when needed. A careful thyroid monitoring would be opportune during the follow-up of these patients. PMID- 28674524 TI - Psoriasis, Psoriatic Arthritis, and Thyroid Autoimmunity. AB - Psoriasis (PsO) is a chronic relapsing/remitting autoimmune skin disease, associated with an increased risk of other autoimmune disorders. Psoriatic arthritis (PsA) is a chronic inflammatory arthritis occurring approximately in 30% of PsO patients. Sporadic cases of association between PsO and autoimmune thyroid disorders (AITDs) have been reported. However, two different recent studies did not find any association between them. In patients with PsO and PsA, an association with AITD has been shown by most of the studies in adults, but not in the juvenile form. In PsA women and men, thyroid autoimmunity [positive antithyroid peroxidase (AbTPO) antibodies, hypoechoic thyroid pattern] and subclinical hypothyroidism were more prevalent than in the general population. An association has been shown also in patients with PsO, arthritis, and inflammatory bowel disease, who have more frequently AITD. A Th1 immune predominance has been shown in early PsO, and PsA, with high serum CXCL10 (Th1 prototype chemokine), overall in the presence of autoimmune thyroiditis. This Th1 immune predominance might be the immunopathogenetic base of the association of these disorders. A raised incidence of new cases of hypothyroidism, thyroid dysfunction, positive AbTPO, and appearance of a hypoechoic thyroid pattern in PsA patients, especially in women, has been shown recently, suggesting to evaluate AbTPO levels, thyroid function, and thyroid ultrasound, especially in PsA women. Thyroid function follow-up and suitable treatments should be performed regularly in PsA female patients at high risk (thyroid-stimulating hormone within the normal range but at the higher limit, positive AbTPO, hypoechoic, and small thyroid). PMID- 28674526 TI - Induction of Cryptic and Bioactive Metabolites through Natural Dietary Components in an Endophytic Fungus Colletotrichum gloeosporioides (Penz.) Sacc. AB - Grape skin and turmeric extracts having the major components resveratrol and curcumin, respectively, were used for the induction of cryptic and bioactive metabolites in an endophytic fungus Colletotrichum gloeosporioides isolated from Syzygium cumini. The increase in total amount of crude compounds in grape skin and turmeric extract treated cultures was 272.48 and 174.32%, respectively, compared to the untreated control. Among six human pathogenic bacteria tested, the maximum inhibitory activity was found against Aeromonas hydrophila IMS/GN11 while no inhibitory activity was observed against Enterococcus faecalis IMS/GN7. The crude compounds derived from turmeric extract treated cultures showed the highest DPPH free radicals scavenging activity (86.46% inhibition) followed by compounds from grape skin treated cultures (11.80% inhibition) and the control cultures (1.92% inhibition). Both the treatments significantly (p <= 0.05) increased the antibacterial and antioxidant activities of crude metabolites compared to the control. HPLC profiling of crude compounds derived from grape skin and turmeric extract treated cultures revealed the presence of additional 20 and 14 cryptic compounds, respectively, compared to the control. These findings advocate the future use of such dietary components in induced production of cryptic and bioactive metabolites. PMID- 28674525 TI - Deciphering Physiological Functions of AHL Quorum Quenching Acylases. AB - N-Acylhomoserine lactone (AHL)-acylase (also known as amidase or amidohydrolase) is a class of enzyme that belongs to the Ntn-hydrolase superfamily. As the name implies, AHL-acylases are capable of hydrolysing AHLs, the most studied signaling molecules for quorum sensing in Gram-negative bacteria. Enzymatic degradation of AHLs can be beneficial in attenuating bacterial virulence, which can be exploited as a novel approach to fight infection of human pathogens, phytopathogens or aquaculture-related contaminations. Numerous acylases from both prokaryotic and eukaryotic sources have been characterized and tested for the interference of quorum sensing-regulated functions. The existence of AHL-acylases in a multitude of organisms from various ecological niches, raises the question of what the physiological roles of AHL-acylases actually are. In this review, we attempt to bring together recent studies to extend our understanding of the biological functions of these enzymes in nature. PMID- 28674527 TI - Temporal Dynamics of Soil Microbial Communities below the Seedbed under Two Contrasting Tillage Regimes. AB - Agricultural productivity relies on a wide range of ecosystem services provided by the soil biota. Plowing is a fundamental component of conventional farming, but long-term detrimental effects such as soil erosion and loss of soil organic matter have been recognized. Moving towards more sustainable management practices such as reduced tillage or crop residue retention can reduce these detrimental effects, but will also influence structure and function of the soil microbiota with direct consequences for the associated ecosystem services. Although there is increasing evidence that different tillage regimes alter the soil microbiome, we have a limited understanding of the temporal dynamics of these effects. Here, we used high-throughput sequencing of bacterial and fungal ribosomal markers to explore changes in soil microbial community structure under two contrasting tillage regimes (conventional and reduced tillage) either with or without crop residue retention. Soil samples were collected over the growing season of two crops (Vicia faba and Triticum aestivum) below the seedbed (15-20 cm). Tillage, crop and growing stage were significant determinants of microbial community structure, but the impact of tillage showed only moderate temporal dependency. Whereas the tillage effect on soil bacteria showed some temporal dependency and became less strong at later growing stages, the tillage effect on soil fungi was more consistent over time. Crop residue retention had only a minor influence on the community. Six years after the conversion from conventional to reduced tillage, soil moisture contents and nutrient levels were significantly lower under reduced than under conventional tillage. These changes in edaphic properties were related to specific shifts in microbial community structure. Notably, bacterial groups featuring copiotrophic lifestyles or potentially carrying the ability to degrade more recalcitrant compounds were favored under conventional tillage, whereas taxa featuring more oligotrophic lifestyles were more abundant under reduced tillage. Our study found that, under the specific edaphic and climatic context of central Belgium, different tillage regimes created different ecological niches that select for different microbial lifestyles with potential consequences for the ecosystem services provided to the plants and their environment. PMID- 28674528 TI - Host Differences Affecting Resistance and Susceptibility of the Second Generation of a Pekin Duck Flock to Duck Hepatitis A Virus Genotype 3. AB - Earlier work suggested the possibility to anti duck hepatitis A virus genotype 3 (DHAV-3) using the resistance breeding strategy. Here, we report the creation of the second generations of a resistant Pekin duck flock (designated Z8R2) and a highly susceptible Pekin duck flock (designated Z8S2) and the investigation of their responses to DHAV-3. Experimental infection with DHAV-3 at 7 days of age resulted in a high mortality (66.3%) in 11 susceptible Z8S2 families and an extremely low mortality rate (2.67%) in 32 Z8R2 families, indicating that Z8R2 exhibits strong resistance to DHAV-3, while Z8S2 is highly susceptible to the virus. Detection of DHAV-3 in the liver between 1 and 60 hours post inoculation (hpi) suggests that DHAV-3 can be replicated rapidly and efficiently in the liver of Z8S2, whereas the replication of the virus in the liver of Z8R2 is suppressed greatly. High levels of serum biochemical markers (e.g., ALT, AST, ALP and GGT) were detected in Z8S2 at 24 hpi, which were significantly higher than those in Z8R2. Analysis of transcripts in the liver revealed that the expression levels of several pattern recognition receptors (PRRs) (e.g., TLR4/7, RIG-1 and MDA5) and cytokines (e.g., IL-2, IL-6, IL-8, IFN-alpha, and IFN-gamma) in Z8S2 were significantly higher than those in Z8R2 at 12 and 24 hpi. Together these findings suggest that Z8R2 and Z8S2 Pekin ducks, which were derived from the same Z8 line, exhibit disparate pathogenic outcomes following DHAV-3 infection. Therefore, it is possible to select a Pekin duck flock resistant to DHAV-3 employing the strategy described here. It is likely that the high viral load and the strong inflammatory response correlate with the high susceptibility of Z8S2 Pekin ducks to DHAV-3. PMID- 28674529 TI - Abl Tyrosine Kinase Regulates Hepatitis C Virus Entry. AB - Abl is a central regulator of multiple cellular processes controlling actin dynamics, proliferation, and differentiation. Here, we showed that knockdown of Abl impaired hepatitis C virus (HCV) propagation. Treatment of Abl tyrosine kinase-specific inhibitor, imatinib and dasatinib, also significantly decreased HCV RNA and protein levels in HCV-infected cells. We showed that both imatinib and dasatinib selectively inhibited HCV infection at the entry step of HCV life cycle, suggesting that Abl kinase activity may be necessary for HCV entry. Using HCV pseudoparticle infection assays, we verified that Abl is required for viral entry. By employing transferrin uptake and immunofluorescence assays, we further demonstrated that Abl was involved in HCV entry at a clathrin-mediated endocytosis step. These data suggest that Abl may represent a novel host factor for HCV entry. PMID- 28674530 TI - Endoplasmic Reticulum Stress Sensor IRE1alpha Enhances IL-23 Expression by Human Dendritic Cells. AB - Human monocyte-derived dendritic cells (DCs) exposed to pathogen-associated molecular patterns (PAMPs) undergo bioenergetic changes that influence the immune response. We found that stimulation with PAMPs enhanced glycolysis in DCs, whereas oxidative phosphorylation remained unaltered. Glucose starvation and the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) modulated cytokine expression in stimulated DCs. Strikingly, IL23A was markedly induced upon 2-DG treatment, but not during glucose deprivation. Since 2-DG can also rapidly inhibit protein N glycosylation, we postulated that this compound could induce IL-23 in DCs via activation of the endoplasmic reticulum (ER) stress response. Indeed, stimulation of DCs with PAMPs in the presence of 2-DG robustly activated inositol-requiring protein 1alpha (IRE1alpha) signaling and to a lesser extent the PERK arm of the unfolded protein response. Additional ER stressors such as tunicamycin and thapsigargin also promoted IL-23 expression by PAMP-stimulated DCs. Pharmacological, biochemical, and genetic analyses using conditional knockout mice revealed that IL-23 induction in ER stressed DCs stimulated with PAMPs was IRE1alpha/X-box binding protein 1-dependent upon zymosan stimulation. Interestingly, we further evidenced PERK-mediated and CAAT/enhancer-binding protein beta-dependent trans-activation of IL23A upon lipopolysaccharide treatment. Our findings uncover that the ER stress response can potently modulate cytokine expression in PAMP-stimulated human DCs. PMID- 28674532 TI - Changes in Host Immune-Endocrine Relationships during Tuberculosis Treatment in Patients with Cured and Failed Treatment Outcomes. AB - A bidirectional communication between the immune and endocrine systems exists and facilitates optimum responses in the host during infections. This is in part achieved through changes in secretion patterns of hypothalamic hormones induced by inflammatory cytokines. The aim of this study was to elucidate the immune endocrine alterations during tuberculosis (TB) treatment in patients with cured and failed TB treatment outcomes. Blood samples were collected from 27 cured and 10 failed patients and hormone as well as cytokine concentrations quantified at baseline, week 4, and month 6 of TB treatment. Hormone profiles of the two treatment outcome groups were different from each other prior to as well as during TB treatment. Treatment response effects were observed for cortisol, estradiol, T3, T4 ghrelin, leptin, amylin, adiponectin, and dehydroepiandrosterone (DHEA). Trends suggest that T4, amylin, and DHEA concentrations were different between treatment outcomes, although these did not reach statistical significance. Relationships between endocrine and inflammatory markers and the biological pathways involved differed between cured and failed treatment patients. These results highlight the complex interaction between the endocrine and immune system during active TB disease and throughout treatment and suggest that endocrine markers in conjunction with inflammatory markers may be useful in predicting unfavorable treatment outcomes. PMID- 28674531 TI - Recurrent and Sustained Viral Infections in Primary Immunodeficiencies. AB - Viral infections are commonplace and often innocuous. Nevertheless, within the population of patients with primary immunodeficiencies (PIDDs), viral infections can be the feature that drives a diagnostic evaluation or can be the most significant morbidity for the patient. This review is focused on the viral complications of PIDDs. It will focus on respiratory viruses, the most common type of viral infection in the general population. Children and adults with an increased frequency or severity of respiratory viral infections are often referred for an immunologic evaluation. The classic teaching is to investigate humoral function in people with recurrent sinopulmonary infections, but this is often interpreted to mean recurrent bacterial infections. Recurrent or very severe viral infections may also be a harbinger of a primary immunodeficiency as well. This review will also cover persistent cutaneous viral infections, systemic infections, central nervous system infections, and gastrointestinal infections. In each case, the specific viral infections may drive a diagnostic evaluation that is specific for that type of virus. This review also discusses the management of these infections, which can become problematic in patients with PIDDs. PMID- 28674533 TI - Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner. AB - The IL-17-producing CD4+ T helper cell (Th17) differentiation is affected by stimulation of the aryl hydrocarbon receptor (AhR) pathway and by hypoxia inducible factor 1 alpha (HIF-1alpha). In some cases, Th17 become non-pathogenic and produce IL-10. However, the initiating events triggering this phenotype are yet to be fully understood. Here, we show that such cells may be differentiated at low oxygen and regardless of AhR ligand treatment such as cigarette smoke extract. Hypoxia led to marked alterations of the transcriptome of IL-10 producing Th17 cells affecting genes involved in metabolic, anti-apoptotic, cell cycle, and T cell functional pathways. Moreover, we show that oxygen regulates the expression of CD52, which is a cell surface protein that has been shown to suppress the activation of other T cells upon release. Taken together, these findings suggest a novel ability for Th17 cells to regulate immune responses in vivo in an oxygen-dependent fashion. PMID- 28674534 TI - Human CD56dimCD16dim Cells As an Individualized Natural Killer Cell Subset. AB - Human natural killer (NK) cells can be subdivided in several subpopulations on the basis of the relative expression of the adhesion molecule CD56 and the activating receptor CD16. Whereas blood CD56brightCD16dim/- NK cells are classically viewed as immature precursors and cytokine producers, the larger CD56dimCD16bright subset is considered as the most cytotoxic one. In peripheral blood of healthy donors, we noticed the existence of a population of CD56dimCD16dim NK cells that was frequently higher in number than the CD56bright subsets and even expanded in occasional control donors but also in transporter associated with antigen processing-deficient patients, two familial hemophagocytic lymphohistiocytosis type II patients, and several common variable immunodeficiency patients. This population was detected but globally reduced in a longitudinal cohort of 18 HIV-1-infected individuals. Phenotypically, the new subset contained a high percentage of relatively immature cells, as reflected by a significantly stronger representation of NKG2A+ and CD57- cells compared to their CD56dimCD16bright counterparts. The phenotype of the CD56dimCD16dim population was differentially affected by HIV-1 infection as compared to the other NK cell subsets and only partly restored to normal by antiretroviral therapy. From the functional point of view, sorted CD56dimCD16dim cells degranulated more than CD56dimCD16bright cells but less than CD56dimCD16- NK cells. The population was also identified in various organs of immunodeficient mice with a human immune system ("humanized" mice) reconstituted from human cord blood stem cells. In conclusion, the CD56dimCD16dim NK cell subpopulation displays distinct phenotypic and functional features. It remains to be clarified if these cells are the immediate precursors of the CD56dimCD16bright subset or placed somewhere else in the NK cell differentiation and maturation pathway. PMID- 28674535 TI - Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation. AB - Leishmania infantum is one of the major parasite species associated with visceral leishmaniasis, a severe form of the disease that can become lethal if untreated. This obligate intracellular parasite has developed diverse strategies to escape the host immune response, such as exoproducts (Exo) carrying a wide range of molecules, including parasite virulence factors, which are potentially implicated in early stages of infection. Herein, we report that L. infantum Exo and its two fractions composed of extracellular vesicles (EVs) and vesicle-depleted exoproducts (VDEs) inhibit human peripheral blood invariant natural killer T (iNKT) cell expansion in response to their specific ligand, the glycolipid alpha GalactosylCeramide (alpha-GalCer), as well as their capacity to promptly produce IL-4 and IFNgamma. Using plate-bound CD1d and alpha-GalCer, we found that Exo, EV, and VDE fractions reduced iNKT cell activation in a dose-dependent manner, suggesting that they prevented alpha-GalCer presentation by CD1d molecules. This direct effect on CD1d was confirmed by the observation that CD1d:alpha-GalCer complex formation was impaired in the presence of Exo, EV, and VDE fractions. Furthermore, lipid extracts from the three compounds mimicked the inhibition of iNKT cell activation. These lipid components of L. infantum exoproducts, including EV and VDE fractions, might compete for CD1-binding sites, thus blocking iNKT cell activation. Overall, our results provide evidence for a novel strategy through which L. infantum can evade immune responses of mammalian host cells by preventing iNKT lymphocytes from recognizing glycolipids in a TCR dependent manner. PMID- 28674536 TI - Primary Immunodeficiency Disorders in India-A Situational Review. AB - Primary immunodeficiency disorders (PIDs) are a group of genetic defects characterized by abnormalities of one or more components of the immune system. While there have been several advances in diagnosis, management, and research in the field of PIDs, they continue to remain underdiagnosed, especially in the less affluent countries. Despite several limitations and challenges, India has advanced significantly in the field of PIDs in the last few years. In this review, we highlight the progress in the field of PIDs in India over the last 25 years, the difficulties faced by clinicians across the country, the current state of PIDs in India and the future prospects. PMID- 28674537 TI - Increased IL-15 Production and Accumulation of Highly Differentiated CD8+ Effector/Memory T Cells in the Bone Marrow of Persons with Cytomegalovirus. AB - Cytomegalovirus (CMV) has been described as a contributor to immunosenescence, thus exacerbating age-related diseases. In persons with latent CMV infection, the CD8+ T cell compartment is irreversibly changed, leading to the accumulation of highly differentiated virus-specific CD8+ T cells in the peripheral blood. The bone marrow (BM) has been shown to play a major role in the long-term survival of antigen-experienced T cells. Effector CD8+ T cells are preferentially maintained by the cytokine IL-15, the expression of which increases in old age. However, the impact of CMV on the phenotype of effector CD8+ T cells and on the production of T cell survival molecules in the BM is not yet known. We now show, using BM samples obtained from persons who underwent hip replacement surgery because of osteoarthrosis, that senescent CD8+ TEMRA cells with a bright expression of CD45RA and a high responsiveness to IL-15 accumulate in the BM of CMV-infected persons. A negative correlation was found between CMV antibody (Ab) titers in the serum and the expression of CD28 and IL-7Ralpha in CD8+ [Formula: see text] cells. Increased IL-15 mRNA levels were observed in the BM of CMV+ compared to CMV- persons, being particularly high in old seropositive individuals. In summary, our results indicate that a BM environment rich in IL-15 may play an important role in the maintenance of highly differentiated CD8+ T cells generated after CMV infection. PMID- 28674538 TI - Involvement of Cytokines in the Pathogenesis of Salt and Water Imbalance in Congestive Heart Failure. AB - Congestive heart failure (CHF) has become a major medical problem in the western world with high morbidity and mortality rates. CHF adversely affects several systems, mainly the kidneys and the lungs. While the involvement of the renin angiotensin-aldosterone system and the sympathetic nervous system in the progression of cardiovascular, pulmonary, and renal dysfunction in experimental and clinical CHF is well established, the importance of pro-inflammatory mediators in the pathogenesis of this clinical setting is still evolving. In this context, CHF is associated with overexpression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6, which are activated in response to environmental injury. This family of cytokines has been implicated in the deterioration of CHF, where it plays an important role in initiating and integrating homeostatic responses both at the myocardium and circulatory levels. We and others showed that angiotensin II decreased the ability of the lungs to clear edema and enhanced the fibrosis process via phosphorylation of the mitogen-activated protein kinases p38 and p42/44, which are generally involved in cellular responses to pro-inflammatory cytokines. Literature data also indicate the involvement of these effectors in modulating ion channel activity. It has been reported that in heart failure due to mitral stenosis; there were varying degrees of vascular and other associated parenchymal changes such as edema and fibrosis. In this review, we will discuss the effects of cytokines and other inflammatory mediators on the kidneys and the lungs in heart failure; especially their role in renal and alveolar ion channels activity and fluid balance. PMID- 28674539 TI - Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft versus-Host Disease. AB - Chronic graft-versus-host disease (cGVHD) is a debilitating complication arising in around half of all patients treated with an allogeneic hematopoietic stem cell transplantation. Even though treatment of severe cGVHD has improved during recent years, it remains one of the main causes of morbidity and mortality in affected patients. Biomarkers in blood that could aid in the diagnosis and classification of cGVHD severity are needed for the development of novel treatment strategies that can alleviate symptoms and reduce the need for painful and sometimes complicated tissue biopsies. Methods that comprehensively profile complex biological systems such as the immune system can reveal unanticipated markers when used with the appropriate methods of data analysis. Here, we used mass cytometry, flow cytometry, enzyme-linked immunosorbent assay, and multiplex assays to systematically profile immune cell populations in 68 patients with varying grades of cGVHD. We identified multiple subpopulations across T, B, and NK-cell lineages that distinguished patients with cGVHD from those without cGVHD and which were associated in varying ways with severity of cGVHD. Specifically, initial flow cytometry demonstrated that patients with more severe cGVHD had lower mucosal-associated T cell frequencies, with a concomitant higher level of CD38 expression on T cells. Mass cytometry could identify unique subpopulations specific for cGVHD severity albeit with some seemingly conflicting results. For instance, patients with severe cGVHD had an increased frequency of activated B cells compared to patients with moderate cGVHD while activated B cells were found at a reduced frequency in patients with mild cGVHD compared to patients without cGVHD. Moreover, results indicate it may be possible to validate mass cytometry results with clinically viable, smaller flow cytometry panels. Finally, no differences in levels of blood soluble markers could be identified, with the exception for the semi-soluble combined marker B-cell activating factor/B cell ratio, which was increased in patients with mild cGVHD compared to patients without cGVHD. These findings suggest that interdependencies between such perturbed subpopulations of cells play a role in cGVHD pathogenesis and can serve as future diagnostic and therapeutic targets. PMID- 28674540 TI - Identification and Characterization of Phospholipase D Genes Putatively Involved in Internal Browning of Pineapple during Postharvest Storage. AB - Phospholipase D (PLD) in plants plays vital roles in growth, development, and stress responses. However, the precise role of PLDs in pineapple remains poorly understood. In this study, 10 putative PLD genes, designated as AcPLD1-AcPLD10, were identified based on the pineapple genome database. The 10 AcPLDs could be clustered into five of the six known PLD families according to sequence characterization. Their deduced amino acid sequences displayed similarities to PLDs from other plant species. Expression analyses of PLD mRNAs from pineapple pulp were performed. The 10 PLDs exhibited differential expression patterns during storage periods of fruits treated with hexaldehyde (a specific PLD inhibitor) which could alleviate internal browning (IB) of pineapple after harvest. Functional subcellular localization signaling assays of two PLD proteins (AcPLD2 and AcPLD9) were performed by fluorescence microscopy. To further detect the potential action mechanism underlying PLD involved in the IB defense response, PLD, hydrogen peroxide (H2O2) and H2O2 associated with antioxidative enzymes such as superoxide dismutase, catalase, NADPH, and ascorbate peroxidase were quantified by enzyme-linked immunosorbent assay. This report is the first to provide a genome-wide description of the pineapple PLD gene family, and the results should expand knowledge of this family. PMID- 28674542 TI - Physiological Mechanism of Enhancing Salt Stress Tolerance of Perennial Ryegrass by 24-Epibrassinolide. AB - Brassinosteroids (BR) regulate plant tolerance to salt stress but the mechanisms underlying are not fully understood. This study was to investigate physiological mechanisms of 24-epibrassinolide (EBR)'s impact on salt stress tolerance in perennial ryegrass (Lolium perenne L.) The grass seedlings were treated with EBR at 0, 10, and 100 nM, and subjected to salt stress (250 mM NaCl). The grass irrigated with regular water without EBR served as the control. Salt stress increased leaf electrolyte leakage (EL), malondialdehyde (MDA), and reduced photosynthetic rate (Pn). Exogenous EBR reduced EL and MDA, increased Pn, chlorophyll content, and stomatal conductance (gs). The EBR applications also alleviated decline of superoxide dismutase (SOD) and catalase (CAT) and ascorbate peroxidase (APX) activity when compared to salt treatment alone. Salt stress increased leaf abscisic acid (ABA) and gibberellin A4 (GA4) content but reduced indole-3-acetic acid (IAA), zeatin riboside (ZR), isopentenyl adenosine (iPA), and salicylic acid (SA). Exogenous EBR at 10 nm and 100 nM increased ABA, and iPA content under salt stress. The EBR treatment at 100 nM also increased leaf IAA, ZR, JA, and SA. In addition, EBR treatments increased leaf proline and ions (K+, Mg2+, and Ca2+) content, and reduced Na+/K+ in leaf tissues. The results of this study suggest that EBR treatment may improve salt stress tolerance by increasing the level of selected hormones and antioxidant enzyme (SOD and CAT) activity, promoting accumulation of proline and ions (K+, Ca2+, and Mg2+) in perennial ryegrass. PMID- 28674543 TI - Losing the Warning Signal: Drought Compromises the Cross-Talk of Signaling Molecules in Quercus ilex Exposed to Ozone. AB - Understanding the interactions between drought and acute ozone (O3) stress in terms of signaling molecules and cell death would improve the predictions of plant responses to climate change. The aim was to investigate whether drought stress influences the responses of plants to acute episodes of O3 exposure. In this study, the behavior of 84 Mediterranean evergreen Quercus ilex plants was evaluated in terms of cross-talk responses among signaling molecules. Half of the sample was subjected to drought (20% of the effective daily evapotranspiration, for 15 days) and was later exposed to an acute O3 exposure (200 nL L-1 for 5 h). First, our results indicate that in well-water conditions, O3 induced a signaling pathway specific to O3-sensitive behavior. Second, different trends and consequently different roles of phytohormones and signaling molecules (ethylene, ET; abscisic acid, ABA; salycilic acid, SA and jasmonic acid, JA) were observed in relation to water stress and O3. A spatial and functional correlation between these signaling molecules was observed in modulating O3-induced responses in well watered plants. In contrast, in drought-stressed plants, these compounds were not involved either in O3-induced signaling mechanisms or in leaf senescence (a response observed in water-stressed plants before the O3-exposure). Third, these differences were ascribable to the fact that in drought conditions, most defense processes induced by O3 were compromised and/or altered. Our results highlight how Q. ilex plants suffering from water deprivation respond differently to an acute O3 episode compared to well-watered plants, and suggest new effect to be considered in plant responses to environmental changes. This poses the serious question as to whether or not multiple high-magnitude O3 events (as predicted) can change these cross-talk responses, thus opening it up possible further investigations. PMID- 28674541 TI - Key Components of Different Plant Defense Pathways Are Dispensable for Powdery Mildew Resistance of the Arabidopsis mlo2 mlo6 mlo12 Triple Mutant. AB - Loss of function mutations of particular plant MILDEW RESISTANCE LOCUS O (MLO) genes confer durable and broad-spectrum penetration resistance against powdery mildew fungi. Here, we combined genetic, transcriptomic and metabolomic analyses to explore the defense mechanisms in the fully resistant Arabidopsis thaliana mlo2 mlo6 mlo12 triple mutant. We found that this genotype unexpectedly overcomes the requirement for indolic antimicrobials and defense-related secretion, which are critical for incomplete resistance of mlo2 single mutants. Comparative microarray-based transcriptome analysis of mlo2 mlo6 mlo12 mutants and wild type plants upon Golovinomyces orontii inoculation revealed an increased and accelerated accumulation of many defense-related transcripts. Despite the biotrophic nature of the interaction, this included the non-canonical activation of a jasmonic acid/ethylene-dependent transcriptional program. In contrast to a non-adapted powdery mildew pathogen, the adapted powdery mildew fungus is able to defeat the accumulation of defense-relevant indolic metabolites in a MLO protein dependent manner. We suggest that a broad and fast activation of immune responses in mlo2 mlo6 mlo12 plants can compensate for the lack of single or few defense pathways. In addition, our results point to a role of Arabidopsis MLO2, MLO6, and MLO12 in enabling defense suppression during invasion by adapted powdery mildew fungi. PMID- 28674544 TI - The Interactions between the Long Non-coding RNA NERDL and Its Target Gene Affect Wood Formation in Populus tomentosa. AB - Long non-coding RNAs (lncRNAs) are important regulatory factors for plant growth and development, but little is known about the allelic interactions of lncRNAs with mRNA in perennial plants. Here, we analyzed the interaction of the NERD (Needed for RDR2-independent DNA methylation) Populus tomentosa gene PtoNERD with its putative regulator, the lncRNA NERDL (NERD-related lncRNA), which partially overlaps with the promoter region of this gene. Expression analysis in eight tissues showed a positive correlation between NERDL and PtoNERD (r = 0.62), suggesting that the interaction of NERDL with its putative target might be involved in wood formation. We conducted association mapping in a natural population of P. tomentosa (435 unrelated individuals) to evaluate genetic variation and the interaction of the lncRNA NERDL with PtoNERD. Using additive and dominant models, we identified 30 SNPs (P < 0.01) associated with five tree growth and wood property traits. Each SNP explained 3.90-8.57% of phenotypic variance, suggesting that NERDL and its putative target play a common role in wood formation. Epistasis analysis uncovered nine SNP-SNP association pairs between NERDL and PtoNERD, with an information gain of -7.55 to 2.16%, reflecting the strong interactions between NERDL and its putative target. This analysis provides a powerful method for deciphering the genetic interactions of lncRNAs with mRNA and dissecting the complex genetic network of quantitative traits in trees. PMID- 28674545 TI - Identification of Novel Associations of Candidate Genes with Resistance to Late Blight in Solanum tuberosum Group Phureja. AB - The genetic basis of quantitative disease resistance has been studied in crops for several decades as an alternative to R gene mediated resistance. The most important disease in the potato crop is late blight, caused by the oomycete Phytophthora infestans. Quantitative disease resistance (QDR), as any other quantitative trait in plants, can be genetically mapped to understand the genetic architecture. Association mapping using DNA-based markers has been implemented in many crops to dissect quantitative traits. We used an association mapping approach with candidate genes to identify the first genes associated with quantitative resistance to late blight in Solanum tuberosum Group Phureja. Twenty nine candidate genes were selected from a set of genes that were differentially expressed during the resistance response to late blight in tetraploid European potato cultivars. The 29 genes were amplified and sequenced in 104 accessions of S. tuberosum Group Phureja from Latin America. We identified 238 SNPs in the selected genes and tested them for association with resistance to late blight. The phenotypic data were obtained under field conditions by determining the area under disease progress curve (AUDPC) in two seasons and in two locations. Two genes were associated with QDR to late blight, a potato homolog of thylakoid lumen 15 kDa protein (StTL15A) and a stem 28 kDa glycoprotein (StGP28). Key message: A first association mapping experiment was conducted in Solanum tuberosum Group Phureja germplasm, which identified among 29 candidates two genes associated with quantitative resistance to late blight. PMID- 28674546 TI - Arabidopsis Glutaredoxin S17 Contributes to Vegetative Growth, Mineral Accumulation, and Redox Balance during Iron Deficiency. AB - Iron (Fe) is an essential mineral nutrient and a metal cofactor required for many proteins and enzymes involved in the processes of DNA synthesis, respiration, and photosynthesis. Iron limitation can have detrimental effects on plant growth and development. Such effects are mediated, at least in part, through the generation of reactive oxygen species (ROS). Thus, plants have evolved a complex regulatory network to respond to conditions of iron limitations. However, the mechanisms that couple iron deficiency and oxidative stress responses are not fully understood. Here, we report the discovery that an Arabidopsis thaliana monothiol glutaredoxin S17 (AtGRXS17) plays a critical role in the plants ability to respond to iron deficiency stress and maintain redox homeostasis. In a yeast expression assay, AtGRXS17 was able to suppress the iron accumulation in yeast ScGrx3/ScGrx4 mutant cells. Genetic analysis indicated that plants with reduced AtGRXS17 expression were hypersensitive to iron deficiency and showed increased iron concentrations in mature seeds. Disruption of AtGRXS17 caused plant sensitivity to exogenous oxidants and increased ROS production under iron deficiency. Addition of reduced glutathione rescued the growth and alleviates the sensitivity of atgrxs17 mutants to iron deficiency. These findings suggest AtGRXS17 helps integrate redox homeostasis and iron deficiency responses. PMID- 28674547 TI - Integrated Transcriptomic and Metabolomic Analysis of Five Panax ginseng Cultivars Reveals the Dynamics of Ginsenoside Biosynthesis. AB - Panax ginseng C.A. Meyer is a traditional medicinal herb that produces bioactive compounds such as ginsenosides. Here, we investigated the diversity of ginsenosides and related genes among five genetically fixed inbred ginseng cultivars (Chunpoong [CP], Cheongsun [CS], Gopoong [GO], Sunhyang [SH], and Sunun [SU]). To focus on the genetic diversity related to ginsenoside biosynthesis, we utilized in vitro cultured adventitious roots from the five cultivars grown under controlled environmental conditions. PCA loading plots based on secondary metabolite composition classified the five cultivars into three groups. We selected three cultivars (CS, SH, and SU) to represent the three groups and conducted further transcriptome and gas chromatography-mass spectrometry analyses to identify genes and intermediates corresponding to the variation in ginsenosides among cultivars. We quantified ginsenoside contents from the three cultivars. SH had more than 12 times the total ginsenoside content of CS, with especially large differences in the levels of panaxadiol-type ginsenosides. The expression levels of genes encoding squalene epoxidase (SQE) and dammarenediol synthase (DDS) were also significantly lower in CS than SH and SU, which is consistent with the low levels of ginsenoside produced in this cultivar. Methyl jasmonate (MeJA) treatment increased the levels of panaxadiol-type ginsenosides up to 4-, 13-, and 31-fold in SH, SU, and CS, respectively. MeJA treatment also greatly increased the quantity of major intermediates and the expression of the underlying genes in the ginsenoside biosynthesis pathway; these intermediates included squalene, 2,3-oxidosqualene, and dammarenediol II, especially in CS, which had the lowest ginsenoside content under normal culture conditions. We conclude that SQE and DDS are the most important genetic factors for ginsenoside biosynthesis with diversity among ginseng cultivars. PMID- 28674548 TI - Photoprotective Strategies of Mediterranean Plants in Relation to Morphological Traits and Natural Environmental Pressure: A Meta-Analytical Approach. AB - Despite being a small geographic extension, Mediterranean Basin is characterized by an exceptional plant biodiversity. Adaptive responses of this biocoenosis are delineated by an unusual temporal dissociation along the year between optimal temperature for growth and water availability. This fact generates the combination of two environmental stress factors: a period of summer drought, variable in length and intensity, and the occurrence of mild to cold winters. Both abiotic factors, trigger the generation of (photo)oxidative stress and plants orchestrate an arsenal of structural, physiological, biochemical, and molecular mechanisms to withstand such environmental injuries. In the last two decades an important effort has been made to characterize the adaptive morphological and ecophysiological traits behind plant survival strategies with an eye to predict how they will respond to future climatic changes. In the present work, we have compiled data from 89 studies following a meta-analytical approach with the aim of assessing the composition and plasticity of photosynthetic pigments and low-molecular-weight antioxidants (tocopherols, glutathione, and ascorbic acid) of wild Mediterranean plant species. The influence of internal plant and leaf factors on such composition together with the stress responsiveness, were also analyzed. This approach enabled to obtain data from 73 species of the Mediterranean flora, with the genus Quercus being the most frequently studied. Main highlights of present analysis are: (i) sort of photoprotective mechanisms do not differ between Mediterranean plants and other floras but they show higher plasticity indexes; (ii) alpha-tocopherol among the antioxidants and violaxanthin-cycle pigments show the highest responsiveness to environmental factors; (iii) both winter and drought stresses induce overnight retention of de-epoxidised violaxanthin-cycle pigments; (iv) this retention correlates with depressions of Fv/Fm; and (v) contrary to what could be expected, mature leaves showed higher accumulation of hydrophilic antioxidants than young leaves, and sclerophyllous leaves higher biochemical photoprotective demand than membranous leaves. In a global climatic change scenario, the plasticity of their photoprotective mechanisms will likely benefit Mediterranean species against oceanic ones. Nevertheless, deep research of ecoregions other than the Mediterranean Basin will be needed to fully understand photoprotection strategies of this extremely biodiverse floristic biome: the Mediterranean ecosystem. PMID- 28674549 TI - Genome-Wide Association Mapping Reveals the Genetic Control Underlying Branch Angle in Rapeseed (Brassica napus L.). AB - Plant architecture is vital not only for crop yield, but also for field management, such as mechanical harvesting. The branch angle is one of the key factors determining plant architecture. With the aim of revealing the genetic control underlying branch angle in rapeseed (Brassica napus L.), the positional variation of branch angles on individual plants was evaluated, and the branch angle increased with the elevation of branch position. Furthermore, three middle branches of individual plants were selected to measure the branch angle because they exhibited the most representative phenotypic values. An association panel with 472 diverse accessions was estimated for branch angle trait in six environments and genotyped with a 60K Brassica Infinium(r) SNP array. As a result of association mapping, 46 and 38 significantly-associated loci were detected using a mixed linear model (MLM) and a multi-locus random-SNP-effect mixed linear model (MRMLM), which explained up to 62.2 and 66.2% of the cumulative phenotypic variation, respectively. Numerous highly-promising candidate genes were identified by annotating against Arabidopsis thaliana homologous, including some first found in rapeseed, such as TAC1, SGR1, SGR3, and SGR5. These findings reveal the genetic control underlying branch angle and provide insight into genetic improvements that are possible in the plant architecture of rapeseed. PMID- 28674550 TI - Enhanced Drought Stress Tolerance by the Arbuscular Mycorrhizal Symbiosis in a Drought-Sensitive Maize Cultivar Is Related to a Broader and Differential Regulation of Host Plant Aquaporins than in a Drought-Tolerant Cultivar. AB - The arbuscular mycorrhizal (AM) symbiosis has been shown to improve maize tolerance to different drought stress scenarios by regulating a wide range of host plants aquaporins. The objective of this study was to highlight the differences in aquaporin regulation by comparing the effects of the AM symbiosis on root aquaporin gene expression and plant physiology in two maize cultivars with contrasting drought sensitivity. This information would help to identify key aquaporin genes involved in the enhanced drought tolerance by the AM symbiosis. Results showed that when plants were subjected to drought stress the AM symbiosis induced a higher improvement of physiological parameters in drought-sensitive plants than in drought-tolerant plants. These include efficiency of photosystem II, membrane stability, accumulation of soluble sugars and plant biomass production. Thus, drought-sensitive plants obtained higher physiological benefit from the AM symbiosis. In addition, the genes ZmPIP1;1, ZmPIP1;3, ZmPIP1;4, ZmPIP1;6, ZmPIP2;2, ZmPIP2;4, ZmTIP1;1, and ZmTIP2;3 were down-regulated by the AM symbiosis in the drought-sensitive cultivar and only ZmTIP4;1 was up regulated. In contrast, in the drought-tolerant cultivar only three of the studied aquaporin genes (ZmPIP1;6, ZmPIP2;2, and ZmTIP4;1) were regulated by the AM symbiosis, resulting induced. Results in the drought-sensitive cultivar are in line with the hypothesis that down-regulation of aquaporins under water deprivation could be a way to minimize water loss, and the AM symbiosis could be helping the plant in this regulation. Indeed, during drought stress episodes, water conservation is critical for plant survival and productivity, and is achieved by an efficient uptake and stringently regulated water loss, in which aquaporins participate. Moreover, the broader and contrasting regulation of these aquaporins by the AM symbiosis in the drought-sensitive than the drought-tolerant cultivar suggests a role of these aquaporins in water homeostasis or in the transport of other solutes of physiological importance in both cultivars under drought stress conditions, which may be important for the AM-induced tolerance to drought stress. PMID- 28674551 TI - High miR156 Expression Is Required for Auxin-Induced Adventitious Root Formation via MxSPL26 Independent of PINs and ARFs in Malus xiaojinensis. AB - Adventitious root formation is essential for the vegetative propagation of perennial woody plants. During the juvenile-to-adult phase change mediated by the microRNA156 (miR156), the adventitious rooting ability decreases dramatically in many species, including apple rootstocks. However, the mechanism underlying how miR156 affects adventitious root formation is unclear. In the present study, we showed that in the presence of the synthetic auxin indole-3-butyric acid (IBA), semi-lignified leafy cuttings from juvenile phase (Mx-J) and rejuvenated (Mx-R) Malus xiaojinensis trees exhibited significantly higher expression of miR156, PIN FORMED1 (PIN1), PIN10, and rootless concerning crown and seminal roots-like (RTCS like) genes, thus resulting in higher adventitious rooting ability than those from adult phase (Mx-A) trees. However, the expression of SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE26 (SPL26) and some auxin response factor (ARF) gene family members were substantially higher in Mx-A than in Mx-R cuttings. The expression of NbRTCS-like but not NbPINs and NbARFs varied with miR156 expression in tobacco (Nicotiana benthamiana) plants transformed with 35S:MdMIR156a6 or 35S:MIM156 constructs. Overexpressing the miR156-resistant MxrSPL genes in tobacco confirmed the involvement of MxSPL20, MxSPL21&22, and MxSPL26 in adventitious root formation. Together, high expression of miR156 was necessary for auxin-induced adventitious root formation via MxSPL26, but independent of MxPINs and MxARFs expression in M. xiaojinensis leafy cuttings. PMID- 28674552 TI - Exogenous Silicon Attenuates Cadmium-Induced Oxidative Stress in Brassica napus L. by Modulating AsA-GSH Pathway and Glyoxalase System. AB - Cadmium (Cd) brings a devastating health hazard to human being as a serious consequence of agricultural and environmental contamination. We demonstrated the protective effect of silicon (Si) on cadmium (Cd)-stressed rapeseed (Brassica napus L. cv. BINA Sharisha 3) plants through regulation of antioxidant defense and glyoxalase systems. Twelve-day-old seedlings were exposed to Cd stress (0.5 and 1.0 mM CdCl2) separately and in combination with Si (SiO2, 1.0 mM) for 2 days. Cadmium toxicity was evident by an obvious oxidative stress through sharp increases in H2O2 content and lipid peroxidation (malondialdehyde, MDA content), and visible sign of superoxide and H2O2. Cadmium stress also decreased the content of ascorbate (AsA) and glutathione (GSH) as well as their redox pool. The activities of monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and catalase (CAT) were decreased by Cd while ascorbate peroxidase (APX) and glutathione S-transferase (GST) activities were increased. The enzymes of glyoxalase system (glyoxalase I, Gly I and glyoxalase II, Gly II) were also inefficient under Cd stress. However, exogenous application of Si in Cd treated seedlings reduced H2O2 and MDA contents and improved antioxidant defense mechanism through increasing the AsA and GSH pools and activities of AsA-GSH cycle (APX, MDHAR, DHAR and GR) and glyoxalase system (Gly I and Gly II) enzymes and CAT. Thus Si reduced oxidative damage in plants to make more tolerant under Cd stress through augmentation of different antioxidant components and methylglyoxal detoxification system. PMID- 28674553 TI - Expression of Genes for Si Uptake, Accumulation, and Correlation of Si with Other Elements in Ionome of Maize Kernel. AB - The mineral composition of cells, tissues, and organs is decisive for the functioning of the organisms, and is at the same time an indicator for understanding of physiological processes. We measured the composition of the ionome in the different tissues of maize kernels by element microanalysis, with special emphasis on silicon (Si). We therefore also measured the expression levels of the Si transporter genes ZmLsi1, ZmLsi2 and ZmLsi6, responsible for Si uptake and accumulation. Two weeks after pollination ZmLsi1 and ZmLsi6 genes were expressed, and expression continued until the final developmental stage of the kernels, while ZmLsi2 was not expressed. These results suggest that exclusively ZmLsi1 and ZmLsi6 are responsible for Si transport in various stages of kernel development. Expression level of ZmLsi genes was consistent with Si accumulation within kernel tissues. Silicon was mainly accumulated in pericarp and embryo proper and the lowest Si content was detected in soft endosperm and the scutellum. Correlation linkages between the distribution of Si and some other elements (macroelements Mg, P, S, N, P, and Ca and microelements Cl, Zn, and Fe) were found. The relation of Si with Mg was detected in all kernel tissues. The Si linkage with other elements was rather specific and found only in certain kernel tissues of maize. These relations may have effect on nutrient uptake and accumulation. PMID- 28674554 TI - Free fatty acids and cardiovascular outcome: a Chinese cohort study on stable coronary artery disease. PMID- 28674556 TI - EFS: an ensemble feature selection tool implemented as R-package and web application. AB - BACKGROUND: Feature selection methods aim at identifying a subset of features that improve the prediction performance of subsequent classification models and thereby also simplify their interpretability. Preceding studies demonstrated that single feature selection methods can have specific biases, whereas an ensemble feature selection has the advantage to alleviate and compensate for these biases. RESULTS: The software EFS (Ensemble Feature Selection) makes use of multiple feature selection methods and combines their normalized outputs to a quantitative ensemble importance. Currently, eight different feature selection methods have been integrated in EFS, which can be used separately or combined in an ensemble. CONCLUSION: EFS identifies relevant features while compensating specific biases of single methods due to an ensemble approach. Thereby, EFS can improve the prediction accuracy and interpretability in subsequent binary classification models. AVAILABILITY: EFS can be downloaded as an R-package from CRAN or used via a web application at http://EFS.heiderlab.de. PMID- 28674555 TI - A design-build-test cycle using modeling and experiments reveals interdependencies between upper glycolysis and xylose uptake in recombinant S. cerevisiae and improves predictive capabilities of large-scale kinetic models. AB - BACKGROUND: Recent advancements in omics measurement technologies have led to an ever-increasing amount of available experimental data that necessitate systems oriented methodologies for efficient and systematic integration of data into consistent large-scale kinetic models. These models can help us to uncover new insights into cellular physiology and also to assist in the rational design of bioreactor or fermentation processes. Optimization and Risk Analysis of Complex Living Entities (ORACLE) framework for the construction of large-scale kinetic models can be used as guidance for formulating alternative metabolic engineering strategies. RESULTS: We used ORACLE in a metabolic engineering problem: improvement of the xylose uptake rate during mixed glucose-xylose consumption in a recombinant Saccharomyces cerevisiae strain. Using the data from bioreactor fermentations, we characterized network flux and concentration profiles representing possible physiological states of the analyzed strain. We then identified enzymes that could lead to improved flux through xylose transporters (XTR). For some of the identified enzymes, including hexokinase (HXK), we could not deduce if their control over XTR was positive or negative. We thus performed a follow-up experiment, and we found out that HXK2 deletion improves xylose uptake rate. The data from the performed experiments were then used to prune the kinetic models, and the predictions of the pruned population of kinetic models were in agreement with the experimental data collected on the HXK2-deficient S. cerevisiae strain. CONCLUSIONS: We present a design-build-test cycle composed of modeling efforts and experiments with a glucose-xylose co-utilizing recombinant S. cerevisiae and its HXK2-deficient mutant that allowed us to uncover interdependencies between upper glycolysis and xylose uptake pathway. Through this cycle, we also obtained kinetic models with improved prediction capabilities. The present study demonstrates the potential of integrated "modeling and experiments" systems biology approaches that can be applied for diverse applications ranging from biotechnology to drug discovery. PMID- 28674557 TI - Metabolic profiling of type 1 diabetes mellitus in children and adolescents: a case-control study. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) is one of the most common pediatric diseases and its incidence is rising in many countries. Recently, it has been shown that metabolites other than glucose play an important role in insulin deficiency and the development of diabetes. The aim of our study was to look for discriminating variation in the concentrations of small-molecule metabolites in the plasma of T1DM children as compared to non-diabetic matched controls using proton nuclear magnetic resonance (1H-NMR)-based metabolomics. METHODS: A cross sectional study was set-up to examine the metabolic profile in fasting plasma samples from seven children with poorly controlled T1DM and seven non-diabetic controls aged 8-18 years, and matched for gender, age and BMI-SDS. The obtained plasma 1H-NMR spectra were rationally divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used as statistical variables to construct (train) a classification model in discriminating between T1DM patients and controls. RESULTS: The total amount of variation explained by the model between the groups is 81.0% [R2Y(cum)] and within the groups is 75.8% [R2X(cum)]. The predictive ability of the model [Q2(cum)] obtained by cross-validation is 50.7%, indicating that the discrimination between the groups on the basis of the metabolic phenotype is valid. Besides the expected higher concentration of glucose, the relative concentrations of lipids (triglycerides, phospholipids and cholinated phospholipids) are clearly lower in the plasma of T1DM patients as compared to controls. Also the concentrations of the amino acids serine, tryptophan and cysteine are slightly decreased. CONCLUSIONS: The present study demonstrates that metabolic profiling of plasma by 1H-NMR spectroscopy allows to discriminate between T1DM patients and controls. The metabolites that significantly differ between both groups might point to disturbances in biochemical pathways including (1) choline deficiency, (2) increased gluconeogenesis, and (3) glomerular hyperfiltration. Although the sample size of this study is still somewhat limited and a validation should be performed, the proof of principle looks promising and justifies a deeper investigation of the diagnostic possibilities of 1H-NMR metabolomics in follow-up studies. Trial registration NCT03014908. Registered 06/01/2017. Retrospectively registered. PMID- 28674558 TI - Analysis of Stable Isotope Assisted Metabolomics Data Acquired by High Resolution Mass Spectrometry. AB - Stable isotope assisted metabolomics (SIAM) uses stable isotope tracers to support studies of biochemical mechanisms. We report a suite of data analysis algorithms for automatic analysis of SIAM data acquired on a high resolution mass spectrometer. To increase the accuracy of isotopologue assignment, metabolites detected in the unlabeled samples were used as reference metabolites to generate possible isotopologue candidates for analysis of peaks detected in the labeled samples. An iterative linear regression model was developed to deconvolute the overlapping isotopic peaks of isotopologues present in a full MS spectrum, where the threshold for the weight factor was determined by a simulation study assuming different levels of Gaussian white noise contamination. A normalization method enabling isotope ratio-based normalization was implemented to study the difference of isotopologue abundance distribution between sample groups. The developed method can analyze SIAM data acquired by direct infusion MS and LC-MS, and can handle metabolite tracers containing different tracer elements. Analysis of SIAM data acquired from mixtures of known compounds showed that the developed algorithms accurately identify metabolites and quantify stable isotope enrichment. Application of SIAM data acquired from a biological study further demonstrated the effectiveness and accuracy of the developed method for analysis of complex samples. PMID- 28674559 TI - [Resistant phenotypes of Escherichia coli strains responsible for urinary tract infection in the laboratory of the University Hospital Joseph Raseta Befelatanana, Antananarivo]. AB - INTRODUCTION: Urinary tract infection caused by Escherichia coli frequently occurs in the hospital environment. This study aims to describe resistant phenotypes of Escherichia coli strains to monitor their occurrence. METHODS: We conducted a descriptive retrospective study of 102 Escherchia coli strains responsible for urinary tract infection in the laboratory of the University Hospital Joseph Raseta Befelatanana, Antananarivo from January 2014 to October 2016. RESULTS: Beta-lactam antibiotic resistance screening identified high-level penicillinases 50% (n=51), Escherichia coli producing extended-spectrum beta lactamases (ESBLs) 22.5% (n=23), high-level cephalosporinases 14.7% (n=15), penicillinases low level 5.9% (n=6), wild type strains 5.9% (n=6) and a strain ofEscherichia coli emerging strain high-level resistance. Aminoglycosides resistance was identified in 58 (56.9%) wild type phenotype, 29 (28.4%) strains sensitive to amikacin and 15 (14.7%) resistant to all aminoglycosides. Fluoroquinolones resistance was identified in 52 (51%) wild type strains, 9 (8.8%) strains sensitive to ciprofloxacin and 41 (40.2%) resistant to all fluoroquinolones. Women (25, 7%) (p= 0.25, NS), patients more than 60 years (38.7%) (p=0.02), patients hospitalized in the Department of Nephrology (53.8%) (p=0.04), with urinary disorder and kidney disease (29, 7%) (p= 0.2, NS) were the most affected by E-ESBL. CONCLUSION: Based on high multidrug resistance in Escherichia coli strains guidelines for the empirical treatment of urinary tract infections need to be revised. PMID- 28674560 TI - [Management of chronic hemodialysis patients with anemia: case study conducted in the Department of Nephrology and Hemodialysis at the University Hospital Point G in Mali]. AB - INTRODUCTION: Anemia is a frequent complication of Chronic Kidney Disease CKD commonly found in chronic haemodialysis patients. Patients management is mainly based on erythropoietin administration and iron supplementation. This study aimed to evaluate the management of chronic hemodialysis patients with anemia in the Department of Nephrology and Hemodialysis at the University Hospital Point G in Mali. METHODS: We conducted a cross-sectional study from 1 to 31 August 2016. RESULTS: 63 patients out of a total of 174 participants were selected, 34 men and 29 women with a sex-ratio of 1.17 in favor of men. The average age of patients was 48,79 years +/-11.59, the average duration of hemodialysis treatment time was 3,77years+/-2.6. Hospitalization rate for anemia in our dialysis patients was 84,12%. 92.1% of patients required blood transfusion, with an annual average of 5,81 blood bags +/-5.91. 87.3% of cases required iron supplementation. Mean ferritin concentration and TSC were 1245 ng/ml+/-629,52 and 46,16%+/-19.12 respectively. Occasional administration of EPO doses not exceeding the 4000IU was reported by 79.4% of patients. The main difficulty in using EPO was its cost (74.6%). HCV infection was found in 60.1% of patients who were assessed. CONCLUSION: The management of chronic dialysis patients with anemia should be integrated into the framework of the national health policy. PMID- 28674561 TI - [A rare cause of talalgia]. AB - Talalgie is one of the most common symptoms involving the foot. Intra-bone lipoma is one of the most rare bone tumors of the calcaneus. We report the case of a patient presenting with intermittent and spontaneous chronic heel pain. Clinical and radiological examinations confirmed the diagnosis of lipoma of the calcaneus. This study aimed to educate clinicians about the existence of this rare lesion. PMID- 28674562 TI - [Ameloblastoma of the maxillary sinus treated with radiation therapy]. AB - Ameloblastoma is a benign aggressive odontogenic tumor which requires early diagnosis and appropriate treatment. It commonly affects the mandible and radical surgery is the gold standard treatment. We report the case of a patient with ameloblastoma in extremely advanced phase affecting the maxillary sinus who was treated with intensity modulated conformal radiation therapy. Patient's evolution was marked by complete remission maintained after 24 months follow-up. Maxillary ameloblastoma is not well documented in the literature. It is usually diagnosed at the later stage when optimal surgery cannot be performed. This case study aimed to demonstrate that radiation therapy is a real therapeutic alternative in the treatment of advanced and inoperable forms of ameloblastoma. PMID- 28674563 TI - [Type I diabetes mellitus in children less than 5 years: case study conducted at the university clinics of Lubumbashi and review of the literature]. AB - Worldwide trends in type I diabetes mellitus (T1DM) are changing. It is increasingly affecting children of less than 5 years. The smaller the child, the greater the complexity of patient management. A delay in diagnosis or poor treatment can cause sudden death due to acute severe complications. It would be worth looking at this, raising public awareness, adapting our healthcare system to face this epidemic of noncommunicable diseases in Africa and establishing registers to analyze the epidemiological characteristics of type I diabetes mellitus in our environment. The aim of our study was to highlight the seriousness of type I diabetes mellitus occurrence at an early stage in children in our environment. PMID- 28674564 TI - [Lumbosciatica revealing intramedullary ependymoma]. PMID- 28674565 TI - [Anorectal adenocarcinoma after Infliximab treatment for fistulizing Crohn's disease]. PMID- 28674566 TI - Pseudotumoral form of granulomatosis with polyangiitis. PMID- 28674567 TI - [Biological disturbances affecting people with malaria: about thirty cases]. PMID- 28674568 TI - [Severe acute pancreatitis during pregnancy among black African women: about a case]. AB - Acute pancreatitis is rare during pregnancy. It is associated with high maternofoetal mortality. It is mainly caused by biliary lithiasis but, in many cases, the cause of acute pancreatitis is undetermined. We here report the case of a 37-year old patient presenting with acute pancreatitis revealed by acute febrile bowel obstruction at 29 weeks of amenorrhea. The diagnosis was made during surgery. The patient had a miscarriage in the postoperative period. She died on the 8th postoperative day. PMID- 28674569 TI - [Glory morning syndrome]. PMID- 28674570 TI - Paediatric otogenic tetanus: an evidence of poor immunization in Nigeria. AB - Suppurative otitis media is a common childhood infection that predisposes to otogenic tetanus. Tetanus is a vaccine preventable disease that is associated with high cost of care and mortality. This study highlights reasons for otogenic tetanus in Nigerian children and way of reducing the menace. This is a 5-year retrospective review of all patients managed for otogenic tetanus in at the Department of Otorhinolaryngology, University College Hospital, Ibadan. The data collected include demographic, clinical presentations, tetanus immunisation history, and duration of hospital admission, and management- outcome. There were 23 patients comprising of 13(56.5 %) males and 10 (43.5%) females, male to female ratio was 1.3:1. The age ranged between 11 months and12 years (mean age 3.4 years +/- 2.1). All the patients presented with discharging ear, trismus and spasms. The onset of symptoms prior hospital presentation ranged between 2 - 11 days (mean 3.0 days +/- 1.3). Only 12(52.1%) patients had complete childhood tetanus immunisation, 6(26.1) % had no tetanus immunisation and no other childhood immunisation, while 5(21.7%) had partial tetanus immunisation. The discharging ears were managed by self-medication and other harmful health practices. The hospital admission ranged from 20 days - 41days (average of 23days) and there were 3(13.0 %) death. Tetanus immunization was not received because of; non- availability of the vaccine at health centers, lack of health facility in communities, fear of complications from immunization, poor awareness of the immunization programme. Tetanus, an immunisable disease, is still a major problem in Nigeria. PMID- 28674571 TI - [Endobronchial sarcoidosis]. PMID- 28674572 TI - Upward closed talocrural dislocation without fracture. PMID- 28674573 TI - Current problematic and emergence of carbapenemase-producing bacteria: a brief report from a Libyan hospital. AB - A collection of 94 Gram-negative bacteria isolates, showing different antimicrobial resistance phenotypes including to the carbapenem classes was investigated. Strains were originated form clinical sources from a single hospital in Tripoli, Libya during 2015 and were identified based on cultural and phenotypic characteristics, and fully characterized by the VITEK automated system. Forty-eight percent (48%) of the collection was identified as Acinetobacter baumannii, 50% Klebsiella pneumoniae and 2% Escherichia coli. Resistance to the carbapenem classes was reported in 96% of the A. baumannii strains and 94% of the K. pneumonia strains. Seventy-eight percent (78%) of the isolates showed different multidrug-resistant (MDR) phenotypes, of which K. pneumoniae expressing the highest rates of MDRs(i.e. 91%). Emergence of resistance to carbapenems in the Gram-negative bacteria is a challenging global problem, particularly for Africa. Surveillance of these pathogens and appropriate actions are urgently required in Libyan healthcare settings. PMID- 28674574 TI - Band ligation for a gastroesophageal junction Dieulafoy's lesion. PMID- 28674576 TI - [Imaging findings of degenerative spondyloptosis in young subject]. PMID- 28674575 TI - [Study of maternal and perinatal prognosis for vaginal delivery in adolescent girls in Lubumbashi, Democratic Republic of the Congo]. PMID- 28674577 TI - Ascaris lumbricoides roundworms visible on a plain -non-contrast- abdominal x-ray in a patient presenting with gastric outlet obstruction. PMID- 28674578 TI - Ring enhancing lesions in the brain of an HIV infected patient: a diagnostic challenge. PMID- 28674579 TI - Skeletal fluorosis: a rare cause of diffuse bone condensation. PMID- 28674580 TI - [Mucinous tubular and spindle cell carcinoma: a rare renal tumor]. PMID- 28674581 TI - Sunbeds and skin cancer risk: quantifying a baseline estimate of sunbed facilities in South Africa prior to implementation of sunbed regulations. AB - INTRODUCTION: In 2009, ultraviolet-emitting tanning devices, i.e. sunbeds and tanning booths, were officially classified as carcinogenic to human health (Group 1) by the International Agency for Research on Cancer. METHODS: Here, we aim to estimate South African-based facilities with indoor tanning services advertised in the printed Yellow Pages and online in two directories. Printed Yellow Pages telephone directory beauty salon facilities listings (2010-14) for all provinces were examined and those mentioning "sunbed" and/or "tanning bed" recorded. Beauty/spa facilities were also identified using two sunbed listing webpages. RESULTS: A total of 40 web-advertised facilities had a sunbed. Beauty facilities in the Yellow Pages specifically mentioning sunbeds declined by 62% between 2010 (n=53) and 2014 (n=20). Gauteng had the highest number of facilities (n=25) with a sunbed. Facilities with sunbeds exist in South Africa, as evidenced by the Yellow Pages and web-advertised data, but their true prevalence remains largely unknown. It is likely that online and walk-by advertising is increasingly more common than print. CONCLUSION: Given that sunbeds may likely soon become regulated in South Africa, further research is needed to better quantify sunbed provision, determine advice provided by facility operators to new users, investigate whether age restrictions or limits exist for sunbed use, and describe typical patterns of sunbed use in South Africa. PMID- 28674582 TI - Intramedullary spinal cord metastasis from laryngeal carcinoma: case report and review of literature. AB - Laryngeal cancer metastases are relatively rare and mainly affect the lung. The medullary localization remains exceptional. We report the case of a patient followed for operated laryngeal cancer and whose oncologic control revealed a medullary localization. A patient followed for squamous cell carcinoma of the larynx, treated in 2010 by a partial surgery whose endoscopic control at 5 years revealed the presence of right arytenoid edema without suspicious lesions, multiple biopsies were made and which returned negative. A month later, the patient presented a rebel cervical spine pain and a feeling of heaviness of the upper limbs, for which a radiological assessment was done finally objectifying a right hypopharyngeal process and a suspicious right internal jugular lymphadenopathy (biopsy confirmed the squamous type), as well as an intramedullary metastasis. This case is an illustration of an exceptional evolution of this type of cancer and a are metastatic localization difficult to highlight, which leads us to ask the question on the need of simultaneous and systematic radiological and endoscopic control treatment for operated laryngeal cancer. PMID- 28674583 TI - [Scrotal fistulas revealing mucinous adenocarcinoma of the scrotum: about a case]. AB - Scrotales fistulas are rare and often represent secondary lesions of tuberculosis. Mucinous adenocarcinomas are tumors containing at least 50% of extracellular mucus. They occur most commonly in the rectosigmoid; scrotal location is rare. We report the case of a 54-year old patient, with no particular past medical history, with secondary mucinous adenocarcinoma of the scrotum revealed by scrotal fistulas. The patient had suffered from recurrent scrotal fistulas for two years, with no other associated signs. Clinical examination showed multiple scrotal fistulas with discharge of thick pus. Rectal examination was normal. Urological examinations (IVU, UCRM, cystoscopy, ...) were normal, the assessment of infectious diseases as well as the detection of BK virus in urine and sputum were negative. Biopsy of sample of scrotal tissue was in favor of moderately differentiated mucinous adenocarcinoma. Immunohistochemical examination was in favor of primary colorectal cancer. Patient's evolution was marked by the occurrence of complex anal fistulas, which appeared on MRI as active, supplying several pelvic peritoneal collections resulting in fleshy buds. There is no consensus on the therapeutic approach due to the rarity of this cancer. Surgical resection is the treatment of choice for this disease. Preoperative chemotherapy and radiation therapy are recommended for this type of cancer, but their role is not well established. The patient underwent primary neoadjuvant chemotherapy and radiation therapy, before abdominoperineal excision. PMID- 28674584 TI - Mesenteric cyst in infancy: presentation and management. AB - Mesenteric cysts are documented as a rare entity in pediatric population. They are considered as benign intra-abdominal tumors with an unknown etiology. Symptoms are not specific and knowledge of such condition is essential in order to establish a proper management. We report three pediatrics cases of mesenteric cysts managed between 2000 and 2009 in the pediatric surgery Department of Monastir College Hospital. We described the clinical, radiological and operative findings. Two males and a female were managed (age range: 10 days-5years, mean age: 6,3years). Two patients were presented with an intestinal obstruction. A preoperative diagnosis was made basing on imaging. Thus, abdominal ultrasonography was performed in all of our reported cases and showed a cystic mass in all cases. The cystic nature of the mass, its margins and its extension were better described on tomographic images. The mesenteric cyst was completely and successfully removed in all cases. The histopathological report confirmed the diagnosis and showed a multiloculated cyst with columnar mesothelial lining, without any defined muscular layer or cellular atypia and without any evidence of malignancy. The children were evaluated post-operatively with a mean follow-up of 2 years and a half. No recurrence was noted in our patients during the follow-up period. It is known that clinical features are not specific of such anomaly but once the diagnosis is made, the complete surgical removal of the cyst remains the treatment of choice with excellent outcomes. PMID- 28674586 TI - [Epidemiological, clinical aspects and management of urethral stenosis in adult patients in a District Hospital in Ngaoundere, Cameroon]. AB - INTRODUCTION: The aim was to determine the epidemiological, clinical aspects and the management of these patients in Ngaoundere Protestant Hospital (HPN). METHODS: We conducted a retrospective review of complete medical records of patients hospitalized for urethral stenosis in the Department of Urology at the Protestant Hospital of Ngaoundere over a one-year period (January 2013 to January 2014). RESULTS: Out of 69 registered medical records, a total of 57 patients files (all male) were identified for review. The average age was 52.6 (19 -85 years). The most represented age group was 41-60 years. Urethral stenosis accounted for 0.6% of consultations, 11.36 % of surgical hospitalizations and 6.96% of surgical procedures. Dysuria (70, 17%) was the main reason for consultation. Etiologies included infections (52,63%), traumas (26.32%) and iatrogenic problems (21.05%). All patients underwent CBEU which allowed to isolate gonococci (14,03%) and Escherichia coli (21.05%), the remainder of the urine culture was sterile (64.91%). 28 patients (49.12%) underwent retrograde uretrocystography (RUC), of whom 26 with anterior stenosis (92,85%). Internal endoscopic urethrotomy (IEU) was the most common surgical procedure (58%). Stenosis mainly occurred at the level of the bulbar and peno-bulbar regions. The rate of healing was 87,73% vs 12.27% of recurrences. CONCLUSION: Urethral stenosis is frequent in the Protestant Hospital of Ngaoundere; patients requiring medical consultations are often in complex medical conditions. Internal endoscopic urethrotomy has shown plausible results. PMID- 28674585 TI - [A rare case of spontaneous massive pneumoperitoneum]. AB - Spontaneous pneumoperitoneum is a rare disorder characterized by the presence of free air in the peritoneal cavity, in the absence of any obvious cause. We here report the case of a patient with massive pneumoperitoneum, detected by scan, in whom clinical, biological, radiological and laparoscopic examinations showed no detectable etiology. This case study describes a clinical entity rarely seen in our practice constituting a real diagnostic trap; accurate knowledge about the disease would avoid unnecessary and especially aggressive laparotomies revealing no signs of perforation. The laparoscopy seems to be a minimally invasive surgical procedure for doubtful cases allowing visual diagnosis by eliminating hollow organ perforation. PMID- 28674587 TI - Mycobacterium tuberculosis endocarditis in native valves. PMID- 28674589 TI - [Hidradenoma papilliferum]. PMID- 28674588 TI - Four years into the Indian ocean field epidemiology training programme. AB - INTRODUCTION: Following the 2005-6 chikungunya outbreak, a project to strengthen regional Public Health preparedness in the Indian Ocean was implemented. It includes the Comoros, Madagascar, Mauritius, Reunion (France) and Seychelles. A Field Epidemiology Training Programme (FETP-OI) was started in 2011 to develop a pool of well-trained intervention epidemiologists. METHODS: The FETP-OI consists of two years of supervised, learning-by-doing, on-the-job training at national sites involved in disease surveillance and response. It includes work placements at the Madagascar Pasteur Institute and the French regional epidemiology unit in Reunion and up to three training courses per year. Training objectives include epidemiological surveillance, outbreak investigations, research studies, scientific communication and transfer of competencies. RESULTS: In four years, two cohorts of in total 15 fellows originating from four countries followed the FETP-OI. They led 42 surveillance projects (71% routine management, 14% evaluations, 12% setup, 3% other) and investigated 36 outbreak alerts, 58% of them in Madagascar; most investigations (72%) concerned foodborne pathogens, plague or malaria. Fellows performed 18 studies (44% descriptive analyses, 22% disease risk factors, and 34% on other subjects), and presented results during regional and international conferences through 26 oral and 15 poster presentations. Four articles were published in regional Public Health bulletins and several scientific manuscripts are in process. CONCLUSION: The FETP-OI has created a regional force of intervention consisting of field epidemiologists and trained supervisors using the same technical language and epidemiological methods. The third cohort is now ongoing. Technically and financially sustainable FETP-OI projects help addressing public health priorities of the Indian Ocean. PMID- 28674590 TI - [Proteus mirabilis septic arthritis]. AB - Acute septic arthritis is rare. It is associated with poor prognosis in terms of mortality and morbidity. We report the case of a 61-year old patient with spontaneous Proteus mirabilis septic arthritis. He suffered from complicated diabetes associated with positive blood cultures and synovial fluid cultures. Patient's evolution was favorable thanks to early diagnosis and initiation of adequate antibiotic therapy. Proteus mirabilis septic arthritis is rare. On that basis we conducted a literature review of cases of Proteus mirabilis pyogenic arthritis to highlight the risk factors, pathogenesis, treatment and evolution of these diseases. Diagnosis is commonly based on microbiological analysis, early articular puncture biopsy is performed before the initiation of antibiotic treatment, direct examination, culture and antibiogram which are useful as guidance for antibiotic therapy. Septic arthritis is a diagnostic and therapeutic emergency; early management of this disease allows total healing without after effects. PMID- 28674591 TI - Adult-type granulosa cell tumor of the testis: report of a case and review of literature. AB - Granulosa cell tumors is classified into juvenile and adult types and comprise less than 5% of ovarian tumors in women and are much rarer in men which only 45 have been previously reported. We report here a 40-year young man with a left testicular adult type granulosa cell tumor. The tumor measured 5.5X5X4cm; Immunohistochemical stains showed the tumor diffusely positive for inhibin and vimentin. Post operative CT scans shows a lomboaortic lymphnodes treated by four cycles of chemotherapy type BEP (bleomycin, etoposide, cisplatin). The thoraco abdominal CT scans post chemotherapy shows the disappearance of the right testicular nodule and the lomboaortic lymphnodes. 2 years after treatment, the patient is alive and well with no signs of recurrence. Our report highlights one more case of this very rare tumor of the testis, which is quite problematic In terms of prognosis and management, and for this reason seems to have attracted the interest of many researchers recently. PMID- 28674593 TI - [Focal myositis of the thigh]. PMID- 28674592 TI - [Use of modern contraceptive methods in the Democratic Republic of the Congo: prevalence and barriers in the health zone of Dibindi, Mbuji-Mayi]. AB - INTRODUCTION: This study aimed to determine modern contraceptive prevalence and the barriers to using modern contraceptive methods among the couples in Dibindi health zone, Mbuji-Mayi, in the Democratic Republic of the Congo. METHODS: We conducted a cross-sectional descriptive study from May to June 2015. Nonpregnant married women aged 15-49 years old at the time of the investigation, living in Dibindi health zone for two years and having freely consented to participate in the study were included. Data were collected by open-ended interview of these women. Modern contraceptive prevalence was referred to women who were currently using, at the time of the investigation, modern contraceptives. The comparison between proportions was performed at the significance threshold of 5%. Bonferroni's test was used to compare, two by two, the proportions of barriers to using modern contraceptive methods. RESULTS: Modern contraceptive prevalence in Dibindi was 18.4% in 2015. It was low with regard to family planning services available in this health zone. Several women refused to use modern contraceptive methods despite available information because of their desire for motherhood, religious prohibition, opposition on the part of their husband and fear of side effects. CONCLUSION: Sufficient client-centered or couple-centered information and family planning information should be strengthened in order to eliminate the false beliefs and to increase the use of modern contraceptive methods. PMID- 28674594 TI - Physical Activity and Physical Fitness in Pediatric Obesity: What are the First Steps for Clinicians? Expert Conclusion from the 2016 ECOG Workshop. AB - One of the main aims of the European Childhood Obesity Group (ECOG) is to assist healthcare workers in delivering evidence-based assessment and treatment of childhood obesity. Every year the ECOG Congress includes working groups whose objective is to highlight concerns faced by clinicians and practitioners who work in the field of pediatric obesity. This year, a working group was devoted to the assessment of physical activity and physical fitness in this population. The present commentary attempts to summarize the main themes identified by practitioners during these workshops in order to provide the basic and essential first steps required to address physical activity and fitness in children with obesity. PMID- 28674595 TI - Rollers Versus Trainers: 10-Km Time Trial. AB - The primary aim of this investigation was to determine which cycling training device, Rollers or Trainers, was most effective in improving 10-km time trial. Eight male and 6 female volunteers (N = 14; age = 23.6 +/- 4.6 yrs; height = 172.7 +/- 9.9 cm; body mass = 68.4 +/- 10.4 kg; % body fat = 16.9 +/- 7.7; VO2max = 61.0 +/- 9.4 ml.kg-1.min-1) provided informed consent prior to participation. Participants performed a10-km time trial at baseline and were then randomly assigned into one of three groups: Rollers (R), Trainers (T), or Control (C). Participants assigned to the R or T groups attended 24 supervised workout sessions throughout an 8-wk period (F: 3 days/week; I: 65-80% HRmax; D: 40 min; M: R or T). There were no significant differences in baseline 10-km time trial between R, T, and C groups [F(2,12) = 0.34, p = .72]. There was a significant difference in 10-km time trial improvement between groups post-assessment when controlling for baseline values (F = 17.04, p <.001). R participants improved by 20.4s [t(4) = 4.86, p = .008] and T participants improved by 12.8s [t(4) = 4.57, p = .01], while there was no significant improvement for subjects in C. Participants using R and T displayed significant decrements in time with respect to the 10-km time trial. However, R had a greater improvement in 10-km time trial when compared to T. PMID- 28674596 TI - Effects of Nasal or Oral Breathing on Anaerobic Power Output and Metabolic Responses. AB - Nasal and oral exclusive breathing modes have benefits and drawbacks during submaximal exercise. It is unknown whether these responses would extend to anaerobic work performed at high intensity. Nine individuals (males N = 7, females N = 2) performed a standard Wingate Anaerobic cycle test on a cycle ergometer under nose (N) and mouth (M) only respiratory conditions, performed in a counterbalanced order. A 2 (condition: nose, mouth) * 6 (time: 0-5 sec, 5-10 sec, 10-15 sec, 15-20 sec, 20-25 sec, 25-30 sec) repeated measures ANOVA was used to analyze the data with significance accepted at the p<0.05 level. No differences between breathing mode were observed for any power output or performance measures associated with the Wingate Anaerobic cycle test. Respiratory exchange ratio (RER) was significantly higher in the oral respiration condition from 10 seconds to 25 seconds during the test (p<0.05). On the other hand, heart rate (HR) in the nasal condition was significantly greater during the final two time intervals (p<0.05). Nasal breathing was effective in reducing hyperventilation as RER remained below 1.0. However, elevated HR with nasal breathing indicates increased cardiovascular stress associated with this mode. As breathing mode does not affect power output or performance measures during completion of a high-intensity anaerobic test, preference of the participant should be the determining factor if a choice is available. PMID- 28674597 TI - Sleep-hygiene Education improves Sleep Indices in Elite Female Athletes. AB - The importance of sleep in providing psychophysiological recovery in elite athletes is often overlooked. In other populations (eg shift workers and adolescent students), sleep hygiene education may serve to acutely improve sleep indices. However, this is yet to be examined in an elite athlete setting. Therefore, the aim of the current study was to evaluate the effect of a sleep hygiene education session on sleep indices in elite athletes. The study involved 26 elite female netball athletes performing one week of baseline sleep monitoring (PRE), followed by a sleep hygiene education session and a further week of sleep monitoring (POST) in a single group, pre- post design. The sleep hygiene education session focused on providing information on the importance of sleep for athletes and practical tips to improve sleep quality and quantity. Sleep monitoring was performed using wrist actigraphy to assess total sleep time (TST), sleep efficiency (SE%), total time in bed (TTB), sleep latency (SL), wake episodes per night (WE), sleep onset variance (SOV), wake variance (WV) wake episode duration (WED), sleep onset time (SOT), and wake time (WT). There was a significant improvement in TST (mean +/- SD; 22.3 +/- 39.9 minutes, p=0.01) PRE to POST sleep hygiene education session, the difference associated with a small effect (ES: 0.39). A significant improvement PRE to POST was found for WV (p=0.03), and for WED (p=0.03). There were no significant differences for SE%, SL, TTB, WE, SOV, SOT, WT. The current study reports that a sleep hygiene education session is effective in improving sleep quantity in elite female athletes in an acute setting. PMID- 28674598 TI - Cortisol and Alpha-amylase changes during an Ultra-Running Event. AB - Elevated stress hormone concentrations can positively affect an athlete's overall performance during a competition, and in many cases, are necessary to be able to perform exercise. During extreme exercise, the body's ability to utilize energy efficiently can affect an athlete's performance. Elevated hormonal concentrations can have many benefits in regards to an athlete's overall performance during a competition. The purpose of this study was to examine the effects of long distance running, such as seen during an ultra-running event (distances beyond 26.2 miles), on the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis production of cortisol (CORT) as compared to autonomic nervous system production of salivary alpha-amylase (AA). Despite the well-known effects of exercise on CORT and AA response, it is unclear what effect running beyond the marathon distance has on these levels. This study investigates what effect long duration cardio exercise, such as running up to 100K (kilometers) distance, has on the neuroendocrine system, by means of saliva samples provided by participants signed up for an ultra-marathon event. The findings of this study show that the autonomic nervous system may present a response signal during physical stress that is independent of the HPA axis response. At distances beyond the marathon length, the production of CORT and AA was found to be suppressed for athletes, which could help them in their continued performance. Furthermore, this study recognizes a difference in the overall male and female response to stress in regards to CORT and AA production. PMID- 28674599 TI - The Effect of Betaine on Nitrate and Cardiovascular Response to Exercise. AB - Betaine (BT) supplementation improves selected markers of physical performance, however, the mechanism(s) by which this change occurs remains largely unknown. Some speculate that BT may increase circulating nitrate concentrations, improving physical performance by augmentation of endothelial nitric oxide production. The purpose of this study was to investigate the effects of acute BT supplementation and exercise on plasma nitrate levels and related cardiovascular response (CVR). Placebo and BT trials were administered in a cross-over, randomized, double blind, and counterbalanced fashion. Ten healthy college-aged volunteers consumed either a 250 ml placebo (carbohydrate-electrolyte beverage, CHO) or 250 ml CHO + 2.5 g BT. Subjects rested for 45 min, then cycled for 30 min at 60 rpm with a resistance of 2.5% body weight. Blood was drawn before and 45 min after BT supplementation, and immediately post exercise to assess plasma nitrate levels. Repeated measures ANOVA across treatments and times assessed differences in plasma nitrate and CVR variables with an alpha level set at 0.05. No significant interactions nor differences between groups were found for plasma nitrate levels or CVR variables with acute BT supplementation. A significant time effect (p < 0.013) for all CVR variables was found and expected due to the effect of exercise. Acute BT supplementation did not increase plasma nitrate levels nor alter CVR at rest or during light to moderate cycling. PMID- 28674600 TI - Effects of 12 Weeks of Physical Training on Body Composition and Physical Fitness in Military Recruits. AB - The aim of this study was to analyze the morphological and functional changes in military recruits after twelve weeks of physical training. The sample consisted of 130 volunteer recruits aged 18-19 years. Anthropometric variables were assessed (body weight, height, body mass index, arm, waist, and hip circumference, waist/hip ratio, skinfold thickness of the triceps, suprailiac, and abdomen, and body fat percentage) and the sit-up test (1 minute), push-up test, and 12-minute running test. The physical training protocol involved running workouts, strength, agility, and flexibility. Descriptive statistical procedures were performed with mean, standard deviation, variance, and percentage and the comparison between the two moments was performed using the Student t test for dependent samples. The significance level was set at p <0.05. The results demonstrated a decrease in the sum of the three skinfolds (42.7+/-25.2mm to 33.9+/-17.7mm), a decrease in fat percentage (14.1+/-7.3% to 11.8+/-6.1%), an increase in lean mass (57.6+/-6.0kg to 58.6+/-8.0kg), and decreased fat mass (10.1+/-6.4kg to 8.3+/-5.2kg). They also showed improvements in push-up test (21.3+/-9.0 to 33.5+/-8.9), sit-up test (35.2+/-8.3 to 49.8+/-7.4), the 12 minute test (2212+/-316m to 2760+/-214m), and VO2max (35.2+/-8.3ml.kg-1.min-1 to 49.8+/ 7.4 ml.kg-1.min-1). No differences were observed in body mass, height, body mass index, or hip circumference. According to the above, it was found that the methodology adopted in the physical training was effective in reducing the percentage of fat and increasing cardiorespiratory fitness, improving the physical capacity and health of the military recruits. PMID- 28674601 TI - Physiological Characteristics of Projected Starters and Non-Starters in the Field Positions from a Division I Women's Soccer Team. AB - NCAA soccer features different substitution rules compared to FIFA-sanctioned matches, with a greater availability of players who can enter the game. This could influence the physiological characteristics of the field position starters (ST) and non-starters (NST) within a collegiate women's team, which has not been previously analyzed. Thus, 22 field players from the same Division I women's soccer squad completed: vertical and standing broad jumps; 30-meter (m) sprint (0 5, 0-10, 0-30 m intervals); pro-agility and 60-yard shuttle; and the Yo-Yo Intermittent Recovery Test Level 1. Players were defined into ST (n=10) and NST (n=12) by the coaching staff. A one-way ANOVA derived any significant (p<=0.05) between-group differences, and effect sizes were used for a magnitude-based inference analysis. Z-scores were also calculated to document worthwhile differences above or below the squad mean for the groups. The results showed no significant between-group differences for any of the performance tests. ST did have a worthwhile difference above the squad mean in the 0-10 and 0-30 m sprint intervals, while NST had a worthwhile difference below the squad mean in the 0-30 m interval. Physiological characteristics between ST and NST from the analyzed Division I squad were similar, although ST were generally faster. The similarities between ST and NST may be a function of the team's training, in that all players may complete the same workouts. Nonetheless, if all players exhibit similar physiological capacities, with appropriate substitutions by the coach a collegiate team should be able to maintain a high work-rate throughout a match. PMID- 28674602 TI - The Effects of Work-to-Rest Ratios on Torque, Electromyographic, and Mechanomyographic Responses to Fatiguing Workbouts. AB - The purpose of the present study was to examine the effects of 2 different work to-rest ratios, but the same mean load, cycle time, and total duration of the exercise bout, on maximal voluntary isometric contraction torque and neuromuscular responses to fatiguing, intermittent, submaximal, isometric, forearm flexion muscle actions. Ten men performed 2 fatiguing protocols with different work-to-rest ratios (4 s contraction, 4 s rest vs. 4 s contraction, alternating 6 and 2 s rest) that consisted of 50 intermittent, submaximal (65% of maximal voluntary isometric contraction), isometric, forearm flexion muscle actions. Electromyographic and mechanomyographic signals from the biceps brachii were recorded before, during, immediately and 5 min after performing the fatiguing protocols. In addition, maximal voluntary isometric contraction torque was assessed before, immediately and 5 min after. Both protocols resulted in decreases in maximal voluntary isometric contraction torque, electromyographic mean power frequency, and mechanomyographic mean power frequency, but no changes in electromyographic amplitude or mechanomyographic amplitude. The results of the present study indicated that differences in work-to-rest ratio did not affect maximal voluntary isometric contraction torque or the associated neuromuscular parameters as a result of fatiguing, intermittent, isometric muscle actions when mean load, cycle time, and total duration of exercise were equivalent. PMID- 28674603 TI - Mathematical Modeling and Expression of Heart Rate Deflection Point using Heart Rate and Oxygen Consumption. AB - Heart rate deflection point (HRDP) can be determined through different mathematical-modeling procedures, such as bi-segmental linear regression (2SEG) or maximal distance model (Dmax). The purpose was to compare heart rate (HR) and oxygen consumption (VO2) at HRDP when using 2SEG and Dmax, and to examine their relationships with respiratory compensation point (RCP) and running performance. Nineteen participants completed a graded exercise test (GXT), to determine HRDP and RCP, and a 5km treadmill time trial (5Ktime). No differences were found in HR or VO2 when comparing HRDP2SEG, HRDPDmax, and RCP. Strong correlations were found between HRDP2SEG, HRDPDmax, and RCP when using HR and VO2. No relationships were found between 5Ktime and HR at HRDP or RCP; however, strong relationships were found with VO2. While 2SEG and Dmax may be interchangeable in determining HRDP, VO2 at HRDP and RCP yielded stronger relationships to 5Ktime than HR. Therefore, VO2 at HRDP may be a better predictor of running performance than HR. PMID- 28674604 TI - Mood and Performance Anxiety in High School Basketball Players: A Pilot Study. AB - Participation in competitive sport may impact psychological measures, such as mood and performance anxiety, which in turn may impact enjoyment, adherence, continued participation, and so on. This study assessed the feasibility - in terms of process, resources, management, and potential scientific value- of measuring the effect of varying competitive challenges upon the mood and performance anxiety measures of high school athletes. The participants (n=12) consisted of the boys' varsity basketball team at a high school in a rural Midwestern community. Participants completed the Profile of Mood States (POMS) to assess mood and the Sport Anxiety Scale-2 (SAS-2) to assess performance anxiety, respectively. Survey administration occurred at baseline and prior to games designated as non-conference, conference, and state tournament. A-priori feasibility measures were achieved in this prospective design. Significant correlations on the subscale measures were found on the POMS and SAS-2 administered before the four conditions in this study; Chronbach's alpha ranged from 0.54-0.94 across conditions for POMS subscales, and Chronbach's alpha ranged from 0.73-0.97 across all conditions for SAS-2 subscales, respectively. Significant differences were found across conditions in the POMS subscale confusion [F(3,33) = 5.71, p = 0.01] and in the SAS-2 subscale worry [F(3,33) = 6.13, p=0.01]. These preliminary findings suggest that the competitive conditions in this study significantly affected some measures of mood and performance anxiety in high school basketball players. These findings warrant further investigation, as well as suggest coaches could gather such information from their players, ultimately aiding in player development and team performance. PMID- 28674605 TI - Changes in Running Economy, Respiratory Exchange Ratio and VO2max in Runners following a 10-day Altitude Training Camp. AB - Running economy (RE) and VO2max are important predictors of endurance performance for elite and semi-elite endurance athletes, with RE being an appropriate predictor in a homogenous running population. Altitude training has been observed to change RE (mL.kg-1.min-1), and VO2max due to alterations resulting from acclimatization. This study tracked changes in RE and VO2max before and after a 10-day altitude training camp at 1828 meters. VO2max, RE expressed calorically, and respiratory exchange ratio (RER), were measured below anaerobic threshold (AT) to observe differences between pre-and post-altitude training. Eight varsity cross-country runners between the ages of 18 and 22 years performed an incremental treadmill test, pre- and post-10-day altitude training. Paired samples t-tests were used to statistically analyze the data. Average RE (VO2 mL.kg-1.min-1) improved following altitude intervention (M= 56.44 +/- 4.28) compared to pre-altitude training (61.30 +/- 7.56). These differences were statistically significant t(7)= 2.71, p =.014. RE expressed as kcals.kg-1.km-1 improved following altitude training (16.73 +/- 2.96) compared to (18.44 +/- 4.04) pre-altitude training and was statistically significant t(7) =3.08, p = .008. RER taken during the last minute of steady-state was higher (0.97, +/- .019) post-altitude training, compared to (0.90 +/- .043) pre-altitude. These differences were statistically significant t(7) -3.62, p =.008. VO2max (mL.kg 1.min-1) was lower in 6 out of 8 participants (63.91, +/- 8.65) post-altitude compared to (69.90, +/- 10.80) pre-altitude and was statistically significant t(7) = 2.33, p =.026. The observed improvements in RE may be beneficial for endurance athletes competing and/or training at moderate altitudes near 1828 meters. PMID- 28674606 TI - Comparison of Ventilatory Measures and 20 km Time Trial Performance. AB - Performance threshold measures are used to predict cycling performance. Previous research has focused on long time trials (>= 40 km) using power at ventilatory threshold and respiratory threshold to estimate time trial performance. As intensity greatly differs during shorter time trails applying findings from longer time trials may not be appropriate. The use of heart rate measures to determine 20 km time trial performance has yet to be examined. The purpose of this study was to determine the effectiveness of heart rate measures at ventilatory threshold (VE/VO2 Plotted and VT determined by software) and respiratory threshold (RER of 0.95, 1.00, and 1.05) to predict 20 km time trial performance. Eighteen cyclists completed a VO2max protocol and two 20 km time trials. Average heart rates from 20 km time trials were compared with heart rates from performance threshold measures (VT plotted, VT software, and an RER at 0.95, 1.00, and 1.05) using repeated measures ANOVA. Significance was set a priori at P <= 0.05. The only measure not found to be significantly different in relation to time trial performance was HR at an RER of 1.00 (166.61+/-12.70 bpm vs. 165.89 +/ 9.56 bpm, p = .671). VT plotting and VT determined by software were found to underestimate time trial performance by 3% and 8% respectively. From these findings it is recommended to use heart rate at a RER of 1.00 in order to determine 20 km time trial intensity. PMID- 28674608 TI - Experiences with Lean Six Sigma as improvement strategy to reduce parenteral medication administration errors and associated potential risk of harm. AB - In this controlled before-after study the effect of improvements, derived from Lean Six Sigma strategy, on parenteral medication administration errors and the potential risk of harm was determined. During baseline measurement, on control versus intervention ward, at least one administration error occurred in 14 (74%) and 6 (46%) administrations with potential risk of harm in 6 (32%) and 1 (8%) administrations. Most administration errors with high potential risk of harm occurred in bolus injections: 8 (57%) versus 2 (67%) bolus injections were injected too fast with a potential risk of harm in 6 (43%) and 1 (33%) bolus injections on control and intervention ward. Implemented improvement strategies, based on major causes of too fast administration of bolus injections, were: Substitution of bolus injections by infusions, education, availability of administration information and drug round tabards. Post intervention, on the control ward in 76 (76%) administrations at least one error was made (RR 1.03; CI95:0.77-1.38), with a potential risk of harm in 14 (14%) administrations (RR 0.45; CI95:0.20-1.02). In 40 (68%) administrations on the intervention ward at least one error occurred (RR 1.47; CI95:0.80-2.71) but no administrations were associated with a potential risk of harm. A shift in wrong duration administration errors from bolus injections to infusions, with a reduction of potential risk of harm, seems to have occurred on the intervention ward. Although data are insufficient to prove an effect, Lean Six Sigma was experienced as a suitable strategy to select tailored improvements. Further studies are required to prove the effect of the strategy on parenteral medication administration errors. PMID- 28674607 TI - Fluoroacetate in plants - a review of its distribution, toxicity to livestock and microbial detoxification. AB - Fluoroacetate producing plants grow worldwide and it is believed they produce this toxic compound as a defence mechanism against grazing by herbivores. Ingestion by livestock often results in fatal poisonings, which causes significant economic problems to commercial farmers in many countries such as Australia, Brazil and South Africa. Several approaches have been adopted to protect livestock from the toxicity with limited success including fencing, toxic plant eradication and agents that bind the toxin. Genetically modified bacteria capable of degrading fluoroacetate have been able to protect ruminants from fluoroacetate toxicity under experimental conditions but concerns over the release of these microbes into the environment have prevented the application of this technology. Recently, a native bacterium from an Australian bovine rumen was isolated which can degrade fluoroacetate. This bacterium, strain MFA1, which belongs to the Synergistetes phylum degrades fluoroacetate to fluoride ions and acetate. The discovery and isolation of this bacterium provides a new opportunity to detoxify fluoroacetate in the rumen. This review focuses on fluoroacetate toxicity in ruminant livestock, the mechanism of fluoroacetate toxicity, tolerance of some animals to fluoroaceate, previous attempts to mitigate toxicity, aerobic and anaerobic microbial degradation of fluoroacetate, and future directions to overcome fluoroacetate toxicity. PMID- 28674609 TI - Reducing DNA Rates and Increasing Positive Contacts in an Outpatient Chronic Fatigue Service. AB - The Chronic Fatigue Service at East London NHS Foundation Trust recognised and coalesced around its major issue of engaging its service users. Using the systematic approach of quality improvement, and the infrastructure provided within East London NHS FT's quality improvement programme, it tested a number of change ideas which saw a significant reduction in non-attendance at appointments, an increase in patient cancellations when they could not attend, and an increase in positive contacts with the service. All these improvements surpassed the initial aims set within the project, and have been sustained over the course of 18 months. PMID- 28674610 TI - The Handy Approach - Quick Integrated Person Centred Support Preparation. AB - Cost effective care requires comprehensive person-centred formulation of solutions. The East London NHS Foundation Trust Community Health Services in Newham have piloted models of Integrated Care called 'Virtual Wards' which aim to keep people living with multiple long-term conditions, well at home by minimising system complexity. These Virtual Wards comprise Interdisciplinary Teams (IDTs) with a General Practitioner (GP) seconded to provide leadership. Historically assessments have been dominated by biomedical approaches with disability emphasised over personal aspirations and ability. New professional skills are needed to organise information from diverse approaches into a common framework, which can enable agreed goals of care to be delivered collaboratively. From June 2014 to January 2016 we aimed to improve the documentation of person-centred goals of care in 100% of our assessments. Change ideas were tested and team development addressed to improve documentation of aspirations for care for people being referred and if achieved, then to test ideas to improve coproduction of care. Change ideas included Enhanced Clinical Supervision (ECS) by a GP with additional expert skills; Flash Teaching (FT) defined as five-minute weekly discussion on topics generated from the case-mix to develop a shared understanding of Integrated Care; Structured Formulation using a novel, quick, integrated assessment framework called the Handy Approach (HA) with the hand as a memory prompt to bring the personal together with the mental, social and physical domains and finally we tested focusing on 'Team Primacy' (mutual regard within the team) to embed behaviour change. 181 cases were tracked and documentation of personal aspirations for care by case showed: ECS 0/21 (0%); FT 5/50 (10%); ECS/FT plus the HA 35/83 (42%); Team Primacy plus ECS/FT/HA 27/27 (100%). By January 2016 prompted by using the Handy Approach in a highly functional team, all members of the IDT consistently documented personal aspirations. PMID- 28674611 TI - Reducing the number of unnecessary liver function tests requested on the Paediatric Intensive Care Unit. AB - Between January and October 2014, Great Ormond Street Hospital Paediatric Intensive Care Unit (PICU) was spending an average L23,392 on blood tests per month. Blood tests should be requested based on previous results and the patient's clinical condition, medication and nutritional status. However, more blood tests were being ordered than clinically indicated: an audit in October 2014 showed liver function tests (LFTs) were requested daily on most patients, even with previous normal results. A driver diagram identified three primary drivers for blood test requesting: decision-making, situational awareness and computer-based ordering. Decision-making for routine blood tests was the responsibility of the bedside nurses on each night shift. The communication between the nurses and doctors was an identified secondary driver. The project's primary aim was to reduce unnecessary LFTs requests on PICU over 6 months by implementing a blood test request form, a table of common investigations to facilitate and document discussion between the nursing and medical teams. The secondary aims were to reduce other unnecessary blood test requests, including full blood counts (FBC), coagulation screens and CRP. This project was conducted in three phases: construction, testing and implementation of the blood test form. PDSA cycles were used within each phase. Two PICU nurse champions were engaged to provide bedside support, education and feedback. In the 8-month period following implementation, there was a significant sustained reduction in LFTs requests. A similar pattern of sustained reduction also occurred for FBC, coagulation screens and CRP requests. This sustained reduction in blood tests requested equated to a saving in excess of L36,000. This project was successful: the reduction in the number of inappropriate blood tests had clear financial benefit for PICU and reduced blood loss for patients. Early engagement and support from key stakeholders avoided conflict, guaranteed data sharing and aided engagement of bedside nurses. PMID- 28674612 TI - Acute kidney injury; improving the communication from secondary to primary care. AB - Acute kidney injury (AKI) is a common but preventable event in secondary care. It is known to be associated with poorer outcomes for the patient's future health. Patients therefore require specific after-care in the community following an AKI, both in the short and long term. However, information about an inpatient AKI is often not communicated to primary care at discharge. Only 11.0% of discharge summaries contained full information about an AKI (including stage of AKI, changes to medications and follow-up required) in August 2015. We aimed to improve communication about AKI on discharge summaries via implementation of a series of interventions between June 2015 and March 2016. A specific section was added to the discharge summary software to prompt inclusion of information regarding AKI. An automatic warning message was added later as an additional prompt. A programme of education was provided for the junior doctors. A ward based campaign was rolled out using the animated character 'Ned the Nephron,' using posters, emails and screen savers. We also introduced an AKI warning sticker for drug charts, which reminds the discharging doctor that the patient has had an AKI during the admission. Our primary outcome was the percentage of discharge summaries that had the AKI section completed, as this contained all the desired information, including stage of AKI and frequency of follow up blood tests in primary care. Monthly data collections showed that this gradually increased from 4.7% in September 2015 to 35.0% in January 2016. We expect further increases with the recent introduction of the drug chart sticker. PMID- 28674613 TI - An intimal sarcoma of pulmonary artery mimicking pulmonary embolism: a case report and literature review. AB - Pulmonary artery intimal sarcoma is a highly aggressive disease, and is most often misdiagnosed as pulmonary thromboembolism (PTE) due to the similar clinical symptoms and its rarity, which leads to the use of inappropriate treatments such as prolonged anticoagulant therapy. We reported a case of pulmonary artery intimal sarcoma in a patient who was misdiagnosed as having PTE. Pathology after surgery confirmed malignant disease. We concluded that when a patient presents with mild clinical manifestations yet with strong imaging manifestations, pulmonary artery malignancy should be suspected. PMID- 28674614 TI - An eFP browser for visualizing strawberry fruit and flower transcriptomes. AB - Wild strawberry Fragaria vesca is emerging as an important model system for the cultivated strawberry due to its diploid genome and availability of extensive transcriptome data and a range of molecular genetic tools. Being able to better utilize these tools, especially the transcriptome data, will greatly facilitate research progress in strawberry and other Rosaceae fruit crops. The electronic fluorescent pictograph (eFP) software is a useful and popular tool to display transcriptome data visually, and is widely used in other model organisms including Arabidopsis and mouse. Here we applied eFP to display wild strawberry RNA sequencing (RNA-seq) data from 42 different tissues and stages, including various flower and fruit developmental stages. In addition, we generated eight additional RNA-seq data sets to represent tissues from ripening-stage receptacle fruit from yellow-colored and red-colored wild strawberry varieties. Differential gene expression analysis between these eight data sets provides additional information for understanding fruit-quality traits. Together, this work greatly facilitates the utility of the extensive transcriptome data for investigating strawberry flower and fruit development as well as fruit-quality traits. PMID- 28674615 TI - In vivo biocompatibility and pacing function study of silver ion-based antimicrobial surface technology applied to cardiac pacemakers. AB - INTRODUCTION: Evidence suggests that the rate of cardiovascular implantable electronic device (CIED) infections is increasing more rapidly than the rates of CIED implantation and is associated with considerable mortality, morbidity and health economic impact. Antimicrobial surface treatments are being developed for CIEDs to reduce the risk of postimplantation infection within the subcutaneous implant pocket. METHODS AND ANALYSIS: The feasibility of processing cardiac pacemakers with the Agluna antimicrobial silver ion surface technology and in vivo biocompatibility were evaluated. Antimicrobially processed (n=6) and control pacemakers (n=6) were implanted into subcutaneous pockets and connected to a part of the sacrospinalis muscle using an ovine model for 12 weeks. Pacemaker function was monitored preimplantation and postimplantation. RESULTS: Neither local infection nor systemic toxicity were detected in antimicrobial or control devices, and surrounding tissues showed no abnormal pathology or over-reactivity. Semiquantitative scores of membrane formation, cellular orientation and vascularity were applied over five regions of the pacemaker capsule and average scores compared. Results showed no significant difference between antimicrobially processed and control pacemakers. Silver analysis of whole blood at 7 days found that levels were a maximum of 10 parts per billion (ppb) for one sample, more typically <=2 ppb, compared with <<2 ppb for preimplantation levels, well below reported toxic levels. CONCLUSIONS: There was no evidence of adverse or abnormal pathology in tissue surrounding antimicrobially processed pacemakers, or deleterious effect on basic pacing capabilities and parameters at 12 weeks. This proof of concept study provides evidence of basic biocompatibility and feasibility of applying this silver ion-based antimicrobial surface to a titanium pacemaker surface. PMID- 28674616 TI - Biological effect of microengineered grooved stents on strut healing: a randomised OCT-based comparative study in humans. AB - OBJECTIVE: To evaluate the biological effect of microengineered stent grooves (MSG) on early strut healing in humans by performing optical coherence tomography (OCT) analysis 3 weeks following the implantation. BACKGROUND: In the experimental setting, MSG accelerate endothelial cell migration and reduce neointimal proliferation compared with bare metal stent (BMS). METHODS: A total of 37 patients undergoing percutaneous coronary intervention with de novo coronary lesions were randomly assigned to either MSG (n=19) or an identical BMS controls (n=18). All patients underwent OCT imaging at 3 weeks. A total of 7959 struts were included in the final analysis. RESULTS: At 3 weeks following stent implantation, almost all struts analysed (~97%) had evidence of tissue coverage. The percentage of partially covered struts was comparable between both groups. However, the percentage of fully embedded struts was higher in the BMS group (81.22%, 49.75-95.52) compared with the MSG group (74.21%, 58.85-86.38). The stent-level analysis demonstrated reduction in neointimal formation (neointimal hyperplasia area and volume reduction of ~14% and ~19%, respectively) in the MSG versus the BMS group. In the strut-level analysis, an even greater reduction (~22% in neointimal thickness) was seen in the MSG group. Layered neointimal was present in ~6% of the OCT frames in the BMS group while it was not present in the MSG group. CONCLUSIONS: MSG induced a more homogeneous and predictable pattern of surface healing in the early stages following stent implantation. The biological effect of MSG on stent healing has the potential to improve the safety profile of current generation drug-eluting stents. CLASSIFICATIONS: BMS, OCT, clinical trials. PMID- 28674617 TI - An FFRCT diagnostic strategy versus usual care in patients with suspected coronary artery disease planned for invasive coronary angiography at German sites: one-year results of a subgroup analysis of the PLATFORM (Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts) study. AB - AIM: Diagnostic evaluation practices for suspected coronary artery disease (CAD) may vary between countries. Our objective was to compare a CT-derived fractional flow reserve (FFRCT) diagnostic strategy with usual care in patients with planned invasive coronary angiography (ICA) enrolled in the PLATFORM (Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts) study at German sites. METHODS: Patients were divided into two consecutive observational cohorts, receiving either usual care or CT angiography (CTA)/FFRCT. The primary endpoint was the percentage of patients planned for ICA, with no obstructive CAD on ICA within 90 days. Secondary endpoints included death, myocardial infarction, unstable angina, hospitalisation leading to unplanned revascularisation, cumulative radiation exposure, estimated medical costs and quality of life (QOL) at 1 year. RESULTS: 116 patients were included. The primary endpoint occurred in 4 of the 52 patients (7.7%) in the CTA/FFRCT group and in 55 of the 64 patients (85.9%) in the usual care group (risk difference 78.2%, 95% CI 67.1% to 89.4%, p<0.001). ICA was cancelled in 40 of the 52 patients (77%) who underwent CTA/FFRCT. Clinical event rates were low overall. The mean radiation exposure was lower in the FFRCT versus the usual care group (7.28 vs 9.80 mSv, p<0.001). Mean estimated medical costs were ?4217 (CTA/FFRCT) versus ?6894 (usual care), p<0.001. Improvement in QOL (EQ-5D score) was greater in the FFRCT (+0.09 units) versus the usual care cohort (+0.03 units), p=0.04. CONCLUSIONS: In patients with suspected CAD planned for ICA at German sites, initial CTA/FFRCT compared with usual care was associated with a markedly reduced rate of ICA showing no obstructive CAD, lower cumulative radiation exposure and estimated costs and greater improvement in QOL. PMID- 28674618 TI - Higher number of live births is associated with left ventricular diastolic dysfunction and adverse cardiac remodelling among US Hispanic/Latina women: results from the Echocardiographic Study of Latinos. AB - INTRODUCTION: Female sex is a risk factor for heart failure with preserved ejection fraction (HFpEF). Previous literature suggests that some diastolic dysfunction (DD) develops during pregnancy and may persist postdelivery. Our objective was to examine the relationship between parity and cardiac structure and function in a population-based cohort. METHODS: Participants included 1172 Hispanic/Latina women, aged >=45 years, enrolled in the Echocardiographic Study of Latinos from four US communities (Bronx, Miami, San Diego and Chicago). Standard echocardiographic techniques were used to measure cardiac volumes, left ventricular mass, systolic and diastolic function. Using sampling weights and survey statistics, multivariable linear and logistic regression models were constructed adjusting for age, body mass index, diabetes or prediabetes, systolic blood pressure, use of antihypertensive medications, smoking, total cholesterol and high-density lipoprotein cholesterol. RESULTS: In the target population, 5.0% were nulliparous (no live births) and 10.5% were grand multiparous (>=5 live births). Among the nulliparous women, 46% had DD as compared with 51%-58% of women with 1-4 live births and 81% of women with >=5 live births (p<0.01). In full multivariate models, higher parity was significantly associated with greater left ventricular end-systolic volumes, end-diastolic volumes, left atrial volume indices and presence of DD (all p<0.01) but was not associated with ejection fraction. The log odds for having any grade of DD in grand-multiparous women was over three times that seen in nulliparous women (OR=3.4, 95% CI 1.5 to 7.9, p<0.01) in models further adjusted for income and education. CONCLUSIONS: Higher parity is associated with increased cardiac mass, volumes and the presence of DD. Further studies are needed to elucidate this apparent deleterious relation and whether parity can help explain the increased risk of HFpEF in women. PMID- 28674619 TI - On-X versus St Jude Medical Regent mechanical aortic valve prostheses: early haemodynamics. AB - OBJECTIVE: We aimed to compare the early haemodynamic data of the On-X and St Jude Medical (SJM) Regent bileaflet mechanical prostheses in the aortic position. METHODS: A retrospective study was performed using data collected prospectively for a national database. Thirty-three patients who had aortic On-X valve (On-X group) and 33 matched patients who had aortic SJM Regent valve (SJM group) were included. The intraoperative and early postoperative data were collected. The same echocardiographer reviewed all the echocardiograms and obtained the required parameters. RESULTS: The peak gradient across the prosthetic valve was comparable between the two groups except for the labelled valve size of 25 mm for which the On-X group had lower peak gradient when compared with the SJM group. Mean gradients and effective orifice area indices of the two valve types within each valve size subgroup were comparable. CONCLUSIONS: The current study confirms that in the early postoperative period, the two valve types had comparable haemodynamic outcomes. PMID- 28674620 TI - Risk and outcomes of aortic valve endocarditis among patients with bicuspid and tricuspid aortic valves. AB - OBJECTIVE: Patients with structural abnormalities of cardiac valves, including bicuspid aortic valve (BAV), are said to be at higher risk of infective endocarditis (IE). We sought to determine the risk of IE of the BAV compared with the tricuspid aortic valve (TAV) and to determine the risk of aortic valve replacement and mortality after IE. METHODS: From medical records of two US and one Italian hospitals, patients with their first episode of IE of any native valve were identified. In the US cohort 42 patients with BAV and 393 patients with TAV with IE occurring between 1 January 2000 and 30 June 2014 were identified. In the Italian cohort 48 patients with BAV and 341 patients with TAV with IE underwent valve replacement surgery between 1 January 2000 and1 November 2015. The risk of IE for BAV and TAV and subsequent outcomes were determined after matching to patients without IE. RESULTS: After adjustment for risk factors, the risk of IE in the US cohort was 23.1 (95% CI 8.1 to 100, p <0.0001) times greater for BAV than TAV. Patients with BAV with IE were more likely to have an aortic root abscess. Within the subsequent 5 years, BAV patients with IE were more likely to undergo valve replacement (85%) than TAV patients with IE (46%). Patients with IE were at increased risk of death. The findings were similar in the Italian cohort. CONCLUSIONS: Patients with BAV are at markedly increased risk of IE and aortic root abscess than patients with TAV. Increased risk of IE in patients with BAV indicates they may be a candidate group for long term trials of antibiotic prophylaxis of IE. PMID- 28674621 TI - Predicting hospitalisation duration after transcatheter aortic valve implantation. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) is widely used as an alternative to conventional surgical aortic valve replacement. The aim of this study was to identify preprocedural predictors of duration of length of stay (LoS) after transfemoral TAVI (TF-TAVI). METHODS: We included all consecutive patients who underwent TF-TAVI at our centre between November 2010 and June 2013. Preprocedural, periprocedural and postprocedural variables were collected and evaluated to LoS. Linear regression was performed to find preprocedural predictors for total LoS. RESULTS: The population consisted of 114 patients (mean age: 79.6+/-8.7, 32.5% male). The median total LoS was 6.5 days (5-9 days). Multivariate analysis showed that the Metabolic Equivalent score (METs) (beta= 0.084, p=0.011) and diastolic blood pressure (beta=-0.011, p=0.016) independently contributed to the log-transformed LoS. CONCLUSION: Multivariate linear regression showed that lower METs and lower diastolic blood pressure were associated with prolonged LoS. Understanding patients' physical functionality can improve logistical planning of hospital stay and selecting patients eligible for early discharge. PMID- 28674622 TI - Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic. AB - OBJECTIVE: Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are preventive against cardiovascular disease (CVD) and several cancer types, but long-term use has been associated with significant health risks, resulting in conflicting recommendations on NSAID use for prevention of CVD and cancer. Previous research indicates that aspirin use increases with age and CVD risk factors and that a large percentage of the US population regularly use analgesics, including NSAIDs, but there has not been a recent, in-depth assessment of NSAID use prevalence, changes in use over time or predictors of NSAID use in the USA. METHODS: We used the cross-sectional, National Health And Nutrition Examination Survey (NHANES) from 1988 to 1994 and three continuous cycles (1999-2004) to assess regular NSAID use prevalence, changes over time and predictors of regular NSAID use. RESULTS: Overall, regular NSAID use increased over time and varied by demographic features. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users. By contrast, non-Hispanic African American and Mexican American participants were significantly less likely to regularly use NSAIDs. CONCLUSIONS: This study uses a nationally representative data set (NHANES) to provide an exploration of regular NSAID use patterns over time, highlighting several demographic, lifestyle and clinical conditions associated with regular NSAID use. Understanding who is likely to regularly use NSAIDs enables more targeted messaging both for increasing the preventive benefits and for limiting the toxicities associated with regular use of NSAIDs. PMID- 28674623 TI - The systolic paradox in hypertrophic cardiomyopathy. AB - OBJECTIVE: We explored cardiac volumes and the effects on systolic function in hypertrophic cardiomyopathy (HCM) patients with left ventricular hypertrophy (HCM LVH+) and genotype-positive patients without left ventricular hypertrophy (HCM LVH-). METHODS: We included 180 HCM LVH+, 100 HCM LVH- patients and 80 healthy individuals. End-Diastolic Volume Index (EDVI), End-Systolic Volume Index (ESVI) and ejection fraction (EF) were assessed by echocardiography. Left ventricular (LV) global longitudinal strain (GLS) was measured by speckle tracking echocardiography. RESULTS: EDVI and ESVI were significantly smaller in HCM LVH+ compared with HCM LVH- patients (41+/-14 mL/m2 vs 49+/-13 mL/m2 and 16+/-7 mL/m2 vs 19+/-6 mL/m2, respectively, both p<0.001) and in healthy individuals (41+/-14 mL/m2 vs 57+/-14 mL/m2 and 16+/-7 mL/m2 vs 23+/-9 mL/m2, respectively, both p<0.001). HCM LVH- patients had significantly lower EDVI and ESVI compared with healthy individuals (49+/-13 mL/m2 vs 57+/-14 mL/m2 and 19+/-6 mL/m2 vs 23+/-9 mL/m2, both p<0.001). EF was similar (61%+/-7% vs 60%+/-8% vs 61%+/-6%, p=0.43) in the HCM LVH+, HCM LVH- and healthy individuals, despite significantly worse GLS in the HCM LVH+ (-16.4%+/-3.7% vs -21.3%+/-2.4% vs -22.3%+/-3.7%, p<0.001). GLS was worse in the HCM LVH- compared with healthy individuals in pairwise comparison (p=0.001). Decrease in ESVI was closely related to EF in HCM LVH+ and HCM LVH- (R=0.45, p<0.001 and R=0.43, p<0.001) as expected, but there was no relationship with GLS (R=0.02, p=0.77 and R=0.11, p=0.31). Increased maximal wall thickness (MWT) correlated significantly with worse GLS (R=0.58, p<0.001), but not with EF (R=0.018, p=0.30) in the HCM LVH+ patients. CONCLUSION: HCM LVH+ had smaller cardiac volumes that could explain the preserved EF, despite worse GLS that was closely related to MWT. HCM LVH- had reduced cardiac volumes and subtle changes in GLS compared with healthy individuals, indicating a continuum of both volumetric and systolic changes present before increased MWT. PMID- 28674624 TI - Left atrial strain predicts recurrence of atrial arrhythmias after catheter ablation of persistent atrial fibrillation. AB - INTRODUCTION: Success rates of catheter ablation (CA) of persistent atrial fibrillation (AF) are very variable. Identifying patients in whom sinus rhythm maintenance cannot be achieved after CA is a critical issue. METHODS: 2D speckle tracking echocardiography was performed before the first CA procedure in consecutive patients with persistent AF. Left atrial (LA) strain was correlated with recurrence of atrial arrhythmias during the follow-up period of 15 months after one CA procedure with or without antiarrhythmic drugs (primary endpoint). In a secondary analysis, recurrences after two CA procedures were analysed. RESULTS: 102 patients were included. Patients with recurrence of atrial arrhythmias after one CA procedure (n=55) had significantly lower LA strain than those without recurrence (LA strain 9.7+/-2.4% vs 16.2+/-3.0%; p<0.001). Recurrence rate was significantly higher in patients with LA strain <10% than in those with LA strain between 10% and 14.5% and >14.5% (97.7%, 42.1% and 10.3%, respectively; p<0.001). In Cox regression analysis including age, comorbidities, left ventricular dysfunction and LA enlargement, low LA strain (<10%) was the strongest factor associated with recurrence of AF (HR 6.4 (2.4-16.9), p<0.001). Even after inclusion of a second CA procedure, LA strain <10% maintained a high predictive value for recurrence of atrial arrhythmias (86.4% (95% CI 73.3% to 93.6%)). CONCLUSION: In patients with persistent AF, LA strain imaging could be very useful to select those patients who have a high risk of not benefiting from CA. PMID- 28674625 TI - Gender-related differences in self-reported dental care in adults with congenital heart disease at increased risk of infective endocarditis. AB - OBJECTIVE: Adults with congenital heart disease (CHD) are at increased risk of infective endocarditis (IE). Women with CHD have a lower IE risk, potentially due to gender-related differences in dental care. We aimed to assess self-reported dental hygiene measures in adults with CHD, and to identify factors associated with good oral hygiene. METHODS AND RESULTS: Descriptive study includes 187 adults with CHD at increased risk of IE. The patients' IE knowledge was assessed using an adapted version of the Leuven Knowledge Questionnaire for CHD. Their mean age was 34.9+/-14.9 years, 73 of them (39%) were women, 91 (49%) were at high risk for IE, including 66 (35%) with a prosthetic valve, 14 (7%) with a history of IE and 11 (6%) with cyanotic CHD or residual shunts/valvular regurgitation in the proximity of prosthetic material. The self-defined IE knowledge score did not differ between men and women (21.6+/-10.0 vs 23.4+/-10.0; p=0.225). 126 patients (67%) reported to have a good oral hygiene. Female gender (OR 2.4, 95% CI 1.1 to 4.4), and a higher IE knowledge score (OR 1.2, 95% CI 1.1 to 1.5, per 5 points) were the variables independently associated with good oral hygiene. CONCLUSIONS: In adults with CHD, patients with a higher IE knowledge score and women are more likely to practise dental care as recommended. Gender differences in oral hygiene practise may explain the observed lower female IE incidence rate. Efforts to improve patients' knowledge on IE are encouraged. PMID- 28674626 TI - Implications of the PEGASUS-TIMI 54 trial for US clinical practice. AB - OBJECTIVES: This study aims to determine the proportion of real-world patients with myocardial infarction (MI) who would have been eligible for the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial, to characterise their current use of P2Y12 inhibitors and to explore the estimated costs and ischaemic event consequences of increasing P2Y12 inhibitor use among these patients. METHODS: In the US national ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines), we identified 273 328 patients with MI and determined the proportion that would have met the eligibility criteria for the PEGASUS trial. We described longitudinal P2Y12 inhibitor use among patients eligible for PEGASUS and estimated the cost and ischaemic consequences of increasing P2Y12 use among eligible patients. RESULTS: A total of 112 222 (41.1%) patients with MI in ACTION Registry-GWTG met eligibility for the PEGASUS trial. Among 83 871 eligible patients with pharmacy claims data, 23 042 (27.5%) were on a P2Y12 inhibitor at 1 year, 9661 (11.5%) at 2 years and 5246 (6.3%) at 3 years, with the majority (79.2%) of these patients on clopidogrel. The use of ticagrelor in eligible patients not yet on a P2Y12 inhibitor at 1 year post-MI would cost an estimated US$885 000 per MI, stroke or cardiovascular death averted over a 3-year time horizon, while the use of clopidogrel would cost an estimated US$19 800 per ischaemic event averted. CONCLUSION: In contemporary clinical practice, a minority of patients are on a P2Y12 inhibitor beyond 1-year post-MI. Applying PEGASUS trial findings to clinical practice would result in a large increase in P2Y12 inhibitor use, with a cost per ischaemic event averted that is strongly influenced by the choice of therapy. PMID- 28674627 TI - Clinical and cost-effectiveness of adapted cognitive behaviour therapy for non cardiac chest pain: a multicentre, randomised controlled trial. AB - OBJECTIVE: To investigate the cost-effectiveness of a modified form of cognitive behavioural therapy (CBT) for recurrent non-cardiac chest pain. METHODS: We tested the effectiveness and cost-effectiveness of a modified form of CBT for chest pain (CBT-CP)(4-10 sessions) in patients who attended cardiology clinics or emergency medical services repeatedly. Patients were randomised using a remote web-based system to CBT-CP or to standard care in the clinic. Assessments were made at baseline and at 6 months and 12 months. The primary outcome was the change in the Health Anxiety Inventory Score at 6 months. Other clinical measures, social functioning, quality of life and costs of services were also recorded. RESULTS: Sixty-eight patients were randomised with low attrition rates at 6 months and 12 months with 81% of all possible assessments completed at 6 months and 12 months. Although there were no significant group differences between any of the outcome measures at either 6 months or 12 months, patients receiving CBT-CP had between two and three times fewer hospital bed days, outpatient appointments, and A&E attendances than those allocated to standard care and total costs per patient were L1496.49 lower, though the differences in costs were not significant. There was a small non-significant gain in quality adjusted life years in those allocated to CBT-CP compared with standard care (0.76 vs 0.74). CONCLUSIONS: It is concluded that CBT-CP in the context of current hospital structures is not a viable treatment, but is worthy of further research as a potentially cost-effective treatment for non-cardiac chest pain. TRIAL REGISTRATION NUMBER: ISRCTN 14711101. PMID- 28674628 TI - Syndromes of orthostatic intolerance and syncope in young adults. AB - OBJECTIVE: To explore the clinical and neuroendocrine characteristics of syndromes of orthostatic intolerance and syncope in young adults. METHODS: Two hundred and thirty-six patients aged 18-40 years with orthostatic intolerance and/or syncope were examined by head-up tilt test (HUT). Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT proAVP), C-terminal-endothelin-1 and mid-regional-fragment of pro-atrial natriuretic-peptide (MR-proANP) were analysed. Patients' history, haemodynamic parameters and plasma biomarkers were related to main diagnoses such as vasovagal syncope (VVS), postural tachycardia syndrome (POTS), orthostatic hypotension (OH) and negative HUT. RESULTS: No self-reported symptom of orthostatic intolerance was highly specific for any diagnosis. Patients with VVS (n=103) were more likely to be men (p=0.011) and had lower resting heart rate (HR; 66+/-11) compared with POTS (73+/-11; n=72; p=0.001) and negative HUT (74+/-11; n=39; p=0.001). Patients with POTS demonstrated greater rise in norepinephrine (p=0.008) and CT-proAVP (p=0.033) on standing compared with negative HUT, and lower resting MR-proANP compared with VVS (p=0.04) and OH (p=0.03). Patients with OH had lower resting renin (p=0.03). Subjects with a resting HR <70 and MR-proANP >45 pm/L had an OR of 3.99 (95 % CI 1.68 to 9.52; p=0.002) for VVS compared with subjects without any of these criteria; if male sex was added the OR was 21.8 (95% CI 3.99 to 119; p<0.001). CONCLUSIONS: Syndromes of orthostatic intolerance and syncope share many characteristics in younger persons. However, patients with VVS are more likely to be men, have lower HR and higher MR-proANP at rest compared with POTS, which might be taken into account at an early stage of evaluation. PMID- 28674629 TI - Morbidity outcomes after surgical aortic valve replacement. AB - OBJECTIVE: In patients with mild to moderate operative risk, surgical aortic valve replacement (SAVR) is still the preferred treatment for patients with severe symptomatic aortic stenosis (AS). Aiming to broaden the knowledge of postsurgical outcomes, this study reports a broad set of morbidity outcomes following surgical intervention. METHODS: Our cohort comprised 442 patients referred for severe AS; 351 had undergone SAVR, with the remainder (91) not operated on. All patients were evaluated using the 6-minute walk test (6MWT), were assigned a New York Heart Association class (NYHA) and Canadian Cardiovascular Society class (CCS), with additional scores for health-related quality of life (HRQoL), cognitive function (Mini-Mental State Examination (MMSE)) and myocardial remodelling (at inclusion and at 1-year follow-up). Adverse events and mortality were recorded. RESULTS: Three-year survival after SAVR was 90.0%. SAVR was associated with an improved NYHA class, CCS score and HRQoL, and provoked reverse ventricular remodelling. The 6MWT decreased, while the risks of major adverse cardiovascular events (death, non-fatal stroke/transient ischaemic attack or myocardial infarction) and all-cause hospitalisation (incidence rate per 100 patient-years) were 13.5 and 62.4, respectively. The proportion of cognitive disability measured by MMSE increased after SAVR from 3.2% to 8.8% (p=0.005). Proportion of patients living independently at home, having attained NYHA class I, was met by 49.1% at 1 year. Unoperated individuals had a poor prognosis in terms of any outcome. CONCLUSION: This study provides knowledge of outcomes beyond what is known about the mortality benefit after SAVR to provide insight into the morbidity burden of modern-day SAVR. PMID- 28674630 TI - A specialty-specific, multimodality educational quality improvement initiative to deimplement rarely appropriate myocardial perfusion imaging. AB - OBJECTIVE: Investigations of Appropriate Use Criteria (AUC) education have shown a mixed effect on changing provider behaviour. At our facility, rarely appropriate myocardial perfusion imaging (MPI) differs by specialty; awareness of AUC is low. Our objective is to investigate if specialty-specific, multimodality education could reduce rarely appropriate MPI. METHODS: We designed education focused on the rarely appropriate MPI ordered most often by each specialty. We tracked appropriateness of MPI in three cohorts: pre, post (immediately after) and late-post (4 months after) intervention. RESULTS: A total of 889 MPI were evaluated (n=287 pre, n=313 post, n=289 late-post), 95.3% were men. Chest pain was the most common symptom (n=530, 59.6%), while 14.1% (n=125) had no symptoms. Rarely appropriate testing decreased from 4.9% to 1.3% and remained at 1.4% in the late-post cohort (p<0.0001). In logistic regression, lack of symptoms (OR 31.3, 95% CI 10.3 to 94.8, p<=0.0001) and being in the post or late-post cohorts (OR 0.27, 95% CI 0.11 to 0.68, p=0.006) were associated with rarely appropriate MPI. Preoperative MPI in patients with good exercise capacity was a common rarely appropriate indication. Ischaemia was not observed among patients with rarely appropriate indication for MPI. CONCLUSIONS: In certain clinical settings, education may be an effective approach for deimplementing rarely appropriate MPI. The effect of education may be enhanced when focused on improving patient care, delivered by a peer, and needs assessment indicates low awareness of guidelines. Lack of symptoms and preoperative MPI continue to be the predominant rarely appropriate MPI ordered. PMID- 28674631 TI - Liver stiffness assessed by Fibrosis-4 index predicts mortality in patients with heart failure. AB - OBJECTIVE: Liver dysfunction due to heart failure (HF) is known as congestive hepatopathy. It has recently been reported that liver stiffness assessed by transient elastography reflects increased central venous pressure. The Fibrosis-4 (FIB4) index (age (years) * aspartate aminotransferase (IU/L)/platelet count (109/L) * square root of alanine aminotransferase (IU/L)) is expected to be useful for evaluating liver stiffness in patients with non-alcoholic fatty liver disease. We aimed to investigate the impact of the FIB4 index on HF prognosis, with consideration for liver fibrosis markers and underlying cardiac function. METHODS: Consecutive 1058 patients with HF who were admitted to our hospital were divided into three groups based on their FIB4 index: first (FIB4 index <1.72, n=353), second (1.72<=FIB4 index <3.01, n=353) and third tertiles (3.01<=FIB4 index, n=352). We prospectively followed for all-cause mortality. RESULTS: During the follow-up period (mean 1047 days), 246 deaths occurred. In the Kaplan-Meier analysis, all-cause mortality progressively increased from the first to third groups (12.2%, 21.0% and 36.6%, p<0.01). In the Cox proportional hazard analysis, FIB4 index was an independent predictor of all-cause mortality in patients with HF (p<0.05). In comparisons of laboratory and echocardiographic findings, the third tertile had higher levels of type IV collagen 7S, procollagen type III peptide, hyaluronic acid, left atrial volume, mitral valve E/e', inferior vena cava diameter and right atrial end systolic area (p<0.01, respectively). CONCLUSION: The FIB4 index, a marker of liver stiffness, is associated with higher all-cause mortality in patients with HF. PMID- 28674633 TI - Corrigendum: Novel variation at chr11p13 associated with cystic fibrosis lung disease severity. AB - [This corrects the article DOI: 10.1038/hgv.2016.20.]. PMID- 28674632 TI - Boosting endogenous production of vasoprotective hydrogen sulfide via supplementation with taurine and N-acetylcysteine: a novel way to promote cardiovascular health. PMID- 28674634 TI - Erratum to Genetic and molecular changes in ovarian cancer. AB - [This corrects the article on p. 236 in vol. 13, PMID: 27458531.]. PMID- 28674635 TI - Initiating Mechanisms of Surgery-induced Memory Decline: The Role of HMGB1. PMID- 28674636 TI - Diabetes during Pregnancy: Influence of Body Mass Index on Composite Morbidity. AB - Objective This study aims to compare composite maternal and neonatal morbidities (MM, NM) among pregnant women with diabetes mellitus whose body mass index (BMI) at delivery was < 30 (group 1), 30.0 to 39.9 (group 2), and >= 40 kg/m 2 (group 3). We hypothesized that increased BMI class at delivery would be associated with worsening maternal and neonatal outcomes. Methods This is a retrospective cohort study. MM was defined as: chorioamnionitis, wound infection, eclampsia, diabetic ketoacidosis, hypoglycemia admission, third/fourth degree laceration, and/or death. NM was defined as umbilical arterial pH < 7.0, 5 minute Apgar < 4, respiratory distress syndrome, mechanical ventilation, neonatal sepsis, stillbirth, and/or death. Odds ratios were adjusted for possible confounders. Results MM was noted in 8, 13, and 24% of groups 1, 2, and 3, respectively, and significantly more common in group 2 versus 1 (adjusted odds ratio [aOR]: 1.66) and group 3 versus 1 (aOR: 3.06). NM was noted in 7, 8, and 15% of each BMI group, respectively, and differed significantly between group 3 vs. 2 (aOR: 1.77). Conclusions The increased rate of morbidities between the BMI groups is useful to inform diabetic women and highlights the need for further investigation of diabetes and obesity as comorbidities in pregnancy. PMID- 28674637 TI - Recurrent Staphylococcal Scalded Skin Syndrome in an Extremely Low-Birth-Weight Neonate. AB - Staphylococcal scalded skin syndrome (SSSS) in premature infants is a rare condition. We present SSSS in an extremely low-birth-weight (ELBW) infant with recurrent and confirmed bacterial sepsis. We present it to emphasize the importance for clinicians to not only recognize the clinical manifestations of SSSS, but also the need to closely monitor infants, especially very low-birth weight (VLBW) and ELBW infants with SSSS for recurrence and bacterial sepsis. SSSS in preterm infants is a potentially lethal condition and early recognition and appropriate supportive care could be life-saving. PMID- 28674638 TI - Orbital Subperiosteal Hematoma in the Newborn Causing Unilateral Proptosis: Ultrasound as First-Line Imaging Modality. AB - Proptosis in the neonatal period is relatively infrequent and has diverse underlying etiologies. One of the more common causes appears to be orbital subperiosteal hematoma. Early detection, differentiation from other causes, and regular follow-up are essential as loss of vision can occur. We describe two cases of neonatal proptosis caused by orbital subperiosteal hematoma highlighting different diagnostic and management approaches, and provide a summary of previously reported cases. Spontaneous resolution occurs in most cases; however, emergent surgical evacuation is warranted in cases of optic nerve compression. This is the first report to provide orbital ultrasound images of uncomplicated neonatal orbital subperiosteal hematoma. Orbital ultrasound followed by magnetic resonance imaging (MRI) is a valid nonradiation approach for assessing neonatal proptosis due to subperiosteal orbital hematoma. PMID- 28674639 TI - The Relationship between Infant Facial Expressions and Food Acceptance. AB - PURPOSE OF REVIEW: To highlight the range of methodological approaches used to objectively measure hedonic responses to taste stimuli during the first year of life and how these behavioral responses change with experience. Challenges inherent to this type of research are discussed. RECENT FINDINGS: Although newborns display characteristic orofacial reactivity to four of the five basic tastes, the facial expressions made and the amount of food consumed can be modified by experience: children learn to like what they are fed. In some cases changes in facial responses are concordant with infant consumption, whereas in other cases facial reactivity follows changes in intake. SUMMARY: Together with ingestive measurements, precise and objective measurements of orofacial reactivity provide an understanding of how early experiences shift the hedonic tone of the taste of foods, the foundation of dietary preferences. PMID- 28674640 TI - In-silico prediction and modeling of the Entamoeba histolytica proteins: Serine rich Entamoeba histolytica protein and 29 kDa Cysteine-rich protease. AB - BACKGROUND: Amoebiasis is the third most common parasitic cause of morbidity and mortality, particularly in countries with poor hygienic settings. There exists an ambiguity in the diagnosis of amoebiasis, and hence there arises a necessity for a better diagnostic approach. Serine-rich Entamoeba histolyticaprotein (SREHP), peroxiredoxin and Gal/GalNAc lectin are pivotal in E. histolyticavirulence and are extensively studied as diagnostic and vaccine targets. For elucidating the cellular function of these proteins, details regarding their respective quaternary structures are essential. However, studies in this aspect are scant. Hence, this study was carried out to predict the structure of these target proteins and characterize them structurally as well as functionally using appropriate in-silicomethods. METHODS: The amino acid sequences of the proteins were retrieved from National Centre for Biotechnology Information database and aligned using ClustalW. Bioinformatic tools were employed in the secondary structure and tertiary structure prediction. The predicted structure was validated, and final refinement was carried out. RESULTS: The protein structures predicted by i-TASSER were found to be more accurate than Phyre2 based on the validation using SAVES server. The prediction suggests SREHP to be an extracellular protein, peroxiredoxin a peripheral membrane protein while Gal/GalNAc lectin was found to be a cell-wall protein. Signal peptides were found in the amino-acid sequences of SREHP and Gal/GalNAc lectin, whereas they were not present in the peroxiredoxin sequence. Gal/GalNAc lectin showed better antigenicity than the other two proteins studied. All the three proteins exhibited similarity in their structures and were mostly composed of loops. DISCUSSION: The structures of SREHP and peroxiredoxin were predicted successfully, while the structure of Gal/GalNAc lectin could not be predicted as it was a complex protein composed of sub-units. Also, this protein showed less similarity with the available structural homologs. The quaternary structures of SREHP and peroxiredoxin predicted from this study would provide better structural and functional insights into these proteins and may aid in development of newer diagnostic assays or enhancement of the available treatment modalities. PMID- 28674641 TI - Quantifying the human vaginal community state types (CSTs) with the species specificity index. AB - The five community state types (CSTs) first identified by Ravel et al. (2011) offered a powerful scheme to classify the states of human vaginal microbial communities (HVMC). The classification is a significant advance because it devised an effective handle to deal with the enormous inter-subject heterogeneity and/or intra-subject temporal variability, the quantification of which is extremely difficult but of critical importance such as the understanding of BV (bacterial vaginosis) etiology. Indeed, arguably the most plausible ecological hypothesis for interpreting the BV etiology heavily depends on the CST classification (Gajer et al., 2012; Ma, Forney & Ravel, 2012; Ravel et al., 2011). Nevertheless, the current form of CSTs is still qualitative and lacks a quantitative criterion to determine the CSTs. In this article, we develop a quantitative tool that can reliably distinguish the CSTs by applying the species specificity of Mariadassou, Pichon & Ebert (2015) and the specificity aggregation index (SAI) we propose in this study. The new tool accurately characterized the classifications of the five CSTs with both 400-crosssectional cohort (Ravel et al., 2011) and 32-longitudinal cohort (Gajer et al., 2012) studies originally utilized to develop the CST scheme. Furthermore, it offers a mechanistic interpretation of the original CST scheme by invoking the paradigm of specificity continuum for species adaptation and distribution. The advances we made may not only facilitate the accurate applications of the CST scheme, but also offer hints towards an effective tool for microbiome typing such as classifying gut enterotypes. PMID- 28674642 TI - A fossil unicorn crestfish (Teleostei, Lampridiformes, Lophotidae) from the Eocene of Iran. AB - Lophotidae, or crestfishes, is a family of rare deep-sea teleosts characterised by an enlarged horn-like crest on the forehead. They are poorly represented in the fossil record, by only three described taxa. One specimen attributed to Lophotidae has been described from the pelagic fauna of the middle-late Eocene Zagros Basin, Iran. Originally considered as a specimen of the fossil lophotid ?Protolophotus, it is proposed hereby as a new genus and species ?Babelichthys olneyi, gen. et sp. nov., differs from the other fossil lophotids by its relatively long and strongly projecting crest, suggesting a close relationship with the modern unicorn crestfish, Eumecichthys. This new taxon increases the diversity of the deep-sea teleost fauna to which it belongs, improving our understanding of the taxonomic composition of the early Cenozoic mesopelagic ecosystems. PMID- 28674643 TI - Does colorectal cancer significantly influence the assembly of gut microbial communities? AB - Colorectal cancer (CRC) is the third commonest malignant tumor. Previous studies have revealed that the composition change of the human gut microbiome, measured by community diversity, is associated with the progression of CRC. However, a further question, whether or not the mechanism of community assembly and diversity maintenance of the gut microbiome is influenced by CRC has not been addressed. To address this question, we applied Hubbell's neutral theory for biodiversity to reanalyze the dataset from Wang et al.'s (2012) study of the gut microbiome sampled from 46 CRC patients and 56 healthy individuals. Our reanalysis presents two important findings. Firstly, our analysis demonstrated that only around 4% (4/102) samples (in total of both the CRC and control groups) have their species abundance distribution (SAD) satisfied the prediction of the neutral theory null model. No significant difference in the number of the samples satisfying the neutral null model was detected between the healthy individuals and CRC patients, suggesting that the nature or mechanism of community assembly and diversity maintenance of the gut microbiome is not significantly influenced by CRC. That is, the stochasticity of survival, reproduction and migration of gut microbes, as implied by the neutral theory model, does not play a significant role in shaping the community assembly and diversity maintenance. We further infer that the alternative hypothesis to the neutral null model, i.e., the deterministic niche differentiations should be the driving forces that shape the assembly and diversity maintenance of the gut microbiome in both the healthy individuals and CRC patients. Secondly, although CRC does not seem to influence the nature of community assembly, we postulate that it may indirectly influence the outcome (i.e., the community composition as measured by community diversity) of the community assembly, possibly by influencing niche differentiations. This postulation is supported by our second finding: the diversity of the gut microbiome in CRC patients is significantly lower than that in the healthy individuals as demonstrated by the fundamental diversity parameter (theta) of the neutral theory model. This second finding offers an independent confirmation of the relationship between the CRC disease and diversity of the gut microbiome, about which existing studies have presented conflicting evidences. Finally, we suggest that hybrid modeling which integrates both the neutral and niche theories should be explored in future studies to further understanding of the CRC influence on the human gut microbiome. PMID- 28674644 TI - Europatitan eastwoodi, a new sauropod from the lower Cretaceous of Iberia in the initial radiation of somphospondylans in Laurasia. AB - The sauropod of El Oterillo II is a specimen that was excavated from the Castrillo de la Reina Formation (Burgos, Spain), late Barremian-early Aptian, in the 2000s but initially remained undescribed. A tooth and elements of the axial skeleton, and the scapular and pelvic girdle, represent it. It is one of the most complete titanosauriform sauropods from the Early Cretaceous of Europe and presents an opportunity to deepen our understanding of the radiation of this clade in the Early Cretaceous and study the paleobiogeographical relationships of Iberia with Gondwana and with other parts of Laurasia. The late Barremian-early Aptian is the time interval in the Cretaceous with the greatest diversity of sauropod taxa described in Iberia: two titanosauriforms, Tastavinsaurus and Europatitan; and a rebbachisaurid, Demandasaurus. The new sauropod Europatitan eastwoodi n. gen. n. sp. presents a series of autapomorphic characters in the presacral vertebrae and scapula that distinguish it from the other sauropods of the Early Cretaceous of Iberia. Our phylogenetic study locates Europatitan as the basalmost member of the Somphospondyli, clearly differentiated from other clades such as Brachiosauridae and Titanosauria, and distantly related to the contemporaneous Tastavinsaurus. Europatitan could be a representative of a Eurogondwanan fauna like Demandasaurus, the other sauropod described from the Castrillo de la Reina Formation. The presence of a sauropod fauna with marked Gondwananan affinities in the Aptian of Iberia reinforces the idea of faunal exchanges between this continental masses during the Early Cretaceous. Further specimens and more detailed analysis are needed to elucidate if this Aptian fauna is caused by the presence of previously unnoticed Aptian land bridges, or it represents a relict fauna from an earlier dispersal event. PMID- 28674645 TI - Infestation of parasitic rhizocephalan barnacles Sacculina beauforti (Cirripedia, Rhizocephala) in edible mud crab, Scylla olivacea. AB - Screening of mud crab genus Scylla was conducted in four locations (Marudu Bay, Lundu, Taiping, Setiu) representing Malaysia. Scylla olivacea with abnormal primary and secondary sexual characters were prevalent (approximately 42.27% of the local screened S. olivacea population) in Marudu Bay, Sabah. A total of six different types of abnormalities were described. Crabs with type 1 and type 3 were immature males, type 2 and type 4 were mature males, type 5 were immature females and type 6 were mature females. The abdomen of all crabs with abnormalities were dented on both sides along the abdomen's middle line. Abnormal crabs showed significant variation in their size, weight, abdomen width and/or gonopod or pleopod length compared to normal individuals. The mean body weight of abnormal crabs (type 1-5) were higher than normal crabs with smaller body size, while females with type 6 abnormality were always heavier than the normal counterparts at any given size. Sacculinid's externa were observed in the abdomen of crabs with type 4 and type 6 abnormalities. The presence of embryos within the externa and subsequent molecular analysis of partial mitochondrial COI region confirmed the rhizocephalan parasite as Sacculina beauforti. Future in-depth descriptions of the life cycle and characteristics of S. beauforti are recommended as it involves a commercially important edible crab species and the effect on human health from the consumption of crabs is of crucial concern. PMID- 28674646 TI - Construction, internal validation and implementation in a mobile application of a scoring system to predict nonadherence to proton pump inhibitors. AB - BACKGROUND: Other studies have assessed nonadherence to proton pump inhibitors (PPIs), but none has developed a screening test for its detection. OBJECTIVES: To construct and internally validate a predictive model for nonadherence to PPIs. METHODS: This prospective observational study with a one-month follow-up was carried out in 2013 in Spain, and included 302 patients with a prescription for PPIs. The primary variable was nonadherence to PPIs (pill count). Secondary variables were gender, age, antidepressants, type of PPI, non-guideline recommended prescription (NGRP) of PPIs, and total number of drugs. With the secondary variables, a binary logistic regression model to predict nonadherence was constructed and adapted to a points system. The ROC curve, with its area (AUC), was calculated and the optimal cut-off point was established. The points system was internally validated through 1,000 bootstrap samples and implemented in a mobile application (Android). RESULTS: The points system had three prognostic variables: total number of drugs, NGRP of PPIs, and antidepressants. The AUC was 0.87 (95% CI [0.83-0.91], p < 0.001). The test yielded a sensitivity of 0.80 (95% CI [0.70-0.87]) and a specificity of 0.82 (95% CI [0.76-0.87]). The three parameters were very similar in the bootstrap validation. CONCLUSIONS: A points system to predict nonadherence to PPIs has been constructed, internally validated and implemented in a mobile application. Provided similar results are obtained in external validation studies, we will have a screening tool to detect nonadherence to PPIs. PMID- 28674647 TI - Switching spatial scale reveals dominance-dependent social foraging tactics in a wild primate. AB - When foraging in a social group, individuals are faced with the choice of sampling their environment directly or exploiting the discoveries of others. The evolutionary dynamics of this trade-off have been explored mathematically through the producer-scrounger game, which has highlighted socially exploitative behaviours as a major potential cost of group living. However, our understanding of the tight interplay that can exist between social dominance and scrounging behaviour is limited. To date, only two theoretical studies have explored this relationship systematically, demonstrating that because scrounging requires joining a competitor at a resource, it should become exclusive to high-ranking individuals when resources are monopolisable. In this study, we explore the predictions of this model through observations of the natural social foraging behaviour of a wild population of chacma baboons (Papio ursinus). We collected data through over 800 h of focal follows of 101 adults and juveniles across two troops over two 3-month periods. By recording over 7,900 social foraging decisions at two spatial scales we show that, when resources are large and economically indefensible, the joining behaviour required for scrounging can occur across all social ranks. When, in contrast, dominant individuals can aggressively appropriate a resource, such joining behaviour becomes increasingly difficult to employ with decreasing social rank because adult individuals can only join others lower ranking than themselves. Our study supports theoretical predictions and highlights potentially important individual constraints on the ability of individuals of low social rank to use social information, driven by competition with dominant conspecifics over monopolisable resources. PMID- 28674648 TI - To call a cloud 'cirrus': sound symbolism in names for categories or items. AB - The aim of the present paper is to experimentally test whether sound symbolism has selective effects on labels with different ranges-of-reference within a simple noun-hierarchy. In two experiments, adult participants learned the make up of two categories of unfamiliar objects ('alien life forms'), and were passively exposed to either category-labels or item-labels, in a learning-by-guessing categorization task. Following category training, participants were tested on their visual discrimination of object pairs. For different groups of participants, the labels were either congruent or incongruent with the objects. In Experiment 1, when trained on items with individual labels, participants were worse (made more errors) at detecting visual object mismatches when trained labels were incongruent. In Experiment 2, when participants were trained on items in labelled categories, participants were faster at detecting a match if the trained labels were congruent, and faster at detecting a mismatch if the trained labels were incongruent. This pattern of results suggests that sound symbolism in category labels facilitates later similarity judgments when congruent, and discrimination when incongruent, whereas for item labels incongruence generates error in judgements of visual object differences. These findings reveal that sound symbolic congruence has a different outcome at different levels of labelling within a noun hierarchy. These effects emerged in the absence of the label itself, indicating subtle but pervasive effects on visual object processing. PMID- 28674649 TI - Non-bleached colonies of massive Porites may attract fishes for selective grazing during mass bleaching events. AB - In this study we investigated the variation in grazing scar densities between bleached and non-bleached colonies of massive Porites species in Sekisei Lagoon (Okinawa, southwestern Japan) during a mass bleaching event in 2016. The grazing scar densities and bleaching susceptibility varied among neighboring colonies of massive Porites spp. However, non-bleached colonies had significantly more surface scars than bleached colonies. One explanation for these variations is that corallivorous fishes may selectively graze on non-bleached, thermally tolerant colonies. This is the first report of a relationship between grazing scars and the bleaching status of massive Porites spp. colonies during a mass bleaching event. PMID- 28674650 TI - An adaptive singular spectrum analysis method for extracting brain rhythms of electroencephalography. AB - Artifacts removal and rhythms extraction from electroencephalography (EEG) signals are important for portable and wearable EEG recording devices. Incorporating a novel grouping rule, we proposed an adaptive singular spectrum analysis (SSA) method for artifacts removal and rhythms extraction. Based on the EEG signal amplitude, the grouping rule determines adaptively the first one or two SSA reconstructed components as artifacts and removes them. The remaining reconstructed components are then grouped based on their peak frequencies in the Fourier transform to extract the desired rhythms. The grouping rule thus enables SSA to be adaptive to EEG signals containing different levels of artifacts and rhythms. The simulated EEG data based on the Markov Process Amplitude (MPA) EEG model and the experimental EEG data in the eyes-open and eyes-closed states were used to verify the adaptive SSA method. Results showed a better performance in artifacts removal and rhythms extraction, compared with the wavelet decomposition (WDec) and another two recently reported SSA methods. Features of the extracted alpha rhythms using adaptive SSA were calculated to distinguish between the eyes open and eyes-closed states. Results showed a higher accuracy (95.8%) than those of the WDec method (79.2%) and the infinite impulse response (IIR) filtering method (83.3%). PMID- 28674652 TI - The influence of storage time and temperature on propofol concentrations in canine blood and plasma. AB - Propofol is an intravenous anesthetic commonly used due to its favorable pharmacokinetic and pharmacodynamic profile. There are discrepancies in the literature about the most appropriate sample for determining propofol concentrations. Although plasma has been used for determining propofol concentrations, whole blood has been the preferred sample. There is also a lack of consistency in the literature on the effect of storage time and temperature on propofol concentrations and this may lead to errors in the design of pharmacokinetic/pharmacodynamics studies. The purpose of this study was to determine the difference in propofol concentrations in whole blood versus plasma and to evaluate the influence of storage time (56 days) and temperature (4 degrees C, -20 degrees C, -80 degrees C) on the stability of propofol concentrations in blood and plasma samples. Results from the study indicate that whole blood and plasma samples containing propofol stored at -80 degrees C have concentrations as high as or higher than those stored at 4 degrees C or -20 degrees C for 56 days; thus, -80 degrees C is an appropriate temperature for propofol sample storage. Plasma propofol concentrations were consistently higher than whole blood for all three storage temperatures. Consequently, plasma is the most appropriate sample for propofol analysis due to its consistent determinations. PMID- 28674651 TI - A new parrot taxon from the Yucatan Peninsula, Mexico-its position within genus Amazona based on morphology and molecular phylogeny. AB - Parrots (Psittaciformes) are a diverse group of birds which need urgent protection. However, many taxa from this order have an unresolved status, which makes their conservation difficult. One species-rich parrot genus is Amazona, which is widely distributed in the New World. Here we describe a new Amazona form, which is endemic to the Yucatan Peninsula. This parrot is clearly separable from other Amazona species in eleven morphometric characters as well as call and behavior. The clear differences in these features imply that the parrot most likely represents a new species. In contrast to this, the phylogenetic tree based on mitochondrial markers shows that this parrot groups with strong support within A. albifrons from Central America, which would suggest that it is a subspecies of A. albifrons. However, taken together tree topology tests and morphometric analyses, we can conclude that the new parrot represents a recently evolving species, whose taxonomic status should be further confirmed. This lineage diverged from its closest relative about 120,000 years ago and was subjected to accelerated morphological and behavioral changes like some other representatives of the genus Amazona. Our phylogenies, which are so far the most comprehensive for Amazona taxa enabled us to consider the most feasible scenarios about parrot colonization of the Greater and Lesser Antilles and Central America from South America mainland. The molecular dating of these migrations and diversification rate were correlated with climatic and geological events in the last five million years, giving an interesting insight into Amazon parrot phylogeography and their evolution in general. PMID- 28674653 TI - The comparative osteology of Plesiochelys bigleri n. sp., a new coastal marine turtle from the Late Jurassic of Porrentruy (Switzerland). AB - BACKGROUND: During the Late Jurassic, several groups of eucryptodiran turtles inhabited the shallow epicontinental seas of Western Europe. Plesiochelyidae are an important part of this first radiation of crown-group turtles into coastal marine ecosystems. Fossils of Plesiochelyidae occur in many European localities, and are especially abundant in the Kimmeridgian layers of the Swiss Jura Mountains (Solothurn and Porrentruy). In the mid-19th century, the quarries of Solothurn (NW Switzerland) already provided a large amount of fossil turtles, most notably Plesiochelys etalloni, the best-known plesiochelyid species. Recent excavations in the Porrentruy area (NW Switzerland) revealed new fossils of Plesiochelys, including numerous well-preserved shells with associated cranial and postcranial material. METHODS/RESULTS: Out of 80 shells referred to Plesiochelys, 41 are assigned to a new species, Plesiochelys bigleri n. sp., including a skull-shell association. We furthermore refer 15 shells to Plesiochelys etalloni, and 24 shells to Plesiochelys sp. Anatomical comparisons show that Plesiochelys bigleri can clearly be differentiated from Plesiochelys etalloni by cranial features. The shell anatomy and the appendicular skeleton of Plesiochelys bigleri and Plesiochelys etalloni are very similar. However, a statistical analysis demonstrates that the thickness of neural bones allows to separate the two species based on incomplete material. This study furthermore illustrates the extent of intraspecific variation in the shell anatomy of Plesiochelys bigleri and Plesiochelys etalloni. PMID- 28674654 TI - Ureteral stricture formation after removal of proximal ureteral stone: retroperitoneal laparoscopic ureterolithotomy versus ureteroscopy with holmium: YAG laser lithotripsy. AB - OBJECTIVE: To compare the risk of postoperative ureteral stricture formation following retroperitoneal laparoscopic ureterolithotomy (RPLU) and ureteroscopy with holmium: YAG laser lithotripsy (URSL) in patients with proximal ureteral stones. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent RPLU or URSL for proximal ureteral stones between April 2011 and May 2015. Patients were allocated into URSL group or RPLU group and the outcomes were compared. RESULTS: A total of 201 patients who underwent 209 procedures including 159 URSL and 50 RPLU with a median follow-up of 30 months were included. No significant difference was observed among the two groups in most baseline parameters, while the stone size was significantly larger in the RPLU group (11.37 +/- 2.97 vs 14.04 +/- 4.38 mm, p = 0.000). Patients in RPLU group had markedly longer operative time (p = 0.000) and longer postoperative hospital stay (p = 0.000). The initial and one-month stone-free rates were significantly higher in the RPLU group (78.6% vs 100%, p = 0.000 and 82.4% vs 100%, p = 0.001, respectively). Patients in the RPLU had a higher complication rate (18.0% vs 9.4%, p = 0.098) and lower ureteral stricture rate (2.5% vs 2.0%, p = 1.000), while the difference was not significant. Further logistic regression model identified RPLU and female sex as independent risk factors for postoperative complication (Odds Ratio[OR] = 3.57, p = 0.035 and OR = 3.57, p = 0.025, respectively); however, URSL was not an independent risk factor for the formation of postoperative ureteral stricture after adjusting confounding variables (OR = 0.90, p = 0.935). CONCLUSION: RPLU and URSL have similar postoperative ureteral stricture formation risks. RPLU can provide significantly higher stone clearance rate, but relates with more postoperative complications. PMID- 28674655 TI - Contrasting biological features in morphologically cryptic Mediterranean sponges. AB - Sponges are key organisms in the marine benthos where they play essential roles in ecological processes such as creating new niches, competition for resources, and organic matter recycling. Despite the increasing number of taxonomical studies, many sponge species remain hidden, whether unnoticed or cryptic. The occurrence of cryptic species may confound ecological studies by underestimating biodiversity. In this study, we monitored photographically growth, fusions, fissions, and survival of two morphologically cryptic species Hemimycale mediterranea Uriz, Garate & Agell, 2017 and H. columella (Bowerbank, 1874). Additionally, we characterized the main environmental factors of the corresponding species habitats, trying to ascertain whether some abiotic factors were correlated with the distribution of these species. Sponge monitoring was performed monthly. Seawater samples were collected the same monitoring days in the vicinity of the target sponges. Results showed contrasting growth and survival patterns for each species: H. mediterranea totally disappeared after larval release while 64% of individuals of H. columella survived the entire two years we monitored. The species also differed in the number of fissions and fusions. These events were evenly distributed throughout the year in the H. mediterranea population but concentrated in cold months in H. columella. No measured environmental factor correlated with H. mediterranea growth rates, while temperature and dissolved organic nitrogen were negatively correlated with H. columella growth rates. The strong differences in depth distribution, survival, growth, fusions, and fissions found between these two cryptic species, highlights the importance of untangling cryptic species before ecological studies are performed in particular when these species share geographical distribution. PMID- 28674656 TI - SubVis: an interactive R package for exploring the effects of multiple substitution matrices on pairwise sequence alignment. AB - Understanding how proteins mutate is critical to solving a host of biological problems. Mutations occur when an amino acid is substituted for another in a protein sequence. The set of likelihoods for amino acid substitutions is stored in a matrix and input to alignment algorithms. The quality of the resulting alignment is used to assess the similarity of two or more sequences and can vary according to assumptions modeled by the substitution matrix. Substitution strategies with minor parameter variations are often grouped together in families. For example, the BLOSUM and PAM matrix families are commonly used because they provide a standard, predefined way of modeling substitutions. However, researchers often do not know if a given matrix family or any individual matrix within a family is the most suitable. Furthermore, predefined matrix families may inaccurately reflect a particular hypothesis that a researcher wishes to model or otherwise result in unsatisfactory alignments. In these cases, the ability to compare the effects of one or more custom matrices may be needed. This laborious process is often performed manually because the ability to simultaneously load multiple matrices and then compare their effects on alignments is not readily available in current software tools. This paper presents SubVis, an interactive R package for loading and applying multiple substitution matrices to pairwise alignments. Users can simultaneously explore alignments resulting from multiple predefined and custom substitution matrices. SubVis utilizes several of the alignment functions found in R, a common language among protein scientists. Functions are tied together with the Shiny platform which allows the modification of input parameters. Information regarding alignment quality and individual amino acid substitutions is displayed with the JavaScript language which provides interactive visualizations for revealing both high-level and low-level alignment information. PMID- 28674657 TI - Variation in the pelvic and pectoral girdles of Australian Oligo-Miocene mekosuchine crocodiles with implications for locomotion and habitus. AB - Australian Oligo-Miocene mekosuchines (Crocodylia; Crocodyloidea) display wide diversity in cranial shape and inferred hunting strategies. Terrestrial habitus has been inferred for these distinctive predators. A direct morphological signal for locomotion can be expected in the postcrania, particularly the pelvic and pectoral girdles. Here we describe fossil materials of the girdles, which chart their morphological variation in the subfamily from Eocene through to Middle Miocene. Over this period, both girdles undergo significant morphological changes. Notably, an enclosed, ventrally orientated acetabulum in the ilium is developed in one lineage. This recapitulates the erect parasagittal configuration of the pelvic limb seen in many Mesozoic crocodylomorph lineages, suggesting consistent use of erect high-walking in these mekosuchines. Other pelves from the same Oligo-Miocene deposits display morphology closer to modern crocodilians, suggesting a partitioning of locomotory strategy among sympatric mekosuchines. Plesiomorphic and derived pelvic girdles are distinguishable by parsimony analysis, and the earliest examples of the mekosuchine pelvis more closely resemble gavialids and alligatorids while latter forms converge on crown group crocodylids in the morphology of the iliac crest. This suggests that a revaluation of the base relationship of Mekosuchinae within Eusuchia is necessary. PMID- 28674658 TI - Confluence does not affect the expression of miR-375 and its direct targets in rat and human insulin-secreting cell lines. AB - MicroRNAs are small non-coding RNAs, which negatively regulate the expression of target genes. They have emerged as important modulators in beta cell compensation upon increased metabolic demand, failure of which leads to reduced insulin secretion and type 2 diabetes. To elucidate the function of miRNAs in beta cells, insulin-secreting cell lines, such as the rat insulinoma INS-1 832/13 and the human EndoC-betaH1, are widely used. Previous studies in the cancer field have suggested that miRNA expression is influenced by confluency of adherent cells. We therefore aimed to investigate whether one of the most enriched miRNAs in the pancreatic endocrine cells, miR-375, and two of its validated targets in mouse, Cav1 and Aifm1, were differentially-expressed in cell cultures with different confluences. Additionally, we measured the expression of other miRNAs, such as miR-152, miR-130a, miR-132, miR-212 and miR-200a, with known roles in beta cell function. We did not see any significant expression changes of miR-375 nor any of the two targets, in both the rat and human beta cell lines at different confluences. Interestingly, among the other miRNAs measured, the expression of miR-132 and miR-212 positively correlated with confluence, but only in the INS-1 832/13 cells. Our results show that the expression of miR-375 and other miRNAs with known roles in beta cell function is independent of, or at least minimally influenced by the density of proliferating adherent cells, especially within the confluence range optimal for functional assays to elucidate miRNA-dependent regulatory mechanisms in the beta cell. PMID- 28674659 TI - Pleistocene reefs of the Egyptian Red Sea: environmental change and community persistence. AB - The fossil record of Red Sea fringing reefs provides an opportunity to study the history of coral-reef survival and recovery in the context of extreme environmental change. The Middle Pleistocene, the Late Pleistocene, and modern reefs represent three periods of reef growth separated by glacial low stands during which conditions became difficult for symbiotic reef fauna. Coral diversity and paleoenvironments of eight Middle and Late Pleistocene fossil terraces are described and characterized here. Pleistocene reef zones closely resemble reef zones of the modern Red Sea. All but one species identified from Middle and Late Pleistocene outcrops are also found on modern Red Sea reefs despite the possible extinction of most coral over two-thirds of the Red Sea basin during glacial low stands. Refugia in the Gulf of Aqaba and southern Red Sea may have allowed for the persistence of coral communities across glaciation events. Stability of coral communities across these extreme climate events indicates that even small populations of survivors can repopulate large areas given appropriate water conditions and time. PMID- 28674660 TI - Maternal alcohol consumption during pregnancy and child's cognitive performance at 6-8 years of age in rural Burkina Faso: an observational study. AB - BACKGROUND: In Burkina Faso, it is not uncommon for mothers to drink alcohol, even during pregnancy. We aimed to study the association between maternal alcohol consumption during pregnancy and the child's cognitive performance using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II) and the Children's Category Test Level 1 (CCT-1) in rural Burkina Faso. METHODS: We conducted a follow-up study of a community cluster-randomised Exclusive breastfeeding trial, and re-enrolled the children in rural Burkina Faso. A total of 518 children (268 boys and 250 girls) aged 6-8 years were assessed using the KABC-II and the CCT-1. We examined the effect size difference using Cohen's d and conducted a linear regression analysis to examine the association. RESULTS: Self-reported alcohol consumption during pregnancy was 18.5% (96/518). Children whose mothers reported alcohol consumption during pregnancy performed significantly poorly for memory and spatial abilities tests from small effect size difference for 'Atlantis' (0.27) and 'Triangle' (0.29) to moderate effect size difference for 'Number recall' (0.72) compared to children whose mothers did not consume alcohol during pregnancy; the exposed children scored significantly higher errors with a small effect size (0.37) at problem solving (CCT-1) test compared to unexposed children. At unstandardized and standardized multivariable analysis, children whose mothers reported alcohol consumption during pregnancy performed significantly poorer for memory-'Atlantis' (p = 0.03) and 'Number recall' (p = 0.0001), and spatial ability tests-'Triangle' (p = 0.03); they scored significantly higher errors at problem solving CCT-1 test (p = 0.002); all the results were adjusted for age, sex, schooling, stunting, father's education, mother's employment and the promotion of exclusive breastfeeding. No statistical association was found for visual abilities-'Conceptual Thinking', 'Face recognition', 'Story completion', and reasoning tests-'Rover', 'Block counting', and 'Pattern Reasoning'. CONCLUSION: Maternal alcohol consumption during pregnancy is associated with poorer cognitive performance for memory, spatial ability, and problem solving tests in the offspring in rural Burkina Faso. Futures studies needs to assess in more detail the maternal alcohol consumption patterns in Burkina Faso and possible preventive strategies. PMID- 28674661 TI - Design process and preliminary psychometric study of a video game to detect cognitive impairment in senior adults. AB - INTRODUCTION: Assessment of episodic memory has been traditionally used to evaluate potential cognitive impairments in senior adults. Typically, episodic memory evaluation is based on personal interviews and pen-and-paper tests. This article presents the design, development and a preliminary validation of a novel digital game to assess episodic memory intended to overcome the limitations of traditional methods, such as the cost of its administration, its intrusive character, the lack of early detection capabilities, the lack of ecological validity, the learning effect and the existence of confounding factors. MATERIALS AND METHODS: Our proposal is based on the gamification of the California Verbal Learning Test (CVLT) and it has been designed to comply with the psychometric characteristics of reliability and validity. Two qualitative focus groups and a first pilot experiment were carried out to validate the proposal. RESULTS: A more ecological, non-intrusive and better administrable tool to perform cognitive assessment was developed. Initial evidence from the focus groups and pilot experiment confirmed the developed game's usability and offered promising results insofar its psychometric validity is concerned. Moreover, the potential of this game for the cognitive classification of senior adults was confirmed, and administration time is dramatically reduced with respect to pen-and-paper tests. LIMITATIONS: Additional research is needed to improve the resolution of the game for the identification of specific cognitive impairments, as well as to achieve a complete validation of the psychometric properties of the digital game. CONCLUSION: Initial evidence show that serious games can be used as an instrument to assess the cognitive status of senior adults, and even to predict the onset of mild cognitive impairments or Alzheimer's disease. PMID- 28674662 TI - BMI prediction within a Korean population. AB - BACKGROUND: Body Mass Index (BMI) is widely regarded as an important clinical trait for obesity and other diseases such as Type 2 diabetes, coronary heart disease, and osteoarthritis. METHODS: This study uses 6,011 samples of genotype data from ethnic Korean subjects. The data was retrieved from the Korea Association Resource. To identify the BMI-related markers within the Korean population, we collected genome-wide association study (GWAS) markers using a GWAS catalog and also obtained other markers from nearby regions. Of the total 6,011 samples, 5,410 subjects were used as part of a single nucleotide polymorphism (SNP) selection set in order to identify the overlapping BMI associated SNPs within a 10-fold cross validation. RESULTS: We selected nine SNPs (rs12566985 (FPGT-TNNI3K), rs6545809 (ADCY3), rs2943634 (located near LOC646736), rs734597 (located near TFAP2B), rs11030104 (BDNF), rs7988412 (GTF3A), rs2241423 (MAP2K5), rs7202116 (FTO), and rs6567160 (located near LOC105372152) to assist in BMI prediction. The calculated weighted genetic risk scores based on the selected 9 SNPs within the SNP selection set were applied to the final validation set consisting of 601 samples. Our results showed upward trends in the BMI values (P < 0.0001) within the 10-fold cross validation process for R2 > 0.22. These trends were also observed within the validation set for all subjects, as well as within the validation sets divided by gender (P < 0.0001, R2 > 0.46). DISCUSSION: The set of nine SNPs identified in this study may be useful for prospective predictions of BMI. PMID- 28674663 TI - The identification of Oligo-Miocene mammalian palaeocommunities from the Riversleigh World Heritage Area, Australia and an appraisal of palaeoecological techniques. AB - Fourteen of the best sampled Oligo-Miocene local faunas from the Riversleigh World Heritage Area, north-western Queensland, Australia are analysed using classification and ordination techniques to identify potential mammalian palaeocommunities and palaeocommunity types. Abundance data for these faunas are used, for the first time, in conjunction with presence/absence data. An early Miocene Faunal Zone B and two middle Miocene Faunal Zone C palaeocommunities are recognised, as well as one palaeocommunity type. Change in palaeocommunity structure, between the early Miocene and middle Miocene, may be the result of significant climate change during the Miocene Carbon Isotope Excursion. The complexes of local faunas identified will allow researchers to use novel palaeocommunities in future analyses of Riversleigh's fossil faunas. The utility of some palaeoecological multivariate indices and techniques is examined. The Dice index is found to outperform other binary similarity/distance coefficients, while the UPGMA algorithm is more useful than neighbour joining. Evidence is equivocal for the usefulness of presence/absence data compared to abundance. PMID- 28674664 TI - Recombinant expression in E. coli of human FGFR2 with its transmembrane and extracellular domains. AB - Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases containing three domains: an extracellular receptor domain, a single transmembrane helix, and an intracellular tyrosine kinase domain. FGFRs are activated by fibroblast growth factors (FGFs) as part of complex signal transduction cascades regulating angiogenesis, skeletal formation, cell differentiation, proliferation, cell survival, and cancer. We have developed the first recombinant expression system in E. coli to produce a construct of human FGFR2 containing its transmembrane and extracellular receptor domains. We demonstrate that the expressed construct is functional in binding heparin and dimerizing. Size exclusion chromatography demonstrates that the purified FGFR2 does not form a complex with FGF1 or adopts an inactive dimer conformation. Progress towards the successful recombinant production of intact FGFRs will facilitate further biochemical experiments and structure determination that will provide insight into how extracellular FGF binding activates intracellular kinase activity. PMID- 28674665 TI - Local application of osteoprotegerin-chitosan gel in critical-sized defects in a rabbit model. AB - BACKGROUND: Osteoprotegerin (OPG) is used for the systemic treatment of bone diseases, although it has many side effects. The aim of this study was to investigate a newly formulated OPG-chitosan gel for local application to repair bone defects. Recent studies have reported that immunodetection of osteopontin (OPN) and osteocalcin (OC) can be used to characterise osteogenesis and new bone formation. METHODS: The osteogenic potential of the OPG-chitosan gel was evaluated in rabbits. Critical-sized defects were created in the calvarial bone, which were either left unfilled (control; group I), or filled with chitosan gel (group II) or OPG-chitosan gel (group III), with rabbits sacrificed at 6 and 12 weeks. Bone samples from the surgical area were decalcified and treated with routine histological and immunohistochemical protocols using OC, OPN, and cathepsin K (osteoclast marker) antibodies. The toxicity of the OPG-chitosan gel was evaluated by biochemical assays (liver and kidney function tests). RESULTS: The mean bone growth in defects filled with the OPG-chitosan gel was significantly higher than those filled with the chitosan gel or the unfilled group (p < 0.05). At 6 and 12 weeks, the highest levels of OC and OPN markers were found in the OPG-chitosan gel group, followed by the chitosan gel group. The number of osteoclasts in the OPG-chitosan gel group was lower than the other groups. The results of the liver and kidney functional tests indicated no signs of harmful systemic effects of treatment. In conclusion, the OPG-chitosan gel has many characteristics that make it suitable for bone repair and regeneration, highlighting its potential benefits for tissue engineering applications. PMID- 28674666 TI - Who are the important predators of sea turtle nests at Wreck Rock beach? AB - Excessive sea turtle nest predation is a problem for conservation management of sea turtle populations. This study assessed predation on nests of the endangered loggerhead sea turtle (Caretta caretta) at Wreck Rock beach adjacent to Deepwater National Park in Southeast Queensland, Australia after a control program for feral foxes was instigated. The presence of predators on the nesting dune was evaluated by tracking plots (2 * 1 m) every 100 m along the dune front. There were 21 (2014-2015) and 41 (2015-2016) plots established along the dune, and these were monitored for predator tracks daily over three consecutive months in both nesting seasons. Predator activities at nests were also recorded by the presence of tracks on top of nests until hatchlings emerged. In addition, camera traps were set to record the predator activity around selected nests. The tracks of the fox (Vulpes vulpes) and goanna (Varanus spp) were found on tracking plots. Tracking plots, nest tracks and camera traps indicated goanna abundance varied strongly between years. Goannas were widely distributed along the beach and had a Passive Activity Index (PAI) (0.31 in 2014-2015 and 0.16 in 2015-2016) approximately seven times higher than that of foxes (PAI 0.04 in 2014-2015 and 0.02 in 2015-2016). Five hundred and twenty goanna nest visitation events were recorded by tracks but no fox tracks were found at turtle nests. Camera trap data indicated that yellow-spotted goannas (Varanus panoptes) appeared at loggerhead turtle nests more frequently than lace monitors (V. varius) did, and further that lace monitors only predated nests previously opened by yellow-spotted goannas. No foxes were recorded at nests with camera traps. This study suggests that large male yellow-spotted goannas are the major predator of sea turtle nests at the Wreck Rock beach nesting aggregation and that goanna activity varies between years. PMID- 28674668 TI - 3D-Analysis of a non-planispiral ammonoid from the Hunsruck Slate: natural or pathological variation? AB - We herein examine the only known non-planispirally coiled early Devonian ammonoid, the holotype specimen of Ivoites opitzi, to investigate if the host was encrusted in vivo and if these sclerobionts were responsible for the trochospiral coiling observed in this unique specimen. To test if the presence of runner-like sclerobionts infested the historically collected specimen of Ivoites opitzi during its life, we used microCT to produce a three-dimensional model of the surface of the specimen. Our results indicate that sclerobionts grew across the outer rim (venter) on both sides of the ammonoid conch at exactly the location where the deviation from the planispiral was recognized, and where subsequent ammonoid growth would likely preclude encrustation. This indicates in vivo encrustation of the I. opitzi specimen, and represents the earliest documentation of the phenomenon. Further, this suggests that non-planispiral coiling in I. opitzi was likely pathologically induced and does not represent natural morphological variation in the species. Despite the observed anomalies in coiling, the specimen reached adulthood and retains important identifying morphological features, suggesting the ammonoid was minimally impacted by encrustation in life. As such, appointing a new type specimen-as suggested by some authors-for the species is not necessary. In addition, we identify the sclerobionts responsible for modifying the coiling of this specimen as hederelloids, a peculiar group of sclerobionts likely related to phoronids. Hederelloids in the Devonian are commonly found encrusting on fossils collected in moderately deep environments within the photic zone and are rarely documented in dysphotic and aphotic samples. This indicates that when the ammonoid was encrusted it lived within the euphotic zone and supports the latest interpretations of the Hunsruck Slate depositional environment in the Bundenbach Gemunden area. PMID- 28674667 TI - -Glial and stem cell expression of murine Fibroblast Growth Factor Receptor 1 in the embryonic and perinatal nervous system. AB - BACKGROUND: Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in the development and function of multiple organs and organ systems, including the central nervous system (CNS). FGF signaling via FGFR1, one of the three FGFRs expressed in the CNS, stimulates proliferation of stem cells during prenatal and postnatal neurogenesis and participates in regulating cell-type ratios in many developing regions of the brain. Anomalies in FGFR1 signaling have been implicated in certain neuropsychiatric disorders. Fgfr1 expression has been shown, via in situ hybridization, to vary spatially and temporally throughout embryonic and postnatal development of the brain. However, in situ hybridization lacks sufficient resolution to identify which cell-types directly participate in FGF signaling. Furthermore, because antibodies raised against FGFR1 commonly cross-react with other members of the FGFR family, immunocytochemistry is not alone sufficient to accurately document Fgfr1 expression. Here, we elucidate the identity of Fgfr1 expressing cells in both the embryonic and perinatal mouse brain. METHODS: To do this, we utilized a tgFGFR1-EGFPGP338Gsat BAC line (tgFgfr1 EGFP+) obtained from the GENSAT project. The tgFgfr1-EGFP+ line expresses EGFP under the control of a Fgfr1 promoter, thereby causing cells endogenously expressing Fgfr1 to also present a positive GFP signal. Through simple immunostaining using GFP antibodies and cell-type specific antibodies, we were able to accurately determine the cell-type of Fgfr1 expressing cells. RESULTS: This technique revealed Fgfr1 expression in proliferative zones containing BLBP+ radial glial stem cells, such as the cortical and hippocampal ventricular zones, and cerebellar anlage of E14.5 mice, in addition to DCX+ neuroblasts. Furthermore, our data reveal Fgfr1 expression in proliferative zones containing BLBP+ cells of the anterior midline, hippocampus, cortex, hypothalamus, and cerebellum of P0.5 mice, in addition to the early-formed GFAP+ astrocytes of the anterior midline. DISCUSSION: Understanding when during development and where Fgfr1 is expressed is critical to improving our understanding of its function during neurodevelopment as well as in the mature CNS. This information may one day provide an avenue of discovery towards understanding the involvement of aberrant FGF signaling in neuropsychiatric disorders. PMID- 28674669 TI - Childhood and adult socioeconomic position interact to predict health in mid life in a cohort of British women. AB - BACKGROUND: Low childhood socioeconomic position (cSEP) is associated with poorer adult health, even after adult socioeconomic position (aSEP) is adjusted for. However, whether cSEP and aSEP combine additively or non-additively in predicting adult health is less well studied. Some evidence suggests that the combination of low cSEP and low aSEP is associated with worse health than would be predicted from the sum of their individual effects. METHODS: Using data from female members of the British National Child Development Study cohort, we developed continuous quantitative measures of aSEP and cSEP, and used these to predict self-rated health at ages 23, 33, and 42. RESULTS: Lower aSEP predicted poorer heath at all ages. Lower cSEP predicted poorer health at all ages, even after adjustment for aSEP, but the direct effects of cSEP were substantially weaker than those of aSEP. At age 23, the effects of cSEP and aSEP were additive. At ages 33 and 42, cSEP and aSEP interacted, such that the effects of low aSEP on health were more negative if cSEP had also been low. CONCLUSIONS: As women age, aSEP and cSEP may affect their health interactively. High cSEP, by providing a good start in life, may be partially protective against later negative impacts of low aSEP. We relate this to the extended 'silver spoon' principle recently documented in a non-human species. PMID- 28674670 TI - Movements and use of space by Mangrove Cuckoos (Coccyzus minor) in Florida, USA. AB - I used radio-telemetry to track the movements of Mangrove Cuckoos (Coccyzus minor) captured in southwest Florida. Relatively little is known about the natural history of Mangrove Cuckoos, and my goal was to provide an initial description of how individuals use space, with a focus on the size and placement of home ranges. I captured and affixed VHF radio-transmitters to 32 individuals between 2012 and 2015, and obtained a sufficient number of relocations from 16 of them to estimate home-range boundaries and describe patterns of movement. Home range area varied widely among individuals, but in general was roughly four times larger than expected based on the body size of Mangrove Cuckoos. The median core area (50% isopleth) of a home range was 42 ha (range: 9-91 ha), and the median overall home range (90% isopleth) was 128 ha (range: 28-319 ha). The median distance between estimated locations recorded on subsequent days was 298 m (95% CI [187 m-409 m]), but variation within and among individuals was substantial, and it was not uncommon to relocate individuals >1 km from their location on the previous day. Site fidelity by individual birds was low; although Mangrove Cuckoos were present year-round within the study area, I did not observe any individuals that remained on a single home range throughout the year. Although individual birds showed no evidence of avoiding anthropogenic edges, they did not incorporate developed areas into their daily movements and home ranges consisted almost entirely of mangrove forest. The persistence of the species in the study area depended on a network of conserved lands-mostly public, but some privately conserved land as well-because large patches of mangrove forest did not occur on tracts left unprotected from development. PMID- 28674671 TI - Long-term monitoring reveals an avian species credit in secondary forest patches of Costa Rica. AB - Degraded and secondary forests comprise approximately 50% of remaining tropical forest. Bird community characteristics and population trends in secondary forests are infrequently studied, but secondary forest may serve as a "safety net" for tropical biodiversity. Less understood is the occurrence of time-delayed, community-level dynamics such as an extinction debt of specialist species or a species credit resulting from the recolonization of forest patches by extirpated species. We sought to elucidate patterns and magnitudes of temporal change in avian communities in secondary forest patches in Southern Costa Rica biannually over a 10 year period during the late breeding season and mid-winter. We classified birds caught in mist nets or recorded in point counts by residency status, and further grouped them based on preferred habitat, sensitivity to disturbance, conservation priority, foraging guild, and foraging strata. Using hierarchical, mixed-effects models we tested for trends among species that share traits. We found that permanent-resident species increased over time relative to migrants. In both seasons, primary forest species generally increased while species typical of secondary forest, scrub, or edge declined. Species relatively sensitive to habitat disturbance increased significantly over time, whereas birds less sensitive to disturbance decreased. Similarly, generalists with higher habitat breadth scores declined. Because, we found very few changes in vegetation characteristics in secondary forest patches, shifts in the avian community toward primary forest species represent a species credit and are likely related to vegetation changes in the broader landscape. We suggest that natural regeneration and maturation of secondary forests should be recognized as a positive conservation development of potential benefit even to species typical of primary forest. PMID- 28674672 TI - Socioeconomic status influences sex ratios in a Chinese rural population. AB - According to the logic of the Trivers-Willard hypothesis, in a human population, if socioeconomic status is transmitted across generations to some extent, and if sons of high-status parents tend to have higher reproductive success than daughters, while daughters of low-status parents tend to have higher reproductive success than sons, then we should expect that offspring sex ratio is positively associated with socioeconomic status. This study examines whether the assumptions and prediction of this hypothesis apply to a rural population in northern China. Results show that (1) current family socioeconomic status is positively related to family head's father's socioeconomic status in around 1950, (2) low-status family heads have more grandchildren through their daughters than their sons, whereas high- or middle-status family heads have more grandchildren through sons, and (3) as family heads' status increases, they tend to produce a higher offspring sex ratio. Therefore, the assumptions and prediction of the hypothesis are met in the study population. These results are discussed in reference to past studies on sex ratio manipulation among humans. PMID- 28674673 TI - Pediatric Medicine Development: An Overview and Comparison of Regulatory Processes in the European Union and United States. AB - Pediatric legislation in the US and the EU is driving pediatric product development on an international scale. To facilitate harmonization and global development of pediatric medicines, it is important to understand the legislative requirements that must be met along with incentives that exist in the US and the EU to include pediatric patients in therapeutic clinical trials. Although there are many similarities, differences exist. This review is an effort to enhance understanding of the pediatric legislation in both regions. It is intended as an overview to supplement the region-specific legislation and guidance documents that are available on the websites of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite differences, the goal of the legislation in both the EU and the US is to incentivize and require timely, ethical, and sound scientific development of pharmaceutical products for the pediatric population and to provide information for their safe and effective use. PMID- 28674674 TI - Targeting the Immune System with Pharmacotherapy in Schizophrenia. PMID- 28674675 TI - The Role of Central Neck Lymph Node Dissection in the Management of Papillary Thyroid Cancer. AB - Papillary thyroid cancer (PTC) is the most common thyroid malignancy, and cervical nodal metastases are frequent at presentation. The most common site for nodal metastases from PTC is the central compartment of the ipsilateral neck in the paratracheal and pretracheal regions. The decision to resect these lymph nodes at the time of thyroidectomy often depends on if nodes with suspected malignancy can be identified preoperatively. If nodal spread to the central neck nodes is known, then the consensus is to remove all nodes in this area. However, there remains significant controversy regarding the utility of removing central neck lymph nodes for prophylactic reasons. Herein, we review the potential utility of central neck lymph node dissection as well as the risks of performing this procedure. As well, we review the potential of molecular testing to stratify patients who would most benefit from this procedure. We advocate a selective approach in which patients undergo clinical neck examination coupled with ultrasound to detect any concerning lymph nodes that warrant additional evaluation with either fine needle aspiration or excisional biopsy in the operating room. In lieu of clinical lymphadenopathy, we suggest the use of patient and disease characteristics as identified by multiple groups, such as the American Thyroid Association and European Society of Endocrine Surgeons, which include extremes of ages, large primary tumor size, and male gender, when deciding to perform central neck lymph node dissection. Patients should be educated on the potential long-terms risks versus the lack of known long-term benefits. PMID- 28674676 TI - Hypothesis about Transdifferentiation As Backbone of Malignancy. AB - BACKGROUND: Cancer is mainly watched through the prism of random mutations and related corruption of signaling pathways. However, it would seem puzzling to explain the tumor organization, pugnacity and steady evolution of the tumorous disease and, moreover, a systematic ascendancy over the healthy tissues, only through stochastic genomic alterations. MALIGNANCY SPECIFIC PROPERTIES: Considering the core characteristics of cancer cells, it appears that two major sets of properties are emerging, corresponding to well-identified physiological phenotypes, i.e., (1) the trophoblastic logistical functions for cell survival, protection, expansion, migration, and host-tissue conditioning for angiogenesis and immune tolerance and (2) the sexual functions for genome maintenance. To explain the resurgence of these trophoblastic and sexual phenotypes, a particular cell reprogramming, to be called "malignant transdifferentiation" in view of its key role in the precancer-to-cancer shift, appears to be a convincing hypothesis. PERSPECTIVES: The concept of malignant transdifferentiation, in addition to oncogenic mutations, would determine a more rational approach of oncogenesis and would open so far unexplored ways of therapeutic actions. Indeed, the trophoblastic phenotype would be a good candidate for therapeutic purposes because, on the one hand, it covers numerous properties that all are vital for the tumor, and on the other hand, it can be targeted with potentially no risk of affecting the healthy tissues as it is not expressed there after birth. PMID- 28674677 TI - Autophagy in Cancer Therapy. AB - Autophagy represents a catabolic program involved in the degradation of cellular components via lysosomes. It serves to mitigate cellular stress and to provide metabolic precursors especially upon starvation. Thereby, autophagy can support the survival of cancer cells. In addition, there is now convincing evidence showing that under certain conditions autophagy can also foster cell death. This dual function of autophagy is also relevant upon anticancer treatment, as many chemotherapeutic agents engage autophagy. A better understanding of the molecular mechanisms that are critical for mediating autophagic cell death in cancer cells will be instrumental to selectively interfere with this cellular program in order to increase the cancer cell's response to cytotoxic drugs. This review illustrates how anticancer drug-induced autophagy is involved in mediating cell death. PMID- 28674678 TI - Tangential Field Radiotherapy for Breast Cancer-The Dose to the Heart and Heart Subvolumes: What Structures Must Be Contoured in Future Clinical Trials? AB - BACKGROUND AND PURPOSE: The aim of the present study was to evaluate if it is feasible for experienced radiation oncologists to visually sort out patients with a large dose to the heart. This would facilitate large retrospective data evaluations. And in case of an insufficient visual assessment, to define which structures should be contoured and which structures can be skipped as their dose can be derived from other easily contoured structures for future clinical trials. MATERIAL AND METHODS: Planning CTs of left-sided breast cancer patients treated with 3D-conformal radiotherapy by tangential fields were visually divided into two groups: with an estimated high dose (HiD) and with an estimated low dose (LoD) to the heart. For 46 patients (22 HiD and 24 LoD), the heart, the left ventricle, the left anterior descending artery (LAD), the right coronary artery, and the ramus circumflexus were contoured. A helper structure (HS) around the LAD was generated in order to consider if contouring uncertainties of the LAD could be acceptable. We analyzed the mean dose (Dmean), the maximum dose, the V10, V20, V30, V40, and the length of the LAD that received 20 and 40 Gy. RESULTS: The two groups had a significant different Dmean of the heart (p < 0.001). The average Dmean to the heart was 4.0 +/- 1.3 Gy (HiD) and 2.3 +/- 0.8 Gy (LoD). The average Dmean to the LAD was 26.2 +/- 7.4 Gy (HiD) and 13.0 +/- 7.5Gy (LoD) with a very strong positive correlation between Dmean LAD and Dmean HS in both groups. The Dmean heart is not a good surrogate parameter for the dose to the LAD since it might underestimate clinically significant doses in 1/3 of the patients in LoD group. CONCLUSION: A visual assessment of the dose to the heart could be reliable if performed by experienced radiation oncologists. However, the Dmean heart is not always a good surrogate parameter for the dose to the LAD or for the Dmean to the left ventricle. Thus, if specific late toxicities are evaluated, we strongly recommend contouring of the specific heart substructures as a heart Dmean is not highly specific. PMID- 28674679 TI - The Metabolic Phenotype of Prostate Cancer. AB - Prostate cancer is the most common non-cutaneous cancer in men in the United States. Cancer metabolism has emerged as a contemporary topic of great interest for improved mechanistic understanding of tumorigenesis. Prostate cancer is a disease model of great interest from a metabolic perspective. Prostatic tissue exhibits unique metabolic activity under baseline conditions. Benign prostate cells accumulate zinc, and this excess zinc inhibits citrate oxidation and metabolism within the citric acid cycle, effectively resulting in citrate production. Malignant cells, however, actively oxidize citrate and resume more typical citric acid cycle function. Of further interest, prostate cancer does not exhibit the Warburg effect, an increase in glucose uptake, seen in many other cancers. These cellular metabolic differences and others are of clinical interest as they present a variety of potential therapeutic targets. Furthermore, understanding of the metabolic profile differences between benign prostate versus low- and high-grade prostate cancers also represents an avenue to better understand cancer progression and potentially develop new diagnostic testing. In this paper, we review the current state of knowledge on the metabolic phenotypes of prostate cancer. PMID- 28674680 TI - Giant Gastric Bezoar Complicating Congenital Esophageal Atresia Repaired by Gastric Interposition-A Case Report. AB - We describe a giant gastric phytobezoar in a child with repaired congenital esophageal atresia. At age two, a gastric interposition (pull-up) procedure was performed for severe and recurrent esophageal strictures. For 12 months post gastric interposition, he experienced frequent respiratory illnesses requiring hospital admissions but it was not initially appreciated that these episodes were likely secondary to recurrent aspiration from a gastric bezoar with "spill-over" aspiration. PMID- 28674683 TI - Infusion of Sibling Marrow in a Patient with Purine Nucleoside Phosphorylase Deficiency Leads to Split Mixed Donor Chimerism and Normal Immunity. AB - Purine nucleoside phosphorylase (PNP) deficiency, a rare autosomal recessive metabolic disease causes combined immunodeficiency and developmental delay, hypotonia, and spasticity. Patients present with recurrent infections associated with T-lymphocytopenia, characteristically presenting later than patients with classical severe combined immunodeficiency (SCID). PNP, with adenosine deaminase (ADA), is part of the purine salvage pathway. The only curative therapy is hematopoietic stem cell transplantation. Myeloablative conditioning is recommended to prevent rejection caused by residual immune function. However, HLA identical sibling stem cell infusions in ADA-SCID result in some donor stem cell engraftment and long-term thymopoiesis. We report a patient with PNP deficiency, who received HLA-identical sibling marrow without chemotherapy because of disseminated cytomegalovirus (CMV) infection. The patient presented at 14 months of age following recurrent infections, from early infancy, with persistent irritability, developmental delay, and hypotonia. She had neutropenia, pan lymphocytopenia, and hypogammaglobulinemia with low plasma urate and erythrocyte PNP activity. Diagnosis was confirmed with a homozygous mutation in PNP. The patient was viremic with CMV detected in blood and CSF by PCR. Dual antiviral therapy improved the clinical condition and reduced the viral load. In view of the disseminated CMV infection, the decision was made to infuse stem cells without any pre-conditioning chemotherapy. She received a matched sibling donor unconditioned stem cell infusion at 16 months of age. The post-transplant course was uneventful. Blood PCR became negative for CMV. Global hypotonia persisted, although with significant improvement in irritability. At 4 years of age and 29 months post-transplant, the patient demonstrated normal T-lymphocyte and natural killer cell numbers. Recent thymic emigrants represented 12% of the total T lymphocyte population. Lymphocyte proliferative responses to phytohemagglutinin were normal. Memory and class-switched B-lymphocytes were present. Immunoglobulin replacement had been discontinued, and there were normal IgG responses to tetanus vaccine, Haemophilus influenzae type B and pneumococcal conjugate vaccine antigens. There was 93% donor T-lymphocytes, 20% donor B-lymphocytes, and 5% donor myeloid cells, indicative of some donor stem cell engraftment. There was no significant infection history despite regular nursery attendance. Height and weight were following the 50th centile. Split mixed donor chimerism has corrected the immunological defect. PMID- 28674682 TI - The Microbiome and Blood Pressure: Can Microbes Regulate Our Blood Pressure? AB - The surfaces of the human body are heavily populated by a highly diverse microbial ecosystem termed the microbiota. The largest and richest among these highly heterogeneous populations of microbes is the gut microbiota. The collection of microbes and their genes, called the microbiome, has been studied intensely through the past few years using novel metagenomics, metatranscriptomics, and metabolomics approaches. This has enhanced our understanding of how the microbiome affects our metabolic, immunologic, neurologic, and endocrine homeostasis. Hypertension is a leading cause of cardiovascular disease worldwide; it contributes to stroke, heart disease, kidney failure, premature death, and disability. Recently, studies in humans and animals have shown that alterations in microbiota and its metabolites are associated with hypertension and atherosclerosis. In this review, we compile the recent findings and hypotheses describing the interplay between the microbiome and blood pressure, and we highlight some prospects by which utilization of microbiome related techniques may be incorporated to better understand the pathophysiology and treatment of hypertension. PMID- 28674681 TI - Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. AB - Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established. While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis. This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep. Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems. While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound. Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common. Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms. The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors. PMID- 28674684 TI - Effect of Fetal Sex on Maternal and Obstetric Outcomes. AB - Fetal sex plays an important role in modifying the course and complications related to pregnancy and may also have an impact on maternal health and well being both during and after pregnancy. The goal of this article is to review and summarize the findings from published research on physiologic and pathologic changes that may be affected by fetal sex and the effect of these changes on the maternal and obstetrical outcomes. This will help create awareness that fetal sex is not just a random chance event but an interactive process between the mother, the placenta, and the fetus. The reported effects of male sex on the course of pregnancy and delivery include higher incidence of preterm labor in singletons and twins, failure of progression in labor, true umbilical cord knots, cord prolapse, nuchal cord, higher cesarean section rate, higher heart rate variability with increased frequency, and duration of decelerations without acidemia and increased risk of gestational diabetes mellitus through the poor beta cells function. Similarly, female fetal sex has been reported to modify pregnancy and delivery outcomes including altered fetal cardiac hemodynamics, increased hypertensive diseases of pregnancy, higher vulnerability of developing type 2 DM after pregnancy possibly because of influences on increased maternal insulin resistance. Placental function is also influenced by fetal sex. Vitamin D metabolism in the placenta varies by fetal sex; and the placenta of a female fetus is more responsive to the relaxing action of magnesium sulfate. Male and female feto-placental units also vary in their responses to environmental toxin exposure. The association of fetal sex with stillbirths is controversial with many studies reporting higher risk of stillbirth in male fetuses; although some smaller and limited studies have reported more stillbirths with female fetus pregnancies. Maternal status such as BMI may in turn also affect the fetus and the placenta in a sex-specific manner. There is probably a sex-specific maternal placental-fetal interaction that has significant biological implications of which the mechanisms may be genetic, epigenetic, or hormonal. Determination of fetal sex may therefore be an important consideration in management of pregnancy and childbirth. PMID- 28674685 TI - Risk Factors, Prophylaxis, and Treatment of Venous Thromboembolism in Congenital Heart Disease Patients. AB - Congenital heart disease (CHD) is a common condition in the pediatric population, affecting up to 1% of all live births (i.e., around 40,000 newborns/year in the United States). Although CHD does have a wide range of severity, by the age of 5 years approximately 80% of patients will require at least one surgical intervention to achieve a complete/palliative cardiac repair. Today, in light of their much-improved surgical survival, the care of these patients focuses on morbidity prevention and/or treatment. One such morbidity has been the increased frequency of thrombotic occlusions [e.g., cardioembolic arterial ischemic strokes; arterial, cardiac, and/or newly created shunt thrombosis; venous thromboembolism (VTE)]. Patients with CHD are at high risk of developing thrombosis due to the disruption of blood flow, CHD-related coagulopathy, inflammation, and/or platelet activation secondary to extracorporeal circulation support required during open-heart surgery or as a bridge to recovery, which can increase thrombus formation. In this article, we will discuss how the coagulation system is altered in patients with CHD in regard to the patient's anatomy, procedures they undergo to correct their congenital heart defect, and other risk factors that may increase their thrombotic risk, focusing on VTE. We will also discuss the most recently published reports pertaining to guidelines on prophylaxis and treatment of VTE in this population. Finally, we will briefly address the long-term VTE outcomes for patients with CHD. PMID- 28674686 TI - Batch Sedimentation Studies for Freshwater Green Alga Scenedesmus abundans Using Combination of Flocculants. AB - Microalga is the only feedstock that has the theoretical potential to completely replace the energy requirements derived from fossil fuels. However, commercialization of this potential source for fuel applications is hampered due to many technical challenges with harvesting of biomass being the most energy intensive process among them. The fresh water microalgal species, Scenedesmus abundans, has been widely recognized as a potential feedstock for production of biodiesel (Mandotra et al., 2014). The present work deals with sedimentation of algal biomass using extracted chitosan and natural bentonite clay powder as flocculant. The effect of flocculant combination and different factors such as temperature, pH, and concentration of algal biomass on sedimentation rates has been analyzed. A high flocculation efficiency of 76.22 +/- 7.81% was obtained at an algal biomass concentration of 1 +/- 0.05 g/L for a settling time of 1 h at 50 +/- 5 degrees C with a settling velocity of 103.2 +/- 0.6 cm/h and a maximum surface conductivity of 2,260 +/- 2 MUS/cm using an optimal design in response surface methodology (RSM). Biopolymer flocculant such as chitosan exhibited better adsorption property along with bentonite clay powder that reduced the settling time significantly. PMID- 28674687 TI - Effect of Chemical Grafting Parameters on the Manufacture of Functionalized PVOH Films Having Controlled Water Solubility. AB - This study investigated the chemical grafting of a single-layer poly(vinyl alcohol) (PVOH) film. The effect of the grafting parameters (grafting time, grafting temperature, and concentration of fatty acid chloride) on the hydrophobicity of the film surface and the film solubility were evaluated. The PVOH substrate film (cold-water soluble at 20 degrees C) was manufactured by flat extrusion and had a thickness of 50 MUm (+/-5 MUm). The chemical grafting was performed using the transfer method with palmitoyl chloride (C16). The solubility, surface energy, and water vapor transmission rate of the grafted films were measured. The process parameters which produced the most hydrophobic PVOH film were found to be a fatty acid concentration of 3%, a grafting time of 14 min, and a grafting temperature of 130 degrees C. These studies involved systematic adjustment of the hydrophobicity of one side of PVOH films. The results open up opportunities for packing fluids in water soluble packaging. PMID- 28674688 TI - D-BMAP18 Antimicrobial Peptide Is Active In vitro, Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection. AB - The spread of antibiotic resistant-pathogens is driving the search for new antimicrobial compounds. Pulmonary infections experienced by cystic fibrosis (CF) patients are a dramatic example of this health-care emergency. Antimicrobial peptides could answer the need for new antibiotics but translating them from basic research to the clinic is a challenge. We have previously evaluated the potential of the small membranolytic peptide BMAP-18 to treat CF-related infections, discovering that while this molecule had a good activity in vitro it was not active in vivo because of its rapid degradation by pulmonary proteases. In this study, we synthesized and tested the proteases-resistant all-D enantiomer. In spite of a good antimicrobial activity against Pseudomonas aeruginosa and Stenotrophomonas maltophilia clinical isolates and of a tolerable cytotoxicity in vitro, D-BMAP18 was ineffective to treat P. aeruginosa pulmonary infection in mice, in comparison to tobramycin. We observed that different factors other than peptide degradation hampered its efficacy for pulmonary application. These results indicate that D-BMAP18 needs further optimization before being suitable for clinical application and this approach may represent a guide for optimization of other anti-infective peptides eligible for the treatment of pulmonary infections. PMID- 28674690 TI - Racing on the Wrong Track. AB - The preclinical in vitro and in vivo benchmark figures of cationic antimicrobial peptides have to be revisited based on the newly discovered alternative modes of action. PMID- 28674689 TI - Allosteric Control of Substrate Specificity of the Escherichia coli ADP-Glucose Pyrophosphorylase. AB - The substrate specificity of enzymes is crucial to control the fate of metabolites to different pathways. However, there is growing evidence that many enzymes can catalyze alternative reactions. This promiscuous behavior has important implications in protein evolution and the acquisition of new functions. The question is how the undesirable outcomes of in vivo promiscuity can be prevented. ADP-glucose pyrophosphorylase from Escherichia coli is an example of an enzyme that needs to select the correct substrate from a broad spectrum of alternatives. This selection will guide the flow of carbohydrate metabolism toward the synthesis of reserve polysaccharides. Here, we show that the allosteric activator fructose-1,6-bisphosphate plays a role in such selection by increasing the catalytic efficiency of the enzyme toward the use of ATP rather than other nucleotides. In the presence of fructose-1,6-bisphosphate, the kcat/S0.5 for ATP was near ~600-fold higher that other nucleotides, whereas in the absence of activator was only ~3-fold higher. We propose that the allosteric regulation of certain enzymes is an evolutionary mechanism of adaptation for the selection of specific substrates. PMID- 28674691 TI - Influence of Cigarette Smoking on Rheumatoid Arthritis Risk in the Han Chinese Population. AB - OBJECTIVES: Cigarette smoking has been shown in European populations to be associated with rheumatoid arthritis (RA) susceptibility. This study aims to examine the association of smoking with RA in the Han Chinese population. METHODS: 718 Han Chinese RA patients and 404 healthy controls were studied. The associations of cigarette smoking (current, former or ever vs. never smokers, and pack-years of exposure) with RA, anti-cyclic citrullinated peptide antibody (ACPA) positive RA, IgM rheumatoid factor (RF) positive RA, and baseline radiographic erosions (modified van der Heijde-Sharp scores) were assessed. The interaction between smoking and the HLA-DRB1 shared epitope (SE) in RA was also examined. RESULTS: In this study, 11 (1.53%) cases and 6 (1.49%) controls were former smokers (p = 0.95), while 95 (13.23%) cases and 48 (11.88%) controls were current smokers (p = 0.52). Trends toward associations between smoking status (ever vs. never) with RA-overall (p = 0.15, OR = 1.44), ACPA-positive RA (p = 0.24, OR = 1.37), RF-positive RA (p = 0.14, OR = 1.46), or the presence of radiographic erosions (p = 0.66, OR = 1.28) were observed although individually here were not statistically significant. There was no evidence of statistical interaction between smoking status (ever vs. never) and SE for all RA, ACPA positive RA, ACPA-negative RA, RF-positive RA, RF-negative RA (p = 0.37, 0.50, 0.24, 0.26, and 0.81 respectively), and the 95% CI for the attributable proportion for all interactions included 0. CONCLUSION: This is the first study to examine the association of cigarette smoking with RA in the Han Chinese population. This study shows a trend toward an interaction between smoking and SE carriage influencing the risk of RA, though findings were not statistically significant. It is possible that in the presence of universal exposure to heavy air pollution the effect of smoking on RA risk may be obscured. PMID- 28674692 TI - Polysaccharides As Viscosupplementation Agents: Structural Molecular Characteristics but Not Rheology Appear Crucial to the Therapeutic Response. AB - INTRODUCTION: Most clinical studies and basic research document viscosupplementation (VS) in terms of effectiveness and safety, but only a few highlight its molecular mechanisms of action. Besides, there is generally focus on hyaluronic acid (HA) as being the most relevant polysaccharide to reach the clinical endpoints, attributing its effect mainly to its unique viscoelastic properties, related to a high-molecular weight and gel formulation. Usually, studies do not approach the possible biological pathways where HA may interfere, and there is a lack of reports on other biocompatible polysaccharides that could be of use in VS. AIM: We briefly review the main proposed mechanisms of action of intra-articular hyaluronic acid (IA-HA) treatment and discuss its effectiveness focusing on the role of rheological and intrinsic structural molecular properties of polysaccharides in providing a therapeutic effect. METHODS: We conducted a literature search using PubMed database to find articles dealing with the mechanisms of action of IA-HA treatment and/or emphasizing how the structural properties of the polysaccharide used influenced the clinical outcomes. DISCUSSION/CONCLUSION: HA is involved in numerous biochemical interactions that may explain the clinical benefits of VS, most of them resulting from HA-cluster of differentiation 44 receptor interaction. There are other important aspects apart from the molecular size or the colloidal state of the IA-HA involved in VS efficiency that still need to be consolidated. Indeed, it seems that clinical response may be dependent on the intrinsic properties of the polysaccharide, regardless of being HA, rather than to rheology, posing some controversy to previous beliefs. PMID- 28674693 TI - Improving the Prediction of Total Surgical Procedure Time Using Linear Regression Modeling. AB - For efficient utilization of operating rooms (ORs), accurate schedules of assigned block time and sequences of patient cases need to be made. The quality of these planning tools is dependent on the accurate prediction of total procedure time (TPT) per case. In this paper, we attempt to improve the accuracy of TPT predictions by using linear regression models based on estimated surgeon controlled time (eSCT) and other variables relevant to TPT. We extracted data from a Dutch benchmarking database of all surgeries performed in six academic hospitals in The Netherlands from 2012 till 2016. The final dataset consisted of 79,983 records, describing 199,772 h of total OR time. Potential predictors of TPT that were included in the subsequent analysis were eSCT, patient age, type of operation, American Society of Anesthesiologists (ASA) physical status classification, and type of anesthesia used. First, we computed the predicted TPT based on a previously described fixed ratio model for each record, multiplying eSCT by 1.33. This number is based on the research performed by van Veen-Berkx et al., which showed that 33% of SCT is generally a good approximation of anesthesia controlled time (ACT). We then systematically tested all possible linear regression models to predict TPT using eSCT in combination with the other available independent variables. In addition, all regression models were again tested without eSCT as a predictor to predict ACT separately (which leads to TPT by adding SCT). TPT was most accurately predicted using a linear regression model based on the independent variables eSCT, type of operation, ASA classification, and type of anesthesia. This model performed significantly better than the fixed ratio model and the method of predicting ACT separately. Making use of these more accurate predictions in planning and sequencing algorithms may enable an increase in utilization of ORs, leading to significant financial and productivity related benefits. PMID- 28674694 TI - Visualization of Global Disease Burden for the Optimization of Patient Management and Treatment. AB - BACKGROUND: The assessment and treatment of complex disorders is challenged by the multiple domains and instruments used to evaluate clinical outcome. With the large number of assessment tools typically used in complex disorders comes the challenge of obtaining an integrative view of disease status to further evaluate treatment outcome both at the individual level and at the group level. Radar plots appear as an attractive visual tool to display multivariate data on a two dimensional graphical illustration. Here, we describe the use of radar plots for the visualization of disease characteristics applied in the context of tinnitus, a complex and heterogeneous condition, the treatment of which has shown mixed success. METHODS: Data from two different cohorts, the Swedish Tinnitus Outreach Project (STOP) and the Tinnitus Research Initiative (TRI) database, were used. STOP is a population-based cohort where cross-sectional data from 1,223 non tinnitus and 933 tinnitus subjects were analyzed. By contrast, the TRI contained data from 571 patients who underwent various treatments and whose Clinical Global Impression (CGI) score was accessible to infer treatment outcome. In the latter, 34,560 permutations were tested to evaluate whether a particular ordering of the instruments could reflect better the treatment outcome measured with the CGI. RESULTS: Radar plots confirmed that tinnitus subtypes such as occasional and chronic tinnitus from the STOP cohort could be strikingly different, and helped appreciate a gender bias in tinnitus severity. Radar plots with greater surface areas were consistent with greater burden, and enabled a rapid appreciation of the global distress associated with tinnitus in patients categorized according to tinnitus severity. Permutations in the arrangement of instruments allowed to identify a configuration with minimal variance and maximized surface difference between CGI groups from the TRI database, thus affording a means of optimally evaluating the outcomes in individual patients. CONCLUSION: We anticipate such a tool to become a starting point for more sophisticated measures in clinical outcomes, applicable not only in the context of tinnitus but also in other complex diseases where the integration of multiple variables is needed for a comprehensive evaluation of treatment response. PMID- 28674695 TI - Minor Immediate Effects of a Dog on Children's Reading Performance and Physiology. AB - Literacy is a key factor in occupational success and social integration. However, an increasing number of children lack appropriate reading skills. There is growing evidence that dogs have positive effects on reading performance. We investigated the short-term effects of dogs on reading performance in 36 third graders and monitored physiological parameters [heart rate (HR), heart rate variability (HRV), and salivary cortisol] as well as behavioral variables. Each child took part in two test sessions at the presence of a tutor, in one of which a dog and its handler were present. To assess reading performance two reading tests were used: two subtests of the standardized "Ein Leseverstandnistest fur Erst- bis Sechstklassler", where the children have to carry out time-limited reading tasks, to assess sentence and text comprehension, and repeated reading (RR), where the children have to read the same text twice, to assess reading speed and short-term improvement. Although the dog had no effect on reading performance scores, within the first test session the children improved from the first to the second run of RR when a dog was present but not without dog. The behavior of the children indicated a calming effect of the dog in the first test session with less nervous movements and the children being less talkative. We found no impact of the dog on HR and HRV. However, the excitement about the dog in combination with the unknown situation in the first test session was reflected in a higher difference in the mean HR difference between the two test sessions for the children, who in the first test session had a dog present, compared to the children, who had the dog in the second test session. In the second test session, the children were more aroused with a dog present than with no dog present, as indicated by the area under the curve increase (AUCi) of salivary cortisol values. We conclude that the presence of a dog had a minor short-term positive effect on the children's motivation and reading performance. More substantial effects could probably be achieved with repeated sessions. PMID- 28674696 TI - Accommodative intraocular lenses: where are we and where we are going. AB - Presbyopia still remains the last frontier of refractive surgery. Its surgical management is under constant evolution due to the limitations that exist today with respect to its management, which is probably in relation with the multifactorial basis in which presbyopia is clinically developed in the human. Until currently, virtually all surgical techniques that have been proposed for its correction are based on the induction of pseudoaccommodation in the presbyopic eye, including multifocality. However, the real restoration of accommodation is more complex, and it has been tried by the use of different, so called, "accommodative" pseudophakic intraocular lenses (AIOL). Overall, the reported results with these lenses by independent authors have been modest in relation with the restoration of the accommodative power of the eye and these modest benefits are usually lost with time due to the long term changes in the capsular bag. This fact made these lenses to be almost abandoned in the last few years, but there are currently other AIOL models being used with innovative mechanisms of action and different anatomical support outside the capsular bag that offer encouraging preliminary results that could bring a new potential of application to these types of lenses. In this article, we will update the modern refractive surgeon about the fundamentals and provide updated information about the outcomes of AIOLs by reviewing the concept of accommodation, the different attempts that have been accomplished in the past, their demonstrated published results in human clinical trials, and the future alternatives that may arrive in the near future. PMID- 28674697 TI - Cell-free vascular grafts: Recent developments and clinical potential. AB - Recent advances in vascular tissue engineering have led to the development of cell-free grafts that are available off-the-shelf for on demand surgery. Challenges associated with cell-based technologies including cell sourcing, cell expansion and long-term bioreactor culture motivated the development of completely cell-free vascular grafts. These are based on decellularized arteries, decellularized cultured cell-based tissue engineered grafts or biomaterials functionalized with biological signals that promote in situ tissue regeneration. Clinical trials undertaken to demonstrate the applicability of these grafts are also discussed. This comprehensive review summarizes recent developments in vascular graft technologies, with potential applications in coronary artery bypass procedures, lower extremity bypass, vascular injury and trauma, congenital heart diseases and dialysis access shunts, to name a few. PMID- 28674700 TI - Editorial: Oral health and cancer patients - in need of preventive dentistry interventions. PMID- 28674698 TI - Distinct Correlation Structure Supporting a Rate-Code for Sound Localization in the Owl's Auditory Forebrain. AB - While a topographic map of auditory space exists in the vertebrate midbrain, it is absent in the forebrain. Yet, both brain regions are implicated in sound localization. The heterogeneous spatial tuning of adjacent sites in the forebrain compared to the midbrain reflects different underlying circuitries, which is expected to affect the correlation structure, i.e., signal (similarity of tuning) and noise (trial-by-trial variability) correlations. Recent studies have drawn attention to the impact of response correlations on the information readout from a neural population. We thus analyzed the correlation structure in midbrain and forebrain regions of the barn owl's auditory system. Tetrodes were used to record in the midbrain and two forebrain regions, Field L and the downstream auditory arcopallium (AAr), in anesthetized owls. Nearby neurons in the midbrain showed high signal and noise correlations (R NC s), consistent with shared inputs. As previously reported, Field L was arranged in random clusters of similarly tuned neurons. Interestingly, AAr neurons displayed homogeneous monotonic azimuth tuning, while response variability of nearby neurons was significantly less correlated than the midbrain. Using a decoding approach, we demonstrate that low R NC in AAr restricts the potentially detrimental effect it can have on information, assuming a rate code proposed for mammalian sound localization. This study harnesses the power of correlation structure analysis to investigate the coding of auditory space. Our findings demonstrate distinct correlation structures in the auditory midbrain and forebrain, which would be beneficial for a rate-code framework for sound localization in the nontopographic forebrain representation of auditory space. PMID- 28674701 TI - Efficacy of Three In-Office Dentin Hypersensitivity Treatments. AB - PURPOSE: This study assessed the comparative efficacy of three in-office treatment agents in patients presenting with dentin hypersensitivity (DH) at a university teaching hospital. MATERIALS AND METHODS: A randomised, controlled study was conducted to compare the efficacy of Gluma desensitiser, Pro-Relief and Copal F in relieving the pain of DH. In 68 subjects with 508 hypersensitive teeth, the agents and placebo (distilled water) were applied to 127 hypersensitive teeth each. At baseline, the pain of DH to tactile and evaporative stimuli was measured using the visual analogue scale (VAS) and verbal rating scale (VRS). Post-application assessment was carried out at 10 min, 1 week, 2 and 4 weeks. RESULTS: The mean difference in VAS between baseline and post-treatment periods significantly increased for all the desensitising agents (p < 0.05) with both tactile and air-blast stimuli, except for the placebo. Gluma desensitiser had the highest mean difference at 10 min (3.7 +/- 1.8) and 4 weeks (5.4 +/- 2.3) for tactile and air-blast stimuli, respectively. However, using the VAS, no statistical significance was noted in the mean differences between the agents. With the application of Gluma desensitiser, a significantly higher number of teeth had no pain at 4 weeks using the VRS. CONCLUSION: Gluma desensitiser can be suggested as an appropriate desensitising agent for in-office treatment of DH. PMID- 28674699 TI - Long-Term Deficits in Cortical Circuit Function after Asphyxial Cardiac Arrest and Resuscitation in Developing Rats. AB - Cardiac arrest is a common cause of global hypoxic-ischemic brain injury. Poor neurologic outcome among cardiac arrest survivors results not only from direct cellular injury but also from subsequent long-term dysfunction of neuronal circuits. Here, we investigated the long-term impact of cardiac arrest during development on the function of cortical layer IV (L4) barrel circuits in the rat primary somatosensory cortex. We used multielectrode single-neuron recordings to examine responses of presumed excitatory L4 barrel neurons to controlled whisker stimuli in adult (8 +/- 2-mo-old) rats that had undergone 9 min of asphyxial cardiac arrest and resuscitation during the third postnatal week. Results indicate that responses to deflections of the topographically appropriate principal whisker (PW) are smaller in magnitude in cardiac arrest survivors than in control rats. Responses to adjacent whisker (AW) deflections are similar in magnitude between the two groups. Because of a disproportionate decrease in PW evoked responses, receptive fields of L4 barrel neurons are less spatially focused in cardiac arrest survivors than in control rats. In addition, spiking activity among L4 barrel neurons is more correlated in cardiac arrest survivors than in controls. Computational modeling demonstrates that experimentally observed disruptions in barrel circuit function after cardiac arrest can emerge from a balanced increase in background excitatory and inhibitory conductances in L4 neurons. Experimental and modeling data together suggest that after a hypoxic ischemic insult, cortical sensory circuits are less responsive and less spatially tuned. Modulation of these deficits may represent a therapeutic approach to improving neurologic outcome after cardiac arrest. PMID- 28674702 TI - Do Oral Health Educational Programmes for Expectant Mothers Prevent Early Childhood Caries? - Systematic Review. AB - PURPOSE: To summarise the evidence for the efficacy of oral health educational programmes provided to expectant mothers for preventing Early Childhood Caries (ECC) and to determine the most effective intervention programme. MATERIALS AND METHODS: The search strategy included clinical trials in the Cochrane Oral Health Group's Trials Register, PubMed, Science Direct, Google Scholar, LILACS and ClinicalKey (up to 26 August 2013) in English. Reference lists of identified randomised controlled trials (RCTs) and review articles were also hand searched. Studies were selected according to predefined inclusion and exclusion criteria. RESULTS: The search identified 392 studies, only four of which were included. Risk ratios (RR) were calculated. The quality of the evidence was assessed by the GRADE approach. Results showed statistically significant decreases in caries incidence (RR = 0.18, 95% CI [from 0.06 to 0.52]) in one study. Meta-analysis could not be performed. CONCLUSION: Oral health educational programmes for expectant mothers may have a positive impact in preventing ECC, although the evidence is weak. PMID- 28674704 TI - Antibacterial Orthodontic Adhesive Incorporating Polyethyleneimine Nanoparticles. AB - PURPOSE: To evaluate the antibacterial, mechanical and biocompatibility characteristics of an orthodontic adhesive that contains quaternary ammonium polyethyleneimine (QPEI) nanoparticles. MATERIALS AND METHODS: QPEI nanoparticles were added to an orthodontic adhesive at 0%, 1% and 1.5% wt/wt. Antibacterial activity was tested after aging for 14 days using the direct contact test (DCT). The degree of monomer conversion (DC) was measured using Fourier transform infrared (FTIR) spectroscopy. Shear bond atrength (SBS) was tested on the etched enamel of extracted human teeth. Biocompatibility was tested using keratinocyte and neutrophil cell lines in the XTT assay. RESULTS: The DCT results showed significant bacterial growth inhibition in the test group incorporating 1.5% wt/wt QPEI nanoparticles (p < 0.05). The DC of the 0%, 1%, and 1.5% wt/wt samples measured immediately and after 10 min was 62.2-71.0%, 59.1-68.7%, and 52.9-58.6%, respectively, and the average SBS were 9.25 MPa, 11.57 MPa, and 9.10 MPa, respectively. Keratinocyte and neutrophil viability did not change following the addition of QPEI to the orthodontic adhesives. CONCLUSIONS: The incorporation of QPEI nanoparticles into orthodontic cement provides long-lasting antibacterial activity against Streptococcus mutans without reducing the strength of adhesion to enamel, the degree of double bond conversion during the polymerisation, or the biocompatibility of the orthodontic cement. PMID- 28674703 TI - Changes in Oral Health Related Quality of Life (OHRQoL) ?and Satisfaction with Conventional Complete Dentures Among Elderly People. AB - PURPOSE: To assess the changes in oral health-related quality of life (OHRQoL) and satisfaction among older adults after receiving new complete dentures, and the association of age, gender, education, medical history, past prosthetic history (number of previous complete dentures and time since current complete dentures) and quality of existing complete dentures with patients' ratings of satisfaction with their complete dentures. MATERIALS AND METHODS: The study comprised 114 community-dwelling adults >= 65 year of age, all wearing complete dentures in both jaws. The sample was selected from four senior day centres. Data were collected using clinical oral examinations and a self-administered questionnaire. Dentures were clinically evaluated for retention, stability, occlusion, articulation and vertical dimension. The questionnaire recorded data on sociodemographic information, previous denture history, oral satisfaction scale (OSS), and OHRQoL through the Oral Impacts on Daily Performance (OIDP) scale. RESULTS: There was a significant improvement in OHRQoL after treatment (mean OIDP score: 2.7) compared to before treatment (mean OIDP score: 6.6). The largest changes were in relation to impacts on eating (33.3% to 15.9%) and smiling (17.5% to 4.5%). Six months after placement of the dentures, patient satisfaction improved compared to before treatment (p < 0.001). The results of this study demonstrated that satisfaction was correlated with age, gender, and past prosthetic history in the patients rehabilitated with complete dentures. CONCLUSIONS: The provision of new dentures among older adults resulted in significantly better satisfaction and OHRQoL than wearing existing dentures. There was no significant correlation between the clinical assessment of the dentures and patients' satisfaction with them. PMID- 28674705 TI - Antibacterial Effects of Toothpastes Evaluated in an ?In Vitro Biofilm Model. AB - PURPOSE: To test the antibacterial effects of different toothpastes with the slurry method of toothpaste application in an in vitro oral biofilm model including relevant periodontal pathogens. MATERIALS AND METHODS: Four commercially available toothpastes, two containing sodium fluoride (NaF) at different concentrations (1450 and 2500 ppm), two NaF with either triclosan or stannous fluoride, and a control phosphate-buffered saline (PBS) were used. Multispecies biofilms containing 6 species of oral bacteria were grown on hydroxyapatite disks for 72 h and then exposed for 2 min to the toothpaste slurries or phosphate buffer saline (PBS) by immersion, under continuous agitation at 37 degrees C. Biofilms were then analysed by means of real-time polymerase chain reaction (PCR), combined with propidium monoazide (PMA). Statistical evaluation was performed using ANOVA and Student's t-test, with Bonferroni correction for multiple comparisons. RESULTS: The toothpastes containing NaF and stannous fluoride demonstrated superior antimicrobial activity for A. actinomycetencomitans, P. gingivalis and F. nucleatum when compared to those containing NaF and triclosan, 1450 ppm NaF or 2500 ppm NaF in this multispecies biofilm model. CONCLUSION: The proposed model for the evaluation of toothpastes in the form of slurries detected significant differences in the antimicrobial effects among the tested NaF-containing toothpastes, with the stannous fluoride-based formulation achieving better results than the other formulations. The use of toothpaste as slurries and real-time PCR with PMA is an adequate method for comparing the in vitro antimicrobial effect of different toothpastes. PMID- 28674706 TI - The Effect of Treatment of Denture-related Stomatitis on Peripheral T Cells and Monocytes. AB - PURPOSE: Systemic immune activation has been recently linked to chronic inflammatory disorders of the oral cavity, particularly to periodontitis. The purpose of this study was to determine whether treatment of a fungus-induced oral inflammation, namely denture-related stomatitis (DRS), can affect the activation of the systemic immune response. MATERIALS AND METHODS: Peripheral blood from patients with denture-related stomatitis caused by Candida albicans infection (n = 15) was collected at three time points: before treatment with nystatin, at the end of therapy and 2 months after finishing therapy. Activation of T cells and monocytes was assessed by flow cytometry. RESULTS: The percentages of peripheral lymphocytes, T cells and their subpopulations, as well as monocytes were similar before, immediately following and two months after nystatin treatment. Cells expressing early activation marker CD69 and RANTES C-C chemokine receptor type 5 significantly increased immediately after treatment and returned to baseline levels after two months. Th17 cells, which have been implicated in the pathogenesis of DRS, remained unchanged. Central memory CD4+ subset and intermediate subset of monocytes were lower after therapy and this effect was sustained for two months. CONCLUSION: Treatment of denture-related stomatitis does not seem to affect the general state of the cellular components of the immune system. The results suggest a potential proinflammatory effect of the antifungal agent, nystatin. Although transient and not intense, this effect might be of particular clinical importance, because of relationships between inflammation and certain diseases. Further studies are required to clarify this aspect. PMID- 28674707 TI - Propolis Extracted from the Stingless Bee Trigona sirindhornae Inhibited S. mutans Activity In Vitro. AB - PURPOSE: The aim of this study was to determine the antimicrobial effects of propolis extracted from an endemic species of stingless bee, T. sirindhornae, on the cariogenic bacterium Streptococcus mutans. MATERIALS AND METHODS: Dichloromethane extracts (DME) of propolis (DMEP) were prepared and analysed by reverse-phase high-performance liquid chromatography. The antibacterial growth and antibiofilm formation effects of DMEP on S. mutans were compared with those of apigenin, a commercial propolis product. The effects of DMEP and apigenin on glucosyltransferase (gtf) B expression in S. mutans were investigated using real time polymerase chain reaction. Chlorhexidine (CHX) was used as a positive control in the experiments. RESULTS: Apigenin, pinocembrin, p-coumaric acid, and caffeic acid were not detected in the propolis extracts. DMEP and apigenin significantly inhibited S. mutans growth (IC50 = 43.5 and 17.36 mg/ml, respectively). DMEP and apigenin also exhibited antiadherence effects on S. mutans as shown by reduced biofilm formation. Furthermore, a significant inhibition in gtfB expression was observed in DMEP and apigenin treated S. mutans. CONCLUSION: Propolis produced by T. sirindhornae demonstrated antibacterial and antibiofilm effects, and reduced gtfB expression in S. mutans. The antibacterial activities of propolis observed were not due to apigenin, pinocembrin, p-coumaric acid, or caffeic acid. PMID- 28674708 TI - The Association of Periodontopathic Bacteria Levels ?in Saliva and Tongue Coating with Oral Malodor in Periodontitis Patients. AB - PURPOSE: To elucidate the association oral malodor with the levels of periodontopathic bacteria in saliva and tongue coating of periodontitis patients with oral malodor. MATERIALS AND METHODS: In 25 periodontitis patients, the organoleptic test (OLT) was performed, the levels of volatile sulfur compounds (VSCs) were measured, tongue coating (TC) score was determined, and periodontal parameters and the proportions of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola, Tannerella forsythia and Prevotella intermedia in the saliva and the tongue coating were evaluated. RESULTS: The proportions of T. denticola and T. forsythia in the saliva of patients with an OLT score >= 2 were significantly higher than those with OLT scores < 2. The proportion of P. gingivalis in the saliva significantly correlated with periodontal parameters, whereas T. denticola and T. forsythia levels in the tongue coating correlated with VSC levels. However, the five periodontopathic bacteria were found in the tongue coating at levels approximately 12 times lower than in the saliva. CONCLUSIONS: The findings suggest that the levels of T. denticola and T. forsythia in the saliva of periodontitis patients correlate with oral malodor, and that the prevalence of P. gingivalis in the saliva is related to periodontitis. Periodontopathic bacteria in the tongue coating contribute minimally to oral malodor in periodontitis patients. PMID- 28674709 TI - Occurrence of Dental Injuries and Periodontal Complications in Tongue-piercing Jewellery Users. AB - PURPOSE: Tongue piercing (TP) has been gaining in popularity, mainly among adolescents and young adults, and there has been a corresponding increase in reports of dental injury and adverse effects on periodontal tissue due to TP jewellery. The purpose of this study was to assess the type and prevalence of dental injury and periodontal complications in a group of Slovenian adolescents and young adults with TP in comparison with a control group. MATERIALS AND METHODS: This case-control study included 17 subjects with TP (study group) and 28 subjects without TP (control group). Subjects were clinically examined for dental injuries, as classified according to Andreasen. Periodontal complications were evaluated using an estimation of clinical attachment loss (CAL) and gingival recession (GR). Differences in categorical variables were analyzed using the chi squared or Fisher's exact test as appropriate. Differences between the groups in numerical variables were analyzed with the Mann-Whitney U-test. A multiple logistic regression model was built to test the association between dental injuries and TP when controlling for cofounders, namely age and gender of study participants. The significance level was set at alpha = 0.05 (two-tailed). RESULTS: Subjects with TP had 12.2 higher odds of dental injury (CI = 2.2-67.7, p = 0.004) compared with subjects without TP. Enamel fractures were more prevalent in the study group (p = 0.002). Frequencies of other dental injuries in the two groups were similar. GR was significantly associated with TP (p = 0.008), while differences in CAL between the groups were not statistically significant. CONCLUSION: Subjects with tongue piercing had more dental injuries and gingival recession. PMID- 28674710 TI - Current advances in the chemistry of silicon: not exactly a carbon copy. PMID- 28674711 TI - Improving bioassay sensitivity through immobilization of bio-probes onto reactive micelles. AB - An antigen probe (HIV-1 p24) immobilized onto N-succinimidyl ester based micelles was used as a solid phase coating in ELISA test, and induced a significant improvement in antibody detection sensitivity as compared to the standard free antigen coating. The relevance of this straightforward approach to improve the bioassay sensitivity was confirmed by using biotin as a generic probe. PMID- 28674712 TI - Expression of sex-determining region Y-box protein 2 in breast cancer and its clinical significance. AB - Sex-determining region Y-box protein 2 (SOX2) is an embryo transcription factor located on chromosome 3q26.3-q27. It plays an important role in the maintenance of differentiation and self-renewal of pluripotent stem cells. Studies have shown that SOX2 is associated with multiple cancers and is overexpressed in many different phenotypes of breast cancer. To study the relationship between SOX2 and clinicopathological parameters of breast cancer patients, we found that the expression of SOX2 was closely related to the increase in tumor size, histological grade, lymph node metastasis, and high invasiveness. Therefore, studies on the role of SOX2 in breast cancer may provide effective biomarkers and potential therapeutic targets for the diagnosis and treatment of breast cancer. This article will discuss the role of SOX2 in breast cancer, including its occurrence, invasion and metastasis, diagnosis and treatment, relapse, resistance, and prognosis. PMID- 28674713 TI - Are we prepared to implement a Lean philosophy within cancer-care service in Oman? AB - Lean, as it applies to business, has come to signify simplicity, swift response, and efficiency. The concept is to do more with less; namely, to use resources in the most productive way possible through the elimination of all types of waste. The Lean approach can be applied to any field, including healthcare, in which the exponential growth of costs is widespread. Hospitals began experimenting with Lean healthcare in 1990s. Equal accessibility to healthcare is consistent with the tenets of social justice and a society's duty to ensure basic healthcare to everyone. However, the gap between a state's constitutional responsibility and resource availability is widening, creating a need for an evolution in healthcare provision based on relevance, objectivity, and impartiality. Health-services providers must juggle limited resources to ensure even-handed healthcare availability to all in the era of cost explosion. PMID- 28674714 TI - GeneXpert technology. A breakthrough for the diagnosis of tuberculous pericarditis and pleuritis in less than 2 hours. AB - OBJECTIVES: To evaluate the diagnostic validity of GeneXpert for the detection of Mycobacterium tuberculosis (MTB) in pericardial and pleural effusions samples. METHODS: A cross sectional study was conducted at the Mycobacteriology Laboratory, Allama Iqbal Medical College, Lahore, Pakistan. A total of 286 (158 pleural and 128 pericardial fluids) samples were received from tuberculosis (TB) suspects between January 2014 and August 2016. Every sample was processed for Ziehl-Neelsen (Zn) smear, Lowenstein Jensen (LJ) culture, GeneXpert MTB/RIF assay according to standard protocols. Validity of GeneXpert assay for the detection of MTB was evaluated using LJ culture as gold standard. RESULTS: Out of 286 effusions samples, MTB was isolated by LJ culture in 51 (17.8%) samples followed by GeneXpert in 43 (15%), and acid- fast bacilli (AFB) was detected by Zn smear microscopy in 11 (3.8%) samples. GeneXpert showed high sensitivity (84.3%), specificity (100%), with positive predictive value (100%), and negative predictive value (96.7%), while Zn smear showed sensitivity 18.3%, specificity 99.1%, positive predictive value 81.8%, and negative predictive value 85.4%. A strikingly high sensitivity of 72.2% was observed for pericardial fluid by GeneXpert. CONCLUSION: GeneXpert assay is an innovative tool, for prompt detection of MTB and drug resistance. It is definitely an attractive point of care test, with high sensitivity and specificity along with turn around time of 2 hours, which facilitates timely diagnosis and appropriate management of TB pleuritis and pericarditis. PMID- 28674715 TI - Urinary neutrophil gelatinase-associated lipocalin is an excellent predictor of mortality in intensive care unit patients. AB - OBJECTIVES: To assess urine neutrophil gelatinase-associated lipocalin (uNGAL) level as a potential predictor of acute kidney injury (AKI), and both intensive care unit (ICU) and in-hospital mortality. METHODS: Patients presenting to our ICU with a systolic blood pressure (SBP) less than 90 mmHg or mean arterial pressure (MAP) less than 65 mmHg, and no prior kidney disease were followed prospectively. Baseline data were collected on patient demographics, admission diagnosis, APACHE II and SOFA scores, SBP, MAP, serum creatinine and cystatin C, and uNGAL. Patients were monitored throughout hospitalization, including daily uNGAL, serum creatinine and cystatin C, and continuous MAP. Bivariate analysis compared those dying in the ICU and in-hospital versus survivors; with hierarchical binary logistic regression used to identify predictors of mortality. Areas under receiver-operating-characteristic curves (AUC) were used to measure sensitivity and specificity at different uNGAL thresholds. RESULTS: Among 75 patients followed, 16 died in the ICU, and another 24 prior to hospital discharge. Mortality rates were greatest in trauma and sepsis patients. The ICU survivors differed from non-survivors in almost all clinical variables; but only 2 predicted ICU mortality on multivariate analysis: day one uNGAL (p=0.01) and 24 hour APACHE II score (p=0.07). Only the APACHE II score significantly predicted in-hospital mortality (p=0.003). The AUC for day one uNGAL was greater for ICU (AUC=0.85) than in-hospital mortality (AUC=0.74). CONCLUSIONS: Day one uNGAL is a highly accurate predictor of ICU, but less so for in-hospital mortality. PMID- 28674716 TI - Intensive care unit nurses' perceptions of the obstacles to the end of life care in Saudi Arabia. AB - OBJECTIVES: To explore nurses' perceptions of obstacles to the provision of end of life care (EoLC) in the intensive care unit (ICU) in Saudi Arabia. METHODS: A modified version of a questionnaire developed by Beckstrand and Kirchhoff was administered in one setting at Riyadh, Saudi Arabia between March and April 2015. RESULTS: A total of 87 questionnaires were returned from 140 potential respondents, representing a 62% response rate. Findings highlighted concerns associated with patient's family, physicians who differed in opinions, cultural differences and language barriers. The nurses also noted issues in awareness and involvement in education about EoLC and futile care. CONCLUSION: Findings highlight a number of key obstacles to the provision of quality EoLC in ICUs for nurses. Further development of both EoLC guidelines and education about EoLC in ICUs is recommended. PMID- 28674717 TI - Obstetric brachial plexus injury. Knowledge among health care providers in Saudi Arabia. AB - OBJECTIVES: To assess the basic knowledge on obstetric brachial plexus injury among obstetricians, pediatricians, and physio-/occupational therapists in major hospitals in Riyadh. We aimed to identify if inadequate knowledge is the reason behind delayed referrals to the Hand Clinic. Methods: This is a cross-sectional questionnaire-based study conducted at 5 major hospitals in Riyadh, Saudi Arabia between June 2015 and August 2015. A questionnaire of 6 questions (multiple choice closed-ended questions) was given to obstetricians, pediatricians, and physio-/occupational therapists' in these selected hospitals. The total score out of 6 was categorized as good, adequate, and inadequate knowledge if the score is 5-6, 3-4, and less than 3; respectively. The data were analyzed with Chi-square, fisher exact, Analysis of Variance, and Post-hoc tests where appropriate. Results: A total of 323 subjects participated in the study. For positions, the best mean score (for all 6 questions) was scored by consultants and the score was only 2.95 out of 6. For hospitals, Hospital IV scored the best mean score (2.99). The mean scores were not significantly different between different specialties. Conclusion: Inadequate knowledge seems to be a reason for delayed referrals of cases of obstetric brachial plexus injury to Hand Clinics in Riyadh, Saudi Arabia. PMID- 28674718 TI - Seroprevalence of Toxoplasma gondii, Rubella virus and Cytomegalovirus among pregnant women and the importance of avidity assays. AB - OBJECTIVES: To determine the seroprevalence of Toxoplasma gondii (T. gondii), Rubella virus, and Cytomegalovirus (CMV) among pregnant women in Izmir, Turkey. METHODS: Medical records of pregnant women attending Izmir Tepecik Training and Research Hospital, Izmir, Turkey between January 2014 and January 2016 were analyzed in this retrospective cross-sectional study. The 7513 T. gondii IgM/IgG results, 7189 Rubella IgM/IgG results, 906 CMV IgM/IgG results and 146 avidity test results were evaluated. Specific IgM and IgG antibodies were detected by an automated chemiluminescent enzyme immunoassay method. Immunoglobulin G avidity tests were performed using a multiparametric immunoassay system. RESULTS: The rates of IgG positivity for T. gondii was 32.3%, Rubella virus 93.5%, and CMV 98.9%. Immunoglobulin M antibodies were found to be positive in 138 (1.9%) cases for T. gondii, 88 (1.2%) cases for Rubella, and 14 (1.5%) cases for CMV. Avidity tests were ordered from 146 of 218 patients who were found both IgM and IgG positive. Among 146 patients, 6 patients had a low avidity index (all for T. gondii), 11 patients showed borderline avidity, and 129 patients revealed high avidity. CONCLUSION: In our region, whereas the rates of IgG positivity for Rubella and CMV are high, most pregnant women were susceptible to T. gondii infections. In order to enhance the reliability of the serological diagnosis, avidity tests should be performed in all IgM positivities detected together with IgG positivity. PMID- 28674719 TI - Prostate cancer screening in a low prevalence population. Is it worth it? AB - OBJECTIVES: To embrace a national screening program for prostate cancer, putting into consideration the cost, and the attitude of the general population towards such screening. METHODS: Men aged greater than 45 and less than 70 years were invited to participate in the current prospective study conducted at King Saud University Medical City, Riyadh, Saudi Arabia between December 2014 and July 2015. Those with confirmed high prostate-specific antigen (PSA) (>=4 ng/ml) were referred to the urology clinic, then subjected to magnetic resonance imaging. RESULTS: The total cohort screened were 2898, we found 118 cases with high PSA (>=4 ng/ml). Fifty-two cases (60.4%) were confirmed high PSA. All of them were subjected to MRI and biopsy. The confirmed prostate cancer were 7 cases (0.24%). The age of confirmed prostate cancer cases ranged from 49 years to 68 years, Gleason score for 4 cases was low grade (3+3), while it was 3+4 for 2 cases, and only one case had advanced cancer (3+5). Approximately 12% of cases with high PSA did not show up for confirmation of their results for further examination. CONCLUSIONS: The present study recommends against mass screening among Saudi population; however, men before 50 years of age should start PSA blood testing until before 70 years after discussing the benefits and harms of such screening through shared decision making. PMID- 28674720 TI - Trends and demographic characteristics of Saudi cosmetic surgery patients. AB - OBJECTIVES: To present the demographic characteristics of Saudi patients undergoing cosmetic procedures. Methods: This prospective study survey was conducted in 3 private cosmetic surgery centers in different regions of Saudi Arabia (Riyadh and Jeddah) between January and August 2016. Validated questionnaire with modification was used and the following patient's information were provided: age group, height and weight, marital status, number of children, age of the patient's spouse, educational level, monthly income, name of the cosmetic procedure, names of any previous cosmetic procedures and their reason for cosmetic procedure. Results: The present study revealed that a typical Saudi cosmetic surgery patients are university graduates, married (46.8%), employed (68.3%), and middle aged 20-40 years of age (70%), with a fairly high typical monthly income. Conclusion: There is a possible positive correlation between gender and undergoing cosmetic procedure. Laser hair removal, botox, liposuction, filler, and scar revision are common among females, while rhinoplasty is a common procedure among males. PMID- 28674721 TI - Attitude of the Saudi community towards heart donation, transplantation, and artificial hearts. AB - OBJECTIVES: To understand the attitudes of the Saudi population towards heart donation and transplantation. Methods: A survey using a questionnaire addressing attitudes towards organ transplantation and donation was conducted across 18 cities in Saudi Arabia between September 2015 and March 2016. Results: A total of 1250 respondents participated in the survey. Of these, approximately 91% agree with the concept of organ transplantation but approximately 17% do not agree with the concept of heart transplantation; 42.4% of whom reject heart transplants for religious reasons. Only 43.6% of respondents expressed a willingness to donate their heart and approximately 58% would consent to the donation of a relative's organ after death. A total of 59.7% of respondents believe that organ donation is regulated and 31.8% fear that the doctors will not try hard enough to save their lives if they consent to organ donation. Approximately 77% believe the heart is removed while the donor is alive; although, the same proportion of respondents thought they knew what brain death meant. Conclusion: In general, the Saudi population seem to accept the concept of transplantation and are willing to donate, but still hold some reservations towards heart donation. PMID- 28674722 TI - Carious lesions of permanent molars and oral health practices of parents and peers in Saudi male adolescents. AB - OBJECTIVES: To assess the association between carious lesions in first and second permanent molars in adolescents and their parents' and peers' oral health practices. Methods: This cross-sectional study of 12-15 year-old male adolescents was conducted in Dammam, Kingdom of Saudi Arabia, on February 2016. Data collection included dental examination to measure carious lesions and plaque. There was a questionnaire to assess oral health practices such as brushing with fluoridated toothpaste, current daily tobacco use, and daily consumption of sugary food and drinks. Logistic regression models assessed the association between first and second molars carious lesions with adolescents', parents', and peers' oral health practices. Results: Of 302 students, 294 participated. The mother's brushing was significantly associated with a lower odds of carious lesions in the first molar (odds ratio [OR] = 0.17, 95% confidence interval [CI]: 0.04 - 0.77). The mothers' sugary food intake and students' own brushing were significantly associated with carious lesions in the second molar (OR = 1.95 and 0.36, 95% CI: 1.01-9.89 and 0.12-0.89). Friends' intake of sugary drinks had a strong, but non-significant, association with second molar's carious lesions (OR=3.61, 95% CI: 0.35 - 7.44). Conclusion: In Saudi society, mothers have a major influence on their adolescent sons' carious lesions. Adolescents' oral health strategies should involve parents to reduce their risk of caries. PMID- 28674723 TI - Preference and usage of intracanal medications during endodontic treatment. AB - OBJECTIVES: To investigate the preferences of general dental practitioners (GDPs) and endodontists in using endodontic intra-canal medications (ICMs). METHODS: This observational and descriptive study was conducted in 2014 in the western province of Saudi Arabia. Following ethical clearance and 2 pilot studies, a web based questionnaire was electronically sent to 375 randomly and systematically selected GDPs and all endodontists in the western province (n=49). An accompanying e-mail explained the study's aims and confirmed that the data yielded would remain confidential. The responses were collected, and the data was analyzed using the Chi-square test at p=0.05. RESULTS: Significantly, the highest proportion of respondents (53.7%) reported disinfection of the root canals as the main function of ICMs. Calcium hydroxide (CH) was the preferred material of the majority of those who used the same ICM in all cases (85.7%). While the vast majority of all endodontists (87.5%) used CH after pulp extirpation, 48.5% of GDPs used formocresol (p less than 0.001). Almost 30% of those who used ICMs after pulp extirpation did not do so after cleaning and shaping of vital cases. Most endodontists used CH (62.5%) and antibiotics (37.5%) in necrotic pulp cases without apical lesions, which were significantly greater than those of GDPs who did the same (43.8% and 17.2%). CONCLUSIONS: Participants were aware that the main function of ICMs is disinfection of the root canal system. However, it is clear that GDPs should reduce their reliance on phenol- and formaldehyde-based medications. There was a distinct trend toward the use of ICMs, especially CH, in necrotic pulp cases. PMID- 28674724 TI - Infantile scimitar syndrome with unusual associations. AB - Scimitar syndrome is a variant of partial anomalous pulmonary venous connection (PAPVC), in which all or part of the right lung is drained by right pulmonary veins that anomalously connect to the inferior vena cava (IVC). The affected lung and its associated airways are often hypoplastic. In addition, aortopulmonary collateral vessels may be involved on the affected side, causing sequestration of that side; such involvement is commonly associated with cardiac defects. We report a case of infantile scimitar syndrome that involved a typical association with the right lung, but with extremely unusual associations with congenital hydrocephalus and heart blockage. The presentation of this case and the role of different diagnostic approaches and management are discussed. PMID- 28674725 TI - Female patients' perception of pain caused by mammography in the Western Region of Saudi Arabia. AB - OBJECTIVES: To determine the association of different factors in the mammography related pain perception of women who attended their screening and diagnostic mammography appointments and whether the pain perceived was equal to the pain experienced. Methods: This prospective study was conducted at the Breast Unit of King Abdulaziz University (KAU) Hospital, Jeddah, Kingdom of Saudi Arabia (KSA), in the period between April and May 2015. A structured questionnaire with close ended questions was given to a sample of 100 women before and after their mammogram, asking about their pain perception and whether it had changed. Results: The factors that affected anticipated mammography pain for the surveyed women were past mammography experiences, previous breast procedures, and the knowledge that was gathered beforehand about mammography. After the mammography, the women who thought the procedure was going to be painful experienced what they expected. The majority of the women who did not expect the mammography to be painful experienced pain during their mammogram. Most of the women who did not know whether it would be painful or not experienced the mammography as painful. Conclusion: Pain expectation can be approached in various ways to make the mammography experience much more tolerable for women, encouraging them to attend and return for their scans. PMID- 28674726 TI - Lung damage analyzed by machine vision on tissue sections of mice. AB - The inhalation of environmental toxicants can induce lung damage. Many methods are currently available to analyze lung tissue damage and are based on empirical visual judgment; however, the accuracy of the assessments are influenced by individual differences among pathologists. Here, we establish new methods of analysis for lung tissue sections based on machine vision and verify this new automatic high-flux method with the model of mice inhaling aqueous aerosol with different concentrations of CdCl2 (0, 1, 3, 5 mM 2 h/day) for 7 days through analyses of pulmonary porosity, mucus, pneumonia and co-localized staining. Additionally, the correlation analysis among the concentrations of CdCl2 in aqueous aerosol, the high-flux analyses and empirical visual judgment methods demonstrate the practicality of the new automatic method. The comparison between the high-flux analyses and the empirical visual judgment methods demonstrates the superiority of the new automatic method. In the future, these new automatic high flux analyses based on machine vision could be conducive to pulmonary histology and pathology research. PMID- 28674727 TI - Cellular and molecular mechanisms of alcohol-induced osteopenia. AB - Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs. PMID- 28674728 TI - New imaging probes to track cell fate: reporter genes in stem cell research. AB - Cell fate is a concept used to describe the differentiation and development of a cell in its organismal context over time. It is important in the field of regenerative medicine, where stem cell therapy holds much promise but is limited by our ability to assess its efficacy, which is mainly due to the inability to monitor what happens to the cells upon engraftment to the damaged tissue. Currently, several imaging modalities can be used to track cells in the clinical setting; however, they do not satisfy many of the criteria necessary to accurately assess several aspects of cell fate. In recent years, reporter genes have become a popular option for tracking transplanted cells, via various imaging modalities in small mammalian animal models. This review article examines the reporter gene strategies used in imaging modalities such as MRI, SPECT/PET, Optoacoustic and Bioluminescence Imaging. Strengths and limitations of the use of reporter genes in each modality are discussed. PMID- 28674729 TI - Expression of a SOX1 overlapping transcript in neural differentiation and cancer models. AB - SOX1 is a member of the SOXB1 subgroup of transcription factors involved in early embryogenesis, CNS development and maintenance of neural stem cells. The structure and regulation of the human SOX1 locus has been less studied than that of SOX2, another member of the SOXB1 subgroup for which an overlapping transcript has been reported. Here we report that the SOX1 locus harbours a SOX1 overlapping transcript (SOX1-OT), and describe expression, splicing variants and detection of SOX1-OT in different stem and cancer cells. RT-PCR and RACE experiments were performed to detect and characterise the structure of SOX1-OT in neuroprogenitor cultures and across different cancer cell lines. SOX1-OT was found to present a complex structure including several unannotated exons, different transcript variants and at least two potential transcription start sites. SOX1-OT was found to be highly expressed in differentiated neural stem cells across different time points of differentiation, and its expression correlated with SOX1 gene expression. Concomitant expression of SOX1 and SOX1-OT was further observed in several cancer cell models. While the function of this transcript is unknown, the regulatory role reported for other lncRNAs strongly suggests a possible role for SOX1-OT in regulating SOX1 expression, as previously observed for SOX2. The elucidation of the genetic and regulatory context governing SOX1 expression will contribute to clarifying its role in stem cell differentiation and tumorigenesis. PMID- 28674730 TI - Cauliflower waste utilization for sustainable biobutanol production: revelation of drying kinetics and bioprocess development. AB - Efficient yet economic production of biofuel(s) using varied second-generation feedstock needs to be explored in the current scenario to cope up with global fuel demand. Hence, the present study was performed to reveal the use of cauliflower waste for acetone-butanol-ethanol (ABE) production using Clostridium acetobutylicum NRRL B 527. The proximate analysis of cauliflower waste demonstrated to comprise 17.32% cellulose, 9.12% hemicellulose, and 5.94% lignin. Drying of cauliflower waste was carried out in the temperature range of 60-120 degrees C to investigate its effect on ABE production. The experimental drying data were simulated using moisture diffusion control model. The cauliflower waste dried at 80 degrees C showed maximum total sugar yield of 26.05 g L-1. Furthermore, the removal of phenolics, acetic acid, and total furans was found to be 90-97, 10-40, and 95-97%, respectively. Incidentally, maximum ABE titer obtained was 5.35 g L-1 with 50% sugar utilization. PMID- 28674731 TI - Tractography guides the approach for resection of thalamopeduncular tumors. AB - BACKGROUND: Thalamopeduncular tumors arise at the junction of the inferior thalamus and cerebral peduncle, and present with a common clinical syndrome of progressive spastic hemiparesis. METHOD: Formal preoperative magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed. Postoperative MRI was obtained to evaluate the extent of tumor resection. A prospective analysis of clinical outcomes was then conducted by the senior author. CONCLUSIONS: Preoperative tractography is a useful adjunct to surgical planning in tumors that displace motor pathways. Gross total resection of pilocytic astrocytomas usually results in cure, and therefore should be entertained when developing treatment strategies for thalamopeduncular tumors of childhood. PMID- 28674732 TI - Preservation of hearing following awake surgery via the retrosigmoid approach for vestibular schwannomas in eight consecutive patients. AB - BACKGROUND: Hearing preservation in patients with vestibular schwannomas remains difficult by microsurgery or radiosurgery. METHOD: In this study, awake surgery via the retrosigmoid approach was performed for vestibular schwannomas (volume, 11.6 +/- 11.2 ml; range, 1.3-26.4 ml) in eight consecutive patients with preoperative quartering of pure tone audiometry (PTA) of 53 +/- 27 dB. RESULTS: After surgery, hearing was preserved in seven patients and improved in one patient. The postoperative quartering PTA was 51 +/- 21 dB. Serviceable hearing (class A + B + C) using the American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) classification was preserved in all patients. Preoperative useful hearing (AAO-HNS class A + B) was observed in three patients, and useful hearing was preserved in all three of these patients after surgery. In addition, useful facial nerve function (House-Blackmann Grade 1) was preserved in all patients. CONCLUSIONS: These results suggest that awake surgery for vestibular schwannomas is associated with low patient morbidity, including with respect to hearing and facial nerve function. PMID- 28674733 TI - MicroRNAs modulate core-clock gene expression in pancreatic islets during early postnatal life in rats. AB - AIMS/HYPOTHESIS: Evidence continues to emerge detailing a fine-tuning of the regulation of metabolic processes and energy homeostasis by cell-autonomous circadian clocks. Pancreatic beta cell functional maturation occurs after birth and implies transcriptional changes triggered by a shift in the nutritional supply that occurs at weaning, enabling the adaptation of insulin secretion. So far, the developmental timing and exact mechanisms involved in the initiation of the circadian clock in the growing pancreatic islets have never been addressed. METHODS: Circadian gene expression was measured by quantitative RT-PCR in islets of rats at different postnatal ages up to 3 months, and by in vitro bioluminescence recording in newborn (10-day-old) and adult (3-month-old) islets. The effect of the microRNAs miR-17-5p and miR-29b-3p on the expression of target circadian genes was assessed in newborn rat islets transfected with microRNA antisense or mimic oligonucleotides, and luciferase reporter assays were performed on the rat insulin-secreting cell line INS832/13 to determine a direct effect. The global regulatory network between microRNAs and circadian genes was computationally predicted. RESULTS: We found up to a sixfold-change in the 24 h transcriptional oscillations and overall expression of Clock, Npas2, Bmal1, Bmal2, Rev-erbalpha, Per1, Per2, Per3 and Cry2 between newborn and adult rat islets. Synchronisation of the clock machinery in cultured islet cells revealed a delayed cell-autonomous rhythmicity of about 1.5 h in newborn compared with adult rats. Computational predictions unveiled the existence of a complex regulatory network linking over 40 microRNAs displaying modifications in their expression profiles during postnatal beta cell maturation and key core-clock genes. In agreement with these computational predictions, we demonstrated that miR-17-5p and miR-29b-3p directly regulated circadian gene expression in the maturing islet cells of 10-day-old rats. CONCLUSIONS/INTERPRETATION: These data show that the circadian clock is not fully operational in newborn islets and that microRNAs potently contribute to its regulation during postnatal beta cell maturation. Defects in this process may have long-term consequences on circadian physiology and pancreatic islet function, favouring the manifestation of metabolic diseases such as diabetes. PMID- 28674734 TI - Nonbiologic factors that impact management in women with urinary incontinence: review of the literature and findings from a National Institute of Diabetes and Digestive and Kidney Diseases workshop. AB - INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI)-defined as a complaint of involuntary loss of urine-is common in women, with major public health, financial, and quality of life (QoL) implications. Despite the high toll of UI and the availability of effective conservative treatments, many women with UI do not seek care. Those who do often continue to experience symptoms. Improving UI treatment may require a comprehensive approach to urology research, including a broad set of potentially influential factors beyond biologic. METHODS: To explore the effects of nonbiologic factors (NBF) on UI management and treatment response, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop for clinical and psychosocial researchers. Participants proposed a UI treatment pathway: recognizing the problem, willingness to seek treatment, access to care, receiving quality treatment, engaging in self-management, and adhering to chosen treatments; discussed potential NBFs that may affect the pathway; and identified areas for future research. After the meeting, a rapid literature review was conducted to assess the current state of research on NBFs in women with UI. RESULTS: Participants identified several patient-level NBFs that may influence the UI management pathway, including QoL and perceived bother; stigma, shame, and embarrassment; knowledge and perceptions; social determinants of health; cultural and language characteristics; personal characteristics and skills; and physical abilities. Additionally, participants acknowledged that provider- and system-level factors also play a role and likely interact with patient-level factors. CONCLUSIONS: NBFs that potentially affect the UI management pathway are not well understood, and a comprehensive, interdisciplinary approach to research is needed to understand and appropriately support effective UI treatment. PMID- 28674735 TI - Reoperation for pelvic organ prolapse: a Danish cohort study with 15-20 years' follow-up. AB - INTRODUCTION AND HYPOTHESIS: The objectives were to determine the reoperation rate of primary pelvic organ prolapse (POP) surgery, to describe the age distribution of the women at primary surgery for those undergoing a reoperation, and to describe the incidence of second and third reoperations. METHODS: We carried out a population-based registry study of Danish women above the age of 18 years when undergoing primary surgery for POP during the period 1996-2000. Data were retrieved from the Danish National Patient Register. All women were followed until one of the following events occurred: reoperation for POP, death, emigration, or end of follow-up period. Reoperation was defined as "repeated surgery in same compartment". The cumulative incidence rate of reoperation was divided into three compartments (anterior, apical, and posterior) and was calculated using Kaplan-Meier plots. RESULTS: A total of 18,382 procedures were performed on 11,805 women. After 20 years' follow-up, the cumulated incidence rate of reoperation for POP in the anterior, apical, and posterior compartments was 12.4%, 7.9%, and 12.1% respectively. The overall rate of reoperation was 11.5%. Of women aged between 18 and 49 years of age at primary surgery, 26.9% had a reoperation, whereas in women between 50 and 90+ years of age at primary surgery, only 10.1% had a reoperation. CONCLUSIONS: This large study with up to 20 years' follow-up has found that reoperation for POP is modest, that the reoperation rate is lowest for the apical compartment, but highest in all three compartments during the first year after primary surgery. The reoperation rate peaks in the group of women who had their primary surgery before the menopause in all three compartments. PMID- 28674736 TI - The impact of hepatitis C virus infection on 90-day outcomes following major orthopaedic surgery: a propensity-matched analysis. AB - INTRODUCTION: The impact of hepatitis C virus (HCV) infection on outcomes following major orthopaedic interventions, such as joint arthroplasty or spine surgery, has not been effectively studied in the past. Most prior studies are impaired by small samples, limited surveillance for adverse events, or the potential for selection bias to confound results. In this context, we sought to evaluate the impact of HCV infection on 90-day outcomes following joint arthroplasty or spine surgery using propensity-matched techniques. MATERIALS AND METHODS: This study utilized 2006-2014 claims from TRICARE insurance. Adults who received spine surgical procedures, total knee and hip arthroplasty were identified. Covariates included demographic factors, a diagnosis of HCV and medical co-morbidities defined by International Classification of Disease-9th revision (ICD-9) code. Outcomes consisted of 30- and 90-day mortality, complications and readmission. A propensity score was used to balance the cohorts with logistic regression techniques employed to determine the influence of HCV infection on post-operative outcomes. RESULTS: The propensity-matched cohort consisted of 2262 patients (1131 with and without HCV). Following logistic regression, patients with HCV were found to have increased odds of 30-day complications (OR 1.87; 95% CI 1.33, 2.64; p < 0.001), 90-day complications (OR 1.55; 95% CI 1.16, 2.08; p = 0.003) and 30-day readmission (OR 1.46; 95% CI 1.04, 2.05; p = 0.03). CONCLUSION: HCV infection was found to increase the risk of complication and readmission following spine surgery and total joint arthroplasty. Patients should be counseled on their increased risk prior to surgery. Health systems that treat a higher percentage of patients with HCV need to consider the increased risk of complications and readmission when negotiating with insurance carriers. PMID- 28674737 TI - Systematic review of the outcome of total hip arthroplasty in patients with sequelae of Legg-Calve-Perthes disease. AB - BACKGROUND: Total hip arthroplasty (THA) in patients with sequelae of Legg-Calve Perthes disease (LCP) is technically demanding because of the disease related deformities occuring in the proximal femur and/or the multiplanar deformities secondary to corrective osteotomies in childhood. Little is known about the long term outcome of the procedure in this challenging group of patients. METHODS: We carried out a systematic review of the literature to determine the functional outcome, complications and revision rate of THA in patients with sequelae of LCP disease. Six out of 148 potential studies involving 245 hips met the inclusion criteria. The mean age was 45.7 years (19-74) and follow-up was 8.4 years (2-21). RESULTS: There were 221 cementless THAs (90%), 22 hybrid THAs (9%) and 2 cemented THAs (1%). The femoral components used included 187 standard stems (76%), 43 modular stems (18%) and 15 custom-made stems (6%). The modular implants used were reamed S-Rom stems. All studies reported a significant improvement in hip function following THA. There were 16 revision THAs (7%) occurring at a mean of 7.5 years (0.4-10.3). Complications included intra-operative fracture (11%, n = 27), aseptic loosening (5%, n = 13), sciatic nerve palsy (3%, n = 7) and heterotopic ossification (2%, n = 4). All intra-operative fractures occurred when standard femoral stems were used. The average limb lengthening in the patients with a post-operative sciatic nerve injury was 1.9 cm. All patients with this complication had a history of previous hip surgery. CONCLUSIONS: THA in patients with LCP disease results in similar functional outcome compared to patients with primary osteoarthritis; however, the revision rate at mid-term follow-up is slightly increased. Reamed modular (S-Rom) and custom femoral implants appear to be associated with a decreased risk of intra-operative fracture. Care should be taken when addressing leg length discrepancy in this group of patients due to the increased risk of sciatic nerve palsy, especially in patients with prior surgical procedures. PMID- 28674738 TI - Three single loops enhance the biomechanical behavior of the transtibial pull-out technique for posterior meniscal root repair. AB - PURPOSE: To investigate the effect of applying an additional suture to enhance the biomechanical behavior of the suture-meniscus construct used during the transtibial pull-out repair technique. METHODS: A total of 20 fresh-frozen porcine tibiae with intact medial menisci were used. In one half of all specimens (N = 10), two non-absorbable sutures were passed directly over the meniscal root from the tibia side of the meniscus to the femoral side (2SS). In other ten specimens, three sutures were passed over the meniscal root (3SS). All specimens were subjected to cyclic loading followed by load-to-failure testing. Displacement of the construct was recorded at 100, 500, and 1000 cycles. Further, stiffness (500-1000 cycles) and ultimate load and modes of failure of the suture meniscus construct were also recorded. RESULTS: There was no statistically significant difference between the Group 2SS and Group 3SS at the 1st (1.6 +/- 0.7 vs 1.4 +/- 0.4 mm) and the 100th cycle (2 +/- 0.7 vs 1.8 +/- 0.4 mm). At 500 and 1000 cycles, the 2SS fixation technique resulted in significantly more displacement than the 3SS fixation technique (2.8 +/- 0.6 vs 2.3 +/- 0.5 mm; 3.1 +/- 0.7 vs 2.5 +/- 0.5 mm) (p < 0.05). No differences between two groups were noted concerning ultimate load to failure and stiffness (500-1000 cycles). CONCLUSION: Three single sutures technique provided superior biomechanical properties compared with the two single sutures technique during the conducted fatigue tests. CLINICAL RELEVANCE: Applying three simple stitches during meniscal root repair might be beneficial for healing of the posterior meniscal root, potentially reducing the post-operative immobilization time. PMID- 28674739 TI - Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro. AB - Alveolar macrophages are key contributors to both the promotion and resolution of inflammation in the lung and are categorized into pro-inflammatory (M1) and anti inflammatory (M2) phenotypes. The change in M1/M2 balance has been reported in various pulmonary diseases and is a target for therapeutic intervention. The aim of this study was to assess the modulation of M1/M2 phenotype in alveolar macrophages by water-soluble carbon monoxide-releasing molecule-3 (CORM-3). Rat alveolar macrophages (AM) (NR8383) in culture were stimulated with LPS (5 ng/ml)/IFN-gamma (10 U/ml) or IL-4 (10 ng/ml)/IL-13 (10 ng/ml) to induce M1 and M2 phenotypes, respectively. Expression of M1 phenotype markers, iNOS and TNF alpha, and M2 phenotype markers, CD206 and Ym-1, was assessed by western blotting after 1, 3, 6, or 24 h in the absence or presence of CORM-3 (0.15 mM) treatment. Inactive CORM-3 (iCORM-3) was used as a control. Treatment of naive (unstimulated) AM with CORM-3 promoted progression of the M2 phenotype as evidenced by the increased expression of CD206 (at 1 h; 1.8-fold) and Ym-1 (at 3 h; 1.9-fold), respectively. Surprisingly, CORM-3 treatment also upregulated the expression of iNOS protein as assessed 6 h following stimulation of AM with CORM 3 (2.6-fold). On the contrary, CORM-3 effectively reduced LPS/IFN-gamma-induced expression of iNOS protein (0.6-fold); however, it had no effect on TNF-alpha expression. Finally, CORM-3 acutely (1-3 h) upregulated CD206 (1.4-fold) and Ym-1 (1.6-fold) levels in IL-4-/IL-13-treated (M2-stimulus) macrophages. These findings indicate that CORM-3 modulates macrophage M1 and M2 phenotypes in vitro with respect to continuous suppression of iNOS expression in M1-polarized macrophages and transient (early-phase) upregulation of CD206 and Ym-1 proteins in M2-polarized macrophages. PMID- 28674740 TI - Changes in gait pattern and early functional results after ACL repair are comparable to those of ACL reconstruction. AB - PURPOSE: Dynamic intraligamentary stabilization (DIS) has been introduced as a new technique to repair the torn anterior cruciate ligament (ACL) and to restore knee joint kinematics after an acute ACL tear. Aim of the present study was to compare the early post-operative activity, restoration of gait pattern and functional results after DIS in comparison with primary ACL reconstruction (ACLR) for acute ACL tears. It was hypothesized that functional results, post-operative activity and changes in gait pattern after DIS are comparable to those after ACLR. METHODS: Sixty patients with acute ACL tears were included in this study and underwent either DIS or ACLR with an anatomic semitendinosus autograft in a randomized manner. Patients were equipped with an accelerometric step counter for the first 6 weeks after surgery in order to monitor their early post-operative activity. 3D gait analysis was performed at 6 weeks and 6 months after surgery. Temporal-spatial, kinematic and kinetic parameters were extracted and averaged for each subject. Functional results were recorded at 6 weeks, 6 months and 12 months after surgery using the Tegner activity scale, International Knee Documentation Committee score and Lysholm score. RESULTS: Patients who underwent DIS showed an increased early post-operative activity with significant differences at week 2 and 3 (p = 0.0241 and 0.0220). No significant differences between groups were found for knee kinematic and kinetic parameters or the functional scores at any time of the follow-up. Furthermore, the difference in anterior tibial translation was not significantly different between the two groups (n.s.). CONCLUSION: Early functional results and changes in gait pattern after DIS are comparable to those of primary ACLR. Therefore, ACL repair may be an alternative to ACLR in this cohort of patients. LEVEL OF EVIDENCE: I. PMID- 28674741 TI - New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bone tumours. AB - The latest (4th) edition of the World Health Organization Classification of Head and Neck tumours has recently been published with a number of significant changes across all tumour sites. In particular, there has been a major attempt to simplify classifications and to use defining criteria which can be used globally in all situations, avoiding wherever possible the use of complex molecular techniques which may not be affordable or widely available. This review summarises the changes in Chapter 8: Odontogenic and maxillofacial bone lesions. The most significant change is the re-introduction of the classification of the odontogenic cysts, restoring this books status as the only text which classifies and defines the full range of lesions of the odontogenic tissues. The consensus group considered carefully the terminology of lesions and were concerned to ensure that the names used properly reflected the best evidence regarding the true nature of specific entities. For this reason, this new edition restores the odontogenic keratocyst and calcifying odontogenic cyst to the classification of odontogenic cysts and rejects the previous terminology (keratocystic odontogenic tumour and calcifying cystic odontogenic tumour) which were intended to suggest that they are true neoplasms. New entities which have been introduced include the sclerosing odontogenic carcinoma and primordial odontogenic tumour. In addition, some previously poorly defined lesions have been removed, including the ameloblastic fibrodentinoma, ameloblastic fibro-odontoma, which are probably developing odontomas, and the odontoameloblastoma, which is not regarded as an entity. Finally, the terminology "cemento" has been restored to cemento-ossifying fibroma and cemento-osseous dysplasias, to properly reflect that they are of odontogenic origin and are found in the tooth-bearing areas of the jaws. PMID- 28674743 TI - Whole genome duplication enhances the photosynthetic capacity of Chrysanthemum nankingense. AB - Whole genome duplication has a major effect on the phenotype and physiology of higher plants. A comparison between the diploid and tetraploid forms of Chrysanthemum nankingense showed that the latter's leaf contained a higher content of chlorophyll a/b and harbored a larger number of chloroplasts per cell, leading to an enhancement in its photosynthetic capacity and an improved level of productivity with respect to biomass. A transcriptomic analysis of the two ploidy level forms revealed 21,559 differentially transcribed genes. Compared with diploid progenitor, a number of genes associated with chlorophyll synthesis and those encoding components of photosystems I and II were up-regulated in the tetraploid form, while those associated with chlorophyll degradation were down regulated. These results indicated that whole genome duplication can directly affect chlorophyll synthesis/degradation and photosynthesis pathways associated with plant growth ratio and biomass accumulation. PMID- 28674742 TI - Characterization of gliomas: from morphology to molecules. AB - This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist. PMID- 28674744 TI - Ectopic expression of CSD1 and CSD2 targeting genes of miR398 in grapevine is associated with oxidative stress tolerance. AB - MicroRNAs (miRNAs) are endogenous small RNAs of -21 nucleotides that play an important role in diverse plant physiological processes at the post transcriptional level by directing mRNA cleavage or translational inhibition. Previous studies have indicated that down-regulation of miR398 in response to oxidative stress allows up-regulation of the two target genes, cytosolic CSD1 and chloroplastic CSD2 (copper/zinc superoxide dismutase), resulting in protecting the plants to tolerate oxidative stress. In this study, we provide evidence that grapevine miR398 (Vv-miR398), by regulating the expression of its target genes, VvCSD1 and VvCSD2, mediates responses of grapevine to copper (Cu) stress which have been magnified due to increase in Cu-containing pesticide application. The expression of Vv-miR398 was inhibited by different concentrations of Cu stress; on the other hand, there was a steady increase in the activity of VvCSD1 and VvCSD2 genes. The function of VvCSD1 and VvCSD2 under Cu stress was thoroughly examined by overexpressing the use of the VvCSD1 and VvCSD2 in transgenic tobacco (Nicotiana tabacum). We found that both the overexpressed transgenic lines had lower Cu sensitivity and higher Cu tolerance compared with the wild type. In addition, lower levels of ROS and higher levels of SOD activities were accumulated in the transgenic lines in comparison with the wild type under the higher Cu conditions. Furthermore, these transgenic tobacco lines also recorded a higher UV and salt tolerance than the WT plants. These results suggested that overexpressing the VvCSDs will enhance the ROS-scavenging systems and protect the plant against more oxidative damage. Also, more investigations in this line are needed that would provide significant improvements in our understanding the resistance of fruit crops to environmental stress. PMID- 28674745 TI - Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice. AB - RATIONALE: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. OBJECTIVES: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. RESULTS: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [3H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. CONCLUSIONS: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction. PMID- 28674746 TI - The relationship between protein quantity, BMD and fractures in older adults. AB - BACKGROUND: Previously, no large-scale literature reviews have focussed on the relationship between dietary protein and its impact on bone mineral density (BMD) and fracture risk-as measures of bone health-in older adults and its potential impact as a primary prevention tool. AIMS: The aim of this study was to assess the impact of varying dietary protein levels on bone health. METHODS: A literature review of trials concerning older adults' (>50 years of age) and animals' varying protein intake in the diet and its effect on BMD (human and animal) and fracture risk (human only) was carried out. Additionally, a review of dietary assessment tools used in these studies was also analysed. RESULTS: Ten out of fourteen trials assessing BMD and dietary protein quantity in humans and 3/4 in animal trials found a positive relationship between these two parameters. Four out of seven trials investigating the relationship between dietary protein quantity and fracture risk displayed a positive, protective effect of dietary protein levels on fracture risk. Sixty-two percent of studies used the Food Frequency Questionnaire assessment method. DISCUSSION: Increased protein intake in the diet is beneficial to bone health and reduces morbidity and mortality. The importance of using dietary protein, along with calcium and vitamin D, as a primary preventative strategy should be stressed, given the health and cost benefits that this would deliver, with a possible need for a higher level of protein in the diet of an elderly person than what is currently recommended. PMID- 28674747 TI - Oral administration of azithromycin ameliorates trypanosomosis in Trypanosoma congolense-infected mice. AB - Animal trypanosomosis is a devastating parasitic disease that is of economic importance to livestock production. The infection includes animal African trypanosomosis, surra, and dourine. The treatment is based solely on few compounds that were discovered decades ago and which are associated with severe toxicity. Furthermore, it is likely that the parasite has developed resistance towards them. Thus, there is an urgent need for new, accessible, and less toxic drugs. Azithromycin is an antibiotic with documented efficacy against Toxoplasma, Babesia, and Plasmodium. The current study investigated its effects against animal trypanosomes. An in vitro system was used to determine the trypanocidal effects of azithromycin against Trypanosoma congolense, Trypanosoma brucei brucei, and Trypanosoma evansi, and cytotoxicity in Madin-Darby bovine kidney (MDBK) and NIH 3T3 cells. Furthermore, the trypanocidal effects of azithromycin were investigated in T. congolense-infected mice. In vitro, azithromycin had an IC50 of 0.19 +/- 0.17; 3.69 +/- 2.26; 1.81 +/- 1.82 MUg/mL against T. congolense, T. b. brucei, and T. evansi, respectively. No cytotoxic effects were observed in MDBK and NIH 3T3 cells. The efficacy of orally administered azithromycin was investigated in short-term and long-term treatment protocols. Although the short term treatment protocol showed no curative effects, the survival rate of the mice was significantly prolonged (p < 0.001) in comparison to the control group. The long-term treatment yielded satisfying curative effects with doses of 300 and 400 mg/kg achieving 80 and 100% survival, respectively. In conclusion, long-term oral azithromycin treatment has trypanocidal effects against T. congolense. PMID- 28674749 TI - [Alzheimer dementia: course and burden on caregivers : Data over 18 months from German participants of the GERAS study]. AB - The GERAS study is an international observational study with dementia patients of the Alzheimer type (AD) and their caregivers in everyday care. The 18-month data recorded in Germany are presented. Disease progression, medical and psychosocial consequences for both patients and caregivers were recorded using commonly used tests in clinical care: the mini mental status examination (MMSE), Alzheimer's disease assessment scale (ADAS-Cog14), Alzheimer's disease cooperative study activities of daily living inventory (ADCS-ADL), neuropsychiatric inventory (NPI 12), resource utilization in dementia (RUD) and the Zarit burden interview (ZBI). Definition of AD severity level (MMSE): 21-26 mild (miAD), 15-20 moderate (moAD), <15 moderately severe to severe (m/sAD). For the 550 participants (mean age: 75.2 years, SD 7.6 years), miAD (41.5%), moAD (28.4%) and m/sAD (30.2%), the MMSE worsened: in miAD by -2.4 (CI -3.1/-1.7), in moAD by -3.9 (CI -5.0/-2.8) and in m/sAD by -2.5 (CI -3.5/-1.5) at 18 months and the ADAS-Cog14 by 6.2 (miAD-CI 4.6/7.8) and 7.1 points (moAD CI 3.9/10.3). Changes in overall ADCS-ADL amounted to -8.4 (CI -10.1/-6.2) for miAD, -12.9 (CI -15.3/-10.4) for moAD and -10.2 points (CI-12.8/-7.7) for m/sAD. Caregiver burden (NPI-12) rose in miAD by 1.2 points (CI -0.2/2.2), in moAD by 3.4 (CI 1.8/5.1) and in m/sAD by 1.5 points (CI 0.2/3.3). At study start, the total time required by caregivers (RUD) was 3.1 h/day (SD 5.4 h/day) for miAD, 6.6 (SD 7.5) for moAD and 12.7 (SD 9.3) for m/sAD. With 4.4 (SD 9.4) h/day, the increase after 18 months was highest in moAD. Caregiver burden (ZBI) increased most markedly in moAD with 7.2 (CI 4.2/9.7), 90.7% of the patients received antidementia drugs, while 26.6% received psychotropic medication. PMID- 28674748 TI - Platelet-activating factor podoplanin: from discovery to drug development. AB - Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). The podoplanin research was originally started from the cloning of highly metastatic NL-17 subclone from mouse colon 26 cancer cell line and from the establishment of 8F11 monoclonal antibody (mAb) that could neutralize NL-17-induced platelet aggregation and hematogenous metastasis. Later on, podoplanin was identified as the antigen of 8F11 mAb, and its ectopic expression brought to cells the platelet aggregating abilities and hematogenous metastasis phenotypes. From the 8F11 mAb recognition epitopes, podoplanin is found to contain tandemly repeated, highly conserved motifs, designated platelet aggregation-stimulating (PLAG) domains. Series of analyses using the cells expressing the mutants and the established neutralizing anti-podoplanin mAbs uncovered that both PLAG3 and PLAG4 domains are associated with the CLEC-2 binding. The neutralizing mAbs targeting PLAG3 or PLAG4 could suppress podoplanin-induced platelet aggregation and hematogenous metastasis through inhibiting the podoplanin-CLEC-2 binding. Therefore, these domains are certainly functional in podoplanin-mediated metastasis through its platelet-aggregating activity. This review summarizes the platelet functions in metastasis formation, the role of platelet aggregation-inducing factor podoplanin in pathological and physiological situations, and the possibility to develop podoplanin-targeting drugs in the future. PMID- 28674751 TI - Cognitive-behavioral or psychodynamic therapy for people with bulimia nervosa. PMID- 28674750 TI - Characteristics of hypertension in premature infants with and without chronic lung disease: a long-term multi-center study. AB - BACKGROUND: Many causes for neonatal hypertension in premature infants have been described; however in some cases no etiology can be attributed. Our objectives are to describe such cases of unexplained hypertension and to compare hypertensive infants with and without chronic lung disease (CLD). METHODS: We reviewed all cases of hypertension in premature infants referred from 18 hospitals over 16 years. Inclusion criteria were hypertension occurring at <6 months of age and birth at <37 weeks gestation; the main exclusion criterion was known secondary hypertension. Continuous variables were compared using analysis of variance. Nominal variables were compared using chi-square tests. RESULTS: A total of 97 infants met the inclusion criteria, of whom 37 had CLD. Among these infants, hypertension presented at a mean of 11.3 +/- 3.2 chronological weeks of age and a postmenstrual age of 39.6 +/- 3.6 weeks. Diagnostic testing was notable for plasma renin activity (PRA) being <11 ng/mL/h in 98% of hypertensive infants. Spironolactone was effective monotherapy in 51 of 56 cases of hypertension. Hypertension resolved in all infants, with an average treatment duration of 25 weeks. Significant differences between the two groups of infants were a 0.4 kg lower birthweight and a 2.5 weeks younger gestational age at birth in those with CLD (p < 0.01, p < 0.01, respectively). Hypertension presented in those with CLD 1.8 weeks later, but at the same postmenstrual age as those without CLD (p < 0.01, p = 0.45, respectively). CONCLUSION: Premature infants with unexplained hypertension, with and without CLD, presented at a postmenstrual age of 40 weeks with low PRA, transient time course, and a favorable response to spironolactone treatment. PMID- 28674752 TI - [Operative access for treatment of pilon fractures]. AB - BACKGROUND: Under optimal conditions, fractures of the tibial pilon can be definitively managed operatively within 6 h after the trauma. Under suboptimal conditions, preoperative antiphlogistic treatment, possibly after approximate correction and external fixation of the alignment, is a reasonable option. Osteosynthesis implies reconstruction of good joint congruency in anatomical orientation. The soft tissue coverage of the distal lower leg is relatively poorly constructed and there is a high risk of devascularization, necrosis and ensuing infection. THERAPY: Several local accesses with complete visual control of the joint surface enable a strain-free soft tissue handling and thus reduction of the incidence of complications. Besides a specific access to the fibula fracture, two anterior and two posterior accesses are proposed based on normal vascularization. These accesses can be simultaneously combined. Using a bone distractor facilitates control of the joint surface. CONCLUSION: Open reduction and stabilization of pilon fractures enables rapid restoration of joint mobility. After having analyzed the fracture and setting the priorities, the treatment strategy should include a well-thought out selection of possible accesses. PMID- 28674753 TI - Regulation of FATTY ACID ELONGATION1 expression and production in Brassica oleracea and Capsella rubella. AB - MAIN CONCLUSION: The contribution of variations in coding regions or promoters to the changes in FAE1 expression levels have be quantified and compared in parallel by specifically designed swapping constructs. FATTY ACID ELONGATION1 (FAE1) is a key gene in control of erucic acid synthesis in plant seeds. The expression of FAE1 genes in Brassica oleracea and Capsella rubella, representatives of high and low erucic acid species, respectively, was characterized to provide insight into the regulation of very long-chain fatty-acid biosynthesis in seeds. Virtually, no methylation was detected either in B. oleracea or in C. rubella, suggesting that modification of promoter methylation might not be a predominant mechanism. Swapping constructs were specifically designed to quantify and compare the contribution of variations in coding regions or promoters to the changes in FAE1 expression levels in parallel. A significantly higher fold change in erucic acid content was observed when swapping coding regions rather than when swapping promoters, indicating that the coding region is a major determinant of the catalytic power of beta-ketoacyl-CoA synthase proteins. Common motifs have been proposed as essential for the preservation of basic gene expression patterns, such as seed-specific expression. However, the occurrence of variation in common cis-elements or the presence of species-specific cis-elements might be plausible mechanisms for changes in the expression levels in different organisms. In addition, conflicting observations in previous reports associated with FAE1 expression are discussed, and we suggest that caution should be taken when selecting a plant transformation vector and in interpreting the results obtained from vectors carrying the CaMV 35S promoter. PMID- 28674754 TI - Issues related to family history of cancer at the end of life: a palliative care providers' survey. AB - Addressing the concerns of end-of-life patients or their relatives about their family history of cancer could benefit patients and family members. Little is known about how palliative care providers respond to these concerns. The purpose of this pilot study was to assess palliative care providers' knowledge about familial and hereditary cancers and explore their exposure to patients' and relatives' concerns about their family history of cancer, and their self perceived ability to deal with such concerns. A cross-sectional survey was conducted in the Quebec City (Canada) catchment area among palliative care professionals. Fifty-eight palliative care professionals working in hospice, home care and hospital-based palliative care units completed the questionnaire. All physicians and 63% of nurses occasionally addressed concerns of patients and relatives about their family history of cancer, but they reported a low confidence level in responding to such concerns. They also showed knowledge gaps in defining features of a significant family history of cancer, and most (78%) would welcome specific training on the matter. Our findings highlight the relevance of offering education and training opportunities about familial cancers and associated risks to palliative care providers. The needs and concerns of end of-life patients and their families need to be explored to ensure palliative care providers can adequately assist patients and their relatives about their family history of cancer. Ethical implications should be considered. PMID- 28674755 TI - Modulation of the FMRFamide-gated Na+ channel by external Ca2. AB - FMRFamide-gated Na+ channel (FaNaC) is a member of the DEG/ENaC family. Amino acid sequence of the second transmembrane region (TM2) of FaNaC is quite similar to that of the acid-sensing ion channels (ASIC) of the same family. In the upper part of TM2, there are two aspartate residues (D552 and D556 in Aplysia FaNaC, AkFaNaC) which construct two negative rings in the external vestibule. In the present study, we examined the function of D552/D556 mutants of AkFaNaC in Xenopus oocytes with special interest in Ca2+ sensitivity of FaNaC. The FMRFamide evoked current through AkFaNaC was depressed by submillimolar Ca2+ such that the current in Ca2+-free condition was 2-3-fold larger than that in the control solution which contained 1.8 mM CaCl 2. Both D552 and D556 were found to be indispensable for the sensitivity of FaNaC to submillimolar Ca2+. Unexpectedly, however, both acidic residues were not essential for the inhibition by millimolar Ca2+ concentrations. The Ca2+-sensitive gating of FaNaC was recapitulated by an allosteric model in which Ca2+-bound channels are more difficult to open. The desensitization of FaNaC was also inhibited by Ca2+, which was abolished in some D552/D556 mutants. Structural models of FaNaC made by homology modeling showed that the distance between oxygen atoms of D552 and D556 on the adjacent subunits is close enough to coordinate Ca2+ in the nonconducting desensitized channel but not in the open channel. The results suggest that Ca2+ coordination between oxygen atoms of D552 and D556 disturbs the opening transition as well as the desensitization of FaNaC. PMID- 28674756 TI - Immune biomarkers for chronic inflammation related complications in non-cancerous and cancerous diseases. AB - Chronic inflammation arising in a diverse range of non-cancerous and cancerous diseases, dysregulates immunity and exposes patients to a variety of complications. These include immunosuppression, tissue damage, cardiovascular diseases and more. In cancer, chronic inflammation and related immunosuppression can directly support tumor growth and dramatically reduce the efficacies of traditional treatments, as well as novel immune-based therapies, which require a functional immune system. Nowadays, none of the immune biomarkers, regularly used by clinicians can sense a developing chronic inflammation, thus complications can only be detected upon their appearance. This review focuses on the necessity for such immune status biomarkers, which could predict complications prior to their appearance. Herein we bring examples for the use of cellular and molecular biomarkers in diagnosis, prognosis and follow-up of patients suffering from various cancers, for prediction of response to immune-based anti-cancer therapy and for prediction of cardiovascular disease in type 2 diabetes patients. Monitoring such biomarkers is expected to have a major clinical impact in addition to unraveling of the entangled complexity underlying dysregulated immunity in chronic inflammation. Thus, newly discovered biomarkers and those that are under investigation are projected to open a new era towards combating the silent damage induced by chronic inflammation. PMID- 28674757 TI - Assessment of particulate emissions from a sinter plant in steelmaking works in China. AB - In this paper, five particulate emission points from a sinter plant in China, including anthracite crusher, raw material blender, sinter strand, screener, and circular cooler, were selected for particle sampling. The particle size distribution, the toxic element content (As, Cd, Co, Cr, Cu, Ni, Pb, Ti, and Zn), and the morphology of the samples were determined by the gravimetric method, the ICP-OES, and the SEM-EDS, respectively. In addition, the gray relational analysis method was used to evaluate the rank of the particulate emission points in the sinter plant. The results show that the emission factor of PMTSP, PM10, and PM2.5 of the whole sintering process is 0.121, 0.075, and 0.039 kg/t-sinter, respectively. Furthermore, the total toxic element emission factor is 5282.49 mg/t-sinter. The sinter strand is the most important emitter and contributes 43.8% of PMTSP, 53.3% of PM10, 56.4% of PM2.5, and 81.1% of total toxic element in the sinter plant. Nevertheless, particles emitted from the post-sintering process are non-negligible and contribute 48.8% of PMTSP, 41.3% of PM10, 38.5% of PM2.5, and 15.5% of total toxic element in the sinter plant. PMID- 28674758 TI - Dimethyl sulfide emission behavior from landfill site with air and water control. AB - Municipal solid waste landfills are responsible for odors affecting the environment and human health. Dimethyl sulfide (DMS) is one of the major odorous compounds known for its low odor threshold and wide distribution. This study examined the generation, migration and emission of DMS in four artificial landfill-simulating reactors: Reactor 1 and Reactor 2, running under anaerobic and semi-aerobic conditions, respectively, without leachate recirculation; and Reactor 3 and Reactor 4, running under anaerobic and semi-aerobic conditions, respectively, with leachate recirculation. From the odor control perspective, aeration can efficiently inhibit maximum DMS headspace concentration by 31.7 93.7%, especially with the functioning of leachate recirculation. However, leachate recirculation in anaerobic conditions may double the DMS emission concentration but may also shorten the period over which DMS is effective because of the upward migration of liquid DMS in the recirculated leachate. The DMS generation was active in the acidification and methane fermentation phase of the simulated landfill and was possibly affected by the volatile fatty acid concentration, chemical oxygen demand, total organic carbon concentration and pH of the leachate, as well as total organic carbon in the refuse. Most significantly, DMS emission can be effectually dealt with by aeration along with leachate recirculation. PMID- 28674759 TI - Impaired sensory processing measured by functional MRI in Bipolar disorder manic and depressed mood states. AB - Bipolar disorder is characterized by recurring episodes of depression and mania. Defining differences in brain function during these states is an important goal of bipolar disorder research. However, few imaging studies have directly compared brain activity between bipolar mood states. Herein, we compare functional magnetic resonance imaging (fMRI) responses during a flashing checkerboard stimulus between bipolar participants across mood states (euthymia, depression, and mania) in order to identify functional differences between these states. 40 participants with bipolar I disorder and 33 healthy controls underwent fMRI during the presentation of the stimulus. A total of 23 euthymic-state, 16 manic state, 15 depressed-state, and 32 healthy control imaging sessions were analyzed in order to compare functional activation during the stimulus between mood states and with healthy controls. A reduced response was identified in the visual cortex in both the depressed and manic groups compared to euthymic and healthy participants. Functional differences between bipolar mood states were also observed in the cerebellum, thalamus, striatum, and hippocampus. Functional differences between mood states occurred in several brain regions involved in visual and other sensory processing. These differences suggest that altered visual processing may be a feature of mood states in bipolar disorder. The key limitations of this study are modest mood-state group size and the limited temporal resolution of fMRI which prevents the segregation of primary visual activity from regulatory feedback mechanisms. PMID- 28674760 TI - Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review. AB - Somatic disorders occur more often in adult psychiatric patients than in the general adult population. However, in child and adolescent psychiatry this association is unclear, mainly due to a lack of integration of existing data. To address this issue, we here present a systematic review on medical comorbidity in the two major developmental disorders autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) and formulate clinical recommendations. The literature was searched using the PubMed and PsycINFO databases (2000-1 May 2016) with the keywords "[((child and adolescent) AND (Autism OR Attention Deficit Hyperactivity Disorder* OR ADHD)) AND ("Cardiovascular Diseases" [Mesh] OR "Endocrine System Diseases" [Mesh] OR "Immune System Diseases" [Mesh] OR "Neurobehavioral Manifestations" [Mesh] OR "Gastrointestinal Disorders" [Mesh] OR Somatic OR Autoimmune disease OR Nervous system disease OR Infection OR Infectious disease)]. Two raters independently assessed the quality of the eligible studies. The initial search identified 5278 articles. Based on inclusion and exclusion criteria 104 papers were selected and subsequently subjected to a quality control. This quality was assessed according to a standardized and validated set of criteria and yielded 29 studies for inclusion. This thorough literature search provides an overview of relevant articles on medical comorbidity in ADHD and/or ASD, and shows that medical disorders in these children and adolescents appear to be widespread. Those who work with children with ASD and/or ADHD should be well aware of this and actively promote routine medical assessment. Additionally, case-control studies and population-based studies are needed to provide reliable prevalence estimates. Future studies should furthermore focus on a broader evaluation of medical disorders in children and adolescents with ADHD and/or ASD to improve treatment algorithm in this vulnerable group. PMID- 28674761 TI - A simple and efficient method for successful gene silencing of HspA1 in Trametes hirsuta AH28-2. AB - Trametes sp. are among the most extensively studied basidiomycetes due to their importance in biotechnology. However, they are difficult to genetically modify. For instance, the low incidence of homologous integration hampers gene inactivation. To overcome this, we here constructed two post-transcriptional gene silencing vectors that contain an antisense and a RNA interference mediating hairpin sequence, respectively. These vectors were used to knock down transcription of the heat shock protein 70 family gene HspA1. The two vectors were transformed into Trametes hirsuta AH28-2 by using a PEG/CaCl2 mediated transformation method. Based on Southern blot analysis, target sequences were integrated into the genome as multi-copies. Transcription analysis revealed that the antisense and hairpin sequences reduced the transcript number of HspA1 when compared to the wild type strain. Moreover, the antisense sequence resulted in a higher gene silencing efficiency when compared to the RNA interference vector. Together, antisense methodology provides a simple method for gene silencing in Trametes sp. PMID- 28674762 TI - Erratum to: Bioethics and Biopolitics: Presents and Futures of Reproduction. PMID- 28674763 TI - In response to "outcomes of patients with inflammatory breast cancer treated by breast conserving surgery": the argument against breast conservation and sentinel lymph node biopsy in IBC. PMID- 28674764 TI - A pilot study of cabergoline for the treatment of metastatic breast cancer. AB - PURPOSE: The prolactin (PRL) receptor is over-expressed in breast cancer, and pre clinical data indicate that it contributes to breast oncogenesis. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary PRL secretion. METHODS: A phase II study of cabergoline in patients with metastatic breast cancer was conducted. The primary end point of the study was to determine the clinical benefit rate (CBR) at 2 months. Eligible patients had tumors of any receptor status with no limit of prior lines of therapy. Measurable and unmeasurable diseases were allowed. Cabergoline 1 mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. PRL receptor immunohistochemical staining was performed on available baseline tumor tissue; serial serum PRL levels were assessed. RESULTS: Twenty women were enrolled; 18 were evaluable for CBR. Tumor receptor status was distributed as follows: HR-any/HER2+ 2(10%), HR+/HER2- 18 (90%). The CBR was 33% (6/18), median progression free survival was 1.8 months, and median overall survival was 10.4 months. Two patients experienced disease control for over 12 months. Most common treatment-related adverse events were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). Nine patients had baseline tissue for analysis; there was no association between baseline tumor PRL receptor expression and clinical benefit (p = 0.24). Change in serum PRL level and response were not correlated after 2 months of treatment (p = 0.64). CONCLUSION: Cabergoline was well tolerated, and while the ORR was low, a small subset of patients experienced extended disease control. PMID- 28674765 TI - Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer. AB - PURPOSE: The INTENS study was designed to determine whether delivering neoadjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600-T 100 mg/m2) or six cycles of TAC as triplet chemotherapy (75/50/500 mg/m2) every 3 weeks. The primary outcome was the pathologic complete response (pCR), with disease-free and overall survival as secondary endpoints. RESULTS: In total, 201 patients were included. The pCR rates were 28% for patients treated with AC-T and 19% for patients treated with TAC, with an odds ratio of 1.60 (95% CI 0.90-3.21). With a median follow-up of 6 years (range 0.04-8.41 years), the five-year disease-free survival was 81% for patients treated with sequentially AC T and 71% for patients treated with concurrent triplet TAC chemotherapy with a stratified hazard ratio (HR) of 0.50 (95% CI 0.29-0.86). Five-year overall survival was 84% versus 76%, respectively, with a stratified HR of 0.55 (95% CI 0.29-1.03). CONCLUSIONS: No differences were observed between the two treatment arms with respect to pCR rate, but the sequentially delivered chemotherapy outperformed the triplet combination chemotherapy in terms of survival, despite a lower cumulative dose per agent. GOV nr NCT00314977. PMID- 28674766 TI - Reduction of quality-adjusted life years (QALYs) in patients with premenstrual dysphoric disorder (PMDD). AB - PURPOSE: Premenstrual dysphoric disorder (PMDD) refers to the depression that occurs during the premenstrual phase and remits soon after the onset of menses. It affects the quality of life (QOL) of patients with PMDD. Therefore, this preliminary survey from chart recordings aimed to understand the symptom appearance and QOL reduction patterns in patients with PMDD, and to examine the extent of the loss of their quality-adjusted life years (QALYs). METHODS: Participants were 66 untreated female patients with PMDD. Data on symptom appearance and QOL reduction during the menstrual cycle, and the EuroQoL-5D (EQ 5D) scores during the premenstrual phase and immediately after the completion of a menstrual period were collected. RESULTS: The mean EQ-5D score of the 66 patients with PMDD was 0.795 +/- 0.120 (range 0.362-0.949), indicating that their expected mean loss of QALYs was about 0.14 years. CONCLUSIONS: If untreated, PMDD is expected to cause a mean loss of QALYs of about 0.14 years. However, on accounting for the period from disease development to menopause, and subtracting the menstruation-free periods such as pregnancy and breastfeeding, patients with untreated PMDD are expected to experience a QALY loss of about 3 years during their lifetime. PMID- 28674767 TI - Use-of-time and health-related quality of life in 10- to 13-year-old children: not all screen time or physical activity minutes are the same. AB - PURPOSE: To investigate associations between aspects of time use and health related quality of life (HRQoL) in youth. METHODS: 239 obese and healthy-weight 10- to 13-year-old Australian children completed the Pediatric Quality of Life Inventory (PedsQLTM) quantifying their health-related quality of life. Time use was evaluated over four days using the Multimedia Activity Recall for Children and Adolescents (MARCA), a validated 24 h recall tool. The average number of minutes/day spent in physical activity (divided into sport, active transport and play), screen time (divided into television, videogames and computer use), and sleep were calculated. Percent fat was measured using dual-energy X-ray absorptiometry, Tanner stage by self-report, and household income by parental report. Sex-stratified analysis was conducted using Partial Least Squares regression, with percent fat, Tanner stage, household income, and use-of-time as the independent variables, and PedsQLTM total, physical and psychosocial subscale scores as the dependent variables. RESULTS: For boys, the most important predictors of HRQoL were percent fat (negative), videogames (negative), sport (positive), and Tanner stage (negative). For girls, the significant predictors were percent fat (negative), television (negative), sport (positive), active transport (negative), and household income (positive). CONCLUSION: While body fat was the most significant correlate of HRQoL, sport was independently associated with better HRQoL, and television and videogames with poorer HRQoL. Thus, parents and clinicians should be mindful that not all physical activity and screen-based behaviours have equivocal relationships with children's HRQoL. Prospective research is needed to confirm causation and to inform current activity guidelines. PMID- 28674768 TI - Examining gender-related differential item functioning of the Veterans Rand 12 item Health Survey. AB - PURPOSE: Previous research suggests that gender differences in patient-reported outcome measures (PROMs) may reflect measurement bias rather than true differences in underlying health status. The aim of this study is to examine whether the Veterans Rand 12-item Health Survey (VR-12) allows for unbiased comparisons of physical and mental health scores across gender. The VR-12 is a generic PROM consisting of 12 items with 3-6 response options for the measurement of mental and physical health. METHODS: Study data were from the 2015 Health Outcomes Survey pertaining to the Medicare beneficiaries. A total of 277,518 participants included 116,817 (42.1%) males and 160,701 (57.9%) females. Scale level and item-level differential functioning methods were applied using multiple group confirmatory factor analysis and ordinal logistic regression, respectively. RESULTS: The scale-level differential functioning showed support for strict invariance (RMSEA = 0.045; CFI = 0.995) across gender. Although we found statistically significant differential item functioning for several items, the magnitude was negligible (maximum DeltaR 2 = 0.007). CONCLUSION: The VR-12 physical and mental health status scores are unbiased with respect to gender. PMID- 28674769 TI - Antibiotic growth promoter olaquindox increases pathogen susceptibility in fish by inducing gut microbiota dysbiosis. AB - Low dose antibiotics have been used as growth promoters in livestock and fish. The use of antibiotics has been associated with reduced pathogen infections in livestock. In contrast, antibiotic growth promoter has been suspected of leading to disease outbreaks in aquaculture. However, this phenomenon is circumstantial and has not been confirmed in experimental conditions. In this study, we showed that antibiotic olaquindox increased the susceptibility of zebrafish to A. hydrophila infection. Olaquindox led to profound alterations in the intestinal microbiota of zebrafish, with a drastic bloom of Enterobacter and diminishing of Cetobacterium. Moreover, the innate immune responses of zebrafish were compromised by olaquindox (P<0.05). Transfer of microbiota to GF zebrafish indicated that while the immuo-suppression effect of olaquindox is a combined effect mediated by both OLA-altered microbiota and direct action of the antibiotic (P<0.05), the increased pathogen susceptibility was driven by the OLA altered microbiota and was not dependent on direct antibiotic effect. Taken together, these data indicate that low level of OLA induced gut microbiota dysbiosis in zebrafish, which led to increased pathogen susceptibility. PMID- 28674770 TI - Choosing between Higher and Lower Resolution Microarrays: do Pregnant Women Have Sufficient Knowledge to Make Informed Choices Consistent with their Attitude? AB - Developments in prenatal testing allow the detection of more findings. SNP arrays in prenatal diagnosis (PND) can be analyzed at 0.5 Mb resolution detecting more clinically relevant anomalies, or at 5 Mb resolution. We investigated whether women had sufficient knowledge to make informed choices regarding the scope of their prenatal test that were consistent with their attitude. Pregnant women could choose between testing at 5 or at 0.5 Mb array. Consenting women (N = 69) received pre-test genetic counseling by phone and filled out the Measure of Informed Choice questionnaire designed for this study. Choices based on sufficient knowledge and consistent with attitude were considered informed. Sixty two percent of the women made an adequately informed choice, based on sufficient knowledge and attitude-consistent with their choice of microarray resolution. Women who made an informed choice, opted for 0.5 Mb array resolution more often. There were no differences between women making adequately informed or less informed choices regarding level of experienced anxiety or doubts. Over time on T0 and T1, anxiety and doubts significantly decreased. While previous studies demonstrated that knowledge is an important component in informed decision making, this study underlines that a consistent attitude might be equally important for decision-making. We advocate more focus on attitude-consistency and deliberation as compared to only a strong focus on knowledge. PMID- 28674771 TI - A review of the physiology of a survival expert of big freeze, deep snow, and an empty stomach: the boreal raccoon dog (Nyctereutes procyonoides). AB - The raccoon dog (Nyctereutes procyonoides) is an invasive canid originating from eastern Asia. Here, we review its physiological adaptations to wintering, with an emphasis on northern Europe, where the raccoon dog spends the coldest part of the year in winter sleep. The timing of physiological changes related to wintering is connected to photoperiod by melatonin. In preparation to winter, raccoon dogs display autumnal hyperphagia and fattening probably regulated by the interaction of several peptide hormones. Sufficient fat deposition is essential for survival through the cold season and for reproduction in spring. The wintering strategy includes alternating periods of physical activity and passivity. Effective arousal and foraging during warmer bouts are enabled by normoglycaemia. During active periods, raccoon dogs are opportunistic participants in the food web, and they mainly utilize ungulate carcasses, plant material, and small mammals. Preferred wintertime habitats include watersides, forests, wetlands, and gardens. However, many food items become limited in mid-winter and snow restricts foraging leading to a negative energy balance. During passivity, energy is preserved by denning and by modest metabolic suppression, probably enabled by decreased thyroid hormone levels. Sleepiness and satiety could be maintained by high growth hormone and leptin concentrations. Several hormones participate in the extension of phase II of fasting with selective fatty acid mobilization and efficient protein conservation. The blood count, organ function tests, bone mass, and bone biomechanical properties exhibit high resistance against catabolism, and breeding can be successful after significant weight loss. The flexible physiological response to wintering is probably one reason enabling the successful colonization of this species into new areas. PMID- 28674772 TI - Detection of unexpected emergency diseases using FDG-PET/CT in oncology patients. AB - PURPOSE: To evaluate the frequency of emergency diseases that were detected unexpectedly using FDG-PET/CT. MATERIALS AND METHODS: Interpretation reports for 11,663 FDG-PET/CT studies in our hospital were retrospectively reviewed. Patients with major emergency diseases were extracted according to the following exclusion criteria: (1) relevant findings had been recognized prior to the PET/CT; (2) an intervention or operation that may have been relevant to the present findings was performed within 1 month prior to the PET/CT; and (3) the clinical course could not be investigated sufficiently (e.g., in cases where the patients were introduced from other hospitals). RESULTS: Forty-one patients (0.35%) with unexpected emergency diseases were identified. The most frequent disease was pneumothorax (8 patients), followed by chronic subdural hematoma (CSH) (7 patients), ureteral stone (7 patients), and abdominal aortic aneurysm (AAA) with a dirty fat sign or a high-attenuation crescent sign visualized on CT (4 patients). Nine patients (2 pneumothorax, 3 CSH, 1 cerebral hemorrhage, 1 acute cholecystitis, 1 acute pancreatitis, and 1 acute appendicitis) were hospitalized and/or underwent therapeutic intervention within 1 week after the PET/CT. CONCLUSION: Although rare, an unexpected emergency disease requiring urgent management can be detected using FDG-PET/CT in oncology patients. PMID- 28674773 TI - Influenza A virus-induced downregulation of miR-26a contributes to reduced IFNalpha/beta production. AB - Innate immunity provides immediate defense against viral infection. Influenza A virus (IAV) is able to get past the first line of defense. Elucidation of the molecular interaction between influenza factors and the newly recognized host players in the innate response might help in our understanding of the root causes of virulence and pathogenicity of IAV. In this study, we show that expression of miR-26a leads to a significant inhibition of IAV replication. miR-26a does not directly target IAV genome. Instead, miR-26a activates the type I interferon (IFN) signaling pathway and promotes the production of IFN-stimulated genes, thus suppressing viral replication. Furthermore, ubiquitin-specific protease 3 (USP3), a negative regulator of type I IFN pathway, is targeted by miR-26a upon IAV challenge. However, miR-26a is significantly downregulated during IAV infection. Thus, downregulation of miR-26a is a new strategy evolved by IAV to counteract cellular antiviral responses. Our findings indicate that delivery of miR-26a may be a potential strategy for anti-IAV therapies. PMID- 28674774 TI - Antagonistic Interactions and Biofilm Forming Capabilities Among Bacterial Strains Isolated from the Egg Surfaces of Lake Sturgeon (Acipenser fulvescens). AB - Characterization of interactions within a host-associated microbiome can help elucidate the mechanisms of microbial community formation on hosts and can be used to identify potential probiotics that protect hosts from pathogens. Microbes employ various modes of antagonism when interacting with other members of the community. The formation of biofilm by some strains can be a defense against antimicrobial compounds produced by other taxa. We characterized the magnitude of antagonistic interactions and biofilm formation of 25 phylogenetically diverse taxa that are representative of isolates obtained from egg surfaces of the threatened fish species lake sturgeon (Acipenser fulvescens) at two ecologically relevant temperature regimes. Eight isolates exhibited aggression to at least one other isolate. Pseudomonas sp. C22 was found to be the most aggressive strain, while Flavobacterium spp. were found to be one of the least aggressive and the most susceptible genera. Temperature affected the prevalence and intensity of antagonism. The aggressive strains identified also inhibited growth of known fish pathogens. Biofilm formations were observed for nine isolates and were dependent on temperature and growth medium. The most aggressive of the isolates disrupted biofilm formation of two well-characterized isolates but enhanced biofilm formation of a fish pathogen. Our results revealed the complex nature of interactions among members of an egg associated microbial community yet underscored the potential of specific microbial populations as host probiotics. PMID- 28674775 TI - Hypothalamo-pituitary-adrenal axis after a single epidural triamcinolone injection. AB - PURPOSE: To quantify adrenocorticotropin and cortisol secretion after epidural glucocorticoid injection. METHODS: Eight men (ages 25-63 year) were studied at baseline, 1, 4, and 12 weeks after triamcinolone (80 mg) injection epidurally. Adrenocorticotropin (pg/mL) and cortisol (ug/dL) were measured every 10 min for 4 h, and after Corticotropin-releasing hormone (CRH) (1 ug/kg) injection. RESULTS: Epidural triamcinolone markedly suppressed: (1) pre-CRH injection ACTH (from 18 +/- 3.1 to 4.8 +/- 0.4: P < 0.01) and cortisol (from 12.2 +/- 1.6 to 1.6 +/- 0.3: P < 0.0001) at week 1, with recovery at 4 weeks, and (2) CRH-stimulated 3-h summed ACTH (from 633 +/- 116 to 129 +/- 10 pg/mL, P < 0.0001), and 3-h summed cortisol at week 1 (from 385 +/- 29 to 56 +/- 22 ug/dL, P < 0.0001) and 4 weeks (284 +/- 53; P < 0.01). Serum cortisol was <18 ug/dL in eight of eight men at 4 weeks, and six of eight men at week 12. Urinary-free cortisol (ug/24 h) remained low at week 12: baseline (60 +/- 6.5); week 1 (9.0 +/- 1.3, P < 0.01); week 4 (36 +/- 8.6) and week 12 (38 +/- 4.1). Urinary cortisol/cortisone ratios rose at week 4 only. Serum triamcinolone peaked at week 1 (16/16 samples), declining at week 4 (13/16 samples) and week 12 (6/16 samples). LIMITATIONS: Relatively small group. CONCLUSION: Epidural triamcinolone suppresses unstimulated and CRH-stimulated ACTH and cortisol secretion for 1-4 weeks but urinary free cortisol >=12 weeks. Suppression of ACTH and cortisol after glucocorticoid treatment is thus complex. PMID- 28674776 TI - Investigating beta-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways. AB - The chronic stimulation of beta-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In beta-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3beta and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of beta-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of beta-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of beta-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of beta2 receptors out of total cardiac beta-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of beta adrenergic-induced hypertrophy is noticeable and variations in beta1/beta2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3beta deactivation after beta-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in beta adrenergic signaling. PMID- 28674777 TI - OSA and Prolonged Oxygen Desaturation During Sleep are Strong Predictors of Poor Outcome in IPF. AB - PURPOSE: Sleep Breathing Disorders (SBD) are frequently found in idiopathic pulmonary fibrosis (IPF) and they are associated with worse quality of sleep and life and with higher mortality. The study aimed at evaluating the impact of SBD on prognosis (mortality or disease progression) in 35 patients with mild to moderate IPF. METHODS AND RESULTS: Obstructive sleep apnea (OSA) was diagnosed in 25/35 patients with IPF: 14/35 mild, 7/35 moderate, and 4/35 severe. According to the American Academy of Sleep Medicine (AASM) definition, sleep-related hypoxemia was found in 9/35 patients with IPF. According to the presence/absence of SBD, IPF patients were divided into 4 groups: NO-SBD group (Group A, 25.7%), OSA without sleep-related hypoxemia (Group B, 48.5%), OSA with sleep-related hypoxemia group (Group C, 22.8%), and only 1/35 had sleep-related hypoxemia without OSA(Group D, 2.8%). Statistical analysis was focused only on group A, B, and C. Patients with OSAS and sleep-related hypoxemia (Group C) had the worse prognosis, both in terms of mortality or clinical deterioration. SBD were the only independent risk factor (Cox Proportional Hazards Multiple Regression Analysis) for mortality (HR 7.6% IC 1.2-36.3; p = 0.029) and disease progression (HR 9.95% IC 1.8-644.9; p = 0.007). CONCLUSIONS: SBD are associated with a worse prognosis, both in terms of mortality or clinical progression. The presence of SBD should be explored in all IPF patients. PMID- 28674778 TI - The temporal behavior and consistency of bipolar atrial electrograms in human persistent atrial fibrillation. AB - The unstable temporal behavior of atrial electrical activity during persistent atrial fibrillation (persAF) might influence ablation target identification, which could explain the conflicting persAF ablation outcomes in previous studies. We sought to investigate the temporal behavior and consistency of atrial electrogram (AEG) fractionation using different segment lengths. Seven hundred ninety-seven bipolar AEGs were collected with three segment lengths (2.5, 5,and 8 s) from 18 patients undergoing persAF ablation. The AEGs with 8-s duration were divided into three 2.5-s consecutive segments. AEG fractionation classification was applied off-line to all cases following the CARTO criteria; 43% of the AEGs remained fractionated for the three consecutive AEG segments, while nearly 30% were temporally unstable. AEG classification within the consecutive segments had moderate correlation (segment 1 vs 2: Spearman's correlation rho = 0.74, kappa score kappa = 0.62; segment 1 vs 3: rho = 0.726, kappa = 0.62; segment 2 vs 3: rho = 0.75, kappa = 0.68). AEG classifications were more similar between AEGs with 5 and 8 s (rho = 0.96, kappa = 0.87) than 2.5 versus 5 s (rho = 0.93, kappa = 0.84) and 2.5 versus 8 s (rho = 0.90, kappa = 0.78). Our results show that the CARTO criteria should be revisited and consider recording duration longer than 2.5 s for consistent ablation target identification in persAF. PMID- 28674779 TI - Analysis of three-dimensional endocardial and epicardial strains from cardiac magnetic resonance in healthy subjects and patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a genetic disease that leads to left ventricle (LV) hypertrophy with or without the presence of LV outflow tract obstruction. The aim of this study was to find an easy and useful indicator based on cardiac magnetic resonance (CMR) images for control subjects and patients with and without obstruction. CMR scans were performed for 19 control subjects and 19 HCM patients. Endocardial strain was defined as [Formula: see text], with [Formula: see text] being the length of endocardium at end-diastole (end systole); similarly for epicardial strain ([Formula: see text]). The strains were evaluated in cine CMR two-, three- and four-chamber views. Six atrioventricular junction (AVJ) points from three CMR views were semi-automatically tracked. The peak systolic velocity (Sm1), peak early diastolic velocity and late diastolic velocity (Em, Am) were extracted and analysed. Compared with control subjects, HCM patients had significantly smaller three-dimensional strains and AVJ motion incorporating measurements from three long-axis views (all P < 0.05). Moreover, ROC analysis found that three-dimensional global epicardial strain <17.2% had the best sensitivity 94.4% and specificity 94.7% to differentiate HCM from control (AUC = 0.97). Therefore, three-dimensional endocardial and epicardial strains provide an easy and effective approach to manage and triage hypertrophic cardiomyopathy patients. PMID- 28674780 TI - Delivery devices for exposure of biological cells to nanosecond pulsed electric fields. AB - In this paper, delivery devices for nanosecond pulsed electric field exposure of biological samples in direct contact with electrodes or isolated are presented and characterized. They are based on a modified electroporation cuvette and two transverse electromagnetic cells (TEM cells). The devices were used to apply pulses with high intensity (4.5 kV) and short durations (3 and 13 ns). The delivery devices were electromagnetically characterized in the frequency and time domains. Field intensities of around 5, 0.5, and 12 MV m-1 were obtained by numerical simulations of the biological sample positioned in the three delivery devices. Two delivery systems had a homogenous electric field spatial distribution, and one was adapted to permit a highly localized exposure in the vicinity of a needle. Experimental biological investigations were carried out at different field intensities for five cancer cell lines. The results using flow cytometry showed that cells kept polarized mitochondrial membrane but lost plasma membrane integrity following a dose-response trend after exposure to different electric field intensities. Certain cell types (U87, MCF7) showed higher sensitivities to nsPEFs than other lines tested. PMID- 28674781 TI - Spike densities of the amygdala and neocortex reflect progression of kindled motor seizures. AB - Amygdala kindling is a common temporal lobe-like seizure model. In the present study, temporal and spectral analyses of the ictal period were investigated throughout amygdala kindling in response to different behavioral seizures. Right side amygdala was kindled to induce epileptiform afterdischarges (ADs). ADs of both the frontal cortex and amygdala were analyzed. Powers of the low (0-9 Hz)- and high (12-30 Hz)-frequency bands in response to different behavioral seizures were calculated. Densities of upward and downward peaks of spikes, which reflected information of spike count and spike pattern, throughout kindle-induced ADs were calculated. Progression was seen in the temporal and spectral characteristics of amygdala-kindled ADs in response to behaviors. Numbers of significant differences of all 1-s AD segments between two Racine's seizure stages were significantly higher in upward and downward indexes of the temporal spike than those using the spectral method in both the amygdala and neocortex. Ability for distinguishing seizure stages was significantly higher in temporal spike density of amygdala ADs compared to those of frontal ADs. Our results showed that amygdala kindling caused spectrotemporal changes of activities in the amygdala and frontal cortex. The density of spike-related peaks had better distinguishability in response to behavioral seizures, particularly in a seizure zone of amygdala. The present study provides a new temporal index of spike's peak density to understand progression of motor seizures in the kindling process. PMID- 28674784 TI - Vitamin B6 intake and the risk of incident kidney stones. AB - Higher vitamin B6 intake might reduce urinary excretion of oxalate, one of the major determinants of risk for calcium oxalate kidney stones. Previous studies investigating the association between intake of vitamin B6 and risk of stones found conflicting results. We sought to investigate the association in three large prospective cohorts. We prospectively examined the association in the Health Professionals Follow-up Study (HPFS; n = 42,919 men), Nurses' Health Study I (NHS I; n = 60,003 older women), and Nurses' Health Study II (NHS II; n = 90,629 younger women). Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident stones across categories of total vitamin B6 intake (<3.0, 3.0-4.9, 5.0 9.9, 10.0-39.9, >=40.0 mg/day) were generated with Cox proportional hazards regression models adjusted for potential confounders. During 3,316,846 person years of follow-up, 6576 incident kidney stones were confirmed. In univariate and multivariate analyses, there was no association between intake of vitamin B6 and incident stones. The HR for stones in the highest category compared with the lowest was 1.05 (95% CI 0.85, 1.30; p value for trend = 0.61) for HPFS, 0.95 (95% CI 0.76, 1.18; p value for trend = 0.42) for NHS I, and 1.06 (95% CI 0.91, 1.24; p value for trend = 0.34) for NHS II. The pooled adjusted HR for the highest category compared with the lowest was 1.03 (95% CI 0.92, 1.15; p value for trend = 0.60). Intake of vitamin B6 is not associated with risk of incident kidney stones. PMID- 28674785 TI - Follicular sensitivity index (FSI): a novel tool to predict clinical pregnancy rate in IVF/ICSI cycles. AB - PURPOSE: This study aims to introduce a new tool (the Follicular Sensitivity Index; FSI) for objective assessment of follicular responsiveness to exogenous gonadotropins and to evaluate its ability to predict the clinical pregnancy rate in women with unexplained infertility or tubal factor undergoing IVF/ICSI. METHODS: FSI was calculated as preovulatory follicle count (PFC) * 100,000/[antral follicle count (AFC) * total received FSH doses]. One thousand women were included and were divided according to the FSI tertile values into three groups. The primary outcome was clinical pregnancy defined by the presence of an intrauterine gestational sac 5 weeks after embryo transfer. RESULTS: There was progressive increase in the clinical pregnancy rate from the low to the high FSI groups (0.27 +/- 0.4 vs 0.4 +/- 0.4 and 0.58 +/- 0.4; p < 0.001). Receiver operator curves showed that FSI had a greater area under the curve than those of the AFC, PFC, and the FSH dose (0.638 vs 0.509, 0.538, and 0.589 respectively). Multivariate logistic regression analysis showed that the correlation between FSI and pregnancy was independent of potential confounding factors like age and body mass index (p < 0.001). CONCLUSION: FSI can predict the clinical pregnancy rate in women with unexplained infertility or tubal factor undergoing IVF/ICSI using GnRH agonist protocol. Higher FSI values had significantly higher oocyte yield and fertilization and clinical pregnancy rates. Wider implications of these findings include the potential use of FSI to define absolute criteria of poor/good ovarian response in IVF/ICSI cycles, guide future IVF cycle management for the same couples, and guide cycle cancelation criteria for poor ovarian response. PMID- 28674786 TI - Fully covered self-expanding metallic stent placement for benign refractory esophageal strictures. AB - AIMS: Treatment options for benign refractory esophageal stricture are limited. We retrospectively analyzed data of 11 patients who underwent fully covered self expanding metallic stent (FC-SEMS) placement for refractory benign esophageal stricture at our institute. METHODS: Refractory benign esophageal stricture was defined as inability to dilate a stricture to a diameter of 14 mm after a minimum of five sessions at 2-week intervals or inability to maintain diameter of 14 mm for at least 4 weeks. Eleven patients with refractory benign esophageal stricture (corrosive-6, peptic-3, and post-sclerotherapy-2) underwent FC-SEMS placement. The stent was removed after 4-6 weeks as per manufacturer's recommendation. Patients were followed up for 1 year. RESULTS: Three patients with peptic strictures [length of stricture 2, 3, and 3 cm] and two patients with post sclerotherapy stricture [length 2 and 1.5 cm] had complete response. Two of 6 patients with corrosive stricture (10 cm, 12 cm) developed recurrence of symptoms within 1 month of stent removal, and two after 2 months (8 cm, 3 cm). One patient with corrosive stricture (6 cm) had recurrence after 6 months, and responded to single session of dilatation. One patient with corrosive stricture was asymptomatic for last 12 months. Four stents were migrated. Four patients developed severe retrosternal pain following stent placement, which was managed with analgesics. There were no serious adverse events after placement of stent and removal of stent. CONCLUSIONS: Fully covered SEMS is safe and effective for refractory benign non-corrosive esophageal strictures. PMID- 28674787 TI - The transpedicular surgical approach for the development of intervertebral disc targeting regenerative strategies in an ovine model. AB - PURPOSE: To investigate the suitability of the transpedicular approach (TPA) in a sheep model of IVD regenerative strategies METHODS: 24 IVD from four sheep were used. TPA and biopsies of the Nucleus pulposus (NP) were performed in 18 IVD (6 IVD control). Seven discographies were performed to assess the feasibility of injecting contrast agent. MRI, micro-CT scan, and histological analyses were performed and the accuracy of the TPA was evaluated. The effects on the vertebra and endplates were analyzed. RESULTS: 83% of our biopsies or injections were located in the NP. Osseous fragments in IVD were observed in 50%. We observed two cases (11%) of rostral endplate fracture and five cases (27%) of breaching of the cortical pedicle and encroachment into the spinal canal. Two cases of perivertebral venous embolism and two of backflow through the canal of the TPA inside the vertebra were noted. Significant damage occurred to the bone structure of the vertebra and to the rostral endplate on which the IVD had been inserted. CONCLUSIONS: TPA induces damage to the endplates, and it may lead to neurological impairment and leakage of injected materials into the systemic circulation. These adverse effects must be fully considered before proceeding with TPA for IVD regenerative strategies. PMID- 28674788 TI - The Bold and the Beautiful: a Neurotoxicity Comparison of New World Coral Snakes in the Micruroides and Micrurus Genera and Relative Neutralization by Antivenom. AB - Coral snake envenomations are well characterized to be lethally neurotoxic. Despite this, few multispecies, neurotoxicity and antivenom efficacy comparisons have been undertaken and only for the Micrurus genus; Micruroides has remained entirely uninvestigated. As the USA's supplier of antivenom has currently stopped production, alternative sources need to be explored. The Mexican manufacturer Bioclon uses species genetically related to USA species, thus we investigated the efficacy against Micrurus fulvius (eastern coral snake), the main species responsible for lethal envenomations in the USA as well as additional species from the Americas. The use of Coralmyn(r) coral snake antivenom was effective in neutralizing the neurotoxic effects exhibited by the venom of M. fulvius but was ineffective against the venoms of Micrurus tener, Micrurus spixii, Micrurus pyrrhocryptus, and Micruroides euryxanthus. Our results suggest that the Mexican antivenom may be clinically useful for the treatment of M. fulvius in the USA but may be of only limited efficacy against the other species studied. PMID- 28674789 TI - Gold-coated magnetic nanoparticle as a nanotheranostic agent for magnetic resonance imaging and photothermal therapy of cancer. AB - Because of their great scientific and technological potentials, iron oxide nanoparticles (IONPs) have been the focus of extensive investigations in biomedicine over the past decade. Additionally, the surface plasmon resonance effect of gold nanoparticles (AuNPs) makes them a good candidate for photothermal therapy applications. The unique properties of both IONPs (magnetic) and AuNPs (surface plasmon resonance) may lead to the development of a multi-modal nanoplatform to be used as a magnetic resonance imaging (MRI) contrast agent and as a nanoheater for photothermal therapy. Herein, core-shell gold-coated IONPs (Au@IONPs) were synthesized and investigated as an MRI contrast agent and as a light-responsive agent for cancer photothermal therapy.The synthesized Au@IONPs were characterized by UV-visible spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis. The transverse relaxivity (r 2) of the Au@IONPs was measured using a 3-T clinical MRI scanner. Through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicity of the Au@IONs was examined on a KB cell line, derived from the epidermal carcinoma of a human mouth. Moreover, the photothermal effects of Au@IONPs in the presence of a laser beam (lambda = 808 nm; 6.3 W/cm2; 5 min) were studied.The results show that the Au@IONPs are spherical with a hydrodynamic size of 33 nm. A transverse relaxivity of 95 mM-1 S-1 was measured for the synthesized Au@IONPs. It is evident from the MTT results that no significant cytotoxicity in KB cells occurs with Au@IONPs. Additionally, no significant cell damage induced by the laser is observed. Following the photothermal treatment using Au@IONPs, approximately 70% cell death is achieved. It is found that cell lethality depended strongly on incubation period and the Au@IONP concentration.The data highlight the potential of Au@IONPs as a dual function MRI contrast agent and photosensitizer for cancer photothermal therapy. PMID- 28674790 TI - Curcumin photodynamic effect in the treatment of the induced periodontitis in rats. AB - This study assessed the effect of curcumin as a photosensitizer in antimicrobial photodynamic therapy (aPDT) for the treatment of induced periodontitis in rats. Periodontitis was induced via a ligature around the mandibular first molar on the left side of 96 rats. The ligature was removed 7 days later, and the animals were randomized into four groups: NT, no local treatment; CUR, irrigation with curcumin solution (40 MUM); LED, irradiation with a light-emitting diode (LED, InGaN, 465-485 nm, 200 mW/cm2, 60 s); and aPDT, irrigation with curcumin solution (40 MUM) followed by irradiation with LED. Eight animals from each group were euthanized at 7, 15, and 30 days post-treatment. Treatments were assessed using alveolar bone loss (ABL) in the furcation region using histological, histometric, and immunohistochemical analyses. Rats treated with aPDT exhibited less ABL at 7 days compared to the NT group, moderate pattern immunolabeling for osteoprotegerin at 30 days, and a pattern of immunolabeling for RANKL from moderate to low. Treatments resulted in smaller numbers of TRAP-positive cells compared to the NT group. aPDT as monotherapy using curcumin as a photosensitizer and LED as the light source was effective in the treatment of induced periodontitis in rats. PMID- 28674791 TI - Effects of the GaAlAs diode laser (780 nm) on the periodontal tissues during orthodontic tooth movement in diabetes rats: histomorphological and immunohistochemical analysis. AB - The purposes of the present study are to assess the effects of the GaAlAs diode laser on the periodontal tissues and to investigate its action on the alveolar bone remodeling process during orthodontic tooth movement in normoglycemic and diabetic rats. Sixty adult male Wistar rats were divided into four groups of 15 rats: normoglycemic (N), diabetic (D), laser-normoglycemic (LN), and laser diabetic (LD) rats. Diabetes mellitus was induced by a single intravenous injection of 40 mg/kg monohydrated alloxan. The orthodontically moved tooth underwent a force magnitude of 20 cN. The laser irradiation with a continuous emission of a 780-nm wavelength, an output power of 20 mW, and a fiber probe with a spot size of 0.04 cm in diameter and an area of 0.00126 cm2 were used. Moreover, an energy density of 640 J/cm2 was applied in an exposition time of 40 s. Histomorphological and immunohistochemical analysis was performed. The photobiomodulation (PBM) strongly stimulated the periodontal tissue response, establishing mainly the balance between the bone formation and resorption. Intense inflammatory cell infiltration and extensive loss of bone tissue were mainly found in the D group from 14 days. The number of osteopontin-positive osteocytes was significantly greater in the LN group, followed by the LD, especially at 7 and 14 days, whereas osteoprotegerin-positive osteoblasts were significantly higher in the LN and LD groups than in the N and D groups, respectively, in all periods. The PBM strongly stimulated the alveolar bone remodeling and favored the continuous reorganization of the soft periodontal tissues, leading to the maintenance and integrity of the periodontal microstructure under orthodontic force, especially in uncontrolled diabetic rats. PMID- 28674792 TI - Adipose Tissue Inflammation and Oxidative Stress: the Ameliorative Effects of Vitamin D. AB - Obesity is a low-grade inflammatory disease and is associated with numerous comorbidities. The current study was aimed to evaluate the effects of vitamin D administrations on markers of inflammation and oxidative stress in adipose tissue of high-fat diet-induced obese rats. In the beginning of the study, 40 rats were divided into two groups: normal diet and high-fat diet (HFD) for 16 weeks; then, each group was subdivided into two groups including ND, ND + vitamin D, HFD, and HFD + vitamin D. Vitamin D supplementation was done for 5 weeks at 500 IU/kg dosage. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-beta and IL-6 concentrations and markers of oxidative stress including glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA), and catalase (CAT) concentrations in adipose tissue of rats were determined using ELISA kits and spectrophotometry methods, respectively. Vitamin D treatment led to a significant reduction in adipose tissue TNF-alpha concentrations in both ND + vitamin D and HFD + vitamin D groups (P < 0.05). Adipose tissue MCP-1 concentration also reduced in HFD + vitamin D group compared with HFD group. Among markers of oxidative stress in adipose tissue, SOD and GPx concentrations significantly increased in adipose tissue of HFD + vitamin D treated group compared with other groups (P < 0.05). Reduced food intake and weight gain was also occurred after vitamin D treatment. Vitamin D improved adipose tissue oxidative stress and inflammatory parameters in obese rats. Vitamin D treatment was also associated with decreased food intake and decreased weight gain in animals under a high-fat diet. Further studies are needed to better clarify the underlying mechanisms. PMID- 28674794 TI - Introduction to the Special Issue - a Personal Note. PMID- 28674793 TI - Intravenous vs. oral hydration administration for optimal ureteral opacification in computer tomographic urography. AB - PURPOSE: Computed tomographic urography (CTU) is the gold standard in the radiologic detection of urinary tract disease. The goals of CTU protocols are to garner fully distended and opacified collecting systems, ureters, and bladder for adequate evaluation. Multiple techniques have been reported in the literature to optimize urinary tract visualization and enhance genitourinary assessment. However, currently no strict guidelines exist regarding the preferred method for optimal urinary tract opacification in CTU. MATERIALS AND METHODS: During the year 2013, a retrospective chart review of CTU examinations were done at either an academic institution where IV hydration was routinely administered or at an outpatient imaging center where oral hydration was preferred. Two attending radiologists experienced in cross-sectional body imaging, retrospectively reviewed all the images, blinded to the method of hydration. The reviewers were asked to quantify ureteral distension as well as to grade urinary tract opacification. RESULTS: A total of 176 patients and 344 ureters were analyzed. Mean maximal ureteral widths were largest in the mid ureter, followed closely by the proximal ureter. Mean opacification scores showed no statistical significance between hydration methods, stratified by ureteral segment. CONCLUSION: Our study results show that oral hydration is easy to implement, produces ureteral distention and opacification similar to CTU studies with IV hydration, without loss of diagnostic quality in our select patient population. Although not statistically significant, the oral hydration protocol is more cost effective, requires less hospital resources, and may be a useful step toward cost containment strategies pertinent in today's healthcare landscape. PMID- 28674795 TI - "I feel how you feel": reflections about empathy in the relationship between ICU physicians and relatives. PMID- 28674796 TI - Focus on acute kidney injury. PMID- 28674797 TI - RNAi Technique in Stem Cell Research: Current Status and Future Perspectives. AB - RNAi is a mechanism displayed by most eukaryotic cells to rid themselves of foreign double-strand RNA molecules. In the 18 years since the initial report, RNAi has now been demonstrated to function in mammalian cells to alter gene expression and has been used as a means for genetic discovery as well as a possible strategy for genetic correction and genetic therapy in cancer and other disease. The aim of this review is to provide a general overview of how RNAi suppresses gene expression and to examine some published RNAi approaches that have resulted in changes in stem cell function and suggest the possible clinical relevance of this work in cancer therapy through targeting cancer stem cells. PMID- 28674798 TI - RNAi and MicroRNA-Mediated Gene Regulation in Stem Cells. AB - Recently, RNAi and microRNAs (miRNAs) have become important tools to investigate the regulatory mechanism of stem cell maintenance and differentiation. In this short review, we give a brief overview of the discovery history, functions, and mechanisms of RNAi and miRNAs. We also discuss the RNAi as a tool to study the stem cell function and the potential future practical applications. PMID- 28674799 TI - Forward RNAi Screens in Human Hematopoietic Stem Cells. AB - Identifying the genes and pathways that regulate self-renewal and differentiation in somatic stem cells is a central goal in stem cell and cancer biology. Here, we describe a method for RNA interference (RNAi)-based screens combined with next generation sequencing (NGS) in primary human hematopoietic stem and progenitor cells (HSPCs). These cells are suitable targets for complex, selection-based screens using pooled lentiviral short hairpin RNA (shRNA) libraries. The screening approach presented in this chapter is a promising tool to dissect regulatory mechanisms in hematopoietic stem cells (HSCs) and somatic stem cells in general, and may be particularly useful to identify gene targets and modifiers that can be further exploited in strategies for ex vivo stem cell expansion. PMID- 28674800 TI - Silencing of ATP11B by RNAi-Induced Changes in Neural Stem Cell Morphology. AB - RNA interference (RNAi) technology is one of the main research tools in many studies of neural stem cells. This study describes effects of ATP11B on the morphology change of neural stem cells by using RNAi. ATP11B belongs to P4 ATPases family, which is preferential translocate phosphatidylserine of cell membrane. Although it exists in neural stem cells, its physiological function is poorly understood. By using RNAi technology to downregulate expression of ATP11B, we found distinct morphological changes in neural stem cells. More important, psiRNA-ATP11B-transfected cells displayed short neurite outgrowth compared to the control cells. These data strongly suggest that ATP11B plays a key role in the morphological change of neural stem cells. PMID- 28674801 TI - High-Efficiency Transfection of Glioblastoma Cells and a Simple Spheroid Migration Assay. AB - Despite international research efforts, patients with glioblastoma multiforme (GBM)-the most common malignant brain tumors in adults-exhibit a very unfavorable prognosis. Their aggressive local growth pattern and increased invasiveness, due to a high motility of the tumor cells, hamper treatment. However, the molecular mechanisms regulating glioblastoma cell migration are still elusive. Here, we describe the combination of a highly efficient cell transfection by Nucleofection(r) technology and the generation of spheroids from these transfected glioblastoma cell lines. Nucleofection allows the manipulation of protein expression by overexpression and siRNA mediated protein knockdown. Transfection efficiencies >70% can be achieved with some GBM cell lines. Transfected neurospheres then can be used for migration assays (as described here in detail) and a multitude of other functional assays. In comparison to monolayer cultures, the advantage of spheroids is their resemblance with organized tissue in combination with the accuracy of in vitro methodology and marked experimental flexibility. PMID- 28674802 TI - Construction and Application of Random dsRNA Interference Library for Functional Genetic Screens in Embryonic Stem Cells. AB - RNA interference (RNAi) libraries have been proven to be a powerful tool for large-scale functional genetic screens. To facilitate high-throughput functional genetic screens in embryonic stem cells, a system for construction of random dsRNA-expressing RNAi libraries was developed. Previous studies have demonstrated that sequence-specific gene silencing could be induced by long dsRNA in mouse embryos, mouse oocytes, embryonic stem cells, and some other mammalian cells. Our study demonstrated that the dsRNA interference library can be used for functional genetic screens of genes involved in self-renewal of embryonic stem cells (ES cells). The random RNAi library is easy to construct and provides a useful tool for investigation of molecular mechanisms of cellular development and differentiation. PMID- 28674803 TI - Efficient Depletion of Essential Gene Products for Loss-of-Function Studies in Embryonic Stem Cells. AB - The development of the CRISPR/Cas9 technology has provided powerful methods to target genetic alterations. However, investigating the function of genes essential for cell survival remains problematic, because genetic ablation of these genes results in cell death. As a consequence, cells recombined at the targeted gene and fully depleted of the gene product cannot be obtained. RNA interference is well suited for the study of essential genes, but this approach often results in a partial depletion of the targeted gene product, which can lead to misinterpretations. We previously developed the pHYPER shRNA vector, a high efficiency RNA interference vector, which is based on a 2.5-kb mouse genomic fragment encompassing the H1 gene. We provide here a pHYPER-based protocol optimized to study the function of essential gene products in mouse embryonic stem cells. PMID- 28674804 TI - Regulation and/or Repression of Cholinergic Differentiation of Murine Embryonic Stem Cells Using RNAi Directed Against Transcription Factor L3/Lhx8. AB - Techniques for controlling the expression of a specific gene in embryonic stem cells are effective and important for clarifying the functions of the gene. Regarding differentiation of cells into nervous system components, these techniques would play key roles in elucidating, not only the differentiation mechanisms of neuronal and glial cells but also how neuronal phenotypes are determined. In this chapter, we describe a RNA interference method for suppressing cholinergic differentiation in murine embryonic stem cells by knockdown of expression of the transcription factor L3/Lhx8, a Lim homeobox gene family protein. This method will greatly facilitate functional analyses of the factors involved in neuronal differentiation and regeneration and will contribute to cell transplantation studies. PMID- 28674805 TI - A Recessive Genetic Screen for Components of the RNA Interference Pathway Performed in Mouse Embryonic Stem Cells. AB - Several key components of the RNA interference (RNAi) pathway were identified in genetic screens performed in non-mammalian model organisms. To identify components of the mammalian RNAi pathway, we developed a recessive genetic screen in mouse embryonic stem (ES) cells. Recessive genetic screens are feasible in ES cells that are Bloom-syndrome protein deficient (Blm-deficient). We constructed a reporter cell line in Blm-deficient ES cells to isolate RNAi mutants using a simple drug selection scheme. This chapter describes how we used retroviral gene traps to mutagenize the reporter cell line and select for RNAi mutants. Putative RNAi mutants were confirmed using a separate functional assay. The location of the gene-trap was then identified using molecular techniques such as splinkerette PCR. Our screening strategy successfully isolated several mutant clones of Argonaute 2, a vital component of the RNAi pathway. PMID- 28674806 TI - RNAi Knockdown of Ape1 Gene in the Differentiation of Mouse Embryonic Stem Cells. AB - Murine embryonic stem cells (ES) are pluripotent cells and have the potential to become a wide variety of specialized cell types. Mouse ES cell differentiation can be regarded as a valuable biological tool that has led to major advances in our understanding of cell and developmental biology. In vitro differentiation of mouse ES cells can be directed to a specific lineage formation, such as hematopoietic lineage, by appropriate cytokine and/or growth factor stimulation. To study specific gene function in early developmental events, gene knockout approaches have been traditionally used, however, this is a time-consuming and expensive approach. Recently, we have shown that siRNA is an effective strategy to knock down target gene expression, such as Ape1, during ES cell differentiation, and consequently, one can alter cell fates in ES-derived differentiated cells. This approach will be applicable to test the function of a wide variety of gene products using the ES cell differentiation system. PMID- 28674807 TI - An Efficient Transfection Method for Differentiation and Cell Proliferation of Mouse Embryonic Stem Cells. AB - Embryonic stem (ES) cells are an important source of stem cells in tissue engineering and regenerative medicine because of their high self-renewal capacities and differentiation potentials. However, the detailed molecular mechanisms controlling the differentiation and renewal programs in ES cells remained unclear. One of the difficulties in understanding these mechanisms substantially results from the low efficacies of gene manipulation by delivering exogenous gene expression or knockdown of endogenous gene expression with small interfering RNA (siRNA) in ES cells. Here we describe an optimized protocol for efficiently transfecting mouse ES cells by Effectene, a liposome-based method. The high transfection efficiency in mouse ES cells is demonstrated in this chapter by (1) achieving a percentage of enhanced green fluorescence protein (EGFP) expression in >98% embryoid bodies after introducing plasmids encoding the protein; (2) decreased SOX-2 and Oct-3/4 expression and subsequent morphological evidences of cell differentiation after introducing siRNA expression for suppressing SOX-2 and Oct-3/4, which are known to be essential for maintenance of stem cell properties in mouse ES cells; and (3) overexpression or attenuated expression of 14-3-3sigma to regulate cell proliferation of mouse ES cells. PMID- 28674808 TI - Implanting Glioblastoma Spheroids into Rat Brains and Monitoring Tumor Growth by MRI Volumetry. AB - The outcome of patients suffering from glioblastoma multiforme (GBM) remains poor with a median survival of less than 15 months. To establish innovative therapeutical approaches or to analyze the effect of protein overexpression or protein knockdown by RNA interference in vivo, animal models are mandatory. Here, we describe the implantation of C6 glioma spheroids into the rats' brain and how to follow tumor growth by MRI scans. We show that C6 cells grown in Sprague Dawley rats share several morphologic features of human glioblastoma like pleomorphic cells, areas of necrosis, vascular proliferation, and tumor cell invasion into the surrounding brain tissue. In addition, we describe a method for tumor volumetry utilizing the CISS 3D- or contrast-enhanced T1-weighted 3D sequence and freely available post-processing software. PMID- 28674810 TI - In vivo RNAi in the Drosophila Follicular Epithelium: Analysis of Stem Cell Maintenance, Proliferation, and Differentiation. AB - In vivo RNAi in Drosophila facilitates simple and rapid analysis of gene functions in a cell- or tissue-specific manner. The versatility of the UAS-GAL4 system allows to control exactly where and when during development the function of a gene is depleted. The epithelium of the ovary is a particularly good model to study in a living animal how stem cells are maintained and how their descendants proliferate and differentiate. Here I provide basic information about the publicly available reagents for in vivo RNAi, and I describe how the oogenesis system can be applied to analyze stem cells and epithelial development at a histological level. Moreover, I give helpful hints to optimize the use of the UAS-GAL4 system for RNAi induction in the follicular epithelium. Finally, I provide detailed step-by-step protocols for ovary dissection, antibody stainings, and ovary mounting for microscopic analysis. PMID- 28674809 TI - RNAi-Based Techniques for the Analysis of Gene Function in Drosophila Germline Stem Cells. AB - Elucidating the full repertoire of molecular mechanisms that promote stem cell maintenance requires sophisticated techniques for identifying and characterizing gene function in stem cells in their native environment. Ovarian germline stem cells in the fruit fly, Drosophila melanogaster, are an ideal model to study the complex molecular mechanisms driving stem cell function in vivo. A variety of new genetic tools make RNAi a useful complement to traditional genetic mutants for the investigation of the molecular mechanisms guiding ovarian germline stem cell function. Here, we provide a detailed guide for using targeted RNAi knockdown for the discovery of gene function in ovarian germline stem cells and their progeny. PMID- 28674811 TI - A Phenotype-Based RNAi Screening for Ras-ERK/MAPK Signaling-Associated Stem Cell Regulators in C. elegans. AB - Stem cells have the ability to self-renew and to generate differentiated cell types. A regulatory network that controls this balance is critical for stem cell homeostasis and normal animal development. Particularly, Ras-ERK/MAPK signaling pathway is critical for stem cell self-renewal and differentiation in mammals, including humans. Aberrant regulation of Ras-ERK/MAPK signaling pathway results in either stem cell or overproliferation. Therefore, the identification of Ras ERK/MAPK signaling pathway-associated regulators is critical to understand the mechanism of stem cell (possibly cancer stem cell) control. In this report, using the nematode C. elegans mutants, we developed a methodology for a phenotype-based RNAi screening that identifies stem cell regulator genes associated with Ras ERK/MAPK signaling within the context of a whole organism. Importantly, this phenotype-based RNAi screening can be applied for other stem cell-associated signaling pathways such as Wnt/beta-catenin and Notch using the C. elegans. PMID- 28674812 TI - Engineering Human Mesenchymal Stem Cells to Release Adenosine Using miRNA Technology. AB - Adenosine is an important modulator of metabolic activity with powerful tissue and cell protective functions. Adenosine kinase (ADK), the major adenosine regulating enzyme, is critical to adapt its intra- and extracellular levels in response to environmental changes. Lentiviral RNAi-mediated downregulation of ADK in human mesenchymal stem cells (hMSCs) has therefore been considered an effective tool for engineering therapeutically effective adenosine-releasing cell grafts that could constitute patient-identical autologous implants for clinical application. We constructed lentiviral vectors that co-express miRNA directed against ADK and an emerald green fluorescent protein (EmGFP) reporter gene. Following lentiviral transduction of hMSCs, we demonstrated up to 80% downregulation of ADK and 98% transduction efficiency. Transduced hMSCs continued to express EmGFP after four to six consecutive passages, and EmGFP-positive hMSC grafts survived in the hippocampal fissure of mouse brains and provided efficient adenosine-dependent neuroprotection in a mouse model of seizure-induced cell loss. PMID- 28674813 TI - Efficient Gene Knockdowns in Mouse Embryonic Stem Cells Using MicroRNA-Based shRNAs. AB - RNA interference (RNAi) is a powerful gene knockdown technology that has been applied for functional genetic loss-of-function studies in many model eukaryotic systems, including embryonic stem cells (ESCs). Application of RNAi in ESCs allows for dissection of mechanisms by which ESCs self-renew and maintain pluripotency and also for specifying particular cell types needed for cell replacement therapies. Potent RNAi response can be induced by expression of a microRNA-embedded short-hairpin RNA (shRNAmir) cassette that is integrated in the genome by virus infection or site-specific recombination at a defined locus. In this chapter, I will provide detailed protocols to perform shRNAmir-mediated RNAi studies in mouse ESCs using retrovirus infection and loxP site-directed recombination for efficient constitutive and inducible gene knockdown, respectively. PMID- 28674814 TI - Using Quantitative Real-Time PCR to Detect MicroRNA Expression Profile During Embryonic Stem Cell Differentiation. AB - Quantitative real-time PCR (qRT-PCR) is a reliable method to determine and monitor microRNA (miRNA) expression profiles in different cells, tissues, and organisms. Although there are several different strategies in performing qRT-PCR to determine miRNA expression, all of them have two steps in common: reverse transcription for obtaining cDNA from mature miRNA sequencing and standard real time PCR for amplification of cDNA. This chapter demonstrates the application of quantitative real-time PCR for determining miRNA expression profiles during mouse embryonic stem cell differentiation. In this method, a mature miRNA sequence is first reverse transcribed into a long cDNA with a 40-50 nt miRNA-specific stem loop primer; then, a standard real-time PCR reaction is performed for determining miRNA expression using a forward miRNA-specific primer and a universal reverse primer. PMID- 28674815 TI - Genetic Tools for Self-Organizing Culture of Mouse Embryonic Stem Cells via Small Regulatory RNA-Mediated Technologies, CRISPR/Cas9, and Inducible RNAi. AB - Approaches to investigate gene functions in experimental biology are becoming more diverse and reliable. Furthermore, several kinds of tissues and organs that possess their original identities can be generated in petri dishes from stem cells including embryonic, adult and induced pluripotent stem cells. Researchers now have several choices of experimental methods and their combinations to analyze gene functions in various biological systems. Here, as an example we describe one of the better protocols, which combines three-dimensional embryonic stem cell culture with small regulatory RNA-mediated technologies, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), and inducible RNA interference (RNAi). This protocol allows investigation of genes of interest to better understand gene functions in target tissues (or organs) during in vitro development. PMID- 28674816 TI - CRISPR-Cas9-Mediated Gene Editing in Mouse Spermatogonial Stem Cells. AB - Precise genome editing is a powerful tool for analysis of gene function. However, in spermatogonial stem cells (SSCs), this still remains a big challenge mainly due to low efficiency and complexity of currently available gene editing techniques. The CRISPR-Cas9 system from bacteria has been applied to modifying genome in different species at a very high efficiency and specificity. Here we describe CRISPR-Cas9-mediated gene editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in SSCs. This protocol provides guidelines for derivation of SSCs, nucleofection of SSCs with the CRISPR-Cas9 system, transplantation of the gene-modified SSCs into the recipient testes, and production of mice using transplanted SSC-derived round spermatids. PMID- 28674818 TI - Cytokine storms in infectious diseases. PMID- 28674817 TI - Update on the role of endothelial cells in trauma. AB - PURPOSE: This review gives an overview of physiological processes, mainly regarding vascular endothelial cells and their important role in hemostasis, information processing, and communication during trauma. An insight is given into molecules and cells involved in the first innate immune response through to the behavior of endothelial cells in developing trauma. The goal of this review is to show the overlap of crucial factors related to the endothelium and the development of trauma. METHODS: A systemic literature search was performed using Google scholar and PubMed. RESULTS: The results of the literature search showed that the endothelium, especially the vascular endothelium, is involved in various cellular and subcellular pathways of activation, suppression, and transfer of information. A variety of molecules and cells are orchestrated, subsequently the endothelium gets in contact with a traumatizing event. CONCLUSION: The endothelium is one of the first barriers that comes into contact with exo- and endogenous trauma-related signals and is a pivotal point in activating subsequent pathways and cascades by transfer of information. PMID- 28674819 TI - Does a face-bow lead to better occlusion in complete dentures? A randomized controlled trial: part I. AB - OBJECTIVES: In a double-blinded randomized controlled clinical trial, the impact of face-bow registration for remounting complete dentures (CDs) on the occlusal parameters (part I) was evaluated. MATERIALS AND METHODS: New CDs of 32 patients were duplicated and mounted after intraoral pin registration according to mean settings (group 1) and (group 2) using a face-bow (arbitrary hinge axis). The vertical dimension was reduced to the first occlusal contact point, and a bite record was fabricated in the articulator. The number of contacts and the number of teeth in contact were evaluated by a computer program (laboratory result). After randomization, half of the CDs were adjusted according to protocol of group 1 and group 2 and delivered to the patients. After 3 days (T1) and 84 days (T2), clinical static contact points and teeth in contact were counted. Contact points and teeth in contact of both groups (laboratory results) and at different moments (clinical results) were analyzed statistically with the F test and bootstrapping. RESULTS: Laboratory: No. 2 (face-bow) showed more occlusal contact points than no. 1 (mean setting), p > 0.05. The number of teeth with at least one occlusal contact was significantly higher in no. 2 (p = 0.027). Clinic: The mean number of teeth with at least one clinical contact point was significantly higher in no. 1 (no. 1 = 7.13, no. 2 = 5.31; p = 0.042). Extent of the vertical shift poorly correlated with number of laboratory occlusal contact points (R 2 = 0.017). CONCLUSIONS: Considering the complex multistep study design, a limited number of participants, and referring to one specific arbitrary face-bow, the following conclusion could be drawn: no substantial difference by the use of the arbitrary face-bow compared to a mean setting could be determined, when changing the vertical dimension in the articulator within a remounting procedure of complete dentures. CLINICAL RELEVANCE: Further research is necessary to determine the effects of different arbitrary face-bows on the fabrication and adaptation of removable dentures. PMID- 28674820 TI - Detection of the tremorgenic mycotoxin paxilline and its desoxy analog in ergot of rye and barley: a new class of mycotoxins added to an old problem. AB - A newly developed enzyme immunoassay (EIA) for the detection of the tremorgenic indole-diterpene alkaloid paxilline (PAX) and closely related analogs was used to analyze ergot sclerotia collected from rye and barley fields. The mean EIA standard curve detection limit was 0.47 +/- 0.14 ng/mL; relative cross-reactivity of toxin standard solutions was found for 11-hydroxy-paspaline (terpendole E, 1.1%) but not for lolitrem B or ergot alkaloids. Sclerotia from all fields were positive in the PAX-EIA at concentration levels of 620 +/- 200 and 160 +/- 37 MUg/kg in ergot of rye and 130 +/- 47 MUg/kg in ergot of barley. Confirmatory analyses of sclerotia by liquid chromatography-tandem mass spectrometric detection identified PAX and its analog 13-desoxypaxilline. To the best of our knowledge, this is the first report on the natural occurrence of tremorgenic indole-diterpene alkaloid mycotoxins in ergot sclerotia from rye and barley. Along with details on the analytical methodology developed in this study, particularly PAX-antibody production, the relevance and implications of these findings for food and feed safety are discussed. Presence or absence of elevated levels of tremorgenic mycotoxins, along with the ergot alkaloids, would help in explaining the difference between the two distinct manifestations of historic ergotism, the convulsive and the gangrenous form. Further method development for paxilline and other tremorgenic mycotoxins in cereals used for food and feed is a prerequisite for a comprehensive risk assessment, which seems to be necessary in light of the findings reported here. Paxilline in ergot of rye. PMID- 28674822 TI - A fully automated simultaneous single-stage separation of Sr, Pb, and Nd using DGA Resin for the isotopic analysis of marine sediments. AB - A novel, fast and reliable sample preparation procedure for the simultaneous separation of Sr, Pb, and Nd has been developed for subsequent isotope ratio analysis of sediment digests. The method applying a fully automated, low-pressure chromatographic system separates all three analytes in a single-stage extraction step using self-packed columns filled with DGA Resin. The fully automated set-up allows the unattended processing of three isotopic systems from one sediment digest every 2 h, offering high sample throughput of up to 12 samples per day and reducing substantially laboratory manpower as compared to conventional manual methods. The developed separation method was validated using the marine sediment GBW-07313 as matrix-matched certified reference material and combines quantitative recoveries (>90% for Sr, >93% for Pb, and >91% for Nd) with low procedural blank levels following the sample separation (0.07 MUg L-1 Sr, 0.03 MUg L-1 Pb, and 0.57 MUg L-1 Nd). The average delta values for Sr, Pb, and Nd of the separated reference standards were within the certified ranges (delta (87Sr/86Sr)NIST SRM 987 of -0.05(28) 0/00, delta(208Pb/206Pb)NIST SRM 981 of 0.21(14) 0/00, and delta(143Nd/144Nd)JNdi-1 of 0.00(7) 0/00). The DGA Resin proved to be reusable for the separation of >10 sediment digests with no significant carry-over or memory effects, as well as no significant on-column fractionation of Sr, Pb, and Nd isotope ratios. Additional spike experiments of NIST SRM 987 with Pb, NIST SRM 981 with Sr, and JNdi-1 with Ce revealed no significant impact on the measured isotopic ratios, caused by potential small analyte peak overlaps during the separation of Sr and Pb, as well as Ce and Nd. PMID- 28674821 TI - The analysis of tetracyclines, quinolones, macrolides, lincosamides, pleuromutilins, and sulfonamides in chicken feathers using UHPLC-MS/MS in order to monitor antibiotic use in the poultry sector. AB - In The Netherlands, all antibiotic treatments should be registered at the farm and in a central database. To enforce correct antibiotic use and registration, and to enforce prudent use of antibiotics, there is a need for methods that are able to detect antibiotic treatments. Ideally, such a method is able to detect antibiotic applications during the entire lifespan of an animal, including treatments administered during the first days of the animals' lives. Monitoring tissue, as is common practice, only provides a limited window of opportunity, as residue levels in tissue soon drop below measurable quantities. The analysis of feathers proves to be a promising tool in this respect. Furthermore, a qualitative confirmatory method was developed for the analyses of six major groups of antibiotics in ground chicken feathers, aiming for a detection limit as low as reasonably possible. The method was validated according to Commission Decision 2002/657/EC. All compounds comply with the criteria and, as a matter of fact, 58% of the compounds could also be quantified according to regulations. Additionally, we demonstrated that a less laborious method, in which whole feathers were analyzed, proved successful in the detection of applied antibiotics. Most compounds could be detected at levels of 2 MUg kg-1 or below with the exception of sulfachloropyridazine, tylosin, and tylvalosin. This demonstrates the effectiveness of feather analysis to detect antibiotic use to allow effective enforcement of antibiotic use and prevent the illegal, off-label, and nonregistered use of antibiotics. PMID- 28674823 TI - Comparison of Scrub Typhus With and Without Meningitis. AB - OBJECTIVE: To compare the children admitted with scrub typhus with and without meningitis. METHODS: All children admitted with scrub typhus over a 62 mo period were reviewed. Statistical analysis was performed to compare those with and without meningitis for demographic, clinical, investigations and outcome parameters. RESULTS: Four hundred twenty seven children were admitted with scrub typhus and 63 (14.8%) had meningitis. The mean cerebrospinal fluid white blood cell (CSF WBC) count was 71 cells/cu.mm. with mean lymphocyte proportion of 92%. The mean CSF protein was 67 mg/dl and mean CSF glucose, 55 mg/dl. Of those who had meningitis, 24 (38.1%) had seizures, 17 (27%) had altered sensorium and 37 (58.7%) had nuchal rigidity. Finding an eschar, being male, breathing difficulty, and hepatomegaly were significantly more common in those without meningitis. Children with meningitis also had shorter duration of fever at presentation (median [IQR] 7 [3] days vs. 10 [4] days; p = 0.028). Headache and vomiting were significantly more common in those with meningitis. Hemoglobin and platelet were significantly lower in those without meningitis. Duration of hospitalization was significantly longer in those with meningitis, whereas acute respiratory distress syndrome (ARDS) was significantly more common in those without meningitis. There was no neurological deficit in both the groups. There was no mortality in the meningitis group compared to 3.6% mortality in the non-meningitis group (p = 0.213). CONCLUSIONS: Meningitis occurs in 15% of those with scrub typhus; those with meningitis have good neurological outcome with little mortality; those without meningitis have more complications and poorer outcome. PMID- 28674824 TI - An Update on Retinopathy of Prematurity (ROP). AB - Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease affecting the retina of premature infants. The clinical spectrum of ROP varies from spontaneous regression to bilateral retinal detachment and total blindness. Between these two extremes lies the form of ROP, which is amenable to treatment with laser photocoagulation, anti-vascular endothelial growth factor drugs or surgery. Increasing rates of preterm births coupled with better survival rates but lack of uniform quality of neonatal care and delays in diagnosis have led to increasing ROP blindness. Atypical forms of Aggressive Posterior ROP are seen in heavier birth weight babies in developing countries. Prevention of ROP by following stringent protocols for supplemental oxygen, prevention of sepsis, timely screening and laser treatment by a concerted and collaborative effort of neonatologists and ophthalmologists are required to fight the blindness from ROP. PMID- 28674825 TI - Calibration of GENEActiv accelerometer wrist cut-points for the assessment of physical activity intensity of preschool aged children. AB - : This study sought to validate cut-points for use of wrist-worn GENEActiv accelerometer data, to analyse preschool children's (4 to 5 year olds) physical activity (PA) levels via calibration with oxygen consumption values (VO2). This was a laboratory-based calibration study. Twenty-one preschool children, aged 4.7 +/- 0.5 years old, completed six activities (ranging from lying supine to running) whilst wearing the GENEActiv accelerometers at two locations (left and right wrist), these being the participants' non-dominant and dominant wrist, and a Cortex face mask for gas analysis. VO2 data was used for the assessment of criterion validity. Location specific activity intensity cut-points were established via receiver operator characteristic curve (ROC) analysis. The GENEActiv accelerometers, irrespective of their location, accurately discriminated between all PA intensities (sedentary, light, and moderate and above), with the dominant wrist monitor providing a slightly more precise discrimination at light PA and the non-dominant at the sedentary behaviour and moderate and above intensity levels (area under the curve (AUC) for non-dominant = 0.749-0.993, compared to AUC dominant = 0.760-0.988). CONCLUSION: This study establishes wrist-worn physical activity cut-points for the GENEActiv accelerometer in preschoolers. What is Known: * GENEActiv accelerometers have been validated as a PA measurement tool in adolescents and adults. * No study to date has validated the GENEActiv accelerometers in preschoolers. What is New: * Cut-points were determined for the wrist-worn GENEActiv accelerometer in preschoolers. * These cut-points can be used in future research to help classify and increase preschoolers' compliance rates with PA. PMID- 28674826 TI - Conifer Diterpene Resin Acids Disrupt Juvenile Hormone-Mediated Endocrine Regulation in the Indian Meal Moth Plodia interpunctella. AB - Diterpene resin acids (DRAs) are important components of oleoresin and greatly contribute to the defense strategies of conifers against herbivorous insects. In the present study, we determined that DRAs function as insect juvenile hormone (JH) antagonists that interfere with the juvenile hormone-mediated binding of the JH receptor Methoprene-tolerant (Met) and steroid receptor coactivator (SRC). Using a yeast two-hybrid system transformed with Met and SRC from the Indian meal moth Plodia interpunctella, we tested the interfering activity of 3704 plant extracts against JH III-mediated Met-SRC binding. Plant extracts from conifers, especially members of the Pinaceae, exhibited strong interfering activity, and four active interfering DRAs (7alpha-dehydroabietic acid, 7-oxodehydroabietic acid, dehydroabietic acid, and sandaracopimaric acid) were isolated from roots of the Japanese pine Pinus densiflora. The four isolated DRAs, along with abietic acid, disrupted the juvenile hormone-mediated binding of P. interpunctella Met and SRC, although only 7-oxodehydroabietic acid disrupted larval development. These results demonstrate that DRAs may play a defensive role against herbivorous insects via insect endocrine-disrupting activity. PMID- 28674828 TI - [Erratum to: Management of chronic pain using extended release tilidine : Quality of life and implication of comedication on tilidine metabolism]. PMID- 28674827 TI - Evaluation of Host-Derived Volatiles for Trapping Culicoides Biting Midges (Diptera: Ceratopogonidae). AB - Culicoides biting midges (Diptera: Ceratopognidae) cause pain and distress through blood feeding, and transmit viruses that threaten both animal and human health worldwide. There are few effective tools for monitoring and control of biting midges, with semiochemical-based strategies offering the advantage of targeting host-seeking populations. In previous studies, we identified the host preference of multiple Culicoides species, including Culicoides impunctatus, as well as cattle-derived compounds that modulate the behavioral responses of C. nubeculosus under laboratory conditions. Here, we test the efficacy of these compounds, when released at different rates, in attracting C. impunctatus under field conditions in Southern Sweden. Traps releasing 1-octen-3-ol, decanal, phenol, 4-methylphenol or 3-propylphenol, when combined with carbon dioxide (CO2), captured significantly higher numbers of C. impunctatus compared to control traps baited with CO2 alone, with low release rates (0.1 mg h-1, 1 mg h 1) being generally more attractive. In contrast, traps releasing octanal or (E)-2 nonenal at 1 mg h-1 and 10 mg h-1 collected significantly lower numbers of C. impunctatus than control traps baited with CO2 only. Nonanal and 2-ethylhexanol did not affect the attraction of C. impunctatus when compared to CO2 alone at any of the release rates tested. The potential use of these semiochemicals as attractants and repellents for biting midge control is discussed. PMID- 28674829 TI - [Neuromodulation using matrix stimulation : A treatment for acute pain?] AB - BACKGROUND: There is currently a lack of studies that evaluate the effects of matrix electrode neuromodulation on acute pain. In this prospective and randomized cross-over study, we investigated the efficacy of 4 Hz-matrix stimulation on venipuncture-induced pain in 30 healthy subjects. METHODS: We compared two conditions of neurostimulation: in EC1 (experimental condition 1), we performed venipuncture during stimulation, with 2.5 min of prestimulation with 600 stimuli; in EC2 (experimental condition 2), the length of stimulation was 5 min, at 1200 stimuli, with subsequent venipuncture. A group with no stimulation was used as control condition. RESULTS: The EC2 group did not only show a 77% reduction in puncture pain when compared to the control group (p < 0.001; effect size [ES] d = 1.45), but also had a significant effect compared with EC1 (p < 0.001; ES d = 1.33). EC1, on the other hand, did not demonstrate a significant difference to the control group. The status of the veins was evaluated based on visibility and did not differ significantly between the conditions. CONCLUSION: The results of this study showed for the first time that pre-emptive matrix stimulation could be an effective way to reduce acute pain. The duration of stimulation seems to play a key role in the effectiveness of the neurophysiological mechanism of action. Matrix stimulation is a therapeutic intervention with very few side effects, which could, in the future, expand our pain-management options for the treatment of acute pain. PMID- 28674830 TI - Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia. AB - Telomere shortening represents an established mechanism connecting aging and cancer development. We sequentially analyzed telomere length (TL) of 49 acute myeloid leukemia (AML) patients at diagnosis (n = 24), once they achieved complete cytological remission (CCR) and/or during refractory disease or relapse and after 1-year follow-up, with all patients having at least two sequential samples. TL was analyzed by monochrome multiplex quantitative polymerase chain reaction. We have observed substantially shortened TL in the cells of patients at diagnosis compared to age-adjusted controls. In patients reaching CCR after chemotherapy, telomere shortening was less pronounced than in persistence or relapse but still significantly shortened compared to controls. We estimate patients harboring approximately 20 years of premature telomere loss compared to healthy aged-matched subjects at the time of AML onset. Our data indicate a pre existing telomere deficit in non-clonal hematopoiesis of AML patients providing a link between age and AML development. PMID- 28674831 TI - Quantification and comparison of acidic polysaccharides in edible fish intestines and livers using HPLC-MS/MS. AB - Fish intestines and livers are usually considered as delicious and nutritious food in China. Acidic polysaccharides are important nutrients in these food of animal origin, but there is currently little information regarding their quantitative distributions. The present study demonstrated a method to quantify acidic polysaccharides simultaneously by analyzing their disaccharides produced from the acid hydrolysis using high-performance liquid chromatography (HPLC) coupled with triple quadrupole mass spectrometry. The recoveries for these acidic polysaccharides were all 97%-115% with relative standard deviation of 3.0%-9.0%. All of the acidic polysaccharides had good linearities. Then this method was applied to determine the composition of acidic polysaccharides in 5 edible fish livers and intestines. Besides well-known glycosaminoglycans (GAGs) including hyaluronic acid (HA), Chondroitin sulfate (CS), dermatan sulfate (DS) and heparin (HP), 4 novel acidic polysaccharides including 2 GAGs and 2 non-GAGs comprised of hexose-hexuronic acid repeating units were also found. CS and HP were the major acidic polysaccharides components in fish intestines and livers, respectively. The absolute amounts of acidic polysaccharides differed greatly in these fish tissues, but their proportions showed similarity in the same type of tissues. The present study demonstrated an effective method for acidic polysaccharides quantification, and revealed acidic polysaccharides compositions of edible fish livers and intestines. PMID- 28674832 TI - Heterologous Expression and Characterization of an Acidic GH11 Family Xylanase from Hypocrea orientalis. AB - A gene encoding glycoside hydrolase family 11 xylanase (HoXyn11B) from Hypocrea orientalis EU7-22 was expressed in Pichia pastoris with a high activity (413 IU/ml). HoXyn11B was partly N-glycosylated and appeared two protein bands (19-29 kDa) on SDS-PAGE. The recombinant enzyme exhibited optimal activity at pH 4.5 and 55 degrees C, and retained more than 90% of the original activity after incubation at 50 degrees C for 60 min. The determined apparent K m and V max values using beechwood xylan were 10.43 mg/ml and 3246.75 IU/mg, respectively. The modes of action of recombinant HoXyn11B on xylo-oligosaccharides (XOSs) and beechwood xylan were investigated by thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), which indicated that the modes of action of HoXyn11B are different from HoXyn11A since it is able to release a significant amount of xylose from various substrates. This study provides an opportunity to better understand the hydrolysis mechanisms of xylan by xylanases from Trichoderma. PMID- 28674833 TI - Cloning, Purification, and Characterization of Tripeptidyl Peptidase from Streptomyces herbaricolor TY-21. AB - Tripeptidyl peptidase (TPP) is an exopeptidase that sequentially hydrolyzes tripeptides from the N-terminus of oligopeptides or polypeptides. We performed screening for isolating novel TPP-producing microorganisms from soil samples. TPP activity was observed in the culture supernatant of Streptomyces herbaricolor TY 21 by using Ala-Ala-Phe-p-nitroanilide (pNA) as the substrate. TPP from the culture supernatant was purified to approximately 790-fold. It was shown to cleave oxidized insulin B-chain, thereby with releasing tripeptide units, but not the N-terminal-protected peptide, Cbz-Ala-Ala-Phe-pNA. The TPP gene, designated tpp, was isolated from a partial genomic DNA library of S. herbaricolor TY-21. The TPP gene consisted of 1488 bp, and encoded a 133-amino acid pre-pro-peptide and a 362-amino acid mature enzyme containing conserved amino acid residues (Asp 36, His-77, and Ser-282) similar to the catalytic residues in subtilisin. TY-21 TPP belonged to the peptidase S8A family in the MEROPS database. The mature TY-21 TPP showed approximately 49% identity with tripeptidyl peptidase subtilisin-like (TPP S) from Streptomyces lividans strain 66. PMID- 28674834 TI - Intraocular silicone implant to treat chronic ocular hypotony: an in vivo trial. AB - PURPOSE: The management of chronic ocular hypotony and complicated proliferative vitreoretinopathy-related retinal detachment represents a challenge. Being non absorbable and non-biodegradable, a silicone oil implant is expected to restore the volume and the intraocular pressure of the globe, as well as to approximate the detached retina. Further advantages could be a long-term tamponade potential, absence of toxicity, and prevention of silicone oil emulsification or anterior chamber oil-prolapse. The aim of this study was to assess the histological tolerance of the silicone oil implant in a pig model. METHODS: A seamless silicone balloon implant with optional surface modifications was developed. Mini pigs were used as experimental animals, and three variants of silicone implants with different surfaces were tested: uncoated, NCO-sP(EO-stat-PO) coated, and heparin-NCO-sP(EO-stat-PO) coated silicone implants. An extracapsular lens extraction was achieved via a standard phacoemulsification followed by a standard three-port vitrectomy. The implant was then placed in the posterior segment and filled with 5000 centistoke silicone oil. One month later, the pigs were euthanized, the eyes were enucleated, and histological specimens were prepared for microscopy. RESULTS: The analysis of the histology revealed that adverse histological changes in conjunctiva, cornea, iris, and ciliary body could be excluded in all eyes operated on regardless of which variant of implant had been employed. The retina as the implant-contacting ocular tissue showed overall good tolerance, although some inflammatory reaction and fibrous proliferation was evident in some cases. CONCLUSIONS: The silicone oil implant is a promising candidate and has the potential to fulfill clinical requirements to act as a long term intraocular tamponade agent. The heparin-NCO-sP(EO-stat-PO) coating approach could lead to a novel bioactive surface for intraocular devices with excellent properties to hinder cell adhesion and protein adsorption, although further studies will be necessary to evaluate long-term biocompatibility and long-term resistance to biological attacks. PMID- 28674835 TI - Photodynamic therapy in chronic central serous chorioretinopathy with subretinal fluid outside the fovea. AB - PURPOSE: To assess the efficacy of photodynamic therapy (PDT) in patients with chronic central serous chorioretinopathy (cCSC), in whom subretinal fluid (SRF) was solely present outside the foveal area. METHODS: In this retrospective study, 16 eyes of 15 cCSC patients who received half-dose PDT because of notable subjective visual complaints due to the presence of extrafoveal SRF, were included. An ophthalmic examination was performed before treatment, including Early Treatment Diabetic Retinopathy Study best-corrected visual acuity measurement, applanation tonometry, slit-lamp examination, and indirect ophthalmoscopy, followed by multimodal imaging, including fundus photography, fundus autofluorescence, spectral-domain optical coherence tomography (OCT), enhanced-depth imaging OCT of the choroid, fluorescein angiography, and indocyanine green angiography. RESULTS: In 7 treated patients (47%), PDT led to a decrease in visual complaints at the first evaluation visit. At this visit, extrafoveal SRF on OCT had resolved in 14 eyes (88%), whereas a complete resolution of extrafoveal SRF had occurred in all eyes at final follow-up visit. At baseline, posterior cystoid retinal degeneration was also present in 5 eyes (31%) and this remained present at all evaluation visits in these patients. Choroidal thickness decreased statistically significantly in the treated eyes, both foveally and at the location of the maximum height of extrafoveal SRF. No complications of PDT were observed. CONCLUSIONS: Half-dose PDT treatment of cCSC patients with visual complaints due to extrafoveal SRF accumulation is a safe procedure leading to complete SRF resolution, a decrease in choroidal thickness, and a reduction in visual symptoms. PMID- 28674836 TI - Qualitative analysis of direction of public hospital reforms in China. AB - Reforms in public hospitals are among the most important improvements in China's health care system over the last two decades. However, the reforms that should be implemented in public hospitals are unclear. Thus, a feasible direction of reforms in Chinese public hospitals is suggested and reliable policy suggestions are provided for the government to reform public hospitals. The data used in this study were mainly derived from a qualitative study. Focus group discussions and in-depth interviews were conducted in Shanghai, Guangdong, and Gansu between May and December 2014. Government funding accounted for approximately eight percent of the total annual revenue of public hospitals in China, and the insufficient government subsidy considerably affects the operation mechanism of public hospitals. However, solely increasing this subsidy cannot address the inappropriate incentives of public hospitals in China. The most crucial step in setting the direction of reforms in public hospitals in China is transforming inappropriate incentives by implementing a new evaluation index system for directors and physicians in public hospitals. PMID- 28674837 TI - A novel method for constructing continuous intrinsic surfaces of nanoparticles. AB - In recent years, the field of nanotechnology has become increasingly prevalent in the disciplines of science and engineering due to it's abundance of application areas. Therefore, the ability to study and characterize these materials is more relevant than ever. Despite the wealth of simulation and modeling studies of nanoparticles reported in the literature, a rigorous description of the interface of such materials is rarely included in analyses which are pivotal to understanding interfacial behavior. We propose a novel method for constructing the continuous intrinsic surface of nanoparticles, which has been applied to a model system consisting of a sodium dodecyl sulfate micelle in the presence of testosterone propionate. We demonstrate the advantages of using our continuous intrinsic surface definition as a means to elucidate the true interfacial structure of the micelle, the interfacial properties of the hydrating water molecules, and the position of the drug (testosterone propionate) within the micelle. Additionally, we discuss the implications of this algorithm for future work in the simulation of nanoparticles. Graphical Abstract ?. PMID- 28674838 TI - Metabolic Effects of Sleeve Gastrectomy and Laparoscopic Greater Curvature Plication: an 18-Month Prospective, Observational, Open-Label Study. AB - BACKGROUND: Laparoscopic greater curvature plication (LGCP) is an innovative restrictive technique designed to reduce gastric volume by plication at the region of greater curvature. The long-term efficacy, safety, and the metabolic effects of this procedure are the subject of this study. METHODS: One hundred twenty-seven patients were enrolled; 84 underwent laparoscopic sleeve gastrectomy (LSG) and 43, LGCP. LSG and LGCP were then compared during long-term follow-ups in terms of glycemic control, hormone and lipid secretion, and changes in body composition. Measured parameters included serum glucose, triglycerides, high- and low-density lipoprotein cholesterol, testosterone, estradiol, leptin, adiponectin, ghrelin, fatmass, and lean body mass. RESULTS: Significant weight loss and a reduced body composition resulted from either procedure vs. baseline (i.e., pre-surgery), with levels of fasting glucose and glycated hemoglobin also showing statistically significant reductions (at 3 and 18 months for either surgery). Intergroup comparisons for glycemic parameters yielded no statistically significant differences. However, a dramatic reduction in ghrelin was detected following LSG, falling from pre-surgery levels of 140.7 to 69.6 ng/L by 6 months (P < 0.001). Subsequently, ghrelin levels increased, reaching 107.8 ng/L by month 12. Conversely, after LGCP, a statistically significant increase in ghrelin was seen, rising from 130.0 ng/L before surgery to 169.0 ng/L by month 12, followed by a slow decline. CONCLUSIONS: Good metabolic outcomes were obtained following LGCP, which might be mediated via altered glucose metabolism and GI hormones. Nevertheless, this method is less effective than LSG, possibly due to its preservation of the entire stomach, including secretory regions. PMID- 28674839 TI - The Role of Aprepitant in Prevention of Postoperative Nausea and Vomiting After Bariatric Surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is common with bariatric surgery. We examined the PONV rate in bariatric surgical patients who received triple antiemetic prophylaxis (dexamethasone, droperidol, and ondansetron) with and without antiemetic aprepitant. METHODS: Medical records of female patients undergoing laparoscopic bariatric surgery from January 1, 2014, to July 28, 2016, were reviewed for PONV episodes during 48 postoperative hours. RESULTS: In total, 338 patients received triple antiemetic, of whom 172 (51%) also received aprepitant. Rates of PONV in the postanesthesia care unit (PACU) among patients with and without aprepitant therapy were 11 vs 17% (P = .09). Within 1 h after PACU discharge, fewer patients in the aprepitant group had PONV (19 vs 31%; odds ratio [OR] [95% CI], 0.5 [0.30-0.80]; P = .007). During the first 48 postoperative hours, PONV rates were similar between the groups (68 and 66%; P = .73), but fewer emesis episodes occurred in the aprepitant group (6 vs 13%; OR [95% CI], 0.45 [0.21-0.95]; P = .04). Analyses were also performed with a subset of patients matched on propensity for receiving aprepitant. In this subset, OR estimates quantifying aprepitant effect on PONV were similar to those obtained from multivariable regression analyses. CONCLUSION: Addition of aprepitant to a multimodal antiemetic prophylactic regimen may be associated with significant reduction of PONV during early recovery and potentially with reduced incidence of vomiting during the first 48 postoperative hours. The high PONV rate in the first 48 postoperative hours is suggestive that introduction of scheduled anti-PONV prophylactic treatment may be desirable. PMID- 28674840 TI - A Multimodal Analgesic Protocol Reduces Opioid-Related Adverse Events and Improves Patient Outcomes in Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is one of the most commonly performed procedures for the treatment of obesity. Patients with obesity are more prone to experience opioid-related adverse events (ORAE). OBJECTIVES: The objective of this study is to determine if a multimodal analgesia protocol (MAP) reduces ORAE and provides effective pain relief for patients after LSG. SETTING: This study was conducted at University Hospital, Singapore. METHODS: The MAP consists of mandatory pre-operative etoricoxib, intra-operative acetaminophen, and post-operative acetaminophen with optional post-operative tramadol. We identified and collected data for patients who underwent LSG between May 2010 and November 2015 and compared patients before and after the implementation of the MAP. RESULTS: One hundred fifty-eight patients were included and 68 patients were treated with the MAP. There were no differences in age, gender, body mass index, ethnicity, or comorbidities between the two groups except for the incidence of hypertension (p = 0.015). There was a significant reduction in the incidence of ORAE from 33.3 to 8.8% (p < 0.001) after the implementation of the MAP. There was also a significant reduction in the use of opioids intra-operatively from 58.2 to 43.6 mg (p < 0.001) and post-operatively from 23.7 to 0.7 mg (p < 0.001). Pain scores were similar at 1, 6, and 48 post-operatively, while pain scores were significantly reduced at 12 (p = 0.033) and 24 h (p = 0.02) post-operatively. Multivariate analysis showed that these results remained significant. CONCLUSION: Our study suggests that a MAP reduces ORAE and provides effective pain relief for patients undergoing LSG. PMID- 28674841 TI - A Novel Smartphone Accelerometer Application for Low-Intensity Activity and Energy Expenditure Estimations in Overweight and Obese Adults. AB - Physical inactivity and sedentary behaviors are on the rise worldwide and contribute to the current overweight and obesity scourge. The loss of healthy life style benchmarks and the lack of the need to move make it necessary to provide feedback about physical and sedentary activities in order to promote active ways of life. The aim of this study was to develop a specific function adapted to overweight and obese people to identify four physical activity (PA) categories and to estimate the associated total energy expenditure (TEE). This function used accelerometry data collected from a smartphone to evaluate activity intensity and length, and TEE. The performance of the proposed function was estimated according to two references (Armband(r) and FitmatePro(r)) under controlled conditions (CC) for a 1.5-h scenario, and to the Armband(r) device in free-living conditions (FLC) over a 12-h monitoring period. The experiments were carried out with overweight and obese volunteers: 13 in CC and 27 in FLC. The evaluation differences in time spent in each category were lower than 7% in CC and 6% in FLC, in comparison to the Armband(r) and FitmatePro(r) references. The TEE mean gap in absolute value between the function and the two references was 9.3% and 11.5% in CC, and 8.5% according to Armband(r) in FLC. PMID- 28674843 TI - Bioactive L acidissima protein hydrolysates using Box-Behnken design. AB - This study examines the extraction and hydrolysis of proteins using single factor and Box-Behnken Design (BBD). From single factor tests, optimised extraction parameters were 1% alkali concentration, 40 degrees C temperature, 60 min time, and 1:20 solid to alkali ratio. Under these conditions; 924.31 mg/g of total protein was obtained from Limonia acidissima (L acidissima). The maximum degree of hydrolysis was 39.82% at pH 2, enzyme to substrate ratio 2.5% (w/w), and hydrolysis time was 42.41 min using BBD design. L acidissima seed protein hydrolysate showed 32.94% DPPH and 88.18% of ABTS activity at concentration of 100 ug/ml and 1 mg/ml, respectively. Reducing power of 0.16 and metal chelating activity of 87.39% was obtained from 5 mg/ml protein hydrolysates. This implied that L acidissima seed protein hydrolysate could be utilised in protein rich product or as protein supplements. PMID- 28674842 TI - Clinical Relevance and Predictive Value of Damage Biomarkers of Drug-Induced Kidney Injury. AB - Nephrotoxin exposure accounts for up to one-fourth of acute kidney injury episodes in hospitalized patients, and the associated consequences are as severe as acute kidney injury due to other etiologies. As the use of nephrotoxic agents represents one of the few modifiable risk factors for acute kidney injury, clinicians must be able to identify patients at high risk for drug-induced kidney injury rapidly. Recently, significant advancements have been made in the field of biomarker utilization for the prediction and detection of acute kidney injury. Such biomarkers may have a role both for detection of drug-induced kidney disease and implementation of preventative and therapeutic strategies designed to mitigate injury. In this article, basic principles of renal biomarker use in practice are summarized, and the existing evidence for six markers specifically used to detect drug-induced kidney injury are outlined, including liver-type fatty acid binding protein, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 times insulin-like growth factor-binding protein 7 ([TIMP-2].[IGFBP7]), kidney injury molecule-1 and N-acetyl-beta-D glucosaminidase. The results of the literature search for these six kidney damage biomarkers identified 29 unique articles with none detected for liver-type fatty acid binding protein and [TIMP-2].[IGFBP7]. For three biomarkers, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-beta-D glucosaminidase, the majority of the studies suggest utility in clinical practice. While many questions need to be answered to clearly articulate the use of biomarkers to predict drug-induced kidney disease, current data are promising. PMID- 28674844 TI - Current perspectives on genetically modified crops and detection methods. AB - Genetically modified (GM) crops are the fastest adopted commodities in the agribiotech industry. This market penetration should provide a sustainable basis for ensuring food supply for growing global populations. The successful completion of two decades of commercial GM crop production (1996-2015) is underscored by the increasing rate of adoption of genetic engineering technology by farmers worldwide. With the advent of introduction of multiple traits stacked together in GM crops for combined herbicide tolerance, insect resistance, drought tolerance or disease resistance, the requirement of reliable and sensitive detection methods for tracing and labeling genetically modified organisms in the food/feed chain has become increasingly important. In addition, several countries have established threshold levels for GM content which trigger legally binding labeling schemes. The labeling of GM crops is mandatory in many countries (such as China, EU, Russia, Australia, New Zealand, Brazil, Israel, Saudi Arabia, Korea, Chile, Philippines, Indonesia, Thailand), whereas in Canada, Hong Kong, USA, South Africa, and Argentina voluntary labeling schemes operate. The rapid adoption of GM crops has increased controversies, and mitigating these issues pertaining to the implementation of effective regulatory measures for the detection of GM crops is essential. DNA-based detection methods have been successfully employed, while the whole genome sequencing using next-generation sequencing (NGS) technologies provides an advanced means for detecting genetically modified organisms and foods/feeds in GM crops. This review article describes the current status of GM crop commercialization and discusses the benefits and shortcomings of common and advanced detection systems for GMs in foods and animal feeds. PMID- 28674845 TI - Discrete Event Simulation-Based Resource Modelling in Health Technology Assessment. AB - OBJECTIVE: The objective of this article was to conduct a systematic review of published research on the use of discrete event simulation (DES) for resource modelling (RM) in health technology assessment (HTA). RM is broadly defined as incorporating and measuring effects of constraints on physical resources (e.g. beds, doctors, nurses) in HTA models. METHODS: Systematic literature searches were conducted in academic databases (JSTOR, SAGE, SPRINGER, SCOPUS, IEEE, Science Direct, PubMed, EMBASE) and grey literature (Google Scholar, NHS journal library), enhanced by manual searchers (i.e. reference list checking, citation searching and hand-searching techniques). RESULTS: The search strategy yielded 4117 potentially relevant citations. Following the screening and manual searches, ten articles were included. Reviewing these articles provided insights into the applications of RM: firstly, different types of economic analyses, model settings, RM and cost-effectiveness analysis (CEA) outcomes were identified. Secondly, variation in the characteristics of the constraints such as types and nature of constraints and sources of data for the constraints were identified. Thirdly, it was found that including the effects of constraints caused the CEA results to change in these articles. CONCLUSION: The review found that DES proved to be an effective technique for RM but there were only a small number of studies applied in HTA. However, these studies showed the important consequences of modelling physical constraints and point to the need for a framework to be developed to guide future applications of this approach. PMID- 28674846 TI - Reporting and Analysis of Trial-Based Cost-Effectiveness Evaluations in Obstetrics and Gynaecology. AB - BACKGROUND AND OBJECTIVES: The aim was to systematically review whether the reporting and analysis of trial-based cost-effectiveness evaluations in the field of obstetrics and gynaecology comply with guidelines and recommendations, and whether this has improved over time. DATA SOURCES AND SELECTION CRITERIA: A literature search was performed in MEDLINE, the NHS Economic Evaluation Database (NHS EED) and the Health Technology Assessment (HTA) database to identify trial based cost-effectiveness evaluations in obstetrics and gynaecology published between January 1, 2000 and May 16, 2017. Studies performed in middle- and low income countries and studies related to prevention, midwifery, and reproduction were excluded. DATA COLLECTION AND ANALYSIS: Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) statement (a modified version with 21 items, as we focused on trial-based cost effectiveness evaluations) and the statistical quality was assessed using a literature-based list of criteria (8 items). Exploratory regression analyses were performed to assess the association between reporting and statistical quality scores and publication year. RESULTS: The electronic search resulted in 5482 potentially eligible studies. Forty-five studies fulfilled the inclusion criteria, 22 in obstetrics and 23 in gynaecology. Twenty-seven (60%) studies did not adhere to 50% (n = 10) or more of the reporting quality items and 32 studies (71%) did not meet 50% (n = 4) or more of the statistical quality items. As for the statistical quality, no study used the appropriate method to assess cost differences, no advanced methods were used to deal with missing data, and clustering of data was ignored in all studies. No significant improvements over time were found in reporting or statistical quality in gynaecology, whereas in obstetrics a significant improvement in reporting and statistical quality was found over time. LIMITATIONS: The focus of this review was on trial-based cost effectiveness evaluations in obstetrics and gynaecology, so further research is needed to explore whether results from this review are generalizable to other medical disciplines. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The reporting and analysis of trial-based cost-effectiveness evaluations in gynaecology and obstetrics is generally poor. Since this can result in biased results, incorrect conclusions, and inappropriate healthcare decisions, there is an urgent need for improvement in the methods of cost-effectiveness evaluations in this field. PMID- 28674847 TI - A new integrated dual time-point amyloid PET/MRI data analysis method. AB - PURPOSE: In the initial evaluation of patients with suspected dementia and Alzheimer's disease, there is no consensus on how to perform semiquantification of amyloid in such a way that it: (1) facilitates visual qualitative interpretation, (2) takes the kinetic behaviour of the tracer into consideration particularly with regard to at least partially correcting for blood flow dependence, (3) analyses the amyloid load based on accurate parcellation of cortical and subcortical areas, (4) includes partial volume effect correction (PVEC), (5) includes MRI-derived topographical indexes, (6) enables application to PET/MRI images and PET/CT images with separately acquired MR images, and (7) allows automation. METHODS: A method with all of these characteristics was retrospectively tested in 86 subjects who underwent amyloid (18F-florbetaben) PET/MRI in a clinical setting (using images acquired 90-110 min after injection, 53 were classified visually as amyloid-negative and 33 as amyloid-positive). Early images after tracer administration were acquired between 0 and 10 min after injection, and later images were acquired between 90 and 110 min after injection. PVEC of the PET data was carried out using the geometric transfer matrix method. Parametric images and some regional output parameters, including two innovative "dual time-point" indexes, were obtained. RESULTS: Subjects classified visually as amyloid-positive showed a sparse tracer uptake in the primary sensory, motor and visual areas in accordance with the isocortical stage of the topographic distribution of the amyloid plaque (Braak stages V/VI). In patients classified visually as amyloid-negative, the method revealed detectable levels of tracer uptake in the basal portions of the frontal and temporal lobes, areas that are known to be sites of early deposition of amyloid plaques that probably represented early accumulation (Braak stage A) that is typical of normal ageing. There was a strong correlation between age and the indexes of the new dual time point amyloid imaging method in amyloid-negative patients. CONCLUSIONS: The method can be considered a valuable tool in both routine clinical practice and in the research setting as it will standardize data regarding amyloid deposition. It could potentially also be used to identify early amyloid plaque deposition in younger subjects in whom treatment could theoretically be more effective. PMID- 28674848 TI - Epidemiology of extended-spectrum beta-lactamase-producing Enterobacteriaceae in an intensive care unit with no single rooms. AB - BACKGROUND: The transmission of extended-spectrum beta-lactamase-producing enterobacteriaceae (ESBL) is prevented by additional contact precautions, mainly relying on isolation in a single room and hand hygiene. Contact isolation cannot be achieved in our 12-bed ICU, which has only double rooms. We report the epidemiology of ESBL imported, acquired and transmitted in an ICU with no single rooms. METHODS: We prospectively conducted an observational and non interventional study in a French 12-bed ICU. Inclusion criteria were patients >18 years of age treated by at least two successive nursing teams. Patient characteristics at admission and clinical data during hospital stay were collected prospectively. ESBL carriage was monitored using rectal swabs collected at admission and once weekly during the ICU stay. Potential cross-transmission was studied (1) by identifying index patients defined as possible ESBL sources for transmission, (2) by classifying each ESBL strain according to the cefotaximase Munchen (CTXM) 1 and 9 groups and (3) by gene sequencing for remaining cases of possible transmission. RESULTS: From June 2014 to April 2015, of 550 patients admitted to the ICU, 470 met the inclusion criteria and 221 had at least two rectal swabs. The rate of ESBL colonization, mainly by Escherichia coli, at admission was 13.2%. The incidence of ESBL acquisition, mainly with E. coli too, was 4.1%. Mortality did not differ between ESBL carriers and non carriers. In univariate analysis, ESBL acquisition was associated with male gender, SAPS II, SOFA, chronic kidney disease at admission, duration of mechanical ventilation, need for catecholamine and the ICU LOS. In multivariate analysis, SAPS II at admission was the only risk factor for ESBL acquisition. We confirmed cross-transmission, emanating from the same index patient, in two of the nine patients with ESBL acquisition (0.8%, 2/221). No case of cross transmission in the same double room was observed. DISCUSSION AND CONCLUSION: Prevalence of ESBL colonization in our ICU was 13.2%. Despite the absence single rooms, the incidence of ESBL acquisition was 4.1% and cross-transmission was proven in only two cases, resulting from the same index patient who was not hospitalized in the same double room. PMID- 28674849 TI - Metagenome-derived haloalkane dehalogenases with novel catalytic properties. AB - Haloalkane dehalogenases (HLDs) are environmentally relevant enzymes cleaving a carbon-halogen bond in a wide range of halogenated pollutants. PCR with degenerate primers and genome-walking was used for the retrieval of four HLD encoding genes from groundwater-derived environmental DNA. Using specific primers and the environmental DNA as a template, we succeeded in generating additional amplicons, resulting altogether in three clusters of sequences with each cluster comprising 8-13 closely related putative HLD-encoding genes. A phylogenetic analysis of the translated genes revealed that three HLDs are members of the HLD I subfamily, whereas one gene encodes an enzyme from the subfamily HLD-II. Two metagenome-derived HLDs, eHLD-B and eHLD-C, each from a different subfamily, were heterologously produced in active form, purified and characterized in terms of their thermostability, pH and temperature optimum, quaternary structure, substrate specificity towards 30 halogenated compounds, and enantioselectivity. eHLD-B and eHLD-C showed striking differences in their activities, substrate preferences, and tolerance to temperature. Profound differences were also determined in the enantiopreference and enantioselectivity of these enzymes towards selected substrates. Comparing our data with those of known HLDs revealed that eHLD-C exhibits a unique combination of high thermostability, high activity, and an unusually broad pH optimum, which covers the entire range of pH 5.5-8.9. Moreover, a so far unreported high thermostability for HLDs was determined for this enzyme at pH values lower than 6.0. Thus, eHLD-C represents an attractive and novel biocatalyst for biotechnological applications. PMID- 28674850 TI - Enhanced mannitol biosynthesis by the fruit origin strain Fructobacillus tropaeoli CRL 2034. AB - Mannitol is a natural low-calorie sugar alcohol produced by certain (micro)organisms applicable in foods for diabetics due to its zero glycemic index. In this work, we evaluated mannitol production and yield by the fruit origin strain Fructobacillus tropaeoli CRL 2034 using response surface methodology with central composite design (CCD) as optimization strategy. The effect of the total saccharide (glucose + fructose, 1:2) content (TSC) in the medium (75, 100, 150, 200, and 225 g/l) and stirring (S; 50, 100, 200, 300 and 350 rpm) on mannitol production and yield by this strain was evaluated by using a 22 full-factorial CCD with 4 axial points (alpha = 1.5) and four replications of the center point, leading to 12 random experimental runs. Fermentations were carried out at 30 degrees C and pH 5.0 for 24 h. Minitab-15 software was used for experimental design and data analyses. The multiple response prediction analysis established 165 g/l of TSC and 200 rpm of S as optimal culture conditions to reach 85.03 g/l [95% CI (78.68, 91.39)] of mannitol and a yield of 82.02% [95% CI (71.98, 92.06)]. Finally, a validation experiment was conducted at the predicted optimum levels. The results obtained were 81.91 g/l of mannitol with a yield of 77.47% in outstanding agreement with the expected values. The mannitol 2-dehydrogenase enzyme activity was determined with 4.6-4.9 U/mg as the highest value found. To conclude, F. tropaeoli CRL 2034 produced high amounts of high-quality mannitol from fructose, being an excellent candidate for this polyol production. PMID- 28674851 TI - Screening and transcriptomic analysis of Crypthecodinium cohnii mutants with high growth and lipid content using the acetyl-CoA carboxylase inhibitor sethoxydim. AB - The heterotrophic microalga Crypthecodinium cohnii is well known for its lipid accumulation, with a high proportion of docosahexaenoic acid (DHA). In this study, we report a novel screening approach to obtain mutants of C. cohnii with high growth and lipid content using the acetyl-CoA carboxylase (ACCase) inhibitor sethoxydim. C. cohnii mutants were generated using atmospheric and room temperature plasma (ARTP) and then screened for two rounds in media supplemented with sethoxydim. These efforts led to the identification of mutant M-1-2, which had 24.32% higher growth and 7.05% higher lipid content than the wild type, demonstrating the effectiveness of the sethoxydim-based screening. Consistently, the M-1-2 mutant displayed a 16.15% increase in ACCase enzymatic activity and 1.53-fold upregulation of its ACCase-encoding gene based on comparative ACCase activity analysis and transcriptomic analysis, respectively. In addition, transcriptomic analysis showed that transcripts involved in fatty acid biosynthesis, energy, central carbohydrate, and amino acid metabolism were upregulated in the mutant compared to the wild type. PMID- 28674852 TI - Effects of long-term treatment with haloperidol, clozapine and aripiprazole on mice isolated vas deferens. AB - PURPOSE: Sexual dysfunction is a common condition in patients taking antipsychotics and is the most bothersome symptom and adverse drug effect, resulting in a negative effect on treatment compliance. Pharmacology research into human ejeculatory disorders is limited to clinical studies with registered drugs affecting the ejaculation process; therefore, animal research has become the need. We aimed to investigate the effects of haloperidol, clozapine and aripiprazole on serotonin, noradrenaline, adenosine triphosphate (ATP) and potassium chloride (KCl)-induced contractions of the vas deferens in order to evaluate the effect of haloperidol, clozapine and aripiprazole on the contraction of the vas deferens. METHODS: Male inbred BALB/c ByJ mice aged 7 weeks upon arrival to the laboratory were used in this study. Haloperidol, clozapine, aripiprazole, serotonin, noradrenaline, ATP and KCl were dissolved in 0.9% physiological saline. The mice were randomly divided into experimental groups as follows: saline; haloperidol 0.125 mg/kg; haloperidol 0.25 mg/kg; clozapine 1.25 mg/kg; clozapine 2.5 mg/kg; aripiprazole 3 mg/kg; aripiprazole 6 mg/kg. Mice were treated by ip injection of drugs during 21 days. Mice receiving only the vehicle ip (0.9% saline) during 21 days served as control group (n = 7). Each experimental group consisted of 7 mice. After 21 days of treatment, epididymal and prostatic portions of vas deferens were surgically dissected free and immersed in 20-mL organ baths containing Krebs' solution. The effects of chronic treatment with haloperidol (0.125 and 0.25 mg/kg), clozapine(1.25 and 2.5 mg/kg) and aripiprazole (3 and 6 mg/kg) were investigated on serotonin [10 (-8) to 10 ( 4) M], noradrenaline [10 (-8) to 10 (-4) M], ATP [10 (-8) to 10 (-4) M] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of mice isolated vas deferens strips. Statistical comparison between the groups was performed using ANOVA supported by Dunnett's post hoc test. RESULTS: Serotonin induced contractile responses were significantly increased in the epididymal and prostatic portions of the vas deferens obtained from the haloperidol-treated group and clozapine-treated group. However, aripiprazole treatment had no effect on serotonin responses in both epididymal and prostatic portions of mice vas deferens. On the other hand, haloperidol and clozapine treatments significantly inhibited both noradrenaline and ATP-induced contractions of the prostatic and epididymal portions of the mice vas deferens, but had no effect on KCl-induced contractions of the vas deferens in both portions. There were no significant differences in KCl-induced contractile responses among the groups. CONCLUSIONS: These results revealed that induced contractions of vas deferens were affected after chronic treatment with haloperidol and clozapine but not aripiprazole. Serotonergic, noradrenergic and purinergic receptors may, at least in part, contribute to changes in vas deferens contractions in mice with chronic treatment of haloperidol and clozapine but not aripiprazole. PMID- 28674853 TI - FDG-PET/CT for response evaluation of invasive bladder cancer following neoadjuvant chemotherapy. AB - PURPOSE: We investigated the accuracy of FDG-PET/CT response identification following neoadjuvant or induction chemotherapy (NAIC) for invasive bladder cancer (BC) as to better select patients for radical cystectomy (RC). METHODS: Between 2010 and 2014, 37 cT1-4N1-3 BC patients received a FDG-PET/CT before and after NAIC followed by RC. Metabolic lymph node (LN) response was evaluated according to EORTC recommendations. Additionally, primary tumor response was evaluated for 23 patients by means of delayed pelvic imaging after forced diuresis. Gold standard was response on pathologic analysis of RC specimens. Response was defined as partial response (pPR, any pathologic downstaging) or complete response (pCR, 0.05). Mean IOP levels were significantly lower in the treatment groups than in the control group at postoperative hours 6 and 24 and days 3 and 5 (p < 0.001). Administration of one drop of FCBT or FCBZT demonstrated similar effects on preventing IOP spikes within 24 h of phacoemulsification cataract surgery. FCBZT more effectively lowered IOP than FCBT at days 3 and 5 (p < 0.05). CONCLUSIONS: We demonstrate that the postoperative administration of FCBT or FCBZT is effective in lowering IOP after phacoemulsification cataract surgery; FCBZT more effectively lowered IOP than FCBT at postoperative days 3 and 5. PMID- 28674857 TI - An uncommon case of intermittent Pourfour du Petit Syndrome associated with acute angle-closure glaucoma successfully treated by laser iridotomy. AB - PURPOSE: To describe a case of acute angle-closure glaucoma secondary to intermittent mydriasis related to Pourfour du Petit Syndrome caused by tracheal deviation. MATERIALS AND METHODS: A 70-year-old Caucasian woman visited the Emergency Room of the University Eye Clinic complaining of blurring of vision and difficulty to move superior eyelid in her right eye. Examination revealed reactive mydriasis, and upper lid retraction on the right side. The rest of the ophthalmological examination was normal, and a cranial computed tomography (CT) did not identify any abnormalities. A cervical CT showed the presence of an accentuated lateral right convex deviation of the trachea, attributable to a fibrothorax. A right Pourfour du Petit syndrome was suspected. Although the mydriasis had in the meantime vanished, the patient was admitted to the Neurological Clinic. RESULTS: Five days later she suffered acute pain in her right eye. Ophthalmological examination of the right eye revealed conjunctival hyperemia, marked corneal edema, reduced depth of anterior chamber, permanent mydriasis. As assessed by Goldmann applanation tonometry, intraocular pressure (IOP) was 48 mm Hg. Fundus examination was normal in both eyes. Gonioscopy revealed angle closure in all quadrants. Slit lamp examination of the contralateral eye was normal; IOP was 10 mm Hg. After hypotensive medical therapy, iridotomy with YAG laser was performed. Thereafter, IOP stabilized at 12 mm Hg. CONCLUSIONS: This is the first report in the literature of a case of acute angle-closure glaucoma secondary to mydriasis related to Pourfour du Petit Syndrome caused by tracheal deviation. PMID- 28674858 TI - Self-made cryopreservative fibrin glue applied in pterygium surgery: a novel practical technique. AB - PURPOSE: To introduce a novel practical technique of self-made cryopreservative fibrin glue (SMC) applied in pterygium surgery and to assess its safety and efficacy. METHODS: Forty-eight eyes of 48 patients with nasal primary pterygium were enrolled. The patients were equally assigned to 6 groups. Self-made fibrin glue was subpackaged and, respectively, cryopreserved for 3, 7, 15 days and 1, 2 and 3 months. At each time point, the asepsis of SMC was confirmed by bacterial culture and colony counting. In each group, corresponding SMC was applied to fix the autograft after the pterygium was removed (e.g., SMC 3d for group 1 and SMC 3m for group 6). All the patients were followed up postoperatively on days 1, 3, 7 and 14 and then at months 1, 3, 6. The main outcome measures included fixation success rate within two tries, postoperative discomfort, recurrence rate and complications. RESULTS: No colony growth was observed in all the fibrinogen and thrombin tubes sent. Five patients needed a second try with respective SMC during the autograft fixation, and there were no significant differences in SMC use times among the groups (P = 0.885). There were no significant differences in postoperative discomfort (day 1, 3, 7; P = 0.651, P = 0.269, P = 0.180, respectively) among the groups. By the end of 6-m follow-up, no infections and severe complications were observed in any group. The total recurrence rate was 3/48 (6%), and there were no significant differences in recurrences among the groups (P = 1.000). CONCLUSION: SMC is safe and effective for autograft fixation in pterygium surgery. This new practical technique will benefit the patients and surgeons in developing and underdeveloped country. PMID- 28674859 TI - Comparison of central corneal thickness and endothelial cell measurements by Scheimpflug camera system and two noncontact specular microscopes. AB - PURPOSE: To investigate the correlation of Scheimpflug camera system and two noncontact specular microscopes in terms of central corneal thickness (CCT) and corneal endothelial cell morphology measurements. METHODS: One hundred eyes of 50 healthy subjects were examined by Pentacam Scheimpflug Analyzer, CEM-530 (Nidek Co, Ltd, Gamagori, Japan) and CellChek XL (Konan Medical, California, USA) via fully automated image analysis with no corrections made. Measurement differences and agreement between instruments were determined by intraclass correlation analysis. RESULTS: The mean age of the subjects was 36.74 +/- 8.59 (range 22-57). CCTs were well correlated among all devices, with having CEM-530 the thinnest and CellChek XL the thickest measurements (intraclass correlation coefficient (ICC) = 0.83; p < 0.001 and ICC = 0.78; p < 0.001, respectively). Mean endothelial cell density (ECD) given by CEM-530 was lower than CellChek XL (2613.17 +/- 228.62 and 2862.72 +/- 170.42 cells/mm2, respectively; ICC = 0.43; p < 0.001). Mean value for coefficient of variation (CV) was 28.57 +/- 3.61 in CEM-530 and 30.30 +/- 3.53 in CellChek XL. Cell hexagonality (HEX) with CEM-530 was higher than with CellChek XL (68.70 +/- 4.16% and 45.19 +/- 6.58%, respectively). CONCLUSIONS: ECDs with CellChek XL and CEM-530 have good correlation, but the values obtained by CellChek XL are higher than CEM-530. Measurements for HEX and CV differ significantly and show weak correlation. Thus, we do not recommend interchangeable use of CellChek XL and CEM-530. In terms of CCTs, Pentacam, CEM 530 and CellChek XL specular microscopy instruments are reliable devices. PMID- 28674861 TI - The muddle of medicalization: pathologizing or medicalizing? AB - Medicalization appears to be an issue that is both ubiquitous and unquestionably problematic as it seems to signal at once a social and existential threat. This perception of medicalization, however, is nothing new. Since the first main writings in the 1960s and 1970s, it has consistently been used to describe inappropriate or abusive instances of medical authority. Yet, while this standard approach claims that medicalization is a growing problem, it assumes that there is simply one "medical model" and that the expanding realm of "the medical" can be more or less clearly delineated. Moreover, while intended to establish the reality of this growing threat, this research often requires making arbitrary or unjustified distinctions between different practices. To better clarify the concept of medicalization, I will focus more on capturing the variety of medical practices than on the sociological aspects of medical discourse. In doing so, I will explore the distinction between medicalization and pathologization, a distinction that is often overlooked and that brings with it many conceptual and practical implications. After defining these terms, I will use some examples to show that while pathologizing is closely tied to medicalizing, both can occur independently. I will then further develop this distinction in terms of the different individual and social effects of these practices. PMID- 28674862 TI - Recent approaches for asymmetric synthesis of alpha-amino acids via homologation of Ni(II) complexes. AB - This review article critically discusses examples of asymmetric synthesis of tailor-made alpha-amino acids via homologation of Ni(II) complexes of glycine and alanine Schiff bases, reported in the literature from 2013 through the end of 2016. Where it is possible, reaction mechanism and origin of the stereochemical outcome is discussed in detail. Special attention is given to various aspects of practicality and scalability of the reported methods. Among the most noticeable developments in this area are novel designs of axially chiral ligands, application of electro- and mechano-chemical (ball-milling) conditions, and development of dynamic kinetic resolution procedures. PMID- 28674863 TI - Complete genome analysis of highly pathogenic bovine ephemeral fever virus isolated in Turkey in 2012. AB - Relatively high prevalence and mortality rates of bovine ephemeral fever (BEF) have been reported in recent epidemics in some countries, including Turkey, when compared with previous outbreaks. A limited number of complete genome sequences of BEF virus (BEFV) are available in the GenBank Database. In this study, the complete genome of highly pathogenic BEFV isolated during an outbreak in Turkey in 2012 was analyzed for genetic characterization. The complete genome of the Turkish BEFV isolate was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and sequenced. It was found that the complete genome of the Turkish BEFV isolate was 14,901 nt in length. The complete genome sequence obtained from the study showed 91-92% identity at nucleotide level to Australian (BB7721) and Chinese (Bovine/China/Henan1/2012) BEFV isolates. Phylogenetic analysis of the glycoprotein gene of the Turkish BEFV isolate also showed that Turkish isolates were closely related to Israeli isolates. Because of the limited number of complete BEFV genome sequences, the results from this study will be useful for understanding the global molecular epidemiology and geodynamics of BEF. PMID- 28674860 TI - Adjuvant radiochemotherapy in locally advanced gastric cancer : Treatment results and analysis of possible prognostic factors. AB - BACKGROUND: The aim of this study was to report the clinical outcome and toxicity of radiochemotherapy in locally advanced gastric cancer (LAGC) patients treated according to the Intergroup 116 trial protocol in our institution. METHODS: We retrospectively reviewed 105 patients with LAGC treated with radical surgery and adjuvant radiochemotherapy. We analyzed overall survival (OS), disease-free survival (DFS), locoregional failure-free survival (LFS), prognostic factors and toxicity. RESULTS: The mean follow-up was 96.48 months. The majority of tumors were T3-T4 (75%) and 86.6% had nodal metastases. The OS, DFS and LFS rates to 3 years were 53.48%, 52.75% and 81.65%, respectively and to 5 years 40%, 46.73% and 76.77% respectively. The univariate analysis showed that N stage < N2, TN stage < IIIA, R0 resection and N-ratio < 3 were statistically significant prognostic factors for OS and DFS, T stage < T4 for OS and N-ratio < 3 for LFS. The group with D2 lymphadenectomy had worse LFS than the D1 group (65.2% vs 88.1%, respectively, p = 0.039) probably due to a significant difference in the proportion node positive patients in the D2 group (94% vs. 78%; p = 0.027). In the multivariate analysis, only R0 resection was statistically significant factor for improved OS (p = 0.018). Acute grade III-IV gastrointestinal and hematologic toxicity rates were 8.5% and 15.2%, respectively and 89.5% completed treatment as planned. CONCLUSION: Our results are consistent with those of the Intergroup-0116 trial for LAGC in terms of survival. This regimen is well tolerated and with acceptable toxicity. An R0 resection was an independent prognostic factor for improved OS. PMID- 28674864 TI - Phylogenetic analysis of H9N2 avian influenza viruses in Afghanistan (2016-2017). AB - Avian influenza A virus (AIV) subtype H9N2 is the most prevalent subtype found in terrestrial poultry throughout Eurasia and has been isolated from poultry outbreaks worldwide. Tracheal tissue specimens from 100 commercial broiler flocks in Afghanistan were collected between 2016 and 2017. After real-time RT-PCR, AI positive samples were further characterized. A part of the HA gene was amplified using RT-PCR and sequenced. The results of real-time RT-PCR showed that 40 percent of the flocks were AI positive. Phylogenetic studies showed that these H9N2 AIVs grouped within the Eurasian-lineage G1 AIVs and had a correlation with H9N2 AIV circulating in the poultry population of the neighboring countries over the past decade. Analysis of the amino acid sequence of HA revealed that the detected H9N2 viruses possessed molecular profiles suggestive of low pathogenicity and specificity for the avian-like SAalpha2,3 receptor, demonstrating their specificity for and adaptation to domestic poultry. The results of the current study provide great insights into H9N2 viruses circulating in Afghanistan's poultry industry and demonstrate the necessity of planning an applied policy aimed at controlling and managing H9N2 infection in Afghan poultry. PMID- 28674865 TI - Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia. AB - PURPOSE: To report the use of intranasal dexmedetomidine, an alpha2-adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. METHODS: Case series. RESULTS: Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43 year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. CONCLUSIONS: Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population. PMID- 28674866 TI - Differential diagnosis of suspected neurogenic orthostatic hypotension in a patient with Parkinson disease. PMID- 28674867 TI - Adding droxidopa to fludrocortisone or midodrine in a patient with neurogenic orthostatic hypotension and Parkinson disease. PMID- 28674868 TI - Polypharmacy: droxidopa to treat neurogenic orthostatic hypotension in a patient with Parkinson disease and type 2 diabetes mellitus. PMID- 28674869 TI - Muscle sympathetic nerve activity peaks in the first trimester in healthy pregnancy: a longitudinal case study. AB - OBJECTIVE AND METHODS: Muscle sympathetic nerve activity and baroreflex sensitivity were examined at rest before, during (weeks 6, 11, 17, 22, 25, 33 and 36) and after a normotensive pregnancy. RESULTS: Muscle sympathetic nerve activity is elevated during pregnancy with a large peak in the first trimester (Delta17 bursts/min) and a secondary peak in the third trimester (Delta11 bursts/min). Cardiac baroreflex sensitivity peaked in the first trimester (10 vs. 6 ms/mmHg pre-pregnancy), whereas sympathetic baroreflex sensitivity was greater throughout. INTERPRETATION: The increase in sympathetic outflow early in pregnancy cannot be explained by a reduction in baroreflex sensitivity, while the secondary increase in burst frequency in the third trimester may, in part, be explained by the elevated heart rate. PMID- 28674870 TI - Heart-rate response to alpha2-adrenergic receptor antagonism by antipsychotics. AB - PURPOSE: To explore the relationship between antipsychotic-associated antagonism of alpha2-adrenergic receptors and resting heart rate in individuals with schizophrenia. METHODS: Thirty-one inpatients treated with antipsychotics were included in this exploratory analysis. Antipsychotic doses were converted to haloperidol equivalents for alpha2-adrenergic receptor antagonism. Resting heart rate was measured with the patient in the seated upright posture. RESULTS: After controlling for confounding variables, the relationship between alpha2-adrenergic receptor antagonism and resting heart rate demonstrated a positive linear effect (P = 0.002) as well as a nonlinear effect that accounted for an additional 14% of the variability in resting heart rate (P = 0.005). CONCLUSION: The observed inverted-U relationship between alpha2-adrenergic receptor antagonism and resting heart rate can possibly be attributed to an altered response of beta1-adrenergic receptors to increased norepinephrine release. Further investigations are required to confirm this exploratory finding, taking into account additional variables that include other receptors which either directly or indirectly influence heart rate. CLINICALTRIALS. GOV IDENTIFIER: NCT01392885. PMID- 28674871 TI - Real-life use of Rivaroxaban in the Netherlands: data from the Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation (XANTUS) registry. AB - BACKGROUND: The Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation (XANTUS) registry investigated the safety and efficacy of the factor Xa inhibitor rivaroxaban. We studied the Dutch XANTUS cohort to a ssess drug safety and prescription patterns in the Netherlands. METHODS: The XANTUS registry was designed as a European prospective, observational study among patients with non-valvular atrial fibrillation. Major bleeding and all-cause mortality were assessed every three months during a 1-year follow-up period. In this Dutch sub cohort we were also specifically interested in dosing regimens and the incidence and reasons for temporary or permanent discontinuation. RESULTS: Patients (n = 899) had a mean age of 69 (SD +/- 9) years and 64.8% were male. The median CHA2DS2-VASc score was 2 (IQR 2-4) and the median HAS-BLED score was 2 (IQR 1-2). Major bleeding occurred in 19 patients (2.4 per 100 patient-years) and 8 patients (1.0 per 100 patient-years) died during the 1-year follow-up period. According to renal function, label-discordant dosing was observed in 48 (8.3%) patients. Finally, 124 patients (13.8%) reported a temporary interruption of rivaroxaban treatment and 11.8% switched to another oral anticoagulant therapy after permanent discontinuation of rivaroxaban. CONCLUSION: In the Dutch subset of the XANTUS registry, we observed low rates of major bleeding and label-discordant dosing and high persistence rates during one year of follow-up in patients receiving rivaroxaban in routine clinical practice. However, documenting the motivation of novel oral anticoagulant (NOAC) type and dose is essential to study label-discordant prescription, a potential safety paradox and identify patient characteristics to optimise NOAC use and adherence. PMID- 28674872 TI - Efficacy of wearing compression garments during post-exercise period after two repeated bouts of strenuous exercise: a randomized crossover design in healthy, active males. AB - BACKGROUND: The efficacy of wearing [a] compression garment (CG) between repeated bouts of exercise within a same day has not been fully understood. The present study determined the effect of wearing a CG after strenuous exercise sessions (consisting of sprint exercise, resistance exercise, drop jump) twice a day on exercise performance, muscle damage, and inflammatory responses. METHODS: Eleven physically active males (age, 22.7 +/- 0.9 years; height, 175.7 +/- 6.7 cm; body mass, 73.6 +/- 10.2 kg; BMI, 23.8 +/- 2.7 kg/m2) performed two trials (a randomized crossover design), consisting of the trial with either wearing a whole body CG during post-exercise period (CG trial) or the trial with wearing a normal garment without specific pressure (CON trial). Two exercise sessions were conducted in the morning (09:00-10:00, Ex1) and afternoon (14:00-15:00, Ex2). Immediately after completing 60 min of each exercise, the subjects in the CG trial changed into a whole-body CG. Time-course changes in exercise performance (bench press power, jump performances, repeated sprint ability), blood variables (lactate, glucose, myoglobin, creatine kinase, interleukin-6, leptin), and scores of subjective feeling (fatigue, muscle soreness) were compared between the CG and CON trials before Ex1 (8:40), immediately before Ex2 (14:00, 4 h after Ex1), 4 h after Ex2 (19:00), and 24 h after the onset of Ex1 (9:00). RESULTS: Two bouts of exercise significantly decreased performances of counter movement jump (main effect for time: P = 0.04, F = 3.75, partial eta 2 = 0.27) and rebound jump (main effect for time: P = 0.00, F = 12.22, partial eta 2 = 0.55), while no significant difference was observed between the two trials (interaction: P = 0.10, F = 1.96, partial eta 2 = 0.16 for counter movement jump, P = 0.93, F = 0.01, partial eta 2 = 0.001 for rebound jump). Repeated sprint ability (power output during 10 * 6 s maximal sprint, 30-s rest periods between sprints) did not differ significantly between the two trials at any time points. Power output during bench press exercise was not significantly different between the two trials (interaction: P = 0.46, F = 0.99, partial eta 2 = 0.09 for Ex1, P = 0.74, F = 0.38, partial eta 2 = 0.04 for Ex2, P = 0.22, F = 1.54, partial eta 2 = 0.13 for 24 h after the onset of Ex1). Serum myoglobin, creatine kinase, leptin, and plasma interleukin-6 were not significantly different between the two trials (interaction: P = 0.16, F = 2.23, partial eta 2 = 0.18 for myoglobin; P = 0.39, F = 0.81, partial eta 2 = 0.08 for creatine kinase; P = 0.28, F = 1.30, partial eta 2 = 0.13 for leptin; P = 0.34, F = 1.05, partial eta 2 = 0.12 for interleukin-6). Muscle soreness at 24 h during post-exercise period was significantly lower in the CG trial than in the CON trial for pectoralis major muscle (P = 0.04), while the value was inversely lower in the CON trial for hamstring (P = 0.047). CONCLUSIONS: Wearing a whole body CG during the post-exercise period after two bouts of strenuous exercise sessions separated with 4 h of rest did not promote recovery of muscle function for lower limb muscles nor did it attenuate exercise-induced muscle damage in physically active males. PMID- 28674873 TI - Direct Assessment of Plasma/Serum Sample Quality for Proteomics Biomarker Investigation. AB - Blood proteome analysis for biomarker discovery represents one of the most challenging tasks to be achieved through clinical proteomics due to the sample complexity, such as the extreme heterogeneity of proteins in very dynamic concentrations, and to the observation of proper sampling and storage conditions. Quantitative and qualitative proteomics profiling of plasma and serum could be useful both for the early detection of diseases and for the evaluation of pathological status. Two main sources of variability can affect the precision and accuracy of the quantitative experiments designed for biomarker discovery and validation. These sources are divided into two categories, pre-analytical and analytical, and are often ignored; however, they can contribute to consistent errors and misunderstanding in biomarker research. In this chapter, we review critical pre-analytical and analytical variables that can influence quantitative proteomics. According to guidelines accepted by proteomics community, we propose some recommendations and strategies for a proper proteomics analysis addressed to biomarker studies. PMID- 28674874 TI - A Protocol for the Preparation of Cryoprecipitate and Cryo-depleted Plasma for Proteomic Studies. AB - Cryoprecipitate is a concentrate of high-molecular-weight plasma proteins that precipitate when frozen plasma is slowly thawed at 1-6 degrees C. The concentrate contains factor VIII (antihemophilic factor), von Willebrand factor (vWF), fibrinogen, factor XIII, fibronectin, and small amounts of other plasma proteins. Clinical grade preparations of cryoprecipitate are mainly used to treat fibrinogen deficiency caused by acute bleeding or functional abnormalities of the fibrinogen protein. In the past, cryoprecipitate was used to treat von Willebrand disease and hemophilia A (factor VIII deficiency), but the availability of more highly purified coagulation factor concentrates or recombinant protein preparations has superseded the use of cryoprecipitate for these coagulopathies. Cryo-depleted plasma ("cryosupernatant") is the plasma supernatant remaining following removal of the cryoprecipitate from frozen-thawed plasma. It contains all the other plasma proteins and clotting factors present in plasma that remain soluble during cold-temperature thawing of the plasma. This protocol describes the clinical-scale preparation of cryoprecipitate and cryo-depleted plasma for proteomic studies. PMID- 28674875 TI - Preparation of Platelet Concentrates for Research and Transfusion Purposes. AB - Platelets are specialized cellular elements of the blood that play central roles in physiologic and pathologic processes of hemostasis, wound healing, host defense, thrombosis, inflammation, and tumor metastasis. Activation of platelets is crucial for platelet function that includes a complex interplay of adhesion, signaling molecules, and release of bioactive factors. Transfusion of platelet concentrates is an important treatment component for thrombocytopenia and bleeding. Recent progress in high-throughput mRNA and protein profiling techniques has advanced the understanding of platelet biological functions toward identifying novel platelet-expressed and secreted proteins, analyzing functional changes between normal and pathologic states, and determining the effects of processing and storage on platelet concentrates for transfusion. It is important to understand the different standard methods of platelet preparation and how they differ from the perspective for use as research samples in clinical chemistry. Two simple methods are described here for the preparation of research-scale platelet samples from whole blood, and detailed notes are provided about the methods used for the preparation of platelet concentrates for transfusion. PMID- 28674876 TI - Bead-Based and Multiplexed Immunoassays for Protein Profiling via Sequential Affinity Capture. AB - Antibody microarrays offer high-throughput immunoassays for multiplexed analyses of clinical samples. For such approaches, samples are either labeled in solution to enable a direct readout on the single binder assay format or detected by matched pairs of capture and detection antibodies in dual binder assay format, also known as sandwich assays. Aiming to benefit from the flexibility and capacity offered by single binder assay readout and the specificity and sensitivity of dual binder assays, we developed a multiplexed dual binder procedure that is based on a sequential, rather than combined, antigen binding. The method, entitled dual capture assay (DCA), is composed of an initial antigen capture by antibodies on beads, followed by labeling of captured protein targets on beads, combinatorial elution steps at high and low pH, and a readout using a secondary bead array. Compared to classical single binder assays, the described method demonstrated several advantages such as reduced contribution of off-target binding, lower noise levels, and improved correlation when comparing with clinical reference values. This procedure describes a novel and versatile immunoassay strategy for proteome profiling in body fluids. PMID- 28674877 TI - Affinity Proteomics for Fast, Sensitive, Quantitative Analysis of Proteins in Plasma. AB - The improving efficacy of many biological therapeutics and identification of low level biomarkers are driving the analytical proteomics community to deal with extremely high levels of sample complexity relative to their analytes. Many protein quantitation and biomarker validation procedures utilize an immunoaffinity enrichment step to purify the sample and maximize the sensitivity of the corresponding liquid chromatography tandem mass spectrometry measurements. In order to generate surrogate peptides with better mass spectrometric properties, protein enrichment is followed by a proteolytic cleavage step. This is often a time-consuming multistep process. Presented here is a workflow which enables rapid protein enrichment and proteolytic cleavage to be performed in a single, easy-to-use reactor. Using this strategy Klotho, a low-abundance biomarker found in plasma, can be accurately quantitated using a protocol that takes under 5 h from start to finish. PMID- 28674878 TI - Characterization of the Low-Molecular-Weight Human Plasma Peptidome. AB - The human plasma proteome represents an important secreted sub-proteome. Proteomic analysis of blood plasma with mass spectrometry is a challenging task. The high complexity and wide dynamic range of proteins as well as the presence of several proteins at very high concentrations complicate the profiling of the human plasma proteome. The peptidome (or low-molecular-weight fraction, LMF) of the human plasma proteome is an invaluable source of biological information, especially in the context of identifying plasma-based markers of disease. Peptides are generated by active synthesis and proteolytic processing, often yielding proteolytic fragments that mediate a variety of physiological and pathological functions. As such, degradomic studies, investigating cleavage products via peptidomics and top-down proteomics in particular, have warranted significant research interest. However, due to their molecular weight, abundance, and solubility, issues with identifying specific cleavage sites and coverage of peptide fragments remain challenging. Peptidomics is currently focused toward comprehensively studying peptides cleaved from precursor proteins by endogenous proteases. This protocol outlines a standardized rapid and reproducible procedure for peptidomic profiling of human plasma using centrifugal ultrafiltration and mass spectrometry. Ultrafiltration is a convective process that uses anisotropic semipermeable membranes to separate macromolecular species on the basis of size. We have optimized centrifugal ultrafiltration (cellulose triacetate membrane) for plasma fractionation with respect to buffer and solvent composition, centrifugal force, duration, and temperature to facilitate recovery >95% and enrichment of the human plasma peptidome. This method serves as a comprehensive and facile process to enrich and identify a key, underrepresented sub-proteome of human blood plasma. PMID- 28674879 TI - In-Depth, Reproducible Analysis of Human Plasma Using IgY 14 and SuperMix Immunodepletion. AB - Identification of cancer and other disease biomarkers in human plasma has been exceptionally challenging due to the complex nature of plasma and the presence of a moderate number of high- and medium-abundance proteins which mask low-abundance proteins of interest. As a result, immunoaffinity depletion formats combining multiple antibodies to target the most abundant plasma proteins have become the first stage in most plasma proteome discovery schemes. This protocol describes the use of tandem IgY 14 and SuperMix immunoaffinity depletion to reproducibly remove >99% of total plasma protein. This greatly increases the depth of analysis of human plasma proteomes. Depleted plasma samples can then be analyzed in a single high-resolution LC-MS/MS run on a Q Exactive Plus mass spectrometer, followed by label-free quantitation. If greater depth of analysis is desired, the depleted plasma can be further fractionated by separating the sample for a short distance on a 1D SDS gel and cutting the gel into uniform slices prior to trypsin digestion. Alternatively, the depleted plasma can be reduced, alkylated, and digested with trypsin followed by high-pH reversed-phase HPLC separation. PMID- 28674880 TI - Low-Molecular-Weight Plasma Proteome Analysis Using Top-Down Mass Spectrometry. AB - While human plasma has a wealth of diagnostic information regarding the state of the human body in heath and disease, low molecular weight (LMW) proteome (<30 kDa) has been shown to contain a rich source of diagnostic biomarkers. Here we describe a protocol for top-down proteomic analysis to identify and characterize the LMW proteoforms present in four types of human plasma samples without immunoaffinity depletion and with depletion of the top two, six, and seven high abundance proteins. Each type of plasma sample was first fractionated based on molecular weight using gel-eluted liquid fraction entrapment electrophoresis (GELFrEE). Then, the GELFrEE fractions containing up to 30 kDa were subjected to nanocapillary-LC-MS/MS, and the high-resolution MS and MS/MS data were processed using ProSightPC software. As a result, a total of 442 LMW proteins and cleaved products, including those with posttranslational modifications (PTMs) and single amino acid variations (SAAVs), were identified with a threshold E-value of 1 * 10 4 from the four types of plasma samples. PMID- 28674881 TI - Identification of Post-Translational Modifications from Serum/Plasma by Immunoaffinity Enrichment and LC-MS/MS Analysis Without Depletion of Abundant Proteins. AB - Immunoaffinity enrichment combined with LC-MS/MS enables identification of Post translational modifications (PTMs) from serum/plasma samples without abundant protein depletion. Here we described the workflow in details in identifying various types of PTMs such as lysine acetylation and arginine methylation from cancer serum. The method described is compatible with all common proteomic analysis platforms and quantitative methods. PMID- 28674882 TI - Identification of Core-Fucosylated Glycoproteome in Human Plasma. AB - The core-fucosylated (CF) glycoproteins are widely distributed in mammalian tissues and regulated under pathological conditions, especially in cancer progression. The Food and Drug Administration (FDA) has approved the core fucosylated alpha-fetoprotein as a biomarker for the early diagnosis of hepatocellular carcinoma (HCC). An approach for identifying CF glycoproteins has significantly practical value. Here we introduce a novel method for identification of CF glycoproteome in human plasma. The method integrates tandem glycopeptide enrichment, stepped fragmentation, and "glycan diagnostic ion"-based spectrum refinement. With this method, the productivity of identifying CF glycopeptides will be significantly improved. We anticipate that this method could be widely utilized to explore the CF glycoproteins and their regulation under physiological or pathological condition. PMID- 28674883 TI - Proteomic Analysis of Blood Extracellular Vesicles in Cardiovascular Disease by LC-MS/MS Analysis. AB - Extracellular vesicles are membrane vesicles related to cell communication. These vesicles consist of proteins, RNA, and microRNA and are an interesting and important tool to understand the processes taking place in the secreting cell, especially in diseases in which its release is often enhanced. The used of blood extracellular vesicles in cardiovascular disease as a low invasive, easily accessible source of circulating markers could give us important information related to pathological process even more with the use of proteomic analysis. In this chapter, we describe a protocol to isolate and proteomic analyze extracellular vesicles from blood associated with cardiovascular disease. PMID- 28674884 TI - Targeted Approach for Proteomic Analysis of a Hidden Membrane Protein. AB - Given the properties of plasma membrane proteins, namely, their hydrophobicity, low solubility, and high resistance to digestion and extraction, their identification by traditional mass spectrometry (MS) has been a challenging task. Hence, proteomic studies involving the transmembrane protein connexin43 (Cx43) are scarce. Additionally, studies demonstrating the presence of proteins embedded in the lipid bilayer of extracellular vesicles (EVs) are difficult to perform and require specific changes and fine adjustments in the experimental and technical procedure to allow their detection by MS. In this review, we provide a detailed description of the protocol we have used to detect Cx43 in EVs of human peripheral blood. This includes some of the modifications that we have introduced in order to improve the detection of Cx43 in EVs, including an optimization of vesicle isolation, Cx43 purification, MS acquisition data, and further analysis. PMID- 28674885 TI - Red Blood Cells in Clinical Proteomics. AB - Red blood cells (RBCs) are known for their role in oxygen and carbon dioxide transport. The main function of RBCs is directly linked to many diseases that cause low oxygen levels in tissues such as congenital heart disease in adults, chronic obstructive pulmonary disease, sleep apnea, sickle cell disease, etc. Red blood cells are a direct target for a number of parasitic diseases such as malaria (Plasmodium) and similar parasites of the phylum Apicomplexa (Toxoplasma, Theileria, Eimeria, Babesia, and Cryptosporidium). RBC membrane components, in particular, are suitable targets for the discovery of drugs against parasite interaction. There is also evidence that RBCs release growth and survival factors, thereby linking RBCs with cancer. RBCs are abundant and travel throughout the body; consequently changes in RBC proteome potentially reflect other diseases as well. This chapter describes erythrocyte isolation from blood and its fractionation into RBC membrane and soluble cytosolic fractions. Alternative procedures for mass spectrometry analysis of RBC membrane proteome will be presented. PMID- 28674886 TI - High-Throughput Quantitative Lipidomics Analysis of Nonesterified Fatty Acids in Plasma by LC-MS. AB - Nonesterified fatty acids are important biological molecules which have multiple functions such as energy storage, gene regulation, or cell signaling. Comprehensive profiling of nonesterified fatty acids in biofluids can facilitate studying and understanding their roles in biological systems. For these reasons, we have developed and validated a high-throughput, nontargeted lipidomics method coupling liquid chromatography to high-resolution mass spectrometry for quantitative analysis of nonesterified fatty acids. Sufficient chromatographic separation is achieved to separate positional isomers such as polyunsaturated and branched-chain species and quantify a wide range of nonesterified fatty acids in human plasma samples. However, this method is not limited only to these fatty acid species and offers the possibility to perform untargeted screening of additional nonesterified fatty acid species. PMID- 28674887 TI - Simultaneous Enrichment of Plasma Extracellular Vesicles and Glycoproteome for Studying Disease Biomarkers. AB - To detect disease at an early stage and to develop effective disease treatment therapies, reliable biomarkers of diagnosis, disease progression, and its status remain a research priority. A majority of disease pathologies are primarily associated with different subsets of cells of different tissues, discrete compartments, and areas. These subsets of cells release glycoproteins and specific extracellular vesicles (EVs) including microvesicles and exosomes that carry bioactive cargoes of proteins, nucleic acids, and metabolites. Body fluids like blood plasma are considered as a golden source of disease biomarkers since it contains glycoprotein and EVs released by almost all cell types. The contents of glycoproteome and EV cargo change with cell status, and they act as mirror of cell's intracellular events and status; hence, EVs and glycoproteins are promising disease biomarkers. However, their abundance in blood plasma remains low posing a serious technical problem in their identification and quantification. Until recently, technical advances and exhaustive research devised a technique for either enrichment of plasma glycoprotein or EVs, but no methodologies exist that can enrich and identify both plasma glycoprotein and EVs. To overcome this technical challenge, a method that can eliminate high abundance entities without depleting disease-modifying molecules is required. Therefore, here we describe the detailed protocol of simultaneous enrichment of glycoproteins and EVs from blood plasma by prolonged ultracentrifugation coupled to electrostatic repulsion-hydrophilic interaction chromatography (PUC-ERLIC) and their identification and quantification by mass spectrometry-based proteomic technique. PMID- 28674888 TI - Lipidomics of Human Blood Plasma by High-Resolution Shotgun Mass Spectrometry. AB - Clinical lipidomics is an emerging biomarker discovery approach that compares lipid profiles under pathologically and physiologically normal conditions. Here we describe a method for the absolute (molar) quantification of more than 200 molecules from 14 major lipid classes from 5 MUL of human blood plasma using high resolution top-down shotgun mass spectrometry. Because of its technical simplicity and robustness, the protocol lends itself for high-throughput clinical lipidomics screens. PMID- 28674889 TI - Proteomics Analysis of Circulating Serum Exosomes. AB - Proteomics characterization of biofluids, such as urine and plasma, has been explored for the discovery of predictive, prognostic, and mechanistic biomarkers of diseases and tissue injury. Here we describe comprehensive characterization of protein cargos from cell-derived secreted vesicles (extracellular vesicles or exosome) for biomarker discovery using the mass spectrometry-based technology. PMID- 28674890 TI - High-Density Serum/Plasma Reverse Phase Protein Arrays. AB - In-depth exploration and characterization of human serum and plasma proteomes is an attractive strategy for the identification of potential prognostic or diagnostic biomarkers. The possibility of analyzing larger numbers of samples in a high-throughput fashion has markedly increased with affinity-based microarrays, thus providing higher statistical power to these biomarker studies. Here, we describe a protocol for high-density serum and plasma reverse phase protein arrays (RPPAs). We demonstrate how a biobank of 12,392 samples was immobilized and analyzed on a single microarray slide, allowing high-quality profiling of abundant target proteins across all samples in one assay. PMID- 28674891 TI - Antibody Colocalization Microarray for Cross-Reactivity-Free Multiplexed Protein Analysis. AB - Measuring many proteins at once is of great importance to the idea of personalized medicine, in order to get a snapshot of a person's health status. We describe the antibody colocalization microarray (ACM), a variant of antibody microarrays which avoids reagent-induced cross-reactivity by printing individual detection antibodies atop their corresponding capture antibodies. We discuss experimental parameters that are critical for the success of ACM experiments, namely, the printing positional accuracy needed for the two printing rounds and the need for protecting dried spots during the second printing round. Using small sample volumes (less than 30 MUL) and small quantities of reagents, up to 108 different targets can be measured in hundreds of samples with great specificity and sensitivity. PMID- 28674892 TI - Surface Profiling of Extracellular Vesicles from Plasma or Ascites Fluid Using DotScan Antibody Microarrays. AB - DotScan antibody microarrays were initially developed for the extensive surface profiling of live leukemia and lymphoma cells. DotScan's diagnostic capability was validated with an extensive clinical trial using mononuclear cells from the blood or bone marrow of leukemia or lymphoma patients. DotScan has also been used for the profiling of surface proteins on peripheral blood mononuclear cells (PBMC) from patients with HIV, liver disease, and stable and progressive B-cell chronic lymphocytic leukemia (CLL). Fluorescence multiplexing allowed the simultaneous profiling of cancer cells and leukocytes from disaggregated colorectal and melanoma tumor biopsies after capture on DotScan. In this chapter, we have used DotScan for the surface profiling of extracellular vesicles (EV) recovered from conditioned growth medium of cancer cell lines and the blood of patients with CLL. The detection of captured EV was performed by enhanced chemiluminescence (ECL) using biotinylated antibodies that recognized antigens expressed on the surface of the EV subset of interest. DotScan was also used to profile EV from the blood of healthy individuals and the ascites fluid of ovarian cancer patients. DotScan binding patterns of EV from human plasma and other body fluids may yield diagnostic or prognostic signatures for monitoring the incidence, treatment, and progression of cancers. PMID- 28674893 TI - Serum Profiling for Identification of Autoantibody Signatures in Diseases Using Protein Microarrays. AB - Protein microarrays are platforms for studying protein-protein interactions and identifying disease-related self-antigens/autoantigens, which elicit an immune response in a high-throughput format. Protein arrays have been extensively used over the past two decades for several clinical applications. By using this platform, serum containing autoantibodies against potential self-antigens can be screened on proteome-wide arrays, harboring a large repertoire of full-length human proteins. Identification of such autoantigens can help deducing early diagnostic, as well as, prognostic markers in case of malignancies, autoimmune disorders, and other systemic diseases. Here, we provide an overview of the protein microarray technology along with details of an established method to study autoantibody profiles from patient sera. PMID- 28674894 TI - Quantitative Comparisons of Large Numbers of Human Plasma Samples Using TMT10plex Labeling. AB - One strategy for improving the throughput of human plasma proteomic discovery analysis while maintaining good depth of analysis is to multiplex using isobaric tags. At present, the greatest multiplexing that is commercially available uses the TMT10plex kit. As an example of this approach, we describe efficient shotgun discovery proteomics of large numbers of human plasma to identify potential biomarkers. In the analysis strategy, a common pooled reference was used to enable comparisons across multiple experiments. Duplicate samples showed excellent overall reproducibility across different TMT experiments. Data filters that improved the quality of individual peptide and protein quantitation included using a filter for purity of the targeted precursor ion in the isolation window and using only unique peptides. PMID- 28674895 TI - Efficient Quantitative Comparisons of Plasma Proteomes Using Label-Free Analysis with MaxQuant. AB - Mass spectrometry (MS)-based quantitation of plasma proteomes is challenging due to the extremely wide dynamic range and molecular heterogeneity of plasma samples. However, recent advances in technology, MS instrumentation, and bioinformatics have enabled in-depth quantitative analyses of very complex proteomes, including plasma. Specifically, recent improvements in both label based and label-free quantitation strategies have allowed highly accurate quantitative comparisons of expansive proteome datasets. Here we present a method for in-depth label-free analysis of human plasma samples using MaxQuant. PMID- 28674896 TI - Blood and Plasma Proteomics: Targeted Quantitation and Posttranslational Redox Modifications. AB - Proteome profiling using mass spectrometry is extensively utilized to understand the physiological characteristics of cells, tissues, fluids, and many other biological matrices. From the earliest days of the proteomics era, exploratory analyses of the blood protein complement have attracted a great deal of interest, owing to the pivotal importance of blood cells and biofluids (serum, plasma) for research and biomedical purposes. Once challenged by the high dynamic range of protein concentrations, low sensitivity of mass spectrometers, and poor annotation of proteomics databases, the techniques in this field have quickly evolved in recent years, particularly in the areas of absolute quantification of proteins and in mapping of posttranslational modifications. Here we describe (a) the design and production of heavy isotope-labeled peptides used as reporter internal standards for absolute protein quantification and (b) a redox proteomics approach to optimize sample preparation and database searching to elucidate oxidative modifications to protein amino acids. The two methods achieve complimentary goals in the field of blood research and pave the way for future translation of next-generation proteomics technologies into clinical practice. PMID- 28674897 TI - SWATH Mass Spectrometry for Proteomics of Non-Depleted Plasma. AB - The limitations commonly observed in data-dependent acquisition (DDA) mass spectrometric investigation of non-depleted human plasma are mainly due to the large dynamic concentration range of protein expression. Less abundant proteins are usually masked by highly abundant proteins and are therefore difficult to reliably detect. Sequential window acquisition of all theoretical fragment-ion spectra (SWATH) mass spectrometry (MS), as a representative of data-independent acquisition (DIA) approaches, provides an opportunity to improve plasma-based biomarker discovery studies because this approach does not rely on precursor intensity for fragmentation selection but rather analyzes all precursors in specified mass ranges. Here, we describe a workflow for SWATH-MS-based analysis of non-depleted plasma including sample preparation, data acquisition, and statistical analysis. PMID- 28674898 TI - Shotgun and Targeted Plasma Proteomics to Predict Prognosis of Non-Small Cell Lung Cancer. AB - Lung cancer is the leading cause of cancer deaths worldwide. Clinically, the treatment of non-small cell lung cancer (NSCLC) can be improved by the early detection and risk screening among population. To meet this need, here we describe in detail a shotgun following the targeted proteomics workflow that we previously applied for human plasma analysis, which involves (1) the application of extensive peptide-level fractionation coupled with label-free quantitative proteomics for the discovery of plasma biomarker candidates for lung cancer and (2) the usage of the multiple reaction monitoring (MRM) assays for the follow-up validations in the verification phase. The workflow features simplicity, low cost, high transferability, high robustness, and flexibility with specific instrumental settings. PMID- 28674899 TI - High-Throughput Parallel Proteomic Sample Preparation Using 96-Well Polyvinylidene Fluoride (PVDF) Membranes and C18 Purification Plates. AB - Meaningful proteomic-based biomarker discovery projects using primary human derived specimens require the analysis of hundreds of samples in order to address the issue of interpersonal variability. Thus, robust high-throughput methods for the digestion of plasma samples are a prerequisite for such large clinical proteomic studies with hundreds of samples. Commonly used sample preparation methods are often difficult to parallelize and/or automate. Herein we describe a method for parallel 96-well plate-based sample preparation. Protein digestion is performed in 96-well polyvinylidene fluoride (PVDF) membrane plates and the subsequent purification in 96-well reversed phase C18 purification plates, enabling the usage of multichannel pipettes in all steps. The protocol can be applied using neat or depleted plasma/serum samples, but has also proven effective with other sample types. PMID- 28674900 TI - Targeted Quantification of the Glycated Peptides of Human Serum Albumin. AB - Glycated human serum albumin (HSA) serves as an important marker for monitoring the glycemic status. Developing methods for unambiguous identification and quantification of glycated peptides of HSA using high-throughput technologies such as mass spectrometry has a great clinical significance. The following protocol describes the construction of reference spectral libraries for Amadori modified lysine (AML), N(epsilon)-(carboxymethyl) lysine (CML)-, and N(epsilon) (carboxyethyl)lysine (CEL)-modified peptides of synthetically modified HSA using high-resolution mass spectrometers. The protocol also describes work flows, for unambiguous identification and quantification of glycated modified peptides of HSA in clinical plasma using standard spectral libraries by various mass spectrometry approaches such as parallel reaction monitoring (PRM), sequential window acquisition of all theoretical fragment ion spectra (SWATH), and MSE. PMID- 28674901 TI - Absolute Quantification of Middle- to High-Abundant Plasma Proteins via Targeted Proteomics. AB - The increasing number of peptide and protein biomarker candidates requires expeditious and reliable quantification strategies. The utilization of liquid chromatography coupled to quadrupole tandem mass spectrometry (LC-MS/MS) for the absolute quantitation of plasma proteins and peptides facilitates the multiplexed verification of tens to hundreds of biomarkers from smallest sample quantities. Targeted proteomics assays derived from bottom-up proteomics principles rely on the identification and analysis of proteotypic peptides formed in an enzymatic digestion of the target protein. This protocol proposes a procedure for the establishment of a targeted absolute quantitation method for middle- to high abundant plasma proteins waiving depletion or enrichment steps. Essential topics as proteotypic peptide identification and LC-MS/MS method development as well as sample preparation and calibration strategies are described in detail. PMID- 28674902 TI - A Highly Automated Shotgun Proteomic Workflow: Clinical Scale and Robustness for Biomarker Discovery in Blood. AB - With recent technological developments, protein biomarker discoveries directly from blood have regained interest due to elevated feasibility. Mass spectrometry (MS)-based proteomics can now characterize human plasma proteomes to a greater extent than has ever been possible before. Such deep proteome coverage comes, however, with important limitations in terms of analysis time which is a critical factor in the case of clinical studies. As a consequence, compromises still need to be made to balance the proteome coverage with realistic analysis time frame in clinical research. The analysis of a sufficient number of samples is compulsory to empower statistically robust candidate biomarker findings. We have, therefore, recently developed a scalable automated proteomic pipeline (ASAP2) to enable the proteomic analysis of large numbers of plasma and cerebrospinal fluid (CSF) samples, from dozens to a thousand of samples, with the latter number being currently processed in 15 weeks. A distinct characteristic of ASAP2 relies on the possibility to prepare samples in a highly automated way, mostly using 96-well plates. We describe herein a sample preparation procedure for human plasma that includes internal standard spiking, abundant protein removal, buffer exchange, reduction, alkylation, tryptic digestion, isobaric labeling, pooling, and sample purification. Other key elements of the pipeline (i.e., study design, sample tracking, liquid chromatography (LC) tandem MS (MS/MS), data processing, and data analysis) are also highlighted. PMID- 28674904 TI - Metabolomics Toward Biomarker Discovery. AB - Metabolomics has been used as practical tool in the discovery of novel biomarkers in a broad area in the clinic. The analytical platforms including nuclear magnetic resonance (NMR) and mass spectrometry (MS) can cover thousands of metabolites. With the help of multivariate data analysis, many potential biomarkers can be defined in the studies. Since metabolites stand at the end point of metabolism, it remains difficult to find novel biomarkers with good diagnostic or prognostic performance. In this chapter, we will introduce a general protocol for biomarker discovery within the scope of metabolomics using MS. PMID- 28674903 TI - Mass Spectrometry-Based Serum Proteomics for Biomarker Discovery and Validation. AB - Blood protein measurements are used frequently in the clinic in the assessment of patient health. Nevertheless, there remains the need for new biomarkers with better diagnostic specificities. With the advent of improved technology for bioanalysis and the growth of biobanks including collections from specific disease risk cohorts, the plasma proteome has remained a target of proteomics research toward the characterization of disease-related biomarkers. The following protocol presents a workflow for serum/plasma proteomics including details of sample preparation both with and without immunoaffinity depletion of the most abundant plasma proteins and methodology for selected reaction monitoring mass spectrometry validation. PMID- 28674905 TI - Plasma Biomarker Identification and Quantification by Microparticle Proteomics. AB - Plasma biomarker discovery necessitates a method for deep proteomic profiling, as well as for highly accurate quantification of the proteins in the sample. Furthermore, to obtain strong candidates for potential biomarkers, the method should be high throughput to enable a large scale analysis. Here we describe in detail PROMIS-Quan (PROteomics of MIcroparticles using Super-SILAC Quantification), a method for a simple and robust fractionation of the plasma samples by extraction of plasma microparticles, followed by SILAC-based relative and absolute quantification. PMID- 28674906 TI - Bronchoalveolar Lavage: Quantitative Mass Spectrometry-Based Proteomics Analysis in Lung Diseases. AB - Bronchoalveolar lavage (BAL) fluid, obtained by a relatively noninvasive procedure, is used as a practice for diagnosis of various lung diseases as source of cells for cytology analysis. The acellular component of BAL potentially can complement and be a key for the establishment of diagnostic or as a prognostic indicator. This chapter discusses the aspects of standardization of BAL sample preparation and processing and its implications on the BAL fluid proteome quantitative analysis by high-throughput mass spectrometry. The detailed conditions for quantitative analysis of BAL proteome in the context of biomarker discovery are introduced. PMID- 28674907 TI - Protein Multiplexed Immunoassay Analysis with R. AB - Plasma samples from 177 control and type 2 diabetes patients collected at three Australian hospitals are screened for 14 analytes using six custom-made multiplex kits across 60 96-well plates. In total 354 samples were collected from the patients, representing one baseline and one end point sample from each patient. R methods and source code for analyzing the analyte fluorescence response obtained from these samples by Luminex Bio-Plex(r) xMap multiplexed immunoassay technology are disclosed. Techniques and R procedures for reading Bio-Plex(r) result files for statistical analysis and data visualization are also presented. The need for technical replicates and the number of technical replicates are addressed as well as plate layout design strategies. Multinomial regression is used to determine plate to sample covariate balance. Methods for matching clinical covariate information to Bio-Plex(r) results and vice versa are given. As well as methods for measuring and inspecting the quality of the fluorescence responses are presented. Both fixed and mixed-effect approaches for immunoassay statistical differential analysis are presented and discussed. A random effect approach to outlier analysis and detection is also shown. The bioinformatics R methodology present here provides a foundation for rigorous and reproducible analysis of the fluorescence response obtained from multiplexed immunoassays. PMID- 28674908 TI - Transperineal reanastomosis for treatment of highly recurrent anastomotic strictures after radical retropubic prostatectomy: extended follow-up. AB - OBJECTIVES: To re-evaluate safety and efficacy of transperineal reanastomosis (TPRA) as a viable therapeutic option in highly recurrent anastomotic strictures (AS) after radical retropubic prostatectomy (RRP). METHODS: Retrospective analysis by standardized questionnaire inquiring for recurrence of stricture, stress urinary incontinence (SUI), sexual function, satisfaction, and changes in quality of life (QoL) was performed in all patients undergoing TPRA. Validated questionnaires (ICIQ-UI, EQ-5D, and IPSS) were included. RESULTS: Median follow up was 45.0 months. The average number of prior operations was 4.69. Success rate was 87% (20/23). Three recurrences were successfully treated via endoscopic means. All patients had urinary incontinence pre-op and post-op. Implantation of an artificial urinary sphincter (AUS) has been performed successfully in 73.9% (17/23). Rate of complications was low (8.7%; 2/23, Clavien-Dindo Grade II + III). EQ-5D-VAS showed a good general state of health (73.5/100). An improvement in QoL was noted in 63.6% (14/22) and patient satisfaction was high (72.7%; 16/22). CONCLUSIONS: This extended follow-up confirms the initial results for TPRA as an excellent treatment option for highly recurrent AS after RRP. Postoperative SUI as a consequence of transsphincteric urethral mobilization can be satisfactorily treated by the implantation of AUS. In case of AS recalcitrant to endoscopic treatment, the described procedure-even though technically challenging-represents a valuable treatment option. PMID- 28674909 TI - Comparative X-ray morphometry of prenatal osteogenesis imperfecta type 2 and thanatophoric dysplasia: a contribution to prenatal differential diagnosis. AB - OBJECTIVE: The purpose of the paper was to assess the morphometric parameters to improve the specificity of the ultrasound (US) signs for the early differential diagnosis between two lethal dysplasias, as thanatophoric dysplasia (TD) and osteogenesis imperfecta type 2 (OI-2). METHOD: The diaphyseal length and the bowed shape of long bones associated with vertebral body dimension assessment were investigated in a group of 14 pregnancy terminations carried out in the time period 2007-2013. The definitive diagnosis was established after pregnancy termination by means of skeletal standardized X-rays, histopathology and gene analysis. RESULTS: TD and OI-2 long bones were significantly shorter than controls. No significant differences were observed between the two dysplasias. The bowing angle was higher in OI-2; a true angulation or eventually axial displacement was present only in the latter. Furthermore, they did not show any evidence of vertebral collapse. The thanatophoric dysplasia presented less bowed long bones, and never true angulation. The spine was steadily characterized by flattened anterior vertebral bodies. CONCLUSION: Long bone shortening is not a sufficient and accurate sign for early sonographic differential diagnosis between TD and OI-2. Angled diaphysis, axial diaphyseal displacement and a conserved vertebral body height in the prenatal period support the diagnosis of osteogenesis imperfecta type 2, while moderately regular bowed diaphysis associated with platyspondyly that of thanatophoric dysplasia. PMID- 28674910 TI - Diagnostic Imaging in pediatric thoracic trauma. AB - Thoracic trauma accounts for approximately 14% of blunt force traumatic deaths, second only to head injuries. Chest trauma can be blunt (90% of cases) or penetrating. In young patients, between 60 and 80% of chest injuries result from blunt trauma, with over half as a consequence of impact with motor vehicles, whereas in adolescents and adults, penetrating trauma has a statistically more prominent role. Pulmonary contusions and rib fractures are the most frequent injuries occurring. Chest X-ray is the first imaging modality of choice to identify patients presenting with life-threatening conditions (i.e., tension pneumothorax, huge hemothorax, and mediastinal hematoma) and those who require a CT examination. Multi-Slice Computed Tomography is the gold standard to evaluate chest injuries. In fact, the high spatial resolution, along with multiplanar reformation and three-dimensional (3D) reconstructions, makes MDCT the ideal imaging method to recognize several chest injuries such as rib fractures, pneumothorax, hemothorax, lung contusions and lacerations, diaphragmatic rupture, and aortic injuries. Nevertheless, when imaging a young patient, one should always keep into account the ALARA concept, to balance an appropriate and low dose technique with imaging quality and to reduce the amount of ionizing radiation exposure. According to this concept, in the recent years, the current trends in pediatric imaging support the rising use of alternative imaging modalities, such as US and MRI, to decrease radiation exposure and to answer specific clinical questions and during the observation period also. As an example, ultrasound is the first technique of choice for the diagnosis and treatment of pleural and pericardial effusion; its emerging indications include the evaluation of pneumothoraces, costocondral and rib fractures, and even pulmonary contusions. PMID- 28674912 TI - Liver Transplantation for Hepatocellular Carcinoma at Inonu University. AB - There is a great effort in the world to find a new drug in hepatocellular carcinoma (HCC) treatment. Turkey has a limited number of basic science studies to discover a new therapeutic drug for HCC. It seems that Turkey is distanced from the global drug discovery race and competition, however, Turkey has the advantage of a wide experience in living donor liver transplantation, like South Korea and Japan. Turkey can plan new studies on HCC, particularly with living donor liver transplantation. Neoadjuvant treatment methods before living donor liver transplantation for advanced tumors would be a good idea for study in Turkey. Because Inonu University has the busiest liver transplantation program in Turkey, the contribution of Inonu University to trials like this can improve the depth of the studies. To conclude, the Inonu University Liver Transplantation Institute has the busiest program in Turkey with 1,600 transplantations in eight years. The program is based on living donor liver transplantations (80%). Living donor liver transplantation for advanced HCC patients is our favorite topic to study. PMID- 28674911 TI - The Basic Metabolic Profile in Heart Failure-Marker and Modifier. AB - PURPOSE OF REVIEW: The physiologic determinants of each of the components of the basic metabolic profile in patients with heart failure will be explored. Additionally, the review will discuss the prognostic value of alterations in the basic metabolic profile as well as their effects on management. RECENT FINDINGS: Abnormalities in the basic metabolic profile have significant correlation with clinical outcomes and can modify treatment in heart failure. Hypochloremia has recently received increased attention for these reasons. Elevated creatinine, increased blood urea nitrogen, hyponatremia, and hypochloremia correlate with worse mortality and diuretic resistance in heart failure. Hypokalemia, even when mild, has proven to be a worse clinical indicator than modest elevations in serum potassium. Hypochloremia is mechanistically linked to hyponatremia and metabolic alkalosis, but recent compelling data suggests that it can provide more discriminating prognostic information. Knowledge of the physiologic basis for each of these alterations informs their management. PMID- 28674913 TI - Primary Care Versus Oncology-Based Surveillance Following Adjuvant Chemotherapy in Resected Pancreatic Cancer. AB - INTRODUCTION: High level evidence to guide surveillance following curative intent treatment for pancreatic cancer is lacking and this has likely resulted in wide variations in practice. We aim to describe patterns of surveillance and evaluate their impact on outcomes. METHODS: A total of 147 adult patients who received at least one cycle of adjuvant gemcitabine or 5-fluorouracil-based chemotherapy at any one of five British Columbia Cancer Agency centers between 2001 and 2015 were included. Surveillance strategies were classified into two categories: discharged to primary care physicians (PCPs) or follow-up at cancer centers (CC) that included regular clinical assessments, laboratory testing, and/or diagnostic imaging. RESULTS: Median age at diagnosis was 64 (range 38-85) years and 48% were men. More patients were followed by CC than by PCPs (66 vs. 44%). Among the measured prognostic factors, only patients with advanced tumor stage (T3/4) were more likely to be followed by cancer specialists (78 vs. 62%, P = 0.03), while other patient and disease characteristics were balanced between the two groups. In the entire cohort, 100 (68%) patients had a documented recurrence. Patients followed by CC were more likely to receive palliative chemotherapy at recurrence than those followed by PCPs (58 vs. 34%, respectively, P = 0.03). The median overall survival (OS) was 2.82 (95% CI 2.17-3.32) years in the CC group and 3.35 (95% CI 2.85-5.06) years in the PCP group while the median relapse-free survival (RFS) was 1.4 (95% CI 1.37-1.77) and 2.4 (95% CI 2.07-4.59) years, respectively. On multivariate analysis, there was no significant difference in OS between CC and PCP-based surveillance (HR 1.23; 95% CI 0.74-2.04, P = 0.40); however, RFS favored the PCP group (HR 1.62; 95% CI 1.01-2.56, P = 0.04, for the CC group). CONCLUSION: In this population-based analysis, surveillance tests and imaging performed by CC detected recurrences earlier when compared to follow-up by PCPs, but this did not result in OS differences. Patients with more advanced tumors were more likely to be seen at CC. PCPs may play a larger role in the follow-up care of selected low risk patients with resected pancreatic cancer. PMID- 28674914 TI - The relevance of serum vitamin D in psoriasis: a review. AB - Observational research has identified low serum levels of 25-hydroxyvitamin D (25[OH]D) in many non-skeletal diseases. Whether this is causal or due to underlying illness is unknown. Low serum 25[OH]D levels are also reported in the general population. Observational and experimental studies identify that vitamin D supplementation may be beneficial in reducing all-cause mortality in elderly women, as well as cancer mortality. Our aim was to review the literature to identify the relevance of serum 25[OH]D levels in psoriasis. Forty-five studies were included in our analysis. Most of these studies identified low serum 25[OH]D levels in psoriasis patients. Evidence of causality is lacking. Treatment with phototherapy leads to an increase in serum 25[OH]D. There is little evidence that the increase in 25[OH]D after phototherapy correlates with improved disease severity. Multiple studies report an improvement in psoriasis with vitamin D supplementation. These data are predominantly from small observational or non randomised interventional studies. Randomised controlled trials to date have had small numbers and short follow-up periods. The optimal dose of supplementation is unknown and dosing is not standardised across different studies. The definition of vitamin D insufficiency varies across studies. Low serum 25[OH]D levels may be associated with comorbidities in psoriasis patients, including metabolic syndrome and cardiovascular risk. Evidence of causation is absent. Until further high quality evidence is available, the relevance of low serum 25[OH]D levels in psoriasis patients is unknown, as is the benefit of supplementation on disease control. Supplementation in patients with low 25[OH]D is of benefit to those at risk of impaired bone health. PMID- 28674915 TI - Autoantibodies to desmogleins 1 and 3 in patients with lichen planus. AB - There is controversy about the role of autoantibodies against desmoglein 1 and 3 (Dsg1 and 3) in the pathogenesis of lichen planus (LP); the authors planned this study to determine the presence of circulating levels of these antibodies in patients with different types of oral LP and to compare that with cutaneous LP and healthy controls. The enzyme-linked immunosorbent assay test was performed on serum samples of 24 cases of erosive oral LP, 29 cases of reticular oral LP, 30 cases of cutaneous LP and 30 healthy controls. The severity of oral LP was evaluated by Reticulation, Erosion and Ulceration scoring system. There were no significant differences in the concentrations of autoantibodies to Dsg1 between the four groups. Autoantibodies to Dsg3 were increased in erosive oral LP compared with healthy controls (p value = 0.005) but no increase was observed between other groups. We did not detect a correlation between the severity of the disease and the levels of anti-Dsg1 and 3 in patients with erosive and reticular types of oral LP. In conclusion, regardless of the increased level of anti-Dsg3 antibody in erosive oral LP, serum concentrations of antibodies were under cut off values. Moreover, the pathogenic role of anti-Dsg3 antibodies in erosive oral LP is uncertain. PMID- 28674916 TI - 2H-13C correlation solid-state NMR for investigating dynamics and water accessibilities of proteins and carbohydrates. AB - Site-specific determination of molecular motion and water accessibility by indirect detection of 2H NMR spectra has advantages over dipolar-coupling based techniques due to the large quadrupolar couplings and the ensuing high angular resolution. Recently, a Rotor Echo Short Pulse IRrAdiaTION mediated cross polarization (RESPIRATIONCP) technique was developed, which allowed efficient transfer of 2H magnetization to 13C at moderate 2H radiofrequency field strengths available on most commercial MAS probes. In this work, we investigate the 2H-13C magnetization transfer characteristics of one-bond perdeuterated CD n spin systems and two-bond H/D exchanged C-(O)-D and C-(N)-D spin systems in carbohydrates and proteins. Our results show that multi-bond, broadband 2H-13C polarization transfer can be achieved using 2H radiofrequency fields of ~50 kHz, relatively short contact times of 1.3-1.7 ms, and with sufficiently high sensitivity to enable 2D 2H-13C correlation experiments with undistorted 2H spectra in the indirect dimension. To demonstrate the utility of this 2H-13C technique for studying molecular motion, we show 2H-13C correlation spectra of perdeuterated bacterial cellulose, whose surface glucan chains exhibit a motionally averaged C6 2H quadrupolar coupling that indicates fast trans-gauche isomerization about the C5-C6 bond. In comparison, the interior chains in the microfibril core are fully immobilized. Application of the 2H-13C correlation experiment to H/D exchanged Arabidopsis primary cell walls show that the O-D quadrupolar spectra of the highest polysaccharide peaks can be fit to a two component model, in which 74% of the spectral intensity, assigned to cellulose, has a near-rigid-limit coupling, while 26% of the intensity, assigned to matrix polysaccharides, has a weakened coupling of 50 kHz. The latter O-D quadrupolar order parameter of 0.22 is significantly smaller than previously reported C-D dipolar order parameters of 0.46-0.55 for pectins, suggesting that additional motions exist at the C-O bonds in the wall polysaccharides. 2H-13C polarization transfer profiles are also compared between statistically deuterated and H/D exchanged GB1. PMID- 28674917 TI - Fire Distribution in Peninsular Malaysia, Sumatra and Borneo in 2015 with Special Emphasis on Peatland Fires. AB - In this paper, we analyze the spatio-temporal distribution of vegetation fires in Peninsular Malaysia, Sumatra, and Borneo in the severe El Nino year of 2015, concentrating on the distribution of fires between mineral soils and peatland areas, and between land cover types in peatland areas. The results reveal that 53% of all Moderate Resolution Imaging Spectroradiometer (MODIS) fire detections were recorded in peatlands that cover only 12% of the study area. However, fire occurrence in the peatland areas was highly dependent on land cover type. Pristine peat swamp forests (PSF) experienced only marginal fire activity (30 fire detections per 1000 km2) compared to deforested undeveloped peatlands (831 915 fire detections per 1000 km2). Our results also highlight the extreme fire vulnerability of the southern Sumatran and Bornean peatlands under strong El Nino conditions: 71% of all peatland hotspots were detected in the provinces of South Sumatra and Central Kalimantan, which contain 29% of peatlands in the study area. Degraded PSF and all deforested peatland land cover types, including managed areas, in the two provinces were severely affected, demonstrating how difficult it is to protect even managed drained agricultural areas from unwanted fires during dry periods. Our results thereby advocate rewetting and rehabilitation as the primary management option for highly fire prone degraded undeveloped peatland areas, whenever feasible, as a means to reduce fire risk during future dry episodes. PMID- 28674918 TI - Role of implantable cardioverter defibrillator in non-ischemic cardiomyopathy: a systematic review and meta-analysis of prospective randomized clinical trials. AB - INTRODUCTION: A mortality benefit in patients with implantable cardioverter defibrillator (ICD) in ischemic cardiomyopathy is well established. However, the benefit of ICD implantation in non-ischemic cardiomyopathy (NICM) on total mortality remains uncertain. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) evaluating the role of primary prevention ICD in NICM patients. METHODS: We performed a systematic review on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through February 2017 to identify RCT evaluating the role of ICD in NICM patients. Mantel-Haenszel risk ratio (RR) fixed effects model was used to summarize data across treatment arms. If heterogeneity (I 2) >=25, random effects model was used instead. RESULTS: We analyzed a total of 2573 patients from five RCTs comparing ICD with medical therapy in patients with NICM. The mean follow up for the trials was 48 +/- 22 months. There was a significant reduction in (a) all cause mortality (RR 0.84, 95% CI 0.71-0.99, p = 0.03) and (b) sudden cardiac death (RR 0.47, 95% CI 0.30-0.73, p < 0.001) in ICD group versus medical therapy. CONCLUSION: Our analysis demonstrates that the use of ICD for primary prevention is associated with a reduction in all-cause mortality and SCD in patients with NICM. PMID- 28674919 TI - Creating diagnostic criteria for perforated appendicitis using cross-sectional imaging. AB - INTRODUCTION: Preoperative determination of perforated versus acute appendicitis can be difficult. We compared CT and MRI performance in diagnosing perforated appendicitis, and created diagnostic criteria. METHODS: We retrospectively reviewed all pediatric patients who underwent appendectomy within one day of CT or MRI between 1/1/2013 and 1/16/2016. True diagnosis was determined by pathology report. Findings on CT/MRI were grouped into "hard" findings (abscess, pneumoperitoneum, extruded fecalith, appendiceal wall with visible hole) and "soft" findings (extensive/diffuse inflammation/free fluid, phlegmon). Correlation of white blood cell count (WBC), temperature, peritoneal signs, and symptom duration >72 h with perforation was assessed using logistic regression. Significant correlates were incorporated in clinical criteria. RESULTS: 135 patients underwent appendectomy after CT/MRI. Fifty patients underwent MRI and 85 CT. Using hard and/or soft findings, MRI was 86.7% sensitive and 74.3% specific, compared to 68.4% (p = 0.19) and 92.4% (p = 0.025) for CT. WBC > 15, temperature >38.0 degrees C, and peritoneal signs predicted perforation. Diagnostic accuracy of MRI was highest using imaging findings alone. Accuracy of CT was improved by mandating at least one of the previous three clinical correlates, resulting in 68.4% sensitivity and 93.9% specificity. CONCLUSIONS: MRI trended toward more sensitive and CT was more specific for complicated appendicitis. CT specificity is improved by our algorithm. PMID- 28674920 TI - Tethered cord in patients affected by anorectal malformations: a survey from the ARM-Net Consortium. AB - PURPOSE: The goal of this study was to determine the degree of consensus in the management of spinal cord tethering (TC) in patients with anorectal malformation (ARM) in a large cohort of European pediatric centers. METHODS: A survey was sent to pediatric surgeons (one per center) members of the ARM-Net Consortium. RESULTS: Twenty-four (86%) from ten different countries completed the survey. Overall prevalence of TC was: 21% unknown, 46% below 15, and 29% between 15 and 30%. Ninety-six agreed on screening all patients for TC regardless the type of ARM and 79% start screening at birth. Responses varied in TC definition and diagnostic tools. Fifty percent of respondents prefer ultrasound (US), 21% indicate either US or magnetic resonance (MRI) based on a pre-defined risk of presenting TC, and 21% perform both. Discrepancy exists in complementary test: 82% carry out urodynamic studies (UDS) and only 37% perform somatosensory-evoked potentials (SSEP). Prophylactic untethering is performed in only two centers (8%). CONCLUSIONS: Survey results support TC screening in all patients with ARM and conservative management of TC. There is discrepancy in the definition of TC, screening tools, and complementary test. Protocols should be developed to avoid such variability in management. PMID- 28674922 TI - Effects of training programs based on ipsilateral voluntary and stimulated contractions on muscle strength and monopedal postural control of the contralateral limb. AB - PURPOSE: To compare the effects of unilateral strength training by stimulated and voluntary contractions on muscle strength and monopedal postural control of the contralateral limb. METHODS: 36 non-active healthy male subjects were recruited and split randomly into three groups. Two groups of 12 subjects took part in a strength-training program (3 sessions a week over 8 weeks) comprising 43 contractions of the quadriceps femoris of the ipsilateral limb (at 20% of the MVC). One group carried out voluntary contractions exclusively (VOL group), while the other group benefited exclusively from electro-induced contractions (NMES group). The other 12 subjects formed the control (CON) group. Assessments of MVC and monopedal postural control in static and dynamic postural tasks were performed with the ipsilateral (ISPI) and contralateral (CONTRA) limbs before (PRE) and after (POST) completion of the training program. RESULTS: After the training program, the MVC of the IPSI and CONTRA limbs increased similarly for both experimental groups (VOL and NMES). There were no significant improvements of monopedal postural control for the IPSI or CONTRA limbs in either the VOL or NMES experimental group. No change was observed for the CON group over the protocol period. CONCLUSION: The purposed training program with NMES vs VOL contractions induced strength gains but did not permit any improvement of contralateral monopedal postural control in healthy young subjects. This has potential for therapeutic application and allows clinicians to focus their training programs on dynamic and poly-articular exercises to improve the postural control in young subjects. PMID- 28674921 TI - Power output and fatigue properties using spatially distributed sequential stimulation in a dynamic knee extension task. AB - PURPOSE: The low power output and fatigue resistance during functional electrical stimulation (FES) limits its use for functional applications. The aim of this study was to compare the power output and fatigue properties of spatially distributed sequential stimulation (SDSS) against conventional single electrode stimulation (SES) in an isokinetic knee extension task simulating knee movement during recumbent cycling. METHODS: M. vastus lateralis and m. vastus medialis of eight able-bodied subjects were stimulated for 6 min on both legs with both setups. In the SES setup, target muscles were each stimulated by a pair of electrodes. In SDSS, four small electrodes replaced the SES active electrodes, but reference electrodes were the same. Torque was measured during knee extension movement by a dynamometer at an angular velocity of 110 degrees /s. Mean power (P mean) was calculated from stimulated extensions for the first 10 extensions, the final 20 extensions and overall. Fatigue is presented as an index, calculated as the decrease with respect to initial power. RESULTS: P mean was significantly higher for SDSS than for SES in the final phase (9.9 +/- 4.0 vs. 7.4 +/- 4.3 W, p = 0.035) and overall (11.5 +/- 4.0 vs. 9.2 +/- 4.5 W, p = 0.037). With SDSS, the reduction in P mean was significantly smaller compared to SES (from 14.9 to 9.9 vs. 14.6 to 7.4 W, p = 0.024). The absolute mean pulse width was substantially lower with SDSS (62.5 vs. 90.0 us). CONCLUSION: Although less stimulation was applied, SDSS showed a significantly higher mean power output than SES. SDSS also had improved fatigue resistance when compared to conventional stimulation. The SDSS approach may provide substantial performance benefits for cyclical FES applications. PMID- 28674923 TI - Pulmonary hemorrhage in acute heroin overdose: a report of two cases. AB - Diffuse alveolar hemorrhage (DAH) is a clinical syndrome characterized by pulmonary hemorrhage, respiratory failure, and high early mortality rates. DAH typically appears on chest radiographs as bilateral parenchymal consolidations. To our knowledge, pulmonary hemorrhage associated with heroin overdose has not been reported. We report the clinical and radiographic findings in two cases of acute DAH following heroin overdose. We speculate that an adulterating agent may be the underlying etiology in these cases. While pulmonary edema as a consequence of heroin overdose is well-documented and usually first suspected when consolidations are present on a chest radiograph in a patient with a history of recent heroin use, we believe that DAH should also be considered in the proper clinical context. PMID- 28674925 TI - Biosorption of lead phosphates by lead-tolerant bacteria as a mechanism for lead immobilization. AB - The study of metal-tolerant bacteria is important for bioremediation of contaminated environments and development of green technologies for material synthesis due to their potential to transform toxic metal ions into less toxic compounds by mechanisms such as reduction, oxidation and/or sequestration. In this study, we report the isolation of seven lead-tolerant bacteria from a metal contaminated site at Zacatecas, Mexico. The bacteria were identified as members of the Staphylococcus and Bacillus genera by microscopic, biochemical and 16S rDNA analyses. Minimal inhibitory concentration of these isolates was established between 4.5 and 7.0 mM of Pb(NO3)2 in solid and 1.0-4.0 mM of Pb(NO3)2 in liquid media. A quantitative analysis of the lead associated to bacterial biomass in growing cultures, revealed that the percentage of lead associated to biomass was between 1 and 37% in the PbT isolates. A mechanism of complexation/biosorption of lead ions as inorganic phosphates (lead hydroxyapatite and pyromorphite) in bacterial biomass, was determined by Fourier transform infrared spectroscopy and X-ray diffraction analyses. Thus, the ability of the lead-tolerant isolates to transform lead ions into stable and highly insoluble lead minerals make them potentially useful for immobilization of lead in mining waste. PMID- 28674924 TI - Engineering application of anaerobic ammonium oxidation process in wastewater treatment. AB - Anaerobic ammonium oxidation (Anammox), a promising biological nitrogen removal process, has been verified as an efficient, sustainable and cost-effective alternative to conventional nitrification and denitrification processes. To date, more than 110 full-scale anammox plants have been installed and are in operation, treating industrial NH4+-rich wastewater worldwide, and anammox-based technologies are flourishing. This review the current state of the art for engineering applications of the anammox process, including various anammox-based technologies, reactor selection and attempts to apply it at different wastewater plants. Process control and implementation for stable performance are discussed as well as some remaining issues concerning engineering application are exposed, including the start-up period, process disturbances, greenhouse gas emissions and especially mainstream anammox applications. Finally, further development of the anammox engineering application is proposed in this review. PMID- 28674926 TI - Enhancement of gamma-aminobutyric acid (GABA) levels using an autochthonous Lactobacillus futsaii CS3 as starter culture in Thai fermented shrimp (Kung-Som). AB - Gamma-aminobutyric acid (GABA) is a non-proteinogenic amino acid, which has a variety of well-characterized beneficial physiological functions. In order to improve GABA levels and the fermentation process of Thai fermented shrimp (Kung Som), autochthonous Lactobacillus futsaii CS3 was inoculated as a starter culture into Kung-Som, and its effects on the quality of Kung-Som were studied. The optimal conditions for GABA production in Kung-Som as obtained by response surface methodology (RSM) using a central composite design (CCD) were an inoculum size of roughly 107 CFU/g (X1) of L. futsaii cells together with the addition of 0.5% (w/w) monosodium glutamate (MSG) (X2), resulting in maximum GABA levels of 10,500 mg per kg fresh product. Under these optimized conditions, the experimental GABA content of Kung-Som with an added starter culture was up to four times higher than that of the control (without starter culture) or commercial Kung-Som products (10,120 mg/kg product). Kung-Som produced by inoculation with L. futsaii CS3 but without addition of MSG showed a considerably increased GABA content of 7790 mg/kg compared to the control. Fermentation time was reduced to less than 1 week for these samples compared to the control batches, which took up to 19 days. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) revealed that L. futsaii CS3 remained prominently throughout the Kung-Som fermentation, and that lactic acid bacteria (LAB) rapidly dominated the total microflora because of this inoculation with L. futsaii CS3. Kung-Som samples with starter culture were accepted as well as commercial ones by 30 panelists (p > 0.05). In conclusion, L. futsaii CS3 is a good starter culture for GABA production, resulting in, improved microbiological safety as well as reduced fermentation time. PMID- 28674927 TI - Influence of glycosides on behavior of Oenococcus oeni in wine conditions: growth, substrates and aroma compounds. AB - Autochthonous Oenococcus oeni strains (MS9, MS20 and MS46) with good malolactic performance and yielding adequate diacetyl levels, were selected to investigate the effect of synthetic and grape glycosides on bacterial growth, substrate utilization and beta-glucosidase (betaGlu), alpha-arabinofuranosidase (alphaAra) and alpha-rhamnopyranosidase (alphaRha) activities in a wine-like medium containing 6% ethanol, pH 4.0 (WBM). Then, changes in the volatile compounds profile were evaluated at the end of malolactic fermentation (MLF) carried out by the MS46 strain in WBM containing 1 mg L-1 of natural glycoside. All strains grew and efficiently degraded L-malic acid in WBM where betaGlu and alphaAra activities were found but not alphaRha. In presence of a synthetic glycoside (eriodictyol 7-O-beta-rutinoside) betaGlu activity was significantly enhanced for two of the cultures tested (MS20 and MS460) while a low alphaRha activity was induced, presenting MS46 the better performance. Glycosides extracted from fermented grape musts under different conditions allowed maximum growths, L-malic acid utilization rates and glycosidase activities in the MS46 strain. Thus, betaGlu, alphaAra and alphaRha activities increased between 30-50 and 3-11% respectively. This indirectly correlated to significant changes in total esters and higher alcohols at the end of MLF, which increased by up to 140 and 30% respectively. Moreover, ethyl and acetate esters formed up to 100-fold than alcohols or esters degraded highlighted the main role of this microorganism in the esters synthesis. Results obtained encourage the potential use of selected indigenous O. oeni strains as a tool to enhance wine complexity through MLF, mainly on highly fruity aroma. PMID- 28674928 TI - Stochastic population growth in spatially heterogeneous environments: the density dependent case. AB - This work is devoted to studying the dynamics of a structured population that is subject to the combined effects of environmental stochasticity, competition for resources, spatio-temporal heterogeneity and dispersal. The population is spread throughout n patches whose population abundances are modeled as the solutions of a system of nonlinear stochastic differential equations living on [Formula: see text]. We prove that r, the stochastic growth rate of the total population in the absence of competition, determines the long-term behaviour of the population. The parameter r can be expressed as the Lyapunov exponent of an associated linearized system of stochastic differential equations. Detailed analysis shows that if [Formula: see text], the population abundances converge polynomially fast to a unique invariant probability measure on [Formula: see text], while when [Formula: see text], the population abundances of the patches converge almost surely to 0 exponentially fast. This generalizes and extends the results of Evans et al. (J Math Biol 66(3):423-476, 2013) and proves one of their conjectures. Compared to recent developments, our model incorporates very general density-dependent growth rates and competition terms. Furthermore, we prove that persistence is robust to small, possibly density dependent, perturbations of the growth rates, dispersal matrix and covariance matrix of the environmental noise. We also show that the stochastic growth rate depends continuously on the coefficients. Our work allows the environmental noise driving our system to be degenerate. This is relevant from a biological point of view since, for example, the environments of the different patches can be perfectly correlated. We show how one can adapt the nondegenerate results to the degenerate setting. As an example we fully analyze the two-patch case, [Formula: see text], and show that the stochastic growth rate is a decreasing function of the dispersion rate. In particular, coupling two sink patches can never yield persistence, in contrast to the results from the non degenerate setting treated by Evans et al. which show that sometimes coupling by dispersal can make the system persistent. PMID- 28674929 TI - Frequency of a large drift caused by pressure wire using optical fibers. AB - The frequency of a large pressure signal drift (PDs) caused by pressure wire using optical fibers and its effect on fractional flow reserve (FFR)-based decision-making is not clear. We used pressure wires using optical fibers as "workhorse wires" for 95 consecutive lesions. The wire was normalized at the tip of the guiding catheter just before performing the percutaneous coronary intervention (PCI) and was used without re-normalization until the end of the PCI. The drift value at the end of the procedures was evaluated. Four per cent (n = 4) of patients showed a large drift (PD >3 mmHg). Classification discordance between read-out and PD-corrected FFR values was detected in 8 (8%) measurements in total. The decision changed from FFR <=0.80 to >0.80 in 7 (7%) measurements and vice versa in 1 (1%) measurement. PD showed no effect on decision-making when the FFR read-out value was <0.78 or >0.82. The frequency of large drifts caused by pressure wires using optical fibers was 4%. However, no case showed decision changes when the FFR gray zone was considered. PMID- 28674931 TI - Why We Should Create Artificial Offspring: Meaning and the Collective Afterlife. AB - This article argues that the creation of artificial offspring could make our lives more meaningful (i.e. satisfy more meaning-relevant conditions of value). By 'artificial offspring' I mean beings that we construct, with a mix of human and non-human-like qualities. Robotic artificial intelligences are paradigmatic examples of the form. There are two reasons for thinking that the creation of such beings could make our lives more meaningful and valuable. The first is that the existence of a collective afterlife-i.e. a set of human-like lives that continue after we die-is likely to be an important source and sustainer of meaning in our present lives (Scheffler in Death and the afterlife, OUP, Oxford, 2013). The second is that the creation of artificial offspring provides a plausible and potentially better pathway to a collective afterlife than the traditional biological pathway (i.e. there are reasons to favour this pathway and there are no good defeaters to trying it out). Both of these arguments are defended from a variety of objections and misunderstandings. PMID- 28674930 TI - Trojan Horse Strategy for Non-invasive Interference of Clock Gene in the Oyster Crassostrea gigas. AB - RNA interference is a powerful method to inhibit specific gene expression. Recently, silencing target genes by feeding has been successfully carried out in nematodes, insects, and small aquatic organisms. A non-invasive feeding-based RNA interference is reported here for the first time in a mollusk bivalve, the pacific oyster Crassostrea gigas. In this Trojan horse strategy, the unicellular alga Heterocapsa triquetra is the food supply used as a vector to feed oysters with Escherichia coli strain HT115 engineered to express the double-stranded RNA targeting gene. To test the efficacy of the method, the Clock gene, a central gene of the circadian clock, was targeted for knockout. Results demonstrated specific and systemic efficiency of the Trojan horse strategy in reducing Clock mRNA abundance. Consequences of Clock disruption were observed in Clock-related genes (Bmal, Tim1, Per, Cry1, Cry2, Rev.-erb, and Ror) and triploid oysters were more sensitive than diploid to the interference. This non-invasive approach shows an involvement of the circadian clock in oyster bioaccumulation of toxins produced by the harmful alga Alexandrium minutum. PMID- 28674932 TI - Use of transcription activator-like effector for efficient gene modification and transcription in the filamentous fungus Trichoderma reesei. AB - Filamentous fungi have wide applications in the field of biotechnology. The use of transcription activator-like effectors (TALEs) is a powerful genome engineering tool, which can facilitate genome editing and transcriptional modulation, and has been used for genetic modification in a variety of organisms. However, a transcription activator-like effectors nuclease (TALEN) approach has not been used in filamentous fungi so far. Here, we aimed to establish the shortest TALEN and TALE-transcription factor (TALE-TF) proteins for use in gene modification and transcription in the filamentous fungus Trichoderma reesei. The alternative tandem repeat unit of the TALEs was first established by the ligation of two isocaudamers: XbaI and SpeI, instead of the natural unit. In addition, we adopted T. reesei expression assays to monitor the activities of the TALENs and TALE-TF in vivo in T. reesei. Our results showed that TALEs are a powerful genome manipulating tool for use in T. reesei and other filamentous fungal species and that their use might facilitate studies on functional genomics and strain improvement in these filamentous fungi. PMID- 28674933 TI - Challenging Investigation of a Norovirus Foodborne Disease Outbreak During a Military Deployment in Central African Republic. AB - In January 2016, a large-scale outbreak of acute gastroenteritis was reported among French armed forces deployed in the Central African Republic. Challenging investigations, conducted from France, made it possible to identify a norovirus genogroup II in both stool and food samples, confirming a norovirus foodborne disease outbreak. Infected food handler management is discussed. PMID- 28674934 TI - Improvement of the Bag-Mediated Filtration System for Sampling Wastewater and Wastewater-Impacted Waters. AB - Environmental surveillance of poliovirus (PV) plays an important role in the global program for eradication of wild PV. The bag-mediated filtration system (BMFS) was first developed in 2014 and enhances PV surveillance when compared to the two-phase grab method currently recommended by the World Health Organization (WHO). In this study, the BMFS design was improved and tested for its usability in wastewater and wastewater-impacted surface waters in Nairobi, Kenya. Modifications made to the BMFS included the size, color, and shape of the collection bags, the filter housing used, and the device used to elute the samples from the filters. The modified BMFS concentrated 3-10 L down to 10 mL, which resulted in an effective volume assayed (900-3000 mL) that was 6-20 times greater than the effective volume assayed for samples processed by the WHO algorithm (150 mL). The system developed allows for sampling and in-field virus concentration, followed by transportation of the filter for further analysis with simpler logistics than the current methods. This may ultimately reduce the likelihood of false-negative samples by increasing the effective volume assayed compared to samples processed by the WHO algorithm, making the BMFS a valuable sampling system for wastewater and wastewater-impacted surface waters. PMID- 28674935 TI - The paths of Andrew A. Benson: a radio-autobiography. AB - Andrew A. Benson, one of the greatest biochemists of our time, is celebrated on his centennial by the authors with whom he interacted performing experiments or contemplating metabolic pathways in a wide range of biological kingdoms. He charted the chemical flow of energy in cells, tissues, organs, plants, animals, and ecosystems. Benson collaborated with hundreds of colleagues to examine the natural history of autotrophy, mixotrophy, and heterotrophy while elucidating metabolic pathways. We present here a biological perspective of his body of studies. Benson lived from September 24, 1917, to January 16, 2015. Out of over 1000 autoradiograms he produced in his life, he left a legacy of 50 labeled autoradiograms to the authors who tell the story of his life's work that resulted in Benson's Protocol (Nonomura et al., Photosynth Res 127:369-378, 2016) that has been applied, over the years, for the elucidation of major metabolic pathways by many scientists. PMID- 28674937 TI - Scaffold-Based and Scaffold-Free Testicular Organoids from Primary Human Testicular Cells. AB - Organoid systems take advantage of the self-organizing capabilities of cells to create diverse multi-cellular tissue surrogates that constitute a powerful novel class of biological models. Clearly, the formation of a testicular organoid (TO) in which human spermatogenesis can proceed from a single-cell suspension would exert a tremendous impact on research and development, clinical treatment of infertility, and screening of potential drugs and toxic agents. Recently, we showed that primary adult and pubertal human testicular cells auto-assembled in TOs either with or without the support of a natural testis scaffold. These mini tissues harboured both the spermatogonial stem cells and their important niche cells, which retained certain specific functions during long-term culture. As such, human TOs might advance the development of a system allowing human in vitro spermatogenesis. Here we describe the methodology to make scaffold-based and scaffold-free TOs. PMID- 28674936 TI - The FOF1 ATP synthase: from atomistic three-dimensional structure to the rotary chemical function. AB - Molecular motors are multi-subunit complexes that are indispensable for accomplishing various tasks of the living cells. One such molecular motor is the FOF1 ATP synthase that synthesizes ATP at the expense of the membrane proton gradient. Elucidating the molecular origin of the motor function is challenging despite significant advances in various experimental fields. Currently atomic simulations of whole motor complexes cannot reach to functionally relevant time scales that extend beyond the millisecond regime. Moreover, to reveal the underlying molecular origin of the function, one must model the coupled chemical and conformational events using physically and chemically meaningful multiscaling techniques. In this review, we discuss our approach to model the action of the F1 and FO molecular motors, where emphasis is laid on elucidating the molecular origin of the driving force that leads to directional rotation at the expense of ATP hydrolysis or proton gradients. We have used atomic structures of the motors and used hierarchical multiscaling techniques to generate low dimensional functional free energy surfaces of the complete mechano-chemical process. These free energy surfaces were studied further to calculate important characteristics of the motors, such as, rotational torque, temporal dynamics, occurrence of intermittent dwell states, etc. We also studied the result of mutating various parts of the motor domains and our observations correspond very well with the experimental findings. Overall, our studies have generated a cumulative understanding of the motor action, and especially highlight the crucial role of electrostatics in establishing the mechano-chemical coupling. PMID- 28674938 TI - Herbaspirillum rubrisubalbicans, a mild pathogen impairs growth of rice by augmenting ethylene levels. AB - KEY MESSAGE: Herbaspirillum rubrisubalbicans decreases growth of rice. Inoculation of rice with H. rubrisubalbicans increased the ACCO mRNA levels and ethylene production. The H. rubrisubalbicans rice interactions were further characterized by proteomic approach. Herbaspirillum rubrisubalbicans is a well known growth-promoting rhizobacteria that can also act as a mild phyto-pathogen. During colonisation of rice, RT-qPCR analyses showed that H. rubrisubalbicans up regulates the methionine recycling pathway as well as phyto-siderophore synthesis genes. mRNA levels of ACC oxidase and ethylene levels also increased in rice roots but inoculation with H. rubrisubalbicans impaired growth of the rice plant. A proteomic approach was used to identify proteins specifically modulated by H. rubrisubalbicans in rice and amongst the differentially expressed proteins a V ATPase and a 14-3-3 protein were down-regulated. Several proteins of H. rubrisubalbicans were identified, including the type VI secretion system effector Hcp1, suggesting that protein secretion play a role colonisation in rice. Finally, the alkyl hydroperoxide reductase, a primary scavenger of endogenous hydrogen peroxide was also identified. Monitoring the levels of reactive oxygen species in the epiphytic bacteria by flow cytometry revealed that H. rubrisubalbicans is subjected to oxidative stress, suggesting that the alkyl hydroperoxide reductase is an important regulator of redox homeostasis in plant bacteria interactions. PMID- 28674939 TI - The Care Dialog: the "ethics of care" approach and its importance for clinical ethics consultation. AB - Ethics consultation in institutions of the healthcare system has been given a standard form based on three pillars: education, the development of guidelines and concrete ethics consultation in case conferences. The spread of ethics committees, which perform these tasks on an organizational level, is a remarkable historic achievement. At the same time it cannot be denied that modern ethics consultation neglects relevant aspects of care ethics approaches. In our essay we present an "ethics of care" approach as well as an empirical pilot project "Ethics from the bottom up"-which organizes ethics consultation based on this focus. Findings and philosophy of the project will be discussed as far as relevant for ethics consultation in the healthcare system. PMID- 28674940 TI - Characterization of the CDK5 gene in Apis cerana cerana (AccCDK5) and a preliminary identification of its activator gene, AccCDK5r1. AB - Cyclin-dependent kinase 5 (CDK5) is an unusual CDK whose function has been implicated in protecting the central nervous system (CNS) from oxidative damage. However, there have been few studies of CDK5 in insects. In this study, we identified the AccCDK5 gene from Apis cerana cerana and investigated its role in oxidation resistance. We found that AccCDK5 is highly conserved across species and contains conserved features of the CDK5 family. The results of qPCR analysis indicated that AccCDK5 is highly expressed during the larval and pupal stages and in the adult head and muscle. We further observed that AccCDK5 is induced by several environmental oxidative stresses. Moreover, the overexpression of the AccCDK5 protein in E. coli enhances the resistance of the bacteria to oxidative stress. The activation of CDK5 requires binding to its activator. Therefore, we also identified and cloned cyclin-dependent kinase 5 regulatory subunit 1, which we named AccCDK5r1, from Apis cerana cerana. AccCDK5r1 contains a conserved cell localization targeting domain as well as binding and activation sites for CDK5. Yeast two-hybrid analysis demonstrated the interaction between AccCDK5 and AccCDK5r1. The expression patterns of the two genes were similar after stress treatment. Collectively, these results suggest that AccCDK5 plays a pivotal role in the response to oxidative stresses and that AccCDK5r1 is a potential activator of AccCDK5. PMID- 28674941 TI - Coffee extract and caffeine enhance the heat shock response and promote proteostasis in an HSF-1-dependent manner in Caenorhabditis elegans. AB - As the population ages, there is a critical need to uncover strategies to combat diseases of aging. Studies in the soil-dwelling nematode Caenorhabditis elegans have demonstrated the protective effects of coffee extract and caffeine in promoting the induction of conserved longevity pathways including the insulin like signaling pathway and the oxidative stress response. We were interested in determining the effects of coffee and caffeine treatment on the regulation of the heat shock response. The heat shock response is a highly conserved cellular response that functions as a cytoprotective mechanism during stress, mediated by the heat shock transcription factor HSF-1. In the worm, HSF-1 not only promotes protection against stress but is also essential for development and longevity. Induction of the heat shock response has been suggested to be beneficial for diseases of protein conformation by preventing protein misfolding and aggregation, and as such has been proposed as a therapeutic target for age associated neurodegenerative disorders. In this study, we demonstrate that coffee is a potent, dose-dependent, inducer of the heat shock response. Treatment with a moderate dose of pure caffeine was also able to induce the heat shock response, indicating caffeine as an important component within coffee for producing this response. The effects that we observe with both coffee and pure caffeine on the heat shock response are both dependent on HSF-1. In a C. elegans Huntington's disease model, worms treated with caffeine were protected from polyglutamine aggregates and toxicity, an effect that was also HSF-1-dependent. In conclusion, these results demonstrate caffeinated coffee, and pure caffeine, as protective substances that promote proteostasis through induction of the heat shock response. PMID- 28674942 TI - Performance: Bridging the Gap After ACL Surgery. AB - PURPOSE OF REVIEW: The purpose of this paper is to identify strategies for a successful transition to sports in patients following rehabilitation for ACL reconstruction surgery (ACLR). RECENT FINDINGS: Recent research continues to demonstrate a relatively low rate of return to previous level of play among athletes following ACLR combined with a significant risk of injury to either the ipsi or the contralateral ACL. Recent research also demonstrates a growing use of a varied battery of assessments to determine readiness to return to sport as well as a lack of consensus on the ideal rehabilitation program, the criteria for clearance for return to play (both in time from surgery and functional milestones), and the nature of a conditioning program designed specifically for transitioning the cleared athlete back to competition. Due to the lack of consensus and consistency regarding rehabilitation protocols and criteria for clearance to play after ACLR, deficits in strength, neuromuscular control, and psychological readiness may exist in "cleared" athletes. These deficits may not only negatively impact sports performance but also raise the risk of re-injury. Programs designed to successfully return an athlete to previous level of play should include not only strength and conditioning aimed at restoring fitness that was compromised as a result of the injury but also include attention to psychological readiness and address deficits in neuromuscular control. Problems that exist following ACLR cannot be solved by one professional; successful rehabilitation and return to play require a coordinated effort among the surgeon, physical therapist, athletic trainer, and fitness professional. Future research is needed to determine the optimal strategy to restore the neuromuscular control, functional strength, and psychological readiness necessary for a successful return to competition following ACLR. PMID- 28674944 TI - A Functional Genomics Approach to Henipavirus Research: The Role of Nuclear Proteins, MicroRNAs and Immune Regulators in Infection and Disease. AB - Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are zoonotic RNA viruses that cause lethal disease in humans and are designated as Biosafety Level 4 (BSL4) agents. Moreover, henipaviruses belong to the same group of viruses that cause disease more commonly in humans such as measles, mumps and respiratory syncytial virus. Due to the relatively recent emergence of the henipaviruses and the practical constraints of performing functional genomics studies at high levels of containment, our understanding of the henipavirus infection cycle is incomplete. In this chapter we describe recent loss-of function (i.e. RNAi) functional genomics screens that shed light on the henipavirus-host interface at a genome-wide level. Further to this, we cross reference RNAi results with studies probing host proteins targeted by henipavirus proteins, such as nuclear proteins and immune modulators. These functional genomics studies join a growing body of evidence demonstrating that nuclear and nucleolar host proteins play a crucial role in henipavirus infection. Furthermore these studies will underpin future efforts to define the role of nucleolar host virus interactions in infection and disease. PMID- 28674943 TI - Host-Induced Silencing of Pathogenicity Genes Enhances Resistance to Fusarium oxysporum Wilt in Tomato. AB - This study presents a novel approach of controlling vascular wilt in tomato by RNAi expression directed to pathogenicity genes of Fusarium oxysporum f. sp. lycopersici. Vascular wilt of tomato caused by Fusarium oxysporum f. sp. lycopersici leads to qualitative and quantitative loss of the crop. Limitation in the existing control measures necessitates the development of alternative strategies to increase resistance in the plants against pathogens. Recent findings paved way to RNAi, as a promising method for silencing of pathogenicity genes in fungus and provided effective resistance against fungal pathogens. Here, two important pathogenicity genes FOW2, a Zn(II)2Cys6 family putative transcription regulator, and chsV, a putative myosin motor and a chitin synthase domain, were used for host-induced gene silencing through hairpinRNA cassettes of these genes against Fusarium oxysporum f. sp. lycopersici. HairpinRNAs were assembled in appropriate binary vectors and transformed into tomato plant targeting FOW2 and chsV genes, for two highly pathogenic strains of Fusarium oxysporum viz. TOFOL-IHBT and TOFOL-IVRI. Transgenic tomatoes were analyzed for possible attainment of resistance in transgenic lines against fungal infection. Eight transgenic lines expressing hairpinRNA cassettes showed trivial disease symptoms after 6-8 weeks of infection. Hence, the host-induced posttranscriptional gene silencing of pathogenicity genes in transgenic tomato plants has enhanced their resistance to vascular wilt disease caused by Fusarium oxysporum. PMID- 28674946 TI - Toxin Transport by A-B Type of Toxins in Eukaryotic Target Cells and Its Inhibition by Positively Charged Heterocyclic Molecules. AB - A-B types of toxins are among the most potent bacterial protein toxins produced by gram-positive bacteria. Prominent examples are the tripartite anthrax toxin of Bacillus anthracis and the different A-B type clostridial toxins that are the causative agents of severe human and animal diseases and could serve as biological weapons. The components of all these toxins comprise one binding/transport (B) subunit and one or two separate, non-linked enzymatically active (A) subunits. The A and B subunits are separately produced and secreted by the pathogenic gram-positive bacteria and must assemble on the surface of eukaryotic target cells to form biologically active toxin complexes. The B components are cleaved by proteases to generate the biologically active species that binds to receptors on the surface of the target cells and form there oligomers which bind the A subunits. The AB complexes are internalized by receptor-mediated endocytosis and reach early or late endosomes that become acidified. Subsequently, the B components form channels in endosomal membranes that are indispensable for the transport of the enzymatic subunits across these membranes into the cytosol of target cells via the trans-membrane channels. In addition to the channels formed by the B components, host cell factors including chaperones and further folding helper enzymes are involved in the import of the enzymatic subunits into the cytosol of eukaryotic cells. Positively charged heterocyclic molecules, such as chloroquine and related aminoquinolinium and azolopyridinium salts have been shown in recent years to bind with high affinity to the channels formed by the B components of binary toxins. Since binding to the B components is also a prerequisite for transport of the A components across the endosomal membranes the channel blockers also prevent transport of the A subunits into the host cell cytosol. The inhibition of toxin uptake into cells by such pharmacological compounds should also be of clinically interest because the toxins are the major virulence factors causing anthrax on the one hand and severe enteric disease on the other hand. Therefore, the novel toxin inhibitors should be attractive compounds for an application in combination with antibiotics to prevent or treat the diseases associated with binary toxins. Here the different processes involved in channel block in vitro and inhibition of intoxication of living target cells are reviewed in some detail. PMID- 28674945 TI - Roles of Non-coding RNAs During Herpesvirus Infection. AB - Non-coding RNAs (ncRNAs) play essential roles in multiple aspects of the life cycles of herpesviruses and contribute to lifelong persistence of herpesviruses within their respective hosts. In this chapter, we discuss the types of ncRNAs produced by the different herpesvirus families during infection, some of the cellular ncRNAs manipulated by these viruses, and the overall contributions of ncRNAs to the viral life cycle, influence on the host environment, and pathogenesis. PMID- 28674947 TI - Rectal axis and enterocele on proctogram may predict laparoscopic ventral mesh rectopexy outcomes for rectal intussusception. AB - BACKGROUND: Laparoscopic ventral mesh rectopexy (LVMR) has become a well established treatment for symptomatic high-grade internal rectal prolapse. The aim of this study was to identify proctographic criteria predictive of a successful outcome. METHODS: One hundred and twenty consecutive patients were evaluated from a prospectively maintained pelvic floor database. Pre- and post operative functional results were assessed with the Wexner constipation score (WCS) and Fecal Incontinence Severity Index (FISI). Proctogram criteria were analyzed against functional results. These included grade of intussusception, presence of enterocele, rectocele, excessive perineal descent and the orientation of the rectal axis at rest (vertical vs. horizontal). RESULTS: Ninety-one patients completed both pre- and post-operative follow-up questionnaires. Median pre-operative WCS was 14 (range 10-17), and median FISI was 20 (range 0-61), with 28 patients (31%) having a FISI above 30. The presence of an enterocele was associated with more frequent complete resolution of obstructed defecation (70 vs. 52%, p = 0.02) and fecal incontinence symptoms (71 vs. 38%, p = 0.01) after LVMR. Patients with a more horizontal rectum at rest pre-operatively had significantly less resolution of symptoms post-operatively (p = 0.03). CONCLUSIONS: These data show that proctographic findings can help predict functional outcomes after LVMR. Presence of an enterocele and a vertical axis of the rectum at rest may be associated with a better resolution of symptoms. PMID- 28674948 TI - Transitional health care for patients with Hirschsprung disease and anorectal malformations. AB - BACKGROUND: Hirschsprung disease (HD) and anorectal malformations (ARM) are congenital disorders with potentially lifelong consequences. Although follow-up is performed in most pediatric patients, transfer to adult health care is often problematic. This study assesses transitional care with the help of questionnaires in consultation with adult patients. METHODS: This study was conducted in an outpatient clinic of a pediatric surgical center in the Netherlands. All patients born and treated for ARM or HD before 1992 were invited to visit our clinic. Patients completed questionnaires concerning disease specific functioning and quality of life at an initial visit to in response to which individual treatment plans were modified. Patients were reviewed 1 year later. RESULTS: Twenty-seven patients (17 ARM and 10 HD), mean age 27.9 years (range 17-64 years) of the 168 invited visited the transitional clinic (17%). Passive fecal incontinence was reported by 7/27, other defecatory problems, including urge incontinence and incomplete evacuation in 17/27 and anal or abdominal pain reported by 9/27. Quality of life was lower than a matched population. Only 13/27 returned for repeat assessment at 1 year; however, a further 8 reported that that their problems had resolved. In those attending follow-up, negative thoughts and feelings about their condition had decreased and one more patient was fully continent. There was no change in quality of life, bowel function or pain recorded. Twelve out of thirteen patients reported that they had found the transitional clinic satisfactory. CONCLUSIONS: The transitional outpatient clinic provides care adapted to the needs and wishes of adult HD and ARM patients. It is a novel addition to quality of care of patients with complex congenital disorders. PMID- 28674949 TI - Dynamic translabial ultrasound versus echodefecography combined with the endovaginal approach to assess pelvic floor dysfunctions: How effective are these techniques? AB - BACKGROUND: The aim of this study was to evaluate the role of dynamic translabial ultrasound (TLUS) in the assessment of pelvic floor dysfunction and compare the results with echodefecography (EDF) combined with the endovaginal approach. METHODS: Consecutive female patients with pelvic floor dysfunction were eligible. Each patient was assessed with EDF combined with the endovaginal approach and TLUS. The diagnostic accuracy of the TLUS was evaluated using the results of EDF as the standard for comparison. RESULTS: A total of 42 women were included. Four sphincter defects were identified with both techniques, and EDF clearly showed if the defect was partial or total and additionally identified the pubovisceral muscle defect. There was substantial concordance regarding normal relaxation and anismus. Perfect concordance was found with rectocele and cystocele. The rectocele depth was measured with TLUS and quantified according to the EDF classification. Fair concordance was found for intussusception. There was no correlation between the displacement of the puborectal muscle at maximum straining on EDF with the displacement of the anorectal junction (ARJ), compared at rest with maximal straining on TLUS to determine perineal descent (PD). The mean ARJ displacement was similar in patients with normal and those with excessive PD on TLUS. CONCLUSIONS: Both modalities can be used as a method to assess pelvic floor dysfunction. The EDF using 3D anorectal and endovaginal approaches showed advantages in identification of the anal sphincters and pubodefects (partial or total). There was good correlation between the two techniques, and a TLUS rectocele classification based on size that corresponds to the established classification using EDF was established. PMID- 28674950 TI - Confocal laser endomicroscopy in ulcerative colitis: beyond endoscopic assessment of disease activity. AB - BACKGROUND: The aim of this study was to investigate the role of confocal laser endomicroscopy (CLE) in the assessment of disease activity in ulcerative colitis (UC). METHODS: Consecutive patients with UC referred to our inflammatory bowel disease unit for colonoscopy were enrolled. Patients without UC were used as controls. UC activity was evaluated by white light endoscopy and classified according to the Mayo Ulcerative Colitis Endoscopic Score of Severity. Endoscopic biopsies were also taken for histological assessment of disease activity and then assessed with CLE. Three parameters were evaluated; crypt architecture (crypt diameter, inter-crypt distance, presence of fused crypts, crypts regularity), microvascular pattern (regular, dilated, irregular and deformed), fluorescein leakage. RESULTS: Fifty patients with UC and 10 controls were enrolled. At colonoscopy, 11 patients (22%), 19 patients (38%), 12 patients (24%) and 8 patients (16%) presented a Mayo score of 0, 1, 2 and 3, respectively. At CLE, fused crypts were present in all the patients with UC and absent in controls. Crypt diameter and inter-crypt distance showed a parallel increase with the Mayo score. Fluorescein leakage and irregular vessels were more frequently found in case of a high level of endoscopic severity, but were also identified in about 20% of UC patients with normal mucosa. Biopsies also demonstrated the presence of histological activity in 4 patients with endoscopically inactive colitis. CONCLUSIONS: CLE might be a useful tool to determine inflammatory activity in UC. Fused crypts appeared to be a CLE marker of UC, while other abnormalities, like microvascular alteration and fluorescein leakage, have also been identified in patients with mucosal healing at endoscopy. Larger series are required to validate these results and the advantages of a CLE-based assessment of UC activity. PMID- 28674951 TI - The Impact of Refugee Mothers' Trauma, Posttraumatic Stress, and Depression on Their Children's Adjustment. AB - The mechanisms linking refugee parents' trauma onto their children's functioning are not well understood. The current study sought to identify how Somali refugee mothers' past trauma and current mental health impact their children's psychosocial adjustment. One hundred and ninety-eight Somali mothers (M age = 39 years) and their children (M age = 10 years; 56% male) were studied. On average, mothers spent 7 years in refugee camps, experienced significant trauma, and some had been tortured. Measures of mothers' posttraumatic stress and depression were analyzed as three symptom clusters: volatility/panic, withdrawn/detached, and depressed mood. Most children were born in the U.S. and their indirect exposure to trauma was statistically controlled. Results from structural equation modeling indicated that there was no direct association between trauma of the mother and their children's well-being, however, mothers' posttraumatic stress and depressive symptoms significantly mediated the effects of mothers' past torture on their children's adjustment-a pattern indicative of intergenerational traumatization. Findings enhance our understanding of how refugees' traumatization lingers and possibly affects their and their children's health and well-being. PMID- 28674952 TI - A new genus and species of the trypanorhynch family Otobothriidae Dollfus, 1942 from the slender weasel shark Paragaleus randalli Compagno, Krupp & Carpenter (Hemigaleidae) in the Persian Gulf. AB - A survey on the cestode fauna of Paragaleus randalli Compagno, Krupp & Carpenter in the Persian Gulf resulted in the discovery of a new trypanorhynch species of the family Otobothriidae Dollfus, 1942, the second otobothrioid species hosted by the family Hemigaleidae Hasse. The new species exhibits the closest morphological similarity to Pristiorhynchus palmi Schaeffner & Beveridge, 2013, the type- and only species of its genus. However, the new species differs from P. palmi in the position of the bothrial pits, the morphology and oncotaxy of the basal armature, the commencement of the hook files on the internal surface, a wider scolex peduncle in the pars bulbosa than in the pars vaginalis, a long neck and the presence of a lateral bothrial groove connecting the two bothrial pits to each other. The latter character is a unique trait within the Otobothrioidea Dollfus, 1942. Considering such differences, a new genus, Olgaella n. g., was erected to accommodate O. elenae n. g., n. sp. within the Otobothriidae. The evolutionary relatedness of the bothrial pits of the Otobothrioidea and the bothrial grooves of the Lacistorhynchoidea Guiart, 1927 is discussed. PMID- 28674953 TI - A comparative analysis of in vitro toxicity of diesel exhaust particles from combustion of 1st- and 2nd-generation biodiesel fuels in relation to their physicochemical properties-the FuelHealth project. AB - Biodiesels represent more carbon-neutral fuels and are introduced at an increasing extent to reduce emission of greenhouse gases. However, the potential impact of different types and blend concentrations of biodiesel on the toxicity of diesel engine emissions are still relatively scarce and to some extent contradictory. The objective of the present work was to compare the toxicity of diesel exhaust particles (DEP) from combustion of two 1st-generation fuels: 7% fatty acid methyl esters (FAME; B7) and 20% FAME (B20) and a 2nd-generation 20% FAME/HVO (synthetic hydrocarbon biofuel (SHB)) fuel. Our findings indicate that particulate emissions of each type of biodiesel fuel induce cytotoxic effects in BEAS-2B and A549 cells, manifested as cell death (apoptosis or necrosis), decreased protein concentrations, intracellular ROS production, as well as increased expression of antioxidant genes and genes coding for DNA damage response proteins. The different biodiesel blend percentages and biodiesel feedstocks led to marked differences in chemical composition of the emitted DEP. The different DEPs also displayed statistically significant differences in cytotoxicity in A549 and BEAS-2B cells, but the magnitude of these variations was limited. Overall, it seems that increasing biodiesel blend concentrations from the current 7 to 20% FAME, or substituting 1st-generation FAME biodiesel with 2nd generation HVO biodiesel (at least below 20% blends), affects the in vitro toxicity of the emitted DEP to some extent, but the biological significance of this may be moderate. PMID- 28674954 TI - Biosynthesis of staphylococcal enterotoxin A by genetic engineering technology and determination of staphylococcal enterotoxin A in water by HPLC-ESI-TOF. AB - Staphylococcal enterotoxin A (SEA) was the major virulence factor of Staphylococcus aureus and a biomarker of S. aureus. To establish a fast, low cost, high accuracy, reliable, and simple method for detecting S. aureus, SEA was analyzed by HPLC-ESI-TOF. SEA was not yet commercially available in universal, so SEA was prepared before it was analyzed by HPLC-ESI-TOF. The result showed that high purified SEA was successfully prepared and SEA has normal distribution in mass spectra. A large amount of recombinant SEA (rSEA) was obtained by engineering technology and was purified by Ni affinity chromatography column, and the expression and purity of rSEA and SEA were analyzed by SDS-PAGE. The factors effected on ionization of SEA were studied, and the qualitative analysis of SEA by HPLC-ESI-TOF. The result showed that large amount of SEs expressed within a short time at 28 degrees C or thereabouts, and there was no impurity bands in electrophorogram after rSEA was purified by Ni affinity chromatography column. In addition, the SEA which had homologous AA sequence with wild SEA was made by rSEA. The retention of SEA in column and ionization of SEA in ESI-TOF were studied for qualitative analysis of S. aureus. The result showed that the content of formic acid in mobile phase was an important factor for ionization of SEs in ESI-TOF. And the result provided theoretical foundation for qualitative detection of S. aureus. [SEs + nH+ + mNH4+] n+m+ was shown on ESI-TOF spectra when SEA was detected by ESI-TOF in positive ion mode, and the numerical value of n+m was less than or equal to the number of basic amino acids in SEs. This method was applied to determine SEA in water samples preliminarily, and the detection limit of SEA in spiked water sample was 3 mg/kg. The limit of detection of 3 mg/kg was low sensitivity for low molecular weight matters, but it was high sensitivity for SEA which had a high molecular weight of 27 kDa. Of SEA, 3 mg/kg was equivalent to 10 4 mmol/kg of SEA. This study can provide evidence for establishing method to determine SEA in real samples. PMID- 28674955 TI - Herbicide/Zn-Al-layered double hydroxide hybrid composite: synthesis and slow/controlled release properties. AB - The herbicide glyphosate (GLY) or 2,4-dichlorophenoxyacetic acids (2,4D) was intercalated in the interlayer region of a Zn-Al-layered double hydroxide (LDH) to obtain LDH-GLY or the LDH-2,4D hybrid composite because of its controlled release. Compared to the physically mixed herbicides, the LDH-herbicide hybrid composite displayed slow-release properties in decarbonated distilled water. The release rate of herbicides was found to be dependent on the carbonate and chloride anion concentrations in solution. The time at which 50% of the herbicides were released from the hybrid composite into solution, t 50, ranged from 6.5 to 18.6 h for LDH-GLY and from 10 to 21.5 h for LDH-2,4D. Our results indicate that the application of LDH-GLY or LDH-2,4D hybrid composite to agricultural areas could reduce the maximum 2,4D or GLY contamination and result in the retardation of herbicides leaching through the soil. This study demonstrates the potential applicability of LDHs as supports for the slow release of acid herbicides. PMID- 28674956 TI - Preparation of modified waterworks sludge particles as adsorbent to enhance coagulation of slightly polluted source water. AB - Without treatment, waterworks sludge is ineffective as an adsorbent. In this study, raw waterworks sludge was used as the raw material to prepare modified sludge particles through high-temperature calcination and alkali modification. The feasibility of using a combination of modified particles and polyaluminum chloride (PAC) as a coagulant for treatment of slightly polluted source water was also investigated. The composition, structure, and surface properties of the modified particles were characterized, and their capabilities for removing ammonia nitrogen and turbidity were determined. The results indicate that the optimal preparation conditions for the modified sludge particles were achieved by preparing the particles with a roasting temperature of 483.12 degrees C, a roasting time of 3.32 h, and a lye concentration of 3.75%. Furthermore, enhanced coagulation is strengthened with the addition of modified sludge particles, which is reflected by reduction of the required PAC dose and enhancement of the removal efficiency of ammonia nitrogen and turbidity by over 80 and 93%, respectively. Additional factors such as pH, temperature, dose, and dosing sequence were also evaluated. The optimum doses of modified particles and PAC were 40 and 15 mg/L, respectively, and adding modified particles at the same time as or prior to adding PAC improves removal efficiency. PMID- 28674958 TI - Monovision Versus Multifocality for Presbyopia: Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Refractive surgery in presbyopia tends to achieve spectacle independence with minimal optical disturbances. We compared monovision to multifocality procedures regarding these outcomes. METHODS: We conducted a systematic review of published (till November 21, 2016) randomized controlled trials (RCTs) comparing any monovision to any multifocality method or comparing different monovision/multifocality methods to each other that enabled direct or indirect comparisons between particular monovision and particular multifocality procedures in presbyopic patients undergoing cataract-related or unrelated surgery in respect to spectacle independence, unaided binocular visual acuity (VA), contrast sensitivity (CS), and adverse events. RESULTS: Three trials comparing monovision (monofocal lenses, LASIK) to multifocal intraocular lenses (MFIOLs; Isert refractive or Tecnis diffractive) and 6 comparing other MFIOLs to Tecnis were included (1-12 months duration). Spectacle independence. All reporting trials were of sufficient quality. Directly, pseudophakic monovision was inferior to Isert (1 trial, N = 75, RR = 0.49, 95% CI 0.28-0.80) and Tecnis (1 trial, N = 211, RR = 0.36, 95% CI 0.25-0.52) in cataract patients, and LASIK was comparable to Tecnis (1 trial, N = 100, RR = 0.93, 0.78-1.10) in refractive surgery. In network meta-regression (6 trials, 14 arms) pseudophakic monovision in cataract patients was inferior to Tecnis. Indirect data suggest also that it is inferior (ReZoom refractive, TwinSet diffractive) or tends to be inferior (Array refractive) to other MFIOLs. LASIK was comparable to Tecnis in refractive surgery. Indirect data suggest also that it tends to superiority vs. ReZoom or Array refractive MFIOLs. Adverse events. No pooling was possible (heterogeneity of assessment and reporting). One quality direct RCT indicated less glare/dazzle with pseudophakic monovision vs. Tecnis in cataract patients. Unaided VA and CS data were burdened with heterogeneity (assessment, reporting) and insufficient quality. CONCLUSIONS: Randomized comparisons of monovision to multifocality are scarce. Existing estimates regarding spectacle independence (imprecision, indirectness) and particularly regarding unaided VA and CS (assessment/reporting heterogeneity, bias, imprecision, indirectness) are burdened with uncertainty. Dysphotopsia is less common with monovision, but estimate uncertainty is high (bias, imprecision). PMID- 28674957 TI - A Review of the Long-Term Efficacy, Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes. AB - INTRODUCTION: Exenatide once weekly (ExeOW, Bydureon(r), Astra Zeneca), a drug belonging to the class of glucagon-like peptide-1 (GLP-1) receptor agonists, is the first agent approved for treatment of type 2 diabetes (T2D) that can be administered on a weekly basis. METHODS: Data concerning treatment of T2D with ExeOW are reviewed with special reference to its long-term efficacy, tolerability, and safety. Relevant literature was identified through the PubMed database from inception to January 2015. RESULTS: In randomized clinical trials ExeOW, as add-on to oral antidiabetics, achieved significantly improved glycemic control compared to maximum recommended doses of exenatide twice daily, sitagliptin, pioglitazone, and insulin glargine, as measured by HbA1c. In drug naive patients ExeOW was superior to sitagliptin and non-inferior to metformin, whereas non-inferiority to pioglitazone and liraglutide was not proven. In different trials reductions in HbA1c ranged from -1.1% to -2.0%. ExeOW therapy over 6 months was also associated with a mean weight loss of -2 to -4 kg, improved systolic blood pressure and lipid profile, and no hypoglycemia unless associated to sulfonylurea. ExeOW long-term therapy up to 3-6 years allowed persistent glycemic control (HbA1c -1.6%), sustained decreases in blood pressure (-2 mmHg), and improvements of lipid profile. ExeOW tolerability was comparable to that of the other GLP-1 receptor agonists, with better gastrointestinal tolerability when direct comparison was done (namely liraglutide and exenatide BID), but higher incidence of injection site reactions and few treatment discontinuations mainly due to gastrointestinal events. CONCLUSION: ExeOW is a well-tolerated and convenient option for long-term treatment of T2D allowing significant and persistent glycemic control with moderate weight loss and low risk of hypoglycemia unless associated with sulfonylureas. PMID- 28674959 TI - Treatment Persistence and Clinical Outcomes of Tumor Necrosis Factor Inhibitor Cycling or Switching to a New Mechanism of Action Therapy: Real-world Observational Study of Rheumatoid Arthritis Patients in the United States with Prior Tumor Necrosis Factor Inhibitor Therapy. AB - INTRODUCTION: To examine treatment persistence and clinical outcomes associated with switching from a tumor necrosis factor inhibitor (TNFi) to a medication with a new mechanism of action (MOA) (abatacept, anakinra, rituximab, tocilizumab, or tofacitinib) versus cycling to another TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) among patients with rheumatoid arthritis. METHODS: This retrospective, longitudinal study included patients with rheumatoid arthritis in the JointMan(r) US clinical database who received a TNFi in April 2010 or later and either cycled to a TNFi or switched to a new MOA therapy by March 2015. Cox proportional hazards models were used for time to non-persistence (switching or discontinuing). An ordinary least squares regression model compared 1-year reduction from baseline for the Clinical Disease Activity Index (CDAI). RESULTS: There were 332 (54.2%) TNFi cyclers and 281 (45.8%) new MOA switchers. During a median follow-up of 29.9 months, treatment persistence was 36.7% overall. Compared with new MOA switchers, TNFi cyclers were 51% more likely to be non-persistent (adjusted hazard ratio, 1.511; 95% CI 1.196, 1.908), driven by a higher likelihood of switching again (adjusted hazard ratio, 2.016; 95% CI 1.428, 2.847). Clinical outcomes were evaluable for 239 (53.3%) TNFi cyclers and 209 (46.7%) new MOA switchers. One-year mean reduction in CDAI from baseline to end of follow-up was significantly higher for new MOA switchers than TNFi cyclers ( 7.54 vs. -4.81; P = 0.037), but the difference was not statistically significant after adjustment for baseline CDAI (-6.39 vs. -5.83; P = 0.607). CONCLUSION: In this study, TNFi cycling was common in clinical practice, but switching to a new MOA DMARD was associated with significantly better treatment persistence and a trend toward greater CDAI reduction that was not significant after adjustment for baseline disease activity. FUNDING: Sanofi and Regeneron Pharmaceuticals. PMID- 28674960 TI - Autopsy histopathology where the prosector is not a histopathologist: a proposal. AB - Forensic pathology is a specialty that involves death investigation while clinical forensic medicine is the application of the practice of medicine to the requests of the law in relation to the living. Around the world, there is diverse practice for these two disciplines. The forensic physician or forensic doctor (sometimes, called a forensic pathologist but not a forensic histopathologist) in parts of the world such as continental Europe, the Middle East and India, practice both clinical forensic medicine and forensic pathology. This is the specialty, for the purposes of this paper, we will call forensic medicine. The forensic doctor will usually receive training in autopsy dissection, perhaps with a short training of a few months in anatomical pathology or surgical histopathology. When undertaking autopsies (involving internal as well as external examination), if it is thought histological assessment is required, the forensic doctor will sample the organs and tissues required and refer the specimens to the hospital histopathologist for microscopic examination. This division of responsibility could compromise the quality of the autopsy unless handled correctly.Where the histological assessment of the autopsy specimen is undertaken by a pathologist other than the one who dissected the body and collected the samples, standard operating procedures need to be developed to minimize the risk to the overall quality of the autopsy. We are not aware that any such procedures have been published, hence we offer an outline of what a set of such procedures might contain. PMID- 28674961 TI - Examples of tramline bruises in clinical forensic medicine. PMID- 28674962 TI - Fabry disease. AB - Fabry disease resulting from a deficiency of alpha-galactosidase A leads to the accumulation of globotriaosylceramide in various organs. Because the disease is an X-linked recessive disorder, males tend to develop more symptoms and more severe symptoms than females. There are also some variants of Fabry disease, and cardiac variant (cardiac Fabry disease) has the dysfunctions only in heart. Cardiac manifestations in Fabry disease are initially symmetrical and concentric left ventricular hypertrophy, and later progressive cardiac dysfunction with localized thinning of the basal posterior wall. In recent years, enzyme replacement therapy has been performed as a treatment for Fabry disease, and the initiation of this therapy is expected before the cardiac fibrosis develops. Therefore, early diagnosis of Fabry disease is essential, and echocardiography is an indispensable tool for clinical practice of this disease. Then, it is necessary to remember this disease as a differential diagnosis when encountering unexplained left ventricular hypertrophy. PMID- 28674963 TI - Evaluation of Mayer-Rokitansky-Kuster-Hauser syndrome with magnetic resonance imaging: Three patterns of uterine remnants and related anatomical features and clinical settings. AB - OBJECTIVE: To characterize the anatomical features and clinical settings of Mayer Rokitansky-Kuster-Hauser (MRKH) syndrome and correlate them with patterns of uterine involvement. METHODS: Pelvic magnetic resonance images and medical records of 92 MRKH patients were retrospectively reviewed. Patients were subgrouped by uterine morphology: uterine agenesis, unilateral rudimentary uterus and bilateral rudimentary uteri. Uterine volume, presence of endometrium, location of ovary, endometriosis and pelvic pain were compared among groups. RESULTS: The mean uterine volume was 33.5 ml (17.5-90.0 ml) for unilateral uterine remnants, and 16.1 ml (3.5-21.5 ml) for bilateral uterine rudiments (p<0.01). The incidence of presence of endometrium (100% vs. 22%, p<0.001), haematometra (56% vs. 3%, p<0.001) and ovarian endometriosis (22% vs. 3%, p<0.01) was significantly increased in the group of unilateral rudimentary uteri as compared with the group of bilateral uterine remnants. Thirty-one patients (38%) showed ectopic ovaries. Pelvic pain was more common in individuals with unilateral rudimentary uterus than those who had no (56% vs. 5%, p<0.01) or bilateral uterine remnants (56% vs. 14%, p<0.05). CONCLUSION: MRKH patients with different patterns of uterine involvement may have differentiated anatomical features and clinical settings. KEY POINTS: * Rudimentary uteri, especially bilateral rudimentary uteri, were quite common in MRKH syndrome. * Uterine remnants can be relatively large, especially the unilateral rudimentary uterus. * Presence of endometrium and related complications are not rare in MRKH syndrome. * Existence of endometrium and complications are more frequent in unilateral rudimentary uterus. PMID- 28674964 TI - Gadobutrol versus gadofosveset-trisodium in MR venography of the lower extremities. AB - OBJECTIVES: MR venography (MRV) protocols have used bloodpool contrast agents and long scan sequences to identify patients suitable for treatment and preoperatively. However, variable availability of bloodpool contrast agents, high costs and a need to shorten acquisition times for routine MR protocols hamper everyday practice. MATERIALS: 20 patients (11 men; mean age 54 +/- 11.8 years; body mass index 23.6 +/- 2.5) were enrolled in this prospective study. An intra individual comparison of image quality, interpretation and findings for two different contrast agents (regular gadolinium contrast agent gadobutrol vs. bloodpool contrast agent gadofosveset-trisodium) and two different scan protocols (long acquisition time protocol using a high-resolution fast field echo (FFE) sequence vs. short acquisition time protocol using an ultra-fast gradient echo (GE) sequence) were performed. RESULTS: Image quality (average of 4.94 vs. 4.92 on a five-point scale), interpretation and contrast-to-noise ratio (44 vs. 45) were equal for both contrast agents. Image findings showed no statistical significant differences between the MR protocols or contrast agents (overall p = 0.328). CONCLUSIONS: For high-resolution MRV, it is possible to replace gadofosveset-trisodium with gadobutrol. Furthermore, an ultra-fast GE sequence for MRV might considerably shorten acquisition time, without loss of image quality or diagnostic yield. KEY POINTS: * High-quality MRV can be performed with a regular gadolinium-based contrast agent. * Ultra-fast GRE vs. HR-FFE MRV: equally suitable for evaluation of venous obstruction. * Regular gadolinium-based contrast agent can supersede a bloodpool contrast agent for MRV. * Equal confidence for gadobutrol vs gadofosveset-trisodium in MRV. * MRV accessible for routine daily practice. PMID- 28674965 TI - Dual energy CT iodine map for delineating inflammation of inflammatory arthritis. AB - : Iodine mapping is an image-processing technique used with dual-energy computed tomography (DECT) to improve iodine contrast resolution. CT, because of its high spatial resolution and thin slice reconstruction, is well suited to the evaluation of the peripheral joints. Recent developments in the treatment of inflammatory arthritis that require early diagnosis and precise therapeutic assessment encourage radiological evaluation. To facilitate such assessment, we describe DECT iodine mapping as a novel modality for evaluating rheumatoid arthritis and psoriatic arthritis of the hands and feet. KEY POINTS: * Dual energy CT iodine mapping can delineate inflammation of peripheral inflammatory arthritis. * DECT iodine mapping has high spatial resolution compared with MRI. * DECT iodine mapping has a high iodine contrast resolution. * DECT iodine mapping may reflect therapeutic effects. PMID- 28674966 TI - Preoperative staging of endometrial cancer using reduced field-of-view diffusion weighted imaging: a preliminary study. AB - OBJECTIVES: To compare the image quality and diagnostic performance of reduced field-of-view (rFOV) versus conventional full field-of-view (fFOV) diffusion weighted (DW) imaging of endometrial cancer. METHODS: Fifty women with endometrial cancer underwent preoperative rFOV and fFOV DW imaging. Two radiologists compared the image qualities of both techniques, and five radiologists assessed superficial and deep myometrial invasion using both techniques. The statistical analysis included the Wilcoxon signed-rank test and paired t-test for comparisons of image quality and mean diagnostic values. RESULTS: Distortion, tumour delineation, and overall image quality were significantly better with rFOV DW imaging, compared to fFOV DW imaging (P < 0.05); however, the former was inferior in noise (P < 0.05). Regarding superficial invasion, the mean accuracies of the techniques did not differ statistically (rFOV, 58.0% versus fFOV, 56.0%; P = 0.30). Regarding deep myometrial invasion, rFOV DW imaging yielded significantly better mean accuracy, specificity, and positive predictive values (88.4%, 97.8%, and 91.7%, respectively), compared with fFOV DW imaging (84.8%, 94.1%, and 77.4%, respectively; P = 0.009, 0.005, and 0.011, respectively). CONCLUSIONS: Compared with fFOV DW imaging, rFOV DW imaging yielded less distortion, improved image quality and, consequently, better diagnostic performance for deep myometrial invasion of endometrial cancer. KEY POINTS: * rFOV DWI yields better assessment of deep myometrial invasion in endometrial cancer. * rFOV DWI could not sufficiently evaluate superficial invasion in endometrial cancer. * Distortion, tumour delineation, and overall image quality were improved with rFOV DWI. PMID- 28674967 TI - Adverse events during CT colonography for screening, diagnosis and preoperative staging of colorectal cancer: a Japanese national survey. AB - OBJECTIVES: To retrospectively evaluate the frequencies and magnitudes of adverse events associated with computed tomographic colonography (CTC) for screening, diagnosis and preoperative staging of colorectal cancer. METHODS: A Japanese national survey on CTC was administered by use of an online survey tool in the form of a questionnaire. The questions covered mortality, colorectal perforation, vasovagal reaction, total number of examinations, and examination procedures. The survey data was collated and raw frequencies were determined. Fisher's exact test was used to determine differences in event rates between groups. RESULTS: At 431 institutions, 147,439 CTC examinations were performed. No deaths were reported. Colorectal perforations occurred in 0.014% (21/147,439): 0.003% (1/29,823) in screening, 0.014% (13/91,007) in diagnosis and 0.028% (7/25,330) in preoperative staging. The perforation risk was significantly lower in screening than in preoperative staging CTC procedures (p = 0.028). Eighty-one per cent of perforation cases (17/21) did not require emergency surgery. Vasovagal reaction occurred in 0.081% (120/147,439): 0.111% (33/29,823) in screening, 0.088% (80/91,007) in diagnosis and 0.028% (7/25,330) in preoperative staging. CONCLUSIONS: The risk of colorectal perforation and vasovagal reaction in CTC is low. The frequency of colorectal perforation associated with CTC is least in the screening group and greatest in the preoperative-staging group. KEY POINTS: * The colorectal perforation rate during preoperative-staging CTC was 0.028 %. * The perforation rates for screening and diagnosis were 0.003 % and 0.014 %, respectively. * The perforation risk is significantly lower in screening than in preoperative staging. * Eighty-one per cent of perforation cases did not require emergency surgery. * Use of an automatic colon insufflator can reduce the risk of bowel perforation. PMID- 28674968 TI - Recommendations for radioembolisation after liver surgery using yttrium-90 resin microspheres based on a survey of an international expert panel. AB - INTRODUCTION: Guidelines on how to adjust activity in patients with a history of liver surgery who are undergoing yttrium-90 radioembolisation (90Y-RE) are lacking. The aim was to study the variability in activity prescription in these patients, between centres with extensive experience using resin microspheres 90Y RE, and to draw recommendations on activity prescription based on an expert consensus. METHODS: The variability in activity prescription between centres was investigated by a survey of international experts in the field of 90Y-RE. Six representative post-surgical patients (i.e. comparable activity prescription, different outcome) were selected. Information on patients' disease characteristics and data needed for activity calculation was presented to the expert panel. Reported was the used method for activity prescription and whether, how and why activity reduction was found indicated. RESULTS: Ten experts took part in the survey. Recommendations on activity reduction were highly variable between the expert panel. The median intra-patient range was 44 Gy (range 18-55 Gy). Reductions in prescribed activity were recommended in 68% of the cases. In consensus, a maximum DTarget of 50 Gy was recommended. CONCLUSION: With a current lack of guidelines, large variability in activity prescription in post-surgical patients undergoing 90Y-RE exists. In consensus, DTarget <=50 Gy is recommended. KEY POINTS: * BSA method does not account for a decreased remnant liver volume after surgery. * In post-surgical patients, a volume-based activity determination method is recommended. * In post-surgical patients, a mean D Target of <= 50Gy should be aimed for. PMID- 28674969 TI - Blastocystis in Cote d'Ivoire: molecular identification and epidemiological data. AB - Blastocystis is an enteric protozoan infecting humans and animals in both developed and developing countries at all latitudes. Despite this, data on Blastocystis infection are not available for several geographical areas, including many African countries. In this study, a survey was conducted on Blastocystis among humans and domestic animals in rural and urban localities in Cote d'Ivoire, in order to investigate the prevalence, the subtype distribution, and the zoonotic potential in association with sociodemographic factors, seasonality, symptoms, and co-infections. A total of 110 fecal samples were collected from patients living in four localities. Molecular and phylogenetic analyses were conducted for Blastocystis detection and subtyping. Positive samples from symptomatic patients were tested by Luminex xTAG(r) Gastrointestinal Pathogen Panel (GPP) to evidence the presence of other common intestinal pathogens. Overall, a prevalence of 58.2% was observed in humans and subtypes ST1(50.0%), ST2 (22.0%) and ST3 (28.1%) were identified. The prevalence values varied significantly among the sites but not in relation to the subtype. The seasonal rains significantly increase the infection rate in all localities. No significant differences in the ST distribution between asymptomatic and symptomatic subjects were observed. As regard the zoonotic transmission, an additional sampling was conducted in another village where fecal samples were simultaneously collected from humans and animals. Blastocystis STs 1-3 and ST7 were identified in eight humans and four chickens, respectively. This study provides the first exhaustive data on the prevalence and molecular epidemiology of Blastocystis in Cote d'Ivoire. PMID- 28674970 TI - Morphologies and phenotypes in Bacillus subtilis biofilms. AB - In this study, we explored Bacillus subtilis biofilm growth under various conditions such as the use of substrates with different stiffnesses and nutrient levels using a well-developed optical imaging technique to spatially and temporally track biofilm growth. We also developed a quantitative method to characterize B. subtilis biofilm morphologies under various growth conditions. To determine biofilm rim irregularities, we used the dimensionless P2A ratio, defined as P2/4piA, where P is the perimeter and A is the area of the biofilm. To estimate biofilm thickness from transmission images, we developed a calibration procedure based on Beer- Lambert's law and cross sectioning. Furthermore, to determine the distributions of different B. subtilis cell phenotypes during biofilm growth, we used a triple-fluorescence-labeled B. subtilis strain that expressed motility, matrix production, and sporulation. Based on this work, we are able to tune biofilm growth by changing its growing environment. PMID- 28674971 TI - A rapid and simple method for identifying bacterial polar lipid components in wet biomass. AB - There are marked differences between wet and freeze-dried cells with regard to the identification of polar lipid components. The determination of the polar lipid composition of freeze-dried cells is well established. However, several approaches to identifying polar lipid components in wet cells have met with limited success owing to the presence of non-polar compounds in the extracts, resulting in a lipid composition with a narrow scope. In this study, we surveyed the lipid profiles of the wet biomasses of three Gram-positive (Microbacterium lacticum, Rhodococcus koreensis, and Streptomyces longwoodensis) and two Gram negative (Pseudomonas aeruginosa and Novosphingobium capsulatum) bacteria; the results were comparable in quality to those obtained using a standard freeze dried approach. Moreover, our improved method ensures simple lipid extraction. Overall, the results of the analysis showed minor lipid profile differences between the two approaches with regard to quantity, and lipid identification was consistent in both methods for all species. PMID- 28674972 TI - Genetic variation and phylogenetic relationships of the ectomycorrhizal Floccularia luteovirens on the Qinghai-Tibet Plateau. AB - Floccularia luteovirens, as an ectomycorrhizal fungus, is widely distributed in the Qinghai-Tibet Plateau. As an edible fungus, it is famous for its unique flavor. Former studies mainly focus on the chemical composition and genetic structure of this species. However, the phylogenetic relationship between genotypes remains unknown. In this study, the genetic variation and phylogenetic relationship between the genotypes of F. luteovirens in Qinghai-Tibet Plateau was estimated through the analysis on two protein-coding genes (rpb1 and ef-1alpha) from 398 individuals collected from 24 wild populations. The sample covered the entire range of this species during all the growth seasons from 2011 to 2015. 13 genotypes were detected and moderate genetic diversity was revealed. Based on the results of network analysis, the maximum likelihood (ML), maximum parsimony (MP), and Bayesian inference (BI) analyses, the genotypes H-1, H-4, H-6, H-8, H-10, and H-11 were grouped into one clade. Additionally, a relatively higher genotype diversity (average h value is 0.722) and unique genotypes in the northeast edge of Qinghai- Tibet plateau have been found, combined with the results of mismatch analysis and neutrality tests indicated that Southeast Qinghai-Tibet plateau was a refuge for F. luteovirens during the historical geological or climatic events (uplifting of the Qinghai-Tibet Plateau or Last Glacial Maximum). Furthermore, the present distribution of the species on the Qinghai-Tibet plateau has resulted from the recent population expansion. Our findings provide a foundation for the future study of the evolutionary history and the speciation of this species. PMID- 28674974 TI - Differentiating radiation necrosis from tumor progression in brain metastases treated with stereotactic radiotherapy: utility of intravoxel incoherent motion perfusion MRI and correlation with histopathology. AB - Radiation necrosis is a serious potential adverse event of stereotactic radiosurgery that cannot be reliably differentiated from recurrent tumor using conventional imaging techniques. Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) based method that uses a diffusion-weighted sequence to estimate quantitative perfusion and diffusion parameters. This study evaluated the IVIM-derived apparent diffusion coefficient (ADC) and perfusion fraction (f), and compared the results to the gold standard histopathological defined outcomes of radiation necrosis or recurrent tumor. Nine patients with ten lesions were included in this study; all lesions exhibited radiographic progression after stereotactic radiosurgery for brain metastases that subsequently underwent surgical resection due to uncertainty regarding the presence of radiation necrosis versus recurrent tumor. Pre-surgical IVIM was performed to obtain f and ADC values and the results were compared to histopathology. Five lesions exhibited pathological radiation necrosis and five had predominantly recurrent tumor. The IVIM perfusion fraction reliably differentiated tumor recurrence from radiation necrosis (fmean = 10.1 +/- 0.7 vs. 8.3 +/- 1.2, p = 0.02; cutoff value of 9.0 yielding a sensitivity/specificity of 100%/80%) while the ADC did not distinguish between the two (ADCmean = 1.1 +/- 0.2 vs. 1.2 +/- 0.4, p = 0.6). IVIM shows promise in differentiating recurrent tumor from radiation necrosis for brain metastases treated with radiosurgery, but needs to be validated in a larger cohort. PMID- 28674973 TI - Breast cancer subtype and stage are prognostic of time from breast cancer diagnosis to brain metastasis development. AB - Breast cancer brain metastasis (BCBM) is associated with high morbidity and mortality. Patients with breast cancer risk factors associated with rapid development of BCBM could potentially benefit from early brain metastasis screening. We retrospectively reviewed all BCBM patients treated with brain radiotherapy at our institution from 1997 to 2015. Interval time to BCBM was defined as date of pathologic breast cancer diagnosis to date of radiographic evidence of brain metastasis. Patients were stratified by breast cancer molecular subtype and stage at diagnosis. Kaplan Meier analysis was conducted on time to development of BCBM. Breast cancer risk factors were correlated with time to BCBM on Cox proportion hazard analysis. The study cohort comprised 121 BCBM patients, with median interval time to BCBM of 46 months. Times to BCBM for Her2+/2HR+, Her2+, Her2-/HR+, and triple-negative (TNBC) subtypes were 70, 44, 42, and 28 months respectively (p = 0.002). Time to BCBM for stages I, II, III, and IV were 70, 54, 29, and 24 months, respectively (p = 0.000). BCBM patients were further stratified by both molecular subtype (TNBC vs. non-TNBC) and stage (I, II vs. III, IV). Median times to BCBM for non-TNBC/stage I-II, TNBC/stage I-II, non-TNBC stage III-IV, and TNBC/stage III-IV were 68, 47, 29, and 6 months respectively (p = 0.000). Subtype and stage were associated with shorter time to BCBM on multivariate analysis. Subtype and initial stage are independently correlated with decreased time to development of BCBM. Patients with advanced high stage and triple negative breast cancer develop brain metastases significantly earlier. PMID- 28674976 TI - Alzheimer's Disease: Insights from Genetic Mouse Models and Current Advances in Human IPSC-Derived Neurons. AB - Alzheimer's disease was first described in 1906 and since then tremendous efforts have been made to fully understand the disease pathology and to find a cure for this neurodegenerative disease. The diagnosis of Alzheimer's is still difficult, especially in early stages of the disease. Current treatment of Alzheimer's only ameliorates the symptoms but fails to provide a therapy. Over the last decades, animal models have been proven valuable in elucidating insights of the pathology. In vitro models using patient-derived cells are currently emerging and hold great promise in understanding the disease pathophysiology. Here, we introduce the neurobiology and genetic features of Alzheimer's and describe what we have learned from studies employing mouse models and patient-derived induced pluripotent stem cells. PMID- 28674977 TI - Clinical Aspects of Alzheimer's Disease. AB - Alzheimer's disease is the most common form of dementia accounting for 50-60% of all dementia cases. This chapter briefly reviews the history of Alzheimer's disease and provides an overview of the clinical syndromes associated with Alzheimer pathology and their associated neuroimaging findings. This chapter also reviews the neuropathology and genetics of Alzheimer's disease and concludes by discussing current work undertaken to identify suitable in vivo biomarkers for the disease. PMID- 28674975 TI - Elderly patients with newly diagnosed glioblastoma: can preoperative imaging descriptors improve the predictive power of a survival model? AB - The purpose of this study was to identify independent prognostic factors among preoperative imaging features in elderly glioblastoma patients and to evaluate whether these imaging features, in addition to clinical features, could enhance the predictive power of survival models. This retrospective study included 108 patients >=65 years of age with newly diagnosed glioblastoma. Preoperative clinical features (age and KPS), postoperative clinical features (extent of surgery and postoperative treatment), and preoperative MRI features were assessed. Univariate and multivariate cox proportional hazards regression analyses for overall survival were performed. The integrated area under the receiver operating characteristic curve (iAUC) was calculated to evaluate the added value of imaging features in the survival model. External validation was independently performed with 40 additional patients >=65 years of age with newly diagnosed glioblastoma. Eloquent area involvement, multifocality, and ependymal involvement on preoperative MRI as well as clinical features including age, preoperative KPS, extent of resection, and postoperative treatment were significantly associated with overall survival on univariate Cox regression. On multivariate analysis, extent of resection and ependymal involvement were independently associated with overall survival and preoperative KPS showed borderline significance. The model with both preoperative clinical and imaging features showed improved prediction of overall survival compared to the model with preoperative clinical features (iAUC, 0.670 vs. 0.600, difference 0.066, 95% CI 0.021-0.121). Analysis of the validation set yielded similar results (iAUC, 0.790 vs. 0.670, difference 0.123, 95% CI 0.021-0.260), externally validating this observation. Preoperative imaging features, including eloquent area involvement, multifocality, and ependymal involvement, in addition to clinical features, can improve the predictive power for overall survival in elderly glioblastoma patients. PMID- 28674978 TI - Parkinson's Disease: Basic Pathomechanisms and a Clinical Overview. AB - PD is a common and a debilitating degenerative movement disorder. The number of patients is increasing worldwide and as yet there is no cure for the disease. The majority of existing treatments target motor symptom control. Over the last two decades the impact of the genetic contribution to PD has been appreciated. Significant discoveries have been made, which have advanced our understanding of the pathophysiological and molecular basis of PD. In this chapter we outline current knowledge of the clinical aspects of PD and the basic mechanistic understanding. PMID- 28674979 TI - Huntington's Disease: Pathogenic Mechanisms and Therapeutic Targets. AB - Huntington's disease (HD) is a tandem repeat disorder involving neurodegeneration and a complex combination of symptoms. These include psychiatric symptoms, cognitive deficits culminating in dementia, and the movement disorder epitomised by motor signs such as chorea. HD is caused by a CAG repeat expansion encoding an extended tract of the amino acid glutamine in the huntingtin protein. This polyglutamine expansion appears to induce a 'change of function', possibly a 'gain of function', in the huntingtin protein, which leads to various molecular and cellular cascades of pathogenesis. In the current review, we will briefly describe these broader aspects of HD pathogenesis, but will then focus on specific aspects where there are substantial bodies of experimental evidence, including oxidative stress, mitochondrial dysfunction, glutamatergic dysfunction and neuroinflammation. Furthermore, we will review recent preclinical therapeutic approaches targeting some of these pathogenic pathways, their clinical implications and future directions. PMID- 28674980 TI - The Complexity of Clinical Huntington's Disease: Developments in Molecular Genetics, Neuropathology and Neuroimaging Biomarkers. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterised by extensive neuronal loss in the striatum and cerebral cortex, and a triad of clinical symptoms affecting motor, cognitive/behavioural and mood functioning. The mutation causing HD is an expansion of a CAG tract in exon 1 of the HTT gene. This chapter provides a multifaceted overview of the clinical complexity of HD. We explore recent directions in molecular genetics including the identification of loci that are genetic modifiers of HD that could potentially reveal therapeutic targets beyond the HTT gene transcript and protein. The variability of clinical symptomatology in HD is considered alongside recent findings of variability in cellular and neurochemical changes in the striatum and cerebral cortex in human brain. We review evidence from structural neuroimaging methods of progressive changes of striatum, cerebral cortex and white matter in pre-symptomatic and symptomatic HD, with a particular focus on the potential identification of neuroimaging biomarkers that could be used to test promising disease-specific and modifying treatments. Finally we provide an overview of completed clinical trials in HD and future therapeutic developments. PMID- 28674981 TI - Motoneuron Disease: Basic Science. AB - ALS is a relentless neurodegenerative disease in which motor neurons are the susceptible neuronal population. Their death results in progressive paresis of voluntary and respiratory muscles. The unprecedented rate of discoveries over the last two decades have broadened our knowledge of genetic causes and helped delineate molecular pathways. Here we critically review ALS epidemiology, genetics, pathogenic mechanisms, available animal models, and iPS cell technologies with a focus on their translational therapeutic potential. Despite limited clinical success in treatments to date, the new discoveries detailed here offer new models for uncovering disease mechanisms as well as novel strategies for intervention. PMID- 28674982 TI - Motoneuron Disease: Clinical. AB - ALS is a neurodegenerative disease in which the primary symptoms result in progressive neuromuscular weakness. Recent studies have highlighted that there is significant heterogeneity with regard to anatomical and temporal disease progression. Importantly, more recent advances in genetics have revealed new causative genes to the disease. New efforts have focused on the development of biomarkers that could aid in diagnosis, prognosis, and serve as pharmacodynamics markers. Although traditional pharmaceuticals continue to undergo trials for ALS, new therapeutic strategies including stem cell transplantation studies, gene therapies, and antisense therapies targeting some of the familial forms of ALS are gaining momentum. PMID- 28674983 TI - Multiple Sclerosis: Basic and Clinical. AB - Multiple sclerosis (MS) is the most common neurodegenerative disease affecting young adults in our community. It is a complex disease influenced by gender, genetic and environmental factors. MS is a chronic inflammatory disease of the central nervous system caused by aberrant immune activation resulting in damage to myelin sheaths within the brain and spinal cord and axonal loss. The demyelinating insult initially impairs the speed and efficiency of nerve cell function. In the majority of cases, this is followed by an innate endogenous repair response that can restore the myelin sheath and nerve cell function to relatively normal levels. However over time and with subsequent demyelinating events, this capacity is lost ultimately leading to neural degeneration. The influences that oligodendrocytes and myelin exert upon nerve cells to sustain their health and viability have begun to be identified. While immune-directed therapies can reduce the frequency of relapses and development of new lesions, they have little effect upon remyelination and nerve cell repair. This presents the next big challenge in MS therapeutics; complementing immune targeted therapies with strategies that directly target the primary cause of disability, that of remyelination. PMID- 28674984 TI - Schizophrenia: Basic and Clinical. AB - Schizophrenia is a chronic severe mental disorder characterized by psychosis, cognitive impairments, and social and motivational deficits. It is associated with a progressive loss of cortical volume after onset of psychosis; nevertheless, cortical atrophy correlates with the cognitive impairments and the negative symptoms but not with the psychosis. The cortical atrophy is not primarily due to neuronal degeneration but rather to neuronal atrophy and loss of glutamatergic synapses. A downregulation of the presynaptic markers for the parvalbumin-expressing GABAergic interneurons that provide recurrent inhibition to cortical pyramidal neurons is another consistent pathologic feature. Antipsychotic drugs continue after 50 years to be the mainstay of treatment although these drugs, with the possible exception of clozapine, have negligible effects on cognition and negative symptoms. Pharmacologic challenge studies, postmortem analyses and a recent sufficiently powered genome-wide association study and copy number variant studies provide compelling evidence that NMDA receptor hypofunction is an important pathophsysiologic feature of schizophrenia. Silencing the gene encoding serine racemase, the enzyme that synthesizes the cortical-limbic NMDA receptor co-agonist, D-serine, replicates the dendritic and GABAergic pathology and cognitive deficits of schizophrenia in mice. Pharmacologic strategies to overcome NMDA receptor hypofunction hold promise of treating the disabling cognitive and negative symptoms. PMID- 28674985 TI - Stroke: Basic and Clinical. AB - Tissue plasminogen activator (tPA) was first approved in the USA 25 years ago for those who had experienced a recent occlusion (<3 h) of a cerebral vessel. Now, advances in clot retrieval (stentriever), in concert with tPA, heralds new optimism for ischemic stroke victims, but adds more pressure to identify therapies that will minimize hypoxic damage, protect compromised cells, and promote rehabilitation. In the past preclinical investigations have been poor at predicting potential clinical therapy, but they have contributed enormously to understanding post-stroke pathology. Current clinical trials ( www.strokecenter.org/trials ) anticipate a broad range of approaches: from hypothermia, to cell therapy, to neuroprotection. PMID- 28674986 TI - Epileptic Encephalopathies as Neurodegenerative Disorders. AB - The epileptic encephalopathies are severe and often treatment-resistant conditions that are associated with a progressive disturbance of brain function, resulting in a broad range of neurological and non-neurological comorbidities. The concept of epileptic encephalopathies entails that the encephalopathy aspect of the overall condition is primarily driven by the epileptic activity of the disease, which often manifests as specific and pathological features on the electroencephalogram. Genetic factors in epileptic encephalopathies are increasingly recognized. As of 2016, more than 30 genes have been securely implicated as causative genes for genetic epileptic encephalopathies. Even though the traditional concept of epileptic encephalopathies entails that the progressive disturbance of brain dysfunction is primarily due to the abnormal hypersynchronous activity that underlies the seizure disorders, this strict concept rarely holds true for patients with identified genetic etiologies. More commonly, an underlying genetic etiology is thought to predispose both to the neurodevelopmental comorbidities and to the seizure phenotype with a complex interaction between both. In this chapter, we will elucidate to what extent neurodegeneration rather than epilepsy-related regression is a feature of the common epileptic encephalopathies, drawing parallels between two relatively separate fields of neurogenetic research. PMID- 28674987 TI - Neurodegeneration and Pathology in Epilepsy: Clinical and Basic Perspectives. AB - Epilepsy is commonly associated with a number of neurodegenerative and pathological alterations in those areas of the brain that are involved in repeated electrographic seizures. These most prominently include neuron loss and an increase in astrocyte number and size but may also include enhanced blood brain barrier permeability, the formation of new capillaries, axonal sprouting, and central inflammation. In animal models in which seizures are either repeatedly elicited or are self-generated, a similar set of neurodegenerative and pathological alterations in brain anatomy are observed. The primary causal agent responsible for these alterations may be the cascade of events that follow a seizure and lead to an hypoperfusion/hypoxic episode. While epilepsy has long and correctly been considered an electrical disorder, the vascular system likely plays an important causal role in the neurodegeneration and pathology that occur as a consequence of repeated seizures. PMID- 28674988 TI - Prion Diseases. AB - Prion diseases are a group of invariably fatal and transmissible neurodegenerative disorders that are associated with the misfolding of the normal cellular prion protein, with the misfolded conformers constituting an infectious unit referred to as a "prion". Prions can spread within an affected organism by directly propagating this misfolding within and between cells and can transmit disease between animals of the same and different species. Prion diseases have a range of clinical phenotypes in humans and animals, with a principle determinant of this attributed to different conformations of the misfolded protein, referred to as prion strains. This chapter will describe the different clinical manifestations of prion diseases, the evidence that these diseases can be transmitted by an infectious protein and how the misfolding of this protein causes disease. PMID- 28674989 TI - Leukodystrophy: Basic and Clinical. AB - Leukodystrophies are serious, progressive, genetic disorders of CNS myelin. They may result from abnormalities of the oligodendrocyte or any of the other of myriad of supporting cells or tissues. With recent developments in neuroimaging, their presence is becoming increasingly noted even in situations where they were not suspected. More importantly, new genetic tools have improved our ability to diagnose. An understanding of pathogenesis is still evolving, but it is expected that this will assist in developing targeted therapies for these devastating disorders. PMID- 28674990 TI - Traumatic Brain Injury as a Trigger of Neurodegeneration. AB - Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities. These include cavum septum pellucidum, brain atrophy and ventricular dilation, together with pathologies in tau, TDP-43, and amyloid beta. However, the establishment and characterization of CTE as a distinct disease entity is in its infancy. Moreover, the relative "dose" of TBI, such as the frequency and severity of injury, associated with risk of CTE remains unknown. As such, there is a clear and pressing need to improve the recognition and diagnosis of CTE and to identify mechanistic links between TBI and chronic neurodegeneration. PMID- 28674991 TI - Cell Death Mechanisms of Neurodegeneration. AB - There are common mechanisms shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. This indicates that although the original cause may differ in individual diseases or even subtypes of certain disorders, these disrupted common cell functions and signaling, together with aging, may lead to final execution of cell death through similar pathways. The variable neurodegenerative disease symptoms are probably caused by the type, location, and connection of the cell populations that suffer from dysfunction and loss. Besides apoptosis, necroptosis, and autophagy, an important form of death termed parthanatos plays a prominent role in stroke and several neurodegenerative diseases, which is due to PARP-1 overactivation, PAR accumulation, nuclear translocation of the mitochondria protein AIF, and large-scale DNA cleavage. Understanding the mechanisms and interactions of cell death signaling will not only help to develop neuroprotective strategies to halt neurodegeneration, but also provide biomarkers for monitoring disease progression and recovery. PMID- 28674992 TI - Neuroglia: Functional Paralysis and Reactivity in Alzheimer's Disease and Other Neurodegenerative Pathologies. AB - The most notable finding in neurodegenerative diseases is the progressive death of neurones cells. Yet, neuroglial changes can precede and facilitate neuronal loss. This is perhaps expected because astroglial cells maintain the brain homoeostasis, and are responsible for defence and regeneration, so that their malfunction manifested as degeneration or asthenia together with reactivity contribute to pathophysiology. Neuroglia may represent a novel target for therapeutic intervention, be that prevention, slowing progression of or possibly curing neurodegenerative diseases. PMID- 28674993 TI - Advances in Neuroimaging for Neurodegenerative Disease. AB - This chapter is intended as a primer to the most widely used neuroimaging methods available in the prediction, diagnosis and monitoring of the neurodegenerative diseases. We describe the imaging methods that allow us to examine brain structure, function and pathology and investigate neurodegenerative mechanisms in vivo. We describe methods to interrogate brain structure with magnetic resonance imaging (MRI), and brain function with molecular imaging, functional MRI and electro- and magneto-encephalography. We highlight the major neuroimaging advances, including brain stimulation and connectomics, which have brought new insights into a wide range of neurodegenerative diseases and describe some of the challenges in imaging clinical populations. Finally, we discuss the future of neuroimaging in neurodegenerative disease and its potential for generating predictive, diagnostic and prognostic biomarkers. PMID- 28674994 TI - Gene Linkage and Systems Biology. AB - In the past two decades it has become increasingly clear that the risk for many neurodegenerative disorders is at least partially genetic. Assignment of causality for a given gene depends on showing that a particular variant shows either segregation within a family or association with disease across a population. In terms of lifetime risk of disease, the former generally show strong effects compared to the latter. In rare, but interesting, circumstances there are genetic loci that contain different variants that encode either highly penetrant Mendelian disease but also that contribute to risk of sporadic disease. Here, we will discuss the current efforts to complete our understanding of the genetic architecture of neurodegenerative diseases of aging with a particular focus on Parkinson's disease. We will also briefly outline attempts to use systematic approaches to infer relationships between genes associated with the same diseases, which likely demonstrate that in each case there are a relatively small number of underlying biological pathways or processes that may explain pathogenesis. PMID- 28674995 TI - Biomarkers in Neurodegenerative Diseases. AB - The past decade has seen tremendous efforts in biomarker discovery and validation for neurodegenerative diseases. The source and type of biomarkers has continued to grow for central nervous system diseases, from biofluid-based biomarkers (blood or cerebrospinal fluid (CSF)), to nucleic acids, tissue, and imaging. While DNA remains a predominant biomarker used to identify familial forms of neurodegenerative diseases, various types of RNA have more recently been linked to familial and sporadic forms of neurodegenerative diseases during the past few years. Imaging approaches continue to evolve and are making major contributions to target engagement and early diagnostic biomarkers. Incorporation of biomarkers into drug development and clinical trials for neurodegenerative diseases promises to aid in the development and demonstration of target engagement and drug efficacy for neurologic disorders. This review will focus on recent advancements in developing biomarkers for clinical utility in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PMID- 28674996 TI - Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan. AB - BACKGROUND: Post-approval research or monitoring is important to determine real world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. METHODS: ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015. RESULTS: Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5-35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient. CONCLUSIONS: EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients. PMID- 28674998 TI - Using Training Images to Build Model Ensembles with Structural Variability. PMID- 28674999 TI - Forecast First: An Argument for Groundwater Modeling in Reverse. PMID- 28675000 TI - The mitral-to-aortic flow-velocity integral ratio in the real world echocardiographic evaluation of functional mitral regurgitation before and after percutaneous repair. AB - INTRODUCTION: Percutaneous mitral valve repair (PMVR) using MitraClip system has emerged as a therapeutic option for patients with functional severe mitral regurgitation (FMR) at prohibitive risk for surgery. In this setting, the echocardiographic assessment of FMR severity is challenging because the traditional echocardiographic methods have important limitations. The aim of this study was to assess the accuracy and reliability of a simple Doppler index, the mitral/aortic flow velocity integral ratio (MAVIR), to evaluate residual FMR severity after PMVR. METHODS: Eighty-five heart failure patients with functional MR and LV dysfunction (LVEF <= 40%) were included. FMR was quantified on the basis of traditional quantitative parameters of MR severity. MAVIR was expressed as the ratio of mitral and aortic time velocity integral (TVI) values. According to MR severity, 25 patients underwent MC implantation and at 6 months a complete echocardiographic follow-up was performed. RESULTS: A significant linear relationship was found between MAVIR and both VC and EROA. A MAVIR >=1.02 identified pts with severe MR with a sensitivity of 86.7% and a specificity of 90.9%. At the 6 months echocardiographic follow-up after the MitraClip implantation, we observed a significant reduction of LAVI, LVED and LVES volume, while LVEF improved. Furthermore, MAVIR significantly decreased its decrease showed a significant linear relationship with LAVI reduction. CONCLUSION: Our data show a close relationship between MAVIR and traditional indexes of MR severity in patients with FMR. This Doppler-derived index seems applicable after PMVR where traditional echocardiographic index of MR severity shows significant limitations. PMID- 28675001 TI - Creativity, Uncertainty, and Automated Model Building. PMID- 28675002 TI - Prediction-Focused Approaches: An Opportunity for Hydrology. PMID- 28674997 TI - Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment. AB - In the young population, binge drinking is a pattern of problematic alcohol consumption, characterized by a short period of heavy drinking followed by abstinence which is frequently repeated over time. This drinking pattern is associated with mental problems, use of other drugs, and an increased risk of excessive alcohol intake during adulthood. However, little is known about the effects of binge drinking on brain function in adolescents and its neurobiological impact during the adulthood. In the present study, we evaluated the effects of alcohol on hippocampal memory, synaptic plasticity, and mitochondrial function in adolescent rats after a binge drinking episode in vivo. These effects were analyzed at 1, 3, or 7 weeks post alcohol exposure. Our results showed that binge-like ethanol pre-treated (BEP) rats exhibited early alterations in learning and memory tests accompanied by an impairment of synaptic plasticity that was total and partially compensated, respectively. These changes could be attributed to a rapid increase in oxidative damage and a late inflammatory response induced by post ethanol exposure. Additionally, BEP alters the regulation of mitochondrial dynamics and modifies the expression of mitochondrial permeability transition pore (mPTP) components, such as cyclophilin D (Cyp-D) and the voltage-dependent anion channel (VDAC). These mitochondrial structural changes result in the impairment of mitochondrial bioenergetics, decreasing ATP production progressively until adulthood. These results strongly suggest that teenage alcohol binge drinking impairs the function of the adult hippocampus including memory and synaptic plasticity as a consequence of the mitochondrial damage induced by alcohol and that the recovery of hippocampal function could implicate the activation of alternative pathways that fail to reestablish mitochondrial function. PMID- 28675003 TI - Stereotactic Radiosurgery (SRS) / Stereotactic body radiotherapy (SBRT): Benefit to Irish patients and Irish Healthcare Economy. AB - Cancer incidence across Europe is projected to rise rapidly over the next decade. This rising cancer incidence is mirrored by increasing use of and indications for stereotactic radiation. This paper seeks to summarize the exponential increase in indications for stereotactic radiotherapy as well as the evolving economic advantages of stereotactic radiosurgery and stereotactic body radiotherapy. PMID- 28675004 TI - [Confusion and solution for vital pulp therapy]. AB - Dental pulp tissue plays a role in forming dentin, providing nutrition, conducting pain, and generating protective responses to environmental stimuli. Bacterial infection is the main cause of pulp disease, where histopathological changes are the histological basis for determining the choice of treatment and the evaluation of therapeutic effect. Thus, particular attention should be given to eliminate infection, as well as preserve and maintain pulpal health in teeth that show reversible or limited pulpal injuries. Vital pulp therapy, especially its indications and prognostic factors, has been a research hotspot that often causes confusion among clinicians. In this paper, we briefly introduce the confusion and solution for vital pulp therapy in terms of indications, pulp condition assessment, infection elimination, and capping material selection. In addition, we develop a clinical pathway and an operation normalization of vital pulp therapy to better perform the therapy. PMID- 28675005 TI - [Difficulties and misunderstandings of root canal filling]. AB - Root canal filling is performed as the final and most important procedure of root canal treatment. The superior 3D filling is the key determinant of endodontic success. However, such procedure remains a challenge because of the complexity of the root canal system and the limitation of root canal filling materials and methods. This paper provides an overview of current principles and practices in root canal filling, focusing on advantages, disadvantages and indications. The process errors and countermeasures in various root canal filling methods are also discussed. This review provides guidance and help for clinical and practice to achieve a satisfactory root canal filling and improve root canal treatment outcome. PMID- 28675006 TI - [Construction of a low-pH-sensing system in Streptococcus mutans]. AB - OBJECTIVE: To construct a low-pH-sensing system in Streptococcus mutans (S. mutans) and to visually detect the pH in situ. METHODS: Promoter of ureaseI(PureI) and green fluorescence protein (gfp) DNA fragments were amplified by polymerase chain reaction (PCR) from the genome of Streptococcus salivarius 57.I and S. mutans containing the gfp fragment. The two amplified DNA fragments were ligated together and further integrated into pDL278 to construct the recombinant plasmid pDL278-pureI-gfp. This recombinant plasmid was then transformed into S. mutans UA159 cells. Subsequently, the intensity of the optical density per unit area of the low-pH-sensing system was measured and compared under different pH conditions and different processing times. RESULTS: PureI and gfp DNA fragments were amplified successfully with the correct molecule sizes (450 and 717 bp, respectively). The recombinant plasmid pDL278-pureI-gfp was constructed and further verified by PCR and sequencing. The intensity of the optical density per unit area of the low-pH-sensing system increased with decreasing pH and increasing processing time. CONCLUSIONS: A low-pH-sensing system was constructed successfully in S. mutans. Our research verified that pureI of Streptococcus salivarius can function well in S. mutans as an acid induced promoter, and provided a new method of detecting the pH of plaque biofilms in situ. PMID- 28675007 TI - [Effect of hypoxia on the biological characteristics of human dental follicle cells]. AB - OBJECTIVE: This study aimed to investigate the effects of hypoxia on the characteristics of human dental follicle cells (hDFCs). METHODS: The tissue explant collagenase method was used to isolate hDFCs from young permanent teeth. The immunofluorescence technique was used to detect cell surface markers, and the multi-differentiation potential was detected by multilineage differentiation induction assay. Then, the hypoxic microenvironment was physically mimicked, and the cells were divided into the normoxia group (20%O2) and the hypoxia group (2%O2). The effects of hypoxia on cell migration and proliferation were examined by Transwell chamber test and CCK-8 assay, respectively. The gene and protein expression levels of stemness-related markers at both oxygen concentrations were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. After osteogenic induction of both groups, qRT-PCR was performed to evaluate the osteogenesis-related gene, and alizarin red staining was used to assess the formation of mineralized nodules. RESULTS: With the multi-differentiation capacity of osteogenic cells, adipogenic cells, and nerves, hDFCs demonstrate strong stem cell characteristics and possess the criteria of mesenchymal stem cells, which can meet the requirements of seed cells in dental tissue engineering. Hypoxia was conducive to the maintenance of hDFC stemness. Hypoxia promoted the migration and proliferation of hDFCs. The hDFCs were induced to osteogenic differentiation under hypoxic conditions, thereby enhancing osteogenesis. CONCLUSIONS: Hypoxic microenvironment plays an important role in maintaining the stemness and promoting the proliferation, migration, and differentiation of hDFCs. Thus, this microenvironment could also serve several important functions in future clinical applications. PMID- 28675008 TI - [Establishment of rat models with altered anterior guidance and observation of histological changes in temporomandibular joint synovium]. AB - OBJECTIVE: This study aims to establish a stable animal model with altered anterior guidance and investigate histological changes on temporomandibular joint (TMJ) synovium in rats. METHODS: Thirty-two rats were divided into four groups, namely, control group, anterior-guidance-deficient group (T1), and anterior guidance inclined up to 15 degree (T2) and 30 degree (T3) groups. Metal crowns that add 15 and 30 degrees to the palatal side were cemented to the incisors of maxilla to increase the inclination of anterior guidance. The low-speed diamond wheel shorts for both upper and lower incisors of rats were applied to avoid contact between anterior teeth in all direction, thus establishing an anterior guidance deletion model. TMJ joints on one side of two animals in each group were harvested after 3, 7, 14, and 28 days. Pathological changes were investigated in the TMJ synovium using hematoxylin-eosin (HE) staining. RESULTS: The weight of T1 decreased briefly at first, and then increased slightly (P<0.05). The weight of T3 obviously reduced and then slowly increased, but remained below the initial weight (P<0.05). T3 manifested obvious synovial lining proliferation and vascular dilation (P<0.05). CONCLUSIONS: The rat model of anterior guidance inclined up to 30 degree could imitate the pathological features of TMJ synovium with excessive increase in anterior guidance. A higher inclination of anterior guidance might cause more damage of TMJ synovium. The effect of anterior guidance deletion on TMJ synovium is yet to be determined.?. PMID- 28675009 TI - [Alteration of metabolic characteristics on the masseter muscle fiber of unilateral chewing rats and its adenosine monophosphate activated protein kinase regulatory mechanism]. AB - OBJECTIVE: This study aims to determine the influence of unilateral chewing on metabolic characteristics of masseter muscle fibers in rats and the regulatory effect of an adenosine monophosphate activated protein kinase (AMPK) signal pathway on metabolism. METHODS: Rats were submitted to exodontia of all the right maxillary molars and divided into 2, 4, 6, and 8 weeks groups, and corresponding control groups were set as well. Sections were stained by nicotine adenine dinucleotide tetrazolim reductase(NADH-TRase) to demonstrate the types, proportion, and density of masseter muscle fibers. AMPKalpha1 and p-AMPK(Thr172) levels in bilateral masseter muscles were detected by Western blot. RESULTS: In the 2-week group, the percentage of dark fibers augmented in the ipsilateral side, whereas the percentage of intermediary fibers in the contralateral side was increased accompanied by a decrease of light fibers, compared with the control group (P<0.05). The percentage of dark fibers was increased in the bilateral sides, whereas the percentage of dark fiber in the ipsilateral sides surpassed that of the contralateral sides in the 4, 6, and 8-week groups. The percentage of intermediary fibers was decreased in the bilateral sides in the 6 and 8-week groups (P<0.05). The percentage of light fibers was reduced in the ipsilateral sides in the 8-week group, whereas no alteration was observed in contralateral sides (P>0.05). In the ipsilateral sides, p-AMPK (Thr172)/AMPKalpha1 levels were increased in the 2 and 4-week groups (P<0.05), whereas no change was observed in the contralateral sides in either group (P>0.05). CONCLUSIONS: Unilateral chewing increases the oxidative metabolic ability in bilateral masseter muscle fibers especially in the non-working side accompanied with change of muscle fiber types. The improvement of aerobic metabolism ability is related to the AMPK signal pathway.?. PMID- 28675010 TI - [Therapeutic effect of enhancer of Zeste homolog 2 inhibitor GSK343 on periodontitis by regulating macrophage differentiation]. AB - OBJECTIVE: To explore the therapeutic effect of enhancer of Zeste homolog 2 (EZH2) inhibitor GSK343 on periodontitis by regulating microphage differentiation. METHODS: Macrophage RAW264.7 cells were divided into the blank (A group), control (B group), lipopolysaccharide (LPS) stimulation (C group), and LPS+GSK343 (D group) groups. Phenotype transformations was determined through Western blot analysis and enzyme-linked immunosorbent assay by detecting the differentiation of phenotypic biological markers, including tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), interleukin-10 (IL 10), and Arginase-1 (Arg-1). Metergasis was identified by performing a phagocytosis test on Escherichia coli (E. coli). RESULTS: Macrophage RAW264.7 cells produced classical phenotypic biomarkers (M1) TNF-alpha and iNOS under LPS stimulation. The expression levels of IL-10 and Arg-1 increased after adding GSK343 into the culture medium. GSK343 also induced the conversion of M1 macrophages into M2 macrophages. Macrophage RAW264.7 cells exerted a phagocytic effect on E. coli, and this effect was enhanced after adding LPS into the culture medium. GSK343 regulated the macrophage RAW264.7 phagocytosis of E. coli. CONCLUSIONS: GSK343 possibly participates in the regulation of macrophage differentiation and, consequently, in the latent treatment of periodontitis. PMID- 28675011 TI - [Characterization of microRNAs profiles of induced pluripotent stem cells reprogrammed from human dental pulp stem cells and stem cells from apical papilla]. AB - OBJECTIVE: To compare characterization of microRNAs (miRNAs) expression profiles of induced pluripotent stem cells (iPSCs) reprogrammed from human dental pulp stem cells (DPSCs) and stem cells from apical papilla (SCAP) and screen-specific microRNA. METHODS: Human DPSCs and SCAP were reprogrammed into iPSCs using a Sendai virus vector. Total RNA of human DPSCs-iPSCs and SCAP-iPSCs were extracted. miRNAs were labeled and hybridized. Slides were scanned, and images were imported into GenePix Pro 6.0 for grid alignment and data extraction. Significant differentially expressed miRNAs between the two groups were identified using fold change and P-value and were analyzed. RESULTS: Both human DPSCs and SCAP were successfully reprogrammed into iPSCs. Among miRNA genes analyzed by miRNA microarray, 68 were differentially expressed by more than 10 fold in DPSCs-iPSCs; 37 of these genes were up-regulated, and 31 were down regulated. In SCAP-iPSCs, 107 genes were differentially expressed by more than 10 fold; 68 were up-regulated, and 39 were down-regulated. In both cells, only miR 302e was up-regulated, whereas 9 miRNAs were down-regulated: miR-29b-3p, miR-181b 5p, miR-4328, miR-22-5p, miR-145-5p, miR-4324, let-7b-5p, miR-181a-5p, and miR 27b-3p. CONCLUSIONS: Multiple miRNAs participated in reprogramming of human DPSCs and SCAP into iPSCs. Most miRNAs are related to cell cycle, transforming growth factor-beta signaling pathways and epithelial-mesenchymal transition. PMID- 28675012 TI - [Effect of naringin combined with bone morphogenetic protein-2 on the proliferation and differentiation of MC3T3-E1 cells]. AB - OBJECTIVE: This study evaluates the biological effects of naringin (NAR) joint bone morphogenetic protein (BMP)-2 on the proliferation, alkaline phosphatase (ALP) activity, and expression of osteoblastogenic genes, such as Runt-related transcription factor 2 (Runx2), collagen I (ColI), ALP, and osteocalcin (OCN) of pre-osteoblasts. METHODS: Three different NAR concentrations (10, 100, and 1 000 MUmol.L-1) were applied, alone or combined with BMP-2(50 ng.mL-1), to restore the osteoblastogenesis of pre-osteoblasts (MC3T3-E1 cell line). Cell numbers (proliferation) were evaluated at first, fourth, and seventh days by Alamar blue assay. ALP activity and the expression of osteoblastogenic genes, such as Runx2, ColI, ALP, and OCN were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) at fourth and seventh day. RESULTS: Stimulation by NAR alone and in combination with BMP-2 for 1 day and 4 days could promote cell proliferation, which peaked at a concentration of 100 MUmol.L-1 NAR combined with BMP-2 could promote cell proliferation significantly (P<0.05). Stimulation by NAR alone and in combination with BMP-2 for 4 and 7 days could promote ALP activity and bone-related gene(ALP, OCN, Runx2, ColI) expression. ALP expression was significantly promoted after stimulation of 100 MUmol.L-1 NAR and BMP-2 (P<0.05). CONCLUSIONS: NAR exhibits promising potential for improving MC3T3-E1 proliferation and differentiation, and appropriate concentrations of NAR and BMP 2 show synergistic effect.?. PMID- 28675013 TI - [Comparison among three translucency parameters]. AB - OBJECTIVE: This study aims to compare the three commonly used translucency parameters in prosthodontics: transmittance (T), contrast ratio (CR), and translucency parameter (TP). METHODS: Six platelet specimens were composed of Vita enamel and dental porcelain. The initial thickness was 1.2 mm. The specimens were gradually ground to 1.0, 0.8, 0.6, 0.4, and 0.2 mm. T, color parameters, and reflection were measured by a spectrocolorimeter for each corresponding thickness. T, CR and TP were calculated and compared. RESULTS: TP increased, whereas CR decreased, with decreasing thickness. Moreover, ?T increased with decreasing thickness, and exponential relationships were found. Two-way ANOVA showed statistical significance between T and thickness, except between T and the 1.2 mm and 1.0 mm enamel porcelain groups. No difference was found among the coefficient variations (CV) of T, CR and TP. Curve fitting indicated the existence of exponential relationships between T and CR and between T and TP. The values for goodness of fit with statistical significance were 0.951 and 0.939, respectively (P<0.05). CONCLUSIONS: Under the experimental conditions, T, TP and CR achieved the same CV. T and TP, as well as T and CR, were found with exponential relationships. The value of CR and TP could not represent the translucency precisely, especially when comparing the changing ratios. PMID- 28675014 TI - [Soluble programmed death-1 and soluble programmed death ligand 1 protein expression and immune status in patients with recurrent aphthous ulcer]. AB - OBJECTIVE: This study aims to investigate the possible role and significance of soluble programmed death-1 (sPD-1) /soluble programmed death ligand 1 (sPD-L1) in the immune pathogeneses of recurrent aphthous ulcer (RAU). METHODS: A total of 30 RAU cases (18 cases of minor RAU, 5 cases of major RAU, and 7 cases of herpetiform ulcers) were enrolled in this study. A total of 18 healthy people served as controls. Lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD16++56+) were investigated by flow cytometric analysis. Humoral immunity (IgG, IgA, IgM, C3, and C4) was explored by nephelometry immunoassay. The sPD-1 and sPD-L1 protein levels in the sera of RAU patients were investigated by enzyme-linked immunosorbent assay. The correlations of the sPD-1 and sPD-L1 protein levels with the immune status and clinical characteristics of the RAU patients were analyzed by SPSS 19.0. RESULTS: The number of CD4+ T cells decreased and the levels of IgM antibodies increased in the RAU patients relative to those in the normal controls (P<0.05). The sPD-1 and sPD-L1 protein levels in the RAU patients were significantly higher than those in the control group (P<0.05). Meanwhile, the sPD 1 and sPD-L1 protein levels in the patients with minor and major RAU were significantly higher than those in the control group (P<0.05). By contrast, no significant difference was found in the patients with herpetiform RAU (P>0.05). Positive correlations were noted between the sPD-1 protein level and the CD19+ cell frequency or C4 level (r1=0.389, P1=0.034; r2=0.382, P2=0.037). CONCLUSIONS: Cellular immune hypofunction and humoral immunity disorders were found in the RAU patients. The PD-1/PD-L1 signaling pathway, which might be influenced by the involvement of sPD-1 and sPD-L1 proteins to a certain extent, may play some roles in the immune pathogenesis of RAU. PMID- 28675015 TI - [Association between non-syndromic cleft lip with or without cleft palate and environmental factors in Ningxia]. AB - OBJECTIVE: To investigate the association between non-syndromic cleft lip with or without cleft palate (NSCL/P) and environmental factors in Ningxia population. METHODS: This case-control study involved 453 NSCL/P patients and 452 normal newborns from Ningxia. A questionnaire focusing on various factors, including family history, pregnancy reaction, drug use during pregnancy, and infections, was used and responses were analyzed through Chi-square test and Logistic regression analysis with SPSS 16.0. RESULTS: The constituent ratio of different types of NSCL/P was cleft lip?cleft lip and palate?cleft palate equal to 1?2.02?1.51. Logistic regression analysis revealed that abnormal pregnancy, infection, abortion, drugs, drinking, smoking, and living near factories likely increased the risk of NSCL/P (P<0.05). Single fetus, pregnancy-related nausea, vomiting, parents' moderate tastes, and eating soy foods and fruits decreased the risk of NSCL/P (P<0.05). CONCLUSIONS: The incidence of NSCL/P should be reduced to enhance the conditions of women during pregnancy by maintaining a balanced diet and avoiding infections, abortion, drugs, and negative habits. ?. PMID- 28675016 TI - [Velopharyngeal closure pattern and speech performance among submucous cleft palate patients]. AB - OBJECTIVE: To characterize the velopharyngeal closure patterns and speech performance among submucous cleft palate patients. METHODS: Patients with submucous cleft palate visiting the Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University between 2008 and 2016 were reviewed. Outcomes of subjective speech evaluation including velopharyngeal function, consonant articulation, and objective nasopharyngeal endoscopy including the mobility of soft palate, pharyngeal walls were retrospectively analyzed. RESULTS: A total of 353 cases were retrieved in this study, among which 138 (39.09%) demonstrated velopharyngeal competence, 176 (49.86%) velopharyngeal incompetence, and 39 (11.05%) marginal velopharyngeal incompetence. A total of 268 cases were subjected to nasopharyngeal endoscopy examination, where 167 (62.31%) demonstrated circular closure pattern, 89 (33.21%) coronal pattern, and 12 (4.48%) sagittal pattern. Passavant's ridge existed in 45.51% (76/167) patients with circular closure and 13.48% (12/89) patients with coronal closure. Among the 353 patients included in this study, 137 (38.81%) presented normal articulation, 124 (35.13%) consonant elimination, 51 (14.45%) compensatory articulation, 36 (10.20%) consonant weakening, 25 (7.08%) consonant replacement, and 36 (10.20%) multiple articulation errors. CONCLUSIONS: Circular closure was the most prevalent velopharyngeal closure pattern among patients with submucous cleft palate, and high-pressure consonant deletion was the most common articulation abnormality. Articulation error occurred more frequently among patients with a low velopharyngeal closure rate. PMID- 28675017 TI - [Analysis of the current status of research on human papillomavirus-associated head and neck cancers based on recent Chinese literature]. AB - OBJECTIVE: To analyze the current status of research on human papillomavirus (HPV)-associated head and neck cancers in China using national and international references. METHODS: We searched for bibliographies in the electronic databases of Sichuan University, including Chinese Biological and Medical Database (CBM), China Science and Technology Journal Database (VIP), and Wanfang Journal Database. Then, data was selected and extracted to analyze the basic characteristics of HPV-related head and neck cancers, the general prevalence of HPV, and the effects of various clinic pathological indicators on HPV patients. RESULTS: The general prevalence of HPV was 34.05% among civil patients with head and neck cancers. Our analysis of different clinical and pathological indices that affect HPV-associated oral squamous cell carcinomas revealed that non smoking and non-drinking groups had higher HPV infection rates compared with smoking (P=0.002) and drinking (P=50% in the stented coronary artery segment at follow-up angiography. The mean CHA2DS2-VASc score was 3.42 +/- 1.35 (range 1-7). The CHA2DS2-VASc scores and high-sensitivity C-reactive protein (hs-CRP) levels were higher in the ISR group compared to the non-ISR group. At multivariable analysis, CHA2DS2-VASc score (odds ratio [OR]: 2.004, 95% confidence interval: 1.361-2.949, P < .001), total stent length (OR: 1.093, P = .001), stent diameter (OR: 0.129, P < .001), and hs CRP (OR: 1.224, P < .001) emerged as independent risk factors for ISR. In conclusion, preprocedural CHA2DS2-VASc is an easily calculated score that provides an additional level of risk stratification beyond that provided by conventional risk factors. Thus, this score can be used as a simple and effective tool to predict ISR in patients undergoing BMS implantation. PMID- 28675047 TI - 'I believe high blood pressure can kill me:' using the PEN-3 Cultural Model to understand patients' perceptions of an intervention to control hypertension in Ghana. AB - OBJECTIVES: Currently in Ghana, there is an on-going task-shifting strategy in which nurses are trained in hypertension management. While this study will provide useful information on the viability of this approach, it is not clear how patients in the intervention perceive hypertension, the task-shifting strategy, and its effects on blood pressure management. The objective of this paper is to examine patients' perceptions of hypertension and hypertension management in the context of an on-going task-shifting intervention to manage blood pressure control in Ghana. DESIGN: Forty-two patients participating in the Task Shifting Strategy for Hypertension program (23 males, 19 females, and mean age 61. 7 years) completed in-depth, qualitative interviews. Interviews were transcribed, and key words and phrases were extracted and coded using the PEN-3 Cultural Model as a guide through open and axial coding techniques, thus allowing rich exploration of the data. RESULTS: Emergent themes included patients' perceptions of hypertension, which encompassed misperceptions of hypertension and blood pressure control. Additional themes included enablers and barriers to hypertension management, and how the intervention nurtured lifestyle change associated with blood pressure control. Primary enabling factors included the supportive nature of TASSH nurses, while notable barriers were financial constraints and difficulty accessing medication. Nurturing factors included the motivational interviewing and patient counseling which instilled confidence in the patients that they could make lasting behavior changes. CONCLUSIONS: This study offers a unique perspective of blood pressure control by examining how patients view an on-going task-shifting initiative for hypertension management. The results of this study shed light on factors that can help and hinder individuals in low-resource settings with long-term blood pressure management. PMID- 28675049 TI - Importance of material parameters and strain energy function on the wall stresses in the left ventricle. AB - Patient-specific estimates of the stress distribution in the left ventricles (LV) may have important applications for therapy planning, but computing the stress generally requires knowledge of the material behaviour. The passive stress-strain relation of myocardial tissue has been characterized by a number of models, but material parameters (MPs) remain difficult to estimate. The aim of this study is to implement a zero-pressure algorithm to reconstruct numerically the stress distribution in the LV without precise knowledge of MPs. We investigate the sensitivity of the stress distribution to variations in the different sets of constitutive parameters. We show that the sensitivity of the LV stresses to MPs can be marginal for an isotropic constitutive model. However, when using a transversely isotropic exponential strain energy function, the LV stresses become sensitive to MPs, especially to the linear elastic coefficient before the exponential function. This indicates that in-vivo identification efforts should focus mostly on this MP for the development of patient-specific finite-element analysis. PMID- 28675048 TI - Biomechanical causes of trapeziometacarpal arthroplasty failure. AB - Trapeziometacarpal joint prosthesis revision has been widely reported, mainly due to loosening of the trapezium cup. Our hypothesis is that current prostheses do not sufficiently respect the kinematics of this joint. CT scan acquisitions enabled us to determine the position of the first metacarpal relative to the trapezium in three different characteristic postures, in subjects in different stages of arthrosis. A CAD model of a current prosthesis was inserted into the numerical 3D model of the joint under the different postures. In the numerical model, we observe penetration of the cup by the head of the prosthesis. This virtual penetration could, in vivo, amount to overstressing the prosthetic elements, which would lead to loosening of the cup or of the metacarpal stem and luxation of the prosthesis. PMID- 28675050 TI - Microfluidic accumulation assay probes attachment of biofilm forming diatom cells. AB - Testing of fouling release (FR) technologies is of great relevance for discovery of the next generation of protective marine coatings. In this paper, an accumulation assay to test diatom interaction under laminar flow with the model organism Navicula perminuta is introduced. Using time lapse microscopy with large area sampling allows determination of the accumulation kinetics of the diatom on three model surfaces with different surface properties at different wall shear stresses. The hydrodynamic conditions within the flow cell are described and a suitable shear stress range to perform accumulation experiments is identified at which statistically significant discrimination of surfaces is possible. The observed trends compare well to published adhesion preferences of N. perminuta. Also, previously determined trends of critical wall shear stresses required for cell removal from the same set of functionalized interfaces shows consistent trends. Initial attachment mediated by extracellular polymeric substances (EPS) present outside the diatoms leads to the conclusion that the FR potential of the tested coating candidates can be deducted from dynamic accumulation experiments under well-defined hydrodynamic conditions. As well as testing new coating candidates for their FR properties, monitoring of the adhesion process under flow provides additional information on the mechanism and geometry of attachment and the population kinetics. PMID- 28675051 TI - Impact of sludge retention time on MBR fouling: role of extracellular polymeric substances determined through membrane autopsy. AB - The impact of sludge retention time (SRT) on the biofouling of a membrane bioreactor (MBR) by extracellular polymeric substances (EPS) was investigated. The MBR was operated at 60 and 20 d SRT. The gel layer (recovered through optimized membrane autopsy methods) and the cake layer were analyzed for their content and profile of EPS proteins and polysaccharides. The change to a shorter SRT led to decreased membrane filterability, concomitant with a higher expression of EPS proteins in the cake layer, which were identified as being mainly related with biosynthesis and stress functions. The gel layer was more substantial in internal fibers, with polysaccharides being the major component in this layer. With the decrease in SRT (and filterability decrease), the overall polysaccharide content and sugar variety increased. In conclusion, SRT impacted not only on the quantity but also the composition of EPS molecules, and both were shown to be important in biofouling. PMID- 28675053 TI - Relationship between perceptions of ageing and frailty in English older adults. AB - Older adults' negative beliefs about ageing are related to their health and functioning, but little is known about how perceptions of ageing (POA) relate to frailty status. This study aimed to explore the relationship between POA and frailty. Secondary analysis of data used were from the English Longitudinal Study of Ageing Waves 2 and 5. A POA score was based on participants' responses to 12 statements using a five-point Likert scale at baseline, and a Frailty Index (FI) score was calculated for each participant for both waves. Multiple linear regression models were conducted to assess the relationship between POA and frailty cross-sectionally and longitudinally in models controlled for age, gender, depression symptoms, and socioeconomic status. Older adults with more negative POA had greater frailty (beta = .12, p < .001). Negative POA predicted greater frailty 6 years later (beta = .03, p < .05). Future work regarding the mechanisms of this relationship is needed to identify ways of intervening to improve health. PMID- 28675054 TI - Psychiatric disorders and suicide attempts among adolescents victimized by school bullying. AB - OBJECTIVE: We conducted a cross-sectional school-based study to investigate psychiatric disorders and suicide risk among adolescents victimized by bullying. METHOD: The study was designed in two stages. In the screening stage, 33,038 middle school students were screened for psychopathology. Next, in the face-to face interview stage, 1196 participants were assessed for psychiatric disorders using a structured diagnostic instrument. We also collected information about the participants' experiences of bullying and history of suicidal ideation/attempts. RESULTS: The results indicate that adolescents with a history of bullying victimization were more likely to be diagnosed with depression and psychosis than those without such a history. Multivariate logistic regression models revealed that bullying victimization was significantly associated with suicide attempts even after adjusting for demographic characteristics, depression and psychosis. CONCLUSIONS: Bullying victimization is a risk factor for depression, psychosis, and suicide ideation and attempts. The findings warrant an early intervention and suicide prevention program for victimized students and anti-bullying policies in schools. PMID- 28675055 TI - Biodiversity characterisation and hydrodynamic consequences of marine fouling communities on marine renewable energy infrastructure in the Orkney Islands Archipelago, Scotland, UK. AB - As part of ongoing commitments to produce electricity from renewable energy sources in Scotland, Orkney waters have been targeted for potential large-scale deployment of wave and tidal energy converting devices. Orkney has a well developed infrastructure supporting the marine energy industry; recently enhanced by the construction of additional piers. A major concern to marine industries is biofouling on submerged structures, including energy converters and measurement instrumentation. In this study, the marine energy infrastructure and instrumentation were surveyed to characterise the biofouling. Fouling communities varied between deployment habitats; key species were identified allowing recommendations for scheduling device maintenance and preventing spread of invasive organisms. A method to measure the impact of biofouling on hydrodynamic response is described and applied to data from a wave-monitoring buoy deployed at a test site in Orkney. The results are discussed in relation to the accuracy of the measurement resources for power generation. Further applications are suggested for future testing in other scenarios, including tidal energy. PMID- 28675056 TI - MicroRNA-133b expression associates with clinicopathological features and prognosis in glioma. AB - BACKGROUND: Recently, microRNA-133b (miR-133b) dysregulation has been shown to play a key role in several human cancers, as well as glioma. In this study, we aimed to investigate the clinical significance and prognostic value of miR-133b in glioma. METHODS: Real-time quantitative PCR was employed to measure the expression level of miR-133b in tissues. Survival analysis was carried out by using the log-rank test and Kaplan-Meier method. Prognostic factors for overall survival were identified by univariate and multivariate analyses using the Cox proportional hazards regression model. RESULTS: The expression level of miR-133b was significantly lower in glioma tissues compared with matched non-cancerous brain tissues (p < .05). Its level was strongly correlated with Karnofsky Performance Scale score (p < .001) and WHO grade (p < .001). Kaplan-Meier survival and log-rank analysis indicated that the decreased expression of miR 133b was strongly correlated with shorter overall survival of patients with glioma (log-rank test, p = .03). CONCLUSIONS: The current investigation demonstrated that miR-133b level is useful for predicting the prognosis of patients with glioma. PMID- 28675057 TI - Multiple receptors shape the estrogen response pathway and are critical considerations for the future of in vitro-based risk assessment efforts. AB - Current in life toxicity testing paradigms are being challenged as the future of risk assessment moves towards more comprehensive mode of action/adverse outcome pathway based approaches. In particular, endocrine disruption screening is now a global activity and key initiatives in the United States focus on the use of high throughput in vitro assays to prioritize compounds for further testing of estrogen, androgen or thyroid disruption. Of these pathways, much of the emphasis to date has been on high-throughput methods for estrogenic activity primarily using ligand binding and trans-activation assays. However, as the knowledge regarding estrogen receptor signaling pathways continues to evolve, it is clear that the assumption of a simple one-receptor pathway underlying current in vitro screening assays is out of date. To develop more accurate models for estrogen initiated pathways useful for quantitative safety assessments, we must design assays that account for the key signaling processes driving cellular dose response based on up-to-date understanding of the biological network. In this review, we summarize the state of the science for the estrogen receptor signaling network, particularly with regard to proliferative effects, and highlight gaps in current high throughput approaches. From the sum of this literature, we propose a model for the estrogen-signaling pathway that should serve as a starting point for development of new in vitro methods fit for the purpose of predicting dose response for estrogenic chemicals in the human. PMID- 28675058 TI - Selumetinib for the treatment of non-small cell lung cancer. AB - INTRODUCTION: KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seem to remain 'undruggable', with any effective targeted therapy approved at the moment. The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supportive of KRAS testing in clinical practice of NSCLC therapy. Areas covered: A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone. Disappointing data emerged from the next phase III trial in which the addition of selumetinib to docetaxel in patients with advanced KRAS mutant lung cancer did not improve survival or show clinical benefit. Expert opinion: Promising strategies against this common mutation are under evaluation in clinical trials. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents, by simultaneous inhibition of the RAS-RAF-MEK-MAPK pathway. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors. PMID- 28675060 TI - Exploring clinical metrics to assess the health impact of traffic injuries. AB - In order to allow a deep knowledge of the nonfatal injuries, recently the European Commission adopted the maximum abbreviated injury scale classification which is based on medical diagnosis. This classification will open the door to a new source of information based on international hospital data such as diagnosis related group and international classification of diseases. In this study, we seek to explore these clinical metrics, which are used to describe the diagnosis and the medical treatment, and to infer consequences of crashes mainly through the costs and severity. Therefore, statistical analyses were applied using generalized linear models selected depending on the type of response variable, i.e. discrete or continuous. Relationships between these metrics were identified revealing for instance that head is the region of the body associated with high severity as well as to higher health care costs. Additionally, a discussion is presented regarding study results and future developments of clinical metrics are pointed out. PMID- 28675059 TI - Immunogenetic predisposing factors for mesial temporal lobe epilepsy with hippocampal sclerosis. AB - PURPOSE: Neuroinflammation appears as an important epileptogenic mechanism. Experimental and clinical studies have demonstrated an upregulation of pro inflammatory cytokines such as IL-1beta and TNF-alpha, in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Expression of these cytokines can be modulated by polymorphisms such as rs16944 and rs1800629, respectively, both of which have been associated with febrile seizures (FS) and MTLE-HS development. The human leukocyte antigen (HLA) system has also been implicated in diverse epileptic entities, suggesting a variable role of this system in epilepsy. Our aim was to analyse the association between immunogenetic factors and MTLE-HS development. For that rs16944 (-511 T>C, IL-1beta), rs1800629 (-308 G>A, TNF alpha) polymorphisms and HLA-DRB1 locus were genotyped in a Portuguese Population. METHODS: We studied 196 MTLE-HS patients (108 females, 88 males, 44.7 +/- 12.0 years, age of onset = 13.6 +/- 10.3 years, 104 with FS antecedents) and 282 healthy controls in a case-control study. RESULTS: The frequency of rs16944 TT genotype was higher in MTLE-HS patients compared to controls (14.9% in MTLE-HS vs. 7.7% in controls, p = 0.021, OR [95% CI] = 2.20 [1.13-4.30]). This association was independent of FS antecedents. No association was observed between rs1800629 genotypes or HLA-DRB1 alleles and MTLE-HS susceptibility. Also, no correlation was observed between the studied polymorphisms and disease age of onset. CONCLUSION: The rs16944 TT genotype is associated with MTLE-HS development what may be explained by the higher IL-1beta levels produced by this genotype. High IL-1beta levels may have neurotoxic effects or imbalance neurotransmission leading to seizures. PMID- 28675061 TI - Postnatal depression, maternal-infant bonding and social support: a cross cultural comparison of Nigerian and British mothers. AB - OBJECTIVES: The high prevalence of Post-Natal Depression (PND) in low and lower middle income countries of Africa raises questions about the functionality of the abundant informal support accessed in the enmeshed family structure. This study examined the interaction between social support, parity and culture in the development of PND and maternal-infant bonding (MIB) among Nigerian, British and Nigerian Immigrant mothers in the UK. METHODS: Participants (N = 124) were recruited from the UK and Nigeria via local support groups for mothers, websites offering motherhood-related content and social media. Questionnaires including the Edinburgh Postnatal Depression Scale (EPDS), Postpartum Bonding Questionnaire and Norbeck's Social Support Questionnaire were uploaded onto SurveyMonkey(r). RESULTS: Findings revealed significant cultural differences in PND and social support. Multiple regression analyses revealed that PND, social support and culture could predict MIB, with PND being the only significant independent predictor. CONCLUSIONS: Our findings highlight the importance that cultural factors play in the development of PND and the establishment of MIB in the context of culturally attuned healthcare services. PMID- 28675062 TI - Lung regeneration using amniotic fluid mesenchymal stem cells. AB - Respiratory diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary hypertension and lung fibrosis, are yet a major challenge in the world and they result in irreversible structural lung damage. Lung transplantation as the only therapeutic option face some major challenges like graft rejection and cancer, arising as a result of immunosuppression. A low survival rate faced by lung transplantation patients is presently limited to approximately 5 years. Lungs shortage therefore calls for a mechanism that would increase the availability of suitable organs for transplantation. In this review, we give an update on the use of amniotic fluid mesenchymal stem cells (AFMSCs) as an optimal source for lungs scaffold re-cellularization, due to their limitless accessibility and possibility for proliferation and differentiation. Further studies will be required in tissue engineering (TE) and regenerative medicine (RM), especially shifting our focus towards AFMSCs as a cell source for this regeneration. PMID- 28675063 TI - Joinpoint regression analysis to evaluate traffic public health policies by national temporal trends from 2000 to 2015. AB - In the past 16 years, a variety of factors might have impacted traffic accidents in Chile. In order to identify and quantify differential rates of change over time this study employed a novel analytic method to assess temporal trends in traffic morbi-mortality. Overall death and injury rates and associated to alcohol per 100,000 inhabitants were monitored between 2000 and 2015. Joinpoint regression was used to calculate annual percent changes (APCs) and average APCs. Permutation tests were used to determine joinpoints. P < 0.05 was considered statistically significant. The rate of traffic deaths related to alcohol declined from 2006 until 2015 at a rate of 9.53% per year. The rate of traffic injuries related to alcohol decreased at a rate of 4.32% per year since 2008 to 2015. The use of the most sensitive approach to trend analysis brings new ele-ments to form the epidemiological analyses in Chile and similar countries. PMID- 28675064 TI - Differential expression of circulating vascular cell adhesion molecule-1 in subjects with coronary artery disease and cardiac syndrome X without known diabetes mellitus. AB - CONTEXT: Inflammation is one of the mechanisms underlying cardiac syndrome X (CSX). OBJECTIVES: Few studies have compared the expression of inflammatory or adhesion molecules between coronary artery disease (CAD) versus CSX. MATERIALS AND METHODS: Ninety-two CSX and 145 CAD subjects without known diabetes mellitus underwent coronary angiogram for angina. RESULTS: Vascular cell adhesion molecule (VCAM)-1 (median, 507 versus 431 ng/ml, p = 0.001) was significantly higher in the CAD group. In the binary regression, VCAM-1 was a significant differential factor for CAD versus CSX. DISCUSSION AND CONCLUSION: Adhesion molecules might be implicated in the differential expression of macro versus microvascular coronary disease. TRIAL REGISTRATION NUMBER: NCT01198730 at https://clinicaltrials.gov. PMID- 28675066 TI - Inadequacy of self-assessment of vision, and fitness to drive. AB - The author, a retired neurosurgeon then aged 81, describes his own right upper quadrantic homonymous visual field defect which did not impair any normal daily activities. His own occupation allowed him to recognise the defect. It is unlikely that such a defect would have been noticed by other elderly persons. The field defect shown by perimetry (illustrated) debarred him from driving. Self assessment of visual acuity, and especially fields, is inadequate when applying for renewal of a driving licence. Effective steps to prevent such licensing and the damage that may follow are discussed. PMID- 28675065 TI - Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings. AB - INTRODUCTION: Hypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear. Areas covered: With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure. Expert opinion/commentary: HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment. PMID- 28675068 TI - Fecal calprotectin is a strong predictive marker of relapse in Chinese patients with Crohn's disease: a two-year prospective study. AB - OBJECTIVE: To evaluate the predictive value of fecal calprotectin (FC) for clinical relapse in Chinese patients with quiescent Crohn's disease (CD) and to further investigate the correlation between FC and intestinal inflammation. METHODS: Sixty-two patients with a diagnosis of quiescent CD were consecutively enrolled in this prospective study. Fecal samples were collected and enteroscopy were performed to detect mucosal lesions at the beginning of the study. Patients were followed until the first relapse or by the end of the two-year follow-up. The calprotectin concentration was measured using a quantitative enzyme-linked immunoassay. RESULTS: Of the 62 CD patients, 29 had a relapse (median time of relapse: 8.44 months). The median follow-up months was 8.16 (4.98-13.59). The cut off level of 225 MUg/g provided the maximal area under the receiver operating characteristic curve (AUC) of .775 for detecting the relapse of CD patients. Meanwhile, fecal occult blood had an added value. The multivariate Cox regression model showed that FC was the strongest predictor of the risk of relapse (risk ratio (RR): 6.315; p = .001). FC correlated most closely with the simple endoscopic score for Crohn's disease (SES-CD) (r = 0.524, p < .001). CONCLUSIONS: FC correlated significantly with gut inflammation and could be a reliable predictor of relapse in Chinese patients with CD. PMID- 28675067 TI - Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. AB - INTRODUCTION: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ. PATIENTS AND METHODS: Patients, after surgery for GBM or AA, age <=60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m2 days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety. RESULTS: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome. CONCLUSIONS: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA. PMID- 28675069 TI - Clarification of the role of the Jaydess(Skyla) LNG- IUS 13.5mg and Kyleena LNG IUS 19.5mg as intrauterine contraceptive systems. AB - INTRODUCTION: Jaydess/Skyla and Kyleena are 'low dose' levonorgestrel releasing intrauterine systems(LNG-IUS). They differ from Mirena and other similar LNG-IUSs in terms of pharmacological properties and physical dimensions. There are currently no defined guidelines to decide when to use Jaydess or Kyleena or Mirena. Areas covered: MEDLINE, POPLINE, PubMed and clinicaltrials.gov were searched using the terms 'Jaydess', 'Skyla', LNG-IUS 13.5mg and 'Kyleena' LNG-IUS 19.5mg. Only clinical research articles as opposed to generalised reviews and opinion papers on the newer LNG-IUSs were considered for review. There were 10 clinical research articles and 11 clinical research abstracts relating to Jaydess/Skyla(LNG-IUS13.5mg) and Kyleena(LNG-IUS 19.5mg). All the studies were sponsored by the manufacturer. There were no independent clinical research studies. Expert commentary: The clinical research information from studies on Jaydess/Skyla and Kyleena does not adequately inform the clinician when and where these IUSs should be used in preference to other LNG-containing IUSs. The terminology used for describing the new low dose LNG-IUSs is inconsistent. The clinical differences between Jaydess, Kyleena and Mirena and the clinical differences in parity of subjects using Jaydess or Kyleena is used to generate an algorithm for helping clinicians choose between Mirena and Jaydess/Skyla or Kyleena. PMID- 28675070 TI - Validity of heart rate measurements by the Garmin Forerunner 225 at different walking intensities. AB - The accuracy of wrist worn heart rate monitors based on photoplethysmography (PPG) is not fully clinically accepted. Therefore, we aimed to validate heart rate measurements of a commercially available PPG heart rate monitor, i.e. the Garmin Forerunner(r) 225. Twelve healthy volunteers (six women; mean age: 28 years) performed a treadmill protocol consisting of: five minutes sitting, five minutes standing, 10 minutes walking at 4 km/h, 10 minutes walking at a gradient of 5% and intensity of 4-6 metabolic equivalents (METs), 10 minutes walking at a gradient of 8% and intensity of seven METs or more. Walking speeds were individually determined. Walking bouts were separated by a standardised five minute rest period. Heart rate was measured as the average of the last three minutes standing and of each walking bout. A three lead patch-based electrocardiogram (ECG; Zensor(r)) was used as criterion method. Statistical analyses included Pearson's correlation (r), paired t-tests, root mean squared error (RMSE) and Bland?Altman plots. The mean values per three minutes of every condition did not differ significantly between the Garmin Forerunner(r) 225 and the Zensor(r). RMSE was 3.01 beats per minute (bpm) or 2.89%. The Bland-Altman bias was 1.57 bpm. Limits of agreement (LoA) were wide, ranging from 32.53 to 29.40 bpm. However, Pearson's r ranged from 0.650 to 0.868 suggesting moderate to strong validity. Generally, mean heart rates, r values, RMSE and the Bland-Altman bias indicated good overall agreement in this sample of healthy adults, but wide LoA are making it difficult to trust individual measurements. PMID- 28675071 TI - From the pathogenesis to the cure of indolent B-cell lymphoproliferative disorders associated with hepatitis C virus infection: which role for direct acting antivirals? AB - INTRODUCTION: Hepatitis C virus (HCV) causes monoclonal B cell lymphoproliferative disorders ranging from benign, such as in mixed cryoglobulinemia (MC), to indolent or aggressive lymphomas. MC and indolent lymphomas commonly regress when HCV is eradicated with interferon (IFN) therapy; however, sustained virologic response (SVR) to IFN is achieved only in ~50% of patients. The new all oral direct-acting antivirals (DAA), yielding nearly 100% SVR, promise a breakthrough in the treatment of HCV-associated lymphoproliferative disorders, but experience is still scanty. Areas covered: A literature search was performed to summarize current pathogenetic hypotheses in HCV-associated indolent lymphoproliferative disorders and to identify clinical trials focused on the use of antiviral therapy. Hematological outcomes of IFN based and IFN-free DAA-based regimens were compared. Expert commentary: While MC appears to regress in most patients after DAA therapy, the still very limited experience with indolent lymphomas suggests that hematologic responses might be less than those observed with IFN. Furthermore, anecdotal observations of early progression to aggressive lymphoma after DAA are disquieting. Large studies are needed to determine the values and limits of DAA for treating HCV-associated indolent lymphomas and to identify subgroups at risk of non-response. PMID- 28675072 TI - Embryonic stem cells and the next generation of developmental toxicity testing. AB - INTRODUCTION: The advent of stem cell technology has seen the establishment of embryonic stem cells (ESCs) as molecular model systems and screening tools. Although ESCs are nowadays widely used in research, regulatory implementation for developmental toxicity testing is pending. Areas Covered: This review evaluates the performance of current ESC, including human (h)ESC testing systems, trying to elucidate their potential for developmental toxicity testing. It shall discuss defining parameters and mechanisms, their relevance and contemplate what can realistically be expected. Crucially this includes the question of how to ascertain the quality of currently employed cell lines and tests based thereon. Finally, the use of hESCs will raise ethical concerns which should be addressed early on. Expert Opinion: While the suitability of (h)ESCs as tools for research and development goes undisputed, any routine use for developmental toxicity testing currently still seems premature. The reasons for this comprise inherent biological deficiencies as well as cell line quality and system validation. Overcoming these issues will require collaboration of scientists, test developers and regulators. Also, validation needs to be made worthwhile for academia. Finally we have to continuously rethink existing strategies, making room for improved testing and innovative approaches. PMID- 28675073 TI - Designing interaction, voice, and inclusion in AAC research. AB - The ISAAC 2016 Research Symposium included a Design Stream that examined timely issues across augmentative and alternative communication (AAC), framed in terms of designing interaction, designing voice, and designing inclusion. Each is a complex term with multiple meanings; together they represent challenging yet important frontiers of AAC research. The Design Stream was conceived by the four authors, researchers who have been exploring AAC and disability-related design throughout their careers, brought together by a shared conviction that designing for communication implies more than ensuring access to words and utterances. Each of these presenters came to AAC from a different background: interaction design, inclusive design, speech science, and social science. The resulting discussion among 24 symposium participants included controversies about the role of technology, tensions about independence and interdependence, and a provocation about taste. The paper concludes by proposing new directions for AAC research: (a) new interdisciplinary research could combine scientific and design research methods, as distant yet complementary as microanalysis and interaction design, (b) new research tools could seed accessible and engaging contextual research into voice within a social model of disability, and PMID- 28675074 TI - Talking about suicide may not be enough: family reaction as a mediator between disclosure and interpersonal needs. AB - BACKGROUND: Although most people who make an attempt do not die, attempt survivors remain at particularly elevated risk for suicide in the short- and long term. Moreover, the research on suicide-related disclosure and subsequent family reactions on risk factors for the development of suicidal desire is limited. AIMS: This study examined the relationships between disclosure, family reaction and two interpersonal needs connected to the development of suicidal desire. METHODS: Data from 74 attempt survivors who participated in a larger study were analyzed to assess the relationships between degree of suicide-related disclosure, quality of family reaction and thwarted belongingness and perceived burdensomeness. RESULTS: Results indicated that higher rates of disclosure predicted more positive family reactions, which in turn predicted lower levels of thwarted belongingness and perceived burdensomeness. Although there was no direct relationship between disclosure and the outcome variables, bootstrapping analyses indicated that family reaction mediated the relationship between disclosure and both belongingness and burdensomeness. CONCLUSIONS: These findings suggest the need for more family interventions that promote healthy reactions following suicide-related disclosure in order to facilitate the recovery and treatment process. PMID- 28675075 TI - Factors Associated With Body Image Perception Among Brazilian Students From Low Human Development Index Areas. AB - This study aimed to evaluate sociodemographic, behavioral, and individual factors associated with body image perception in a sample of adolescents from schools in low Human Development Index areas in Brazil. This cross-sectional study included 609 boys and 573 girls (aged 11-17 years). Body image perception (nine silhouettes scale) and sociodemographic, behavioral, and individual variables were included. Multinomial logistic regression analysis was used. Most boys (76.9%) and girls (77.5%) were dissatisfied with their body image. Body mass index status and healthy body image evaluation were significantly associated with body image dissatisfaction in both boys and girls ( p < .001), and daily fruit consumption was associated with body image dissatisfaction only in boys ( p = .035). Education and health care focused on body image can pay special attention to young people from vulnerable areas with unhealthy nutritional status and focus on strategies that enable improving the perception of a healthy body and a healthy diet. PMID- 28675076 TI - Impact of Perceived Risk and Friend Influence on Alcohol and Marijuana Use Among Students. AB - We performed a secondary analysis of Adolescent Health Risk Behavior Survey data ( N = 937), examining associations between lifetime alcohol and marijuana use with intrapersonal (i.e., risk perceptions) and interpersonal (e.g., peer approval and behavior) factors. Multinomial and binary logistic regression analyses contend students reporting lifetime alcohol use-compared to students who had never used alcohol or marijuana-perceived lower alcohol risk ( p < .001), higher friend drinking approval ( p < .001), and greater friend drinking ( p = .003). Using both alcohol and marijuana in one's life was associated with being in public schools ( p = .010), higher grade levels ( p = .001), lower perceived alcohol ( p = .011) and marijuana use risk ( p = .003), higher friend approval of alcohol ( p < .001) and marijuana use ( p < .001), and believed more friends used alcohol ( p < .001). Compared to lifetime alcohol only, perceived friend academic performance decreased the risk of lifetime alcohol and marijuana use ( p = .043). Findings are beneficial to school nurses with students experiencing effects associated with substance use. PMID- 28675077 TI - Effective Recruitment of Schools for Randomized Clinical Trials: Role of School Nurses. AB - In school settings, nurses lead efforts to improve the student health and well being to support academic success. Nurses are guided by evidenced-based practice and data to inform care decisions. The randomized controlled trial (RCT) is considered the gold standard of scientific rigor for clinical trials. RCTs are critical to the development of evidence-based health promotion programs in schools. The purpose of this article is to present practical solutions to implementing principles of randomization to RCT trials conducted in school settings. Randomization is a powerful sampling method used to build internal and external validity. The school's daily organization and educational mission provide several barriers to randomization. Based on the authors' experience in conducting school-based RCTs, they offer a host of practical solutions to working with schools to successfully implement randomization procedures. Nurses play a critical role in implementing RCTs in schools to promote rigorous science in support of evidence-based practice. PMID- 28675078 TI - Evaluation of the Parkinson's KinetiGraph in monitoring and managing Parkinson's disease. AB - INTRODUCTION: While objective measurement is routine in clinical care of most conditions, this has not been the case for Parkinson's Disease. Recent innovations make objective measurement in Parkinson's Disease possible and its utility and how this should be assessed is discussed here. Areas covered: Whilst therapies are effective in Parkinson's Disease, symptoms fluctuate in relation to treatment over the course of the day. Objective measurement makes it possible to assess symptom control, whether treatment is required and whether it achieved control. Objective measurement makes it possible to consider targets for therapeutic control and to begin an assessment of the value of improved control. Evidence for the effect of improved measurement on outcomes is only beginning to emerge. As symptom severity relates to quality of life and costs, reducing clinical scores and fluctuations through objective measurement is in the interest of both the patient and the health system. Expert commentary: In broad terms objective measurement should be used to identify patients whose symptoms lie outside the target range and then to assess whether therapy was effective in bringing them into control. While this is relevant to all stages of Parkinson's Disease specific clinical situations where this had greatest impact are discussed. PMID- 28675079 TI - Cochlear Nerve Aplasia and Hypoplasia: Predictors of Cochlear Implant Success. AB - Objective To identify factors predicting performance outcomes following cochlear implantation in patients with cochlear nerve aplasia or hypoplasia. Data Sources Individual patient data extracted from published case series and reports. Review Methods The MEDLINE database, Cochrane Library, Embase, Web of Science, and Google Scholar were queried for "cochlear implant" in conjunction with "aplasia" or "hypoplasia" between 1985 and 2015. Eighteen studies were included describing 97 subjects with individual postimplant auditory data. Postimplant performance was categorized as follows: level 1, nonstimulation/minimal detection; level 2, improved detection; level 3, closed-set speech perception; or level 4, open-set speech perception. The subjects achieving speech perception (levels 3 and 4) were descriptively compared with those who did not. Results Subjects with a hypoplastic cochlear nerve on magnetic resonance imaging had higher reported rates of achieving speech perception than those with an aplastic nerve. Subjects with syndromic medical comorbidities had higher reported rates of nonstimulation than nonsyndromic subjects. The data showed that some children with an aplastic cochlear nerve or those with partial electrode insertion could obtain levels of speech discrimination. Reporting of patient characteristics and auditory outcomes was extremely variable across studies. Conclusion As previously shown, cochlear implant in patients with cochlear nerve aplasia or hypoplasia can provide meaningful hearing for select patients. The current study suggests that presence of a cochlear nerve on magnetic resonance imaging and lack of comorbid medical syndrome are associated with better auditory outcomes in such patients. Future efforts to report individual data in a consistent manner may allow better determination of predictive factors. PMID- 28675080 TI - Radiodensity of the Ostiomeatal Complex in Recurrent Acute Rhinosinusitis. AB - Objective Recurrent acute rhinosinusitis (RARS) can be an elusive diagnosis due to the lack of clinical and radiographic findings in between acute episodes. This study aims to identify objective computed tomography (CT) characteristics in RARS. Study Design Case series with chart review. Setting Tertiary academic medical center. Subjects and Methods Patients meeting diagnostic criteria for RARS were identified retrospectively from the senior author's practice. Patients were diagnosed with RARS if they experienced 3 or more episodes of acute sinusitis within the past year with complete resolution of symptoms in between episodes. At least 1 episode was confirmed via CT or endoscopy. CT scans showing prior surgery were excluded. The scans for these patients were compared with those from a normal control group. Bone radiodensity of the entire ostiomeatal complex (OMC), including the ethmoid bulla, middle turbinate, and uncinate, was measured in Hounsfield units. Maximum radiodensity was noted for each side. Results A total of 16 patients meeting inclusion criteria for RARS were compared with 16 healthy patients. The mean Lund-MacKay score was 1.6 in the RARS group and 1.3 in the control group. The maximum radiodensity of the OMC was significantly higher in the RARS group (556) compared with that of the control group (327) ( P < .0001). Conclusion Patients with RARS had significantly greater radiodensity of the OMC compared with those in the control group despite minimal differences in mucosal disease. Radiodensity measurement of the OMC using Hounsfield units may help to identify patients with this elusive diagnosis. PMID- 28675081 TI - Neoadjuvant chemotherapy by bronchial arterial infusion in patients with unresectable stage III squamous cell lung cancer. AB - BACKGROUND: We investigated the effects of neoadjuvant chemotherapy administered via bronchial arterial infusion (BAI) on unresectable stage III lung squamous cell carcinoma (SCC). METHODS: This was a single-arm retrospective study of chemotherapy with gemcitabine plus cisplatin (GP) administered via BAI to patients with unresectable lung SCC. Data regarding the post-treatment response rate, downstage rate, and surgery rate, as well as progression-free survival (PFS), overall survival (OS), quality of life, and post-BAI side effects were collected. RESULTS: A total of 36 patients were enrolled in this study between August 2010 and May 2014. The response rate was 72.2%, and the downstage rate was 22.2%. Among the patients who were downstaged, 16 (44.4%) patients were because of their T stage, and 5 (13.9%) patients were downstaged due to to their N stage. The surgery rate was 52.8%, the 1-year survival rate was 75.4%, and the 2-year survival rate was 52.1%. The median PFS was 14.0 months [95% confidence interval (CI): 8.6-19.4], and the median OS was 25.0 months (95% CI: 19.1-30.9). The quality of life was significantly improved, and the chemotherapy was well tolerated. CONCLUSIONS: Compared with intravenous neoadjuvant chemotherapy, BAI chemotherapy significantly improved the surgery rate, prolonged PFS and OS, and improved the quality of life in patients with unresectable stage III lung SCC. PMID- 28675083 TI - Gender and gender typicality in autobiographical memory: A replication and extension. AB - Gender differences in autobiographical memory (AM) are commonly reported, but often inconsistent across studies using varied measurement techniques. The current study aimed to provide more clarity to where and why gender differences emerge by carefully controlling for factors hypothesised to be relevant to gender; thus, it tested shorter and longer term AM using both narrative and questionnaire measures, and further tested whether subscription to feminine typical traits mediated these differences. Results demonstrate that women's memory narratives score higher than men's on measures of affect, connection to others, factual and interpretive elaboration, and thematic coherence. Women scoring high on feminine-typical traits demonstrated larger differences when compared to men scoring low on these measures than did average men and women, but these latter groups still differed substantially. Gender differences were present in narrative measures of longer term events (often more than two years) and shorter term events (one day-one week), but effect sizes were larger in longer term events. Gender differences were not common on questionnaire measures. These findings replicate previous narrative-based gender differences and highlight the need for carefully constructed studies of socio-cultural, individual, and developmental influences. PMID- 28675084 TI - Expert system application for prioritizing preventive actions for shift work: shift expert. AB - INTRODUCTION: Shift patterns, work hours, work arrangements and worker motivations have increasingly become key factors for job performance. The main objective of this article is to design an expert system that identifies the negative effects of shift work and prioritizes mitigation efforts according to their importance in preventing these negative effects. The proposed expert system will be referred to as the shift expert. METHODS: A thorough literature review is conducted to determine the effects of shift work on workers. Our work indicates that shift work is linked to demographic variables, sleepiness and fatigue, health and well-being, and social and domestic conditions. These parameters constitute the sections of a questionnaire designed to focus on 26 important issues related to shift work. The shift expert is then constructed to provide prevention advice at the individual and organizational levels, and it prioritizes this advice using a fuzzy analytic hierarchy process model, which considers comparison matrices provided by users during the prioritization process. An empirical study of 61 workers working on three rotating shifts is performed. After administering the questionnaires, the collected data are analyzed statistically, and then the shift expert produces individual and organizational recommendations for these workers. PMID- 28675082 TI - Predictors of mid-term prognosis and adverse factors in acute pulmonary embolism. AB - BACKGROUND: To explore the differences in short and middle term adverse factors of pulmonary embolism (PE) outcome. METHODS: This was a single-center retrospective study of inpatients admitted from Zhongshan Hospital, Fudan University, with first-time PE. Clinical data were collected from patients with objectively confirmed PE, and a 2-year follow up was conducted. RESULTS: The sample contained 310 patients with PE, ranging in age from 18 to 86 years old (mean 63.28 +/- 15.30) and including 165 men (53.2%) and 145 women (46.8%). Successful treatment was achieved in 285 cases (91.9%) and unsuccessful treatment turned out in 25 cases (8.1%). Logistical regression analysis showed that massive PE [odds ratio (OR) = 23.625, 95% confidence interval (CI) 6.248-89.333], hypoxemia (OR = 11.915, 95% CI 1.900-74.727), leukocytosis (OR = 9.120, 95% CI 2.227-37.349) and active cancer (OR = 6.142, 95% CI 1.233-30.587) were associated with a poor prognosis for acute PE in the short term (in hospital). Seventy-seven PE cases with complete electronic records were finally included in the follow up. Cox regression analysis showed that elevated pulmonary artery systolic pressure (PASP, ?50 mmHg) (HR = 9.240, 95% CI, 2.307-37.013) and active cancer with PE (HR = 3.700, 95% CI, 1.010-13.562) were associated with an increased risk of mid-term mortality after a follow-up period of 2 years. CONCLUSIONS: Massive PE, hypoxemia, leukocytosis and active cancer may contribute to a poor prognosis for patients with acute PE in hospital. Elevated PASP and active cancer may negatively impact survival time and increase the risk of death for patients with acute PE after 2-year follow up. Short-term adverse factors of acute PE are not exactly the same as the mid-term risk factors of acute PE. PMID- 28675085 TI - Impact of Adjuvant Radiotherapy for Malignant Salivary Gland Tumors. AB - Objective Using the National Cancer Database (NCDB), we investigated the characteristics, outcomes, and benefits of adjuvant therapy for patients diagnosed with malignant salivary gland tumors between 2004 and 2012. Study Design Retrospective analysis. Setting NCDB. Subject and Methods The cases of patients diagnosed with a nonmetastatic major salivary gland tumor who underwent resection between 2004 and 2012 were abstracted from the NCDB. Patients were further included if they had pT1-4NX-1M0 high-grade disease or pT3-4NX-0M0 or pT1 4N1M0 low-grade disease. Patients were identified as having no postoperative radiation therapy or having received postoperative radiation therapy to a dose of 5000 and 7000 cGy to the head and neck region or the parotid region, and their characteristics and outcomes were compared. Results During the study period, 4068 patients met the inclusion criteria for this analysis, of which 2728 (67.1%) received postoperative radiation and 1340 (32.9%) did not. With a median follow up of 49.1 months, there was a significant improvement in overall survival associated with those receiving postoperative radiation (5 years, 56% vs 50.6%). On multivariable analysis, radiation utilization (hazard ratio, 0.78; 95% CI, 0.71-0.86; P < 0.001) and female sex (hazard ratio, 0.88) were associated with improved survival. When the analysis was limited to patients <=65 years old, the survival benefit was persistent on multivariable analysis. Conclusion In conclusion, in this large NCDB study of 4068 patients with locally advanced malignant salivary gland carcinoma, administering adjuvant radiotherapy was associated with improved overall survival. PMID- 28675086 TI - Cardiac sarcoidosis: a diagnostic and therapeutic challenge. AB - OBJECTIVE: Cardiac involvement in sarcoidosis can present in various ways, with atrioventricular (AV) block and ventricular arrhythmias being the most common signs. Because of initial non-specific findings, diagnosis can be a challenge. Very few data can support treatment decisions as cardiac manifestations of this systemic disorder are rare. METHODS AND RESULTS: We reviewed current guidelines, cohort studies, and expert opinions concerning diagnosis and treatment of cardiac sarcoidosis. CONCLUSIONS: Longitudinal follow-up studies are necessary to improve the diagnostic process and risk stratification of cardiac sarcoidosis. The optimal dose of steroids, indications for internal cardioverter-defibrillator (ICD), and technique and optimal timing of ablation are still under debate. PMID- 28675087 TI - Erratum. PMID- 28675089 TI - The Challenge of Guideline Development When Evidence Is Sparse. AB - Although best-practice standards for clinical guidelines have been released by the Institute of Medicine and Guidelines International Network, a great challenge remains for guideline development for patients afflicted with rare diseases. This article reviews the challenge of guideline development under these circumstances with an emphasis on strategies to overcome these challenges. Guideline development and use in practice have become integral components in the contemporary care of patients to optimize outcome results. The guidelines are developed through an objective, evidence-based process conducted by experts and stakeholders for a given disease process. PMID- 28675088 TI - Sensitivity to Angular and Radial Source Movements as a Function of Acoustic Complexity in Normal and Impaired Hearing. AB - In contrast to static sounds, spatially dynamic sounds have received little attention in psychoacoustic research so far. This holds true especially for acoustically complex (reverberant, multisource) conditions and impaired hearing. The current study therefore investigated the influence of reverberation and the number of concurrent sound sources on source movement detection in young normal hearing (YNH) and elderly hearing-impaired (EHI) listeners. A listening environment based on natural environmental sounds was simulated using virtual acoustics and rendered over headphones. Both near-far ('radial') and left-right ('angular') movements of a frontal target source were considered. The acoustic complexity was varied by adding static lateral distractor sound sources as well as reverberation. Acoustic analyses confirmed the expected changes in stimulus features that are thought to underlie radial and angular source movements under anechoic conditions and suggested a special role of monaural spectral changes under reverberant conditions. Analyses of the detection thresholds showed that, with the exception of the single-source scenarios, the EHI group was less sensitive to source movements than the YNH group, despite adequate stimulus audibility. Adding static sound sources clearly impaired the detectability of angular source movements for the EHI (but not the YNH) group. Reverberation, on the other hand, clearly impaired radial source movement detection for the EHI (but not the YNH) listeners. These results illustrate the feasibility of studying factors related to auditory movement perception with the help of the developed test setup. PMID- 28675090 TI - Unsafe cycling behaviours and near crashes among Italian cyclists. AB - This study investigates the direct and indirect effect of three types of unsafe behaviours (i.e. errors, generic violations and smartphone-specific violations) on the likelihood of near crashes and actual crashes among Italian cyclists. We considered smartphone-specific violations as a different unsafe behaviour subtype that enhances the probability of committing errors, thus increasing the likelihood of being involved in near crashes. Furthermore, we hypothesized that near crashes will predict actual crashes. Results revealed that errors predicted near crashes, whereas generic and smartphone-specific violations did not. Near crashes mediated the effect of errors on crashes. Moreover, smartphone-specific violations predicted crashes throughout its consecutive effects on errors and near crashes. These findings contribute to deepen our understanding of the relationship between cyclists' unsafe behaviours, near crashes and actual crashes. To our knowledge, the present study is the first that links errors to near crashes among cyclists. PMID- 28675091 TI - Coffee polyphenols extracted from green coffee beans improve skin properties and microcirculatory function. AB - Coffee polyphenols (CPPs), including chlorogenic acid, exert various physiological activities. The purpose of this study was to investigate the effects of CPPs on skin properties and microcirculatory function in humans. In this double-blind, placebo-controlled study, 49 female subjects with mildly xerotic skin received either a test beverage containing CPPs (270 mg/100 mL/day) or a placebo beverage for 8 weeks. The ingestion of CPPs significantly lowered the clinical scores for skin dryness, decreased transepidermal water loss, skin surface pH, and increased stratum corneum hydration and the responsiveness of skin blood flow during local warming. Moreover, the amounts of free fatty acids and lactic acid in the stratum corneum significantly increased after the ingestion of CPPs. These results suggest that an 8-week intake of CPPs improve skin permeability barrier function and hydration, with a concomitant improvement in microcirculatory function, leading to efficacy in the alleviation of mildly xerotic skin. PMID- 28675092 TI - Introducing experiment in pedestrian behaviour and risk perception study at urban level crossing. AB - Given the high risk of severe accidents at level crossings (LCs), this study examined legal and illegal crossings by pedestrians and cyclists at a high traffic LC in Zagreb, Croatia. Survey data and field observations were collected to identify reasons for risky behaviour. Behaviour was observed under normal conditions and in the presence of various safety measures in order to identify measures that can reduce risky behaviour. Results show that the presence of police officer at the LC was most effective at reducing illegal crossings, while the presence of cameras contributes significantly as well, especially after safety educational campaign when illegal crossing decreases for 59.23%. We can assume that in future the improvement regarding human behaviour on LC could be made with cameras on LC and more frequent educational campaigns. This is the first reported use of field survey and video surveillance methods to analyse user behaviour at LCs in Croatia. PMID- 28675093 TI - Who's Managing Otolaryngologic Conditions in the United States? AB - Growth of an aging US population, coupled with implementation of the Patient Protection and Affordable Care Act, will pose logistical challenges for the primary care provider (PCP) workforce for the foreseeable future. In particular, the burden of otolaryngologic care placed on PCPs is substantial, based on research dating back to the 1970s and confirmed by a recent analysis of the US National Ambulatory Medical Care Survey. Collaboration between the otolaryngology and primary care communities will be needed to ensure that PCPs gain adequate exposure and training in routine otolaryngology care to improve the clinical management of ear, nose, and throat conditions in an expanding population. PMID- 28675094 TI - Effect of Increased Body Mass Index on Complication Rates during Laryngotracheal Surgery Utilizing Jet Ventilation. AB - Objective Jet ventilation has been used for >30 years as an anesthetic modality for laryngotracheal surgery. Concerns exist over increased risk with elevated body mass index (BMI). We reviewed our experience using jet ventilation for laryngotracheal stenosis to assess for complication rates with substratification by BMI. Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods A total of 126 procedures with jet ventilation were identified from October 2006 to December 2014. Complications were recorded, including intubation, unplanned admission, readmission, dysphonia, oral trauma, pneumothorax, pneumomediastinum, and tracheostomy. Lowest intraoperative oxygen saturation and maximum end-tidal CO2 (ETCO2) levels were recorded. Results Among 126 patients, 43, 77, and 6 had BMIs of <25, 25-35, and 36-45, respectively. In the BMI <25 group, there was 1 unplanned intubation. Mean maximum ETCO2 was 36.51 with no hypoxemia observed. In the BMI 25-35 group, 2 patients required intubation, and 1 sustained minor oral trauma. The mean maximum ETCO2 was 38.85, with 4 patients having oxygen saturation <90%. In the BMI 36-45 group, 2 patients required intubation. The mean maximum ETCO2 was 41 with no hypoxemia observed. BMI and length of stenosis were statistically significant variables associated with incidence of intraoperative intubation. Conclusion Increased BMI was associated with an increase in highest ETCO2 intraoperatively. However, this was not associated with an increase in major complications. Jet ventilation was performed without significant adverse events in this sample, and it is a viable option if used with an experienced team in the management of laryngotracheal stenosis. PMID- 28675095 TI - Development and Pilot Testing of an Objective Structured Clinical Examination for Obstructive Sleep Apnea. AB - Objective Our aim was (1) to develop an objective structured clinical examination (OSCE) for obstructive sleep apnea (OSA) and (2) to test the reliability and evaluate the feasibility of this OSCE while assessing residents' clinical skills in multiple core competencies via the standardized patient methodology. Study Design Development of assessment tool. Setting Johns Hopkins Medicine Simulation Center. Subjects and Methods Residents of the Department of Otolaryngology-Head and Neck Surgery at The Johns Hopkins University School of Medicine were invited to participate. A 2-station OSCE was developed. The first station used a standardized patient, and the encounter was videotaped for later evaluation by medical faculty not familiar with the participants being tested. The second was a computer-based station developed per a modified Delphi technique, based on feedback from otolaryngology and sleep medicine faculty involved in the care of patients with OSA. Checklists were developed for each station to standardize the evaluation of each trainee's performance. Results The OSCE that we developed is a feasible tool for assessing residents' performance and skills to diagnose and manage a patient with OSA. Internal consistency, as assessed by Krippendorff's alpha, was 0.699 for station 1 and 0.95 for station 2. Conclusion This OSCE was found to be feasible for assessment of clinical competency in OSA. Our model provides targeted assessment of multiple competencies and opportunity to improve clinical knowledge and skills. PMID- 28675096 TI - Adverse Events in Endoscopic Sinus Surgery for Infectious Orbital Complications of Sinusitis: 30-Day NSQIP Pediatric Outcomes. AB - Objective Identify predictors of adverse events for children who underwent endoscopic sinus surgery for treatment of orbital complications associated with sinusitis. Study Design Cross-sectional analysis of a US national database. Setting American College of Surgeons National Surgical Quality Improvement Program (NSQIP), pediatric version (2012-2015). Subjects and Methods Patients were identified with a combination of codes from the International Classification of Diseases, Ninth Revision and 2014 Current Procedural Terminology. Our primary outcome measure was adverse events, which were compared with clinical risk factors to examine for any associations. Results A total of 57 patients were included for analysis. No significant relationship was identified between 30-day postoperative adverse events and age, sex, race, body mass index, prematurity, history of asthma, steroid use (within 30 days), and preoperative white blood cell count. There was a statistically significant increase in adverse events for those patients who underwent delayed surgery ( P < .0001). No serious adverse events related to death, sepsis, nerve injury (eg, visual loss), or other organ space infections (eg, intracranial infection) were identified. After controlling for age group and race, delayed operative intervention was a significant clinical predictor of adverse events (odds ratio = 25.65; 95% CI, 3.86-170.45; P = .0008). We observed unplanned reoperation and readmission rates of 5.3% and 7%, respectively. Conclusions Endoscopic surgical drainage for infectious orbital complications of sinusitis in children appears to be safe. Serious or significant adverse events were uncommon. Areas for improvement include limiting and reducing unplanned reoperations and readmissions. PMID- 28675097 TI - Adenotonsillectomy for Obstructive Sleep Apnea and Quality of Life: Systematic Review and Meta-analysis. AB - Objective To determine the impact of adenotonsillectomy on the quality of life of pediatric patients with obstructive sleep apnea (OSA) and to identify gaps in the current research. Data Sources The MEDLINE, EMBASE, and Cochrane databases were systematically searched via the Ovid portal on June 18, 2016, for English language articles. Review Methods Full-text articles were selected that studied boys and girls <18 years of age who underwent adenotonsillectomy for OSA or sleep disordered breathing and that recorded validated, quantitative quality-of-life outcomes. Studies that lacked such measures, performed adenotonsillectomy for indications other than OSA or sleep-disordered breathing, or grouped adenotonsillectomy with other procedures were excluded. Results Of the 328 articles initially identified, 37 were included for qualitative analysis. The level of evidence was generally low. All studies involving short-term follow-up (<=6 months) showed improvement in quality-of-life scores after adenotonsillectomy as compared with preoperative values. Studies involving long term follow-up (>6 months) showed mixed results. Modifications to and concurrent procedures with conventional adenotonsillectomy were also identified that showed quality-of-life improvements. Three studies were identified for meta-analysis that compared pre- and postoperative Obstructive Sleep Apnea-18 scores. Short- and long-term follow-up versus preoperative scores showed significant improvement ( P < .001). Short- and long-term scores showed no significant difference. Conclusion This systematic review and meta-analysis demonstrate adenotonsillectomy's effectiveness in improving the quality of life of pediatric patients with OSA. This is well demonstrated in the short term and has strong indications in the long term. PMID- 28675099 TI - Lengthening Temporalis Myoplasty: Objective Outcomes and Site-Specific Quality-of Life Assessment. AB - Objective Evaluate outcomes of the lengthening temporalis myoplasty in facial reanimations. Study Design Case series with planned data collection. Setting Ospedali Riuniti, Bergamo, and AOUC Careggi, Florence, Italy. Subjects and Methods From 2011 to 2016, 11 patients underwent lengthening temporalis myoplasty; demographic data were collected for each. Pre- and postoperative photographs and videos were recorded and used to measure the smile angle and the excursion of the oral commissure, according to the SMILE system (Scaled Measurements of Improvement in Lip Excursion). All patients were tested with the Facial Disability Index, and they also completed a questionnaire about the adherence to physiotherapy indications. Results All patients demonstrated a significant improvement in functional parameters and in quality of life. On the reanimated side, the mean z-line and a-value, measured when smiling, significantly improved in all patients: from 22.6 mm (95% CI, 20.23-25.05) before surgery to 30.9 mm (95% CI, 27.82-33.99) after surgery ( P < .001) and from 100.5 degrees (95% CI, 93.96 degrees -107.13 degrees ) to 111.6 degrees (95% CI, 105.63 degrees -117.64 degrees ; P < .001), respectively. The mean postoperative dynamic gain, passing from rest to a full smile at the reanimated side, was 3.1 mm (95% CI, 1.30-4.88) for the z-line and 3.3 degrees (95% CI, 1.26 degrees 5.29 degrees ) for the a-value. The Facial Disability Index score increased from a preoperative mean of 33.4 points (95% CI, 28.25-38.66) to 49.9 points (95% CI, 47.21-52.60) postoperatively ( P < .001). Conclusions The lengthening temporalis myoplasty can be successfully used for smile reanimation, with satisfying functional and quality-of-life outcomes. PMID- 28675098 TI - Production of a novel wheat gluten hydrolysate containing dipeptidyl peptidase-IV inhibitory tripeptides using ginger protease. AB - Wheat gluten is a Pro-rich protein complex comprising glutenins and gliadins. Previous studies have reported that oral intake of enzymatic hydrolysates of gluten has beneficial effects, such as suppression of muscle injury and improvement of hepatitis. Here, we utilized ginger protease that preferentially cleaves peptide bonds with Pro at the P2 position to produce a novel type of wheat gluten hydrolysate. Ginger protease efficiently hydrolyzed gluten, particularly under weak acidic conditions, to peptides with an average molecular weight of <600 Da. In addition, the gluten hydrolysate contained substantial amounts of tripeptides, including Gln-Pro-Gln, Gln-Pro-Gly, Gln-Pro-Phe, Leu-Pro Gln, and Ser-Pro-Gln (e.g. 40.7 mg/g at pH 5.2). These gluten-derived tripeptides showed high inhibitory activity on dipeptidyl peptidase-IV with IC50 values of 79.8, 70.9, 71.7, 56.7, and 78.9 MUM, respectively, suggesting that the novel gluten hydrolysate prepared using ginger protease can be used as a functional food for patients with type 2 diabetes. PMID- 28675100 TI - Distraction Osteogenesis Maxillary Expansion (DOME) for Adult Obstructive Sleep Apnea Patients with High Arched Palate. AB - A narrow maxilla with high arched palate characterizes a phenotype of obstructive sleep apnea (OSA) patients that is associated with increased nasal resistance and posterior tongue displacement. Current maxillary expansion techniques for adults are designed to correct dentofacial deformity. We describe distraction osteogenesis maxillary expansion (DOME) tailored to adult patients with OSA with narrow nasal floor and high arched palate without soft tissue redundancy. DOME is performed with placement of maxillary expanders secured by mini-implants along the midpalatal suture. This minimizes the maxillary osteotomies necessary to re create sutural separation for reliable expansion at the nasal floor and palatal vault. We report the safety and efficacy profile of the first 20 patients at Stanford who underwent DOME. PMID- 28675101 TI - Tympanoplasty following Blast Injury. AB - Objectives To assess outcomes following tympanoplasty for blast-induced tympanic membrane perforations in a military population. Study Design Case series with chart review. Setting Tertiary care medical centers. Subjects and Methods Military personnel (N = 254) undergoing tympanoplasty for blast-related tympanic membrane perforations sustained between April 2005 and July 2014 were identified from the Expeditionary Medical Encounter Database. Descriptive statistics were obtained regarding demographics, primary and revision surgery success rates, hearing status pre- and postsurgery, and frequency of ossicular reconstruction. Rates of successful perforation closure were assessed against perforation size and character (central vs marginal) and time to surgery. Rates and types of complications were additionally explored. Results There were a total of 352 operations among 254 subjects, with an 82.1% rate of successful closure following primary surgery. For successful primary tympanoplasty, the mean improvement in pure tone average was 11.7 +/- 12.1 dB. Ossiculoplasty was performed in 9.1% (32 of 352) of cases. There was no significant relationship between successful perforation closure and perforation size, perforation character, or time between injury and surgery. Cholesteatoma complicated 4.3% (15 of 352) of cases. A significant relationship was identified between risk of cholesteatoma development and increasing perforation size and marginal perforations. Conclusion Tympanoplasty success rates for blast-induced tympanic membrane perforations are lower than for other common injury mechanisms. Due to appreciable rates of postoperative cholesteatoma development, close clinical surveillance is recommended. PMID- 28675102 TI - The occurrence, exposure and risk assessment of perfluoroalkyl acids in food from mainland, China. AB - To study the contamination of perfluoroalkyl acids (PFAAs) in Chinese food and the risk of dietary exposure for the Chinese population, the data of 17 PFAAs covering 38 cities throughout China in 15 groups of foods were collected for meta analysis from published and available research literature. Using food consumption and body weight parameters, estimated dietary intakes (EDIs) were calculated for evaluation using the Scenario-Based Risk Assessment (SceBRA) modelling. Among food groups, the highest SigmaPFAAs concentrations and EDI contributions were both found in poultry (363 ng/g), fish and shrimp (313 ng/g), dark vegetables (309 ng/g), fruits (116 ng/g) and pork (25 ng/g). The EDI of adults in the high exposure scenario was about twice that of the intermediate-exposure scenario, while the EDI of children was about twice that of adults' EDI in the intermediate exposure scenario. In addition, the PFOS EDI for children under high exposure approached its tolerable daily intake (TDI). Therefore high dietary exposure to PFAAs is giving rise to an increased health risk, especially for children. PMID- 28675103 TI - Carotid Artery Plaques, Carotid Intima-Media Thickness, and Risk of Cardiovascular Events and All-Cause Death in Older Adults: A 5-Year Prospective, Community-Based Study. AB - We assessed the effect of asymptomatic carotid atherosclerosis (CAS) on the development of cardiovascular diseases (CVDs) in a community-based population aged >=55 years in China. A total of 1376 residents underwent CAS assessment by ultrasonography in July 2009. New CVD events, including stroke and coronary heart events, were collected at the follow-up survey at the end of 2014. After adjusting for baseline demographic characteristics and traditional CVD risk factors, the risk of CVD in patients with minimal CAS (mean common carotid artery intima-media thickness [CCA-IMT] >=1 mm and no plaques), nonstenotic plaques (carotid stenosis <50%), and stenotic plaques (carotid stenosis >=50%) was 0.8 (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.33-1.69), 2.0 (HR: 2.01, 95% CI: 1.24-3.25), and 3.1 (HR: 3.05, 95% CI: 1.62-5.74) times greater, respectively, than that of patients without CAS (CCA-IMT <1 mm and no plaques). Our findings provide direct evidence of the independent predictive value of the severity of asymptomatic CAS for the development of CVD in older Chinese adults. PMID- 28675104 TI - Meat quality, free fatty acid concentration, and oxidative stability of pork from animals fed diets containing different sources of selenium. AB - This study evaluates the effect of the source of dietary selenium supplementation (organic versus mineral) and the combined effect of organic selenium and vitamin E on the fatty acid composition and lipolysis in pork intramuscular fat and other meat quality characteristics such as drip loss and lipid stability. Higher vitamin E deposition, lower drip loss, and higher stability against oxidation were detected in muscle from pigs fed organic selenium. Also higher proportion of free fatty acids was observed in intramuscular fat from pigs fed organic selenium than those fed inorganic selenium, being these mainly coming from neutral lipid fraction. In addition, the inclusion of vitamin E in the diet enhanced such effect. Dietary organic selenium also increased Delta9-desaturase and elongase indexes and C18:1n-9 concentration. A related decrease of C18:0 concentration was also observed. Described differences in the lipid fraction composition could affect sensory characteristics of meat and meat products. PMID- 28675105 TI - Salt microspheres and potassium chloride usage for sodium reduction: Case study with sushi. AB - The aim of the study was to estimate possibilities of salt substitutes usage in the preparation of two sushi types (nigiri and maki) prepared with different seafood (salmon: Salmo salar, tuna: Thunnus albacares, and shrimp: Pleoticus muelleri). Potassium chloride (Mary samples), Soda-Lo (hollowed microsphere of regular salt crystals), and regular salt (sodium chloride) were used in the experiment. Sushi samples (n = 1960) were evaluated by 40 trained panelists who noticed that maki shrimp samples prepared with Mary salt had higher bitterness (21.48 +/- 28.01) in comparison with 2% sodium chloride (7.91 +/- 8.80). The saltiness was lower in nigiri tuna prepared with Mary (49.59 +/- 17.47) than 2% sodium chloride (61.11 +/- 15.75). The study clearly showed the possibility of lowering sodium content in sushi meal with the usage of salt substitutes, with emphasis that Soda-Lo should be considered as a better option due to the retention of sensory properties in sushi samples prepared with this salt substitute. PMID- 28675106 TI - West Nile Virus Infection in Ruffed Grouse ( Bonasa umbellus): Experimental Infection and Protective Effects of Vaccination. AB - Ruffed grouse ( Bonasa umbellus) population numbers in Pennsylvania dramatically declined during the early 2000s and have subsequently remained depressed throughout much of the state. While this decline has been temporally associated with the presence of West Nile virus (WNV), lack of information on the WNV susceptibility of this popular game bird species has limited the ability to interpret the potential impacts of WNV. To address this knowledge gap, virologic, immunologic, pathologic, and clinical responses as well as protective effects of vaccination following experimental WNV inoculation in ruffed grouse were assessed. Four of 10 (40%) naive, WNV-inoculated grouse succumbed to infection within 8 days and had moderate mean peak viremia titers (107.0 plaque-forming units [PFU]/ml serum); severe necrotizing myocarditis with widespread, corresponding immunohistochemical labeling; and minimal encephalitis. Grouse that survived to the prescribed end point of 14 days postinoculation (6/10; 60%) had slightly lower mean peak viremia titers (106.8 PFU/ml serum), moderate myocardial lesions, and more widespread brain lesions with rare corresponding immunohistochemical labeling. Vaccinated, WNV-inoculated birds ( n = 5) had lower mean peak viremia titers (103.6 PFU/ml serum) and minimal lesions, and sham inoculated, in-contact control birds ( n = 3) had no evidence of infection. All surviving, inoculated birds seroconverted, and WNV-specific antibodies were detectable in serum and Nobuto filter paper strip-eluted blood samples. These data suggest that WNV could serve as an additional population pressure on ruffed grouse in regions where transmission levels are high and WNV competent, ornithophilic vectors exist. PMID- 28675107 TI - Inhibition of hedgehog pathway reveals the regulatory role of SMO in gastric cancer cells. AB - Previous studies report aberrant activation of the hedgehog signaling pathway in the progression of various cancers. This study aimed to investigate the expressions of smoothened and downstream glioma-associated oncogene homology-1 in gastric cancer and the underlying molecular mechanisms. Here, we first detected the expression in 58 cases of primary gastric cancer tissue and matched normal tissue specimens by western blot analysis and quantitative reverse transcription polymerase chain reaction. Cell proliferation and cycle were assayed in gastric cancer cells after blocking the hedgehog pathway by lentiviral-short hairpin RNA knockdown. In vitro inhibition of hedgehog pathway resulted in decreased cell proliferation and migration. Our studies demonstrate an important role for smoothened and glioma-associated oncogene homology-1 in gastric cancer and suggest inhibition of hedgehog pathway as a novel and potent strategy to treat gastric cancer patients. PMID- 28675108 TI - Radiation-induced Epstein-Barr virus reactivation in gastric cancer cells with latent EBV infection. AB - Epstein-Barr virus, a ubiquitous human herpes virus with oncogenic activity, can be found in 6%-16% of gastric carcinomas worldwide. In Epstein-Barr virus associated gastric carcinoma, only a few latent genes of the virus are expressed. Ionizing irradiation was shown to induce lytic Epstein-Barr virus infection in lymphoblastoid cell lines with latent Epstein-Barr virus infection. In this study, we examined the effect of ionizing radiation on the Epstein-Barr virus reactivation in a gastric epithelial cancer cell line (SNU-719, an Epstein-Barr virus-associated gastric carcinoma cell line). Irradiation with X-ray (dose = 5 and 10 Gy; dose rate = 0.5398 Gy/min) killed approximately 25% and 50% of cultured SNU-719 cells, respectively, in 48 h. Ionizing radiation increased the messenger RNA expression of immediate early Epstein-Barr virus lytic genes (BZLF1 and BRLF1), determined by real-time reverse transcription polymerase chain reaction, in a dose-dependent manner at 48 h and, to a slightly lesser extent, at 72 h after irradiation. Similar findings were observed for other Epstein-Barr virus lytic genes (BMRF1, BLLF1, and BcLF1). After radiation, the expression of transforming growth factor beta 1 messenger RNA increased and reached a peak in 12-24 h, and the high-level expression of the Epstein-Barr virus immediate early genes can convert latent Epstein-Barr virus infection into the lytic form and result in the release of infectious Epstein-Barr virus. To conclude, Ionizing radiation activates lytic Epstein-Barr virus gene expression in the SNU-719 cell line mainly through nuclear factor kappaB activation. We made a brief review of literature to explore underlying mechanism involved in transforming growth factor beta-induced Epstein-Barr virus reactivation. A possible involvement of nuclear factor kappaB was hypothesized. PMID- 28675109 TI - Titanium surfaces immobilized with the major antimicrobial fragment FK-16 of human cathelicidin LL-37 are potent against multiple antibiotic-resistant bacteria. AB - Infections on implanted medical devices are a challenging problem, especially when bacteria form difficult-to-treat biofilms. Antimicrobial peptides are considered to be a solution due to their potency against antibiotic-resistant superbugs. Previously, the authors' laboratory demonstrated the prevention of staphylococcal biofilm formation in an animal catheter model by injecting merecidin (formerly known as 17BIPHE2), a peptide engineered based on the only human cathelicidin. This study documents an alternative solution via covalent immobilization of FK-16, amino acid sequence FKRIVQRIKDFLRNLV-amide, which corresponds to the major antimicrobial region (residues 17-32) of LL-37. FK-16 is superior to the longer peptide LL-37 in terms of synthesis cost and the shorter peptide KR-12 in terms of activity spectrum. Indeed, the FK16-coated titanium surface showed a broad-spectrum activity against the ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. It also demonstrated anti-adhesion and biofilm inhibition capabilities against both S. aureus and E. coli. PMID- 28675111 TI - Outcomes of Tracheostomy With Concomitant and Delayed Percutaneous Endoscopic Gastrostomy in the Neuroscience Critical Care Unit. AB - BACKGROUND: In patients with severe neurologic conditions, percutaneous endoscopic gastrostomy (PEG) is typically performed either alone or with a tracheostomy. The characteristics and outcomes of patients receiving PEG concomitantly with a tracheostomy (CTPEG) and those receiving delayed PEG (DPEG) after a tracheostomy were compared. METHODS: Retrospective cohort study in a 24 bed neuroscience critical care unit (NCCU) at a tertiary care hospital. Consecutive patients admitted to the NCCU from April 2007 to July 2013 who underwent percutaneous tracheostomy and gastrostomy by the percutaneous tracheostomy team were included and grouped according to the timing of PEG placement: CTPEG versus DPEG. RESULTS: Of the 290 patients, 234 (81%) received CTPEG. Demographic and clinical characteristics were similar among the 2 groups except for a lower median (interquartile range [IQR]) body mass index (BMI; 27 [22.67-31.60] versus 30.8 [24.55-40.06], P = .017) and lower rate of acute respiratory distress syndrome (3.85% vs 10.71%, P = .048) in the CTPEG cohort. Furthermore, 59% of CTPEG cohort were neurology patients while 63% of DPEG were neurosurgery patients, P = .004. Primary outcomes showed shorter mean NCCU length of stay (LOS; 25 [12] vs 33 [17] days, P < .001) and median hospital LOS (32 [25 43] vs 37 [31-56] days, P = .002) for the CTPEG cohort. Secondary outcomes showed higher predischarge prealbumin levels (15.6 [7.75] vs 11.58 [5.41], P = .021) and lower median overall hospital cost (US$123 860.20 [US$99 024-US$168 713.40] vs US$159 633.50 [US$121 312-US$240 213.10], P = .0003) in the CTPEG group. Anatomic contraindications were the most common reason for DPEG (30%). CONCLUSIONS: Among institutions with a tracheostomy team, the practice of tracheostomy with concomitant PEG placement may be considered as feasible as delayed PEG in carefully selected neurocritically ill patients with possible advantages of overall shorter NCCU and hospital LOS, higher predischarge prealbumin, and lower hospital costs. These findings may aid in decisions regarding the timing of PEG placement in the NCCU. Further prospective studies are warranted. PMID- 28675110 TI - Metabolic regional and network changes in Alzheimer's disease subtypes. AB - Clinical variants of Alzheimer's disease (AD) include the common amnestic subtype as well as subtypes characterised by leading visual processing impairments or by multimodal neurocognitive deficits. We investigated regional metabolic patterns and networks between AD subtypes. The study comprised 9 age-matched controls and 25 patients with mild to moderate AD. Methods included clinical and neuropsychological assessment, high-resolution FDG PET and T1-weighted 3D MR imaging with PET-MR coregistration, grey matter segmentation, atlas-based regions of-interest, linear mixed effects and regional correlation analysis. Regional metabolic patterns differed significantly between groups, but significant hypometabolism in the posterior cingulate cortex (PCC) was common to all subtypes. The most distinctive regional abnormality was occipital hypometabolism in the visual subtype. In controls, two large clusters of positive regional metabolic correlations were observed. The most pronounced breakdown of the normal correlation pattern was found in amnestic patients who, in contrast, showed the least regional focal metabolic deficits. The normal positive correlation between PCC and hippocampus was lost in all subtypes. In conclusion, PCC hypometabolism and metabolic correlation breakdown between PCC and hippocampus are the common functional core of all AD subtypes. Network alterations exceed focal regional impairment and are most prominent in the amnestic subtype. PMID- 28675112 TI - The Relationship of Paranasal Sinus Opacification to Hospital-Acquired Pneumonia in the Neurologic Intensive Care Unit Patient. AB - BACKGROUND: The association between intensive care unit (ICU) sinusitis and the development of lower airway infections remains unclear. The objective of this study was to determine the correlation between the development of radiographic sinus opacification and pneumonia in the neurologic ICU setting. METHODS: A retrospective review of head computed tomography or magnetic resonance imaging of 612 patients admitted to the neurocritical care unit at a tertiary care center from April 2013 through April 2014 was performed. Paranasal sinus opacification was measured using Lund-Mackay scores (LMS). A diagnosis of pneumonia was determined by the ICU team from radiographic, laboratory, and pulmonary data. Exclusion criteria included a history of endonasal surgery, sinonasal malignancy, facial fractures, ICU admission less than 3 days, or inadequate imaging. RESULTS: Worsening sinus opacification occurred in 42.6% of patients and pneumonia in 18.5% of patients during ICU admission. Of the patients who developed pneumonia, 71.7% also developed worsening sinus opacification ( P < .001). In 80.2% of cases, the sinus opacification developed prior to the diagnosis of pneumonia. The mean highest LMS for patients who developed pneumonia was 4.24 compared to 1.99 in patients who did not develop pneumonia ( P < .001). Sinus air-fluid levels or complete sinus opacification occurred in a larger proportion of patients who developed pneumonia (46.9% vs 19.4%, P < .001). Mortality rates for patients with no pneumonia or sinusitis, pneumonia only, sinusitis only, and sinusitis with pneumonia were 7.6%, 15.6%, 18.3%, and 25.9%, respectively ( P < .001). CONCLUSIONS: This study finds a strong relationship between worsening sinus opacification in the neurologic ICU patient to the development of hospital acquired pneumonia and increased mortality. PMID- 28675113 TI - Low Levels of Physical Activity During Critical Illness and Weaning: The Evidence Reality Gap. AB - BACKGROUND: Physical rehabilitation can benefit critically ill patients during intensive care unit (ICU) admission, but routine clinical practice remains inconsistent nor examined in prolonged mechanical ventilation patients transferred to a specialist ventilator weaning unit (VWU). Behavioral mapping is a sampling approach that allows detailed reporting of physical activity profiles. The objective of this study was to characterize the physical activity profile of critically ill patients in a UK ICU and VWU. METHODS: Single-center, prospective observational study in a university teaching hospital. Patient observations, conducted Monday through Sunday from 08:30 am to 08:00 pm and for 1 minute every 10 minutes, included data points of patient location, people in attendance, and highest level of activity. Descriptive statistics were utilized to analyze and report data. RESULTS: Forty-two ICU and 11 VWU patients were recruited, with 2646 and 693 observations, respectively, recorded. In the ICU, patients spent a median (interquartile range) of 100% (96%-100%) of the day (10.5 [10.0-10.5] hours) located in bed, with minimal/no activity for 99% (96%-100%) of the day (10.4 [9.7 10.5] hours). Nursing staff were most frequently observed in attendance with patients irrespective of ventilation or sedation status, although patients still spent approximately two-thirds of the day alone. Bed-to-chair transfer was the highest activity level observed. In the VWU, patients spent 94% (73%-100%) of the day (9.9 [7.7-10.5] hours) in bed and 56% (43%-60%) of time alone. Physical activity levels were higher and included ambulation. All physical activities occurred during physical rehabilitation sessions. CONCLUSIONS: These profiles of low physical activity behavior across both patients in the ICU and VWU highlight the need for targeted strategies to improve levels beyond therapeutic rehabilitation and support for a culture shift toward providing patients with, and engaging them in, a multidisciplinary, multiprofessional environment that optimizes overall physical activity. PMID- 28675114 TI - Nicotine enhances an auditory Event-Related Potential component which is inversely related to habituation. AB - Nicotine is a psychoactive substance that is commonly consumed in the context of music. However, the reason why music and nicotine are co-consumed is uncertain. One possibility is that nicotine affects cognitive processes relevant to aspects of music appreciation in a beneficial way. Here we investigated this possibility using Event-Related Potentials. Participants underwent a simple decision-making task (to maintain attentional focus), responses to which were signalled by auditory stimuli. Unlike previous research looking at the effects of nicotine on auditory processing, we used complex tones that varied in pitch, a fundamental element of music. In addition, unlike most other studies, we tested non-smoking subjects to avoid withdrawal-related complications. We found that nicotine (4.0 mg, administered as gum) increased P2 amplitude in the frontal region. Since a decrease in P2 amplitude and latency is related to habituation processes, and an enhanced ability to disengage from irrelevant stimuli, our findings suggest that nicotine may cause a reduction in habituation, resulting in non-smokers being less able to adapt to repeated stimuli. A corollary of that decrease in adaptation may be that nicotine extends the temporal window during which a listener is able and willing to engage with a piece of music. PMID- 28675115 TI - Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus. AB - Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS- (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning. PMID- 28675116 TI - Acute alcohol effects on explicit and implicit motivation to drink alcohol in socially drinking adolescents. AB - Alcohol-related cues can evoke explicit and implicit motivation to drink alcohol. Concerning the links between explicit and implicit motivation, there are mixed findings. Therefore, we investigated both concepts in 51 healthy 18- to 19-year old males, who are less affected by neuropsychological deficits in decision making that are attributed to previous alcohol exposure than older participants. In a randomized crossover design, adolescents were infused with either alcohol or placebo. Self-ratings of alcohol desire, thirst, well-being and alcohol effects comprised our explicit measures of motivation. To measure implicit motivation, we used money and drink stimuli in a Pavlovian conditioning (Pc) task and an Approach-Avoidance Task (AAT). Alcohol administration increased explicit motivation to drink alcohol, reduced Pc choices of alcoholic drink-conditioned stimuli, but had no effect on the AAT. This combination of results might be explained by differences between goal-directed and habitual behavior or a temporary reduction in rewarding outcome expectancies. Further, there was no association between our measures of motivation to drink alcohol, indicating that both self-reported motivation to drink and implicit approach tendencies may independently contribute to adolescents' actual alcohol intake. Correlations between Alcohol Use Disorders Identification Test (AUDIT) scores and our measures of motivation to drink alcohol suggest that interventions should target high-risk adolescents after alcohol intake. Clinical trials: Project 4: Acute Effects of Alcohol on Learning and Habitization in Healthy Young Adults (LeAD_P4); NCT01858818; https://clinicaltrials.gov/ct2/show/NCT01858818. PMID- 28675117 TI - Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving. AB - BACKGROUND: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined. METHODS: A total of 39 early abstinent, treatment seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFalpha), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points. RESULTS: The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFalpha and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving. CONCLUSIONS: Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol. PMID- 28675118 TI - Young Men's Preferences for Design and Delivery of Physical Activity and Nutrition Interventions: A Mixed-Methods Study. AB - Young adult men are under-represented in health research, and little is known about how to reach and engage them in lifestyle interventions. This mixed-methods study aimed to explore young males' preferences for recruitment strategies, content, format (delivery mode and program duration and frequency), and facilitator characteristics for future physical activity and nutrition interventions. Ten focus groups involving 61 men (aged 18-25 years) in the Hunter region, New South Wales, Australia and an online survey distributed within Australia were completed by 282 males (aged 18-25 years). Key focus group themes included a preference for recruitment via multiple sources, ensuring images and recruiters were relatable; intervention facilitators to be engaging and refrain from discussing negative consequences of being unhealthy. Key program content preferences included skill development and individualized goals and feedback. Focus groups and the survey confirmed a preference for multiple delivery modes, including; face-to-face (group and individual), with support using eHealth technologies. Survey results confirmed the most favored program content as: "healthy eating on a budget," "quick and easy meals," and "resistance training." Focus group responses suggested a program duration of >=6 months, with 2-3 combined face-to-face and supportive eHealth sessions per week. Survey intervention duration preference was 3 months with 4 face-to-face sessions per month. Findings can guide the design, conduct, and evaluation of relevant contemporary physical activity and or nutrition interventions for young men. There is a need to identify the most effective ways to address young men's individual preferences in intervention research. PMID- 28675119 TI - What Do Patients Want from Otolaryngologists? A Discrete Choice Experiment. AB - Objectives Patient preferences are crucial for the delivery of patient-centered care. Discrete choice experiments (DCEs) are an emerging quantitative methodology used for understanding these preferences. In this study, we employed DCE techniques to understand the preferences of patients presenting for an ear, nose, and throat clinic visit. Study Design DCE. Setting Decision science laboratory. Methods A DCE survey of 5 attributes-wait time, physician experience, physician personality, utilization of visit time, and cost/copayment-was constructed with structured qualitative interviews with patients. The DCE was administered to participants from the general population, who chose among hypothetical scenarios that varied across these attributes. A conditional logit model was used to determine relative attribute importance, with a separate logit model for determining subject effects. Results A total of 161 participants were included. Cost/copayment had the greatest impact on decision making (importance, 32.2%), followed by wait time and physician experience (26.5% and 24.7%, respectively). Physician personality mattered least (4.7%), although all attributes were significantly correlated to decision making. Participants preferred doctors who spent more time performing physical examination than listening or explaining. Participants were willing to pay $52 extra to avoid a 4-week delay in appointment time; $87 extra for a physician with 10 years of experience (vs 0 years); and $9 extra for a caring, friendly, and compassionate doctor (vs formal, efficient, and business-like). Conclusion DCEs allow for powerful economic analyses that may help physicians understand patient preferences. Our model showed that cost is an important factor to patients and that patients are willing to pay extra for timely appointments, experience, and thorough physical examination. PMID- 28675120 TI - Inflammatory breast cancer: High incidence of GCC haplotypes (-1082A/G, -819T/C, and -592A/C) in the interleukin-10 gene promoter correlates with over-expression of interleukin-10 in patients' carcinoma tissues. AB - Interleukin-10 is involved in carcinogenesis by supporting tumor escape from the immune response. The aim of this study was to assess the single nucleotide polymorphisms, -1082A/G, -819T/C and -592A/C, in interleukin-10 gene promoter in inflammatory breast cancer compared to non-inflammatory breast cancer and association of these polymorphisms with interleukin-10 gene expression. We enrolled 105 breast cancer tissue (72 non-inflammatory breast cancer and 33 inflammatory breast cancer) patients and we determined the three studied single nucleotide polymorphisms in all samples by polymerase chain reaction restriction fragment length polymorphism and investigated their association with the disease and with various prognostic factors. In addition, we assessed the expression of interleukin-10 gene by real-time quantitative reverse transcription polymerase chain reaction and the correlation between studied single nucleotide polymorphisms and interleukin-10 messenger RNA expression. We found co-dominant effect as the best inheritance model (in the three studied single nucleotide polymorphisms in non-inflammatory breast cancer and inflammatory breast cancer samples), and we didn't identify any association between single nucleotide polymorphisms genotypes and breast cancer prognostic factors. However, GCC haplotype was found highly associated with inflammatory breast cancer risk (p < 0.001, odds ratio = 43.05). Moreover, the expression of interleukin-10 messenger RNA was significantly higher (p < 0.001) by 5.28-fold and 8.95-fold than non inflammatory breast cancer and healthy control, respectively, where GCC haplotype significantly increased interleukin-10 gene expression (r = 0.9, p < 0.001). PMID- 28675121 TI - Comparison of WBRT alone, SRS alone, and their combination in the treatment of one or more brain metastases: Review and meta-analysis. AB - Whole brain radiotherapy has been a standard treatment of brain metastases. Stereotactic radiosurgery provides more focal and aggressive radiation and normal tissue sparing but worse local and distant control. This meta-analysis was performed to assess and compare the effectiveness of whole brain radiotherapy alone, stereotactic radiosurgery alone, and their combination in the treatment of brain metastases based on randomized controlled trial studies. Electronic databases (PubMed, MEDLINE, Embase, and Cochrane Library) were searched to identify randomized controlled trial studies that compared treatment outcome of whole brain radiotherapy and stereotactic radiosurgery. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were hazard ratios with 95% confidence intervals calculated for time-to-event data extracted from survival curves and local tumor control rate curves. Odds ratio with 95% confidence intervals were calculated for dichotomous data, while mean differences with 95% confidence intervals were calculated for continuous data. Fixed-effects or random effects models were adopted according to heterogeneity. Five studies (n = 763) were included in this meta-analysis meeting the inclusion criteria. All the included studies were randomized controlled trials. The sample size ranged from 27 to 331. In total 202 (26%) patients with whole brain radiotherapy alone, 196 (26%) patients receiving stereotactic radiosurgery alone, and 365 (48%) patients were in whole brain radiotherapy plus stereotactic radiosurgery group. No significant survival benefit was observed for any treatment approach; hazard ratio was 1.19 (95% confidence interval: 0.96-1.43, p = 0.12) based on three randomized controlled trials for whole brain radiotherapy only compared to whole brain radiotherapy plus stereotactic radiosurgery and hazard ratio was 1.03 (95% confidence interval: 0.82-1.29, p = 0.81) for stereotactic radiosurgery only compared to combined approach. Local control was best achieved when whole brain radiotherapy was combined with stereotactic radiosurgery. Hazard ratio 2.05 (95% confidence interval: 1.36-3.09, p = 0.0006) and hazard ratio 1.84 (95% confidence interval: 1.26-2.70, p = 0.002) were obtained from comparing whole brain radiotherapy only and stereotactic radiosurgery only to whole brain radiotherapy + stereotactic radiosurgery, respectively. No difference in adverse events for treatment difference; odds ratio 1.16 (95% confidence interval: 0.77-1.76, p = 0.48) and odds ratio 0.92 (95% confidence interval: 0.59-1.42, p = 71) for whole brain radiotherapy + stereotactic radiosurgery versus whole brain radiotherapy only and whole brain radiotherapy + stereotactic radiosurgery versus stereotactic radiosurgery only, respectively. Adding stereotactic radiosurgery to whole brain radiotherapy provides better local control as compared to whole brain radiotherapy only and stereotactic radiosurgery only with no difference in radiation related toxicities. PMID- 28675122 TI - MiR-204/ZEB2 axis functions as key mediator for MALAT1-induced epithelial mesenchymal transition in breast cancer. AB - Long non-coding RNAs recently were identified as key mediators of cancer metastasis. This study provided evidence that long non-coding RNA MALAT1 was up regulated in breast cancer tissues and cell lines. MALAT1 promoted cancer cell invasion through inducing epithelial-mesenchymal transition. Interestingly, we revealed there was a reciprocal repression between MALAT1 and miR-204. ZEB2 was identified as a downstream target of miR-204 and MALAT1 exerted its function mainly through the miR-204/ZEB2 axis. Our findings suggested that MALAT1 may serve as a new diagnostic biomarker and therapy target for breast cancer. PMID- 28675123 TI - ADAM9 expression promotes an aggressive lung adenocarcinoma phenotype. AB - A disintegrin and metalloproteinase 9 (ADAM9) possesses potent metastasis inducing capacities and is highly expressed in several cancer cells. Previous work has shown that ADAM9 participates in the adhesive-invasive phenotype in lung cancer cells in vitro. In this study, we evaluated whether ADAM9 expression plays a critical role in metastatic processes in vivo and in angiogenesis. We first found that high ADAM9 expression was correlated with poor lung adenocarcinoma patient prognosis on Prognoscan data base. In vivo model based on intravenous injection in nude mice showed that a stable downregulation of ADAM9 in A549 (TrA549 A9-) cells was associated with a lower number of nodules in the lung, suggesting lower potentials for extravasation and metastasis. On a subcutaneous xenograft we showed that TrA549 A9- produced significantly smaller tumours and exhibited fewer neovessels. In addition, in vitro human umbilical vein endothelial cells exposed to supernatant from TrA549 A9- could reduce the formation of more vessel-like structures. To further understand the mechanism, a human antibody array analysis confirmed that five cytokines were downregulated in TrA549 A9- cells. Interleukin 8 was the most significantly downregulated, and its interaction with CXCR2 was implicated in angiogenesis on an in vitro model. These results emphasize the critical influence of ADAM9 on lung cancer progression and aggressiveness. ADAM9 should at least be a marker of cancer aggressiveness and a potential therapeutic target for cancer treatment. PMID- 28675124 TI - Combined individual scrummaging kinetics and muscular power predict competitive team scrum success. AB - Scrummaging is a major component of Rugby Union gameplay. Successful scrummaging is dependent on the coordination of the forward players and the strength of the eight individuals. The study aim was to determine whether individual scrummaging kinetics and other candidate factors associated with scrummaging performance discriminate team scrum performances. Sixteen club-level forwards (stature: 1.80 +/- 0.1 m; mass: 99.0 +/- 18.2 kg) were initially divided into two scrummaging packs. A total of 10 various scrum permutations were tested, where players were randomly swapped between the two packs. Winning scrums were determined by two observers on opposite sides of the scrum. Fatigue (100 mm visual analogue scale (VAS)) and scrummaging effort (6-20 rating of perceived exertion (RPE)) were assessed following each scrum contest. Individual scrummaging kinetics were acquired through an instrumented scrum ergometer and muscular power indicated through vertical jump heights. Student's t-tests were used to differentiate between winning and losing scrum packs. VAS and RPE were assessed using repeated measures ANOVAs. Winning scrum packs had significantly larger combined force magnitudes (p < .002), regardless of the player contribution calculations. Additionally, winning packs had less individual movement (p = .033) and higher combined vertical jump heights (p < .001) but were not significantly heavier (p = .759) than losing scrum packs. While perceived VAS and RPE values progressively increased (p < .001), no differences in the individual scrum magnitudes were observed between the 1st and 10th scrum (p = .418). The results indicated that the combination of individual forces, variation in movement and factors related to scrummaging performance, such as vertical jump height, were associated with team scrummaging success. PMID- 28675125 TI - Toxic and essential metals in Cyprinus carpio, Carassius gibelio, and Luciobarbus esocinus tissues from Keban Dam Lake, Pertek, Turkey. AB - In various tissues of Luciobarbus esocinus, Cyprinus carpio, and Carassius gibelio which were taken from Keban Dam Lake Pertek region's freshwaters, Turkey in January-February 2016, concentrations of mercury, nickel, lead, cadmium, arsenic, manganese, chromium, and cobalt were analysed by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion. In fish muscle mean chromium concentration (0.614 mg kg-1 in C. carpio muscle) was higher than the maximum limits as set by the Federal Environmental Protection Agency and World Health Organisation. Additionally, mean concentration of lead (0.380 mg kg-1 in C. gibelio muscle) was higher compared to the maximum limit as set by Turkish Standards. Furthermore, in the assessment of the potential health risk, estimated weekly and daily intake of all metals were considerably below permissible tolerable weekly intake (PTWI) and permissible tolerable daily intake values. As a result, consumption of these fish species from this region does not pose a problem on human health. PMID- 28675126 TI - Characteristics of bone marrow cell dysplasia and its effectiveness in diagnosing myelodysplastic syndrome. AB - BACKGROUND: Although dysplasia plays an important role in the diagnosis of myelodysplasia syndrome (MDS), its morphologic variety and irregularity result in difficulties in its clinical application. METHODS: Bone marrow smears from cases with MDS and non-clonal disease were collected and performed microscopy analysis. We respectively recorded the percentage of specific dysplastic cells (PSDC) and incidence of specific dysplasia (ISD) of each dysplastic type in three hematopoietic cell lineages for the comprehensive analysis of diagnostic efficacy to MDS. RESULTS: Compared with non-clonal anemia, the PSDCs and ISDs of the four specific dysplastic types as petal nucleus and internuclear bridging in erythroid lineage, pseudo-Pelger-Huet in granulocytic lineage and lymphoid small megakaryocyte in megakaryocytic lineage were significantly higher in MDS; and their area under the curves were all greater than 0.600. If the dysplastic rate in each lineage was higher than 10%, their corresponding false positive rates (FPRs) were below 0.033, 1 * 10-4 and 1 * 10-4, respectively. If the dysplastic rates in three cell lineages reached 0.065, 0.045 and 0.040, respectively, their corresponding FPRs were all below 0.050. CONCLUSION: Four specific dysplastic types possess higher diagnostic efficacy for the diagnosis of MDS. Though the dysplastic rate over 10% in any hematopoietic cell lineage presents a lower FPR, it is possibly considered to lower the diagnostic threshold of MDS if a specific dysplastic type with higher diagnostic efficacy presents. PMID- 28675127 TI - Foreword: HIV in Military Populations. PMID- 28675129 TI - Strengthening policy research on infant and young child feeding: An imperative to support countries in scaling up impact on nutrition. AB - Enabling policy environments for nutrition require require evidence to support best practice and engagement with political and policy contexts, as well as leadership, resourcing, advocacy, and technical support. However, research on nutrition policy contexts is limited. The papers in this special supplement on policy contexts for infant and young child feeding (IYCF) in South Asia makes a valuable contribution to understanding the policy landscape and political dynamics in the region and the global literature. Studies included in this special supplement analyzed policy content and stakeholder influence on IYCF in Bangladesh, India, Nepal, Pakistan and Sri Lanka, and assess the role of advocacy in addressing multiple elements of the policy environment. These analyses highlight opportunities to harmonize and manage the demands and interests of multiple actors while strengthening policy to strategically support optimal IYCF as the ultimate goal. They also provide robust examples of research on policy environments and policy change. Further investments in research on policy contexts for nutrition can help to understand and support continued progress towards improved actions for nutrition. PMID- 28675130 TI - Analysis of stakeholders networks of infant and young child nutrition programmes in Sri Lanka, India, Nepal, Bangladesh and Pakistan. AB - BACKGROUND: Effective public policies are needed to support appropriate infant and young child feeding (IYCF) to ensure adequate child growth and development, especially in low and middle income countries. The aim of this study was to: (i) capture stakeholder networks in relation to funding and technical support for IYCF policy across five countries in South Asia (i.e. Sri Lanka, India, Nepal, Bangladesh and Pakistan); and (ii) understand how stakeholder networks differed between countries, and identify common actors and their patterns in network engagement across the region. METHODS: The Net-Map method, which is an interview based mapping technique to visualise and capture connections among different stakeholders that collaborate towards achieving a focused goal, has been used to map funding and technical support networks in all study sites. Our study was conducted at the national level in Bangladesh, India, Nepal, and Sri Lanka, as well as in selected states or provinces in India and Pakistan during 2013-2014. We analysed the network data using a social network analysis software (NodeXL). RESULTS: The number of stakeholders identified as providing technical support was higher than the number of stakeholders providing funding support, across all study sites. India (New Delhi site - national level) site had the highest number of influential stakeholders for both funding (43) and technical support (86) activities. Among all nine study sites, India (New Delhi - national level) and Sri Lanka had the highest number of participating government stakeholders (22) in their respective funding networks. Sri Lanka also had the highest number of participating government stakeholders for technical support (34) among all the study sites. Government stakeholders are more engaged in technical support activities compared with their involvement in funding activities. The United Nations Children's Emergency Fund (UNICEF) and the World Health Organization (WHO) were highly engaged stakeholders for both funding and technical support activities across all study sites. CONCLUSION: International stakeholders were highly involved in both the funding and technical support activities related to IYCF practices across these nine study sites. Government stakeholders received more support for funding and technical support activities from other stakeholders compared with the support that they offered. Stakeholders were, in general, more engaged for technical support activities compared with the funding activities. PMID- 28675131 TI - Changes in the policy environment for infant and young child feeding in Vietnam, Bangladesh, and Ethiopia, and the role of targeted advocacy. AB - BACKGROUND: There is limited literature examining shifts in policy environments for nutrition and infant and young child feeding (IYCF) over time, and on the potential contribution of targeted advocacy to improved policy environments in low- and middle-income countries. This study tracked changes in the policy environment over a four-year period in three countries, and examined the role of targeted nutrition and IYCF advocacy strategies by a global initiative. METHODS: Qualitative methods, including key informant interviews, social network mapping, document and literature review, and event tracking, were used to gather data on nutrition and IYCF policies and programs, actor networks, and perceptions and salience of nutrition as an issue in 2010 and 2014 in Bangladesh, Ethiopia, and Vietnam. Theoretical frameworks from the policy sciences were used to analyze policy change over time, and drivers of change, across countries. RESULTS: The written policy environment improved to differing extents in each country. By 2014, the discourse in all three countries mirrored international priorities of stunting reduction and exclusive breastfeeding. Yet competing nutrition priorities such as acute malnutrition, food insecurity, and nutrition transitions remained in each context. Key actor groups in each country were government, civil society, development partners and the private sector. Infant formula companies, in particular, emerged as key players against enforcement of IYCF legislation. The role of a targeted IYCF advocacy and policy support initiative was well recognized in supporting multiple facets of the policy environment in each country, ranging from alliances to legislation and implementation support. Despite progress, however, government commitment to funding, implementation, and enforcement is still emerging in each country, thus challenging the potential impact of new and improved policies. CONCLUSION: Targeted policy advocacy can catalyze change in national nutrition and IYCF policy environments, especially actor commitment, policy guidance, and legislation. Implementation constraints - financing, capacity and commitment of systems, and competing priorities and actors - are essential to address to sustain further progress. The lack of pressing political urgency for nutrition and IYCF, and the uncertain role of international networks in national policy spaces, has implications for the potential for change. PMID- 28675132 TI - Policy and stakeholder analysis of infant and young child feeding programmes in Sri Lanka. AB - BACKGROUND: Infant and young child feeding practices (IYCF) play a critical role in growth and development of children. A favourable environment supported by appropriate policies and positive contributions from all stakeholders are prerequisites for achieving optimal IYCF practices. This study aimed to assess the IYCF-related policy environment and role of stakeholders in policy making in Sri Lanka, in order to identify opportunities to strengthen the policy environment to better support appropriate IYCF and reduce childhood malnutrition. METHODS: We mapped national level policy-related documents on IYCF, and conducted a stakeholder analysis of IYCF policy making. A matrix was designed to capture data from IYCF policy-related documents using a thematic approach. A narrative synthesis of data from different documents was conducted to achieve the first objective. We then conducted an analysis of technical and funding links of stakeholders who shape IYCF policies and programmes in Sri Lanka using the Net Map technique, to achieve the second objective. A total of 35 respondents were purposively selected based on their knowledge on the topic, and individual interviews were conducted. RESULTS: Twenty four policies were identified that contained provisions in line with global recommendations for best-practice IYCF, marketing of breast milk substitutes, strengthening health and non-health systems, maternity benefits, inter-sectoral collaboration, capacity building, health education and supplementation. However, there is no separate, written policy on IYCF in Sri Lanka. Participants identified 56 actors involved in shaping IYCF policies and programmes through technical support, and 36 through funding support. The Government Health Sector was the most connected as well as influential, followed by development partners. Almost all actors in the networks were supportive for IYCF policies and programmes. CONCLUSIONS AND RECOMMENDATIONS: All evidence-based recommendations are covered in related policies. However, advocacy should be targeted towards strategic support for IYCF in high-level policy documents. The stakeholder analysis confirmed a network led by the government health sector. Enhancing the multi-sectoral commitments stressed in policy documents is an opportunity to strengthen IYCF policy process in Sri Lanka. PMID- 28675133 TI - Policy content and stakeholder network analysis for infant and young child feeding in Nepal. AB - BACKGROUND: Despite concerted effort from government and partners, Nepal continues to have a high burden of under nutrition among children. Identifying opportunities to strengthen policy support for infant and young child feeding (IYCF) is a key component to improve child survival, growth and development. This study aims to explore policy support for IYCF and to identify the influential stakeholders for IYCF for effective future policy development and programmatic action. METHODS: Policies relevant to IYCF were identified through web searches and direct approaches to relevant government ministries. Policy content was analysed based on four key domains focussed on mothers, using a qualitative synthesis approach. Three group interviews were conducted using the participatory tool "Net-Map", to identify the influential stakeholders in IYCF policy and programming processes. RESULTS: Twenty-six relevant policy documents were analysed for content relating to IYCF. General support for IYCF was found in most of the development plans and high-level health sector policies. Most implementation level documents included support for provision of correct information to mothers. Capacity building of frontline workers for IYCN and system strengthening were well supported through sectoral plans and policies. However, gaps were identified regarding maternity protection, support for monitoring and evaluation, and translation of high-level policy directives into implementation level guidelines, resulting in a lack of clarity over roles and responsibilities. Both government and non-governmental stakeholders, particularly donors, emerged as influential drivers of IYCF policy decisions in Nepal, through technical assistance and funding. The Nutrition Technical Committee under the Ministry of Health, UNICEF, Suaahara, USAID and WHO were identified as key actors providing technical assistance. Key funding agencies were identified as UNICEF and USAID. CONCLUSIONS: This study reveals strong policy support for key dimensions of IYCF, supported by a highly networked stakeholder environment. Opportunities to further strengthen IYCF policy in Nepal include: further support for training of frontline workers and complementary feeding interventions; extending maternity leave provisions; and clarifying roles and responsibilities of actors, particularly non-governmental actors. Engaging technical and funding agencies and developing partnerships with other relevant actors will be crucial for ensuring effective policy translates into effective practice. PMID- 28675134 TI - Overview of the infant and young child feeding policy environment in Pakistan: Federal, Sindh and Punjab context. AB - BACKGROUND: Appropriate infant and young child feeding (IYCF) practices have been identified as important for appropriate child growth and development. (Ministry of Planning and Development, Ministry of National Health Services, Regulations and Coordination (2012)) Children in Pakistan still experience high rates of malnutrition, indicating a likely need for stronger IYCF policy. The purpose of this study was to identify major stakeholders who shape the IYCF policy environment and analyze which policies protect, promote and support IYCF practices, either directly or indirectly. METHODS: This study was conducted at the federal level, and in the provinces of Sindh and Punjab. We identified policies relevant to IYCF using a matrix developed by the South Asian Infant Feeding Research Network (SAIFRN), designed to capture policies at a range of levels (strategic policy documents through to implementation guidelines) in sectors relevant to IYCF. We analyzed the content using predetermined themes focused on support for mothers, and used narrative synthesis to present our findings. For the stakeholder analysis, we conducted four Net-Map activities with 49 interviewees using the Net-Map methodology. We analyzed the quantitative data using Organizational Risk Analyzer ORA and used the qualitative data to elucidate further information regarding relationships between stakeholders. RESULTS: We identified 19 policy documents for analysis. Eleven of these were nutrition and/or IYCF focused and eight were broader policies with IYCF as a component. The majority lacked detail relevant to implementation, particularly in terms of: ownership of the policies by a specific government body; sustainability of programs/strategies (most are donor funded), multi-sectoral collaboration; and effective advocacy and behavior change communication. Data collected through four Net-Map activities showed that after devolution of health ministry, provincial health departments were the key actors in the government whereas UNICEF and WHO were the key donors who were also highly influential and supportive of the objective. CONCLUSION: This analysis identified opportunities to strengthen IYCF policy in Pakistan through increased clarity on roles and responsibilities, improved multisectoral collaboration, and strong and consistent training guidelines and schedules for community health workers. The current policy environment presents opportunities, despite limitations. Our Net-Map analysis indicated several key government and international stakeholders, who differed across Federal and Provincial study sites. The detailed information regarding stakeholder influence can be used to strengthen advocacy. PMID- 28675135 TI - Opportunities for strengthening infant and young child feeding policies in South Asia: Insights from the SAIFRN policy analysis project. AB - BACKGROUND: South Asian countries experience some of the highest levels of child undernutrition in the world, strongly linked to poor infant and young child feeding (IYCF) practices. Strong and responsive policy support is essential for effective interventions to improve IYCF. This study aimed to identify opportunities for strengthening the policy environment in the region to better support appropriate infant and young child feeding. METHODS: We mapped policies relevant to infant and young child feeding in India, Pakistan, Bangladesh, Sri Lanka and Nepal, based on a common matrix. The matrix described potentially relevant policies ranging from high-level strategic policy documents to implementation-level guidelines. We analyzed the data based on themes focused on caregiver interactions with IYCF interventions: provision of correct information to mothers, training of frontline workers, enabling mothers to engage with service providers and strategic support for IYCF. RESULTS: Policy support for IYCF was present in relation to each of the themes assessed. In all countries, there was support for nutrition in National Development Plans, and all countries had some level of maternity protection and restrictions on marketing of breast milk substitutes. Sectoral and implementation-level policy documents contained provisions for system strengthening for IYCF and for training of frontline workers. CONCLUSIONS: The key opportunities for strengthening IYCF policy support were in relation to translating strategic directives into implementation level documents; improving multi-sectoral support and coordination; and increased clarity regarding roles and responsibilities of frontline workers interacting with mothers. These findings can support efforts to strengthen IYCF policy at the national and regional level. PMID- 28675136 TI - Policy content and stakeholder network analysis for infant and young child feeding in India. AB - BACKGROUND: Over the last decade, infant and young child feeding (IYCF) indicators in India have improved. However, poor IYCF practices are still apparent, associated with pervasive high rates of child under-nutrition. Interventions to improve IYCF need augmentation by appropriate policy support to consolidate gains. The aim of this study was to identify opportunities to strengthen and support IYCF policies through a policy content and stakeholder network analysis. METHODS: IYCF policies and guidelines were systematically mapped and coded using predetermined themes. Six 'net-map' group interviews were conducted for stakeholder analysis with data analyzed using ORA (organizational risk analyzer, copyright Carley, Carnegie Mellon University) software. The study was carried out at a national level and in the states of Maharashtra and unified Andhra Pradesh. RESULTS: Thirty relevant policy documents were identified. Support for IYCF was clearly apparent and was actioned within sectoral policies and strategic plans. We identified support for provision of information to mothers and caregivers in both sectoral and high-level/strategic policy documents. At a sectoral level, there was support for training health care workers and for enabling mothers to access IYCF. Opportunities to strengthen policy included expanding coverage and translating policy goals into implementation level documents. At the national level, Ministry of Women and Child Development [MoWCD], Ministry of Health and Family Welfare [MoHFW] and the Prime Minister's Nutrition Council [PMNC] were the most influential actors in providing technical support while MoHFW, MoWCD, and Bill Melinda Gates Foundation were the most influential actors in providing funding and were therefore influential stakeholders in shaping IYCF policies and programs. CONCLUSION: We identified a wide range of strengths in the IYCF policy environment in India and also opportunities for improvement. One key strength is the integration of IYCF policies into a range of agendas and guidelines related to health and child development service delivery at the national and state level. However, the lack of a specific national policy on IYCF means that there is no formal mechanism for review and monitoring implementation across sectors and jurisdictions. Another opportunity identified is the development of IYCF policy guidelines in emergencies and for tribal populations. PMID- 28675138 TI - Comparison of QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) for diagnosis of latent tuberculosis in haemodialysis (HD) patients: a meta analysis of kappa estimates - Erratum. PMID- 28675137 TI - Policy content and stakeholder network analysis for infant and young child feeding in Bangladesh. AB - BACKGROUND: Appropriate infant and young child feeding (IYCF) practices are essential for nutrition of infants and young children. Bangladesh has one of the highest levels of malnutrition globally along with sub-optimal IYCF practices. A supportive policy environment is essential to ensure that effective IYCF interventions are scaled up. The objectives of our study were to assess the support for IYCF in the national policy environment through policy analysis and stakeholder analysis and in so doing identify opportunities to strengthen the policy environment. METHODS: We used a matrix developed by SAIFRN (the South Asian Infant Feeding Research Network) to systematically identify supportive national policies, plans and guidelines for IYCF. We adapted narrative synthesis and descriptive approaches to analyze policy content, based on four themes with a focus on support for mothers. We conducted three Net-Map interviews to identify stakeholders who influenced the policies and programs related to IYCF. RESULTS: We identified 19 national policy documents relevant to IYCF. Overall, there was good level of support for IYCF practices at policy level - particularly regarding general support for IYCF and provision of information to mothers - but these were not consistently supported at implementation level, particularly regarding specificity and population coverage. We identified gaps regarding the training of health workers, capacity building, the monitoring and targeting of vulnerable mothers and providing an enabling environment to mothers, specifically with respect to maternity leave for working women. Urban populations and providers outside the public sector remained uncovered by policy. Our stakeholder analysis identified government entities such as the National Nutrition Service, as the most influential in terms of both technical and funding support as they had the mandate for formulation and implementation of policies and national programs. Stakeholders from different sectors played important roles, demonstrating the salience of IYCF. CONCLUSIONS: Although there is strong supportive policy environment for IYCF, it is important that policies cover all populations. Our analysis indicated that opportunities to strengthen the policy environment include: expanding population coverage, increasing inter-sector coordination, improving translation of policy objectives to implementation-level documents, and the engagement of non-public sectors. In addition, we recommend explicit strategies to engage diverse stakeholders in the formulation and implementation of IYCF policies. PMID- 28675139 TI - An Efficient, Simple, and Noninvasive Procedure for Genotyping Aquatic and Nonaquatic Laboratory Animals. AB - Various animal models are indispensible in biomedical research. Increasing awareness and regulations have prompted theadaptation of more humane approaches in the use of laboratory animals. With the development of easier and faster methodologies to generate genetically altered animals, convenient and humane methods to genotype these animals are important for research involving such animals. Here, we report skin swabbing as a simple and noninvasive method for extracting genomic DNA from mice and frogs for genotyping. We show that this method is highly reliable and suitable for both immature and adult animals. Our approach allows a simpler and more humane approach for genotyping vertebrate animals. PMID- 28675142 TI - Unusual ground states in [Formula: see text] (R = rare earth; T = Rh, Ir; and X = Si, Ge, Sn): a review. AB - Rare earth compounds of the type [Formula: see text] (R = rare earth; T = Rh, Ir, and X = Si, Ge, Sn) display a variety of phase transitions towards exotic states, including charge density waves (CDW), local moment magnetism, antiferromagnetism in the heavy fermion state, superconductivity and giant positive magnetoresistance. They support strongly correlated electron systems. In particular, R 5Ir4 [Formula: see text] (R = Dy-Lu) exhibit strong coupling CDWs with high transition temperatures, and superconductivity or magnetic ordering at lower temperatures. [Formula: see text] [Formula: see text] (R = Gd-Tm; T = Co, Rh, Ir) show multiple magnetic transitions with large magnetoresistance below the magnetic transitions. Finally, the light rare earth series [Formula: see text] [Formula: see text] (R = Ce, Pr, Nd; T = Rh, Ir) display heavy fermion behaviour (for Ce and Pr) or possess giant positive magnetoresistance (for Nd) at low temperatures. This review provides a comprehensive overview of compounds, crystal structures and phase transitions. This is followed by an in-depth discussion of the mechanisms of the phase transitions and the properties of the ordered states. PMID- 28675140 TI - Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. AB - Autophagy has been linked to longevity in many species, but the underlying mechanisms are unclear. Using a GFP-tagged and a new tandem-tagged Atg8/LGG-1 reporter, we quantified autophagic vesicles and performed autophagic flux assays in multiple tissues of wild-type Caenorhabditis elegans and long-lived daf 2/insulin/IGF-1 and glp-1/Notch mutants throughout adulthood. Our data are consistent with an age-related decline in autophagic activity in the intestine, body-wall muscle, pharynx, and neurons of wild-type animals. In contrast, daf-2 and glp-1 mutants displayed unique age- and tissue-specific changes in autophagic activity, indicating that the two longevity paradigms have distinct effects on autophagy during aging. Although autophagy appeared active in the intestine of both long-lived mutants, inhibition of intestinal autophagy significantly abrogated lifespan extension only in glp-1 mutants. Collectively, our data suggest that autophagic activity normally decreases with age in C. elegans, whereas daf-2 and glp-1 long-lived mutants regulate autophagy in distinct spatiotemporal-specific manners to extend lifespan. PMID- 28675141 TI - Longevity is impacted by growth hormone action during early postnatal period. AB - Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life. Our data suggest that developmental programming of aging importantly contributes to (and perhaps explains) the well documented developmental origins of adult disease. PMID- 28675143 TI - Diatom frustules decorated with zinc oxide nanoparticles for enhanced optical properties. AB - Zinc oxide (ZnO) nanoparticles were synthesized on diatomite (DE) surface by a low temperature sol gel technique, starting from zinc acetate dihydrate (Zn(CH3COO)2 . 2H2O) solution in water/ethyl alcohol, in presence of triethanolamine (TEA) with functions of Zn2+ chelating agent, catalyst and mediator of nanoparticle growth on DE surface. Microstructural features were investigated by field emission scanning electron microscopy and x-ray diffraction. ZnO crystalline nanoparticles, well distributed both on the surface and into the porous architecture of diatomite, were obtained just after the synthesis carried out at 80 degrees C without the need of calcination treatments. The optical properties of ZnO/DE hybrid powders were measured for the first time by means of photoacoustic spectroscopy (PAS). A new method to retrieve both the optical absorption and scattering coefficients from PAS is here discussed for powder aggregates. The fingerprint of the zinc oxide nanoparticles has been highlighted in the Mie scattering resonance in the UV-Vis range, and in the enhancement of the optical absorption with respect to diatomite. PMID- 28675144 TI - A soft multi-module manipulator with variable stiffness for minimally invasive surgery. AB - This work presents a soft manipulator for minimally invasive surgery inspired by the biological capabilities of the octopus arm. The multi-module arm is composed of three identical units, which are able to move thanks to embedded fluidic actuators that allow omnidirectional bending and elongation, typical movements of the octopus. The use of soft materials makes the arm safe, adaptable and compliant with tissues. In addition, a granular jamming-based stiffening mechanism is integrated in each module with the aim of tuning the stiffness of the manipulator and controlling the interactions with biological structures. A miniaturized camera and a pneumatic gripper have been purposely designed and integrated on the tip of the manipulator making it usable in real working conditions. This work reports the design and the fabrication process of the manipulator, the theoretical and experimental evaluation of the stiffness and the analysis of the motion workspace. Finally, pick and place tests with the fully integrated system are shown. PMID- 28675146 TI - Evaluation of the effectiveness of a bMSC and BMP-2 polymeric trilayer system in cartilage repair. AB - In this study a poly(lactide-co-glycolide) acid (PLGA) tri-layer scaffold is proposed for cartilage repair. The trilayer system consists of a base layer formed by a tablet of PLGA microspheres, a second layer composed of a microsphere suspension placed on top of the tablet, and the third layer, which constitutes an external electrospun PLGA thin polymeric membrane. Combinations of bone morphogenetic protein-2 (BMP-2) encapsulated in the microspheres of the suspension layer, and bone marrow mesenchymal stem cells (bMSC) seeded on the electrospun membrane, are evaluated by histologic analyses and immunohistochemistry in a critical size osteochondral defect in rabbits. Five experimental groups, including a control group (empty defect), a blank group (blank scaffold), a bMSC treated group, two groups treated with 2.5 MUg or 8.5 MUg of BMP-2 and another two groups implanted with bMSC-BMP-2 combination are evaluated. The repair area increases throughout the experimental time (24 weeks). The repair observed in the treated groups is statistically higher than in control and blank groups. However, the bMSC-BMP-2 combination does not enhance the BMP-2 response. In conclusion, BMP-2 and bMSC repaired effectively the osteochondral defect in the rabbits. The bMSC-BMP-2 combination did not produce synergism. PMID- 28675145 TI - Nanoporous MoS2 monolayer as a promising membrane for purifying hydrogen and enriching methane. AB - We present a theoretical prediction of a highly efficient membrane for hydrogen purification and natural gas upgrading, i.e. laminar MoS2 material with triangular sulfur-edged nanopores. We calculated from first principles the diffusion barriers of H2 and CO2 across monolayer MoS2 to be, respectively, 0.07 eV and 0.17 eV, which are low enough to warrant their great permeability. The permeance values for H2 and CO2 far exceed the industrially accepted standard. Meanwhile, such a porous MoS2 membrane shows excellent selectivity in terms of H2/CO, H2/N2, H2/CH4, and CO2/CH4 separation (>103, > 103, > 106, and > 104, respectively) at room temperature. We expect that the findings in this work will expedite theoretical or experimental exploration on gas separation membranes based on transition metal dichalcogenides. PMID- 28675147 TI - Observation of partial relaxation mechanisms via anisotropic strain relief on epitaxial islands using semiconductor nanomembranes. AB - In this work we attempt to directly observe anisotropic partial relaxation of epitaxial InAs islands using transmission electron microscopy (TEM) and synchrotron x-ray diffraction on a 15 nm thick InAs:GaAs nanomembrane. We show that under such conditions TEM provides improved real-space statistics, allowing the observation of partial relaxation processes that were not previously detected by other techniques or by usual TEM cross section images. Besides the fully coherent and fully relaxed islands that are known to exist above previously established critical thickness, we prove the existence of partially relaxed islands, where incomplete 60 degrees half-loop misfit dislocations lead to a lattice relaxation along one of the <110> directions, keeping a strained lattice in the perpendicular direction. Although individual defects cannot be directly observed, their implications to the resulting island registry are identified and discussed within the frame of half-loops propagations. PMID- 28675148 TI - Owl-inspired leading-edge serrations play a crucial role in aerodynamic force production and sound suppression. AB - Owls are widely known for silent flight, achieving remarkably low noise gliding and flapping flights owing to their unique wing morphologies, which are normally characterized by leading-edge serrations, trailing-edge fringes and velvet-like surfaces. How these morphological features affect aerodynamic force production and sound suppression or noise reduction, however, is still not well known. Here we address an integrated study of owl-inspired single feather wing models with and without leading-edge serrations by combining large-eddy simulations (LES) with particle-image velocimetry (PIV) and force measurements in a low-speed wind tunnel. With velocity and pressure spectra analysis, we demonstrate that leading edge serrations can passively control the laminar-turbulent transition over the upper wing surface, i.e. the suction surface at all angles of attack (0 degrees < AoA < 20 degrees ), and hence play a crucial role in aerodynamic force and sound production. We find that there exists a tradeoff between force production and sound suppression: serrated leading-edges reduce aerodynamic performance at lower AoAs < 15 degrees compared to clean leading-edges but are capable of achieving both noise reduction and aerodynamic performance at higher AoAs > 15 degrees where owl wings often reach in flight. Our results indicate that the owl inspired leading-edge serrations may be a useful device for aero-acoustic control in biomimetic rotor designs for wind turbines, aircrafts, multi-rotor drones as well as other fluid machinery. PMID- 28675150 TI - Ground-state phase diagram, fermionic entanglement and kinetically-induced frustration in a hybrid ladder with localized spins and mobile electrons. AB - We introduce an exactly solvable hybrid spin-ladder model containing localized nodal Ising spins and interstitial mobile electrons, which are allowed to perform a quantum-mechanical hopping between the ladder's legs. The quantum-mechanical hopping process induces an antiferromagnetic coupling between the ladder's legs that competes with a direct exchange coupling of the nodal spins. The model is exactly mapped onto the Ising spin ladder with temperature-dependent two- and four-spin interactions, which is subsequently solved using the transfer-matrix technique. We report the ground-state phase diagram and compute the fermionic concurrence to characterize the quantum entanglement between the pair of interstitial mobile electrons. We further provide a detailed analysis of the local spin ordering including the pair and four-spin correlation functions around an elementary plaquette, as well as, the local ordering diagrams. It is shown that a complex sequence of distinct local orderings and frustrated correlations takes place when the model parameters drive the investigated system close to a zero-temperature triple coexistence point. PMID- 28675149 TI - UAS stealth: target pursuit at constant distance using a bio-inspired motion camouflage guidance law. AB - The aim of this study is to derive a guidance law by which an unmanned aerial system(s) (UAS) can pursue a moving target at a constant distance, while concealing its own motion. We derive a closed-form solution for the trajectory of the UAS by imposing two key constraints: (1) the shadower moves in such a way as to be perceived as a stationary object by the shadowee, and (2) the distance between the shadower and shadowee is kept constant. Additionally, the theory presented in this paper considers constraints on the maximum achievable speed and acceleration of the shadower. Our theory is tested through Matlab simulations, which validate the camouflage strategy for both 2D and 3D conditions. Furthermore, experiments using a realistic vision-based implementation are conducted in a virtual environment, where the results demonstrate that even with noisy state information it is possible to remain well camouflaged using the constant distance motion camouflage technique. PMID- 28675151 TI - The relationship between retinal damage and current intensity in a pre-clinical suprachoroidal-transretinal stimulation model using a laser-formed microporous electrode. AB - OBJECTIVE: Suprachoroidal-transretinal stimulation (STS) is a stimulation method for retinal prostheses. For STS-type retinal prostheses, we developed a new type of stimulating electrode called a femtosecond laser-induced porous electrode (FLiP electrode). To verify the safety of the FLiP electrode for STS, we investigated the characteristics of STS-induced retinal injury. APPROACH: Sixteen eyes of pigmented rabbits were studied in this in vivo study. For each examined eye, we implanted a single-channel FLiP electrode (diameter, 0.5 mm; height, 0.3 mm; geometric surface area, 0.43 mm2) in a scleral pocket created at the posterior pole of the eye. A return electrode (diameter, 0.5 mm; length, 3 mm) was inserted into the vitreous cavity. The eyes were divided into five groups, and each group was stimulated with a different current intensity. The stimulus intensities and the number of eyes in each group were as follows: 1.0 mA (n = 2), 1.5 mA (n = 3), 2.0 mA (n = 3), 2.5 mA (n = 4), and 3.0 mA (n = 2). Continuous biphasic pulses (0.5 ms/phase) were applied under general anesthesia at a frequency of 20 Hz for 48 h. Fundus photography, fluorescein angiography (FA), and optical coherence tomography were performed before and after applying the electrical stimulation to evaluate the retinal injury. MAIN RESULTS: The 1.0 mA and 1.5 mA groups showed little or no retinal damage. Fluorescent dye leakage in FA and punctate pigmentation in the fundus were observed around the stimulation site with stimulation of 2.0 mA (1/3), 2.5 mA (1/4), and 3.0 mA (2/2). SIGNIFICANCE: Our findings indicate that the threshold current for inducing retinal damage is greater than that for eliciting electrical phosphenes (<1 mA) with STS observed in human trials. Therefore, STS by the FLiP electrode is a safe and feasible stimulation method for retinal prostheses as long as it is used with these pulse parameters. PMID- 28675152 TI - Molybdenum disulfide nanoparticles decorated reduced graphene oxide: highly sensitive and selective hydrogen sensor. AB - In this work, we report on the hydrogen (H2) sensing behavior of reduced graphene oxide (RGO)/molybdenum disulfide (MoS2) nano particles (NPs) based composite film. The RGO/MoS2 composite exhibited a highly enhanced H2 response (~15.6%) for 200 ppm at an operating temperature of 60 degrees C. Furthermore, the RGO/MoS2 composite showed excellent selectivity to H2 with respect to ammonia (NH3) and nitric oxide (NO) which are highly reactive gas species. The composite's response to H2 is 2.9 times higher than that of NH3 whereas for NO it is 3.5. This highly improved H2 sensing response and selectivity of RGO/MoS2 at low operating temperatures were attributed to the structural integration of MoS2 nanoparticles in the nanochannels and pores in the RGO layer. PMID- 28675153 TI - Sperm DNA damage has a negative effect on early embryonic development following in vitro fertilization. AB - Sperm DNA damage is recognized as an important biomarker of male infertility. To investigate this, sperm DNA damage was assessed by the sperm chromatin dispersion (SCD) test in semen and motile spermatozoa harvested by combined density gradient centrifugation (DGC) and swim-up in 161 couples undergoing in vitro fertilization (IVF). Semen analysis and sperm DNA damage results were compared between couples who did or did not achieve pregnancy. The sperm DNA damage level was significantly different between the two groups (P < 0.05) and was negatively correlated with IVF outcomes. Logistic regression analysis confirmed that it was an independent predictor for achieving clinical pregnancy. The effects of different levels of sperm DNA damage on IVF outcomes were also compared. There were significant differences in day 3 embryo quality, blastocyst formation rate, and implantation and pregnancy rates (P < 0.05), but not in the basic fertilization rate between the two groups. Thus, sperm DNA damage as measured by the SCD appears useful for predicting the clinical pregnancy rate following IVF. PMID- 28675154 TI - Redo surgery for failed hypospadias treatment using a novel single-stage repair. PMID- 28675156 TI - Corrigendum: Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbalpha. AB - This corrects the article DOI: 10.1038/ncomms15559. PMID- 28675155 TI - The m6A pathway facilitates sex determination in Drosophila. AB - The conserved modification N6-methyladenosine (m6A) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the m6A pathway. We first apply miCLIP to map m6A across embryogenesis, characterize its m6A 'writer' complex, validate its YTH 'readers' CG6422 and YT521-B, and generate mutants in five m6A factors. While m6A factors with additional roles in splicing are lethal, m6A-specific mutants are viable but present certain developmental and behavioural defects. Notably, m6A facilitates the master female determinant Sxl, since multiple m6A components enhance female lethality in Sxl sensitized backgrounds. The m6A pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic m6A target, and female-specific Sxl splicing is compromised in multiple m6A pathway mutants. YT521-B is a dominant m6A effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila m6A pathway. PMID- 28675157 TI - Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis. AB - Abnormal development of multiciliated cells is a hallmark of a variety of human conditions associated with chronic airway diseases, hydrocephalus and infertility. Multiciliogenesis requires both activation of a specialized transcriptional program and assembly of cytoplasmic structures for large-scale centriole amplification that generates basal bodies. It remains unclear, however, what mechanism initiates formation of these multiprotein complexes in epithelial progenitors. Here we show that this is triggered by nucleocytoplasmic translocation of the transcription factor E2f4. After inducing a transcriptional program of centriole biogenesis, E2f4 forms apical cytoplasmic organizing centres for assembly and nucleation of deuterosomes. Using genetically altered mice and E2F4 mutant proteins we demonstrate that centriole amplification is crucially dependent on these organizing centres and that, without cytoplasmic E2f4, deuterosomes are not assembled, halting multiciliogenesis. Thus, E2f4 integrates nuclear and previously unsuspected cytoplasmic events of centriole amplification, providing new perspectives for the understanding of normal ciliogenesis, ciliopathies and cancer. PMID- 28675159 TI - The evolution of host-symbiont dependence. AB - Organisms across the tree of life form symbiotic partnerships with microbes for metabolism, protection and resources. While some hosts evolve extreme dependence on their symbionts, others maintain facultative associations. Explaining this variation is fundamental to understanding when symbiosis can lead to new higher level individuals, such as during the evolution of the eukaryotic cell. Here we perform phylogenetic comparative analyses on 106 unique host-bacterial symbioses to test for correlations between symbiont function, transmission mode, genome size and host dependence. We find that both transmission mode and symbiont function are correlated with host dependence, with reductions in host fitness being greatest when nutrient-provisioning, vertically transmitted symbionts are removed. We also find a negative correlation between host dependence and symbiont genome size in vertically, but not horizontally, transmitted symbionts. These results suggest that both function and population structure are important in driving irreversible dependence between hosts and symbionts. PMID- 28675160 TI - Corrigendum: The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing. AB - This corrects the article DOI: 10.1038/ncomms15533. PMID- 28675158 TI - Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis. AB - Both environmental cues and intracellular bioenergetic states profoundly affect intracellular pH (pHi). How a cell responds to pHi changes to maintain bioenergetic homeostasis remains elusive. Here we show that Smad5, a well characterized downstream component of bone morphogenetic protein (BMP) signaling responds to pHi changes. Cold, basic or hypertonic conditions increase pHi, which in turn dissociates protons from the charged amino acid clusters within the MH1 domain of Smad5, prompting its relocation from the nucleus to the cytoplasm. On the other hand, heat, acidic or hypotonic conditions decrease pHi, blocking the nuclear export of Smad5, and thus causing its nuclear accumulation. Active nucleocytoplasmic shuttling of Smad5 induced by environmental changes and pHi fluctuation is independent of BMP signaling, carboxyl terminus phosphorylation and Smad4. In addition, ablation of Smad5 causes chronic and irreversible dysregulation of cellular bioenergetic homeostasis and disrupted normal neural developmental processes as identified in a differentiation model of human pluripotent stem cells. Importantly, these metabolic and developmental deficits in Smad5-deficient cells could be rescued only by cytoplasmic Smad5. Cytoplasmic Smad5 physically interacts with hexokinase 1 and accelerates glycolysis. Together, our findings indicate that Smad5 acts as a pHi messenger and maintains the bioenergetic homeostasis of cells by regulating cytoplasmic metabolic machinery. PMID- 28675161 TI - Structural insights into the mechanism of the membrane integral N-acyltransferase step in bacterial lipoprotein synthesis. AB - Lipoproteins serve essential roles in the bacterial cell envelope. The posttranslational modification pathway leading to lipoprotein synthesis involves three enzymes. All are potential targets for the development of new antibiotics. Here we report the crystal structure of the last enzyme in the pathway, apolipoprotein N-acyltransferase, Lnt, responsible for adding a third acyl chain to the lipoprotein's invariant diacylated N-terminal cysteine. Structures of Lnt from Pseudomonas aeruginosa and Escherichia coli have been solved; they are remarkably similar. Both consist of a membrane domain on which sits a globular periplasmic domain. The active site resides above the membrane interface where the domains meet facing into the periplasm. The structures are consistent with the proposed ping-pong reaction mechanism and suggest plausible routes by which substrates and products enter and leave the active site. While Lnt may present challenges for antibiotic development, the structures described should facilitate design of therapeutics with reduced off-target effects. PMID- 28675162 TI - AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability. AB - AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function. PMID- 28675163 TI - Long-Term Efficacy and Safety of Cyclosporine in a Cohort of Steroid-Refractory Acute Severe Ulcerative Colitis Patients from the ENEIDA Registry (1989-2013): A Nationwide Multicenter Study. AB - OBJECTIVES: To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to establish predictors of efficacy and adverse events. METHODS: Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators. RESULTS: Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P=0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P=0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P<0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed. CONCLUSIONS: Treatment with CyA showed a lower rate of SAE and a similar efficacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefit of sequential CyA-IFX for CyA non-responders is acceptable. PMID- 28675166 TI - Correlated rotational switching in two-dimensional self-assembled molecular rotor arrays. AB - Molecular devices are capable of performing a number of functions from mechanical motion to simple computation. Their utility is somewhat limited, however, by difficulties associated with coupling them with either each other or with interfaces such as electrodes. Self-assembly of coupled molecular devices provides an option for the construction of larger entities that can more easily integrate with existing technologies. Here we demonstrate that ordered organometallic arrays can be formed spontaneously by reaction of precursor molecular rotor molecules with a metal surface. Scanning tunnelling microscopy enables individual rotors in the arrays to be switched and the resultant switches in neighbouring rotors imaged. The structure and dimensions of the ordered molecular rotor arrays dictate the correlated switching properties of the internal submolecular rotor units. Our results indicate that self-assembly of two dimensional rotor crystals produces systems with correlated dynamics that would not have been predicted a priori. PMID- 28675164 TI - Antibody-drug conjugates in glioblastoma therapy: the right drugs to the right cells. AB - Glioblastomas are high-grade brain tumours with a poor prognosis and, currently, few available therapeutic options. This lack of effective treatments has been linked to diverse factors, including target selection, tumour heterogeneity and poor penetrance of therapeutic agents through the blood-brain barrier and into tumours. Therapies using monoclonal antibodies, alone or linked to cytotoxic payloads, have proved beneficial for patients with different solid tumours; these approaches are currently being explored in patients with glioblastoma. In this Review, we summarise clinical data regarding antibody-drug conjugates (ADCs) against a variety of targets in glioblastoma, and compare the efficacy and toxicity of targeting EGFR with ADCs versus naked antibodies in order to illustrate key aspects of the use of ADCs in this malignancy. Finally, we discuss the complex challenges related to the biology and mutational changes of glioblastoma that can affect the use of ADC-based therapies in patients with this disease, and highlight potential strategies to improve efficacy. PMID- 28675167 TI - Urinary incontinence: Evaluating bladder wall properties with vibrometry. PMID- 28675165 TI - Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. AB - Epigenetic alterations are a common hallmark of human cancer. Single epigenetic markers are starting to be incorporated into clinical practice; however, the translational use of these biomarkers has not been validated at the 'omics' level. The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings, addressing an unmet need in the diagnostic and clinical management of these patients. Despite the great diagnostic advances made in the past decade, the use of traditional diagnostic procedures only enables the tissue of origin to be determined in ~30% of patients with CUP. Thus, development of molecularly guided diagnostic strategies has emerged to complement traditional procedures, thereby improving the clinical management of patients with CUP. In this Review, we present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, and we highlight areas warranting further research to engage the medical community in this unmet need. PMID- 28675169 TI - Infection: Proceed with CAUTIon. PMID- 28675170 TI - Urothelial carcinoma: Genomic characterization of UTUC. PMID- 28675168 TI - Varicocele and male infertility. AB - The link between varicoceles and male infertility has been a matter of debate for more than half a century. Varicocele is considered the most common correctable cause of male infertility, but some men with varicoceles are able to father children, even without intervention. In addition, improvements in semen quality after varicocelectomy do not always result in spontaneous pregnancy. Studies regarding possible pathophysiological mechanisms behind varicocele-induced infertility have tried to address these controversies. Oxidative stress seems to be a central mechanism; however, no single theory is able to explain the differential effect of varicoceles on infertility. As a consequence, careful patient selection for treatment based on couple fertility status, varicocele grade, and semen quality is critical for achieving a chance of a subsequent pregnancy. A substantial amount of data on the effects of varicocelectomy has been gathered, but inadequate study design and considerable heterogeneity of available studies mean that these data are rarely conclusive. Current evidence suggests a beneficial effect of varicocelectomy on semen quality and pregnancy outcomes in couples with documented infertility only if the male partner has a clinically palpable varicocele and affected semen parameters. PMID- 28675171 TI - Sexual dysfunction: Shortened CCH treatment for Peyronie's disease. PMID- 28675172 TI - Prostate cancer: Epigenetic AR regulation. PMID- 28675173 TI - Prostate cancer: Mechanisms of cancer metabolism: mTORC1 mediates AMD1. PMID- 28675176 TI - Urinary incontinence: Stem cell therapy for chronic bladder ischaemia. PMID- 28675174 TI - Landmarks in the treatment of muscle-invasive bladder cancer. AB - Muscle-invasive bladder cancer is an aggressive disease associated with high morbidity and mortality. Radical cystectomy is the mainstay of treatment and has evolved since the first reported cystectomy in 1887 to include pelvic lymph node dissection and the creation of increasingly sophisticated urinary diversions, such as neobladders and pouches, which enable patients to maintain continence. Pioneering work in the 1970s established the therapeutic activity of cisplatin in patients with bladder cancer and resulted in the introduction of cisplatin-based neoadjuvant chemotherapy, which led to the first improvement in survival outcomes in decades. Other notable advances include the development of bladder-sparing protocols, which combine surgery, chemotherapy, and radiotherapy. Molecular profiling of bladder cancer has helped to enhance our understanding of tumour biology and identify several therapeutic targets, such as programmed death (PD-1) and its ligand programmed cell death ligand 1 (PD-L1). Over the past 3 years, immune checkpoint inhibitors targeting the PD-1-PD-L1 axis have demonstrated the ability to achieve durable objective responses in trials of patients with metastatic disease. If the current momentum continues, immunotherapy is poised to change the landscape of muscle-invasive bladder cancer treatment, promising improved survival outcomes for patients with this disease. PMID- 28675178 TI - What big data could achieve in Scotland. PMID- 28675177 TI - Norrin-induced Frizzled4 endocytosis and endo-lysosomal trafficking control retinal angiogenesis and barrier function. AB - Angiogenesis and blood-brain barrier formation are required for normal central nervous system (CNS) function. Both processes are controlled by Wnt or Norrin (NDP) ligands, Frizzled (FZD) receptors, and beta-catenin-dependent signalling in vascular endothelial cells. In the retina, FZD4 and the ligand NDP are critical mediators of signalling and are mutated in familial exudative vitreoretinopathy. Here, we report that NDP is a potent trigger of FZD4 ubiquitination and induces internalization of the NDP receptor complex into the endo-lysosomal compartment. Inhibition of ubiquitinated cargo transport through the multivesicular body (MVB) pathway using a dominant negative ESCRT (endosomal sorting complexes required for transport) component VPS4 EQ strongly impairs NDP/FZD4 signalling in vitro and recapitulates CNS angiogenesis and blood-CNS-barrier defects caused by impaired vascular beta-catenin signalling in mice. These findings provide evidence for an important role of FZD4 endocytosis in NDP/FZD4 signalling and in CNS vascular biology and disease. PMID- 28675179 TI - Prevention through Learning: working together to drive high-quality care. PMID- 28675175 TI - Telomeres and telomerase in prostate cancer development and therapy. AB - Aberrations in telomere biology are among the earliest events in prostate cancer tumorigenesis and continue during tumour progression. Substantial telomere shortening occurs in prostate cancer cells and high-grade prostatic intraepithelial neoplasia. Not all mechanisms of telomere shortening are understood, but oxidative stress from local inflammation might accelerate prostatic telomere loss. Critically short telomeres can drive the accumulation of tumour-promoting genomic alterations; however, continued telomere erosion is unsustainable and must be mitigated to ensure cancer cell survival and unlimited replication potential. Prostate cancers predominantly maintain telomeres by activating telomerase, but alternative mechanisms of telomere extension can occur in metastatic disease. Telomerase activity and telomere length assessment might be useful in prostate cancer diagnosis and prognosis. Telomere shortening in normal stromal cells has been associated with prostate cancer, whereas variable telomere lengths in prostate cancer cells and telomere shortening in cancer associated stromal cells correlated with lethal disease. Single-agent telomerase targeted treatments for solid cancers were ineffective in clinical trials but have not been investigated in prostate cancer and might be useful in combination with established regimens. Telomere-directed strategies have not been explored as extensively. Telomere deprotection strategies have the advantage of being effective in both telomerase-dependent and telomerase-independent cancers. Disruption of androgen receptor function in prostate cancer cells results in telomere dysfunction, indicating telomeres and telomerase as potential therapeutic targets in prostate cancer. PMID- 28675180 TI - Temporal artery biopsies in south-east Scotland: a five year review. AB - Temporal artery biopsy is the gold standard investigation for the diagnosis of giant cell arteritis. The aim of this retrospective study was to investigate the use of temporal artery biopsy in diagnosing giant cell arteritis in south-east Scotland over a five-year period. We aimed to quantify success rates, and predictive factors for a positive biopsy, as well as compare the different specialities performing the biopsies. The data should enable the development of better criteria for referral for investigation of giant cell arteritis. Methods Patients were identified using a database of temporal artery biopsies generated by the pathology department in NHS Lothian (south east Scotland), for all biopsies examined between January 2010 and December 2015. An electronic patient record was used to retrospectively examine the records of patients in the database. Results A total of 715 biopsies were included in the study, of which 250 (35.0%) showed features of giant cell arteritis. The main predictors for a positive biopsy were age at biopsy, specialty performing biopsy, erythrocyte sedimentation rate, jaw claudication/pain, and ophthalmic symptoms. The most important predictor of a positive biopsy was erythrocyte sedimentation rate. The length of biopsy was not found to be a predictor of positive biopsy; however, diameter of biopsy was predictive. Conclusions We have shown that many temporal artery biopsies are negative, and finding ways to reduce the number of patients unnecessarily undergoing biopsy will be essential in reducing workload and streamlining services. This study demonstrates some key predictive factors for patients with positive biopsies. The study also shows that a large proportion of biopsies taking place do not result in the recommended length of specimen, but this does not necessarily reduce the likelihood of a positive biopsy. PMID- 28675181 TI - Missed opportunities to diagnose syphilis prior to the development of sight losing uveitis. AB - The incidence of syphilis in the UK is rapidly rising. Uveitis (intraocular inflammation) usually occurs in the secondary or later stages of syphilis infection and is sight-threatening. Methods A retrospective analysis of the demographics, presentation, diagnosis, treatment and outcomes of patients with syphilitic uveitis managed in Newcastle from 2005-2016 was carried out. Results Ten males (19 eyes) with syphilitic uveitis had a generally good visual and serological response to penicillin treatment. In eight of the patients there had been a failure to test for syphilis during assessments by various medical practitioners for unexplained symptoms that were attributable to syphilis prior to the eye involvement. Conclusion Uveitis associated with syphilis can be sight threatening but responds well to treatment. In our case series there were multiple missed opportunities to diagnose syphilis prior to presentation with eye disease, with a general failure of healthcare professionals to take an adequate sexual history. PMID- 28675182 TI - Unilateral atrial fibrillation - how common is atrial divorce? AB - Atrial fibrillation is the most common pathologic supraventricular tachycardia. It has many causes, is an expensive disease, impairs quality of life and leads to an increased risk of death. Atrial dissociation is characterised by the presence of two independent sets of P-waves. This peculiar abnormality may give rise to the scenario where one atrium is in atrial fibrillation while the other is in sinus rhythm. This is the first published case of atrial dissociation where the phenomenon is demonstrated by transmitral and transtricuspid pulsed wave Doppler. PMID- 28675183 TI - Communication breakdown between physicians and IBS sufferers: what is the conundrum and how to overcome it? AB - Irritable bowel syndrome is a disorder of gut-brain interaction that leads to a significant healthcare burden worldwide. A good physician-patient relationship is fundamental in managing patients who suffer from this poorly understood chronic disease. We highlight possible reasons for breakdown in communication between physicians and irritable bowel syndrome sufferers and suggest possible ways to overcome such pitfalls. PMID- 28675184 TI - Phlegmasia dolens. PMID- 28675185 TI - An enigmatic trio of Klinefelter's syndrome, autoimmune hypothyroidism and nephrotic syndrome. AB - Klinefelter's syndrome is the most common chromosomal disorder associated with testicular dysfunction and male infertility. Those affected by Klinefelter's syndrome are at increased risk of systemic lupus erythematosus, breast cancer, non-Hodgkin's lymphoma, and lung cancer. Nephrotic syndrome in association with Klinefelter's syndrome has never been reported in the literature. PMID- 28675186 TI - A successful re-trial after clozapine myopericarditis. AB - Clozapine-induced myopericarditis is a well-described adverse drug reaction. Clozapine is also the most efficacious agent in refractory schizophrenia. We report a case of a patient who was successfully re-trialled on clozapine two years after developing myopericarditis, after which multiple lines of alternative treatment failed. We propose a protocol for safely attempting a re-trial of clozapine in such cases. PMID- 28675187 TI - The iron paradox: a case of acaeruloplasminaemia. AB - Acaeruloplasminaemia is a rare neurodegenerative disorder in which dysfunction of the caeruloplasmin gene results in brain iron accumulation alongside systemic iron overload. We discuss the case of a 53-year-old male who presented to neurology with a 4-year history of progressive neuropsychiatric symptoms and was eventually diagnosed with this condition. We discuss the characteristic clinical features and supporting laboratory and radiological findings as well as clinical pointers to help differentiate it from other conditions which might cause diagnostic confusion. PMID- 28675188 TI - Predicting Alzheimer's disease: a polygenic hazard score. PMID- 28675189 TI - Evolocumab and clinical outcomes in patients with cardiovascular disease. PMID- 28675190 TI - Feasibility of a respiratory nurse specialist-led sleep disorder service in a district general hospital. AB - Aim The burden of referrals to investigate sleep disorders has escalated considerably. In order to address this, the feasibility of a nurse-led sleep disorder clinic was investigated. Methods Sleep referrals were stratified on the basis of information contained within the primary care referral, and appropriate home-based sleep studies arranged if obstructive sleep apnoea was considered the most likely working diagnosis. Selected patients were started on continuous positive airway pressure treatment if deemed appropriate. Education was almost exclusively provided by specialist nursing staff or by means of validated information by the British Lung Foundation. Results Eighty patients were included in the respiratory nurse-led sleep service. Feedback from the patient questionnaire was positive and 59 patients were managed without requirement to attend consultant-led outpatient services. Non-sleep breathing disorders as the reason for daytime somnolence, and patients requiring referral to tertiary services, were identified. Conclusion Developing a respiratory nurse-led sleep service is adequate to identify non-sleep breathing disorders, is fit for purpose, functions broadly in accordance with American Sleep Society guidelines, and is well received by patients. PMID- 28675191 TI - Establishing a deanery teaching programme for trainees sitting the MRCPCH clinical examination. AB - Objectives MRCPCH is an essential qualification that all paediatric trainees in the UK must obtain to progress with their specialty training. In August 2009 a structured clinical teaching programme was initiated in the West of Scotland deanery to provide teaching in the clinical examination curriculum, the structure and examination standards. Design The training programme runs three times a year, commencing two months prior to each exam. Trainees are sent questionnaires to enable improvement of the programme. Results A total of 127 trainees have participated in the programme over five years (August 2009-2014). Trainees report strengths of the programme include communication teaching (n = 14) and general teaching (n = 11). Challenges encountered include difficulties attending teaching sessions due to clinical commitments (n = 5). Conclusions Future development will focus on creating a robust system enabling this programme to continue and establishment of a key group of paediatric consultants, who can provide consistent teaching reflecting the realities of the examination. PMID- 28675192 TI - Tablet computers in assessing performance in a high stakes exam: opinion matters. AB - Background Tablet computers have emerged as a tool to capture, process and store data in examinations, yet evidence relating to their acceptability and usefulness in assessment is limited. Methods We performed an observational study to explore opinions and attitudes relating to tablet computer use in recording performance in a final year objective structured clinical examination at a single UK medical school. Examiners completed a short questionnaire encompassing background, forced choice and open questions. Forced choice questions were analysed using descriptive statistics and open questions by framework analysis. Results Ninety two (97% response rate) examiners completed the questionnaire of whom 85% had previous use of tablet computers. Ninety per cent felt checklist mark allocation was 'very/quite easy', while approximately half considered recording 'free-type' comments was 'easy/very easy'. Greater overall efficiency of marking and resource savings were considered the main advantages of tablet computers, while concerns relating to technological failure and ability to record free type comments were raised. Discussion In a context where examiners were familiar with tablet computers, they were preferred to paper checklists, although concerns were raised. This study adds to the limited literature underpinning the use of electronic devices as acceptable tools in objective structured clinical examinations. PMID- 28675193 TI - Putting insulin resistance into context by dietary reversal of type 2 diabetes. AB - It has long been assumed that type 2 diabetes is caused by the combined effects of insulin resistance and loss of pancreatic islet beta cells. Much therapeutic effort has been directed towards decreasing insulin resistance even though results have been generally disappointing. Now that type 2 diabetes can be understood as a simple reversible condition, its component parts can be examined during the period of return to normal glucose tolerance. PMID- 28675194 TI - Aortic stenosis - pathogenesis, prediction of progression, and percutaneous intervention. AB - Aortic stenosis is common and an important cause of morbidity and mortality. Prevalence will increase significantly in forthcoming decades as a function of the ageing population; treatment by means of surgery or percutaneous intervention is expensive. Epidemiological, mechanistic and interventional studies are therefore vital to determine optimal and innovative treatments and their funding. Recent studies suggest that aortic stenosis is not a passive degenerative disease, but an active process involving several pathways, including lipid infiltration, chronic inflammation, fibrosis formation, osteoblast activation, and active valve mineralisation. Despite similarities with atherosclerosis, randomised statin trials proved negative in aortic stenosis, underlining the need to explore alternative pathophysiological pathways. Left ventricular hypertrophy in response to pressure overload in aortic stenosis is initially adaptive but ultimately decompensates, leading to progressive left ventricular impairment, symptoms and adverse cardiovascular events. This transition is driven primarily by myocyte death and myocardial fibrosis. Cardiac magnetic resonance imaging can visualise and quantify myocardial fibrosis and may provide additional and independent prognostic information in aortic stenosis. Moreover, new markers of fibrosis utilising novel imaging techniques are rapidly emerging. Transcatheter aortic valve implantation is a disruptive technology that has transformed the management of aortic stenosis, and encouraged a wider multidisciplinary approach to the management of valvular heart disease. While originally applied in older, high-risk patients, recent trends for its use in intermediate risk patients have been supported by the findings of key clinical trials in 2016. PMID- 28675195 TI - How to deal with violent and aggressive patients in acute medical settings. AB - Dealing with violence and aggression is an area where health professionals often feel uncertain. Standing at the interface between medicine, psychiatry and law, the best actions may not be clear, and guidelines neither consistently applicable nor explicit. An aggressive, violent or abusive patient may be behaving anti socially or criminally. But in acute medical settings it is more likely that a medical, mental health or emotional problem, or some combination thereof, is the explanation and usually we will not know the relative contribution of each element. We must assume that difficult behaviour represents the communication of distress or unmet need. We can prevent and de-escalate situations by understanding why they have arisen, identifying the need, and trying to anticipate or meet it. In these situations 'challenging behaviour' is much like any other presenting problem: the medical approach is to diagnose and treat, while trying to maintain safety and function. In addition, the person-centred approach of trying to understand and address psychological and emotional distress is required. Skilled communication, non-confrontation, relationship-building and negotiation represent the best way to manage situations and avoid harm. If an incident is becoming dangerous, doctors need to know how to act to defuse the situation, or make it safe. Doctors must know about de-escalation and non-drug approaches, but also be confident about when physical restraint and drug treatment are necessary, and how to go about using appropriate drugs, doses, monitoring and aftercare. There are necessary safeguards around using these approaches, from the perspectives of physical health, mental wellbeing, and human rights. PMID- 28675196 TI - St Hugh's Military Hospital (Head Injuries), Oxford 1940-1945. AB - Despite being open for only five years, St Hugh's Military Hospital (Head Injuries) has a seminal place in the history of neurology, neurosurgery and rehabilitation medicine. At its peak, during the Normandy campaign of 1944, it provided 430 beds for the treatment of service personnel. Between 1940 and 1945, 13,000 patients were referred to St Hugh's providing a unique opportunity for ground-breaking research into the management of head injuries. The doctors at St Hugh's collaborated with research scientists at Oxford University in many areas of fundamental research including the treatment of infection, the mechanics of brain injury, brain surgery, neuropsychiatry and rehabilitation, and the use of electroencephalograms. This paper documents these scientific advances and considers their influence on the practice of neurology and neurosurgery in the UK. PMID- 28675197 TI - James Parkinson's Chimera: syndrome or disease? AB - It is 200 years since James Parkinson published An Essay on the Shaking Palsy. While his monograph continues to be acclaimed for its precedence and clarity of description, what is often overlooked is the originality of Parkinson's ideas. Here we show that he appreciated the weakness of the systematic 18th century nosologies, which presupposed that medical species, the building blocks of these Linnaean taxonomic schemes, were as distinct as plant and animal species; and that Parkinson made a conceptual leap about combinations of clinical phenomena in recurring patterns, now recognised to be one of the germs of neurological thinking about syndromes. The Essay's written style underpins another aspect of significance to contemporary neurological practice - an inherent intellectual humility. In this commemorative year we locate the continuing importance of the related notions of syndrome and disease in successive frameworks of knowledge about the shaking palsy. Syndrome and disease are interpreted as dual character concepts, one clinically-based and the other restricted to pathophysiological causation. They both remain fundamental to understanding Parkinson's syndrome disease today. PMID- 28675198 TI - The 'bloody Moloch': Osler and van Helmont on bloodletting. AB - In a passage on the treatment of pneumonia, Osler quoted van Helmont's remark that 'a bloody Moloch presides in the chairs of medicine'. This paper explores Helmont's use of 'Moloch' as a term of abuse against the bloodletting of traditional Galenist physicians and his vigorous opposition to the use of bleeding in treating diseases. The possible reasons for Helmont's opposition to the practice of bloodletting are discussed, leading to the conclusion that it arose from his theories of the origin of diseases, reinforced by some observations of its malign effects on a patient who had been bled excessively. The question of whether Helmont knew of Harvey's discovery of the circulation of the blood is explored and the conclusion reached that, if he did, he ignored it completely. Helmont believed that 'pure' and 'impure' blood coexisted in disease and could be affected selectively by bloodletting which, in effect, concentrated the 'impure' at the expense of the 'pure' blood to the great detriment of the patient. PMID- 28675199 TI - Hyperglycaemia and chorea PMID- 28675200 TI - Complexes of Ni(i): a "rare" oxidation state of growing importance. AB - Nickel plays an important role in areas as diverse as metallurgy, magnetism and biology as well as in chemical applications such as the catalytic transformation of organic substrates. Despite nickel's importance, the investigation of its compounds in various oxidation states remains uneven and those in the +1 oxidation are less common than those in the neighboring 0 and +2 oxidation states. Nonetheless, in recent years, the volume of work on Ni(i) complexes has increased to the extent that they can be no longer regarded as rare. This review focuses on the syntheses and structures of Ni(i) complexes and shows that they display a range of structures, reactivity and magnetic behavior that places them in the forefront of current nickel chemistry research. PMID- 28675201 TI - Multi-spectroscopic and theoretical analyses on the diphenyl ether-tert-butyl alcohol complex in the electronic ground and electronically excited state. AB - Aromatic ethers such as diphenyl ether (DPE) represent molecules with different docking sites for alcohols leading to competing OH-O and OH-pi interactions. In a multi-spectroscopic approach in combination with quantum chemical calculations the complex of DPE with tert-butyl alcohol (t-BuOH) is investigated in the electronic ground state (S0) and the electronically excited state (S1). FTIR, microwave as well as mass- and isomer-selective IR/R2PI spectra are recorded, revealing co-existing OH-O and OH-pi isomers in the S0 state. Surprisingly, they are predicted to be of almost equal stability in contrast to the previously investigated DPE-MeOH complex, where the OH-pi structure is preferred by both theory and experiment. The tert-butyl group in t-BuOH allows for a simultaneous optimization of hydrogen-bonding and dispersion interactions, which provides a sensitive meeting point between theory and experiment. In the electronically excited state of DPE-t-BuOH, vibrational spectra could be recorded separately for both isomers using UV/IR/UV spectroscopy. In the S1 state the same structural binding motifs are obtained as in the S0 state with the OH-O bond being weakened for the OH-O arrangement and the OH-pi interaction being strengthened in the case of the OH-pi isomer compared to the S0 state. PMID- 28675202 TI - Natural product analogues: towards a blueprint for analogue-focused synthesis. AB - For the first time a general overview of approaches to the synthesis of natural product analogues is presented. This reflects a process of evolution of natural product synthesis which has accelerated in the years since the implementation of diversity-oriented synthesis, which has emerged in parallel with collective synthesis, diverted total synthesis and the preparation of truncated natural products optimised for biological activity. A method involving computational assessment for the validation of core-modified natural product analogues is discussed. PMID- 28675203 TI - Electrospun poly(N-isopropyl acrylamide)/poly(caprolactone) fibers for the generation of anisotropic cell sheets. AB - Cell alignment in muscle, nervous tissue, and cartilage is requisite for proper tissue function; however, cell sheeting techniques using the thermosensitive polymer poly(N-isopropyl acrylamide) (PNIPAAm) can only produce anisotropic cell sheets with delicate and resource-intensive modifications. We hypothesized that electrospinning, a relatively simple and inexpensive technique to generate aligned polymer fibers, could be used to fabricate anisotropic PNIPAAm and poly(caprolactone) (PCL) blended surfaces that both support cell viability and permit cell sheet detachment via PNIPAAm dissolution. Aligned electrospun PNIPAAm/PCL fibers (0%, 25%, 50%, 75%, 90%, and 100% PNIPAAm) were electrospun and characterized. Fibers ranged in diameter from 1-3 MUm, and all fibers had an orientation index greater than 0.65. Fourier transform infrared spectroscopy was used to confirm the relative content of PNIPAAm and PCL. For advancing water contact angle and mass loss studies, only high PNIPAAm-content fibers (75% and greater) exhibited, temperature-dependent properties like 100% PNIPAAm fibers, whereas 25% and 50% PNIPAAm fibers behaved similarly to PCL-only fibers. 3T3 fibroblasts seeded on all PNIPAAm/PCL fibers had high cell viability and spreading except for the 100% PNIPAAm fibers. Cell sheet detachment by incubation with cold medium was successful only for 90% PNIPAAm fibers, which had a sufficient amount of PCL to allow cell attachment and spreading but not enough to prevent detachment upon PNIPAAm dissolution. This study demonstrates the feasibility of using anisotropic electrospun PNIPAAm/PCL fibers to generate aligned cell sheets that can potentially better recapitulate anisotropic architecture to achieve proper tissue function. PMID- 28675204 TI - Effect of soybean protein on blood pressure in postmenopausal women: a meta analysis of randomized controlled trials. AB - The effect of soybean protein on blood pressure (BP) in postmenopausal women is controversial, so we aimed to conduct a systematic review and a meta-analysis of published randomized controlled trials (RCTs) to investigate whether supplementation with soy protein improves their blood pressure. PubMed and Embase were searched up to February 2016. Weighted mean differences were calculated for net changes in BP by using fixed-effect or random-effect models. Subgroup and meta-regression analyses were performed to clarify heterogeneity among the trials. A total of twelve trials (1551 postmenopausal women participants) were included in the present meta-analysis. The overall pooled estimates of the effect of soy protein indicated a significant effect on systolic blood pressure (SBP) (mean difference: -3.03 mmHg; 95% CI: -5.03, -1.02; P = 0.003) and diastolic blood pressure (DBP) (mean difference: -0.71 mmHg; 95% CI: -1.26, -0.16; P = 0.012). Subgroup analyses further demonstrated that soy protein intake >=25 g d-1 significantly reduced BP, and the mean difference in SBP and DBP was -4.62 mmHg (95% CI: -8.42, -0.81; P = 0.04) and -1.63 mmHg (95% CI: -2.85, -0.41; P = 0.009), respectively. Soy isoflavone intake >=100 mg d-1 had a better reduction effect both in SBP (-5.47 mmHg; 95% CI: -8.42, -2.51; P = 0.00) and DBP (-2.03 mmHg; 95% CI: -3.35, -0.72; P = 0.002). However, soy protein intake <25 g d-1 or soy isoflavone intake <100 mg d-1 had no such effects (P > 0.05). This meta analysis suggests that ingestion of >=25 g soy protein per day has BP-lowering effects, and the improvements in BP may be due to the isoflavones component of soy protein. More high-quality RCTs need to be carried out to confirm the present findings. PMID- 28675205 TI - Energetic and spectroscopic properties of the low-lying C7H2 isomers: a high level ab initio perspective. AB - We use high-level ab initio CCSD(T) and CCSDT(Q) methods to investigate the energetic and spectroscopic properties of nine low-lying isomers of C7H2, which lie within 1 eV. Among these, heptatriynylidene (1), 1-(buta-1,3 diynyl)cyclopropenylidene (2) and heptahexaenylidene (9) have been detected experimentally. The other six isomers, 1,2-(diethynyl)cyclopropenylidene (3), bicyclo[4.1.0]hepta-1,2,4,5-tetraene-7-ylidene (4), cyclohepta-1,2,3,4-tetraen-6 yne (5), bicyclo[4.1.0]hepta-4,6-diene-2-yne-7-ylidene (6), bicyclo[4.1.0]hepta 1,5-diene-3-yne-7-ylidene (7) and 1-(buta-1,3-diynyl)propadienylidene (8), remain hypothetical to date. Except for 1, all of the isomers are associated with a non zero dipole moment (MU? 0). Although Fourier-transform microwave spectroscopy had detected 2 and 9, our study reveals that six hypothetical isomers (3-8) are thermodynamically sandwiched between the experimentally known and astronomically relevant isomers 2 and 9. The structural parameters, dipole moments, rotational and centrifugal distortion constants, harmonic vibrational frequencies, and infra red intensities presented here may be useful for the laboratory detection of these previously unidentified isomers (3-8) and also all others (2-9) in astronomical sources. PMID- 28675206 TI - The fabrication and application of magnetite coated N-doped carbon microtubes hybrid nanomaterials with sandwich structures. AB - In this work, N-doped carbon microtubes have been synthesized using MoO3 microrods as the sacrificial template. Then, the Fe3O4 nanoparticles were integrated into N-doped carbon microtubes to obtain triple-walled Fe3O4@N-doped carbon@Fe3O4 microtubes via a high temperature decomposition process. Due to the coordination ability of nitrogen and the unique structures of the N-doped carbon microtubes, the Fe3O4 nanoparticles were closely attached to both the external and internal surfaces of the N-doped carbon microtubes and thus, assured a relatively good response to an external magnetic field. All these features make the nanocomposites well fitted for adsorption, catalysis, energy storage etc. Moreover, the N-doped carbon microtubes can be used as versatile templates to synthesize other triple-walled composites M@N-doped carbon@M microtubes (such as M = Cu(Cu2O), MnO2, MoS2), which greatly widens the applications of N-doped carbon microtubes. PMID- 28675207 TI - Spectrally-resolved third-harmonic generation and the fundamental role of O-HCl hydrogen bonding in Oh, Td-cobalt(ii) tetraphenylmethane-based coordination polymers. AB - The reaction of a phosphonate-diester tetraphenylmethane-based tecton, tetrakis[4 (diethoxyphosphoryl)phenyl]methane, (L) with cobalt(ii) chloride afforded a centrosymmetric coordination polymer (CP), [L.2Co(H2O)42+.2CoCl42-]n, 2-Cl, possessing simultaneously octahedral (Oh) and tetrahedral (Td) metal centers. This material served as a model compound for the demonstration of factors influencing the spectral dependence of one of the nonlinear optical (NLO) phenomena, the third-harmonic generation (THG). The spectrally-resolved THG (SR THG) measurements in the range from 1125 to 1750 nm revealed that a maximum of THG response is obtained when the fundamental beam is around 1300 nm. The SR-THG study was combined with an analysis of the self-absorption effects of pumping and of third-harmonic radiation; based on these results, we put forward a hypothesis that the THG action spectrum is influenced more by the ability of the material to self-absorb the third harmonic rather than by the extent of self-absorption of the pumping radiation. Apart from investigations of NLO properties, we have explored coordination and particularly the supramolecular interactions that build up the 2-Cl CP. Despite the tetrahedral, spatial shape of the ligand L, CP 2-Cl has a two-dimensional net. The structure was found to be strongly supported by O HCl hydrogen bonds, since each CoCl42- complex anion is an acceptor of eight of such interactions within a distorted square grid layer of cobalt(ii) ions. While coordination and hydrogen-bonded nets are both featuring the sql topology when treated separately, the consideration of both of them as topological paths yields a trinodal 4,4,6-connected net, described by the point symbol (42.84)(45.6)2(46.66.83)2. SR-THG and structural studies of 2-Cl have been also supported by far- and mid-infrared spectroscopy, UV-Vis-NIR solid state absorption analysis, thermogravimetry and preliminary magnetic characterization. PMID- 28675208 TI - Novel bifunctional DATA chelator for quick access to site-directed PET 68Ga radiotracers: preclinical proof-of-principle with [Tyr3]octreotide. AB - Molecular imaging of tumors with the PET radionuclide 68Ga has gained momentum in clinical oncology due to the expanding availability of commercial 68Ge/68Ga generators in combination with state-of-the-art PET/CT and PET/MRI hybrid imaging systems. Concurrently, interesting peptide-based or small-size vectors have been developed for theranostic use in cancer patients. Owing to the short half-life of 68Ga (t1/2 = 67.7 min) and the sensitivity of many targeting biomolecules, labeling and kit reconstitution in mild conditions allowing for quick access to ready-for-injection PET-tracers are highly desirable. The novel DATA ((6 pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate) chelator previously showing promising qualities for kit type labeling, was coupled to TOC ([Tyr3]octreotide). We herein report results from a first proof-of-principle study directly comparing 67Ga-DATA-TOC with the well-established 67Ga-DOTA-TOC in a series of preclinical models. Both analogs were shown to be sst2-preferring and specifically internalized in AR42J and HEK293-hsst2 cells, with 67Ga-DOTA-TOC internalizing faster in both cell lines. Similarly, after injection in mice bearing either AR42J or HEK293-hsst2 tumors, both tracers efficiently and specifically localized in the implants. Whereas 67Ga-DOTA-TOC exhibited higher tumor values, 67Ga-DATA-TOC cleared faster from background tissues. These findings support the suitability of the newly introduced bifunctional chelator DATA as a reliable, quick and convenient means for labeling medically relevant vectors with the PET radiometal 68Ga. PMID- 28675210 TI - Magnetic field-induced enhancement of the nitrogen-vacancy fluorescence quantum yield. AB - The nitrogen-vacancy (NV) centre in diamond is a unique optical defect that is used in many applications today and methods to enhance its fluorescence brightness are highly sought after. We observed experimentally an enhancement of the NV quantum yield by up to 7% in bulk diamond caused by an external magnetic field relative to the field-free case. This observation is rationalised phenomenologically in terms of a magnetic field dependence of the NV excited state triplet-to-singlet transition rate. The theoretical model is in good qualitative agreement with the experimental results at low excitation intensities. Our results significantly contribute to our fundamental understanding of the photophysical properties of the NV defect in diamond. PMID- 28675211 TI - Mechanistic insights into the photocatalytic properties of metal nanocluster/graphene ensembles. Examining the role of visible light in the reduction of 4-nitrophenol. AB - Metal nanoclusters (MNCs) based on silver and gold, abbreviated as AgNCs and AuNCs, respectively, were synthesized and combined with functionalized graphene, abbreviated as f-G, forming novel MNC/f-G ensembles. The preparation of MNCs/f-G was achieved by employing attractive electrostatic interactions developed between negatively charged MNCs, attributed to the presence of carboxylates due to alpha lipoic acid employed as a stabilizer, and positively charged f-G, attributed to the presence of ammonium units as addends. The realization of MNC/f-G ensembles was established via titration assays as evidenced by electronic absorption and photoluminescence spectroscopy as well as scanning transmission electron microscopy (STEM) and energy-dispersive X-ray (EDX) spectroscopy analyses. Photoinduced charge-transfer phenomena were inferred within MNCs/f-G, attributed to the suppression of MNC photoluminescence by the presence of f-G. Next, the MNC/f-G ensembles were successfully employed as proficient catalysts for the model reduction of 4-nitrophenol to the corresponding 4-aminophenol as proof for the photoinduced hydrogen production. Particularly, the reduction kinetics decelerated by half when bare MNCs were employed vs. the MNC/f-G ensembles, highlighting the beneficial role of MNCs/f-G in catalysing the process. Furthermore, AuNCs/f-G displayed exceptionally higher catalytic activity both in the dark and under visible light illumination conditions, which is ascribed to three synergistic mechanisms, namely, (a) hydride transfer from Au-H, (b) hydride transfer from photogenerated Au-H species, and (c) hydrogen produced by the photoreduction of water. Finally, recycling and re-employing MNCs/f-G in successive catalytic cycles without loss of activity toward the reduction of 4 nitrophenol was achieved, thereby highlighting their wider applicability. PMID- 28675212 TI - Enzymatic self-assembly of an immunoreceptor tyrosine-based inhibitory motif (ITIM). AB - Here we show the first example of an immunoreceptor tyrosine-based inhibitory motif (ITIM), LYYYYL, as well as its enantiomeric or retro-inverso peptide, to self-assemble in water via enzyme-instructed self-assembly. Upon enzymatic dephosphorylation, the phosphohexapeptides become hexapeptides, which self assemble in water to result in supramolecular hydrogels. This work illustrates a new approach to design bioinspired soft materials from a less explored, but important pool of immunomodulatory peptides. PMID- 28675213 TI - Catching the chloride: searching for non-Hofmeister selectivity behavior in systematically varied polyamide macrocyclic receptors. AB - The binding selectivity of structurally simple anion receptors is governed by the Hofmeister series (SO42- > HPO42- > carboxylates ~ H2PO4- > HCO3- > Cl-), and exceptions to this rule are rare and require utilization of structurally sophisticated receptors. In this paper we examined a set of 48 structurally diverse anion receptors, barely one fourth of which exhibit selectivity for chloride over more basic dihydrogen phosphate (H2PO4-) or carboxylates (MeCO2- and PhCO2-). Searching for regularities in the properties of these mainly macrocyclic-derived receptors across quite systematic changes in structure, combined with analysis of multiple crystal structures, allowed us to identify the crucial structural features that are likely required for the occurrence of the phenomenon of selective chloride binding. Examination of a subset of other 'case study' receptors reported in the literature as being particularly chloride selective served as a confirmation of our hypotheses. As such, our findings are valid for all artificial receptors with exceptional selectivity for chloride, as well as for natural chloride channel proteins (ClC). PMID- 28675215 TI - Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases. AB - Copper is a trace element essential for almost all living organisms. But the level of intracellular copper needs to be tightly regulated. Dysregulation of cellular copper homeostasis leading to various diseases demonstrates the importance of this tight regulation. Copper homeostasis is regulated not only within the cell but also within individual intracellular compartments. Inactivation of export machinery results in excess copper being redistributed into various intracellular organelles. Recent evidence suggests the involvement of glutathione in playing an important role in regulating copper entry and intracellular copper homeostasis. Therefore interplay of both homeostases might play an important role within the cell. Similar to copper, glutathione balance is tightly regulated within individual cellular compartments. This review explores the existing literature on the role of glutathione in regulating cellular copper homeostasis. On the one hand, interplay of glutathione and copper homeostasis performs an important role in normal physiological processes, for example neuronal differentiation. On the other hand, perturbation of the interplay might play a key role in the pathogenesis of copper homeostasis disorders. PMID- 28675217 TI - G2-S16 dendrimer as a candidate for a microbicide to prevent HIV-1 infection in women. AB - Unprotected heterosexual intercourse is the first route for sustaining the global spread of human immunodeficiency virus type 1 (HIV-1), being responsible for 80% of new HIV-1 infections in the world. The presence of inflammation in the female reproductive tract and the presence of semen increases the risk of heterosexual HIV-1 transmission. This state-of-the-art research based on an innovative nanotechnology design was focused on a toxicological study of the limitation of the activity of the novel H2O-soluble anionic carbosilane dendrimer G2-S16 in the adult cervical and foreskin epithelia. The G2-S16 dendrimer did not cause any irritation or inflammation in the vaginal epithelium, proving that this dendrimer is a safe nanocompound for vaginal application to control viral transmission. It was shown that no significant differences were found in mortality, sublethal or teratogenic effects when the zebra fish embryos were treated with G2-S16. In short, G2-S16 seems to be an ideal candidate for the development of a topical microbicide against HIV-1 infection and the next step is try in clinical trials, because of its great in vivo biocompatibility, as well as its ability to halt HIV 1 infection in the presence of semen. PMID- 28675218 TI - Multi-layer transfer and lamination (MTL) process assisted by a high-pressure air jet for highly efficient solution-processed polymer light emitting diodes. AB - This research reports fabrication of highly efficient polymer light-emitting diodes (PLEDs) by a thermally activated multi-layer transfer and lamination (MTL) process. As the first stage of the fabrication process, multiple layers consisting of a light-emitting polymer, electron transport/electron injection layer and metal cathode were sequentially deposited onto a hydrophobic low surface energy self-assembled monolayer (SAM)-coated glass substrate. Subsequently, a very rapid delamination of PLEDs multi-layers from the SAM-coated glass was achieved by applying a high-pressure air jet. The custom air jet system ensures the excellent multi-film quality and also prevents the occurrence of common buckling and cracks. In addition, the adhesiveness of polyamide (PA) onto polyethylene terephthalate (PET), which serves as a protective barrier from atmospheric water and oxygen, is thermally activated by heating PA above its glass transition temperature. Finally, once delaminated from the PA/PET, the multi-layer structure (light-emitting polymer/electron transport layer/electron injection layer/metal cathode) was successfully laminated onto the target glass (hole transport layer/transparent anode) with a soft roller under mild pressure for the realization of the PLED device. The maximum brightness of the device fabricated by a thermally activated lamination process was around 13 120 cd m-2 at 8.4 V, whereas the maximum current efficiency and the power efficiency were 5.2 cd A-1 and 4.0 lm W-1, respectively. PMID- 28675216 TI - Comparative studies on the therapeutic benefit of targeted alpha-particle radiation therapy for the treatment of disseminated intraperitoneal disease. AB - Identification of the appropriate combination of radionuclide, target and targeting vehicle is critical for successful radioimmunotherapy. For the treatment of disseminated peritoneal diseases such as pancreatic or ovarian cancer, alpha-emitting radionuclides have been proposed for targeted radiation therapy. This laboratory has taken a systematic approach investigating targeted alpha-radiation therapy, allowing comparisons to now be made between 211At, 227Th, 213Bi and 212Pb. Herein, trastuzumab radiolabeled with 211At and 227Th was evaluated for therapeutic efficacy in the LS-174T i.p. tumor model. A dose escalation study was conducted with each radioimmunoconjugate (RIC). Therapeutic benefit was realized with 211At-trastuzumab with doses of 20, 30 and 40 MUCi. At doses >40 MUCi, toxicity was observed with greater weight loss and 2-fold higher decrease in the platelet counts. Following a second study comparing the effect of 20, 30 and 40 MUCi of 211At-trastuzumab, 30 MUCi was selected as the dose for future studies. A parallel study was performed evaluating 0.25, 0.5, 1.0, 2.0 and 5.0 MUCi of 227Th-trastuzumab. The 0.5 and 1.0 MUCi injected dose resulted in a therapeutic response; a lower degree of weight loss was experienced by the mice in the 0.5 MUCi cohort. When the data is normalized for comparing 211At, 227Th, 213Bi and 212Pb, the choice of radionuclide for RIT is perhaps not entirely based on simple therapeutic efficacy, other factors may play a role in choosing the "right" radionuclide. PMID- 28675219 TI - Fluorine-containing bistolanes as light-emitting liquid crystalline molecules. AB - We synthesised a series of dissymmetric bistolane derivatives and evaluated their liquid-crystalline (LC) and photoluminescence properties in detail. In measuring LC behaviours, rational structural design based on the dissymmetric molecular structure and electron-density distribution facilitated the production of the LC phase with a wide temperature range (up to 97 degrees C). In addition, dissymmetric bistolane derivatives were shown to strongly emit blue photoluminescence in dilute solution and in crystalline states. It was found that dissymmetric bistolanes possess emissive features in even the LC phase and photoluminescence behaviours such as emission intensity and colour were sensitively switched depending on the molecular aggregate structure caused by applying a thermal stimulus. PMID- 28675220 TI - Mechanism of mechanically induced optoelectronic and spintronic phase transitions in 1D graphene spirals: insight into the role of interlayer coupling. AB - Graphene spirals (GSs), an emerging carbonic nano-material with a Riemann surface, demonstrate extraordinary topological electronic signatures: interlayer coupling similar to van der Waals (vdW) heterojunctions and intralayer coupling within the spiral conformation. Based on the state-of-the-art first-principles technique, the electronic properties of the periphery-modified GSs with geometry deformation are explored under axial strain. For all GSs, there emerges a remarkable phase transition from metal to semiconductor, due to the attenuation of interlayer "sigma-bonds" reducing the interlayer tunneling probability for carriers. Analogous to graphene, GSs consist of bipartite sublattices with carbonic sp2 hybridization as well. Once the balance of the bipartite sublattices is lost, there will emerge intense edge (corner) states, contributed by the pz orbitals. In contrast to isolated graphene nanoflakes, GSs realize the continuous spin-polarized edge (corner) state coupling with 1D morphology. However, the spin polarization is blocked by the robust interlayer "sigma-bonds" so that the spintronic transition takes place until this interlayer coupling is broken. More intriguingly, an indirect-direct bandgap transition is observed, revealing excellent optical on-off features. Their tunable properties provide great potential for their application in optoelectronics, spintronics and chemical or biological sensors. PMID- 28675221 TI - Platinum(ii) photo-catalysis for highly selective difluoroalkylation reactions. AB - The platinum(ii) photo-catalyzed difluoroalkylation of cinnamic acids and alkynes for selective construction of E-,Z-difluoroalkyl alkenes and difluoroalkyl alkenyl iodides, respectively, were achieved under mild conditions. The high efficiency, good substrate scope and high selectivity altogether highlight the prospect of Pt(ii) photocatalysts in visible-light-driven organic transformation reactions. PMID- 28675222 TI - The memristive effect as a novelty in drug monitoring. AB - Nanoscale devices exhibiting memristive properties show great potential in a plethora of applications. In this work, memristive nanowires are presented for the first time as ideal candidates for absolutely novel, ultrasensitive, highly specific and selective drug-biosensors, also paving the way for real-time monitoring applications, in coupling with the restoration properties of DNA aptamers. The hysteretic properties exhibited by the hereby-presented special nanodevices, modified via surface treatments, are leveraged along the complete cycle consisting of DNA-aptamer immobilization, target binding, and DNA-aptamer regeneration for successful and effective detection of Tenofovir, an antiviral drug for HIV treatment, in buffer as well as in non-diluted human serum. This results in ultrasensitive, label-free monitoring of the therapeutic compound with a limit of detection of 3.09 pM in buffer and 1.38 nM in full serum. These LODs demonstrate 10 times higher sensitivity for the in-buffer drug detection, and twice better performance for drug sensing in full human serum, ever obtained. The selectivity of the memristive biosensor for Tenofovir detection was verified through both positive and negative controls in full human serum. In addition, the DNA-aptamer regeneration character is portrayed for the first time through a memristive effect, and scanning electron microscopy throws more light on the binding mechanism efficiency through the variation of the nanodevice surface properties at the nanoscale.The results presented in this work demonstrate that the coupling of the memristive effect and aptamer regeneration provides the best ever realized nano-biosensor for drug detection also in full human serum. PMID- 28675223 TI - Carbon nanowalls: a new versatile graphene based interface for the laser desorption/ionization-mass spectrometry detection of small compounds in real samples. AB - Carbon nanowalls, vertically aligned graphene nanosheets, attract attention owing to their tunable band gap, high conductivity, high mechanical robustness, high optical absorbance and other remarkable properties. In this paper, we report for the first time the use of hydrophobic boron-doped carbon nanowalls (CNWs) for laser desorption/ionization of small compounds and their subsequent detection by mass spectrometry (LDI-MS). The proposed method offers sensitive detection of various small molecules in the absence of an organic matrix. The CNWs were grown by microwave plasma enhanced chemical vapor deposition (MW-PECVD), using a boron carbon gas flow ratio of 1200 in H2/CH4 plasma, on silicon <100> wafer. The hydrophobicity of the surface offers a straightforward MS sample deposition, consisting of drop casting solutions of analytes and drying in air. Limits of detection in the picomolar and femtomolar ranges (25 fmol MUL-1 for neurotensin) were achieved for different types of compounds (fatty acids, lipids, metabolites, saccharides and peptides) having clinical or food industry applications. This rapid and sensitive procedure can also be used for quantitative measurements without internal standards with RSDs <19%, as in the case of glucose in aqueous solutions (LOD = 0.32 +/- 0.02 pmol), blood serum or soft drinks. Moreover, melamine (63 +/- 8.19 ng MUL-1), a toxic compound, together with creatinine and paracetamol, was detected in urine samples, while lecithin was detected in food supplements. PMID- 28675224 TI - Correction: A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding. AB - Correction for 'A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding' by Jie Hu et al., Phys. Chem. Chem. Phys., 2017, 19, 13629-13639. PMID- 28675225 TI - Synthesis and characterization of rhenium(iii) complexes with (Ph2PCH2CH2)2NR diphosphinoamine ligands. AB - The synthesis and characterization of a new series of neutral, six-coordinated compounds [ReIIIX3(PNPR)], where X is Cl or Br and PNPR is a diphosphinoamine having the general formula (Ph2PCH2CH2)2NR (R = H, CH3, CH2CH3, CH2CH2CH3, CH2CH2CH2CH3 and CH2CH2OCH3) are reported. Stable [ReIIIX3(PNPR)] complexes were synthesized, in variable yields, starting from precursors where the metal was in different oxidation states (iii and v), by ligand-exchange and/or redox substitution reactions. The compounds were characterized by elemental analysis, proton NMR spectroscopy, cyclic voltammetry, UV/vis spectroscopy, positive-ion electrospray ionization mass spectrometry (ESI(+)-MS) and X-ray diffraction analysis. Although the formulation of the complexes allows either meridional or facial isomers, the latter arrangement was prevalent both in the solid and solution states. Only [ReCl3(PNPH)] showed a meridional configuration both in solution and in the crystalline state. [ReBr3(PNPme)] prefers the meridional configuration in the crystalline state and the facial one in solution. While ESI(+)-MS and voltammetric data seem to indicate some dependency from the nature of the alkyl substituent at the nitrogen, the available structural data of the complexes show only slight differences both for angles and bond lengths upon change of the alkyl chain tethered to the nitrogen. PMID- 28675226 TI - Effects of annealing atmosphere and rGO concentration on the optical properties and enhanced photocatalytic performance of SnSe/rGO nanocomposites. AB - The photocatalytic properties of SnSe nanostructures (NSs) and SnSe/graphene nanocomposites with different graphene concentrations (5, 10, and 15 wt%/v) were investigated. The products were synthesized by a simple and cost-effective co precipitation method. The samples obtained demonstrated that graphene concentration at an optimum amount was an important factor in enhancing the photocatalytic performance of the products. The graphene source was graphene oxide (GO) sheets and several characterization results indicated, which were used to remove Methylene blue (MB) dye, that the GO sheets were changed into reduced graphene oxide (rGO) sheets during the synthesis process. The optical properties of the products were studied using a room temperature photoluminescence (PL) spectrometer and it was observed that the near-band-edge (NBE) position of the samples was at the end of the red region between 729 and 756 nm of the electromagnetic spectrum, which was confirmed by a UV-vis spectrometer. The PL spectra of the samples also demonstrated three emissions from the violet, green, and orange regions of the visible spectrum, which were from different defects. The samples were annealed in a hydrogen and air atmosphere at 300 degrees C and it was found that defect concentrations were increased by annealing for the SnSe/rGO nanocomposites. The photocatalyst studies of the post-annealed samples revealed that the photocatalytic performance of the products was enhanced by annealing in hydrogen, while it was reduced by annealing in air. In addition to MB, the photocatalytic performance of the products for the degradation of phenol as a colorless pollutant was examined. It was observed that rGO in this process also had a significant role in the enhancement of photocatalytic performance. In fact, the electron spin resonance (ESR) test showed the role of rGO in photocatalytic activity very well. PMID- 28675227 TI - Synthesis and interconversions of reduced, alkali-metal supported iron-sulfur carbonyl complexes. AB - We report the synthesis, interconversions and X-ray structures of a set of [mFe nS]-type carbonyl clusters (where S = S2-, S22- or RS-; m = 2-3; n = 1-2). All of the clusters have been identified and characterized by single crystal X-ray diffraction, IR and 13C NMR. Reduction of the parent neutral dimer [MU2 (SPh)2Fe2(CO)6] (1) with KC8 affords an easily separable ~1 : 1 mixture of the anionic, dimeric thiolate dimer K[Fe2(SPh)(CO)6(MU-CO)] (2) and the dianionic, sulfido trimer [K(benzo-15-crown-5)2]2[Fe3(MU3-S)(CO)9] (3). Oxidation of 2 with diphenyl-disulfide (Ph2S2) cleanly returns the starting material 1. The Ph-S bond in 1 can be cleaved to form sulfide trimer 3. Oxidation of sulfido trimer 3 with [Fc](PF6) in the presence of S8 cleanly affords the all-inorganic persulfide dimer [MU2-(S)2Fe2(CO)6] (4), a thermodynamically stable product. The inverse reactions to form 3 (dianion) from 4 (neutral) were not successful, and other products were obtained. For example, reduction of 4 with KC8 afforded the mixed valence Fe(i)/Fe(ii) species [((FeS2)(CO)6)2FeII]2- (5), in which the two {Fe2S2(CO)6}2- units serve as bidendate ligands to a Fe(ii) center. Another isolated product (THF insoluble portion) was recrystallized in MeCN to afford [K(benzo-15-crown-5)2]2[((Fe2S)(CO)6)2(MU-S)2] (6), in which a persulfide dianion bridges two {2Fe-S} moieties (dimer of dimers). Finally, to close the interconversion loop, we converted the persulfide dimer 4 into the thiolate dimer 1 by reduction with KC8 followed by reaction with the diphenyl iodonium salt [Ph2I](PF6), in modest yield. These reactions underscore the thermodynamic stability of the dimers 1 and 4, as well as the synthetic and crystallization versatility of using the crown/K+ counterion system for obtaining structural information on highly reduced iron-sulfur-carbonyl clusters. PMID- 28675228 TI - A reduced graphene oxide/covalent cobalt porphyrin framework for efficient oxygen reduction reaction. AB - A reduced graphene oxide/covalent cobalt porphyrin framework has been synthesized by using pyridine-functionalized reduced graphene oxide (G-dye) as the building block. Due to the unique 3-dimensional architecture and good electronic properties of graphene, as well as the electron accepting ability of the nitrogen atoms in the G-dye, the as-synthesized CoCOF-Py-0.05rGO catalyst exhibits excellent oxygen reduction reaction (ORR) activity with superior long-term stability and methanol tolerance. PMID- 28675229 TI - Oxidative coupling of Michael acceptors with aryl nucleophiles produced through rhodium-catalyzed C-C bond activation. AB - Utilizing rhodium catalysis, aryl nucleophiles generated via carbon-carbon single bond activation successfully undergo oxidative coupling with Michael acceptors. The reaction scope encompasses a broad range of nucleophiles generated from quinolinyl ketones as well as a series of electron deficient terminal alkenes, illustrating the broad potential of intersecting carbon-carbon bond activation with synthetically useful coupling methodologies. The demonstrated oxidative coupling produces a range of cinnamyl derivatives, several of which are challenging to prepare via conventional routes. PMID- 28675231 TI - Effect of ligand sequence-specific modification on DNA hybrid catalysis. AB - Development of a stereoselective asymmetric catalytic system with high conversion is the key to success for acquiring chiral materials. In recent years, DNA hybrid catalysts have attracted significant interest due to their excellent abilities in accelerating reactions and achieving high enantioselectivity. We report here that bipyridine linked with polyamide as a sequence-specific catalytic ligand was designed to perform a DNA hybrid asymmetric reaction. The products presented different stereoselectivities compared to the results of reactions catalyzed by bipyridine. Comparing catalytic experiments based on alternative oligonucleotides verified that sequence-locating of the ligand affected the catalytic microenvironment. Circular dichroism spectra, combined with singular value decomposition, proposed that different binding modes could exist somewhere between the ligand and alternative sequences. The current work provides a strategy to extend the chemical range of DNA-based catalysis. PMID- 28675230 TI - One-pot synthesis of nanochain particles for targeting brain tumors. AB - To synthesize multi-component nanochains, we developed a simple 'one-pot' synthesis, which exhibited high yield and consistency. The nanochains particles consist of parent nanospheres chemically linked into a higher-order, chain-like assembly. The one-pot synthesis is based on the addition of two types of parent nanospheres in terms of their surface chemical functionality (e.g., decorated with PEG-NH2 or PEG-COOH). By reacting the two types of parent nanospheres at a specific ratio (~2 : 1) for a short period of time (~30 min) under rigorous stirring, nanochains were formed. For example, we show the synthesis of iron oxide nanochains with lengths of about 125 nm consisting of 3-5 constituting nanospheres. The chain-like shaped nanoparticle possessed a unique ability to target and rapidly deposit on the endothelium of glioma sites via vascular targeting. To target and image invasive brain tumors, we used iron oxide nanochains with the targeting ligand being the fibronectin-targeting peptide CREKA. Overexpression of fibronectin is strongly associated with the perivascular regions of glioblastoma multiforme and plays a critical role in migrating and invasive glioma cells. In mice with invasive glioma tumors, 3.7% of the injected CREKA-targeted nanochains was found in gliomas within 1 h. Notably, the intratumoral deposition of the nanochain was ~2.6-fold higher than its spherical variant. Using MR imaging, the precise targeting of nanochains to gliomas provided images with the exact topology of the disease including their margin of infiltrating edges and distant invasive sites. PMID- 28675233 TI - Integrated sudomotor axon reflex sweat stimulation for continuous sweat analyte analysis with individuals at rest. AB - Eccrine sweat has rapidly emerged as a non-invasive, ergonomic, and rich source of chemical analytes with numerous technological demonstrations now showing the ability for continuous electrochemical sensing. However, beyond active perspirers (athletes, workers, etc.), continuous sweat access in individuals at rest has hindered the advancement of both sweat sensing science and technology. Reported here is integration of sudomotor axon reflex sweat stimulation for continuous wearable sweat analyte analysis, including the ability for side-by-side integration of chemical stimulants & sensors without cross-contamination. This integration approach is uniquely compatible with sensors which consume the analyte (enzymatic) or sensors which equilibrate with analyte concentrations. In vivo validation is performed using iontophoretic delivery of carbachol with ion selective and impedance sensors for sweat analysis. Carbachol has shown prolonged sweat stimulation in directly stimulated regions for five hours or longer. This work represents a significant leap forward in sweat sensing technology, and may be of broader interest to those interested in on-skin sensing integrated with drug-delivery. PMID- 28675234 TI - Selective turn-on fluorescence sensing of sulfate in aqueous-organic mixtures by an uncharged bis(diamidocarbazole) receptor. AB - A linear, uncharged, hydrogen bonding receptor A with two carbazole-based binding domains was synthesised and evaluated for its anion binding properties in DMSO/H2O mixtures. 1H NMR titrations revealed that, in DMSO/H2O 0.5%, A forms both 1 : 1 and 1 : 2 complexes with SO42-, H2PO4-, PhCOO- and Cl-. In 1 : 1 complexes the receptor encloses the tetrahedral anions tightly, forming a helical structure, while Cl- binds with a single carbazole unit only. In the presence of 10% of water the 1 : 2 complexes with SO42- and PhCOO- disappear, and the respective 1 : 1 binding constants decrease sufficiently to be quantified by UV Vis titration. In this highly competitive medium, A binds sulfate with K1:1 = 105.47 M-1, i.e., it binds approx. 30, 360 and >1000 times more strongly than H2PO4-, PhCOO- and Cl-, respectively. Furthermore, the association with sulfate is over 50 times stronger than that for a model diamidocarbazole 1 under identical conditions, suggesting a very strong chelating effect due to the diglycoyl linker. Increasing the amount of water to 25% (the solubility limit of A) lowers the 1 : 1 binding constant with SO42- to 103.73 M-1. Receptor A was shown to act as a selective turn-on fluorescent sensor for sulfate, able to sense sulfate in sulfate-rich mineral water. PMID- 28675235 TI - Hot-electron transfer from the semiconductor domain to the metal domain in CdSe@CdS{Au} nano-heterostructures. AB - Semiconductor-metal hybrid nanostructures are recognized as great materials due to their high level of light-induced charge separation, which has direct relevance in photocatalysis and solar energy conversion. To understand the mechanism of charge separation processes, hybrid CdSe@CdS{Au} nano heterostructures containing Au nanoparticles (NPs) with different sizes were synthesized, and the ultrafast charge-transfer dynamics were monitored using femtosecond transient absorption spectroscopy. Steady-state optical absorption studies suggest the formation of charge-transfer complexes between core shell nanocrystals (NCs) and Au NPs. Steady-state and time-resolved luminescence spectroscopy suggest electron transfer from the photo-excited CdSe@CdS core shell QDs NCs to the Au NPs within the heterostructure. The ultrafast interfacial electron-transfer dynamics in the heterostructures were monitored by femtosecond transient absorption spectroscopy. The results revealed that both hot and thermalized electrons are transferred from the core shell QDs to the metal NPs with time constants of 150 and 300 fs, respectively. Hot-electron transfer from QDs to Au NPs was found to take place predominantly in the heterostructures depending on the sizes of the metal NPs. The photo-degradation of rhodamin B in the presence of the CdSe@CdS{Au} heterostructures under visible-light radiation suggests that the hot electrons in the heterostructures play a major role in photocatalytic degradation. PMID- 28675236 TI - Extremely permeable porous graphene with high H2/CO2 separation ability achieved by graphene surface rejection. AB - Fabrication of a graphene separation sheet is difficult because of the necessity for leakage-free graphene transfer onto a substrate. In this study, porous graphene sheets with thicknesses of one, two, and four layers were directly fabricated on stainless-steel mesh substrates and demonstrated to display high separation ability for H2, CO2, and CH4. The single-layer graphene sample exhibited higher permeance for these molecules than double- and four-layer graphene and displayed similar high selectivity to that of other porous materials. Permeance was proportional to molecular velocity and inversely proportional to interaction strength with graphene; molecular size-dependent permeance was not seen. Molecules that interacted strongly with graphene were attracted to the graphene surface, which hindered permeation. Such graphene surface rejection allowed graphene containing larger pores than the molecular size to provide both high molecular permeance and selectivity. The relationship between the permeance of porous graphene for H2 and H2/CO2 with selectivity suggested that its permeance was higher than that of other materials with high separation performance. Therefore, the porous graphene samples separated molecules with extremely high permeance by graphene surface rejection. PMID- 28675237 TI - Ursolic acid induces mitochondrial biogenesis through the activation of AMPK and PGC-1 in C2C12 myotubes: a possible mechanism underlying its beneficial effect on exercise endurance. AB - Mitochondrial biogenesis, which involves an increase in mitochondrial number and the overall capacity of oxidative phosphorylation, is a critical determinant of skeletal muscle function. Recent findings have shown that some natural products can enhance mitochondrial adaptation to aerobic exercise, which in turn improves exercise performance, presumably by delaying muscle fatigue. Ursolic acid (UA), a natural triterpene, is commonly found in various vegetables and fruits. In the current study, UA was shown to increase mitochondrial mass and ATP generation capacity, with a concomitant production of a low level of mitochondrial reactive oxygen species (ROS) in C2C12 myotubes. Mitochondrial ROS, in turn, activated the redox sensitive adenosine monophosphate-dependent protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1) pathway. The activation of AMPK/PGC-1 further increased the expression of cytochrome c oxidase (COX) and uncoupling protein 3. Animal studies showed that UA can also dose-dependently increase the endurance exercise capacity in mice, as assessed by a weight-loaded swimming test and a hanging wire test. Our findings suggest that UA may induce mitochondrial biogenesis through the activation of AMPK and PGC-1 pathways in skeletal muscle, thereby offering a promising prospect for its use to enhance exercise endurance and alleviating fatigue in humans. PMID- 28675238 TI - Indirect photodegradation of the lampricides TFM and niclosamide. AB - 3-Trifluromethyl-4-nitrophenol (TFM) and 2',5-dichloro-4'-nitrosalicylanilide (niclosamide) are lampricides used in tributaries of the Great Lakes to kill the invasive parasitic sea lamprey (Petromyzon marinus). Although the lampricides have been applied since the late 1950s, their photochemical behavior in natural environments is still not well understood. This study examines the indirect photodegradation of these two compounds and the resulting yields of organic and inorganic photoproducts in water samples collected from five tributaries of Lake Michigan. The tributaries were selected to span the length of Lake Michigan and its natural carbonate geologic gradient. In the presence of dissolved organic matter (DOM), the niclosamide photodegradation rate triples, while the rate of TFM photodegradation is unchanged. Additionally, the yield of lampricide organic products is influenced by DOM because many of the organic photoproducts themselves are prone to DOM-mediated indirect photodegradation. The indirect photodegradation of niclosamide is primarily mediated by reaction with singlet oxygen, which accounts for more than 50% of the increased photodegradation rate. Additionally, hydroxyl radicals and carbonate radicals (CO3-) influence niclosamide indirect photolysis, and their contribution is dependent on the specific river water chemistry. For example, CO3- contribution to niclosamide photodegradation, while small, is greater in southern tributaries where there is higher carbonate alkalinity. PMID- 28675240 TI - A multi-dielectric-layered triboelectric nanogenerator as energized by corona discharge. AB - Triboelectric nanogenerators (TENGs) have been invented recently for meeting the power requirements of small electronics and potentially solving the worldwide energy crisis. Here, we developed a vertical contact-separation mode TENG based on a novel multi-dielectric-layered (MDL) structure, which was comprised of parylene C, polyimide and SiO2 films. By using the corona discharge approach, the surface charge density was enhanced to as high as 283 MUC m-2, and especially the open-circuit voltage could be increased by a factor of 55 compared with the original value. Furthermore, the theoretical models were built to reveal the output characteristics and store the electrostatic energy of the TENG. The influences of the structural parameters and operation conditions including the effective dielectric thickness, dielectric constant, gap distance and air breakdown voltage were investigated systematically. It was found that the output performances such as the peak voltage and power density are approximately proportional to the thickness of the MDL film, but they would be restricted by the air breakdown voltage. These unique structures and models could be used to deepen the understanding of the fundamental mechanism of TENGs, and serve as an important guide for designing high performance TENGs. PMID- 28675241 TI - A chromogenic and ratiometric fluorogenic probe for rapid detection of a nerve agent simulant DCP based on a hybrid hydroxynaphthalene-hemicyanine dye. AB - A new cyanine dye (CYD) based on hybrid hydroxynaphthalene-hemicyanine has been synthesized and characterized. The chromogenic and ratiometric fluorogenic probe (CYD) enables a fast and highly sensitive response to an OP nerve agent mimic diethyl chlorophosphate (DCP) through tandem phosphorylation and intramolecular cyclization reaction within 1 min and with the detection limit as low as 18.86 nM. To our knowledge this is the first report of a hydroxyl assisted bathochromic shift in a selective chemodosimeter for DCP exhibiting a ratiometric response. TDDFT calculations were performed in order to demonstrate the electronic properties of the probe and the cyclized product. Moreover, the utility of the probe CYD for the detection of DCP in live cells, in the gas phase and in a spiked soil sample has also been demonstrated. PMID- 28675242 TI - The sigma factor SigD of Mycobacterium tuberculosis putatively enhances gene expression of the septum site determining protein under stressful environments. AB - This work examined the expression of the septum site determining gene (ssd) of Mycobacterium tuberculosis CDC1551 and its ?sigD mutant under different growing conditions. The results showed an up-regulation of ssd during stationary phase and starvation conditions, but not during in vitro dormancy, suggesting a putative role for SigD in the control of ssd expression mainly under lack-of nutrients environments. Furthermore, we elucidated a putative link between ssd expression and cell elongation of bacilli at stationary phase. In addition, a -35 sigD consensus sequence was found for the ssd promoter region, reinforcing the putative regulation of ssd by SigD, and in turn, supporting this protein role during the adaptation of M. tuberculosis to some stressful environments. PMID- 28675243 TI - Biotech innovations in the prevention of respiratory infectious diseases. AB - Acute respiratory infections place a huge burden on society in terms of disability, premature mortality, and also direct health service costs (drugs prescriptions) and the indirect costs related to lost production. Therefore, prevention of respiratory infections is an important goal for public health interventions. In this context, silver nanoparticles (AgNPs) represent an interesting perspective for research and development by virtue of their favorable antimicrobial activity against many respiratory pathogens. One of the latest innovations in the biotech field discussed in this review is the creation of a biocompatible, biogel-based nasal filter enriched with AgNPs. Compared to traditional personal protective equipment (PPE), this type of nasal filter has the advantage of combining the antibacterial and antiviral activity of AgNPs with the common filtration capacity shared by other PPEs. This dual mechanism means that AgNP-enriched nasal filters serve to reduce the infecting microbial-load and protect the lower airways, without interfering with the normal respiratory capacity (airflow-resistance <5%). Given their antimicrobial characteristics and performance, AgNP-enriched nasal filters can meet many community and occupational currently unmet needs in the prevention of airborne infectious diseases, by ensuring an excellent respiratory-comfort and a continuous day-use. PMID- 28675244 TI - A catheter-related bloodstream infection caused by Chryseobacterium indologenes successfully treated with antibiotic-lock rescue therapy. AB - We report the case of a catheter-related bloodstream infection caused by Chryseobacterium indologenes, an uncommon and multi-resistant pathogen, in a pediatric patient with a long-term vascular access device placed for chemotherapy treatment. The infection was successfully treated with ciprofloxacin antibiotic lock therapy. This is the first report on successful salvage of a long-term device colonized by multi-resistant Chryseobacterium indologenes. PMID- 28675245 TI - Plasmodium knowlesi malaria in a traveller returning from the Philippines to Italy, 2016. AB - Plasmodium knowlesi is a simian parasite responsible for most human cases of malaria in Malaysian Borneo. A timely recognition of infection is crucial because of the risk of severe disease due to the rapid increase in parasitemia. We report a case of P. knowlesi infection in a traveller who developed fever and thrombocytopenia after returning from the Philippines in 2016. Rapid antigen test was negative, microscopy examination showed parasites similar to Plasmodium malariae, with a parasite count of 10,000 parasites per MUL blood, while molecular testing identified P. knowlesi infection. Treatment with atovaquone proguanil led to resolution of fever and restoration of platelet count in two days. P. knowlesi infection should be suspected in febrile travellers returning from South East Asia. Due to the low sensitivity of rapid antigen tests and the low specificity of microscopy, confirmation by molecular tests is recommended. PMID- 28675246 TI - Clinical and in vitro efficacy of colistin plus vancomycin and rifampin against colistin-resistant Acinetobacter baumannii causing ventilator-associated pneumonia. AB - We present the case of a patient with ventilator-associated pneumonia (VAP) caused by a pan-resistant Acinetobacter baumannii successfully treated with the combination colistin plus vancomycin plus rifampin, whose in vitro activity was investigated by checkerboard method and killing testing. Furthermore, the serum bactericidal activity (SBA) was assessed. Our case shows that an innovative regimen consisting of colistin plus antimicrobials active only against Gram positive microorganisms might represent a valid therapeutic option for severe infections caused by colistin-resistant A. baumannii. PMID- 28675247 TI - Protection by humoral elements independent of virus neutralization activity against an influenza virus challenge. AB - To investigate the protective efficacy of a seasonal trivalent inactivated whole virion influenza vaccine (TIV) adjuvanted with aluminum phosphate (Fluval AB, referred to here as TIV+Al), we immunized mice with the TIV+Al, and as controls, with TIV, TIV+Al combined with Freund adjuvant (TIV+Al+F), inactivated A/PR/8/34(H1N1) (PR8) strain or PBS, and challenged them with a lethal dose of a mouse-adapted PR8 virus. Serum pools from immunized mice were passively transferred to recipient mice that were then challenged similarly. All actively immunized mice survived the challenge. Of recipient mice receiving serum from mice actively immunized with TIV, TIV+Al or TIV+Al+F, 20%, 80%, and 100% survived, respectively. Rates of mortality and morbidity of recipient mice were inversely proportional to the hemagglutination inhibition (HI) antibody level to the vaccine virus in the absence of detectable PR8-specific HI, neuraminidase inhibition (NI) and virus neutralization (VN) antibodies. No cross-reactivity was observed between vaccine and PR8 strains in in vitro HI, NI or VN assays. In splenocytes from TIV+Al-immunized mice production of IFN-gamma or granzyme-B protein and mRNA expression increased (p<0.05). Thus, antibodies play a major role in the protection against a mismatched challenge infection independent of HI, NI and VN activity, but cellular immune responses may contribute to full protection in actively immunized mice. PMID- 28675248 TI - Quick bacteriophage-mediated bioluminescence assay for detecting Staphylococcus spp. in sonicate fluid of orthopaedic artificial joints. AB - Staphylococcus spp. accounts for up to two thirds of all microorganisms causing prosthetic joint infections, with Staphylococcus aureus and Staphylococcus epidermidis being the major cause. The present study describes a diagnostic model to detect staphylococci using a specific bacteriophage and bioluminescence detection, exploring the possibility of its use on sonicate fluid of orthopaedic artificial joints. Intracellular adenosine-5'-triphosphate release by bacteriophage mediated lysis of staphylococci was assessed to determine optimal parameters for detection. With the optimized method, a limit of detection of around 103 CFU/mL was obtained after incubation with bacteriophage for 2 h. Importantly, sonicate fluid did not prevent the ability of bacteriophage to infect bacteria and all simulated infected sonicate fluid as well as 6 clinical samples with microbiologically proven staphylococcal infection were detected as positive. The total assay took approximately 4 h. Collectively, the results indicate that the developed method promises a rapid, inexpensive and specific diagnostic detection of staphylococci in sonicate fluid of infected prosthetic joints. In addition, the unlimited pool of different existing bacteriophages, with different specificity for all kind of bacteria gives the opportunity for further investigations, improvements of the current model and implementation in other medical fields for the purpose of the establishment of a rapid diagnosis. PMID- 28675249 TI - Mosquito species involved in the circulation of West Nile and Usutu viruses in Italy. AB - Usutu (USUV) and West Nile (WNV) are mosquito-borne Flavivirus emerged in Italy in 1996 and 1998, respectively, and reappeared 10 years later. The aim of this work is to review the Italian mosquito species found positive for WNV and USUV between 2008 and 2014. Moreover, the role of mosquitoes in promoting the overwintering of these viruses is discussed, as a result of the mosquito collections performed in Molise region between September 2010 and April 2011. Overall 99,000 mosquitoes were collected: 337 and 457 mosquito pools tested positive by real time reverse transcriptase polymerase chain reaction (real time RT-PCR) for WNV and USUV, respectively. West Nile virus was detected in pools of Culex pipiens s.l. (329), Ochlerotatus caspius (4), Culex modestus (2), and Culex spp. (2). Positive USUV pools were from Cx. pipiens s.l. (435), Aedes albopictus (12), Oc. caspius (5), Culex spp. (2), Anopheles maculipennis s.l. (1), Culiseta annulata (1), and Ochlerotatus detritus (1). In Molise region, 1,694 mosquitoes were collected, and USUV was identi ed in Cx. pipiens s.l., Cs. annulata, and Oc. detritus pools. This paper shows that Cx. pipiens s.l. is the mosquito species most involved in the WNV and USUV circulation in Italy, although other species would also support the spread of both the viruses during Winter. PMID- 28675250 TI - Effects of different rest-stop durations at control posts during a long journey on the welfare of sheep. AB - All livestock transport within the European Union must comply with the EC Regulation 1/2005. For sheep, this law prescribes a maximum journey of 29 hours after which animals must rest in control posts (CP) for 24 hours before further transportation. However, there is no scientific evidence de ning the effects of di erent stop duration on sheep recovery during long journeys. The aim of this study was to assess if a shorter stop could be provided without impairing ewes' welfare. Ninety-six adult ewes were divided into 4 homogenous groups. One group stayed at the farm (control) and the other 3 were transported for 29 hours (long transport, LT), stopped at CP for di erent times (8 hours (S8 group); 16 hours (S16 group); 24 hours (S24 group)) and were re-transported for 6 hours (short transport, ST). Blood and saliva were collected to assess dehydration, muscular damage, and adrenocortical stress before departure, after LT, after the stop, and after ST. The LT a ected the hydration of all transported groups (i.e. higher BUN/creatinine levels than controls, p<0.001), but basal values were restored after the ST, regardless of the stop duration. After the ST, S8 group had higher muscular damage than the other groups (p<0.05). No di erences in stress level were observed. These results suggest that, in this trial, ewe's welfare was not impaired by a stop reduction from 24 hours to 16 hours. PMID- 28675251 TI - Diet effect on short- and long-term glycaemic response in adult healthy cats. AB - In the paper the short- and long-term glycaemic response after 4 diet programmes was evaluated. Each diet programme was alternatively administered to 6 healthy cats for 30 days. At the end of each period cats were weighed and underwent blood sampling for glucose and fructosamine determination. Glycaemia was measured every 2 hours for 24 hours using an automated glucometer. Very high protein level and low starch (VHP/LS) and high protein and moderate starch level (HP/LS) diets showed glucose (Mean and Peak) and fructosamine values signi cantly lower compared to the moderate protein and high starch diets (MP/HS). It is likely that these results are due to the contemporary e ect of the following nutritional characteristics: protein level, protein/starch ratio and dietary bre. All these parameters were higher in VHP/LS and HP/MS diets. These preliminary results suggest that the use of diets with high protein/starch ratio and soluble bre levels favours the carbohydrate metabolism of healthy cats. PMID- 28675252 TI - Diversity and distribution of ticks from domestic ruminants in Lebanon. AB - Ticks (Acari: Ixodidae) are ectoparasites infesting livestock in every geographic area in the world and they are vectors of several viral, bacterial, and protozoan pathogens to animals and humans worldwide. A deep knowledge of the geographical distribution of these arthropods would have a key role in the control of tick borne diseases. Few data are available about tick presence in domestic ruminants in Lebanon. The study aimed at providing an analysis of tick presence and distribution in Lebanon. Ticks were collected from cattle, sheep, and goats farms distributed in 6 Lebanese provinces between June and September 2014. A total of 272 adult hard ticks were randomly collected from domestic ruminants (cattle, sheep, and goats) located at 37 Lebanese farms, distributed among 30 villages. Ticks belonged to 4 Ixodidae genera: Rhipicephalus (72.4%), Haemaphysalis (11.4%), Dermacentor (8.1%), and Hyalomma (8.1%). They included the following species: Rhipicephalus annulatus (50.7%), Rhipicephalus turanicus (18.8%), Hyalomma anatolicum (8.1%), Haemaphylasis punctata (11.4%), Dermacentor marginatus (8.1%), Rhipicephalus sanguineus (2.5%), and Rhipicephalus bursa (0.4%). Rhipicephalus turanicus and H. anatolicum were found on cattle, sheep, and goats, R. annulatus on cattle and sheep, R. sanguineus, D. marginatus and Hea. punctata on sheep and goats, while R. bursa was collected only on sheep. Tick species involved in pathogen transmission were found and some of the identi ed species were recorded in Lebanon for the rst time. PMID- 28675253 TI - Flight and swarming behaviour of Culicoides species (Diptera: Ceratopogonidae) on a livestock farm in Northern Spain. AB - The efficacy of sweep nets and a CDC white light-suction trap for the sampling of Culicoides species (Diptera: Ceratopogonidae) were compared on a livestock farm in Northern Spain during the Summer of 2013. A total of 6,082 specimens representing 26 species were collected with sweep nets in 4 areas at di erent heights (ground level, 1.5 m, and 3 m), and 8,463 specimens representing 28 species with a single white light trap. Eight species - Culicoides brunnicans, Culicoides punctatus, Culicoides obsoletus/Culicoides scoticus, Culicoides lupicaris, Culcoides picturatus, Culicoides achrayi, and Culicoides simulator - were dominant and accounted for 97.4% and 97.2% of the total specimens collected with both methods, sweep nets, and light traps, respectively. The sex ratios with sweep netting and light trapping were strongly female biased (78.4% and 97.1%, respectively). Nulliparous and parous females were predominantly captured with both methods. A high percentage (17%) of gravid females was, however, captured on manure at ground level while sweeping. Searches for male swarms revealed the presence of several C. punctatus swarms consisting of 26 to 196 males and 3 swarms of C. obsoletus that ranged from 1 to 12 males in size. This study suggested that both methods are suitable and complementary tools for Culicoides sampling. PMID- 28675254 TI - A case of diprosopiasis in Trachemys scripta scripta. AB - This short communication describes a case of diprosopiasis in Trachemys scripta scripta imported from Florida and farmed for about 4 months by a private owner in Palermo, Sicily, Italy. The water turtle showed the morphological and radiological features characterizing such deformity. This communication aims to advance the knowledge of the reptile's congenital anomalies and suggests the need for more detailed investigations to better understand its pathogenesis. PMID- 28675255 TI - [Communicative and social-adaptive profile in children with autism spectrum disorder: a new approach based on the DSM-5 criteria]. AB - INTRODUCTION: Following the adoption of the new international diagnosis classification from the Diagnostic and Statistical Manual (DSM-5), autism spectrum disorder (ASD) has been established as a dimensional category that includes other disorders that were previously considered as separate entities. Previous research has shown that some people with this disorder exhibit different communicative and linguistic profiles. Therefore, contradictory results could be found among people who receive the same diagnosis. AIM: To distinguish structural language aspects (expression and comprehension), interactive aspects (pragmatics), and social adaptation between children with an ASD-level 1 of support and children with typical development. SUBJECTS AND METHODS: Seventeen children with Asperger syndrome (according to the DSM-IV-TR), and 20 children with typical development between 7 and 12 years old. We have equated diagnosis of Asperger syndrome with ASD-level 1 of support. We have evaluated intelligence quotient, communication, and social adaptation with direct and indirect standardized parental scales. RESULTS: We have found significant differences in comprehension (p = 0.025), interaction (p = 0.001), and social adaptation (p = 0.001) between the two groups. CONCLUSIONS: Subjects with ASD-level 1 of support demonstrate an average intelligence quotient, and good expressive structure (syntax and semantic level), which may be different from other children who receive the same diagnosis, due to the wide heterogeneity of the disorder. Nevertheless, our subjects have problems related to comprehension of grammar structure, pragmatics, and social adaptation. These difficulties could be related to emotional and social problems. PMID- 28675256 TI - [Prevalence and risk factors for periventricular leukomalacia in preterm infants. A systematic review]. AB - INTRODUCTION: There is a huge disparity in the description of the prevalence and risk factors of periventricular leukomalacia in preterm infants. AIMS: To describe and compare, through a systematic review of the literature, the prevalence of periventricular leukomalacia in preterm infants, as well as to determine the main risk factors associated with its presentation. SUBJECTS AND METHODS: A systematic review was conducted consulting multiple databases of the last 20 years. The search terms were: periventricular leukomalacia, prevalence, risk factors and premature birth. We included all studies that mention or led to the prevalence of periventricular leukomalacia and those that referred to its risk factors. RESULTS: Of the 209 studies identified, we selected 107 studies in which the prevalence of periventricular leukomalacia was mentioned or the risk factors were described. A stratified analysis was performed for the diagnostic technique and gestational age, in addition to a narrative synthesis. Ultrasound detected a prevalence of 14.7% and magnetic resonance of 32.8%. Prevalence in children under 28 weeks was 39.6%; 27.4% in children under 32 weeks and 7.3% in children under 37 weeks. Risk factors include gestational age, intrauterine infection, premature rupture of membranes and chorioamnionitis. CONCLUSIONS: The prevalence of periventricular leukomalacia in preterm infants is heterogeneous, increases according to the degree of prematurity and is better detected by magnetic resonance. There are multiple factors related to its presentation, the main factor is gestational age. PMID- 28675257 TI - [Influence of depression on the initial diagnosis and the evolution of cognitive impairment]. AB - INTRODUCTION: Depression and cognitive impairment maintain a close and complex relationship, which could be modified by pharmacological treatment. AIM: To analyze the influence of depression and antidepressive medication on the initial diagnosis and the evolution of cognitive impairment. PATIENTS AND METHODS: All the patients derived to a Neurology clinic due to complaints or suspicion of cognitive impairment, during a period of nine years, were studied. The influence of demographic and depression-related variables on initial cognitive diagnosis, cognitive-functional situation and 1-year evolution were analyzed. RESULTS: A total of 582 patients were included (mean age: 77.6 +/- 7.0; 64.9% women). Frequency of current and past depression were, respectively, 25.4% and 17.2%. In addition, 20.6% of the patients were taking antidepressant medication and 31.2% were on anxiolytic/hypnotic treatment. One-year follow-up visit was available in 320 (59.8%) of patients. In the adjusted analysis, anxiolytic/hypnotic treatment was associated with a worse cognitive-functional situation in the initial visit, while past depression and presence of dystimia were associated with a favorable evolution (p < 0.05). CONCLUSIONS: Past or current depression are not associated with bad prognosis in patients derived to neurologist due to possible cognitive impairment. PMID- 28675258 TI - Narcolepsy-cataplexy and psychosis: a case study. AB - AIMS: To report a challenging patient a girl who developed narcolepsyy with cataplexy (NT1) and a psychosis during adolescence. To discuss diagnostic and therapeutic challenges of the comorbid cases. CASE REPORT: A 14-year-old girl was referred to Sleep and Epilepsy Unit for excessive daytime sleepiness, impaired nocturnal sleep, binge eating and weight gain, over the last year. After being diagnosed with a NT1 the patient was treated with modafinil and sodium oxybate. She was hospitalized for psychotic symptoms after starting NT1 treatment. Withdrawal of the narcolepsy treatment and initiation of haloperidol 1 mg/day (the only antipsychotic treatment she could tolerate) improved the delusions, hallucinations and dysphoria but worsened the narcolepsy symptoms. Polysomnography showed fragmented nocturnal sleep and five sleep REM onset periods in MSLT. Positive HLA-QB1*06:02 and undetectable level of hypocretine in the cerebrospinal fluid were found. MRI and CT-scan were normal. Diagnostic Interview for Genetic Studies Adapted for Narcolepsy (DIGSAN) questionnaire confirmed that patient presented a dual diagnostic NT1 and psychotic symptoms. The last sleep follow-up while on psychopharmacological treatment, showed an increased sleep efficiency index. She currently has severe somnolence, obesity, and partial cataplectic attacks along with normal mood, academic failure and social isolation. CONCLUSION: The coexistence of narcolepsy with psychoses is a rare clinical entity, more frequent in adolescents than in adults. The comorbidity of the two illnesses worsens clinical and therapeutic prognosis and also suggests interesting pathophysiological hypotheses. PMID- 28675260 TI - [XXXI Reunion da Sociedade Galega de Neuroloxia. Communications]. PMID- 28675259 TI - Review of the novelties from the 32nd ECTRIMS Congress, 2016, presented at the 9th Post-ECTRIMS Meeting (II). AB - For the ninth year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain) with the aim of presenting and discussing the hottest issues debated at the ECTRIMS Congress by renowned specialists in multiple sclerosis in our country. One outcome of this scientific activity, endorsed by the Spanish Neurology Society, is this review article, which is published in two parts. This second part reflects the current controversy over the management of multiple sclerosis, especially as regards the progressive forms and their differential diagnosis. The work presents the latest advances in remyelination, where the use of the micropillar technique in laboratory stands out, and in neuroprotection, which is reviewed through a study of the optic nerve. Anti-CD20 antibodies are a very promising development and we find ourselves before a new mechanism of action and therapeutic target in cells to which little attention has been paid to date. Another notable fact is the high correlation between the levels of neurofilaments in cerebrospinal fluid and in serum, which could make it possible to avoid the use of cerebrospinal fluid as a biological sample in future studies of biomarkers. The review also provides a preview of the advances in clinical research, which will converge in clinical practice in the future, thereby conditioning the steps that should be taken in the therapeutic management of multiple sclerosis. PMID- 28675261 TI - [Cervantes and Shakespeare, two Renaissance neurologists]. PMID- 28675262 TI - Intravenous immunoglobulins for epilepsy. AB - BACKGROUND: Epilepsy is a common neurological condition, with an estimated incidence of 50 per 100,000 persons. People with epilepsy may present with various types of immunological abnormalities, such as low serum immunoglobulin A (IgA) levels, lack of the immunoglobulin G (IgG) subclass and identification of certain types of antibodies. Intravenous immunoglobulin (IVIg) treatment may represent a valuable approach and its efficacy has important implications for epilepsy management. This is an updated version of the original Cochrane review published in Issue 1, 2011. OBJECTIVES: To examine the effects of IVIg on the frequency and duration of seizures, quality of life and adverse effects when used as monotherapy or as add-on treatment for people with epilepsy. SEARCH METHODS: For the latest update, we searched the Cochrane Epilepsy Group Specialized Register (2 February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (2 February 2017), MEDLINE (Ovid, 1946 to 2 February 2017), Web of Science (1898 to 2 February 2017), ISRCTN registry (2 February 2017), WHO International Clinical Trials Registry Platform (ICTRP, 2 February 2017), the US National Institutes of Health ClinicalTrials.gov (2 February 2017), and reference lists of articles. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of IVIg as monotherapy or add-on treatment in people with epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the trials for inclusion and extracted data. We contacted study authors for additional information. Outcomes included percentage of people rendered seizure-free, 50% or greater reduction in seizure frequency, adverse effects, treatment withdrawal and quality of life. MAIN RESULTS: We included one study (61 participants). The included study was a randomized, double blind, placebo-controlled, multi-centre trial which compared the treatment efficacy of IVIg as an add-on with a placebo add-on in patients with refractory epilepsy. There was no significant difference between IVIg and placebo in 50% or greater reduction in seizure frequency. The study reported a statistically significant effect for global assessment in favour of IVIg. No adverse effects were demonstrated. We found no randomized controlled trials that investigated the effects of IVIg monotherapy for epilepsy. Overall, the included study was rated as low/unclear risk of bias. Using GRADE methodology, the quality of the evidence was rated as low. AUTHORS' CONCLUSIONS: We cannot draw any reliable conclusions regarding the efficacy of IVIg as a treatment for epilepsy. Further randomized controlled trials are needed. PMID- 28675263 TI - Specific and Cross-reactive Plasmablast Response in Humans after Primary and Secondary Immunization with Vi Capsular Polysaccharide Typhoid Vaccine. AB - Secondary immunization with polysaccharide vaccines may imply a risk of hyporesponsiveness. Despite the wide use of typhoid Vi capsular polysaccharide vaccine, its potential tendency to hyporesponsiveness has been inadequately addressed. While previous studies have explored serum antibody responses, we applied a more sensitive approach, a single-cell assay for circulating plasmablasts, to compare primary and secondary responses. Twelve subjects received primary and booster doses of the Vi vaccine (Typherix(r) ) at 30- to 37 month intervals. Plasmablasts specific to the Vi or typhoidal O antigens or cross reactive with paratyphoid and non-typhoidal Salmonella strains were identified as antibody-secreting cells (ASC) with ELISPOT. Before vaccinations, none had plasmablasts specific to the antigens tested. Twelve of 12 subjects showed a Vi specific response after primary, but only eight of 12 after booster vaccination. All responded to typhoidal O-9,12 antigen after both immunizations. The geometric mean of plasmablasts specific to the Vi antigen was 59 (95% CI 24-119) and 1 (0 54) IgA + IgG + IgM-ASC/106 peripheral blood mononuclear cell (PBMC) after primary and booster immunizations, respectively, and 20 (9-49) and 56 (29-103) to the O-9,12 antigen. We detected 1 (0-28) and 17 (6-36) ASC/106 PBMC cross reactive with Salmonella Paratyphi A; 3 (0-30) and 22 (8-48) with S. Paratyphi B; 3 (0-29) and 18 (7-47) with S. Paratyphi C; 19 (10-34) and 51 (26-94) with Salmonella Enteritidis; and 1 (0-35) and 23 (9-52) with Salmonella Typhimurium, respectively. One-third of the vaccinees, although responding to the O-9,12 antigen, failed to respond to the Vi antigen after booster immunization, suggesting hyporesponsiveness in part of the vaccinees. The findings warrant further investigation. PMID- 28675264 TI - ? PMID- 28675265 TI - [Direct oral anticoagulants : some practical considerations]. AB - Prevention and management of thromboembolic events are historically based on the use of anti-vitamines K (AVK) and heparins. Since 2009, emerging direct oral anticoagulants (DOAC) with successive validated indications, changed progressively the way of managing oral anticoagulation. The main advantages of this new generation of medication are a better safety profile and the lack of need for monitoring anticoagulation activity. However, a number of situations in clinical practice still require careful use of these DOAC. This article review some practical considerations and specific situations of hospital and ambulatory settings. PMID- 28675266 TI - [Diarrhea caused by systemic anti-cancer treatments]. AB - Diarrhea is one of the most common complaints in oncologic patients. Causes are multiple including bowel resection, infections, radiation and systemic anti cancer treatments. In the latter case, the pathophysiology is partially elucidated and requires the etiology to be precisely identified : chemotherapy, targeted therapy or immunotherapy. Loperamide remains central in uncomplicated cases. However, with development of immunotherapy, autoimmune mechanism should be recognized and requires different approach based mainly on corticosteroids. Physician taking care of patients with diarrhea should therefore identify possible causes in order to offer adapted treatments and therefore reduce morbidity and mortality. PMID- 28675267 TI - [Antimicrobials : some practical considerations]. AB - Antibiotics are frequently prescribed in hospitalized and in outpatients. We review four important aspects for their daily prescription. In elderly patients, the prescription should take into account changes in the volume of distribution and the usual decline in renal function even in the absence of chronic kidney disease. Particular antibiotics can trigger infection with Clostridium difficile. We discuss actual and novel strategies for its prevention. Renal toxicity of antibiotics includes acute tubular necrosis, interstitial nephritis and crystals obstructing renal tubule, depending on the class of antibiotics. Plasmatic levels of particular antibiotics should be measured either at trough or at peak levels depending of the antibiotic prescribed. PMID- 28675268 TI - [News about pericardial diseases in 2016]. AB - The European Society of Cardiology published in 2015 the new Guidelines on the management of pericardial diseases. Based on experts' opinions and recent clinical studies of respectable size, the new guidelines thoroughly revisit the criteria for hospitalization and precisely define severe cases. Another highlight regards medication. From now, first-line medical therapy should include the association of colchicine to the traditional non steroidal anti-inflammatory drugs or aspirin. The bi-therapy is recommended as soon as the first episode of pericarditis, for duration of 3 months. The experts also recommend systematically performing a heart ultrasound for any form of pericardial disease and restricting physical activities especially if myocardial damage (perimyocarditis) is associated. PMID- 28675269 TI - [New therapeutics]. AB - Daily medical practice triggers reflexes in the use of drugs which must nevertheless always be adapted to new knowledge. Physician assistants and residents in the clinical ward of Internal Medicine of Sion Hospital summarize six recently published clinical treatments to which primary care physicians or in hospital-based internal medicine have to pay a particular attention. Quinolones are widely used but associated with QT interval widening, morphine delays and attenuate ticagrelor action in patients with myocardial infarction, evolocumab, a monoclonal antibody impact in reducing lipids and cardiovascular events, impact of statins on influenza vaccine effectiveness, vitamin D treatment for the prevention of functional decline, high dose dexamethasone for the treatment of immune thrombocytopenia. PMID- 28675271 TI - ? PMID- 28675270 TI - [Bronchodilatation during spirometry : indications, realization and interpretation]. AB - Spirometry with response to short-acting bronchodilators is a key element in the diagnostic work-up of patients with obstructive airways diseases and should be systematically assessed. Response to bronchodilators (RBD) is useful to differentiate asthma from COPD and to grade the severity of obstruction in COPD cases. RBD should not be used to decide for a bronchodilator therapy. An increase in Forced Expiratory Volume in 1 sec (FEV1) or Forced Vital Capacity (FVC) by > 200 ml and 12 % of baseline value is considered as criteria for significant bronchodilator response. With the exception of asthma diagnostic work-up, inhaled therapy should not be interrupted before spirometry. Paradoxical loss of lung function after administration of beta 2 agonists is rarely observed. When present, choice of an alternative bronchodilator agent should be considered. PMID- 28675272 TI - ? PMID- 28675273 TI - ? PMID- 28675274 TI - ? PMID- 28675276 TI - ? PMID- 28675275 TI - ? PMID- 28675277 TI - ? PMID- 28675278 TI - [Management of patients with alcoholic hepatitis : why can't we do better?] AB - Alcoholic steatohepatitis is a severe and frequent manifestation of alcoholic liver disease which is associated with high mortality. This poor outcome is strongly influenced by several aspects of the disease, including the absence of medical treatment with proven benefit other than steroids, the elevated risk of infections, the ineffectiveneness of proregenerative strategies, the high prevalence of concomitant malnutrition, and the elevated rate of alcohol relapse during follow-up. All these parameters should be considered as major therapeutic targets in the near future in order to improve the management and outcome of these patients. PMID- 28675279 TI - [Benign esophageal strictures : endoscopic treatment options]. AB - Bening strictures of the esophagus are a frequently encountered problem in endoscopy. Dilation by Savary-Gilliard dilators or balloon dilators is the first line treatment and relieves dysphagia in about 75 % of cases. Complex strictures are at higher risk of treatment failure than simple ones and are considered as refractory after repetitive unsuccessful dilations. Adjunction of locally injected corticoids favors outcome in strictures of peptic origin. Further treatment options of refractory strictures are endoscopic incision therapy in short ones and temporary self expandable metallic (SEMS), plastic (SEPS) or biodegradable stent insertion in complex ones. Ultimate rescue treatment consists in self bouginage or esophageal surgery. PMID- 28675280 TI - [Is there hope for hepatitis delta ?] AB - Hepatitis D or delta is a chronic liver disease globally reaching 15-20M people. Its agent, hepatitis D virus (HDV) requires the presence of hepatitis B virus (HBV) to complete its life cycle. It represents one of the most severe forms of viral hepatitis. Current therapy with pegylated interferon alpha leads to viral eradication only in 25 % of cases. New treatments targeting the virus life cycle are sought. For example Myrcludex-B, which inhibits the entry into hepatocytes, lonafarnib which prevents the assemblage of the viral particle and the molecule REP 2139 which, among other unclear mechanisms, impedes the exit of the virus. This allows considering a better management of a condition for which there is currently no satisfactory treatment. PMID- 28675281 TI - [Diagnostic and treatment of mesenteric ischemia]. AB - Mesenteric ischemia results from acute or chronic blood flow reduction in the mesenteric arterial or venous vascular supply. This is usually due to an embolus, thrombosis or intestinal hypoperfusion. Radiologic and / or endoscopic imaging and histology allow for diagnosis in high-risk patients with suggestive clinical symptoms and signs. Treatment aims at preventing multi-organ failure through medical treatment, saving intestinal integrity and resecting necrotic bowel segments. Rapid and multidisciplinary management is key in order to optimize treatment and avoid long-term debilitating consequences. PMID- 28675282 TI - [Oral nutritive supplements : efficiency and clinical use in community-dwelling patients]. AB - Undernutrition represents a wide-spread clinical state in outpatients and inpatients. It is associated with a high morbidity and mortality, an impaired quality of life, and increased healthcare costs. Early diagnosis and treatement help to reduce these medical and economic consequences. Oral nutritive supplements (ONS) are simple, effective and economic medical treatments to fight against undernutrition. However, they are insufficiently used for outpatients because of lack of knowledge. This article reviews the impact of ONS, their indications and contraindications and their modalities of prescription and focuses especially on community-dwelling patients. PMID- 28675283 TI - [Eosinophilic gastrointestinal disorders]. AB - The term " eosinophilic gastrointestinal disorders " describes a group of diseases that comprises eosinophilic esophagitis, gastritis, enteritis, and colitis. Eosinophilic esophagitis is the most prevalent form while eosinophilic gastritis, enteritis, and colitis are rare. Food antigens have increasingly been found to trigger the inflammatory response. This review will highlight the epidemiology, clinical manifestations, diagnostic modalities and therapeutic options of eosinophilic gastritis, enteritis, and colitis. PMID- 28675284 TI - [Transthyretin-related hereditary amyloidosis]. AB - Transthyretin-related hereditary amyloidosis (ATTR) is a progressive and potentially lethal genetic disorder, transmitted as an autosomal dominant trait. Tissue injury is induced by amyloid fibrils consisting of mutated transthyretin. The symptomatology and clinical course of ATTR is highly variable but typically causes peripheral polyneuropathy and autonomic dysfunction, leading to death within 10 years. As transthyretin is produced mainly in the liver, liver transplantation was the first successful therapeutic approach. Several disease modifying treatments, including transthyretin stabilizers and gene therapy, are now available or in clinical development, with promising results. PMID- 28675285 TI - ? PMID- 28675286 TI - ? PMID- 28675287 TI - ? PMID- 28675288 TI - ? PMID- 28675289 TI - ? PMID- 28675290 TI - ? PMID- 28675291 TI - Efficacy of carboxymethyl beta-glucan in cervical intraepithelial neoplasia: a retrospective, case-control study. AB - BACKGROUND: Persistent human papillomavirus (HPV) infection constitutes the principal risk factor for the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. For this reason, new drugs have been studied to support the host immune system against the HPV infection. The aim of this retrospective, case-control study was to detect the efficacy and safety of carboxymethyl beta-glucan (Colpofix(r)) gel as adjuvant therapy in HPV infection. METHODS: The medical records of patients attending the Colposcopy Service of four hospitals in Rome from 2011 to 2013 were collected. Case arm consisted of patients submitted to local therapy with Colpofix(r). Control arm comprised patients who did not receive this therapy. A total of 999 patients were included, divided into four groups, according to their cytological and histological specimens, colposcopy and subsequent management. RESULTS: Local therapy with Colpofix(r) gel resulted effective with respect to no therapy for the regression of low-grade CIN (CIN1) in patients submitted to follow up (P=0.0204), while it was no effective for the regression of CIN1 submitted to ablative therapy and high-grade CIN (CIN 2+) (P value not significant). CONCLUSIONS: In conclusion, Colpofix(r) gel represents a valid alternative to "wait and see" strategy in patients affected by CIN1. Further prospective studies are warranted to confirm these results. PMID- 28675292 TI - Substrate Specificity of the Secreted Nisin Leader Peptidase NisP. AB - Nisin (NisA) is an antimicrobial peptide produced by Lactococcus lactis and belongs to the class of lanthipeptides, more specifically to the class of lantibiotics. They are ribosomally synthesized as a precursor peptide and are comprised of an N-terminal leader peptide and a C-terminal core peptide. The core peptide is post-translationally modified and contains dehydrated amino acids in addition to five (methyl)-lanthionine rings, which are crucial for its activity. The leader peptide serves as a signal sequence and ensures that NisA remains inactive but secretion-competent within the cell. After translocation into the extracellular space, the leader peptide is cleaved by the leader peptidase NisP, resulting in active nisin. NisP is an extracellular subtilisin-like serine protease, which recognizes the cleavage site GASPR|IT located at the C-terminal end of the leader peptide. Here, we present the biochemical characterization of secreted and purified NisP (NisPs) with its natural substrate, the fully modified NisA (mNisA). Furthermore, we determined the kinetic parameters of NisPs in the presence of NisA containing different modification states. Additionally, in vitro data revealed that NisPs can efficiently cleave the leader peptide of mNisA. However, it is strictly dependent on the modification state of the core peptide. Thus, NisPs has a sequence-based cleavage activity, and the presence of at least one lanthionine ring is crucial for optimal substrate recognition and subsequent cleavage. PMID- 28675293 TI - Enhanced Photocarrier Separation in Hierarchical Graphitic-C3N4-Supported CuInS2 for Noble-Metal-Free Z-Scheme Photocatalytic Water Splitting. AB - The effective separation of photogenerated electrons and holes in photocatalysts is a prerequisite for efficient photocatalytic water splitting. CuInS2 (CIS) is a widely used light absorber that works properly in photovoltaics but only shows limited performance in solar-driven hydrogen evolution due to its intrinsically severe charge recombination. Here, we prepare hierarchical graphitic C3N4 supported CuInS2 (denoted as GsC) by an in situ growth of CIS directly on exfoliated thin graphitic C3N4 nanosheets (g-C3N4 NS) and demonstrate efficient separation of photoinduced charge carriers in the GsC by forming the Z-scheme system for the first time in CIS-catalyzed water splitting. Under visible light illumination, the GsC features an enhanced hydrogen evolution rate up to 1290 MUmol g-1 h-1, which is 3.3 and 6.1 times higher than that of g-C3N4 NS and bare CIS, respectively, thus setting a new performance benchmark for CIS-based water splitting photocatalysts. PMID- 28675294 TI - Quantifying Protection in Disordered Proteins Using Millisecond Hydrogen Exchange Mass Spectrometry and Peptic Reference Peptides. AB - The extent and location of transient structure in intrinsically disordered proteins (IDPs) provide valuable insights into their conformational ensembles and can lead to a better understanding of coupled binding and folding. Millisecond amide hydrogen exchange (HX) can provide such information, but it is difficult to quantify the degree of transient structuring. One reason is that transiently disordered proteins undergo HX at rates only slightly slower than the rate of amide HX by an unstructured random coil, the chemical HX rate. In this work, we evaluate several different methods of obtaining an accurate model for the chemical HX rate suitable for millisecond hydrogen exchange mass spectrometry (HX MS) analysis of disordered proteins: (1) calculations using the method of Englander [Bai, Y., et al. (1993) Proteins 17, 75-86], (2) measurement of HX in the presence of 6 M urea or 3 M guanidinium chloride, and (3) measurement of HX by peptide fragments derived directly from the proteins of interest. First, using unstructured model peptides and disordered domains of the activator for thyroid and retinoid receptors and the CREB binding protein as the model IDPs, we show that the Englander method has slight inaccuracies that lead to underestimation of the chemical exchange rate. Second, HX-MS measurements of model peptides show that HX rates are changed dramatically by high concentrations of the denaturant. Third, we find that measurements of HX by reference peptides from the proteins of interest provide the most accurate approach for quantifying the extent of transient structure in disordered proteins by millisecond HX-MS. PMID- 28675295 TI - Printable and Flexible Copper-Silver Alloy Electrodes with High Conductivity and Ultrahigh Oxidation Resistance. AB - Printable and flexible Cu-Ag alloy electrodes with high conductivity and ultrahigh oxidation resistance have been successfully fabricated by using a newly developed Cu-Ag hybrid ink and a simple fabrication process consisting of low temperature precuring followed by rapid photonic sintering (LTRS). A special Ag nanoparticle shell on a Cu core structure is first created in situ by low temperature precuring. An instantaneous photonic sintering can induce rapid mutual dissolution between the Cu core and the Ag nanoparticle shell so that core shell structures consisting of a Cu-rich phase in the core and a Ag-rich phase in the shell (Cu-Ag alloy) can be obtained on flexible substrates. The resulting Cu Ag alloy electrode has high conductivity (3.4 MUOmega.cm) and ultrahigh oxidation resistance even up to 180 degrees C in an air atmosphere; this approach shows huge potential and is a tempting prospect for the fabrication of highly reliable and cost-effective printed electronic devices. PMID- 28675296 TI - Restoring the Electrical Properties of CVD Graphene via Physisorption of Molecular Adsorbates. AB - Chemical vapor deposition (CVD) is a powerful technique to produce graphene for large-scale applications. Polymer-assisted wet transfer is commonly used to move the graphene onto silicon substrates, but the resulting devices tend to exhibit p doping, which decreases the device quality and reproducibility. In an effort to better understand the origin of this effect, we coated graphene with n-methyl-2 pyrrolidone (NMP) and hexamethyldisilazane (HMDS) molecules that exhibit negligible charge transfer to graphene but bind more strongly to graphene than ambient adsorbents. Using Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), electrical transport measurements, and quantum mechanical computer simulations, we show that the molecules help in the removal of p-doping, and our data indicate that the molecules do this by replacing ambient adsorbents (typically O2 and water) on the graphene surface. This very simple method of improving the electronic properties of CVD graphene by passivating its surface with common solvent molecules will accelerate the development of CVD graphene based devices. PMID- 28675298 TI - Separating Bulk and Surface Contributions to Electronic Excited-State Processes in Hybrid Mixed Perovskite Thin Films via Multimodal All-Optical Imaging. AB - A comprehensive understanding of electronic excited-state phenomena underlying the impressive performance of solution-processed hybrid halide perovskite solar cells requires access to both spatially resolved electronic processes and corresponding sample morphological characteristics. Here, we demonstrate an all optical multimodal imaging approach that enables us to obtain both electronic excited-state and morphological information on a single optical microscope platform with simultaneous high temporal and spatial resolution. Specifically, images were acquired for the same region of interest in thin films of chloride containing mixed lead halide perovskites (CH3NH3PbI3-xClx) using femtosecond transient absorption, time-integrated photoluminescence, confocal reflectance, and transmission microscopies. Comprehensive image analysis revealed the presence of surface- and bulk-dominated contributions to the various images, which describe either spatially dependent electronic excited-state properties or morphological variations across the probed region of the thin films. These results show that PL probes effectively the species near or at the film surface. PMID- 28675297 TI - A Human Tyrosine Phosphatase Interactome Mapped by Proteomic Profiling. AB - Tyrosine phosphatases play a critical role in many cellular processes and pathogenesis, yet comprehensive analysis of their functional interacting proteins in the cell is limited. By utilizing a proteomic approach, here we present an interaction network of 81 human tyrosine phosphatases built on 1884 high confidence interactions of which 85% are unreported. Our analysis has linked several phosphatases with new cellular processes and unveiled protein interactions genetically linked to various human diseases including cancer. We validated the functional importance of an identified interaction network by characterizing a distinct novel interaction between PTPN5 and Mob1a. PTPN5 dephosphorylates Mob1a at Y26 residue. Further, we identify that PTPN5 is required for proper midbody abscission during cytokinesis through regulation of Mob1a dephosphorylation. In conclusion, our study provides a valuable resource of tyrosine phosphatase interactions, which can be further utilized to dissect novel cellular functions of these enzymes. PMID- 28675299 TI - Synthesis of Spiro[indazole-3,3'-indolin]-2'-ones via [3 + 2] Dipolar Cycloaddition of Arynes with 3-Diazoindolin-2-ones and Indazolo[2,3-c]quinazolin 6(5H)-ones by Subsequent Thermal Isomerization. AB - An efficient protocol for facile construction of spiro[indazole-3,3'-indolin]-2' ones was developed via [3 + 2] dipolar cycloaddition of arynes with 3 diazoindolin-2-ones under mild conditions in excellent yields. Subsequent thermal isomerization of the spiro[indazole-3,3'-indolin]-2'-ones readily afforded indazolo[2,3-c]quinazolin-6(5H)-ones. PMID- 28675300 TI - Fundamental Insights into the Degradation and Stabilization of Thin Layer Black Phosphorus. AB - Herein, we have developed a systematic study on the oxidation and passivation of mechanically exfoliated black phosphorus (BP). We analyzed the strong anisotropic behavior of BP by scanning Raman microscopy providing an accurate method for monitoring the oxidation of BP via statistical Raman spectroscopy. Furthermore, different factors influencing the environmental instability of the BP, i.e., thickness, lateral dimensions or visible light illumination, have been investigated in detail. Finally, we discovered that the degradation of few-layer BP flakes of <10 nm can be suppressed for months by using ionic liquids, paving the way for the development of BP-based technologies. PMID- 28675301 TI - Tunable Strain in Magnetoelectric ZnO Microrod Composite Interfaces. AB - The intrinsic strain at coupled components in magnetoelectric composites plays an important role for the properties and function of these materials. In this in situ X-ray nanodiffraction experiment, the coating-induced as well as the magnetic-field-induced strain at the coupled interface of complex magnetoelectric microcomposites were investigated. These consist of piezoelectric ZnO microrods coated with an amorphous layer of magnetostrictive (Fe90Co10)78Si12B10. While the intrinsic strain is in the range of 10-4, the magnetic-field-induced strain is within 10-5, one order of magnitude smaller. Additionally, the strain relaxation distance of around 5 MUm for both kinds of strain superposes indicating a correlation. The value of both intrinsic and magnetic-field-induced strain can be manipulated by the diameter of the rodlike composite. The intrinsic interface strain within the ZnO increases exponentially by decreasing the rod diameter while the magnetic-field-induced strain increases linearly within the given range. This study shows that miniaturizing has a huge impact on magnetoelectric composite properties, resulting in a strongly enhanced strain field and magnetic response. PMID- 28675302 TI - Development of a practical approach to expert elicitation for randomised controlled trials with missing health outcomes: Application to the IMPROVE trial. AB - BACKGROUND/AIMS: The analyses of randomised controlled trials with missing data typically assume that, after conditioning on the observed data, the probability of missing data does not depend on the patient's outcome, and so the data are 'missing at random' . This assumption is usually implausible, for example, because patients in relatively poor health may be more likely to drop out. Methodological guidelines recommend that trials require sensitivity analysis, which is best informed by elicited expert opinion, to assess whether conclusions are robust to alternative assumptions about the missing data. A major barrier to implementing these methods in practice is the lack of relevant practical tools for eliciting expert opinion. We develop a new practical tool for eliciting expert opinion and demonstrate its use for randomised controlled trials with missing data. METHODS: We develop and illustrate our approach for eliciting expert opinion with the IMPROVE trial (ISRCTN 48334791), an ongoing multi-centre randomised controlled trial which compares an emergency endovascular strategy versus open repair for patients with ruptured abdominal aortic aneurysm. In the IMPROVE trial at 3 months post-randomisation, 21% of surviving patients did not complete health-related quality of life questionnaires (assessed by EQ-5D-3L). We address this problem by developing a web-based tool that provides a practical approach for eliciting expert opinion about quality of life differences between patients with missing versus complete data. We show how this expert opinion can define informative priors within a fully Bayesian framework to perform sensitivity analyses that allow the missing data to depend upon unobserved patient characteristics. RESULTS: A total of 26 experts, of 46 asked to participate, completed the elicitation exercise. The elicited quality of life scores were lower on average for the patients with missing versus complete data, but there was considerable uncertainty in these elicited values. The missing at random analysis found that patients randomised to the emergency endovascular strategy versus open repair had higher average (95% credible interval) quality of life scores of 0.062 (-0.005 to 0.130). Our sensitivity analysis that used the elicited expert information as pooled priors found that the gain in average quality of life for the emergency endovascular strategy versus open repair was 0.076 (-0.054 to 0.198). CONCLUSION: We provide and exemplify a practical tool for eliciting the expert opinion required by recommended approaches to the sensitivity analyses of randomised controlled trials. We show how this approach allows the trial analysis to fully recognise the uncertainty that arises from making alternative, plausible assumptions about the reasons for missing data. This tool can be widely used in the design, analysis and interpretation of future trials, and to facilitate this, materials are available for download. PMID- 28675303 TI - Plasma miR-200b-3p level for oral squamous cell carcinoma diagnosis. PMID- 28675304 TI - Immune markers, diurnal blood pressure profile and cardiac function in virologically suppressed HIV-infected patients. AB - PURPOSE: Non-dipping nocturnal blood pressure (BP) pattern has been reported prevalent among HIV-infected patients and is associated with adverse cardiovascular outcomes. The aims of this observational study were to identify predictors of nocturnal BP decline, and to explore whether diurnal BP profile is associated with alterations in cardiac structure and function. MATERIALS AND METHODS: A total of 108 treated HIV-infected patients with suppressed viremia underwent ambulatory BP measurement, 51 of these patients also underwent echocardiography. RESULTS: Non-dipping nocturnal BP pattern was present in 51% of the patients. Decreased nocturnal decline in systolic BP (SBP) correlated with lower CD4 count (rsp = 0.21, p = 0.032) and lower CD4/CD8 ratio (rsp = 0.26, p = 0.008). In multivariate linear regression analyses, lower BMI (p = 0.015) and CD4/CD8 ratio <0.4 (p = 0.010) remained independent predictors of nocturnal decline in SBP. Nocturnal decline in SBP correlated with impaired diastolic function, e' (r = 0.28, p = 0.049) as did nadir CD4 count (rsp = 0.38, p = 0.006). In multivariate linear regression analyses, nadir CD4 count <100 cells/MUL (p = 0.037) and age (p < 0.001) remained independent predictors of e'. CONCLUSIONS: Compromised immune status may contribute to attenuated diurnal BP profile as well as impaired diastolic function in well-treated HIV infection. PMID- 28675305 TI - Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) with Raman Imaging Applied to Lunar Meteorites. AB - Lunar meteorites provide a more random sampling of the surface of the Moon than do the returned lunar samples, and they provide valuable information to help estimate the chemical composition of the lunar crust, the lunar mantle, and the bulk Moon. As of July 2014, ~96 lunar meteorites had been documented and ten of these are unbrecciated mare basalts. Using Raman imaging with multivariate curve resolution-alternating least squares (MCR-ALS), we investigated portions of polished thin sections of paired, unbrecciated, mare-basalt lunar meteorites that had been collected from the LaPaz Icefield (LAP) of Antarctica-LAP 02205 and LAP 04841. Polarized light microscopy displays that both meteorites are heterogeneous and consist of polydispersed sized and shaped particles of varying chemical composition. For two distinct probed areas within each meteorite, the individual chemical species and associated chemical maps were elucidated using MCR-ALS applied to Raman hyperspectral images. For LAP 02205, spatially and spectrally resolved clinopyroxene, ilmenite, substrate-adhesive epoxy, and diamond polish were observed within the probed areas. Similarly, for LAP 04841, spatially resolved chemical images with corresponding resolved Raman spectra of clinopyroxene, troilite, a high-temperature polymorph of anorthite, substrate adhesive epoxy, and diamond polish were generated. In both LAP 02205 and LAP 04841, substrate-adhesive epoxy and diamond polish were more readily observed within fractures/veinlet features. Spectrally diverse clinopyroxenes were resolved in LAP 04841. Factors that allow these resolved clinopyroxenes to be differentiated include crystal orientation, spatially distinct chemical zoning of pyroxene crystals, and/or chemical and molecular composition. The minerals identified using this analytical methodology-clinopyroxene, anorthite, ilmenite, and troilite-are consistent with the results of previous studies of the two meteorites using electron microprobe analysis. To our knowledge, this is the first report of MCR-ALS with Raman imaging used for the investigation of both lunar and other types of meteorites. We have demonstrated the use of multivariate analysis methods, namely MCR-ALS, with Raman imaging to investigate heterogeneous lunar meteorites. Our analytical methodology can be used to elucidate the chemical, molecular, and structural characteristics of phases in a host of complex, heterogeneous geological, geochemical, and extraterrestrial materials. PMID- 28675306 TI - Use of Monte Carlo Simulation as a Tool for the Nondestructive Energy Dispersive X-ray Fluorescence (ED-XRF) Spectroscopy Analysis of Archaeological Copper-Based Artifacts from the Chalcolithic Site of Perdigoes, Southern Portugal. AB - This work is part of a broader research line that aims to develop and implement a nondestructive methodology for the chemical characterization of archaeological metals based on a protocol that combines energy dispersive X-ray fluorescence spectrometry (ED-XRF) with a Monte Carlo (MC) simulation algorithm. In this paper, the ED-XRF-MC protocol has been applied to estimate the chemical composition of a selected group of 26 copper-based artifacts and fragments recovered at Perdigoes, one of the larger Chalcolithic sites of southwest Iberia. All the analyzed artifacts have a multilayered structure composed of the alloy substrate and of a superficial layer common in each metal buried for hundreds of years and consisting of the patina mixed with soil. Due to the difficulty in determining the quantitative composition of these alloys in the presence of this complex patina/encrustation layer, the spectrometric protocol applied in this paper allows to simulate and to determine the composition of the bulk alloy without any prior removal of the overlying corrosion patina layer and soil derived crust, even in the presence of rough and irregular surfaces, thus preserving the physical integrity of the artifacts. The overall results obtained with the ED-XRF-MC protocol indicates that the artifacts from Perdigoes are almost pure coppers with a low amount of arsenic (<3.0 wt%) and reduced concentration of elements such as Pb, Bi, and Sb, in agreement with the third millennium metallurgy known in southwestern Iberia. Also based on previously theoretical-experimental studies, the data presented in this paper show how the applied analytical methodology can be a fast and completely nondestructive analytical tool reliable for routine and large-scale chemical analysis of archaeological metals, thus representing a major advance to be broadly applied within the field of cultural heritage studies. PMID- 28675307 TI - Pharmacokinetic drug evaluation of paliperidone in the treatment of schizoaffective disorder. AB - INTRODUCTION: This paper reviews the pharmacokinetics, receptor binding, clinical efficacy and safety of paliperidone in the treatment of patients with schizoaffective disorder. Areas covered: We reviewed the literature using keywords 'paliperidone', 'schizoaffective disorder' and 'clinical trials' with a focus on seminal data papers and information that is clinically relevant to the treatment of schizoaffective disorder. The purpose of this paper is to provide a clinically oriented review of the pharmacokinetic and pharmacodynamic properties of paliperidone including receptor binding, clinical efficacy, safety and tolerability. Expert opinion: Paliperidone is currently the only medication FDA approved specifically for the treatment of schizoaffective disorder. Paliperidone is an active metabolite of risperidone, is minimally metabolized in the liver and is primarily known to be cleared through the kidneys. For this reason, paliperidone could be considered for some patients with schizoaffective disorder who also have hepatic impairment. After correcting for the reduced protein binding that is characteristic of hepatically impaired patients, the Cmax was 12% lower than in healthy subjects while the AUC and CL/F were comparable [14]. In addition, the availability of long acting injectable formulations may be useful for patients who are non-adherent with oral medications. The cost of paliperidone may be a disadvantage. PMID- 28675308 TI - Traumatic bifrontoparietal extradural hematomas with detachment of superior sagittal sinus: a case report and review of the literature. AB - A 45-year-old man suffered bifrontoparietal extradural hematoma resulting from head injury, which cause superior sagittal sinus detachment from its subperiosteal loggia. We present the patient who was treated by early surgical evacuation of the hematoma with an excellent outcome and we also perform a review of the current literature. PMID- 28675309 TI - A meta-analysis of the core essence of psychopathological entities: an historical exercise in phenomenological psychiatry. AB - Two fundamentally different approaches among phenomenological psychopathologists can be discerned. One is what we call fixed essentialism, where the pathognomonic element of, say, schizophrenia is conceived of as a single, enduring and intrinsically morbid way of grasping all entities in the world, including self and body. The other, which we call dialectical essentialism, accounts for the same manifestations of, say, schizophrenia, but through a process which is not life-enduring, and, most critically vis-a-vis the former formulation, is not in itself a single morbid defect: a morbid pattern of world, self and body is achieved by an imbalance between two or more otherwise healthy constituents of the 'normal' human being, whose imbalance and attempts to resolve this - the dialectic - induce the 'morbidity'. PMID- 28675310 TI - Effect of crude protein concentration and dietary electrolyte balance on litter quality, foot pad dermatitis, growth performance and processing yields in two medium heavy turkey hybrids. AB - 1. An experiment was conducted to investigate the effect of crude protein (CP) concentration and dietary electrolyte balance (DEB) on growth performance, processing yields, litter quality and foot pad dermatitis (FPD) in male turkeys from two commercial hybrids. Soya bean meal was replaced by vegetable protein sources selected for lower K concentrations to lower DEB in order to improve litter quality and subsequent quality of foot pads. 2. Effects of CP on litter friability and wetness were not consistent during the production period. FPD in turkeys fed on diets with low CP was significantly lower than FPD in turkeys fed on diets with high CP until 84 d. Growth performance was adversely affected at low CP. Processing yields were not affected by CP. 3. Litter was significantly dryer in pens of turkeys fed on diets with low DEB than in pens of turkeys fed on diets with high DEB. FPD in turkeys fed on diets with low DEB was significantly lower than in turkeys fed on diets with high DEB. Growth performance and processing yields were adversely affected at low DEB. 4. FPD in turkey hybrid A was higher than in turkey hybrid B at 28 d of age. Thereafter, no differences in FPD between turkey hybrids were observed. Growth performance and processing yields were not affected by turkey hybrid. 5. Overall, a significant interaction effect of CP * DEB was observed for FCR: in turkeys fed on the high DEB treatment, FCR of turkeys fed on the high CP diets was lower than FCR of turkeys fed on the low CP (LCP) diets whereas on the low DEB treatment, FCR was not affected by CP treatment. 6. It was concluded that litter quality can be improved and FPD may be decreased in turkeys fed on diets containing lower CP and DEB levels. PMID- 28675311 TI - Microwave-Induced Plasma Optical Emission Spectrometry (MIP OES) and Standard Dilution Analysis to Determine Trace Elements in Pharmaceutical Samples. AB - In this work, we evaluate the application of microwave-induced plasma optical emission spectrometry (MIP OES) to determine of Al, Cr, Co, Cu, Fe, Mn, Ni and Zn in children's cough syrup, eye drops, and oral antiseptic using standard dilution analysis (SDA). The SDA method is simple, with only two calibration solutions prepared per sample. The first solution (S1), composed of 50% sample +50% of a standard solution, is introduced into the plasma and the analytical signals are monitored in a time-resolved fashion. Then, the second solution (S2), composed of 50% sample +50% blank, is poured into the vial containing S1. As the solutions mix, the analytical signals gradually drop to a stable baseline. The calibration curve is computed by plotting the ratio of the analyte signal (SA) over the internal standard signal (which is also part of S1) (SIS) on the y-axis, versus the inverse of the IS concentration on the x-axis (i.e., SA/SIS versus 1/CIS). In this study, SDA results were compared with values obtained with the traditional methods of external calibration (EC), internal standardization (IS), and standard additions (SA) in MIP OES determinations. The precision (represented as percent RSD) for SDA showed values in the range of 2.50-8.00% for all samples, while conventional calibration methods showed RSDs in the range of 6.40-32.50% for EC, 8.30-21.80% for IS, and 5.20-17.40% for SA. The LODs calculated for SDA are below the maximum limits allowed by the major pharmaceutical regulatory agencies, and presents superior precision and accuracy compared to the traditional calibration methods. Considering its simplicity and efficiency, SDA is an important new tool for accurate analyses of pharmaceuticals. PMID- 28675312 TI - An investigation of the psychometric properties of the Geriatric Anxiety Scale (GAS) in an Italian sample of community-dwelling older adults. AB - BACKGROUND: The Italian older adult population is increasing and psychiatric problems, such as anxiety among older adults, represent major challenges for public welfare. A strong need exists for instruments specifically developed to assess anxiety among Italian older adults. The Geriatric Anxiety Scale (GAS) is a 30-item self-report questionnaire that evaluates anxiety among older adults and has demonstrated strong psychometric properties in several languages. OBJECTIVE: The present study aimed to validate an Italian version of the GAS (GAS-I) and to preliminarily investigate its psychometric properties. METHOD: The translation was performed using a five-stage procedure, following a forward-back process and paying attention to cultural issues. The GAS-I was administered to 231 community dwelling older adults with other commonly-used questionnaires of anxiety, depression, and quality of life. RESULTS: Results confirmed good psychometric qualities of the questionnaire. Confirmatory factor analyses evidenced a unidimensional structure of the GAS-I, in accordance with other validated versions. Convergent and discriminant validity were highly satisfactory. The three-factor model also provided an acceptable fit to the data. Receiver operating characteristic curve analyses revealed good discriminatory power of the GAS-I. CONCLUSION: These findings demonstrate that the GAS-I is a reliable and valid self-report questionnaire to measure anxiety among Italian older adults. PMID- 28675313 TI - Values of vanillylmandelic acid and homovanillic acid in the urine as potential prognostic biomarkers in ischaemic stroke patients. AB - BACKGROUND: Suitable biomarkers that have prognostic values are one of the key points of interest in ischaemic stroke. Increased sympathetic nervous system activity in ischaemic stroke causes multiple local and systemic effects that can be detrimental to the outcome. The mechanism of action is increased secretion and activity of catecholamines, whose end metabolic products are vanillylmandelic acid and homovanilic acid. Aim of our study was to determine whether these compounds can be used as potential prognostic biomarkers in ischaemic stroke, as a unique insight into the activity of the sympathetic nervous system. METHODS: Urine samples of 96 patients with ischaemic stroke and transitory ischaemic attacks were analysed. Values of vanillylmandelic and homovanillic acids in urine were tested using liquid chromatography on the first and third day post-stroke. Severity of stroke was determined using the NIHSS scale, while functional outcome was determined using the Modified Rankin Scale. RESULTS: Values of vanillylmandelic and homovanillic acids positively correlated with functional outcome of ischaemic stroke. Favorable outcomes correlated with decreased values, on contrary to increased values, which were associated with unfavourable outcomes. CONCLUSION: Determining the values of these compounds in the urine is an easily available prognostic tool for the ischaemic stroke outcome, while also influencing potential therapeutic changes. PMID- 28675314 TI - Con Drury: philosopher and psychiatrist. AB - Maurice O'Connor Drury (1907-76), an Irish psychiatrist, is best known for his accounts of his close friendship with the eminent twentieth-century philosopher, Ludwig Wittgenstein. His only book, The Danger of Words (1973), was well received by those who had an interest in the relationship between psychiatry, psychology and philosophy. This article concentrates on Drury's experiences, studies and writings in these fields. PMID- 28675315 TI - A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3 acetyl-rac-glycerol. AB - To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 degrees C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, Cmax, and Tmax values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG. PMID- 28675316 TI - The relations between conscientiousness and mental health in a North-European and a West-Asian culture. AB - BACKGROUND: The relationship between conscientiousness, mental health and mental illness has been an issue for the last two decades. AIMS: By using a dual model of mental health, the present study examined a non-linear relationship between conscientiousness and healthy or non-healthy symptoms in two different cultures. METHOD: Participants in this study were 296 Iranian and 310 Swedish university students (18-24 years of age). We used two different conscientiousness scales; the 12-item conscientiousness subscale of the NEO/FFI as an imported (etic) scale, and a 10-item Iranian conscientiousness scale as an indigenous (emic) and culture-dependent scale. RESULTS: In both conscientiousness scales, multivariate analysis of variance showed that conscientiousness differentiated among four mental health groups (languishing, troubled, symptomatic and flourishing), although languishing and troubled individuals were less conscientious than flourishing and symptomatic individuals. Furthermore, the non-healthy symptomatic individuals were more conscientiousness than flourishing individuals. The results showed no significant differences between the two cultures in terms of the four mental health categories. CONCLUSIONS: It was concluded that the relationship between conscientiousness and mental health/mental illness is more a non-linear relationship than a linear one. PMID- 28675317 TI - Emerging applications of gene edited T cells for the treatment of leukemia. PMID- 28675318 TI - Immunomodulatory and antioxidant protective effect of Sarcocornia perennis L. (swampfire) in lead intoxicated rat. AB - Lead (Pb) is a very toxic metal present in the environment, causing disturbances of several functions. Preventive or curative effects of halophytic plants against these disorders may be a promising and safe therapeutic strategy. Thus, this study was designed to evaluate in vivo immunomodulatory and antioxidant effects of Sarcocornia perennis extract (Sp) against lead toxicity in rats. Groups of six animals each were treated with plant extract (via food), 6 g/L lead acetate (via drinking water) or a combination of both. At the end of the three-week period, rat exposure to lead caused reduction of liver weight but an increase of that of kidney. Moreover, lead intoxication-induced oxidative stress manifested by significant increases of inflammatory cytokines (except IL-10) and lipid peroxidation (TBARS), compared with the control group. Meanwhile, interleukin-10 (IL-10) and glutathione levels (GSH), as well as antioxidant activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), were decreased. Considering liver and renal markers, lead treatment induced a significant increase in the activities of aminotransferases (AST, ALT), and in the levels of urea, creatinine and phosphorous, whereas total plasma protein, albumin and calcium levels were significantly decreased. S. perennis extract alone did not induce any significant changes in hepatic or renal markers, whereas the antioxidant markers were significantly increased. S. perennis supplementation significantly reduced the lead-induced elevation of serum IL-1beta, IL-6, TNF alpha, IFN-gamma and TBARS but increased the IL-10 and antioxidant enzyme activities. Overall, plant components ameliorated hepatorenal damages caused by lead. PMID- 28675319 TI - Nrf2: a potential therapeutic target for naturally occurring anticancer drugs? AB - INTRODUCTION: Nuclear factor (erythroid-derived-2)-like 2 is one of the most efficient cytoprotective rheostats against exogenous or endogenous oxidative insults. At present, the modulation of the Nrf2 pathway represents an interesting and highly explored strategy in the oncological area. Area covered: In this review, we present and discuss the different modulation of the Nrf2 pathway by some natural compounds with a well demonstrated anticancer activity, and critically analyze the challenges associated with the development of an Nrf2 based anticancer strategy. Expert opinion: Many natural compounds with a well defined anticancer activity are able to modulate this pathway. Both Nrf2 inducers and inhibitors can be useful as anticancer strategy. However, since Nrf2 modulates many networks potentially involved in the detoxification process of anticancer drugs, its activation in cancer cells could lead to chemoresistance. The switch between a beneficial or detrimental role of Nrf2 in cancer cells essentially depends on the tight control of its activity, the specific conditions of tumor microenvironment, and cell type. In line with the paucity of clear data related to the mechanisms underpinning the role of Nrf2 in cancer development and chemoresistance, discovery and development of Nrf2-based strategies is one of the most critical and challenging assignments for fighting cancers. PMID- 28675320 TI - Flow cytometry for feline lymphoma: a retrospective study regarding pre analytical factors possibly affecting the quality of samples. AB - Objectives Flow cytometry (FC) is becoming increasingly popular among veterinary oncologists for the diagnosis of lymphoma or leukaemia. It is accurate, fast and minimally invasive. Several studies of FC have been carried out in canine oncology and applied with great results, whereas there is limited knowledge and use of this technique in feline patients. This is mainly owing to the high prevalence of intra-abdominal lymphomas in this species and the difficulty associated with the diagnostic procedures needed to collect the sample. The purpose of the present study is to investigate whether any pre-analytical factor might affect the quality of suspected feline lymphoma samples for FC analysis. Methods Ninety-seven consecutive samples of suspected feline lymphoma were retrospectively selected from the authors' institution's FC database. The referring veterinarians were contacted and interviewed about several different variables, including signalment, appearance of the lesion, features of the sampling procedure and the experience of veterinarians performing the sampling. Statistical analyses were performed to assess the possible influence of these variables on the cellularity of the samples and the likelihood of it being finally processed for FC. Results Sample cellularity is a major factor in the likelihood of the sample being processed. Moreover, sample cellularity was significantly influenced by the needle size, with 21 G needles providing the highest cellularity. Notably, the sample cellularity and the likelihood of being processed did not vary between peripheral and intra-abdominal lesions. Approximately half of the cats required pharmacological restraint. Side effects were reported in one case only (transient swelling after peripheral lymph node sampling). Conclusions and relevance FC can be safely applied to cases of suspected feline lymphomas, including intra-abdominal lesions. A 21 G needle should be preferred for sampling. This study provides the basis for the increased use of this minimally invasive, fast and cost-effective technique in feline medicine. PMID- 28675321 TI - The impact of a person-centred community pharmacy mental health medication support service on consumer outcomes. AB - BACKGROUND: Mental illness is a worldwide health priority. As medication is commonly used to treat mental illness, community pharmacy staff is well placed to assist consumers. AIM: To evaluate the effectiveness of a multifaceted, community pharmacy medication support service for mental health consumers. METHOD: Pharmacists and pharmacy support staff in three Australian states were trained to deliver a flexible, goal-oriented medication support service for adults with mental illness over 3-6 months. Consumer-related outcome measures included perceptions of illness and health-related quality of life, medication beliefs, treatment satisfaction and medication adherence. RESULTS: Fifty-five of 100 trained pharmacies completed the intervention with 295 of the 418 recruited consumers (70.6% completion rate); 51.2% of consumers received two or more follow ups. Significant improvements were reported by consumers for overall perceptions of illness (p < 0.001), the mental health domain of quality of life (p < 0.001), concerns about medication (p = 0.001) and global satisfaction with medication (p < 0.001). Consumers also reported an increase in medication adherence (p = 0.005). CONCLUSIONS: A community pharmacy mental health medication support service that is goal-oriented, flexible and individualised, improved consumer outcomes across various measures. While further research into the cost effectiveness and sustainability of such a service is warranted, this intervention could easily be adapted to other contexts. PMID- 28675322 TI - Assessing vocational outcome expectancy in individuals with serious mental illness: a factor-analytic approach. AB - BACKGROUND: Self-determination theory (SDT) and self-efficacy theory (SET) can be used to conceptualize self-determined motivation to engage in mental health and vocational rehabilitation (VR) services and to predict recovery. To incorporate SDT and SET as a framework for vocational recovery, developing and validating SDT/SET measures in vocational rehabilitation is warranted. Outcome expectancy is an important SDT/SET variable affecting rehabilitation engagement and recovery. AIMS: The purpose of this study was to validate the Vocational Outcome Expectancy Scale (VOES) for use within the SDT/SET vocational recovery framework. METHODS: One hundred and twenty-four individuals with serious mental illness (SMI) participated in this study. Measurement structure of the VOES was evaluated using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). RESULTS: Both EFA and CFA results supported a two-factor structure: (a) positive outcome expectancy, and (b) negative outcome expectancy. The internal consistency reliability coefficients for both factors were acceptable. In addition, positive outcome expectancy correlated stronger than negative outcome expectancy with other SDT/SET constructs in the expected directions. CONCLUSIONS: The VOES is a brief, reliable and valid instrument for assessing vocational outcome expectancy in individuals with SMI that can be integrated into SDT/SET as a vocational rehabilitation engagement and recovery model in psychiatric rehabilitation. PMID- 28675323 TI - The clinical use of Subjective Units of Distress scales (SUDs) in child mental health assessments: a thematic evaluation. AB - BACKGROUND: Despite the ubiquitous use of Subjective Units of Distress scales (SUDs) in mental health settings to establish levels of distressing emotion, there has been little empirical research in this area. SUDs are commonly used in therapy and assessments, and are a particularly useful tool for establishing current and previous levels of distress in children and young people. AIMS: To explore the use of the SUD analogue rating scale in initial child mental health assessments to better understand its application in this context. METHOD: The data corpus consisted of 28 naturally-occurring video recordings of children and young people attending their first assessment appointment at Child and Adolescent Mental Health Services (CAMHS). A thematic analysis was utilised to explore the specific interactional use of SUDs. RESULTS: Four themes were identified; recency, longevity, context and miscommunication. The first three themes were found to supplement the child's emotional score on the scale and were important in establishing the necessity for further therapeutic support. Miscommunication as a theme highlighted the need for clarity when using SUDs with children and young people. CONCLUSIONS: Recommendations were suggested for practitioners working with children and young people relating to the extended use of rating scales in clinical assessments. PMID- 28675324 TI - Cost-effectiveness analysis of single-session walk-in counselling. AB - BACKGROUND: An increasing number of family service agencies and community-based mental health service providers are implementing a single-session walk-in counselling (SSWIC) as an alternative to traditional counselling. However, few economic evaluations have been undertaken. AIMS: To conduct a cost-effectiveness analysis of two models of service delivery, SSWIC compared to being waitlisted for traditional counselling. METHODS: A quasi-experimental design was employed. Data were collected from two community-based Family Service Agencies, one using SSWIC and one using traditional counselling. Participants were assessed at baseline and four weeks after the baseline. Cost-effectiveness was estimated from the societal and payer's perspective. RESULTS: The societal and payer's costs for SSWIC were higher than for those waiting for traditional counselling, and health outcomes were better. SSWIC is not cost-effective compared to being on the waitlist for traditional counselling (or, for a few patients, having received counselling, but after a wait of several weeks). CONCLUSIONS: SSWIC has the potential to reduce the pressure on the mental health care system by reducing emergency visits and wait lists for ongoing mental health services and eliminating costly-no shows at counselling appointments. Long-term studies involving multiple walk-in counselling services and comparison services are needed to support the findings of this study. PMID- 28675325 TI - Cross-Informant Agreement on the Child Behavior Checklist for Youths: A Meta Analysis. AB - This meta-analysis of 169 studies examines the rank-order and mean-level agreements for the Child Behavior Checklist. The correlations between parents and teachers (.18-.35) and those between teachers and youths (.19-.32) were from small to moderate and generally moderate for those between parents and youths (.33-.40). The mean-level disagreements between parents and youths were small, while those between parents and teachers and those between teachers and youths varied. The rank-order agreement estimates were global, unlike those at mean level. The magnitude of mean-level disagreement was related to youth characteristics, parent characteristics, assessment contexts, and scale measured. Further research is needed on the agreement between teachers and youths, for which relatively few studies have been conducted. PMID- 28675326 TI - Mixed Frames and Risky Decision-Making. AB - By applying unitive vocabulary, "die" or "save," to respective frames of the Asian disease problem, Tversky and Kahneman were able to define framing effect. In this study, we preliminarily explored the effect of mixed frames, which are characterized by the use of different vocabulary in one frame. In study 1, we found that only the sure option description had significant effect on decision making, while the effects of risky option descriptions were not significant, nor were interactions between descriptions. In study 2, the results suggested that after controlling the effects of the hedonic tone of the sure options, risky option description did not significantly predict decision-making. In study 3, we found that neither the sure-to-risky option presentation order nor presentation order within risky options had significant effect on decision-making. We thus concluded that sure option description can serve as the decision-making foundation (reference point) for decision-makers in mixed frames. PMID- 28675327 TI - Measuring mental health in the clinical setting: what is important to service users? The Mini-Service user Recovery Evaluation scale (Mini-SeRvE). AB - BACKGROUND: Since 2001, a policy of positive mental health recovery has been promoted in the UK, with service user involvement. This has not been easy to implement in the clinical setting. AIMS: To develop and validate a brief self report, service user-designed, outcome measure (Mini-SeRvE), for clinical use, including spiritual and religious issues. METHODS: From the previously developed Service user Recovery Evaluation scale (SeRvE), 15 questions were selected for Mini-SeRvE which was self-completed by 207 people; 100 service users and, for comparison, 107 staff. Results were analysed using SPSS software (SPSS Inc., Chicago, IL). RESULTS: Mini-SeRvE is reliable, Cronbach's alpha 0.852. Correlation with another recovery scale, Mental Health Recovery Measure, was high, r = 0.819. Three reliable subscales emerged; existential well-being (EWB), mental ill-being (MIB) and religious well-being (RWB). Scores of the EWB and MIB subscales were higher for staff, consistent with higher mental well-being. Religious well-being scores were higher in service users, who also rated religion as more important to them. CONCLUSIONS: Mini-SeRvE is a valid measure of service user recovery. The importance of religion/spiritual belief for our users is highlighted, this being reflected in the subject matter of Mini-SeRvE. Mini-SeRvE assessments could show individual priorities, evaluate therapy and aid clinical decision-making. PMID- 28675328 TI - Sex Differences in Drop Landing: More Apparent in Recreational Surfers Than in Competitive Surfers or Nonsurfers. AB - We suspected that the observed inconsistency of sex differences in drop-landing motor skills might be due to the confounding factor of prior experience. Thus, in this study, we explored the role of experience in shaping male and female surfboard riders' motor skill kinematics during drop landings while surfboard riding. We recruited 42 participants (21 females and 21 males) from three groups of surfing experience levels (competitive surfers, recreational surfers, and nonsurfers), each equally comprising seven males and seven females. Sagittal plane kinematics and vertical ground reaction force data were collected from all participants during a laboratory-based 60-cm drop-landing task. Knee flexion and ankle dorsiflexion at initial ground contact were greater among male participants, independent of experience level. In both sexes, greater range of motion at these joints was related to greater experience. Recreational female surfers landed in a more upright posture with more extended ankle and knee angles and less ankle dorsiflexion at the end of landing than participants in all other groups. We discuss our results in the context of possible remaining experience differences between male and female participants despite being grouped in the same experience levels in our study, individualized motor patterns that may still achieve similar success, and a need for continued research. PMID- 28675329 TI - Switched on or switched off? A survey of mobile, computer and Internet use in a community mental health rehabilitation sample. AB - BACKGROUND: UK society is undergoing a technological revolution, including meeting health needs through technology. Government policy is shifting towards a "digital by default" position. Studies have trialled health technology interventions for those experiencing psychosis and shown them to be useful. AIMS: To gauge levels of engagement with mobile phones (Internet-enabled or cell phone), computers and the Internet in the specific population of community mental health rehabilitation. METHOD: Two surveys were conducted: with service-users on use/non-use of technologies, and interest in technology interventions and support; and with placements on facilities and support available to service users. RESULTS: Levels of engagement in this population were substantially less than those recorded in the general UK and other clinical populations: 40.2% regularly use mobiles, 17.5% computers, and 14.4% the Internet. Users of all three technologies were significantly younger than non-users. Users of mobiles and computers were significantly more likely to live in lower support/higher independence placements. Of surveyed placements, 35.5% provide a communal computer and 38.7% IT skills sessions. CONCLUSIONS: Community mental health rehabilitation service-users risk finding themselves excluded by a "digital divide". Action is needed to ensure equal access to online opportunities, including healthcare innovations. Clinical and policy implications are discussed. PMID- 28675330 TI - Prevalence and attitudes on female genital mutilation/cutting in Egypt since criminalisation in 2008. AB - Female genital mutilation/cutting (FGM/C), which can result in severe pain, haemorrhage and poor birth outcomes, remains a major public health issue. The extent to which prevalence of and attitudes toward the practice have changed in Egypt since its criminalisation in 2008 is unknown. We analysed data from the 2005, 2008 and 2014 Egypt Demographic and Health Surveys to assess trends related to FGM/C. Specifically, we determined whether FGM/C prevalence among ever married, 15-19-year-old women had changed from 2005 to 2014. We also assessed whether support for FGM/C continuation among ever-married reproductive-age (15-49 years) women had changed over this time period. The prevalence of FGM/C among adolescent women statistically significantly decreased from 94% in 2008 to 88% in 2014 (standard error [SE] = 1.5), after adjusting for education, residence and religion. Prevalence of support for the continuation of FGM/C also statistically significantly decreased from 62% in 2008 to 58% in 2014 (SE = 0.6). The prevalence of FGM/C among ever-married women aged 15-19 years in Egypt has decreased since its criminalisation in 2008, but continues to affect the majority of this subgroup. Likewise, support of FGM/C continuation has also decreased, but continues to be held by a majority of ever-married women of reproductive age. PMID- 28675332 TI - A potential role for outdoor, interactive spaces as a healthcare intervention for older persons. PMID- 28675331 TI - Qualitative analysis of social network influences on quitting smoking among individuals with serious mental illness. AB - OBJECTIVE: The prevalence of cigarette smoking among adults with serious mental illness (SMI) remains high in the United States despite the availability of effective smoking cessation treatment. Identifying social influences on smoking and smoking cessation may help enhance intervention strategies to help smokers with SMI quit. The objective of this qualitative study was to explore social network influences on efforts to quit smoking among adults with SMI enrolled in a cessation treatment program. METHODS: Participants were 41 individuals with SMI enrolled in a Medicaid Demonstration Project of smoking cessation at community mental health centers. A convenience sampling strategy was used to recruit participants for social network interviews exploring the influence of family, friends, peers, and significant others on quitting smoking. A team-based analysis of qualitative data involved descriptive coding, grouping coded data into categories, and identifying themes across the data. RESULTS: Social barriers to quitting smoking included pro-smoking social norms, attitudes, and behaviors of social network members, and negative interactions with network members, either specific to smoking or that triggered smoking. Social facilitators to quitting included quitting with network members, having cessation role models, and social support for quitting from network members. CONCLUSIONS: Similar to the general population, social factors appear to influence efforts to quit smoking among individuals with SMI enrolled in cessation treatment. Interventions that leverage positive social influences on smoking cessation have the potential to enhance strategies to help individuals with SMI quit smoking. PMID- 28675333 TI - Why is it difficult to evaluate the effectiveness and cost-effectiveness of complex public health interventions in the community? A health economics perspective. PMID- 28675334 TI - Health is wealth. PMID- 28675338 TI - Making every contact count: the potential role of healthy living pharmacies in weight management. PMID- 28675340 TI - Is a review of the current Smoke-Free legislation and guidance required in the United Kingdom? Considering smoking shelters design, planning requirements and Smoke-Free legislation enforcement. PMID- 28675341 TI - Sustainable development goals: implementing the hygiene indicator in schools. PMID- 28675342 TI - Keeping the focus on Vision 2020. PMID- 28675343 TI - State of the art in the validation of screening methods for the control of antibiotic residues: is there a need for further development? AB - Screening methods are used as a first-line approach to detect the presence of antibiotic residues in food of animal origin. The validation process guarantees that the method is fit-for-purpose, suited to regulatory requirements, and provides evidence of its performance. This article is focused on intra-laboratory validation. The first step in validation is characterisation of performance, and the second step is the validation itself with regard to pre-established criteria. The validation approaches can be absolute (a single method) or relative (comparison of methods), overall (combination of several characteristics in one) or criterion-by-criterion. Various approaches to validation, in the form of regulations, guidelines or standards, are presented and discussed to draw conclusions on their potential application for different residue screening methods, and to determine whether or not they reach the same conclusions. The approach by comparison of methods is not suitable for screening methods for antibiotic residues. The overall approaches, such as probability of detection (POD) and accuracy profile, are increasingly used in other fields of application. They may be of interest for screening methods for antibiotic residues. Finally, the criterion-by-criterion approach (Decision 2002/657/EC and of European guideline for the validation of screening methods), usually applied to the screening methods for antibiotic residues, introduced a major characteristic and an improvement in the validation, i.e. the detection capability (CCbeta). In conclusion, screening methods are constantly evolving, thanks to the development of new biosensors or liquid chromatography coupled to tandem-mass spectrometry (LC-MS/MS) methods. There have been clear changes in validation approaches these last 20 years. Continued progress is required and perspectives for future development of guidelines, regulations and standards for validation are presented here. PMID- 28675344 TI - The optimization of technological processes, stability and microbiological evaluation of innovative natural ingredients-based multiple emulsion. AB - For the last couple of decades, multiple emulsions were prepared either by the re emulsification of primary emulsion or they were produced by an emulsion inversion and their technological peculiarities were widely investigated. The aim of our study was to investigate and determine the optimal technological parameters of innovative multiple emulsion, prepared directly-by addition of ethanolic rosemary extract in the presence of polymeric emulsifier-and evaluate its stability by experimental surface response design approach. The results revealed that simplified W/O/W emulsification process is stirring time and stirring speed sensitive: the change of stirring time from 5 to 15 min at 600 rpm resulted in increased viscosity (from 1705.6 +/- 62.2 to 3364.1 +/- 112.5 mPA/s) and smaller oil droplet size (from 33.09 +/- 1.51 to 17.81 +/- 0.78 MUm), though the conductivity increased from 800 +/- 2 to 882 +/- 2 MUS/cm (p < .05). The second mixing stage (1000 rpm) had a negative effect on the conductivity of W/O/W emulsion because of the inner aqueous phase encapsulation efficiency. Ethanolic rosemary extract was used as multifunctional agent: not only to form multiple emulsion but also to preserve it; microbiological assay confirmed its effectiveness. A stable W/O/W type drug delivery system was successfully created without additional technological stages, phase inversion or surfactants. PMID- 28675345 TI - Transvenous retrograde AVM embolization: Indications, techniques, complications and outcomes. AB - Objective Transvenous retrograde arteriovenous malformation (AVM) embolization (TRAE) has been proposed. The present study was to review the techniques, their conjunctions and effectiveness. Methods Eligible related articles were identified by searching the PubMed and Web of Science databases using "transvenous" and "arteriovenous malformation." Results A total of 16 eligible studies, with 60 cases of AVM treated with TRAE, were analyzed. Prior to TRAE procedure, transarterial Onyx 18 was performed in 23 (38.3%), cyanoacrylate in three (5%) and coiling in two (3.3%), neurosurgery in one (1.7%) and radiosurgery in three (5%). These prior treatments were used to reduce the size of the nidus to <3 cm and TRAE was performed. One anterior choroidal artery aneurysm was coiled before TRAE. Systemic hypotension (blood pressure<100 mmHg) occurred in six (10%) patients and local hypotension (proximal arterial temporary balloon protection) in five (8.3%) patients. Complete obliteration was achieved in 56 (93.3%) AVMs, four (6.7%) with residual, of which one was supplemented with radiosurgery. During mean one-year follow-up (1 month to 3.2 years), there were five cases (8.3%) of permanent disability and one (1.7%) mortality resulting from initial hemorrhage. Fifty-four (90%) patients were independent (mRS <= 2) at follow-up. Ruptured AVMs and Spetzler-Martin I-III were associated with a high cure rate. Conclusion According to previous reports, selected AVMs could undergo TRAE. TRAE is safe and curative with Onyx after the nidus size is reduced sufficiently by transarterial embolization, neurosurgery or radiosurgery, with or without the aid of proximal arterial temporary balloon protection. PMID- 28675346 TI - Trigeminal neuralgia caused by a new variant of persistent trigeminal artery associated with agenesis of internal carotid artery. AB - We report a hitherto undescribed persistent carotid vertebral anastomosis associated with ipsilateral internal carotid artery agenesis and bilateral duplication of the intradural vertebral arteries. This rare anomaly was detected on MRI, supplemented by CT angiography while evaluating for cause trigeminal neuralgia in a 37-year-old woman. The aberrant vessel was seen to cause thinning and lateral displacement of the left trigeminal nerve on CISS 3D images. Also noted was a bilateral vertebral artery duplication of the PSA variant with the posterior inferior cerebellar artery arising from the medial limb of the duplication on the left. PMID- 28675347 TI - Rare association between spinal dural arteriovenous fistulas and dysraphisms: Report of two cases and review of the literature with a focus on pitfalls in diagnosis and treatment. AB - Spinal vascular malformations are uncommon yet important spinal pathologies commonly classified in congenital and acquired lesions. Spinal lipomas consist of three subtypes: intramedullary lipomas, lipomyelo(meningo)celes and lipomas of the filum. Although the association of spinal arteriovenous malformations (AVM) with other congenital anomalies is well known, the coexistence of dural arteriovenous fistulas (AVF) and tethered spinal cord is exceptionally rare and only eight cases have been reported. We present two cases from our institution and speculate on the possible origin of such a rare but insidious association. We review the current literature with a focus on possible pitfalls in diagnosis and treatment. PMID- 28675348 TI - Navien catheter experience in neuroendovascular interventions. AB - Purpose Advancements in catheter technology have allowed for greater flexibility and trackability. We report 265 consecutive, single-center neurointerventional cases using the Navien guide catheter. Materials and methods Retrospective analysis was performed of consecutive intracranial endovascular procedures utilizing the Navien catheter. Data collected included procedure type, catheters, guide catheter position, cervical access artery tortuosity grade and complications. Results The 5 French catheter was used in 130 cases. The 6 French catheter was used in 135 cases. Access was via the internal carotid artery in 204, external carotid artery in 10, and vertebral artery in 51 cases. Catheter tip position was in the petrous segment of the internal carotid artery in 36.6% (97/265), distal cervical internal carotid artery in 13.9% (37/265), cavernous internal carotid artery in 10.2% (27/265), proximal or mid cervical internal carotid artery in 5.6% (15/265), supraclinoid internal carotid artery in 0.8% (2/265), and intradural vertebral artery in 0.8% (2/265) of cases. Catheter position was not determined in 18.9% (50/265) of cases. Proximal vessel tortuosity (grade B or C) was present in 98 cases (37%), and the catheter was tracked distal to the tortuosity in 93% (91/98) of these cases. The overall success rate without catheter complication was 97% (258/265). The Navien was replaced by another catheter in 1.9% (5/265) of cases. There was one cervical artery dissection (0.4%) and one severe vasospasm (0.4%) necessitating Navien removal. Conclusions The Navien guide catheter provided distal access support for neuroendovascular interventions in nearly all cases, including cases with proximal artery tortuosity, with a low rate of catheter-related complications. PMID- 28675349 TI - Novel solution for luminal access loss into the double-layered LVIS BlueTM construct. AB - We described a novel solution for a challenging case of double-layered LVIS BlueTM (LB) stent construct retraction into a large cavernous aneurysm. The double-layered LB stent construct was used as a flow diverter for treatment of a large cavernous aneurysm. Our solution comprised a balloon angioplasty and placement of balloon-mounted cardiac-stent construct through the side wall of the LB construct, with eventual placement of a Pipeline Flex inside of the final conduit. PMID- 28675350 TI - One-year efficacy and safety of the Trufill DCS Orbit and Orbit Galaxy detachable coils in the endovascular treatment of intracranial aneurysms: Results from the TRULINE study. AB - Background and purpose No series reported the mid-term results of Trufill DCS Orbit and Orbit Galaxy detachable coils with independent evaluation. We present the one-year safety and efficacy of these coils in real-life routine clinical practice. Methods A total of 167 patients with 167 aneurysms (39.1% ruptured) were enrolled in the prospective TRULINE study. The primary endpoint was the safety, assessed by the combined morbidity-mortality rate observed since the time of the procedure and up to one-year follow-up. For safety, primary analyses were performed on intent-to-treat population (attempted coils procedure) and all adverse events have been reviewed by an independent Data Safety Monitoring Board. For efficacy, primary analyses were performed on the per-protocol population (patients treated with more than 70% of Trufill coils and not retreated during the follow-up period) and an independent core laboratory evaluated angiographic results. Results At one-year post-procedure, neurologic impairment was observed in 6.5% (95% confidence interval: 3.5-11.8) of the patients, and 2.6% (95% confidence interval: 1.0-6.8) had a permanent neurological deterioration. Three deaths were observed, unrelated to the procedure or coils. At one year, complete occlusion was seen in 52 aneurysms (54.2%), neck remnant in 28 aneurysms (29.2%), and aneurysm remnant in 16 aneurysms (16.7%). During the one-year follow-up, the overall incidence of recurrence was 30.2% with a mean interval of 13.8 +/- 4.5 months and the retreatment for major recanalization was needed in nine patients (6.3%). Conclusions The TRULINE study confirms that endovascular coiling with Trufill DCS Orbit and Orbit Galaxy detachable coils is safe and effective. PMID- 28675351 TI - On the origin and timing of Zika virus introduction in Brazil. AB - The timing and origin of Zika virus (ZIKV) introduction in Brazil has been the subject of controversy. Initially, it was assumed that the virus was introduced during the FIFA World Cup in June-July 2014. Then, it was speculated that ZIKV may have been introduced by athletes from French Polynesia (FP) who competed in a canoe race in Rio de Janeiro in August 2014. We attempted to apply mathematical models to determine the most likely time window of ZIKV introduction in Brazil. Given that the timing and origin of ZIKV introduction in Brazil may be a politically sensitive issue, its determination (or the provision of a plausible hypothesis) may help to prevent undeserved blame. We used a simple mathematical model to estimate the force of infection and the corresponding individual probability of being infected with ZIKV in FP. Taking into account the air travel volume from FP to Brazil between October 2013 and March 2014, we estimated the expected number of infected travellers arriving at Brazilian airports during that period. During the period between December 2013 and February 2014, 51 individuals travelled from FP airports to 11 Brazilian cities. Basing on the calculated force of ZIKV infection (the per capita rate of new infections per time unit) and risk of infection (probability of at least one new infection), we estimated that 18 (95% CI 12-22) individuals who arrived in seven of the evaluated cities were infected. When basic ZIKV reproduction numbers greater than one were assumed in the seven evaluated cities, ZIKV could have been introduced in any one of the cities. Based on the force of infection in FP, basic reproduction ZIKV number in selected Brazilian cities, and estimated travel volume, we concluded that ZIKV was most likely introduced and established in Brazil by infected travellers arriving from FP in the period between October 2013 and March 2014, which was prior to the two aforementioned sporting events. PMID- 28675352 TI - Salipiger nanhaiensis Dai et al. 2015 is a later heterotypic synonym of Thiobacimonas profunda Li et al. 2015. AB - Salipiger nanhaiensis ZH114T was compared with Thiobacimonas profunda JLT2016T to clarify their taxonomic relationship. The results of the 16S rRNA gene sequence comparison indicated that the two strains had 99.7 % sequence similarity. Results of phylogenetic analysis indicated that the two strains formed a tight cluster, distinctly branching from Salipiger mucosus A3T and other representatives in the family Rhodobacteraceae. Whole genomic comparison between the two strains yielded a digital DDH estimate of 97.3 % and ANI value of 99.7 %, strongly supporting the hypothesis that the two strains represented a single species. In addition, the two strains displayed no striking differences in physiological and biochemical properties, fatty acid composition or polar lipids profile. Due to priority, Salipiger nanhaiensis is reclassified as a later heterotypic synonym of Thiobacimonas profunda based on the phylogenetic relationship inferred from the 16S rRNA gene sequence, whole genomic comparison, fatty acid composition and polar lipid profile and other phenotypic and biochemical properties. PMID- 28675353 TI - Saccharospirillum correiae sp. nov., an endophytic bacterium isolated from the halophyte Halimione portulacoides. AB - A Gram-stain negative, oxidase- and catalase- positive, motile, aerobic, non pigmented spirillum, designated CPA1T, was isolated from the surface-sterilized tissues of a halophyte, Halimione portulacoides, collected from a salt marsh in Aveiro, Portugal. The isolate was mesophilic, facultatively alkaliphilic and halophilic, and grew between 18 and 42.5 degrees C (optimum 30 degrees C), from pH 5.0 to 11.5 (optimum 7.0-7.5), from 0.5 to 5 % NaCl (w/v, optimum 2 %). Analysis of the 16S rRNA gene sequence showed that this strain belongs to the genus Saccharospirillum, as the highest sequence similarities were observed with Saccharospirillum impatiens EL-105T (96.46 %), Saccharospirillum salsuginis YIM Y25T (96.32 %) and Saccharospirillum aestuariiIMCC 4453T (95.17 %). The next closest matches were with other genera and below 95.0 %. Phylogenetic analyses revealed that the strain forms a robust clade with other species of the genus Saccharospirillum. The main respiratory quinone was Q-8 and the major fatty acids were C16 : 0 and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The DNA G+C content was 55.2 mol%. Molecular, physiological and biochemical differences between strain CPA1T and other type strains of species of the genus Saccharospirillum support the addition of this novel species to the genus, and the name Saccharospirillum correiae sp. nov. is proposed, with CPA1T (=CECT 9131T=LMG 29516T) as the type strain. PMID- 28675354 TI - Corrigendum: Micromonospora terminaliae sp. nov., an endophytic actinobacterium isolated from the surface-sterilized stem of the medicinal plant Terminalia mucronata. PMID- 28675355 TI - Induction of interferon and interferon-induced antiviral effector genes following a primary bovine herpesvirus-1 (BHV-1) respiratory infection. AB - Invitro investigations have identified a variety of mechanisms by which herpesviruses evade interferon-stimulated antiviral effector mechanisms. However, these immune evasion mechanisms have not been evaluated during a bovine herpesvirus-1 (BHV-1) infection. This study investigated the transcription and secretion of type I and II interferons (IFNs) and the transcription of IFN stimulated genes (ISGs) during a primary BHV-1 infection of the upper respiratory tract (URT) in naive calves. IFN-alpha, -beta and -gamma transcription in nasal turbinates and protein levels in nasal secretions increased following infection. Increased IFN type I and II secretion was detected 3 days post-infection (p.i.) and IFN production increased in parallel with virus shedding. Expression of ISGs, including Mx1, OAS and BST-2, also increased significantly (P<0.05) in nasal turbinates on day 3 p.i. and elevated ISG expression persisted throughout the period of viral shedding. In contrast, RNAase L gene expression was not induced during the BHV-1 infection in the nasal turbinates, but was induced on day 10 p.i. in the trachea. In vitro studies confirmed that recombinant bovine (rBo)IFN alpha, -beta and -gamma induced expression of Mx1, OAS and BST-2, but decreased RNAse L transcript in bovine epithelial cells. Relative to vesicular stomatitisvirus (VSV), BHV-1 was resistant to the antiviral activity of rBoIFN alpha and -gamma, but treatment of epithelial cells with 10 ng rBoIFN-beta ml-1 effected an 80 % inhibition of BHV-1 replication and complete inhibition of VSV replication. These observations confirm that the transcription and translation of type I and II IFNs increase during BHV-1 infection, while the transcription of some ISGs is not inhibited. PMID- 28675356 TI - Current Management of Perihilar Cholangiocarcinoma and Future Perspectives. AB - Perihilar cholangiocarcinoma is the most common type of biliary tract cancer and is associated with a high mortality, usually due to late presentation. High resolution cross-sectional imaging modalities are necessary for diagnosis and preoperative planning. Although surgical resection with negative margins offers the only hope for cure, only a small subset of patients are amenable for surgery at the time of diagnosis. Portal vein embolization and biliary tract decompression are important in some patients prior to surgical resection. Liver transplantation in combination with neoadjuvant therapy has resulted in excellent 5-year recurrence-free survival rates in highly selected patients with inoperable disease. Gemcitabine plus cisplatin constitute the backbone of chemotherapy in patients with inoperable metastatic perihilar cholangiocarcinoma. Recent advances in understanding the molecular pathogenesis of CCA have created a growing interest in identifying novel therapies targeting key molecular pathways. Herein, we provide an overview of the most current principles of management of patients with perihilar cholangiocarcinoma. PMID- 28675357 TI - The European Policy for Liver Allocation in Patients Affected by Hepatocellular Carcinoma. AB - The main goal of allocation system is to guarantee an equal access to the limited resource of liver grafts for every class of patients on the waiting list, balancing between the ethical principles of equity, utility, benefit, need, and fairness. The aim of this review was to analyze liver allocation policies among these organizations, focusing on HCC. The European area considered for this analysis included 6 macro-areas or countries, which are congregated from the same policy of liver sharing and allocation. By this definition, the 6 areas identified are: Centro Nazionale Trapianti (CNT) in Italy; Eurotransplant (Germany, the Netherlands, Belgium, Luxembourg, Austria, Hungary, Slovenia, and Croatia); Organizacion Nacional de Transplantes (ONT) in Spain; Etablissement francais des Greffes (EfG) in France; NHS Blood Transplant (NHSBT) in the United Kingdom and Ireland; Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland); Romanian National Policy. Each identified area, as network for organ sharing in Europe, adopts a basic allocation system that consider a policy center oriented or patient oriented. Priorization of patients affected by HCC in the waiting list for deceased donors liver transplant worldwide is dominated by 2 main principles: urgency and utility. The main message of this review is the absence of a common organs allocation policy over the Eurpean countries. Despite that, long-term survival of the community of patients listed for transplant due to HCC results, however, highly acceptable in Europe and comparable to the long term survial reported in the UNOS register. PMID- 28675358 TI - Living Donor Liver Transplantation. AB - In 50 years after the first liver transplantation, the medical world has witnessed the liver transplantation to become one of the widely recognized and leading branches of surgery. In this period, liver transplantation combined with surgical technique, patient selection, advancements in anesthesia and postoperative care and increased experience has become the most effective treatment option in treatment of several acute and chronic liver diseases. Yet, the worldwide organ restriction and associated high mortality rates in organ transplantation waiting list has compelled referring to living donors in order to expand the donor pool. This paper explains liver transplantation indications from living donors, the surgical technique involved, the complications of the procedure and the medical treatments used. PMID- 28675359 TI - The Romanian National Program for Liver Transplantation - 852 Procedures in 815 Patients over 17 Years (2000-2017): A Continuous Evolution to Success. AB - Background: Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT. Methods: Between April 2000 and April 2017, 817 pts received 852 LTs in Romania. Male/female ratio was 487/330, while adult/pediatric ratio was 753/64, with a mean age of 46 years (median 50 yrs; range 7 months - 68 yrs). Main LT indications were HBV cirrhosis (230 pts; 28.2%), HCC (173 pts; 21.2%), and HCV cirrhosis (137 pts; 16.8%). Waiting time and indications for LT, patient and donor demographics, graft features, surgical procedures, and short and long-term outcomes were analyzed. Results: DDLT was performed in 682 pts (83.9%): whole LT in 662 pts (81%), split LT in 16 pts (2.3%), reduced LT in 2 pts (0.2%), and domino LT in 1 pts (0.1%). LDLT was performed in 135 pts (16.5%): right hemiliver in 93 pts (11.4%), left lateral section in 28 pts (3.4%), left hemiliver in 8 pts (1%), left hemiliver with segment 1 in 4 pts (0.5%), and dual graft LDLT in 2 pts (0.2%). Overall major morbidity rate was 31.4% (268 pts), while perioperative mortality was 7.9% (65 pts). Retransplantation rate was 4.3% (35 pts): 27 whole LTs, 3 reduced LTs, 3 split LTs, and 2 LDLT. Long-term overall 1-, 3-, and 5-year estimated survival rates for patients were 87.9%, 81.5%, and 79.1%, respectively. One-, 3-, and 5-year overall mortality on waiting list also decreased significantly over time from 31.4%, 54.1% and 63.5%, to 4.4%, 13.9% and 23.6%, respectively. Conclusions: The Romanian National program for liver transplantation addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques, with good long-term outcome. The program constantly evolved over time, leading to decreased mortality rate on the waiting list. PMID- 28675360 TI - Four Years of Hepatic Transplantation in the Republic of Moldova. AB - Ever since the first liver transplant in the Republic of Moldova in 2013 we have performed 30 liver transplantations, the first having been performed in collaboration with the surgical team from Romania, led by Professor Irinel Popescu. The serious deficit of available cadaveric organs has forced us to begin with right hemi-liver transplantation from a living donor. In one third of liver transplantations we used right hemi-liver graft from a living donor, and in 2/3 of cases whole liver graft was harvested from brain-dead donors. The indication for surgical intervention in most cases was hepatic cirrhosis of viral aetiology in terminal stages, three cases of hepatocellular carcinoma, and one case for each of primary biliary cirrhosis, drug-induced toxic hepatitis, and liver retransplantation caused by hepatic arterial thrombosis. 10 cadaveric grafts were harvested from elderly donors ( 65 years). In the early postoperative period, four recipients died (2 live donor graft recipients and 2 graft recipients from donors with brain death). Causes of death were: intracerebral haemorrhage in the early postoperative period - 1, acute graft rejection - 1, hepatic artery thrombosis - 1, primary graft dysfunction - 1. There were no deaths during the late postoperative period. Of the complications that occurred during the early postoperative period we can highlight acute graft rejection -2, hepatic arterial thrombosis - 1, intraabdominal postoperative haemorrhage - 1, hepatic artery thrombosis -1, biliary peritonitis - 1, primary graft dysfunction -1, seizures 1. Complications during the postoperative period: biliary peritonitis after choledochal drainage removal - 1, "small-for-size" - 2. The accumulated experience and the use of modern technologies has allowed us to reduce the postoperative mortality rate, as well as the rate of occurring complications, in order to transfer this surgical intervention from the category of exclusivity operations to the category of daily interventions. PMID- 28675361 TI - A Lesser-Known Hepatic Anatomical and Surgical Structure: the Rouviere-Gans Incisura (RGI). AB - Rouviere-Gans incisura (RGI) is a relatively frequent hepatic anatomosurgical structure (it appears in 52%-80% of cases), but it is not wellknown in hepatic surgery. The presence of RGI is an important landmark to avoid biliary lesions during laparoscopic cholecystectomy, since it allows the isolation of the right posterior glissonean pedicle in 70% of cases, therefore simplifying the resection of the posterior right hepatic section or its segments (Sg6 and Sg7). While performing a right posterior hepatic resection for living-donor liver transplantation, the presence of the RGI facilitates the dissection of the vasculo-biliary structures in the right posterior glissonean pedicle. PMID- 28675362 TI - Liver Resections in a High-Volume Center: Form Standard Procedures to Extreme Surgery and Ultrasound-guided Resections. AB - : Background: Liver resection (LR) is the treatment of choice for most benign and malignant focal liver lesions, as well as in selected patients with liver trauma. Few other therapies can compete with LR in selected cases, such as liver transplantation in hepatocellular carcinoma (HCC) and ablative therapies in small HCCs or liver metastases. The present paper analyses a single center experience in LR, reviewing the indications of LR, the operative techniques and their short term results. MATERIAL AND METHOD: Between January 2000 and December 2016, in "?Dan Setlacec" Center of General Surgery and Liver Transplantation were performed 3165 LRs in 3016 patients, for pathologic conditions of the liver. In the present series, liver resections for living-donor liver transplantation were excluded. The median age of the patients was 56 years (mean 58 years; range 1 88), with male/female ratio 1524/1492 and adult/pediatric patient ratio 2973/43. Results: Malignant lesions were the main indication for LR (2372 LRs; 74.9%). Among these, colorectal liver metastases were the most frequent indication (952 LRs; 30.1%), followed by hepatocellular carcinoma (575 patients, 18.2%). The highest number of resected tumors per patient was 21, and the median diameter of the largest tumor was 40 mm (mean 51 mm; range 3-250). Major resections rate was 18.6% (588 LRs) and anatomical LRs were performed in 789 patients (24.9%). The median operative time was 180 minutes (mean 204 minutes; range 45-920). The median blood loss was 500 ml (mean 850 ml; range 500-9500), with a transfusion rate of 41.6% (1316 LRs). The morbidity rate was 40.1% (1270 LRs) and the rate of major complications (Dindo-Clavien IIIa or more) was 13.2% (418 LRs). Mortality rate was 4.2% (127 pts). CONCLUSION: LRs should be performed in specialized high volume centers to achieve the best results (low morbidity and mortality rates). PMID- 28675363 TI - Comparative Analysis between Simultaneous Resection and Staged Resection for Synchronous Colorectal Liver Metastases - A Single Center Experience on 300 Consecutive Patients. AB - : Introduction: In synchronous colorectal liver metastases (SCLMs), simultaneous resection (SR) of the primary tumor and liver metastases has not gained wide acceptance. Most authors prefer staged resections (SgR), especially in patients presenting rectal cancer or requiring major hepatectomy. Methods: Morbidity, mortality, survival rates and length of hospital stay were compared between the two groups of patients (SR vs. SgR). A subgroup analysis was performed for patients with similar characteristics (e.g. rectal tumor, major hepatectomy, bilobar metastases, metastatic lymph nodes, preoperative chemotherapy). Results: Between 1995 and 2016, SR was performed in 234 patients, while 66 patients underwent SgR. Comparative morbidity (41% vs. 31.8%, respectively, p = 0.1997), mortality (3.8% vs. 3%, respectively, p = 1) and overall survival rates (85.8%, 51.3% and 30% vs. 87%, 49.6% and 22.5%, at 1-, 3- and 5-years, respectively, p = 0.386) were similar between the SR and SgR group. Mean hospital stay was significantly shorter in patients undergoing SR than SgR (15.11 ?+- 8.60 vs. 19.42 ?+- 7.36 days, respectively, p 0.0001). The characteristics of SR and SgR groups were similar, except the following parameters: rectal tumor (34.1% vs. 19.7%, respectively, p = 0.0245), metastatic lymph nodes (68.1% vs. 86.3%, respectively, p = 0.0383), bilobar liver metastases (22.6% vs. 37.8%, respectively, p = 0.0169), major hepatectomies (13.2% vs. 30.3%, respectively, p= 0.0025) and neo-adjuvant chemotherapy (13.2% vs. 77.2%, respectively, p 0.0001). A comparative analysis of morbidity, mortality and survival rates between SR and SgR was performed for subgroups of patients presenting these parameters. In each of these subgroups, SR was associated with similar morbidity, mortality and survival rates compared with SgR (p value 0.05). CONCLUSION: In patients with SCLMs, SR provides similar short-term and long-term outcomes as SgR, with a shorter hospital stay. Therefore, in most patients with SCLMs, SR might be considered the treatment of choice. PMID- 28675365 TI - Extension of Hepatic Resection Ameliorates Survival in Patients with Type IIIa or IIIb Klatskin Tumors Despite Surgical Complications. AB - Background: Major hepatectomies for hilar cholangiocarcinoma (HC) are associated with high rates of morbidity and mortality. We aimed to evaluate how and if surgical complications related to extended hepatectomies for HC type III and IV according to Bismuth-Corlette classification influence patients long-term survival. Methods: The files of all patients with major hepatectomy for HC and postoperative complications were retrospectively reviewed. Only patients with a complete postoperative follow up have be taken into account for the study. Postoperative morbidity and mortality, length of hospital stay (LOS) as well as overall survival (OS) and disease free survival (DFS) were recorded. Results: Five patients have been found to respond to all inclusion criteria. Three of them required re-operation with one in hospital death. Two patients are still alive and two other died because of the tumor recurrence with a DFS of 36 and 49 months respectively. The actuarial mean OS for the group was 30 months and the actuarial DFS was 26 months. Conclusions: In patients with HC, extensive resections bring a clearly benefit in terms of survival, even though there is an increase in postoperative morbidity and mortality. However, postoperative complications, if managed susccesfully do not interfere with the long-term survival. PMID- 28675364 TI - Curative Intent Treatment of Hepatocellular Carcinoma - 844 Cases Treated in a General Surgery and Liver Transplantation Center. AB - Background: The objective of this study is to assess the outcome of the patients treated for hepatocellular carcinoma (HCC) in a General Surgery and Liver Transplantation Center. Methods: This retrospective study includes 844 patients diagnosed with HCC and surgically treated with curative intent methods. Curative intent treatment is mainly based on surgery, consisting of liver resection (LR), liver transplantation (LT). Tumor ablation could become the choice of treatment in HCC cases not manageable for surgery (LT or LR). 518 patients underwent LR, 162 patients benefited from LT and in 164 patients radiofrequency ablation (RFA) was performed. 615 patients (73%) presented liver cirrhosis. Results: Mordidity rates of patient treated for HCC was 30% and mortality was 4,3% for the entire study population. Five year overall survival rate was 39 % with statistically significant differences between transplanted, resected, or ablated patients (p 0.05) with better results in case of LT followed by LR and RFA. Conclusions: In HCC patients without liver cirrhosis, liver resection is the treatment of choice. For early HCC occurred on cirrhosis, LT offers the best outcome in terms of overall and disease free survival. RFA colud be a curative method for HCC patients not amenable for LT of LR. PMID- 28675366 TI - Curative-intent Surgery for Perihilar Cholangiocarcinoma with and without Portal Vein Resection - A Comparative Analysis of Early and Late Outcomes. AB - : Introduction: The safety of portal vein resection (PVR) during surgery for perihilar cholangiocarcinoma (PHC) has been demonstrated in Asia, America, and Western Europe. However, no data about this topic are reported from Eastern Europe. The aim of the present study is to comparatively assess the early and long-term outcomes after resection for PHC with and without PVR. PATIENTS AND METHODS: The data of 21 patients with PVR were compared with those of 102 patients with a curative-intent surgery for PHC without PVR. The appropriate statistical tests were used to compare different variables between the groups. Results: A PVR was performed in 17% of the patients. In the PVR group, significantly more right trisectionectomies (p=0.031) and caudate lobectomies (0.049) were performed and, as expected, both the operative time (p=0.015) and blood loss (p=0.002) were significantly higher. No differences between the groups were observed regarding the severe postoperative morbidity and mortality rates, and completion of adjuvant therapy. However, in the PVR group the postoperative clinicallyrelevant liver failure rate was significantly higher (p=0.001). No differences between the groups were observed for the median overall survival times (34 vs. 26 months, p = 0.566). A histological proof of the venous tumor invasion was observed in 52% of the patients with a PVR and was associated with significantly worse survival (p=0.027). CONCLUSION: A PVR can be safely performed during resection for PHC, without significant added severe morbidity or mortality rates. However, clinically-relevant liver failure rates are significantly higher when a PVR is performed. Furthermore, increased operative times and blood loss should be expected when a PVR is performed. Histological tumor invasion of the portal vein is associated with significantly worse survival. PMID- 28675367 TI - State of the Art of Intraoperative Ultrasound in Liver Surgery: Current Use for Resection-guidance. AB - The performance of hepatic surgery without a parenchyma-sparing strategy carries significant risks for patient survival because of the not negligible occurrence of postoperative liver failure. In the modern liver surgery the use of the intraoperative ultrasound (IOUS) allows the performance of the so-called A?AcA?A?A?A?radical but conservative surgeryA?AcA?A?A?A?, which is the pivotal factor to offer a chance of cure to an increasing proportion of patients, who until few years ago were considered only for palliative care. The present article details the rationale of IOUS for resection-guidance in liver surgery. PMID- 28675368 TI - Ante-situm Liver Resection for Giant Hepatic Tumour - Case Report and Review of Literature. AB - Ex-situ liver surgery refers to complex liver resections involving hepatic vascular exclusion and a warm ischemia time (WIT) of more than 90 minutes that allows liver resection and vascular reconstruction in patients with giant liver tumours with a difficult approach . Ante-situm liver resections, otherwise called "?ex-situ in-vivo"? resections is achieved through externalization of the liver outside of the abdominal cavity by clamping and sectioning of the efferent pedicles (suprahepatic veins) ("ex situ"?) without cutting the afferent vascular pedicle ("in vivo"?), thus leaving the hepatic pedicle intact. We present a case report of a 36 yo male patient diagnosed by MRI scan with giant liver tumor in the left hemiliver. A left "ex-situ in-vivo" hepatectomy was performed by dissecting and ligating the left and middle hepatic veins, clamping and sectioning the right hepatic vein, Pringle maneuver, externalization of the liver followed by the tumor resection and right hepatic vein reimplantation. The short warm ischemia time (hepatic resection + liver reimplantation - 30 minutes) allowed us to perform the procedure without installing a veno-venous or porto caval shunt otherwise used in all of ex-situ procedures described in the literature reviewed in this presentation. Ex-situ liver resection is a viable procedure for giant liver tumours in highly selected cases. It facilitates resection of large liver tumours that would be otherwise unresectable, extending the indications of surgical treatment. PMID- 28675369 TI - GOOD TO KNOW: The ALPPS Procedure - Embracing a New Technique. AB - BACKGROUND: Hepatic resection is the only potentially curative treatment for primary liver tumorsand hepatic metastases. The most frightening postoperative complication of extensive hepatectomiesis liver failure due to insufficient future liver remnant (FLR). The ALPPS technique(Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) effectively increasedthe resectability of otherwise inoperable liver tumors (primary or secondary malignant liver tumor)by achieving a rapid and an effective hypertrophy of the FLR, which lowers postoperative liverfailure risk. AIM: To present the ALPPS classic right trisectionectomy and its technical variants which wereinvented to decrease the high rate of post-operative morbidity and mortality, reported in early caseseries. TECHNIQUE: ALPPS involves two stages. The first surgical procedure consists in the ligation of the rightportal branch and the partition of the liver at the site of the falciform ligament (insitu splitting). Incontrast to a classical hepatectomy, the tumoral hemiliver is left in situ and remains vascularized by theright hepatic artery only. The biliary and systemic venous drainages represented by the right biliaryduct and respectively the hepatic veins, are preserved. The second step of the procedure is usuallyperformed within 7 to 15 days after the firststage. The tumoral hemiliver is removed by sectioning theright hepatic artery, the biliary duct and the systemic venous pedicle. Conclusions: The ALPPS technique is a therapeutic method for inoperable liver tumors by standardmethods of hepatectomy +/- portal vein ligation (PVL). By careful patient selection and technicaladjustment to the particular conditions of each case, better outcomes have been achieved, leadingtoan increasing number of surgeons who perform ALPPS. PMID- 28675370 TI - Early Spontaneous Graft Intra- and Perihepatic Hematoma after Liver Transplantation. AB - Hematoma of the graft is a life threatening complication of liver transplantation (LT) and there has been no overt conclusion in the literature about optimal management except in scarcely reported cases. It may be either intrahepatic or subcapsular, then again it may develop spontaneously or following parenchimal injuries or transhepatic percutaneous invasive manoeuvers. In this report we describe a rare case of large spontaneous graft intra- and perihepatic hematoma. A 62 year-old man underwent a whole graft orthotopic liver transplantation (OLT) for decompensated chronic liver disease due to alcoholic cirrhosis. The surgical procedure was uneventful. During the early postoperative course, routine Doppler ultrasound examination and CT-scan revealed an extrahepatic paracaval hematoma, 7 days after transplantation, which was stable and conservatively managed until the 18-th postoperative day, when rapidly expanding intraparenchimal hematoma involving the right hemiliver, several other perihepatic hematomas, significant right pleural effusion and hemorrhagic ascites were described. The patient was successfully treated conservatively (nonsurgically) with slow recovery of the liver allograft and discharged one month later in good general status. PMID- 28675371 TI - Proximal femoral derotation osteotomy for idiopathic excessive femoral anteversion and intoeing gait. AB - AIM: The purpose of this study is to assess the symptoms caused by excessive femoral anteversion and the outcomes of femoral derotation osteotomy. METHODS: We reviewed data on patients who underwent proximal femoral derotation osteotomy for symptomatic intoeing gait caused by femoral anteversion. Only symptomatic patients were considered for corrective derotation osteotomy. Degree of femoral anteversion was confirmed on computed tomography (CT) scan. RESULTS: Thirty-five extremities were operated in 21 patients with an average age of 13.3 (8-18) years. Mean follow-up was 16 months (6-36 months). Mean femoral anteversion angle was 40.8 degrees (28 degrees -53 degrees ). External rotation of extended hips improved significantly, from 30 degrees to 51.8 degrees (p < 0.0001). Mean foot progressing angle improved from 15.2 degrees internally rotated preoperatively to 7.7 degrees externally rotated. Intoeing completely resolved in all except two patients. Thirteen out of 21 children complained about tripping and frequent falling while running and playing sports, eight patients had hip pain while 13 children had knee pain preoperatively. Tripping, falling and hip pain resolved in all patients postoperatively, while three patients whose primary complaint was knee pain failed to improve postsurgery. Eighteen of the 21 parents were satisfied with the decision to perform surgical correction. CONCLUSION: Excessive femoral anteversion can present with unexplained hip or knee pain refractory to conservative treatments. Careful assessment of lower limb malalignment is a valuable tool in such circumstances and derotation proximal femoral osteotomy can certainly be a procedure of choice in carefully selected cases. PMID- 28675372 TI - Boundary Dpp promotes growth of medial and lateral regions of the Drosophila wing. AB - The gradient of Decapentaplegic (Dpp) in the Drosophila wing has served as a paradigm to characterize the role of morphogens in regulating patterning. However, the role of this gradient in regulating tissue size is a topic of intense debate as proliferative growth is homogenous. Here, we combined the Gal4/UAS system and a temperature-sensitive Gal80 molecule to induce RNAi mediated depletion of dpp and characterise the spatial and temporal requirement of Dpp in promoting growth. We show that Dpp emanating from the AP compartment boundary is required throughout development to promote growth by regulating cell proliferation and tissue size. Dpp regulates growth and proliferation rates equally in central and lateral regions of the developing wing appendage and reduced levels of Dpp affects similarly the width and length of the resulting wing. We also present evidence supporting the proposal that graded activity of Dpp is not an absolute requirement for wing growth. PMID- 28675373 TI - Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc. AB - The Dpp morphogen gradient derived from the anterior stripe of cells is thought to control growth and patterning of the Drosophila wing disc. However, the spatial-temporal requirement of dpp for growth and patterning remained largely unknown. Recently, two studies re-addressed this question. By generating a conditional null allele, one study proposed that the dpp stripe is critical for patterning but not for growth (Akiyama and Gibson, 2015). In contrast, using a membrane-anchored nanobody to trap Dpp, the other study proposed that Dpp dispersal from the stripe is required for patterning and also for medial wing disc growth, at least in the posterior compartment (Harmansa et al., 2015). Thus, growth control by the Dpp morphogen gradient remains under debate. Here, by removing dpp from the stripe at different time points, we show that the dpp stripe source is indeed required for wing disc growth, also during third instar larval stages. PMID- 28675375 TI - Specific Immunotherapy in Hymenoptera Venom Allergy and Concomitant Malignancy: A Retrospective Follow-up Focusing on Effectiveness and Safety. AB - BACKGROUND: Malignancies are often considered a contraindication for allergen specific immunotherapy. Consequently, patients with severe Hymenoptera venom allergy and cancer require specific care. The aim of this retrospective study was to assess patients with Hymenoptera venom allergy and cancer undergoing venom immunotherapy (VIT). METHODS: The study population comprised all patients referred for evaluation of Hymenoptera venom allergy or for a routine check-up during VIT from January 1, 2004 to December 31, 2008. RESULTS: Of the patients assessed, 2% (51 of 2594) had a documented Hymenoptera venom allergy and cancer (25 female, 26 male; mean age 58 years). Of these, 42 patients received VIT (82%): 25 patients had a previously diagnosed malignancy, 16 were diagnosed with malignancy during VIT, and 1 patient was diagnosed with cancer after completion of VIT. The most frequent type of tumor was breast cancer in female patients (60%) and prostate cancer in male patients (39%). Systemic allergic reactions during VIT were recorded in 7% of patients. A total of 19 patients experienced a field sting or underwent a sting challenge test during VIT: 95% tolerated the sting well. VIT was halted definitively in 9 patients (new diagnosis of cancer in 7 patients, reactivation of cancer in 1, and progressive polyneuropathy in 1). CONCLUSIONS: The effectiveness and adverse effects of VIT in patients with Hymenoptera venom allergy and cancer in remission are comparable to those of patients without malignancy. Our findings show that patients with Hymenoptera venom allergy and cancer are eligible for VIT. PMID- 28675374 TI - Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. AB - Dpp, a member of the BMP family, is a morphogen that specifies positional information in Drosophila wing precursors. In this tissue, Dpp expressed along the anterior-posterior boundary forms a concentration gradient that controls the expression domains of target genes, which in turn specify the position of wing veins. Dpp also promotes growth in this tissue. The relationship between the spatio-temporal profile of Dpp signalling and growth has been the subject of debate, which has intensified recently with the suggestion that the stripe of Dpp is dispensable for growth. With two independent conditional alleles of dpp, we find that the stripe of Dpp is essential for wing growth. We then show that this requirement, but not patterning, can be fulfilled by uniform, low level, Dpp expression. Thus, the stripe of Dpp ensures that signalling remains above a pro growth threshold, while at the same time generating a gradient that patterns cell fates. PMID- 28675376 TI - Model-based Bayesian signal extraction algorithm for peripheral nerves. AB - OBJECTIVE: Multi-channel cuff electrodes have recently been investigated for extracting fascicular-level motor commands from mixed neural recordings. Such signals could provide volitional, intuitive control over a robotic prosthesis for amputee patients. Recent work has demonstrated success in extracting these signals in acute and chronic preparations using spatial filtering techniques. These extracted signals, however, had low signal-to-noise ratios and thus limited their utility to binary classification. In this work a new algorithm is proposed which combines previous source localization approaches to create a model based method which operates in real time. APPROACH: To validate this algorithm, a saline benchtop setup was created to allow the precise placement of artificial sources within a cuff and interference sources outside the cuff. The artificial source was taken from five seconds of chronic neural activity to replicate realistic recordings. The proposed algorithm, hybrid Bayesian signal extraction (HBSE), is then compared to previous algorithms, beamforming and a Bayesian spatial filtering method, on this test data. An example chronic neural recording is also analyzed with all three algorithms. MAIN RESULTS: The proposed algorithm improved the signal to noise and signal to interference ratio of extracted test signals two to three fold, as well as increased the correlation coefficient between the original and recovered signals by 10-20%. These improvements translated to the chronic recording example and increased the calculated bit rate between the recovered signals and the recorded motor activity. SIGNIFICANCE: HBSE significantly outperforms previous algorithms in extracting realistic neural signals, even in the presence of external noise sources. These results demonstrate the feasibility of extracting dynamic motor signals from a multi fascicled intact nerve trunk, which in turn could extract motor command signals from an amputee for the end goal of controlling a prosthetic limb. PMID- 28675377 TI - Investigation of novel superparamagnetic Ni0.5Zn0.5Fe2O4@albumen nanoparticles for controlled delivery of anticancer drug. AB - In the present work, multifunctional Ni0.5Zn0.5Fe2O4@albumen (NZF@Alb) and doxorubicin-loaded Ni0.5Zn0.5Fe2O4@albumen (NZF@Alb-Dox) core-shell nanoparticles have been prepared by a green and simple method using inexpensive chicken egg albumen and have been characterized for different physiochemical properties. The structural, morphological, thermal, and magnetic properties of the prepared nanoparticles have been investigated by an x-ray diffractometer, high-resolution transmission electron microscopy (HRTEM), field emission scanning electron microscopy, Fourier-transformed infrared, thermogravimetric analysis, and vibrating sample magnetometer techniques. Superparamagnetic Ni0.5Zn0.5Fe2O4 nanoparticles (NZF NPs) with the mean size ~20 nm were coated with albumen matrix by an ultrasonication process. Inverse fast Fourier transform-assisted HRTEM micrographs and FTIR analysis revealed the coating of amorphous albumen on crystalline NZF NPs. NZF@Alb and NZF@Alb-Dox NPs have the mean size (D50) of ~100 nm, good stability, and magnetic controllability. Magnetic measurements (field (H)-dependent magnetization (M)) show all samples to be super-paramagnetic in nature. Biocompatibilities of the NZF and NZF@Alb NPs were confirmed by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against RAW 264.7 cells. NZF@Alb NPs have been found to be more biocompatible than bare NZF. In Vitro Dox release behavior from NZF@Alb-Dox NPs has been studied at pH 7.4 and 5, and a sustained and pH-dependent drug release profile were observed. In vitro cytotoxicity or anticancer activity of the blank NZF@Alb NPs, free Dox, and NZF@Alb-Dox NPs against HeLa cells (cancer cell line) were also examined by MTT assay. The obtained results suggest that this scalable egg-albumen-based magnetic nanoformulation is suitable for targeted drug delivery applications. Thus, the present study could be extremely useful for the advancement of albumin based nanocarrier design and development for biomedical applications such as targeted and controlled delivery of anticancer drugs. PMID- 28675378 TI - Application of dual-energy CT to suppression of metal artefact caused by pedicle screw fixation in radiotherapy: a feasibility study using original phantom. AB - The objective of the present study was the determination of the potential dosimetric benefits of using metal-artefact-suppressed dual-energy computed tomography (DECT) images for cases involving pedicle screw implants in spinal sites. A heterogeneous spinal phantom was designed for the investigation of the dosimetric effect of the pedicle-screw-related artefacts. The dosimetric comparisons were first performed using a conventional two-directional opposed (AP PA) plan, and then a volumetric modulated arc therapy (VMAT) plan, which are both used for the treatment of spinal metastases in our institution. The results of Acuros(r) XB dose-to-medium (Dm) and dose-to-water (Dw) calculations using different imaging options were compared with experimental measurements including the chamber and film dosimetries in the spinal phantom. A dual-energy composition image with a weight factor of -0.2 and a dual-energy monochromatic image (DEMI) with an energy level of 180 keV were found to have superior abilities for artefact suppression. The Dm calculations revealed greater dosimetric effects of the pedicle screw-related artefacts compared to the Dw calculations. The results of conventional single-energy computed tomography showed that, although the pedicle screws were made from low-Z titanium alloy, the metal artefacts still have dosimetric effects, namely, an average (maximum) Dm error of 4.4% (5.6%) inside the spinal cord for a complex VMAT treatment plan. Our findings indicate that metal-artefact suppression using the proposed DECT (DEMI) approach is promising for improving the dosimetric accuracy near the implants and inside the spinal cord (average (maximum) Dm error of 1.1% (2.0%)). PMID- 28675379 TI - Non-steady state mass action dynamics without rate constants: dynamics of coupled reactions using chemical potentials. AB - Comprehensive and predictive simulation of coupled reaction networks has long been a goal of biology and other fields. Currently, metabolic network models that utilize enzyme mass action kinetics have predictive power but are limited in scope and application by the fact that the determination of enzyme rate constants is laborious and low throughput. We present a statistical thermodynamic formulation of the law of mass action for coupled reactions at both steady states and non-stationary states. The formulation uses chemical potentials instead of rate constants. When used to model deterministic systems, the method corresponds to a rescaling of the time dependent reactions in such a way that steady states can be reached on the same time scale but with significantly fewer computational steps. The relationships between reaction affinities, free energy changes and generalized detailed balance are central to the discussion. The significance for applications in systems biology are discussed as is the concept and assumption of maximum entropy production rate as a biological principle that links thermodynamics to natural selection. PMID- 28675380 TI - Corrigendum: Metagenome sequencing and 98 microbial genomes from Juan de Fuca Ridge flank subsurface fluids. AB - This corrects the article DOI: 10.1038/sdata.2017.37. PMID- 28675381 TI - Matched computed tomography segmentation and demographic data for oropharyngeal cancer radiomics challenges. AB - Cancers arising from the oropharynx have become increasingly more studied in the past few years, as they are now epidemic domestically. These tumors are treated with definitive (chemo)radiotherapy, and have local recurrence as a primary mode of clinical failure. Recent data suggest that 'radiomics', or extraction of image texture analysis to generate mineable quantitative data from medical images, can reflect phenotypes for various cancers. Several groups have shown that developed radiomic signatures, in head and neck cancers, can be correlated with survival outcomes. This data descriptor defines a repository for head and neck radiomic challenges, executed via a Kaggle in Class platform, in partnership with the MICCAI society 2016 annual meeting.These public challenges were designed to leverage radiomics and/or machine learning workflows to discriminate HPV phenotype in one challenge (HPV status challenge) and to identify patients who will develop a local recurrence in the primary tumor volume in the second one (Local recurrence prediction challenge) in a segmented, clinically curated anonymized oropharyngeal cancer (OPC) data set. PMID- 28675382 TI - An ab initio electronic transport database for inorganic materials. AB - Electronic transport in materials is governed by a series of tensorial properties such as conductivity, Seebeck coefficient, and effective mass. These quantities are paramount to the understanding of materials in many fields from thermoelectrics to electronics and photovoltaics. Transport properties can be calculated from a material's band structure using the Boltzmann transport theory framework. We present here the largest computational database of electronic transport properties based on a large set of 48,000 materials originating from the Materials Project database. Our results were obtained through the interpolation approach developed in the BoltzTraP software, assuming a constant relaxation time. We present the workflow to generate the data, the data validation procedure, and the database structure. Our aim is to target the large community of scientists developing materials selection strategies and performing studies involving transport properties. PMID- 28675383 TI - A web platform for landuse, climate, demography, hydrology and beach erosion in the Black Sea catchment. AB - The Black Sea catchment (BSC) is facing important demographic, climatic and landuse changes that may increase pollution, vulnerability and scarcity of water resources, as well as beach erosion through sea level rise. Limited access to reliable time-series monitoring data from environmental, statistical, and socio economical sources is a major barrier to policy development and decision-making. To address these issues, a web-based platform was developed to enable discovery and access to key environmental information for the region. This platform covers: landuse, climate, and demographic scenarios; hydrology and related water vulnerability and scarcity; as well as beach erosion. Each data set has been obtained with state-of-the-art modelling tools from available monitoring data using appropriate validation methods. These analyses were conducted using global and regional data sets. The data sets are intended for national to regional assessments, for instance for prioritizing environmental protection projects and investments. Together they form a unique set of information, which lay out future plausible change scenarios for the BSC, both for scientific and policy purposes. PMID- 28675384 TI - Deeply divergent archaic mitochondrial genome provides lower time boundary for African gene flow into Neanderthals. AB - Ancient DNA is revealing new insights into the genetic relationship between Pleistocene hominins and modern humans. Nuclear DNA indicated Neanderthals as a sister group of Denisovans after diverging from modern humans. However, the closer affinity of the Neanderthal mitochondrial DNA (mtDNA) to modern humans than Denisovans has recently been suggested as the result of gene flow from an African source into Neanderthals before 100,000 years ago. Here we report the complete mtDNA of an archaic femur from the Hohlenstein-Stadel (HST) cave in southwestern Germany. HST carries the deepest divergent mtDNA lineage that splits from other Neanderthals ~270,000 years ago, providing a lower boundary for the time of the putative mtDNA introgression event. We demonstrate that a complete Neanderthal mtDNA replacement is feasible over this time interval even with minimal hominin introgression. The highly divergent HST branch is indicative of greater mtDNA diversity during the Middle Pleistocene than in later periods. PMID- 28675385 TI - Eco-evolutionary dynamics in a contemporary human population. AB - Recent studies of the joint dynamics of ecological and evolutionary processes show that changes in genotype or phenotype distributions can affect population, community and ecosystem processes. Such eco-evolutionary dynamics are likely to occur in modern humans and may influence population dynamics. Here, we study contributions to population growth from detailed genealogical records of a contemporary human population. We show that evolutionary changes in women's age at first reproduction can affect population growth: 15.9% of variation in individual contribution to population growth over 108 years is explained by mean age at first reproduction and at least one-third of this variation (6.1%) is attributed to the genetic basis of this trait, which showed an evolutionary response to selection during the period studied. Our study suggests that eco evolutionary processes have modulated the growth of contemporary human populations. PMID- 28675386 TI - Unique prefrontal GABA and glutamate disturbances in co-occurring bipolar disorder and alcohol dependence. AB - Bipolar disorder (BD) and alcohol dependence (AD) frequently co-occur, and co occurring BD and AD are associated with devastating public health costs. Minimal neurobiological research exists to guide the development of effective treatments for this treatment-resistant population. We believe the present study represents the first investigation of prefrontal gamma-aminobutyric acid (GABA) and glutamate levels in co-occurring BD and current AD. The participants were 78 individuals who met DSM-IV criteria for BD I/II and current AD (n=20), BD I/II alone (n=19), current AD alone (n=20) or no diagnosis (n=19). The participants completed a baseline diagnostic visit, then returned approximately 4 days later for a two-dimensional J-resolved proton magnetic resonance spectroscopy (1H-MRS) acquisition in dorsal anterior cingulate cortex (dACC). All participants were required to demonstrate ?1 week of abstinence from alcohol/drugs via serial biomarker testing before 1H-MRS. A 2 * 2 factorial analysis of variance of cerebrospinal fluid (CSF)-corrected GABA/water concentrations demonstrated a significant BD * AD interaction (F=2.91, P<0.05), signifying uniquely low levels of GABA in BD+AD; this effect doubled when the sample was restricted to individuals who consumed alcohol within 2 weeks of 1H-MRS. There were no overall effects of BD/AD on CSF-corrected glutamate/water levels. However, the BD * AD interaction, signifying uniquely low levels of glutamate in BD+AD, approached statistical significance (F=3.83, P=0.06) in individuals who consumed alcohol within 2 weeks of 1H-MRS. The dACC GABA levels were significantly, negatively associated with Barratt Impulsiveness Scale (r=-0.28, P=0.02) and Obsessive Compulsive Drinking Scale (r=-0.35, P<0.01) scores. If replicated, these results may suggest that future treatment studies should preferentially evaluate therapeutics in BD+AD known to increase prefrontal GABA and glutamate levels. PMID- 28675387 TI - Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity. AB - A polymorphism in the promoter region of the human serotonin transporter (5-HTT) coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5 HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine-phosphate-guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36+/-10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36+/ 7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10 associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype. PMID- 28675388 TI - Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide. AB - Neuregulin-1 (NRG1) and ErbB receptors have been associated with psychopathology, and NRG1-ErbB3 signaling has been shown to increase hippocampal neurogenesis and induce antidepressant-like effects. In this study, we aimed to determine whether deficits in NRG1 or ErbBs might be present in the hippocampus of suicide completers. In well-characterized postmortem hippocampal samples from suicides and matched sudden-death controls, we assessed gene expression and methylation using qRT-PCR and EpiTYPER, respectively. Moreover, in hippocampal tissues stained with cresyl violet, stereology was used to quantify numbers of granule cells and of glia. Granule cell body size was examined with a nucleator probe, and granule cell layer volume with a Cavalieri probe. Unmedicated suicides showed sharply decreased hippocampal ErbB3 expression and decreased numbers of ErbB3 expressing granule cell neurons in the anterior dentate gyrus; a phenomenon seemingly reversed by antidepressant treatment. Furthermore, we found ErbB3 expression to be significantly decreased in the dentate gyrus of adult mice exposed to chronic social defeat stress. Taken together, these results reveal novel suicidal endophenotypes in the hippocampus, as well as a putative etiological mechanism underlying suicidality, and suggest that antidepressant or NRG1 treatment may reverse a potential deficit in anterior dentate gyrus granule cell neurons in individuals at risk of dying by suicide. PMID- 28675390 TI - Modifiable predictors of depression following childhood maltreatment: a systematic review and meta-analysis. AB - Although maltreatment experiences in childhood increase the risk for depression, not all maltreated children become depressed. This review aims to systematically examine the existing literature to identify modifiable factors that increase vulnerability to, or act as a buffer against, depression, and could therefore inform the development of targeted interventions. Thirteen databases (including Medline, PsychINFO, SCOPUS) were searched (between 1984 and 2014) for prospective, longitudinal studies published in English that included at least 300 participants and assessed associations between childhood maltreatment and later depression. The study quality was assessed using an adapted Newcastle-Ottawa Scale checklist. Meta-analyses (random effects models) were performed on combined data to estimate the effect size of the association between maltreatment and depression. Meta-regressions were used to explore effects of study size and quality. We identified 22 eligible articles (N=12 210 participants), of which 6 examined potential modifiable predictors of depression following maltreatment. No more than two studies examined the same modifiable predictor; therefore, it was not possible to examine combined effects of modifiable predictors with meta regression. It is thus difficult to draw firm conclusions from this study, but initial findings indicate that interpersonal relationships, cognitive vulnerabilities and behavioral difficulties may be modifiable predictors of depression following maltreatment. There is a lack of well-designed, prospective studies on modifiable predictors of depression following maltreatment. A small amount of initial research suggests that modifiable predictors of depression may be specific to maltreatment subtypes and gender. Corroboration and further investigation of causal mechanisms is required to identify novel targets for intervention, and to inform guidelines for the effective treatment of maltreated children. PMID- 28675391 TI - Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children. AB - This corrects the article DOI: 10.1038/tp.2017.27. PMID- 28675389 TI - Topologically convergent and divergent functional connectivity patterns in unmedicated unipolar depression and bipolar disorder. AB - Bipolar disorder (BD), particularly BD II, is frequently misdiagnosed as unipolar depression (UD), leading to inappropriate treatment and poor clinical outcomes. Although depressive symptoms may be expressed similarly in UD and BD, the similarities and differences in the architecture of brain functional networks between the two disorders are still unknown. In this study, we hypothesized that UD and BD II patients would show convergent and divergent patterns of disrupted topological organization of the functional connectome, especially in the default mode network (DMN) and the limbic network. Brain resting-state functional magnetic resonance imaging (fMRI) data were acquired from 32 UD-unmedicated patients, 31 unmedicated BD II patients (current episode depressed) and 43 healthy subjects. Using graph theory, we systematically studied the topological organization of their whole-brain functional networks at the following three levels: whole brain, modularity and node. First, both the UD and BD II patients showed increased characteristic path length and decreased global efficiency compared with the controls. Second, both the UD and BD II patients showed disrupted intramodular connectivity within the DMN and limbic system network. Third, decreased nodal characteristics (nodal strength and nodal efficiency) were found predominantly in brain regions in the DMN, limbic network and cerebellum of both the UD and BD II patients, whereas differences between the UD and BD II patients in the nodal characteristics were also observed in the precuneus and temporal pole. Convergent deficits in the topological organization of the whole brain, DMN and limbic networks may reflect overlapping pathophysiological processes in unipolar and bipolar depression. Our discovery of divergent regional connectivity that supports emotion processing could help to identify biomarkers that will aid in differentiating these disorders. PMID- 28675396 TI - A membrane-anchored aptamer sensor for probing IFNgamma secretion by single cells. AB - Insight into the behavior of individual immune cells, in particular cytokine secretion, will contribute to a more fundamental understanding of the immune system. In this work, we have developed a cell membrane-anchored sensor for the detection of cytokines secreted by single cells using a combination of aptamer based sensors and droplet microfluidics. PMID- 28675392 TI - Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice. AB - Late-onset Alzheimer's disease (AD) remains a medical mystery. Recent studies have linked it to impaired repair of aged neurons. Potential involvement of interleukin33 (IL33) in AD has been reported. Here we show that IL33, which was expressed by up to 75% astrocytes in the aged brains, was critical for repair of aged neurons. Mice lacking Il33 gene (Il33-/-) developed AD-like disease after 60 80 weeks, which was characterized by tau abnormality and a heavy loss of neurons/neurites in the cerebral cortex and hippocampus accompanied with cognition/memory impairment. We detected an abrupt aging surge in the cortical and hippocampal neurons at middle age (40 weeks). To counter the aging surge, wild-type mice rapidly upregulated repair of DNA double-strand breaks (DSBs) and autophagic clearance of cellular wastes in these neurons. Il33-/- mice failed to do so, but instead went on to develop rapid accumulation of abnormal tau, massive DSBs and abnormal autophagic vacuoles in these neurons. Thus, uncontrolled neuronal aging surge at middle age due to lack of IL33 resulted in neurodegeneration and late-onset AD-like symptome in Il33-/- mice. Our study also suggests that the aging surge is a time to search for biomarkers for early diagnosis of AD before massive neuron loss. PMID- 28675397 TI - Electrovariable nanoplasmonics: general discussion. PMID- 28675393 TI - ErbB4 signaling in the prelimbic cortex regulates fear expression. AB - Many psychiatric diseases such as post-traumatic stress disorder (PTSD) are characterized by abnormal processing of emotional stimuli particularly fear. The medial prefrontal cortex (mPFC) is critically involved in fear expression. However, the molecular mechanisms underlying this process are largely unknown. Neuregulin-1 (NRG1) reportedly regulates pyramidal neuronal activity via ErbB4 receptors, which are abundant in parvalbumin (PV)-expressing interneurons in the PFC. In this study, we aimed to determine how NRG1/ErbB4 signaling in the mPFC modulates fear expression and found that tone-cued fear conditioning increased NRG1 expression in the mPFC. Tone-cued fear conditioning was inhibited following neutralization of endogenous NRG1 and specific inhibition or genetic ablation of ErbB4 in the prelimbic (PL) cortex but not in the infralimbic cortex. Furthermore, ErbB4 deletion specifically in PV neurons impaired tone-cued fear conditioning. Notably, overexpression of ErbB4 in the PL cortex is sufficient to reverse impaired fear conditioning in PV-Cre;ErbB4-/- mice. Together, these findings identify a previously unknown signaling pathway in the PL cortex that regulates fear expression. As both NRG1 and ErbB4 are risk genes for schizophrenia, our study may shed new light on the pathophysiology of this disorder and help to improve treatments for psychiatric disorders such as PTSD. PMID- 28675399 TI - Nanotribology and voltage-controlled friction: general discussion. PMID- 28675400 TI - Chemical physics of electroactive materials: concluding remarks. AB - It is an honour to be charged with providing the concluding remarks for a Faraday Discussion. As many have remarked before, it is nonetheless a prodigious task, and what follows is necessarily a personal, and probably perverse, view of a watershed event in the Chemical Physics of Electroactive materials. The spirit of the conference was captured in a single sentence during the meeting itself."It is the nexus between rheology, electrochemistry, colloid science and energy storage". The current scientific climate is increasingly dominated by a limited number of global challenges, and there is thus a tendency for research to resemble a football match played by 6 year olds, where everyone on the field chases the (funding) ball instead of playing to their "discipline". It is thus reassuring to see how the application of rigorous chemical physics is leading to ingenious new solutions for both energy storage and harvesting, via, for example, nanoactuation, electrowetting, ionic materials and nanoplasmonics. In fact, the same language of chemical physics allows seamless transition between applications as diverse as mechano-electric energy generation, active moisture transport and plasmonic shutters - even the origins of life were addressed in the context of electro-autocatalysis! PMID- 28675401 TI - Electrotunable wetting, and micro- and nanofluidics: general discussion. PMID- 28675404 TI - Electroactuators: from understanding to micro-robotics and energy conversion: general discussion. PMID- 28675405 TI - Targeting a cell wall biosynthesis hot spot. AB - Covering: up to 2017History points to the bacterial cell wall biosynthetic network as a very effective target for antibiotic intervention, and numerous natural product inhibitors have been discovered. In addition to the inhibition of enzymes involved in the multistep synthesis of the macromolecular layer, in particular, interference with membrane-bound substrates and intermediates essential for the biosynthetic reactions has proven a valuable antibacterial strategy. A prominent target within the peptidoglycan biosynthetic pathway is lipid II, which represents a particular "Achilles' heel" for antibiotic attack, as it is readily accessible on the outside of the cytoplasmic membrane. Lipid II is a unique non-protein target that is one of the structurally most conserved molecules in bacterial cells. Notably, lipid II is more than just a target molecule, since sequestration of the cell wall precursor may be combined with additional antibiotic activities, such as the disruption of membrane integrity or disintegration of membrane-bound multi-enzyme machineries. Within the membrane bilayer lipid II is likely organized in specific anionic phospholipid patches that form a particular "landing platform" for antibiotics. Nature has invented a variety of different "lipid II binders" of at least 5 chemical classes, and their antibiotic activities can vary substantially depending on the compounds' physicochemical properties, such as amphiphilicity and charge, and thus trigger diverse cellular effects that are decisive for antibiotic activity. PMID- 28675406 TI - DNA or protein? Capillary zone electrophoresis-mass spectrometry rapidly elucidates metallodrug binding selectivity. AB - A novel capillary zone electrophoresis-mass spectrometry (CZE-MS) approach allows the simultaneous characterization and quantification of the binding of metal based anticancer agents to biomolecules. Moreover, for the first time, oligonucleotide metallation was resolved at single-nucleotide resolution by MS. PMID- 28675407 TI - [Patient involvement from rhetoric to practice]. PMID- 28675408 TI - [The quality of radical prostatectomies must be ensured]. PMID- 28675410 TI - ? PMID- 28675409 TI - [The Swedish Association for Obstetrics and Gynecology's national guidelines for NIPT are unethical]. PMID- 28675412 TI - ? PMID- 28675411 TI - ? PMID- 28675413 TI - ? AB - Engineered nanomaterials are produced for a wide range of applications, not least in medicine. Indeed, the field of nanomedicine is rapidly attaining maturity, with novel nanoscale constructs for diagnosis or therapy, or both (so-called theranostics). However, close attention should be paid to the potential environmental and human health impact of the emerging nanotechnologies. More information on human and environmental exposure is needed, along with a more detailed understanding of the hazard potential of different classes of nanomaterials. Animal studies have suggested that certain carbon nanotubes possess asbestos-like pathogenicity and IARC recently classified some but not all carbon nanotubes as potential carcinogens for humans. On the other hand, carbon nanotubes are also, under certain conditions, susceptible to enzymatic degradation by cells of the innate immune system, and this may serve to mitigate the (pulmonary) toxicity of such materials. Finally, recent research has served to shed light on the bio-corona of molecules adsorbed onto the surface of nanomaterials and its role in cellular uptake and cytotoxicity and for biodistribution in vivo. PMID- 28675414 TI - ? AB - Nanoparticles for cancer therapy Nanoparticles carry a big promise in oncology, for diagnosis/imaging, therapy, or both (theragnostics). As common in medical history, there is a huge gap between the exciting experimental possibilities and data and clinical studies making use of it. Of the cell-containing nanoparticles, only one formulation using gene-directed enzyme prodrug therapy (GDEPT) with CYP2B1 and ifosfamide was used in early clinical studies. Of the cell-free nanoparticles, some drug-releasing (doxorubicin) ones are in clinical use for trans-arterial chemo-embolization (TACE) in liver tumors and metastasis. Using liposomes, both paclitaxel and irinotecan have been used in pancreatic cancer as the model indication. Nanoparticle-albumin-bound paclitaxel (NAB-paclitaxel) has also been developed and is now registered as a drug for first-line therapy of pancreatic cancer, as is the liposomal irinotecan. The novel nanoparticle formulations carry a big promise for even better performance, both in diagnosis and therapy; however, few of these has entered the clinic as of today. PMID- 28675415 TI - ? AB - Nano materials need stricter EU regulation REACH is the EU regulation adopted to protect health and environment from the risks that can be posed by chemicals. Companies have the responsibility of collecting information on the uses of manufactured or imported substances above one tonne per year. They also have to make an assessment of the potential risks presented by the substance. Nanomaterials contain chemical substances which are regulated by REACH. However, nanomaterials have unique characteristics and are manufactured and used on a very small scale. Therefore, REACH is at present not well adjusted to regulate nanomaterials. Neither is the approval process for new drugs well adjusted for compounds containing nanomaterial. Improvement of the European medical technology regulation that takes nanomaterial into consideration is under way although it is delayed. There is a lack of data on the degree of exposure to nanomaterial and effects on human health and environment. Such information is needed to obtain adequate regulation. PMID- 28675416 TI - ? AB - Nanotechnology can improve diagnostics The unique properties of nanoparticles make them tailorable into diagnostic agents on a molecular level, which allow more sensitive and precise in vitro diagnostics and in vivo imaging. While in vitro applications already have impact on diagnostics, in vivo use remains challenging due to difficulties in preparing nanoparticles with acceptable properties regarding toxicity, specific target accumulation and degradation. This article describes the innovative work of developing such platforms, and concludes that while nanotechnology-based diagnostics and imaging are still scarce at the clinical level, the rapid development of many new concepts, devices and processes that are now in the laboratory pipeline promises significant impact in the near future. PMID- 28675417 TI - [Great expectations on small materials]. PMID- 28675418 TI - The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation. AB - Interleukin (IL)-6 binds to IL-6R and the complex of IL-6 and IL-6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. IL-6R is cleaved by the ADAM17, generating a soluble IL-6R (sIL-6R). The sIL-6R binds IL-6 and the complex of IL-6 and sIL-6R binds to gp130 even on cells that do not express IL-6R. This process, which has been called IL-6 trans signaling, increases the spectrum of target cells for IL-6. We generated a protein, sgp130Fc, which inhibits IL-6 trans-signaling without affecting IL-6 classic signaling. Using the sgp130Fc protein we demonstrated that IL-6 classic signaling is antiinflammatory and protective, whereas IL-6 trans-signaling is proinflammatory. Blocking IL-6 trans-signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL-6 or IL-6R antibodies to block IL-6. The sgp130Fc protein is in phase II clinical trials. PMID- 28675419 TI - Shock progression and survival after use of a condom uterine balloon tamponade package in women with uncontrolled postpartum hemorrhage. AB - OBJECTIVE: To examine the outcomes of women in advanced shock from uncontrolled postpartum hemorrhage (PPH) who underwent placement of an Every Second Matters for Mothers and Babies Uterine Balloon Tamponade (ESM-UBT) device. METHODS: In a prospective case series, data were collected for women who received an ESM-UBT device at healthcare facilities in Kenya, Senegal, Sierra Leone, and Tanzania between September 1, 2012, and September 30, 2016. Shock class was assigned on the basis of recorded blood pressures and mental status at the time of UBT placement. RESULTS: Data for 306 women with uncontrolled PPH from uterine atony across 117 facilities were analyzed. Normal vital signs or class I/II shock were reported for 166 (54.2%). In this group, one death occurred and was attributed to PPH (survival rate 99.4%). There were no cases of shock progression. One hundred and eleven (36.3%) were in class III shock and 29 (9.5%) in class IV shock; the respective survival rates were 97.3% (n=108) and 86.2% (n=25). CONCLUSION: The ESM-UBT device arrests hemorrhage, prevents shock progression, and is associated with high survival rates among women with uncontrolled PPH from uterine atony. PMID- 28675420 TI - Seizure-associated aphasia has good lateralizing but poor localizing significance. AB - OBJECTIVE: To investigate the occurrence of ictal and postictal aphasia in different focal epilepsy syndromes. METHODS: We retrospectively analyzed the video-electroencephalographic monitoring data of 1,118 patients with focal epilepsy for seizure-associated aphasia (SAA). Statistical analysis included chi square analysis and Fisher's exact test. RESULTS: We identified 102 of 1,118 patients (9.1%) in whom ictal or postictal aphasia (SAA) was part of their recorded seizures (n = 59 of 102; 57.8%) or who reported aphasia by history (n = 43; 42.2% only reported aphasia by history). Postictal aphasia was present in 18 patients (30.5%). Six of the 59 patients had both ictal and postictal aphasia (10.2%). SAA occurred either with left hemisphere seizure onset or with seizures spreading from the right to the left hemisphere. SAA was most common in patients with parieto-occipital epilepsy (10.9%; five of 46 patients), followed by patients with temporal (6.7%; 28 of 420 patients), focal (not further localized; 4.8%; 22 of 462 patients), and frontal epilepsy (2.1%; four of 190 patients; p = 0.04). SAA was more common in parieto-occipital epilepsy than in frontal epilepsy (p = 0.02). In contrast, there was no significant difference in SAA between temporal and parieto-occipital epilepsy (p = 0.36). SIGNIFICANCE: SAA has a high lateralizing but limited localizing value, as it often reflects spread of epileptic activity into speech-harboring brain regions. PMID- 28675422 TI - Reviving Cochrane's contribution to evidence-based medicine: bridging the gap between evidence of efficacy and evidence of effectiveness and cost effectiveness. AB - Throughout the quarter century since the advent of evidence-based medicine (EBM), medical research has prioritized 'efficacy' (i.e. internal validity) using randomized controlled trials. EBM has consistently neglected 'effectiveness' and 'cost-effectiveness', identified in the pioneering work of Archie Cochrane as essential for establishing the external (i.e. clinical) validity of health care interventions. Neither Cochrane nor other early pioneers appear to have foreseen the extent to which EBM would be appropriated by the pharmaceutical and medical devices industries, which are responsible for extensive biases in clinical research due to selective reporting, exaggeration of benefits, minimization of risks, and misrepresentation of data. The promise of EBM to effect transformational change in health care will remain unfulfilled until (i) studies of effectiveness and cost-effectiveness are pursued with some of the same fervour that previously succeeded in elevating the status of the randomized controlled trial, and (ii) ways are found to defeat threats to scientific integrity posed by commercial conflicts of interest. PMID- 28675421 TI - Associations Between Self-Reported Physical Activity and Physical Performance Measures Over Time in Postmenopausal Women: The Women's Health Initiative. AB - OBJECTIVES: To examine prospective associations between changes in physical activity (PA) and changes in physical performance measures (PPMs) over 6 years in older women. DESIGN: Prospective cohort study. SETTING: Forty clinical centers in the United States. PARTICIPANTS: Women aged 65 and older (mean age 69.8) enrolled in the Women's Health Initiative Clinical Trials with gait speed, timed chair stand, grip strength, and self-reported recreational PA data assessed at baseline (1993-98) and follow-up Years 1, 3, and 6 (N = 5,092). MEASUREMENTS: Mixed effects linear regression models were used to determine the association between time-varying PA and change in each PPM. Potential interactions between time varying PA and age (<70, >=70) were also tested. RESULTS: Significan, dose response associations between PA and improvements in all PPMs were observed over the 6 years of follow-up after adjusting for important covariates. High PA groups (>=1,200 metabolic equivalent (MET)-min/wk) had stronger grip strength (0.48 kg greater; P < .01), more chair stands (0.35 more; P < .001), and faster gait speeds (0.06 m/s faster; P < .001) than sedentary women (<100 MET-min/wk). Higher PA levels were associated with a greater increase in chair stands over time in women aged 70 and older (P < .001) than in those younger than 70 (Pinteraction for age = .01). CONCLUSION: In postmenopausal women, maintaining high PA levels over time is associated with better lower extremity function. These data support the view that regular PA plays an important role in maintaining functional status during aging in older women. PMID- 28675423 TI - Poly-pharmacokinetic Study of a Multicomponent Herbal Medicine in Healthy Chinese Volunteers. AB - The advent of mass spectrometry-based analytical technologies coupled with multivariate statistical methods offer tremendous new opportunities for understanding the pharmacokinetics (PKs) of multicomponent herbal medicines (HMs). We recently proposed a poly-PK strategy to characterize the concentration time profile and the metabolic response profile of multicomponent HMs using an integrated phytochemical and metabolomics approach. Here, we provided the first example of the poly-PK strategy, in which we simultaneously characterized the PK as well as the metabolic response profiles of a Chinese HM, Huangqi decoction (HQD, consisting of Radix Astragali and Radix Glycyrrhizae), in healthy Chinese volunteers. Using the poly-PK approach, we identified 56 HQD-derived compounds and 292 biotransformed HQD metabolites in human plasma. Additionally, we acquired the concentration-time profiles of these plasma HQD metabolites and correlated them with a plasma metabolomics profile consisting of 166 human endogenous metabolites that were significantly altered in response to HQD intervention. PMID- 28675424 TI - Predicting QRS and PR interval prolongations in humans using nonclinical data. AB - BACKGROUND AND PURPOSE: Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. EXPERIMENTAL APPROACH: Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model. KEY RESULTS: Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav 1.5 block (3-7%) and Cav 1.2 binding (13-21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3 4.6% and PR 2.3-10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data. CONCLUSION AND IMPLICATIONS: Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non-arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies. PMID- 28675425 TI - Foxc2 influences alveolar epithelial cell differentiation during lung development. AB - FOXC2, a forkhead transcriptional factor, is a candidate gene for congenital heart diseases and lymphedema-distichiasis syndrome and yellow nail syndrome; however, there are no reports on Foxc2 and the development of the lung. We have identified lung abnormalities in Foxc2-knockout embryos during investigation of cardiac development. The aim of this study was to clarify the morphological characteristics during lung development using ICR-Foxc2 knockout lungs. Mutant fetuses at embryonic days 10.5-18.5 were obtained from mating of Foxc2+/- mice and then analyzed. Notably, Foxc2-knockout lungs appeared parenchymatous and much smaller than those of the wild-type littermates. In the Foxc2 knockout lungs, the capillary beds remained distant from the alveolar epithelium until the late stages, the number of type2 alveolar cells per alveolar progenitor cell was lower and the type1 alveolar cells were thicker in Foxc2 knockout mice. In contrast, Foxc2 expression was only detected in the mesenchyme of the lung buds at E10.5, and it disappeared at E11.5 in Foxc2-LacZ knockin mice. Furthermore, the expression of Lef1 was significantly inhibited in E11.5 lungs. All of these results suggest that the abnormalities in Foxc2 knockout mice may involve maldifferentiation of alveolar epithelial cells and capillary vessel endothelial alveolar epithelial approach as well as lymph vessel malformation. This is the first report about relationship between Foxc2 and lung development. This animal model might provide an important clue for elucidating the mechanism of lung development and the cause of respiratory diseases. PMID- 28675426 TI - Stage of labor at admission among Ugandan women with a prior cesarean, and its impact on management and delivery outcomes. AB - OBJECTIVE: To describe stage of labor at admission among women with a prior cesarean, and examine its impact on intrapartum management and delivery mode. METHODS: In a prospective cohort study, women admitted to Mbarara Regional Referral Hospital, Uganda, for delivery were enrolled between March and June 2015. Rates of vaginal delivery (VBAC) and in-hospital trial of labor (TOL) were compared between early (<4 cm dilation) and late (>=4 cm) presenters. Women were interviewed after delivery about decision making and labor preferences. RESULTS: Overall, 188 women comprised the study sample; 98 (52.1%) and 65 (34.6%) women presented at >=4 cm and >=6 cm, respectively, and 18 (9.6%) were fully dilated. In-hospital TOL and VBAC rates were 25.5% (42/165) and 9.6% (18/188), respectively. Compared with early presenters, late presenters were significantly more likely to undergo TOL (28/88 [31.8%] vs 14/77 [18.2%]; odds ratio [OR] 2.3, 95% confidence interval [CI] 1.1-5.0), and achieve VBAC (16/98 [16.3%] vs 2/90 [2.2%]; OR 7.6, 95% CI 1.7-35.1). CONCLUSION: Most women arrived in active labor, but most had a repeat cesarean. Work is needed to understand the clinical decision making and provider management driving low TOL and VBAC rates. PMID- 28675427 TI - Opinion leadership types or continuous opinion leadership traits? AB - Opinion leadership is typically conceptualised as a continuous personality trait. However, many authors adhere to the view of qualitatively different opinion leadership types and apply arbitrary criteria to split continuous trait scores into two groups (i.e., opinion leaders vs. non-leaders). The present study is the first to empirically evaluate this approach. A sample of N = 3812 adults (67% women) was administered a validated opinion leadership scale. Finite mixture models examined whether the latent trait distribution can be represented by a set of discrete trait levels that reflected distinct opinion leadership types. The results did not give support to a discrete typology that distinguished leaders from non-leaders. Rather, opinion leadership was best characterised as a continuous trait. PMID- 28675428 TI - Are country level prevalences of rule violations associated with knowledge overclaiming among students? AB - Cultural norms of behaviour influence desirable and problematic behaviours of individuals. In particular, cultural norms should influence individuals' dishonesty. In a recent Nature study, prevalence of rule violations was introduced as a new country-level measure of behavioural norms. However, information on individuals' actual honesty was not available due to characteristics of the experimental design. Overcoming this limitation, we show that country-level behavioural norms are related to individual-level knowledge overclaiming behaviour (i.e., claiming to know concepts that do not exist, a measure of individuals' actual behavioural dishonesty) among 290,954 students from 57 countries (from the 2012 PISA study). Our study represents a crucial test of the argument that cultural norms influence individual's behaviour and of the validity of the measurement of countries' prevalences of rule violations. These results imply that shaping the behaviour of today's students may result in new behavioural norms that emphasise honesty and rule adherence more strongly. PMID- 28675429 TI - Evaluation of a multifaceted postpartum hemorrhage-management intervention in community hospitals in Southern Thailand. AB - OBJECTIVE: To assess a multifaceted postpartum hemorrhage (PPH)-management intervention in community hospitals in Southern Thailand. METHODS: The present prospective study was conducted from November 1, 2012 to April 30, 2015. The medical records of women with PPH were collected before (January 1, 2011, and October 31, 2012) and after (March 1, 2013, and December 31, 2014) the implementation of a multifaceted PPH-management intervention at three community hospitals in Southern Thailand; these patients were compared with patients diagnosed with PPH at three control hospitals in the same provinces during the same time periods. The intervention, delivered to general practitioners and nurses, utilized previously developed PPH-management guidelines. PPH management was compared between the intervention and control hospitals and factors associated with PPH management were evaluated using univariate and multiple logistic regressions. RESULTS: The post-intervention median blood loss within 2 hours of delivery was lower in intervention hospitals (P<0.001) and post intervention indwelling bladder catheterization was higher (P=0.004). Increased odds of indwelling bladder catheterization were recorded among patients treated at intervention hospitals (adjusted odds ratio [aOR] 2.79, 95% confidence interval [CI] 1.40-5.55) and patients who experienced more than 500 mL of blood loss (501-1000 mL [aOR 2.41, 95% CI 1.22-4.76] or >1000 mL [aOR 16.45, 95% CI 2.04-132.80]). CONCLUSION: Implementation of the multifaceted intervention improved PPH management at community hospitals. PMID- 28675430 TI - Parvalbumin-expressing ependymal cells in rostral lateral ventricle wall adhesions contribute to aging-related ventricle stenosis in mice. AB - Aging-associated ependymal-cell pathologies can manifest as ventricular gliosis, ventricle enlargement, or ventricle stenosis. Ventricle stenosis and fusion of the lateral ventricle (LV) walls is associated with a massive decline of the proliferative capacities of the stem cell niche in the affected subventricular zone (SVZ) in aging mice. We examined the brains of adult C57BL/6 mice and found that ependymal cells located in the adhesions of the medial and lateral walls of the rostral LVs upregulated parvalbumin (PV) and displayed reactive phenotype, similarly to injury-reactive ependymal cells. However, PV+ ependymal cells in the LV-wall adhesions, unlike injury-reactive ones, did not express glial fibrillary acidic protein. S100B+/PV+ ependymal cells found in younger mice diminished in the LV-wall adhesions throughout aging. We found that periventricular PV immunofluorescence showed positive correlation to the grade of LV stenosis in nonaged mice (<10-month-old), and that the extent of LV-wall adhesions and LV stenosis was significantly lower in mid-aged (>10-month-old) PV-knock out (PV-KO) mice. This suggests an involvement of PV+ ependymal cells in aging-associated ventricle stenosis. Additionally, we observed a time-shift in microglial activation in the LV-wall adhesions between age-grouped PV-KO and wild-type mice, suggesting a delay in microglial activation when PV is absent from ependymal cells. Our findings implicate that compromised ependymal cells of the adhering ependymal layers upregulate PV and display phenotype shift to "reactive" ependymal cells in aging-related ventricle stenosis; moreover, they also contribute to the progression of LV-wall fusion associated with a decline of the affected SVZ-stem cell niche in aged mice. PMID- 28675431 TI - A comprehensive review on anticancer mechanisms of the main carotenoid of saffron, crocin. AB - OBJECTIVES: Crocin is derived from dried stigmas of Crocus sativus L. (saffron). It has long been used to prevent and treat various diseases. Although crocin is suggested as one of the most effective cancer therapeutic constituents of saffron stigma, its exact molecular mechanisms are not fully understood. In this study, we reviewed anticancer effects of crocin and its underlying molecular mechanisms. KEY FINDINGS: While several mechanisms may account for the antitumour activity of crocin, alteration of expression/activity of the genes and also epigenetic changes may be considered as necessary phenomena. These alternations may lead to inhibition of cancer cells' proliferation or/and induction of apoptosis through various mechanism including inhibition of synthesis of DNA and RNA, interaction with cellular topoisomerase, suppression of the telomerase activity and active STAT3, and targeting of microtubules. Moreover, this carotenoid could reverse the epithelial-mesenchymal transition and inhibit metastasis. CONCLUSIONS: Knowing molecular mechanisms of antitumoral agents could guide us to choose the best chemotherapeutic compound especially for targeted therapy and also provide insights about possible side effects. PMID- 28675432 TI - Economic and social distance: Perceived income inequality negatively predicts an interdependent self-construal. AB - Previous research has shown that economic inequality influences how people are related with others. In this article, we suggest that perceived economic inequality influences self-construal. Specifically, we propose that higher economic inequality leads to an independent self-construal, whereas lower economic inequality leads to an interdependent self-construal. Correlational data from Studies 1a and 1b revealed that people who perceive lower levels of economic inequality tend to show higher levels of interdependent self-construal, even after controlling for social class. In Study 2, using an experimental design, we found that perceived high economic inequality leads to a more independent and less interdependent self-construal compared to the low economic inequality condition. These results expand the literature bridging the gap between a macro social factor, such as economic inequality, and a micro-social factor, such as self-construal. PMID- 28675434 TI - Coumarins as potential antidiabetic agents. AB - OBJECTIVES: Even with great advances in modern medicine and therapeutic agent development, the search for effective antidiabetic drugs remains challenging. Coumarins are secondary metabolites found widely in nature plants and used mainly in anticoagulation and antithrombotic therapy. Over the past two decades, however, there has been an increasing body of literatures related to the effects of coumarins and their derivatives on diabetes and its complications. This review aimed to focus on research findings concerning the effects of coumarins against diabetes and its complications using in-vitro and in-vivo animal models, and also to discuss cellular and molecular mechanisms underlying these effects. KEY FINDINGS: The search for new coumarins against diabetes and it complications, either isolated from traditional medicine or chemically synthesized, has been constantly expanding. The cellular and molecular mechanisms involved include protecting pancreatic beta cells from damage, improving abnormal insulin signalling, reducing oxidative stress/inflammation, activating AMP-activated protein kinase (AMPK), inhibiting alpha-glucosidases and ameliorating diabetic complications. CONCLUSIONS: The effects and mechanisms of coumarins and their derivatives upon diabetes and its complications are discussed in current review. Further investigations remain to be carried out to develop a promising antidiabetic agent based on coumarin cores. PMID- 28675435 TI - Bilateral flexural deformity in a six-week-old kitten. PMID- 28675433 TI - Development of the anterior visual input pathway to the Drosophila central complex. AB - The anterior visual pathway (AVP) conducts visual information from the medulla of the optic lobe via the anterior optic tubercle (AOTU) and bulb (BU) to the ellipsoid body (EB) of the central complex. The anatomically defined neuron classes connecting the AOTU, BU, and EB represent discrete lineages, genetically and developmentally specified sets of cells derived from common progenitors (Omoto et al., Current Biology, 27, 1098-1110, 2017). In this article, we have analyzed the formation of the AVP from early larval to adult stages. The immature fiber tracts of the AVP, formed by secondary neurons of lineages DALcl1/2 and DALv2, assemble into structurally distinct primordia of the AOTU, BU, and EB within the late larval brain. During the early pupal period (P6-P48) these primordia grow in size and differentiate into the definitive subcompartments of the AOTU, BU, and EB. The primordium of the EB has a complex composition. DALv2 neurons form the anterior EB primordium, which starts out as a bilateral structure, then crosses the midline between P6 and P12, and subsequently bends to adopt the ring shape of the mature EB. Columnar neurons of the central complex, generated by the type II lineages DM1-4, form the posterior EB primordium. Starting out as an integral part of the fan-shaped body primordium, the posterior EB primordium moves forward and merges with the anterior EB primordium. We document the extension of neuropil glia around the nascent EB and BU, and analyze the relationship of primary and secondary neurons of the AVP lineages. PMID- 28675436 TI - Effect of teapot materials on the chemical composition of oolong tea infusions. AB - BACKGROUND: The flavor and quality of tea are widely believed to be associated with the pot in which the tea is made. However, this claim is mostly by experiences and lacks solid support from scientific evidence. The current study investigated and compared the chemical compositions of oolong tea made with six different teapot materials, namely Zisha, Zhuni, stainless steel, ceramic, glass and plastic. RESULTS: For each tea sample, polyphenols and caffeine were examined by HPLC-UV, volatile compounds by GC/MS, amino acids by LC/MS and minerals by ICP MS. The results suggested that tea infusions from Zisha and Zhuni pots contain higher levels of EGC, EGCG and total catechins and less caffeine than those from ceramic, glass and plastic pots and tend to have the lowest total mineral contents, potassium and volatile compounds in tea soup. The statistical differences were not all significant among Zisha, Zhuni and stainless steel pots. CONCLUSION: Based on the overall chemical composition of the tea infusion, Yixing clay pots (Zisha and Zhuni) produce tea infusions that are presumably less bitter and more fragrant and tend to contain more healthful compounds than tea infusions from other pots. The results could partially explain why Yixing clay pots are among the most popular teapots. The beneficial effects of long-term repeated use of these teapots warrants further study. (c) 2017 Society of Chemical Industry. PMID- 28675437 TI - The moderating role of socially desirable responding in implicit-explicit attitudes toward asylum seekers. AB - Implicit and explicit attitudes correlate under certain conditions and researchers are interested in the moderating factors of this relationship. This paper explored the role of socially desirable responding in this relationship by testing the hypothesis that impression management (IM; i.e., deliberate response modification) and self-deceptive enhancement (SDE; i.e., positive self-bias) play moderating roles in the relationship of implicit-explicit attitudes toward asylum seekers in Australia. Seventy-four students responded to a battery of measures and the results revealed that IM (but not SDE) moderated this relationship to the extent that higher IM scores weakened the correspondence between implicit and explicit attitude scores. This suggests that attitudes toward asylum seekers might be susceptible to socially desirable response tendencies and in combination with the finding that IM was negatively related to explicit attitudes, it is argued that self-presentation concerns result in the deliberate attenuation of reported negative explicit attitudes. PMID- 28675439 TI - The microbiota revolution: Excitement and caution. AB - Scientific progress is characterized by important technological advances. Next generation DNA sequencing has, in the past few years, led to a major scientific revolution: the microbiome revolution. It has become possible to generate a fingerprint of the whole microbiota of any given environment. As it becomes clear that the microbiota affects several aspects of our lives, each new scientific finding should ideally be analyzed in light of these communities. For instance, animal experimentation should consider animal sources and husbandry; human experimentation should include analysis of microenvironmental cues that might affect the microbiota, including diet, antibiotic, and drug use, genetics. When analyzing the activity of a drug, we should remember that, according to the microbiota of the host, different drug activities might be observed, either due to modification or degradation by the microbiota, or because the microbiota changes the immune system of the host in a way that makes that drug more or less effective. This minireview will not be a comprehensive review on the interaction between the host and microbiota, but it will aim at creating awareness on why we should not forget the contribution of the microbiota in any single aspect of biology. PMID- 28675438 TI - Biological monitoring of dermal and air exposure to cobalt at a Swedish hard metal production plant: does dermal exposure contribute to uptake? AB - BACKGROUND: Occupational exposure to cobalt is well established in hard metal manufacture. Cobalt is known to cause contact allergy, asthma, hard metal lung disease, and lung cancer. The relationship between skin exposure and uptake determined in blood has not been extensively investigated. OBJECTIVE: To examine whether skin and inhalable air exposure to cobalt contributes to uptake, determined as cobalt in blood, in a hard metal manufacturing factory. METHODS: The amount of cobalt on the skin found with an acid wash technique, the air concentrations of inhalable cobalt and cobalt blood concentrations were determined and correlated in exposed workers. RESULTS: We found a significant rank correlation for cobalt concentrations on the skin, in inhalable air, and in blood (0.376-0.498). Multiple linear regression showed significant regression coefficients for cobalt skin exposure and blood (B = 0.01, p < 0.05) and for inhalable cobalt in air and blood (B = 49.1, p < 0.001). According to our model based on data from the regression analyses, a twofold increase in skin exposure levels at different air concentrations caused a 3-14% increase in blood levels. CONCLUSIONS: Our data suggest that skin exposure to cobalt in the hard metal industry could affect the total uptake at the same order of magnitude as air exposure. PMID- 28675440 TI - Regulatory behavior and frontal activity: Considering the role of revised-BIS in relative right frontal asymmetry. AB - Essential to human behavior are three core personality systems: approach, avoidance, and a regulatory system governing the two motivational systems. Decades of research has linked approach motivation with greater relative left frontal-cortical asymmetry. Other research has linked avoidance motivation with greater relative right frontal-cortical asymmetry. However, past work linking withdrawal motivation with greater relative right frontal asymmetry has been mixed. The current article reviews evidence suggesting that activation of the regulatory system (revised Behavioral Inhibition System [r-BIS]) may be more strongly related to greater relative right frontal asymmetry than withdrawal motivation. Specifically, research suggests that greater activation of the r-BIS is associated with greater relative right frontal activity, and reduced r-BIS activation is associated with reduced right frontal activity (greater relative left frontal activity). We review evidence examining trait and state frontal activity using EEG, source localization, lesion studies, neuronal stimulation, and fMRI supporting the idea that r-BIS may be the core personality system related to greater relative right frontal activity. In addition, the current review seeks to disentangle avoidance motivation and r-BIS as substrates of relative right frontal asymmetry. PMID- 28675441 TI - Two proteases with caspase-3-like activity, cathepsin B and proteasome, antagonistically control ER-stress-induced programmed cell death in Arabidopsis. AB - Programmed cell death (PCD) induced by endoplasmic reticulum (ER) stress is implicated in various plant physiological processes, yet its mechanism is still elusive. An activation of caspase-3-like enzymatic activity was clearly demonstrated but the role of the two known plant proteases with caspase-3-like activity, cathepsin B and proteasome subunit PBA1, remains to be established. Both genetic downregulation and chemical inhibition were used to investigate the function of cathepsin B and PBA1 in ER-stress-induced PCD (ERSID). Transcript level and activity labelling of cathepsin B were used to assess activation. To study tonoplast rupture, a plant PCD feature, both confocal and electronic microscopies were used. Cathepsin B downregulation reduced reactive oxygen species (ROS) accumulation and ERSID without affecting the induction of the unfolded protein response (UPR), but downregulation of PBA1 increased UPR and ERSID. Tonoplast rupture was not altered in the cathepsin B mutant and cathepsin B activation was independent of vacuolar processing enzyme (VPE). VPE activity was independent of cathepsin B. ERSID is regulated positively by cathepsin B and negatively by PBA1, revealing a complex picture behind caspase-3-like activity in plants. Cathepsin B may execute its function after tonoplast rupture and works in parallel with VPE. PMID- 28675442 TI - A generic multimodule phantom for testing geometry of a linac c-arm as a part of quality control in radiotherapy. AB - PURPOSE: To develop an assumption-free methodology for testing geometry of linacs. METHODS: The problem of projecting a fiducial positioned in a predefined point in a 3D space and attached rigidly to a treatment table of a radiotherapeutic device onto an imaging plane with unknown characteristics from a source with unknown coordinates is formulated. The problem of determining these unknowns is formulated as an optimization problem. The problem of determining the gantry/the collimator rotation axis and angle from projection of additional fiducials is also formulated and solved. Analytical methodology is developed for determining isocenter position and an error of estimating isocenter position. The developed methodology is tested in simulations. RESULTS: Very good agreement between preset and calculated values of quantities of interest was found in the simulations. In all cases, the proposed schemes enabled determination of the geometric characteristics of a radiotherapeutic device with accuracy better than one hundredth of a millimeter and one hundredth of a degree. CONCLUSIONS: A concept of a multimodule multifiducial phantom has been introduced. Analytical framework has been developed to extract geometric characteristics of radiotherapy devices from projection images of a phantom. The phantom design and the methodology developed have been tested in simulations. PMID- 28675443 TI - Rapid and accurate assessment of GPCR-ligand interactions Using the fragment molecular orbital-based density-functional tight-binding method. AB - The reliable and precise evaluation of receptor-ligand interactions and pair interaction energy is an essential element of rational drug design. While quantum mechanical (QM) methods have been a promising means by which to achieve this, traditional QM is not applicable for large biological systems due to its high computational cost. Here, the fragment molecular orbital (FMO) method has been used to accelerate QM calculations, and by combining FMO with the density functional tight-binding (DFTB) method we are able to decrease computational cost 1000 times, achieving results in seconds, instead of hours. We have applied FMO DFTB to three different GPCR-ligand systems. Our results correlate well with site directed mutagenesis data and findings presented in the published literature, demonstrating that FMO-DFTB is a rapid and accurate means of GPCR-ligand interactions. (c) 2017 Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 28675444 TI - Occupational ocular incidents in dentists: a multicentre study in southwestern Saudi Arabia. AB - BACKGROUND: Dental practitioners are at high risk of occupational ocular incidents during their daily work practice. The aim of this study was to assess the prevalence, pattern and determinants of ocular incidents and to establish the use of eye protection by dental staff in southwestern Saudi Arabia. METHODS: This multicentre cross-sectional study was conducted among dental practitioners working in private, military and Ministry of Health dental clinics in southwestern Saudi Arabia. A predesigned self-report questionnaire was used to elicit information on demographics, splash or foreign body ocular incidents, postincident practices and use of eye protection. RESULTS: Of the 233 dental practitioners examined, 29.6% and 51.1% reported ocular incidents as a result of foreign bodies and fluid splashing, respectively. The risk of ocular incidents as a result of fluid splashing was significantly higher in the absence of postgraduate qualification [odds ratio (OR) = 3.04, 95% confidence interval (95% CI): 1.70-5.43], poor compliance with wearing eye protection (OR = 2.52, 95% CI: 1.49-4.28) and long work hours (OR = 2.16, 95% CI: 1.17-3.96). The most frequent postexposure practice was to rinse eyes under running water (87.5%). Approximately 4.2% and 9.2% of dental practitioners reported incidents of ocular injury and infection, respectively, and 14% reported that they never wore any eye protection. CONCLUSION: Occupational ocular incidents as a result of splashing and foreign bodies are relatively common among dental practitioners in southwestern Saudi Arabia. The absence of postgraduate qualification, poor compliance with wearing eye protection and working long hours are predictors of ocular incidents. Awareness about eye safety is therefore considered mandatory for dental practitioners in southwestern Saudi Arabia. Also, dental clinic administrators should provide and promote the use of eye protection. PMID- 28675445 TI - Europium-155 as a source for dual energy cone beam computed tomography in adaptive proton therapy: A simulation study. AB - PURPOSE: To investigate the feasibility of a 3D imaging system utilizing a 155 Eu source and pixelated cadmium-zinc-telluride (CZT) detector for applications in adaptive radiotherapy. Specifically, to compare the reconstructed stopping power ratio (SPR) values of a head phantom obtained with the proposed imaging technique with theoretical SPR values. METHOD: A Geant4 Monte Carlo simulation was performed with the novel imaging system. The simulation was repeated with a typical 120 kV X-ray tube spectrum while maintaining all other parameters. Dual energy 155 Eu source cone beam computed tomography (CBCT) images were reconstructed with an iterative projection algorithm known as total variation superiorization with diagonally relaxed orthogonal projections (TVS-DROP). Single energy 120 kV source CBCT images were also reconstructed with TVS-DROP. Reconstructed images were converted to SPR with stoichiometric calibration techniques based on ICRU 44 tissues. Quantitative accuracy of reconstructed attenuation coefficient images as well as SPR images were compared. RESULTS: Images generated by gamma emissions of 155 Eu showed superior contrast resolution to those generated by the 120 kV spectrum. Quantitatively, all reconstructed images correlated with reference attenuation coefficients of the head phantom within 1 standard deviation. Images generated with the 155 Eu source showed a smaller standard deviation of pixel values. Use of a dual energy conversion into SPR resulted in superior SPR accuracy with the 155 Eu source. CONCLUSION: 155 Eu was found to display desirable qualities when used as a source for dual energy CBCT. Further work is required to demonstrate whether the simulation results presented here can be translated into an experimental prototype. PMID- 28675446 TI - Role of fungi in chronic rhinosinusitis through ITS sequencing. AB - OBJECTIVE: Next-generation sequencing increases the sensitivity of fungal identification and may improve our understanding of the role that fungi play in sinus health and disease, which remains incompletely understood. We sequenced the internal transcribed spacer (ITS) amplicon to explore the role of the mycobiome in chronic rhinosinusitis (CRS). METHODS: Swabs were collected intraoperatively from the middle meatus of 90 patients (63 with CRS; 27 controls). DNA was extracted, and ITS amplicon concentration was measured using fluorometry. Internal transcribed spacer amplicons were sequenced on the Illumina MiSeq (Illumina Inc San Diego CA). Sequencing data were analyzed using QIIME. RESULTS: Using conventional detection techniques of culture and histology, fungi only were identified in nine of 63 (14.3%) CRS patients (fungus-identified group); the remaining 54 CRS patients and all controls did not have fungus identified using the traditional techniques. This fungus-identified group had a significantly higher average ITS concentration and a significantly lower Shannon's diversity index compared to the other two groups. The most abundant organism sequenced was Aspergillus (35.22% of all sequences). Multivariate analysis showed that positive fungal detection using traditional techniques and computed tomography (CT) double densities were the most important clinical predictors of a high fungal biomass, whereas Lund-Mackay score, polyps, eosinophilia, and eosinophilic mucus were not significant in comparison. CONCLUSION: Fungal biomass estimated through ITS amplicon concentration correlated with traditional fungal detection techniques and CT double densities. Our results suggest that fungal dysbiosis only occurs in the sinuses of a selected subset of patients, and therefore could not be a universal determinant of sinus disease pathogenesis in all CRS patients. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:16-22, 2018. PMID- 28675447 TI - Cosmetic potentials of Prunus domestica L. leaves. AB - BACKGROUND: The current study presents new insight on the phytochemical content and biological activities of five Prunus domestica L. varieties ('Quetsche blanche de Letricourt', 'Mirabelle de Nancy', 'Perdrigon violet', 'Mirabelle de Provence', 'Reine-claude doree'). RESULTS: The plum leaves were found to possess promising anti-aging activities by their capacity to inhibit 1,1-diphenyl-2 picrylhydrazyl (DPPH), elastase, hyaluronidase and lipoxygenase. After solid phase extraction (SPE), chlorogenic acid, rutin, quercetin and their derivatives were putatively identified by high-performance liquid chromatography coupled with tandem mass spectrometry using an electrospray ionization source (HPLC/ESI MS/MS). CONCLUSION: The plum leaf, a by-product, provides an interesting valuable resource for use as a natural cosmetic product or as a food supplement. (c) 2017 Society of Chemical Industry. PMID- 28675449 TI - Evaluation of the accuracy of nine electronic apex locators by using Micro-CT. AB - AIM: To determine the accuracy of locating the apical constriction using apex locators. METHODOLOGY: Extracted teeth were micro-CT scanned preoperatively to localize the apical constriction. Electronic length measurements of 91 root canals were made using nine electronic apex locators (EAL) connected to a mounting model. Distances from the major foramen were recorded at each scale bar of the EALs, and a file was fixed in the canal at a position indicated by each EAL to be the apical constriction. A second micro-CT scan was conducted, and distances from the file tip to constriction and major foramen were calculated for each EAL. The accuracy of EALs was determined with a tolerance of 0.1, 0.25, 0.5 and 1 mm, and the 95% confidence interval was used to compare the EALs. A rank analysis was performed in which measurements beyond the major foramen were considered as inaccurate. RESULTS: Regardless of the type of teeth, there was no significant difference in the accuracy of determining the apical constriction and major foramen between the nine EALs within a tolerance of +/-0.5 mm and 1 mm, but there was a significant difference for the tolerances of +/-0.1 and 0.25 mm. The highest ranks close to the constriction (98% and 94%) and to the major foramen (86% and 73%) were observed in Dentaport ZX and Elements Diagnostic Unit, respectively. Overestimation of working length beyond the major foramen was observed in all EALs (5% to 71%) when the scale for the major foramen, as recommended by the manufacturers, was used. However, when the scale for the constriction was used, only 3% of the measurements were beyond the major foramen. CONCLUSION: Electronic apex locators were able to determine the apical constriction. Using EALs to determine the major foramen led to overestimation of the working length. Therefore, it may be recommended to use the EAL scale of the constriction. PMID- 28675448 TI - Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2 : a safer alternative to COX-2 inhibition. AB - BACKGROUND AND PURPOSE: The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE2 from COX-derived PGH2 . This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels. EXPERIMENTAL APPROACH: The vascular tone and prostanoid release from internal mammary artery (IMA) and saphenous vein (SV) incubated for 30 min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions. KEY RESULTS: In inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE2 and PGI2 were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenaline-induced contractions in both vessels. This effect was reversed by an IP (PGI2 receptor) antagonist but not modified by NOS inhibition. Moreover, PGI2 release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE2 release. CONCLUSIONS AND IMPLICATIONS: In contrast to COX-2 inhibition, inhibition of mPGES-1 reduced vasoconstriction by increasing PGI2 synthesis. Targeting mPGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc. PMID- 28675450 TI - Synthetic essentiality: Targeting tumor suppressor deficiencies in cancer. AB - In this review, we summarize recent work exploring a novel conceptual approach termed "synthetic essentiality" as a means for targeting specific tumor suppressor gene deficiencies in cancer. With the aid of extensive publically available cancer genome and clinical databases, "synthetic essentiality" could be utilized to identify synthetic essential genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency. Synthetic essentiality expands the existing concepts for therapeutic strategies, including oncogene addiction, tumor maintenance, synthetic, and collateral lethality, to provide a framework for the discovery of cancer-specific vulnerabilities. Enabled by ever-expanding large-scale genome datasets and genome-scale functional screens, the "synthetic essentiality" framework provides an avenue for the identification of context-specific therapeutic targets and development of patient responder hypotheses for novel and existing therapies. PMID- 28675451 TI - Rates of Delirium Diagnosis Do Not Improve with Emergency Risk Screening: Results of the Emergency Department Delirium Initiative Trial. AB - OBJECTIVES: To determine whether a bundled risk screening and warning or action card system improves formal delirium diagnosis and person-centered outcomes in hospitalized older adults. DESIGN: Prospective trial with sequential introduction of screening and interventional processes. SETTING: Two tertiary referral hospitals in Australia. PARTICIPANTS: Individuals aged 65 and older presenting to the emergency department (ED) and not requiring immediate resuscitation (N = 3,905). INTERVENTION: Formal ED delirium screening algorithm and use of a risk warning card with a recommended series of actions for the prevention and management of delirium during the subsequent admission MEASUREMENTS: Delirium diagnosis at hospital discharge, proportion discharged to new assisted living arrangements, in-hospital complications (use of sedation, falls, aspiration pneumonia, death), hospital length of stay. RESULTS: Participants with a positive risk screen were significantly more likely (relative risk = 6.0, 95% confidence interval = 4.9-7.3) to develop delirium, and the proportion of at-risk participants with a positive screen was constant across three study phases. Delirium detection rate in participants undergoing the final intervention (Phase 3) was 12.1% (a 2% absolute and 17% relative increase from the baseline rate) but this was not statistically significant (P = .29), and a similar relative increase was seen over time in participants not receiving the intervention CONCLUSION: A risk screening and warning or action card intervention in the ED did not significantly improve rates of delirium detection or other important outcomes. PMID- 28675452 TI - Estimating the cost of school sealant programs with minimal data. AB - OBJECTIVE: Develop methodology to estimate the annual cost of resources used by school sealant programs (SSPs) and demonstrate its use. METHODS: We used existing literature and expert opinion to identify SSP cost components and the most appropriate units for their measurement (e.g., per operator) and collection frequency (e.g., per day). For equipment and reusable instruments, costs were sufficiently homogenous across SSPs that we could provide default per unit cost estimates (2016 US$) that SSPs can use in lieu of collecting their own data. We also provide default costs for supply items such that SSPs can estimate total supply costs with program-specific information on sealant material used, as well as number of: sealant stations, operators, service delivery days, children screened/sealed, and number of teeth sealed. For the remaining three categories (labor, mileage, and administrative), costs varied substantially by SSP and required us to develop and pilot collection logs for program-specific data. RESULTS: The annual cost per sealant station ranged from $584 to $797 depending on program characteristics. For a hypothetical SSP that staffed each of two stations with two operators (hygienist and assistant) compensated at the national rate, hourly labor costs would equal $77.97. Assuming this SSP used disposable instruments, light-cured sealants and delivered sealants (3 per child) to 60 percent of the 3,390 children screened over 100 service days, infection control/supply costs per child would equal $5.30. CONCLUSION: This methodology allows SSPs to estimate costs with minimal data collection and time. PMID- 28675453 TI - New Dancing Couple: PD-L1 and MicroRNA. AB - Lung cancer (LC) is the most common cause of cancer death in the world. A great challenge in treating NSCLC is the discovery of advanced, molecular tools to diagnose the disease in early stages as well as the development of immunotherapy. MicroRNAs are regulatory molecules (~20 nt in length) with the ability to regulate the expression of genes. The recently described PD-1 and PD-L1 molecules have great importance for potential use in immunotherapy of many cancers. These molecules are associated with immune checkpoints and provide an opportunity for the treatment of advanced NSCLC patients with synthetic monoclonal antibodies. PD L1 expression is strictly associated with microRNA function in lung cancer cells. The group of microRNAs related to PD-L1 includes, among others, miR-200, miR-197 or miRNA-34. Expression of these molecules may be useful in lung cancer diagnosis, qualification to anti-PD-1 or anti-PD-L1 antibody therapy and could be a potential therapeutic target. However, studies on PD-L1-related microRNAs are necessary to develop advanced targeted molecular therapies. PMID- 28675454 TI - Molecular mechanics models for the image charge, a comment on "including image charge effects in the molecular dynamics simulations of molecules on metal surfaces". AB - We re-investigate the image charge model of Iori and Corni (Iori and Corni, J. Comput. Chem. 2008, 29, 1656). We find that a simple symmetrization of their model allows to obtain quantitatively correct results for the electrostatic interaction of a water molecule with a metallic surface. This symmetrization reduces the magnitude of the electrostatic interaction to less than 10% of the total interaction energy. (c) 2017 Wiley Periodicals, Inc. PMID- 28675455 TI - LPS-Induced ex vivo Cytokine Production is Not Augmented in Patients with Von Hippel-Lindau Disease. PMID- 28675456 TI - Implicit identification with death predicts change in suicide ideation during psychiatric treatment in adolescents. AB - BACKGROUND: Suicidal thoughts and behaviors are major public health concerns in youth. Unfortunately, knowledge of reliable predictors of suicide risk in adolescents is limited. Promising research using a death stimuli version of the Implicit Association Test (Death IAT) indicates that stronger identification with death differs between adults with and without a history of suicidal thoughts and behaviors and uniquely predicts suicide ideation and behavior. However, research in adolescents is lacking and existing findings have been mixed. This study extends previous research by testing whether implicit identification with death predicts changes in suicide ideation during psychiatric treatment in adolescents. METHODS: Participants included 276 adolescents, ages 13-19, admitted to a short term residential treatment program. At hospital admission and discharge, adolescents completed the Death IAT and measures of recent suicidal thoughts. RESULTS: At admission, implicit identification with death was associated with recent suicide ideation, but did not differ between those who engaged in prior suicidal behavior and those who did not. Prospectively, adolescents' implicit identification with death at admission significantly predicted their suicide ideation severity at discharge, above and beyond explicit suicide ideation. However, this effect only was significant for adolescents with longer treatment stays (i.e., more than 13 days). CONCLUSIONS: Implicit identification with death predicts suicidal thinking among adolescents in psychiatric treatment. Findings clarify over what period of time implicit cognition about death may predict suicide risk in adolescents. PMID- 28675457 TI - Metastatic sarcomatoid renal cell carcinoma manifesting as a subcutaneous soft tissue mass. AB - Metastases from visceral malignancies to subcutaneous soft tissues are relatively rare and their diagnosis requires a high level of suspicion. It is even more challenging if a metastatic lesion shows non-specific high-grade spindle cell morphology overlapping with various primary cutaneous and soft tissue tumors. We describe a unique case of subcutaneous metastasis of sarcomatoid renal cell carcinoma which was the first manifestation of the occult malignancy. The patient had a history of lipomas and dysplastic nevi and presented with an upper back mass. The mass, located superficially within the subcutis, was composed of atypical spindle cells arranged in a storiform pattern. By immunohistochemistry, the tumor cells were strongly diffusely positive for cytokeratin AE1/AE3 and vimentin and negative for Melan-A, S-100 protein, SOX10, melanoma cocktail, epithelial membrane antigen (EMA), p63, CK7, CK18, CK20, smooth muscle actin (SMA), desmin, CD34, TTF-1, CD21, CD99 and bcl-2. Scattered tumor cells were positive for MDM2 immunostain, but MDM2 amplification was not detected using fluorescent in situ hybridization (FISH). Co-expression of cytokeratin and vimentin by the tumor raised the possibility of metastatic renal cell carcinoma and positivity of the tumor for PAX8 supported this hypothesis. A large renal mass was detected radiologically and the subsequent nephrectomy specimen showed high-grade clear cell renal cell carcinoma with sarcomatoid features. PMID- 28675458 TI - Morphologies of Bacillus subtilis communities responding to environmental variation. AB - Bacterial communities exhibit a variety of growth morphologies in constructing robust systems under different environmental conditions. We review the diverse morphologies of Bacillus subtilis communities and their mechanisms of self organization. B. subtilis uses different cell types to suit environmental conditions and cell density. The subpopulation of each cell type exhibits various environment-sensitive properties. Furthermore, division of labor among the subpopulations results in flexible development for the community as a whole. We review how B. subtilis community morphologies and growth strategies respond to environmental perturbations. PMID- 28675459 TI - Stimulation of adrenergic activity by desipramine enhances hematopoietic stem and progenitor cell mobilization along with G-CSF in multiple myeloma: A pilot study. AB - Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the beta3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected >=5 * 106 CD34+ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 * 106 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 * 106 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation. PMID- 28675461 TI - Diagnosis: more than a numbers game? PMID- 28675460 TI - Real-life Use of Anticoagulants in Venous Thromboembolism With a Focus on Patients With Exclusion Criteria for Direct Oral Anticoagulants. AB - We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy. PMID- 28675462 TI - EMB2738, which encodes a putative plastid-targeted GTP-binding protein, is essential for embryogenesis and chloroplast development in higher plants. AB - In higher plants, chloroplasts carry out many important functions, and normal chloroplast development is required for embryogenesis. Numerous chloroplast targeted proteins involved in embryogenesis have been identified. Nevertheless, their functions remain unclear. In this study, a chloroplast-localized protein, EMB2738, was reported to be involved in Arabidopsis embryogenesis. EMB2738 knockout led to defective embryos, and the embryo development in emb2738 was interrupted after the globular stage. Complementation experiments identified the AT3G12080 locus as EMB2738. Cellular observation indicated that severely impaired chloroplast development was observed in these aborted embryos. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that chloroplast-encoded photosynthetic genes, which are transcribed by plastid encoded RNA polymerase (PEP), are predominantly decreased in defective embryogenesis, compared with those in the wild-type. In contrast, genes encoding PEP core subunits, which are transcribed by nucleus-encoded RNA polymerase (NEP), were increased. These results suggested that the knockout of EMB2738 strongly blocked chloroplast-encoded photosynthesis gene expression in embryos. Silencing of the EMB2738 orthologue in tobacco through a virus-induced genome silencing technique resulted in an albinism phenotype, vacuolated chloroplasts and decreased PEP-dependent plastid transcription. These results suggested that NtEMB2738 might be involved in plastid gene expression. Nevertheless, genetic analysis showed that the NtEMB2738 coding sequence could not fully rescue the defective embryogenesis of the emb2738 mutant, which suggested functional divergence between NtEMB2738 and EMB2738 in embryogenesis. Taken together, these results indicated that both EMB2738 and NtEMB2738 are involved in the expression of plastid genes in higher plants, and there is a functional divergence between NtEMB2738 and EMB2738 in embryogenesis. PMID- 28675463 TI - Pharmacokinetic depletion phase of doxycycline in healthy and Mycoplasma gallisepticum-infected chicken broilers after coadministration of enrofloxacin traces. AB - The objective of this study was to investigate the influence of enrofloxacin (ENR) traces on doxycycline (DC) pharmacokinetic depletion phase parameters in plasma and lungs of healthy and Mycoplasma gallisepticum (MG)-infected chicken broilers. The multiple-dose oral administration of DC to chickens which were permanently exposed on ENR traces significantly increased concentration of DC in plasma and lung. It also prolonged the DC elimination time in both healthy and infected animals after final dose. The obtained result indicated that simultaneous administration of DC and ENR in chicken broilers therapy should be avoided. PMID- 28675464 TI - Chemical composition, antimicromicrobial activity and insecticidal activity against the lesser mealworm Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) of Origanum vulgare L. ssp. hirtum (Link) and Artemisia dracunculus L. essential oils. AB - BACKGROUND: Essential oils (EOs) from Artemisia dracunculus L. and Origanum vulgare L. ssp. hirtum were obtained and the qualitative and quantitative chemical composition of the extracts was investigated. The insecticidal activity of EOs against the larval stages of Alphitobius diaperinus (Panzer) was studied. Moreover, the antimicrobial activity of these oils against pathogens transmitted by this pest was also investigated. RESULTS: The obtained results indicate the possibility of using Greek oregano EO with a high content of carvacrol as a feed additive in poultry nutrition. The use of the Greek oregano oil at 1% (w/w) dose showed stronger reduction of body weight gain of stage IV larvae. Their body mass was only 10.92% of the control. Moreover, EOs from O. vulgare strongly inhibited the growth of tested bacterial strains as well as Candida albicans. CONCLUSION: Greek oregano EO may be a good alternative to antibiotic growth promoters and coccidiostats whose use in feeding farm animals has been prohibited since January 2006 under European Union directives. The introduction of O. vulgare L. ssp. hirtum EO into the premises of farm and poultry houses may help to improve sanitary conditions and control of the lesser mealworm inhabiting these buildings. (c) 2017 Society of Chemical Industry. PMID- 28675465 TI - Brain volumetric correlates of inhibition and cognitive flexibility 16 years following childhood traumatic brain injury. AB - Executive functions (EFs), such as inhibition and cognitive flexibility, are essential for everyday functioning, including regulation of socially appropriate emotional responses. These skills develop during childhood and continue maturing into early adulthood. The current study aimed to investigate the very long-term impact of childhood traumatic brain injury (TBI) on inhibition and cognitive flexibility, and to examine whether global white matter is associated with these abilities. Twenty-eight young adult survivors of childhood TBI (mean age at 16 year follow-up = 21.67 years, SD = 2.70) and 16 typically developing controls (TDCs), group-matched for age, sex, and socioeconomic status, completed tests of inhibition and cognitive flexibility and underwent structural MRI. Survivors of childhood TBI did not significantly differ from TDCs on EF or white matter volume. However, the relationship between EF and white matter volume differed between survivors of TBI and TDCs. Survivors of TBI did not mimic the brain behavior relationship that characterized EF in TDCs. The inverse brain behavior relationship, exhibited by childhood TBI survivors, suggests disruptions in the whole brain underpinning EF following childhood TBI. PMID- 28675466 TI - Does a comprehensive family-centred early intervention service affect stress reactivity and emotion regulation in very low birthweight preterm infants at toddler age? PMID- 28675467 TI - Isomer Dependence on the Reactivity of Diazenes with Pentaphenylborole. AB - Reactions of the anti-aromatic pentaphenylborole with diazenes indicate that both the substitution and the isomer influence the reaction outcome. With respect to trans isomers, azobenzene underwent coordination and C-H addition across the diene of the borole, and 2',6'-dimethylazobenzene furnished a fused tricyclic system. Under photolytic conditions, both of the aforementioned diazenes generate the first 1,3,2-diazaborepin heterocycles, rationalized through reactivity with the cis isomers. This notion is corroborated by the reaction of pentaphenylborole with benzo[c]cinnoline, the tethered variant of azobenzene, that only exists as the cis conformer as the corresponding 1,3,2-diazaborepin was produced regardless if the reaction is conducted in the dark or light. The more aromatic pyridazine proved to be less reactive, forming a resilient adduct. PMID- 28675468 TI - Acral angiokeratoma-like pseudolymphoma in a middle-aged woman. AB - Acral angiokeratoma-like pseudolymphoma is a rare type of pseudolymphoma presenting as dark-red papules on the hand or foot. We describe a 59-year-old woman who presented with an unusual unilateral, clustered aggregate of scaly violaceous papules on the toe with an indolent course. Skin biopsy showed a prominent vascular proliferation associated with a dermal infiltrate of monoclonally rearranged T-follicular helper phenotype T-cells, in keeping with CD4+ small/medium T-cell lymphoproliferative disorder (SMPTC-LPD). Based on the unique clinical morphology, distribution of the lesions and dermoscopic appearance, a clinicopathologic diagnosis of acral angiokeratoma-like pseudolymphoma was favored. This case demonstrates the importance of clinicopathological correlation in such diagnostically challenging patients who present with overlapping features on the spectrum of pseudolymphoma and cutaneous T-cell lymphoma. PMID- 28675469 TI - Letter to the Editor. PMID- 28675470 TI - Brain serotoninergic nervous system is involved in bombesin-induced frequent urination through brain 5-HT7 receptors in rats. AB - BACKGROUND AND PURPOSE: Psychological stress exacerbates symptoms of urinary bladder dysfunction; however, the underlying brain mechanisms are unclear. We have demonstrated that centrally administered bombesin, a stress-related neuropeptide, facilitates the rat micturition reflex. Brain bombesin-like peptides modulate the serotoninergic nervous system activity under stress conditions; therefore, we examined whether brain 5-HT is involved in the bombesin induced increased frequency of urination in urethane-anaesthetised male Sprague Dawley rats. EXPERIMENTAL APPROACH: Evaluation of intercontraction intervals (ICI) and maximal voiding pressure (MVP) during cystometrograms were started 1 h before i.c.v. administration of bombesin or i.c.v. pretreatment with the 5-HT receptor antagonists. KEY RESULTS: Bombesin (0.03 nmol per animal, i.c.v.) significantly reduced ICI without affecting MVP. The bombesin-induced response was significantly suppressed by acute depletion of brain 5-HT, which was induced by pretreatment with p-chlorophenylalanine, a 5-HT synthesis inhibitor. Bombesin at a lower dose (0.01 nmol per animal, i.c.v.) showed no significant effect on ICI, while it significantly reduced ICI in the presence of WAY-100635 (5-HT1A receptor antagonist, 0.1 or 0.3 MUg per animal, i.c.v.), which can block the negative feedback control of 5-HT release. Bombesin (0.03 nmol per animal) induced ICI reduction was significantly attenuated by SB269970 (5-HT7 receptor antagonist, 0.1 or 0.3 MUg per animal, i.c.v.) but not by ritanserin (5-HT2 receptor antagonist, 0.3 or 1 MUg per animal, i.c.v.). CONCLUSIONS AND IMPLICATIONS: The brain serotoninergic nervous system is involved in the facilitation of the rat micturition reflex induced by bombesin-like peptides at least in part through brain 5-HT7 receptors. PMID- 28675472 TI - Retrieving overlapping crystals information from TEM nano-beam electron diffraction patterns. AB - The diffraction patterns acquired with a transmission electron microscope (TEM) contain Bragg reflections related to all the crystals superimposed in the thin foil and crossed by the electron beam. Regarding TEM-based orientation and phase characterisation techniques, the nondissociation of these signals is usually considered as the main limitation for the indexation of diffraction patterns. A new method to identify the information related to the distinct but overlapped grains is presented. It consists in subtracting the signature of the dominant crystal before reindexing the diffraction pattern. The method is coupled to the template matching algorithm used in a standard automated crystal orientation mapping tool (ACOM-TEM). The capabilities of the approach are illustrated with the characterisation of a NiSi thin film stacked on a monocrystalline Si layer. Then, a subtracting-indexing cycle applied to a 70 nm thick thin foil containing polycrystalline tungsten electrical contacts shows the capability of the technique to recognise small nondominant grains. PMID- 28675471 TI - Assessment of skin conductance in African American and Non-African American participants in studies of conditioned fear. AB - Skin conductance (SC) is a psychophysiological measure of sympathetic nervous system activity that is commonly used in research to assess conditioned fear responses. A portion of individuals evidence very low or unmeasurable SC levels (SCL) and/or response (SCR) during fear conditioning, which precludes the use of their SC data. The reason that some individuals do not produce measurable SCL and/or SCR is not clear; some early research suggested that race may be an influencing factor. In the current article, archival data from five fear conditioning samples collected from four different laboratories were examined to explore SCL and SCR magnitude in African American (AA) and non-African American (non-AA) participants. Across studies, the aggregate group difference for exclusion due to unmeasurable SCL or no measurable SCR to an unconditioned stimulus reflected a significant medium effect size (d = 0.54). Furthermore, 24.3% (range: 0-48.3%) of AA participants met SC exclusion criteria versus 14.3% (range: 4.3-24.2%) of non-AA participants. AA participants also displayed significantly lower SCL during habituation (d = 0.58). The low SC levels and responses in AA individuals and the consequent exclusion of their contributions to fear conditioning study results impacts the generalizability of findings across races. Given higher rates of posttraumatic stress disorder (PTSD) and chronic anxiety in AA individuals, it is important that AA individuals not be excluded from fear conditioning research, which informs the treatment of anxiety and PTSD. Examination of the basis of very low SCL and/or SCR is a potentially informative direction for future research. PMID- 28675474 TI - PhERF6, interacting with EOBI, negatively regulates fragrance biosynthesis in petunia flowers. AB - In petunia, the production of volatile benzenoids/phenylpropanoids determines floral aroma, highly regulated by development, rhythm and ethylene. Previous studies identified several R2R3-type MYB trans-factors as positive regulators of scent biosynthesis in petunia flowers. Ethylene response factors (ERFs) have been shown to take part in the signal transduction of hormones, and regulation of metabolism and development processes in various plant species. Using virus induced gene silencing technology, a negative regulator of volatile benzenoid biosynthesis, PhERF6, was identified by a screen for regulators of the expression of genes related to scent production. PhERF6 expression was temporally and spatially connected with scent production and was upregulated by exogenous ethylene. Up-/downregulation of the mRNA level of PhERF6 affected the expression of ODO1 and several floral scent-related genes. PhERF6 silencing led to a significant increase in the concentrations of volatiles emitted by flowers. Yeast two-hybrid, bimolecular fluorescence complementation and co-immunoprecipitation assays indicated that PhERF6 interacted with the N-terminus of EOBI, which includes two DNA binding domains. Our results show that PhERF6 negatively regulates volatile production in petunia flowers by competing for the binding of the c-myb domains of the EOBI protein with the promoters of genes related to floral scent. PMID- 28675475 TI - Fumigation of Brazil nuts with allyl isothiocyanate to inhibit the growth of Aspergillus parasiticus and aflatoxin production. AB - BACKGROUND: Brazil produces approximately 40 000 tons of Brazil nuts annually, which is commonly contaminated with fungi and mycotoxins. Gaseous allyl isothiocyanate (AITC) was used to inhibit the growth of Aspergillus parasiticus and its production of aflatoxins (AFs) in Brazil nuts. RESULTS: Nuts were inoculated with 104 spores g-1 of A. parasiticus and placed in airtight glass jars with controlled relative humidity (RH = 95 or 85%). Samples were treated with 0, 0.5, 1.0 or 2.5 uL L-1 of gaseous AITC and analyzed after 30 days to determine the fungal population and AFs content. Samples were also submitted to sensory evaluation. AITC at 2.5 uL L-1 could completely inhibit the fungal growth and AFs production in both the RH tested. AITC at 0.5 and 1 uL L-1 did not affect the microbial growth at RH = 95%, but 1 uL L-1 reduced the production of AFs by ~50%. All AITC treatments reduced the fungal population and AFs to undetectable levels at RH = 85%. None of the concentrations altered sensory characteristics of Brazil nuts. CONCLUSION: Gaseous AITC could be used as an alternative to inhibit the growth of A. parasiticus during storage and transport of Brazil nuts. (c) 2017 Society of Chemical Industry. PMID- 28675473 TI - Localization of orofacial representation in the corona radiata, internal capsule and cerebral peduncle in Macaca mulatta. AB - Subcortical white matter injury is often accompanied by orofacial motor dysfunction, but little is known about the structural substrates accounting for these common neurological deficits. We studied the trajectory of the corticobulbar projection from the orofacial region of the primary (M1), ventrolateral (LPMCv), supplementary (M2), rostral cingulate (M3) and caudal cingulate (M4) motor regions through the corona radiata (CR), internal capsule (IC) and crus cerebri of the cerebral peduncle (ccCP). In the CR each pathway was segregated. Medial motor area fibers (M2/M3/M4) arched over the caudate and lateral motor area fibers (M1/LPMCv) curved over the putamen. At superior IC levels, the pathways were widespread, involving the anterior limb, genu and posterior limb with the M3 projection located anteriorly, followed posteriorly by projections from M2, LPMCv, M4 and M1, respectively. Inferiorly, all pathways maintained this orientation but shifted posteriorly, with adjacent fiber bundles overlapping minimally. In the ccCP, M3 fibers were located medially and M1 fibers centromedially, with M2, LPMCv, and M4 pathways overlapping in between. Finally, at inferior ccCP levels, all pathways overlapped. Following CR and superior IC lesions, the dispersed pathway distribution may correlate with acute orofacial dysfunction with spared pathways contributing to orofacial motor recovery. In contrast, the gradually commixed nature of pathway representation inferiorly may enhance fiber vulnerability and correlate with severe, prolonged deficits following lower subcortical and midbrain injury. Additionally, in humans these findings may assist in interpreting orofacial movements evoked during deep brain stimulation, and neuroimaging tractography efforts to localize descending orofacial motor pathways. PMID- 28675476 TI - Nitrene Radical Intermediates in Catalytic Synthesis. AB - Nitrene radical complexes are reactive intermediates with discrete spin density at the nitrogen-atom of the nitrene moiety. These species have become important intermediates for organic synthesis, being invoked in a broad range of C-H functionalization and aziridination reactions. Nitrene radical complexes have intriguing electronic structures, and are best described as one-electron reduced Fischer type nitrenes. They can be generated by intramolecular single electron transfer to the "redox non-innocent" nitrene moiety at the metal. Nitrene radicals generated at open-shell cobalt(II) have thus far received most attention in terms of spectroscopic characterization, reactivity screening, catalytic nitrene-transfer reactions and (computational and experimental) mechanistic studies, but some interesting iron and precious metal catalysts have also been employed in related reactions involving nitrene radicals. In some cases, redox active ligands are used to facilitate intramolecular single electron transfer from the complex to the nitrene moiety. Organic azides are among the most attractive nitrene precursors in this field, typically requiring pre-activated organic azides (e.g. RSO2 N3 , (RO)2 P(=O)N3 , ROC(=O)N3 and alike) to achieve efficient and selective catalysis. Challenging, non-activated aliphatic organic azides were recently added to the palette of reagents useful in synthetically relevant reactions proceeding via nitrene radical intermediates. This concept article describes the electronic structure of nitrene radical complexes, emphasizes on their usefulness in the catalytic synthesis of various organic products, and highlights the important developments in the field. PMID- 28675477 TI - Risk Prioritization in the Food Domain Using Deliberative and Survey Methods: Differences between Experts and Laypeople. AB - This study examined how experts and laypeople using both a deliberative and a survey method prioritized 28 hazards related to food and everyday items. To enable them to make deliberative decisions, participants received detailed descriptions of the hazards. The participants prioritized the hazards before and after a group discussion, in which the group's average prioritization was discussed. The rankings of the hazards before and after the group discussion were highly correlated. However, laypeople and experts differed significantly in their rankings for 18 of the 28 hazards. Trust and confidence were important predictors for laypeople's risk rankings. To test the influence of the deliberative method (e.g., providing detailed information about each hazard), data from a second group of laypeople were collected with a no-information survey. This group did not receive specific information about the hazards. The risk rankings of the laypeople who received information were highly correlated with the risk rankings of laypeople who did not receive information. Overall, the results suggest that deliberative methods of risk-ranking or no-information survey methods with no information about hazards provide similar results among laypeople. The conclusion is that government agencies should not only base their risk prioritization on evidence from risk assessments but also need to consider laypeople's hazard rankings. This procedure may result in an efficient and publicly accepted risk management strategy. PMID- 28675478 TI - Full-spectrum versus standard colonoscopy for improving polyp detection rate: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Full-spectrum endoscopy represents a new endoscopic platform allowing a panoramic 330 degree view of the colon, but evidence of its superiority over standard colonoscopy is still lacking. Our study is the first meta-analysis comparing the efficacy of full-spectrum endoscopy with standard colonoscopy. METHODS: Through a systematic literature review until May 2017, we identified eight randomized-controlled trials. Primary outcomes were polyp detection rate and adenoma detection rate, while cecal intubation time and total colonoscopy time were secondary outcomes. Direct meta-analysis was performed using a random effects model. RESULTS: No difference in terms of polyp detection rate and adenoma detection rate was found (risk ratio: 1.00, 95% confidence interval 0.89-1.12, P = 0.96, and 1.05, 0.94-1.17, P = 0.40, respectively). Adenoma miss rate resulted significantly in favor of full-spectrum endoscopy (risk ratio: 0.35, 0.25-0.48, P < 0.01), although the difference was not significant for greater (>5 mm) and pedunculated lesions (risk ratio: 0.38, 0.09 1.60, P = 0.19, and risk ratio: 0.15, 0.01-3.00, P = 0.21, respectively). Cecal intubation time was not different between the two techniques (mean standardized difference: 0.22 min, -1.18 to 1.62, P = 0.76), while total colonoscopy time was significantly shorter when adopting full-spectrum endoscopy (mean difference: 2.60, -4.60 to -0.61, P = 0.01). Sensitivity analysis confirmed all the findings. CONCLUSIONS: Full-spectrum endoscopy appears as a promising and reliable technology able to significantly decrease the number of adenomas missed and procedural times, while its superiority over standard colonoscopy in terms of adenoma detection rate results is still unclear. PMID- 28675479 TI - Nitrogen-doped C60 as a robust catalyst for CO oxidation. AB - The O2 activation and CO oxidation on nitrogen-doped C59 N fullerene are investigated using first-principles calculations. The calculations indicate that the C59 N fullerene is able to activate O2 molecules resulting in the formation of superoxide species ( O2-) both kinetically and thermodynamically. The active superoxide can further react with CO to form CO2 via the Eley-Rideal mechanism by passing a stepwise reaction barrier of only 0.20 eV. Ab initio molecular dynamics (AIMD) simulation is carried out to evidence the feasibility of the Eley-Rideal mechanism. In addition, the second CO oxidation takes place with the remaining atomic O without any activation energy barrier. The full catalytic reaction cycles can occur energetically favorable and suggest a two-step Eley-Rideal mechanism for CO oxidation with O2 catalyzed by the C59 N fullerene. The catalytic properties of high percentage nitrogen-doped fullerene (C48 N12 ) is also examined. This work contributes to designing higher effective carbon-based materials catalysts by a dependable theoretical insight into the catalytic properties of the nitrogen-doped fullerene. (c) 2017 Wiley Periodicals, Inc. PMID- 28675480 TI - Omics approaches on fresh-cut lettuce reveal global molecular responses to sodium hypochlorite and peracetic acid treatment. AB - BACKGROUND: Lettuce is a leafy vegetable that is extensively commercialized as a ready-to-eat product because of its widespread use in human nutrition as salad. It is well known that washing treatments can severely affect the quality and shelf-life of ready-to-eat vegetables. The study presented here evaluated the effect of two washing procedures on fresh-cut lettuce during storage. RESULTS: An omics approach was applied to reveal global changes at molecular level induced by peracetic acid washing in comparison with sodium hypochlorite treatment. Microbiological analyses were also performed to quantify total bacterial abundance and composition. The study revealed wide metabolic alterations induced by the two sanitizers. In particular, transcriptomic and proteomic analyses pointed out a number of transcripts and proteins differentially accumulated in response to peracetic acid washing, mainly occurring on the first day of storage. In parallel, different microbiota composition and significant reduction in total bacterial load following washing were also observed. CONCLUSION: The results provide useful information for the fresh-cut industry to select an appropriate washing procedure preserving fresh-like attributes as much as possible during storage of the end product. Molecular evidence indicated peracetic acid to be a valid alternative to sodium hypochlorite as sanitizer solution. (c) 2017 Society of Chemical Industry. PMID- 28675481 TI - Recognition/Appreciation of Guest Reviewers-2016. PMID- 28675482 TI - Commentary on: Rerolle C, Faisant M, Lefrancq T, Saint-Martin P. Sudden death due to undiagnosed rheumatic heart disease in a child. J Forensic Sci 2016;61(3):848 50. PMID- 28675483 TI - Authors' Response. PMID- 28675484 TI - Erratum. PMID- 28675486 TI - Missed opportunities for adolescent friendly care in hospital. AB - AIM: To investigate whether adolescent friendly care, as defined by current best practice, was being provided within a hospital setting. METHODS: All patients aged 12-18 presenting to Tauranga Hospital over a 5-week period were invited to complete a questionnaire on their experience of care. Responses were obtained from 319 adolescents (40% response rate). RESULTS: Adolescents reported that staff were generally friendly (>80%) and respectful (>90%) and that they trusted staff to care for them (90%). Explanations were considered clear by 87% of adolescents, but 20% felt uncomfortable asking questions. Confidentiality was discussed with some adolescents (52%). Privacy was provided (93%), and most adolescents (86%) were satisfied with the extent of their involvement in consultations. Adolescents reported that staff did not routinely undertake psychosocial assessments. The physical environment and resources did not always meet the needs of adolescents, with 70% complaining about a lack of access to other adolescents. CONCLUSION: While adolescents rated the care they received highly, the care did not always align with best practices regarding adolescent friendly care. There is ample opportunity for improvement. PMID- 28675487 TI - Mild Cobalt(III)-Catalyzed Allylative C-F/C-H Functionalizations at Room Temperature. AB - Sustainable, cobalt-catalyst enabled, synthetically significant C-F/C-H functionalizations were achieved with an ample substrate scope at an ambient temperature of 25 degrees C, thereby delivering perfluoroallylated heteroarenes. Detailed experimental and computational mechanistic studies on the C-F/C-H functionalizations provided strong support for a facile C-F cleavage. PMID- 28675488 TI - Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo control human clinical trials. AB - BACKGROUND: Over 200 clinical trials have examined the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplements on risk factors associated with cardiovascular disease. However, an updated analysis of the evidence is lacking. The aim of the present meta-analysis was to quantify the effect of supplements containing EPA and DHA on risk factors for cardiovascular disease. METHODS: An analysis was carried on 171 clinical trials with acceptable quality (Jadad score >=3) that were identified from a comprehensive electronic search strategy of two databases (Pubmed and Cochrane Library). A random effect model was used to obtain an overall estimate on outcomes of interest. Heterogeneity between trial results was tested for using a standard chi-squared test. RESULTS: Compared with control, EPA and DHA supplements produced significant reductions of triglycerides of 0.368 mmol L-1 [95% confidence interval (CI) = -0.427 to 0.309], systolic blood pressure of 2.195 mmHg (95% CI = -3.172 to -1.217), diastolic blood pressure of 1.08 mmHg (95% CI = -1.716 to -0.444), heart rate of 1.37 bpm (95% CI = -2.41 to -0.325) and C-reactive protein of 0.343 mg L-1 (95% CI = -0.454 to -0.232). This analysis indicates an increase in both low-density lipoprotein cholesterol (mean difference = 0.150 mmol L-1 ; 95% CI = 0.058-0.243) and high-density lipoprotein cholesterol (mean difference = 0.039 mmol L-1 ; 95% CI = 0.024-0.054). The triglyceride-lowering effect was dose-dependent. CONCLUSIONS: The lipid-lowering, hypotensive, anti-arrhythmic and anti inflammatory actions of EPA and DHA supplements were confirmed in this analysis of randomised placebo-control blinded clinical trials. PMID- 28675489 TI - Synergy between Auraptene, Ionizing Radiation, and Anticancer Drugs in Colon Adenocarcinoma Cells. AB - Colorectal cancer is a growing health concern with increasing mortality rates, and resistance to anticancer drugs and radiotherapy is a serious drawback in its treatment. Auraptene is a natural prenyloxycoumarin with valuable anticancer effects. The aim of current study was to determine the synergy between auraptene, ionizing radiation, and chemotherapeutic drugs in colon adenocarcinoma cells for the first time. To do so, HT29 cells were treated with combination of auraptene + cisplatin, + doxorubicin, or + vincristine. Furthermore, cells were pretreated with nontoxic auraptene and then exposed to various doses of X-radiation. Assessment of cell viability not only indicated significant (p < 0.05) synergic effects of auraptene and anticancer agents, also revealed more significant (p < 0.01) increase in the toxicity of applied radiations in auraptene pretreated cells. Interesting synergy between auraptene and radiotherapy was then confirmed by morphological alterations, DAPI staining, and flow cytometric analysis of the cell cycle. Moreover, real-time reverse transcription polymerase chain reaction analysis indicated significant (p < 0.01) overexpression of p21, but not GATA6, in auraptene pretreated cells after radiotherapy, and also significant (p < 0.01) down regulation of CD44 and ALDH1 by auraptene. According to present results, auraptene could be considered as an effective natural coumarin to improve the outcome of current chemoradiotherapy options. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28675490 TI - The significance of negative correlations in brain connectivity. AB - Understanding the modularity of functional magnetic resonance imaging (fMRI) derived brain networks or "connectomes" can inform the study of brain function organization. However, fMRI connectomes additionally involve negative edges, which may not be optimally accounted for by existing approaches to modularity that variably threshold, binarize, or arbitrarily weight these connections. Consequently, many existing Q maximization-based modularity algorithms yield variable modular structures. Here, we present an alternative complementary approach that exploits how frequent the blood-oxygen-level-dependent (BOLD) signal correlation between two nodes is negative. We validated this novel probability-based modularity approach on two independent publicly-available resting-state connectome data sets (the Human Connectome Project [HCP] and the 1,000 functional connectomes) and demonstrated that negative correlations alone are sufficient in understanding resting-state modularity. In fact, this approach (a) permits a dual formulation, leading to equivalent solutions regardless of whether one considers positive or negative edges; (b) is theoretically linked to the Ising model defined on the connectome, thus yielding modularity result that maximizes data likelihood. Additionally, we were able to detect novel and consistent sex differences in modularity in both data sets. As data sets like HCP become widely available for analysis by the neuroscience community at large, alternative and perhaps more advantageous computational tools to understand the neurobiological information of negative edges in fMRI connectomes are increasingly important. PMID- 28675491 TI - Electrocortical components of anticipation and consumption in a monetary incentive delay task. AB - In order to improve our understanding of the components that reflect functionally important processes during reward anticipation and consumption, we used principle components analyses (PCA) to separate and quantify averaged ERP data obtained from each stage of a modified monetary incentive delay (MID) task. Although a small number of recent ERP studies have reported that reward and loss cues potentiate ERPs during anticipation, action preparation, and consummatory stages of reward processing, these findings are inconsistent due to temporal and spatial overlap between the relevant electrophysiological components. Our results show three components following cue presentation are sensitive to incentive cues (N1, P3a, P3b). In contrast to previous research, reward-related enhancement occurred only in the P3b, with earlier components more sensitive to break-even and loss cues. During feedback anticipation, we observed a lateralized centroparietal negativity that was sensitive to response hand but not cue type. We also show that use of PCA on ERPs reflecting reward consumption successfully separates the reward positivity from the independently modulated feedback-P3. Last, we observe for the first time a new reward consumption component: a late negativity distributed over the left frontal pole. This component appears to be sensitive to response hand, especially in the context of monetary gain. These results illustrate that the time course and sensitivities of electrophysiological activity that follows incentive cues do not follow a simple heuristic in which reward incentive cues produce enhanced activity at all stages and substages. PMID- 28675492 TI - Development of patient-controlled respiratory gating system based on visual guidance for magnetic-resonance image-guided radiation therapy. AB - PURPOSE: The aim of this study is to develop a visual guidance patient-controlled (VG-PC) respiratory gating system for respiratory-gated magnetic-resonance image guided radiation therapy (MR-IGRT) and to evaluate the performance of the developed system. METHODS: The near-real-time cine planar MR image of a patient acquired during treatment was transmitted to a beam projector in the treatment room through an optical fiber cable. The beam projector projected the cine MR images inside the bore of the ViewRay system in order to be visible to a patient during treatment. With this visual information, patients voluntarily controlled their respiration to put the target volume into the gating boundary (gating window). The effect of the presence of the beam projector in the treatment room on the image quality of the MRI was investigated by evaluating the signal-to noise ratio (SNR), uniformity, low-contrast detectability, high-contrast spatial resolution, and spatial integrity with the VG-PC gating system. To evaluate the performance of the developed system, we applied the VG-PC gating system to a total of seven patients; six patients received stereotactic ablative radiotherapy (SABR) and one patient received conventional fractionated radiation therapy. RESULTS: The projected cine MR images were visible even when the room light was on. No image data loss or additional time delay during delivery of image data were observed. Every indicator representing MRI quality, including SNR, uniformity, low-contrast detectability, high-contrast spatial resolution, and spatial integrity exhibited values higher than the tolerance levels of the manufacturer with the VG-PC gating system; therefore, the presence of the VG-PC gating system in the treatment room did not degrade the MR image quality. The average beam-off times due to respiratory gating with and without the VG-PC gating system were 830.3 +/- 278.2 s and 1264.2 +/- 302.1 s respectively (P = 0.005). Consequently, the total treatment times excluding the time for patient setup with and without the VG-PC gating system were 1453.3 +/- 297.3 s and 1887.2 +/- 469.6 s, respectively, on average (P = 0.005). The average number of beam-off events during whole treatment session was reduced from 457 +/- 154 times to 195 +/- 90 times by using the VG-PC gating system (P < 0.001). CONCLUSIONS: The developed system could improve treatment efficiency when performing respiratory gated MR-IGRT. The VG-PC gating system could be applied to any kind of bore-type radiotherapy machine. PMID- 28675493 TI - Quantitation of nasal development in the early prenatal period using geometric morphometrics and MRI: a new insight into the critical period of Binder phenotype. AB - OBJECTIVES: Disturbance of the development of the nasal septum in the early prenatal period causes congenital facial anomalies characterized by a flat nose and defects of the anterior nasal spine (ANS), such as Binder phenotype. The present research aimed to assess the development of the nasal septum and the ANS with growth in the early prenatal period. METHODS: Magnetic resonance images were obtained from 56 specimens. Mid-sagittal images were analyzed by using geometric morphometrics for the development of the nasal septum, and angle analysis was performed for the development of the ANS. Additionally, we calculated and visualized the ontogenetic allometry of the nasal septum. RESULTS: Our results showed that the nasal septum changed shape in the anteroposterior direction in smaller specimens, while it maintained an almost isometric shape in larger specimens. Furthermore, mathematical evidence revealed that the maturation periods of the shapes of the ANS and the nasal septum were around 12 and 14 weeks of gestation, respectively. CONCLUSION: The anteroposterior development of the nasal septum is specific until 14 weeks of gestation, and it is important for nasal protrusion and the development of the ANS. Therefore, the disturbance of such development could induce low nasal deformity, including Binder phenotype. (c) 2017 John Wiley & Sons, Ltd. PMID- 28675494 TI - W4-17: A diverse and high-confidence dataset of atomization energies for benchmarking high-level electronic structure methods. AB - Atomization reactions are among the most challenging tests for electronic structure methods. We use the first-principles Weizmann-4 (W4) computational thermochemistry protocol to generate the W4-17 dataset of 200 total atomization energies (TAEs) with 3sigma confidence intervals of 1 kJ mol-1 . W4-17 is an extension of the earlier W4-11 dataset; it includes first- and second-row molecules and radicals with up to eight non-hydrogen atoms. These cover a broad spectrum of bonding situations and multireference character, and as such are an excellent benchmark for the parameterization and validation of highly accurate ab initio methods (e.g., CCSD(T) composite procedures) and double-hybrid density functional theory (DHDFT) methods. The W4-17 dataset contains two subsets (i) a non-multireference subset of 183 systems characterized by dynamical or moderate nondynamical correlation effects (denoted W4-17-nonMR) and (ii) a highly multireference subset of 17 systems (W4-17-MR). We use these databases to evaluate the performance of a wide range of CCSD(T) composite procedures (e.g., G4, G4(MP2), G4(MP2)-6X, ROG4(MP2)-6X, CBS-QB3, ROCBS-QB3, CBS-APNO, ccCA-PS3, W1, W2, W1-F12, W2-F12, W1X-1, and W2X) and DHDFT methods (e.g., B2-PLYP, B2GP PLYP, B2K-PLYP, DSD-BLYP, DSD-PBEP86, PWPB95, omegaB97X-2(LP), and omegaB97X 2(TQZ)). (c) 2017 Wiley Periodicals, Inc. PMID- 28675495 TI - Painful Flexor Carpi Radialis Brevis Muscle: An Ultrasound and Magnetic Resonance Imaging Assessment. PMID- 28675496 TI - Knowing When Help Is Needed: A Developing Sense of Causal Complexity. AB - Research on the division of cognitive labor has found that adults and children as young as age 5 are able to find appropriate experts for different causal systems. However, little work has explored how children and adults decide when to seek out expert knowledge in the first place. We propose that children and adults rely (in part) on "mechanism metadata," information about mechanism information. We argue that mechanism metadata is relatively consistent across individuals exposed to similar amounts of mechanism information, and it is applicable to a wide range of causal systems. In three experiments, we show that adults and children as young as 5 years of age have a consistent sense of the causal complexity of different causal systems, and that this sense of complexity is related to decisions about when to seek expert knowledge, but over development there is a shift in focus from procedural information to internal mechanism information. PMID- 28675497 TI - Intracellular water preexchange lifetime in neurons and astrocytes. AB - PURPOSE: To determine the intracellular water preexchange lifetime, taui , the "average residence time" of water, in the intracellular milieu of neurons and astrocytes. The preexchange lifetime is important for modeling a variety of MR data sets, including relaxation, diffusion-sensitive, and dynamic contrast enhanced data sets. METHODS: Herein, taui in neurons and astrocytes is determined in a microbead-adherent, cultured cell system. In concert with thin-slice selection, rapid flow of extracellular media suppresses extracellular signal, allowing determination of the transcytolemmal-exchange-dominated, intracellular T1 . With this knowledge, and that of the intracellular T1 in the absence of exchange, taui can be derived. RESULTS: Under normal culture conditions, taui for neurons is 0.75 +/- 0.05 s versus 0.57 +/- 0.03 s for astrocytes. Both neuronal and astrocytic taui s decrease within 30 min after the onset of oxygen-glucose deprivation, with the astrocytic taui showing a substantially greater decrease than the neuronal taui . CONCLUSIONS: Given an approximate intra- to extracellular volume ratio of 4:1 in the brain, these data imply that, under normal physiological conditions, an MR experimental characteristic time of less than 0.012 s is required for a nonexchanging, two-compartment (intra- and extracellular) model to be valid for MR studies. This characteristic time shortens significantly (i.e., 0.004 s) under injury conditions. Magn Reson Med 79:1616-1627, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28675498 TI - Antitumour bioactive peptides isolated from marine organisms. AB - Marine organisms are an important source of antitumour active substances. Thus, pharmaceutical research in recent years has focused on exploring new antitumour drugs derived from marine organisms, and, many peptide drugs with strong antitumour activities have been successfully extracted. Based on different mechanisms, this paper reviews the research on several typical antitumour bioactive peptides in marine drugs and the latest progress therein. Additionally, the development prospects for these antitumour bioactive peptide-based drugs are discussed so as to provide a reference for future research in this field. PMID- 28675499 TI - Ultra-short-course booster is effective in recurrent grass pollen-induced allergic rhinoconjunctivitis. AB - BACKGROUND: A relevant proportion of allergic rhinoconjunctivitis (ARC) patients experience recurrent symptoms after successfully completing allergen immunotherapy (AIT). This prospective, controlled, noninterventional study used internationally standardized instruments to determine the clinical effects of a preseasonal, ultra-short-course booster AIT on clinical outcome parameters. METHODS: This two-arm study included patients aged >=12 years with recurrent grass pollen-induced seasonal AR who had completed a successful course of any grass pollen AIT at least 5 years before enrolment. Overall, 56 patients received one preseasonal short-course booster AIT using tyrosine-absorbed grass pollen allergoids containing the adjuvant monophosphoryl lipid A (MPL(r) ); 51 control patients received symptomatic medication. The combined symptom and medication score (CSMS) was recorded in the (peak) grass pollen season. Furthermore, concomitant (antiallergic) medication use, the patients' state of health, Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ) results and safety/tolerability of the treatment were assessed. RESULTS: The CSMS in the peak grass pollen season was significantly lower in the booster AIT group (Delta=38.4%, P<.01). Moreover, significantly more patients in this group used no concomitant antiallergic medication throughout the peak grass pollen season. Twice as many patients in the booster AIT group as in the control group reported having a better state of health than in the preceding season. MiniRQLQ results showed significant differences favouring the booster AIT. The booster AIT was generally well tolerated, with only two patients reporting mild, grade 1 systemic adverse events. CONCLUSION: Booster AIT using tyrosine-absorbed allergoids containing the adjuvant MPL(r) effectively prevents re-occurrence of symptoms in patients with grass pollen-induced ARC. PMID- 28675500 TI - FAM107B is regulated by S100A4 and mediates the effect of S100A4 on the proliferation and migration of MGC803 gastric cancer cells. AB - FAM107B expression was decreased in stomach cancer and many other kinds of cancer. The forced expression of FAM107B in HeLa cells diminished proliferation in response to growth factors, suggesting that FAM107B might play important roles in many types of cancers. But the mechanisms underlying the decreased expression of FAM107B in cancers are not clear, the functional significance needs to be further clarified. Our previous findings from cDNA microarray showed that there are 179 differentially expressed genes after S100A4 inhibition in gastric cancer cells MGC803. FAM107B was an upregulated one among them. In the present study, we confirmed that FAM107B expression was upregulated in MGC803 cells after S100A4 inhibition by qRT-PCR. We demonstrated for the first time that FAM107B was downregulated by S100A4. The results from CCK-8 and transwell assay showed that FAM107B inhibition by siRNA led to significantly increased proliferation and migrating abilities of MGC803 cells, respectively, indicating that FAM107B plays important roles in inhibiting the proliferation and migration of MGC803 cells. The rescue experiment showed that FAM107B-siRNA transfection reversed the reduced proliferation and migration abilities induced by S100A4 inhibition in the cells. These findings suggest that, as a downstream effector, FAM107B at least partly mediates the effect of S100A4 on the proliferation and migration of MGC803 cells. In conclusion, we first provide experimental evidence suggesting that FAM107B was downregulated by S100A4 in gastric cancer MGC803 cells. And FAM107B at least partially mediates the biological effect of S100A4 in the cells. PMID- 28675501 TI - ASSESSING ANGELS IN THE NURSERY: A PILOT STUDY OF CHILDHOOD MEMORIES OF BENEVOLENT CAREGIVING AS PROTECTIVE INFLUENCES. AB - This pilot study provides the first empirical test of the concept of "Angels in the Nursery" by examining whether childhood memories of benevolent caregiving experiences protect against heightened levels of psychopathology in high-risk mothers. The study hypothesized that (a) elaborated childhood memories of feeling loved by a caregiver ("angel memories") would moderate adulthood posttraumatic stress disorder (PTSD) symptoms in mothers with childhood maltreatment histories, and (b) spontaneous traumatic intrusions ("ghost memories") would mediate childhood maltreatment and adulthood PTSD symptoms. Participants were 54 mothers (M = 32.79 years, SD = 8.91; 59.2% African American, 13.0% Caucasian, 5.6% Latina, 22.2% biracial/multiracial) who completed standardized assessments of childhood maltreatment and adulthood PTSD symptoms, and a novel instrument, the Angels in the Nursery Interview ("Angels Interview," Van Horn, Lieberman, & Harris, 2008). Results showed that angel memories significantly moderated childhood maltreatment and adulthood PTSD symptoms, consistent with a protective effect. Higher levels of ghost memories during the Angels Interview were significantly associated with more extensive childhood maltreatment, but did not mediate maltreatment and PTSD symptoms. Findings indicate that the Angels Interview can identify pathogenic intrusions rooted in childhood maltreatment and protective factors to promote maternal mental health and buffer the intergenerational transmission of trauma. PMID- 28675502 TI - Dmrt1 polymorphism and sex-chromosome differentiation in Rana temporaria. AB - Sex-determination mechanisms vary both within and among populations of common frogs, opening opportunities to investigate the molecular pathways and ultimate causes shaping their evolution. We investigated the association between sex chromosome differentiation (as assayed from microsatellites) and polymorphism at the candidate sex-determining gene Dmrt1 in two Alpine populations. Both populations harboured a diversity of X-linked and Y-linked Dmrt1 haplotypes. Some males had fixed male-specific alleles at all markers ("differentiated" Y chromosomes), others only at Dmrt1 ("proto-" Y chromosomes), while still others were genetically indistinguishable from females (undifferentiated X chromosomes). Besides these XX males, we also found rare XY females. The several Dmrt1 Y haplotypes differed in the probability of association with a differentiated Y chromosome, which we interpret as a result of differences in the masculinizing effects of alleles at the sex-determining locus. From our results, the polymorphism in sex-chromosome differentiation and its association with Dmrt1, previously inferred from Swedish populations, are not just idiosyncratic features of peripheral populations, but also characterize highly diverged populations in the central range. This implies that an apparently unstable pattern has been maintained over long evolutionary times. PMID- 28675503 TI - A population-based study of self-reported skin exposures and symptoms in relation to contact allergy in adolescents. AB - BACKGROUND: Knowledge about the relations between skin exposures, skin symptoms and contact allergy in adolescents is limited. OBJECTIVES: To explore self reported skin exposures and skin symptoms in girls and boys, and to assess the associations between exposures, symptoms and contact allergy at age 16 years. PARTICIPANTS AND METHODS: In all, 3115 adolescents from the population-based BAMSE birth cohort answered a questionnaire at age 16 concerning various skin exposures and related skin symptoms. Of these, 2285 were patch tested. RESULTS: The prevalences of self-reported piercing (55.4%), hair dyeing (50.1%) and related skin symptoms were high, particularly in girls. Piercing and itchy rash after contact with metal items were associated with increased risks of nickel allergy [respectively: odds ratio (OR) 1.77, 95%CI: 1.04-3.03, and OR 2.25, 95%CI: 1.57-3.23]. An itchy rash resulting from the use of personal hygiene products or makeup was associated with a positive patch test reaction to fragrance mix I (OR 2.11, 95%CI: 1.02-4.35). CONCLUSIONS: Adolescents are exposed to skin-sensitizing substances, for example because of piercing, hair dyeing, and tattooing. Such early-life skin exposure may lead to lifelong contact allergy and future allergic contact dermatitis and hand eczema. PMID- 28675504 TI - Ultrasound assessment of gastric emptying after breakfast in healthy preschool children. AB - BACKGROUND: In current guidelines, 6 hours of fasting is recommended for solids to limit the risk of pulmonary aspiration during anesthesia in children. Ultrasonography has recently been introduced to evaluate gastric volumes in children in the context of preanesthetic fasting. Therefore, in this study, we firstly evaluated the precision of ultrasound assessment of gastric volume in an experimental setting and secondly studied gastric emptying times after a normal breakfast in healthy preschool children using ultrasound. METHODS: In a preliminary experiment, a pear-shaped elastic balloon was filled and emptied in 50 mL steps from 0 to 500 mL with water. After each step, the balloon antral area was measured using ultrasonography. Thereafter, gastric emptying was examined in healthy preschool children after normal breakfast by sonographic measurements of the gastric antral area in right lateral decubitus position at two consecutive timepoints. Correlation coefficients (Pearson, 95% CI) between the balloon antral area and the balloon volume or gastric antral area and fasting time were calculated and gastric emptying time was extrapolated by linear regression. Data are presented as mean (range). RESULTS: In the balloon experiment, the balloon volume correlated significantly with the balloon antral area (63 measurements, r=.96, P<.0001, 95% CI 0.93 to 0.97). In the preschool child measurements, a total of 30 children (age 47 (36-66) months) were included. The gastric antral area correlated significantly with fasting time (r=-.69, P<.0001, 95% CI -0.8 to 0.51). The first gastric antral area after breakfast was significantly higher when compared to the second gastric antral area before lunch (10.4 +/- 3.7 (1.7 17.8) vs 5.5 +/- 2.6 (1.4-11.8) cm2 ; mean difference -5.04, 95% CI -6.3 to -3.8, P<.0001). The calculated mean gastric emptying time was 236 minutes. CONCLUSION: The results of the balloon experiment showed a high correlation between balloon antral area and balloon volume. In the preschool child measurements, gastric antral area correlated with fasting time, and the mean gastric emptying time was lower than 4 hours after breakfast. These results support a more liberal perioperative fasting regimen after a light meal or breakfast in routine pediatric anesthesia. PMID- 28675505 TI - Supramolecular interactions between beta-lapachone with cyclodextrins studied using isothermal titration calorimetry and molecular modeling. AB - Supramolecular interactions between beta-lapachone (beta-lap) and cyclodextrins (CDs) were investigated by isothermal titration calorimetry. The most favorable host: guest interaction was characterized using X-ray powder diffraction (XRD), differential scanning calorimetry and thermogravimetry (DSC/TG), spectroscopy (FT IR), spectroscopy (2D ROESY) nuclear magnetic resonance (NMR), and molecular modeling. Phase solubility diagrams showed beta-, HP-beta-, SBE-beta-, gamma-, and HP-gamma-CDs at 1.5% (w/w) allowed an increase in apparent solubility of beta lap with enhancement factors of 12.0, 10.1, 11.8, 2.4, and 2.2, respectively. beta-lap has a weak interaction with gamma- and HP-gamma-CDs and tends to interact more favorably with beta-CD and its derivatives, especially SBE-beta-CD (K = 4160 M-1 ; DeltaG = -20.66 kJ.mol-1 ). Thermodynamic analysis suggests a hydrophobic interaction associated with the displacement of water from the cavity of the CD by the beta-lap. In addition, van der Waals forces and hydrogen bonds were responsible for the formation of complexes. Taken together, the results showed intermolecular interactions between beta-lap and SBE-beta-CD, thereby confirming the formation of the inclusion complex. Molecular docking results showed 2 main orientations in which the interaction of benzene moiety at the wider rim of the SBE-beta-CD is the most stable (average docking energy of -7.0 kcal/mol). In conclusion, beta-lap:SBE-beta-CD is proposed as an approach for use in drug delivery systems in cancer research. PMID- 28675506 TI - Determination of the cell tropism of serotype 1 feline infectious peritonitis virus using the spike affinity histochemistry in paraffin-embedded tissues. AB - Unlike for serotype II feline coronaviruses (FCoV II), the cellular receptor for serotype I FCoV (FCoV I), the most prevalent FCoV serotype, is unknown. To provide a platform for assessing the pattern by which FCoV I attaches to its host receptor(s), HEK293 cell lines that stably express the ectodomains of the spike (S) proteins derived from a FCoV I feline enteric coronavirus strain UU7 (FECV UU7) and a feline infectious peritonitis virus strain UU4 (FIPV UU4) were established. Using the recombinant S proteins as probes to perform S protein affinity histochemistry in paraffin-embedded tissues, although no tissue or enteric binding of FECV UU7 S protein was detected, it was found that by immunohistochemistry that the tissue distribution of FIPV UU4 S protein-bound cells correlated with that of FIPV antigen-positive cells and lesions associated with FIP and that the affinity binding of FIPV UU4 S protein on macrophages was not affected by enzymatic removal of host cell-surface sialic acid with neuraminidase. These findings suggest that a factor(s) other than sialic acid contribute(s) to the macrophage tropism of FIPV strain UU4. This approach allowed obtaining more information about both virus-host cell interactions and the biological characteristics of the unidentified cellular receptor for FCoV I. PMID- 28675507 TI - Frontal cortical effects on feedback processing and reinforcement learning: Relation of EEG asymmetry with the feedback-related negativity and behavior. AB - Reinforcement learning refers to the acquisition of approach or avoidance action tendencies through repeated reward/nonreward feedback. Although much research on reinforcement learning has focused on the striatum, the prefrontal cortex likely modulates this process. Given prior research demonstrating a consistent pattern of lateralized frontal cortical activity in affective responses and approach/avoidance tendencies in the EEG literature, we aimed to elucidate the role of frontal EEG asymmetry in reinforcement learning. Thirty-two participants completed a probabilistic selection task in which they learned to select some targets and avoid others though correct/incorrect feedback. EEG indices of frontal cortical asymmetry were computed from alpha power recorded at baseline and during task completion. We also examined the feedback-related negativity ERP component to assess feedback processing associated with activity in the dorsal anterior cingulate cortex. Results revealed that greater right-lateralized frontal cortical activity during learning was associated with better avoidance learning, but neither left- nor right-sided asymmetry reliably related to approach learning. Results also suggested that left frontal activity may relate to reinforcement feedback processing, as indicated by the feedback-related negativity (FRN). These findings offer preliminary evidence regarding the role of frontal cortical activity in reinforcement learning while integrating classic and contemporary research on lateralized frontal cortical functions. PMID- 28675508 TI - Chronic total occlusion in an infarct-related coronary artery and the risk of appropriate ICD therapies. AB - INTRODUCTION: Risk stratification for ventricular arrhythmias in patients with ischemic cardiomyopathy needs to be improved. Coronary chronic total occlusions in an infarct-related artery (IRA-CTOs) have been associated with an increased arrhythmic risk. This study aimed to evaluate the association between IRA-CTOs and appropriate implantable cardioverter-defibrillator (ICD) therapies. METHODS AND RESULTS: Observational cohort study that included 342 patients with ischemic cardiomyopathy, an ICD implanted for primary or secondary prevention, and a coronary angiography performed shortly before ICD implantation. The ICD was implanted for primary prevention in 163 patients (48%). IRA-CTO was found in 161 patients (47%). During a median follow-up of 33 months, 41% of patients experienced at least one appropriate ICD therapy. Patients with IRA-CTO had higher proportions of appropriate ICD therapies (57% vs. 26%, P < 0.001) and appropriate ICD shocks (40% vs. 17%, P < 0.001). At multivariate Cox regression, IRA-CTO was the only variable that consistently resulted as independent predictor of appropriate ICD therapies and shocks both in the global population of the study (HR 2.3, P < 0.001 and HR 3, P < 0.001, respectively) and when analyzing separately patients with primary or secondary prevention ICD. CONCLUSIONS: IRA CTO is an independent predictor of appropriate ICD therapies, including appropriate ICD shocks. This association is consistent across all the subgroups analyzed. Patients with IRA-CTO have a very high risk of appropriate ICD therapies. These findings may help improving risk stratification as well as the management of ventricular arrhythmias in patients with ischemic cardiomyopathy. PMID- 28675509 TI - Stepwise Light-Induced Dual Compaction of Single-Chain Nanoparticles. AB - A photochemical strategy for the sequential dual compaction of single polymer chains is introduced. Two photoreactive methacrylates, with side chains bearing either a phenacyl sulfide (PS) or an alpha-methylbenzaldehyde (photoenol, PE) moiety, are selectively incorporated by one-pot iterative reversible-addition fragmentation chain transfer copolymerization into the outer blocks of a well defined poly(methyl methacrylate) based ABC triblock copolymer possessing a nonfunctional spacer block (Mn = 23 400 g mol-1 , D = 1.2; ~15 units of each photoreactive moieties of each type) as well as in model statistical copolymers bearing only one type of photoreactive unit. Upon UVA irradiation, PS and PE lead to highly reactive thioaldehydes and o-quinodimethanes, which rapidly react with dithiol and diacrylate linkers, respectively. The monomerfunctional copolymers are employed to establish the conditions for controlled intramolecular photo crosslinking, which are subsequently applied to the bifunctional triblock copolymer. All compaction/folding experiments are monitored by size-exclusion chromatography and dynamic light scattering. The dual compaction consists of two events of dissimilar amplitude: the first folding step reveals a large reduction in hydrodynamic diameters, while the second compaction lead to a far less pronounced reduction of the single-chain nanoparticles size, consistent with the reduced degrees of freedom available after the first covalent compaction step. PMID- 28675511 TI - Electrophysiological relation between the superior vena cava and right superior pulmonary vein in patients with paroxysmal atrial fibrillation. AB - INTRODUCTION: The superior vena cava (SVC) is a main source of nonpulmonary vein (PV) ectopies initiating atrial fibrillation (AF). Empiric SVC isolation may improve rhythm outcomes after catheter ablation of AF. Because the SVC passes immediately adjacent to the right superior PV (RSPV), an electrophysiological relation could be present between the two structures. The present study aimed to estimate the interrelation between the SVC and RSPV by evaluating arrhythmogenic activities observed during catheter ablation of AF. METHODS AND RESULTS: Study subjects comprised 121 consecutive patients referred for catheter ablation of paroxysmal AF. Isoproterenol infusion was used to induce ectopies and AF. Patients were divided into two groups depending on the presence of arrhythmogenic SVC: arrhythmogenic-SVC (A-SVC) and nonarrhythmogenic SVC (Non-A-SVC) groups. The prevalence of females was higher and body surface area was smaller in the A-SVC group (N = 22) than Non-A-SVC group (N = 99). Arrhythmogenic activities were observed in 60 (49%) RSPVs, 24 (20%) right inferior PVs, 72 (59%) left superior PVs, and 31 (25%) left inferior PVs. Arrhythmogenic RSPVs were more prevalent in the A-SVC group than Non-A-SVC group (86% vs. 41%, P = 0.0001), whereas these prevalences in the other three PVs were not different between groups (P >0.3). In multivariable analysis, arrhythmogenic RSPV was the only independent predictor of arrhythmogenicity of the SVC (OR, 8.53; 95% CI 2.31-31.46; P = 0.001). CONCLUSIONS: An electrophysiological interrelation may be present between the SVC and RSPV in patients with paroxysmal AF. Semiempiric SVC isolation limited to patients with an arrhythmogenic RSPV may be a more efficient treatment strategy. PMID- 28675510 TI - The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer. AB - Tumor suppressor genes (TSGs) and oncogenes (OG) are involved in carcinogenesis. MiRNAs also contribute to cellular pathways leading to cancer. We use data from 217 colorectal cancer (CRC) cases to evaluate differences in TSGs and OGs expression between paired CRC and normal mucosa and evaluate how TSGs and OGs are associated with miRNAs. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were used. We focus on genes most strongly associated with CRC (fold change (FC) of >=1.5 or <=0.67) that were statistically significant after adjustment for multiple comparisons. Of the 74 TSGs evaluated, 22 were associated with carcinoma/normal mucosa differential expression. Ten TSGs were up-regulated (FAM123B, RB1, TP53, RUNX1, MSH2, BRCA1, BRCA2, SOX9, NPM1, and RNF43); six TSGs were down-regulated (PAX5, IZKF1, GATA3, PRDM1, TET2, and CYLD); four were associated with MSI tumors (MLH1, PTCH1, and CEBPA down-regulated and MSH6 up-regulated); and two were associated with MSS tumors (PHF6 and ASXL1 up-regulated). Thirteen of these TSGs were associated with 44 miRNAs. Twenty-seven of the 59 OGs evaluated were dysregulated: 14 down regulated (KLF4, BCL2, SSETBP1, FGFR2, TSHR, MPL, KIT, PDGFRA, GNA11, GATA2, FGFR3, AR, CSF1R, and JAK3), seven up-regulated (DNMT1, EZH2, PTPN11, SKP2, CCND1, MET, and MYC); three down-regulated for MSI (FLT3, CARD11, and ALK); two up-regulated for MSI (IDH2 and HRAS); and one up-regulated with MSS tumors (CTNNB1). These findings suggest possible co-regulatory function between TSGs, OGs, and miRNAs, involving both direct and indirect associations that operate through feedback and feedforward loops. PMID- 28675512 TI - Approaching ultimate intrinsic signal-to-noise ratio with loop and dipole antennas. AB - PURPOSE: Previous work with body-size objects suggested that loops are optimal MR detectors at low fields, whereas electric dipoles are required to maximize signal to-noise ratio (SNR) at ultrahigh fields ( >= 7 T). Here we investigated how many loops and/or dipoles are needed to approach the ultimate intrinsic SNR (UISNR) at various field strengths. METHODS: We calculated the UISNR inside dielectric cylinders mimicking different anatomical regions. We assessed the performance of various arrays with respect to the UISNR. We validated our results by comparing simulated and experimental coil performance maps. RESULTS: Arrays with an increasing number of loops can rapidly approach the UISNR at fields up to 3 T, but are suboptimal at ultrahigh fields for body-size objects. The opposite is true for dipole arrays. At 7 T and above, 16 dipoles provide considerably larger central SNR than any possible loop array, and minimal g factor penalty for parallel imaging. CONCLUSIONS: Electric dipoles can be advantageous at ultrahigh fields because they can produce both curl-free and divergence-free currents, whereas loops are limited to divergence-free contributions only. Combining loops and dipoles may be optimal for body imaging at 3 T, whereas arrays of loops or dipoles alone may perform better at lower or higher field strengths, respectively. Magn Reson Med 79:1789-1803, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28675513 TI - ITACA: A new validated international erythropoietic stimulating agent-response score that further refines the predictive power of previous scoring systems. AB - BACKGROUND: In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. OBJECTIVES: To validate existing ESA predictive scores and develop a new score that identifies non-responders. METHODS: ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS CAN, and IPSS-R-based ESA scores were calculated and documented ESA responses compared. RESULTS: 996 ESA-treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level <100 IU/L, and IPSS low-risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0-3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The 'ITACA' score had the highest discriminating power of response. CONCLUSION: ITACA is an internally-validated predictive SS of ESA response in real-life 'good risk' MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non-responders is still needed. PMID- 28675514 TI - Asking what matters: The relevance and use of patient-reported outcome measures that were developed without patient involvement. AB - BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly used to establish the value of health care. In order to reflect value, PROMs should measure outcomes that matter to patients. However, patients are not always involved in the development of PROMs. This study therefore aimed to investigate whether PROMs, which were developed without patient involvement, are relevant to patients and whether the level of importance allocated towards aspects of these PROMs varies between patient groups. METHODS: All patients from 20 Dutch hospitals undergoing hip or knee surgery in 2014 were invited to a PROMs survey. Participants were asked to rate the importance of each of the items in the HOOS Physical Function Short form or the KOOS-Physical Function Short form, the EQ-5D and the NRS pain. RESULTS: Most outcomes were considered important. However, 77.7% of hip surgery patients rated being able to run as unimportant. Being able to kneel (32.7%) or squat (39.6%) was not important to a considerable minority of knee surgery patients. Pain, especially during rest, was considered very important by both hip (68.2%) and knee (66.5%) surgery patients. Patients who were older, male, experienced overall bad health and psychological health considered many items from the PROMs less important than other patients. DISCUSSION: Patients differ in what they consider important. Health-care professionals should explore patients' preferences and discuss which treatment options best fit patients' preferences. Additionally, if PROMs are used in performance measurement, further research is needed to look at whether and how variation in patient preferences can be taken into account. PMID- 28675515 TI - Micrometastatic gastric glomus tumour confirmed by next-generation sequencing. PMID- 28675516 TI - Psoriasiform graft-versus-host disease distributed along Blaschko's lines. AB - This case presents an unusual manifestation of cutaneous chronic graft-vs-host disease (cGVHD) mimicking psoriasis along Blaschko's lines. Such a presentation may pose a particular challenge to providers as it is quite rarely reported, and, therefore, it is possibly misdiagnosed. cGVHD may mimic psoriasis and should be considered in any patient previously transplanted even with a previous history of psoriasis. A Blaschkoid pattern of cGVHD is unusual and may be the manifestation of an immune reaction unveiling a previously masked mosaicism. PMID- 28675517 TI - Wildfire Policy in Mediterranean France: How Far is it Efficient and Sustainable? AB - A new fire policy reinforcing aggressive fire suppression was established in Mediterranean France in response to the devastating wildfires of the 1990s, but to what extent this has changed fire activity yet remains poorly understood. For this purpose, we compared the number and location of ignitions and of burned areas between two 20-year periods (1975-1994 vs. 1995-2014), in parallel to the changes in fuel covering, human activity promoting ignitions, and fire weather. The number of fires decreased almost continuously since 1975, but sharply after 1994, suggesting an effect of better fire prevention due to the new policy. But the major change in fire activity is a considerable reduction in fire size and burned areas after 1994, especially during summer and in the most fire-prone places, in response to massive efforts put into fire suppression. These reductions have occurred while the covering by fuel biomass, the human pressure on ignition, and the fire weather index increased, thus making the study area more hazardous. Our results suggest that a strategy of aggressive fire suppression has great potential for counterbalancing the effects of climate changes and human activities and for controlling fire activity in the short term. However, we discuss whether such a suppression-oriented approach is sustainable in the context of global changes, which cast new fire challenges as demonstrated by the devastative fires of 2003 and 2016. We advocate for a more comprehensive fire policy to come. PMID- 28675518 TI - Clarifying the methods of fixation of intraocular lenses. PMID- 28675519 TI - Outcomes Following Possible Undiagnosed Aneurysmal Subarachnoid Hemorrhage: A Contemporary Analysis. AB - OBJECTIVES: Existing literature suggests that patients with aneurysmal subarachnoid hemorrhage (aSAH) and "sentinel" aSAH symptoms prompting healthcare evaluations prior to aSAH diagnosis are at increased risk of unfavorable neurologic outcomes and death. Accordingly, these encounters have been presumed to be unrecognized opportunities to diagnose aSAH and the worse outcomes representative of the added risks of delayed diagnoses. We sought to reinvestigate this paradigm among a contemporary cohort of patients with aSAH. METHODS: A case-control cohort was retrospectively assembled among patients diagnosed with aSAH between January 1, 2007 and June 30, 2013 within an integrated healthcare delivery system. Patients with a discrete clinical evaluation for headache or neck pain within 14 days prior to formal aSAH diagnosis were identified as cases, and the remaining patients served as controls. Modified Rankin Scale scores at 90 days and 1 year were determined by structured chart review. Multivariable logistic regression controlling for age, sex, ethnicity, presence of intracerebral or intraventricular hemorrhage at diagnosis, and aneurysm size was used to compare adjusted outcomes. Sensitivity analyses were performed using varying definitions of favorable neurologic outcomes, a restricted control subgroup of patients with normal mental status at hospital admission, inclusion of additional cases that were diagnosed outside of the integrated health system, and exclusion of patients without evidence of subarachnoid blood on initial noncontrast cranial computed tomography (CT) at the diagnostic encounter (i.e. "CT-negative" SAH). RESULTS: A total of 450 patients with aSAH were identified, 46 (10%) of whom had clinical evaluations for possible aSAH-related symptoms in the 14 days preceding formal diagnosis (cases). In contrast to prior reports, no differences were observed among cases compared to control patients in adjusted odds of death or unfavorable neurologic status at 90 days (0.35, 95% confidence interval [CI] = 0.11-1.15; 0.59, 95% CI = 0.22-1.60, respectively) or at 1 year (0.58, 95% CI = 0.19-1.73; 0.52, 95% CI = 0.18-1.51, respectively). Likewise, neither restricting the analysis to a control subgroup of patients with normal mental status at hospital admission, varying the dichotomous definition of unfavorable neurologic outcome, inclusion of cases diagnosed outside the integrated health system, or exclusion of patients with CT negative SAH resulted in significant adjusted outcome differences. CONCLUSION: In a contemporary cohort of patients with aSAH, we observed no statistically significant increase in the adjusted odds of death or unfavorable neurologic outcomes among patients with clinical evaluations for possible aSAH-related symptoms in the 14 days preceding formal diagnosis of aSAH. While these findings cannot exclude a smaller risk difference than previously reported, they can help refine decision analyses and testing threshold determinations for patients with possible aSAH. PMID- 28675521 TI - Corrigendum. PMID- 28675520 TI - A randomized phase I comparative pharmacokinetic study comparing SB5 with reference adalimumab in healthy volunteers. AB - WHAT IS KNOWN AND OBJECTIVE: SB5 is a biosimilar to the reference adalimumab (ADL) currently in development. The primary study objective was to demonstrate pharmacokinetic (PK) equivalence of SB5 to European Union-sourced adalimumab (EU ADL), and United States-sourced adalimumab (US-ADL) in healthy subjects. Safety, tolerability and immunogenicity were also assessed as secondary objectives. METHODS: In this phase I, single-blind trial, 189 healthy volunteers were randomized to a single 40 mg dose of SB5, EU-ADL or US-ADL and PK was evaluated for 71 days afterwards. Serum adalimumab concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) test. PK parameters were calculated based on actual sampling times relative to dosing and non-compartmental analysis methods, and equivalence was determined using predefined margins of 0.8-1.25. RESULTS AND DISCUSSION: Baseline characteristics and demographics were comparable between the three groups. Mean values of area under the concentration-time curve from time zero to infinity (AUCinf ), maximum serum concentration (Cmax ) and AUC from time zero to the last quantifiable concentration (AUClast ) were similar between groups, and 90% confidence interval for these parameters were within the predefined equivalence margins for all pairwise comparisons. No discontinuations due to treatment-emergent adverse events (TEAEs) or deaths were reported. Number and kind of TEAEs were comparable between the three groups and considered mild to moderate. The incidence of subjects with antidrug antibodies (ADA) and the overall incidence of neutralizing antibody (NAb) were comparable across the three groups. WHAT IS NEW AND CONCLUSION: The PK of SB5 was equivalent to that of EU ADL and US-ADL. SB5 was well tolerated with similar safety and immunogenicity profile to EU-ADL and US-ADL. PMID- 28675522 TI - Polymer:Fullerene Bimolecular Crystals for Near-Infrared Spectroscopic Photodetectors. AB - Spectroscopic photodetection is a powerful tool in disciplines such as medical diagnosis, industrial process monitoring, or agriculture. However, its application in novel fields, including wearable and biointegrated electronics, is hampered by the use of bulky dispersive optics. Here, solution-processed organic donor-acceptor blends are employed in a resonant optical cavity device architecture for wavelength-tunable photodetection. While conventional photodetectors respond to above-gap excitation, the cavity device exploits weak subgap absorption of intermolecular charge-transfer states of the intercalating poly[2,5-bis(3-tetradecylthiophen-2-yl)thieno[3,2-b]thiophene] (PBTTT):[6,6] phenyl-C61-butyric acid methyl ester (PCBM) bimolecular crystal. This enables a highly wavelength selective, near-infrared photoresponse with a spectral resolution down to 14 nm, as well as dark currents and detectivities comparable with commercial inorganic photodetectors. Based on this concept, a miniaturized spectrophotometer, comprising an array of narrowband cavity photodetectors, is fabricated by using a blade-coated PBTTT:PCBM thin film with a thickness gradient. As an application example, a measurement of the transmittance spectrum of water by this device is demonstrated. PMID- 28675523 TI - Allergic contact dermatitis caused by a new temporary blue-black tattoo dye - sensitization to genipin from jagua (Genipa americana L.) fruit extract. AB - BACKGROUND: Temporary tattoos made with an extract of the jagua fruit (Genipa americana L.) are becoming increasingly popular. It is claimed that it is 'dermatologically tested' and does not contain p-phenylenediamine. Extracts of jagua and gardenia fruits have been used by indigenous people in South America, as well as in traditional Chinese medicine, for centuries. Genipin is currently used for its cross-linking effect in the manufacture of polysaccharides, and is being investigated for its anti-inflammatory and other properties. OBJECTIVES: To report the presence of the allergenic substance genipin in a self-administered temporary tattoo dye made from the fruit juice of jagua (Genipa americana L.). PATIENTS AND METHODS: A 39-year-old female who repeatedly applied 'completely natural and 100% safe' Earth Jagua(r) tattoo, obtained via the internet, to her left hand developed allergic contact dermatitis within 6 weeks. Analysis of the dye showed the presence of geniposide and genipin. RESULTS: Patch tests with the dye and with its main components, including genipin, gave strong positive reactions to the latter. There was no sensitization to other ingredients or p amino compounds. CONCLUSIONS: We report an extensively evaluated case of allergic contact dermatitis caused by a temporary Earth Jagua(r) tattoo. The allergen identified is genipin, a substance that is increasingly used for tattoos and as a therapeutic agent in medicine. This could result in an increase in the number of allergic reactions in the future. PMID- 28675524 TI - Biomarkers for visceral hypersensitivity in patients with irritable bowel syndrome. AB - BACKGROUND: Increased visceral sensitivity is observed in up to 60% of patients with Irritable Bowel Syndrome (IBS). Mucosal inflammation, altered neuroendocrine activity and intraluminal metabolic processes may contribute to the development of visceral hypersensitivity. Previously, we demonstrated that biomarkers, indicative for these biological processes, were altered in IBS patients compared to healthy controls. However, how these processes relate to visceral hypersensitivity is unknown. AIM: The aim of this study was to provide insight in biological processes associated with visceral hypersensitivity. Fecal and plasma biomarkers were measured in normosensitive and hypersensitive IBS patients. METHODS: A total of 167 IBS patients underwent a rectal barostat procedure to assess visceral sensitivity to pain. Based on the outcome, patients were classified into a normosensitive or hypersensitive group. Calprotectin, human beta-defensin 2 (HBD2), chromogranin A (CgA), and short chain fatty acids (SCFAs) were measured in feces, citrulline in plasma, and serotonin and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) in platelet-poor plasma. KEY RESULTS: Fecal markers and plasma citrulline were measured in 83 hypersensitive and 84 normosensitive patients, while platelet-poor plasma for the assessment of serotonin and 5-HIAA was available for a subgroup, i.e. 53 hypersensitive and 42 normosensitive patients. No statistically significant differences were found in concentrations of biomarkers between groups. Adjustment of the analyses for potential confounders, such as medication use, did not alter this conclusion. CONCLUSIONS & INFERENCES: Our findings do not support a role for the biological processes as ascertained by biomarkers in visceral hypersensitivity in IBS patients. This study is registered in the US National Library of Medicine (clinicaltrials.gov, NCT00775060). PMID- 28675525 TI - How to look for deep dynamic mechanical sensitivity? PMID- 28675527 TI - Rumpel-Leede phenomenon in a patient being treated with prasugrel. PMID- 28675526 TI - Synthesis of WOn -WX2 (n=2.7, 2.9; X=S, Se) Heterostructures for Highly Efficient Green Quantum Dot Light-Emitting Diodes. AB - Preparation of two-dimensional (2D) heterostructures is important not only fundamentally, but also technologically for applications in electronics and optoelectronics. Herein, we report a facile colloidal method for the synthesis of WOn -WX2 (n=2.7, 2.9; X=S, Se) heterostructures by sulfurization or selenization of WOn nanomaterials. The WOn -WX2 heterostructures are composed of WO2.9 nanoparticles (NPs) or WO2.7 nanowires (NWs) grown together with single- or few layer WX2 nanosheets (NSs). As a proof-of-concept application, the WOn -WX2 heterostructures are used as the anode interfacial buffer layer for green quantum dot light-emitting diodes (QLEDs). The QLED prepared with WO2.9 NP-WSe2 NS heterostructures achieves external quantum efficiency (EQE) of 8.53 %. To our knowledge, this is the highest efficiency in the reported green QLEDs using inorganic materials as the hole injection layer. PMID- 28675528 TI - Donors and data-increasing deficits. PMID- 28675531 TI - Hot and bothered: management and outcomes for patients with febrile nonhemolytic transfusion reactions. PMID- 28675532 TI - Erratum: Plasma is a strategic resource. PMID- 28675533 TI - Appearance of hemolysis during antibody titration in a case with high titer anti A and anti-B isoagglutinins. PMID- 28675534 TI - Emergent chemodiversity: The case of stereoisomerism in acyclic alkanes. AB - The objective of this pen-and-paper study is to witness the emergence of stereoisomeric properties when comparing lower to higher families of homologs. Specifically, the study compares all acyclic hexanes (five constitutional isomers, a.k.a. regioisomers), all nine heptanes, all 18 octanes, all 35 nonanes, and all 75 decanes. The first part of the work examines the nature and number of stereoisomeric properties seen to emerge in chemical structures featuring one chiral center (i.e., enantiomerism) or two such centers, in which case more complex stereoisomeric features emerge (enantiomerism, diastereoisomerism, pseudoasymmetry, and meso-isomers). The first emergence of chirality (i.e., enantiomerism) occurred in some heptanes. Diastereoisomerism and meso-isomers appear with some octanes, while a pseudoasymmetric center exists in a decane regioisomer. The second part of the work is an attempt to rationalize the numbers of regioisomers, chiral centers, and stereoisomers as these numbers grow from one family of regioisomers to the higher ones. Far from being random, such increases prove regular and ordered. PMID- 28675535 TI - Letter to the Editor. PMID- 28675536 TI - Structure, function and evolution of the cyanobacterial orange carotenoid protein and its homologs. AB - Contents 937 I. 937 II. 938 III. 939 IV. 943 V. 947 VI. 948 948 References 949 SUMMARY: The orange carotenoid protein (OCP) is a water-soluble, photoactive protein involved in thermal dissipation of excess energy absorbed by the light harvesting phycobilisomes (PBS) in cyanobacteria. The OCP is structurally and functionally modular, consisting of a sensor domain, an effector domain and a keto-carotenoid. On photoactivation, the OCP converts from a stable orange form, OCPO , to a red form, OCPR . Activation is accompanied by a translocation of the carotenoid deeper into the effector domain. The increasing availability of cyanobacterial genomes has enabled the identification of new OCP families (OCP1, OCP2, OCPX). The fluorescence recovery protein (FRP) detaches OCP1 from the PBS core, accelerating its back-conversion to OCPO ; by contrast, other OCP families are not regulated by FRP. N-terminal domain homologs, the helical carotenoid proteins (HCPs), have been found among diverse cyanobacteria, occurring as multiple paralogous groups, with two representatives exhibiting strong singlet oxygen (1 O2 ) quenching (HCP2, HCP3) and another capable of dissipating PBS excitation (HCP4). Crystal structures are presently available for OCP1 and HCP1, and models of other HCP subtypes can be readily produced as a result of strong sequence conservation, providing new insights into the determinants of carotenoid binding and 1 O2 quenching. PMID- 28675537 TI - Evaluation of pelvic floor kinematics in continent and incontinent women during running: An exploratory study. AB - AIMS: Impact activity like running is associated with an increase in intra abdominal pressure which needs to be sufficiently countered by pelvic floor muscle (PFM) activity to secure continence. The aim of this study was to investigate and compare PFM kinematics in continent and incontinent women during running. METHOS: Three-dimensional position and orientation was measured with the electromagnetic tracking device trakSTARTM. One sensor was attached to the vaginal probe and a second one was secured to the subjects' skin at the height of the second sacral vertebrae. Cranial-caudal and forward-backward displacement of the vaginal probe was measured during 10 sec running on a treadmill at the speeds 7, 11, and 15 km/h. Displacement data from 100 ms before to 300 ms after heel strike were analyzed. RESULTS: Nineteen incontinent and twenty-seven continent women were included in this study. Before the foot touched the ground caudal translation and forward rotation of the vaginal probe was detected, whereas after heel-strike a cranial translation and backward rotation was measured. Cranial caudal translation as well as backward-forward-rotation did not differ significantly between continent and incontinent subjects for the three speeds. Analysis of maximum displacements showed significantly increasing displacement with increasing speeds. CONCLUSIONS: Kinematic measurements during impact activity of running demonstrated caudal translation before and cranial translation after heel-strike. The hypothesis of caudal translation through impact activity was not confirmed. Patterns seem similar between continent and incontinent subjects. Associations between the direction of displacement and muscle action of PFMs remain assumptions. PMID- 28675538 TI - Frequency and risk factors of colorectal adenoma in patients with early gastric cancer. AB - BACKGROUND/AIM: The authors aimed to determine the clinical value of colonoscopy by evaluating the frequency of colorectal neoplasm (CRN) detection in patients with early gastric cancer (EGC) as compared with healthy controls and analysed the risk factors of advanced CRN in patients with EGC. METHODS: The medical records of 201 patients diagnosed as EGC and age- and gender-matched healthy controls were retrospectively reviewed. Frequencies and clinical features of colorectal polyps of patients and controls were compared. Risk factors of advanced CRN in patients with EGC were also analysed. RESULTS: Frequencies of CRN in patients and controls were 49.8 and 49.3% respectively (P = 0.90). They were more common in the right colon in patients (P < 0.05). Advanced CRN were found in 10.3% of patients and in 3% of controls (P < 0.05). Multivariate analysis revealed that old age and smoking history were risk factors of an advanced CRN in patients with EGC. CONCLUSION: The prevalence of a coexisting advanced CRN was higher in EGC patients. The study shows colonoscopy plays an important role with respect to the detection of synchronous advanced CRN in patients with EGC. PMID- 28675540 TI - Understanding the health of veterans who are homeless: A review of the literature. AB - The United States Department of Housing and Urban Development estimates that almost 50,000 veterans are homeless on any given night. Homeless veterans are at greater risk of health disparities than their housed counterparts due to the multifactorial nature of their health and social needs. The Department of Veterans Affairs, in collaboration with more than a dozen other federal agencies, has concentrated efforts to improve the health of this vulnerable population while enacting a plan to eliminate veteran homelessness within the near future. Understanding the unique health needs of veterans who are homeless allows the profession of nursing to better support these efforts. The purpose of this literature review was to provide comprehensive knowledge to nurses about the health of homeless veterans for their use in clinical practice, research, and in contributing to the positive health outcomes for this vulnerable population. PMID- 28675539 TI - The association between patient activation and self-care practices: A cross sectional study of an Australian population with comorbid diabetes and chronic kidney disease. AB - OBJECTIVE: This study aimed to examine the association between performance of self-care activities and patient or disease factors as well as patient activation levels in patients with diabetes and chronic kidney disease (CKD) in Australia. METHODS: A cross-sectional study was conducted among adults with diabetes and CKD (eGFR <60 mL/min/1.73m2 ) who were recruited from renal and diabetes clinics of four tertiary hospitals in Australia. Demographic and clinical data were collected, as well as responses to the Patient Activation Measure (PAM) and the Summary of Diabetes Self-Care Activities (SDSCA) scale. Regression analyses were performed to determine the relationship between activation and performance of self-care activities. RESULTS: A total of 317 patients (70% men) with a mean age of 66.9 (SD=11.0) years participated. The mean (SD) PAM and composite SDSCA scores were 57.6 (15.5) % (range 0-100) and 37.3 (11.2) (range 0-70), respectively. Younger age, being male, advanced stages of CKD and shorter duration of diabetes were associated with lower scores in one or more self-care components. Patient activation was positively associated with the composite SDSCA score, and in particular the domains of general diet and blood sugar checking (P<.05), but not specific diet, exercising and foot checking. CONCLUSION: In people with diabetes and CKD, a high level of patient activation was positively associated with a higher overall level of self-care. Our results identify subgroups of people who may benefit from tailored interventions to further improve their health outcomes. Further prospective studies are warranted to confirm present findings. PMID- 28675541 TI - Novel approach to maxillary reconstruction using osteocutaneous free tissue transfer with a customized stent. AB - BACKGROUND: Computer-guided 3D virtual planning and customized templates are novel and effective methods aiding maxillary reconstruction, particularly during osteocutaneous free tissue transfer of complex defects. However, virtual planning and modelling is often expensive. METHODS: We present a new method to reconstruct complex defects with a surgical stent designed from presurgical casts. We present 2 patients who underwent this technique. Reconstruction in both cases was aided by a surgical stent fashioned preoperatively to approximate the anatomic dimensions of the defect, guiding the shape and orientation of the flap during inset to aid in dental rehabilitation. RESULTS: Surgery was performed without evidence of malocclusion, oronasal separation, or osteoradionecrosis with both patients undergoing successful rehabilitation and showing good postoperative oral intake. CONCLUSION: Utilization of our novel surgical stent allowed reconstruction of complex maxillectomy defects and facilitated the design of a reconstructive flap without the need of pre-bent plates, cutting guides, or associated expenses. PMID- 28675542 TI - White matter maturation in the neonatal brain is predictive of school age cognitive capacities in children born very preterm. AB - AIM: To investigate the association between white matter organization in the neonatal brain and cognitive capacities at early school age in children born very preterm. METHOD: Thirty children born very preterm (gestational age median 27.5wks, interquartile range [IQR] 25.5-29.5; 18 males, 12 females) were included in this retrospective observational cohort study. Diffusion-weighted imaging (DWI) had been performed on a 3T system in the neonatal period (median 41.3 [IQR 40.0-42.6]wks) and cognitive functioning was formally assessed at age 5 years and 7 months (IQR 5.4-5.9y) using the Wechsler Preschool and Primary Scale of Intelligence. Structural connectivity maps were reconstructed from the DWI data using deterministic streamline tractography. Network metrics of global and local communication and mean fractional anisotropy of white matter pathways were related to IQ and processing speed at age 5 years using linear regression analyses. RESULTS: Mean fractional anisotropy was significantly related to Performance IQ at age 5 years (F=8.48, p=0.007). Findings persisted after adjustment for maternal education level. INTERPRETATION: Our findings provide evidence that the blueprint of later cognitive achievement is already present at term-equivalent age and suggest that white matter connectivity strength may be a valuable predictor for long-term cognitive functioning. PMID- 28675543 TI - Chiral Side Groups Trigger Second Harmonic Generation Activity in 3D Octupolar Bipyrimidine-Based Organic Liquid Crystals. AB - The design of efficient noncentrosymmetric materials remains the ultimate goal in the field of organic second-order nonlinear optics. Unlike inorganic crystals currently used in second-order nonlinear optical applications, organic materials are an attractive alternative owing to their fast electro-optical response and processability, but their alignment into noncentrosymmetric film remains challenging. Here, symmetry breaking by judicious functionalization of 3D organic octupoles allows the emergence of multifunctional liquid crystalline chromophores which can easily be processed into large, flexible, thin, and self-oriented films with second harmonic generation responses competitive to the prototypical inorganic KH2 PO4 crystals. The liquid-crystalline nature of these chiral organic films also permits the modulation of the nonlinear optical properties owing to the sensitivity of the supramolecular organization to temperature, leading to the development of tunable macroscopic materials. PMID- 28675544 TI - Erratum. PMID- 28675545 TI - Cost-effectiveness analysis of fulvestrant versus anastrozole as first-line treatment for hormone receptor-positive advanced breast cancer. AB - Although recent studies demonstrated that fulvestrant is superior to anastrozole as first-line treatment for hormone receptor (HR)-positive advanced breast cancer, the cost-effectiveness of fulvestrant versus anastrozole remained uncertain. Thus, the current study aimed to evaluate the cost-effectiveness of fulvestrant compared with anastrozole in the first-line setting. A Markov model consisting of three health states (stable, progressive and dead) was constructed to simulate a hypothetical cohort of patients with HR-positive advanced breast cancer. Costs were calculated from a Chinese societal perspective. Health outcomes were measured in quality-adjusted life-year (QALY). The incremental cost effectiveness ratio (ICER) was expressed as incremental cost per QALY gained. Model results suggested that fulvestrant provides an additional effectiveness gain of 0.11 QALYs at an incremental cost of $32,654 compared with anastrozole, resulting in an ICER of $296,855/QALY exceeding the willingness-to-pay threshold of $23,700/QALY. Hence, fulvestrant is not a cost-effective strategy compared with anastrozole as first-line treatment for HR-positive advanced breast cancer. PMID- 28675546 TI - Core Outcome Sets: reaching consensus on what to measure in research. PMID- 28675547 TI - Baroreceptor reflex failure: Review of the literature and the potential impact on patients with head and neck cancer. AB - BACKGROUND: Baroreceptor dysfunction and reflex failure may occur after surgery affecting the carotid artery. The implications for patients undergoing treatment for head and neck cancer are not well described. METHODS: A literature search of PubMed was performed between March 2016 and May 2016. Search terms used individually and in combination included: "baroreflex failure," "carotid sinus sensitivity," "carotid endarterectomy," "carotid body tumor," and "head and neck cancer." Bibliographies of included articles were also reviewed for additional pertinent articles. RESULTS: There is evidence of baroreceptor failure in certain patients after interventions associated with the carotid artery, including carotid endarterectomy and carotid body tumor excision. Few studies have been performed investigating the potential effect of head and neck surgery treatment, including surgery and/or radiation, on baroreflex function. CONCLUSION: Head and neck cancer treatment has the potential to cause baroreflex failure, and this is likely an underrecognized and underdiagnosed condition. PMID- 28675548 TI - Neopuff T-piece resuscitator mask ventilation: Does mask leak vary with different peak inspiratory pressures in a manikin model? AB - AIM: The aim of this study was to compare mask leak with three different peak inspiratory pressure (PIP) settings during T-piece resuscitator (TPR; Neopuff) mask ventilation on a neonatal manikin model. METHODS: Participants were neonatal unit staff members. They were instructed to provide mask ventilation with a TPR with three PIP settings (20, 30, 40 cm H2 O) chosen in a random order. Each episode was for 2 min with 2-min rest period. Flow rate and positive end expiratory pressure (PEEP) were kept constant. Airway pressure, inspiratory and expiratory tidal volumes, mask leak, respiratory rate and inspiratory time were recorded. Repeated measures analysis of variance was used for statistical analysis. RESULTS: A total of 12 749 inflations delivered by 40 participants were analysed. There were no statistically significant differences (P > 0.05) in the mask leak with the three PIP settings. No statistically significant differences were seen in respiratory rate and inspiratory time with the three PIP settings. There was a significant rise in PEEP as the PIP increased. Failure to achieve the desired PIP was observed especially at the higher settings. CONCLUSIONS: In a neonatal manikin model, the mask leak does not vary as a function of the PIP when the flow rate is constant. With a fixed rate and inspiratory time, there seems to be a rise in PEEP with increasing PIP. PMID- 28675549 TI - Visible-Light-Mediated Excited State Relaxation in Semi-Synthetic Genetic Alphabet: d5SICS and dNaM. AB - The excited state dynamics of an unnatural base pair (UBP) d5SICS/dNaM were investigated by accurate ab-initio calculations. Time-dependent density functional and high-level multireference calculations (MS-CASPT2) were performed to elucidate the excitation of this UBP and its excited state relaxation mechanism. After excitation to the bright state S2 (pipi*), it decays to the S1 state and then undergoes efficient intersystem crossing to the triplet manifold. The presence of sulfur atom in d5SICS leads to strong spin-orbit coupling (SOC) and a small energy gap that facilitates intersystem crossing from S1 (ns pi*) to T2 (pipi*) followed by internal conversion to T1 state. Similarly in dNaM, the deactivation pathway follows analogous trends. CASPT2 calculations suggest that the S1 (pipi*) state is a dark state below the accessible S2 (pipi*) bright state. During the ultrafast deactivation, it exhibits bond length inversion. From S1 state, significant SOC leads the population transfer to T3 due to a smaller energy gap. Henceforth, fast internal conversion occurs from T3 to T2 followed by T1 . From time-dependent trajectory surface hopping dynamics, it is found that excited state relaxation occurs on a sub-picosecond timescale in d5SICS and dNaM. Our findings strongly suggest that there is enough energy available in triplet state of UBP to generate reactive oxygen species and induce phototoxicity with respect to cellular DNA. PMID- 28675550 TI - Single-Handed Helical Carbonaceous Nanotubes: Preparation, Optical Activity, and Applications. AB - Carbon-based nanomaterials have been widely studied in the past decade. Three approaches have been developed for the preparation of single-handed helical carbonaceous nanotubes. The first approach uses the carbonization of organopolymeric nanotubes, where the organic polymers are polypyrrole, 3 aminophenol-formaldehyde resin, and m-diaminobenzene-formaldehyde resin. The second approach uses the carbonization of aromatic ring-bridged polybissilsesquioxane followed by the removal of silica. Micropores exist within the walls of the carbonaceous nanotubes. The third approach uses the carbonization of organic compounds within silica nanotubes. This hard-templating approach drives the formation of helical carbonaceous nanotubes containing twisted carbonaceous nanoribbons. All of these helical carbonaceous nanotubes exhibit optical activity, which is believed to originate from the chiral pi-pi stacking of aromatic rings. They can be used as chirality inducers, and for lithium-ion storage. PMID- 28675551 TI - Incidence, Treatment Patterns, and Health Care Costs of Infantile Hemangioma: Results of a Retrospective German Database Analysis. AB - OBJECTIVES: To determine the incidence, effect (defined according to treatment rate), and health care costs of infantile hemangiomas (IHs) in Germany from 2007 to 2012 by analyzing patient data of German statutory health insurances. METHODS: A retrospective analysis using data from a database matched with the overall population covered by German statutory health insurance was performed. To describe the treatment rate and costs of IHs, a search algorithm was developed dividing the study population into three groups (patients with IHs, patients with IHs possibly requiring treatment, and patients with IHs receiving treatment). RESULTS: The incidence of IHs was 2.0% to 3.2%, with a slight increase during the later years of the study period and a female:male ratio of 1.4:1. IH incidence was lower and girls were less likely to present with IHs than in previous reports. The mean treatment rate of IHs was 11.3%. Mean health care costs during first year of life for infants diagnosed with IHs in 2012 were slightly lower (?2,396) than for all infants (?2,649), whereas costs for infants diagnosed and treated for IHs were considerably higher (?10,550). The majority of these costs were due to hospitalization (?8,658). CONCLUSION: This retrospective study is the first to analyze the incidence and sex ratio of IHs based on German claims data. The treatment rate of IHs was consistent with previous reports. The mean health care costs for treated patients with IHs were substantially higher than those for all newborns. Limitations of this study are coding bias, a limited sample size, and claims perspective (nonclinical approach). PMID- 28675552 TI - Towards a Comprehensive Understanding of the Reaction Mechanisms Between Defective MoS2 and Thiol Molecules. AB - Sulfur vacancies (SVs) inherent in MoS2 are generally detrimental for carrier mobility and optical properties. Thiol chemistry has been explored for SV repair and surface functionalization. However, the resultant products and reaction mechanisms are still controversial. Herein, a comprehensive understanding on the reactions is provided by tracking potential energy surfaces and kinetic studies. The reactions are dominated by two competitive mechanisms that lead to either functionalization products or repair SVs, and the polarization effect from decorating thiol molecules and thermal effect are two determining factors. Electron-donating groups are conducive to the repairing reaction whereas electron withdrawing groups facilitate the functionalization process. Moreover, the predominant reaction mechanism can be switched by increasing the temperature. This study fosters a way of precisely tailoring the electronic and optical properties of MoS2 by means of thiol chemistry approaches. PMID- 28675553 TI - A combined intervention to reduce interruptions during medication preparation and double-checking: a pilot-study evaluating the impact of staff training and safety vests. AB - AIM: The aim was to evaluate the impact of staff training and wearing safety vests as a combined intervention on interruptions during medication preparation and double-checking. BACKGROUND: Interruptions and errors during the medication process are common and an important issue for patient safety in the hospital setting. METHODS: We performed a pre- and post-intervention pilot-study using direct structured observation of 26 nurses preparing and double-checking 431 medication doses (225 pre-intervention and 206 post-intervention) for 36 patients (21 pre-intervention and 15 post-intervention). RESULTS: With staff training and the introduction of safety vests, the interruption rate during medication preparation was reduced from 36.8 to 28.3 interruptions per hour and during double-checking from 27.5 to 15 interruptions per hour. CONCLUSION: This pilot study showed that the frequency of interruptions decreased during the critical tasks of medication preparation and double-checking after the introduction of staff training and wearing safety vests as part of a quality improvement process. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing management should acknowledge interruptions as an important factor potentially influencing medication safety. Unnecessary interruptions can be successfully reduced by considering human and system factors and increasing both staff and nursing managers' awareness of 'interruptive communication practices' and implementing physical barriers. This is the first pilot-study specifically evaluating the impact of staff training and wearing safety vests on the reduction of interruptions during medication preparation and double-checking. PMID- 28675554 TI - Osteocutaneous radial forearm free flap in nonmandible head and neck reconstruction. AB - BACKGROUND: The osteocutaneous radial forearm free flap (RFFF) is a versatile flap primarily used to reconstruct composite defects involving the mandible. The purpose of this study was to describe our experience with this flap for nonmandible reconstruction. METHODS: All patients undergoing nonmandible osseous reconstruction with free-tissue transfer were reviewed. Patients with osteocutaneous RFFF reconstructions were evaluated. The retrospective review of all osteocutaneous RFFFs was performed from 1998 to 2014. RESULTS: One hundred forty-two nonmandible osseous reconstructions were performed. Twenty-five patients underwent nonmandible osteocutaneous RFFF reconstruction. Eleven patients failed previous nonmicrovascular reconstruction. Reconstruction was for defects of the: palatomaxillary complex (n = 15), orbitomaxillary complex (n = 4), nasomaxillary complex (n = 4), larynx (n = 1), and clavicle (n = 1). There were no flap compromises. Postoperative complications included: 2 partial intraoral dehiscences; 1 recipient-site infection; and 1 seroma. Eight reconstructions required secondary procedures to improve functional and/or cosmetic outcomes. CONCLUSION: The osteocutaneous RFFF is a robust flap that can be used to reconstruct composite defects involving bone and soft-tissue beyond the mandible. PMID- 28675555 TI - RNA sequencing in post-mortem human brains of neuropsychiatric disorders. AB - RNA sequencing (RNA-Seq), a revolutionary tool for transcriptome profiling, is becoming increasingly important for neuroscientists in studying the transcriptional landscape of the human brain. Studies using this next-generation sequencing technique have already revealed novel insights into the complexity of neurons in the human brain and pathogenesis of complex neurological diseases. In clinical neuroscience, RNA-Seq provides exciting opportunities for improving diagnosis and treatment of neurological diseases by facilitating the development of pharmacotherapies able to modulate gene expression. Furthermore, integrative whole genome sequencing and transcriptome sequencing can provide additional information for the functional role of mutated genes, prioritization of variants, and intron/exon splicing. This review describes the current state of RNA-Seq studies in neuropsychiatric disorders using post-mortem human brains, a brief survey of best practices for experimental design and sequencing data analysis, and the challenges associated with its application in the human brain. PMID- 28675556 TI - Prospective clinical trials to investigate clinical and molecular biomarkers. AB - Among clinical studies, randomized studies as well as well-designed observational studies are providing the highest quality data. In addition, these studies represent a good opportunity to examine biomarkers of ictogenesis and epileptogenesis. To date, no validated molecular or cellular biomarker exists for any aspect of epilepsy. We provide an overview of the inflammatory biomarkers under investigation in prospective clinical studies in epilepsy: proinflammatory cytokines in prolonged febrile seizure; High Mobility Group Box 1 (HMGB1) as a prognosis biomarker in epilepsy and the interaction between inflammation and metabolism, in particular, iron metabolism, in epilepsy. The designs of the European Union EPISTOP project following prospectively patients with tuberous sclerosis from birth to the start of the epilepsy and of the Standard and New Antiepileptic Drugs-II study illustrate how such studies can be used to find new inflammatory biomarkers of ictogenesis and epileptogenesis. If we want to bridge the current gap between having numerous biomarker candidates from preclinical studies and their selective use in clinical practice, we need to explore multiple biologic systems, not just including inflammation. In addition, it is crucial that those involved in the design and support of relevant clinical studies recognize this gap and act accordingly, and in the interests of improving the diagnosis and prognosis for epilepsy. PMID- 28675557 TI - Neurobehavioral comorbidities of epilepsy: Role of inflammation. AB - Epilepsy is associated with a high incidence of comorbid neurologic and psychiatric disorders. This review focuses on the association of epilepsy with autism spectrum disorder (ASD) and depression. There is high concordance of these behavioral pathologies with epilepsy. We review data that unambiguously reveal that epilepsy, ASD, and depression are associated with elevated brain inflammatory markers and that these may interact with serotoninergic pathways. Interference with inflammatory pathways or actions can reduce the severity of seizures, depression, and ASD-like behavior. Inflammation in the brain can be induced by seizure activity as well as by behavioral, environmental, and physiologic stressors. Furthermore, induction of inflammation at an early time point during gestation and in early neonatal life can precipitate both an ASD like phenotype as well as a more excitable brain. It appears likely that priming of the brain due to early inflammation could provide a means by which subsequent inflammatory processes associated with epilepsy, ASD, and depression may lead to comorbidity. PMID- 28675559 TI - Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy. AB - Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology-specific therapies for the epilepsies and attendant comorbidities, including the drug-resistant forms. PMID- 28675560 TI - Neuroinflammation imaging markers for epileptogenesis. AB - Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development. PMID- 28675561 TI - Introduction to the 2nd Meeting on Immunity and Inflammation in Epilepsy (IIE2016). AB - We report about the main topics presented during this meeting which was devoted to discuss the new emerging evidence for a role of immune- and inflammation related mechanisms in various autoimmune and nonautoimmune forms of epilepsy. Major emphasis was given to novel immune/inflammatory mechanisms contributing to seizures and neurological comorbidities as well as to the discovery and validation of noninvasive biomarkers of brain inflammation which may be used to monitor epileptogenesis and predict the therapeutic effects of treatments. The key question was whether our scientific community is ready for the translation of the results of laboratory research to clinical studies, and how to best design clinical trials of anti-inflammatory drugs with potential disease-modifying effects. PMID- 28675558 TI - Clinical studies and anti-inflammatory mechanisms of treatments. AB - In this exciting era, we are coming closer and closer to bringing an anti inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both "conventional, broad spectrum" anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain. PMID- 28675564 TI - Activation of serotonergic neurons in the medullary caudal raphe shortens the laryngeal chemoreflex in anaesthetized neonatal rats. AB - NEW FINDINGS: What is the central question of this study? Does activation of serotonergic neurons in the caudal medullary raphe, some of which project to the nucleus of the solitary tract, shorten the laryngeal chemoreflex? What is the main finding and its importance? We found that serotonin originating from neurons in the caudal raphe acts through a 5-HT3 receptor located in the nucleus of the solitary tract to terminate reflex apnoea. Failure or deficiency of this arousal related process is likely to be relevant to the pathogenesis of sudden infant death syndrome. Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who have died of SIDS. We tested the hypothesis that activation of serotoninergic neurons in the caudal medullary raphe, some of which project to the nucleus of the solitary tract (NTS), would shorten the laryngeal chemoreflex (LCR). We studied anaesthetized neonatal rat pups between postnatal days 9 and 17. We injected 5-40 MUl of water into the larynx to elicit the LCR and measured the duration of respiratory disruption. Microinjection of 50 nl of 100 MUm AMPA into the caudal medullary raphe shortened the apnoeas (P < 0.001) and respiratory inhibition (P < 0.005) associated with the LCR. When 50 nl of 30 mm ondansetron, a 5-HT3 antagonist, was microinjected bilaterally into the NTS, AMPA microinjected into the caudal raphe no longer shortened the LCR. After bilateral microinjection of vehicle into the NTS, AMPA microinjection into the caudal raphe significantly shortened the LCR. AMPA, a glutamate receptor agonist, may activate many neurons within the caudal raphe, but blocking the 5-HT3 receptor-dependent responses in the NTS prevented the shortening of the LCR associated with AMPA microinjections into the caudal raphe. Thus, serotonin originating from neurons in the caudal raphe acts through a 5-HT3 receptor located in the NTS to terminate or shorten the LCR. Serotonin is deficient in the brainstems of babies who have died of SIDS, and deficient serotonergic termination of apnoea is likely to be relevant to the pathogenesis of SIDS. PMID- 28675562 TI - Innate and adaptive immunity in human epilepsies. AB - Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medically refractory and, as such, could be used for diagnostic, prognostic, or therapeutic purposes. Establishing an autoimmune basis in patients with drug-resistant epilepsy allows for efficacious and targeted immunotherapy. Although current immunotherapies can give great benefit to the correctly identified patient, there are limitations to their efficacy and they may have considerable side effects. Thus the identification of new immunomodulatory compounds remains of utmost importance. PMID- 28675563 TI - Neuroinflammatory targets and treatments for epilepsy validated in experimental models. AB - A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries. PMID- 28675565 TI - Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. AB - Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in myriad dominant and recessive disease phenotypes. Glycyl-tRNA synthetase (GARS) is a bifunctional ARS that charges tRNAGly in the cytoplasm and mitochondria. GARS variants have been associated with dominant Charcot-Marie-Tooth disease but have not been convincingly implicated in recessive phenotypes. Here, we describe a patient from the NIH Undiagnosed Diseases Program with a multisystem, developmental phenotype. Whole-exome sequence analysis revealed that the patient is compound heterozygous for one frameshift (p.Glu83Ilefs*6) and one missense (p.Arg310Gln) GARS variant. Using in vitro and in vivo functional studies, we show that both GARS variants cause a loss-of-function effect: the frameshift variant results in depleted protein levels and the missense variant reduces GARS tRNA charging activity. In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARS-related recessive diseases, including features associated with variants in both cytoplasmic and mitochondrial ARSs; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants. PMID- 28675566 TI - Effects of two different glutamine-containing enteral supplements on stool frequency and density in elderly patients recovering from acute critical illness. AB - AIM: Glutamine has various beneficial functions in the gastrointestinal tract. The present study was designed to investigate the effect of two different glutamine supplements on bowel movement at the start of enteral feeding in elderly inpatients. METHODS: This was a double-blind, prospective, randomized comparison study. A total of 25 patients aged >75 years recovering from a critical illness in a non-intensive care unit and scheduled for tube feeding were recruited. Of them, 22 consenting patients were randomly assigned to two groups: glutamine-fiber-oligosaccharide treatment group (n = 11) and glutamine F treatment group (n = 11). They were given glutamine three times daily at a dosage of 9 g/day. Enteral nutrition was given at the same dosage to both groups for the duration of the study. The end-points were stool frequency, Bristol Scale Form Score, bowel function index (Bristol Scale Form Score * stool frequency), the percentage of patients with stool frequency over three per day and those with a BSFS of 6 or 7 in each group. RESULTS: There were no significant differences between the two groups in terms of patient characteristics before the study. All the end-points in the glutamine F group were significantly lower than those in the glutamine-fiber-oligosaccharide group. CONCLUSIONS: Compared with glutamine fiber-oligosaccharide, glutamine F administration resulted in stool hardening and reduced stool frequency in elderly inpatients recovering from acute critical illness in non-intensive care units. The effects might be caused by the different additive components of glutamine supplements. Geriatr Gerontol Int 2017; 17: 2514 2519. PMID- 28675568 TI - Sciatic nerve regeneration by transplantation of Schwann cells via erythropoietin controlled-releasing polylactic acid/multiwalled carbon nanotubes/gelatin nanofibrils neural guidance conduit. AB - The current study aimed to enhance the efficacy of peripheral nerve regeneration using an electrically conductive biodegradable porous neural guidance conduit for transplantation of allogeneic Schwann cells (SCs). The conduit was produced from polylactic acid (PLA), multiwalled carbon nanotubes (MWCNTs), and gelatin nanofibrils (GNFs) coated with the recombinant human erythropoietin-loaded chitosan nanoparticles (rhEpo-CNPs). The PLA/MWCNTs/GNFs/rhEpo-CNPs conduit had the porosity of 85.78 +/- 0.70%, the contact angle of 77.65 +/- 1.91 degrees and the ultimate tensile strength and compressive modulus of 5.51 +/- 0.13 MPa and 2.66 +/- 0.34 MPa, respectively. The conduit showed the electrical conductivity of 0.32 S cm-1 and lost about 11% of its weight after 60 days in normal saline. The produced conduit was able to release the rhEpo for at least 2 weeks and exhibited favorable cytocompatibility towards SCs. For functional analysis, the conduit was seeded with 1.5 * 104 SCs and implanted into a 10 mm sciatic nerve defect of Wistar rat. After 14 weeks, the results of sciatic functional index, hot plate latency, compound muscle action potential amplitude, weight-loss percentage of wet gastrocnemius muscle and Histopathological examination using hematoxylin-eosin and Luxol fast blue staining demonstrated that the produced conduit had comparable nerve regeneration to the autograft, as the gold standard to bridge the nerve gaps. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1463-1476, 2018. PMID- 28675567 TI - A modulatory role of the Rax homeobox gene in mature pineal gland function: Investigating the photoneuroendocrine circadian system of a Rax conditional knockout mouse. AB - The retinal and anterior neural fold homeobox gene (Rax) controls development of the eye and the forebrain. Postnatal expression of Rax in the brain is restricted to the pineal gland, a forebrain structure devoted to melatonin synthesis. The role of Rax in pineal function is unknown. In order to investigate the role of Rax in pineal function while circumventing forebrain abnormalities of the global Rax knockout, we generated an eye and pineal-specific Rax conditional knockout mouse. Deletion of Rax in the pineal gland did not affect morphology of the gland, suggesting that Rax is not essential for pineal gland development. In contrast, deletion of Rax in the eye generated an anophthalmic phenotype. In addition to the loss of central visual pathways, the suprachiasmatic nucleus of the hypothalamus housing the circadian clock was absent, indicating that the retinohypothalamic tract is required for the nucleus to develop. Telemetric analyses confirmed the lack of a functional circadian clock. Arylalkylamine N acetyltransferase (Aanat) transcripts, encoding the melatonin rhythm-generating enzyme, were undetectable in the pineal gland of the Rax conditional knockout under normal conditions, whereas the paired box 6 homeobox gene, known to regulate pineal development, was up-regulated. By injecting isoproterenol, which mimics a nocturnal situation in the pineal gland, we were able to induce pineal expression of Aanat in the Rax conditional knockout mouse, but Aanat transcript levels were significantly lower than those of Rax-proficient mice. Our data suggest that Rax controls pineal gene expression and via Aanat may modulate melatonin synthesis. PMID- 28675569 TI - On Atoms-in-Molecules Energies from Kohn-Sham Calculations. AB - Herein, we discuss three methods to partition the total molecular energy into additive atomic contributions within the framework of Bader's atoms-in-molecules theory and in the particular context of Kohn-Sham density functional theory. The first method is derived from the virial theorem, whereas the two other schemes, termed "standard" and "model", are based on Pendas' interacting-quantum-atoms decomposition. The methods are then compared for a dataset of molecules of interest for direct application in organic chemistry and biochemistry. Finally, the relevance of the three methods for the prediction of intrinsic reactivity properties (e.g., electrophilicity) or for unravelling the nature of chemical bonding (e.g., in halogen bonds, beyond the pure electrostatic point of view), is examined and paves the way for their more systematic use for the in silico design of new reactants. PMID- 28675570 TI - Predicting the level of tumor-infiltrating lymphocytes in patients with triple negative breast cancer: Usefulness of breast MRI computer-aided detection and diagnosis. AB - PURPOSE: To evaluate the usefulness of magnetic resonance imaging (MRI) computer aided detection and diagnosis (CAD) for the detection of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC) patients. TNBC is a heterogeneous malignancy with a varying prognosis. Recently, the importance of TILs in TNBC has been determined. MATERIALS AND METHODS: We retrospectively enrolled 60 lesions of TNBC. Either at 1.5T or 3T MRI, including T1 , T2 weighted, and dynamic contrast-enhanced, images were obtained. The CAD results for all lesions were obtained, and we analyzed quantitative kinetic features including the initial peak enhancement and enhancement profiles. We divided the tumors into two groups: those with a TIL level of less than 50%, and those with a TIL level of 50% or more. Kinetic parameters were compared using Student's t tests and chi-square tests. RESULTS: There were 48 low-TIL lesions and 12 high TIL lesions. The portion of persistent enhancement of tumors was negatively associated with the TIL levels (P = 0.003). The persistent minus washout value of the low-TIL group was higher than that of the high-TIL group (P = 0.008). The odds ratios were 0.944 (P = 0.012) for the persistent portion and 0.971 (P = 0.008) for the persistent minus washout value. CONCLUSION: The prediction model using kinetic enhancement parameters, particularly persistent proportion and plateau minus washout value, could be helpful for identifying TIL levels in TNBC and may be used as an imaging biomarker to guide the treatment plan. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:760-766. PMID- 28675571 TI - Five-year survival after surgery in nonagenarian patients. AB - AIM: In countries with longer life expectancies, the nonagenarian population is increasing. Therefore, there is greater demand for healthcare, including surgical procedures. The aim of the present study was to determine the outcomes of surgery carried out on nonagenarians in terms of long-term survival after the procedure. METHODS: We carried out a cross-longitudinal study on a cohort of 159 nonagenarian patients, who underwent a non-cardiac, non-traumatic surgical procedure in our institution between January 1999 and December 2011. The following variables were recorded: sociodemographic characteristics, American Society of Anesthesiologists score, Charlson Comorbidity Index, surgical site, postoperative complications, operative mortality and long-term survival. The output variable was long-term survival. RESULTS: Of the 159 patients,99 women (62%) and 60 men (38%), with a mean age of 91.8 years (SD +/- 2.0 years), 44 cases were operations for malignant disorders (28%), 117 cases (74%) under emergency conditions and 42 cases (26%) were elective treatments. The operative mortality was 29%, 4.8% for elective surgery and 37.6% for emergency surgery (P < 0.001). The postoperative complication rate, including death, was 60%. The probability of survival at 1, 3, and 5 years was 59.6%, 35.8% and 24.1%, respectively. In multivariate analysis, American Society of Anesthesiologists score (HR 2.07, 95% CI 1.58-2.72), emergency surgery (HR 1.64, 95% CI 1.05-2.57) and postoperative medical complications (HR 2.58, 95% CI 1.73-3.85) were independently related to 5-year survival. CONCLUSIONS: These findings support the perioperative safety of elective general surgery in nonagenarian patients. In selected nonagenarian patients with no cognitive impairment, surgery must not be denied. These data might be useful for surgical decision-making or informed consent for nonagerians. Geriatr Gerontol Int 2017; 17: 2389-2395. PMID- 28675572 TI - Association between frailty and carotid intima media thickness and inflammatory marker in an elderly population. AB - AIM: Frailty is a highly prevalent geriatric syndrome, characterized by increased vulnerability to subsequent morbidity and mortality. The association between frailty and preclinical atherosclerosis remains uncertain. The aim of the present study was to clarify the relationship between frailty, preclinical atherosclerosis and inflammatory markers in older adults. METHODS: We enrolled 1798 inhabitants of I-Lan County of Taiwan (855 men, 47.5%; mean age 64 +/- 9 years, range 50-92 years). Assessment of frailty was based on the Cardiovascular Health Study criteria. Common carotid artery intima-media thickness (CIMT) was determined using carotid Doppler ultrasonography. RESULTS: Overall, 955 participants (53.1%) were non-frail, 724 (40.2%) were pre-frail and 119 (6.7%) were frail. Frail and pre-frail participants had significantly increased CIMT, high-sensitivity C-reactive protein, glycated hemoglobin and urine albumin-to creatinine ratio, but had lower insulin-like growth factor-1 level and decreased femoral neck bone mineral density (BMD). By multivariate analysis, age (OR 2.53, 95% CI 1.92-3.33), C-reactive protein (OR 1.19, 95% CI 1.00-1.42), CIMT (OR 1.27, 95% CI 1.04-1.55) and femoral neck BMD (OR 0.49, 95% CI 0.38-0.65) were independently associated with frailty. CONCLUSIONS: The present study showed the epidemiology of frailty, and the strong connection to aging, increased CIMT, enhanced inflammation and decreased femoral neck BMD. These results suggested that preclinical atherosclerosis, inflammation and femoral neck BMD were potentially modifiable risk factors for frailty. Geriatr Gerontol Int 2017; 17: 2449-2454. PMID- 28675573 TI - Dinaphthotetrathiafulvalene Bisimides: A New Member of the Family of pi-Extended TTF Stable p-Type Semiconductors. AB - Air-stable organic semiconductors based on tetrathiafuluvalene (TTF) were developed by synthesising a series of dinaphthotetrathiafulvalene bisimides (DNTTF-Im) using electron-donating TTF, pi-extended naphthalene, and electron withdrawing imide. Electron-spin-resonance spectroscopy and X-ray single-crystal structure analysis of aryl-substituted DNTTF-Im radical cations confirmed that localisation of the spin resides on the electron-donating TTF moiety. The organic field-effect transistor properties derived from the use of highly crystalline n butyl (C4) and n-hexyl(C6)-substituted DNTTF-Im were assessed. The hole carrier mobility of C6-DNTTF-Im was improved from 3.7*10-3 cm2 V-1 s-1 to 0.30 cm2 V 1 s-1 in ambient conditions. This is attributed to the raise of the substrate temperature from 25 degrees C to 200 degrees C during sublimation. The XRD and microscopy analysis suggested that increasing the substrate temperature accelerates the end-on packing resulting in larger grains suitable for hole charge transport parallel to the substrate. PMID- 28675574 TI - Prevalence of hypertension and prehypertension in children and adolescents with intellectual disability in southeastern Poland. AB - BACKGROUND: There is insufficient information on the prevalence of hypertension (HPT) among children and adolescents with ID. AIM: The aim of this study was to determine the prevalence of HPT in children and adolescents with ID in comparison with the control group, which accounted for children and adolescents without ID. METHODS: The study included 568 students with ID, aged from 7 to 18, attending special education institutions in southeastern Poland. The control group consisted of 568 students (matched to the study group for age and gender) without ID, attending randomly selected elementary and secondary schools located in the same area. Blood pressure was measured in compliance with the European Society of Hypertension recommendations. RESULTS: The overall prevalence of HPT and pre-HPT in children and adolescents with ID were 18.5 and 20.6% respectively. Prevalence of HPT and pre-HPT in children and adolescents without ID were 5.8 and 18.5% respectively. Children and adolescents with a higher level of ID were found to be at a greater risk of HPT. An excessive body mass and older age were predisposing factors to a significantly higher prevalence of HPT in children and adolescents with ID. CONCLUSION: The prevalence of HPT among students with ID was more than three times higher than in the general population. The level of ID, age, sex and body mass significantly correlated with HPT in the study group. PMID- 28675575 TI - Clinical implications of transient myeloproliferative disorder in a neonate without Down syndrome features. PMID- 28675576 TI - Polymer Nanoassembly as Delivery Systems and Anti-Bacterial Toolbox: From PGMAs to MSN@PGMAs. AB - Researches on cargo delivery systems have received burgeoning attention and advanced rapidly. For synthetic nanodevices, polymer nanoassemblies and their inorganic-organic hybrid materials, especially smart mesoporous silica nanoparticle (MSN)-polymer hybrids (e. g., MSN@PGMAs), have attracted increasing attention in recent years. Their superior characteristics and unique features such as dynamic transition of morphology endow them the ability to efficiently entrap cargo molecules and undergo smart cargo delivery and release in response to various external stimuli. In this Personal Account, we present our recent research progress in the construction of cargo delivery systems based on polymers, poly(glycidyl methacrylate) (PGMA) and its derivatives in particular, ranging from polymer nanoparticles, reverse micelles, to vesicles and reverse vesicles, and their performance in the delivery and controlled release of model molecules and therapeutic agents. Significantly, MSN-PGMA hybrid nanoassemblies (MSN@PGMAs), constructed with the aid of atom transfer radical polymerization, host-guest interactions, or layer-by-layer self-assembly techniques, and their potential bio-related applications and anti-bacterial applications as new nanocarriers are reviewed. Finally, the prospects and challenges of such nanoplatforms are also discussed. PMID- 28675577 TI - In support of the Choosing Wisely campaign: Perceived higher risk leads to unnecessary imaging in accelerated partial breast irradiation? AB - Accelerated partial breast irradiation (APBI) is an increasingly utilized modality for early stage breast cancer as part of breast conservation therapy (BCT). There remains concern regarding local recurrence, requiring more frequent post-radiation surveillance imaging. The purpose of this study is to determine clinical significance of frequent surveillance in this perceived higher risk population. Patients treated at a community academic medical center from 2005 to 2013 with partial breast radiation were retrospectively identified. All patients were treated with lumpectomy followed by balloon based APBI. Diagnostic, clinical, radiographic, and outcomes data were collected. One hundred and sixty nine patients were identified. Median age at time of diagnosis was 63. Stage was 0, I, and II in 27%, 64%, and 9%, respectively. Most patients had pure invasive ductal cancer. Ninety-two percent and 99% of patients had imaging performed by 6 and 12 months (+/- 3 months) respectively. Median interval between end of radiation and first image, and subsequent 3 images were 6, 6, 9, and 12 months, respectively. Median follow-up was 49 months for all patients (range 7-106). Six patients experienced local recurrence: 4 invasive, all clinically detected, and none within the first 2 years. One patient had mammographically detected recurrent ductal carcinoma in situ. No mammographic images within the first year lead to diagnosis of recurrent cancer. APBI via balloon base brachytherapy offered women excellent locoregional control rates. Frequent mammographic surveillance did not result in increased detection of early recurrent disease. The result of our study are in line with the Choosing Wisely campaign recommendations to perform no more than annual follow-up for women who have completed radiation as part of BCT, with first imaging done at 6-12 months. We recommend mammographic surveillance be performed no more frequently than annually, with first image after BCT to be done 12 months from completion of radiation. PMID- 28675578 TI - A time series analysis of the effects of financial incentives and mandatory clinical applications as interventions to improve spontaneous adverse drug reaction reporting by hospital medical staff in China. AB - RATIONALE, AIMS, AND OBJECTIVES: Spontaneous reporting of adverse drug reactions (ADRs) in hospitals is often under-reported, which may lead to problems in patient management. This study was aimed to assess the effectiveness of a financial intervention based on a fine and a bonus for improving spontaneous reporting of ADRs by physicians in a hospital setting. METHODS: This study was conducted at the First Affiliated Hospital of Zhengzhou University (China). Starting in 2009, a bonus of 20 RMB (Chinese currency) was given for each spontaneous ADR report, and a fine of 50 RMB was given for any withheld ADR report. A time series analysis using autoregressive integrated moving average models was performed to assess the changes in the total number of spontaneous ADR reports between the preintervention period (2006-2008) and during the first (2009 2011) and second (2012-2014) intervention periods. RESULTS: The median number of reported ADRs per year increased from 29 (range 27-72) in the preintervention period to 277 (range 199-284) in the first intervention period and to 666 in the second (range 644-691). The monthly number of reported ADRs was stable during the 3 periods: 3.56 +/- 3.60/month (95% confidence interval (CI), 2.42-4.75) during the preintervention period, 21 +/- 13/month (95% CI, 16.97-25.80) in the first intervention period, and 56 +/- 20/month (95% CI, 48.81-62.17) in the second intervention period. CONCLUSION: A financial incentive and ADR management regulations had a significant effect on the increase of reported ADRs. PMID- 28675579 TI - Interlead heterogeneity of R- and T-wave morphology in standard 12-lead ECGs predicts sustained ventricular tachycardia/fibrillation and arrhythmic death in patients with cardiomyopathy. AB - INTRODUCTION: Nonuniformities in depolarization and repolarization morphology are critical factors in ventricular arrhythmogenesis. METHODS AND RESULTS: We assessed interlead R-wave heterogeneity (RWH) and T-wave heterogeneity (TWH) in standard 12-lead electrocardiograms (ECGs) using second central moment analysis. This technique quantifies variance about the mean morphology of beats in adjoining precordial leads, V4 , V5 , and V6 in this study. The study was conducted in 120 consecutive patients without an apparent reversible trigger for ventricular tachycardia (VT), recent myocardial infarction, or active ischemia, who presented for electrophysiologic study, implantable cardioverter defibrillator (ICD) placement, or generator change at our institution from 2008 to 2011. Primary outcome was sustained VT/ventricular fibrillation (VF) or appropriate ICD therapies. Secondary outcome was arrhythmic death or resuscitated cardiac arrest. Cutpoints for elevated RWH (>160 MUV) and TWH (>80 MUV) identified 67% of primary outcome cases and 85% of secondary outcome cases. Cardiomyopathy patients who met the primary outcome (n = 42) had significantly higher TWH than those who did not (n = 28) (TWH: 95 +/- 11 MUV vs. 44 +/- 9 MUV, P < 0.002). Likewise, cardiomyopathy patients who met secondary outcome (N = 13) had VT/VF during follow-up and also had significantly higher TWH than survivors (N = 57) (TWH: 105 +/- 24 MUV vs. 67 +/- 8 MUV, P < 0.002). Kaplan-Meier analysis revealed significant differences in arrhythmia-free survival (P = 0.012) and total survival (P = 0.011) among cardiomyopathy patients with (n = 37) compared to without (n = 33) elevated RWH and/or TWH independent of age, sex, and left ventricular ejection fraction (LVEF). CONCLUSION: Interlead RWH and TWH in 12 lead ECGs predict sustained ventricular arrhythmia, appropriate ICD therapies, and arrhythmic death or cardiac arrest in cardiomyopathy patients independent of LVEF and other standard variables. PMID- 28675580 TI - Impact of disease on the survival of three commercially fished species. AB - Recent increases in emergent infectious diseases have raised concerns about the sustainability of some marine species. The complexity and expense of studying diseases in marine systems often dictate that conservation and management decisions are made without quantitative data on population-level impacts of disease. Mark-recapture is a powerful, underutilized, tool for calculating impacts of disease on population size and structure, even in the absence of etiological information. We applied logistic regression models to mark-recapture data to obtain estimates of disease-associated mortality rates in three commercially important marine species: snow crab (Chionoecetes opilio) in Newfoundland, Canada, that experience sporadic epizootics of bitter crab disease; striped bass (Morone saxatilis) in the Chesapeake Bay, USA, that experience chronic dermal and visceral mycobacteriosis; and American lobster (Homarus americanus) in the Southern New England stock, that experience chronic epizootic shell disease. All three diseases decreased survival of diseased hosts. Survival of diseased adult male crabs was 1% (0.003-0.022, 95% CI) that of uninfected crabs indicating nearly complete mortality of infected crabs in this life stage. Survival of moderately and severely diseased striped bass (which comprised 15% and 11% of the population, respectively) was 84% (70-100%, 95% CI), and 54% (42 68%, 95% CI) that of healthy striped bass. The disease-adjusted yearly natural mortality rate for striped bass was 0.29, nearly double the previously accepted value, which did not include disease. Survival of moderately and severely diseased lobsters was 30% (15-60%, 95% CI) that of healthy lobsters and survival of mildly diseased lobsters was 45% (27-75%, 95% CI) that of healthy lobsters. High disease mortality in ovigerous females may explain the poor recruitment and rapid declines observed in this population. Stock assessments should account for disease-related mortality when resource management options are evaluated. PMID- 28675581 TI - Understanding the demographic drivers of realized population growth rates. AB - Identifying the demographic parameters (e.g., reproduction, survival, dispersal) that most influence population dynamics can increase conservation effectiveness and enhance ecological understanding. Life table response experiments (LTRE) aim to decompose the effects of change in parameters on past demographic outcomes (e.g., population growth rates). But the vast majority of LTREs and other retrospective population analyses have focused on decomposing asymptotic population growth rates, which do not account for the dynamic interplay between population structure and vital rates that shape realized population growth rates (lambdat=Nt+1/Nt) in time-varying environments. We provide an empirical means to overcome these shortcomings by merging recently developed "transient life-table response experiments" with integrated population models (IPMs). IPMs allow for the estimation of latent population structure and other demographic parameters that are required for transient LTRE analysis, and Bayesian versions additionally allow for complete error propagation from the estimation of demographic parameters to derivations of realized population growth rates and perturbation analyses of growth rates. By integrating available monitoring data for Lesser Scaup over 60 yr, and conducting transient LTREs on IPM estimates, we found that the contribution of juvenile female survival to long-term variation in realized population growth rates was 1.6 and 3.7 times larger than that of adult female survival and fecundity, respectively. But a persistent long-term decline in fecundity explained 92% of the decline in abundance between 1983 and 2006. In contrast, an improvement in adult female survival drove the modest recovery in Lesser Scaup abundance since 2006, indicating that the most important demographic drivers of Lesser Scaup population dynamics are temporally dynamic. In addition to resolving uncertainty about Lesser Scaup population dynamics, the merger of IPMs with transient LTREs will strengthen our understanding of demography for many species as we aim to conserve biodiversity during an era of non-stationary global change. PMID- 28675582 TI - Optimization of dual-energy CT acquisitions for proton therapy using projection based decomposition. AB - PURPOSE: Dual-energy computed tomography (DECT) has been presented as a valid alternative to single-energy CT to reduce the uncertainty of the conversion of patient CT numbers to proton stopping power ratio (SPR) of tissues relative to water. The aim of this work was to optimize DECT acquisition protocols from simulations of X-ray images for the treatment planning of proton therapy using a projection-based dual-energy decomposition algorithm. METHODS: We have investigated the effect of various voltages and tin filtration combinations on the SPR map accuracy and precision, and the influence of the dose allocation between the low-energy (LE) and the high-energy (HE) acquisitions. For all spectra combinations, virtual CT projections of the Gammex phantom were simulated with a realistic energy-integrating detector response model. Two situations were simulated: an ideal case without noise (infinite dose) and a realistic situation with Poisson noise corresponding to a 20 mGy total central dose. To determine the optimal dose balance, the proportion of LE-dose with respect to the total dose was varied from 10% to 90% while keeping the central dose constant, for four dual energy spectra. SPR images were derived using a two-step projection-based decomposition approach. The ranges of 70 MeV, 90 MeV, and 100 MeV proton beams onto the adult female (AF) reference computational phantom of the ICRP were analytically determined from the reconstructed SPR maps. RESULTS: The energy separation between the incident spectra had a strong impact on the SPR precision. Maximizing the incident energy gap reduced image noise. However, the energy gap was not a good metric to evaluate the accuracy of the SPR. In terms of SPR accuracy, a large variability of the optimal spectra was observed when studying each phantom material separately. The SPR accuracy was almost flat in the 30-70% LE-dose range, while the precision showed a minimum slightly shifted in favor of lower LE-dose. Photon noise in the SPR images (20 mGy dose) had lower impact on the proton range accuracy as comparable results were obtained for the noiseless situation (infinite dose). Root-mean-square range errors averaged over all irradiation angles associated to dual-energy imaging were comprised between 0.50 mm and 0.72 mm for the noiseless situation and between 0.51 mm and 0.77 mm for the realistic scenario. CONCLUSIONS: The impact of the dual-energy spectra and the dose allocation between energy levels on the SPR accuracy and precision determined through a projection-based dual-energy algorithm were evaluated to guide the choice of spectra for dual-energy CT for proton therapy. The dose balance between energy levels was not found to be sensitive for the SPR estimation. The optimal pair of dual-energy spectra was material dependent but on a heterogeneous anthropomorphic phantom, there was no significant difference in range accuracy and the choice of spectra could be driven by the precision, i.e., the energy gap. PMID- 28675583 TI - Experiencing health-related quality of life in paediatric short stature - a cross cultural analysis of statements from patients and parents. AB - OBJECTIVES: Direct assessment of the patient perspective is necessary to thoroughly understand patients' experiences of disease. We aimed to examine information from children with short stature on their perceived HrQoL within 5 European countries. METHODS: Patients, identified through clinical databases, were approached by their clinicians according to the inclusion criteria regarding a diagnosis of growth hormone deficiency or idiopathic short stature and age requirements. A focus group methodology was applied in 84 children and 112 parents. Based on a category system, individual statements were allocated to domains. To evaluate the emerging topics, qualitative content analysis was conducted. Domains and respective coding frequencies per category were compared across countries and respondents. RESULTS: The highest number of statements produced by the children and parents were related to social (29%) and emotional needs and concerns (28%). In particular, children stressed their experience of social exclusion but also their perception of social support. Regarding emotional needs, they stated mainly the desire to be taller in order to be less teased by peers. National differences were identified, for example, Swedish (22%) and British (16%) children and their parents (Sweden 26%; Britain 23%) stressed physical HrQoL aspects, whereas German children (21%) strongly focused on treatment aspects, mainly the benefit of treatment. CONCLUSION: Comprehensive knowledge of the impact of a chronic condition such as short stature on wellbeing is an important precondition of effective treatment. Because socioemotional topics were rated in all the countries to be most important, interventions aimed at improving HrQoL should target social and emotional responses to short stature. PMID- 28675584 TI - Does Secretory Clearance Follow Glomerular Filtration Rate in Chronic Kidney Diseases? Reconsidering the Intact Nephron Hypothesis. AB - Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive (n = 3; group A) or negative (n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs. PMID- 28675585 TI - A new method using Scanning Electron Microscopy (SEM) for preparation of anisopterous odonates. AB - Anisopterous odonate male's secondary genitalia is a complex of several structures, among them the vesica spermalis is the most informative with important specific characters. The observation of those characters, mostly of membranous nature, is difficult in the Scanning Electron Microscope due to dehydration and metallization processes. In this contribution, we discuss a new and low cost procedure for the observation of these characters in the SEM, compatible with the most common agents used for preserving specimens. PMID- 28675586 TI - Experimentally increased nutrient availability at the permafrost thaw front selectively enhances biomass production of deep-rooting subarctic peatland species. AB - Climate warming increases nitrogen (N) mineralization in superficial soil layers (the dominant rooting zone) of subarctic peatlands. Thawing and subsequent mineralization of permafrost increases plant-available N around the thaw-front. Because plant production in these peatlands is N-limited, such changes may substantially affect net primary production and species composition. We aimed to identify the potential impact of increased N-availability due to permafrost thawing on subarctic peatland plant production and species performance, relative to the impact of increased N-availability in superficial organic layers. Therefore, we investigated whether plant roots are present at the thaw-front (45 cm depth) and whether N-uptake (15 N-tracer) at the thaw-front occurs during maximum thaw-depth, coinciding with the end of the growing season. Moreover, we performed a unique 3-year belowground fertilization experiment with fully factorial combinations of deep- (thaw-front) and shallow-fertilization (10 cm depth) and controls. We found that certain species are present with roots at the thaw-front (Rubus chamaemorus) and have the capacity (R. chamaemorus, Eriophorum vaginatum) for N-uptake from the thaw-front between autumn and spring when aboveground tissue is largely senescent. In response to 3-year shallow belowground fertilization (S) both shallow- (Empetrum hermaphroditum) and deep rooting species increased aboveground biomass and N-content, but only deep rooting species responded positively to enhanced nutrient supply at the thaw front (D). Moreover, the effects of shallow-fertilization and thaw-front fertilization on aboveground biomass production of the deep-rooting species were similar in magnitude (S: 71%; D: 111% increase compared to control) and additive (S + D: 181% increase). Our results show that plant-available N released from thawing permafrost can form a thus far overlooked additional N-source for deep rooting subarctic plant species and increase their biomass production beyond the already established impact of warming-driven enhanced shallow N-mineralization. This may result in shifts in plant community composition and may partially counteract the increased carbon losses from thawing permafrost. PMID- 28675587 TI - Invasive pneumococcal disease in children with sickle cell disease in the pneumococcal conjugate vaccine era. AB - Invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) can be devastating. We sought to assess the impact of IPD in children with SCD since licensure of the pneumococcal conjugate vaccines (PCVs). We found 11 cases of IPD giving an incidence of 417 per 100,000 person-years, much higher than that reported in children without SCD. Although all isolates were sensitive to penicillin, 89% of isolates were nonvaccine serotypes. Further study is needed to characterize the incidence of and risk factors for the development of IPD in SCD in the PCV era to help drive better prevention strategies. PMID- 28675588 TI - A casualty of climate change? Loss of freshwater forest islands on Florida's Gulf Coast. AB - Sea level rise elicits short- and long-term changes in coastal plant communities by altering the physical conditions that affect ecosystem processes and species distributions. While the effects of sea level rise on salt marshes and mangroves are well studied, we focus on its effects on coastal islands of freshwater forest in Florida's Big Bend region, extending a dataset initiated in 1992. In 2014 2015, we evaluated tree survival, regeneration, and understory composition in 13 previously established plots located along a tidal creek; 10 plots are on forest islands surrounded by salt marsh, and three are in continuous forest. Earlier studies found that salt stress from increased tidal flooding prevented tree regeneration in frequently flooded forest islands. Between 1992 and 2014, tidal flooding of forest islands increased by 22%-117%, corresponding with declines in tree species richness, regeneration, and survival of the dominant tree species, Sabal palmetto (cabbage palm) and Juniperus virginiana (southern red cedar). Rates of S. palmetto and J. virginiana mortality increased nonlinearly over time on the six most frequently flooded islands, while salt marsh herbs and shrubs replaced forest understory vegetation along a tidal flooding gradient. Frequencies of tidal flooding, rates of tree mortality, and understory composition in continuous forest stands remained relatively stable, but tree regeneration substantially declined. Long-term trends identified in this study demonstrate the effect of sea level rise on spatial and temporal community reassembly trajectories that are dynamically re-shaping the unique coastal landscape of the Big Bend. PMID- 28675589 TI - Determination of methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid by derivatization followed by high-performance liquid chromatography with ultraviolet detection. AB - Methanesulfonic acid is routinely used in pharmaceuticals but can contain potentially genotoxic impurities such as methyl methanesulfonate and ethyl methanesulfonate. The aim of this study was to develop a simple high-performance liquid chromatography with ultraviolet detection method for determining methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid. Samples (250 mg) in water/acetonitrile (200 MUL) were first combined with 10.0 mol/L sodium hydroxide solution (270 MUL). Then they were mixed with 2.0 mg/mL N,N diethyldithiocarbamate (500 MUL), diluted to 5 mL with N,N-dimethylacetamide and allowed to react at 80 degrees C for 1 h. The derivatives were analyzed using gradient high-performance liquid chromatography with ultraviolet detection (277 nm) and structurally elucidated by liquid chromatography with mass spectrometry. With acetonitrile/5 mmol/L ammonium acetate solution as the eluent and 1 mL/min as the flow rate on a C18 column, the derivatives were eluted at 10.6 and 14.8 min. Good linearity (correlation coefficients > 0.999) and low limits of quantitation (0.6 ppm) were obtained. The recoveries were in the range of 80-115% with relative standard deviation < 5.0%. Finally, the established method was successfully used for the determination of methyl methanesulfonate and ethyl methanesulfonate in methanesulfonic acid. PMID- 28675590 TI - Highly Oriented Growth of Catalytically Active Zeolite ZSM-5 Films with a Broad Range of Si/Al Ratios. AB - Highly b-oriented zeolite ZSM-5 films are critical for applications in catalysis and separations and may serve as models to study diffusion and catalytic properties in single zeolite channels. However, the introduction of catalytically active Al3+ usually disrupts the orientation of zeolite films. Herein, using structure-directing agents with hydroxy groups, we demonstrate a new method to prepare highly b-oriented zeolite ZSM-5 films with a broad range of Si/Al ratios (Si/Al=45 to infinity). Fluorescence micro-(spectro)scopy was used to monitor misoriented microstructures, which are invisible to X-ray diffraction, and show Al3+ framework incorporation and illustrate the differences between misoriented and b-oriented films. The methanol-to-hydrocarbons process was studied by operando UV/Vis diffuse reflectance micro-spectroscopy with on-line mass spectrometry, showing that the b-oriented zeolite ZSM-5 films are active and stable under realistic process conditions. PMID- 28675591 TI - Ultrasound-assisted, hybrid ionic liquid, dispersive liquid-liquid microextraction for the determination of insecticides in fruit juices based on partition coefficients. AB - An ultrasound-assisted, hybrid ionic liquid, dispersive liquid-liquid microextraction method coupled to high-performance liquid chromatography with a variable-wavelength detector was developed to detect ten insecticides, including diflubenzuron, triflumuron, hexaflumuron, flufenoxuron, lufenuron, diafenthiuron, transfluthrin, fenpropathrin, gamma-cyhalothrin and deltamethrin, in fruit juices. In this method, an appropriate extraction solvent was chosen based on the partition coefficient of the target compounds. A mixture of 1-octyl-2,3 dimethylimidazolium bis(trifluoromethylsulfonyl)imide and 1-hexyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide was used as the extractant. The extraction efficiency was screened using Plackett-Burman design and optimized using central composite design. Under the optimal conditions, good linearity was obtained for all the analytes in the pure water model and the fruit juice samples. In pure water, the recoveries of the ten insecticides ranged from 85.7 to 108.9%, with relative standard deviations for one day ranging from 1.24 to 2.64%. The limits of detection were in the range of 0.19-0.69 MUg/L, and the enrichment factors were in the range of 123-160. The logarithm of the n octanol/water partition coefficient in this experiment is a useful reference to select a suitable extraction solvent, and the proposed technique was applied for the analysis of ten insecticides in fruit juice with satisfactory results. PMID- 28675593 TI - Analysis of admixture proportions in seven geographical regions of the state of Guerrero, Mexico. AB - OBJECTIVE: Mexico's current population structure has been defined by admixture between European, Native American, and to some extent African, groups that started in the sixteenth century. The aim of this research was to analyze the relative contributions of these continental population groups to the seven regions of the state of Guerrero, Mexico. METHODS: A total of 104 ancestry informative markers were analyzed in 480 unrelated women from the seven regions of the state of Guerrero. The individual ancestry proportions were estimated using the software ADMIXMAP v3.2. RESULTS: The relative Native American, European and African ancestral contributions to the whole sample were estimated to be 69%, 27%, and 1.9%, respectively. We observed significant differences in admixture proportions across the regions. The highest average Native American ancestry was found in the Montana region and the lowest in Costa Grande. Conversely, the highest European contribution was observed in Costa Grande. The highest African contributions were observed in the regions of Costa Chica and Costa Grande. CONCLUSIONS: The genetic structure of the population of Guerrero reflects quite well the historical processes that have occurred in this state. Native American population settlements were mainly in the regions of Montana, Norte, and Centro, where the highest indigenous genetic contribution is observed today. European settlers came from the center of the state to regions with significant agricultural and mining activities. The highest African contributions are observed in coastal regions, in agreement with historical evidence about slave trade routes in the Americas. PMID- 28675592 TI - Exploring Types of Family Environments in Youth with Eating Disorders. AB - While many studies have explored the relationship between different eating disorder diagnoses and the familial social environment, current evidence does not support associations between distinct family interaction patterns (e.g. high enmeshment) and particular diagnoses (e.g. anorexia nervosa). The current study seeks to move beyond the current literature to explore whether empirically derived subtypes of family environment are associated with clinical features within a transdiagnostic sample of youth seeking treatment for eating disorders (n = 123). Latent class modelling of the Family Environment Scale identified three classes (i.e. different Family Environment Scale profiles): (1) Control Oriented; (2) System Maintenance-Oriented; and (3) Conflict-Oriented. Data are presented to characterize the classes (e.g. age, gender, rates of different eating disorders, severity of eating disorder pathology and rates of comorbid disorders). These preliminary results suggest that family interaction types may help personalize treatment for eating disorders and encourage future research to guide such efforts. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28675595 TI - Prenatal genetic testing by late amniocentesis to guide delivery management in haemophilia carriers. PMID- 28675594 TI - Intravenous Hydroxypropyl beta-Cyclodextrin Formulation of Letermovir: A Phase I, Randomized, Single-Ascending, and Multiple-Dose Trial. AB - Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl beta-cyclodextrin (HPbetaCD)-based intravenous formulation of letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 letermovir, 2 placebo per cohort) or multiple, once-daily doses (240 mg; 8 letermovir, 4 placebo) of HPbetaCD-formulated letermovir and the associated pharmacokinetic profiles and adverse events were investigated. Single-dose and multiple-dose regimens were generally well tolerated. Single-dose escalation resulted in a slightly more-than dose-proportional increase in the area under the letermovir plasma concentration time curve (AUC), whereas increase in the maximal observed letermovir plasma concentration (Cmax ) was dose proportional. After once-daily dosing, accumulation ratios in AUC and Cmax were 1.22 and 1.03, respectively. The terminal half-life was 28.3 h, supporting once-daily dosing (EudraCT Number: 2012 001603-20). PMID- 28675596 TI - Colloidal Rings by Site-Selective Growth on Patchy Colloidal Disc Templates. AB - Anisotropic colloidal building blocks are quite attractive as they enable the self-assembly towards new materials with designated hierarchical structures. Although many advances have been achieved in colloidal synthetic methodology, synthesis of colloidal rings with low polydispersity and on a large scale remains a challenge. To address this issue we introduce a new site-selective growth strategy, which relies on using patchy particles. For example, by using patchy discs as templates, silica can selectively be grown on only side surfaces, resulting in formation of silica rings. We demonstrate that shape parameters are tunable and find that these silica rings can be used as secondary template to synthesize other types of rings. This method for synthesizing ring-like colloids provides possibilities for studying their self-assembly and associated phase transitions, and this patchy particles template strategy paves a new route for fabricating other new colloidal particles. PMID- 28675597 TI - Using quality improvement methods to reduce clear fluid fasting times in children on a preoperative ward. AB - OBJECTIVES: We applied quality improvement (QI) methodology to identify the different aspects of why children fasted for prolonged periods in our institution. Our aim was for 75% of all children to be fasted for clear fluid for less than 4 hours. BACKGROUND: Prolonged fasting in children can increase thirst and irritability and have adverse effects on haemodynamic stability on induction. By reducing this, children may be less irritable, more comfortable and more physiologically stable, improving the preoperative experience for both children and carers. METHODS: We conducted a QI project from January 2014 until August 2016 at a large tertiary pediatric teaching hospital. Baseline data and the magnitude of the problem were obtained from pilot studies. This allowed us to build a key driver diagram, a process map and conduct a failure mode and effects analysis. Using a framework of Plan-Do-Study-Act cycles our key interventions primarily focused on reducing confusion over procedure start times, giving parents accurate information, empowering staff and reducing variation by allowing children to drink on arrival (up to one hour) before surgery. RESULTS: Prior to this project, using the 6,4,2 fasting rule for solids, breast milk, and clear fluids, respectively, 19% of children were fasted for fluid for less than 4 hours, mean fluid fasting time was 6.3 hours (SD 4.48). At the conclusion 72% of patients received a drink within 4 hours, mean fluid fasting reduced to 3.1 hours (SD 2.33). The secondary measures of aspiration (4.14:10 000) and cancellations have not increased since starting this project. CONCLUSIONS: By using established QI methodology we reduced the mean fluid fasting time for day admissions at our hospital to 3.1 hours and increased the proportion of children fasting for less than 4 hours from 19% to 72%. PMID- 28675598 TI - MR-based truncation and attenuation correction in integrated PET/MR hybrid imaging using HUGE with continuous table motion. AB - PURPOSE: The objective of this study was to introduce and evaluate a method for MR-based attenuation and truncation correction in phantom and patient measurements to improve PET quantification in PET/MR hybrid imaging. METHODS: The fully MR-based method HUGE (B0 Homogenization using gradient enhancement) provides field-of-view extension in MR imaging, which can be used for truncation correction and improved PET quantification in PET/MR hybrid imaging. The HUGE method in this recent implementation is combined with continuously moving table data acquisition to provide a seamless nontruncated whole-body data set of the outer patient contours to complete the established standard MR-based Dixon-VIBE data for attenuation correction. The method was systematically evaluated in NEMA standard phantom experiments to investigate the impact of HUGE truncation correction on PET quantification. The method was then applied to 24 oncologic patients in whole-body PET/MR hybrid imaging. The impact of MR-based truncation correction with HUGE on PET data was compared to the impact of the established PET-based MLAA algorithm for contour detection. RESULTS: In phantom and in all patient measurements, the standard Dixon-VIBE attenuation correction data show geometric distortions and signal truncations at the edges of the MR imaging field of-view. In contrast, the Dixon-VIBE-based attenuation correction data additionally extended by applying HUGE shows significantly less distortion and truncations and due to the continuously moving table acquisition robustly provides smooth outer contours of the patient arms. In the investigated patient cases, MLAA frequently showed an overestimation of arm volume and associated artifacts limiting contour detection. When applying HUGE, an average relative increase in SUVmean in patients' lesion of 4.2% and for MLAA of 4.6% were measured, when compared to standard Dixon-VIBE only. In specific lesions maximal differences in SUVmean up to 13% for HUGE and 14% for MLAA were measured. Quantification in truncated regions showed maximal differences up to 40% for both, MLAA and HUGE. Average differences in those regions in SUVmean for HUGE are 13.3% and 14.6% for MLAA. In a patient with I-124 radiotracer PET-based MLAA contour detection completely failed in this specific case, whereas HUGE as MR based approach provided accurate truncation correction. CONCLUSIONS: The HUGE method for truncation correction combined with continuous table movement extends the lateral MR field-of-view and effectively reduces truncations along the outer contours of the patient's arms in whole-body PET/MR imaging. HUGE as a fully MR based approach is independent of the choice of radiotracer, thus also offering robust truncation correction in patients that are not injected with Fluordesoxyglucose (FDG) as radiotracer. Therefore, this method improves the standard Dixon MR-based attenuation correction and PET image quantification in whole-body PET/MR imaging applications. PMID- 28675599 TI - A Hollow NaGdF4 /AFn Nanosystem Based on "Relay Race" Release for Therapy. AB - To develop a multifunctional nanomaterial for dual-mode imaging and synergetic chemotherapy, curcumin (CUR) was physically entrapped into hollow upconversion NaGdF4 nanomaterial, then apoferritin (AFn) loaded with doxorubicin (DOX) was attached to the NaGdF4 surface. Subsequent modification with the targeting reagent folic acid (FA) led to generation of the CUR/NaGdF4 -DOX/AFn-FA conjugate for cancer treatment. X-ray diffraction, scanning (SEM) and transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy demonstrated the successful preparation of hexagonal-phase NaGdF4 and NaGdF4 -AFn-FA. Moreover, no toxicity was observed for NaGdF4 -AFn-FA. In vitro and in vivo experiments demonstrated that the two drugs are sequentially released from the nanocomposites. This two-drug system showed strong growth inhibitory effects on MCF-7 cells. Upconversion luminescence imaging and magnetic resonance (MR) imaging of NaGdF4 -AFn-FA were carried out. The results of this study show that NaGdF4 -AFn-FA can be used for targeted anticancer drug delivery as well as imaging, a novel multi-pronged theranostic system for tumor treatment. PMID- 28675600 TI - Risk of genetic maladaptation due to climate change in three major European tree species. AB - Tree populations usually show adaptations to their local environments as a result of natural selection. As climates change, populations can become locally maladapted and decline in fitness. Evaluating the expected degree of genetic maladaptation due to climate change will allow forest managers to assess forest vulnerability, and develop strategies to preserve forest health and productivity. We studied potential genetic maladaptation to future climates in three major European tree species, Norway spruce (Picea abies), silver fir (Abies alba), and European beech (Fagus sylvatica). A common garden experiment was conducted to evaluate the quantitative genetic variation in growth and phenology of seedlings from 77 to 92 native populations of each species from across Switzerland. We used multivariate genecological models to associate population variation with past seed source climates, and to estimate relative risk of maladaptation to current and future climates based on key phenotypic traits and three regional climate projections within the A1B scenario. Current risks from climate change were similar to average risks from current seed transfer practices. For all three climate models, future risks increased in spruce and beech until the end of the century, but remained low in fir. Largest average risks associated with climate projections for the period 2061-2090 were found for spruce seedling height (0.64), and for beech bud break and leaf senescence (0.52 and 0.46). Future risks for spruce were high across Switzerland. However, areas of high risk were also found in drought-prone regions for beech and in the southern Alps for fir. Genetic maladaptation to future climates is likely to become a problem for spruce and beech by the end of this century, but probably not for fir. Consequently, forest management strategies should be adjusted in the study area for spruce and beech to maintain productive and healthy forests in the future. PMID- 28675601 TI - Proteasomal activity-based probes mark protein homeostasis in muscles. AB - BACKGROUND: Protein homeostasis, primarily regulated by the ubiquitin-proteasome system is crucial for proper function of cells. In tissues of post-mitotic cells, the impaired ubiquitin-proteasome system is found in a wide range of neuromuscular disorders. Activity-based probes (ABPs) measure proteasomal proteolytic subunits and can be used to report protein homeostasis. Despite the crucial role of the proteasome in neuromuscular pathologies, ABPs were not employed in muscle cells and tissues, and measurement of proteasomal activity was carried out in vitro using low-throughput procedures. METHODS: We screened six ABPs for specific application in muscle cell culture using high throughput call based imaging procedures. We then determined an in situ proteasomal activity in myofibers of muscle cryosections. RESULTS: We demonstrate that LWA300, a pan reactive proteasomal probe, is most suitable to report proteasomal activity in muscle cells using cell-based bio-imaging. We found that proteasomal activity is two-fold and three-fold enhanced in fused muscle cell culture compared with non fused cells. Moreover, we found that proteasomal activity can discriminate between muscles. Across muscles, a relative higher proteasomal activity was found in hybrid myofibers whereas fast-twitch myofibers displayed lower activity. CONCLUSIONS: Our study demonstrates that proteasomal activity differ between muscles and between myofiber types. We suggest that ABPs can be used to report disease progression and treatment efficacy. PMID- 28675602 TI - Minimizing imbalances on patient characteristics between treatment groups in randomized trials using classification tree analysis. AB - RATIONALE, AIMS, AND OBJECTIVES: Randomization ensures that treatment groups do not differ systematically in their characteristics, thereby reducing threats to validity that may otherwise explain differences in outcomes. Large observed imbalances in patient characteristics may indicate that selection bias is being introduced into the treatment allocation process. We introduce classification tree analysis (CTA) as a novel algorithmic approach for identifying potential imbalances in characteristics and their interactions when provisionally assigning each new participant to one or the other treatment group. The participant is then permanently assigned to the treatment group that elicits either no or less imbalance than if assigned to the alternate group. METHOD: Using data on participant characteristics from a clinical trial, we compare 3 different treatment allocation approaches: permuted block randomization (the original allocation method), minimization, and CTA. Treatment allocation performance is assessed by examining balance of all 17 patient characteristics between study groups for each of the allocation techniques. RESULTS: While all 3 treatment allocation techniques achieved excellent balance on main effect variables, Classification tree analysis further identified imbalances on interactions and in the distributions of some of the continuous variables. CONCLUSIONS: Classification tree analysis offers an algorithmic procedure that may be used with any randomization methodology to identify and then minimize linear, nonlinear, and interactive effects that induce covariate imbalance between groups. Investigators should consider using the CTA approach as a real-time complement to randomization for any clinical trial to safeguard the treatment allocation process against bias. PMID- 28675603 TI - Differences in the frequency of Alzheimer's disease-associated genomic variations in populations of different races. AB - AIM: The general genetic background is important when studying major common diseases, such as Alzheimer's disease (AD). Determining the underlying genetic factors in populations of different races might allow for the tailored management of such diseases. The aim of the present study was to identify potential single nucleotide polymorphisms (SNP) and genes associated with racial differences. METHODS: We identified AD-associated SNP with different carrier frequencies among races through the National Human Genome Research Institute and 1000 Genome Project databases. We generated heatmaps and carried out principle component analysis and pathway analysis. A total of 99 AD-associated SNP from genome-wide association studies were found to have different frequencies among races. Principle component analysis showed that specific SNP had higher or lower frequencies in specific races, and that similar races were clustered together. RESULTS: Pathway analysis showed that a total of 15 pathways involving intracellular endocytosis, inflammation, immune response and lipid metabolism were significant, and that apolipoprotein E was involved in the most significant pathways. A literature review showed that 16 genes were involved in the pathogenesis of AD, and that the identified SNP could be used to cluster different races, suggesting that these SNP represented different genomic backgrounds of races. CONCLUSIONS: As disease-associated genes might have several functional variants across different populations, these genes could be candidates for further studies, such as target gene sequencing or functional follow up of putative loci regarding racial differences. Geriatr Gerontol Int 2017; 17: 2184 2193. PMID- 28675604 TI - A narrower gap of grazing intensity. Reply to Fetzel et al., 2017. Seasonality constrains to livestock grazing intensity. PMID- 28675605 TI - Intrahost milieu modulates production of outer membrane vesicles, vesicle associated Shiga toxin 2a and cytotoxicity in Escherichia coli O157:H7 and O104:H4. AB - Outer membrane vesicles (OMVs) are important virulence tools of enterohaemorrhagic Escherichia coli (EHEC), but other biological functions of these nanostructures are unknown. We tested the hypothesis that modulation of OMV production enables EHEC to resist the intrahost environment during infection by investigating if simulated human gastrointestinal conditions affect OMV production in EHEC O157:H7 and O104:H4. All the conditions tested including a low pH, simulated ileal and colonic media, presence of mucin, intestinal epithelial cell lysate or antimicrobial peptides, as well as iron limitation, significantly increased OMV production by these pathogens. Accordingly, a maximum vesiculation in EHEC O104:H4 was observed immediately after its isolation from a patient's intestine, and rapidly decreased during passages in vitro. Most of the simulated intrahost conditions also upregulated the OMV-associated Shiga toxin 2a (Stx2a), the major EHEC virulence factor, and, as a result, OMV cytotoxicity. The data indicates that upregulation of OMV production by the human gastrointestinal milieu contributes to EHEC survival and adaptation within the host during infection. Moreover, the intrahost increase of vesiculation and OMV-associated Stx2a may augment EHEC virulence. PMID- 28675606 TI - Isolation, Detection, and Antigen-Based Profiling of Circulating Tumor Cells Using a Size-Dictated Immunocapture Chip. AB - Even though the diagnostic and prognostic value of circulating tumor cells (CTCs) has been demonstrated, their clinical utility and widespread adoption have been limited. Herein, we describe a new device, size-dictated immunocapture chip (SDI Chip), for efficient, sensitive, and spatially resolved capture and detection of CTCs. SDI-Chip enables selective, frequent, and extended interaction of CTCs with hydrodynamically optimized immunocoated micropillar surfaces. CTCs with different antigen expression levels can be efficiently captured and spatially resolved around the micropillars. Capture efficiency greater than 92 % with a purity of 82 % was achieved with blood samples. CTCs were detected in non-metastasis colorectal (CRC) patients, while none was detected from healthy volunteers. We believe that SDI-Chip will facilitate the transition of tumor diagnosis from anatomical pathology to molecular pathology in localized CRC patients. PMID- 28675607 TI - Comparison of the Mini-Mental State Examination and Montreal Cognitive Assessment executive subtests in detecting post-stroke cognitive impairment. AB - AIM: The Montreal Cognitive Assessment (MoCA) has been shown to be more sensitive in detecting executive dysfunction than the Mini-Mental State Examination (MMSE). However, it is still not known whether all the MoCA executive subtests contribute to the superior sensitivity. Thus, the present study aimed to determine how much executive abnormality was detected by the MMSE and MoCA executive subtests in a population-based cohort of Chinese post-stroke patients. METHODS: The MMSE and MoCA were collected from post-stroke patients (within 15 days to 1 month after stroke, including ischemic stroke and hemorrhagic stroke) in 14 hospitals of northern and southern China (including 10 top-graded hospitals and 4 community hospitals) between June 2011 and September 2013. The proportions of patients with incorrect MoCA executive subtests and the proportions of patients with incorrect MMSE executive subtests were compared. RESULTS: A total of 1222 patients (703 men and 519 women, aged 62.06 +/- 10.68 and 62.76 +/- 9.86 years, respectively) were recruited. The MoCA detected more patients with executive dysfunction than the MMSE (OR 15.399, 95% CI 12.631-18.773; P < 0.001). The likelihood of incorrect MMSE executive tasks increased across decreasing scores of MoCA executive tasks (P < 0.001 for trend). Compared with the MMSE three-step command test (15.5%), the MoCA trail-making (57.8%), abstraction (48.0%) and abstraction (measurement tool; 45.7%) detected more patients with executive dysfunction (P < 0.001), whereas the MoCA digit span forwards (4.3%) and backwards (11.6%) detected fewer patients (P < 0.001 and P = 0.005, respectively). CONCLUSIONS: The MoCA executive tasks are more sensitive in detecting executive dysfunction compared with the MMSE executive tasks. Geriatr Gerontol Int 2017; 17: 2329-2335. PMID- 28675608 TI - Research priorities about stoma-related quality of life from the perspective of people with a stoma: A pilot survey. AB - BACKGROUND: There is a recognized need to include patients in setting research priorities. Research priorities identified by people with a stoma are rarely elicited. OBJECTIVES: To improve the quality of life of people with a stoma through use of evidence-based practice based on research priorities set by patients. DESIGN AND METHODS: Online pilot survey publicized in 2016 via United Kingdom stoma charities. People ranked nine stoma-related quality of life topics in order of research priority. PARTICIPANTS: People 16 years of age and over who currently have or have had a stoma for treatment for any medical condition. ANALYSIS: Distributions of the priority scores for each of the nine research topics were examined. Group differences were explored using either the Mann Whitney U-test or the Kruskal-Wallis test depending on the number of groups. RESULTS: In total, 225 people completed the survey. The most important research priority was pouch leak problems and stoma bag/appliance problems followed by hernia risk. There were statistically significant differences in ranking research priorities between males and females, age, underlying disease that led to a stoma, stoma type and length of time with a stoma. CONCLUSION: People with a stoma are willing to engage in and set research priorities. The results should contribute towards future research about setting the research agenda for the study of stoma-related concerns that impact quality of life. PMID- 28675609 TI - Effects of intravenous fentanyl around the end of surgery on emergence agitation in children: Systematic review and meta-analysis. AB - BACKGROUND: Emergence agitation is a serious postoperative problem in children undergoing general anesthesia. The use of fentanyl around the end of surgery has been proposed to prevent emergence agitation. However, the efficacy and disadvantages of this method remain uncertain because previous results have not been consistent, depending on the variable assessed. METHODS: In July 2016, the PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, and KoreaMed were searched for randomized controlled trials that compared fentanyl (1 MUg/kg) and placebo administered around the end of surgery to prevent emergence agitation after general anesthesia in children between birth and 14 years of age. The collected outcomes included the incidence or score of emergence agitation, variables regarding anesthesia recovery, and adverse events (eg, postoperative nausea or vomiting). RESULTS: A total of 10 randomized controlled trials (718 patients, 357 receiving fentanyl) were included. Fentanyl around the end of surgery significantly decreased emergence agitation incidence (emergence agitation: relative risk 0.43, 95% confidence interval 0.35 to 0.53, I2 =0.0%; severe emergence agitation: relative risk 0.50, 95% confidence interval 0.31 to 0.81, I2 =0.0%). From subgroup analyses, fentanyl at the end of surgery was associated with a prolonged postanesthesia care unit stay and increased postoperative nausea or vomiting incidence (weighted mean difference 6.09, 95% confidence interval 2.77 to 9.41, I2 =58.6%; relative risk 2.61, 95% confidence interval 1.58 to 4.33, I2 =32.4%), whereas fentanyl at 10-20 minutes before the end of surgery did not increase postanesthesia care unit stay or postoperative nausea or vomiting risk (weighted mean difference -1.15, 95% confidence interval 5.15 to 2.85, I2 =89.0%; relative risk 1.32, 95% confidence interval 0.66 to 2.66, I2 =0.0%). CONCLUSIONS: The current analyses indicate that fentanyl around the end of surgery reduces the incidence of emergence agitation in children undergoing general anesthesia. PMID- 28675611 TI - Palladium-Catalyzed Asymmetric Synthesis of Silicon-Stereogenic 5,10 Dihydrophenazasilines via Enantioselective 1,5-Palladium Migration. AB - A palladium-catalyzed asymmetric synthesis of silicon-stereogenic 5,10 dihydrophenazasilines was developed that proceeds via an unprecedented enantioselective 1,5-palladium migration. High enantioselectivity was achieved by employing 4,4'-bis(trimethylsilyl) (R)-Binap as the chiral ligand, and a series of mechanistic investigations were carried out to probe the catalytic cycle of this process. PMID- 28675612 TI - Low-Voltage Gaseous HCl Electrolysis with an Iron Redox-Mediated Cathode for Chlorine Regeneration. AB - Gaseous HCl as a by-product is often produced from chlorination processes using Cl2 gas. Onsite Cl2 regeneration from HCl is highly desirable as it eliminates the need to buy new Cl2 and dispose HCl waste. A gaseous HCl electrolysis with Fe3+ /Fe2+ redox-mediated cathode is demonstrated for Cl2 regeneration. HCl is oxidized to generate Cl2 and protons in the anode while Fe3+ is reduced to Fe2+ in the cathode. Simultaneously Fe3+ is regenerated by chemical oxidation of Fe2+ by oxygen (air) that also produces water. A low operational voltage and high coulombic efficiency are achieved by using a novel composite porous membrane and hydrophobic anode. Specifically, a cell voltage of only 0.64 V is needed at the typical current density of 4 kA m-2 , leading to a low energy consumption of 483 kWh per ton of Cl2 (124 kJ molCl2 -1 ) which is about 50-55 % of state-of-the-art HCl electrolysis processes. PMID- 28675613 TI - Activity behavior, nutritional status and perceived health in older Brazilian adults: Does the number of chronic diseases matter? AB - AIM: The present study examined activity behavior, nutritional status and perceived health in relation to the number of chronic diseases (ChrD) in a representative sample of Brazilians aged >=60 years. METHODS: A cross-sectional, population-based study was carried out in a midsize Brazilian city to evaluate different health risk factors. Using a stratified random sampling procedure to select a representative sample of adults, this study interviewed 1572 individuals face-to-face. Our analytical sample focused on those aged >=60 years (n = 355). Statistical procedures were carried out using spss software, with the significance level set as P < 0.05. RESULTS: Older adults diagnosed with >=2 ChrD were significantly less active during leisure time physical activity (P = 0.03), presented with significant higher body mass index values (P < 0.001) and were approximately fivefold (1.69-17.93) more likely to perceive their health as poor compared with those with zero ChrD. The group with >=2 ChrD reported a similar amount of sitting time compared with older adults with zero or one ChrD (P > 0.05). CONCLUSIONS: Having multiple ChrD has a negative impact on older adults' leisure time physical activity, body mass index and the perception of health. The findings of the present study underscore the need for more infusive approaches tackling ChrD in Brazil focusing on healthy lifestyle behaviors, such as physical activity. Geriatr Gerontol Int 2017; 17: 2376-2382. PMID- 28675610 TI - Vitamin D, a modulator of musculoskeletal health in chronic kidney disease. AB - The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non-genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25-hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions. PMID- 28675614 TI - Form Follows Function: Designer Chemistry at the 52nd Burgenstock Conference. AB - The 52nd Burgenstock Conference on Stereochemistry took place from April 30-May 4, 2017, and showed how chemistry and design go hand-in-hand (as reflected in the image of the Bauhausarchiv in Berlin). In this Conference Report, Philipp Heretsch outlines the program. PMID- 28675615 TI - Betamethasone-based chiral electrochemical sensor coupled to chemometric methods for determination of mandelic acid enantiomers. AB - A chiral biosensing platform was developed using betamethasone (BMZ) as chiral recognition element through multilayered electrochemical deposition of BMZ, overoxidized polypyrrole, and nanosheets of graphene (OPPy-BMZ/GR), for enantio recognition of mandelic acid (MA) enantiomers. The deposited film was characterized by scanning electron microscopy, differential pulse voltammetry, cyclic voltammetry, and electrochemical impedance spectroscopy. It was shown that the chiral sensing platform can discriminate R- and S-MA differential pulse voltammetry signals, at the voltages of 1.35 and 1.33 V (vs Ag/AgCl), respectively. To tackle the problem of highly overlapping peaks of these enantiomers, the partial least squares (PLS) regression and genetic algorithm-PLS (GA-PLS) were used for simultaneous quantification of MA enantiomers. Generally, variable selection by genetic algorithm provided an improvement in prediction results when compared to full-voltammogram PLS. Good analytical performances were obtained despite the inherent complexity of the simultaneous determination. PMID- 28675616 TI - Covalently Interlocked Cyclohexa-m-phenylenes and Their Assembly: En Route to Supramolecular 3D Carbon Nanostructures. AB - In our search to cluster as many phenylene units as possible in a given space, we have proceeded to the three-dimensional world of benzene-based molecules by employing covalently interlocked cyclohexa-m-phenylenes, as present in the unique paddlewheel-shaped polyphenylene 10. A precursor was conceived, in which freely rotating m-chlorophenylene units provide sufficient solubility along with the necessary proximity for the final ring closure to give 10. Monitoring the assembly of solubilized tert-butyl derivatives of 10 into supramolecular carbon nanostructures by dynamic light scattering (DLS) and Brillouin light scattering (BLS) revealed the dimensions of the initially formed aggregates as well as the amorphous character of the solid state. PMID- 28675617 TI - Developing a practical suicide risk prediction model for targeting high-risk patients in the Veterans health Administration. AB - OBJECTIVES: The US Veterans Health Administration (VHA) has begun using predictive modeling to identify Veterans at high suicide risk to target care. Initial analyses are reported here. METHODS: A penalized logistic regression model was compared with an earlier proof-of-concept logistic model. Exploratory analyses then considered commonly-used machine learning algorithms. Analyses were based on electronic medical records for all 6,360 individuals classified in the National Death Index as having died by suicide in fiscal years 2009-2011 who used VHA services the year of their death or prior year and a 1% probability sample of time-matched VHA service users alive at the index date (n = 2,112,008). RESULTS: A penalized logistic model with 61 predictors had sensitivity comparable to the proof-of-concept model (which had 381 predictors) at target thresholds. The machine learning algorithms had relatively similar sensitivities, the highest being for Bayesian additive regression trees, with 10.7% of suicides occurred among the 1.0% of Veterans with highest predicted risk and 28.1% among the 5.0% of with highest predicted risk. CONCLUSIONS: Based on these results, VHA is using penalized logistic regression in initial intervention implementation. The paper concludes with a discussion of other practical issues that might be explored to increase model performance. PMID- 28675618 TI - Restoring jawline contour with calcium hydroxylapatite: A prospective, observational study. AB - BACKGROUND: Jawline reshaping by replacing volume has become an indispensable component of modern facial rejuvenation. AIM: To evaluate calcium hydroxylapatite (CaHA) for the treatment of an aging jawline in a routine setting. METHODS: Five investigators enrolled 35 subjects requesting jawline rejuvenation with CaHA. Injections were performed according to investigators usual practice. Baseline and post-treatment scores were evaluated using Merz Aesthetics Scales(r). Follow-up visits took place at Day 30 (Day 60 for those with touch-up at Day 30), 180, and 360. Physician and patient satisfaction, esthetic impact of treatment, and adverse events were recorded. RESULTS: Improvements in jawline contour compared with baseline were statistically significant at each visit, with scores of 2.42 (moderate to severe sagging) at baseline, 1.02 (mild) at Day 30/60 (P<=.0001), 1.11 at Day 180 (P<=.0001), and 1.45 at Day 360 (P=.0015). Statistically significant improvements in marionette line scores were also observed. Investigators rated results as "improved" to "very much improved" in all subjects up to Day 180, and in 81% of subjects at Day 360. Satisfaction with treatment was very high. Adverse events were mostly mild and related to either the procedure or injection technique. CONCLUSION: CaHA is a very effective agent for restoring jawline contour in routine practice and is associated with high levels of physician and patient satisfaction. PMID- 28675619 TI - Rivaroxaban recanalized occlusive superior mesenteric vein thrombosis, but increased the risk of bleeding in a cirrhotic patient. PMID- 28675620 TI - Site-Specific SERS Assay for Survivin Protein Dimer: From Ensemble Experiments to Correlative Single-Particle Imaging. AB - An assay for Survivin, a small dimeric protein which functions as modulator of apoptosis and cell division and serves as a promising diagnostic biomarker for different types of cancer, is presented. The assay is based on switching on surface-enhanced Raman scattering (SERS) upon incubation of the Survivin protein dimer with Raman reporter-labeled gold nanoparticles (AuNP). Site-specificity is achieved by complexation of nickel-chelated N-nitrilo-triacetic acid (Ni-NTA) anchors on the particle surface by multiple histidines (His6 -tag) attached to each C-terminus of the centrosymmetric protein dimer. Correlative single-particle analysis using light sheet laser microscopy enables the simultaneous observation of both elastic and inelastic light scattering from the same sample volume. Thereby, the SERS-inactive AuNP-protein monomers can be directly discriminated from the SERS-active AuNP-protein dimers/oligomers. This information, i.e. the percentage of SERS-active AuNP in colloidal suspension, is not accessible from conventional SERS experiments due to ensemble averaging. The presented correlative single-particle approach paves the way for quantitative site-specific SERS assays in which site-specific protein recognition by small chemical and in particular supramolecular ligands can be tested. PMID- 28675621 TI - A Highly Fluorinated Chiral Aldehyde for Enantioselective Fluorescent Recognition in a Biphasic System. AB - A 1,1'-bi-2-naphthol (BINOL)-based aldehyde containing four perfluoroalkyl groups has been designed and synthesized. It shows enantioselective fluorescence enhancement at 420 nm when treated with the enantiomers of trans-1,2 diaminocyclohexane in an organic/fluorous biphasic system. The enantiomeric excess of the diamine in methanol can be linearly correlated with the emission intensity of of the aldehyde in perfluorohexane (FC-72). This is the first example to determine the enantiomeric composition of a chiral molecule by using a fluorescent sensor in a fluorous/organic biphasic system. The mechanism of the reaction was investigated by NMR spectroscopy and mass spectrometry. PMID- 28675622 TI - Early radiological intervention and haematology screening is associated with excellent outcomes in Budd-Chiari syndrome. AB - BACKGROUND: Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder, resulting from thrombosis of the hepatic veins. Various treatments, including pharmacological, radiological and surgical interventions, have been used. AIM: To describe retrospectively our institution's experience with management of patients with BCS. METHODS: A retrospective study of all cases of primary Budd-Chiari syndrome presenting to our institution between January 2000 and August 2012 was performed. Patients with secondary Budd-Chiari syndrome due to malignancy or local mass compression were excluded. RESULTS: Between 2000 and 2012, 27 patients with primary BCS presented with a median Rotterdam score of 1.16 (range: 0.07 2.11). A total of 24 patients (89%) had at least one risk factor, with the commonest being myeloproliferative neoplasm (MPN), detected in 17 of 24 (71%) of the tested patients, including four patients with normal blood counts at diagnosis. All patients were anticoagulated with warfarin or low-molecular-weight heparin (LMWH). A total of 25 (92.6%) patients also had primary radiological interventions, consisting of transjugular intrahepatic portosystemic shunt (TIPS) in 18 (67%) patients and/or angioplasty/stenting in 11 (40%). A total of 14 patients developed TIPS stenoses, requiring a median of 1.5 (range: 1-14) revisions. No patient developed TIPS failure requiring alternative therapy. Two patients were lost to follow-up. At a median follow up of 59 months (range: 2-248 months), the overall survival was 96% at 1 year and 81% at 5 years, much greater than predicted by the Rotterdam score. No patients required liver transplantation. CONCLUSION: There is a high incidence of MPN in patients with primary BCS, including patients with normal peripheral blood counts at the time of diagnosis. Our approach of anticoagulation, aggressive and early radiological intervention aimed at rapid decompression of the congested liver resulted in excellent medium-term outcomes. PMID- 28675623 TI - Association between mental health and meal patterns among elderly Koreans. AB - AIM: The present cross-sectional study analyzed the differences in mental health among community-dwelling elderly Koreans based on type of meal skipping and family meal frequency. METHODS: We carried out a secondary data analysis using data from 4742 older adults aged >=65 years from the Korea National Health and Nutrition Examination Survey V (2010-2012), a nationally representative sample. RESULTS: In the final model, after adjusting for covariates, we found differences in stress, depression and suicidal ideation based on the type of meal skipping. Specifically, breakfast skippers showed a greater odds ratio for depression and suicidal ideation than breakfast eaters; dinner skippers showed a greater odds ratio for suicidal ideation than dinner eaters. We also found differences in stress, depression and suicidal ideation per family meal frequency. CONCLUSIONS: It is necessary to consider the type of meal skipping and family meal frequency while providing limited social resources to improve the mental health of older adults. Geriatr Gerontol Int 2018; 18: 161-168. PMID- 28675624 TI - Response to "Noninvasive prenatal screening at low fetal fraction: comparing whole-genome sequencing and single-nucleotide polymorphism methods". PMID- 28675625 TI - Comment on "Noninvasive prenatal screening at low fetal fraction: comparing whole genome sequencing and single-nucleotide polymorphism methods". PMID- 28675626 TI - Epidemiology of tuberculosis and HIV coinfections in Singapore, 2000-2014. AB - Cross-matching of records between Singapore's tuberculosis and HIV registries showed that 3.3% of individuals with tuberculosis (TB) were coinfected with HIV (2000-2014), the TB incidence among individuals with HIV infection was 1.65 per 100 person-years, and 53% of coinfections were diagnosed within 1 month of each other. The findings supported joint prevention programmes for early diagnosis and treatment. PMID- 28675627 TI - Fifty years of herbicide research: comparing the discovery of trifluralin and halauxifen-methyl. AB - Fifty years separate the commercialization of the herbicides trifluralin and halauxifen-methyl. Despite the vast degree of technological change that occurred over that time frame, some aspects of their discovery stories are remarkably similar. For example, both herbicides were prepared very early in the iterative discovery process and both were developed from known lead compound structures by hypothesis-driven research efforts without the use of in vitro assays or computer aided molecular design. However, there are aspects of the halauxifen-methyl and trifluralin discovery stories that are substantially different. For example, the chemical technology required for the cost-effective production of halauxifen methyl simply did not exist just two decades prior to its commercial launch. By contrast, the chemical technology required for the cost-effective production of trifluralin was reported in the chemical literature more than two decades prior to its commercial launch. In addition, changes in regulatory environment since the early 1960s ensured that their respective discovery to commercial launch stories would also differ in substantial ways. Ultimately, the time and cost required to develop and register halauxifen-methyl demanded a global initial business case while the lower registration hurdles that trifluralin cleared enabled a narrow initial business case mainly focused on the USA. (c) 2017 Society of Chemical Industry. PMID- 28675628 TI - A sensitive UHPLC-MS/MS method for the simultaneous quantification of three lignans in human plasma and its application to a pharmacokinetic study. AB - The aim of this study was to develop an analytical method to simultaneously analyze schizandrin, schizandrol B, and gomisin N lignans in human plasma using ultra high performance liquid chromatography with tandem mass spectrometry. The three lignans were separated using a mobile phase of water and acetonitrile containing 0.02% acetic acid equipped with a Kinetex C18 column (2.1 mm * 50 mm, 1.7 MUm). This analysis was achieved by multiple reaction monitoring mode in an electrospray interface. The mass transitions were m/z 433.1->384.0 for schizandrin, 398.8->367.8 for schizandrol B, and 400.6->299.8 for gomisin N. Liquid-liquid extraction with methyl tert-butyl ether was used to obtain the three lignans. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. The calibration curves for the three lignans in human plasma were 0.05-50 ng/mL and displayed excellent linearity with correlation coefficients greater than 0.99. Precision for all three lignans was within 11.23%. The accuracy was 88.3-99.0% for schizandrin, 90.6-103.4% for schizandrol B, and 90.2-103.5% for gomisin N. The developed simultaneous analytical method satisfied the criteria of international guidance and could be successfully applied to the pharmacokinetic study of three lignans after oral administration of Schisandrae Fructus extract powder to humans. PMID- 28675629 TI - Long-term follow-up after left atrial appendage occlusion with comparison of transesophageal echocardiography versus computed tomography to guide medical therapy and data about postclosure cardioversion. AB - AIMS: The use of left atrial appendage (LAA) occluders in atrial fibrillation is increasing. There are few data on the comparison between transesophageal echocardiography (TEE) and computed tomography (MDCT) assessing peridevice flow and outcome of electrical cardioversion (ECV) in these patients. METHODS AND RESULTS: Single-center prospective registry from 2009 to 2015 including all LAA occluders to analyze success and complications during implantation and follow-up. Patients having >=1 ECV were further analyzed. TEE was performed during implantation and at 6 weeks. In a subgroup of 77 patients, we compared MDCT with TEE at 6 weeks. Overall, 135 patients (69 +/- 9 years; 70% male; CHA2 DS2 -VASc score: 3.6 +/- 1.4; HAS-BLED score: 2.5 +/- 0.6) received a LAA occluder (Watchman, n = 73; ACP-1, n = 59; Amulet, n = 3; PVI + LAA occluder, n = 91; and LAA occluder only, n = 44). Device implantation was successful in 131 (97%). Eight patients (5.9%) had major periprocedural complications (ischemic stroke/transient ischemic attacks, n = 4, tamponade, n = 2, device thrombosis, n = 2, Dressler syndrome, n = 1). The periprocedural complication rate was similar between concomitant procedure and LAA occluder only (8/91 vs. 5/44; P = 0.6). Twelve patients (9%) died (procedure-related, n = 2; 1%) during follow-up of 44 months (IQR: 43). MDCT (n = 77) at 6 weeks showed similar peridevice flow compared to TEE (TEE: 1.5 +/- 1.9 mm vs. MDCT: 1.1 +/- 2.2 mm, P = 0.25). Thromboembolic events occurred in 3 patients (CVA, n = 1; TIA, n = 2) during follow-up. In total, 41 ECV were performed in 26 patients (1.6 +/- 0.9/patient), 13 months (IQR: 24) after implantation (<1 month: n = 8). No ECV-related clinical complications were observed. CONCLUSION: LAA occlusion is feasible with an acceptable safety profile and few events during long-term follow-up. ECV after LAA occlusion is feasible. MDCT could help to evaluate peridevice flow. PMID- 28675631 TI - Place of Cyclization Mode in the Adjustment of Parameters for Motor Cortex Stimulation Used to Treat Neuropathic Pain. PMID- 28675630 TI - Erwinia amylovora catalases KatA and KatG are virulence factors and delay the starvation-induced viable but non-culturable (VBNC) response. AB - The life cycle of the plant pathogen Erwinia amylovora comprises periods inside and outside the host in which it faces oxidative stress caused by hydrogen peroxide (H2 O2 ) and other compounds. The sources of this stress are plant defences, other microorganisms and/or exposure to starvation or other environmental challenges. However, the functional roles of H2 O2 -neutralizing enzymes, such as catalases, during plant-pathogen interactions and/or under starvation conditions in phytopathogens of the family Erwiniaceae or closely related families have not yet been investigated. In this work, the contribution of E. amylovora catalases KatA and KatG to virulence and survival in non-host environments was determined using catalase gene mutants and expression, as well as catalase activity analyses. The participation of E. amylovora exopolysaccharides (EPSs) in oxidative stress protection was also investigated. Our study revealed the following: (i) a different growth phase regulation of each catalase, with an induction by H2 O2 and host tissues; (ii) the significant role of E. amylovora catalases as virulence and survival factors during plant-pathogen interactions; (iii) the induction of EPSs by H2 O2 despite the fact that apparently they do not contribute to protection against this compound; and (iv) the participation of both catalases in the detoxification of the starvation induced intracellular oxidative stress, favouring the maintenance of culturability, and hence delaying the development of the viable but non culturable (VBNC) response. PMID- 28675632 TI - The Neurostimulation Appropriateness Consensus Committee (NACC) Recommendations for Infection Prevention and Management. PMID- 28675633 TI - Increased Urine Production Due to Leg Fluid Displacement Reduces Hours of Undisturbed Sleep. AB - OBJECTIVE: To investigate whether or not the leg fluid displacement observed when moving from the standing to recumbent position at bedtime reduces the hours of undisturbed sleep (HUS). METHODS: Men aged 50 years or older who were hospitalized for urological diseases were investigated. Body water evaluation was performed three times with a bioelectric impedance method: (i) 17:00, (ii) 30 min after (short-term), and (iii) waking up (long-term). A frequency volume chart was used to evaluate the status of nocturnal urine production, and the factors affecting HUS were investigated. RESULTS: A total of 50 patients (mean age: 68 years) were enrolled. Short-term changes in extracellular fluid (ECF in the legs showed a significant positive correlation with urine production per unit of time at the first nocturnal voiding (UFN/HUS) (r = 0.45, P = 0.01). In the comparison between patients who had <3 HUS vs. those who had >=3 HUS, the <3 HUS group showed significantly greater short-term changes in leg fluid volume, night-time water intake (17:00-06:00), and UFN/HUS. Multivariate analysis to assess the risk factors for <3 HUS indicated UFN/HUS as a risk factor in the overall model, and short-term changes in leg ECF and night-time water intake as risk factors in the model that only considered factors before sleep. CONCLUSIONS: Nocturnal leg fluid displacement may increase urine production leading up to first voiding after going to bed, and consequently, induce early awakening after falling asleep. PMID- 28675635 TI - Deep peat warming increases surface methane and carbon dioxide emissions in a black spruce-dominated ombrotrophic bog. AB - Boreal peatlands contain approximately 500 Pg carbon (C) in the soil, emit globally significant quantities of methane (CH4 ), and are highly sensitive to climate change. Warming associated with global climate change is likely to increase the rate of the temperature-sensitive processes that decompose stored organic carbon and release carbon dioxide (CO2 ) and CH4 . Variation in the temperature sensitivity of CO2 and CH4 production and increased peat aerobicity due to enhanced growing-season evapotranspiration may alter the nature of peatland trace gas emission. As CH4 is a powerful greenhouse gas with 34 times the warming potential of CO2 , it is critical to understand how factors associated with global change will influence surface CO2 and CH4 fluxes. Here, we leverage the Spruce and Peatland Responses Under Changing Environments (SPRUCE) climate change manipulation experiment to understand the impact of a 0-9 degrees C gradient in deep belowground warming ("Deep Peat Heat", DPH) on peat surface CO2 and CH4 fluxes. We find that DPH treatments increased both CO2 and CH4 emission. Methane production was more sensitive to warming than CO2 production, decreasing the C-CO2 :C-CH4 of the respired carbon. Methane production is dominated by hydrogenotrophic methanogenesis but deep peat warming increased the delta13 C of CH4 suggesting an increasing contribution of acetoclastic methanogenesis to total CH4 production with warming. Although the total quantity of C emitted from the SPRUCE Bog as CH4 is <2%, CH4 represents >50% of seasonal C emissions in the highest-warming treatments when adjusted for CO2 equivalents on a 100-year timescale. These results suggest that warming in boreal regions may increase CH4 emissions from peatlands and result in a positive feedback to ongoing warming. PMID- 28675634 TI - Predictors for fatal human infections with avian H7N9 influenza, evidence from four epidemic waves in Jiangsu Province, Eastern China, 2013-2016. AB - BACKGROUND: Four epidemic waves of human infection with H7N9 have been recorded in China up to 1 June 2016, including in Jiangsu Province. However, few studies have investigated the differences in patients' characteristics among the four epidemic waves, and the analyses of factors associated with fatal infection lacked statistical power in previous studies due to limited sample size. METHODS: All laboratory-confirmed A(H7N9) patients in Jiangsu province were analysed. Patients' characteristics were compared across four waves and between survivors and those who died. Multivariate analyses were used to identify independent predictors of death. RESULTS: Significant differences were found in the lengths of several time intervals (from onset of disease to laboratory confirmation, to onset of ARDS and respiratory failure, and to death) and in the development of heart failure. The proportions of overweight patients and rural patients increased significantly across the four waves. Administration of glucocorticoids and double-dose neuraminidase inhibitors became the norm. Predictors of death included complications such as ARDS, heart failure and septic shock, administration of glucocorticoids, and disease duration. CONCLUSION: Characteristics of H7N9 patients and clinical treatment options changed over time. Particular complications and the use of particular treatment, along with disease duration, could help clinicians predict the outcome of H7N9 infections. PMID- 28675636 TI - Prevalence of Urinary Incontinence During Pregnancy and Associated Risk Factors. AB - OBJECTIVE: To investigate the prevalence of urinary incontinence during pregnancy and associated risk factors. METHODS: The study is a cross-sectional and descriptive study. A questionnaire was conducted with a total of 750 pregnant women about their urinary incontinence complaints between April and December 2013. RESULTS: The prevalence of urinary incontinence during pregnancy was 300 in 750 (40%). Stress urinary incontinence was the most common type of incontinence during pregnancy. 41.7% of nulliparous women, 38% of primipara women, and 20.3% of multipara women experienced urinary incontinence. Among women reporting UI, 29.3% experienced leakage a few times a day and the amount of leakage was generally (59.7%) moderate. Factors significantly associated with urinary incontinence included age group, gestational age, parity, previous urinary incontinence, constipation, mode of delivery at last childbirth, previous urinary tract infection, body mass index during pregnancy. But on multivariable analysis, the risk factors for urinary incontinence during pregnancy were previous urinary tract infection (OR = 3.8, 95%CI 1.5-9.3), constipation (OR 3.1, 95%CI 1.7-5.6) and gestational age (OR 0.5, 95%CI 0.3-0.9). CONCLUSION: As a result of this study, urinary incontinence is a common condition during pregnancy. Results would help the design of more intensive training programs to prevent incontinence during pregnancy by increasing the awareness about urinary incontinence of healthcare staff engaging in the care of pregnant women. PMID- 28675637 TI - Nanostructured Mineral Coatings Stabilize Proteins for Therapeutic Delivery. AB - Proteins tend to lose their biological activity due to their fragile structural conformation during formulation, storage, and delivery. Thus, the inability to stabilize proteins in controlled-release systems represents a major obstacle in drug delivery. Here, a bone mineral inspired protein stabilization strategy is presented, which uses nanostructured mineral coatings on medical devices. Proteins bound within the nanostructured coatings demonstrate enhanced stability against extreme external stressors, including organic solvents, proteases, and ethylene oxide gas sterilization. The protein stabilization effect is attributed to the maintenance of protein conformational structure, which is closely related to the nanoscale feature sizes of the mineral coatings. Basic fibroblast growth factor (bFGF) released from a nanostructured mineral coating maintains its biological activity for weeks during release, while it maintains activity for less than 7 d during release from commonly used polymeric microspheres. Delivery of the growth factors bFGF and vascular endothelial growth factor using a mineral coated surgical suture significantly improves functional Achilles tendon healing in a rabbit model, resulting in increased vascularization, more mature collagen fiber organization, and a two fold improvement in mechanical properties. The findings of this study demonstrate that biomimetic interactions between proteins and nanostructured minerals provide a new, broadly applicable mechanism to stabilize proteins in the context of drug delivery and regenerative medicine. PMID- 28675638 TI - Azacitidine successfully maintained the second remission in an infant with KMT2A rearranged acute lymphoblastic leukemia who relapsed after unrelated cord blood transplantation. AB - The outcome for infants with KMT2A (MLL)-rearranged acute lymphoblastic leukemia (MLL-r ALL) is dismal despite intensive therapy, including hematopoietic stem cell transplantation (HSCT). Epigenetic dysregulation is considered a key driver of MLL-r leukemogenesis, which theoretically supports the use of epigenetic modifiers as a treatment option. We report an infant MLL-r ALL case with post HSCT relapse. After achieving a second remission, which was maintained for 10 months using only the DNA methyltransferase inhibitor, azacitidine, the patient successfully received the second HSCT. This report describes the clinical effectiveness of azacitidine for the treatment of infant MLL-r ALL. PMID- 28675639 TI - Prevalence and associations of psychological distress in Australian junior medical officers. AB - BACKGROUND/AIMS: To determine the prevalence of psychological distress in Australian junior medical officers (JMO) and investigate the determinants associated with psychological distress over a 3-year (2014-2016) period. METHODS: JMO were surveyed using the 2014-2016 JMO Census (n = 220, 399 and 466 each year; response rate approximately 15%). Levels of psychological distress were assessed using the Kessler Psychological Distress Scale (K10). A K10 >= 25 was chosen to indicate high psychological distress, and this determinant was compared to various demographic and work-related factors. RESULTS: Australian JMO experience a high level of psychological distress (mean: 18.1, median 16.0). There were no differences in demographical variables, such as age, gender, marital status, dependants and between postgraduate years 1 and 2. Increasing hours worked per week was associated with a higher K10, with every hour worked increasing odds by 3%. Attitudinal items, including feeling unwilling to study medicine again, feeling poorly trained and experiences of bullying, were related to high psychological distress. Coping strategies like exercise and spending time with friends correlated positively with lower distress, while time off work, frequent alcohol use, smoking and drug use were associated with increased distress levels. Of those with a high K10, 54.5% indicated that they did not use any form of professional support; 17.83% expressed that given their time again, they would not choose to study medicine. CONCLUSION: A focused approach to JMO support and education regarding significant risk factors identified is likely to assist health policies that aim to improve the mental well-being of Australian JMO. PMID- 28675640 TI - Characterization of serum proteins attached to distinct sol-gel hybrid surfaces. AB - The success of a dental implant depends on its osseointegration, an important feature of the implant biocompatibility. In this study, two distinct sol-gel hybrid coating formulations [50% methyltrimethoxysilane: 50% 3-glycidoxypropyl trimethoxysilane (50M50G) and 70% methyltrimethoxysilane with 30% tetraethyl orthosilicate (70M30T)] were applied onto titanium implants. To evaluate their osseointegration, in vitro and in vivo assays were performed. Cell proliferation and differentiation in vitro did not show any differences between the coatings. However, four and eight weeks after in vivo implantation, the fibrous capsule area surrounding 50M50G-implant was 10 and 4 times, respectively, bigger than the area of connective tissue surrounding the 70M30T treated implant. Thus, the in vitro results gave no prediction or explanation for the 50M50G-implant failure in vivo. We hypothesized that the first protein layer adhered to the surface may have direct implication in implant osseointegration, and perhaps correlate with the in vivo outcome. Human serum was used for adsorption analysis on the biomaterials, the first layer of serum proteins adhered to the implant surface was analyzed by proteomic analysis, using mass spectrometry (LC-MS/MS). From the 171 proteins identified; 30 proteins were significantly enriched on the 50M50G implant surface. This group comprised numerous proteins of the immune complement system, including several subcomponents of the C1 complement, complement factor H, C4b-binding protein alpha chain, complement C5 and C-reactive protein. This result suggests that these proteins enriched in 50M50G surface might trigger the cascade leading to the formation of the fibrous capsule observed. The implications of these results could open up future possibilities to predict the biocompatibility problems in vivo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1477-1485, 2018. PMID- 28675641 TI - Cu-catalyzed Cascade Cyclization of Isothiocyanates, Alkynes, and Diaryliodonium Salts: Access to Diversely Functionalized Quinolines. AB - Herein, we report a copper-catalyzed novel, highly efficient, and modular cascade annulation reaction for the synthesis of quinoline derivatives starting from easily available alkynes, isothiocyanates, and diaryliodonium salts. The reaction displayed excellent regioselectivities, when unsymmetrical alkynes were employed as partners, giving access to diversely functionalized quinolines in good to excellent yields for a wide range of functional groups. PMID- 28675642 TI - Phosphorylated ribosomal protein S6 correlation with p21 expression and inverse association with tumor size in oral squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to investigate the clinical relevance of phosphorylated ribosomal protein S6 (p-S6), a surrogate marker of mammalian target of rapamycin (mTOR) activation, and p21 in a series of 125 patients with oral squamous cell carcinomas (OSCCs). METHODS: Immunohistochemical analysis was performed to ascertain the phosphorylation status of p-S6 at Ser235/236 and Ser240/244, p21, and p53 protein expression. RESULTS: Expression of phosphorylated S6 protein on either serine 235/236 or serine 240/244 was detected in 83% and 88% tumors, respectively, and both of them were inversely and significantly correlated with the tumor size and local infiltration. Positive p21 expression was found in 91.5% of the cases, and was inversely correlated with tumor size. In OSCC, p21 expression correlates with p-S6 levels, a surrogate marker of mTOR activation, independently of p53 status. CONCLUSION: Expression of both p21 and p-S6 was found to inversely associate with tumor size but not survival outcomes in patients with OSCC. PMID- 28675643 TI - Separation and identification of lipids in the photosynthetic cousins of Apicomplexa Chromera velia and Vitrella brassicaformis. AB - The alveolate algae Chromera velia and Vitrella brassicaformis (chromerids) are the closest known phototrophic relatives to apicomplexan parasites. Apicomplexans are responsible for fatal diseases of humans and animals and severe economic losses. Availability of the genome sequences of chromerids together with easy and rapid culturing of C. velia makes this alga a suitable model for investigating elementary biochemical principals potentially important for the apicomplexan pathogenicity. Such knowledge allows us to better understand processes during the evolutionary transition from a phototrophy to the parasitism in Apicomplexa. We explored lipidomes of both algae using high-performance liquid chromatography with mass spectrometry or gas chromatography with flame ionization detection. A single high-performance liquid chromatography with mass spectrometry analysis in both ionization modes was sufficient for the separation and semi-quantification of lipids in chromerid algae. We detected more than 250 analytes belonging to five structural lipid classes, two lipid classes of precursors and intermediates, and triacylglycerols as storage lipids. Identification of suggested structures was confirmed by high-resolution mass spectrometry with an Orbitrap mass analyzer. An outstandingly high accumulation of storage triacylglycerols was found in both species. All the investigated aspects make C. velia a prospective organism for further applications in biotechnology. PMID- 28675644 TI - Characterization of controlled cortical impact devices by high-speed image analysis. AB - As a consequence of their commercial availability, ease of use, and reproducibility, controlled cortical impact (CCI) devices have attained significant prevalence in preclinical traumatic brain injury research. With a CCI, the severity of injury is controlled by varying the impact depth, velocity, and duration, but the actual performance of the device is not well appreciated, partly because of the velocity and short travel distance to impact. This study used a high-speed video digital camera to investigate the performance of five electromagnetically driven CCI devices of the same model. Videography indicated that the impactor tip made a series of distinctive vertical advances and retractions before it attained the desired preset depth; this was also observed in male mouse CCI tests. The impactor tip was also observed to move in the horizontal direction by .8-1.6 mm. On the first advance, the tip extended a distance that was shorter than the preset depth and the velocity of impactor tip was slightly faster than the preset values for three of the five machines. One of the devices was evaluated on four separate occasions over a 14-month period and was found to operate consistently over time. Overall, differences in impact depth and velocity between the devices were modest, suggesting that comparisons of experimental results from different laboratories will generally be informative, particularly if reports provide relevant descriptions of neuropathology. However, the repetitive extension and retraction and horizontal movement of the tip suggests caution in modeling CCI as a single injurious event. PMID- 28675645 TI - Adult Onset Nocturnal Enuresis: Identifying Causes, Cofactors and Impact on Quality of Life. AB - OBJECTIVES: The objectives of the present study were: (i) Evaluate common co pathologies associated with, and potentially contributing to adult onset Nocturnal enuresis (NE) in a tertiary referral population; and (ii) quantify its impact on QoL with validated questionnaires. METHODS: Following Institutional Review Board approval, patients with adult onset NE were reviewed with history, physical examination, urodynamic studies, questionnaires: Overactive bladder questionnaire short-form (OAB-qSF), Urogenital Distress Inventory (UDI-6), AUA symptom score (AUA-SS) and Patient Global Impression scale (PGIS). RESULTS: Between 2004 and 2016, 45 NE patients (19 male, 26 female) were identified. Twenty-five patients (56%) had an associated diagnosis of neurogenic bladder (NGB). Five (11%) reported no other LUTS or associated conditions. Forty (89%) had at least one of the following contributing factors: sedative use, OAB (bothersome symptoms based on UDI-6), voiding dysfunction (also based on UDI-6 or AUA-SS), abnormal UDS finding, and/or confirmed obstructive sleep apnea (OSA). Overall, 20% had two contributing factors, and 31% each had three and four factors. Among all patients, 76% reported sedative use and of 36 patients with UDS, 75% had abnormal findings. Of the 41 questionnaire respondents, mean AUA-SS among men was 22.5 (range 8-35) and mean UDI-6 score among women was 9.3 (range 2 16). Mean PGI-S score was 3.1 (range 1-4) and mean Health Related Quality of Life (HRQL) subscale, as part of the OAB-q SF was 44 (range 22-78). CONCLUSIONS: Nocturnal enuresis is associated with multiple possible co-factors in all populations with majority reporting use of sedating medications. NE is associated with significant symptom bother and impacts greatly on QoL. PMID- 28675646 TI - The Burden of the "False-Negatives" in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures. AB - The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures. PMID- 28675647 TI - Environmental filtering is the main assembly rule of ground beetles in the forest and its edge but not in the adjacent grassland. AB - In a fragmented landscape, transitional zones between neighboring habitats are common, and our understanding of community organizational forces across such habitats is important. Edge studies are numerous, but the majority of them utilize information on species richness and abundance. Abundance and taxonomic diversity, however, provide little information on the functioning and phylogeny of the co-existing species. Combining the evaluation of their functional and phylogenetic relationships, we aimed to assess whether ground beetle assemblages are deterministically or stochastically structured along grassland-forest gradients. Our results showed different community assembly rules on opposite sides of the forest edge. In the grassland, co-occurring species were functionally and phylogenetically not different from the random null model, indicating a random assembly process. Contrary to this, at the forest edge and the interior, co-occurring species showed functional and phylogenetic clustering, thus environmental filtering was the likely process structuring carabid assemblages. Community assembly in the grassland was considerably affected by asymmetrical species flows (spillover) across the forest edge: more forest species penetrated into the grassland than open-habitat and generalist species entered into the forest. This asymmetrical species flow underlines the importance of the filter function of forest edges. As unfavorable, human-induced changes to the structure, composition and characteristics of forest edges may alter their filter function, edges have to be specifically considered during conservation management. PMID- 28675648 TI - Boronic Acid Functionalized Photosensitizers: A Strategy To Target the Surface of Bacteria and Implement Active Agents in Polymer Coatings. AB - Advanced methods for preventing and controlling hospital-acquired infections via eradication of free-floating bacteria and bacterial biofilms are of great interest. In this regard, the attractiveness of unconventional treatment modalities such as antimicrobial photodynamic therapy (aPDT) continues to grow. This study investigated a new and innovative strategy for targeting polysaccharides found on the bacterial cell envelope and the biofilm matrix using the boronic acid functionalized and highly effective photosensitizer (PS) silicon(IV) phthalocyanine. This strategy has been found to be successful in treating planktonic cultures and biofilms of Gram-negative E. coli. An additional advantage of boronic acid functionality is a possibility to anchor the tailor made PS to poly(vinyl alcohol) and to fabricate a self-disinfecting coating. PMID- 28675649 TI - Reticulocyte count and extended reticulocyte parameters by Mindray BC-6800: Reference intervals and comparison with Sysmex XE-5000. AB - INTRODUCTION: In this study, analytic performance (imprecision, carryover, time stability) and diagnostic efficiency of Mindray BC-6800 analyzer to quantify reticulocytes and extended reticulocyte parameters was evaluated. Moreover, reference intervals on adult population were determined. Results were compared with those obtained by Sysmex XE-5000 analyzer. METHODS: One hundred and eighty four healthy adults of both sexes, and 368 subjects affected by various pathologic conditions (nutritional anemias before and after treatment, hemolytic and posthemorragic anemias, acute and chronic inflammations, malignancy under therapy, and beta thalassemia trait) were selected. RESULTS: Reference intervals were as follows: reticulocytes (*109 /L): 23.2-93.2; immature reticulocyte fraction: 0.015-0.14; mean reticulocyte hemoglobin equivalent (RHE) (pg): 30.9 35.7; mean reticulocyte volume (fL): 97.8-118. Imprecision on reticulocyte count at all concentrations was close to analytic goal based on within-subject biological variation. Carryover (2.3%) was negligible, and time-stability was excellent up to 8 hours. CONCLUSION: When compared with XE-5000, BC-6800 shows a good overall correlation on counting despite evidence of difference in the upper limit of reference intervals (93.2 vs 101.3). Comparison of diagnostic efficiency of extended parameters shows a good total agreement of RHE (91.6%). PMID- 28675650 TI - Fabrication of Mesoporous-Silica-Coated Upconverting Nanoparticles with Ultrafast Photosensitizer Loading and 808 nm NIR-Light-Triggering Capability for Photodynamic Therapy. AB - A novel photodynamic therapy nanoplatform based on mesoporous-silica-coated upconverting nanoparticles (UCNP) with electrostatic-driven ultrafast photosensitizer (PS) loading and 808 nm near infrared (NIR)-light-triggering capabilities has been fabricated. By positively charging inner channels of the mesoporous silica shell with amino groups, a quantitative dosage of negatively charged PS, exemplified with Rose Bengal (RB) molecules, can be loaded in 2 min. In addition, the electrostatic-driven technique simultaneously provides the platform with both excellent PS dispersity and leak-proof properties due to the repulsion between the same-charged molecules and the electrostatic attraction between different-charged PS and silica channel walls, respectively. The as coated silica shell with an ultrathin thickness of 12+/-2 nm is delicately fabricated to facilitate ultrafast PS loading and efficient energy transfer from UCNP to PS. The outside surface of the silica shell is capped with hydrophilic beta-cyclodextrin, which not only enhances the dispersion of resulting nanoparticles in water but also plays a role of "gatekeeper", blocking the pore opening and preventing PS leaking. The in vitro cellular lethality experiment demonstrates that RB molecules can be activated to effectively generate singlet oxygen and kill cancer cells upon 808 nm NIR light irradiation. PMID- 28675651 TI - Finding genes and lineages under selection in speciation. AB - What are the genes and traits that respond to selection and cause prezygotic reproductive isolation between species? This question has been hard to answer because genomes are large, the targets of selection may be scattered across the genome (Sabeti et al., ) and different genes may respond to the same selective pressure in different populations (Scheinfeldt et al., ). In this issue of Molecular Ecology, Weber et al. () use a clever comparative approach and leading edge transcriptomic methods to identify the species and genes under positive selection for divergence between brittle stars (the echinoderm class Ophiuroidea) in the Ophioderma longicauda species complex. They found convincing evidence of positive or diversifying selection acting on two genes encoding ion channels that form part of the signal transduction cascade within the sperm in response to pheromones. Evidence for selection was concentrated in genes from one species (called C5, with internal fertilization and female parental care of brooded juveniles and not in the other species (called C3, with more conventional broadcast spawning and planktonic development of embryos and larvae). That analysis greatly extends the range of taxa, life history traits and molecules that are associated with positive selection in speciation. It also illustrates some of the current limitations on the application of RNAseq methods in the search for the targets of selection in nonmodel organisms like brittle stars. From both points of view, the new work by Weber et al. () has important implications for our understanding of speciation in the ocean. PMID- 28675652 TI - Adaptive maintenance of European alleles in the Brazilian Africanized honeybee. AB - The Anthropocene is an epoch hallmarked by intensified human intrusion across ecosystems. One such intrusion is the movement and re-introduction of long separated populations. By facilitating introgression - intraspecific genetic admixture - secondary contact can facilitate range expansion and the establishment of invasive species. The proximate mechanisms through which introgression facilitates expansion are rarely known (Bock et al., ; Rius & Darling, ), but managed species provide a useful avenue for exploration. Bee keepers have been interbreeding highly diverged honeybee clades for centuries, often to introduce "useful" phenotypic variation to their stocks. Across the Western honeybee's (Apis mellifera) European range, this practice has not resulted in range expansion (Moritz, Hartel, & Neumann, ). In the Americas, however, introgression of European with African subspecies resulted in a widely publicized invasive population: The Africanized honeybee (AHB). In this issue of Molecular Ecology, Nelson, Wallberg, Simoes, Lawson, and Webster () have made the first step towards understanding how this invasive species successfully spread across the Americas. PMID- 28675653 TI - CORRIGENDUM. PMID- 28675655 TI - Current Status and Open Issues Concerning Global Clinical Trials (GCTs) in Japan and East Asia. AB - When global clinical trials are carried out, it is important to consider the influence of racial and ethnic differences on the outcome. From this viewpoint, global clinical trials in East Asia, where racial differences are estimated to be small, are now attracting close attention. Under such circumstances, we conducted a survey using the data registered with ClinicalTrial.gov to investigate the status of participation of East Asian countries in global clinical trials and differences in the regions selected for drug development between Japanese enterprises and non-Japanese enterprises. This survey revealed that about 90% of all global clinical trials and those involving East Asian countries were sponsored by non-Japanese enterprises. Global clinical trials involving only East Asia have been accepted as one of the development strategies by Japanese enterprises, but this strategy has not spread widely among non-Japanese enterprises. PMID- 28675656 TI - Direct Creation of Highly Conductive Laser-Induced Graphene Nanocomposites from Polymer Blends. AB - The current state-of-the-art mixing strategies of nanoparticles with insulating polymeric components have only partially utilized the unique electrical conductivity of graphene in nanocomposite systems. Herein, this paper reports a nonmixing method of direct creation of polymer/graphene nanocomposites from polymer blends via laser irradiation. Polycarbonate-laser-induced graphene (PC LIG) nanocomposite is produced from a PC/polyetherimide (PC/PEI) blend after exposure to commercially available laser scribing with a power of ~6 W and a speed of ~2 cm s-1 . Extremely high electrical conductivities are obtained for the PC-LIG nanocomposites, ranging from 26 to 400 S m-1 , depending on the vol% of the starting PEI phase in the blend. To the authors' knowledge, these conductivity values are at least one order of magnitude higher than the values that are previously reported for conductive polymer/graphene nanocomposites prepared via mixing strategies. The comprehensive microscopy and spectroscopy characterizations reveal a complete graphitization of the PEI phase with columnar microstructure embedded in the PC phase. PMID- 28675657 TI - Impact of anesthesiologists on parental perioperative satisfaction scores. AB - BACKGROUND: While the focus on patient experience as an important outcome has significantly increased over the past decade, there is paucity of data on predictive factors associated with parental recommendation of a surgical facility to friends and family. METHODS: Data for this report were obtained from a Hospital Information System and Picker Health validated surveys completed by 538 parents whose children underwent outpatient surgery from July 2014 to March 2016. Bivariate, chi-squared, and multivariate logistic regression analysis were carried out using the Picker Health item "Would you recommend this outpatient surgical facility to your friends and family?" as the primary outcome. Demographic data and 53 Picker Health items were used as potential predictors. RESULTS: Multivariate logistic regression analysis found the following variables as independent predictors for parental recommendation: quality of perioperative communication by anesthesiologists (odds ratio [95% confidence interval]=0.23 [0.09, 0.58]); provision of information on whom to call for help after discharge (0.22 [0.07, 0.64]); child's perceived baseline health (0.37 [0.15, 0.90]); and ill-informed staff about child's procedure (0.30 [0.21, 0.79]). Variables such as child's pain and child's nausea and vomiting were not predictive for referral pattern. CONCLUSION: Parental recommendation of a surgical facility to friends and family depends on a number of variables with the quality of perioperative communication with the anesthesiologist being the most predictive item. PMID- 28675654 TI - Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC. PMID- 28675658 TI - Spectroscopic Study of the Interaction between Horse Heart Myoglobin and Zirconium(IV)-Substituted Polyoxometalates as Artificial Proteases. AB - A recent study [Angew. Chem. Int. Ed. 2015, 54, 7391-7394] has shown that horse heart myoglobin (HHM) is selectively hydrolyzed by a range of zirconium(IV) substituted polyoxometalates (POMs) under mild conditions. In this study, the molecular interactions between the Zr-POM catalysts and HHM are investigated by using a range of complementary techniques, including circular dichroism (CD), UV/Vis spectroscopy, tryptophan fluorescence spectroscopy, and 1 H and 31 P NMR spectroscopy. A tryptophan fluorescence quenching study reveals that, among all examined Zr-POMs, the most reactive POM, 2:2 ZrIV -Keggin, exhibits the strongest interaction with HHM. 31 P NMR spectroscopy studies show that this POM dissociates in solution, resulting in the formation of a monomeric 1:1 ZrIV Keggin structure, which is likely to be a catalytically active species. In the presence of ZrIV -POMs, HHM does not undergo complete denaturation, as evidenced by CD, UV/Vis, tryptophan fluorescence, and 1 H NMR spectroscopy. CD spectroscopy shows a gradual decrease in the alpha-helical content of HHM upon addition of ZrIV -POMs. The largest effect is observed in the presence of a large ZrIV -Wells Dawson structure, whereas small ZrIV -Lindqvist POM has the least influence on the decrease in the alpha-helical content of HHM. In all cases, the Soret band at lambda=409 nm is maintained in the presence of all examined Zr-POMs, which indicates that no conformational changes in the protein occur near the heme group. PMID- 28675659 TI - Characterization of a Deinococcus radiodurans MazF: A UACA-specific RNA endoribonuclease. AB - Microbes are known to withstand environmental stresses by using chromosomal toxin antitoxin systems. MazEF is one of the most extensively studied toxin-antitoxin systems. In stressful environments, MazF toxins modulate translation by cleaving single-stranded RNAs in a sequence-specific fashion. Previously, a chromosomal gene located at DR0417 in Deinococcus radiodurans was predicted to code for a MazF endoribonuclease (MazFDR0417 ); however, its function remains unclear. In the present study, we characterized the molecular function of MazFDR0417 . Analysis of MazFDR0417 -cleaved RNA sites using modified massively parallel sequencing revealed a unique 4-nt motif, UACA, as a potential cleavage pattern. The activity of MazFDR0417 was also assessed in a real-time fluorometric assay, which revealed that MazFDR0417 strictly recognizes the unique tetrad UACA. This sequence specificity may allow D. radiodurans to alter its translation profile and survive under stressful conditions. PMID- 28675660 TI - Meta-analysis of first-line therapies with maintenance regimens for advanced non small-cell lung cancer (NSCLC) in molecularly and clinically selected populations. AB - Evidence has suggested survival benefits of maintenance for advanced NSCLC patients not progressing after first-line chemotherapy. Additionally, particular first-line targeted therapies have shown survival improvements in selected populations. Optimal first-line and maintenance therapies remain unclear. Here, currently available evidence was synthesized to elucidate optimal first-line and maintenance therapy within patient groups. Literature was searched for randomized trials evaluating first-line and maintenance regimens in advanced NSCLC patients. Bayesian network meta-analysis was performed within molecularly and clinically selected groups. The primary outcome was combined clinically meaningful OS and PFS benefits. A total of 87 records on 56 trials evaluating first-line treatments with maintenance were included. Results showed combined clinically meaningful OS and PFS benefits with particular first-line with maintenance treatments, (1) first-line intercalated chemotherapy+erlotinib, maintenance erlotinib in patients with EGFR mutations, (2) first-line afatinib, maintenance afatinib in patients with EGFR deletion 19, (3) first-line chemotherapy + bevacizumab, maintenance bevacizumab in EGFR wild-type patients, (4) chemotherapy+conatumumab, maintenance conatumumab in patients with squamous histology, (5) chemotherapy+cetuximab, maintenance cetuximab or chemotherapy + necitumumab, maintenance necitumumab in EGFR FISH-positive patients with squamous histology, and (6) first-line chemotherapy+bevacizumab, maintenance bevacizumab or first-line sequential chemotherapy+gefitinib, maintenance gefitinib in patients clinically enriched for EGFR mutations with nonsquamous histology. No treatment showed combined clinically meaningful OS and PFS benefits in patients with EGFR L858R or nonsquamous histology. Particular first-line with maintenance treatments show meaningful OS and PFS benefits in patients selected by EGFR mutation or histology. Further research is needed to achieve effective therapy for patients with EGFR mutation L858R or nonsquamous histology. PMID- 28675661 TI - Intensive Short-Term Dynamic Psychotherapy for generalized anxiety disorder: A pilot effectiveness and process-outcome study. AB - The objective of this study was to evaluate the clinical- and cost-effectiveness of Intensive Short-Term Dynamic Psychotherapy (ISTDP) for generalized anxiety disorder (GAD). We further aimed to examine if a key clinical process within the ISTDP framework, termed the level of mobilization of unprocessed complex emotions (MUCE), was related to outcome. The sample consisted of 215 adult patients (60.9% female) with GAD and comorbid conditions treated in a tertiary mental health outpatient setting. The patients were provided an average of 8.3 sessions of ISTDP delivered by 38 therapists. The level of MUCE in treatment was assessed from videotaped sessions by a rater blind to treatment outcome. Year-by-year healthcare costs were derived independently from government databases. Multilevel growth models indicated significant decreases in psychiatric symptoms and interpersonal problems during treatment. These gains were corroborated by reductions in healthcare costs that continued for 4 years post-treatment reaching normal population means. Further, we found that the in-treatment level of MUCE was associated with larger treatment effects, underlining the significance of emotional experiencing and processing in the treatment of GAD. We conclude that ISTDP appears to reduce symptoms and costs associated with GAD and that the ISTDP framework may be useful for understanding key therapeutic processes in this challenging clinical population. Controlled studies of ISTDP for GAD are warranted. PMID- 28675662 TI - Separate and coincident expression of Hes1 and Hes5 in the developing mouse eye. AB - BACKGROUND: Notch signaling is broadly required during embryogenesis, frequently activating the transcription of two basic helix-loop-helix transcription factors, Hes1 and Hes5. But, it remains unresolved when and where Hes1 and Hes5 act alone or together during development. Here, we analyzed a Hes5-green fluorescent protein (GFP) bacterial artificial chromosome (BAC) transgenic mouse, as a proxy for endogenous Hes5. We directly compared transgenic GFP expression with Hes1, and particular markers of embryonic lens and retina development. RESULTS: Hes5 GFP is dynamic within subsets of retinal and lens progenitor cells, and differentiating retinal ganglion neurons, in contrast to Hes1 found in all progenitor cells. In the adult retina, only Muller glia express Hes5-GFP. Finally, Hes5-GFP is up-regulated in Hes1 germline mutants, consistent with previous demonstration that Hes1 suppresses Hes5 transcription. CONCLUSIONS: Hes5 GFP BAC transgenic mice are useful for identifying Hes5-expressing cells. Although Hes5-GFP and Hes1 are coexpressed in particular developmental contexts, we also noted cohorts of lens or retinal cells expressing just one factor. The dynamic Hes5-GFP expression pattern, coupled with its derepressed expression in Hes1 mutants, suggests that this transgene contains the relevant cis-regulatory elements that regulate endogenous Hes5 in the mouse lens and retina. Developmental Dynamics 247:212-221, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28675663 TI - Postural Control in Children with Dyslexia: Effects of Emotional Stimuli in a Dual-Task Environment. AB - The aim of this study was to compare the visual exploration strategies used during a postural control task across participants with and without dyslexia. We simultaneously recorded eye movements and postural control while children were viewing different types of emotional faces. Twenty-two children with dyslexia and twenty-two aged-matched children without dyslexia participated in the study. We analysed the surface area, the length and the mean velocity of the centre of pressure for balance in parallel with visual saccadic latency, the number of saccades and the time spent in regions of interest. Our results showed that postural stability in children with dyslexia was weaker and the surface area of their centre of pressure increased significantly when they viewed an unpleasant face. Moreover, children with dyslexia had different strategies to those used by children without dyslexia during visual exploration, and in particular when they viewed unpleasant emotional faces. We suggest that lower performance in emotional face processing in children with dyslexia could be due to a difference in their visual strategies, linked to their identification of unpleasant emotional faces. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28675665 TI - Effects of different rehabilitation models on erythrocyte deformability and nitrite plus nitrate as end-products of nitric oxide levels in elderly women. AB - AIM: The aim of the present study was to analyze the effects of two rehabilitation protocols, dance movement therapy exercises (DMT) and general rehabilitation exercises (GRE), on erythrocyte deformability and plasma levels of nitrite plus nitrate as end products of nitric oxide (NOx) in elderly women. METHODS: The study included 39 women aged 61-82 years, subjected to either GRE (n = 20) or DMT (n = 19). Women were subjected to 5-months programs of GRE and DMT, with each session lasting no longer than 45-50 min, and the intensity of exercising corresponding to no more than 40-60% of heart rate reserve. Plasma levels of NOx were determined spectrophotometrically before and at the end of the intervention. RESULTS: A significant increase in the total nitrate/nitrite concentration from 1.341 MUmol/L to 1.590 MUmol/L (7.3%) was observed in women subjected to the DMT rehabilitation program. Furthermore, an increase in erythrocyte deformability was observed in this group at shear stress 0.30. No significant difference was found between the pre- and post-rehabilitation NOx levels of women participating in the GRE program. CONCLUSIONS: Participation in DMT rehabilitation program might be reflected by an increase in plasma NOx levels and an improvement of erythrocyte deformability at lesser shear stress, and thus could potentially result in better vascular function. DMT should be offered to older adults, especially to persons who do not find conventional forms of rehabilitation as attractive, as they might refrain from physical activity and suffer from a faster decline in nitric oxide production. Geriatr Gerontol Int 2017; 17: 2479-2484. PMID- 28675664 TI - Obestatin controls the ubiquitin-proteasome and autophagy-lysosome systems in glucocorticoid-induced muscle cell atrophy. AB - BACKGROUND: Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid-induced and wasting disorder-related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid induced muscle cell atrophy. METHODS: In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes. RESULTS: The activation of the obestatin/GPR39 system protects from glucocorticoid-induced atrophy by regulation of Akt, PKD/PKCMU, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin-proteasome system and autophagy-lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post-translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes. CONCLUSIONS: Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions. PMID- 28675666 TI - Characterization of poly(L-glutamic acid)-grafted hyaluronan as a novel candidate medicine and biomedical device for intra-articular injection. AB - A novel hyaluronan (HA) derivative, poly(L-glutamic acid)-grafted hyaluronan (PGA g-HA), was synthesized to improve the durability of conventional HA products for intra-articular injection. The purpose of this study was to investigate the characteristics of the novel HA derivative in terms of viscoelasticity, degradation behavior, non-immunogenicity, and bioactivity using preliminary in vitro and in vivo experiments. The storage modulus (G') and loss modulus (G") of PGA-g-HA were similar to those of HA80 (approximately 8.0 * 105 Da) rather than those of original HA200 (approximately 2.0 * 106 Da). PGA-g-HA showed strong resistance against hyaluronidase hydrolysis compared to unmodified HA200. The immunogenicity resulting from grafting PGA to HA200 was not detected in bone marrow derived dendritic cells. The anti-inflammatory activity of PGA-g-HA was confirmed in IL-1beta-stimulated chondrocytes. In addition, compared to unmodified HA200, the intra-articular injection of PGA-g-HA produced greater chondroprotective effects on a monoiodoacetic acid-induced model of rat knee osteoarthritis at two weeks after a single treatment. Therefore, PGA-g-HA is expected to be a promising medicine and biomedical device for intra-articular injection. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3006 3016, 2017. PMID- 28675667 TI - Towards a global bioeconomy - what is our role? PMID- 28675668 TI - Editorial: The European Symposium on Biochemical Engineering Sciences, Dublin 2016. AB - The European Symposium on Biochemical Engineering Sciences, Dublin 2016. PMID- 28675669 TI - Two-year audit of outcomes of pituitary surgery at an Australian teaching hospital. AB - BACKGROUND: There is evidence that cure rates and complications are influenced by the caseload in neurosurgical centres performing transsphenoidal pituitary surgery. Although Australian centres may perform relatively small numbers of these procedures, there have been few published audits of their performance. AIMS: To conduct an audit of surgery for pituitary tumours between 2012 and 2014 in the only public hospital neurosurgical unit in the state of Western Australia. METHODS: A retrospective chart review was conducted, with standardised extraction of data relating to indications for surgery, tumour type, procedure and postoperative endocrinological and other outcomes. RESULTS: Of 53 patients identified, most (91%) underwent transsphenoidal surgery. Most tumours were non functioning (71.7%), and most of these extended outside the sella turcica (86.8 vs 73.3% of functioning tumours). There was complete removal in 43.4% of patients and evidence of biochemical cure in 33.3% of functioning tumours, but readmission for further surgery was infrequent (5.7%). Persistent cerebrospinal fluid leakage, photophobia and deep venous thrombosis occurred in <4% of patients. There were no deaths. There was a relatively high rate of permanent diabetes insipidus (DI) (13.2 vs <5% in published series), while the frequency of new postoperative anterior pituitary dysfunction (9.4%) was within the range reported in the literature (3-14%). CONCLUSION: The outcomes of pituitary surgery in this audit were largely comparable to those reported from other neurosurgical units in Australia and other countries. The increased risk of permanent postoperative DI may reflect the high proportion of non-functioning tumours with extension outside the sella turcica. PMID- 28675670 TI - Predicting the abundance of forest types across the eastern United States through inverse modelling of tree demography. AB - Global environmental change is expected to induce widespread changes in the geographic distribution and biomass of forest communities. Impacts have been projected from both empirical (statistical) and mechanistic (physiology-based) modelling approaches, but there remains an important gap in accurately predicting abundance across species' ranges from spatial variation in individual-level demographic processes. We address this issue by using a cohort-based forest dynamics model (CAIN) to predict spatial variation in the abundance of six plant functional types (PFTs) across the eastern United States. The model simulates tree-level growth, mortality, and recruitment, which we parameterized from data on both individual-level demographic rates and population-level abundance using Bayesian inverse modelling. Across a set of 1 degrees grid cells, we calibrated local growth, mortality, and recruitment rates for each PFT to obtain a close match between predicted age-specific PFT basal area in forest stands and that observed in 46,603 Forest Inventory and Analysis plots. The resulting models produced a strong fit to PFT basal area across the region (R2 = 0.66-0.87), captured successional changes in PFT composition with stand age, and predicted the overall stem diameter distribution well. The mortality rates needed to accurately predict basal area were consistently higher than observed mortality, possibly because sampling effects led to biased individual-level mortality estimates across spatially heterogeneous plots. Growth and recruitment rates did not show consistent directional changes from observed values. Relative basal area was most strongly influenced by recruitment processes, but the effects of growth and mortality tended to increase as stands matured. Our study illustrates how both top-down (population-level) and bottom-up (individual-level) data can be combined to predict variation in abundance from size, environmental, and competitive effects on tree demography. Evidence for how demographic processes influence variation in abundance, as provided by our model, can help in understanding how these forests may respond to future environmental change. PMID- 28675671 TI - Accent detection and social cognition: evidence of protracted learning. AB - How and when do children become aware that speakers have different accents? While adults readily make a variety of subtle social inferences based on speakers' accents, findings from children are more mixed: while one line of research suggests that even infants may be acutely sensitive to accent unfamiliarity, other studies suggest that 5-year-olds have difficulty identifying accents as different from their own. In an attempt to resolve this paradox, the current study assesses American children's sensitivity to American vs. Dutch accents in two situations. First, in an eye-tracked sentence processing paradigm where children have previously shown sensitivity to a salient social distinction (gender) from voice cues, 3-5-year-old children showed no sensitivity to accent differences. Second, in a social decision-making task where accent sensitivity has been found in 5-year-olds, an age gradient appeared, suggesting that familiar accent preferences emerge slowly between 3 and 7 years. Counter to claims that accent is an early, salient signal of social group, results are more consistent with a protracted learning hypothesis that children need extended exposure to native-language sound patterns in order to detect that an accent deviates from their own. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=BQAgy3IFYXA. PMID- 28675672 TI - Multidate, multisensor remote sensing reveals high density of carbon-rich mountain peatlands in the paramo of Ecuador. AB - Tropical peatlands store a significant portion of the global soil carbon (C) pool. However, tropical mountain peatlands contain extensive peat soils that have yet to be mapped or included in global C estimates. This lack of data hinders our ability to inform policy and apply sustainable management practices to these peatlands that are experiencing unprecedented high rates of land use and land cover change. Rapid large-scale mapping activities are urgently needed to quantify tropical wetland extent and rate of degradation. We tested a combination of multidate, multisensor radar and optical imagery (Landsat TM/PALSAR/RADARSAT 1/TPI image stack) for detecting peatlands in a 2715 km2 area in the high elevation mountains of the Ecuadorian paramo. The map was combined with an extensive soil coring data set to produce the first estimate of regional peatland soil C storage in the paramo. Our map displayed a high coverage of peatlands (614 km2 ) containing an estimated 128.2 +/- 9.1 Tg of peatland belowground soil C within the mapping area. Scaling-up to the country level, paramo peatlands likely represent less than 1% of the total land area of Ecuador but could contain as much as ~23% of the above- and belowground vegetation C stocks in Ecuadorian forests. These mapping approaches provide an essential methodological improvement applicable to mountain peatlands across the globe, facilitating mapping efforts in support of effective policy and sustainable management, including national and global C accounting and C management efforts. PMID- 28675673 TI - Optimization of multiwalled carbon nanotubes reinforced hollow-fiber solid-liquid phase microextraction for the determination of polycyclic aromatic hydrocarbons in environmental water samples using experimental design. AB - A novel design of hollow-fiber liquid-phase microextraction containing multiwalled carbon nanotubes as a solid sorbent, which is immobilized in the pore and lumen of hollow fiber by the sol-gel technique, was developed for the pre concentration and determination of polycyclic aromatic hydrocarbons in environmental water samples. The proposed method utilized both solid- and liquid phase microextraction media. Parameters that affect the extraction of polycyclic aromatic hydrocarbons were optimized in two successive steps as follows. Firstly, a methodology based on a quarter factorial design was used to choose the significant variables. Then, these significant factors were optimized utilizing central composite design. Under the optimized condition (extraction time = 25 min, amount of multiwalled carbon nanotubes = 78 mg, sample volume = 8 mL, and desorption time = 5 min), the calibration curves showed high linearity (R2 = 0.99) in the range of 0.01-500 ng/mL and the limits of detection were in the range of 0.007-1.47 ng/mL. The obtained extraction recoveries for 10 ng/mL of polycyclic aromatic hydrocarbons standard solution were in the range of 85-92%. Replicating the experiment under these conditions five times gave relative standard deviations lower than 6%. Finally, the method was successfully applied for pre-concentration and determination of polycyclic aromatic hydrocarbons in environmental water samples. PMID- 28675674 TI - Polymers and Light. PMID- 28675675 TI - Flash Vacuum Pyrolysis: Techniques and Reactions. AB - Flash vacuum pyrolysis (FVP) had its beginnings in the 1940s and 1950s, mainly through mass spectrometric detection of pyrolytically formed free radicals. In the 1960s many organic chemists started performing FVP experiments with the purpose of isolating new and interesting compounds and understanding pyrolysis processes. Meanwhile, many different types of apparatus and techniques have been developed, and it is the purpose of this review to present the most important methods as well as a survey of typical reactions and observations that can be achieved with the various techniques. This includes preparative FVP, chemical trapping reactions, matrix isolation, and low temperature spectroscopy of reactive intermediates and unstable molecules, the use of online mass, photoelectron, microwave, and millimeterwave spectroscopies, gas-phase laser pyrolysis, pulsed pyrolysis with supersonic jet expansion, very low pressure pyrolysis for kinetic investigations, solution-spray and falling-solid FVP for involatile compounds, and pyrolysis over solid supports and reagents. Moreover, the combination of FVP with matrix isolation and photochemistry is a powerful tool for investigations of reaction mechanism. PMID- 28675677 TI - Warmer winters increase the rhizosphere carbon flow to mycorrhizal fungi more than to other microorganisms in a temperate grassland. AB - A decisive set of steps in the terrestrial carbon (C) cycle is the fixation of atmospheric C by plants and the subsequent C-transfer to rhizosphere microorganisms. With climate change winters are expected to become milder in temperate ecosystems. Although the rate and pathways of rhizosphere C input to soil could be impacted by milder winters, the responses remain unknown. To address this knowledge-gap, a winter-warming experiment was established in a seminatural temperate grassland to follow the C flow from atmosphere, via the plants, to different groups of soil microorganisms. In situ 13 CO2 pulse labelling was used to track C into signature fatty acids of microorganisms. The winter warming did not result in any changes in biomass of any of the groups of microorganisms. However, the C flow from plants to arbuscular mycorrhizal (AM) fungi, increased substantially by winter warming. Saprotrophic fungi also received large amounts of plant-derived C-indicating a higher importance for the turnover of rhizosphere C than biomass estimates would suggest-still, this C flow was unaffected by winter warming. AM fungi was the only microbial group positively affected by winter warming-the group with the closest connection to plants. Winter warming resulted in higher plant productivity earlier in the season, and this aboveground change likely induced plant nutrient limitation in warmed plots, thus stimulating the plant dependence on, and C allocation to, belowground nutrient acquisition. The preferential C allocation to AM fungi was at the expense of C flow to other microbial groups, which were unaffected by warming. Our findings imply that warmer winters may shift rhizosphere C-fluxes to become more AM fungal-dominated. Surprisingly, the stimulated rhizosphere C flow was matched by increased microbial turnover, leading to no accumulation of soil microbial biomass. PMID- 28675676 TI - Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants. AB - Early subclinical inflammation in kidney transplants is associated with later graft fibrosis and dysfunction. Regulatory T cells (Tregs) can reverse established inflammation in animal models. We conducted a pilot safety and feasibility trial of autologous Treg cell therapy in three kidney transplant recipients with subclinical inflammation noted on 6-month surveillance biopsies. Tregs were purified from peripheral blood and polyclonally expanded ex vivo using medium containing deuterated glucose to label the cells. All patients received a single infusion of ~320 * 106 (319, 321, and 363.8 * 106 ) expanded Tregs. Persistence of the infused Tregs was tracked. Graft inflammation was monitored with follow-up biopsies and urinary biomarkers. Nearly 1 * 109 (0.932, 0.956, 1.565 * 109 ) Tregs were successfully manufactured for each patient. There were no infusion reactions or serious therapy-related adverse events. The infused cells demonstrated patterns of persistence and stability similar to those observed in non-immunosuppressed subjects receiving the same dose of Tregs. Isolation and expansion of Tregs is feasible in kidney transplant patients on immunosuppression. Infusion of these cells was safe and well tolerated. Future trials will test the efficacy of polyclonal and donor alloantigen-reactive Tregs for the treatment of inflammation in kidney transplants. PMID- 28675678 TI - 3D bioprinting and the current applications in tissue engineering. AB - Bioprinting as an enabling technology for tissue engineering possesses the promises to fabricate highly mimicked tissue or organs with digital control. As one of the biofabrication approaches, bioprinting has the advantages of high throughput and precise control of both scaffold and cells. Therefore, this technology is not only ideal for translational medicine but also for basic research applications. Bioprinting has already been widely applied to construct functional tissues such as vasculature, muscle, cartilage, and bone. In this review, the authors introduce the most popular techniques currently applied in bioprinting, as well as the various bioprinting processes. In addition, the composition of bioink including scaffolds and cells are described. Furthermore, the most current applications in organ and tissue bioprinting are introduced. The authors also discuss the challenges we are currently facing and the great potential of bioprinting. This technology has the capacity not only in complex tissue structure fabrication based on the converted medical images, but also as an efficient tool for drug discovery and preclinical testing. One of the most promising future advances of bioprinting is to develop a standard medical device with the capacity of treating patients directly on the repairing site, which requires the development of automation and robotic technology, as well as our further understanding of biomaterials and stem cell biology to integrate various printing mechanisms for multi-phasic tissue engineering. PMID- 28675679 TI - Iron-Catalyzed Intramolecular Aminations of C(sp3 )-H Bonds in Alkylaryl Azides. AB - The nucleophilic iron complex Bu4 N[Fe(CO)3 (NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of unactivated C(sp3 )-H bonds in alkylaryl azides, which results in the formation of substituted indoline and tetrahydroquinoline derivatives. PMID- 28675680 TI - Electrocatalytic Water Oxidation Promoted by 3 D Nanoarchitectured Turbostratic delta-MnOx on Carbon Nanotubes. AB - The development of manganese-based water oxidation electrocatalysts is desirable for the production of solar fuels, as manganese is earth-abundant, inexpensive, non-toxic, and has been employed by the Photosystem II in nature for a billion years. Herein, we directly constructed a 3 D nanoarchitectured turbostratic delta MnOx on carbon nanotube-modified nickel foam (MnOx /CNT/NF) by electrodeposition and a subsequent annealing process. The MnOx /CNT/NF electrode gives a benchmark catalytic current density (10 mA cm-2 ) at an overpotential (eta) of 270 mV under alkaline conditions. A steady current density of 19 mA cm-2 is obtained during electrolysis at 1.53 V for 1.0 h. To the best of our knowledge, this work represents the most efficient manganese-oxide-based water oxidation electrode and demonstrates that manganese oxides, as a structural and functional model of oxygen-evolving complex (OEC) in Photosystem II, can also become comparable to those of most Ni- and Co-based catalysts. PMID- 28675681 TI - Reply: Letter to the Editor. PMID- 28675682 TI - Imaging and management of fetuses and neonates with alloimmune thrombocytopenia. AB - Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of severe neonatal thrombocytopenia and intracranial bleeding in term newborns. Intracranial hemorrhage (ICH) commonly results in death or severe, lasting neurologic disability. The timing of ICH is also important for management of the next affected pregnancy in cases of FNAIT. This manuscript reviews the advantages and disadvantages of the different radiologic methodologies to identify and characterize ICH. It discusses the limits of ultrasound and the advantages of magnetic resonance imaging allowing avoidance of the radiation associated with computed tomography (CT) scans. PMID- 28675683 TI - Pediatric cancer pathology review from a single institution: Neuropathology expert opinion is essential for accurate diagnosis of pediatric brain tumors. AB - BACKGROUND AND OBJECTIVES: Second pathology review has been reported to improve accuracy in oncologic diagnoses, including pediatric malignancies. We assessed the impact of second review on the diagnosis of pediatric malignancies at a tertiary care referral center in Beirut, Lebanon. METHODS: Pathology reports of patients treated at the Children's Cancer Institute in Lebanon were retrospectively reviewed for the period 2008-2016 and compared with same samples' diagnoses at St. Jude Children's Research Hospital. Diagnostic disagreements were divided into major, minor, and none based on their effect on diagnosis and/or patient management. RESULTS: Second review was requested for 171 cases, accounting for 19% of all cases during that period. Second opinion was mostly requested for brain tumors (62% of all brain tumor cases) and neuroblastoma for NMYC testing (65% of all neuroblastoma), while hematologic malignancies had the fewest referrals (3% of all hematologic cases). Major disagreements in second review occurred in 20 cases (12% of total), and minor disagreements in 21 cases (12% of total). The largest proportion of major disagreements (71%) occurred in pediatric brain tumors, and novel molecular tests contributed to the diagnosis in 55% of these cases. CONCLUSIONS: The availability of a specialized pediatric neuropathologist and a basic panel of relevant molecular testing are essential for appropriate diagnosis of pediatric brain tumors. Centers that do not have the available infrastructure in place can benefit greatly from second review referrals for this challenging subset of tumors. PMID- 28675684 TI - High-Performance Liquid Chromatography Method for Rich Pharmacokinetic Sampling Schemes in Translational Rat Toxicity Models With Vancomycin. AB - A translational need exists to understand and predict vancomycin-induced kidney toxicity. We describe: (i) a vancomycin high-performance liquid chromatography (HPLC) method for rat plasma and kidney tissue homogenate; (ii) a rat pharmacokinetic (PK) study to demonstrate utility; and (iii) a catheter retention study to enable future preclinical studies. Rat plasma and pup kidney tissue homogenate were analyzed via HPLC for vancomycin concentrations ranging from 3-75 and 15.1-75.5 MUg/mL, respectively, using a Kinetex Biphenyl column and gradient elution of water with 0.1% formic acid: acetonitrile (70:30 v/v). Sprague-Dawley rats (n = 10) receiving 150 mg/kg of vancomycin intraperitoneally had plasma sampled for PK. Finally, a catheter retention study was performed on polyurethane catheters to assess adsorption. Precision was <6.1% for all intra-assay and interassay HPLC measurements, with >96.3% analyte recovery. A two-compartment model fit the data well, facilitating PK exposure estimates. Finally, vancomycin was heterogeneously retained by polyurethane catheters. PMID- 28675685 TI - Challenges and difficulties in pathological diagnosis of autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) with acute presentation is widely recognized as a distinct clinical entity, and its clinicopathology has been extensively studied. In most cases, AIH with acute presentation is merely acute exacerbation of classical chronic AIH, but pure acute-onset AIH without previous symptoms of chronic liver disease is also encountered. Rapid diagnosis and initiation of immunosuppressive treatment are necessary for both acute exacerbation and acute onset to prevent fatal liver failure. The diagnostic criteria commonly used for classical AIH are generally applicable to acute exacerbation, but acute-onset AIH may present with additional pathological features. These features include an acute hepatitis phase characterized by centrilobular necrosis. However, centrilobular necrosis is also a feature of drug-induced liver injury, and there are no known histological characteristics exclusive to acute-onset AIH. Moreover, the possibilities of drug-induced AIH and immune-mediated drug-induced liver injury make diagnosis even more difficult. At present, liver biopsy is mandatory for the diagnosis of AIH with acute presentation, but careful consideration of all clinicopathological signs is necessary for differential diagnosis. PMID- 28675687 TI - Disruptive physiology: olfaction and the microbiome-gut-brain axis. AB - This review covers the field of olfaction and chemosensation of odorants and puts this information into the context of interactions between microbes and behaviour; the microbiome-gut-brain axis (MGBA). Recent emphasis has also been placed on the concept of the holobiome which states that no single aspect of an organism should be viewed separately and thus must include examination of their associated microbial populations and their influence. While it is known that the microbiome may be involved in the modulation of animal behaviour, there has been little systematized effort to incorporate into such studies the rapidly developing knowledge of the wide range of olfactory systems. The classical olfactory system is evolutionarily conserved in multiple taxa from insects through to fish, reptiles and mammals, and is represented by the largest gene families in vertebrates. Mice have over 1000 different olfactory receptors and humans about 400. They are distributed throughout the body and are even found in spermatozoa where they function in chemotaxis. Each olfactory receptor has the unique functional capability of high-affinity binding to several different molecular ligands. These and other properties render the cataloguing of odorants (odorome) with specific actions a difficult task. Some ectopic olfactory receptors have been shown to have functional effects in the gut and kidney, highlighting the complexity of the systems engaged by odorants. However, there are, in addition to classical olfactory receptors, at least two other families of receptors involved in olfaction that are also widely found expressed on tissues in many different organs in addition to the nervous system and brain: the trace-amine associated and formyl peptide receptors. Bacteria can make many if not most odorants and are responsible for recognition of species and relative relatedness, as well as predator presence, among many other examples. Activation of different combinations of olfactory receptors by bacterial products such as beta phenylethylamine have been shown even to control expression of emotions such as fear and aggression. The number of examples of bacterial products and volatile odorants influencing brain function and behaviour is expanding rapidly. Since it is recognized that many different bacterial products and metabolites also function as social cues, and may themselves be directly or indirectly causative of behavioural change, it becomes ever more important to include olfaction into studies of the MGBA. Clearly there are broader implications for the involvement of olfaction in this rapidly evolving field. These include improvement in our understanding of the pathways engaged in various behaviours, and the identification of novel approaches and new targets in efforts to modulate behavioural changes. PMID- 28675686 TI - The challenges of achieving postprandial glucose control using closed-loop systems in patients with type 1 diabetes. AB - For patients with type 1 diabetes, closed-loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared with conventional therapy. Yet, reducing glucose excursion and simplification of prandial insulin doses remain a challenge. The objective of this literature review is to examine current meal-time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post-meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with carbohydrate-matched bolus in the post-meal period. The latter strategy has been efficient in controlling post-meal glucose using different algorithms and in various settings, but at the cost of a meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal-priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and dynamic profiles of available rapid insulins as well as sensor accuracy and lag time. New and upcoming faster acting insulins could provide important benefits. Multi-hormone CLS (eg, dual-hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (eg, GLP-1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined. PMID- 28675688 TI - Whole mitochondrial genome capture from faecal samples and museum-preserved specimens. AB - Population-scale molecular studies of endangered and cryptic species are often limited by access to high-quality samples. The use of noninvasively collected samples or museum-preserved specimens reduces the pressure on modern populations by removing the need to capture and handle live animals. However, endogenous DNA content in such samples is low, making shotgun sequencing a financially prohibitive approach. Here, we apply a target enrichment method to retrieve mitochondrial genomes from 65 museum specimens and 56 noninvasively collected faecal samples of two endangered great ape species, Grauer's gorilla and the eastern chimpanzee. We show that the applied method is suitable for a wide range of sample types that differ in endogenous DNA content, increasing the proportion of target reads to over 300-fold. By systematically evaluating biases introduced during target enrichment of pooled museum samples, we show that capture is less efficient for fragments shorter or longer than the baits, that the proportion of human contaminating reads increases postcapture although capture efficiency is lower for human compared to gorilla fragments with a gorilla-generated bait, and that the rate of jumping PCR is considerable, but can be controlled for with a double-barcoding approach. We succeed in capturing complete mitochondrial genomes from faecal samples, but observe reduced capture efficiency as sequence divergence increases between the bait and target species. As previously shown for museum specimens, we demonstrate here that mitochondrial genome capture from field-collected faecal samples is a robust and reliable approach for population wide studies of nonmodel organisms. PMID- 28675689 TI - Psoas as a sentinel muscle for sarcopenia: a flawed premise. PMID- 28675690 TI - Caregiver-infant's feeding behaviours are associated with energy intake of 9-11 month-old infants in rural Ethiopia. AB - Inappropriate complementary feeding, both in quantity and quality, is a major determinant of undernutrition. However, little is known about how infant caregiver's feeding behaviours affect infants' energy intake. Therefore, the objective of this study was to characterize infant-caregiver feeding behaviours and investigate their association with infants' energy intake. The study involved 106 mother-child pairs recruited from seven randomly selected kebeles of Mecha district, West Gojam, Ethiopia. The feeding styles were assessed through observations of 1-day, in-home, feeding episodes that were videotaped and coded into self-feeding, responsive, active, distracting, and social feeding behaviours. Infants' haemoglobin and anthropometric measurements were taken. The association between feeding behaviour scores and energy intake per meal was investigated. The mean food intake of the infants was very low (11.4 +/- 7.0 g/kg body weight per meal) compared to the minimum theoretical gastric capacity (30 g/kg body weight per meal). Infants' haemoglobin concentration was negatively associated with energy intake (rho = 0.178, p = .03). Infants' responsive and active positive feeding styles were positively associated with energy intakes (rho = 0.258 and 0.432, p = .004 and p < .001, respectively) as well as caregivers' responsive positive feeding styles (rho = 0.237, p = .007). Both haemoglobin concentrations and feeding styles were associated with infant's energy intake. Anaemia prevention and control measures should be reinforced. Current nutrition education programmes should give emphasis on ways to effectively incorporate culturally adapted responsive feeding messages in this and similar settings. PMID- 28675691 TI - PD-1 inhibition in congenital pigment synthesizing metastatic melanoma. AB - A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF), NF 1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease. PMID- 28675692 TI - Development of the Korean Pregnancy Stress Scale. AB - AIM: This study was conducted in order to develop and evaluate a Pregnancy Stress Scale (PSS). METHODS: The PSS was developed according to Devellis' scale development process. Data that were collected from 388 pregnant women were used to evaluate the validity and reliability of the tool. An item analysis, factor analysis, Pearson's correlation coefficients, and Cronbach's alpha were used. RESULTS: The PSS comprised seven factors that can be applied to all pregnant women, with one additional factor that is dedicated specifically for working pregnant women, resulting in a total of eight factors with 43 items: physical and psychological changes, coping in daily life, health of the mother and baby, maternal role, family support, healthcare services, social atmosphere, and reconciliation of work life. The criterion validity was supported by the Revised Prenatal Distress Questionnaire and Edinburgh Postnatal Depression Scale. The reliability of the overall scale was adequate. CONCLUSION: This scale would be useful for understanding the complex factors that contribute to pregnant women's stress and also would contribute to the process of developing nursing interventions to reduce pregnancy stress. PMID- 28675693 TI - Application of iterative robust model-based optimal experimental design for the calibration of biocatalytic models. AB - The aim of model calibration is to estimate unique parameter values from available experimental data, here applied to a biocatalytic process. The traditional approach of first gathering data followed by performing a model calibration is inefficient, since the information gathered during experimentation is not actively used to optimize the experimental design. By applying an iterative robust model-based optimal experimental design, the limited amount of data collected is used to design additional informative experiments. The algorithm is used here to calibrate the initial reaction rate of an omega transaminase catalyzed reaction in a more accurate way. The parameter confidence region estimated from the Fisher Information Matrix is compared with the likelihood confidence region, which is not only more accurate but also a computationally more expensive method. As a result, an important deviation between both approaches is found, confirming that linearization methods should be applied with care for nonlinear models. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1278-1293, 2017. PMID- 28675694 TI - Benzyl isothiocyanate (BITC) induces apoptosis of GBM 8401 human brain glioblastoma multiforms cells via activation of caspase-8/Bid and the reactive oxygen species-dependent mitochondrial pathway. AB - Benzyl isothiocyanate (BITC) is one of member of the isothiocyanate family which has been shown to induce cancer cell apoptosis in many human cancer cells. In the present study, we investigated the effects of BITC on the growth of GBM 8401 human brain glioblastoma multiforms cells. Results indicated that BITC-induced cell morphological changes decreased in the percentage of viable GBM8401 cells and these effects are dose-dependent manners. Results from flow cytometric assay indicated that BITC induced sub-G1 phase and induction of apoptosis of GBM 8401 cells. Furthermore, results also showed that BITC promoted the production of reactive oxygen species (ROS) and Ca2+ release, but decreased the mitochondrial membrane potential (DeltaPsim ) and promoted caspase-8, -9, and -3 activates. After cells were pretreated with Z-IETD-FMK, Z-LEHD-FMK, and Z-DEVD-FMK (caspase 8, -9, and -3 inhibitors, respectively) led to decrease in the activities of caspase-8, -9, and -3 and increased the percentage of viable GBM 8401 cells that indicated which BITC induced cell apoptosis through caspase-dependent pathways. Western blotting indicated that BITC induced Fas, Fas-L, FADD, caspase-8, caspase -3, and pro-apoptotic protein (Bax, Bid, and Bak), but inhibited the ant apoptotic proteins (Bcl-2 and Bcl-x) in GBM 8401 cells. Furthermore, BITC increased the release of cytochrome c, AIF, and Endo G from mitochondria that led to cell apoptosis. Results also showed that BITC increased GADD153, GRP 78, XBP 1, and ATF-6beta, IRE-1alpha, IRE-1beta, Calpain 1 and 2 in GBM 8401 cells, which is associated with ER stress. Based on these observations, we may suggest that BITC-induced apoptosis might be through Fas receptor, ROS induced ER stress, caspase-3, and mitochondrial signaling pathways. Taken together, these molecular alterations and signaling pathways offer an insight into BITC-caused growth inhibition and induced apoptotic cell death of GBM 8401 cells. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1751-1760, 2016. PMID- 28675695 TI - Predictors of treatment response to psychological interventions in people at clinical high risk of first-episode psychosis. AB - AIM: Psychological interventions, such as cognitive behavioural therapy (CBT) and supportive counselling (SC), are used to treat people with schizophrenia and people at clinical high risk (CHR) of psychosis. However, little information is available on predictors of treatment response. This study aims to identify such predictors of psychological interventions in CHR. METHODS: A total of 128 help seeking CHR outpatients were randomized into two groups-integrated psychological intervention (IPI), including CBT, and SC-for 12 months. Multiple regression analysis was used to identify demographic, symptomatic and functional variables that predict improvement in positive (PANSS Positive), negative (PANSS Negative) and basic symptoms (Basic symptom total score) and improvement in functioning (GAF) at 1-year follow up. RESULTS: In the merged group (IPI + SC), people who lived independently, were younger and presented with higher baseline functioning showed more improvement in symptomatic outcomes at follow up. Negative symptoms at baseline predicted less improvement in positive and basic symptoms. Being married or cohabiting and living in the primary family were found to correlate with good functioning at 1-year follow up. CONCLUSIONS: Younger CHR individuals and those who are functioning well may particularly benefit from early intervention. Treatment might need to be modified for low-functioning CHR and those who already display higher scores of negative symptoms. Registration number: NCT00204087. PMID- 28675696 TI - Myocardial bridges: Overview of diagnosis and management. AB - A myocardial bridge is a segment of a coronary artery that travels into the myocardium instead of the normal epicardial course. Although it is general perception that myocardial bridges are normal variants, patients with myocardial bridges can present with symptoms, such as exertional chest pain, that cannot be explained by a secondary etiology. Such patients may benefit from individualized medical/surgical therapy. This article describes the prevalence, clinical presentation, classification, evaluation, and management of children and adults with symptomatic myocardial bridges. PMID- 28675697 TI - Erratum. PMID- 28675699 TI - Immunization with a Synthetic Human MUC1 Glycopeptide Vaccine against Tumor Associated MUC1 Breaks Tolerance in Human MUC1 Transgenic Mice. AB - Breaking tolerance is crucial for effective tumor immunotherapy. We showed that vaccines containing tumor-associated human MUC1 glycopeptides induce strong humoral antitumor responses in mice. The question remained whether such vaccines work in humans, in systems where huMUC1 is a self-antigen. To clarify the question, mice transgenic in expressing huMUC1, mimicking the self-tolerant environment, and wild-type mice were vaccinated with a synthetic vaccine. This vaccine comprised STn and Tn antigens bound to a MUC1 tandem repeat peptide coupled to tetanus toxoid. The vaccine induced strong immune responses in wild type and huMUC1-transgenic mice without auto-aggressive side effects. All antisera exhibited almost equivalent binding to human breast tumor cells. Similar increases of activated B-, CD4+ T-, and dendritic cells was found in the lymph nodes. The results demonstrate that tumor-associated huMUC1 glycopeptides coupled to tetanus toxoid are promising antitumor vaccines. PMID- 28675698 TI - The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma. AB - Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long-lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient-induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL-induced autophagy and cytotoxicity in HepG2 and MHCC97-H hepatocellular carcinoma cells. These results imply that the GL-related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97-H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97-H cells (P < 0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC. PMID- 28675700 TI - Conjugated Trimeric Scaffolds Accessible from Indolyne Cyclotrimerizations: Synthesis, Structures, and Electronic Properties. AB - We report the design and synthesis of a new class of indole-based conjugated trimers. The targeted compounds are accessed from in situ generated, highly reactive indolyne intermediates using Pd-catalyzed cyclotrimerization reactions. By harnessing three indolyne isomers, six isomeric indole trimers are accessible, none of which have been previously synthesized. Using computational analysis, we describe the structural and photophysical properties of these unique compounds. This study showcases the use of indolynes in transition metal-catalyzed reactions, while providing access to a new class of conjugated trimers, including highly bent heteroaromatic compounds. Computations indicate that, despite differences in planarity between the molecules, the photophysical properties of each trimer are derived from the N-methylindole building block. Excited state behavior follows predicable patterns. PMID- 28675701 TI - Mechanism and Selectivity of Cooperatively Catalyzed Meyer-Schuster Rearrangement/Tsuji-Trost Allylic Substitution. Evaluation of Synergistic Catalysis by Means of Combined DFT and Kinetics Simulations. AB - The reaction between propargylic alcohols and allylic carbonates, engaging vanadium and palladium catalysts, is an exemplary case of a cooperatively catalyzed process. This combined Meyer-Schuster rearrangement/Tsuji-Trost allylic substitution clearly illustrates the enormous advantages offered by the simultaneous use of two catalysts, but also the inherent challenges regarding selectivity associated with such a reaction design. These challenges originate from the fact that the desired product of the combined process is formed by a bimolecular coupling of the two substrates activated by the respective catalysts. However, these two processes may also occur in a detached way via the reactions of the catalytic intermediates with the starting propargylic alcohol present in the reaction mixture, leading to the formation of two side-products. Herein, we investigate the overall mechanism of this reaction using density functional theory (DFT) methodology. The mechanistic details of the catalytic cycles for all the individual processes are established. In particular, it is shown that the diphosphine ligand, dppm, used in the reaction promotes the formation of dinuclear palladium complexes, wherein only a single metal center is directly involved in the catalysis. Due to the complexity of the combined reaction network, kinetics simulation techniques are employed in order to analyze the overall selectivity. The simulations directly link the results of the DFT calculations with the experimental data and confirm that the computed free energy profiles indeed reproduce the observed selectivities. In addition, a sensitivity analysis is carried out to assess the importance of the individual steps on the product distribution. The observed behavior of the kinetic network is rationalized, and trends in the reaction outcome upon changing the initial conditions, such as the catalysts amounts and ratio, are discussed. The results provide a general framework for understanding the factors governing the selectivity of the cooperatively catalyzed reactions. PMID- 28675702 TI - Combined Theoretical and Experimental Studies of Nickel-Catalyzed Cross-Coupling of Methoxyarenes with Arylboronic Esters via C-O Bond Cleavage. AB - Nickel(0)-catalyzed cross-coupling of methoxyarenes through C-O bond activation has been the subject of considerable research because of their favorable features compared with those of the cross-coupling of aryl halides, such as atom economy and efficiency. In 2008, we have reported nickel/PCy3-catalyzed cross-coupling of methoxyarenes with arylboronic esters in which the addition of a stoichiometric base such as CsF is essential for the reaction to proceed. Recently, we have also found that the scope of the substrate in the Suzuki-Miyaura-type cross-coupling of methoxyarenes can be greatly expanded by using 1,3-dicyclohexylimidazol-2 ylidene (ICy) as the ligand. Interestingly, a stoichiometric amount of external base is not required for the nickel/ICy-catalyzed cross-coupling. For the mechanism and origin of the effect of the external base to be elucidated, density functional theory calculations are conducted. In the nickel/PCy3-catalyzed reactions, the activation energy for the oxidative addition of the C(aryl)-OMe bond is too high to occur under the catalytic conditions. However, the oxidative addition process becomes energetically feasible when CsF and an arylboronic ester interact with a Ni(PCy3)2/methoxyarene fragment to form a quaternary complex. In the nickel/ICy-catalyzed reactions, the oxidative addition of the C(aryl)-OMe bond can proceed more easily without the aid of CsF because the nickel-ligand bonds are stronger and therefore stabilize the transition state. The subsequent transmetalation from an Ar-Ni-OMe intermediate is determined to proceed through a pathway with lower energies than those required for beta-hydrogen elimination. The overall driving force of the reaction is the reductive elimination to form the carbon-carbon bond. PMID- 28675703 TI - Changing the conversation about hormone therapy. PMID- 28675704 TI - The metabolic syndrome is associated with carotid atherosclerosis and arterial stiffness in asymptomatic, nondiabetic postmenopausal women. AB - The menopause transition is associated with adverse changes in cardiometabolic risk factors. We aimed to examine the association of the metabolic syndrome (MS) and its features with indices of vascular structure and function in a population of asymptomatic postmenopausal women. A total of 473 informed-consenting, nondiabetic postmenopausal women were included in the study. The MS was defined according to the Joint Definition. We evaluated the association between the presence of MS and indices of vascular structure (carotid artery intima-media thickness (IMT); atherosclerotic plaques) and function (flow-mediated dilatation (FMD); pulse wave velocity (PWV)). The mean age of women was 56.4 +/- 6.7 and the mean menopausal age was 7.91 +/- 6.31. The MS was present in 17.3% of our population. Mean values of PWV increased linearly with the accumulation of features of the MS. IMT was higher in women with the MS compared to women without the MS (0.78 +/- 0.12 mm vs. 0.74 +/- 0.11, p = .003). Multivariate analysis showed that the presence of the MS was independently associated with common carotid artery IMT (b = 0.149, p = .001), PWV (b = 0.114, p = .012) as well as central systolic and diastolic blood pressure (b = 0.293, p < .001 and b = 0.163, p < .001 respectively). The presence of the MS is associated with subclinical atherosclerosis already in the first postmenopausal decade of this sample of asymptomatic, nondiabetic women. Additional evidence is required to support the causative effect of these associations. PMID- 28675705 TI - Assessment of insulin resistance in Chinese PCOS patients with normal glucose tolerance. AB - The study aimed to investigate insulin resistance (IR) status in polycystic ovary syndrome (PCOS) women with normal glucose tolerance (NGT), and further to evaluate feasible diagnostic method for those patients. Three hundred and twenty five PCOS women with NGT and ninety-five healthy age-matched controls were recruited with Rotterdam criterion and 75 g oral glucose tolerance test (OGTT). IR status was estimated following a glycemic and insulinemic OGTT (0, 30, 60, 120, and 180 min). A modified HOMA-IR formula was applied to each time-course value of glycemia and insulinemia. The predictive performance of each IR index was analyzed with the use of ROC curves. Compared with healthy controls, both non obese and obese PCOS patients with NGT had a higher BMI, serum glucose, insulin value (p < .05). The best predictive index of IR in non-obese PCOS-NGT was a HOMA M30 value of 20.36 or more (AUC: 0.753). In obese PCOS-NGT population, the best predictive performance was obtained by a HOMA-M60 value of 32.17 or more (AUC: 0.868). IR was common in Chinese PCOS women with NGT, and the early assessment of IR should be heeded. We recommended HOMA-M30 (Cutoff: 20.36) and HOMA-M60 (Cutoff: 32.17) as the best predictive parameters for non-obese and obese PCOS NGT patients, respectively. PMID- 28675707 TI - Thera-prov: a pilot study of improv used to treat anxiety and depression. AB - BACKGROUND: Improvisational theater exercises (improv) are used in various settings to improve mental health and medical outcomes. However, there is little documented evidence of the effectiveness of these interventions. AIMS: We developed a short-term, group intervention that used improv exercises in a therapeutic manner to treat psychiatric patients. METHODS: We evaluated the feasibility, acceptability and five clinical outcomes (depressive symptoms, anxious symptoms, self-esteem, perfectionism and satisfaction with social roles) of this intervention in an outpatient setting. Participants were 32 patients with symptoms of anxiety and depression and who had variable exposure to psychiatric treatment. RESULTS: In paired samples t-tests, participants demonstrated reduced symptoms of anxiety (t(31) = 4.67, p < 0.001) and depression (t(31) = 3.78, p = 0.001), and improved self-esteem (t(31)= -3.31, p = 0.002) following the intervention. There was a trend towards reduction of perfectionism (t(31) = 1.77, p = 0.087), but no substantial change in rated satisfaction with social roles. Effect sizes were medium for reduction in symptoms of depression and anxiety. CONCLUSIONS: The results of this study indicate that a brief intervention based on improv exercises may provide a strong and efficient treatment for patients with anxiety and depression. PMID- 28675708 TI - Role of long-term acute care in reducing hospital readmission. AB - Long-term acute care hospitals (LTACs) are health care facilities capable of admitting complex patients with high acuity that are unable to return home after hospitalization in acute care. Its defining characteristic is to accommodate patients for a length of stay greater than 25 days, however, little is known about its role of preventing hospital readmissions. Created in the 1980s, these facilities were designed to help acute care facilities improve their resource management, expenditures, and quality of care. Although these units were initially created for chronic ventilator weaning, their scope of practice has broadened. This article analyzes studies and suggests role of LTACs in reducing hospital readmissions. PMID- 28675709 TI - Posttraumatic stress disorder following asthma attack: the role of agency beliefs in mediating psychiatric morbidity. AB - BACKGROUND: The link between serious illness and subsequent posttraumatic stress disorder (PTSD) and psychiatric comorbidity has been established. In populations with asthma, however, few studies have investigated this link, or what psychological mechanisms mediate it. Healthcare guidance for chronic conditions, and PTSD literature, highlight "agency beliefs" as a direction for investigation. AIMS: To determine the prevalence of PTSD following asthma attack, and investigate whether agency beliefs mediate PTSD and comorbid psychiatric symptoms in this population. METHOD: We recruited 110 adults with asthma from online peer support forums. Participants completed the Asthma Symptom Checklist, PTSD Checklist, GHQ-28, General Self-Efficacy scale, and Multidimensional Health Locus of Control scale. RESULTS: 20% of our sample met criteria for PTSD. Regression results indicated that higher asthma severity significantly predicted PTSD and psychiatric co-morbidity. Lower self-efficacy significantly predicted PTSD symptoms while controlling for asthma severity, however Locus of Control (LoC) did not improve the model further. Self-efficacy, but not LoC, significantly partially mediated the effect of asthma severity on PTSD severity and psychiatric co-morbidity. CONCLUSIONS: PTSD and other psychiatric symptoms in asthma populations are mediated in part by self-efficacy. Safeguarding and improving self-efficacy in this population is an important area for future research and intervention. PMID- 28675710 TI - Keep calm and carry on: are we really coping with current events? PMID- 28675711 TI - Modification of anti-tumor immunity by tolerogenic dendritic cells. AB - Immunosuppressive functions of glucocorticoids (GC) can be mediated via various mechanisms, including the modulation of dendritic cells (DC). Our study investigates the effects of tolerogenic GC-treated DCs on NK and T cell anti tumor responses in OT-1/Rag-/- mice, expressing a transgenic TCR in CD8+ T cells. The effects caused by GC-treated DCs were compared to the responses to immunogenic, CpG-activated DCs. The effects of DCs on anti-tumor immune responses were analyzed using the EG7 tumor model, where the tumor cells express the peptide epitope recognized by OT-1 T cells. We observed that immunization with CpG and peptide-treated DCs protected against tumor growth by activation of NK cell response. Also, immunogenic DCs induced the expansion of cytotoxic CD8+OT-1 cells, expressing activation markers CD44 and CD69 and producing IFNgamma. In contrast, the peptide and GC-treated DCs in OT-1 mice increased the numbers of immature Mac-1+CD27- NK cells as well as Foxp3+ and IL-10 secreting CD8+OT-1 cells with suppressive properties. We conclude that the generation of tolerogenic DCs is one of many immunosuppressive mechanisms that can be induced by GC. Our study demonstrated that tolerogenic DCs modify anti-tumor immune response by suppressing NK cell activity and stimulating the formation of IL-10-secreting CD8+ Tregs. PMID- 28675712 TI - Association of the polymorphisms in the gene encoding thyroglobulin with the development and prognosis of autoimmune thyroid disease. AB - Graves' disease (GD) and Hashimoto's disease (HD) are autoimmune thyroid diseases (AITDs), and the prognosis of AITDs is different for each patient. We examined the association of polymorphisms in the Thyroglobulin (TG) gene with the pathogenesis of AITD. We genotyped TG rs180195G/A, rs853326G/A, rs2076740C/T, rs2703013G/T, rs2958692C/T and rs733735A/G polymorphisms in 137 HD patients, 131 GD patients and 89 healthy controls and also examined the levels of TG mRNA expression and serum TG. The TG rs180195 GG genotype was more frequent in HD patients (p = .0277), and the proportion of CD4+ cells with high levels of TG mRNA was greater in individuals with the GG genotype than in A carriers (p = .0107). The TG rs2703013 TT genotype was less frequent in AITD (p = .0186), and serum TG levels were lower in individuals with the TT genotype than in G carriers (p = .0170). In the TG rs2958692 polymorphism, the T allele was more frequent in intractable GD than in GD in remission (p = .0055), and serum titres of anti thyroglobulin antibody (TgAb) were lower in GD patients with the TT genotype than in C carriers (p = .0151). In the TG rs2076740 polymorphism, serum titres of TgAb were higher in HD patients who were T carriers than in those with the CC genotype (p = .0359). SNPs in the TG gene were associated with the development of HD and GD, the intractability of GD, and the levels of TG mRNA expression, serum TG, and serum TgAb. PMID- 28675713 TI - Obesity in pregnancy as a model to identify women at risk for later metabolic syndrome. AB - The aim of our study is to identify - in a cohort of obese women - cardiovascular and clinical risk factors in women with previous complicated pregnancies and protective factors in women with previous physiological pregnancies. A total of 135 nonpregnant obese women referring to Policlinico Gemelli in Rome were prospectively collected in 2009-2010. Thirty-two women matched inclusion criteria: 16 reported a previous physiological pregnancy and 16 reported previous obstetric complications. A clinical, instrumental and laboratory evaluation has been performed for each patient. Statistical analysis was performed using StatView Software. Values are expressed as mean +/- standard error (SEM). All tests were two-tailed with a confidence level of 95% (p < .05). Statistically significant reduced flow-mediated dilatation (p = .0338), increased serum values of vascular cell adhesion molecule (p = .0154) and higher systolic blood pressure values (p = .0427) have been detected in obese women with previous complicated pregnancies due to gestational diabetes and/or hypertension. In conclusion, obese patients with previous complicated pregnancies develop signs of endothelial dysfunction in the postpartum period. Future research should focus on the early identification of possible molecular mechanisms implicated in the development of glyco-metabolic and cardiovascular diseases in obese patients, since they are at higher risk of metabolic syndrome. PMID- 28675714 TI - Processes of recovery through routine or specialist treatment for borderline personality disorder (BPD): a qualitative study. AB - BACKGROUND: Recovery processes in borderline personality disorder (BPD) are poorly understood. AIMS: This study explored how recovery in BPD occurs through routine or specialist treatment, as perceived by service users (SUs) and therapists. METHODS: SUs were recruited from two specialist BPD services, three community mental health teams, and one psychological therapies service. Semi structured interviews were conducted with 48 SUs and 15 therapists. The "framework" approach was used to analyse the data. RESULTS: The findings were organized into two domains of themes. The first domain described three parallel processes that constituted SUs' recovery journey: fighting ambivalence and committing to taking action; moving from shame to self-acceptance and compassion; and moving from distrust and defensiveness to opening up to others. The second domain described four therapeutic challenges that needed to be addressed to support this journey: balancing self-exploration and finding solutions; balancing structure and flexibility; confronting interpersonal difficulties and practicing new ways of relating; and balancing support and independence. CONCLUSIONS: Therapies facilitating the identified processes may promote recovery. The recovery processes and therapeutic challenges identified in this study could provide a framework to guide future research. PMID- 28675715 TI - Identification of potential biomarkers for systemic lupus erythematosus diagnosis using two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease of the connective tissue with a large spectrum of clinical manifestations. Immune deregulation leads to autoantibody and immune complexes overproduction, complement activation, and persistent tissue inflammation. Considering that the current diagnosis depends on the interpretation of the complex criteria established by the American College of Rheumatology and that the disease course is characterized by unpredictable activations and remissions, each patient develops different manifestations, and therefore, the discovery of specific biomarkers is urgently required. Therefore, this study aimed to identify putative biomarkers for active and inactive SLE potentially capable in distinguishing laboratorial SLE from other autoimmune diseases. The 2D-DIGE proteomics technique was used to evaluate the differential abundance of proteins between patients with active SLE, inactive SLE, patients with other autoimmune disease, and healthy individuals. Six proteins showed increased abundance in active SLE (A) and inactive SLE (I) compared to the C and O groups, but not between groups A and I. There were two transthyretin (TTR) fragments or proteins with a structure similar to TTR (accession numbers: PDB: 1GKO_A and 2PAB_A), retinol-binding protein 4 (RBP4) isoform X1 (no information in databases such as UNIPROT), and antibody fragments. Two proteins, APO-AIV and SP-40,40, were upregulated in group A than in O and C and in group I versus C, but not in group I versus O. Therefore, we suggest these proteins to be considered as candidates for the diagnosis of SLE. PMID- 28675747 TI - Progress in understanding the molecular oxygen paradox - function of mitochondrial reactive oxygen species in cell signaling. AB - The molecular oxygen (O2) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O2 is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H2O2, are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H2O2 elimination pathways are well characterized in mitochondria. However, less is known about how H2O2 production is controlled. The present review examines the importance of mitochondrial H2O2 in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H2O2 can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H2O2 production. PMID- 28675748 TI - A preliminary study for the assessment of hypertension using static and dynamic IR thermograms. AB - Structural changes in blood vessels occur due to prolonged hypertension. Early detection of blood pressure (mm Hg) is essential for disease prevention. The aim of this work is to propose a computer-aided diagnostic (CADx) model for the diagnosis of hypertension using variables derived from non-contact static and dynamic thermal imaging in comparison with the pulse wave velocity (PWV)-derived parameters. Static and dynamic infrared (IR) thermograms of selected skin areas of the body from known hypertensive (n=14) and age- and sex-matched normal subjects were captured. The average skin surface temperature [SST ( degrees C)] of selected skin areas of the body was calculated from a static IR thermogram. After denoising the dynamic IR thermogram using wavelets, the statistical variables power, mean, standard deviation (SD), variance, skewness and kurtosis were calculated. The variables derived from both static and dynamic thermograms were used to develop the CADx model. The performance of the CAD model was also tested by feature selection using principal component analysis (PCA). An accuracy of 75% (sensitivity=78.6%, specificity=71.4%) could be achieved with the average SST ( degrees C) of the static IR thermogram alone. The statistical variables derived from the dynamic IR thermogram alone gave an accuracy of 82% (and 85% after feature selection by PCA), whereas the accuracy using standard methods like variables derived from PWV was only 71.4% (with and without feature selection). The highest accuracy of 89% could be achieved by combining variables like average SST ( degrees C) measured from static and dynamic IR thermograms and PWV-derived variables. PMID- 28675749 TI - Randomization Strategies Affect Motif Significance Analysis in TF-miRNA-Gene Regulatory Networks. AB - Gene-regulatory networks are an abstract way of capturing the regulatory connectivity between transcription factors, microRNAs, and target genes in biological cells. Here, we address the problem of identifying enriched co regulatory three-node motifs that are found significantly more often in real network than in randomized networks. First, we compare two randomization strategies, that either only conserve the degree distribution of the nodes' in- and out-links, or that also conserve the degree distributions of different regulatory edge types. Then, we address the issue how convergence of randomization can be measured. We show that after at most 10 * |E| edge swappings, converged motif counts are obtained and the memory of initial edge identities is lost. PMID- 28675751 TI - Role of sulphur atoms on stress relaxation and crack propagation in monolayer MoS2. AB - We present in-situ transmission electron microscopy of crack propagation in a freestanding monolayer MoS2 and molecular dynamic analysis of the underlying mechanisms. Chemical vapor deposited monolayer MoS2 was transferred from sapphire substrate using interfacial etching for defect and contamination minimization. Atomic resolution imaging shows crack tip atoms sustaining 14.5% strain before bond breaking, while the stress field decays at unprecedented rate of 2.15 GPa A 1. Crack propagation is seen mostly in the zig-zag direction in both model and experiment, suggesting that the mechanics of fracture is not brittle. Our computational model captures the mechanics of the experimental observations on crack propagation in MoS2. While molybdenum atoms carry most of the mechanical load, we show that the sliding motion of weakly bonded sulphur atoms mediate crack tip stress relaxation, which helps the tip sustain very high, localized stress levels. PMID- 28675750 TI - Expression of placental regulatory genes is associated with fetal growth. AB - The placenta is the principal organ regulating respiratory, nutritional, endocrine and metabolic functions on behalf of the developing fetus. Changes in gene expression patterns of placenta-specific genes may influence fetal growth. We profiled the expression of 17 genes related to placenta functioning in term placentas (n=677) to identify genes differentially expressed across birth weight categories [small (SGA), appropriate (AGA) and large (LGA) for gestational age]. ABCG2, CEBPB, CRH, GCM1, GPC3, INSL4, PGF and PLAC1 were inversely associated with LGA status, with odds ratios (ORs) and 95% confidence intervals (CI) ranging from GCM1 (OR=0.44, 95% CI: 0.29, 0.70) to CRH (OR=0.73, 95% CI: 0.61, 0.88). NR3C1 was positively associated with LGA status (OR=2.33, 95% CI: 1.43, 3.78). PLAC1 (OR=0.66, 95% CI: 0.47, 0.92) and ABCG2 (OR=0.63, 95% CI: 0.44, 0.91) were additionally inversely associated with SGA status, and PGF was positively associated with SGA status (OR=1.59, 95% CI=1.08, 2.35). General trends were confirmed in an independent cohort (n=306). Given that aberrant fetal growth may have long-lasting effects, our results suggest the potential utility of placental gene expression profiles as potential early markers of disease onset later in life. PMID- 28675752 TI - Re: The high price of public fear of low-dose radiation. PMID- 28675753 TI - Experimental and theoretical investigation on photocatalytic activities of 1D Ag/Ag2WO4 nanostructures. AB - Ag2WO4 is a significant photocatalyst that responds to UV light irradiation only, which greatly hinders it for further practical application for solar light. To address this problem, herein, 1D plasmonic Ag/Ag2WO4 photocatalysts have been fabricated by a successive process including hydrothermal synthesis to obtain Ag2WO4 followed by an additional in situ chemical-reduction process for Ag decoration. Then, the structural features, optical properties, and electronic structures of Ag2WO4 and Ag/Ag2WO4 nanowires were systematically investigated via a combination of theoretical calculations and experimental evidence. The plasmon enhanced Ag/Ag2WO4 nanowires exhibited higher visible-light-driven photocatalytic activity, which performed a desired photodestruction ratio of 91.2% on methylene blue within 60 min and good stability in five cycles. The Ag decoration greatly facilitates visible-light harvesting and thus promotes photogenerated radical oxidation to dye, which is evidenced by the higher hydroxyl radical level of Ag/Ag2WO4 detected in the ESR test during the photocatalytic process. The theoretical calculation based on density functional theory indicates that Ag nanoparticles formed on the surface of Ag2WO4 could narrow the band gap of Ag2WO4. In addition, the surface plasmon resonance absorption effect and fast charge transfer effect in the metal-semiconductor system contribute to the photocatalytic performance of Ag/Ag2WO4. PMID- 28675754 TI - Inverted structural quantum dot light-emitting diodes based on Al-doped ZnO electrode. AB - As an indium-free transparent conducting film, Al-doped zinc oxide (AZO) was prepared by magnetron sputtering technique, exhibiting good electrical, optical and surface characteristics. UPS/XPS measurements show that AZO and zinc oxide nanoparticles (ZnO NPs) have matched energy level that can facilitate the electron injection from AZO to ZnO NPs. Inverted structural green quantum dot light-emitting diodes based on AZO cathode were fabricated, which exhibits a maximum luminance up to 178 000 cd m-2, and a maximum current efficiency of 10.1 cd A-1. Therewith, combined with the simulated space-charge-limited current (SCLC) theory, the measured current density-voltage characteristics of charge only devices were analyzed. It demonstrated that AZO and ZnO NPs had much better electron injection efficiency than ITO, showing a electron injection efficiency close to 100%. By studying the relationship between the electric field and the current density, the measured curve of AZO-based devices nearly fits the theoretical curve of SCLC and the AZO electrode has a better ohmic contact with ZnO NPs than ITO. PMID- 28675755 TI - Optical anisotropy in vertically oriented TiO2 nanotube arrays. AB - Nanofabricated optically anisotropic uniaxial thin films with deep submicron feature sizes are emerging as potential platforms for low-loss all-dielectric metamaterials, and for Dyakonov surface wave-based subwavelength optical confinement and guiding at interfaces with isotropic media. In this context, we investigate the optical properties of one such uniaxial platform, namely self organized titania nanotube arrays (TNTAs) grown by the bottom-up nanofabrication process of electrochemical anodization on silicon wafer substrates, and subsequently annealed at different temperatures, i.e. 500 degrees C and 750 degrees C. We performed detailed quantitative analysis of the structure of the TNTAs using x-ray diffraction and Raman spectroscopy, which revealed a measurable phonon confinement in TNTAs annealed at 500 degrees C. Variable angle spectroscopic ellipsometry was used to investigate the optical anisotropy in two kinds of TNTAs-those constituted by anatase-phase and those containing a mixture of anatase and rutile phases. Both kinds of TNTAs were found to have positive birefringence (Deltan) exceeding 0.06 in the spectral region of interest while mixed phase TNTAs exhibited Deltan as high as 0.15. The experimentally measured anisotropy in the refractive index of the TNTAs was compared with the predictions of two different effective medium approximations incorporating the uniaxial geometry. The measured value of Deltan for TNTAs exceeded that of bulk anatase single crystals, indicating the potential of nanostructured dielectrics to outperform dielectric crystals of the same material with respect to the magnitude of the achievable directional refractive index contrast. PMID- 28675756 TI - Fabrication of single Ga-doped ZnS nanowires as high-gain photosensors by focused ion beam deposition. AB - ZnS nanowires were synthesized via a vapor-liquid-solid mechanism and then fabricated into a single-nanowire field-effect transistor by focused ion beam (FIB) deposition. The field-effect electrical properties of the FIB-fabricated ZnS nanowire device, namely conductivity, mobility and hole concentration, were 9.13 Omega-1 cm-1, 13.14 cm2 V-1 s-1and 4.27 * 1018 cm-3, respectively. The photoresponse properties of the ZnS nanowires were studied and the current responsivity, current gain, response time and recovery time were 4.97 * 106 A W 1, 2.43 * 107, 9 s and 24 s, respectively. Temperature-dependent I-V measurements were used to analyze the interfacial barrier height between ZnS and the FIB deposited Pt electrode. The results show that the interfacial barrier height is as low as 40 meV. The energy-dispersive spectrometer elemental line scan shows the influence of Ga ions on the ZnS nanowire surface on the FIB-deposited Pt contact electrodes. The results of temperature-dependent I-V measurements and the elemental line scan indicate that Ga ions were doped into the ZnS nanowire, reducing the barrier height between the FIB-deposited Pt electrodes and the single ZnS nanowire. The small barrier height results in the FIB-fabricated ZnS nanowire device acting as a high-gain photosensor. PMID- 28675757 TI - Designing quantum information processing via structural physical approximation. AB - In quantum information processing it may be possible to have efficient computation and secure communication beyond the limitations of classical systems. In a fundamental point of view, however, evolution of quantum systems by the laws of quantum mechanics is more restrictive than classical systems, identified to a specific form of dynamics, that is, unitary transformations and, consequently, positive and completely positive maps to subsystems. This also characterizes classes of disallowed transformations on quantum systems, among which positive but not completely maps are of particular interest as they characterize entangled states, a general resource in quantum information processing. Structural physical approximation offers a systematic way of approximating those non-physical maps, positive but not completely positive maps, with quantum channels. Since it has been proposed as a method of detecting entangled states, it has stimulated fundamental problems on classifications of positive maps and the structure of Hermitian operators and quantum states, as well as on quantum measurement such as quantum design in quantum information theory. It has developed efficient and feasible methods of directly detecting entangled states in practice, for which proof-of-principle experimental demonstrations have also been performed with photonic qubit states. Here, we present a comprehensive review on quantum information processing with structural physical approximations and the related progress. The review mainly focuses on properties of structural physical approximations and their applications toward practical information applications. PMID- 28675758 TI - Metformin Suppresses Proliferation and Viability of Rat Pheochromocytoma Cells. AB - BACKGROUND Previous studies have clearly demonstrated that metformin inhibits cell proliferation and cell growth in many types of human cancers. Increased survival rates in patients with breast and lung cancer receiving metformin have also been observed. However, the effect of metformin on pheochromocytoma cells remains unexplored. MATERIAL AND METHODS Rat pheochromocytoma cells (PC12 cells) were cultured and treated with metformin or vehicle control. Cell proliferation, cell-cycle, apoptosis, genes expression, and the signaling pathways involved were analyzed in PC12 cells. RESULTS The metformin treatment reduced cell viability and proliferation in rat pheochromocytoma PC12 cells in a dose- and time dependent manner. Furthermore, metformin exposure led to an increased apoptosis rate and cell-cycle arrest accompanied with downregulation of Ccna2 and Ccnb2. At the molecular level, the AMPK signaling pathway was activated, whereas the mTOR and ERK1/2 signaling pathways were inhibited by metformin. CONCLUSIONS Our data suggest an antiproliferative role of metformin in pheochromocytoma development, which may provide a novel option for future cancer therapy. PMID- 28675759 TI - Sensory and Physical Effects of Sugar Reduction in a Caramel Coating System. AB - Sugar reduction in processed foods is a pressing and complex problem, as sugars contribute important sensory and physical properties to foods. Composed of sugars and lipids, caramel coating systems, like the coating in caramel popcorns, exemplify this challenge. In order to probe the feasibility and consequences of sugar reduction, both sensory and physical properties were measured for 3 types of caramel coating systems. Four commonly used sugar alcohols, isomalt, maltitol, mannitol, and sorbitol, with different thermal properties and relative sweetness values were chosen to replace sugar in the caramel coating systems at 25% and 50% sugar reduction levels. Full sugar (control) and reduced sugar caramel coating samples were prepared in duplicate. Ten trained panelists participated in a 6-wk descriptive analysis panel to define and quantify the intensity of important sensory characteristics. All 24 sensory terms generated by the panel differed significantly across caramel type and sugar replacer. Thermal properties were measured through differential scanning calorimetry, and textural properties were measured through texture profile analysis. Replacement of sugar with sugar alcohols was found to decrease the glass transition temperature and systematically alter the hardness and resilience of caramel samples. Principal component analysis of sensory and physical data revealed that caramel coating type dictates caramel aroma, aroma by mouth, taste, and aftertaste, while sugar replacer and replacement level dictate texture. This research represents the first comprehensive study of the effects of sugar reduction in a caramel coating system and suggests successful strategies for sugar reduction and key parameters to control in reduced sugar systems. PMID- 28675760 TI - Association of perceived physical health and physical fitness in two Swedish national samples from 1990 and 2015. AB - : Perceived health and physical fitness have been shown to correlate, and low levels of either variable increase the risk for future illness and mortality. However, risk factors and their interrelationship may vary between societies and over time. In this study, the associations of physical fitness and perceived health were therefore assessed in two Swedish national samples 25 years apart. Perceived physical health, dichotomized as "good" or "bad," maximal oxygen uptake (VO2 max), counter movement jump (CMJ), balance (one-legged 60 second stance), and self-reported demographics and lifestyle were recorded in two cross-sectional samples (sample size, number of eligible participants) of Swedish adults, aged 20 65 years, in 1990-1991 (2203, 1365), and 2013-2015 (3357, 422). The odds for good perceived physical health increased by 5% per mL.kg-1 .min-1 of VO2 max, 3% per cm CMJ height, and decreased by 4% per 1 time of overbalancing, in both samples. Mutually adjusted regression models showed that perceived physical health was best predicted by VO2 max and chronic illness in 1990 and by age, BMI, and educational level in 2015. CONCLUSION: Perceived physical health was related to physical fitness in two samples of Swedish adults from 1990 and 2015. However, multivariate and mutually adjusted models indicate that the most important covariates of perceived physical health may have changed from VO2 max and chronic illness in 1990, to age, BMI, and educational level in 2015. PMID- 28675761 TI - Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization. AB - BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC). METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or beta-estimates with 95% confidence interval (CI). RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: beta=-0.0012 (95% CI: -0.0019, 0.0006) and FVC: beta=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m2 higher BMI. CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy. PMID- 28675762 TI - Management of mood and anxiety disorders in patients receiving opioid agonist therapy: Review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Patients with opioid use disorders and mood and anxiety symptoms have a variable prognosis. Few randomized controlled trials (RCTs) have evaluated treatment of depression or anxiety in patients receiving opioid agonist therapies (OAT). This review evaluates studies of pharmacotherapy/psychotherapy for treating symptoms of depression or anxiety in patients receiving OAT. METHODS: Public databases were searched for clinical trials of pharmacotherapy or psychotherapy for managing depression or anxiety symptoms in adults receiving OAT. Subsequently, we conducted a random effects meta-analysis model of RCTs by antidepressants subclasses. RESULTS: In our literature search, we identified 22 RCTs, eight of which were eligible for meta analysis. Seven studies evaluated antidepressants in patients already maintained on OAT; two studies reported significant results for antidepressant effects versus placebo. Similarly, two of the seven studies that initiated antidepressants with OAT had advantages over placebo. Meta-analysis of grouped data revealed that tricyclic antidepressants (TCAs) (n = 235) significantly improved mean depression scores (SMD = -2.35, 95%CI: [-4.35, -0.34], z = -2.29, p = .022) while Selective Serotonin Reuptake Inhibitors (SSRIs) (n = 311) were not significantly different than placebo (SMD = 0.47, 95%CI: [-0.35, 1.30], z = 1.12, p = .263). Four out of five studies that implemented psychotherapeutic approaches reported a greater reduction of depressive symptoms than the comparison group. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: To date, psychotherapy has the most documented evidence for efficacy. TCAs appears effective but with more adverse effects than SSRIs. Further studies of OAT and adjunct antidepressant treatments for dual diagnosis patients are warranted. (Am J Addict 2017;26:551-563). PMID- 28675764 TI - Convenient Access to meta-Substituted Phenols by Palladium-Catalyzed Suzuki Miyaura Cross-Coupling and Oxidation. AB - We report a new approach to the synthesis of meta-substituted phenols in which a single palladium catalyst accomplishes a Suzuki-Miyaura cross-coupling between a beta-chlorocyclohexenone and an arylboronic acid, and oxidation of the resulting cyclohexenone to the corresponding phenol upon introduction of a terminal oxidant and electron transfer mediator. Notably, this method also allows ready access to ortho, meta-disubstituted phenols, sterically congested biaryl phenols, and more highly substituted phenols. PMID- 28675763 TI - Resveratrol derivatives as a pharmacological tool. AB - Prodrugs of resveratrol are under development. Among the long-term goals, still largely elusive, are (1) modulating physical properties (e.g., water-soluble derivatives bearing polyethylene glycol chains), (2) changing distribution in the body (e.g., galactosyl derivatives restricted to the intestinal lumen), (3) increasing absorption from the gastrointestinal tract (e.g., derivatives imitating the natural substrates of endogenous transporters), and (4) hindering phase II metabolism (e.g., temporarily blocking the hydroxyls), all contributing to (5) increasing bioavailability. The chemical bonds that have been tested for functionalization include carboxyester, acetal, and carbamate groups. A second approach, which can be combined with the first, seeks to reinforce or modify the biochemical activities of resveratrol by concentrating the compound at specific subcellular sites. An example is provided by mitochondria-targeted derivatives. These proved to be pro-oxidant and cytotoxic in vitro, selectively killing fast growing and tumor cells when supplied in the low micromolar range. This suggests the possibility of anticancer applications. PMID- 28675765 TI - Ultrafast Molecular Rotors and Their CO2 Tuning in MOFs with Rod-Like Ligands. AB - A metal organic framework (MOF) engineered to contain in its scaffold rod-like struts featuring ultrafast molecular rotors showed extremely rapid 180 degrees flip reorientation with rotational rates of 1011 Hz at 150 K. Crystal-pore accessibility of the MOF allowed the CO2 molecules to enter the cavities and control the rotor spinning speed down to 105 Hz at 150 K. Rotor dynamics, as modulated by CO2 loading/unloading in the porous crystals, was described by proton T1 and 2 H NMR spectroscopy. This strategy enabled the regulation of rotary motion by the diffusion of the gas within the channels and the determination of the energetics of rotary dynamics in the presence of CO2 . PMID- 28675766 TI - Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies. AB - OBJECTIVES: To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. METHODS: we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium >=11 mg/dL) at diagnosis. RESULTS: Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate (eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. CONCLUSION: Hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium. PMID- 28675767 TI - Sirtuin7 is involved in protecting neurons against oxygen-glucose deprivation and reoxygenation-induced injury through regulation of the p53 signaling pathway. AB - Sirtuin7 (SIRT7) is known to regulate apoptosis and stress responses. So far, very little is known about the role of SIRT7 in cerebral ischemia/reperfusion injury. In this study, we aimed to investigate the potential role of SIRT7 in regulating oxygen-glucose deprivation and reoxygenation (OGD/R)-induced injury in neurons. We found a significant increase of SIRT7 expression in neurons in response to OGD/R treatment. Knockdown of SIRT7 aggravated OGD/R-induced injury. Knockdown of SIRT7 augmented the levels of total and acetylated p53 protein. Moreover, knockdown of SIRT7 markedly increased the transcriptional activity of p53 toward apoptosis and activated the p53-mediated proapoptotic signaling pathway. By contrast, overexpression of SIRT7 showed the opposite effects. Taken together, the results of our study suggest that SIRT7 is involved in protecting neurons against OGD/R-induced injury, possibly through regulation of the p53 mediated proapoptotic signaling pathway, indicating a potential therapeutic target for cerebral ischemia/reperfusion injury. PMID- 28675768 TI - Experimental evolution reveals differences between phenotypic and evolutionary responses to population density. AB - Group living can select for increased immunity, given the heightened risk of parasite transmission. Yet, it also may select for increased male reproductive investment, given the elevated risk of female multiple mating. Trade-offs between immunity and reproduction are well documented. Phenotypically, population density mediates both reproductive investment and immune function in the Indian meal moth, Plodia interpunctella. However, the evolutionary response of populations to these traits is unknown. We created two replicated populations of P. interpunctella, reared and mated for 14 generations under high or low population densities. These population densities cause plastic responses in immunity and reproduction: at higher numbers, both sexes invest more in one index of immunity [phenoloxidase (PO) activity] and males invest more in sperm. Interestingly, our data revealed divergence in PO and reproduction in a different direction to previously reported phenotypic responses. Males evolving at low population densities transferred more sperm, and both males and females displayed higher PO than individuals at high population densities. These positively correlated responses to selection suggest no apparent evolutionary trade-off between immunity and reproduction. We speculate that the reduced PO activity and sperm investment when evolving under high population density may be due to the reduced population fitness predicted under increased sexual conflict and/or to trade-offs between pre- and post-copulatory traits. PMID- 28675769 TI - Outcomes of allogeneic stem cell transplantation in patients with paroxysmal nocturnal hemoglobinuria with or without aplastic anemia. AB - OBJECTIVE: The aim of this study was to evaluate the long-term outcomes of allogeneic stem cell transplantation (SCT) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia (AA). METHOD: A total of 33 patients with PNH clones who underwent allogeneic SCT were analyzed. RESULTS: After a median follow-up of 57 months (range, 6.0-151.3), the 5-year estimated overall survival rate was 87.9+/-5.7%. Four patients died of transplant-related mortality (TRM). With the exception of one patient with early TRM, 32 patients were engrafted. Two patients who had developed delayed GF received a second transplant and recovered. The cumulative incidences of acute graft-vs-host disease (GVHD) (>=grade II) and chronic GVHD (>=moderate) were 27.3+/-7.9% and 18.7+/-7.0%, respectively. Twenty-one patients receiving SCT with reduced intensity conditioning (RIC) had available follow-up data for PNH cell population for the first 6 months post-transplant. Analysis of these data revealed that the PNH clones disappeared within approximately 2 months. CONCLUSION: RIC regimen was sufficient to eradicate PNH clones with sustained donor-type engraftment after allogeneic SCT. Therefore, application of allogeneic SCT with RIC should be considered in patients with PNH, in accordance with the severity of the underlying bone marrow failure. PMID- 28675771 TI - Kinematic chain-related risk factors in the development of lower extremity injuries in women: A prospective study. AB - The link between dynamic range of motion (dROM) parameters within the kinematic chain and the development of lower extremity (LE) injury has gained attention; however, very few longitudinal studies have been conducted. Therefore, we wanted to prospectively determine dROM-related risk factors for the development of LE injury. Within this study, 90 female physical education students aged 19.33+/ 0.87 years were tested. Full-body kinematic and vertical ground reaction force (VGRF) parameters were measured during a triple hop jump (THJ). Cox regression analysis was used to identify potential risk factors for the development of LE injury. The injury follow-up was assessed using a weekly online questionnaire and a tri-monthly retrospective control questionnaire. Lower extremity injury was diagnosed by an experienced medical doctor. During the follow-up, 39 percent of the participants were diagnosed with a LE injury. Decreased dROM of the pelvic segment (P=.043) and increased dROM of the knee and ankle joint (P=.041 and P=.028, respectively) in the sagittal plane during landing phase were identified as predictive parameters for the development of LE injury in women. No VGRF parameters were identified as predictive variables. It can be concluded that an altered dROM within the LE kinematic chain was observed within the group at risk for LE injury. More specifically, this group showed reduced proximal dROM that was coupled with increased dROM in the distal segments during a THJ. The THJ can be seen as a practical screening tool for LE injury. PMID- 28675770 TI - Oral complications at 6 months after radiation therapy for head and neck cancer. AB - OBJECTIVE: To examine oral complications 6 months after modern radiation therapy (RT) for head and neck cancer (HNC). METHODS: Prospective multicenter cohort study of patients with HNC receiving intensity-modulated radiation therapy or more advanced RT. Stimulated whole salivary flow, maximal mouth opening, oral mucositis, oral pain, oral health-related quality of life (OH-QOL), and oral hygiene practices were measured in 372 subjects pre-RT and 216 subjects at 6 months from the start of RT. RESULTS: Mean stimulated whole salivary flow declined from 1.09 to 0.47 ml/min at 6 months (p < .0001). Mean maximal mouth opening reduced from 45.58 to 42.53 mm at 6 months (p < .0001). 8.1% of subjects had some oral mucositis at 6 months, including 3.8% with oral ulceration. Mean overall pain score was unchanged. OH-QOL was reduced at 6 months, with changes related to dry mouth, sticky saliva, swallowing solid foods, and sense of taste (p <= .0001). At 6 months, there was greater frequency of using dental floss and greater proportion using supplemental fluoride (p < .0001). CONCLUSIONS: Despite advances in RT techniques, patients with HNC experience oral complications 6 months after RT, with resulting negative impacts on oral function and quality of life. PMID- 28675772 TI - Constructing High-Generation Sierpinski Triangles by Molecular Puzzling. AB - Three generations of metalated trigonal supramolecular architectures, so-called metallo-triangles, were assembled from terpyridine (tpy) complexes. The first generation (G1) metallo-triangles were directly obtained by reacting a bis(terpyridinyl) ligand with a 60 degrees bite angle and ZnII ions. The direct self-assembly of G2 and G3 triangles by mixing organic ligands and ZnII , however, only generated a mixture of G1 and G2, as well as a trace amount of insoluble polymer-like precipitate. Therefore, a modular strategy based on the connectivity of ?tpy-Ru2+ -tpy? was employed to construct two metallo-organic ligands for the assembly of G2 and G3 Sierpinski triangles. The metallo-organic ligands LA and LB with multiple free terpyridines were obtained through Suzuki cross-coupling of the RuII complexes, and then assembled with ZnII or CdII to obtain high-generation metallo-triangular architectures in nearly quantitative yield. The G1-G3 architectures were characterized by NOESY and DOSY NMR spectroscopy, ESI-MS, TWIM-MS, and transmission electron microscopy. PMID- 28675773 TI - A Polymer Chemistry Point of View on Mucoadhesion and Mucopenetration. AB - Although oral is the preferred route of administration of pharmaceutical formulations, the long-standing challenge for medically active compounds to efficiently cross the mucus layer barrier limits its wider applicability. Efforts in nanomedicine to overcome this hurdle consider mucoadhesive and mucopenetrating drug carriers by selectively designing (macromolecular) building blocks. This review highlights and critically discusses recent strategies developed in this context including poly(ethylene glycol)-based modifications, cationic and thiolated polymers, as well as particles with high charge density, zeta-potential shifting ability, or mucolytic properties. The latest advances in ex vivo test platforms are also reviewed. PMID- 28675774 TI - Nature of Bonding in Donor-Acceptor Interactions Exemplified by Complexes of N Heterocyclic Carbenes with 1,2,5-Telluradiazoles. AB - Comprehensive structural, spectroscopic, and quantum chemical analyses of new donor-acceptor complexes between N-heterocyclic carbenes and 1,2,5 telluradiazoles and a comparison with previously known complexes involving tellurenyl cations showed that the dative C-Te bonds cannot be solitarily described with only one Lewis formula. Canonical Lewis formulas that denote covalency and arrows emphasizing ionicity complement each other in varying extents. Evaluation of the relative weights of these resonance forms requires proper bonding description with a well-balanced toolbox of analytical methods. If for conciseness only, one resonance form is used, it must be the most significant one according to the analytical evaluation. If unclear, all significant resonance forms should be displayed. PMID- 28675775 TI - Structural characterization of the linked NS2B-NS3 protease of Zika virus. AB - The Zika virus (ZIKV) NS2B-NS3 protease is an important drug target. The conventional flaviviral protease constructs used for structural studies contain the NS2B cofactor region linked to the NS3 protease domain via a glycine-rich flexible linker. Here, we examined the structural dynamics of this conventional Zika protease (gZiPro) using NMR spectroscopy. Although the glycine-rich linker in gZiPro does not alter the overall folding of the protease in solution, gZiPro is not homogenous in ion exchange chromatography. Compared to the unlinked protease construct, the artificial linker affects the chemical environment of many residues including H51 in the catalytic triad. Our study provides a direct comparison of ZIKV protease constructs with and without an artificial linker. PMID- 28675776 TI - Vitamin D supplementation in primary allergy prevention: Systematic review of randomized and non-randomized studies. AB - BACKGROUND: To date, a systematic review of the evidence regarding the association between vitamin D and allergic diseases development has not yet been undertaken. OBJECTIVE: To review the efficacy and safety of vitamin D supplementation when compared to no supplementation in pregnant women, breastfeeding women, infants, and children for the prevention of allergies. METHODS: Three databases were searched through January 30, 2016, including randomized (RCT) and nonrandomized studies (NRS). Two reviewers independently extracted data and assessed the certainty in the body of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Among the 1932 articles identified, one RCT and four NRS were eligible. Very low certainty in the body of evidence across examined studies suggests that vitamin D supplementation for pregnant women, breastfeeding women, and infants may not decrease the risk of developing allergic diseases such as atopic dermatitis (in pregnant women), allergic rhinitis (in pregnant women and infants), asthma and/or wheezing (in pregnant women, breastfeeding women, and infants), or food allergies (in pregnant women). We found no studies of primary prevention of allergic diseases in children. CONCLUSION: Limited information is available addressing primary prevention of allergic diseases after vitamin D supplementation, and its potential impact remains uncertain. PMID- 28675777 TI - Effects of Myricetin-Containing Ethanol Solution on High-Fat Diet Induced Obese Rats. AB - Myricetin is a natural flavonol widely occurring in wines. Many beneficial effects of myricetin in alcoholic beverages have been reported before, but never including anti-obesity. In the present study, we fed obese male Sprague-Dawley rats with ethanol solutions containing various concentrations of myricetin and found that myricetin may maintain the food intake while reduce the weight-gain, feed efficiency, level of blood lipids, adipocyte size, and weight and size of the perirenal and epididymal adipose tissues (P < 0.01). Our experiment data also show that the anti-obesity effect may be associated with the upregulation of adropin and beta-endorphin levels. Based on the above-described findings, we propose the potential for myricetin-containing alcoholic beverages to be developed into anti-obesity health food. PMID- 28675778 TI - Hip abductor muscle activity during walking in individuals with gluteal tendinopathy. AB - The external hip adduction moment during walking is greater in individuals with gluteal tendinopathy (GT) than pain-free controls. Although this likely represents a greater demand on the hip abductor muscles implicated in GT, no study has investigated activation of these muscles in GT. For this purpose, fine wire electrodes were inserted into the segments of the gluteus minimus and medius muscles, and surface electrodes placed on the tensor fascia lata, upper gluteus maximus, and vastus lateralis muscles of eight individuals with, and eight without, GT. Participants underwent six walking trials. Individual muscle patterns were compared between groups using a wavelet-based linear effects model and muscle synergy analysis performed using non-negative matrix factorization to evaluate muscle activation patterns, within- and between-participant variability. Compared to controls, individuals with GT exhibited a more sustained initial burst of the posterior gluteus minimus and middle gluteus medius muscle segments. Two muscle synergies were identified; Synergy-1 activated in early-mid stance and Synergy-2 in early stance. In GT participants, posterior gluteus minimus and posterior gluteus medius and tensor fascia lata contributed more to Synergy-1 active during the period of single leg support. Participants with GT exhibited reduced within-participant variability of posterior gluteus medius and reduced between-participant variability of anterior gluteus minimus and medius and upper gluteus maximus. In conclusion, individuals with GT exhibit modified muscle activation patterns of the hip abductor muscles during walking, with potential relevance for gluteal tendon loading. PMID- 28675779 TI - Neurosteroidogenesis and progesterone anti-inflammatory/neuroprotective effects. AB - Progesterone shows anti-inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Because neurosteroids have been implicated as protective factors for MS and EAE, we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5alpha reductase, 3alpha-hydroxysteroid dehydrogenase (3alpha-HSOR) and aromatase, whereas changes of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were not significant. mRNA translocator protein (18 kDa) (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNAs. Progesterone pretreatment before EAE induction increased Star, VDAC, P450scc, 5alpha-reductase type I, 3alpha-HSOR and aromatase mRNAs and did not modify 3beta-HSD. TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNAs. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3beta-HSD, 3alpha-HSOR and 5alpha-reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS. The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti-inflammatory effects of exogenous progesterone given to EAE mice. PMID- 28675780 TI - Ternary Alloys Encapsulated within Different MOFs via a Self-Sacrificing Template Process: A Potential Platform for the Investigation of Size-Selective Catalytic Performances. AB - Functional nanoparticles encapsulated within metal-organic frameworks (MOFs) as an emerging class of composite materials attract increasing attention owing to their enhanced or even novel properties caused by the synergistic effect between the two functional materials. However, there is still no ideal composite structure as platform to systematically analyze and evaluate the relation between the enhanced catalytic performance of composites and the structure of MOF shells. In this work, taking RhCoNi ternary alloy nanoflowers, for example, first the RhCoNi@MOF composite catalysts sheathed with different structured MOFs via a facile self-sacrificing template process are successfully fabricated. The structure type of MOF shells is easily adjustable by using different organic molecules as etchant and coordination reagent (e.g., 2,5-dihydroxyterephthalic acid or 2-methylimidazole), which can dissolve out the Co or Ni element in the alloy template in a targeted manner, thereby producing ZIF-67(Co) or MOF-74(Ni) shells accordingly. With the difference between the two MOF shells in the aperture sizes, the as-prepared two RhCoNi@MOF composites preform distinct size selectivity during the alkene hydrogenation. This work would help us to get more comprehensive understanding of the intrinsic role of MOFs behind the enhanced catalytic performance of nanoparticle@MOF composites. PMID- 28675781 TI - Telling the whole story about simulation-based education. PMID- 28675782 TI - Alternative or Nontraditional Sexualities and Therapy: A Case Report. AB - A traditionally marginalized subset of couples engage in consensual nonmonogamy (CNM: open marriage, polyamory, swinging, etc.) or alternative sexualities, such as kink or bondage/discipline, dominance/submission, and sadism/masochism. Nonmonogamous and sexually diverse individuals often experience discrimination or stigma in various domains of professional services, including mental healthcare. These cases require knowledge, skills, and awareness to provide culturally sensitive care, which is often called "kink aware therapy" or "poly-friendly therapy" within alternative sexuality communities. This article explores one application of a kink-focused and CNM-focused therapeutic framework for working with a couple who is exploring nontraditional sexualities. This case incorporates evidence-based clinical practice and identifies the limitations and significant gaps in the empirical research literature. PMID- 28675783 TI - Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels. AB - Pro-opiomelanocortin (POMC) neurones within the hypothalamic arcuate nucleus are vital anorexigenic neurones. Both the insulin receptor and leptin receptor are coupled to activation of phosphatidylinositide-3 kinase (PI3K) to regulate multiple functions that increase POMC neuronal excitability. Using whole-cell recording in several mammalian species, we have found that both insulin and leptin depolarised POMC neurones via activation of transient receptor potential (TRPC)5 channels. TRPC5 channels have been rigorously characterised as the downstream effector based on their biophysical properties, pharmacological profile, and localisation by immunocytochemistry and single-cell reverse transcriptase-polymerase chain reaction. By contrast, insulin and leptin hyperpolarise and inhibit neuropeptide Y/agouti-related peptide neurones via activation of KATP channels. As proof of principle, insulin given i.c.v. robustly inhibits food intake and increases O2 utilisation, CO2 production and metabolic heat production. Therefore, these findings indicate that the depolarisation/excitation of POMC neurones by insulin and leptin is preserved across mammalian species and the activation of TRPC5 channels is likely a major mechanism by which insulin and leptin regulate energy homeostasis in mammals. PMID- 28675784 TI - A compendium of ERK targets. AB - The RAF-MEK-ERK cascade is one of the most studied signaling pathways as it controls many vital cellular programs. There has been an immense amount of effort to determine ERK target proteins involved in regulating these programs. Classical biochemical and genetic approaches have elicited hundreds of direct ERK substrates, and with the advent of phospho-proteomic technologies, numerous studies have expanded the number of ERK target proteins. Here, we compile a comprehensive ERK target phospho-site archive, in which we gathered information from various research studies, and we provide this archive as an online database to form a searchable compendium of ERK targets. PMID- 28675785 TI - GAS6-expressing and self-sustaining cancer cells in 3D spheroids activate the PDK RSK-mTOR pathway for survival and drug resistance. AB - AXL receptor tyrosine kinase (RTK) inhibition presents a promising therapeutic strategy for aggressive tumor subtypes, as AXL signaling is upregulated in many cancers resistant to first-line treatments. Furthermore, the AXL ligand growth arrest-specific gene 6 (GAS6) has recently been linked to cancer drug resistance. Here, we established that challenging conditions, such as serum deprivation, divide AXL-overexpressing tumor cell lines into non-self-sustaining and self sustaining subtypes in 3D spheroid culture. Self-sustaining cells are characterized by excessive GAS6 secretion and TAM-PDK-RSK-mTOR pathway activation. In 3D spheroid culture, the activation of the TAM-PDK-RSK-mTOR pathway proves crucial following treatment with AXL/MET inhibitor BMS777607, when the self-sustaining tumor cells react with TAM-RSK hyperactivation and enhanced SRC-AKT-mTOR signaling. Thus, bidirectional activated mTOR leads to enhanced proliferation and counteracts the drug effect. mTOR activation is accompanied by an enhanced AXL expression and hyperphosphorylation following 24 h of treatment with BMS777607. Therefore, we elucidate a double role of AXL that can be assigned to RSK-mTOR as well as SRC-AKT-mTOR pathway activation, specifically through AXL Y779 phosphorylation. This phosphosite fuels the resistance mechanism in 3D spheroids, alongside further SRC-dependent EGFR Y1173 and/or MET Y1349 phosphorylation which is defined by the cell-specific addiction. In conclusion, self-sustenance in cancer cells is based on a signaling synergy, individually balanced between GAS6 TAM-dependent PDK-RSK-mTOR survival pathway and the AXLY779/EGFR/MET-driven SRC-mTOR pathway. PMID- 28675786 TI - Meta-Selective C-H Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold. AB - The first example of meta-selective C-H arylations of arene alcohol-based substrates is described. The strategy involves the combination of the transient norbornene strategy with the quinoline-based acetal scaffold to achieve the formation of biaryl compounds. Both a two-step meta-arylation/scaffold cleavage process and a total telescoping procedure are described, highlighting the convenient attributes of attachment, removal, and recovery of the acetal scaffold. Moreover, the meta-arylated compounds can be further derivatized via ortho-selective functionalizations. These processes establish a foundation for catalytic polyfunctionalization of alcohol-based compounds. PMID- 28675787 TI - Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands. AB - Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3 g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3 carboxamide-based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interactions. Any of the new synthesized compounds showed high affinity for CB2 receptor with Ki values superior to 314 nm, whereas some of them showed moderate affinity for CB1 receptor with Ki values inferior to 400 nm. 7 Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3 g]indolizine-3-carboxamide (2j) exhibited good affinity for CB1 receptor (Ki CB1 = 81 nm) and the highest CB2 /CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed using the hCB1 X-ray in complex with the close pyrazole analogue AM6538 and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands. PMID- 28675788 TI - Proteomics Profiling of Exosomes from Primary Mouse Osteoblasts under Proliferation versus Mineralization Conditions and Characterization of Their Uptake into Prostate Cancer Cells. AB - Osteoblasts communicate both with normal cells in the bone marrow and with tumor cells that metastasized to bone. Here we show that osteoblasts release exosomes, we termed osteosomes, which may be a novel mechanism by which osteoblasts communicate with cells in their environment. We have isolated exosomes from undifferentiated/proliferating (D0 osteosomes) and differentiated/mineralizing (D24 osteosomes) primary mouse calvarial osteoblasts. The D0 and D24 osteosomes were found to be vesicles of 130-140 nm by dynamic light scattering analysis. Proteomics profiling using tandem mass spectrometry (LC-MS/MS) identified 206 proteins in D0 osteosomes and 336 in D24 osteosomes. The proteins in osteosomes are mainly derived from the cytoplasm (~47%) and plasma membrane (~31%). About 69% of proteins in osteosomes are also found in Vesiclepedia, and these canonical exosomal proteins include tetraspanins and Rab family proteins. We found that there are differences in both protein content and levels in exosomes isolated from undifferentiated and differentiated osteoblasts. Among the proteins that are unique to osteosomes, 169 proteins are present in both D0 and D24 osteosomes, 37 are unique to D0, and 167 are unique to D24. Among those 169 proteins present in both D0 and D24 osteosomes, 10 proteins are likely present at higher levels in D24 than D0 osteosomes based on emPAI ratios of >5. These results suggest that osteosomes released from different cellular state of osteoblasts may mediate distinct functions. Using live-cell imaging, we measured the uptake of PKH26 labeled osteosomes into C4-2B4 and PC3-mm2 prostate cancer cells. In addition, we showed that cadherin-11, a cell adhesion molecule, plays a role in the uptake of osteosomes into PC3-mm2 cells as osteosome uptake was delayed by neutralizing antibody against cadherin-11. Together, our studies suggest that osteosomes could have a unique role in the bone microenvironment under both physiological and pathological conditions. PMID- 28675790 TI - Fluorescent Phthalocyanine Assembly Distinguishes Chiral Isomers of Different Types of Amino Acids and Sugars. AB - The functions of some natural supramolecular architectures, such as ribosomes, are dependent on the recognition of different types of chiral biomolecules. However, the recognition of different types of chiral molecules (multiobject chiral recognition), such as amino acids and sugars, by independent and identically artificial supramolecular assembly, was rarely achieved. In this article, simple amphiphilic achiral phthalocyanine was found to form supramolecular chiral assemblies with charged water-soluble polymers upon host guest interactions at the air/water interface. Among these systems, one identical phthalocyanine/poly(l-lysine) assembly not only can distinguish enantiomers of different amino acids but also can recognize several epimers of monose. The chiral recognitions were achieved by comparing either the steady-state fluorescence intensity or fluorescence quenching rate of phthalocyanine/poly(l lysine) assemblies, before and after interaction with different small chiral molecules. It was demonstrated that the interactions between poly(l-lysine) and different small chiral molecules could change the aggregation of phthalocyanines. And the sensitivity of fluorescence and the excellent multiobject chiral recognition properties of the phthalocyanine/poly(l-lysine) assembly are dependent on the subtle molecular packing mode and the cooperation of different noncovalent interactions. PMID- 28675789 TI - Coupled Valence-Bond State Molecular Dynamics Description of an Enzyme-Catalyzed Reaction in a Non-Aqueous Organic Solvent. AB - Enzymes are widely used in nonaqueous solvents to catalyze non-natural reactions. While experimental measurements showed that the solvent nature has a strong effect on the reaction kinetics, the molecular details of the catalytic mechanism in nonaqueous solvents have remained largely elusive. Here we study the transesterification reaction catalyzed by the paradigm subtilisin Carlsberg serine protease in an organic apolar solvent. The rate-limiting acylation step involves a proton transfer between active-site residues and the nucleophilic attack of the substrate to form a tetrahedral intermediate. We design the first coupled valence-bond state model that simultaneously describes both reactions in the enzymatic active site. We develop a new systematic procedure to parametrize this model on high-level ab initio QM/MM free energy calculations that account for the molecular details of the active site and for both substrate and protein conformational fluctuations. Our calculations show that the reaction energy barrier changes dramatically with the solvent and protein conformational fluctuations. We find that the mechanism of the tetrahedral intermediate formation during the acylation step is similar to that determined under aqueous conditions, and that the proton transfer and nucleophilic attack reactions occur concertedly. We identify the reaction coordinate to be mostly due to the rearrangement of some residual water molecules close to the active site. PMID- 28675791 TI - Olprinone protects the liver from ischemia-reperfusion injury through oxidative stress prevention and protein kinase Akt activation. AB - Liver ischemia-reperfusion (IR) injury is inevitable in surgical procedures such as hepatic resection and liver transplantation. It represents a leading cause of liver graft dysfunction and primary nonfunction after transplantation. Phosphodiesterase (PDE) inhibitors are emerging as effective drugs able to reduce IR damage. The aim of this study was to investigate the effect of selective PDE-3 inhibitor olprinone (Olp) against liver IR injury. Male Wistar rats were subjected to 1 h of partial warm ischemia (70%) followed by 6 h of reperfusion. Before ischemia, rats were treated with saline (IR group), Olp (Olp group), or Olp with Akt inhibitor LY294002 (Olp plus LY group). After reperfusion, hepatic injury (transaminase activities), mitochondrial damage (glutamate dehydrogenase activity), oxidative stress (malondialdehyde and glutathione concentrations and catalase and superoxide dismutase activities), and protein kinase Akt activation were evaluated. Rat treatment with Olp reduced liver injury, prevented mitochondrial damage, decreased lipid peroxidation, and enhanced antioxidant enzymes. Also, Olp induced a significant activation in protein kinase Akt. Inhibition of Akt with LY294002 abolished all of the protective effects of Olp. In conclusion, Olp treatment may be an effective strategy in reducing liver IR injury through oxidative stress prevention and Akt activation. PMID- 28675792 TI - Nonlocalized postactivation performance enhancement (PAPE) effects in trained athletes: a pilot study. AB - Fifteen trained athletes were assessed for postactivation performance enhancement (PAPE) of squat jumps (SJs) and power push-ups (PPUs) following upper body activation, lower body activation, upper and lower body activation, and rest. SJ improved similarly across all 4 conditions. PPU could not be assessed. Since the test protocol of SJ and PPU involved upper and lower body activation and caused PAPE in SJ, future work is required to determine if a nonlocalized PAPE effect exists. PMID- 28675793 TI - Chelating effects of carnosine in ameliorating nickel-induced nephrotoxicity in rats. AB - The kidney is one of the main organs affected by nickel toxicity. We investigated the protective effects of carnosine on nickel-induced oxidative stress in kidney of rats. Animals received NiSO4 (20 mg.kg-1.day-1 intragastrically) and (or) carnosine (10 mg.kg-1.day-1 intragastrically) for 21 days and then were evaluated for biochemical, molecular, and histopathological alterations. Nickel caused an increase in renal levels of malondialdehyde and a decrease in reduced glutathione, catalase, and superoxide dismutase levels and total antioxidant capacity. Carnosine prevented the prooxidant and antioxidant imbalance induced by nickel. Nickel-treated rats showed an increase in serum creatinine, urea, and uric acid with a concomitant decrease in albumin. Nickel markedly accumulated in kidney of exposed rats, but its concentration was effectively reduced by carnosine treatment. Carnosine corrected the biochemical abnormalities and the elevated renal TNF-alpha and IL-6 levels in the nickel-treated group. It also attenuated nickel-induced abnormalities in renal architecture. Although carnosine showed antioxidant and anti-inflammatory effects in renal tissue of nickel exposed rats, we cannot clearly attribute the protective effect of carnosine to these effects. Instead, the beneficial effect of carnosine observed in the current study may be due to chelation between nickel and carnosine. Thus, carnosine may represent a therapeutic option to protect against nickel-induced nephrotoxicity that deserves further consideration and examination. PMID- 28675795 TI - Announcement of a new award-The Anaesthesia and Intensive Care Biennial History Award and the inaugural winner. PMID- 28675794 TI - Beneficial effects of rosmarinic acid against alcohol-induced hepatotoxicity in rats. AB - Alcohol is a severe hepatotoxicant that causes a variety of liver disorders. Rosmarinic acid (RA), a natural phenol, shows some biological activities, including antioxidant and anti-inflammatory effects. We investigated the effects of RA (10 mg/kg) against ethanol-induced oxidative damage and hepatotoxicity in rats. Animals received ethanol (4 g/kg, i.g.) and (or) RA (10 mg/kg, i.g.) daily for 4 weeks. At the end of the treatment period, rats were weighed and use for biochemical, molecular, and histopathological examinations. Ethanol increased hepatic lipid peroxidation (P < 0.001) and decreased hepatic levels of reduced glutathione (P < 0.01), catalase (P < 0.05), and superoxide dismutase (P < 0.001) compared with control group. RA prevented the prooxidant and antioxidant imbalance induced by ethanol in liver. Furthermore, RA ameliorated the increased liver mass, serum levels of ALT, AST, LDH, TNF-alpha, and IL-6 in ethanol group. Necrosis and infiltration of inflammatory cells in liver parenchyma were attenuated by RA treatment. Our findings showed that RA prevents ethanol-induced oxidant/antioxidant imbalance and liver injury in an experimental model of ethanol-induced hepatotoxicity. Therefore, RA may be a good candidate to protect against ethanol-induced hepatotoxicity; this deserves consideration and further examination. PMID- 28675796 TI - Negative or positive? The iron lung and poliomyelitis-Zurich, 1951. AB - During the poliomyelitis epidemics of the last century hospitals were inundated with patients in acute respiratory failure. Between 1946 and 1949, Nandor (Ferdinand) Eichel documented the use of the iron lung in children with acute poliomyelitis at the University Children's Hospital, Zurich. The aim was to assess the effectiveness of the Iron lung and negative pressure respiratory support for this indication and to establish its role in the context of other existing therapies at the time. Eichel produced his review and data as the Inaugural Dissertation towards his medical degree from the the University of Zurich, published in 1951. The dissertation was written in German and first translated into English in 2014. The current paper explores the findings of the dissertation and explains why there has been the transition to techniques of respiratory support today. It includes a biography of Dr F. N. Eichel and an update on the current status of poliomyelitis. The original dissertation was found in the home of Nandor's son and was of great interest to the current authors, Nandor's granddaughter and her colleague. PMID- 28675797 TI - Delivery of anoxic gas mixtures in anaesthesia: case report and review of the struggle towards safer standards of care. AB - In 1983 a patient at The Alfred Hospital, Melbourne died during general anaesthesia for emergency surgery, in the weeks following maintenance to the operating theatre gas supply. In the ensuing investigation, it was revealed that he had been given 100% nitrous oxide throughout the anaesthetic due to the inadvertent crossing of the nitrous oxide and oxygen pipelines during the repair work. In this article we review the published literature on the delivery of hypoxic and anoxic gas mixtures, and the associated morbidity and mortality. We explore the developments that took place in the delivery of anaesthetic gases, and the unforeseen dangers associated with these advances. We consider the risks to patient safety when technological advances outpaced the implementation of essential safety standards. We investigate the events that pushed the development of safer standards of anaesthetic practice and patient monitoring, which have contributed to modern day theatre practice. Finally, we consider the risks that still exist in the hospital environment, and the need for on-going vigilance. PMID- 28675798 TI - St John's Hospital (Morton House), Launceston, Australia: A history of the hospital and Dr William Russ Pugh's first operations under ether. AB - On 7 June 1847, William Russ Pugh, MD, performed two operations at the St John's Hospital and Self-Supporting Dispensary, Launceston, Tasmania, while his patients were rendered insensible by the inhalation of sulphuric ether. These operations are the earliest documented surgical operations under ether in Australia. St John's Hospital officially opened on 1 September 1845. The hospital may have closed in late 1853 because of financial difficulties. The two-storey Georgian style building which served as the hospital was completed c1831-1832. It has served as a residence, school, boarding school, hospital, medical consulting rooms and commercial offices. The building is now known as Morton House. We could not identify the date when the name Morton House was adopted, or explain the origin of the name. The earliest identified use of this name is in May 1873 in a newspaper advertisement for boarders. No person with the surname Morton is known to have been associated with the building as an owner or as a tenant. The name Morton House may honour William T.G. Morton, MD, the Boston dentist who performed the first public demonstration of surgical etherisation on 16 October 1846. PMID- 28675799 TI - Dr Snow killed a bird: The genesis of pharmacokinetics and pharmacodynamics in anaesthesia. AB - This essay presents a pharmacologist's perspective of what would be now called 'preclinical research' and 'uncontrolled clinical trials' surrounding the first public demonstration by William Thomas Green Morton of painless surgery achieved by the inhalation of ether in a patient at the Massachusetts General Hospital on 16 October 1846. Of the many people who made history in those earliest days of surgical anaesthesia in both the United States and Great Britain, John Snow stands out for his personal research that spanned basic science and clinical medicine. Primarily, Snow used the relationship between the vapour pressure of a volatile liquid and temperature to design a vaporiser. This allowed control of the inspired concentration of the volatile liquid epitomised by diethyl ether, and thus the time-course and depth of anaesthesia. In an era when developments in anaesthesia were almost exclusively based on empirical modifications to apparatus and technique, Snow, and to a lesser extent his contemporary Andrew Buchanan, stood out from all others in advancing the quantitative basis of anaesthesia. Both described the physiological basis of control over gas uptake whereby they related that gas moved across concentration gradients in the body: alveolar to arterial to tissue to venous gas tensions, and Snow devised a progressional semi quantitative scale of five 'stages' of ether anaesthesia. They thereby introduced the elements of what would be referred to 'pharmacokinetics' and 'pharmacodynamics', a century later. This essay attempts to place them and their scientific insights into context with contemporaneous principal personae and knowledge. PMID- 28675800 TI - High altitude hypoxia, a mask and a Street. Donation of an aviation BLB oxygen mask apparatus from World War 2. AB - The history of hypoxia prevention is closely inter-related with high altitude mountain and aviation physiology. One pioneering attempt to overcome low inspired oxygen partial pressures in aviation was the BLB mask-named after the three designers-Walter M Boothby, W Randolph Lovelace II and Arthur H Bulbulian. This mask and its variations originated just prior to World War 2 when aircraft were able to fly higher than 10,000 feet and pilot hypoxia affecting performance was an increasing problem. We give a brief description of the mask and its designers and discuss the donation of a model used by the British War Office in October 1940 and donated to the Harry Daly Museum at the Australian Society of Anaesthetists by the family of Dr Fred Street. Dr Street was a pioneering paediatric surgeon in Australia and served as a doctor in the Middle East and New Guinea in World War 2. He received the Military Cross. PMID- 28675801 TI - Some reminiscences from the archives-the Australian Society of Anaesthetists Newsletter of April 1971. AB - Comments are made about the items of news and some of the personalities involved from a historical perspective in the Australian Society of Anaesthetists Newsletter of April 1971. PMID- 28675802 TI - This Yankee dodge. PMID- 28675804 TI - The Eye of a Stranger. PMID- 28675805 TI - Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders. AB - Multicentric carpal-tarsal osteolysis; multicentric osteolysis, nodulosis, and arthropathy; and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase (MMP) 2, and MMP14, respectively; however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and epiphyseal bone development. Normal neonatal mouse forepaws were imaged by micro-computed tomography and examined histologically. Murine forepaw ossification occurred sequentially. Subarticular regions of endochondral ossification showed morphologic and calcification patterns that were distinct from archetypical physeal endochondral ossification. This suggests that two different forms of endochondral ossification occur. The skeletal sites showing the greatest abnormality in the carpal-tarsal osteolysis syndromes are regions of subarticular ossification. Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal-tarsal osteolysis phenotype. MafB, Mmp-2, and Mmp-14 were expressed widely, and tartrate resistant acid phosphatase staining notably was absent in the subarticular regions of the cartilage anlagen and entheses at a time point most relevant to the human osteolysis syndromes. Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes. PMID- 28675806 TI - The future perspective: metabolomics in laboratory medicine for inborn errors of metabolism. AB - Metabolomics can be described as a simultaneous and comprehensive analysis of small molecules in a biological sample. Recent technological and bioinformatics advances have facilitated large-scale metabolomic studies in many areas, including inborn errors of metabolism (IEMs). Despite significant improvements in the diagnosis and treatment of some IEMs, it is still challenging to understand how genetic variation affects disease progression and susceptibility. In addition, a search for new more personalized therapies and a growing demand for tools to monitor the long-term metabolic effects of existing therapies set the stage for metabolomics integration in preclinical and clinical studies. While targeted metabolomics approach is a common practice in biochemical genetics laboratories for biochemical diagnosis and monitoring of IEMs, applications of untargeted metabolomics in the clinical laboratories are still in infancy, facing some challenges. It is however, expected in the future to dramatically change the scope and utility of the clinical laboratory playing a significant role in patient management. This review provides an overview of targeted and global, large-scale metabolomic studies applied to investigate various IEMs. We discuss an existing and prospective clinical applications of metabolomics in IEMs for better diagnosis and deep understanding of complex metabolic perturbations associated with the etiology of inherited metabolic disorders. PMID- 28675807 TI - Autophagy inhibition enabled efficient photothermal therapy at a mild temperature. AB - The heterogeneously-distributed hyperthermia in nanomaterial-mediated photothermal therapy commonly results in incomplete tumor eradication and serious damage of health tissue. Here, we found autophagy was activated in cancer cells underwent photothermal therapy and the inhibition of autophagy significantly enhanced the efficacy of photothermal killing of cancer cells. A formulation of chloroquine-loaded polydopamine nanoparticles was developed for sensitized photothermal cancer therapy, and the in vitro and in vivo study demonstrated that inhibition of autophagy remarkably augmented the efficacy of photothermal therapy, leading to efficient tumor suppression at a mild temperature. The regulation of autophagy provides a new route to increase the efficacy of photothermal cancer therapy. PMID- 28675808 TI - Delayed primary palatal closure in resource-poor countries: Speech results in Ugandan older children and young adults with cleft (lip and) palate. AB - AIMS: Unrepaired clefts still regularly occur in resource-poor countries as a result of limited health-care access. The purpose of the present study was to report resonance, airflow and articulation characteristics following delayed (>=8years) primary palatal closure. METHODS: Fifteen Ugandan participants with cleft (lip and) palate (CP+/-L) were included as well as 15 age- and gender matched Ugandan subjects without clefts. Palatal closure was performed at a mean age of 15;10 years using the Sommerlad technique. Speech evaluations were carried out on a single occasion postoperatively (mean age: 18;10 years). Resonance and nasal airflow were perceptually evaluated and detailed phonetic and phonological assessments were carried out. Additionally, nasalance values were determined. RESULTS: Nasal emission occurred postoperatively in only 27% (4/15) of the patients, whereas resonance disorders and articulation errors were prevalent in 87% (13/15) of the patient group. Compared with the control group, a significantly higher prevalence of hypernasality and significantly higher nasalance values for all oral and oronasal speech samples were obtained in the CP+/-L group. Moreover, significantly smaller consonant inventories and significantly more phonetic and phonological disorders were observed. CONCLUSIONS: Delayed palatal repair (>=8years) seems to be insufficient to eliminate nasal airflow errors, resonance abnormalities, and articulation disorders. In order to prevent patients' late presentation at specialized centers, the availability of high quality surgical cleft palate treatment should increase as well as people's awareness of the possibility and importance of early surgical intervention. Moreover, speech therapy following delayed palatal closure would be beneficial. Furthermore, a standardized and validated protocol for speech assessment in future studies is advocated. PMID- 28675809 TI - Does modifying personal responsibility moderate the mental contamination effect? AB - BACKGROUND AND OBJECTIVES: Mental contamination is the psychological sense of internal dirtiness that arises in the absence of physical contact with a perceived contaminant. Mental contamination can be evoked through imagining perpetrating a moral transgression. This study experimentally evoked mental contamination by asking men to imagine perpetrating a non-consensual kiss. It explored whether reducing sense of personal responsibility for the kiss moderated the mental contamination effect. METHODS: Male students (N = 60) imagined giving either a consensual or non-consensual kiss. Personal responsibility for the kiss was manipulated in one of two non-consensual kiss conditions by way of the inclusion of social influence information. Feelings of mental contamination were assessed by self-report and through a behavioural index. RESULTS: Mental contamination was successfully induced in the two non-consensual kiss conditions. There was evidence to support the hypothesis that reducing personal responsibility might moderate specific components of mental contamination (shame, dirtiness and urge to cleanse). The effect of responsibility modification was evident in the self-report measures, but not in the behavioural index. LIMITATIONS: The sample comprised male university students which limits generalizability of the findings. The behavioural assessment of mental contamination was limited to a proxy measure. CONCLUSIONS: Imagined moral violations are associated with increases in indices of mental contamination. Further research should investigate whether feelings of shame, dirtiness and urge to cleanse are particularly responsive to responsibility modifications. PMID- 28675810 TI - Use of Leukocyte- and Platelet-Rich Fibrin in the Treatment of Medication-Related Osteonecrosis of the Jaws. AB - Lesions associated with medication-related osteonecrosis of the jaws (MRONJ) are refractory to different treatment approaches. Hence, auxiliary approaches capable of improving patient outcomes should be explored. Leukocyte- and platelet-rich fibrin (LPRF) is a second-generation platelet concentrate (natural autologous fibrin matrix). It shows anti-infectious activity through immune regulation and accelerates the angiogenesis and multiplication of fibroblasts and osteoblasts; in consequence, it stimulates soft tissue healing and prevents exposure of the alveolar bone in the oral cavity. This report describes 2 cases involving women with breast cancer who were being treated with zoledronic acid and exhibited advanced MRONJ. In case 1, MRONJ developed in the maxilla after dental extraction; in case 2, it was assumed that MRONJ arose spontaneously in the mandible because no other risk factors could be detected. These cases were managed with surgical resection of the necrotic bone followed by placement of an LPRF membrane. Complete wound healing and intact mucosal cover were achieved. At clinical and tomographic follow-up after 2 years, there were no oral lesions or complaints. Therefore, this could be a noninvasive, quick, and alternative approach to manage bone exposure. The LPRF membrane contributes to a successful outcome and acts as a physical barrier against micro-organisms, thus preventing secondary infections. PMID- 28675811 TI - Effects of Expansion Sphincter Pharyngoplasty on the Apnea-Hypopnea Index and Heart Rate Variability. AB - PURPOSE: Heart rate variability (HRV) is a noninvasive and sensitive method used to evaluate autonomic function of the heart based on specific polysomnographic parameters. This study aimed to determine the effect of expansion sphincter pharyngoplasty (ESP) on HRV and the apnea-hypopnea index (AHI) in patients with obstructive sleep apnea (OSA). MATERIALS AND METHODS: This retrospective cohort study included patients who presented to the Department of Otorhinolaryngology, Hacettepe University Hospital (Ankara, Turkey), were diagnosed with OSA, and underwent ESP. Patient medical records, including demographic data, polysomnographic findings, and HRV parameters, were reviewed. The predictor variable was the effect of ESP on the AHI and the primary outcome variables were HRV parameters. Descriptive and bivariate statistics were computed using chi2 test, t test, and Mann-Whitney U test. RESULTS: The mean age of the 28 patients (20 men and 8 women) was 43 +/- 9.9 years. Surgical success (AHI, <20; 50% decrease in the AHI) was achieved in 16 patients (57.1%). The AHI decreased in 22 patients (78.6%) but increased in 6 patients (21.4%) after ESP. The ratio of low frequency power (LF) to high-frequency power (HF) decreased significantly in the patients with successful surgery and in those whose AHI decreased after surgery (P = .02 and P = .001, respectively). For the change in the LF/HF ratio, 19 patients had a decrease in sympathetic activity, whereas 9 had an increase in sympathetic activity, after ESP. A decrease in sympathetic activity after ESP was significantly associated with surgical success and a decrease in the AHI (P = .033 and P = .001, respectively). CONCLUSION: ESP is an effective surgical option for the treatment of OSA and lowers the AHI. Successful ESP plays a role in decreasing sympathetic activity of the heart, which might be associated with a decrease in the risk of cardiovascular disease. PMID- 28675812 TI - Pre-Emptive Effect of Dexamethasone and Diclofenac Sodium Associated With Codeine on Pain, Swelling, and Trismus After Third Molar Surgery: A Split-Mouth, Randomized, Triple-Blind, Controlled Clinical Trial. AB - PURPOSE: We aimed to compare the effect of dexamethasone, 8 mg, and diclofenac sodium, 50 mg, associated with codeine, 50 mg, on the control of pain, swelling, and trismus after extraction of impacted third molars. MATERIALS AND METHODS: Fifteen healthy patients with a mean age of 22.8 years (SD, 12.62 years) received a single oral dose of either drug 1 hour before each surgical procedure (left and right teeth). At 24, 48, and 72 hours after surgery, swelling was determined by use of linear measurements on the face and trismus was determined by maximal mouth opening. Postoperative pain was self-recorded by the patients using a numerical rating scale at 24-hour intervals for a period of 72 hours. Data analysis involved descriptive statistics and Shapiro-Wilk, Wilcoxon, and paired t tests (P < .05). RESULTS: Dexamethasone controlled pain (P = .016) and edema (P = .08) within 48 hours better than diclofenac sodium associated with codeine. No statistically significant differences were found between drugs regarding trismus and consumption of rescue analgesics (acetaminophen). CONCLUSIONS: The results of this study suggest that pre-emptive administration of dexamethasone, 8 mg, showed better control of pain and swelling in bilateral extractions of third impacted mandibular molars. PMID- 28675813 TI - Radiological assessment of ankle syndesmotic reduction. AB - INTRODUCTION: The intraoperative assessment of adequacy of syndesmotic reduction is challenging. The aim of this study was to develop a radiographic measure based on the lateral ankle view to assess both the normal and abnormal relationship between the tibia and fibula after simulated syndesmotic malreduction and to evaluate the effect on commonly used mortise measurements. METHODS: Mortise and talar dome lateral radiographs were obtained in eight fresh-frozen cadaveric specimens before and following syndesmosis division and posterior fibular displacement of 2mm increments. Using the technique described, on the lateral radiograph the anterior fibular line ratio (AFL ratio) and posterior fibular line distance (PFL distance) were measured. Both measures were based on the anterior and posterior distal tibia articular margins and flat borders of the fibula. RESULTS: Inter- and intraobserver reliability of the AFL ratio and PFL distance measured almost perfect agreement. In all uninjured specimens the AFL lay just anterior to the midpoint of the tibia and the PFL intersected the posterior tibia articular margin or lay just anterior to it, not posterior. At 2, 4 and 6mm of posterior fibular displacement the decrease in AFL ratio and PFL distance showed significant differences between all pairwise comparisons. CONCLUSION: The proposed new measures of syndesmotic reduction are reproducible and capable of detecting from 2mm of sagittal fibula displacement and can be useful adjuncts in the assessment of syndesmotic reduction. PMID- 28675814 TI - Gender, violence and resilience among Ugandan adolescents. AB - Resilience, commonly understood as the ability to maintain adaptive functioning in the face of adversity, has emerged as a salient entry point in the field of positive youth development. This study makes a unique contribution by exploring dimensions of resilience among adolescents in Uganda, examining associations between violence from different perpetrators and resilience, and testing whether sex moderates these relationships. Analyses are based on data from 3706 primary school students. Exploratory factor analysis (EFA) identified five factors underlying the construct of resilience: Emotional Support; Family Connectedness; School Connectedness; Social Assets; and Psychological Assets. We used regression analysis to investigate associations between these dependent variables, background characteristics, and experiences of violence (including exposure to intimate partner violence against female caregivers). Results reflect a complex relationship between violence and resilience, with patterns varying by perpetrator (e.g., teacher, peers, caregivers) and some evidence that the sex of the student moderates these dynamics. Overall, there is a consistently negative relationship between all violence measures and Psychological Assets. In addition, teacher violence is associated with lower resilience across factors and both caregiver violence and exposure to IPV are consistently associated with decreased Family Connectedness. These findings suggest that adolescents experiencing (and exposed to) violence from adults may be particularly vulnerable to internalizing and/or externalizing behaviors and withdrawal from the family. Findings point to preventing violence from teachers complemented with enhancing family relationships as promising avenues for resilience-strengthening interventions, and also emphasize the need to consider gendered strategies to ensure girls and boys benefit equally. PMID- 28675816 TI - Expanding the boundaries of cryo-EM with phase plates. AB - Phase plates have long been considered as a means for improving the performance of cryo-electron microscopy (cryo-EM). But practical limitations, such as a short lifespan or cumbersome usage have prevented their widespread adoption. The recently developed Volta phase plate overcomes most of the practical issues and it is now commercially available. Results from both, electron cryo-tomography (cryo-ET) and single particle analysis (SPA), have demonstrated the benefits of using a phase plate. In CET phase plates have helped to visualize cellular ultrastructure in unprecedented detail. In SPA phase plates allowed to determine the structures of small proteins at near-atomic resolutions. Further improvements in phase plate technology are possible and new designs are already under development. PMID- 28675815 TI - The heaviness of invisible objects: Predictive weight judgments from observed real and pantomimed grasps. AB - Observation of others' actions has been proposed to provide a shared experience of the properties of objects acted upon. We report results that suggest a similar form of shared experience may be gleaned from the observation of pantomimed grasps, i.e., grasps aimed at pretended objects. In a weight judgment task, participants were asked to observe a hand reaching towards and grasping either a real or imagined glass, and to predictively judge its weight. Results indicate that participants were able to discriminate whether the to-be-grasped glass was empty, and thus light, or full, and thus heavy. Worthy of further investigation, this finding suggests that by observing others' movements we can make predictions, and form expectations about the characteristics of objects that exist only in others' minds. PMID- 28675817 TI - Indicators of dependence for different types of tobacco product users: Descriptive findings from Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) study. AB - BACKGROUND AND AIMS: With no established standard for assessing tobacco dependence (TD) across tobacco products in surveys, the Population Assessment of Tobacco and Health (PATH) Study provides a unique platform for examining the psychometric properties and validity of multiple indicators of tobacco dependence across a range of tobacco products. PARTICIPANTS: A U.S. nationally representative sample from the 32,320 adult Wave 1 interviews with analyses focused on 14,287 respondents who were current established users of tobacco products. FINDINGS: This analysis confirms a single primary latent construct underlying responses to TD indicators for cigarettes, e-cigarettes, cigars, hookah, and smokeless tobacco products. Mutually exclusive past year tobacco-user groups included: cigarette only (n=8689), e-cigarette only (n=437), cigar only (traditional, cigarillo, or filtered) (n=706), hookah only (n=461), smokeless tobacco only (n=971), cigarette plus e-cigarette (n=709), and multiple tobacco product users (n=2314). Differential Item Functioning (DIF) analyses supported use of 16 of the 24 examined TD indicators for comparisons across tobacco users. With cigarette users as a reference (mean=0.0, SD=1.0), we observed a range of TD with hookah (mean=-1.71) and cigar (mean=-1.92) only users being the lowest, and cigarette plus e-cigarette product users being the highest (mean=0.35). Regression models including sociodemographic factors supported concurrent validity with increased product use frequency and TD among cigarette-only (p<0.001), e-cigarette only (p<0.002), cigar (p<0.001), hookah only (p<0.001), and smokeless tobacco users (p<0.001). CONCLUSION: The PATH Study Adult Wave 1 Questionnaire provided psychometrically valid measures of TD that enables future regulatory investigations of nicotine dependence across tobacco products. PMID- 28675818 TI - Nuclear localization and transactivation by Vitis CBF transcription factors are regulated by combinations of conserved amino acid domains. AB - The highly conserved CBF pathway is crucial in the regulation of plant responses to low temperatures. Extensive analysis of Arabidopsis CBF proteins revealed that their functions rely on several conserved amino acid domains although the exact function of each domain is disputed. The question was what functions similar domains have in CBFs from other, overwintering woody plants such as Vitis, which likely have a more involved regulation than the model plant Arabidopsis. A total of seven CBF genes were cloned and sequenced from V. riparia and the less frost tolerant V. vinifera. The deduced species-specific amino acid sequences differ in only a few amino acids, mostly in non-conserved regions. Amino acid sequence comparison and phylogenetic analysis showed two distinct groups of Vitis CBFs. One group contains CBF1, CBF2, CBF3 and CBF8 and the other group contains CBF4, CBF5 and CBF6. Transient transactivation assays showed that all Vitis CBFs except CBF5 activate via a CRT or DRE promoter element, whereby Vitis CBF3 and 4 prefer a CRT element. The hydrophobic domains in the C-terminal end of VrCBF6 were shown to be important for how well it activates. The putative nuclear localization domain of Vitis CBF1 was shown to be sufficient for nuclear localization, in contrast to previous reports for AtCBF1, and also important for transactivation. The latter highlights the value of careful analysis of domain functions instead of reliance on computer predictions and published data for other related proteins. PMID- 28675819 TI - Anti-Neuronal Autoantibodies in Both Drug Responsive and Resistant Focal Seizures with Unknown Cause. AB - BACKGROUND: and Objective Autoimmunity is an emerging field of research in the etiology of different neurological disorders including epilepsy. We aimed to investigate the presence of neuronal autoantibodies in focal epilepsy with unknown cause and their clinical correlates in both drug-responsive and resistant patients. METHOD: Between 2009 and 2010 94 patients were prospectively enrolled, had their antibodies tested and clinically followed." An additional 50 age- and gender-matched controls were also tested for antibodies. Age at examination, gender, age at onset, seizure frequency, risk factors, seizure precipitants, and type of seizures were noted. Plasma obtained from patients was frozen at -80 degrees C and analysed for autoantibodies against VGKC-complex, VGCC, GAD, LGI1, CASPR2, NMDA, AMPA and GABAB receptors with immunocytochemistry and radioimmunoassay as required. RESULTS: Thirteen (13.8%) patients, but none of the controls, had antibodies (p=0.003). Antibodies were directed against the uncharacterized components of VGKC-complex in 5 patients (5.3%), GAD in 4 patients (4.2%), NMDA-R in 1 patient (1%), AMPA-R in 1 patient (1%) and both GAD and VGKC-complex in 2 patients (2.1%). Prognosis of epilepsy, in subsequent follow-up, did not correlate to general presence of anti-neuronal antibodies with slightly more patients with antibodies epilepsy control than without (76.9% vs. 69.1%, not-statistically significant. Three patients with suspected active autoimmunity and epilepsy who were treated, showed a response to treatment with a reduction in the seizure frequency. Although most clinical features were identical between seropositive and seronegative patient groups, seropositive patients were more likely to have inflammatory/autoimmune disorders in their medical history. DISCUSSION: In keeping with previous studies, we have shown anti neuronal antibodies in a proportion of focal epilepsy patients. Although autoimmunity might merely occur as a bystander effect in many chronic neurological disorders, association of anti-neuronal antibodies with good response to immunotherapy and coexisting autoimmune disorders suggests that anti neuronal autoimmunity might participate in seizure formation at least in a subgroup of focal epilepsy patients. CONCLUSION: Immunity may play a role in some patients with unknown etiology regardless of prognosis and immunmodulatuar treatment may be helpful in seropositive group. PMID- 28675821 TI - Vibrational two-dimensional correlation spectroscopy (2DCOS) study of proteins. AB - A tutorial is provided for the generalized two-dimensional correlation spectroscopy (2DCOS), which is applicable to the vibrational spectroscopic study of proteins and related systems. In 2DCOS, similarity or dissimilarity among variations of spectroscopic intensities, which are induced by applying an external perturbation to the sample, is examined by constructing correlation spectra defined by two independent spectral variable axes. By spreading congested or overlapped peaks along the second dimension, apparent spectral resolution is enhanced and interpretation of complex spectra becomes simplified. A set of simple rules for the intensities and signs of correlation peaks is used to extract insightful information. Simulated IR spectra for a model protein are used to demonstrate the specific utility of 2DCOS. Additional tools useful in the 2DCOS analysis of proteins, such as data segmentation assisted with moving-window analysis, 2D codistribution analysis, Pareto scaling, and null-space projection are also discussed. PMID- 28675820 TI - Grazing of Nuclearia thermophila and Nuclearia delicatula (Nucleariidae, Opisthokonta) on the toxic cyanobacterium Planktothrix rubescens. AB - During the last decades, the planktonic cyanobacterium Planktothrix rubescens became a dominant primary producer in many deep pre-alpine lakes. While altered physiochemical conditions due to lake warming seem to favour this cyanobacterial species, its dominance is partly attributed to factors conferring grazing resistance. The rigid structure of the cyanobacterial filaments and toxic secondary metabolites (e.g. microcystins) protect against diverse grazers. Nonetheless, species of the protistan genus Nuclearia (Nucleariidae, Opisthokonta) are able to overcome this grazing protection. Time lapse video documentation served as tool to record slow feeding processes of N. thermophila and N. delicatula. Three different feeding strategies could be distinguished: (i) Phagocytosis of small fragments, (ii) serial break-ups of cyanobacterial cells and (iii) bending and breaking of filaments. While observations revealed mechanical manipulation to be important for the efficient breakdown of P. rubescens filaments, the toxin microcystin had no pronounced negative effects on nucleariid cells. Growth experiments with N. thermophila/N. delicatula and different accompanying bacterial assemblages pointed to a pivotal role of distinct prokaryotic species for toxin degradation and for the growth success of the protists. Thus, the synergistic effect of nucleariids and specific bacteria favours an efficient degradation of P. rubescens along with its toxin. PMID- 28675822 TI - The use of a Competence Fair to validate nursing competence. AB - Strategies to ensure that nursing competence is maintained and validated are of increasing importance and are much discussed in the nursing literature. Professional bodies, employers, nurses themselves and most importantly patients need to have reassurance that competence across the profession is uniform and is maintained. This is of particular concern in the increasingly globalised and multinational workforces which exist in many health care institutions. This paper describes an educational initiative, and the evaluation thereof, which aimed to validate and enhance nurse competency in a multinational workforce in a medical city in the Kingdom of Saudi Arabia. Results indicate that there was variability in competencies across the organisation which allowed for targeted educational interventions. The initiative was well received by the nurses in the organisation and the evaluation points to the need for ongoing strategies to ensure that competence in maintained. PMID- 28675823 TI - Endothelial immunocytochemical expression of pituitary IL-1beta and its relation to ACTH-positive cells is regulated by corticosterone in the male rat. AB - Interleukin-1 beta (IL-1beta) is a cytokine linking the neuroendocrine system and metabolic homeostasis. We have previously demonstrated the relevance of IL-1beta for maintaining the pituitary ACTH-producing cells by immuno-blocking its effects in pituitary cultures. However, the morphological characteristics and the intimate relationship of the pituitary cells expressing IL-1beta and ACTH remain unknown. For determining pituitary variations of immunoreactivity for IL-1beta and its relation with ACTH-positive cells under stress situations, we performed an immunohistochemical analysis of the expression of IL-1beta and ACTH in the pituitary gland of adult rats, in the absence or presence of corticosterone, by establishing different groups: untreated, sham-operated, and bilaterally adrenalectomized animals. In the rats subjected to surgery, the glucocorticoid was administered on the same day of the intervention and on the third day post surgery. Interestingly, it was observed that IL-1beta was located in the pituitary endothelial cells at the hypophyseal portal vessels, regardless of the treatment schedule. When comparing the pituitary immunoreactive surface to IL 1beta expression without corticosterone, adrenalectomized animals displayed a significantly greater area than the sham-operated animals. Corticosterone significantly inhibited the effect of adrenalectomy depending on the time interval it was administered. By in situ hybridization, IL-1beta mRNA expression was also correlated with immnunocytochemical expression of pituitary IL-1beta. Our results demonstrate that IL-1beta is a constitutive element in endothelial portal pituitary vessels and under stress experimental conditions IL-1beta increases its expression and its relation with ACTH-positive cells, suggesting that IL-1beta could participate in an autocrine-paracrine fashion thereby modulating the pituitary population of ACTH-positive cells. PMID- 28675824 TI - A new type of swaddling clothing improved development of preterm infants in neonatal intensive care units. AB - BACKGROUND: Preterm infants undergo stress owing to essential treatments and exposure to the extrauterine environment in neonatal intensive care units. AIMS: The aim of this study was to enable preterm infants to maintain adequate positioning with a newly developed swaddling clothing, in order to improve low muscle tone and sleep quality, and to confirm the safety of the clothing. STUDY DESIGN: This prospective clinical trial included an intervention group (preterm infants wearing bag-shaped clothing, allowing only exposure of the head, n=27), and a control group (preterm infants managed only with conventional swaddling, n=12). OUTCOME MEASURES: We used the Dubowitz method to analyze behavior, recorded the frequency of vomiting and apnea in both groups, and assessed the sleep state in the intervention group. RESULTS: Muscle tone and total score for the Dubowitz method significantly improved in the intervention group, compared with those in the control group. We evaluated the sleep state before and after the introduction of the device in the intervention group, and State 1 increased from 53.5% to 69.2% after introduction. No significant difference was seen in the frequency of vomiting and apnea between the groups. CONCLUSIONS: The new swaddling clothing with enhanced stretch capacity improved the muscle tone and increased sleep time by decreasing the state level of preterm infants. This is an effective tool to assist in infant development in neonatal intensive care units. PMID- 28675826 TI - Recent advances in systems metabolic engineering tools and strategies. AB - Metabolic engineering has been playing increasingly important roles in developing microbial cell factories for the production of various chemicals and materials to achieve sustainable chemical industry. Nowadays, many tools and strategies are available for performing systems metabolic engineering that allows systems-level metabolic engineering in more sophisticated and diverse ways by adopting rapidly advancing methodologies and tools of systems biology, synthetic biology and evolutionary engineering. As an outcome, development of more efficient microbial cell factories has become possible. Here, we review recent advances in systems metabolic engineering tools and strategies together with accompanying application examples. In addition, we describe how these tools and strategies work together in simultaneous and synergistic ways to develop novel microbial cell factories. PMID- 28675825 TI - The association between in vivo central noradrenaline transporter availability and trait impulsivity. AB - The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8+/-9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS 11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior. PMID- 28675827 TI - Hyperglycemia-induced hyponatremia: Reevaluation of the Na+ correction factor. AB - This study addresses the clinically important relationship between the decreases in plasma Na+ and the increases in plasma glucose concentrations seen in diabetes and other hyperglycemic syndromes. This plasma 'Na+ correction factor', is generally accepted as 1.6mM Na+ per 100mg% glucose (0.29mM/mM in SI units) assuming osmotic equilibrium, although much larger numbers have been measured in experiments on normal humans. To resolve this controversy, a mathematical model of whole-body fluid-electrolyte balance was used to perform the experiment wherein plasma glucose concentration was increased to diabetic levels and the plasma Na+ concentration changes assessed, without the complications seen in human experiments. The findings, based on osmotic grounds, were that the factor 1) was significantly <1.6, approaching 1 in some cases, 2) depended upon the anthropometry of the subject; it was inversely proportional to the ratio of extracellular to total body water, which increases with higher fat content and 3) was approximately linear up to glucose concentrations of about 800mg%, but decreased up to 10% for higher glucose concentrations. To explain the experimental data, a hypothesis of Na+ sequestration in cells was incorporated in the model, resulting in close prediction of measured transient Na+ changes. PMID- 28675828 TI - Comparison of three-dimensional facial morphology between upright and supine positions employing three-dimensional scanner from live subjects. AB - Facial soft tissue thicknesses (FSTT) measurements collected from Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) imaging techniques are most commonly taken in the supine position for forensic craniofacial reconstruction. FSTT have been shown to be different in comparison to the upright position due to gravity. The variation of facial morphology between the upright and supine position of laser-scanned images taken from 44 individuals was investigated using volumetric analysis with deviation maps. Between 82.4% and 86.7% of the facial surface area were within the error range of +/-2mm between the supine and the upright position. This indicates that most anatomical landmarks taken from the MRI and CT data can be an accurate representative of the FSTT in the upright position. Seven landmarks located around the buccal region, masseteric region and the nasolabial region of the face showed the greatest FSTT deviation between the upright and supine position, thus these landmarks may affect the accuracy of facial reconstructions when using a CT or MRI database. PMID- 28675829 TI - Polyprenylated acylphloroglucinols from Hypericum scabrum. AB - Fourteen phloroglucinols, named hyperciumoxide A-N, and a known compound were isolated from air-dried aerial parts of Hypericum scabrum. The structures of these compounds were deduced on the basis of extensive 1D- and 2D-NMR experiments. Hepatoprotective properties against D-galactosamine-induced HL-7702 cell damage of isolated compounds were evaluated. Meanwhile, these compounds were also tested for antidepressant activity by inhibiting reuptake of tritiated serotonin ([3H]-5-HT) and Noradrenalinet ([3H]-NE) in rat brain synaptosomes. PMID- 28675830 TI - Polyketide derivatives from a marine-sponge-associated fungus Pestalotiopsis heterocornis. AB - Twelve previously undescribed polyketide derivatives, heterocornols A-L, and seven known analogues were isolated from a culture of the fungus Pestalotiopsis heterocornis associated with sponge. Their structures were elucidated by a comprehensive spectroscopic data analysis and CD Cotton effects. These compounds were evaluated for cytotoxic and antibacterial activities in vitro. Among them, heterocornols A-C, F-H, methyl-(2-formyl-3-hydroxyphenyl)propanoate, agropyrenol, and vaccinol G exhibited cytotoxicities against four human cancer cell lines with IC50 values 15-100 MUM, and they also showed antibacterial activities against Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis with MIC values ranging from 25 to 100 MUg/mL. Moreover, compounds heterocornol C, heterocornol G, agropyrenol, and vaccinol G showed weak antifungal activities against Candida parapsilosis and Cryptococcus neoformans with MIC values 100 MUg/mL. PMID- 28675831 TI - Incidence, outcome and risk stratification tools for venous thromboembolism in advanced pancreatic cancer - A retrospective cohort study. AB - INTRODUCTION: Venous thromboembolism (VTE) is frequent in advanced pancreatic cancer (APC). Recent studies demonstrated that the Khorana score - an established risk stratification tool for VTE in cancer - performs poorly in identifying pancreatic cancer patients at high risk for VTE. MATERIALS AND METHODS: We performed a retrospective cohort study in order to define incidence, treatment and outcome of VTE as well as the performance of VTE risk stratification tools (Khorana score, CONKO score and aPTT ratio) in a "real life" clinical cohort of APC patients undergoing palliative chemotherapy. RESULTS AND CONCLUSIONS: One hundred and seventy-two eligible APC patients from our comprehensive cancer center were identified. VTE after start of palliative chemotherapy was diagnosed in 71 patients (41.3%). Most VTE events were asymptomatic (n=50, 29.1%) with only 21 symptomatic events (12.2%). On multivariate analysis - including age, performance status and carbohydrate antigen 19-9 (CA 19-9) - symptomatic VTE was an independent risk factor for death (hazard ratio [HR]: 2.22, 95% CI: 1.05-2.60, p<0.05). Khorana score, CONKO score and aPTT ratio alone were not able to predict the risk for symptomatic VTE. High risk patients could only be identified by using a combination of either Khorana or CONKO score with aPTT ratio (30% vs. 10% symptomatic VTE events in high vs. low risk patients, p<0.05). The combination of Khorana or CONKO score with aPTT thus may represent a novel risk stratification tool for symptomatic VTE in APC and should further be validated within prospective clinical trials. PMID- 28675832 TI - Epigenetic control of retrotransposons in adult tissues: implications for immune regulation. AB - Retrotransposons tune immune reactivity in differentiated cells because when they are transcribed, their nucleic acids can be viewed as non-self leading to innate immune sensing. Most retrotransposons, however, are subject to transcriptional regulation by a multitude of epigenetic pathways, which have coevolved with them for millions of years. While a lot is known about the epigenetic control of retrotransposons in germ cells and early embryos, surprisingly little is understood about these pathways in adult tissues, particularly in human cells. Recent evidence suggests that retrotransposon repression persists in differentiated cells and is dynamic. Future insight into this topic may teach us how to reactivate or silence specific retrotransposon families, to promote anti tumor immunity or dampen autoimmunity through epigenetic modulation. PMID- 28675833 TI - Evaluation of compliance with the Spanish Code of self-regulation of food and drinks advertising directed at children under the age of 12 years in Spain, 2012. AB - OBJECTIVE: To evaluate compliance levels with the Spanish Code of self-regulation of food and drinks advertising directed at children under the age of 12 years (Publicidad, Actividad, Obesidad, Salud [PAOS] Code) in 2012; and compare these against the figures for 2008. STUDY DESIGN: Cross-sectional study. METHODS: Television advertisements of food and drinks (AFD) were recorded over 7 days in 2012 (8am-midnight) of five Spanish channels popular to children. AFD were classified as core (nutrient-rich/low-calorie products), non-core (nutrient poor/rich-calorie products) or miscellaneous. Compliance with each standard of the PAOS Code was evaluated. AFD were deemed to be fully compliant when it met all the standards. RESULTS: Two thousand five hundred and eighty-two AFDs came within the purview of the PAOS Code. Some of the standards that registered the highest levels of non-compliance were those regulating the suitability of the information presented (79.4%) and those prohibiting the use of characters popular with children (25%). Overall non-compliance with the Code was greater in 2012 than in 2008 (88.3% vs 49.3%). Non-compliance was highest for advertisements screened on children's/youth channels (92.3% vs. 81.5%; P < 0.001) and for those aired outside the enhanced protection time slot (89.3% vs. 86%; P = 0.015). CONCLUSIONS: Non-compliance with the PAOS Code is higher than for 2008. Given the lack of effectiveness of self-regulation, a statutory system should be adopted to ban AFD directed at minors, or at least restrict it to healthy products. PMID- 28675834 TI - Effects of levodopa on corticostriatal circuits supporting working memory in Parkinson's disease. AB - Working memory dysfunction is common in Parkinson's disease, even in its early stages, but its neural basis is debated. Working memory performance likely reflects a balance between corticostriatal dysfunction and compensatory mechanisms. We tested this hypothesis by examining working memory performance with a letter n-back task in 19 patients with mild-moderate Parkinson's disease and 20 demographically matched healthy controls. Parkinson's disease patients were tested after an overnight washout of their usual dopamine replacement therapy, and again after a standard dose of levodopa. FMRI was used to assess task-related activation and resting state functional connectivity; changes in BOLD signal were related to performance to disentangle pathological and compensatory processes. Parkinson's disease patients off dopamine replacement therapy displayed significantly reduced spatial extent of task-related activation in left prefrontal and bilateral parietal cortex, and poorer working memory performance, compared to controls. Amongst the Parkinson's disease patients off dopamine replacement therapy, relatively better performance was associated with greater activation of right dorsolateral prefrontal cortex compared to controls, consistent with compensatory right hemisphere recruitment. Administration of levodopa remediated the working memory deficit in the Parkinson's disease group, and resulted in a different pattern of performance-correlated activity, with a shift to greater left ventrolateral prefrontal cortex activation in patients on, compared to off dopamine replacement therapy. Levodopa also significantly increased resting-state functional connectivity between caudate and right parietal cortex (within the right fronto-parietal attentional network). The strength of this connectivity contributed to better performance in patients and controls, suggesting a general compensatory mechanism. These findings argue that Parkinson's disease patients can recruit additional neural resources, here, the right fronto-parietal network, to optimize working memory performance despite impaired corticostriatal function. Levodopa seems to both boost engagement of a task-specific prefrontal region, and strengthen a putative compensatory caudate cortical network to support this executive function. PMID- 28675836 TI - Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer. AB - The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The major contributing factor for this resistance is efflux of the drugs by the p-glycoprotein pump. Over the years, inhibitors of this pump have been discovered to administer them in combination with chemotherapeutic agents. The clinical failure of first and second generation P-gp inhibitors (such as verapamil and cyclosporine analogs) has led to the discovery of third generation potent P-gp inhibitors (tariquidar, zosuquidar, laniquidar). Most of these inhibitors are nitrogenous compounds and recently a natural alkaloid CBT-01(r) (tetrandrine) has advanced to the clinical phase. CBT-01 demonstrated positive results in Phase-I study in combination with paclitaxel, which warranted conducting it's Phase II/III trial. Apart from this, there exist a large number of natural alkaloids possessing potent inhibition of P-gp efflux pump and other related pumps responsible for the development of resistance. Despite the extensive contribution of alkaloids in this area, has never been reviewed. The present review provides a comprehensive account on natural alkaloids possessing P gp inhibition activity and their potential for multidrug resistance reversal in cancer. PMID- 28675837 TI - Perylenyltriazoles inhibit reproduction of enveloped viruses. AB - 1-Substituted 4-perylen-2(3)-yl-1,2,3-triazoles, easily accessible by 'click' reaction and combining in one molecule a polyaromatic unit and a nitrogen heterocycle, were found to strongly inhibit the reproduction of enveloped viruses. 5-[4-(Perylen-3-yl)-1,2,3-triazol-1-yl]-uridine and 2-[1-(2 hydroxyethyl)-1,2,3-triazol-4-yl]perylene show EC50 of 0.031 and 0.023 MUM, respectively, against tick-borne encephalitis virus (TBEV). Remarkably, the nucleoside unit appears to be not essential for antiviral activity. These results provide deeper understanding of structural basis of activity for this new class of antivirals. PMID- 28675835 TI - New insights into influenza A specificity: an evolution of paradigms. AB - Understanding the molecular origin of influenza receptor specificity is complicated by the paucity of quantitative affinity measurements, and the qualitative and variable nature of glycan array data. Further obstacles arise from the varied impact of viral glycosylation and the relatively narrow spectrum of biologically relevant receptors present on glycan arrays. A survey of receptor conformational properties is presented, leading to the conclusion that conformational entropy plays a key role in defining specificity, as does the newly reported ability of biantennary receptors that terminate in Siaalpha2-6Gal sequences to form bidentate interactions to two binding sites in a hemagglutinin trimer. Bidentate binding provides a functional explanation for the observation that Siaalpha2-6 receptors adopt an open-umbrella topology when bound to hemagglutinins from human-infective viruses, and calls for a reassessment of virus avidity and tissue tropism. PMID- 28675838 TI - Therapeutic application of human leukocyte antigen-G1 improves atopic dermatitis like skin lesions in mice. AB - Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that plays critical roles in immune response and in triggering inhibitory signaling to immune cells such as T cells, natural killer cells, and antigen-presenting cells. Thus, the application of HLA-G can be considered for treating immune response related inflammatory disorders. We have previously reported that treatment with HLA-G1 and HLA-G2 ameliorates the joint swelling associated with collagen-induced arthritis of DBA/1 mice, an animal model for rheumatoid arthritis. In this study, we further investigated the effects of HLA-G1 on atopic dermatitis (AD), the most common inflammatory skin disorder. AD-like lesions were induced with the extract of the house dust mite Dermatophagoides farinae in NC/Nga mice. Continuous administration of HLA-G1 ameliorated the AD-like skin lesions in the mice. Furthermore, production of immunoglobulin E, interleukin (IL)-13, and IL-17A was significantly reduced in HLA-G1-treated mice, suggesting a Th2/Th17-mediated immune-inhibitory function of HLA-G1 in vivo. Our studies shed light on novel therapeutic strategies with recombinant HLA-G proteins for immune reaction mediated chronic inflammatory disorders. PMID- 28675839 TI - Embroidered electrochemical sensors on gauze for rapid quantification of wound biomarkers. AB - Electrochemical sensors are an attractive platform for analytical measurements due to their high sensitivity, portability and fast response time. These attributes also make electrochemical sensors well suited for wearable applications which require excellent flexibility and durability. Towards this end, we have developed a robust electrochemical sensor on gauze via a unique embroidery fabrication process for quantitative measurements of wound biomarkers. For proof of principle, this biosensor was used to detect uric acid, a biomarker for wound severity and healing, in simulated wound fluid which exhibits high specificity, good linearly from 0 to 800uM, and excellent reproducibility. Continuous sensing of uric acid was also performed using this biosensor which reveals that it can generate consistent and accurate measurements for up to 7h. Experiments to evaluate the robustness of the embroidered gauze sensor demonstrate that it offers excellent resilience against mechanical stress and deformation, making it a promising wearable platform for assessing and monitoring wound status in situ. PMID- 28675840 TI - Biosurfactant production by Aureobasidium pullulans in stirred tank bioreactor: New approach to understand the influence of important variables in the process. AB - Surfactants are amphiphilic molecules with large industrial applications produced currently by chemical routes mainly derived from oil industry. However, biotechnological process, aimed to develop new sustainable process configurations by using favorable microorganisms, already requires investigations in more details. Thus, we present a novel approach for biosurfactant production using the promising yeast Aureobasidium pullulans LB 83, in stirred tank reactor. A central composite face-centered design was carried out to evaluate the effect of the aeration rate (0.1-1.1min-1) and sucrose concentration (20-80g.L-1) in the biosurfactant maximum tensoactivity and productivity. Statistical analysis showed that the use of variables at high levels enhanced tensoactivity, showing 8.05cm in the oil spread test and productivity of 0.0838cm.h-1. Also, unprecedented investigation of aeration rate and sucrose concentration relevance in biosurfactant production by A. pullulans in stirred tank reactor was detailed, demonstrating the importance to establish adequate conditions in bioreactors, aimed to scale-up process. PMID- 28675841 TI - Comparison of microwave and conduction-convection heating autohydrolysis pretreatment for bioethanol production. AB - This work describes the application of two forms of heating for autohydrolysis pretreatment on isothermal regimen: conduction-convection heating and microwave heating processing using corn stover as raw material for bioethanol production. Pretreatments were performed using different operational conditions: residence time (10-50 min) and temperature (160-200 degrees C) for both pretreatments. Subsequently, the susceptibility of pretreated solids was studied using low enzyme loads, and high substrate loads. The highest conversion was 95.1% for microwave pretreated solids. Also solids pretreated by microwave heating processing showed better ethanol conversion in simultaneous saccharification and fermentation process (92% corresponding to 33.8g/L). Therefore, microwave heating processing is a promising technology in the pretreatment of lignocellulosic materials. PMID- 28675842 TI - Pyrolysis of Lantana camara and Mimosa pigra: Influences of temperature, other process parameters and incondensable gas evolution on char yield and higher heating value. AB - Pyrolysis of invasive non-indigenous plants, Lantana camara (LC) and Mimosa pigra (MP) was conducted at milligram-scale for optimisation of temperature, heating rate and hold time on char yield and higher heating value (HHV). The impact of scaling-up to gram-scale was also studied, with chromatography used to correlate gas composition with HHV evolution. Statistically significant effects of temperature on char yield and HHV were obtained, while heating rate and hold time effects were insignificant. Milligram-scale maximised HHVs were 30.03MJkg-1 (525 degrees C) and 31.01MJkg-1 (580 degrees C) for LC and MP, respectively. Higher char yields and HHVs for MP were attributed to increased lignin content. Scaling up promoted secondary char formation thereby increasing HHVs, 30.82MJkg-1 for LC and 31.61MJkg-1 for MP. Incondensable gas analysis showed that temperature increase beyond preferred values caused dehydrogenation that decreased HHV. Similarly, CO evolution profile explained differences in optimal HHV temperatures. PMID- 28675843 TI - Evaluation of key parameters on simultaneous sulfate reduction and sulfide oxidation in an autotrophic biocathode. AB - Bioelectrochemical systems (BESs) are being studied as an alternative technology for the treatment of several kinds of wastewaters with a lack of electron donor such as high-strength sulfate wastewaters. This study evaluates different parameters that influence the simultaneous sulfate reduction and sulfide oxidation in an autotrophic biocathode: ion-exchange membrane (IEM), cathodic pH and cathode potential. Two different membranes were studied to evaluate sulfate and sulfide adsorption and diffusion from the cathode to the anode, observing that a cation-exchange membrane (CEM) widely decreased these effects. Three different cathode pH (5.5, 7 and 8.5) were studied in a long-term operation observing that pH = 7 was the optimal for sulfate removal, achieving reduction rates around 150 mg S-SO42- L-1 d-1. Microbial community analysis of the cathode biofilm demonstrated a high abundance of sulfate-reducing bacteria (SRB, 67% at pH 7, 60% at pH 8.5 and 42% at pH 5.5), mainly Desulfovibrio sp. at pH 5.5 and 7 and Desulfonatronum sp. at pH 8.5. The cathode potential also was studied from 0.7 to -1.2 V vs. SHE achieving sulfate removal rates higher than 700 mg S-SO42- L-1 d-1 at cathode potentials from -1.0 to -1.2 V vs. SHE. Also, the highest cathodic recovery and the highest sulfur species imbalance were observed at a cathode potential of -1.0 V vs. SHE, which indicated a higher elemental sulfur production. PMID- 28675844 TI - Treatment of radioactive liquid effluents by reverse osmosis membranes: From lab scale to pilot-scale. AB - The recent use of the reverse osmosis (RO) process at the damaged Fukushima Daiichi nuclear power plant generated a growing interest in the application of this process for decontamination purposes. This study focused on the development of a robust RO process for decontamination of two kinds of liquid effluents: a contaminated groundwater after a nuclear disaster and a contaminated seawater during a nuclear accident. The SW30 HR membrane was selected among other in this study due to higher retentions (96% for Cs and 98% for Sr) in a true groundwater. Significant fouling and scaling phenomenon, attributed to calcium and strontium precipitation, were evidenced in this work: this underscored the importance of the lab scale experiment in the process. Validation of the separation performances on trace radionuclides concentration was performed with similar retention around 96% between surrogates Cs (inactive) and 137Cs (radioactive). The scale up to a 2.6 m2 spiral wound membrane led to equivalent retentions (around 96% for Cs and 99% for Sr) but lower flux values: this underlined that the hydrodynamic parameters (flowrate/cross-flow velocity) should be optimized. This methodology was also applied on the reconstituted seawater effluent: retentions were slightly lower than for the groundwater and the same hydrodynamic effects were observed on the pilot scale. Then, ageing of the membrane through irradiation experiments were performed. Results showed that the membrane active layer composition influenced the membrane resistance towards gamma irradiation: the SW30 HR membrane performances (retention and permeability) were better than the Osmonics SE at 1 MGy. Finally, to supplement the scale up approach, the irradiation of a spiral wound membrane revealed a limited effect on the permeability and retention. This indicated that irradiation conditions need to be controlled for a further development of the process. PMID- 28675845 TI - Rubidium extraction from seawater brine by an integrated membrane distillation selective sorption system. AB - The ultimate goal of seawater reverse osmosis (SWRO) brine management is to achieve minimal liquid discharge while recovering valuable resources. The suitability of an integrated system of membrane distillation (MD) with sorption for the recovery of rubidium (Rb+) and simultaneous SWRO brine volume reduction has been evaluated for the first time. Polymer encapsulated potassium copper hexacyanoferrate (KCuFC(PAN)) sorbent exhibited a good selectivity for Rb+ sorption with 10-15% increment at 55 degrees C (Langmuir Qmax = 125.11 +/- 0.20 mg/g) compared to at 25 degrees C (Langmuir Qmax = 108.71 +/- 0.20 mg/g). The integrated MD-KCuFC(PAN) system with periodic membrane cleaning, enabled concentration of SWRO brine to a volume concentration factor (VCF) of 2.9 (65% water recovery). A stable MD permeate flux was achieved with good quality permeate (conductivity of 15-20 MUS/cm). Repeated cycles of MD-KCuFC(PAN) sorption with SWRO brine enabled the extraction of 2.26 mg Rb+ from 12 L of brine (equivalent to 1.9 kg of Rb/day, or 0.7 tonne/yr from a plant producing 10,000 m3/day brine). KCuFC(PAN) showed a high regeneration and reuse capacity. NH4Cl air stripping followed by resorcinol formaldehyde (RF) resin filtration enabled to recover Rb+ from the desorbed solution. PMID- 28675846 TI - Chronic nonbacterial osteomyelitis involving the mandible: A case report. AB - INTRODUCTION: Chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO), is a very rare condition of unknown aetiology. It is characterised by focal sterile inflammatory disease with prolonged, self limiting and recurrent episodes. CASE PRESENTATION: We report the discovery of this very rare disease following a mandibular abscess in a 10-year-old female. We initially focus on the difference between the preoperative orthopantomography and the maxillofacial computed tomography and magnetic resonance images obtained, and then on the improvement of strategies for correct diagnosis and treatment of this disease. DISCUSSION: Bone pain and localised swelling can occur in a single bone or can spread to soft tissue and adjacent bone; areas commonly affected by CMRO include the metaphyseal plates of the long bones, as well as the spine, clavicle and, rarely, the maxillofacial area. The clinical presentation of CMRO includes pain, functional impairment, and swelling, similar to our case. CONCLUSIONS: We report a very rare case of this unifocal mandibular disease in a child who presented for an abscess and was then diagnosed and treated for CNO. PMID- 28675848 TI - The micro-damage process zone during transverse cortical bone fracture: No ears at crack growth initiation. AB - OBJECTIVE: Apply high-resolution benchtop micro-computed tomography (micro-CT) to gain greater understanding and knowledge of the formation of the micro-damage process zone formed during traverse fracture of cortical bone. METHODS: Bovine cortical bone was cut into single edge notch (bending) fracture testing specimens with the crack on the transverse plane and oriented to grow in the circumferential direction. We used a multi-specimen technique and deformed the specimens to various individual secant modulus loss levels (P-values) up to and including maximum load (Pmax). Next, the specimens were infiltrated with a BaSO4 precipitation stain and scanned at 3.57-MUm isotropic voxel size using a benchtop high resolution-micro-CT. Measurements of the micro-damage process zone volume, width and height were made. These were compared with the simple Irwin's process zone model and with finite element models. Electron and confocal microscopy confirmed the formation of BaSO4 precipitate in micro-cracks and other porosity, and an interesting novel mechanism similar to tunneling. RESULTS: Measurable micro-damage was detected at low P values and the volume of the process zone increased according to a second order polynomial trend. Both width and height grew linearly up to Pmax, at which point the process zone cross-section (perpendicular to the plane of the crack) was almost circular on average with a radius of approximately 550um (approximately one quarter of the unbroken ligament thickness) and corresponding to the shape expected for a biological composite under plane stress conditions. CONCLUSION: This study reports details of the micro-damage fracture process zone previously unreported for cortical bone. High resolution micro-CT enables 3D visualization and measurement of the process zone and confirmation that the crack front edge and process zone are affected by microstructure. It is clear that the process zone for the specimens studied grows to be meaningfully large, confirming the need for the J-integral approach and it does not achieve steady state at Pmax in most specimens. With further development, this approach may become valuable towards better understanding the role of the process zone in cortical bone fracture and the effects of relevant modifications towards changes in fracture toughness in a cost effective way. PMID- 28675847 TI - Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib. AB - Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen kappaN7)] (1) and [AuCl3(4,7-phen-kappaN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89MUM, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128MUM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance. PMID- 28675849 TI - Diet and habitat use influence Hg and Cd transfer to fish and consequent biomagnification in a highly contaminated area: Augusta Bay (Mediterranean Sea). AB - Total mercury (T-Hg) and cadmium (Cd) were measured in twenty species of fish to study their bioaccumulation patterns and trophodynamics in the Augusta Bay food web. Adult and juvenile fish were caught in 2012 in Priolo Bay, south of the Augusta harbour (Central Mediterranean Sea), which is known for the high trace element and polycyclic aromatic hydrocarbon contamination level. T-Hg concentration was found to significantly increase along delta15N and from pelagic to benthic sedentary fish, revealing a marked influence of trophic position and habitat use (sensu Harmelin 1987) on T-Hg accumulation within ichthyofauna. Cd showed the opposite pattern, in line with the higher trace element (TE) excretion rates of high trophic level fish and the lower level of Cd environmental contamination. Trophic pathways were first characterised in the Priolo Bay food web using carbon and nitrogen stable isotopes (delta13C, delta15N) and a single main trophic pathway characterised the Priolo Bay food web. Biomagnification was then assessed, including basal sources (surface sediment, macroalgae), zooplankton, benthic invertebrates and fish. T-Hg and Cd were found to biomagnify and biodilute respectively based on the significant linear regressions between log[T-Hg] and log[Cd] vs. delta15N of sources and consumers and the trophic magnification factors (TMFs) of 1.22 and 0.83 respectively. Interestingly, different Cd behaviour was found considering only the benthic pathway which leads to the predatory gastropod Hexaplex trunculus. The positive slope and the higher TMF indicated active biomagnification in this benthic food web due to the high bioaccumulation efficiency of this benthic predator. Our findings provide new evidences about the role of Priolo sediments as a sources of pollutants for the food web, representing a threat to fish and, by domino effect, to humans. PMID- 28675850 TI - Emissions of fine particulate nitrated phenols from the burning of five common types of biomass. AB - Nitrated phenols are among the major constituents of brown carbon and affect both climates and ecosystems. However, emissions from biomass burning, which comprise one of the most important primary sources of atmospheric nitrated phenols, are not well understood. In this study, the concentrations and proportions of 10 nitrated phenols, including nitrophenols, nitrocatechols, nitrosalicylic acids, and dinitrophenol, in fine particles from biomass smoke were determined under three different burning conditions (flaming, weakly flaming, and smoldering) with five common types of biomass (leaves, branches, corncob, corn stalk, and wheat straw). The total abundances of fine nitrated phenols produced by biomass burning ranged from 2.0 to 99.5 MUg m-3. The compositions of nitrated phenols varied with biomass types and burning conditions. 4-nitrocatechol and methyl nitrocatechols were generally most abundant, accounting for up to 88-95% of total nitrated phenols in flaming burning condition. The emission ratios of nitrated phenols to PM2.5 increased with the completeness of combustion and ranged from 7 to 45 ppmm and from 239 to 1081 ppmm for smoldering and flaming burning, respectively. The ratios of fine nitrated phenols to organic matter in biomass burning aerosols were comparable to or lower than those in ambient aerosols affected by biomass burning, indicating that secondary formation contributed to ambient levels of fine nitrated phenols. The emission factors of fine nitrated phenols from flaming biomass burning were estimated based on the measured mass fractions and the PM2.5 emission factors from literature and were approximately 0.75-11.1 mg kg-1. According to calculations based on corn and wheat production in 31 Chinese provinces in 2013, the total estimated emission of fine nitrated phenols from the burning of corncobs, corn stalks, and wheat straw was 670 t. This work highlights the apparent emission of methyl nitrocatechols from biomass burning and provides basic data for modeling studies. PMID- 28675851 TI - Bioremediation of PAHs contaminated river sediment by an integrated approach with sequential injection of co-substrate and electron acceptor: Lab-scale study. AB - In this study, the feasibility of employing an integrated bioremediation approach in contaminated river sediment was evaluated. Sequential addition of co-substrate (acetate) and electron acceptor (NO3-) in a two-phase treatment was capable of effectively removing polycyclic aromatic hydrocarbons (PAHs) in river sediment. The residual concentration of total PAHs decreased to far below effect range low (ERL) value within 91 days of incubation, at which concentration it could rarely pose biological impairment. The biodegradation of high molecular weight PAHs were found to be mainly occurred in the sediment treated with co-substrates (i.e. acetate or methanol), in which acetate was found to be more suitable for PAHs degradation. The role of co-substrates in influencing PAHs biodegradation was tentatively discussed herein. Additionally, the sediment odorous problem and blackish appearance were intensively addressed by NO3- injection. The results of this study demonstrated that integrating two or more approaches/processes would be a helpful option in sediment remediation. It can lead to a more effective remediation performance, handle multiple contamination issues, as well as mitigate environmental risks caused by one of the single methods. PMID- 28675852 TI - Experimental determination of drift and PM10 cooling tower emissions: Influence of components and operating conditions. AB - Cooling tower emissions have become an increasingly common hazard to the environment (air polluting, ice formation and salts deposition) and to the health (Legionella disease) in the last decades. Several environmental policies have emerged in recent years limiting cooling tower emissions but they have not prevented an increasing intensity of outbreaks. Since the level of emissions depends mainly on cooling tower component design and the operating conditions, this paper deals with an experimental investigation of the amount of emissions, drift and PM10, emitted by a cooling tower with different configurations (drift eliminators and distribution systems) and working under several operating conditions. This objective is met by the measurement of cooling tower source emission parameters by means of the sensitive paper technique. Secondary objectives were to contextualize the observed emission rates according to international regulations. Our measurements showed that the drift rates included in the relevant international standards are significantly higher than the obtained results (an average of 100 times higher) and hence, the environmental problems may occur. Therefore, a revision of the standards is recommended with the aim of reducing the environmental and human health impact. By changing the operating conditions and the distribution system, emissions can be reduced by 52.03% and 82% on average. In the case of drift eliminators, the difference ranges from 18.18% to 98.43% on average. As the emissions level is clearly influenced by operating conditions and components, regulation tests should be referred to default conditions. Finally, guidelines to perform emission tests and a selection criterion of components and conditions for the tested cooling tower are proposed. PMID- 28675853 TI - Histopathological effects, responses of oxidative stress, inflammation, apoptosis biomarkers and alteration of gene expressions related to apoptosis, oxidative stress, and reproductive system in chlorpyrifos-exposed common carp (Cyprinus carpio L.). AB - In this study, we aimed to identify the toxic effects of chlorpyrifos exposure on the tissues of common carp. For this purpose, we evaluated histopathological changes in the brain, gills, liver, kidney, testis, and ovaries after 21 days of chlorpyrifos exposure. Activation of 8-OHdG, cleaved caspase-3, and iNOS were assesed by immunofluorescence assay in chlorpyrifos-exposed brain and liver tissue. Additionally, we measured the expression levels of caspase-3, caspase-8, iNOS, MT1, CYP1A, and CYP3A genes in chlorpyrifos-exposed brain tissue, as well as the expression levels of FSH and LH genes in chlorpyrifos-exposed ovaries, using qRT-PCR. We observed severe histopathological lesions, including inflammation, degeneration, necrosis, and hemorrhage, in the evaluated tissues of common carp after both high and low levels of exposure to chlorpyrifos. We detected strong and diffuse signs of immunofluorescence reaction for 8-OHdG, iNOS, and cleaved caspase-3 in the chlorpyrifos-exposed brain and liver tissues. Furthermore, we found that chlorpyrifos exposure significantly upregulated the expressions of caspase-3, caspase-8, iNOS, and MT1, and also moderately upregulated CYP1A and CYP3A in the brain tissue of exposed carp. We also noted downregulation of FSH and LH gene expressions in chlorpyrifos-exposed ovary tissues. Based on our results, chlorpyrifos toxication caused crucial histopathological lesions in vital organs, induced oxidative stress, inflammation, and apoptosis in liver and brain tissues, and triggered reproductive sterility in common carp. Therefore, we can propose that chlorpyrifos toxication is highly dangerous to the health of common carp. Moreover, chlorpyrifos pollution in the water could threaten the common carp population. Use of chlorpyrifos should be restricted, and aquatic systems should be monitored for chlorpyrifos pollution. PMID- 28675854 TI - Air-sea exchange and gas-particle partitioning of polycyclic aromatic hydrocarbons over the northwestern Pacific Ocean: Role of East Asian continental outflow. AB - We measured 15 parent polycyclic aromatic hydrocarbons (PAHs) in atmosphere and water during a research cruise from the East China Sea (ECS) to the northwestern Pacific Ocean (NWP) in the spring of 2015 to investigate the occurrence, air-sea gas exchange, and gas-particle partitioning of PAHs with a particular focus on the influence of East Asian continental outflow. The gaseous PAH composition and identification of sources were consistent with PAHs from the upwind area, indicating that the gaseous PAHs (three-to five-ring PAHs) were influenced by upwind land pollution. In addition, air-sea exchange fluxes of gaseous PAHs were estimated to be -54.2-107.4 ng m-2 d-1, and was indicative of variations of land based PAH inputs. The logarithmic gas-particle partition coefficient (logKp) of PAHs regressed linearly against the logarithmic subcooled liquid vapor pressure (logPL0), with a slope of -0.25. This was significantly larger than the theoretical value (-1), implying disequilibrium between the gaseous and particulate PAHs over the NWP. The non-equilibrium of PAH gas-particle partitioning was shielded from the volatilization of three-ring gaseous PAHs from seawater and lower soot concentrations in particular when the oceanic air masses prevailed. Modeling PAH absorption into organic matter and adsorption onto soot carbon revealed that the status of PAH gas-particle partitioning deviated more from the modeling Kp for oceanic air masses than those for continental air masses, which coincided with higher volatilization of three-ring PAHs and confirmed the influence of air-sea exchange. Meanwhile, significant linear regressions between logKp and logKoa (logKsa) for PAHs were observed for continental air masses, suggesting the dominant effect of East Asian continental outflow on atmospheric PAHs over the NWP during the sampling campaign. PMID- 28675855 TI - Inter-laboratory skin distribution study of 4-n-butyl resorcinol: The importance of liquid chromatography/mass spectrometry (HPLC-MS/MS) bioanalytical validation. AB - In the present study, three laboratories independently compared percutaneous absorption and distribution of 4-n-butylresorcinol, using human skin from five donors. Each laboratory used the same protocol for percutaneous absorption studies but different LC-MS/MS analytical methods to quantify the test compound. All laboratories respected the mass balance criteria (i.e. 100+/-15%; average 96.5-102% of applied dose). Regarding usual inter-lab variability, good agreement was observed for all compartments with the greatest difference in the epidermis: 3.3 fold increase. The data obtained demonstrate that robustness of skin absorption data rely on properly validated analytical methods including sample extraction and LC-MS/MS method. It also includes clearly defined cutaneous absorption protocol for dose skin preparation, application, washing and tape stripping. PMID- 28675856 TI - Plant bioactive molecules bearing glycosides as lead compounds for the treatment of fungal infection: A review. AB - Despite therapeutic advancement in the treatment of fungal infections, morbidity and mortality caused by these infections are still very high. There are approximately 300 fungal species that are infectious and can cause a variety of diseases. At present, several synthetic antifungal drugs are in clinical practice, many of them, however, are vulnerable to multidrug-resistant strains of microbes, and thus compromising the overall treatment outcomes. Glycosides are naturally occurring plant secondary metabolites with important therapeutic potential and clinical utility. The aim of this review was to focus on the antifungal effects of glycosides in preclinical studies with possible mechanism(s) wherein described. Published research show significant susceptibility of different fungi towards phytoglycosides, mediated through multiple mechanisms. Further detailed studies are needed to explain the clinical applications and limitations of these glycosides. PMID- 28675857 TI - Anti-colon cancer activity of Murraya koenigii leaves is due to constituent murrayazoline and O-methylmurrayamine A induced mTOR/AKT downregulation and mitochondrial apoptosis. AB - In recent years, many alkaloids of plant origin have attracted great attention due to their diverse range of biological properties including anti-hyperglycemic, anti-oxidant, anti-inflammatory, anti-diabetic and anti-tumor activity. Herein, the pyranocarbazole alkaloids were isolated from leaves of Murraya koenigii and their anti-cancer potential was investigated in different cancer cell lines. Among all tested compounds, murrayazoline and O-methylmurrayamine A demonstrated potent anti-cancer activity against DLD-1 colon cancer cells with the IC50 values of 5.7MUM and 17.9MUM, respectively, without any non-specific cytotoxicity against non-cancer HEK-293 and HaCaT cells. Further, studies of pure compounds revealed that the anti-cancer activity of compounds corresponds with altered cellular morphology, cell cycle arrest in G2/M phase, reactive oxygen species level and mitochondrial membrane depolarization of colon cancer cells. In addition, these compounds activated caspase-3 protein and upregulated Bax/Bcl-2 protein expression ratio leading to induction of caspase-dependent apoptosis in DLD-1 cells. These event induced by carbazole alkaloids also coincides with downregulation of Akt/mTOR suggesting downstream targeting of cell survival pathway. Thus, our in vitro studies not only provided scientific basis of the use of M. koenigii leaves in the traditional Indian Ayurveda medicines, but also expands possibilities of medicinal uses of M. koenigii leaves against colon cancer. Particularly, these findings will help in further investigating murrayazoline and O-methylmurrayamine A or their improvised derivatives as new therapeutics for the treatment of colon cancer. PMID- 28675858 TI - Mentalization in adults with attention deficit hyperactivity disorder: Comparison with controls and patients with borderline personality disorder. AB - Emotion dysregulation and interpersonal hardships constitute core features of borderline personality disorder (BPD). Research has established the link between these core dysregulations and fluctuations in the capacity to appreciate the mental states that underlie behavior (mentalizing, operationalized as reflective functioning (RF)). As emotion dysregulation and interpersonal hardships also characterize adults with attention deficit hyperactivity disorder (ADHD), this study sought to examine the potential RF impairments affecting this population. 101 adults with ADHD, 108 with BPD and 236 controls were assessed using the RF questionnaire (RFQ), evaluating how individuals employ information about mental states to better understand their own and others' behaviors. The RFQ comprises two dimensions, certainty (RF_c) and uncertainty (RF_u) about mental states. RF scores helped distinguish ADHD from controls, but also from BPD (F = 48.1(2/441); p < 0.0001 for RF_c and F = 92.5(2/441); p < 0.0001 for RF_u). The ADHD group showed intermediary RF scores compared to the controls (b = -0.70; p < 0.0001 and b = 0.89; p < 0.0001 for RF_c and RF_u) and BPD group (b = 0.44; p = 0.001 and b = -0.56; p = 0.001 for RF_c and RF_u). Lower RF scores correlated with poor anger control and high levels of impulsivity. Higher severity of ADHD (more attentional and hyperactive/impulsive symptoms) was correlated with RF impairments. In conclusion, RF may constitute an important process underlying attentional, hyperactive/impulsive as well as emotional symptoms in ADHD; it should therefore be considered in the assessment of these patients. PMID- 28675859 TI - Indirect task instructions better reveal theory-of-mind impairment, independent of executive dysfunction, in schizophrenia. AB - Theory of mind (TOM) impairments associate significantly with executive deficits in schizophrenia, consistent with the proposal that executive abilities can limit TOM task performance, and confounding identification of those patients who would benefit most from targeted mentalising interventions. 50 schizophrenia patients and 30 healthy controls completed an executive battery and four TOM tasks that were alike with regards generating overt measures of causal false-belief reasoning, but differed with regards using indirect (vs. more direct) instructions. Only the TOM tasks that used indirect instructions to elicit spontaneous false-belief inferences revealed impairment, independent of executive dysfunction, in the schizophrenia patients. PMID- 28675861 TI - Synthesis of biochar from residues after biogas production with respect to cadmium and nickel removal from wastewater. AB - The objective of the study was to investigate the ability of biochars prepared under different temperatures (400 degrees C and 600 degrees C) from the residue of biogas production (RBP) for the adsorption of cadmium (Cd(II)) and nickel (Ni(II)) ions from aqueous solution. Furthermore, the RBP biochars adsorption capacity was compared with adsorption capacity of biochar produced from wheat straw at 600 degrees C (BCS600). The kinetics of the adsorption, the sorption isotherms, the influence of solution pH and the interfering ions (chlorides and nitrates) were investigated. The desorption of Cd(II) and Ni(II) by hydrochloric and nitric acid from biochars was also investigated. The different types of feedstock used for biochar (BC) preparation (RBP and biomass) determined the physico-chemical properties of biochars and hence their adsorption abilities. Generally, biochars produced from RBPs (regardless of temperature) had the greater capacity to adsorb Cd(II) and Ni(II) than the biochar produced from wheat straw. Of the tested models (Freundlich and Langmuir), the Langmuir model was demonstrated to be the best to describe the sorption of Cd(II) and Ni(II). For the kinetic study, the adsorption process proceeded the fastest for BCU400 than BCU600. Furthermore, BCU600 was the most resistant to the influence of interfering ions on adsorption. For the desorption study, BCU400 was characterized by the highest reproducibility of the surface. The comparison of the results obtained in each adsorption step between RBP biochars and BCS600 suggested that the residue from biogas production could be successfully applied for the removal of Cd(II) and Ni(II) ions from aqueous solutions. PMID- 28675860 TI - The role of stressful life events preceding death by suicide: Evidence from two samples of suicide decedents. AB - Stressful life events (SLEs) are associated with increased risk for suicidal behavior. Less is known regarding the intensity of SLEs and how this may vary as a function of suicide attempt history. As a large percentage of suicide decedents do not have a history of suicidal behavior, SLEs precipitating suicide may help characterize suicidality in this understudied population. This paper examines the intensity, number, and accumulation of SLEs preceding death by suicide among decedents with varying suicide attempt histories. Suicide attempts, SLEs, and suicide methods were examined in two samples: 62 prison-based and 117 community based suicide decedents. Regression was used to compare the level of stressor precipitating death by suicide in decedents who died on a first attempt versus multiple previous attempts. A non-significant trend was observed in the prison population which was supported by significant findings in the community-based sample. Decedents who died on a first attempt experienced a stressor of a lower magnitude when compared to decedents with multiple previous suicide attempts. We discuss the implications of these findings in relation to the stress-diathesis model for suicide. PMID- 28675862 TI - Bone char with antibacterial properties for fluoride removal: Preparation, characterization and water treatment. AB - In the present work, it was established a new method for the preparation of bone chars with a double purpose, i.e., the removal of fluoride from water and the antibacterial character. These adsorbents were obtained by doping a commercial bone char with Ag using different reagents. The optimal conditions for the enrichment with silver were established by following the Taguchi method and using as response variable the removal of fluoride from water. Optimal bone chars were thus prepared and they were characterized using FT-IR spectroscopy, SEM/EDX analysis, adsorption isotherms of N2 at -196 degrees C and X-ray diffraction. All adsorbents were used in the removal of fluoride from water and the antibacterial character was assessed using the technique of total viable count employing standard solutions of Escherichia coli and drinking water. Results clearly indicated that doping of bone chars with silver provides with suitable antibacterial properties, however the fluoride adsorption capacity was not affected by the presence of Ag degrees on the carbon surface. PMID- 28675863 TI - Polychlorinated biphenyls in Nepalese surface soils: Spatial distribution, air soil exchange, and soil-air partitioning. AB - Regardless of the ban on the polychlorinated biphenyls (PCBs) decade ago, significant measures of PCBs are still transmitted from essential sources in cities and are all inclusive ecological contaminants around the world. In this study, the concentrations of PCBs in soil, the air-soil exchange of PCBs, and the soil-air partitioning coefficient (KSA) of PCBs were investigated in four noteworthy urban areas in Nepal. Overall, the concentrations of ?30PCBs ranged from 10 to 59.4ng/g dry weight; dw (mean 12.2ng/g +/-11.2ng/g dw). The hexa-CBs (22-31%) was most dominant among several PCB-homologues, followed by tetra-CBs (20-29%), hepta-CBs (12-21%), penta-CBs (15-17%) and tri-CBs (9-19%). The sources of elevated level of PCBs discharge in Nepalese soil was identified as emission from transformer oil, lubricants, breaker oil, cutting oil and paints, and cable insulation. Slightly strong correlation of PCBs with TOC than BC demonstrated that amorphous organic matter (AOM) assumes a more critical part in holding of PCBs than BC in Nepalese soil. The fugacity fraction (ff) results indicated the soil being the source of PCB in air through volatilization and net transport from soil to air. The soil-air partitioning coefficient study suggests the absorption by soil organic matter control soil-air partitioning of PCBs. Slightly weak but positive correlation of measured Log KSA with Log KOA (R2 = 0.483) and Log KBC-A (R2 = 0.438) suggests that both Log KOA and Log KBC-A can predict soil-air partitioning to lesser extent for PCBs. PMID- 28675864 TI - De novo characterization of the Iris lactea var. chinensis transcriptome and an analysis of genes under cadmium or lead exposure. AB - Iris lactea var. chinensis (I. lactea var. chinensis) is tolerant to accumulations of cadmium (Cd) and lead (Pb). In this study, the transcriptome of I. lactea var. chinensis was investigated under Cd or Pb stresses. Using the gene ontology database, 31,974 unigenes were classified into biological process, cellular component and molecular function. In total, 13,132 unigenes were involved in enriched Encyclopedia of Genes and Genomes (KEGG) metabolic pathways, and the expression levels of 5904 unigenes were significantly changed after exposure to Cd or Pb stresses. Of these, 974 were co-up-regulated and 1281 were co-down-regulated under the two stresses. The transcriptome expression profiles of I. lactea var. chinensis under Cd or Pb stresses obtained in this study provided a resource for identifying common mechanisms in the detoxification of different heavy metals. Furthermore, the identified unigenes may be used for the genetic breeding of heavy-metal tolerant plants. PMID- 28675865 TI - Arsenic removal in aqueous solution by a novel Fe-Mn modified biochar composite: Characterization and mechanism. AB - The aim of this study was to develop a cost-effective method for As removal from aqueous systems. To this end, pristine biochar (BC) was impregnated with Fe-Mn oxides and a comparative analysis was conducted on the adsorption capacities of BC, Fe-Mn binary oxide (FMO), and Fe/Mn modified biochar (FMBC). The ferromanganese oxides increased the specific surface areas of BC. FMBC presented greater adsorption of As (Qmax = 8.25mgg-1) than FMO and BC. Energy dispersive spectrometer analysis and electron microscope scanning revealed numerous pores of FMBC with the existence of Fe-Mn oxide using. Distinguished binding energy shifting of the As3d, Fe2p, O1s, and Mn2p3/2 regions after As sorption were found, indicating that Mn(III) oxidation and interaction of oxygen-containing function groups in the FMBC promoted the conversion of As(III) to As(V). Furthermore, chemisorption was found to be the main mechanism for As sorption on FMBC. Thus, the results suggest that FMBC could be used as an inexpensive and highly efficient adsorbent for As removal from water environment. PMID- 28675866 TI - Assessing human health risks and strategies for phytoremediation in soils contaminated with As, Cd, Pb, and Zn by slag disposal. AB - Soils impacted by metallurgy activities pose serious risks to the health of exposed populations, whether by ingestion of soil or contaminated food and water. The municipality of Santo Amaro, Bahia state, presents the most important case of human lead contamination in Brazil. It occurred because of inadequate slag disposal. The aims of this research were to: (i) determine the environmentally available concentrations and the distribution of As, Cd, Pb, and Zn in soil fractions; (ii) estimate the non-carcinogenic and carcinogenic risks of these elements for children; and (iii) to evaluate the use of corn (Zea mays) and castor bean (Ricinus communis) either for phytoextraction induced by chelating agents or phytostabilization. Our data demonstrated that the environmentally available concentrations of As, Cd, Pb, and Zn in soils surrounding the Pb smelting plant are among the highest that have been reported. Apart from Cd, sequential extraction demonstrated that most metals are in recalcitrant forms in the soil. However, the daily exposure of children to Pb, Zn, Cd, and As exceeded the acceptable daily intake as established by the World Health Organization. Non carcinogenic risk modeling indicated probable adverse health effects from chronic exposure to soil Pb. The mean estimated time for remediation of the area using phytoextraction was high, ranging from 76 to 259 years; therefore, this is not a viable alternative for remediating soils in the studied area. However, good development in the contaminated soil along with restriction of the metal(oid) translocation to shoots enables castor bean to phytostabilize metal(oid)s. Additionally, castor bean cultivation may be an alternative for an economic return because of biofuel production. PMID- 28675867 TI - The Lambert-Beer law in time domain form and its application. AB - The majority of current radioisotope gauges utilize measurements of intensity for a chosen sampling time interval using a detector. Such an approach has several disadvantages: temporal resolution of the gauge is fixed and the accuracy of the measurements is not the same for different count rate. The solution can be the use of a stronger radioactive source, but it will be conflicted with ALARA (As Low As Reasonably Achievable) principle. Therefore, the article presents an alternative approach which is based on modified Lambert-Beer law. The basis of the approach is the registration of time intervals instead of the registration of counts. It allows to increase the temporal resolution of a gauge without the necessity of using a stronger radioactive source and the accuracy of the measurements will not depend on count rate. PMID- 28675868 TI - Photo-peak area ratios for estimation of elemental concentration in aqueous solutions using prompt gamma measurements. AB - The use of photo-peak area ratios are investigated for quantitative estimation of elements, particularly chlorine, in aqueous solutions using neutron induced prompt gamma measurements. A ratio of prompt gamma intensities avoids the need for estimating the incident total neutron fluence and is demonstrated for chlorine concentration estimation in NaCl solutions. Monte Carlo simulation results validated with experimental measurements support the present analysis. Use of several prompt gamma intensities instead of a single one improves the accuracy of the estimated results. PMID- 28675869 TI - Flame retardant and hydrophobic coatings on cotton fabrics via sol-gel and self assembly techniques. AB - Nanocoatings consisting of ammonium polyphosphate (APP), sodium montmorillonite (MMT), and vinyltrimethoxysilane (VTMS) were prepared via self-assembly and in situ sol-gel techniques and applied onto cotton fabrics to achieve both flame retardancy and hydrophobicity. The impacts of APP concentration on the hydrophobicity and fire resistance of the coated fabrics were investigated. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) characterization results verified the hydrolysis-condensation reaction of VTMS and the formation of Si-O-Si network structure. X-ray diffraction (XRD) proved the formation of a layered structure based on MMT nanosheets in the coatings. Both vertical flame test (VFT), limiting oxygen index (LOI), thermogravimetric analysis (TGA) and microscale combustion calorimeter (MCC) characterization were conducted to evaluate the flame retardancy, thermostability and heat release behavior of the coated cotton fabrics, respectively. The results suggested that a higher concentration of APP is beneficial for both hydrophobicity and flame retardancy of the coated substrates. Overall, our research provides a facile and very effective approach to prepare flame retardant and hydrophobic multifunctional coating for cotton fabric and other substrates. PMID- 28675871 TI - Ozone treatment of graphitic carbon nitride with enhanced photocatalytic activity under visible light irradiation. AB - An efficient and stable catalyst with fragment-exfoliating structure was prepared by directly ozone treatment of bulk graphitic carbon nitride (g-C3N4). The photocatalytic performances of the as-prepared catalysts were evaluated by degradation of methylene blue (MB) and photocatalytic hydrogen evolution reaction under visible light irradiation. Compared with untreated g-C3N4, the ozone treated g-C3N4 (OCN) exhibited almost 5 times higher photodegradation activity and 2 times H2 evolution rate. The enhanced photocatalysis capability could be assigned to a narrowed band gap (2.62eV), the increased defects and active sites, and the reduced recombination efficiency of photoinduced carriers in OCN. Furthermore, the photocatalytic mechanism in degradation process of MB was discussed and the hydroxyl radical and superoxide radical have proven to be the predominant active species. It is reasonable to believe that chemical modifying of catalysts through ozone treatment could efficiently regulate its catalytic activity. PMID- 28675870 TI - Urea-derived graphitic carbon nitride (u-g-C3N4) films with highly enhanced antimicrobial and sporicidal activity. AB - In this manuscript, we describe the fabrication of photoactive biocidal or sporicidal films from urea-derived graphitic carbon nitride (u-g-C3N4). Co deposited films of u-g-C3N4 and Escherichia coli O157:H7 (IC50=14.1+/-0.2mJ) or Staphylococcus aureus (methicillin resistant IC50=33.5+/-0.2mJ, methicillin sensitive IC50=42.7+/-0.5mJ) demonstrated significantly enhanced bactericidal behavior upon administration of visible radiation (400nm<=lambda<=426nm). In all cases, complete eradication of the microbial sample was realized upon administration of 100mJ of visible radiation, while no antimicrobial activity was observed for non-irradiated samples. In contrast, Bacillus anthracis endospores were more resistant to u-g-C3N4 mediated killing with only a ca. 25% reduction in spore viability when treated with a 200mJ dose of visible radiation. Characterization of u-g-C3N4 reveals that the improved activity results from enhancements of both the surface area and reduction potential of the material's conduction band edge, coupled with fast injection of charge carriers into localized states and a decline in radiative recombination events. The results of this study demonstrate that g-C3N4-based materials offer a viable scaffold for the development of new, visible light driven technologies for controlling potentially pathogenic microorganisms. PMID- 28675872 TI - Study on the influences of two thiazole flavor ingredients on Cu corrosion caused by chloride ion. AB - Green corrosion inhibitors are of great benefit to the protection of pipes or tanks in seawater systems. The properties of the corrosion inhibitor such as toxicity and anticorrosion performance are closely related to its molecular structure. Some thiazole derivatives are commonly known as food flavors. The influences of two thiazole flavor ingredients on Cu corrosion in NaCl solution were analyzed in this study, namely, 4-methyl-5-vinylthiazole (MVT) and 5-(2 hydroxyethyl)-4-methylthiazole (HMT). Potentiodynamic polarization and electrochemical impedance spectroscopy measurements were employed to evaluate their anti-corrosion abilities. Theoretical calculations were conducted to investigate their possible adsorption modes. The thiazole ring endows the two compounds with the high inhibition performace. However, with a conjugated system, the ethenyl has a more pronounced contribution to electron donation and adsorption ability on the Cu surface than hydroxyethyl group. PMID- 28675873 TI - Changes in the fecal microbiota of beef cattle caused by change in management and the use of virginiamycin as a growth promoter. AB - Several factors are known to affect the intestinal microbiota of cattle. However, how these changes occur over time is poorly understood. This study aimed to investigate the consequences of entrance into a feedlot and the effects of virginiamycin used as a growth promoter on the bovine fecal microbiota. Two batches of beef cattle (B1, n=50 and B2, n=36) entering a feedlot operation were randomly divided into two pens: one receiving virginiamycin and one group not receiving antibiotic (control group). Fecal samples were collected at arrival, mid feedlot and at exit to slaughter. The V4 region of 16S rRNA gene was amplified and sequenced. Escherichia coli strains isolated in samples from arrival and exit of B2 were also isolated and used as indicators of antimicrobial susceptibility. Marked changes in membership and structure of fecal microbiota occurred following entrance into the feedlot. At mid feedlot, virginiamycin affected bacterial community membership, but not structure, suggesting that the antibiotic had a stronger effect on the rare, but not on the most abundant species. The use of virginiamycin had no demonstrable effect on antibiotic resistance in E. coli. The differences found between batches are suggestive that variations in study conditions are important and can strongly affect the intestinal microbiota. PMID- 28675874 TI - Source apportionment of fine particulate matter and risk of term low birth weight in California: Exploring modification by region and maternal characteristics. AB - Previous studies have demonstrated associations between fine particulate matter (PM2.5) and risk of term low birth weight (TLBW; birth weight<2500g and gestational weeks>=37weeks). However, it remains unclear which PM2.5 sources mainly contribute to these associations, and which subgroups (e.g. by residential region and maternal characteristics) may be more susceptible to these exposures. Using California birth records and PM2.5 data from eight monitoring sites from 2002 to 2009, we examined the relationship between exposures to total PM2.5 and PM2.5 sources and risk of TLBW. Source apportionment was performed for each site using Positive Matrix Factorization, and five PM2.5 sources (i.e., secondary ammonium sulfate, secondary ammonium nitrate, vehicular emissions, biomass burning, and resuspended soil) were included in our analysis. Mean gestational and trimester exposures were calculated for mothers with ZIP codes located within a 20km radius of monitors (N=1,050,330). Logistic regression was conducted and adjusted for maternal age, race/ethnicity, and education, as well as gestational age, year of birth, apparent temperature exposure during gestation, and neighborhood level percentage of households below poverty level. Increased risks of TLBW associated with each interquartile range increase in exposure were 4.9% (95% confidence interval: 2.6, 7.3) for total PM2.5, 7.7% (4.7, 10.7) for secondary ammonium sulfate, 5.6% (3.5, 7.7) for resuspended soil, and 3.1% (1.3, 4.9) for secondary ammonium nitrate. Differences in associations were found between inland and coastal regions, and between northern and southern regions for several sources. Results also showed effect measure modification by maternal race/ethnicity and education, with the lowest risk of TLBW associated with PM2.5 exposures found in mothers with at least a college education and Asian mothers. Some PM2.5 sources may be more harmful than others, and a better understanding of the relative toxicity of PM2.5 from each source could lead to more targeted and cost-effective regulations to protect public health. PMID- 28675875 TI - Predictive quality of 26 pesticide risk indicators and one flow model: A multisite assessment for water contamination. AB - Stakeholders need operational tools to assess crop protection strategies in regard to environmental impact. The need to assess and report on the impacts of pesticide use on the environment has led to the development of numerous indicators. However, only a few studies have addressed the predictive quality of these indicators. This is mainly due to the limited number of datasets adapted to the comparison of indicator outputs with pesticide measurement. To our knowledge, evaluation of the predictive quality of pesticide indicators in comparison to the quality of water as presented in this article is unprecedented in terms of the number of tested indicators (26 indicators and the MACRO model) and in terms of the size of datasets used (data collected for 4 transfer pathways, 20 active ingredients (a.i.) for a total of 1040 comparison points). Results obtained on a.i. measurements were compared to the indicator outputs, measured by: (i) correlation tests to identify linear relationship, (ii) probability tests comparing measurements with indicator outputs, both classified in 5 classes, and assessing the probability i.e. the percentage of correct estimation and overestimation (iii) by ROC tests estimating the predictive ability against a given threshold. Results showed that the correlation between indicator outputs and the observed transfers are low (r<0.58). Overall, more complex indicators taking into account the soil, the climatic and the environmental aspects yielded comparatively better results. The numerical simulation model MACRO showed much better results than those for indicators. These results will be used to help stakeholders to appropriately select their indicators, and will provide them with advice for possible use and limits in the interpretation of indicator outputs. PMID- 28675876 TI - Key parameters influencing metallic element mobility associated with sediments in a daily-managed reservoir. AB - In a hydroelectric reservoir, sediments are subject to remobilization events, water-level fluctuations and physicochemical changes. Depending on their associated metallic content, surficial oxic to suboxic sediments could constitute a major source of metals. To identify the key parameters that control metallic elements in terms of their mobility and sensitivity to reservoir management, sediments were subject to resuspension and drying/wetting cycle experiments over a wide range of pH values, solid/liquid ratios (S/L) and redox (Eh) conditions. During these tests, special attention was also paid to the influence of pretreatments on samples, i.e., drying, aeration and the leachate composition (ultrapure water vs. natural water); on the preservation of the sediment characteristics; and especially on metallic element release. The results of this study show that the pH, S/L ratio and Eh parameters are key variables in metal solubilization; the pH influences metal mobility primarily through sorption desorption phenomena as well as the dissolution of metallic-bearing phases, the S/L ratio modifies the sorption-desorption equilibria, and the Eh primarily affects the reducible sensitive phases and associated metallic elements through dissolution-precipitation processes. Under environmental conditions, evolution of these parameters can lead to a >20% solubilization of the most mobile elements, i.e., As and Cd. These results are influenced by the sample pretreatment and experimental conditions. In fact, even if the solubilization patterns show no significant differences between dry and wet sediment depending on the physicochemical conditions, the magnitude of their release is significantly affected. Drying pretreatment induces changes in metal speciation, notably altering the distribution of the most weakly bound elements; there is almost half the amount of metallic elements associated with the exchangeable fraction in dry compared to wet sediments. The solubilization percentages were higher in the ultrapure phase than in reservoir water primarily due to the low pH, which influenced the sorption equilibria. PMID- 28675877 TI - Production of added value bacterial lipids through valorisation of hydrocarbon contaminated cork waste. AB - This work demonstrates that cork used as oil-spill sorbents, contaminated with liquid hydrocarbons, herein demonstrated with hexadecane, can be biologically treated by Rhodococcus opacus B4 with concomitant lipids production. R. opacus B4 consumed up to 96% of hexadecane (C16) impregnated in natural and regranulated cork sorbents after 48h incubation, producing 0.59+/-0.06g of triacylglycerol (TAG) g-1 of C16 consumed with a TAG content of 0.60+/-0.06gg-1 of cellular dry weight (CDW) and 0.54+/-0.05g TAG g-1 of C16 consumed with a TAG content of 0.77+/-0.04gg-1 (CDW), respectively. TAG was mainly composed by fatty acids of 16 and 18 carbon chains demonstrating the feasibility of using it as raw material for biodiesel production. In addition, the obtained lipid-rich biomass (whole cells) can be used for biomethane production, at a yield of 0.4L CH4 g-1 (CDW). The obtained results support a novel approach for management of oil-spill contaminated cork sorbents through its valorisation by producing bacterial lipids, which can be used as feedstocks for biofuels production. PMID- 28675878 TI - Contrasting habitats but comparable microbial decomposition in the benthic and hyporheic zone. AB - Input of allochthonous leaf litter is the main carbon source for heterotrophic metabolism in low-order forested streams. A major part of this leaf litter is accumulated at benthic retention structures or buried in the hyporheic zone. As a result of hyporheic sediment characteristics, hyporheic physicochemistry differs from that of the benthic zone selecting the microbial community. The present study aimed at understanding the influence of the hydrological and physiochemical differences between the benthic and hyporheic zone on microbial leaf litter decomposition and on the structure and function of the associated microbial community. Leached leaves of Alnus glutinosa were exposed for 62days in 250-MUm mesh bags in the benthic zone and buried in the hyporheic zone at a depth of 2 3cm. Decomposition rates were comparable for both zones. In contrast, respiration, bacterial abundance, ergosterol content, fungal spore production and richness of fungal morphotypes were lower associated with hyporheic than with benthic leaves. Microbial community structure displayed zone-dependent temporal dynamics. Thus, the microbial community carried out leaf litter decomposition independently of its structure. These results suggest that carbon processing is not necessarily impaired by environmental constraints because the community structure may compensate those constraints (i.e. functional redundancy). PMID- 28675879 TI - Three methods for integration of environmental risk into the benefit-risk assessment of veterinary medicinal products. AB - Veterinary medicinal products (VMPs) require, as part of the European Union (EU) authorization process, consideration of both risks and benefits. Uses of VMPs have multiple risks (e.g., risks to the animal being treated, to the person administering the VMP) including risks to the environment. Environmental risks are not directly comparable to therapeutic benefits; there is no standardized approach to compare both environmental risks and therapeutic benefits. We have developed three methods for communicating and comparing therapeutic benefits and environmental risks for the benefit-risk assessment that supports the EU authorization process. Two of these methods support independent product evaluation (i.e., a summative classification and a visual scoring matrix classification); the other supports a comparative evaluation between alternative products (i.e., a comparative classification). The methods and the challenges to implementing a benefit-risk assessment including environmental risk are presented herein; how these concepts would work in current policy is discussed. Adaptability to scientific and policy development is considered. This work is an initial step in the development of a standardized methodology for integrated decision-making for VMPs. PMID- 28675880 TI - Comparative analysis of spatio-temporal exposure assessment methods for estimating odor-related responses in non-urban populations. AB - The assessment of air pollution exposures in epidemiological studies does not always account for spatio-temporal variability of pollutants concentrations. In the case of odor studies, a common approach is to use yearly averaged odorant exposure estimates with low spatial resolution, which may not capture the spatio temporal variability of emissions and therefore distort the epidemiological results. This study explores the use of different exposure assessment methods for time-variant ammonia exposures with high spatial resolution, in rural communities exposed to odors from agricultural and livestock farming activities. Exposure estimations were based on monthly ammonia concentrations from emission-dispersion models. Seven time-dependent residential NH3 exposures variables were investigated: 1) Annual mean of NH3 exposures; 2) Maximum annual NH3 exposure; 3) Area under the exposure curve; 4) Peak area; 5) Peak-to-mean ratio; 6) Area above the baseline (annual mean of NH3 exposures); and 7) Maximum positive slope of the exposure curve. We developed binomial and multinomial logistic regression models for frequency of odor perception and odor annoyance responses based on each temporal exposure variable. Odor responses estimates, goodness of fit and predictive abilities derived from each model were compared. All time-dependent NH3 exposure variables, except peak-to-mean ratio, were positively associated with odor perception and odor annoyance, although the results differ considerably in terms of magnitude and precision. The best goodness of fit of the predictive binomial models was obtained when using maximum monthly NH3 exposure as exposure assessment variable, both for odor perception and annoyance. The best predictive performance for odor perception was found when annual mean was used as exposure variable (accuracy=71.82%, Cohen's Kappa=0.298) whereas odor annoyance was better predicted when using peak area (accuracy=68.07%, Cohen's Kappa=0.290). Our study highlights the importance of taking temporal variability into account when investigating odor-related responses in non-urban residential areas. PMID- 28675881 TI - Making sense of the noise: The effect of hydrology on silver carp eDNA detection in the Chicago area waterway system. AB - Environmental DNA (eDNA) sampling is an emerging tool for monitoring the spread of aquatic invasive species. One confounding factor when interpreting eDNA sampling evidence is that eDNA can be present in the water in the absence of living target organisms, originating from excreta, dead tissue, boats, or sewage effluent, etc. In the Chicago Area Waterway System (CAWS), electric fish dispersal barriers were built to prevent non-native Asian carp species from invading Lake Michigan, and yet Asian carp eDNA has been detected above the barriers sporadically since 2009. In this paper the influence of stream flow characteristics in the CAWS on the probability of invasive Asian carp eDNA detection in the CAWS from 2009 to 2012 was examined. In the CAWS, the direction of stream flow is mostly away from Lake Michigan, though there are infrequent reversals in flow direction towards Lake Michigan during dry spells. We find that the flow reversal volume into the Lake has a statistically significant positive relationship with eDNA detection probability, while other covariates, like gage height, precipitation, season, water temperature, dissolved oxygen concentration, pH and chlorophyll concentration do not. This suggests that stream flow direction is highly influential on eDNA detection in the CAWS and should be considered when interpreting eDNA evidence. We also find that the beta-binomial regression model provides a stronger fit for eDNA detection probability compared to a binomial regression model. This paper provides a statistical modeling framework for interpreting eDNA sampling evidence and for evaluating covariates influencing eDNA detection. PMID- 28675882 TI - Characterizing spatiotemporal dynamics in phenology of urban ecosystems based on Landsat data. AB - Seasonal phenology of vegetation plays an important role in global carbon cycle and ecosystem productivity. In urban environments, vegetation phenology is also important because of its influence on public health (e.g., allergies), and energy demand (e.g. cooling effects). In this study, we studied the potential use of remotely sensed observations (i.e. Landsat data) to derive some phenology indicators for vegetation embedded within the urban core domains in four distinctly different U.S. regions (Washington, D.C., King County in Washington, Polk County in Iowa, and Baltimore City and County in Maryland) during the past three decades. We used all available Landsat observations (circa 3000 scenes) from 1982 to 2015 and a self-adjusting double logistic model to detect and quantify the annual change of vegetation phenophases, i.e. indicators of seasonal changes in vegetation. The proposed model can capture and quantify not only phenophases of dense vegetation in rural areas, but also those of mixed vegetation in urban core domains. The derived phenology indicators show a good agreement with similar indicators derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) and in situ observations, suggesting that the phenology dynamic depicted by the proposed model is reliable. The vegetation phenology and its seasonal and interannual dynamics demonstrate a distinct spatial pattern in urban domains with an earlier (9-14days) start-of-season (SOS) and a later (13 20days) end-of-season (EOS), resulting in an extended (5-30days) growing season length (GSL) when compared to the surrounding suburban and rural areas in the four study regions. There is a general long-term trend of decreasing SOS ( 0.30day per year), and increasing EOS and GSL (0.50 and 0.90day per year, respectively) over past three decades for these study regions. The magnitude of these trends varies among the four urban systems due to their diverse local climate conditions, vegetation types, and different urban-rural settings. The Landsat derived phenology information for urban domains provides more details when compared to the coarse-resolution datasets such as MODIS, thus improves our understanding of human-natural systems interactions (or feedbacks) in urban domains. Such information is very valuable for urban planning in light of rapid urbanization and expansion of major metropolitans at the national and global levels. PMID- 28675883 TI - Mass loading of typical artificial sweeteners in a pig farm and their dissipation and uptake by plants in neighboring farmland. AB - Pig farm is an important potential source for artificial sweeteners (ASs) in the environment due to their wide use as additives in pig feed. The objective of this study was to evaluate the fate of typical ASs in pig farm and neighboring farmland. For this purpose, the levels of four typical artificial ASs, i.e. saccharin (SAC), cyclamate (CYC), acesulfame (ACE) and sucralose (SUC), in pig feed and manure from a pig farm and water samples from an on-farm wastewater treatment plant (WWTP) in Tianjin, China were measured and the mass loadings and removal efficiencies were assessed. Moreover, the levels of ASs in different layers of soil and vegetables in neighboring farmland that received manure fertilizers and wastewater from the farm were consecutively monitored for 60 80days. The SAC, CYC and ACE were widely determined in all kinds of the samples, while SUC was only found in few soil samples. The mass loadings of the ASs in pig feed were estimated up to 311kg/year for SAC, 59.1kg/year for CYC, and 17.1kg/year for ACE, respectively. The fractions of the total mass of ASs excreted via manure were estimated to be 36.0% for SAC, 59.4% for CYC, and 36.7% for ACE as compared to those in pig feed. High removal efficiencies (>90%) of ASs in the on-farm WWTP was achieved. In greenhouse soils, CYC, SAC, ACE, and SUC were degraded quickly, with half-lives of 4.3-5.9 d, 2.7-4.2 d, 8.4-12.3 d, and 7.3-10.8 d, respectively. Lower levels of ASs were found in deeper soil layer (20 30cm). The ASs were considerably absorbed by plants when the ASs' concentrations were high in soil. This study presents the first comprehensive overview of ASs fate from a pig farm to the neighboring agricultural ecosystem. PMID- 28675884 TI - Single cell transcriptomics of pluripotent stem cells: reprogramming and differentiation. AB - Single-cell transcriptomics serves as a powerful tool to identify cell states within populations of cells, and to dissect underlying heterogeneity at high resolution. Single-cell transcriptomics on pluripotent stem cells has provided new insights into cellular variation, subpopulation structures and the interplay of cell cycle with pluripotency. The single-cell perspective has helped to better understand gene regulation and regulatory networks during exit from pluripotency, cell-fate determination as well as molecular mechanisms driving cellular reprogramming of somatic cells to induced pluripotent stage. Here we review the recent progress and significant findings from application of single-cell technologies on pluripotent stem cells along with a brief outlook on new combinatorial single-cell approaches that further unravel pluripotent stem cell states. PMID- 28675885 TI - High-Performance Membrane Dialyzers and Mortality in Hemodialysis Patients: A 2 Year Cohort Study from the Annual Survey of the Japanese Renal Data Registry. AB - BACKGROUND: Little information is available regarding the type of dialyzer which results in good prognosis. This study is aimed at investigating the association between 7 types of dialyzers and 2-year mortality. METHODS: We conducted a cohort study using data from a nationwide registry of the Japanese Society for Dialysis Therapy. Subjects were 136,676 patients on maintenance hemodialysis (HD) between 2009 and 2011 who underwent maintenance HD for at least 2 years and were treated with one of the following 7 types of high-performance membrane dialyzers: cellulose triacetate (CTA), ethylene vinyl alcohol (EVAL), polyacrylonitrile (PAN), polyester polymer alloy (PEPA), polyethersulfone (PES), polymethylmethacrylate (PMMA), and polysulfone (PS). Cox regression was used to estimate the association between baseline dialyzers and all-cause 2-year mortality, adjusting for potential confounders. RESULTS: Data were adjusted using basic factors, with PS as a reference group, and the hazard ratio (HR) was significantly higher in CTA, PMMA, PAN, and EVAL groups. Further data adjustment for Kt/V yielded the same results as were obtained from data adjusted for basic factors. After further adjustment for nutrition- and inflammation-related factors, HR was significantly lowered for the PES and PMMA groups compared with the PS group (HR 0.88; 95% CI 0.82-0.94 and HR 0.84 95% CI 0.76-0.93, respectively). After propensity score matching, HR for the PES and PMMA groups was significantly lowered compared with the PS group. CONCLUSIONS: The use of different membrane types may affect mortality. Further long-term prospective studies are needed to clarify whether the PES and PMMA membranes can improve prognosis. PMID- 28675887 TI - Prenatal Imaging Findings of Pontine Tegmental Cap Dysplasia: Report of Four Cases. AB - OBJECTIVES: To describe the prenatal imaging findings in pontine tegmental cap dysplasia (PTCD), a rare congenital malformation of the hindbrain so far reported postnatally only and characterized by a typical appearance of the pons with malformations of the vermis and the cerebellar peduncles. METHODS: This retrospective multicenter study retrieved 4 cases of PTCD over a 10-year period. Prenatal ultrasonography and fetal magnetic resonance imaging (MRI) findings were reviewed and compared to postnatal or postmortem data. RESULTS: In all cases, the parents were referred between 22 and 27 weeks of gestation for characterization of a small cerebellar diameter <3rd centile. The prenatal diagnosis of PTCD was suspected in 1/4 cases, while in 3/4 cases the suggested prenatal diagnosis was pontocerebellar hypoplasia. In all cases, PTCD was characterized by ventral pontine hypoplasia with absence of bulging of the pons and by the tegmental cap protruding into the fourth ventricle on prenatal MRI. Parents opted for termination of pregnancy in 1 case. In the 3 other cases, the children presented with global developmental delay and multiple cranial nerve impairment. CONCLUSION: PTCD is a differential diagnosis of pontocerebellar hypoplasia and should be discussed on prenatal MRI in the presence of the tegmental cap protruding into the fourth ventricle. PMID- 28675886 TI - International Society for the Study of Fatty Acids and Lipids 2016 Debate: For Science-Based Dietary Guidelines on Fats, Meta-Analysis and Systematic Reviews Are Decisive. AB - This paper summarizes a debate on whether meta-analyses and systematic reviews are decisive in formulating guidelines for dietary fat. Held during the 12th congress of the International Society for the Study of Fatty Acids and Lipids in Stellenbosch, South Africa, September 7, 2016, the debate was hosted by the International Union of Nutritional Sciences and the International Expert Movement to Improve Dietary Fat Quality (IEM, www.theiem.org). Clemens von Schacky, Ludwig Maximilians-University, Munich, Germany, supported the statement, describing the types of weaknesses in individual studies and clinical trials. With examples of how to overcome such limitations, he concluded that nutritional guidelines on fat need a proper scientific basis in which randomized controlled trials (RCTs) with clinical endpoints and their meta-analyses are essential and decisive. In contention, Ingeborg Brouwer, Vrije Universiteit, Amsterdam, declared that recommendations on dietary fat intake should always be based on the totality of the evidence, including physiologic and biochemical knowledge and associations from observational epidemiology. RCTs and meta-analyses have their shortcomings, but well-conducted systematic reviews and meta-analyses support a transparent process for developing dietary fat guidelines. Participants agreed that evidence based decision-making for dietary guidance should consider all the best available evidence using a transparent, systematic review. PMID- 28675888 TI - Relationship between Lower Tendency to Deceive in Aging and Inhibitory Compromise. AB - BACKGROUND: Deception can be associated with a heterogeneous network of concepts such as exaggeration, misleading, white lies, and faking. This paper assesses the tendency to deceive in aging. OBJECTIVE: Our main aim was to assess whether older adults would demonstrate a low tendency to deceive. METHODS: A total of 42 older adults (mean age 67.64 years, SD 7.87) and 45 younger adults (mean age 21.71 years, SD 2.66) were administered a deception scale including items such as "I sometimes tell lies if I have to" or "I never take things that don't belong to me." Participants were also administered an inhibition task. RESULTS: The results demonstrated a low tendency to deceive and low inhibition in older adults compared with younger ones. The low tendency to deceive in the older adults was significantly correlated with their diminished inhibitory ability. DISCUSSION: The low tendency to deceive in aging seems to be related to a difficulty in inhibiting an honest response. Since inhibitory compromise has been considered mainly to trigger negative consequences for cognition, the present paper illustrates how this age-related compromise can be associated with positive social outcomes, i.e., a low tendency to deceive. PMID- 28675889 TI - Individual Characteristics and Physical Activity in Older Adults: A Systematic Review. AB - BACKGROUND: People aged 50 years and older are regularly identified as the most sedentary group in the population. However, even within this group, there are considerable interindividual variations in physical activity (PA) levels. They have been the subject of many studies. Based on single studies, no clear picture as to which characteristics are important has emerged. OBJECTIVE: The goal of our contribution was to identify which individual characteristics are consistently linked to high PA levels in older adults. METHODS: We conducted a systematic review of the literature considering demographic characteristics (gender, education, marital status, employment), health (subjective, health problems), and psychological factors (motivation, self-efficacy, locus of control). A systematic search of abstracts in the database Web of Science and a thorough screening process according to a priori specified criteria yielded 63 studies for inclusion in this review. RESULTS: Two psychological factors - motivation and self-efficacy - and the perception of one's health seem to be consistently linked to higher PA levels in older adults. Selected demographic variables - gender and education - may be important for some types of PA. CONCLUSION: Our review suggests that differentiation of PA by domains is important for identifying and understanding which individual characteristics are associated with PA levels and how. Pinpointing what reliably distinguishes older adults who are active from those who are not is essential for designing effective interventions to promote PA in later life. PMID- 28675890 TI - Acute Radiological Abnormalities after Bronchial Thermoplasty: A Prospective Cohort Trial. AB - BACKGROUND: Bronchial thermoplasty (BT) is a novel treatment for severe asthma based on radiofrequency energy delivery to the larger airways. Although impressive radiological abnormalities have been reported, the incidence, pattern, and behavior over time of acute radiological abnormalities following BT are not well established. OBJECTIVE: To assess the incidence pattern and behavior over time of acute radiological abnormalities following BT. METHODS: This is a prospective, observational imaging study of severe asthma patients participating in the TASMA trial. Imaging of the lung (chest X-ray and/or computed tomography [CT]) was performed routinely before and directly after BT, within 6 weeks and at 6 months' follow-up. RESULTS: Thirty-four chest X-rays were performed within <5 h following 34 BT procedures in 12 patients. In 91% of cases, radiological abnormalities were seen, designated as peribronchial consolidations (97%) and/or atelectasis (29%). Ultra-low-dose (ULD) chest CTs were performed following 16 BT procedures showing abnormalities in all. Four different radiological patterns were identified: peribronchial consolidations with surrounding ground glass opacities (94%), atelectasis (38%), partial bronchial occlusions (63%), and bronchial dilatations (19%). No bronchoscopic intervention was needed. At 6 months' follow-up, in a single patient, high-resolution chest CT showed a focal bronchiectasis in a single airway. CONCLUSIONS: There is a high incidence of acute radiological abnormalities after BT. Four distinct radiological patterns can be identified on ULD chest CT, which resolve without clinical impact in virtually all cases. PMID- 28675891 TI - The Role of Radical Prostatectomy and Radiotherapy in Treatment of Locally Advanced Prostate Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The role of radical prostatectomy (RP) is still controversial for locally advanced prostate cancer (PC). Radiotherapy (RT) and hormonal therapy (HT) are usually used as a primary treatment. MATERIAL AND METHODS: A systematic online search was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Eligible publications reporting the overall survival (OS) and/or disease-specific survival (DSS) were included. A total of 14 studies, including 17,869 patients, were considered for analysis. The impact of therapeutic modalities on survival was assessed, with a risk of bias assessment according to the Newcastle Ottawa Scale. RESULTS: For RP, RT, and HT, the mean 10 year OS was 70.7% (95% CI 61.3-80.2), 65.8% (95% CI 48.1-83.3), and 22.6% (95% CI 4.9-40.3; p = 0.001), respectively. The corresponding 10-year DSS was 84.1% (95% CI 75.1-93.2), 89.4% (95% CI 70.1-108.6), and 50.4% (95% CI 31.2-69.6; p = 0.0127), respectively. Among all treatment combinations, RP displayed significant improvement in OS when included in the treatment (Z = 4.01; p < 0.001). Adjuvant RT significantly improved DSS (Z = 2.7; p = 0.007). Combination of RT and HT favored better OS in comparison to monotherapy with RT or HT (Z = 3.61; p < 0.001). CONCLUSION: Improved outcomes in advanced PC were detected for RP plus adjuvant RT vs. RP alone and RT plus adjuvant HT vs. RT alone with comparable survival results between both regimens. RP with adjuvant RT may present the modality of choice when HT is contraindicated. PMID- 28675892 TI - Treatment of Chronic Lower Back Pain: Study Protocol of a Comparative Effectiveness Study on Yoga, Eurythmy Therapy, and Physiotherapeutic Exercises. AB - BACKGROUND: We aim to compare the effectiveness of 3 active interventions, i.e., yoga, eurythmy therapy, and physiotherapeutic exercise, on chronic lower back pain. METHODS: In this randomized controlled trial over 16 weeks (8 weeks of intervention, 8 weeks of follow-up), data of individuals with chronic lower back pain will be analyzed. Interventions are implemented as group sessions (75 min) once per week. Participants receive a manual for home-based practice and are assessed before and at the end of the 8-week intervention period, and at the end of an 8-week follow-up period. Standardized questionnaires are: the Roland-Morris Disability Score, visual analog scales measuring intensity of pain, the Brief Multidimensional Life Satisfaction Scale, the Perceived Stress Scale, the Inner Correspondence with the Practices questionnaire, the Freiburg Mindfulness Questionnaire, the General Self-Efficacy Scale, a self-regulation questionnaire, the Internal Coherence Scale, a pain diary (registering the need of analgesic medication), and a questionnaire on the patients' expectation that the interventions will be effective in reducing pain and how strong this reduction might be (2 single items), etc. DISCUSSION: This large multicenter study will provide evidence on the effectiveness of 3 contrasting movement-orientated treatments that share some similarities but differ in essential details: yoga, eurythmy therapy, and physiotherapeutic exercises. It will provide important data on non-pharmacological options to treat lower back pain in a large group of affected individuals. PMID- 28675893 TI - Using High-Resolution 3D Magnetic Resonance Imaging to Quantitatively Analyze the Shape of Eyeballs with High Myopia and Provide Assistance for Posterior Scleral Reinforcement. AB - PURPOSE: To quantitatively analyze the shape of eyes with high myopia and provide assistance for posterior scleral reinforcement (PSR) using high-resolution three dimensional (3D) magnetic resonance imaging (MRI). METHOD: In all, 260 eyes of 134 patients with high myopia were assessed in this study; 120 emmetropic volunteers were enrolled as a control group. The subjects were examined using 3D T2-weighted CUBE sequences. RESULTS: The eyeballs' axial, horizontal, and vertical lengths were longer and their volume was larger in the subjects with high myopia than in those with emmetropia. The sites of the four recti and optic nerve attachment to the eye were clearly seen on 3D MRI, and the geometric information could be quantified for PSR preparation. The scleral strip was revealed by 3D MRI after surgery. CONCLUSIONS: 3D MRI can quantitatively analyze the shape of eyes with high myopia. 3D MRI examination might be necessary before and after PSR for preoperative preparation and postoperative assessment. PMID- 28675894 TI - Low Oxygen Consumption is Related to a Hypomethylation and an Increased Secretion of IL-6 in Obese Subjects with Sleep Apnea-Hypopnea Syndrome. AB - BACKGROUND: Deoxyribonucleic acid (DNA) methylation is an epigenetic modification involved in gene expression regulation, usually via gene silencing, which contributes to the risks of many multifactorial diseases. The aim of the present study was to analyze the influence of resting oxygen consumption on global and gene DNA methylation as well as protein secretion of inflammatory markers in blood cells from obese subjects with sleep apnea-hypopnea syndrome (SAHS). METHODS: A total of 44 obese participants with SAHS were categorized in 2 groups according to their resting oxygen consumption. DNA methylation levels were evaluated using a methylation-sensitive high resolution melting approach. RESULTS: The analyzed interleukin 6 (IL6) gene cytosine phosphate guanine (CpG) islands showed a hypomethylation, while serum IL-6 was higher in the low compared to the high oxygen consumption group (p < 0.05). Moreover, an age-related loss of DNA methylation of tumor necrosis factor (B = -0.82, 95% CI -1.33 to -0.30) and long interspersed nucleotide element 1 (B = -0.46; 95% CI -0.87 to -0.04) gene CpGs were found. Finally, studied CpG methylation levels of serpin peptidase inhibitor, clade E member 1 (r = 0.43; p = 0.01), and IL6 (r = 0.41; p = 0.02) were positively associated with fat-free mass. CONCLUSIONS: These findings suggest a potential role of oxygen in the regulation of inflammatory genes. Oxygen consumption measurement at rest could be proposed as a clinical biomarker of metabolic health. PMID- 28675895 TI - Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib. AB - BACKGROUND/AIM: Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. METHODS: Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. RESULTS: The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status >=1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS. CONCLUSIONS: Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib. PMID- 28675896 TI - Two Siblings with a Mutation in CCDC8 Presenting with Mild Short Stature: A Case of 3-M Syndrome. AB - BACKGROUND: Short stature can be caused by mutations in a multitude of different genes. 3-M syndrome is a rare growth disorder marked by severe pre- and postnatal growth retardation along with subtle dysmorphic features. There have only been 2 prior reports of mutations in CCDC8 causing 3-M syndrome. METHODS: Two patients presenting with mild short stature underwent whole exome sequencing. The mutation was confirmed via Sanger sequencing. We compare the clinical characteristics of our 2 patients to patients previously reported with mutations in the same gene. RESULTS: Exome sequencing identified a homozygous frameshift mutation in CCDC8 in both patients. They presented with a much milder phenotype than previously described patients with the same mutation. CONCLUSION: In this study, we report a case of 2 sisters with relatively mild short stature who were found via exome sequencing to carry a previously reported homozygous mutation in CCDC8. These patients expand the anthropometric phenotype of 3-M syndrome and demonstrate the power of exome sequencing in the diagnosis of children with short stature. 3-M syndrome should be considered in children with mild skeletal abnormalities, normal/high growth hormone-IGF axis parameters, and normal intelligence. PMID- 28675897 TI - High and Low Responders in a Comprehensive Lifestyle Program for Weight Loss - Secondary Analysis of a Randomized Controlled Trial. AB - BACKGROUND/OBJECTIVES: Unhealthy lifestyle is often related to overweight and obesity and thus to chronic diseases. Web-based programs might be an option for a comprehensive approach to improving long-term weight management. Data from a randomized controlled trial (RCT) evaluating the impact of a lifestyle program on weight reduction were used for a secondary analysis. The objectives were (a) to identify potential predictors for marked weight loss, (b) to explore associations of weight reduction with changes in health-related variables, and (c) to evaluate whether self-monitoring of the daily lifestyle is associated with weight loss. METHODS: 67 subjects with a body mass index of 28-35 who underwent the 1-year 'Individual Health Management' (IHM) program were included in the analysis (mean age 49.8 years, 79% female). Two subgroups (high response: >=7.5% weight reduction vs. low response: <7.5%) were compared in terms of sociodemographic data, baseline values, and pre-post changes of various risk and protective factors. A logistic regression was performed to identify potential predictors of weight loss. RESULTS: 70% of the subjects fulfilled the criterion of high response. There were no statistically significant differences between the two subgroups with respect to sociodemographic and baseline data. Regression analysis failed to identify any predictors for the amount of weight reduction. Subjects with high response showed a more distinct improvement in life satisfaction and neurovegetative stability. The findings indicated an association between the level of self-monitoring and weight loss. CONCLUSIONS: More research is needed to establish optimal strategies for maximizing the longer-term maintenance of weight loss and prevention effects. For weight reduction, support strategies like feedback learning through self-monitoring, reporting systems, and self performance measurement with questionnaires might ameliorate high-intensity lifestyle modification programs. PMID- 28675898 TI - The SARC-F Questionnaire: Diagnostic Overlap with Established Sarcopenia Definitions in Older German Men with Sarcopenia. AB - BACKGROUND: The high relevance of sarcopenia for the aging societies of most developed nations is emphasized by its recent inclusion in the ICD-10-CM (M62.84). However, diagnosing sarcopenia is a daunting task. Apart from varying definitions, the proper assessment of recognized sarcopenia criteria is time and cost consuming. A short and inexpensive screening tool may thus be welcome for clinicians and others working in the area of gerontology. Recently, a simple questionnaire was provided (SARC-F) that may adequately realize this aim. OBJECTIVE: The purpose of this study is to compare established sarcopenia definitions (European Working Group on Sarcopenia in Older People [EWGSOP], Foundation National Institute of Health [FNIH], International Working Group on Sarcopenia [IWGS]) with the SARC-F. Our hypothesis was that the diagnostic overlap between the SARC-F and sarcopenia as determined by these recognized definitions was too low to reliably diagnose sarcopenia. METHODS: Seventy-four community-dwelling German men aged 70 years and older with established sarcopenia according to EWGSOP and/or FNIH and/or IWGS were screened with the SARC-F questionnaire. RESULTS: Applying the definitions of EWGSOP, IWGS, and FNIH, 66.2, 43.2, and 50% of the cohort were classified sarcopenic, respectively. The SARC-F identified 33.5% of the cohort as sarcopenic. The predictive power of the SARC-F increased when men were classified as sarcopenic according to 2 (57.1%) or all (78.8%) sarcopenia definitions. The diagnostic overlap with the 3 sarcopenia definitions varied between 38.8% (SARC-F-FNIH) and 54.1% (SARC-F-IWGS). In comparison, the overlap of diagnosed sarcopenia ranged from 27.0% (FNIH-IWGS) to 49.0% (IWGS-EWGSOP) among the definitions themselves. Only 12.2% of the men met all 3 sarcopenia definitions. CONCLUSION: The diagnostic overlap with respect to sensitivity of the SARC-F and present sarcopenia definitions was at least as high as the range of the diagnostic overlap of these approaches themselves. Thus, although the sensitivity of the SARC-F may be debatable, for want of a better option it seems reasonable to consider the SARC-F as a first simple step within a hierarchical screening procedure. Independently of this procedure, a universally accepted mandatory sarcopenia definition along with comprehensive criteria and fixed cutoff points should be provided promptly. PMID- 28675899 TI - Serum Anticytokine Autoantibody Levels Are Not Increased in Hidradenitis Suppurativa: A Case-Control Pilot Study. AB - BACKGROUND: Hidradenitis suppurativa is a skin disease of recurrent episodes of inflammatory nodules, abscesses, and scarring of the intertriginous regions, e.g. the axillae and groin. A dysregulated immune response to one or more unknown antigens in hidradenitis suppurativa has been suggested. One hypothetical element of this dysregulation may be the functionality of the cytokines. This study examines the serum level of anticytokine autoantibodies for interleukin (IL) 1alpha, IL-6, IL-10, IL-17A, IL-17E, IL-17F, and interferon-alpha. METHOD: Recombinant, carrier-free cytokines were coupled to microspheres. The coupled beads were incubated for 1 h in the dark with assay buffer-diluted sera, and subsequently for 30 min with polyclonal goat F(ab')2 anti-human IgG phycoerythrin conjugated antibody. Data are presented as the median fluorescence intensity of samples. RESULTS: No difference in levels of anticytokine autoantibodies was demonstrated for any of the autoantibodies studied. DISCUSSION: The data suggest that endogenously produced autoantibodies only play a minor role, if any, in hidradenitis suppurativa. PMID- 28675900 TI - HIV-1 Subtype Diversity and Prevalence of Primary Drug Resistance in a Single Center Pediatric Cohort in Germany. AB - OBJECTIVES: Data on drug-resistant mutations (DRMs) in HIV-1-infected therapy naive children are scarce. The aim of this study was to determine the HIV-1 subtype distribution and the prevalence of DRMs in therapy-naive HIV-1-infected children who received routine care at the University Hospital Dusseldorf, Dusseldorf, Germany. METHODS: Records of all HIV-1-infected children who received routine care between January 2005 and December 2015 were analyzed retrospectively. The collected data included demographics, clinical characteristics, CD4 cell count, viral load, HIV-1 subtype, and resistance genotype at baseline. RESULTS: 83 HIV-1-infected children received routine care during the observation period. HIV-1 subtypes were available in 61/83 patients (73.5%) and baseline HIV-1 resistance in 24 (29%). The prevalence of major DRMs was 29% (21% nucleoside reverse-transcriptase inhibitors [NRTIs], 12.5% non NRTIs, and 4% protease inhibitors). Minor mutations in the protease gene were common (58%). Non-B subtypes were predominant (77%). CONCLUSIONS: We report a predominance of non-subtype-B infections and a higher prevalence of DRMs compared to other pediatric cohorts from resource-rich settings. The difference in HIV-1 subtype distribution is due to the fact that a relevant proportion of pediatric patients in Germany are immigrants from high-prevalence settings in sub-Saharan Africa where non-B subtypes predominate. PMID- 28675901 TI - Visual Ratings of Medial Temporal Lobe Atrophy Correlate with CSF Tau Indices in Clinical Variants of Early-Onset Alzheimer Disease. AB - BACKGROUND/AIMS: Prior studies of late-onset Alzheimer disease (AD) have reported that cerebrospinal fluid (CSF) tau levels correlate with hippocampal/medial temporal lobe atrophy. These findings suggest that CSF tau indices in AD may reflect tau-related neurodegeneration in the medial temporal lobe. However, it remains uncertain whether elevated CSF tau levels in the clinically heterogeneous subtypes of early-onset AD (EOAD; amnestic, posterior cortical atrophy [PCA], and logopenic progressive aphasia [LPA]) are attributable to similar underlying mechanisms. METHODS: We identified 41 EOAD patients (18 amnestic, 14 with LPA, and 9 with PCA) with CSF and brain MRI data. Semiquantitative ratings were used to assess medial temporal lobe atrophy and PCA, which were compared to CSF biomarker indices. RESULTS: Lower CSF tau levels were seen in PCA relative to amnestic EOAD and LPA, but similar ratings for medial temporal lobe atrophy and PCA were seen across the groups. After adjustments for demographics and cognitive performance, both total (p = 0.004) and hyperphosphorylated (p = 0.026) tau levels correlated with medial temporal lobe atrophy across this EOAD cohort. CONCLUSIONS: These results replicate prior findings in late-onset AD and support the hypothesis that CSF tau levels primarily reflect tau-related neurodegenerative changes in the hippocampus/medial temporal lobe across the clinical subtypes of EOAD. PMID- 28675902 TI - The Diagnostic Value of IGF-2 and the IGF/IGFBP-3 System in Silver-Russell Syndrome. AB - BACKGROUND/AIMS: Recently, we have described a family of 4 members presenting with intrauterine and postnatal growth failure, low IGF-2 levels, and signs of Silver-Russell syndrome (SRS) who carried a genomic IGF2 mutation. Here, we assess the value of IGF-2 in relation to SRS. METHODS: We collected data from 48 SRS children and 48 short children born small for gestational age (SGA) seen at our center. The SRS children were 4.6 +/- 2.0 years of age, and the SGA children were 4.8 +/- 1.8 years of age. All patients were prepubertal and growth hormone naive. An 11p15 ICR1 loss of methylation (11p15LOM) was present in 22, maternal uniparental disomy of chromosome 7 (upd(7)mat) in 7, and IGF2 genomic mutation (IGF2mut) in 3 patients. Growth factors were measured by in-house radioimmunoassays. RESULTS: The median IGF-2 standard deviation scores (SDSs) were: IGF2mut -1.75, upd(7)mat -1.69, nonsyndromic SGA -1.52, 11p15LOM -0.61, and clinical (tested negative) -0.55. The median IGF-2:IGF-1 concentration ratio was 2.57 in IGF2mut compared to 5.44 in 11p15LOM (p = 0.036), 7.84 in clinical, and 7.98 in upd(7)mat. Upd(7)mat patients had significantly lower IGF-1 and IGFBP-3 SDSs than patients with 11p15LOM (p <= 0.002). CONCLUSION: Serum IGF-2 in combination with IGF-1 and IGFBP-3 can add to the clinical signs of SRS patients and help to perform targeted genetic testing. Further studies are needed. PMID- 28675903 TI - Predictors of Photographic Quality with a Handheld Nonmydriatic Fundus Camera Used for Screening of Vision-Threatening Diabetic Retinopathy. AB - PURPOSE: To analyze predictors of image quality for a handheld nonmydriatic fundus camera used for screening of vision-threatening diabetic retinopathy. METHODS: An ophthalmic photographer at an Aravind Eye Hospital obtained nonmydriatic and mydriatic fundus images from 3 fields in 275 eyes of 155 participants over 13 months using a Smartscope camera (Optomed, Oulu, Finland) and a Topcon tabletop fundus camera (Topcon, Tokyo, Japan). Two fellowship trained retina specialists graded the images. Repeated-measures logistic regression assessed predictors of the main outcome measure: gradability of the fundus images. RESULTS: Of 2,475 images, 76.2% of the Smartscope nonmydriatic images, 90.1% of the Smartscope mydriatic images, and 92.0% of the Topcon mydriatic images were gradable. Eyes with vitreous hemorrhage (OR = 0.24, p < 0.0001) or advanced cataract (OR = 0.08, p < 0.0001) had decreased odds of image gradability. Excluding eyes with cataract or vitreous hemorrhage, nonmydriatic macular image gradability improved from 68.4% in the first set of 55 eyes to 94.6% in the final set of 55 eyes. CONCLUSION: With sufficient training, paraprofessional health care staff can obtain high-quality images with a portable nonmydriatic fundus camera, particularly in patients with clear lenses and clear ocular media. PMID- 28675904 TI - In vivo Lipopolysaccharide Tolerance Recruits CD11b+ Macrophages to the Liver with Enhanced Bactericidal Activity and Low Tumor Necrosis Factor-Releasing Capability, Resulting in Drastic Resistance to Lethal Septicemia. AB - OBJECTIVES: In vivo lipopolysaccharide (LPS) tolerance on bacterial infection was investigated, focusing on liver macrophages. METHODS: LPS tolerance was induced by intraperitoneal injections with 5 MUg/kg of LPS for 3 consecutive days, and then mice were intravenously infected with Escherichia coli. RESULTS: All LPS primed mice survived lethal bacterial infection. Drastic enhancement of bactericidal activity of liver macrophages strongly contributed to bacterial clearance. Although LPS-primed mice produced substantial amounts of tumor necrosis factor (TNF) inside the liver, TNF efflux into the systemic circulation was markedly suppressed. These mice showed a dramatic increase in CD11b+ monocyte derived macrophages in the liver. The CD11b+ macrophages that increased in LPS primed mice were those with strong phagocytic/bactericidal activity and an upregulated expression of Fcgamma receptor I, but the subfraction with a potent TNF-producing capacity and poor phagocytic activity diminished. The adoptive transfer of CD11b+ macrophages from LPS-primed mice to control mice increased survival after bacterial infection and reduced the elevation of plasma TNF. LPS priming did not affect the CD68+ resident Kupffer cells, and CD68+ Kupffer cell depleted mice still exhibited LPS tolerance with strong resistance to bacteremia. CONCLUSIONS: LPS tolerance recruits CD11b+ macrophages to the liver with enhanced bactericidal activity, which plays a central role in resistance to lethal bacteremia. PMID- 28675906 TI - Early Evaluation of the Fetal Heart. AB - Evaluation of the fetal heart at 11-13 + 6 weeks of gestation is indicated for women with a family history of congenital heart defects (CHD), a previous child with CDH, or an ultrasound finding associated with cardiac anomalies. The accuracy for early detection of CHD is highly related to the experience of the operator. The 4-chamber view and outflow tracts are the most important planes for identification of an abnormal heart, and can be obtained in the majority of fetuses from 11 weeks of gestation onward. Transvaginal ultrasound is the preferred route for fetal cardiac examination prior to 12 weeks of gestation, whereas, after 12 weeks, the fetal heart can be reliably evaluated by transabdominal ultrasound. Cardiac defects, such as ventricular septal defects, tetralogy of Fallot, Ebstein's anomaly, or cardiac tumors, are unlikely to be identified at <=14 weeks of gestation. Additional ultrasound techniques such as spatiotemporal image correlation and the evaluation of volumes by a fetal-heart expert can improve the detection of congenital heart disease. The evaluation of the fetal cardiac function at 11-13 + 6 weeks of gestation can be useful for early identification of fetuses at risk of anemia due to hemoglobinopathies, such as hemoglobin Bart's disease. PMID- 28675905 TI - Do We Need to Add Postoperative Radiotherapy in Patients Undergoing Trimodality Therapy for Esophageal Squamous Cell Carcinoma with Positive Lymph Nodes Disease? AB - BACKGROUND: The role of adjuvant radiotherapy for positive lymph nodes (LN) in patients with esophageal cancer who received neoadjuvant concurrent chemoradiotherapy (CCRT) is not well established. This study is aimed at determining the impact of positive LN and the survival benefit of postoperative radiotherapy (PORT) after CCRT plus surgery on esophageal cancer patients. METHODS: Seventy patients with positive LN after neoadjuvant CCRT followed by esophagectomy were enrolled in the study. Patients were grouped into surgery alone following neoadjuvant CCRT (n = 41) and surgery plus PORT following neoadjuvant CCRT (n = 29) groups. The preoperative radiation dose was 36-45 Gy (mean 40 Gy) and the postoperative radiation dose was 20 Gy in 10 fractions. RESULTS: The 5-year survival rate and mean survival was 40% and 58.6 +/- 53.9 months for patients with a pathologic complete response (pCR) compared with 8.3% and 22.7 +/- 35.5 months, respectively, for non-pCR patients (p = 0.026). Local and distant recurrent patterns were similar for patients who did and did not receive PORT (p = 0.876). The mean survival did not differ significantly between the 2 groups (p = 0.889). Pathological complete response to CCRT was the only significant factor influencing survival (p = 0.026). CONCLUSIONS: Postoperative RT did not improve survival in patients with positive LN after CCRT followed by curative surgery for esophageal cancer. PMID- 28675907 TI - The Role of Leisure Activities in Mediating the Relationship between Physical Health and Well-Being: Differential Patterns in Old and Very Old Age. AB - BACKGROUND: Recently, Paggi et al. [Gerontology 2016;62:450-458] for the very first time showed in a cross-sectional sample of 259 adults aged 18-81 years that the relation of physical health to psychological well-being was mediated via frequency of leisure activity participation. OBJECTIVE: To extend this framework, we followed theories on successful aging and vulnerability to propose to add a differential perspective predicting that certain individuals may be more vulnerable than others and therefore may show differences in the mediation pattern. Specifically, we examined whether mediation patterns were differential in certain populations, such as in old-old (compared to young-old) adults and in individuals who carried out a low (compared to those with a high) number of activities. METHODS: We analyzed data from 3,080 individuals on physical health (number of chronic diseases, subjective health status, and subjective evaluation of change in health over the last 10 years), frequency of participation in 18 leisure activities, and physical and psychological well-being using moderated mediation models with a path model approach that allowed the simultaneous estimation of all model paths, including their significance. RESULTS: We found that the relation of physical health to physical and psychological well-being was mediated via frequency of activity participation. For physical (but not for psychological) well-being, this mediation was more pronounced in old-old (compared to young-old) adults and in individuals who carried out a low (compared to those with a high) number of activities. These moderated mediations were attributable to differential relations of physical health to frequency of activity participation and to differential relations of frequency of activity participation to physical well-being between the investigated moderator levels. CONCLUSION: Present data suggest that participation in leisure activities may play a key role in mediating the relationship between physical health and well being, particularly in very old age. Findings are discussed with respect to theories of successful aging and differences between physical and psychological well-being. PMID- 28675910 TI - Stentless Bioprostheses for Aortic Valve Replacement in Octogenarians: The Influence of Coronary Artery Disease. AB - BACKGROUND: We sought to determine the long-term results of stentless biological heart valve replacement in octogenarians to find out whether coronary artery disease or the coronary artery bypass grafting (CABG) procedure itself influences survival in these aged patients. METHODS: From 4,012 patients undergoing aortic valve replacement (AVR) with a stentless prosthesis (Freestyle, Medtronic) at a single center, 721 patients were older than 80 years. They had a mean age of 83 +/- 2 (2,320 patient years), the male/female ratio was 42:58, NYHA (New York Heart Association) class I and II was prevalent in 22.8%, preoperative atrial fibrillation (AF) in 20.6%, coronary artery disease in 56.1%, mitral valve disease in 12.5%, and aortic disease in 3.5%. Follow-up included a total of 11,546 patient years (mean follow-up time: 74 +/- 53 months); follow-up mortality data were 96.3% complete. RESULTS: In these aged patients, 30-day mortality in the isolated AVR group (10.3%) was similar to that in the AVR + CABG group (13.4%). Although long-term survival (15 years) in the octogenarian population is low (9% in the AVR group and 6% in the AVR + CABG group), it was not different (p = 0.191) between patients with and without coronary artery disease. The stroke rate and the myocardial infarction rate, respectively, in the AVR + CABG group (0.43%/100 patient years and 0.17%/100 patient years) were only insignificantly higher than that in the isolated AVR group (each 0.01%/100 patient years). The actuarial freedom from reoperation was 99% in both the groups. CONCLUSION: Use of the Freestyle stentless valve prosthesis for AVR is feasible also in octogenarians. The existence of coronary artery disease leads to concomitant bypass surgery, but not a higher level of perioperative or long-term mortality. PMID- 28675911 TI - Patients' Knowledge about Prescribed Antipsychotics and Medication Adherence in Schizophrenia: A Cross-Sectional Survey. AB - Introduction Data on the knowledge about antipsychotic medications prescribed in patients with schizophrenia are very limited. Moreover, it remains unclear how patients' knowledge about prescribed antipsychotics affects medication adherence. Methods ighty-one Japanese outpatients with schizophrenia according to the International Classification of Diseases, 10th edition, were included. Patients' knowledge of the primary antipsychotics prescribed to them in terms of therapeutic effects, type, and implicated neurotransmitters was assessed with a multiple-choice questionnaire developed for this study. Medication possession ratios (MPRs) were compared between patients who answered correctly and those who did not in each category. Results The percentages of subjects who answered correctly regarding antipsychotic effects, type, and implicated neurotransmitters were low at 30.9%, 30.9%, and 7.4%, respectively. No differences were found in MPRs between subjects who answered correctly and those who did not. Discussion Our preliminary results indicate that patients lack knowledge about their antipsychotic medications. More concerning, they suggest that knowledge about prescribed antipsychotics may not directly translate into actual medication adherence in patients with schizophrenia. PMID- 28675912 TI - Influence of Long-Term Benzodiazepine use on Neurocognitive Skills Related to Driving Performance in Patient Populations: A Review. AB - Acute benzodiazepine intoxication produces severe impairment of neurocognitive skills related to driving. It is less clear whether such impairments also occur in patients who use benzodiazepines chronically. The current review evaluated neurocognitive skills of long-term benzodiazepine users and addressed 2 major questions: do long-term users develop tolerance for the impairing effects of benzodiazepines on neurocognitive performance, and if so, does tolerance warrant a change in driver fitness classification systems that currently deem users of benzodiazepines unfit to drive? Neurocognitive impairments were reported in patients who on average used benzodiazepines for 5-15 years. In addition, sensitivity to acute benzodiazepine impairment decreased in long-term users, suggesting (partial) tolerance. Definitions of clinical relevance of neurocognitive impairments in long-term users and how these were affected by duration of benzodiazepine use were generally lacking. Also, sensitivity of neurocognitive tasks to drug effects and their validity to predict fitness to drive were generally unknown. Because of these limitations, no firm conclusion can be drawn regarding a re-classification of long-term benzodiazepine effects on driver fitness. PMID- 28675913 TI - Institutional Outcomes of Leech Therapy for Venous Congestion in 87 Patients. PMID- 28675915 TI - ? AB - AIM: To identify risk factors for early death in diabetes patients who undergo amputations below the ankle. METHODS: A retrospective study, where all hospital records of all diabetes patients who had undergone minimum one amputation below the ankle at the CWHC Bispebjerg Hospital, Denmark, in the period 1996-2013, were examined. The amputations were mainly trans-metatarsal amputations and partial amputations of toes. The participants were found via ICD10-codes. The included patients were followed from their first contact to the last registered contact. The statistical analysis in this article is performed on patients with a of minimum 5-year follow-up. RESULTS: The 5 year mortality was 42% for patients with type 2 diabetes, and 29% for patients with type 1 diabetes. For patients with type 2 diabetes, multivariable analysis showed that high age, peripheral arterial insufficiency and short time from first admission to amputation were independently statistically significantly associated with increased 5-years mortality. Use of statins was associated with decreased mortality. 35% died as a result of their diabetes, mostly due to cardiovascular causes. CONCLUSION: Short time from first admission to amputation is a risk factor for early death. Arterial insufficiency and high age is also associated with increased mortality, whereas use of statin is associated with decreased mortality, in patients with type 2 diabetes. PMID- 28675914 TI - Plasmatic and Intracellular Markers of Oxidative Stress in Normal Weight and Obese Patients with Polycystic Ovary Syndrome. AB - Introduction Insulin resistance (IR) is associated with polycystic ovary syndrome (PCOS). Oxidative stress (OS) is, in turn, related to IR. Studies in PCOS evidenced an increase in OS markers, but they are mainly performed in obese patients, while the complex picture of normal weight PCOS is still poorly investigated. Matherials and Methods To investigate OS in PCOS and relationship with hormonal and metabolic picture, we performed a case-control study in 2 PCOS groups: normal weight (N-PCOS, n=21, age 18-25 ys, mean+/-SEM BMI 20.7+/-0.2 kg/m2) and obese (OB-PCOS, n=15, 20-30 ys, BMI 32.8+/-1.1), compared with control groups matched for BMI: normal (N-C, n=10, 20-30 ys, BMI 21.6+/-0.9) and obese (OB-C, n=20, 21-31ys, BMI 36.8+/-1.0). Malondialdehyde (MDA) in blood plasma and peripheral mononuclear cells, obtained by density-gradient centrifugation, was assayed spectrophotometrically by TBARS assay. CoenzymeQ10 (CoQ10) in plasma and cells was assayed by HPLC. Plasma Total Antioxidant Capacity (TAC) was also measured by spectrophotometric method. Results PCOS patients exhibited higher Testosterone levels than controls, but OB-PCOS had highest HOMA (Homeostasis Model Assessment) index, suggesting marked insulin resistance. Despite plasma MDA levels were not significantly different (N-PCOS 3380+/-346.94 vs. N-C 7 120+/ 541.66; OB-PCOS 5 517.5+/-853.9 vs. OB. 3 939.66+/-311.2 pmol/ml), intracellular MDA levels were significantly higher in N-PCOS than controls (mean 3 259+/-821.5 vs. 458+/-43.2 pmol/106/cells) and higher than OB-PCOS, although not significantly (1363.1+/-412.8 pmol/106/cells). Intracellular CoenzymeQ10 was higher in N-PCOS than in N-C, but the highest levels were found in OB-C. Conclusions Our data, while confirming the presence of OS in obese PCOS patients in agreement with literature, suggest that OS could be present also in normal weight PCOS, but it can be revealed in tissue rather than in plasma. The relationship with metabolic status remains to be established, but could be a physiopathological basis for antioxidant treatment in such patients. PMID- 28675916 TI - [Termination of Reimbursement of Arthroscopy in Osteoarthritis of the Knee: Is This Decision Based on Scientific Grounds?] AB - Background In Germany, arthroscopy of the knee used to be an accepted procedure in the treatment of osteoarthritis of the knee. However, as of April 1, 2016 reimbursement for this procedure has been discontinued. This was a decision of the Joint Federal Committee (Gemeinsamer Bundesausschuss, G-BA). That decision was based on a report of the German Institute for Quality and Efficiency in Health Care (IQWiG). This report is essentially based on a few studies, three of which have been published in the renowned New England Journal of Medicine. According to the IQWiG, there is "no hint, indication or proof of a benefit of therapeutic arthroscopy" in osteoarthritis of the knee. Since this statement does not coincide with clinical observations commonly made by orthopaedic surgeons, the aim of this analysis was to evaluate the aforementioned studies according to criteria of evidence-based medicine. Material and Methods The three studies on which the IQWiG report is essentially based (Moseley et al. 2002, Kirkley et al. 2008 and Katz et al. 2013), all published in the New England Journal of Medicine, were analyzed according to the standards of evidence-based medicine. Results Although all of the evaluated studies were randomized controlled studies, there were considerable and serious deficiencies. These deficiencies include, among others, sampling bias that affects external validity and selection bias that affects internal validity. While a sham operation was performed in one study, resulting in an ideal blinding of study participants, that study used a non validated primary outcome measure. That outcome score has not been used in subsequent publications and the algorithm presented for the calculation of the outcome score was incorrect. Although the other studies used validated main outcome measures, patients in those studies were not blinded. A number of further deficiencies were identified as well. Conclusion The studies on which the decision of the Joint Federal Committee is based do have several significant and at times severe methodological deficiencies. For instance, the results of these studies cannot be generalized to all patients suffering from osteoarthritis of the knee, solely on the basis of patient selection. Many of these deficiencies have not been mentioned till now, neither in the literature nor in the final report authored by the IQWiG. Therefore, it seems unlikely that the Joint Federal Committee was aware of these deficiencies when it decided to discontinue reimbursement for arthroscopy in patients with osteoarthritis of the knee. Unfortunately, not all patients suffering from osteoarthritis of the knee respond to conservative therapy. By discontinuing reimbursement for arthroscopy in this patient group, a commonly used treatment option has been withdrawn. The proportion of such patients was 30% after 6 months and 35% after 12 months in one of the studies considered by the IQWiG. It is hence conceivable that the indication for joint replacement surgery could become more generous after the withdrawal of arthroscopy as an alternative treatment option. In summary, it became clear that, given the variety and severity of the deficiencies of the underlying studies, the decision of the Joint Federal Committee could not have been based on scientific criteria. To this extent, it seems appropriate to revive the discussion about the exclusion of arthroscopy from the performance catalogue of the German Health Insurance System. PMID- 28675917 TI - The Impact of Coffee on Health. AB - Coffee is one of the most popular and widely consumed beverages worldwide due to its stimulating effects on the central nervous system as well as its taste and aroma. Coffee is a complex mixture of more than 800 volatile compounds whereas caffeine and chlorogenic acids are the most common compounds. During the last years, coffee has progressively moved to a less negative position on health due to its better-known pharmacology. Caffeine, e.g., in a cup of coffee, appears to exert most of its effects through an antagonism of the adenosine receptors. Novel approaches in epidemiological studies and experimental researches suggest that coffee consumption may help to prevent several chronic diseases, including type 2 diabetes mellitus and liver disease. Most prospective cohort studies have not found coffee consumption to be associated with a significantly increased cardiovascular disease risk. There is also evidence that decaffeinated coffee may, in some respect, have similar benefits as regular coffee, indicating that besides caffeine other components contribute to the health protecting effects. For adults consuming moderate amounts of coffee (3 - 4 cups/d providing 300 - 400 mg/d of caffeine), there is little evidence of health risks and some evidence of health benefits. This review provides up-to-date information about coffee on health. Topics addressed include the cardiovascular system, liver diseases, and diabetes as well as gastrointestinal disorders. PMID- 28675918 TI - [Upper Jaw Malignoma: Results of a Monocentric Study Over 45 Years]. AB - BACKGROUND: Malignancies originating from the upper jaw are comparatively rare. This study aimed to evaluate the histological features, grading and staging in upper jaw carcinomas. MATERIALS AND METHODS: A total of 199 malignancies of the maxillary sinus were analysed over 45 years and matched for age, gender, tumour size, and histological differentiation. Cases of squamous cell carcinomas were classified based on the TNM system, grading and five-year survival time. RESULTS: Squamous cell carcinomas (60%) were the most frequent malignant tumours. The five year survival rate of squamous cell carcinomas was more than 60% and hence superior to that of other oral squamous cell carcinomas, although approximately 2/3 of these tumours were T4 cases. More than 60% of squamous cell carcinomas were highly differentiated and characterised as G1 tumours. G2 and G3 tumours were considerably less common. CONCLUSION: The risk of local recurrence was inversely disproportional to the grade of histological differentiation. All in all, an optimal surgical and radiological treatment may lead to good aesthetic and satisfactory functional results. PMID- 28675919 TI - Composite and multicomponent end points in clinical trials. AB - In January 2017, the FDA released the draft guidance to industry on multiple end points in clinical trials. A class of multiplicity problems arise from the testing of individual or subset of components of a composite or multicomponent end point. This commentary attempts to further clarify these problems. Discussions include general consideration on the use of the composite and multicomponent end points, situations when multiplicity adjustments are needed, and the relevant multiple testing methods. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28675920 TI - The meaning of home for ageing women living alone: An evolutionary concept analysis. AB - The concept of home to women ageing should be visited in the light of ongoing cultural, political, temporal and disciplinary evolutions. In part, to compliment policies increasing focus on supporting older adults to age in place and a growing attention on the home as a place where healthcare is designed and provided. The following concept analysis utilises Rodgers' evolutionary method to inductively analyse literature in order to elicit the meaning and experience of home among older women who are ageing at home. Literature was collected over an 18-month period during 2014-2015 and the sample was made up of 49 articles. The analysis led to the concept of home among women ageing in communities to be defined by four attributes. These attributes are home as (i) a resource, (ii) an attachment, (iii) the precariousness of maintaining and sustaining home and (iv) a cultural expectation. This analysis of the meaning and experience of home among women ageing at home has shed light on the needs for this group of women, while highlighting the need to continue to further clarify and define the concept through research. PMID- 28675921 TI - Cycle regimens for frozen-thawed embryo transfer. AB - BACKGROUND: Among subfertile couples undergoing assisted reproductive technology (ART), pregnancy rates following frozen-thawed embryo transfer (FET) treatment cycles have historically been found to be lower than following embryo transfer undertaken two to five days following oocyte retrieval. Nevertheless, FET increases the cumulative pregnancy rate, reduces cost, is relatively simple to undertake and can be accomplished in a shorter time period than repeated in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles with fresh embryo transfer. FET is performed using different cycle regimens: spontaneous ovulatory (natural) cycles; cycles in which the endometrium is artificially prepared by oestrogen and progesterone hormones, commonly known as hormone therapy (HT) FET cycles; and cycles in which ovulation is induced by drugs (ovulation induction FET cycles). HT can be used with or without a gonadotrophin releasing hormone agonist (GnRHa). This is an update of a Cochrane review; the first version was published in 2008. OBJECTIVES: To compare the effectiveness and safety of natural cycle FET, HT cycle FET and ovulation induction cycle FET, and compare subtypes of these regimens. SEARCH METHODS: On 13 December 2016 we searched databases including Cochrane Gynaecology and Fertility's Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. Other search sources were trials registers and reference lists of included studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing the various cycle regimens and different methods used to prepare the endometrium during FET. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth rates and miscarriage. MAIN RESULTS: We included 18 RCTs comparing different cycle regimens for FET in 3815 women. The quality of the evidence was low or very low. The main limitations were failure to report important clinical outcomes, poor reporting of study methods and imprecision due to low event rates. We found no data specific to non-ovulatory women. 1. Natural cycle FET comparisons Natural cycle FET versus HT FETNo study reported live birth rates, miscarriage or ongoing pregnancy.There was no evidence of a difference in multiple pregnancy rates between women in natural cycles and those in HT FET cycle (odds ratio (OR) 2.48, 95% confidence interval (CI) 0.09 to 68.14, 1 RCT, n = 21, very low-quality evidence). Natural cycle FET versus HT plus GnRHa suppressionThere was no evidence of a difference in rates of live birth (OR 0.77, 95% CI 0.39 to 1.53, 1 RCT, n = 159, low-quality evidence) or multiple pregnancy (OR 0.58, 95% CI 0.13 to 2.50, 1 RCT, n = 159, low-quality evidence) between women who had natural cycle FET and those who had HT FET cycles with GnRHa suppression. No study reported miscarriage or ongoing pregnancy. Natural cycle FET versus modified natural cycle FET (human chorionic gonadotrophin (HCG) trigger)There was no evidence of a difference in rates of live birth (OR 0.55, 95% CI 0.16 to 1.93, 1 RCT, n = 60, very low-quality evidence) or miscarriage (OR 0.20, 95% CI 0.01 to 4.13, 1 RCT, n = 168, very low quality evidence) between women in natural cycles and women in natural cycles with HCG trigger. However, very low-quality evidence suggested that women in natural cycles (without HCG trigger) may have higher ongoing pregnancy rates (OR 2.44, 95% CI 1.03 to 5.76, 1 RCT, n = 168). There were no data on multiple pregnancy. 2. Modified natural cycle FET comparisons Modified natural cycle FET (HCG trigger) versus HT FETThere was no evidence of a difference in rates of live birth (OR 1.34, 95% CI 0.88 to 2.05, 1 RCT, n = 959, low-quality evidence) or ongoing pregnancy (OR 1.21, 95% CI 0.80 to 1.83, 1 RCT, n = 959, low-quality evidence) between women in modified natural cycles and those who received HT. There were no data on miscarriage or multiple pregnancy. Modified natural cycle FET (HCG trigger) versus HT plus GnRHa suppressionThere was no evidence of a difference between the two groups in rates of live birth (OR 1.11, 95% CI 0.66 to 1.87, 1 RCT, n = 236, low-quality evidence) or miscarriage (OR 0.74, 95% CI 0.25 to 2.19, 1 RCT, n = 236, low-quality evidence) rates. There were no data on ongoing pregnancy or multiple pregnancy. 3. HT FET comparisons HT FET versus HT plus GnRHa suppressionHT alone was associated with a lower live birth rate than HT with GnRHa suppression (OR 0.10, 95% CI 0.04 to 0.30, 1 RCT, n = 75, low quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 0.64, 95% CI 0.37 to 1.12, 6 RCTs, n = 991, I2 = 0%, low quality evidence) or ongoing pregnancy (OR 1.72, 95% CI 0.61 to 4.85, 1 RCT, n = 106, very low-quality evidence).There were no data on multiple pregnancy. 4. Comparison of subtypes of ovulation induction FET Human menopausal gonadotrophin(HMG) versus clomiphene plus HMG HMG alone was associated with a higher live birth rate than clomiphene combined with HMG (OR 2.49, 95% CI 1.07 to 5.80, 1 RCT, n = 209, very low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 1.33, 95% CI 0.35 to 5.09,1 RCT, n = 209, very low-quality evidence) or multiple pregnancy (OR 1.41, 95% CI 0.31 to 6.48, 1 RCT, n = 209, very low-quality evidence).There were no data on ongoing pregnancy. AUTHORS' CONCLUSIONS: This review did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for FET in subfertile women with regular ovulatory cycles. The most common modalities for FET are natural cycle with or without HCG trigger or endometrial preparation with HT, with or without GnRHa suppression. We identified only four direct comparisons of these two modalities and there was insufficient evidence to support the use of either one in preference to the other. PMID- 28675922 TI - How to control for unmeasured confounding in an observational time-to-event study with exposure incidence information: the treatment choice Cox model. AB - In an observational study of the effect of a treatment on a time-to-event outcome, a major problem is accounting for confounding because of unknown or unmeasured factors. We propose including covariates in a Cox model that can partially account for an unknown time-independent frailty that is related to starting or stopping treatment as well as the outcome of interest. These covariates capture the times at which treatment is started or stopped and so are called treatment choice (TC) covariates. Three such models are developed: first, an interval TC model that assumes a very general form for the respective hazard functions of starting treatment, stopping treatment, and the outcome of interest and second, a parametric TC model that assumes that the log hazard functions for starting treatment, stopping treatment, and the outcome event include frailty as an additive term. Finally, a hybrid TC model that combines attributes from the parametric and interval TC models. As compared with an ordinary Cox model, the TC models are shown to substantially reduce the bias of the estimated hazard ratio for treatment when data are simulated from a realistic Cox model with residual confounding due to the unobserved frailty. The simulations also indicate that the bias decreases or levels off as the sample size increases. A TC model is illustrated by analyzing the Women's Health Initiative Observational Study of hormone replacement for post-menopausal women. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA. PMID- 28675923 TI - Reporting guidelines for diagnostic accuracy studies that use Bayesian latent class models (STARD-BLCM). PMID- 28675924 TI - A statistical framework for biomedical literature mining. AB - In systems biology, it is of great interest to identify new genes that were not previously reported to be associated with biological pathways related to various functions and diseases. Identification of these new pathway-modulating genes does not only promote understanding of pathway regulation mechanisms but also allow identification of novel targets for therapeutics. Recently, biomedical literature has been considered as a valuable resource to investigate pathway-modulating genes. While the majority of currently available approaches are based on the co occurrence of genes within an abstract, it has been reported that these approaches show only sub-optimal performances because 70% of abstracts contain information only for a single gene. To overcome such limitation, we propose a novel statistical framework based on the concept of ontology fingerprint that uses gene ontology to extract information from large biomedical literature data. The proposed framework simultaneously identifies pathway-modulating genes and facilitates interpreting functions of these new genes. We also propose a computationally efficient posterior inference procedure based on Metropolis Hastings within Gibbs sampler for parameter updates and the poor man's reversible jump Markov chain Monte Carlo approach for model selection. We evaluate the proposed statistical framework with simulation studies, experimental validation, and an application to studies of pathway-modulating genes in yeast. The R implementation of the proposed model is currently available at https://dongjunchung.github.io/bayesGO/. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28675925 TI - Registered Nurses' experiences of patient participation in hospital care: supporting and hindering factors patient participation in care. AB - BACKGROUND: Promoting patient participation in care is an international priority identified by the World Health Organization and various national bodies around the world and an important aspect of person-centred care. AIM: The aim of this study was to describe Registered Nurses' experiences with patient participation in nursing care including their barriers and facilitators for participation. METHOD: The study setting was a University Hospital in Sweden. Interviews were conducted with twenty Registered Nurses working at medical wards in 2013. Thematic data analysis was used to analyse the transcribed interview data. RESULTS: Twenty nurses from four wards in two hospitals were included. Five themes emerged from the analysis including listening to the patient, engaging the patient, relinquishing some responsibility, sharing power and partnering with patients. The core theme 'partnering with patients' was enacted when nurses listened to and engaged patients and when they relinquished responsibility and shared power with patients. In addition, hindering and facilitating factors to participation were identified, such as patients wanted to take on a passive role, lack of teamwork which participants understood would enhance interprofessional understanding and improve patient safety. Patient participation was hindered by medical jargon during the ward round, there was a risk of staff talking over patients' heads but sometimes inevitable having conversations at the patient's bedside. However, nurses preferred important decisions to be made away from bedside. CONCLUSIONS: It all came down to partnering with the patient and participants described how they made an effort to respect the patients' view and accept patient as a part of the care team. Identified hindering factors for participation were lack of teamwork, patients' taking on passive roles and communication during ward rounds having conversations at the patient's bedside. Nurses wished for a change but lacked strategies on how. Nurses preferred important decisions to be made away from bedside. PMID- 28675926 TI - Efficient Receptor Mediated siRNA Delivery in Vitro by Folic Acid Targeted Pentablock Copolymer-Based Micelleplexes. AB - Novel, biocompatible polyplexes, based on the combination of cationic pentablock copolymers with folic acid functionalized copolymers, were designed and developed for target-specific siRNA delivery. The resulting micelleplexes spontaneously formed polymeric micelles with a hydrophobic core surrounded directly by a cationic poly-2-(4-aminobutyl)-oxazole (PABOXA) and subsequently shielded by hydrophilic poly-2-methyl-oxazole (PMOXA) layer. The described micelleplexes form highly stable particles even in complete serum after 24 h compared with the highly cationic polymer PEI, which show aggregate formation in serum containing buffer solution. Targeted siRNA delivery and gene knockdown could be shown using green fluorescent protein (GFP) expressing HeLa cells, resulting in ~31% and ~8% suppression of the expression of GFP for targeted and nontargeted micelleplexes, respectively. Comparison studies of folic-receptor positive HeLa cells with normal folic-receptor-negative HEK293 cells revealed involvement of receptor mediated cellular uptake of fluorescently labeled siRNA. The new designed nanocarrier showed no cytotoxicity, having a potential application. The presented concept of shielding a nucleic-acid complexing cationic chains with a stealth layer and combining it with receptor ligand overcomes typical problems with undesired protein and cell interactions in delivery of nucleic acids using polymeric systems, opening new doors for application if RNA inhibition in the organism. PMID- 28675927 TI - Predicted Structures of the Active Sites Responsible for the Improved Reduction of Carbon Dioxide by Gold Nanoparticles. AB - Gold (Au) nanoparticles (NPs) are known experimentally to reduce carbon dioxide (CO2) to carbon monoxide (CO), with far superior performance to Au foils. To obtain guidance in designing improved CO2 catalysts, we want to understand the nature of the active sites on Au NPs. Here, we employed multiscale atomistic simulations to computationally synthesize and characterize a 10 nm thick Au NP on a carbon nanotube (CNT) support, and then we located active sites from quantum mechanics (QM) calculations on 269 randomly selected sites. The standard scaling relation is that the formation energy of *COOH (DeltaE*COOH) is proportional to the binding energy of *CO (Ebinding*CO); therefore, decreasing DeltaE*COOH to boost the CO2 reduction reaction (CO2RR) causes an increase of Ebinding*CO that retards CO2RR. We show that the NPs have superior CO2RR because there are many sites at the twin boundaries that significantly break this scaling relation. PMID- 28675928 TI - Multielectron Chemistry within a Model Nickel Metalloprotein: Mechanistic Implications for Acetyl-CoA Synthase. AB - The acetyl coenzyme A synthase (ACS) enzyme plays a central role in the metabolism of anaerobic bacteria and archaea, catalyzing the reversible synthesis of acetyl-CoA from CO and a methyl group through a series of nickel-based organometallic intermediates. Owing to the extreme complexity of the native enzyme systems, the mechanism by which this catalysis occurs remains poorly understood. In this work, we have developed a protein-based model for the NiP center of acetyl coenzyme A synthase using a nickel-substituted azurin protein (NiAz). NiAz is the first model nickel protein system capable of accessing three (NiI/NiII/NiIII) distinct oxidation states within a physiological potential range in aqueous solution, a critical feature for achieving organometallic ACS activity, and binds CO and -CH3 groups with biologically relevant affinity. Characterization of the NiI-CO species through spectroscopic and computational techniques reveals fundamentally similar features between the model NiAz system and the native ACS enzyme, highlighting the potential for related reactivity in this model protein. This work provides insight into the enzymatic process, with implications toward engineering biological catalysts for organometallic processes. PMID- 28675929 TI - Red, Yellow, and Blue Luminescence by Graphene Quantum Dots: Syntheses, Mechanism, and Cellular Imaging. AB - Owing to their excellent photoluminescence (PL) properties, good biocompatibility, and low toxicity, graphene quantum dots (GQDs) are widely applied in bioimaging, biosensing, and so forth. However, further development of GQDs is limited by their synthetic methodology and unclear PL mechanism. Therefore, it is urgent to find efficient and universal methods for the synthesis of GQDs with high stability, controllable surface properties, and tunable PL emission wavelength. By coating with polyethyleneimine (PEI) of different molecular weights, blue-, yellow-, and red-emitting GQDs were successfully prepared. By transmission electron microscopy, atomic force microscopy, and dynamic light scattering, the characterization of size and morphology revealed that blue-emitting PEI1800 GQDs were monocoated, like jelly beans, and red emitting PEI600 GQDs were multicoated, like capsules. The amidation reaction between carboxyl and amide functional groups played an important role in the coating process, as evidenced by IR spectroscopy and theoretical calculation with density functional theory B3LYP/6-31G*. The PL-tunable GQDs exhibited an excellent chemical stability and extremely low cytotoxicity, and they had been shown to be feasible for bioimaging, making these GQDs highly attractive for a wide variety of applications, including multicolor imaging and bioanalysis. PMID- 28675930 TI - Proteomic Analysis of the E3 Ubiquitin-Ligase Hakai Highlights a Role in Plasticity of the Cytoskeleton Dynamics and in the Proteasome System. AB - Carcinoma, the most common type of cancer, arises from epithelial cells. The transition from adenoma to carcinoma is associated with the loss of E-cadherin and, in consequence, the disruption of cell-cell contacts. E-cadherin is a tumor suppressor, and it is down-regulated during epithelial-to-mesenchymal transition (EMT); indeed, its loss is a predictor of poor prognosis. Hakai is an E3 ubiquitin-ligase protein that mediates E-cadherin ubiquitination, endocytosis and finally degradation, leading the alterations of cell-cell contacts. Although E cadherin is the most established substrate for Hakai activity, other regulated molecular targets for Hakai may be involved in cancer cell plasticity during tumor progression. In this work we employed an iTRAQ approach to explore novel molecular pathways involved in Hakai-driven EMT during tumor progression. Our results show that Hakai may have an important influence on cytoskeleton-related proteins, extracellular exosome-associated proteins, RNA-related proteins and proteins involved in metabolism. Moreover, a profound decreased expression in several proteasome subunits during Hakai-driven EMT was highlighted. Since proteasome inhibitors are becoming increasingly used in cancer treatment, our findings suggest that the E3 ubiquitin-ligase, such as Hakai, may be a better target than proteasome for using novel specific inhibitors in tumor subtypes that follow EMT. PMID- 28675931 TI - New Insights on Gas Hydroquinone Clathrates Using in Situ Raman Spectroscopy: Formation/Dissociation Mechanisms, Kinetics, and Capture Selectivity. AB - Hydroquinone (HQ) is known to form organic clathrates with different gaseous species over a wide range of pressures and temperatures. However, the enclathration reaction involving HQ is not fully understood. This work offers new elements of understanding HQ clathrate formation and dissociation mechanisms. The kinetics and selectivity of the enclathration reaction were also investigated. The focus was placed on HQ clathrates formed with CO2 and CH4 as guest molecules for potential use in practical applications for the separation of a CO2/CH4 gas mixture. The structural transition from the native form (alpha-HQ) to the clathrate form (beta-HQ), as well as the reverse process, were tracked using in situ Raman spectroscopy. The clathrate formation was conducted at 323 K and 3.0 MPa, and the dissociation was conducted at 343 K and 1.0 kPa. The experiments with CH4 confirmed that a small amount of gas can fill the alpha-HQ before the phase transition from alpha- to beta-HQ begins. The dissociation of the CO2-HQ clathrates highlighted the presence of a clathrate structure with no guest molecules. We can therefore conclude that HQ clathrate formation and dissociation are two-step reactions that pass through two distinct reaction intermediates: guest-loaded alpha-HQ and guest-free beta-HQ. When an equimolar CO2/CH4 gas mixture is put in contact with either the alpha-HQ or the guest-free beta-HQ, the CO2 is preferentially captured. Moreover, the guest-free beta-HQ can retain the CO2 quicker and more selectively. PMID- 28675932 TI - Push-Pull Type Non-Fullerene Acceptors for Polymer Solar Cells: Effect of the Donor Core. AB - There has been a growing interest in the design and synthesis of non-fullerene acceptors for organic solar cells that may overcome the drawbacks of the traditional fullerene-based acceptors. Herein, two novel push-pull (acceptor donor-acceptor) type small-molecule acceptors, that is, ITDI and CDTDI, with indenothiophene and cyclopentadithiophene as the core units and 2-(3-oxo-2,3 dihydroinden-1-ylidene)malononitrile (INCN) as the end-capping units, are designed and synthesized for non-fullerene polymer solar cells (PSCs). After device optimization, PSCs based on ITDI exhibit good device performance with a power conversion efficiency (PCE) as high as 8.00%, outperforming the CDTDI-based counterparts fabricated under identical condition (2.75% PCE). We further discuss the performance of these non-fullerene PSCs by correlating the energy level and carrier mobility with the core of non-fullerene acceptors. These results demonstrate that indenothiophene is a promising electron-donating core for high performance non-fullerene small-molecule acceptors. PMID- 28675933 TI - Molecular Modeling Clarifies the Mechanism of Chromophore Maturation in the Green Fluorescent Protein. AB - We report the first complete theoretical description of the chain of elementary reactions resulting in chromophore maturation in the green fluorescent protein (GFP). All reaction steps including cyclization, dehydration, and oxidation are characterized at the uniform quantum mechanics/molecular mechanics (QM/MM) computational level using density functional theory in quantum subsystems. Starting from a structure of the wild-type protein with the noncyclized Ser65 Tyr66-Gly67 tripeptide, we modeled cyclization and dehydration reactions. We then added molecular oxygen to the system and modeled the oxidation reaction resulting in the mature protein-bound chromophore. Computationally derived structures of the reaction product and several reaction intermediates agree well with the relevant crystal structures, validating the computational protocol. The highest computed energy barriers at the cyclization-dehydration (17 kcal/mol) and oxidation (21 kcal/mol) steps agree well with the values derived from the kinetics measurements (20.7 and 22.7 kcal/mol, respectively). The simulations provide strong support to the mechanism involving the cyclization-dehydration oxidation sequence of the chromophore's maturation reactions. The results also establish a solid basis for predictions of maturation mechanisms in other fluorescent proteins. PMID- 28675936 TI - The Analytical Chemistry Virtual Issue Featuring Our Advisory Boards. PMID- 28675934 TI - Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics. AB - The extracellular matrix (ECM) is a complex meshwork of insoluble fibrillar proteins and signaling factors interacting together to provide architectural and instructional cues to the surrounding cells. Alterations in ECM organization or composition and excessive ECM deposition have been observed in diseases such as fibrosis, cardiovascular diseases, and cancer. We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues, digest the proteins into peptides, analyze ECM peptides by mass spectrometry, and interpret the mass spectrometric data. In addition, we present here two novel R-script based web tools allowing rapid annotation and relative quantification of ECM proteins, peptides, and intensity/abundance in mass spectrometric data output files. We illustrate this protocol with ECMs obtained from two pairs of tissues, which differ in ECM content and cellularity: triple-negative breast cancer and adjacent mammary tissue, and omental metastasis from high-grade serous ovarian cancer and normal omentum. The complete proteomics data set generated in this study has been deposited to the public repository ProteomeXchange with the data set identifier: PXD005554. PMID- 28675937 TI - D.176: Sextants, numbers, and the Hydrographic Office of the Admiralty. AB - In the 1830s and 1840s, the Hydrographic Office of the British Admiralty developed and oversaw one of the major state-run surveying projects of the nineteenth century. This involved a range of instruments whose circulation was increasingly regulated. Using extant museum collections and the correspondence of those involved, this article explores how such objects can be used to discuss both bureaucratic organization at a time of expanding government and the complex issues of sociability involved in hydrographic surveying. Surveying officers worked in a context in which the propriety of property on public service was a pervasive question. Instruments might be given as gifts between officers, appropriated as recompense, absorbed as state property, and disputed between friends. The ownership, provision, and treatment of instruments in particular could be used to demonstrate an officer's peculiar zeal or institutional neglect. To those outside the ship, what was understood as over-instrumentation became amusing spectacle. On board, their use was part of a deeply hierarchical order of work in regions of colonial and mercantile importance. In examining the relationships around these instruments of survey, the paper proposes a richer understanding of the material culture of hydrography in the early nineteenth century. PMID- 28675938 TI - Self-harm hospitalised morbidity and mortality risk using a matched population based cohort design. AB - OBJECTIVE: Prior and repeated self-harm hospitalisations are common risk factors for suicide. However, few studies have accounted for pre-existing comorbidities and prior hospital use when quantifying the burden of self-harm. The aim is to quantify hospitalisation in the 12 months preceding and re-hospitalisation and mortality risk in the 12 months post a self-harm hospitalisation. METHOD: A population-based matched cohort using linked hospital and mortality data for individuals ?18 years from four Australian jurisdictions. A non-injured comparison cohort was matched on age, gender and residential postcode. Twelve month pre- and post-index self-harm hospitalisations and mortality were examined. RESULTS: The 11,597 individuals who were hospitalised following self-harm in 2009 experienced 21% higher health service use in the 12 months pre and post the index admission and a higher mortality rate (2.9% vs 0.3%) than their matched counterparts. There were 133 (39.0%) deaths within 2 weeks of hospital discharge and 342 deaths within 12 months of the index hospitalisation in the self-harm cohort. Adjusted rate ratios for hospital readmission were highest for females (2.86; 95% confidence interval: [2.33, 2.52]) and individuals aged 55-64 years (3.96; 95% confidence interval: [2.79, 5.64]). CONCLUSION: Improved quantification of the burden of self-harm-related hospital use can inform resource allocation for intervention and after-care services for individuals at risk of repeated self-harm. Better assessment of at-risk self-harm behaviour, appropriate referrals and improved post-discharge care, focusing on care continuity, are needed. PMID- 28675939 TI - Homoisoflavanones with estrogenic activity from the rhizomes of Polygonatum sibiricum. AB - A new homoisoflavanone, (3R)-5-hydroxy-7-methoxyl-3-(2'-hydroxy-4'- methoxybenzyl)-chroman-4-one (1), together with six known analogs, were isolated from the rhizomes of Polygonatum sibiricum. Their structures were elucidated on the basis of extensive spectroscopic analysis. All compounds were tested for their estrogenic activity using the MCF-7 estrogenresponsive human breast cancer cell lines. At a dose of 0.1 MUmol/L, compounds 1-7 exhibited significant proliferative effects on MCF-7 cells compared with E2. The molecular docking study results indicated that the activity of compounds 3, 5, 6, and 7 may be the binding with ERR. PMID- 28675940 TI - Influence of Geometry and Depth of Resections on Bone Support for Total Ankle Replacement. AB - BACKGROUND: Aseptic component loosening is a leading cause of revision for total ankle replacement. Different operative approaches for resecting the tibia and talus impact the bony support for the prostheses due to variations in both bone density and resection area, and may therefore impact loosening performance. METHODS: Computed tomography data from 116 subjects were obtained, and solid models of the talus and tibia were generated. Bone density, resection area, and bony support were measured on a series of flat resections for each subject, at multiple resection depths. Similar measurements were performed using a series of subject-specific, anatomic radius-based resections ("round resections") at multiple depths. Results were compared to assess the impact of both resection type (flat vs round) and resection depth (6-16 mm for the tibia, 2-6 mm for the talus) on bony support. RESULTS: Statistically significant decreases in bony support for both the talus and the tibia were obtained for flat resections as compared to round resections. A decrease of 8% to 19% for the tibia was seen for all resection depths; a decrease of 8% to 46% for the talus was seen, with greater decreases seen for shallower flat-cut resections. CONCLUSION: Bony support in total ankle arthroplasty may be decreased using flat resections compared to round resections at comparable resection depths. Estimated differences are resection-level dependent and different for the distal tibia vs the proximal talus. CLINICAL RELEVANCE: Biomechanical characteristics of total ankle replacement impacted by bony support of the prostheses, including implant stability and resistance to subsidence, may be improved with round resections as compared to flat-cut resections. PMID- 28675941 TI - Implementing a Manualized, Classroom Transition Intervention for Students With ASD in Underresourced Schools. AB - Children with autism spectrum disorder (ASD) in public education settings experience difficulties with transitions during classroom routines, which can result in challenging behavior. Single-subject research supports techniques for transitions, but school-based approaches often require resources and training unavailable in low-resource districts, limiting implementation. We developed and evaluated the Schedules, Tools, and Activities for Transitions (STAT) program, a short-term, manualized intervention of behavioral supports to support daily routine transitions for students with ASD (K-5) in underresourced districts. We utilized a multisite, cluster-randomized, group comparison design (immediate treatment versus waitlist) with matched pairs ( n = 150 students, 57 educators). Data indicated (a) no group differences for academic engagement or classroom independence, and (b) an advantage for STAT in reducing challenging behavior and increasing teacher fidelity. Results show preliminary support for an intervention that is feasible and perceived as sustainable in real-world settings. PMID- 28675942 TI - Three new elemanolides from the seeds of Vernonia anthelmintica. AB - Three new elemanolides, named vernonilides D (1), E (2), and F (3), along with four known sesquiterpenoids, including two elemanolides (4, 5), a guaianolide (6), and a germacranolide (7) were isolated from the seeds of Vernonia anthelmintica. The structures of them were elucidated based on 1D and 2D NMR experiments and comparison with published data. Cytotoxicity of the compounds against four human tumor cell lines was assayed. 6 showed strongly inhibitory effect against HCT-15 and PC-3 cell lines with IC50 values of 0.56 and 0.69 MUM, respectively. The new compounds showed moderate cytotoxicity against four cell lines with IC50 values ranging from 9.1 to 28.1 MUM. PMID- 28675943 TI - Do Activity Level Outcome Measures Commonly Used in Neurological Practice Assess Upper-Limb Movement Quality? AB - BACKGROUND: Movement is described in terms of task-related end point characteristics in external space and movement quality (joint rotations in body space). Assessment of upper-limb (UL) movement quality can assist therapists in designing effective treatment approaches for retraining lost motor elements and provide more detailed measurements of UL motor improvements over time. OBJECTIVE: To determine the extent to which current activity level outcome measures used in neurological practice assess UL movement quality. METHODS: Outcome measures assessing arm/hand function at the International Classification of Function activity level recommended by neurological clinical practice guidelines were reviewed. Measures assessing the UL as part of a general mobility assessment, those strictly evaluating body function/structure or participation, and paediatric measures were excluded. RESULTS: In all, 15 activity level outcome measures were identified; 9 measures assess how movement is performed by measuring either end point characteristics or movement quality. However, except for the Reaching Performance Scale for Stroke and the Motor Evaluation Scale for Upper Extremity in Stroke Patients, these measures only account for deficits indirectly by giving a partial score if movements are slower or if the person experiences difficulties. Six outcome measures neither assess any parameters related to movement quality, nor distinguish between improvements resulting from motor compensation or recovery of desired movement strategies. CONCLUSION: Current activity measures may not distinguish recovery from compensation and adequately track changes in movement quality over time. Movement quality may be incorporated into clinical assessment using observational kinematics with or without low-cost motion tracking technology. PMID- 28675944 TI - Correction to: Sousa P et al., Periconceptional CMV infection prevention in Portugal: population subgroup study in a tertiary perinatal care center. PMID- 28675945 TI - Impact of dietary fat on gut microbiota and low-grade systemic inflammation: mechanisms and clinical implications on obesity. AB - Dietary fat strongly affects human health by modulating gut microbiota composition and low-grade systemic inflammation. High-fat diets have been implicated in reduced gut microbiota richness, increased Firmicutes to Bacteroidetes ratio, and several changes at family, genus and species levels. Saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA) and conjugated linolenic fatty acids share important pathways of immune system activation/inhibition with gut microbes, modulating obesogenic and proinflammatory profiles. Mechanisms that link dietary fat, gut microbiota and obesity are mediated by increased intestinal permeability, systemic endotoxemia, and the activity of the endocannabinoid system. Although the probiotic therapy could be a complementary strategy to improve gut microbiota composition, it did not show permanent effects to treat fat-induced dysbiosis. Based upon evidence to date, we believe that high-fat diets and SFA consumption should be avoided, and MUFA and omega-3 PUFA intake should be encouraged in order to regulate gut microbiota and inflammation, promoting body weight/fat control. PMID- 28675946 TI - Well-being and perceptions of everyday activities among those who attend community-based day centres for people with mental illness in Sweden - Does an immigrant background make a difference? AB - BACKGROUND: Community-based day centres (CBDCs) for people with mental illness are a common service for both people with an immigrant background and native Swedes. AIM: The aim was to compare CBDC attendees with an immigrant background with attendees who were native Swedes in terms of well-being and perceptions of everyday activities and investigate whether ethnic background could predict these factors. METHODS: Attendees at nine CBDCs were invited to participate. In all, 56 with an immigrant background and 69 native Swedes completed self-report questionnaires that addressed various aspects of well-being and everyday activities. RESULTS: Attendees with an immigrant background had a worse situation regarding perceived self-esteem, empowerment and satisfaction with everyday activities. In multivariate logistic regression analyses, ethnic background only became a significant predictor in regard to empowerment. Quality of life and activity level were of importance for satisfaction with everyday activities. Empowerment and self-esteem mutually influenced each other. CONCLUSION: Having a mental illness and an immigrant background may infer a particular risk for low empowerment. The mental health services and society at large should consider measures for adjusting the support to this group, including an analysis of how environments and contexts may act as barriers to activity enrichment and culturally congruent support. PMID- 28675947 TI - Pulmonary Blastoma in Children: Report of a Rare Case and Review of the Literature. AB - Pulmonary blastoma is a rare malignant lung tumor with aggressive behavior and dismal prognosis. It is extremely rare in children aged <18 years, and little is known about its genetic alteration and pathogenesis. Although surgical resection and adjuvant chemotherapy or radiotherapy have been applied in several cases, no standard treatment guidelines with sufficient evidence have been established. In this article, we report a case of a large pulmonary blastoma in a 7-year-old girl whose initial presentation was progressive dyspnea and productive cough. We subsequently present a review on cases involving young patients as well as genetic analysis data available in the literature. PMID- 28675948 TI - Use of prokineticin-1 (PROK1), pregnancy-associated plasma protein A (PAPP-A) and PROK1/PAPP-A ratio to predict adverse pregnancy outcomes in the first trimester: a prospective study. AB - INTRODUCTION: To compare the predictive effectiveness levels of prokineticin-1 (PROK1), pregnancy-associated plasma protein A (PAPP-A) and the PROK1/PAPP-A ratio in the first trimester for preeclampsia (PE), foetal growth restriction (FGR), gestational diabetes mellitus (GDM) and spontaneous preterm birth (SPB). MATERIALS AND METHODS: A total of randomly selected 162 pregnant women were included. Peripheral blood samples were obtained between 110/7 and 136/7 gestational weeks (GWs). All women were followed throughout the pregnancy and classified into five groups as having PE, FGR, GDM, SPB and uncomplicated pregnancies. The cut-off levels of the markers were identified to predict adverse outcomes. RESULTS: PROK1 predicted PE with 83.3% sensitivity, 85.7% specificity at a value of >293.4 pg/mL; at a value of >260.2 pg/mL, PROK1 predicted FGR with 85.7% sensitivity, 72.5% specificity in the first trimester. The area under receiver operating characteristic (ROC) curve of PAPP-A was lower than that of PROK1 and PROK1/PAPP-A in differentiating PE and FGR from the uncomplicated group (p < .001). PROK1 levels and the PROK1/PAPP-A ratios in the SPB and GDM groups were lower than in the uncomplicated group (p < .01). CONCLUSIONS: Elevated PROK1 in the first trimester is a more effective marker than PAPP-A in the prediction of PE and FGR. Lower PROK1 levels are associated with the development of SPB and GDM. PMID- 28675950 TI - Endovascular Treatment of Dialysis Access-Induced Hand Ischemia Using a Flared Stent-Graft. AB - PURPOSE: To report an investigation of a purely endovascular procedure to address access-induced hand ischemia in dialysis patients. CASE REPORT: Two dialysis patients presented with stage III steal syndrome consisting of severe pain and numbness in their fingers. Preoperative fistulograms distal to the anastomosis showed alternating antegrade and retrograde flow. Under ultrasound guidance, the fistula was accessed and a 4-F micropuncture sheath placed. An angled guidewire was then advanced proximally into the brachial artery. A 6-F short sheath with marker was placed followed by a 4-F straight guide catheter inserted into the proximal brachial artery. A 9-F Flair endovascular stent-graft was advanced over a 0.035-inch stiff angled Glidewire into the fistula just distal to the arterial anastomosis and deployed. Postoperatively, pain and numbness resolved in both patients immediately. Postoperative fistulograms documented antegrade flow. Access flow velocity readings decreased significantly and pulse oximetry readings increased significantly in both patients, who were followed for >6 months with no reported complications. CONCLUSION: These 2 cases suggest that this endovascular approach to access-induced hand ischemia may be a viable alternative to open/hybrid surgery. PMID- 28675949 TI - COMT and DAT1 polymorphisms moderate the indirect effect of parenting behavior on youth ADHD symptoms through neurocognitive functioning. AB - Although gene * environment interactions contribute to youth attention deficit/hyperactivity disorder (ADHD) symptoms, the pathways mediating these influences are unknown. We tested genetic moderation of indirect effects from parenting behavior to youth ADHD symptoms through multiple neurocognitive factors. Two hundred and twenty-nine youth with and without ADHD were assessed at baseline (Wave 1; ages 5-10) and at a 2-year follow-up (Wave 2; ages 7-13). At Wave 1, youth completed a neurocognitive battery including measures of response inhibition, visuospatial working memory, and fluid reasoning, and a standardized parent-child interaction task yielding observational measures of positive and negative parenting. At Wave 2, youth psychopathology was rated by parents and teachers using multiple methods (i.e., structured interview, rating scale). We employed moderated multiple mediation and compared conditional indirect effects across youth genotypes at two biologically plausible genetic loci. Controlling for parent ADHD symptoms as well as youth demographic factors and co-occurring externalizing symptoms, these genetic factors moderated the indirect effect from Wave 1 parenting to multi-method/informant Wave 2 ADHD symptoms through Wave 1 neurocognitive functioning. This preliminary study is the first to identify genetic moderation of mediated effects underlying ADHD symptoms and suggests that specific gene * parenting interactions may underlie neurocognitive functioning deficits and subsequent ADHD. PMID- 28675951 TI - Impact of Cilostazol Administration on Femoropopliteal In-Stent Restenosis. AB - PURPOSE: To investigate whether administering cilostazol after treatment for femoropopliteal in-stent restenosis (ISR) can have a positive impact on recurrent ISR (Re-ISR). METHODS: The database of a multicenter, retrospective, observational registry was interrogated to identify 338 consecutive patients (mean age 72.3+/-8.8 years; 148 men) who underwent endovascular therapy for femoropopliteal ISR in 379 limbs from January 2010 to December 2014. Ninety-seven patients (103 limbs) who received cilostazol after the initial stent implantation procedure were excluded. This left 24 ISR patients (30 limbs) who received cilostazol initially after ISR treatment for comparison with 217 ISR patients (246 limbs) who did not receive the drug. The primary endpoint was 2-year Re-ISR after treatment. The secondary endpoints were recurrent target lesion revascularization (Re-TLR) and reocclusion at 2 years. Restenosis was determined by a peak systolic velocity ratio >2.4 on a duplex scan or >50% stenosis on angiography. RESULTS: The mean follow-up was 23.3+/-15.5 months. At 2 years, freedom from Re-ISR was significantly higher in the cilostazol group than in the no cilostazol group (48.6% vs 32.4%, p=0.047). However, freedom from Re-TLR and reocclusion between the 2 groups did not differ significantly [64.7% vs 53.8% (p=0.15) and 88.3% vs 73.9% (p=0.11), respectively]. After adjusting for prespecified risk factors, cilostazol administration was a negative predictor of Re-ISR. CONCLUSION: This small comparative study suggests that administering cilostazol for ISR lesions after femoropopliteal stenting reduces recurrent ISR. PMID- 28675952 TI - A novel fine tuning scheme of miR-200c in modulating lung cell redox homeostasis. AB - Oxidative stress induces miR-200c, the predominant microRNA (miRNA) in lung tissues; however, the antioxidant role and biochemistry of such induction have not been clearly defined. Therefore, a lung adenocarcinoma cell line (A549) and a normal lung fibroblast (MRC-5) were used as models to determine the effects of miR-200c expression on lung antioxidant response. Hydrogen peroxide (H2O2) upregulated miR-200c, whose overexpression exacerbated the decrease in cell proliferation, retarded the progression of cells in the G2/M-phase, and increased oxidative stress upon H2O2 stimulation. The expression of three antioxidant proteins, superoxide dismutase (SOD)-2, haem oxygenase (HO)-1, and sirtuin (SIRT) 1, was reduced upon H2O2 stimulation in miR-200c-overexpressed A549 cells. This phenomenon of increased oxidative stress and antioxidant protein downregulation also occurs simultaneously in miR-200c overexpressed MRC-5 cells. Molecular analysis revealed that miR-200c inhibited the gene expression of HO-1 by directly targeting its 3'-untranslated region. The downregulation of SOD2 and SIRT1 by miR 200c was mediated through zinc finger E-box-binding homeobox 2 (ZEB2) and extracellular signal-regulated kinase 5 (ERK5) pathways, respectively, where knockdown of ZEB2 or ERK5 decreased the expression of SOD2 or SIRT1 in A549 cells. LNA anti-miR-200c transfection in A549 cells inhibited the endogenous miR 200c expression, resulting in increased expressions of antioxidant proteins, reduced oxidative stress and recovered cell proliferation upon H2O2 stimulation. These findings indicate that miR-200c fine-tuned the antioxidant response of the lung cells to oxidative stress through several pathways, and thus this study provides novel information concerning the role of miR-200c in modulating redox homeostasis of lung. PMID- 28675953 TI - Utility of nociceptive flexion reflex threshold and bispectral index to predict movement responses under propofol anaesthesia. AB - INTRODUCTION: The nociceptive flexion reflex threshold (NFRT) is a promising tool to monitor analgesia during general anaesthesia. Clinical studies have shown that the NFRT allows to predict movement responses to painful stimuli under a combined anaesthetic regime of sedative and opioid agents. Experimental studies indicated that the NFRT is also able to predict such movement responses under an exclusively sedative regime like propofol mono-anaesthesia. Therefore, we performed this study to investigate the ability of the NFRT to predict movement responses to painful stimuli in patients during a clinical propofol mono anaesthesia. METHODS: We investigated 140 cardiac surgery patients during their postoperative phase under propofol mono-anaesthesia. NFRT and bispectral index (BIS) were determined in each patient right before endotracheal suctioning or painful electrical test stimulation. Prediction probabilities were calculated to quantify how accurate each measure is able to predict movement responses to the stimuli. RESULTS: The 124 patients included in the analysis received a median propofol dosage of 3.2 (2.5-3.9) [median (IQR)] mg/kg/h. The included patients showed 287 movement responses after a total of 725 investigated stimuli. The prediction probabilities for positive movement responses were 0.63 (95%CI: 0.59 0.67) for the NFRT and 0.69 (95%CI: 0.65-0.73) for the BIS. CONCLUSIONS: The NFRT allows the prediction of movement responses under propofol mono-anaesthesia, which confirms its utility as a monitor to predict movement responses under general anaesthesia. The BIS allows an even more accurate prediction, although it does not reflect the physiological structures of movement suppression, but correlates closely with the dose of propofol. TRIAL REGISTRATION: German clinical trial register (DRKS00003062, Deutsches Register Klinischer Studien). PMID- 28675954 TI - Effect of population breast screening on breast cancer mortality to 2005 in England and Wales: A nested case-control study within a cohort of one million women. AB - Objectives To evaluate the effectiveness of the NHS breast screening programme (NHSBSP) on breast cancer mortality in England and Wales and to compare findings with a cohort analysis of the same underlying population. Methods A nested case control study within a cohort of 959,738 women in England and Wales aged 49-64 who were eligible for routine NHSBSP screening during 1991-2005. Cases who died from breast cancer in 1991-2005 were matched to controls without breast cancer at the case diagnosis date and alive when the case died. Risk of breast cancer mortality associated with intention to screen (ITS) (7047 cases/28,188 controls) and screening attendance (4707 cases/9413 controls) was examined. Bias was minimised in accordance with currently advocated best practice. Odds ratios (ORs) were calculated using conditional logistic regression. Results were compared with findings from an incidence-based breast cancer mortality cohort analysis. Results ITS was associated with a 21% breast cancer mortality reduction (OR = 0.79, 95% confidence interval [CI]: 0.71-0.88, P < 0.001). Attendance <=5 years before diagnosis was associated with a 47% reduction in breast cancer mortality after self-selection correction (OR = 0.53, 95% CI: 0.46-0.62, P < 0.001). Breast cancer mortality reduction associated with ITS was 21% in both the case-control and cohort analyses, but the impact of attendance was marginally greater in the case-control analysis (36% vs. 32%). Conclusions Case-control studies designed and analysed according to current best practice guidelines offer an effective means of evaluating population breast screening. PMID- 28675955 TI - Psychiatric disorders in children with demyelinating diseases of the central nervous system. AB - INTRODUCTION: The profile of psychiatric disorders associated with multiple sclerosis (MS) may differ in children. We aimed to assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa. PATIENTS AND METHODS: We analyzed linked English Hospital Episode Statistics, and mortality data, 1999-2011. Cohorts were constructed of children admitted with MS and other central nervous system (CNS) demyelinating diseases. We searched for any subsequent episode of care with psychiatric disorders in these cohorts and compared to a reference cohort. RESULTS: Children with CNS demyelinating diseases had an increased rate of psychotic disorders (rate ratio (RR) = 5.77 (95% confidence interval (CI) = 2.48-11.41)); anxiety, stress-related, and somatoform disorders (RR = 2.38 (1.39-3.81)); intellectual disability (RR = 6.56 (3.66 10.84)); and other behavioral disorders (RR = 8.99 (5.13-14.62)). In analysis of the pediatric MS cohort as the exposure, there were elevated rates of psychotic disorders (RR = 10.76 (2.93-27.63)), mood disorders (RR = 2.57 (1.03-5.31)), and intellectual disability (RR = 6.08 (1.25-17.80)). In reverse analyses, there were elevated rates of a recorded hospital episode with CNS demyelinating disease after a previous recorded episode with anxiety, stress-related, and somatoform disorders; attention-deficit hyperactivity disorder (ADHD); autism; intellectual disability; and other behavioral disorders. CONCLUSION: This analysis of a national diagnostic database provides strong evidence for an association between pediatric CNS demyelinating diseases and psychiatric disorders, and highlights a need for early involvement of mental health professionals. PMID- 28675956 TI - Executive functioning in relapsing-remitting multiple sclerosis patients without cognitive impairment: A task-switching protocol. AB - BACKGROUND: Cognitive dysfunction affects 40%-65% of multiple sclerosis (MS) patients, most often affecting information processing speed and working memory, mediated by the pre-frontal cortex (PFC). OBJECTIVE: Our study aimed to investigate PFC functioning through a task-switching protocol in relapsing remitting multiple sclerosis (RRMS) patients without cognitive impairment. METHODS: A total of 24 RRMS patients and 25 controls were enrolled. Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called switch cost (SC). RESULTS: Patients had worse performance than controls only in the switch trials, as indicated by increased SC and reaction times. Moreover, patients showed a reduced ability to reconfigure the task-set for the execution of a new task and to disengage from the previous one. CONCLUSION: Our results showed a primary deficit in executive control processes involved in the task switching performance in RRMS patients without cognitive impairment. This deficit may depend on the functional impairment of the PFC, which is essential to adjust behaviour rapidly and flexibly in response to environmental changes, representing one of the most sophisticated human abilities. PMID- 28675957 TI - Protective mechanism of turmeric (Curcuma longa) on carbofuran-induced hematological and hepatic toxicities in a rat model. AB - CONTEXT: Turmeric (Curcuma longa L. [Zingiberaceae]) is used in the treatment of a variety of conditions including pesticide-induced toxicity. OBJECTIVE: The study reports the antioxidant properties and the protective effects of turmeric against carbofuran (CF)-induced toxicity in rats. MATERIALS AND METHODS: The antioxidant potential was determined by using free radicals scavenging activity and ferric reducing antioxidant power values. Male Wistar rats were randomly divided into four groups, designated as control, turmeric (100 mg/kg/day), CF (1 mg/kg/day) and turmeric (100 mg/kg/day) + CF (1 mg/kg/day) treatments. All of the doses were administered orally for 28 consecutive days. The biological activity of the turmeric and CF was determined by using several standard biochemical methods. RESULTS: Turmeric contains high concentrations of polyphenols (8.97 +/- 0.15 g GAEs), flavonoids (5.46 +/- 0.29 g CEs), ascorbic acid (0.06 +/- 0.00 mg AEs) and FRAP value (1972.66 +/- 104.78 MUM Fe2+) per 100 g of sample. Oral administration of CF caused significant changes in some of the blood indices, such as, mean corpuscular volume, corpuscular hemoglobin, white blood cell, platelet distribution width and induced severe hepatic injuries associated with oxidative stress, as observed by the significantly higher lipid peroxidation (LPO) levels when compared to control, while the activities of cellular antioxidant enzymes (including superoxide dismutase and glutathione peroxidase) were significantly suppressed in the liver tissue. DISCUSSION AND CONCLUSION: Turmeric supplementation could protect against CF-induced hematological perturbations and hepatic injuries in rats, plausibly by the up-regulation of antioxidant enzymes and inhibition of LPO to confer the protective effect. PMID- 28675958 TI - Congenital Myoepithelial Carcinoma of Soft Tissue Associated With Cystic Myoepithelioma. AB - Myoepithelial neoplasms of soft tissue represent a heterogeneous group of lesions, encompassing both benign entities as myoepithelioma (ME) and highly aggressive tumors as myoepithelial carcinoma (MEC). We describe a case of pediatric soft tissue MEC with peculiar features that may lead to misdiagnosis: congenital onset and presence of a benign component with predominant cystic structure. Few cases of congenital MEC have been reported, but the coexistence of MEC with ME is even more rare, accounting for less than 1% of myoepithelial tumors. Moreover, an extensive cystic appearance had never been described in either ME or MEC of soft tissue. Despite several predictors of poor prognosis, the patient has been showing a favorable clinical course since the administration of ICpE (ifosfamide, cisplatin, and etoposide) chemotherapy. This report provides valuable information in the differential diagnosis of cystic congenital tumors and supports a possible efficacy of adjuvant combined treatment for patients with localized disease after surgery. PMID- 28675959 TI - Adding Events to a Markov Model Using DICE Simulation. AB - BACKGROUND: Health care decisions are often made under uncertainty and modeling is used to inform the choices and possible consequences. State-transition ("Markov") models are commonly used but they represent the problem solely in terms of states; events are not explicitly considered. METHODS: Discretely integrated condition event (DICE) simulation provides for both aspects that persist over time ("conditions") and for those happening at a point in time ("events"). A Markov model can be specified in DICE by representing states as conditions with a recurrent transition event processing transition probabilities, and other events added explicitly. RESULTS: The DICE specification of a Markov model is compact because transitions are enumerated only once; it is very transparent, as these specifications are tabulated rather than programmed in code; and flexibility is enhanced by the ease with which alternative structures are specified. Events can be added to represent clinical occurrences, treatment features, health care activities, and any other relevant aspect of this type. They may coincide with the transition event or occur at their own times. Varying cycle times and structural sensitivity analyses are easy to implement. LIMITATIONS: Execution of a DICE simulation using a macro in spreadsheet software can be slow, especially for complex models requiring stochastic analyses replicated thousands of times. Modelers wishing to use other software can still use the tabular specification ideas to expand their Markov models, but the descriptions provided here may not be entirely applicable. Another limitation is the inability of these simulations to handle constrained resources or interactions among patients. CONCLUSIONS: With DICE simulation, it is possible to expand the Markov formulation to include explicitly many events occurring at various times. PMID- 28675960 TI - Mass transfer kinetics of biosorption of nitrogenous matter from palm oil mill effluent by aerobic granules in sequencing batch reactor. AB - Understanding of mass transfer kinetics is important for biosorption of nitrogen compounds from palm oil mill effluent (POME) to gain a mechanistic insight into future biological processes for the treatment of high organic loading wastewater. In this study, the rates of global and sequential mass transfer were determined using the modified mass transfer factor equations for the experiments to remove nitrogen by aerobic granular sludge accumulation in a sequencing batch reactor (SBR). The maximum efficiencies as high as 97% for the experiment run at [kLa]g value of 1421.8 h-1 and 96% for the experiment run at [kLa]g value of 9.6 * 1037 h-1 were verified before and after the addition of Serratia marcescens SA30, respectively. The resistance of mass transfer could be dependent on external mass transfer that controls the transport of nitrogen molecule along the experimental period of 256 days. The increase in [kLa]g value leading to increased performance of the SBR was verified to contribute to the future applications of the SBR because this phenomenon provides new insight into the dynamic response of biological processes to treat POME. PMID- 28675961 TI - Maxillary deformity following CPAP treatment in myasthenia gravis. AB - OBJECTIVE: Patients with Myasthenia gravis (MG) are characterized by muscle weakness that may cause obstructive sleep apnea (OSA). The use of a continuous positive airway pressure (CPAP) device is often needed in order to maintain free breathing during the night and sometimes even during the day. CLINICAL PRESENTATION: A 29-year-old MG patient is presented who used a CPAP continuously since the age of 12. Tight fitting of a nasal mask applied enough force to cause severe maxillary deformity. CLINICAL RELEVANCE: Masks with additional forehead and chin support or a regular full face mask are recommended for patients with muscle weakness, in order to spread forces more evenly. PMID- 28675962 TI - Impairments in the Visual Processing of Global Biological Motion Cues in Down Syndrome. AB - Down syndrome (DS) is one of the most common chromosomal disorders and is often associated with a number of motor and cognitive impairments. Little research has been dedicated to investigating the perceptual abilities of individuals with DS. The visual processing of biological motion has been shown to be impaired in DS. It has been proposed that these impairments may stem from an inability to process the global patterns of full-body motion produced by a moving actor; however, this has not been explicitly investigated. We tested groups of participants with and without DS on a task requiring the visual discrimination of point-light walkers from spatially scrambled versions of point-light walkers. Participants with DS demonstrated poorer performance and slower reaction times on the task than healthy controls. From these results, we conclude that biological motion processing is impaired in DS and that this deficit is related to an inability to integrate global configural cues. In a second experiment, individuals with DS were able to discriminate the direction in which laterally translating walkers moved, suggesting that the global motion processing deficit observed in Experiment 1 is specific to biological motion recognition and does not generalise to other types of global motion. PMID- 28675963 TI - Oversampling as a methodological strategy for the study of self-reported health among lesbian, gay and bisexual populations. AB - AIMS: Epidemiological research on lesbian, gay and bisexual populations raises concerns regarding self-selection and group sizes. The aim of this research was to present strategies used to overcome these challenges in a national population based web survey of self-reported sexual orientation and living conditions exemplified with a case of daily tobacco smoking. METHODS: The sample was extracted from pre-established national web panels. Utilizing an oversampling strategy, we established a sample including 315 gay men, 217 bisexual men, 789 heterosexual men, 197 lesbian women, 405 bisexual women and 979 heterosexual women. We compared daily smoking, representing three levels of differentiation of sexual orientation for each gender. RESULTS: The aggregation of all non heterosexuals into one group yielded a higher odds ratio (OR) for non heterosexuals being a daily smoker. The aggregation of lesbian and bisexual women indicated higher OR between this group and heterosexual women. The full differentiation yielded no differences between groups except for bisexual compared with heterosexual women. CONCLUSIONS: The analyses demonstrated the advantage of differentiation of sexual orientation and gender, in this case bisexual women were the main source of group differences. We recommend an oversampling procedure, making it possible to avoid self-recruitment and to increase the transferability of findings. PMID- 28675964 TI - Postoperative blood pressure variability exerts an influence on clinical outcome after coil embolization of ruptured intracranial aneurysms. AB - OBJECTIVE: The present study was conducted to evaluate the effect of postoperative blood pressure (BP) variability on functional outcome in patients after coil embolization of ruptured aneurysms. METHODS: The authors retrospectively reviewed their database of patients undergoing endovascular coiling to treat subarachnoid hemorrhage (SAH) between November 2011 and December 2014. BP values were recorded every 2 hours in the initial 24 hours after endovascular obliteration of ruptured aneurysms. BP variability was determined as standard deviation (SD) and successive variation (SV). Clinical outcome at discharge was assessed by the modified Rankin Scale (mRS) and Glasgow Coma Scale (GCS) Score. BP variability obtained were correlated to patient outcome and analyzed statistically. RESULTS: Favorable outcomes (mRS 0-1) achieved in 308 (83.7%) of the 368 patients. On univariate logistic analysis, postoperative systolic blood pressure variability (SBPV)-SD, SBPV-SV, diastolic blood pressure variability (DBPV)-SD and DBPV-SV were associated with clinical outcome at discharge. SBPV-SV remained to be an independent predictor for functional recovery (OR, 0.93; 95% CI, 0.88-0.98; P = 0.009) after adjusting for age, postoperative fever, and Hunt-Hess grade by multivariate analysis. Furthermore, patients with higher SBPV had lower GCS grade at discharge (P < 0.001). There was no association between clinical outcome and mean systolic BP (SBP) (P = 0.360) or mean diastolic BP (DBP) (P = 0.105) after coiling. CONCLUSION: Postoperative SBPV was a strong predictor of clinical outcome in patients undergoing coil embolization of aneurysms, independent of mean SBP or DBP and seemed to be a potential therapeutic target in aneurysmal SAH. PMID- 28675965 TI - Editorial: Innovative Practice. PMID- 28675966 TI - Apple snack enriched with L-arginine using vacuum impregnation/ohmic heating technology. AB - Modern life has created a high demand for functional food, and in this context, emerging technologies such as vacuum impregnation and ohmic heating have been applied to generate functional foods. The aim of this research was to enrich the content of the semi-essential amino acid L-arginine in apple cubes using vacuum impregnation, conventional heating, and ohmic heating. Additionally, combined vacuum impregnation/conventional heating and vacuum impregnation/ohmic heating treatments were evaluated. The above treatments were applied at 30, 40 and 50 C and combined with air-drying at 40 C in order to obtain an apple snack rich in L arginine. Both the impregnation kinetics of L-arginine and sample color were evaluated. The impregnated samples created using vacuum impregnation/ohmic heating at 50 C presented a high content of L-arginine, an effect attributed primarily to electropermeabilization. Overall, vacuum impregnation/ohmic heating treatment at 50 C, followed by drying at 40 C, was the best process for obtaining an apple snack rich in L-arginine. PMID- 28675967 TI - Survival of a native toxigenic isolate of Listeria monocytogenes CFR 1302 during storage of milk-based foods can be a potential cause of health risk. AB - The ability of a native toxigenic culture of Listeria monocytogenes CFR 1302 to survive and elaborate associated toxigenic trait in ice cream and mango pulp based lactic fermented milk was studied. The culture of L. monocytogenes inoculated at two initial levels of 4.6 and 5.6 log10 CFU/ml almost remained unaltered during storage of the food products. However, in both the milk-based products, a marginal increase in viable population was observed during 2-4 d of storage as against the initial inoculum levels. The toxigenic trait, listeriolysin "O" was detected by PCR based on species-specific hlyA primers in the two products without any step of enrichment. The positive amplification in PCR was evidenced with initial population levels of 6.3, 7.3, and 8.3 log10 CFU/ml of the respective products. In culture broth, PCR detection was positive with the lowest level of 2.3 log10 CFU/ml. The established pathogenic strain of L. monocytogenes Scott A used as a reference culture revealed almost the same behavior to that of native culture in the food products. The findings of present study bring into focus that, irrespective of low storage temperatures, there exists the potential health hazard associated with foods initially contaminated with risk population levels of L. monocytogenes. PMID- 28675968 TI - Effects of a high O2 dynamic-controlled atmosphere technology on the browning of postharvest white mushroom ( Agaricus bisporus) in relation to energy metabolism. AB - Browning is one of the main problems in senescence of mushrooms, and it is also one of the most important attributes accounting for the loss of the quality and reduction in market value. In order to study the relationship between the energy metabolism and the browning of white mushroom under high O2 dynamic-controlled atmosphere (HO-DCA), mushrooms were stored in 100% O2 (SCA1), 80% O2 + 20% CO2 (SCA2), 100% O2 for three days and then transferred into the treatment of 80% O2 + 20% CO2 (HO-DCA) at 2 +/- 1 C and air as control. In this study, adenosine triphosphate (ATP) content, energy charge level, sensory evaluation, browning of surface and flesh, cell membrane integrity, exogenous ATP, polyphenol oxidase (PPO) and peroxidase (POD) activity and genes encoding PPO of the white mushroom were investigated. These were all closely related to the browning of products. The optimal storage condition of the HO-DCA treatment could delay the browning of pericarp and flesh tissues of the mushrooms, inhibit PPO activity and reduce the relative expression levels of the three genes encoding PPO. Meanwhile, it maintained moderate POD activity, good sensory properties and cell membrane integrity in a certain extent and thus slowed down the senescence of mushrooms. Results indicated that there was a positive correlation between the ATP content and whitening index ( r = 0.901). In addition, HO-DCA maintained a higher ATP level, prolonged the storage time to 28 days and it might be an ideal strategy for preserving the quality of mushroom during storage. PMID- 28675969 TI - The dietary fiber profile of fruit peels and functionality modifications induced by high hydrostatic pressure treatments. AB - The effect of high hydrostatic pressure (HHP) and temperature on composition of non-conventional dietary fiber (DF) sources and functional properties were evaluated. Mango, orange, or prickly pear peels were processed at 600 MPa during 10 min at 22 C and 55 C. Total (TDF), soluble (SDF), and insoluble (IDF) dietary fiber, water/oil holding, and retention capacity, solubility, swelling capacity, and bulk density were assayed. An increment in the SDF content was observed due to the effect of pressure with the greatest changes noticed in mango peel, increasing from 37.4% (control) to 45.7% (SDF/TDF) in the HHP-treated (55 C) sample. Constant values of TDF after the treatments suggest a conversion of IDF to SDF in mango (38.9%-40.5% dw) and orange (49.0%-50.8% dw) peels. The highest fiber solubility values were observed for mango peel ranging between 80.3% and 83.9%, but the highest increase, from 55.1% to 62.3%, due to treatment was displayed in orange peel processed at 22 C. A relationship between DF modifications induced by HHP treatment and changes in the functional properties of the materials was established. Application of HHP opens up the opportunity to modify non-conventional sources of DF and to obtain novel functional properties for different food applications. PMID- 28675970 TI - Effect of microalgae incorporation on physicochemical and textural properties in wheat bread formulation. AB - The objective of this study was to evaluate the effect of the incorporation of different microalgae on physicochemical and textural properties of bread. Four species of microalgae Isochrysis galbana, Tetraselmis suecica, Scenedesmus almeriensis, and Nannochloropsis gaditana were used in this study. Properties such as water activity, pH, microbiological counts, viscosity, and color were analyzed to determine the effect of microalgae addition on sourdough. The technological quality of breads was analyzed in terms of physicochemical properties, color, texture profile, and porosity. The main effect of microalgae addition was changes in bread color, crust, and crumb that implies an increase of browning and an evolution to more green-yellow tonalities. The textural parameters of breads such as hardness, chewiness, and resilience are not modified by microalgae addition. PMID- 28675971 TI - Effects of natural antimicrobials on prevention and reduction of bacterial cross contamination during the washing of ready-to-eat fresh-cut lettuce. AB - Microbiological safety of the fresh-cut produce may not be guaranteed if the quality of wash water is not maintained. The use of natural antimicrobials as alternative to chlorine may offer interesting possibilities for disinfecting wash water. Antimicrobial properties of allyl- and benzyl-isothiocyanates, respectively, and chitosan against Salmonella spp. were evaluated by standard plate count. Minimal inhibitory concentration values were observed for benzyl isothiocyanate and chitosan, corresponding to 50 and 1000 mgl-1, respectively. A 5 min washing of 25 g fresh-cut lettuce was performed. Transfer of Salmonella from the water to the produce was observed. Benzyl-isothiocyanate addition of 75 mgl-1 before starting the washing process gave rise to a complete removal of total bacteria and Salmonella in the wash water after 24 h before starting the second cycle. Antimicrobial benzyl-isothiocyanate effects have been demonstrated to persist after 48 h. PMID- 28675972 TI - The flow properties of honey-malt spread. AB - In this study, the effect of barley malt extract at two brix levels (74 and 79 degrees Bx) and three ratios of malt extract/honey (65:35, 70:30 and 75:25) on the flow behavior properties of honey-malt spread at three temperature levels (35 C, 45 C and 55 C) was investigated. Time-dependent behavior data of the spread samples were appropriately fitted to the Weltman, first-order stress decay with a zero stress value and first-order stress decay with a non-zero stress value models. Also, the Power-law, Herschel-Bulkley, Casson and Bingham models were used for curve fitting the time-independent behavior data. Regarding the R2 and root mean square error coefficients, the first-order stress decay with a non-zero stress value and Herschel-Bulkley models were selected as the suitable models to describe the flow behavior of samples. The results for time-dependent properties showed that spread samples exhibit a thixotropic behaviour, as the viscosity for all samples decreased with increase in shearing time at a constant shear rate of 50 s-1. PMID- 28675973 TI - Diffuse Melanosis in Pericolic Lymph Nodes Associated With Laxative Abuse and Colorectal Cancer. PMID- 28675974 TI - Toward generally accepted forensic assessment practices among clinical neuropsychologists: a survey of professional practice and common test use. AB - OBJECTIVE: This study investigated professional practice and common test use among clinical neuropsychologists engaging in forensic assessment. METHOD: Doctorate-level psychologists active in the practice of neuropsychology and on the INS and NAN membership listings (n = 502) were surveyed about their demographics, professional practice, and common test use. Participants who reported engaging in forensic practice (n = 255) were further surveyed about their forensic practice. RESULTS: Forensic participants were more likely to be male and Caucasian, and reported higher ages, more years of professional experience, and a higher prevalence of board certification. While characteristics of their professional and forensic practice varied, forensic participants reported spending most of their professional time conducting neuropsychological assessments with adult clients in a private or group practice setting, focusing on civil referrals and civil legal questions involving older adult issues, developmental issues, head injury, and psychiatric issues. Common test use across neuropsychological assessment domains is presented for board-certified forensic participants (n = 77). An examination of these results reveals that the current pattern of test use is similar to the results of a more general survey of neuropsychological test use. CONCLUSIONS: The findings provide insight into the practice of forensic neuropsychological assessment, and further establish the admissibility of neuropsychological evidence in the United States legal system. Results will be useful for clinical neuropsychologists, field leaders, and legal professionals hoping to gain insight into the role of clinical neuropsychology in civil and criminal legal decision-making. PMID- 28675975 TI - Effect of intraoperative autologous transfusion techniques on perioperative hemoglobin level in idiopathic scoliosis patients undergoing posterior spinal fusion: A prospective randomized trial. AB - BACKGROUND: Massive blood loss during posterior spinal fusion for adolescent idiopathic scoliosis remains a significant risk for patients. There is no consensus on the benefit of acute normovolemic hemodilution (ANH) or intraoperative cell salvage (ICS) in scoliosis surgery. METHODS: Patients were randomized to one of two groups. Group A received ANH and ICS during operation, while group B received only ICS. Patients' age, sex, height, weight, body blood volume, number of fusion level, Cobb angle, number of screws, duration of surgery, and skin incision length were recorded. Hemoglobin and hematocrit levels were obtained preoperatively and postoperatively (0 h and 24 h). RESULTS: There were 22 patients in each group. There was no significant difference in total blood loss. The perioperative decrease in hemoglobin levels between preoperation and postoperation 24 h (group A 2.79 +/- 1.15 and group B 2.76 +/- 1.00) showed no significant difference ( p = 0.93). Group A observed a larger decrease in hemoglobin levels at postoperative 0 h relative to preoperative level (2.57 +/- 0.82 g/dl), followed by a smaller decrease within the next 24 h (0.22 +/- 1.33 g/dl). Group B showed a continued drop in hemoglobin levels of similar magnitude at postoperation 0 h (1.60 +/- 0.67 g/dl) and within the next 24 h (1.16 +/- 0.78 g/dl). One patient from group B received 1 unit of allogenic blood transfusion ( p = 0.33). CONCLUSIONS: The addition of ANH to ICS in posterior spinal fusion surgery for AIS resulted in a similar decrease in hemoglobin levels between preoperative values and at 24 h postoperatively. PMID- 28675976 TI - Post-osteomyelitic-acquired radial club hand deformity in children treated by centralization of ulna. AB - INTRODUCTION: Radial club hand deformity acquired post haematogenous osteomyelitis of radius bone is a very rare disease. Resulting in functional and cosmetic deficit of upper limb which is similar to congenital cases. For a long time various surgeons attempted to reconstruct the deformity by bone grafting, plating, Ilizarov, monorail external fixator, callus distraction and so on. Keeping in mind that creating single bone forearm we proposed centralization of ulna on wrist to correct the deformity. MATERIALS AND METHODS: In our institute, we conducted a rare study involving small number of patients ( n = 5), between February 2013 and November 2106. The study participants comprised four male children and one female child whose average age was 1.8 months. Participant inclusion criteria were no active infection, no distal end of radius (cartilage remnant) and only haematogenous osteomyelitis. Exclusion criteria were congenital radial club hand and active infection. RESULT: Decrease in the angle of radial deviation (radiologically) preoperatively from 54 degrees to 5 degrees and angle of volar flexion from 34 degrees to 4 degrees were measured. Preoperatively no ulnar angulations were observed. Length of ulna remains similar to the opposite side. No neurovascular complication noted and full range of movement regained. DISCUSSION: Our case series is unique in terms of massive bone loss, that is, distal metaphysic and epiphysis, so we followed the statement of Ono et al. and did centralization of ulna over carpus and achieved good functional and cosmetic outcome at the cost of loss of motion at the wrist, concluding that treatment is primarily considered as salvage only. PMID- 28675977 TI - The reliability of measuring acetabular component position on radiographs using everyday diagnostic imaging software. AB - BACKGROUND: It is standard practice for total hip arthroplasty (THA) patients to have post-operative imaging, and one of the reasons is to assess the adequacy of acetabular component position. Correct positioning of the acetabular component is important for successful outcome in THA. Acetabular component position can be measured from either computed tomography (CT) or plain radiographs. While CT is the gold standard for accurately measuring acetabular component position, radiographs are routinely used for post-operative evaluation. However, measurement of acetabular component position from plain radiographs is not straightforward and numerous methods have been proposed. As most imaging is now digital, the aim of this study was to investigate the reliability of one method to measure acetabular component position using a basic diagnostic imaging software program that is readily available to orthopaedic surgeons. METHODS: We investigated the reliability Lewinnek's method using a basic Picture Archiving and Communication System program, InteleViewer TM . We measured 69 post-operative anteroposterior (AP) radiographs of patients who underwent primary THA. Intra observer and inter-observer reliability for Lewinnek's method was calculated using the intraclass correlation coefficient. RESULTS: Our results showed excellent intra- and inter-observer reliability for both inclination (0.99, 95% confidence interval (CI): 0.99-1.0; and 0.97, 95% CI: 0.95-0.99) and anteversion (0.99, 95% CI: 0.98-0.99; and 0.93, 95% CI: 0.89-0.96) measurements. CONCLUSION: This study has shown that using Lewinnek's method, acetabular component position can be reliably measured on post-operative AP digital radiographs using readily available software tools. PMID- 28675978 TI - Concomitant SLAP repair does not influence the surgical outcome for arthroscopic Bankart repair of traumatic shoulder dislocations. AB - BACKGROUND: Prior studies revealed the presence of superior labrum anterior-to posterior (SLAP) injury together with Bankart lesions in some patients. The purpose of the study is to compare the clinical results of isolated Bankart repairs with the clinical results of Bankart repairs when performed with concomitant SLAP repairs. METHODS: The patients who underwent arthroscopic surgery for treatment of anterior glenohumeral instability were evaluated retrospectively. Group 1 consisted of 19 patients who had arthroscopic SLAP repair together with Bankart repair. The mean age of the patients was 23. Group 2 consisted of 38 patients who underwent isolated Bankart repair. The mean age was 24. Knotless anchors were used in both groups. RESULTS: The mean follow-up was 34 months (range: 26-72). In group 1, the mean preoperative Constant score was 84 (range: 74-90, standard deviation (SD): 5.91) and Rowe score was 64.1 (range: 40 70, SD: 8.14). In group 2, the preoperative Constant score was 84.4 (range: 70 96, SD: 5.88) and Rowe score was 60 (range: 45-70, SD: 7.95). In group 1, the postoperative mean Constant score raised to 96.8 (range: 88-100, SD: 2.91) and the mean Rowe score raised to 92.3 (range: 85-100, SD: 5.17). In group 2, the postoperative mean Constant score was 94.9 (range: 88-100, SD: 3.70) and the mean Rowe score was 94.2 (range: 80-100, SD: 4.71). The difference between the scores of two groups was insignificant ( p > 0.05). When the numbers of redislocations and range of motion were compared, no significant difference was found ( p > 0.05). CONCLUSION: Accompanying SLAP repair in surgical treatment with Bankart repair for shoulder instability does not affect the results negatively. Properly repaired labral tears extending from anterior inferior to the posterior superior of the glenoid in instability treatment have the same outcome in overall results as repaired isolated Bankart lesions. PMID- 28675979 TI - Evaluation of consistency for multiple experiments of a single combination in the time-dependence mixture toxicity assay. AB - Test-to-test consistency was evaluated for a single binary combination of organic chemicals using an assay that examined toxicity over multiple exposure times. Six experiments were conducted. The toxicities of 3-chloro-2-butanone (3C2B), methyl crotonate (MC) and the mixture of both (MX) were evaluated in each experiment at 15, 30 and 45 min of exposure using the Microtox(r) system. Concentration response (x/y) curves were generated via the five-parameter logistic minus one parameter (5PL - 1P) curve-fitting function and were used to develop predicted x/y curves for the dose-addition (DA) and independence (I) models of combined effect. A variety of toxicity (e.g. effective concentration, EC50) and time dependent toxicity (TDT) endpoints, 5PL - 1P parameters and various combined effects metrics (e.g. MX/DA) were calculated. Test-to-test consistency was evaluated via the coefficient of variation (CV) or, for TDT, the standard deviation of mean values. In the study, CVs obtained for single-chemical and mixture toxicity endpoints (EC25, EC50 and EC75) at each exposure time were <20, as were those for the predicted DA and I curves. For the MX/DA metric, mixture toxicity was consistent with that predicted for DA at each exposure time in each experiment with CVs <6, despite some substantial variation in TDT for MC-alone at the EC25 and for the 30-45 min time-interval. There was a lower variation in TDT for 3C2B and MX. Mean and CV values for 5PL - 1P-derived slope and asymmetry parameters were also assessed to provide bases for comparisons in future reports. PMID- 28675980 TI - A Combined Deposition of Lanthanum and beta2-Microglobulin-Related Amyloid in the Gastroduodenal Mucosa of Hemodialysis-Dependent Patients: An Immunohistochemical, Electron Microscopic, and Energy Dispersive X-Ray Spectrometric Analysis. AB - Lanthanum carbonate (LC) is a new type of phosphate adsorbent used to treat patients with hyperphosphatemia caused by chronic kidney diseases. Recent studies have pointed out that lanthanum deposition can be found in the cytoplasm of histiocytes in the gastroduodenal mucosa of these patients. On the other hand, it is well known that patients on long-term hemodialysis can develop deposition of beta2-microglobulin-related amyloid (Abeta2M) mainly around joints. However, involvement of the gastrointestinal tract by hemodialysis-associated amyloidosis has been thought to be rare, and therefore only Abeta2M, if any, has been reported to accumulate in the vascular walls of the submucosa and muscularis propria. Thus, in contrast to AA amyloid, biopsy from gastrointestinal mucosa has long been considered to have little significance in detecting amyloid. We present unusual histologic findings on biopsy specimens taken from the gastroduodenal mucosa of 7 hemodialysis-dependent patients taking LC for more than a year. These findings were due to a combined deposition of lanthanum and beta2-microglobulin related amyloid in the cytoplasm of histiocytes. The deposition of amyloid was confirmed by conventional histochemistry, immunohistochemistry, and transmission electron microscopy, and that of lanthanum by transmission electron microscopy and scanning electron microscopy/energy dispersive X-ray spectrometry. This is the first report of such a peculiar combined deposition of lanthanum and amyloid in the gastroduodenal mucosa of hemodialysis patients. Although the exact mechanism of combination and pathogenesis is unclear, we believe that histologic examination of the gastrointestinal mucosa should be considered in the careful follow-up and observation of hemodialysis patients taking LC. PMID- 28675981 TI - Frailty Syndrome and Risk of Sepsis in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Cohort. AB - BACKGROUND: Frailty is associated with increased morbidity and mortality in older persons. We sought to characterize the associations between the frailty syndrome and long-term risk of sepsis in a large cohort of community-dwelling adults. METHODS: We analyzed data on 30 239 community-dwelling adult participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We defined frailty as the presence of at least 2 frailty indicators (weakness, exhaustion, and low physical activity). We defined sepsis as hospitalization for a serious infection with >=2 system inflammatory response syndrome criteria, identified for the period 2003-2012. We determined the associations between frailty and risk of first sepsis and sepsis 30-day case fatality. RESULTS: Among REGARDS participants, frailty was present in 6018 (19.9%). Over the 10-year observation period, there were 1529 first-sepsis hospitalizations. Frailty was associated with increased risk of sepsis (adjusted hazard ratio [HR] 1.44; 95% CI: 1.26 to 1.64). The total number of frailty indicators was associated with increased risk of sepsis ( P trend <.001). Among first-sepsis hospitalizations, frailty was associated with increased sepsis 30-day case fatality (adjusted OR 1.62; 95% CI: 1.06 to 2.50). CONCLUSIONS: In the REGARDS cohort, frailty was associated with increased long-term risk of sepsis and sepsis 30-day case fatality. PMID- 28675982 TI - Oncologists' and Intensivists' Attitudes Toward the Care of Critically Ill Patients with Cancer. AB - BACKGROUND: Patients with cancer represent an important proportion of intensive care unit (ICU) admissions. Oncologists and intensivists have distinct knowledge backgrounds, and conflicts about the appropriate management of these patients may emerge. METHODS: We surveyed oncologists and intensivists at 2 academic cancer centers regarding their management of 2 hypothetical patients with different cancer types (metastatic pancreatic cancer and metastatic breast cancer with positive receptors for estrogen, progesterone, and HER-2) who develop septic shock and multiple organ failure. RESULTS: Sixty intensivists and 46 oncologists responded to the survey. Oncologists and intensivists similarly favored withdrawal of life support measures for the patient with pancreatic cancer (33/46 [72%] vs 48/60 [80%], P = .45). On the other hand, intensivists favored more withdrawal of life support measures for the patient with breast cancer compared to oncologists (32/59 [54%] vs 9/44 [21%], P < .001). In the multinomial logistic regression, the oncology specialists were more likely to advocate for a full-code status for the patient with breast cancer (OR = 5.931; CI 95%, 1.762-19.956; P = .004). CONCLUSIONS: Oncologists and intensivists share different views regarding life support measures in critically ill patients with cancer. Oncologists tend to focus on the cancer characteristics, whereas intensivists focus on multiple organ failure when weighing in on the same decisions. Regular meetings between oncologists and intensivists may reduce possible conflicts regarding the critical care of patients with cancer. PMID- 28675983 TI - Fluid supplementation in management of neonatal hyperbilirubinemia: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of oral or intravenous fluid supplementation in accelerating the decline of serum bilirubin with intensive phototherapy among healthy term and late preterm neonates with hyperbilirubinemia. STUDY DESIGN: This open-label randomized controlled trial randomized neonates with severe hyperbilirubinemia (serum total bilirubin >=18 mg/dL or within 2 mg/dL of threshold for exchange transfusion) to receive 50 mL/kg of intravenous fluid over 8 h (IVF group, n = 51), 50 mL of oral rehydration solution over 8 h (oral rehydration solution (ORS) group, n = 50) or only standard therapy (control group, n = 49). Intensive phototherapy was administered in all the three study groups. RESULT: Over 8 h of intervention, serum bilirubin declined by 15.5% (95% CI: 11.7-19.4%) in IVF group, by 9.1% (95% CI: 7.3-10.9%) in ORS group and by 8.0% (95% CI: 6.2-9.7%) in control group (p < .001). Percent decline in serum bilirubin serum total bilirubin (STB) was significantly greater in IVF group as compared to ORS (mean difference: -6.4% 95% CI: -1.9 to -11.0) and control (mean difference: -7.6% 95% CI: -3.0 to -12.1) groups. Duration of phototherapy and proportion of neonates needing exchange transfusion were comparable in the three study groups. CONCLUSIONS: Intravenous fluid supplementation may result in a faster decline of STB in first few hours of treatment. However, with the use of intensive phototherapy, there was no effect on overall duration of phototherapy or need of exchange transfusion. CLINICAL TRIAL REGISTRATION: Clinical trial registry of India: REF/2015/09/009775. PMID- 28675984 TI - VitD3-loaded solid lipid nanoparticles: stability, cytotoxicity and cytokine levels. AB - Vitamin D3 (VitD3) has several beneficial effects on many metabolic pathways such as immunity system, bone development. The aim of the study, encapsulation of VitD3 with solid lipids, determine encapsulation efficiency and biocompatibility of nanoparticles. Therefore, VitD3-loaded solid lipid nanoparticles (SLNPs) were developed by optimising ratios of VitD3, stearic acid, beeswax and sodium dodecyl sulphate (SDS). Thermal stability, degradation profile, crystallinity rate, encapsulation efficiency and release profile of SLNPs were determined. Cytotoxicity of SLNPs on HaCaT, L929 and HUVEC cells were investigated. Negatively charged and VitD3-loaded nanoparticles with diameters between 30 and 60 nm were obtained. SLNPs containing up to 5.1 mg VitD3 per 10 mg powder samples were obtained. Cell proliferations were stimulated after exposure with VitD3 loaded SLNPs. Besides, inflammatory response after exposure to VitD3-loaded SLNPs was evaluated via determining IL10 and TNF-alpha levels on THP-1 cells. According to the results, no inflammatory response was observed. PMID- 28675985 TI - Hydrogen alleviates hyperoxic acute lung injury related endoplasmic reticulum stress in rats through upregulation of SIRT1. AB - Hyperoxic acute lung injury (HALI) is a major clinical problem for patients undergoing supplemental oxygen therapy. Currently in clinical settings there exist no effective means of prevention or treatment methods. Our previous study found that: hydrogen could reduce HALI, as well as oxidative stress. This research will further explore the mechanism underlying the protective effect of hydrogen on oxygen toxicity. Rats were randomly assigned into three experimental groups and were exposed in a oxygen chamber for 60 continuous hours: 100% balanced air (control); 100% oxygen (HALI); 100% oxygen with hydrogen treatment (HALI + HRS). We examined lung function by wet to dry ratio of lung, lung pleural effusion and cell apoptosis. We also detected endoplasmic reticulum stress (ERS) by examining the expression of CHOP, GRP78 and XBP1. We further investigated the role of Sirtuin 1 (SIRT1) in HALI, which contributes to cellular regulation including ERS, by examining its expression after hydrogen treatment with SIRT1 inhibitor. Hydrogen could significantly reduce HALI by reducing lung edema and apoptosis, inhibiting the elevating of ERS and increased SIRT1 expression. By inhibition of SIRT1 expression, the effect of hydrogen on prevention of HALI is significantly weakened, the inhibition of the ERS was also reversed. Our findings indicate that hydrogen could reduce HALI related ERS and the mechanism of hydrogen may be associated with upregulation of SIRT1, this study reveals the molecular mechanisms underlying the protective effect of hydrogen, which provides a new theoretical basis for clinical application of hydrogen. PMID- 28675987 TI - Material Properties of Human Ocular Tissue at 7-um Resolution. AB - Quantitative assessment of the material properties of ocular tissues can provide valuable information for investigating several ophthalmic diseases. Quantitative acoustic microscopy (QAM) offers a means of obtaining such information, but few QAM investigations have been conducted on human ocular tissue. We imaged the optic nerve (ON) and iridocorneal angle in 12-um deparaffinized sections of the human eye using a custom-built acoustic microscope with a 250-MHz transducer (7 um lateral resolution). The two-dimensional QAM maps of ultrasound attenuation (alpha), speed of sound ( c), acoustic impedance ( Z), bulk modulus ( K), and mass density (rho) were generated. Scanned samples were then stained and imaged by light microscopy for comparison with QAM maps. The spatial resolution and contrast of scanning acoustic microscopy (SAM) maps were sufficient to resolve anatomic layers of the retina (Re); anatomic features in SAM maps corresponded to those seen by light microscopy. Significant variations of the acoustic parameters were found. For example, the sclera was 220 MPa stiffer than Re, choroid, and ON tissue. To the authors' knowledge, this is the first systematic study to assess c, Z, K, rho, and alpha of human ocular tissue at the high ultrasound frequencies used in this study. PMID- 28675986 TI - Clinical determinants of clopidogrel responsiveness in a heterogeneous cohort of Puerto Rican Hispanics. AB - BACKGROUND: Clopidogrel is by far the most prescribed platelet adenosine diphosphate (ADP) antagonist in Puerto Rico despite the advent of newer agents (prasugrel and ticagrelor). Given the paucity of data on clopidogrel responsiveness in Hispanics, we sought to determine the association between clinical characteristics and platelet reactivity in Puerto Rican patients on clopidogrel therapy. STUDY POPULATION: A total of 100 Puerto Rican patients on clopidogrel therapy were enrolled and allocated into two groups: Group I, without high on-treatment platelet reactivity (HTPR); and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow(r) P2Y12 assay. RESULTS: The cohort was comprised of Hispanic patients with coronary artery disease (57%), peripheral artery disease (32%), carotid artery stenosis (7%), cerebral artery aneurysm (2%), and stroke (2%). Mean platelet reactivity was 200 +/- 61 P2Y12 reaction units (PRUs) (range: 8-324), and 35% of patients had HTPR (PRUs ? 230). Multivariable logistic regression analysis determined that diabetes mellitus (DM) [odds ratio (OR) = 3.27; 95% confidence interval (CI): 1.20-8.96], use of proton pump inhibitors (PPIs) (OR = 3.60; 95% CI: 1.09-11.82), and calcium channel blockers (CCBs) (OR = 3.10; 95% CI: 1.09-8.83) were independent predictors of HTPR ( p < 0.05) after adjusting for other clinical variables. CONCLUSIONS: In a sample of 100 Puerto Rican Hispanic patients on clopidogrel, 35% had HTPR. Furthermore, DM, PPIs and CCBs predicted HTPR. Clinical outcome data are needed to identify appropriate PRU thresholds for risk prediction in the Puerto Rican population. PMID- 28675988 TI - Sources for isolation of extracellular polymeric substances (EPSs) producing bacterial strains which are capable of using wastewater sludge as solo substrate. AB - Isolation of extracellular polymeric substances (EPSs) producing bacterial strains capable of using sludge as low-cost growth substrate was carried out in this study. A total of 110 EPS-producing strains were isolated from different sources, which include sludge of beer and winery wastewater treatment plant (WWTP); young, 2-month-old and 10-year-old leachate. Thirty-seven isolated strains showed good growth in sludge medium with cell count varying from 106 to 1010 most probable number (MPN)/mL and total EPS concentration from 2737 to 6639 mg/L. Twenty-one strains produced EPS with high flocculation activity (FAmax varied from 72.0% to 80.2%). The highest FAmax (80.2%) was observed with EPS produced by strain BES 19, which was isolated from sludge of beer WWTP. Sludge of beer WWTP, young leachate and 10-year-old leachate were good sources for isolation of EPS-producing bacteria. PMID- 28675989 TI - SCI Facts and Figures. PMID- 28675990 TI - Evolving Together: JSCM and Life after Spinal Cord Injury. PMID- 28675991 TI - Small Molecule Inhibitors of Hepatitis B Virus Nucleocapsid Assembly: A New Approach to Treat Chronic HBV Infection. AB - Hepatitis B virus (HBV) infection is still a major health problem worldwide. The current available antiviral drugs for the treatment of chronic HBV infection do not achieve satisfactory results. Thus, it is desirable to develop novel anti-HBV drugs based on the recent advances of basic research on molecular biology of HBV. HBV nucleocapsid assembly is now considered as a potential target of anti-HBV therapy. Structural and functional analysis provided essential insight of molecular interaction of the components of HBV nucleocapsid. Prototypes of small molecule modulators of HBV nucleocapsid assembly were developed and partly tested in clinical phase I. In the present review, the recent advances in HBV molecular biology and approach to develop inhibitors for anti-HBV treatment based on the disruption of viral nucleocapsids by either prevention of assembly or induction of misassembly will be summarized. We will discuss the future concepts of anti HBV treatment based on such new approaches. PMID- 28675992 TI - A Microbolometer System for Radiation Detection in the THz Frequency Range with a Resonating Cavity Fabricated in the CMOS Technology. AB - BACKGROUND: The THz sensors using microbolometers as a sensing element are reported as one of the most sensitive room-temperature THz detectors suitable for THz imaging and spectroscopic applications. Microbolometer detectors are usually fabricated using different types of the MEMS technology. The patent for the detection system presented in this paper describes a method for microbolometer fabrication using a standard CMOS technology with advanced micromachining techniques. The measured sensitivity of the sensors fabricated by the patented method is 1000 V/W at an optimal frequency and is determined by the performance of a double-dipole antenna and quarter-wavelength resonant cavity. METHOD: The paper presents a patented method for fabrication of a microbolometer system for radiation detection in the THz frequency range (16). The method is divided into several stages regarding the current silicon micromachining process. Main stages are fabrication of supporting structures for micro bridge, creation of micro cavities and fabrication of Aluminum antenna and Titanium microbolometer. Additional method for encapsulation in the vacuum is described which additionally improves the performance of bolometer. The CMOS technology is utilized for fabrication as it is cost effective and provides the possibility of larger sensor systems integration with included amplification. At other wavelengths (e.g. IR region) thermistors are usually also the receivers with the sensor resistance change provoked by self-heating. In the THz region the energy is received by an antenna coupled to a thermistor. Depending on the specific application requirement, two types of the antenna were designed and used; a narrow-band dipole antenna and a wideband log-periodic antenna. RESULTS: With method described in the paper, the microbolometer detector reaches sensitivities up to 500 V/W and noise equivalent power (NEP) down to 10 pW/?Hz. Additional encapsulation in the vacuum improves its performance at least by a factor of 2, therefore the sensitivity reaches approximately 1000 V/W and NEP down to 5 pW/?Hz. The thermal response time of bolometer is 0.5 us. The thermistor biasing current drops with its resistance (defined by microbolometer active area), but the sensitivity rises. Typical value of biasing current is 300 uA at 680 Omega of resistance, where the sensitivity reaches highest level. Air pressure decrease highly influences the sensitivity due to lower thermal dissipation to surrounding air. The sensitivity is therefore doubled when packaged in the high vacuum (0.1Pa). CONCLUSION: The main advantage of the presented approach is that the detection devices can be fabricated by a standard silicon micromachining process. Their overall dimension is defined by the receiving antenna and they do not need any additional optic source for the operation. They are robust and appropriate for mass production and can be easily embedded or merged with other vision system in use. The developed microbolometer is highly sensitive, its noise is low and it operates at a room temperature with no additional cooling system at a normal atmospheric pressure. The output of the THz detector connected to a discrete low noise amplifier increases the total sensitivity up to 106 V/W with no impact on the noise equivalent power of 5 pW/?HZ. PMID- 28675993 TI - Deficient Phagocytosis Among HIV-1 Infected Adults Over Time Even in HAART Setting. AB - BACKGROUND: Phagocytosis is regarded to be impaired in HIV-1 infected adults, leading to high frequency and severity of several infections in this population. Data is contradictory with regards to individual facets in HIV infection. OBJECTIVE: Aim of this study was to assess the phagocytic activity during the natural course of HIV infection. METHOD: It is a longitudinal study assessing natural course and impairment of neutrophil and monocyte phagocytosis in both naive and HAART treated patients. RESULTS: A lower neutrophil phagocytic activity was recorded in naive patients compared to treated patients. Interestingly, a downward trend of neutrophil phagocytic activity was recorded in both groups, irrespectively of HAART intake, within 48 weeks of observation. CONCLUSION: Defects of innate immunity appear to be present in HIV infected patients regarding phagocytic activity of monocytes and of neutrophils which seems to decline over time. These deficiencies are influenced by the levels of CD4 cell counts and viral load. PMID- 28675994 TI - Effect of Treatment with Caspofungin on the Diagnosis of Fungal Infections by Gamma Scintigraphy. AB - : The aim of this work was to assess the influence of treatment with U Caspofungin, on the quality of diagnostic scintigraphic images of induced lesions in nude mice undergoing both bacterial and fungal infections and to determine the level of specificity of 99mTc-tricarbonyl-Caspofungin to discriminate between fungal or bacterial infections. In vitro studies on the behaviour of the 99mTc tricarbonyl-Caspofungin complex binding percentage at different yeast concentrations of Candida albicans or Staphyolococcus aureus were determined. The incubation was performed with and without U-Caspofungin. In vivo evaluation was performed of 6 groups of athymic mice: sham, inflammation (LPS), fungal infection with Candida albicans (CA) and bacterial infection with Staphylocuccus aureus (SA). In vitro studies showed that the uptake of the complex by both yeasts and bacteria, depends on the concentration of colony forming units (cfu), and that this uptake is favoured by the presence of UCaspofungin that increases the membrane permeability to the 99mTc-tricarbonyl-Caspofungin complex. In vivo evaluation showed low uptake in sterile inflammation model and moderate to high uptake in infections models both treated or not with U-Caspofungin. The results of biodistributions were compatible with scintigraphic images. CONCLUSION: The uptake of the complex depends on the load of microorganisms, but it presents high sensibility, even at low concentrations of the infecting agent. The treatment with U-Caspofungin has no influence on the quality of the scintigraphic images used for diagnosis and localization of infection foci. PMID- 28675995 TI - WIthdrawn: Ebola Epidemics Control, Origin and Therapeutics. AB - Withdrawn by the publisher. PMID- 28675996 TI - Ongoing Electroencephalographic Activity Associated with Cortical Arousal in Transgenic PDAPP Mice (hAPP V717F). AB - BACKGROUND: It has been shown that theta (6-10 Hz) and delta (1-6 Hz) ongoing electroencephalographic (EEG) rhythms revealed variations in the cortical arousal in C57 Wild Type (WT) mice during cage exploration (active condition) compared to awake quiet behavior (passive condition; IMI PharmaCog project, www.pharmacog.eu). OBJECTIVE: The objective was to test if these EEG rhythms might be abnormal in old PDAPP mice modeling Alzheimer's disease (AD) with a hAPP Indiana V717F mutation (They show abnormal neural transmission, cognitive deficits, and brain accumulation of Abeta1-42). METHODS: Ongoing EEG rhythms were recorded by a frontoparietal bipolar channel in 15 PDAPP and 23 WT C57 male mice (mean age of 22.8 months +/-0.4 and 0.3 standard error, respectively). EEG absolute power (density) was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during passive and active states in the wakefulness. RESULTS: Compared with the WT group, the PDAPP group showed higher frequency of the IDF during the passive condition and lower frequency of the ITF during the active state. Furthermore, the WT but not PDAPP group showed significant changes in the frontoparietal EEG power (IDF, ITF) during active over passive state. CONCLUSION: PDAPP mice were characterized by less changes in the brain arousal during an active state as revealed by frontoparietal EEG rhythms. Future studies will have to cross-validate the present results on large animal groups, clarify the neurophysiological underpinning of the effect, and test if the disease modifying drugs against AD amyloidosis normalize those candiate EEG biomarkers in PDAPP mice. PMID- 28675997 TI - Cold-induced Anaphylaxis: The Case of a 9-year-old Child and Review of the Literature. AB - BACKGROUND AND OBJECTIVE: The present review investigated cold-induced anaphylaxis, a potentially life-threatening condition that occurs after exposure to cold stimuli and is characterized by respiratory distress and/or hypotension. Anaphylaxis is rarely associated to cold-induced urticarial (CU), a particular form of physical urticaria that is difficult to diagnose and manage. The incidence of cold-induced urticaria has been estimated at about 0.05%, higher in colder regions and in women; its pathological mechanisms are still unknown. METHODS: The literature was searched via the Medline/PubMed database (http://www.ncbi.nlm.gov/ pubmed). RESULTS AND CONCLUSION: Patients affected by CU should be well-informed about the risk of anaphylaxis and preventive measures. The prevention of CU is based on the avoidance of cold exposure. The most effective treatment is antihistamines symptomatic therapy. Anyway, patients should also carry with them an emergency kit containing corticosteroids, antihistamines and an epinephrine injector. Future studies are necessary to determine the CU pathophysiology so to establish a more targeted management of this important and potentially life-threatening condition. PMID- 28675998 TI - Cardiovascular and Pulmonary Manifestations of Systemic Lupus Erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by various clinical manifestations and immunologic abnormalities. Cardiovascular and respiratory system involvement are increasingly recognized as critical for patients' prognosis. In this review, current knowledge concerning diagnosis, pathogenesis and treatment of the cardiac and pulmonary lupus manifestations are discussed. METHOD: Review of the literature. RESULTS: Although pericarditis is the most frequent heart manifestation in the context of lupus, valvular disease and less often myocarditis may be detected. In the latter, treatment should be prompt and aggressive to prevent chronic sequelae like congestive heart failure. Later on disease course, accelerated atherosclerosis is considered as one of the most important co-morbidities of SLE with cardiovascular events being one of the leading causes of death at relatively young ages. Stratification of the patients at risk and stringent management of the traditional risk factors are warranted. Respiratory system involvement affects all anatomic structures of the lungs, pleura and pulmonary vasculature while its severity ranges from asymptomatic pleural disease to acute respiratory failure. The most common features include pleuritis, interstitial lung disease and pulmonary embolism on the background of antiphospholipid syndrome. Less usual complications include lupus pneumonitis, diffuse alveolar hemorrhage, shrinking lung syndrome and pulmonary arterial hypertension. CONCLUSION: There are no specific guidelines for the management of these manifestations and therapeutic approach remains empiric. PMID- 28675999 TI - Subduing the green-eyed monster: bridging the psychopharmacological and psychosocial treatment perspective in understanding pathological jealousy. AB - Human being is not spared from a broad-ranged emotional state, including being jealous. Jealousy has both affective-cognitive and behavioural-evaluative dimension where the person perceives, or experiences a real threat on a valued relationship. As this complex emotion becomes irrational and not amenable to reason, it later transforms into a dangerously 'green-eyed monster'. This perilous situation which is viewed as pathological jealousy is a form of delusion, which is maintained by a fixed and false reasoning in an originally entrusted intimate relationship. Pathological jealousy is equally prevailing among both gender, and with a greater ubiquitous among the geriatric population. The role of dopamine hyperactivity in the fronto-parietal-temporal region was implicated, with the anatomical mapping of the ventromedial prefrontal cortex (vmPFC), cingulate gyrus (CG), and amygdala involvement in the context of the disease's neurobiology. The etiology of pathological jealousy includes major psychiatric disorders, i.e. delusional disorder, schizophrenia, mood disorder, organic brain syndrome, and among others, the drug-induced psychosis. The role of relationship issues and psychodynamic perspective, i.e. psychological conflicts with dependence on a romantic partner, and low self-esteem are involved. Pathological jealousy inherits high-risk forensic psychiatry entanglement, which may warrant intensive intervention, including hospital admission and antipsychotic treatment. Treatment options include an early recognition, managing underlying neuropsychiatric disorders, psycho education, cognitive psychotherapy, and choosing an effective psychopharmacological agent. The management strategy may also resort to a geographical intervention, i.e. separation between both persons to complement the biological treatment. PMID- 28676000 TI - Urinary Bone Turnover Markers as Target Indicators for Monitoring Bisphosphonate Drug Treatment in the Management of Osteoporosis. AB - BACKGROUND: Osteoporosis is a debilitating disease characterized by bone micro architecture degradation contributing to fragility fractures. Currently, determining bone mineral density (BMD) via dual-energy X-ray absorptiometry (DXA) is the most reliable form of diagnosing osteoporosis and managing pharmacological treatment regimens. However, changes in BMD occur slowly (i.e., several months) and DXA does not reflect the metabolic rate of bone turnover. Alternatively, biochemical bone turnover markers are metabolic indicators released into serum and/or urine, and their quantity reflects the metabolic activity of bone. bone turnover markers show a rapid response following antiresorptive drug administration, and enzyme-linked immunosorbent assays (ELISA) have been established and used in clinical trials to help assess and predict fracture risk independent of BMD. OBJECTIVE: This review highlights various established bone turnover markers that have found utility in the clinic as reliable and standardized indicators of bone turnover, with attention to those used to assess efficacy of bisphosphonate drug therapy - particularly in monitoring medication adherence in patients with postmenopausal osteoporosis. RESULTS: We posit that the use of urinary bone turnover markers values determined by immunoassay or ELISA at routine clinic visits might serve as valuable feedback to healthcare professionals and patients to help monitor the efficacy and adherence of bisphosphonate therapy and disease progression. CONCLUSION: Our belief is that when assessed in combination with an algorithm of independent risk factors, measuring urinary bone turnover markers using a point of care kit may find utility in the osteoporosis clinic as an accessible, non-invasive and cost effective alternative for the routine assessment of efficacy of bisphosphonate therapies. PMID- 28676001 TI - Antitumor Activity of Polysaccharides: An Overview. AB - BACKGROUND: Polysaccharides are widely found in animals, plants and micro- organisms, and are closely related to various physiological functions. It is one of the four basic substances that constitute life activities. Polysaccharide has antitumor, antivirus, antioxidant, immune regulation and other biological activities. OBJECTIVE: Because the polysaccharide has significant antitumor effect and small side-effects, it has become the focus of the current antitumor drug research. RESULTS: Herein, the polysaccharide species with antitumor effect were summarized in recent years, and the antitumor activity mechanisms of polysaccharides were analyzed and discussed. CONCLUSION: Many polysaccharides have good antitumor activity, and they have broad application prospects. PMID- 28676002 TI - Recent Advances in Polymer-based Wound Dressings for the Treatment of Diabetic Foot Ulcer: An Overview of State-of-the-art. AB - BACKGROUND: Diabetic foot ulcers (DFUs) are the chronic, non-healing complications of diabetic mellitus which compels a significant burden to the patients and the healthcare system. Peripheral vascular disease, diabetic neuropathy, and abnormal cellular and cytokine/chemokine activity are among the prime players which exacerbate the severity and prevent wound repair. Unlike acute wounds, DFUs impose a substantial challenge to the conventional wound dressings and demand the development of novel and advanced wound healing modalities. In general, an ideal wound dressing should provide a moist wound environment, offer protection from secondary infections, eliminate wound exudate and stimulate tissue regeneration. OBJECTIVE: To date, numerous conventional wound dressings are employed for the management of DFUs but there is a lack of absolute and versatile choice. The current review was therefore aimed to summarize and critically discuss the available evidences related to pharmaceutical and therapeutic viability of polymer-based dressings for the treatment of DFUs. RESULTS: A versatile range of naturally-originated polymers including chitosan (CS), hyaluronic acid (HA), cellulose, alginate, dextran, collagen, gelatin, elastin, fibrin and silk fibroin have been utilized for the treatment of DFUs. These polymers have been used in the form of hydrogels, films, hydrocolloids, foams, membranes, scaffolds, microparticles, and nanoparticles. Moreover, the wound healing viability and clinical applicability of various mutually modified, semi-synthetic or synthetic polymers have also been critically discussed. CONCLUSION: In summary, this review enlightens the most recent developments in polymer-based wound dressings with special emphasis on advanced polymeric biomaterials, innovative therapeutic strategies and delivery approaches for the treatment of DFUs. PMID- 28676003 TI - Synthesis, Structural Characterization and Antinociceptive Activities of New Arylated Quinolines via Suzuki-Miyaura Cross Coupling Reaction. AB - BACKGROUND: The quinoline ring system is one of the most commonly encountered heterocycles in medicinal chemistry, due to the pharmaceutical and medicinal uses of derivatives containing this ring. These quinoline-based compounds have remarkable biological activity, as they are employed as antimalarial, antibacterial, antifungal, and antitumor agents. The quinoline nucleus can be synthesized by various traditional methods such as the Skraup reaction, Friedlaender synthesis, Combes quinoline synthesis, Larock quinoline synthesis, among others. METHODS: The aim of the present work is to synthesize a number of new arylated quninolines having significant antinoceciptive effect through the Suzuki-Miyaura cross coupling reaction using 3- bromoquinoline as a starting material. RESULTS: A number of new quinoline derivatives have been synthesized. Structures of the newly synthesized compounds were confirmed by means of IR, NMR, and mass spectrometry, and by elemental analysis. In addition, the molecular structures of two representative derivatives were determined with the aid of X ray crystallography. Additionally, the antinociceptive activity of the prepared compounds was evaluated in vivo; results revealed that most of the tested compounds exhibited a dosedependent antinociceptive effect. CONCLUSION: Prepared compounds were found to exhibit significant antinociceptive activities and could be used as potential analgesic agents. Further work, however, may be required to establish the safety and efficacy of these compounds. PMID- 28676004 TI - Evaluation of 1,3-benzoxathiol-2-one Derivatives as Potential Antifungal Agents. AB - BACKGROUND: Over the last few years, fungal infections have emerged as a worrisome global public health problem. Candidiasis is a disease caused by Candida species and has been a problem worldwide mainly for immunosuppressed patients. Lately, the resistant strains and side effects have been reported as important issues for treating Candidiasis, which have to be solved by identifying new drugs. OBJECTIVE: The goal of this work was to synthesize a series of 1,3 benzoxathiol-2-one derivatives, XYbenzo[ d][1,3]oxathiol-2-ones, and evaluate their antifungal activity against five Candida species. METHODS: In vitro antifungal screening test and minimum inhibitory concentration determination were performed according to CLSI protocols using ketoconazole as the reference drug. The cytotoxicity of the most active compounds was evaluated by hemolysis and MTT (Vero cells) assays. RESULTS: Compounds 2 (XY = 6-hydroxy-5-nitro, MIC = 4-32 ug/mL) and 7 (XY = 6-acetoxy-5-nitro, MIC =16-64 ug/mL) showed good results when compared with current antifungals in CLSI values (MIC = 0.04-250 ug/mL). These compounds exhibited a safer cytotoxicity as well as a lower hemolytic profile than ketoconazole. CONCLUSION: Overall, the in vitro results pointed to the potential of compounds 2 and 7 as new antifungal prototypes to be further explored. PMID- 28676005 TI - Opioids in the Frame of New Psychoactive Substances Network: A Complex Pharmacological and Toxicological Issue. AB - BACKGROUND: New psychoactive substances (NPS), often referred to as "legal highs" or "designer drugs", are derivatives and analogues of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. OBJECTIVE: This systematic review aims to gather the state of the art regarding chemical, molecular pharmacology and toxicological information of opioid class of NPS. METHODS: Chemical, pharmacological, toxicological and clinical effects of opioid class of NPS were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. RESULTS: Within this class, fentanyl analogues are among the most frequently abused and pose several clinical concerns and therefore will be thoroughly discussed. Other opioid sub-categories of NPS frequently misused include AH-7921, MT-45, U-47700, U-50488, desomorphine, mitragynine, tramadol, tapentadol, salvinorin A and its analogue herkinorin. CONCLUSION: Due to inefficient monitoring techniques, as well as limited knowledge regarding the acute and long-term effects of opioids NPS, further clinical and forensic toxicological studies are required. PMID- 28676006 TI - Carnosine Treatment Diminished Oxidative Stress and Glycation Products in Serum and Tissues of D-Galactose-Treated Rats. AB - BACKGROUND: Chronic administration of D-galactose (GAL) induces changes that resemble natural aging in rodents. Oxidative stress and Advanced Glycation End products (AGE) formation play a role in GAL-induced aging. Carnosine (CAR; beta alanyl-L-histidine) has antioxidant and anti-glycating actions and may be a potential therapeutic agent in aging due to these properties. The effect of CAR supplementation on AGE levels and oxidative stress parameters was investigated in serum, liver and brain tissues in GAL-treated rats. METHODS: GAL (300 mg/kg; s.c.; 5 days per week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days per week) was applied to male rats for two months. AGE, Advanced Oxidized Protein Products (AOPP), Protein Carbonyl (PC) and Malondialdehyde (MDA) levels together with Reactive Oxygen Species (ROS) formation and Ferric Reducing Antioxidant Power (FRAP) values were determined. RESULTS: GAL treatment elevated AGE levels, ROS formation and protein and lipid oxidation products in serum and examined tissues. CAR treatment was observed to decrease significantly glycooxidative stress in serum, liver and brain tissues of GAL-treated rats. CONCLUSION: Our results indicate that CAR may be useful for decreasing oxidative stress and glycation products in GAL-induced aging model in rats. PMID- 28676007 TI - The Role of N-Acetylcysteine in Platelet Aggregation and Reperfusion Injury in Recent Years. AB - BACKGROUND: N-acetylcysteine (NAC) is an amino acid that contains a cysteine group and is currently used widely in various fields of medical research especially in cardiology. In this review, potential benefits of NAC in the aggregation of platelet and reperfusion injury are evaluated. METHODS: The available evidence was collected by searching Scopus, Pub-Med, Medline, Cochrane central register of controlled trials, and Cochrane database systematic reviews. Our searching was performed without time limitation and only English language articles were included in this review. Key words used as search terms included "N acetylcysteine", "platelet aggregation", "reperfusion injury". RESULTS: Over the past decade, several investigations were carried out to ascertain reperfusion injury and antiplatelet properties of NAC, and in this article the results of investigations in both models (human and animal) were addressed in detail. The results revealed that NAC has an important antiplatelet property in animal models while this effect is not very significant in human models and needs more investigations. However, its reperfusion injury in both models is worth noticing. CONCLUSION: Due to the limited data about effectiveness of NAC in both human and animal as antiplatelet agent, more investigation is needed to evaluate NAC efficacy in platelet aggregation and reperfusion injury especially in human studies in the future. PMID- 28676008 TI - Repurposing Pharmaceuticals as Neuroprotective Agents for Cerebral Malaria. AB - BACKGROUND: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection which may result in death or developmental disability. The pathologic processes leading to CM are not fully elucidated; however, widely accepted mechanisms include parasite sequestration, release of infected red blood cell contents, activation of endothelial cells, increased inflammatory responses, and ultimately dysfunction of the neurovascular unit (NVU). The endothelium plays a central role in these processes as the site of parasitized erythrocyte sequestration and as the regulator of fluid extravasation into the central nervous system. Modulating endothelial barrier function at the NVU may provide new therapeutic approaches to improve outcomes in CM. METHODS: Here we provide a narrative review of the literature of peer-reviewed research relating to adjunctive therapies for CM. We discuss regulatory pathways of the NVU, with a focus on the potential for pharmacologic modulation of the NVU to improve CM outcomes. RESULTS: Recently licensed pharmaceuticals, developed as therapies for cancer or neurologic disease, could be re-purposed for use as host-directed therapies in CM to target pathways involved in endothelial stability and activation. CONCLUSION: The findings of this review highlight recently licensed pharmaceuticals that may be developed as future adjunctive therapies for CM. PMID- 28676009 TI - Aging Eye Microbiota in Dry Eye Syndrome in Patients Treated with Enterococcus faecium and Saccharomyces boulardii. AB - BACKGROUND: Aging and oxidative stress seem to play a key role in the onset and progression of ocular surface diseases. Dry Eye Syndrome (DES) is a multifactorial disease of the tears and ocular surface in which symptoms may interfere with the ability to work and carry out daily functions. METHODS: This clinical trial was a pilot study to evaluate the effects of supplementation with mixture (Saccharomyces boulardii MUCL 53837 and Enterococcus faecium LMG S-28935) on the tear film. Following the run-in period subjects were randomized in two groups: group A (n.30 subjects) and group B (n.30 subjects). Group A (control) treated only with substitute tear and group B treated with substitute tear + mixture (probiotic). RESULTS: The data obtained in the two study groups A and B were, respectively the following: Schirmer I: 9.2+/-0.2 vs. 12.8+/-0.4 (p< 0.001); Schirmer II: 3.6+/-0.1 vs. 4.6+/-0.2 (p<0.001); BUT 3.8+/-0.3 vs. 6.2+/ 0.2 (p<0.001). Culture test showed initial bacterial growth in group "A" (placebo) 27 out of 60 samples tested, corresponding to 45.0% and "B" after treatment (probiotic) was found positive culture whit growth of bacteria in 18 tests equal to 30.0%. The total numbers of isolations of aerobic and anaerobic bacteria found group A and B after treatment. A reduction of 23 to 16 strains of aerobic and anaerobic isolates from 13 to 7 has been found. CONCLUSION: The administration of probiotics strains was effective in reducing DES. In light of these results, we have identified our probiotic (Saccharomyces boulardii MUCL 53837 and Enterococcus faecium LMG S-28935) activity integration with the action of tear substitutes, along with standardization of clinical parameters of the tear film and microbiological activity in restoring of the microbiota ocular surface subject with DES. PMID- 28676010 TI - KCa3.1 Channel Modulators as Potential Therapeutic Compounds for Glioblastoma. AB - BACKGROUND: The intermediate-conductance Ca2+-activated K+ channel KCa3.1 is widely expressed in cells of the immune system such as T- and B-lymphocytes, mast cells, macrophages and microglia, but also found in dedifferentiated vascular smooth muscle cells, fibroblasts and many cancer cells including pancreatic, prostate, leukemia and glioblastoma. In all these cell types KCa3.1 plays an important role in cellular activation, migration and proliferation by regulating membrane potential and Ca2+ signaling. METHODS AND RESULTS: KCa3.1 therefore constitutes an attractive therapeutic target for diseases involving excessive proliferation or activation of one more of these cell types and researchers both in academia and in the pharmaceutical industry have developed several potent and selective small molecule inhibitors of KCa3.1. This article will briefly review the available compounds (TRAM-34, senicapoc, NS6180), their binding sites and mechanisms of action, and then discuss the potential usefulness of these compounds for the treatment of brain tumors based on their brain penetration and their efficacy in reducing microglia activation in animal models of ischemic stroke and Alzheimer's disease. CONCLUSION: Senicapoc, which has previously been in Phase III clinical trials, would be available for repurposing, and could be used to quickly translate findings made with other KCa3.1 blocking tool compounds into clinical trials. PMID- 28676012 TI - Statins and the Brain: More than Lipid Lowering Agents? AB - BACKGROUND: Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-betahydroxy 3beta methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statinsare able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions. OBJECTIVE: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information. METHODS: Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke. RESULTS: 315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect. CONCLUSION: Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies. PMID- 28676011 TI - Resilience Dysregulation in Major Depressive Disorder: Focus on Glutamatergic Imbalance and Microglial Activation. AB - BACKGROUND: Many studies have been shown an important role of glutamatergic system as well microglial activation in the pathophysiology of major depressive disorder (MDD). In humans most resistant to the development of psychiatric disorders, including MDD, are observed a greater degree of resilience resulting from stress. Less resilience is associated with neuroendocrine and neuroinflammatory markers, as well as with glutamatergic system dysregulation. Thus, this review we highlighted findings from literature identifying the function of glutamatergic system, microglial activation and inflammation in resilience. METHODS: We conducted a review of computerized databases from 1970 to 2017. RESULTS: There is an association between microglial activation and glutamatergic system activation with stress vulnerability and resilience. CONCLUSIONS: Glutamate neurotransmission, including neurotransmitter synthesis, signalling, and glutamate receptor functions and expression all seem to be involved with both stress vulnerability and resilience. Moreover, inflammation and microglial activation mediate individual differences in resilience and the risk of stress-induced MDD. PMID- 28676013 TI - The Challenge of microRNA as a Biomarker of Epilepsy. AB - BACKGROUND: Epilepsy is one of chronic severe neurological disorders possess to recurring seizures. And now anti-epileptic drugs are only effective in less than one third of epilepsy patients, and biomarkers predicting are not available when the specific antiepileptic drugs treated. Advanced studies have showed that miRNA may be a key in the pathogenesis of epilepsy beginning in the early 2000 years. Several target genes and pathways of miRNA which related to the therapeutic methods to epilepsy. METHOD: We searched PubMed from Jan 1,2000 to Jan 1, 2017, using the terms "epilepsy AND microRNA AND biomarker" and "seizure AND microRNA AND biomarker". We selected articles that featured novel miRNAs in vivo epilepsy models and patients. We then selected the most relevant articles based on a subjective appraisal of their quality and mechanistic insight that could be relevant to epilepsy. RESULTS: Decrease the expression of has-miR134 could be a potential non-invasive biomarker to use in diagnosis for the epilepsy patients for using hsa-miR-134 also be identified to distinguish patients with and without epilepsy. miR-181a show significant downregulation in the acute stage, but up regulation in the chronic stage and in the latent stage there is no changing and how about this phenomenon appearance in different stage still should be discussed in the future. Besides that, miR- 146a can down-regulated in the patients using genome-wide for serum in circulating miRNAs.miR- 124, miR-199a, and miR-128 etc. could be a candidate for the biomarker in future. miR-15a-5p and -194-5p down regulated in epilepsy patients, in the future, it may be used as a novel biomarker for improve diagnosis. CONCLUSION: These observations give a chance that new development for diagnosis and treatment of epilepsy patients. Advanced technique and miRNA combination may product more effective roles in epilepsy and other disease. These reports will be available to solve the application of miRNAs as biomarkers and novel therapy approaches for epilepsy. In summary, researcher who focus on miRNAs should be understanding of the causes, treatment, and diagnosis of epilepsy. exploration of any of these effects on the efficacy of these drugs is worthwhile. PMID- 28676014 TI - Citicoline and Retinal Ganglion Cells: Effects on Morphology and Function. AB - BACKGROUND: Retinal ganglion cells (RGCs) are the nervous retinal elements which connect the visual receptors to the brain forming the nervous visual system. Functional and/or morphological involvement of RGCs occurs in several ocular and neurological disorders and therefore these cells are targeted in neuroprotective strategies. Cytidine 5-diphosphocholine or Citicoline is an endogenous compound that acts in the biosynthesis of phospholipids of cell membranes and increases neurotransmitters' levels in the Central Nervous System. Experimental studies suggested the neuromodulator effect and the protective role of Citicoline on RGCs. This review aims to present evidence of the effects of Citicoline in experimental models of RGCs degeneration and in human neurodegenerative disorders involving RGCs. METHODS: All published papers containing experimental or clinical studies about the effects of Citicoline on RGCs morphology and function were reviewed. RESULTS: In rodent retinal cultures and animal models, Citicoline induces antiapoptotic effects, increases the dopamine retinal level, and counteracts retinal nerve fibers layer thinning. Human studies in neurodegenerative visual pathologies such as glaucoma or non-arteritic ischemic neuropathy showed a reduction of the RGCs impairment after Citicoline administration. By reducing the RGCs' dysfunction, a better neural conduction along the post-retinal visual pathways with an improvement of the visual field defects was observed. CONCLUSION: Citicoline, with a solid history of experimental and clinical studies, could be considered a very promising molecule for neuroprotective strategies in those pathologies (i.e. Glaucoma) in which morpho-functional changes of RGCc occurs. PMID- 28676018 TI - Can Serum Uric Acid Lowering Therapy Contribute to the Prevention or Treatment of Nonalcoholic Fatty Liver Disease? AB - Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries with potential progression to nonalcoholic steatohepatitis (NASH) and cirrhosis, is associated with cardiovascular disease (CVD) mortality. Several studies have reported a relationship between uric acid and NAFLD/NASH and it seems that serum uric acid (SUA) is a significant independent factor for the development of NAFLD. Potential mediating mechanisms include insulin resistance, endothelial dysfunction, and activation of inflammasome, especially NLRP3. Moreover, emerging evidence indicates a strong association between elevated SUA, metabolic syndrome (MetS), NAFLD, and CVD. The emphasis of the present review is whether common therapy of elevated SUA levels and NAFLD can improve compliance. There are several drugs with "off target" properties that show some separate benefit on SUA reduction (e.g. losartan) or NAFLD/NASH (pioglitazone); however, there is no randomized controlled trial (RCT) of a single drug with beneficial outcome for both diseases. Allopurinol reduces SUA levels and ameliorates NAFLD/NASH; however, no RCTs have been performed up to now to explore potential survival benefits. Atorvastatin, which has proven safe in NAFLD/NASH, reduces SUA levels, ameliorates NAFLD/NASH, prevents liver fibrosis, and above all substantially reduces CVD morbidity and mortality in comparison with those on statins but without NAFLD/NASH. This drug could be a solution to improve compliance in both diseases, which are prevalent and becoming even more common with the obesity, MetS, and type 2 diabetes mellitus epidemic. PMID- 28676019 TI - Statins: An Under-Appreciated Asset for the Prevention and the Treatment of NAFLD or NASH and the Related Cardiovascular Risk. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease (30% of the general population) and up to 40% of cases advance to the more severe form of the disease: nonalcoholic steatohepatitis (NASH), which is causally related to cirrhosis and cardiovascular disease (CVD). There is no generally accepted effective treatment for NAFLD/NASH. The joint guidelines of the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity (EASO) suggest the "off label" use of pioglitazone in patients without type 2 diabetes mellitus (T2DM) and pioglitazone in subjects with T2DM or vitamin E or their combination for the treatment of NASH; however pioglitazone has considerable limitations: weight gain, bone fractures in women, and heart failure. The aim of this narrative review is to assess the existing evidence supporting statin use for the treatment of NASH and the reduction of the high CVD risk of these patients. Animal data suggest that there is some benefit from statin use in liver histology in models of NASH. In humans, 3 post hoc analyses of randomised controlled trials (n=1,600, n=1,123, n=8,864) suggest that the use of atorvastatin (even in 80 mg/day) has a beneficial effect on NAFLD/NASH, in terms of liver enzyme reduction and ultrasonographic amelioration. Moreover, and most importantly, statin treatment halved CVD morbidity and mortality in statin treated NAFLD/NASH patients compared with statin-treated participants with normal liver structure and function and reduced by 2/3rds CVD events in comparison with NAFLD/NASH patients that were not on a statin (90% of this population is not on statins because of the unjustified fear for liver damage). Three biopsy studies (n=20, n=107 and n=356) showed that statin treatment had a protective effect on steatosis, steatohepatitis and fibrosis. Data suggest that statin treatment in humans substantially improve or cure NAFLD/NASH, but above all substantially reduce CVD morbidity and mortality. Administration of potent statins appears safe and effective in saving lives in NAFLD/NASH patients. PMID- 28676015 TI - Effects of Resveratrol and other Polyphenols on Sirt1: Relevance to Brain Function During Aging. AB - BACKGROUND: Classically the oxidative stress and more recently inflammatory processes have been identified as the major causes of brain aging. Oxidative stress and inflammation affect each other, but there is more information about the effects of oxidative stress on aging than regarding the contribution of inflammation on it. METHODS: In the intense research for methods to delay or mitigate the effects of aging, are interesting polyphenols, natural molecules synthesized by plants (e.g. resveratrol). Their antioxidant and anti-inflammatory properties make them useful molecules in the prevention of aging. RESULTS: The antiaging effects of polyphenols could be due to several related mechanisms, among which are the prevention of oxidative stress, SIRT1 activation and inflammaging modulation, via regulation of some signaling pathways, such as NF kappaB. CONCLUSION: In this review, we describe the positive effects of polyphenols on the prevention of the changes that occur during aging in the brain and their consequences on cognition, emphasizing the possible modulation of inflammaging by polyphenols through a SIRT1-mediated mechanism. PMID- 28676020 TI - Current and Potential Future Pharmacological Approaches for Non- Alcoholic Fatty Liver Disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the general population. The disease ranges from simple steatosis, to non alcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. Several drugs are used in daily clinical practice to manage the disease. However, data on their efficacy in liver histology are not consistent. AIM: We discuss current treatment options for NAFLD and NASH and preliminary results from novel drugs under investigation. RESULTS: Among various drugs assessed for the management of NAFLD and NASH, only pioglitazone and vitamin E have provided consistent benefits on liver histology, and are recommended by the European and American guidelines. Statins were shown to produce clinically meaningful results in patients with NAFLD or NASH. Other drugs such as metformin and polyunsaturated fatty acids that are being used in clinical practice off-label have provided benefits on terms of hepatic biochemical and diabetesrelated markers; data on liver histology with these drugs are scarce and from small studies. Several new approaches to reduce inflammation, steatosis or fibrosis have shown promising results in experimental models of NAFLD or NASH lesions and are being evaluated in humans. CONCLUSION: Pioglitazone and vitamin E are the only drugs providing consistent benefits and are currently recommended for NASH. Various pathogenetic pathways are being targeted to reduce steatosis, inflammation and fibrosis and early data on several novel drugs are very promising. On-going human trials will unveil their true impact. PMID- 28676017 TI - Antipsychotic Drugs: From Receptor-binding Profiles to Metabolic Side Effects. AB - BACKGROUND: Antipsychotic-induced metabolic side effects are major concerns in psychopharmacology and clinical psychiatry. Their pathogenetic mechanisms are still not elucidated. METHODS: Herein, we review the impact of neurotransmitters on metabolic regulation, providing insights into antipsychotic-induced metabolic side effects. RESULTS: Antipsychotic drugs seem to interfere with feeding behaviors and energy balance, processes that control metabolic regulation. Reward and energy balance centers in central nervous system constitute the central level of metabolic regulation. The peripheral level consists of skeletal muscles, the liver, the pancreas, the adipose tissue and neuroendocrine connections. Neurotransmitter receptors have crucial roles in metabolic regulation and they are also targets of antipsychotic drugs. Interaction of antipsychotics with neurotransmitters could have both protective and harmful effects on metabolism. CONCLUSION: Emerging evidence suggests that antipsychotics have different liabilities to induce obesity, diabetes and dyslipidemia. However this diversity cannot be explained merely by drugs'pharmacodynamic profiles, highlighting the need for further research. PMID- 28676021 TI - Medical Management and Risk Reduction of the Cardiovascular Effects of Underwater Diving. AB - Undersea diving is a sport and commercial industry. Knowledge of potential problems began with Caisson disease or "the bends", first identified with compressed air in the construction of tunnels under rivers in the 19th century. Subsequently, there was the commercially used old-fashioned diving helmet attached to a suit, with compressed air pumped down from the surface. Breathhold diving, with no supplementary source of air or other breathing mixture, is also a sport as well as a commercial fishing tool in some parts of the world. There has been an evolution to self-contained underwater breathing apparatus (SCUBA) diving with major involvement as a recreational sport but also of major commercial importance. Knowledge of the physiology and cardiovascular plus other medical problems associated with the various forms of diving have evolved extensively. The major medical catastrophes of SCUBA diving are air embolism and decompression sickness (DCS). Understanding of the essential referral to a hyperbaric recompression chamber for these problems is critical, as well as immediate measures until that recompression is achieved. These include the administration of 100% oxygen and rehydration with intravenous normal saline. Undersea diving continues to expand, especially as a sport, and a basic understanding of the associated preventive and emergency medicine will decrease complications and save lives. PMID- 28676022 TI - Patients with Acute Coronary Syndrome are at High Risk Prior to the Event and Lipid Management is Underachieved Pre- and Post- Hospitalization. AB - BACKGROUND: Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). OBJECTIVE: We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. METHODS: We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. RESULTS: The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p<0.001). The majority (96%) of patients received statins at discharge; however, most of them (60.4%) received low/moderate intensity statins and just 35.9% received the suggested by the Guidelines high-intensity dose of statins. At follow-up, the rate of patients at high-intensity dose of statins remained similar (34.8%); 6% received no statins at all at follow-up. CONCLUSION: According to our study, the majority of ACS patients are already at high risk prior to their admission. Further, LDL-C targets are underachieved prior to the event and high-intensity statins are underutilized in ACS patients at, and post discharge. PMID- 28676023 TI - Vascular Endothelial Growth Factor Inhibitor Therapy and Cardiovascular and Renal Damage in Renal Cell Carcinoma. AB - BACKGROUND: Sunitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF), is approved for first and second line treatment of advanced renal cell carcinoma (RCC). Knowledge on the effects of sunitinib on cardiovascular (CV) risk and renal damage is limited. AIM: To evaluate possible renal and CV damage in patients with RCC treated with sunitinib. MATERIALS AND METHODS: Patients with metastatic RCC treated with sunitinib were enrolled. This population was evaluated before starting treatment (T0) and after 3 months (T1). Laboratory and instrumental parameters, including interventricular septum (IVS) and left ventricular mass index (LVMI) were recorded before and after treatment. RESULTS: Thirty-two patients (13 female, 19 male, mean age 62.7+/-9.9 years) were enrolled. We observed overtime, a significant reduction in estimated glomerular filtration rate (eGFR) (p=0.01), hemoglobin (Hb) (p=0.04) and 25-hydroxyvitamin D (25-OH-VitD) (p=0.002), in association with a significant increase in serum phosphorus (p<0.001), systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (DBP) (p<0.001), IVS (p=0.03) and proteinuria (p<0.001), while we showed no significant differences in glycosuria, phosphaturia, serum uric acid, intact parathormone, and LVMI. CONCLUSION: We observed the development of renal damage and worsening of CV indices in patients treated with sunitinib. We suggest to consider a careful assessment of renal function and CV risk factors, before initiation and during administration of this drug. PMID- 28676024 TI - NAFLD-NASH: An Under-Recognized Epidemic. AB - First described in 1980, nonalcoholic fatty liver disease (NAFLD) has become more common although the exact incidence and prevalence is unknown. While the exact prevalence varies from region to region, the overall trend shows an increased number of patients with NAFLD. Risk factors for the development of NAFLD includes advanced age, male gender, obesity, and having elements of the metabolic syndrome. There is also an association between the presence of NAFLD and coronary atherosclerosis. Persons of Hispanic descent tend to have higher rates of NAFLD when compared with other populations. Genetics, specifically polymorphisms in the gene PNPLA3, may explain the difference among these different groups. As the rates of obesity increases throughout the world, it is anticipated that the rate of NAFLD will continue to increase. This has large scale implications on the rates of cirrhosis, hepatocellular carcinoma, liver transplantation and cardiovascular events that could impact hundreds of millions of people. PMID- 28676025 TI - Nonalcoholic Fatty Liver Disease vs. Nonalcoholic Steatohepatitis: Pathological and Clinical Implications. AB - The implications and prognosis of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are substantially different. The aim of the present review is to describe and compare the pathological and clinical implications of these two conditions. Patients with NASH have a higher risk of progressing to cirrhosis than patients with NAFL but without steatohepatitis, who tend to have a non-progressive disease and only a minority progresses to NASH. Patients with NASH also are at greater risk to develop hepatocellular cancer (HCC) and NASH is the third commonest cause of HCC. In contrast, only few cases of HCC have been reported in patients with isolated NAFL. Given that nonalcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, it is also strongly related to cardiovascular disease (CVD). Again, it appears that patients with NASH have higher cardiovascular risk than patients with NAFL. Finally, all-cause mortality is also higher in patients with NASH than in patients with NAFL; mortality rates in the latter patients do not differ from the general population. In conclusion, NAFL and NASH have different prognosis and therefore it is imperative to develop accurate, noninvasive methods that will identify the presence of steatohepatitis in this population. PMID- 28676026 TI - A Critical Approach of Guideline Therapeutic Recommendations for NAFLD. AB - Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as progressive form of the disease are associated with cardiovascular risk factors including obesity, dyslipidaemia, hyperglycaemia and hypertension. When NAFLD is associated with cardiovascular disease, mortality of NAFLD patients is increased due to cardiovascular disease. Prevalence of NAFLD and NASH is high, but it seems that epidemic of the disease is under-recognized and under appreciated. Linking pathophysiological mechanisms are complex and still not well understood. The main related pathophysiological mechanisms are lipid factors, insulin resistance, inflammation, proinflammatory cytokines, oxidative stress, pro-coagulant status, hyperglycaemia and adipokines. First-line management focuses on lifestyle modifications in both diseases. Several therapeutic interventions, insulin sensitizer agents, lipid lowering drugs, antioxidants, such as vitamin E, have been proposed. Statins appear to be safe, but their use in the treatment of NAFLD and NASH is under-appreciated. Many different agents are being investigated as future drugs for the treatment of this clinical entity. The aim of the review is to examine the extent of the epidemic and the mediating mechanisms, to critically evaluate current guideline recommendations, and to consider current and future medications for this disease. PMID- 28676027 TI - The Co-Existence of NASH and Chronic Kidney Disease Boosts Cardiovascular Risk: Are there any Common Therapeutic Options? AB - Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease. NAFLD may evolve to non-alcoholic steatohepatitis (NASH), which is causally related to cirrhosis and cardiovascular disease (CVD) mortality. There is no generally accepted effective treatment for NAFLD/NASH. Chronic kidney disease (CKD) is relatively common and might co-exist with NAFLD/NASH, aggravate one another, and increase CVD risk. Common therapies could improve outcome. Potent statins at high doses, such as atorvastatin and rosuvastatin, ameliorate NAFLD/NASH and reduce the mortality rates by half as compared with those on the same statins but without liver disease and CVD-related events are reduced by atorvastatin for patients with all stages of CKD. The new anti-diabetic medication classes, the sodium-glucose co-transporter-2 inhibitors (SGLT2i) and the glucagon like peptide receptor agonists (GLP1 RA) for patients with NAFLD/NASH, CKD and T2DM are useful because they ameliorate NAFLD/NASH, delay the evolution of CKD, and substantially reduce CVD and all-cause mortality. Thus, the common use of high potency statins, renin-angiotensin-aldosterone system inhibitors, and the newer anti-diabetic agents increase compliance and can substantially reduce CVD risk and the rate of liver and kidney adverse events, improving quality of life and survival. PMID- 28676028 TI - Editorial (Thematic Issue: Fc-related Antibody Engineering). PMID- 28676029 TI - Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists. AB - BACKGROUND: The serotonin 2B receptor subtype (5-HT2BR), located in central nervous system (CNS), cardiovascular system (CVS) and the gastrointestinal tract (GIT), is an important target for the treatment of migraine, obesity and irritable bowel syndrome. 5-HT2BR is necessary for the myocardial cell proliferation and differentiation at the embroyonic stage for healthy development of heart. Recently, its involvement in drug induced valvulopathy and other myocardial disorders, have paved a way for selective antagonist for the treatment of cardiac disorders. CONCLUSION: The current review summarizes the limited progress made in the past decade for design and development of 5-HT2BR antagonists for the treatment of disorders related to heart. We focus primarily on the different scaffolds reported in both manuscripts and patents, that have led to selectivity for 5-HT2B over subtype 5-HT2A/2C. Opportunities in cardiovascular drug development for novel 5-HT2BR antagonists are also presented. PMID- 28676030 TI - Heart Failure with Preserved Ejection Fraction: Entresto a Possible Option. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) makes up half of diagnosed heart failure (HF) cases and has similar outcomes compared to heart failure with reduced ejection fraction (HFrEF) but a discrepancy in knowledge and approach to treatment. HFpEF is diagnosed using the following criteria: symptoms, preserved ejection fraction (greater than 50%), and evidence of abnormal left ventricular filling or relaxation, or diastolic distensibility or stiffness. Studies conducted to examine the efficacy of angiotensin receptor blockers (ARB) (irbesartan and candesartan), thiazide diuretics (chlorthalidone), and angiotensin converting enzyme inhibitors (ACEI) (perindopril) in the treatment of HFpEF, showed moderate efficacy but no clear benefit. Recently, the FDA has approved a novel drug, which combines an angiotensin receptor neprilysin inhibitor and ARB (valsartan) named LCZ696 (entresto) for possible treatment of HFrEF. CONCLUSION: In this article, we will discuss the failure of previous treatment modalities and the promise that LCZ696 (entresto) may hold for treating patients with HFpEF. PMID- 28676031 TI - The Intriguing Occurrence of Segmental Arterial Mediolysis: Case Report and Concise Literature Review. AB - BACKGROUND: Segmental medial arteriolysis (SAM) is a unique arteriopathy highlighted by significant lytic changes in the medial wall of the blood vessels and can present from vague gastrointestinal discomfort to catastrophic abdominal bleeding and shock. We hereby present a concise review of this rare phenomenon with historic perspectives, epidemiology, and current concepts of etiology, pathogenesis, relevant clinical associations, treatment modalities, prognosis and future directions in SAM. CONCLUSION: In addition, we present an interesting occurrence of this intriguing phenomenon in a forty-eight year old lady at our institution who presented with vague symptomatology and was an extremely challenging diagnosis. This highlights the importance of timely detection and institution of therapeutic or preventive strategies to minimize future catastrophic events. PMID- 28676032 TI - Is Anticoagulation with Novel Oral Anticoagulants an Effective Treatment for Tuberculosis Patients not Achieving a Therapeutic Range with Vitamin K Antagonists? A Systematic Review. AB - BACKGROUND: Approximately 3% of Tuberculosis (TB) patients have a venous thromboembolic events (VTE). The use of Vitamin K antagonists (VKAs), as anticoagulant, in patients receiving anti TB antimicrobials is often complicated by drug interactions, especially with rifampicin. These patients require frequent monitoring of the International Normalized Ratio (INR), and it is reported that warfarin can not achieve a therapeutic INR. In such cases, abruptly stopping the rifampicin once the course of anti TB antimicrobials is not completed is potentially hazardous. The most recent alternative to prevent thrombotic episodes by using oral agents is represented by novel oral anticoagulants (NOAs) an important breakthrough since they do not require strict laboratory monitoring, frequent dosing adjustments, or dietary restrictions; moreover, they and they are linked with far fewer drug-drug interactions. OBJECTIVE: We have performed a Systematic Review to retrieve information about studies that have assessed the effect of NOAs administered in combination with anti TB antimicrobials in order to investigate if NOAs could be used in TB patients with VTE that do not achieve a therapeutic INR with VKAs. METHOD: The MEDLINE and Google Scholar databases were screened from the inception to 5th of February 2017, using two search strategies: the first one was antimicrobials AND novel oral anticoagulants; the second was antibiotics AND novel oral anticoagulants. RESULTS: 1011 titles were identified on PubMed and Google Scholar published from the inception to February 5, 2017, of these 17 studies were included in the qualitative synthesis Conclusion: No published data were found that properly assessed the effect of NOAs administered in combination with anti TB antimicrobials. Further studies are needed to establish the safety of NOAs in this clinical scenario. In the meanwhile, a viable alternative to VKAs, in order to prevent complications of VTE related to TB, may be represented by Low Molecular Weight Heparin (LMWH), notwithstanding the limitation of the parental route of administration. PMID- 28676033 TI - The effects of probiotic Bacillus subtilis on the cytotoxicity of Clostridium perfringens type a in Caco-2 cell culture. AB - BACKGROUND: Some Bacillus strains have recently been identified for potential use as probiotics and food additives. The present study evaluated the antimicrobial effects of Bacillus subtilis ATCC 6633 and its metabolite on the enterotoxin and vegetative cells, spore and germinated spore of Clostridium perfringens type A in Caco-2 cells. RESULTS: We used flow cytometry and MTT assays to evaluate the cytotoxicity effect of treatments. According to the results, the most cell survival was found in the 4% crude antimicrobial substance (CAS) with the vegetative form of C. perfringens among co-cultured groups. Furthermore, the apoptosis and necrosis in co-cultured groups were significantly decreased (P < 0.05). CONCLUSION: The present results suggested the crucial role of the current probiotic in the control of various forms of C. perfringens type A which was investigated for the first time. Also, the majority of treatments showed higher cell viability in flow cytometry compared to the MTT assay. PMID- 28676034 TI - Cathepsin B inhibitor improves developmental competency and cryo-tolerance of in vitro ovine embryos. AB - BACKGROUND: Cathepsin B is a lysosomal cysteine protease involved in apoptosis and oocytes which have lower developmental competence show higher expression of Cathepsin B. Furthermore, expression of Cathepsin B show a decreasing trend from oocyte toward blastocyst stage. RESULTS: Present study assessed the effect of cathepsin B inhibitor, E-64, on developmental competency and cryo-survival of pre implantation ovine IVF derived embryos. Cathepsin B inhibitor was added during day 3 to 8 of development. One MUM E-64 was defined as the optimal concentration required for improving blastocyst rate. This concentration also reduced DNA fragmentation and BAX as apoptotic markers while increasing total cell number per blastocyst and improving anti-apoptotic marker, the BCL2. We further showed that addition of 1.0 MUM of E-64 during day 3 to 8 of development improved re expansion and hatching rates of blastocysts post vitrification. E-64 also reduced rate of DNA fragmentation and BAX expression and increased total cell number per blastocyst and BCL2 expression post vitrification. However, addition of E-64 post vitrification reduced the hatching rate. CONCLUSION: Therefore, it can be concluded that inhibition of cathepsin B in IVC, not only improves quality and quantity of blastocysts but also improves the cryo-survival of in vitro derived blastocysts. PMID- 28676035 TI - White matter damage in maintenance hemodialysis patients: a diffusion tensor imaging study. AB - BACKGROUND: Patients treated with dialysis have high rates of brain infarcts, brain atrophy, and white matter disease. There are limited data regarding the presence of more subtle damage to brain white matter. METHODS: In the Cognition and Dialysis Study, we compared brain structure using diffusion tensor imaging in hemodialysis (HD) patients to individuals without known kidney disease, using tract based spatial statistics (TBSS) to compare Fractional Anisotropy (FA) and Mean Diffusivity (MD). Statistical comparison of each overlaid voxel was age controlled using a permutation based corrected p value of <0.05. RESULTS: Thirty four HD patients and twenty six controls (52 vs 51 years for HD vs control) had adequate magnetic resonance imaging for analysis. The HD group had fewer women (38% vs 23%) and a higher prevalence of diabetes (29% vs 8%), heart failure (29% vs 0%) and clinical stroke (15% vs 0%). Hemodialysis patients had significantly lower FA across multiple white matter fiber tracts, with fronto-temporal connections, the genu of the corpus callosum and the fornix more significantly affected than posterior regions of the brain. Similarly, HD patients had significantly higher mean diffusivity in multiple anterior brain regions. Results remained similar when those with a prior history of stroke were excluded. CONCLUSIONS: In HD patients, there is more white matter disease in the anterior than posterior parts of the brain compared to controls without kidney disease. This pattern of injury is most similar to that seen in aging, suggesting that developing chronic kidney disease and ultimately kidney failure may result in a phenotype consistent with accelerated aging. PMID- 28676036 TI - Tobacco use among Kyrgyzstan medical students: an 11-year follow-up cross sectional study. AB - BACKGROUND: Medical students are the first line active force to combat tobacco epidemic, but they may suffer from high smoking prevalence and wrong attitude themselves. The aim of the study was to assess the effect of current curriculum on smoking behavior of medical students in Kyrgyzstan. METHODS: 20% random sample of all 6 years of the School of Medicine in Kyrgyz State Medical Academy were interviewed in spring 2016. The questionnaire included sections on tobacco products consumption and knowledge and attitude to counseling. We verified smoking status with exhaled CO measurement using Bedfont Smokelyzer. RESULTS: In 618 students (48% female), the overall daily cigarette smoking prevalence was 21% (34% in males and 6% in females), being highest in years 1 and 3 and least in year 5 (prevalence difference 14%). With very low smokeless products and electronic cigarettes use prevalence, ever-smoking prevalence of waterpipe use was very high, reaching 85% in 6-year male students with alarmingly high prevalence in female students also. Only 74% students responded there was 100% evidence of harmful effects of tobacco, unchanged throughout the course of study. CONCLUSIONS: The use of tobacco products, especially smoking waterpipe, in Kyrgyzstan medical students remains very high. Coupled with poor knowledge and high demand for more information, this demonstrates urgent need for more active and advanced training on tobacco control in medical school. PMID- 28676037 TI - Challenges and outcomes of haemodialysis among patients presenting with kidney diseases in Dodoma, Tanzania. AB - BACKGROUND: Kidney Diseases contribute a significant proportion to the global burden of non-communicable diseases. Haemodialysis services as the main modality of renal replacement therapy in most resource limited countries is only available in few cities and at higher costs. The aim of this study was to determine the challenges and outcomes of patients who were on haemodialysis at the University of Dodoma (UDOM) haemodialysis unit in Tanzania. METHODS: In this retrospective study; we reviewed haemodialysis registers and charts of 116 patients dialyzed from January 2013 to June 2015 at The UDOM haemodialysis unit. Data were descriptively and inferentially analysed using Stata version 11 software. RESULTS: Of the 116 patients, 52 (44.9%) were male, and 38(32.8%) were married. Their median age was 45 years. Thirty-two (27.6%) had acute kidney injury, of them 26 (81.3%) patients had recovery of renal function after haemodialysis. Indications for hemodialysis were anuria (18), intoxications (14), electrolyte imbalance (9), uraemia (7) infections (6) and fluid overload (4). Eighty-four (72.4%) patients had End Stage Renal Diseases (ESRD), of which 37 (44.1%) absconded/lost to follow up, 15 (17.9%) died, 22 (26.2%) were referred to Muhimbili National Hospital (MNH), 12 for possible kidney transplant abroad after haemodialysis, and 10 (11.9%) were still attending our unit for haemodialysis. Residing outside Dodoma was predictive for poor outcomes while on haemodialysis (OR 5.2, 95% CI 3.2-8.6, p < 0.001). In addition the odds ratio for poor outcomes was 7.3 times for a patient ESRD (OR7.34, 95% CI 3.26-18.17, p < 0.001). Patients who had no National Health Insurance Fund (NHIF) coverage (OR 6.6, 95% CI 5.4 12.7, p < 0.001) also had higher odds of poor outcomes after starting haemodialysis. CONCLUSION: Unavailability and high costs related to utilization of haemodialysis services among patients needing dialysis are the challenges for better outcomes. Therefore, haemodialysis and renal transplants services should be made easily available in regional referral hospitals at reasonable costs. In addition, members of the public should be educated on joining health insurance schemes and on making healthy life style choices for preventing chronic kidney disease and its progression. PMID- 28676038 TI - Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension. AB - BACKGROUND: Despite the increased risk for pulmonary hypertension in children with Down syndrome, the response to treatment with targeted therapies for pulmonary hypertension in these patients is not well characterized. The Sildenafil in Treatment-naive children, Aged 1-17 years, with pulmonary arterial hypertension (STARTS-1) trial was a dose-ranging study of the short-term efficacy and safety of oral sildenafil in children with pulmonary arterial hypertension. We assessed the safety and efficacy of oral sildenafil in children with Down syndrome and pulmonary arterial hypertension. METHODS: This was a post-hoc analysis of children with Down syndrome and pulmonary arterial hypertension enrolled in the STARTS-1 trial. Mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), and cardiac index (CI) were assessed at baseline and following 16 weeks of treatment with sildenafil. RESULTS: Of 234 patients randomized and treated in the STARTS-1 trial, 48 (20.5%) had Down syndrome. Although sildenafil produced dose-related reductions in PVRI and mPAP, compared with placebo, in non-Down syndrome patients and children developmentally able to exercise, this was not satisfactorily marked in patients with Down syndrome. The dose-related reductions in PVRI, compared with placebo, occurred in all subgroups, with the exception of the Down syndrome subgroup. Sildenafil appeared to be well tolerated in the Down syndrome subpopulation and the most frequently reported AEs were similar to those reported for the entire STARTS-1 population. CONCLUSION: Sildenafil treatment for 16 weeks had no effect on PVRI or mPAP in children with Down syndrome and pulmonary arterial hypertension. The results suggest that children with Down syndrome may be less responsive to sildenafil for pulmonary arterial hypertension, but the incomplete work-up for the etiology of pulmonary arterial hypertension may have introduced a potential bias. TRIAL REGISTRATION: Study received, September 8, 2005 (retrospectively registered); Study start, August 2003; ClinicalTrials.gov identifier, NCT00159913 . PMID- 28676039 TI - The relationship between socio-demographic factors, health status, treatment type, and employment outcome in patients with inflammatory bowel disease in Japan. AB - BACKGROUND: Inflammatory Bowel Disease (IBD) constitutes a huge burden for patients and studies show that IBD patients have difficulties remaining in employment. Because there is no data about the unemployment of IBD patients in Japan. METHODS: We surveyed a representative sample of 1068 Japanese IBD patients regarding their employment status. RESULTS: We found that the labor force participation rate is lower and unemployment higher for patients with IBD compared to the general population. Factors associated with unemployment in the IBD sample are older age, female gender, and the prevalence of depression. DISCUSSION: IBD constitutes a high burden for patients in Japan regarding employment outcome. PMID- 28676040 TI - Congenital aniridia with cataract: case series. AB - BACKGROUND: This study evaluates patients with congenital aniridia and cataract who underwent phacoemulsification, capsular tension ring placement, and foldable intraocular lens implantation. METHODS: In this prospective case series, 10 patients (17 eyes) underwent cataract surgery via a 3.2 mm clear corneal incision. A continuous circular capsulorhexis with <6 mm diameter was employed. A capsular tension ring and HOYA yellow foldable posterior chamber intraocular lens was implanted. All patients wore color contact lenses postoperatively. Paired t test was used to compare visual acuity, intraocular pressure, and corneal endothelial changes before and after surgery. RESULTS: A single surgeon performed all surgeries. The best-corrected visual acuity improved from value 1.03 +/- 0.27LogMAR preoperatively to value 0.78 +/- 0.26LogMAR postoperatively (p = 0.000). The photophobic symptoms improved significantly after surgery. The mean corneal endothelial cell density before and after surgery was 3280 +/- 473 cells/mm2 and 2669 +/- 850 cells/mm2, respectively (p = 0.006). None of the patients developed corneal endothelial decompensation or secondary glaucoma after surgery. CONCLUSIONS: Treatment of congenital aniridia and coexistent cataract by phacoemulsification, posterior chamber foldable lens implantation, capsular tension ring placement was safe and effective. Use of colored contact lenses in the postoperative period can reduce photophobic symptoms in this group of patients. TRIAL REGISTRATION: ChiCTR-OOC-17011638 (retrospectively registered at 12,June,2017). PMID- 28676041 TI - Erratum to: Genome-wide analysis of an avirulent strain that induces protective immunity against challenge with virulent Streptococcus Suis serotype 2. PMID- 28676042 TI - Estimating the direct costs of ischemic heart disease: evidence from a teaching hospital in BRAZIL, a retrospective cohort study. AB - BACKGROUND: Coronary artery disease is the most prevalent cardiovascular disease. In the United States, 7% of adults over 20 years of age are estimated to have coronary artery disease. In Brazil, a prevalence of 5 to 8% has been estimated in adults over 40 years of age, with an increased number of hospitalizations associated with both stable and acute clinical manifestations; and health care costs have quadrupled in the last decade. To estimate the direct costs of managing ischemic heart disease patient care in a teaching hospital in Brazil from the perspective of the service payer, the Brazilian Unified Health System. METHODS: This study was a retrospective cohort study for the identification and valuation of resources used at both the outpatient and in-hospital levels in a sample of 330 patients selected from the hospital's ischemic heart disease clinic. Data were collected from computerized hospital records and patients' hospital bills from January 2000 to October 2015. A bivariate analysis and binary logistic regression were performed with p < 0.05 considered statistically significant. RESULTS: The study population consisted of 330 patients with a mean age 61 +/- 10 years and a follow-up period of 107 +/- 2.6 months; of the patients, 55% were male, 89% had hypertension, 48% had diabetes, and 65% had acute myocardial infarction. The mean annual cost of outpatient management was US $1,521 per patient. The mean cost per hospitalization was US $1,976, and the expenses were higher in the first and last years of follow-up. Unstable angina, revascularization procedures, diabetes, hypertension and obesity were predictors of higher hospitalization costs (p <0.05). CONCLUSION: The cost estimates in this study indicate a high proportion of drug treatment costs in the treatment of ischemic heart disease. Treatment costs are higher in the first year and at the end of treatment, and some clinical factors are associated with greater hospital care costs. These results may serve as a basis for the evaluation of existing public policies and inputs for cost-effectiveness studies in coronary artery disease. TRIAL REGISTRATION: CEP HCPA 11-0460 . Ethics Committee of Hospital de Clinicas de Porto Alegre. PMID- 28676043 TI - Association of baseline, longitudinal serum high-sensitive C-reactive protein and its change with mortality in peritoneal dialysis patients. AB - BACKGROUND: The prognostic values of baseline, longitudinal high-sensitivity C reactive protein (hs-CRP) and its change over time on mortality in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) remain uncertain. METHODS: We retrospectively studied 1228 consecutive CAPD patients from 2007 to 2012, and followed up through December 2014. Cox regression models were performed to assess the association of hs-CRP on outcomes using serum hs-CRP levels as: (1) stratified by tertile of baseline or longitudinal hs-CRP levels; (2) baseline or longitudinal hs-CRP levels as continuous variables; and (3) categorized by tertile of slopes of hs-CRP change per year for each subject. RESULTS: Higher baseline hs-CRP levels were not associated with clinical outcomes after adjustment for potential confounders. However, patients with the upper tertile of longitudinal hs-CRP had a nearly twice-fold increased risk of both all-cause and cardiovascular mortality [adjusted hazard ratio (HR) 1.77; (95% CI 1.16-2.70) and 2.08 (1.17-3.71), respectively], as compared with those with lower tertile. Results were similar when baseline or longitudinal hs-CRP was assessed as continuous variable. Additionally, the risk of all-cause and cardiovascular mortality in patients with increased trend in serum hs-CRP levels over time (tertile 3) was significantly higher [adjusted HR 2.48 (1.58-3.87) and 1.99 (1.11 3.56), respectively] when compared to those with relatively stable hs-CRP levels during follow-up period. These associations persisted after excluding subjects with less than 1-year follow up. CONCLUSIONS: Higher longitudinal serum hs-CRP levels and its elevated trend over time, but not baseline levels were predictive of worse prognosis among CAPD patients. PMID- 28676044 TI - Effectiveness of secondary and tertiary prevention for violence against women in low and low-middle income countries: a systematic review. AB - BACKGROUND: Violence against women (VAW) is a major problem worldwide, with one in three women experiencing violence in their lifetime. While interventions to prevent violence (primary prevention) are extremely important, they can take many years. This review focuses on secondary and tertiary prevention interventions that address the needs of survivors of violence and aim to prevent recurrence. This review also focuses on studies taking place in low and low-middle income countries, where rates of VAW are highest. METHODS: Searches of peer-reviewed and grey literature took place from March-June 2016 through databases (Embase, CINAHL, WHO Global Index Medicus, Medline, PsychINFO, Web of Science, Cochrane Library, Applied Social Sciences Index and Abstracts and Sociological Abstracts) and by consulting experts in the field. Only primary research was eligible for inclusion and studies had to focus on secondary or tertiary prevention for survivors of VAW in low or low-middle income countries. All study designs were eligible, as long as the study examined client-related outcome measures (e.g., incidence of violence, health outcomes or client satisfaction). Data were extracted and quality of the studies was assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies and a qualitative quality assessment tool developed by Mays and Pope. Due to the low number of results and heterogeneity of the study populations and outcomes, a narrative synthesis was conducted and evidence was summarized. RESULTS: One thousand two hundred fifteen studies were identified through the search strategy and 22 of these met the eligibility criteria. Overall, the evidence for interventions is weak and study limitations prevent definitive conclusions on what works. There is some evidence that interventions targeting alcohol use, both among perpetrators and survivors, may be effective at reducing VAW through secondary prevention, and that psychotherapy might be effective for survivors of non-partner sexual violence through tertiary prevention. Finally, some evidence exists for crisis centres increasing survivors' access to services (through both secondary and tertiary prevention), however, assessment of their impact on future VAW are needed. CONCLUSIONS: Though some interventions for survivors of VAW have shown evidence of effectiveness, further research is needed, especially high quality studies with quantitative outcome data. PMID- 28676045 TI - Folded bandage contact lens retention in a patient with bilateral dry eye symptoms: a case report. AB - BACKGROUND: Bandage contact lenses are commonly used by ophthalmic practitioners to protect the patient's cornea. We report a case of folded bandage contact lens retained for six and a half years in the upper subtarsal space. To our knowledge, no other cases of retained bandage contact lens have previously been reported in the literature. CASE PRESENTATION: A patient was applied a pair of bandage contact lenses due to persistent ocular pain secondary to dry eye symptoms. At her subsequent visit, bandage contact lens was removed from her left eye, but none was found in the right eye. Documentation from further visit stated that the bandage contact lenses were no longer in situ. 6.5 years since the lens insertion, lid eversion revealed a 'foreign body' retained beneath her right upper eyelid, which was noted to be a folded, discoloured bandage contact lens. CONCLUSIONS: The 'upper fornix trap', where the contact lens may be retained by the upper tarsal edge, presents an anatomical hazard for contact lens users. Moreover, soft contact lenses may be more likely to retain asymptomatically and to fold onto itself compared to hard lenses. Our case report highlights the importance of performing a thorough eye examination, which includes double eversion of the upper eyelids and sweeping of the fornices with cotton buds, and maintaining clinical suspicion of contact lens retention. PMID- 28676046 TI - Retention of functional variation despite extreme genomic erosion: MHC allelic repertoires in the Lynx genus. AB - BACKGROUND: Demographic bottlenecks erode genetic diversity and may increase endangered species' extinction risk via decreased fitness and adaptive potential. The genetic status of species is generally assessed using neutral markers, whose dynamic can differ from that of functional variation due to selection. The MHC is a multigene family described as the most important genetic component of the mammalian immune system, with broad implications in ecology and evolution. The genus Lynx includes four species differing immensely in demographic history and population size, which provides a suitable model to study the genetic consequences of demographic declines: the Iberian lynx being an extremely bottlenecked species and the three remaining ones representing common and widely distributed species. We compared variation in the most variable exon of the MHCI and MHCII-DRB loci among the four species of the Lynx genus. RESULTS: The Iberian lynx was characterised by lower number of MHC alleles than its sister species (the Eurasian lynx). However, it maintained most of the functional genetic variation at MHC loci present in the remaining and genetically healthier lynx species at all nucleotide, amino acid, and supertype levels. CONCLUSIONS: Species wide functional genetic diversity can be maintained even in the face of severe population bottlenecks, which caused devastating whole genome genetic erosion. This could be the consequence of divergent alleles being retained across paralogous loci, an outcome that, in the face of frequent gene conversion, may have been favoured by balancing selection. PMID- 28676047 TI - A longitudinal study of early childhood caries incidence in Wenzhou preschool children. AB - BACKGROUND: Early childhood caries (ECC) is a serious public health problem in China. Few studies, however, have described the incidence of ECC in China. The purpose of this study was to assess the prevalence and incidence of ECC among preschool children in Wenzhou China. METHODS: Preschool children aged 3-4 years old were surveyed and followed up when they reached 5-6 years of age in the city of Wenzhou in southeast China. The rates of dental caries were determined with prevalence, and incidence density for risk of caries of a person (IDp) and of a tooth surface (IDs). RESULTS: The prevalence and decayed, missing, and filled primary teeth (dmft) score of 3-4, 4-5, and 5-6 years old children were 59.8% and 2.9, 71.8% and 4.2, and 76.4% and 4.6, respectively. The IDp was 29.7 and 14.8 persons/100 person-year during the first and second year. The IDs was 5.9 and 2.7 newly affected surfaces/100 surface-year, respectively. The percentage of molars with caries experience increased obviously; the percentage of maxillary central incisors and mandibular incisors with caries experience increased during the first follow-up, whereas it declined during the second follow-up; the others increased gradually. CONCLUSIONS: The prevalence and incidence of dental caries in Wenzhou preschool children were very high with most of the carious teeth left untreated. The molars were the most affected teeth during the observation period. PMID- 28676048 TI - How clinicians analyze movement quality in patients with non-specific low back pain: a cross-sectional survey study with Dutch allied health care professionals. AB - BACKGROUND: Observation of movement quality (MQ) is an indelible element in the process of clinical reasoning for patients with non-specific low back pain (NS LBP). However, the observation and evaluation of MQ in common daily activities are not standardized within allied health care. This study aims to describe how Dutch allied health care professionals (AHCPs) observe and assess MQ in patients with NS-LBP and whether AHCPs feel the need to have a specific outcome measure for assessing MQ in patients with NS-LBP. METHODS: In this cross-sectional digital survey study, Dutch primary care AHCPs (n = 114) answered one open and three closed questions about MQ in NS-LBP management. Qualitative and quantitative analyses were applied. RESULTS: Qualitative analyses of the answers to the open questions revealed four main themes: 1) movement pattern features, 2) motor control features, 3) environmental influences and 4) non-verbal expressions of pain and exertion. Quantitative analyses clearly indicated that AHCPs observe MQ in the diagnostic (92%), therapeutic (91%) and evaluation phases (86%), that they do not apply any objective measurement of MQ and that 63% of the AHCPs consider it important to have a specific outcome measure to assess MQ. The AHCPs expressed added benefits and critical notes regarding clinical reasoning and quality of care. CONCLUSION: AHCPs recognize the importance of observing MQ in the assessment and management of LBP in a standardized way. However, there is no consensus amongst AHCPs how MQ should be standardized. Prior to standardization, it will be important to develop a theoretical framework to determine which observable and measurable dimensions of MQ are most valid and relevant for patients with NS-LBP to include in the assessment. PMID- 28676049 TI - Chenopodium ambrosioides as a bone graft substitute in rabbits radius fracture. PMID- 28676052 TI - Comparison of different feeding regimes after pancreatoduodenectomy - a retrospective cohort analysis. AB - BACKGROUND: Delayed gastric emptying (DGE) is the most frequent pancreatic specific complication (PSC) after pancreaticoduodenectomy (PD). Several gastric decompression systems exist to manage DGE. Patients with a pancreatic tumor require prolonged nutrition; however, controversies exist concerning nutrition protocol after PD. The aim of the study was to assess the safety and efficacy of nasogastric (NG), gastrostomy (GT), and gastrojejunostomy (GJ) tubes with different feeding systems on postoperative courses. METHODS: Between January 2013 and March 2016, 86 patients underwent PD with pancreaticogastrostomy. Patients were divided into three groups: GJ group with enteral nutrition (EN, n = 12, 14%), NG (n = 31, 36%) and GT groups (n = 43, 50%), both with total parenteral nutrition (TPN). RESULTS: Patients in the GJ (n = 9, 75%) and GT (n = 18, 42%) groups had an American Society of Anesthesiologists (ASA) score of 3 more often than those in the NG group (n = 5, 16%, p <= 0.01). Multivariate analysis identified the GT tube with TPN as an independent risk factor of severe morbidity (p = 0.02) and DGE (p < 0.01). An ASA score of 3, jaundice, common pancreatic duct size <=3 mm and soft pancreatic gland texture (p < 0.05) were found as independent risk factors of PSCs. Use of a GJ tube with EN, GT tube with TPN, jaundice, and PSCs were identified as independent risk factors for greater postoperative length of hospital stay (p < 0.01). Mean global hospitalization cost did not differ between groups. CONCLUSION: GT tube insertion with TPN was associated with increased severe postoperative morbidity and DGE and should not be recommended. EN through a GJ tube after PD is feasible but does not have clear advantages on postoperative courses compared to an NG tube. PMID- 28676051 TI - Community perceptions on outdoor malaria transmission in Kilombero Valley, Southern Tanzania. AB - BACKGROUND: The extensive use of indoor residual spraying (IRS) and insecticide treated nets (ITNs) in Africa has contributed to a significant reduction in malaria transmission. Even so, residual malaria transmission persists in many regions, partly driven by mosquitoes that bite people outdoors. In areas where Anopheles gambiae s.s. is a dominant vector, most interventions target the reduction of indoor transmission. The increased use of ITNs/LLINs and IRS has led to the decline of this species. As a result, less dominant vectors such as Anopheles funestus and Anopheles arabiensis, both also originally indoor vectors but are increasingly biting outdoors, contribute more to residual malaria transmission. The study reports the investigated community perceptions on malaria and their implications of this for ongoing outdoor malaria transmission and malaria control efforts. METHODS: This was a qualitative study conducted in two rural villages and two peri-urban areas located in Kilombero Valley in south eastern Tanzania. 40 semi-structured in-depth interviews and 8 focus group discussions were conducted with men and women who had children under the age of five. The Interviews and discussions focused on (1) community knowledge of malaria transmission, and (2) the role of such knowledge on outdoor malaria transmission as a contributing factor to residual malaria transmission. RESULTS: The use of bed nets for malaria prevention has been stressed in a number of campaigns and malaria prevention programmes. Most people interviewed believe that there is outdoor malaria transmission since they use interventions while indoors, but they are unaware of changing mosquito host-seeking behaviour. Participants pointed out that they were frequently bitten by mosquitoes during the evening when outdoors, compared to when they were indoors. Most participants stay outdoors in the early evening to undertake domestic tasks that cannot be conducted indoors. House structure, poor ventilation and warm weather conditions were reported to be the main reasons for staying outdoors during the evening. Participants reported wearing long sleeved clothes, fanning and slapping themselves, using repellents, and burning cow dung and neem tree leaves to chase away mosquitoes. CONCLUSIONS: Community understanding of multiple prevention strategies is crucial given changes in mosquito host seeking behaviour and the increased incidence of outdoor biting. The current low use of outdoor control measures is attributed largely to limited awareness of outdoor transmission. Improved community understanding of outdoor malaria transmission is critical: efforts to reduce or eliminate malaria transmission will not be successful if the control of outdoor transmission is not emphasized. PMID- 28676053 TI - Bronchial thermoplasty: activations predict response. AB - BACKGROUND: Bronchial thermoplasty (BT) is an emerging bronchoscopic intervention for the treatment of severe asthma. The predictive factors for clinical response to BT are unknown. We examined the relationship between the number of radiofrequency activations applied and the treatment response observed. METHODS: Data were collected from 24 consecutive cases treated at three Australian centres from June 2014 to March 2016. The baseline characteristics were collated along with the activations delivered. The primary response measure was change in the Asthma Control Questionnaire-5 (ACQ-5) score measured at 6 months post BT. The relationship between change in outcome parameters and the number of activations delivered was explored. RESULTS: All patients met the ERS/ATS definition for severe asthma. At 6 months post treatment, mean ACQ-5 improved from 3.3 +/- 1.1 to 1.5 +/- 1.1, p < 0.001. The minimal clinically significant improvement in ACQ 5 of >=0.5 was observed in 21 out of 24 patients. The only significant variable that differed between the 21 responders and the three non-responders was the number of activations delivered, with 139 +/- 11 activations in the non responders, compared to 221 +/- 45 activations in the responders (p < 0.01). A significant inverse correlation was found between change in ACQ-5 score and the number of activations, r = -0.43 (p < 0.05). CONCLUSIONS: The number of activations delivered during BT has a role in determining clinical response to treatment. PMID- 28676050 TI - Reconstruction of the microalga Nannochloropsis salina genome-scale metabolic model with applications to lipid production. AB - BACKGROUND: Nannochloropsis salina (= Eustigmatophyceae) is a marine microalga which has become a biotechnological target because of its high capacity to produce polyunsaturated fatty acids and triacylglycerols. It has been used as a source of biofuel, pigments and food supplements, like Omega 3. Only some Nannochloropsis species have been sequenced, but none of them benefit from a genome-scale metabolic model (GSMM), able to predict its metabolic capabilities. RESULTS: We present iNS934, the first GSMM for N. salina, including 2345 reactions, 934 genes and an exhaustive description of lipid and nitrogen metabolism. iNS934 has a 90% of accuracy when making simple growth/no-growth predictions and has a 15% error rate in predicting growth rates in different experimental conditions. Moreover, iNS934 allowed us to propose 82 different knockout strategies for strain optimization of triacylglycerols. CONCLUSIONS: iNS934 provides a powerful tool for metabolic improvement, allowing predictions and simulations of N. salina metabolism under different media and genetic conditions. It also provides a systemic view of N. salina metabolism, potentially guiding research and providing context to -omics data. PMID- 28676054 TI - A qualitative analysis of the effectiveness of telehealthcare devices (i) are they meeting the needs of end-users? AB - BACKGROUND: There are many telehealthcare devices currently available ranging from personal alarms, automated pill dispensers and fall detectors through to monitoring devices for blood sugar, blood pressure and heart rate. Many devices remain unused once acquired or shortly after a period of initial use. METHODS: The study used a qualitative design involving focus groups and interviews. End users' opinions of telehealthcare devices were examined through focus groups along with the views of market experts and key supply chain players through telephone interviews to ascertain their views on the devices. The data were recorded, transcribed and analysed thematically. RESULTS: Amongst the wide range of user issues associated with telehealthcare devices two themes merited particular attention: design characteristics and the lack of focus on end-user needs. Our findings suggested that few telehealthcare devices appear to be developed based on the principles of user-centred design. Consequently, many were non-intuitive to use, with the majority of the focus group participants not recognising the purpose of the devices from their appearance alone. CONCLUSIONS: Greater input from real end-users rather than "proxy" users such as carers, professional users or technologists is required when developing telehealthcare devices or systems. Design should be focussed on intuitive use to enable the user to successfully achieve what is required from the devices. This may require the existing supplier-driven market focus to be challenged, but could improve the contribution of technology to improving healthcare. PMID- 28676056 TI - Investigation of implantable signal transmission characteristics based on visible data of the human leg. AB - BACKGROUND: Signal transmission characteristics between implanted medical devices and external equipment has been a common key issue, as has the problem of supplying energy to the devices. It can be used to enable signal transmission from implanted devices that the human body's conductive properties. Using signal transmission by galvanic coupling is one of the most effective signal transmission methods. METHODS: The signal transmission characteristics by galvanic coupling of implantable devices using a frequency range of 10 kHz to 1 MHz was analyzed in this article. A finite element (FEM) model and a phantom model established by visible human leg data were used to investigate the signal transmission characteristics of implant-to-surface, with implantable receiver electrodes at different locations. RESULTS: The results showed that the FEM model and the phantom model had similar implantable signal transmission characteristics, with an increase of frequency, signal attenuation basically remained unchanged. The gain in signal attenuation in the fixed attenuation values fluctuated no more than 5 dB and signal attenuation values rose as the channel length increased. CONCLUSIONS: Our results of signal transmission characteristics of surface-to-implant will provide a theoretical basis for implantable transceiver design, and for realization of a recharging method for implanted medical devices. PMID- 28676057 TI - Prevalence of neurological disorders in French bulldog: a retrospective study of 343 cases (2002-2016). AB - BACKGROUND: French Bulldog (FB) has significantly gained in popularity over the last few years, and seems to be frequently affected by various neurological conditions. The purpose of this retrospective study was to report the prevalences of neurological diseases in a large population of FB, presented with neurological signs between 2002 and 2016, and for which a definitive diagnosis was established. A secondary objective was to identify epidemiological characteristics regarding specific diseases in this singular breed. RESULTS: During the study period, 533 FBs were presented for neurological signs, representing 18.7% of all admitted FBs (N = 2846). In total, 343 FBs with definitive diagnosis were included in this descriptive epidemiological study. Hansen type I intervertebral disk herniation (IVDH) was by far the most common neurological disorder (45.5% of all cases). The IVDH location was cervical in 39.8%, and thoracolumbar in 60.2% of cases. The median ages for cervical and thoracolumbar IVDH were 4.2 and 4 years, respectively. C3-C4 was the most commonly affected disk (57.8% of cervical IDVH) all locations combined. Spinal arachnoid diverticulum (SAD) was detected in 25 FBs, representing the second most common myelopathy (11.3%). A concurrent spinal abnormality was identified in 64.0% of SAD cases. Brain tumours represented 36.8% of encephalopathies, with glioma (confirmed or suspected) being the most common. Meningoencephalitis of unknown origin (MUO) represented 25.0% of brain disorders, females less than 5.5 years being more likely to be affected. Aside from central nervous system conditions, otitis interna associated with peripheral vestibular signs and bilateral congenital deafness (associated with white coat) were also common. CONCLUSIONS: The findings of this study suggest that FB seems to be prone to several neurological diseases. IVDH is clearly predominant in FB and cervical location seems more represented than in other breeds. FBs affected by IVDH tend to be younger than previously described, either for both cervical and thoracolumbar locations. Thoracic SAD was the second most common myelopathy, with a concurrent spinal anomaly identified in two thirds of the cases. MUO was more likely to affect young to middle-aged females. These findings could be of interest for owners, breeders, practicing veterinarians and insurance companies. PMID- 28676058 TI - Chemical constituents, antibacterial and antioxidant properties of the essential oil flower of Tagetes minuta grown in Cala community Eastern Cape, South Africa. AB - BACKGROUND: Tagetes minuta has a long record of human use for the treatment of stomach and intestinal diseases. Most drugs used for diseases treatment are less efficacious with side effects and this brought the search for new treatment regimens mainly from medicinal plants. METHOD: The essential oil (EO) was extracted by Clevenger's-type apparatus and its chemical composition, antioxidant and antibacterial properties were determined by GC-MS, spectrophotometric and broth dilution methods respectively. S. uberis, E. cloacae, S. aureus, M. smegmatis, L. ivanovii, Vibrio spp. and E. coli bacteria strains were used as test bacteria. RESULTS: GC-MS analysis revealed 98 compounds in the EO flower of T. minuta and beta-Ocimene (14. 40%) was the major chemical constituents. The EO exhibited highest inhibitory effect against DPPH radical, followed by its effect on ABTS, while LP radical showed the least sensitivity with IC50 values of 2.45 mg/mL, 2.76 mg/mL and 3.23 mg/mL respectively. The EO showed antibacterial activities against all test organisms with MIC value for S. aureus, M. smegatis and S. uberis at 0.125 mg/mL and for L. ivanovii, Vibrio spp., E. cloacae and E. coli at 0.06 mg/mL. The EO showed MBC against E. cloacae and E. coli at 0.06 mg/mL at 0.5 mg/mL for S. uberis and 0.125 mg/mL for Vibrio spp. CONCLUSION: Findings from this study suggest that the EO of T. minuta flower may be a useful candidate in the search for lead constituents for the synthesis of new potent antibacterial and antioxidant agent. PMID- 28676059 TI - Potent long-acting rhFGF21 analog for treatment of diabetic nephropathy in db/db and DIO mice. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is an endocrine-acting hormone that has the potential to treat diabetic nephropathy. However, development of FGF21 into a therapeutic has been hindered due to its low intrinsic bio stability. In our previous study, we have developed a recombinant human FGF21 (rhFGF21) variant by site-directed mutagenesis and solid-phase PEGylation, which retained its biological function. The aim of this study is to elucidate whether the therapeutic effect of PEGylated rhFGF21 (PEG-rhFGF21) on diabetic nephropathy in DIO (diet induced obesity) mice is more significant than rhFGF21 in vivo. RESULTS: After administration with rhFGF21 and PEG-rhFGF21 for 2 months, biochemical data and histological examination showed that PEG-rhFGF21 significantly lowered lipid levels in the kidney, decreased urine albumin/creatinine ratio (ACR) and improved mesangial expansion, demonstrating that PEG-rhFGF21 was more efficacious in ameliorating functional and morphological abnormalities induced by diabetic nephropathy in db/db and DIO mice. CONCLUSIONS: Our findings suggest that PEG-rhFGF21 treatment is more effective in treating diabetic nephropathy than rhFGF21, through enhancements of systemic metabolic alterations and anti-inflammatory mechanisms. These findings help provide a theoretical basis to develop more long-acting and efficacious protein drugs for diabetic nephropathy. PMID- 28676060 TI - The development of a health-related quality-of-life instrument for young people with narcolepsy: NARQoL-21. AB - BACKGROUND: Narcolepsy is a lifelong sleep disorder with a prevalence of between 0.03% and 0.06% and onset at around puberty. It is associated with psychiatric comorbidities and cognitive difficulties. No valid and reliable condition specific health-related quality-of-life (HrQoL) instrument has been developed for this population. METHODS: A questionnaire based on four mixed-gender age-defined focus group discussions and a patient panel analysis was administered to young people with narcolepsy and a control group. External reliability was measured by a test-retest procedure and internal reliability was measured using Cronbach's alpha. Convergent validity with the KIDSCREEN-10 index was assessed using with intraclass correlation coefficients (ICC) and receiver operating characteristic (ROC) curves. Factor analysis techniques were used to identify suitable items and confirm the factor structure. Baseline values were assessed for convergent validity, ceiling effects, agreement and sensitivity. Comparison with KIDSCREEN 10 was made on the basis of area under the curve (AUC). RESULTS: One hundred young people with narcolepsy and 95 control subjects returned questionnaires. The factor structure revealed two main factors with five domains and 21 questions, which was confirmed with confirmatory factor analysis. The domains of the NARQoL 21 showed good independence while the floor and ceiling effects were acceptable. The external reliability (0.928), convergent validity (rs = 0.769) and internal consistency (Cronbach's alpha = 0.886) were excellent. A Bland-Altman plot revealed some proportional bias. Good discriminant validity was detected for control/patient (Cohen's d = 2.114). ROC analysis showed significantly better AUC for NARQoL-21 (0.939) than KIDSCREEN (0.877). A cut-off score equivalent to KIDSCREEN-10 for suboptimal HrQoL which maximized sensitivity (84%) and specificity (92%) was found at NARQoL-21 score below 42. CONCLUSIONS: Establishing the validity of a disease-specific HrQoL instrument in a population of people with a rare condition poses significant challenges. The mixed-methods approach adopted here has resulted in a questionnaire of 21 items with good discrimination and convergent validity, and excellent internal and external reliability, allowing precise and stable measurements. The cut-off score can be useful to identify patients with very poor HrQoL and thus improve the design of treatment options. Further testing in a longitudinal cohort is recommended in order to establish responsiveness. PMID- 28676055 TI - Malaria in Brazil, Colombia, Peru and Venezuela: current challenges in malaria control and elimination. AB - In spite of significant progress towards malaria control and elimination achieved in South America in the 2000s, this mosquito-transmitted tropical disease remains an important public health concern in the region. Most malaria cases in South America come from Amazon rain forest areas in northern countries, where more than half of malaria is caused by Plasmodium vivax, while Plasmodium falciparum malaria incidence has decreased in recent years. This review discusses current malaria data, policies and challenges in four South American Amazon countries: Brazil, Colombia, Peru and the Bolivarian Republic of Venezuela. Challenges to continuing efforts to further decrease malaria incidence in this region include: a significant increase in malaria cases in recent years in Venezuela, evidence of submicroscopic and asymptomatic infections, peri-urban malaria, gold mining related malaria, malaria in pregnancy, glucose-6-phosphate dehydrogenase (G6PD) deficiency and primaquine use, and possible under-detection of Plasmodium malariae. Some of these challenges underscore the need to implement appropriate tools and procedures in specific regions, such as a field-compatible molecular malaria test, a P. malariae-specific test, malaria diagnosis and appropriate treatment as part of regular antenatal care visits, G6PD test before primaquine administration for P. vivax cases (with weekly primaquine regimen for G6PD deficient individuals), single low dose of primaquine for P. falciparum malaria in Colombia, and national and regional efforts to contain malaria spread in Venezuela urgently needed especially in mining areas. Joint efforts and commitment towards malaria control and elimination should be strategized based on examples of successful regional malaria fighting initiatives, such as PAMAFRO and RAVREDA/AMI. PMID- 28676061 TI - Hemorrhage promotes inflammation and myocardial damage following acute myocardial infarction: insights from a novel preclinical model and cardiovascular magnetic resonance. AB - BACKGROUND: Myocardial hemorrhage is a frequent complication following reperfusion in acute myocardial infarction and is predictive of adverse outcomes. However, it remains unsettled whether hemorrhage is simply a marker of a severe initial ischemic insult or directly contributes to downstream myocardial damage. Our objective was to evaluate the contribution of hemorrhage towards inflammation, microvascular obstruction and infarct size in a novel porcine model of hemorrhagic myocardial infarction using cardiovascular magnetic resonance (CMR). METHODS: Myocardial hemorrhage was induced via direct intracoronary injection of collagenase in a novel porcine model of ischemic injury. Animals (N = 27) were subjected to coronary balloon occlusion followed by reperfusion and divided into three groups (N = 9/group): 8 min ischemia with collagenase (+HEM); 45 min infarction with saline (I-HEM); and 45 min infarction with collagenase (I+HEM). Comprehensive CMR was performed on a 3 T scanner at baseline and 24 h post-intervention. Cardiac function was quantified by cine imaging, edema/inflammation by T2 mapping, hemorrhage by T2* mapping and infarct/microvascular obstruction size by gadolinium enhancement. Animals were subsequently sacrificed and explanted hearts underwent histopathological assessment for ischemic damage and inflammation. RESULTS: At 24 h, the +HEM group induced only hemorrhage, the I-HEM group resulted in a non-hemorrhagic infarction, and the I+HEM group resulted in infarction and hemorrhage. Notably, the I+HEM group demonstrated greater hemorrhage and edema, larger infarct size and higher incidence of microvascular obstruction. Interestingly, hemorrhage alone (+HEM) also resulted in an observable inflammatory response, similar to that arising from a mild ischemic insult (I-HEM). CMR findings were in good agreement with histological staining patterns. CONCLUSIONS: Hemorrhage is not simply a bystander, but an active modulator of tissue response, including inflammation and microvascular and myocardial damage beyond the initial ischemic insult. A mechanistic understanding of the pathophysiology of reperfusion hemorrhage will potentially aid better management of high-risk patients who are prone to adverse long-term outcomes. PMID- 28676063 TI - The associations between religion, bereavement and depression among Hong Kong nurses. AB - BACKGROUND: This paper is to examine the associations between religion, bereavement and depression among nursing professionals using a cross-sectional survey design. There is little empirical evidence in Asia suggesting that religion may either increase or lower the likelihood of nursing professionals being depressed. METHODS: We analyzed the results of a Mental Health Survey soliciting data from 850 Hong Kong nurses (aged 21-59, 178 males) regarding their mental well-being and associated factors, including participants' socio-economic profile and recent life-events. Multiple linear regression analyses examined associations between religion, bereavement and depression. RESULTS: Religious faith is weakly associated with lower self-reported depression in bereavement. CONCLUSIONS: Our findings confirm those studies suggesting that religion positively affects mental health and yet healthcare providers have yet to assimilate this insight. PMID- 28676062 TI - Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy a literature review. AB - Spinal muscular atrophy linked to chromosome 5q (SMA) is a recessive, progressive, neuromuscular disorder caused by bi-allelic mutations in the SMN1 gene, resulting in motor neuron degeneration and variable presentation in relation to onset and severity. A prevalence of approximately 1-2 per 100,000 persons and incidence around 1 in 10,000 live births have been estimated with SMA type I accounting for around 60% of all cases. Since SMA is a relatively rare condition, studies of its prevalence and incidence are challenging. Most published studies are outdated and therefore rely on clinical rather than genetic diagnosis. Furthermore they are performed in small cohorts in small geographical regions and only study European populations. In addition, the heterogeneity of the condition can lead to delays and difficulties in diagnosing the condition, especially outside of specialist clinics, and contributes to the challenges in understanding the epidemiology of the disease. The frequency of unaffected, heterozygous carriers of the SMN1 mutations appears to be higher among Caucasian and Asian populations compared to the Black (Sub-Saharan African ancestry) population. However, carrier frequencies cannot directly be translated into incidence and prevalence, as very severe (death in utero) and very mild (symptom free in adults) phenotypes carrying bi-allelic SMN1 mutations exist, and their frequency is unknown. More robust epidemiological data on SMA covering larger populations based on accurate genetic diagnosis or newborn screening would be helpful to support planning of clinical studies, provision of care and therapies and evaluation of outcomes. PMID- 28676064 TI - Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis. AB - BACKGROUND: This study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts. METHODS: A retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry. RESULTS: Either after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI. CONCLUSIONS: The results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect. PMID- 28676066 TI - Avoidable waste related to inadequate methods and incomplete reporting of interventions: a systematic review of randomized trials performed in Sub-Saharan Africa. AB - BACKGROUND: Randomized controlled trials (RCTs) are needed to improve health care in Sub-Saharan Africa (SSA). However, inadequate methods and incomplete reporting of interventions can prevent the transposition of research in practice which leads waste of research. The aim of this systematic review was to assess the avoidable waste in research related to inadequate methods and incomplete reporting of interventions in RCTs performed in SSA. METHODS: We performed a methodological systematic review of RCTs performed in SSA and published between 1 January 2014 and 31 March 2015. We searched PubMed, the Cochrane library and the African Index Medicus to identify reports. We assessed the risk of bias using the Cochrane Risk of Bias tool, and for each risk of bias item, determined whether easy adjustments with no or minor cost could change the domain to low risk of bias. The reporting of interventions was assessed by using standardized checklists based on the Consolidated Standards for Reporting Trials, and core items of the Template for Intervention Description and Replication. Corresponding authors of reports with incomplete reporting of interventions were contacted to obtain additional information. Data were descriptively analyzed. RESULTS: Among 121 RCTs selected, 74 (61%) evaluated pharmacological treatments (PTs), including drugs and nutritional supplements; and 47 (39%) nonpharmacological treatments (NPTs) (40 participative interventions, 1 surgical procedure, 3 medical devices and 3 therapeutic strategies). Overall, the randomization sequence was adequately generated in 76 reports (62%) and the intervention allocation concealed in 48 (39%). The primary outcome was described as blinded in 46 reports (38%), and incomplete outcome data were adequately addressed in 78 (64%). Applying easy methodological adjustments with no or minor additional cost to trials with at least one domain at high risk of bias could have reduced the number of domains at high risk for 24 RCTs (19%). Interventions were completely reported for 73/121 (60%) RCTs: 51/74 (68%) of PTs and 22/47 (46%) of NPTs. Additional information was obtained from corresponding authors for 11/48 reports (22%). CONCLUSION: Inadequate methods and incomplete reporting of published SSA RCTs could be improved by easy and inexpensive methodological adjustments and adherence to reporting guidelines. PMID- 28676067 TI - Chronic scrotal pain in young adults. AB - OBJECTIVE: Chronic scrotal pain (CSP) is a common and well recognized symptom of young males presenting to primary care units. Historically, CSP is defined as a testicular pain lasting for over 3 months. However, its etiology and outcome are poorly understood and its management is largely empirical. This study was conducted to examine the frequency, spectrum of pathology and outcome of CSP among young adults. RESULTS: The medical records of 382,036 young males were reviewed for anamnestic information, physical findings, primary care physician decisions, and final outcome. CSP, defined as scrotal pain longer than 14 days, was recorded in 3084 patients (0.8%). The total number of primary physician's visits due to this complaint was 16,222, with a mean of 5.3 visits per patient (range 1-37). Varicocele was the most common physical finding (54.1%). Other common findings were inguinal hernia (4.5%), genital infection (4.3%), hydrocele (4.2%) and referred pain (3.3%). 252 patients (8.2%) underwent surgical treatment but orchiectomy was not necessary in any patient. In 34.4% no specific etiology could be found. Neither malignant tumors nor testicular torsion were diagnosed in any patient. The prevalence of the diagnoses was similar between the different time groups-15-29 days, 30-59 days and more than 60 days. Considering the similar etiologies CSP over a wide spectrum of time we suggest defining CSP as testicular pain lasting longer than 14 days. PMID- 28676065 TI - Prior balloon valvuloplasty versus DIRECT transcatheter Aortic Valve Implantation (DIRECTAVI): study protocol for a randomized controlled trial. AB - BACKGROUND: Balloon predilatation of the aortic valve has been regarded as an essential step during the transcatheter aortic valve implantation (TAVI) procedure. However, recent evidence has suggested that aortic valvuloplasty may cause complications and that high success rates may be obtained without prior dilatation of the valve. We hypothesize that TAVI performed without predilatation of the aortic valve and using new-generation balloon-expandable transcatheter heart valves is associated with a better net clinical benefit than TAVI performed with predilatation. METHODS/DESIGN: The transcatheter aortic valve implantation without prior balloon dilatation (DIRECTAVI) trial is a randomized controlled open label trial that includes 240 patients randomized to TAVI performed with prior balloon valvuloplasty (control arm) or direct implantation of the valve (test arm). All patients with an indication for TAVI will be included excepting those requiring transapical access. The trial tests the hypothesis that the strategy of direct implantation of the new-generation balloon-expandable SAPIEN 3 valve is noninferior to current medical practice using predilatation of the valve. The primary endpoint assessing efficacy and safety of the procedure consists of immediate procedural success and secondary endpoints include complications at 30-day follow-up (VARC-2 criteria). A subgroup analysis evaluates neurological ischemic events with cerebral MRI imaging (25 patients in each strategy group) performed before and between 1 and 3 days after the procedure. DISCUSSION: This prospective randomized study is designed to assess the efficacy and safety of TAVI performed without prior dilatation of the aortic valve using new-generation balloon-expandable transcatheter heart valves. We aim to provide robust evidence of the advantages of this strategy to allow the interventional cardiologist to use it in everyday practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02729519 . Registered on 15 July 2016. PMID- 28676068 TI - Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea & vomiting toxicity in patients with head and neck cancers - an observational clinical trial. AB - OBJECTIVE: Today intensity modulated radiation therapy (IMRT) can be considered the standard of care in patients with head and neck tumors. IMRT treatment plans are proven to reduce acute treatment related side effects by optimal sparing of organs at risk (OAR). At the same time, areas that were out of the former 3D fields now receive low radiation doses. Amongst those areas the brainstem (BS) and the vestibular system (VS) are known to be physiologically connected to nausea and vomiting (NV). In our study we tried to find out, if doses to these areas are linked to NV. MATERIAL & METHODS: NV were assessed at different time points during treatment in 26 patients leading to 98 documented toxicity scores that were later correlated to dose deposition in the described areas. Patients were either treated with normo-fractionated or simultaneously integrated boost IMRT plans in a curative approach. Subareas of the BS as well as the VS were delineated. Toxicity was rated based on the common toxicity criteria (CTCAE Version 4.0). Other factors such as age, gender, chemotherapy, location of the tumor, irradiated volume and unilateral dose to the VS were taken into account and analyzed also. RESULTS: The majority (65.4%) of our patients experienced an episode of NV at least once during treatment. NV was more frequent when treating the oropharyngeal region compared to the hypopharyngeal region, as well as when patients were female and/ or of a younger age. Nevertheless, upon statistical analysis (ROC analysis, 'within/ between analysis') no significant association between delivered doses to subareas and toxicity could be demonstrated. CONCLUSION: In our analysis, no significant correlation between radiation dose to the BS or the VS and the occurrence of NV could be found. Therefore, until conclusive data are available, we recommend to rely on the published data regarding OAR tolerance within the BS and not to compromise on dose coverage. PMID- 28676069 TI - Limited cutaneous systemic sclerosis skin demonstrates distinct molecular subsets separated by a cardiovascular development gene expression signature. AB - BACKGROUND: Systemic sclerosis (SSc; scleroderma) is an uncommon autoimmune rheumatic disease characterised by autoimmunity, vasculopathy and fibrosis. Gene expression profiling distinguishes scleroderma from normal skin, and can detect different subsets of disease, with potential to identify prognostic biomarkers of organ involvement or response to therapy. We have performed gene expression profiling in skin samples from patients with limited cutaneous SSc (lcSSc). METHODS: Total RNA was extracted from clinically uninvolved skin biopsies of 15 patients with lcSSc and 8 healthy controls (HC). Gene expression profiling was performed on a DNA oligonucleotide microarray chip. Differentially expressed genes (DEG) were identified using significance analysis of microarrays (SAM). Functional enrichment analysis of gene signatures was done via g:Profiler. RESULTS: There were 218 DEG between lcSSc and HC samples (false discovery rate <10%): 181/218 DEG were upregulated in lcSSc samples. Hierarchical clustering of DEG suggested the presence of two separate groups of lcSSc samples: "limited 1" and "limited 2". The limited-1 group (13 samples, 10 unique patients) showed upregulation of genes involved in cell adhesion, cardiovascular system (CVS) development, extracellular matrix and immune and inflammatory response. The CVS development signature was of particular interest as its genes showed very strong enrichment in response to wounding, response to transforming growth factor (TGF) beta and kinase cascade. Neither limited-2 samples (six samples, five unique patients) nor HC samples showed functional enrichment. There were no significant differences in demographic or clinical parameters between these two groups. These results were confirmed using a second independent cohort. CONCLUSIONS: Our study suggests the presence of molecular subsets in lcSSc based on gene expression profiling of biopsies from uninvolved skin. This may reflect important differences in pathogenesis within these patient groups. We identify differential expression of a subset of genes that relate to CVS and are enriched in fibrotic signalling. This may shed light on mechanisms of vascular disease in SSc. The enrichment in profibrotic profile suggests that dysregulated gene expression may contribute to vasculopathy and fibrosis in different disease subsets. PMID- 28676070 TI - The potential of shifting recombination hotspots to increase genetic gain in livestock breeding. AB - BACKGROUND: This study uses simulation to explore and quantify the potential effect of shifting recombination hotspots on genetic gain in livestock breeding programs. METHODS: We simulated three scenarios that differed in the locations of quantitative trait nucleotides (QTN) and recombination hotspots in the genome. In scenario 1, QTN were randomly distributed along the chromosomes and recombination was restricted to occur within specific genomic regions (i.e. recombination hotspots). In the other two scenarios, both QTN and recombination hotspots were located in specific regions, but differed in whether the QTN occurred outside of (scenario 2) or inside (scenario 3) recombination hotspots. We split each chromosome into 250, 500 or 1000 regions per chromosome of which 10% were recombination hotspots and/or contained QTN. The breeding program was run for 21 generations of selection, after which recombination hotspot regions were kept the same or were shifted to adjacent regions for a further 80 generations of selection. We evaluated the effect of shifting recombination hotspots on genetic gain, genetic variance and genic variance. RESULTS: Our results show that shifting recombination hotspots reduced the decline of genetic and genic variance by releasing standing allelic variation in the form of new allele combinations. This in turn resulted in larger increases in genetic gain. However, the benefit of shifting recombination hotspots for increased genetic gain was only observed when QTN were initially outside recombination hotspots. If QTN were initially inside recombination hotspots then shifting them decreased genetic gain. DISCUSSION: Shifting recombination hotspots to regions of the genome where recombination had not occurred for 21 generations of selection (i.e. recombination deserts) released more of the standing allelic variation available in each generation and thus increased genetic gain. However, whether and how much increase in genetic gain was achieved by shifting recombination hotspots depended on the distribution of QTN in the genome, the number of recombination hotspots and whether QTN were initially inside or outside recombination hotspots. CONCLUSIONS: Our findings show future scope for targeted modification of recombination hotspots e.g. through changes in zinc-finger motifs of the PRDM9 protein to increase genetic gain in production species. PMID- 28676072 TI - Giant desmoplastic cutaneous squamous cell carcinoma of the gluteal region. AB - Cutaneous squamous cell carcinoma (cSCC) is the most common type of skin tumour with the ability of metastatic spread. It represents about 20% of all malignancies diagnosed worldwide each year. Despite increased knowledge regarding the causes of skin cancer, the incidence of cSCC rises. The disease originates from epidermal keratinocytes, but it may occur on all areas of the body. It has an invasive nature and the potential to metastasise. We report unusual case of a giant metastatic desmoplastic cSCC of the gluteal region in a patient with previously resected desmoplastic cSCC presenting 8 months later with multiple liver and lung metastases. PMID- 28676071 TI - Effectiveness of an intervention to improve supportive care for family caregivers of patients with lung cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: Family caregivers (FC) often experience higher distress levels than their relative with cancer. Many cancer centers have implemented distress screening programs, but most of them concentrate their efforts on patients, with little attention to their FC. To fill this gap, a pragmatic intervention has been designed to improve supportive care for FC of patients with lung cancer. This article describes the study protocol of a single-center randomized controlled trial to assess its effectiveness. METHODS/DESIGN: A total of 120 lung cancer patients and their FC are randomly assigned to the experimental group (exposed to intervention, N = 60) or to the control group (usual care, N = 60). The intervention includes: (1) systematic FC distress screening and problem assessment near their relative's cancer diagnosis, and every 2 months, (2) privileged contact with an oncology nurse (ON) away from the patient to address FC problems and (3) liaison by the ON with the family physician of FC reporting high distress (thermometer score >=5/10), or problems relying on FP expertise. In both groups, FC, patient and process-of-care outcomes are measured at baseline and every 3 months, up to 9 months. The primary endpoint is FC distress measured by the Hospital Anxiety and Depression Scale (HADS) and the Psychological Distress Index used in the Quebec Health Survey (PDQHS). Individual interviews with 10 FC and a focus group with the oncology team will be conducted at the study end to further document the effectiveness of the intervention and its impact on quality of life (for FC) and practice organization (for the oncology team). DISCUSSION: This trial will assess the effectiveness of an innovative intervention based on interprofessional collaboration between primary care and oncology care. It targets a population in great need, yet often neglected, and has the potential to clearly improve patient and caregiver experience of cancer care, and reduce the burden of disease. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02531464 . Registered on 15 July 2015. PMID- 28676073 TI - One year symptom severity and health-related quality of life changes among Black African patients undergoing uterine fibroid embolisation. AB - BACKGROUND: The main aim in the treatment of symptomatic fibroids by various modalities including uterine fibroid embolisation (UFE) is to alleviate symptoms and ultimately improve the quality of life. The efficacy of this modality of treatment in Black African women with significant fibroid burden and large uterine volumes is not clear. The main objective of the study was to examine potential changes in symptom severity among Black African patients 1 year following UFE for symptomatic uterine fibroids in a resource-constrained setting, rated using a validated questionnaire (UFS-QOL). Secondary outcomes examined were changes in quality of life and potential associations with age, parity, uterine volume and fibroid number prior to UFE. Additional interventions after UFE were also recorded. METHODS: A prospective before and after study of Black African patients undergoing UFE was undertaken. Participants underwent pelvic MR imaging prior to UFE and completed the UFS-QOL, a validated condition-specific questionnaire at baseline and at 1 year. Ninety five participants were recruited and data from 80 completing 1 year of follow up were available for analysis of changes in the symptom severity scores. RESULTS: The mean reduction in symptom severity score was 29.6 [95% CI 23.6 to 35.6, P < 0.001] and the mean improvement in HRQOL score was 35.7 [95% CI 28.4 to 42.9, P < 0.001]. A greater number of fibroids identified prior to UFE was associated with a more substantial improvement in symptom severity score (rs = 0.28, n = 80, P = 0.013) and participants of higher parity reported a greater improvement in HRQOL score (r = 0.336, P = 0.002). Major and minor surgical interventions were needed in 5 (6.3%) and 10 (12.5%) participants respectively. CONCLUSIONS: UFE is associated with clinically useful and statistically significant symptom relief in Black African patients. Symptom improvement following UFE is not compromised by a large fibroid burden and the rate of subsequent intervention is within an acceptable range. UFE is a safe alternative and efforts are needed to widen access to this non-surgical treatment modality. PMID- 28676074 TI - Immunoregulatory effects of multipotent adult progenitor cells in a porcine ex vivo lung perfusion model. AB - BACKGROUND: Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways. METHODS: Lungs of domestic pigs (n = 6/group) were subjected to 90 minutes of warm ischemia. Lungs were cold flushed, cannulated on ice and placed on EVLP for 6 hours. At the start of EVLP, 40 ml of an albumin plasmalyte mixture was distributed in the airways (CONTR group). In the MAPC cell group, 150 million MAPC cells (ReGenesys/Athersys, Cleveland, OH, USA) were added to this mixture. At the end of EVLP, a physiological evaluation (pulmonary vascular resistance, lung compliance, PaO2/FiO2), wet-to-dry weight ratio (W/D) sampling and a multiplex analysis of bronchoalveolar lavage (BAL) (2 * 30 ml) was performed. RESULTS: Pulmonary vascular resistance, lung compliance, PaO2/FiO2 and W/D were not statistically different at the end of EVLP between both groups. BAL neutrophilia was significantly reduced in the MAPC cell group. Moreover, there was a significant decrease in TNF-alpha, IL-1beta and IFN-gamma in the BAL, but not in IFN-alpha; whereas IL-4, IL-10 and IL-8 were below the detection limit. CONCLUSIONS: Although no physiologic effect of MAPC cell distribution in the airways was detected during EVLP, we observed a reduction in pro-inflammatory cytokines and neutrophils in BAL in the MAPC cell group. This effect on the innate immune system might play an important role in critically modifying the process of PGD after transplantation. Further experiments will have to elucidate the immunoregulatory effect of MAPC cell administration on graft function after transplantation. PMID- 28676075 TI - sgnesR: An R package for simulating gene expression data from an underlying real gene network structure considering delay parameters. AB - BACKGROUND: sgnesR (Stochastic Gene Network Expression Simulator in R) is an R package that provides an interface to simulate gene expression data from a given gene network using the stochastic simulation algorithm (SSA). The package allows various options for delay parameters and can easily included in reactions for promoter delay, RNA delay and Protein delay. A user can tune these parameters to model various types of reactions within a cell. As examples, we present two network models to generate expression profiles. We also demonstrated the inference of networks and the evaluation of association measure of edge and non edge components from the generated expression profiles. RESULTS: The purpose of sgnesR is to enable an easy to use and a quick implementation for generating realistic gene expression data from biologically relevant networks that can be user selected. CONCLUSIONS: sgnesR is freely available for academic use. The R package has been tested for R 3.2.0 under Linux, Windows and Mac OS X. PMID- 28676077 TI - Malaria among rice farming communities in Kilangali village, Kilosa district, Central Tanzania: prevalence, intensity and associated factors. AB - BACKGROUND: Malaria remains the most important cause of morbidity and mortality in Tanzania. However, its prevalence varies from area to area depending on various ecological, socio-economic and health system factors. This study was carried out to determine malaria prevalence and associated factors among rice farming communities in the Kilangali village of Kilosa District in Central Tanzania. METHODS: A cross-sectional study was conducted in May 2015, involving randomly selected persons living in the six sub-villages of the Kilangali village, namely Mlegeni, Kisiwani, Makuruwili, Kwamtunga, Upogoroni and Chamwino. A finger prick blood sample was obtained for diagnosis of malaria infection using Giemsa-stained thick smears and a rapid malaria diagnostic test. Study participants were also screened for haemoglobin levels and a total of 570 children aged <= 12 years of age were examined for spleen enlargement using the palpation method. RESULTS: A total of 1154 persons were examined for malaria infection with mean age of 21.9 +/- 19.69 years. The overall malaria prevalence was 14.2% and 17.5% based on microscopic examination and rapid diagnostic test, respectively. Plasmodium falciparum accounted for the majority (89%) of the malaria infections. The overall geometrical mean parasite density was 20.5 parasites/MUL (95% CI: 14.6-28.8). Malaria prevalence and parasitaemia was highest among individuals living in the Mlegeni (23.9%) and Makuruwili (24.4%) sub-villages. Among the children examined for splenomegaly, 2.98% (17/570) had it. The overall prevalence of anaemia was 34.6%. Malaria infection was associated with the age groups of 1-10 years (aOR = 4.41, 95% CI: 1.96-9.93, P < 0.001) and 11-20 years (aOR = 6.68, 95% CI: 2.91-15.37, P < 0.001); and mild anaemia (aOR = 1.71, 95% CI: 1.11-2.62, P < 0.014) and moderate anaemia (aOR = 1.55, 95% CI: 1.01-2.39, P < 0.045). CONCLUSIONS: Malaria was found at the study setting and its prevalence varied according to the demographic characteristics of the study participants and between sub-villages that are closely located. PMID- 28676076 TI - Prevalence of hepatitis B and delta according to HIV-type: a multi-country cross sectional survey in West Africa. AB - BACKGROUND: In West Africa where HIV-1 and HIV-2 co-circulate, the co-infection with hepatitis B virus (HBV) and hepatitis Delta virus (HDV) is not well described. This study aimed at estimating the prevalence of HBV and HBV/HDV co infection according to HIV types and risk factors for HBV infection among West African HIV-infected patients. METHOD: A cross-sectional survey was conducted within the IeDEA West Africa cohort from March to December 2012 in Cote d'Ivoire (three sites), Burkina Faso and Mali (one site each). All HIV-infected adult patients on antiretroviral therapy (ART) or not who attended one of the participating HIV clinics during the study period and agreed to participate were included. Blood samples were collected and re-tested for HIV type discrimination, HBV and HDV serology as well as HBV viral load. Logistic regression was used to identify risk factors for HBV infection. RESULTS: A total of 791 patients were included: 192 HIV-1, 447 HIV-2 and 152 HIV-1&2 dually reactive. At time of sampling, 555 (70.2%) were on ART and median CD4+ cell count was 472/mm3 (inter quartile range [IQR]: IQR: 294-644). Sixty-seven (8.5%, 95% CI 6.6-10.6) patients were HBsAg positive without any difference according to HIV type (7.9% in HIV-1, 7.2% in HIV-1&2 dually reactive and 9.4% in HIV-2; p = 0.61). In multivariate logistic analysis, age <= 30 years old (adjusted odds ratio [aOR] 5.00, 95% CI 1.96-12.76), age between 31 and 49 years old (aOR 1.78, 95% CI 1.00-2.21) and male gender (aOR 2.15, 95% CI 1.25-3.69) were associated with HBsAg positivity. HBV DNA testing was performed in 36 patients with blood sample available (25 on ART) and 8 (22.2%) had detectable HBV DNA. Among the HBsAg-positive individuals, 14.9% (95% CI 7.4-25.7) were also positive for anti-HDV antibody without any difference according to HIV type (28.6% in HIV-1, 14.3% in HIV-2 and 0.0% in HIV 1&2 dually reactive; p = 0.15). CONCLUSION: HBV and HBV/HDV co-infection are common in West Africa, irrespective of HIV type. Therefore, screening for both viruses should be systematically performed to allow a better management of HIV infected patients. Follow-up studies are necessary to determine the impact of these two viruses on HIV infection. PMID- 28676078 TI - A systematic review of suture-button versus syndesmotic screw in the treatment of distal tibiofibular syndesmosis injury. AB - BACKGROUND: Now, using a suture-button device to treat distal tibiofibular syndesmotic injuries is overwhelming due to its advantages over screw fixation. Current systematic review was conducted to make a comparison between suture button fixation and traditionally screw fixation in the treatment of syndesmotic injuries. The outcomes included functional outcomes, implant removal, implant failure, malreduction, post-operative complications (except implant failure and malreduction), and cost-effectiveness aspects. METHOD: A literature search in the electronic databases of Medline, Embase, the Cochrane Library, Web of Science was conducted to identify studies until March 2017. The references of the included articles were also checked for potentially relevant studies. Only English articles were included. We followed the Preferred Reporting Items for Systematics reviews and Meta-Analysis (PRISMA) guidelines in this review. RESULTS: Finally, 10 studies were identified, encompassing a total of 390 patients. The mean American Orthopaedic Foot and Ankle Society ankle score (AOFAS) score of 150 patients treated with the suture-button device was 91.06 points, with an average follow-up of 17.58 months, and the mean AOFAS score of 150 patients treated with syndesmotic screws was 87.78 points, with an average follow-up of 17.73 months. Implant removal was reported in 5 of 134 (3.7%) patients treated with the suture button device, and in 54 of 134 (40.2%) patients treated with the syndesmotic screw. No patient in the suture-button fixation group had implant failure, however the rate of implant failure in the screw fixation group was 30.9%. Malreduction was reported in 1 of 93 (1.0%) patients treated with the suture button device, and in 12 of 95 (12.6%) patients treated with the syndesmotic screw. The rate of post-operative complications in the suture-button fixation group was 12.0% and 16.4% in the screw fixation group. There was only one publication demonstrated about cost-effectiveness aspects, it showed that patients treated with the suture-button device spent on average $1482 less and had a higher quality of life by 0.058 quality-adjusted life-year compared with patients who received fixation with 2 syndesmotic screws in supination-external rotation type 4 injuries. CONCLUSION: Based on our research, though the suture button fixation group had similar functional outcome (measured on the AOFAS score) and post-operative complication rate compared with the syndesmotic screw fixation group, the suture-button device could lead to better objective range of motion (ROM) measurements and earlier return to work. Besides, the suture-button fixation group had lower rate of implant removal, implant failure, and malreduction. However, high-quality randomized controlled trials with more uniformity in outcome reporting are desirable to determine the long-term effects and cost-effectiveness of the suture-button device. PMID- 28676079 TI - "Pseudo aortoiliac bifurcation" leading to significant plaque shifting in the endovascular treatment of an aortoiliac bifurcation lesion: a case report. AB - BACKGROUND: Plaque shifting is a serious complication of endovascular treatment (EVT) for aortoiliac bifurcation lesions. It is challenging to predict the occurrence of unfavorable plaque shifting correctly. CASE PRESENTATION: We report the case of an 88-year-old Japanese woman who experienced constant pain at rest in her left leg. The ankle-brachial pressure index of her left leg was 0.57. Computed tomography (CT) angiography revealed severe stenosis of the left common iliac artery (CIA) and total occlusion of the left external iliac artery (EIA). We diagnosed the patient with acute exacerbation of a chronic limb ischemia and administered endovascular treatment (EVT) to treat the left CIA and EIA. The results of initial angiography agreed with those of CT angiography. After placing a self-expandable stent for the left CIA lesion, significant unfavorable plaque shifting occurred. From a comparison between pre- and post-stenting angiography, we realized that the plaque protrusion into the terminal aorta had formed a "pseudo aortoiliac bifurcation" that was situated more proximally compared to the true bifurcation. We had incorrectly assessed the height of the aortoiliac bifurcation and exact plaque position and had underestimated the risk of plaque shifting because of this misunderstanding. The patient ultimately developed fatal cholesterol embolization after EVT. CONCLUSIONS: Plaque protrusion into the terminal aorta can form a "pseudo aortoiliac bifurcation", causing the wrong estimation of the height of the aortoiliac bifurcation; "angiographically", the highest point is not always the true bifurcation. Careful assessment of initial angiography to detect the true aortoiliac bifurcation and exact plaque position is essential to avoid unfavorable plaque shifting. PMID- 28676080 TI - Pharmacokinetic and pharmacodynamic modeling of oral mitiglinide on glucose lowering in healthy Chinese volunteers. AB - BACKGROUND: Mitiglinide is a widely used agent for diabetic treatment. We established a pharmacokinetic-pharmacodynamic (PK-PD) model to illustrate the relationship between mitiglinide plasma concentration and its glucose lowering effects in healthy volunteers. METHODS: The volunteers participated in the test after the administration of a single dose of 10 mg mitiglinide. The drug concentration in Plasma and the values of glucose levels were determined by LC MS/MS assay and hexokinase method. A PK-PD model was established with a series of equations to describe the relationship between plasma medicine and glucose, and the equations were solved numerically and fitted to the data with the Phoenix NLME software. RESULTS: The results of the two-compartment model analysis were based on the maximum likelihood criterion and visual inspection of the fittings. The terminal elimination half-life (t 1/2) was 1.69 +/- 0.16 h and the CL/F was 7.80 +/- 1.84 L/h. The plasma glucose levels began to decline by 0.2 h, and hit its bottom decreasing values of 2.6 mg/L at 0.5 h after administration. The calculated parameter and fitting curve indicated that the model established in our experiment fitted well. CONCLUSIONS: A PK/PD model illustrates that the relationship between mitiglinide concentration in plasma and glucose lowering effect in healthy volunteers was established. The results of our experiment suggested that the model can be used reasonably to predict the relationship between PK and PD in mitiglinide, which could be used in diabetes mellitus dosage control in clinical trials and other fields. PMID- 28676081 TI - Gender differences in physical activity motivators and context preferences: a population-based study in people in their sixties. AB - BACKGROUND: Although regular participation in physical activity (PA) has health benefits across the life span, the proportion of people doing sufficient activity for these benefits decreases with age. The aim of this study was to identify motivating factors and context preferences for PA in people in their sixties, and to examine gender differences in these factors. METHODS: Data were used from people aged 60-67 years who responded to a mail survey in Brisbane, Australia, in 2009. Respondents indicated their agreement/disagreement with seven PA motivators and 14 PA context preferences. Data were analyzed using multi-level multinomial logistic regression, adjusted for sociodemographic and health variables, and PA level. RESULTS: Of the 1845 respondents, 59% was female. Based on self-reported PA, one in three respondents (35%) did not meet the PA guidelines of at least 150 min of moderate intensity PA per week. The three leading motivating factors for both women and men were to prevent health problems, to feel good and to lose weight. Women were more likely than men to be motivated by improving appearance (OR 2.93, 95%CI 2.07-4.15), spending time with others (1.76, 1.31-2.37), meeting friends (1.76, 1.31-2.36) or losing weight (1.74, 1.12-2.71). The three leading context preferences for both women and men were for activities close to home, at low cost and that could be done alone. Women were more likely than men to prefer activities that are with people of the same sex (OR 4.67, 95%CI 3.14-6.94), supervised (2.79, 1.94-4.02), with people the same age (2.00, 1.43-2.78) and at a fixed time (1.42, 1.06-1.91). Women were less likely than men to prefer activities that are competitive (OR 0.32, 95%CI 0.22-0.46), are vigorous (0.33, 0.24-0.47), require skill and practice (0.40, 0.29-0.55) and done outdoors (0.51, 0.30-0.86). CONCLUSION: Although there was overlap in motivating factors and context preferences for PA in women and men aged 60-67 years, there were also marked gender differences. These results suggest that PA options for people in their sixties should be tailored to meet gender specific interests in order to promote PA participation in this rapidly growing population group. PMID- 28676083 TI - Measuring individual hierarchy of anxiety invoking sports related activities: development and validation of the Photographic Series of Sports Activities for Anterior Cruciate Ligament Reconstruction (PHOSA-ACLR). AB - BACKGROUND: Fear of harm (FoH) after Anterior Cruciate Ligament Reconstruction (ACLR) should be addressed in physical therapy as it hampers return to sports. However, there are no instruments assessing FoH specific for ACLR. The objective of this study is to describe the development and measurement properties of the Photograph Series of Sports Activities for ACLR (PHOSA-ACLR) measuring ACL injury related FoH. METHODS: Based on literature and opinion of physical therapists with extensive experience in ACLR treatment, photographs depicting FoH inducing situations in ACL injury were considered for inclusion in the instrument. For each photograph the patients is asked to report perceived harmfulness. The set of photographs was completed by two samples of patients with ACLR: 1 cross-sectional sample (n = 55), and 1 test-retest reliability sample (n = 58). Internal consistency and structural validity were assessed in 109 patients. In 58 patients criterion validity was assessed by calculating pearson correlations with the Tampa Scale of Kinesiophobia (TSK). Correlations with self-reported knee function (KOOS and Lysholm score), and Knee Self-efficacy Scale (K-SES) were computed for hypothesis testing. Test-retest reliability was determined in a group of 55 patients, assessed twice with 1 week between assessments. RESULTS: Twelve photographs depicting sports related movements that are likely to invoke FoH after ACLR were selected. Two items were deleted because of lack of discrimination. The remaining 10 items were included in the PHOSA-ACLR, and the scale showed excellent internal consistency (Cronbach's Alpha is .95). Items reflected one dimension, and was strongly correlated with TSK (r = .59). A priori formulated hypotheses are confirmed and test-retest correlation was excellent (ICC = .86). CONCLUSION: The PHOSA-ACLR showed acceptable measurement properties. The PHOSA-ACLR gives specific information about fear invoking sports situations that are not measured by other kinesophobia measures. Therefore, the PHOSA-ACLR might be a valuable additional tool in rehabilitation of ACLR patients. Additional research is needed to determine responsiveness to change. PMID- 28676082 TI - Cell sex affects extracellular matrix protein expression and proliferation of smooth muscle progenitor cells derived from human pluripotent stem cells. AB - BACKGROUND: Smooth muscle progenitor cells (pSMCs) differentiated from human pluripotent stem cells (hPSCs) hold great promise for treating diseases or degenerative conditions involving smooth muscle pathologies. However, the therapeutic potential of pSMCs derived from men and women may be very different. Cell sex can exert a profound impact on the differentiation process of stem cells into somatic cells. In spite of advances in translation of stem cell technologies, the role of cell sex and the effect of sex hormones on the differentiation towards mesenchymal lineage pSMCs remain largely unexplored. METHODS: Using a standard differentiation protocol, two human embryonic stem cell lines (one male line and one female line) and three induced pluripotent stem cell lines (one male line and two female lines) were differentiated into pSMCs. We examined differences in the differentiation of male and female hPSCs into pSMCs, and investigated the effect of 17beta-estradiol (E2) on the extracellular matrix (ECM) metabolisms and cell proliferation rates of the pSMCs. Statistical analyses were performed by using Student's t test or two-way ANOVA, p < 0.05. RESULTS: Male and female hPSCs had similar differentiation efficiencies and generated morphologically comparable pSMCs under a standard differentiation protocol, but the derived pSMCs showed sex differences in expression of ECM proteins, such as MMP-2 and TIMP-1, and cell proliferation rates. E2 treatment induced the expression of myogenic gene markers and suppressed ECM degradation activities through reduction of MMP activity and increased expression of TIMP-1 in female pSMCs, but not in male pSMCs. CONCLUSIONS: hPSC-derived pSMCs from different sexes show differential expression of ECM proteins and proliferation rates. Estrogen appears to promote maturation and ECM protein expression in female pSMCs, but not in male pSMCs. These data suggest that intrinsic cell-sex differences may influence progenitor cell biology. PMID- 28676084 TI - Social and demographic drivers of trend and seasonality in elective abortions in Denmark. AB - BACKGROUND: Elective abortions show a secular decline in high income countries. That general pattern, however, may mask meaningful differences-and a potentially rising trend-among age, income, and other racial/ethnic groups. We explore these differences in Denmark, a high-income, low-fertility country with excellent data on terminations and births. METHODS: We examined monthly elective abortions (n = 225,287) from 1995 to 2009, by maternal age, parity, income level and mother's country of origin. We applied time-series methods to live births as well as spontaneous and elective abortions to approximate the denominator of pregnancies at risk of elective abortion. We used linear regression methods to identify trend and seasonal patterns. RESULTS: Despite an overall declining trend, teenage women show a rising proportion of pregnancies that end in an elective termination (56% to 67%, 1995 to 2009). Non-Western immigrant women also show a slight increase in incidence. Heightened economic disadvantage among non-Western immigrant women does not account for this rise. Elective abortions also show a sustained "summer peak" in June, July and August. Low-income women show the most pronounced summer peak. CONCLUSIONS: Identification of the causes of the increase over time in elective abortion among young women, and separately among non-Western immigrant women, represents key areas of further inquiry. The unexpected increase over time in elective abortions among teens and non-Western immigrants in Denmark may signal important social and cultural impediments to contraception. The summer peak in abortions among low-income women, moreover, conflicts with the conventional assumption that the social and demographic composition of mothers who electively end their pregnancy remains stable within a calendar year. PMID- 28676085 TI - Nasal administration of the neuroprotective candidate NeuroEPO to healthy volunteers: a randomized, parallel, open-label safety study. AB - BACKGROUND: Delivery of therapeutic agents as erythropoietin (EPO) into Central Nervous System through intranasal route could benefit patients with neurological disorders. A new nasal formulation containing a non-hematopoietic recombinant EPO (NeuroEPO) has shown neuroprotective actions in preclinical models. In the current study, the safety of NeuroEPO was evaluated for the first time in humans. METHODS: A phase I, randomized, parallel, open-label study was carried out in healthy volunteers. They received, intranasally, 1 mg of NeuroEPO every 8 h during 4 days (Group A) or 0.5 mg of NeuroEPO (Group B) with the same schedule. The working hypothesis was that intranasal NeuroEPO produce <10% of severe adverse reactions in the evaluated groups. Therefore, a rigorous assessment of possible adverse events was carried out, which included tolerance of the nasal mucosa and the effect on hematopoietic activity. Clinical safety evaluation was daily during treatment and laboratory tests were done before and on days 5 and 14 after starting treatment. RESULTS: Twenty-five volunteers, 56% women, with a mean age of 27 yrs. were included. Twelve of them received the highest NeuroEPO dose. Twenty types of adverse events occurred, with headache (20%) and increase of hepatic enzymes (20%) as the most reported ones. Nasopharyngeal itching was the most common local event but only observed in four patients (16%), all of them from the lowest dose group. About half of the events were very probably or probably caused by the studied product. Most of the events were mild (95.5%), did not require treatment (88.6%) and were completely resolved (81.8%). No severe adverse events were reported. During the study the hematopoietic variables were kept within reference values. CONCLUSIONS: NeuroEPO was a safe product, well tolerated at the nasal mucosa level and did not stimulate erythropoiesis in healthy volunteers. TRIAL REGISTRATION: Cuban Public Registry of Clinical Trials RPCEC00000157 , June 10, 2013. PMID- 28676086 TI - A DAG-based comparison of interventional effect underestimation between composite endpoint and multi-state analysis in cardiovascular trials. AB - BACKGROUND: Composite endpoints comprising hospital admissions and death are the primary outcome in many cardiovascular clinical trials. For statistical analysis, a Cox proportional hazards model for the time to first event is commonly applied. There is an ongoing debate on whether multiple episodes per individual should be incorporated into the primary analysis. While the advantages in terms of power are readily apparent, potential biases have been mostly overlooked so far. METHODS: Motivated by a randomized controlled clinical trial in heart failure patients, we use directed acyclic graphs (DAG) to investigate potential sources of bias in treatment effect estimates, depending on whether only the first or multiple episodes are considered. The biases first are explained in simplified examples and then more thoroughly investigated in simulation studies that mimic realistic patterns. RESULTS: Particularly the Cox model is prone to potentially severe selection bias and direct effect bias, resulting in underestimation when restricting the analysis to first events. We find that both kinds of bias can simultaneously be reduced by adequately incorporating recurrent events into the analysis model. Correspondingly, we point out appropriate proportional hazards based multi-state models for decreasing bias and increasing power when analyzing multiple-episode composite endpoints in randomized clinical trials. CONCLUSIONS: Incorporating multiple episodes per individual into the primary analysis can reduce the bias of a treatment's total effect estimate. Our findings will help to move beyond the paradigm of considering first events only for approaches that use more information from the trial and augment interpretability, as has been called for in cardiovascular research. PMID- 28676087 TI - Incidence, temporal trend and factors associated with ventilator-associated pneumonia in mainland China: a systematic review and meta-analysis. AB - BACKGROUND: Data to date is far from sufficient to describe the recent epidemiology of ventilator-associated pneumonia (VAP) in mainland China. This study aimed to estimate the overall incidence of VAP, with a special focus on its temporal trend and associated factors. METHODS: Meta-analyses of 195 studies published from 2010 to 2015 were conducted, followed by subgroup analyses by methodological quality, pre-defined setting characteristics and attributes of populations. RESULTS: The overall cumulative VAP incidence in mainland China was 23.8% (95% confidence interval (CI) 20.6-27.2%), with the results showing high heterogeneity. The pooled incidence densities were 24.14 (95% CI 21.19-27.51) episodes and 22.83 (95% CI 19.88-26.23) patients per 1000 ventilator-days. A decline in the cumulative incidence was observed from 2006 (49.5%, 95% CI 40.0 59.0%) to 2014 (19.6%, 95% CI 10.4-31.0%); differences in the incidence rates were also documented according to Chinese provinces and diagnostic criteria (p < 0.001). Older age (>=60 years), coma, re-intubation, tracheotomy and prolonged ventilation were the factors significantly associated with the occurrence of VAP. CONCLUSIONS: The incidence of VAP remains high in mainland China but has decreased since 2006. The reported rates vary considerably across individual studies, probably due to variations in diagnosis and geographical region. More studies using standard definitions and cut-off points are needed to better clarify the epidemiology of VAP across the country. PMID- 28676088 TI - Parasitological and biochemical studies on cutaneous leishmaniasis in Shara'b District, Taiz, Yemen. AB - BACKGROUND: The leishmaniasis is a group of diseases caused by intracellular haemoflagellate protozoan parasites of the genus Leishmania. Leishmaniasis has diverse clinical manifestations; cutaneous leishmaniasis (CL) is the most common form of leishmaniasis which is responsible for 60% of disability-adjusted life years. CL is endemic in Yemen. In Shara'b there is no reference study available to identify the prevalence of endemic diseases and no investigation has been conducted for diagnosing the diseases. METHODS: This study was conducted in villages for CL which collected randomly. The study aimed at investigating the epidemiological factors of CL in Shara'b by using questioner. Symptoms of lesions in patients suffering from CL, confirmed by laboratory tests, gave a new evidence of biochemical diagnosis in 525 villagers aged between 1 and 60 years old. Venous bloods were collected from 99 patients as well as from 51 control after an overnight fast. RESULTS: The percentage prevalence of CL was found 18.8%. The prevalence rate of infection among males (19.3%) was higher than females (18.40%). Younger age group (1-15) had a higher prevalence rate (20.3%) than the other age groups. Furthermore, the population with no formal education had the higher rate of infection (61% of the total). A significant increase of serum malondialdehyde (P < 0.001) in CL patients was obtained. The highest level of MDA may be due to over production of ROS and RNS results in oxidative stress and the acceleration of lipid peroxidation in CL patients. CONCLUSIONS: There were high prevalence rates of CL in Shara'b. The patient who had CL has been found with many changes in some biochemical levels. This study provides a clear indication on the role of MDA as an early biochemical marker of peroxidation damage occurring during CL. Increased uric acid, and catalase activity was provided of free radical. PMID- 28676090 TI - Clustering patient mobility patterns to assess effectiveness of health-service delivery. AB - BACKGROUND: Analysis of patient mobility in a country not only gives an idea of how the health-care system works, but also can be a guideline to determine the quality of health care and health disparity among regions. Even though determination of patient movement is important, it is not often realized that patient mobility could have a unique pattern beyond health-related endowments (e.g., facilities, medical staff). This study therefore addresses the following research question: Is there a way to identify regions with similar patterns using spatio-temporal distribution of patient mobility? The aim of the paper is to answer this question and improve a classification method that is useful for populous countries like Turkey that have many administrative areas. METHODS: The data used in the study consist of spatio-temporal information on patient mobility for the period between 2009 and 2013. Patient mobility patterns based on the number of patients attracted/escaping across 81 provinces of Turkey are illustrated graphically. The hierarchical clustering method is used to group provinces in terms of the mobility characteristics revealed by the patterns. Clustered groups of provinces are analyzed using non-parametric statistical tests to identify potential correlations between clustered groups and the selected basic health indicators. RESULTS: Ineffective health-care delivery in certain regions of Turkey was determined through identifying patient mobility patterns. High escape values obtained for a large number of provinces suggest poor health care accessibility. On the other hand, over the period of time studied, visualization of temporal mobility revealed a considerable decrease in the escape ratio for inadequately equipped provinces. Among four of twelve clusters created using the hierarchical clustering method, which include 64 of 81 Turkish provinces, there was a statistically significant relationship between the patterns and the selected basic health indicators of the clusters. The remaining eight clusters included 17 provinces and showed anomalies. CONCLUSIONS: The most important contribution of this study is the development of a way to identify patient mobility patterns by analyzing patient movements across the clusters. These results are strong evidence that patient mobility patterns provide a useful tool for decisions concerning the distribution of health-care services and the provision of health care equipment to the provinces. PMID- 28676089 TI - Effects of silica nanoparticle exposure on mitochondrial function during neuronal differentiation. AB - BACKGROUND: Nanomedicine offers a promising tool for therapies of brain diseases, but potential effects on neuronal health and neuronal differentiation need to be investigated to assess potential risks. The aim of this study was to investigate effects of silica-indocyanine green/poly (epsilon-caprolactone) nanoparticles (PCL-NPs) engineered for laser tissue soldering in the brain before and during differentiation of SH-SY5Y cells. Considering adaptations in mitochondrial homeostasis during neuronal differentiation, metabolic effects of PCL-NP exposure before and during neuronal differentiation were studied. In addition, kinases of the PI3 kinase (PI3-K/Akt) and the MAP kinase (MAP-K/ERK) pathways related to neuronal differentiation and mitochondrial function were investigated. RESULTS: Differentiation resulted in a decrease in the cellular respiration rate and the extracellular acidification rate (ECAR). PCL-NP exposure impaired mitochondrial function depending on the time of exposure. The cellular respiration rate was significantly reduced compared to differentiated controls when PCL-NPs were given before differentiation. The shift in ECAR was less pronounced in PCL-NP exposure during differentiation. Differentiation and PCL-NP exposure had no effect on expression levels and the enzymatic activity of respiratory chain complexes. The activity of the glycolytic enzyme phosphofructokinase was significantly reduced after differentiation with the effect being more pronounced after PCL-NP exposure before differentiation. The increase in mitochondrial membrane potential observed after differentiation was not found in SH-SY5Y cells exposed to PCL-NPs before differentiation. The cellular adenosine triphosphate (ATP) production significantly dropped during differentiation, and this effect was independent of the PCL-NP exposure. Differentiation and nanoparticle exposure had no effect on superoxide levels at the endpoint of the experiments. A slight decrease in the expression of the neuronal differentiation markers was found after PCL-NP exposure, but no morphological variation was observed. CONCLUSIONS: PCL-NP exposure affects mitochondrial function depending on the time of exposure before and during neuronal differentiation. PCL-NP exposure during differentiation was associated with impaired mitochondrial function, which may affect differentiation. Considering the importance of adaptations in cellular respiration for neuronal differentiation and function, further studies are needed to unravel the underlying mechanisms and consequences to assess the possible risks including neurodegeneration. PMID- 28676091 TI - Assessment of the efficiency of language interpreter services in a busy surgical and procedural practice. AB - BACKGROUND: Surgical and procedural patient care settings require efficient patient flow. The primary goal of this study was to assess use and efficiency of language services for our limited English proficiency (LEP) patients undergoing surgical and outpatient procedures. METHODS: Patient language services needs were recorded from our operating room and procedural locations over a two and a half month period in 2016. Time from in-person interpreter request to arrival was recorded. Frequency of language service modality used and reason for telephone and professional video remote interpreting (VRI) rather than in person professional services was queried. RESULTS: Mean time from in-person interpreter request until arrival was 19 min. Variation was high. No cases were cancelled due to lack of available interpretive services and no LEP patient underwent a procedure without requested interpretative service assistance. CONCLUSIONS: Time for in person professional interpreter assistance was short but highly variable. Access to telephone interpretive services and VRI services ensured assistance when in person interpreters were immediately unavailable. With the numbers of LEP patients increasing over time along with any new mandates for providing language assistance, the stress on hospital patient service units and the financial implications for many health care facilities will likely continue as challenges. PMID- 28676093 TI - The invasive shrub Prosopis juliflora enhances the malaria parasite transmission capacity of Anopheles mosquitoes: a habitat manipulation experiment. AB - BACKGROUND: A neglected aspect of alien invasive plant species is their influence on mosquito vector ecology and malaria transmission. Invasive plants that are highly attractive to Anopheles mosquitoes provide them with sugar that is critical to their survival. The effect on Anopheles mosquito populations was examined through a habitat manipulation experiment that removed the flowering branches of highly attractive Prosopis juliflora from selected villages in Mali, West Africa. METHODS: Nine villages in the Bandiagara district of Mali were selected, six with flowering Prosopis juliflora, and three without. CDC-UV light traps were used to monitor their Anopheles spp. vector populations, and recorded their species composition, population size, age structure, and sugar feeding status. After 8 days, all of the flowering branches were removed from three villages and trap catches were analysed again. RESULTS: Villages where flowering branches of the invasive shrub Prosopis juliflora were removed experienced a threefold drop in the older more dangerous Anopheles females. Population density dropped by 69.4% and the species composition shifted from being a mix of three species of the Anopheles gambiae complex to one dominated by Anopheles coluzzii. The proportion of sugar fed females dropped from 73 to 15% and males from 77 to 10%. CONCLUSIONS: This study demonstrates how an invasive plant shrub promotes the malaria parasite transmission capacity of African malaria vector mosquitoes. Proper management of invasive plants could potentially reduce mosquito populations and malaria transmission. PMID- 28676092 TI - Host-seeking activity of a Tanzanian population of Anopheles arabiensis at an insecticide treated bed net. AB - BACKGROUND: Understanding how mosquitoes respond to long lasting insecticide treated nets (LLINs) is fundamental to sustaining the effectiveness of this essential control tool. We report on studies with a tracking system to investigate behaviour of wild anophelines at an LLIN, in an experimental hut at a rural site in Mwanza, Tanzania. METHODS: Groups of adult female mosquitoes (n = 10 per replicate) reared from larvae of a local population, identified as predominantly (95%) Anopheles arabiensis, were released in the hut. An infrared video tracking system recorded flight and net contact activity over 1 h as the mosquitoes attempted to reach a supine human volunteer within a bed net (either a deltamethrin-treated LLIN or an untreated control net). A range of activities, including flight path, position in relation to the bed net and duration of net contact, were quantified and compared between treatments. RESULTS: The total time that female An. arabiensis spent in flight around LLINs was significantly lower than at untreated nets [F(1,10) = 9.26, p = 0.012], primarily due to a substantial reduction in the time mosquitoes spent in persistent 'bouncing' flight [F(1,10) = 18.48, p = 0.002]. Most activity occurred at the net roof but significantly less so with LLINs (56.8% of total) than untreated nets [85.0%; Chi2 (15) = 234.69, p < 0.001]. Activity levels at the bed net directly above the host torso were significantly higher with untreated nets (74.2%) than LLINs [38.4%; Chi2 (15) = 33.54, p = 0.004]. 'Visiting' and 'bouncing' rates were highest above the volunteer's chest in untreated nets (39.9 and 50.4%, respectively) and LLINs [29.9 and 42.4%; Chi2 (13) = 89.91, p < 0.001; Chi2 (9) = 45.73, p < 0.001]. Highest resting rates were above the torso in untreated nets [77%; Chi2 (9) = 63.12, p < 0.001], but in LLINs only 33.2% of resting occurred here [Chi2 (9) = 27.59, p = 0.001], with resting times spread between the short vertical side of the net adjacent to the volunteer's head (21.8%) and feet (16.2%). Duration of net contact by a single mosquito was estimated at 204-290 s on untreated nets and 46-82 s on LLINs. While latency to net contact was similar in both treatments, the reduction in activity over 60 min was significantly more rapid for LLINs [F(1,10) = 6.81, p = 0.026], reiterating an 'attract and kill' rather than a repellent mode of action. CONCLUSIONS: The study has demonstrated the potential for detailed investigations of behaviour of wild mosquito populations under field conditions. The results validate the findings of earlier laboratory studies on mosquito activity at LLINs, and reinforce the key role of multiple brief contacts at the net roof as the critical LLIN mode of action. PMID- 28676094 TI - Cultured epidermal stem cells in regenerative medicine. AB - Transplantation of cultured epidermal cell sheets (CES) has long been used to treat patients with burns, chronic wounds, and stable vitiligo. In patients with large area burns this can be a life-saving procedure. The ultimate goal, however, is to restore all normal functions of the skin and prevent scar formation. Increased focus on the incorporation of epidermal stem cells (EpiSCs) within CES transplants may ultimately prove to be key to achieving this. Transplanted EpiSCs contribute to restoring the complete epidermis and provide long-term renewal.Maintenance of the regenerative potential of EpiSCs is anchorage dependent. The extracellular matrix (ECM) provides physical cues that are interpreted by EpiSCs and reciprocal signaling between cells and ECM are integrated to determine cell fate. Thus, the carrier scaffold chosen for culture and transplant influences maintenance of EpiSC phenotype and may enhance or detract from regenerative healing following transfer.Long-term effectiveness and safety of genetically modified EpiSCs to correct the severe skin blistering disease epidermolysis bullosa has been shown clinically. Furthermore, skin is gaining interest as an easily accessible source of adult epithelial stem cells potentially useful for restoration of other types of epithelia. This review highlights the role of EpiSCs in the current treatment of skin injury and disease, as well as their potential in novel regenerative medicine applications involving other epithelia. PMID- 28676095 TI - Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal alpha synucleinopathy. AB - BACKGROUND: Alpha-synuclein (alpha-syn) aggregation represents the pathological hallmark of alpha-synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Toll-like receptors (TLRs) are a family of highly conserved molecules that recognize pathogen-associated molecular patterns and define the innate immunity response. It was previously shown that TLR4 plays a role in the clearance of alpha-syn, suggesting that TLR4 up-regulation in microglia may be a natural mechanism to improve the clearance of alpha-syn. However, administration of TLR4 ligands could also lead to dangerous adverse effects associated with the induction of toxic inflammatory responses. Monophosphoryl lipid A (MPLA) is a TLR4 selective agonist and a potent inducer of phagocytosis which does not trigger strong toxic inflammatory responses as compared to lipopolysaccharide (LPS). We hypothesize that MPLA treatment will lead to increased clearance of alpha-syn inclusions in the brain of transgenic mice overexpressing alpha-syn in oligodendrocytes under the proteolipid protein promoter (PLP-alpha-syn mouse model of MSA), without triggering toxic cytokine release, thus leading to a general amelioration of the pathology. METHODS: Six month old PLP-alpha-syn mice were randomly allocated to four groups and received weekly intraperitoneal injections of MPLA (50 or 100 MUg), LPS or vehicle. After a 12-week treatment period, motor behavior was assessed with the pole test. Brains and plasma samples were collected for neuropathological and immunological analysis. RESULTS: Chronic systemic MPLA treatment of PLP-alpha-syn mice led to increased uptake of alpha-syn by microglial cells, a significant motor improvement, rescue of nigral dopaminergic and striatal neurons and region specific reduction of the density of oligodendroglial alpha-syn cytoplasmic inclusions in the absence of a marked systemic inflammatory response. CONCLUSION: Our findings demonstrate beneficial effects of chronic MPLA treatment in transgenic PLP-alpha-syn mice. MPLA appears to be an attractive therapeutic candidate for disease modification trials in MSA and related alpha synucleinopathies. PMID- 28676096 TI - Global gene expression profiling and senescence biomarker analysis of hESC exposed to H2O2 induced non-cytotoxic oxidative stress. AB - BACKGROUND: Human embryonic stem cells (hESCs) potentially offer new routes to study, on the basis of the Developmental Origins of Health and Disease (DOHaD) concept, how the maternal environment during pregnancy influences the offspring's health and can predispose to chronic disease in later life. Reactive oxygen species (ROS), antioxidant defences and cellular redox status play a key function in gene expression regulation and are involved in diabetes and metabolic syndromes as in ageing. METHODS: We have, therefore, designed an in vitro cell model of oxidative stress by exposing hESCs to hydrogen peroxide (H2O2) during 72 h, in order to resemble the period of preimplantation embryonic development. RESULTS: We have analysed the global gene expression profiles of hESCs (HUES3) exposed to non-cytotoxic H2O2 concentrations, using Illumina microarray HT-12 v4, and we found the differential expression of 569 upregulated and 485 downregulated genes. The most affected gene ontology categories were those related with RNA processing and splicing, oxidation reduction and sterol metabolic processes. We compared our findings with a published RNA-seq profiling dataset of human embryos developed in vitro, thereupon exposed to oxidative stress, and we observed that one of the common downregulated genes between this publication and our data, NEDD1, is involved in centrosome structure and function. CONCLUSIONS: Therefore, we assessed the presence of supernumerary centrosomes and showed that the percentage of cells with more than two centrosomes increased acutely with H2O2 treatment in hESCs (HUES3 and 7) and in a control somatic cell line (Hs27), inducing a premature entry into senescence. PMID- 28676097 TI - Genetic diversity of Plasmodium falciparum populations in southeast and western Myanmar. AB - BACKGROUND: The genetic diversity of malaria parasites reflects the complexity and size of the parasite populations. This study was designed to explore the genetic diversity of Plasmodium falciparum populations collected from two southeastern areas (Shwekyin and Myawaddy bordering Thailand) and one western area (Kyauktaw bordering Bangladesh) of Myanmar. METHODS: A total of 267 blood samples collected from patients with acute P. falciparum infections during 2009 and 2010 were used for genotyping at the merozoite surface protein 1 (Msp1), Msp2 and glutamate-rich protein (Glurp) loci. RESULTS: One hundred and eighty four samples were successfully genotyped at three genes. The allelic distributions of the three genes were all significantly different among three areas. MAD20 and 3D7 were the most prevalent alleles in three areas for Msp1 and Msp2, respectively. The Glurp allele with a bin size of 700-750 bp was the most prevalent both in Shwekyin and Myawaddy, whereas two alleles with bin sizes of 800-850 bp and 900 1000 bp were the most prevalent in the western site Kyauktaw. Overall, 73.91% of samples contained multiclonal infections, resulting in a mean multiplicity of infection (MOI) of 1.94. Interestingly, the MOI level presented a rising trend with the order of Myawaddy, Kyauktaw and Shwekyin, which also paralleled with the increasing frequencies of Msp1 RO33 and Msp2 FC27 200-250 bp alleles. Msp1 and Msp2 genes displayed higher levels of diversity and higher MOI rates than Glurp. PCR revealed four samples (two from Shwekyin and two from Myawaddy) with mixed infections of P. falciparum and P. vivax. CONCLUSIONS: This study genotyped parasite clinical samples from two southeast regions and one western state of Myanmar at the Msp1, Msp2 and Glurp loci, which revealed high levels of genetic diversity and mixed-strain infections of P. falciparum populations at these sites. The results indicated that malaria transmission intensity in these regions remained high and more strengthened control efforts are needed. The genotypic data provided baseline information for monitoring the impacts of malaria elimination efforts in the region. PMID- 28676098 TI - Noncontiguous multi-tiered spinal tuberculosis associated with sternal localization: a case report. AB - BACKGROUND: Tuberculous spondylodiscitis is a frequent localization of tuberculosis. Multi-tiered involvement and an association with sternal localization are rare. CASE PRESENTATION: We report a case of multi-tiered tuberculous spondylodiscitis with sternal localization in an immunocompetent 41 year-old Arab woman who had inflammatory bilateral sciatica L5 and S1 and a history of low back pain caused by a trauma. Radiography, computed tomography, and a vertebral biopsy were useful for diagnosis. She reacted well to anti bacillary treatment despite the occurrence of multiple paravertebral and subcutaneous abscesses. The medullar magnetic resonance imaging control performed at 4 months, 12 months, and 1 year after the end of treatment showed a favorable evolution. CONCLUSIONS: To avoid the delay of diagnosis, especially in our endemic context, tuberculosis must be evoked usually. This will improve the prognosis of our patients. PMID- 28676101 TI - Does anti-VEGF bevacizumab improve survival in experimental sepsis? PMID- 28676100 TI - Superior GVHD-free, relapse-free survival for G-BM to G-PBSC grafts is associated with higher MDSCs content in allografting for patients with acute leukemia. AB - BACKGROUND: Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (G-PBSC) has largely replaced unstimulated bone marrow (un-BM) for allografting because of accelerated engraftment, but with a higher morbidity and mortality of graft-versus-host-disease (GVHD). Recent studies suggested that G-CSF-primed BM (G-BM) had similar engraftment but lower morbidity and mortality of GVHD comparing to G-PBSC. A prospective, randomized, multicenter study was conducted to compare G-BM with G-PBSC as the grafts in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia in first complete remission (CR1). METHODS: Totally 101 adult leukemia in CR1 undergoing HLA identical sibling transplants were randomized into G-BM or G-PBSC group. The primary study endpoint was GVHD-free/relapse-free survival (GRFS). RESULTS: Both the engraftment of neutrophil and platelet were 2 days later in G-BM than in G PBSC group (P = 0.412, P = 0.39). G-BM group showed significantly lower II-IV acute GVHD (aGVHD) and similar III-IV aGVHD compared with G-PBSC group (12.2% vs 28.8% for II-IV, P = 0.048; 4.1% vs 9.6% for III-IV aGVHD, P = 0.267, respectively). The overall cumulative incidence of chronic GVHD (cGVHD) at 3 years were 22.3% +/- 6.3% and 44.8% +/- 7.6% (P = 0.026), respectively, and extensive cGHVD were 4.5% +/- 3.1% and 15% +/- 5.3% (P = 0.08), respectively, in G-BM and G-PBSC groups. Two groups had similar 3-year relapse, transplant-related mortality (TRM), overall survival (OS), and disease-free survival (DFS) (all P > 0.05). G-BM group showed significantly higher probability of GRFS than G-PBSC group (73.5% +/- 6.3% vs 55.8% +/- 6.9% at 1 year, P = 0.049; 69.0% +/- 6.7% vs 49.7% +/- 7.0% at 2 and 3 years, P = 0.03, respectively). Graft content analysis revealed statistically higher frequency of myeloid-derived suppressor cells (MDSCs) in the G-BM than in G-PBSC grafts (P < 0.01), and recipients received statistically higher numbers of MDSCs in G-BM than in G-PBSC group (P = 0.045). Numbers of MDSCs infused to patients were negatively correlated with the severity of aGVHD (P = 0.032, r = -0.214). Multivariate analysis showed that MDSC cell dose below the median (HR = 3.49, P < 0.001), recipient age (HR = 2.02, P = 0.039), and high risk of disease (HR = 2.14, P = 0.018) were independent risk factors for GRFS. CONCLUSIONS: G-BM grafts lead a better GRFS and less GVHD associated with a higher MDSCs content compared with G-PBSC grafts. PMID- 28676102 TI - Effects of an interactive mHealth innovation for early detection of patient reported symptom distress with focus on participatory care: protocol for a study based on prospective, randomised, controlled trials in patients with prostate and breast cancer. AB - BACKGROUND: Cancer patients are predominantly treated as out-patients and as they often experience difficult symptoms and side effects it is important to facilitate and improve patient-clinician communication to support symptom management and self-care. Although the number of projects within supportive cancer care evaluating mobile health is increasing, few evidence-based interventions are described in the literature and thus there is a need for good quality clinical studies with a randomised design and sufficient power to guide future implementations. An interactive information and communications technology platform, including a smartphone/computer tablet app for reporting symptoms during cancer treatment was created in collaboration with a company specialising in health care management. The aim of this paper is to evaluate the effects of using the platform for patients with breast cancer during neo adjuvant chemotherapy treatment and patients with locally advanced prostate cancer during curative radiotherapy treatment. The main hypothesis is that the use of the platform will improve clinical management, reduce costs, and promote safe and participatory care. METHOD: The study is a prospective, randomised, controlled trial for each patient group and it is based on repeated measurements. Patients are consecutively included and randomised. The intervention groups report symptoms via the app daily, during treatment and up to three weeks after end of treatment, as a complement to standard care. Patients in the control groups receive standard care alone. Outcomes targeted are symptom burden, quality of life, health literacy (capacity to understand and communicate health needs and promote healthy behaviours), disease progress and health care costs. Data will be collected before and after treatment by questionnaires, registers, medical records and biomarkers. Lastly, participants will be interviewed about participatory and meaningful care. DISCUSSION: Results will generate knowledge to enhance understanding about how to develop person-centred care using mobile technology. Supporting patients' involvement in their care to identify problems early, promotes more timely initiation of necessary treatment. This can benefit patients treated outside the hospital setting in regard to maintaining their safety. CLINICAL TRIAL REGISTRATION: June 12 2015 NCT02477137 (Prostate cancer) and June 12 2015 NCT02479607 (Breast cancer). PMID- 28676104 TI - Identification of long non-coding RNA in the horse transcriptome. AB - BACKGROUND: Efforts to resolve the transcribed sequences in the equine genome have focused on protein-coding RNA. The transcription of the intergenic regions, although detected via total RNA sequencing (RNA-seq), has yet to be characterized in the horse. The most recent equine transcriptome based on RNA-seq from several tissues was a prime opportunity to obtain a concurrent long non-coding RNA (lncRNA) database. RESULTS: This lncRNA database has a breadth of eight tissues and a depth of over 20 million reads for select tissues, providing the deepest and most expansive equine lncRNA database. Utilizing the intergenic reads and three categories of novel genes from a previously published equine transcriptome pipeline, we better describe these groups by annotating the lncRNA candidates. These lncRNA candidates were filtered using an approach adapted from human lncRNA annotation, which removes transcripts based on size, expression, protein-coding capability and distance to the start or stop of annotated protein-coding transcripts. CONCLUSION: Our equine lncRNA database has 20,800 transcripts that demonstrate characteristics unique to lncRNA including low expression, low exon diversity and low levels of sequence conservation. These candidate lncRNA will serve as a baseline lncRNA annotation and begin to describe the RNA-seq reads assigned to the intergenic space in the horse. PMID- 28676105 TI - Antipsychotic-associated psoriatic rash - a case report. AB - BACKGROUND: Antipsychotics are a heterogeneous group of drugs. Although, antipsychotics have been used for years, unexpected side effects may still occur. With this case report we focus on a possible association between psoriasis and antipsychotics. Data on the patient's course of psychiatric disease, onset of psoriasis and its evolution were extracted from the patient's medical files. CASE PRESENTATION: We present a case of a 21-year-old female diagnosed with schizophrenia. She was initially treated with quetiapine, and later switched to aripiprazole due to weight gain. After initiation of antipsychotic treatment, the patient suffered from severe psoriasis lesions. CONCLUSIONS: Antipsychotics may possess immunological properties that may be involved in immune-mediated conditions, such as psoriatic rash. Further studies are warranted to determine causality and mechanism. PMID- 28676103 TI - Pre-diagnostic metabolite concentrations and prostate cancer risk in 1077 cases and 1077 matched controls in the European Prospective Investigation into Cancer and Nutrition. AB - BACKGROUND: Little is known about how pre-diagnostic metabolites in blood relate to risk of prostate cancer. We aimed to investigate the prospective association between plasma metabolite concentrations and risk of prostate cancer overall, and by time to diagnosis and tumour characteristics, and risk of death from prostate cancer. METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition, pre-diagnostic plasma concentrations of 122 metabolites (including acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose and sphingolipids) were measured using targeted mass spectrometry (AbsoluteIDQ p180 Kit) and compared between 1077 prostate cancer cases and 1077 matched controls. Risk of prostate cancer associated with metabolite concentrations was estimated by multi-variable conditional logistic regression, and multiple testing was accounted for by using a false discovery rate controlling procedure. RESULTS: Seven metabolite concentrations, i.e. acylcarnitine C18:1, amino acids citrulline and trans-4-hydroxyproline, glycerophospholipids PC aa C28:1, PC ae C30:0 and PC ae C30:2, and sphingolipid SM (OH) C14:1, were associated with prostate cancer (p < 0.05), but none of the associations were statistically significant after controlling for multiple testing. Citrulline was associated with a decreased risk of prostate cancer (odds ratio (OR1SD) = 0.73; 95% confidence interval (CI) 0.62-0.86; p trend = 0.0002) in the first 5 years of follow-up after taking multiple testing into account, but not after longer follow-up; results for other metabolites did not vary by time to diagnosis. After controlling for multiple testing, 12 glycerophospholipids were inversely associated with advanced stage disease, with risk reduction up to 46% per standard deviation increase in concentration (OR1SD = 0.54; 95% CI 0.40-0.72; p trend = 0.00004 for PC aa C40:3). Death from prostate cancer was associated with higher concentrations of acylcarnitine C3, amino acids methionine and trans 4-hydroxyproline, biogenic amine ADMA, hexose and sphingolipid SM (OH) C14:1 and lower concentration of glycerophospholipid PC aa C42:4. CONCLUSIONS: Several metabolites, i.e. C18:1, citrulline, trans-4-hydroxyproline, three glycerophospholipids and SM (OH) C14:1, might be related to prostate cancer. Analyses by time to diagnosis indicated that citrulline may be a marker of subclinical prostate cancer, while other metabolites might be related to aetiology. Several glycerophospholipids were inversely related to advanced stage disease. More prospective data are needed to confirm these associations. PMID- 28676106 TI - Comparative analysis of gut microbiota associated with body mass index in a large Korean cohort. AB - BACKGROUND: Gut microbiota plays an important role in the harvesting, storage, and expenditure of energy obtained from one's diet. Our cross-sectional study aimed to identify differences in gut microbiota according to body mass index (BMI) in a Korean population. 16S rRNA gene sequence data from 1463 subjects were categorized by BMI into normal, overweight, and obese groups. Fecal microbiotas were compared to determine differences in diversity and functional inference analysis related with BMI. The correlation between genus-level microbiota and BMI was tested using zero-inflated Gaussian mixture models, with or without covariate adjustment of nutrient intake. RESULTS: We confirmed differences between 16Sr RNA gene sequencing data of each BMI group, with decreasing diversity in the obese compared with the normal group. According to analysis of inferred metagenomic functional content using PICRUSt algorithm, a highly significant discrepancy in metabolism and immune functions (P < 0.0001) was predicted in the obese group. Differential taxonomic components in each BMI group were greatly affected by nutrient adjustment, whereas signature bacteria were not influenced by nutrients in the obese compared with the overweight group. CONCLUSIONS: We found highly significant statistical differences between normal, overweight and obese groups using a large sample size with or without diet confounding factors. Our informative dataset sheds light on the epidemiological study on population microbiome. PMID- 28676107 TI - Study protocol: multi-parametric magnetic resonance imaging for therapeutic response prediction in rectal cancer. AB - BACKGROUND: Response to neoadjuvant chemoradiotherapy (CRT) of rectal cancer is variable. Accurate imaging for prediction and early assessment of response would enable appropriate stratification of management to reduce treatment morbidity and improve therapeutic outcomes. Use of either diffusion weighted imaging (DWI) or dynamic contrast enhanced (DCE) imaging alone currently lacks sufficient sensitivity and specificity for clinical use to guide individualized treatment in rectal cancer. Multi-parametric MRI and analysis combining DWI and DCE may have potential to improve the accuracy of therapeutic response prediction and assessment. METHODS: This protocol describes a prospective non-interventional single-arm clinical study. Patients with locally advanced rectal cancer undergoing preoperative CRT will prospectively undergo multi-parametric MRI pre CRT, week 3 CRT, and post-CRT. The protocol consists of DWI using a read-out segmented sequence (RESOLVE), and DCE with pre-contrast T1-weighted (VIBE) scans for T1 calculation, followed by 60 phases at high temporal resolution (TWIST) after gadoversetamide injection. A 3-dimensional voxel-by-voxel technique will be used to produce colour-coded ADC and Ktrans histograms, and data evaluated in combination using scatter plots. MRI parameters will be correlated with surgical histopathology. Histopathology analysis will be standardized, with chemoradiotherapy response defined according to AJCC 7th Edition Tumour Regression Grade (TRG) criteria. Good response will be defined as TRG 0-1, and poor response will be defined as TRG 2-3. DISCUSSION: The combination of DWI and DCE can provide information on physiological tumour factors such as cellularity and perfusion that may affect radiotherapy response. If validated, multi parametric MRI combining DWI and DCE can be used to stratify management in rectal cancer patients. Accurate imaging prediction of patients with a complete response to CRT would enable a 'watch and wait' approach, avoiding surgical morbidity in these patients. Consistent and reliable quantitation from standardised protocols is essential in order to establish optimal thresholds of ADC and Ktrans and permit the role of multi-parametric MRI for early treatment prediction to be properly evaluated. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448 (retrospectively registered 8/12/2016). PMID- 28676108 TI - Incidence, prevalence and mortality rates of malaria in Ethiopia from 1990 to 2015: analysis of the global burden of diseases 2015. AB - BACKGROUND: In Ethiopia there is no complete registration system to measure disease burden and risk factors accurately. In this study, the 2015 global burden of diseases, injuries and risk factors (GBD) data were used to analyse the incidence, prevalence and mortality rates of malaria in Ethiopia over the last 25 years. METHODS: GBD 2015 used verbal autopsy surveys, reports, and published scientific articles to estimate the burden of malaria in Ethiopia. Age and gender specific causes of death for malaria were estimated using cause of death ensemble modelling. RESULTS: The number of new cases of malaria declined from 2.8 million [95% uncertainty interval (UI) 1.4-4.5 million] in 1990 to 621,345 (95% UI 462,230-797,442) in 2015. Malaria caused an estimated 30,323 deaths (95% UI 11,533.3-61,215.3) in 1990 and 1561 deaths (95% UI 752.8-2660.5) in 2015, a 94.8% reduction over the 25 years. Age-standardized mortality rate of malaria has declined by 96.5% between 1990 and 2015 with an annual rate of change of 13.4%. Age-standardized malaria incidence rate among all ages and gender declined by 88.7% between 1990 and 2015. The number of disability-adjusted life years lost (DALY) due to malaria decreased from 2.2 million (95% UI 0.76-4.7 million) in 1990 to 0.18 million (95% UI 0.12-0.26 million) in 2015, with a total reduction 91.7%. Similarly, age-standardized DALY rate declined by 94.8% during the same period. CONCLUSIONS: Ethiopia has achieved a 50% reduction target of malaria of the millennium development goals. The country should strengthen its malaria control and treatment strategies to achieve the sustainable development goals. PMID- 28676111 TI - A study on the epidemiological characteristics and infectious forecast model of malaria at Guangzhou Airport among Chinese returnees from Africa. AB - BACKGROUND: Cross-border malaria transmission in China is a major component of Chinese imported malaria cases. Such cases mostly are travellers returning from malaria endemic countries in Africa. By investigating malaria infectious status among Chinese worker in Africa, this study analysed the malaria risk factors, in order to establish infectious forecast model. METHODS: Chinese returnees data from Africa were collected at Guangzhou Baiyun International Airport, Guangzhou, China between August 2015 and March 2016 and were included in the cross-sectional and retrospective survey. RESULTS: A total of 1492 respondents were included in the study with the majority consisting of junior middle school educated male. Most of them are manual and technical workers hired by companies, with average of 37.04 years of age. Overall malaria incidence rate of the population was 8.98% (134/1492), and there were no significant differences regarding age, gender, occupation, or team. Forecast model was developed on the basis of malaria risk factors including working country, local ecological environment type, work duration and intensity of mosquito bite prevention. CONCLUSIONS: The survey suggested that malaria incidence was high among Chinese travellers who had worked in Africa countries of heavy malaria burden. Further research on the frequency and severity of clinical episodes among Chinese travellers having worked in Africa is needed. PMID- 28676110 TI - Heterogeneous oxygen availability affects the titer and topology but not the fidelity of plasmid DNA produced by Escherichia coli. AB - BACKGROUND: Dissolved oxygen tension (DOT) is hardly constant and homogenously distributed in a bioreactor, which can have a negative impact in the metabolism and product synthesis. However, the effects of DOT on plasmid DNA (pDNA) production and quality have not been thoroughly investigated. In the present study, the effects of aerobic (DOT >=30% air sat.), microaerobic (constant DOT = 3% air sat.) and oscillatory DOT (from 0 to 100% air sat.) conditions on pDNA production, quality and host performance were characterized. RESULTS: Microaerobic conditions had little effect on pDNA production, supercoiled fraction and sequence fidelity. By contrast, oscillatory DOT caused a 22% decrease in pDNA production compared with aerobic cultures. Although in aerobic cultures the pDNA supercoiled fraction was 98%, it decreased to 80% under heterogeneous DOT conditions. The different oxygen availabilities had no effect on the fidelity of the produced pDNA. The estimated metabolic fluxes indicated substantial differences at the level of the pentose phosphate pathway and TCA cycle under different conditions. Cyclic changes in fermentative pathway fluxes, as well as fast shifts in the fluxes through cytochromes, were also estimated. Model-based genetic modifications that can potentially improve the process performance are suggested. CONCLUSIONS: DOT heterogeneities strongly affected cell performance, pDNA production and topology. This should be considered when operating or scaling-up a bioreactor with deficient mixing. Constant microaerobic conditions affected the bacterial metabolism but not the amount or quality of pDNA. Therefore, pDNA production in microaerobic cultures may be an alternative for bioreactor operation at higher oxygen transfer rates. PMID- 28676109 TI - Comparative genomics shows that viral integrations are abundant and express piRNAs in the arboviral vectors Aedes aegypti and Aedes albopictus. AB - BACKGROUND: Arthropod-borne viruses (arboviruses) transmitted by mosquito vectors cause many important emerging or resurging infectious diseases in humans including dengue, chikungunya and Zika. Understanding the co-evolutionary processes among viruses and vectors is essential for the development of novel transmission-blocking strategies. Episomal viral DNA fragments are produced from arboviral RNA upon infection of mosquito cells and adults. Additionally, sequences from insect-specific viruses and arboviruses have been found integrated into mosquito genomes. RESULTS: We used a bioinformatic approach to analyse the presence, abundance, distribution, and transcriptional activity of integrations from 425 non-retroviral viruses, including 133 arboviruses, across the presently available 22 mosquito genome sequences. Large differences in abundance and types of viral integrations were observed in mosquito species from the same region. Viral integrations are unexpectedly abundant in the arboviral vector species Aedes aegypti and Ae. albopictus, in which they are approximately ~10-fold more abundant than in other mosquito species analysed. Additionally, viral integrations are enriched in piRNA clusters of both the Ae. aegypti and Ae. albopictus genomes and, accordingly, they express piRNAs, but not siRNAs. CONCLUSIONS: Differences in the number of viral integrations in the genomes of mosquito species from the same geographic area support the conclusion that integrations of viral sequences is not dependent on viral exposure, but that lineage-specific interactions exist. Viral integrations are abundant in Ae. aegypti and Ae. albopictus, and represent a thus far underappreciated component of their genomes. Additionally, the genome locations of viral integrations and their production of piRNAs indicate a functional link between viral integrations and the piRNA pathway. These results greatly expand the breadth and complexity of small RNA-mediated regulation and suggest a role for viral integrations in antiviral defense in these two mosquito species. PMID- 28676112 TI - Unusual acylation of chloramphenicol in Lysobacter enzymogenes, a biocontrol agent with intrinsic resistance to multiple antibiotics. AB - BACKGROUND: The environmental gliding bacteria Lysobacter are emerging as a new group of biocontrol agents due to their prolific production of lytic enzymes and potent antibiotic natural products. These bacteria are intrinsically resistant to many antibiotics, but the mechanisms behind the antibiotic resistance have not been investigated. RESULTS: Previously, we have used chloramphenicol acetyltransferase gene (cat) as a selection marker in genetic manipulation of natural product biosynthetic genes in Lysobacter, because chloramphenicol is one of the two common antibiotics that Lysobacter are susceptible to. Here, we found L. enzymogenes, the most studied species of this genus, could still grow in the presence of a low concentration of chloramphenicol. Three chloramphenicol derivatives (1-3) with an unusual acylation pattern were identified in a cat containing mutant of L. enzymogenes and in the wild type. The compounds included chloramphenicol 3'-isobutyrate (1), a new compound chloramphenicol 1'-isobutyrate (2), and a rare chloramphenicol 3'-isovalerate (3). Furthermore, a mutation of a global regulator gene (clp) or a Gcn5-related N-acetyltransferase (GNAT) gene in L. enzymogenes led to nearly no growth in media containing chloramphenicol, whereas a complementation of clp restored the chloramphenicol acylation as well as antibiotic HSAF production in the clp mutant. CONCLUSIONS: The results indicated that L. enzymogenes contains a pool of unusual acyl donors for enzymatic modification of chloramphenicol that confers the resistance, which may involve the Clp-GNAT regulatory system. Because Lysobacter are ubiquitous inhabitants of soil and water, the finding may have important implications in understanding microbial competitions and bioactive natural product regulation. PMID- 28676113 TI - Community perceptions and attitudes on malaria case management and the role of community health workers. AB - BACKGROUND: Community Case Management of malaria (CCMm) is one of the new approaches adopted by the World Health Organization for malaria endemic countries to reduce the burden of malaria for vulnerable populations. It is based on the evidence that well-trained and supervised community health workers (CHWs) can provide prompt and adequate treatment to fever cases within 24 h to help reduce morbidity and mortality associated with malaria among under-five children. The perception and attitudes of the community members on the CHWs' role is of greater importance for acceptance of their services. The aim of the study was to assess community's perception and attitude towards CCMm and on CHWs who undertake it. METHODS: This study was conducted in five districts in western Kenya where Community Case Management was being undertaken. This was a qualitative cross sectional study in which in-depth interviews and focus group discussions were conducted with mothers of under-five children and key stakeholders. RESULTS: Overall, there were more positive expressions of perceptions and attitudes of the community members towards the CCMm programme and the role of CHWs. The positive perceptions included among others; recognition and appreciation of services of CHWs, bringing health services to close proximity to the community, avoiding long queues in the health facilities, provision of health education that encourages good health practices, and promotion of positive health-seeking behaviour from within the communities. This programme is not without challenges as some of the negative perceptions expressed by the community members included the fact that some clinicians doubt the capacity of CHWs on dispensing drugs in the community, some CHWs do not keep client's secrets and mistrust of CHWs due to conflicting information by government. CONCLUSIONS: It was evident that the community had more positive perceptions and attitudes towards the role of CHWs in CCMm than negative ones. There should however, be deliberate efforts towards sustaining the positive aspects and addressing the negative concerns raised by the community and the health care practitioners. PMID- 28676114 TI - Antibacterial activities and toxicological study of the aqueous extract from leaves of Alchornea cordifolia (Euphorbiaceae). AB - BACKGROUND: A. cordifolia is a plant widely used in Africa to solve many health problems. In Cameroon, it is used in the treatment of urogenital infections. As a continuation of our search for pharmacologically active agents from natural sources, the antimicrobial activity of A. cordifolia leaf extracts against E. coli and the toxicity of this extract were investigated. METHODS: The antibacterial activity of the aqueous extract from leaves of Alchornea cordifolia was carried out in vitro on Escherichia coli, as well as in vivo on E. coli infected rat model. Phytochemical screening was performed using standard methods. The acute toxicity was investigated in mice, while at the end of treatment of infected rats, some biochemical, hematological and histological markers of toxicity were evaluated. RESULTS: The extract exhibited a bacteriostatic activity with MIC value of 1500 MUg/ml. Phytochemical screening revealed the presence of phenols, tannins, triterpens, flavonoids, alkaloids, anthraquinones, anthocyanins, saponins and coumarins in the extract. The acute toxicity study showed LD50 values of 8.6 g/kg and 3.8 g/kg in male and female mice respectively. In vivo, the oral administration of the extract showed a dose-dependent decrease of the bacterial load as the extract at 232, 112 and 58 g/kg were able to eradicate the infection after 9, 11 and 13 days of treatment. The infected rats showed a significant (p < 0.05) increase in the level of serum creatinine, ALAT, white blood cells, and a significant (p < 0.05) decrease in the level of food and water intake, the relative weight of lungs, heart and spleen. In the treated rats, a significant (p < 0.05) increase in food and water intake and ALAT was observed at the doses of 116 and 232 mg/kg. A decrease in the red blood cells count and serum protein levels was also observed. These observations corroborate liver damages as revealed by the histopathological examination of the cross sections of this organ. CONCLUSION: The results of this assay thus showed that the extract of A. cordifolia is bacteriostatic, therapeutic at 58 g/kg bw and may be considered as slightly and almost non-toxic on females and males mice respectively. PMID- 28676116 TI - Metabolic syndrome and its predictors in an urban population in Kenya: A cross sectional study. AB - BACKGROUND: The metabolic syndrome (MetS) is a clustering of interrelated risk factors which doubles the risk of cardio-vascular disease (CVD) in 5-10 years and increases the risk of type 2 diabetes 5 fold. The identification of modifiable CVD risk factors and predictors of MetS in an otherwise healthy population is necessary in order to identify individuals who may benefit from early interventions. We sought to determine the prevalence of MetS as defined by the harmonized criteria and its predictors in subjectively healthy black Africans from various urban centres in Kenya. METHOD: We used data collected from healthy black Africans in Kenya as part of a global study on establishing reference intervals for common laboratory tests. We determined the prevalence of MetS and its components using the 2009 harmonized criterion. Receiver operator characteristic (ROC) curve analysis was used to determine the area under the curves (AUC) for various predictors of MetS. Youden index was used to determine optimum cut-offs for quantitative measurements such as waist circumference (WC). RESULTS: A total of 528 participants were included in the analysis. The prevalence of MetS was 25.6% (95% CI: 22.0%-29.5%). Among the surrogate markers of visceral adiposity, lipid accumulation product was the best predictor of MetS with an AUC of 0.880 while triglyceride was the best predictor among the lipid parameters with an AUC of 0.816 for all participants. The optimal WC cut-off for diagnosing MetS was 94 cm and 86 cm respectively for males and females. CONCLUSIONS: The prevalence of MetS was high for a healthy population highlighting the fact that one can be physically healthy but have metabolic derangements indicative of an increased CVD risk. This is likely to result in an increase in the cases of CVD and type 2 diabetes in Kenya if interventions are not put in place to reverse this trend. We have also demonstrated the inappropriateness of the WC cut-off of 80 cm for black African women in Kenya when defining MetS and recommend adoption of 86 cm. PMID- 28676117 TI - A 5 year trend analysis of malaria prevalence with in the catchment areas of Felegehiwot referral Hospital, Bahir Dar city, northwest-Ethiopia: a retrospective study. AB - BACKGROUND: Malaria is one of the killer diseases in Ethiopia and it is still the first leading cause of death in health facilities. However, there is no information yet regarding the trends of malaria prevalence at health institution and particularly at Felegehiwot referral Hospital. Hence , knowing the trends of malaria prevalence at each health facilities is essential to design appropriate interventions. Therefore, the present study addressed the above gaps. RESULTS: Overall, 14,750 blood films were diagnosed for malaria. Of these, 740 (5%) were confirmed with microscope. Plasmodium falciparum and Plasmodium vivax accounted for 397 (53%) and 331 (45%), respectively. Age groups >20 year (p < 0.02) and males (p < 0.025) were significantly affected. CONCLUSIONS: In conclusion, P. falciparum was predominant as compared to P. vivax. Hence, it needs close monitoring and intervention measures for control activities. PMID- 28676115 TI - Pro-Adrenomedullin predicts 10-year all-cause mortality in community-dwelling patients: a prospective cohort study. AB - BACKGROUND: Several studies found mid-regional pro-adrenomedullin (ProADM), the prohormone of the cardiovascular protein adrenomedullin, to be strongly associated with short-term mortality, mostly in the inpatient setting. We evaluated associations of ProADM levels with 10-year mortality in community dwelling primary care patients with respiratory tract infections. METHODS: This is a post-hoc analysis using clinical and biomarker data of 134 primary care patients with respiratory tract infections. ProADM was measured on admission and after 7 days in batch-analysis. 10-year follow-up data was collected by GP, patient and relative tracing through phone interviews. We calculated Cox regression models and area under the receiver operating characteristics curves to assess associations of ProADM with 10-year all-cause mortality. RESULTS: During the 10-year follow-up 6% of included patients died. Median baseline ProADM blood levels (nmol/l) were significantly higher in non-survivors compared to survivors (0.5, IQR 0.4-1.3; vs. 0.2, IQR 0.1-0.5; p = 0.02) and showed a significant association with 10-year all-cause mortality in an age-adjusted cox regression model (HR: 2.5, 95%-CI: 1.0-6.1, p = 0.04). ProADM levels on day 7 showed similar results. CONCLUSIONS: This posthoc analysis found an association of elevated ProADM blood levels and 10-year all-cause mortality in a primary care cohort with respiratory tract infections. Due to the methodological limitations including incomplete data regarding follow-up information and biomarker measurement, this study warrants validation in future larger studies. TRIAL REGISTRATION: Current Controlled Trials, SRCTN73182671. PMID- 28676118 TI - Dissemination of Carbapenem-resistant Klebsiella pneumoniae clinical isolates with various combinations of Carbapenemases (KPC-2, NDM-1, NDM-4, and OXA-48) and 16S rRNA Methylases (RmtB and RmtC) in Vietnam. AB - METHODS: Twenty-seven clinical isolates of carbapenem-resistant Klebsiella pneumoniae with MICs >=4 mg/L for imipenem or meropenem were obtained from inpatients in a hospital in Vietnam. Antimicrobial susceptibility tests and whole genome sequencing were performed. Multilocus sequence typing and the presence of drug resistant genes were determined and a maximum-likelihood phylogenetic tree was constructed by SNP alignment of whole genome sequencing data. RESULTS: All the isolates harbored one of genes encoding carbapenemases, including KPC-2, NDM 1, NDM-4 and OXA-48. Of the isolates, 13 were resistant to arbekacin with MICs >=256 mg/L and to amikacin with MICs >=512 mg/L. These isolates harbored a gene encoding a 16S rRNA methylase, either RmtB or RmtC. Eighteen and 4 isolates belonged to international clones, ST15 and ST16, respectively. None of the isolates had colistin-resistant factors. CONCLUSION: Carbapenem-resistant K. pneumoniae isolates belonged to international clones spread in a medical setting in Vietnam, and that these isolates harbored genes encoding various combinations of carbapenemases and 16S rRNA methylases. This is the first report of KPC-2, NDM 4 and OXA-48 producers in a medical setting in Vietnam. PMID- 28676120 TI - The 'Dream Team' for sexual, reproductive, maternal, newborn and adolescent health: an adjusted service target model to estimate the ideal mix of health care professionals to cover population need. AB - BACKGROUND: A competent, enabled and efficiently deployed health workforce is crucial to the achievement of the health-related sustainable development goals (SDGs). Methods for workforce planning have tended to focus on 'one size fits all' benchmarks, but because populations vary in terms of their demography (e.g. fertility rates) and epidemiology (e.g. HIV prevalence), the level of need for sexual, reproductive, maternal, newborn and adolescent health (SRMNAH) workers also varies, as does the ideal composition of the workforce. In this paper, we aim to provide proof of concept for a new method of workforce planning which takes into account these variations, and allocates tasks to SRMNAH workers according to their competencies, so countries can assess not only the needed size of the SRMNAH workforce, but also its ideal composition (the 'Dream Team'). METHODS: An adjusted service target model was developed, to estimate (i) the amount of health worker time needed to deliver essential SRMNAH care, and (ii) how many workers from different cadres would be required to meet this need if tasks were allocated according to competencies. The model was applied to six low- and middle-income countries, which varied in terms of current levels of need for health workers, geographical location and stage of economic development: Azerbaijan, Malawi, Myanmar, Peru, Uzbekistan and Zambia. RESULTS: Countries with high rates of fertility and/or HIV need more SRMNAH workers (e.g. Malawi and Zambia each need 44 per 10,000 women of reproductive age, compared with 20-27 in the other four countries). All six countries need between 1.7 and 1.9 midwives per 175 births, i.e. more than the established 1 per 175 births benchmark. CONCLUSIONS: There is a need to move beyond universal benchmarks for SRMNAH workforce planning, by taking into account demography and epidemiology. The number and range of workers needed varies according to context. Allocation of tasks according to health worker competencies represents an efficient way to allocate resources and maximise quality of care, and therefore will be useful for countries working towards SDG targets. Midwives/nurse-midwives who are educated according to established global standards can meet 90% or more of the need, if they are part of a wider team operating within an enabled environment. PMID- 28676121 TI - Developing nurse medication safety training in a health partnership in Mozambique using behavioural science. AB - BACKGROUND: Globally, safe and effective medication administration relies on nurses being able to apply strong drug calculation skills in their real-life practice, in the face of stressors and distractions. These may be especially prevalent for nurses in low-income countries such as Mozambique and Continuing Professional Development post-registration may be important. This study aimed to 1) explore the initial impact of an international health partnership's work to develop a drug calculation workshop for nurses in Beira, Mozambique and 2) reflect upon the role of health psychologists in helping educators apply behavioural science to the training content and evaluation. METHODS: In phase one, partners developed a training package, which was delivered to 87 Portuguese speaking nurses. The partnership's health psychologists coded the training's behaviour change content and recommended enhancements to content and delivery. In phase two, the refined training, including an educational game, was delivered to 36 nurses in Mozambique and recoded by the health psychologists. Measures of participant confidence and intentions to make changes to healthcare practice were collected, as well as qualitative data through post-training questions and 12 short follow-up participant interviews. RESULTS: In phase one six BCTs were used during the didactic presentation. Most techniques targeted participants' capability to calculate drug doses accurately; recommendations aimed to increase participants' motivation and perceived opportunity, two other drivers of practice change. Phase two training included an extra seven BCTs, such as action planning and further skills practice. Participants reported high confidence before and after the training (p = 0.25); intentions to use calculators to check drug calculations significantly increased (p = 0.031). Qualitative data suggested the training was acceptable, enjoyable and led to practice changes, through improved capability, opportunity and motivation. Opportunity barriers to medication safety were highlighted. CONCLUSIONS: Reporting and measuring medication errors and related outcomes is a complex challenge affecting global efforts to improve medication safety. Through strong partnership working, a multi-disciplinary team of health professionals including health psychologists developed, refined and begin to evaluate a locally-led drug calculation CPD workshop for nurses in a low resource setting. Applying behavioural science helped to collect feasible evaluation data and hopefully improved impact and sustainability. PMID- 28676122 TI - Genome-wide search for Zelda-like chromatin signatures identifies GAF as a pioneer factor in early fly development. AB - BACKGROUND: The protein Zelda was shown to play a key role in early Drosophila development, binding thousands of promoters and enhancers prior to maternal-to zygotic transition (MZT), and marking them for transcriptional activation. Recently, we showed that Zelda acts through specific chromatin patterns of histone modifications to mark developmental enhancers and active promoters. Intriguingly, some Zelda sites still maintain these chromatin patterns in Drosophila embryos lacking maternal Zelda protein. This suggests that additional Zelda-like pioneer factors may act in early fly embryos. RESULTS: We developed a computational method to analyze and refine the chromatin landscape surrounding early Zelda peaks, using a multichannel spectral clustering. This allowed us to characterize their chromatin patterns through MZT (mitotic cycles 8-14). Specifically, we focused on H3K4me1, H3K4me3, H3K18ac, H3K27ac, and H3K27me3 and identified three different classes of chromatin signatures, matching "promoters," "enhancers" and "transiently bound" Zelda peaks. We then further scanned the genome using these chromatin patterns and identified additional loci-with no Zelda binding-that show similar chromatin patterns, resulting with hundreds of Zelda-independent putative enhancers. These regions were found to be enriched with GAGA factor (GAF, Trl) and are typically located near early developmental zygotic genes. Overall our analysis suggests that GAF, together with Zelda, plays an important role in activating the zygotic genome. CONCLUSIONS: As we show, our computational approach offers an efficient algorithm for characterizing chromatin signatures around some loci of interest and allows a genome-wide identification of additional loci with similar chromatin patterns. PMID- 28676123 TI - Antimicrobial peptides secreted by equine mesenchymal stromal cells inhibit the growth of bacteria commonly found in skin wounds. AB - BACKGROUND: The prevalence of chronic skin wounds in humans is high, and treatment is often complicated by the presence of pathogenic bacteria. Therefore, safe and innovative treatments to reduce the bacterial load in cutaneous wounds are needed. Mesenchymal stromal cells (MSC) are known to provide paracrine signals that act on resident skin cells to promote wound healing, but their potential antibacterial activities are not well described. The present study was designed to examine the antibacterial properties of MSC from horses, as this animal model offers a readily translatable model for MSC therapies in humans. Specifically, we aimed to (i) evaluate the in vitro effects of equine MSC on the growth of representative gram-negative and gram-positive bacterial species commonly found in skin wounds and (ii) define the mechanisms by which MSC inhibit bacterial growth. METHODS: MSC were isolated from the peripheral blood of healthy horses. Gram-negative E. coli and gram-positive S. aureus were cultured in the presence of MSC and MSC conditioned medium (CM), containing all factors secreted by MSC. Bacterial growth was measured by plating bacteria and counting viable colonies or by reading the absorbance of bacterial cultures. Bacterial membrane damage was detected by incorporation of N-phenyl-1-naphthylamine (NPN). Antimicrobial peptide (AMP) gene and protein expression by equine MSC were determined by RT-PCR and Western blot analysis, respectively. Blocking of AMP activity of MSC CM was achieved using AMP-specific antibodies. RESULTS: We found that equine MSC and MSC CM inhibit the growth of E. coli and S. aureus, and that MSC CM depolarizes the cell membranes of these bacteria. In addition, we found that equine MSC CM contains AMPs, and blocking these AMPs with antibodies reduces the effects of MSC CM on bacteria. CONCLUSIONS: Our results demonstrate that equine MSC inhibit bacterial growth and secrete factors that compromise the membrane integrity of bacteria commonly found in skin wounds. We also identified four specific AMPs produced by equine MSC. The secretion of AMPs may contribute to the value of MSC as a therapy for cutaneous wounds in both horses and humans. PMID- 28676124 TI - Evaluation of rational nonsteroidal anti-inflammatory drugs and gastro-protective agents use; association rule data mining using outpatient prescription patterns. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and gastro-protective agents should be co-prescribed following a standard clinical practice guideline; however, adherence to this guideline in routine practice is unknown. This study applied an association rule model (ARM) to estimate rational NSAIDs and gastro protective agents use in an outpatient prescriptions dataset. METHODS: A database of hospital outpatients from October 1st, 2013 to September 30th, 2015 was searched for any of following drugs: oral antacids (A02A), peptic ulcer and gastro-oesophageal reflux disease drugs (GORD, A02B), and anti-inflammatory and anti-rheumatic products, non-steroids or NSAIDs (M01A). Data including patient demographics, diagnoses, and drug utilization were also retrieved. An association rule model was used to analyze co-prescription of the same drug class (i.e., prescriptions within A02A-A02B, M01A) and between drug classes (A02A-A02B & M01A) using the Apriori algorithm in R. The lift value, was calculated by a ratio of confidence to expected confidence, which gave information about the association between drugs in the prescription. RESULTS: We identified a total of 404,273 patients with 2,575,331 outpatient visits in 2 fiscal years. Mean age was 48 years and 34% were male. Among A02A, A02B and M01A drug classes, 12 rules of associations were discovered with support and confidence thresholds of 1% and 50%. The highest lift was between Omeprazole and Ranitidine (340 visits); about one-third of these visits (118) were prescriptions to non-GORD patients, contrary to guidelines. Another finding was the concomitant use of COX-2 inhibitors (Etoricoxib or Celecoxib) and PPIs. 35.6% of these were for patients aged less than 60 years with no GI complication and no Aspirin, inconsistent with guidelines. CONCLUSIONS: Around one-third of occasions where these medications were co-prescribed were inconsistent with guidelines. With the rapid growth of health datasets, data mining methods may help assess quality of care and concordance with guidelines and best evidence. PMID- 28676125 TI - Antimicrobial drug use in food-producing animals and associated human health risks: what, and how strong, is the evidence? AB - BACKGROUND: Antimicrobial resistance is a public health threat. Because antimicrobial consumption in food-producing animals contributes to the problem, policies restricting the inappropriate or unnecessary agricultural use of antimicrobial drugs are important. However, this link between agricultural antibiotic use and antibiotic resistance has remained contested by some, with potentially disruptive effects on efforts to move towards the judicious or prudent use of these drugs. MAIN TEXT: The goal of this review is to systematically evaluate the types of evidence available for each step in the causal pathway from antimicrobial use on farms to human public health risk, and to evaluate the strength of evidence within a 'Grades of Recommendations Assessment, Development and Evaluation'(GRADE) framework. The review clearly demonstrates that there is compelling scientific evidence available to support each step in the causal pathway, from antimicrobial use on farms to a public health burden caused by infections with resistant pathogens. Importantly, the pathogen, antimicrobial drug and treatment regimen, and general setting (e.g., feed type) can have significant impacts on how quickly resistance emerges or spreads, for how long resistance may persist after antimicrobial exposures cease, and what public health impacts may be associated with antimicrobial use on farms. Therefore an exact quantification of the public health burden attributable to antimicrobial drug use in animal agriculture compared to other sources remains challenging. CONCLUSIONS: Even though more research is needed to close existing data gaps, obtain a better understanding of how antimicrobial drugs are actually used on farms or feedlots, and quantify the risk associated with antimicrobial use in animal agriculture, these findings reinforce the need to act now and restrict antibiotic use in animal agriculture to those instances necessary to ensure the health and well-being of the animals. PMID- 28676126 TI - Umbilical cord-derived mesenchymal stromal cells: predictive obstetric factors for cell proliferation and chondrogenic differentiation. AB - BACKGROUND: The umbilical cord is becoming a notable alternative to bone marrow (BM) as a source of mesenchymal stromal cells (MSC). Although age-dependent variations in BM-MSC are well described, less data are available for MSC isolated from Wharton's jelly (WJ-MSC). We initiated a study to identify whether obstetric factors influenced MSC properties. We aimed to evaluate the correlation between a large number of obstetric factors collected during pregnancy and until peripartum (related to the mother, the labor and delivery, and the newborn) with WJ-MSC proliferation and chondrogenic differentiation parameters. METHODS: Correlations were made between 27 obstetric factors and 8 biological indicators including doubling time at passage (P)1 and P2, the percentage of proteoglycans and collagens, and the relative transcriptional expression of Sox-9, aggrecans, and total type 2 collagen (Coll2T). RESULTS: Amongst the obstetric factors considered, birth weight, the number of amenorrhea weeks, placental weight, normal pregnancy, and the absence of preeclampsia were identified as relevant factors for cell expansion, using multivariate linear regression analysis. Since all the above parameters are related to term, we concluded that WJ-MSC from healthy, full-term infants exhibit greater proliferation capacity. As for chondrogenesis, we also observed that obstetric factors influencing proliferation seemed beneficial, with no negative impact on MSC differentiation. CONCLUSIONS: Awareness of obstetric factors influencing the proliferation and/or differentiation of WJ-MSC will make it possible to define criteria for collecting optimal umbilical cords with the aim of decreasing the variability of WJ-MSC batches produced for clinical use in cell and tissue engineering. PMID- 28676127 TI - Bites from the same dog, different outcomes for two patients: a case report. AB - BACKGROUND: Rabies is a serious reemerging zoonosis in China. At present human rabies cases are primarily diagnosed based on clinical presentation. CASE PRESENTATION: In August 2012, a woman and her son were attacked by a stray dog in Henan, China. The son received rabies postexposure prophylaxis (wound treatment followed by vaccine, no immunoglobulin), however, the mother did not. Rabies infection was subsequently laboratory confirmed in the mother and she died in December; her son is alive and healthy after 2 years of follow-up. CONCLUSION: This report documents that the timely utilization of postexposure prophylaxis is a required measure in preventing rabies after exposure to an animal bite. PMID- 28676128 TI - Phenotype prediction for mucopolysaccharidosis type I by in silico analysis. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease due to deficiency of alpha-L-iduronidase (IDUA), a lysosomal enzyme that degrades glycosaminoglycans (GAG) heparan and dermatan sulfate. To achieve optimal clinical outcomes, early and proper treatment is essential, which requires early diagnosis and phenotype severity prediction. RESULTS: To establish a genotype/phenotype correlation of MPS I disease, a combination of bioinformatics tools including SIFT, PolyPhen, I-Mutant, PROVEAN, PANTHER, SNPs&GO and PHD-SNP are utilized. Through analyzing single nucleotide polymorphisms (SNPs) by these in silico approaches, 28 out of 285 missense SNPs were predicted to be damaging. By integrating outcomes from these in silico approaches, a prediction algorithm (sensitivity 94%, specificity 80%) was thereby developed. Three dimensional structural analysis of 5 candidate SNPs (P533R, P496R, L346R, D349G, T374P) were performed by SWISS PDB viewer, which revealed specific structural changes responsible for the functional impacts of these SNPs. Additionally, SNPs in the untranslated region were analyzed by UTRscan and PolymiRTS. Moreover, by investigating known pathogenic mutations and relevant patient phenotypes in previous publications, phenotype severity (severe, intermediate or mild) of each mutation was deduced. CONCLUSIONS: Collectively, these results identified potential candidate SNPs with functional significance for studying MPS I disease. This study also demonstrates the effectiveness, reliability and simplicity of these in silico approaches in addressing complexity of underlying genetic basis of MPS I disease. Further, a step-by-step guideline for phenotype prediction of MPS I disease is established, which can be broadly applied in other lysosomal diseases or genetic disorders. PMID- 28676129 TI - Evaluation of newly proposed remission cut-points for disease activity score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition. AB - BACKGROUND: Stringent remission criteria are crucial in rheumatoid arthritis (RA) assessment. Disease activity score in 28 joints (DAS28)-remission has not been included among American College of Rheumatology/European League Against Rheumatism definitions, because of its association with significant residual disease activity, partly due to high weighting of acute-phase reactants (APR). New, more stringent cut-points for DAS28-remission have recently been proposed that are suggested to reflect remission by clinical and simplified disease activity indices (clinical disease activity index (CDAI), simple disease activity index (SDAI)). However, their stringency in therapies directly influencing APR, like IL-6-blockers, has not been tested. We tested the new cut-points in patients with RA receiving tocilizumab. METHODS: We used data from randomised controlled trials of tocilizumab and evaluated patients in remission according to new DAS28 C-reactive protein (DAS-CRP) and DAS-erythrocyte sedimentation rate (DAS-ESR) cut points (1.9 and 2.2). We assessed their disease activity state using the CDAI, SDAI and Boolean criteria and analysed their individual residual core set variables, like swollen joint counts (SJC28). RESULTS: About 50% of patients in DAS28-CRP-remission (<1.9) fell into higher disease activity states when assessed with CDAI, SDAI or Boolean criteria. Also, 15% had three or more (up to eight) SJC. Even higher disease activity was seen in patients classified as being in DAS28-ESR-remission (<2.2). CONCLUSIONS: Even with new, more stringent cut points, DAS28-remission is frequently associated with considerable residual clinical disease activity, indicating that this limitation of the DAS28 is related to score construction rather than the choice of cut-points. PMID- 28676131 TI - ASSOCIATION OF AGE AT MENOPAUSE WITH POST-MENOPAUSAL SYMPTOMS, MENARCHE AGE AND OTHER REPRODUCTIVE FACTORS AMONG RURAL FEMALES IN SHIMLA, HIMACHAL PRADESH. AB - This study analysed the association between menopause, menarche and number of live births using cross-sectional primary data for 75 post-menopausal rural women from Shimla in the Indian state of Himachal Pradesh. The mean/median ages at menarche of the 75 women were 14.23/14 years, and those at menopause 45.35/45 years. There were no significant differences in these values between women in the age groups 40-55 and 56-65 years. Age at menopause was found to be significantly associated with age at menarche and maternal age at birth of the first and last child, but not with menopausal symptom severity score. The majority of the 75 post-menopausal women (70.7%) had very mild or no menopausal symptoms. Three principal components were identified that explained 72.43% of the underlying variation in menopausal symptoms. PMID- 28676130 TI - Skeletal muscle-derived interstitial progenitor cells (PICs) display stem cell properties, being clonogenic, self-renewing, and multi-potent in vitro and in vivo. AB - BACKGROUND: The development of cellular therapies to treat muscle wastage with disease or age is paramount. Resident muscle satellite cells are not currently regarded as a viable cell source due to their limited migration and growth capability ex vivo. This study investigated the potential of muscle-derived PW1+/Pax7- interstitial progenitor cells (PICs) as a source of tissue-specific stem/progenitor cells with stem cell properties and multipotency. METHODS: Sca 1+/PW1+ PICs were identified on tissue sections from hind limb muscle of 21-day old mice, isolated by magnetic-activated cell sorting (MACS) technology and their phenotype and characteristics assessed over time in culture. Green fluorescent protein (GFP)-labelled PICs were used to determine multipotency in vivo in a tumour formation assay. RESULTS: Isolated PICs expressed markers of pluripotency (Oct3/4, Sox2, and Nanog), were clonogenic, and self-renewing with >60 population doublings, and a population doubling time of 15.8 +/- 2.9 h. PICs demonstrated an ability to generate both striated and smooth muscle, whilst also displaying the potential to differentiate into cell types of the three germ layers both in vitro and in vivo. Moreover, PICs did not form tumours in vivo. CONCLUSION: These findings open new avenues for a variety of solid tissue engineering and regeneration approaches, utilising a single multipotent stem cell type isolated from an easily accessible source such as skeletal muscle. PMID- 28676132 TI - Consumption of ultra-processed foods and body fat during childhood and adolescence: a systematic review. AB - OBJECTIVE: To review the available literature on the association between consumption of ultra-processed foods and body fat during childhood and adolescence. DESIGN: A systematic review was conducted in the PubMed, Web of Science and LILACS databases. Studies that evaluated the association between consumption of ultra-processed food (exposure) and body fat (outcome) during childhood and adolescence were eligible. SUBJECTS: Healthy children and adolescents. RESULTS: Twenty-six studies that evaluated groups of ultra-processed foods (such as snacks, fast foods, junk foods and convenience foods) or specific ultra-processed foods (soft drinks/sweetened beverages, sweets, chocolate and ready-to-eat cereals) were selected. Most of the studies (n 15) had a cohort design. Consumption was generally evaluated by means of FFQ or food records; and body composition, by means of double indirect methods (bioelectrical impedance analysis and skinfolds). Most of the studies that evaluated consumption of groups of ultra-processed foods and soft drinks/sweetened beverages found positive associations with body fat. CONCLUSIONS: Our review showed that most studies have found positive associations between consumption of ultra-processed food and body fat during childhood and adolescence. There is a need to use a standardized classification that considers the level of food processing to promote comparability between studies. PMID- 28676133 TI - Caffeine supplementation of ewes during lambing may increase lamb survival. AB - Perinatal mortality of lambs is on average 20% of lambs born in extensive Australian grazing systems, constituting a substantial production loss and welfare concern. Hypoxia resulting from prolonged or difficult births contributes to lower rates of lamb survival, and caffeine may reduce the effects of hypoxia. This study evaluated whether oral supplementation of grazing ewes with caffeine could improve lamb survival. Pregnant Merino ewes (n=492) which had been naturally mated to Merino rams in February/March were allocated to three replicates of control (no caffeine) or caffeine treatments. Caffeine was fed daily in troughs in each paddock at a rate of 1.6 g/ewe per day (estimated at 20 mg/kg live weight) from the day before the first lamb was born, for 14 days, with lambing continuing for 6 weeks. Intake was facilitated using 320 g/day per ewe of barley grain with molasses, which was fed to both treatments. The proportion of lambs born alive during the period of supplementation did not differ (P>0.05) between treatments. The proportion mortality of lambs to 1 day of age was lower (P=0.029) in the caffeine (0.01) compared with the control (0.16) treatment for lambs born during the 1st week of supplementation, but not in later weeks. This difference in mortality for lambs born in the 1st week of supplementation was maintained to marking age (caffeine 0.09; control 0.30; P=0.027). Extreme weather during the 2nd week of supplementation may have prevented any reduction in mortality due to caffeine in that week. Feeding caffeine to a naturally lambing flock of grazing ewes may be a highly effective and commercially practical method of increasing lamb survival, but further research is needed to confirm these results, and caffeine be regulated for use. PMID- 28676134 TI - Infant and young child feeding patterns in Kuwait: results of a cross-sectional survey. AB - OBJECTIVE: The beneficial role of breast-feeding for maternal and child health is now well established. Its possible role in helping to prevent diabetes and obesity in children in later life means that more attention must be given to understanding how patterns of infant feeding are changing. The present study describes breast-feeding profiles and associated factors in Kuwait. Design/Setting/Subjects Interviews with 1484 recent mothers were undertaken at immunisation clinics across Kuwait. Descriptive analysis and binary logistic regression of results were performed. RESULTS: Rates of breast-feeding initiation in Kuwait were high (98.1 %) but by the time of discharge from hospital, only 36.5 % of mothers were fully breast-feeding, 37.0 % were partially breast-feeding and 26.5 % were already fully formula-feeding. Multiple social and health reasons were given for weaning the child, with 87.6 % of mothers who had stopped breast feeding completely doing so within 3 months postpartum. Nationality (P<0.001), employment status 6 months prior to delivery (P<0.001), mode of delivery (P=0.01), sex of the child (P=0.026) and breast-feeding information given by nurses (P=0.026) were all found to be significantly associated with breast feeding. Few women (5.6 %) got information on infant nutrition and feeding from nursing staff, but those who did were 2.54 times more likely to be still breast feeding at discharge from hospital. Over 70 % of mothers had enjoyed breast feeding and 74 % said they would be very likely to breast-feed again. CONCLUSIONS: In Kuwait where the prevalence of both obesity and type 2 diabetes is growing rapidly, the public health role of breast-feeding must be recognised and acted upon more than it has in the past. PMID- 28676135 TI - Dietary fibre in Europe: current state of knowledge on definitions, sources, recommendations, intakes and relationships to health. AB - Research into the analysis, physical properties and health effects of dietary fibre has continued steadily over the last 40-50 years. From the knowledge gained, countries have developed guidelines for their populations on the optimal amount of fibre to be consumed each day. Food composition tables from many countries now contain values for the dietary fibre content of foods, and, from these, combined with dietary surveys, population intakes have been determined. The present review assessed the uniformity of the analytical methods used, health claims permitted, recommendations and intakes, particularly from national surveys across Europe and around the world. It also assessed current knowledge on health effects of dietary fibre and related the impact of different fibre types on health. The overall intent was to be able to provide more detailed guidance on the types of fibre which should be consumed for good health, rather than simply a total intake figure, the current situation. Analysis of data indicated a fair degree of uniformity in the definition of dietary fibre, the method used for analysis, the recommended amount to be consumed and a growing literature on effects on digestive health and disease risk. However, national dietary survey data showed that intakes do not reach recommendations and very few countries provide guidance on the types of fibre that are preferable to achieve recommended intakes. Research gaps were identified and ideas suggested to provide information for more detailed advice to the public about specific food sources that should be consumed to achieve health benefits. PMID- 28676137 TI - The past and future of Functional Neurology. PMID- 28676138 TI - European core curriculum in neurorehabilitation. AB - To date, medical education lacks Europe-wide standards on neurorehabilitation. To address this, the European Federation of NeuroRehabilitation Societies (EFNR) here proposes a postgraduate neurorehabilitation training scheme. In particular, the European medical core curriculum in neurorehabilitation should include a two year residency in a neurorehabilitation setting where trainees can gain practical experience. Furthermore, it should comprise six modules of classroom training organized as weekend seminars or summer/winter schools. In conclusion, after defining the European medical core curriculum in neurorehabilitation, the next activities of the EFNR will be to try and reach the largest possible consensus on its content among all national societies across Europe in order to further validate it and try to extend it to the other, non-medical, professionals on the neurorehabilitation team in line with their core curricula defined by each professional association. PMID- 28676139 TI - Object decision and multiple sclerosis: a preliminary study. AB - The aim of this research was to study cognitive dysfunctions in multiple sclerosis (MS) by exploring subtle cognitive tasks, usually not included in the standard neuropsychological assessment. We wished to investigate whether it is possible to identify object decision deficits in MS patients without evident cognitive impairment; secondary objectives were to understand whether these deficits can be detected in the early stages of the disease and whether there are differences related to different phenotypes. Participants were divided into four groups: (a) 12 patients with early relapsing-remitting MS [ERR]; (b) 14 with late relapsing-remitting MS [LRR]; (c) 10 with secondary progressive MS [SP]; (d) 36 healthy controls [HCs]. All participants performed a series of experimental tasks: an object decision task (recognition of chimeric and real figures) and naming and visual discrimination tasks. Our results suggest that object decision disorders are detectable in patients without overt cognitive impairments and that performances on these tasks are related to phenotypes. On the other hand, the Chimeric Figures task is not appropriate for identifying cognitive dysfunctions in early MS. PMID- 28676140 TI - Cerebellar transcranial static magnetic field stimulation transiently reduces cerebellar brain inhibition. AB - The aim of this study was to investigate whether transcranial static magnetic field stimulation (tSMS) delivered using a compact cylindrical NdFeB magnet over the cerebellum modulates the excitability of the cerebellum and contralateral primary motor cortex, as measured using cerebellar brain inhibition (CBI), motor evoked potentials (MEPs), and resting motor threshold (rMT). These parameters were measured before tSMS or sham stimulation and immediately, 5 minutes and 10 minutes after stimulation. There were no significant changes in CBI, MEPs or rMT over time in the sham stimulation condition, and no changes in MEPs or rMT in the tSMS condition. However, CBI was significantly decreased immediately after tSMS as compared to that before and 5 minutes after tSMS. Our results suggest that tSMS delivered to the cerebellar hemisphere transiently reduces cerebellar inhibitory output but does not affect the excitability of the contralateral motor cortex. PMID- 28676141 TI - HLA-DRB1*15 association with multiple sclerosis is confirmed in a multigenerational Italian family. AB - Environmental and genetic factors seem to play a pathogenetic role in multiple sclerosis (MS). The genetic component is partly suggested by familial aggregation of cases; however, MS families with affected subjects over different generations have rarely been described. The aim of this study was to report clinical and genetic features of a multigenerational MS family and to perform a review of the literature on this topic. We describe a multigenerational Italian family with six individuals affected by MS, showing different clinical and neuroradiological findings. HLA-DRB1* typing revealed the presence of the DRB1*15:01 allele in all the MS cases and in 4/5 non-affected subjects. Reports on six multigenerational MS families have previously been published, giving similar results. The HLA DRB1*15:01 allele was confirmed to be linked to MS disease in this family; moreover, its presence in non-affected subjects suggests the involvement of other susceptibility factors in the development and expression of the disease, in accordance with the complex disease model now attributed to MS. PMID- 28676142 TI - The Italian real-life post-stroke spasticity survey: unmet needs in the management of spasticity with botulinum toxin type A. AB - The present national survey seeking to identify unmet needs in the management of spasticity with botulinum toxin type A focused on the use of OnabotulinumoxinA, since this is the brand with the widest range of licensed indications in Italy. Physicians from twenty-four Italian neurorehabilitation units compiled a questionnaire about "real-life" post-stroke spasticity management. OnabotulinumtoxinA was reported to be used in the following average doses: upper limb 316.7 +/- 79.1 units; lower limb 327.8 +/- 152.3; upper and lower limb 543.7 +/- 123.7 units. Of the physicians surveyed, 37.5% felt that increasing the frequency of OnabotulinumtoxinA injection would improve its efficacy; 70.8% use electrical stimulation/electromyography guidance (one fourth of injections with no instrumental guidance). Instrumental evaluation was used by 41.7% of the physicians. The participants expressed the view that early identification of post stroke spasticity would be facilitated by the availability of a post-stroke checklist, and that this should be used by physiotherapists (91.7%), physiatrists (58.3%), family doctors (50%), stroke unit physicians (25%), patients and caregivers (79.2%). According to our findings, the management of poststroke spasticity has several unmet needs that, were they addressed, might improve these patients' clinical outcomes and quality of life. These needs concern patient follow-up, where a clearly defined pathway is lacking; furthermore, there is a need to use maximum doses per treatment and to ensure early intervention on post stroke spasticity. PMID- 28676143 TI - Sensitivity of multi-shell NODDI to multiple sclerosis white matter changes: a pilot study. AB - Diffusion tensor imaging (DTI) is sensitive to white matter (WM) damage in multiple sclerosis (MS), not only in focal lesions but also in the normal appearing WM (NAWM). However, DTI indices can also be affected by natural spatial variation in WM, as seen in crossing and dispersing white matter fibers. Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion weighted imaging technique that provides distinct indices of fiber density and dispersion. We performed NODDI of lesion tissue and NAWM in five MS patients and five controls, comparing the technique with traditional DTI. Both DTI and NODDI identified tissue damage in NAWM and in lesions. NODDI was able to detect additional changes and it provided better contrast in MS-NAWM microstructure, because it distinguished orientation dispersion and fiber density better than DTI. We showed that NODDI is viable in MS patients and that it offers, compared with DTI parameters, improved sensitivity and possibly greater specificity to microstructure features such as neurite orientation. PMID- 28676144 TI - Ixcellence Network(r): an international educational network to improve current practice in the management of cervical dystonia or spastic paresis by botulinum toxin injection. AB - Botulinum toxin is a well-established treatment for a number of conditions involving muscle hyperactivity, such as focal dystonia and spastic paresis. However, current injection practice is not standardized and there is a clear need for structured training. An international group of experts in the management of patients with cervical dystonia (CD) and spastic paresis created a steering committee (SC). For each therapeutic area, the SC developed a core slide set on best practice, based on the literature. International sites of expertise were identified for training and courses were designed to include lectures and casebased learning. Where possible, courses received accreditation from the European Union of Medical Specialists (UEMS). Each course was peer reviewed by the SC, the UEMS accreditation board and the attendees themselves (through evaluation questionnaires). Attendees' feedback was shared with the SC and the trainers to tailor future training sessions. From the program launch in 2012 to December 2014, 328 physicians from 34 countries were trained in a total of 58 courses; 67% of the courses focused on spastic paresis and 33% on CD. Of the 225 (69%) physicians who completed feedback forms, 95% rated their course as 'above average/excellent' in meeting the preset learning objectives. Most (90%) physicians declared that attending a course would lead them to change their practice. The development of the 'Ixcellence Network' for continuous medical education in the fields of spastic paresis and CD has provided a novel and interactive way of training physicians with previous experience in botulinum toxin injection. PMID- 28676145 TI - RF-Scalp cooling. PMID- 28676146 TI - Clinical, Dermoscopic, and Histopathologic Features of a Dermatofibroma With Sebaceous Induction. PMID- 28676147 TI - Knowledge of Preservatives: A Key Competence in Dermatology. PMID- 28676148 TI - The Single-Stage Paramedian Forehead Flap. PMID- 28676149 TI - Modeling of ultrasonic wave propagation in composite laminates with realistic discontinuity representation. AB - This paper presents a method for embedding realistic defect geometries of a fiber reinforced material in a finite element modeling environment in order to simulate active ultrasonic inspection. When ultrasonic inspection is used experimentally to investigate the presence of defects in composite materials, the microscopic defect geometry may cause signal characteristics that are difficult to interpret. Hence, modeling of this interaction is key to improve our understanding and way of interpreting the acquired ultrasonic signals. To model the true interaction of the ultrasonic wave field with such defect structures as pores, cracks or delamination, a realistic three dimensional geometry reconstruction is required. We present a 3D-image based reconstruction process which converts computed tomography data in adequate surface representations ready to be embedded for processing with finite element methods. Subsequent modeling using these geometries uses a multi-scale and multi-physics simulation approach which results in quantitative A-Scan ultrasonic signals which can be directly compared with experimental signals. Therefore, besides the properties of the composite material, a full transducer implementation, piezoelectric conversion and simultaneous modeling of the attached circuit is applied. Comparison between simulated and experimental signals provides very good agreement in electrical voltage amplitude and the signal arrival time and thus validates the proposed modeling approach. Simulating ultrasound wave propagation in a medium with a realistic shape of the geometry clearly shows a difference in how the disturbance of the waves takes place and finally allows more realistic modeling of A-scans. PMID- 28676150 TI - Volar Radioscapholunate Arthrodesis and Distal Scaphoidectomy After Malunited Distal Radius Fractures. AB - PURPOSE: The purpose of this study was to assess range of motion (ROM), pain, and incidence of radiographic degenerative joint disease (DJD) after volar radioscapholunate (RSL) arthrodesis and distal scaphoidectomy (DSE) following malunited distal radius fractures (DRF). METHODS: Fourteen patients with malunited DRF and DJD limited to the radiocarpal joint underwent RSL arthrodesis and DSE between 2006 and 2014. These were retrospectively analyzed both clinically and radiologically. Eleven patients with a mean follow-up of 63 months (range, 30-97 months) were included in the final analysis because 1 was unavailable and 2 had died. The outcome was evaluated using parameters of pain, ROM, grip strength, nonunion rate, and DJD of the adjacent joints. In addition, self-assessment by patients was registered on the Disability of the Arm, Shoulder and Hand score, Patient-Rated Wrist Evaluation score, and Michigan Hand Outcomes Questionnaire. To investigate DJD and union, a computed tomography (CT) scan at the final follow-up visit was performed. RESULTS: All patients showed union and no midcarpal DJD in the CT scans at final follow-up. The mean ROM in extension was 53 degrees , flexion 42 degrees , supination 81 degrees , pronation 85 degrees , radial deviation 10 degrees and ulnar deviation 25 degrees . The ROM in extension, extension/flexion arc, and supination improved significantly after surgery. Patients achieved a mean of 80% of grip strength compared with the other hand. CONCLUSIONS: Volar angular stable plate RSL arthrodesis with resection of the distal scaphoid pole is a safe and effective method for treating malunited DRF. This leads to an improved ROM and low pain level. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28676152 TI - Early vs. late-presenting urethroplasty complications after hypospadias repair: A retrospective analysis of patient follow-up. AB - INTRODUCTION: Complications after primary hypospadias repair often present late, that is, more than 1 year postoperatively. This has important implications for clinical practice and prospective research protocols. Follow-up regimen-or lack thereof-may contribute to delayed diagnosis of complications. OBJECTIVE: To characterize and compare the follow-up regimens of patients with early and late presenting urethroplasty complications after primary hypospadias repair, specifically noting the length of time between encounters during which complications emerged. PATIENTS AND METHODS: Boys who underwent repair of urethroplasty complications after hypospadias surgery were identified, and retrospective chart reviews were performed. Late complications were defined by presentation more than 1 year after primary repair; all others were designated as early. We recorded the encounter at which each patient was first noted to have a complication, as well as the last encounter prior to this. Follow-up intervals during which complications emerged were determined. Comparisons of the type of primary repairs, complications, and follow-up regimens (prescribed as well as actual) were performed between patients with early and late complications. RESULTS: A total of 51 patients underwent repair of 57 hypospadias complications. Eighteen patients (35%) had complications that presented late. Complications after a midshaft/distal hypospadias repair were more likely to present late than complications following a one- or two-stage proximal repair (59% vs. 31% vs. 6%, respectively; p = 0.003). The median interval between encounters during which late complications emerged was 24 months (IQR 16-43), compared with 1.2 (0.7-2.2) months for early-presenting complications (p < 0.001). Eleven of the 18 patients with late complications (61%) had not had an encounter beyond 3 months postoperatively prior to presentation of their complications; only four patients (8%) had a late complication that was unrecognized at a follow-up visit more than 6 months postoperatively (Figure). Patients with late complications had a greater discrepancy between prescribed and actual follow-up intervals, averaging 11 months (p = 0.001). CONCLUSIONS: Late presentation of urethroplasty complications after hypospadias repair is relatively common. There is typically a lengthy follow-up interval during which late complications emerge. Many patients who presented with late complications had not previously been examined beyond the early postoperative period. Adherence to a more structured follow-up regimen that includes a visit outside of the early postoperative period (e.g. routine encounters at 6 months postoperatively) may facilitate earlier detection and reduce late presentation of complications, especially among patients with midshaft or distal primary repairs. Earlier diagnosis would allow secondary procedures to be completed sooner. PMID- 28676151 TI - Circulating tumor cells in patients with advanced urothelial carcinoma of the bladder: Association with tumor stage, lymph node metastases, FDG-PET findings, and survival. AB - BACKGROUND: There are currently no methods in clinical use that can detect early systemic dissemination of urothelial tumor cells. OBJECTIVE: To evaluate measurement of circulating tumor cells (CTCs) as a biomarker for disseminated disease in patients with advanced bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: Between March 2013 and October 2015, 88 patients were prospectively included in the study: 78 were scheduled for radical cystectomy (RC) +/- perioperative chemotherapy and 10 treated with palliative chemotherapy. The CellSearch CTC test was further assessed in this context by investigating expression of epithelial cell adhesion molecule (EpCAM) in primary tumors obtained at cystectomy from an independent cohort of 409 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Presence of CTCs was tested for association with tumor stage, lymph node metastases, metastatic disease on [18 F] fluorodeoxyglucose-positron emission tomography (FDG-PET), and cancer-specific and progression-free survival. RESULTS: CTCs were detected in 17/88 patients (19%). In 61 patients who underwent FDG-PET-computed tomography (CT), a statistically significant association with presence of CTCs was found for radiological metastatic disease but not for normal PET-CT results (12/35 [34%] vs. 2/26 [8%], P = 0.014). After a median follow-up time of 16.5 months (95% CI: 9.6-21.4), presence of CTCs was associated with an increased risk of progression among patients treated with RC with or without perioperative chemotherapy (n = 75, P = 0.049). A multivariate analysis adjusted for clinical tumor stage, clinical lymph node status, and age showed that CTCs were an independent marker of progression (n = 75; hazard ratio = 2.78; 95% CI: 1.005-7.69; P = 0.049) but not of cancer-specific death (P = 0.596). In 409 cystectomised patients, more than 392 (96%) of the bladder tumors expressed EpCAM. CONCLUSIONS: CTCs were present in 19% of patients with advanced urothelial tumors and were associated with metastatic disease on FDG-PET-CT and with increased risk of disease progression after RC. A significant portion of urothelial cancer cells do express EpCAM and can thus be identified using EpCAM-antigen-based CTC detection methods. PMID- 28676153 TI - Picking apart surgical pick lists - Reducing variation to decrease surgical costs. AB - BACKGROUND: Average costs associated with common procedures can vary by surgeon without a corresponding variation in outcome or case complexity. METHODS: De identified cost and equipment utilization data were collected from our hospital for elective laparoscopic cholecystectomy performed by 17 different surgeons over a 6-month period. A group of surgeons used this data to design a standardized equipment pick list that became optional (not mandated) for laparoscopic cholecystectomy. Cost and consumable surgical supply utilization data were collected for six months prior to and following the creation of the standardized pick-list. RESULTS: 280 elective laparoscopic cholecystectomies were performed during the study interval. In the 6 months after standardized pick list creation, the cost of disposable supplies utilized per case decreased by 32%. CONCLUSIONS: Surgical cost savings can be achieved with standardized procedure pick lists and attention to the cost of consumable surgical supplies. PMID- 28676154 TI - New Generalized Equation for Predicting Maximal Oxygen Uptake (from the Fitness Registry and the Importance of Exercise National Database). AB - Impaired cardiorespiratory fitness (CRF) is closely linked to chronic illness and associated with adverse events. The American College of Sports Medicine (ACSM) regression equations (ACSM equations) developed to estimate oxygen uptake have known limitations leading to well-documented overestimation of CRF, especially at higher work rates. Thus, there is a need to explore alternative equations to more accurately predict CRF. We assessed maximal oxygen uptake (VO2 max) obtained directly by open-circuit spirometry in 7,983 apparently healthy subjects who participated in the Fitness Registry and the Importance of Exercise National Database (FRIEND). We randomly sampled 70% of the participants from each of the following age categories: <40, 40 to 50, 50 to 70, and >=70 and used the remaining 30% for validation. Multivariable linear regression analysis was applied to identify the most relevant variables and construct the best prediction model for VO2 max. Treadmill speed and treadmill speed * grade were considered in the final model as predictors of measured VO2 max and the following equation was generated: VO2 max in ml O2/kg/min = speed (m/min) * (0.17 + fractional grade * 0.79) + 3.5. The FRIEND equation predicted VO2 max with an overall error >4 times lower than the error associated with the traditional ACSM equations (5.1 +/- 18.3% vs 21.4 +/- 24.9%, respectively). Overestimation associated with the ACSM equation was accentuated when different protocols were considered separately. In conclusion, The FRIEND equation predicts VO2 max more precisely than the traditional ACSM equations with an overall error >4 times lower than that associated with the ACSM equations. PMID- 28676155 TI - Characteristics and spending patterns of high cost, non-elderly adults in Massachusetts. AB - BACKGROUND: Given that health care costs in Massachusetts continue to grow despite great efforts to contain them, we seek to understand characteristics and spending patterns of the costliest non-elderly adults in Massachusetts based on type of insurance. METHODS: We used the Massachusetts All-Payer Claims Database (APCD) from 2012 and analyzed demographics, utilization patterns and spending patterns across payers (Medicaid, Medicaid managed care, and private insurers) for high cost patients (those in the top 10% of spending) and non-high cost patients (the remaining 90%). RESULTS: We identified 3,712,045 patients between the ages of 18-64 years in Massachusetts in 2012 who met our inclusion criteria. Of this group, 8.5% had Medicaid fee-for-service, 11.1% had Medicaid managed care, and 80.3% had private insurance. High cost patients accounted for 65% of total spending in our sample. We found that high cost patients were more likely to be older (median age 48 vs 40, p<0.001), female (60.2% vs. 51.2%, p<0.001), and have multiple chronic conditions (4.4 vs. 1.3, p<0.001) compared to non-high cost patient patients. Medicaid patients were the most likely to be designated high cost (18.1%) followed by Medicaid managed care (MCO) (13.9%) and private insurance (8.6%). High cost Medicaid patients also had the highest mean annual spending and incurred the most preventable spending compared to high cost MCO and high cost private insurance patients. CONCLUSIONS & IMPLICATIONS: We used 2012 claims data from Massachusetts to examine characteristics and spending patterns of the state's costliest patients based on type of insurance. Providers and policymakers seeking to reduce costs and increase value under delivery system reform may wish to target the Medicaid population. PMID- 28676156 TI - Anatomy of the Skin and the Pathogenesis of Nonmelanoma Skin Cancer. AB - Skin is composed of the epidermis, dermis, and adnexal structures. The epidermis is composed of 4 layers-the stratums basale, spinosum, granulosum, and corneum. The dermis is divided into a superficial papillary dermis and deeper reticular dermis. Collagen and elastin within the reticular dermis are responsible for skin tensile strength and elasticity, respectively. The 2 most common kinds of nonmelanoma skin cancers are basal cell and squamous cell carcinoma. Both are caused by a host of environmental and genetic factors, although UV light exposure is the single greatest predisposing factor. PMID- 28676157 TI - Mohs Micrographic Surgery for the Management of Cutaneous Malignancies. AB - Mohs micrographic surgery is a specialized form of skin cancer surgery in which the Mohs surgeon acts as both surgeon and pathologist. The procedure is characterized by its histopathologic margin control and ability to spare tissue, particularly in cosmetically sensitive locations. Mohs surgery is known for both limiting the size of the final defect and its high cure rate. In this review, the authors highlight indications for the procedure, detail the technique itself, discuss cutaneous tumors for which Mohs micrographic surgery is indicated, and present the economic benefit of Mohs surgery. PMID- 28676158 TI - The Physiology and Biomechanics of Skin Flaps. AB - Facial skin defects created by Mohs micrographic surgery are commonly reconstructed using local cutaneous flaps from surrounding skin. To provide optimal survival and aesthetic outcomes, the cutaneous surgeon must command a thorough understanding of the complex vascular anatomy and physiology of the skin as well as the imperative physiologic and biomechanical considerations when elevating and transferring tissue via local skin flaps. PMID- 28676159 TI - Flap Basics I: Rotation and Transposition Flaps. AB - In many cases of complex facial defects, because of advanced cutaneous malignancies, primary wound closure is impossible. In these instances, ideal results can be obtained through recruitment of adjacent tissue with the use of local flaps. Advances in local flap techniques have raised the bar in facial reconstruction; however, acceptable results to the surgeon and patient require high levels of planning and surgical technique. Defects resulting from Mohs surgery and other traumatic injuries can typically be repaired with local flaps. A well-planned and executed local flap can lead to excellent cosmetic results with minimal distortion of the surrounding facial landmarks. PMID- 28676160 TI - Flap Basics II: Advancement Flaps. AB - A mastery of advancement flap design, selection, and execution greatly aids the surgeon in solving reconstructive dilemmas. Advancement flaps involve carefully planned incisions to most efficiently close a primary defect in a linear vector. Advancement flaps are subcategorized as unipedicle, bipedicle, V-to-Y, and Y-to-V flaps, each with their own advantages and disadvantages. When selecting and designing an advancement flap, the surgeon must account for primary and secondary movement to prevent distortion of important facial structural units and boundaries. PMID- 28676161 TI - Flap Basics III: Interpolated Flaps. AB - Paramedian forehead and melolabial flaps are the most common examples of interpolated flaps used by facial plastic surgeons and are excellent options for reconstruction of the midface after Mohs surgery. They provide superior tissue match in terms of thickness, texture, and color, while leaving minimal defects at the tissue donor sites. The main advantage of interpolated flaps is the robust blood supply, which can be either axial of randomly based, and the maintenance of the integrity of facial landmarks. The main disadvantage is the frequent need for a multistage procedure, which eliminates some patients from consideration. PMID- 28676162 TI - Skin and Composite Grafting Techniques in Facial Reconstruction for Skin Cancer. AB - Skin and composite grafting provide effective resurfacing and reconstruction for cutaneous defects after excision of the malignancy. The goal is to restore a natural appearance and function while preventing distortion of the eyelid, nose, or lips. With careful planning and attention to aesthetic subunits, the surgeon can camouflage incisions and avoid blunting aesthetically sensitive sulci. The surgical plan is also informed by the pathology, as basal or squamous cell carcinomas removed by Mohs micrographic excision have different prognostic and logistical considerations from melanoma. Skin and composite grafting are useful as stand-alone procedures or may complement local flaps and other soft tissue reconstructions. PMID- 28676163 TI - Scalp and Forehead Defects in the Post-Mohs Surgery Patient. AB - Scalp and forehead reconstruction after Mohs micrographic surgery can encompass subcentimeter defects to entire scalp reconstruction. Knowledge of anatomy, flap design, and execution will prepare surgeons who operate in the head and neck area to confidently approach a variety of reconstructive challenges in this area. PMID- 28676164 TI - Defect of the Eyelids. AB - Eyelid defects disrupt the complex natural form and function of the eyelids and present a surgical challenge. Detailed knowledge of eyelid anatomy is essential in evaluating a defect and composing a reconstructive plan. Numerous reconstructive techniques have been described, including primary closure, grafting, and a variety of local flaps. This article describes an updated reconstructive ladder for eyelid defects that can be used in various permutations to solve most eyelid defects. PMID- 28676165 TI - Repair of Auricular Defects. AB - Repairing defects of the auricle requires an appreciation of the underlying 3 dimensional framework, the flexible properties of the cartilages, and the healing contractile tendencies of the surrounding soft tissue. In the analysis of auricular defects and planning of their reconstruction, it is helpful to divide the auricle into subunits for which different techniques may offer better functional and aesthetic outcomes. This article reviews many of the reconstructive options for defects of the various auricular subunits. PMID- 28676166 TI - Reconstruction of Cutaneous Nasal Defects. AB - Mohs micrographic surgery has become the standard of care for the treatment of cutaneous malignancies. Reconstructing cutaneous defects of the nose can be challenging, as form and function must be respected to the greatest extent possible. A wide range of reconstructive techniques are used. Secondary intent, primary closure, skin grafts, local flaps, and the interpolated workhorse flaps represent the spectrum of options, each with specific advantages and disadvantages. Vigilant postoperative care, including judicious use of adjunctive procedures, can improve outcomes. A subunit approach to reconstruction aids with surgical planning in order to achieve the best possible results. PMID- 28676167 TI - Reconstruction of Mohs Defects of the Lips and Chin. AB - Reconstruction of defects of the lips after Mohs micrographic surgery should encompass functional and aesthetic concerns. The lower lip and chin compose two thirds of the lower portion of the face. The focus of this article is local tissue transfer for primarily cutaneous defects after Mohs surgery. Various flaps exist for repair. For small defects, elliptical excision with primary closure is a viable option. During reconstruction of the lip, all of the involved layers need to be addressed, including mucosa, muscle, and the vermillion or cutaneous lip. It is especially important to realign the vermillion border precisely for optimal results. PMID- 28676168 TI - Reconstruction of Cheek Defects Secondary to Mohs Microsurgery or Wide Local Excision. AB - Successful reconstruction of the cheek following excision for cutaneous malignancy requires careful consideration of defect location, size, and depth in relation to the anatomic properties of the affected cheek unit. Various reconstructive options are available to the surgeon, ranging from simple excisions to complex cervicofacial advancements to meet the needs for functional and aesthetically pleasing reconstructive outcomes. The surgeon must prevent distortion of mobile structures, such as the eyelid, nose, and lips; respect aesthetic subunits; and avoid blunting natural creases. This discussion covers choice of flap, techniques, and technical considerations for medial/perinasal, perilabial, preauricular, lateral, and zygomatic cheek defects. PMID- 28676169 TI - Scar Revision and Recontouring Post-Mohs Surgery. AB - Following Mohs reconstruction, several options are available to improve the appearance of the resulting scars. It is critical that the patient has realistic goals before beginning any treatment because scars can be improved but never erased. The surgical and nonsurgical options aim to replace pre-existing scars with ones that are less conspicuous. This article addresses the different available options (listed in order of invasiveness) for improving scarring following Mohs reconstruction. PMID- 28676170 TI - In Pursuit of Perfection: The Art of Facial Restoration. PMID- 28676171 TI - Using a liver cell culture from Epinephelus coioides as a model to evaluate the nonylphenol-induced oxidative stress. AB - The present study aimed to use primary liver cell culture derived from the orange spotted grouper, Epinephelus coioides, to assess the toxic effects of nonylphenol (NP) on the hepatocyte viability and the liver antioxidant system. E. coioides was selected due to its commercial importance. NP was used in this study because of its high potential of producing oxidative stress due to increased reactive oxygen species (ROS). A liver of E. coioides was digested with PBS containing 0.1% collagenase IV. The digested cells were moved to Leibovitz L-15 culture medium with 20% fetal bovine serum (FBS), 100IUmL-1 penicillin, 100MUgmL-1 streptomycin. Aliquots of cell suspension were seeded as a monolayer into sterile 25cm2 tissue culture flasks and incubated at 30 degrees C for 14days. The medium, containing non-attached cells, was removed after 24 to 48h and a new medium was added. The IC50 of 10-4molL-1 was determined for nonylphenol using MTT assay. Cells were then incubated with L-15 medium containing 10-5, 2*10-5, 3*10-5molL-1 of NP and samples were taken after 6, 12 and 24h of incubation for analysis of LPO, SOD, CAT, GPx, LDH, AST, ALT, and ALP. Based on the results, the lowest concentration of NP was not markedly cytotoxic to primary hepatocytes and the cell sensitivity to NP increased dose-dependently. The activities of SOD, CAT and GPx decreased significantly, while activities of LPO, LDH, AST, ALT and ALP, increased significantly in a dose-related pattern in NP-treated cells. In conclusion, this study revealed that NP could induce the oxidative stress in cultivated hepatocytes of E. coioides during a short-term exposure. NP toxicity is mainly due to the induction of the reactive oxygen species (ROS), which lead to cell membrane disruption, damage of cellular metabolism, and interference with cellular macromolecules. PMID- 28676172 TI - Metal concentrations and toxicity in South African snoek (Thyrsites atun) and yellowtail (Seriola lalandi). AB - The concentrations of 16 metals were assessed in snoek(Thyrsites atun; n=20) and yellowtail (Seriola lalandi; n=37) sampled from the West and South-East coasts of South Africa. Variability was observed at both small (Al, Cr, Hg, Pb, Mn and Cu) and large (As and Cu) spatial scales while inter-specific examination revealed diverse metal concentrations in snoek (Higher levels: Cr, Mn, Co, Hg and Pb) and yellowtail (higher levels: Fe and Cu). Zn, As and Hg were positively correlated with yellowtail size with no such correlations in snoek. Mean concentrations of As (0.61mg.kg-1; 0.98mg.kg-1), Cd (0.008mg.kg-1; 0.004mg.kg-1), Hg (0.27mg.kg-1; 0.16mg.kg-1) and Pb (0.009mg.kg-1; 0.005mg.kg-1) for snoek and yellowtail respectively were within regulatory guidelines. However, 10% (n=2) of snoek exceeded Hg maximum allowable limit, suggesting caution and further investigation. Overall, two meals (150g) per week of snoek or larger yellowtail (12-15kg) can be safe for human (adult) consumption. PMID- 28676173 TI - Mapping Mediterranean seagrasses with Sentinel-2 imagery. AB - Mediterranean seagrasses have been hailed for their numerous ecosystem services, yet they are undergoing a decline in their coverage. The major complication with resolving this tendency is the sparsity of data on their overall distribution. This study addresses the suitability of the recently launched Sentinel-2 satellite for mapping the distribution of Mediterranean seagrass meadows. A comprehensive methodology is presented which applies atmospheric and analytical water column corrections and compares the performance of three different supervised classifiers. Remote sensing of the Thermaikos Gulf, northwestern Aegean Sea (Greece, eastern Mediterranean Sea) reveals that the utilization of Support Vector Machines on water column corrected reflectances yields best accuracies. Two Mediterranean seagrasses, Posidonia oceanica and Cymodocea nodosa, cover a total submerged area of 1.48km2 between depths of 1.4-16.5m. With its 10-m spatial resolution and 5-day revisit frequency, Sentinel-2 imagery can mitigate the Mediterranean seagrass distribution data gap and allow better management and conservation in the future in a retrospective, time- and cost effective fashion. PMID- 28676174 TI - Vascular lesions of the breast. AB - Vascular lesions of the breast comprise a heterogeneous group that includes a variety of benign, atypical, and malignant lesions. The presentation of these lesions ranges from those that are microscopic and discovered incidentally, to large tumors that may extensively involve the breast parenchyma and skin. In addition, some non-vascular breast lesions have features that may mimic those of vascular lesions and need to be distinguished from them in order to avoid an erroneous diagnosis. In this review, we discuss the spectrum of vascular lesions of the breast with particular emphasis on those lesions of greatest clinical importance, angiosarcoma and atypical vascular lesions. We also discuss lesions that may be mistaken for vascular lesions. PMID- 28676175 TI - Watershed soil Cd loss after long-term agricultural practice and biochar amendment under four rainfall levels. AB - Some heavy metals in farmland soil can be transported into the waterbody, affecting the water quality and sediment at the watershed outlet, which can be used to determine the historical loss pattern. Cd is a typical heavy metal leached from farmland that is related to phosphate fertilizers and carries serious environmental risk. The spatial-vertical pattern of Cd in soil and the vertical trend of Cd in the river sediment core were analyzed, which showed the migration and accumulation of Cd in the watershed. To prevent watershed Cd loss, biochar was employed, and leaching experiments were conducted to investigate the Cd loss from soil depending on the initial concentration. Four rainfall intensities, 1.25 mm/h, 2.50 mm/h, 5.00 mm/h, and 10.00 mm/h, were used to simulate typical rainfall scenarios for the study area. Biochar was prepared from corn straw after pretreatment with ammonium dihydrogen phosphate (ADP) and pyrolysis at 400 degrees C under anoxic conditions. To identify the effects of biochar amendment on Cd migration, the biochar was mixed with soil for 90 days at concentrations of 0%, 0.5%, 1.0%, 3.0%, and 5.0% soil by weight. The results showed that the Cd leaching load increased as the initial load and rainfall intensity increased and that eluviation caused surface Cd to diffuse to the deep soils. The biochar application caused more of the heavy metals to be immobilized in the amended soil rather than transported into the waterbody. The sorption efficiency of the biochar for Cd increased as the addition level increased to 3%, which showed better performance than the 5% addition level under some initial concentration and rainfall conditions. The research indicated that biochar is a potential material to prevent diffuse heavy metal pollution and that a lower addition makes the application more feasible. PMID- 28676176 TI - Corrigendum to "Systematic review of systemic sclerosis-specific instruments for the EULAR Outcome Measures Library: An evolutional database model of validated patient-reported outcomes [Semin Arthritis Rheum 46(5) (2017) 609-614]. PMID- 28676177 TI - Visualization of vortex flow and shear stress in the aortic root during left ventricular assist device support. PMID- 28676178 TI - Unusual case of tracheoesophageal fistula caused by impacted denture. PMID- 28676179 TI - Transaortic edge-to-edge mitral valve repair for moderate secondary/functional mitral regurgitation in patients undergoing aortic root/valve intervention. AB - OBJECTIVE: The present study evaluates the feasibility, safety, and efficacy of edge-to-edge repair for moderate secondary/functional mitral regurgitation in patients undergoing aortic valve/root interventions. METHODS: Sixteen patients underwent transaortic edge-to-edge mitral valve repair. Mitral regurgitation was 2+ in 8 patients and 3+ in 6 patients. Two patients in whom cardiac arrest developed preoperatively had severe (4+) mitral regurgitation. Patients underwent operation for severe aortic regurgitation +/- aortic root lesions. The mean left ventricular systolic and diastolic diameters were 51.5 +/- 12.8 mm and 70.7 +/- 10.7 mm, respectively. Left ventricular ejection fraction ranged from 20% to 60%. Primary surgical procedure included Bentall's +/- hemiarch replacement in 10 patients, aortic valve replacement in 5 patients, and noncoronary sinus replacement with aortic valve repair in 1 patient. RESULTS: Severity of mitral regurgitation decreased to trivial or zero in 13 patients, 1+ in 2 patients, and 2+ in 1 patient. There were no gradients across the mitral valve in 9 patients, less than 5 mm Hg in 6 patients, and 9 mm Hg in 1 patient. There was no operative mortality. Follow-up ranged from 2 weeks to 54 months. Echocardiography showed trivial or no mitral regurgitation in 12 patients, 1+ in 2 patients, and 2+ in 2 patients. None of the patients had significant mitral stenosis. The mean left ventricular systolic and diastolic diameters decreased to 40.5 +/- 10.3 mm and 58.7 +/- 11.6 mm, respectively. Ejection fraction also improved slightly (22% 65%). CONCLUSIONS: Transaortic edge-to-edge mitral valve repair is a safe and effective technique to abolish secondary/functional mitral regurgitation. However, its impact on overall survival needs to be studied. PMID- 28676180 TI - To be or not to be: Mechanical versus biological prosthesis at the pulmonary valvular position. PMID- 28676181 TI - From tennis balls to pearls: Bridging the communication gap to surgical trainees. PMID- 28676182 TI - The Tin Man finally gets his heart. PMID- 28676183 TI - Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common complication occurring after cardiac surgery. Multiple studies have shown significantly increased risks of stroke, myocardial infarction, and death associated with POAF. Current prophylaxis strategies are inadequate to eliminate this problem. We examined the preclinical efficacy and safety of KCNH2-G628S gene transfer to prevent POAF. METHODS: Domestic pigs received AdKCNH2-G628S by epicardial atrial gene painting and atrial pacemaker implantation for continuous burst pacing to induce atrial fibrillation. In an initial dose-ranging evaluation, 3 pigs received 5 * 1010 to 5 * 1011 virus particles. In the formal study, 16 pigs were randomized to 3 groups: 5 * 1011 virus particles of AdKCNH2 G628S with 20% Pluronic P407 in saline, 20% Pluronic P407 in saline with no virus, and saline alone. Animals were followed with daily efficacy and safety evaluations through the period of peak adenovirus-mediated transgene expression. After 14 days, pacing was discontinued, and the animals were followed in sinus rhythm for an additional 14 days to assess any longer-term toxicity. RESULTS: In the primary efficacy analysis, the G628S animals exhibited a significant increase in the average time in sinus rhythm compared with the Pluronic control group (59 +/- 7% vs 14 +/- 6%; P = .009). There was no significant difference between the Pluronic and saline controls (14 +/- 6% vs 32 +/- 12%; P = .16). Safety assessment showed improved left ventricular function in the G628S animals; otherwise there were no significant differences among the groups in any safety measure. CONCLUSIONS: These data indicate that KCNH2-G628S gene therapy can successfully and safely reduce the risk of AF. PMID- 28676184 TI - Meta-analysis to assess the effectiveness of topically used vancomycin in reducing sternal wound infections after cardiac surgery. PMID- 28676185 TI - Expanding the applications of transcatheter aortic valve replacement: Wave of the future, or not so fast? PMID- 28676186 TI - Defining quality in the surgical care of lung cancer patients. PMID- 28676187 TI - Anesthetic Techniques in Transcatheter Aortic Valve Replacement and the Evolving Role of the Anesthesiologist. AB - The development of transcatheter aortic valve replacement (TAVR) has transformed the treatment of patients with aortic valve disease. This procedure now is used widely for patients at high and intermediate risk for surgical aortic valve replacement. The rapid acceptance and popularity of TAVR most clearly was enabled by advancements in device technology and procedural experience. Such a dramatic change to the standard medical practice is not without consequence to fields of medicine beyond cardiology and cardiac surgery. Anesthesiologists have witnessed this movement first hand, and while improved anesthetic techniques have contributed to the success of the procedure, in return these improved outcomes likely will result in further changes to perioperative anesthetic management. In this review the authors sought to evaluate the role and responsibility of the cardiac anesthesiologist in the development of TAVR. Future advancements in device technology and considerations of how the anesthetic technique for TAVR may continue to evolve in future years are discussed. PMID- 28676188 TI - Why are we still talking about chromosomal heteromorphisms? PMID- 28676189 TI - Changes in renal function after discontinuation of vitamin D analogues in advanced chronic kidney disease. AB - BACKGROUND: In routine clinical practice, the prescription of vitamin D analogues (VDA) in patients with chronic kidney disease (CKD) is often associated with a decline of the estimated renal function. The reason for this is not fully understood. AIMS: To analyse the effects of VDA discontinuation in advanced CKD and to determine the factors associated with changes in renal function. MATERIAL AND METHODS: Retrospective cohort study of adult patients with advanced CKD. The case subgroup was treated with VDA and this medication was discontinued at baseline (the first visit). The control subgroup was not treated with VDA and they were selected according to comparability principles for CKD progression by propensity score matching. The primary outcome measure was a change to both the estimated glomerular filtration rate (MDRD-GFR) and the measured glomerular filtration rate (mGFR by combined creatinine and urea clearances). Baseline parameters related to mineral metabolism and creatinine generation were analysed as potential determinants of renal function changes. RESULTS: The study sample consisted of 67 cases and 67 controls. Renal function improved in 67% of cases and worsened in 72% of controls (p<0.0001). Changes in MDRD-GFR for the case subgroup and the control subgroup were +0.455+/-0.997 vs. -0.436+/ 1.103ml/min/1.73 m2/month (p<0.0001), respectively. Total creatinine excretion was slightly higher in cases than in controls but the difference was not significant. According to multivariate logistic and linear regression analyses, baseline total serum calcium was one of the best determinants of both renal function recovery (Odds ratio=3.49; p=0.001), and of the extent of renal function recovery (beta=0.276; p=0.001). CONCLUSIONS: Discontinuation of VDA treatment in CKD patients is associated with significant recovery of estimated renal function. The extent of these changes is mainly associated with baseline total serum calcium. PMID- 28676190 TI - Barriers to Addressing Social Determinants of Health in Pediatric Nursing Practice: An Integrative Review. AB - PROBLEM: Despite a substantial body of knowledge regarding the importance of the social determinants of health, recognizing and responding to the psychosocial circumstances of seriously and chronically ill children and their families is not well established in routine pediatric nursing care. ELIGIBILITY CRITERIA: The search process focused on psychological and social determinants and care in the healthcare setting. Searches were limited to research and review publications written in the English language. The quality of evidence was graded using the National Health and Medical Research Council evidence hierarchy. RESULTS: Thirteen publications were identified for inclusion. Healthcare providers do recognize emotional distress experienced by patients, but feel unable to address psychosocial issues due to the lack of time, a lack of confidence in their own communication skills, and the perception that patients and their families prioritize physical care over psychosocial care. For patients and their families the main issue was that the healthcare system was focused on physical care with little opportunity to talk about psychosocial concerns. CONCLUSIONS: The greatest barrier to addressing the social determinants of health in the pediatric context is the dominance of the 'medical model' of care. Also, many healthcare providers believe that they lack the communication skills necessary to talk about psychosocial issues. IMPLICATIONS: The way forward will be to empower nurses through the sharing of knowledge of the social determinants of health, the development of skills in relationship building and therapeutic communication, and the mentorship of compassionate family-centered care. PMID- 28676191 TI - "Being there" and remembering it: Presence improves memory encoding. AB - Few studies have investigated the link between episodic memory and presence: the feeling of "being there" and reacting to a stimulus as if it were real. We collected data from 244 participants after they had watched the movie Avengers: Age of Ultron. They answered questions about factual (details of the movie) and temporal memory (order of the scenes) about the movie, as well as their emotion experience and their sense of presence during the projection. Both higher emotion experience and sense of presence were related to better factual memory, but not to temporal order memory. Crucially, the link between emotion and factual memory was mediated by the sense of presence. We interpreted the role of presence as an external absorption of the attentional focus toward the stimulus, thus enhancing memory encoding. Our findings could shed light on the cognitive processes underlying memory impairments in psychiatric conditions characterized by an altered sense of reality. PMID- 28676192 TI - Eosinophilic esophagitis. The North against the South? A bio-economic-social mechanistic approach and clinical implications. AB - Eosinophilic esophagitis is a chronic antigen-mediated disease characterized by esophageal symptoms, esophageal eosinophilia, and the absence of response to proton pump inhibitors. It is the most frequent cause of dysphagia and food impaction in adults. Its incidence and prevalence is very high in the developed countries (USA, Europe, Australia), where its connotation is that of an emerging epidemic. While studies have been published with large case series in the developed countries, those published in Latin America are small or consist of isolated case reports. The differences in the prevalence of the disease between the developed and developing regions are unknown. Genetic or racial causes have been cited. Nevertheless, the epidemic nature of the disease suggests that environmental causes are the most powerful. Based on the published hypotheses, as well as on epidemiologic studies, the present review discusses some of the possible causes of the disparity in the prevalence of eosinophilic esophagitis between the two types of countries. The 'hygiene hypothesis' is reviewed, together with the possible relation of Helicobacter pylori, intestinal parasites, and modifications of the esophageal microbiota in patients with eosinophilic esophagitis. In reference to studies conducted in the United States, the clinical behavior and progression of eosinophilic esophagitis in Hispanics is reviewed and a possible predominant phenotype in Mexican and other Latin American patients is discussed. Finally, based on the above, an algorithm for studying the disease in the Latin American countries is proposed. PMID- 28676193 TI - Fournier's gangrene caused by Streptococcus anginosus, a rare etiologic agent. PMID- 28676194 TI - Chronic diarrhea and deep vein thrombosis during treatment with olmesartan. PMID- 28676195 TI - Atypical case of diaphragmatic pseudo myoclonus. PMID- 28676196 TI - Enteral feeding in Parkinson's patients receiving levodopa/carbidopa intestinal gel. PMID- 28676197 TI - Erratum Regarding "Phosphate-Binding Agents in Adults With CKD: A Network Meta analysis of Randomized Trials" (Am J Kidney Dis. 2016;68[5]:691-702). PMID- 28676198 TI - Treatment of Gabapentin Toxicity With Peritoneal Dialysis: Assessment of Gabapentin Clearance. AB - Gabapentin is almost exclusively cleared by the kidney and thus presents challenges in patients with kidney failure. Gabapentin is known to be effectively cleared by hemodialysis, but the efficiency of clearance by peritoneal dialysis (PD) has not been previously described. We report a case of gabapentin toxicity in a patient on long-term PD who was treated with continuous automated cycling PD. We find that continuous PD provides significant clearance of gabapentin. With 2-L exchanges every 2 hours, we document an apparent elimination half-life of 41.33 hours, which is substantially shorter than the reported elimination half life of 132 hours in the absence of kidney function. Further, our patient's symptoms of gabapentin toxicity gradually improved and had fully resolved after about 36 hours of dialysis. Gabapentin clearance by PD was estimated at 94% of urea clearance. We conclude that intensive PD provides gabapentin clearance that approximates that of urea and is an effective but slow method to treat gabapentin overdose and toxicity. PMID- 28676200 TI - Cigar Box Arthroscopy: A Randomized Controlled Trial Validates Nonanatomic Simulation Training of Novice Arthroscopy Skills. AB - PURPOSE: The goal of this study was to validate the cigar box arthroscopy trainer (CBAT) as a training tool and then compare its effectiveness to didactic training and to another previously validated low-fidelity but anatomic model, the anatomic knee arthroscopy trainer (AKAT). METHODS: A nonanatomic knee arthroscopy training module was developed at our institution. Twenty-four medical students with no prior arthroscopic or laparoscopic experience were enrolled as subjects. Eight subjects served as controls. The remaining 16 subjects were randomized to participate in 4 hours of either the CBAT or a previously validated AKAT. Subjects' skills were assessed by 1 of 2 faculty members through repeated attempts at performing a diagnostic knee arthroscopy on a cadaveric specimen. Objective scores were given using a minimally adapted version of the Basic Arthroscopic Knee Skill Scoring System. Total cost differences were calculated. RESULTS: Seventy-five percent of subjects in the CBAT and AKAT groups succeeded in reaching minimum proficiency in the allotted time compared with 25% in the control group (P < .05). There was no significant difference in the number of attempts to reach proficiency between the CBAT and AKAT groups. The cost to build the CBAT was $44.12, whereas the cost was $324.33 for the AKAT. CONCLUSIONS: This pilot study suggests the CBAT is an effective knee arthroscopy trainer that may decrease the learning curve of residents without significant cost to a residency program. This study demonstrates the need for an agreed-upon objective scoring system to properly evaluate residents and compare the effectiveness of different training tools. PMID- 28676199 TI - The ART-SCORE is not an effective tool for optimizing patient selection for DEB TACE retreatment. A multicentre Spanish study. AB - INTRODUCTION: The appropriate selection of hepatocellular carcinoma (HCC) patients who are eligible for transarterial chemoembolization (TACE) remains a challenge. The ART score has recently been proposed as a method of identifying patients who are eligible or not for a second TACE procedure. OBJECTIVE: To assess the validity of the Assessment for Retreatment with TACE (ART) score in a cohort of patients treated with drug-eluting bead TACE (DEB-TACE). SECONDARY OBJECTIVE: to identify clinical determinants associated with overall survival (OS). METHOD: A retrospective, multicentre study conducted in Spain in patients with HCC having undergone two or more DEB-TACE procedures between January 2009 and December 2014. The clinical characteristics and OS from the day before the second DEB-TACE of patients with a high ART score (ART>=2.5) and a low ART score (ART 0-1) were compared. Risk factors for mortality were identified using Cox's proportional hazards model. RESULTS: Of the 102 patients included, 51 scored 0 1.5 and 51 scored >=2.5. Hepatitis C was more frequent in patients scoring >=2.5. Median OS from the day before the second DEB-TACE was 21 months (95% CI, 15-28) in the group scoring 0-1.5, and 17 months (95% CI, 10-25) in the group scoring >=2.5 (P=0.3562). Platelet count and tumour size, but not the ART score, were independent baseline predictors of OS. CONCLUSIONS: The ART score is not suitable for guiding DEB-TACE retreatment according to Spanish clinical practice standards. PMID- 28676201 TI - A novel wearable device for continuous, non-invasion blood pressure measurement. AB - In this paper, we have developed a wearable cuffless device for daily blood pressure (BP) measurement. We incorporated the light based sensor and other hard wares in a small volume for BP detection. With optimized algorithm, the real-time BP reading could be achieved, the data could be presented in the screen and be transmitted by internet of things (IoT) for history data comparison and multi terminal viewing. Thus, further analysis provides the probability for diet or sports suggestion and alarm. We have measured BP from more than 60 subjects, compare to traditional mercury blood pressure meter, no obvious error in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) are detected. Such device can be used for continues non-invasion BP detection, and further data docking and health analysis could be achieved. PMID- 28676202 TI - Hexacosanol reduces plasma and hepatic cholesterol by activation of AMP-activated protein kinase and suppression of sterol regulatory element-binding protein-2 in HepG2 and C57BL/6J mice. AB - Policosanols have hypocholesterolemic activity; however, the molecular mechanism of the policosanol effects is currently poorly characterized. We hypothesized that hexacosanol, a policosanol compound derived from barley sprout, may decrease cellular and plasma cholesterol levels; we thus investigated the hypocholesterolemic activity and mechanism of hexacosanol on both hepatocytes and high-fat-induced obese C57BL/6J mice. The reduction of total cholesterol, free cholesterol, and cholesteryl ester concentrations was confirmed in hexacosanol stimulated hepatocytes (-38%, -33%, and -53%, respectively). Plasma, hepatic cholesterol concentrations, and hepatic steatosis were significantly reduced in high-fat-fed mice orally administered with hexacosanol (0.7 mg/kg body weight a day) for 8 weeks compared with those of vehicle-fed control mice (-15% and -40%, respectively). Hexacosanol in fact bound to the allosteric regulation site of AMP activated protein kinase (AMPK)-beta subunit and thus activated AMPK that inhibited the activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase by inhibitory phosphorylation. In addition, activation of AMPK by hexacosanol induced hepatic autophagy activity, which could further reduce hepatic lipid accumulation. Alternatively, hexacosanol suppressed the nuclear translocation and activation of sterol regulatory element-binding protein-2 (SREBP-2), a key transcription factor in cholesterol biosynthesis. These results collectively suggest that hexacosanol is a major hypocholesterolemic compound in barley sprouts with regulation of AMPK activation and SREBP-2 suppression. These suppress 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase at both mRNA expression and protein activity levels. In conclusion, hexacosanol activates AMPK and hepatic autophagy and inhibits SREBP2, resulting in hypocholesterolemic activities and improvement of hepatic steatosis. PMID- 28676203 TI - [Frequency and type of pleuropulmonary complications and their predictors during the first thirty days after cardiopulmonary bypass surgery in children]. AB - OBJECTIVE: To determine the frequency and type of pleuropulmonary complications and their predictors in the first thirty postoperative days of patients undergoing surgery without cardiopulmonary bypass. METHODS: A retrospective cohort study was carried out between January 2013 and December 2014. It included all patients with congenital heart disease who underwent cardiac surgery using a sternal or thoracic approach, without cardiopulmonary bypass with a registered admission to a Neonatal or Paediatric Intensive Care. The frequency of events of pleuropulmonary complications and logistic regression analysis was performed, and the adjusted odds ratio (OR) and confidence intervals at 95% (95% CI) were calculated. RESULTS: A total of 139 patients were included. The frequency of pleuropulmonary complications was 42.4% (N=59), and the most frequent types were atelectasis (28 events), ventilator-associated pneumonia (24 events), pneumothorax (20 events), with more than one complication per patient occasionally being found. Significant risk factors were cyanogenic congenital heart disease (OR=3.58, 95% CI: 1.10-7.50, P=.001), thoracotomy approach (OR=1.46, 95% CI: 1.18-1.12, P=.008), and an emergency surgical event (OR=3.46, 95% CI: 1.51-7.95, P=.002). CONCLUSIONS: The main pleuropulmonary complication was atelectasis, which is consistent with that reported in the international literature. Patients with any of the predictors identified in the present study should be closely monitored in order to prevent, detect and/or treat pleuropulmonary complications in a timely manner after cardiac surgery. PMID- 28676204 TI - [Clinical value of cardiovascular physical examination: A review of evidence]. PMID- 28676206 TI - Manganese testing under a clean air act test rule and the application of resultant data in risk assessments. AB - In the 1990's, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use. Among the uncertainties identified were: the chemical forms of Mn emitted in automotive exhaust; the relative toxicity of different Mn species; the potential for exposure among sensitive subpopulations including females, the young and elderly; differences in sensitivity between test species and humans; differences between inhalation and oral exposures; and the influence of dose rate and exposure duration on tissue accumulation of Mn. It was anticipated that development of specific sets of pharmacokinetic (PK) information and models regarding Mn could help resolve many of the identified uncertainties and serve as the best foundation for available data integration. The results of the test program included development of several unique Mn datasets, and a series of increasingly sophisticated Mn physiologically based pharmacokinetic (PBPK) models. These data and models have helped address each of the uncertainties originally identified in the Test Rule. The output from these PBPK models were used by the Agency for Toxic Substances and Disease Registry (ATSDR) in 2012 to inform the selection of uncertainty factors for deriving the manganese Minimum Risk Level (MRL) for chronic exposure durations. The EPA used the MRL in the Agency's 2015 evaluation of potential residual risks of airborne manganese released from ferroalloys production plants. This resultant set of scientific data and models likely would not exist without the CAA section 211(b) test rule regulatory procedure. PMID- 28676208 TI - Epinephrine use for anaphylaxis: Too seldom, too late: Current practices and guidelines in health care. PMID- 28676205 TI - Small molecules to the rescue: Inhibition of cytokine signaling in immune mediated diseases. AB - Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, interferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines' signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3'-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies. PMID- 28676209 TI - Sustainable utilization of waste palm oil and sulfonated carbon catalyst derived from coconut meal residue for biodiesel production. AB - In this study, an inexpensive, environmental benign acid catalyst is prepared using coconut meal residue (CMR) and employed for biodiesel production from waste palm oil (WPO). The total acid density of the catalyst is found to be 3.8mmolg-1. The catalyst shows a unique amorphous structure with 1.33m2g-1 of surface area and 0.31cm3g-1 of mean pore volume. Successful activation is confirmed by Fourier transform infrared (FT-IR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The highest biodiesel yield of 92.7% was obtained from WPO in an open reflux system using the catalyst. Results show that biodiesel yield increases with increasing methanol:oil (molar ratio) and reaction time up to an optimum value. It is found that the catalyst can be reused for at least four cycles for >80% biodiesel yield. Fuel properties of the produced biodiesel meet international biodiesel standards. PMID- 28676210 TI - Good use and risks of opioid drugs. PMID- 28676207 TI - Effects of allergen sensitization on response to therapy in children with eosinophilic esophagitis. AB - BACKGROUND: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. OBJECTIVE: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. METHODS: Patients 2 to 18 years old who were referred to the Arkansas Children's Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count <15 per high power field [HPF]) and nonresponders (>25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. RESULTS: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with non-PPI responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (>=1 but <=25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). CONCLUSION: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01779154. PMID- 28676211 TI - Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial. AB - PURPOSE: Malignant pleural mesothelioma (MPM) is a rare malignancy, and pemetrexed/cisplatin (PC) is the gold standard first-line regime. This study evaluated the cost-effectiveness of the addition of bevacizumab to PC (with maintenance bevacizumab) for unresectable MPM based on a phase III trial that showed a survival benefit compared with chemotherapy alone. METHODS: To estimate the incremental cost-effectiveness ratio (ICER) of the incorporation of bevacizumab, a Markov model based on the MAPS trial, including the disease states of progression-free survival, progressive disease and death, was used. Total costs were calculated from a Chinese payer perspective, and health outcomes were converted into quality-adjusted life year (QALY). Model robustness was explored in sensitivity analyses. RESULTS: The addition of bevacizumab to PC was estimated to increase the cost by $81446.69, with a gain of 0.112 QALYs, resulting in an ICER of $727202.589 per QALY. In both one-way sensitivity and probabilistic sensitivity analyses, the ICER exceeded the commonly accepted willingness-to-pay threshold of 3 times the gross domestic product per capita of China ($23970.00 per QALY). The cost of bevacizumab had the most important impact on the ICER. CONCLUSIONS: The combination of bevacizumab with PC chemotherapy is not a cost effective treatment option for MPM in China. Given its positive clinical value and extremely low incidence of MPM, an appropriate price discount, assistance programs and medical insurance should be considered to make bevacizumab more affordable for this rare patient population. PMID- 28676212 TI - Patterns of care and outcomes for stage IIIB non-small cell lung cancer in the TNM-7 era: Results from the Netherlands Cancer Registry. AB - OBJECTIVES: There is limited data on the pattern of care for locally advanced, clinical (c) IIIB non-small cell lung cancer (NSCLC) in the TNM-7 staging era. The primary aim of this study was to investigate national patterns of care and outcomes in the Netherlands, with a secondary focus on the use of surgery. MATERIAL AND METHODS: Data from patients treated for TNM-7 cIIIB NSCLC between 2010 and 2014, was extracted from the Netherlands Cancer Registry (NCR). Survival data was obtained from the automated Civil Registry. RESULTS: 43.762 patients with NSCLC were recorded in the NCR during this 5-year period, with cIIIB accounting for 10% (n=4.401). Clinical N2 (37%) and N3 (63%) nodal involvement was pathologically confirmed in 50.8%. The use of endobronchial ultrasound (EBUS) increased with time from 9% to 29% (p<0.001), while the rate of pathological confirmation of N2 or N3 nodes increased from 44% to 54% (p<0.001). 48% of patients received chemoradiotherapy (CRT), 19% chemotherapy (CT), RT in 10% and surgery in 2.2%. 22% received best supportive care (BSC). The percentage of patients treated with CRT decreased from 65% for patients aged <60 years to 13% for patients aged 80 years or older. Overall survival for surgery was 28 months, followed by CRT (19mths), CT (9mths), RT (8mths) and BSC (3mths). CONCLUSION: In the Netherlands, CRT is the most frequent treatment for cIIIB NSCLC in the TNM-7 era. The use of surgery is limited. Accurate staging requires specific attention and the scarce use of radical treatment in elderly patients merits further evaluation. PMID- 28676213 TI - Urine circulating-tumor DNA (ctDNA) detection of acquired EGFR T790M mutation in non-small-cell lung cancer: An outcomes and total cost-of-care analysis. AB - OBJECTIVES: Third-generation tyrosine kinase inhibitors (TKIs) have proven effective in patients with the acquired EGFR T790M resistance mutation who progress on prior EGFR TKI therapy. Median progression-free survival (PFS) on a 3rd-gen TKI was 9-10 months for T790M+ patients compared to 2.8 months for T790M- patients. PFS is similar regardless of the specimen used to assess T790M, such as tissue, plasma, or urine ctDNA. This study aimed to assess the total cost of care of a urine-testing strategy (UTS) versus a tissue-testing strategy (TTS) for T790M detection, in patients with EGFR-mutation positive lung adenocarcinoma and progression on prior TKI therapy. MATERIALS AND METHODS: Long-term outcomes and economic implications were assessed from a US payer perspective. Endpoints were PFS, overall survival (OS), medical resource use and related costs. DATA SOURCES: We included published randomized drug trials and Medicare fee schedules. A state transition analysis and Markov model tracked patients from stable disease to progression and death. Univariate and multivariate sensitivity analyses were performed to assess the robustness of findings and identify factors that most influenced outcomes and costs. RESULTS: UTS increased the rate of detection of patients with T790M mutation eligible for treatment with 3rd generation TKI by 7% compared with TTS; urine ctDNA testing detected T790M mutation in some patients for whom biopsy could not be performed or when tissue testing yielded indeterminate results. Due to enhanced targeting of TKI therapy, UTS increased PFS and OS by 0.44 and 0.35 months, respectively. UTS yields a savings of $1243 $1680 per patient due to avoidance of biopsy, potential biopsy-associated complications, and tissue-based molecular testing in approximately 55.6% of patients. Probability of T790M detection by tissue and cost of biopsy procedure were the most influential factors. CONCLUSION: UTS prolonged PFS/OS due to increased detection of T790M mutation and decreased biopsies and complication related costs. PMID- 28676214 TI - DNA mismatch repair deficiency in surgically resected lung adenocarcinoma: Microsatellite instability analysis using the Promega panel. AB - OBJECTIVES: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas. MATERIALS AND METHODS: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015. Genomic DNA extracted from tumors and corresponding normal lung tissues were used for MSI analysis using the Promega panel (5 mononucleotide markers: BAT 25, BAT-26, NR-21, NR-24, and MONO-27; and 2 pentanucleotide markers: Penta C and Penta D). RESULTS: MSI was identified in only 1 pan-negative tumor from a 64-year old male heavy smoker. MSI was found in 4 mononucleotide markers. Although no clinical background of Lynch syndrome was evident, somatic MLH1 gene mutation was identified. MLH1 was expressed in tumor-infiltrating lymphocytes and was not expressed in cancer cells. PD-L1 was not expressed in cancer cells, and PD-1 was not expressed in tumor-infiltrating lymphocytes. CONCLUSION: MSI is a rare event in lung adenocarcinoma regardless of smoking status and mutation status of driver oncogenes. Accordingly, MMR deficiency status cannot be used as a biomarker for immune checkpoint inhibitor treatment for lung adenocarcinoma. PMID- 28676215 TI - Identification of a novel T1151K ALK mutation in a patient with ALK-rearranged NSCLC with prior exposure to crizotinib and ceritinib. AB - Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) derive significant clinic benefit from treatment with ALK inhibitors. Crizotinib was the first approved tyrosine kinase inhibitor (TKI) for this distinct molecular subset of NSCLC. Disease progression on TKI inevitably arises secondary to diverse resistance mechanisms among which emergence of secondary ALK mutations is one of many ways in which tumor cells have adapted to survive. Therefore there is a clinical imperative to identify acquired ALK mutations via repeat tissue biopsy if clinically feasible. If such is present, switching to a different TKI with known clinical activities against the emergent resistance mutation (s) may pose a viable treatment option. Here we report for the first time a novel ALK T1151K mutation in a patient with metastatic ALK rearranged NSCLC who progressed on crizotinib and then ceritinib. The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the beta3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure. It is predicated that the T1151K mutation weakens these interactions leading to drug resistance, or causes conformational changes of the ALK catalytic domain resulting in higher affinity for ATP and therefore diminished inhibitor binding. We conclude that the T1151K ALK mutation confers resistance to ceritinib, which may be rescued by alectinib or lorlatinib as evidenced by this clinical narrative. PMID- 28676216 TI - Functional analysis of Discoidin domain receptor 2 mutation and expression in squamous cell lung cancer. AB - OBJECTIVES: Discoidin domain receptor (DDR) 2 mutations have recently been reported to be candidate targets of molecular therapy in lung squamous cell carcinoma (SQCC). However, the status of DDR2 expression and mutations, as well as their precise roles in lung SQCC, have not been clarified. We here report DDR2 mutation and expression status in clinical samples and its role of lung SQCC. MATERIALS AND METHODS: We investigated DDR2 expression and mutation status in 44 human clinical samples and 7 cell lines. Biological functions of DDR2 were assessed by in vitro cell invasion assay and animal model experiments. RESULTS: Endogenous DDR2 protein expression levels were high in one cell line, PC-1, and immunohistochemistry of lung cancer tissue array showed high levels of DDR2 protein in 29% of lung SQCC patients. A mutation (T681I) identified in lung SQCC and the cell line EBC-1 was detected among 44 primary lung SQCC samples and 7 lung SQCC cell lines. Although Forced expression of DDR2 and its mutant (T681I) led to induce SQCC cell invasion in vitro, only wild type DDR2 enhanced lung metastasis in an animal model. We also found that ectopic expression of DDR2 induced MMP-1 mRNA expression accompanied by phosphorylation of c-Jun after treatment with its ligand, collagen type I, but DDR2 with the T681I mutation did not, suggesting that T681I mutation is an inactivating mutation. CONCLUSION: Overexpression of DDR2 might contribute to tumor progression in lung SQCC. The overexpression of DDR2 could be potential molecular target of lung SQCC. PMID- 28676218 TI - GTF2I mutation frequently occurs in more indolent thymic epithelial tumors and predicts better prognosis. AB - OBJECTIVES: A missense mutation in GTF2I was previously identified in thymic epithelioid tumor (TET). However, the clinicopathological relevance of GTF2I mutation has not been illustrated. We studied the prognostic importance of GTF2I mutation as well as its relation to histological subtypes in a large number of TETs. METHODS: TET samples from 296 patients with clinical and follow-up data were collected, and histological subtypes were classified. Analysis of the GTF2I (chromosome 7 c.74146970T>A) mutation was undertaken by using quantitative real time polymerase chain reaction (qPCR) and direct sequencing. The association of GTF2I mutation with clinicopathological features as well as prognosis was analyzed. RESULTS: One hundred twenty-four out of 296 (41.9%) patients harbored the GTF2I mutation (chromosome 7 c.74146970T>A). GTF2I mutation was observed in 20 (87.0%) cases of type A thymoma, 70 (78.7%) of type AB thymoma, and the frequency decreased with the degree of histological subtype aggressiveness, with the lowest rate in thymic carcinoma (7.7%). The difference of GTF2I mutation distribution in histological subtypes was statistically significant (p<0.001). The GTF2I mutation was found more frequently in patients with early Masaoka stage (I-II, n=112, 90.3%) than in those with advanced stage (III-IV) disease (n=12, 9.6%, p<0.001). However, only histological subtype significantly predicted the presence of the GTF2I mutation in patients with TETs. The presence of the GTF2I mutation correlated with better prognosis (90.0% compared to 72.0% 5-year survival, and 86% compared to 56% 10-year survival, respectively; log-rank p=0.001). Moreover, it was an independent prognostic factor [hazard ratio (HR), 0.35; 95% confidential interval (CI), 0.15-0.81; p=0.014)]. CONCLUSIONS: The frequency of the GTF2I mutation is higher in more indolent TETs, and correlates with better prognosis. Further studies are required to elucidate the role of the GTF2I mutation in TETs and its clinical application. PMID- 28676217 TI - Calcium plus vitamin D supplementation and lung cancer incidence among postmenopausal women in the Women's Health Initiative. AB - BACKGROUND: Magnesium and calcium are antagonistic in many physiologic processes. However, few studies have investigated the associations of supplemental calcium with lung cancer risk taking this antagonism into account. We evaluated the effect of calcium and vitamin D supplementation on lung cancer incidence and explored whether the ratio of baseline calcium to magnesium (Ca:Mg) intake modifies the association in the Women's Health Initiative (WHI) calcium plus vitamin D supplementation (CaD) trial. METHODS: The intervention phase of the WHI CaD was a double-blinded, randomized, placebo-controlled trial in 36,382 postmenopausal women aged 50-79 years, recruited at 40U.S. centers. Post intervention follow-up continued among 29,862 (86%) of the surviving participants. Risk of lung cancer in association with CaD supplementation was evaluated using proportional hazard regression models. RESULTS: After 11 years' cumulative follow-up, there were 207 lung cancers (incidence 0.11% per year) in the supplement arm and 241 (0.12%) in the placebo arm (hazard ratio (HR) for the intervention, 0.91; 95% confidence interval (CI), 0.71-1.17). Subgroup analyses suggested that the HR for lung cancer varied by baseline Ca:Mg intake ratio among women who were current smokers at enrollment (p=0.04 for interaction). CONCLUSIONS: Over the entire follow-up period, calcium and vitamin D supplementation did not reduce lung cancer incidence among postmenopausal women. In exploratory analyses, an interaction was found for the baseline Ca:Mg intake ratio on lung cancer among current smokers at the trial entry. This findings need to be further studied for the role of calcium with magnesium in lung carcinogenesis in current smokers. PMID- 28676219 TI - De novo cystic brain lesions mimicking neurocysticercosis in ALK-positive lung cancer. AB - Cystic brain metastases (CBM) have been recently reported in a minority of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). All previously reported ALK-positive CBM developed during crizotinib treatment and were often asymptomatic and indolent, even without CNS directed therapy. Thus, crizotinib was suggested as an etiologic agent for the development of CBM. Here, we report a case of de novo CBM in a patient with ALK positive NSCLC prior to crizotinib treatment; the ALK-positive NSCLC had initially been misdiagnosed as neurocysticercosis because of the atypical radiological presentation of brain metastases. PMID- 28676220 TI - Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. AB - OBJECTIVE: Approximately 10%-15% patients with epidermal growth factor receptor (EGFR) mutations harbor non-classical mutations. However, the effects of EGFR tyrosine kinases (TKIs), particularly second-generation EGFR-TKI (afatinib) compared to first-generation EGFR-TKIs (gefitinib/erlotinib), in patients with non-classical EGFR mutations remain unknown. METHODS: We conducted this retrospective study at the China Medical University Hospital (Taichung, Taiwan) from June 2011 to July 2016. Specimens from 1632 patients were tested for EGFR mutations. We surveyed the effectiveness of afatinib and gefitinib/erlotinib in stage IIIb-IV lung adenocarcinoma patients with non-classical EGFR mutations. RESULTS: Fifty-six patients with advanced-stage (stage IIIB-IV) lung adenocarcinoma with non-classical mutations and receiving EGFR-TKI treatment had completed follow-up and were further analyzed. Afatinib versus gefitinib/erlotinib showed that the objective response rates were 62.5% versus 50.0% (p=0.35). Median progression-free survival (PFS) of 11.0 versus 3.6 months (p=0.03), respectively, was observed for the 51 non-classical EGFR mutated (excluding 5 patients with exon 20 insertions) lung adenocarcinomas. Subset analysis showed that PFS curves of afatinib were more easily distinguished in non classical EGFR mutations lacking a combination with a classical mutation (non classical with classical complex mutations group: median PFS, 11.0 versus 8.2 months, p=0.19; non-classical mutation alone or in combination with other non classical mutations group: median PFS, 18.3 versus 2.8 months, p=0.07). CONCLUSIONS: Afatinib may be a first-choice EGFR-TKI for patients with advanced stage lung adenocarcinomas harboring non-classical mutations. PMID- 28676221 TI - MYC expression correlates with PD-L1 expression in non-small cell lung cancer. AB - Objectives Programmed death-ligand 1 (PD-L1) is a widely used biomarker for predicting immune checkpoint inhibitors, but is of limited usefulness in the prediction of drug response. MYC, a transcription factor that is overexpressed in cancers, is involved in preventing immune cells from attacking tumor cells through inducing PD-L1 expression. This study evaluated the relationship between MYC and PD-L1 expression in 84 non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection. Materials and Methods The relationship between MYC and PD-L1 was investigated by introducing pcDNA3-cMYC into A549 and H1299 cells with low PD-L1 expression and siRNA against MYC into H60 and H2009 cells with high PD-L1 expression. Expression of PD-L1 in NSCLC tissues was analyzed by immunostaining using a PD-L1 (22C3) PharmDx protocol using the Dako Automated Link 48 platform and expression of MYC was determined using anti-c-MYC (Y69) (ab320720). Results Of 84 patients, PD-L1 was expressed in 14 (16.7%) and MYC was overexpressed in 30 (35.7%). We investigated the relationship between PD L1 and MYC expression. There were 49 (58.3%) double-negative patients and 9 (10.7%) double-positive patients. Significant positive correlation was observed between PD-L1 and MYC expression (gamma=0.210, P=0.029). Double-negative patients showed better disease free (31.1 vs. 7.1 months, P=0.011) and overall survival (56.1 vs. 14.4 months, P=0.032) than double-positive patients. Conclusion Taken together, MYC expression significantly correlated with PD-L1 expression in NSCLC. The usefulness of MYC expression as a surrogate marker of treatment response assessment is worth evaluating for immune checkpoint inhibitor therapy and special interest are required for the subgroup of NSCLC patients, whose tumor expresses PD-L1 and MYC double positive. PMID- 28676222 TI - Optimal management of EGFR-mutant non-small cell lung cancer with disease progression on first-line tyrosine kinase inhibitor therapy. AB - The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, and the second-generation EGFR-TKI, afatinib, have all been approved as standard first-line treatments for advanced EGFR-mutant non-small cell lung cancer (NSCLC) based on superior progression-free survival results compared to platinum doublet chemotherapy regimens. Acquired resistance to an EGFR-TKI inevitably develops after a period of effective drug treatment. After tumor progression, many combination therapy regimens that include an EGFR-TKI, or EGFR-TKI monotherapy, have been tested in prospective trials with the aim of extending survival. Third-generation EGFR-TKIs such as osimertinib have been developed with the aim of overcoming the effects of EGFR T790M resistance mutation, which occurs in half of the patients with disease progression on EGFR-TKI therapy. Osimertinib has become the standard treatment in patients for whom tumor re-biopsy reveals an acquired EGFR T790M mutation following EGFR-TKI therapy. Other third-generation EGFR-TKIs, such as olmutinib, EGF816, and ASP8273, are still in the trial phase. PMID- 28676223 TI - Prevalence of Peyronie's Disease-Like Symptoms in Men Presenting With Dupuytren Contractures. AB - INTRODUCTION: Peyronie's disease (PD) and Dupuytren contractures (DC) are often comorbid and are believed to have a similar underlying pathophysiologic mechanism. AIM: To investigate the prevalence of PD-like symptoms (PDLS) in men with DC. METHODS: From October 2013 to December 2016, men who were seen and evaluated for DC were offered the opportunity to participate in an anonymous survey. The survey assessed several basic demographic and sexual health factors and included items from the International Index of Erectile Function and the Erection Hardness Scale. Men who reported PDLS were asked a series of questions derived from the Peyronie's Disease Questionnaire and for their opinions on theoretical treatment modalities for sexual problems and penile deformity. MAIN OUTCOME MEASURE: Prevalence of PDLS in men with DC. RESULTS: One hundred forty men with DC were invited to participate; 85 surveys were returned (response rate = 61%). Twenty-two respondents (26%, 95% confidence interval = 17-35) reported PDLS. Approximately one fourth of all respondents had an Erection Hardness Scale score lower than 3. The most common specific PDLS concerns were penile curvature (91%), length loss (55%), narrowing (36%), and hinging (32%). In men with PDLS, 73% felt at least a little bothered by the symptoms when attempting sexual activity and 40% reported having sex less frequently because of the symptoms. Just 27% of men with PDLS had ever used a treatment for a sexual concern. In terms of treatments for penile deformities, 64% of men with PDLS expressed an interest in treatment administered in the form of an in-office procedure; 41% were potentially amenable to a surgical procedure. CONCLUSION: The prevalence of PDLS in men with DC is similar to the prevalence of DC in men diagnosed with PD. A substantial number of these men have distress and would consider standard-of care treatments for PD. Shindel AW, Sweet G, Thieu W, et al. Prevalence of Peyronie's Disease-Like Symptoms in Men Presenting With Dupuytren Contractures. Sex Med 2017;5:e135-e141. PMID- 28676224 TI - Pediatric non-fatal drowning events: do they warrant trauma team activation? PMID- 28676225 TI - Identification of cytidine-5-triphosphate synthase1-selective inhibitory peptide from random peptide library displayed on T7 phage. AB - Cytidine triphosphate synthase 1 (CTPS1) is an enzyme expressed in activated lymphocytes that catalyzes the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP) with ATP-dependent amination, using either L glutamine or ammonia as the nitrogen source. Since CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialyation, CTPS1 inhibition is expected to control lymphocyte proliferation and size expansion in inflammatory diseases. In contrast, CTPS2, an isozyme of CTPS1 possessing 74% amino acid sequence homology, is expressed in normal lymphocytes. Thus, CTPS1 selective inhibition is important to avoid undesirable side effects. Here, we report the discovery of CTpep-3: Ac-FRLGLLKAFRRLF-OH from random peptide libraries displayed on T7 phage, which exhibited CTPS1-selective binding with a KD value of 210nM in SPR analysis and CTPS1-selective inhibition with an IC50 value of 110nM in the enzyme assay. Furthermore, two fundamentally different approaches, enzyme inhibition assay and HDX-MS, provided the same conclusion that CTpep-3 acts by binding to the amidoligase (ALase) domain on CTPS1. To our knowledge, CTpep-3 is the first CTPS1-selective inhibitor. PMID- 28676226 TI - Late toxicity and outcomes following radiation therapy for chest wall sarcomas in pediatric patients. AB - PURPOSE: To investigate the contribution of radiation therapy to acute and late toxicity in pediatric chest wall sarcoma patients and evaluate dosimetric correlates of higher incidence toxicities such as scoliosis and pneumonitis. METHODS AND MATERIALS: The data from 23 consecutively treated pediatric patients with chest wall sarcomas of various histologies (desmoid, Ewing, rhabdomyosarcoma, nonrhabdomyosarcoma-soft tissue sarcomas) were reviewed to evaluate the relationship between end-organ radiation dose, clinical factors, and the risk of subsequent late effects (scoliosis, pneumonitis). Cobb angles were used to quantify the extent of scoliosis. Doses to the spine and lung were calculated from the radiation treatment plan. RESULTS: The range of scoliosis identified on follow-up imaging ranged from -47.6 to 64 degrees (median, 2.95 degrees ). No relationship was identified between either radiation dose to the ipsilateral or contralateral vertebral body or tumor size and the degree or direction of scoliosis. The extent of surgical resection and number and location of resected ribs affected the extent of scoliosis. The dominant predictor of extent of scoliosis at long-term follow-up was the extent of scoliosis following surgical resection. Radiation pneumonitis was uncommon and was not correlated with mean dose or volume of lung receiving 24 Gy; however, 1 of 3 surviving patients who received whole pleural surface radiation therapy developed significant restrictive lung disease. CONCLUSIONS: Acute and late radiation therapy-associated toxicities in pediatric chest wall sarcoma patients are modest. The degree of scoliosis following resection is a function of the extent of resection and of the number and location of ribs resected, and the degree of scoliosis at the last follow-up visit is a function of the extent of scoliosis following surgery. Differential radiation therapy dose across the vertebral body does not increase the degree of scoliosis. Severe restrictive pulmonary disease is a late complication of survivors after whole pleural surface radiation therapy. PMID- 28676227 TI - The Call. PMID- 28676228 TI - Room Service Improves Nutritional Intake and Increases Patient Satisfaction While Decreasing Food Waste and Cost. AB - BACKGROUND: Room service is a foodservice model that has been increasingly implemented across health care facilities in an effort to improve patient satisfaction and reduce food waste. In 2013, Mater Private Hospital Brisbane, Australia, was the first hospital in Australia to implement room service, with the aim of improving patient nutrition care and reducing costs. OBJECTIVE: The aim of this study was to comprehensively evaluate the nutritional intake, plate waste, patient satisfaction, and patient meal costs of room service compared to a traditional foodservice model. DESIGN: A retrospective analysis of quality assurance data audits was undertaken to assess patient nutritional intake between a facility utilizing a traditional foodservice model and a facility utilizing room service and in a pre-post study design to assess plate waste, patient satisfaction, and patient meal costs before and after the room service implementation. PARTICIPANTS: Audit data were collected for eligible adult inpatients in Mater Private Hospital Brisbane and Mater Hospital Brisbane, Australia, between July 2012 and May 2015. MAIN OUTCOME MEASURES: The primary outcome measures were nutritional intake, plate waste, patient satisfaction, and patient meal costs. STATISTICAL ANALYSES PERFORMED: Independent samples t-tests and chi2 analyses were conducted between pre and post data for continuous data and categorical data, respectively. Pearson chi2 analysis of count data for sex and reasons for plate waste for data with counts more than five was used to determine asymptotic (two-sided) significance and n-1 chi2 used for the plate waste analysis. Significance was assessed at P<0.05. RESULTS: This study reported an increased nutritional intake, improved patient satisfaction, and reduced plate waste and patient meal costs with room service compared to a traditional foodservice model. Comparison of nutritional intake between a traditional foodservice model (n=85) and room service (n=63) showed statistically significant increases with room service in both energy (1,306 kcal/day vs 1,588 kcal/day; P=0.005) and protein (52 g/day vs 66 g/day, P=0.003) intake, as well as energy and protein intake as a percentage of requirements (63% vs 75%; P=0.024 and 65% vs 85%; P=0.011, respectively). Total mean plate waste decreased from 29% (traditional foodservice model) to 12% (room service) (P<0.001). Patient satisfaction ratings indicated improvement with room service across all Press Ganey meal scores: 68th to 86th percentile overall; 64th to 95th percentile for "quality of food"; and 60th to 99th percentile for "flavor of food." Evaluated during comparable times of the year, patient meal costs decreased by 15% with room service. CONCLUSIONS: A patient-centered foodservice model, such as room service, can improve patient nutritional intake and enhance patient satisfaction in a budget constrained health care environment. PMID- 28676229 TI - Development, Construct Validity, and Reliability of the Questionnaire on Infant Feeding: A Tool for Measuring Contemporary Infant-Feeding Behaviors. AB - BACKGROUND: The breastfeeding surveillance tool in the United States, the National Immunization Survey, considers the maternal-infant dyad to be breastfeeding for as long as the infant consumes human milk (HM). However, many infants consume at least some HM from a bottle, which can lead to health outcomes different from those for at-the-breast feeding. OBJECTIVE: Our aim was to develop a construct-valid questionnaire that categorizes infants by nutrition source, that is, own mother's HM, another mother's HM, infant formula, or other and feeding mode, that is, at the breast or from a bottle, and test the reliability of this questionnaire. DESIGN: The Questionnaire on Infant Feeding was developed through a literature review and modified based on qualitative research. Construct validity was assessed through cognitive interviews and a test-retest reliability study was conducted among mothers who completed the questionnaire twice, 1 month apart. PARTICIPANTS/SETTING: Cognitive interviews were conducted with ten mothers from upstate New York between September and December 2014. A test-retest reliability study was conducted among 44 mothers from across the United States between March and May 2015. MAIN OUTCOME MEASURES: Equivalence of questions with continuous responses about the timing of starting and stopping various behaviors and the agreement between responses to questions with categorical responses on the two questionnaires completed 1 month apart. STATISTICAL ANALYSES PERFORMED: Reliability was assessed using paired-equivalence tests for questions about the timing of starting and stopping behaviors and weighted Cohen's kappa for questions about the frequency and intensity of behaviors. RESULTS: Reliability of the Questionnaire on Infant Feeding was moderately high among mothers of infants aged 19 to 35 months, with most questions about the timing of starting and stopping behaviors equivalent to within 1 month. Weighted Cohen's kappa for categorical questions indicated substantial agreement. CONCLUSIONS: The Questionnaire on Infant Feeding is a construct-valid tool to measure duration, intensity, and mode of infant HM consumption and duration of maternal HM production that is reliable within 19 to 35 months postpartum. Criterion-validity testing of these questions will improve the utility of the Questionnaire on Infant Feeding as a surveillance tool. PMID- 28676230 TI - Incidence of asthma in young adults from Castellon, Spain: A prospective cohort study. AB - BACKGROUND: The objective was to estimate the incidence of asthma in young adults from 13-15 years old to 23-25 years old, and associated factors. METHODS: In 2012, a population-based prospective cohort study was carried out in Castellon from the cohort who had participated in the International Study of Asthma and Allergy in Childhood in 1994 and 2002. A telephone survey was undertaken using the same questionnaires. A new case of asthma was defined as a participant free of the disease in 2002 who suffered asthma, was diagnosed with asthma, or took medications against asthma based on self-report from 2002 to 2012. RESULTS: The mean age of participants was 24.9+/-0.6 with a follow-up of 79.1%. Asthma cumulative incidence was 3.4%: 44 new cases occurred among 1280 participants. The incidence was higher in females than males with relative risk (RR)=2.02 (95% confidence interval [CI] 1.1-3.8). A significant decrease of asthma incidence density was observed (8.2 cases to 3.5 cases per 1000 person/year). Factors associated with the incidence of asthma were allergic rhinitis (RR=4.05; 95% CI 1.7-9.6), bronchitis (RR=2.13; 95% CI 1.0-4.5), mother's age at time of birth (RR=0.87; 95% CI 0.8-0.9) and a pet other than a dog or cat (RR=0.42; 95% CI 0.2 0.9). For gender, some variations in the risk factors were observed. CONCLUSIONS: A significant decrease in the incidence of asthma was observed. Several risk and protective factors were found. PMID- 28676232 TI - MHC class II deficiency: Report of a novel mutation and special review. AB - The MHC II deficiency is a rare autosomal recessive primary immunodeficiency syndrome with increased susceptibility to respiratory and gastrointestinal infections, failure to thrive and early mortality. This syndrome is caused by mutations in transcription regulators of the MHC II gene and results in development of blind lymphocytes due to the lack of indicatory MHC II molecules. Despite homogeneity of clinical manifestations of patients with MHC II deficiency, the genetic defects underlying this disease are heterogeneous. Herein, we report an Iranian patient with MHC II deficiency harbouring a novel mutation in RFXANK and novel misleading clinical features. He had ataxic gait and dysarthria from 30 months of age. Epidemiology, clinical and immunological features, therapeutic options and prognosis of patients with MHC II are reviewed in this paper. PMID- 28676231 TI - Oral immunotherapy for food allergy: A Spanish guideline. Egg and milk immunotherapy Spanish guide (ITEMS GUIDE). Part 2: Maintenance phase of cow milk (CM) and egg oral immunotherapy (OIT), special treatment dosing schedules. Models of dosing schedules of OIT with CM and EGG. AB - INTRODUCTION: Cow's milk and egg are the most frequent causes of food allergy in the first years of life. Treatments such as oral immunotherapy (OIT) have been investigated as an alternative to avoidance diets. No clinical practice guides on the management of OIT with milk and egg are currently available. OBJECTIVES: To develop a clinical guide on OIT based on the available scientific evidence and the opinions of experts. METHODS: A review was made of studies published in the period between 1984 and June 2016, Doctoral Theses published in Spain, and summaries of communications at congresses (SEAIC, SEICAP, EAACI, AAAAI), with evaluation of the opinion consensus established by a group of experts pertaining to the scientific societies SEICAP and SEAIC. RESULTS: Recommendations have been established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of suffering adverse reactions. CONCLUSIONS: A clinical practice guide is presented for the management of OIT with milk and egg, based on the opinion consensus of Spanish experts. PMID- 28676233 TI - Customized workflow development and data modularization concepts for RNA Sequencing and metatranscriptome experiments. AB - RNA-Sequencing (RNA-Seq) has become a widely used approach to study quantitative and qualitative aspects of transcriptome data. The variety of RNA-Seq protocols, experimental study designs and the characteristic properties of the organisms under investigation greatly affect downstream and comparative analyses. In this review, we aim to explain the impact of structured pre-selection, classification and integration of best-performing tools within modularized data analysis workflows and ready-to-use computing infrastructures towards experimental data analyses. We highlight examples for workflows and use cases that are presented for pro-, eukaryotic and mixed dual RNA-Seq (meta-transcriptomics) experiments. In addition, we are summarizing the expertise of the laboratories participating in the project consortium "Structured Analysis and Integration of RNA-Seq experiments" (de.STAIR) and its integration with the Galaxy-workbench of the RNA Bioinformatics Center (RBC). PMID- 28676234 TI - Computational proteomics tools for identification and quality control. AB - Computational proteomics is a constantly growing field to support end users with powerful and reliable tools for performing several computational steps within an analytics workflow for proteomics experiments. Typically, after capturing with a mass spectrometer, the proteins have to be identified and quantified. After certain follow-up analyses, an optional targeted approach is suitable for validating the results. The de.NBI (German network for bioinformatics infrastructure) service center in Dortmund provides several software applications and platforms as services to meet these demands. In this work, we present our tools and services, which is the combination of SearchGUI and PeptideShaker. SearchGUI is a managing tool for several search engines to find peptide spectra matches for one or more complex MS2 measurements. PeptideShaker combines all matches and creates a consensus list of identified proteins providing statistical confidence measures. In a next step, we are planning to release a web service for protein identification containing both tools. This system will be designed for high scalability and distributed computing using solutions like the Docker container system among others. As an additional service, we offer a web service oriented database providing all necessary high-quality and high-resolution data for starting targeted proteomics analyses. The user can easily select proteins of interest, review the according spectra and download both protein sequences and spectral library. All systems are designed to be intuitively and user-friendly operable. PMID- 28676235 TI - The need for hands-on defibrillation during the late downstroke phase of ongoing abdominal compressions only CPR. PMID- 28676236 TI - White coat effect in hypertensive patients: the role of hospital environment or physician presence. AB - This study was to evaluate the role of hospital environment or physician presence for white coat effect (WCE) in hypertensive patients. At first, 54 hypertensive outpatients diagnosed on office blood pressure (OBP) were included for 2-week placebo run in. During the second week of the run in period, home BP was measured using electronic BP monitors for 5-7 days. Finally, 26 sustained hypertensive patients with home systolic BP/diastolic BP over 135/85 (but <180/110) mm Hg were enrolled for 8-week treatment of nifedipine controlled-release tablet. In the visit day, BP was measured by patient-self (OBP-p) or by doctor (OBP-d) according to order determined with randomization method. The self-BP measurement was performed in a reception room of hospital. The differences between home BP and OBP-d or OBP-p were calculated as WCE calculated on doctor-measurement (WCE-d) or WCE calculated on patient-measurement (WCE-p), respectively. The home and OBP were measured with the same BP device for each patient during the study period. In the total 54 outpatients received placebo, the WCE-d was similar to the WCE-p (for systolic BP 6.6 +/- 14.4 vs. 6.8 +/- 15.8 mm Hg, NS; for diastolic BP 3.3 +/ 8.8 vs. 2.9 +/- 9.2 mm Hg, NS). Meanwhile, the 26 sustained hypertensive patients had similar systolic WCE-d and WCE-p (4.8 +/- 10.3 vs. 5.0 +/- 12.2 mm Hg, NS) at placebo stage. Similarly, these values were comparable (3.0 +/- 14.0 vs. 2.2 +/- 14.4 mm Hg, NS) in treatment stage. Hospital environment plays a main role for the WCE in hypertensive patients. PMID- 28676238 TI - Port catheter-associated Aureobasidium melanigenum fungemia. PMID- 28676237 TI - Spinal muscular atrophy carriers with two SMN1 copies. AB - BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Over 95% of SMA patients have homozygous deletions of the SMA-causative gene, SMN1. Thus, SMA carriers are usually diagnosed based on SMN1 copy number, with one copy indicating SMA carrier status. However, two SMN1 copies do not always exclude carrier status. In this study, we identified SMA carriers with two SMN1 copies. SUBJECTS AND METHODS: From 33 families, 65 parents of genetically confirmed SMA patients were tested to determine SMA carrier status. Molecular genetic analyses, including multiplex ligation-dependent probe amplification (MLPA) assay, were performed using blood samples from family members. RESULTS: Of the 65 parents, three parents from three families had two SMN1 copies. Accordingly, the frequency of carriers with two SMN1 copies was 4.6%. Two of these families were further studied. Patient 1 was homozygous for SMN1 deletion. Patient 1's mother had two SMN1 copies on one chromosome, with deletion of SMN1 on the other chromosome ([2+0] genotype). Patient 1 inherited SMN1-deleted chromosomes from both parents. Patient 2 was compound heterozygous for two SMN1 mutations: whole-gene deletion and intragenic missense mutation, c.826T>C (p.Tyr276His). Patient 2's father had two SMN1 copies with the same intragenic mutation in one copy ([1+1d] genotype, d intragenic mutation). Patient 2 inherited the chromosome with an SMN1 mutation from the father and SMN1-deleted chromosome from the mother. CONCLUSION: SMA carriers with two SMN1 copies may be rare, but its possibility should be taken into consideration in carrier testing and counseling for SMA families or population-based carrier screening. PMID- 28676239 TI - Elucidation of the molecular mechanism of heat shock proteins and its correlation with K722Q mutations in Lon protease. AB - Cells withstand the effects of temperature change with the help of small heat shock proteins IbpA and IbpB. The IbpAB protein complex interacts with Lon protease in their free form and gets degraded at physiological temperature when there is no temperature stress. However, the proteolytic degradation of IbpAB is diminished when Lon is mutated. The mutation K722Q in Lon brings about some structural changes so that the proteolytic interactions between the heat shock proteins with that of the mutated Lon protease are lost. However, the detailed molecular aspects of the interactions are not yet fully understood. In the present, we made an attempt to analyze the biochemical aspects of the interactions between the small heat shock proteins IbpAB with wild type and mutant Lon protease. We for the first time deciphered the molecular details of the mechanism of interaction of small heat shock proteins with Lon protease bearing K722Q mutation i.e. the interaction pattern of heat shock proteins with mutant Lon protease at physiological temperature in absence of proteolytic machinery. Our study may therefore be useful to elucidate the mechanistic details of the correlation with IbpA, IbpB and Lon protease. PMID- 28676240 TI - Local NMDA receptor hypofunction evokes generalized effects on gamma and high frequency oscillations and behavior. AB - The NMDA receptor (NMDAr) hypofunction theory of schizophrenia suggests that aberrant signaling through NMDAr underlies the pathophysiology of this disease. This is commonly modeled in rodents via treatment with NMDAr antagonists, which causes a range of behavioral effects that represent endophenotypes related to schizophrenia. These drugs also disrupt high-frequency neural oscillations within the brain, also potentially relevant to disease. We studied the effect of localized NMDAr hypofunction on the generation of neural oscillations occurring both locally and in distant brain regions, and on behaviors routinely used as endophenotypes to model psychosis in rodents. Wistar rats were implanted with local field potential recording electrodes in the prefrontal cortex, dorsal hippocampus and nucleus accumbens, as well as cannulae in these regions to facilitate drug infusion. Rats received bilateral infusions of MK801 (0, 5MUg, 20MUg, 50MUg) into one of the three target regions and their behavior measured in an open field. We also assessed the effects of systemic MK801 injection (0.16mg/kg sc). Electrophysiological signals were recorded continuously, allowing assessment of gamma oscillations (30-80Hz) and high-frequency oscillations (HFO: 130-180Hz) occurring as a result of infusions. Regardless of MK801 infusion location, gamma oscillations and HFOs significantly and consistently increased in all three regions studied, similar to that observed following systemic injection. Locomotor activity, stereotypies and ataxia were also observed following infusion into all regions. We conclude that localized regions exhibiting NMDAr hypofunction are sufficient to disrupt local as well as diffuse neural circuits and global brain function, and concomitantly cause psychosis-related behavioral effects. PMID- 28676242 TI - Early clinics of the cardiac forms of Chagas' disease: Discovery and study of original medical files (1909-1915). AB - We have uncovered 80 medical files corresponding to original cases of Chagas' disease used for the classical description of the acute and cardiac forms of the disease. Sixty of them were diagnosed cardiac forms of the disease. The detailed clinical description of these 60 files is in excellent agreement with the nosography of progressive heart disease given by Chagas in his original 1922 paper. The reports we had access to, characterize a novel form of cardiac disease, dominated by progressive AV block, enlargement and displacement of the heart and sudden death, in relatively young adults including juveniles. In contrast to that remarkable clinical description, the assertion made by Chagas that this set of clinical signs was the consequence of an earlier infection by Trypanosoma cruzi rests on weak evidence, due to the difficulty to identify the parasite in most patients. Moreover, the association of thyroid dysfunction with cardiac disease emphasized by Chagas cannot be deduced from the files we have examined. Finally, the main reason why the disease had not been recognized for long as a defined clinical entity, is likely the absence of markedly distinctive clinical signs compared to most other parasitic diseases, poor sanitary conditions and the probable lack of clinical skills of the rare doctors working in the area where the disease was described. PMID- 28676241 TI - Age-Dependent Sexual Dimorphism in Susceptibility to Develop Chronic Pain in the Rat. AB - Neonatal pain has been suggested to contribute to the development and/or persistence of adult pain. Observations from animal models have shown that neonatal inflammation produces long-term changes in sensory neuron function, which can affect the susceptibility of adults to develop persistent pain. We used a preclinical model of transition to chronic pain, hyperalgesic priming, in which a previous inflammatory stimulus triggers a long-lasting increase in responsiveness to pro-algesic mediators, prototypically prostaglandin E2 (PGE2), to investigate if post-natal age influences susceptibility of adult rats to develop chronic pain. Priming was induced by tumor necrosis factor alpha (TNFalpha), in male and female rats, 1, 2, 3, 4, 5 or 7weeks after birth. When adults (8weeks after birth), to evaluate for the presence of priming, PGE2 was injected at the same site as TNFalpha. In males that had received TNFalpha at post-natal weeks 1, 2 or 3, priming was attenuated compared to the 4-, 5- and 7 week-old treated groups, in which robust priming developed. In contrast, in females treated with TNFalpha at post-natal week 1, 2, 3, or 4, but not at 5 or 7, priming was present. This age and sex difference in the susceptibility to priming was estrogen-dependent, since injection of TNFalpha in 3-week-old males and 5-week-old females, in the presence of the estrogen receptor antagonist ICI 182,780, did produce priming. These results suggest that estrogen levels, which vary differently in males and females over the post-natal period, until they stabilize after puberty, impact pain as an adult. PMID- 28676243 TI - Characteristics of hospitalizations for cardiogenic shock after acute myocardial infarction in the United States. AB - BACKGROUND: Multiple studies have reported a decline in mortality for patients with cardiogenic shock after acute myocardial infarction (CS-AMI), a finding which has been attributed to an increase in revascularization over the past decade. However, other studies that have focused on CS-AMI patients treated with early percutaneous coronary intervention (PCI) have found no improvement in risk adjusted mortality. To reconcile these discordances, we hypothesize that the clinical complexity of the PCI-population has changed over time, in ways not precisely adjusted for in previous studies. METHODS: We conducted a retrospective analysis of the 2005-2012 Nationwide Inpatient Sample. Patients with CS-AMI who underwent PCI within 24h of hospitalization were identified. Temporal trends in clinical characteristics and in-hospital mortality were analyzed. RESULTS: There was no significant change in un-adjusted in-hospital mortality (30% in 2005-2006 and 27.8% in 2011-2012, OR: 0.90; 95% CI: 0.79-1.01, p=0.07). There was an increase in the proportion of patients with >=3 Elixhauser comorbidities and comorbidity scores >=5. The population of patients that suffered from cardiac arrest or needed intubation on the first hospital day increased from 27.8% to 42.6% (ptrend<0.001). In a multivariate analysis, mortality rates in 2011-2012 versus 2005-2006 decreased significantly (OR: 0.75; 95% CI: 0.65-0.85, p<0.001). CONCLUSIONS: During a period that corresponds to expanded PCI use and improved prehospital survival, risk-adjusted mortality declined. Much of the survival benefit attributable to early revascularization has been neutralized by an increase in prevalence of "extreme-risk" patients. This may contribute to the null effect on in-hospital mortality. PMID- 28676244 TI - Diagnostic yield of cardiovascular magnetic resonance in young-middle aged patients with high-grade atrio-ventricular block. AB - BACKGROUND: Atrio-ventricular block (AVB) is a rare finding in young or middle aged adults, often leading to pacemaker implantation (PM) without further investigation. We sought to assess the diagnostic role of cardiovascular magnetic resonance (CMR) in young and middle-aged adults with high-grade AVB. METHODS: We consecutively enrolled young-middle aged (18-65years) patients with high grade AVB referred to CMR after standard clinical assessment (history, electrocardiogram and cardiac rhythm monitoring) prior to PM implantation. Cine and post-contrast imaging were performed in a 1.5T scanner. RESULTS: 34 patients (59% male, mean age 42+/-12years) with high grade AVB were referred to CMR for suspected ischemic heart disease (IHD)(n=4) and non-ischemic heart disease (NIHD)(n=20); no clear cause was found in 9 patients prior to CMR and 1 patient had suspected lung disease. A pathologic substrate was found on CMR in 15 patients (44%), while a structurally normal heart was reported in 18 (53%). Non specific findings were reported in 1 patient (3%). There was a fair agreement between CMR and echocardiographic findings (Cohen's kappa 0.243), and CMR provided an entirely new diagnosis in 34% of patients. As compared to the standard clinical assessment, CMR had an additional role in 65% of patients and guided further testing (genetic testing, extra-cardiac imaging) in 9%. CONCLUSIONS: CMR found a pathologic substrate in 44% of patients, mainly NIHD (32%). Half of the patients (53%) had a structurally normal heart. When added to the standard clinical assessment, CMR had an incremental diagnostic role in two thirds of patients. PMID- 28676245 TI - Epidemiology, Clinical Presentation, and Prognosis of Posterior Circulation Ischemic Stroke in Children. AB - BACKGROUND: Anterior and posterior circulation strokes are often different in terms of presentation and recurrence risk, but there are few studies that focused on posterior circulation stroke. METHODS: We performed a longitudinal retrospective study of children, birth to 18 years, with posterior circulation ischemic stroke at the Children's Hospital Winnipeg from January 1992 to December 2012. Clinical and radiological features and outcomes were collected using standardized tools. RESULTS: Of the 158 children with arterial ischemic stroke, 23 (14.5%) children, 21 non-neonates, and 11 males were identified. For posterior circulation ischemic stroke, mean crude incidence of 0.38 and crude mortality rate of 0.11 per 100,000 person-years was estimated. The crude total period prevalence rate for the study period was estimated as 8.1 per 100,000 children. Nonspecific symptoms before stroke presentation were present in 38% and impaired consciousness in 71%. Identifiable risk factors were present in two thirds: vasculopathy 24%, infection 19%, trauma 14%, and congenital heart disease 9.5%. Average Pediatric National Institutes of Health Stroke Scale score at presentation was 11. Poor outcome was noted in 45%. Outcome did not change significantly between 12 and 24 months. Aboriginal ethnicity (P = 0.01), high Pediatric National Institutes of Health Stroke Scale score (P = 0.001), bilateral infarction (P = 0.001), and large caliber artery territory infarction (P = 0.02) predicted poor outcome. CONCLUSIONS: Our hospital-based incidence and outcome data provide valuable information to help direct treatment strategies and prognosticate children with posterior circulation ischemic stroke. Our study calls for close observation and early management of children with posterior circulation stroke, in particular with aboriginal ancestry and bilateral and large artery territory infarction. PMID- 28676246 TI - Subclinical Neuroaxonal Damage in Patients With Clinically Mild Encephalitis/Encephalopathy With a Reversible Splenial Lesion. PMID- 28676247 TI - A Series of Experiences: The 2016 Hower Award Lecture. PMID- 28676248 TI - The Weekend Effect on Morbidity and Mortality Among Pediatric Epilepsy Admissions. AB - BACKGROUND: Pediatric epilepsy is one of the most common neurological disorders with low mortality and high morbidity, often requiring hospitalization. Weekend admissions have been shown to be associated with worse outcomes compared with their weekday counterparts. To date, no study has assessed the impact of weekend admission on clinical and quality outcomes in the pediatric epilepsy population. METHODS: Children with epilepsy were identified from the 2000, 2003, 2006, and 2009 Kids Inpatient Database. Quality outcomes were identified using the Centers of Medicare and Medicaid Services' hospital acquired conditions International Classification of Diseases, Ninth Edition; Clinical Modification (ICD-9CM) codes. Multivariable analyses were conducted to assess the association between weekend admission and inpatient mortality and hospital acquired condition occurrence. RESULTS: A total of 526,765 pediatric epilepsy discharges were identified, with 80% occurring on weekdays and 20% on weekends. Overall, the hospital acquired condition rate was 3.6% (3.2% vs 5.2% for weekday versus weekend) and inpatient mortality was 1.5% (1.2% vs 1.7%). Patients admitted on the weekend had 28% higher rates of hospital acquired conditions and 21% higher inpatient mortality rates compared with their weekday counterparts. Patients seen at nonpediatric centers had 10% to 28% lower rates of mortality, but 5% to 13% higher hospital acquired condition rates than those at pediatric centers. CONCLUSIONS: Weekend admission is significantly associated with worse clinical and quality outcomes compared with weekday admissions among pediatric epilepsy inpatients. Weekend admissions likely represent unplanned, at risk admissions, coupled with less staffing. Further study is needed to isolate clinical and systemic factors to decrease this disparity in this highly comorbid pediatric subgroup. PMID- 28676249 TI - Clinicopathologic Conference: A Newborn With Hypotonia, Cleft Palate, Micrognathia, and Bilateral Club Feet. PMID- 28676250 TI - Trends in Antiepileptic Drug Use in Children and Adolescents With Epilepsy. AB - OBJECTIVE: We describe the trends in antiepileptic drug (AED) use in children and adolescents with epilepsy in the United States. METHODS: We undertook a cross sectional study based on Medicaid Analytic eXtract data set from 26 US states. Children and adolescents aged three to 18 years with at least one year continuous Medicaid fee-for-service coverage after the second outpatient or the first inpatient diagnosis of epilepsy in each calendar year during 1999 to 2009 were included in the study; therefore, 11 cohorts were established. A patient was defined as being exposed to a specific AED if he or she had at least one-day supply of the AED during the 1-year follow-up period. The annual prevalence of AEDs was reported, stratified by gender and age. The trends in AED use were evaluated through linear regression. RESULTS: The sample sizes of the 11 cohorts ranged between 17,304 and 22,672. The annual prevalence of valproic acid use declined from 42.4% in 1999 to 26.5% in 2009, and the prevalence of carbamazepine use declined from 37.1% to 10.2%. Meanwhile, the prevalence of levetiracetam use increased from 5.1% to about 32.0% in 2009, and the prevalence of oxcarbazepine use increased from 1.3% to 19.1%. Since 2008, levetiracetam (29.6%) has replaced valproic acid (27.8%) as the most commonly used AED in children and adolescents with epilepsy. The prevalence of diazepam use increased from 11.6% to 28.1%. SIGNIFICANCE: Compared with first- and second-generation antiepileptic drugs, third-generation AEDs have fewer adverse side effects, resulting in increased patient treatment adherence. Equally important is the economic impact of these newer AEDs. This first-of-its-kind study underscores the need for large database studies that objectively assess the cost-effectiveness of third-generation AEDs versus first- and second-generation AEDs in the treatment of childhood epilepsy. PMID- 28676251 TI - The not-so-bitter pill: Effects of combined oral contraceptives on peripheral physiological indicators of emotional reactivity. AB - Combined oral contraceptives (COC) are used by millions of women worldwide. Although findings are not entirely consistent, COC have been found to impact on brain function and, thus, to modulate affective processes. Here, we investigated electro-physiological responses to emotional stimuli in free cycling women in both the early follicular and late luteal phase as well as in COC users. Skin conductance response (SCR), startle reflex, corrugator and zygomaticus activity were assessed. COC users showed reduced overall startle magnitude and SCR amplitude, but heightened overall zygomaticus activity, although effect sizes were small. Thus, COC users displayed reduced physiological reactions indicating negative affect and enhanced physiological responses signifying positive affect. In free cycling women, endogenous 17beta-estradiol levels were associated with fear potentiated startle in both cycle phases as well as with SCR and zygomaticus activity during the follicular phase. Testosterone was associated with corrugator and zygomaticus activity during the luteal phase, while progesterone levels correlated with corrugator activity in the follicular phase. To the contrary, in COC users, endogenous hormones were not associated with electro-physiological measures. The results further underscore the importance of considering COC use in psychophysiological studies on emotional processing. PMID- 28676252 TI - A functional MRI study on how oxytocin affects decision making in social dilemmas: Cooperate as long as it pays off, aggress only when you think you can win. AB - We investigate if the neuropeptide oxytocin (OT), known to moderate social behaviour, influences strategic decision making in social dilemmas by facilitating the integration of incentives and social cues. Participants (N=29) played two economic games with different incentive structures in the fMRI scanner after receiving OT or placebo (following a double blind, within-subject design). Pictures of angry or neutral faces (the social cues) were displayed alongside the game matrices. Consistent with a priori hypotheses based on the modulatory role of OT in mesolimbic dopaminergic brain regions, the results indicate that, compared to placebo, OT significantly increases the activation of the nucleus accumbens during an assurance (coordination) game that rewards mutual cooperation. This increases appetitive motivation so that cooperative behaviour is facilitated for risk averse individuals. OT also significantly attenuates the amygdala, thereby reducing the orienting response to social cues. The corresponding change in behaviour is only apparent in the chicken (or anti coordination) game, where aggression is incentivized but fatal if the partner also aggresses. Because of this ambiguity, decision making can be improved by additional information, and OT steers decisions in the chicken game in accordance with the valence of the facial cue: aggress when face is neutral; retreat when it is angry. Through its combined influence on amygdala and nucleus accumbens, OT improves the selection of a cooperative or aggressive strategy in function of the best match between the incentives of the game and the social cues present in the decision environment. PMID- 28676253 TI - Incidence and Impact of Upper Airway Symptoms in Patients With Chronic Obstructive Pulmonary Disease. PMID- 28676254 TI - Patient Navigation for Colonoscopy Completion: Results of an RCT. AB - INTRODUCTION: Colorectal cancer is a leading cause of cancer-related death in the U.S. Although screening reduces colorectal cancer incidence and mortality, screening rates among U.S. adults remain less than optimal, especially among disadvantaged populations. This study examined the efficacy of patient navigation to increase colonoscopy screening. STUDY DESIGN: RCT. SETTING/PARTICIPANTS: A total of 843 low-income adults, primarily Hispanic and non-Hispanic blacks, aged 50-75 years referred for colonoscopy at Boston Medical Center were randomized into the intervention (n=429) or control (n=427) groups. Participants were enrolled between September 2012 and December 2014, with analysis following through 2015. INTERVENTION: Two bilingual lay navigators provided individualized education and support to reduce patient barriers and facilitate colonoscopy completion. The intervention was delivered largely by telephone. MAIN OUTCOME MEASURE: Colonoscopy completion within 6 months of study enrollment. RESULTS: Colonoscopy completion was significantly higher for navigated patients (61.1%) than control group patients receiving usual care (53.2%, p=0.021). Based on regression analysis, the odds of completing a colonoscopy for navigated patients was one and a half times greater than for controls (95% CI=1.12, 2.03, p=0.007). There were no differences between navigated and control groups in regard to adequacy of bowel preparation (95.3% vs 97.3%, respectively). CONCLUSIONS: Navigation significantly improved colonoscopy screening completion among a racially diverse, low-income population. Results contribute to mounting evidence demonstrating the efficacy of patient navigation in increasing colorectal cancer screening. Screening can be further enhanced when navigation is combined with other evidence-based practices implemented in healthcare systems and the community. PMID- 28676255 TI - An ontology-based approach to patient follow-up assessment for continuous and personalized chronic disease management. AB - OBJECTIVE: Chronic diseases are complex and persistent clinical conditions that require close collaboration among patients and health care providers in the implementation of long-term and integrated care programs. However, current solutions focus partially on intensive interventions at hospitals rather than on continuous and personalized chronic disease management. This study aims to fill this gap by providing computerized clinical decision support during follow-up assessments of chronically ill patients at home. METHODS: We proposed an ontology based framework to integrate patient data, medical domain knowledge, and patient assessment criteria for chronic disease patient follow-up assessments. A clinical decision support system was developed to implement this framework for automatic selection and adaptation of standard assessment protocols to suit patient personal conditions. We evaluated our method in the case study of type 2 diabetic patient follow-up assessments. RESULTS: The proposed framework was instantiated using real data from 115,477 follow-up assessment records of 36,162 type 2 diabetic patients. Standard evaluation criteria were automatically selected and adapted to the particularities of each patient. Assessment results were generated as a general typing of patient overall condition and detailed scoring for each criterion, providing important indicators to the case manager about possible inappropriate judgments, in addition to raising patient awareness of their disease control outcomes. Using historical data as the gold standard, our system achieved a rate of accuracy of 99.93% and completeness of 95.00%. CONCLUSIONS: This study contributes to improving the accessibility, efficiency and quality of current patient follow-up services. It also provides a generic approach to knowledge sharing and reuse for patient-centered chronic disease management. PMID- 28676256 TI - Neurotoxicity of propofol on rat hypoglossal motoneurons in vitro. AB - Although propofol is a widely used intravenous general anaesthetic, many studies report its toxic potential, particularly on the developing central nervous system. We investigated its action on hypoglossal motoneurons (HMs) that control two critical functions in neonates, namely tongue muscle activity and airway patency. Thus, clinically relevant concentrations of propofol (1 and 5MUM) were applied (4h) to neonatal rat brainstem slices to evaluate the expression of apoptosis-inducing factor (AIF) as biomarker of toxicity. This anaesthetic strongly increased AIF in the cytoplasm and the nucleus, without early loss of HMs. Electrophysiological recordings from HMs showed that propofol (5MUM) enhanced GABA- and glycine-evoked current amplitude and lengthened GABAergic current decay time. Propofol also depressed NMDA receptor-mediated responses without affecting AMPA receptors. Since GABA and glycine depolarize neonatal HMs, we propose that the damaging action by propofol on these motoneurons might arise from the facilitated action of these transmitters with subsequent cytoplasmic Ca2+ overload. This phenomenon, in turn, may trigger cell death mechanisms manifested as increased expression of AIF and its translocation into the nucleus. Since propofol is also employed for induction and maintenance of paediatric surgery, caution is needed because its potential neurotoxicity might negatively impact neurodevelopment. PMID- 28676257 TI - Baicalein blocks alpha-synuclein secretion from SN4741 cells and facilitates alpha-synuclein polymerization to big complex. AB - The secretion of alpha-synuclein (alpha-syn) acts as an essential driver in the propagation of synucleinopathies in brain. The clearance of extracellular alpha syn or blockade of the cell-to-cell transmission of alpha-syn is a promising approach to prohibiting synucleinopathies propagation. Baicalein (BAI), a flavonoid from Chinese herb, has been reported to bind covalently to alpha-syn to inhibit alpha-syn fibrillation and degrade its fibrils. However, whether BAI inhibits alpha-syn secretion is unclear. Here we showed that BAI reduced alpha syn in the media of dopaminergic cell lines (SN4741) overexpressing wild-type alpha-syn (W-syn) or A53T mutant type alpha-syn (A53T-syn), while increased alpha syn expression in cell lysates, upregulated the cell viability and increased the ratio of LC3 II/LC3 I, the latter is an indicator reflects the macroautophagic level. Intriguingly, BAI did not clear extracellular alpha-syn directly but facilitated alpha-syn polymerization to big complex (over 72kDa), which revealed that BAI probably reduced alpha-syn transmission by facilitating alpha-syn polymerization to big complex. Taken together, BAI could be a potential drug to inhibit alpha-syn propagation among the neurons. PMID- 28676258 TI - Discovery of a novel Picornavirales, Chequa iflavirus, from stressed redclaw crayfish (Cherax quadricarinatus) from farms in northern Queensland, Australia. AB - In 2014, northern Queensland crayfish from farms affected by particularly transportation and translocation stress, started to die with mortality reaching 20-40% after about three weeks and then mortalities subsided. Crayfish from 1 farm had 65% mortalities within 11 weeks. With histological examination of broodstock and juveniles, the muscle fibres were fractured with haemocytic infiltration reminiscent of viral infection or vitamin E/selenium deficiencies. Sequence dependent and independent PCRs failed to identify a viral aetiology. However, the whole transcriptomes of a case crayfish and an unaffected crayfish from a different population were assembled producing over 500,000 contigs. The complete sequence of a positive sense, single stranded RNA virus (+ve ssRNA virus; 9933bp) and the large and medium segments of a bunya-like virus were detected. Transcript back-mapping and newly developed PCRs indicated that the viruses were in the case crayfish but not the control crayfish. The +ve ssRNA virus is clearly in the order Picornavirales, marginally in the genus Iflavirus in a clade of Chinese and Northern American terrestrial arthropod viruses. The internal Picornavirales motifs; RNA-dependent RNA polymerase, helicase (P-loop) and 2 viral capsids genes were easily identified. This is the first iflavirus identified from crustacea and is named Chequa iflavirus. Whether these viruses are responsible for the stress-related mortalities is unproven but the Chequa virus' role seems limited as it appears it has been present in crayfish from at least the early 1990s; unless low-grade, chronic mortalities have been largely unnoticed. PMID- 28676259 TI - Introduction of external magnetic fields in entropic moment modelling for radiotherapy. AB - One of the big challenges of the emerging MRI-guided radiotherapy is the prediction of an external magnetic field effect on the deposited dose induced by a beam of charged particles. In this paper, we present the results of the implementation of the Lorentz force in the deterministic M1 model. The validation of our code is performed by comparisons with the Monte-Carlo code FLUKA. The relevant examples show a significant modification of the shape of dose deposition volume induced by the external magnetic field in presence of heterogeneities. A gamma-index analysis 3%/3mm shows a good agreement of our model with FLUKA simulations. PMID- 28676260 TI - Quantitative iTRAQ-based secretome analysis reveals species-specific and temporal shifts in carbon utilization strategies among manganese(II)-oxidizing Ascomycete fungi. AB - Fungi generate a wide range of extracellular hydrolytic and oxidative enzymes and reactive metabolites, collectively known as the secretome, that synergistically drive plant litter decomposition in the environment. While secretome studies of model organisms have greatly expanded our knowledge of these enzymes, few have extended secretome characterization to environmental isolates, particularly filamentous Ascomycetes, or directly compared temporal patterns of enzyme utilization among diverse species. Thus, the mechanisms of carbon (C) degradation by many ubiquitous soil fungi remain poorly understood. Here we use a combination of iTRAQ proteomics and extracellular enzyme activity assays to compare the protein composition of the secretomes of four manganese(II)-oxidizing Ascomycete fungi over a three-week time course. We demonstrate that the fungi exhibit striking differences in the regulation of extracellular lignocellulose-degrading enzymes among species and over time, revealing species-specific and temporal shifts in C utilization strategies as they degrade the same substrate. Specifically, our findings suggest that Alternaria alternata SRC1lrK2f and Paraconiothyrium sporulosum AP3s5-JAC2a employ sequential enzyme secretion patterns concomitant with decreasing resource availability. Stagonospora sp. SRC1lsM3a preferentially degrades proteinaceous substrate before switching to carbohydrates, and Pyrenochaeta sp. DS3sAY3a utilizes primarily peptidases to aggressively attack carbon sources in a concentrated burst. This work highlights the diversity of operative metabolic strategies among understudied yet ubiquitous cellulose-degrading Ascomycetes, enhancing our understanding of their contribution to C turnover in the environment. PMID- 28676261 TI - An assay to detect DNA-damaging agents that induce nucleotide excision-repairable DNA lesions in living human cells. AB - Biochemical risk assessment studies of chemicals that induce DNA lesions are important, because lesions in genomic DNA frequently result in cancer, neurodegeneration, and aging in humans. Many classes of DNA lesions induced by chemical agents are eliminated via DNA repair mechanisms, such as nucleotide excision repair (NER) and base excision repair (BER), for the maintenance of genomic integrity. Individuals with NER-defective xeroderma pigmentosum (XP), in which bulky DNA lesions are not efficiently removed, are cancer-prone and suffer neurodegeneration. For research into cancer and neurological diseases, therefore, it might be important to identify DNA damage from agents that induce NER repairable bulky DNA lesions. However, simple and quick assays to detect such damaging agents have not been developed using human cells. Here, we report a simple, non-isotopic assay for determining DNA damaging agents that induce NER repairable DNA lesions by visualizing gene expression from treated fluorescent protein vectors in a mammalian cell system. This assay is based on a comparison of fluorescent protein expression in NER-proficient and NER-deficient cells. When we tested UV-irradiated fluorescent protein vectors, the fluorescent protein was observed in NER-proficient cells, but not in NER-deficient cells. Similar results were obtained for vectors treated with the anticancer drug, cisplatin. In contrast, when treated with the DNA alkylating agent methyl methanesulfonate, believed to cause BER-repairable damage, no difference in gene expression between NER-proficient and NER-deficient cells was observed. These results suggest that our assay can specifically detect DNA-damaging agents that induce NER-repairable DNA lesions, and could be used to analyze chemicals with the potential to cause cancer and neurological diseases. With further validation, the assay might be also applicable to XP diagnosis. PMID- 28676262 TI - Adaptive response in mouse bone marrow stromal cells exposed to 900MHz radiofrequency fields: Impact of poly (ADP-ribose) polymerase (PARP). AB - This study examined whether non-ionizing radiofrequency fields (RF) exposure is capable of inducing poly (ADP-ribose) polymerase-1 (PARP-1) in bone marrow stromal cells (BMSCs) and whether it plays a role in RF-induced adaptive response (AR). Bone marrow stromal cells (BMSCs) were exposed to 900MHz RF at 120MUW/cm2 power flux density for 3h/day for 5days and then challenged with a genotoxic dose of 1.5Gy gamma-radiation (GR). Some cells were also treated with 3-aminobenzamide (3-AB, 2mM final concentration), a potent inhibitor of PARP-1. Un-exposed and sham (SH)-exposed control cells as well as positive control cells exposed to gamma radiation (GR) were included in the experiments. The expression of PARP-1 mRNA and its protein levels as well as single strand breaks in the DNA and the kinetics of their repair were evaluated at several times after exposures. The results indicated the following. (a) Cells exposed to RF alone showed significantly increased PARP-1 mRNA expression and its protein levels compared with those exposed to SH- and GR alone. (b) Treatment of RF-exposed cells with 3 AB had diminished such increase in PARP-1. (c) Cells exposed to RF+GR showed significantly decreased genetic damage as well as faster kinetics of repair compared with those exposed to GR alone. (d) Cells exposed to RF+3-AB+GR showed no such decrease in genetic damage. Thus, the overall date suggested that non ionizing RF exposure was capable of inducing PARP-1 which has a role in RF induced AR. PMID- 28676263 TI - Slight hypercalcemia is not associated with positive responses in the Comet Assay in male rat liver. AB - Maintenance of physiological levels of intracellular and extracellular calcium is essential for life. Increased intracellular calcium levels are involved in cell death (apoptosis and necrosis) and are associated with positive responses in the Comet assay in vitro. In addition, high calcium and vitamin D intakes were reported to induce apoptosis in adipose tissue in obese mice and to increase DNA migration in the Comet assay. To investigate increased serum concentration of calcium as a potential confounding factor in the regulatory Comet assay in vivo, we induced mild hypercalcemia in male Wistar rats by 3-day continuous intravenous infusion of calcium gluconate and performed the Comet assay in the liver in line with regulatory guidelines. The results of the study showed that mild increases in serum calcium concentration (up to 1.4 times above the concurrent control) and increased urinary calcium concentration (up to 27.8 times above the concurrent control) results in clinical signs like mild tremor, faster respiration rate and decreased activity in a few animals. However, under the conditions of the study, no increase in the %Tail DNA in the Comet assay and no indication of liver damage as determined by histopathological means were observed. Thus, mild increases in plasma calcium did not lead to positive results in a genotoxicity assessment by the Comet assay in the rat liver. This result is important as it confirms the reliability of this assay for regulatory evaluation of safety. PMID- 28676264 TI - In vivo genotoxicity evaluation of efavirenz (EFV) and tenofovir disoproxil fumarate (TDF) alone and in their clinical combinations in Drosophila melanogaster. AB - This study focuses on the antiretrovirals efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir analog of adenosine 5'-monophosphate, which belongs to the class of nucleotide reverse transcriptase inhibitors. Both compounds act on the mechanisms of HIV replication, inhibiting the action of reverse transcriptase and thus preventing viral DNA synthesis. The toxic and genotoxic potential of EFV and TDF alone and in combinations {EFV+combivir [zidovudine (AZT)+lamivudine (3TC)] and TDF+3TC} were assessed using the comet assay and the somatic mutation and recombination test (SMART) in Drosophila melanogaster. The results indicate that EFV was toxic at high concentrations and induced genotoxicity using the comet assay, but showed neither mutagenic nor recombinogenic effects using SMART. In combination with combivir, EFV exhibited antagonic genotoxic effects in both tests. Inversely, TDF did not show toxicity but induced genotoxicity at all concentrations tested in both the comet assay and SMART. The prevalence of recombinogenic events in all treatments with TDF alone and in combination with 3TC was detected using SMART. Homologous recombination is an important parameter to be taken into consideration in the evaluation of carcinogenicity of medicines used in antiretroviral therapy regimens, due to the need for lifelong adherence and the unknown effects of long-term treatments. PMID- 28676265 TI - Ultrafine particles (UFPs) from domestic wood stoves: genotoxicity in human lung carcinoma A549 cells. AB - In this paper, results on the potential toxicity of ultrafine particles (UFPs d<100nm) emitted by the combustion of logwood and pellet (hardwood and softwood) are reported. The data were collected during the TOBICUP (TOxicity of BIomass COmbustion generated Ultrafine Particles) project, carried out by a team composed of interdisciplinary research groups. The genotoxic evaluation was performed on A549 cells (human lung carcinomacells) using UFPs whose chemical composition was assessed by a suite of analytical techniques. Comet assay and gamma-H2AX evaluation show a significant DNA damage after 24h treatment. The interpretation of the results is based on the correlation among toxicological results, chemical physical properties of UFPs, and the type and efficiency conditions in residential pellet or logwood stoves. PMID- 28676266 TI - Frequencies of micronucleated reticulocytes, a dosimeter of DNA double-strand breaks, in infants receiving computed tomography or cardiac catheterization. AB - The use of computed tomography (CT scans) has increased dramatically in recent decades, raising questions about the long-term safety of CT-emitted x-rays especially in infants who are more sensitive to radiation-induced effects. Cancer risk estimates for CT scans typically are extrapolated from models; therefore, new approaches measuring actual DNA damage are needed for improved estimations. Hence, changes in a dosimeter of DNA double-strand breaks, micronucleated reticulocytes (MN-RETs) measured by flow cytometry, were investigated in mice and infants exposed to CT scans. In male C57BL/6N mice (6-8 weeks-of-age), there was a dose-related increase in MN-RETs in blood samples collected 48h after CT scans delivering targeted exposures of 1-130 cGy x-rays (n=5-10/group, r=0.994, p=0.01), with significant increases occurring at exposure levels as low as 0.83 cGy x-rays compared to control mice (p=0.002). In paired blood specimens from infants with no history of a prior CT scan, there was no difference in MN-RET frequencies found 2h before (mean, 0.10+/-0.07%) versus 48h after (mean, 0.11+/ 0.05%) a scheduled CT scan/cardiac catheterization. However, in infants having prior CT scan(s), MN-RET frequencies measured at 48h after a scheduled CT scan (mean=0.22+/-0.12%) were significantly higher than paired baseline values (mean, 0.17+/-0.07%; p=0.032). Increases in baseline (r=0.722, p<0.001) and 48-h post exposure (r=0.682, p<0.001) levels of MN-RETs in infants with a history of prior CT scans were significantly correlated with the number of previous CT scans. These preliminary findings suggest that prior CT scans increase the cellular responses to subsequent CT exposures. Thus, further investigation is needed to characterize the potential cancer risk from single versus repeated CT scans or cardiac catheterizations in infants. PMID- 28676268 TI - A short cut to the past: Cueing via concrete objects improves autobiographical memory retrieval in Alzheimer's disease patients. AB - Older adults diagnosed with Alzheimer's disease (AD) have difficulties accessing autobiographical memories. However, this deficit tends to spare memories dated to earlier parts of their lives, and may partially reflect retrieval deficits rather than complete memory loss. Introducing a novel paradigm, the present study examines whether autobiographical memory recall can be improved in AD by manipulating the sensory richness, concreteness and cultural dating of the memory cues. Specifically, we examine whether concrete everyday objects historically dated to the participants' youth (e.g., a skipping rope), relative to verbal cues (i.e., the verbal signifiers for the objects) facilitate access to autobiographical memories. The study includes 49 AD patients, and 50 healthy, older matched control participants, all tested on word versus object-cued recall. Both groups recalled significantly more memories, when cued by objects relative to words, but the advantage was significantly larger in the AD group. In both groups, memory descriptions were longer and significantly more episodic in nature in response to object-cued recall. Together these findings suggest that the multimodal nature of the object cues (i.e. vision, olfaction, audition, somatic sensation) along with specific cue characteristics, such as time reference, texture, shape, may constrain the retrieval search, potentially minimizing executive function demands, and hence strategic processing requirements, thus easing access to autobiographical memories in AD. PMID- 28676267 TI - Neurologic consultation and use of therapeutic hypothermia for cardiac arrest. AB - OBJECTIVE: To determine whether neurologic consultation influences the use of therapeutic hypothermia. METHODS: We identified adult patients treated for cardiac arrest from October 2009 through September 2015 at 149 academic medical centers and their affiliate hospitals using discharge diagnosis codes in Vizient database. Neurology consultation was defined as a neurologist participating in patient care at any point during the hospitalization. Use of therapeutic hypothermia was identified using procedure codes. We used multivariable models to evaluate the association between neurologic consultation and therapeutic hypothermia before and after adjustment for patient baseline characteristics and hospital factors including inpatient volume and relative volume of cardiac arrest cases. RESULTS: We identified 136,830 hospitalizations for cardiac arrest. The 9,336 (6.8%) encounters involving a neurologist had higher severity of illness, longer hospital stay, and longer intensive care unit stay. There were 5,034 (3.7%) encounters where patients underwent therapeutic hypothermia. Hypothermia use was significantly more common when neurologists were involved during hospitalization (7.9% vs. 3.4%; OR 2.44, 95% CI 2.2-2.6; p<0.01). After adjustment, neurologic consultation continued to be associated with the use of therapeutic hypothermia (adjusted OR 2.5, 95% CI 2.3-2.8), particularly among hospitals in the highest quartile of total inpatient volume (OR 4.6, 95% CI 4.0 5.3). Lower in-hospital mortality was also associated with neurological consultation after adjusting for therapeutic hypothermia (59.2% vs. 61.3%, p<0.01). CONCLUSIONS: The involvement of a neurologist in cardiac arrest patients is associated with increased use of therapeutic hypothermia, though therapeutic hypothermia for cardiac arrest likely remains underutilized. PMID- 28676269 TI - Substituted alpha-mercaptoketones, new types of specific neprilysin inhibitors. AB - New neprilysin inhibitors containing an alpha-mercaptoketone HSC(R1R2)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S1, S1' or S2' domain of the enzyme and the nature of the substituents R1, R2 of the mercaptoketone group. Introduction of a cyclohexyl chain in R1, R2 position and a (3-thiophen)benzyl group in position R3 (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2+/-0.3nM. This result suggests that this new inhibitor interacts within the S1, S1' domain of NEP allowing a pentacoordination of the catalytic Zn2+ ion by the mercaptoketone moiety. PMID- 28676270 TI - Synthesis of novel 2-pyrazoline analogues with potent anti-inflammatory effect mediated by inhibition of phospholipase A2: Crystallographic, in silico docking and QSAR analysis. AB - Oxidative-stress induces inflammatory diseases. Further, infections caused by drug-resistant microbial strains are on the rise. This necessitates the discovery of novel small-molecules for intervention therapy. A series of 3-(2,3 dichlorophenyl)-1-(aryl)prop-2-en-1-ones are synthesized as intermediates via Claisen-Schmidt reaction approach. Subsequently, these intermediates were transformed into 2-pyrazolines by their reaction with phenylhydrazine hydrochlorides in methanol and few drops of acetic acid under reflux conditions. Synthesized compounds were characterized by spectroscopic, crystallographic and elemental analyses studies and then, were evaluated for their in vitro antimicrobial and anti-inflammatory activities. Amongst the series, 3-(4 chlorophenyl)-5-(2,3-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5e), 5 (2,3-dichlorophenyl)-3-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5c) and 5-(2,3-dichlorophenyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5h) showed significant inhibition of phospholipase A2 with IC50 values of 10.2, 11.1 and 11.9uM, respectively. Protein structure modelling and docking studies indicated that the compounds showed binding to a highly conserved calcium-binding pocket on the enzyme. Further, compounds (5e), 1-(3-chlorophenyl)-5-(2,3 dichlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (5b), and 1-(3-chlorophenyl)-3 (4-chlorophenyl)-5-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazole (5f) showed excellent antimicrobial activities against various bacterial and fungal strains. In conclusion, this study is a successful attempt at the synthesis and characterization of chalcone derivatives that can target phospholipase A2, an enzyme that is a prominent player in the physiological inflammatory cascade. Thus, these compounds show promise for development as next-generation nonsteroidal anti-inflammatory drugs. PMID- 28676271 TI - One-pot two-step facile synthesis of 2,3,4,5-tetra substituted dihydrooxazoles and their antimicrobial activity. AB - New 2,3,4,5-tetra substituted dihydrooxazoles derivatives were efficiently synthesized starting from benzaldehyde, aryl thiosemicarbazide and benzoin using designed synthetic route. Newly synthesized 2,3,4,5-tetra substituted dihydrooxazole derivatives were screened for their antibacterial and antifungal activities against different strains of pathogenic bacteria and fungi. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) were determined for the test compounds using positive and negative control. Compounds 4b, 4d, 4f, 4i, 4k and 4m, have shown good antibacterial activity whereas compounds 4e, 4g, 4h, 4j, 4l and 4n have displayed better antifungal activity. PMID- 28676272 TI - Synthesis, antioxidant, antifungal, molecular docking and ADMET studies of some thiazolyl hydrazones. AB - Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2 carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide and various phenacyl bromides which were preliminarily screened for in vitro antioxidant and antifungal activities. Excellent DPPH and H2O2 radical scavenged antioxidant activities were observed with almost all the tested compounds. Compounds 4a, 4b, 4c, 4e, 4f and 4i showed comparable DPPH scavenged antioxidant potential (90.26 96.56%) whereas H2O2 scavenged antioxidant activity (90.98-92.08%) was noticeable in case of 4a and 4f; showing significant antioxidant potential comparable with the standard ascorbic acid (95.3%). In vitro antifungal activity of synthesized compounds against fungal species Candida albicance, Aspergillus niger and Aspergillus flavus was found to be moderate to good as compared with the standard fluconazole and MIC values were found in the range of 3.12-25MUg/mL. Molecular docking studies revealed that the compounds 4a, 4b and 4c have a potential to become lead molecules in drug discovery process. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the synthesized antioxidants which expressed good oral drug like behaviour and non-toxic nature. PMID- 28676273 TI - 3-Oxo-gamma-costic acid fungal-transformation generates eudesmane sesquiterpenes with in vitro tumor-inhibitory activity. AB - While select eudesmane sesquiterpenes exhibit anti-neoplastic activity, tumor inhibition for costic-acids has not been established. Here biological activity of 3-oxo-gamma-costic acid (1), previously isolated from Chiliadenus montanus, as well as new sesquiterpenes (2-5) and the known derivative, 3-oxoeudesma 1,4,11(13)-trien-7-1061alphaH-l2-oic acid (6), all produced from 1 by the fungus Athelia rolfsii, are reported. Structures were elucidated using MS and NMR spectroscopy with activity-screening utilizing human colon- and lung-tumor lines, Caco-2 and A549 respectively. Compound 1 exhibited anti-proliferative activity against Caco-2 (IC50 39uM) and 2 was active against A549 (IC50 74uM) suggesting therapeutic potential for the original substrate and a bio-transformed product. PMID- 28676274 TI - Multifunctional human serum albumin-therapeutic nucleotide conjugate with redox and pH-sensitive drug release mechanism for cancer theranostics. AB - We report on the synthesis and properties of a new multimodal theranostic conjugate based on an anticancer fluorinated nucleotide conjugated with a dual labeled albumin. A fluorine-labeled homocysteine thiolactone has been used as functional handle to synthesize the fluorinated albumin and couple it with a chemotherapeutic agent 5-trifluoromethyl-2'-deoxyuridine 5'-monophosphate (pTFT). The conjugate allows for direct optical and 19F magnetic resonance cancer imaging and release of the drug upon addition of glutathione. Interestingly, the pTFT release from albumin conjugate could only be promoted by the increased acidity (pH 5.4). The in vitro study and primary in vivo investigations showed stronger antitumor activity than free pTFT. PMID- 28676275 TI - Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia is one of the most common autosomal recessive genetic disorders. Testicular adrenal tumors are significant complications of congenital adrenal hyperplasia. We would like to present two patients of testicular adrenal rest tumors. Patient 1 24 year-old male, he was diagnosed with congenital adrenal hyperplasia at the age of 8 due to precocious puberty. He received hydro-cortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied 6 months ago and reported as testicular adrenal rest tumor. In scrotal ultrasound, a mixed type mass lesion (6 * 4x3 cm) covering a large part of left testis was observed. The imaging findings were consistent with adrenal rest tumor. The patient took adrenocorticotropic hormone supressive therapy with dexamethasone 0.75 mg once a day. Patient 2, 38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent right orchiectomy operation due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor. In scrotal ultrasound, small multifocal lesions were detected on the left testis and resection was done. It was reported as testicular adrenal rest tumor. He is being followed-up with glucocorticoid treatment according to androgen and adrenocorticotropic hormone levels. Early diagnosis of testicular adrenal rest tumor is significant in preventing irreversible testicular damage and infertility. In the differential diagnosis, we should keep in mind that testicular adrenal rest tumor can mimic other testicular tumors such as primary germ cell tumors. PMID- 28676276 TI - Deuterium off-magic-angle spinning NMR spectroscopy for pure-quadrupole spectra of paramagnetic solids. AB - We examined a simple two-dimensional 2H nuclear magnetic resonance spectroscopy for paramagnetic solids utilizing off-magic-angle spinning (OMAS). By adding a rotor-synchronized 180 degrees pulse to rotational echo (RE) measurement, the effect of the shift interaction was removed from the indirect dimension. The obtained pure-quadrupole spectrum could be simulated by calculating a quasi-one dimensional NMR signal without considering the shift interaction. The sensitivity of the proposed method was compared with that of previous static NMR methods. PMID- 28676277 TI - Standardization of 68Ge/68Ga using the 4pibeta-gamma coincidence method based on Cherenkov counting. AB - In the framework of an international BIPM comparison (Bureau International des Poids et Mesures), the activity standardization of 68Ge in a solution of 68Ge/68Ga in equilibrium provided by NIST was carried out at LNHB. This exercise was organized to meet the growing interest in 68Ga as a radiopharmaceutical in nuclear medicine services (e.g. as a surrogate of 18F for PET imaging). Due to the volatility of germanium, the activity standardization of 68Ge was investigated at LNHB by means of 4pibeta-gamma coincidence counting based on Cherenkov measurements. This technique was applied to take advantage of the Cherenkov threshold (~ 260keV in aqueous solutions) in order to prevent counting from electron-capture events associated with 68Ge disintegrations. Cherenkov counting was performed using glass and polyethylene vials and the resulting activity concentrations were compared with 4pibeta-gamma coincidence measurements based on liquid scintillation. The efficiency-extrapolation curve obtained with Cherenkov measurements in glass vials was compared to Monte Carlo simulations based on the Geant4 code. PMID- 28676278 TI - Complete genome sequence of bacteriocin-producing Lactobacillus plantarum KLDS1.0391, a probiotic strain with gastrointestinal tract resistance and adhesion to the intestinal epithelial cells. AB - Lactobacillus plantarum KLDS1.0391 is a probiotic strain isolated from the traditional fermented dairy products and identified to produce bacteriocin against Gram-positive and Gram-negative bacteria. Previous studies showed that the strain has a high resistance to gastrointestinal stress and has a high adhesion ability to the intestinal epithelial cells (Caco-2). We reported the entire genome sequence of this strain, which contains a circular 2,886,607-bp chromosome and three circular plasmids. Genes, which are related to the biosynthesis of bacteriocins, the stress resistance to gastrointestinal tract environment and adhesive performance, were identified. Whole genome sequence of Lactobacillus plantarum KLDS1.0391 will be helpful for its applications in food industry. PMID- 28676279 TI - Projection-Resolved Optical Coherence Tomography Angiography of Macular Retinal Circulation in Glaucoma. AB - PURPOSE: To detect macular perfusion defects in glaucoma using projection resolved optical coherence tomography (OCT) angiography. DESIGN: Prospective observation study. PARTICIPANTS: A total of 30 perimetric glaucoma and 30 age matched normal participants were included. METHODS: One eye of each participant was imaged using 6*6-mm macular OCT angiography (OCTA) scan pattern by 70-kHz 840 nm spectral-domain OCT. Flow signal was calculated by the split-spectrum amplitude-decorrelation angiography algorithm. A projection-resolved OCTA (PR OCTA) algorithm was used to remove flow projection artifacts. Four en face OCTA slabs were analyzed: the superficial vascular complex (SVC), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and all-plexus retina (SVC + ICP + DCP). The vessel density (VD), defined as the percentage area occupied by flow pixels, was calculated from en face OCTA. A novel algorithm was used to adjust the vessel density to compensate for local variations in OCT signal strength. MAIN OUTCOME MEASURES: Macular retinal VD, ganglion cell complex (GCC) thickness, and visual field (VF) sensitivity. RESULTS: Focal capillary dropout could be visualized in the SVC, but not the ICP and DVP, in glaucomatous eyes. In the glaucoma group, the SVC and all-plexus retinal VD (mean +/- standard deviation: 47.2%+/-7.1% and 73.5%+/-6.6%) were lower than in the normal group (60.5%+/-4.0% and 83.2%+/-4.2%, both P < 0.001, t test). The ICP and DCP VD were not significantly lower in the glaucoma group. Among the overall macular VD parameters, the SVC VD had the best diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AROC). The accuracy was even better when the worse hemisphere (inferior or superior) was used, achieving an AROC of 0.983 and a sensitivity of 96.7% at a specificity of 95%. Among the glaucoma participants, the hemispheric SVC VD values were highly correlated with the corresponding GCC thickness and VF sensitivity (P < 0.003). The reflectance compensation step in VD calculation significantly improved repeatability, normal population variation, and correlation with VF and GCC thickness. CONCLUSIONS: On the basis of PR-OCTA, glaucoma preferentially affects perfusion in the SVC in the macula more than the deeper plexuses. Reflectance-compensated SVC VD measurement by PR-OCTA detected glaucoma with high accuracy and could be useful in the clinical evaluation of glaucoma. PMID- 28676281 TI - Chronic Kidney Disease and Eye Diseases: The Beijing Eye Study. PMID- 28676282 TI - Anterior-Segment Ocular Findings and Microphthalmia in Congenital Zika Syndrome. PMID- 28676280 TI - Evidence-based Criteria for Assessment of Visual Field Reliability. AB - PURPOSE: Assess the impact of false-positives (FP), false-negatives (FN), fixation losses (FL), and test duration (TD) on visual field (VF) reliability at different stages of glaucoma severity. DESIGN: Retrospective. PARTICIPANTS: A total of 10 262 VFs from 1538 eyes of 909 subjects with suspect or manifest glaucoma and >=5 VF examinations. METHODS: Predicted mean deviation (MD) was calculated with multilevel modeling of longitudinal data. Differences between predicted and observed MD (DeltaMD) were calculated as a reliability measure. The impact of FP, FN, FL, and TD on DeltaMD was assessed using multilevel modeling. MAIN OUTCOME MEASURES: DeltaMD associated with a 10% increment in FP, FN, and FL, or a 1-minute increase in TD. RESULTS: FL had little impact on DeltaMD (<0.2 decibels [dB] per 10% abnormal catch trials), and no level of FL produced >=1 dB of DeltaMD at any disease stage. FP yielded greater than expected MD, with a 10% increment in abnormal catch trials associated with a DeltaMD = 0.42, 0.73, and 0.66 dB in mild (MD >-6 dB), moderate (-6 <=MD <-12 dB), and severe (-12 <=MD <= 20 dB) disease, respectively, up to 20% abnormal catch trials, and a DeltaMD = 1.57, 2.06, and 3.53 dB beyond 20% abnormal catch trials. FNs generally produced observed MDs below expected MDs. FN were minimally impactful up to 20% abnormal catch trials (DeltaMD per 10% increment >-0.14 dB at all levels of severity). Beyond 20% abnormal catch trials, each 10% increment in abnormal catch trials was associated with a DeltaMD = -1.27, -0.53, and -0.51 dB in mild, moderate, and severe disease, respectively. |DeltaMD| >=1 dB occurred with 22% FP and 26% FN in early, 14% FP and 34% FN in moderate, and 16% FP and 51% FN in severe disease. A 1-minute increment in TD produced DeltaMDs between -0.35 and -0.40 dB. CONCLUSIONS: FL have little impact on reliability in patients with established glaucoma. FP, and to a lesser extent FNs and TD, significantly affect reliability. The impact of FP and FN varies with disease severity and over the range of abnormal catch trials. On the basis of our findings, we present evidence based, severity-specific standards for classifying VF reliability for clinical or research applications. PMID- 28676283 TI - Chinese versus English: Insights on Cognition during Reading. AB - Chinese reading experiments have introduced important caveats to theories of reading that have been largely informed by studies of English reading - especially in relation to our understanding of lexical processing and eye movement control. This article provides a brief primer on Chinese reading and examples of questions that arise from its study. PMID- 28676284 TI - IncX3 plasmid mediated occurrence of blaNDM-4 within Escherichia coli ST448 from India. AB - This study was designed to investigate blaNDM-4 encoded within IncX3 type plasmid and their copy number alteration under carbapenem pressure within clinical isolates of Escherichia coli. NDM-4 producing E. coli isolates were collected from an Indian hospital and transferability as well as plasmid incompatibility typing was determined. Genetic environment and antibiogram profiling was carried out. Quantitative Real Time PCR was done to determine the change in plasmid copy number under concentration gradient carbapenem stress. Multilocus sequence typing and pulsed field gel electrophoresis was performed for typing of isolates. Four multidrug resistant isolates were found to harbour transconjugable blaNDM-4 carrying within IncX3 type plasmid. The blaNDM-4 was flanked by insertion sequences ISAba125 and IS5 in the upstream region whereas bleMBL was present in the downstream area. Copy number results indicated that the blaNDM-4 gene was maintained high in plasmid under exposure of ertapenem. All the strains belonged to ST448 and PFGE analysis revealed three different pulsotypes. This is the first report of blaNDM-4 encoded IncX3 type plasmid in E. coli of ST448 and needs a systematic screening policy to rapid detection of NDM-4 poducing strains to prevent dissemination of this resistant determinant in future. PMID- 28676285 TI - "It feels like I'm the dirtiest person in the world.": Exploring the experiences of healthcare providers who survived MERS-CoV in Saudi Arabia. AB - In summer 2015, a Saudi 1000-bed tertiary care hospital experienced a serious outbreak among patients of Middle Eastern Respiratory Syndrome (MERS); during which, some healthcare providers contracted the virus, but none died. The outbreak provoked not only fear and stress; but also professional, emotional, ethical, and social conflicts and tension among healthcare providers and patients alike. Therefore, this study aims to explore what healthcare providers, who survived coronavirus infection, have experienced as a MERS patient and how the infection affected their relationship with their colleagues. Semi-structured, face-to-face interviews were conducted individually with seven survivors (healthcare providers). Each interview lasted up to 90min, and the data were analyzed using the thematic analysis technique. Within the participants' rich and illuminating experiences, four themes were identified: caring for others in the defining moments, perceived prejudice behaviours and stigmatization, lived moments of traumatic fear and despair, and denial and underestimation of the seriousness of the disease at the individual and organizational levels. Survivors still suffered as a result of their traumatic experiences, which might negatively influence their performance. As these survivors are vulnerable, it is their organization's responsibility to provide a system that embraces HCPs during and after disastrous events. PMID- 28676286 TI - A viewpoint on considering physiological principles to study stress resistance and resilience with aging. AB - Adaptation to stress is identified as one of the seven pillars of aging research. Our viewpoint discusses the importance of the distinction between stress resistance and resilience, highlights how integration of physiological principles is critical for further understanding in vivo stress resistance and resilience, and advocates for the use of early warning signs to prevent a tipping point in stress resistance and resilience. PMID- 28676287 TI - Analysis of effectiveness, safety and optimization of tocilizumab in a cohort of patients with rheumatoid arthritis in clinical practice. AB - OBJECTIVE: To evaluate the effectiveness and safety of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in clinical practice, establishing the optimized regimen and switching from intravenous (IV) to subcutaneous (SC) therapy. MATERIAL AND METHODS: Retrospective observational study. We included 53 RA patients treated with TCZ. The main outcome was TCZ effectiveness at week 24. Secondary outcome variables included effectiveness at week 52, therapeutic maintenance, physical function and safety. The effectiveness of optimization and the switch from IV to SC was evaluated at 3 and 6 months. The efficacy was measured with the Disease Activity Score. Paired t-tests or Wilcoxon were used to evaluate effectiveness and survival time using Kaplan-Meier. RESULTS: The proportion of patients who achieved remission or low disease activity at weeks 24 and 52 was 75.5% and 87.3%, respectively. The mean retention time (95% confidence interval [95% CI] was 81.7 months [76.6-86.7]). Twenty-one of 53 patients (39.6%) optimized the TCZ dose and 35 patients switched from IV TCZ to SC, with no changes in effectiveness. The adverse event rate was 13.6 events/100 patient years. CONCLUSIONS: Tocilizumab appears to be effective and safe in RA in clinical practice. The optimized regimen appears to be effective in most patients in remission, even when they change from IV to SC. PMID- 28676288 TI - Tophaceous gout of the shoulder joint. PMID- 28676289 TI - Differential Characteristics of Skeletal Muscle in Community-Dwelling Older Adults. AB - BACKGROUND: Sarcopenia is diagnosed on the basis of skeletal muscle mass and muscle strength/function. However, more simple and accurate measures for muscle mass and muscle strength/function should be explored. OBJECTIVE: The aim of this study was to compare the skeletal muscle characteristics at each stage of sarcopenia (normal, presarcopenia, dynapenia, and sarcopenia) via ultrasonography, multifrequency bioelectrical impedance analysis (BIA), and physical assessment batteries in community-dwelling older adults. By evaluating the relationship between muscle quality/quantity indicators and muscle mass/muscle function, we attempted to identify better muscle quantity and quality indicators for the diagnosis of sarcopenia. SETTING AND SUBJECTS: Community dwelling older men (n = 100, 81.6 +/- 7.4 years) and women (n = 247, 79.7 +/- 6.9 years) participated in this study. MEASUREMENTS: Skeletal muscle quantity and quality were measured by ultrasonography and multifrequency BIA. Ultrasonographic (thickness and echo intensity) and multifrequency BIA (volume and density) indicators, as well as physical assessment measures, were compared among each stage of sarcopenia. In addition, receiver-operating characteristic analysis was used to assess the sensitivity and specificity of each indicator. RESULTS: Most of the muscle quantity indicators were lower in the sarcopenia and presarcopenia groups than in the other groups, whereas most of the muscle quality indicators were lower in the sarcopenia and dynapenia groups than in the other groups. According to the receiver-operating characteristic analysis, quadriceps muscle thickness and thigh muscle volume were better indicators of muscle mass, whereas the quadriceps muscle echo intensity and thigh muscle density were more robust indicators of muscle function. CONCLUSIONS: In this study, we found potential muscle quality and quantity indicators for sarcopenia diagnosis by ultrasonography and multifrequency BIA. Future longitudinal studies are warranted to define the role of these indicators for the diagnosis of sarcopenia. PMID- 28676290 TI - Completion of an Outpatient Visit After Skilled Nursing Facility Discharge and Readmission Risk. AB - OBJECTIVES: Examine the association between completion of an outpatient visit with a physician or advanced practice provider (PCP) within 7 days of discharge from a short skilled nursing facility (SNF) stay and 30-day readmission and determine if functional status at discharge moderates visit effectiveness. DESIGN: Retrospective cohort study. SETTING: Large integrated health care system. PARTICIPANTS: Adults 65 years and older, discharged home from a short SNF stay (n = 4073). INTERVENTION: None. MEASUREMENTS: Exposure is completion of an outpatient visit with a PCP within 7 days of discharge from an SNF. Primary outcome is readmission within 30 days of SNF discharge. Covariates included gender, risk score for readmission or early death, medical or surgical hospitalization, SNF facility, SNF length of stay, SNF stay in the previous 12 months, discharge to home or home health, and discharge functional independence measures (FIM). RESULTS: A total of 476 (11.6%) patients were readmitted within 30 days of SNF discharge. Patients who completed an outpatient visit with a PCP within 7 days of SNF discharge had a 23% higher risk of being readmitted compared to patients who did not complete any visit (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01-1.50). Patients who had FIM scores >=80 and completed a visit had an increased readmission risk (HR 1.37, 95% CI 1.04-1.79); the increased risk was not seen for those with worse functional impairment, FIM <80 (HR 1.11, 95% CI 0.85-1.46). CONCLUSION: The finding of increased risk of readmission post SNF discharge with completion of an outpatient visit likely reflects inadequate adjustment for selection bias in this observational study, which strongly argues for the need to design prospective studies to test transitional care services post SNF discharge. PMID- 28676291 TI - Metformin Safety Warnings and Diabetes Drug Prescribing Patterns for Older Nursing Home Residents. AB - OBJECTIVE: Diabetes mellitus is common in US nursing homes (NHs), and the mainstay treatment, metformin, has US Food and Drug Administration (FDA) boxed warnings indicating safety concerns in those with advanced age, heart failure, or renal disease. Little is known about treatment selection in this setting, especially for metformin. We quantified the determinants of initiating sulfonylureas over metformin with the aim of understanding the impact of FDA labeled boxed warnings in older NH residents. DESIGN AND SETTING: National retrospective cohort in US NHs. PARTICIPANTS: Long-stay NH residents age >=65 years who initiated metformin or sulfonylurea monotherapy following a period of >=6 months with no glucose-lowering treatment use between 2008 and 2010 (n = 7295). MEASUREMENTS: Measures of patient characteristics were obtained from linked national Minimum Data Set assessments; Online Survey, Certification and Reporting (OSCAR) records; and Medicare claims. Odds ratios (ORs) comparing patient characteristics and treatment initiation were estimated using univariable and multivariable multilevel logistic regression models with NH random intercepts. RESULTS: Of the 7295 residents in the study population, 3066 (42%) initiated metformin and 4229 (58%) initiated a sulfonylurea. In multivariable analysis, several factors were associated with sulfonylurea initiation over metformin initiation, including heart failure (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1-1.4) and renal disease (OR 2.1, 95% CI 1.7-2.5). Compared with those aged 65 to <75 years, residents 75 to <85 (OR 1.3, 95% CI 1.2 1.5), 85 to <95 (OR 2.0, 95% CI 1.7-2.3), and >=95 (OR 4.3, 95% CI 3.2-5.8) years were more likely to initiate sulfonylureas over metformin. CONCLUSIONS: In response to FDA warnings, providers initiated NH residents on a drug class with a known, common adverse event (hypoglycemia with sulfonylureas) over one with tenuous evidence of a rare adverse event (lactic acidosis with metformin). PMID- 28676292 TI - Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging. AB - INTRODUCTION: Increased gut permeability ("leaky gut") has been proposed as a potential contributor to age-related inflammation and gut dysbiosis. However, information on the relationship between a leaky gut and inflammation and physical frailty during aging are limited. OBJECTIVE: To investigate the hypothesis that an aging-associated leaky gut is linked to the age-related inflammation and frailty. METHODS: Two cohorts of healthy adults were studied: young (18-30 years old, n = 19) and older (>=70 years old, n = 18). Serum concentrations of the tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, zonulin (a marker for leaky gut), and high-mobility group box protein (HMGB1, a nuclear protein triggering inflammation) were measured. Correlations of serum levels of zonulin and HMGB1 with strength of plantar flexor muscles and number of steps taken per day were analyzed. RESULTS: Serum concentration of zonulin and HMGB1 were 22% (P = .005) and 16% (P = .010) higher in the older versus young adults. Serum zonulin was positively associated with concentrations of TNF-alpha (r = 0.357, P = .032) and IL-6 (r = 0.345, P = .043). Importantly, both zonulin and HMGB1 were negatively correlated with skeletal muscle strength (zonulin: r = -0.332, P = .048; HMGB1: r = -0.383, P = .023), and habitual physical activity (zonulin: r = 0.410, P = .016; HMGB1: r = -0.483, P = .004). CONCLUSIONS: Serum zonulin was associated with both systemic inflammation and 2 key indices of physical frailty. These data suggest that a leaky gut may play a critical role in the development of age-related inflammation and frailty. PMID- 28676293 TI - Attitudes Toward Advance Directives Among Patients and Their Family Members in China. AB - OBJECTIVES: Chinese people are generally unfamiliar with the concept of advance care planning or advance directives (ACP/ADs), which raises dilemmas in life support choice and can even affect clinical decision making. To understand and address the issues involved better, we investigated the awareness of ACP/ADs in China, as well as people's attitudes toward medical autonomy and end-of-life care. DESIGN: A multicenter cross-sectional survey, conducted from August 1 to December 31, 2016. SETTING: Twenty-five hospitals located in 15 different provinces throughout mainland China. PARTICIPANTS: Pairs of adult patients without dementia or malignancies, and a family member. MEASUREMENTS: Participants self-filled anonymous questionnaires, and the data collected were analyzed to relate patients' sociodemographic characteristics to their awareness of ACP/ADs and attitudes to health care autonomy and end-of-life care. RESULTS: Among 1084 patients who completed the questionnaire, 415 (38.3%) had heard about ACP/ADs. Having been informed about ACP/ADs, 995 (91.8%) were willing to find out their true health status and decide for themselves; 549 (50.6%) wanted to institute ACP/ADs. Regarding end-of-life care, 473 (43.6%) chose Do Not Resuscitate, and 435 (40.1%) wished to forgo life-support treatment if irreversibly moribund. Patients predominantly (481, 44.4%) chose general hospital as their preferred place to spend their last days of life; only 114 (10.5%) favored a special hospice facility. Patients' main concerns during end-of-life care were symptom control (35.1%), followed by functional maintenance and quality of life (29.8%), and prolonging life (18.9%). More highly educated patients had significantly greater awareness of ACP/ADs than less well educated ones (chi2 = 59.22, P < .001) and were more willing to find out the truth for themselves (chi2 = 58.30, P <= .001) and make medical decisions in advance (chi2 = 55.92, P < .001). Younger patients were also more willing than older ones to know the truth (chi2 = 38.23, P = .001) and make medical decisions in advance (chi2 = 18.42, P = .018), and were also more likely to wish to die at home (chi2 = 96.25, P < .001). Only 212 patients' family members (19.6%) wanted life-support treatment for themselves if irreversibly moribund, whereas 592 (54.6%) would want their relative to receive such procedures in the same circumstances; a similar discrepancy was evident for end-of-life invasive treatment (18.3% vs 42.7%). CONCLUSIONS: Awareness about ACP/ADs in China is still low. Providing culturally sensitive knowledge, education, and communication regarding ACP/ADs is a feasible first step to promoting this sociomedical practice. PMID- 28676294 TI - Psychological stress-relieving effects of chewing - Relationship between masticatory function-related factors and stress-relieving effects. AB - PURPOSE: The objective of the present study was to investigate the relationship between masticatory function-related factors (masticatory performance, occlusal contact area, maximum bite force, number of chewing strokes, and muscle activity) and the stress-relieving effects of chewing. METHODS: A total of 28 healthy male subjects were instructed to rest or chew for 10min after 30min of stress loading with arithmetic calculations. Their stress state was assessed by measuring salivary cortisol levels. Saliva was collected at three time points: before stress loading, immediately after stress loading, and 10min after stress loading. Compared to resting, chewing produced a significantly greater reduction in the rate of change in salivary cortisol levels 10min after stress loading. RESULTS: A negative correlation was observed between the rate of decrease in salivary cortisol levels and the number of chewing strokes. No significant correlation was observed between the rate of decrease in salivary cortisol levels and other measurement items. CONCLUSION: In healthy dentulous people, the number of chewing strokes has been shown to be a masticatory function-related factor that affects stress relief from chewing, suggesting the possibility that more appropriate chewing would produce a greater effect psychological stress relief. PMID- 28676295 TI - Deep convolutional neural networks for automatic classification of gastric carcinoma using whole slide images in digital histopathology. AB - Deep learning using convolutional neural networks is an actively emerging field in histological image analysis. This study explores deep learning methods for computer-aided classification in H&E stained histopathological whole slide images of gastric carcinoma. An introductory convolutional neural network architecture is proposed for two computerized applications, namely, cancer classification based on immunohistochemical response and necrosis detection based on the existence of tumor necrosis in the tissue. Classification performance of the developed deep learning approach is quantitatively compared with traditional image analysis methods in digital histopathology requiring prior computation of handcrafted features, such as statistical measures using gray level co-occurrence matrix, Gabor filter-bank responses, LBP histograms, gray histograms, HSV histograms and RGB histograms, followed by random forest machine learning. Additionally, the widely known AlexNet deep convolutional framework is comparatively analyzed for the corresponding classification problems. The proposed convolutional neural network architecture reports favorable results, with an overall classification accuracy of 0.6990 for cancer classification and 0.8144 for necrosis detection. PMID- 28676296 TI - Contributing factors of frequent use of the emergency department: A synthesis. AB - INTRODUCTION: Overcrowding in emergency departments is an issue that has a negative impact worldwide. As attendance in emergency departments has increased, the ability to provide critical services to patients suffering from actual medical emergencies in a timely manner has decreased as these departments are many times at or over capacity. One patient population whose negative influence has been researched with regard to their impact on the overcrowding issue is that of the frequent user. METHODS: A search of two electronic databases was conducted to identify factors that frequent users state as their reasoning for using an emergency department. Peer reviewed articles in English were searched for in CINAHL Plus and PubMed, as well as a review of reference lists. RESULTS: A review of the literature identified two predominant factors related to frequent users in the emergency department: a lack of awareness of medical necessity and issues of access. DISCUSSION: To address the frequent users in emergency departments, implications for practice need to be explored and implemented. Implications for practice include education of medical necessity for the frequent users, expansion of the pre-hospital role in primary care and inappropriate use prevention, and improvement of access to alternative healthcare services. PMID- 28676297 TI - Inferring synaptic excitation/inhibition balance from field potentials. AB - Neural circuits sit in a dynamic balance between excitation (E) and inhibition (I). Fluctuations in E:I balance have been shown to influence neural computation, working memory, and information flow, while more drastic shifts and aberrant E:I patterns are implicated in numerous neurological and psychiatric disorders. Current methods for measuring E:I dynamics require invasive procedures that are difficult to perform in behaving animals, and nearly impossible in humans. This has limited the ability to examine the full impact that E:I shifts have in cognition and disease. In this study, we develop a computational model to show that E:I changes can be estimated from the power law exponent (slope) of the electrophysiological power spectrum. Predictions from the model are validated in published data from two species (rats and macaques). We find that reducing E:I ratio via the administration of general anesthetic in macaques results in steeper power spectra, tracking conscious state over time. This causal result is supported by inference from known anatomical E:I changes across the depth of rat hippocampus, as well as oscillatory theta-modulated dynamic shifts in E:I. Our results provide evidence that E:I ratio may be inferred from electrophysiological recordings at many spatial scales, ranging from the local field potential to surface electrocorticography. This simple method for estimating E:I ratio-one that can be applied retrospectively to existing data-removes a major hurdle in understanding a currently difficult to measure, yet fundamental, aspect of neural computation. PMID- 28676298 TI - Joint prediction of multiple scores captures better individual traits from brain images. AB - To probe individual variations in brain organization, population imaging relates features of brain images to rich descriptions of the subjects such as genetic information or behavioral and clinical assessments. Capturing common trends across these measurements is important: they jointly characterize the disease status of patient groups. In particular, mapping imaging features to behavioral scores with predictive models opens the way toward more precise diagnosis. Here we propose to jointly predict all the dimensions (behavioral scores) that make up the individual profiles, using so-called multi-output models. This approach often boosts prediction accuracy by capturing latent shared information across scores. We demonstrate the efficiency of multi-output models on two independent resting state fMRI datasets targeting different brain disorders (Alzheimer's Disease and schizophrenia). Furthermore, the model with joint prediction generalizes much better to a new cohort: a model learned on one study is more accurately transferred to an independent one. Finally, we show how multi-output models can easily be extended to multi-modal settings, combining heterogeneous data sources for a better overall accuracy. PMID- 28676299 TI - Adolescent maturation of the relationship between cortical gyrification and cognitive ability. AB - There are changes to the degree of cortical folding from gestation through adolescence into young adulthood. Recent evidence suggests that degree of cortical folding is linked to individual differences in general cognitive ability in healthy adults. However, it is not yet known whether age-related cortical folding changes are related to maturation of specific cognitive abilities in adolescence. To address this, we examined the relationship between frontoparietal cortical folding as measured by a Freesurfer-derived local gyrification index (lGI) and performance on subtests from the Wechsler Abbreviated Scale of Intelligence and scores from Conner's Continuous Performance Test-II in 241 healthy adolescents (ages 12-25 years). We hypothesized that age-related lGI changes in the frontoparietal cortex would contribute to cognitive development. A secondary goal was to explore if any gyrification-cognition relationships were either test-specific or sex-specific. Consistent with previous studies, our results showed a reduction of frontoparietal local gyrification with age. Also, as predicted, all cognitive test scores (i.e., Vocabulary, Matrix Reasoning, the CPT-II Commission, Omission, Variabiltiy, d') showed age * cognitive ability interaction effects in frontoparietal and temporoparietal brain regions. Mediation analyses confirmed a causal role of age-related cortical folding changes only for CPT-II Commission errors. Taken together, the results support the functional significance of cortical folding, as well as provide the first evidence that cortical folding maturational changes play a role in cognitive development. PMID- 28676300 TI - Can Residents Be Trained and Safety Maintained? AB - INTRODUCTION: Teaching hospitals and faculty need to balance the educational mission for training residents with patient safety. There are no data studying the change in trauma patient outcomes before and after implementation of a surgical residency. The objective of this study was to compare trauma center outcomes before and after the advent of a surgical training program. We predicted that patient-centric outcome metrics would not be affected by the integration of surgical residents into trauma patient care. METHODS: A retrospective review was performed using the Crimson Continuum of Care (CCC) dataset and the Trauma Injury Severity Scores (TRISS) for the year before implementation of a surgical residency, compared to the 6 months following initiation of the residency. Severity and risk-adjusted performance measures included mortality, readmissions, complications, and length of stay. Using TRISS, actual, and predicted mortality was compared. RESULTS: There were 1535 trauma admissions to the acute Care Trauma Service the year before starting the residency, and 856 admissions for the 6 months following the implementation of the program. The demographics were similar between the 2 groups. There was no clinically significant difference in observed mortality after the initiation of a surgery residency, based on CCC dataset variables and TRISS datasets. There were also no significant differences in complications and readmission rates. CONCLUSIONS: We found that initiating a surgical training program did not affect mortality rates or complications of trauma patients. Training of general surgery residents in a high-performing trauma center can be effectively implemented without compromising patient safety. PMID- 28676301 TI - Toward the identification of viral cap-methyltransferase inhibitors by fluorescence screening assay. AB - Two highly pathogenic human coronaviruses associated with severe respiratory syndromes emerged since the beginning of the century. The severe acute respiratory syndrome SARS-coronavirus (CoV) spread first in southern China in 2003 with about 8000 infected cases in few months. Then in 2012, the Middle East respiratory syndrome (MERS-CoV) emerged from the Arabian Peninsula giving a still on-going epidemic associated to a high fatality rate. CoVs are thus considered a major health threat. This is especially true as no vaccine nor specific therapeutic are available against either SARS- or MERS-CoV. Therefore, new drugs need to be identified in order to develop antiviral treatments limiting CoV replication. In this study, we focus on the nsp14 protein, which plays a key role in virus replication as it methylates the RNA cap structure at the N7 position of the guanine. We developed a high-throughput N7-MTase assay based on Homogenous Time Resolved Fluorescence (HTRF(r)) and screened chemical libraries (2000 compounds) on the SARS-CoV nsp14. 20 compounds inhibiting the SARS-CoV nsp14 were further evaluated by IC50 determination and their specificity was assessed toward flavivirus- and human cap N7-MTases. Our results reveal three classes of compounds: 1) molecules inhibiting several MTases as well as the dengue virus polymerase activity unspecifically, 2) pan MTases inhibitors targeting both viral and cellular MTases, and 3) inhibitors targeting one viral MTase more specifically showing however activity against the human cap N7-MTase. These compounds provide a first basis towards the development of more specific inhibitors of viral methyltransferases. PMID- 28676302 TI - Comparison of three dimensional synergistic analyses of percentage versus logarithmic data in antiviral studies. AB - Cell culture antiviral experiments were conducted in order to understand the relationship between percentage data generated by plaque reduction (PR) and logarithmic data derived by virus yield reduction (VYR) assays, using three dimensional MacSynergy II software. The relationship between percentage and logarithmic data has not been investigated previously. Interpretation of drug drug interactions is based on a Volume of Synergy (VS) calculation, which can be positive (synergy), negative (antagonistic), or neutral (no or minimal interaction). Interactions of two known inhibitors of vaccinia virus replication, cidofovir and 6-azauridine, used in combination by PR assay yielded a VS value of 265, indicative of strong synergy. By VYR, the VS value was only 37, or weak synergy using the same criterion, even though profound log10 reductions in virus titer occurred at multiple drug combinations. These results confirm that the differences in VS values is dependent of the measurement scale, and not that the degree of synergy differed between the assays. We propose that for logarithmic data, the calculated VS values will be lower for significant synergy and antagonism and that volumes of >10 MUM2log10 PFU/ml (or other units such as MUM2log10 genomic equivalents/ml or MUM2log10 copies/ml) and <-10 MUM2log10 PFU/ml are likely to be indicative of strong synergy and strong antagonism, respectively. Data presented here show that the interaction of cidofovir and 6 azauridine was strongly synergistic in vitro. PMID- 28676303 TI - Central and peripheral administrations of insulin-like growth factor-1 suppress food intake in chicks. AB - A number of studies have been made on the physiological actions of insulin-like growth factor-1 (IGF-1) in mammals and birds. In mammals, the effects of central administration of IGF-1 on food intake have been examined. For example, intracerebroventricular administration of IGF-1 significantly decreased food intake in diabetic rats, but not in sheep and nondiabetic rats. The chicken is known to be a hyperglycemic animal. Like satiety hormones, plasma IGF-1 levels are elevated postprandially in chickens. In this study, we hypothesized that IGF 1 is involved in the regulation of food intake in chickens. Intracerebroventricular administration of IGF-1 significantly suppressed food intake in chicks in a dose dependent manner. Both the mRNAs of IGF-1 and its receptor were expressed throughout the brain. However, the mRNA levels of IGF-1 were not influenced by fasting and refeeding in all regions of the brain. On the other hand, 6h of fasting significantly suppressed mRNA expression of hepatic IGF 1, and this effect was significantly reversed by 6h of refeeding. Furthermore, intravascular administration of IGF-1 significantly suppressed food intake in chicks. These findings suggest that IGF-1 may function as a satiety hormone in chickens. PMID- 28676304 TI - Imaging Trends in Acute Venous Thromboembolic Disease: 2000 to 2015. AB - PURPOSE: To measure diffusion of new knowledge and correlate imaging utilization for suspected acute venous thromboembolism (VTE) with d-dimer utilization, landmark publications, and institutional guidelines. MATERIALS: Between 2000 and 2015, the number of CT pulmonary angiograms (CTPAs), CTPA combined with indirect CT venography (CTV), ventilation-perfusion (VQ) scans, and lower extremity venous Doppler ultrasound (US) examinations were obtained for inpatients and emergency department (ED) patients and correlated with d-dimer utilization, landmark publications regarding radiation and VTE imaging, and an institutional inpatient best-practice alert requiring VTE prophylaxis assessment (2008). Volume data were normalized per 1,000 patients. RESULTS: CTPA and d-dimer utilization were correlated (ED: r = 0.94, inpatient: r = 0.87; P < .001). VQ volume peaked in 2004 to 2005 (20 of 1,000 ED patients; 14 of 1,000 inpatients) and decreased since to a low of 1 of 1,000 and 3 of 1,000, respectively. US volume increased since 2002 and was higher than CT volume for inpatients (annual mean 149 of 1,000 patients [US], 46 of 1,000 patients [CT]), but not ED patients (annual mean 18 of 1,000 patients [US], 35 of 1,000 patients [CT]). For ED patients, CTPA volume peaked in 2008 at 57 of 1,000 patients, declined through 2012 to 30 of 1,000 patients, and rose annually since to 37 of 1,000 patients (2015). For inpatients, CTPA volume also peaked in 2008 at 70 of 1,000, but continued to decline through 2015 to 27 of 1,000 patients. CONCLUSION: After the Prospective Investigation of Pulmonary Embolism II and Brenner and Hall publications, there was a transient 4 year decline in ED CTPA utilization. The decline was sustained in inpatients, where a best-practice VTE prophylaxis alert was implemented. Best-practice alerts may sustain the impact of new knowledge. PMID- 28676305 TI - Socioeconomic and Demographic Predictors of Missed Opportunities to Provide Advanced Imaging Services. AB - PURPOSE: The extent to which racial and socioeconomic disparities exist in accessing clinically appropriate, advanced diagnostic imaging has not been well studied. This study assesses the relationship between demographic and socioeconomic factors and the incidence of imaging missed care opportunities (IMCOs). METHODS: We performed a retrospective review of outpatient CT and MRI appointments at a quaternary academic medical center and affiliated outpatient facilities during a 12-month period. Missed appointments not rescheduled in advance were classified as IMCOs. Appropriateness criteria scores and demographics were also obtained. Univariate and multivariate analyses were performed to determine if demographic and socioeconomic factors were predictive of IMCOs. RESULTS: Overall, 57,847 patients met inclusion criteria, representing 89,943 scheduled unique imaging appointments of which 5,840 (6.1%) were IMCOs; 0.8% of IMCO appointments had low appropriateness scores compared with 1.2% of completed appointments (P < .01). Appointments covered by commercial insurance (5.2%) had a significantly lower rate of IMCOs than other payers: Medicare = 6.3%, Medicaid = 14.5%, self-pay = 12.0% (P < .05). The following factors were independent predictors of a patient having >= 1 IMCO: noncommercial insurance [odds ratio (OR) = 1.7-2.6], African American (OR = 1.8), Hispanic (OR = 1.2), other race (OR = 1.1), language other than English or Spanish (OR = 1.2), male gender (OR = 1.2), age >= 65 (OR = 0.71), and median household income of patient home zip code <$50,000 (OR = 1.4). CONCLUSIONS: Race and socioeconomic status are independent predictors of IMCOs. In efforts to enhance patient engagement, radiologists should be aware of the impact of race and socioeconomic status on access to clinically appropriate advanced diagnostic imaging. PMID- 28676306 TI - Looming Physician Shortage? PMID- 28676307 TI - New immunomodulatory role of neuropeptide Y (NPY) in Salmo salar leucocytes. AB - Neuropeptide Y (NPY) plays different roles in mammals such as: regulate food intake, memory retention, cardiovascular functions, and anxiety. It has also been shown in the modulation of chemotaxis, T lymphocyte differentiation, and leukocyte migration. In fish, NPY expression and functions have been studied but its immunomodulatory role remains undescribed. This study confirmed the expression and synthesis of NPY in S. salar under inflammation, and validated a commercial antibody for NPY detection in teleost. Additionally, immunomodulatory effects of NPY were assayed in vitro and in vivo. Phagocytosis and superoxide anion production in leukocytes and SHK cells were induced under stimulation with a synthetic peptide. IL-8 mRNA was selectively and strongly induced in the spleen, head kidney, and isolated cells, after in vivo challenge with NPY. All together suggest that NPY is expressed in immune tissues and modulates the immune response in teleost fish. PMID- 28676308 TI - Using electrocorticography for presurgical language mapping in epilepsy patients. AB - Of five epilepsy patients with implanted subdural electrodes, electrical cortical stimulation (ECS) on left posterior inferior frontal gyri (LPIFG) of dominant language hemisphere, did not elicit language production related symptoms. These patients were then subjected to six language production tasks with simultaneously electrocorticographic (ECoG) recording. Dada analysis revealed several cortical sites showed event-related cortical high gamma activities. These sites were linked to certain functions, e.g., auditory, visual, and sensorimotor, according to their different activation patterns among tasks. Sites labeled as sensorimotor related by ECoG showed high accordance with those identified via ECS. Yet ECoG identified few extra crucial sites in LPIFG either. These results demonstrated consistency between ECS and ECoG and reaffirmed the utility of ECoG in preoperative functional cortical mapping. PMID- 28676310 TI - An investigation into the effects and prognostic factors of cognitive decline following subthalamic nucleus stimulation in patients with Parkinson's disease. AB - We retrospectively investigated the effects of subthalamic nucleus stimulation (STN-DBS) on new postoperative onset of cognitive decline and prognostic factors for advanced Parkinson's disease (PD). We studied 39 PD patients who had received bilateral STN-DBS. Clinical symptoms, cognitive function, psychiatric function, and health-related quality of life (HRQOL) were assessed before and six months after surgery. Based on the results of neuropsychological examinations six months after the surgery, the subjects were divided into those with and those without cognitive decline. We compared pre- and post-operative assessments between the two groups. Prognostic factors were investigated using multiple logistic regression analyses. Seven patients had cognitive decline six months after the operation (17.9%); they were significantly older than those without cognitive decline. Preoperative neuropsychological examinations revealed impairments in language and executive function. No differences were found in clinical symptoms. Patients with cognitive decline had significantly worse apathy scale scores. The HRQOL revealed significant declines in the Mental Component Summary (MCS), vitality, and mental health (MH) domains. Postoperative comparisons revealed novel significant differences in activities of daily living in the "on" and "off" states and in daytime drowsiness. Preoperative differences seen in the MCS and vitality indices were no longer present. Word fluency, and apathy scale and MH scores were independent preoperative prognostic factors for cognitive decline. New postoperative onset of cognitive decline due to STN-DBS affected activities of daily living and psychiatric function. Preoperative non-motor symptoms may be prognostic factors for new onset of cognitive decline. PMID- 28676309 TI - Correlation of clinical findings and brain volume data in multiple sclerosis. AB - Brain volume measurements are becoming an important tool for assessing success in controlling multiple sclerosis (MS) activity. MSmetrix (icometrix) is an easy-to use platform, specific for MS magnetic resonance imaging (MRI) of the brain. It provides data on total brain volume, grey matter volume and lesion load volume. The objective of the present study was to assess whether disability and the number of relapses during the previous year correlated with brain volume measurements from MSmetrix. Data on 185 icometrix reports from patients with MS were used to evaluate the potential correlation between brain volume measurements and clinical parameters. There was a significant correlation between higher disability and decreased brain volume (total and grey matter). Increased lesion load in the brain and higher number of relapses in the previous year were also independently correlated with decreased brain tissue volume and with increased disability. This is the first study with real-world data to show that icometrix is a relevant tool for the study of brain volume loss in MS. PMID- 28676311 TI - The Seattle spine score: Predicting 30-day complication risk in adult spinal deformity surgery. AB - BACKGROUND: Complication rates in complex spine surgery range from 25% to 80% in published studies. Numerous studies have shown that surgeons are not able to accurately predict whether patients are likely to face post-operative complications, in part due to biases based on individual experience. The purpose of this study was to develop and evaluate a predictive risk model and decision support system that could accurately predict the likelihood of 30-day postoperative complications in complex spine surgery based on routinely measured preoperative variables. METHODS: Preoperative and postoperative data were collected for 136 patients by reviewing medical records. Logistic regression analysis (LRA) was applied to develop the predictive algorithm based on patient demographic parameters, including age, gender, and co-morbidities, including obesity, diabetes, hypertension and anemia. We additionally compared the performance of the predictive model to a spine surgeon's ability to predict patient complications using signal detection theory statistics representing sensitivity and response bias (A' and B" respectively). We developed a decision support system tool, based on the LRA predictive algorithm, that was able to provide a numeric probabilistic likelihood statistic representing an individual patient's risk of developing a complication within the first 30days after surgery. RESULTS: The predictive model was significant (chi2=16.242, p<0.05), showed good fit, and was calibrated by using area under the receiver operating characteristics curve analysis (AUROC=0.712, p<0.01). The model yielded a predictive accuracy of 75.0%. It was validated by splitting the data set, comparing subset models, and testing them with unknown data. Validation also involved comparing the classification of cases by experts with the classification of cases by the model. The model significantly improved the classification accuracy of physicians involved in the delivery of complex spine surgical care. CONCLUSIONS: The application of technology and data-driven tools to advanced surgical practice has the potential to improve decision making quality, service quality and patient safety. PMID- 28676312 TI - Multiple sclerosis: Frequency, cost, and economic burden in the United States. AB - Multiple sclerosis (MS) is one of the most common neurological diseases, affecting young and middle-aged adults. The full economic cost of managing chronic MS is substantial. To investigate the recent trend of medical cost and economic burden of MS management in the United States (U.S.), we inquired for available data from the National Inpatient Sample database (NIS; from 1994 to 2013). The annual rates of changes were determined by linear regression analysis. We found an estimated half million increase in MS admissions, annually, which was projected to exceed 43.5 million by the end of year 2017. We also found the charge and the costs associated with MS care increased at rates of US$ 40 million a year and US$ 8 million a year, respectively. We revealed a 1.6 fold increase in the inflation of medical bill in the past decade, and the inflation of medical bills was inversely correlated to the cost-to-charge ratios. In sum, we outline the national trends of medical care use and the expenditure of caring for patients with MS. Periodic reviews and characterizations of expenditure trends are critical for formulating future policy. PMID- 28676313 TI - Ganglion cell complex loss precedes retinal nerve fiber layer thinning in patients with pituitary adenoma. PMID- 28676314 TI - Cerebrospinal fluid leaks after transsphenoidal surgery - Effect of a polyethylene glycol hydrogel dural sealant. AB - To investigate cerebrospinal fluid (CSF) leak rates after mainly endoscopic endonasal transsphenoidal surgery with and without polyethylene glycol hydrogel dural sealant (DuraSeal(r)), we prospectively collected data from a single-centre consecutive case series over four years from January 2007 to December 2010 inclusive. 250 patients were identified (135 male, 115 female; median age 52years, range 14-83). 180 patients received DuraSeal(r) (72%). 85 (34%) had intra-operative dural breach and 13 (5.2%) developed post-operative CSF leaks (3 without intra-operative dural breach) requiring lumbar drainage or formal repair. Of this group 5/251 (2.0%) patients required a formal repair. Post-operative CSF leak was seen in 5/189 (2.7%) of patients with pituitary adenoma, of which 2/5 (40%) were in cases undergoing revision surgery. 5/13 (38.4%) patients who developed a CSF leak presented with either Rathke's cleft cyst or craniopharyngioma. 3/71 patients not receiving DuraSeal(r) leaked (4.2%) and 10/180 patients receiving DuraSeal(r) leaked (5.6%). 11/234 patients without Tisseel (4.7%) and 2/16 receiving Tisseel (12.5%) leaked. 54 patients (22%) received intra-operative lumbar drains, one of whom developed subsequent CSF leak (1.9%), in contrast to 12/197 (6.1%) of patients without intra-operative lumbar drains who later developed CSF leak. The rate of post-operative CSF leak requiring re-exploration and nasoseptal flap repair was low (2.0%) in this mainly endoscopic case series without statistically significant benefit from either DuraSeal(r) or Tisseel. Intra-operative and post-operative lumbar drainage appears beneficial in patients at higher risk of post-operative CSF leak. PMID- 28676315 TI - Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients. AB - Vagus nerve stimulation (VNS) is a promising neurostimulation tool for the treatment of treatment-resistant depression. Here, we report the effects of positive remission rates and tuning parameters in a group of 18 (6 female, 12 male, mean age 54) long-term treated patients. Treatment varied between 3 and 200months (mean 104.9months). Mean stimulation intensity was 1.46mA, ranging from 0.5 to 2.0mA and high-frequency stimulation of 20-25Hz (mean 23.61Hz). The remission rates in our study population clearly indicate ongoing positive effects of VNS and highlight stimulation tunings between 0.5 and 2.0mA and 20-25Hz as best dosage for achieving remittance in long-term treatment of VNS. PMID- 28676316 TI - A meta-analysis comparing ALIF, PLIF, TLIF and LLIF. AB - INTRODUCTION: Lumbar interbody fusions have been widely used to treat degenerative lumbar disease that fails to respond to conservative treatment. This procedure is divided according to its approach: anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), transforaminal lumbar interbody fusion (TLIF) and lateral lumbar interbody fusion (LLIF). Each approach has its own theoretical advantages and disadvantages; however, there have been no studies that compared these. METHODS: Various full-text databases were systematically searched through December 2015. Data regarding the radiological, operative and clinical outcomes of each lumbar interbody fusion were extracted. All outcomes were pooled using random effects meta-analysis, with the relative risk (RR) and/or weighted mean difference (WMD) as the summary statistic. RESULTS: Thirty studies met the inclusion criteria. The ALIF procedure has been studied most intensively, followed by PLIF, TLIF and LLIF respectively. All four approaches had similar fusion rates (p=0.320 & 0.703). ALIF has superior radiological outcome, achieving better postoperative disc height (p=0.002 & 0.005) and postoperative segmental lordosis (p=0.013 & 0.000). TLIF had better Oswestry Disability Index scores (p=0.025 & 0.000) while PLIF had the greatest blood loss (p=0.032 & 0.006). Complication rates were similar between approaches. Other comparisons were either inconclusive or lacked data. There was marked less studies comparing against LLIF. CONCLUSIONS: Each approach has their own risks and benefits but similar fusion rates. Despite the large number of studies, there is little data overall when comparing specific aspects of lumbar interbody fusions. More studies, especially RCTs are needed to further explore this topic. PMID- 28676317 TI - Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing. AB - : The Glasgow Coma Scale (GCS) only assesses orientation after traumatic brain injury (TBI). 'Post-traumatic amnesia' (PTA) comprises orientation, anterograde amnesia (AA) and retrograde amnesia (RA). However, RA is often disregarded in formalized PTA assessment. Drugs can potentially confound PTA assessment: e.g. midazolam can cause AA. However, potential drug confounders are also often disregarded in formalized PTA testing. One study of medium-stay elective-surgery orthopaedic patients (without TBI) demonstrated AA in 80% taking opiates after general anesthesia. However, RA was not assessed. Opiates/opioids are frequently administered after TBI. We compared AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after opiate/opioid/benzodiazepine-free spinal anesthesia. In a prospective cohort, the Westmead PTA Scale (WPTAS) was used to assess AA (WPTAS<12), whilst RA was assessed using the Galveston Orientation and Amnesia Test RA item. Results were obtained in n=25 (60+/-14yrs, M:F 17:8). Surgery was uncomplicated: all were discharged by Day-4. All were taking regular oxycodone as a new post-operative prescription. Only one co-administered non-opioid was potentially confounding (temezepam, n=4). Of 25, 14 (56%) demonstrated AA: five (20%) were simultaneously disorientated. Mean WPTAS was 11.08+/-1.22. RA occurred in 0%. CONCLUSIONS: AA and disorientation, but not RA, were associated with in-patients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory was robust and more reliable: even in older patients with iatrogenic AA and disorientation. RA assessment should therefore be integral to assessing TBI severity in all formalized PTA and GCS testing. PMID- 28676318 TI - Postoperative alar base symmetry in complete unilateral cleft lip and palate:A prospective study. AB - In the evolution of cleft lip repair, there have been continuous attempts to minimize local trauma and to improve lip and nasal appearances. In order to obtain an aesthetically balanced development of midface, the primary surgical correction of the nasolabial area is of paramount importance. In this study, the importance of a back-cut extending cephalically above the inferior turbinate at the mucocutaneous junction which elevates the nostril floor on the cleft side for the purpose of achieving symmetry of the alar bases are analyzed by pre and postoperative photographic anthropometry. This study comprised of fifty cases of the unilateral complete cleft lip. At the time of surgery, the patient age ranged from 3-9 months. The surgeries, performed by a single surgeon, employed the standard Millard technique, incorporating Mohler modifications of lip repair. Anthropometric analysis revealed that the preoperative mean difference between the normal side and the cleft side was 0.2056 with a standard deviation of 0.133. In the postoperative analysis, the mean difference was reduced to 0.0174 with a standard deviation of 0.141. The paired t-test showed that the p-value is <0.001, indicating high statistical significance. To conclude, in complete unilateral cleft lip and palate, the geometrically placed nasal back-cut incision has a definite role in the correction of the alar base symmetry during primary surgery. PMID- 28676319 TI - Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on perioperative outcomes of breast reconstruction. AB - PURPOSE: Hormone (anti-estrogen) therapy (HT) plays a major role in hormone receptor-positive breast cancer management. The latest guidelines propose to extend the duration of adjuvant treatment from 5 to 10 years. The association between HT and thromboembolic or microvascular complications during breast reconstruction has been investigated. However, while estrogens play a crucial role in wound healing, no study has assessed the impact of tamoxifen or aromatase inhibitors on other postoperative complications, including wound healing complications. This study aimed to assess the impact of HT on surgical outcomes after breast reconstruction. METHODS: All patients who underwent breast reconstruction between January 2012 and December 2013 were reviewed. Rates of wound healing complications, prosthesis complications, microvascular thrombosis, flap failures, and venous thromboembolism were retrospectively compared between patients treated and not treated with HT at the time of surgery. RESULTS: A total of 233 operations were performed: 78 free flaps, 12 autologous latissimus dorsi flaps, 47 implants, 42 lipofilling, and 54 secondary symmetrization. At the time of surgery, 38% of patients were treated with HT. Those who received HT experienced significantly more wound healing complications (61% versus 28%; p < 0.001), including fat necrosis (26% versus 8.3%; p < 0.001), infections (15% versus 2.8%; p < 0.001), delayed wound healing (49% versus 13%; p < 0.001), and grade III/IV capsular contracture (55% versus 9.1%; p = 0.001). No significant difference was observed in the occurrence of microvascular thrombosis and venous thromboembolism. CONCLUSIONS: HT seems to be associated with an increased risk of wound healing complications. Currently, there is no guideline on perioperative HT discontinuation. Further investigations are required. PMID- 28676320 TI - Body contouring procedures in three or more anatomical areas are associated with long-term body mass index decrease in massive weight loss patients: A retrospective cohort study. AB - BACKGROUND: Massive weight loss (MWL) patients who undergo body contouring plastic surgery (BCPS) display superior long-term weight maintenance. The effect of the number of anatomical areas contoured on weight dynamics is undetermined. OBJECTIVES: To determine whether body mass index (BMI) dynamics following BCPS are associated with the number of anatomical areas operated. METHODS: A retrospective cohort study was conducted. Study groups were defined by the number of anatomical areas operated (1, 2, and 3+). BMI velocity was defined as a ratio between BMI change following BCPS and follow-up time. Multinomial logistic regression was performed to assess the independent association with BMI velocity. RESULTS: A total of 222 patients undergoing 513 BCPSs between 2009 and 2014 were included in the study (mean age 36.8 +/- 10.9 years, 77% females). Group 3+ (n = 88) had a negative mean BMI velocity compared with positive values in Groups 1 and 2 (-0.11 +/- 1.0 vs. 0.44 +/- 1.4 and 0.03 +/- 1.2, respectively; p = 0.03). Independent risk factors for positive BMI velocity (>0.5 kg/m2/year) included single anatomical area BCPS compared to three or more (OR = 3.37; CI 95% 1.24 9.14; p = 0.017) and psychiatric medication use (OR = 6.73; CI 95% 1.15-39.35; p = 0.034). Independent protective factors included diabetes mellitus (OR = 0.094; CI 95% 0.01-0.99; p = 0.049). CONCLUSIONS: BCPS in three or more anatomical areas following MWL is associated with a long-term weight loss following BCPS. As part of the health strategy to maintain normal BMI values and achieve overall quality of life improvement in MWL patients, clinicians and health policy makers should positively consider recommending BCPS in multiple anatomical areas. PMID- 28676321 TI - Corrigendum to "Ultra-low dose abdominal MDCT: Using a knowledge-based Iterative Model Reconstruction technique for substantial dose reduction in a prospective clinical study" [Eur. J. Radiol. 84 (2015) 2-10]. PMID- 28676322 TI - Cleavage of the Drosophila seminal protein Acp36DE in mated females enhances its sperm storage activity. AB - Sperm storage in the mated female reproductive tract (RT) is required for optimal fertility in numerous species with internal fertilization. In Drosophila melanogaster, sperm storage is dependent on female receipt of seminal fluid proteins (SFPs) during mating. The seminal fluid protein Acp36DE is necessary for the accumulation of sperm into storage. In the female RT, Acp36DE localizes to the anterior mating plug and also to a site in the common oviduct, potentially "corralling" sperm near the entry sites into the storage organs. Genetic studies showed that Acp36DE is also required for a series of conformational changes of the uterus that begin at the onset of mating and are hypothesized to move sperm towards the entry sites of the sperm storage organs. After Acp36DE is transferred to the female RT, the protein is cleaved by the astacin-metalloprotease Semp1. However, the effect of this cleavage on Acp36DE's function in sperm accumulation into storage is unknown. We used mass spectrometry to identify the single cleavage site in Acp36DE. We then mutated this site and tested the effects on sperm storage. Mutations of Acp36DE's cleavage site that slowed or prevented cleavage of the protein slowed the accumulation of sperm into storage, although they did not affect uterine conformational changes in mated females. Moreover, the N-terminal cleavage product of Acp36DE was sufficient to mediate sperm accumulation in storage, and it did so faster than versions of Acp36DE that could not be cleaved or were only cleaved slowly. These results suggest that cleavage of Acp36E may increase the number of bioactive molecules within the female RT, a mechanism similar to that hypothesized for Semp1's other substrate, the seminal fluid protein ovulin. PMID- 28676323 TI - Visual cues of oviposition sites and spectral sensitivity of Cydia strobilella L. AB - We investigated whether the spruce seed moth (Cydia strobilella L., Tortricidae: Grapholitini), an important pest in seed orchards of Norway spruce (Picea abies (L.) Karst.), can make use of the spectral properties of its host when searching for flowers to oviposit on. Spectral measurements showed that the flowers, and the cones they develop into, differ from a background of P. abies needles by a higher reflectance of long wavelengths. These differences increase as the flowers develop into mature cones. Electroretinograms (ERGs) in combination with spectral adaptation suggest that C. strobilella has at least three spectral types of photoreceptor; an abundant green-sensitive receptor with maximal sensitivity at wavelength lambdamax=526nm, a blue-sensitive receptor with lambdamax=436nm, and an ultraviolet-sensitive receptor with lambdamax=352nm. Based on our spectral measurements and the receptor properties inferred from the ERGs, we calculated that open flowers, which are suitable oviposition sites, provide detectable achromatic, but almost no chromatic contrasts to the background of needles. In field trials using traps of different spectral properties with or without a female sex pheromone lure, only pheromone-baited traps caught moths. Catches in baited traps were not correlated with the visual contrast of the traps against the background. Thus, visual contrast is probably not the primary cue for finding open host flowers, but it could potentially complement olfaction as a secondary cue, since traps with certain spectral properties caught significantly more moths than others. PMID- 28676324 TI - 24-Norursodeoxycholic acid in patients with primary sclerosing cholangitis: A new "urso saga" on the horizon? PMID- 28676325 TI - Involvement of aryl hydrocarbon receptor (AhR) in polyphenol inhibition of benzo[a]pyrene-induced oxidative stress and neoplastic transformation. PMID- 28676326 TI - Discrepancy between the clinical and histopathologic diagnosis of soft tissue vascular malformations. AB - BACKGROUND: Soft tissue vascular malformations are generally diagnosed clinically, according to the International Society for the Study of Vascular Anomalies (ISSVA) classification. Diagnostic histopathologic examination is rarely performed. OBJECTIVE: We sought to evaluate the validity of the current diagnostic workup without routinely performed diagnostic histopathology. METHODS: We retrospectively determined whether there were discrepancies between clinical and histopathologic diagnoses of patients with clinically diagnosed vascular malformations undergoing therapeutic surgical resections in our center (2000 2015). Beforehand, a pathologist revised the histopathologic diagnoses according to the ISSVA classification. RESULTS: Clinical and histopathologic diagnoses were discrepant in 57% of 142 cases. In these cases, the pathologist indicated the diagnosis was not at all a vascular malformation (n = 24; 17%), a completely different type of vascular malformation (n = 26; 18%), or a partially different type with regard to the combination of vessel-types involved (n = 31; 22%). Possible factors associated with the discrepancies were both clinician-related (eg, diagnostic uncertainty) and pathology-related (eg, lack of immunostaining). LIMITATIONS: Retrospective analysis of a subgroup of patients undergoing surgery. CONCLUSION: The large discrepancy between clinical and histopathologic diagnoses raises doubt about the validity of the current diagnostic workup for vascular malformations. Clear clinical and histopathologic diagnostic criteria might be essential for a uniform diagnosis. PMID- 28676327 TI - Anatomic mapping and clinicopathologic analysis of benign acral melanocytic neoplasms: A comparison between adults and children. AB - BACKGROUND: The clinicopathologic features of benign acral melanocytic neoplasms (BAMNs) remain poorly understood. OBJECTIVE: To define the clinicopathologic features of BAMNs. METHODS: We analyzed clinical data and mapped BAMNs anatomically. We also reviewed the histopathologic features of BAMNs and compared these between adults and children. RESULTS: We included 396 cases of BAMN: 335 adults and 61 children (376 acquired and 20 congenital lesions). Anatomic mapping revealed that the nonweight-bearing portion of the foot was the most common site in adults (120/335, 35.8%) and the forefoot the most common site in children (17/61, 27.9%) for BAMNs. The long axes of the BAMNs paralleled the dermatoglyphic lines on the palms and soles, as did most tissue sections. The lesion diameters were <5.7 mm in all acquired lesions. Histopathologically, we diagnosed 69 lentigo simplex, 201 junctional, 114 compound, 8 intradermal, and 4 blue nevi. Corneal pigmentation, nests located between rete ridges, dendrite prominence, and cytologic atypia were all significantly more common in children than adults. LIMITATIONS: The retrospective study design and acquiring patients from a single institution of a single country limited the research results. CONCLUSION: BAMNs develop most commonly on nonweight-bearing regions of the soles in adults and on the forefoot in children. The long axis of the lesion follows the dermatoglyphics, and cytologic atypia is more common in children. PMID- 28676328 TI - CD8+ mycosis fungoides: A low-grade lymphoproliferative disorder. AB - BACKGROUND: The prognosis of the CD8+ subtype of mycosis fungoides (MF) is controversial. Although most authors believe that determining the presence of this cell surface antigen has no prognostic value, others have observed a more indolent course for CD8+ MF compared with CD4+ MF. OBJECTIVES: To review the cases of CD8+ MF in the pediatric and adult populations seen at our institution. METHODS: This is a retrospective review of clinical and pathologic data. Age, stage at presentation, and outcomes of patients at our institution were compared with those of 2 large MF cohorts that predominantly were CD4+ from the relevant literature. RESULTS: Sixty-seven patients of a median age of 46 years were included. A higher frequency of early-stage disease was observed for CD8+ MF patients at diagnosis when compared with other cohorts, including 31 (47%) patients with stage IA, 33 (50%) with stage IB, and 2 (3%) with stage IIB (P = .001, P = .001, and P = .002, respectively). With a median follow-up (5.5 years, range 0.2-21 years) similar to other cohorts, a higher rate of complete remission was achieved (65.5%, P = .001), and a lower rate of progression was observed (P = .004). LIMITATIONS: This is a retrospective review. CONCLUSION: Our experience with CD8+ MF confirms a more indolent course of disease with this MF variant. Our results warrant a conservative treatment approach limited to skin-directed therapies and observation in most patients. PMID- 28676329 TI - Multiple and repeated sampling increases the sensitivity of direct immunofluorescence testing for the diagnosis of mucous membrane pemphigoid. AB - BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune disease characterized by the predominant blistering of mucosal surfaces and the linear deposition of complement, IgG, or IgA along the basement membrane detected by direct immunofluorescence (DIF) test. OBJECTIVE: To assess the impact of multiple and repeated DIF sampling on establishing the diagnosis of MMP. METHODS: We reviewed the results of DIF studies in 136 nonlesional biopsies from 78 patients who were immunologically confirmed to have MMP. RESULTS: Thirty-six of 52 patients (69%) who underwent only 1 biopsy at the first workup were positive. In 13 cases, the initial single biopsy was negative, and later biopsies were positive. Twenty-two of 26 patients (85%) who underwent multiple biopsies at the initial workup showed >=1 positive DIF test result. Simultaneously obtained biopsies yielded discordant positive and negative findings in 11 patients. Overall, 74 of 78 patients (95%) had >=1 positive result by DIF test. In the remaining 4 cases, the diagnosis was confirmed by the detection of circulating autoantibodies against BP180. LIMITATIONS: This is a retrospective, single-center study. CONCLUSION: Our data demonstrate that multiple and repeated biopsies increase the sensitivity of the DIF test for MMP diagnosis. Negative DIF test findings in cases clinically suggestive of MMP should prompt repeat biopsies. PMID- 28676330 TI - Trends in prescribing behavior of systemic agents used in the treatment of acne among dermatologists and nondermatologists: A retrospective analysis, 2004-2013. AB - BACKGROUND: Despite recommendations to limit the use of oral antibiotics and increasing support for hormonal agents in the treatment of acne, it is unclear whether there have been any significant changes in practice patterns. OBJECTIVE: To characterize changes in prescribing behavior for systemic agents in the treatment of acne in the United States between 2004 and 2013. METHODS: We conducted a retrospective analysis using the OptumInsight Clinformatics DataMart (Optum, Eden Prairie, MN). RESULTS: The number of courses of spironolactone prescribed per 100 female patients being managed for acne by dermatologists and nondermatologists increased from 2.08 to 8.13 and from 1.43 to 4.09, respectively. The median duration of therapy with oral antibiotics was 126 and 129 days among patients managed by dermatologists and nondermatologists, respectively, and did not change significantly over the study period. LIMITATIONS: The OptumInsight Clinformatics DataMart lacks information on acne severity and clinical outcomes. CONCLUSIONS: Additional work to identify patients who would benefit most from alternative therapies such as spironolactone, oral contraceptives, or isotretinoin represents a potential opportunity to improve the care of patients with acne. PMID- 28676331 TI - The relationship between partial upper-airway obstruction and inter-breath transition period during sleep. AB - Short pauses or "transition-periods" at the end of expiration and prior to subsequent inspiration are commonly observed during sleep in humans. However, the role of transition periods in regulating ventilation during physiological challenges such as partial airway obstruction (PAO) has not been investigated. Twenty-nine obstructive sleep apnea patients and eight controls underwent overnight polysomnography with an epiglottic catheter. Sustained-PAO segments (increased epiglottic pressure over >=5 breaths without increased peak inspiratory flow) and unobstructed reference segments were manually scored during apnea-free non-REM sleep. Nasal pressure data was computationally segmented into inspiratory (TI, shortest period achieving 95% inspiratory volume), expiratory (TE, shortest period achieving 95% expiratory volume), and inter-breath transition period (TTrans, period between TE and subsequent TI). Compared with reference segments, sustained-PAO segments had a mean relative reduction in TTrans (-24.7+/-17.6%, P<0.001), elevated TI (11.8+/-10.5%, P<0.001), and a small reduction in TE (-3.9+/-8.0, P<=0.05). Compensatory increases in inspiratory period during PAO are primarily explained by reduced transition period and not by reduced expiratory period. PMID- 28676333 TI - Postoperative infections represent a major determinant of outcome after pancreaticoduodenectomy: Results from a high-volume center. AB - BACKGROUND: Despite improvements in perioperative care, mortality and morbidity rates associated with pancreatic operation still reach 2% and >50%, respectively. Infectious complications after pancreaticoduodenectomy occur in about one-third of the cases. The aim of the study is to define the real burden of infectious complications after pancreaticoduodenectomy and to analyze the risk factors associated with their onset. METHODS: Data of consecutive pancreaticoduodenectomies performed at the authors' institution from January 2011 to June 2016 were retrieved from a prospectively maintained database. Based on the presence of infectious complications, the population was separated into 2 groups (infection group positive [IG+] and infection group negative [IG-]) and then compared. RESULTS: During the study period 893 pancreaticoduodenectomies were performed. Overall, infectious complications were detected in 409 out of 893 patients (45.8%). Preoperative biliary drain was the only independent preoperative risk factor for the development of infectious complications (P < .001, odds ratio 3.8). Each complication was found to be statistically more frequent in IG+. In addition, IG+ also had a prolonged hospital stay (P < .020, odds ratio 1.1) and all deaths occurred in this group. The overall multisite infection rate was 41.6%. Multidrug-resistant bacteria were detected in 78.5% of patients. The development of multisite infection was the best predictor of outcome after pancreaticoduodenectomy. CONCLUSION: The development of postoperative infectious complications is a major determinant of outcome after pancreaticoduodenectomy. In this setting, the reliable negative predictors of the outcome include preoperative biliary drain, site of infection, multidrug resistant bacteria infections and type of bacteria. Multisite infection was found to be the best predictor of a worse postoperative course after pancreaticoduodenectomy. PMID- 28676334 TI - A patient with monoclonal gammopathy-related nephrotic syndrome revealed no electrophoretic "nephrotic pattern" or skewed free light chain ratio. PMID- 28676335 TI - Thymoglobuline plus basiliximab a mixed cocktail to start? AB - Recent results reported by Ciancio et al. have demonstrated the long term successful use of dual induction therapy in kidney transplant recipients. Our experience using an "induction cocktail", thymoglobuline plus basiliximab, started in 2007 and we have treated 235 patients through the past 10years. In our population, we used a combination of CNIs and MMF or mTORi as maintenance therapy. Our results in term of patient and graft survival, acute rejection rate, renal function and incidence of post-transplant lymphoproliferative disorder support the data reported by Ciancio. We believe that double induction therapy allows on one hand to delay the CNIs introduction, reducing delayed graft function, and on the other hand protects the patient while building the targeted drugs exposures, so reducing the incidence of acute rejection. PMID- 28676336 TI - Quantitative proteomic analysis of iron-regulated outer membrane proteins in Aeromonas hydrophila as potential vaccine candidates. AB - The iron-regulated outer membrane protein (OMP) of Aeromonas hydrophila is an effective vaccine candidate, but its intrinsic functional components are largely unknown. In this study, we compared the differentially expressed sarcosine insoluble fractions of A. hydrophila in iron-limited and normal medium using tandem mass tag labeling-based quantitative proteomics, and identified 91 upregulated proteins including 21 OMPs and 83 downregulated proteins including 10 OMPs. Subsequent bioinformatics analysis showed that iron chelate transport related proteins were enriched in increasing abundance, whereas oxidoreductase activity and translation-related proteins were significantly enriched in decreasing abundance. The proteomics results were further validated in selected altered proteins by Western blotting. Finally, the vaccine efficacy of five iron related recombinant OMPs (A0KGW8, A0KFG8, A0KQ46, A0KIU8, and A0KQZ1) that were increased abundance in iron-limited medium, were evaluated when challenged with virulent A. hydrophila against zebrafish, suggesting that these proteins had highly efficient immunoprotectivity. Our results indicate that quantitative proteomics combined with evaluation of vaccine efficacy is an effective strategy for screening novel recombinant antigens for vaccine development. PMID- 28676337 TI - Proliferation, survival and cell death in fish gills remodeling: From injury to recovery. AB - Pollutants found dispersed in water can cause irritations on the gills, challenge the immune system and prejudice the welfare of the fish. Here we investigated molecules linked to proliferation, survival, and cell death, as well as inflammatory and vascular control, in a model of fish gill remodeling, from injury to recovery. We assessed the gill histology and immunohistochemistry for PCNA, iNOS, HSP70, and Bax in Hypostomus francisci obtained from a river subjected to chronic anthropic influences and then after they were placed in water of good quality. A total of 30 H. francisci adult individuals were collected and distributed into two groups: euthanized on the day of capture (group 1) and maintained for 30 days in an aquarium (group 2). In all the fish from group 1, the primary and secondary lamellae showed hypertrophy of the respiratory epithelium, lamellar fusion, lifting of the epithelium, aneurysm, hyperemia, and vascular congestion. On the other hand, in all the fish from group 2, restoration of gill integrity was observed, and the primary and secondary lamellae showed a simple epithelium, absence of lamellar fusion, hypertrophy, and aneurysm. Gills of fish from group 1 had higher frequency of cells immunopositive for PCNA, iNOS, HSP70, and Bax than those of fish from group 2 (p < 0.05). The molecular and cellular mechanisms from injury to recovery were proposed, with a balance between survival and cell death signals being essential for determining the gill structure. In addition, the findings indicate that recovery of the structural organization of gills is possible if fishes are maintained in good quality water, indicating the importance of the conservation of aquatic environments. PMID- 28676332 TI - Circulating exosomes in obstructive sleep apnea as phenotypic biomarkers and mechanistic messengers of end-organ morbidity. AB - Obstructive sleep apnea (OSA), the most severe form of sleep disordered breathing, is characterized by intermittent hypoxia during sleep (IH), sleep fragmentation, and episodic hypercapnia. OSA is associated with increased risk for morbidity and mortality affecting cardiovascular, metabolic, and neurocognitive systems, and more recently with non-alcoholic fatty liver disease (NAFLD) and cancer-related deaths. Substantial variability in OSA outcomes suggests that genetically-determined and environmental and lifestyle factors affect the phenotypic susceptibility to OSA. Furthermore, OSA and obesity often co-exist and manifest activation of shared molecular end-organ injury mechanisms that if properly identified may represent potential therapeutic targets. A challenge in the development of non-invasive diagnostic assays in body fluids is the ability to identify clinically relevant biomarkers. Circulating extracellular vesicles (EVs) include a heterogeneous population of vesicular structures including exosomes, prostasomes, microvesicles (MVs), ectosomes and oncosomes, and are classified based on their size, shape and membrane surface composition. Of these, exosomes (30-100nm) are very small membrane vesicles derived from multi vesicular bodies or from the plasma membrane and play important roles in mediating cell-cell communication via cargo that includes lipids, proteins, mRNAs, miRNAs and DNA. We have recently identified a unique cluster of exosomal miRNAs in both humans and rodents exposed to intermittent hypoxia as well as in patients with OSA with divergent morbid phenotypes. Here we summarize such recent findings, and will focus on exosomal miRNAs in both adult and children which mediate intercellular communication relevant to OSA and endothelial dysfunction, and their potential value as diagnostic and prognostic biomarkers. PMID- 28676338 TI - Dyrk2 involved in regulating LPS-induced neuronal apoptosis. AB - The activation of relevant signaling pathways plays a very important role in LPS induced neuronal damage. Dual-specificity tyrosine-phosphorylation-regulated kinase 2(Dyrk2), as a phosphokinase that can directly or indirectly phosphorylate signal molecules, was recently reported to down-regulate Type I Interferon(TIF) by promoting ser527 phosphorylation of TBK1. To further investigate the role of Dyrk2 in neuroinflammation, we for the first time focused on its function in LPS induced neuronal damage. We found LPS stimulation increased the expression of Dyrk2 in the nucleus and cytoplasm of neurons. In addition, overexpression of Dyrk2 not only reduced the level of TNF-alpha induction, but also obviously inhibited LPS-induced neuronal apoptosis. We further found that Dyrk2 promoted the induction of phospho-Akt, phospho-p65 and phospho-p38MAPK (p38 mitogen activated protein kinase), but immunoprecipitation showed Dyrk2 interacted with and Akt, p38MAPK and IkappaBalpha (IkappaB-alpha), except NF-kappaB subunit p65. These findings suggest Dyrk2 can inhibit LPS-induced neuronal apoptosis and plays key roles in LPS-indcued signaling pathways by its phosphokinase function. These data provide a novel viewpoint that Dyrks family may have an important role in neuroinflammation, and provide a potential molecular target for improving neuronal apoptosis. PMID- 28676339 TI - Characterization of CNL like protein fragment (CNL-LPF) from mature Lageneria siceraria seeds. AB - Coiled coil domain-nucleotide binding site-leucine rich repeat (CC-NBS-LRR; CNL) proteins are highly conserved family of plant disease resistance proteins, remarkably comprise of coiled-coil domain, which plays significant role in plant innate immunity. The present study reports that moderately elicited oligomerization of plant CNL like protein fragment (CNL-LPF) in presence of ATP/Mg using various biophysical methods Circular dichroism (CD) results depicted a substantial increase in beta-sheet structure content of CNL-LPF. ATP/Mg induced conformational change in protein was observed by increase in blue shift with extrinsic fluorescence measurement, which indicates the exposure of hydrophobic regions of CNL-LPF and leads to self-association i.e. oligomerization. Likewise, cluster of protein oligomer and alteration in protein surface morphology were observed in presence of ATP/Mg by Transmission electron microscopy (TEM) and Atomic force microscopy (AFM), respectively. Also, augmented antiproliferation of HT1376 cells (urinary bladder cancer cell lines) was observed by CNL-LPF in presence of ATP/Mg. In conclusion, the current study illustrates that extent of CNL-LPF oligomerization was enhanced in presence of ATP/Mg (as compared to its absence). Utilization of enhanced oligomerization property of CNL-LPF as an anti proliferative agent needs more assessment. PMID- 28676340 TI - Molecular and morphological characterization of Acanthamoeba isolated from corneal scrapes and contact lens wearers in Argentina. AB - In this study, we describe the frequency of Acanthamoeba keratitis (AK) in patients that assisted in the Ophthalmology Department and determine the species/genotypes of free living amoebas (FLA) isolates. FLA from Corneal scrapes (CS) and contact lens (CL) wearers were studied by morphological and molecular characterization. A database was constructed with sociodemographic, clinical findings and history of use of CL variables. During January 2000 and September 2016 patients with corneal pathology admitted to the Ophthalmology Service of the University Hospital in Cordoba city, Argentina were included in the study. FLA were detected in 1.5% (11/739) and in 17% (11/65) of CS and CL analyzed respectively. FLA isolates from CL users evidenced an 80.9% of inappropriate lens maintenance, 4.8% (1/21) were not CL users that have been in contact with waters in outdoor environment and 14,3% (3/21) with no data about CL users. Acanthamoeba was confirmed in 100% and 82% of CS and LC respectively. The most frequent symptom associated with AK was red eye and photophobia. FLA from CS belonged to group II but 82% (9/11) and 18% (2/11) from CL belonged to group II and III respectively. T4 genotype and A. polyphaga species were detected in 100% of Acanthamoeba isolates. Poor CL hygiene practices, highlights the need for improved education about the severity of AK and consequences of improper CL hygiene. Genotype T4 detected in 100% of both CS and CL samples, consistently with previous findings indicating that this genotype is by far the most prevalent isolated from ocular infection. PMID- 28676341 TI - The Circular RNA Interacts with STAT3, Increasing Its Nuclear Translocation and Wound Repair by Modulating Dnmt3a and miR-17 Function. AB - Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically. PMID- 28676342 TI - Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase. AB - We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB CD3zeta signaling domain lysed ALK-expressing tumor lines and produced interferon gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells. In addition, ALK CAR T cells demonstrated rapid and complete antigen-induced loss of receptor from the T cell surface via internalization. Using a model that simultaneously modulated antigen density and CAR expression, we demonstrated that CAR functionality is regulated by target antigen and CAR density and that low expression of either contributes to limited anti-tumor efficacy of the ALK CAR. These data suggest that stoichiometric relationships between CAR receptors and target antigens may significantly impact the anti-tumor efficacy of CAR T cells and that manipulation of these parameters could allow precise tuning of CAR T cell activity. PMID- 28676345 TI - A six-month longitudinal evaluation significantly improves accuracy of predicting incipient Alzheimer's disease in mild cognitive impairment. AB - RATIONALE AND OBJECTIVES: Early prediction of incipient Alzheimer's disease (AD) dementia in individuals with mild cognitive impairment (MCI) is important for timely therapeutic intervention and identifying participants for clinical trials at greater risk of developing AD. Methods to predict incipient AD in MCI have mostly utilized cross-sectional data. Longitudinal data enables estimation of the rate of change of variables, which along with the variable levels have been shown to improve prediction power. While some efforts have already been made in this direction, all previous longitudinal studies have been based on observation periods longer than one year, hence limiting their practical utility. It remains to be seen if follow-up evaluations within shorter intervals can significantly improve the accuracy of prediction in this problem. Our aim was to determine the added value of incorporating 6-month longitudinal data for predicting progression from MCI to AD. MATERIALS AND METHODS: Using 6-months longitudinal data from 247 participants with MCI, we trained two Random Forest classifiers to distinguish between progressive MCI (n=162) and stable MCI (n=85) cases. These models utilized structural MRI, neurocognitive assessments, and demographic information. The first model (cross-sectional) only used baseline data. The second model (longitudinal) used data from both baseline and a 6-month follow-up evaluation allowing the model to additionally incorporate biomarkers' rate of change. RESULTS: The longitudinal model (AUC=0.87; accuracy=80.2%) performed significantly better (P<0.05) than the cross-sectional model (AUC=0.82; accuracy=71.7%). CONCLUSION: Short-term longitudinal assessments significantly enhance the performance of AD prediction models. PMID- 28676344 TI - CRISPR Epigenome Editing of AKAP150 in DRG Neurons Abolishes Degenerative IVD Induced Neuronal Activation. AB - Back pain is a major contributor to disability and has significant socioeconomic impacts worldwide. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to back pain, but a better understanding of the interactions between the degenerative IVD and nociceptive neurons innervating the disc and treatment strategies that directly target these interactions is needed to improve our understanding and treatment of back pain. We investigated degenerative IVD-induced changes to dorsal root ganglion (DRG) neuron activity and utilized CRISPR epigenome editing as a neuromodulation strategy. By exposing DRG neurons to degenerative IVD-conditioned media under both normal and pathological IVD pH levels, we demonstrate that degenerative IVDs trigger interleukin (IL)-6-induced increases in neuron activity to thermal stimuli, which is directly mediated by AKAP and enhanced by acidic pH. Utilizing this novel information on AKAP-mediated increases in nociceptive neuron activity, we developed lentiviral CRISPR epigenome editing vectors that modulate endogenous expression of AKAP150 by targeted promoter histone methylation. When delivered to DRG neurons, these epigenome-modifying vectors abolished degenerative IVD-induced DRG-elevated neuron activity while preserving non-pathologic neuron activity. This work elucidates the potential for CRISPR epigenome editing as a targeted gene-based pain neuromodulation strategy. PMID- 28676343 TI - Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1. AB - The successful immunotherapy of acute myeloid leukemia (AML) has been hampered because most potential antigenic targets are shared with normal hematopoietic stem cells (HSCs), increasing the risk of sustained and severe hematopoietic toxicity following treatment. C-type lectin-like molecule 1 (CLL-1) is a membrane glycoprotein expressed by >80% of AML but is absent on normal HSCs. Here we describe the development and evaluation of CLL-1-specific chimeric antigen receptor T cells (CLL-1.CAR-Ts) and we demonstrate their specific activity against CLL-1+ AML cell lines as well as primary AML patient samples in vitro. CLL-1.CAR-Ts selectively reduced leukemic colony formation in primary AML patient peripheral blood mononuclear cells compared to control T cells. In a human xenograft mouse model, CLL-1.CAR-Ts mediated anti-leukemic activity against disseminated AML and significantly extended survival. By contrast, the colony formation of normal progenitor cells remained intact following CLL-1.CAR-T treatment. Although CLL-1.CAR-Ts are cytotoxic to mature normal myeloid cells, the selective sparing of normal hematopoietic progenitor cells should allow full myeloid recovery once CLL-1.CAR-T activity terminates. To enable elective ablation of the CAR-T, we therefore introduced the inducible caspase-9 suicide gene system and we show that exposure to the activating drug rapidly induced a controlled decrease of unwanted CLL-1.CAR-T activity against mature normal myeloid cells. PMID- 28676346 TI - Bloodstream infections caused by Acinetobacter species with reduced susceptibility to tigecycline: clinical features and risk factors. AB - INTRODUCTION: During recent decades, the rates of multidrug resistance, including resistance to carbapenems, have increased dramatically among Acinetobacter species. Tigecycline has activity against multidrug-resistant Acinetobacter spp, including carbapenem-resistant isolates. However, reports of tigecycline resistant Acinetobacter spp are emerging from different parts of the world. The purpose of this study was to evaluate potential risk factors associated with tigecycline non-susceptible Acinetobacter bacteremia. METHODS: The medical records of 152 patients with Acinetobacter bacteremia attending Samsung Medical Center between January 2010 and December 2014 were reviewed. Non-susceptibility to tigecycline was defined as a minimum inhibitory concentration (MIC) of tigecycline >=4MUg/ml. Cases were patients with tigecycline non-susceptible Acinetobacter bacteremia and controls were those with tigecycline-susceptible Acinetobacter bacteremia. RESULTS: Of the 152 patients included in the study, 61 (40.1%) had tigecycline non-susceptible Acinetobacter bacteremia (case group). These patients were compared to 91 patients with tigecycline-susceptible Acinetobacter bacteremia (control group). The case group showed high resistance to other antibiotics (>90%) except colistin (6.6%) and minocycline (9.8%) when compared to the control group, which exhibited relatively low resistance to other antibiotics (<50%). Multivariate analysis showed that recent exposure to corticosteroids (minimum 20mg per day for more than 5 days within 2 weeks) (adjusted odds ratio (OR) 2.887, 95% confidence interval (CI) 1.170-7.126) and carbapenems (within 2 weeks) (adjusted OR 4.437, 95% CI 1.970-9.991) were significantly associated with tigecycline non-susceptible Acinetobacter bacteremia. Although prior exposure to tigecycline was more common in the case group than in the control group (9.8%, 6/61 vs. 2.2%, 2/91; p=0.046), this variable was found not to be a significant factor associated with tigecycline non susceptibility after adjustment for other variables (adjusted OR 1.884, 95% CI 0.298-11.920; p=0.501). CONCLUSIONS: These data suggest that tigecycline non susceptible Acinetobacter spp have emerged and disseminated in the hospital in association with a recent exposure to carbapenems and an immunosuppressed state. This indicates that the rational use of antibiotics through a comprehensive antimicrobial stewardship program, especially in immunosuppressed patients, may be essential in limiting the emergence and spread of multidrug-resistant organisms such as tigecycline-resistant Acinetobacter spp, which are difficult to treat. PMID- 28676347 TI - Monotherapy of ceftazidime-avibactam and ceftolozane-tazobactam: two effective antimicrobial agents against multidrug-resistant organisms except for NDM-1 isolates. PMID- 28676348 TI - Monotherapy of ceftazidime-avibactam and ceftolozane-tazobactam against multidrug resistant organisms. PMID- 28676349 TI - Immunoregulatory effect of mast cells influenced by microbes in neurodegenerative diseases. AB - When related to central nervous system (CNS) health and disease, brain mast cells (MCs) can be a source of either beneficial or deleterious signals acting on neural cells. We review the current state of knowledge about molecular interactions between MCs and glia in neurodegenerative diseases such as Multiple Sclerosis, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Epilepsy. We also discuss the influence on MC actions evoked by the host microbiota, which has a profound effect on the host immune system, inducing important consequences in neurodegenerative disorders. Gut dysbiosis, reduced intestinal motility and increased intestinal permeability, that allow bacterial products to circulate and pass through the blood-brain barrier, are associated with neurodegenerative disease. There are differences between the microbiota of neurologic patients and healthy controls. Distinguishing between cause and effect is a challenging task, and the molecular mechanisms whereby remote gut microbiota can alter the brain have not been fully elucidated. Nevertheless, modulation of the microbiota and MC activation have been shown to promote neuroprotection. We review this new information contributing to a greater understanding of MC microbiota-neural cells interactions modulating the brain, behavior and neurodegenerative processes. PMID- 28676350 TI - The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman's disease. AB - Cytokines, including interleukin-6 (IL-6), modulate neuronal plasticity and stress coping. Depressive symptoms and major depressive disorder (MDD) have been associated with changes in cytokines and their signaling. The current study examined the effect of IL-6 monoclonal antibody administration on depressive symptoms in patients with rheumatoid arthritis (RA) or multicentric Castleman's disease (MCD). The data were obtained from two phase 2, double-blind, placebo controlled trials designed to test the efficacy of sirukumab in RA (N=176) or of siltuximab in MCD (N=65), and were analyzed post hoc to investigate the effects of these IL-6 antibodies on depressive symptoms. The SF-36 questionnaire items on depressed-mood and anhedonia were combined as the measure for depressive symptoms. The study participants were grouped by the presence/absence of prevalent depressed mood and anhedonia (PDMA, meaning either depressed mood or anhedonia was present at least 'most of the time' and the other at least 'some of the time' for four weeks) at baseline; 26.1% of the RA sample and 15.4% of the MCD sample met criteria for PDMA at baseline. Compared with placebo, sirukumab and siltuximab produced significantly greater improvements on depressive symptoms. To account for an effect on mood due to changes in RA or MCD, the analysis was (1) adjusted for symptom severities using DAS28-CRP for RA and MCDOS for MCD alone or together with bodily pain and physical functioning, and (2) performed within RA and MCD non-responders. Improvement in depressive symptoms remained significant in the treated group for both drugs. The significance over placebo was also observed in the siltuximab study. The improvement in depressive symptoms by sirukumab correlated positively with the baseline soluble IL-6 receptor levels. The data together suggest that the IL-6 antibodies improve depressive symptoms in patients with RA and MCD. Further studies are needed to elucidate to what extents the IL-6 antibodies improve depressive symptoms through improving primary disease dependent and independent mechanisms, especially in RA patients, and the brain mechanisms underlying depressive symptom improvements. PMID- 28676351 TI - Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice. AB - OBJECTIVES: Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. METHODS: Moderate-level TBI was induced in C57BL/6mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. RESULTS: Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglial-mediated inflammation. CONCLUSION: These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury. PMID- 28676352 TI - Assessment of neuro-optometric rehabilitation using the Developmental Eye Movement (DEM) test in adults with acquired brain injury. AB - PURPOSE: This pilot study sought to determine the efficacy of using the Developmental Eye Movement (DEM) test in the adult, acquired brain injury (ABI) population to quantify clinically the effects of controlled, laboratory performed, oculomotor-based vision therapy/vision rehabilitation. METHODS: Nine adult subjects with mild traumatic brain injury (mTBI) and five with stroke were assessed before and after an eight-week, computer-based, versional oculomotor (fixation, saccades, pursuit, and simulated reading) training program (9.6h total). The protocol incorporated a cross-over, interventional design with and without the addition of auditory feedback regarding two-dimensional eye position. The clinical outcome measure was the Developmental Eye Movement (DEM) test score (ratio, errors) taken before, midway, and immediately following training. RESULTS: For the DEM ratio parameter, improvements were found in 80-89% of the subjects. For the DEM error parameter, improvements were found in 100% of the subjects. Incorporation of the auditory feedback component revealed a trend toward enhanced performance. The findings were similar for both DEM parameters, as well as for incorporation of the auditory feedback, in both diagnostic groups. DISCUSSION: The results of the present study demonstrated considerable improvements in the DEM test scores following the oculomotor-based training, thus reflecting more time-optimal and accurate saccadic tracking after the training. The DEM test should be considered as another clinical test of global saccadic tracking performance in the ABI population. PMID- 28676353 TI - More sensitive correlation of afferent pupillary defect with ganglion cell complex. AB - PURPOSE: This study investigated the correlation between the relative afferent pupillary defect (RAPD) and retinal nerve fiber layer thickness (RNFLT) in optic neuropathy. METHODS: RAPD assessment was performed using a log unit neutral density filter bar. Spectral domain optical coherence tomography RTVue-100 (Optovue) was used to examine the subjects. The optic nerve head pattern (ONH) was subdivided and identified for the purpose of the study into circumpapillary RNFLT (cpRNFLT) and peripheral circumpapillary RNFLT (pcpRNFLT). The cpRNFLT, pcpRNFLT and ganglion cell complex (GCC) parameters were analyzed. RESULTS: Eighteen females and twenty three males with asymmetric optic neuropathy and a RAPD participated. Thirty-three subjects had glaucoma and eight had optic neuropathy other than glaucoma. Significant correlations (p<0.02) were obtained for the RAPD and the percentage difference loss of the GCC and RNFLT parameters. The grouped mean percentage difference loss for RNFLT was significantly different from that of the GCC (p<0.001). At a 0.6log unit RAPD, the average mean percentage difference loss was 23% for the CRNFLT, 15% for the GCC, 12% for the global loss volume percentage and 6% for the focal loss volume percentage (FLV%). CONCLUSIONS: Significant correlations between RNFLT loss for cpRNFLT, pcpRNFLT and GCC parameters with RAPD were observed. Approximately a 35% higher sensitivity was obtained using GCC compared to CRNFL parameters. The expected change in GCC average for every 0.3log unit increment was approximately 8.49MUm. The FLV% corresponded more sensitively to a RAPD but appeared to be influenced by disease severity. PMID- 28676354 TI - Cry46Ab from Bacillus thuringiensis TK-E6 is a new mosquitocidal toxin with aerolysin-type architecture. AB - Cry46Ab is a Cry toxin derived from Bacillus thuringiensis TK-E6. Cry46Ab is not significantly homologous to other mosquitocidal Cry or Cyt toxins and is classified as an aerolysin-type pore-forming toxin based on structural similarity. In this study, the potency of Cry46Ab was assessed for its potential application to mosquito control. A synthetic Cry46Ab gene, cry46Ab-S1, was designed to produce recombinant Cry46Ab as a glutathione-S-transferase fusion in Escherichia coli. Recombinant Cry46Ab showed apparent toxicity to Culex pipiens larvae, with a 50% lethal dose of 1.02 MUg/ml. In an artificial lipid bilayer, Cry46Ab activated by trypsin caused typical current transitions between open and closed states, suggesting it functions as a pore-forming toxin similar to other Cry and Cyt toxins. The single-channel conductance was 103.3 +/- 4.1 pS in 150 mM KCl. Co-administration of recombinant Cry46Ab with other mosquitocidal Cry toxins, especially the combination of Cry4Aa and Cry46Ab, resulted in significant synergistic toxicity against C. pipiens larvae. Co-administration of multiple toxins exhibiting different modes of action is believed to prevent the onset of resistance in insects. Our data, taken in consideration with the differences in its structure, suggest that Cry46Ab could be useful in not only reducing resistance levels but also improving the insecticidal activity of Bt-based bio insecticides. PMID- 28676356 TI - BmCHSA-2b, a Lepidoptera specific alternative splicing variant of epidermal chitin synthase, is required for pupal wing development in Bombyx mori. AB - Insect chitin synthase A (CHSA) is an epidermis-specific enzyme that plays an essential role in insect development. In this study, the function and regulation of CHSA-2b, an alternative splicing variant of Bombxy mori CHSA that is discovered only in Lepidopteran insects, were investigated. Analysis of mRNA level showed that BmCHSA-2b was responsive to 20-hydroxyecdysone (20E) in pupal wing unlike BmCHSA-2a, which shares almost the identical sequence as BmCHSA-2b except the first 31 amino acids, suggesting that the expression of these two alternative splicing variants is driven by different promoters of CHSA gene. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis showed that BmCHSA-2b was up-regulated in the wing of mid-pupa unlike BmCHSA-2a, which was up-regulated in epidermis and wing disc at the beginning and end of pupal stage. Further analysis reveals that the up-regulations of BmCHSA-2a and BmCHSA-2b in pupal wing were consistent with the increase of chitin content and wing area at the same stages, respectively. Furthermore, the higher transcription level of BmCHSA-2b in the mid-pupal wing of male than that in female was consistent with the chitin content of pupal wing between genders. Injection of double-stranded RNAs of BmCHSA-2b resulted in the decrease in the area and chitin content of the wing, and irregular and crimpled vein. All these results together suggest that B. mori evolves an extra promoter in CHSA gene to activate BmCHSA-2b expression in the wing of mid-pupal stage in response to 20E, and BmCHSA-2b is required for the wing development in the mid-pupa of B. mori. PMID- 28676357 TI - Pelvic Pain: An Overview. AB - Although the cause of chronic pelvic pain (CPP) is multifactorial, a substantial number of cases have musculoskeletal and neuromuscular causes. Multiple stakeholders, including physicians with varying degrees of pain training ranging from primary care physicians, obstetricians, gynecologists, urologists, neurologists, gastroenterologists, psychologists, physical therapists, and physiatrists, are involved in the care of these patients. Physiatrists play a pivotal role in the treatment of patients with CPP because their training focuses on improving quality of life through a holistic approach to patient management and on the musculoskeletal and neuromuscular systems. PMID- 28676355 TI - nanos-Driven expression of piggyBac transposase induces mobilization of a synthetic autonomous transposon in the malaria vector mosquito, Anopheles stephensi. AB - Transposons are a class of selfish DNA elements that can mobilize within a genome. If mobilization is accompanied by an increase in copy number (replicative transposition), the transposon may sweep through a population until it is fixed in all of its interbreeding members. This introgression has been proposed as the basis for drive systems to move genes with desirable phenotypes into target species. One such application would be to use them to move a gene conferring resistance to malaria parasites throughout a population of vector mosquitos. We assessed the feasibility of using the piggyBac transposon as a gene-drive mechanism to distribute anti-malarial transgenes in populations of the malaria vector, Anopheles stephensi. We designed synthetic gene constructs that express the piggyBac transposase in the female germline using the control DNA of the An. stephensi nanos orthologous gene linked to marker genes to monitor inheritance. Two remobilization events were observed with a frequency of one every 23 generations, a rate far below what would be useful to drive anti-pathogen transgenes into wild mosquito populations. We discuss the possibility of optimizing this system and the impetus to do so. PMID- 28676358 TI - Anatomy and Physiology of the Pelvic Floor. AB - Understanding the anatomic relationship of the pelvic floor muscles with the pelvic girdle, spine, and hips aids the rehabilitation provider in diagnosis, management, and appropriate referrals. The bony anatomy of the pelvic girdle consists of 3 bones and 3 joints. The pelvic floor muscles are comprised mainly of the levator ani muscles with somatic innervation from the lumbosacral plexus. The bony and muscular pelvis is highly interconnected to the hip and gluteal musculature, which together provide support to the internal organs and core muscles. Pelvic floor physiology is centered on bladder and bowel control, sexual functioning, and pregnancy. PMID- 28676359 TI - Office Evaluation of Pelvic Pain. AB - The history and physical examination are important keys to diagnosis and treatment of patients with chronic pelvic pain. The comprehensive history should include questioning regarding patient's pain complaint and a thorough history and review of any body system that may be involved, including neuromusculoskeletal, obstetric, gynecologic, gastrointestinal, urologic, dermatologic, infectious, oncologic, and psychiatric. The physical examination should also follow a focused systems-based approach and includes examination of gastrointestinal, dermatologic, neurologic, and musculoskeletal (including lumbosacral spine, sacroiliac joints, pelvis, and hips) systems, and the pelvic floor (internal and external examination, including neuromuscular anatomy). PMID- 28676361 TI - Myofascial Pelvic Pain and Related Disorders. AB - Myofascial pelvic pain refers to pain in the pelvic floor muscles, the pelvic floor connective tissue, and the surrounding fascia. The cause is often multifactorial and requires treatment that encompasses multiple modalities. This type of pain is often associated with other abdominopelvic disorders, so providers in these specialties need to be aware of these connections. A comprehensive musculoskeletal examination, including evaluation of the pelvic floor muscles, and history are key to diagnosing myofascial pelvic pain. Treatments include physical therapy, muscle relaxers, oral neuromodulators, cognitive-behavioral therapy, and pelvic floor muscle injections. PMID- 28676360 TI - Diagnostic Evaluation of Chronic Pelvic Pain. AB - Chronic pelvic pain can result from various intra- and extra-pelvic etiologies. Although patient history and physical examination may narrow the differential diagnosis, frequently, the different etiologies have overlapping presentations. Imaging examinations such as US and/or MR imaging may help delineate the cause of pain, particularly when related to intra-pelvic organs, pelvic floor dysfunction or prolapse, synthetic material such as pelvic mesh or slings, and in some cases of neuropathic pain. Etiologies of neuropathic pain can also be assessed with non imaging tests such as nerve conduction studies, electromyography, and testing of sacral reflexes. PMID- 28676362 TI - Musculoskeletal Approach to Pelvic Pain. AB - Visceral and somatic causes of pelvic pain are often inter-related, and a musculoskeletal examination should always be considered for the successful diagnosis and treatment of pelvic pain. For the diverse etiologies of hip pain, there are many unique considerations for the diagnosis and treatment of these various disorders. Pelvic pain is often multidimensional due to the overlap between lumbo-hip-pelvic diagnoses and may require a multidisciplinary approach to evaluation and management. PMID- 28676363 TI - Coccydynia: Tailbone Pain. AB - Coccyx (tailbone) pain substantially decreases the quality of life for patients who suffer with this condition. Classic symptoms include midline pain located below the sacrum and above the anus. Symptoms are worse while sitting or during transitions from sitting to standing. Physical examination typically reveals focal tenderness during palpation of the coccyx. Diagnostic tests include radiographs. Advanced studies may include MRI, computerized tomography scans, or nuclear medicine bone scans. Treatments may include the use of cushions, medications by mouth, topical medications, local pain management injections, pelvic floor physical therapy, and (in rare cases) surgical removal of the coccyx (coccygectomy). PMID- 28676364 TI - Neurogenic Pelvic Pain. AB - Pelvic neuralgias frequently cause severe pain and may have associated bladder, bowel, or sexual dysfunctions which also impact quality of life. This article explores the etiology, epidemiology, presentation and treatment of common causes of neurogenic pelvic pain, including neuralgia of the border nerves (ilioinguinal, iliohypogastric, and genitofemoral), pudendal neuralgia, clunealgia, sacral radiculopathies caused by Tarlov cysts, and cauda equina syndrome. Treatment of pelvic neuralgia includes conservative measures such as pelvic physical therapy, lifestyle modification, and medications with escalation to more invasive and novel treatments such as nerve blocks, radiofrequency ablation, cryoablation, neuromodulation and neurectomy/neurolysis if conservative treatments are ineffective. PMID- 28676365 TI - Urologic and Gynecologic Sources of Pelvic Pain. AB - Gynecologic and urologic etiologies are the sources of pelvic pain for many individuals. This article aims to provide a comprehensive review of the various genitourinary sources of pelvic pain. It is important to recognize that although these disorders predominantly affect women, there are various conditions that affect both men and women, and these should be considered in the differential diagnosis of patients presenting with pelvic pain. Providers who encounter patients with pelvic pain should attempt to localize these symptoms and obtain a comprehensive history from the patient to help direct diagnostic evaluation. PMID- 28676366 TI - Physical Therapy Treatment of Pelvic Pain. AB - Physical therapists offer a valuable service in the treatment of chronic pelvic pain (CPP). Physical therapists are trained in functional restoration of the whole body. The physical therapist is in the unique position to assess and treat CPP in restoration of transitional movement ease and tolerance for improved functional control with the ultimate goal of wellness. It is imperative that pelvic floor muscle overactivity, underactivity, or a combination there of is accurately assessed and treated to avoid exacerbation of symptoms. The physical therapist has treatment options to restore the function with education in independent management of CPP. PMID- 28676367 TI - Iatrogenic Pelvic Pain: Surgical and Mesh Complications. AB - Female stress urinary incontinence and pelvic organ prolapse are prevalent conditions in adult women. Among treatment alternatives, more traditional methods of surgical intervention have been supplanted by synthetic polypropylene mesh kits. However, novel complications with mesh-related exposure, pelvic pain alone or with dyspareunia, and increased incidence of revision surgeries, resulted in 2 FDA warnings on transvaginal mesh use for prolapse repair. This review examines the anatomy of the vagina and urethra, the etiology of pain related to mesh use, and the relevant surgical techniques for management of this complication along with their outcomes. PMID- 28676368 TI - Interventional Management for Pelvic Pain. AB - Interventional procedures can be applied for diagnostic evaluation and treatment of the patient with pelvic pain, often once more conservative measures have failed to provide relief. This article reviews interventional management strategies for pelvic pain. We review superior and inferior hypogastric plexus blocks, ganglion impar blocks, transversus abdominis plane blocks, ilioinguinal, iliohypogastric and genitofemoral blocks, pudendal nerve blocks, and selective nerve root blocks. Additionally, we discuss trigger point injections, sacroiliac joint injections, and neuromodulation approaches. PMID- 28676369 TI - Foreword. PMID- 28676370 TI - Pelvic Pain. PMID- 28676372 TI - Computerized modeling of the human heart. PMID- 28676371 TI - Modeling tumor control probability for spatially inhomogeneous risk of failure based on clinical outcome data. AB - PURPOSE: Objectives of this work are (1) to derive a general clinically relevant approach to model tumor control probability (TCP) for spatially variable risk of failure and (2) to demonstrate its applicability by estimating TCP for patients planned for photon and proton irradiation. METHODS AND MATERIALS: The approach divides the target volume into sub-volumes according to retrospectively observed spatial failure patterns. The product of all sub-volume TCPi values reproduces the observed TCP for the total tumor. The derived formalism provides for each target sub-volume i the tumor control dose (D50,i) and slope (gamma50,i) parameters at 50% TCPi. For a simultaneous integrated boost (SIB) prescription for 45 advanced head and neck cancer patients, TCP values for photon and proton irradiation were calculated and compared. The target volume was divided into gross tumor volume (GTV), surrounding clinical target volume (CTV), and elective CTV (CTVE). The risk of a local failure in each of these sub-volumes was taken from the literature. RESULTS: Convenient expressions for D50,i and gamma50,i were provided for the Poisson and the logistic model. Comparable TCP estimates were obtained for photon and proton plans of the 45 patients using the sub-volume model, despite notably higher dose levels (on average +4.9%) in the low-risk CTVE for photon irradiation. In contrast, assuming a homogeneous dose response in the entire target volume resulted in TCP estimates contradicting clinical experience (the highest failure rate in the low-risk CTVE) and differing substantially between photon and proton irradiation. CONCLUSIONS: The presented method is of practical value for three reasons: It (a) is based on empirical clinical outcome data; (b) can be applied to non-uniform dose prescriptions as well as different tumor entities and dose-response models; and (c) is provided in a convenient compact form. The approach may be utilized to target spatial patterns of local failures observed in patient cohorts by prescribing different doses to different target regions. Its predictive power depends on the uncertainty of the employed established TCP parameters D50 and gamma50 and to a smaller extent on that of the clinically observed pattern of failure risk. PMID- 28676373 TI - Middle age exacerbates acute respiratory distress syndrome in a double hit murine model. AB - RATIONALE: In a recent systematic review, aging has been identified as the only factor independently associated with mortality during human acute respiratory distress syndrome (ARDS). We explored this age-dependent severity in a clinically relevant double hit murine ARDS model. METHODS: Young adult (Y, 10-12weeks) and middle-old (O, 12-13months) male C57BL6 mice underwent an aspiration of Escherichia coli lipopolysaccharide (LPS) or control saline vehicle. Twenty hours later, four groups of mice were sacrificed [Y(control), O(control), Y(LPS) and O(LPS)]. Four other groups of mice underwent 3h of low tidal volume (8mL/kg) mechanical ventilation (MV) [Y(MV), O(MV), Y(LPS+MV) and O(LPS+MV)]. Lung mechanics were assessed hourly during MV. Right ventricular pressure and cardiac output were measured at the end of the MV. After sacrifice, lung inflammation, edema and injury were explored with bronchoalveolar lavage (BAL) and histology. RESULTS: After saline aspiration, middle-old mice had a higher respiratory system compliance than young adult mice. LPS aspiration dramatically altered the baseline compliance in middle-old (O(LPS)), but not in young adult (Y(LPS)) mice. Middle-old mice had a more pronounced alteration in lungs mechanics during MV as compared to young adult mice. Lung inflammation (as assessed by the total cell count, IL-6, TNFalpha and MIP-2 concentrations in BAL fluid), systemic inflammation (as assessed by plasma IL-6 concentration) and alveolocapillary leak (as assessed by the total protein concentration of BAL fluid) were higher in O(LPS) and O(LPS+MV) mice as compared to Y(LPS) and Y(LPS+MV) mice, respectively. The combination of LPS+MV induced a higher lung injury as compared to LPS alone in middle-old mice but not in young adult mice. Hemodynamics (systemic blood pressure, cardiac output and pulmonary vascular resistances) were similar between Y(MV) and O(MV) on the one hand and between Y(LPS+MV) and O(LPS+MV) on the other hand. CONCLUSION: Middle-old mice were more susceptible to both LPS alone and the combination of LPS and low tidal volume MV as compared to their young adult counterparts. The synergism between LPS and MV was amplified in middle-old mice. PMID- 28676374 TI - Reduced Incidence of Intraoperative Femur Fracture With a Second-Generation Tapered Wedge Stem. AB - BACKGROUND: Intraoperative fractures during total hip arthroplasty (THA) are more common when using cementless stems. The purpose of this study was to investigate the impact of a new shorter second-generation cementless, tapered wedge stem with improved proximal femoral fit in reducing the incidence of intraoperative fracture. METHODS: A retrospective study was conducted on primary THA cases performed at a single institution using a first-generation or second-generation cementless stem from 2006-2016. All intraoperative femur fractures were identified, as well as early 30-day postoperative periprosthetic femur fractures, which could represent nondisplaced intraoperative fractures that were initially missed. Risk for intraoperative femur fracture was analyzed using logistic regression, accounting for demographic covariates and surgeon. RESULTS: Of 6473 primary THA performed with a cementless, tapered wedge stem during the study period, 3126 used a first-generation stem and 3347 used a second-generation stem. The incidence of intraoperative fracture was 1.79% for first-generation stems and 0.24% for second-generation stems, representing a 7.5-fold reduction of risk for fracture. After accounting for covariates, the odds of intraoperative fracture were 0.33 using the second-generation stem relative to the first-generation stem (P = .01). However, there was no significant difference in the odds of early 30 day postoperative fractures using the second-generation stem (odds ratio 0.93, P = .56). CONCLUSION: A new second-generation cementless stem resulted in a 7.5 fold decrease in the incidence of intraoperative femur fracture compared with the preceding stem. PMID- 28676375 TI - The family of berberine bridge enzyme-like enzymes: A treasure-trove of oxidative reactions. AB - Biological oxidations form the basis of life on earth by utilizing organic compounds as electron donors to drive the generation of metabolic energy carriers, such as ATP. Oxidative reactions are also important for the biosynthesis of complex compounds, i.e. natural products such as alkaloids that provide vital benefits for organisms in all kingdoms of life. The vitamin B2 derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) enable an astonishingly diverse array of oxidative reactions that is based on the versatility of the redox-active isoalloxazine ring. The family of FAD linked oxidases can be divided into subgroups depending on specific sequence features in an otherwise very similar structural context. The sub-family of berberine bridge enzyme (BBE)-like enzymes has recently attracted a lot of attention due to the challenging chemistry catalyzed by its members and the unique and unusual bi-covalent attachment of the FAD cofactor. This family is the focus of the present review highlighting recent advancements into the structural and functional aspects of members from bacteria, fungi and plants. In view of the unprecedented reaction catalyzed by the family's namesake, BBE from the California poppy, recent studies have provided further insights into nature's treasure chest of oxidative reactions. PMID- 28676376 TI - Cutaneous inflammation regulates THIK1 expression in small C-like nociceptor dorsal root ganglion neurons. AB - Tandem pore-domain Halothane Inhibited K+ channel (THIK1) is a two-pore-domain potassium channel (K2P) present in dorsal root ganglia (DRG). We previously demonstrated that THIK1 mRNA levels in the DRG dropped ipsilaterally 1day after CFA-induced cutaneous inflammation (CFA1). In this study we aimed to identify the currently unknown DRG subpopulations expressing THIK1, and to investigate the relationship between the channel and both inflammatory and spontaneous pain in normal rats. Using a combination of immunohistochemistry, western blotting and behavioural tests, we found that all small neurons and large groups of medium and large DRG neurons express THIK1. Myelinated and unmyelinated fibers, nerve endings in the skin and lamina I and II of the spinal cord also express the channel. THIK1 staining co-localizes with IB4-binding and trkA suggesting that the channel is expressed by nociceptors. At CFA1, both cytoplasmic and edge (membrane-associated) THIK1 staining were significantly reduced only in small neurons ipsilaterally compared to normal. At 4days after inflammation (CFA4), edge THIK1 staining levels in small neurons decreased bilaterally compared to normal. Medium and large size DRG neurons showed no change in THIK1 expression either at CFA1 or CFA4. Ipsilateral (but not contralateral) mean %intensities of THIK1 in small neurons at CFA1 correlated strongly negatively with spontaneous foot lifting (SFL) duration (a marker of spontaneous pain). Thus, nociceptors express THIK1 that can be regulated by cutaneous inflammation. Finally, in vivo siRNA knockdown of THIK1 resulted in longer SFL duration than siRNA scramble treated rats. Taken together our evidence suggests a potential involvement for THIK1 in pain processing following inflammation. PMID- 28676377 TI - Is there a connection between postprandial hyperglycemia and IGT related sensory nerve dysfunction? AB - BACKGROUND AND AIMS: To assess the risk factors for sensory nerve dysfunction in subjects with isolated impaired glucose tolerance (IGT). METHODS AND RESULTS: Seventy-two people with isolated IGT (WHO 1999 criteria) and 39 gender and age matched healthy volunteers underwent detailed clinical and neurological assessment including quantitative sensory testing using the Neurometer device (current perception threshold measurement on four limbs at three different frequencies). Sensory nerve dysfunction was defined as at least two abnormalities on any frequencies on the upper or lower limbs. Sensory nerve dysfunction was more prevalent among subjects with IGT compared to controls (58.3 vs. 10.3%, OR: 11.23, 95%CI: 3.57-35.35). This association was not influenced by BMI, systolic and diastolic blood pressure, heart rate and autonomic neuropathy (multiple adjusted OR: 13.87, 95%CI: 3.18-60.58), but further adjustment for glycaemic measures abolished the association (OR: 1.58, 95%CI: 0.07-35.68). Assessing the components of glycaemic measures separately, the association between sensory nerve dysfunction and IGT was not affected by HbA1c (OR: 13.94, 95%CI: 1.84 105.5). It was, however, substantially attenuated by fasting plasma glucose (OR: 6.75, 95%CI: 1.33-34.27) while the significance was lost after adjustment for 120 min postload glucose level (OR: 3.76, 95%CI: 0.26-54.10). In the pooled population assessed, independent determinants of sensory nerve dysfunction were older age, 120 min glucose, higher height and cardiovascular autonomic neuropathy at near significance. CONCLUSIONS: Sensory nerve dysfunction amongst subjects with IGT was not explained by cardiovascular covariates, only by glycaemic measures. In addition to 120 min glucose, cardiovascular autonomic neuropathy at borderline significance, age, and height were the independent determinants of sensory nerve dysfunction. PMID- 28676378 TI - Fitness costs and inheritance of Cry2Ab2 resistance in Spodoptera frugiperda (J.E. Smith). AB - Cry2Ab2 is a Bacillus thuringiensis (Bt) protein expressed in transgenic corn and cotton targeting above-ground lepidopteran pests including the fall armyworm, Spodoptera frugiperda (J.E. Smith). The objective of this study was to characterize fitness costs and inheritance of Cry2Ab2 resistance in S. frugiperda. To determine if fitness costs were associated with the resistance, life history parameters (larval survival, growth, development and egg production) of Cry2Ab2-resistant, -susceptible, and two reciprocal F1 colonies of S. frugiperda were assayed on non-toxic diet and non-Bt corn leaf tissue. The results showed that there were no significant differences among the four insect colonies for all the biological parameters measured with few exceptions, suggesting that the resistance in the colony was not associated with significant fitness costs in the test conditions. To examine the inheritance of resistance, susceptibilities of the resistant and susceptible parents, as well as eight additional colonies generated from various genetic crosses, were assayed using Cry2Ab2-treated diet and Cry2Ab2 corn leaf tissue. The Cry2Ab2 resistance in S. frugiperda in the colony was inherited as a single autosomal recessive or incompletely recessive gene. The results of the study suggest a potential risk of resistance development in S. frugiperda to the Cry2Ab2 protein and thus effective management strategies should be implemented for the sustainable use of the Bt corn technology for pest management. PMID- 28676379 TI - Effects of nutrient and water restriction on thermal tolerance: A test of mechanisms and hypotheses. AB - Nutritional deprivation or desiccation can influence thermal tolerance by impacting the insects' ability to evaporatively cool, maintain cell membrane integrity and conduct protective or repair processes. Recovery from chilling is also linked to the re-establishment of iono- and osmo-regulatory homeostasis. Here, using Mediterranean fruit fly (Ceratitis capitata, Diptera: Tephritidae), we manipulated water and nutrient availability to test the mechanistic expectation that changes in whole organism lipid and water content can elicit variation in cold or heat tolerance (scored as chill coma recovery time and heat knockdown time). We measured body condition (body water and lipid content) as well as heat shock protein 70 gene (hsp70) and protein (HSP70) levels. A significant reduction in body water content with water restriction did not translate into differences in chill coma recovery. When nutrient restriction was coupled with water deprivation, this resulted in a significant reduction (-54%) of heat knockdown time in females but male flies were unaffected. There was no evidence for an hsp70 or HSP70 response under any of the stress treatments and therefore no correlation with heat or cold tolerance. Heat hardening decreased all hsp levels. Therefore, although body water and total body lipid content differed between the treatment groups, the contribution of these factors to thermal tolerance was inconsistent with mechanistic expectations in heat knockdown time and insignificant for chill coma recovery. These results therefore highlight that the effects of resource restriction on thermal limits in insects are mechanistically more complex than previous models of stress resistance have suggested. PMID- 28676380 TI - Investigation of the biodistribution, breakdown and excretion of delta inulin adjuvant. AB - Insoluble, nanostructured delta inulin particles enhance the immunogenicity of co administered protein antigens and consequently are used as a vaccine adjuvant (AdvaxTM). To better understand their immunomodulatory properties, the in vitro hydrolysis and in vivo distribution of delta inulin particles were investigated. Delta inulin particle hydrolysis under bio-relevant acidic conditions resulted in no observable change to the bulk morphology using SEM, and HPLC results showed that only 6.1% of the inulin was hydrolysed over 21days. However, 65% of the terminal glucose groups were released, showing that acid hydrolysis relatively rapidly releases surface bound chemistries. This was used to explain in vivo biodistribution results in which delta inulin particles surface-labelled with fluorescein-5-thiosemicabizide were administered to mice using intramuscular (I.M.) or subcutaneous (S.C.) routes. Comparison analysis of the fluorescence of soluble inulin in the supernatants of homogenised tissues maintained at room temperature or heated to 100 degrees C to solubilise particulate inulin was used to distinguish between fluorescent probe on soluble inulin and probe bound to inulin within particles. Following both I.M. and S.C. injection delta inulin exhibited a depot behaviour with local injection site residence for several weeks. Over this time, as injection site inulin reduced, there was measurable transport of intact delta inulin particles by macrophages to secondary lymphoid organs and the liver. Ultimately, the injected delta inulin became solubilised resulting in its detection in the plasma and in the urine. Thus injected delta inulin particles are initially taken up by macrophages at the site of injection, trafficked to secondary lymphoid tissue and the liver, and hydrolysed resulting in their becoming soluble and diffusing into the blood stream, from whence they are glomerularly filtered and excreted into the urine. These results provide important insights into the biodistribution of I.M. or S.C. injected delta inulin particles when used as vaccine adjuvants and their method of excretion. PMID- 28676381 TI - Knowledge of influenza vaccination recommendation and early vaccination uptake during the 2015-16 season among adults aged >=18years - United States. AB - BACKGROUND: Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended that all persons aged >=6months receive annual influenza vaccination. METHODS: We analyzed data from the 2015 National Internet Flu Survey (NIFS), to assess knowledge and awareness of the influenza vaccination recommendation and early influenza vaccination coverage during the 2015-16 season among adults. Predictive marginals from a multivariable logistic regression model were used to identify factors independently associated with adults' knowledge and awareness of the vaccination recommendation and early vaccine uptake during the 2015-16 influenza season. RESULTS: Among the 3301 respondents aged >=18years, 19.6% indicated knowing that influenza vaccination is recommended for all persons aged >=6months. Of respondents, 62.3% indicated awareness that there was a recommendation for influenza vaccination, but did not indicate correct knowledge of the recommended age group. Overall, 39.9% of adults aged >=18years reported having an influenza vaccination. Age 65years and older, being female, having a college or higher education, not being in work force, having annual household income >=$75,000, reporting having received an influenza vaccination early in the 2015-16 season, having children aged <=17years in the household, and having high risk conditions were independently associated with a higher correct knowledge of the influenza vaccination recommendation. CONCLUSIONS: Approximately 1 in 5 had correct knowledge of the recommendation that all persons aged >=6months should receive an influenza vaccination annually, with some socio-economic groups being even less aware. Clinic based education in combination with strategies known to increase uptake of recommended vaccines, such as patient reminder/recall systems and other healthcare system-based interventions are needed to improve vaccination, which could also improve awareness. PMID- 28676382 TI - New perspectives for hexavalent vaccines. AB - With the increase in the number of routine vaccinations the development of pentavalent and hexavalent combination vaccines fitting the routine vaccination schedules became a necessity. In this respect, Europe has taken the lead in comparison with other world regions, and routine vaccination with pentavalent and hexavalent combinations including DTPa, Hib, HepB and IPV has been on European vaccination programs for >15years. Since the marketing authorization of Hexavac(r) and Infanrix Hexa(r) in 2000, immunization schedules in most European countries have included hexavalent vaccines. In the last years, two new hexavalent vaccines have been licensed and commercialized worldwide. This paper presents a review of the pharmaceutical profiles of the three hexavalent vaccines currently available. In addition, we aim to review safety, co-administration, tolerability and other practical concerns of their use. PMID- 28676383 TI - Hepatectomy after down-staging of hepatocellular carcinoma with portal vein tumor thrombus using chemoradiotherapy: A retrospective cohort study. AB - BACKGROUND: This study evaluates the survival benefit and safety of hepatectomy after down-staging by 3-dimensional conformal radiation therapy (3D-CRT) for major portal vein tumor thrombus (PVTT) combined with hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC). METHODS: Fifty two patients with unresectable advanced HCC treated with HAIC combined with 3D CRT for PVTT, from January 2002 to March 2015, were analyzed in this retrospective study. Hepatectomy was offered to patients if, based on radiologic findings, all gross lesions were considered resectable. The safety of hepatectomy was investigated and overall survival (OS) was compared between the resection group (n = 7) and non-resection group (n = 43). RESULTS: OS was significantly higher in the resection group than in the non-resection group. Results of multivariate analysis identified conversion to surgery (hazard ratio, 0.35; 95% confidence interval, 0.10-0.99; P = 0.048) as an independent factor influencing OS. There were no serious postoperative complications and no case of mortality in patients who underwent hepatectomy. CONCLUSIONS: Our findings suggest that hepatectomy after down-staging by 3D-CRT for PVTT combined with HAIC for advanced HCC is safe and results in good long term outcome. PMID- 28676384 TI - The efficiency, accuracy and acceptability of smartphone-delivered data collection in a low-resource setting - A prospective study. AB - Smartphones are increasingly used in healthcare, yet little is known about their utility in medical research as a means of data collection in low- and middle income countries (LMIC). In this letter, we discuss results from our experiences with data collection on smartphones in an LMIC setting. Our experience found smartphones a secure and reliable data collection tool for medical research that can empower researchers in countries to participate in surgical studies. PMID- 28676385 TI - Syncope workup: Greater yield in select trauma population. AB - BACKGROUND: There is great variation in practice regarding the assessment of trauma patients who present with syncope. The purpose of this study was to determine the yield of screening studies (electrocardiogram, echocardiogram, and carotid duplex) and define characteristics to identify groups that may benefit from these investigations. METHODS: We conducted a retrospective cohort study of all trauma patients from 2003 to 2015 who received a carotid duplex as part of a syncope evaluation at our urban Level 1 Trauma Center. Demographics, clinical findings as well as interventions undertaken (ie: placement of defibrillators/pacemakers) as a result of the syncope evaluation were collected. Data analysis was performed with STATA 14 and relationships between comorbidities, positive findings and interventions were assessed. Significance was assumed for p < 0.05. RESULTS: 736 trauma patients were included in the study. The most common mechanism of injury was fall (592, 82%). A history of congestive heart failure (CHF) and/or coronary artery disease (CAD) and age >= 65 were significantly associated with abnormal ECG and ECHO findings, but not with severe carotid stenosis. Elevated Injury Severity Scale (ISS) was significantly associated with an abnormal ECHO on both univariate and multivariate analysis. An abnormal ECG was predictive of an abnormal ECHO (p = 0.02). Ten patients (1.4%) underwent placement of a defibrillator and/or pacemaker, all of whom reported having CHF. Only 11 patients (1.7%) had severe carotid stenosis (>70%) requiring intervention. CONCLUSION: The screening studies used in a syncope evaluation have low yield in the general trauma population. Carotid duplex should not be routinely performed. Cardiac evaluation should be tailored to individuals with cardiac comorbidities, older age and elevated ISS. An ECG should be used as initial screening in this patient cohort. PMID- 28676386 TI - Prodrugs in medicinal chemistry and enzyme prodrug therapies. AB - Prodrugs are cunning derivatives of therapeutic agents designed to improve the pharmacokinetics profile of the drug. Within a prodrug, pharmacological activity of the drug is masked and is recovered within the human body upon bioconversion of the prodrug, a process that is typically mediated by enzymes. This concept is highly successful and a significant fraction of marketed therapeutic formulations is based on prodrugs. An advanced subset of prodrugs can be engineered such as to achieve site-specific bioconversion of the prodrug - to comprise the highly advantageous "enzyme prodrug therapy", EPT. Design of prodrugs for EPT is similar to the prodrugs in general medicinal use in that the pharmacological activity of the drug is masked, but differs significantly in that site-specific bioconversion is a prime consideration, and the enzymes typically used for EPT are non mammalian and/or with low systemic abundance in the human body. This review focuses on the design of prodrugs for EPT in terms of the choice of an enzyme and the corresponding prodrug for bioconversion. We also discuss the recent success of "self immolative linkers" which significantly empower and diversify the prodrug design, and present methodologies for the design of prodrugs with extended blood residence time. The review aims to be of specific interest for medicinal chemists, biomedical engineers, and pharmaceutical scientists. PMID- 28676387 TI - Application of Lean Healthcare methodology in a urology department of a tertiary hospital as a tool for improving efficiency. AB - OBJECTIVE: To describe the application of the Lean methodology as a method for continuously improving the efficiency of a urology department in a tertiary hospital. MATERIAL AND METHODS: The implementation of the Lean Healthcare methodology in a urology department was conducted in 3 phases: 1) team training and improvement of feedback among the practitioners, 2) management by process and superspecialisation and 3) improvement of indicators (continuous improvement). The indicators were obtained from the Hospital's information systems. The main source of information was the Balanced Scorecard for health systems management (CUIDISS). The comparison with other autonomous and national urology departments was performed through the same platform with the help of the Hospital's records department (IASIST). A baseline was established with the indicators obtained in 2011 for the comparative analysis of the results after implementing the Lean Healthcare methodology. RESULTS: The implementation of this methodology translated into high practitioner satisfaction, improved quality indicators reaching a risk-adjusted complication index (RACI) of 0.59 and a risk-adjusted mortality rate (RAMR) of 0.24 in 4 years. A value of 0.61 was reached with the efficiency indicator (risk-adjusted length of stay [RALOS] index), with a savings of 2869 stays compared with national Benchmarking (IASIST). The risk-adjusted readmissions index (RARI) was the only indicator above the standard, with a value of 1.36 but with progressive annual improvement of the same. CONCLUSIONS: The Lean methodology can be effectively applied to a urology department of a tertiary hospital to improve efficiency, obtaining significant and continuous improvements in all its indicators, as well as practitioner satisfaction. Team training, management by process, continuous improvement and delegation of responsibilities has been shown to be the fundamental pillars of this methodology. PMID- 28676388 TI - Four new neolignans isolated from Eleutherococcus senticosus and their protein tyrosine phosphatase 1B inhibitory activity (PTP1B). AB - Four new compounds, erythro-7'E-4-hydroxy-3,3'-dimethoxy-8,5'-oxyneoligna-7'-ene 7,9-diol-9'-al (1), (7S,8S)-4-hydroxy-3,1',3'-trimethoxy-4',7-epoxy-8,5'-neolign 9-ol (5), (7S,8S,7'E)-5-hydroxy-3,3'-dimethoxy-4',7-epoxy-8,5'-neolign-7'-ene 9,9'-diol (6) and (7S,8S,7'E)-5-hydroxy-3,3',9'-trimethoxy-4'-7-epoxy-8,5' neolign-7'-ene-9-ol (7). Along with four known compounds (2-4, 8) were isolated from the EtOAc-soluble extract of Eleutherococcus senticosus. Their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the compounds were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, compounds 1-4 and 6-8 were found to exhibit selective inhibitory activity on PTP1B with IC50 values ranging from 17.2+/-1.6 to 32.7+/ 1.2MUM. PMID- 28676389 TI - De-escalating and escalating treatment beyond endocrine therapy in patients with luminal breast cancer. AB - Luminal breast cancers demonstrate significant molecular and clinical heterogeneity, despite the commonality of shared expression of the estrogen receptor (ER). To date, no clinical trial has prospectively investigated the optimal chemotherapy regime according to luminal type, highlighting a paucity of data furthermore required to guide treatment decisions. Current methods of predicting advantage from adjuvant chemotherapy lack refinement and can over estimate the risk of relapse, inevitably leading to a proportion of patients being unnecessarily exposed to chemotherapy. This paper will explore the evidence behind modalities which may add further value to existing known clinicopathological and molecular profiling techniques in predicting clinical benefit from chemotherapy. Adjuvant chemotherapy regime choice in the context of early luminal breast cancer types will be discussed, and areas for further research and debate identified. PMID- 28676390 TI - Effects of bisphenol A analogues on reproductive functions in mice. AB - This study was performed to examine whether bisphenol (BP) A analogues, BPE and BPS, negatively impacts reproductive functions using mice as a model. CD-1 mice were exposed to control treatment (corn oil), BPA, BPE and BPS (50MUg/kg or 10mg/kg) from birth to postnatal day (PND) 60 by s.c. injection every three days. Sperm counts or motility was significantly reduced by BPA, BPE or BPS exposure on PND 60 or PND 90. Exposure of BPA, BPE and BPS disrupted the progression of germ cell development, as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis. In females, postnatal BPA and BPE exposure accelerated the onset of puberty, and increased body weight after parturition. Furthermore, postnatal exposure of BPA, BPE and/or BPS increased steroid hormone levels in serum. These results suggest that BPA analogues (BPS and BPE) affects male and female reproductive functions. PMID- 28676391 TI - BCL-2 proteins and apoptosis: Recent insights and unknowns. AB - Proteins of the B-cell lymphoma-2 (BCL-2) family control the intrinsic apoptosis pathway. The pro-apoptotic BCL-2 proteins BAX and BAK can commit a cell to its programmed death by permeabilizing the outer mitochondrial membrane (OMM) and subsequent initiation of the caspase cascade. Therefore, the activities of BAX and BAK are precisely controlled by a complex network of proteins inside and outside the BCL-2 family. Cells survive by constant control of dynamic translocation and retrotranslocation of BAX and BAK to the mitochondria and back into the cytosol. Recent insights into BAX/BAK shuttling, BCL-2 protein interactions, the role of BH3-only proteins in apoptosis signaling and the active BAX complex set the stage for the development of novel strategies in cancer therapy and the analysis of cellular predisposition to apoptosis. PMID- 28676392 TI - S1PR2 antagonist protects endothelial cells against high glucose-induced mitochondrial apoptosis through the Akt/GSK-3beta signaling pathway. AB - Vascular complications are the main cause of morbidity and mortality associated with type 2 diabetes mellitus. An early hallmark of the onset of vascular complications is endothelial dysfunction and apoptosis. We aimed to explore the role of sphingosine-1-phosphatereceptor 2 (S1PR2) in high glucose-induced endothelial cells apoptosis and to elaborate the underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were cultured in a high glucose with or without S1PR2 antagonist. The apoptosis of the cells was measured by flow cytometry and mitochondrial membrane permeability was detected by the fluorescent probe JC-1. The expression of the related protein was determined by western blot. Cell apoptosis and the loss of mitochondrial membrane permeability were induced under high glucose conditions in HUVECs. The expression of mitochondrial apoptosis related protein bax increased and bcl-2 decreased in high glucose induced HUVECs. The level of cytochrome c released into the cytoplasm increased when cells were exposed to high glucose. In addition, the expression of p-AKT and p-GSK3beta was reduced when HUVECs were treated with high glucose. However, these effects were reversed in HUVECs when cells treated with S1PR2 antagonist. In conclusion, S1PR2 antagonist protects endothelial cells against high glucose induced mitochondrial apoptosis through the Akt/GSK-3beta signaling pathway. PMID- 28676394 TI - The glycine hinge of transmembrane segment 2 modulates the subcellular localization and gating properties in TREK channels. AB - TWIK-Related K+ channels (TREK), including TREK-1 and TREK-2, belong to the TREK/TRAAK subclass of two-pore domain K+ (K2P) family. The important functions of transmembrane segment 4 (M4)-glycine hinge in TREK channel gating have been characterized, but the roles of M2-hinge (the equivalent residue of M4-hinge) remain unclear. Here, by characterizing the macroscopic currents, subcellular localization and gating properties of their M2-hinge mutants (G166A for TREK-1 and G196A for TREK-2), we investigated the functions of M2-hinge. G166A displayed decreased whole-cell currents, whereas no current was produced by G196A. Subcellular analysis indicated that both mutants were aggregated near the perinuclear region, and most of them were retented within the endoplasmic reticulum (ER). Next, to explore the roles of M2-hinge in the gating mechanism, we tested the responses of the related M2-hinge mutants to 2-Aminoethoxydiphenyl borate (2-APB) and extracellular pH alteration (DeltapHo). TREK-1mut7-G166A displayed reduced sensitivity to 2-APB activation, but similar sensitivity to DeltapHo, when compared with TREK-1mut7. WT-DeltapCt, a TREK-2 tandom dimer, was used to assess the function of M2-hinge in the cis-type gating of TREK-2. The sensitivities of G196A-DeltapCt to both 2-APB and DeltapHo decreased compared with WT-DeltapCt. Taken together, our results reveal that the M2-hinge of TREK channels control their macroscopic current, subcellular localization and gating process. PMID- 28676393 TI - Mitochondrial anchors: Positioning mitochondria and more. AB - The shape and position of mitochondria are intimately connected to both mitochondrial and cellular function. Mitochondrial anchors play a central role in mitochondrial positioning by exerting spatial, temporal, and contextual control over the cellular position of the organelle. Investigations into the molecular mechanisms of mitochondrial anchoring are still in the early stages, and we are beginning to appreciate the number and variety of anchors that exist. From the insight gained thus far, it is clear that mitochondrial anchoring has functional and physiological consequences that extend beyond mitochondrial positioning to other critical cellular processes. PMID- 28676395 TI - Phosphorylation of rat brain purified mitochondrial Voltage-Dependent Anion Channel by c-Jun N-terminal kinase-3 modifies open-channel noise. AB - The drift kinetic energy of ionic flow through single ion channels cause vibrations of the pore walls which are observed as open-state current fluctuations (open-channel noise) during single-channel recordings. Vibration of the pore wall leads to transitions among different conformational sub-states of the channel protein in the open-state. Open-channel noise analysis can provide important information about the different conformational sub-state transitions and how biochemical modifications of ion channels would affect their transport properties. It has been shown that c-Jun N-terminal kinase-3 (JNK3) becomes activated by phosphorylation in various neurodegenerative diseases and phosphorylates outer mitochondrion associated proteins leading to neuronal apoptosis. In our earlier work, JNK3 has been reported to phosphorylate purified rat brain mitochondrial voltage-dependent anion channel (VDAC) in vitro and modify its conductance and opening probability. In this article we have compared the open-state noise profile of the native and the JNK3 phosphorylated VDAC using Power Spectral Density vs frequency plots. Power spectral density analysis of open-state noise indicated power law with average slope value alpha ~1 for native VDAC at both positive and negative voltage whereas average alpha value < 0.5 for JNK3 phosphorylated VDAC at both positive and negative voltage. It is proposed that 1/f1 power law in native VDAC open-state noise arises due to coupling of ionic transport and conformational sub-states transitions in open-state and this coupling is perturbed as a result of channel phosphorylation. PMID- 28676397 TI - Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells. AB - The current study evaluated the potential anti-colorectal cancer (CRC) activity by Ku-0060648, a novel DNA-PKcs and PI3K duel inhibitor. In both CRC cell lines (HCT-116 and HT-29) and primary human colon cancer cells, Ku-0060648 exposure at nM concentrations efficiently inhibited cell proliferation. Meanwhile, Ku-0060648 provoked apoptosis in CRC cells. Ku-0060648 was yet ineffective to the normal colon epithelial cells. Ku-0060648 blocked PI3K-AKT-mTOR cascade and in-activated DNA-PKcs in CRC cells. Intriguingly, Ku-0060648 treatment induced feedback autophagy activation in HCT-116 cells. On the other hand, pharmacological autophagy inhibitors (3-methyladenine or chloroquine) or silencing key autophagy proteins (Beclin-1 or ATG-7) dramatically potentiated Ku-0060648-induced HCT-116 cell apoptosis. Together, these results suggest that feedback autophagy activation is a key resistance factor of Ku-0060648 in CRC cells, and autophagy inhibition sensitizes Ku-0060648-induced anti-CRC activity. PMID- 28676398 TI - Spatiotemporal control of mitochondrial network dynamics in astroglial cells. AB - Mitochondria are increasingly recognized for playing important roles in regulating the evolving metabolic state of mammalian cells. This is particularly true for nerve cells, as dysregulation of mitochondrial dynamics is invariably associated with a number of neuropathies. Accumulating evidence now reveals that changes in mitochondrial dynamics and structure may play equally important roles also in the cell biology of astroglial cells. Astroglial cells display significant heterogeneity in their morphology and specialized functions across different brain regions, however besides fundamental differences they seem to share a surprisingly complex meshwork of mitochondria, which is highly suggestive of tightly regulated mechanisms that contribute to maintain this unique architecture. Here, we summarize recent work performed in astrocytes in situ indicating that this may indeed be the case, with astrocytic mitochondrial networks shown to experience rapid dynamic changes in response to defined external cues. Although the mechanisms underlying this degree of mitochondrial re shaping are far from being understood, recent data suggest that they may contribute to demarcate astrocyte territories undergoing key signalling and metabolic functions. PMID- 28676396 TI - The regulation of tumor cell physiology by mitochondrial dynamics. AB - Mitochondrial dynamics are increasingly recognized to play an important role in regulating mitochondrial function in response to diverse stimuli. Given the overlap in the physiological processes influenced by mitochondria and the physiological processes disrupted in tumor cells, we speculate that tumor cells alter mitochondrial shape to promote the tumorigenic phenotype. Here, we briefly review the evidence linking changes in mitochondrial fusion and fission to a number of key tumorigenic processes, including metabolic rewiring, inhibition of cell death, cell migration, cell proliferation and self-renewal capacity. The role of mitochondrial dynamics in tumor growth is an important emerging area of research, a better understanding of which may lead to promising new therapeutic options for the treatment of cancer. PMID- 28676399 TI - Plant E3 ligases ubiquitinate Escherichia coli sigma32in vitro. AB - Ubiquitin-like proteins (UBLs) are extremely well-conserved among eukaryotes and prokaryotes allowing interactions between proteins from different organisms. For example, the prokaryotic ubiquitin-like proteins (Pups) and the Proteasome accessory factor A (PafA) of Mycobacterium tuberculosis are sufficient to pupylate at least 51 Escherichia coli proteins. This work shows that the plant E3 ligases BnTR1 and AT1G02860 can ubiquitinate E. coli sigma32, but not Hsp70 DnaK in vitro. Molecular biology and biochemical studies confirm that the RING finger domain of BnTR1 and AT1G02860 is essential for their function. These results suggest that the substrates of plant E3 ligases can be prokaryotic protein and therefore the plant ubiquitylation system may have evolved from prokaryote. PMID- 28676400 TI - Inhibition of B7-H3 reverses oxaliplatin resistance in human colorectal cancer cells. AB - B7-H3, an immunoregulatory protein, has been found highly expressed in several cancer types, and involved in cancer cell migration and invasion. Here, we investigated the role of B7-H3 in oxaliplatin resistance in colorectal cancer (CRC) cells. Transient silencing of B7-H3 enhanced oxaliplatin sensitivity by increasing oxaliplatin-induced DNA damage. The overexpression of B7-H3 increased oxaliplatin resistance reducing the formation of phosphorylated histone H2AX (gammaH2AX) loci. The silencing of X-ray repair cross complementing group 1 (XRCC1), upregulated in B7-H3 overexpressing cells, induced an increase in cell death following oxaliplatin treatment. Finally, the upregulation of XRCC1 expression induced by B7-H3 involved PI3K-AKT pathway. In conclusion, B7-H3 promotes the oxaliplatin resistance in CRC cells upregulating the expression of XRCC1 via PI3K-AKT pathway. PMID- 28676401 TI - Hv1 proton channel facilitates production of ROS and pro-inflammatory cytokines in microglia and enhances oligodendrocyte progenitor cells damage from oxygen glucose deprivation in vitro. AB - The contribution of microglial activation to oligodendrocyte precursor cell (OPC) damage in the brain is considered to be a principal pathophysiological feature of periventricular leukomalacia (PVL). Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-dependent reactive oxygen species (ROS) produced in microglia has been shown to be significantly toxic to OPCs. The voltage-gated proton channel Hv1 is selectively expressed in microglia and is essential for NOX-dependent ROS production in the central nervous system. This study aimed to investigate the effects of microglial Hv1 deficiency on the protection of OPCs from oxygen glucose deprivation (OGD)-induced injury in vitro. In the present study, the levels of OGD-induced ROS and pro-inflammatory cytokine production were dramatically lower in Hv1-deficient microglia (Hv1-/-) than in wild-type (WT) microglia. Following OGD, OPCs co-cultured with WT microglia had increased apoptosis and decreased proliferation and maturation, while those co-cultured with Hv1-/- microglia had attenuated apoptosis and greater proliferation and differentiation. Furthermore, the attenuated damage and enhanced regeneration of OPCs were associated with decreases in extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase phosphorylation. These results indicate that the protective effects of Hv1 deficiency on OPCs are due to the suppression of ROS and pro-inflammatory cytokine production in microglia. We thus suggest that the microglial proton channel Hv1 may be a potential therapeutic target in PVL. PMID- 28676402 TI - Transthoracic echocardiography and electrical cardiometry elucidate the hemodynamics of autotransfusion during labor under epidural analgesia. PMID- 28676403 TI - Obstetric interventions and maternal morbidity among women who experience severe postpartum hemorrhage during cesarean delivery. AB - BACKGROUND: Compared to vaginal delivery, women undergoing cesarean delivery are at increased risk of postpartum hemorrhage. Management approaches may differ between those undergoing prelabor cesarean delivery compared to intrapartum cesarean delivery. We examined surgical interventions, blood component use, and maternal outcomes among those experiencing severe postpartum hemorrhage within the two distinct cesarean delivery cohorts. METHODS: We performed secondary analyses of data from two cohorts who underwent prelabor cesarean delivery or intrapartum cesarean delivery at a tertiary obstetric center in the United States between 2002 and 2012. Severe postpartum hemorrhage was classified as an estimated blood loss >=1500mL or receipt of a red blood cell transfusion up to 48h post-cesarean delivery. We examined blood component use, medical and surgical interventions and maternal outcomes. RESULTS: The prelabor cohort comprised 269 women and the intrapartum cohort comprised 278 women. In the prelabor cohort, one third of women received red blood cells intraoperatively or postoperatively, respectively. In the intrapartum cohort, 18% women received red blood cells intraoperatively vs. 44% postoperatively (P<0.001). In the prelabor and intrapartum cohorts, methylergonovine was the most common second-line uterotonic (33% and 43%, respectively). Women undergoing prelabor cesarean delivery had the highest rates of morbidity, with 18% requiring hysterectomy and 16% requiring intensive care admission. CONCLUSION: Our findings provide a snapshot of contemporary transfusion and surgical practices for severe postpartum hemorrhage management during cesarean delivery. To determine optimal transfusion and management practices in this setting, large pragmatic studies are needed. PMID- 28676404 TI - Nasal capnography during remifentanil patient-controlled analgesia in labour. PMID- 28676405 TI - Pan-assay interference compounds (PAINS) that may not be too painful for chemical biology projects. PMID- 28676406 TI - Switching off CD73: a way to boost the activity of conventional and targeted antineoplastic therapies. AB - Over the past few years, several preclinical studies have highlighted the value of CD73 (ecto-5'-nucleotidase) as a potential therapeutic target for cancer therapy. Indeed, the pharmacological blockade of CD73, via monoclonal antibodies or small molecules, has promise in counteracting cancer development, growth and spread. Synergistic combinations of anti-CD73 drugs with conventional cancer treatments (i.e., chemotherapy, radiation therapy, immunotherapy, targeted therapy) have increased therapeutic potential. In this review, we discuss the potential synergistic effects of CD73 blockers and conventional antineoplastic therapies in the treatment of cancer. PMID- 28676407 TI - The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. AB - 1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compounds characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active molecules. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples. PMID- 28676408 TI - Respiratory syncytial virus in adults with severe acute respiratory illness in a high HIV prevalence setting. AB - BACKGROUND: There are limited data on the epidemiology of respiratory syncytial virus (RSV) illness in HIV-infected adults or the elderly in Africa. We studied the epidemiology of RSV-associated severe acute respiratory illness (SARI) hospitalizations in adults in South Africa from 2009 through 2013. METHODS: Individuals admitted to sentinel surveillance hospitals were investigated by respiratory tract swabs for RSV, using a multiplex real-time polymerase chain reaction assay. The incidence of RSV-associated SARI was calculated for the one site with population denominators. RESULTS: Of 7796 participants investigated, 329 (4%) tested positive for RSV. On multivariable analysis, HIV-infected individuals with RSV-associated SARI had greater odds of being in the age groups 18-44 and 45-64 years (odd ratios (OR) 26.3; 95% confidence interval (CI) 6.2 112.1 and OR 11.4; 95% CI 2.6-50.0) compared with those >=65 years and being female (OR 2.7; 95% CI 1.4-5.4). The relative risk of hospitalization with RSV associated SARI was 12-18 times higher in HIV infected individual compared to that of HIV-uninfected. CONCLUSION: The incidence of RSV-associated SARI was higher in HIV-infected individuals and those aged 65 years and older. Further studies are warranted to describe the disease association of RSV detected in adults with SARI. PMID- 28676409 TI - Enterococci in orthopaedic infections: Who is at risk getting infected? AB - : Some orthopaedic patients might be at risk for enterococcal infections and might benefit from adapted perioperative prophylaxis. METHODS: We performed a single-center cohort of adult patients with orthopaedic infections. RESULTS: Among 2740 infection episodes, 665 surgeries (24%) involved osteosynthesis material, including total joint arthroplasties. The recommended perioperative prophylaxis was cefuroxime (or vancomycin in case of documented MRSA body carriage). Patients had received antibiotic therapy before surgery in 1167 episodes (43%); among them with potential anti-enterococcal activity (penicillins, glycopeptides, imipenem, linezolid, daptomycin, aminoglycosids, tetracyclins) in 725 (62%) cases. Overall, enterococci were identified in intraoperative samples of 100 different infections (3.6%) (Enterococcus faecalis, 95; Enterococcus faecium, 2; and other enterococci, 3). However, only 15/100 (15%) enterococcal infections were monomicrobial and 19 were nosocomial (19/2740; 0.7%), of which 15 had previous cephalosporin perioperative prophylaxis without other antibiotic exposure. This association to prior cephalosporin use was significant (Pearson-chi2-test; 148/2640 vs. 15/100, p < 0.01). By multivariate analysis, the presence of diabetic foot infection (odds ratio 1.9, 95% confidence interval 1.2-2.9), and polymicrobial infection (OR 6.0, 95%CI 3.9-9.4) were the main predictors of enterococcal infection, while sex, age, and type of material were not. CONCLUSIONS: Community-acquired or nosocomial enterococcal infections in orthopaedic surgery are mostly polymicrobial, rare and very seldom attributed to a nosocomial origin. Thus, even if they are formally associated with prior cephalosporin use, we do not see a rational for changing our antibiotic prophylaxis. PMID- 28676410 TI - Tuberculosis transmission in public locations in Tanzania: A novel approach to studying airborne disease transmission. AB - OBJECTIVES: For tuberculosis (TB) transmission to occur, an uninfected individual must inhale the previously infected breath. Our objective was to identify potential TB transmission hotspots in metropolitan city of Dar es Salaam, Tanzania and to model the annual risk of TB transmission in different locations of public importance. METHODS: We collected indoor carbon dioxide (CO2) data from markets, prisons, night clubs, public transportation, religious and social halls, and from schools. Study volunteers recorded social contacts at each of the locations. We then estimated the annual risks of TB transmission using a modified Wells-Riley equation for different locations. RESULTS: The annual risks of TB transmission were highest among prison inmates (41.6%) and drivers (20.3%) in public transport. Lower transmission risks were found in central markets (4.8% for traders, but 0.5% for their customers), passengers on public transport (2.4%), public schools (4.0%), nightclubs (1.7%), religious (0.13%), and social halls (0.12%). CONCLUSION: For the first time in a country representative of sub Saharan Africa, we modelled the risk of TB transmission in important public locations by using a novel approach of studying airborne transmission. This approach can guide identification of TB transmission hotspots and targeted interventions to reach WHO's ambitious End TB targets. PMID- 28676411 TI - Incidence of herpes zoster amongst adults varies by severity of immunosuppression. AB - OBJECTIVES: We examined the incidence of herpes zoster in immunocompromised adults (>=18 years) with different severities of immunosuppression and assessed the prevalence of complications and of various kinds of healthcare resource utilisation. METHODS: German claims data from more than ten million adults were used to calculate annual incidence rates of herpes zoster for the years 2006-2012 and to analyse the prevalence of complications, physician visits, hospitalisations, and antiviral and analgesic treatments using a cohort design. The analyses were stratified by age, sex, and severity of immunosuppression, defined by immunocompromising conditions and drug therapies. RESULTS: The incidence rate per 1000 person-years of herpes zoster was almost twice as high in immunocompromised patients (11.5 (95% confidence interval (CI): 11.4-11.6)) compared to immunocompetent subjects (5.9 (95% CI: 5.8-5.9)). The incidence rate was higher in highly immunocompromised patients (13.4 (95% CI: 13.2-13.6)) than in patients with a low severity of immunosuppression (10.0 (95% CI: 9.8-10.1)). These differences were observed for both sexes and in all age groups. Complications, outpatient physician visits, hospitalisations, and analgesic treatments occurred more frequently in immunocompromised patients as well. CONCLUSIONS: Our results show that immunocompromised individuals are affected by the disease in particular and that the burden of herpes zoster is highest in severely immunocompromised patients. PMID- 28676412 TI - Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease. AB - AIMS: Cardiovascular disease, one of the most common causes of death in western populations, is characterized by changes in RNA splicing and expression. Circular RNAs (circRNA) originate from back-splicing events, which link a downstream 5' splice site to an upstream 3' splice site. Several back-splicing junctions (BSJ) have been described in heart biopsies from human, rat and mouse hearts (Werfel et al., 2016; Jakobi et al., 2016 ). Here, we use human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to identify circRNA and host gene dynamics in cardiac development and disease. In parallel, we explore candidate interactions of selected homologs in mouse and rat via RIP-seq experiments. METHODS AND RESULTS: Deep RNA sequencing of cardiomyocyte development and beta adrenergic stimulation uncovered 4518 circRNAs. The set of circular RNA host genes is enriched for chromatin modifiers and GTPase activity regulators. RNA-seq and qRT-PCR data showed that circular RNA expression is highly dynamic in the hiPSC-CM model with 320 circRNAs showing significant expression changes. Intriguingly, 82 circRNAs are independently regulated to their host genes. We validated the same circRNA dynamics for circRNAs from ATXN10, CHD7, DNAJC6 and SLC8A1 in biopsy material from human dilated cardiomyopathy (DCM) and control patients. Finally, we could show that rodent homologs of circMYOD, circSLC8A1, circATXN7 and circPHF21A interact with either the ribosome or Argonaute2 protein complexes. CONCLUSION: CircRNAs are dynamically expressed in a hiPSC-CM model of cardiac development and stress response. Some circRNAs show similar, host-gene independent expression dynamics in patient samples and may interact with the ribosome and RISC complex. In summary, the hiPSC-CM model uncovered a new signature of potentially disease relevant circRNAs which may serve as novel therapeutic targets. PMID- 28676413 TI - Atypical pyoderma gangrenosum simulating pectoral abscess managed using negative pressure wound therapy. PMID- 28676414 TI - Cultural Competency Training in Emergency Medicine. AB - BACKGROUND: The Emergency Department is widely regarded as the epicenter of medical care for diverse and largely disparate types of patients. Physicians must be aware of the cultural diversity of their patient population to appropriately address their medical needs. A better understanding of residency preparedness in cultural competency can lead to better training opportunities and patient care. OBJECTIVE: The objective of this study was to assess residency and faculty exposure to formal cultural competency programs and assess future needs for diversity education. METHODS: A short survey was sent to all 168 Accreditation Council for Graduate Medical Education program directors through the Council of Emergency Medicine Residency Directors listserv. The survey included drop-down options in addition to open-ended input. Descriptive and bivariate analyses were used to analyze data. RESULTS: The response rate was 43.5% (73/168). Of the 68.5% (50/73) of residency programs that include cultural competency education, 90% (45/50) utilized structured didactics. Of these programs, 86.0% (43/50) included race and ethnicity education, whereas only 40.0% (20/50) included education on patients with limited English proficiency. Resident comfort with cultural competency was unmeasured by most programs (83.6%: 61/73). Of all respondents, 93.2% (68/73) were interested in a universal open-source cultural competency curriculum. CONCLUSIONS: The majority of the programs in our sample have formal resident didactics on cultural competency. Some faculty members also receive cultural competency training. There are gaps, however, in types of cultural competency training, and many programs have expressed interest in a universal open-source tool to improve cultural competency for Emergency Medicine residents. PMID- 28676415 TI - Emergency Department Flow Measures for Adult and Pediatric Patients in British Columbia and Ontario: A Retrospective, Repeated Cross-Sectional Study. AB - BACKGROUND: Evidence suggests emergency department (ED) overcrowding is associated with poor health outcomes. Children comprise 20-25% of general ED visits, yet few studies have examined the differential impact of ED overcrowding on pediatric and adult populations. OBJECTIVE: The primary objective of this study was to compare flow measures, such as wait time to see a physician, length of stay (LOS), and rate of patients leaving without being seen by a physician (LWBS) between adults and children in British Columbia and Ontario, clustered by province, and then stratified by acuity level during the study period. METHODS: We conducted a retrospective, repeated cross-sectional study using administrative data from all community EDs in Ontario and 10 EDs in the Vancouver Lower Mainland, British Columbia. Visits from January 1, 2008 and December 31, 2012 were included. RESULTS: Visit volumes increased 13.9% per year in British Columbia and 2.2% per year in Ontario, with a more pronounced rise in adult visits. Both groups displayed a shift toward higher-acuity presentations. Adults spent more time in the ED compared to children (36 to 53 min longer), and were more likely to be admitted. Children consistently spent a greater portion of their visit awaiting assessment compared to adults. CONCLUSIONS: In the context of system incentives to reduce overcrowding, ED LOS and the LWBS rate did not significantly change for either children or adults, despite increased visit volume and acuity. Our findings suggest that measures to improve patient flow might have provided EDs with the means to meet increased demands on departmental resources. PMID- 28676416 TI - Noise slows the rate of Michaelis-Menten reactions. AB - Microscopic randomness and the small volumes of living cells combine to generate random fluctuations in molecule concentrations called "noise". Here I investigate the effect of noise on biochemical reactions obeying Michaelis-Menten kinetics, concluding that substrate noise causes these reactions to slow. I derive a general expression for the time evolution of the joint probability density of chemical species in arbitrarily connected networks of non-linear chemical reactions in small volumes. This equation is a generalization of the chemical master equation (CME), a common tool for investigating stochastic chemical kinetics, extended to reaction networks occurring in small volumes, such as living cells. I apply this equation to a generalized Michaelis-Menten reaction in an open system, deriving the following general result:

<=p- and >=s-, where s- and p- denote the deterministic steady-state concentration of reactant and product species, respectively, and and

denote the steady-state ensemble average over independent realizations of a stochastic reaction. Under biologically realistic conditions, namely when substrate is degraded or diluted by cell division,

<=p-. Consequently, noise slows the rate of in vivo Michaelis-Menten reactions. These predictions are validated by extensive stochastic simulations using Gillespie's exact stochastic simulation algorithm. I specify the conditions under which these effects occur and when they vanish, therefore reconciling discrepancies among previous theoretical investigations of stochastic biochemical reactions. Stochastic slowdown of reaction flux caused by molecular noise in living cells may have functional consequences, which the present theory may be used to quantify. PMID- 28676417 TI - EU ambition to build the world's leading bioeconomy-Uncertain times demand innovative and sustainable solutions. AB - This article outlines the current context and the development of the European Bioeconomy Strategy. It analyses the current situation, challenges and needs for EU action and concludes with the next steps that the European Commission will undertake to review and update the Bioeconomy Strategy. Bioeconomy offers great opportunities to realising a competitive, circular and sustainable economy with a sound industrial base that is less dependent on fossil carbon. A sustainable bioeconomy also contributes to climate change mitigation, with oceans, forests and soils being major carbon sinks and fostering negative CO2 emissions. The EU has invested significantly in research and innovation in this field and the European Commission is committed to lead on European bioeconomy strategy. PMID- 28676418 TI - Waste derived bioeconomy in India: A perspective. AB - Environmental and climatic change issues, population explosion, rapid urbanisation, depletion of fossil reserves, need for energy security, huge waste generation, etc. are some of the inherent issues associated with the fossil based linear economy which need greater attention. In this context, the world is gradually transforming from fossil-based economy to a sustainable circular bio economy. The biogenic waste which is generated in enormous quanties in India can be considered as potential feedstock for structuring the bio-based economy. This communication depicts the need for developing waste derived bioeconomy in the Indian perspective. Waste is now being perceived as a resource with value and believed to supplement petroleum feedstock to a great extent if properly utilized. The necessity to introduce waste as the core element for the future economic models which also allows sustainable development is discussed. The review also establishes drivers for the bioeconomy and structures the waste derived bioeconomy in a sustainable format to address the futuristic needs, scope and opportunities envisaged in the business and economic realm. The enabling technologies/processes that can be applied for biogenic wastes valorisation are elaborated. Circularizing the economy in a waste biorefinery model for the production of biobased products including bioenergy is discussed. PMID- 28676419 TI - Portal vein stenting for portal vein stenosis caused by bile duct cancer. PMID- 28676420 TI - Prevalence of and risk factors for HBV infection in a metropolitan Southern Italian area: Evidence for the effectiveness of universal Hepatitis B vaccination. AB - BACKGROUND: Available data on HBV prevalence in Italy are outdated and assessed with studies conducted in small towns. We aimed to evaluate prevalence of and risk factors for HBV infection in the metropolitan area of Naples, 24 years after the introduction of mass vaccination campaign against Hepatitis B in Italy. METHODS: A random systematic sample of the adult general population of Naples was selected from the register of 3 general practitioners in 3 different socio economic districts. Independent predictors of the likelihood of HBV infection were identified by logistic regression analysis. RESULTS: Among 900 selected subjects, 772 (85.8%) participated in the study. The overall HBsAg and anti-HBc prevalences were 1.7% and 14.4%, respectively. Both markers were more likely detected in the district at low socioeconomic status than in those at medium-high status (p<0.01). Anti-HBc prevalence linearly increased from 0% in subjects 30 years old or younger to 28.0% in those older than 60 years of age (p<0.01). At multivariate analysis, age >60 years (OR3.38; 95%CI:1.98-5.74), low socioeconomic district of residence (OR3.26; 95%CI:1.72-6.18), and low educational qualification (OR2.73; 95%CI:1.45-5.16) were independent predictors of anti-HBc positivity. CONCLUSION: Differences in socioeconomic conditions have played a major role in the past spread of HBV infection in Naples. Hepatitis B vaccination has resulted very effectively in preventing HBV infection, regardless of the district of residence, as none of the subjects in the vaccinated cohorts was exposed to the infection. PMID- 28676422 TI - Kinetics of transport through the nuclear pore complex. AB - Single molecule microscopy techniques allow to visualize the translocation of single transport receptors and cargo molecules or particles through nuclear pore complexes. These data indicate that cargo molecule import into the nucleus takes less than 10ms and nuclear export of messenger RNA (mRNA) particles takes 50 350ms, up to several seconds for extremely bulky particles. This review summarizes and discusses experimental results on transport of nuclear transport factor 2 (NTF2), importin beta and mRNA particles. Putative regulatory functions of importin beta for the NPC transport mechanism and the RNA helicase Dbp5 for mRNA export kinetics are discussed. PMID- 28676423 TI - Functional interplay between secreted ligands and receptors in melanoma. AB - Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR. Accordingly, MC1R is a major determinant of susceptibility to melanoma. Despite extensive phenotypic heterogeneity and high mutation loads, the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood. Mutations of intracellular effectors of receptor tyrosine kinase (RTK) signalling, notably NRAS and BRAF, are major driver events more frequent than mutations in RTKs. Nevertheless, melanomas often display aberrant signalling from RTKs such as KIT, ERRB1-4, FGFR, MET and PDGFR, which contribute to disease progression and resistance to targeted therapies. Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche. However, key aspects of the melanoma-stroma interplay, such as the molecular determinants of dormancy, remain poorly understood. PMID- 28676421 TI - How cells channel their stress: Interplay between Piezo1 and the cytoskeleton. AB - Cells constantly encounter mechanical stimuli in their environment, such as dynamic forces and mechanical features of the extracellular matrix. These mechanical cues are transduced into biochemical signals, and integrated with genetic and chemical signals to modulate diverse physiological processes. Cells also actively generate forces to internally transport cargo, to explore the physical properties of their environment and to spatially position themselves and other cells during development. Mechanical forces are therefore central to development, homeostasis, and repair. Several molecular and biophysical strategies are utilized by cells for detecting and generating mechanical forces. Here we discuss an important class of molecules involved in sensing and transducing mechanical forces - mechanically-activated ion channels. We focus primarily on the Piezo1 ion channel, and examine its relationship with the cellular cytoskeleton. PMID- 28676424 TI - Nuclear pore complex tethers to the cytoskeleton. AB - The nuclear envelope is tethered to the cytoskeleton. The best known attachments of all elements of the cytoskeleton are via the so-called LINC complex. However, the nuclear pore complexes, which mediate the transport of soluble and membrane bound molecules, are also linked to the microtubule network, primarily via motor proteins (dynein and kinesins) which are linked, most importantly, to the cytoplasmic filament protein of the nuclear pore complex, Nup358, by the adaptor BicD2. The evidence for such linkages and possible roles in nuclear migration, cell cycle control, nuclear transport and cell architecture are discussed. PMID- 28676425 TI - Functional proteomics of cellular mechanosensing mechanisms. AB - Mechanosensing enables cells to coordinate their phenotype with the mechanical properties of their tissue microenvironment. In this process, cells probe their surroundings by applying contractile forces, which produces different amounts of mechanical strain within the cells as a function of the stiffness of their extracellular substrates. Tension within cells can then affect the structure and composition of most cellular organelles, including cell adhesions, the cytoskeleton, the plasma membrane and the nucleus. On a molecular level, the conformations, modifications, interactions, and subcellular localizations of proteins have been shown to be altered by biomechanical forces. Functional proteomics aims at the analysis of these effects in a proteome wide, unbiased and high throughput manner. Emerging methods, such as crosslinking mass spectrometry and advanced protein correlation profiling, will enable future analysis of mechanosensing on the level of protein interactions in situ, and subcellular protein localization, which can now be determined with very high accuracy from whole cell analysis for thousands of proteins at once. Combined use of these mass spectrometry toolsets with the analysis of posttranslational modifications will ultimately move the field to a comprehensive list of molecular alterations in cellular mechanosensing. We will give an overview on current developments in functional proteomics and the latest applications on questions related to mechanobiology. PMID- 28676426 TI - Minimal important difference to infer changes in health-related quality of life-a systematic review. AB - OBJECTIVES: The objective of the study was to assess the usability of minimal important difference (MID) and minimal clinically important difference (MCID) for measuring meaningful changes in disease-specific and generic health-related quality-of-life (HRQoL) outcomes in patient-centered care. STUDY DESIGN AND SETTING: We adopted a two-step literature review process. First, we used PubMed and Google scholar to identify a broad range of search terms. Next, we searched OVID Medline, JSTOR, and PubMed for terms "MID," and "MCID." We excluded non English language studies, articles older than 1995, those not related to generic- and disease-specific HRQoL measures, and protocols of future studies. Studies were grouped according to generic- and disease-specific measures. We assessed MID or MCID calculation methods, effect sizes, estimated values, and significance. RESULTS: Eighty articles satisfied the inclusion criteria. Our synthesis provides a comprehensive assessment of MID or MCID for 10 generic-specific and 80 disease specific instruments. We observed a lack of consistency in the application of methods for computing MID or MCID for generic and disease-specific HRQoL measures. Only 43 (54%) studies used both anchor and distribution methods to elicit MID or MCID. Thirty-four articles estimated MID values only, whereas 47 articles estimated MCID. CONCLUSION: The anchor-based method yields conservative estimates of MID or MCID, compared to the distribution-based method. The distribution method does not take into account patient perspectives and should be accompanied by anchor method while computing MID. The MID should be interpreted with caution, and available estimates for a particular instrument must be used. This will help in integrating the MID estimates into the overall research or clinical plan for a specific context. PMID- 28676427 TI - A plastid phylogeny and character evolution of the Old World fern genus Pyrrosia (Polypodiaceae) with the description of a new genus: Hovenkampia (Polypodiaceae). AB - The Old World fern genus Pyrrosia (Polypodiaceae) offers a rare system in ferns to study morphological evolution because almost all species of this genus are well studied for their morphology, anatomy, and spore features, and various hypotheses have been proposed in terms of the phylogeny and evolution in this genus. However, the molecular phylogeny of the genus lags behind. The monophyly of the genus has been uncertain and a modern phylogenetic study of the genus based on molecular data has been lacking. In the present study, DNA sequences of five plastid markers of 220 accessions of Polypodiaceae representing two species of Drymoglossum, 14 species of Platycerium, 50 species of Pyrrosia, and the only species of Saxiglossum (subfamily Platycerioideae), and 12 species of other Polypodiaceae representing the remaining four subfamilies are used to infer a phylogeny of the genus. Major results and conclusions of this study include: (1) Pyrrosia as currently circumscribed is paraphyletic in relation to Platycerium and can be divided into two genera: Pyrrosia s.s. and Hovenkampia (gen. nov.), with Hovenkampia and Platycerium forming a strongly supported clade sister to Pyrrosia s.s.; (2) Subfamily Platycerioideae should contain three genera only, Hovenkampia, Platycerium, and Pyrrosia s.s.; (3) Based on the molecular phylogeny, macromorphology, anatomical features, and spore morphology, four major clades in the genus are identified and three of the four are further resolved into four, four, and six subclades, respectively; (4) Three species, P. angustissima, P. foveolata, and P. mannii, not assigned to any groups by Hovenkamp (1986) because of their unusual morphology, each form monospecific clades; (5) Drymoglossum is not monophyletic and those species previously assigned to this genus are resolved in two different subclades; (6) Saxiglossum is resolved as the first lineage in the Niphopsis clade; and (7) The evolution of ten major morphological characters in the subfamily is inferred based on the phylogeny and various morphological synapomorphies for various clades and subclades are identified. PMID- 28676428 TI - American Brachytherapy Society consensus report for accelerated partial breast irradiation using interstitial multicatheter brachytherapy. AB - PURPOSE: To develop a consensus report for the quality practice of accelerated partial breast irradiation (APBI) using interstitial multicatheter brachytherapy (IMB). METHODS AND MATERIALS: The American Brachytherapy Society Board appointed an expert panel with clinical and research experience with breast brachytherapy to provide guidance for the current practice of IMB. This report is based on a comprehensive literature review with emphasis on randomized data and expertise of the panel. RESULTS: Randomized trials have demonstrated equivalent efficacy of APBI using IMB compared with whole breast irradiation for select patients with early-stage breast cancer. Several techniques for placement of interstitial catheters are described, and importance of three-dimensional planning with appropriate optimization is reviewed. Optimal target definition is outlined. Commonly used dosing schemas include 50 Gy delivered in pulses of 0.6-0.8 Gy/h using pulsed-dose-rate technique and 34 Gy in 10 fractions, 32 Gy in eight fractions, or 30 Gy in seven fractions using high-dose-rate technique. Potential toxicities and strategies for toxicity avoidance are described in detail. Dosimetric constraints include limiting whole breast volume that receives >=50% of prescription dose to <60%, skin dose to <=100% of prescription dose (<=60-70% preferred), chest wall dose to <=125% of prescription dose, Dose Homogeneity Index to >0.75 (>0.85 preferred), V150 < 45 cc, and V200 < 14 cc. Using an optimal implant technique coupled with optimal planning and appropriate dose constraints, a low rate of toxicity and a good-to-excellent cosmetic outcome of >=90% is expected. CONCLUSIONS: IMB is an effective technique to deliver APBI for appropriately selected women with early-stage breast cancer. This consensus report has been created to assist clinicians in the appropriate practice of APBI using IMB. PMID- 28676429 TI - The role of ARMC5 in human cell cultures from nodules of primary macronodular adrenocortical hyperplasia (PMAH). AB - The participation of aberrant receptors and intra-adrenal ACTH in hyperplastic tissue are considered mechanisms that regulate hypercortisolism in PMAH. Additionally, germline ARMC5 mutations have been described as the most frequent genetic abnormality found in patients diagnosed with PMAH. Previous functional studies analyzed ARMC5 role using H295R cells. Therefore, we investigated the role of ARMC5 in cell cultures obtained from PMAH nodules containing steroidogenic cells, aberrant receptors and intra-adrenal ACTH. ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related genes and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability. Additionally, ARMC5 overexpression induced cell death in PMAH mutated cell cultures, thereby decreasing cell viability. We confirmed the role of ARMC5 as an important pro-apoptotic protein involved in PMAH-related steroidogenesis. We also report for the first time the involvement of ARMC5 in controlling proliferation and regulating cell cycle in PMAH cell cultures; these effects need to be explored further. PMID- 28676430 TI - Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner. AB - Titin, a giant sarcomeric protein, is largely responsible for the diastolic properties of the heart. It has two major isoforms, N2B and N2BA due to pre-mRNA splicing regulated mainly by a splicing factor RNA binding motif 20 (RBM20). Mis splicing of titin pre-mRNA in response to external stimuli may lead to altered ratio of N2B to N2BA, and thus, impaired cardiac contractile function. However, little is known about titin alternative splicing in response to external stimuli. Here, we reported the detailed mechanisms of titin alternative splicing in response to insulin. Insulin treatment in cultured neonatal rat cardiomyocytes (NRCMs) activated the PI3K-Akt-mTOR kinase axis, leading to increased N2B expression in the presence of RBM20, but not in NRCMs in the absence of RBM20. By inhibiting this kinase axis with inhibitors, decreased N2B isoform was observed in NRCMs and also in diabetic rat model treated with streptozotocin, but not in NRCMs and diabetic rats in the absence of RBM20. In addition to the alteration of titin isoform ratios in response to insulin, we found that RBM20 expression was increased in NRCMs with insulin treatment, suggesting that RBM20 levels were also regulated by insulin-induced kinase axis. Further, knockdown of p70S6K1 with siRNA reduced both RBM20 and N2B levels, while knockdown of 4E-BP1 elevated expression levels of RBM20 and N2B. These findings reveal a major signal transduction pathway for insulin-induced titin alternative splicing, and place RBM20 in a central position in the pathway, which is consistent with the reputed role of RBM20 in titin alternative splicing. Findings from this study shed light on gene therapeutic strategies at the molecular level by correction of pre-mRNA mis-splicing. PMID- 28676431 TI - Efficacy of oral immunotherapy with a rice-based edible vaccine containing hypoallergenic Japanese cedar pollen allergens for treatment of established allergic conjunctivitis in mice. AB - BACKGROUND: We have previously shown that prophylactic oral administration of transgenic rice seeds expressing hypoallergenic modified antigens suppressed the development of allergic conjunctivitis induced by Japanese cedar pollen. We have now investigated the efficacy of oral immunotherapy with such transgenic rice for established allergic conjunctivitis in mice. METHODS: BALB/c mice were sensitized with two intraperitoneal injections of Japanese cedar pollen in alum, challenged with pollen in eyedrops, and then fed for 16 days with transgenic rice seeds expressing modified Japanese cedar pollen allergens Cry j 1 and Cry j 2 or with nontransgenic rice seeds as a control. They were then challenged twice with pollen in eyedrops, with clinical signs being evaluated at 15 min after the first challenge and the eyes, blood, spleen, and lymph nodes being isolated at 24 h after the second challenge. RESULTS: The number of eosinophils in the conjunctiva and the clinical score for conjunctivitis were both significantly lower in mice fed the transgenic rice than in those fed nontransgenic rice. Oral vaccination with transgenic rice seeds also resulted in a significant increase in the production of IFN-gamma by splenocytes, whereas it had no effect on the number of CD4+CD25+Foxp3+ regulatory T cells in the spleen or submandibular or mesenteric lymph nodes. CONCLUSIONS: Oral administration of transgenic rice seeds expressing hypoallergenic allergens ameliorated allergic conjunctivitis in the established setting. Such a rice-based edible vaccine is potentially both safe and effective for oral immunotherapy in individuals with allergic conjunctivitis. PMID- 28676432 TI - Pathophysiological mechanisms involved in the relationship between diabetes and major depressive disorder. AB - Diabetes mellitus (DM) and major depressive disorder (MDD) are diseases that are expanding globally. Separately, each presents with several comorbidities for patients. When the two diseases present simultaneously in the same subject, there is a drastic worsening in the quality of life of the patient. This study reviewed the literature relating to the relationship between MDD and DM, bringing forward studies showing that DM develops due to MDD, and others that report the opposite. According to the studies reviewed, DM and MDD are both debilitating conditions that are associated with significant morbidity, mortality, and healthcare costs. When these two diseases coexist, the association results in a decreased adherence to treatment, poor metabolic control, higher rates of complications, a decrease in the quality of life for the patient, increased healthcare use and cost, increased disability and lost productivity, and an increased risk of death. Therefore, it becomes essential that there are larger studies targeting the association of these two diseases, as for the patient, preventing even one of them will ensure improvements in their quality of life. PMID- 28676433 TI - The neurotoxicant PCB-95 by increasing the neuronal transcriptional repressor REST down-regulates caspase-8 and increases Ripk1, Ripk3 and MLKL expression determining necroptotic neuronal death. AB - Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases RE1-silencing transcription factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation. Our results demonstrated that in cortical neurons PCB 95 increased RIPK1, RIPK3, and MLKL expression and decreased caspase-8 at the gene and protein level. Furthermore, the RIPK1 inhibitor necrostatin-1 or siRNA mediated RIPK1, RIPK3 and MLKL expression knockdown significantly reduced PCB-95 induced neuronal death. Intriguingly, PCB-95-induced increases in RIPK1, RIPK3, MLKL expression and decreases in caspase-8 expression were reversed by knockdown of REST expression with a REST-specific siRNA (siREST). Notably, in silico analysis of the rat genome identified a REST consensus sequence in the caspase-8 gene promoter (Casp8-RE1), but not the RIPK1, RIPK3 and MLKL promoters. Interestingly, in PCB-95-treated neurons, REST binding to the Casp8-RE1 sequence increased in parallel with a reduction in its promoter activity, whereas under the same experimental conditions, transfection of siREST or mutation of the Casp8 RE1 sequence blocked PCB-95-induced caspase-8 reduction. Since RIPK1, RIPK3 and MLKL rat genes showed no putative REST binding site, we assessed whether the transcription factor cAMP Responsive Element Binding Protein (CREB), which has a consensus sequence in all three genes, affected neuronal death. In neurons treated with PCB-95, CREB protein expression decreased in parallel with a reduction in binding to the RIPK1, RIPK3 and MLKL gene promoter sequence. Furthermore, CREB overexpression was associated with reduced promoter activity of the RIPK1, RIPK3 and MLKL genes. Collectively, these results indicate that PCB-95 was associated with REST-induced necroptotic cell death by increasing RIPK1, RIPK3 and MLKL expression and reducing caspase-8 levels. In addition, since REST is involved in several neurological disorders, therapies that block REST-induced necroptosis could be a new strategy to revert the neurodetrimental effects associated to its overexpression. PMID- 28676434 TI - Multifunctional bioactive glass and glass-ceramic biomaterials with antibacterial properties for repair and regeneration of bone tissue. AB - : Bioactive glasses (BGs) and related glass-ceramic biomaterials have been used in bone tissue repair for over 30years. Previous work in this field was comprehensively reviewed including by their inventor Larry Hench, and the key features and properties of BGs are well understood. More recently, attention has focused on their modification to further enhance the osteogenic behaviour, or further compositional changes that may introduce additional properties, such as antimicrobial activity. Evidence is emerging that BGs and related glass-ceramics may be modified in such a way as to simultaneously introduce more than one desirable property. The aim of this review is therefore to consider the evidence that these more recent inorganic modifications to glass and glass-ceramic biomaterials are effective, and whether or not these new compositions represent sufficiently versatile systems to underpin the development of a new generation of truly multifunctional biomaterials to address pressing clinical needs in orthopaedic and dental surgery. Indeed, a number of classical glass compositions exhibited antimicrobial activity, however the structural design and the addition of specific ions, i.e. Ag+, Cu+, and Sr2+, are able to impart a multifunctional character to these systems, through the combination of, for example, bioactivity with bactericidal activity. STATEMENT OF SIGNIFICANCE: In this review we demonstrate the multifunctional potential of bioactive glasses and related glass ceramics as biomaterials for orthopaedic and craniofacial/dental applications. Therefore, it considers the evidence that the more recent inorganic modifications to glass and glass-ceramic biomaterials are able to impart antimicrobial properties alongside the more classical bone bonding and osteoconduction. These properties are attracting a special attention nowadays that bacterial infections are an increasing challenge in orthopaedics. We also focus the manuscript on the versatility of these systems as a basis to underpin the development of a new generation of truly multifunctional biomaterials to address pressing clinical needs in orthopaedic, craniofacial and dental surgery. PMID- 28676435 TI - Enhancing the educational value of direct-to-consumer advertising of prescription drugs. AB - OBJECTIVES: The educational value of direct-to-consumer advertising (DTCA) of prescription drugs hinges on its ability to convey important benefit and risk information to consumers. However, the literacy level required to understand some of the information presented in print advertisements may hinder DTCA's ability to educate consumers. The objective of this study was to compare the comprehension and retention of benefit and risk information between consumers who viewed an original print DTCA and those who viewed an advertisement modified according to health literacy principles. DESIGN: An experimental design was used to conduct the study. Participants were randomly assigned to view a modified print advertisement (experimental group) or the original print advertisement (control group) for an antidepressant medication. SETTING AND PARTICIPANTS: Study participants were recruited from the University of Wisconsin Kidney Clinic. OUTCOME MEASURES: Ten true-false and 10 multiple-choice questions were developed to assess participants' comprehension and retention of benefit and risk information. RESULTS: A total of 120 participants were randomized to view either the original or the modified version of the advertisement. Regarding the comprehension and retention of only the benefit information, no significant differences were observed between the 2 groups. Significant differences were observed for comprehension and retention of only the risk information. The experimental group had significantly higher scores in comprehension (U = 1224; P < 0.01) and retention (U = 965; P < 0.01) of the risk information compared with the control group. These differences were also significant in multivariate analyses controlling for extraneous variables that were found to have associations with comprehension and retention of information. CONCLUSION: Study results demonstrated that the health literacy techniques used to modify the advertisement were successful in enhancing both consumers' comprehension and their retention of information presented in a print DTCA. This was especially apparent for the risk information. PMID- 28676436 TI - Functional significance of men's testosterone reactivity to social stimuli. AB - Rapid testosterone fluctuations in response to social stimuli are observed across a wide range of species, and the highly conserved nature of these fluctuations suggests an adaptive function. This paper reviews the current literature on testosterone reactivity, primarily in human males, and illustrates how life history theory provides an adequate theoretical framework to interpret findings. The review is structured around supporting evidence suggesting that situations implicated in mating effort either directly (e.g., interactions with a mate) or indirectly (e.g., intrasexual competition) are generally associated with a brief elevation of testosterone, while situations implicated in parenting effort (e.g., nurturant interactions with offspring) are generally associated with a decline in testosterone. Further, we discuss how these fluctuations in testosterone have been linked to future behaviors, and how situational, motivational, and physiological variables moderate the interplay between social stimuli, testosterone reactivity, and behavior. Supporting the notion that testosterone can play a causal role in modulating behavior in response to social stimuli, we also summarize recent single administration studies examining the effects of testosterone on physiology, neurobiology, and behavior. A conceptual model provides links between supported findings, and hypothesized pathways requiring future testing. PMID- 28676437 TI - Deep brain stimulation and treatment-resistant obsessive-compulsive disorder: A systematic review. AB - INTRODUCTION: At least 10% of patients with Obsessive-compulsive Disorder (OCD) are refractory to psychopharmacological treatment. The emergence of new technologies for the modulation of altered neuronal activity in Neurosurgery, deep brain stimulation (DBS), has enabled its use in severe and refractory OCD cases. The objective of this article is to review the current scientific evidence on the effectiveness and applicability of this technique to refractory OCD. METHOD: We systematically reviewed the literature to identify the main characteristics of deep brain stimulation, its use and applicability as treatment for obsessive-compulsive disorder. Therefore, we reviewed PubMed/Medline, Embase and PsycINFO databases, combining the key-words 'Deep brain stimulation', 'DBS' and 'Obsessive-compulsive disorder' 'OCS'. The articles were selected by two of the authors independently, based on the abstracts, and if they described any of the main characteristics of the therapy referring to OCD: applicability; mechanism of action; brain therapeutic targets; efficacy; side-effects; co therapies. All the information was subsequently extracted and analysed. RESULTS: The critical analysis of the evidence shows that the use of DBS in treatment resistant OCD is providing satisfactory results regarding efficacy, with assumable side-effects. However, there is insufficient evidence to support the use of any single brain target over another. Patient selection has to be done following analyses of risks/benefits, being advisable to individualize the decision of continuing with concomitant psychopharmacological and psychological treatments. CONCLUSIONS: The use of DBS is still considered to be in the field of research, although it is increasingly used in refractory-OCD, producing in the majority of studies significant improvements in symptomatology, and in functionality and quality of life. It is essential to implement random and controlled studies regarding its long-term efficacy, cost-risk analyses and cost/benefit. PMID- 28676439 TI - The effect of stress fracture interventions in a single elite infantry training unit (1983-2015). AB - Stress fractures can be seen as an undesired byproduct of demanding physical training. The threshold value of stress that places an individual bone at high risk for stress fracture has not been identified. In a prospective study of stress fractures in 1983, a 31% incidence was found during demanding Israeli infantry basic training by bone scan criteria. Within a subgroup of these recruits, an elite infantry unit was found to have a 40% incidence. Since then and until 2015, eight additional induction companies of the same elite infantry unit were prospectively monitored for stress fractures during their basic training. In all of the studies, stress fracture surveillance and the examining orthopedist were the same. A retrospective review of all nine studies and of eight training changes was performed to look for a temporal trend in stress fracture incidence and to see if these might be related to training changes. There was a statistically significant trend for lower radiological proven stress fractures (p=0.0001) and radiological proven stress fractures plus clinical stress fractures (p=0.0013), as well as lower stress fracture severity by radiological criteria (p=0.0001) between 1983 and 2015. The only training change that was associated, by multivariate logistic regression, with a decreased incidence of stress fracture was restricting training to the authorized training protocol (odds ratio, 3874; 95% CI, 1.526 to 9.931; p=0.004). Increased recruit weight was found by multivariate analysis to be associated with lower stress fracture incidence (odds ratio 1.034; 95% CI, 1.00 to 1.070; p=0.051). Moving the training to a base with flatter terrain and reducing the formal marching distance by 1/3 was associated with a decrease in high grade stress fractures (odds ratio, 10.03; 95% CI, 3.5 to 28.4; p=0.0001). Neither the combined changes of enforcing a seven hour a night sleep regimen, training in more comfortable boots and adding a physical therapist to the unit nor stopping specific running exercises and adding lower body strengthening exercises were associated with a decrease in stress fracture. 67% of recruits who sustained stress fractures and 69% who did not sustain stress fracture finished their military service as combat soldiers in the unit (p=0.87). There are no magic bullets to prevent stress fractures. Stress cannot be lowered beyond the level which compromises the training goals. It is a problem that can be managed by awareness that identifies and treats stress fractures while they are still in the micro stage and not in the more dangerous macro stage. PMID- 28676438 TI - Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes. AB - Parathyroid hormone (PTH) and Notch receptors regulate bone formation by governing the function of osteoblastic cells. To determine whether PTH interacts with Notch signaling as a way to control osteoblast function, we tested the effects of PTH on Notch activity in osteoblast- and osteocyte-enriched cultures. Notch signaling was activated in osteoblast-enriched cells from wild-type C57BL/6J mice following exposure to the Notch ligand Delta-like (Dll)1 or by the transient transfection of the Notch intracellular domain (NICD), the transcriptionally active fragment of Notch1. To induce Notch signaling in osteocyte-enriched cultures, a murine model of Notch2 gain-of-function was used. PTH opposed the stimulatory effects of Dll1 on Hey1, Hey2 and HeyL mRNA levels in osteoblast-enriched cells and suppressed the expression of selected Notch target genes in osteocyte-enriched cultures, either under basal conditions or in the context of Notch2 gain-of-function. Induction of Notch signaling in osteocytes did not alter the inhibitory effect of PTH on Sost expression, but reduced the stimulation of Tnfsf11 mRNA levels by PTH. In agreement with these in vitro observations, male mice administered with PTH displayed suppressed Hey1 and HeyL expression in parietal bones. Transactivation experiments with a Notch reporter construct and electrophoretic mobility shift assays in osteoblast-enriched cells suggest that PTH acts by decreasing the capacity of Rbpjkappa to bind to DNA. In conclusion, downregulation of Notch in osteoblasts and osteocytes may represent a mechanism contributing to the anabolic effects of PTH in bone. PMID- 28676440 TI - Severe bone loss and multiple fractures in SCN8A-related epileptic encephalopathy. AB - Mutations in the SCN8A gene encoding the neuronal voltage-gated sodium channel Nav1.6 are known to be associated with epileptic encephalopathy type 13. We identified a novel de novo SCN8A mutation (p.Phe360Ala, c.1078_1079delTTinsGC, Exon 9) in a 6-year-old girl with epileptic encephalopathy accompanied by severe juvenile osteoporosis and multiple skeletal fractures, similar to three previous case reports. Skeletal assessment using dual energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) and serum analyses revealed a combined trabecular and cortical bone loss syndrome with elevated bone resorption. Likewise, when we analyzed the skeletal phenotype of 2week-old Scn8a-deficient mice we observed reduced trabecular and cortical bone mass, as well as increased osteoclast indices by histomorphometric quantification. Based on this cumulative evidence the patient was treated with neridronate (2mg/kg body weight administered every 3months), which fully prevented additional skeletal fractures for the next 25months. Taken together, our data provide evidence for a negative impact of SCN8A mutations on bone mass, which can be positively influenced by anti-resorptive treatment. PMID- 28676441 TI - Chronic toxicity and oncogenicity of octamethylcyclotetrasiloxane (D4) in the Fischer 344 rat. AB - Octamethylcyclotetrasiloxane (D4) is a cyclic volatile methylsiloxane primarily used in the synthesis of silicon-based materials used in a variety of consumer products. This paper details the chronic toxicity and oncogenicity evaluation of D4 in the Fischer 344 rat. Animals were exposed to 0, 10, 30, 150, or 700ppm D4 vapor for 6h/day, 5days/week for up to 104 weeks in whole-body inhalation chambers. Effects of two year chronic exposure included increased liver, kidney, testes, and uterine weight with correlating microscopic findings of hepatocellular hypertrophy (males only), chronic nephropathy (both sexes), interstitial cell hyperplasia, and cystic endometrial hyperplasia and endometrial adenoma, respectively. Upper respiratory tract irritation and lymphocytic leukocytosis were evident in both sexes. Increased neoplasia was demonstrated only in the uterus. Uterine endometrial adenomas were present in four of sixty animals exposed to 700ppm D4 for 24 months. None were present in the other treatment groups. In contrast, in 700ppm D4 group males the incidence of pituitary and pancreatic neoplasia was reduced as was thyroid c-cell adenoma/carcinoma in 700ppm females. This study has identified that D4 is a mild respiratory irritant and increases liver and kidney weight without inducing neoplasia in these tissues. The increased incidence of uterine adenoma was the only treatment-related neoplastic finding associated with chronic exposure to D4. PMID- 28676442 TI - A biochip-based combined immunoassay for detection of serological status of Borrelia burgdorferi in Lyme borreliosis. AB - BACKGROUND: Dithiobis (succinimidyl undecanoate) modified gold surface biochip were used as a combined immunoassay platform for concurrently detecting immune responses to Borrelia burgdorferi (B. burgdorferi) sensu lato antigens, flagellin, outer surface protein C, variable major protein-like sequence proteins, and 3 VlsE protein IR6 peptides. The peptides represented intrinsic Borrelia genospecies: B. burgdorferi sensu stricto, B. garinii, and B. afzelii, respectively. METHODS: Fourier transform infrared spectroscopy was utilized to validate the surface chemical characteristics on the modified gold surface. RESULTS: The limits in detection of IgG antibody on the biochips were as little as 0.39MUg/ml for anti-VlsE and 0.78MUg/ml for anti-flagellin and anti-OspC, respectively. Samples from 56 neuroborreliosis (NB) patients and 114 healthy individuals were analyzed by the combined biochip. We found that the seroprevalences of IgM or IgG antibody against the 6 antigens were contributed to increased overall sensitivity by the multiplex immunobiochip assay. Serum combined positive rates of the 6 antigens in the patients were 92.86% for IgM antibody and 91.07% for IgG antibody. Part of the patients bore antibody responses against the 3 VlsE IR6 variant peptides, indicating that Lyme borreliosis would attribute to consequence of multiple infections by one or more Borrelia burgdorferi strains. Concurrent assessment for both IgM and IgG antibodies against the protein antigens and B. burgdorferi IR6 peptides in the sera of NB patients was beneficial from the biochip format, enabling detection of expanded serologic infection status and therapy strategy-making more efficiently. CONCLUSIONS: The combined biochip-based immunoassay, as a potential substitution of ELISA, provided a promising approach to extend the detection spectrum of infectious antibodies against a panel of Borrelia antigens. PMID- 28676443 TI - A modified tongue depressor facilitates the insertion of ProSeal laryngeal mask airway: Comparison with digital and introducer techniques. AB - BACKGROUND: The larger and softer cuff of the ProSeal laryngeal mask airway (LMA) may cause difficulty in insertion. We introduced a novel technique using a modified tongue depressor to aid the ProSeal LMA insertion. METHODS: A total of 150 patients were randomly allocated into three groups of 50 each, digital (D), introducer (I), and tongue depressor (TD). The ProSeal LMA was inserted by the aid of digit, introducer and a modified tongue depressor, respectively. The primary outcomes included insertion time, insertion frequency, pre- and post insertion blood pressure/heart rate, presence of blood on the ProSeal LMA cuff after removal, and postoperative sore throat. RESULTS: The insertion time was significantly shorter in the TD group than in the D and I groups (23.3 +/- 5.1 s vs. 26.8 +/- 9.3 s and 27.8 +/- 9.5 s; p = 0.025 and p = 0.004). The rate of successful intubation on the first attempt was significantly higher in the TD group than in the D and I groups (98% vs. 84% and 82%; p = 0.035 and p = 0.02). The incidence of blood staining on the LMA cuff after removal was significantly lower in the TD group than in the D and I groups (6% vs. 22% and 24%; p = 0.044 and p = 0.025). The incidence of sore throat in the post-anesthesia care unit was significantly lower in the TD group than in the D and I groups (8% vs. 26% and 28%; p = 0.033 and p = 0.019). CONCLUSION: The modified tongue depressor-aided technique is superior to the digital manipulation and introducer tool techniques for ProSeal LMA insertion. PMID- 28676444 TI - The expression of transglutaminase 2 (TG-2) in oral squamous cell carcinoma and its clinical significance. AB - BACKGROUND: Glutamine has a very important role in the human body, including pH balance in an acidic environment, as well as supporting the TCA cycle in cancer cell growth. However, the expression of transglutaminase-2 (TG-2) in oral cancer growth related to renal function is unknown. Here we examined TG-2 and its expression as a prognostic tool. METHODS: Fifty-six oral squamous cell carcinoma (OSCC) tissues were collected with the inclusion of tumor in any region of oral area, and patients with creatinine (Cr) and blood urea nitrogen (BUN) results. The tissues were stained using immunohistochemistry (IHC) with a TG-2 antibody [N3C3], then observed under the microscope. The staining were calculated using Adobe Photoshop CS software and statistical analyses using SPSS ver. 21. RESULTS: We found that TG-2 expression showed a significant difference in the expression levels between tumor and the adjacent groups without disease-free survival, disease-specific survival, and recurrence between, with p < 0.05. The average staining intensity with 25th percentile of TG-2 becomes a vital score for the diagnosis. Furthermore, our study demonstrates a good prognosis outcome if the intensity score showed a difference in TG-2 expression between the adjacent and tumor tissue. CONCLUSION: To our knowledge, this is the first clinical study on TG-2 expression in OSCC, and it demonstrates that TG-2 can serve as a predictor of tumorigenesis and prognosis outcome. PMID- 28676445 TI - Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats. AB - BACKGROUND: Liver fibrosis causes portal hypertension which dilates collateral vasculature and enhances extra-hepatic angiogenesis including intrapulmonary shunts, which subsequently complicates with hepatopulmonary syndrome. Metformin is an anti-diabetic agent which possesses anti-inflammation and anti-angiogenesis properties. This study evaluated the effect of metformin treatment on liver and lung in a non-diabetic rat model with biliary cirrhosis induced via common bile duct ligation (CBDL). METHODS: CBDL rats were fed with metformin 150 mg/kg/day during the 8th-28th day post operation. The hemodynamic and biochemistry parameters were tested, and blood gas analysis was performed. The liver and lung were dissected for protein analysis and immuno-histochemical stains. Intrapulmonary shunting degree was determined using color microsphere method. RESULTS: Metformin treatment neither induced obvious hypoglycemic event nor altered hemodynamics in cirrhotic rats. The plasma levels of alanine aminotransferase were significantly reduced by metformin (control vs. metformin: 269 +/- 56 vs. 199 +/- 21 IU/L, P = 0.02). Sirius Red stains and CD-68 stains showed that metformin reduced intrahepatic fibrosis and CD-68-positive macrophages. Metformin did not influence hypoxia and intrapulmonary angiogenesis; however, it significantly reduced intrapulmonary shunts (31.7 +/- 10.1 vs. 15.0 +/- 6.6%, P = 0.006.). Furthermore, metformin reduced the protein expressions of COX-2 and PI3K in liver and COX-1 in lung. CONCLUSION: Metformin reduced liver injury and improved hepatic fibrosis in cirrhotic rats. It also attenuated the intrapulmonary shunts. However, the effects of metformin on pulmonary angiogenesis and hypoxia were insignificant. PMID- 28676446 TI - Identification and expression profiling of Oryza sativa nucleotidyl transferase protein (NTP) genes under various stress conditions. AB - Nucleotidyl transferase proteins (NTPs) modify the 3' ends of mature small RNAs, leading to their stabilization or degradation. The first two plant NTPs, HESO1 and URT1, were identified in Arabidopsis. These two NTPs act cooperatively to uridylate the 3' terminal nucleotide of specific miRNAs, leading to their degradation and thereby affecting the expression of genes regulated by these miRNAs. Little is known about NTPs in other plants. Here, we performed a comprehensive analysis of 13 putative NTP genes in Oryza sativa, a major crop in global food production. Phylogenetic analysis showed homology among the NTPs from diverse plant species. Analysis of cis-acting promoter elements at OsNTP loci identified several stress response elements, indicating the potential involvement of NTPs in plant stress responses. The promoter analysis results were validated by expression of the OsNTP genes under abiotic stress treatments, with some OsNTPs clearly induced by salt, drought or cold stress. Moreover, the RT-PCR data showed that the OsNTP genes were differentially expressed in different developmental stages and tissues. These findings suggest that NTPs, which are involved in small RNA metabolic pathways, might play roles in plant stress resistance. PMID- 28676447 TI - Profiling conserved biological pathways in Autosomal Dominant Polycystic Kidney Disorder (ADPKD) to elucidate key transcriptomic alterations regulating cystogenesis: A cross-species meta-analysis approach. AB - PURPOSE: Initiation and progression of fluid filled cysts mark Autosomal Dominant Polycystic Kidney Disease (ADPKD). Thus, improved therapeutics targeting cystogenesis remains a constant challenge. Microarray studies in single ADPKD animal models species with limited sample sizes tend to provide scattered views on underlying ADPKD pathogenesis. Thus we aim to perform a cross species meta analysis to profile conserved biological pathways that might be key targets for therapy. METHODS: Nine ADPKD microarray datasets on rat, mice and human fulfilled our study criteria and were chosen. Intra-species combined analysis was performed after considering removal of batch effect. Significantly enriched GO biological processes and KEGG pathways were computed and their overlap was observed. For the conserved pathways, biological modules and gene regulatory networks were observed. Additionally, Gene Set Enrichment Analysis (GSEA) using Molecular Signature Database (MSigDB) was performed for genes found in conserved pathways. RESULTS: We obtained 28 modules of significantly enriched GO processes and 5 major functional categories from significantly enriched KEGG pathways conserved in human, mice and rats that in turn suggest a global transcriptomic perturbation affecting cyst - formation, growth and progression. Significantly enriched pathways obtained from up-regulated genes such as Genomic instability, Protein localization in ER and Insulin Resistance were found to regulate cyst formation and growth whereas cyst progression due to increased cell adhesion and inflammation was suggested by perturbations in Angiogenesis, TGF-beta, CAMs, and Infection related pathways. Additionally, networks revealed shared genes among pathways e.g. SMAD2 and SMAD7 in Endocytosis and TGF-beta. CONCLUSION: Our study suggests cyst formation and progression to be an outcome of interplay between a set of several key deregulated pathways. Thus, further translational research is warranted focusing on developing a combinatorial therapeutic approach for ADPKD redressal. PMID- 28676448 TI - See food diet? Cultural differences in estimating fullness and intake as a function of plate size. AB - Previous research has suggested that manipulations of plate size can have a direct impact on perception of food intake, measured by estimated fullness and intake. The present study, involving 570 individuals across Canada, China, Korea, and New Zealand, is the first empirical study to investigate cultural influences on perception of food portion as a function of plate size. The respondents viewed photographs of ten culturally diverse dishes presented on large (27 cm) and small (23 cm) plates, and then rated their estimated usual intake and expected fullness after consuming the dish, using 100-point visual analog scales. The data were analysed with a mixed-model ANCOVA controlling for individual BMI, liking and familiarity of the presented food. The results showed clear cultural differences: (1) manipulations of the plate size had no effect on the expected fullness or the estimated intake of the Chinese and Korean respondents, as opposed to significant effects in Canadians and New Zealanders (p < 0.05); (2) Canadian (88.91 +/- 0.42) and New Zealanders (90.37 +/- 0.41) reported significantly higher estimated intake ratings than Chinese (80.80 +/- 0.38) or Korean (81.69 +/- 0.44; p < 0.05), notwithstanding the estimated fullness ratings from the Western respondents were comparable or even higher than those from the Asian respondents. Overall, these findings, from a cultural perspective, support the notion that estimation of fullness and intake are learned through dining experiences, and highlight the importance of considering eating environments and contexts when assessing individual behaviours relating to food intake. PMID- 28676449 TI - Associations between sociocultural home environmental factors and vegetable consumption among Norwegian 3-5-year olds: BRA-study. AB - The home environment is the first environment to shape childhood dietary habits and food preferences, hence greater understanding of home environmental factors associated with vegetable consumption among young children is needed. The objective has been to examine questionnaire items developed to measure the sociocultural home environment of children focusing on vegetables and to assess the psychometric properties of the resulting factors. Further, to explore associations between the environmental factors and vegetable consumption among Norwegian 3-5 year olds. Parents (n 633) were invited to participate and filled in a questionnaire assessing the child's vegetable intake and factors potentially influencing this, along with a 24-h recall of their child's fruit and vegetable intake. Children's fruit and vegetable intakes at two meals in one day in the kindergarten were observed by researchers. Principal components analysis was used to examine items assessing the sociocultural home environment. Encouragement items resulted in factors labelled "reactive encouragement", "child involvement" and "reward". Modelling items resulted in the factors labelled "active role model" and "practical role model". Items assessing negative parental attitudes resulted in the factor labelled "negative parental attitudes" and items assessing family pressure/demand resulted in the factor labelled "family demand". The psychometric properties of the factors were for most satisfactory. Linear regression of the associations between vegetable intake and the factors showed, as expected, generally positive associations with "child involvement", "practical role model" and "family demand", and negative associations with "negative parental attitudes" and "reward". Unexpectedly, "reactive encouragement" was negatively associated with vegetable consumption. In conclusion, associations between sociocultural home environmental factors and children's vegetable consumption showed both expected and unexpected associations some of which differed by maternal education - pointing to a need for further comparable studies. PMID- 28676450 TI - Real-world data of 197 patients treated with ulipristal acetate for uterine fibroids: PREMYA study French population main outcomes. AB - OBJECTIVES: To characterize and describe treatment with ulipristal acetate (UPA) in a preoperative setting and to evaluate the safety, effectiveness, and Health Related Quality of Life (HRQoL) outcomes in a French population treated according to standard clinical practice. MATERIALS AND METHODS: Multicentre, prospective, non-interventional study (PREMYA) of patients diagnosed with moderate to severe symptoms of uterine fibroids and undergoing a preoperative treatment with UPA 5mg (Esmya(r)). Patients were followed for a total of 15months (3months UPA treatment and 12months after). Data were collected approximatively every 3months according to centre usual visit schedule. RESULTS: A total of 206 women were enrolled in France, of whom 197 were found to be eligible for data analysis. Physicians' assessments of patients' overall symptomatic changes, as measured on the Clinical Global Impression-Improvement (CGI-I) scale, indicated that 83.7% of patients were improved at end of treatment (month 3). On the patients' treatment benefit scale (PTBS), 94.7% of patients reported an improvement. These 2 measurements, pain and quality of life, remained improved after treatment cessation and during the entire period of follow-up. Only 58.4% of patients underwent surgery within the timeframe of the study follow-up of which the majority were of a conservative/minimal invasive nature. CONCLUSION: Many patients did not undergo surgery during the planned 12months follow-up period after treatment whereas all patients had an indication of surgery. All measurements of treatment outcome were markedly improved by 3 months of UPA 5mg treatment. CLINICAL TRIAL NUMBER: NCT01635452. PMID- 28676451 TI - Reproducibility of the interpretation of coronal 3D ultrasound view of the uterus to evaluate the position of Essure(r) 3 months after hysteroscopic procedure. AB - OBJECTIVE: Three-dimensional sonography is a good alternative method to assess the position of microinserts. Adequate position after three months allows for the interruption of other contraception. Objective is to evaluate inter-observer reproducibility of the interpretation of coronal transvaginal 3D ultrasound view of the uterus to evaluate the position of Essure(r). STUDY DESIGN: Inter-observer reproducibility study. Fifty women underwent successful bilateral placement of microinserts (Essure(r)) by hysteroscopy in the Department of Gynaecology of a teaching hospital and were included in the study. At three month, 3D ultrasound coronal views of the fifty uterus (accounting for one hundred microinserts) were assessed by five different observers and microinsert position was classified according to the classification described by Legendre et al. Inter-observer reproducibility in reading the 3D coronal view of the uterus was evaluated. RESULTS: The k-value was disparate, from 0.26 to 0.82. Inter-observer reproducibility then ranged from fair to almost perfect, depending on a prior knowledge of the position classification. CONCLUSIONS: Transvaginal 3D coronal view of the uterus is sufficient to assess the positioning of the microinserts when the practionner or the surgeon is familiar with the classification method. PMID- 28676452 TI - Water-extracted tubers of Cyperus rotundus L. enhance endometrial receptivity through leukemia inhibitory factor-mediated expression of integrin alphaVbeta3 and alphaVbeta5. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus rotundus L. (CR) has been traditionally used as an herbal medicine in Asian countries to treat diverse gynecological disorders. However, the potential therapeutic effect of CR on endometrial receptivity for successful embryo implantation to treat female infertility has not been fully studied. AIM OF STUDY: The aim of this study was to evaluate the effect of water-extracted CR on endometrial receptivity by investigating the expression of leukemia inhibitory factor (LIF) and integrins, cell adhesion, and embryo implantation using mifepristone (RU486; RU)-induced implantation failure model. MATERIALS AND METHODS: The water extract of CR was prepared and fingerprinted using high-performance liquid chromatography (HPLC). For the expression and regulation of LIF, reverse transcription polymerase chain reaction (RT-PCR) and western blotting were performed in CR-stimulated Ishikawa cells. To evaluate LIF-mediated integrin expression, knockdown of LIF by shRNA was performed in Ishikawa cells. The effect of CR on endometrial receptivity was determined by an in vitro adhesion assay between JAr cells and CR-induced Ishikawa cells. In vivo, C57BL/6 female mice (n = 7 per group) orally received CR (31.68mg/kg/day), a similar dose as used clinically. Seven days after CR treatment, all female mice were caged with male mice until pregnancy was verified. On day 4 of pregnancy, RU (4mg/kg) was injected subcutaneously to induce embryo implantation failure. RESULT: CR increased the expression of LIF through the phosphatidylinositol-3-kinase/ protein kinase B (PI-3K/AKT) signaling pathway in Ishikawa cells. In addition, CR enhanced adhesion of JAr cells onto Ishikawa cells by inducing the expression of LIF-dependent integrins alphaVbeta3 and alphaVbeta5. Furthermore, CR improved the number of implantation sites in pregnant mice despite RU injection. CONCLUSION: CR increased the expression of LIF-mediated integrins alphaVbeta3 and alphaVbeta5 on the surface of endometrial cells, which is associated with adhesion of trophoblastic cells to endometrial cells for blastocyst implantation. Our findings provide evidence that CR has therapeutic potential against poor endometrial receptivity. PMID- 28676453 TI - Ac2-26 peptide and serine protease of Bothrops atrox similarly induces angiogenesis without triggering local and systemic inflammation in a murine model of dorsal skinfold chamber. PMID- 28676454 TI - Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles. AB - Myostatin (Mstn) deficiency leads to skeletal muscle overgrowth and Mstn inhibition is considered as a promising treatment for muscle-wasting disorders. Mstn gene deletion in mice also causes metabolic changes with decreased mitochondria content, disturbance in mitochondrial respiratory function and increased muscle fatigability. However the impact of MSTN deficiency on these metabolic changes is not fully elucidated. Here, we hypothesized that lack of MSTN will alter skeletal muscle membrane lipid composition in relation with pronounced alterations in muscle function and metabolism. Indeed, phospholipids and in particular cardiolipin mostly present in the inner mitochondrial membrane, play a crucial role in mitochondria function and oxidative phosphorylation process. We observed that Mstn KO muscle had reduced fat membrane transporter levels (FAT/CD36, FABP3, FATP1 and FATP4) associated with decreased lipid oxidative pathway (citrate synthase and beta-HAD activities) and impaired lipogenesis (decreased triglyceride and free fatty acid content), indicating a role of mstn in muscle lipid metabolism. We further analyzed phospholipid classes and fatty acid composition by chromatographic methods in muscle and mitochondrial membranes. Mstn KO mice showed increased levels of saturated and polyunsaturated fatty acids at the expense of monounsaturated fatty acids. We also demonstrated, in this phenotype, a reduction in cardiolipin proportion in mitochondrial membrane versus the proportion of others phospholipids, in relation with a decrease in the expression of phosphatidylglycerolphosphate synthase and cardiolipin synthase, enzymes involved in cardiolipin synthesis. These data illustrate the importance of lipids as a link by which MSTN deficiency can impact mitochondrial bioenergetics in skeletal muscle. PMID- 28676455 TI - Injections of platelet-rich plasma for androgenic alopecia: A systematic review. AB - The aim of this literature review was to evaluate the effects of PRP injections into the scalp of patients with androgenic alopecia. A literature review was conducted using the Pubmed and Google Scholar databases with the search terms "platelet-rich plasma" or "platelet-rich fibrin" and "hair" or "alopecia" or "androgenic alopecia". The publications included had to clinically assess the efficacy of PRP injections in patients with androgenic alopecia. Out of the 32 publications retrieved, 14 publications were included, of which 3 randomized, 4 prospective controlled, 4 prospective uncontrolled and 3 retrospective studies. Seven out of 9 studies reported a significant increase of hair density ranging between 12.3 and 45.9 hairs/cm2, (i.e. 19-31% hairs/cm2). Four studies assessed hair loss with the traction test and found a negative result after treatment in more than 95% of patients. Regarding hair thickness, 1 study reported an increase in hair diameter of 46.4% and 1 reported an increase of 106.4% of the "Hair mass index". Overall, the use of PRP injections in patients with androgenic alopecia seems effective with respect to promoting lost hair regrowth, decreasing hair loss and increasing hair thickness. The effects appear to be progressive from the first injection session, to peak after 3 to 5 sessions and to be attenuated in the absence of further injections. No major adverse effect was reported in the 14 clinical studies. PMID- 28676456 TI - Palmitoylethanolamide and Polydatin combination reduces inflammation and oxidative stress in vascular injury. AB - Acute and chronic inflammation responses are important risk factors for vascular remodeling processes such as in atherosclerosis, arteriosclerosis and restenosis. Inflammation and oxidative stress in the intimal region after vascular damage are a key event in the development of neointimal hyperplasia. In this study, we used this model of vascular damage, which involves the complete ligature of the left carotid artery for 14days, to observe the role of N-palmitoylethanolamine in combination with Polydatin at the dose of 30mg/kg, on regulation of inflammatory process, and oxidative stress. Palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the N-acylethanolamine family, has anti-inflammatory and neuroprotective effects. However, PEA lacks direct capacity to prevent formation of free radicals. Polydatin (PLD) that is a natural precursor of resveratrol has antioxidant activity. Thus, the combination of PEA and PLD could have beneficial effects on inflammatory process and oxidative stress. This model shows that 14days after carotid artery ligation there is a significant structural change within the vessel, and that there is an important involvement of the inflammatory pathway in the progression of this disease. In this study we demonstrated that PEA/PLD combination treatment reduces vessel damage, adhesion molecules expression such as intercellular adhesion molecules-1(ICAM-1) and vascular cell adhesion molecules-1(V-CAM), proinflammatory cytokines production (Tumor Necrosis Factor alpha (TNF-alpha) and Interleukin 1 beta (IL-1beta), the inducible nitric oxide synthase (iNOS) and Poly (ADP-ribose) polymerase (PAR), formation, Nuclear factor kappa-B expression and apoptosis (BAX, Fas-Ligand) activation. Our results clearly demonstrated that treatment with PEA/PLD 30mg/Kg is able to reduce vascular damage and attenuates the inflammatory process. PMID- 28676458 TI - Vitamin D-deficiency and sex-specific dysregulation of placental inflammation. AB - To investigate an immunomodulatory role for vitamin D in pregnancy we used mice raised on vitamin D-sufficient (SUFF), or -deficient (DEF) diets. At embryonic day 14, pregnant mice received intraperitoneal injection of lipopolysaccharide (LPS) or vehicle for 24h, with age-matched non-pregnant mice as controls. In non pregnant mice, 6 serum analytes (IL-1beta, IL-18, MDC/CCL22, MIP-1alpha/CCL3, EGF, IgA) were lower in DEF mice. In pregnant DEF mice only GH was higher. In non pregnant mice LPS induced 28 analytes, with 5 (IL-18, IP-10/CXCL10, MCP-1/CCL2, MIP-1beta/CCL4, MIP-3beta/CCL19) being highest in DEF mice. In pregnant SUFF mice 16 serum analytes increased with LPS, and 6 of these (IP-10/CXCL10, MCP-1/CCL2, SAP, TIMP-1, VCAM-1, vWF) were higher and 1 (GCP-2/CXCL6) lower in DEF mice. Parallel analysis of placental mRNAs showed elevated mRNA for Il-6, Ccl2 and Cxcl10 in placentae from male and female fetuses in LPS-DEF mice. However, LPS induced expression of Ifngamma, Tnfalpha, and Cxcl6 was only observed in female placentae from DEF mice. LPS-DEF mice also showed smaller litter sizes relative to control SUFF mice. Numbers of female fetuses per dam were significantly lower for DEF mice with or without LPS challenge. LPS had no effect on numbers of male fetuses from DEF mothers, but significantly decreased male fetuses from SUFF mothers. These data indicate that vitamin D is an important component of anti inflammatory immune responses during pregnancy, with the placenta and fetal sex playing pivotal roles in this process. PMID- 28676457 TI - On the role of classical and novel forms of vitamin D in melanoma progression and management. AB - Melanoma represents a significant clinical problem affecting a large segment of the population with a relatively high incidence and mortality rate. Ultraviolet radiation (UVR) is an important etiological factor in malignant transformation of melanocytes and melanoma development. UVB, while being a full carcinogen in melanomagenesis, is also necessary for the cutaneous production of vitamin D3 (D3). Calcitriol (1,25(OH)2D3) and novel CYP11A1-derived hydroxyderivatives of D3 show anti-melanoma activities and protective properties against damage induced by UVB. The former activities include inhibitory effects on proliferation, plating efficiency and anchorage-independent growth of cultured human and rodent melanomas in vitro, as well as the in vivo inhibition of tumor growth by 20(OH)D3 after injection of human melanoma cells into immunodeficient mice. The literature indicates that low levels of 25(OH)D3 are associated with more advanced melanomas and reduced patient survivals, while single nucleotide polymorphisms of the vitamin D receptor or the D3 binding protein gene affect development or progression of melanoma, or disease outcome. An inverse correlation of VDR and CYP27B1 expression with melanoma progression has been found, with low or undetectable levels of these proteins being associated with poor disease outcomes. Unexpectedly, increased expression of CYP24A1 was associated with better melanoma prognosis. In addition, decreased expression of retinoic acid orphan receptors alpha and gamma, which can also bind vitamin D3 hydroxyderivatives, showed positive association with melanoma progression and shorter disease-free and overall survival. Thus, inadequate levels of biologically active forms of D3 and disturbances in expression of the target receptors, or D3 activating or inactivating enzymes, can affect melanomagenesis and disease progression. We therefore propose that inclusion of vitamin D into melanoma management should be beneficial for patients, at least as an adjuvant approach. The presence of multiple hydroxyderivatives of D3 in skin that show anti-melanoma activity in experimental models and which may act on alternative receptors, will be a future consideration when planning which forms of vitamin D to use for melanoma therapy. PMID- 28676460 TI - Nutrigenomics in cancer: Revisiting the effects of natural compounds. AB - Nutrigenomics effects have an important role in the manipulation of dietary components for human benefit, particularly in cancer prevention or treatment. The impact of dietary components, including phytochemicals, is largely studied by nutrigenomics, looking at the gene expression and molecular mechanisms interacting with bioactive compounds and nutrients, based on new 'omics' technologies. The high number of preclinical studies proves the relevant role of nutrigenomics in cancer management. By deciphering the network of nutrient-gene connections associated with cancer, relevant data will be transposed as therapeutic interventions for this devastating pathology and for fulfilling the concept of personalized nutrition. All these are presented under the nutrigenomics canopy for a better comprehension of the relation between ingested phytochemicals and chemoprevention or chemotherapy. The profits from the nutrigenomics progress, with a particular focus on the coding and noncoding genes related to the exposure of natural compounds need to be validated. A precise attention receives the evaluation of the role of natural compounds in tandem with conventional therapy using genomic approaches, with emphasis on the capacity to inhibit drug resistance mechanisms. All these relevant nutrigenomics aspects are summarized in the present review paper. It is concluded that further nutrigenomics studies are required to improve our understanding related to the complex mechanisms of action of the natural compounds and for their appropriate application as gears in cancer therapy. PMID- 28676461 TI - Cervical Burst Fracture in a Patient with Contiguous 2-Level Cervical Stand-Alone Cages. AB - BACKGROUND: Cervical stand-alone interbody cages have seen increasingly wider use over the plate-and-screw construct in single-level anterior cervical discectomy and fusion (ACDF) in the treatment of cervical disc herniation and degenerative spondylotic conditions. Despite positive clinical outcomes, the efficacy and safety of using these devices in contiguous multilevel ACDF has remained controversial. This report discusses a burst fracture seen as a complication in multilevel cervical stand-alone cage use. CASE DESCRIPTION: A 39-year-old woman with a history of C5-C6 and C6-C7 ACDF with contiguous stand-alone interbody cages 2 years prior, presented with recurrent arm and neck pain with myelopathy. Computed tomography scan revealed a burst fracture of the C6 vertebral body with retropulsion of fragments compressing the spinal cord. CONCLUSIONS: This case suggests that use of cervical stand-alone cages in contiguous levels may cause late complications despite good instrumentation and illustrates the need for more careful consideration of technique selection in multilevel ACDF. PMID- 28676462 TI - Risks and Benefits of Endoscopic Transsphenoidal Surgery for Nonfunctioning Pituitary Adenomas in Patients of the Ninth Decade. AB - BACKGROUND: The population older than 80 years of age (very elderly) is increasing, and the management of these patients with pituitary surgery is controversial. OBJECTIVE: To determine the prevalence of pituitary tumors in elderly patients and to determine the safety of endoscopic transsphenoidal pituitary surgery for nonfunctioning pituitary adenomas in patients aged older than 80 years. METHODS: This retrospective study included elderly (65-75 years old) and very elderly consecutive patients operated between 2007 and 2015 for nonfunctioning pituitary adenomas. Tumor characteristics, comorbidities, pre- and postoperative visual and endocrinologic status, and postoperative complications were compared. RESULTS: Of the total 623 operated patients, 307 had nonfunctioning pituitary adenomas. Twenty-three percent (n = 143) of all patients were aged older than 65 years, whereas 2.56% (n = 16) were aged older than 80 years. Gonadotroph and nonimmunoreactive tumors occurred in 81% of patients aged older than 65 years. The study groups were Group A, comprising 15 patients aged older than 80 years, and Group B, comprising 49 patients aged 65-75 years. No presurgical statistical differences were noted between the 2 groups. Complete tumor resection was achieved in 53.3% of Group A and 73.5% of Group B. Postsurgical visual status improved significantly in Group A than in Group B (P = 0.0012). No deaths occurred, and no group differences were noted in the postoperative complications. CONCLUSIONS: Age exceeding 80 years is not by itself a predictor of worse clinical outcome of endoscopic transsphenoidal pituitary surgery for nonfunctioning adenomas. Emphasis should be placed on visual pathway decompression for the quality of life in very old people. PMID- 28676463 TI - Pial-Dural Intracranial Arteriovenous Fistula with Flow-Associated Aneurysmal Rupture-Case Report with Review of Literature and Proposal on the Mechanism of Hemorrhage and Treatment Options. AB - BACKGROUND: Vascular anomalies in the form of dural arteriovenous fistulas (DAVFs), arteriovenous malformations, and aneurysms are well described in the literature. Pial arteriovenous fistulas (PAVFs) are described to a lesser extent in the literature. When these anomalies are combined, diagnosis and treatment become complex. CASE DESCRIPTION: A 55-year-old man presented with PAVF/DAVF with a ruptured flow-related aneurysm in the distal left posterior inferior cerebellar artery, which required surgical clipping and disconnection. We performed a PubMed search of all identifiable cases of PAVFs in adults. We then identified which cases had components of DAVFs and flow-related aneurysms. We identified 51 PAVF cases and identified which patients presented with hemorrhage and the treatment modalities of all cases. Of 51 cases identified, 4 were a DAVF/FRA, and 5 were a PAVF/DAVF. One case of PAVF/DAVF/FRA was identified. CONCLUSIONS: The exact mechanism of PAVF/DAVF formation is unknown. Hemorrhage predilection of PAVF/DAVF is more difficult to predict than a sole fistula, likely secondary to the complex flow dynamics. To our knowledge, this literature review is the largest review to date regarding PAVFs in adult patients and can provide insight into decision making when evaluating treatment options. PMID- 28676459 TI - Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk. AB - Colon cancer is a multifactorial disease associated with a variety of lifestyle factors. Alterations in the gut microbiota and the intestinal metabolome are noted during colon carcinogenesis, implicating them as critical contributors or results of the disease process. Diet is a known determinant of health, and as a modifier of the gut microbiota and its metabolism, a critical element in maintenance of intestinal health. This review summarizes recent evidence demonstrating the role and responses of the intestinal microbiota during colon tumorigenesis and the ability of dietary bioactive compounds and probiotics to impact colon health from the intestinal lumen to the epithelium and systemically. We first describe changes to the intestinal microbiome, metabolome, and epithelium associated with colon carcinogenesis. This is followed by a discussion of recent evidence indicating how specific classes of dietary bioactives, prebiotics, or probiotics affect colon carcinogenesis. Lastly, we briefly address the prospects of using multiple 'omics' techniques to integrate the effects of diet, host, and microbiota on colon tumorigenesis with the goal of more fully appreciating the interconnectedness of these systems and thus, how these approaches can be used to advance personalized nutrition strategies and nutrition research. PMID- 28676464 TI - Endonasal Endoscopic Odontoidectomy in Ventral Diseases of the Craniocervical Junction: Results of a Multicenter Experience. AB - BACKGROUND: Over the past decades, supported by preliminary anatomic and clinical studies exploring its feasibility and safety, experience has increased of the use of the endoscopic endonasal approach (EEA) to ventral diseases at the craniocervical junction (CCJ). METHODS: A multicenter study was carried out over a 4-year period of 14 patients managed by EEA odontoidectomy for CCJ diseases causing irreducible atlantoaxial dislocation. The surgical setup included an IGS system based on computed tomography and magnetic resonance images fusion, and 0 degrees and 30 degrees angled endoscopes with dedicated endoscopic tools. RESULTS: Nine men and 5 women, with a mean age of 60.7 years, were included. The mean follow-up was 28.5 months; 9 patients had basilar impression, whereas 5 had a degenerative pannus. The quality of anterior decompression was excellent in all cases; nonetheless, a posterior stabilization was deemed necessary in 13 patients, and no external orthosis was used during the postoperative course. No tracheostomy or gastrostomy was required after surgery; no deaths, no new neurologic deficits/complications, and no postoperative cerebrospinal fluid leak were recorded. At follow-up, the neurologic status assessed with Frankel grade did not deteriorate in any of the patients but improved in 13 of them; and no new listhesis was shown on neuroradiologic follow-up. CONCLUSIONS: The results show that EEA provides a direct surgical corridor to the CCJ, allowing an adequate decompression as with the more invasive transoral route. Morbidity is less than with a transoral approach, resulting in higher patient comfort and faster recovery. PMID- 28676465 TI - Cancer-Related Fatigue in Post-Treatment Cancer Survivors: Theory-Based Development of a Web-Based Intervention. AB - BACKGROUND: Cancer-related fatigue (CrF) is the most common and disruptive symptom experienced by cancer survivors. We aimed to develop a theory-based, interactive Web-based intervention designed to facilitate self-management and enhance coping with CrF following cancer treatment. OBJECTIVE: The aim of our study was to outline the rationale, decision-making processes, methods, and findings which led to the development of a Web-based intervention to be tested in a feasibility trial. This paper outlines the process and method of development of the intervention. METHODS: An extensive review of the literature and qualitative research was conducted to establish a therapeutic approach for this intervention, based on theory. The psychological principles used in the development process are outlined, and we also clarify hypothesized causal mechanisms. We describe decision-making processes involved in the development of the content of the intervention, input from the target patient group and stakeholders, the design of the website features, and the initial user testing of the website. RESULTS: The cocreation of the intervention with the experts and service users allowed the design team to ensure that an acceptable intervention was developed. This evidence-based Web-based program is the first intervention of its kind based on self-regulation model theory, with the primary aim of targeting the representations of fatigue and enhancing self-management of CrF, specifically. CONCLUSIONS: This research sought to integrate psychological theory, existing evidence of effective interventions, empirically derived principles of Web design, and the views of potential users into the systematic planning and design of the intervention of an easy-to-use website for cancer survivors. PMID- 28676466 TI - Brazilian Samba Protocol for Individuals With Parkinson's Disease: A Clinical Non Randomized Study. AB - BACKGROUND: In the 10 most populated countries in the world, Parkinson's disease (PD) affects more than 5 million individuals. Despite optimal treatment options already developed for the disease, concomitant involvement of other areas of health care plays an important role in complementing the treatment. From this perspective, dancing can be viewed as a non-drug alternative that can reduce falls by improving some motor skills, such as mobility, balance, gait, and posture, and can also improve the overall quality of life. Brazilian samba promotes improvement in motor and non-motor symptoms in individuals with PD, providing a new treatment option for this population. OBJECTIVE: The main objective of this quasi-experimental study is to provide a 12-week samba protocol (2x/week) for individuals with PD and to compare its effects with the group without intervention. The hypothesis is that the Brazilian samba protocol will promote improvement in primary (motor) and secondary (non-motor) outcomes in individuals with PD. METHODS: The sample will be selected at random from individuals diagnosed with PD in the city of Florianopolis (SC, Brazil). Sample size calculation was performed with the G*Power 3.1.9.2 software, with 0.447 effect size, at 5% significance level, power of 0.9, and test and sample loss of 20%. This yielded 60 individuals divided between the intervention and control groups. The questionnaires will be filled out before and after the dance intervention. The data collection for the control group will be held simultaneously to the intervention group. The classes will last for 1 hour, twice a week in the evening for 12 weeks, and all classes will be divided into warm-up, main part, and relaxation. Two-way analysis of variance with repeated measures and Sidak post-hoc comparison test will be used for a comparative analysis of the final results of the control group with the experimental group and of the within group changes between pre- and postintervention period. RESULTS: We expect to complete follow-up in September 2017. CONCLUSIONS: The major inspiration for this study was to encourage the creation of new rehabilitation programs that do not emphasize doctor involvement. This is a unique protocol for PD and we believe it can be an important tool to alleviate the motor and non-motor symptoms of individuals with PD. Dance is a simple activity depending on little equipment and few financial resources, facilitating its implementation and improving the cost benefit relationship. In addition, activities that have a cultural aspect for the population in question, and which are pleasant, enable the participants to commit long term. This can enhance patient's compliance with the therapy, which is often a problem for many rehabilitation programs. PMID- 28676467 TI - The Rules of Engagement: Perspectives on Secure Messaging From Experienced Ambulatory Patient Portal Users. AB - BACKGROUND: Patient portals have shown promise in engaging individuals in self management of chronic conditions by allowing patients to input and track health information and exchange secure electronic messages with their providers. Past studies have identified patient barriers to portal use including usability issues, low health literacy, and concerns about loss of personal contact as well as provider concerns such as increased time spent responding to messages. However, to date, studies of both patient and provider perspectives on portal use have focused on the pre-implementation or initial implementation phases and do not consider how these issues may change as patients and providers gain greater experience with portals. OBJECTIVE: Our study examined the following research question: Within primary care offices with high rates of patient-portal use, what do experienced physician and patient users of the ambulatory portal perceive as the benefits and challenges of portal use in general and secure messaging in particular? METHODS: This qualitative study involved 42 interviews with experienced physician and patient users of an ambulatory patient portal, Epic's MyChart. Participants were recruited from the Department of Family Medicine at a large Academic Medical Center (AMC) and included providers and their patients, who had been diagnosed with at least one chronic condition. A total of 29 patients and 13 primary care physicians participated in the interviews. All interviews were conducted by telephone and followed a semistructured interview guide. Interviews were transcribed verbatim to permit rigorous qualitative analysis. Both inductive and deductive methods were used to code and analyze the data iteratively, paying particular attention to themes involving secure messaging. RESULTS: Experienced portal users discussed several emergent themes related to a need for greater clarity on when and how to use the secure messaging feature. Patient concerns included worry about imposing on their physician's time, the lack of provider compensation for responding to secure messages, and uncertainty about when to use secure messaging to communicate with their providers. Similarly, providers articulated a lack of clarity as to the appropriate way to communicate via MyChart and suggested that additional training for both patients and providers might be important. Patient training could include orienting patients to the "rules of engagement" at portal sign-up, either in the office or through an online tutorial. CONCLUSIONS: As secure messaging through patient portals is increasingly being used as a method of physician patient communication, both patients and providers are looking for guidance on how to appropriately engage with each other using this tool. Patients worry about whether their use is appropriate, and providers are concerned about the content of messages, which allow them to effectively manage patient questions. Our findings suggest that additional training may help address the concerns of both patients and providers, by providing "rules of engagement" for communication via patient portals. PMID- 28676468 TI - Rehabilitation-Oriented Serious Game Development and Evaluation Guidelines for Musculoskeletal Disorders. AB - BACKGROUND: The progress in information and communication technology (ICT) led to the development of a new rehabilitation technique called "serious game for functional rehabilitation." Previous works have shown that serious games can be used for general health and specific disease management. However, there is still lack of consensus on development and evaluation guidelines. It is important to note that the game performance depends on the designed scenario. OBJECTIVE: The objective of this work was to develop specific game scenarios and evaluate them with a panel of musculoskeletal patients to propose game development and evaluation guidelines. METHODS: A two-stage workflow was proposed using determinant framework. The development guideline includes the selection of three dimensional (3D) computer graphics technologies and tools, the modeling of physical aspects, the design of rehabilitation scenarios, and the implementation of the proposed scenarios. The evaluation guideline consists of the definition of evaluation metrics, the execution of the evaluation campaign, the analysis of user results and feedbacks, and the improvement of the designed game. RESULTS: The case study for musculoskeletal disorders on the healthy control and patient groups showed the usefulness of these guidelines and associated games. All participants enjoyed the 2 developed games (football and object manipulation), and found them challenging and amusing. In particular, some healthy subjects increased their score when enhancing the level of difficulty. Furthermore, there were no risks and accidents associated with the execution of these games. CONCLUSIONS: It is expected that with the proven effectiveness of the proposed guidelines and associated games, this new rehabilitation game may be translated into clinical routine practice for the benefit of patients with musculoskeletal disorders. PMID- 28676469 TI - Direct-to-Consumer Promotion of Prescription Drugs on Mobile Devices: Content Analysis. AB - BACKGROUND: US Food and Drug Administration (FDA) regulations state that any prescription drug promotion that presents drug benefits to consumers must also disclose certain information about the drug's risks in a similar manner. Nearly three-quarters of all US mobile phone subscribers use a smartphone, and over half report receiving mobile advertisements on their device. OBJECTIVE: The objective of this project was to investigate how prescription drugs are being promoted to consumers using mobile technologies. We were particularly interested in the presentation of drug benefits and risks, with regard to presence, placement, and prominence. METHODS: We analyzed a sample of 51 mobile promotional communications and their associated linked landing pages. We assessed the content and format of the mobile communications and landing pages with regard to presentation of drug benefits and risks. RESULTS: Of the 51 mobile communications we coded, 41% (21/51) were product claim communications (includes the drug name, benefits, and risks), 22% (11/51) were reminder communications (includes drug name only), and 37% (19/51) were help-seeking communications (includes information about the medical condition but not the drug name). Some of the product claim communications (5/21, 24%) required scrolling to see all the benefit information; in contrast, 95% (20/21) required scrolling to see all the risk information. Of the 19 product claim communications that presented both benefits and risks, 95% (18/19) presented benefits before risks and 47% (9/19) used a bigger font for benefits than for risks. Most mobile communications (35/51, 69%) linked to branded drug websites with both benefits and risks, 25% (13/51) linked to a landing page with benefits but no visible risks, and 6% (3/51) linked to a landing page with risks but no visible benefits. Few landing pages (4/51, 8%) required scrolling to see all the benefit information; in contrast, 51% (26/51) required scrolling to see all the risk information. Of the 35 landing pages with both benefit and risk information, 71% (25/35) presented benefits before risks and 51% (18/35) used a bigger font for benefits than for risks. CONCLUSIONS: These results indicate that, while risks and benefits are both represented in mobile communications and their associated landing pages, they are not equally prominent and accessible. This has implications for compliance with FDA fair balance regulations. PMID- 28676470 TI - Desirable Components for a Customized, Home-Based, Digital Care-Management App for Children and Young People With Long-Term, Chronic Conditions: A Qualitative Exploration. AB - BACKGROUND: Mobile apps for mobile phones and tablet devices are widely used by children and young people aged 0-18 years with long-term health conditions, such as chronic kidney disease (CKD), and their healthy peers for social networking or gaming. They are also poised to become a major source of health guidance. However, app development processes that are coproduced, rigorously developed, and evaluated to provide tailored, condition-specific, practical advice on day-to-day care management are seldom systematic or sufficiently described to enable replication. Furthermore, attempts to extrapolate to the real world are hampered by a poor understanding of the effects of key elements of app components. Therefore, effective and cost-effective novel, digital apps that will effectively and safely support care management are critical and timely. To inform development of such an app for children with CKD, a user requirements-gathering exercise was first needed. OBJECTIVE: To explore the views of children with CKD, their parents, and health care professionals to inform future development of a child focused, care-management app. METHODS: Using age- and developmentally appropriate methods, we interviewed 36 participants: 5-10-year-olds (n=6), 11-14-year-olds (n=6), 15-18-year-olds (n=5), mothers (n=10), fathers (n=2), and health care professionals (n=7). Data were analyzed using Framework Analysis and behavior change theories. RESULTS: Of the 27 interviews, 19 (70%) interviews were individual and 8 (30%) were joint-5 out of 8 (63%) joint interviews were with a child or young person and their parent, 1 out of 8 (13%) were with a child and both parents, and 2 out of 8 (25%) were with 2 professionals. Three key themes emerged to inform development of a software requirement specification for a future home-based, digital care-management app intervention: (1) Gaps in current online information and support, (2) Difficulties experienced by children with a long-term condition, and (3) Suggestions for a digital care-management app. Reported gaps included the fact that current online information is not usually appropriate for children as it is "dry" and "boring," could be "scary," and was either hard to understand or not relevant to individuals' circumstances. For children, searching online was much less accessible than using a professional endorsed mobile app. Children also reported difficulty explaining their condition to others, maintaining treatment adherence, coping with feeling isolated, and with trying to live a "normal" life. There was recognition that a developmentally appropriate, CKD-specific app could support the process of explaining the condition to healthy peers, reducing isolation, adhering to care-management plans, and living a "normal" life. Participants recommended a range of media and content to include in a tailored, interactive, age- and developmentally appropriate app. For example, the user would be able to enter their age and diagnosis so that only age-appropriate and condition-specific content is displayed. CONCLUSIONS: Future development of a digital app that meets the identified information and support needs and preferences of children with CKD will maximize its utility, thereby augmenting CKD caregiving and optimizing outcomes. PMID- 28676473 TI - Wendy Patricia Holmes. PMID- 28676471 TI - Patterns of Twitter Behavior Among Networks of Cannabis Dispensaries in California. AB - BACKGROUND: Twitter represents a social media platform through which medical cannabis dispensaries can rapidly promote and advertise a multitude of retail products. Yet, to date, no studies have systematically evaluated Twitter behavior among dispensaries and how these behaviors influence the formation of social networks. OBJECTIVES: This study sought to characterize common cyberbehaviors and shared follower networks among dispensaries operating in two large cannabis markets in California. METHODS: From a targeted sample of 119 dispensaries in the San Francisco Bay Area and Greater Los Angeles, we collected metadata from the dispensary accounts using the Twitter API. For each city, we characterized the network structure of dispensaries based upon shared followers, then empirically derived communities with the Louvain modularity algorithm. Principal components factor analysis was employed to reduce 12 Twitter measures into a more parsimonious set of cyberbehavioral dimensions. Finally, quadratic discriminant analysis was implemented to verify the ability of the extracted dimensions to classify dispensaries into their derived communities. RESULTS: The modularity algorithm yielded three communities in each city with distinct network structures. The principal components factor analysis reduced the 12 cyberbehaviors into five dimensions that encompassed account age, posting frequency, referencing, hyperlinks, and user engagement among the dispensary accounts. In the quadratic discriminant analysis, the dimensions correctly classified 75% (46/61) of the communities in the San Francisco Bay Area and 71% (41/58) in Greater Los Angeles. CONCLUSIONS: The most centralized and strongly connected dispensaries in both cities had newer accounts, higher daily activity, more frequent user engagement, and increased usage of embedded media, keywords, and hyperlinks. Measures derived from both network structure and cyberbehavioral dimensions can serve as key contextual indicators for the online surveillance of cannabis dispensaries and consumer markets over time. PMID- 28676472 TI - Internet Hospitals in China: Cross-Sectional Survey. AB - BACKGROUND: The Internet hospital, an innovative approach to providing health care, is rapidly developing in China because it has the potential to provide widely accessible outpatient service delivery via Internet technologies. To date, China's Internet hospitals have not been systematically investigated. OBJECTIVE: The aim of this study was to describe the characteristics of China's Internet hospitals, and to assess their health service capacity. METHODS: We searched Baidu, the popular Chinese search engine, to identify Internet hospitals, using search terms such as "Internet hospital," "web hospital," or "cloud hospital." All Internet hospitals in mainland China were eligible for inclusion if they were officially registered. Our search was carried out until March 31, 2017. RESULTS: We identified 68 Internet hospitals, of which 43 have been put into use and 25 were under construction. Of the 43 established Internet hospitals, 13 (30%) were in the hospital informatization stage, 24 (56%) were in the Web ward stage, and 6 (14%) were in full Internet hospital stage. Patients accessed outpatient service delivery via website (74%, 32/43), app (42%, 18/43), or offline medical consultation facility (37%, 16/43) from the Internet hospital. Furthermore, 25 (58%) of the Internet hospitals asked doctors to deliver health services at a specific Web clinic, whereas 18 (42%) did not. The consulting methods included video chat (60%, 26/43), telephone (19%, 8/43), and graphic message (28%, 12/43); 13 (30%) Internet hospitals cannot be consulted online any more. Only 6 Internet hospitals were included in the coverage of health insurance. The median number of doctors available online was zero (interquartile range [IQR] 0 to 5; max 16,492). The median consultation fee per time was Y20 (approximately US $2.90, IQR Y0 to Y200). CONCLUSIONS: Internet hospitals provide convenient outpatient service delivery. However, many of the Internet hospitals are not yet mature and are faced with various issues such as online doctor scarcity and the unavailability of health insurance coverage. China's Internet hospitals are heading in the right direction to improve provision of health services, but much more remains to be done. PMID- 28676474 TI - Chief medical officer wants genomic services to be centralised within five years. PMID- 28676475 TI - An unusual cause of finger swelling. PMID- 28676477 TI - Arthur Claude Wilson. PMID- 28676476 TI - Limitations of routine skeletal survey: detection of critical but asymptomatic cervical spine lesion in multiple myeloma. PMID- 28676478 TI - GWAS and cognitive abilities: Why correlations are inevitable and meaningless: GWA studies to identify genetic factors for educational achievements largely ignore underlying social structures and dynamics. PMID- 28676479 TI - Exceptional requests for care surge as rationing deepens. PMID- 28676481 TI - Robert Fischl. PMID- 28676482 TI - Sir Bernard Tomlinson. PMID- 28676480 TI - Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. AB - OBJECTIVE: Proton pump inhibitors (PPIs) are widely used, and their use is associated with increased risk of adverse events. However, whether PPI use is associated with excess risk of death is unknown. We aimed to examine the association between PPI use and risk of all-cause mortality. DESIGN: Longitudinal observational cohort study. SETTING: US Department of Veterans Affairs. PARTICIPANTS: Primary cohort of new users of PPI or histamine H2 receptor antagonists (H2 blockers) (n=349 312); additional cohorts included PPI versus no PPI (n=3 288 092) and PPI versus no PPI and no H2 blockers (n=2 887 030). MAIN OUTCOME MEASURES: Risk of death. RESULTS: Over a median follow-up of 5.71 years (IQR 5.11-6.37), PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28). Risk of death associated with PPI use was higher in analyses adjusted for high-dimensional propensity score (HR 1.16, CI 1.13 to 1.18), in two-stage residual inclusion estimation (HR 1.21, CI 1.16 to 1.26) and in 1:1 time-dependent propensity score-matched cohort (HR 1.34, CI 1.29 to 1.39). The risk of death was increased when considering PPI use versus no PPI (HR 1.15, CI 1.14 to 1.15), and PPI use versus no PPI and no H2 blockers (HR 1.23, CI 1.22 to 1.24). Risk of death associated with PPI use was increased among participants without gastrointestinal conditions: PPI versus H2 blockers (HR 1.24, CI 1.21 to 1.27), PPI use versus no PPI (HR 1.19, CI 1.18 to 1.20) and PPI use versus no PPI and no H2 blockers (HR 1.22, CI 1.21 to 1.23). Among new PPI users, there was a graded association between the duration of exposure and the risk of death. CONCLUSIONS: The results suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Limiting PPI use and duration to instances where it is medically indicated may be warranted. PMID- 28676483 TI - All patients with metal-on-metal hip implants should undergo tests, says MHRA. PMID- 28676484 TI - A therapy for FXS? AB - The antidiabetic drug metformin might be repurposed to treat patients with fragile X syndrome. PMID- 28676489 TI - Voltage-dependent Ca2+ entry into smooth muscle during contraction promotes endothelium-mediated feedback vasodilation in arterioles. AB - Vascular smooth muscle contraction is suppressed by feedback dilation mediated by the endothelium. In skeletal muscle arterioles, this feedback can be activated by Ca2+ signals passing from smooth muscle through gap junctions to endothelial cells, which protrude through holes in the internal elastic lamina to make contact with vascular smooth muscle cells. Although hypothetically either Ca2+ or inositol trisphosphate (IP3) may provide the intercellular signal, it is generally thought that IP3 diffusion is responsible. We provide evidence that Ca2+ entry through L-type voltage-dependent Ca2+ channels (VDCCs) in vascular smooth muscle can pass to the endothelium through positions aligned with holes in the internal elastic lamina in amounts sufficient to activate endothelial cell Ca2+ signaling. In endothelial cells in which IP3 receptors (IP3Rs) were blocked, VDCC-driven Ca2+ events were transient and localized to the endothelium that protrudes through the internal elastic lamina to contact vascular smooth muscle cells. In endothelial cells in which IP3Rs were not blocked, VDCC-driven Ca2+ events in endothelial cells were amplified to form propagating waves. These waves activated voltage-insensitive, intermediate-conductance, Ca2+-activated K+ (IKCa) channels, thereby providing feedback that effectively suppressed vasoconstriction and enabled cycles of constriction and dilation called vasomotion. Thus, agonists that stimulate vascular smooth muscle depolarization provide Ca2+ to endothelial cells to activate a feedback circuit that protects tissue blood flow. PMID- 28676490 TI - TGF-beta promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85alpha. AB - Transforming growth factor-beta (TGF-beta) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-beta are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3'-kinase (PI3K) protein kinase B (AKT) pathway. We found that TGF-beta activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85alpha and promoted the formation of a complex between the TGF-beta type I receptor (TbetaRI) and p85alpha, which led to the activation of PI3K and AKT. Lys63-linked polyubiquitylation of p85alpha on Lys513 and Lys519 in the iSH2 (inter-Src homology 2) domain was required for TGF-beta-induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TbetaRI. In situ proximity ligation assays revealed that polyubiquitylation of p85alpha was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-beta activates the PI3K-AKT pathway to drive cell migration. PMID- 28676491 TI - A perspective on AKT 25-plus years after its discovery. AB - Since its discovery more than 25 years ago, the kinase AKT has become a central figure in cell signaling. We highlight some of the landmark findings in those 25 years that contributed to our understanding of the regulation and function of AKT in directing cellular processes and behavior. Future progress toward fully understanding the roles of AKT in cell, tissue, and organismal biology will depend on technological innovations and the combination of in-depth reductionist analyses with systems-based strategies. PMID- 28676492 TI - Local emergency medical response after a terrorist attack in Norway: a qualitative study. AB - INTRODUCTION: On 22 July 2011, Norway suffered a devastating terrorist attack targeting a political youth camp on a remote island. Within a few hours, 35 injured terrorist victims were admitted to the local Ringerike community hospital. All victims survived. The local emergency medical service (EMS), despite limited resources, was evaluated by three external bodies as successful in handling this crisis. This study investigates the determinants for the success of that EMS as a model for quality improvement in healthcare. METHODS: We performed focus group interviews using the critical incident technique with 30 healthcare professionals involved in the care of the attack victims to establish determinants of the EMS' success. Two independent teams of professional experts classified and validated the identified determinants. RESULTS: Our findings suggest a combination of four elements essential for the success of the EMS: (1) major emergency preparedness and competence based on continuous planning, training and learning; (2) crisis management based on knowledge, trust and data collection; (3) empowerment through multiprofessional networks; and (4) the ability to improvise based on acquired structure and competence. The informants reported the successful response was specifically based on multiprofessional trauma education, team training, and prehospital and in-hospital networking including mental healthcare. The powerful combination of preparedness, competence and crisis management built on empowerment enabled the healthcare workers to trust themselves and each other to make professional decisions and creative improvisations in an unpredictable situation. CONCLUSION: The determinants for success derived from this qualitative study (preparedness, management, networking, ability to improvise) may be universally applicable to understanding the conditions for resilient and safe healthcare services, and of general interest for quality improvement in healthcare. PMID- 28676495 TI - Michael R Pokorny. PMID- 28676496 TI - Law, ethics, and emotion: the Charlie Gard case. PMID- 28676493 TI - Identifying large indels in targeted next generation sequencing assays for myeloid neoplasms: a cautionary tale of the ZRSR1 pseudogene. AB - Targeted next generation sequencing platforms have been increasingly utilised for identification of novel mutations in myeloid neoplasms, such as acute myeloid leukaemia (AML), and hold great promise for use in routine clinical diagnostics. In this study, we evaluated the utility of an open source variant caller in detecting large indels in a targeted sequencing of AML samples. While we found that this bioinformatics pipeline has the potential to accurately capture large indels (>20 bp) in patient samples, we highlighted the pitfall of a confounding ZRSR1 pseudogene that led to an erroneous ZRSR2 variant call. We further discuss possible clinical implications of the ZRSR1 pseudogene in myeloid neoplasms based on its molecular features. Knowledge of the confounding ZRSR1 pseudogene in ZRSR2 sequencing assays could be particularly important in AML diagnostics because the detection of ZRSR2 in AML patients is highly specific for an s-AML diagnosis. PMID- 28676497 TI - Farrell valve relieves bloating in gastrostomy patient. AB - Dysphagia and weight loss are experienced by up to 80% of patients with motor neuron disease (MND). Enteral tube feeding can benefit these patients but side effects including fullness, bloating, diarrhoea and constipation are frequent and can lead to non-compliance. Changes in feed formulation, regimens and the use of prokinetic medication can help symptoms. We describe a case where the use of gastric pressure relief bags during enteral feeding improved symptoms of bloating in a hospice inpatient with MND. Symptoms recurred when these were not used, which were only partially relieved by manual venting of the gastrostomy tube. We suggest that this simple, non-pharmacological approach to bloating may provide opportunities for symptom relief in the palliative care setting. PMID- 28676498 TI - Health and death literacy and cultural diversity: insights from hospital-employed interpreters. AB - OBJECTIVES: 001225The aim of this qualitative study is to better understand, through the experiences and insights of hospital interpreters, how people from culturally and linguistic diverse (CALD) communities might respond to advance care planning (ACP) and end-of-life discussions. METHODS: Hospital interpreters from five Melbourne metropolitan health services were recruited for in-depth semi structured interviews that explored the question, 'What can be learnt from hospital interpreters about cultural issues related to ACP and end-of-life decision-making?' Thirty-nine interpreters, representing 22 language groups, were interviewed. Analysis of the transcribed interviews used qualitative description. RESULTS: Thematic analysis identified three major themes: (1) moral difference; (2) health and death literacy; and (3) diversity within culture. CONCLUSION: A value-based approach to ACP is recommended as a way to capture the person's individual values and beliefs. Health and death literacy have been identified as areas that may be over-estimated; areas that can be addressed and improved, if recognised. Health and death literacy is a particular area that needs to be assessed and addressed as a pre-requisite to ACP discussions. PMID- 28676499 TI - Kinetic and structural analyses reveal residues in phosphoinositide 3-kinase alpha that are critical for catalysis and substrate recognition. AB - Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that activate signaling cascades controlling cell survival, proliferation, protein synthesis, and vesicle trafficking. PI3Ks have dual kinase specificity: a lipid kinase activity that phosphorylates the 3'-hydroxyl of phosphoinositides and a protein kinase activity that includes autophosphorylation. Despite the wealth of biochemical and structural information on PI3Kalpha, little is known about the identity and roles of individual active-site residues in catalysis. To close this gap, we explored the roles of residues of the catalytic domain and the regulatory subunit of human PI3Kalpha in lipid and protein phosphorylation. Using site directed mutagenesis, kinetic assays, and quantitative mass spectrometry, we precisely mapped key residues involved in substrate recognition and catalysis by PI3Kalpha. Our results revealed that Lys-776, located in the P-loop of PI3Kalpha, is essential for the recognition of lipid and ATP substrates and also plays an important role in PI3Kalpha autophosphorylation. Replacement of the residues His 936 and His-917 in the activation and catalytic loops, respectively, with alanine dramatically changed PI3Kalpha kinetics. Although H936A inactivated the lipid kinase activity without affecting autophosphorylation, H917A abolished both the lipid and protein kinase activities of PI3Kalpha. On the basis of these kinetic and structural analyses, we propose possible mechanistic roles of these critical residues in PI3Kalpha catalysis. PMID- 28676500 TI - Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF. AB - Pituitary tumor-transforming gene 1-binding factor (PTTG1IP; PBF) is a multifunctional glycoprotein, which is overexpressed in a wide range of tumours, and significantly associated with poorer oncological outcomes, such as early tumour recurrence, distant metastasis, extramural vascular invasion and decreased disease-specific survival. PBF transforms NIH 3T3 fibroblasts and induces tumours in nude mice, while mice harbouring transgenic thyroidal PBF expression show hyperplasia and macrofollicular lesions. Our assumption that PBF becomes an oncogene purely through increased expression has been challenged by the recent report of mutations in PBF within the Catalogue of Somatic Mutations in Cancer (COSMIC) database. We therefore sought to determine whether the first 10 PBF missense substitutions in human cancer might be oncogenic. Anisomycin half-life studies revealed that most mutations were associated with reduced protein stability compared to wild-type (WT) PBF. Proliferation assays narrowed our interest to two mutational events which significantly altered cell turnover: C51R and R140W. C51R was mainly confined to the endoplasmic reticulum while R140W was apparent in the Golgi apparatus. Both C51R and R140W lost the capacity to induce cellular migration and significantly reduced cell invasion. Colony formation and soft agar assays demonstrated that, in contrast to WT PBF, both mutants were unable to elicit significant colony formation or anchorage-independent growth. However, C51R and R140W retained the ability to repress radioiodide uptake, a functional hallmark of PBF. Our data reveal new insight into PBF function and confirm that, rather than being oncogenic, mutations in PBF are likely to be passenger effects, with overexpression of PBF the more important aetiological event in human cancer. PMID- 28676501 TI - Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans. AB - Reactive oxygen species (ROS), originally characterized based on their harmful effects on cells or organisms, are now recognized as important signal molecules regulating various biological processes. In particular, low levels of ROS released from mitochondria extend lifespan. Here, we identified a novel mechanism of generating appropriate levels of ROS at the plasma membrane through a peroxidase and dual oxidase (DUOX) system, which could extend lifespan in Caenorhabditis elegans A redox co-factor, pyrroloquinoline quinone (PQQ), activates the C. elegans DUOX protein BLI-3 to produce the ROS H2O2 at the plasma membrane, which is subsequently degraded by peroxidase (MLT-7), eventually ensuring adequate levels of ROS. These ROS signals are transduced mainly by the oxidative stress transcriptional factors SKN-1 (Nrf2 or NFE2L2 in mammals) and JUN-1, and partially by DAF-16 (a FOXO protein homolog). Cell biology experiments demonstrated a similarity between the mechanisms of PQQ-induced activation of human DUOX1 and DUOX2 and that of C. elegans BLI-3, suggesting that DUOXs are potential targets of intervention for lifespan extension. We propose that low levels of ROS, fine-tuned by the peroxidase and dual oxidase system at the plasma membrane, act as second messengers to extend lifespan by the effect of hormesis. PMID- 28676502 TI - Neurological letter from Kilimanjaro. PMID- 28676503 TI - Jonathan Gerwyn Evans. PMID- 28676504 TI - Overcoming Socioeconomic Differences in the Equitable Delivery of Peritoneal Dialysis. PMID- 28676505 TI - In Memory of Fred Boen (1927 - 2017). PMID- 28676506 TI - Peritoneal Dialysis Access and Start Practices that Affect Dialysate Leak and Technique Failure: Acts of Commission and Omission. PMID- 28676507 TI - Length of Time on Peritoneal Dialysis and Encapsulating Peritoneal Sclerosis - Position Paper for ISPD: 2017 Update. PMID- 28676508 TI - The Potential Cardiovascular Benefits of Low-Glucose Degradation Product, Biocompatible Peritoneal Dialysis Fluids: A Review of the Literature. AB - Cardiovascular mortality in the end-stage renal disease (ESRD) population remains the leading cause of death. Targeting traditional cardiovascular risk factors has proven unsuccessful in this patient population, and therefore attention has turned to risk factors related to chronic kidney disease (CKD). The toxicity of high-glucose peritoneal dialysis (PD) solutions has been well documented. The breakdown of glucose into glucose degradation products (GDP) and advanced glycation end-products (AGE) has the ability to alter cell viability and cause premature apoptosis and is strongly correlated with interstitial fibrosis and microvascular sclerosis. Biocompatible solutions have been introduced to combat the hostile milieu to which PD patients are exposed.Given the considerable cardiovascular burden for PD patients, little is known about the cardiovascular impact the new biocompatible solutions may have. This review analyzes the existing literature regarding the mechanisms through which low-GDP solutions may modulate cardiovascular risk. Interventions using low-GDP solutions have provided encouraging changes in structural cardiovascular measures such as left ventricular mass (LVM), although metabolic changes from reduced GDP and AGE exposure yield inconclusive results on vascular remodelling. It is thought that the local effects of reduced glucose exposure may improve membrane integrity and therefore fluid status. Further research in the form of a robust randomized controlled trial should be carried out to assess the true extent of the cardiovascular benefits these biocompatible solutions may hold. PMID- 28676509 TI - Peritoneal Dialysis for Patients with Autosomal Dominant Polycystic Kidney Disease. AB - End-stage renal disease secondary to autosomal dominant polycystic kidney (ADPKD) is a common issue worldwide. Peritoneal dialysis (PD) is a reasonable option for renal replacement therapy for these patients and should not be withheld due to concerns that the patient may not tolerate the fluid volumes in the peritoneal cavity. This review covers the existing data on the outcomes and complications associated with the use of PD in the polycystic kidney disease patient. In general, PD is well tolerated and outcomes in ADPKD patients are equivalent to or better than other patient groups. PMID- 28676510 TI - Peritoneal Dialysis in Very Low Birth Weight Neonates. AB - BACKGROUND: The aim of this retrospective study is to evaluate clinical characteristics and outcomes of very low birth weight (VLBW) neonates with acute kidney injury (AKI) treated with peritoneal dialysis (PD). METHODS: This retrospective study included 10 VLBW neonates treated with PD. Intravenous (IV) cannula and umbilical venous catheter were used for the peritoneal access. RESULTS: Mean age at the moment of starting PD was 14.9 +/- 9.3 days. Mean body weight (BW) was 825 +/- 215 g. The average gestational age was 26.3 +/- 1.1 weeks. The average duration of dialysis was 20.5 +/- 14.7 h. The average ultrafiltration was 7.7 +/- 4.2 mL/kg/h. At the moment of starting PD, the average BW was 302 +/- 317g (22 +/- 13%), higher than at birth (in patients who had PD started in first 2 weeks of their lives) or higher than the BW before AKI was diagnosed (patients who had PD started when they were older than 2 weeks). The main cause of AKI was sepsis (n = 8/10). Dialysate leak was registered in 2 patients, 1 patient had peritonitis and the other had a blocked PD catheter. Six patients died during PD (severe sepsis), 1 died due to hypoxic encephalopathy and coma, and 2 patients survived. One patient (with hypoxic encephalopathy and coma) died 10 days after PD was stopped due to sepsis. The overall mortality was 80%. CONCLUSION: Acute PD is still an appropriate treatment choice for VLBW neonates with AKI. In VLBW neonates, PD can be performed with an improvised PD system and catheters. PMID- 28676511 TI - Absence of Post-Transplantation Encapsulating Peritoneal Sclerosis after Relatively Short Exposure to Peritoneal Dialysis: Prospective Analysis Using Repeated Abdominal CT Scanning. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is the most severe complication of peritoneal dialysis (PD). Several retrospective reports published between 2007 and 2009 have suggested an increasing incidence of EPS occurring after kidney transplantation. We conducted a prospective observational study to determine the incidence of post-transplantation EPS and identify possible risk factors. METHODS: Consecutive PD patients undergoing kidney transplantation between 2009 and 2013 were included. Encapsulating peritoneal sclerosis was defined as gastrointestinal obstruction combined with radiological evidence of EPS. Gastrointestinal symptoms were assessed using a self-administered Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Abdominal computed tomography (CT) was performed prospectively at 6 and 18 months post transplantation. The primary end point was EPS during follow-up. RESULTS: Fifty three PD patients were included (age 51 +/- 14 years). Mean PD duration was 31.3 months. Peritoneal dialysis solutions low in glucose degradation products and icodextrin were used by 86.8% of patients. A fast or average-fast transport status was documented in 83.0%. After a median follow-up of 19 months, complete data of 47 patients were available for analysis. None of the patients developed clinical or radiological signs of EPS. The GSRS score improved from 1.87 to 1.55 (p = 0.024) and body weight increased from 75.9 to 78.3 kg (p = 0.003). Only 1 patient had new onset localized (< 20%) peritoneal thickening on CT 22 months post-transplantation. CONCLUSION: Post-transplantation EPS did not develop in this cohort of patients with a relatively short time of PD exposure. This suggests that these patients can be transplanted safely without concern for the development of EPS, at least within the follow-up period of 19 months. PMID- 28676513 TI - Antibiotic Lock in Tenckhoff Catheter for Biofilm-Associated Peritonitis. AB - Biofilm bacteria in the Tenckhoff catheter are notoriously difficult to eradicate. They are the potential sources of relapsing or repeat peritonitis among peritoneal dialysis (PD) patients. Inadequate penetration into biofilms by standard intraperitoneal antibiotics, as well as a lack of effective adjunctive treatment, leads to a high rate of Tenckhoff catheter loss as a result of biofilm bacteria. In hemodialysis, on the other hand, catheter-related bloodstream infection caused by biofilm bacteria does not necessarily lead to a loss of catheter. Here, the use of antibiotic lock in conjunction with systemic antibiotics has been shown to be an effective treatment. In this case report, we present 2 cases of biofilm-associated PD peritonitis. The success in salvaging the Tenckhoff catheters by antibiotic lock suggested a potentially similar efficacy in PD patients using this adjunctive treatment, which has not been thoroughly investigated in the literature. Relevant clinical trials are necessary to evaluate whether antibiotic lock is also effective in eradicating biofilm bacteria in the Tenckhoff catheter. PMID- 28676512 TI - Anemia Is Correlated with Malnutrition and Inflammation in Croatian Peritoneal Dialysis Patients: A Multicenter Nationwide Study. AB - Malnutrition, inflammation, and anemia are common in peritoneal dialysis (PD) patients. In this study, correlations between Malnutrition Inflammation Score (MIS), laboratory and anthropometric parameters, and anemia indices in Croatian PD patients were analyzed. One hundred and one PD patients (males/females 54/47, age 58.71 +/- 14.68 years, mean PD duration 21.82 +/- 21.71 months) were included. Clinical, laboratory, and anthropometric parameters were measured. Statistically significant correlations between MIS and erythropoietin weekly dose per kg of body weight (ESA weekly dose), hemoglobin (Hb), and erythrocytes were found (r = 0.439, p < 0.001; r = -0.032, p < 0.001; r = -0.435, p < 0.001), respectively. Also, statistically significant correlations were found between MIS and mean corpuscular volume (r = 0.344, p < 0.001), iron (r = -0.229, p = 0.021), and total iron binding capacity (TIBC) (r = -0.362, p < 0.001), respectively. Furthermore, statistically significant correlations between ESA weekly dose and serum albumin level and body mass index (BMI) were found (r = -0.272, p = 0.006; r = -0.269, p = 0.006), respectively. When we divided PD patients into 2 groups according Hb level (Hb >= 110 [N = 60, 59.41 %]) and Hb < 110 [N = 41, 40.59%]), statistically significant differences were found in MIS score (3.02 +/- 2.54 vs 4.54 +/- 3.54, p = 0.014), C-reactive protein (CRP) (3.52 +/- 6.36 vs 7.85 +/- 7.96, p = 0.005), and serum albumin level (44.22 +/- 8.54 vs 39.94 +/- 8.56, p = 0.003), respectively. Our findings suggest that anemia is correlated with malnutrition and inflammation in Croatian PD patients. Further studies are needed to assess whether modulating inflammatory or nutritional processes can improve anemia management in PD patients. PMID- 28676514 TI - Rapid Change in Residual Renal Function Decline Is Associated with Lower Survival and Worse Residual Renal Function Preservation in Peritoneal Dialysis Patients. AB - The survival advantage observed among peritoneal dialysis patients early on after dialysis initiation has been largely attributed to residual renal function (RRF) preservation due to higher baseline residual function and fewer comorbidities. We hypothesize that a rapid decline in RRF is associated with higher risk of anuria and mortality. In a retrospective cohort study of 581 subjects on peritoneal dialysis with longitudinal prevalent data, we assessed whether RRF change over time, in addition to baseline RRF, increased risk of mortality and anuria using Kaplan-Meier analysis and Cox proportional hazard analysis to control for known risk factors. Rapid RRF decline (>= 0.09 decline) over a 12-month period was associated with a 2.6-fold increase in the risk of death (hazard ratio [HR] 2.60, 95% confidence interval [CI] 1.66 - 4.07, compared with < 0.09 decline) and a 2 fold increase in anuria (HR 2.06, 95% CI 1.24 - 3.42). Each quartile of increasing severity of RRF decline over a 12-month period increased risk incrementally for death (2nd quartile: HR 3.04, CI 1.26 - 7.34; 3rd quartile: HR 4.01, CI 1.71 - 9.83; 4th quartile HR 5.78, CI 2.10 - 15.9) and generally for anuria (quartiles with HR 5.72 - 7.21). The escalating risk of mortality and anuria was greater for those with diabetes mellitus. In conclusion, rapid decline in RRF over a 12-month period increased the risk of mortality and likewise anuria, beyond previously established risk factors for mortality and anuria. The impact on mortality and RRF preservation was particularly severe for those with diabetes mellitus. PMID- 28676515 TI - Peritoneal Dialysis Catheters to Treat Refractory Non-Malignant Ascites. AB - Refractory non-malignant ascites is associated with significant morbidity. Serial, large-volume paracentesis is a common treatment. Tunneled peritoneal dialysis (PD) catheters are an effective treatment for refractory malignant ascites, but there are limited data on complications and effectiveness for non malignant ascites. We reviewed all 13 PD catheter insertions between 2010 - 2015 for this indication at our center. The median catheter survival time was 146 days. No complications occurred during catheter insertion, and no mechanical complications occurred after catheter insertion. One case of peritonitis developed over 217 catheter months. Peritoneal dialysis catheters may be a safe and effective option to manage refractory non-malignant ascites. Prospective, randomized trials are needed to better evaluate potential risks and benefits. PMID- 28676516 TI - Simultaneous Streptococcus canis and Pasteurella multocida Peritonitis in a Peritoneal Dialysis Patient. PMID- 28676517 TI - Communication with Peritoneal Dialysis Patients Post-Kumamoto Earthquake. PMID- 28676518 TI - Successful Diagnosis and Treatment of Peritoneal Dialysis-Related Pleuroperitoneal Communication by Contrast-Enhanced Ultrasonography and Thoracoscopic Surgery. PMID- 28676519 TI - Erratum: Association Between Peritoneal Glucose Exposure and Peritonitis in Peritoneal Dialysis Patients: The balANZ. PMID- 28676521 TI - European Commission issues advice on use of antimicrobials. PMID- 28676520 TI - Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants. AB - BACKGROUND: PCTP (phosphatidylcholine transfer protein) regulates the intermembrane transfer of phosphatidylcholine. Higher platelet PCTP expression is associated with increased platelet responses on activation of protease-activated receptor 4 thrombin receptors noted in black subjects compared with white subjects. Little is known about the regulation of platelet PCTP. Haplodeficiency of RUNX1, a major hematopoietic transcription factor, is associated with thrombocytopenia and impaired platelet responses on activation. Platelet expression profiling of a patient with a RUNX1 loss-of-function mutation revealed a 10-fold downregulation of the PCTP gene compared with healthy controls. METHODS: We pursued the hypothesis that PCTP is regulated by RUNX1 and that PCTP expression is correlated with cardiovascular events. We studied RUNX1 binding to the PCTP promoter using DNA-protein binding studies and human erythroleukemia cells and promoter activity using luciferase reporter studies. We assessed the relationship between RUNX1 and PCTP in peripheral blood RNA and PCTP and death or myocardial infarction in 2 separate patient cohorts (587 total patients) with cardiovascular disease. RESULTS: Platelet PCTP protein in the patient was reduced by ~50%. DNA-protein binding studies showed RUNX1 binding to consensus sites in ~1 kB of PCTP promoter. PCTP expression was increased with RUNX1 overexpression and reduced with RUNX1 knockdown in human erythroleukemia cells, indicating that PCTP is regulated by RUNX1. Studies in 2 cohorts of patients showed that RUNX1 expression in blood correlated with PCTP gene expression; PCTP expression was higher in black compared with white subjects and was associated with future death/myocardial infarction after adjustment for age, sex, and race (odds ratio, 2.05; 95% confidence interval 1.6-2.7; P<0.0001). RUNX1 expression is known to initiate at 2 alternative promoters, a distal P1 and a proximal P2 promoter. In patient cohorts, there were differential effects of RUNX1 isoforms on PCTP expression with a negative correlation in blood between RUNX1 expressed from the P1 promoter and PCTP expression. CONCLUSIONS: PCTP is a direct transcriptional target of RUNX1. PCTP expression is associated with death/myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of PCTP may play a role in the pathogenesis of platelet-mediated cardiovascular events. PMID- 28676522 TI - Pressure on NHS finances drives new wave of postcode rationing. PMID- 28676524 TI - In utero vitamin D deficiency predisposes offspring to long-term adverse adipose tissue effects. AB - The fetal period represents an important window of susceptibility for later obesity and metabolic disease. Maternal vitamin D deficiency (VDD) during pregnancy is a global concern that may have long-lasting consequences on offspring metabolic health. We sought to determine whether a VDD in utero environment affects fetal adipose tissue development and offspring metabolic disease predisposition in adulthood. Furthermore, we sought to explore the extent to which the VDD intrauterine environment interacts with genetic background or postnatal environment to influence metabolic health. Eight-week-old P0 female C57BL/6J mice were fed either a VDD diet or sufficient diet (VDS) from four weeks before pregnancy (periconception) then bred to male Avy/a mice. Females were maintained on the diets throughout gestation. At weaning, Avy/a and a/a male F1 offspring were randomized to low-fat (LFD) or high-fat diet (HFD) until 19 weeks of age, at which point serum and adipose tissue were harvested for analyses. Mice born to VDD dams weighed less at weaning than offspring born to VDS dams but experienced rapid weight gain in the four weeks post weaning, and acquired a greater ratio of perigonadal (PGAT) to subcutaneous (SQAT) than control offspring. Additionally, these mice were more susceptible to HFD-induced adipocyte hypertrophy. Offspring of VDD dams also had greater expression of Pparg transcript. These novel findings demonstrate that in utero VDD, an easily correctable but highly prevalent health concern, predisposes offspring to long term adipose tissue consequences and possible adverse metabolic health complications. PMID- 28676523 TI - Macrophage 11beta-HSD-1 deficiency promotes inflammatory angiogenesis. AB - 11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11beta-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11beta-HSD1 deficiency or inhibition. However, 11beta-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11beta HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM Cre mediated deletion of Hsd11b1 to investigate whether 11beta-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11beta-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11beta-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11beta-HSD1 in macrophages may be beneficial in tissue repair. PMID- 28676525 TI - TNFRp55 deficiency promotes the development of ectopic endometriotic-like lesions in mice. AB - Endometriosis is an inflammatory disease depending on estradiol, with TNF-alpha being one of the most representative cytokines involved in its pathogenesis. TNF alpha acts through its bond to the TNFRp55 and TNFRp75 membrane receptors. The aim of this study was to analyze the effect of the TNFRp55 deficiency on the development of ectopic endometriotic-like lesions. Endometriosis was induced surgically in mice of the C57BL/6 strain, wild type (WT) and TNFRp55-/- (KO). After four weeks, the peritoneal fluid was collected and the lesions were counted, measured with a caliper, removed, weighed, fixed or kept at -80 degrees C. We evaluated the cell proliferation by proliferating cell nuclear antigen (PCNA) immunohistochemistry and apoptosis by TUNEL technique in the ectopic lesions. MMP-2 and MMP-9 activities (factors involved in invasiveness) were measured by zymography in the peritoneal fluid; estradiol and progesterone levels were measured by radioimmunoassay in the lesions and in the peritoneal fluid. We found that in KO animals the mean number of lesions established per mouse, the lesion volume, weight and cell proliferation increased and apoptosis decreased. In addition, the activity of MMP-2 and the estradiol level increased, whereas the progesterone level was not significantly modified. In conclusion, the deficiency of TNFRp55 promoted the establishment and development of endometriosis through an increase in the lesion size and high levels of estradiol which correlate with an increase in the MMP-2 activity. This is evidence of the possible association of the deregulation of the TNFRp55 expression and the survival of the endometriotic tissue in ectopic sites. PMID- 28676526 TI - Dexamethasone increases production of C-type natriuretic peptide in the sheep brain. AB - Although C-type natriuretic peptide (CNP) has high abundance in brain tissues and cerebrospinal fluid (CSF), the source and possible factors regulating its secretion within the central nervous system (CNS) are unknown. Here we report the dynamic effects of a single IV bolus of dexamethasone or saline solution on plasma, CSF, CNS and pituitary tissue content of CNP products in adult sheep, along with changes in CNP gene expression in selected tissues. Both CNP and NTproCNP (the amino-terminal product of proCNP) in plasma and CSF showed dose responsive increases lasting 12-16 h after dexamethasone, whereas other natriuretic peptides were unaffected. CNS tissue concentrations of CNP and NTproCNP were increased by dexamethasone in all of the 12 regions examined. Abundance was highest in limbic tissues, pons and medulla oblongata. Relative to controls, CNP gene expression (NPPC) was upregulated by dexamethasone in 5 of 7 brain tissues examined. Patterns of responses differed in pituitary tissue. Whereas the abundance of CNP in both lobes of the pituitary gland greatly exceeded that of brain tissues, neither CNP nor NTproCNP concentration was affected by dexamethasone, despite an increase in NPPC expression. This is the first report of enhanced production and secretion of CNP in brain tissues in response to a corticosteroid. Activation of CNP secretion within CNS tissues by dexamethasone, not exhibited by other natriuretic peptides, suggests an important role for CNP in settings of acute stress. Differential findings in pituitary tissues likely relate to altered processing of proCNP storage and secretion. PMID- 28676527 TI - The ID genotype of MDM2 40 bp insertion/deletion polymorphism was associated with lower risk of SLE. AB - BACKGROUND: In patients with systemic lupus erythematosus (SLE), loss of immunological tolerance to self-nuclear antigens and abnormal activation of self reactive T and B cells lead to self-antibodies and immune complex production. The autoreactive lymphocytes are removed by the apoptotic process in healthy individuals; however, apoptosis disruption could cause accumulation of apoptotic bodies and nuclear debris. Therefore, apoptosis plays a crucial role in the pathogenesis of autoimmune diseases. PURPOSE: To investigate the association between two polymorphisms in an apoptotic-related gene, MDM2, and SLE. STUDY DESIGN: A case-control study was conducted on 200 patients with SLE and 206 healthy volunteers matched for age, sex, and ethnicity. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and PCR methods were used for genotyping. RESULTS: No association was found between the MDM2 T309G polymorphism (rs2279744) and SLE. The ID genotype of the insertion/deletion (I/D) polymorphism (rs3730485) was significantly lower in patients with SLE, and the ID genotype could be a protective factor for SLE. The DD genotype was not associated with SLE. The frequency of combined TT/ID and GG/ID genotypes of MDM2 T309G and I/D polymorphisms was lower in the patients with SLE and was associated with a lower risk of SLE. The frequency of the TD haplotype of MDM2 T309G and I/D polymorphisms was significantly lower in patients with SLE and could reduce the SLE risk. CONCLUSIONS: The ID genotype of the MDM2 I/D polymorphism was associated with a lower risk of SLE. There was no association between MDM2 T309G polymorphism and SLE. PMID- 28676528 TI - ? Evolocumab as an adjunct to statins for CVD. PMID- 28676530 TI - EMA issues guide to biosimilars in the EU. PMID- 28676529 TI - Combined contraceptive pill and long-term cancer risk. PMID- 28676531 TI - mtDNA polymorphism and metabolic inhibition affect sperm performance in conplastic mice. AB - Whereas a broad link exists between nucleotide substitutions in the mitochondrial genome (mtDNA) and a range of metabolic pathologies, exploration of the effect of specific mtDNA genotypes is on-going. Mitochondrial DNA mutations are of particular relevance for reproductive traits, since they are expected to have profound effects on male specific processes as a result of the strict maternal inheritance of mtDNA. Sperm motility is crucially dependent on ATP in most systems studied. However, the importance of mitochondrial function in the production of the ATP necessary for sperm function remains uncertain. In this study, we test the effect of mtDNA polymorphisms upon mouse sperm performance and bioenergetics by using five conplastic inbred strains that share the same nuclear background while differing in their mitochondrial genomes. We found that, while genetic polymorphisms across distinct mtDNA haplotypes are associated with modification in sperm progressive velocity, this effect is not related to ATP production. Furthermore, there is no association between the number of mtDNA polymorphisms and either (a) the magnitude of sperm performance decrease, or (b) performance response to specific inhibition of the main sperm metabolic pathways. The observed variability between strains may be explained in terms of additive effects of single nucleotide substitutions on mtDNA coding sequences, which have been stabilized through genetic drift in the different laboratory strains. Alternatively, the decreased sperm performance might have arisen from the disruption of the nuclear DNA/mtDNA interactions that have coevolved during the radiation of Mus musculus subspecies. PMID- 28676532 TI - Decreased PGF may contribute to trophoblast dysfunction in fetal growth restriction. AB - Fetal growth restriction (FGR) threatens perinatal health and is correlated with increased incidence of fetal original adult diseases. Most cases of FGR were idiopathic, which were supposed to be associated with placental abnormality. Decreased circulating placental growth factor (PGF) was recognized as an indication of placental deficiency in FGR. In this study, the epigenetic regulation of PGF in FGR placentas and the involvement of PGF in modulation of trophoblast activity were investigated. The expression level of PGF in placental tissues was determined by RT-qPCR, immunohistochemistry and ELISA. DNA methylation profile of PGF gene was analyzed by bisulfite sequencing. Trophoblastic cell lines were treated with ZM-306416, an inhibitor of PGF receptor FLT1, to observe the effect of PGF/FLT1 signaling on cell proliferation and migration. We demonstrated that PGF was downregulated in placentas from FGR pregnancies compared with normal controls. The villous expression of PGF was positively correlated with placental and fetal weight. The CpG island inside PGF promoter was hypomethylated without obvious difference in both normal and FGR placentas. However, the higher DNA methylation at another CpG island downstream exon 7 of PGF was demonstrated in FGR placentas. Additionally, we found FLT1 was expressed in trophoblast cells. Inhibition of PGF/FLT1 signaling by a selective inhibitor impaired trophoblast proliferation and migration. In conclusion, our data suggested that the PGF expression was dysregulated, and disrupted PGF/FLT1 signaling in trophoblast might contribute to placenta dysfunction in FGR. Thus, our results support the significant role of PGF in the pathogenesis of FGR. PMID- 28676533 TI - Kisspeptin-10 inhibits OHSS by suppressing VEGF secretion. AB - The aim of the present study was to elucidate the effects of kisspeptin-10 (Kp 10) on ovarian hyperstimulation syndrome (OHSS) and its related mechanism in OHSS rat models, human umbilical vein endothelial cells (HUVECs) and human luteinized granulosa cells. OHSS is a systemic disorder with high vascular permeability (VP) and ovarian enlargement. KISS1R (KISS1 receptor) is the specific receptor of kisspeptin. The kisspeptin/KISS1R system inhibits the expression of vascular endothelial growth factor (VEGF), which is the main regulator of VP. In our study, decreased expression of Kiss1r was observed in both ovaries and lung tissue of OHSS rats. Injection of exogenous Kp-10 inhibited the increase of VP and VEGF while promoting the expression of Kiss1r in both the ovarian and lung tissue of OHSS rats. Using HUVECs, we revealed that a high level of 17-beta estradiol (E2), a feature of OHSS, suppressed the expression of KISS1R and increased VEGF and nitric oxide (NO) through estrogen receptors (ESR2). Furthermore, KISS1R mRNA also decreased in the luteinized human granulosa cells of high-risk OHSS patients, and was consistent with the results in rat models and HUVECs. In conclusion, Kp-10 prevents the increased VP of OHSS by the activation of KISS1R and the inhibition of VEGF. PMID- 28676535 TI - Outcomes in a nurse-led peripherally inserted central catheter program: a retrospective cohort study. AB - BACKGROUND: Peripherally inserted central catheters (PICCs) provide enormous benefit to patients. However, recent publications have highlighted relatively high PICC-associated complication rates. We report on patient and device outcomes from a nurse-led program. METHODS: We performed a retrospective analysis of a prospective cohort of consecutive patients undergoing PICC insertion at The Ottawa Hospital between Jan. 1, 2013 and Dec. 31, 2014. Of the 8314 BioFlo PASV PICCs inserted, we randomly selected a sample of 700 and obtained a complete data set for 656. We measured the cumulative incidence of major complications (catheter-related bloodstream infections and deep vein thrombosis) and use of a thrombolytic to alleviate occlusions. RESULTS: The total number of catheter days was 58 486, and the median dwell time 45 days. We observed 4 cases of catheter related bloodstream infection (0.6% [95% CI 0.17%-1.55%]) (0.07/1000 catheter days). Ten patients (1.5% [95% CI 0.83%-2.78%]) (0.17/1000 catheter days) had catheter-related deep venous thrombosis. At least 1 dose of thrombolytic was required in 75 catheters (11.4% [95% CI 8.61%-13.39]), 31 (7.1%) of the 436 single-lumen catheters and 113 (25.7%) of the 440 lumina of dual-lumen catheters (p < 0.001). INTERPRETATION: We attribute our low rates of major complications to a nurse-led expert insertion team, standardized care and maintenance protocols, high insertion volumes, novel catheter material and continuous quality improvement initiatives that are implemented and evaluated regularly. We conclude that the considerable benefits PICCs provide to patients are attained with a low risk of major complications. PMID- 28676536 TI - John Kenneth Oyston. PMID- 28676534 TI - Expression patterns of HENMT1 and PIWIL1 in human testis: implications for transposon expression. AB - This study aimed to define the expression patterns of HENMT1 and PIWI proteins in human testis and investigate their association with transposon expression, infertility sub-type or development of testicular germ cell tumours (TGCTs). Testis biopsies showing normal spermatogenesis were used to identify normal localisation patterns of HENMT1 and PIWIL1 by immunolocalisation and RT-PCR after laser microdissection. 222 testis biopsies representing normal spermatogenesis, hypospermatogenesis, spermatogenic arrests, Sertoli cell-only (SCO) tumours and TGCTs were analysed by RT-qPCR for expression of HENMT1/PIWIL1/PIWIL2/PIWIL3/PIWIL4 and LINE-1 Additionally, HENMT1-overexpressing TCam2 seminoma cell lines were analysed for the same parameters by RT-qPCR. We found that HENMT1 and PIWIL1 are coexpressed in pachytene spermatocytes and spermatids. Expression of HENMT1, PIWIL1 and PIWIL2 was mainly dependent on germ cell content but low levels of expression were also detected in some SCO samples. Levels of HENMT1, PIWIL1 and PIWIL2 expression were low in TGCT. Samples with HENMT1, PIWIL2 and PIWIL4 expression showed significantly (P < 0.05) lower transposon expression compared to samples without expression in the same histological group. HENMT1-overexpressing TCam2 cells showed lower LINE-1 expression than empty vector-transfected control lines. Our findings support that the transposon-regulating function of the piRNA pathway found in the mouse is conserved in adult human testis. HENMT1 and PIWI proteins are expressed in a germ cell-specific manner and required for transposon control. PMID- 28676539 TI - Correction: 'Authors' response to comment on 'Postpartum contraception: a missed opportunity to prevent unintended pregnancy and short inter-pregnancy intervals'. PMID- 28676538 TI - Correction: 'Postponing menstruation: choices and concerns'. PMID- 28676540 TI - What is the future for sexual and contraceptive services? PMID- 28676541 TI - Off-piste in practice: efficacy, awkward questions and the power of relationship. PMID- 28676542 TI - Evidence and reality must trump Trump's ideology: an international perspective. PMID- 28676543 TI - Access to contraception: why patient choice matters. PMID- 28676544 TI - End of the road for Essure?(r). PMID- 28676545 TI - Safety issue with TT380 Slimline intrauterine contraceptive device. PMID- 28676546 TI - Comment on 'Care of patients using progestogen-only injectables'. PMID- 28676547 TI - Reproductive history and fracture risk in postmenopausal women in a US national survey. PMID- 28676549 TI - Venus. PMID- 28676548 TI - Response to 'Safety issue with TT380 Slimline intrauterine contraceptive device'. PMID- 28676551 TI - Increased FNDC5 is associated with insulin resistance in high fat-fed mice. AB - FNDC5/irisin, has recently been identified as a novel protein that stimulates the "browning" of white adipose by inducing thermogenesis via increased uncoupling protein 1 (UCP1). We tested the hypothesis that high fat diet-induced prediabetic mice would exhibit increased FNDC5 and this effect would be attenuated by chronic exercise. C57BL/6 mice were randomized into three groups for the 4 week intervention: Standard diet (Std, n = 12), High fat diet (HF, n = 14), or High fat diet and free access to a running wheel (HFEX, n = 14). Body weight, glucose, insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) were greater in HF compared to Std and HFEX after the 4 week intervention. In support of our hypothesis, FNDC5 was higher in HF in both skeletal muscle and adipose compared to Std and was lower in adipose only in HFEX compared to HF mice. Following the same pattern, PGC-1alpha was significantly higher in HF compared to Std in skeletal muscle and significantly lower in HFEX compared to HF in adipose. UCP1 was significantly lower in HFEX versus Std (in skeletal muscle) and versus HF (in adipose). HOMA-IR was significantly correlated with FNDC5 protein levels in adipose. Increased FNDC5 in adipose and skeletal muscle may be a compensatory mechanism to offset high fat diet-induced weight gain and insulin resistance by increasing energy expenditure. PMID- 28676552 TI - Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle. AB - Emerging evidence implicates ghrelin, a gut-derived, orexigenic hormone, as a potential mediator of insulin-responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin-stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser473 AKT or Thr172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin-dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle. PMID- 28676553 TI - Voluntary physical activity counteracts the proliferative tumor growth microenvironment created by adipose tissue via high-fat diet feeding in female rats. AB - The adipokine secretion profile created from adipose tissue may represent the molecular mechanism behind the obesity-breast cancer association. Two adipokines, adiponectin (ADIPO), and leptin (LEP), are altered with obesity and exert antagonistic effects on breast cancer proliferation. We set out to determine whether the adipose-dependent tumor promoting growth environment created by a high-fat diet (HFD) in female Sprague-Dawley rats is altered compared to established responses in male rats and whether voluntary physical activity (PA) ameliorates any HFD-dependent effects. We found that conditioned media (CM) created from the adipose tissue of female HFD-fed rats increased the proliferation of MCF7 cells compared to those cells grown in CM prepared from lean adipose tissue. HFD-CM inhibited AMPK and activated Akt signaling, decreased p27 phosphorylation at T198, reduced total p27 and AdiporR1 protein levels and promoted cell-cycle entry. PA reversed the proliferative effects of HFD-CM on MCF7 cells by preventing the effects of HFD on AMPK, Akt, p27 and AdipoR1, ultimately resulting in cell-cycle withdrawal. Overexpressing AdipoR1 abolished the proliferative effects of the HFD-CM on MCF7 cells and enhanced the anti proliferative effects PA on the HFD-CM Thus, PA represents a means to prevent deleterious obesity-related alterations in tumor growth environment which are brought about by changes in adipokine secretion profile from adipose tissue in the presence of estrogen. Furthermore, although adipose produces hundreds of adipokines, the ADIPO:LEP ratio may serve to indicate the contribution of adipose in creating a tumor growth microenvironment. PMID- 28676555 TI - Composition of two-week change in body weight under unrestricted free-living conditions. AB - The composition of weight change has a large impact on energy balance calculations. Composition of long-term weight change interventions is well documented, but information on short-term weight change under unrestricted free living conditions is limited. The composition and energy density of the changes in body weight during 2-week free-living conditions were analyzed in adults from two cohorts: cohort 1 (n = 24) included participants from the reproducibility subset of the Observing Protein and Energy Nutrition study; cohort 2 (n = 22) included participants who were studied under free-living conditions in an ongoing study in the Chicago area. Change in body weight, total body water (TBW) by stable isotope dilution (cohort 1), and fat mass (FM) and fat-free mass (FFM) by serial DXA (cohort 2) were measured. To determine the fractional composition of the change in body weight we analyzed the linear associations between changes in body weight and changes in body composition. In the combined dataset, the average change in body weight (0.26 +/- 1.2 kg) was consistent with being in energy balance. Average change in body weight was associated with the change in TBW (P < 0.0001) in cohort 1 and the change in FFM (P = 0.0002) in cohort 2. A unit change in body weight was composed of 84% change in FFM in the combined dataset indicating that 2-week fluctuation in body weight is largely composed of FFM The energy density of 1-3 kg short-term changes in body weight averaged 2380 kcal/kg. PMID- 28676554 TI - Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR. AB - Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC-5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24-h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC-5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real-time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC-5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low-molecular-weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats. PMID- 28676556 TI - Influence of longitudinal radiation exposure from microcomputed tomography scanning on skeletal muscle function and metabolic activity in female CD-1 mice. AB - Microcomputed tomography (MUCT) is an imaging technology to assess bone microarchitecture, a determinant of bone strength. When measured in vivo, MUCT exposes the skeletal site of interest to a dose of radiation, in addition to nearby skeletal muscles as well. Therefore, the aim of this study was to determine the effects of repeated radiation exposure from in vivo MUCT on muscle health - specifically, muscle morphometrics, contractile function, and enzyme activity. This study exposed the right hind limb of female mice to either a low (26 cGy) or moderate (46 cGy) dose, at 2, 4, and 6 months of age, while the left hind limb of the same animal was exposed to a single dose at 6 months to serve as a nonirradiated control. Muscle weight, cross-sectional area, isometric contractile function, and representative maximal enzyme activities of amino acid, fatty acid, glucose, and oxidative metabolism in extensor digitorum longus (EDL) and soleus were assessed. Low-dose radiation had no effect. In contrast, moderate dose radiation resulted in a 5% increase in time-to-peak tension and 16% increase in half-relaxation time of isometric twitches in EDL, although these changes were not seen when normalized to force. Moderate-dose radiation also resulted in an ~33% decrease in citrate synthase activity in soleus but not EDL, with no changes to the other enzymes measured. Thus, three low doses of radiation over 6 months had no effect on contractile function or metabolic enzyme activity in soleus and EDL of female mice. In contrast, three moderate doses of radiation over 6 months induced some effects on metabolic enzyme activity in soleus but not EDL Future studies that wish to investigate muscle tissue that is adjacent to scanned bone should take radiation exposure dose into consideration. PMID- 28676557 TI - Effect of specialist palliative care services on quality of life in adults with advanced incurable illness in hospital, hospice, or community settings: systematic review and meta-analysis. AB - Objective To assess the effect of specialist palliative care on quality of life and additional outcomes relevant to patients in those with advanced illness.Design Systematic review with meta-analysis.Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and trial registers searched up to July 2016.Eligibility criteria for selecting studies Randomised controlled trials with adult inpatients or outpatients treated in hospital, hospice, or community settings with any advanced illness. Minimum requirements for specialist palliative care included the multiprofessional team approach. Two reviewers independently screened and extracted data, assessed the risk of bias (Cochrane risk of bias tool), and evaluated the quality of evidence (GRADE tool).Data synthesis Primary outcome was quality of life with Hedges' g as standardised mean difference (SMD) and random effects model in meta-analysis. In addition, the pooled SMDs of the analyses of quality of life were re-expressed on the global health/QoL scale (item 29 and 30, respectively) of the European Organization for Research and Treatment of Cancer QLQ-C30 (0-100, high values=good quality of life, minimal clinically important difference 8.1).Results Of 3967 publications, 12 were included (10 randomised controlled trials with 2454 patients randomised, of whom 72% (n=1766) had cancer). In no trial was integration of specialist palliative care triggered according to patients' needs as identified by screening. Overall, there was a small effect in favour of specialist palliative care (SMD 0.16, 95% confidence interval 0.01 to 0.31; QLQ C30 global health/QoL 4.1, 0.3 to 8.2; n=1218, six trials). Sensitivity analysis showed an SMD of 0.57 (-0.02 to 1.15; global health/QoL 14.6, -0.5 to 29.4; n=1385, seven trials). The effect was marginally larger for patients with cancer (0.20, 0.01 to 0.38; global health/QoL 5.1, 0.3 to 9.7; n=828, five trials) and especially for those who received specialist palliative care early (0.33, 0.05 to 0.61, global health/QoL 8.5, 1.3 to 15.6; n=388, two trials). The results for pain and other secondary outcomes were inconclusive. Some methodological problems (such as lack of blinding) reduced the strength of the evidence.Conclusions Specialist palliative care was associated with a small effect on QoL and might have most pronounced effects for patients with cancer who received such care early. It could be most effective if it is provided early and if it identifies though screening those patients with unmet needs.Systematic review registration PROSPERO CRD42015020674. PMID- 28676558 TI - Willingness to change behaviours to reduce the risk of pharyngeal gonorrhoea transmission and acquisition in men who have sex with men: a cross-sectional survey. AB - OBJECTIVES: The aim of this study was to examine the willingness of men who have sex with men (MSM) to change their behaviours to potentially reduce the risk of pharyngeal gonorrhoea transmission and acquisition. METHODS: A cross-sectional questionnaire-based study was conducted among MSM attending the Melbourne Sexual Health Centre, Australia, between March and September 2015. Participants were asked how likely they would change their behaviours to reduce the risk of pharyngeal gonorrhoea. Six different potential preventive interventions were asked: (1) stop tongue kissing; (2) stop having receptive oral sex; (3) stop performing rimming; (4) stop using saliva as a lubricant during anal sex; (5) use of condoms during oral sex; and (6) use of alcohol-containing mouthwash daily. RESULTS: Of the 926 MSM who completed the questionnaire, 65.4% (95% CI 62.3% to 68.5%) expressed they were likely to use mouthwash daily to reduce the risk of pharyngeal gonorrhoea, 63.0% (95% CI 59.8% to 66.1%) would stop using saliva as a lubricant, and 49.5% (95% CI 46.2% to 52.7%) would stop rimming. In contrast, 77.6% (95% CI 74.8% to 80.3%) of MSM expressed they were unlikely to stop tongue kissing. MSM who were younger and had less male partners expressed they were unlikely to use mouthwash daily as an intervention to reduce risk of pharyngeal gonorrhoea acquisition. CONCLUSIONS: The practices MSM are willing to change to reduce the risk of pharyngeal gonorrhoea transmission and acquisition vary greatly; however, the majority of men are likely to use mouthwash daily to reduce the risk of pharyngeal gonorrhoea. PMID- 28676559 TI - A third of junior doctors say rota gaps have worsened their training, GMC finds. PMID- 28676560 TI - Congenital microcephaly in Quebec: baseline prevalence, risk factors and outcomes in a large cohort of neonates. AB - OBJECTIVE: We assessed baseline prevalence, risk factors and outcomes of microcephaly in a large population of neonates. DESIGN: Retrospective cohort study. SETTING: All hospitals in the province of Quebec, Canada. PARTICIPANTS: 794 microcephalic and 1 944 010 non-microcephalic infants born between 1989 and 2012. MAIN OUTCOME MEASURES: Baseline prevalence of microcephaly and occurrence of other congenital anomalies. We estimated the association of (1) pregnancy risk factors including TORCH infections (toxoplasmosis, rubella, cytomegalovirus, herpes, other), exposure to teratogens, diabetes and maternal congenital anomalies with risk of microcephaly, and (2) microcephaly with risk of infant mortality and severe morbidity, adjusted for maternal characteristics. RESULTS: The overall prevalence of microcephaly was 4.1 per 10 000, ranging between 3.0 and 5.3 per 10 000 over time. Only 37% of microcephalic infants presented with other congenital anomalies. Maternal infection during pregnancy was the strongest risk factor, with 32 times the risk of microcephaly (prevalence ratio 32.38; 95% CI 22.42 to 46.75) compared with no infection. Exposure to teratogens was the next most important risk factor, with three times greater risk (prevalence ratio 3.10; 95% CI 2.37 to 4.07). Microcephaly was associated with 20 times the risk of infant mortality compared with no microcephaly (prevalence ratio 20.52; 95% CI 15.57 to 27.04) and significantly greater infant morbidity. CONCLUSIONS: In Canada, infectious exposure during pregnancy is a strong risk factor for microcephaly, and affected infants are at higher risk of poor birth outcomes. Better monitoring of microcephaly is needed in the event that Zika or other novel viruses affect future risk. PMID- 28676561 TI - Determining the pattern and prevalence of alcohol consumption in pregnancy by measuring biomarkers in meconium. AB - OBJECTIVE: To investigate the feasibility of determining the pattern and prevalence of alcohol consumption in pregnancy by measuring ethanol biomarkers in meconium. DESIGN: Population-based observational study. SETTING: Inner-city maternity unit in Scotland, UK. POPULATION: Random sample of singleton infants delivered after 36 completed weeks' gestation. METHODS: Fatty acid ethyl esters (FAEEs) and ethyl glucuronide (EtG) in meconium were measured by liquid chromatography-mass spectroscopy. Samples were frozen at -20 degrees C before analysis. Results were compared anonymously with demographic data including maternal age, parity, smoking, ethnicity and postcode and with infant gestation, birth weight and head circumference. Written informed consent was obtained from all subjects. RESULTS: 235 samples of meconium were analysed (70% of eligible babies). Only four (1%) of mothers declined to participate. FAAEs were detected in all, including four samples below the limit of quantification (10 ng/g). 98 (42%) samples had FAEE concentrations >600 ng/g. EtG was detectable in 93 (40%) samples; in 35 (15%) EtG concentration was >30 ng/g. No mother reported heavy alcohol consumption in pregnancy. FAAE concentration correlated with EtG (Pearson's coefficient; p<0.001). There was no association between either biomarker and maternal age, parity, smoking, ethnicity or postcode, or infant gestation, birth weight or head circumference. CONCLUSION: Measurement of ethanol biomarkers in meconium is a feasible tool for determining the pattern and prevalence of alcohol consumption in pregnancy. Data suggest that at least 15% of pregnant women in the west of Scotland are consuming significant quantities of alcohol during latter pregnancy. PMID- 28676562 TI - Assessing the accuracy of the National Neonatal Audit Programme calculated central line-associated bloodstream infection rate from local data. PMID- 28676563 TI - Melatonin mediates vasodilation through both direct and indirect activation of BKCa channels. AB - Melatonin, synthesized primarily by the pineal gland, is a neuroendocrine hormone with high membrane permeability. The vascular effects of melatonin, including vasoconstriction and vasodilation, have been demonstrated in numerous studies. However, the mechanisms underlying these effects are not fully understood. Large conductance Ca2+-activated K+ (BKCa) channels are expressed broadly on smooth muscle cells and play an important role in vascular tone regulation. This study explored the mechanisms of myocyte BKCa channels and endothelial factors underlying the action of melatonin on the mesenteric arteries (MAs). Vascular contractility and patch-clamp studies were performed on myocytes of MAs from Wistar rats. Melatonin induced significant vasodilation on MAs. In the presence of Nomega-nitro-l-arginine methyl ester (l-NAME), a potent endothelial oxide synthase (eNOS) inhibitor, melatonin elicited concentration-dependent relaxation, with lowered pIC50 The effect of melatonin was significantly attenuated in the presence of BKCa channel blocker iberiotoxin or MT1/MT2 receptor antagonist luzindole in both (+) l-NAME and (-) l-NAME groups. In the (+) l-NAME group, iberiotoxin caused a parallel rightward shift of the melatonin concentration relaxation curve, with pIC50 lower than that of luzindole. Both inside-out and cell-attached patch-clamp recordings showed that melatonin significantly increased the open probability, mean open time and voltage sensitivity of BKCa channels. In a cell-attached patch-clamp configuration, the melatonin-induced enhancement of BKCa channel activity was significantly suppressed by luzindole. These findings indicate that in addition to the activation of eNOS, melatonin induced vasorelaxation of MAs is partially attributable to its direct (passing through the cell membrane) and indirect (via MT1/MT2 receptors) activation of the BKCa channels on mesenteric arterial myocytes. PMID- 28676565 TI - An interview with Bill Harris. AB - William 'Bill' Harris is Head of the Department of Physiology, Development and Neuroscience at the University of Cambridge, UK, and a Fellow of both the Royal Society and Academy of Medical Sciences. His lab works on the development of the vertebrate nervous system, with a particular focus on cell lineage in the retina. In 2017 he was awarded the British Society for Developmental Biology's Waddington Medal for outstanding research performance and services to the community. We met Bill in his Cambridge lab to talk science, art and ice hockey. PMID- 28676566 TI - MicroRNAs in neural development: from master regulators to fine-tuners. AB - The proper formation and function of neuronal networks is required for cognition and behavior. Indeed, pathophysiological states that disrupt neuronal networks can lead to neurodevelopmental disorders such as autism, schizophrenia or intellectual disability. It is well-established that transcriptional programs play major roles in neural circuit development. However, in recent years, post transcriptional control of gene expression has emerged as an additional, and probably equally important, regulatory layer. In particular, it has been shown that microRNAs (miRNAs), an abundant class of small regulatory RNAs, can regulate neuronal circuit development, maturation and function by controlling, for example, local mRNA translation. It is also becoming clear that miRNAs are frequently dysregulated in neurodevelopmental disorders, suggesting a role for miRNAs in the etiology and/or maintenance of neurological disease states. Here, we provide an overview of the most prominent regulatory miRNAs that control neural development, highlighting how they act as 'master regulators' or 'fine tuners' of gene expression, depending on context, to influence processes such as cell fate determination, cell migration, neuronal polarization and synapse formation. PMID- 28676564 TI - Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR). AB - OBJECTIVE: Although evidence suggests an inverse association between calcium intake and the risk of colorectal cancer, the mechanisms remain unclear. The calcium-sensing receptor (CASR) is expressed abundantly in normal colonic epithelium and may influence carcinogenesis. We hypothesized that calcium intake might be associated with lower risk of CASR-positive, but not CASR-negative, colorectal cancer. DESIGN: We assessed tumour CASR protein expression using immunohistochemistry in 779 incident colon and rectal cancer cases that developed among 136 249 individuals in the Nurses' Health Study and Health Professionals Follow-Up Study. Duplication method Cox proportional hazards regression analysis was used to assess associations of calcium intake with incidence of colorectal adenocarcinoma subtypes by CASR status. RESULTS: Total calcium intake was inversely associated with the risk of developing colorectal cancer (ptrend=0.01, comparing >=1200 vs <600 mg/day: multivariable HR=0.75, 95% CI 0.60 to 0.95). For the same comparison, higher total calcium intake was associated with a lower risk of CASR-positive tumours (ptrend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (ptrend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; pheterogeneity=0.06 between the CASR subtypes). The stronger inverse associations of calcium intake with CASR-positive but not CASR-negative tumours generally appeared consistent regardless of sex, tumour location and source of calcium. CONCLUSIONS: Our molecular pathological epidemiology data suggest a causal relationship between higher calcium intake and lower colorectal cancer risk, and a potential role of CASR in mediating antineoplastic effect of calcium. PMID- 28676567 TI - Human haematopoietic stem cell development: from the embryo to the dish. AB - Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and medical sciences, but our knowledge is still limited compared with what we know of adult HSCs and their microenvironment. This is particularly true for human haematopoiesis, and is reflected in our current inability to recapitulate the development of HSCs from pluripotent stem cells in vitro In this Review, we discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. We also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field. PMID- 28676568 TI - Extended C termini of CPC-LIKE MYB proteins confer functional diversity in Arabidopsis epidermal cell differentiation. AB - The CAPRICE (CPC) gene encodes a R3-type MYB transcription factor that promotes differentiation of root hair cells in Arabidopsis thaliana Here, we have compared the functions of five CPC-homologous genes for epidermal cell differentiation using CPC promoter-driven transgenic plants. Our results show that TRIPTYCHON (TRY) and ENHANCER OF TRY AND CPC2 (ETC2) were less effective in root hair cell differentiation and were unstable in root epidermal cells when compared with CPC, ETC1 or CPC LIKE MYB3 (CPL3). The deletion of the extended C-terminal domain of TRY and ETC2 enhanced protein stability and conferred the ability to induce root hair cell differentiation on them. Treatment with MG132, a proteasome inhibitor, also led to the accumulation of TRY, indicating that TRY proteolysis is mediated by the proteasome-dependent pathway. Our results indicate that the CPC family includes relatively stable (CPC, ETC1 and CPL3) and unstable (TRY and ETC2) proteins that might be degraded by the proteasome. Our findings provide new insights into the regulatory mechanism of CPC family proteins that mediate root hair cell differentiation and should be useful in understanding epidermal development. PMID- 28676570 TI - Correction: A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord. PMID- 28676569 TI - VEGF-A and neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels. AB - Visual information is relayed from the eye to the brain via retinal ganglion cell (RGC) axons. Mice lacking NRP1 or NRP1-binding VEGF-A isoforms have defective RGC axon organisation alongside brain vascular defects. It is not known whether axonal defects are caused exclusively by defective VEGF-A signalling in RGCs or are exacerbated by abnormal vascular morphology. Targeted NRP1 ablation in RGCs with a Brn3bCre knock-in allele reduced axonal midline crossing at the optic chiasm and optic tract fasciculation. In contrast, Tie2-Cre-mediated endothelial NRP1 ablation induced axon exclusion zones in the optic tracts without impairing axon crossing. Similar defects were observed in Vegfa120/120 and Vegfa188/188 mice, which have vascular defects as a result of their expression of single VEGF A isoforms. Ectopic midline vascularisation in endothelial Nrp1 and Vegfa188/188 mutants caused additional axonal exclusion zones within the chiasm. As in vitro and in vivo assays demonstrated that vessels do not repel axons, abnormally large or ectopically positioned vessels are likely to present physical obstacles to axon growth. We conclude that proper axonal wiring during brain development depends on the precise molecular control of neurovascular co-patterning. PMID- 28676574 TI - Aberrant Sodium Channel Currents and Hyperexcitability of Medial Entorhinal Cortex Neurons in a Mouse Model of SCN8A Encephalopathy. AB - SCN8A encephalopathy, or early infantile epileptic encephalopathy 13 (EIEE13), is caused predominantly by de novo gain-of-function mutations in the voltage-gated Na channel Nav1.6. Affected individuals suffer from refractory seizures, developmental delay, cognitive disability, and elevated risk of sudden unexpected death in epilepsy (SUDEP). A knock-in mouse model carrying the patient mutation p.Asn1768Asp (N1768D) reproduces many features of the disorder, including spontaneous seizures and SUDEP. We used the mouse model to examine the effects of the mutation on layer II stellate neurons of the medial entorhinal cortex (mEC), which transmit excitatory input to the hippocampus. Heterozygous (Scn8aD/+), homozygous (Scn8aD/D)), and WT (Scn8a+/+) littermates were compared at 3 weeks of age, the time of seizure onset for homozygous mice. Heterozygotes remain seizure free for another month. mEC layer II neurons of heterozygous and homozygous mice were hyperexcitable and generated long-lasting depolarizing potentials with bursts of action potentials after synaptic stimulation. Recording of Na currents revealed proexcitatory increases in persistent and resurgent currents and rightward shifts in inactivation parameters, leading to significant increases in the magnitude of window currents. The proexcitatory changes were more pronounced in homozygous mice than in heterozygotes, consistent with the earlier age of seizure onset in homozygotes. These studies demonstrate that the N1768D mutation increases the excitability of mEC layer II neurons by increasing persistent and resurgent Na currents and disrupting channel inactivation. The aberrant activities of mEC layer II neurons would provide excessive excitatory input to the hippocampus and contribute to hyperexcitability of hippocampal neurons in this model of SCN8A encephalopathy.SIGNIFICANCE STATEMENTSCN8A encephalopathy is a devastating neurological disorder that results from de novo mutations in the Na channel Nav1.6. In addition to seizures, patients suffer from cognitive and developmental delays and are at high risk for sudden unexpected death in epilepsy (SUDEP). A mouse knock-in model expressing the patient mutation N1768D reproduces several pathological phenotypes, including spontaneous seizures and sudden death. We demonstrate that medial entorhinal cortex (mEC) neurons from the mouse model exhibit proexcitatory alterations in Na channel activity, some of which were not seen in hippocampal or cortical neurons, and resulting in neuronal hyperexcitability. Because mEC neurons regulate the activity of the hippocampus, which plays an important role in seizure onset, we propose that these profound changes in mEC neuron excitability associated with the gain-of-function mutation of Nav1.6 may increase excitatory drive into the hippocampus, culminating in seizure activity and SUDEP. PMID- 28676575 TI - Maintenance of Mouse Gustatory Terminal Field Organization Is Disrupted following Selective Removal of Peripheral Sodium Salt Taste Activity at Adulthood. AB - Neural activity plays a critical role in the development of central circuits in sensory systems. However, the maintenance of these circuits at adulthood is usually not dependent on sensory-elicited neural activity. Recent work in the mouse gustatory system showed that selectively deleting the primary transduction channel for sodium taste, the epithelial sodium channel (ENaC), throughout development dramatically impacted the organization of the central terminal fields of three nerves that carry taste information to the nucleus of the solitary tract. More specifically, deleting ENaCs during development prevented the normal maturation of the fields. The present study was designed to extend these findings by testing the hypothesis that the loss of sodium taste activity impacts the maintenance of the normal adult terminal field organization in male and female mice. To do this, we used an inducible Cre-dependent genetic recombination strategy to delete ENaC function after terminal field maturation occurred. We found that removal of sodium taste neural activity at adulthood resulted in significant reorganization of mature gustatory afferent terminal fields in the nucleus of the solitary tract. Specifically, the chorda tympani and greater superficial petrosal nerve terminal fields were 1.4* and 1.6* larger than age matched controls, respectively. By contrast, the glossopharyngeal nerve, which is not highly sensitive to sodium taste stimulation, did not undergo terminal field reorganization. These surprising results suggest that gustatory nerve terminal fields remain plastic well into adulthood, which likely impacts central coding of taste information and taste-related behaviors with altered taste experience.SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. However, the importance of sensory-driven activity in maintaining these circuits at adulthood, especially in subcortical structures, appears to be much less. Here, we tested whether the loss of sodium taste activity in adult mice impacts the maintenance of how taste nerves project to the first central relay. We found that specific loss of sodium elicited taste activity at adulthood produced dramatic and selective reorganization of terminal fields in the brainstem. This demonstrates, for the first time, that taste-elicited activity is necessary for the normal maintenance of central gustatory circuits at adulthood and highlights a level of plasticity not seen in other sensory system subcortical circuits. PMID- 28676577 TI - Trade and public health. PMID- 28676576 TI - Stimulating Multiple-Demand Cortex Enhances Vocabulary Learning. AB - It is well established that networks within multiple-demand cortex (MDC) become active when diverse skills and behaviors are being learnt. However, their causal role in learning remains to be established. In the present study, we first performed functional magnetic resonance imaging on healthy female and male human participants to confirm that MDC was most active in the initial stages of learning a novel vocabulary, consisting of pronounceable nonwords (pseudowords), each associated with a picture of a real object. We then examined, in healthy female and male human participants, whether repetitive transcranial magnetic stimulation of a frontal midline node of the cingulo-opercular MDC affected learning rates specifically during the initial stages of learning. We report that stimulation of this node, but not a control brain region, substantially improved both accuracy and response times during the earliest stage of learning pseudoword object associations. This stimulation had no effect on the processing of established vocabulary, tested by the accuracy and response times when participants decided whether a real word was accurately paired with a picture of an object. These results provide evidence that noninvasive stimulation to MDC nodes can enhance learning rates, thereby demonstrating their causal role in the learning process. We propose that this causal role makes MDC candidate target for experimental therapeutics; for example, in stroke patients with aphasia attempting to reacquire a vocabulary.SIGNIFICANCE STATEMENT Learning a task involves the brain system within which that specific task becomes established. Therefore, successfully learning a new vocabulary establishes the novel words in the language system. However, there is evidence that in the early stages of learning, networks within multiple-demand cortex (MDC), which control higher cognitive functions, such as working memory, attention, and monitoring of performance, become active. This activity declines once the task is learnt. The present study demonstrated that a node within MDC, located in midline frontal cortex, becomes active during the early stage of learning a novel vocabulary. Importantly, noninvasive brain stimulation of this node improved performance during this stage of learning. This observation demonstrated that MDC activity is important for learning. PMID- 28676578 TI - Impact of the North American Free Trade Agreement on high-fructose corn syrup supply in Canada: a natural experiment using synthetic control methods. AB - BACKGROUND: Critics of free trade agreements have argued that they threaten public health, as they eliminate barriers to trade in potentially harmful products, such as sugar. Here we analyze the North American Free Trade Agreement (NAFTA), testing the hypothesis that lowering tariffs on food and beverage syrups that contain high-fructose corn syrup (HFCS) increased its use in foods consumed in Canada. METHODS: We used supply data from the Food and Agriculture Organization of the United Nations to assess changes in supply of caloric sweeteners including HFCS after NAFTA. We estimate the impact of NAFTA on supply of HFCS in Canada using an innovative, quasi-experimental methodology - synthetic control methods - that creates a control group with which to compare Canada's outcomes. Additional robustness tests were performed for sample, control groups and model specification. RESULTS: Tariff reductions in NAFTA coincided with a 41.6 (95% confidence interval 25.1 to 58.2) kilocalorie per capita daily increase in the supply of caloric sweeteners including HFCS. This change was not observed in the control groups, including Australia and the United Kingdom, as well as a composite control of 16 countries. Results were robust to placebo tests and additional sensitivity analyses. INTERPRETATION: NAFTA was strongly associated with a marked rise in HFCS supply and likely consumption in Canada. Our study provides evidence that even a seemingly modest change to product tariffs in free trade agreements can substantially alter population-wide dietary behaviour and exposure to risk factors. PMID- 28676579 TI - Type 2 diabetes in a four-year-old child. PMID- 28676580 TI - Testing for heritable thrombophilia in acute venous thromboembolism. PMID- 28676581 TI - Complications after long-term inferior vena cava filter placement. PMID- 28676582 TI - Johns Hopkins: A Canadian medical school? PMID- 28676583 TI - Priority reviews: innovation and safety. PMID- 28676584 TI - The new medical model: why medicine needs philosophy. PMID- 28676585 TI - The "new" medical model, fragmented clinical care and philosophy of medicine. PMID- 28676586 TI - Fewer Canadian MDs heading to the US. PMID- 28676587 TI - Drug pricing reforms promising but problematic. PMID- 28676588 TI - Ukrainians battle escalating HIV epidemic. PMID- 28676589 TI - Association between Catechol-O-Methyltransferase Val158Met (158G/A) Polymorphism and Suicide Susceptibility: A Meta-analysis. AB - BACKGROUND: Common functional Val158Met polymorphism in the Catechol-O methyltransferase (COMT) gene may have an impact on an individual's susceptibility to suicide, but individually published results are inconclusive. Therefore, we performed this meta-analysis to provide a more precise estimation of the association between COMT 158G/A (COMT Val158Met) polymorphism and suicide susceptibility. STUDY DESIGN: A cross-sectional study. METHODS: This systematic review and meta-analysis is a comprehensive literature search of PubMed, Scopus, Web of Science and Google Scholar databases was conducted on case-control studies published up to Mar 2017. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: We identified 14 eligible case-control studies, including 2353 suicide attempters and 2593 controls. The pooled results indicated that COMT 158G/A (COMT Val158Met) polymorphism was not significantly associated with increased overall suicide risk. The same results were revealed based on ethnicity, Hardy-Weinberg equilibrium (HWE) status and genotyping technique. However, there was significant association between COMT Val158Met polymorphism and suicide risk among females under the homozygote (AA vs. GG: OR=1.829, 95% CI=1.158-2.889, P=0.010) and recessive (AA vs. AG +GG: OR = 1.787, 95% CI=1.195, 2.671, P=0.005) models, but not among males. CONCLUSIONS: COMT 158G/A (COMT Val158Met) polymorphism was associated with suicide susceptibility only in females. PMID- 28676590 TI - Modeling the Geographic Consequence and Pattern of Dengue Fever Transmission in Thailand. AB - BACKGROUND: Dengue fever is one of the infectious diseases that is still a public health problem in Thailand. This study considers in detail, the geographic consequence, seasonal and pattern of dengue fever transmission among the 76 provinces of Thailand from 2003 to 2015. STUDY DESIGN: A cross-sectional study. METHODS: The data for the study was from the Department of Disease Control under the Bureau of Epidemiology, Thailand. The quarterly effects and location on the transmission of dengue was modeled using an alternative additive log-linear model. RESULTS: The model fitted well as illustrated by the residual plots and the Again, the model showed that dengue fever is high in the second quarter of every year from May to August. There was an evidence of an increase in the trend of dengue annually from 2003 to 2015. CONCLUSIONS: There was a difference in the distribution of dengue fever within and between provinces. The areas of high risks were the central and southern regions of Thailand. The log-linear model provided a simple medium of modeling dengue fever transmission. The results are very important in the geographic distribution of dengue fever patterns. PMID- 28676591 TI - Predictors of Readiness to Quit Stages and Intention to Quit Cigarette Smoking in 2 and 6 Months in Lebanon. AB - BACKGROUND: We aimed at examining quitting behaviors among Lebanese cigarette smokers in order to clarify characteristics of adults who were more likely to intend to quit smoking. STUDY DESIGN: A cross-sectional study. METHODS: This study was conducted between March 2014 and March 2015, involving 382 patients randomly chosen from 5 outpatient clinics in 5 hospitals in Lebanon. A standardized questionnaire was completed including socio-demographic characteristics, smoking behavior, chronic respiratory symptoms, Fagerstrom scale, Mondor scale, packaging perception, quitting behavior and readiness to quit ladder. RESULTS: 40.8% of participants reported having higher stages of readiness to quit while 33% and 7.9% of them intended to quit in 2 and 6 months later, respectively. Higher stages of readiness to quit were associated with high motivation to quit smoking (ORa=1.98; P=0.007), chronic wheezing and real quit attempt duration of >= 1 month (ORa=2.35, P=0.020 and ORa=2.15, P=0.003, respectively). Highly motivated smokers (ORa=1.83, P=0.040), who would have changed their favorite pack due to the graphical warnings (ORa=2.11, P=0.010) and who had past quit attempt (ORa=4.39, P<0.001) had more intention to quit in 2 months. Having past quit attempts would increase the intention to quit in 6 months by 7.48 times (ORa=7.48, P=0.007). CONCLUSIONS: Significantly higher intentions to quit cigarette smoking were associated with a higher motivation and influenced by shocking images and health related warnings on tobacco boxes. We hope our results will initiate public health educational programs and interventions to surge the intention to quit cigarette smoking as the first step of quitting. PMID- 28676592 TI - Epidemiologic Trend of Smear-Positive, Smear-Negative, Extra Pulmonary and Relapse of Tuberculosis in Iran (2001-2015); A Repeated Cross-Sectional Study. AB - BACKGROUND: Trend analysis is an important tool to monitor epidemiological changes of disease over time to guide resource allocation. This study aimed to study incidence trends and change-points of smear positive, smear negative, extra pulmonary and relapse of tuberculosis (TB) in Iran from 2001 to 2015. STUDY DESIGN: Repeated cross-sectional study METHODS: Nonlinear segmented regression was used to describe TB incidence trends; annual percent change (APC), average annual percent changes (AAPC) and change points for each disease separately. RESULTS: Of 154930 TB cases, 49.8% were smear positive, 19.7% smear negative, 27.32% extra-pulmonary and 3.18% relapse. For all TB types, the peak of incidence was in 2001. Two change point were estimated for all TB types (P<0.05). The APC of all TB types were -6.51 (95% CI: -7.4, -5.4) for first and 2.4 (95% CI: 0. 7, 4.1) for second segment. Although the trends were significantly decreasing from 2001 to 2015 for smear positive (AAPC=2.06%), smear negative (AAPC=3.57%), extra pulmonary (AAPC=3.2%) and relapse (AAPC=3.3%), the AAPCs of trends were not significant from 2006 to 2015. Except for Extra pulmonary TB (APC=4-.9%, 95%CI: 10, 1.2), the APCs of the last segments were significant. CONCLUSIONS: Even though the TB incidence rates were decreasing, the amount of reductions seem inadequate, to reach the goals of TB control in Iran. Especially, the increase in the extra-pulmonary TB rates is a point of concern that highlights more attention is required for these cases. It is essential to improve economic supports toward TB control, illegal immigrants, data registry systems and physician's sensitivity in TB detection. PMID- 28676593 TI - The Relationship between Food Insecurity and Esophageal and Gastric Cancers: A Case-Control Study. AB - BACKGROUND: Food insecurity is defined as the limited or uncertain availability of enough food for permanent active and healthy life. Upper gastrointestinal (GI) cancers (esophagus and stomach) are one of five most common cancers in Iran. This study aimed to determine the association of food insecurity and upper GI cancers in newly diagnosed patients. STUDY DESIGN: Case-control study. METHODS: Overall, 120 patients with upper GI cancers as cases and 120 patients with orthopedic, ear nose-throat (ENT), and neurologic diseases as controls were recruited from Imam Khomeini Hospital, Tehran, Iran in 2013. The patients were newly diagnosed using endoscopy or imaging or biopsy methods. They were individually matched for age, sex, and residential area. The general and United States Department of Agriculture (USDA) household food security questionnaires were completed. The univariate and multivariate conditional logistic regression tests were applied using the Stata 11SE statistical software. RESULTS: The food insecurity prevalence was 69.2% and 43.3% in cases and controls, respectively. Food insecurity, low economic level and family history of cancer were significantly associated with cancer (P<0.05). CONCLUSIONS: Food insecurity was one of the important risk factors for upper GI cancers that health care providers should consider it. PMID- 28676595 TI - [Introduction]. PMID- 28676594 TI - Suicide Mortality Trends in Four Provinces of Iran with the Highest Mortality, from 2006-2016. AB - BACKGROUND: Suicide is a major cause of unnatural deaths in the world. Its incidence is higher in western provinces of Iran. So far, there has not been any time series analysis of suicide in western provinces. The purpose of this study was to analyze suicide mortality data from 2006 to 2016 as well as to forecast the number of suicides for 2017 in four provinces of Iran (Ilam, Kermanshah and Lorestan and Kohgiluyeh and Boyer-Ahmad). STUDY DESIGN: Descriptive-analytic study. METHODS: Data were analyzed by time- series analysis using R software. Three automatic methods (Auto.arima, ETS (Error Transitional Seasonality) and time series linear model (TSLM)) were fitted on the data. The best model after cross validation according to the mean absolute error measure was selected for forecasting. RESULTS: Totally, 7004 suicidal deaths occurred of which, 4259 were male and 2745 were female. The mean age of the study population was (32.05 +/- 15.48 yr). Hanging and self-immolation were the most frequent types of suicide in men and women, respectively. The maximum and minimum number of suicides was occurred in July and August as well as January respectively. CONCLUSIONS: It is suggested that intervention measures should be designed in order to decrease the suicide rate particularly in the age group of 15-29 yr, and implemented as a pilot study, especially in these four provinces of Iran, which have a relatively high suicide rate. PMID- 28676597 TI - [Significance of Cooperation in the Outpatient Chemotherapy Room - Consideration from 2 Cases]. PMID- 28676596 TI - [Brief Report on the 69th Annual Meeting of the Japanese Cancer Association - Conquering Cancer with Collective Wisdom]. AB - The 69th Annual Meeting was held from September 22nd through 24th, at Osaka International Convention Center and RIHGA ROYAL HOTEL Osaka. The president of this meeting was professor Morito Monden, Osaka University Medical School. In this meeting, there were many scientific meetings including Special Remarks, symposiums, workshops, international sessions, oral and poster sessions and others, English workshops, morning lectures. Especially, as a special session, Now, what are the elements expected to cancer research ? - Special proposals for cancer research, was one of the most impressive session among many. PMID- 28676598 TI - [Retrospective Evaluation of the Effect of Aprepitant for Nausea and Vomiting Induced by Cisplatin Chemotherapy]. PMID- 28676599 TI - [Approach by Nurse Regarding to Education of Cancer Patients for Introduction of Home Parental Nutrition(HPN)]. PMID- 28676600 TI - [Management of Adverse Reaction of Anticancer Agents in Patients Undergoing Ambulant Chemotherapy - Promotion of Patient Self-Control as to Adverse Reaction Utilizing Brochure]. PMID- 28676601 TI - [Nutritional Support Systems at Cancer Centers: Highlighting the Role of the Dietitian as a Key Manager]. AB - For real-time nutritional management of in-hospital patients, a system for updated nutritional assessment is required. In our institution, we changed the conventional passive style of our nutrition support team(NST). The goal of the new NST is to provide comprehensive nutritional support based on weekly monitoring of each patient's nutritional status. In July 2013, we introduced a system where the dietitian acts as a key manager of the NSTto select patients who really need nutritional support based on the data of nutritional intake and nutritional assessment by nurses. PMID- 28676602 TI - [The Questionnaire Analysis of Monitoring the Side Effect of Cancer Chemotherapy Based on the Participation of Patients in Ambulatory Therapy Center]. PMID- 28676603 TI - [Liver, Pancreas, Biliary Tract Cancer Surgical Strategy for Bilobar Multiple Hepatic Metastasis]. PMID- 28676604 TI - [I. Hepatectomy for Colorectal Liver Metastasis Using Preoperative Portal Vein Embolization]. PMID- 28676605 TI - [II. Two-Stage Hepatectomy]. PMID- 28676606 TI - [III .ALPPS Up to Date]. PMID- 28676607 TI - [Lower G. I./Colon and Rectum Cancer]. PMID- 28676609 TI - [II. Significance of Lateral Lymph Node Dissection for Rectal Cancer]. PMID- 28676608 TI - [I. Immune Checkpoint Inhibitors in Colorectal Cancer]. PMID- 28676610 TI - [III. The Association between Location and Colorectal Cancer Characteristics]. PMID- 28676611 TI - [New Era of Estrogen Related Signal Transduction Research]. PMID- 28676612 TI - [I. ESR1 Gene Alteration and Hormone Resistance in Breast Cancer]. PMID- 28676613 TI - [II. Forkhead-Box Transcription Factors and Estrogen Signaling in Breast Cancer]. PMID- 28676614 TI - [III. Novel Endocrine Therapy with Signal Transduction Inhibitors for Hormone Dependent Breast Cancer]. PMID- 28676615 TI - [Four Questions about Prostate Cancer in Japan]. PMID- 28676616 TI - [I. Does the Epidemiological Trend of Prostate Cancer in Japan Truly Trace the Western Countries ?] PMID- 28676617 TI - [II. What Is the Future of Robot-Assisted Laparoscopic Radical Prostatectomy in Japan ?] PMID- 28676618 TI - [III. The Advantages and Disadvantages of IMRT and Particle Therapy for Prostate Cancer]. PMID- 28676619 TI - [IV. Therapies for CRPC - The Indication of the New Medicine from the Medical Economical Aspect ?] PMID- 28676620 TI - [Current Status and Future Perspectives of Chemotherapy for Gynecologic Cancers]. PMID- 28676621 TI - [I. Current Topics of Chemotherapy for Ovarian Cancer]. PMID- 28676622 TI - [II. Current Topics and Perspective of Chemotherapy for Uterine Cervical Cancer]. PMID- 28676623 TI - [III. Endometrial Carcinoma and Uterine Sarcoma]. PMID- 28676624 TI - Recurrent Pleural Effusion Secondary to a Pancreatic-Pleural Fistula Treated Endoscopically. AB - BACKGROUND Pancreatic-pleural fistula (PPF) is an uncommon complication of pancreatitis. Pleural effusions secondary to PPF are caused by fistulization of pancreatic secretions to the thorax derived from the rupture or leakage of a pseudocyst. CASE REPORT We describe the case of a 44-year-old male with recurrent right-sided pleural effusions and alcoholic pancreatitis who presented with epigastric pain and shortness of breath. Pleural fluid analysis revealed an amylase of 7002 U/lt. MRCP showed segmental narrowing and stricture of the proximal main pancreatic duct and an area of walled-off necrosis. The fistula was managed endoscopically with ERCP and placement of a plastic stent into the pancreatic duct. The pleural effusion resolved and subsequent examinations showed no evidence of recurrence. CONCLUSIONS The diagnosis of PPF is challenging. Endoscopic treatment of PPF can be a safe and effective approach. PMID- 28676625 TI - Liver X Receptor Gene Expression is Enhanced in Children with Obstructive Sleep Apnea-Hyperpnoea Syndrome and Cyclooxygenase-2 (COX-2) is Correlated with Severity of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS). AB - BACKGROUND Liver X receptor (LXR) is a nuclear receptor presenting in macrophages; it works indispensably in lipid metabolism control and also negatively regulates the expression of inflammatory genes in macrophages. There are many LXR-related studies in adults with metabolic syndrome but rare reports in obese children with obstructive sleep apnea-hypopnea syndrome (OSAHS). The aim of this study was to investigate the expression of LXR, cholesterol ester transfer protein (CETP), and cyclooxygenase-2 (COX-2) genes in obese children with OSAHS compared with obese children without OSAHS and non-obese children. MATERIAL AND METHODS Sleep monitoring was conducted in 80 obese children with sleep disorders. Fasting morning blood samples from the 80 obese children and 51 normal children were collected and separated, so that macrophages were obtained after culture. Fluorescence quantitative real-time PCR (RT-PCR) was used to detect expression levels of the LXR, CETP, and COX-2 genes. RESULTS LXR, COX-2, and CETP levels in the OSAHS group were higher than those in the other two groups (P<0.05), and the LXR levels in the group of obese children without OSAHS were higher than those in control group (P<0.05). COX-2 expression in the group with moderate to severe OSAHS was higher than that in the group with mild OSAHS (P<0.05). Meanwhile, there were no significant differences in the LXR and CETP levels between the moderate to severe OSAHS group and the mild OSAHS group (P>0.05). CONCLUSIONS LXR gene expression was significantly increased in obese children with OSAHS. The severity of OSAHS was positively correlated with COX-2 levels. PMID- 28676626 TI - Yeast Cip1 is activated by environmental stress to inhibit Cdk1-G1 cyclins via Mcm1 and Msn2/4. AB - Upon environmental changes, proliferating cells delay cell cycle to prevent further damage accumulation. Yeast Cip1 is a Cdk1 and Cln2-associated protein. However, the function and regulation of Cip1 are still poorly understood. Here we report that Cip1 expression is co-regulated by the cell-cycle-mediated factor Mcm1 and the stress-mediated factors Msn2/4. Overexpression of Cip1 arrests cell cycle through inhibition of Cdk1-G1 cyclin complexes at G1 stage and the stress activated protein kinase-dependent Cip1 T65, T69, and T73 phosphorylation may strengthen the Cip1and Cdk1-G1 cyclin interaction. Cip1 accumulation mainly targets Cdk1-Cln3 complex to prevent Whi5 phosphorylation and inhibit early G1 progression. Under osmotic stress, Cip1 expression triggers transient G1 delay which plays a functionally redundant role with another hyperosmolar activated CKI, Sic1. These findings indicate that Cip1 functions similarly to mammalian p21 as a stress-induced CDK inhibitor to decelerate cell cycle through G1 cyclins to cope with environmental stresses.A G1 cell cycle regulatory kinase Cip1 has been identified in budding yeast but how this is regulated is unclear. Here the authors identify cell cycle (Mcm1) and stress-mediated (Msn 2/4) transcription factors as regulating Cip1, causing stress induced CDK inhibition and delay in cell cycle progression. PMID- 28676627 TI - Sorghum Dw2 Encodes a Protein Kinase Regulator of Stem Internode Length. AB - Sorghum is an important C4 grass crop grown for grain, forage, sugar, and bioenergy production. While tall, late flowering landraces are commonly grown in Africa, short early flowering varieties were selected in US grain sorghum breeding programs to reduce lodging and to facilitate machine harvesting. Four loci have been identified that affect stem length (Dw1-Dw4). Subsequent research showed that Dw3 encodes an ABCB1 auxin transporter and Dw1 encodes a highly conserved protein involved in the regulation of cell proliferation. In this study, Dw2 was identified by fine-mapping and further confirmed by sequencing the Dw2 alleles in Dwarf Yellow Milo and Double Dwarf Yellow Milo, the progenitor genotypes where the recessive allele of dw2 originated. The Dw2 locus was determined to correspond to Sobic.006G067700, a gene that encodes a protein kinase that is homologous to KIPK, a member of the AGCVIII subgroup of the AGC protein kinase family in Arabidopsis. PMID- 28676628 TI - A Low-cost, Highly-stable Surface Enhanced Raman Scattering Substrate by Si Nanowire Arrays Decorated with Au Nanoparticles and Au Backplate. AB - We present a facile and cost-effective manner to fabricate a highly sensitive and stable surface enhanced Raman scattering (SERS) substrate. First, a silicon nanowire array (SiNWA) is tailored by metal-assisted chemical etching (MaCE) method as a scaffold of the desired SERS substrate. Next, with an oblique angle deposition (OAD) method, optimized gold nanoparticles (AuNPs) are successfully decorated on the surface of the SiNWA. These AuNPs enable a strong localized electric field, providing abundant hot spots to intensify the Raman signals from the targeting molecules. By applying a well-established methodology, Taguchi method, which is invented for designing experiments, the optimized combination of parameters is obtained efficiently. The experimental results are also confirmed by finite-difference time-domain (FDTD) simulation calculations. Besides, a gold metal backplate (AuMBP) is applied to further enhancing the Raman signal intensity. Based on this developed SERS substrate, we demonstrated an enhancement factor (EF) of 1.78 * 106 and a coefficient of variation (CV) of 4.2%. Both EF and CV indicate a highly stable property and the optimized SERS substrate substantially outperform the commercial product. In the end, we also demonstrate a quantitative measurement on practical application of detecting malachite green (MG) with concentration from 10 nM to 100 MUM. PMID- 28676629 TI - Generation of megahertz-band spin currents using nonlinear spin pumping. AB - Spin pumping enables the generation of d.c. and gigahertz-band (GHz-band) voltages from an applied microwave via magnetization dynamics when combined with inverse spin Hall effects. However, generating such voltages in the in-between frequency region, or the megahertz (MHz) band, has been difficult since ferromagnetic resonance usually occurs in the GHz band. Here we show that in spite of GHz-band microwaves applied, MHz-band voltages can be generated by spin pumping with use of nonlinear magnetization dynamics in Y3Fe5O12. The mechanism is ascribed to the MHz-band oscillation of the amplitude of the magnetization precession, which is projected onto a rectified voltage component via spin pumping. The present finding could be useful for frequency down-conversion thanks to the simple and durable structure, continuous-wave operation, and the tunability of an output frequency with low magnetic fields. PMID- 28676630 TI - Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol. AB - Activation of G protein-gated inwardly rectifying potassium (GIRK) channels leads to a hyperpolarization of the neuron's membrane potential, providing an important component of inhibition in the brain. In addition to the canonical G protein activation pathway, GIRK channels are activated by small molecules but less is known about the underlying gating mechanisms. One drawback to previous studies has been the inability to control intrinsic and extrinsic factors. Here we used a reconstitution strategy with highly purified mammalian GIRK2 channels incorporated into liposomes and demonstrate that cholesterol or intoxicating concentrations of ethanol, i.e., >20 mM, each activate GIRK2 channels directly, in the absence of G proteins. Notably, both activators require the membrane phospholipid PIP2 but appear to interact independently with different regions of the channel. Elucidating the mechanisms underlying G protein-independent pathways of activating GIRK channels provides a unique strategy for developing new types of neuronal excitability modulators. PMID- 28676631 TI - RNA editing of the AMD1 gene is important for ascus maturation and ascospore discharge in Fusarium graminearum. AB - Ascospores are the primary inoculum in the wheat scab fungus Fusarium graminearum that was recently shown to have sexual stage-specific A-to-I RNA editing. One of the genes with premature-stop-codons requiring A-to-I editing to encode full length functional proteins is AMD1 that encodes a protein with a major facilitator superfamily (MFS) domain. Here, we characterized the functions of AMD1 and its UAG to UGG editing event. The amd1 deletion mutant was normal in growth and conidiation but defective in ascospore discharge due to the premature breakdown of its ascus wall in older perithecia, which is consistent with the specific expression of AMD1 at later stages of sexual development. Expression of the wild-type or edited allele of AMD1 but not un-editable allele rescued the defects of amd1 in ascospore discharge. Furthermore, Amd1-GFP localized to the ascus membrane and Amd1 orthologs are only present in ascocarp-forming fungi that physically discharge ascospores. Interestingly, deletion of AMD1 results in the up-regulation of a number of genes related to transporter activity and membrane functions. Overall, these results indicated that Amd1 may play a critical role in maintaining ascus wall integrity during ascus maturation, and A-to-I editing of its transcripts is important for ascospore discharge in F. graminearum. PMID- 28676632 TI - Clinicopathological features and prognosis of gastric adenosquamous carcinoma. AB - Data about primary gastric adenosquamous carcinoma (ASC) was limited due to rare incidence. Thus, the present study aims to investigate clinicopathological features and prognosis of gastric ASC. Cases of gastric ASC were obtained from our center and from case reports and series extracted from Medline. Clinicopathological features and prognosis of gastric ASC were analyzed and compared with gastric adenocarcinoma (AC) in our center. The commonest location was lower third (45.0%), followed by upper (26.2%) and middle third (24.2%). The median tumor size was 6 cm (0.8-17). The commonest differentiation status was well for both AC (44.4%) and SCC components (40.9%). Half of tumors (52.7%) were stage T4 and most patients (86.2%) suffered from lymph node metastasis (LNM). Tumor depth and TNM stage were risk factors for overall survival (OS) (both P < 0.05). The distribution of age, tumor size, tumor location, tumor depth, LNM and TNM stage were significantly different between gastric ASC and AC (all P < 0.05). The OS of gastric ASC was significantly worse than AC (P < 0.001), especially in stage III disease (P < 0.001). Gastric ASC differ significantly from AC with respect to clinicopathological features. The prognosis of gastric ASC was worse than AC. PMID- 28676633 TI - Boronic Acid-Modified Magnetic Fe3O4@mTiO2 Microspheres for Highly Sensitive and Selective Enrichment of N-Glycopeptides in Amniotic Fluid. AB - Although mesoporous materials and magnetic materials are used to enrich glycopeptides, materials sharing both mesoporous structures and magnetic properties have not been reported for glycopeptide analyses. Here we prepared boronic acid-modified magnetic Fe3O4@mTiO2 microspheres by covalent binding of boronic acid molecules onto the surfaces of silanized Fe3O4@mTiO2 microspheres. The final particles (denoted as B-Fe3O4@mTiO2) showed a typical magnetic hysteresis curve, indicating superparamagnetic behavior; meanwhile, their mesoporous sizes did not change in spite of the reduction in surface area and pore volume. By using these particles together with conventional poly(methyl methacrylate) (PMMA) nanobeads, we then developed a synergistic approach for highly specific and efficient enrichment of N-glycopeptides/glycoproteins. Owing to the introduction of PMMA nanobeads that have strong adsorption towards nonglycopeptides, the number of N-glycopeptides detected and the signal-to-noise ratio in analyzing standard proteins mixture both increased appreciably. The recovery of N-glycopeptides by the synergistic method reached 92.1%, much improved than from B-Fe3O4@mTiO2 alone that was 75.3%. Finally, we tested this approach in the analysis of amniotic fluid, obtaining the maximum number and ratio of N-glycopeptides compared to the use of B-Fe3O4@mTiO2 alone and commercial SiMAG-boronic acid particles. This ensemble provides an interesting and efficient enrichment platform for glycoproteomics research. PMID- 28676634 TI - Observation of vortex-antivortex pairing in decaying 2D turbulence of a superfluid gas. AB - In a two-dimensional (2D) classical fluid, a large-scale flow structure emerges out of turbulence, which is known as the inverse energy cascade where energy flows from small to large length scales. An interesting question is whether this phenomenon can occur in a superfluid, which is inviscid and irrotational by nature. Atomic Bose-Einstein condensates (BECs) of highly oblate geometry provide an experimental venue for studying 2D superfluid turbulence, but their full investigation has been hindered due to a lack of the circulation sign information of individual quantum vortices in a turbulent sample. Here, we demonstrate a vortex sign detection method by using Bragg scattering, and we investigate decaying turbulence in a highly oblate BEC at low temperatures, with our lowest being ~0.5T c , where T c is the superfluid critical temperature. We observe that weak spatial pairing between vortices and antivortices develops in the turbulent BEC, which corresponds to the vortex-dipole gas regime predicted for high dissipation. Our results provide a direct quantitative marker for the survey of various 2D turbulence regimes in the BEC system. PMID- 28676635 TI - Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells. AB - During the pregnancy associated syndrome preeclampsia (PE), there is increased release of placental syncytiotrophoblast extracellular vesicles (STBEVs) and free foetal haemoglobin (HbF) into the maternal circulation. In the present study we investigated the uptake of normal and PE STBEVs by primary human coronary artery endothelial cells (HCAEC) and the effects of free HbF on this uptake. Our results show internalization of STBEVs into primary HCAEC, and transfer of placenta specific miRNAs from STBEVs into the endoplasmic reticulum and mitochondria of these recipient cells. Further, the transferred miRNAs were functional, causing a down regulation of specific target genes, including the PE associated gene fms related tyrosine kinase 1 (FLT1). When co-treating normal STBEVs with HbF, the miRNA deposition is altered from the mitochondria to the ER and the cell membrane becomes ruffled, as was also seen with PE STBEVs. These findings suggest that STBEVs may cause endothelial damage and contribute to the endothelial dysfunction typical for PE. The miRNA mediated effects on gene expression may contribute to the oxidative and endoplasmic reticulum stress described in PE, as well as endothelial reprogramming that may underlay the increased risk of cardiovascular disease reported for women with PE later in life. PMID- 28676636 TI - Atomic structure and domain wall pinning in samarium-cobalt-based permanent magnets. AB - A higher saturation magnetization obtained by an increased iron content is essential for yielding larger energy products in rare-earth Sm2Co17-type pinning controlled permanent magnets. These are of importance for high-temperature industrial applications due to their intrinsic corrosion resistance and temperature stability. Here we present model magnets with an increased iron content based on a unique nanostructure and -chemical modification route using Fe, Cu, and Zr as dopants. The iron content controls the formation of a diamond shaped cellular structure that dominates the density and strength of the domain wall pinning sites and thus the coercivity. Using ultra-high-resolution experimental and theoretical methods, we revealed the atomic structure of the single phases present and established a direct correlation to the macroscopic magnetic properties. With further development, this knowledge can be applied to produce samarium cobalt permanent magnets with improved magnetic performance.Understanding the factors that determine the properties of permanent magnets, which play a central role in many industrial applications, can help in improving their performance. Here, the authors study how changes in the iron content affect the microstructure of samarium cobalt magnets. PMID- 28676638 TI - Cbl-mediated K63-linked ubiquitination of JAK2 enhances JAK2 phosphorylation and signal transduction. AB - JAK2 activation is crucial for cytokine receptor signal transduction and leukemogenesis. However, the underlying processes that lead to full activation of JAK2 are unclear. Here, we report a positive role for ubiquitination of JAK2 during GM-CSF-induced activation. Upon GM-CSF stimulation, JAK2 ubiquitination is significantly enhanced through K63-linked poly-ubiquitination. Studies employing both knockout and overexpression of Cbl, an E3 ubiquitin ligase, led to the conclusion that Cbl specifically promotes JAK2 ubiquitination, and this was further confirmed in vitro using a Cbl ubiquitination assay. Moreover, following GM-CSF stimulation, the levels of phospho-JAK2 and -STAT5 and a STAT5 luciferase reporter assay were all reduced in Cbl knockout cells and this effect could be rescued by Cbl expression. Mechanistically, Cbl can interact with, and ubiquitinate JAK2 FERM and kinase domains via the Cbl TKB domain. Using lysine-to arginine site-directed mutagenesis, K970 in the kinase domain of JAK2 was identified as the ubiquitination site important for promoting full JAK2 activation by Cbl via K63-conjugated poly-ubiquitination. Our study suggests that GM-CSF-induced JAK2 activation is enhanced by Cbl-mediated ubiquitination of JAK2. Targeting ubiquitination of JAK2 might offer a novel therapeutic strategy against JAK2-mediated disorders. PMID- 28676637 TI - Transcriptomic profiling of Melilotus albus near-isogenic lines contrasting for coumarin content. AB - Coumarin and its derivatives are widely used as fragrances in industrial products and have medical value. The goal of the present study was to discover genes and pathways related to coumarin biosynthesis in Melilotus albus using transcriptome analysis. The genes of five M. albus near-isogenic lines (NILs) that had different coumarin content and beta-glucosidase activity according to the investigation of pedigree were quantified and then analysed by RNA-Seq. Using transcriptome analysis, differentially expressed genes (DEGs) were identified in two pairwise comparisons that differed in coumarin content as well as in two pairwise comparisons that differed in beta-glucosidase activity. Gene expression pattern analysis suggested similar transcriptional trends in the genotypes with the same coumarin levels. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database of DEGs was used to identify functional pathways associated with coumarin biosynthesis. We identified 111 unigenes, with several DEGs among them possibly being related to coumarin synthesis pathways. Unigenes encoding a hexokinase, an abscisic acid receptor, a phenylalanine ammonia-lyase (PAL) and two peroxidases particularly showed correspondence with the coumarin content of different genotypes. These results will contribute to a better understanding of the coumarin biosynthesis in M. albus. PMID- 28676639 TI - Coherent scatter-controlled phase-change grating structures in silicon using femtosecond laser pulses. AB - Periodic structures of alternating amorphous-crystalline fringes have been fabricated in silicon using repetitive femtosecond laser exposure (800 nm wavelength and 120 fs duration). The method is based on the interference of the incident laser light with far- and near-field scattered light, leading to local melting at the interference maxima, as demonstrated by femtosecond microscopy. Exploiting this strategy, lines of highly regular amorphous fringes can be written. The fringes have been characterized in detail using optical microscopy combined modelling, which enables a determination of the three-dimensional shape of individual fringes. 2D micro-Raman spectroscopy reveals that the space between amorphous fringes remains crystalline. We demonstrate that the fringe period can be tuned over a range of 410 nm - 13 um by changing the angle of incidence and inverting the beam scan direction. Fine control over the lateral dimensions, thickness, surface depression and optical contrast of the fringes is obtained via adjustment of pulse number, fluence and spot size. Large-area, highly homogeneous gratings composed of amorphous fringes with micrometer width and millimeter length can readily be fabricated. The here presented fabrication technique is expected to have applications in the fields of optics, nanoelectronics, and mechatronics and should be applicable to other materials. PMID- 28676640 TI - Human neutrophils phagocytose and kill Acinetobacter baumannii and A. pittii. AB - Acinetobacter baumannii is a common cause of health care associated infections worldwide. A. pittii is an opportunistic pathogen also frequently isolated from Acinetobacter infections other than those from A. baumannii. Knowledge of Acinetobacter virulence factors and their role in pathogenesis is scarce. Also, there are no detailed published reports on the interactions between A. pittii and human phagocytic cells. Using confocal laser and scanning electron microscopy, immunofluorescence, and live-cell imaging, our study shows that immediately after bacteria-cell contact, neutrophils rapidly and continuously engulf and kill bacteria during at least 4 hours of infection in vitro. After 3 h of infection, neutrophils start to release neutrophil extracellular traps (NETs) against Acinetobacter. DNA in NETs colocalizes well with human histone H3 and with the specific neutrophil elastase. We have observed that human neutrophils use large filopodia as cellular tentacles to sense local environment but also to detect and retain bacteria during phagocytosis. Furthermore, co-cultivation of neutrophils with human differentiated macrophages before infections shows that human neutrophils, but not macrophages, are key immune cells to control Acinetobacter. Although macrophages were largely activated by both bacterial species, they lack the phagocytic activity demonstrated by neutrophils. PMID- 28676642 TI - Label Free Detection of Sensitive Mid-Infrared Biomarkers of Glomerulonephritis in Urine Using Fourier Transform Infrared Spectroscopy. AB - More reliable biomarkers using near-patient technologies are needed to improve early diagnosis and intervention for patients with renal disease. Infrared (IR) vibrational spectroscopy/microspectroscopy is an established analytical method that was first used in biomedical research over 20 years ago. With the advances in instrumentation, computational and mathematical techniques, this technology has now been applied to a variety of diseases; however, applications in nephrology are just beginning to emerge. In the present study, we used attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy to analyze urine samples collected from rodent models of inflammatory glomerulonephritis (GN) as well as from patients with crescentic GN, with the aim of identifying potential renal biomarkers; several characteristic mid-IR spectral markers were identified in urine samples. Specifically, a 1545 cm-1 band increased in intensity with the progression and severity of GN in rats, mice and humans. Furthermore, its intensity declined significantly in response to corticosteroid treatment in nephritic rats. In conclusion, our results suggest that specific urinary FTIR biomarkers may provide a rapid, sensitive and novel non-invasive means of diagnosing inflammatory forms of GN, and for real-time monitoring of progress, and response to treatment. PMID- 28676641 TI - Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells. AB - Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM. PMID- 28676643 TI - Past summer upwelling events in the Gulf of Oman derived from a coral geochemical record. AB - We used a high-resolution oxygen isotope (delta18Ocoral), carbon isotope (delta13Ccoral) and Sr/Ca ratios measured in the skeleton of a reef-building coral, Porites sp., to reveal seasonal-scale upwelling events and their interannual variability in the Gulf of Oman. Our delta13Ccoral record shows sharp negative excursions in the summer, which correlate with known upwelling events. Using delta13Ccoral anomalies as a proxy for upwelling, we found 17 summer upwelling events occurred in the last 26 years. These anomalous negative excursions of delta13Ccoral result from upwelled water depleted in 13C (dissolved inorganic carbon) and decreased water-column transparency. We reconstructed biweekly SSTs from coral Sr/Ca ratios and the oxygen isotopic composition of seawater (delta18OSW) by subtracting the reconstructed Sr/Ca-SST from delta18Ocoral. Significant delta18OSW anomalies occur during major upwelling events. Our results suggest delta13Ccoral anomalies can be used as a proxy for seasonal upwelling intensity in the Gulf of Oman, which, driven by the Indian/Arabian Summer Monsoon, is subject to interannual variability. PMID- 28676644 TI - Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo. AB - Afatinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, afatinib's clinical application is still hampered by acquired resistance. Recently, autophagy is considered as an important mechanism of resistance to TKI. Herein, we investigated the autophagy induction as well as its influence on anti-lung adenocarcinoma activity of afatinib in two activating EGFR mutants H1975 and H1650 cells. First, Growth inhibition and caspase-dependent apoptosis were observed in afatinib-treated H1975 and H1650 cells. Then we confirmed afatinib-induced autophagy in H1975 and H1650 cells. Importantly, autophagy inhibition using chloroquine (CQ) and 3-MA enhanced the cytotoxicity of afatinib, elucidating the cytoprotective role of autophagy in lung adenocarcinoma therapy with afatinib. Further study suggested that Akt/mTOR and Erk signaling pathways were involved in afatinib-induced autophagy, and reactive oxygen species (ROS) acted as an intracellular transducer regulating both autophagy and apoptosis in afatinib-treated H1975 and H1650 cells. Moreover, the in vivo experiment in xenograft model using H1975 cell line confirmed the enhanced anti lung adenocarcinoma efficacy of afatinib when combined with autophagy inhibitor CQ. Thus, blocking autophagy may be a promising strategy to overcome resistance and increase sensitivity to afatinib in lung adenocarcinoma harboring activating EGFR mutations. PMID- 28676646 TI - Identifying the neck margin status of ductal adenocarcinoma in the pancreatic head by multiphoton microscopy. AB - Complete surgical resection is the only option for improving the survival of patients with ductal adenocarcinoma in the pancreatic head. After resection, determining the status of resection margins (RMs) is crucial for deciding on the nature of the follow-up treatment. The purpose of this study was to evaluate whether multiphoton microscopy (MPM) could be considered a reliable tool for determining the status of pancreatic neck margins by identifying tumour cells of ductal adenocarcinoma in these margins in the pancreatic head, and our results were affirmative. In particular, MPM could identify tumour cells in the nerves. It was also found that the quantification of the difference between normal duct cells and tumour cells was possible. In addition, the content of collagen could be quantified and used as a marker for differentiating ductal adenocarcinoma in the pancreatic head from normal pancreatic tissues, eventually leading to the identification of R0 and R1 resections of the pancreatic neck margin. With the development of the clinical applications of the multiphoton endoscope, MPM has the potential to provide in vivo real-time identification of RM status during surgery. PMID- 28676645 TI - KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis. AB - Fibrosis involves the production of extracellular matrix proteins in tissues and is often preceded by injury or trauma. In pleural fibrosis excess collagen deposition results in pleural thickening, increased stiffness and impaired lung function. Myofibroblasts are responsible for increased collagen deposition, however the molecular mechanism of transportation of procollagen containing vesicles for secretion is unknown. Here, we studied the role of kinesin on collagen-1 (Col-1) containing vesicle transportation in human pleural mesothelial cells (HPMCs). Among a number of cargo transporting kinesins, KIF5A was notably upregulated during TGF-beta induced mesothelial-mesenchymal transition (MesoMT). Using superresolution structured illumination microscopy and the DUO-Link technique, we found that KIF5A colocalized with Col-1 containing vesicles. KIF5A knock-down significantly reduced Col-1 secretion and attenuated TGF-beta induced increment in Col-1 localization at cell peripheries. Live cell imaging revealed that GFP-KIF5A and mCherry-Col-1 containing vesicles moved together. Kymography showed that these molecules continuously move with a mean velocity of 0.56 MUm/sec, suggesting that the movement is directional but not diffusion limited process. Moreover, KIF5A was notably upregulated along with Col-1 and alpha smooth muscle actin in pleural thickening in the carbon-black bleomycin mouse model. These results support our hypothesis that KIF5A is responsible for collagen transportation and secretion from HPMCs. PMID- 28676647 TI - Genetic associations for keratoconus: a systematic review and meta-analysis. AB - Genetic associations for keratoconus could be useful for understanding disease pathogenesis and discovering biomarkers for early detection of the disease. We conducted a systematic review and meta-analysis to summarize all reported genetic associations for the disease. We searched in the MEDLINE, Embase, Web of Science, and HuGENET databases for genetic studies of keratoconus published from 1950 to June 2016. The summary odds ratio and 95% confidence intervals of all polymorphisms were estimated using the random-effect model. Among 639 reports that were retrieved, 24 fulfilled required criteria as eligible studies for meta analysis, involving a total of 53 polymorphisms in 28 genes/loci. Results of our meta-analysis lead to the prioritization of 8 single-nucleotide polymorphisms (SNPs) in 6 genes/loci for keratoconus in Whites. Of them 5 genes/loci were originally detected in genome-wide association studies, including FOXO1 (rs2721051, P = 5.6 * 10-11), RXRA-COL5A1 (rs1536482, P = 2.5 * 10-9), FNDC3B (rs4894535, P = 1.4 * 10-8), IMMP2L (rs757219, P = 6.1 * 10-7; rs214884, P = 2.3 * 10-5), and BANP-ZNF469 (rs9938149, P = 1.3 * 10-5). The gene COL4A4 (rs2229813, P = 1.3 * 10-12; rs2228557, P = 4.5 * 10-7) was identified in previous candidate gene studies. We also found SNPs in 10 genes/loci that had a summary P value < 0.05. Sensitivity analysis indicated that the results were robust. Replication studies and understanding the roles of these genes in keratoconus are warranted. PMID- 28676648 TI - Interactions between LHX3- and ISL1-family LIM-homeodomain transcription factors are conserved in Caenorhabditis elegans. AB - LIM-Homeodomain (LIM-HD) transcription factors are highly conserved in animals where they are thought to act in a transcriptional 'LIM code' that specifies cell types, particularly in the central nervous system. In chick and mammals the interaction between two LIM-HD proteins, LHX3 and Islet1 (ISL1), is essential for the development of motor neurons. Using yeast two-hybrid analysis we showed that the Caenorhabditis elegans orthologs of LHX3 and ISL1, CEH-14 and LIM-7 can physically interact. Structural characterisation of a complex comprising the LIM domains from CEH-14 and a LIM-interaction domain from LIM-7 showed that these nematode proteins assemble to form a structure that closely resembles that of their vertebrate counterparts. However, mutagenic analysis across the interface indicates some differences in the mechanisms of binding. We also demonstrate, using fluorescent reporter constructs, that the two C. elegans proteins are co expressed in a small subset of neurons. These data show that the propensity for LHX3 and Islet proteins to interact is conserved from C. elegans to mammals, raising the possibility that orthologous cell specific LIM-HD-containing transcription factor complexes play similar roles in the development of neuronal cells across diverse species. PMID- 28676649 TI - CRISPR-Cas9 targeted disruption of the yellow ortholog in the housefly identifies the brown body locus. AB - The classic brown body (bwb) mutation in the housefly Musca domestica impairs normal melanization of the adult cuticle. In Drosophila melanogaster, a reminiscent pigmentation defect results from mutations in the yellow gene encoding dopachrome conversion enzyme (DCE). Here, we demonstrate that the bwb locus structurally and functionally represents the yellow ortholog of Musca domestica, MdY. In bwb Musca strains, we identified two mutant MdY alleles that contain lesions predicted to result in premature truncation of the MdY open reading frame. We targeted wildtype MdY by CRISPR-Cas9 RNPs and generated new mutant alleles that fail to complement existing MdY alleles, genetically confirming that MdY is the bwb locus. We further found evidence for Cas9-mediated interchromosomal recombination between wildtype and mutant bwb alleles. Our work resolves the molecular identity of the classic bwb mutation in Musca domestica and establishes the feasibility of Cas9-mediated genome editing in the Musca model. PMID- 28676650 TI - Decreased Estimated Glomerular Filtration Rate (eGFR), Not Proteinuria, Is Associated with Asymptomatic Intracranial Arterial Stenosis in Chinese General Population. AB - ABSTARCT: The relationship between chronic kidney disease (CKD), which is defined by declined estimated glomerular filtration rate (eGFR) and/or proteinuria, and asymptomatic intracranial arterial stenosis (ICAS) is largely unknown. We conducted a population-based, cross-sectional study by recruiting 5209 participants free of previous stroke, transient ischemic attack and coronary heart disease. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and proteinuria was estimated with urine dipstick. The presence of ICAS was assessed by transcranial color-coded Doppler (TCD). Out of the whole population, 684 (13.1%) participants suffered ICAS. After adjusting for the confounding factors, eGFR < 45 ml/min/m2 was an independent risk factor of asymptomatic ICAS (odds ratio [OR], 3.29, 95% confidence interval [CI], 1.67-6.51), but the trend was different between the two groups stratified by the age of 60 (P = 0.01). However, the association between proteinuria and asymptomatic ICAS was not statistically significant. In conclusion, declined eGFR, not proteinuria, is associated with asymptomatic ICAS in Chinese general population, especially in people over 60 years old. PMID- 28676651 TI - Age-related diagnostic value of D-dimer testing and the role of inflammation in patients with suspected deep vein thrombosis. AB - Previous reports have investigated the impact of age on D-Dimer testing in elderly individuals with suspected deep vein thrombosis (DVT), but data on the age-related diagnostic value of D-dimer in a sample covering a broad age range are limited. The present study determined age-specifically the diagnostic accuracy of D-dimer and compared it to C-reactive protein (CRP), a marker of inflammation, in 500 patients with suspected DVT from the VTEval project (NCT02156401). Sensitivity of D-dimer was lower in patients < 60 years in comparison to patients >= 60 years (?-16.8%), whereas specificity was 27.9% higher. Lowest levels of sensitivity were detected for female sex, unprovoked DVT, low thrombotic burden, and distal DVT. A fixed D-dimer threshold of 0.25 mg/L FEU resulted in elevated sensitivity for patients < 60 with a reduction of false negatives by 40.0% for proximal DVT and by 50.0% for distal DVT. In patients < 60 years, D-dimer and CRP demonstrated comparable diagnostic performance for both proximal and distal DVT (p > 0.05). In conclusion, these data outline a clinically-relevant limitation of D-dimer testing among younger patients with suspected DVT indicating a necessity for age-adapted cut-off values. Further research is required to decrypt the role of inflammation in the pathophysiology and diagnosis of venous thrombosis. PMID- 28676652 TI - Anaerobic consortia of fungi and sulfate reducing bacteria in deep granite fractures. AB - The deep biosphere is one of the least understood ecosystems on Earth. Although most microbiological studies in this system have focused on prokaryotes and neglected microeukaryotes, recent discoveries have revealed existence of fossil and active fungi in marine sediments and sub-seafloor basalts, with proposed importance for the subsurface energy cycle. However, studies of fungi in deep continental crystalline rocks are surprisingly few. Consequently, the characteristics and processes of fungi and fungus-prokaryote interactions in this vast environment remain enigmatic. Here we report the first findings of partly organically preserved and partly mineralized fungi at great depth in fractured crystalline rock (-740 m). Based on environmental parameters and mineralogy the fungi are interpreted as anaerobic. Synchrotron-based techniques and stable isotope microanalysis confirm a coupling between the fungi and sulfate reducing bacteria. The cryptoendolithic fungi have significantly weathered neighboring zeolite crystals and thus have implications for storage of toxic wastes using zeolite barriers.Deep subsurface microorganisms play an important role in nutrient cycling, yet little is known about deep continental fungal communities. Here, the authors show organically preserved and partly mineralized fungi at 740 m depth, and find evidence of an anaerobic fungi and sulfate reducing bacteria consortium. PMID- 28676653 TI - Diffraction phase microscopy imaging and multi-physics modeling of the nanoscale thermal expansion of a suspended resistor. AB - We studied the nanoscale thermal expansion of a suspended resistor both theoretically and experimentally and obtained consistent results. In the theoretical analysis, we used a three-dimensional coupled electrical-thermal mechanical simulation and obtained the temperature and displacement field of the suspended resistor under a direct current (DC) input voltage. In the experiment, we recorded a sequence of images of the axial thermal expansion of the central bridge region of the suspended resistor at a rate of 1.8 frames/s by using epi illumination diffraction phase microscopy (epi-DPM). This method accurately measured nanometer level relative height changes of the resistor in a temporally and spatially resolved manner. Upon application of a 2 V step in voltage, the resistor exhibited a steady-state increase in resistance of 1.14 Omega and in relative height of 3.5 nm, which agreed reasonably well with the predicted values of 1.08 Omega and 4.4 nm, respectively. PMID- 28676654 TI - Identifying Human SIRT1 Substrates by Integrating Heterogeneous Information from Various Sources. AB - Most proteins undergo different kinds of modification after translation. Protein acetylation is one of the most crucial post-translational modifications, which causes direct or indirect impact on various biological activities in vivo. As a member of Class III HDACs, SIRT1 was the closest one to the yeast sir2 and drew most attention, while a small number of known SIRT1 substrates caused difficulties to clarify its function. In this work, we designed a novel computational method to screen SIRT1 substrates based on manually collected data and Support Vector Machines (SVMs). Unlike other approaches, we took both primary sequence and protein functional features into consideration. Through integrating functional features, the Matthews correlation coefficient (MCC) for the prediction increased from 0.10 to 0.65. The prediction results were verified by independent dataset and biological experiments. The validation results demostrated that our classifier could effectively identify SIRT1 substrates and filter appropriate candidates for further research. Furthermore, we provide online tool to support SIRT1 substrates prediction, which is freely available at http://bioinfo.bjmu.edu.cn/huac/ . PMID- 28676655 TI - Non-Darcy interfacial dynamics of air-water two-phase flow in rough fractures under drainage conditions. AB - Two-phase flow interfacial dynamics in rough fractures is fundamental to understanding fluid transport in fractured media. The Haines jump of non-Darcy flow in porous media has been investigated at pore scales, but its fundamental processes in rough fractures remain unclear. In this study, the micron-scale Haines jump of the air-water interface in rough fractures was investigated under drainage conditions, with the air-water interface tracked using dyed water and an imaging system. The results indicate that the interfacial velocities represent significant Haines jumps when the meniscus passes from a narrow "throat" to a wide "body", with jump velocities as high as five times the bulk drainage velocity. Locally, each velocity jump corresponds to a fracture aperture variation; statistically, the velocity variations follow an exponential function of the aperture variations at a length scale of ~100 um to ~100 mm. This spatial scale-invariant correlation may indicate that the high-speed local velocities during the Haines jump would not average out spatially for a bulk system. The results may help in understanding the origin of interface instabilities and the resulting non-uniform phase distribution, as well as the micron-scale essence of the spatial and temporal instability of two-phase flow in fractured media at the macroscopic scale. PMID- 28676656 TI - Detecting the Orbital Angular Momentum of Electro-Magnetic Waves Using Virtual Rotational Antenna. AB - Orbital Angular Momentum (OAM) is a typical spatial mode of an Electro-Magnetic (EM) wave. Correctly detecting the OAM mode is fundamental and of foremost importance when applying the phenomenon to wireless transmission in free space. It is found that when rotating an OAM wave, a rotational Doppler shift that is proportional to the rotation speed and the OAM mode number can be observed. This property can be used for OAM detection, i.e., different OAM modes are identified by measuring the corresponding rotational Doppler frequency shifts. In previous work, this method was implemented by mechanically rotating the OAM wave, resulting in a small frequency shift. Since the high-speed mechanical rotation is hard to manufacture in a real system, it brings limitations to the bandwidth for each OAM wave. In this paper, we report on an OAM mode detection method based on digitally rotating a virtual antenna. The transmitter and receiver are physically fixed, but the Virtual Rotational Antenna (VRA) is obtained by interpolating the signals received from transverse-mounted receiving antennas. A large rotational Doppler shift occurs as a consequence of using digital processing, resulting in more capability for wideband wireless data transmission with the larger shifted frequency. PMID- 28676657 TI - Stability limits of tin-based electrocatalyst supports. AB - Tin-based oxides are attractive catalyst support materials considered for application in fuel cells and electrolysers. If properly doped, these oxides are relatively good conductors, assuring that ohmic drop in real applications is minimal. Corrosion of dopants, however, will lead to severe performance deterioration. The present work aims to investigate the potential dependent dissolution rates of indium tin oxide (ITO), fluorine doped tin oxide (FTO) and antimony doped tin oxide (ATO) in the broad potential window ranging from -0.6 to 3.2 VRHE in 0.1 M H2SO4 electrolyte. It is shown that in the cathodic part of the studied potential window all oxides dissolve during the electrochemical reduction of the oxide - cathodic dissolution. In case an oxidation potential is applied to the reduced electrode, metal oxidation is accompanied with additional dissolution - anodic dissolution. Additional dissolution is observed during the oxygen evolution reaction. FTO withstands anodic conditions best, while little and strong dissolution is observed for ATO and ITO, respectively. In discussion of possible corrosion mechanisms, obtained dissolution onset potentials are correlated with existing thermodynamic data. PMID- 28676658 TI - Band Structure of Topological Insulator BiSbTe1.25Se1.75. AB - We present our angle resolved photoelectron spectroscopy (ARPES) and density functional theory results on quaternary topological insulator (TI) BiSbTe1.25Se1.75 (BSTS) confirming the non-trivial topology of the surface state bands (SSBs) in this compound. We find that the SSBs, which are are sensitive to the atomic composition of the terminating surface have a partial 3D character. Our detailed study of the band bending (BB) effects shows that in BSTS the Dirac point (DP) shifts by more than two times compared to that in Bi2Se3 to reach the saturation. The stronger BB in BSTS could be due to the difference in screening of the surface charges. From momentum density curves (MDCs) of the ARPES data we obtained an energy dispersion relation showing the warping strength of the Fermi surface in BSTS to be intermediate between those found in Bi2Se3 and Bi2Te3 and also to be tunable by controlling the ratio of chalcogen/pnictogen atoms. Our experiments also reveal that the nature of the BB effects are highly sensitive to the exposure of the fresh surface to various gas species. These findings have important implications in the tuning of DP in TIs for technological applications. PMID- 28676659 TI - Mutations in BRCA2 and taxane resistance in prostate cancer. AB - Mutations in BRCA1 or BRCA2 define a subset of prostate cancer patients. Herein, we address the question whether BRCA1/2 mutations have a predictive impact on chemotherapy with docetaxel, a widely used drug in patients with metastatic castration resistant prostate cancer (mCRPC). Fifty-three men treated with docetaxel for mCRPC were tested for somatic BRCA1/2 mutations of the primary tumor. In a subgroup of patients, BRCA1/2 protein expression was tested as a potential surrogate marker for BRCA1/2 inactivation. Eight of 53 patients (15.1%) harbored a deleterious BRCA2 mutation. No BRCA1 mutation was found. Patients with a BRCA2 mutation showed a response rate of 25% to docetaxel in comparison to 71.1% in men with wildtype BRCA2 (p = 0.019). While the time to develop castration resistance was similar in both subgroups, the overall survival was significantly shorter in patients harboring a BRCA2 mutation. No correlation between the BRCA1/2 protein expression and the response to docetaxel was found. While the presence of a BRCA2 mutation does not preclude a response to docetaxel, there is overall a significant correlation between BRCA2 inactivation and a poor response rate. Our results suggest that a close oncological monitoring of patients with BRCA2 mutations for taxane resistance is warranted. PMID- 28676661 TI - Tailoring hydrophobic branch in polyzwitterionic resin for simultaneous capturing of Hg(II) and methylene blue with response surface optimization. AB - A new highly efficient cross-linked polymer was synthesized via cyclotetrapolymerization of hydrophilic [(diallylamino)propyl]phosphonic acid hydrochloride (72 mol%), hydrophobic N,N-diallyl-1-[6-(biphenyl-4 yloxy)hexylammonium chloride (18 mol%), cross-linker 1,1,4,4 tetraallylpiperazinium dichloride (10 mol%) with an equivalent amount of alternating SO2 units (100 mol%). The pH-responsive resin chemically tailored with the aminopropylphosphonate chelating ligand and hydrophobic chain of (CH2)6OC6H4-C6H5 is designed to capture toxic metal ions and organic contaminants simultaneously. The developed resin was used for the remediation of Hg(II) ions and methylene blue from aqueous solutions as models. The experimental conditions were optimized utilizing the response surface methodology as an environmentally friendly method. The adsorption efficiency for Hg(II) was ~100% at 10 ppm initial concentration at pH 5 at 25 degrees C, while it was 80% for removal of the dye in a single pollutant system. Interestingly, the resin demonstrated its remarkable efficacy in the simultaneous and complete removal of Hg(II) and the dye from their mixture. Increased removal of the dye (~100%) in the presence of Hg(II) was attributed to the synergistic effect. The equilibrium data were evaluated by employing the Langmuir and Freundlich isotherm models. PMID- 28676660 TI - DRP3 and ELM1 are required for mitochondrial fission in the liverwort Marchantia polymorpha. AB - Mitochondria increase in number by the fission of existing mitochondria. Mitochondrial fission is needed to provide mitochondria to daughter cells during cell division. In Arabidopsis thaliana, four kinds of genes have been reported to be involved in mitochondrial fission. Two of them, DRP3 (dynamin-related protein3) and FIS1 (FISSION1), are well conserved in eukaryotes. The other two are plant-specific ELM1 (elongated mitochondria1) and PMD (peroxisomal and mitochondrial division). To better understand the commonality and diversity of mitochondrial fission factors in land plants, we examined mitochondrial fission related genes in a liverwort, Marchantia polymorpha. As a bryophyte, M. polymorpha has features distinct from those of the other land plant lineages. We found that M. polymorpha has single copies of homologues for DRP3, FIS1 and ELM1, but does not appear to have a homologue of PMD. Citrine-fusion proteins with MpDRP3, MpFIS1 and MpELM1 were localized to mitochondria in M. polymorpha. MpDRP3 and MpELM1-defective mutants grew slowly and had networked mitochondria, indicating that mitochondrial fission was blocked in the mutants, as expected. However, knockout of MpFIS1 did not affect growth or mitochondrial morphology. These results suggest that MpDRP3 and MpELM1 but neither MpFIS1 nor PMD are needed for mitochondrial fission in M. polymorpha. PMID- 28676662 TI - Directing the Self-assembly of Tumour Spheroids by Bioprinting Cellular Heterogeneous Models within Alginate/Gelatin Hydrogels. AB - Human tumour progression is a dynamic process involving diverse biological and biochemical events such as genetic mutation and selection in addition to physical, chemical, and mechanical events occurring between cells and the tumour microenvironment. Using 3D bioprinting we have developed a method to embed MDA-MB 231 triple negative breast cancer cells, and IMR-90 fibroblast cells, within a cross-linked alginate/gelatin matrix at specific initial locations relative to each other. After 7 days of co-culture the MDA-MB-231 cells begin to form multicellular tumour spheroids (MCTS) that increase in size and frequency over time. After ~15 days the IMR-90 stromal fibroblast cells migrate through a non cellularized region of the hydrogel matrix and infiltrate the MDA-MB-231 spheroids creating mixed MDA-MB-231/IMR-90 MCTS. This study provides a proof-of concept that biomimetic in vitro tissue co-culture models bioprinted with both breast cancer cells and fibroblasts will result in MCTS that can be maintained for durations of several weeks. PMID- 28676664 TI - iTRAQ-Based Quantitative Proteomic Analysis of the Inhibitory Effects of Polysaccharides from Viscum coloratum (Kom.) Nakai on HepG2 Cells. AB - Viscum coloratum (Kom.) Nakai is one of active medicinal plants, and its active components, especially polysaccharides, have been shown to exhibit bioactivity. In this study, we examined the effects of three polysaccharide fractions from Viscum coloratum (Kom.) Nakai on HepG2 cell growth in a dose-dependent manner by using a CCK-8 assay kit. Flow cytometry analysis showed that VCP2 treatment delayed the cell cycle in the G1 phase and induced apoptosis in HepG2 cells, a result possibly due to the increased expression of p21Wafl/Cip1 and Cyclin D and the decreased expression of Cyclin E and CDK4. The increased expression of Bad, Smac and Caspase-3 and the decreased expression of Bcl-XL and XIAP may be some of the reasons for the induction of apoptosis in VCP2-treated HepG2 cells. Through iTRAQ and 2D-LC-MSMS, 113 and 198 differentially expressed proteins were identified in normal and VCP2-treated HepG2 and Caco2 cells. The mRNA and protein levels of Histone H3.1, Cytoskeletal 9 and Vitronectin agreed with iTRAQ proteomic results. GO, pathways and the PPI of differentially expressed proteins were further analyzed. These findings broaden the understanding of the anti-tumor mechanisms of mistletoe polysaccharides and provide new clues for screening proteins that are responsive to polysaccharides. PMID- 28676665 TI - New insights on the complex dynamics of two-phase flow in porous media under intermediate-wet conditions. AB - Multiphase flow in porous media is important in a number of environmental and industrial applications such as soil remediation, CO2 sequestration, and enhanced oil recovery. Wetting properties control flow of immiscible fluids in porous media and fluids distribution in the pore space. In contrast to the strong and weak wet conditions, pore-scale physics of immiscible displacement under intermediate-wet conditions is less understood. This study reports the results of a series of two-dimensional high-resolution direct numerical simulations with the aim of understanding the pore-scale dynamics of two-phase immiscible fluid flow under intermediate-wet conditions. Our results show that for intermediate-wet porous media, pore geometry has a strong influence on interface dynamics, leading to co-existence of concave and convex interfaces. Intermediate wettability leads to various interfacial movements which are not identified under imbibition or drainage conditions. These pore-scale events significantly influence macro-scale flow behaviour causing the counter-intuitive decline in recovery of the defending fluid from weak imbibition to intermediate-wet conditions. PMID- 28676663 TI - 3D models of the hematopoietic stem cell niche under steady-state and active conditions. AB - Hematopoietic stem cells (HSCs) in the bone marrow are able to differentiate into all types of blood cells and supply the organism each day with billions of fresh cells. They are applied to cure hematological diseases such as leukemia. The clinical need for HSCs is high and there is a demand for being able to control and multiply HSCs in vitro. The hematopoietic system is highly proliferative and thus sensitive to anti-proliferative drugs such as chemotherapeutics. For many of these drugs suppression of the hematopoietic system is the dose-limiting toxicity. Therefore, biomimetic 3D models of the HSC niche that allow to control HSC behavior in vitro and to test drugs in a human setting are relevant for the clinics and pharmacology. Here, we describe a perfused 3D bone marrow analog that allows mimicking the HSC niche under steady-state and activated conditions that favor either HSC maintenance or differentiation, respectively, and allows for drug testing. PMID- 28676666 TI - A Light-Activated Explosive Micropropeller. AB - Self-propelled micro/nanomotors possess tremendous exciting promise in diverse fields. We describe an asymmetric, fuel-free and near-infrared light-powered torpedo micromotor, which is constructed by using a porous membrane-assisted layer-by-layer sol-gel method to form silica multilayer inside the pores, following by the deposition of gold nanoparticles on one end of the pores. In the absence of chemical fuels, the high propulsion of microtorpedoes under illumination of near-infrared light is owing to the photo-thermal effect of gold clusters, generating a thermal gradient inside the microtorpedoes. The speed of microtorpedoes is dependent on the laser powers and media. More interestingly, such fuel free-powered microtorpedoes could explode triggered by higher laser power at the predefined site and thus provide a new platform for future biomedical applications. PMID- 28676667 TI - Eimeria tenella protein trafficking: differential regulation of secretion versus surface tethering during the life cycle. AB - Eimeria spp. are intracellular parasites that have a major impact on poultry. Effective live vaccines are available and the development of reverse genetic technologies has raised the prospect of using Eimeria spp. as recombinant vectors to express additional immunoprotective antigens. To study the ability of Eimeria to secrete foreign antigens or display them on the surface of the sporozoite, transiently transfected populations of E. tenella expressing the fluorescent protein mCherry, linked to endogenous signal peptide (SP) and glycophosphatidylinositol-anchor (GPI) sequences, were examined. The SP from microneme protein EtMIC2 (SP2) allowed efficient trafficking of mCherry to cytoplasmic vesicles and following the C-terminal addition of a GPI-anchor (from surface antigen EtSAG1) mCherry was expressed on the sporozoite surface. In stable transgenic populations, mCherry fused to SP2 was secreted into the sporocyst cavity of the oocysts and after excystation, secretion was detected in culture supernatants but not into the parasitophorous vacuole after invasion. When the GPI was incorporated, mCherry was observed on the sporozites surface and in the supernatant of invading sporozoites. The proven secretion and surface exposure of mCherry suggests that antigen fusions with SP2 and GPI of EtSAG1 may be promising candidates to examine induction of protective immunity against heterologous pathogens. PMID- 28676668 TI - The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. AB - The calreticulin (CALR) exon 9 mutations are found in ~30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically recognize CALRmut cells. First, we established a T-cell culture specific for a CALRmut epitope. These specific T cells were able to recognize several epitopes in the CALRmut C terminus. Next, we established a CALRmut-specific CD4+ T-cell clone by limiting dilution. These CD4+ T cells recognized autologous CALRmut monocytes and hematopoietic stem cells, and T-cell recognition of target cells was dependent on the presence of CALR. Furthermore, we showed that the CALRmut response was human leukocyte antigen (HLA)-DR restricted. Finally, we demonstrated that the CALRmut specific CD4+ T cells, despite their phenotype, were cytotoxic to autologous CALRmut cells, and that the cytotoxicity was mediated by degranulation of the T cells. In conclusion, the CALR exon 9 mutations are targets for specific T cells and thus are promising targets for cancer immune therapy such as peptide vaccination in patients harboring CALR exon 9 mutations. PMID- 28676669 TI - Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma. AB - Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients' bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ. PMID- 28676670 TI - Species-specific antifungal activity of blue light. AB - Fungal pathogens represent a significant threat to immunocompromised patients or individuals with traumatic injury. Strategies to efficiently remove fungal spores from hospital surfaces and, ideally, patient skin thus offer the prospect of dramatically reducing infections in at-risk patients. Photodynamic inactivation of microbial cells using light holds considerable potential as a non-invasive, minimally destructive disinfection strategy. Recent data indicate that high intensity blue light effectively removes bacteria from surfaces, but its efficacy against fungi has not been fully tested. Here we test a wide range of fungi that are pathogenic to humans and demonstrate that blue light is effective against some, but not all, fungal species. We additionally note that secondary heating effects are a previously unrecognized confounding factor in establishing the antimicrobial activity of blue light. Thus blue light holds promise for the sterilization of clinical surfaces, but requires further optimization prior to widespread use. PMID- 28676671 TI - The Arctic-Subarctic sea ice system is entering a seasonal regime: Implications for future Arctic amplification. AB - The loss of Arctic sea ice is a conspicuous example of climate change. Climate models project ice-free conditions during summer this century under realistic emission scenarios, reflecting the increase in seasonality in ice cover. To quantify the increased seasonality in the Arctic-Subarctic sea ice system, we define a non-dimensional seasonality number for sea ice extent, area, and volume from satellite data and realistic coupled climate models. We show that the Arctic Subarctic, i.e. the northern hemisphere, sea ice now exhibits similar levels of seasonality to the Antarctic, which is in a seasonal regime without significant change since satellite observations began in 1979. Realistic climate models suggest that this transition to the seasonal regime is being accompanied by a maximum in Arctic amplification, which is the faster warming of Arctic latitudes compared to the global mean, in the 2010s. The strong link points to a peak in sea-ice-related feedbacks that occurs long before the Arctic becomes ice-free in summer. PMID- 28676672 TI - Study on Optimal Selection of Wavelet Vanishing Moments for ECG Denoising. AB - The frequency characteristics of wavelets and the vanishing moments of wavelet filters are both important parameters of wavelets. Clarifying the relationship between the wavelet frequency characteristics and the vanishing moments of the wavelet filter can provide a theoretical basis for selecting the best wavelet. In this paper, the frequency characteristics of wavelets were analyzed by mathematical modeling, the mathematical relationship between wavelet frequency characteristics and vanishing moments was clarified, the optimal wavelet base function was selected hierarchically according to the amplitude frequency characteristics of ECG signal, and an accurate notch filter was realized according to the frequency characteristics of the noise. The experimental results showed that the optimal orthogonal wavelet analysis for the ECG signals with different frequency characteristics could make the high frequency energy distribution sparser, and the method proposed in this paper could effectively preserve the singularity of the signal and reduce the signal distortion. PMID- 28676673 TI - Formulation and candidacidal activity of magnetic nanoparticles coated with cathelicidin LL-37 and ceragenin CSA-13. AB - Fungal infections caused by Candida spp. represent an emerging problem during treatment of immunocompromised patients and those hospitalized with serious principal diseases. The ever-growing number of fungal strains exhibiting drug resistance necessitates the development of novel antimicrobial therapies including those based on membrane-permeabilizing agents and nanomaterials as drug carriers. In this study, the fungicidal activities of LL-37 peptide, ceragenin CSA-13 and its magnetic derivatives (MNP@LL-37, MNP@CSA-13) against laboratory and clinical strains of C. albicans, C. glabrata and C. tropicalis were evaluated. These experiments confirm the high anti-fungal activity of these well characterized agents mediated by their interaction with the fungal membrane and demonstrate elevated activity following immobilization of LL-37 and CSA-13 on the surface of magnetic nanoparticles (MNPs). Furthermore, MNP-based nanosystems are resistant to inhibitory factors present in body fluids and effectively inhibit formation of fungal biofilm. Simultaneously, synthesized nanostructures maintain immunomodulatory properties, described previously for free LL-37 peptide and CSA 13 substrate and they do not interfere with the proliferation and viability of osteoblasts, confirming their high biocompatibility. PMID- 28676674 TI - The Enterococcus faecalis virulence factor ElrA interacts with the human Four-and a-Half LIM Domains Protein 2. AB - The commensal bacterium Enterococcus faecalis is a common cause of nosocomial infections worldwide. The increasing prevalence of multi-antibiotic resistant E. faecalis strains reinforces this public health concern. Despite numerous studies highlighting several pathology-related genetic traits, the molecular mechanisms of E. faecalis virulence remain poorly understood. In this work, we studied 23 bacterial proteins that could be considered as virulence factors or involved in the Enterococcus interaction with the host. We systematically tested their interactions with human proteins using the Human ORFeome library, a set of 12,212 human ORFs, in yeast. Among the thousands of tested interactions, one involving the E. faecalis virulence factor ElrA and the human protein FHL2 was evidenced by yeast two-hybrid and biochemically confirmed. Further molecular characterizations allowed defining an FHL2-interacting domain (FID) of ElrA. Deletion of the FID led to an attenuated in vivo phenotype of the mutated strain clearly indicating that this interaction is likely to contribute to the multifactorial virulence of this opportunistic pathogen. Altogether, our results show that FHL2 is the first host cellular protein directly targeted by an E. faecalis virulence factor and that this interaction is involved in Enterococcus pathogenicity. PMID- 28676675 TI - HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardiovascular risk. AB - Diabetes increases the risk of Cardio-vascular disease (CVD). CVD is more prevalent in type 2 diabetes (T2D) than type 1 diabetes (T1D), but the mortality risk is higher in T1D than in T2D. The pathophysiology of CVD in T1D is poorly defined. To learn more about biological pathways that are potentially involved in T1D with cardiac dysfunction, we sought to identify differentially expressed genes in the T1D heart. Our study used T1D mice with severe hyperglycemia along with significant deficits in echocardiographic measurements. Microarray analysis of heart tissue RNA revealed that the T1D mice differentially expressed 10 genes compared to control. Using Ingenuity Pathway Analysis (IPA), we showed that these genes were significantly involved in ketogenesis, cardiovascular disease, apoptosis and other toxicology functions. Of these 10 genes, the 3-Hydroxy-3 Methylglutaryl-CoA Synthase 2 (HMGCS2) was the highest upregulated gene in T1D heart. IPA analysis showed that HMGCS2 was center to many biological networks and pathways. Our data also suggested that apart from heart, the expression of HMGCS2 was also different in kidney and spleen between control and STZ treated mice. In conclusion, The HMGCS2 molecule may potentially be involved in T1D induced cardiac dysfunction. PMID- 28676676 TI - Identifying pathways modulating sleep duration: from genomics to transcriptomics. AB - Recognizing that insights into the modulation of sleep duration can emerge by exploring the functional relationships among genes, we used this strategy to explore the genome-wide association results for this trait. We detected two major signalling pathways (ion channels and the ERBB signalling family of tyrosine kinases) that could be replicated across independent GWA studies meta-analyses. To investigate the significance of these pathways for sleep modulation, we performed transcriptome analyses of short sleeping flies' heads (knockdown for the ABCC9 gene homolog; dSur). We found significant alterations in gene expression in the short sleeping knockdowns versus controls flies, which correspond to pathways associated with sleep duration in our human studies. Most notably, the expression of Rho and EGFR (members of the ERBB signalling pathway) genes was down- and up-regulated, respectively, consistently with the established role of these genes for sleep consolidation in Drosophila. Using a disease multifactorial interaction network, we showed that many of the genes of the pathways indicated to be relevant for sleep duration had functional evidence of their involvement with sleep regulation, circadian rhythms, insulin secretion, gluconeogenesis and lipogenesis. PMID- 28676677 TI - HLA-E Presents Glycopeptides from the Mycobacterium tuberculosis Protein MPT32 to Human CD8+ T cells. AB - Infection with Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis, remains a global health concern. Both classically and non classically restricted cytotoxic CD8+ T cells are important to the control of Mtb infection. We and others have demonstrated that the non-classical MHC I molecule HLA-E can present pathogen-derived peptides to CD8+ T cells. In this manuscript, we identified the antigen recognized by an HLA-E-restricted CD8+ T cell clone isolated from an Mtb latently infected individual as a peptide from the Mtb protein, MPT32. Recognition by the CD8+ T cell clone required N-terminal O-linked mannosylation of MPT32 by a mannosyltransferase encoded by the Rv1002c gene. This is the first description of a post-translationally modified Mtb-derived protein antigen presented in the context of an HLA-E specific CD8+ T cell immune response. The identification of an immune response that targets a unique mycobacterial modification is novel and may have practical impact in the development of vaccines and diagnostics. PMID- 28676678 TI - Changes in telomere length 3-5 years after gastric bypass surgery. AB - Increased inflammation and oxidative stress associated with obesity can accelerate aging. Telomere length (TL) has the capacity to serve as an aging indicator at the cellular level. Obesity has a known association with shorter TL. This study evaluated TL of immune cells in a population of obese individuals who underwent gastric bypass surgery. Pre- and post-operative DNA samples were available for 50 subjects who had gastric bypass surgery. DNA was analyzed via quantitative polymerase chain reaction to determine TL. Changes in TL were evaluated by comparing TL at baseline to TL at 3-5 years post gastric bypass surgery. Sixty percent of the individuals in the study observed an increase in TL. Significant lengthening was observed for those with the shortest baseline TL (P=0.0011), but not for those with intermediate baseline TL (P=0.411) or longest baseline TL (P=0.207). Change in TL was negatively correlated with age and triglycerides but not correlated with weight loss induced by bariatric surgery. This study confirms that TL lengthening is observed post bariatric surgery and is the first to detect TL lengthening 3-5 years after surgery. PMID- 28676679 TI - Disinhibited eating mediates differences in attachment insecurity between bariatric surgery candidates/recipients and lean controls. AB - Previous research has shown that attachment anxiety is a good predictor of body mass index. This relationship is significantly mediated by disinhibited (over-) eating and is likely to reflect a specific form of affect regulation. This study explored whether obese bariatric surgery candidates (BSC; N=34) and bariatric surgery recipients (BSR; N=15) would show higher levels of attachment insecurity (higher attachment anxiety and/or higher attachment avoidance) than a group of age and gender-matched lean controls (N=54). Mediation analyses showed that compared to lean controls (M=2.96, SE=0.1), both BSC (M=3.5, SE=0.2) and BSR (M=3.4, SE=0.2) groups had a more insecure attachment orientation. These relationships were significantly mediated by disinhibited eating (BSC: lower limit confidence interval (LLCI)=0.06 and upper limit confidence interval (ULCI)=0.62; BSR: LLCI=0.02 and ULCI=0.76). There was no such relationship when the BSC and BSR groups were compared (LLCI=-0.15 & ULCI=0.3). These observations suggest that attachment insecurity may be a risk factor for obesity and bariatric surgery because of associated disinhibited eating. Moreover, these factors may be important to consider when bariatric surgery results in poor outcomes. PMID- 28676680 TI - The development and validation of the Addiction-like Eating Behaviour Scale. AB - BACKGROUND: Overeating and obesity are frequently attributed to an addiction to food. However, there is currently a lack of evidence to support the idea that certain foods contain any specific addictive substance. An alternative approach is to focus on dimensions of observable behaviour, which may underpin a behavioural addiction to eating. To facilitate this, it is necessary to develop a tool to quantify addiction-like eating behaviour, which is not based on the clinical criteria for substance dependence. The current study provides initial validation of the Addiction-like Eating Behaviour Scale (AEBS). METHODS: English speaking male and female participants (N=511) from a community sample completed the AEBS, alongside a range of other health- and eating-related questionnaires including the Yale Food Addiction Scale (YFAS) and Binge Eating Scale (BES). Participants also provided their height and weight to enable calculation of body mass index (BMI). Finally, to assess test-retest reliability, an additional 70 participants completed the AEBS twice, 2 weeks apart. RESULTS: Principle components analysis revealed that a two-factor structure best accounted for the data. Factor 1 consisted of items that referred to appetitive drive, whereas factor two consisted of items that referred to dietary control practices. Both subscales demonstrated good internal reliability and test-retest reliability, and a confirmatory factor analysis confirmed the two-factor scale structure. AEBS scores correlated positively with body mass index (BMI) (P<0.001) and other self report measures of overeating. Importantly, the AEBS significantly predicted variance in BMI above that accounted for by both the YFAS and BES (P=0.027). CONCLUSIONS: The AEBS provides a valid and reliable tool to quantify the behavioural features of a potential 'eating addiction'. In doing so, the AEBS overcomes many limitations associated with applying substance-dependence criteria to eating. PMID- 28676681 TI - Maternal vitamin D, DNA methylation at imprint regulatory regions and offspring weight at birth, 1 year and 3 years. AB - BACKGROUND/OBJECTIVE: Vitamin D deficiency during pregnancy is associated with poor birth outcomes in some studies, but few have examined weight beyond birth. In addition, little is known about how vitamin D influences DNA methylation of regulatory regions known to be involved in growth, as possible mediators to weight status in offspring. SUBJECTS/METHODS: We conducted linear regressions to assess maternal plasma 25-hydroxyvitamin D (25(OH)D) by quartile and birth weight for gestational age z-score, 1-year weight-for-length z-score and 3-year body mass index (BMI) z-score among 476 mother/infant dyads from a prospective cohort. We assessed maternal 25(OH)D and infant DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes with known functions in fetal growth, including H19, IGF2, MEG3, MEG3-IG, MEST, NNAT, PEG3, PLAGL1 and SGCE/PEG10. RESULTS: Mean (standard deviation, s.d.) maternal 25(OH)D was 41.1 (14.2) nmol l-m at a mean (s.d.) of 13.2 (5.5) weeks gestation. After adjustment for potential confounders, the first (Q1) and second (Q2) quartiles of 25(OH)D, compared to the fourth (Q4), were associated with lower birth weight for gestational age z-scores (-0.43 units; CI: -0.79, -0.07; P=0.02 for Q1 and -0.56 units; CI: -0.89, -0.23; P=0.001 for Q2). Q1 compared to Q4 was associated with higher 1-year weight-for-length z-scores (0.78 units; 0.08, 1.54; P=0.04) and higher 3-year BMI z-scores (0.83 units; 0.11, 0.93; P=0.02). We did not observe associations between maternal 25(OH)D and methylation for any of the nine DMRs after correcting for multiple testing. CONCLUSIONS: Reduced maternal 25(OH)D was associated with lower birth weight for gestational age z-scores but higher 1-year weight-for-length and 3-year BMI z-scores in offspring. However, 25(OH)D does not appear to be operating through the regulatory sequences of the genomically imprinted genes we examined. PMID- 28676682 TI - Obesity during pregnancy affects sex steroid concentrations depending on fetal gender. AB - BACKGROUND/OBJECTIVE: It is not clear whether maternal obesity along with fetal gender affect sex steroid metabolism during pregnancy. Therefore, we compared sex steroid concentrations and placental expression of steroidogenic enzymes between non-obese and obese pregnant women with non-pathological pregnancies, and investigated the influence of fetal gender on these parameters. METHODS: In 35 normal weight (body mass index (BMI) 20-24.9 kg m-2) (controls) and 36 obese women (BMI 30-36 kg m-2) (obese), a fasting blood sample was obtained at first and at third trimester of gestation to measure progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone and estradiol by liquid chromatography-tandem mass spectrometry and estrone by radioimmunoassay. In a subset of women, placental mRNA and protein expression of steroidogenic enzymes was measured by quantitative PCR and western blot, respectively. The comparisons were primarily made between controls and obese, and then separately according to fetal gender. RESULTS: At first and third trimesters of gestation serum progesterone was lower whereas testosterone was higher in obese women (P<0.05, respectively). Upon analyzing according to fetal gender, lower progesterone levels were present in obese pregnant women with male fetuses at first trimester and with female fetuses at third trimester (P<0.05, respectively). Testosterone was higher in obese women with male fetuses compared to control women with male fetuses (P<0.05). The placental protein expression of P450scc was higher in obese women compared to controls (P<0.05). P450 aromatase was higher in obese women with female fetuses (P=0.009), whereas in obese women with male fetuses P450 aromatase was lower compared to control women (P=0.026). CONCLUSIONS: Obesity in non-pathological pregnancies alters the maternal serum progesterone and testosterone concentrations depending on fetal gender. These changes can be attributed to gender-related placental adaptations, as the expression of P450 aromatase is different in placentas from females compared to males. PMID- 28676683 TI - Thermal conductivities of phosphorene allotropes from first-principles calculations: a comparative study. AB - Phosphorene has attracted tremendous interest recently due to its intriguing electronic properties. However, the thermal transport properties of phosphorene, especially for its allotropes, are still not well-understood. In this work, we calculate the thermal conductivities of five phosphorene allotropes (alpha-, beta , gamma-, delta- and zeta-phase) by using phonon Boltzmann transport theory combined with first-principles calculations. It is found that the alpha phosphorene exhibits considerable anisotropic thermal transport, while it is less obvious in the other four phosphorene allotropes. The highest thermal conductivity is found in the beta-phosphorene, followed by the delta-, gamma- and zeta-phase. The much lower thermal conductivity of the zeta-phase can be attributed to its relatively complex atomic configuration. It is expected that the rich thermal transport properties of phosphorene allotropes can have potential applications in the thermoelectrics and thermal management. PMID- 28676684 TI - Erratum: Diurnal variation of urinary sodium-to-potassium ratio in free-living Japanese individuals. AB - This corrects the article DOI: 10.1038/hr.2016.187. PMID- 28676685 TI - Understanding the role of damping and Dzyaloshinskii-Moriya interaction on dynamic domain wall behaviour in platinum-ferromagnet nanowires. AB - Heavy metal layers, exemplified by Pt, are known to play a significant role in the magnetization behaviour of thin-film ferromagnets by three distinct mechanisms that can each contribute to the reversal process. These include modifying the local magnetization state via an interfacial Dzyaloshinskii-Moriya interaction (IDMI), enhancement of the damping, via d-d hybridisation and spin pumping across the interface, and the mediation of the magnetization switching, with the flow of current through a system, via the spin-Hall effect. Here we show for a system with weak interfacial DMI (NiFe/Pt) that the measurement of magnetic field-driven magnetization reversal, mediated by domain wall (DW) motion, is dominated by the enhanced intrinsic damping contribution as a function of the Pt capping layer thickness. But, we also show micromagnetically that the IDMI and damping also combine to modify the domain wall velocity behaviour when the damping is larger. It is also noted that Walker breakdown occurs at lower fields and peak DW velocity decreases in the presence of IDMI. These results highlight the significance of the relative contributions of the damping and the IDMI from the heavy metal layer on the magnetization reversal and provide a route to controlling the DW behaviour in nanoscale device structures. PMID- 28676686 TI - Two T7-like Bacteriophages, K5-2 and K5-4, Each Encodes Two Capsule Depolymerases: Isolation and Functional Characterization. AB - Two Klebsiella bacteriophages K5-2 and K5-4, which are able to infect and grow on either capsular types K30/K69 and K5 or K8 and K5 of Klebsiella strains, were isolated and characterized. Each phage contained two open reading frames (ORFs), which encoded two putative capsule depolymerases, respectively. The first ORF encoded tail fiber proteins, which have K30/K69 depolymerase and K8 depolymerase activities. The second ORF encoded hypothetical proteins, which are almost identical in amino acid sequences, and have K5 depolymerase activity. Alcian blue staining of enzyme-treated capsular polysaccharides (CPS) showed that purified depolymerases can cleave purified Klebsiella CPS in vitro and liberate monosaccharaides. Capsule K5 deletion mutants were not lysed by either phage, suggesting that the capsule was essential for phage infection. Bacterial killing was observed when incubated Klebsiella strains with phages but not with purified depolymerases. Treatment with the K5-4 phage significantly increased the survival of mice infected with a K. pneumoniae K5 strain. In conclusion, two dual host specific Klebsiella phages and their tailspikes exhibit capsule depolymerase activity were characterized. Each phage and phage-encoded depolymerase has specificity for capsular type K30/K69, K8 or K5, and could be used for the typing and treatment of K. pneumoniae infection. PMID- 28676687 TI - Maternal HtrA3 optimizes placental development to influence offspring birth weight and subsequent white fat gain in adulthood. AB - High temperature requirement factor A3 (HtrA3), a member of the HtrA protease family, is highly expressed in the developing placenta, including the maternal decidual cells in both mice and humans. In this study we deleted the HtrA3 gene in the mouse and crossed females carrying zero, one, or two HtrA3-expressing alleles with HtrA3+/- males to investigate the role of maternal vs fetal HtrA3 in placentation. Although HtrA3-/- mice were phenotypically normal and fertile, HtrA3 deletion in the mother resulted in intra-uterine growth restriction (IUGR). Disorganization of labyrinthine fetal capillaries was the major placental defect when HtrA3 was absent. The IUGR caused by maternal HtrA3 deletion, albeit being mild, significantly altered offspring growth trajectory long after birth. By 8 months of age, mice born to HtrA3-deficient mothers, independent of their own genotype, were significantly heavier and contained a larger mass of white fat. We further demonstrated that in women serum levels of HtrA3 during early pregnancy were significantly lower in IUGR pregnancies, establishing an association between lower HtrA3 levels and placental insufficiency in the human. This study thus revealed the importance of maternal HtrA3 in optimizing placental development and its long-term impact on the offspring well beyond in utero growth. PMID- 28676688 TI - Engaging narratives evoke similar neural activity and lead to similar time perception. AB - It is said that we lose track of time - that "time flies" - when we are engrossed in a story. How does engagement with the story cause this distorted perception of time, and what are its neural correlates? People commit both time and attentional resources to an engaging stimulus. For narrative videos, attentional engagement can be represented as the level of similarity between the electroencephalographic responses of different viewers. Here we show that this measure of neural engagement predicted the duration of time that viewers were willing to commit to narrative videos. Contrary to popular wisdom, engagement did not distort the average perception of time duration. Rather, more similar brain responses resulted in a more uniform perception of time across viewers. These findings suggest that by capturing the attention of an audience, narrative videos bring both neural processing and the subjective perception of time into synchrony. PMID- 28676689 TI - Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice. AB - Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with immunomodulatory and anti-inflammatory effects. Beyond its direct effects, the metabolic products of EPA also regulate various immune responses. Animal experiments demonstrated that EPA reduces adipose inflammation in high fat diet-induced obese mouse. However, the effects of EPA on infiltrated immune cell populations in adipose tissue and underlying mechanisms remain to be elucidated. We performed flow cytometry of stromal vascular fraction of epididymal adipose tissues from C57BL/6J and ob/ob mice fed normal chow mixed with or without 5% EPA. The numbers of hematopoietic cells, including Tregs, were higher in both C57BL/6J and ob/ob mice fed EPA diet compared with control diet. EPA enhanced the induction of Tregs in co-cultures of adipose tissue macrophages (ATMs) and naive T cells. Among EPA metabolites, 5 HEPE was the most potent inducer of Tregs. GPR119 and GPR120 are receptors for 5 HEPE and EPA, respectively, and antagonist of GPR119 blocked Treg induction by EPA in the presence of ATMs. Alox5 gene encodes 5-lipoxygenase enzyme catalyzing EPA into 5-HEPE, and inhibitor of 5-lipoxygenase down-regulated EPA-mediated induction of adipose tissue Tregs in ob/ob mice. The study findings demonstrated that both EPA and 5-HEPE enhance ATM-mediated Treg induction. PMID- 28676690 TI - Screening Specific Biomarkers of Herbs Using a Metabolomics Approach: A Case Study of Panax ginseng. AB - Medicinal herbs belonging to the same genus are always easily confused due to their extremely similar morphology and metabolites. Previously, to differentiate them, inherently specific biomarkers were screened out via intuitive comparison of their metabolite profiles. Unfortunately, the selected biomarkers have worked only partially. Most significant specific biomarkers have been neglected. Herein, a novel method for screening specific biomarkers of medicinal herbs using a metabolomics technique was developed. Firstly, the profiles of a group of easily confused herbs belonging to the same genus were analyzed by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry to detect all components, including low-response metabolites. Then, all components were compared between the different samples, and specific biomarkers were extracted by the metabolomics techniques of alignment, normalization, defining the sample sets, filtering by frequency and Venn diagram analysis with Mass Profiler Professional (MPP) software. Thirdly, the correlations of these biomarkers were investigated via partial correlational analysis to obtain the most representative specific biomarkers. As an example, selection of specific biomarkers for ginseng (Panax ginseng) was performed, and three specific biomarkers including chikusetsusaponin IVa, ginsenoside Rf and ginsenoside Rc were finally selected and verified as the most representative specific biomarkers of Panax ginseng. PMID- 28676691 TI - Near-field fault slip of the 2016 Vettore Mw 6.6 earthquake (Central Italy) measured using low-cost GNSS. AB - The temporal evolution of slip on surface ruptures during an earthquake is important for assessing fault displacement, defining seismic hazard and for predicting ground motion. However, measurements of near-field surface displacement at high temporal resolution are elusive. We present a novel record of near-field co-seismic displacement, measured with 1-second temporal resolution during the 30th October 2016 Mw 6.6 Vettore earthquake (Central Italy), using low cost Global Navigation Satellite System (GNSS) receivers located in the footwall and hangingwall of the Mt. Vettore - Mt. Bove fault system, close to new surface ruptures. We observe a clear temporal and spatial link between our near-field record and InSAR, far-field GPS data, regional measurements from the Italian Strong Motion and National Seismic networks, and field measurements of surface ruptures. Comparison of these datasets illustrates that the observed surface ruptures are the propagation of slip from depth on a surface rupturing (i.e. capable) fault array, as a direct and immediate response to the 30th October earthquake. Large near-field displacement ceased within 6-8 seconds of the origin time, implying that shaking induced gravitational processes were not the primary driving mechanism. We demonstrate that low-cost GNSS is an accurate monitoring tool when installed as custom-made, short-baseline networks. PMID- 28676692 TI - Copy number alteration of neuropeptides and receptors in multiple cancers. AB - Neuropeptides are peptide hormones used as chemical signals by the neuroendocrine system to communicate between cells. Recently, neuropeptides have been recognized for their ability to act as potent cellular growth factors on many cell types, including cancer cells. However, the molecular mechanism for how this occurs is unknown. To clarify the relationship between neuropeptides and cancer, we manually curated a total of 127 human neuropeptide genes by integrating information from the literature, homologous sequences, and database searches. Using human ligand-receptor interaction data, we first identified an interactome of 226 interaction pairs between 93 neuropeptides and 133 G-protein coupled receptors. We further identified four neuropeptide-receptor functional modules with ten or more genes, all of which were highly mutated in multiple cancers. We have identified a number of neuropeptide signaling systems with both oncogenic and tumour-suppressing roles for cancer progression, such as the insulin-like growth factors. By focusing on the neuroendocrine prostate cancer mutational data, we found prevalent amplification of neuropeptide and receptors in about 72% of samples. In summary, we report the first observation of abundant copy number variations on neuropeptides and receptors, which will be valuable for the design of peptide-based cancer prognosis, diagnosis and treatment. PMID- 28676693 TI - Selective breeding and selection mapping using a novel wild-derived heterogeneous stock of mice revealed two closely-linked loci for tameness. AB - Tameness is a major behavioral factor for domestication, and can be divided into two potential components: motivation to approach humans (active tameness) and reluctance to avoid humans (passive tameness). We identified genetic loci for active tameness through selective breeding, selection mapping, and association analysis. In previous work using laboratory and wild mouse strains, we found that laboratory strains were predominantly selected for passive tameness but not active tameness during their domestication. To identify genetic regions associated with active tameness, we applied selective breeding over 9 generations for contacting, a behavioural parameter strongly associated with active tameness. The prerequisite for successful selective breeding is high genetic variation in the target population, so we established and used a novel resource, wild-derived heterogeneous stock (WHS) mice from eight wild strains. The mice had genetic variations not present in other outbred mouse populations. Selective breeding of the WHS mice increased the contacting level through the generations. Selection mapping was applied to the selected population using a simulation based on a non selection model and inferred haplotype data derived from single-nucleotide polymorphisms. We found a genomic signature for selection on chromosome 11 containing two closely linked loci. PMID- 28676694 TI - Resonant Dipolar Coupling of Microwaves with Confined Acoustic Vibrations in a Rod-shaped Virus. AB - In this letter, we treat a rod-shaped virus as a free homogenous nanorod and identify its confined acoustic vibration modes that can cause strong resonant microwave absorption through electric dipolar excitation with a core-shell charge distribution. They are found to be the n = 4N-2 modes of the longitudinal modes of the nanorods, where N is an integer starting from 1 and n is the mode order quantum number. This study was confirmed by measuring the microwave absorption spectra of white spot syndrome virus (WSSV), which is a rod-shaped virus. This is also the first study to identify the "dipolar-like" mode in a rod-shaped nano object. Our study is not only an important step to achieve rapid and sensitive detection of rod-shaped viruses based on their microwave spectroscopic features and a non-contact method to measure the Young's modulus of rod-shaped viruses, but also is critical to formulate an efficient epidemic prevention strategy to deactivate viruses with the structure-resonant microwaves. PMID- 28676695 TI - Functional PIN1 promoter polymorphisms associated with risk of nasopharyngeal carcinoma in Southern Chinese populations. AB - Our previous work reported the association between two single nucleotide polymorphisms (SNPs) in PIN1 promoter and nasopharyngeal carcinoma (NPC) risk with a small sample size in a low incidence area. This study investigated the association between the two SNPs and NPC risk in 733 patients and 895 controls from a high incidence area. The results indicated the genotype and allele frequencies of -842G > C and -667C > T were both significantly different between patients and controls even using the resampling statistics. The -842GC and -667TT genotypes showed a significantly increased risk of NPC (OR = 1.977, 95% CI = 1.339-2.919, P = 0.001 and OR = 1.438, 95% CI = 1.061-1.922, P = 0.019, respectively). Compared to the most common -842G-667C haplotype, -842G-667T haplotype and -842C-667C haplotype showed a significantly increased risk of NPC (OR = 1.215, 95% CI = 1.053-1.402, P = 0.008 and OR = 2.268, 95% CI = 1.530 3.362, P = 0.001, respectively). Further reporter gene expression suggested that variant -842C-667C and -842G-667T were associated with an enhanced transcriptional activity. In conclusion, our findings suggest that -842G > C and 667C > T in PIN1 promoter are associated with NPC risk; as well as the promoter activity is mediated by functional PIN1 variants. PMID- 28676696 TI - Ribo-attenuators: novel elements for reliable and modular riboswitch engineering. AB - Riboswitches are structural genetic regulatory elements that directly couple the sensing of small molecules to gene expression. They have considerable potential for applications throughout synthetic biology and bio-manufacturing as they are able to sense a wide range of small molecules and regulate gene expression in response. Despite over a decade of research they have yet to reach this considerable potential as they cannot yet be treated as modular components. This is due to several limitations including sensitivity to changes in genetic context, low tunability, and variability in performance. To overcome the associated difficulties with riboswitches, we have designed and introduced a novel genetic element called a ribo-attenuator in Bacteria. This genetic element allows for predictable tuning, insulation from contextual changes, and a reduction in expression variation. Ribo-attenuators allow riboswitches to be treated as truly modular and tunable components, thus increasing their reliability for a wide range of applications. PMID- 28676697 TI - A novel 3D-printed head phantom with anatomically realistic geometry and continuously varying skull resistivity distribution for electrical impedance tomography. AB - Phantom experiments are an important step for testing during the development of new hardware or imaging algorithms for head electrical impedance tomography (EIT) studies. However, due to the sophisticated anatomical geometry and complex resistivity distribution of the human head, constructing an accurate phantom for EIT research remains challenging, especially for skull modelling. In this paper, we designed and fabricated a novel head phantom with anatomically realistic geometry and continuously varying skull resistivity distribution based on 3D printing techniques. The skull model was constructed by simultaneously printing the distinct layers inside the skull with resistivity-controllable printing materials. The entire phantom was composed of saline skin, a 3D-printed skull, saline cerebrospinal fluid (CSF) and 3D-printed brain parenchyma. The validation results demonstrated that the resistivity of the phantom was in good agreement with that of human tissue and was stable over time, and the new phantom performed well in EIT imaging. This paper provides a standardized, efficient and reproducible method for the construction of a head phantom for EIT that could be easily adapted to other conditions for manufacturing head phantoms for brain function research, such as transcranial direct current stimulation (TDCS) and electroencephalography (EEG). PMID- 28676698 TI - Stem cells: Colonic organoids for drug testing and colorectal disease modelling. PMID- 28676699 TI - Circadian rhythms: Replication keeps the clock ticking. PMID- 28676701 TI - Self-compensation in arsenic doping of CdTe. AB - Efficient p-type doping in CdTe has remained a critical challenge for decades, limiting the performance of CdTe-based semiconductor devices. Arsenic is a promising p-type dopant; however, reproducible doping with high concentration is difficult and carrier lifetime is low. We systematically studied defect structures in As-doped CdTe using high-purity single crystal wafers to investigate the mechanisms that limit p-type doping. Two As-doped CdTe with varying acceptor density and two undoped CdTe were grown in Cd-rich and Te-rich environments. The defect structures were investigated by thermoelectric-effect spectroscopy (TEES), and first-principles calculations were used for identifying and assigning the experimentally observed defects. Measurements revealed activation of As is very low in both As-doped samples with very short lifetimes indicating strong compensation and the presence of significant carrier trapping defects. Defect studies suggest two acceptors and one donor level were introduced by As doping with activation energies at ~88 meV, ~293 meV and ~377 meV. In particular, the peak shown at ~162 K in the TEES spectra is very prominent in both As-doped samples, indicating a signature of AX-center donors. The AX-centers are believed to be responsible for most of the compensation because of their low formation energy and very prominent peak intensity in TEES spectra. PMID- 28676700 TI - The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. AB - Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers. Understanding the role of PARP1 in maintaining genome integrity is not only important for the design of novel chemotherapeutic agents, but is also crucial for gaining insights into the mechanisms of chemoresistance in cancer cells. In this Review, we discuss the roles of PARP1 in mediating various aspects of DNA metabolism, such as single strand break repair, nucleotide excision repair, double-strand break repair and the stabilization of replication forks, and in modulating chromatin structure. PMID- 28676702 TI - Extracellular matrix promotes clathrin-dependent endocytosis of prolactin and STAT5 activation in differentiating mammary epithelial cells. AB - The hormone prolactin promotes lactational differentiation of mammary epithelial cells (MECs) via its cognate receptor and the downstream JAK2-STAT5a signalling pathway. In turn this regulates transcription of milk protein genes. Prolactin signalling depends on a cross-talk with basement membrane extracellular matrix (ECM) via beta1 integrins which activate both ILK and Rac1 and are required for STAT5a activation and lactational differentiation. Endocytosis is an important regulator of signalling. It can both enhance and suppress cytokine signalling, although the role of endocytosis for prolactin signalling is not known. Here we show that clathrin-mediated endocytosis is required for ECM-dependent STAT5 activation. In the presence of ECM, prolactin is internalised via a clathrin dependent, but caveolin-independent, route. This occurs independently from JAK2 and Rac signalling, but is required for full phosphorylation and activation of STAT5. Prolactin is internalised into early endosomes, where the master early endosome regulator Rab5b promotes STAT5 phosphorylation. These data reveal a novel role for ECM-driven endocytosis in the positive regulation of cytokine signalling. PMID- 28676703 TI - Selective mass enhancement close to the quantum critical point in BaFe2(As1-x P x )2. AB - A quantum critical point (QCP) is currently being conjectured for the BaFe2(As1-x P x )2 system at the critical value x c ~ 0.3. In the proximity of a QCP, all thermodynamic and transport properties are expected to scale with a single characteristic energy, given by the quantum fluctuations. Such a universal behavior has not, however, been found in the superconducting upper critical field H c2. Here we report H c2 data for epitaxial thin films extracted from the electrical resistance measured in very high magnetic fields up to 67 Tesla. Using a multi-band analysis we find that H c2 is sensitive to the QCP, implying a significant charge carrier effective mass enhancement at the doping-induced QCP that is essentially band-dependent. Our results point to two qualitatively different groups of electrons in BaFe2(As1-x P x )2. The first one (possibly associated to hot spots or whole Fermi sheets) has a strong mass enhancement at the QCP, and the second one is insensitive to the QCP. The observed duality could also be present in many other quantum critical systems. PMID- 28676705 TI - WFPHA: World Federation of Public Health Associations : Call for Global Public Health Leaders: Provision of Safe Dentistry for All. PMID- 28676704 TI - Biomaterial-Free Three-Dimensional Bioprinting of Cardiac Tissue using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes. AB - We have developed a novel method to deliver stem cells using 3D bioprinted cardiac patches, free of biomaterials. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), fibroblasts (FB) and endothelial cells (EC) were aggregated to create mixed cell spheroids. Cardiac patches were created from spheroids (CM:FB:EC = 70:15:15, 70:0:30, 45:40:15) using a 3D bioprinter. Cardiac patches were analyzed with light and video microscopy, immunohistochemistry, immunofluorescence, cell viability assays and optical electrical mapping. Cardiac tissue patches of all cell ratios beat spontaneously after 3D bioprinting. Patches exhibited ventricular-like action potential waveforms and uniform electrical conduction throughout the patch. Conduction velocities were higher and action potential durations were significantly longer in patches containing a lower percentage of FBs. Immunohistochemistry revealed staining for CM, FB and EC markers, with rudimentary CD31+ blood vessel formation. Immunofluorescence revealed the presence of Cx43, the main cardiac gap junction protein, localized to cell-cell borders. In vivo implantation suggests vascularization of 3D bioprinted cardiac patches with engraftment into native rat myocardium. This constitutes a significant step towards a new generation of stem cell-based treatment for heart failure. PMID- 28676708 TI - IBD: To switch or not to switch: that is the biosimilar question. PMID- 28676706 TI - Hepatitis B and C virus infection and diabetes mellitus: A cohort study. AB - The role of hepatitis virus infection in glucose homeostasis is uncertain. We examined the associations between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and the development of diabetes in a cohort (N = 439,708) of asymptomatic participants in health screening examinations. In cross-sectional analyses, the multivariable-adjusted odds ratio for prevalent diabetes comparing hepatitis B surface antigen (HBsAg) (+) to HBsAg (-) participants was 1.17 (95% CI 1.06-1.31; P = 0.003). The corresponding odds ratio comparing hepatitis C antibodies (HCV Ab) (+) to HCV Ab (-) participants was 1.43 (95% CI 1.01-2.02, P = 0.043). In prospective analyses, the multivariable-adjusted hazard ratio for incident diabetes comparing HBsAg (+) to HbsAg (-) participants was 1.23 (95% CI 1.08-1.41; P = 0.007). The number of incident cases of diabetes among HCV Ab (+) participants (10 cases) was too small to reliably estimate the prospective association between HCV infection and diabetes. In this large population at low risk of diabetes, HBV and HCV infections were associated with diabetes prevalence and HBV infection with the risk of incident diabetes. Our studies add evidence suggesting that diabetes is an additional metabolic complication of HBV and HCV infection. PMID- 28676709 TI - Rectal cancer: No benefit for local excision over rectal excision. PMID- 28676710 TI - Neurogastroenterology: Tasting the gut - enterochromaffin cells are chemosensitive and modulate sensory neurons. PMID- 28676711 TI - Rotavirus: Inflammasome modulates rotavirus infection. PMID- 28676707 TI - The gut microbiome and liver cancer: mechanisms and clinical translation. AB - Hepatocellular carcinoma (HCC) is the third leading cause of worldwide cancer mortality. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Increasing evidence points towards a key role of the bacterial microbiome in promoting the progression of liver disease and the development of HCC. Here, we will review mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on the leaky gut, bacterial dysbiosis, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. On the basis of accumulating evidence from preclinical studies, we propose the intestinal-microbiota-liver axis as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We will review in detail therapeutic modalities and discuss clinical settings in which targeting the gut-microbiota-liver axis for the prevention of disease progression and HCC development seems promising. PMID- 28676712 TI - NAFLD: Increased familial risk of fibrosis in NAFLD. PMID- 28676713 TI - Effect of the meropenem MIC on the killing activity of meropenem and polymyxin B in combination against KPC-producing Klebsiella pneumoniae. PMID- 28676716 TI - Synthesis and antibacterial activity of novel lincomycin derivatives. III. Optimization of a phenyl thiadiazole moiety. AB - Lincomycin derivatives that have a 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl thio moiety at the 7-position were synthesized. 5-Substituted 2-nitrophenyl derivatives showed potent antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene. Antibacterial activities of the 4,5-di-substituted 2-nitrophenyl derivatives were generally comparable to those of telithromycin (TEL) against S. pneumoniae with erm gene and clearly superior to those of TEL against S. pyogenes with erm gene. Compounds 6 and 10c that have a methoxy group at the 5-position of the benzene ring exhibited activities comparable to TEL against Haemophilus influenzae. These results suggest that lincomycin derivatives modified at the 7-position would be promising compounds as a clinical candidate. We would like to dedicate this article to the special issue for late Professor Dr. Hamao Umezawa in The Journal of Antibiotics.The Journal of Antibiotics advance online publication, 5 July 2017; doi:10.1038/ja.2017.59. PMID- 28676715 TI - Allantopyrone A interferes with multiple components of the TNF receptor 1 complex and blocks RIP1 modifications in the TNF-alpha-induced signaling pathway. AB - Allantopyrone A is a fungal metabolite that uniquely possesses two alpha,beta unsaturated carbonyl moieties. We recently reported that allantopyrone A inhibited the nuclear factor-kappaB (NF-kappaB) signaling pathway induced by tumor necrosis factor (TNF)-alpha in human lung carcinoma A549 cells. In the present study, the mechanism by which allantopyrone A inhibits the TNF-alpha induced signaling pathway was investigated in more detail. Allantopyrone A blocked extensive modifications to receptor-interacting protein 1 (RIP1) in the TNF receptor 1 (TNF-R1) complex. Allantopyrone A augmented the high-MW bands of TNF-R1, TNF receptor-associated factor 2, RIP1, the NF-kappaB subunit RelA and inhibitor of NF-kappaB kinase beta in A549 cells, suggesting that it binds to and promotes the crosslinking of these proteins. The extracellular cysteine-rich domains of TNF-R1 were crosslinked by allantopyrone A more preferentially than its intracellular portion. The present results demonstrate that allantopyrone A interferes with multiple components of the TNF-R1 complex and blocks RIP1 modifications in the TNF-alpha-induced NF-kappaB signaling pathway. PMID- 28676717 TI - Trichopeptides A and B, trichocyclodipeptides A-C, new peptides from the ascomycete fungus Stagonospora trichophoricola. AB - Trichopeptides A (1) and B (2), new linear tetrapeptide and tripeptide, respectively, and three new diketopiperazines trichocyclodipeptides A-C (3-5) were isolated from the fermentation of the ascomycete fungus Stagonospora trichophoricola, a fungus isolated from the soil sample surrounding the fruiting body of Ophiocordyceps sinensis in Maqin Country, Qinghai Province, People's Republic of China. Their structures were primarily elucidated by interpretation of NMR and MS experiments. The absolute configurations of 1-5 were assigned through Marfey's method on their acid hydrolyzates. Compound 3 showed antifungal activity against Candida albicans with the IC50 and MIC values of 22 and 90 MUg ml-1, respectively. PMID- 28676718 TI - Toward the total synthesis of luminamicin; an anaerobic antibiotic: construction of highly functionalized cis-decalin containing a bridged ether moiety. AB - Synthesis of a cis-decalin moiety, containing an oxa-bridged cis-decalin ring system (11-oxatricyclo(5.3.1.1,703,8)undecane), as a key intermediate of the total synthesis of luminamicin (1) was accomplished. One of the essential steps in our synthetic route is construction of a cis-decaline framework using a one pot Michael addition-aldol reaction. Additionally, the bridged ether moiety was obtained by an intramolecular 1,6-oxa-Michael reaction of a conjugated aldehyde. PMID- 28676714 TI - A brief history of antibiotics and select advances in their synthesis. AB - The advent of modern antibiotics contributed enormously to the dramatic extension of human lifespan since their discovery by virtue of their lethal and selective action against pathogenic microbes. And yet despite our powerful arsenal of weapons against these pathogens, the war against them has not been won. And it may never be. Drug resistance is still menacing the society with many lives being lost due to deadly infections caused by continuously evolving strains spread beyond our means to eradicate them or prevent their spreading. Herein, the emergence and evolution of antibiotics is briefly reviewed, and a select number of total syntheses of naturally occurring antibiotics from the authors' laboratories are highlighted. The article concludes with a strong endorsement of the current efforts to intensify our fight against these dangerous pathogens with the hope that, this time, these initiatives will be sufficiently focused and serious enough so as to achieve our set goals of, at least, being prepared and ahead of them as part of our drive to improve humanity's healthcare and wellbeing. PMID- 28676719 TI - sRNA and cis-antisense sRNA identification in Staphylococcus aureus highlights an unusual sRNA gene cluster with one encoding a secreted peptide. AB - The human pathogen Staphylococcus aureus expresses a set of transcriptional factors and small RNAs (sRNAs) to adapt to environmental variations. Recent harmonization of staphylococcal sRNA data allowed us to search for novel sRNAs using DETR'PROK, a computational pipeline for identifying sRNA in prokaryotes. We performed RNA-Seq on Newman strain and identified a set of 48 sRNA candidates. To avoid bioinformatic artefacts, we applied a series of cut-offs and tested experimentally each selected intergenic region. This narrowed the field to 24 expressed sRNAs, of which 21 were new and designated with Srn identifiers. Further examination of these loci revealed that one exhibited an unusual condensed sRNA cluster of about 650 nucleotides. We determined the transcriptional start sites within this region and demonstrated the presence of three contiguous sRNA genes (srn_9342, srn_9344 and srn_9345) expressed from the positive strand, and two others (srn_9343 and srn_9346) transcribed from the opposite one. Using comparative genomics, we showed that genetic organization of the srn_9342-9346 locus is specific to Newman and that its expression is growth phase dependent and subjected to nutrient deprivation and oxidative stress. Finally, we demonstrated that srn_9343 encodes a secreted peptide that could belong to a novel S. aureus toxin-antitoxin system. PMID- 28676721 TI - Nonlinear climatic sensitivity to greenhouse gases over past 4 glacial/interglacial cycles. AB - The paleoclimatic sensitivity to atmospheric greenhouse gases (GHGs) has recently been suggested to be nonlinear, however a GHG threshold value associated with deglaciation remains uncertain. Here, we combine a new sea surface temperature record spanning the last 360,000 years from the southern Western Pacific Warm Pool with records from five previous studies in the equatorial Pacific to document the nonlinear relationship between climatic sensitivity and GHG levels over the past four glacial/interglacial cycles. The sensitivity of the responses to GHG concentrations rises dramatically by a factor of 2-4 at atmospheric CO2 levels of >220 ppm. Our results suggest that the equatorial Pacific acts as a nonlinear amplifier that allows global climate to transition from deglacial to full interglacial conditions once atmospheric CO2 levels reach threshold levels. PMID- 28676720 TI - A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia. AB - Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix of the voltage-sensing domain and results in the substitution of the highly conserved phenylalanine 303 by valine (p.F303V). The contributions of F303 towards K+ channel voltage gating are unclear and here have been assessed biophysically and by performing structural analysis using rat Kv1.2 coordinates. We observed significant positive shifts of voltage-dependence, changes in the activation, deactivation and slow inactivation kinetics, reduced window currents, and decreased current amplitudes of both Kv1.1 and Kv1.1/1.2 channels. Structural analysis revealed altered interactions between F303V and L339 and I335 of the S5 helix of a neighboring subunit. The substitution of an aromatic phenylalanine with an aliphatic valine within the voltage-sensor destabilizes the open state of the channel. Thus, F303 fine-tunes the Kv1.1 gating properties and contributes to the interactions between the S4 segment and neighboring alpha helices. The resulting channel's loss of function validates the clinical relevance of the mutation for EA1 pathogenesis. PMID- 28676722 TI - The Role of the Notch Signal Pathway in Mucosal Cell Metaplasia in Mouse Acute Otitis Media. AB - Otitis media (OM) is a major cause of morbidity in pediatric and adult patients. This inflammatory condition is characterized by mucous cell hyperplasia that is thought to produce mucins from the middle ear mucosa. We are interested in the role of Notch signalling pathway in this inflammatory process. Using an acute otitis media (AOM) mouse model through injection of Streptococcus Pneumoniae into the middle ear, histopathologic examination and quantitative RT-PCR, acute inflammation with the thickness of mucosa, Goblet cell hyperplasia, and cilia loss were determined and gene expression related to the Notch signaling pathway were evaluated. Upregulation of the mucous cell markers, Argr2 and Muc5AC, and downregulation of the cilia cell marker, Foxj1 and Dnai2, were observed in AOM. In addition, genes encoding Notch receptors and ligands (Notch1, Notch2, Notch3, Notch4 and Dll1) and the Notch target genes (Hes1, Hes5, Hey1, NRARP) in AOM decreased significantly. The expression of the Notch1 and Jagged1 also showed down-regulation throughout the mouse middle ear epithelium. Taken together, this study suggests that downregulation of the Notch signaling pathway is involved in the mucosa hyperplasia during AOM. PMID- 28676723 TI - Analysis of reactive oxygen and nitrogen species generated in three liquid media by low temperature helium plasma jet. AB - In order to identify aqueous species formed in Plasma activated media (PAM), quantitative investigations of reactive oxygen and nitrogen species (ROS, RNS) were performed and compared to Milli-Q water and culture media without and with Fetal Calf Serum. Electron paramagnetic resonance, fluorometric and colorimetric analysis were used to identify and quantify free radicals generated by helium plasma jet in these liquids. Results clearly show the formation of ROS such as hydroxyl radical, superoxide anion radical and singlet oxygen in order of the micromolar range of concentrations. Nitric oxide, hydrogen peroxide and nitrite nitrate anions (in range of several hundred micromolars) are the major species observed in PAM. The composition of the medium has a major impact on the pH of the solution during plasma treatment, on the stability of the different RONS that are produced and on their reactivity with biomolecules. To emphasize the interactions of plasma with a complex medium, amino acid degradation by means of mass spectrometry was also investigated using methionine, tyrosine, tryptophan and arginine. All of these components such as long lifetime RONS and oxidized biological compounds may contribute to the cytotoxic effect of PAM. This study provides mechanistic insights into the mechanisms involved in cell death after treatment with PAM. PMID- 28676724 TI - A Mie resonant antenna with high sensitivity for force and strain measurement. AB - We demonstrate the experimental and simulated performances of a Mie resonant antenna for force sensing with high sensitivity for compressive force and strain measurements inside soft materials. The proposed sensor is compatible with biological specimens and has small dimensions. It comprises a pair of dielectric cubes and an elastic layer of silicone rubber. The applied force is determined by measuring the redshift of the operating frequency when a mechanical load applied. Both simulated and experimental results demonstrate that the relationship between the frequency shift of the sensor and the applied compressive load could be fitted well using a quadratic equation with a maximum fitting error less than 17%, which enables highly sensitive telemetric force measurements to be performed inside structures by observing the operating frequency shift. The proposed design provides a simple and low-cost approach to realizing highly-efficient telemetric measurement inside soft materials such as biological tissues. PMID- 28676725 TI - Inter-individual variability in the foraging behaviour of traplining bumblebees. AB - Workers of social insects, such as bees, ants and wasps, show some degree of inter-individual variability in decision-making, learning and memory. Whether these natural cognitive differences translate into distinct adaptive behavioural strategies is virtually unknown. Here we examined variability in the movement patterns of bumblebee foragers establishing routes between artificial flowers. We recorded all flower visitation sequences performed by 29 bees tested for 20 consecutive foraging bouts in three experimental arrays, each characterised by a unique spatial configuration of artificial flowers and three-dimensional landmarks. All bees started to develop efficient routes as they accumulated foraging experience in each array, and showed consistent inter-individual differences in their levels of route fidelity and foraging performance, as measured by travel speed and the frequency of revisits to flowers. While the tendency of bees to repeat the same route was influenced by their colony origin, foraging performance was correlated to body size. The largest foragers travelled faster and made less revisits to empty flowers. We discuss the possible adaptive value of such inter-individual variability within the forager caste for optimisation of colony-level foraging performances in social pollinators. PMID- 28676726 TI - [Traumatic cyclodialysis treated with cryopexy]. AB - Cyclodialysis is the result of the separation of the longitudinal fibres of the ciliary muscle from their scleral insertion, creating states of ocular hypotony. It is mainly caused by traumatisms. Gonioscopy has traditionally been the diagnostic test for this entity, however, at present it is being replaced by other techniques, such as ultrasound biomicroscopy (UBM). We present the case of a 57-year-old male who, following a traumatism in the left eye caused by the disc of a radial saw, presented corneal perforation and vitreous haemorrhage with pan retinal edema. The gonioscopy was normal in spite of the existence of persistent ocular hypotony. The realization of a UBM enabled diagnosis of a small cyclodialysis of less than ten degrees. Surgical treatment made it possible to recover normal intraocular pressure. PMID- 28676727 TI - [Effects on the elbow of radial head resection following isolated radial head fracture in young patients]. AB - BACKGROUND: Radial head resection has been a widely used procedure in cases of non-reconstructable radial head fracture. Some authors propose the use of radial head arthroplasty. The purpose of this study was to evaluate the long-term outcome of radial head resection for isolated fracture, without instability at the time of the fracture, and its radiological and functional repercussions at the elbow level. METHODS: We reviewed 44 clinical records with acute resection of the radial head following isolated radial head fracture, with absence of associated injuries, younger than forty, with a minimum follow-up of 15 years. Information was collected on elbow pain, biomechanical function, flexion and extension elbow strength and elbow instability compared with the non-affected side. A radiological study was conducted on all patients to determine the presence of degenerative changes, calcifications and measurement of the carrying angle. Outcomes were evaluated with Disabilities of the Arm, Shoulder and Hand score as an instrument to measure the patient's perceived disability. RESULTS: The group under study is made up of ten women and thirty-four men, with an average age at the time of fracture of 28.6 years (ranging from 15-40) and an average time since the fracture or follow-up time of 28.5 years (ranging from 16 38). The affectation was on the dominant side in thirty cases (23 right-handed and 7 left-handed). Thirty-nine patients (88.6%) had no elbow pain, and in all other cases was mild or moderate. Loss of mobility and strength was 1.5% for flexo-extension, 3.5% for prono-supination, 7.9% for flexion strength and 3.5% for extension strength. We appreciated four cases of valgus instability and two of postero-lateral instability. The average DASH score was 6.9 points. Radiographic changes of arthritis were present in 93.3% and 54.4% of calcifications. The mean increase of carrying angle was 7.7o compared with non affected gide (ranking from 0.9-15.8o). CONCLUSION: Radial head resection for isolated fracture in young patients presents satisfactory results, with very low losses of elbow mobility and strength. Despite the high presence of osteoarthritic changes or lower clinical signs of instability, elbow pain and disability are very low. Our conclusion, based in these results, is that radial head resection is still a useful surgical procedure for isolated fractures even in young patients. PMID- 28676728 TI - [Olmesartan-associated enteropathy: attention to an emerging iatrogenic phenomenon]. AB - Olmesartan is an angiotensin II type 1 receptor blocker commonly used in the treatment of hypertension. Several cases of sprue-like enteropathy associated with the use of this drug have been described which, even with important signs and limitations for the patient, present a full recovery after discontinuing the use of olmesartan. The case of a 64 year-old patient is presented, diagnosed with hypertension, under treatment with olmesartan-amlodipine, with chronic diarrhoea and villous atrophy on intestinal biopsies without diagnostic criteria for celiac disease and with complete remission after suspending discontinuing the use of olmesartan. Based on the clinical features presented by the case reported, the clinical and anatomopathological findings are described as well as the evolution of drug-induced enteropathy. PMID- 28676729 TI - [Spontaneous hepatic haematoma in a pregnant woman during labour]. AB - Spontaneous hepatic rupture during labour is a rare condition. Because of the difficulty in diagnosing hepatic rupture in pregnant women, it is often associated with a high mortality rate. Although pregnant women with HELLP syndrome are more prone to hepatic rupture, it can also occur with other liver pathologies and even in healthy women. We should be vigilant in case of suspicious clinical signs even if we have no evidence of preeclampsia. An early diagnosis will be the key to reducing the mortality and morbidity rate. PMID- 28676730 TI - [Beyond the do-not-resuscitate (DNR) order]. PMID- 28676732 TI - Proinflammatory Cytokines IL-6 and TNF-alpha Increased Telomerase Activity through NF-kappaB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells. AB - There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-alpha, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-alpha phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-kappaB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF-alpha stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-alpha stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-alpha-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-kappaB interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer. PMID- 28676733 TI - Evaluation of Paracervical Block and IV Sedation for Pain Management during Hysteroscopic Polypectomy: A Randomized Clinical Trial. AB - BACKGROUND: The aim of this study was to compare the effectiveness of paracervical block (PB) and IV sedation (IVS) on women's pain perception during operative hysteroscopy. METHODS: A total of 84 patients with uterine polyps were randomized to either PB or IV sedation or general anesthesia (GA) as control group. In PB group, the patients received oral diazepam 10 mg and 100 mg diclofenac Na suppository 60 min before surgery and 10 cc of 2% buffered lidocaine was injected at cervix. Conscious sedation was performed with the IV administration of 2-3 mg/kg/h propofol 1% and midazolam 0.02 mg/kg and fentanyl (1-2 MUg/kg) with o2 4-5 lit/min via face mask. RESULTS: There were no significant differences between groups on VAS score at 3 hours after operation (PB: 1.22 +/- (1.31), IVS: 1.10 +/- (1.68), GA: 1.29 +/- (2.03), P = 0.671) and during recovery (PB: 0.85 +/- (1.06), IVS: 0.68 +/- (1.33), GA: 1.21 +/- (2.04), P = 0.458). There was no difference between PB (3.33 +/- (2.81)) and IVS (2.31 +/ (2.63)) groups at hysteroscopy (P = 0.182). Patients undergoing IVS reported lower VAS score than PB group at dilation and curettage, although the difference was not statistically significant (PB: 2.59 +/- (1.78), IVS: 1.72 +/- (2.34), P = 0.051). Moreover, patients undergoing IVS obtained lower VAS score than PB group at polypectomy, while the difference was not statistically significant (PB: 1.81 +/- (1.52), IVS: 1.10 +/- (1.32), P = 0.073). CONCLUSION: The finding of the present study revealed that IVS and PB showed the same effect in reducing pain during and after gynecological surgical procedures. The study was registered in Iranian Registry of Clinical Trial with the number IRCT2016031426855N3, on April 28, 2016. PMID- 28676734 TI - Fuzzy Decision-Making Fuser (FDMF) for Integrating Human-Machine Autonomous (HMA) Systems with Adaptive Evidence Sources. AB - A brain-computer interface (BCI) creates a direct communication pathway between the human brain and an external device or system. In contrast to patient-oriented BCIs, which are intended to restore inoperative or malfunctioning aspects of the nervous system, a growing number of BCI studies focus on designing auxiliary systems that are intended for everyday use. The goal of building these BCIs is to provide capabilities that augment existing intact physical and mental capabilities. However, a key challenge to BCI research is human variability; factors such as fatigue, inattention, and stress vary both across different individuals and for the same individual over time. If these issues are addressed, autonomous systems may provide additional benefits that enhance system performance and prevent problems introduced by individual human variability. This study proposes a human-machine autonomous (HMA) system that simultaneously aggregates human and machine knowledge to recognize targets in a rapid serial visual presentation (RSVP) task. The HMA focuses on integrating an RSVP BCI with computer vision techniques in an image-labeling domain. A fuzzy decision-making fuser (FDMF) is then applied in the HMA system to provide a natural adaptive framework for evidence-based inference by incorporating an integrated summary of the available evidence (i.e., human and machine decisions) and associated uncertainty. Consequently, the HMA system dynamically aggregates decisions involving uncertainties from both human and autonomous agents. The collaborative decisions made by an HMA system can achieve and maintain superior performance more efficiently than either the human or autonomous agents can achieve independently. The experimental results shown in this study suggest that the proposed HMA system with the FDMF can effectively fuse decisions from human brain activities and the computer vision techniques to improve overall performance on the RSVP recognition task. This conclusion demonstrates the potential benefits of integrating autonomous systems with BCI systems. PMID- 28676731 TI - The Ratio of C-Reactive Protein/Albumin is a Novel Inflammatory Predictor of Overall Survival in Cisplatin-Based Treated Patients with Metastatic Nasopharyngeal Carcinoma. AB - The C-reactive protein/albumin (CRP/Alb) ratio has been recently identified as a prognostic factor in various cancers, whereas its role remains unclear in metastatic nasopharyngeal carcinoma (NPC). The current study retrospectively analyzed 148 patients with metastatic NPC who underwent cisplatin-based chemotherapy and further evaluated the prognostic value of the CRP/Alb ratio and its association with clinical characteristics in these patients. The optimal cut off value was 0.189 for the CRP/Alb ratio. The high CRP/Alb ratio was significantly associated with elevated NLR, platelet-to-lymphocyte ratio (PLR), and EBV-DNA levels and decreased haemoglobin level (all p < 0.05). The results of multivariate analysis showed that the CRP/Alb ratio was an independent prognostic factor of overall survival. Patients with a high CRP/Alb ratio (>=0.189) had a 1.867 times (p = 0.024, 95% CI = 1.085-3.210) greater risk of mortality compared with those with a low CRP/Alb ratio (<0.189). In addition, combining the CRP/Alb ratio with GPS could accurately discriminate the prognosis of our patients. Our results suggested that the CRP/Alb ratio is a feasible and inexpensive tool for predicting survival outcomes and is a valuable coadjutant for the GPS to further identify differences in survivals of patients with metastatic NPC. PMID- 28676735 TI - Non-invasive Prefrontal/Frontal Brain Stimulation Is Not Effective in Modulating Food Reappraisal Abilities or Calorie Consumption in Obese Females. AB - Background/Objectives: Previous studies suggest that non-invasive transcranial direct current stimulation (tDCS) applied to the prefrontal cortex modulates food choices and calorie intake in obese humans. Participants/Methods: In the present fully randomized, placebo-controlled, within-subject and double-blinded study, we applied single sessions of anodal, cathodal, and sham tDCS to the left dorsolateral prefrontal cortex (DLPFC) and contralateral frontal operculum in 25 hungry obese women and investigated possible influences on food reappraisal abilities as well as calorie intake. We hypothesized that tDCS, (i) improves the ability to regulate the desire for visually presented foods and, (ii) reduces their consumption. Results: We could not confirm an effect of anodal or cathodal tDCS, neither on the ability to modulate the desire for visually presented foods, nor on calorie consumption. Conclusions: The present findings do not support the notion of prefrontal/frontal tDCS as a promising treatment option for obesity. PMID- 28676736 TI - Lower In vivo Myo-Inositol in the Anterior Cingulate Cortex Correlates with Delayed Melatonin Rhythms in Young Persons with Depression. AB - Myo-inositol, a second messenger glucose isomer and glial marker, is potentiated by melatonin. In addition to common abnormalities in melatonin regulation, depressive disorders have been associated with reduced myo-inositol in frontal structures. This study examined associations between myo-inositol in the anterior cingulate cortex and the timing of evening melatonin release. Forty young persons with unipolar depression were recruited from specialized mental health services (20.3 +/- 3.8 years old). Healthy controls were recruited from the community (21.7 +/- 2.6 years old). The timing of dim light melatonin onset (DLMO) was estimated using salivary melatonin sampling. Myo-inositol concentrations (MI/CrPCr ratio) in the anterior cingulate cortex were obtained using proton magnetic resonance spectroscopy. After controlling for age, sex, and CrPCr concentration the depression group had significantly lower MI/CrPCr ratios than healthy controls [F(4, 75) = 11.4, p = 0.001]. In the depression group, later DLMO correlated with lower MI/CrPCr ratio (r = -0.48, p = 0.014). These findings suggest that neurochemical changes in the frontal cortex are associated with circadian disruptions in young persons with depression. PMID- 28676737 TI - Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa. AB - Despite mutations in the rod phosphodiesterase 6-alpha (PDE6A) gene being well recognized as a cause of human retinitis pigmentosa, no definitive treatments have been developed to treat this blinding disease. We performed a trial of retinal gene augmentation in the Pde6a mutant dog using Pde6a delivery by capsid mutant adeno-associated virus serotype 8, previously shown to have a rapid onset of transgene expression in the canine retina. Subretinal injections were performed in 10 dogs at 29-44 days of age, and electroretinography and vision testing were performed to assess functional outcome. Retinal structure was assessed using color fundus photography, spectral domain optical coherence tomography, and histology. Immunohistochemistry was performed to examine transgene expression and expression of other retinal genes. Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination. Photoreceptor layer thickness in the treated area was preserved compared with the contralateral control vector treated or uninjected eye. Improved rod and cone photoreceptor survival, rhodopsin localization, cyclic GMP levels and bipolar cell dendrite distribution was observed in treated areas. Some adverse effects including foci of retinal separation, foci of retinal degeneration and rosette formation were identified in both AAV-Pde6a and control vector injected regions. This is the first description of successful gene augmentation for Pde6a retinitis pigmentosa in a large animal model. Further studies will be necessary to optimize visual outcomes and minimize complications before translation to human studies. PMID- 28676738 TI - The Multiple Correspondence Analysis Method and Brain Functional Connectivity: Its Application to the Study of the Non-linear Relationships of Motor Cortex and Basal Ganglia. AB - The complexity of basal ganglia (BG) interactions is often condensed into simple models mainly based on animal data and that present BG in closed-loop cortico subcortical circuits of excitatory/inhibitory pathways which analyze the incoming cortical data and return the processed information to the cortex. This study was aimed at identifying functional relationships in the BG motor-loop of 24 healthy subjects who provided written, informed consent and whose BOLD-activity was recorded by MRI methods. The analysis of the functional interaction between these centers by correlation techniques and multiple linear regression showed non linear relationships which cannot be suitably addressed with these methods. The multiple correspondence analysis (MCA), an unsupervised multivariable procedure which can identify non-linear interactions, was used to study the functional connectivity of BG when subjects were at rest. Linear methods showed different functional interactions expected according to current BG models. MCA showed additional functional interactions which were not evident when using lineal methods. Seven functional configurations of BG were identified with MCA, two involving the primary motor and somatosensory cortex, one involving the deepest BG (external-internal globus pallidum, subthalamic nucleus and substantia nigral), one with the input-output BG centers (putamen and motor thalamus), two linking the input-output centers with other BG (external pallidum and subthalamic nucleus), and one linking the external pallidum and the substantia nigral. The results provide evidence that the non-linear MCA and linear methods are complementary and should be best used in conjunction to more fully understand the nature of functional connectivity of brain centers. PMID- 28676739 TI - PID Controller Design for FES Applied to Ankle Muscles in Neuroprosthesis for Standing Balance. AB - Closed-loop controlled functional electrical stimulation (FES) applied to the lower limb muscles can be used as a neuroprosthesis for standing balance in neurologically impaired individuals. The objective of this study was to propose a methodology for designing a proportional-integral-derivative (PID) controller for FES applied to the ankle muscles toward maintaining standing balance for several minutes and in the presence of perturbations. First, a model of the physiological control strategy for standing balance was developed. Second, the parameters of a PID controller that mimicked the physiological balance control strategy were determined to stabilize the human body when modeled as an inverted pendulum. Third, this PID controller was implemented using a custom-made Inverted Pendulum Standing Apparatus that eliminated the effect of visual and vestibular sensory information on voluntary balance control. Using this setup, the individual specific FES controllers were tested in able-bodied individuals and compared with disrupted voluntary control conditions in four experimental paradigms: (i) quiet standing; (ii) sudden change of targeted pendulum angle (step response); (iii) balance perturbations that simulate arm movements; and (iv) sudden change of targeted angle of a pendulum with individual-specific body-weight (step response). In paradigms (i) to (iii), a standard 39.5-kg pendulum was used, and 12 subjects were involved. In paradigm (iv) 9 subjects were involved. Across the different experimental paradigms and subjects, the FES-controlled and disrupted voluntarily-controlled pendulum angle showed root mean square errors of <1.2 and 2.3 deg, respectively. The root mean square error (all paradigms), rise time, settle time, and overshoot [paradigms (ii) and (iv)] in FES-controlled balance were significantly smaller or tended to be smaller than those observed with voluntarily-controlled balance, implying improved steady-state and transient responses of FES-controlled balance. At the same time, the FES-controlled balance required similar torque levels (no significant difference) as voluntarily controlled balance. The implemented PID parameters were to some extent consistent among subjects for standard weight conditions and did not require prolonged individual-specific tuning. The proposed methodology can be used to design FES controllers for closed-loop controlled neuroprostheses for standing balance. Further investigation of the clinical implementation of this approach for neurologically impaired individuals is needed. PMID- 28676740 TI - Modulation of Illusory Auditory Perception by Transcranial Electrical Stimulation. AB - The aim of the present study was to test whether transcranial electrical stimulation can modulate illusory perception in the auditory domain. In two separate experiments we applied transcranial Direct Current Stimulation (anodal/cathodal tDCS, 2 mA; N = 60) and high-frequency transcranial Random Noise Stimulation (hf-tRNS, 1.5 mA, offset 0; N = 45) on the temporal cortex during the presentation of the stimuli eliciting the Deutsch's illusion. The illusion arises when two sine tones spaced one octave apart (400 and 800 Hz) are presented dichotically in alternation, one in the left and the other in the right ear, so that when the right ear receives the high tone, the left ear receives the low tone, and vice versa. The majority of the population perceives one high-pitched tone in one ear alternating with one low-pitched tone in the other ear. The results revealed that neither anodal nor cathodal tDCS applied over the left/right temporal cortex modulated the perception of the illusion, whereas hf tRNS applied bilaterally on the temporal cortex reduced the number of times the sequence of sounds is perceived as the Deutsch's illusion with respect to the sham control condition. The stimulation time before the beginning of the task (5 or 15 min) did not influence the perceptual outcome. In accordance with previous findings, we conclude that hf-tRNS can modulate auditory perception more efficiently than tDCS. PMID- 28676741 TI - The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models. AB - Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo. PMID- 28676742 TI - Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage. AB - Background: Photoreceptor cell death due to extensive light exposure and induced oxidative-stress are associated with retinal degeneration. A correlated dysregulation of the complement system amplifies the damaging effects, but the local and time-dependent progression of this mechanism is not thoroughly understood. Methods: Light-induced photoreceptor damage (LD) was induced in Balb/c mice with white light illumination either for 24 h with 1000 lux (constant model) or 0.5 h with 5000 lux (acute model). Complement protein and mRNA expression levels were compared at 1 and 3 days post-LD for C1s, complement factor B (CFB), mannose binding lectin A, mannose-binding protein-associated serine protease 1 (MASP-1), C3, C4, C9, and complement factor P in retina and RPE/choroid. Histological analyses visualized apoptosis, microglia/macrophage migration, gliosis and deposition of the complement activation marker C3d. Systemic anaphylatoxin serum concentrations were determined using an ELISA. Results: Apoptosis, gliosis and microglia/macrophage migration into the outer nuclear layer showed similar patterns in both models. Local complement factor expression revealed an early upregulation of complement factor mRNA in the acute and constant light regimen at 1 day post-treatment for c1s, cfb, masp-1, c3, c4 and c9 in the RPE/choroid. However, intraretinal complement mRNA expression for c1s, cfb, c3 and c4 was increased at 1 day in the constant and at 3 days in the acute model. A corresponding regulation on protein level in the retina following both LD models was observed for C3, which was upregulated at 1 day and correlated with increased C3d staining in the ganglion cell layer and at the RPE. In the RPE/choroid C1s-complex protein detection was increased at 3 days after LD irrespectively of the light intensities used. Conclusion: LD in mouse eyes is correlated with local complement activity. The time-dependent local progression of complement regulation on mRNA and protein levels were equivalent in the acute and constant LD model, except for the intraretinal, time-dependent mRNA expression. Knowing the relative time courses of local complement expression and cellular activity can help to elucidate novel therapeutic options in retinal degeneration indicating at which time point of disease complement has to be rebalanced. PMID- 28676743 TI - Differential Alteration in Expression of Striatal GABAAR Subunits in Mouse Models of Huntington's Disease. AB - Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor symptoms that are preceded by cognitive deficits and is considered as a disorder that primarily affects forebrain striatal neurons. To gain a better understanding of the molecular and cellular mechanisms associated with disease progression, we analyzed the expression of proteins involved in GABAergic neurotransmission in the striatum of the R6/1 transgenic mouse model. Western blot, quantitative PCR and immunohistochemical analyses were conducted on male R6/1 mice and age-matched wild type littermates. Analyses were performed on 2 and 6 month-old animals, respectively, before and after the onset of motor symptoms. Expression of GAD 67, GAD 65, NL2, or gephyrin proteins, involved in GABA synthesis or synapse formation did not display major changes. In contrast, expression of alpha1, alpha3 and alpha5 GABAAR subunits was increased while the expression of delta was decreased, suggesting a change in tonic- and phasic inhibitory transmission. Western blot analysis of the striatum from 8 month-old Hdh Q111, a knock-in mouse model of HD with mild deficits, confirmed the alpha1 subunit increased expression. From immunohistochemical analyses, we also found that alpha1 subunit expression is increased in medium-sized spiny projection neurons (MSN) and decreased in parvalbumin (PV)-expressing interneurons at 2 and 6 months in R6/1 mice. Moreover, alpha2 subunit labeling on the PV and MSN cell membranes was increased at 2 months and decreased at 6 months. Alteration of gene expression in the striatum and modification of GABAA receptor subtypes in both interneurons and projection neurons suggested that HD mutation has a profound effect on synaptic plasticity at an early stage, before the onset of motor symptoms. These results also indicate that cognitive and other behavioral deficits may be associated with changes in GABAergic neurotransmission that consequently could be a relevant target for early therapeutic treatment. PMID- 28676744 TI - Trace Conditioning in Drosophila Induces Associative Plasticity in Mushroom Body Kenyon Cells and Dopaminergic Neurons. AB - Dopaminergic neurons (DANs) signal punishment and reward during associative learning. In mammals, DANs show associative plasticity that correlates with the discrepancy between predicted and actual reinforcement (prediction error) during classical conditioning. Also in insects, such as Drosophila, DANs show associative plasticity that is, however, less understood. Here, we study associative plasticity in DANs and their synaptic partners, the Kenyon cells (KCs) in the mushroom bodies (MBs), while training Drosophila to associate an odorant with a temporally separated electric shock (trace conditioning). In most MB compartments DANs strengthened their responses to the conditioned odorant relative to untrained animals. This response plasticity preserved the initial degree of similarity between the odorant- and the shock-induced spatial response patterns, which decreased in untrained animals. Contrary to DANs, KCs (alpha'/beta'-type) decreased their responses to the conditioned odorant relative to untrained animals. We found no evidence for prediction error coding by DANs during conditioning. Rather, our data supports the hypothesis that DAN plasticity encodes conditioning-induced changes in the odorant's predictive power. PMID- 28676745 TI - Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness. AB - There has been controversy regarding the precise mechanisms of anesthetic-induced unconsciousness, with two salient approaches that have emerged within systems neuroscience. One prominent approach is the "bottom up" paradigm, which argues that anesthetics suppress consciousness by modulating sleep-wake nuclei and neural circuits in the brainstem and diencephalon that have evolved to control arousal states. Another approach is the "top-down" paradigm, which argues that anesthetics suppress consciousness by modulating the cortical and thalamocortical circuits involved in the integration of neural information. In this article, we synthesize these approaches by mapping bottom-up and top-down mechanisms of general anesthetics to two distinct but inter-related dimensions of consciousness: level and content. We show how this explains certain empirical observations regarding the diversity of anesthetic drug effects. We conclude with a more nuanced discussion of how levels and contents of consciousness interact to generate subjective experience and what this implies for the mechanisms of anesthetic-induced unconsciousness. PMID- 28676746 TI - Regulation of Fear Extinction in the Basolateral Amygdala by Dopamine D2 Receptors Accompanied by Altered GluR1, GluR1-Ser845 and NR2B Levels. AB - The amygdala, a critical structure for both Pavlovian fear conditioning and fear extinction, receives sparse but comprehensive dopamine innervation and contains dopamine D1 and D2 receptors. Fear extinction, which involves learning to suppress the expression of a previously learned fear, appears to require the dopaminergic system. The specific roles of D2 receptors in mediating associative learning underlying fear extinction require further study. Intra-basolateral amygdala (BLA) infusions of a D2 receptor agonist, quinpirole, and a D2 receptor antagonist, sulpiride, prior to fear extinction and extinction retention were tested 24 h after fear extinction training for long-term memory (LTM). LTM was facilitated by quinpirole and attenuated by sulpiride. In addition, A-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid receptor glutamate receptor 1 (GluR1) subunit, GluR1 phospho-Ser845, and N-methyl-D-aspartic acid receptor NR2B subunit levels in the BLA were generally increased by quinpirole and down-regulated by sulpiride. The present study suggests that activation of D2 receptors facilitates fear extinction and that blockade of D2 receptors impairs fear extinction, accompanied by changes in GluR1, GluR1-Ser845 and NR2B levels in the amygdala. PMID- 28676747 TI - Inflammation: The Common Pathway of Stress-Related Diseases. AB - While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%-90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases. PMID- 28676748 TI - Regularity of Center of Pressure Trajectories in Expert Gymnasts during Bipedal Closed-Eyes Quiet Standing. AB - We compared postural control of expert gymnasts (G) to that of non-gymnasts (NG) during bipedal closed-eyes quiet standing using conventional and nonlinear dynamical measures of center of foot pressure (COP) trajectories. Earlier findings based on COP classical variables showed that gymnasts exhibited a better control of postural balance but only in demanding stances. We examined whether the effect of expertise in Gymnastic can be uncovered in less demanding stances, from the analysis of the dynamic patterns of COP trajectories. Three dependent variables were computed to describe the subject's postural behavior: the variability of COP displacements (ACoP), the variability of the COP velocities (VCoP) and the sample entropy of COP (SEnCoP) to quantify COP regularity (i.e., predictability). Conventional analysis of COP trajectories showed that NG and G exhibited similar amount and control of postural sway, as indicated by similar ACoP and VCoP values observed in NG and G, respectively. These results suggest that the specialized balance training received by G may not transfer to less challenging balance conditions such as the bipedal eyes-closed stance condition used in the present experiment. Interestingly, nonlinear dynamical analysis of COP trajectories regarding COP regularity showed that G exhibited more irregular COP fluctuations relative to NG, as indicated by the higher SEnCoP values observed for the G than for the NG. The present results showed that a finer grained analysis of the dynamic patterns of the COP displacements is required to uncover an effect of gymnastic expertise on postural control in nondemanding postural stance. The present findings shed light on the surplus value in the nonlinear dynamical analysis of COP trajectories to gain further insight into the mechanisms involved in the control of bipedal posture. PMID- 28676749 TI - Preliminary Evidence for Training-Induced Changes of Morphology and Phantom Limb Pain. AB - The aim of this study was to investigate whether a special prosthetic training in phantom limb pain patients aimed at increasing the functional use of the prosthesis leads to neural morphological plasticity of brain structures and a reduction in phantom limb pain. For chronic pain disorders, it was shown that morphological alterations due to pain might become at least partially reversed by pain therapies. Phantom limb pain is a chronic pain disorder that is frequently followed by neural plasticity of anatomical brain structures. In our study, 10 patients with amputation of the upper limb participated in a two-week training with a myoelectric prosthesis with somatosensory feedback. Grip strength was fed back with electrocutaneous stimulus patterns applied to the stump. Phantom limb pain was assessed before and after the two-week training. Similarly, two T1 weighted MRI scans were conducted for longitudinal thickness analyses of cortical brain structures. As result of this treatment, patients experienced a reduction in phantom limb pain and a gain in prosthesis functionality. Furthermore, we found a change of cortical thickness in small brain areas in the visual stream and the post-central gyrus ipsilateral to the amputation indicating morphological alterations in brain areas involved in vision and pain processing. PMID- 28676750 TI - Multi-Trial Gait Adaptation of Healthy Individuals during Visual Kinematic Perturbations. AB - Optimizing rehabilitation strategies requires understanding the effects of contextual cues on adaptation learning. Prior studies have examined these effects on the specificity of split-belt walking adaptation, showing that contextual visual cues can be manipulated to modulate the magnitude, transfer, and washout of split-belt-induced learning in humans. Specifically, manipulating the availability of vision during training or testing phases of learning resulted in differences in adaptive mechanisms for temporal and spatial features of walking. However, multi-trial locomotor training has been rarely explored when using visual kinematic gait perturbations. In this study, we investigated multi-trial locomotor adaptation in ten healthy individuals while applying visual kinematic perturbations. Subjects were instructed to control a moving cursor, which represented the position of their heel, to follow a prescribed heel path profile displayed on a monitor. The perturbations were introduced by scaling all of the lower limb joint angles by a factor of 0.7 (i.e., a gain change), resulting in visual feedback errors between subjects' heel trajectories and the prescribed path profiles. Our findings suggest that, with practice, the subjects learned, albeit with different strategies, to reduce the tracking errors and showed faster response time in later trials. Moreover, the gait symmetry indices, in both the spatial and temporal domains, changed significantly during gait adaptation (P < 0.001). After-effects were present in the temporal gait symmetry index whens the visual perturbations were removed in the post-exposure period (P < 0.001), suggesting adaptation learning. These findings may have implications for developing novel gait rehabilitation interventions. PMID- 28676751 TI - The Role of Autobiographical Memory in the Development of a Robot Self. AB - This article briefly reviews research in cognitive development concerning the nature of the human self. It then reviews research in developmental robotics that has attempted to retrace parts of the developmental trajectory of the self. This should be of interest to developmental psychologists, and researchers in developmental robotics. As a point of departure, one of the most characteristic aspects of human social interaction is cooperation-the process of entering into a joint enterprise to achieve a common goal. Fundamental to this ability to cooperate is the underlying ability to enter into, and engage in, a self-other relation. This suggests that if we intend for robots to cooperate with humans, then to some extent robots must engage in these self-other relations, and hence they must have some aspect of a self. Decades of research in human cognitive development indicate that the self is not fully present from the outset, but rather that it is developed in a usage-based fashion, that is, through engaging with the world, including the physical world and the social world of animate intentional agents. In an effort to characterize the self, Ulric Neisser noted that self is not unitary, and he thus proposed five types of self-knowledge that correspond to five distinct components of self: ecological, interpersonal, conceptual, temporally extended, and private. He emphasized the ecological nature of each of these levels, how they are developed through the engagement of the developing child with the physical and interpersonal worlds. Crucially, development of the self has been shown to rely on the child's autobiographical memory. From the developmental robotics perspective, this suggests that in principal it would be possible to develop certain aspects of self in a robot cognitive system where the robot is engaged in the physical and social world, equipped with an autobiographical memory system. We review a series of developmental robotics studies that make progress in this enterprise. We conclude with a summary of the properties that are required for the development of these different levels of self, and we identify topics for future research. PMID- 28676752 TI - An Adaptive Neuromuscular Controller for Assistive Lower-Limb Exoskeletons: A Preliminary Study on Subjects with Spinal Cord Injury. AB - Versatility is important for a wearable exoskeleton controller to be responsive to both the user and the environment. These characteristics are especially important for subjects with spinal cord injury (SCI), where active recruitment of their own neuromuscular system could promote motor recovery. Here we demonstrate the capability of a novel, biologically-inspired neuromuscular controller (NMC) which uses dynamical models of lower limb muscles to assist the gait of SCI subjects. Advantages of this controller include robustness, modularity, and adaptability. The controller requires very few inputs (i.e., joint angles, stance, and swing detection), can be decomposed into relevant control modules (e.g., only knee or hip control), and can generate walking at different speeds and terrains in simulation. We performed a preliminary evaluation of this controller on a lower-limb knee and hip robotic gait trainer with seven subjects (N = 7, four with complete paraplegia, two incomplete, one healthy) to determine if the NMC could enable normal-like walking. During the experiment, SCI subjects walked with body weight support on a treadmill and could use the handrails. With controller assistance, subjects were able to walk at fast walking speeds for ambulatory SCI subjects-from 0.6 to 1.4 m/s. Measured joint angles and NMC provided joint torques agreed reasonably well with kinematics and biological joint torques of a healthy subject in shod walking. Some differences were found between the torques, such as the lack of knee flexion near mid-stance, but joint angle trajectories did not seem greatly affected. The NMC also adjusted its torque output to provide more joint work at faster speeds and thus greater joint angles and step length. We also found that the optimal speed-step length curve observed in healthy humans emerged for most of the subjects, albeit with relatively longer step length at faster speeds. Therefore, with very few sensors and no predefined settings for multiple walking speeds or adjustments for subjects of differing anthropometry and walking ability, NMC enabled SCI subjects to walk at several speeds, including near healthy speeds, in a healthy-like manner. These preliminary results are promising for future implementation of neuromuscular controllers on wearable prototypes for real-world walking conditions. PMID- 28676753 TI - Filopodia: A Rapid Structural Plasticity Substrate for Fast Learning. AB - Formation of new synapses between neurons is an essential mechanism for learning and encoding memories. The vast majority of excitatory synapses occur on dendritic spines, therefore, the growth dynamics of spines is strongly related to the plasticity timescales. Especially in the early stages of the developing brain, there is an abundant number of long, thin and motile protrusions (i.e., filopodia), which develop in timescales of seconds and minutes. Because of their unique morphology and motility, it has been suggested that filopodia can have a dual role in both spinogenesis and environmental sampling of potential axonal partners. I propose that filopodia can lower the threshold and reduce the time to form new dendritic spines and synapses, providing a substrate for fast learning. Based on this proposition, the functional role of filopodia during brain development is discussed in relation to learning and memory. Specifically, it is hypothesized that the postnatal brain starts with a single-stage memory system with filopodia playing a significant role in rapid structural plasticity along with the stability provided by the mushroom-shaped spines. Following the maturation of the hippocampus, this highly-plastic unitary system transitions to a two-stage memory system, which consists of a plastic temporary store and a long term stable store. In alignment with these architectural changes, it is posited that after brain maturation, filopodia-based structural plasticity will be preserved in specific areas, which are involved in fast learning (e.g., hippocampus in relation to episodic memory). These propositions aim to introduce a unifying framework for a diversity of phenomena in the brain such as synaptogenesis, pruning and memory consolidation. PMID- 28676754 TI - 16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer's Post Mortem Brain. AB - The neurological deterioration associated with Alzheimer's disease (AD), involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene specific Next generation sequencing (NGS) of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal. PMID- 28676756 TI - Inhibition of PirB Activity by TAT-PEP Improves Mouse Motor Ability and Cognitive Behavior. AB - Paired immunoglobulin-like receptor B (PirB), a functional receptor for myelin associated inhibitory proteins, plays an important role in axon regeneration in injured brains. However, its role in normal brain function with age has not been previously investigated. Therefore in this study, we examined the expression level of PirB in the cerebral cortex, hippocampus and cerebellum of mice at 1 month, 3 months and 18 months of age. The results showed that the expression of PirB increased with age. We further demonstrated that overexpression of PirB inhibited neurite outgrowth in PC12 cells, and this inhibitory activity of PirB could be reversed by TAT-PEP, which is a recombinant soluble PirB ectodomain fused with TAT domain for blood-brain barrier penetration. In vivo study, intraperitoneal administration of TAT-PEP was capable of enhancing motor capacity and spatial learning and memory in mice, which appeared to be mediated through regulation of brain-derived neurotrophic factor (BDNF) secretion. Our study suggests that PirB is associated with aging and TAT-PEP may be a promising therapeutic agent for modulation of age-related motor and cognitive dysfunctions. PMID- 28676757 TI - Greater Cortical Thickness in Elderly Female Yoga Practitioners-A Cross-Sectional Study. AB - Yoga, a mind-body activity that requires attentional engagement, has been associated with positive changes in brain structure and function, especially in areas related to awareness, attention, executive functions and memory. Normal aging, on the other hand, has also been associated with structural and functional brain changes, but these generally involve decreased cognitive functions. The aim of this cross-sectional study was to compare brain cortical thickness (CT) in elderly yoga practitioners and a group of age-matched healthy non-practitioners. We tested 21 older women who had practiced hatha yoga for at least 8 years and 21 women naive to yoga, meditation or any mind-body interventions who were matched to the first group in age, years of formal education and physical activity level. A T1-weighted MPRAGE sequence was acquired for each participant. Yoga practitioners showed significantly greater CT in a left prefrontal lobe cluster, which included portions of the lateral middle frontal gyrus, anterior superior frontal gyrus and dorsal superior frontal gyrus. We found greater CT in the left prefrontal cortex of healthy elderly women who trained yoga for a minimum of 8 years compared with women in the control group. PMID- 28676755 TI - Variants in SNCA Gene Are Associated with Parkinson's Disease Risk and Cognitive Symptoms in a Brazilian Sample. AB - Genetic susceptibility contributes to the etiology of sporadic Parkinson's Disease (PD) and worldwide studies have found positive associations of polymorphisms in the alpha-synuclein gene (SNCA) with the risk for PD. However, little is known about the influence of variants of SNCA in individual traits or phenotypical aspects of PD. Further, there is a lack of studies with Latin American samples. We evaluated the association between SNCA single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs - rs2583988, rs356219, rs2736990, and rs11931074) and PD risk in a Brazilians sample. In addition, we investigated their potential interactions with environmental factors and specific clinical outcomes (motor and cognitive impairments, depression, and anxiety). A total of 105 PD patients and 101 controls participated in the study. Single locus analysis showed that the risk allele of all SNPs were more frequent in PD patients (p < 0.05), and the associations of SNPs rs2583988, rs356219, and rs2736990 with increased PD risk were confirmed. Further, the G-rs356219 and C rs2736990 alleles were associated with early onset PD. T-rs2583988, G-rs356219 and C-2736990 alleles were significantly more frequent in PD patients with cognitive impairments than controls in this condition. In addition, in a logistic regression model, we found an association of cognitive impairment with PD, and the practice of cognitive activity and smoking habits had a protective effect. This study shows for the first time an association of SNCA polymorphism and PD in a South-American sample. In addition, we found an interaction between SNP rs356219 and a specific clinical outcome, i.e., the increased risk for cognitive impairment in PD patients. PMID- 28676758 TI - Loss of Peripheral Sensory Function Explains Much of the Increase in Postural Sway in Healthy Older Adults. AB - Postural sway increases with age and peripheral sensory disease. Whether, peripheral sensory function is related to postural sway independent of age in healthy adults is unclear. Here, we investigated the relationship between tests of visual function (VISFIELD), vestibular function (CANAL or OTOLITH), proprioceptive function (PROP), and age, with center of mass sway area (COM) measured with eyes open then closed on firm and then a foam surface. A cross sectional sample of 366 community dwelling healthy adults from the Baltimore Longitudinal Study of Aging was tested. Multiple linear regressions examined the association between COM and VISFIELD, PROP, CANAL, and OTOLITH separately and in multi-sensory models controlling for age and gender. PROP dominated sensory prediction of sway across most balance conditions (beta's = 0.09-0.19, p's < 0.001), except on foam eyes closed where CANAL function loss was the only significant sensory predictor of sway (beta = 2.12, p < 0.016). Age was not a consistent predictor of sway. This suggests loss of peripheral sensory function explains much of the age-associated increase in sway. PMID- 28676759 TI - A New Perspective on Liver Injury by Traditional Chinese Herbs Such As Polygonum multiflorum: The Geographical Area of Harvest As an Important Contributory Factor. AB - Herbal medicine has been widely used in the treatment of various diseases; however, the adverse reactions cannot be ignored. Most previous studies have ignored the relationship between the factors of geographical areas/batches and toxicity. This study used Polygonum multiflorum (PM) as an example to analyze the relationship between the geographical areas/batches and toxicity and speculated on the hepatotoxicity-inducing components in PM based on high content screening, UHPLC-Q-TOF/MS and Progenesis QI software analysis. The results of the study show that the toxicity of PM was obviously different among the different geographical areas, and the most toxic PM was from the Sichuan province. To obtain more accurate results and to reduce the false-positive rate, two methods were used to evaluate the speculative results. It was noteworthy that emodin was not the main hepatocyte toxicity constituent of PM. The analysis methods suggested that PM toxicity may be associated with tetrahydroxystilbene-O-(galloyl)-hex and emodin-O hex-sulfate. The toxicity of these two components requires further study. PMID- 28676760 TI - Combined Oral Administration of GABA and DPP-4 Inhibitor Prevents Beta Cell Damage and Promotes Beta Cell Regeneration in Mice. AB - gamma-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin. Oral drug administration was initiated 1 week before STZ injection and maintained for 6 weeks. GABA or sitagliptin administration decreased ambient blood glucose levels and improved the glucose excursion rate. This was associated with elevated plasma insulin and reduced plasma glucagon levels. Importantly, combined use of GABA and sitagliptin significantly enhanced these effects as compared with each of the monotherapies. An additive effect on reducing water consumption was also observed. Immunohistochemical analyses revealed that combined GABA and sitagliptin therapy was superior in increasing beta cell mass, associated with increased small-size islet numbers, Ki67+ and PDX-1+ beta cell counts; and reduced Tunel+ beta cell counts. Thus, beta cell proliferation was increased, whereas apoptosis was reduced. We also noticed a suppressive effect of GABA or sitagliptin on alpha cell mass, which was not significantly altered by combining the two agents. Although either GABA or sitagliptin administration delays the onset of MDSD, our study indicates that combined use of them produces superior therapeutic outcomes. This is likely due to an amelioration of beta cell proliferation and a decrease of beta cell apoptosis. PMID- 28676761 TI - Asymmetrical Polymer Vesicles for Drug delivery and Other Applications. AB - Scientists have been attracted by polymersomes as versatile drug delivery systems since the last two decades. Polymersomes have the potential to be versatile drug delivery systems because of their tunable membrane formulations, stabilities in vivo, various physicochemical properties, controlled release mechanisms, targeting abilities, and capacities to encapsulate a wide range of drugs and other molecules. Asymmetrical polymersomes are nano- to micro-sized polymeric capsules with asymmetrical membranes, which means, they have different outer and inner coronas so that they can exhibit better endocytosis rate and endosomal escape ability than other polymeric systems with symmetrical membranes. Hence, asymmetrical polymersomes are highly promising as self-assembled nano-delivery systems in the future for in vivo therapeutics delivery and diagnostic imaging applications. In this review, we prepared a summary about recent research progresses of asymmetrical polymersomes in the following aspects: synthesis, preparation, applications in drug delivery and others. PMID- 28676762 TI - Personalized or Precision Medicine? The Example of Cystic Fibrosis. AB - The advent of the knowledge on human genetics, by the identification of disease associated variants, culminated in the understanding of human variability. With the genetic knowledge, the specificity of the clinical phenotype and the drug response of each individual were understood. Using the cystic fibrosis (CF) as an example, the new terms that emerged such as personalized medicine and precision medicine can be characterized. The genetic knowledge in CF is broad and the presence of a monogenic disease caused by mutations in the CFTR gene enables the phenotype-genotype association studies (including the response to drugs), considering the wide clinical and laboratory spectrum dependent on the mutual action of genotype, environment, and lifestyle. Regarding the CF disease, personalized medicine is the treatment directed at the symptoms, and this treatment is adjusted depending on the patient's phenotype. However, more recently, the term precision medicine began to be widely used, although its correct application and understanding are still vague and poorly characterized. In precision medicine, we understand the individual as a response to the interrelation between environment, lifestyle, and genetic factors, which enabled the advent of new therapeutic models, such as conventional drugs adjustment by individual patient dosage and drug type and response, development of new drugs (read through, broker, enhancer, stabilizer, and amplifier compounds), genome editing by homologous recombination, zinc finger nucleases, TALEN (transcription activator-like effector nuclease), CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated endonuclease 9), and gene therapy. Thus, we introduced the terms personalized medicine and precision medicine based on the CF. PMID- 28676763 TI - Sleep Deprivation in Young and Healthy Subjects Is More Sensitively Identified by Higher Frequencies of Electrodermal Activity than by Skin Conductance Level Evaluated in the Time Domain. AB - We analyzed multiple measures of the autonomic nervous system (ANS) based on electrodermal activity (EDA) and heart rate variability (HRV) for young healthy subjects undergoing 24-h sleep deprivation. In this study, we have utilized the error awareness test (EAT) every 2 h (13 runs total), to evaluate the deterioration of performance. EAT consists of trials where the subject is presented words representing colors. Subjects are instructed to press a button ("Go" trials) or withhold the response if the word presented and the color of the word mismatch ("Stroop No-Go" trial), or the screen is repeated ("Repeat No-Go" trials). We measured subjects' (N = 10) reaction time to the "Go" trials, and accuracy to the "Stroop No-Go" and "Repeat No-Go" trials. Simultaneously, changes in EDA and HRV indices were evaluated. Furthermore, the relationship between reactiveness and vigilance measures and indices of sympathetic control based on HRV were analyzed. We found the performance improved to a stable level from 6 through 16 h of deprivation, with a subsequently sustained impairment after 18 h. Indices of higher frequencies of EDA related more to vigilance measures, whereas lower frequencies index (skin conductance leve, SCL) measured the reactiveness of the subject. We conclude that indices of EDA, including those of the higher frequencies, termed TVSymp, EDASymp, and NSSCRs, provide information to better understand the effect of sleep deprivation on subjects' autonomic response and performance. PMID- 28676764 TI - Bed Rest and Hypoxic Exposure Affect Sleep Architecture and Breathing Stability. AB - Objective: Despite over 50 years of research on the physiological effects of sustained bed rest, data characterizing its effects on sleep macrostructure and breathing stability in humans are scarce. This study was conducted to determine the effects of continuous exposure to hypoxia and sustained best rest, both individually and combined, on nocturnal sleep and breathing stability. Methods: Eleven participants completed three randomized, counter-balanced, 21-days trials of: (1) normoxic bed rest (NBR, PIO2 = 133.1 +/- 0.3), (2) hypoxic ambulatory confinement (HAMB, PIO2 = 90.0 +/- 0.4) and (3) hypoxic bed rest (HBR, PIO2 = 90.0 +/- 0.4; ~4,000 m equivalent altitude). Full objective polysomnography was performed at baseline, on Night 1 and Night 21 in each condition. Results: In NBR Night 1, more time was spent in light sleep (10 +/- 2%) compared to baseline (8 +/- 2%; p = 0.028); Slow-wave sleep (SWS) was reduced from baseline in the hypoxic-only trial by 18% (HAMB Night 21, p = 0.028) and further reduced by 33% (HBR Night 1, p = 0.010), and 36% (HBR Night 21, p = 0.008) when combined with bed rest. The apnea-hypopnea index doubled from Night 1 to Night 21 in HBR (32-62 events.h-1) and HAMB (31-59 events.h-1; p = 0.002). Those who experienced greatest breathing instability from Night 1 to Night 21 (NBR) were correlated to unchanged or higher (+1%) night SpO2 concentrations (R2 = 0.471, p = 0.020). Conclusion: Bed rest negatively affects sleep macrostructure, increases the apnea hypopnea index, and worsens breathing stability, each independently exacerbated by continuous exposure to hypoxia. PMID- 28676765 TI - Molecular Basis of N,N-Diethyl-3-Methylbenzamide (DEET) in Repelling the Common Bed Bug, Cimex lectularius. AB - As the most extensively used chemical repellent, N,N-diethyl-3-methylbenzamide (DEET) displayed repellency to a wide range of insects, including the common bed bug, Cimex lectularius. While the neuronal or molecular basis involved in DEET's repellency have been majorly focused on mosquitos and fruit flies, DEET's repellency to the common bed bug is largely unreached. To gain new insights into the cellular and molecular mechanisms in DEET's repellency to the common bed bug, we characterized the neuronal response of bed bugs to DEET, identified the olfactory receptors targeted by DEET and demonstrated the interfering effect of DEET on bed bug's responses to human odorants. High doses of DEET were required for activating the olfactory receptor neurons in the sensilla of bed bugs and at least three DEET-sensitive receptors were functionally deciphered. These DEET sensitive receptors presented even more sensitive to certain botanical terpenes/terpenoids which also displayed repellency at varying levels for bed bugs. In addition, DEET produced a blocking effect on the neuronal responses of bed bugs to specific human odors and showed inhibitory effect on the function of odorant receptors in responding to certain human odors. Taken together, our results indicate that DEET may function as a stimulus that triggers avoidance behaviors and a molecular "confusant" for interrupting the host odor recognition in the odorant receptors of bed bugs. The receptors that coincidently responded to both synthetic DEET and botanical terpenes/terpenoids suggested that DEET probably target on receptors that originally responded to terpenes/terpenoids. This study gave novel insight into the mechanisms of DEET's repellency to bed bugs and also provided valuable information for developing new reagents for bed bug control. PMID- 28676768 TI - Beyond "Monologicality"? Exploring Conspiracist Worldviews. AB - Conspiracy theories (CTs) are widespread ways by which people make sense of unsettling or disturbing cultural events. Belief in CTs is often connected to problematic consequences, such as decreased engagement with conventional political action or even political extremism, so understanding the psychological and social qualities of CT belief is important. CTs have often been understood to be "monological," displaying the tendency for belief in one conspiracy theory to be correlated with belief in (many) others. Explanations of monologicality invoke a nomothetical or "closed" mindset whereby mutually supporting beliefs based on mistrust of official explanations are used to interpret public events as conspiracies, independent of the facts about those events (which they may ignore or deny). But research on monologicality offers little discussion of the content of monological beliefs and reasoning from the standpoint of the CT believers. This is due in part to the "access problem": CT believers are averse to being researched because they often distrust researchers and what they appear to represent. Using several strategies to address the access problem we were able to engage CT believers in semi-structured interviews, combining their results with analysis of media documents and field observations to reconstruct a conspiracy worldview - a set of symbolic resources drawn on by CT believers about important dimensions of ontology, epistemology, and human agency. The worldview is structured around six main dimensions: the nature of reality, the self, the outgroup, the ingroup, relevant social and political action, and possible future change. We also describe an ascending typology of five types of CT believers, which vary according to their positions on each of these dimensions. Our findings converge with prior explorations of CT beliefs but also revealed novel aspects: A sense of community among CT believers, a highly differentiated representation of the outgroup, a personal journey of conversion, variegated kinds of political action, and optimistic belief in future change. These findings are at odds with the typical image of monological CT believers as paranoid, cynical, anomic and irrational. For many, the CT worldview may rather constitute the ideological underpinning of a nascent pre-figurative social movement. PMID- 28676767 TI - When Is a Sprint a Sprint? A Review of the Analysis of Team-Sport Athlete Activity Profile. AB - The external load of a team-sport athlete can be measured by tracking technologies, including global positioning systems (GPS), local positioning systems (LPS), and vision-based systems. These technologies allow for the calculation of displacement, velocity and acceleration during a match or training session. The accurate quantification of these variables is critical so that meaningful changes in team-sport athlete external load can be detected. High velocity running, including sprinting, may be important for specific team-sport match activities, including evading an opponent or creating a shot on goal. Maximal accelerations are energetically demanding and frequently occur from a low velocity during team-sport matches. Despite extensive research, conjecture exists regarding the thresholds by which to classify the high velocity and acceleration activity of a team-sport athlete. There is currently no consensus on the definition of a sprint or acceleration effort, even within a single sport. The aim of this narrative review was to examine the varying velocity and acceleration thresholds reported in athlete activity profiling. The purposes of this review were therefore to (1) identify the various thresholds used to classify high velocity or -intensity running plus accelerations; (2) examine the impact of individualized thresholds on reported team-sport activity profile; (3) evaluate the use of thresholds for court-based team-sports and; (4) discuss potential areas for future research. The presentation of velocity thresholds as a single value, with equivocal qualitative descriptors, is confusing when data lies between two thresholds. In Australian football, sprint efforts have been defined as activity >4.00 or >4.17 m.s-1. Acceleration thresholds differ across the literature, with >1.11, 2.78, 3.00, and 4.00 m.s-2 utilized across a number of sports. It is difficult to compare literature on field-based sports due to inconsistencies in velocity and acceleration thresholds, even within a single sport. Velocity and acceleration thresholds have been determined from physical capacity tests. Limited research exists on the classification of velocity and acceleration data by female team-sport athletes. Alternatively, data mining techniques may be used to report team-sport athlete external load, without the requirement of arbitrary or physiologically defined thresholds. PMID- 28676766 TI - Site-Specific Variations in Bone Mineral Density under Systemic Conditions Inducing Osteoporosis in Minipigs. AB - Osteoporosis is a systemic bone disease with an increasing prevalence in the elderly population. There is conflicting opinion about whether osteoporosis affects the alveolar bone of the jaws and whether it poses a risk to the osseointegration of dental implants. The aim of the present study was to evaluate the effects of systemic glucocorticoid administration on the jaw bone density of minipigs. Thirty-seven adult female minipigs were randomly divided into two groups. Quantitative computed tomography (QCT) was used to assess bone mineral density BMD of the lumbar spine as well as the mandible and maxilla, and blood was drawn. One group of minipigs initially received 1.0 mg prednisolone per kg body weight daily for 2 months. The dose was tapered to 0.5 mg per kg body weight per day thereafter. The animals in the other group served as controls and received placebo. QCT and blood analysis were repeated after 6 and 9 months. BMD was compared between the two groups by measuring Hounsfield units, and serum levels of several bone metabolic markers were also assessed. A decrease in BMD was observed in the jaws from baseline to 9 months. This was more pronounced in the prednisolone group. Statistically significant differences were reached for the mandible (p < 0.001) and the maxilla (p < 0.001). The administration of glucocorticoids reduced the BMD in the jaws of minipigs. The described model shows promise in the evaluation of osseointegration of dental implants in bone that is compromised by osteoporosis. PMID- 28676770 TI - How We Think about Temporal Words: A Gestural Priming Study in English and Chinese. AB - Spatial metaphors are used to represent and reason about time. Such metaphors are typically arranged along the sagittal axis in most languages. For example, in English, "The future lies ahead of us" and "We look back on our past." This is less straightforward for Chinese. Specifically, both the past and future can either be behind or ahead. The present study aims to explore these cross linguistic differences by priming auditory targets (e.g., tomorrow) with either a congruent (i.e., pointing forwards) or incongruent (i.e., pointing backwards) gesture. Two groups of college-age young adult participants (English and Chinese speakers) made temporal classifications of words after watching a gestural prime. If speakers represent time along the sagittal axis, they should respond faster if the auditory target is preceded with a gesture indicating a congruent vs. incongruent spatial location. Results showed that English speakers responded faster to congruent gesture-word pairs than to incongruent pairs, mirroring spatio-temporal metaphors commonly recruited to talk about time in their native language. However, such an effect of congruency was not found for Chinese speakers. These findings suggest that while the spatio-temporal metaphors commonly recruited to talk about time help to structure the mental timelines of English speakers, the varying instances in how time is represented along the sagittal axis in Chinese may lead to a more variable mental timeline as well. In addition, our findings demonstrate that gestures may not only be a means of accessing concrete concepts in the mind, as shown in previous studies, but may be used to access abstract ones as well. PMID- 28676769 TI - Spacing Repetitions Over Long Timescales: A Review and a Reconsolidation Explanation. AB - Recent accounts of the spacing effect have proposed molecular explanations that explain spacing over short, but not long timescales. In the first half of this paper, we review research on the spacing effect that has employed spaces of 24 h or more across skill-related tasks, language-related tasks and generalization for adults and children. Throughout this review, we distinguish between learning and retention by defining learning (or acquisition) as performance at the end of training and retention as performance after a delay period. Using this distinction, we find age- and task-related differences in the manifestation of the spacing effect over long timescales. In the second half of this paper, we discuss a reconsolidation account of the spacing effect. In particular, we review the evidence that suggests the spacing of repetitions influences the subsequent consolidation and reconsolidation processes; we explain how a reconsolidation account may explain the findings for learning; the inverted-U curve for retention; and compare the reconsolidation account with previous consolidation accounts of the spacing effect. PMID- 28676771 TI - Differences in Executive Functioning in Children with Attention Deficit and Hyperactivity Disorder (ADHD). AB - In recent years, the interest in Attention Deficit and Hyperactivity Disorder (ADHD) and its relation to deficits in working memory (WM) and more specifically the different executive functions (EFs) has grown, to the point of confirming that these are quite frequent in this disorder. The aim of this study was precisely to explore differences in executive functioning of WM in fourth grade Primary school children with and without ADHD (26 and 29 children, respectively), introducing rigorous control measures in the tests used. Four EFs were analyzed: divided attention, updating, attentional shifting and inhibition, measured through four tasks, the dual-task paradigm (digits and box-crossing), the N-Back task, the Trail Making Test and the Stroop task, respectively. The results showed that participants with ADHD, compared to children with typical development (TD), exhibited a smaller verbal memory span as well as deficits in the attentional shifting and updating functions. However, a similar performance for the EF of inhibition was found for both groups of participants. Finally, an unexpected result was obtained with regard to the role of divided attention, as children with ADHD were less impaired when performing the double task than participants in the TD group. PMID- 28676773 TI - Intuitive Face Judgments Rely on Holistic Eye Movement Pattern. AB - Non-verbal signals such as facial expressions are of paramount importance for social encounters. Their perception predominantly occurs without conscious awareness and is effortlessly integrated into social interactions. In other words, face perception is intuitive. Contrary to classical intuition tasks, this work investigates intuitive processes in the realm of every-day type social judgments. Two differently instructed groups of participants judged the authenticity of emotional facial expressions, while their eye movements were recorded: an 'intuitive group,' instructed to rely on their "gut feeling" for the authenticity judgments, and a 'deliberative group,' instructed to make their judgments after careful analysis of the face. Pixel-wise statistical maps of the resulting eye movements revealed a differential viewing pattern, wherein the intuitive judgments relied on fewer, longer and more centrally located fixations. These markers have been associated with a global/holistic viewing strategy. The holistic pattern of intuitive face judgments is in line with evidence showing that intuition is related to processing the "gestalt" of an object, rather than focusing on details. Our work thereby provides further evidence that intuitive processes are characterized by holistic perception, in an understudied and real world domain of intuition research. PMID- 28676772 TI - Executive Functions of Divers Are Selectively Impaired at 20-Meter Water Depth. AB - Moving and acting underwater within recreational or occupational activities require intact executive functions, since they subserve higher cognitive functions such as successful self-regulation, coping with novel situations, and decision making; all of which could be influenced by nitrogen narcosis due to elevated partial pressure under water. However, specific executive functions that could provide a differentiated view on humans' cognitive performance ability have not yet been systematically analyzed in full-water immersion, which is a research gap addressed within this approach to contribute to a better understanding of nitrogen narcosis. In this study, 20 young, healthy, and certified recreational divers participated and performed three different executive-function tests: the Stroop test (Inhibition), the Number/Letter test (Task switching), the 2-back test (Updating/Working memory), and a simple reaction time test (Psychomotor performance). These tests were performed once on land, at 5-meter (m) water depth, and at 20-meter (m) water depth of an indoor diving facility in standardized test conditions (26 degrees C in all water depths). A water-proofed and fully operational tablet computer was used to present visual stimuli and to register reaction times. Performance of the simple reaction time test was not different between underwater and land testing, suggesting that reaction times were not biased by the utilization of the tablet in water immersion. Executive functions were not affected by the shallow water immersion of 5-m water depth. However, performance scores in 20-m water depth revealed a decreased performance in the incongruent test condition (i.e., an index of inhibitory control ability) of the Stroop test, while all other tests were unaffected. Even though only one out of the three tested cognitive domains was affected, the impairment of inhibitory control ability even in relatively shallow water of 20-m is a critical component that should be considered for diver's safety, since inhibition is required in self-control requiring situations where impulsive and automatic behavior must be inhibited. Our interpretation of these selective impairments is based on a discussion suggesting that different neural networks within the central nervous system, which process specific executive functions, are affected differently by nitrogen narcosis. PMID- 28676774 TI - Look Who's Talking NOW! Parentese Speech, Social Context, and Language Development Across Time. AB - In previous studies, we found that the social interactions infants experience in their everyday lives at 11- and 14-months of age affect language ability at 24 months of age. These studies investigated relationships between the speech style (i.e., parentese speech vs. standard speech) and social context [i.e., one-on-one (1:1) vs. group] of language input in infancy and later speech development (i.e., at 24 months of age), controlling for socioeconomic status (SES). Results showed that the amount of exposure to parentese speech-1:1 in infancy was related to productive vocabulary at 24 months. The general goal of the present study was to investigate changes in (1) the pattern of social interactions between caregivers and their children from infancy to childhood and (2) relationships among speech style, social context, and language learning across time. Our study sample consisted of 30 participants from the previously published infant studies, evaluated at 33 months of age. Social interactions were assessed at home using digital first-person perspective recordings of the auditory environment. We found that caregivers use less parentese speech-1:1, and more standard speech-1:1, as their children get older. Furthermore, we found that the effects of parentese speech-1:1 in infancy on later language development at 24 months persist at 33 months of age. Finally, we found that exposure to standard speech-1:1 in childhood was the only social interaction that related to concurrent word production/use. Mediation analyses showed that standard speech-1:1 in childhood fully mediated the effects of parentese speech-1:1 in infancy on language development in childhood, controlling for SES. This study demonstrates that engaging in one-on-one interactions in infancy and later in life has important implications for language development. PMID- 28676775 TI - Construction and Validation of a Measurement Instrument for Attitudes towards Teamwork. AB - Cooperative, collaborative learning and other forms of group learning methods are increasingly used in classrooms. Knowing students' attitudes toward teamwork has great value since they influence the students' learning results as well as their social development. So it is necessary to have robust instruments to provide a better understanding of these attitudes and preferences concerning teamwork. Such instruments also help to identify the factors that promote positive or negative attitudes within the context of group activities. Using a sample of 750 first and second year university students studying a degree in Kindergarten, Primary and Social Education, an instrument measuring attitudes toward team learning has been developed. Two distinct factors were obtained through various factorial analyses and structural equations: Academic attitudes and Social and emotional attitudes. Our study reveals that the instrument is both valid and reliable. Its application is both simple and fast and it has important implications for planning teaching and learning activities that contribute to an improvement in attitudes as well as the practice of teaching in the context of learning through teamwork. PMID- 28676776 TI - Consumer Behavior in the Choice of Mode of Transport: A Case Study in the Toledo Madrid Corridor. AB - Within the context of the consumption of goods or services the decisions made by individuals involve the choice between a set of discrete alternatives, such as the choice of mode of transport. The methodology for analyzing the consumer behavior are the models of discrete choice based on the Theory of Random Utility. These models are based on the definition of preferences through a utility function that is maximized. These models also denominated of disaggregated demand derived from the decision of a set of individuals, who are formalized by the application of probabilistic models. The objective of this study is to determine the behavior of the consumer in the choice of a service, namely of transport services and in a short-distance corridor, such as Toledo-Madrid. The Toledo Madrid corridor is characterized by being short distance, with high speed train available within the choice options to get the airport, along with the bus and the car. And where offers of HST and aircraft services can be proposed as complementary modes. By applying disaggregated transport models with revealed preference survey data and declared preferences, one can determine the most important variables involved in the choice and determine the arrangements for payment of individuals. These payment provisions may condition the use of certain transport policies to promote the use of efficient transportation. PMID- 28676777 TI - Inhibition of Return Is Modulated by Negative Stimuli: Evidence from Subliminal Perception. AB - Inhibition of return (IOR) is considered as a "blindness mechanism" that emotional stimuli have no impact on it. Most previous studies suggested that IOR was not modulated by emotional cues. However, one key question they ignored was that only supraliminal presentation of emotional stimuli was used in their experiments. The present experiment is aimed at exploring the possible interaction between the IOR effect and subliminal emotional process. We manipulated three different kinds of valence strength of negative stimuli (high negative, HN; moderate negative, MN; low negative, LN) which were presented under the subliminal perception level and an event-related potentials (ERPs) recording was adopted. The results showed that, compared to MN and HN, the IOR effect triggered by peripheral cues was more significant for LN with aspects of behavioral and electrophysiological data (a reduction P1 effect, more negative on cued trials than on uncued trials for both early posterior Nd and Nd components). This indicated that IOR can be modulated by emotionally relevant stimuli. The automatic processing that was triggered by subliminally negative stimuli of peripheral cues had an influence on the shifting of spatial attention that was triggered by IOR. These two mechanisms may occur in the perceptual stage simultaneously. PMID- 28676778 TI - Children's First Experience of Taking Anabolic-Androgenic Steroids can Occur before Their 10th Birthday: A Systematic Review Identifying 9 Factors That Predicted Doping among Young People. AB - Taking performance-enhancing drugs (PEDs) can cause serious and irreversible health consequences, which can ultimately lead to premature death. Some young people may take PEDs without fully understanding the ramifications of their actions or based on the advice from others. The purpose of this systematic review was to identify the main factors that predicted doping among young people. The literature was systematically reviewed using search engines, manually searching specialist journals, and pearl growing. Fifty-two studies, which included 187,288 young people aged between 10 and 21 years of age, 883 parents of adolescent athletes, and 11 adult coaches, who were interviewed regarding young athletes, were included in this review. Nine factors predicted doping among young people: gender; age; sports participation; sport type; psychological variables; entourage; ethnicity; nutritional supplements; and health harming behaviors. In regards to psychological variables, 22 different constructs were associated with doping among young people. Some psychological constructs were negatively associated with doping (e.g., self-esteem, resisting social pressure, and perfectionist strivings), whereas other were positively associated with doping (e.g., suicide risk, anticipated regret, and aggression). Policy makers and National Anti-Doping Organizations could use these findings to help identify athletes who are more at risk of doping and then expose these individuals to anti doping education. Based on the current findings, it also appears that education programs should commence at the onset of adolescence or even late childhood, due to the young age in which some individuals start doping. PMID- 28676779 TI - Alcohol and Illicit Drug Use Are Important Factors for School-Related Problems among Adolescents. AB - The aim of this study was to investigate the association between alcohol and drug use, and school-related problems measured by low grade point average (GPA) and high school attendance. We also examined potential confounding effects from mental health problems. Although the issue is not new within current literature, the present study has its strengths in a large number of participants and the utilization of registry-based data on school-related functioning. A cross sectional design is employed in this study using data from a large population based sample of adolescents, youth@hordaland, in a linkage to official school registry data, and the current study presents data from N = 7,874. The main independent variables were alcohol use and drug use, as well as potential alcohol and drug-related problems. The dependent variables were registry-based school attendance and grades. All the alcohol- and drug measures included were consistently associated with low GPA (Odds ratios (OR) ranging 1.82-2.21, all p < 0.001) and high levels of missed days from school (ORs ranging 1.79-3.04, all p < 0.001) and high levels of hours missed from school (ORs ranging 2.17-3.44, all p < 0.001). Even after adjusting for gender, age, socioeconomic status and mental health problems all the associations between alcohol and illicit drug use and the school-related outcomes remained statistically significant. Increasing number of indications on alcohol/drug-related problems and increasing levels of alcohol consumption were associated with more negative school-related outcomes. The results suggest that alcohol- and drug use, and particularly alcohol/drug-related problems, are important factors for school-related problems independently of mental health problems. PMID- 28676780 TI - Prolonged Interruption of Cognitive Control of Conflict Processing Over Human Faces by Task-Irrelevant Emotion Expression. AB - As documented by Darwin 150 years ago, emotion expressed in human faces readily draws our attention and promotes sympathetic emotional reactions. How do such reactions to the expression of emotion affect our goal-directed actions? Despite the substantial advance made in the neural mechanisms of both cognitive control and emotional processing, it is not yet known well how these two systems interact. Here, we studied how emotion expressed in human faces influences cognitive control of conflict processing, spatial selective attention and inhibitory control in particular, using the Eriksen flanker paradigm. In this task, participants viewed displays of a central target face flanked by peripheral faces and were asked to judge the gender of the target face; task-irrelevant emotion expressions were embedded in the target face, the flanking faces, or both. We also monitored how emotion expression affects gender judgment performance while varying the relative timing between the target and flanker faces. As previously reported, we found robust gender congruency effects, namely slower responses to the target faces whose gender was incongruent with that of the flanker faces, when the flankers preceded the target by 0.1 s. When the flankers further advanced the target by 0.3 s, however, the congruency effect vanished in most of the viewing conditions, except for when emotion was expressed only in the flanking faces or when congruent emotion was expressed in the target and flanking faces. These results suggest that emotional saliency can prolong a substantial degree of conflict by diverting bottom-up attention away from the target, and that inhibitory control on task-irrelevant information from flanking stimuli is deterred by the emotional congruency between target and flanking stimuli. PMID- 28676781 TI - Psychometric Characteristics of a New Scale for Measuring Self-efficacy in the Regulation of Gambling Behavior. AB - Since its introduction in 1977, self-efficacy has proven to be a fundamental predictor of positive adjustment and achievement in many domains. In problem gambling studies, self-efficacy has been defined mainly as an individual's ability to avoid gambling in risky situations. The interest in this construct developed mainly with regard to treatment approaches, where abstinence from gambling is required. Very little is known, however, regarding self-efficacy as a protective factor for problem gambling. This study aims to fill this gap, proposing a new self-efficacy scale which measures not only the ability to restrain oneself from gambling but also the ability to self-regulate one's gambling behavior. Two studies were conducted in which the data from two Italian prevalence surveys on problem gambling were considered. A total of about 6,000 participants were involved. In the first study, the psychometric characteristics of this new self-efficacy scale were investigated through exploratory and confirmatory factor analyses. The results indicated the presence of two different factors: self-efficacy in self-regulating gambling behavior and self-efficacy in avoiding risky gambling behavior. The second study confirmed the replicability of the two-factor solution and displayed high correlations among these two self efficacy dimensions and different measures of gambling activities as well as other psychological variables related to gambling (gambling beliefs, gambling motivation, risk propensity, and impulsiveness). The results of logistic regression analyses showed the particular importance of self-regulating gaming behavior in explaining problem gambling as measured by Problem Gambling Severity Index and South Oaks Gambling Screen, thus proving the role of self-efficacy as a pivotal protective factor for problem gambling. PMID- 28676782 TI - Thought Field Therapy Compared to Cognitive Behavioral Therapy and Wait-List for Agoraphobia: A Randomized, Controlled Study with a 12-Month Follow-up. AB - Background: Thought field therapy (TFT) is used for many psychiatric conditions, but its efficacy has not been sufficiently documented. Hence, there is a need for studies comparing TFT to well-established treatments. This study compares the efficacy of TFT and cognitive behavioral therapy (CBT) for patients with agoraphobia. Methods: Seventy-two patients were randomized to CBT (N = 24), TFT (N = 24) or a wait-list condition (WLC) (N = 24) after a diagnostic procedure including the MINI PLUS that was performed before treatment or WLC. Following a 3 months waiting period, the WL patients were randomized to CBT (n = 12) or TFT (n = 12), and all patients were reassessed after treatment or waiting period and at 12 months follow-up. At first we compared the three groups CBT, TFT, and WL. After the post WL randomization, we compared CBT (N = 12 + 24 = 36) to TFT (N = 12 + 24 = 36), applying the pre-treatment scores as baseline for all patients. The primary outcome measure was a symptom score from the Anxiety Disorders Interview Scale that was performed by an interviewer blinded to the treatment condition. For statistical comparisons, we used the independent sample's t-test, the Fisher's exact test and the ANOVA and ANCOVA tests. Results: Both CBT and TFT showed better results than the WLC (p < 0.001) at post-treatment. Post-treatment and at the 12-month follow-up, there were not significant differences between CBT and TFT (p = 0.33 and p = 0.90, respectively). Conclusion: This paper reports the first study comparing TFT to CBT for any disorder. The study indicated that TFT may be an efficient treatment for patients with agoraphobia. Trial Registration: https://clinicaltrials.gov/, identifier NCT00932919. PMID- 28676783 TI - The Word Composite Effect Depends on Abstract Lexical Representations But Not Surface Features Like Case and Font. AB - Prior studies have shown that words show a composite effect: When readers perform a same-different matching task on a target-part of a word, performance is affected by the irrelevant part, whose influence is severely reduced when the two parts are misaligned. However, the locus of this word composite effect is largely unknown. To enlighten it, in two experiments, Portuguese readers performed the composite task on letter strings: in Experiment 1, in written words varying in surface features (between-participants: courier, notera, alternating-cAsE), and in Experiment 2 in pseudowords. The word composite effect, signaled by a significant interaction between alignment of the two word parts and congruence between parts was found in the three conditions of Experiment 1, being unaffected by NoVeLtY of the configuration or by handwritten form. This effect seems to have a lexical locus, given that in Experiment 2 only the main effect of congruence between parts was significant and was not modulated by alignment. Indeed, the cross-experiment analysis showed that words presented stronger congruence effects than pseudowords only in the aligned condition, because when misaligned the whole lexical item configuration was disrupted. Therefore, the word composite effect strongly depends on abstract lexical representations, as it is unaffected by surface features and is specific to lexical items. PMID- 28676784 TI - Development and Plasticity of Cognitive Flexibility in Early and Middle Childhood. AB - Cognitive flexibility, the ability to flexibly switch between tasks, is a core dimension of executive functions (EFs) allowing to control actions and to adapt flexibly to changing environments. It supports the management of multiple tasks, the development of novel, adaptive behavior and is associated with various life outcomes. Cognitive flexibility develops rapidly in preschool and continuously increases well into adolescence, mirroring the growth of neural networks involving the prefrontal cortex. Over the past decade, there has been increasing interest in interventions designed to improve cognitive flexibility in children in order to support the many developmental outcomes associated with cognitive flexibility. This article provides a brief review of the development and plasticity of cognitive flexibility across early and middle childhood (i.e., from preschool to elementary school age). Focusing on interventions designed to improve cognitive flexibility in typically developing children, we report evidence for significant training and transfer effects while acknowledging that current findings on transfer are heterogeneous. Finally, we introduce metacognitive training as a promising new approach to promote cognitive flexibility and to support transfer of training. PMID- 28676785 TI - Atypical Teratoid Rhabdoid Tumor: Two Case Reports and an Analysis of Adult Cases with Implications for Pathophysiology and Treatment. AB - We present the first quantitative analysis of atypical teratoid rhabdoid tumors (ATRT) in adults, including two patients from our own institutions. These are of interest as one occurred during pregnancy and one is a long-term survivor. Our review of pathological findings of 50 reported cases of adult ATRT leads us to propose a solely ectodermal origin for the tumor and that epithelial-mesenchymal transition (EMT) is a defining feature. Thus, the term ATRT may be misleading. Our review of clinical findings shows that ATRT tends to originate in mid-line structures adjacent to the CSF, leading to a high rate of leptomeningeal dissemination. Thus, we hypothesize that residual undifferentiated ectoderm in the circumventricular organs, particularly the pituitary and pineal glands, is the most common origin for these tumors. We note that if growth is not arrested soon after diagnosis, or after the first relapse/progression, death is almost universal. While typically rapidly fatal (as in our first case), long-term remission is possible (as in our second). Significant predictors of prognosis were the extent of resection and the use of chemotherapy. Glial differentiation (GFAP staining) was strongly associated with leptomeningeal metastases (chi squared p = 0.02) and both predicted markedly worse outcomes. Clinical trials including adults are rare. ATRT is primarily a disease of infancy and radiotherapy is generally avoided in those aged less than 3 years old. Treatment options in adults differ from infants in that cranio-spinal irradiation is a viable adjunct to systemic chemotherapy in the adult population. Given the grave prognosis, this combined approach appears reasonable. As effective chemotherapy is likely to cause myelosuppression, we recommend that stem-cell rescue be available locally. PMID- 28676786 TI - Alterations in Localized Electrical Impedance Myography of Biceps Brachii Muscles Paralyzed by Spinal Cord Injury. AB - This study assessed electrical impedance myography (EIM) changes after spinal cord injury (SCI) with a localized multifrequency technology. The EIM measurement was performed on the biceps brachii muscle at rest condition of 17 cervical SCI subjects, and 23 neurologically intact subjects as control group. The results showed that there was a significant decrease in muscle reactance (X) and phase angle (theta) at selected frequencies (i.e., 50 and 100 kHz) in SCI compared to control. There was no significant difference in muscle resistance (R) between the two groups. The anisotropy examination revealed that SCI group had a decreased anisotropy ratio in resistance. In addition, the multifrequency spectrum analysis showed a decreased slope of the log(freq)-resistance regression in SCI group when compared to healthy control. Findings of the EIM changes are related to inherit muscle changes after the injury. Since EIM requires no patient effort and is quick and convenient to conduct, it may provide a useful tool for examination of paralyzed muscle changes after SCI. PMID- 28676787 TI - Slowed Prosaccades and Increased Antisaccade Errors As a Potential Behavioral Biomarker of Multiple System Atrophy. AB - Current clinical diagnostic tools are limited in their ability to accurately differentiate idiopathic Parkinson's disease (PD) from multiple system atrophy (MSA) and other parkinsonian disorders early in the disease course, but eye movements may stand as objective and sensitive markers of disease differentiation and progression. To assess the use of eye movement performance for uniquely characterizing PD and MSA, subjects diagnosed with PD (N = 21), MSA (N = 11), and age-matched controls (C, N = 20) were tested on the prosaccade and antisaccade tasks using an infrared eye tracker. Twenty of these subjects were retested ~7 months later. Saccade latencies, error rates, and longitudinal changes in saccade latencies were measured. Both PD and MSA patients had greater antisaccade error rates than C subjects, but MSA patients exhibited longer prosaccade latencies than both PD and C patients. With repeated testing, antisaccade latencies improved over time, with benefits in C and PD but not MSA patients. In the prosaccade task, the normal latencies of the PD group show that basic sensorimotor oculomotor function remain intact in mid-stage PD, whereas the impaired latencies of the MSA group suggest additional degeneration earlier in the disease course. Changes in antisaccade latency appeared most sensitive to differences between MSA and PD across short time intervals. Therefore, in these mid-stage patients, increased antisaccade errors combined with slowed prosaccade latencies might serve as a useful marker for early differentiation between PD and MSA, and, antisaccade performance, a measure of MSA progression. Together, our findings suggest that eye movements are promising biomarkers for early differentiation and progression of parkinsonian disorders. PMID- 28676788 TI - A Systematic Review of Treatment of Painful Diabetic Neuropathy by Pain Phenotype versus Treatment Based on Medical Comorbidities. AB - BACKGROUND: Painful diabetic neuropathy (PDN) is a serious, polymorphic, and prevalent complication of diabetes mellitus. Most PDN treatment guidelines recommend a selection of drugs based on patient comorbidities. Despite the large numbers of medications available, most randomized clinical trials (RCTs) conducted so far have yielded unsatisfactory outcomes. Therefore, treatment may require a personalized approach based on pain phenotype or comorbidities. METHODS: To evaluate whether or not a patient's pain phenotype or comorbidities can influence the response to a specific PDN treatment, we conducted a systematic review using two different approaches: pain phenotype and associated comorbidities-based treatment. RESULTS: Out of 45 identified papers, 7 were thoroughly reviewed. We found four RCTs stratified according to pain phenotype with three main results: (1) paroxysmal pain had a better response to pregabalin; (2) the preservation of thermal sensation or nociception anticipated a positive response to the topical treatment of pain; and, (3) after a failure to duloxetine (60 mg/day), the patients with evoked pain or severe deep pain had a better response to association of duloxetine/pregabalin while those with paresthesia/dysesthesia benefited from duloxetine monotherapy (120 mg/day). By contrast, the other three papers provided weak and even contradictory evidence about PDN treatment based on comorbidities. CONCLUSION: Although more studies are needed to provide an adequate recommendation for clinical practice, our systematic review has provided some evidence that PDN phenotyping may optimize clinical outcomes and could, in the future, lead to both less empirical medicine and more personalized pain therapeutics. PMID- 28676789 TI - Importance of the Sequence-Directed DNA Shape for Specific Binding Site Recognition by the Estrogen-Related Receptor. AB - Most nuclear receptors (NRs) bind DNA as dimers, either as hetero- or as homodimers on DNA sequences organized as two half-sites with specific orientation and spacing. The dimerization of NRs on their cognate response elements (REs) involves specific protein-DNA and protein-protein interactions. The estrogen related receptor (ERR) belongs to the steroid hormone nuclear receptor (SHR) family and shares strong similarity in its DNA-binding domain (DBD) with that of the estrogen receptor (ER). In vitro, ERR binds with high affinity inverted repeat REs with a 3-bps spacing (IR3), but in vivo, it preferentially binds to single half-site REs extended at the 5'-end by 3 bp [estrogen-related response element (ERREs)], thus explaining why ERR was often inferred as a purely monomeric receptor. Since its C-terminal ligand-binding domain is known to homodimerize with a strong dimer interface, we investigated the binding behavior of the isolated DBDs to different REs using electrophoretic migration, multi angle static laser light scattering (MALLS), non-denaturing mass spectrometry, and nuclear magnetic resonance. In contrast to ER DBD, ERR DBD binds as a monomer to EREs (IR3), such as the tff1 ERE-IR3, but we identified a DNA sequence composed of an extended half-site embedded within an IR3 element (embedded ERRE/IR3), where stable dimer binding is observed. Using a series of chimera and mutant DNA sequences of ERREs and IR3 REs, we have found the key determinants for the binding of ERR DBD as a dimer. Our results suggest that the sequence-directed DNA shape is more important than the exact nucleotide sequence for the binding of ERR DBD to DNA as a dimer. Our work underlines the importance of the shape-driven DNA readout mechanisms based on minor groove recognition and electrostatic potential. These conclusions may apply not only to ERR but also to other members of the SHR family, such as androgen or glucocorticoid, for which a strong well conserved half-site is followed by a weaker one with degenerated sequence. PMID- 28676790 TI - Nanotechnology in Sustainable Agriculture: Recent Developments, Challenges, and Perspectives. AB - Nanotechnology monitors a leading agricultural controlling process, especially by its miniature dimension. Additionally, many potential benefits such as enhancement of food quality and safety, reduction of agricultural inputs, enrichment of absorbing nanoscale nutrients from the soil, etc. allow the application of nanotechnology to be resonant encumbrance. Agriculture, food, and natural resources are a part of those challenges like sustainability, susceptibility, human health, and healthy life. The ambition of nanomaterials in agriculture is to reduce the amount of spread chemicals, minimize nutrient losses in fertilization and increased yield through pest and nutrient management. Nanotechnology has the prospective to improve the agriculture and food industry with novel nanotools for the controlling of rapid disease diagnostic, enhancing the capacity of plants to absorb nutrients among others. The significant interests of using nanotechnology in agriculture includes specific applications like nanofertilizers and nanopesticides to trail products and nutrients levels to increase the productivity without decontamination of soils, waters, and protection against several insect pest and microbial diseases. Nanotechnology may act as sensors for monitoring soil quality of agricultural field and thus it maintain the health of agricultural plants. This review covers the current challenges of sustainability, food security and climate change that are exploring by the researchers in the area of nanotechnology in the improvement of agriculture. PMID- 28676791 TI - Interplay between 4-Hydroxy-3-Methyl-2-Alkylquinoline and N-Acyl-Homoserine Lactone Signaling in a Burkholderia cepacia Complex Clinical Strain. AB - Species from the Burkholderia cepacia complex (Bcc) share a canonical LuxI/LuxR quorum sensing (QS) regulation system named CepI/CepR, which mainly relies on the acyl-homoserine lactone (AHL), octanoyl-homoserine lactone (C8-HSL) as signaling molecule. Burkholderia ambifaria is one of the least virulent Bcc species, more often isolated from rhizospheres where it exerts a plant growth-promoting activity. However, clinical strains of B. ambifaria display distinct features, such as phase variation and higher virulence properties. Notably, we previously reported that under laboratory conditions, only clinical strains of the B. ambifaria species produced 4-hydroxy-3-methyl-2-alkylquinolines (HMAQs) via expression of the hmqABCDEFG operon. HMAQs are the methylated counterparts of the 4-hydroxy-2-alkylquinolines (HAQs) produced by the opportunistic human pathogen Pseudomonas aeruginosa, in which they globally contribute to the bacterial virulence and survival. We have found that unlike P. aeruginosa's HAQs, HMAQs do not induce their own production. However, they indirectly regulate the expression of the hmqABCDEFG operon. In B. ambifaria, a strong link between CepI/CepR-based QS and HMAQs is proposed, as we have previously reported an increased production of C8-HSL in HMAQ-negative mutants. Here, we report the identification of all AHLs produced by the clinical B. ambifaria strain HSJ1, namely C6-HSL, C8-HSL, C10-HSL, 3OHC8-HSL, 3OHC10-HSL, and 3OHC12-HSL. Production of significant levels of hydroxylated AHLs prompted the identification of a second complete LuxI/LuxR type QS system relying on 3OHC10-HSL and 3OHC12-HSL, that we have named CepI2/CepR2. The connection between these two QS systems and the hmqABCDEFG operon, responsible for HMAQs biosynthesis, was investigated. The CepI/CepR system strongly induced the operon, while the second system appears moderately involved. On the other hand, a HMAQ-negative mutant overproduces AHLs from both QS systems. Even if HMAQs are not classical QS signals, their effect on AHL-based QS system still gives them a part to play in the QS circuitry in B. ambifaria and thus, on regulation of various phenotypes. PMID- 28676792 TI - Long-Read Isoform Sequencing Reveals a Hidden Complexity of the Transcriptional Landscape of Herpes Simplex Virus Type 1. AB - In this study, we used the amplified isoform sequencing technique from Pacific Biosciences to characterize the poly(A)+ fraction of the lytic transcriptome of the herpes simplex virus type 1 (HSV-1). Our analysis detected 34 formerly unidentified protein-coding genes, 10 non-coding RNAs, as well as 17 polycistronic and complex transcripts. This work also led us to identify many transcript isoforms, including 13 splice and 68 transcript end variants, as well as several transcript overlaps. Additionally, we determined previously unascertained transcriptional start and polyadenylation sites. We analyzed the transcriptional activity from the complementary DNA strand in five convergent HSV gene pairs with quantitative RT-PCR and detected antisense RNAs in each gene. This part of the study revealed an inverse correlation between the expressions of convergent partners. Our work adds new insights for understanding the complexity of the pervasive transcriptional overlaps by suggesting that there is a crosstalk between adjacent and distal genes through interaction between their transcription apparatuses. We also identified transcripts overlapping the HSV replication origins, which may indicate an interplay between the transcription and replication machineries. The relative abundance of HSV-1 transcripts has also been established by using a novel method based on the calculation of sequencing reads for the analysis. PMID- 28676793 TI - Immune Responses of Chickens Infected with Wild Bird-Origin H5N6 Avian Influenza Virus. AB - Since April 2014, new infections of H5N6 avian influenza virus (AIV) in humans and domestic poultry have caused considerable economic losses in the poultry industry and posed an enormous threat to human health worldwide. In previous research using gene sequence and phylogenetic analysis, we reported that H5N6 AIV isolated in February 2015 (ZH283) in Pallas's sandgrouse was highly similar to that isolated in a human in December 2015 (A/Guangdong/ZQ874/2015), whereas a virus (i.e., SW8) isolated in oriental magpie-robin in 2014 was highly similar to that of A/chicken/Dongguan/2690/2013 (H5N6). However, the pathogenicity, transmissibility, and host immune-related response of chickens infected by those wild bird-origin H5N6 AIVs remain unknown. In response, we examined the viral distribution and mRNA expression profiles of immune-related genes in chickens infected with both viruses. Results showed that the H5N6 AIVs were highly pathogenic to chickens and caused not only systemic infection in multiple tissues, but also 100% mortality within 3-5 days post-infection. Additionally, ZH283 efficiently replicated in all tested tissues and transmitted among chickens more rapidly than SW8. Moreover, quantitative real-time polymerase chain reaction analysis showed that following infection with H5N6, AIVs immune-related genes remained active in a tissue-dependent manner, as well as that ZH283 induced mRNA expression profiles such as TLR3, TLR7, IL-6, TNF-alpha, IL-1beta, IL-10, IL-8, and MHC-II to a greater extent than SW8 in the tested tissues of infected chickens. Altogether, our findings help to illuminate the pathogenesis and immunologic mechanisms of H5N6 AIVs in chickens. PMID- 28676795 TI - Electricity Generation by Shewanella decolorationis S12 without Cytochrome c. AB - Bacterial extracellular electron transfer (EET) plays a key role in various natural and engineering processes. Outer membrane c-type cytochromes (OMCs) are considered to be essential in bacterial EET. However, most bacteria do not have OMCs but have redox proteins other than OMCs in their extracellular polymeric substances of biofilms. We hypothesized that these extracellular non-cytochrome c proteins (ENCP) could contribute to EET, especially with the facilitation of electron mediators. This study compared the electrode respiring capacity of wild type Shewanella decolorationis S12 and an OMC-deficient mutant. Although the OMC deficient mutant was incapable in direct electricity generation in normal cultivation, it regained electricity generation capacity (26% of the wide type) with the aid of extracellular electron mediator (riboflavin). Further bioelectrochemistry and X-ray photoelectron spectroscopy analysis suggested that the ENCP, such as proteins with Fe-S cluster, may participate in the falvin mediated EET. The results highlighted an important and direct role of the ENCP, generated by either electricigens or other microbes, in natural microbial EET process with the facilitation of electron mediators. PMID- 28676794 TI - Bacteriophages Contribute to the Spread of Antibiotic Resistance Genes among Foodborne Pathogens of the Enterobacteriaceae Family - A Review. AB - Foodborne illnesses continue to have an economic impact on global health care systems. There is a growing concern regarding the increasing frequency of antibiotic resistance in foodborne bacterial pathogens and how such resistance may affect treatment outcomes. In an effort to better understand how to reduce the spread of resistance, many research studies have been conducted regarding the methods by which antibiotic resistance genes are mobilized and spread between bacteria. Transduction by bacteriophages (phages) is one of many horizontal gene transfer mechanisms, and recent findings have shown phage-mediated transduction to be a significant contributor to dissemination of antibiotic resistance genes. Here, we review the viability of transduction as a contributing factor to the dissemination of antibiotic resistance genes in foodborne pathogens of the Enterobacteriaceae family, including non-typhoidal Salmonella and Shiga toxin producing Escherichia coli, as well as environmental factors that increase transduction of antibiotic resistance genes. PMID- 28676796 TI - Cell Cycle-Dependent Expression Dynamics of G1/S Specific Cyclin, Cellulose Synthase and Cellulase in the Dinoflagellate Prorocentrum donghaiense. AB - Dinoflagellates undergo a typical eukaryotic cell cycle consisting of G1, S, G2, and M phases and some of the typical cell cycle related genes have been computationally identified. However, very few of these genes have been experimentally linked to the cell cycle phases. Besides, although thecate dinoflagellates are known to possess theca composed of cellulose, information on cellulose synthesis and degradation associated with the cell cycle is also limited. In this study, we isolated G1/S cyclin, cellulose synthase and cellulase encoding genes in dinoflagellate Prorocentrum donghaiense. Further, using reverse transcription quantitative PCR (RT-qPCR), we characterized the expression profiles of the three genes throughout the cell cycle. All three showed clear expression dynamics throughout the cell cycle, with fold changes of 26, 2.4 and 9.3 for G1/S cyclin, cellulose synthase and cellulase gene, respectively. The transcript abundance of G1/S cyclin increased in late G1 phase and dropped in early S phase, indicating that this protein is involved in the G1/S transition. Throughout the cell cycle, the average transcript level of cellulose synthase was 4.5-fold higher than that of cellulase. Cellulose synthase and cellulase gene expressions showed peak transcript abundances at middle G1 phase and G2M phase, respectively, indicating the respective roles of these enzymes in the growth of newly divided cells and in cytokinesis. Our results suggest that G1/S cyclin, cellulase, and cellulose synthase genes associated with G1/S transition, G2M, and G1 phases of the cell cycle and are candidates of biomarkers for assessing growth status of P. donghaiense. PMID- 28676797 TI - The Arbuscular Mycorrhizal Fungus Funneliformis mosseae Alters Bacterial Communities in Subtropical Forest Soils during Litter Decomposition. AB - Bacterial communities and arbuscular mycorrhizal fungi (AMF) co-occur in the soil, however, the interaction between these two groups during litter decomposition remains largely unexplored. In order to investigate the effect of AMF on soil bacterial communities, we designed dual compartment microcosms, where AMF (Funneliformis mosseae) was allowed access (AM) to, or excluded (NM) from, a compartment containing forest soil and litterbags. Soil samples from this compartment were analyzed at 0, 90, 120, 150, and 180 days. For each sample, Illumina sequencing was used to assess any changes in the soil bacterial communities. We found that most of the obtained operational taxonomic units (OTUs) from both treatments belonged to the phylum of Proteobacteria, Acidobacteria, and Actinobacteria. The community composition of bacteria at phylum and class levels was slightly influenced by both time and AMF. In addition, time and AMF significantly affected bacterial genera (e.g., Candidatus Solibacter, Dyella, Phenylobacterium) involved in litter decomposition. Opposite to the bacterial community composition, we found that overall soil bacterial OTU richness and diversity are relatively stable and were not significantly influenced by either time or AMF inoculation. OTU richness at phylum and class levels also showed consistent results with overall bacterial OTU richness. Our study provides new insight into the influence of AMF on soil bacterial communities at the genus level. PMID- 28676798 TI - Effect of Sunflower and Marine Oils on Ruminal Microbiota, In vitro Fermentation and Digesta Fatty Acid Profile. AB - This study using the rumen simulation technique (RUSITEC) investigated the changes in the ruminal microbiota and anaerobic fermentation in response to the addition of different lipid supplements to a ruminant diet. A basal diet with no oil added was the control, and the treatment diets were supplemented with sunflower oil (2%) only, or sunflower oil (2%) in combination with fish oil (1%) or algae oil (1%). Four fermentation units were used per treatment. RUSITEC fermenters were inoculated with rumen digesta. Substrate degradation, fermentation end-products (volatile fatty acids, lactate, gas, methane, and ammonia), and microbial protein synthesis were determined. Fatty acid profiles and microbial community composition were evaluated in digesta samples. Numbers of representative bacterial species and microbial groups were determined using qPCR. Microbial composition and diversity were based on T-RFLP spectra. The addition of oils had no effect on substrate degradation or microbial protein synthesis. Differences among diets in neutral detergent fiber degradation were not significant (P = 0.132), but the contrast comparing oil-supplemented diets with the control was significant (P = 0.039). Methane production was reduced (P < 0.05) with all oil supplements. Propionate production was increased when diets containing oil were fermented. Compared with the control, the addition of algae oil decreased the percentage C18:3 c9c12c15 in rumen digesta, and that of C18:2 c9t11 was increased when the control diet was supplemented with any oil. Marine oils decreased the hydrogenation of C18 unsaturated fatty acids. Microbial diversity was not affected by oil supplementation. Cluster analysis showed that diets with additional fish or algae oils formed a group separated from the sunflower oil diet. Supplementation with marine oils decreased the numbers of Butyrivibrio producers of stearic acid, and affected the numbers of protozoa, methanogens, Selenomonas ruminantium and Streptococcus bovis, but not total bacteria. In conclusion, there is a potential to manipulate the rumen fermentation and microbiota with the addition of sunflower, fish or algae oils to ruminant diets at appropriate concentrations. Specifically, supplementation of ruminant mixed rations with marine oils will reduce methane production, the acetate to propionate ratio and the fatty acid hydrogenation in the rumen. PMID- 28676799 TI - Impact of Aeolian Dry Deposition of Reactive Iron Minerals on Sulfur Cycling in Sediments of the Gulf of Aqaba. AB - The Gulf of Aqaba is an oligotrophic marine system with oxygen-rich water column and organic carbon-poor sediments (<=0.6% at sites that are not influenced by anthropogenic impact). Aeolian dust deposition from the Arabian, Sinai, and Sahara Deserts is an important source of sediment, especially at the deep-water sites of the Gulf, which are less affected by sediment transport from the Arava Desert during seasonal flash floods. Microbial sulfate reduction in sediments is inferred from the presence of pyrite (although at relatively low concentrations), the presence of sulfide oxidation intermediates, and by the sulfur isotopic composition of sulfate and solid-phase sulfides. Saharan dust is characterized by high amounts of iron minerals such as hematite and goethite. We demonstrated, that the resulting high sedimentary content of reactive iron(III) (hydr)oxides, originating from this aeolian dry deposition of desert dust, leads to fast re oxidation of hydrogen sulfide produced during microbial sulfate reduction and limits preservation of reduced sulfur in the form of pyrite. We conclude that at these sites the sedimentary sulfur cycle may be defined as cryptic. PMID- 28676800 TI - Atribacteria from the Subseafloor Sedimentary Biosphere Disperse to the Hydrosphere through Submarine Mud Volcanoes. AB - Submarine mud volcanoes (SMVs) are formed by muddy sediments and breccias extruded to the seafloor from a source in the deep subseafloor and are characterized by the discharge of methane and other hydrocarbon gasses and deep sourced fluids into the overlying seawater. Although SMVs act as a natural pipeline connecting the Earth's surface and subsurface biospheres, the dispersal of deep-biosphere microorganisms and their ecological roles remain largely unknown. In this study, we investigated the microbial communities in sediment and overlying seawater at two SMVs located on the Ryukyu Trench off Tanegashima Island, southern Japan. The microbial communities in mud volcano sediments were generally distinct from those in the overlying seawaters and in the well stratified Pacific margin sediments collected at the Peru Margin, the Juan de Fuca Ridge flank off Oregon, and offshore of Shimokita Peninsula, northeastern Japan. Nevertheless, in-depth analysis of different taxonomic groups at the sub species level revealed that the taxon affiliated with Atribacteria, heterotrophic anaerobic bacteria that typically occur in organic-rich anoxic subseafloor sediments, were commonly found not only in SMV sediments but also in the overlying seawater. We designed a new oligonucleotide probe for detecting Atribacteria using the catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH). CARD-FISH, digital PCR and sequencing analysis of 16S rRNA genes consistently showed that Atribacteria are abundant in the methane plumes of the two SMVs (0.58 and 1.5 * 104 cells/mL, respectively) but not in surrounding waters, suggesting that microbial cells in subseafloor sediments are dispersed as "deep-biosphere seeds" into the ocean. These findings may have important implications for the microbial transmigration between the deep subseafloor biosphere and the hydrosphere. PMID- 28676801 TI - CD25 + B-1a Cells Express Aicda. AB - B-1a cells are innate-like B-lymphocytes producing natural antibodies. Activation induced cytidine deaminase (AID), a product of the Aicda gene, plays a central role in class-switch recombination and somatic hypermutation in B cells. Although a role for Aicda in B-1a cells has been suggested on the basis of experiments with knock out (KO) mice, whether B-1a cells express Aicda, and if so, which B-1a cell subpopulation expresses Aicda, remains unknown. Here, we demonstrate that B 1 cells express Aicda, but at a level below that expressed by germinal center (GC) B cells. We previously reported that B-1a cells can be subdivided based on CD25 expression. We show here that B-1a cell Aicda expression is concentrated in the CD25+ B-1a cell subpopulation. These results suggest the possibility that previous studies of memory B cells identified on the basis of Aicda expression may have inadvertently included an unknown number of CD25+ B-1a cells. Although B 1a cells develop normally in the absence of Aicda, a competitive reconstitution assay reveals enhanced vigor for AID KO B-1a cell bone marrow (BM) progenitors, as compared with wild-type BM B-1 cell progenitors. These results suggest that AID inhibits the development of B-1a cells from BM B-1 cell progenitors in a competitive environment. PMID- 28676802 TI - A Taylor-Made Design of Phenoxyfuranone-Type Strigolactone Mimic. AB - Strigolactones are a class of plant hormones that inhibit axillary bud outgrowth and are released from plant roots to act as a rhizosphere communication signal. The Orobanchaceae parasitic plant Striga hermonthica perceives strigolactone as its germination signal, indicating host presence. After germination, the Striga plant parasitises the host plant and suppresses host growth by draining photosynthetic products, water and other essential nutrients. Because of this way of life, this parasite threatens crop production in sub-Saharan Africa with infestation in crop fields and crop devastation. Crop protection in such areas is among the most concerning problems to be dealt with as immediately as possible. With respect to crop protection from Striga, many strigolactone agonists have been developed and used in research to reveal Striga biology, and have contributed to development of crop protection methods. However, an effective method has yet to be found. In a previous study, we reported debranones as a group of strigolactone mimics that inhibit axillary buds outgrowth with moderate stimulation activity for Striga germination. Debranones would be accessible because they are simply synthesized from commercially available phenols and bromo butenolide. Taking this advantage of debranones for Striga research, we tried to find the debranones stimulating Striga seed germination. To modulate functional selectivity and to enhance germination inducing activity of debranones, we studied structure-activity relationships. We investigated effects of substituent position and functional group on debranone activity and selectivity as a strigolactone mimic. As a result, we improved stimulation activity of debranones for Striga seed germination by chemical modification, and demonstrated the pharmacophore of debranones for selective modulation of distinct strigolactone responses. PMID- 28676803 TI - Spatial Spread of the Root Parasitic Weed Phelipanche aegyptiaca in Processing Tomatoes by Using Ecoinformatics and Spatial Analysis. AB - Egyptian broomrape (Phelipanche aegyptiaca) is one of the main threats to tomato production in Israel. The seed bank of P. aegyptiaca rapidly develops and spreads in the field. Knowledge about the spatio-temporal distribution of such weeds is required in advance of emergence, as they emerge late in their life cycle when they have already caused major crop damage. The aim of this study is to reveal the effects of two major internal infestation sources: crop rotation and infestation history; and one external source: proximity to infested tomato fields; on infestation of P. aegyptiaca in processing tomatoes. Ecoinformatics, spatial analysis and geostatistics were used to examine these effects. A regional survey was conducted to collect data on field history from 238 tomato fields between 2000 and 2012, in a major tomato-growing region in Israel. Multivariate logistic regression in the framework of generalized linear models (GLM) has demonstrated the importance of all three variables in predicting infestation in tomato fields. The parameters of the overall model indicated a high specificity between tomatoes and P. aegyptiaca, which is potentially responsible for aggravating infestation. In addition, P. aegyptiaca infestation levels were intensively mapped in 43 of the 238 tomato fields in the years 2010-2012. Geostatistical measures showed that 40% of the fields had clustered infestation spatial patterns with infestation clusters located along the fields' borders. Strong linear and negative relationships were found between infestation level and distance from a neighboring infested field, strengthening the role of infested tomato fields in P. aegyptiaca spread. An experiment specifically designed for this study showed that during harvest, P. aegyptiaca seeds are blown from an infested field to a distance of at least 90 m, and may initiate infestation in neighboring fields. Integrating current knowledge about the role of agricultural practices on the spread of P. aegyptiaca with the results of this study enabled us to propose a mechanism for the spread of P. aegyptiaca. Given the major effect of agricultural practices on infestation levels, it is assumed that the spread of this weed can be suppressed by implementing sanitation and using decision support tools for herbicide application. PMID- 28676804 TI - Simultaneous Downregulation of MTHFR and COMT in Switchgrass Affects Plant Performance and Induces Lesion-Mimic Cell Death. AB - Switchgrass (Panicum virgatum) has been developed into a model lignocellulosic bioenergy crop. Downregulation of caffeic acid O-methyltransferase (COMT), a key enzyme in lignin biosynthesis, has been shown to alter lignification and increase biofuel yield in switchgrass. Methylenetetrahydrofolate reductase (MTHFR) mediates C1 metabolism and provides methyl units consumed by COMT. It was predicted that co-silencing of MTHFR and COMT would impact lignification even more than either of the single genes. However, our results showed that strong downregulation of MTHFR in a COMT-deficient background led to altered plant growth and development, but no significant change in lignin content or composition was found when compared with COMT plants. Another unexpected finding was that the double MTHFR/COMT downregulated plants showed a novel lesion-mimic leaf phenotype. Molecular analyses revealed that the lesion-mimic phenotype was caused by the synergistic effect of MTHFR and COMT genes, with MTHFR playing a predominant role. Microarray analysis showed significant induction of genes related to oxidative and defense responses. The results demonstrated the lack of additive effects of MTHFR and COMT on lignification. Furthermore, this research revealed an unexpected role of the two genes in the modulation of lesion-mimic cell death as well as their synergistic effects on agronomic performance. PMID- 28676806 TI - Effects of Drought Stress on Pollen Sterility, Grain Yield, Abscisic Acid and Protective Enzymes in Two Winter Wheat Cultivars. AB - Drought stress induced pollen sterility is a detrimental factor reducing grain number in wheat. Exploring the mechanisms underlying pollen fertility under drought conditions could assist breeding high-yielding wheat cultivars with stress tolerance. Here, by using two Chinese wheat cultivars subjected to different levels of polyethylene glycol (PEG)-induced drought stress, possible links between pollen fertility and stress tolerance were analyzed under different levels of drought stress at the young microspore stage. In both cultivars, higher grain number reduction was observed under condition of lower water availability. Overall, the drought tolerant cultivar (Jinmai47) exhibited less grain number reduction than the drought sensitive cultivar (Shiluan02-1) under all stress conditions. Compared with Shiluan02-1, Jinmai47 exhibited superior physiological performance in terms of leaf photosynthetic rate, ear carbohydrate accumulation, pollen sink strength, pollen development and fertility under stress. Moreover, Jinmai47 showed a lower increase in endogenous abscisic acid in ears than Shiluan02-1. Furthermore, higher levels of superoxide dismutase (SOD) and peroxidase (POD) activities were also found in the drought tolerant cultivar Jinmai47 under PEG stress, compared with the drought sensitive cultivar Shiluan02 1. Changes in these physiological traits could contribute to better pollen development and male fertility, ultimately leading to the maintenance of grain number under drought stress. PMID- 28676805 TI - The Journey of Arsenic from Soil to Grain in Rice. AB - Arsenic (As) is a non-essential toxic metalloid whose elevated concentration in rice grains is a serious issue both for rice yield and quality, and for human health. The rice-As interactions, hence, have been studied extensively in past few decades. A deep understanding of factors influencing As uptake and transport from soil to grains can be helpful to tackle this issue so as to minimize grain As levels. As uptake at the root surface by rice plants depends on factors like iron plaque and radial oxygen loss. There is involvement of a number of transporters viz., phosphate transporters and aquaglyceroporins in the uptake and transport of different As species and in the movement to subcellular compartments. These processes are also affected by sulfur availability and consequently on the level of thiol (-SH)-containing As binding peptides viz., glutathione (GSH) and phytochelatins (PCs). Further, the role of phloem in As movement to the grains is also suggested. This review presents a detailed map of journey of As from soil to the grains. The implications for the utilization of available knowledge in minimizing As in rice grains are presented. PMID- 28676807 TI - Mechanism of Resistance in Mungbean [Vigna radiata (L.) R. Wilczek var. radiata] to bruchids, Callosobruchus spp. (Coleoptera: Bruchidae). AB - Mungbean [Vigna radiata (L.) R. Wilczek var. radiata] is an important pulse crop in Asia, and is consumed as dry seeds and as bean sprouts. It is an excellent source of digestible protein. Bruchids [Callosobruchus chinensis (L.) and Callosobruchus maculatus (F.)] are the important pests of mungbean and cause damage in the field and in storage. Bruchid infestation reduces the nutritional and market value of the grain and renders seeds unfit for human consumption, agricultural and commercial uses. These pests are controlled mainly by fumigation with highly toxic chemicals such as carbon disulfide, phosphene, and methyl bromide, or by dusting with several other insecticides, which leave residues on the grain, thus, threatening food safety. Some plant-based extracts have been found useful in controlling bruchids, but are not fully successful due to their short-term activity, rapid degradability, and potentially negative effect on seed germination. Although some wild sources of bruchid resistance in mungbean have been reported, which have been used to develop bruchid- resistant lines, undesirable genetic linkages threaten the proper exploitation of genetic diversity from wild germplasm into commercial cultivars. Further, biotype variation in bruchids has rendered some mungbean lines susceptible that otherwise would have been resistant to the pest. Host plant resistance is a cost-effective and a safe alternative to control bruchids in mungbean and is associated with morphological, biochemical, and molecular traits. These traits affect insect growth and development, thereby, reduce the yield losses by the pests. Understanding the defense mechanisms against insect pests could be utilized in exploiting these traits in crop breeding. This review discusses different traits in mungbean involved in defense against bruchids and their utility in pest management. We also highlight the breeding constraints for developing bruchid resistant mungbean and how can these constraints be minimized. We further highlight the importance of supporting conventional breeding techniques by molecular techniques such as molecular markers linked to bruchid resistance. PMID- 28676809 TI - Phylogenomic Analysis and Dynamic Evolution of Chloroplast Genomes in Salicaceae. AB - Chloroplast genomes of plants are highly conserved in both gene order and gene content. Analysis of the whole chloroplast genome is known to provide much more informative DNA sites and thus generates high resolution for plant phylogenies. Here, we report the complete chloroplast genomes of three Salix species in family Salicaceae. Phylogeny of Salicaceae inferred from complete chloroplast genomes is generally consistent with previous studies but resolved with higher statistical support. Incongruences of phylogeny, however, are observed in genus Populus, which most likely results from homoplasy. By comparing three Salix chloroplast genomes with the published chloroplast genomes of other Salicaceae species, we demonstrate that the synteny and length of chloroplast genomes in Salicaceae are highly conserved but experienced dynamic evolution among species. We identify seven positively selected chloroplast genes in Salicaceae, which might be related to the adaptive evolution of Salicaceae species. Comparative chloroplast genome analysis within the family also indicates that some chloroplast genes are lost or became pseudogenes, infer that the chloroplast genes horizontally transferred to the nucleus genome. Based on the complete nucleus genome sequences from two Salicaceae species, we remarkably identify that the entire chloroplast genome is indeed transferred and integrated to the nucleus genome in the individual of the reference genome of P. trichocarpa at least once. This observation, along with presence of the large nuclear plastid DNA (NUPTs) and NUPTs-containing multiple chloroplast genes in their original order in the chloroplast genome, favors the DNA-mediated hypothesis of organelle to nucleus DNA transfer. Overall, the phylogenomic analysis using chloroplast complete genomes clearly elucidates the phylogeny of Salicaceae. The identification of positively selected chloroplast genes and dynamic chloroplast-to-nucleus gene transfers in Salicaceae provide resources to better understand the successful adaptation of Salicaceae species. PMID- 28676808 TI - Gibberellins Promote Brassinosteroids Action and Both Increase Heterosis for Plant Height in Maize (Zea mays L.). AB - Brassinosteroids (BRs) and Gibberellins (GAs) are two classes of plant hormones affecting plant height (PHT). Thus, manipulation of BR and GA levels or signaling enables optimization of crop grain and biomass yields. We established backcross (BC) families, selected for increased PHT, in two elite maize inbred backgrounds. Various exotic accessions used in the germplasm enhancement in maize project served as donors. BC1-derived doubled haploid lines in the same two elite maize inbred backgrounds established without selection for plant height were included for comparison. We conducted genome-wide association studies to explore the genetic control of PHT by BR and GA. In addition, we used BR and GA inhibitors to compare the relationship between PHT, BR, and GA in inbred lines and heterozygotes from a physiological and biological perspective. A total of 73 genomic loci were discovered to be associated with PHT, with seven co-localized with GA, and two co-localized with BR candidate genes. PHT determined in field trials was significantly correlated with seedling stage BR and GA inhibitor responses. However, this observation was only true for maize heterozygotes, not for inbred lines. Path analysis results suggest that heterozygosity increases GA levels, which in turn promote BR levels. Thus, at least part of heterosis for PHT in maize can be explained by increased GA and BR levels, and seedling stage hormone inhibitor response is promising to predict heterosis for PHT. PMID- 28676810 TI - Evaluating Spatially Resolved Influence of Soil and Tree Water Status on Quality of European Plum Grown in Semi-humid Climate. AB - In orchards, the variations of fruit quality and its determinants are crucial for resource effective measures. In the present study, a drip-irrigated plum production (Prunus domestica L. "Tophit plus"/Wavit) located in a semi-humid climate was studied. Analysis of the apparent electrical conductivity (ECa) of soil showed spatial patterns of sand lenses in the orchard. Water status of sample trees was measured instantaneously by means of leaf water potential, Psileaf [MPa], and for all trees by thermal imaging of canopies and calculation of the crop water stress index (CWSI). Methods for determining CWSI were evaluated. A CWSI approach calculating canopy and reference temperatures from the histogram of pixels from each image itself was found to suit the experimental conditions. Soil ECa showed no correlation with specific leaf area ratio and cumulative water use efficiency (WUEc) derived from the crop load. The fruit quality, however, was influenced by physiological drought stress in trees with high crop load and, resulting (too) high WUEc, when fruit driven water demand was not met. As indicated by analysis of variance, neither ECa nor the instantaneous CWSI could be used as predictors of fruit quality, while the interaction of CWSI and WUEc did succeed in indicating significant differences. Consequently, both WUEc and CWSI should be integrated in irrigation scheduling for positive impact on fruit quality. PMID- 28676811 TI - Yellow Rust Epidemics Worldwide Were Caused by Pathogen Races from Divergent Genetic Lineages. AB - We investigated whether the recent worldwide epidemics of wheat yellow rust were driven by races of few clonal lineage(s) or populations of divergent races. Race phenotyping of 887 genetically diverse Puccinia striiformis isolates sampled in 35 countries during 2009-2015 revealed that these epidemics were often driven by races from few but highly divergent genetic lineages. PstS1 was predominant in North America; PstS2 in West Asia and North Africa; and both PstS1 and PstS2 in East Africa. PstS4 was prevalent in Northern Europe on triticale; PstS5 and PstS9 were prevalent in Central Asia; whereas PstS6 was prevalent in epidemics in East Africa. PstS7, PstS8 and PstS10 represented three genetic lineages prevalent in Europe. Races from other lineages were in low frequencies. Virulence to Yr9 and Yr27 was common in epidemics in Africa and Asia, while virulence to Yr17 and Yr32 were prevalent in Europe, corresponding to widely deployed resistance genes. The highest diversity was observed in South Asian populations, where frequent recombination has been reported, and no particular race was predominant in this area. The results are discussed in light of the role of invasions in shaping pathogen population across geographical regions. The results emphasized the lack of predictability of emergence of new races with high epidemic potential, which stresses the need for additional investments in population biology and surveillance activities of pathogens on global food crops, and assessments of disease vulnerability of host varieties prior to their deployment at larger scales. PMID- 28676812 TI - Cultivar Differences in Root Nitrogen Uptake Ability of Maize Hybrids. AB - Although, considerable differences in root size in response to nitrogen (N) application among crop species and cultivars have been widely reported, there has been limited focus on the differences in root N uptake ability. In this study, two maize (Zea mays L.) hybrids, Zhenghong 311 (ZH 311, N-efficient) and Xianyu 508 (XY 508, N-inefficient), were used to compare differences in root N uptake ability. The two cultivars were grown in field pots Experiment I (Exp. I) and hydroponic cultures Experiment II (Exp. II) supplemented with different concentrations of N fertilizer. In both experiments, the levels of accumulated N were higher in ZH 311 than in XY 508 under low- and high-N supply, and the increment in accumulated N was greater under N deficiency. The maximum N uptake rate (Vm) and average N uptake rate (Va) in Exp. I, the root N kinetic parameter maximum uptake rate (Vmax) per fresh weight (FW) and Vmax per plant in Exp. II, and the root N uptake rate in both experiments were significantly higher for ZH 311 than for XY 508. In contrast, the root-to-shoot N ratio in both experiments and the root N kinetic parameter Michaelis constant (Km) in in Exp. II were markedly higher in XY 508 than in ZH 311, particularly under N-deficient conditions. Higher root N kinetic parameters Vmax per FW and Vmax per plant and lower Km values contributed to higher N affinity and uptake potential, more coordinated N distribution in the root and shoot, and higher root N uptake rates throughout the growth stages, thus enhancing the N accumulation and yield of the N-efficient maize cultivar. We conclude that the N uptake ability of roots in the N-efficient cultivar ZH 311 is significantly greater than that in the N inefficient cultivar XY 508, and that this advantage is more pronounced under N deficient conditions. The efficient N acquisition in ZH 311 is due to higher N uptake rate per root FW under optimal N conditions and the comprehensive effects of root size and N uptake rate per root FW under N deficiency. PMID- 28676813 TI - A Concise Review on Multi-Omics Data Integration for Terroir Analysis in Vitis vinifera. AB - Vitis vinifera (grapevine) is one of the most important fruit crops, both for fresh consumption and wine and spirit production. The term terroir is frequently used in viticulture and the wine industry to relate wine sensory attributes to its geographic origin. Although, it can be cultivated in a wide range of environments, differences in growing conditions have a significant impact on fruit traits that ultimately affect wine quality. Understanding how fruit quality and yield are controlled at a molecular level in grapevine in response to environmental cues has been a major driver of research. Advances in the area of genomics, epigenomics, transcriptomics, proteomics and metabolomics, have significantly increased our knowledge on the abiotic regulation of yield and quality in many crop species, including V. vinifera. The integrated analysis of multiple 'omics' can give us the opportunity to better understand how plants modulate their response to different environments. However, 'omics' technologies provide a large amount of biological data and its interpretation is not always straightforward, especially when different 'omic' results are combined. Here we examine the current strategies used to integrate multi-omics, and how these have been used in V. vinifera. In addition, we also discuss the importance of including epigenomics data when integrating omics data as epigenetic mechanisms could play a major role as an intermediary between the environment and the genome. PMID- 28676814 TI - Overexpression of a Grapevine Sucrose Transporter (VvSUC27) in Tobacco Improves Plant Growth Rate in the Presence of Sucrose In vitro. AB - The import of sugar from source leaves and it further accumulation in grape berries are considerably high during ripening, and this process is mediated via sucrose transporters. In this study, a grape sucrose transporter (SUT) gene, VvSUC27, located at the plasma membrane, was transferred to tobacco (Nicotiana tabacum). The transformants were more sensitive to sucrose and showed more rapid development, especially roots, when cultured on MS agar medium containing sucrose, considering that the shoot/root dry weight ratio was only half that of the control. Moreover, all transformed plants exhibited light-colored leaves throughout their development, which indicated chlorosis and an associated reduction in photosynthesis. The total sugar content in the roots and stems of transformants was higher than that in control plants. No significant difference was observed in the leaves between the transformants and control plants. The levels of growth-promoting hormones were increased, and those of stress-mediating hormones were reduced in transgenic tobacco plants. The qRT-PCR analysis revealed that the expression of VvSUC27 was 1,000 times higher than that of the autologous tobacco sucrose transporter, which suggested that the markedly increased growth rate of transformants was because of the heterogeneously expressed gene. The transgenic tobacco plants showed resistance to abiotic stresses. Strikingly, the overexpression of VvSUC27 leaded to the up regulation of most reactive oxygen species scavengers and abscisic acid-related genes that might enable transgenic plants to overcome abiotic stress. Taken together, these results revealed an important role of VvSUC27 in plant growth and response to abiotic stresses, especially in the presence of sucrose in vitro. PMID- 28676815 TI - Once for All: A Novel Robust System for Co-expression of Multiple Chimeric Fluorescent Fusion Proteins in Plants. AB - Chimeric fluorescent fusion proteins have been employed as a powerful tool to reveal the subcellular localizations and dynamics of proteins in living cells. Co expression of a fluorescent fusion protein with well-known organelle markers in the same cell is especially useful in revealing its spatial and temporal functions of the protein in question. However, the conventional methods for co expressing multiple fluorescent tagged proteins in plants have the drawbacks of low expression efficiency, variations in the expression level and time-consuming genetic crossing. Here, we have developed a novel robust system that allows for high-efficient co-expression of multiple chimeric fluorescent fusion proteins in plants in a time-saving fashion. This system takes advantage of employing a single expression vector which consists of multiple semi-independent expressing cassettes for the protein co-expression thereby overcoming the limitations of using multiple independent expressing plasmids. In addition, it is a highly manipulable DNA assembly system, in which modification and recombination of DNA molecules are easily achieved through an optimized one-step assembly reaction. By employing this effective system, we demonstrated that co-expression of two chimeric fluorescent fusion reporter proteins of vacuolar sorting receptor and secretory carrier membrane protein gave rise to their perspective subcellular localizations in plants via both transient expression and stable transformation. Thus, we believed that this technical advance represents a promising approach for multi-color-protein co-expression in plant cells. PMID- 28676816 TI - The Effect of Spectral Quality on Daily Patterns of Gas Exchange, Biomass Gain, and Water-Use-Efficiency in Tomatoes and Lisianthus: An Assessment of Whole Plant Measurements. AB - Advancements in light-emitting diode (LED) technology have made them a viable alternative to current lighting systems for both sole and supplemental lighting requirements. Understanding how wavelength specific LED lighting can affect plants is thus an area of great interest. Much research is available on the wavelength specific responses of leaves from multiple crops when exposed to long term wavelength specific lighting. However, leaf measurements do not always extrapolate linearly to the complexities which are found within a whole plant canopy, namely mutual shading and leaves of different ages. Taken together, both tomato (Solanum lycopersicum) leaves under short-term illumination and lisianthus (Eustoma grandiflorum) and tomato whole plant diurnal patterns of plants acclimated to specific lighting indicate wavelength specific responses of both H2O and CO2 gas exchanges involved in the major growth parameters of a plant. Tomato leaves grown under a white light source indicated an increase in transpiration rate and internal CO2 concentration and a subsequent decrease in water-use-efficiency (WUE) when exposed to a blue LED light source compared to a green LED light source. Interestingly, the maximum photosynthetic rate was observed to be similar. Using plants grown under wavelength specific supplemental lighting in a greenhouse, a decrease in whole plant WUE was seen in both crops under both red-blue (RB) and red-white (RW) LEDs when compared to a high pressure sodium (HPS) light. Whole plant WUE was decreased by 31% under the RB LED treatment for both crops compared to the HPS treatment. Tomato whole plant WUE was decreased by 25% and lisianthus whole plant WUE was decreased by 15% when compared to the HPS treatment when grown under RW LED. The understanding of the effects of wavelength specific lighting on both leaf and whole plant gas exchange has significant implications on basic academic research as well as commercial greenhouse production. PMID- 28676817 TI - Cloning and Functional Analysis of MADS-box Genes, TaAG-A and TaAG-B, from a Wheat K-type Cytoplasmic Male Sterile Line. AB - Wheat (Triticum aestivum L.) is a major crop worldwide. The utilization of heterosis is a promising approach to improve the yield and quality of wheat. Although there have been many studies on wheat cytoplasmic male sterility, its mechanism remains unclear. In this study, we identified two MADS-box genes from a wheat K-type cytoplasmic male sterile (CMS) line using homology-based cloning. These genes were localized on wheat chromosomes 3A and 3B and named TaAG-A and TaAG-B, respectively. Analysis of TaAG-A and TaAG-B expression patterns in leaves, spikes, roots, and stems of Chinese Spring wheat determined using quantitative RT-PCR revealed different expression levels in different tissues. TaAG-A had relatively high expression levels in leaves and spikes, but low levels in roots, while TaAG-B had relatively high expression levels in spikes and lower expression in roots, stems, and leaves. Both genes showed downregulation during the mononucleate to trinucleate stages of pollen development in the maintainer line. In contrast, upregulation of TaAG-B was observed in the CMS line. The transcript levels of the two genes were clearly higher in the CMS line compared to the maintainer line at the trinucleate stage. Overexpression of TaAG-A and TaAG-B in Arabidopsis resulted in phenotypes with earlier reproductive development, premature mortality, and abnormal buds, stamens, and stigmas. Overexpression of TaAG-A and TaAG-B gives rise to mutants with many deformities. Silencing TaAG-A and TaAG-B in a fertile wheat line using the virus-induced gene silencing (VIGS) method resulted in plants with green and yellow striped leaves, emaciated spikes, and decreased selfing seed set rates. These results demonstrate that TaAG-A and TaAG-B may play a role in male sterility in the wheat CMS line. PMID- 28676818 TI - Photosynthetic Properties and Potentials for Improvement of Photosynthesis in Pale Green Leaf Rice under High Light Conditions. AB - Light is the driving force of plant growth, providing the energy required for photosynthesis. However, photosynthesis is also vulnerable to light-induced damage caused by the production of reactive oxygen species (ROS). Plants have therefore evolved various protective mechanisms such as non-photochemical quenching (NPQ) to dissipate excessively absorbed solar energy as heat; however, photoinhibition and NPQ represent a significant loss in solar energy and photosynthetic efficiency, which lowers the yield potential in crops. To estimate light capture and light energy conversion in rice, a genotype with pale green leaves (pgl) and a normally pigmented control (Z802) were subjected to high (HL) and low light (LL). Chlorophyll content, light absorption, chloroplast micrographs, abundance of light-harvesting complex (LHC) binding proteins, electron transport rates (ETR), photochemical and non-photochemical quenching, and generation of ROS were subsequently examined. Pgl had a smaller size of light harvesting chlorophyll antenna and absorbed less photons than Z802. NPQ and the generation of ROS were also low, while photosystem II efficiency and ETR were high, resulting in improved photosynthesis and less photoinhibition in pgl than Z802. Chlorophyll synthesis and solar conversion efficiency were higher in pgl under HL compared to LL treatment, while Z802 showed an opposite trend due to the high level of photoinhibition under HL. In Z802, excessive absorption of solar energy not only increased the generation of ROS and NPQ, but also exacerbated the effects of increases in temperature, causing midday depression in photosynthesis. These results suggest that photosynthesis and yield potential in rice could be enhanced by truncated light-harvesting chlorophyll antenna size. PMID- 28676819 TI - Comparative Proteomic Analysis of Flag Leaves Reveals New Insight into Wheat Heat Adaptation. AB - Hexaploid wheat (Triticum aestivum L.) is an important food crop but it is vulnerable to heat. The heat-responsive proteome of wheat remains to be fully elucidated because of previous technical and genomic limitations, and this has hindered our understanding of the mechanisms of wheat heat adaptation and advances in improving thermotolerance. Here, flag leaves of wheat during grain filling stage were subjected to high daytime temperature stress, and 258 heat responsive proteins (HRPs) were identified with iTRAQ analysis. Enrichment analysis revealed that chlorophyll synthesis, carbon fixation, protein turnover, and redox regulation were the most remarkable heat-responsive processes. The HRPs involved in chlorophyll synthesis and carbon fixation were significantly decreased, together with severe membrane damage, demonstrating the specific effects of heat on photosynthesis of wheat leaves. In addition, the decrease in chlorophyll content may result from the decrease in HRPs involved in chlorophyll precursor synthesis. Further analysis showed that the accumulated effect of heat stress played a critical role in photosynthesis reduction, suggested that improvement in heat tolerance of photosynthesis, and extending heat tolerant period would be major research targets. The significantly accumulation of GSTs and Trxs in response to heat suggested their important roles in redox regulation, and they could be the promising candidates for improving wheat thermotolerance. In summary, our results provide new insight into wheat heat adaption and provide new perspectives on thermotolerance improvement. PMID- 28676820 TI - Arabinogalactan Proteins Are Involved in Salt-Adaptation and Vesicle Trafficking in Tobacco by-2 Cell Cultures. AB - Arabinogalactan proteins (AGPs) are a highly diverse family of glycoproteins that are commonly found in most plant species. However, little is known about the physiological and molecular mechanisms of their function. AGPs are involved in different biological processes such as cell differentiation, cell expansion, tissue development and somatic embryogenesis. AGPs are also involved in abiotic stress response such as salinity modulating cell wall expansion. In this study, we describe how salt-adaptation in tobacco BY-2 cell cultures induces important changes in arabinogalactan proteins distribution and contents. Using the immuno dot blot technique with different anti-AGP antibodies (JIM13, JIM15, and others), we observed that AGPs were highly accumulated in the culture medium of salt adapted tobacco cells, probably due to the action of phospholipases. We located these AGP epitopes using immunogold labeling in the cytoplasm associated to the endoplasmic reticulum, the golgi apparatus, and vesicles, plasma membrane and tonoplast. Our results show that salt-adaptation induced a significant reduction of the cytoplasm, plasma membrane and tonoplast content of these epitopes. Yariv reagent was added to the control and salt-adapted tobacco cell cultures, leading to cell death induction in control cells but not in salt-adapted cells. Ultrastructural and immunogold labeling revealed that cell death induced by Yariv reagent in control cells was due to the interaction of Yariv reagent with the AGPs linked to the plasma membranes. Finally, we propose a new function of AGPs as a possible sodium carrier through the mechanism of vesicle trafficking from the apoplast to the vacuoles in salt-adapted tobacco BY-2 cells. This mechanism may contribute to sodium homeostasis during salt-adaptation to high saline concentrations. PMID- 28676821 TI - Intraoperative Imaging Modalities and Compensation for Brain Shift in Tumor Resection Surgery. AB - Intraoperative brain shift during neurosurgical procedures is a well-known phenomenon caused by gravity, tissue manipulation, tumor size, loss of cerebrospinal fluid (CSF), and use of medication. For the use of image-guided systems, this phenomenon greatly affects the accuracy of the guidance. During the last several decades, researchers have investigated how to overcome this problem. The purpose of this paper is to present a review of publications concerning different aspects of intraoperative brain shift especially in a tumor resection surgery such as intraoperative imaging systems, quantification, measurement, modeling, and registration techniques. Clinical experience of using intraoperative imaging modalities, details about registration, and modeling methods in connection with brain shift in tumor resection surgery are the focuses of this review. In total, 126 papers regarding this topic are analyzed in a comprehensive summary and are categorized according to fourteen criteria. The result of the categorization is presented in an interactive web tool. The consequences from the categorization and trends in the future are discussed at the end of this work. PMID- 28676822 TI - The Best Anticoagulation Strategy for Cirrhotic Patients who Underwent Splenectomy: A Network Meta-Analysis. AB - OBJECTIVE: To determine the best anticoagulation strategy for the patients who underwent splenectomy with cirrhosis through network meta-analysis. METHODS: We conducted a systematic review of the literature in PubMed, Embase, and the Cochrane Library database. We extracted data on incidence of Portal vein system thrombosis (PVST) from studies that compared various anticoagulation strategies for use with patients who underwent splenectomy with cirrhosis. Network meta analysis was conducted in ADDIS by evaluating the different incidence of PVST. Consistency and inconsistency models were developed to identify differences among the therapeutic strategies. Cumulative probability was utilized to rank the strategies under examination. Results. A total of 11 studies containing 1153 patients were included in the network meta-analysis. The results revealed that the application of Antithrombin III was the best anticoagulation option for patients who underwent splenectomy with cirrhosis (P = 0.59). The data of consistency and inconsistency models exhibited basically consistent and showed good convergence. CONCLUSIONS: Application of Antithrombin III seemed to be the best anticoagulation strategy for cirrhotic patients who underwent splenectomy and should be considered a first-choice clinical reference. PMID- 28676823 TI - Corrigendum to "Osteoporosis, Fractures, and Diabetes". AB - [This corrects the article DOI: 10.1155/2014/820615.]. PMID- 28676824 TI - Prognostic Impact of miR-224 and RAS Mutations in Medullary Thyroid Carcinoma. AB - Little is known about the function of microRNA-224 (miR-224) in medullary thyroid cancer (MTC). This study investigated the role of miR-224 expression in MTC and correlated it with mutation status in sporadic MTCs. A consecutive series of 134 MTCs were considered. Patients had a sporadic form in 80% of cases (107/134). In this group, REarranged during transfection (RET) and rat sarcoma (RAS) mutation status were assessed by direct sequencing in the tumor tissues. Quantitative real time polymerase chain reaction was used to quantify mature hsa-miR-224 in tumor tissue. RAS (10/107 cases, 9%) and RET (39/107 cases, 36%) mutations were mutually exclusive in sporadic cases. miR-224 expression was significantly downregulated in patients with the following: high calcitonin levels at diagnosis (p = 0.03, r = -0.3); advanced stage (p = 0.001); persistent disease (p = 0.001); progressive disease (p = 0.002); and disease-related death (p = 0.0001). We found a significant positive correlation between miR-224 expression and somatic RAS mutations (p = 0.007). Patients whose MTCs had a low miR-224 expression tended to have a shorter overall survival (log-rank test p = 0.005). On multivariate analysis, miR-224 represented an independent prognostic marker. Our data indicate that miR-224 is upregulated in RAS-mutated MTCs and in patients with a better prognosis and could represent an independent prognostic marker in MTC patients. PMID- 28676825 TI - Comment on "Assessment of Bone Mineral Density in Male Patients with Chronic Obstructive Pulmonary Disease by DXA and Quantitative Computed Tomography". PMID- 28676826 TI - Subchronic Infection of Porphyromonas gingivalis and Tannerella forsythia Stimulates an Immune Response but Not Arthritis in Experimental Murine Model. AB - Studies have proposed that Porphyromonas gingivalis (Pg) and Tannerella forsythia (Tf) promote a nonspecific inflammatory response that could produce systemic disease. Oral inoculation of Pg and Tf on the immune and arthritis response was evaluated in BALB/C mice divided into four groups: (1) sham; (2) food contaminated with Pg/Tf; (3) complete Freund's adjuvant (CFA) + Pg/Tf; and (4) CFA alone. CFA was administered subcutaneously on days 1 and 14. The arthritis response was monitored for 21 days after day 14 of CFA administration. IL-1beta and IL-6 were determined in serum. T cell activation was evaluated by CD25 in salivary lymph nodes or mouse spleen. Pad inflammation appeared by day 19 in the CFA group, but animals with bacteria inoculation presented a delay. A significant increase in IL-6 was found in Groups 3 and 4, but not with respect to IL-1beta. We observed an increase in CD25 in cells derived from cervical nodes and in animals with bacteria inoculation and CFA. A local immune response was observed in mice inoculated with Pg and Tf (T cell activation); a systemic response was observed with CFA. Since pad inflammation was delayed by bacterial inoculation this suggests that local T cell activation could decrease pad inflammation. PMID- 28676827 TI - Isolation and Characterization of Yeasts Able to Assimilate Sugarcane Bagasse Hemicellulosic Hydrolysate and Produce Xylitol Associated with Veturius transversus (Passalidae, Coleoptera, and Insecta). AB - Yeasts are an important component of insect gut microbial content, playing roles such as degradation of polymers and toxic compounds, biological control, and hormone, vitamin, and digestive enzyme production. The xylophagous beetle gut is a hyperdiverse habitat and a potential source of new species with industrial abilities such as enzyme production, pentose fermentation, and biodetoxification. In this work, samples of Veturius transversus (Passalidae, Coleoptera, and Insecta) were collected from the Central Amazon Rainforest. Their guts were dissected and a total of 20 microbial colonies were isolated using sugarcane bagasse hemicellulosic hydrolysate. They were identified as having 10 distinct biochemical profiles, and genetic analysis allowed identification as three clades in the genera Candida, Williopsis, and Geotrichum. All colonies were able to assimilate D-xylose and 18 were able to produce xylitol, especially a strain of Geotrichum, with a maximum yield of 0.502 g.g-1. These results agree with a previous prediction that the microbial community associated with xylophagous insects is a promising source of species of biotechnological interest. PMID- 28676828 TI - Prevalence of Virulence Genes Associated with Diarrheagenic Pathotypes of Escherichia coli Isolates from Water, Sediment, Fish, and Crab in Aby Lagoon, Cote d'Ivoire. AB - This study was conducted to characterize virulence genes of Escherichia coli isolates from water, sediment, fish, and crab in Aby Lagoon. Serogrouping was performed by EPEC antisera in 113 E. coli strains. The presence of diarrhea associated genes (eae, stx, AggR, elt, and est) was assessed by multiplex PCR using specific primers. Based on the multiplex PCR, sixty-two isolates (42 from water, 19 from sediment, and 1 from crab) were positive for virulence genes, including 34 positive for elt (ETEC), 46 positive for est (ETEC), 24 positive for both elt and est, 6 positive for stx (EHEC), 1 positive for both stx + est, and 1 positive for both stx + elt. Genes eae (EPEC) and AggR (EAEC) were not detected. Nine serogroups (O114, O127, O55, O111, O86, O119, O126, O128, and O142) were identified. This study revealed the presence of diarrheagenic and nondiarrheagenic E. coli and potential public health risks if fishery products are not appropriately cooked. PMID- 28676829 TI - Changes in Body Water Caused by Sleep Deprivation in Taeeum and Soyang Types in Sasang Medicine: Prospective Intervention Study. AB - BACKGROUND: There is a negative relationship between sleep deprivation and health. However, no study has investigated the effect of sleep deprivation on individuals with different body composition. The aim of this study was to determine the differential effect of sleep deprivation in individuals with different body compositions (fluid) according to Soyang type (SY) and Taeeum type (TE). METHODS: Sixty-two cognitively normal, middle-aged people with normal sleep patterns were recruited from the local population. The duration of participants' sleep was restricted to 4 h/day during the intervention phase. To examine the physiological changes brought on by sleep deprivation and recovery, 10 ml of venous blood was obtained. RESULTS: Total Body Water (TBW) and Extracellular Water (ECW) were significantly different between the groups in the intervention phase. Physiological parameters also varied from the beginning of the resting phase to the end of the experiment. Potassium levels changed more in SY than TE individuals. CONCLUSION: Participants responded differently to the same amount of sleep deprivation depending on their Sasang constitution types. This study indicated that SY individuals were more sensitive to sleep deprivation and were slower to recover from the effects of sleep deprivation than TE individuals. PMID- 28676830 TI - Nyctanthes arbor-tristis Ameliorated FCA-Induced Experimental Arthritis: A Comparative Study among Different Extracts. AB - Nyctanthes arbor-tristis (NAT) is commonly used traditionally for the treatment of rheumatism and inflammatory diseases. Current study evaluates the antiarthritic potential of NAT using Freund's adjuvant-induced arthritic rat model. Treatments with methanolic, ethyl acetate, and n-hexane extracts were continued for consecutive 20 days. Macroscopic arthritic scoring and water displacement plethysmometry were used to evaluate arthritic development. Hematological and biochemical parameters were investigated and ankle joints were processed for histopathological evaluation. Qualitative phytochemical analysis and GC-MS analysis were conducted for identification of constituents. NAT extracts suppressed arthritic scoring, paw edema, infiltration of inflammatory cells, pannus formation, and bone erosion. The plant extracts ameliorated total leukocytes and platelet counts and nearly normalized red blood cells (RBC) counts and hemoglobin (Hb) content. The extracts were found safe in terms of hepatotoxicity and nephrotoxicity as determined by aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and urea levels. Comparative analysis showed that ethyl acetate extract produced the highest inhibition of paw edema. The major constituents found in ethyl acetate extract can be classified into three major classes, that is, terpenes, terpenoids, fatty acids, and iridoid glycosides. Current study showed that Nyctanthes arbor-tristis ameliorated experimental rheumatoid arthritis and ethyl acetate extract possessed the highest inhibitory activity. PMID- 28676831 TI - The Japanese Version of the Massachusetts General Hospital Acupuncture Sensation Scale: A Validation Study. AB - Acupuncture sensations are considered essential in producing the treatment effect of acupuncture. The Massachusetts General Hospital Acupuncture Sensation Scale (MASS) is a frequently used scale in acupuncture research to measure acupuncture sensations. We translated the MASS into Japanese (Japanese MASS) based on Beaton's guidelines. 30 acupuncturists evaluated the relevancy and meaning of the 12 descriptors included in the Japanese MASS. The content validity ratios for 10 of the 12 descriptors were 0.33 or greater. 42 healthy subjects then evaluated acupuncture sensations evoked by manual acupuncture at LI4 using the Japanese MASS. Cronbach's alpha was 0.86. The correlation coefficient of total MASS scores and total Short Form McGill Pain Questionnaire scores and MASS indices and sensory visual analogue scores were 0.78 and 0.80, respectively. Factor analysis loaded the 12 descriptors onto two meaningful factors. This study demonstrated that the Japanese MASS has good reliability, content validity, criterion-related validity, and construct validity. Therefore, the Japanese MASS is a valid and reliable instrument for use with Japanese populations. PMID- 28676832 TI - The Acupuncture Effect on Median Nerve Morphology in Patients with Carpal Tunnel Syndrome: An Ultrasonographic Study. AB - INTRODUCTION: The aim of this study was to explore the acupuncture effect on the cross-sectional area (CSA) of the median nerve at the wrist in patients with carpal tunnel syndrome (CTS) and, additionally, to identify whether clinical, electrophysiological, and ultrasonographic changes show any association. METHODS: Forty-five limbs of 27 female patients were randomly divided into two groups (acupuncture and control). All patients used night wrist splint. The patients in the acupuncture group received additional acupuncture therapy. Visual analog scale (VAS), Duruoz Hand Index (DHI), Quick Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores, electrophysiologic measurements, and median nerve CSAs were noted before and after the treatment in both groups. RESULTS: VAS, DHI, Quick DASH scores, and electrophysiological measurements were improved in both groups. The median nerve CSA significantly decreased in the acupuncture group, whereas there was no change in the control group. CONCLUSION: After acupuncture therapy, the patients with CTS might have both clinical and morphological improvement. PMID- 28676833 TI - Andrographolide Inhibits Inflammatory Cytokines Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-kappaB/MAPK Signaling Pathway. AB - Andrographolide, the main active component extracted from Andrographis paniculata (Burm.f.) Wall. ex Nees, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the molecular mechanisms of Andrographolide in modifying lipopolysaccharide- (LPS-) induced signaling pathway in RAW264.7 cells. An in vitro model of inflammation was induced by LPS in mouse RAW264.7 cells in the presence of Andrographolide. The concentration and expression levels of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The nuclear level of NF-kappaB was measured by an electrophoretic mobility shift assay (EMSA). The expression levels of NF-kappaB, p38, ERK, and JNK were determined by western blot. Andrographolide dose-dependently inhibited the release and mRNA expression of TNF-alpha, IL-6, and IL-1beta in LPS stimulated RAW264.7 cells. The nuclear level of p65 protein was decreased in Andrographolide treatment group. Western blot analysis showed that Andrographolide suppressed LPS-induced NF-kappaB activation and the phosphorylation of IkBa, ERK1/2, JNK, and p38. These results suggest that Andrographolide exerts an anti-inflammatory effect by inhibiting the activation of NF-kappaB/MAPK signaling pathway and the induction of proinflammatory cytokines. PMID- 28676834 TI - Exponentially Modified Peak Functions in Biomedical Sciences and Related Disciplines. AB - In many cases relevant to biomedicine, a variable time, which features a certain distribution, is required for objects of interest to pass from an initial to an intermediate state, out of which they exit at random to a final state. In such cases, the distribution of variable times between exiting the initial and entering the final state must conform to the convolution of the first distribution and a negative exponential distribution. A common example is the exponentially modified Gaussian (EMG), which is widely used in chromatography for peak analysis and is long known as ex-Gaussian in psychophysiology, where it is applied to times from stimulus to response. In molecular and cell biology, EMG, compared with commonly used simple distributions, such as lognormal, gamma, and Wald, provides better fits to the variabilities of times between consecutive cell divisions and transcriptional bursts and has more straightforwardly interpreted parameters. However, since the range of definition of the Gaussian component of EMG is unlimited, data approximation with EMG may extend to the negative domain. This extension may seem negligible when the coefficient of variance of the Gaussian component is small but becomes considerable when the coefficient increases. Therefore, although in many cases an EMG may be an acceptable approximation of data, an exponentially modified nonnegative peak function, such as gamma-distribution, can make more sense in physical terms. In the present short review, EMG and exponentially modified gamma-distribution (EMGD) are discussed with regard to their applicability to data on cell cycle, gene expression, physiological responses to stimuli, and other cases, some of which may be interpreted as decision-making. In practical fitting terms, EMG and EMGD are equivalent in outperforming other functions; however, when the coefficient of variance of the Gaussian component of EMG is greater than ca. 0.4, EMGD is preferable. PMID- 28676835 TI - Aqueous Photocurrent Measurements Correlated to Ultrafast Electron Transfer Dynamics at Ruthenium Tris Diimine-Sensitized NiO Photocathodes. AB - Understanding the structural and electronic factors governing the efficiency of dye-sensitized NiO photocathodes is essential to optimize solar fuel production in photoelectrochemical cells (PECs). For these purpose, three different ruthenium dyes, bearing either two or four methylphosphonate anchoring groups and either a bipyridine or a dipyridophenazine ancillary ligand, were synthesized and grafted onto NiO films. These photoelectrodes were fully characterized by XPS, ToF-SIMS, UV-vis absorption, time-resolved emission and femtosecond transient absorption spectroscopies. Increasing the number of anchoring groups from two to four proved beneficial for the grafting efficiency. No significant modification of the electronic properties compared to the parent photosensitizer was observed, in accordance with the non-conjugated nature of the grafted linker. The photoelectrochemical activity of the dye-sensitized NiO electrodes was assessed in fully aqueous medium in the presence of an irreversible electron acceptor and photocurrents reaching 190 MUA.cm-2 were recorded. The transient absorption study revealed the presence of two charge recombination pathways for each of the sensitizers and evidenced a stabilized charge separated state in the dppz derivative, supporting its superior photoelectrochemical activity. PMID- 28676837 TI - Repeatability and Reproducibility of Intraocular Pressure and Dynamic Corneal Response Parameters Assessed by the Corvis ST. AB - PURPOSE: To assess the repeatability and reproducibility of dynamic corneal response parameters measured by the Corvis ST (Oculus, Wetzlar, Germany). METHODS: One eye randomly selected from 32 healthy volunteers was examined by the Corvis ST. Three different devices were used in an alternated random order for taking three measurements at each device in each subject. Standard intraocular pressure (IOP), the biomechanical-compensated IOP (bIOP), and DCR parameters were evaluated. The within-subject standard deviation (zetaw) and coefficient of variation (CV) were assessed. RESULTS: Regarding pressure indices, the zetaw was below 1 mmHg for repeatability (0.98 for IOP and 0.89 for bIOP) and the CV was 6.6% for IOP and 6.1% for bIOP. For reproducibility, the zetaw was around 1 mmHg (1.12 for IOP and 1.05 for bIOP) and the CV was 7.6% for IOP and 7.1% for bIOP. Most of DCR indices presented CV for repeatability below 4%. For reproducibility, the CV of most of the indices were below 6%. The deformation amplitude (DA) ratio in 1 mm and integrated radius were below 4% (1.2% and 3.8%, resp.). CONCLUSIONS: The Corvis ST showed good precision (repeatability and reproducibility) for IOP measurements and for DCR in healthy eyes. PMID- 28676836 TI - Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte-Specific c-met Deletion during the Progression of NASH. AB - We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-metfx/fx), single c-met knockouts (c metDeltahepa), and double c-met/Keap1 knockouts (met/Keap1Deltahepa) were then fed a chow or a methionine-choline-deficient (MCD) diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis. Upon MCD feeding, met/Keap1Deltahepa mice displayed increased liver mass albeit decreased triglyceride accumulation. The marked increase of oxidative stress observed in c metDeltahepa was restored in the double mutants as assessed by 4-HNE immunostaining and by the expression of genes responsible for the generation of free radicals. Moreover, double knockout mice presented a reduced amount of liver infiltrating cells and the exacerbation of fibrosis progression observed in c metDeltahepa livers was significantly inhibited in met/Keap1Deltahepa. Therefore, genetic activation of the antioxidant transcription factor Nrf2 improves liver damage and repair in hepatocyte-specific c-met-deficient mice mainly through restoring a balance in the cellular redox homeostasis. PMID- 28676838 TI - Effect of Intranasal Calcitonin in a Patient with McCune-Albright Syndrome, Fibrous Dysplasia, and Refractory Bone Pain. AB - McCune-Albright syndrome (MAS) is a rare disease defined by the triad of polyostotic fibrous dysplasia of bone, cafe-au-lait skin spots, and precocious puberty. No available treatment is effective in changing the course of fibrous dysplasia of bone, but symptomatic patients require therapeutic support to reduce bone pain and prevent fractures and deformities. We report the case of a 27-year old woman with MAS and severe fibrous dysplasia. She was diagnosed with MAS at 4 years of age and, during follow-up, she had multiple pathological fractures and bone pain refractory to treatment with bisphosphonates, tricyclic antidepressants, and opioids. The pain was incapacitating and the patient required a wheelchair. Intranasal calcitonin was then started, and, 30 days later, the patient already showed significant improvement in pain severity at the affected sites. After 3 months, she was able to walk without assistance. No adverse effects were observed, nor were any significant changes in serum levels of calcium, phosphorus, and alkaline phosphatase. Calcitonin has a well recognized analgesic effect on bone tissue. Despite the small number of studies involving patients with MAS, calcitonin may be considered a short-term therapeutic option in cases of severe and refractory bone pain. PMID- 28676839 TI - Mechanisms Underlying Improvement in Obstructive Sleep Apnea Syndrome by Uvulopalatopharyngoplasty. AB - In a previous case report, we determined for the first time that uvulopalatopharyngoplasty (UPPP) does not change the volume of the upper airway but causes morphological changes in the entire upper airway. The objective of this study is to elucidate the mechanisms underlying the improvement in obstructive sleep apnea syndrome (OSAS) by UPPP. We present an additional case involving a patient with OSAS treated using UPPP. Morphological and numerical parameter changes after surgery were compared with the corresponding preoperative values. Anatomically accurate upper airway computational models were reconstructed from computed tomographic imaging data. In addition, computed fluid dynamics analysis was performed to reveal inhalation flow characteristics before and after UPPP and clearly assess the effect of UPPP on airflow patterns in the patient's upper airway. An important benefit of UPPP is the morphological changes in the entire upper airway, in addition to widening the restricted area. These morphological changes induce laminarization of the pharyngeal jet. To obtain sufficient efficacy of UPPP in OSAS, the morphological changes in the upper airway and the airflow pattern after the surgery must be controlled.